PMID- 28583345 TI - Multidisciplinary Management of Sarcomas - Where Are We Now? PMID- 28583346 TI - Insights and Implications from the Science of Healing. PMID- 28583347 TI - Plasma trans-palmitoleic acid is associated with cardio-metabolic risk factors in youth with type 1 diabetes. PMID- 28583348 TI - Robust input design for nonlinear dynamic modeling of AUV. AB - Input design has a dominant role in developing the dynamic model of autonomous underwater vehicles (AUVs) through system identification. Optimal input design is the process of generating informative inputs that can be used to generate the good quality dynamic model of AUVs. In a problem with optimal input design, the desired input signal depends on the unknown system which is intended to be identified. In this paper, the input design approach which is robust to uncertainties in model parameters is used. The Bayesian robust design strategy is applied to design input signals for dynamic modeling of AUVs. The employed approach can design multiple inputs and apply constraints on an AUV system's inputs and outputs. Particle swarm optimization (PSO) is employed to solve the constraint robust optimization problem. The presented algorithm is used for designing the input signals for an AUV, and the estimate obtained by robust input design is compared with that of the optimal input design. According to the results, proposed input design can satisfy both robustness of constraints and optimality. PMID- 28583349 TI - Design and implementation of EP-based PID controller for chaos synchronization of Rikitake circuit systems. AB - This article addresses an evolutionary programming (EP) algorithm technique-based and proportional-integral-derivative (PID) control methods are established to guarantee synchronization of the master and slave Rikitake chaotic systems. For PID synchronous control, the evolutionary programming (EP) algorithm is used to find the optimal PID controller parameters kp, ki, kd by integrated absolute error (IAE) method for the convergence conditions. In order to verify the system performance, the basic electronic components containing operational amplifiers (OPAs), resistors, and capacitors are used to implement the proposed chaotic Rikitake systems. Finally, the experimental results validate the proposed Rikitake chaotic synchronization approach. PMID- 28583350 TI - Indirect adaptive fuzzy wavelet neural network with self- recurrent consequent part for AC servo system. AB - This paper proposes a novel indirect adaptive fuzzy wavelet neural network (IAFWNN) to control the nonlinearity, wide variations in loads, time-variation and uncertain disturbance of the ac servo system. In the proposed approach, the self-recurrent wavelet neural network (SRWNN) is employed to construct an adaptive self-recurrent consequent part for each fuzzy rule of TSK fuzzy model. For the IAFWNN controller, the online learning algorithm is based on back propagation (BP) algorithm. Moreover, an improved particle swarm optimization (IPSO) is used to adapt the learning rate. The aid of an adaptive SRWNN identifier offers the real-time gradient information to the adaptive fuzzy wavelet neural controller to overcome the impact of parameter variations, load disturbances and other uncertainties effectively, and has a good dynamic. The asymptotical stability of the system is guaranteed by using the Lyapunov method. The result of the simulation and the prototype test prove that the proposed are effective and suitable. PMID- 28583352 TI - Editorial Comment. PMID- 28583351 TI - Protein engineering of CYP105s for their industrial uses. AB - Cytochrome P450 enzymes belonging to the CYP105 family are predominantly found in bacteria belonging to the phylum Actinobacteria and the order Actinomycetales. In this review, we focused on the protein engineering of P450s belonging to the CYP105 family for industrial use. Two Arg substitutions to Ala of CYP105A1 enhanced its vitamin D3 25- and 1alpha-hydroxylation activities by 400 and 100 fold, respectively. The coupling efficiency between product formation and NADPH oxidation was largely improved by the R84A mutation. The quintuple mutant Q87W/T115A/H132L/R194W/G294D of CYP105AB3 showed a 20-fold higher activity than the wild-type enzyme. Amino acids at positions 87 and 191 were located at the substrate entrance channel, and that at position 294 was located close to the heme group. Semi-rational engineering of CYP105A3 selected the best performing mutant, T85F/T119S/V194N/N363Y, for producing pravastatin. The T119S and N363Y mutations synergistically had remarkable effects on the interaction between CYP105A3 and putidaredoxin. Although wild-type CYP105AS1 hydroxylated compactin to 6-epi-pravastatin, the quintuple mutant I95T/Q127R/A180V/L236I/A265N converted almost all compactin to pravastatin. Five amino acid substitutions by two rounds of mutagenesis almost completely changed the stereo-selectivity of CYP105AS1. These results strongly suggest that the protein engineering of CYP105 enzymes greatly increase their industrial utility. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone. PMID- 28583354 TI - Narrative science and narrative knowing. Introduction to special issue on narrative science. PMID- 28583353 TI - The recognition and characterisation of Finnish Clostridium difficile isolates resembling PCR-ribotype 027. AB - PURPOSE: To characterise and compare twenty-eight Finnish Clostridium difficile RT027-like isolates, selected based on the presence of 18 bp deletion in the tcdC gene and toxin gene profile (A, B, binary), with eleven RT027 isolates from different Finnish geographical areas and time periods. METHODS: Twenty-eight C. difficile RT027-like isolates and 11 RT027 comparative strains were characterised by capillary-electrophoresis (CE) ribotyping, multi-locus variable tandem-repeats analysis (MLVA), multi-locus sequence typing (MLST), and sequencing of tcdC and gyrA gene fragments. Susceptibility to moxifloxacin was determined by E-test. RESULTS: Of 28 RT027-like isolates, seven RTs (016, 034, 075, 080, 153, 176 and 328), three WEBRIBO types (411, 475, AI-78) and three new profiles (F1-F3) were identified. MLVA revealed six clonal complexes (RTs 016, 027, 176 and F3). MLST showed eleven sequence types (1, 41, 47, 67, 95, 191,192, 223, 229, 264 and new ST). Twenty-two isolates (RTs 016, 080, 176, 328, F1, F2, F3 and WRTAI-78) carried Delta117 in the tcdC gene. Isolates of RTs 016, 027 and 176 were moxifloxacin resistant and harboured Thr82Ile in the GyrA. CONCLUSION: Our results show a high diversity within 28 Finnish RT027-like C. difficile isolates, with twelve CE-ribotyping profiles and eleven STs. MLVA revealed the regional spread of RTs 016, 027, 176 and F3. The presence of Delta117 in the tcdC gene in eight non-027 RTs highlights the importance of careful interpretation of the results from molecular systems targeting this site in the genome of C. difficile and the need of strain typing for epidemiological purposes. PMID- 28583355 TI - In defence of story-telling. AB - We argue that narratives are central to the success of historical reconstruction. Narrative explanation involves tracing causal trajectories across time. The construction of narrative, then, often involves postulating relatively speculative causal connections between comparatively well-established events. But speculation is not always idle or harmful: it also aids in overcoming local underdetermination by forming scaffolds from which new evidence becomes relevant. Moreover, as our understanding of the past's causal milieus become richer, the constraints on narrative plausibility become increasingly strict: a narrative's admissibility does not turn on mere logical consistency with background data. Finally, narrative explanation and explanation generated by simple, formal models complement one another. Where models often achieve isolation and precision at the cost of simplification and abstraction, narratives can track complex changes in a trajectory over time at the cost of simplicity and precision. In combination both allow us to understand and explain highly complex historical sequences. PMID- 28583356 TI - Theories that narrate the world: Ronald A. Fisher's mass selection and Sewall Wright's shifting balance. AB - Theories are composed of multiple interacting components. I argue that some theories have narratives as essential components, and that narratives function as integrative devices of the mathematical components of theories. Narratives represent complex processes unfolding in time as a sequence of stages, and hold the mathematical elements together as pieces in the investigation of a given process. I present two case studies from population genetics: R. A. Fisher's "mas selection" theory, and Sewall Wright's shifting balance theory. I apply my analysis to an early episode of the "R. A. Fisher - Sewall Wright controversy." PMID- 28583357 TI - Narrative possibility and narrative explanation. AB - Narratives are about not only what actually happened, but also what might have. And narrative explanations make productive use of these unrealized possibilities. I discuss narrative explanation as a form of counterfactual, difference-making explanation, with a demanding qualification: the counterfactual conditions are historically or narratively (not merely logically or physically) possible. I consider these issues in connection with literary, historical and scientific narratives. PMID- 28583358 TI - Essentially narrative explanations. AB - This essay argues that narrative explanations prove uniquely suited to answering certain explanatory questions, and offers reasons why recognizing a type of statement that requires narrative explanations crucially informs on their assessment. My explication of narrative explanation begins by identifying two interrelated sources of philosophical unhappiness with them. The first I term the problem of logical formlessness and the second the problem of evaluative intractability. With regard to the first, narratives simply do not appear to instantiate any logical form recognized as inference licensing. But absent a means of identifying inferential links, what justifies connecting explanans and explanandum? Evaluative intractability, the second problem, thus seems a direct consequence. This essay shows exactly why these complaints prove unfounded by explicating narrative explanations in the process of answering three interrelated questions. First, what determines that an explanation has in some critical or essential respect a narrative form? Second, how does a narrative in such cases come to constitute a plausible explanation? Third, how do the first two considerations yield a basis for evaluating an explanation offered as a narrative? Answers to each of these questions include illustrations of actual narrative explanations and also function to underline attendant dimensions of evaluation. PMID- 28583359 TI - Narrative and natural history in the eighteenth century. AB - In the eighteenth century, natural histories of animals incorporated narratives about animal behaviour and narratives of discovery and experimentation. Naturalists used first-person accounts to link the stories of their scientific investigations to the stories of the animal lives they were studying. Understanding nature depended on narratives that shifted back and forth in any given text between animal and human, and between individual cases and generalizations about species. This paper explores the uses of narrative through examples from the work of Rene-Antoine Ferchault de Reaumur and Abraham Trembley. In all cases, narrative took the genre of natural history well beyond straightforward description and classification. Prose accounts of insect actions and mechanisms worked in tandem with visual narratives embedded in the accompanying illustrations, where artists developed strategies for representing sequences of minute changes over time. By throwing into relief the narrative sections of natural histories, the examples considered here expose the role played by these tales of encounters with the insect world in the making of natural historical knowledge. PMID- 28583360 TI - Process tracing in political science: What's the story? AB - Methodologists in political science have advocated for causal process tracing as a way of providing evidence for causal mechanisms. Recent analyses of the method have sought to provide more rigorous accounts of how it provides such evidence. These accounts have focused on the role of process tracing for causal inference and specifically on the way it can be used with case studies for testing hypotheses. While the analyses do provide an account of such testing, they pay little attention to the narrative elements of case studies. I argue that the role of narrative in case studies is not merely incidental. Narrative does cognitive work by both facilitating the consideration of alternative hypotheses and clarifying the relationship between evidence and explanation. I consider the use of process tracing in a particular case (the Fashoda Incident) in order to illustrate the role of narrative. I argue that process tracing contributes to knowledge production in ways that the current focus on inference tends to obscure. PMID- 28583361 TI - Narrative constructs in modern clinical case reporting. AB - Modern clinical case reporting takes the form of problem-solution narratives that redescribe symptoms in terms of disease categories. Authored almost always by those who have played a part in the medical assessment of the patient, reports historicise the salient details of an individual's illness as a complex effect of identifiable antecedent causes. Candidate hypotheses linking illness to pathological mechanisms are suggested by the patient's experience, and by data that emerge from clinical examination and investigation. Observational and interpretive statements from these considerations are fitted into a temporally inflected account of the patient's medical condition, configured from the vantage point of hindsight. Drawing on established forms of deferred telling, readers are invited to follow a story that drip-feeds a mixture of contingent and non incidental information into the account, which engenders and frustrates curiosity, creates expectations, and challenges powers of reasoning and pattern recognition. Whereas case reporting once favoured memoir, the sentimental tale and eccentric biography as the means by which its historical narrative was cast, the preferred genres of contemporary case reporting include detective fiction, and puzzle and riddle narratives, formats that conceptualise the medical consultation in narrow problem-solution terms. PMID- 28583362 TI - On the narrative form of simulations. AB - Understanding complex physical systems through the use of simulations often takes on a narrative character. That is, scientists using simulations seek an understanding of processes occurring in time by generating them from a dynamic model, thereby producing something like a historical narrative. This paper focuses on simulations of the Diels-Alder reaction, which is widely used in organic chemistry. It calls on several well-known works on historical narrative to draw out the ways in which use of these simulations mirrors aspects of narrative understanding: Gallie for "followability" and "contingency"; Mink for "synoptic judgment"; Ricoeur for "temporal dialectic"; and Hawthorn for a related dialectic of the "actual and the possible". Through these reflections on narrative, the paper aims for a better grasp of the role that temporal development sometimes plays in understanding physical processes and of how considerations of possibility enhance that understanding. PMID- 28583363 TI - Narrative ordering and explanation. AB - This paper investigates the important role of narrative in social science case based research. The focus is on the use of narrative in creating a productive ordering of the materials within such cases, and on how such ordering functions in relation to 'narrative explanation'. It argues that narrative ordering based on juxtaposition - using an analogy to certain genres of visual representation - is associated with creating and resolving puzzles in the research field. Analysis of several examples shows how the use of conceptual or theoretical resources within the narrative ordering of ingredients enables the narrative explanation of the case to be resituated at other sites, demonstrating how such explanations can attain scope without implying full generality. PMID- 28583364 TI - A Pictorial Review of Hepatobiliary Magnetic Resonance Imaging With Hepatocyte Specific Contrast Agents: Uses, Findings, and Pitfalls of Gadoxetate Disodium and Gadobenate Dimeglumine. AB - Magnetic resonance imaging (MRI) has a well-established role as a highly specific and accurate modality for characterizing benign and malignant focal liver lesions. In particular, contrast-enhanced MRI using hepatocyte-specific contrast agents (HSCAs) improves lesion detection and characterization compared to other imaging modalities and MRI techniques. In this pictorial review, the mechanism of action of gadolinium-based MRI contrast agents, with a focus on HSCAs, is described. The clinical indications, protocols, and emerging uses of the 2 commercially available combined contrast agents available in the United States, gadoxetate disodium and gadobenate dimeglumine, are discussed. The MRI features of these agents are compared with examples of focal hepatic masses, many of which have been obtained within the same patient therefore allowing direct lesion comparison. Finally, the pitfalls in the use of combined contrast agents in liver MRI are highlighted. PMID- 28583365 TI - Reprint of: Hydrogen sulfide in stroke: Protective or deleterious? AB - Hydrogen sulfide is believed to be a signalling molecule in the central nervous system. It is known to increase rapidly following an ischemic insult in experimental stroke. Is it protective or deleterious? This review surveys the relevant information available in the literature. It appears that there is no definitive answer to this question at present. Current evidence seems to suggest that the presence of H2S in the ischemic brain may either be deleterious or protective depending on its concentration, deleterious when high and protective when low. Therefore, it can be inferred that either an enhancement or a reduction of its concentration may be of potential use in future stroke therapy. PMID- 28583366 TI - Pentoxifylline induces apoptosis of HepG2 cells by reducing reactive oxygen species production and activating the MAPK signaling. AB - AIMS: Pentoxifylline (PTX) is a methylxanthine derivative and has potent anti tumor activity. This study aimed at investigating the anti-HCC effects of PTX and associated molecular mechanisms. MAIN METHODS: The effects of varying doses of PTX on viability, cell cycle and apoptosis of HepG2 cells were determined by MTT and flow cytometry, respectively. The effects of PTX on the production of reactive oxygen species (ROS), expression of pro- and anti-apoptotic regulators and activation of the MAPK signaling in HepG2 cells were analyzed by flow cytometry and Western blot assays. The effects of PTX on the growth of implanted HepG2 cells and their apoptosis in mice were examined. KEY FINDINGS: Our results indicated that PTX inhibited proliferation of HepG2 cells and induced HepG2 cell cycle arrest at G0/G1 phase and apoptosis in a dose- and time-dependent manner. Treatment with PTX reduced levels of ROS and Bcl-XL expression, but increased caspase 3 and caspase 9 expression and JNK and ERK1/2 phosphorylation in HepG2 cells. Pre-treatment with n-acetyl-l-cysteine (NAC), a ROS scavenger, enhanced PTX-mediated cell cycle arrest, apoptosis and the JNK and ERK MAPK activation, while pre-treatment with SP600125 or PD98509 attenuated PTX-mediated effects in HepG2 cells. Treatment with PTX inhibited the growth of implanted HCC and promoted HCC apoptosis in mice. SIGNIFICANCE: Our data demonstrate that PTX inhibits proliferation of HepG2 cells and induces HepG2 cell apoptosis by attenuating ROS production and enhancing the MAPK activation in HepG2 cells. PMID- 28583367 TI - Application of modelling and nanotechnology-based approaches: The emergence of breakthroughs in theranostics of central nervous system disorders. AB - The limited efficiency of the current treatment options against the central nervous system (CNS) disorders has created increasing demands towards the development of novel theranostic strategies. The enormous research efforts in nanotechnology have led to the production of highly-advanced nanodevices and biomaterials in a variety of geometries and configurations for targeted delivery of genes, drugs, or growth factors across the blood-brain barrier. Meanwhile, the richness or reliability of data, drug delivery methods, therapeutic effects or potential toxicity of nanoparticles, occurrence of the unexpected phenomena due to the polydisperse or polymorphic nature of nanomaterials, and personalized theranostics have remained as challenging issues. In this respect, computational modelling has emerged as a powerful tool for rational design of nanoparticles with optimized characteristics including the selectivity, improved bioactivity, and reduced toxicity that might lead to the effective delivery of therapeutic agents. High-performance simulation techniques by shedding more light on the dynamical behaviour of neural networks and pathomechanisms of CNS disorders may provide imminent breakthroughs in nanomedicine. In the present review, the importance of integration of nanotechnology-based approaches with computational techniques for targeted delivery of theranostics to the CNS has been highlighted. PMID- 28583368 TI - The impact of obesity on neurodegenerative diseases. AB - Neurodegenerative diseases are a growing health concern. The increasing incidences of these disorders have a great impact on the patients' quality of life. Although the mechanisms of neurodegenerative diseases are still far from being clarified, several studies look for new discoveries about their pathophysiology and prevention. Furthermore, evidence has shown a strong correlation between obesity and the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Metabolic changes caused by overweight are related to damage to the central nervous system (CNS), which can lead to neural death, either by apoptosis or cell necrosis, as well as alter the synaptic plasticity of the neuron. This review aims to show the association between neurodegenerative diseases, focusing on AD and PD, and metabolic alterations. PMID- 28583369 TI - Innate mechanism of pollen- and cat dander-induced oxidative stress and DNA damage in the airways. PMID- 28583370 TI - Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of T cell-derived IL-22 in their pathogenesis. Although prostaglandin (PG) E2 is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. OBJECTIVES: We sought to investigate whether PGE2 has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. METHODS: T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE2 in IL-22 production. The involvement of PGE2 receptors and their downstream signals was also examined. The effects of PGE2 were evaluated by using the oxazolone-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated by using genomic profiling in human lesional AD skin. RESULTS: PGE2 induces IL-22 from T cells through its receptors, E prostanoid receptor (EP) 2 and EP4, and involves cyclic AMP signaling. Selective deletion of EP4 in T cells prevents hapten-induced IL-22 production in vivo, and limits atopic-like skin inflammation in the oxazolone induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately upregulated in human AD lesional skin but were at less than significant detection levels after corticosteroid or UVB treatments. CONCLUSIONS: Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T cells. PMID- 28583371 TI - Bacterial infections after pediatric heart transplantation: Epidemiology, risk factors and outcomes. AB - BACKGROUND: Bacterial infections represent a major cause of morbidity and mortality in heart transplant recipients. However, data describing the epidemiology and outcomes of these infections in children are limited. METHODS: We analyzed the Pediatric Heart Transplant Study database of patients transplanted between 1993 and 2014 to determine the etiologies, risk factors and outcomes of children with bacterial infections post-heart transplantation. RESULTS: Of 4,458 primary transplants in the database, there were 4,815 infections that required hospitalization or intravenous therapy, 2,047 (42.51%) of which were bacterial. The risk of bacterial infection was highest in the first month post-transplant, and the bloodstream was the most common site (24.82%). In the early post-transplant period (<30 days post-transplant), coagulase-negative staphylococci were the most common pathogens (16.97%), followed by Enterobacter sp (11.99%) and Pseudomonas sp (11.62%). In the late post-transplant period, community-acquired pathogens Streptococcus pneumoniae (6.27%) and Haemophilus influenzae (2.82%) were also commonly identified. Patients' characteristics independently associated with acquisition of bacterial infection included younger age (p < 0.0001) and ventilator (p < 0.0001) or extracorporeal membrane oxygenation (p = 0.03) use at time of transplant. Overall mortality post bacterial infection was 33.78%, and previous cardiac surgery (p < 0.001) and multiple sites of infection (p = 0.004) were independent predictors of death. CONCLUSIONS: Bacteria were the most common causes of severe infections in pediatric heart transplant recipients and were associated with high mortality rates. The risk of acquiring a bacterial infection was highest in the first month post-transplant, and a large proportion of the infections were caused by multidrug-resistant pathogens. PMID- 28583372 TI - Dose-dependent association between amiodarone and severe primary graft dysfunction in orthotopic heart transplantation. AB - BACKGROUND: There is growing concern regarding the association between pre transplant amiodarone exposure and post-transplant adverse outcomes. We hypothesized that amiodarone use would be associated with the development of severe primary graft dysfunction (PGD) in a dose-dependent manner. METHODS: This was a retrospective review of 269 adult orthotopic heart transplantation (OHT) recipients at our institution between 2010 and 2014. At the time of OHT, 100 were receiving amiodarone therapy (Group 1) and 169 were not (Group 2). RESULTS: Pre OHT creatinine was higher in Group 1 (1.49 +/- 0.63 vs 1.27 +/- 0.68 mg/dl, p = 0.011). At time of listing, Group 1 had higher frequency of status 2 (42.0% vs 29.0%), and Group 2 had higher frequency of status 1A (20.7% vs 8.0%; p = 0.009). Severe PGD (mechanical circulatory support within 24 hours post-OHT) was significantly higher in Group 1 (20.0% vs 5.3%, p < 0.001). Pre-OHT amiodarone use was an independent risk factor for severe PGD (odds ratio [OR], 6.05; 95% confidence interval [CI], 2.47-14.83; p < 0.001) and in-hospital mortality (OR, 2.88; 95% CI, 1.05-7.88; p = 0.039) in multivariable analysis. Each 100-mg increase in the day-of-OHT amiodarone dose (OR, 1.55; 95% CI, 1.26-1.90) and each 18,300-mg increase in the 6-month cumulative dose (OR, 1.67; 95% CI, 1.31-2.15) was associated with increased odds of developing severe PGD (p < 0.001 for both). CONCLUSIONS: Amiodarone use pre-OHT is independently associated with increased incidence of severe PGD and in-hospital mortality and linearly associated with increased incidence of severe PGD in a dose-dependent manner. PMID- 28583374 TI - Sirt1 suppresses Wnt/betaCatenin signaling in liver cancer cells by targeting betaCatenin in a PKAalpha-dependent manner. AB - Here, bioinformatics data from Sirt1 knock-out (KO) and knock-in (KI) mice suggest that Sirt1 inhibits Wnt/betaCatenin signaling in the liver. However, it is unclear how this relationship occurs and how it contributes to malignant phenotypes in liver cancer cells. We found that Sirt1 expression promotes phosphorylation of betaCatenin at Ser675, which may subsequently decrease expression of total-betaCatenin. Mechanistically, Sirt1 expression elevates phosphorylation of the alpha subunit of protein kinase A (PKAalpha), and this event is essential for Sirt1-induced phosphorylation of betaCatenin. The negative effects of Sirt1 on betaCatenin stability are also dependent on PKAalpha. Stimulating PKAalpha recruits betaTrCP, a well-known ubiquitin E3 ligase for betaCatenin, to betaCatenin. Interestingly, Sirt1 expression is able to up regulate betaTrCP expression. Finally, we found that malignant phenotypes occur in hepatocytes when Sirt1 and betaCatenin are co-overexpressed, and such effects are enhanced by simultaneous knockdown of PKAalpha. In contrast, malignant phenotypes are abrogated upon knockdown of Sirt1, and this phenotype is magnified by knockdown of betaCatenin. Collectively, we conclude that suppression of both Sirt1 and Wnt/betaCatenin might be effective in treating liver cancer. PMID- 28583375 TI - Short-term storage of human testicular tissue: effect of storage temperature and tissue size. AB - During short-term storage, before cryopreservation, testicular tissue quality can be affected by storage medium, duration, temperature and tissue size. We previously established the best storage medium and time for short-term maintenance of tissue. In this study, three different storage temperatures (4 degrees C, room temperature, 37 degrees C) and four tissue sizes (~6 mm3; ~ 15 mm3; ~ 50 mm3 or ~80 mm3) were assessed over the course of a fixed period of 3 days. Storing human testicular tissue at 37 degrees C caused a significant increase in the number of apoptotic cells per tubule (P = 0.002), compared with fresh control, but this was not the case at 4 degrees C or room temperature. Temperature did not affect viability, tissue morphology or number of spermatogonia in samples. The morphology of the testicular tissue was optimally preserved when stored as large fragments (~50 mm3: P = 0.018; ~ 80 mm3: P = 0.018). Tissue size did not significantly affect viability, number of spermatogonia or apoptotic cells. Adult human testicular tissue can be preserved at 4 degrees C or room temperature without altering tissue morphology, Sertoli cell morphology, number of spermatogonia or number of apoptotic cells. The tissue does not need to be extensively dissected as tissue morphology is better maintained in larger fragments. PMID- 28583373 TI - Mechanisms of mutant PDE6 proteins underlying retinal diseases. AB - Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory Pgamma subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of Pgamma to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of Pgamma with mutant PDE6C that markedly reduced the ability of Pgamma to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases. PMID- 28583376 TI - Depression and health behaviors in women with Peripartum Cardiomyopathy. AB - BACKGROUND: Depression and health behavior engagement are a critical issue for recovery and secondary prevention in heart failure patients. No prior studies have examined these important clinical outcomes in young women diagnosed with Peripartum Cardiomyopathy (PPCM). We sought to characterize the prevalence of depression and health behaviors in PPCM patients and examine whether depression is associated with reduced engagement in health behaviors. METHODS: A nation wide, cohort of 177 PPCM patients (mean age of 34.8 +/- 5.7 years; median time since diagnosis of 3.0 +/- 4.3 years) from a web-based quality of life registry completed questionnaires about depression (Patient Health Questionnaire; a cutoff score >=10 was used for depression screening) and health behaviors. T-tests, chi square and linear regression were used to compare clinical characteristics and health behaviors among depressed and non-depressed women. RESULTS: The prevalence of clinical depression at enrollment was 32.3% and was associated with use of antihypertensive medications, disability insurance status, higher BMI, history of arrhythmia and current or past use of psychotropic medication. Health behavior engagement for diet, physical activity, and tobacco cessation were low in the overall sample and depressed PPCM patients were significantly less likely to attend medical appointments than non-depressed women. CONCLUSIONS: Nearly 1 in 3 PPCM survivors reported symptoms of clinical depression which was associated with worse attendance at medical follow-up visits. Further research is needed to develop risk stratification models and patient-centered interventions to improve clinical outcomes for PPCM survivors. PMID- 28583377 TI - Harnessing the positive potential of wider policy impacts on human health. PMID- 28583379 TI - Prognostic Role of the FGFR4-388Arg Variant in Lung Squamous-Cell Carcinoma Patients With Lymph Node Involvement. AB - BACKGROUND: The identification of prognostic biomarkers for lung squamous-cell carcinoma (SCC) pathology is crucial because of its poor prognosis. A variant of the FGFR4 (fibroblast growth factor receptor 4) gene, FGFR4-388Arg, has been associated with prognosis and is linked to oncogenesis in vitro in several types of cancer. We analyzed the association of this variant with prognosis and downstream signaling alteration in lung SCC patients. METHODS: The presence of the FGFR4-388Arg variant was determined in 114 formalin-fixed, paraffin-embedded lung SCC tissue samples by DNA genotyping and was correlated with clinicopathologic data. The activation of the protein kinase B (AKT) and mitogen activated protein kinase (MAPK) pathways was determined by immunohistochemistry, and its association with the presence of FGFR4-388Arg was analyzed. RESULTS: We found that tumor differentiation status and adjuvant chemotherapy administration could be independent prognostic factors for overall survival (OS) in lymph node affected patients, as expected. The progression-free survival and OS of patients with lymph node involvement (n = 41) and the FGFR4-388Arg genotype were significantly lower than those of patients lacking this variant (P = .035 and P = .042, respectively). Importantly, multivariate analysis supported the independent prognostic role of the FGFR4-388Arg genotype in OS (P = .025). Regarding downstream signaling, the FGFR4-388Arg genotype was not correlated with altered AKT signaling but was associated with increased MAPK activation in the SCC tumor samples (P = .017). CONCLUSION: The FGFR4-388Arg variant may represent a promising prognostic biomarker in SCC patients with lymph node involvement. For these patients, FGFR4 may be a potential therapeutic target. PMID- 28583378 TI - A systematic survey on reporting and methods for handling missing participant data for continuous outcomes in randomized controlled trials. AB - OBJECTIVE: To assess analytic approaches randomized controlled trial (RCT) authors use to address missing participant data (MPD) for patient-important continuous outcomes. STUDY DESIGN AND SETTING: We conducted a systematic survey of RCTs published in 2014 in the core clinical journals that reported at least one patient-important outcome analyzed as a continuous variable. RESULTS: Among 200 studies, 187 (93.5%) trials explicitly reported whether MPD occurred. In the 163 (81.5%) trials that reported the occurrence of MPD, the median and interquartile ranges of the percentage of participants with MPD were 11.4% (2.5% 22.6%).Among the 147 trials in which authors made clear their analytical approach to MPD, the approaches chosen included available data only (109, 67%); mixed effect models (10, 6.1%); multiple imputation (9, 4.5%); and last observation carried forward (9, 4.5). Of the 163 studies reporting MPD, 16 (9.8%) conducted sensitivity analyses examining the impact of the MPD and (18, 11.1%) discussed the risk of bias associated with MPD. CONCLUSION: RCTs reporting continuous outcomes typically have over 10% of participant data missing. Most RCTs failed to use optimal analytic methods, and very few conducted sensitivity analyses addressing the possible impact of MPD or commented on how MPD might influence risk of bias. PMID- 28583380 TI - Comparison of Radiotherapy and Chemoradiotherapy for Locoregional Recurrence of Non-small-cell Lung Cancer Developing After Surgery. AB - BACKGROUND: The optimal treatment strategy for locoregional recurrences developing after surgical resection in patients with non-small-cell lung cancer (NSCLC) is yet to be clearly established. PATIENTS AND METHODS: To investigate the efficacy and safety of radiotherapy (RT) and chemoradiotherapy (CRT), we reviewed the consecutive data of patients with NSCLC with postoperative locoregional recurrences treated at the National Cancer Center Hospital between January 2000 and April 2010. RESULTS: We reviewed the data of 74 patients (including 56 who received RT alone and 18 who received CRT) according to our study criteria. The median age was lower and the N factor at the recurrence site was higher in the CRT group compared with the RT group. Most patients received 60 Gy/30 Fr RT in both groups. The 2-year progression-free survival (PFS) rate, median PFS, and overall survival (OS) were 44.4%, 19.0 months (95% confidence interval [CI], 0-41.9 months), and 79.6 months (95% CI, 8.2-151.0 months), respectively, in the CRT group, although those were 25.0%, 10.6 months (95% CI, 8.7-12.9 months), and 33.1 months (95% CI, 17.9-48.3 months), respectively, in the RT group. The adverse event profile was acceptable, with no treatment-related death in either group. Multivariate analysis identified CRT as being significantly associated with a longer PFS and OS. CONCLUSION: CRT tended to yield better results than RT in terms of the survival outcomes, with acceptable safety profiles of both. We consider that a randomized study comparing RT and CRT is warranted to identify the optimal treatment strategy for patients with NSCLC with postoperative locoregional recurrences. PMID- 28583381 TI - Synergistic activities of meropenem double and triple combinations against carbapenemase-producing Enterobacteriaceae. AB - The increasing emergence of carbapenemase-producing Enterobacteriaceae poses a considerable threat to global health as only limited treatment options are available and has therefore led to efforts to discover antibiotic combination regimens effective. The aim of this study was to evaluate in vitro synergistic activity of 10 meropenem double and triple combinations against the 5 most frequently encountered carbapenemases-producing Enterobacteriaceae. Broth microdilution assays showed that the meropenem and ertapenem combination was the most efficient regimen of the double combinations tested (>5-log2 fold decrease). The triple combination of meropenem, polymyxin and rifampin exhibited highest synergistic activity of the triple combinations. The divergent reports on synergistic activity of antibiotic combinations suggest that it may not be possible to predict synergy based on carbapenemase type alone. Consequently, we recommend that in vitro evaluation of synergistic activity of antibiotic combinations against carbapenemase-producing Enterobacteriaceae is performed on every isolate to ensure effective treatment regimens. PMID- 28583382 TI - Advance directives and individuals with disabilities. PMID- 28583383 TI - Investing in children: The best way to prevent separation from parents and families. AB - The reliable and disaggregated data on children deprived of family care, living in different forms of public care is essential information to implement the UN Guidelines on Alternative Care of Children and its principle on necessity and suitability. At the same time all needed information and data would also be needed on all forms of support, universal, targeted and specialized services provided or not provided to children and their families locally to prevent separation of children, on different forms of informal care. While there have been many efforts made to prevent institutionalization of children worldwide especially in the most developed countries, placement of children out of their families for different reasons, many of them closely related to poverty is still too often accepted. Some current programs in Europe described in the article can contribute to better implementation of the current policies and recommendations globally, however there is a parallel movement towards emphasizing the need and value of institutional care and the lack of alternatives in many cases, that should also be taken into consideration. More research, evidence and data is needed to defend the arguments for deinstitutionalization. PMID- 28583384 TI - Hydrocarbon-induced changes in proteins and fatty acids profiles of Raoultella ornithinolytica M03. AB - : Microorganisms can support environmental restoration by biodegradation of hydrocarbons but the mechanism of this process has been not described in detail yet. We present the effect of benzene derivatives on Raoultella ornithinolytica M03 cell composition. Comparison of the cell response after short-term and long term stress revealed significant differences in surface properties, fatty acid composition and proteins profile. R. ornithinolytica M03 after long-term stress was characterized by lower cell surface hydrophobicity and much higher inner membrane permeability. Also decrease in the content of branched and unsaturated fatty acids was observed. Cells after short- and long-term stress were characterized by analyses of changes related to thirty-nine proteins participating in various metabolic pathways. The presence of benzene derivatives resulted in modifications in the abundance of proteins involved in determination of cell shape and ability to ion transport, lipid biosynthesis, amino-acid biosynthesis, tRNA ligases, chaperone and TCA cycle proteins, gluconeogenesis, transcription and nucleotide synthesis. Uptake and transport associated proteins, cell properties and membrane stability were also found to differ in the cells after short- and long-term stress suggesting the use of different mechanisms for transport and biodegradation of benzene derivatives and modification of cell response depending on the length of exposure to the stressor. BIOLOGICAL SIGNIFICANCE: This is the first comprehensive study whose results may contribute to a better understanding of the changes occurring during short- and long-term contact with benzene derivatives. After long term stress R. ornithinolytica M03 was characterized by lower cell surface hydrophobicity and much higher inner membrane permeability and decrease in the content of branched and unsaturated fatty acids. We identified changes related to multiple proteins engaged in various metabolic pathways such as biogenesis of cell membrane/wall, amino-acid biosynthesis, nucleotide and protein synthesis, gluconeogenesis and tRNA ligases. Changes in proteins participating in uptake and transport associated proteins, cell properties and membrane stability indicate modifications in transport and biodegradation of benzene derivatives, connected with the length of exposure to the stressor. The provided results seem to constitute an important aspect of remediation techniques. PMID- 28583385 TI - Person-centered trajectories of cultural values and behaviors among Chinese American adolescents. AB - This study examined change in acculturation values and behavior among 310 Chinese American adolescents, and how patterns of change were related to key demographic variables and indicators of positive youth development. Dual process group-based trajectory models of change in U.S. and Chinese values and behaviors indicated a six-group solution for each. The results showed that acculturation value patterns were not related to gender, nativity, or parent education, but were related to family cohesion, self-esteem, general and academic self-efficacy, and GPA. Acculturation behavior patterns were not related to gender but were related to nativity and parent education, and were also related to general self-efficacy and family cohesion. Taken together, our findings suggest that most trajectories of acculturation are associated with positive outcomes, but there are small groups of adolescents that function very well (those who maintain higher behavioral involvement in both) and some not very well, especially those whose behaviors are becoming more disparate over time. Special Issue: Explaining Positive Adaptation of Immigrant Youth across Cultures. PMID- 28583386 TI - Laugh or cringe? Common and distinct processes of reward-based schadenfreude and empathy-based fremdscham. AB - Witnessing others' plights can be funny for observers, but may also trigger one to empathically cringe with the victim of the predicament. In the present study, we examined the common and distinct neural networks involved in schadenfreude (i.e. pleasure derived from another's misfortune) and fremdscham (i.e. empathically sharing the embarrassment about another's misfortune). Using functional magnetic resonance imaging we examined a total of N = 34 participants while they observed social integrity threats of a misfortunate other and either reported on their schadenfreude or fremdscham. In this between-subject design, we found that despite a broad overlap in brain regions involved in social cognition, the left anterior insula (AI) was activated less if observers were asked to focus on their schadenfreude. Further, the nucleus accumben's activity exclusively covaried with the intensity of the schadenfreude experience and had a higher functional connectivity with the left AI in the context of schadenfreude than during fremdscham. With the present findings, we demonstrate that the valence and intensity of interpersonal emotions strongly depend on the experimental context and that empathy and reward circuits are involved in shaping the subjective experience. PMID- 28583387 TI - Prefrontally-mediated alterations in the retrieval of negative events: Links to memory vividness across the adult lifespan. AB - Prior research has identified age-by-valence interactions in both behavior and neural recruitment; age has been associated with increased retrieval of positive relative to negative information as well as an increased tendency to recruit prefrontal regions during negative event retrieval and for this recruitment to correspond to decreased hippocampal connectivity. To date, the explicit relation between prefrontal recruitment and memory phenomenology has not been examined. The current study examined the link between these two measures by examining age by-valence interactions in the relation between prefrontal recruitment and subjective ratings of memory vividness. Participants (ages 18-85) encoded visual images paired with verbal titles. During a scanned retrieval session, they were presented with titles and asked whether each had been seen with an image during encoding. Participants provided vividness ratings following retrieval of each image. Age was associated with greater prefrontally-mediated alterations in negative event phenomenology, with age-related increases in the relation between ventral prefrontal regions and negative event vividness and age-related decreases in the relation between dorsal prefrontal regions and negative event vividness. This analysis confirmed a critical role of PFC regions in age-by-valence interactions, where age reversed the relation between PFC recruitment and the subjective richness of retrieved memory representation. These findings are consistent with studies that reveal age-related enhancements in emotion regulation, and suggest that older adults may be engaging in these processes during retrieval of negative events. PMID- 28583389 TI - Fast determination of pesticides and other contaminants of emerging concern in treated wastewater using direct injection coupled to highly sensitive ultra-high performance liquid chromatography-tandem mass spectrometry. AB - It is well known that wastewater treatment plant (WWTP) effluents usually contain micropollutants such as pharmaceuticals (or their transformation products, TPs) or pesticides, which is a major issue when evaluating their possible reuse (e.g. for irrigation in agriculture). In search for an improved accuracy and simplicity, methods based on the direct injection of the sample (DI) represent a recent trend taking advantage of the increasing sensitivity of new mass spectrometry (MS) instruments. Thus, the present study shows the development and validation of a DI-based method by ultra-high-performance liquid chromatography quadrupole-linear ion trap analyser (UHPLC-QqLIT-MS/MS). The proposed method was applied to the monitoring of 115 organic microcontaminants (including pharmaceuticals, TPs and pesticides) at the ngL-1/MUgL-1 level in wastewater effluents from urban WWTPs. Sample pre-treatment was reduced to acetonitrile addition and filtration of the mixture previous to LC-MS analysis. Total analysis time was <15min. A subsequent validation protocol was carried out in treated WW (TWW), following indications of SANTE and Eurachem Guidelines. Linearity and matrix effect were evaluated in the range of 10-1000ngL-1. 70% of the analytes showed a moderate matrix effect (<=25%). Trueness (expressed as recovery) and precision (calculated as relative standard deviation, RSD) were evaluated at four concentration levels (20, 50, 500 and 1000ngL-1) in TWW samples. The LODs ranged from 1 to 357ngL-1 and the LOQs from 10 to 500ngL-1. 92% of the compounds showed limits of quantification <=100ngL-1. In most cases, mean recoveries were in the range 70-120%, and RSD values were <=20%. The validated method was successfully applied to the analysis of 10 TWW samples, demonstrating the occurrence of 67 target compounds at concentration levels from 26705ngL-1 (4-aminoantipyrine) to 10ngL-1 (tebuconazole and bezafibrate). PMID- 28583388 TI - Spatial modulation of motor-sensory recalibration in early deaf individuals. AB - Audition dominates other senses in temporal processing, and in the absence of auditory cues, temporal perception can be compromised. Moreover, after auditory deprivation, visual attention is selectively enhanced for peripheral visual stimuli. In this study, we assessed whether early hearing loss affects motor sensory recalibration, the ability to adjust the timing of an action and its sensory effect based on the recent experience. Early deaf participants and hearing controls were asked to discriminate the temporal order between a motor action (a keypress) and a visual stimulus (a white circle) before and after adaptation to a delay between the two events. To examine the effects of spatial modulation, we presented visual stimuli in both central and peripheral visual fields. Results showed overall higher temporal JNDs (Just Noticeable Difference) for deaf participants as compared to hearing controls suggesting that the auditory information is important for the calibration of motor-sensory timing. Adaptation to a motor-sensory delay induced distinctive effect in the two groups of participants, with hearing controls showing a recalibration effect for central stimuli only whereas deaf individuals for peripheral visual stimuli only. Our results suggest that auditory deprivation affects motor-sensory recalibration and that the mechanism underlying motor-sensory recalibration is susceptible to spatial modulation. PMID- 28583390 TI - Relating saturation capacity to charge density in strong cation exchangers. AB - In this work the relation between physical and chemical resin characteristics and the total amount of adsorbed protein (saturation capacity) for ion-exchange resins is discussed. Eleven different packing materials with a sulfo functionalization and one multimodal resin were analyzed in terms of their porosity, pore size distribution, ligand density and binding capacity. By specifying the ligand density and binding capacity by the total and accessible surface area, two different groups of resins were identified: Below a ligand density of approx. 2.5MUmol/m2 area the ligand density controls the saturation capacity, while above this limit the accessible surface area becomes the limiting factor. This results in a maximum protein uptake of around 2.5mg/m2 of accessible surface area. The obtained results allow estimating the saturation capacity from independent resin characteristics like the saturation capacity mainly depends on "library data" such as the accessible and total surface area and the charge density. Hence these results give an insight into the fundamentals of protein adsorption and help to find suitable resins, thus limiting the experimental effort in early process development stages. PMID- 28583391 TI - Rapid determination of 9 aromatic amines in mainstream cigarette smoke by modified dispersive liquid liquid microextraction and ultraperformance convergence chromatography tandem mass spectrometry. AB - Aromatic amines in mainstream cigarette smoke have long been monitored due to their carcinogenic toxicity. In this work, a reliable and rapid method was developed for the simultaneous determination of 9 aromatic amines in mainstream cigarette smoke by modified dispersive liquid liquid microextraction (DLLME) and ultraperformance convergence chromatography tandem mass spectrometry (UPC2 MS/MS). Briefly, the particulate phase of the cigarette smoke was captured by a Cambridge filter pad, and diluted hydrogen chloride aqueous solution is employed to extract the aromatic amines under mechanical shaking. After alkalization with sodium hydroxide solution, small amount of toluene was introduced to further extract and enrich aromatic amines by modified DLLME under vortexing. After centrifugation, toluene phase was purified by a universal QuEChERS cleanup kit and was finally analyzed by UPC2-MS/MS. Attributing to the superior performance of UPC2-MS/MS, this novel approach allowed the separation and determination of 9 aromatic amines within 5.0min with satisfactory resolution and sensitivity. The proposed method was finally validated using Kentucky reference cigarette 3R4F, and emission levels of targeted aromatic amines determined were comparable to previously reported methods At three different spiked levels, the recoveries of most analytes were ranged from 74.01% to 120.50% with relative standard deviation (RSD) less than 12%, except that the recovery of p-toluidine at low spiked level and 3-aminobiphenyl at medium spiked level was 62.77% and 69.37% respectively. Thus, this work provides a novel alternative method for the simultaneous analysis of 9 aromatic amines in mainstream cigarette smoke. PMID- 28583392 TI - A novel molybdenum disulfide nanosheet self-assembled flower-like monolithic sorbent for solid-phase extraction with high efficiency and long service life. AB - A novel material consisting of molybdenum disulfide (MoS2) nanosheet that self assemble into flower-like microspheres which aggregate to form a monolithic matrix with a micro or nano-scaled mesopore structure was successfully synthesized and used as an efficient sorbent for solid-phase extraction (SPE) due to its large specific adsorption area and good stability. The extraction properties of the as-prepared sorbent were evaluated by high-performance liquid chromatography with variable wavelength detection (HPLC-VWD) by analyzing four flavonoids (apigenin, quercetin, luteolin, and kaempferol). Under optimal conditions, the LODs and LOQs were found to be in the ranges of 0.1-0.25 and 0.4 0.5MUgL-1, respectively, and wide linear ranges were obtained with correlation coefficients (R) ranging from 0.9991 to 0.9996. Compared with commercial C18 and Alumina-N sorbents, the as-prepared sorbent showed high extraction efficiency at different concentrations of flavonoids. After 100 uses, the extraction ability of the self-assembled MoS2 nanosheet monolithic sorbent had no evident decline, denoting a long service life. Finally, the SPE-HPLC-VWD method using the as prepared sorbent was applied to flavonoid analysis in beverage samples with satisfactory results. PMID- 28583393 TI - Separation of the potential G-quadruplex ligands from the butanol extract of Zanthoxylum ailanthoides Sieb. & Zucc. by countercurrent chromatography and preparative high performance liquid chromatography. AB - G-quadruplex DNA structure is considered to be a very attractive target for antitumor drug design due to its unique role in maintaining telomerase activities. Therefore, discovering ligands with high stability of G-quadruplex structure is of great interest. In this paper, pH-zone refining counter current chromatography (CCC) and preparative high performance liquid chromatography (HPLC) were employed for the separation of potent G-quadruplex ligands from the n butanol fraction of the crude extract of Zanthoxylum ailanthoides, which is a traditional Chinese medicine recently found to display high inhibitory activity against several human cancer cells. The 75% aqueous ethanol extract of the stem bark of Z. ailanthoides and its fractions with petroleum ether, ethyl acetate and n-butanol displayed almost the same G-quadruplex stabilization ability. Here, pH zone refining CCC was used for the separation of the alkaloids from the n-butanol fraction by a seldom used solvent system composed of dichloromethane-methanol water (4:1:2.5) with 10mM TEA in the organic stationary phase as retainer and 10mM HCl in the aqueous mobile phase as eluter. Compounds I, II and III were obtained, with purity greater than 95%, in the quantities of 31.2, 94.0, and 26.4mg respectively from 300mg of lipophilic fraction within 80min, which were identified as three tetrahydroprotoberberines isolated for the first time in this plant. In addition, a phenylpropanoid glycoside compound IV (Syringin), an isoquinoline (Magnoflorine, V), and two lignin isomers (+)-lyoniresiol-3alpha-O beta-d-glucopyranoside (VI) and (-)-lyoniresinol -3alpha-O-beta-D glucopyranoside (VII) were isolated by traditional CCC together with preparative HPLC. Compounds IV, V, VI and VII were obtained, with purity greater than 95%, in the quantities of 4.0, 13.2, 6.7, and 6.5mg respectively from 960mg of hydrophilic fraction. Among the seven isolated compounds, tetrahydroprotoberberine I, II and III were found to display remarkable stabilization effects on G-quadruplex by increasing G-quadruplex's Tm approximately 10 degrees C, which may be the most potent G-quadruplex ligands in Z. ailanthoides. PMID- 28583394 TI - Improving precision in the prediction of asthma exacerbations. PMID- 28583395 TI - 2017 American Thoracic Society International Conference. PMID- 28583396 TI - A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials. AB - BACKGROUND: Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx). CompEx needs to strongly mirror results seen with the severe exacerbation-validated outcome, to allow the design of clinical trials of shorter duration and that include fewer patients than trials assessing severe exacerbations. METHODS: Data from 12 asthma trials of 6 months or 12 months duration and, with standardised collection of exacerbations and diary card variables, were used to construct and test CompEx. The study populations had a mean age of 35-53 years, 59-69% were female, and had a mean FEV1 percentage of predicted normal of 63-84%. With data from five trials, we established a series of diary events based on peak expiratory flow (P), reliever use (R), symptoms (S), awakenings (A), and threshold values for change from baseline and slopes to assess trends. For the development phase, we evaluated different variable combinations and deterioration criteria to select the most robust algorithm to define a diary event for the composite outcome. We defined a composite outcome, CompEx, as first occurrence of a diary event or a severe exacerbation. We assessed the performance of CompEx in seven trials by comparing the event frequency, treatment effect (hazard ratio; HR), and the sample size needed for future trials for the CompEx versus episodes of severe exacerbations. FINDINGS: CompEx (based on PRS) was the algorithm that best fulfilled our two-set criteria. When censored at 3 months, CompEx resulted in 2.8 times more events than severe exacerbations, and while preserving the treatment effect observed on severe exacerbations (CompEx over severe exacerbation average HR 1.01). The increased number of events, together with the sustained treatment effect, resulted in a large net gain in power, with a 67% mean reduction in the number of patients required in a drug trial for severe exacerbations. In six of seven comparisons tested, CompEx reduced the sample size needed by at least 50%. Validation of independent test populations confirmed the ability of CompEx to increase event frequencies, preserve treatment effect, and reduce the number of patients needed. INTERPRETATION: CompEx is a composite outcome for evaluation of new asthma therapies. CompEx allows design of shorter trials that require fewer patients than studies of severe exacerbations, while preserving the ability to show a treatment effect compared with severe exacerbations. FUNDING: AstraZeneca. PMID- 28583397 TI - Long-term cardiovascular health in adult cancer survivors. AB - The number of cancer survivors has tremendously increased over the past decades as a result of aging of the population and improvements in early cancer detection and treatment. Ongoing successes in cancer treatment are expected to result in a further increase in the number of long-term survivors. However, cancer treatment can have detrimental cardiovascular side-effects that impact morbidity and mortality, reducing quality of life in cancer survivors. The spectrum of radiotherapy- and chemotherapy-induced cardiovascular disease is broad, varying from subclinical valvular dysfunction to overt congestive heart failure, and such effects may not be apparent for more than twenty years after the initial cancer treatment. Awareness of these long-term side-effects is of crucial value in the management of these patients, in order to reduce the impact of cardiovascular morbidity and mortality. This review provides a comprehensive overview of the long-term cardiovascular complications of cancer treatments (radiotherapy and chemotherapy) in adult cancer survivors. PMID- 28583398 TI - The emerging world of breast cancer immunotherapy. AB - Over the last few years, the developments around cancer immunotherapy (CIT) have led to a paradigm shift in the treatment of many different cancers, in particular melanoma, renal, bladder and lung cancers with a remarkable impact on response rate and, most importantly, overall survival. Breast cancer is most commonly considered to be a 'non-inflamed' cancer and so this shift has been less marked within its treatment. However, some subsets of breast cancer, most notably triple negative breast cancer, are deemed to be more 'inflamed' and therefore may prove to be an appropriate cohort for CIT. This review looks back at the theory of the cancer immunity cycle and mechanism of action behind immune checkpoint inhibitors and goes on to explore their role within the various subtypes of breast cancer. It looks at the first trials performed using CIT monotherapy which demonstrated that breast cancer could respond to CIT with a small population reaping considerable benefit. It then examines the continuing body of work being undertaken to explore CIT in combination with chemotherapy to try to increase the proportion of patients who might reap the considerable rewards on offer. PMID- 28583399 TI - Acute Aortic Arch Perforation During Transcatheter Aortic Valve Replacement in Bicuspid Aortic Stenosis and a Gothic Aortic Arch. AB - Transcatheter aortic valve replacement (TAVR) has evolved from a novel technology to an established therapy for high/intermediate-risk patients with severe symptomatic aortic stenosis (AS). Although TAVR is used to treat bicuspid severe AS, the large randomized trials typically excluded bicuspid AS because of its unique anatomic features. This case report describes an acute aortic perforation during delivery of a transcatheter heart valve to treat a severe bicuspid AS with a "gothic aortic arch"; more careful evaluation of the preprocedural multislice computed tomographic scan would have unveiled a sharply angulated aortic arch. This life-threatening complication was successfully treated by thoracic endovascular aortic repair. PMID- 28583400 TI - Focal choroidal excavaction associated with idiopathic choroidal neovascularization. AB - CASE REPORT: The case is presented of a 45 year-old man with a focal choroidal excavation associated with choroidal neovascularisation not included in the area of excavation. Clinical features were analysed using retinography, fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. The patient was treated with 3 intravitreal injections of bevacizumab, with a good response. DISCUSSION: Focal choroidal excavation can be associated with choroidal neovascularization not included in the area of excavation. Multimodal imaging provides a complete description of clinical features, before and after treatment. PMID- 28583402 TI - Between the Devil and the Deep Blue Sea: Use of Real-Time Tools to Identify Children With Severe Sepsis in the Pediatric Emergency Department. PMID- 28583401 TI - miR-873 suppresses H9C2 cardiomyocyte proliferation by targeting GLI1. AB - MicroRNAs (miRNAs) are a class of endogenous, non-coding small RNAs that regulate the expression of target genes. Previous studies have suggested that miRNAs are key regulators in cardiovascular systems. This study investigated the role of miR 873 in H9C2 cardiomyocytes by targeting glioma-associated oncogene 1 (GLI1). miR 873 was significantly up-regulated in serum samples from congenital heart disease (CHD) patients compared with those from normal individuals. Furthermore, miR-873 over-expression suppressed H9C2 proliferation and induced cell cycle arrest. Bioinformatic algorithms revealed a predicted target site for miR-873 in the 3' untranslated region (3'UTR) of GLI1, which was verified using a dual-luciferase reporter assay. qPCR and western blot analysis also showed that miR-873 negatively regulated GLI1 mRNA and protein expression in H9C2 cells. Conversely, GLI1 over-expression partially reversed the growth-inhibitory effect of miR-873. To summarize, our data suggest that miR-873 is a novel miRNA that regulates H9C2 cell proliferation via targeting GLI1, and miR-873 may serve as a new potential biomarker diagnosis in CHD in the future. PMID- 28583403 TI - Improving Recognition of Pediatric Severe Sepsis in the Emergency Department: Contributions of a Vital Sign-Based Electronic Alert and Bedside Clinician Identification. AB - STUDY OBJECTIVE: Recognition of pediatric sepsis is a key clinical challenge. We evaluate the performance of a sepsis recognition process including an electronic sepsis alert and bedside assessment in a pediatric emergency department (ED). METHODS: This was a cohort study with quality improvement intervention in a pediatric ED. Exposure was a positive electronic sepsis alert, defined as elevated pulse rate or hypotension, concern for infection, and at least one of the following: abnormal capillary refill, abnormal mental status, or high-risk condition. A positive electronic sepsis alert prompted team assessment or huddle to determine need for sepsis protocol. Clinicians could initiate team assessment or huddle according to clinical concern without positive electronic sepsis alert. Severe sepsis outcome defined as activation of the sepsis protocol in the ED or development of severe sepsis requiring ICU admission within 24 hours. RESULTS: There were 182,509 ED visits during the study period, with 86,037 before electronic sepsis alert implementation and 96,472 afterward, and 1,112 (1.2%) positive electronic sepsis alerts. Overall, 326 patients (0.3%) were treated for severe sepsis within 24 hours. Test characteristics of the electronic sepsis alert alone to detect severe sepsis were sensitivity 86.2% (95% confidence interval [CI] 82.0% to 89.5%), specificity 99.1% (95% CI 99.0% to 99.2%), positive predictive value 25.4% (95% CI 22.8% to 28.0%), and negative predictive value 100% (95% CI 99.9% to 100%). Inclusion of the clinician screen identified 43 additional electronic sepsis alert-negative children, with severe sepsis sensitivity 99.4% (95% CI 97.8% to 99.8%) and specificity 99.1% (95% CI 99.1% to 99.2%). Electronic sepsis alert implementation increased ED sepsis detection from 83% to 96%. CONCLUSION: Electronic sepsis alert for severe sepsis demonstrated good sensitivity and high specificity. Addition of clinician identification of electronic sepsis alert-negative patients further improved sensitivity. Implementation of the electronic sepsis alert was associated with improved recognition of severe sepsis. PMID- 28583404 TI - Thermophilic ethanol fermentation from lignocellulose hydrolysate by genetically engineered Moorella thermoacetica. AB - A transformant of Moorella thermoacetica was constructed for thermophilic ethanol production from lignocellulosic biomass by deleting two phosphotransacetylase genes, pdul1 and pdul2, and introducing the native aldehyde dehydrogenase gene (aldh) controlled by the promoter from glyceraldehyde-3-phosphate dehydrogenase. The transformant showed tolerance to 540mM and fermented sugars including fructose, glucose, galactose and xylose to mainly ethanol. In a mixed-sugar medium of glucose and xylose, all of the sugars were consumed to produce ethanol at the yield of 1.9mol/mol-sugar. The transformant successfully fermented sugars in hydrolysate prepared through the acid hydrolysis of lignocellulose to ethanol, suggesting that this transformant can be used to ferment the sugars in lignocellulosic biomass for ethanol production. PMID- 28583405 TI - Pre-aeration of food waste to augment acidogenic process at higher organic load: Valorizing biohydrogen, volatile fatty acids and biohythane. AB - Application of pre-aeration (AS) to waste prior to feeding was evaluated on acidogenic process in a semi-pilot scale biosystem for the production of biobased products (biohydrogen, volatile fatty acids (VFA) and biohythane) from food waste. Oxygen assisted in pre-hydrolysis of waste along with the suppression of methanogenic activity resulting in enhanced acidogenic product formation. AS operation resulted in 97% improvement in hydrogen conversion efficiency (HCE) and 10% more VFA production than the control. Increasing the organic load (OL) of food waste in association with AS application improved the productivity. The application of AS also influenced concentration and composition of fatty acid. Highest fraction of acetic (5.3g/l), butyric (0.7g/l) and propionic acid (0.84g/l) was achieved at higher OL (100g COD/l) with good degree of acidification (DOA). AS strategy showed positive influence on biofuel (biohydrogen and biohythane) production along with the biosynthesis of short chain fatty acids functioning as a low-cost pretreatment strategy in a single stage bioprocess. PMID- 28583406 TI - Transporter engineering for cellobiose fermentation under lower pH conditions by engineered Saccharomyces cerevisiae. AB - The aim of this study was to engineer cellodextrin transporter 2 (CDT-2) from Neurospora crassa for improved cellobiose fermentation under lower pH conditions by Saccharomyces cerevisiae. Through directed evolution, a mutant CDT-2 capable of facilitating cellobiose fermentation under lower pH conditions was obtained. Specifically, a library of CDT-2 mutants with GFP fusion was screened by flow cytometry and then serial subcultured to isolate a CDT-2 mutant capable of transporting cellobiose under acidic conditions. The engineered S. cerevisiae expressing the isolated mutant CDT-2 (I96N/T487A) produced ethanol with a specific cellobiose consumption rate of 0.069g/gcell/h, which was 51% and 55% higher than those of the strains harboring wild-type CDT-1 and CDT-2 in a minimal medium with 2g/L of acetic acid. PMID- 28583407 TI - Resistance training improves aortic structure in Wistar rats. AB - BACKGROUND: Little information is available on the effects of resistance training on the aortic wall. OBJECTIVE: This study aimed to quantify the effects of a resistance-training program on blood pressure and aortic wall structural components. METHODS: Rats (aged three months) were randomized into sedentary group (control group, CG; n=10) or trained group (TG; n=10). The TG rats performed resistance training by climbing a 1.1-m vertical ladder (80 degrees incline) five times a week for 12 weeks, and the CG remained sedentary. The rats were sacrificed and 5mm of the ascending aorta was submitted to histological sections, which were stained with hematoxylin-eosin, Picrosirius red, and Verhoeff's elastin, and used for morphometric studies. Left ventricle (LV) hypertrophy was determined by measuring LV wall thickness and LV internal diameter. RESULTS: The rats had similar repetition maximum before the resistance training. At the end of the resistance training period, the repetition maximum of the TG was 3.04-fold greater than the body weight. In the twelfth month, the left ventricular weight was 15.3% larger in the TG than in the CG, and the left ventricular internal diameter was reduced by 10% in the TG. Rats exposed to resistance training had a significant increase in aortic wall thickness, in both elastic lamina and collagen fibers, and in the thickness of collagen fibrils. CONCLUSION: Resistance training induces the development of concentric cardiac hypertrophy and improves the aortic wall components by producing a morphological expression pattern distinct from aortic pathological adaptation. PMID- 28583408 TI - Discrimination ability of comorbidity, frailty, and subjective health to predict mortality in community-dwelling older people: Population based prospective cohort study. AB - OBJECTIVE: To investigate the added value of comorbidity, frailty, and subjective health to mortality predictions in community-dwelling older people and whether it changes with increasing age. PARTICIPANTS: 36,751 community-dwelling subjects aged 50-100 from the longitudinal Survey of Health, Ageing, and Retirement in Europe. METHODS: Mortality risk associated with Comorbidity Index, Frailty Index, Frailty Phenotype, and subjective health was analysed using Cox regression. The extent to which health indicators modified individual mortality risk predictions was examined and the added ability to discriminate mortality risks was assessed. MAIN OUTCOME MEASURES: Three-year mortality risks, hazard ratios, change in individual mortality risks, three-year area under the receiver operating characteristic curve (AUC). RESULTS: Three-year mortality risks increased 41 folds within an age span of 50years. Hazard ratios per change in health indicator became less significant with increasing age (p-value<0.001). AUC for three-year mortality prediction based on age and sex was 76.9% (95% CI 75.5% to 78.3%). Information on health indicators modified individual three-year mortality risk predictions up to 30%, both upwards and downwards, each adding <2% discriminative power. The added discrimination ability of all health indicators gradually declined from an extra 4% at age 50-59 to <1% in the oldest old. Trends were similar for one-year mortality and not different between sexes, levels of education, and household income. CONCLUSION: Calendar age encompasses most of the discrimination ability to predict mortality. The added value of comorbidity, frailty, and subjective health to mortality predictions decreases with increasing age. PMID- 28583409 TI - Portopulmonary hypertension and hepatorenal syndrome. Two faces of the same coin. AB - Portopulmonary hypertension and hepatorenal syndrome are both severe local hypertensive complications of liver cirrhosis and portal hypertension. Both are characterized by vasoconstrictive manifestations regarding pulmonary and renal vascular network, respectively. This review addresses the mechanisms underlying the development of vasoconstriction that leads to local vascular hypertension in the lung and in the kidney with the result of organ dysfunction. Potential therapeutic options are available for the management of these two syndromes as a bridge for liver transplantation; clinical efficacy depends in part on the time and rapidity of intervention and in part on how serious the chain of events is that has triggered the entire vasoconstrictive process. PMID- 28583410 TI - Reward uncertainty and the dorsomedial striatum: A response to Anselme (2017). PMID- 28583412 TI - The embryonic development of hindbrain respiratory networks is unaffected by mutation of the planar polarity protein Scribble. AB - The central command for breathing arises mainly from two interconnected rhythmogenic hindbrain networks, the parafacial respiratory group (pFRG or epF at embryonic stages) and the preBotzinger complex (preBotC), which are comprised of a limited number of neurons located in confined regions of the ventral medulla. In rodents, both networks become active toward the end of gestation but little is known about the signaling pathways involved in their anatomical and functional establishment during embryogenesis. During embryonic development, epF and preBotC neurons migrate from their territories of origin to their final positions in ventral brainstem areas. Planar Cell Polarity (PCP) signaling, including the molecule Scrib, is known to control the developmental migration of several hindbrain neuronal groups. Accordingly, a homozygous mutation of Scrib leads to severe disruption of hindbrain anatomy and function. Here, we aimed to determine whether Scrib is also involved in the prenatal development of the hindbrain nuclei controlling breathing. We combined immunostaining, calcium imaging and electrophysiological recordings of neuronal activity in isolated in vitro preparations. In the Scrib mutant, despite severe neural tube defects, epF and preBotC neurons settled at their expected hindbrain positions. Furthermore, both networks remained capable of generating rhythmically organized, respiratory related activities and exhibited normal sensitivity to pharmacological agents known to modify respiratory circuit function. Thus Scrib is not required for the proper migration of epF and preBotC neurons during mouse embryogenesis. Our findings thus further illustrate the robustness and specificity of the developmental processes involved in the establishment of hindbrain respiratory circuits. PMID- 28583411 TI - Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175. AB - Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene x environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes. PMID- 28583413 TI - Effect of pulmonary hyperinflation on central blood volume: An MRI study. AB - Pulmonary hyperinflation attained by glossopharyngeal insufflation (GPI) challenges the circulation by compressing the heart and pulmonary vasculature. Our aim was to determine the amount of blood translocated from the central blood volume during GPI. Cardiac output and cardiac chamber volumes were assessed by magnetic resonance imaging in twelve breath-hold divers at rest and during apnea with GPI. Pulmonary blood volume was determined from pulmonary blood flow and transit times for gadolinium during first-pass perfusion after intravenous injection. During GPI, the lung volume increased by 0.8+/-0.6L (11+/-7%) above the total lung capacity. All cardiac chambers decreased in volume and despite a heart rate increase of 24+/-29 bpm (39+/-50%), pulmonary blood flow decreased by 2783+/-1820mL (43+/-20%). The pulmonary transit time remained unchanged at 7.5+/ 2.2s and pulmonary blood volume decreased by 354+/-176mL (47+/-15%). In total, central blood volume decreased by 532+/-248mL (46+/-14%). Voluntary pulmonary hyperinflation leads to ~50% decrease in pulmonary and central blood volume. PMID- 28583414 TI - Mortality, length-of-stay, bloodstream and respiratory viral infections in a pediatric intensive care unit: Comment on data sparsity. PMID- 28583415 TI - The pseudo-normalization of the ratio index of the venous-to-arterial CO2 tension difference to the arterial-central venous O2 difference in hypoxemia combined with a high oxygen consumption condition. PMID- 28583416 TI - Retrieval as a Fast Route to Memory Consolidation. AB - Retrieval-mediated learning is a powerful way to make memories last, but its neurocognitive mechanisms remain unclear. We propose that retrieval acts as a rapid consolidation event, supporting the creation of adaptive hippocampal neocortical representations via the 'online' reactivation of associative information. We describe parallels between online retrieval and offline consolidation and offer testable predictions for future research. PMID- 28583418 TI - Policies for managing emergency medical services in mass casualty incidents. AB - INTRODUCTION: Diverse decision-making is needed in managing mass casualty incidents (MCIs), by emergency medical services (EMS). The aim of the study was to review consensus among international experts concerning policies of EMS management during MCIs. METHODS: Applicability of 21 EMS policies was tested through a 2-cycle modified e-Delphi process, in which 38 multi-disciplinary experts from 10 countries participated. Threshold for approving proposed solutions was defined as consensus of >80%. Policies that did not achieve the targeted consensus were reviewed to detect variability according to respondents' origin country. RESULTS: 16 policies were endorsed in the first cycle including collaboration between ambulance service providers; implementing a unified mode of operation; preparing criteria for ground versus aerial evacuation; and, developing support systems for caregivers exposed to violence. An additional policy which proposed that senior EMS officers should not necessarily act as on site MCI commanders was endorsed in the second cycle. Demographic breakdown of views concerning non-consensual policies revealed differences according to countries of origin. Assigning ambulances to off-duty team members was highly endorsed by experts from Israel and South Africa and strongly rejected by European respondents. Avoiding entry to risk areas until declared safe was endorsed by European, Asian and Oceanic experts, but rejected by Israeli, South African and North American experts. CONCLUSIONS: Despite uniqueness of countries and EMS agencies, solutions to most dilemmas were applicable to all organizations, regardless of location or affiliation. Cultural diversity was found concerning readiness to implement military-civilian collaboration in MCIs and a rigid separation between work-leisure responsibilities. PMID- 28583417 TI - Extremity injuries sustained by the UK military in the Iraq and Afghanistan conflicts: 2003-2014. AB - INTRODUCTION: Extremity injuries predominate in warfare, however their nature, and overall burden to the individual and the health service is yet to be characterised for the UK military in the recent conflicts of Iraq and Afghanistan. METHODS: We reviewed the all extremity injuries in survivors from the Joint Theatre Trauma Registry (JTTR) between 2003 and 2014. All cases recorded in the JTTR between the invasion of Iraq on the 19th March 2003 and cessation of combat operations in Afghanistan on the 27th October 2014, were examined. Casualties who were killed in action or died from their wounds were excluded. All extremity injury codes were included, capturing patients with soft tissue injuries but no fracture or amputation. RESULTS: Of 2348 UK combatants surviving injury in Iraq and Afghanistan, 1813 (77%) had extremity injuries; of these 205 (11%) had at least one amputation at the wrist/ankle or more proximal. Trans-tibial was the most common level of limb loss. Eighty five casualties lost 2 limbs, 83 of these (98%) lost both lower limbs and 17 lost 3 limbs. Aside from amputations, there were 1530 fractures, 501 (33%) involving the upper limb and 1029 (67%) in the lower limb and pelvis. The tibia was the most frequently fractured bone. Of the lower limb fractures, 597 (58%) were open compared with 344 (69%) in the upper limb. Total Length of Stay (LOS) following extremity injury was 24,486days or 69 years and 1 month; there were a total 2817 surgical episodes performed on extremities. Median length of stay Length of Stay (LOS) for major amputations (i.e. those at the wrist/ankle or more proximal) was 51days (IQR 30-65) with a median of 7 surgical procedures on their limbs (IQR 5-9). In casualties with fractures but no amputation, median LOS was 13days (IQR 6-25) with a median of 2 surgical procedures (IQR 1-4). CONCLUSION: Utilising a dedicated injury database, this study illustrates for the first time in the United Kingdom military population, that the extremities are involved in the vast majority of combat injuries and the large surgical workload required for their treatment. PMID- 28583419 TI - Modified dynamic hip screw loaded with autologous bone graft for treating Pauwels type-3 vertical femoral neck fractures. AB - INTRODUCTION: Management of Pauwels type-3 vertical femoral neck fractures has been a challenging clinical problem as they experience high shear forces and thus a greater risk of treatment failure. There is no apparent consensus on the optimal implant type for these injuries. We developed a modified dynamic hip screw (DHS), which was designed to a cage in the lag screw, loaded with autologous bone graft for the treatment of Pauwels type-3 vertical femoral neck fractures. METHODS: Between February 2010 and January 2012, 17 consecutive patients with Pauwels type-3 vertical femoral neck fractures were treated with the modified DHS loaded with autologous bone graft. All patients were followed up for a minimum of 24 months (range, 24-36 months). Surgical details, operative and postoperative complications, the rates of nonunion and osteonecrosis and the Harris hip score were evaluated. RESULTS: There were thirteen men and four women with a mean age of 37.2 years (range, 27-52 years). There were no intraoperative complications related to this technology. All fractures healed within 14.1 weeks (range, 12 to 20 weeks). One patient required total hip replacement because of avascular necrosis of the femoral head at 27 months after surgery. According to the Harris hip score, eleven patients (64.7%) had excellent results, four (23.5%) had good results, one (5.9%) had moderate and one (5.9%) had poor result. CONCLUSIONS: The modified DHS loaded with autologous bone graft appears to be a reliable implant for the treatment of Pauwels type-3 vertical femoral neck fractures with fewer complications. PMID- 28583420 TI - The Boosting Potential of Bacteria in Cancer Immunotherapy. AB - Salmonella Typhimurium, engineered to express flagellin B, recently demonstrated unprecedented tumor control through a TLR-dependent mechanism. Here, we review new observations that support the potential of utilizing modified bacteria to enhance antitumor immunity. We also discuss the implications of these findings for clinical applications, including immune checkpoint blockade therapies. PMID- 28583421 TI - Gene expression profiles in mouse cumulus cells derived from in vitro matured oocytes with and without blastocyst formation. AB - Cumulus cells (CCs) are considered as an important source to predict oocyte quality. Despite numerous candidate genes in CCs have been identified for embryonic developmental competence, the results are inconsistent. The next generation RNA-sequencing was used to investigate the transcriptomic differences in CCs from in vitro matured oocytes did or did not develop to blastocyst stage following in vitro fertilization (IVF). In our study, the corresponding mouse oocytes were traced using a single-cell tracking system, and CCs were pooled into groups based on the embryonic developmental outcomes. In vivo matured oocytes with blastocyst development were set as a reference group. The transcriptomic differences in mouse CCs from in vitro maturated oocytes with or without blastocyst formation were tested by RNA-sequencing. Real-time PCR was used to verify the expression levels of those candidate genes. A total of 103 transcripts were significantly up-regulated, and 97 down-regulated, in the CCs with the oocytes developed to blastocyst stage. The bioinformatics study showed that those genes were involved in tube morphogenesis, cell-cell signaling and cell projection formation. Nine genes were selected from the most significantly changed transcripts after comparison with the reference group: Arrb1, Atp2c1, Cdh5, Cntnap1, Mkln1, Lgr4, Rhobtb1, Smc2 and Six2, as the candidate target genes. They were associated with the regulation of G-protein coupled receptors, Wnt and MAPK signaling, actin filaments and cell adhesion. Real-time PCR verified the up-regulation of all 9 genes, and significantly increased of Rhobtb1, Mkln1, Smc2, Arrb1, Atp2c1, Cdh5 and Lgr4. Based on RNA-sequencing, we found the changes in gene transcription of mouse CCs that were critical for the communication between CCs and oocytes. The results could provide novel insights on non invasively predicting the oocyte quality and improving developmental competence. PMID- 28583422 TI - Assessment of Fibrin Polymerization During Bivalirudin Anticoagulation for Transcatheter Aortic Valve Replacement. PMID- 28583423 TI - Postoperative Bleeding After Change in Heparin Supplier: A Cardiothoracic Center Experience. AB - OBJECTIVE: Unfractionated heparin is a mixture of glycosaminoglycans with different pharmacologic and pharmacokinetic properties. The literature suggests that blood loss after cardiac surgery is related to both elevated postoperative heparin concentrations and the potency of different heparin brands. DESIGN: An audit of the observed increase in the incidence of cardiac surgery-related bleeding after change in heparin supplier. Patient characteristics were compared between groups before and after a change in heparin brands. SETTING: Tertiary cardiothoracic center. PARTICIPANTS: All patients undergoing cardiac surgery between August 1, 2011, and April 30, 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred eighty patients underwent surgery before a change in heparin brands and 216 after a change. Their preoperative and intraoperative characteristics were similar. Postoperative chest tube drainages and blood transfusions were significantly greater after the change in heparin brands (postoperative chest drainage 476.8 +/- 393.1 v 344.8 +/- 323.2 mL/6 h and 1,062.2 +/- 738.8 v 841.8 +/- 567.4 mL/24 h, respectively; both p < 0.001) despite the administration of larger amounts of protamine, fresh frozen plasma/platelet transfusions, and cryoprecipitate. Heparin recirculation within 24 hours of bypass was noted in about 70% of the samples tested using either anti factor X activity or the thromboelastography ratio between nonheparinase R and heparinase-modified R and was not associated with the heparin brand. The likelihood ratio chi-square test for nested models identified an added predictive value of the heparin brand when included as a predictor of bleeding (chest drainage >800 mL/6 h) in a model comprising recirculation, assessed using either an elevated anti-factor X activity or ratio between nonheparinase R and heparinase-modified R. CONCLUSION: It is likely that the observed increase in postoperative bleeding was related to the pharmacologic properties of the new heparin brand rather than a higher incidence of heparin recirculation. PMID- 28583424 TI - Conservative strategy-based ensemble surrogate model for optimal groundwater remediation design at DNAPLs-contaminated sites. AB - The surrogate-based simulation-optimization techniques are frequently used for optimal groundwater remediation design. When this technique is used, surrogate errors caused by surrogate-modeling uncertainty may lead to generation of infeasible designs. In this paper, a conservative strategy that pushes the optimal design into the feasible region was used to address surrogate-modeling uncertainty. In addition, chance-constrained programming (CCP) was adopted to compare with the conservative strategy in addressing this uncertainty. Three methods, multi-gene genetic programming (MGGP), Kriging (KRG) and support vector regression (SVR), were used to construct surrogate models for a time-consuming multi-phase flow model. To improve the performance of the surrogate model, ensemble surrogates were constructed based on combinations of different stand alone surrogate models. The results show that: (1) the surrogate-modeling uncertainty was successfully addressed by the conservative strategy, which means that this method is promising for addressing surrogate-modeling uncertainty. (2) The ensemble surrogate model that combines MGGP with KRG showed the most favorable performance, which indicates that this ensemble surrogate can utilize both stand-alone surrogate models to improve the performance of the surrogate model. PMID- 28583425 TI - Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up. AB - AIMS: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data. METHODS: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (<=53mmol/mol) and weight reduction (by >=3.0%). RESULTS: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, 4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was 3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus >=86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol. CONCLUSIONS: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs. PMID- 28583426 TI - Studying Behaviors Among Neurosurgery Residents Using Web 2.0 Analytic Tools. AB - BACKGROUND: Web 2.0 technologies (e.g., blogs, social networks, and wikis) are increasingly being used by medical schools and postgraduate training programs as tools for information dissemination. These technologies offer the unique opportunity to track metrics of user engagement and interaction. Here, we employ Web 2.0 tools to assess academic behaviors among neurosurgery residents. METHODS: We performed a retrospective review of all educational lectures, part of the core Neurosurgery Residency curriculum at the University of Toronto, posted on our teaching website (www.TheBrainSchool.net). Our website was developed using publicly available Web 2.0 platforms. Lecture usage was assessed by the number of clicks, and associations were explored with lecturer academic position, timing of examinations, and lecture/subspecialty topic. RESULTS: The overall number of clicks on 77 lectures was 1079. Most of these clicks were occurring during the in training examination month (43%). Click numbers were significantly higher on lectures presented by faculty (mean = 18.6, standard deviation +/- 4.1) compared to those delivered by residents (mean = 8.4, standard deviation +/- 2.1) (p = 0.031). Lectures covering topics in functional neurosurgery received the most clicks (47%), followed by pediatric neurosurgery (22%). CONCLUSIONS: This study demonstrates the value of Web 2.0 analytic tools in examining resident study behavior. Residents tend to "cram" by downloading lectures in the same month of training examinations and display a preference for faculty-delivered lectures. PMID- 28583427 TI - Cyclooxygenase-2 inhibitors differentially attenuate pentylenetetrazol-induced seizures and increase of pro- and anti-inflammatory cytokine levels in the cerebral cortex and hippocampus of mice. AB - Seizures increase prostaglandin and cytokine levels in the brain. However, it remains to be determined whether cyclooxygenase-2 (COX-2) derived metabolites play a role in seizure-induced cytokine increase in the brain and whether anticonvulsant activity is shared by all COX-2 inhibitors. In this study we investigated whether three different COX-2 inhibitors alter pentylenetetrazol (PTZ)-induced seizures and increase of interleukin-1beta (IL-1beta), interleukin 6 (IL-6), interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex of mice. Adult male albino Swiss mice received nimesulide, celecoxib or etoricoxib (0.2, 2 or 20mg/kg in 0.1% carboxymethylcellulose (CMC) in 5% Tween 80, p.o.). Sixty minutes thereafter the animals were injected with PTZ (50mg/kg, i.p.) and the latency to myoclonic jerks and to generalized tonic-clonic seizures were recorded. Twenty minutes after PTZ injection animals were killed and cytokine levels were measured. PTZ increased cytokine levels in the cerebral cortex and hippocampus. While celecoxib and nimesulide attenuated PTZ -induced increase of proinflammatory cytokines in the cerebral cortex, etoricoxib did not. Nimesulide was the only COX-2 inhibitors that attenuated PTZ-induced seizures. This effect coincided with an increase of IL-10 levels in the cerebral cortex and hippocampus, constituting circumstantial evidence that IL-10 increase may be involved in the anticonvulsant effect of nimesulide. PMID- 28583428 TI - Multiscale simulation of monoamine oxidase catalyzed decomposition of phenylethylamine analogs. AB - Phenylethylamine (PEA) is an endogenous amphetamine and its levels are increased by physical activity. As other biogenic monoamines, it is decomposed by monoamine oxidase (MAO) enzymes. The chemical mechanism of MAO, and flavoenzymes in general, is a subject of heated debate. We have previously shown that the rate limiting step of MAO catalysis involves a hydride transfer from the substrate methylene group vicinal to the amino group to the N5 atom of the lumiflavin co factor moiety. By using multiscale simulation on the Empirical Valence Bond (EVB) level, we studied the chemical reactivity of the monoamine oxidase B catalyzed decomposition of PEA and its two derivatives: p-chloro-beta-methylphenylamine (p CMP) and p-methoxy-beta-methylphenethylamine (p-MMP). We calculated activation free energies of 17.1kcal/mol (PEA), 18.4kcal/mol (p-MMP) and 20.0kcal/mol (p CMP), which are in excellent agreement with the experimental values of 16.7kcal/mol for PEA and 18.3kcal/mol for p-MMP, while the experimental value for p-CMP is not available. This gives strong support to the validity of our hydride transfer mechanism for both MAO A and B isoforms. The results are discussed in the context of the interplay between MAO point mutations and neuropsychiatric disorders. PMID- 28583429 TI - Towards the virtual human patient. Quantitative Systems Pharmacology in Alzheimer's disease. AB - Development of successful therapeutic interventions in Central Nervous Systems (CNS) disorders is a daunting challenge with a low success rate. Probable reasons include the lack of translation from preclinical animal models, the individual variability of many pathological processes converging upon the same clinical phenotype, the pharmacodynamical interaction of various comedications and last but not least the complexity of the human brain. This paper argues for a re engineering of the pharmaceutical CNS Research & Development strategy using ideas focused on advanced computer modeling and simulation from adjacent engineering based industries. We provide examples that such a Quantitative Systems Pharmacology approach based on computer simulation of biological processes and that combines the best of preclinical research with actual clinical outcomes can enhance translation to the clinical situation. We will expand upon (1) the need to go from Big Data to Smart Data and develop predictive and quantitative algorithms that are actionable for the pharma industry, (2) using this platform as a "knowledge machine" that captures community-wide expertise in an active hypothesis-testing approach, (3) learning from failed clinical trials and (4) the need to go beyond simple linear hypotheses and embrace complex non-linear hypotheses. We will propose a strategy for applying these concepts to the substantial individual variability of AD patient subgroups and the treatment of neuropsychiatric problems in AD. Quantitative Systems Pharmacology is a new 'humanized' tool for supporting drug discovery and development in general and CNS disorders in particular. PMID- 28583430 TI - The EGFR variant III mutant as a target for immunotherapy of glioblastoma multiforme. AB - In epithelial tumors, the epidermal growth factor receptor (EGFR) controls key signaling pathways responsible for growth, proliferation, migration, and survival of tumor cells. The epidermal growth factor receptor variant III (EGFRvIII) is the most common EGFR mutation that occurs in up to 30% of high-grade gliomas especially glioblastoma multiforme (GBM). EGFRvIII arises from the deletion of exon 2-7 that leads to the formation of the constitutively activated mutant receptor incapable of binding any known ligand. EGFRvIII-expressing cells are resistant to EGFR inhibitors and therefore take advantage in survival. Furthermore, EGFRvIII expression in tumors is often correlates with poor prognosis. Indeed, EGFRvIII targeting is of great therapeutic value in order to inhibit GBM progression and invasion. The presence of the unique glycine site in EGFRvIII provides an option to develop EGFRvIII-specific monoclonal antibodies (MAbs). These antibodies are used for detection of EGFRvIII and immunotherapy. Peptide CDX-110 derived from EGFRvIII has high immunogenicity. This peptide was used for the development of anti-EGFRvIII MAbs with improved specificity to the mutant receptor, EGFRvIII-specific dendritic cell vaccine, and CDX-110-KLH peptide vaccine. These immune reagents were successfully tested in preclinical and clinical studies for GBM treatment. PMID- 28583431 TI - Sudden Hip Pain in a Young Woman. PMID- 28583432 TI - Bullying in School-aged Children in Iceland: A Cross-sectional Study. AB - PURPOSE: We describe the frequency and variations in bullying among a representative national sample of school-age children and examine whether sociodemographic characteristics are associated with bullying. DESIGN AND METHODS: This study is based on a cross-sectional school-based survey-the Icelandic contribution to the international research network Health Behaviour in School-aged Children (HBSC). The study population included all students in Iceland in grades 6, 8 and 10 (mean ages: 11, 13 and 15years, respectively) (participation rate: 84%; n=11,018). The students completed an anonymous standardized questionnaire administered in the classroom. RESULTS: The self reported frequency of being victimized by bullying at least 2-3 times every month was 5.5%. A younger age, speaking a foreign language at home, not living with one's parents, and living in a rural area, were all associated with higher frequencies of being bullied. CONCLUSIONS: Despite efforts to reduce bullying in school, experiences of being victimized through bullying are still too common among Icelandic school-age children. Stakeholders and school health administrators should consider sociodemographic antecedents when planning interventions to reduce bullying at school. PMID- 28583433 TI - Non-aqueous capillary electrophoretic separation of cholesterol and 25 hydroxycholesterol after derivatization with Girard P reagent. AB - Capillary electrophoresis (CE) can provide high separation efficiency with very simple instrumentation, but has yet to be explored regarding oxysterols/cholesterol. Cholesterol and 25-hydroxycholesterol (both are 4-ene-3 ketosteroids) were quantitatively transformed into hydrazones using Girard P reagent after enzymatic oxidation by cholesterol oxidase. Separation was achieved using non-aqueous capillary electrophoresis with UV detection at 280nm; the "charge-tagging" Girard P reagent ensured both charge and chromophore (which are requirements for CE-UV). Excess reagent was also separated from the two analytes, eliminating the need for removal prior to the analysis. The compounds were separated in less than 5min with excellent separation efficiency, using separation electrolytes fully compatible with mass spectrometry. The CE-UV method was used to optimize steps for charge-tagging, revealing that the procedure is affected by the analyte/reagent ratio and reaction time, but also the analyte structure. PMID- 28583434 TI - 27-hydroxycholesterol: A novel player in molecular carcinogenesis of breast and prostate cancer. AB - Several studies have suggested an etiological role for hypercholesterolemia in the pathogenesis of breast cancer and prostate cancer (PCa). However, the molecular mechanisms that underlie and mediate the hypercholesterolemia-fostered increased risk for breast cancer and PCa are yet to be determined. The discovery that the most abundant cholesterol oxidized metabolite in the plasma, 27 hydroxycholesterol (27-OHC), is a selective estrogen receptor modulator (SERM) and an agonist of Liver X receptors (LXR) partially fills the void in our understanding and knowledge of the mechanisms that may link hypercholesterolemia to development and progression of breast cancer and PCa. The wide spectrum and repertoire of SERM and LXR-dependent effects of 27-OHC in the context of all facets and aspects of breast cancer and prostate cancer biology are reviewed in this manuscript in a very comprehensive manner. This review highlights recent findings pertaining to the role of 27-OHC in breast cancer and PCa and delineates the signaling mechanisms involved in the governing of different facets of tumor biology, that include tumor cell proliferation, epithelial-mesenchymal transition (EMT), as well as tumor cell invasion, migration, and metastasis. We also discuss the limitations of contemporary studies and lack of our comprehension of the entire gamut of effects exerted by 27-OHC that may be relevant to the pathogenesis of breast cancer and PCa. We unveil and propose potential future directions of research that may further our understanding of the role of 27-OHC in breast cancer and PCa and help design therapeutic interventions against endocrine therapy-resistant breast cancer and PCa. PMID- 28583435 TI - The BD Barricor blood collection tube is an acceptable and robust alternative to the PST for use with the Beckman AccuTnI+3 assay. AB - OBJECTIVES: BD Canada recently released a blood collection tube with a novel mechanical separator called the Barricor. We evaluated this tube as an alternate sample type for cardiac troponin I (cTnI) testing using the Beckman Coulter AccuTnI+3 assay. DESIGN AND METHODS: 3014 paired patient specimens (Barricor, plasma separator tube or PST) were obtained from the emergency departments and cardiac care units of nine hospitals in and around Edmonton, Alberta. After centrifugation, each plasma sample was analyzed for cTnI using the Beckman Coulter AccuTnI+3 assay. In addition, selected samples were analyzed multiple times within a single run or over 4-5days to generate imprecision data for the assay. RESULTS: Repeatability and within-laboratory studies revealed an imprecision of <10% at concentrations above 0.025MUg/L for the Barricor as well as BD's traditional PST. Paired patient sample comparisons over the full range of the assay yielded linear regression slopes ranging from 0.956 to 1.011 and Pearson correlation coefficients ranging from 0.993 to 0.999. At a lower range of results closer to the manufacturer's 99th percentile cutoffs correlation was slightly worse, but still acceptable, with linear regression slopes ranging from 0.967 to 1.211 and Pearson correlation coefficients ranging from 0.983 to 0.987. Notably, at these lower concentrations the agreement between individual PST and Barricor results worsened with decreasing cTnI concentration. Differences between pairs of results became particularly large (-50 to +400%) at PST cTnI concentrations <=0.015MUg/L. Closer inspection of the data around the 0.02 and 0.04MUg/L 99th percentile cutoffs revealed a number of discordances between PST and Barricor results, with at least some of these attributable to false elevations in the PST results. CONCLUSIONS: Together, our results suggest that the Barricor blood collection tube is good alternative to the traditional PST for cTnI testing using the AccuTnI+3 assay. The Barricor appears to minimize spurious, nonreproducible, and false elevations in cTnI results for a subset of patients but additional studies are needed to determine if it reduces overall false elevations. cTnI results below 0.04MUg/L may still be of questionable accuracy even with the use of this new tube. PMID- 28583436 TI - Serum levels of fatty acid binding protein 4 and fat metabolic markers in relation to catecholamines following exercise. AB - BACKGROUND: Lipolysis is stimulated by activation of adrenergic inputs to adipose tissues. Our recent study showed that serum concentrations of fatty acid binding protein 4 (FABP4) are robustly elevated in patients with acute myocardial infarction and ventricular tachyarrhythmia, that display a marked activation of the sympathetic nervous system (SNS). However, it remains unknown whether circulating FABP4 concentrations are associated with exercise-induced SNS activation. METHODS: Thirty one healthy volunteers underwent cardiopulmonary exercise testing on a cycle ergometer up to the workload levels below and above anaerobic threshold, low- and high-intensity exercise, respectively. Serial blood samplings were performed before and after exercise. RESULTS: High-intensity exercise significantly increased serum concentrations of FABP4 and catecholamines, and their concentrations declined fast thereafter in a similar fashion. These changes were accompanied by little, if any, changes in other metabolic markers. Regardless of adiposity, percent change from baseline to peak FABP4 levels (%FABP4) was comparable in all subjects. Stepwise regression analysis revealed that %FABP4 was highly correlated with that in norepinephrine. CONCLUSIONS: Our study reveals the significant correlation between circulating FABP4 and norepinephrine levels during exercise testing. Together with the fact that FABP4 is secreted from adipocytes via beta-adrenergic-mediated lipolytic mechanisms, this study suggests FABP4 as a potential biomarker for adrenergic overdrive. PMID- 28583437 TI - Prediction of synergistic anti-cancer drug combinations based on drug target network and drug induced gene expression profiles. AB - OBJECTIVE: Synergistic drug combinations are promising therapies for cancer treatment. However, effective prediction of synergistic drug combinations is quite challenging as mechanisms of drug synergism are still unclear. Various features such as drug response, and target networks may contribute to prediction of synergistic drug combinations. In this study, we aimed to construct a computational model to predict synergistic drug combinations. METHODS: We designed drug physicochemical features and network features, including drug chemical structure similarity, target distance in protein-protein network and targeted pathway similarity. At the same time, we designed fifteen pharmacogenomics features using drug treated gene expression profiles based on the background of cancer-related biology network. Based on these eighteen features, we built a prediction model for Synergistic Drug combination using Random forest algorithm (SyDRa). RESULTS: Our model achieved a quite good performance with AUC value of 0.89 and Out-of-bag estimate error rate of 0.15 in training dataset. Using the random anti-cancer drug combinations which have transcriptional profile data in the Connectivity Map dataset as the testing dataset, we identified 28 potentially synergistic drug combinations, three out of which had been reported to be effective drug combinations by literatures. CONCLUSIONS: We studied eighteen features for drug combinations and built a computational model using random forest algorithm. The model was evaluated using an independent test dataset. Our model provides an efficient strategy to identify potentially synergistic drug combinations for cancer and may help reduce the search space for high-throughput synergistic drug combinations screening. PMID- 28583438 TI - Editorial commentary: Endothelial-to-mesenchymal transition: When the good one goes bad. PMID- 28583439 TI - Incidental coronary calcifications on routine chest CT: Clinical implications. AB - Coronary artery calcification (CAC) is a marker of atherosclerosis and an independent risk factor for cardiac-related mortality, with much of the 50% decline in mortality over the past 30 years being attributed to early detection of coronary disease and intervention of modifiable risk factors. With over 10 million computed tomography (CT) examinations of the chest performed in the United States yearly, CAC can be identified in a very large number of patients. In this review, we discuss the clinical evidence underlying the relationship between radiologic identification of CAC, atherosclerosis, and cardiac outcomes and the implications of its assessment on standard chest CT. We conclude that reporting of incidental coronary calcification found on non-gated chest CT would have a great impact on both management and mortality and thus, in the appropriate setting, should be noted in the impression of the radiologic report when identified. PMID- 28583441 TI - Herpesvirus tegument and immediate early proteins are pioneers in the battle between viral infection and nuclear domain 10-related host defense. AB - The sophisticated anti-viral functions of nuclear domain 10 (ND10) are revealed by identifying the role of each component and the countermeasures applied by viruses. Several ND10 proteins suppress herpesviruses at initial and early phases of infection. Herpesviruses need to antagonize these anti-viral proteins to start a productive infection. In this review the recently identified similarities and differences among the strategies adopted by the three subfamilies of herpesviruses are discussed, highlighting that one of the significant purposes of incorporating tegument proteins into the viral particles might be to counteract ND10 proteins immediately after the viral genome enters the host nucleus. Once the infection progresses, a sufficient amount of immediate early proteins is expressed to disperse and hydrolyze ND10 proteins, accelerating the development of infection. PMID- 28583440 TI - Proteasome Structure and Assembly. AB - The eukaryotic 26S proteasome is a large multisubunit complex that degrades the majority of proteins in the cell under normal conditions. The 26S proteasome can be divided into two subcomplexes: the 19S regulatory particle and the 20S core particle. Most substrates are first covalently modified by ubiquitin, which then directs them to the proteasome. The function of the regulatory particle is to recognize, unfold, deubiquitylate, and translocate substrates into the core particle, which contains the proteolytic sites of the proteasome. Given the abundance and subunit complexity of the proteasome, the assembly of this ~2.5MDa complex must be carefully orchestrated to ensure its correct formation. In recent years, significant progress has been made in the understanding of proteasome assembly, structure, and function. Technical advances in cryo-electron microscopy have resulted in a series of atomic cryo-electron microscopy structures of both human and yeast 26S proteasomes. These structures have illuminated new intricacies and dynamics of the proteasome. In this review, we focus on the mechanisms of proteasome assembly, particularly in light of recent structural information. PMID- 28583443 TI - Effects of metformin exposure on neurodegenerative diseases in elderly patients with type 2 diabetes mellitus. AB - Epidemiological evidence reveals that patients with type 2 diabetes mellitus (T2DM) have an increased risk of neurodegenerative diseases (NDs), including dementia and Parkinson's disease (PD). The effects of metformin exposure on dementia and PD risk in patients with T2DM are unknown. We evaluated the effects of metformin exposure on the risk of dementia and PD in patients with T2DM. We performed a cohort study by using Taiwan's National Health Insurance Research Database. We recruited 4651 patients in the metformin cohort and a comparable number of nonmetformin controls by using propensity score matching. Multivariate Cox proportional hazards regression was used to estimate the effects of metformin on the risk of dementia and PD after adjustment for several confounding factors. During the 12-year follow-up, the metformin cohort exhibited a higher risk of PD than the nonmetformin cohort (hazard ratio [HR]: 2.27, 95% confidence interval [CI]=1.68-3.07). The metformin cohort had an increased risk of all-cause dementia (HR: 1.66, 95% CI=1.35-2.04). Moreover, metformin exposure increased the risk of Alzheimer's disease (HR: 2.13, 95% CI=1.20-3.79) and vascular dementia (HR: 2.30, 95% CI=1.25-4.22). The effects of exposure duration and dosage on dementia and PD occurrence were also observed. Long-term metformin exposure in patients with T2DM may lead to the development of NDs, including dementia and PD. Additional large scale, prospective controlled trials are required to confirm the observed association in patients with T2DM. PMID- 28583442 TI - Evolution of selective-sequencing approaches for virus discovery and virome analysis. AB - Recent advances in sequencing technologies have transformed the field of virus discovery and virome analysis. Once mostly confined to the traditional Sanger sequencing based individual virus discovery, is now entirely replaced by high throughput sequencing (HTS) based virus metagenomics that can be used to characterize the nature and composition of entire viromes. To better harness the potential of HTS for the study of viromes, sample preparation methodologies use different approaches to exclude amplification of non-viral components that can overshadow low-titer viruses. These virus-sequence enrichment approaches mostly focus on the sample preparation methods, like enzymatic digestion of non-viral nucleic acids and size exclusion of non-viral constituents by column filtration, ultrafiltration or density gradient centrifugation. However, recently a new approach of virus-sequence enrichment called virome-capture sequencing, focused on the amplification or HTS library preparation stage, was developed to increase the ability of virome characterization. This new approach has the potential to further transform the field of virus discovery and virome analysis, but its technical complexity and sequence-dependence warrants further improvements. In this review we discuss the different methods, their applications and evolution, for selective sequencing based virome analysis and also propose refinements needed to harness the full potential of HTS for virome analysis. PMID- 28583444 TI - Nanomedicine for prostate cancer using nanoemulsion: A review. AB - Prostate cancer (PCa) is a worldwide issue, with burgeoning rise in prevalence, morbidity and mortality. Targeted drug delivery, a long sort solution in this regard using controlled release (CR) - nanocarriers, is still a challenge. There is an emerging criticism that, the challenges are due to less appreciation for the biological barriers and lack of corresponding newer technologies. Over the years, more understanding about the biological barriers has come with the progress in characterization techniques. Correspondingly, there is a change in opinion about approaches in clinical trial that; focus of the end point need to be shifted towards disease stabilization for these explorative technologies. Currently, there is a requirement to overcome these newly identified challenges to develop newer affordable therapeutics. The ongoing clinical protocol for therapy using CR-nanocarriers is intravenous injection followed by local targeting to cancer site. This is the most accepted protocol and new CR nanocarriers are being developed to suit this protocol. In this review, recent progress in treatment of PCa using CR-nanocarriers is analyzed with respect to newly identified biological barriers and design challenges. Possibilities of exploring nanoemulsion (NE) platform for targeted drug delivery to PCa are examined. Repurposing of drugs and combination therapy using NE platform targeted to PCa can be explored for design and development of affordable nanomedicine. In 20yrs. from now there expected to be numerous affordable nanomedicine technologies available in market exploring these lines. PMID- 28583445 TI - Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march. AB - Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased innate immune responses, antigen presenting cell stimulation, and priming of overt cutaneous disease. In a TH2 promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases. PMID- 28583449 TI - Correction. PMID- 28583450 TI - Intraprocedural Rupture of Unruptured Cerebral Aneurysms During Coil Embolization: A Single-Center Experience. AB - OBJECTIVE: Incidence of intraprocedural rupture (IPR) during endovascular coiling is reported to be 2%-5%. We reviewed a single-center experience of IPR during coil embolization of unruptured intracranial aneurysms. METHODS: Between January 2011 and April 2016, 849 patients were treated with endovascular therapy for unruptured intracranial aneurysm. IPR was documented in 10 (1.18%) of these patients. We reviewed medical records to evaluate characteristics of the aneurysms, angiographic findings related to rupture, management, and outcomes. RESULTS: Among the 10 patients, there were 4 internal carotid artery aneurysms, 3 anterior communicating artery aneurysms, 2 basilar tip aneurysms, and 1 middle cerebral artery aneurysm. The probable mechanism of IPR in 7 patients was focal coil mass distention. Two patients underwent rupture owing to injury by a microcatheter tip that was related to device-device interaction. In 1 patient who had no other clear etiology, increased intra-arterial pressure induced by contrast injection was suspected as a cause of rupture. In all cases, rapid occlusion at the point of suspected leakage was performed, and final angiography showed complete obliteration of the aneurysm. After the procedure, neurologic deterioration was demonstrated in 2 patients. The modified Rankin Scale score at 6-month follow-up was 0 in 7 of the patients. CONCLUSIONS: Incidence of IPR during endovascular coiling of unruptured aneurysms is relatively low. Early detection followed by rapid occlusion of the aneurysm can lead to a benign clinical course in most cases. PMID- 28583447 TI - Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases. AB - Epithelial barriers of the skin, gastrointestinal tract, and airway serve common critical functions, such as maintaining a physical barrier against environmental insults and allergens and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward loss of differentiation, reduced junctional integrity, and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, and circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism, and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction using both systems biology tools and causality-driven laboratory experimentation will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergic patients. PMID- 28583446 TI - Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients. AB - The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation. PMID- 28583451 TI - Assessment of Cost Drivers in Transsphenoidal Approaches for Resection of Pituitary Tumors Using the Value-Driven Outcome Database. AB - BACKGROUND: Reducing health care costs while improving quality of care has become imperative in neurosurgical care. The Value-Driven Outcome database at the University of Utah identifies cost drivers and tracks changes over time. METHODS: Retrospective review was performed for transsphenoidal resections of pituitary adenomas from July 2012 to September 2016. Total cost, subcategory costs, and potential cost drivers were evaluated. RESULTS: There were 272 patients (mean age 51.5 years +/- 17.7, 45.6% male) with mean length of stay of 4 days +/- 4 evaluated. Total costs included facility utilization (60%), physician professional fees (16%), pharmacy (11%), supplies and implants (7%), laboratory studies (5%), and imaging (1%). Facility costs were driven by neurocritical care unit (30.7%), neurosurgical operating room (16.6%), and neurosurgical floor (11.2%) costs. Multivariable linear regression, after adjusting for length of stay and American Society of Anesthesiologists grade, showed that overall cost was heavily influenced by facility utilization (rho = 0.98, P = 0.001), pharmacy (rho = 0.71, P = 0.001), supplies and implants (rho = 0.51, P = 0.0001), imaging (rho = 0.51, P = 0.0001), and laboratory (rho = 0.79, P = 0.001) costs. The top 10 outlier patients accounted for 18.7% of total costs (mean cost for all patients 0.24% +/- 0.29). CONCLUSIONS: Our results highlight the importance of facility utilization and pharmaceutical, supply/implant, imaging, and laboratory costs as overall cost drivers during transsphenoidal pituitary tumor resection. Facility utilization was a stronger cost driver than any other aspect of care. Strategies to mitigate cost include stratifying low-risk patients to an intermediate care unit and reducing length of stay. PMID- 28583452 TI - Factors Affecting the Visual Outcome of Pituitary Adenoma Patients Treated with Endoscopic Transsphenoidal Surgery. AB - OBJECTIVE: To evaluate visual acuity (VA) and visual fields (VF) quantitatively before and after endoscopic transsphenoidal surgery (ETS), with special attention to prognostic factors such as the pituitary adenoma (PA) suprasellar extension (SSE), volume and the patients' age. METHODS: Medical records of 47 patients with PA undergoing ETS were evaluated. VA, VF, preoperative visual impairment score (VISpre) and postoperative visual impairment score (VISpost) were determined. The PA SSE, volume, chiasmal contact, and their correlation with visual function were assessed preoperatively and postoperatively. RESULTS: The final cohort included 47 patients. VA improved in 54 of 76 eyes (71.0%) after ETS, and 69 of 76 eyes (90.7%) gained normal VA. Postoperative VF recovery occurred in 32 of 37 eyes (86.5%). The mean change in VIS was 12.0 (95% confidence interval [CI], 7.7-16.3) and improved in all patients with tumor-related visual impairment (n = 25). However, visual outcome was poorer when VISpre was greater than 40. When VISpre was 21-40, age linearly correlated with VIS improvement (P = 0.03); younger patients had satisfactory and older poorer visual outcome. The mean SSE in patients with VF defects (n = 20) was 16.6 mm (95% CI, 13.3-19.9). Mean SSE in patients with no VF defects (n = 23) was 6.6 mm (95% CI, 4.9-8.3; P < 0.001), and the cutoff value for visual perturbations was 9.5 mm for SSE and 8.6 mL for PA volume (P < 0.001 for both). CONCLUSIONS: The visual outcome after ETS for PAs was excellent, and serious complications were rare. Severe preoperative visual impairment resulted in poorer postoperative visual outcomes. The SSE of the PA was the most important predictor of visual outcome after ETS. PMID- 28583453 TI - Conservative and Surgical Treatment of Patients with Pineal Cysts: Prospective Case Series of 110 Patients. AB - BACKGROUND: A pineal cyst is a relatively common benign condition of the pineal gland. The clinical management of patients with a pineal cyst remains controversial, especially when patients present with nonspecific symptoms. METHODS: We performed a prospective study between 2000 and 2016. All patients with a pineal cyst >7 mm were included. Epidemiologic data, presenting symptoms, surgical results, and radiographic and clinical follow-up were documented. RESULTS: A total of 110 patients were enrolled in the present study. The most common presenting symptoms were tension headache (62.7%), vertigo (16.4%), migraine (12.7%), syncope (10.9%), nausea (8.2%), and diplopia (8.2%). Symptoms worsened during the follow-up period in 17 patients (15.5%), improved in 13 patients (11.8%), and remained stable in 81 patients (73.6%). The mean follow-up was 79.2 months. A pineal cyst increased in size during the follow-up in 6 patients (5.5%) and decreased in size in 9 patients (8.2%). Twenty-one patients underwent pineal cyst resection; 20 patients (95.2%) reported some improvement in their presenting symptoms, and 10 patients (47.6%) were symptom free after the surgery. CONCLUSION: We present the largest clinical series of patients with pineal cysts. Surgery, if indicated properly, is a legitimate treatment modality for symptomatic patients with satisfactory results. Relief of symptoms, even nonspecific ones, is achieved in the majority of cases. Simple growth of the cyst in the first decades of life is a part of the natural course and should not be considered as an indication for surgery. PMID- 28583454 TI - Functional Connectivity in Frontoparietal Network: Indicator of Preoperative Cognitive Function and Cognitive Outcome Following Surgery in Patients with Glioma. AB - BACKGROUND: Patients with diffuse glioma are known to have impaired cognitive functions preoperatively. However, the mechanism of these cognitive deficits remains unclear. Resting-state functional connectivity in the frontoparietal network (FPN) is associated with cognitive performance in healthy subjects. For this reason, it was hypothesized that functional connectivity of the FPN would be related to cognitive functioning in patients with glioma. To assess this relationship, preoperative cognitive status was correlated to patient-specific connectivity within the FPN. Further, we assessed whether connectivity could predict neuropsychologic outcome following surgery. METHODS: Sixteen patients with diffuse glioma underwent neuropsychologic assessment and preoperative functional magnetic resonance imaging using task (n-back) and resting-state scans. Thirteen patients had postoperative cognitive assessment. An index of patient-specific functional connectivity in the FPN was derived by averaging connectivity values between 2 prefrontal and 2 parietal cortex regions defined by activation during the n-back task. The relationship of these indices with cognitive performance was assessed. RESULTS: Higher average connectivity within the FPN is associated with lower composite cognitive scores. Higher connectivity of the parietal region of the tumor-affected hemisphere is associated specifically with lower fluid cognition. Lower connectivity of the parietal region of the nontumor hemisphere is associated with worse neuropsychologic outcome 1 month after surgery. CONCLUSION: Resting-state functional connectivity between key regions of the FPN is associated with cognitive performance in patients with glioma and is related to cognitive outcome following surgery. PMID- 28583455 TI - Brain Arteriovenous Malformations Located in Premotor Cortex: Surgical Outcomes and Risk Factors for Postoperative Neurologic Deficits. AB - OBJECTIVE: The premotor cortex (PMC) is known to have a dual role in movement and language processing. Nevertheless, surgical outcomes of brain arteriovenous malformations located in PMC (PMC-BAVMs) have not been well defined. The aim of this study was to determine surgical outcomes and risk factors for neurologic deficits (NDs) after surgery in patients with PMC-BAVMs. METHODS: We retrospectively reviewed patients with PMC-BAVMs who underwent surgical resection of the nidus. All patients had undergone preoperative functional magnetic resonance imaging, diffusion tensor imaging, magnetic resonance imaging, three dimensional time-of-flight magnetic resonance angiography, and digital subtraction angiography. Functional and angioarchitectural factors were analyzed with respect to postoperative NDs. Function-related fiber tracts, corticospinal tract, and dominant arcuate fasciculus were tracked. Lesion-to-fiber distance was measured. RESULTS: We identified 36 patients with PMC-BAVMs. Radical resection was achieved in all patients. Four patients (11.1%) presented with limb-kinetic apraxia and bradykinesia. Short-term NDs developed in 12 (33.3%) patients, among which 6 developed aphasias and 7 developed muscle weakness. A shorter lesion-to eloquent fiber distance (P = 0.012) and larger nidus size (P = 0.048) were significantly associated with short-term NDs. Long-term NDs occurred in 5 patients. Larger nidus size was significantly associated (P = 0.015) with long term NDs. CONCLUSIONS: Varying degrees of motor and language deficits can be induced immediately after resection of PMC-BAVMs. Permanent and long-term severe motor or language deficits are rare. Shorter lesion-to-eloquent fiber distance is a risk factor for short-term NDs. Larger nidus size is a risk factor for short term and long-term NDs. PMID- 28583456 TI - Outcomes Following Exploratory Burr Holes for Traumatic Brain Injury in a Resource Poor Setting. AB - BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. The incidence of TBI in low- and middle-income countries (LMICs) is disproportionately high, with an associated increased risk of mortality from TBI relative to high-income countries. Although computed tomography is the diagnostic method of choice, this is often unavailable in LMICs. Exploratory burr holes may provide a suitable choice for diagnosis and treatment of TBI. METHODS: We performed a retrospective review of prospectively collected data at KCH, a tertiary care center in Lilongwe, Malawi. All trauma patients presenting between June 2012 and July 2015 with a deteriorating level of consciousness and localizing signs and who underwent exploratory burr holes were included. Additionally, we included all patients admitted with TBI, requiring higher-level care during 2011. No patients underwent exploratory burr hole during this time. We performed logistic regression to identify predictors of mortality in the total population of TBI patients. RESULTS: Among the 241 patients who presented to KCH with TBI requiring higher-level care, the total mortality was 16.4%. More than half (163, or 68%) underwent exploratory burr hole with a mortality of 6.8%. Mortality in patients who did not undergo exploratory burr hole was 43.9%. Upon adjusted logistic regression, not undergoing exploratory burr hole significantly increased the odds of mortality (odds ratio = 12.0, P = 0.000, 95% confidence interval = 4.48-31.9). CONCLUSION: Exploratory burr holes remain an important diagnostic and therapeutic procedure for TBI in LMICs. Exploratory burr hole technique should be integrated into general surgery education to attenuate TBI-related mortality. PMID- 28583457 TI - Vertebrobasilar Insufficiency Due to Distal Posterior Inferior Cerebellar Artery Compression in Chiari 1.5. AB - BACKGROUND: Chiari malformation is characterized by radiographic evidence of herniation of cerebellar tonsils below the foramen magnum and a symptom complex of headaches; breathing, swallowing, or sleep difficulties; ataxia; restless; and motor and/or sensory deficits. CASE DESCRIPTION: We report a case of a 34-year old woman whose imaging indicated a Chiari 1.5 with brainstem (caudal medulla) herniation and an expansive cervical syrinx. Her symptom complex showed signs both of cervical syringomyelia, as well as ones localizable to the medulla. An intradural exploration revealed the occlusion and caudal displacement of the loop of the right posterior inferior cerebellar artery, which was later confirmed via magnetic resonance angiography. CONCLUSIONS: In the setting of severe Chiari malformations, particularly the Chiari 1.5 variant, assessment of the posterior fossa vasculature may be useful in defining a subset of patients with preoperative compromise in posterior fossa blood flow and postoperative expectations. Preoperative planning and exploration of midline dorsal brain stem along with the tonsilomedullary fissure could be helpful for contribution of vascular pathology among Chiari symptoms complex in these patients. PMID- 28583458 TI - Xanthomatous Hypophysitis Presenting with Diabetes Insipidus Completely Cured Through Transsphenoidal Surgery: Case Report and Literature Review. AB - BACKGROUND: Xanthomatous hypophysitis (XH) is extremely rare. Only 27 cases have been reported in the literature. No XH patient presenting with diabetes insipidus (DI) has been completely cured through surgery. Here, we describe the first XH case of a DI patient whose pituitary function was normalized postoperatively, without hormone replacement therapy. CASE DESCRIPTION: A 41-year-old woman suffered from polydipsia, DI, headache, and breast discharge. Laboratory investigation revealed hyperprolactinemia. Pituitary magnetic resonance imaging showed a 2.0-cm * 1.4-cm * 1.6-cm lesion that demonstrated heterogeneous intensity on T1-weighted imaging and peripheral ring enhancement following contrast; the lesion was totally removed through transsphenoidal surgery. Histopathologic and immunohistochemical examinations confirmed the diagnosis of XH. At the 4- and 15-month follow-up visits, all pituitary-related hormones were normal, and the patient was not taking medication. A repeat pituitary magnetic resonance imaging showed no evidence of recurrence. CONCLUSIONS: To the best of our knowledge, this case is the first documented occurrence of XH with DI completely cured through surgery. If XH is suspected, total surgical resection of the lesion is recommended and normal pituitary tissue should be carefully protected intraoperatively. PMID- 28583459 TI - A Retrospective Study of Clinical Outcomes After Endovascular Treatment in Acute Ischemic Stroke Patients with Complete Anterior Circulation Infarction in the Absence of Multimodal Computed Tomography. AB - OBJECTIVE: To analyze the positive predictive value of large artery occlusion and clinical prognosis in acute ischemic stroke patients with total anterior circulation infarct (TACI) who underwent endovascular treatment in the absence of multimodal CT angiography or CT perfusion. METHODS: The inclusion criteria for the acute ischemic stroke patients to receive endovascular treatment were as the follows: the Oxfordshire Community Stroke Project classification was TACI, Alberta Stroke Program Early Computed Tomography Score (ASPECTS) >= 6, National Institutes of Health stroke scale (NIHSS) score >=8, and less than 4.5 hours since stroke onset. The endovascular treatment was performed on patients who met the inclusion criteria. The endovascular treatment included intra-arterial thrombolysis, mechanical treatments, or both. A retrospective analysis was performed on all eligible acute ischemic stroke patients who underwent endovascular treatment from January 1, 2015 to December 31, 2015. RESULTS: A total of 17 patients met the inclusion criteria and underwent endovascular treatment. The median age was 76 years (range, 59-88 years). 12 patients (70.6%) were diagnosed with atrial fibrillation. 16 patients were diagnosed with large artery occlusion by digital subtraction angiography, and the positive predictive value was 94.1%. 16 patients (94.1%) had recanalization (TICI Grade 3); 12 patients (70.6%) had a modified Rankin Scale score of 0-2, and 1 patient (5.9%) died 90 days after treatment. CONCLUSIONS: In the absence of multimodal CT, endovascular treatment might be beneficial to patients with TACI acute ischemic stroke within 4.5 hours of stroke onset, who had NIHSS score of 8 or greater and ASPECTS of 6 or greater. These inclusion criteria have a high positive predictive value for anterior circulation large artery occlusion. PMID- 28583460 TI - Spinal Cord Compression Secondary to Epidural Fibrosis Associated with Percutaneously Placed Spinal Cord Stimulation Electrodes: Case Report and Review of the Literature. AB - Spinal cord stimulation is a safe method for treating chronic pain syndromes. Spinal cord stimulators can be placed either surgically by creating a laminectomy defect for paddle leads or percutaneously by inserting electrodes. They are usually not associated with major complications. There have been several reports of epidural fibrosis formation after paddle lead placement but only 1 case of excessive fibrosis following percutaneous lead placement. We describe the unique case of excessive cervical fibrosis formation with creation of tolerance phenomenon, clinically significant stenosis, cord compression, and myelopathy after percutaneous lead placement, which improved after surgical removal of the implant. We also reviewed the PubMed and Medline databases for all cases of significant epidural fibrosis related to spinal cord stimulator lead placement, including both surgically implanted paddles and percutaneously implanted leads. This is an uncommon complication after placement of spinal cord stimulators, but it can carry a clinically significant impact and be the source of severe morbidity. It should especially be suspected if the successful placement of the device is followed by development of a "tolerance" phenomenon, with progressive loss of satisfactory pain control and development of new myelopathic symptoms. PMID- 28583461 TI - Repair of V2 Vertebral Artery Injuries Sustained During Anterior Cervical Diskectomy. AB - BACKGROUND: The V2 segment of the vertebral artery (VA) typically runs through the transverse foramen of C2-C6. V2 injury may occur during anterior approaches to the cervical spine and can cause significant morbidity. We describe landmarks and microsurgical V2 repair techniques through the standard anterolateral cervical diskectomy approach. METHODS: Five silicone-injected cadaveric heads (necks-C7) were dissected bilaterally. An anterolateral approach with C3-4, C4-5, and C5-6 diskectomies and an ipsilateral VA injury were simulated. VA approach and repair were performed using microdissection techniques. Landmarks to the VA were identified, and distances from landmarks to the VA were measured in horizontal and vertical planes. Operative photographs of stepwise approach and repair techniques were processed for stereoscopic illustration. An illustrative case describes microsurgery to successfully repair an inadvertent VA injury during a C3-C6 diskectomy and fusion procedure. RESULTS: The anatomic landmarks delineated were the intervertebral disk, uncinate apices, and anterior tubercles of C4-C6 transverse processes. After temporary hemostasis with packing, VA exposure and repair included dissection of the longus colli muscle, removal of the anterior root of the transverse processes above and below the injury level, intertransversarii muscle removal, vertebral plexus opening, VA handling, and microsuturing. In 30 dissected cadaver intertransverse intervals, 13 medial, 7 lateral, and 3 anterior branches of the V2 were encountered at C3-C6 levels. CONCLUSION: Familiarity with relevant vascular surgical anatomy allows neurosurgeons to be prepared in cases of VA injury and may facilitate repair when the VA is injured during anterior cervical spine surgery. PMID- 28583463 TI - Latent Structural Analysis of Health Outcomes in People Living With Spinal Cord Injury. AB - OBJECTIVE: To develop a latent structural model of health outcomes in people with spinal cord injury (SCI) that accounts for the measurement of underlying factors and their association with demographic and injury-related exogenous variables. DESIGN: Cross-sectional study. SETTING: Specialty hospital and medical university. PARTICIPANTS: Participants with traumatic SCI (N=1871) of at least 1 year duration. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exploratory factor analysis was used to identify latent health outcome structures. Several key exogenous variables were also linked with the latent health outcome factors. RESULTS: Six latent health outcome factors were identified by the exploratory factor analysis with excellent model fit (root mean square error of approximation=.040). These latent factors included (1) global health problems; (2) chronic disease; (3) acute treatments; (4) symptoms of SCI complications, (5) pressure ulcers; and (6) subsequent injuries. Sex, race/ethnicity, age, years since injury, and injury severity were all significantly associated with at least 1 latent health outcome factor, which indicates that these latent health outcomes varied as a function of the exogenous variables. CONCLUSIONS: This study improved our understanding of the structure of health outcomes, and utilization of latent health outcome factors provides more stable and comprehensive composite scores than does utilization of a single observed health outcome indicator. PMID- 28583462 TI - Decreased Anticipatory Postural Adjustments During Gait Initiation Acutely Postconcussion. AB - OBJECTIVE: To investigate anticipatory postural adjustments (APAs) during the transitional movement task of gait initiation (GI) in individuals acutely after a concussion. DESIGN: Cohort study. SETTING: University research center. PARTICIPANTS: A population-based sample of participants (N=84) divided into 2 equal groups of acutely postconcussion and healthy student athletes. INTERVENTION: Participants were tested on 2 occasions: a preinjury baseline test and then the concussion group was retested acutely postconcussion and the healthy student athlete group again at a similar time. All participants completed 5 trials of GI on 4 forceplates. MAIN OUTCOME MEASURES: The dependent variables were the displacement and velocity of the center of pressure (COP) during the APA phase and initial step kinematics. Comparisons were made with a 2 (group) * 2 (time) repeated-measures analysis of variance. RESULTS: There was a significant interaction for COP posterior displacement (P<.001) and lateral displacement (P<.001). Posteriorly, post hoc testing identified a significant reduction in the concussion group (pretest: 5.7+/-1.6cm; posttest: 2.6+/-2.1cm; P<.001), but no difference in the healthy student athlete group (pretest: 4.0+/-1.6cm; posttest: 4.0+/-2.5cm; P=.921). Laterally, post hoc testing identified a significant reduction in the concussion group (pretest: 5.8+/-2.1cm; posttest: 3.8+/-1.8cm; P<.001), but no difference in the healthy student athlete group (pretest: 5.0+/ 2.5cm; posttest: 5.2+/-2.4cm; P=.485). CONCLUSIONS: The results of this study suggest difficulty in the planning and execution of GI acutely postconcussion, and posterior APA displacement and velocity are highly effective measures of impaired postural control. Finally, the APA phase is linked to the supplementary motor area, which suggests a supraspinal contribution to postconcussion impaired postural control. PMID- 28583464 TI - Psychometric Properties of 2 Participation Measures in Veterans With Mild Traumatic Brain Injury. AB - OBJECTIVE: To compare the psychometric properties of 2 commonly used participation measures: the Community Reintegration of Service Members (CRIS) and the Participation Assessment with Recombined Tools-Objective (PART-O) in veterans with mild traumatic brain injury (mTBI). DESIGN: Data were collected from 2 cross sectional observation studies conducted in 2 Veterans Affairs medical centers. SETTING: Questionnaires were completed in-person or by mail. PARTICIPANTS: Veterans with mTBI (N=201) were recruited from the Michael E. DeBakey Veterans Affairs Medical Center in Houston (n=94) and the Malcom Randall North Florida/South Georgia Veterans Health System (n=107). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CRIS and PART-O. RESULTS: We conducted Rasch analysis on the PART-O and on 3 subscales of the CRIS (extent of participation, perceived limitation, and satisfaction). For PART-O, results showed PART-O has questionable unidimensionality. For both instruments, some rating categories were underused, and rating scales did not advance accordingly. Compared with PART-O, the CRIS was able to distinguish more categories of person's ability (>5 vs 2 for PART-O) and had better internal consistency as indicated by higher Cronbach alpha (.96-.98 vs .65 for PART-O). CONCLUSIONS: To capture participation unique to veterans with mTBI, CRIS has greater potential to detect a change in participation and is therefore recommended over PART-O. Rating scales of both instruments, however, need further refinement. We suggest future studies examine collapsed rating categories and use qualitative methods to redefine categories. PMID- 28583465 TI - Functional Status Is Associated With 30-Day Potentially Preventable Hospital Readmissions After Inpatient Rehabilitation Among Aged Medicare Fee-for-Service Beneficiaries. AB - OBJECTIVES: To determine the association between patients' functional status at discharge from inpatient rehabilitation and 30-day potentially preventable hospital readmissions. A secondary objective was to examine the conditions resulting in these potentially preventable readmissions. DESIGN: Retrospective cohort study. SETTING: Inpatient rehabilitation facilities submitting claims to Medicare. PARTICIPANTS: National cohort (N=371,846) of inpatient rehabilitation discharges among aged Medicare fee-for-service beneficiaries in 2013 to 2014. The average age was 79.1+/-7.6 years. Most were women (59.7%) and white (84.5%). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: (1) Observed rates and adjusted odds of 30-day potentially preventable hospital readmissions after inpatient rehabilitation and (2) primary diagnoses for readmissions. RESULTS: The overall rate of any 30-day hospital readmission after inpatient rehabilitation was 12.4% (n=46,265), and the overall rate of potentially preventable readmissions was 5.0% (n=18,477). Functional independence was associated with lower observed rates and adjusted odds ratios for potentially preventable readmissions. Observed rates for the highest versus lowest quartiles within each functional domain were as follows: self-care: 3.4% (95% confidence interval [CI], 3.3-3.5) versus 6.9% (95% CI, 6.7-7.1), mobility: 3.3% (95% CI, 3.2-3.4) versus 7.2% (95% CI, 7.0-7.4), and cognition: 3.5% (95% CI, 3.4-3.6) versus 6.2% (95% CI, 6.0-6.4), respectively. Similarly, adjusted odds ratios were as follows: self care: .70 (95% CI, .67-.74), mobility: .64 (95% CI, .61-.68), and cognition: .84 (95% CI, .80-.89). Infection-related conditions (44.1%) were the most common readmission diagnoses followed by inadequate management of chronic conditions (31.2%) and inadequate management of other unplanned events (24.7%). CONCLUSIONS: Functional status at discharge from inpatient rehabilitation was associated with 30-day potentially preventable readmissions in our sample of aged Medicare beneficiaries. This information may help identify at-risk patients. Future research is needed to determine whether follow-up programs focused on improving functional independence will reduce readmission rates. PMID- 28583466 TI - Falls Are Associated With Lower Self-Reported Functional Status in Patients After Stroke. AB - OBJECTIVE: To evaluate the association between falls and functional status after stroke. DESIGN: Secondary analysis of data from the randomized controlled FIT Stroke trial. Outcomes were measured at the time of discharge from inpatient rehabilitation (t0) and after 12 weeks (t1). Between t0 and t1, all patients attended an outpatient rehabilitation program that included the FIT-Stroke intervention. SETTING: Nine centers for rehabilitation medicine. PARTICIPANTS: Outpatients after stroke (N=250) with mild cognitive impairments (Mini-Mental State Examination [MMSE] score >=24), discharged home after inpatient rehabilitation and able to walk 10m independently. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was the change in Stroke Impact Scale (SIS)-16 score. The independent variable was >=1 falls after stroke. The outcome was corrected for type of outpatient rehabilitation (group allocation), severity of hemiplegia (Motricity Index [MI]), and cognition (MMSE) at baseline using multiple regression analysis. RESULTS: Complete data were available for 199 patients, with a mean age of 58+/-10 years, MMSE score of 28.1+/-2, and MI score of 130+/-43. Fifty-five patients (28%) reported falls during the 12 weeks after discharge from inpatient rehabilitation. Falls were significantly associated with less improvement in functional status as assessed with the SIS-16 (P=.009). CONCLUSIONS: Almost 30% of this stroke population with minor cognitive deficits and moderate to high mobility scores reported falls during the 12 weeks of outpatient rehabilitation. Falls were negatively associated with self-reported functional status measured by the change in SIS-16 score. Therefore, it is important to identify patients with high risk of falls and implement strategies to reduce falls. PMID- 28583467 TI - Leucine reduces reactive oxygen species levels via an energy metabolism switch by activation of the mTOR-HIF-1alpha pathway in porcine intestinal epithelial cells. AB - Leucine serves not only as a substrate for protein synthesis, but also as a signal molecule involved in protein metabolism. However, whether the levels of cellular reactive oxygen species (ROS), which have damaging effects on cellular DNA, proteins, and lipids, are regulated by leucine is still unclear. Here, we report that leucine supplementation reduces ROS levels in intestinal epithelial cells of weaned piglets. A proteomics analysis revealed that leucine supplementation induces an energy metabolism switch from oxidative phosphorylation (OXPHOS) towards glycolysis. The leucine-induced ROS reduction and the energy metabolism switch were further validated in cultured cells. Mechanistically, our data revealed that leucine-induced ROS reduction actually depends on the energy metabolism switch from OXPHOS towards glycolysis through the mechanistic target of rapamycin (mTOR)- hypoxia-inducible factor-1alpha (HIF 1alpha) pathway. These findings reveal a vital regulatory role of leucine as the signal molecule involved in an energy metabolism switch in mammals. PMID- 28583468 TI - [Role of quality control for improvement of blood components in the Regional Blood Centre of Ouagadougou in Burkina Faso, 2014]. AB - OBJECTIVES: In Burkina Faso, blood components must comply with national standards. Then, all Transfusion services must implement a quality control process to ensure compliance. Our study aims to establish the main characteristics of blood components of the regional transfusion center of Ouagadougou, and evaluate the capability of this center to improve its manufacturing process. METHODS: We conducted from marsh to December 2014 a pre post study, assessing blood components' characteristics before and after the implementation of a six months' improvement plan. The assessed parameters were: volume, hematocrit (Ht) and hemoglobin (Hb) levels in RBCs; volume and the number of platelets in PPCs; and volume and concentration of clotting factor VIII in fresh frozen plasma (FFP), respectively. Three hundred and twelve RBCs and 280 PCs were randomly selected for the first series of controls, and 215 RBCs, 54 PCs and 60 FFP were selected for the second series of controls. We compared the mean values of the components parameters and the overall non-compliance rates for each series. RESULTS: The average Hb level of RBCs was respectively 47.8+/-8.9g and 54.7+/-7.2g in the first and second series compare to a standard of>=40g. Non compliance rates of Hb level decreased significantly from 17.6% to 1.4%. For PCs units, the mean number of platelets was 0.14+/-0.10*1011 and 0.30+/-0.15*1011 in the first and second period compare to a standard of 0.5*1011. Non-compliance rates for platelets number were high 97.1% and 72.2%. CONCLUSION: The study demonstrates that only RBCs complied with national standards. The study also demonstrates the capability of CRTSO to improve blood components' processing even if for PCs and FFP, NC rates remain high. QC must be maintained and expanded to the others regional blood centers of the country. PMID- 28583469 TI - ACCIDENTAL DUPLICATION: Bilateral medial rectus resection for primary large angle exotropia. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.003. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28583470 TI - Insights Into the Current Management of Older Adults With Type 2 Diabetes in the Ontario Primary Care Setting. AB - OBJECTIVE: The Goal Oriented controL of Diabetes in the Elderly populatioN (GOLDEN) Program assessed the management of older persons with type 2 diabetes in Canadian primary care. METHODS: Data were extracted from the records of 833 consecutively identified persons 65 years of age or older who had type 2 diabetes and were taking 1 antihyperglycemic agent or more; they were managed by 64 physicians from 36 Ontario clinics. RESULTS: More than half (53%) had glycated hemoglobin (A1C) levels of 7.0% or lower, 41% had blood pressure levels below 130/80 mm Hg, and 73% had low-density lipoprotein levels of 2.0 mmol/L or lower; 19% met all 3 criteria. Over the past year, 11% had been assessed for frailty, 16% for cognitive dysfunction and 19% for depression; 88% were referred for eye checkups, and 83% had undergone foot examinations. One-tenth were taking 4 or more antihyperglycemic agents, 87% statins and 52% an angiotensin-converting enzyme inhibitor. More than half of those with high clinical complexity had A1C levels of 7.0% or lower; of these, one-third were taking a sulfonylurea, and one fifth were taking insulin. In the patients with A1C levels of 7.0% or above and low clinical complexity, there was often no up-titration or initiation of additional antihyperglycemic agents. CONCLUSIONS: Older persons with type 2 diabetes often have multiple comorbidities. Unlike eye and foot examinations, there was less emphasis on evaluating for frailty, cognitive dysfunction and depression. The GOLDEN patients had generally well-controlled glycemic, blood pressure and cholesterol profiles, but whether these would be reflected in a "sicker" population is not known. Personalized strategies are necessary to avoid undertreatment of "healthy" older patients and overtreatment of the frail elderly. PMID- 28583471 TI - Placental Expression of Glucose Transporter Proteins in Pregnancies Complicated by Gestational and Pregestational Diabetes Mellitus. AB - Gestational diabetes mellitus and pregestational diabetes mellitus constitute carbohydrate metabolism disorders, which, if not diagnosed and adequately treated, lead to serious and often life-threatening pregnancy complications. According to a recently formulated hypothesis, some diabetes-related complications, such as fetal macrosomia, may be the result of disturbances in the transplacental transport of nutrients-in particular, excessive maternal-fetal glucose transfer. Throughout pregnancy, glucose flux across the placenta is mediated by the group of facilitative glucose transporters (GLUT), the expression of which in different placental compartments is the precondition for effective glucose uptake from maternal blood and its subsequent transfer to the fetal circulation. In diabetes-complicated pregnancies, the location, expression and activity of glucose transporters are modified to an extent that results in alterations in the maternal-fetal glucose exchange, potentially leading to an excessive supply of energy substrates to the fetus. This paper reviews the literature on the expression and activity of glucose transporter proteins-GLUT-1, GLUT-3, GLUT-4, GLUT-8, GLUT-9 and GLUT-12-in the human placenta, with a special focus on diabetes-complicated pregnancy. The characteristics of transporters in conditions of maternal normoglycemia and modifications occurring in the diabetic placenta are summarized, and the factors responsible for the regulation of the expression of selected isoforms are described. Finally, the impact of alterations in the placental expression of the aforementioned members of the GLUT family on intrauterine fetal development in pregnancies complicated by diabetes mellitus is discussed. PMID- 28583472 TI - Prenatal, Obstetric and Perinatal Factors Associated With the Development of Childhood-Onset Type 2 Diabetes. AB - OBJECTIVE: To explore associations among prenatal, obstetric and perinatal factors and the development of childhood-onset type 2 diabetes. METHODS: This retrospective, case-control study utilized administrative data housed at the Manitoba Centre for Health Policy. De-identified health records were examined from a sample of 270 children (aged 10 to 17 years at time of diagnosis) with type 2 diabetes and 1341 children without type 2 diabetes matched for age, sex and geographic location. Patients and control subjects were linked to their de identified biological mothers' health records. Prenatal, obstetric and perinatal factors were investigated. Univariate and multivariable conditional regression analyses were conducted to identify key factors associated with the development of type 2 diabetes in children. RESULTS: The mean age at diagnosis was 13.1 years, and 61% of patients were girls. The majority (71.1%) of children with type 2 diabetes resided in rural areas. Exposure to maternal pregestational diabetes increased the odds of childhood-onset type 2 diabetes nearly 6-fold, and exposure to gestational diabetes carried a 4-fold increased risk. Breastfeeding was found to be protective, decreasing the risk of childhood-onset type 2 diabetes (odds ratio = 0.52, 95% confidence interval = 0.36-0.74). Low maternal income was significantly associated with development of childhood-onset type 2 diabetes (odds ratio = 6.67, 95% confidence interval = 3.01-14.79). CONCLUSIONS: Health and social policies and programs are needed to provide financial, educational and clinical resources that target women whose pregnancies are affected by poverty, type 2 diabetes or gestational diabetes. Breastfeeding should be encouraged to aid in the prevention of childhood-onset type 2 diabetes. PMID- 28583473 TI - Predictors of local recurrence of glottic cancer in patients after transoral laser microsurgery. AB - BACKGROUND: Transoral laser microsurgery (TLM) is used to treat early and select cases of moderately advanced glottic cancer, with results equivalent to those of conventional conservative surgery and radiotherapy (RT). As surgeons and researchers become more experienced and familiar with TLM, they can focus on mechanisms to earlier detect local recurrence, to more effectively preserve laryngeal function. This study analyzed the predictors of local recurrence in glottic cancer patients who underwent TLM. METHODS: Our study focused on 93 consecutive patients with glottic cancer who received TLM between 2003 and 2009, and were analyzed retrospectively. All of these patients were treated by the same surgeon. The local control and survival rate were calculated with Kaplan-Meier method and compared using the log-rank test. Additionally, the Cox proportional hazard model was used for multivariate analysis. RESULTS: The 5-year local control, overall survival, and disease-specific survival rates were 87%, 95%, and 96%, respectively. The final laryngeal preservation rate was 98%. Independent predictors of local recurrence were arytenoid cartilage invasion (hazard ratio [HR], 6.5; 95% confidence interval [CI], 2.1-26.6), difficult laryngeal exposure (HR, 4.6; 95% CI, 1.5-17.3), previous microlaryngoscopic surgery (HR 3.1; 95% CI, 1.3-10.5), positive surgical margin (HR, 2.7; 95% CI, 1.1-9.7), and endophytic tumors (HR, 2.6; 95% CI, 1.1-7.6). CONCLUSION: TLM is a reliable modality to treat early and select cases of moderately advanced glottic cancer with good final laryngeal preservation rate. Our study found that independent factors of local recurrence included arytenoid cartilage invasion, difficult laryngeal exposure, previous microlaryngoscopic surgery, positive surgical margin and endophytic tumors. These findings may help to follow-up glottic cancer patients after TLM. PMID- 28583474 TI - The effects of maternal smoking exposure during pregnancy on postnatal outcomes: A cross sectional study. AB - BACKGROUND: The purpose of this article was to evaluate the effect of maternal smoking exposure during pregnancy on postnatal outcomes. METHODS: This prospective study enrolled 278 pregnant women in the third trimester, who were asked to complete a questionnaire which included inquires about the nature and extent of smoking exposure during their pregnancy. In addition to the questionnaire, each study subject provided urine sample for the measurement of cotinine. Using data generated from this inquiry, we analyzed the association between maternal smoking exposure and birth outcomes. RESULTS: From the 278 enrollees in this study, a minority of subjects (7.2%) smoked, while 40.6% of the study subjects were exposed to environmental tobacco smoke during pregnancy. There was significantly higher birth weight (3205.2 +/- 373.1 vs 3089.7 +/- 363.0 vs 2959.0 +/- 403.7 g, p = 0.004), larger chest size (33.1 +/- 1.7 cm vs 32.7 +/- 1.5 cm vs 32.0 +/- 1.7 cm, p = 0.009), higher bilirubin on postnatal day 3 (8.9 +/- 1.6 vs 8.6 +/- 1.5 vs 7.8 +/- 1.4 mg/dL, p = 0.015), but lower maternal urinary cotinine level (83.7 +/- 132.4 vs 153.2 +/- 96.0 vs 800.5 +/- 1027.8 MUg/g creatinine, p < 0.001) in smoking-free status than in passive or active smoking status. Significant risks of birth weight < 2500 g (AOR 3.93 (95% CI 1.61 9.59), p = 0.003) and maternal urinary cotinine >= 143 MUg/g creatinine (AOR 3.38 (95% CI 2.02-5.66), p < 0.001) were observed as smoking exposure increased. There was significantly higher birth weight (p = 0.048), larger chest size (p = 0.045), and higher bilirubin level on postnatal day 3 (p < 0.001) in the group with cotinine <143 MUg/g creatinine than in the group with cotinine >= 143 MUg/g creatinine. CONCLUSION: Our results demonstrated that maternal smoking exposure during pregnancy is associated with low birth weight and small chest circumference. Although the incidence of active smoking in Taiwanese pregnant women is low, most of them are exposed to passive smoking environment. Further studies are required to evaluate useful interventions to enhance a smoking-free environment during pregnancy. PMID- 28583475 TI - Ubiquitin C-terminal hydrolase-L3 promotes interferon antiviral activity by stabilizing type I-interferon receptor. AB - Type-I interferons (IFN-I) are important antiviral drugs which are widely used in clinical therapy of diverse viral infections. However, understanding the detailed mechanisms for IFN-I antiviral signaling remains a major challenge, and may provide novel targets for IFN-based antiviral therapy. So far, the roles of deubiquitinases (DUBs) in regulating IFN-I antiviral activity are still largely unexplored. Here, we find that Ubiquitin C-terminal hydrolase-L3 (UCHL3) plays an important role in regulating type I-interferon (IFN-I) mediated antiviral response. Interestingly, we find that UCHL3 regulates COPS5-dependent deneddylation of Cullin1, which is an essential component of SCFbeta-TrCP complex and associated with SCFbeta-TrCP activities. Furthermore, we reveal that UCHL3 physically interacts with COPS5, and determines the level and protein stability of cellular COPS5 by deubiquitinating COPS5. We further demonstrate that UCHL3 upregulates the levels of SCFbeta-TrCP substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity. These findings identify COPS5 as a novel in vivo substrate of UCHL3, and uncover the deubiquitination-deneddylation mediated regulation for IFN-I signaling and antiviral function, which may provide a novel strategy for improving IFN-based antiviral therapy. PMID- 28583476 TI - Dexterity: A MATLAB-based analysis software suite for processing and visualizing data from tasks that measure arm or forelimb function. AB - BACKGROUND: Hand function is critical for independence, and neurological injury often impairs dexterity. To measure hand function in people or forelimb function in animals, sensors are employed to quantify manipulation. These sensors make assessment easier and more quantitative and allow automation of these tasks. While automated tasks improve objectivity and throughput, they also produce large amounts of data that can be burdensome to analyze. We created software called Dexterity that simplifies data analysis of automated reaching tasks. NEW METHOD: Dexterity is MATLAB software that enables quick analysis of data from forelimb tasks. Through a graphical user interface, files are loaded and data are identified and analyzed. These data can be annotated or graphed directly. Analysis is saved, and the graph and corresponding data can be exported. For additional analysis, Dexterity provides access to custom scripts created by other users. RESULTS: To determine the utility of Dexterity, we performed a study to evaluate the effects of task difficulty on the degree of impairment after injury. Dexterity analyzed two months of data and allowed new users to annotate the experiment, visualize results, and save and export data easily. COMPARISON WITH EXISTING METHOD(S): Previous analysis of tasks was performed with custom data analysis, requiring expertise with analysis software. Dexterity made the tools required to analyze, visualize and annotate data easy to use by investigators without data science experience. CONCLUSIONS: Dexterity increases accessibility to automated tasks that measure dexterity by making analysis of large data intuitive, robust, and efficient. PMID- 28583477 TI - Measures of spike train synchrony for data with multiple time scales. AB - BACKGROUND: Measures of spike train synchrony are widely used in both experimental and computational neuroscience. Time-scale independent and parameter free measures, such as the ISI-distance, the SPIKE-distance and SPIKE synchronization, are preferable to time scale parametric measures, since by adapting to the local firing rate they take into account all the time scales of a given dataset. NEW METHOD: In data containing multiple time scales (e.g. regular spiking and bursts) one is typically less interested in the smallest time scales and a more adaptive approach is needed. Here we propose the A-ISI-distance, the A SPIKE-distance and A-SPIKE-synchronization, which generalize the original measures by considering the local relative to the global time scales. For the A SPIKE-distance we also introduce a rate-independent extension called the RIA SPIKE-distance, which focuses specifically on spike timing. RESULTS: The adaptive generalizations A-ISI-distance and A-SPIKE-distance allow to disregard spike time differences that are not relevant on a more global scale. A-SPIKE-synchronization does not any longer demand an unreasonably high accuracy for spike doublets and coinciding bursts. Finally, the RIA-SPIKE-distance proves to be independent of rate ratios between spike trains. COMPARISON WITH EXISTING METHODS: We find that compared to the original versions the A-ISI-distance and the A-SPIKE-distance yield improvements for spike trains containing different time scales without exhibiting any unwanted side effects in other examples. A-SPIKE-synchronization matches spikes more efficiently than SPIKE-synchronization. CONCLUSIONS: With these proposals we have completed the picture, since we now provide adaptive generalized measures that are sensitive to firing rate only (A-ISI-distance), to timing only (ARI-SPIKE-distance), and to both at the same time (A-SPIKE distance). PMID- 28583478 TI - Evaluation of the IceTag leg sensor and its derivative models to predict behaviour, using beef cattle on rangeland. AB - BACKGROUND: There is interest in using animal-mounted sensors to provide the detailed timeline of domesticated ruminant behaviour on rangelands. NEW METHOD: Working with beef cattle, we evaluated the pedometer-like IceTag device (IceRobotics, Edinburgh, Scotland) that records step events, leg movement and body position (upright versus lying). We used partition analysis to compare behaviour as inferred from the device data with true behaviour as coded at high resolution from carefully synchronized video observations of 5-min duration. RESULTS: Malfunctions reduced the target dataset by 7%. The correspondence between IceTag and video-coded step counts was excellent (r2=0.97), and the device's indications of upright or lying corresponded well (error rate=1.4%) to the video-coded values. However, the proportion of steps that could be matched individually was relatively low (65% at a tolerance of 0.5s), and the indicated start of a lying bout was often triggered by leg movements of an upright animal. Partition analysis of Grazing versus Not-Grazing yielded an overall error rate of 22%. In both three- and four-way classifications of behaviour (Graze, Rest, Travel; Graze, Stand, Lie, Travel) error rates were low for non-graze behaviours, but only 25% of Graze observations were correctly classified; the overall error rate was 22%. COMPARISON WITH EXISTING METHOD(S): The IceTag device performed well in mapping the diurnal patterns of animal position and step rate, but less well in separating grazing from upright resting. CONCLUSIONS: Our results suggest that pedometry is not the ideal method for classifying behaviour when grazing is of paramount interest. PMID- 28583479 TI - Smoking Cessation as a Possible Risk Factor for the Development of Aspirin Exacerbated Respiratory Disease in Smokers. AB - BACKGROUND: The pathogenesis of aspirin-exacerbated respiratory disease (AERD) is characterized by the low expression of cyclooxygenase-2 (COX-2) in airway epithelia, which decreases the production of prostaglandin E2 (PGE2). Conversely, cigarette smoke stimulates COX-2 expression in airway epithelia. Therefore, it was hypothesized that the development of AERD would be suppressed by elevated PGE2 levels in smokers, and smoking cessation might increase susceptibility to AERD. OBJECTIVE: The objective of this study was to evaluate the relationship between smoking and the risk of AERD development. METHODS: The smoking status of patients with AERD (n = 114) was compared with 2 control groups with aspirin tolerant asthma (ATA), patients diagnosed by a systemic aspirin provocation test (ATA-1, n = 83) and outpatients randomly selected from a large-scale dataset (ATA 2, n = 914), as well as a healthy control group (HC, n = 2313). RESULTS: At the age of asthma onset, there was a low frequency of current smokers (9.7%), but a high frequency of past smokers (20.2%) in the AERD group compared with the ATA-1 (20.5% and 12.0% for current and past smokers, respectively), ATA-2 (24.5% and 10.3%, respectively), and HC group (26.2% and 12.6%, respectively). After adjustment for confounding variables, AERD was positively associated with smoking cessation between 1 and 4 years before disease onset compared with the ATA-2 group (adjusted odds ratio [aOR] 4.63, 95% confidence interval [CI]: 2.16-9.93) and the HC group (aOR 4.09, 95% CI: 2.07-8.05), implying that smoking cessation was followed by the development of AERD. CONCLUSION: Smoking cessation may be a risk factor for the development of AERD. PMID- 28583480 TI - Dietary isoflavone supplementation for food allergy: A pilot study. PMID- 28583481 TI - Long-term outcomes following baked milk-containing diet for IgE-mediated milk allergy. PMID- 28583482 TI - Problems Experienced by Ovarian Cancer Survivors During Treatment. AB - OBJECTIVE: To identify problems at different treatment points (early treatment, mid-treatment, early posttreatment, and late posttreatment) among women with ovarian cancer. DESIGN: Longitudinal and cross-sectional study design. SETTING: An academic and community clinical cancer center in the Southeastern United States. PARTICIPANTS: Sixty-eight women with Stage I to IV ovarian cancer. METHODS: Variables assessed included reported problems (physical, psychosocial, pain, marital, medical interaction), social support, optimism, and responses to open-ended questions. Analysis involved mixed models for longitudinal repeated measures and unpaired t tests and content analysis to describe responses to open ended questions. RESULTS: Physical and psychosocial problems were greatest during early treatment and decreased throughout the treatment trajectory. Women with greater levels of social support and optimism at baseline had fewer problems over time. Women who did not have trouble paying for basics had fewer problems related to pain and psychological problems. CONCLUSION: Problems across all domains must be addressed throughout the treatment trajectory, even after chemotherapy has ended. Nurses are well positioned to refer women appropriately to social workers and clinical navigators across all domains of care and should consider systematic assessment of patient-reported problems as a routine form of practice. PMID- 28583483 TI - Toolkit for automated and rapid discovery of structural variants. AB - Structural variations (SV) are broadly defined as genomic alterations that affect >50bp of DNA, which are shown to have significant effect on evolution and disease. The advent of high throughput sequencing (HTS) technologies and the ability to perform whole genome sequencing (WGS), makes it feasible to study these variants in depth. However, discovery of all forms of SV using WGS has proven to be challenging as the short reads produced by the predominant HTS platforms (<200bp for current technologies) and the fact that most genomes include large amounts of repeats make it very difficult to unambiguously map and accurately characterize such variants. Furthermore, existing tools for SV discovery are primarily developed for only a few of the SV types, which may have conflicting sequence signatures (i.e. read pairs, read depth, split reads) with other, untargeted SV classes. Here we are introduce a new framework, Tardis, which combines multiple read signatures into a single package to characterize most SV types simultaneously, while preventing such conflicts. Tardis also has a modular structure that makes it easy to extend for the discovery of additional forms of SV. PMID- 28583484 TI - Quality and readability of websites for patient information on tonsillectomy and sleep apnea. AB - OBJECTIVES: Tonsillectomy is a common treatment for obstructive sleep apnea (OSA). The Internet allows patients direct access to medical information. Since information on the Internet is largely unregulated, quality and readability are variable. This study evaluates the quality and readability of the most likely visited websites presenting information on sleep apnea and tonsillectomy. METHODS: The three most popular search engines (Google, Bing, Yahoo) were queried with the phrase "sleep apnea AND tonsillectomy." The DISCERN instrument was used to assess quality of information. Readability was evaluated using the Flesch Kincaid Reading Grade Level (FKGL) and Flesch Reading Ease Score (FRES). RESULTS: Out of the maximum of 80, the average DISCERN quality score for the websites was 55.1 (SD- 12.3, Median- 60.5). The mean score for FRES was 42.3 (SD- 15.9, Median 45.5), which falls in the range defined as difficult. No website was above the optimal score of 65. The mean score for the FKGL was US grade-level of 10.7 (SD- 1.6, Median- 11.6). Only 4(27%) websites were in the optimal range of 6-8. There was very weak correlation between FRES and DISCERN (r = 0.07) and FKGL and DISCERN (r = 0.21). CONCLUSIONS: Tonsillectomy is one of the most common surgeries in the US. However, the internet information readily available to patients varies in quality. Additionally, much of the information is above the recommended grade level for comprehension by the public. By being aware of what information patients are reading online, physicians can better explain treatments and address misunderstandings. Physicians may consider using similar methods to test the readability for their own resources for patient education. PMID- 28583485 TI - Demographics and clinical features predictive of allergic versus non-allergic rhinitis in children aged 6-18 years: A single-center experience of 1535 patients. AB - BACKGROUND: Chronic rhinitis (CR) is one of the most common causes accounting for lost-school days, absenteeism and resource utilization in pediatric patients. Distinction between common causes of CR, allergic (AR)and non-allergic rhinitis (NAR), based upon clinical features is critical, especially in primary care settings or facilities with lack of allergen sensitivity testing, as management strategies differ considerably. The current study elucidates clinical factors, particularly facial features associated with AR and NAR using a large cohort. METHODS: In a retrospective cohort analysis of pediatric patients aged 6-18 years, we assessed patient demographics, clinical symptoms, and signs associated with allergic rhinitis using multivariable regression techniques. RESULTS: Overall, 1490 patients (mean age: 10.11 +/- 3.31 years; 48% female; 69% AR and 31% NAR) were included in the study. In multivariable regression analysis, major clinical features associated with AR were: sneezing (OR: 3.53; 95% CI: 2.35-5.32; p < 0.001), rhinorrhea (OR: 1.77; 95% CI: 1.18-2.66; p = 0.006), nasal itching (OR: 17.88; 95% CI: 11.92-26.83; p < 0.001), horizontal nasal crease (OR: 5.09; 95% CI: 1.29-20.01; p = 0.020) and conjunctivitis (OR: 4.66; 95% CI: 3.28-6.62; p < 0.001). On the contrary, we noted presence of Dennie-Morgan fold (OR: 1.67; 95% CI: 1.11-2.56; p = 0.014), moderate to severe persistent or intermittent symptoms to be likely associated with NAR than AR. CONCLUSION: In pediatric patients presenting with symptoms of rhinitis, facial hallmarks serve as an adjunct to sensitivity testing in establishing a diagnosis as well as differentiating between NAR from AR, albeit individualized upon patient history and clinical features. PMID- 28583486 TI - Ototoxicity associated with topical administration of diclofenac sodium as an otic drop: An experimental animal study. AB - OBJECTIVES: The aim of the study is to evaluate the ototoxicity of topical diclofenac sodium in comparison to positive and negative controls prior to the investigation of analgesic and anti-inflammatory efficacy of the agent in otic administration. METHODS: Twenty four ears of 12 guinea pigs were included in the study. Wide myringotomy was performed on all tympanic membranes under general anesthesia and auditory brainstem responses (ABR) were evaluated. The subjects were separated into four groups, two groups received diclofenac sodium at low and high doses, positive controls received gentamicin and negative controls received isotonic sodium chloride topically for 14 days and ABRs were reevaluated. RESULTS: No significant difference were observed between the pre and post treatment click response, 1 kHz and 8 kHz response threshold levels after isotonic sodium chloride administration. All threshold levels were elevated in the positive control group. In the low and high dose diclofenac sodium groups, click response, 1 kHz and 8 kHz response threshold levels were significantly higher compared to the baseline values. Pre and post-treatment mean threshold level changes were not significantly different between the low and high dose diclofenac sodium groups. Pre and post-treatment mean threshold level changes in the gentamicin group were not significantly different from low or high dose diclofenac sodium groups. CONCLUSION: Diclofenac sodium, considered as an analgesic and anti-inflammatory otic preparation, is shown to be as ototoxic as gentamicin in chronic use which may lead to loss of hearing especially when used topically in chronic otitis cases with tympanic membrane damage. PMID- 28583487 TI - Considerations for the successful decannulation of the pediatric patient: A single surgeon's experience. AB - OBJECTIVE: To characterize the steps and interventions necessary for successful decannulation of the chronic pediatric tracheostomy patient. METHODS: This retrospective review analyzed one surgeon's (DJK) pediatric tracheostomy decannulation methods and results at a tertiary academic medical center over a thirteen-year period, from October 2002 through November 2015. It also examined which tests and procedures were conducted on patients prior to their successful decannulation. RESULTS: Over the period of study, 46 patients met inclusion criteria for analysis and underwent decannulation after being followed in the clinic or the hospital. One of these patients had to have the tracheostomy tube replaced. In nearly all cases, these patients underwent a systematic progression from tolerance of daytime tracheostomy capping to a capped sleep study, and endoscopic airway evaluation. In recent years, a subset of patients also underwent sleep endoscopy. In nearly all cases, patients spent a single night in the hospital in a non-acute bed at the time of decannulation. Ninety-eight percent (n = 45) of patients were successfully and safely decannulated after having met the milestones that we employ at our institution. CONCLUSIONS: This study serves as a safe, efficient, and resource-prudent protocol for otolaryngologists to follow when considering tracheostomy decannulation in the pediatric population. Sleep endoscopy can play a helpful role in guiding decannulation decisions. Since it is impossible to employ a single rigid protocol of testing prior to decannulating all patients, clinical judgment must always be exercised in individual circumstances. PMID- 28583488 TI - Non-invasive methods to maintain cervical spine position after pediatric tracheal resections. AB - OBJECTIVES: To present our experience with two methods of neck stabilization after pediatric tracheal resection with primary anastomosis as possible alternatives to the traditional chest-chin suture. METHODS: Children undergoing tracheal resection and/or cricotracheal resection with anastomosis under tension were placed in cervical spine flexion postoperatively with either a chest-chin (Grillo) suture, an Aspen cervical collar or Trulife Johnson cervical-thoracic orthosis (CTO). A retrospective chart review of tracheal resections performed between 2005 and 2016 was completed to evaluate the positive and negative factors associated with each neck flexion technique. RESULTS: Of the 20 patients, there were 13 patients with the Grillo suture, 4 with the Aspen collar and 3 patients with the Johnson CTO. There were 13 tracheal resection procedures and 7 cricotracheal resections, all of which had anastomosis under tension. One major anastomosis dehiscence was noted with the Grillo suture technique which required reoperation. Two patients with the Grillo suture experienced skin breakdown at the suture site. The Aspen cervical collar, which fixed the cervical spine and prevented lateral and rotational motion, was limited in several cases in that it placed the spine in slight hyperextension. The Johnson CTO provided the most support in a flexed position and prevented cervical spine motion in all directions. No anastomosis complications were noted with the Aspen collar or the Johnson CTO, however, several patients sustained minor cutaneous wounds. CONCLUSION: In this series the Aspen cervical collar and Johnson CTO were used successfully as non-Grillo alternatives to postoperative neck stabilization in pediatric tracheal resections. Modifications to both devices are proposed to minimize cutaneous injuries and increase immobilization of the cervical spine in the desired flexed position. Although these devices appear to be safe and may be better tolerated, further innovation is needed to improve the design and fit of these devices. PMID- 28583489 TI - The acceptability and tolerability of nasal douching in children with allergic rhinitis: A systematic review. AB - BACKGROUND: Allergic rhinitis (AR) is a significant issue in children. Treatment options include allergen avoidance, pharmacotherapy and immunotherapy. The use of nasal saline douching (NSD) in children has recently gained acceptability. However, there is limited data regarding the acceptability and tolerability of NSD in children with AR. METHODS: A search was conducted using Medline and Embase databases from January 1946 until June 2015 on the use of NSD in children aged 4 12 years with AR. All publications identified that assessed the beneficial effects, acceptability and tolerability were included. RESULTS: 40 studies were analyzed. Data varied considerably in terms of saline solutions used, modality of application, participant numbers, study design, follow up and outcomes. Factors that appear to influence the acceptability and tolerability of NSD include parental and health professionals' preconceptions, and characteristics of the solution. CONCLUSIONS: Nasal saline douching appears to be effective, being accepted and tolerated in the majority of children (78-100%). NSD has a significant positive impact on the quality of life in children with allergic rhinitis. When used as an adjunctive treatment having mainly a cleansing property, NSD potentiates the effects and may reduce the dose required of AR medications. Among the principal factors that influence the acceptability and tolerability of NSD are the child's age, delivery system and method, and tonicity. Nasal saline douching provides an accessible, low cost, low morbidity, easy to use treatment in children with allergic rhinitis. PMID- 28583490 TI - Polysomnography results versus clinical factors to predict post-operative respiratory complications following pediatric adenotonsillectomy. AB - OBJECTIVE: Systematically review the published literature comparing the presence of clinical features (age, BMI, co-morbidities, etc.) versus polysomnogram (PSG) results in the prediction of major post-operative respiratory complications following pediatric adenotonsillectomy (T/A) for the treatment of Obstructive Sleep Apnea Syndrome (OSAS). METHODS: A systematic review of the PUBMED and EMBASE databases was performed to identify studies containing both clinical and PSG data predicting major post-operative respiratory complications following T/A. Inclusion criteria included English language and extractable data. Major respiratory complications were defined as events that required significant intervention (intubation, CPAP,etc.) and/or altered patient disposition. Random effect modeling was performed and study quality was assessed using the Newcastle Ottawa Scale. RESULTS: Twenty-two studies met the inclusion criteria with a median sample size of 157 (range 26-1735) and published between 1992 and 2015. The most common study design was a case series. Most studies included multiple patients at high risk for respiratory complications (Syndromic, obese, etc.). The summary estimate of the major respiratory complication rate following T/A was only 5.8% (95% CI = 4.2-7.4%, p < 0.001, I2 = 99%). For studies with extractable data, 102 of 112 patients (91.1%) with a post-operative respiratory complication had a clearly identifiable clinical risk factor, the remainder (8.9%) had only moderate or severe OSAS on PSG and no other predictor. CONCLUSION: The major respiratory complication rate following pediatric T/A for OSAS is low even amongst series of high risk patients. The majority of the published literature report that readily identified clinical factors predict the large majority of post-operative respiratory complications following T/A. PMID- 28583491 TI - Adaptation, validity, and reliability of the Preschool Language Scale-Fifth Edition (PLS-5) in the Turkish context: The Turkish Preschool Language Scale-5 (TPLS-5). AB - INTRODUCTION: Speech and language assessment is very important in early diagnosis of children with hearing and speech disorders. Aim of this study is to determine the validity and reliability of Preschool Language Scale (5th edition) test with its Turkish translation and adaptation. METHODS AND MATERIALS: Our study is conducted on 1320 children aged between 0-7 years 11 months. While 1044 of these children have normal hearing, language and speech development, 276 of them have receptive and/or expressive language disorder. After the English-Turkish and Turkish-English translations of PLS-5 made by two experts command of both languages, some of the test items are reorganized because of the grammatical features of Turkish and the cultural structure of the country. The pilot study was conducted with 378 children. The test which is reorganized in the light of data obtained in pilot application, is applied to children chosen randomly with layering technique from different regions of Turkey, then 15 days later the first test applied again to 120 children. RESULTS: While 1044 of 1320 children aged between 0 and 7 years 11 months are normal, 276 of them have receptive and/or expressive language disorder. While 98 of 103 healthy children of 120 taken under the second evaluation have normal language development, 8 of 9 who used to have language development disorder in the past still remaining (Kappa coefficient:0,468, p<0,001). Pearson correaltion coefficient for TPLS-5 standard gauge are; IA raw score:0,937, IED raw score: 0,908 and TDP: 0,887 respectively. Correlation coefficient for age equivalance is found as IA:0,871, IED: 0,896, TDP: 0,887. CONCLUSIONS: TPLS-5 is the first and only language test in our country that can evaluate receptive and/or expressive language skills of children aged between 0-7 years 11 months. Results of the study show that TPLS-5 is a valid and reliable language test for the Turkish children. PMID- 28583492 TI - Silent sinus syndrome and maxillary sinus atelectasis in children. AB - OBJECTIVE: Silent sinus syndrome (SSS) and chronic maxillary atelectasis (CMA) are unusual conditions having subtle symptoms with a possible progressive evolution. They are particularly infrequent in the pediatric population. Our objective was to review our experience with pediatric patients having SSS or CMA, and to review all cases involving patients under 14 years of age reported in the literature. METHODS: A retrospective review of 6 patients diagnosed with SSS or CMA surgically treated from 2001 to 2014 was carried out. All cases reported in literature were reviewed. RESULTS: All patients underwent functional endoscopic sinus surgery with an improvement in symptoms after surgery. Diplopia disappeared in two patients who presented with it and enophthalmos improved in all five patients presenting with it. Only one patient out of four presenting with headache had a persistence of the symptoms which were, however, milder than they had been preoperatively. Endoscopic examination demonstrated a reventilated maxillary sinus in all cases. A radiological examination at follow-up was performed in 5 cases and demonstrated a reexpansion of the maxillary sinus as compared to the contralateral side in all patients except one. None of the patients required an orbital floor reconstruction. Eleven similar cases reported in the literature were analyzed and compared. CONCLUSION: Endoscopic uncinectomy and middle meatal antrostomy should be the treatment of choice for these conditions in patients presenting with enophthalmos and/or hypoglobus and symptoms related to it. Orbital floor reconstruction should be performed as a delayed procedure only in selected cases. Chronic maxillary atelectasis or SSS should be considered as a possible cause of persistent headache of unknown origin in pediatric patients. PMID- 28583493 TI - Endoscopic esophageal and tracheal cauterization for closure of recurrent tracheoesophageal fistula: A case report and review of the literature. AB - OBJECTIVE: Recurrent tracheoesophageal fistula (TEF) can be a diagnostic and therapeutic challenge. Traditional treatment is thoracotomy, which carries significant morbidity and technical difficulty especially in a previously operated field. Recently, endoscopic techniques have been advocated as a primary approach for treatment of recurrent TEF prior to open repair. This case report describes the endoscopic technique used to address a recurrent TEF. The existing literature of all reported endoscopic cauterization methods is reviewed. METHODS: An 8 month old with proximal esophageal atresia and distal TEF underwent endoscopic closure of a recurrent TEF. The fistula was approached endotracheally utilizing Bugbee electrocautery (EC) and endoluminally through the esophagus using argon plasma coagulator and placement of porcine submucosa graft into the tract. Current literature review is presented with a synthesis of data on cases utilizing endoscopically applied EC and the combined results of this closure technique. RESULTS: Our patient has maintained successful closure after a single treatment confirmed on follow up endoscopy 6 months post repair. Including this patient, there have been 30 patients with recurrent TEF treated utilizing endoscopic EC reported in the literature. The overall success rate is 78.8% with a mean of 1.88 procedures per successful closure. Comparing EC alone to EC combined with tissue glues or laser, success rates are 67% and 86% respectively. CONCLUSION: Endoscopic repair of recurrent TEF has proven to be safe and effective in the literature as an alternative to a second thoracotomy/open surgical repair. EC combined with tissue glues or laser is more effective than EC alone based on available data. PMID- 28583494 TI - Spontaneous CSF rhinorrhea from the trigeminal canal in an adolescent. AB - We report a case of a seventeen-year old, healthy, non-obese young woman who presented with retro-orbital headaches and metallictasting, left-sided rhinorrhea. Computed tomography revealed a defect along the medial wall of the canal of V2 within a well-pneumatized lateral recess of the left sphenoid sinus. Prior imaging obtained 4 years earlier in the context of nasal trauma showed no such defect - thus lending support for the arachnoid granulation hypothesis of spontaneous CSF leaks from the sphenoid sinus. We perform a literature review and describe a successful repair through an endoscopic transpterygoid approach, which allowed for resolution of symptoms with minimal postoperative morbidity. PMID- 28583495 TI - Prevalence of hearing-loss among HAART-treated children in the Horn of Africa. AB - OBJECTIVES: The prevalence of hearing loss (HL) in children infected with HIV/AIDS is not well studied. Even fewer studies focus on stable HIV-infected children treated with high-effective antiretroviral therapy (HAART). We aim to compare the prevalence of ear disease and HL in HAART-treated, HIV + children in Addis Ababa, Ethiopia with a well, similarly-aged elementary school population with unknown HIV status (HIVU). METHODS: Children underwent standard head and neck examination and cerumen removal by board certified otolaryngologists. Next, certified audiologists performed hearing screening with pure-tone audiometry using a circumaural headset but without an ambient noise reducing environment. Children failing audiometric screening underwent full behavioral audiometry including air and bone testing. The primary outcome parameter was HL > 25 dB with the audiologist accounting for background noise. A second endpoint was PTA >40 dB (500, 1000, 2000 Hz) without assessment of background noise. RESULTS: 107 HIV+ and 147 HIVU children met inclusion criteria. In the HIV + cohort 17.8% had evidence of TM perforations and 8.4% had otorrhea. In the HIVU group 2.7% had a TM perforation and 0% had otorrhea. Hearing was significantly worse in HIV + children. (Audiologist determination: 38.3% HL HIV+, 12.2% HIVU, Fisher's-Exact Test OR: 4.5, 95% CI 2.4-8.3, p-value <0.0001; Worse-hearing-ear PTA > 40 dB: 19.6% HL HIV+, 6.1% HIVU, OR: 3.7, 95% CI 1.7-8.4, p-value <0.001). CONCLUSIONS: Chronic OM, conductive and mixed hearing losses are significantly more common in HAART-treated HIV + children than in well, similarly-aged controls. Rates of SNHL are similar. PMID- 28583496 TI - The effect of perioperative dexamethasone dosing on post-tonsillectomy hemorrhage risk. AB - OBJECTIVES: Dexamethasone is currently recommended for routine prophylaxis against postoperative nausea and vomiting after tonsillectomy procedures. However, some studies have raised concern that dexamethasone use may lead to higher rates of post-tonsillectomy hemorrhage. Our objective was to determine whether higher doses of dexamethasone administered perioperatively during tonsillectomy procedures are associated with an increased risk of secondary post tonsillectomy hemorrhage. METHODS: We conducted a retrospective review of 9843 patients who underwent tonsillectomy and received dexamethasone at our institution from January 2010 to October 2014. We compared the dose of dexamethasone administered to patients who did and did not develop secondary post tonsillectomy hemorrhage using Mann Whitney U tests. Multivariable logistic regression models were used to evaluate the association between dexamethasone dose and post-tonsillectomy hemorrhage after adjustment for demographic and clinical characteristics. RESULTS: A total of 280 (2.8%) patients developed secondary post-tonsillectomy hemorrhage. Patients who developed hemorrhage tended to be older (median (interquartile range) 7 (4-11) vs. 5 (3-8) years), p < 0.001) and had undergone tonsillectomy more often for chronic tonsillitis but less often for tonsillar or adenotonsillar hypertrophy or sleep disturbances. Dexamethasone dose was significantly lower on average in patients who experienced secondary post-tonsillectomy hemorrhage (median (interquartile range) 0.19 (0.14, 0.23) mg/kg vs. 0.21 (0.17, 0.30), p < 0.001). Multivariable modeling demonstrated that the dose of dexamethasone was not significantly associated with post tonsillectomy hemorrhage after adjustment for age. CONCLUSIONS: There does not appear to be a dose-related increase in the risk of post-tonsillectomy hemorrhage for patients receiving dexamethasone during tonsillectomy procedures. PMID- 28583497 TI - Safety of endoscopic sinus surgery in children with cystic fibrosis. AB - INTRODUCTION: Data on the safety of endoscopic sinus surgery (ESS) are limited in children with cystic fibrosis (CF). We used a multi-institutional surgical registry to examine ESS outcomes in children with CF. METHODS: The 2014-2015 American College of Surgeons' National Surgical Quality Improvement Program Pediatric database was queried for patients age <18 years undergoing elective ESS. Prolonged hospital stay (>1 day), 30-day readmission, and 30-day unplanned reoperation were compared according to presence of CF diagnosis. RESULTS: The data included 213 children with CF (age 10 +/- 5 years, 105/108 male/female) and 821 children without CF (age 10 +/- 5 years, 504/317 male/female). CF patients were more likely than non-CF patients to require prolonged hospital stay (30% vs. 9%, p < 0.001), yet had similar rates of readmission (6% vs. 4%; p = 0.189) and reoperation (0 vs. 1%; p = 0.133). All readmissions but one among CF patients were unrelated to ESS. In the non-CF cohort, reasons for ESS-related readmissions included recurrence of sinusitis, postoperative pain, and bleeding. CONCLUSIONS: We demonstrate the safety of ESS in the largest cohort of children with CF reviewed to date. Multi-institutional review of ESS safety may contribute to monitoring expansion of this intervention in children with CF. PMID- 28583498 TI - Foreign body aspiration in children: A study of children who lived or died following aspiration. AB - Foreign body aspiration (FBA) is a preventable cause of mortality and morbidity in children. We conducted a chart review of children who presented to a university hospital due to FBA in the period 1999-2014. Children were either managed with bronchoscopy for removal of the foreign body or died due to FBA. A total of 103 children were seen due to FBA including 27 deaths. The majority of children were boys and were less than 3 years old. Most aspirated foreign bodies were food-related, mainly peanuts. The majority of children presented with acute choking incidents, a smaller number presented with recurrent chest infections, and few children's choking incidents were unwitnessed. X-ray had a high rate of false negatives and bronchoscopy was the gold standard technique for assessment and management. Aspiration of foreign bodies is a preventable, life-threatening condition that calls for increased parent education and awareness. PMID- 28583499 TI - The effect of blocking Notch signaling by gamma-secretase inhibitor on allergic rhinitis. AB - OBJECTIVE: This study aimed to investigate the effect of blocking Notch signaling by gamma-secretase inhibitor (GSI) on allergic rhinitis. METHOD: GSI, N-[N-(3,5 difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butylester (DAPT) was administered to ovalbumin-induced AR mice models intranasally. We observed symptoms of sneezing and nose rubbing. To detect the inflammatory state, the serum OVA-specific-IgE, IFN-gamma, IL-4, and IL-5 were analyzed by ELISA, and Th cell cytokines in nasal mucosa were analyzed by RT-PCR, including T-bet, IFN gamma, GATA-3, IL-4, and IL-5. In addition, hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) were applied for histopathological examination. As for the evaluation of Notch signaling, we analyzed the Notch-1, Notch signaling target Hes-1, and Hes-5 in mucosa by RT-PCR, besides, used western blotting and immunohistochemistry to assess NICD (Notch intracellular domain). RESULTS: The results showed that the DAPT ameliorated the development of AR and suppressed Th2 cytokine levels significantly, alleviating eosinophils infiltration and goblet cells metaplasia, suggesting that the GSI can regulate Th2 response and weaken airway inflammation in AR. CONCLUSION: Our findings provide evidence that blocking Notch signaling by GSI offers high value in treating AR. PMID- 28583500 TI - Mutation analysis of common GJB2, SCL26A4 and 12S rRNA genes among 380 deafness patients in northern China. AB - OBJECTIVES: The molecular etiology of nonsyndromic deafness in Chinese population has not been investigated systematically, our study is aim to investigate the molecular etiology of nonsyndromic deafness patients from Northern China (Heilongjiang province), in order to provide genetic test and counseling to families. METHODS: 380 unrelated patients with hearing loss who attended to the Department of Otolaryngology, The Fourth Affiliated Hospital of Harbin Medical University were enrolled to our study. All patients were diagnosed with nonsyndromic deafness by audiologic evaluation, 202 normal-hearing individuals were taken as controls. Mutations in three common deafness-causing genes (GJB2, SLC26A4 and 12S rRNA) were screened by direct sequencing. RESULTS: Mutations (homozygote or compound heterozygote) in GJB2 accounted for 8.9% (34/380) of the patients, mutations in SLC26A4 accounted for 10.0% (38/380) of the patients screened. Only one case was found to carry 12S rRNA 1555A > G (1/380, 0.26%). Five types of mutations in GJB2 were identified, GJB2 235delC was the most prevalent mutation in our patient group (76/380, 20.0%), followed by 299-300delAT with a frequency of 7.4% (28/380). Two types of mutations in SLC26A4 were detected in our patient group (IVS7-2A > G and 2168A > G). IVS7-2A > G was identified in 27 patients (27/380, 7.1%) and 2168A > G was identified in 14 patients (14/380, 3.7%). CONCLUSIONS: Our results demonstrate that 19.2% patients with nonsyndromic deafness were caused by mutations in three common deafness genes (GJB2, SLC26A4 and 12S rRNA) in our northern China patient group. GJB2 235delC was the most prevalent mutation, same as in the most Asian populations. These data enrich the database of deafness mutations and provide the standard for clinical diagnose, treatment and genetic counseling in Northern China population. PMID- 28583501 TI - Otorhinolaryngologic manifestations of Hartsfield syndrome: Case series and review of literature. AB - Diagnosis of Hartsfield syndrome includes recognition of three distinct clinical anomalies: holoprosencephaly, ectrodactyly, and bilateral cleft-lip and palate syndrome. A family including three male siblings all affected by Hartsfield syndrome presented to our institution for care. An autosomal dominant variant in Fibroblast Growth Factor Receptor 1 (FGFR1) was identified. This report focuses on otorhinolaryngologic manifestationsof Hartsfield syndrome, previously undescribed, including midline defects of holoprosencephaly, bilateral cleft-lip and palate, retrognathia, gastroesophageal reflux disease, external ear anomalies, eustachian tube dysfunction, and midface abnormalities, in addition to multidisciplinary, long-term management strategies. Multidisciplinary management is imperative in the care of these children with modification of approach based on their medical complexity. PMID- 28583502 TI - The effectiveness of earmuffs on the physiologic and behavioral stability in preterm infants. AB - BACKGROUND: The use of earmuffs can protect preterm infants against negative effects of high noise levels in the neonatal intensive care unit. This study was aimed at assessing the effectiveness of the earmuffs on the physiologic and behavioral responses in preterm infants. METHODS: A crossed over controlled trial was conducted at Aliasghar Hospital (Tehran, Iran) in 2014. Thirty-six preterm infants cared in closed incubators, 18 cases wore a pair of silicon earmuffs in the first day and the others were worn it at the second day. During 2 consecutive days, all subjects were observed as their own controls (without earmuffs). Physiologic (body temperature, heart rate, respiratory rate, systolic, diastolic pressures, arterial Oxygen Saturation) and behavioral responses (according to the Anderson behavioral state scoring system) were assessed every 2 h for 8 h long during daytime for two consecutive days. RESULTS: The application of earmuffs could decrease the rate of the heart and respiratory while could increase the amount of oxygen saturation (p < 0.05). The results also showed that the preterm infants with earmuffs had lower ABSS score and a better light sleep compared to those without earmuffs (2.38 +/- 0.47 versus 4.8 +/- 0.97, p < 0.05). CONCLUSION: The results indicated that using the earmuffs reduces the level of noise in NICUs following by improving the preterm neonates' physiological stability and behavioral states of ABSS. PMID- 28583503 TI - Prevalence of pressure equalization tube placement and hearing loss in children with down syndrome. AB - OBJECTIVE: To determine the prevalence of pressure equalization tube (PET) placement and hearing loss in children with Down syndrome (DS). MATERIAL AND METHODS: We evaluated 90 DS children births between 1 and 11 years old and compared to 90 children without DS paired in sex and age. Medical records were analyzed consecutively. Were collected data about proceedings PET placement, age of the patient at each PET, adenoidectomy, tonsillectomy and results for audiometry and tympanometry. RESULTS: Among the 90 patients with DS, 49 (54.4%) were male, median age of 58 months (15-143 months). In this group, 75 PET were placed in 26/90 children (28.9%) mostly between 3 and 5 years old. In 10/26 (38.5%) was necessary PET replaced. When compared to the control group- 6/90 (6.7%)- children with DS presented OR = 13.7 (95% CI 4.0-47.3) times more likely to use PET. Adenoidectomy and tonsillectomy (44.4% and 42.2% respectively) were significantly more frequent in DS group. The prevalence of hearing loss was 32.1% in the right ear and 26.9% in the left ear. Type B timpanometry was found in more than half of the patients with DS. CONCLUSION: We found a 13-fold higher risk of PET in DS children, especially between the ages of 3-5 years. The high prevalence of hearing loss and PET placement in patients with DS reinforcing the importance of early and regular follow-up for hearing screening in this population, mostly in preschool-aged children. PMID- 28583504 TI - Outcomes and limitations of hospital-based newborn hearing screening. AB - OBJECTIVES: Globally, newborn hearing screening (NHS) is variably incorporated into national healthcare systems. The authors reviewed the set-up and evolution process of a hospital-based NHS program in South Korea, where screening costs for low-income families are paid by the National Health Authority. METHODS: The NHS process for 13805 newborns delivered in a tertiary referral center of South Korea from 2005 through 2014 was reviewed. Hearing screening was conducted using automated auditory brainstem response (AABR); hearing loss was confirmed by auditory brainstem response for newborns who did not pass the screening test. RESULTS: The mean screening rate for hearing loss was 53.6% (7403 of 13805 newborns), which plateaued at 79.6% over time. Of the 14806 ears (7403 newborns), 1030 (7.0%) were assessed as "refer" on the first AABR, with 204 (1.4%) being assessed as "refer" on the second AABR. In hearing confirmation tests, 74 infants (1.0% of 7403 newborns) were diagnosed with hearing loss, including 13 infants (0.2%) with bilateral moderate to profound sensorineural hearing loss (SNHL). Hearing rehabilitation with long-term follow-up was confirmed in 11 infants. CONCLUSIONS: In this hospital-based NHS program, the screening rate plateaued at ~50% when the National Health Authority was not involved, but increased to ~70% when the cost for low-income families was covered by the government. Among infants needing active hearing rehabilitation due to bilateral moderate to profound SNHL, 15% were lost to follow-up. These results demonstrate the need for a universal, mandatory NHS program to systematically register hearing-impaired infants within the government-sponsored public healthcare system. PMID- 28583506 TI - Intergenerational preferences for radio loudness during automobile driving. AB - INTRODUCTION: The comparative contribution to human noise exposure from the vehicular radio is unknown, as are the radio volume preferences of different generations when driving an automobile. MATERIALS AND METHODS: A single vehicle was used to measure radio listening level in decibels of three generations (age 16-17 years, age 32-50 years, and age 51-73 years) in various conditions, ranging from engine off with windows closed to 60 miles per hour (mph) with windows open. RESULTS: No differences in radio loudness based on the sex of the driver were found. Statistically significant differences were identified in preferred signal to noise ratio among multiple vehicular paradigms, with the youngest generation preferring the largest signal to noise ratio in conditions with low background noise. CONCLUSIONS: The youngest generation favored the largest signal to noise ratio (radio level above background noise), a preference which waned with increasing background noise. PMID- 28583505 TI - Novel EYA1 variants causing Branchio-oto-renal syndrome. AB - INTRODUCTION: Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing. METHODS AND MATERIALS: Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study. RESULTS: We identified causative DNA variants in six families including novel c.525delT, c.979T > C, and c.1768delG and a previously reported c.1779A > T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families. CONCLUSIONS: A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing. PMID- 28583507 TI - Recurrent post tonsillectomy bleeds: Presentation and characteristics in the paediatric population. AB - OBJECTIVE: To evaluate the incidence of, features and risk factors for recurrent post tonsillectomy bleeding. METHODS: Audit of all patients 0-15 years of age undergoing tonsillectomy between 01/2004-12/2014 with selection of those with recurrent bleeding post tonsillectomy for subanalysis. RESULTS: Of 5400 single centre tonsillectomies, 234 (4.8%) presented with bleeding and 9 (0.17%) presented with recurrent bleeding. 13 patients in total were treated, 10 surgically. Average patient age: 8.5 years with median time to presentation of the first bleed: 5 days and second bleed: 11 days. There was no association with abnormal coagulation, NSAID usage, severity of the first bleed or surgical technique. The risk of developing a second bleed following treatment for one post tonsillectomy bleeding incident is approximately 1 in 25. CONCLUSION: Recurrent post tonsillectomy bleeds are rare, and cannot be predicted preoperatively. The mainstay of management is surgical cautery, but other interventions are occasionally needed. PMID- 28583508 TI - The adaptive use of a hand-crafted endotracheal-endobronchial tube for airway management in laryngo-tracheo-esophageal cleft type IV. PMID- 28583509 TI - Paediatric tracheomalacia - A review of clinical features and comparison of diagnostic imaging techniques. PMID- 28583510 TI - Lamotrigine induced lymphadenopathy: Case report and literature review. AB - Lamotrigine is an anti-epileptic drug often prescribed to children and young females. Side effects include rash, dizziness and diplopia. Over the last twenty years, two cases of lymphadenopathy due to lamotrigine have been reported. We will present the case of a 17-year old female with persistent lymphadenopathy due to lamotrigine. The purpose of this case report is to inform clinicians that lymphadenopathy is a possible side effect of lamotrigine and to highlight the need for further research. PMID- 28583511 TI - Blood count values and ratios for predicting sleep apnea in obese children. AB - OBJECTIVES: To detect whether the mean platelet volume (MPV), neutrophil-to lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are contributing factors in the diagnosis and severity of sleep apnea in obese children. INTRODUCTION: Obesity is a public health problem, and its prevalence increases daily. Although PSG is the gold standard test in the investigation of sleep apnea, the application of this test requires equipment, personnel, time, and cost. There is no simple laboratory test for diagnosing and determining the severity of sleep apnea. Recently, MPV, NLR, and PLR, known as the inflammatory markers in CBC test parameters, have been investigated in some studies. We aim to investigate whether these parameters could provide a method for diagnosing and determining the severity of OSAS in obese children. METHODS: Clinical records of 180 patients were evaluated. All subjects had venous blood samples collected from the antecubital vein in the morning, after an overnight fasting, one day before PSG. Hemoglobin, RDW, MPV, PLT, platelet distribution width (PDW), and WBC count were measured. After anthropometric and laboratory analysis, 127 obese children were assessed for sleep study. Eighty-three patients who met the required polysomnographic criteria were divided into three groups as follows: group A [non OSAS, apnea-plus-hypopnea index (AHI) < 1], groupB (1 <= AHI < 5), and groupC (AHI >= 5). RESULTS: Total recording time, total sleep time, sleep efficiency, REM, and NREM sleep stage latency values were not statistically significant among groups. However, the number of awakenings, AHI, oxygen desaturation events, mean oxygen saturation, lowest oxygen saturation, average desaturation, and snoring time values had significant difference among the groups. There was no statistically significant difference among the groups in terms of WBC, Hemoglobin, platelets, PDW, neutrophil, and lymphocyte values. However, RDW values showed a statistically significant difference between groups A and C. Although there was no statistically significant difference of MPV values among groups, NLR and PLR values were statistically significant between groups A and C. CONCLUSION: According to our study, NLR, PLR, and RDW were found to be significantly higher in children whose AHI was >=5 than in children from the other groups. However, no correlation was found between MPV levels and OSAS in children. PMID- 28583512 TI - Comprehensive management of congenital choanal atresia. AB - OBJECTIVES: To present results of a one-stage minimally invasive surgical procedure for congenital choanal atresia (CCA). Seven outcome measures were applied. MATERIALS AND METHODS: Retrospective study conducted between 1999 and 2015. The same endonasal endoscopic approach with multiflaps and no stenting was used on 36 children. The flaps were attached with fibrine glue. There were 50% unilateral and 50% bilateral cases, 70% primary and 30% secondary surgery. The mean age at primary surgery for bilateral atresia was 10 days and for unilateral atresia 4 years. Associated loco-regional disorders were: hypoplasia of the inferior turbinate, rhinopharyngeal stenosis and rhinopharyngeal web. RESULTS: The average follow-up time was 6 years, ranging from 1 to 14 years. There was a functionally patent choanae in 94% of children, and 6% showed severe restenosis with a diameter less than 4 mm, which needed one revision surgery each. Charge patients were not associated with worse outcome. There was no external nasal valve stenosis and no permanent Eustachian tube dysfunction. Synechiae occurred in 3 patients with hyperplastic inferior turbinate. No patients showed any disharmonious nasal growth. In neonates with isolated bilateral CCA, breast suction could be started within 1 day (range 1-2 days), and pain-killers were needed on average for 1.5 days (range 1-4 days). The hospital stay for unilateral isolated CCA was on average 1.5 days (range 1-2 days) and for bilateral isolated CCA, 8 days (range 3-20 days). Postoperative procedures under a short general anesthesia were necessary in 12 cases, 10 of them were infants under 6 months of age. CONCLUSION: Surgery could be performed safely in the newborn in the early stage of life, even for unilateral atresia. Tendency for restenosis can be minimized by: 1. the construction of an as large as possible uni-neochoanae by removing the posterior part of the vomer and by drilling away the medial pterygoid; 2. in case of rhinopharyngeal stenosis, part of the endochondral clivus bone should be resected; 3. all raw surfaces should be covered by multiple mucosal flaps secured with fibrin glue; 4. no stenting; 5. appropriate postoperative care. PMID- 28583513 TI - Health-related quality of life in patients with cleft palate: Validity and reliability of the VPI Effects on Life Outcomes (VELO) questionnaire translated to Dutch. AB - BACKGROUND: Disease-specific health-related quality of life (HRQOL) questionnaires provide the clinician with important information regarding the impact of the disease on functioning and well-being. For patients with velopharyngeal insufficiency (VPI), the VPI Effects on Life Outcomes (VELO) questionnaire was developed and validated in English by Skirko et al. (2012). However, a valid and reliable Dutch translation of this questionnaire is not available yet. METHODS: The English questionnaire was translated to Dutch following a forward-backward translation procedure. A linguistic validation and the evaluation of the internal consistency (Cronbach's alpha) of this Dutch version were performed based on the responses of 39 parents of patients with cleft (lip and) palate (mean age: 6.8 years) (parent report) and the responses of 14 patients older than 8 years (mean age: 9.5 years) (child report). Additionally, the concurrent validity was assessed by comparing the scores on the parent report to those on the pediatric voice handicap index. Furthermore, the validity of the parent proxy assessment and the relationship between age and responses on the VELO questionnaire were investigated. Based on the responses of an age and gender matched control group without cleft palate, the discriminant validity was evaluated. RESULTS: The parent report was easy to complete for all parents. Nine of the fourteen (64%) patients were able to complete the child report independently. The median scores on the parent report and the child report were 82.7 and 95.1 respectively. The patient group had a significantly worse perception of HRQOL compared to the control group (p < 0.001; p = 0.029). There were no significant differences between the responses of the parent and their child's (p = 0.345). A significant positive correlation was found between the score on the parent report and the age of the patients (p = 0.001). Furthermore, a significant negative correlation was found between the parent report and the P VHI (p < 0.001). Cronbach's alpha was 0.955 and 0.817 for the parent report and the child report respectively. CONCLUSION: The Dutch VELO questionnaire is a valid, reliable and user-friendly tool that provides important information about HRQOL in patients with cleft (lip and) palate. PMID- 28583514 TI - Pediatric sinonasal malignancies: A population-based analysis. AB - INTRODUCTION: Pediatric Sinonasal Malignancies (PedsSNM) are rare and usually associated with a poor prognosis. We aim to investigate the epidemiology, tumor characteristics, and survival of PedsSNM using a population-based database to augment the scant literature on this topic. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients <=18 years diagnosed with PedsSNM between the years of 1973 and 2013. Data on incidence, tumor characteristics, and survival were analyzed. RESULTS: In total, 210 patients with PedsSNM were identified. Demographically, 54.3% were female, 72.6% were white, and the mean age was 10.7 years. Overall incidence was 0.036 per 100,000 individuals between the years of 2000 and 2013. The nasal cavity was the most frequent primary site (37.1%) and rhabdomyosarcoma was the most frequent malignancy (50.5%). Five-, 10-, and 20-year disease-specific survival (DSS) rates were 60.2%, 46.1%, and 20.6%, respectively. Grade IV tumors made up the largest group (37.3%), and such tumors exhibited the worst 5-, 10-, and 20-year survival (P < 0.05). Distant disease predicted the worst 5-, 10-, and 20-year survival, followed by regional, then localized disease (P < 0.01). Patients treated with surgery alone had a higher 20-year survival (P = 0.0425). No significant differences in survival were observed between race, gender, primary site, or histology. CONCLUSIONS: PedsSNM frequently presented as Grade IV tumors. The nasal cavity was the most common primary site and rhabdomyosarcoma was the most frequent histology. Patients receiving surgery alone had the highest survival; however, this may be a reflection of smaller, less aggressive tumors preferentially being treated with surgery alone. PMID- 28583515 TI - Acoustic Radiation Force Impulse Imaging of the Transplant Kidney: Correlation Between Cortical Stiffness and Arterial Resistance in Early Post-transplant Period. AB - BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is a noninvasive imaging modality for quantitative assessment of tissue stiffness. This study utilized ARFI imaging to assess the stiffness of a transplant renal cortex within the first month after renal transplantation and to explore the correlation between the cortical stiffness and arterial resistance of the transplant kidney. METHODS: Forty renal transplant recipients (male/female = 26/14; mean age: 45.3 years; deceased donor/living related donor = 27/13) were included in this study. ARFI imaging with virtual touch tissue imaging quantification was applied to assess the stiffness of the transplant renal cortex by using a linear ultrasound transducer. Arterial resistance was acquired by spectral Doppler examination of the main artery and intrarenal arteries of the transplant kidney using a curvilinear ultrasound transducer. RESULTS: The stiffness of transplant renal cortex was expressed as shear wave velocity (m/s). The mean value of cortical stiffness was 3.19 +/- 1.01 m/s (range: 1.55-5.54). The stiffness of transplant renal cortex was positively correlated with the resistance index of the main renal artery (r = 0.55, P = .001), segmental artery (r = 0.43, P = .005), and interlobar artery (r = 0.42, P = .006). CONCLUSION: The stiffness of a transplant renal cortex is positively correlated with the arterial resistance of the renal transplant in the early post-transplant period. This result indicates that, in addition to renal fibrosis, the stiffness of the transplant renal cortex is also influenced by the hemodynamics of the transplant kidney. PMID- 28583516 TI - Metabolomics Study for Identification of Potential Biomarkers of Long-term Survival in Kidney Transplantation Recipients. AB - BACKGROUND: The recent progress and appropriate use of immunosuppressive drugs have considerably improved the short-term survival in kidney transplantation recipients (KTRs). The development of new strategies to improve long-term survival outcome after kidney transplantation is also becoming important. Although current diagnosis of allograft dysfunction relies on serum creatinine concentration and biopsy, they are nonspecific indicators of allograft function. Therefore, noninvasive, sensitive, and specific biomarkers for the prediction of long-term survival are needed. The aim of this study was to discover potential biomarkers for long-term survival in KTRs through the use of liquid chromatography-tandem mass spectrometry. METHODS: We used the metabolic approach to explore the change of metabolites in the serum of KTRs. Twenty-four KTRs with long-term good survival (LGS) and 10 KTRs with chronic antibody-mediated rejection (CAMR) were included in this study. After quantile normalization with chromatographic data, multivariate statistical analysis was performed. We attempted to analyze metabolic profiling with LGS and CAMR groups. RESULTS: The orthogonal partial least-squares discriminant analysis score plot showed a separation between 2 groups in the principal component. In the corresponding loading plot, 344 metabolites responsible for the separation observed in the score plot were identified (variable influence on projection >=1.0). We then selected 54 metabolites to compare mass with charge by searching a web database, and 11 compounds were identified. CONCLUSIONS: We found metabolites in serum that differ in LGS and CAMR groups. Further studies are needed to figure out potential metabolomic biomarkers to predict long-term survival in KTRs. PMID- 28583517 TI - Association Studies of Bone Morphogenetic Protein 2 Gene Polymorphisms With Acute Rejection in Kidney Transplantation Recipients. AB - OBJECTIVE: Bone morphogenetic proteins (BMP) belong to the transforming growth factor beta superfamily of proteins. This study was performed to evaluate the association of BMP gene polymorphisms with acute renal allograft rejection (AR) and graft dysfunction (GD) in Koreans. METHODS: Three hundred thirty-one patients who had kidney transplantation procedures were recruited. Transplantation outcomes were determined in terms of AR and GD criteria. We selected six single nucleotide polymorphisms (SNPs): rs1979855 (5' near gene), rs1049007 (Ser87Ser), rs235767 (intron), rs1005464 (intron), rs235768 (Arg190Ser), and rs3178250 (3; untranslated region). RESULTS: Among the six SNPs tested, the rs235767, rs1005464, and rs3178250 SNPs were significantly associated with AR (P < .05). The rs1049007 and rs235768 SNPs also showed an association with GD (P < .05). CONCLUSIONS: In conclusion, these results suggest that the BMP2 gene polymorphism may be related to the development of AR and GD in kidney transplant recipients. PMID- 28583518 TI - Cystatin C-Based Equation for Predicting the Glomerular Filtration Rate in Kidney Transplant Recipients. AB - BACKGROUND: Precise monitoring of the glomerular filtration rate (GFR) is needed to estimate the allograft function in kidney transplant recipients (KTRs). The GFR is widely estimated with the use of formulas based on serum cystatin C (SCys) and serum creatinine (SCr) levels. We compared the efficacy of SCys-based equations with that of SCr-based equations to predict the allograft function. METHODS: We calculated the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Cr), CKD-EPI creatinine cystatin C (CKD-EPI Cr/Cys), and CKD-EPI cystatin C (CKD-EP ICys) equations in 70 KTRs. The measured GFR (mGFR) was defined as the GFR estimated by technetium-99m diethylene triamine pentaacetic acid (99mTc-DTPA) clearance. The accuracy and precision of the equations were compared with the mGFR. The performance characteristics of SCr and SCys were analyzed with the use of receiver operating characteristic (ROC) curves to ascertain the sensitivity and specificity at the cutoff value of <45 mL/min/1.73 m2 DTPA. RESULTS: Overall, MDRD and CKD-EPICys did not show significant differences from mGFR (P = .05 and P = .077, respectively), whereas CKD-EPI Cr and CKD-EPI Cr/Cys significantly underestimated mGFR (P < .001 and P = .005, respectively). In the subgroup of patients with mGFR <45 mL/min/1.73 m2, CKD-EPI Cys showed little bias (P = .122), whereas MDRD significantly underestimated mGFR (P = .037). The area under the ROC curve for predicting mGFR <45 mL/min/1.73 m2 was 0.80 for SCys, which was better than that for SCr at 0.763. CONCLUSIONS: Cystatin C-based equations showed better predictive performance of the allograft function than creatinine-based equations for the KTRs, including patients with lower GFR. Cystatin C level might be a good alternate measurement to monitor the allograft function. PMID- 28583519 TI - Usefulness of Multi-Detector Computed Tomography Scanning as a Replacement for Diethylenetriamine Pentaacetic Acid. AB - BACKGROUND: Diethylenetriamine pentaacetic acid (DTPA) and multi-detector computed tomography (MDCT) can predict postoperative estimated glomerular filtration rate (eGFR) in a live kidney donor. Accordingly, we compared predicted eGFR measured by use of DTPA and MDCT. METHODS: From January 2013 to May 2015, 264 live kidney donors were enrolled. All donors underwent preoperative DTPA and MDCT, and bilateral renal cortex volume was measured by use of MDCT. We estimated DTPA-eGFR [remaining split renal function (%) * preoperative eGFR] and Vol-eGFR [remaining renal volume/total renal volume (%) * preoperative eGFR] and analyzed DTPA-eGFR, Vol-eGFR, and Modification of Diet in Renal Disease (MDRD)-eGFR during week 1 and in months 1, 3, and 6. Additionally, we compared DTPA-eGFR and Vol eGFR by use of the formula DeltaeGFR (maximum eGFR minus minimum eGFR during 6 months). RESULTS: The mean DTPA-eGFR and Vol-eGFR values (mL/min/1.73 m2) were 52.97 +/- 10.32 and 51.26 +/- 10.26, respectively. Predictions of the dominant side did not agree in 113 of 303 (37.3%) cases. Postoperative MDRD-eGFR exhibited a statistically significant correlation with total renal volume, DTPA-eGFR, and Vol-eGFR (P < .0001). A significant correlation was found between DeltaeGFR and total renal volume, DTPA-eGFR, and Vol-eGFR (P < .0001). Receiver operating characteristic curves were generated to predict the possibility of eGFR <60 mL/min/1.73 m2 at 6 months, using DTPA-eGFR and Vol-eGFR, which indicated that DTPA-eGFR (area under the curve = 0.858; P < .0001) and Vol-eGFR (area under the curve = 0.878; P < .0001) could predict chronic kidney disease class III at 6 months. CONCLUSIONS: MDRD-eGFR, Vol-eGFR, and DTPA-eGFR were significantly correlated. Moreover, Vol-eGFR and DTPA-eGFR exhibited high predictive value for chronic kidney disease class III at 6 months, whereas Vol-eGFR was a good predictor of renal function recovery. PMID- 28583520 TI - Long-term Clinical Outcome of Aortic Arch Calcification in Kidney Transplant Recipients. AB - INTRODUCTION: Cardiovascular disease is the most common cause of death in kidney transplant recipients (KTRs). Aortic arch calcification (AoAC) is a major risk factor for cardiovascular disease in KTRs. This study aimed to evaluate the long term outcomes of AoAC in KTRs. METHODS: We retrospectively evaluated AoAC in KTRs between 2000 and 2010 using chest radiography. AoAC was semiquantitatively estimated by calculating calcification score. Associations between clinical and biochemical parameters were evaluated. RESULTS: A total of 258 patients were enrolled; the mean age was 40.7 years, and 135 (52.3%) were males. Diabetes mellitus was present in 28 (10.9%), and deceased donor kidney transplantation (KT) had been performed in 95 (36.8%). Fifty-three (20.5%) patients had AoAC at the time of KT, with an AoAC score of 0.8 +/- 2.0. The proportion of KTRs with AoAC gradually increased to 23.3%, 26.4%, and 28.7% at 1, 3, and 5 years, respectively, after KT. The AoAC score also gradually increased to 1.0 +/- 2.3, 1.2 +/- 2.8, and 1.6 +/- 3.1, respectively, at 1, 3, and 5 years after KT. The 10 year graft survival rate was 83.2% in the AoAC group and 85.1% in the non-AoAC group. The 10-year patient survival rate was 90.6% in the AoAC group and 95.7% in the non-AoAC group. In multivariate analysis, age at KT, deceased-donor KT, and diabetes mellitus were independent predictors for all-cause mortality. CONCLUSIONS: AoAC is an independent predictor of poor cardiovascular outcome in KTRs. Age and dialysis duration were independent risk factors for AoAC. Age at KT, deceased-donor KT, and diabetes mellitus were independent predictors for all cause mortality. Regular follow-up by chest radiography could be a simple and useful method to screen for AoAC and reduce cardiovascular mortality. PMID- 28583521 TI - Progression of Osteoporosis After Kidney Transplantation in Patients With End Stage Renal Disease. AB - BACKGROUND: This study investigated the prevalence of osteoporosis and the risk factors for its progression in kidney transplant recipients (KTRs). METHODS: Dual energy X-ray absorptiometry was used to prospectively measure changes in bone mineral density (BMD) before kidney transplantation (KT) and 1 year after transplantation in 207 individuals. We also analyzed the risk factors of osteoporosis progression during this period. RESULTS: Prior to KT, the mean BMD score (T-score of the femur neck area) was -2.1 +/- 1.2, and the prevalence of osteoporosis was 41.5% (86/207). At 1 year post-transplantation, the mean BMD score significantly decreased to -2.3 +/- 1.1 (P < .001), and the prevalence of osteoporosis increased to 47.3% (98/207; P = .277). The BMD score worsened over the study period in 69.1% (143/207) of patients, improved in 24.1% (50/207), and showed no change in 6.8% (14/207). Minimal intact parathyroid hormone (iPTH) improvement after KT was found to be an independent risk factor of osteoporosis progression. CONCLUSIONS: This study demonstrates progressive loss of BMD after KT and sustained secondary hyperparathyroidism might influence the progression of osteoporosis. PMID- 28583522 TI - Effect of Changes in Body Mass Index on Cardiovascular Outcomes in Kidney Transplant Recipients. AB - BACKGROUND: A higher body mass index (BMI) before kidney transplantation (KT) is associated with increased mortality and allograft loss in kidney transplant recipients (KTRs). However, the effect of changes in BMI after KT on these outcomes remains uncertain. The aim of this study was to investigate the effect of baseline BMI and changes in BMI on clinical outcomes in KTRs. METHODS: A total of 869 KTRs were enrolled from a multicenter observational cohort study from 2012 to 2015. Patients were divided into low and high BMI groups before KT based on a BMI cutoff point of 23 kg/m2. Differences in acute rejection and cardiovascular disease (CVD) between the 2 groups were analyzed. In addition, clinical outcomes across the 4 BMI groups divided by BMI change 1 year after KT were compared. Associations between BMI change and laboratory findings were also evaluated. RESULTS: Patients with a higher BMI before KT showed significantly increased CVD after KT (P = .027) compared with patients with a lower BMI. However, among the KTRs with a higher baseline BMI, only persistently higher BMI was associated with increased CVD during the follow-up period (P = .003). Patients with persistently higher BMI had significantly decreased high-density lipoprotein cholesterol and increased hemoglobin, triglyceride, and hemoglobin A1c levels. Baseline BMI and post-transplantation change in BMI were not related to acute rejection in KTRs. CONCLUSIONS: BMI in the 1st year after KT as well as baseline BMI were associated with CVD in KTRs. More careful monitoring of obese KTRs who do not undergo a reduction in BMI after KT is required. PMID- 28583523 TI - Renal Allograft Function Is a Risk Factor of Left Ventricular Remodeling After Kidney Transplantation. AB - BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplantation (KT) patients. The prevalence of left ventricular hypertrophy increases with the progression of renal insufficiency. METHODS: We investigated the association between the progression of renal insufficiency and left ventricular hypertrophy after KT. We reviewed KT patients at Seoul National University Hospital from January 1973 to December 2009. The creatinine elevation ratio (CER, the percentage change in the creatinine level from 1 month to 5 years after transplant) was calculated as follows: (creatinine level at 5 years minus creatinine level at 1 month)/creatinine level at 1 month * 100. RESULTS: The study population was classified into a high-CER group (CER >=25%) and low-CER group (CER <25%). Mean left ventricular mass index (LVMI) values were 135.7 and 134.7 g/m2 before KT and 101.7 and 123.7 g/m2 at 5 years after KT in the low-CER and high-CER groups, respectively. The LVMI before or 1 year after KT was not different between the 2 groups, but the LVMI at 5 years post-transplant was higher in the high-CER group than in the low-CER group. The LVMI increased after its initial decrease in the high-CER group, whereas its reduction was maintained in the low-CER group during the 5 years after KT (P = .009, repeated-measures analysis of variance). CONCLUSIONS: These data suggest that deterioration of renal allograft function is associated with left ventricular remodeling after KT. PMID- 28583524 TI - Epidemiology and Outcome of Ganciclovir-Resistant Cytomegalovirus Infection After Solid Organ Transplantation: A Single Transplant Center Experience in Thailand. AB - BACKGROUND: Data on drug-resistant cytomegalovirus (CMV) infection in solid organ transplantation (SOT) are not often reported from resource-limited settings. We aimed to investigate the epidemiology and outcomes of this infection in SOT recipients at our institution. METHODS: This was a retrospective study conducted from January 2012 to May 2015. We included all SOT recipients who were suspected for drug-resistant CMV infection. Genotypic assay for UL97 gene mutation was analyzed by real-time polymerase chain reaction. Patients were reviewed for demographic data, clinical presentation, virologic data, treatment, and outcomes. RESULTS: The population consisted of 18 (12 kidney, 6 liver) SOT recipients with a median age of 20 years (interquartile range [IQR], 1-49); 44% were male. Anti CMV resistance testing was analyzed at a median time of 23 days (IQR, 14-33) after initiation of anti-CMV therapy with a median CMV load of log 3.79 copies/mL (IQR, 3.37-4.58). During a median period of 2 years (IQR, 1-3), 6 SOT recipients were identified with UL97 gene mutation in codon 460, conferring ganciclovir (GCV) resistance. Patients with UL97 gene mutation had a longer mean duration of CMV DNAemia compared with those without mutation (263 vs 107 days; P = .04). All patients received high-dose GCV. Two patients received foscarnet and cidofovir. Two patients died (non-CMV-related), and 4 patients developed opportunistic infections other than CMV. CONCLUSIONS: GCV-resistant CMV infection in SOT recipients is an emerging clinical problem in resource-limited country. Those with UL97 mutation CMV infection have prolonged duration of CMV DNAemia. Clinicians should be aware of this condition when caring for SOT recipients. PMID- 28583525 TI - Effective Treatment With Daclatasvir and Asunaprevir in Kidney Transplant Patients Infected With Hepatitis C Virus: A Report of Two Cases. AB - BACKGROUND: Hepatitis C virus (HCV) infection is known to affect long-term patient and graft survivals after kidney transplantation (KT). Recently, combination therapy with the use of 2 oral direct-acting antivirals, daclatasvir (DCV) and asunaprevir (ASV) reportedly showed a high rate of HCV eradication. We report the safety and efficacy of DCV and ASV therapy in 2 KT patients. METHODS: The safety and viral responses were investigated in a prospective study of KT patients infected with HCV genotype 1. Two patients received 60 mg DCV once daily plus 100 mg ASV twice daily for 24 weeks. RESULTS: A 69-year-old woman and a 57 year-old man underwent DCV and ASV therapy for 24 weeks. In both cases, the HCV genotype was 1b. Case 1 had undergone KT twice and had received treatment with pegylated interferon and ribavirin. She received DCV and ASV therapy 12 years after the 2nd KT, and had undetectable virus after only 6 weeks of treatment and at 24 weeks after the end of treatment (SVR24). The post-transplantation immunosuppressive therapy at that time comprised tacrolimus, mycophenolate mofetil, and prednisolone. The other case, after failure of interferon treatment, received DCV and ASV therapy 27 years after his KT and achieved SVR24. His immunosuppressive regimen at that time was mizoribine and prednisolone. DCV and ASV therapy did not affect renal graft function or tacrolimus blood concentrations. CONCLUSIONS: DCV and ASV therapy had high antiviral effect and a low rate of adverse events in KT patients. PMID- 28583526 TI - Gene Expression Profiling of Peripheral Blood From Kidney Transplant Recipients for the Early Detection of Digestive System Cancer. AB - BACKGROUND: Kidney transplant recipients are at increased risk of developing cancer in comparison with the general population. To effectively manage post transplantation malignancies, it is essential to proactively monitor patients. A long-term intensive screening program was associated with a reduced incidence of cancer after transplantation. This study evaluated the usefulness of the gene expression profiling of peripheral blood samples obtained from kidney transplant patients and adopted a screening test for detecting cancer of the digestive system (gastric, colon, pancreas, and biliary tract). STUDY DESIGN AND METHOD: Nineteen patients were included in this study and a total of 53 gene expression screening tests were performed. The gene expression profiles of blood-delivered total RNA and whole genome human gene expression profiles were obtained. We investigated the expression levels of 2665 genes associated with digestive cancers and counted the number of genes in which expression was altered. A hierarchical clustering analysis was also performed. The final prediction of the cancer possibility was determined according to an algorithm. RESULTS: The number of genes in which expression was altered was significantly increased in the kidney transplant recipients in comparison with the general population (1091 +/- 63 vs 823 +/- 94; P = .0024). The number of genes with altered expression decreased after the induction of mechanistic target of rapamycin (mTOR) inhibitor (1484 +/- 227 vs 883 +/- 154; P = .0439). No cases of possible digestive cancer were detected in this study period. CONCLUSION: The gene expression profiling of peripheral blood samples may be a useful and noninvasive diagnostic tool that allows for the early detection of cancer of the digestive system. PMID- 28583527 TI - Using Hematuria as Detection of Post-kidney Transplantation Upper Urinary Tract Urothelial Carcinoma Is Associated With Delayed Diagnosis of Cancer Occurrence. AB - OBJECTIVES: Kidney transplantation (KT) is an important renal replacement therapy for end-stage renal disease (ESRD). The incidence of upper urinary tract urothelial carcinoma (UTUC) is relatively higher in Taiwan. According to our institutional database, early onset of post-KT UTUC is not uncommon. Early detection of post-KT UTUC is an important issue to improve oncologic outcome. Because painless hematuria is a common symptom for UTUC, this study analyzes whether using hematuria as post-KT UTUC screening delayed cancer diagnosis or not. METHODS: From 2005 to 2012, 128 ESRD patients were found to have UTUCs. There were 28 patients who underwent KT and were regularly followed up at our institution. All the patients underwent standard nephroureterectomy. RESULTS: In ESRD patients with UTUC, the post-KT group revealed significantly less gross hematuria and microscopic hematuria at presentation compared with the non-KT group (43% versus 76%, P = .001 and 64% versus 86%, P = .011). For those patients with gross hematuria, non-organ-confined UTUC occurred more in the post-KT group compared with the non-KT group (42% versus 12%, P = .009). For those patients with microscopic hematuria, non-organ-confined UTUC occurred more in the post-KT group compared with the non-KT group with borderline significance (33% versus 16%, P = .085). CONCLUSIONS: According to our observation, using gross or microscopic hematuria as detection of post-KT UTUC is associated with delayed diagnosis of cancer occurrence. Closer upper urinary tract image study such as sonography may help earlier cancer screening. PMID- 28583528 TI - Human Polyomavirus Is Associated With Earlier Onset of Upper Urinary Tract Urothelial Carcinoma in Patients After Kidney Transplantation. AB - OBJECTIVES: Polyomavirus has been reported to be oncogenic due to viral integration into the human genome. A relatively high prevalence of upper urinary tract urothelial carcinoma (UTUC) was noted after kidney transplantation (KT) in Taiwan. However, little was known about the impact of polyomavirus on the urothelial cancer behavior. Therefore, the aim of this study is to analyze the characteristics of polyomavirus-related UTUC after KT. METHODS: From 2005 to 2014, 27 patients were found to have UTUCs after KT. All the patients underwent standard nephroureterectomy. Detailed perioperative parameters were obtained from chart records. A qualified pathologist who is blinded to the clinical outcome examined large T antigen expression and pathological features. All the patients were divided into two groups according to positive or negative expression of large T antigen. RESULTS: In the patient demography, a significantly younger median age was found in patients with large T antigen-positive UTUCs compared with the negative control group (48.1 +/- 8.3 years versus 54.6 +/- 4.1 years, respectively, P = .013). As for the pathological features and oncologic outcome, there were no obvious differences between these two groups. Non-organ-confined status and positive lymphovascular invasion are prognostic factors associated with systemic disease recurrence (P = .017 and .001, respectively). CONCLUSIONS: Although UTUC commonly develops in the elderly, earlier onset of post-KT UTUCs was observed especially in patients with positive large T antigen expression in our cohort. This preliminary result provides valuable experience suggesting more frequent upper urinary tract screening for polyomavirus infected patients after KT in Taiwan. PMID- 28583529 TI - Association Between the Fertile Period and Live Birth Post-Kidney Transplantation: A Retrospective Single-Center Cohort Study. AB - BACKGROUND: Despite restoration of fertility after kidney transplantation, the benefit is limited in female kidney recipients. Our objective is to determine the reasons for this discrepancy. METHODS: We evaluated 315 women who underwent kidney transplantation from 1983 to 2015 (a median of age at transplantation [10th-90th percentile] of 32 years [7-55 years]); 230 recipients between the ages of 15 to 49 years old as of March 2016 were observed. RESULTS: We experienced 10 abortions and 21 live births from our 23 recipients and 2 abortions and 7 live births in 7 recipients from other transplant center. The live birth rate was 8.9 per 1000 female transplant recipients of childbearing age. Seven recipients received either treatments of artificial insemination or in vitro fertilization. Average age at pregnancy was 33.2 +/- 3.2 years old, and the fertile period post transplantation was longer in recipients with live births than those without live births (14.1 +/- 7.1 vs 9.9 +/- 7.3 years, P < .05). In 42.9% of recipients with live birth, pregnancy-induced hypertension was observed in the last trimester. The gestational age and the average birth weight were 32.8 +/- 5.0 months and 2184 +/- 632 g, respectively. During follow-up of 14.5 years, there was one case of graft loss, which is a rate of 2.5 per 1000 female recipients. CONCLUSION: Although pregnancy complications are often observed in kidney recipients, graft survival is less influenced by pregnancy. Importantly, kidney disease at childbearing age disrupts pregnancy even after kidney transplantation. PMID- 28583530 TI - Increased Stiffness of the Remnant Right Lobe Liver After Left Lobectomy or Lateral Segmentectomy in Donors of Living-Donor Liver Transplantation. AB - BACKGROUND: Liver stiffness is associated with the degree of fibrosis along with other factors. Abrupt change of liver perfusion after hepatectomy is one such factor. In this study, we performed ultrasound elastography to explore the stiffness of the right lobe liver before and after hepatectomy in donors who underwent resection of left lobe or lateral segment of liver. METHODS: A total of 32 left lobe liver donors (18 male and 14 female; age range, 21-55 years; mean age, 35.1 years; 19 left lobectomy with middle hepatic reserved for graft and 13 lateral segmentectomy with middle hepatic vein reserved in the remnant liver) were included in this study. Liver stiffness was measured by means of ultrasound elastography with the use of acoustic radiation force impulse imaging. Stiffness of the right lobe liver was obtained by means of right intercostal approach. RESULTS: The stiffness of remnant right lobe liver significantly increased after hepatectomy (1.24 +/- 0.18 vs 1.10 +/- 0.13 m/s; P = .001). Donors of left lobe liver showed higher stiffness in the remnant right lobe liver compared with donors of lateral segment (1.30 +/- 0.18 vs 1.15 +/- 0.14 m/s; P = .027). There was no significant correlation between the remnant right lobe liver stiffness, postoperative liver function, and flow parameters of hepatic artery and portal vein. CONCLUSIONS: The stiffness of remnant liver significantly increased after hepatectomy. Furthermore, the stiffness was higher in donors undergoing left lobectomy compared with those undergoing lateral segmentectomy. PMID- 28583531 TI - Does Activated Clotting Time Help to Predict Innate Coagulopathy in End-Stage Liver Disease Patients? AB - BACKGROUND: Measuring activated clotting time (ACT) is widely performed to monitor heparin therapy. Regardless of anticoagulant use, ACT is affected by coagulopathies such as coagulation factor deficiency and thrombocytopenia. However, its use in end-stage liver disease (ESLD) with complex coagulopathy is not well characterized. We evaluated whether ACT could be used to detect innate coagulopathy in ESLD patients. METHODS: We retrospectively assessed Hemochron (International Technidyne, Edison, NJ, USA) ACT (FTCA 510, normal range 105-167 seconds) and INTEM clotting time (CT) of rotational thromboelastometry (ROTEM; ROTEM delta, Pentapharm GmbH, Munich, Germany) (100-240 seconds) in 366 liver transplantation (LT) recipients, simultaneously measured before anesthetic induction for LT. Multiple linear regression analyses helped identify the factors related to ACT in ESLD patients. The relationship between ACT and INTEM CT was evaluated by Spearman rank correlation analysis and receiver operating characteristic curve. RESULTS: Median ACT was 143 seconds (range 73-295 seconds), and 60 patients (16.4%) had ACTs of >167 seconds. Multiple regression analyses revealed that prolonged prothrombin time, activated partial thromboplastin time, low antithrombin III, and young age were associated with high ACT levels. INTEM CT was associated with ACT independent of liver disease severity, while EXTEM CT was not. ACT was moderately correlated with INTEM CT (r = 0.535), and the optimal cutoff value of ACT for predicting INTEM CT >240 seconds was 151 seconds (area under the curve = 0.787). CONCLUSIONS: In ESLD patients, ACT is effective in detecting prolonged INTEM CT. Therefore, ACT may be used to predict intrinsic pathway defects with a cutoff value of 151 seconds, suggesting feasibility when ROTEM is unavailable. PMID- 28583532 TI - Prediction of Fluid Responsiveness by a Non-invasive Respiratory Systolic Time Interval Variation Using Heart Sound Signals in Recipients Undergoing Liver Transplantation. AB - BACKGROUND: The fluid management of cirrhotic patients undergoing liver transplantation (LT) is challenging. Phonocardiography, a graphic recording of heart sounds, provides valuable information concerning heart function and hemodynamic condition. We assessed whether the systolic time interval (STI) and its respiratory variation could predict fluid responsiveness in cirrhotic patients undergoing LT. METHODS: Thirty LT recipients who needed volume expansion were included. The fluid challenge consisted of 500 mL 5% albumin administered over a period of 10 minutes. STI was measured as the time interval between the maximal amplitude of each heart sound corrected with the corresponding RR interval (cSTI). The respiratory variation in STI (STV) induced by mechanical ventilation was calculated. Responders were defined as those showing a >=10% increase in stroke volume index after volume expansion. RESULTS: In all, 14 of the 30 patients were responders. Significant increases in cSTI were observed after volume expansion in both responders (P < .001) and non-responders (P = .008). Responders showed significant decreases in STV (11.1% +/- 4.3% vs 6.1% +/- 2.6%, P < .001) after fluid loading, whereas STV in non-responders remained unchanged (6.4% +/- 2.6% vs 6.4% +/- 4.2%, P = .86). A cut-off value of >=7.5% STV from baseline could predict fluid responsiveness with an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.618 0.925). CONCLUSIONS: Intra-operative STV can predict fluid responsiveness in patients undergoing LT. Beat-to-beat monitoring of STI and STV may be useful as a non-invasive hemodynamic index and for fluid management. PMID- 28583533 TI - Significance of Portal Venous Velocity in Short-term Graft Function in Living Donor Liver Transplantation. AB - BACKGROUND: Graft regeneration and functional recovery after reperfusion of transplanted graft are very important for successful living donor liver transplantation (LDLT). The aim of this study was to evaluate the significance of postoperative portal venous velocity (PVV) in short-term recovery of graft function in LDLT. PATIENTS AND METHODS: From February 2007 through December 2015, we performed 17 primary LDLTs, which were included in the present study. The patients ranged in age from 12 to 65 years (mean: 50 years), and 11 were female patients. Postoperatively, Doppler ultrasonography was performed daily to measure PVV (cm/s), and liver function parameters were measured daily. The change in PVV (DeltaPVV) was defined as follows: DeltaPVV = PVV on postoperative day (POD) 1 - PVV on POD 7. Maximal value of serum aspartate aminotransferase (ASTmax) and maximal value of serum alanine transaminase (ALTmax) at 24 hours after graft reperfusion were used as parameters of reperfusion injury. Correlation analyses were performed as follows: (1) correlation of DeltaPVV and PVV on POD 1 (PVV-POD 1) with the values such as ASTmax, ALTmax, other liver function parameters on POD 7 and graft regeneration rate; (2) correlation of ASTmax and ALTmax with other liver function parameters on POD 7. RESULTS: DeltaPVV significantly correlated with the values of serum total bilirubin (P < .01), prothrombin time (P < .01), and platelet count (P < .05), and PVV-POD 1 significantly correlated with the values of serum total bilirubin (P < .05) and prothrombin time (P < .05). CONCLUSION: DeltaPVV and PVV-POD 1 may be useful parameters of short-term functional recovery of the transplant liver in LDLT. PMID- 28583534 TI - Pretransplant Resting Heart Rate and Its Association With All-Cause Mortality in Liver Transplant Recipients. AB - BACKGROUND: The importance of heart rate (HR) measurement as a prognostic factor has been recognized in many clinical conditions, such as hypertension, coronary artery disease, or heart failure. Patients with liver cirrhosis tend to have increased resting HR as consequence of hyperdynamic circulation. In the current study, we examined whether pretransplant resting increased HR is associated with overall mortality in cirrhotic patients following liver transplantation (LT). PATIENTS AND METHODS: We retrospectively collected and analyzed the data of 881 liver recipients who underwent LT surgery between October 2009 and September 2012. Patients were categorized into 3 groups by tertile of resting HR as follows: tertile 1 group, HR <= 65 beats per minute (bpm); tertile 2 group, HR 66 to 80 bpm; and tertile 3 group, HR > 80 bpm. RESULTS: Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of HR (P = .016, log-rank test). The multivariate Cox regression analysis showed that tertile 3 group was significantly associated with higher risk for all-cause mortality (hazard ratio 1.83, 95% confidence interval, 1.10 3.07; P = .021) compared with tertile 1 group, after adjusting for clinically significant variables in univariate analysis. CONCLUSIONS: Our results demonstrate that pretransplant resting tachycardia can identify patients at high risk of death in cirrhotic patients following LT, suggesting that further study will be need to clarify relationship between HR burden and sympathetic cardiac neuropathy. PMID- 28583535 TI - Liver Transplantation for Mitochondrial Respiratory Chain Disorder: A Single Center Experience and Excellent Marker of Differential Diagnosis. AB - Mitochondrial respiratory chain disorder (MRCD) can cause liver failure requiring liver transplantation (LT), although it is often difficult to diagnose before LT. From 2005 to 2016, 9 MRCD patients with the median age at LT of 6 months underwent LT in our institute. Their clinical courses were retrospectively reviewed and the laboratory parameters were compared between the MRCD patients and 10 patients with acute liver failure unrelated to MRCD (non-MRCD). Five patients had extrahepatic manifestations, including developmental disorders in 3 and failure to thrive in 3, before LT. Only 3 patients (33.3%) were diagnosed before LT. Between MRCD and non-MRCD, lactate was significantly high and lactate to-pyruvate ratio (L/P ratio) tended to be higher in MRCD. From the receiver operating characteristic curve, the optimal cutoff value of lactate was 50.0 mg/dL and that of L/P ratio was 23.2. Patient survival rate of MRCD was 77.8%, although 2 patients with mitochondrial depletion syndrome suffered from de novo pulmonary hypertension after LT. Our experiences showed the difficulty of preoperative diagnosis, and preoperative extrahepatic manifestations did not always mean poor outcome. Our study showed that lactate value and L/P ratio can be excellent predictors of MRCD. PMID- 28583536 TI - Primary Living-donor Liver Transplantation Is Not the Optimal Treatment Choice in Patients With Early Hepatocellular Carcinoma With Poor Tumor Biology. AB - OBJECTIVE: Liver resection (LR) and living-donor liver transplantation (LDLT) are considered the two potentially curative treatments for hepatocellular carcinoma (HCC). The aim of this study was to investigate whether there is a difference in the oncologic outcomes between LR and LDLT according to tumor biology. METHODS: Patients (137 LDLTs and 199 LRs) were stratified into four groups by tumor biology according to the number of risk factors for recurrence (preoperative alpha-fetoprotein >200 ng/mL, Edmonson grade 3 or 4, tumor size >3 cm, and presence of microvascular invasion). RESULTS: In the favorable tumor biology patients (groups I and II), there was a significantly worse recurrence-free survival rate in those patients who underwent LR compared to those who underwent LDLT (group I, P = .002; group II, P = .001). The overall survival rates in the LR and LDLT groups were not different (group I, P = .798; group II, P = .981). In the poor tumor biology patients (groups III and IV), there was no significant difference between the two groups in terms of recurrence-free survival rate (group III, P = .342; group IV, P = .616). The LDLT group showed a significantly lower overall survival rate (group III, P = .001; group IV, P = .025). CONCLUSIONS: Primary LDLT should not be recommended in early stage HCC patients with poor tumor biology because of lower survival rates and a high chance of HCC recurrence. PMID- 28583537 TI - Usefulness of PIVKA-II After Living-donor Liver Transplantation for Hepatocellular Carcinoma. AB - OBJECTIVE: Prothrombin induced by the absence of vitamin K or antagonist-II (PIVKA-II) is a useful tumor marker for hepatocellular carcinoma (HCC). However, the usefulness of post-transplantation surveillance with PIVKA-II is not clear. We evaluated the clinical value of PIVKA-II in monitoring HCC recurrence after living-donor liver transplantation (LDLT). METHODS: One hundred twenty patients who had undergone LDLT for HCC from February 1999 to December 2010 and whose serum alpha-fetoprotein (AFP) and PIVKA-II had been measured sequentially before and after LDLT were included in this study. Patients were classified into four groups according to the preoperative level of AFP and PIVKA-II (group I, normal AFP and PIVKA-II; group II, elevated AFP; group III, elevated PIVKA-II; and group IV, elevated both AFP and PIVKA-II). RESULTS: Preoperative PIVKA-II level tended to increase with increasing tumor size, number of nodules, presence of microvascular invasion, and poor differentiation. In 27 patients developing recurrent HCC after LDLT, the sensitivity of AFP and PIVKA-II was 59.2% and 88.8%, respectively. When the two markers were combined, the sensitivity increased to 92.5%. Especially, the sensitivity for PIVKA-II was high at groups I and III (100.0% for both, respectively). In patients in groups I, III, and IV, an elevated PIVKA-II level was the most common first sign of HCC recurrence after LDLT. An elevated PIVKA-II level was the most common first sign of recurrence, regardless of recurrence site. CONCLUSIONS: PIVKA-II might be a useful tumor marker in the monitoring of recurrence after LDLT, complementary to AFP. PMID- 28583538 TI - Outcome of Liver Transplantation in Hepatocellular Carcinoma Patients at Siriraj Hospital. AB - BACKGROUND: Liver transplantation (LT) is one of the standard treatments for hepatocellular carcinoma (HCC), and the outcomes have become better after introduction of strict patient selection, such as the Milan criteria. However, several expanded criteria, such as the University of California San Francisco (UCSF) criteria, have demonstrated similar survival outcomes. The aim of this study was to verify survival outcomes of LT for HCC at Siriraj Hospital. METHODS: Sixty-three patients diagnosed with HCC who underwent cadaveric LT at Siriraj Hospital from 2002 to 2011 were included. All patients' characteristics, blood chemistries, size and number of tumors, bridging therapy, and survival and recurrence data were retrospectively reviewed and analyzed. RESULTS: Nearly all (62 patients, 98.4%) fulfilled the Milan criteria based on preoperative imaging. Explant pathology revealed that 40 patients (63.5%) were within Milan criteria and 50 patients (83%) within UCSF criteria. Demographic data, clinical laboratory, and bridging therapy were similar in patients within and outside both Milan and UCSF criteria. The 1-, 3-, and 5-year survival rates of patients within Milan were 85%, 75%, and 67.5%, and of those outside Milan were 69.6%, 52.2%, 52.2%, respectively (P = .25). Interestingly, with the use of the UCSF criteria, the 1-, 3-, and 5-year survival rates of patients within UCSF were significantly better than of those outside UCSF (84%, 76%, and 70% vs 61.5%, 30.8%, and 30.8%, respectively; P = .01). CONCLUSIONS: Outcome of LT in HCC patients within Milan criteria demonstrated good long-term survival. However, providing the opportunity for HCC patients by expanding from Milan to UCSF criteria revealed similar outcomes. PMID- 28583539 TI - Prognostic Factors Predicting Poor Outcome in Living-Donor Liver Transplantation for Fulminant Hepatic Failure. AB - BACKGROUND: Living-donor liver transplantation (LDLT) has been accepted as feasible treatment for fulminant hepatic failure (FHF), although it has generated several debatable issues. In this study, we investigated the prognostic factors predicting fatal outcome after LDLT for FHF. METHODS: From April 1999 to April 2011, 60 patients underwent LT for acute liver failure, including 42 patients for FHF at Samsung Medical Center, Seoul, Korea. Among 42 patients, 30 patients underwent LDLT for FHF, and the database of these patients was analyzed retrospectively to investigate the prognostic factors after LDLT for FHF. RESULTS: Among 30 patients, 7 patients (23%) died during the in-hospital period within 6 months, and 23 patients (77%) survived until recently. In univariate analyses, donor age (>35 years), graft volume (GV)/standard liver volume (SLV) (<50%), cold ischemic time (>120 minutes), hepatic encephalopathy (grade IV), hepato-renal syndrome (HRS), and history of ventilator care were associated with fatal outcome after LDLT for FHF. In multivariate analyses, HRS, GV/SLV (<50%), and donor age (>35 years) were significantly associated with fatal outcome. Although the statistical significance was not shown in this analysis (P = .059), hepatic encephalopathy grade IV also appears to be a risk factor predicting fatal outcome. CONCLUSIONS: The survival of patients with FHF undergoing LDLT was comparable to that in published data. In this study, HRS, GV/SLV <50%, and donor age >35 years are the independent poor prognostic factors. PMID- 28583540 TI - Living Donor Liver Transplantation for Progressive Familial Intrahepatic Cholestasis Type 1: Two Reported Cases. AB - BACKGROUND: Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited disease characterized by cholestatic features. We report two patients with PFIC1 who underwent liver retransplantation. CASE REPORT: One patient was a 3-year-old female who underwent liver transplantation for PFIC1. She presented with severe diarrhea and fatty liver, and went into liver failure. She therefore underwent liver retransplantation and external biliary diversion 8 years after the initial liver transplantation. The explanted liver was histologically diagnosed with chronic rejection. Her intractable diarrhea stopped after the retransplantation. She was diagnosed with a fatty liver 8 months after the retransplantation and died 4 years after retransplantation due to bleeding from an ileostomy. The other patient was a 3-year-old male. This patient underwent liver retransplantation due to liver cirrhosis caused by steatohepatitis 9 years after the initial liver transplantation. The biliary tract was not diverted. He also experienced severe diarrhea after the retransplantation and requires home parenteral nutrition due to an eating disorder. CONCLUSIONS: Liver transplantation is the only treatment to resolve life-threatening issues due to PFIC1, but requires further improvement as a therapeutic modality. PMID- 28583541 TI - Comparative Analysis of the Clinical Outcomes of Liver Transplantation for Probable and Definite Auto-immune Hepatitis by International Diagnostic Scoring Criteria. AB - BACKGROUND: Liver transplantation (LT) is an effective treatment for patients with end-stage liver disease caused by auto-immune hepatitis (AIH). However, diagnosis of AIH can be challenging for patients with end-stage liver disease at the time of transplantation. We classified patients into "probable" or "definite" AIH groups, using the diagnostic criteria of the International Autoimmune Hepatitis Group, and compared the clinical outcomes of AIH after LT in these 2 groups. METHODS: We performed a retrospective study of 18 patients who were diagnosed with AIH and underwent LT from March 2003 to March 2015 at a single institute. Of the 18 patients, 8 were diagnosed with definite AIH and 10 were diagnosed with probable AIH, according to the international scoring criteria. We evaluated the patient characteristics, recurrence rate, graft loss, and survival rates after LT. RESULTS: The mean follow-up duration was 59.3 months. Age, sex, medical condition at transplantation, warm ischemic time, cold ischemic time, and Model for End-Stage Liver Disease score did not differ significantly between the 2 groups. No patient died after LT in either group, but 1 patient in the definite AIH group had graft failure. In Kaplan-Meier analysis, the 5-year recurrence rates of the definite and probable groups were 14.3% and 0%, respectively (P = .992). CONCLUSIONS: The recurrence of definite AIH appeared to be higher than that of probable AIH. However, careful immunosuppressive therapy allowed the long term survival of both definite and probable AIH patients after LT. PMID- 28583542 TI - Splenectomy for Severe Intestinal Bleeding Caused by Portal Hypertensive Enteropathy After Pediatric Living-Donor Liver Transplantation: A Report of Three Cases. AB - BACKGROUND: The incidence of portal vein thrombosis after pediatric living-donor liver transplantation (LDLT) is reported to be higher than that after deceased donor or adult liver transplantation. Portal vein thrombosis can cause portal hypertension and related complications, including portal hypertensive gastropathy or portal hypertensive enteropathy (PHE). PHE, in particular, can lead to severe intestinal bleeding, which is extremely difficult to treat. However, the pathogenesis of and appropriate treatment for PHE are not clearly defined, especially after pediatric LDLT. METHODS: Herein, we report three cases of refractory intestinal bleeding caused by PHE after pediatric LDLT, which were treated with splenectomy. RESULTS: The time between LDLT and splenectomy was 43, 92, and 161 months, respectively. All 3 patients were discharged from the hospital without any peri-operative complications and were doing well, with no adverse effects at 174, 81, and 12 months after splenectomy, respectively. Although shunt surgeries, including the use of a meso-Rex shunt, are reported to be a useful option when the portal vein is completely occluded, adhesiotomy around the liver graft would be required, which could damage the hepatopetal collateral vessels that maintain portal vein flow to the graft. Therefore, shunt surgeries, which can lead to re-transplantation, are considered to be highly risky as a first-line treatment option, particularly considering the limited accessibility to deceased donor organs in our country. CONCLUSIONS: Our data demonstrate that simple splenectomy, although considered a palliative treatment, can be a safe and effective method to control severe intestinal bleeding caused by PHE after pediatric LDLT. PMID- 28583543 TI - Laparoscopy-Assisted Spleen-Preserving Distal Pancreatectomy for Living-Donor Pancreas Transplantation. AB - BACKGROUND: Living pancreas transplantation plays an important role in the treatment of patients with severe type 1 diabetes. However, pancreatectomy is very invasive for the donor, and less-invasive surgical procedures are needed. Although some reports have described hand-assisted laparoscopic surgery for distal pancreatectomy in living-donor operations, less-invasive laparoscopy assisted (LA) procedures are expected to increase the donor pool. We herein report the outcomes of four cases of LA spleen-preserving distal pancreatectomy (Warshaw technique [WT]) in living pancreas donors. PATIENTS AND METHODS: Four living pancreas donors underwent LA-WT at our institution from September 2010 to January 2013. All donors fulfilled the donor criteria established by the Japan Society for Pancreas and Islet Transplantation. RESULTS: The median donor age was 54 years. Two donors underwent left nephrectomy in addition to LA-WT for simultaneous pancreas-kidney transplantation. The median donor operation time for pancreatectomy was 340.5 minutes. The median pancreas warm ischemic time was 3 minutes. The median donor blood loss was 246 g. All recipients immediately achieved insulin independence. One donor required reoperation because of obstructive ileus resulting from a port-site hernia. Another donor developed a pancreatic fistula (International Study Group of Pancreatic Fistula grade B), which was controlled with conservative management. After a maximum follow-up of 73 months, no clinically relevant adverse events had occurred. These results were comparable with those of previous studies concerning living-donor pancreas transplantation. CONCLUSION: The LA-WT is a safe and acceptable operation for living-donor pancreas transplantation. PMID- 28583544 TI - Experiences of Living Donors for Small Bowel Transplantation. AB - INTRODUCTION: Along with developments in surgical and immunosuppression techniques, the success rate of small bowel transplantation has increased. In Korea, the incidence of small bowel transplantations has increased, and the longest surviving living donor recipient has now survived for over 12 years postsurgery. The purpose of this study was to assess the experiences of living donors for small bowel transplantation before, during, and after the transplantation. METHODS: In one hospital, we conducted interviews, based on open ended questions, with three small bowel donors. We asked them about experiences during small bowel donation. The living donor's statements were analyzed using interpretive phenomenological analysis. RESULTS: Donors decided to donate because they felt "sorry for the suffering of a family member" and they had "faith in the medical staff." In the early phase after donation, living donors experienced physical changes in their body, including pain, fatigue, altered bowel habits, and abdominal discomfort. Despite temporary limitations in daily and social activities, support from family members allowed the donors to fully recover and return to normal physical, social, and psychological status. The donors mentioned they experienced love and support from their family, as well as satisfaction and pride from donation, during the entire process. CONCLUSION: We hope that the physical, psychological, and social experience of living donors during small bowel transplantation deduced in this study will serve as a foundation for the establishment of an intervention method to provide education before donation and help recovery after donation. PMID- 28583545 TI - Simultaneous Subtotal Pancreatectomy and Streptozotocin Injection for Diabetes Modeling in Cynomolgus Monkeys. AB - BACKGROUND: In an experimental animal model of islet transplantation, stable induction of insulin-dependent diabetes mellitus (IDDM) and islet isolation from donor pancreas are essential. Total pancreatectomy for IDDM induction and islet procurement in nonhuman primates leads to unwanted loss of exocrine function and may lead to morbidities associated with IDDM. METHODS: IDDM induction with streptozotocin (STZ) is associated with drug toxicity of STZ and necessitates the killing of another animal for islet procurement. In this study, we performed a subtotal pancreatectomy combined with reduced STZ injection to induce IDDM and procure islets in a nonhuman primate model. RESULTS: Twelve cynomolgus monkeys received low-dose STZ injections (60 mg/kg) simultaneously with subtotal pancreatectomy. All monkeys recovered from the procedure without complications. IDDM was induced in the animals. 57,691 +/- 16,050 islets were isolated from the resected pancreas and transplanted into other monkeys. CONCLUSIONS: Simultaneous subtotal pancreatectomy and low-dose STZ injection represent an effective and safe method to create an animal model of insulin dependence diabetes, while at the same time providing sufficient amounts of fresh islet cells for allotransplantation without requiring killing of additional animals. PMID- 28583546 TI - Surgical Techniques of Allogeneic Liver Transplantation in a Nonhuman Primate Model. AB - Herein, we report our experience of performing allogeneic orthotopic liver transplantation (LT) in nonhuman primates. We designed an allogeneic ABO compatible orthotopic LT model in monkeys in a manner similar to that used in humans. We applied almost the same surgical procedures used for human conventional deceased donor LT. A total of 6 monkeys underwent allogeneic LT. One cynomolgus monkey aged 45 months (3.4 kg) and 5 rhesus macaque monkeys aged 50.2 +/- 14.8 months (5.40 +/- 0.33 kg) were used as recipients. In the donor surgery, the liver was perfused in situ through the aorta using cold histidine-tryptophan ketoglutarate solution. The portal vein (diameter, 5-10 mm), supra- and infra hepatic inferior vena cava (IVC) (diameter, 12-15 mm), and common bile duct (diameter, 1.5-3.0 mm) were dissected out. The hepatic artery was kept in continuity with the celiac trunk and abdominal aorta up to the iliac bifurcation (diameter, 5-6 mm). The mean graft weight was 102.0 g (94.8-111.0 g). Recipient surgery was conducted in parallel. After recipient hepatectomy, the graft was implanted. The suprahepatic IVC and portal vein were anastomosed to those of the graft. After reperfusion, the infrahepatic IVC was anastomosed. The aorta conduit of the graft was anastomosed to the infrarenal aorta of the recipient in a retrocolic end-to-side manner. Biliary reconstruction was performed in a duct-to duct anastomosis with cholecystectomy. Mean operative time was 107.0 minutes for donor and 198.2 minutes for recipient. There was one operative death due to unknown cause. In conclusion, for allogeneic orthotopic LT in nonhuman primate model, we can apply almost the same procedure used for human conventional deceased donor LT in a similar manner. PMID- 28583547 TI - Major Histocompatibilty Complex-Restricted Adaptive Immune Responses to CT26 Colon Cancer Cell Line in Mixed Allogeneic Chimera. AB - BACKGROUND: Although the induction of mixed allogeneic chimera shows promising clinical tolerance results in organ transplantation, its clinical relevance as an anti-cancer therapy is yet unknown. We introduced a mixed allogenic chimera setting with the use of a murine colon cancer cell line, CT26, by performing double bone marrow transplantation. METHODS: We analyzed donor- and recipient restricted anti-cancer T-cell responses, and phenotypes of subpopulations of T cells. The protocol involves challenging 1 * 105 cells of CT26 cells intra hepatically on day 50 after bone marrow transplantation, and, by use of CT26 lysates and an H-2Ld-restricted AH1 pentamer, flow cytometric analysis was performed to detect the generation of cancer-specific CD4+ and CD8+ T cells at various time points. RESULTS: We found that immunocompetence against tumors depends heavily on cancer-specific CD8+ T-cell responses in a major histocompatibility complex-restricted manner; the evidence was further supported by the increase of interferon-gamma-secreting CD4+ T cells. Moreover, we demonstrated that during the effector immune response to CT26 cancer challenge, there was a presence of central memory cells (CD62LhiCCR7+) as well as effector memory cells (CD62LloCCR7-). Moreover, mixed allogeneic chimeras (BALB/c to C56BL/6 or vice versa) showed similar or heightened immune responses to CT26 cells compared with that of wild-type mice. CONCLUSIONS: Our results suggest that the responses of primary immunocompetency and of pre-existing memory T cells against allogeneic cancer are sustained and preserved long-term in a mixed allogeneic chimeric environment. PMID- 28583548 TI - Impact of Steroids on Natural Killer Cells Against Cytotoxicity and Hepatitis C Virus Replication. AB - BACKGROUND: Natural killer (NK) cells play important roles in killing tumor and virus-infected cells. Immunosuppression used after organ transplantation is thought to increase the risk of tumor recurrence and viral infections. However, the effect of immunosuppressive drugs on NK cells has not yet been clearly established. Therefore, we examined the effect of immunosuppression on NK cells. METHODS: NK cells were cultured for 7 days in the presence of interleukin-2 (100 U/mL) with or without the following immunosuppressive drugs: tacrolimus, cyclosporine A, corticosteroid (methylprednisolone [MP]), mycophenolate mofetil, and rapamycin. The effect of the drugs on NK cell activation was tested on the basis of the following: NK cell phenotype, NK cell proliferation, cytotoxicity against K562 cells, cytokine production by NK cells, and anti-hepatitis C virus (HCV) activity with HCV genomic replicon cells. RESULTS: NK cells showed relatively robust functions in the presence of tacrolimus and cyclosporine A. Mycophenolate mofetil and rapamycin significantly prevented only NK cell proliferation (P < .05). In contrast, MP significantly inhibited the proliferation, cytotoxicity, and anti-HCV effect (10.9%, 18.5%, and 1.9%, respectively) of NK cells. Furthermore, MP specifically inhibited the expression of NK cell activation markers and the production of interferon-gamma (P < .05). CONCLUSIONS: Corticosteroids have distinct effects on NK cells, which may have important implications for NK cell function in cytotoxicity and HCV effect after transplantation. PMID- 28583549 TI - Reduction of Slit Diaphragm-associated Molecules by Sirolimus: Is it Enough to Induce Proteinuria? AB - Sirolimus (SRL), a mammalian target of rapamycin inhibitor, is widely used in transplantation, but the mechanisms whereby it induces adverse effects, such as proteinuria and edema, remain unclear. To determine whether isolated SRL induces proteinuria or not, the authors intraperitoneally injected C57BL/6 mice with different doses of SRL (0 mg/[kg.d], 3 mg/[kg.d], 10 mg/[kg.d], or 30 mg/[kg.d]) for 24 days. Urinary albumin excretion was then quantified using a double sandwich enzyme-linked immunosorbent assay, and serum creatinine levels were measured using a single dry-film chemistry auto-analyzer. The mRNA expression levels of various genes were also measured by polymerase chain reaction. Urinary albumin was not detected in the SRL-treated mice, but serum creatinine levels were found to increase dose-dependently and were significantly higher in the animals treated with 30 mg/kg of SRL than in untreated controls. Glomerular mRNA expression profiling showed down-regulations of podocyte-related genes (Wilms tumor 1, synaptopodin, nephrin, CD2-associated protein, and podocin) and of transforming growth factor-beta (a marker of fibrosis) in sirolimus-treated mice. In addition, expressions of the antiapoptotic genes Bcl-2 and Bcl-xL were also down-regulated. Furthermore, the protein levels of these genes in mice kidney were also decreased by sirolimus. Although sirolimus treatment reduced the expressions of slit diaphragm-associated molecules and increased serum creatinine levels, it failed to induce proteinuria. Our findings indicate that proteinuria is not induced by isolated SRL treatment. Further studies are required to identify conditions in which sirolimus induces proteinuria. PMID- 28583550 TI - Liver-Wrapping, Nitric Oxide-Releasing Nanofiber Downregulates Cleaved Caspase-3 and Bax Expression on Rat Hepatic Ischemia-Reperfusion Injury. AB - BACKGROUND: Hepatic ischemia-reperfusion injury (IRI) is an important determinant of the outcome of hepatic surgery, including re-section and transplantation. Previous studies have shown that nitric oxide (NO) has a protective effect against IRI. Therefore, many studies have examined methods for supplying NO. In this study, we investigated the effect of NO-releasing nanofibers on hepatic IRI in a rat model. METHODS: Male Sprague-Dawley rats were divided into 4 groups: control, IRI only (n = 3); group 1, hepatic IRI and liver-wrapping with nanofiber lacking NO (n = 4); group 2, hepatic IRI and liver-wrapping with NO rapid releasing nanofiber (n = 4); and group 3, hepatic IRI and liver-wrapping with NO slow-releasing nanofiber (n = 5). RESULTS: The levels of aspartate aminotransferase and alanine aminotransferase were not significantly different between groups. On the basis of Western blots, Bax/beta-actin levels were significantly lower in group 2 than in group 3 (P < .01). Cleaved Caspase-3/beta actin levels were significantly lower in group 2 than in the control, group 1, and group 3 (P < .05, .01, and .01, respectively). However, there were no significant differences in Bcl-2/beta-actin between groups. CONCLUSIONS: The liver-wrapping NO rapid-releasing nanofiber downregulated cleaved Caspase-3 and Bax expression. It has a protective effect by reducing apoptosis in hepatic IRI in rats. PMID- 28583551 TI - Renoprotective Effects of Carbon Monoxide-Releasing Molecule 3 in Ischemia Reperfusion Injury and Cisplatin-Induced Toxicity. AB - BACKGROUND: We investigated the effects of a soluble carbon monoxide-releasing molecule (CORM) in cisplatin-induced cytotoxicity and ischemia-reperfusion injury (IRI) in vitro. METHODS: The effects of CORM-3 (12.5-200 MUM) were assessed in normal kidney epithelial cells (HK-2, LLC-PK1) and renal cancer cells (Caki-1, Caki-2) subjected to cisplatin (50-200 MUM) or IRI. To induce IRI, cells were placed in an anaerobic chamber (37 degrees C, 95% nitrogen, 5% carbon dioxide) for 48 hours. Cells were transferred to complete medium and incubated at 37 degrees C, 5% carbon dioxide for 6 hours. Cell viability (CCK assays), tumor necrosis factor (TNF)-alpha messenger RNA (mRNA) levels (quantitative reverse transcriptase polymerase chain reaction), and protein expression of cleaved caspase 3 and oxidative stress markers (including Erk1/2, JNK, and P38; Western blot) were assessed. RESULTS: Viability after IRI was approximately 40% of control. Protective effects of CORM-3 in the IRI model were dose-dependent. Cell viability was 40% recovered in 200-MUM CORM-3-pretreated cells compared with control. The protective effects of CORM-3 in cells exposed to cisplatin for 24 hours were weaker than in the IRI model. TNF-alpha mRNA was induced by stimulated IRI or cisplatin exposure; CORM-3 pretreatment attenuated the rise in TNF-alpha mRNA. IRI or cisplatin-induced activated oxidative stress markers decreased in CORM-3-pretreated cells. CORM-3 reduced expression of the apoptotic marker cleaved-caspase 3. CONCLUSION: Our data demonstrate the protective effects of CORM-3 in cisplatin cytotoxicity and IRI in both normal kidney cells and renal cancer cells in vitro. CORM-3 exerts these effects by ameliorating inflammatory and oxidative stress pathways. PMID- 28583552 TI - Living Kidney Donation From a Donor With Pulmonary Sarcoidosis: A Case Report and Review of the Literature. AB - BACKGROUND: Sarcoidosis is a chronic systemic disease that is characterized by the formation of noncaseating granuloma and whose etiology is unclear. It is unclear whether patients with sarcoidosis are suitable organ donors. CASE: We treated a 56-year-old woman with pulmonary sarcoidosis who donated her kidney. She was previously in good health and was diagnosed with pulmonary sarcoidosis during her preoperative examination. Because she presented with no symptoms and was otherwise in good condition, donor nephrectomy was performed. RESULTS: Baseline biopsy examination showed no evidence of sarcoidosis. One year after transplantation, both the donor and the recipient had not developed kidney dysfunction or recurrence of sarcoidosis. CONCLUSION: This is a rare case in which a patient with pulmonary sarcoidosis donated a kidney for transplantation, and both the recipient and the donor were clinically healthy. A patient with sarcoidosis and no kidney lesion can donate a living kidney, because transplantation appears to be safe for both the recipient and the donor. PMID- 28583553 TI - Living Donor Kidney Transplantation After Brachytherapy for Prostate Cancer: Case Report. AB - INTRODUCTION: There is no obvious criterion about kidney transplantation for patients with pretransplant malignancy. Minimum tumor-free waiting periods differ according to type of cancer, staging, site of occurrence, response to therapy, and risk of cancer recurrence. We report a case of living donor kidney transplantation (LDKT) in a patient after brachytherapy for prostate cancer. CASE REPORT: The patient was a 65-year-old man with chronic kidney disease due to chronic glomerular nephritis. He received hemodialysis 3 times a week. His prostate-specific antigen level (PSA) was high (6.57 ng/mL), and he was diagnosed with prostate cancer (T1cN0M0, Gleason Score 3 + 4 = 7, 3/10) by needle biopsy in urology. He was treated with maximum androgen blockade (MAB) therapy and brachytherapy in May 2014. He underwent LDKT from a spousal donor at our department in December 2015, because urologists concluded that the prostate cancer was completely cured. Immunosuppression consisted of induction with basiliximab and maintenance with tacrolimus, mizoribine, and steroids. The postoperative course was uneventful. He discharged at postoperative day 29 with a serum creatinine level of 1.30 mg/dL. Three months after LDKT, his PSA level was 0.477 ng/mL, and there was no evidence of prostate cancer recurrence. CONCLUSION: This is the first case of LDKT for patients with prostate cancer after brachytherapy in combination with MAB. There is no recurrence of prostate cancer so far; however, careful follow-up including PSA is necessary and important. PMID- 28583554 TI - Enterobacter cloacae-Related Necrotizing Fasciitis After Peritoneal Dialysis in Delayed Graft Function: A Case Report. AB - INTRODUCTION: Necrotizing fasciitis is an uncommon soft-tissue infection that involves the superficial fascia, subcutaneous fat, and deep fascia. Herein, we report the first case of Enterobacter cloacae-related necrotizing fasciitis after peritoneal dialysis in delayed graft function. CASE: A 58-year-old man, who was a hepatitis B-viral carrier and had atrial fibrillation, received cadaveric renal transplantation with peritoneal dialysis and encountered delayed graft function. On postoperative day 5, we tried hemodialysis via the right jugular dialysis catheter. However, he was unable to endure the hemodynamic changes during hemodialysis, showing rapid ventricular rhythm on electrocardiography. On postoperative day 7, we changed to peritoneal dialysis. However, he presented with fever and pain on his left flank and lower extremity. His white blood cell count and C-reactive protein levels were suddenly elevated. According to the abdomen computed tomography scan, there were subcutaneous fluid and air in the left flank and anterolateral pelvic wall. We performed peritoneal dialysis catheter removal, debridement, and drainage of the left external oblique muscle fascia. In a culture, Enterobacter cloacae was identified. After receiving meropenem for 2 months, his wound healed and delayed graft function was recovered. CONCLUSION: Peritoneal dialysis of delayed graft function seems to be effective in reducing the incidence and severity of delayed recovery of renal function after renal transplantation in some reports. However, it is necessary to be cautious when dealing with a rapidly developing and life-threatening soft tissue infection, such as necrotizing fasciitis. To reduce mortality rates, early diagnosis, recurrent surgical debridement, and aggressive therapy are mandatory. PMID- 28583555 TI - Veno-Arterial-Venous Hybrid Mode of Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome Combined With Septic Shock in a Liver Transplant Patient: A Case Report. AB - BACKGROUND: Post-operative respiratory failure is common in liver transplant patients, with a direct effect on graft and recipient outcomes. We present a case of successful treatment for a patient who had acute respiratory distress syndrome combined with septic shock after living-donor liver transplantation with veno arterial-venous hybrid mode of extracorporeal membrane oxygenation (ECMO) support. METHODS: A 49-year-old male patient underwent successful emergency living-donor liver transplantation for acute-on-chronic liver failure associated with alcoholic liver cirrhosis. The patient was diagnosed with concurrent active pulmonary tuberculosis and tuberculosis peritonitis just before emergency liver transplantation. Intermittent post-operative small-bowel obstruction caused by adhesions from tuberculosis peritonitis was nonresponsive to conservative management. RESULTS: On post-operative day 114, we performed emergency adhesio lysis because of bowel ischemia signs. However, the patient had progressive deterioration of arterial oxygenation despite conventional ventilatory support and nitric oxide gas inhalation, and septic shock resulted from aspiration pneumonia. Therefore, we decided to administer ECMO. After initiation of ECMO support, hemodynamic status, pneumonic consolidation, and oxygenation status gradually improved, and the patient was weaned from ECMO on the 11th day. Finally, the patient was discharged on post-transplant day 204. CONCLUSIONS: ECMO can be a beneficial rescue option for the management of refractory cardiopulmonary failure in liver transplant recipients. In addition, the hybrid mode of ECMO is a helpful salvage option when conventional modes of ECMO are inadequate. PMID- 28583556 TI - Duct-to-duct Biliary Reconstruction in Living-donor Liver Transplantation for Primary Sclerosing Cholangitis: Report of a Case. AB - Although Roux-en Y hepaticojejunostomy was previously recommended for the biliary reconstruction in liver transplantation for primary sclerosing cholangitis (PSC), some recent reports showed no difference in the graft survival between Roux-en Y and duct-to-duct anastomosis in deceased-donor liver transplantation. On the other hand, considering the risk of recurrence and the short length of the bile duct of the graft, duct-to-duct biliary anastomosis has never been reported in a patient undergoing living-donor liver transplantation (LDLT) for PSC. A 45 year old male underwent LDLT using a left-lobe graft donated from his brother. Cholangiography showed no lesion in his common bile duct and duct-to-duct anastomosis was chosen for him. Fifteen months later, he suffered cholangitis due to PSC recurrence and endoscopic retrograde cholangiography was performed. The stents were inserted into his B2 and B3, and he remains well. Because of the ability to easily manage biliary complication, duct-to-duct biliary reconstruction may become the first choice in LDLT for PSC without common bile duct lesions. PMID- 28583557 TI - In Situ Posterior Graft Segmentectomy for Large-for-Size Syndrome in Deceased Donor Liver Transplantation in Adults: A Case Report. AB - Large-for-size syndrome (LFSS) is controversial in pediatric living donor liver transplantation patients and is associated with a poor graft outcome. Similar situations in deceased donor liver transplantation (DDLT) in adults have not been reported frequently, and there are no official guidelines worldwide. Deceased donation is extremely limited in Japan, and when a larger liver is allocated for a very sick small recipient in Japan, transplantation with a plan to address LFSS might be necessary. The patient is a 58-year-old female patient who had acute liver failure with coma. The graft-recipient weight ratio (GRWR) was 2.74%. Although the graft was enlarged by reperfusion, the intraoperative Doppler ultrasound, performed after reperfusion, showed sufficient graft in-flow and out flow. However, when the liver graft was situated appropriately into the right phrenic space supported by the rib cage and diaphragm, the blood flow in the hepatic vein and portal vein was significantly reduced. Graft blood flow did not improve without removing it from the right subphrenic space. Therefore, we decided to perform an in situ graft posterior segmentectomy, so that the graft right lobe was properly accommodated in the patient's right subphrenic space. After the segmentectomy of the graft, an intraoperative Doppler sonogram showed significantly improved blood flow. LFSS could be a significant operative challenge in adult DDLT, especially in areas with limited chances of DDLT. In situ posterior segmentectomy in the demarcated area could be a solution for treating patients with LFSS. PMID- 28583559 TI - Preface. PMID- 28583558 TI - Successful Treatment of a Patient With Diffuse Portosplenomesenteric Thrombosis Using a Pericholedochal Varix for Portal Flow Reconstruction During Deceased Donor Liver Transplantation: A Case Report. AB - Portal vein thrombosis remains a challenging issue in liver transplantation. When thrombectomy is not feasible due to diffuse portosplenomesenteric thrombosis, other modalities are adapted such as the use of a jump graft or portal tributaries or even multivisceral transplantation. For patients with diffuse thrombosis of the splanchnic venous system, a large pericholedochal varix can be a useful vessel for providing splanchnic blood flow to the graft and for relieving portal hypertension. We report our experience of successfully treating a patient with diffuse portosplenomesenteric thrombosis using a pericholedochal varix for portal flow reconstruction during deceased donor liver transplantation and eventually preventing unnecessary multivisceral transplantation. A 56-year old man diagnosed with liver cirrhosis due to hepatitis B underwent deceased donor liver transplantation due to refractory ascites. Preoperative imaging revealed diffuse portosplenomesenteric thrombosis with large amount of ascites. During the operation, dissection of the main portal vein was not possible due to the development of multiple large pericholedochal varices and cavernous change of the main portal vein. After outflow reconstruction, portal inflow was restored by anastomosing the graft portal vein to a large pericholedochal varix. Postoperatively, although abdominal computed tomography scan showed stenosis of portal vein anastomosis site, liver function tests improved, and Doppler sonogram revealed no flow disturbance. During follow-up, the patient repeatedly developed hydrothorax and ascites. In addition, stenosis of the portal vein anastomosis and thrombosis of the portomesenteric system still remained. The patient underwent transhepatic portal vein stent insertion. After portal vein stent insertion, hydrothorax and ascites improved and the extent of thrombosis of the portomesenteric system decreased without anticoagulation therapy. In conclusion, enlarged pericholedochal varix in patients with totally obliterated splanchnic veins can be a source of useful inflow to restore portal flow and decrease the extent of thrombosis, thereby preventing unnecessary multivisceral transplantation. PMID- 28583560 TI - Selection Criteria for Kidney Laterality in Retroperitoneoscopic Living Donor Nephrectomy and the Usefulness of Pretransplant Intervention. AB - OBJECTIVES: To evaluate the selection criteria for kidney laterality and the usefulness of pretransplant intervention in living donor nephrectomy. METHODS: We compared conventional and revised criteria. The conventional criteria were that left kidneys were chosen in preference and provided the kidney with the fewest structural abnormalities and lowest functional decline and that most renal arteries remained in the donor. From April 2013, we allowed the use of left kidneys with double renal arteries. Patient characteristics and surgical outcomes were retrospectively compared between right and left retroperitoneoscopic living donor nephrectomies. RESULTS: We compared data for 30 right kidney and 222 left kidney nephrectomies. Right kidneys were selected because of multiple renal arteries (n = 18), structural abnormalities (n = 10) of the left kidney, or functional decline (n = 2) of the right kidney. Right retroperitoneoscopic nephrectomies were associated with significantly longer operating times (267 minutes vs 241 minutes), larger blood losses (240 g vs 55 g), and higher open conversion rates (10% vs 0.9%). Pretransplant intervention was necessary for structural abnormalities in right kidneys, but the amended selection criteria resulted in fewer right nephrectomies. Pretransplant intervention was still necessary by ex vivo arterial anastomosis for multiple left renal arteries, which increased the total ischemia time (94 minutes vs 64 minutes); however, post transplantation renal function was not significantly different. CONCLUSIONS: Pretransplant intervention was beneficial both for repairing structural abnormalities and for reducing the difficulties of retroperitoneoscopic living donor nephrectomy. PMID- 28583561 TI - Investigating Serum Uric Acid as a Risk Factor in the Development of Delayed Renal Recovery in Living Kidney Donors. AB - BACKGROUND: Hyperuricemia has been associated with kidney disease and remains controversial with regard to its gender-specific differences and impact in living kidney donation. METHODS: Between 2006 and 2015, charts of live kidney donors who underwent nephrectomy and had a minimum follow-up of 1 year were reviewed. A total of 291 donors were included and divided based on gender-specific pre donation serum uric acid (SUA) tertiles. Renal functional outcomes included were estimated glomerular filtration rate (eGFR) at 6-month and 1-year follow-up and percentage of donors with a 1-year eGFR <60 mL/min/1.72 m2. Logistic regression analysis was done. RESULTS: Mean SUA tertiles were 5.8 +/- 1.1 mg/dL in males and 4.1 +/- 1 mg/dL in females. Females in the highest tertile (SUA >4.5 mg/dL) had lower 6-month (59.9 +/- 10.3 vs 66.9 +/- 14.1 vs 67.3 +/- 12.1; P = .018) and 1 year (60.8 +/- 10.6 vs 67.6 +/- 10.8 vs 67.8 +/- 11.8; P = .021) eGFR and a higher percentage of donors with 1-year eGFR <60 mL/min/1.73 m2 (59.5% vs 31.6% vs 23%; P = .002) compared with donors in the lower SUA tertiles (<=4.5 mg/dL). In males, there were similar eGFRs among SUA tertiles at 6-month and 1-year follow-up. In multivariate analysis, SUA was shown to be a significant predictor of developing stage 3 CKD (eGFR <60 mL/min/1.72 m2), 1 year after donation in females but not in males. CONCLUSIONS: Predonation SUA level is associated with the development of delayed renal recovery (GFR <60 mL/min/1.72 m2) 1 year after donation in females but not in males. PMID- 28583562 TI - Clinical Investigation Into Plasma Neutrophil Gelatinase-Associated Lipocalin and Body Adipose Tissue Associated With Remaining Renal Function in Living Kidney Donor. AB - OBJECTIVE: Plasma neutrophil gelatinase-associated lipocalin (pNGAL) is known to increase in proportion to the degree and period of renal damage. This study aimed to evaluate the clinical relevance of pNGAL and body adipose tissue to remaining renal function in living kidney donors. METHODS: Between July 2013 and February 2015, 75 live kidney donors were enrolled. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and VAT/SAT ratio were measured in preoperative CT scan which performed before surgery. We analyzed the correlation among the variables (VAT, SAT, and VAT/SAT ratio), eGFR and pNGAL. DeltapNGAL-max(=Maximum pNGAL-measures), DeltapNGAL-min(=Minimum pNGAL-measures), DeltaeGFR-max(=Maximum eGFR-measures) and DeltaeGFR-min(=Minimum eGFR-measures) were also analyzed. RESULTS: The highest value of pNGAL (207.46 +/- 76 ng/mL) was observed on postoperative day 7, and the lowest value of eGFR (57.52 +/- 11.20 mL/min/1.73 m2) was also measured on postoperative day 7. A significant correlation was found between DeltapNGAL, VAT, and VAT-to-SAT ratio. Moreover, a significant correlation between DeltapNGALmin and DeltaeGFRmin was revealed. Also, VAT-to-SAT ratio was correlated with DeltaeGFRmin during the all of the follow-up periods, and it was also correlated with DeltapNGALmin until postoperative day 3. CONCLUSION: There was a correlation between the elevation of pNGAL until postoperative day 5 and the decrease of eGFR after living donor nephrectomy. VAT to-SAT ratio had a significant correlation with both DeltapNGALmin and eGFRmin. Given the metabolism of pNGAL, the increase of pNGAL seemed to be affected as a consequence of body adipose tissue. PMID- 28583563 TI - Impact of the Ratio of Visceral to Subcutaneous Adipose Tissue in Donor Nephrectomy Patients. AB - OBJECTIVE: It was reported that a metabolic syndrome affected the remaining renal function after living donor nephrectomy. However, the measurement of waist circumference is unclear because it cannot distinguish between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). We investigate the clinical correlation between body adipose tissue and renal function recovery after living donor nephrectomy. METHODS: From July 2013 to February 2015, 75 living kidney donors were enrolled. The VAT and SAT were measured by preoperative computed tomography (CT) scan. Body mass index (BMI), VAT, SAT, and VAT-to-SAT ratio were analyzed according to a postoperative renal function recovery. Receiver operating characteristic (ROC) was performed to predict estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 at postoperative 6 months for BMI, VAT, SAT, and VAT-to-SAT ratio. RESULTS: The lowest value of eGFR (57.52 +/- 11.20 mL/min/1.73 m2) was measured at postoperative day 7. There was no statistically significant difference in eGFR between 1 month and 3 months. BMI, VAT, SAT, and VAT-to-SAT ratio showed a statistically significant correlation with each other (Pearson correlation, P < .05). Also, the recovery time of eGFR was correlated with VAT-to-SAT ratio; it was significant at postoperative 1, 3, and 6 months. VAT-to-SAT ratio (0.654, 95% confidence interval 0.525-0.783, P = .024) had higher predictive value in ROC. CONCLUSION: We developed a new variable to predict the value of lower eGFR (less than 60 mL/min/1.73 m2) at a postoperative 6 months in living kidney donor. According to a CT scan, VAT-to-SAT ratio can predict renal function recovery. PMID- 28583564 TI - Recognition of Kidney Donation by Living Kidney Donors That Accompanies Changes in the Recipients' Physical Condition: Focusing on Its Influences on Donors. AB - INTRODUCTION: In 2013, a total of 1586 kidney transplants were performed in Japan, and 1431 (90.2%) of the organs were from living donors. The purpose of this study is to illuminate the awareness of living kidney donors toward kidney donation after the condition of the recipient changed, thus clarifying the influence of that recognition on the donor. METHODS: This study design was qualitative descriptive research. Transplant coordinators at 4 hospitals were commissioned to screen subject candidates and hand-deliver printed research explanations to them. Candidates who responded were selected as subjects. I conducted semistructured interviews and analyzed them using the grounded theory approach. This research was approved by the Ethics Research Committee, Faculty of Nursing, Toho University. RESULTS: The survey period was from April to November 2014, and consent was obtained from 5 donors and 5 recipients. The outcome of recipients who received kidneys from the 5 donors was as follows: recovered after temporary worsening (n = 3), early graft loss (n = 1), and early death (n = 1). The core category was "to the donor, the meaning of kidney donation is continually redefined." The donors had a strong interest in the physical condition of the recipient. The 3 changes in the recipients' physical condition, defined as "recovery," "temporary worsening," and "complete deterioration," affected the donor's condition. CONCLUSION: Due to changes in the recipient's physical condition, donors' psychological and physical condition and their definition of the meaning of kidney donation also changed. Health care systems that guarantee lifelong follow-up of the physical and psychological condition of donors after donation are needed. PMID- 28583565 TI - Role of Urinary Neutrophil Gelatinase-Associated Lipocalin for Predicting the Severity of Renal Functions in Patients With Autosomal-Dominant Polycystic Kidney Disease. AB - BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) has a feature of disruption of tubular integrity with increased cellular proliferation and apoptosis. There are several known tubular membrane proteins in the pathogenesis of ADPKD, and one of these proteins is the neutrophil gelatinase-associated lipocalin (NGAL). NGAL is a protein expressed on renal tubular cells of which production is markedly increased in response to harmful stimuli such as ischemia or toxicity. OBJECTIVE: We aim to study whether urinary NGAL levels could be used as a marker to identify the severity of ADPKD in patients. METHODS: Urinary NGAL levels were measured in 30 patients with ADPKD compared with 30 control patients who were matched by age, gender, and glomerular filtration rate (GFR). All patients with ADPKD were diagnosed by using both phenotypic and genotypic criteria, which showed that all cases of ADPKD were caused by PKD1 gene mutation. The urinary NGAL level was measured using The NGAL Test by Roche, with analytic range of 25-1000 ng/mL. RESULTS: In the ADPKD group, there was significant negative correlation between urinary NGAL and GFR (Pearson r = -0.472; P = .008) and significant positive correlation between urinary NGAL and serum creatinine (Pearson r = 0.718; P < .01). Elevated urinary NGAL was increased as GFR of ADPKD patients was decreased. CONCLUSION: Urinary NGAL might play role in the pathway of renal tubular damage in patients with ADPKD and might be useful in the prediction of the possibility to progress to chronic kidney disease in patients with ADPKD. PMID- 28583566 TI - Influences of Pre-formed Donor-Specific Anti-Human Leukocyte Antigen Antibodies in Living-Donor Renal Transplantation: Results With Graft Immunocomplex Capture Fluorescence Analysis. AB - BACKGROUND: Advances in immunosuppressants enable organ transplantation for sensitized patients. However, influences of pre-formed donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) have not been fully understood in renal transplantation (RT). On the other hand, immunocomplex capture fluorescence analysis (ICFA) is a reliable method to detect donor-specific anti-HLA antibodies and HLA antigen complexes. Graft ICFA can detect DSA in an allograft (g-DSA). METHODS: To elucidate the consequences of pre-formed DSA, 198 patients who underwent living-donor RT were enrolled for this study (observation period: 57.8 +/- 34.9 months); 187 patients in the DSA- group (excluding ABO-incompatible cases) and 11 patients in the DSA+ group. Before RT, all DSA+ patients had undergone rituximab administration and plasmapheresis. For a graft ICFA, the biopsy specimen (1 * 105 cells) was dissolved, and HLA antigens were captured by anti-HLA beads. Finally, DSA-HLA complexes were detected by means of PE conjugated anti-human IgG antibodies and analyzed by use of a Luminex system. A ratio (sample/blank beads, mean of fluorescence intensity) was calculated: >=1.0 was determined as positive g-DSA. RESULTS: There were no significant differences in 5-year graft survival (87.9%/100% in the DSA-/DSA+ groups, respectively). In terms of antibody-mediated rejection (AMR), within 1 month after RT, pathologically determined AMR occurred 3.2% and 63.4% in the DSA- and DSA+ groups, respectively (P < .0001). However, interestingly, more than half of them (57.1%) indicated only subclinical AMR, that is, no fluctuation of S-Cr. As representative of 2 cases of subclinical AMR, g-DSA deposition could be confirmed (1.15 +/- 0.04) at 1 hour after reperfusion by graft ICFA. Furthermore, g-DSA shifted to 2.20 +/- 0.98 at 3 weeks after transplantation, along with a decline in s-DSA mean of fluorescence intensity (1718-506.5). CONCLUSIONS: Although pathologically determined AMR occurred more frequently in pre-formed DSA+ recipients, it can be argued that a successful de-sensitization protocol inhibits further production of DSA and graft destruction. PMID- 28583567 TI - Influence of Long-term Dialysis on the Outcome of Kidney Transplantation: A Single-Center Study. AB - AIM: We investigated clinical outcomes of patients in Japan with a history of long-term dialysis treatment. METHODS: We conducted 1171 kidney transplantations between 2000 and 2015. Sixty of the patients had undergone dialysis therapy for >20 years before the transplantation. We compared graft and patient survivals between the recipients with >20 years of dialysis (long dialysis group [LGD]) and those with <20 years (control group [CG]) in a case-control study, in which sex and age of both donors and recipients, ABO compatibility, and calendar year of transplantation were matched. RESULTS: Average age of LDG was 52.8 +/- 8.9 years, and that of CG was 54.2 +/- 12.6 (P > .05). Durations of dialysis were 25.4 +/- 1.57 vs 5.8 +/- 5.8 years, respectively (P < .05). The graft survival rates were 91.6%, 89.9%, and 81.8% at 3, 5, and 10 years in LDG vs 90.71%, 84.8%, and 78.3% in CG, respectively (P > .05). The patient survival rates were 96.6%, 93.2%, and 88.6% in LDG vs 94.5%, 91.0%, and 83.9%, respectively (P > .05). There was no significant difference in mean estimated glomerular filtration rates for post transplant 10 years between them. CONCLUSION: LDG showed satisfying clinical outcomes comparable to those of CG both in graft and patient survivals and renal function. PMID- 28583568 TI - Comparison of Flow-cytometric Antibody Secreting Cell Assay and Mabtech Immunoglobulin ELISpot Assay. AB - BACKGROUND: The increase of donor-specific antibodies (DSA) after transplantation could be a more important marker than the level of DSA in pre-transplantation sera. The assessment of sensitized cells that can secrete DSA is needed. We developed an assay for antibody-secreting cells (ASCs) measured with the use of flow cytometry and compared it with the Mabtech immunoglobulin (IgG) ELISpot assay. METHODS: Thirteen patients who were awaiting or received organ transplantation and 15 healthy control subjects were included. All subjects were positive for anti-cytomegalovirus (CMV) IgG. Peripheral blood mononuclear cells (PBMCs) were seeded with CpG 2006 (5'-TCGTCGTTTTGTCGTTTTGTCGTT-3'), 500 ng/mL human CD40 ligand, and 50 ng/mL interleukin-21 in complete RPMI media. Eight micrograms of CMV pp28 antigen were added to test wells and compared with nonstimulated PBMCs. After 72 hours, analysis with the use of the human IgG ELISpot kit (Mabtech) and flow cytometry with anti-CD19-PE, CD27-PE-Cy7, CD38 APC, IgG-FITC antibodies was performed. RESULTS: The flow-cytometric ASC assay was moderately correlated with Mabtech IgG ELISpot assay (r = 0.554; P < .001). The ASCs measured by means of flow cytometry were significantly higher in healthy control subjects compared with patients (P < .001). ASCs measured by means of flow cytometry in CMV antigen-stimulated PBMCs were significantly higher compared with nonstimulated PBMCs (P < .001). The IgG-secreting cells measured by means of Mabtech ELISpot assay was not different between healthy control subjects and patients nor between CMV antigen-stimulated and nonstimulated PBMCs. CONCLUSIONS: Flow-cytometric ASC assay can differentiate ASCs for CMV antigen better than Mabtech IgG ELISpot assay. Flow-cytometric ASC assay might be useful for assessing sensitization status in patients awaiting organ transplantation. PMID- 28583569 TI - Beneficial Effects of High-Dose Mizoribine on ABO-Incompatible Living-Related Kidney Transplantation: Two-Year Results by a Japanese Multicenter Study. AB - BACKGROUND: Mizoribine (MZ) has been developed as an immunosuppressive agent in Japan, but it has a less-potent immunosuppressive effect up to 3 mg/kg/d. In the previous study, a Japanese multicenter study, we reported that high-dose MZ, at 6 mg/kg/d, with a calcineurin inhibitor was effective and safe in reducing the frequency of cytomegalovirus (CMV)-related events in ABO-incompatible (ABO-i) living-related kidney transplantation (LKT). In the present study, therefore, we investigated the effects of high-dose MZ with a CNI in ABO-i LKT recipients in a Japanese multicenter study. METHODS: A total of 37 patients were treated with high-dose MZ (6 mg/kg), a CNI (cyclosporine [CsA] or tacrolimus [Tac]), basiliximab (Bas), rituximab (Rit), and corticosteroids. CsA was started at a dose of 7 mg/kg to maintain blood levels [200 ng/mL (C0), 6000 ng-h/mL (AUC 0 9)]. Tac was started at a dose of 0.2 mg/kg to maintain blood levels [8-10 ng/mL (C0), 100 ng-h/mL (AUC 0-9)]. Bas (20 mg/body) was administrated on day 0 and day 4 after transplantation. Rit (100-200 mg/body) was administrated on day -14 and day -7 before transplantation. MZ was adjusted to maintain target C0 levels of 1.5 to 2.0 MUg/mL. RESULTS: Patient and graft survival rates for 2 years were 100% in the CsA group (n = 22) and 93.3% in the Tac group (n = 15) (not significant, NS). Overall incidence of acute rejection for 2 years was 22.7% in the CsA group and 26.7% in the Tac group. Mean serum creatinine levels at 2 years were 1.29 +/- 0.2 mg/dL in the CsA group and 1.21 +/- 0.34 mg/dL in the Tac group (NS). The incidence of CMV disease was 0% in both groups, and positive rates of CMV antigenemia were 50.0% and 26.7% in the CsA and Tac groups, respectively (NS). Mean serum uric acid levels were 5.5 +/- 1.3 mg/dL and 6.4 +/- 1.2 mg/dL at 2 years (NS) in the CsA and Tac groups, respectively. CONCLUSIONS: A high-dose MZ regimen including calcineurin inhibitor (CsA or Tac), Bas, Rit, and steroids was effective and safe in reducing the frequency of CMV-related events in ABO-i LKT. PMID- 28583570 TI - Clinical Outcomes in Pediatric Renal Transplant Recipients Who Received Steroid Based Immunosuppressive Regimen. AB - BACKGROUND: Although the clinical outcomes of pediatric renal transplantation (RT) in developed countries have improved significantly, the data on clinical outcomes in developing countries are wildly different. METHODS: Children and adolescents who had undergone RT at Ramathibodi Hospital between March 2001 and August 2014 were included. RESULTS: Patients were divided into 2 groups: living related donor (LRD) group (n = 13) and deceased donor (DD) group (n = 30). Prolonged cold ischemic time over 13 hours was significantly associated with delayed graft function (P = .029). The prevalence of infection was 90.7%, in which urinary tract infection (UTI) was the most common infection. Although almost none of the patients in the LRD group received induction therapy, the prevalence of rejection was not significantly different between the 2 groups (P = .817). The comparison of graft survivals between LRD and DD groups were 100% vs 100%, 92.3% vs 100%, and 85.7% vs 81.8% at 1, 3, and 5 years, respectively (P = .938). Recurrent UTI and cytomegalovirus (CMV) infection had a negative effect on graft function at 1-year follow-up (P < .05). Rejections, bladder dysfunction, and donors aged >=50 years were associated with graft deterioration at 3 years after RT (P < .01). None of these patients died with functioning graft. CONCLUSION: This study demonstrated good graft and patient survival in Thai pediatric RT recipients. Although recurrent UTI and CMV infection were related to graft dysfunction at 1-year follow-up, infections had no effect on graft and patient survival in long-term follow-up. PMID- 28583571 TI - Outcomes of En Bloc Kidney Transplantation From Pediatric Donors: A Single-Center Experience. AB - BACKGROUND: To overcome a shortage of donors, cadaveric pediatric en bloc kidneys can be used to expand the donor pool. Recent evidence shows that en bloc kidney transplantation (EBKT) has better outcomes than standard-criteria deceased adult donor kidney transplantation. We reviewed our experiences of EBKT and their outcomes. METHODS: From September 1996 to January 2016, 15 EBKTs were performed in Asan Medical Center. The characteristics of donors and recipients were analyzed. Graft survival was analyzed by means of serum creatinine levels. RESULTS: Nine male and 6 female donors were used. The mean age and body weight of donors was 2.79 years (range, 0.25-14) and 13.14 kg (range, 5.5-35). The mean weight of en bloc kidneys was 117.43 g (range, 36-146). Recipient median age was 39.13 years and body weight was 49.47 kg. Ureteral anastomosis was performed by means of side-to-side anastomosis and then bladder anastomosis in 9 patients and by bladder patch anastomosis in 4 patients. Serum creatinine levels at discharge and latest follow-up were 0.97 mg/dL (range, 0.7-1.54) and 0.89 mg/dL (range, 0.44-2.58). Delayed graft function developed in 3 patients and clinical rejection developed in 2 patients. We performed graftectomy on post-operative day 1 because of graft thrombosis. The rest maintained their graft function well. Graft survival was comparable with that of kidney transplantation from standard donors. CONCLUSIONS: EBKT showed excellent graft function and outcomes at our center. As an approach to expand the donor pool and improve graft utilization, EBKT is acceptable and should be more widely used. PMID- 28583572 TI - Effect of Donor-Recipient Age Match in Expanded Criteria Deceased Donor Kidney Transplantation. AB - PURPOSE: Our objective was to investigate the effects of age on patient and graft survival in expanded criteria donor (ECD) renal transplantation. METHODS: Between February 2000 and December 2015, we analyzed 405 deceased donor renal transplants, including 128 grafts (31.9%) from ECDs. Based on recipient age and ECD criteria classification, the recipients were divided into four groups: Group I, non-ECD to recipient age <50 years; Group II, non-ECD to recipient age >=50 years; Group III, ECD to recipient age <50 years; and Group IV, ECD to recipient age >=50 years. RESULTS: Among the four groups, there were significant differences in baseline characteristics (age, body mass index [BMI], cause of end stage renal disease [ESRD], number of kidney transplantations, and use of induction agent). The mean modification of diet in renal disease (MDRD) glomerular filtration rate (GFR) level at 1 month, 6 months, 1 year, 3 years, and 5 years after transplantation was significantly lower in patients with ECDs but MDRD GFR level at 7, 9, and 10 years did not differ significantly (P = .183, .041, and .388, respectively). There were no significant differences in graft survival (P = .400) and patient survival (P = .147). CONCLUSION: Our result shows that, regardless of recipient age, kidney transplants donated by deceased ECDs have similar graft and patient survival. PMID- 28583573 TI - Kidney Transplantation in Korean Patients With End-Stage Renal Disease Aged 65 and Older: A Single-Center Experience. AB - BACKGROUND: The mean age of patients starting dialysis in Korea has increased to older than 60 years and the proportion of patients aged 65 and older exceeded 40% in 2014. Although the number of elderly dialysis patients is increasing rapidly, percentages of elderly patients undergoing kidney transplantation (KT) are very low. METHODS: We retrospectively reviewed the medical records of patients who underwent KT at Keimyung University Dongsan Medical Center between 1982 and 2016. Elderly patients (>=65 years old) were compared with the control group of patients in their early sixties (60-64 years old). RESULTS: Among a total of 1209 KT patients, those in their early sixties totaled 34 (2.8%) and the elderly totaled only 18 (1.5%). Patient and allograft survival rate showed no significant differences between the elderly and those in their early sixties. Death with a functioning graft accounted for 50% in both groups. However, occurrences of bacterial infection and tuberculosis were higher in the elderly (P = .011 and .047, respectively). In a multivariate analysis, longer duration of renal replacement therapy before KT and the occurrence of malignancy were independent risk factors for patient death (hazard ratio [HR], 1.027; P = .014; HR, 31.934; P = .016, respectively). Also, albuminuria at 6 months after KT was an independent risk factor for allograft loss (HR, 51.155; P = .016). CONCLUSION: The overall survival rate of the elderly was not significantly lower than those in their early sixties. Even in the elderly, KT should not be delayed. In addition, careful surveillance for malignancy and measures to decrease the risk of infection are necessary. PMID- 28583574 TI - Long-term Clinical Outcomes of First and Second Kidney Transplantation in Patients With Biopsy-Proven IgA Nephropathy. AB - INTRODUCTION: The recurrence of IgA nephropathy (IgAN) after kidney transplantation (KT) has an effect on graft survival, but there are few reports about long-term clinical outcomes of KT with recurrent IgAN. This study shows the long-term clinical outcomes of KT in patients with IgAN. METHODS: All recipients who had biopsy-proven IgAN were followed from February 1990 to February 2016. We analyzed overall graft and patient survival rates, incidence of recurrent IgAN, factors affecting graft survival, and IgAN recurrence. RESULTS: There were 88 patients with first KT. The mean follow-up duration was 82.5 months. Twenty patients went through graft loss and 1 patient died due to sepsis. IgAN recurred in 15 patients, and 11 patients experienced graft failure. Among the patients who had failed graft after first KT, 7 patients underwent retransplantation. The graft survival period, presence of rejection, and proteinuria were the relevant risk factors for recurrence of IgAN. In the first KT patients, presence of rejection and 1-year serum creatinine were the significant risk factors for graft loss. But recurrence of IgAN was not a relevant risk factor. Overall graft survival rates at 5 and 10 years were 93.8% and 73.1% in the first transplantation group and 100% and 100% in the retransplantation group, respectively. CONCLUSION: Although IgAN recurrence was a significant risk factor for graft failure, the patient who underwent retransplantation showed favorable results. Retransplantation should be considered in patients who lost their first graft after recurrence of IgAN. PMID- 28583575 TI - Long-term Clinical Outcomes of Kidney Re-transplantation. AB - BACKGROUND: Kidney re-transplantation is commonly considered to have a higher immunological risk than first kidney transplantation. Because of the organ shortage and increasing waiting lists, long-term outcomes of kidney re transplantation are being studied. However, reports of re-transplantation outcomes are not common. We have reported our 30 years of experience with second kidney transplantations. METHODS: Of 1210 kidney transplantations between November 1982 and August 2016 performed in our hospital, 105 were second kidney transplantations (2nd KT). Living donor KT was 44; deceased donor KT was 61. RESULTS: Patient survival rates at 1, 5, and 10 years were 100%, 97.2%, and 90.7%, and graft survival rates were 97.0%, 94.6%, and 71.5%, respectively. The leading cause of graft failure in the 2nd KT was chronic rejection (60%). In addition, induction immunosuppressant, maintenance immunosuppressant, delayed graft function, and graft survival time at the 1st KT had a significant impact on graft survival time at the 2nd KT. CONCLUSIONS: Reasonable results in both patient survival and graft survival rates were found in the 2nd KT. Careful monitoring of immunologic risk is needed. PMID- 28583576 TI - Administration of Huperzine A exerts antidepressant-like activity in a rat model of post-stroke depression. AB - Post-stroke depression (PSD) is the most common mood disorder following a stroke, and is also the main factor limiting recovery and rehabilitation in stroke patients. The present study was aimed to investigate whether Huperzine A (HupA) has antidepressant-like activity in a rat model of PSD, which was developed by middle cerebral artery occlusion followed by an 18-day chronic unpredictable mild stress in conjunction with isolation rearing. The sucrose preference and forced swim tests were used to assess depression-like behavior. Neurological and cognitive functions following ischemia were evaluated by neurological evaluation, the beam-walking test, the forelimb grip force test, and the water maze test. Levels of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) in the hippocampus and prefrontal cortex were assayed by high performance liquid chromatography. Western blot analysis was used to evaluate hippocampal expression of the 5-hydroxytryptamine 1A receptor (5-HT1AR), cAMP response element binding (CREB), phosphorylated CREB (p-CREB) and brain-derived neurotrophic factor (BDNF). The results showed that treatment with HupA for 4weeks ameliorated behavioral abnormalities and the impairment of neurological and cognitive functions in PSD rats. This was accompanied by the upregulated hippocampal expression of 5-HT1AR, p-CREB and BDNF, and increased levels of NE, DA, and 5-HT in the hippocampus and prefrontal cortex. These findings suggest that HupA has antidepressant-like effect and can improve neurological and cognitive functions in PSD rats, which suggest its therapeutic potential for depression after stroke. PMID- 28583577 TI - Antagonism of orexin type-1 receptors (OX1Rs) attenuates naloxone-precipitated morphine withdrawal syndrome in rat dorsal hippocampus. AB - Herein the effect of hippocampal orexin type-1 receptors (OX1Rs) blockade on morphine withdrawal syndrome was studied. Animals were made dependent by subcutaneous (s.c.) administration of morphine sulfate (10mg/kg) at an interval of 12h for 9 consecutive days. Thereafter, on day 10, naloxone hydrochloride (1.5mg/kg, i.p.) was injected and the somatic signs of withdrawal syndrome were monitored during a 25-min period. Two groups of animals received bilateral microinjection of either SB-334867, a selective OX1Rs antagonist, (0.5MUg/0.5MUl), or its vehicle into the dorsal hippocampus immediately before each morphine injection. Other groups of animals were made dependent at first and only received a single microinjection of SB-334867 or vehicle on day 10 before naloxone injection. The results showed that intra-hippocampal microinjection of SB-334867 before each morphine treatment, significantly decreased the signs of morphine withdrawal, including teeth chattering (dependent: 18.5+/-2.3, SB treated: 5+/-1, p<0.001), diarrhea (dependent: 8.7+/-0.6, SB treated: 4.1+/-0.6, p<0.001), ptosis (dependent: 33.8+/-3.7, SB treated: 11.6+/-1.1, p<0.001), and chewing (dependent: 40+/-2.3, SB treated: 29+/-2.4, p<0.01). SB-334867 did not attenuate withdrawal syndrome, when it was microinjected as a single dose immediately before naloxone injection. The present results suggest a role for orexin in naloxone-precipitated withdrawal and thus possibly morphine dependence and this effect is, at least in part, via OX1Rs in the dorsal hippocampus. PMID- 28583579 TI - The changing landscape of A H7N9 influenza virus infections in China. PMID- 28583578 TI - Epidemiology of avian influenza A H7N9 virus in human beings across five epidemics in mainland China, 2013-17: an epidemiological study of laboratory confirmed case series. AB - BACKGROUND: The avian influenza A H7N9 virus has caused infections in human beings in China since 2013. A large epidemic in 2016-17 prompted concerns that the epidemiology of the virus might have changed, increasing the threat of a pandemic. We aimed to describe the epidemiological characteristics, clinical severity, and time-to-event distributions of patients infected with A H7N9 in the 2016-17 epidemic compared with previous epidemics. METHODS: In this epidemiological study, we obtained information about all laboratory-confirmed human cases of A H7N9 virus infection reported in mainland China as of Feb 23, 2017, from an integrated electronic database managed by the China Center for Disease Control and Prevention (CDC) and provincial CDCs. Every identified human case of A H7N9 virus infection was required to be reported to China CDC within 24 h via a national surveillance system for notifiable infectious diseases. We described the epidemiological characteristics across epidemics, and estimated the risk of death, mechanical ventilation, and admission to the intensive care unit for patients admitted to hospital for routine clinical practice rather than for isolation purpose. We estimated the incubation periods, and time delays from illness onset to hospital admission, illness onset to initiation of antiviral treatment, and hospital admission to death or discharge using survival analysis techniques. FINDINGS: Between Feb 19, 2013, and Feb 23, 2017, 1220 laboratory confirmed human infections with A H7N9 virus were reported in mainland China, with 134 cases reported in the spring of 2013, 306 in 2013-14, 219 in 2014-15, 114 in 2015-16, and 447 in 2016-17. The 2016-17 A H7N9 epidemic began earlier, spread to more districts and counties in affected provinces, and had more confirmed cases than previous epidemics. The proportion of cases in middle-aged adults increased steadily from 41% (55 of 134) to 57% (254 of 447) from the first epidemic to the 2016-17 epidemic. Proportions of cases in semi-urban and rural residents in the 2015-16 and 2016-17 epidemics (63% [72 of 114] and 61% [274 of 447], respectively) were higher than those in the first three epidemics (39% [52 of 134], 55% [169 of 306], and 56% [122 of 219], respectively). The clinical severity of individuals admitted to hospital in the 2016-17 epidemic was similar to that in the previous epidemics. INTERPRETATION: Age distribution and case sources have changed gradually across epidemics since 2013, while clinical severity has not changed substantially. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection with A H7N9 virus. FUNDING: The National Science Fund for Distinguished Young Scholars. PMID- 28583580 TI - Acetyl-l-carnitine enhances myelination of regenerated fibers of the lateral olfactory tract. AB - It is well known that acetyl-l-carnitine (ALC) has various neuroprotective effects against neurodegenerative diseases. In addition, it has been reported that ALC facilitates myelination of regenerated axons after peripheral nerve injuries. We previously reported that spontaneous regeneration of the lateral olfactory tract (LOT), the main fiber tract of the central olfactory system, consistently occurred in newborn rats and a majority of these regenerated fibers were unmyelinated in neonatally LOT-transected young adult rats. To investigate the effects of ALC treatment on myelination in LOT, neonatal rats were treated with ALC after LOT transection. Immunohistochemistry for myelin basic protein showed more positive areas in ALC-treated rats than in control rats. Moreover, the number of myelinated axons of regenerated fibers was assessed using electron microscopy and was found to be statistically higher in ALC-treated rats compared to control rats. The study revealed that ALC accelerates myelination of regenerated fibers in neonatally LOT-injured young adult rats. PMID- 28583581 TI - The regulation of SKF38393 on the signaling pathway of dopamine D1 receptor in hippocampus during chronic sleep deprivation. AB - BACKGROUND: Hippocampal functions are sensitive to sleep deficiency. Dopamine D1 receptor (D1R) in hippocampus can regulate the expression of cAMP response element binding protein (CREB) through PKA, MAPK and phosphoinositide pathway, but which pathway plays the major role in hippocampus during Chronic sleep deprivation (CSD) is unclear. METHODS: The CSD model was created, SKF rats were administered the D1R agonist (SKF38363), and hippocampus from each animal was dissected for following molecular detection. The gene and protein levels of CREB and key molecules in D1R pathways were measured by real-time PCR and western blotting, respectively. RESULTS: Both the gene and protein expression of CREB in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). Both the gene and protein expression of PKA in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). SKF38393 just significantly improved the gene level of CaMK IV and the protein level of p-CaMK IV (p<0.05) in CSD rats, but it cannot improve the protein expression of ERK1/2 and p-ERK1/2. DISCUSSION: CSD significantly decreased the expression of CREB in hippocampus. As the key molecules, PKA and CaMK IV play an important role during the improvement of hippocampus by the activation of D1R, and this process might be improved during CSD through the PKA and phosphoinositide pathway. PMID- 28583582 TI - Chronic sucrose intake decreases concentrations of n6 fatty acids, but not docosahexaenoic acid in the rat brain phospholipids. AB - We investigated the influence of high sucrose intake, administered in drinking water, on the lipid profile of the brain and on the expression of SREBP1c and Delta-desaturase genes. Adult male rats received 30% sucrose solution for 20 weeks (Sucrose group), or plain water (Control group). After the 20th week of sucrose treatment, the Sucrose group showed permanent hyperglycemia. Sucrose treatment also increased the amount of total lipids and fatty acids in the brain. The brain fatty acid profile of total lipids as well as phosphatidylethanolamine, phosphatidylcholine and cardiolipin of the Sucrose group was extensively changed. The most interesting change was a significant decrease in n6 fatty acids, including the important arachidonic acid, whereas the content of oleic and docosahexaenoic acid remained unchanged. RT-qPCR revealed an increase in Delta-5 desaturase and SREBP1c gene expression. In conclusion, high sucrose intake via drinking water extensively changes rat brain fatty acid profile by decreasing n6 fatty acids, including arachidonic acid. In contrast, the content of docosahexaenoic acid remains constant in the brain total lipids as well as in phospholipids. Changes in the brain fatty acid profile reflect changes in the lipid metabolism of the rat lipogenic tissues and concentrations in the circulation. PMID- 28583583 TI - Temporal changes of oxidative stress markers in Escherichia coli K1-induced experimental meningitis in a neonatal rat model. AB - Despite advances in antimicrobial therapy and advanced critical care neonatal bacterial meningitis has a mortality rate of over 10% and induces neurological sequelae in 20-50% of cases. Escherichia coli K1 (E. coli K1) is the most common gram-negative organism causing neonatal meningitis and is the second most common cause behind group B streptococcus. We previously reported that an E. coli K1 experimental meningitis infection in neonatal rats resulted in habituation and aversive memory impairment and a significant increase in cytokine levels in adulthood. In this present study, we investigated the oxidative stress profile including malondialdehyde (MDA) levels, carbonyl protein formation, myeloperoxidase activity (MPO) activity, superoxide dismutase (SOD) activity and catalase (CAT) activity 6, 12, 24, 48, 72 and 96h after E. coli K1 experimental meningitis infection. In addition, sulfhydryl groups, nitrite and nitrate levels and activity of the mitochondrial respiratory chain enzymes were also measured in the frontal cortex and hippocampus of neonatal rats. The results from this study demonstrated a significant increase in MDA, protein carbonyls and MPO activity and a simultaneous decrease in SOD activity in the hippocampus of the neonatal meningitis survivors but the same was not observed in frontal cortex. In addition, we also observed a significant increase in complex IV activity in the hippocampus and frontal cortex of meningitis survivor rats. Thus, the results from this study reaffirmed the possible role of oxidative stress, nitric oxide and its related compounds in the complex pathophysiology of E. coli K1-induced bacterial meningitis. PMID- 28583584 TI - Common variants in GRIK4 and major depressive disorder: An association study in the Chinese Han population. AB - Major depressive disorder (MDD) is a common and complex mental disorder. Recent studies found that genetic variants located in GRIK4, which encoded glutamate ionotropic receptor kainate type subunit 4, was associated with the MDD. In this study, we intended to investigate whether GRIK4 gene was associated with MDD. So five single nucleotide polymorphisms (SNPs) were selected and genotyped (rs79526501, rs11218016, rs4582985, rs6589847, rs56275759) in 568 MDD patients and 846 healthy controls from Chinese Han population. The results showed that rs56275759 demonstrated statistically significant differences between MDD patients and control subjects both in allelic frequencies (p value=0.011) and genotypic frequencies (p value=0.029). Rs4582985 was excluded from the further analysis for its deviation from the Hardy-Weinberg equilibrium. Strong linkage disequilibrium (LD) was found among rs11218016, rs6589847 and rs56275759, and this block was significantly associated with MDD. In summary, our results firstly indicated that rs56275759 of GRIK4 gene might be associated with MDD in Chinese Han population. PMID- 28583585 TI - Effects of the Notch signalling pathway on hyperoxia-induced immature brain damage in newborn mice. AB - Hyperoxia exposure can cause dramatic release of proinflammatory cytokines, leading to neuronal apoptosis and inducing white matter damage in newborn mouse brains. Some studies indicated that the Notch activation was provoked during inflammation and might regulate adaptive and innate immune responses. Moreover, the pathway also regulated oligodendrocyte maturation which was disrupted in neonatal mice after hyperoxia exposure. This study sought to investigate whether the Notch signalling activation contributed to immature brain damage after hyperoxia exposure. Cellular changes in the white matter (WM) of neonatal wild type mice exposed to 80% oxygen from postnatal day 3 (P3) to day 5 (P5) were determined. Moreover, in order to further confirm the relationship between the Notch signalling pathway and hyperoxia-induced periventricular white matter injury, mice were pre-treated with a gamma-secretase inhibitor (N-[N-(3,5 difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, DAPT), which inhibits activation of the Notch pathway before exposure to hyperoxia. The results suggested that expression of myelin basic protein (MBP) increased in P12 mice subjected to hyperoxia after DAPT pretreatment. Moreover, hyperoxia could cause mature oligodendrocytes (MBP+) counts decreased with an obvious inverse increase in OPCs (NG2+) after hyperoxia on P12, DAPT pretreatment significantly ameliorated disruption of oligodendrocytes maturation induced by hyperoxia. Our results also demonstrated that DAPT could reduce memory impairment induced by hyperoxia exposure. Taken together, these results suggest that hyperoxia exposure induces both brain damage in the developing brain and behavioural abnormalities through the Notch signalling activation. And modulation of gamma-secretase, selectively interfering with the Notch signalling pathway, could improve adverse outcomes induced by hyperoxia. PMID- 28583586 TI - Attenuating PI3K isoforms in pancreatic cancer: Focus on immune PI3Kgamma. AB - Phosphoinositide 3-kinases PI3Ks are major drug targets in oncology. Their role is far from being completely understood in pancreatic ductal adenocarcinoma. Pancreatic cancer is a dismal disease with limited therapeutic options except for surgery. We highlight here two elegant works demonstrating the role of PI3Kgamma in cancer-associated macrophages applied in particular to pancreatic tumors. These data open new avenues for the use of PI3K-targetting drugs in cancer as anti-stroma therapies. Amongst the classI PI3K isoforms, PI3Kgamma and PI3Kdelta, are highly expressed in immune cells. Isoform-specific or pan-class I PI3K inhibitors which target all classI PI3Ks could be used as a targeted therapy towards cancer cell signaling but also as immunotherapies. Research on immunoregulation of human pancreatic cancer by the other ubiquitous alpha- or beta-isoforms of PI3K needs to be performed. PMID- 28583587 TI - Management of Multifocal Lung Cancer: Results of a Survey. AB - INTRODUCTION: Multifocal lung cancer is an increasingly common clinical scenario, but there is lack of high-level evidence for its optimal treatment. Thus, we surveyed members of the interdisciplinary International Association for the Study of Lung Cancer on their therapeutic approaches and analyzed the resultant practice patterns. METHODS: We described the clinical scenario of an otherwise healthy 60-year-old man with bilateral pulmonary nodules and asked the 6373 members of the International Association for the Study of Lung Cancer whether they would recommend surgery, and if so, the extent of surgery. We also asked what other measures would be recommended to complete the staging and whether radiation therapy or chemotherapy would be suggested. RESULTS: We received 221 responses (response rate 3.5%) from multiple specialists. Most respondents (140 [63%]) recommended surgery for this scenario. Surgeons were significantly more likely to recommend surgery than were those in other specialties. Of those who recommended surgery, most would obtain a PET/CT scan to rule out distant metastases and a magnetic resonance imaging scan to rule out brain metastases; but in the absence of radiographic lymph node involvement, most would not stage the mediastinum by bronchoscopy or mediastinoscopy before resection. When surgery was not recommended or declined, respondents commonly recommended radiation. CONCLUSIONS: This survey suggests that therapeutic recommendations for multifocal lung cancer are influenced to a large extent by physicians' specialty training, probably because of the lack of high-level evidence for its standard treatment. Ongoing systematic and multidisciplinary approaches with robust short-term and long-term patient outcomes may improve the quality of evidence for the optimal management of this clinical entity. PMID- 28583588 TI - Processing thermally labile drugs by hot-melt extrusion: The lesson with gliclazide. AB - The formation of molecularly dispersed amorphous solid dispersions by the hot melt extrusion technique relies on the thermal and mechanical energy inputs, which can cause chemical degradation of drugs and polymeric carriers. Additionally, drug degradation may be exacerbated as drugs convert from a more stable crystalline form to a higher energy amorphous form. Therefore, it is imperative to study how drug degrades and evaluate methods to minimize drug degradation during the extrusion process. In this work, gliclazide was used as a model thermally labile drug for the degradation kinetics and process optimization studies. Preformulation studies were conducted using thermal analyses, and liquid chromatography-mass spectroscopy to identify drug degradation pathways and to determine initial extrusion conditions. Formulations containing 10% drug and 90% AFFINISOLTM HPMC HME 100LV were then extruded using a twin screw extruder, and the extrudates were characterized using X-ray powder diffraction, modulated dynamic scanning calorimetry, and potency testing to evaluate physicochemical properties. The energies of activation for both amorphous gliclazide, crystalline gliclazide, and gliclazide solution were calculated using the Arrhenius equation to further guide the extrusion optimization process. Preformulation studies identify two hydrolysis degradation pathways of gliclazide at elevated temperatures. The activation energy study indicates a significantly higher degradation rate for the amorphous gliclazide compared to the crystalline form. After optimization of the hot-melt extrusion process, including improved screw designs, machine setup, and processing conditions, gliclazide amorphous solid dispersion with ~95% drug recovery was achieved. The ability to process thermally labile drugs and polymers using hot-melt extrusion will significantly expand the possible applications of this manufacturing process. PMID- 28583589 TI - A comparative assessment of nanocomposites vs. amorphous solid dispersions prepared via nanoextrusion for drug dissolution enhancement. AB - Nanoextrusion was used to produce extrudates of griseofulvin, a poorly water soluble drug, with the objective of examining the impact of drug particle size and polymeric matrix type-size of the extrudates on drug dissolution enhancement. Hydroxypropyl cellulose (HPC) and Soluplus(r) were used to stabilize wet-milled drug suspensions and form matrices of the extrudates. The wet-milled suspensions along with additional polymer (HPC/Soluplus(r)) were fed to a co-rotating twin screw extruder, which dried the suspensions and formed various extrudates. The extrudates were dry-milled and sieved into samples with two different sizes. A wet-milled suspension was also spray-dried in comparison to nanoextrusion. Due to differences in polymer-drug miscibility, two forms of the drug were prepared: extrudates with nano/micro-crystalline drug particles dispersed in the HPC matrix as a secondary phase (nano/microcomposites) and extrudates with amorphous drug molecularly dispersed within the Soluplus(r) matrix (amorphous solid dispersion, ASD). Under non-supersaturating conditions in the dissolution medium, drug nanocrystals in the HPC-based nanocomposites dissolved faster than the amorphous drug in Soluplus(r)-based ASD. While smaller extrudate particles led to faster drug release for the ASD, such matrix size effect was weaker for the nanocomposites. These findings suggest that nanocrystal-based formulations could outperform ASDs for fast dissolution of low-dose drugs. PMID- 28583590 TI - Combined treatment of Thymus vulgaris L., Rosmarinus officinalis L. and Myrtus communis L. essential oils against Salmonella typhimurium: Optimization of antibacterial activity by mixture design methodology. AB - To increase the sensibility of Salmonella typhimurium strain, a mixture of Thymus vulgaris L. (T. vulgaris L.), Rosmarinus officinalis L. (R. officinalis L.) and Myrtus communis L. (M. communis L.) essential oils (EOs) was used in combined treatment by experimental design methodology (mixture design). The chemical composition of EOs was firstly identified by GC and GC/MS and their antibacterial activity was evaluated. The results of this first step have shown that thymol and borneol were the major compounds in T. vulgaris and M. communis L. EOs, respectively, while 1,8-cineole and alpha-pinene were found as major compounds in R. officinalis L. The same results have shown a strong antibacterial activity of T. vulgaris L. EO followed by an important power of M. communis L. EO against a moderate activity of R. officinalis L. EO. Besides, 1/20 (v/v) was the concentration giving a strain response classified as sensitive. From this concentration, the mixture design was performed and analyzed. The optimization of mixtures antibacterial activities has highlighted the synergistic effect between T. vulgaris L. and M. communis L. essential oils. A formulation comprising 55% of T. vulgaris L. and 45% of M. communis L. essential oils, respectively, can be considered for the increase of Salmonella typhimurium sensibility. PMID- 28583591 TI - Difficult removal of subdermal contraceptive implants: a multidisciplinary approach involving a peripheral nerve expert. AB - OBJECTIVES: We aim to describe our experiences and identify patients who may benefit from referral to a peripheral nerve surgeon for removal of contraceptive subdermal implants in which neurovascular injury may occur, and describe a treatment pathway for optimal care. STUDY DESIGN: We reviewed the charts of 22 patients who were referred to the Division of Family Planning for difficult removal of etonogestrel contraceptive implants between January 1, 2014, and April, 1 2016. Of these, five were referred to a peripheral nerve surgeon due to pain or location of the implant. We evaluated and described these cases and, from our findings, developed recommendations for care in a multidisciplinary team approach. RESULTS: Two patients reported pain, including one with four previous failed removal attempts. In the two patients with pain, the implants were adherent to a sensory nerve. In another, the implant was within the biceps muscle and difficult to locate. In all cases, ultrasound imaging, general anesthesia and a wide exposure allowed for safe removal and good outcomes. Our multidisciplinary care approach has elucidated important referral and technical considerations that improve patient care and safety. CONCLUSION: When necessary, multidisciplinary care with a Family Planning expert and possibly a peripheral nerve surgeon may be beneficial in safely removing etonogestrel contraceptive implants that would be difficult or risky to remove in an ambulatory setting. PMID- 28583592 TI - Preliminary study on plasma proteins in pregnant and non-pregnant female dogs. AB - In this study, we used a combined approach based on 2-dimensional electrophoresis (2-DE), difference in gel electrophoresis (DIGE), and mass spectrometry (MS) to identify the plasma protein composition in pregnant female dogs and compared it with non-pregnant female dogs. We used the plasma samples obtained from four female dogs during I, II, and III thirds of pregnancy, three days after parturition, as well as from four non-pregnant female dogs in diestrus phase. Analysis of 2-DE gel image exhibited of 249 protein spots. The intensity of staining of 35 spots differed significantly (P < 0.05) between the non-pregnant and pregnant female dogs. We used matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MALDI TOF MS) to identify 47 spots corresponding to 52 different proteins. Five identified protein spots, including zinc finger BED domain-containing protein 5, hemoglobin subunit beta-2, integrator complex subunit 7, apolipoprotein A-I, and glutamyl aminopeptidase were differentially presented in the plasma of pregnant and non-pregnant female dogs. To the best of our knowledge, this is the first report on the plasma protein profile of pregnant and non-pregnant female dogs. In this study, we identified proteins that have not been previously identified in dogs. Our findings showed that numerous protein spots were differentially presented in the plasma of female dogs during normal pregnancy. Although we identified only a limited number of differentially presented proteins, our study demonstrated that the plasma protein profile changed during pregnancy in female dogs, which suggests its importance in maintaining pregnancy. Further studies are necessary to define complete plasma protein profile of pregnant female dogs and to identify all proteins that are differentially presented in the pregnant animals compared with the non-pregnant ones. In addition, studies are warranted to explain the role of those proteins in maintaining the pregnancy and their usefulness in detection of early pregnancy. Furthermore, our results indicated that DIGE technique is useful in the comparison of samples originated from different states and time points in dogs. PMID- 28583593 TI - Altered expression of cytokines IL-1alpha, IL-6, IL-8 and TNF-alpha in bovine follicular persistence. AB - In dairy cattle, cystic ovarian disease (COD) is an important cause of subfertility, and two of the main signs are ovulation failure and follicular persistence. The aim of this study was to examine the expression of the cytokines IL-1alpha, IL-6, IL-8 and TNF-alpha in ovarian follicular structures at different times of persistence in a model of follicular persistence induced by prolonged treatment with progesterone in dairy cows. Protein expression of IL-1alpha, IL-6, IL-8 and TNF-alpha was evaluated by immunohistochemistry. Additionally, IL-6 concentration in follicular fluid and serum was determined by ELISA. IL-1alpha, IL-6, IL-8 and TNF-alpha expression was increased in follicles with different persistence times in relation to the control dominant follicles, in granulosa cells. For IL-6, IL-8 and TNF-alpha, this increase was detected early (P0: expected time of ovulation and/or P5: 5 days of follicular persistence). Additionally, theca cells showed an increase in IL-6 in antral (groups P10 and P15) and persistent follicles (group P10) related to dominant follicles from the control group (p < 0.05). Serum concentration of IL-6 was higher in groups P5, P10 and P15 than in control cows (p < 0.05). The results show evidence that early development of COD in cows is concurrent with altered expression of these cytokines in different ovarian follicular structures and may contribute to the follicular persistence and endocrine changes found in cattle with follicular cysts. PMID- 28583594 TI - Relationship between in vitro growth of bovine oocytes and steroidogenesis of granulosa cells cultured in medium supplemented with bone morphogenetic protein-4 and follicle stimulating hormone. AB - Bone morphogenetic protein-4 (BMP-4) and FSH play important regulatory roles in follicular growth and steroidogenesis in vivo. The purpose of this study was to investigate the effects of BMP-4 and FSH on in vitro growth (IVG) and steroidogenesis of bovine oocyte-cumulus-granulosa complexes (OCGCs). We cultured OCGCs collected from early antral follicles (0.5-1 mm) in medium without BMP-4 and FSH for 4 days and investigated the appearance of OCGCs and their steroidogenesis. During the first 4 days of IVG, morphologically normal OCGCs produced more estradiol-17beta (E2), but less progesterone (P4). Morphologically normal OCGCs were subjected to an additional culture in medium supplemented with BMP-4 (0, 10, and 50 ng/mL) and FSH (0 and 0.5 ng/mL) until day 12. We examined the viability and steroidogenesis of OCGCs after 8 and 12 days of culture. Oocyte growth, characteristics of granulosa cells, and the maturational competence of oocytes were also investigated. On day 8, the viability of OCGCs cultured without FSH was higher in the 10 ng/mL BMP-4 group than in the 50 ng/mL BMP-4 group (P < 0.05). No significant difference was observed in the viability of groups cultured with FSH, regardless of the addition of BMP-4, and FSH improved the viability of 50 ng/mL BMP-4 group similar to 10 ng/mL BMP-4 group. The total number of granulosa cells was larger in 10 ng/mL BMP-4 group cultured with FSH than in 50 ng/mL BMP-4 group cultured with FSH on day 8 (P < 0.05). E2 production decreased from days 8-12, and P4 production increased throughout IVG culture, regardless of the addition of BMP-4 and FSH (P < 0.05). No significant differences in E2 production were observed between groups from days 4-8, regardless of whether BMP 4 was added without FSH; however, E2 production in the group cultured with 50 ng/mL BMP-4 was suppressed by FSH. BMP-4 suppressed E2 production from days 8-12, regardless of whether FSH was added. The group cultured with 10 ng/mL BMP-4 without FSH showed the lowest P4 production among all groups for all culture periods. OCGCs that produced mature oocytes tended to secrete more E2 and less P4 than OCGCs that produced immature oocytes. In conclusion, until day 8 of the IVG culture, P4 production by OCGCs was suppressed by the addition of 10 ng/mL BMP-4 in the absence of FSH, without inhibiting E2 production. These conditions appear to mimic growing follicles until day 8 and mimic degenerating follicles from days 8-12 of culture. PMID- 28583595 TI - The copper transporter (SLC31A1/CTR1) is expressed in bovine spermatozoa and oocytes: Copper in IVF medium improves sperm quality. AB - Adequate dietary intake of copper (Cu) is required for normal reproductive performance in cattle. The objective of this study was to investigate the pregnancy rates from cattle with deficient, marginal and adequate Cu plasma concentration at the beginning of artificial insemination protocol. Moreover, we determined Cu concentrations present in bovine oviductal fluid (OF), and the effects of Cu on fertilizing ability of bovine spermatozoa. Also, the presence of Cu transporter, SLC31A1 (also known as CTR1), in spermatozoa and in vitro matured oocyte were investigated. We found no differences in pregnancy rates among animals with adequate, marginal, and deficient Cu concentrations measured in plasma at the beginning of fixed-time artificial insemination (FTAI) protocol. Copper concentrations in OF were 38.3 +/- 2.17 MUg/dL (mean +/- SEM) regardless of cupremia levels. The addition of 40 MUg/dL Cu to IVF medium enhanced total and progressive motility, sperm viability, functional sperm membrane integrity (HOST), sperm-zona binding, and pronuclear formation. On the other hand, the presence of Cu in IVF medium did not modify acrosome integrity and cleavage rates after IVF, but impaired blastocyst rates. Cu transporter SLC31A1 was detected in bovine spermatozoa in the apical segment of acrosome, and in the oocyte matured in vitro. In conclusion, the results obtained in the present study determined that cupremia levels at the beginning of FTAI protocol did not influence the pregnancy rates at 60 d after insemination. The presence of CTR1 in bovine mature oocyte and spermatozoa, as well as the beneficial effect of Cu on sperm quality would suggest an important role of this mineral during the fertilization process. PMID- 28583596 TI - Sperm maturation in sturgeon (Actinopterygii, Acipenseriformes): A review. AB - The morphology of the reproductive system of acipenseriform fishes is quite different from that of teleostean species, but an associated unique physiological difference in male sturgeons was not discovered until recently; sperm of sturgeons passes through the kidneys then via Wolffian ducts into the environment rather that emptying directly through seminal ducts. The mixing of sperm with excretory products has been found to be a requisite for the capacity to be activated (maturation step) instead of being deleterious. In the current review we summarize results of studies performed in our laboratory on physiological processes involved in sturgeon sperm maturation, namely changes in: 1) ionic environment; 2) sensitivity of spermatozoa to calcium ions (Ca2+); 3) antioxidant enzymes and proteolytic activities; and 4) content in macroergic phosphates arising during this maturation process. We also discuss taxa-specific aspects of sturgeon sperm maturation in relation to hormonal regulation of spermiation, and the unusual features of sturgeon sperm maturation relative to using testicular sturgeon sperm in aquaculture. PMID- 28583597 TI - Equine ovarian tissue viability after cryopreservation and in vitro culture. AB - Ovarian tissue cryopreservation allows the preservation of the female fertility potential for an undetermined period. The objectives of this study were to compare the efficiency of cryoprotective agents (CPAs; dimethyl sulfoxide, DMSO; ethylene glycol, EG; and propylene glycol, PROH) using slow-freezing and vitrification methods, and evaluate the viability of cryopreserved equine ovarian tissue after 7 days of culture. Fresh and cryopreserved ovarian fragments were evaluated for preantral follicle morphology, stromal cell density, EGFR, Ki-67, Bax, and Bcl-2 protein expression, and DNA fragmentation. Vitrification with EG had the highest rate of morphologically normal preantral follicles, while DMSO had the lowest (76.1 +/- 6.1% and 40.9 +/- 14.8%, respectively; P < 0.05). In slow-freezing, despite that DMSO had the highest percentage of morphologically normal follicles (77.7 +/- 5.8%), no difference among the CPAs was observed. Fluorescence intensity of EGFR and Ki-67 was greater when vitrification with EG was used. Regardless of the cryopreservation treatment, DMSO had the highest (P < 0.05) Bax/Bcl-2 ratio; however, DNA fragmentation was similar (P > 0.05) among treatments after thawing. After in vitro culture, the percentage of normal follicles was similar (P > 0.05) between slow-freezing and vitrification methods; however, vitrification had greater (P < 0.05) stromal cell density than slow freezing. In summary, equine ovarian tissue was successfully cryopreserved, increasing the viability of the cells in the ovarian tissue after thawing when using DMSO and EG for slow-freezing and vitrification methods, respectively. Therefore, these results are relevant for fertility preservation programs. PMID- 28583598 TI - Detection of macrophages in rabbit semen and their relationship with semen quality. AB - We aimed at the evaluating the occurrence of macrophages in rabbit semen and finding possible relationship between macrophage concentration and spermatozoa quality. The concentration of macrophages in semen samples from broiler rabbit males of lines M91 and P91 (n = 30) without overt evidence of genital tract infections was determined using monocyte/macrophage lineage antigen CD14 and flow cytometry. Then the rabbits were assigned into three groups according to the macrophage concentration in semen (MPhi1 group with less than 1 * 106 macrophages/mL, MPhi2 group with 1.5-3.5 * 106 macrophages/mL and MPhi3 group with more than 8 * 106 macrophages/mL). Spermatozoa viability parameters such as occurrence of apoptotic (Yo-Pro-1) and dead/necrotic (propidium iodide) spermatozoa and plasma membrane integrity (PNA-Fluos) were evaluated using flow cytometry. Sperm motility parameters were determined by CASA (Computer Assisted Semen Analysis). Ultrastructural detection of macrophages was performed using transmission electron microscopy. Spermatozoa fertility potential was examined after intravaginal artificial insemination of rabbit doses. Significantly higher proportions of the apoptotic and necrotic spermatozoa and spermatozoa with lower plasma membrane integrity were revealed in the MPhi3 group compared to MPhi1 and MPhi2 groups. The percentage value of total motility and progressive movement was significantly highest in the MPhi1 group, whilst lowest in the MPhi3 group. The conception rate and the kindling rate were significantly decreased in the group with the highest macrophage concentration (MPhi3). Based on our results we can conclude that the abundance of seminal macrophages in the rabbit semen may be closely associated with poor spermatozoa quality. PMID- 28583599 TI - Serum concentration dynamic of energy homeostasis hormones, leptin, insulin, thyroid hormones, and cortisol throughout canine pregnancy and lactation. AB - Pregnancy and lactation represent critical periods of canine reproductive life and different hormones are required to maintain homeostasis and the correct energy requirements. The aim of this study was to evaluate leptin, insulin, triiodotyronine (T3), thyroxin (T4) and cortisol serum concentrations to better describe the canine maternal energy metabolism. Twelve Bloodhound bitches that had at least one litter and were considered to be healthy submitted blood samples every 15 days starting from day 0 (ovulation) throughout pregnancy up to the end of lactation (day 120). We found that leptin concentrations increased from day 0 to reach maximum value at day 45 (P < 0.001), decreased at day 60 (P < 0.05) and rose again at day 105 and day 120 (P < 0.05 and P < 0.01 respectively). Insulin concentrations significantly increased during pregnancy peaking at day 60 (P < 0.05). After parturition dropped and reached progressively lower values similar to those at day 0 at the end of lactation. During pregnancy Body Weight was in low correlation with leptin (r = 0.32, P < 0.01) and there was no correlation with insulin (r = 0.13, P > 0.1); moreover, no correlation was found during lactation. T3 concentrations showed a U-shaped trend with a significant reduction at day 75 (P < 0.05). T4 concentrations fluctuated without any significant change (ranging from 27.0 +/- 1.6 nmol/l to 32.1 +/- 1.9 nmol/l). Cortisol concentrations ranged within the reference values (minimal value at day 30 (49.8 +/- 6.3 nm/L) and maximal value at day 45 (72.5 +/- 16.1 nm/L)). Our study states that canine pregnancy and lactation evoke many hormonal changes necessary to mother and fetuses. In particular, this is the first report regarding the pattern of leptin during whole pregnancy and lactation. The present work lays the groundwork for further studies on endocrine homeostatic mechanisms using the dog as a model for human medicine. PMID- 28583601 TI - Concentration dependent antioxidative and apoptotic effects of sulforaphane on bovine granulosa cells in vitro. AB - Sulforaphane (SFN) has received a great deal of research attention because of its ability to induce the production of a battery of antioxidant enzymes in certain concentrations through the activation of the Nuclear factor (erythroid-derived 2) like 2 (Nrf2) signaling pathway, which may effectively neutralize reactive oxygen species (ROS) induced oxidative stress. This study was conducted to investigate the potential of different concentrations of SFN in inducing antioxidative and apoptotic effects in granulosa cells (GCs). For this purpose, bovine GCs were collected from preovulatory antral follicles and cultured with different concentrations of SFN (0-80 MUM) and based on phenotypic evaluation three concentrations were selected: 2 MUM (low), 10 MUM (medium), and 20 MUM (high) for further investigations. The results showed that there was a dramatic loss of cell viability and higher cytotoxic effects of SFN on GCs at higher concentrations (>15 MUM). The expression of NRF2 increased significantly (p < 0.05) with fold change ranged 3-8 in SFN treated GCs, whereas Kelch Like ECH Associated Protein 1 (KEAP1) expression was either downregulated or similar as control group under the same conditions. Moreover, the relative expression of the genes (PRDX1, CAT, TXN1and SOD1) downstream to NRF2 activation was found to be highly expressed (fold change ranged from 2 to 5, p < 0.05) in SFN treated GCs compared to the untreated control. In addition, ROS accumulation was higher in GCs treated with 20 MUM SFN which in turn results in a higher accumulation of lipid droplets. Compared to control, no changes in the mitochondrial activity was observed at 2 and 10 MUM SFN concentrations; however, significantly lower mitochondrial activity was found at high concentration (20 MUM). The results of this study clearly showed that 10 MUM SFN concentration played a crucial role in activating Nrf2 pathway without inducing apoptotic characteristics and this concentration may have beneficial effects in boosting the production of phase II antioxidant enzymes in GCs. However, at high concentration (20 MUM), SFN may generate excessive ROS that causes mitochondrial dysfunction and induces cellular stress and eventually leads to apoptosis. These data strongly suggest a concentration dependent antioxidative and apoptotic effects of SFN on GCs. PMID- 28583600 TI - Administration of 2.5 mg of estradiol followed by 1,500 mg of progesterone to anovulatory mares promote similar uterine morphology, hormone concentrations and molecular dynamics to those observed in cyclic mares. AB - To test the hypothesis that the administration of 2.5 mg of estradiol benzoate (EB) followed by 1500 mg of long acting progesterone (LA P4) causes similar uterine changes and molecular dynamics in anovulatory mares to those observed in cyclic ones, we evaluated the changes of estrogen (ERalpha and ERbeta) and progesterone receptors (PR) in anestrous, transitional and cyclic mares by RT qPCR and immunohistochemistry. In addition, we evaluated uterine edema, tonus and estrogens and progesterone plasma profile. Endometrial biopsies were taken from anestrous and transitional mares immediately before EB injection, 48 h after EB administration and five days after LA P4 was given. In cyclic mares, biopsies were collected at estrus and at five days after ovulation. Similar estrogen peaks were achieved after the injection of the single EB dose between treated and cyclic groups, as well as maximum uterine edema. Uterine tone was increased to diestrus levels after administration of 1500 mg of LA P4. Changes in relative abundance of transcripts for PR, ERalpha and ERbeta when progesterone stimulated endometrium was compared to estrogen stimulated endometrium were similar between cyclic and non-cyclic treated mares. However, apparent decreased PR in the endometrial glandular epithelium was not observed in non-cyclic mares five days after LA P4 administration as observed at five days after ovulation in cyclic mares. The protocol produced similar endometrial edema, uterine tonus and changes in relative abundance of PR, ERalpha and ERbeta transcripts to those observed in cyclic mares during late estrus and early diestrus, as well as similar estradiol and estrogen conjugate plasma concentrations. PMID- 28583602 TI - Effects of environmental temperature and season on hair coat characteristics, physiologic and reproductive parameters in Shetland pony stallions. AB - We hypothesized that housing of stallions in a thermoneutral temperature zone during autumn and winter does not only influence metabolism and hair shedding but also improves the characteristics of raw and processed semen. Fertile Shetland pony stallions were followed from October to June. This time coincided with the seasons autumn, winter and spring. Ponies were kept in outside paddocks (group CON, n = 8) or in indoor stables (group ST, n = 8) from October to March when ST stallions returned to outdoor paddocks, but ponies remained in the same groups. The rectal temperature was measured once weekly. Heart rate, heart rate variability, testosterone and cortisol concentration in blood as well as quality and length of the coat were determined. Semen was collected once weekly and raw semen characteristics were analyzed. The characteristics of cooled-stored and cryopreserved semen were determined once monthly. During the stabling period, environmental temperature for group ST averaged 13.6 +/- 2.3 and for group CON 5.6 +/- 4.2 degrees C. The mean rectal temperature was higher (p < 0.05) in ST than in CON stallions. All hair coat parameters underwent seasonal changes (p < 0.001) and differed between groups (p < 0.05) with shorter guard hair, slower hair regrowth and earlier hair change in ST stallions. Season influenced heart rate which was highest in autumn, lowest in winter and intermediate in spring but did not differ between groups. Testosterone and cortisol concentrations in blood as well as sexual behavior underwent seasonal changes but did not differ between CON and ST stallions. Gel-free semen volume and total sperm count were influenced by season (p < 0.01) and showed a more pronounced increase from winter to spring in CON than in ST stallions (p < 0.05) while no differences with regard to sperm concentration in raw semen were detected. Progressive motility of spermatozoa in raw semen was highest in spring (p < 0.05) but not affected by group. In cooled stored and cryopreserved semen, neither season nor group affected total motility, progressive motility or membrane integrity. In conclusion, environmental temperature during autumn and winter had clear results on body temperature as well as hair coat characteristics in Shetland stallions. Simultaneously determined effects on semen characteristics were minimal indicating that reproductive function in the horse is more dependent on day length i.e. the geophysical year than on other environmental factors. PMID- 28583603 TI - Influence of prenatal maternal corticosteroid therapy on clinical and metabolic features and pulmonary function of preterm newborn puppies. AB - Although the effects of antenatal corticosteroid therapy in clinical improvement and pulmonary maturation in preterm have been described, little is known on premature newborn puppies. This study aimed to evaluate the effect of maternal administration of a single dose of prenatal betamethasone on lung function of preterm newborn puppies in the first hours of life, especially from the clinical point of view and acid-base balance. A prospective study was conducted involving 21 puppies allocated into three experimental groups: Term Group (63 days post ovulation), Preterm-Treated Group (57 days post-ovulation and maternal administration of a single dose of 0.5 mg/kg of betamethasone) and Preterm Control Group (57 days post-ovulation). Puppies were analyzed clinically through the Apgar score, heart rate, respiratory rate and neurological tests (muscular tone and irritability reflex) and for oximetry and blood acid-base balance in distinct experimental moments. Premature puppies had marked degree of prematurity, reversed by maternal administration of betamethasone. Prenatal corticosteroid therapy promoted better pulmonary and metabolic condition, with more efficient compensatory response to acid-base imbalance and better pulmonary gas exchange capacity. Therefore, prenatal treatment with betamethasone can be adopted as clinical lung maturation protocol for pregnancies at risk in order to prevent low vitality and increase neonatal survival. PMID- 28583604 TI - Prediction of the fertility of stallion frozen-thawed semen using a combination of computer-assisted motility analysis, microscopical observation and flow cytometry. AB - Spermatozoa from some stallions do not maintain an acceptable fertility after freezing and thawing. The selection of frozen ejaculates that would be suitable for insemination is mainly based on post-thaw motility, but the prediction of fertility remains limited. A recent study in our laboratory has enabled the determination of a new protocol for the evaluation of fresh stallion semen, combining microscopical observation, computer-assisted motility analysis and flow cytometry, and providing a high level of fertility prediction. The purpose of the present experiment was to perform similar investigations on frozen semen. A panel of tests evaluating a large number of compartments or functions of the spermatozoa was applied to a population of 42 stallions, 33 of which showing widely differing fertilities (17-67% pregnancy rate per cycle [PRC]). Variability was evaluated by calculating the coefficient of variation (CV=SD/mean) and the intra-class correlation or "repeatability" for each variable. For paired variables, mean within-stallion CV% was significantly lower than between-stallion CV%, which was significantly lower than total CV%. Within-ejaculate repeatability, determined by analysing 6 straws for each of 10 ejaculates, ranged from 0.60 to 0.97. Within-stallion repeatability, determined by analysing at least 5 ejaculates for each of 38 stallions, ranged from 0.12 to 0.95. Principal component regression using a combination of 25 variables, including motility, morphology, viability, oxidation level, acrosome integrity, DNA integrity and hypoosmotic resistance, accounted for 94.5% of the variability regarding fertility, and was used to calculate a prediction of the PRC with a mean standard deviation of 2.2. The difference between the observed PRC and the calculated value ranged from -3.4 to 4.2. The 90% confidence interval (90CI) for the prediction of the PRC for the stallions of unknown fertility ranged from 8 to 30 (mean = 17). The best-fit model using only motility variables, evaluated after 10 min at 36 degrees C and 2 h at 36 degrees C or room temperature, accounted for only 74.2% of the variability. The difference between the observed PRC and the calculated value ranged from -7.2 to 14. The 90CI for the prediction of the PRC for the stallions of unknown fertility ranged from 23 to 48 (mean = 33). In conclusion, this study demonstrated that an appropriate combination of computer assisted motility analysis, microscopical observation and flow cytometry can provide a higher prediction of fertility than motility analysis alone. PMID- 28583605 TI - In vitro development and cytological quality of inter-species (porcine->bovine) cloned embryos are affected by trichostatin A-dependent epigenomic modulation of adult mesenchymal stem cells. AB - Artificial epigenomic modulation of in vitro cultured mesenchymal stem cells (MSCs) by applying a non-selective HDAC inhibitor, termed TSA, can facilitate more epigenetic reprogramming of transcriptional activity of the somatic cell descended nuclear genome in NT pig embryos. The results of the present investigation showed that TSA-dependent epigenomic modulation of nuclear donor MSCs highly affects both the in vitro developmental capability and the cytological quality of inter-species (porcine->bovine) cloned embryos. The developmental competences to reach the blastocyst stage among hybrid (porcine >bovine) nuclear-transferred embryos that had been reconstructed with bovine ooplasts and epigenetically modulated porcine MSCs were maintained at a relatively high level. These competences were higher than those noted in studies by other authors, but they were still decreased compared to those of intra species (porcine) cloned embryos that had been reconstituted with porcine ooplasts and either the cell nuclei of epigenetically transformed MSCs or the cell nuclei of epigenetically non-transformed MSCs. In conclusion, MSCs undergoing TSA-dependent epigenetic transformation were used for the first time as a source of nuclear donor cells not only for inter-species somatic cell cloning in pigs but also for inter-species somatic cell cloning in other livestock species. Moreover, as a result of the current research, efficient sequential physicochemical activation of inter-species nuclear-transferred clonal cybrids derived from bovine ooplasm and porcine MSC nuclei was developed. PMID- 28583606 TI - The influence of age, antral follicle count and diestrous ovulations on estrous cycle characteristics of mares. AB - Reproductive aging must be well understood to optimize the reproductive management of older mares and to predict their reproductive life-span. The objectives of this study were to: 1) examine age-related differences in follicular dynamics, endocrine profiles, and primordial follicle counts, 2) evaluate the influence of antral follicle count (AFC) on age-related changes in follicular parameters, and 3) determine the influence of diestrous ovulations on the estrous cycle. Young (3-8yr; n = 10), middle-aged (9-18 yr; n = 16), and old (>18 yr; n = 19) light horse mares were examined with transrectal ultrasonography to monitor follicular growth over two consecutive estrous cycles. Jugular blood samples were taken and plasma progesterone and FSH concentrations were determined by an enzyme immunoassay and radioimmunoassay, respectively. Both interovulatory intervals and follicular phases were longer and the day of follicle deviation occurred later in aged mares. Furthermore, older mares had a tendency to ovulate smaller follicles. Neither follicular growth rate, the number of ovulations nor the length of luteal phase was influenced by mare age. Interestingly, as mare age increased, mares with low AFC had longer interovulatory intervals and follicular phases than mares with medium or high AFC. In addition, the number of primordial follicles declined with an increase in mare age but varied considerably between mares of the same age. Progesterone concentrations were positively influenced by age, whereas FSH concentrations were not, despite that FSH concentrations appeared higher in aged mares during the follicular phase. Estrous cycles with a diestrous ovulation had a longer interovulatory interval as well as a longer follicular and luteal phase while day of deviation occurred later. Progesterone concentrations were significantly higher on day 14 and 16 in estrous cycles with a diestrous ovulation than without a diestrous ovulation. In conclusion, aging in mares is associated with changes in follicular parameters which in turn are closely linked to differences in antral follicle count suggesting a relationship with ovarian reserve. Therefore, determination of antral follicle counts in aged mares can provide valuable information about the reproductive aging process. Finally, diestrous ovulations have a significant influence on different estrous cycle parameters. PMID- 28583607 TI - Birth of healthy calves after intra-follicular transfer (IFOT) of slaughterhouse derived immature bovine oocytes. AB - To circumvent the negative impacts of in vitro culture on bovine embryos, we have recently established a new method, the so called intra-follicular oocyte transfer (IFOT), enabling in vivo fertilization and in vivo development of in vitro matured oocytes up to the blastocyst stage as well as to term. In this study, we raised the question whether immature bovine oocytes could also be transferred into a pre-ovulatory follicle to support in vivo maturation prior to subsequent in vivo fertilization, in vivo development as well as to term. To unravel that question, a total of 791 immature oocytes were transferred in groups of ~50 into pre-ovulatory follicles of 16 recipient heifers. Consequently, we were able to recollect a total of 306 structures 8 days thereafter (38.5%). All in all, 12 heifers (75%) gave embryos developed to the morula or blastocyst stage in addition to the expected native embryos. Among all recollected structures, 40.1% had developed to the morula and/or blastocyst stage, meaning a total efficiency of 17.3% based on all transferred oocytes. Of impact, IFOT-embryos reached significantly higher developmental rates to the Morula and/or blastocyst stage until day 7 compared to in vitro cultured control embryos, despite being derived from the same charge of slaughterhouse ovaries (40.1 vs. 29.3%). This implicates a beneficial effect of the follicular environment for the intrinsic quality of the fertilized embryos during maturation and for subsequent developmental rates up to the blastocyst stage. Finally, the birth of two healthy calves after transfer of frozen-thawed IFOT-derived blastocysts to final recipients established the first proof of principle that IFOT of immature bovine oocytes generates bovine blastocysts bearing developmental capacity to term. Likewise, to the best of our knowledge, these calves are the first calves derived from full in vivo development of immature slaughterhouse derived oocytes. Thus, the results of the present study clearly demonstrate that IFOT of immature slaughterhouse derived oocytes is now a feasible technique. Since efficiencies following IFOT achieved within the present study were improved compared to previous studies, IFOT now offers an attractive option for designing new scientific experiments. PMID- 28583608 TI - The effect of dietary grape pomace supplementation on epididymal sperm quality and testicular antioxidant ability in ram lambs. AB - Wine grape pomace (WGP) contains a rich source of polyphenols that can act as powerful antioxidants. The objective of this study was to investigate the effect of dietary WGP supplementation on antioxidative activity and epididymal sperm quality in rams. The rams were raised either under free-range or pen conditions, and the pen-raised rams were fed a WGP-containing diet (0, 5% and 10% of dry matter basis) for 74 days. An increase in the concentrations of reactive oxygen species (ROS, P < 0.05) and malondialdehyde (MDA, P < 0.05) were observed in the testes of rams subjected to restraint stress, and dietary WGP supplementation effectively decreased their contents (P < 0.05). Restraint stress reduced both weight and volume of testes, and impaired sperm quality. Dietary WGP supplementation increased testes weight, sperm concentration, motility and acrosomal integrity, and decreased sperm deformity in pen-raised animals (P < 0.05). The total antioxidative capacity (T-AOC) and catalase activity were decreased in the testes of pen-raised lambs (P < 0.05), and T-AOC, catalase, glutathione peroxidase 4 (GPx4) and superoxide dismutase (SOD) activity were increased when rams were fed the WGP-containing diet (P < 0.05). With the exception of SOD and GPx4, the mRNA contents of catalase and nuclear factor-like 2 factor (Nrf2) did not vary among the groups, and greater protein levels of SOD, catalase and GPx4 were observed in WGP-treated lambs (P < 0.05). Taken together, these results suggest that WGP can be used as a feed ingredient in rams to alleviate restraint induced oxidative stress and improve epididymal sperm quality. PMID- 28583609 TI - Global hemostasis in healthy bitches during pregnancy and at different estrous cycle stages: Evaluation of routine hemostatic tests and thromboelastometry. AB - This study assessed the global hemostasis (including prothrombin time [PT], activated partial thromboplastin time [aPTT], antithrombin activity [ATA], fibrinogen and d-Dimer concentrations, platelet count, plateletcrit and thromboelastometry) in healthy pregnant bitches, comparing the results with those of healthy bitches at different estrous cycle stages, and assessed whether hemostatic changes during pregnancy are associated with serum progesterone concentration or the presence of fetuses in utero. The results show that pregnant bitches have higher fibrinogen concentration, platelet count and platelatecrit, and that fibrin and global clot formations occur faster than in non-pregnant bitches at different estrous cycle stages. Additionally, clot strength was higher in pregnant bitches than in non-pregnant ones. There were no differences in PT, ATA, and D-dimer concentration between all study groups. The aPTT was significantly shorter in bitches at the fourth and last pregnancy weeks, compared to the anestrus group, and shorter in both the fourth and last pregnancy weeks groups, compared to diestrus group. These results all support a hypercoagulable state in healthy pregnant bitches, unassociated with progesterone concentration. PMID- 28583610 TI - Effects of oocytes exposure to bovine diarrhea viruses BVDV-1, BVDV-2 and Hobi like virus on in vitro-produced bovine embryo development and viral infection. AB - As production of in vitro (IVP) bovine embryos steadily increases, the sanitary risk associated with IVP embryos remains a concern. One of the greatest concerns is how BVDV may be transmitted through IVP embryos. The objective of this study was to evaluate the effects caused by BVDV-1, BVDV-2 and Hobi-like virus exposure during in vitro maturation on embryo development and viral infection. Abittior derived oocytes were randomly assigned for in vitro maturation with serial concentrations of BVDV-1 (3.12 * 102 - 2.50 * 103 TCID50/100 MUL), BVDV-2 (6.25 * 101 - 5.20 * 102 TCID50/100 MUL) or Hobi-like virus (1.90 * 102 - 1.58 * 103 TCID50/100 MUL) for 22-24 h. After maturation, oocytes were fertilized and embryo cultured following standard in vitro procedures. Embryo development was evaluated and percentage of respective, positive BVDV degenerated and viable embryos were evaluated by RT-qPCR. No concentration of BVDV-1 altered embryo development as measured by cleavage and blastocyst rates, compared to negative control group. However 100% of degenerated embryos and 50-100% of viable embryos tested positive for BVDV-1, depending on the viral concentration. BVDV-2 exposed oocytes had higher cleavage rates than the negative control group (60.2-64.1% vs 49.8%; P = 0.003-0.032). However, no difference was detected for blastocyst rates. In aadition, 100% of degenerated embryos and 20-50% of viable embryos tested positive for BVDV-2. Hobi-like virus treated oocytes had reduced cleavage rates for the three highest viral concentrations (33.3-38.0% vs 49.8% for negative controls; P <= 0.001-0.014). Blastocyst rates were only reduced in the 7.9 * 102 Hobi-like virus concentration (6.9 +/- 0.9% vs 15.1 +/- 1.6%; P = 0.009), when calculated by oocyte number. 50-80% of degenerated embryos tested positive for Hobi-like virus. No viable embryos from the Hobi-like virus treated oocytes tested positive. These results suggest that IVP embryos from BVDV-1 and -2 infected oocytes develop normally, but carry the virus. However, Hobi-like virus infected oocytes had reduced cleavage and cause pre-implantation embryo loss, but viable embryos did not carry the virus. PMID- 28583611 TI - Pregnancy-associated glycoproteins (PAGs) concentrations in water buffaloes (Bubalus bubalis) during gestation and the postpartum period. AB - For the first time in literature this study describes the pregnancy-associated glycoprotein (PAG) profile of buffalo cows during gestation and the post-partum period using antiserum raised against PAG-molecules purified from buffalo placenta (AS#860). Ninety-eight buffalo cows, belonging to a buffalo herd subjected to a synchronization and artificial insemination (AI) program, were enrolled in this study. Blood samples were taken on days 0 (AI), 23, 25, 28, 30 and then biweekly until the end of pregnancy. Pregnancy was confirmed by ultrasonography on days 28 and 45, and by rectal palpation from day 60 onwards. Blood samples were suspended for the non-pregnant cows on day 45, while the blood of 20 buffaloes that had calved was tested every five days from the day of calving until day 50 post-calving. A cut-off value of 1.0 ng/mL was used in order to discriminate between pregnant and non-pregnant buffaloes. We used Linear Mixed models after Log(x+1) transformation to analyse the PAG concentrations. Fifty-two buffalo cows had become pregnant out of 98 synchronized (53%) and 46 remained non pregnant (47%) as shown by ultrasonography and the PAG analysis. Significant differences (P < 0.001) in PAG concentrations were observed between the pregnant and non-pregnant buffaloes from day 23 as the PAG of the non-pregnant cows was always close to zero. Conversely, the PAG of the pregnant cows increased progressively from day AI until day 105 post-insemination and then stabilized until the end of pregnancy. Regarding pregnancy diagnosis, the sensitivity of PAG RIA 860 system (ability of the test to correctly identify pregnant buffalo) ranged from 23% on day 23-98% on day 28 post AI; the specificity (ability to correctly identify non-pregnant buffaloes) was 100% throughout the sampling period. PAG progressively decreased from parturition to day 25 post-partum; from day 30 post-partum, the concentrations fell below 1 ng/mL and were close to 0 on the last day of observation (50 d post-partum). In conclusion, our results showed that RIA-860 is highly accurate for diagnosing pregnancy in buffaloes starting from day 28 of gestation. Furthermore, the rapid disappearance of PAG concentration after calving means that a cut-off limit in post-partum for detecting a new pregnancy is not required. PMID- 28583612 TI - Visual ELISA for detection of pregnancy-associated glycoproteins (PAGs) in ewe serum. AB - The aim of the present study was to evaluate the efficiency of visual ELISA-PAG for early pregnancy diagnosis based on the presence of PAG (pregnancy-associated glycoprotein) using sheep blood serum. Experiment 1: 140 ewes were divided into three groups with different stages of pregnancy. In the first group, 41 pregnant ewes were sampled at 26, 28, 30, and 32 days of pregnancy; in the second group, 65 ewes (49 pregnant with 30 days and 16 non-pregnant) were sampled; in the third group, 34 non-pregnant ewes were sampled. Experiment 2: 10 pregnant ewes were sampled weekly from day 35 of gestation until day 70 post-partum to verify the total period in which PAG can be detected in the blood serum by the test. Transrectal ultrasound was used as a gold standard. The detection or non detection of PAG was analyzed by the logistic model PROC GENMOD of SAS; differences were detected by the chi-squared test. In group 1, there were no differences between the results from 28, 30, and 32 days of gestation, but samples from 30 days were easier to interpret in comparison to 28 days, with a sensitivity of 97.56%. In the second group, using 65 sheep, visual ELISA-PAG showed 100% sensitivity and 93.75% specificity, which indicates the diagnosis of an animal as a false positive. In the third group, 97.06% of the sheep were confirmed as negative and 2.94% as positive, again indicating the presence of a false positive. In 100% of the sheep, the PAG remained in the blood circulation throughout the antepartum period until birth and seven days post-partum, declining thereafter. Based on our results, the visual ELISA-PAG is an effective method for the early diagnosis of pregnancy in sheep and can be performed from day 30 of gestation. PMID- 28583613 TI - Associations between activity of arginase or matrix metalloproteinase-8 (MMP-8) and metritis in periparturient dairy cattle. AB - Metritis, a uterine disease caused by bacterial infection, is highly prevalent in dairy cattle after parturition. Uterine disease has negative effects on milk production and reproductive efficiency. Finding markers or indicators that can predict cows at greater risk for uterine disease could be beneficial to mitigating these deleterious effects. This study investigates the immune-derived enzymes arginase and matrix metalloproteinase-8 (MMP-8) as potential markers for development of metritis in dairy cows. In a retrospective matched case-control study, 53 lactating Holstein cows diagnosed with metritis were matched and paired to 53 lactating Holstein control cows. In addition to examining cows for diagnosis of metritis on d 4, 7, 10, and 14 after parturition, occurrence of retained fetal membranes, gender of the calf, and the event of a stillbirth were recorded. Blood samples were collected 7 +/- 3 d before calving, on the day of calving, and 7 +/- 3 d after calving and were assayed for activity of arginase and MMP-8. Associations between metritis and activity of arginase or MMP-8 were determined by conditional logistic regression at each individual sampling time point. An interaction between activity of arginase, before and on the day of parturition, and retained fetal membranes tended (P <= 0.13) to be associated with metritis. After parturition, activity of arginase and the interaction between activity of arginase and retained fetal membranes were not (P >= 0.22) associated with metritis. Activity of MMP-8 was not (P >= 0.20) associated with metritis in the periparturient period. Retained fetal membranes were associated with the odds of developing metritis. Activity of arginase before and at the time of parturition might be a potential marker for occurrence of metritis, especially in cows that develop retained fetal membranes. MMP-8 does not seem to be a potential indicator for metritis. PMID- 28583614 TI - Effects of active immunization against GnRH versus surgical castration on hypothalamic-pituitary function in boars. AB - The objective was to compare effects of anti-GnRH immunization (immunocastration) versus surgical castration on hypothalamic-pituitary function in boars. Thirty six boars were randomly divided into three groups (n = 12/group): control, surgically castrated, or immunized against GnRH at 10 wk of age (boostered 8 wk later). Compared to intact boars, immunocastration reduced (P < 0.05) serum concentrations of LH, FSH, testosterone and inhibin B and caused severe testicular atrophy, whereas surgical castration increased (P < 0.05) serum concentrations of LH and FSH. Both immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis, with decreased (P < 0.05) mRNA expressions of GnRH, GnRH up-stream gatekeeper genes kiss1 and its receptor (GPR54), and androgen receptor in the hypothalamic arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), as well as GnRH content in the median eminence. Inconsistently, mRNA expressions of gonadotropin-inhibitory hormone (GnIH) in ARC and AVPV as well as its receptor (GPR147) in pituitary were selectively reduced (P < 0.05), but mRNA expressions of estrogen receptor alpha and aromatase (CPY17A1) in pituitary were selectively increased (P < 0.05) in surgical castrates. In response to selectively attenuated suppressive signaling from GnIH and testosterone, mRNA expressions of GnRH receptor (GnRHR), LH-beta and FSH-beta in pituitary were increased (P < 0.05) in surgical castrates, whereas these pituitary gene expressions were decreased (P < 0.05) in immunocastrates, due to loss of hypothalamic GnRH signaling. We concluded that immunocastration and surgical castration consistently reduced hypothalamic GnRH synthesis due to a testosterone deficiency disrupting testosterone-Kisspeptin GPR54-GnRH signaling pathways. Furthermore, selectively attenuated GnIH and testosterone signaling in the pituitary increased gonadotropin production in surgical castrates. PMID- 28583615 TI - Identification of differentially-expressed genes in early developmental ovary of Yellow River carp (Cyprinus carpio var) using Suppression Subtractive Hybridization. AB - Ovary development appears to be under polygenic control, and is influenced by multiple genetic factors that may vary from organism to organism. To gain a better insight into the molecular mechanisms of carp ovary development, Suppression Subtractive Hybridization (SSH) DNA libraries in two species of Yellow River carp were analyzed. Primordial gonads and stage II ovaries were used as testers, and adult ovaries as drivers. One hundred and fifty differentially expressed candidate genes were examined by Southern blot microarray hybridization. We identified 41 differentially-expressed genes in the PG (Primordial gonad) library and 37 in the stage II ovary library. Gene Ontology Biological Pathway analysis showed the genes were involved in signal transduction, proteolysis process, cell differentiation, TGF-beta signal and other biological responses. Twenty-two candidate genes were selected and further characterized using qRT-PCR. Pvalb, epd, and MYH were found specifically expressed in PG, while bmp2b, desmin and fp1 were specifically expressed in stage II ovary. Our results indicate that these genes could be used as biomarkers of the early development of carp ovary. This finding will provide a basis for further understanding of the complex gonad developmental molecular mechanisms in Yellow River carp. PMID- 28583616 TI - Effects of season on placental, foetal and neonatal development in horses. AB - Seasonal changes in metabolic rate have been shown in horses and we hypothesized that this leads to the birth of smaller foals early in the year. Mares and their foals were assigned to three groups by day of foaling within the year (e.g. 1 January = day 1): Group 1 (n = 10) day 40-65, group 2 (n = 8) day 67-92, group 3 (n = 9) day 94-121. Groups did not differ with regard to parity. In foals, height at withers and body weight were determined on days 1-5 and weekly until 12 weeks of age. Chest circumference, distances fetlock to carpus, carpus to elbow, poll to nose and crown-rump length were determined on day 5 and weekly until 12 weeks of age. Placental weight (p < 0.05) and surface (p < 0.01) were lower in mares of group 1 than in groups 2 and 3. Foal weight and length measurements increased over time (p < 0.001). Height at withers was consistently lower in group 1 than in groups 2 and 3 (p < 0.05) while foal weight did not differ among groups. Fetlock to carpus, carpus to elbow (both p < 0.01) and poll to nose length (p < 0.05) were lower in group 1 than in groups 2 and 3. Neither gestation length nor sex ratio of foals differed among groups. In conclusion, foetal size is reduced when the final growth phase coincides with the winter months. This also impacts neonatal growth during the first three months of life. PMID- 28583617 TI - Totally Implantable IV Treprostinil Therapy in Pulmonary Hypertension Assessment of the Implantation Procedure. AB - BACKGROUND: Prostacyclins improve symptoms and survival in pulmonary arterial hypertension (PAH). In response to risks associated with external delivery systems, an implantable IV infusion system was developed. A multicenter, prospective, single-arm, clinical trial (DelIVery for PAH) was conducted to evaluate this system for treprostinil in PAH. This analysis describes the findings related to the implant procedure. METHODS: Patients (N = 64) with PAH (World Health Organization group 1) receiving stable IV treprostinil were enrolled. Patients were transitioned to a temporary peripheral IV infusion catheter prior to the procedure. System implantation was performed at 10 centers under general anesthesia or deep IV sedation by clinicians from various specialties. Central venous access was via the cephalic, subclavian, jugular, or axillary vein. Using an introducer and fluoroscopic guidance, the distal tip of the infusion catheter was placed at the superior caval-atrial junction. The catheter was tunneled from the venous access site to an abdominal subcutaneous pocket, where the pump was placed. RESULTS: Of the 64 patients enrolled, four exited prior to implantation. All 60 implant procedures were successful. At baseline, all patients were receiving treprostinil via an external pump at a mean dose of 71.4 +/- 27.8 ng/kg/min (range: 22-142 ng/kg/min). The implant averaged 102 +/- 32 min (range: 47-184 min). Clinically significant implant procedure related complications included one pneumothorax, two infections, and one episode of atrial fibrillation. There were three postimplantation catheter dislocations in two patients. Common implant-related events that were not complications included implant site pain (83%) and bruising (17%). CONCLUSIONS: The procedure for inserting a fully implantable system for treprostinil was successfully performed, with few complications. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01321073; URL: www.clinicaltrials.gov. PMID- 28583618 TI - New Anti-Eosinophil Drugs for Asthma and COPD: Targeting the Trait! AB - Asthma and COPD are prevalent chronic inflammatory airway diseases that are responsible for a large global disease burden. Both diseases are complex and heterogeneous, and they are increasingly recognized as overlapping syndromes that may share similar pathophysiologic mechanisms and treatable traits. Eosinophilic airway inflammation is considered the most influential treatable trait of chronic airway disease, and over the last decade, several monoclonal antibodies and small molecule therapies have been developed to target this trait. These include monoclonal antibodies against IL-5 or IL-5 receptor alpha (mepolizumab, reslizumab, and benralizumab), IL-13 (lebrikizumab and tralokinumab), IL-4 receptor alpha (dupilumab), IgE (omalizumab), and anti-thymic stromal lymphopoietin (tezepelumab) and small molecule therapies such as prostaglandin D2 blockers (fevipiprant and timapiprant). Although these novel biologic agents have shown promising results in many patients with asthma and COPD who have eosinophilic airway inflammation, it is evident that not all patients respond equally well, despite similar clinical, functional, and inflammatory characteristics. This heterogeneity in treatment response is probably related to different molecular pathways or endotypes leading to eosinophilic airway inflammation, including adaptive immune pathways mediated by T helper 2 cells and innate immune pathways mediated by innate lymphoid cells. The relative contribution of these pathways in asthma and COPD is not yet clarified, and there are currently no reliable biomarkers that represent the various pathways. Therefore, there is an urgent need for easily measurable and reproducible biomarkers that are linked to underlying pathophysiologic disease mechanisms and can predict and monitor responses to novel biologic agents. PMID- 28583620 TI - Percutaneous image-guided screws meditated osteosynthesis of impeding and pathological/insufficiency fractures of the femoral neck in non-surgical cancer patients. AB - AIM: To present percutaneous image-guided screw-mediated osteosynthesis (PIGSMO) for fixation of impending fractures (ImF) and non-displaced/mildly displaced pathological/insufficient fractures (PF/InF) of the femoral neck in non-surgical cancer patients. MATERIALS AND METHODS: This is a double-centre single-arm observational study. Retrospective review of electronic records identified all oncologic patients who had undergone femoral neck PIGSMO. Inclusion criteria were: non-displaced or mildly displaced PF/InF, and ImF (Mirels' score >=8); life expectancy >=1 month; unsuitability for surgical treatment due to sub-optimal clinical fitness, refusal of consent, or unacceptable delay to systemic therapy. RESULTS: Eleven patients were treated (mean age 63.7+/-13.5 years) due to ImF (63.6%, mean Mirels' score 10.1), PF (27.3%) or post-radiation InF (9.1%) under CT/fluoroscopy- (36.4%) or CBCT- (63.6%) guidance. Thirty-two screws were implanted and cement injection was added in 36.4% cases. Technical success was 90.9%. No procedure related complications were noted. At 1-month clinical follow up (pain/walking impairment), 63.6% and 27.3% patients reported significant and mild improvement, respectively. Imaging follow-up (available in 63.6% cases) showed no signs of secondary fractures, neither of screws loosening at mean 2.8 months. Five patients (45.5%) died after PIGSMO (mean time interval 3.6 months). CONCLUSIONS: PIGSMO is technically feasible and safe in cancer patients with limited life expectancy; it offers good short-term results. Further prospective studies are required to corroborate mid- and to prove long-term efficacy of the technique. PMID- 28583621 TI - The importance of subpleural fibrosis in the prognosis of patients with idiopathic interstitial pneumonias. AB - PURPOSE: To compare computer-aided diagnostic results with histological findings obtained by surgical biopsy and evaluate whether subpleural lesion volumes can aid identification of idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: We retrospectively analyzed computed tomography (CT) images of 79 patients (43 with fibrosing nonspecific interstitial pneumonia (fNSIP) and 36 with IPF) using the Gaussian Histogram Normalized Correlation (GHNC) system. We determined the H pattern based on honeycomb and/or fibrosis with traction bronchiectasis on CT, and measured the H-pattern volume ratio at the biopsy sites and in the subpleural area. The biopsy site CT data were compared with biopsy specimens using Spearman's correlation. H-pattern volumes in the subpleural area within 2mm under the pleura (H2) were analyzed to predict IPF diagnosis and patients prognosis. RESULTS: The H-pattern volume ratio at the biopsy sites showed significant correlation with histological honeycomb (r=0.355, p<0.001), subpleural collapse (r=0.410, p<0.001), and heterogeneity (r=0.484, p<0.001). Multivariate regression analysis, adjusting for age, sex, and CT results, revealed that the H2 was a significant independent predictor of IPF diagnosis (odds ratio: 1.073; p=0.048). H2 correlated with patients' survival after adjusting for age (p=0.003). CONCLUSION: The computer-aided H-pattern volume ratio of the subpleural area indicates subpleural abnormalities quantitatively and may help diagnose IPF. PMID- 28583619 TI - The impacts of pesticide and nicotine exposures on functional brain networks in Latino immigrant workers. AB - Latino immigrants that work on farms experience chronic exposures to potential neurotoxicants, such as pesticides, as part of their work. For tobacco farmworkers there is the additional risk of exposure to moderate to high doses of nicotine. Pesticide and nicotine exposures have been associated with neurological changes in the brain. Long-term exposure to cholinesterase-inhibiting pesticides, such as organophosphates and carbamates, and nicotine place this vulnerable population at risk for developing neurological dysfunction. In this study we examined whole-brain connectivity patterns and brain network properties of Latino immigrant workers. Comparisons were made between farmworkers and non-farmworkers using resting-state functional magnetic resonance imaging data and a mixed effects modeling framework. We also evaluated how measures of pesticide and nicotine exposures contributed to the findings. Our results indicate that despite having the same functional connectivity density and strength, brain networks in farmworkers had more clustered and modular structures when compared to non farmworkers. Our findings suggest increased functional specificity and decreased functional integration in farmworkers when compared to non-farmworkers. Cholinesterase activity was associated with population differences in community structure and the strength of brain network functional connections. Urinary cotinine, a marker of nicotine exposure, was associated with the differences in network community structure. Brain network differences between farmworkers and non-farmworkers, as well as pesticide and nicotine exposure effects on brain functional connections in this study, may illuminate underlying mechanisms that cause neurological implications in later life. PMID- 28583622 TI - Current CT practice in Germany: Results and implications of a nationwide survey. AB - PURPOSE: To assess patient doses and relative frequencies of standard CT examinations performed in Germany in 2013/14 as well as the effect of modern CT technology on patient exposure. METHODS: All known CT facilities in Germany were requested to complete a questionnaire on the frequency of 34 examinations and the respective parameter settings used. Taking into account type-specific properties of each scanner, effective doses were estimated for each reported examination. The mean and the percentiles of the CT dose index, scan length, dose length product, and effective dose were determined for each type of examination. RESULTS: According to the data provided for about 11% of all medical CT scanners operated in 2013/14, the effective dose was 4.6/5.9mSv per scan/examination. The effective dose was significantly reduced by about 15% compared to the CT practice before 2010. Modern CT technology, such as tube current modulation and iterative image reconstruction reduced the effective dose significantly by 6% and 13%, respectively. The mean effective dose applied at scanners produced by different manufacturers differed by 25%, at maximum. CONCLUSION: Patient exposure was reduced substantially in recent years. There is, however, still a considerable potential for further dose reduction by adapting scan protocols to the medical purpose and by a consequent exploitation of modern CT technologies. PMID- 28583623 TI - Pre-treatment MDCT-based texture analysis for therapy response prediction in gastric cancer: Comparison with tumour regression grade at final histology. AB - PURPOSE: An accurate prediction of tumour response to therapy is fundamental in oncology, so as to prompt personalised treatment options if needed. The aim of this study was to investigate the ability of preoperative texture analysis from multi-detector computed tomography (MDCT) in the prediction of the response rate to neo-adjuvant therapy in patients with gastric cancer. MATERIAL AND METHODS: Thirty-four patients with biopsy-proven gastric cancer were examined by MDCT before neo-adjuvant therapy, and treated with radical surgery after treatment completion. Tumour regression grade (TRG) at final histology was also assessed. Image features from texture analysis were quantified, with and without filters for fine to coarse textures. Patients with TRG 1-3 were considered responders while TRG 4-5 as non- responders. The response rate to neo-adjuvant therapy was assessed both at univariate and multivariate analysis. RESULTS: Fourteen parameters were significantly different between the two subgroups at univariate analysis; in particular, entropy and compactness (higher in responders) and uniformity (lower in responders). According to our model, the following parameters could identify non-responders at multivariate analysis: entropy (<=6.86 with a logarithm of Odds Ratio - Log OR -: 4.11; p=0.003); range (>158.72; Log OR: 3.67; p=0.010) and root mean square (<=3.71; Log OR: 4.57; p=0.005). Entropy and three-dimensional volume were not significantly correlated (r=0.06; p=0.735). CONCLUSION: Pre-treatment texture analysis can potentially provide important information regarding the response rate to neo-adjuvant therapy for gastric cancer, improving risk stratification. PMID- 28583624 TI - Higher breast cancer conspicuity on dbPET compared to WB-PET/CT. AB - OBJECTIVES: The purpose of this study was to evaluate lesion detectability of a dedicated breast positron-emission tomography (dbPET) scanner for breast cancers with an updated reconstruction mode, comparing it to whole-body positron-emission tomography/computed tomography (WB-PET/CT). MATERIALS AND METHODS: A total of 179 histologically-proven breast cancer lesions in 150 females who underwent both WB PET/CT and dbPET with 18F-fluorodeoxyglucose were retrospectively analyzed. The patient/breast/lesion-based sensitivities based on visual analysis were compared between dbPET and WB-PET/CT. For lesions visible on both PET images, SUVmax values of the tumors were measured, and tumor-to-background ratios (T/B ratios) of SUVmax were compared between the two scans. Subgroup analyses according to clinical tumor stage, histopathology and histological grade were also performed. RESULTS: Patient/breast/lesion-based sensitivities were 95%, 95%, and 92%, respectively, for dbPET, and 95%, 94%, and 88%, respectively, for WB-PET/CT. Mean+/-standard deviation SUVmax values of FDG-avid tumors were 13.0+/-9.7 on dbPET and 6.4+/-4.8 on WB-PET. T/B ratios were also significantly higher in dbPET than in WB-PET/CT (8.1+/-7.1 vs. 5.1+/-4.5). In the subgroup analysis, no significant differences in sensitivities between dbPET and WB-PET/CT were found. However, T/B ratios of dbPET were significantly higher than those of WB-PET/CT in cT1c, cT2, cT3, invasive cancer, invasive carcinoma of no special type, mucinous carcinoma and Grades 1-3. CONCLUSION: No significant differences in sensitivities were identified between dbPET using an updated reconstruction mode and WB-PET/CT; however, T/B ratios of dbPET were significantly higher than those of WB-PET/CT, indicating higher tumor conspicuity on dbPET. PMID- 28583625 TI - Residual tumour detection in post-treatment granulation tissue by using advanced diffusion models in head and neck squamous cell carcinoma patients. AB - PURPOSE: To evaluate the detectability of the residual tumour in post-treatment granulation tissue using parameters obtained with an advanced diffusion model in patients with head and neck squamous cell carcinoma (HNSCC) treated by chemoradiation therapy. MATERIALS AND METHODS: We retrospectively evaluated 23 patients with HNSCC after the full course of chemoradiation therapy. The diffusion-weighted image (DWI) acquisition used single-shot spin-echo echo-planar imaging with 11 b-values (0-1000). We calculated 10 DWI parameters using a mono exponential model, a bi-exponential model, a stretched exponential model (SEM), a diffusion kurtosis imaging (DKI) model and a statistical diffusion model (SDM) in the region of interest (ROI) placed on the post-treatment granulation tissue. The presence of residual tumour was determined by histological findings or clinical follow-up. RESULTS: Among the 23 patients, seven patients were revealed to have residual tumour. The univariate analysis revealed significant differences in six parameters between the patients with and without residual tumour. From the receiver operating characteristic curve analysis, the highest area under curve was detected in the center of the Gaussian distribution of diffusion coefficient (Ds) obtained by the SDM. The multivariate analysis revealed that the Ds and diffusion heterogeneity (alpha) obtained by the SEM were predictors for the presence of residual tumour. CONCLUSION: DWI parameters obtained by advanced fitting models will be one of the diagnostic tools for the detection of residual tumour. PMID- 28583626 TI - Does apparent diffusion coefficient predict the degree of liver regeneration of donor and recipient after living donor liver transplantation? AB - OBJECTIVE: To elucidate the relationship between the ADCs of the liver graft and the remnant liver and the degree of liver regeneration in LDLT. MATERIALS AND METHODS: 15 recipients and 15 corresponding donors underwent magnetic resonance imaging and computed tomography 1-2 weeks after living donor liver transplantation (LDLT). For diffusion-weighted imaging (DWI), a single-shot echo planar sequence with b-factors of 0, 500, and 1000s/mm2 was scanned. ADCs of the liver parenchyma were calculated at b factors of 0 and 500 and 1000 (ADC 0-500 1000) or 0 and 500 (ADC 0-500) or 500 and 1000 (ADC 500-1000). The liver volume ratio at LDLT, the mean ADCs and the regeneration rate were compared between the graft and the remnant liver using paired-t tests. RESULTS: The mean liver volume ratio of the recipients (41.3+/-9.8%) tended to be smaller than that of the donors (51.8+/-13.8%). The mean ADC 0-500 of the remnant liver (1.72+/-0.33) was significantly higher than that of the graft (1.43+/-0.32). The regeneration rate of the graft (2.07+/-0.41) was significantly higher than that of the remnant liver (1.53+/-0.49). CONCLUSION: ADC 0-500 can describe differences in blood perfusion between liver grafts and the remnant liver according to the degree of liver regeneration. PMID- 28583627 TI - Resectable pancreatic adenocarcinoma: Role of CT quantitative imaging biomarkers for predicting pathology and patient outcomes. AB - BACKGROUNDS: Patients with a pancreatic cancer amenable to surgery still have a poor prognosis and high risk of post-operative recurrence. We aimed to assess the value of quantitative imaging biomarkers using computed-tomography (CT) texture analysis to evaluate the pathologic tumor aggressiveness and predict disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma. METHODS: We retrospectively performed attenuation measurements and texture analysis on the portal-venous phase of the pre-operative CT scan of 99 patients that underwent resection of a pancreatic ductal adenocarcinoma in two university hospitals. Tumor attenuation parameters included: mean attenuation value of the whole tumor (WHOLE-AV), and of the most hypoattenuating area within the tumor (CENTRAL-AV). Tumor heterogeneity parameters included: standard deviation, entropy, skewness, and kurtosis. RESULTS: Tumor attenuation parameters showed significant association with the tumor differentiation grade (CENTRAL-AV, Odds ratio (OR) 0.968, 95% confidence interval (CI) 0.94-0.998) and lymph node invasion (WHOLE AV, OR 0.886, CI 0.823-0.955). Variables associated with early-recurrence were: lymph node ratio (R2=0.15), kurtosis (R2=0.08), and CENTRAL-AV (R2=0.04). Lymph node ratio (Hazard ratio (HR) 1.02), and CENTRAL-AV (HR 0.98) were independently associated with shorter DFS. Patients with CENTRAL-AV<62 Hounsfield units had a shorter 1-year DFS (35% versus 68%, p=0.004). CONCLUSION: Tumors that are more hypoattenuating on the portal-venous phase on CT scan are potentially more aggressive with higher tumor grade, greater lymph node invasion, and shorter DFS. PMID- 28583628 TI - Lymph node metastasis in head and neck squamous carcinoma: Efficacy of intravoxel incoherent motion magnetic resonance imaging for the differential diagnosis. AB - PURPOSE: To evaluate the value of pure molecular diffusion(D), perfusion-related diffusion (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC) based on intravoxel incoherent motion (IVIM) theory for differential diagnosis of metastatic lymph nodes (LNs) in head and neck squamous cell carcinoma(HNSCC). MATERIALS AND METHODS: 29 patients with HNSCC and 20 patients with lymph node hyperplasia (LNH) were enrolled in this retrospective study, underwent magnetic resonance (MR) examination. IVIM Diffusion-weighted imaging (IVIM-DWI) was performed with 13 b values. D, D*, f and ADC values were compared between two groups. The diagnostic value of ADC, D, D* and D.D* value were evaluated by Receiver operating characteristic (ROC) curve. Two radiologists measured D, D*, f and ADC values independently. RESULTS: 33 malignant LNs in HNSCC group and 22 benign LNs in LNH group (minimum diameter, >=5mm) were successfully examined, ADC(P<0.05), D (P<0.01) and f (P<0.01) were significantly lower in malignant LNs than that in benign LNs, whereas D* was significantly higher (P<0.01). The area under the ROC curve (AUC) for D.D* was 0.983 and was larger than that for D* (0.952), D (0.78) and ADC (0.67). CONCLUSION: Our results indicate that IVIM DWI is feasible in the diagnosis of LN metastasis. D was significantly decreased in malignant LNs reflected increased nuclear-to-cytoplasmic ratio tissue, and D* was significantly increased reflected increased blood vessel generation and parenchymal perfusion in malignant LNs. PMID- 28583629 TI - Evaluation of postoperative lung volume and perfusion changes by dual-energy computed tomography in patients with lung cancer. AB - PURPOSE: The aim of our study was to retrospectively evaluate postoperative physiologic changes in lung cancer patients using dual-energy CT (DECT), and develop modified methods reflecting postoperative change for predicting pulmonary function. METHODS AND MATERIALS: 88 patients (M:F=64:24; mean age, 63.5 years) with lung cancer who underwent DECT and pulmonary function tests before and after operation were included. Volume and iodine values for perfusion of each lobe were quantified. The predicted postoperative FEV1 using the current method was calculated by multiplying the preoperative FEV1 by the fractional contribution of perfusion of the remaining lung. The modified method reflecting postoperative volume change was compared to the current method. RESULTS: Postoperative lung volume showed compensatory increases in the contralateral and remaining ipsilateral lobes, with a significantly greater increase in the ipsilateral lobe than contralateral lobe (21.8%+/-46.2% vs. 10.0%+/-20.8%, P=0.031). Perfusion analysis showed blood volume increases in both ipsilateral and contralateral lobes without statistical differences (blood volume ratio difference, 29.2%+/ 26.7 vs. 24.6%+/-16.5, P=0.368). The performance of the modified method considering postoperative lung volume change was comparable to that of the current method in the development and validation datasets (95% CI, -24.5% to 37.1% vs. -33.3% to 22.2% and -23.6% to 32.0% vs. -31.9% to 16.0%, respectively). CONCLUSIONS: Postoperative compensatory increases in lung volume and perfusion occur in different ways. Our modified method incorporating postoperative lung volume changes can be considered a comparable method for prediction of postoperative lung function. PMID- 28583630 TI - Evaluating the effect of rectal distension on prostate multiparametric MRI image quality. AB - PURPOSE: To evaluate the effect of rectal distension on the quality of anatomical and functional prostate multiparametric (mp) MRI. MATERIALS AND METHODS: Multiparametric (mp) 3T-MRI images of 173 patients were independently evaluated by two radiologists in this retrospective study. Planimetry rectal volumes were derived and a subjective assessment of rectal distension was made using a 5-point Likert scale (1=no stool/gas, 5=large amount of stool/gas). Image quality of diffusion-weighted imaging (DWI) was evaluated using a 5-point Likert scale. DWI was further scored for distortion and artefact. T2W images were evaluated for image sharpness and the presence of motion artefact. The stability of the dynamic contrast-enhancement acquisition was assessed by recording the number of corrupt data points during the wash-out phase. RESULTS: There was a strong correlation between subjective scoring of rectal loading and objectively measured rectal volume (r=0.82), p<0.001. A significant correlation was shown between increased rectal distension and both reduced DW image quality (r=-0.628, p<0.001), and increased DW image distortion (r=0.814, p<0.001). There was also a significant trend for rectal distension to increase artefact at DWI (r=0.154, p=0.042). Increased rectal distension led to increased motion artefact on T2 (p=0.0096), but did not have a significant effect on T2-sharpness (p=0.0638). There was no relationship between rectal distension and DCE image quality (p=0.693). 63 patients underwent lesion-targeted biopsy post MRI, there was a trend to higher positive predictive values in patients with minor rectal distension (34/38, 89.5%) compared to those with moderate/marked distension (18/25, 72%), p=0.09. CONCLUSION: Rectal distension has a significant negative effect on the quality of both T2W and DW images. Consideration should therefore be given to bowel preparation prior to prostate mpMRI to optimise image quality. PMID- 28583631 TI - Repeated surgeries in invasive lobular breast cancer with preoperative MRI: Role of additional carcinoma in situ and background parenchymal enhancement. AB - OBJECTIVES: Analysing the influence of additional carcinoma in situ (CIS) and background parenchymal enhancement (BPE) in preoperative MRI on repeated surgeries in patients with invasive lobular carcinoma (ILC) of the breast. METHODS: Retrospective analysis of 106 patients (mean age 58.6+/-9.9years) with 108 ILC. Preoperative tumour size as assessed by MRI, mammography and sonography was recorded and compared to histopathology. In contrast-enhanced MRI, the degree of BPE was categorised by two readers. The influence of additionally detected CIS and BPE on the rate of repeated surgeries was analysed. RESULTS: Additional CIS was present in 45.4% of the cases (49/108). The degree of BPE was minimal or mild in 80% of the cases and moderate or marked in 20% of the cases. In 17 cases (15.7%) at least one repeated surgery was performed. In n=15 of these cases, repeated surgery was performed after BCT (n=9 re-excisions, n=6 conversions to mastectomy), in n=2 cases after initial mastectomy. The initial surgical procedure (p=0.008) and additional CIS (p=0.046) significantly influenced the rate of repeated surgeries, while tumour size, patient age and BPE did not (p=ns). CONCLUSIONS: Additional CIS was associated with a higher rate of repeated surgeries, whereas BPE had no influence. PMID- 28583632 TI - Alternative imaging strategy of solitary pulmonary nodule by FDG PET/CT: Can be imagined a tailored PET? AB - OBJECTIVE: Patients with solitary pulmonary nodule (SPN) are usually sent to total-body positron emission tomography/computed tomography (PET/CT) examination with 18F-fluorodeoxyglucose (FDG). However, a segmental scan strategy may improve cost/effectiveness in this category of patients. CONCLUSION: A segmental PET/CT scan only at the chest level could be performed in patients with indeterminate SPN. Limiting the PET/CT field to the thoracic region would greatly affect on radiobiology, department organization and health-care costs. PMID- 28583633 TI - Magnetic resonance imaging of the prostate at 1.5 versus 3.0T: A prospective comparison study of image quality. AB - OBJECTIVES: This study prospectively evaluates objective image quality (IQ), subjective IQ, and PI-RADS scoring of prostate MRI at 3.0T (3T) and 1.5T (1.5T) within the same patients. METHODS: Sixty-three consecutive patients (64+/-9years) were prospectively included in this non-inferiority trial, powered at 80% to demonstrate a <=10% difference in signal-to-noise (SNR) and contrast-to-noise ratio (CNR) of T2-weighted and diffusion-weighted imaging (T2WI, DWI) at 1.5T compared to 3T. Secondary endpoints were analysis of subjective IQ and PI-RADS v2 scoring. RESULTS: All patients received multi-parametric prostate MRI on a 3T (T2WI, DWI, DCE) and bi-parametric MRI (T2WI, DWI) on a 1.5T scanner using body coils, respectively. SNR and CNR of T2WI were similar at 1.5T and 3T (p=0.7-1), but of DWI significantly lower at 1.5T (p<0.01). Subjective IQ was significantly better at 3T for both, T2WI and DWI (p<0.01). PI-RADS scores were comparable for both field strengths (p=0.05-1). Inter-reader agreement was excellent for subjective IQ assessment and PI-RADS scoring (k=0.9-1). CONCLUSION: Prostate MRI at 1.5T can reveal comparable objective image quality in T2WI, but is inferior to 3T in DWI and subjective IQ. However, similar PI-RADS scoring and thus diagnostic performance seems feasible independent of the field strength even without an endorectal coil. PMID- 28583634 TI - Texture analysis of baseline multiphasic hepatic computed tomography images for the prognosis of single hepatocellular carcinoma after hepatectomy: A retrospective pilot study. AB - OBJECTIVE: To assess the prognostic value of texture analysis for single hepatocellular carcinomas (HCCs) after hepatectomy. MATERIALS AND METHODS: A total of 61 HCC patients were enrolled in this retrospective study. Textural characteristics of the computed tomography (CT) images were quantified. The differences between the hepatic arterial phase and the portal venous phase were obtained (the Dif.). The receiver operating characteristic (ROC) curves were used for data screening. Cox regression analyses were performed to determine independent factors adjusted with the derived clinical and radiological variables. Model identifications were based on Akaike information criteria. Kaplan-Meier and log-rank tests were performed for overall survival (OS) and disease-free survival (DFS). RESULTS: ROC and Cox regression analyses identified five parameters. Filter 1.0 achieved the best performance, in which the Dif.Scale 1.2 was a superior indicative independent marker for OS (p=0.05). Kaplan-Meier analyses further demonstrated that the Dif.Scale2.2 at filter 0 (p=0.001), Dif.Scale1.2 (p=0.006), Dif.Scale3.2 (p=0.005) at filter 1.0, Dif.Wavelet 8 at filter 1.5 (p<0.001), and corona (p=0.032) were associated with OS. Moreover, Dif.Scale 2.2 at filter 0 (p=0.039), Dif.Scale1.2 at filter 1.0 (p=0.001), and Dif.Wavelet 8 at filter 1.5 (p=0.007) were associated with DFS, while the Barcelona-Clinic Liver Cancer (BCLC) parameters showed no statistical correlation with OS (p=0.057). CONCLUSIONS: For patients with a single HCC treated by hepatectomy, the textural features for Gabor and Wavelet, especially the varying Dif., potentially provided prognostic information beyond traditional indicators such as those of the BCLC. PMID- 28583635 TI - Influence of PET reconstruction technique and matrix size on qualitative and quantitative assessment of lung lesions on [18F]-FDG-PET: A prospective study in 37 cancer patients. AB - PURPOSE: To evaluate the influence of point spread function (PSF)-based reconstruction and matrix size for PET on (1) lung lesion detection and (2) standardized uptake values (SUV). METHODS: This prospective study included oncological patients who underwent [18F]-FDG-PET/CT for staging. PET data were reconstructed with a 2D ordered subset expectation maximization (OSEM) algorithm, and a 2D PSF-based algorithm (TrueX), separately with two matrix sizes (168*168 and 336*336). The four PET reconstructions (TrueX-168; OSEM-168; TrueX-336; and OSEM-336) were read independently by two raters, and PET-positive lung lesions were recorded. Blinded to the PET findings, a third independent rater assessed lung lesions with diameters of >4mm on CT. Subsequently, PET and CT were reviewed side-by side in consensus. Multi-factorial logistic regression analyses and two way repeated measures analyses of variance (ANOVA) were performed. RESULTS: Thirty-seven patients with 206 lung lesions were included. Lesion-based PET sensitivities differed significantly between reconstruction algorithms (P<0.001) and between reconstruction matrices (P=0.022). Sensitivities were 94.2% and 88.3% for TrueX-336; 88.3% and 85.9% for TrueX-168; 67.8% and 66.3% for OSEM-336; and 67.0% and 67.9% for OSEM-168; for rater 1 and rater 2, respectively. SUVmax and SUVmean were significantly higher for images reconstructed with 336*336 matrices than for those reconstructed with 168*168 matrices (P<0.001). CONCLUSION: Our results demonstrate that PSF-based PET reconstruction, and, to a lesser degree, higher matrix size, improve detection of metabolically active lung lesions. However, PSF-based PET reconstructions and larger matrix sizes lead to higher SUVs, which may be a concern when PET data from different institutions are compared. PMID- 28583636 TI - Metabolic profile of liver damage in non-cirrhotic virus C and autoimmune hepatitis: A proton decoupled 31P-MRS study. AB - PURPOSE: To study liver 31P MRS, histology, transient elastography, and liver function tests in patients with virus C hepatitis (HCV) or autoimmune hepatitis (AIH) to test the hypothesis that 31P MR metabolic profile of these diseases differ. MATERIALS AND METHODS: 25 patients with HCV (n=12) or AIH (n=13) underwent proton decoupled 31P MRS spectroscopy performed on a 3.0T MR imager. Intensities of phosphomonoesters (PME) of phosphoethanolamine (PE) and phosphocholine (PC), phosphodiesters (PDE) of glycerophosphoethanolamine (GPE) and glycerophosphocholine (GPC), and gamma, alpha and beta resonances of adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide phosphate (NADPH) were determined. Liver stiffness was measured by transient elastography. Inflammation and fibrosis were staged according to METAVIR from biopsy samples. Activities of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALT) and thromboplastin time (TT) were determined from serum samples. RESULTS: PME had a stronger correlation with AST (z=1.73, p=0.04) and ALT (z=1.77, p=0.04) in HCV than in AIH patients. PME, PME/PDE, PE/GPE correlated positively and PDE negatively with inflammatory activity. PE, PC and PME correlated positively with liver function tests. CONCLUSION: 31P-MRS suggests a more serious liver damage in HCV than in AIH with similar histopathological findings. 31P-MRS is more sensitive in detecting inflammation than fibrosis in the liver. PMID- 28583637 TI - Results of a prospective clinical study on the diagnostic performance of standard magnetic resonance imaging in comparison to a combination of 3T MRI and additional CT imaging in Kienbock's disease. AB - PURPOSE: This prospective clinical study examined standard wrist magnetic resonance imaging (MRI) examinations and the incremental value of computed tomography (CT) in the diagnosis of Kienbock's disease (KD) with regard to reliability and precision in the different diagnostic steps during diagnostic work-up. MATERIALS AND METHODS: Sixty-four consecutive patients referred between January 2009 and January 2014 with positive initial suspicion of KD according to external standard wrist MRI were prospectively included (step one). Institutional review board approval was obtained. Clinical examination by two handsurgeons were followed by wrist radiographs (step two), ultrathin-section CT, and 3T contrast enhanced MRI (step three). Final diagnosis was established in a consensus conference involving all examiners and all examinations results available from step three. RESULTS: In 12/64 patients, initial suspicion was discarded at step two and in 34/64 patients, the initial suspicion of KD was finally discarded at step three. The final external MRI positive predictive value was 47%. The most common differential diagnoses at step three were intraosseous cysts (n=15), lunate pseudarthrosis (n=13), and ulnar impaction syndrome (n=5). A correlation between radiograph-based diagnoses (step two) with final diagnosis (step three) showed that initial suspicion of stage I KD had the lowest sensitivity for correct diagnosis (2/11). Technical factors associated with a false positive external MRI KD diagnosis were not found. CONCLUSION: Standard wrist MRI should be complemented with thin-section CT, and interdisciplinary interpretation of images and clinical data, to increase diagnostic accuracy in patients with suspected KD. PMID- 28583638 TI - A Phase I clinical trial of the knee to assess the correlation of gagCEST MRI, delayed gadolinium-enhanced MRI of cartilage and T2 mapping. AB - PURPOSE: Osteoarthritis (OA) is associated with the loss of glycosaminoglycan (GAG) during disease progression, which can be detected by glycosaminoglycan chemical exchange-dependent saturation transfer (gagCEST) MRI. Delayed gadolinium enhanced MRI of cartilage (dGEMRIC) is considered one of the standard methods for GAG quantification in vivo. This Phase I study assessed the correlation between gagCEST MRI and dGEMRIC in determining cartilage GAG concentration. Standard T2 mapping was used as a comparator with the two other methods. MATERIALS AND METHODS: Eight athletic volunteers with no known knee diseases were recruited in this study. The sagittal images of both knees in each volunteer were obtained by a 3T MRI system. GAG concentration was calculated based on fixed charge density (FCD) within articular cartilage as calculated by T1 values obtained from dGEMRIC sequences. Magnetization transfer ratio asymmetry (MTRasym) of the CEST spectrum at 1ppm was determined with gagCEST MRI. T2 values were calculated using a multi echo turbo spin echo (TSE) sequence. The Pearson correlations among MTRasym were calculated from gagCEST analysis. RESULTS: There was moderate correlation (correlation coefficient r=0.55) between dGEMRIC and gagCEST MRI results. T2 had a low correlation (r=-0.30) with gagCEST and no correlation with dGEMRIC (r=0.003). Both gagCEST and dGEMRIC were able to distinguish between high GAG concentration cartilage compartments (higher than 210mM) and low GAG cartilage compartments (lower than 210mM). CONCLUSION: dGEMRIC was shown to be a more accurate and sensitive clinical imaging tool in evaluating cartilage GAG levels in vivo. While GagCEST showed less sensitivity to GAG concentration variations than dGEMRIC, further improvements may yet enable gagCEST to be a clinically robust methodology. PMID- 28583639 TI - CT and MRI findings of type I and type II epithelial ovarian cancer. AB - OBJECTIVE: To assess whether types I and II epithelial ovarian cancer (EOC) differ in CT and MRI imaging features. METHODS: For this retrospective study, we enrolled 65 patients with 68 ovarian lesions that have been pathologically proven to be EOC. Of these patients, 38 cases underwent MR examinations only, 15 cases underwent CT examinations only, and 12 cases completed both examinations. The clinical information [age, CA-125, menopausal status, and Ki-67] and imaging findings were compared between two types of EOCs. The diagnostic performance of image findings were assessed by receiver-operating characteristic curve(ROC) analysis. The association between EOC type and imaging features was assessed by multivariate logistic regression analysis. The random forest approach was used to build a classifier in differential diagnosis between two types of EOCs. RESULTS: Of the 68 EOC lesions, 24 lesions were categorized as types I and other 44 lesions as type II based on the immunohistochemical results, respectively. Patients in type I EOCs were more likely to involve menopausal women and showed lower CA-125 and Ki-67 values (Ki-67<30%) than patients in type II EOCs. The imaging characteristics of type II EOCs frequently demonstrated a solid or predominantly solid mass (38.6% vs. 12.5%, P<0.05), smaller lesions (diameter <6cm; 27.3% vs. 4.2%, P<0.05), absence of mural nodules (65.9% vs. 25.9%, P=0.001), and mild enhancement (84.1% vs. 54.2%, P<0.05) compared to type I EOCs. Combination of tumor size, morphology, mural nodule, enhancement degrees (AUC=0.808) has a higher specificity (87.50%) and positive predictive value (90.0%) than any single image finding alone in differential diagnosis between two types of EOCs. The multivariate logistic regression analysis showed that enhancement degrees(OR 0.200, P<0.05),mural nodule(OR 0.158, P<0.05) significantly influence EOC classification. Random forests model identified both as the most important discriminating variables. The diagnostic accuracy of the classifier was 73.53%. CONCLUSIONS: Differences in imaging characteristics existed between two types of EOCs. Combination of several image findings improved the preoperative diagnostic performance, which is helpful for the clinical treatment and prognosis evaluation. PMID- 28583640 TI - The role of ultrasound-guided fine needle aspiration biopsy in musculoskeletal diseases. AB - Ultrasonography (US) is a readily available non-invasive tool useful for the detection of musculoskeletal and soft tissue masses. Although X-Ray is often the first imaging study for evaluating both bone and soft tissue lesions, and magnetic resonance imaging and computed tomography are mandatory in lesions staging, US is increasingly used for the early assessment of musculoskeletal and soft-tissue masses and for guiding procedures and biopsies. Surgical biopsy or fine needle aspiration biopsy (FNAB) is needed to ascertain the nature of any lesion. FNAB is a low cost technique, safer and less traumatic than an open surgical biopsy. Significant complications are rare, mostly related to the site of biopsy. Knowledge of indications, limitations, anatomical and pathological access, adequate technical expertise in US imaging and in intervention skills are the critical factors of the appropriate and safe use of FNAB. By now, the role of FNAB in musculoskeletal diseases is controversial and there is still a heated debate in the scientific community. PMID- 28583642 TI - Ultrasonography for the diagnosis of craniosynostosis. AB - OBJECTIVES: The aim of this study was to report our experience with ultrasonography in our routine practice for the diagnosis of cranial deformity in infants. METHODS: We conducted a single-institution retrospective study of infants referred to our department because of skull deformity. We only included in this study infants having undergone both US and 3D-CT to ensure accurate comparisons. Each cranial suture was described as normal or closed (partial or complete closure). Sonography examination results were correlated with 3D-CT findings as a gold-standard. RESULTS: Forty infants were included with a mean age of 5.2+/-4.9months. Thirty had a craniosynostosis and 10 children had a postural deformity with normal sutures. Correlation between US and 3D-CT for the diagnosis of normal or closed suture had a specificity and a sensitivity of 100%. US examination for the diagnosis of complete or incomplete synostosis had a sensitivity of 100%. CONCLUSIONS: Cranial US is an effective technique to make a positive or negative diagnosis of prematurely closed suture. US examination of sutures is a fast and non-radiating technique, which may serve as a first-choice imaging modality in infants with skull deformity. PMID- 28583641 TI - Osteochondral lesion depth on MRI can help predict the need for a sandwich procedure. AB - PURPOSE: Autologous subchondral bone grafting in combination with autologous chondrocyte implantation (ACI) (sandwich procedure) is a well-accepted procedure for the treatment of osteochondral lesions of the knee. This requires a different surgical technique and preoperative planning compared to ACI alone. In addition, pain from bone marrow donor site locations can be expected and should be part of patient consent and expectations. This study evaluates whether the MRI made as part of the standard preoperative cartilage patient work up has the diagnostic accuracy to predict the need for a sandwich procedure. METHODS AND MATERIALS: Retrospectively, 185 preoperative MRI scans (PD and T2 sequences) of patients planned for ACI were included. The integrity of the subchondral bone and lamina was scored by four different observers (3 radiologists, and 1 orthopaedic resident). The depth of the defect was measured perpendicular from articulating surface to the bottom of the bony lesion. The area under the curve (AUC) for subchondral defect on MRI (i.e. lamina or bone defect or expert impression), depth measurements and eventual sandwich procedure were calculated. Also inter observer Kappa values were determined. RESULTS: The AUCs for lamina (0.74-0.80) and bone defect (0.73-0.79) were fair and inter-observer Kappas ranged from 0.49 to 0.76, indicating a moderate-good inter-observer agreement and moderate prediction of the need for a sandwich procedure based on the presence of lamina and or subchondral bone defect on MRI. However, depth measurements resulted in an AUC of 0.90 (95% CI: 0.84-0.95,) with an optimal cut-off point at 6.5mm depth of the lesion (90% sensitivity, 80% specificity) to predict the need for a sandwich procedure. CONCLUSION: Ours is the first study examining MRI as a diagnostic tool in predicting the need for a sandwich procedure. Our results show that the integrity of the subchondral layer on MRI has a moderate role in predicting the need for an eventual autologous bone graft to augment ACI whereas in our cohort a depth of the lesion above 6.5mm accurately predicts the need for a sandwich procedure. This can aid in optimising the preoperative planning and patient consent. PMID- 28583643 TI - Utility of T1-weighted MRI as a predictor of liver lesion visibility on ultrasound: A clinical tool to determine feasibility of ultrasound-guided percutaneous interventions. AB - PURPOSE: To determine the utility of fat-suppressed T1-weighted gradient recalled echo (FS-T1W-GRE) MRI to predict visibility of focal liver lesions (FLL) on abdominal ultrasound (US). MATERIALS AND METHODS: With IRB approval, between 2010 and 2013, 109 patients (28.4% females, age 66.9+/-10.9years) with 177 FLL (hepatocellular carcinoma=132, metastases=44, other=1) underwent MRI and prospective, radiologist-performed treatment-planning US (to determine eligibility for US-guided ablation). MRI examinations were reviewed by a blinded radiologist who assessed: a) size and location of FLL, b) presence of hepatic steatosis on dual-echo T1W-GRE, and c) quantitative signal intensity of FLL relative to liver on FS-T1W-GRE. Associations between MR imaging findings and visibility on US were assessed using independent t-tests and the chi-squares test. RESULTS: 69.5% (123/177) FLL were identified with US and 30.5% (54/177) were not visible. Size of FLL on MRI was associated with visibility on US (p<0.0001) with no association between FLL visibility on US and segmental or subcapsular location (p=0.29 and p=0.25, respectively). 20.2% (22/109) patients had hepatic steatosis on MRI, which was not associated with non-visibility of FLL on US (p=0.67). 38.4% (68/177) FLL were isointense to liver on FS-T1W-GRE which was associated with non-visibility on US (p=0.036) particularly in non-steatotic livers (p=0.014). CONCLUSION: FLL size and isointensity of FLL to liver parenchyma on FS-T1W-GRE MRI are associated with non-visibility on US, particularly in non-steatotic livers. These results have implications when planning US-guided percutaneous interventions of FLL detected with MRI. PMID- 28583644 TI - Improved detection of melanoma metastases by iodine maps from dual energy CT. AB - OBJECTIVE: Metastatic disease in melanoma has an unpredictable nature with deposits in rare locations such as musculature. Dual energy CT (DECT) provides high contrast-visualization of enhancement by using spectral properties of iodine. Purpose of this study was to evaluate whether iodine maps from DECT improve lesion detection in staging examinations of melanoma patients. METHODS: This retrospective study was approved by IRB and written informed consent was obtained from all patients. 75 contrast-enhanced DECT scans (thorax and abdomen) from 75 melanoma patients (n=69 stage IV; n=6 stage III) were analysed. For each patient, conventional CT and iodine maps were reviewed independently by two radiologists. The number of lesions detected by reviewing the iodine maps following conventional CT was recorded. Unweighted Cohens Kappa coefficient (kappa) was used for concordance analysis, Wilcoxon test for comparing lesion detection rates. RESULTS: In 26 patients, at least one reader found additional lesions on iodine maps (inter-reader agreement 89%, kappa=0.74 (0.742-0.747)). Compared to grey-scale images, mean detection rate for metastases improved from 86% (range 82-90) to 94% (90-99%) (p<=0.01), for muscle metastases from 8% (8-8%) to 99% (98-100%) (p<=0.06). Findings included 2 pulmonary emboli. CONCLUSION: Iodine maps from DECT improve detection of metastases, especially muscle metastases, and relevant findings in staging examinations of melanoma patients. PMID- 28583645 TI - Diagnostic value of dynamic contrast-enhanced CT with perfusion imaging in the quantitative assessment of tumor response to sorafenib in patients with advanced hepatocellular carcinoma: A feasibility study. AB - PURPOSE: To investigate the feasibility of perfusion-CT (p-CT) measurements in quantitative assessment of hemodynamic changes related to sorafenib in patients with advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Twenty-two patients with advanced HCC underwent p-CT study (256-MDCT scanner) before and 2 months after sorafenib administration. Dedicated perfusion software generated a quantitative map of arterial and portal perfusion and calculated the following perfusion parameters in target liver lesion: hepatic perfusion (HP), time-to-peak (TTP), blood volume (BV), arterial perfusion (AP), and hepatic perfusion index (HPI). After the follow-up scan, patients were categorized as responders and non responders, according to mRECIST. Perfusion values were analyzed and compared in HCC lesions and in the cirrhotic parenchyma (n=22), such as between baseline and follow-up in progressors and non-progressors. RESULTS: Before treatment, all mean perfusion values were significantly higher in HCC lesions than in the cirrhotic parenchyma (HP 47.8+/-17.2 vs 13.3+/-6.3mL/s per 100g; AP 47.9+/-18.1 vs 12.9+/ 10.7mL/s; p<0.001). The group that responded to sorafenib (n=17) showed a significant reduction of values in HCC target lesions after therapy (HP 29.2+/ 23.3 vs 48.1+/-15.1; AP 29.4+/-24.6 vs 49.2+/-17.4; p<0.01), in comparison with the non-responder group (n=5) that demonstrated no significant variation before and after treatment of HP (46.9+/-25.1 vs 46.7+/-24.1) and AP (43.4+/-21.7 vs 43.5+/-24.6). Among the responder group, HP percentage variation (Delta) in target lesions, during treatment, showed a significantly different (p=0.04) DeltaHP in the group with complete response (79%) compared to the group with partial response or stable disease (16%). CONCLUSIONS: p-CT technique can be used for HCC quantitative assessment of changes related to anti-angiogenic therapy. Identification of response predictors might help clinicians in selection of patients who may benefit from targeted-therapy allowing for optimization of individualized treatment. PMID- 28583646 TI - Transplant renal artery stenosis: Evaluation with contrast-enhanced ultrasound. AB - OBJECTIVE: To assess the efficacy of contrast-enhanced ultrasound (CEUS) in depicting transplant renal artery stenosis (TRAS). MATERIALS AND METHODS: Seventy eight patients (56 men and 22 women; aged 36+/-12.2years) who were suspected of TRAS due to either Doppler ultrasound (DUS) abnormalities or difficult control of blood pressure and/or persistent deterioration of renal function were enrolled to perform CEUS. The reference standard for the TRAS diagnoses was computed tomography angiography (CTA). The diagnostic performance of DUS and CEUS parameters was assessed by the area under the receiver operating characteristic curve (AUC). RESULTS: TRAS was diagnosed in 32 out of 78 cases by CTA. The AUC, accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CEUS in predicting TRAS were 0.92, 92.3%, 87.5%, 95.7%, 93.3%, and 91.7%, respectively. CEUS rectified 13 (28.3%) false-positive cases on DUS, which were confirmed by CTA. Compared to DUS parameters, CEUS showed the highest AUC, statistically significant differences of AUC were found (P=0.006 0.039), except for that of the PSV ratio in the main transplant renal artery to that in interlobar artery (PSV-ratio) (AUC: 0.92 versus 0.86, P=0.422). However, CEUS showed a significantly higher specificity (95.7% versus 76.1%, P=0.008) and the same sensitivity compared to PSV-ratio. CONCLUSIONS: CEUS is superior to DUS in depicting TRAS. Moreover, our results suggest that CEUS might potentially be used as a noninvasive tool to spare many patients from unnecessary CTA. PMID- 28583647 TI - Institutional (local) diagnostic reference levels in fluoroscopically guided spine surgery. AB - In this study, institutional (local) diagnostic reference levels (LDRLs) and action levels (ALs) for spine interventional procedures are reported. Fluoroscopy time (FT), kerma area product (KAP), cumulative dose (CD), as well as anatomical, clinical and technical factors affecting procedure complexity were recorded for 156 patients who underwent cervical and thoraco-lumbar interventions. Patient entrance surface dose (ESD), effective dose (ED), thyroid absorbed dose and gonadal dose were also estimated, based on KAP measurements. The LDRLs and ALs were calculated as the 75th and 10th percentile of FT, KAP and CD values for the total group of patients, as well as utilizing the weight banding method and the size correction method. For the total distribution of patients, the LDRLs for cervical and thoraco-lumbar interventions are 0.15min and 0.29min for FT values, 0.10Gycm2 and 0.71Gycm2 for KAP values, as well as 0.47mGy and 3.24mGy for CD values, respectively. The corresponding ALs are 0.03min and 0.03min, 0.01Gycm2 and 0.07Gycm2, as well as 0.05mGy and 0.33mGy for FT, KAP and CD values, respectively. The age and treated levels had a significant influence on the reference dose values only for cervical interventions, whereas none of the other included factors showed statistically significant association for both cervical and thoraco-lumbar interventions. The weight banding method resulted to reference values comparable to those obtained for the whole group of patients, while the size correction method resulted to lower values. The mean ESD values were 1.58mGy (range 0.02-13.58mGy) for cervical and 23mGy (range 0.004-390.3mGy) for thoraco lumbar interventions. The corresponding mean ED values were 0.012mSv (range 0.001 0.097mSv) and 0.124mSv (range 0.00002-2.11mSv), respectively. The mean thyroid and gonadal doses were 0.14mGy (range 0.002-1.12mGy) and 0.044mGy (range 0.000003 1.56mGy), respectively. The LDRLs and ALs reported could contribute in the effort for establishing national DRLs and for increasing neurosurgeons awareness regarding patient dose and radiation protection issues during spine interventional procedures. PMID- 28583648 TI - Fluorescence optical imaging and 3T-MRI for detection of synovitis in patients with rheumatoid arthritis in comparison to a composite standard of reference. AB - OBJECTIVES: To address whether Indocyanine Green (ICG) enhanced fluorescence optical imaging (FOI) is more sensitive than magnetic resonance imaging (MRI) in the detection of synovitis of the wrist and finger joints in rheumatoid arthritis and to analyze the performance of FOI depending on the grade of synovitis. METHODS: Twenty patients with highly active rheumatoid arthritis (mean DAS28-ESR 5.25+/-1.0) and thirteen healthy volunteers underwent clinical examination, FOI and contrast-enhanced 3T-MRI. Joints were rated by three independent readers semiquantitatively (grade 0-3: no, low, moderate and high grade synovitis) and compared to a semiquantitative composite standard of reference (cSOR, grade 0-3) that incorporated clinical parameters, FOI and MRI results. RESULTS: 2.868 evaluations in 956 joints were performed. FOI had an overall sensitivity of 57.3% and a specificity of 92.1%, whereas MRI had a sensitivity of 89.2% and a specificity of 92.6%. The sensitivity of FOI increased with the degree of synovitis to 65.0% for moderate and severe synovitis (specificity 88.1%) and 76,3% for severe synovitis (specificity 80.5%). The performance of FOI decreased with the degree of synovitis with false negative results predominantly for mild (156/343, 45.5%) and moderate (160/343, 46.6%) synovitis and false positive FOI evaluations predominantly based on weak (grade 1) signals (133/163, 81,6%). CONCLUSION: FOI has a lower sensitivity than 3T-MRI in the detection of synovitis of the hand and finger joints. The diagnostic performance of FOI decreases with the degree of synovitis and with the strength of FOI signals. PMID- 28583649 TI - Spindle cell lesions of the breast: Multimodality imaging and clinical differentiation of pathologically similar neoplasms. AB - Spindle cell lesions of the breast comprise a wide-range of entities including reactive, benign and malignant proliferations. They can be pathologically challenging to differentiate as there is often immunohistochemical and morphologic similarities with characteristic spindle shaped cellular patterns. Radiological and pathological correlation is essential. Radiology detects, defines the size and extent, and assists in localizing the lesions. Pathology confirms the diagnosis and provides prognostic parameters. Familiarity with the clinicoradiological features of these diagnostically challenging lesions helps to establish an accurate pathological diagnosis and subsequent clinical decision making. PMID- 28583650 TI - Early response evaluation using CT-perfusion one day after transarterial chemoembolization for HCC predicts treatment response and long-term disease control. AB - PURPOSE: To determine the value of CT perfusion (CTP) for early response assessment after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between April 2013 and April 2015, 41 HCC (16 patients) were included in this study. CT perfusion was performed before and one day after TACE. Blood flow (BF), blood volume (BV), time to start (TTS), arterial liver perfusion (ALP), portal liver perfusion (PVP) and hepatic perfusion index (HPI) were measured. Quantitative perfusion values before and after TACE were compared to the response assessed using mRECIST criteria six weeks after TACE and long-term outcome was assessed. RESULTS: Twenty-one lesions (51%) had complete remission (CR) and five (12%) had partial response (PR) six weeks after TACE. CTP parameters were significantly reduced after TACE in responders (PR, CR, p<0.001) while no difference was observed in non-responders. ALPpost was superior in the prediction of CR compared to BFpost and BVpost (p<0.001) with a sensitivity, specificity, PPV, NPV, and accuracy of 90%, 90%, 91%, 90%, and 91%, respectively. Only 3/21 lesions with CR recurred, with a mean local-recurrence-free survival of 19.6 months. CONCLUSION: CT perfusion detects lesions with complete response one day after TACE, and is a feasible tool for early response assessment. PMID- 28583651 TI - Dual-energy CT can detect malignant lymph nodes in rectal cancer. AB - BACKGROUND: There is a need for an accurate and operator independent method to assess the lymph node status to provide the most optimal personalized treatment for rectal cancer patients. This study evaluates whether Dual Energy Computed Tomography (DECT) could contribute to the preoperative lymph node assessment, and compared it to Magnetic Resonance Imaging (MRI). The objective of this prospective observational feasibility study was to determine the clinical value of the DECT for the detection of metastases in the pelvic lymph nodes of rectal cancer patients and compare the findings to MRI and histopathology. MATERIALS AND METHODS: The patients were referred to total mesorectal excision (TME) without any neoadjuvant oncological treatment. After surgery the rectum specimen was scanned, and lymph nodes were matched to the pathology report. Fifty-four histology proven rectal cancer patients received a pelvic DECT scan and a standard MRI. The Dual Energy CT quantitative parameters were analyzed: Water and Iodine concentration, Dual-Energy Ratio, Dual Energy Index, and Effective Z value, for the benign and malignant lymph node differentiation. RESULTS: DECT scanning showed statistical difference between malignant and benign lymph nodes in the measurements of iodine concentration, Dual-Energy Ratio, Dual Energy Index, and Effective Z value. Dual energy CT classified 42% of the cases correctly according to N-stage compared to 40% for MRI. CONCLUSION: This study showed statistical difference in several quantitative parameters between benign and malignant lymph nodes. There were no difference in the accuracy of lymph node staging between DECT and MRI. PMID- 28583652 TI - Non-contrast-enhanced magnetic resonance venography using magnetization-prepared rapid gradient-echo (MPRAGE) in the preoperative evaluation of living liver donor candidates: Comparison with conventional computed tomography venography. AB - OBJECTIVE: To compare the diagnostic performance of non-contrast-enhanced magnetic resonance venography using magnetization-prepared rapid gradient-echo (MPRAGE-MRV) and conventional computed tomography venography (CTV) in preoperative evaluation of venous tributaries for living donor liver transplantation. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this prospective study of 73 donor candidates. Of these, 23 underwent right-sided graft hepatectomy without middle hepatic vein. One or more tributaries, other than the right hepatic vein, were reconstructed for 20 of the 23 grafts. For these 20 grafts, the number and location of the tributaries requiring reconstruction were evaluated based on venography, and diagnostic performance was analyzed using surgical records as a reference standard. For each candidate, the number of small tributaries directly joining the inferior vena cava was counted in each venographic image; a paired sample t-test was used to assess differences. The severity of respiratory artifacts in MPRAGE-MRV was qualitatively evaluated, and compared using Wilcoxon's rank-sum test. RESULTS: All reconstructed venous tributaries were prospectively identified using both methods. MPRAGE-MRV tended to provide a greater number of small tributaries than conventional CTV (mean: 2; 95% CI: [1.66, 2.34], and 1.74; [1.44, 2.04], respectively), although the difference was not significant (P=0.10); MPRAGE-MRV was superior or equal to CTV in 52 subjects (71.2%), and inferior in 21 subjects (28.8%). Respiratory artifacts were significantly less severe in the former subjects (P<0.0001). CONCLUSIONS: MPRAGE MRV has the potential to replace conventional CTV in the preoperative evaluation of living liver donor candidates. PMID- 28583653 TI - Prospectively ECG-triggered high-pitch coronary CT angiography at 70 kVp with 30mL contrast agent: An intraindividual comparison with sequential scanning at 120 kVp with 60mL contrast agent. AB - PURPOSE: To investigate image quality, radiation dose, and diagnostic efficiency of prospectively ECG-triggered high-pitch coronary CT angiography (CCTA) at 70 kVp with 30mL contrast agent intra-individually compared with routine CCTA protocol. MATERIALS AND METHODS: One hundred and thirty eight patients with suspected coronary artery disease, body mass index (BMI)<=25kg/m2 and heart rate (HR)<=70 beats per minute (bpm) underwent prospectively ECG-triggered high-pitch CCTA at 70 kVp and 30mL contrast agent (protocol A) and prospectively ECG triggered sequential scanning at 120 kVp and 60mL contrast medium (protocol B). Objective and subjective image quality, radiation doses, and diagnostic accuracy were evaluated and compared between the two protocols. RESULTS: Higher CT attenuation, higher noise, lower signal-to-noise ratios (SNRs) and lower contrast to-noise ratios (CNRs) were found in protocol A than in protocol B (P<0.001). However, image quality of protocol A were diagnostic. In patients with BMI<23kg/m2 or HR<60bpm, subjective image quality scores of some coronary arteries in protocol A were not significantly different from protocol B (P>0.05). Effective dose in protocol A has reduced by 96.7% compared with protocol B (P<0.001). No significant differences were found for diagnostic accuracy between the two protocols on a per-segment (P=0.513), per-vessel (P=0.317) and per patient (P=0.125) basis. CONCLUSIONS: Prospectively ECG-triggered high-pitch CCTA at 70kVp with 30mL contrast agent can reduce radiation dose but maintain image quality and high diagnostic accuracy in a selected, non-obese population. PMID- 28583654 TI - Autistic traits associated with food neophobia but not olfactory sensitivity. AB - Food neophobia has been shown to be associated with a range of personality traits (including anxiety, lower sensation seeking) and additionally sensory aspects of food such as taste and texture. Running parallel to that work, research has demonstrated higher incidences of food neophobia in autistic populations and separately evidence of hypersensitivity in some sensory domains. The aim of the current study was to extend our understanding by exploring whether the broader aspects of autistic traits can predict food neophobia in a non-autistic population and whether this is mediated by differences in olfactory sensitivity. In the present study, student participants (N = 50) completed questionnaires measuring their food neophobia (FNS) and preferences for foreign cuisine, autistic traits (Autistic Quotient, AQ), and then completed an olfactory threshold test for a food related odour. The findings demonstrated a positive association between food neophobia and the magnitude of autistic traits and interestingly, an inverse relation between preference for foreign cuisine and olfactory sensitivity; those individuals less inclined toward foreign cuisine had poorer sensitivity to a food related odour. Since AQ was not related to olfactory sensitivity, these findings suggest the relation between autistic traits and food neophobia is unlikely to be mediated by olfactory sensitivity. More broadly however, our sense of smell is associated with experiencing a wider diet. PMID- 28583655 TI - Cookbooks in U.S. history: How do they reflect food safety from 1896 to 2014? AB - Historical cookbooks as a source of recipes and food preparation information would be expected to document advancements in food safety related to kitchen equipment, cleaning, foodborne illness knowledge, and consumer education materials. In turn, this food safety information might be expected to contribute to consumers' food safety behaviors. Using both quantitative and qualitative research methodology, this study assessed how food safety information in cookbooks changed and how quickly advancements were incorporated. Faster assimilation into cookbooks was associated with kitchen equipment, educational resources (hotlines and websites), and foodborne illness outbreaks. The rate of incorporation of education materials was moderate. Cleaning advances were the slowest to be incorporated. Modern cookbooks published after the 1980's rapidly evolved with advances in food safety knowledge. PMID- 28583656 TI - [Dyslipidemia and suicidal risk in patients with psychiatric disorders]. AB - The aim of this work is to study the association between dyslipidemia and suicidal risk in patients with psychiatric pathology. Our study has involved 155 patients suffering from major depressive disorder and 124 schizophrenic patients aged 40.58+/-12.16 and 43.43+/-10.60 years, respectively. Total cholesterol (TC), triglycerides (TG) and HDL-c were determined by enzymatic methods, LDL-c was calculated by the Friedewald formula. Plasma cholesterol level was significantly lower among suicidal schizophrenic or depressive patients. There were no significant differences in the others lipid levels. The results of our study suggest that total cholesterol values less than 3.59mmol/L could be an indicator of suicide vulnerability in patients with schizophrenia or major depressive disorder. PMID- 28583657 TI - In response to the December 2016 article entitled "Vegetarian diet and all-cause mortality: Evidence from a large population-based Australian cohort - the 45 and Up Study". AB - In response to the December 2016 article entitled "Vegetarian diet and all-cause mortality: Evidence from a large population-based Australian cohort - the 45 and Up Study". A brief analysis of the article with suggestions for interpretation and considerations for future research. PMID- 28583658 TI - Does e-cigarette use predict cigarette escalation? A longitudinal study of young adult non-daily smokers. AB - Recent studies suggest that e-cigarette use among youth may be associated with increased risk of cigarette initiation. The goal of this study was to test the hypothesis that use of e-cigarettes among young adult non-daily cigarette smokers would be associated with increased cigarette consumption. Participants (n=391; 52% male) were 18-24year-old non-daily cigarette smokers recruited from across California. Cigarette and e-cigarette use were assessed online or via mobile phone every three months for one year between March 2015 and December 2016. Longitudinal negative binomial regression models showed that, adjusted for propensity for baseline e-cigarette use, non-daily smokers who reported more frequent use of e-cigarettes upon study entry reported greater quantity and frequency of cigarette smoking at baseline and greater increases in cigarette quantity over 12months than non-daily cigarette only smokers (ps<0.01). During the 12months of assessment, more consistent consumption of e-cigarettes was associated with greater quantity and frequency of cigarette use (ps<0.01); these effects did not vary over time. Findings suggest that among non-daily smokers, young adults who use e-cigarettes tend to smoke more cigarettes and to do so more frequently. Such individuals may be at greater risk for chronic tobacco use and dependence. PMID- 28583659 TI - Do E-cigarettes reduce smoking? PMID- 28583660 TI - The dynamic impact of retirement on health: Evidence from a nationwide ten-year panel survey in Japan. AB - Retirement is a major life-course transition that is closely related to changes in health. This study examined the dynamic impact of retirement on health and health behaviors, distinguishing an immediate change in the level of health at retirement and a change in the rate of change after retirement. We used panel data from 9283 individuals (4441 men and 4842 women) who had retired during a nationwide ten-year panel survey in Japan conducted in 2005-2014. We focused on three health behaviors (current smoking, heavy alcohol drinking, and leisure-time physical activity) and two health indicators (self-rated health and psychological distress). We estimated regression models that controlled for both time-invariant individual attributes and the endogeneity of retirement, using panel data collected during the five years before and after retirement. Results generally confirmed that the transition was accompanied by favorable changes in health and health behaviors with some gender differences. Among men, retirement immediately promoted leisure-time physical activity and reduced poor self-rated health and psychological distress. Retirement also accelerated smoking cessation and leisure time physical activity and decelerated reporting poor health. Among women, retirement immediately promoted leisure-time physical activity and reduced psychological distress, while it did not affect the rate of change in any health variable after retirement. The current study underscores the need for more in depth knowledge of the dynamic impact of retirement on health. This will assist in developing policy measures to help the middle-aged population make healthy transitions from work to retirement. PMID- 28583661 TI - Does retirement benefit health? AB - Currently large postwar baby-boomer generations are retiring from labor market. Transition to retirement is considered an important turning point in life which is accompanied by changes in many aspects of life such as time availability, daily routines, income streams and social networks. Recent longitudinal studies suggest that retirement can have a major influence on people's health behaviors, health and quality of life. Retirement could also be an opportune time at which to intervene with health-promotion activities and support healthy and active aging. PMID- 28583662 TI - Human papillomavirus screening for low and middle-income countries. PMID- 28583663 TI - In response to: Human papillomavirus screening for low and middle-income countries. PMID- 28583665 TI - Overview: NK-cell-based Immunotherapies: Toward & Into Clinical Trials. PMID- 28583666 TI - Safety evaluation of water-soluble palm fruit bioactives. AB - Water-soluble palm fruit bioactives, derived from the aqueous stream of palm oil processing, have shown anti-diabetogenic effects in rodent models. To assess the safety of potential incorporation of this polyphenol-containing material in food, in vitro bacterial reverse mutation and in vitro chromosome aberration assays were conducted along with a 90-day subchronic toxicity study in Sprague-Dawley rats. Water-soluble palm fruit bioactives were inactive in the Ames and in vitro chromosome aberration assays up to the limit doses of 5000 MUg/plate and 5000 MUg/mL, respectively. In the 90-day feeding study, water-soluble palm fruit bioactives were administered via gavage at doses 0, 500, 1000 or 2000 mg/kg body weight/day. No significant effects were noted on body weight, food consumption, hematology, clinical chemistry, organ weights, and histopathological examination. The No Observable Adverse Effect Level was considered to be 2000 mg/kg body weight/day, the highest dose tested. These data provide evidence to support the safe use of water-soluble palm fruit bioactives in food or food ingredients. PMID- 28583664 TI - Urinary triclosan concentrations and diminished ovarian reserve among women undergoing treatment in a fertility clinic. AB - OBJECTIVE: To investigate the association between urinary triclosan concentrations and antral follicle count (AFC), a well-accepted marker of ovarian reserve, among women from a fertility center. DESIGN: Prospective cohort study. SETTING: Hospital fertility center. PATIENT(S): A total of 109 women. INTERVENTION(S): Urinary triclosan concentrations quantified by online solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry. MAIN OUTCOME MEASURE(S): AFC through transvaginal ultrasonography on the third day of an unstimulated menstrual cycle or on the third day of a progesterone withdrawal bleed. RESULT(S): The geometric mean of the specific gravity-adjusted urinary triclosan concentrations for the 225 samples provided by the 109 women was 13.0 MUg/L (95% confidence interval [CI], 8.9, 19.1). Women had median (with interquartile range) AFC of 13 (8, 18). The specific gravity-adjusted urinary triclosan concentrations were inversely associated with AFC (-4%; 95% CI, -7%, -1%). Women with triclosan concentrations above the median had lower AFC compared with those whose triclosan concentrations were equal to or below the median, with an adjusted difference of -3.2 (95% CI, 3.9, -1.6) among those with a body mass index <25 kg/m2 and -1.8 (95% CI, -3.2, 0.3) among those who were <35 years old. CONCLUSION(S): Specific gravity-adjusted urinary triclosan concentrations were inversely associated with AFC in women seeking care at a fertility center. This association was modified by age and body mass index, with the younger and leaner women showing larger decreases in AFC. PMID- 28583667 TI - Dietary safety of a dual-enzyme preparation for animal feed: Acute and subchronic oral toxicity and genotoxicity studies. AB - Animal feed is routinely supplemented with exogenous enzymes to improve nutrient utilization, such as proteases to enhance protein hydrolysis in vivo and xylanases to alleviate feed related anti-nutritional factors. The present studies were conducted to evaluate the potential oral toxicity and genotoxicity of a dual enzyme preparation, Vegpro(r) concentrate (VPr-C). Acute oral toxicity studies were conducted in adult male and female Sprague-Dawley Crl CD rats and CHS Swiss ICO:OFI (IOPS Caw) mice. Thirteen week preliminary and final subchronic oral toxicity studies were conducted in male and female rats. Genotoxicity was evaluated through a bacterial reverse mutation test (Ames test), an in-vitro mammalian chromosomal aberration test, and a mammalian micronucleus test. The LD50 was >2000 mg/kg of BW in mice and rats. In the 13-week oral toxicity study, the No Observed Adverse Effects Level (NOAEL) was 1000 mg/kg BW per day for females and 300 mg/kg BW per day for males. VPr-C showed no mutagenic activity in Salmonella typhimurium, did not induce significant chromosomal aberrations in cultured human lymphocytes, and did not increase the frequency or proportion of micronucleated immature erythrocytes in mice. There was no evidence of acute or subchronic toxicity or genotoxicity associated with the test article at these test dosages. PMID- 28583668 TI - [Pomalidomide for multiple myeloma]. AB - Pomalidomide is a second-generation immunomodulatory drug (IMID). Its efficiency overtakes its predecessors' (thalidomide, lenalidomide), with less toxicity. It is indicated in the treatment of refractory or relapsed multiple myeloma, associated to dexamethasone. It is available in France since 2013, following the results of different studies. PMID- 28583669 TI - Are pioneer mangroves more vulnerable to oil pollution than later successional species? AB - Propagules of Avicennia marina, Bruguiera gymnorrhiza and Rhizophora mucronata were cultivated in rhizotrons (root observation chambers) and subjected to sediment oiling treatments for 409days to determine the effects of oil on root growth. Oiling reduced root length, specific root length, relative root growth rate and root diameter, while specific root volume increased. Oiling reduced root length by 96% in A. marina, 99% in B. gymnorrhiza and 80% in R. mucronata, while specific root volume increased by 34%, 29% and 23% respectively. Relative root growth rate decreased in the oiled treatments by 84%, 80% and 73% respectively. Avicennia exhibits typical root traits of a pioneer species compared to slower growing later successional species like B. gymnorrhiza and R. mucronata. These traits of A. marina not only allow more rapid establishment of seedlings, but also expose a larger root surface area and therefore greater susceptibility to oil contamination than the other species. PMID- 28583670 TI - Hepatic hypoxia-inducible factors inhibit PPARalpha expression to exacerbate acetaminophen induced oxidative stress and hepatotoxicity. AB - Oxidative stress has a critical role in the pathogenesis of acetaminophen (APAP) induced hepatocellular necrosis, and the identification of novel approaches to attenuate oxidative stress is essential to prevent/revert the disease. This study investigated the role of both HIF-1 and HIF-2 in the pathogenesis of APAP-induced oxidative stress, as well as the underlying mechanisms. In the present study, we initially found that knockout of HIF-1alpha or HIF-2alpha reduced APAP toxicity, and double knockout afforded the best protection. APAP treatment led to stabilization of both HIF-1alpha and HIF-2alpha in mouse livers. Moreover, the protective effects of HIF deficiency were related to the attenuated oxidative stress. Further experiments proved that PPARalpha, a master regulator in cellular metabolism accounted for the HIF deficiency-caused protective impact on APAP toxicity. Inactivation of HIFs promoted the expression of peroxisome proliferator activated receptor alpha (PPARalpha) in the liver, which in turn activated nuclear factor erythroid 2-related factor 2 (Nrf2). Knockdown of PPARalpha or Nrf2 negated the hepatoprotection afforded by HIF deficiency. At last,examination of the PPARalpha promoter identified a HIF-binding site and HIF-dependent repression of PPARalpha in hepatocytes by luciferase reporter and EMSA study. Taken together, Our results demonstrate that HIFs are key suppressors of PPARalpha in the liver, thereby compromising the adaptive defense mechanisms against oxidative stress when confronted with APAP. These findings are important to the etiology and therapeutics of APAP hepatotoxicity. The functional link between HIFs and PPARalpha may have more implications in liver physiology and other pathologic conditions than APAP injury. PMID- 28583671 TI - Biomechanical behaviour of craniofacial sutures during distraction: An evaluation all over the entire craniofacial skeleton. AB - OBJECTIVE: Sutures are fibrous joints connecting the bones of the head. Despite the fundamental role played by sutures in dentofacial orthopaedics, their biomechanical properties are not completely understood. This study evaluated anatomy, biomechanics, and acoustic emission (AE) during distraction of the sutural ligament (SL). METHODS: Seventy-two suture samples were removed from a twelve-months-old swine (Sus scrofa) head. Each volume was acquired using micro computed tomography (MUCT), and the linear interdigitation index was calculated on both planes (LIICOR and LIISAG). Mechanical testing till failure was carried at 1mm/min, and four piezoelectric sensors were used for recording of amplitude (A), duration (D), and energy (E) of AE. The relationships between interdigitation, fracture types, tensile stress (sigma0), and AE were statistically analysed with non-parametric tests (alpha=0.05). RESULTS: sigma0 of the SL had median values of 4.0MPa, and AE were characterised by A of 49.3dB (IQR=2.2), D of 826.3MUs (IQR=533.4), and E of 57,715.8 eu (IQR=439,613.5). Most of the fractures happened in the SL (46%), some within the bone (34%), and fewer were combined (19%). LIICOR had correlation with A (0.383, p=0.028), D (0.348, p=0.048), and E (0.437, p=0.011) of the AE, and sigma0 had similar relationship with A (0.500, p=0.003), D (0.495, p=0.003), and E (0.579, p<0.001). Maximum energy values were different between fractures within the bone and within the SL (p=0.021). SIGNIFICANCE: Biomechanical properties under tension of most of the sutures of the craniofacial skeleton were reported. AE provided information about the sequence of events during SL distraction, and had significant relationship with its mechanical properties. Further studies are necessary to confirm these preliminary findings, and to identify their relationship with biological processes and dentofacial treatments. PMID- 28583672 TI - Monascus ruber as cell factory for lactic acid production at low pH. AB - A Monascus ruber strain was isolated that was able to grow on mineral medium at high sugar concentrations and 175g/l lactic acid at pH 2.8. Its genome and transcriptomes were sequenced and annotated. Genes encoding lactate dehydrogenase (LDH) were introduced to accomplish lactic acid production and two genes encoding pyruvate decarboxylase (PDC) were knocked out to subdue ethanol formation. The strain preferred lactic acid to glucose as carbon source, which hampered glucose consumption and therefore also lactic acid production. Lactic acid consumption was stopped by knocking out 4 cytochrome-dependent LDH (CLDH) genes, and evolutionary engineering was used to increase the glucose consumption rate. Application of this strain in a fed-batch fermentation resulted in a maximum lactic acid titer of 190g/l at pH 3.8 and 129g/l at pH 2.8, respectively 1.7 and 2.2 times higher than reported in literature before. Yield and productivity were on par with the best strains described in literature for lactic acid production at low pH. PMID- 28583673 TI - High-level De novo biosynthesis of arbutin in engineered Escherichia coli. AB - Arbutin is a hydroquinone glucoside compound existing in various plants. It is widely used in pharmaceutical and cosmetic industries owing to its well-known skin-lightening property as well as anti-oxidant, anti-microbial, and anti inflammatory activities. Currently, arbutin is usually produced by plant extraction or enzymatic processes, which suffer from low product yield and expensive processing cost. In this work, we established an artificial pathway in Escherichia coli for high-level production of arbutin from simple carbon sources. First, a 4-hydroxybenzoate 1-hydroxylase from Candida parapsilosis CBS604 and a glucosyltransferase from Rauvolfia serpentina were characterized by in vitro enzyme assays. Introduction of these two genes into E. coli led to the production of 54.71mg/L of arbutin from glucose. Further redirection of carbon flux into arbutin biosynthesis pathway by enhancing shikimate pathway genes enabled production of 3.29g/L arbutin, which is a 60-fold increase compared with the initial strain. Final optimization of glucose concentration added in the culture medium was able to further improve the titer of arbutin to 4.19g/L in shake flasks experiments, which is around 77-fold higher than that of initial strain. This work established de novo biosynthesis of arbutin from simple carbon sources and provided a generalizable strategy for the biosynthesis of shikimate pathway derived chemicals. The high titer achieved in our engineered strain also indicates the potential for industrial scale bio-manufacturing of arbutin. PMID- 28583674 TI - Three-dimensional data-tracking dynamic optimization simulations of human locomotion generated by direct collocation. AB - The aim of this study was to perform full-body three-dimensional (3D) dynamic optimization simulations of human locomotion by driving a neuromusculoskeletal model toward in vivo measurements of body-segmental kinematics and ground reaction forces. Gait data were recorded from 5 healthy participants who walked at their preferred speeds and ran at 2m/s. Participant-specific data-tracking dynamic optimization solutions were generated for one stride cycle using direct collocation in tandem with an OpenSim-MATLAB interface. The body was represented as a 12-segment, 21-degree-of-freedom skeleton actuated by 66 muscle-tendon units. Foot-ground interaction was simulated using six contact spheres under each foot. The dynamic optimization problem was to find the set of muscle excitations needed to reproduce 3D measurements of body-segmental motions and ground reaction forces while minimizing the time integral of muscle activations squared. Direct collocation took on average 2.7+/-1.0h and 2.2+/-1.6h of CPU time, respectively, to solve the optimization problems for walking and running. Model-computed kinematics and foot-ground forces were in good agreement with corresponding experimental data while the calculated muscle excitation patterns were consistent with measured EMG activity. The results demonstrate the feasibility of implementing direct collocation on a detailed neuromusculoskeletal model with foot-ground contact to accurately and efficiently generate 3D data-tracking dynamic optimization simulations of human locomotion. The proposed method offers a viable tool for creating feasible initial guesses needed to perform predictive simulations of movement using dynamic optimization theory. The source code for implementing the model and computational algorithm may be downloaded at http://simtk.org/home/datatracking. PMID- 28583676 TI - Second International Symposium-Epigenetic Regulation of Skin Regeneration and Aging: From Chromatin Biology towards the Understanding of Epigenetic Basis of Skin Diseases. PMID- 28583675 TI - Magnetic particle translation as a surrogate measure for synovial fluid mechanics. AB - The mechanics of synovial fluid vary with disease progression, but are difficult to quantify quickly in a clinical setting due to small sample volumes. In this study, a novel technique to measure synovial fluid mechanics using magnetic nanoparticles is introduced. Briefly, microspheres embedded with superparamagnetic iron oxide nanoparticles, termed magnetic particles, are distributed through a 100MUL synovial fluid sample. Then, a permanent magnet inside a protective sheath is inserted into the synovial fluid sample. Magnetic particles translate toward the permanent magnet and the percentage of magnetic particles collected by the magnet in a given time can be related to synovial fluid viscosity. To validate this relationship, magnetic particle translation was demonstrated in three phases. First, magnetic particle translation was assessed in glycerol solutions with known viscosities, demonstrating that as fluid viscosity increased, magnetic particle translation decreased. Next, the relationship between magnetic particle translation and synovial fluid viscosity was assessed using bovine synovial fluid that was progressively degenerated via ultrasonication. Here, particle collection in a given amount of time increased as fluid degenerated, demonstrating that the relationship between particle collection and fluid mechanics holds in non-Newtonian synovial fluid. Finally, magnetic particle translation was used to assess differences between healthy and OA affected joints in equine synovial fluid. Here, particle collection in a given time was higher in OA joints relative to healthy horses (p<0.001). Combined, these data demonstrate potential viability of magnetic particle translation in a clinical setting to evaluate synovial fluid mechanics in limited volumes of synovial fluid sample. PMID- 28583677 TI - How Trialists and Pharmaceutical Sponsors Have Failed Us by Thinking That Acute Heart Failure Is a 48-Hour Illness. AB - Trials of novel therapies for acute heart failure (HF) have followed a convention of short term, most commonly a 48-hour infusion of parenteral therapy compared with placebo or an active drug in a randomized, double-blind study design. Such trials include OPTIME-CHF, SURVIVE, VERITAS, PROTECT, ASCEND-HF, TRUE-HF, and RELAX-AHF-2. This article reviews how this practice in trials began and summarizes the reasons why such a brief exposure of any novel therapy has failed to reduce the end points of rehospitalization or death. Future trials should consider acute and extended use of novel agents to better match the pathophysiology of decompensation and recovery from acute HF. PMID- 28583678 TI - Hospital Inpatient Costs for Single Ventricle Patients Surviving the Fontan Procedure. AB - We estimated the inpatient resource use for a Fontan patient from birth to adulthood and explored factors that might induce cost differences (2014 US dollar). Inpatient costing records from 4 hospitals with greatest numbers of Fontan patients in Australia and New Zealand were linked with the Fontan registry database. Inpatient records between July 1995 and September 2014 for 420 Fontan patients were linked, and the most frequent primary diagnoses were hypoplastic left heart syndrome (20.7%), tricuspid atresia (19.7%), and double inlet left ventricle (17.1%). The mean hospital cost for a Fontan patient from birth to 18 years of age was estimated to be $390,601 (95% confidence interval [CI] $264,703 to $516,499), corresponding to 164 (95% CI 98 to 231) inpatient days. The cost incurred from birth through to Fontan completion (the staged procedures period) was $219,482 (95% CI $202,410 to $236,553) and the cost thereafter over 15 years was $146,820 (95% CI $44,409 to $249,231), corresponding to 82 (95% CI 72 to 92) and 65 (95% CI 18 to 112) inpatient days, respectively. Costs were higher in male and hypoplastic left heart syndrome patients in the staged procedures period (p <0.001). Having fenestration was associated with higher costs in the staged procedures period (p <0.001) and lower cost after Fontan over 15 years (p = 0.66). In conclusion, patients with single ventricle congenital heart disease continue to demand considerable inpatient resources after the staged procedures period. Over 40% of the pediatric hospital costs for Fontan patients were estimated to occur after the last planned surgery. PMID- 28583679 TI - Gender Differences in Anemia and Survival in Patients Hospitalized for Acute Decompensated Heart Failure With Preserved or Reduced Ejection Fraction. AB - In patients with acute decompensated heart failure (HF), the influence of gender on anemia, left ventricular ejection fraction (EF), and outcomes is unclear. We evaluated the association of anemia and left ventricular EF with survival in men or women hospitalized for acute decompensated HF. Of the 4,842 patients enrolled in the Acute Decompensated Heart Failure Syndromes registry, 4,215 patients (2,450 men and 1,765 women) discharged alive after hospitalization for acute decompensated HF were enrolled to evaluate the association of gender, anemia (hemoglobin <13.0 g/dl for men and <12.0 g/dl for women) at discharge, and a preserved or reduced EF with all-cause death or cardiac death after discharge. Men or women were divided into 4 groups based on left ventricular EF (preserved or reduced EF) and anemia status at discharge. The median follow-up period after discharge was 524 days (384 to 791). After adjustment for multiple co morbidities, there was no adverse influence of anemia in men with a preserved EF, whereas anemia was an independent predictor of all-cause death in men with a reduced EF. Conversely, anemia was an independent predictor of all-cause death in women with a preserved EF but not in women with a reduced EF. With respect to cardiac death, multivariable analyses revealed highly similar trends as those for all-cause death in patients of both genders. In conclusion, in acute decompensated patients with HF with a preserved or reduced EF, there were marked differences between men and women with respect to the association of anemia and left ventricular EF with survival. PMID- 28583680 TI - Comparison of Frequency of Referral to Cardiothoracic Surgery for Aortic Valve Disease in Blacks, Hispanics, and Whites. AB - Racial differences in prevalence and in intervention rate of those with severe aortic stenosis have been reported. Our objective was to evaluate health disparities in referral to cardiothoracic surgery (CTS) for aortic stenosis in black and Hispanic compared with white patients before the transcatheter aortic valve replacement program was started in our community. Using a retrospective cohort design, we identified all patients >40 years, who had been captured with aortic valve disease from January 2011 to June 2016. Clinical and echocardiographic data were collected manually. Exposure was race/ethnicity; outcome was referral to CTS. Multivariable logistic regression analysis was conducted with variables that had significance of p <0.20 in univariate model. We included 952 patients in the final analysis (423 white, 376 black, and 153 Hispanic). Compared with whites, black subjects were significantly younger, had more advanced degrees of kidney disease, were more likely to have Medicaid as payer, and had more atherogenic co-morbidities. Black patients had significantly higher aortic valve area indexed for body surface area, more aortic regurgitation, lower peak velocities, lower transvalvular gradients, less calcified valves, and fewer patients in aortic stenosis stage D. The adjusted odds ratio for CTS referral was 0.48 for blacks (p <0.001) and 0.86 for Hispanics (p = 0.73) compared with whites. In conclusion, after adjusting for clinical and echocardiographic variables, black patients were less likely to be referred to CTS for treatment of aortic valve disease. We found no difference in the referral pattern of Hispanic compared with white patients. PMID- 28583681 TI - Usefulness of Intracoronary Brachytherapy for Patients With Resistant Drug Eluting Stent Restenosis. AB - In-stent restenosis (ISR) remains a concern even in the drug-eluting stent (DES) era and carries a high risk of recurrence. Brachytherapy is being used as an alternative treatment for resistant ISR, yet the safety and efficacy of this approach has not been well studied. We analyzed the outcomes of 101 patients who underwent coronary brachytherapy for resistant DES ISR. Baseline demographic, clinical, procedural, and outcome data were collected by phone and from electronic records. Comorbidities and overt cardiovascular disease were highly prevalent. Median previous stent layers were 2 with a maximum of 5 layers. Procedural angiographic success rate was 97% and median time to discharge was 1 day after brachytherapy. The primary outcome of target vessel revascularization was 24% at 1 year, 32% at 2 years, and 42% at 3 years. The rate of nonfatal myocardial infarction was 0% at 1 year, 3.5% at 2 years, and 6% at 3 years. The rate of all-cause mortality was 8.5% at 1 year, 12% at 2 years, and 16% at 3 years. We observed only 1 case of late stent thrombosis. After multivariable adjustment, female gender (hazard ratio 2.37, 95% confidence interval 1.02 to 5.52, p = 0.04) and diffuse ISR pattern (hazard ratio 2.95, 95% confidence interval 1.21 to 7.17, p = 0.01) were independently associated with the primary outcome. In conclusion, brachytherapy is feasible for the treatment of resistant DES ISR and is associated with high immediate procedural success and reasonable efficacy in a complex patient population. This approach might be used as an alternative for these patients. PMID- 28583682 TI - Outcome of Stent Graft Implantation for Treatment of Access Site Bleeding After Transfemoral Transcatheter Aortic Valve Replacement. AB - Vascular complications are common after transcatheter aortic valve replacement (TAVR) and are associated with increased morbidity and mortality. Stent graft implantation enables percutaneous treatment of access site bleeding; however, the efficacy and durability and of this approach are unknown. We studied the immediate outcome of stent graft implantation for control of access site bleeding and the need for repeat vascular interventions after stenting, in a cohort of consecutive patients with severe symptomatic aortic stenosis who underwent transfemoral TAVR. Predictors of access site complications requiring percutaneous or surgical vascular repair were identified. Transfemoral TAVR was performed in 194 patients. Access site complications requiring urgent vascular repair occurred in 34 patients (18%). Stent graft implantation was performed in 31 patients and vascular surgery in 3 patients. When patients who required surgical or percutaneous vascular repair were compared with those who did not, increased body mass index (30 +/- 6 vs 28 +/- 5, p = 0.035) and reduced activated clotting time (233 +/- 47 vs 252 +/- 47, p = 0.030) were the only predictors of need for vascular repair. Stenting achieved adequate hemostasis in all patients with a single minor vascular complication. During median follow-up of 797 days (interquartile range 585 to 1,173), no clinically significant vascular complications were detected after stenting. In conclusion, control of bleeding was achieved in all patients who underwent stent graft implantation for treatment of access site vascular complications after transfemoral TAVR. None of these patients needed further vascular interventions during follow-up. PMID- 28583683 TI - Regional Variation in Outcomes of Hospitalized Patients Having Out-of-Hospital Cardiac Arrest. AB - The aim of this study was to investigate patient outcomes after hospitalization for out-of-hospital cardiac arrest in the United States. We used the 2002 to 2013 Nationwide Inpatient Sample database to identify adults >=18 years with an International Classification of Diseases, Ninth Revision, Clinical Modification, principal diagnosis code of cardiorespiratory arrest (427.5) or ventricular fibrillation (VF) (427.41). In 4 predefined federal geographic regions: Northeast, Midwest, South, and West, means and proportions of survival, survival stratified by initial rhythm, hospital charges, and cost were estimated. Multiple linear and logistic regression models were conducted. Of the 154,177 patients with out-of-hospital cardiac arrest hospitalized in the United States, 25,873 (16.8%) were in the Northeast, 38,296 (24.8%) in the Midwest, 57,305 (37.2%) in the South, and 32,703 (21.2%) in the West. Variability in survival was noted in VF arrests; compared with the Northeast, survival was higher in the Midwest and South (adjusted odds ratio [AOR] 1.16, 95% confidence interval [CI] 1.02 to 1.32 and AOR 1.24, 95% CI 1.09 to 1.40, respectively), with no difference detected in the West (AOR 0.93, 95% CI 0.82 to 1.06). No variability in survival was noted after non-VF arrests (p >0.05). Hospital charges rose significantly across all regions of the United States (p-trend < 0.001) and were higher in the West compared with the Northeast (hospital charges >$109,000/admission, AOR 1.76; 95% CI 1.50 to 2.06). In conclusion, nationwide, we observed significant regional variability in survival of hospitalized patients after out of hospital VF cardiac arrest, no survival variability after non-VF arrests, and a steady increase in hospital charges. PMID- 28583684 TI - Impact of the Management of Type B Aortic Dissection on the Long-Term Blood Pressure. AB - Ambulatory blood pressure (BP) measurement (ABPM) is recommended to assess optimal BP control, and we studied its influence after an acute type B aortic dissection (ATBAD). We retrospectively collected data from 111 patients with ATBAD from January 2004 to September 2014. Controlled BP group was defined according to a 24-hour BP under 130/80 mm Hg during chronic phase. The population consisted of 85 men, with a mean age of 61 +/- 13 years and mean body mass index of 28 +/- 6 kg/m2. The median delay between ambulatory BP measurement and ATBAD was 2 (0.3 to 4) months. The mean 24-hour BP of the entire population was 124/71 +/- 15/8.8 mm Hg. BP was not controlled in 41 patients (37%). The treatment score at discharge was 3.9 +/- 1.4. The mean glomerular filtration rate was 83 +/- 28 ml/min/1.73 m2, with no difference between groups. Visceral stent implantation in the acute phase (odds ratio [OR] 3.857 [1.199 to 12.406], p = 0.023), higher left ventricular ejection fraction (OR 1.092 [1.005 to 1.187], p = 0.038), and higher platelet count at discharge (OR 1.064 [1.018 to 1.112], p = 0.006) were identified as predictors of good BP control by multivariate analysis. The analysis showed that nighttime systolic BP was associated with aortic events during follow-up (hazard ratio [HR] 5.2 [1.01 to 27.2], p = 0.049), particularly for a threshold of 124 mm Hg or more (HR 1.967 [1.052 to 3.678], p = 0.0341). Nighttime pulse pressure showed also its significance (HR 20.1 [1.4 to 282.7], p = 0.026). In conclusion, subclinical renal malperfusion revascularization seems to improve BP control. A greater nighttime systolic BP was associated with the risk of new aortic events during follow-up. PMID- 28583685 TI - Usefulness of the R-Wave Sign as a Predictor for Ventricular Tachyarrhythmia in Patients With Brugada Syndrome. AB - Brugada syndrome (BrS) is an autosomal dominant channelopathy which is responsible for a large number of sudden cardiac deaths in young subjects without structural abnormalities. The most challenging step in management of patients with BrS is identifying who is at risk for developing malignant ventricular tachyarrhythmia (VTA). In patients with BrS, conduction delay in the right ventricular outflow tract (RVOT) causes a prominent R wave in lead aVR. This electrocardiographic parameter can be useful to detect these high-risk patients. The goal of this study was to test the significance of R-wave elevation in lead aVR as a predictor for VTA in patients with BrS. In this retrospective study, we included 132 patients with BrS (47 +/- 15 years, 65% men) who visited the outpatient clinic for cardiogenetic screening. Patients' medical records were examined for the presence of a positive R-wave sign in lead aVR and VTA. A positive R-wave sign in lead aVR was observed in 41 patients (31%). This sign was more frequently observed in patients who experienced VTA (n = 24) before the initial diagnosis, during electrophysiological studies, or during follow-up (p <0.001). The positive R-wave sign occurred more frequently in symptomatic patients with a history of an out of hospital cardiac arrest, VTA, or syncope than asymptomatic patients (60% vs 26%; p = 0.002). During the follow-up period, this sign was more frequently detected in patients who developed either de novo (50%) or recurrent VTA (80%) (p = 0.017). Multivariable regression analysis showed that R-wave sign is an independent predictor for VTA development (odds ratio 4.8, 95% confidence interval 1.79 to 13.27). The presence of a positive R wave sign in lead aVR is associated with the development of VTA. In conclusion, positive R-wave sign in lead aVR can be used to identify patients with BrS at risk for malignant VTA. PMID- 28583686 TI - Relation of Body Mass Index and Gender to Left Atrial Size and Atrial Fibrillation. AB - Increased body mass index (BMI) and obesity are associated with greater risk of atrial fibrillation (AF). However, whether this correlation is independent and gender specific remains unclear. The objective of this study was to characterize the relation between BMI, left atrial (LA) size, and presence of AF and determine whether this association is gender specific. We prospectively studied 499 patients who underwent a transthoracic echocardiogram at an academic tertiary care medical center. Clinical and echocardiographic data were obtained. The primary outcome of interest was the presence of AF. Of 499 patients studied, 240 (48.1%) were men and 259 (51.9%) were women. Of these, 151 (30.1%) had normal BMI, 181 (36.3%) were overweight, and 167 (33.5%) were obese. Obese patients were younger and had larger LA diameters, LA areas (LAAs), and LA volumes (LAVs). Rates of AF were similar among the BMI classes in the overall population and in men and women separately. In multivariate analysis, BMI and gender were both independently associated with LA diameter, LAA, and LAV. Age (odds ratio 1.02, 95% CI 1.00 to 1.04, p = 0.023) and LA diameter (odds ratio 2.52, 95% CI 1.61 to 3.97, p <0.001) were the only determinants of the presence of AF in the overall population. BMI and gender were not independently associated with AF. In this observational study, our findings demonstrate that higher BMI and male gender were independently associated with greater LA diameter, LAA, and LAV. Older age and greater LA diameter were independently associated with higher rates of AF, whereas BMI and gender were not. PMID- 28583688 TI - Neointimal fibrotic lead encapsulation - Clinical challenges and demands for implantable cardiac electronic devices. AB - Every tenth patient with a cardiac pacemaker or implantable cardioverter defibrillator implanted is expected to have at least one lead problem in his lifetime. However, transvenous leads are often difficult to remove due to thrombotic obstruction or extensive neointimal fibrotic ingrowth. Despite its clinical significance, knowledge on lead-induced vascular fibrosis and neointimal lead encapsulation is sparse. Although leadless pacemakers are already available, their clinical operating range is limited. Therefore, lead/tissue interactions must be further improved in order to improve lead removals in particular. The published data on the coherences and issues related to lead associated vascular fibrosis and neointimal lead encapsulation are reviewed and discussed in this paper. PMID- 28583687 TI - Relation of Serum Vitamin D to Risk of Mitral Annular and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis). AB - Serum 25-hydroxyvitamin D [25(OH)D] concentration has been identified as a possible modifiable risk factor for cardiovascular disease (CVD). We hypothesized that serum 25(OH)D concentration would be associated with calcifications of the left-sided heart valves, which are markers of CVD risk. Aortic valve calcium (AVC) and mitral annular calcium (MAC) were quantified from cardiac computed tomography scans performed on 5,530 Multi-Ethnic Study of Atherosclerosis participants at the baseline examination (2000 to 2002) and at a follow-up visit at either Examination 2 (2002 to 2004) or Examination 3 (2004 to 2005). 25(OH)D was measured from serum samples collected at the baseline examination. Using relative risk regression, we evaluated the multivariable-adjusted risk of prevalent and incident AVC and MAC in this ethnically diverse population free of clinical CVD at baseline. The mean age of participants was 62 +/- 10 years; 53% were women, 40% white, 26% black, 21% Hispanic, and 12% Chinese. Prevalent AVC and MAC were observed in 12% and 9% of study sample, respectively. There were no significant associations between 25(OH)D and prevalent AVC or MAC. Over a mean follow-up of 2.5 years, 4% developed incident AVC and 5% developed incident MAC. After adjusting for demographic variables, each 10 ng/ml higher serum 25(OH)D was associated with a 15% (relative risk 0.85, 95% confidence interval 0.74 to 0.98) lower risk of incident MAC but not AVC. However, this association was no longer significant after adjusting for lifestyle and CVD risk factors. Results suggest a possible link between serum 25(OH)D and the risk for incident MAC, but future studies with longer follow-up are needed to further test this association. PMID- 28583689 TI - Granulomatous-Lymphocytic Interstitial Lung Disease in a Patient With Common Variable Immunodeficiency. AB - Common variable immunodeficiency is the most common primary immunodeficiency and consists of impaired immunoglobulin production causing recurrent sinopulmonary infections. The most common cause of mortality for this disorder, however, is from the development of malignancy and autoimmune disorders. One common entity that develops is a systemic granulomatous and lymphoproliferative disorder that can cause an interstitial lung disease more formally referred to as granulomatous lymphocytic interstitial lung disease (GL-ILD). We discuss a case of a 25-year old woman with common variable immunodeficiency and GL-ILD and review the literature to summarize the most common radiological findings to raise the suspicion for GL-ILD on high-resolution computed tomography and delineate this from infection and other mimickers. We will also review key histopathological characteristics for diagnosis and the clinical approach and treatment options for this rare disease. PMID- 28583690 TI - Transition to adult rheumatology care is necessary to maintain DMARD therapy in young people with juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate the outpatient health service utilisation of young people (YP) with juvenile idiopathic arthritis (JIA) during transfer from paediatric to adult care in Germany. METHODS: Based on claims data of a large German statutory health fund (BARMER GEK) we conducted a cohort study of 2008-2014. Insured YP with diagnosis of JIA (ICD: M08 or M09.0) in two quarters at the age of 16 and continuous insurance until the age of 20 were included. Outpatient health care utilisation, prescribed antirheumatic drugs and diagnosis maintenance were analysed over four consecutive years for all YP with JIA and for the subgroup on disease-modifying antirheumatic drugs (DMARDs) at the age of 16. RESULTS: A total of 256 YP with JIA (67% female) were followed during the transfer period, 115 of them received (DMARDs) at the age of 16. At the age of 20, 30% of all 256 YP utilised adult specialty care, 59% still had a JIA diagnosis and 30% were treated with DMARDs. Of those 115 YP, treated with DMARDs at the age of 16 and in need of follow-up, 49% had visited an adult rheumatologist at the age of 20, 75% had a JIA diagnosis and 56% were on DMARDs. Those 49% YP with successful transfer to adult specialty care had a JIA diagnosis in 93% and were treated with DMARDs in 80%. YP, who were only seen by general practitioners, had a JIA diagnosis in 54% and received DMARDs in 27%. CONCLUSIONS: One in two YP with JIA and a clear need for ongoing follow-up do not utilise adult rheumatologic care. The maintenance of JIA diagnosis and DMARD therapy depend on the utilisation of specialised care services. PMID- 28583691 TI - Association between acute gouty arthritis and meteorological factors: An ecological study using a systematic review and meta-analysis. AB - OBJECTIVES: The aims of this study were as follows: (1) to analyze the literature systematically regarding the seasonal and monthly variation of the occurrence of episodes of acute gouty arthritis, and (2) to investigate the relationship between the occurrence of episodes of acute gouty arthritis and meteorological parameters. METHODS: The present authors systematically reviewed databases for articles published before November 2015. Studies with quantitative data on episodes of acute gouty arthritis by months and/or seasons were included. Meteorological data such as the highest temperature, lowest temperature, diurnal temperature range, change in mean temperature between neighboring days, relative humidity and wind speed for the geographic place(s), and study period where and when each study took place were obtained from meteorological websites. RESULTS: Ten studies published between 1920 and 2015 were included. A meta-analysis by season showed that acute gouty arthritis occurred significantly more frequently in spring than in other seasons. Analysis by month showed an increase in episodes of acute gouty arthritis from March to July, being the highest in July. The trend reversed, and episodes of acute gouty arthritis started decreasing from July to September, being the lowest in September. The change in mean temperature between neighboring days was the only meteorological parameter that was significantly correlated with the number of monthly episodes of acute gouty arthritis. CONCLUSIONS: Acute gouty arthritis seems to develop more frequently during the period in which the temperature increases significantly between neighboring days: spring by season and between March and July by month in the northern hemisphere. PMID- 28583692 TI - Learning from failure? Political expediency, evidence, and inaction in global maternal health. PMID- 28583693 TI - The invasive microalga Chrysophaeum taylorii: Interactive stressors regulate cell density and mucilage production. AB - The benthic mucilage producing microalga Chrysophaeum taylorii Lewis and Bryan (Pelagophyceae) has recently received attention for its rapid spread in the Mediterranean Sea, where its blooms have remarkable detrimental effects. So far no information on C. taylorii response to multiple stressors, especially in terms of mucilage hyperproduction, is available in the literature yet, and a manipulative field experiment in this topic was designed in Tavolara Punta Coda Cavallo Marine Protected Area. The aim of the study was to test the effects of nutrient enrichment (addition of nutrients), mechanical disturbance (partial and total benthic organisms removal) and hydrodynamics (increased water turbulence) on C. taylorii cell density and mucilage abundance. To the purpose, the three above mentioned stressors were simulated and the three treatments were assigned to 20 * 20 cm plots following a full-factorial design (n = 3). Interactive effects of the three stressors affected significantly both benthic C. taylorii cell density and mucilage cover although differently. Mechanical disturbance and high hydrodynamics produced consistent effects on cell density and mucilage production (i.e. the former factor enhancing and the latter decreasing). Nutrient enrichment on the contrary led to contrasting effects, promoting cell abundance and inhibiting mucilage production. Therefore, important mucilage blooms are expected in oligotrophic sheltered coastal locations where barren areas are present. PMID- 28583694 TI - Corneal dystrophies. AB - Degenerative or hereditary corneal diseases are sometimes difficult to discriminate. Corneal dystrophies affect approximately 0.09% of the population. They are identified by the IC3D classification based on their phenotype, genotype and evidence gathered for their diagnosis. In practice, the ophthalmologist manages functional symptoms such as recurrent erosions, visual loss and amblyopia, photophobia, foreign body sensation, and sometimes pain and aesthetic concerns. Medical treatments consist of drops to promote healing, ointments, hyperosmotic agents and bandage contact lenses. Less invasive surgical treatments are used as second line therapy (phototherapeutic keratectomy, lamellar keratectomy). More invasive procedures may eventually be utilized (lamellar or penetrating keratoplasty). Anterior lamellar or endothelial keratoplasty are now preferred to penetrating keratoplasty, although the latter still remains the only possible option in some cases. Some rare dystrophies require coordinated and comprehensive medical care. PMID- 28583695 TI - [Neuro-myelitis optica secondary to chronic lymphocytic leukemia]. PMID- 28583696 TI - [Valsalva retinopathy: Role of SD-OCT and Nd:YAG Laser]. PMID- 28583697 TI - [An asynchronous bilateral optic neuropathy with positive MOG antibodies]. PMID- 28583698 TI - Has the quality of health care for the immigrant population changed during the economic crisis in Catalonia (Spain)? Opinions of health professionals and immigrant users. AB - OBJECTIVE: To analyse changes in health professionals' and immigrant users' perceptions of the quality of care provided to the immigrant population during the crisis. METHODS: A qualitative descriptive-interpretative and exploratory study was conducted in two areas of Catalonia. Semi-structured individual interviews were used with a theoretical sample of medical (n=24) and administrative (n=10) professionals in primary care (PC) and secondary care (SC), and immigrant users (n=20). Thematic analysis was conducted and the results were triangulated. RESULTS: Problems related to technical and interpersonal quality emerged from the discourse of both professionals and immigrants. These problems were attributed to cutbacks during the economic crisis. Regarding technical quality, respondents reported an increase in erroneous or non-specific diagnoses, inappropriate use of diagnostic tests and non-specific treatments, due to reduction in consultation times as a result of cuts in human resources. With regard to interpersonal quality, professionals reported less empathy, and users also reported worse communication, due to changes in professionals' working conditions and users' attitudes. Finally, a reduction in the resolution capacity of the health services emerged: professionals described unnecessary repeated PC visits and limited responses in SC, while young immigrants reported an insufficient response to their health problems. CONCLUSION: The results indicate a deterioration in perceived technical and interpersonal quality during the economic crisis, due to cutbacks mainly in human resources. These changes affect the whole population, but especially immigrants. PMID- 28583699 TI - Stem cell therapy with skeletal myoblasts accelerates neointima formation in a mouse model of vein graft disease. AB - Although still a matter of controversial discussion, skeletal myoblasts are one of the options for stem cell transplantation improving cardiac function after myocardial infarction, exhibiting several advantages including the availability, the ability of self-renewal and differentiation, and the lack of ethical and immunological problems. The aim of this study was to investigate the impact of stem cell therapy with skeletal myoblasts on experimental venous bypass grafts in a mouse model of vein graft disease. Forty C57BL/6J mice underwent bypass grafting interposing a venous bypass graft of the donor mouse into the carotid artery of the recipient mouse. Twenty mice received periadventitially treatment with 1 million fluorescence labeled skeletal myoblasts suspended in culture medium (treatment group), the other twenty mice received only culture medium without myoblasts (control group). Two weeks after bypass surgery, the vein grafts of all 40 mice were harvested, stained and histologically investigated under light and immunofluorescence microscope. Against our expectations, skeletal myoblasts stayed in place and were still located in the adventitia after bypass grafting. Additionally, vein grafts of the myoblast group revealed a 2fold increased neoneointima formation, a decreased media thickness, a slightly increased neovascularization, a higher percentage of reendothelialization and also a slightly higher percentage of PDGFR alpha, PDGFR beta, MMP-7 and MMP-9 positive cells, suggesting a paracrine mechanism responsible for accelerated neointima formation. In conclusion, the results of our study do not support the use of skeletal myoblast for the treatment of vein graft disease after coronary artery bypass surgery. PMID- 28583701 TI - The American Academy of Clinical Toxicology Question of the Day. PMID- 28583700 TI - How changes in physical activity relate to fatigue interference, mood, and quality of life during treatment for non-metastatic breast cancer. AB - OBJECTIVE: Physical activity (PA) following surgery for breast cancer may improve depressive symptoms and quality of life (QoL) via reduction in fatigue-related daily interference (FRDI). Less is known about how change in PA may relate to these psychosocial factors throughout the course of treatment. In a secondary analysis of a previous psychosocial intervention trial, we examined relationships between change in PA, depressive symptoms, and functional QoL, as mediated by change in FRDI, and whether naturally occurring change in PA provided benefit independent of the intervention. METHOD: Women (N=240) with non-metastatic stage 0-III breast cancer were randomized to cognitive-behavioral stress management (CBSM) or a control 2-10weeks post-surgery. PA, FRDI, clinician-rated depressive symptoms, self-reported depressed mood, and functional QoL were assessed at baseline and three months post-intervention. RESULTS: Increased PA was associated with reductions in clinician-rated depressive symptoms, depressed mood, and improved QoL, mediated by a reduction in FRDI. This was above and beyond the effect of CBSM. CONCLUSIONS: Increased PA may mitigate FRDI and improve depressive symptoms and functional QoL for women undergoing breast cancer treatment, beyond effects of a psychosocial intervention. Benefits of an integrated PA and psychosocial approach should be investigated further. PMID- 28583702 TI - Barriers to Genetic Testing for Pediatric Medicaid Beneficiaries With Epilepsy. AB - BACKGROUND: Children with public insurance (Medicaid) have increased barriers to specialty care in the United States. For children with epilepsy, the relationship between public insurance and barriers to genetic testing is understudied. METHODS: We surveyed a sample of US child neurology clinicians. We performed quantitative and qualitative analysis of responses. RESULTS: There were 302 responses (of 1982 surveyed; response rate 15%) from clinicians from 46 states, the District of Columbia, and Puerto Rico, including board-certified child neurologists (82%), resident physicians (6%), nurses (3%), and nurse practitioners (3%). Clinicians felt it was more difficult to get genetic testing for patients with Medicaid insurance compared with commercial insurance, (43% vs 12%, P < 0.05), although many felt it was about the same degree of difficulty (25%) or were not sure (20%). Increased availability of testing was associated with less complex testing (P < 0.001), in-house testing (P < 0.001), and no preauthorization requirements (P < 0.001). Qualitative responses described barriers related to cost, clinician familiarity and comfort, commercial laboratories, health care organization, payer, and patient concerns. Descriptions of facilitators included lowered cost, availability of clinical genetics expertise, clinician knowledge, commercial laboratory assistance, health care organizational changes, improved payer coverage, and increased interest by parents. CONCLUSIONS: Pediatric Medicaid beneficiaries with epilepsy have barriers to genetic testing, compared with children with commercial insurance, particularly for more advanced testing. Potential strategies to improve access include broader coverage, lower co-pays, increased capacity for testing outside of specialty laboratories, fewer preauthorization requirements, improved clinician education, ongoing development and dissemination of guidelines, improved availability of clinical genetics services, and continued assistance programs from commercial laboratories. PMID- 28583703 TI - In Reply: Death in Pediatric Mitochondrial Disorders. PMID- 28583704 TI - Thyroid Disease and Type 1 Diabetes in Dutch Children: A Nationwide Study (Young Dudes-3). AB - OBJECTIVE: To investigate the prevalence of overt thyroid disease in children in The Netherlands with and without type 1 diabetes mellitus (T1DM). STUDY DESIGN: Nationwide, retrospective cohort study in The Netherlands. Using the national registry of both healthcare reimbursement and pharmaceutical care, data of all Dutch children (aged 0-14 years) with a diagnosis of T1DM, or a diagnosis of hypothyroidism or hyperthyroidism in the period 2009-2011. RESULTS: The prevalence of thyroid disease was 0.15% in children without T1DM, and 3.43% in children with T1DM (rate ratio 23.59; 95% CI 19.92-27.93; P < .001). Both hyperthyroidism and hypothyroidism were 24 times more likely in children with T1DM than in those without. Thyroid disease was more common in girls than in boys, both in children with T1DM (rate ratio of girls vs boys 3.07; 95% CI 2.10 4.49) and in children without T1DM (rate ratio 1.59; 95% CI 1.49-1.69). This sex difference was more pronounced for hypothyroidism than for hyperthyroidism. CONCLUSIONS: Children with T1DM in The Netherlands are 24 times more likely to develop thyroid disease than their peers without diabetes. Girls with T1DM were more prone to thyroid disease, particularly hypothyroidism. PMID- 28583706 TI - Bronze Baby Syndrome. PMID- 28583705 TI - Associations of Newborn Brain Magnetic Resonance Imaging with Long-Term Neurodevelopmental Impairments in Very Preterm Children. AB - OBJECTIVE: To determine the relationship between brain abnormalities on newborn magnetic resonance imaging (MRI) and neurodevelopmental impairment at 7 years of age in very preterm children. STUDY DESIGN: A total of 223 very preterm infants (<30 weeks of gestation or <1250 g) born at Melbourne's Royal Women's Hospital had a brain MRI scan at term equivalent age. Scans were scored using a standardized system that assessed structural abnormality of cerebral white matter, cortical gray matter, deep gray matter, and cerebellum. Children were assessed at 7 years on measures of general intelligence, motor functioning, academic achievement, and behavior. RESULTS: One hundred eighty-six very preterm children (83%) had both an MRI at term equivalent age and a 7-year follow-up assessment. Higher global brain, cerebral white matter, and deep gray matter abnormality scores were related to poorer intelligence quotient (IQ) (Ps < .01), spelling (Ps < .05), math computation (Ps < .01), and motor function (Ps < .001). Higher cerebellum abnormality scores were related to poorer IQ (P = .001), math computation (P = .018), and motor outcomes (P = .001). Perinatal, neonatal, and social confounders had little effect on the relationships between the MRI abnormality scores and outcomes. Moderate-severe global abnormality on newborn MRI was associated with a reduction in IQ (-6.9 points), math computation (-7.1 points), and motor (-1.9 points) scores independent of the other potential confounders. CONCLUSIONS: Structured evaluation of brain MRI at term equivalent is predictive of outcome at 7 years of age, independent of clinical and social factors. PMID- 28583707 TI - Histologic Chorioamnionitis and Bronchopulmonary Dysplasia in Preterm Infants: The Epidemiologic Study on Low Gestational Ages 2 Cohort. AB - OBJECTIVE: To investigate the association between histologic chorioamnionitis (HCA) and bronchopulmonary dysplasia (BPD) in very preterm infants, both in a general population and for those born after spontaneous preterm labor and after preterm premature rupture of membranes (pPROM). STUDY DESIGN: This study included 2513 live born singletons delivered at 24-31 weeks of gestation from a national prospective population-based cohort of preterm births; 1731 placenta reports were available. HCA was defined as neutrophil infiltrates in the amnion, chorion of the membranes, or chorionic plate, associated or not with funisitis. The main outcome measure was moderate or severe BPD. Analyses involved logistic regressions and multiple imputation for missing data. RESULTS: The incidence of HCA was 28.4% overall: 38% in cases of preterm labor, 64% in cases of pPROM, and less than 5% in cases of vascular disorders. Overall, the risk of BPD after adjustment for gestational age, sex, and antenatal steroids was reduced for infants with HCA (HCA alone: aOR 0.6 [95% CI 0.4-0.9]; associated with funisitis: aOR 0.5 [95% CI 0.3-0.8]). This finding was explained by the high rate of BPD and low rate of chorioamnionitis among children with fetal growth restriction. HCA was not associated with BPD in the preterm labor (13.4% vs 8.5%; aOR 0.9; 95% CI 0.5-1.8) or in the pPROM group (12.9% vs 12.1%; aOR 0.6; 95% CI 0.3-1.3). CONCLUSION: In homogeneous groups of infants born after preterm labor or pPROM, HCA is not associated with BPD. PMID- 28583708 TI - Prefrontal fatty acid composition in schizophrenia and bipolar disorder: Association with reelin expression. AB - OBJECTIVE: The extracellular matrix protein reelin regulates early brain development and synaptic plasticity in adulthood. Reelin is decreased in the postmortem brain in schizophrenia patients. Reelin's two receptors, ApoER2 and VLDLR, are also substrates for ApoE - a key lipoprotein that regulates phospholipid homeostasis in the brain. The goal of the present study was therefore to examine phospholipids and their constituent fatty acids, and determine whether there is an association between reelin, its receptors and phospholipids in the brain. METHODS: Dorsolateral prefrontal cortex (BA9) grey matter was obtained from the Stanley Foundation Neuropathology Consortium. Samples included tissue from 35 controls, 35 schizophrenia and 34 bipolar disorder patients. Phospholipids were measured using gas liquid chromatography. RESULTS: We quantified 15 individual fatty acid or plasmalogen species for phosphatidylethanolamine and phosphatidylcholine fractions, each comprising >0.5% of the total fatty acid pool. There were no group differences in phospholipids or individual fatty acid species after correcting for multiple comparisons. However, for the entire cohort, both the polyunsaturated subclass of fatty acids, and ApoE, correlated significantly with reelin expression, with a number of individual omega-6 fatty acid species also demonstrating a significant positive correlation. There was a non-significant trend for similar effects with VLDLR expression as for reelin. CONCLUSION: Phospholipids and fatty acids in the dorsolateral cortex do not differ in patients with schizophrenia, bipolar disorder and controls. Reelin expression in this brain region is associated with polyunsaturated fatty acids and ApoE, suggesting further study of potential physiological interactions between these substrates is warranted. PMID- 28583709 TI - Imported malaria in pregnant women experienced in Japan. AB - INTRODUCTION: With ever-growing global exchanges, the number of travelers, including pregnant women, to the tropics is increasing, which poses a risk of contracting malaria. Although there are several reports on imported malaria in pregnancy from Western countries, those focusing on cases experienced in Japan are very limited. METHODS: We searched for cases of malaria in pregnancy in the treatment records submitted to the Research Group on Chemotherapy of Tropical Diseases, Japan, during the period 1993-2016. Literature searches were also conducted using an American and a Japanese search system. RESULTS: Ten cases of malaria in pregnant women were identified, including four cases with Plasmodium falciparum. Of eight evaluable cases, only one practiced malaria chemoprophylaxis. Among the nine evaluable cases, eight resulted in uneventful delivery and one P. falciparum case developed severe hepatic disturbance, disseminated intravascular coagulation, and intrauterine fetal death. After the initial attack, none of the Plasmodium vivax/Plasmodium ovale cases practiced chloroquine prophylaxis until delivery. One P. ovale case received a lower dose regimen of chloroquine as acute-stage therapy. CONCLUSION: This study demonstrated additional cases of imported malaria in pregnant women to the literature and highlighted various epidemiological, demographic, and clinical characteristics. Some of the clinical issues raised need to be investigated. Due to the paucity of the cases worldwide, sharing information among various countries is indispensable, and international guidelines which are now increasingly recommending the use of artemisinins in pregnant women should be referred. PMID- 28583711 TI - Short-term efficacy and safety of treatment with febuxostat in kidney transplant recipient. An unicentric observational study. PMID- 28583710 TI - Large Disparities in Receipt of Glaucoma Care between Enrollees in Medicaid and Those with Commercial Health Insurance. AB - PURPOSE: To determine whether the type of health insurance a patient possesses and a patient's race/ethnicity affect receipt of common tests to monitor open angle glaucoma (OAG). DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: A total of 21 766 persons aged >=40 years with newly diagnosed OAG between 2007 and 2011 enrolled in Medicaid or a large United States managed care network. METHODS: We determined the proportion of patients with newly diagnosed OAG who underwent visual field (VF) testing, fundus photography (FP), other ocular imaging (OOI), or none of these tests within the first 15 months after initial OAG diagnosis. Multivariable logistic regression was used to assess the extent by which health insurance type and race/ethnicity affected the odds of undergoing glaucoma testing. MAIN OUTCOME MEASURES: Odds ratios (OR) of undergoing VF testing, FP, OOI, or none of these tests in the 15 months after initial OAG diagnosis with 95% confidence intervals (CI). RESULTS: A total of 18 372 persons with commercial health insurance and 3394 Medicaid recipients met the study inclusion criteria. The proportions of persons with commercial health insurance with newly diagnosed OAG who underwent VF, FP, and OOI were 63%, 22%, and 54%, respectively, whereas the proportions were 35%, 19%, and 30%, respectively, for Medicaid recipients. Compared with those with commercial health insurance, Medicaid recipients were 234% more likely to not receive any glaucoma testing in the 15 months after initial diagnosis (OR = 3.34; 95% CI, 3.07-3.63). After adjustment for confounders, whites with OAG enrolled in Medicaid had 198% higher odds of receiving no glaucoma testing compared with whites possessing commercial health insurance (OR = 2.98; 95% CI, 2.66-3.33). Blacks with Medicaid insurance demonstrated 291% higher odds (OR = 3.91; 95% CI, 3.40-4.49) of not receiving any glaucoma testing compared with blacks with commercial health insurance. CONCLUSIONS: Irrespective of race/ethnicity, Medicaid recipients with OAG are receiving substantially less glaucoma testing compared with persons with commercial health insurance. Disparities in testing are observed across all races/ethnicities but were most notable for blacks. These findings are particularly disconcerting because blacks are more likely than whites to go blind from OAG and there are disproportionately more blacks in Medicaid. Efforts are needed to improve the quality of glaucoma care for Medicaid recipients, especially racial minorities. PMID- 28583712 TI - Structural influences on the activity of bismuth(III) indole-carboxylato complexes towards Helicobacter pylori and Leishmania. AB - Seven new bismuth(III) complexes derived from indole-carboxylic acids have been synthesised: five are homoleptic; [Bi(IAA)3] B1, [Bi(IPA)3] B2, [Bi(IBA)3] B3, [Bi(MICA)3] B4, [Bi(IGA)3] B6, and two are heteroleptic [BiPh(MICA)2] B5 (where IAA-H=2-(1H-indol-3-yl)acetic acid, IPA-H=3-(1H-indol-3-yl)propanoic acid, IBA H=4-(1H-indol-3-yl)butanoic acid, IGA-H=2-(1H-indol-3-yl)-2-oxoacetic acid, and MICA-H=1-methyl-1H-indole-3-carboxylic acid). All complexes were fully characterised by elemental analysis, infrared and mass-spectroscopy, and nuclear magnetic resonance (1H, 13C) spectroscopy. Complex [BiPh(IGA)2] B7 is structurally authenticated by X-ray crystallography as a dimer in the solid state. The in-vitro anti-bacterial activity of the indole-carboxylic acids and their bismuth(III) complexes was assessed against Helicobacter pylori. While the acids were non-toxic at <100MUgmL-1, all the bismuth compounds showed an MIC of 6.25MUgmL-1, indicating that the anti-bacterial activity is insensitive to the degree of substitution at the Bi(III) centre or the composition of the indole carboxylate ligands. All compounds were further tested for their anti-parasitic activity against Leishmania major and for their toxicity towards mammalian cells. From the anti-parasitic studies, it was found that the heteroleptic bismuth(III) complexes are the most active, with B5 and B7 showing comparable activity to Amphotericin B, without any toxicity towards the mammalian cells at their effective concentration. PMID- 28583713 TI - IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis. AB - BACKGROUND: Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia. AIM: In the present study, we assess if disruption of IGF-1R signalling resolves arthritis. MATERIAL AND METHODS: Clinical associations of IGF-1R expression in leukocytes of the peripheral blood were studied in 84 RA patients. Consequences of the IGF-1R signalling inhibition for arthritis were studied in mBSA immunised Balb/c mice treated with NT157 compound promoting degradation of insulin receptor substrates. RESULTS: In RA patients, high expression of IGF-1R in leukocytes was associated with systemic inflammation as verified by higher expression of NF-kB, serum levels of IL6 and erythrocyte sedimentation rate, and higher pain perception. Additionally, phosphorylated IGF-1R and STAT3 enriched T cells infiltrate in RA synovia. Treatment with NT157 inhibited the phosphorylation of IGF-1R and STAT3 in synovia, and alleviated arthritis and joint damage in mice. It also reduced expression of IGF-1R and despaired ERK and Akt signalling in spleen T cells. This limited IL-6 production, changed RoRgt/FoxP3 balance and IL17 levels. CONCLUSION: IGF-1R signalling contributes to T cell dependent inflammation in arthritis. Inhibition of IGF-1R on the level of insulin receptor substrates alleviates arthritis by restricting IL6-dependent formation of Th17 cells and may open for new treatment strategies in RA. PMID- 28583715 TI - Novel insights into the antioxidant role of tauroursodeoxycholic acid in experimental models of Parkinson's disease. AB - Impaired mitochondrial function and generation of reactive oxygen species are deeply implicated in Parkinson's disease progression. Indeed, mutations in genes that affect mitochondrial function account for most of the familial cases of the disease, and post mortem studies in sporadic PD patients brains revealed increased signs of oxidative stress. Moreover, exposure to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I inhibitor, leads to clinical symptoms similar to sporadic PD. The bile acid tauroursodeoxycholic acid (TUDCA) is an anti-apoptotic molecule shown to protect against MPTP-induced neurodegeneration in mice, but the mechanisms involved are still incompletely identified. Herein we used MPTP-treated mice, as well as primary cultures of mice cortical neurons and SH-SY5Y cells treated with MPP+ to investigate the modulation of mitochondrial dysfunction by TUDCA in PD models. We show that TUDCA exerts its neuroprotective role in a parkin-dependent manner. Overall, our results point to the pharmacological up-regulation of mitochondrial turnover by TUDCA as a novel neuroprotective mechanism of this molecule, and contribute to the validation of TUDCA clinical application in PD. PMID- 28583714 TI - IL-21/anti-Tim1/CD40 ligand promotes B10 activity in vitro and alleviates bone loss in experimental periodontitis in vivo. AB - IL-10-expressing regulatory B cells (B10) play an essential role in immune system balance by suppressing excessive inflammatory responses. In this study, we investigated induction of B 10 cell's IL-10 competency in vitro and its effect on ligature-induced experimental periodontitis in vivo. Spleen B cells were isolated from C57BL/6J mice and cultured for 48h under the following conditions: control, CD40L, IL-21, anti-Tim1, CD40L+IL-21, CD40L+anti-Tim1, CD40L+IL-21+anti-Tim1. Silk ligatures were tied around both maxillary second molars of C57BL/6J mice for two weeks. Optimized combination of CD40L, IL-21 and anti-Tim1 and vehicle were injected into contralateral side of palatal gingiva on days 3, 6 and 9. The palatal gingival tissues and maxillary bone were collected on day 14 to determine expressions of IL-10 and periodontal bone resorption respectively. Our results demonstrated that IL-10 expressions of cultured spleen B cells were significantly increased in the presence of CD40L, IL-21 and anti-Tim1 combination when compared with control groups. Gingival IL-10 mRNA and protein expressions were significantly increased after injection of CD40L, IL-21 and anti-Tim1 combination, when compared to the control side. The gingival RANKL expression and periodontal bone loss were significantly decreased on the combination treatment side, as compared to the control side. These results suggest that combination of IL-21, anti-Tim1 and CD40L treatment induced B10 cell's IL-10 competency in vitro and inhibited periodontal bone loss in ligature-induced experimental periodontitis. PMID- 28583716 TI - Need for in-hospital simulation-based educational facilitation for practical patient safety improvement. PMID- 28583717 TI - Prognosis of septic shock. PMID- 28583718 TI - The authors respond. PMID- 28583719 TI - Weak Links in the Early Chain of Care of Acute Lower Limb Ischaemia in Terms of Recognition and Emergency Management. AB - OBJECTIVES: Acute lower limb ischaemia (ALLI) is a potentially fatal, limb threatening medical emergency. Early treatment is essential for a good outcome. The aim was to describe the early chain of care in ALLI focusing on lead times and emergency management in order to identify weak links for improvement. METHODS: This was a retrospective, descriptive case study. This study analysed the medical records of all patients with a main discharge diagnosis of ALLI between January 2009 and December 2014. Predetermined emergency care data on lead times, diagnosis recognition, presenting symptoms, emergency care treatment and outcome were collected for patients who were transported by the Emergency Medical Service (EMS) and those who were not. RESULTS: In total, 552 medical records were audited of which 195 patients fulfilled the inclusion criteria and were analysed. Among them were 117 (60%) transported by the EMS. The median time from symptom onset to revascularisation was 23 (interquartile range [IQR] 10-55; EMS transported) and 93 (IQR 42-152, not EMS transported) hours (p < .01). The time from symptom onset to arrival in hospital was 5 (IQR 2-26; EMS transported) and 48 (IQR 6-108; not EMS transported) hours. After arrival in hospital, the median time to first doctor evaluation was 51 (IQR 28-90; EMS transported) and 80 (IQR 44-169; not EMS transported) minutes, p = .01. Low molecular weight heparin (LMWH) was given to 72% of patients in the emergency department (ED) and a multivariate analysis showed that the use of LMWH was associated with a more favourable outcome. CONCLUSIONS: Both the time spent in the ED and the time from the onset of symptoms to revascularisation were considerably longer than optimal. Time delays in the early treatment chain can mainly be attributed to "patient delay" and a considerable time spent in hospital before revascularisation. The use of LMWH as an integral part of ED management was associated with a better outcome. PMID- 28583720 TI - Disease-modifying drug therapy in cystic fibrosis. AB - Whilst substantial progress has been made in the treatment of cystic fibrosis, the disease still carries a significant burden in terms of symptoms, requirement for treatment and early mortality. The last decade has witnessed a new era in the development of small molecule drugs targeting the CFTR protein, which for the first time may provide a truly disease-modifying approach to treatment. This article reviews progress and highlights some of the current and future challenges in CFTR modulator therapies. PMID- 28583721 TI - Spontaneous mental associations with the words "side effect": Implications for informed and shared decision making. AB - OBJECTIVE: To gain insight into patients' medical decisions by exploring the content of laypeople's spontaneous mental associations with the term "side effect." METHODS: An online cross-sectional survey asked 144 women aged 40-74, "What are the first three things you think of when you hear the words 'side effect?"' Data were analyzed using content analysis, chi-square, and Fisher's exact tests. RESULTS: 17 codes emerged and were grouped into 4 themes and a Miscellaneous category: Health Problems (70.8% of participants), Decision Relevant Evaluations (52.8%), Negative Affect (30.6%), Practical Considerations (18.1%) and Miscellaneous (9.7%). The 4 most frequently identified codes were: Risk (36.1%), Health Problems-Specific Symptoms (35.4%), Health Problems-General Terms (32.6%), and Negative Affect-Strong (19.4%). Code and theme frequencies were generally similar across demographic groups (ps>0.05). CONCLUSION: The term "side effect" spontaneously elicited comments related to identifying health problems and expressing negative emotions. This might explain why the mere possibility of side effects triggers negative affect for people making medical decisions. Some respondents also mentioned decision-relevant evaluations and practical considerations in response to side effects. PRACTICE IMPLICATIONS: Addressing commonly-held associations and acknowledging negative affects provoked by side effects are first steps healthcare providers can take towards improving informed and shared patient decision making. PMID- 28583722 TI - Factors affecting patients' online health information-seeking behaviours: The role of the Patient Health Engagement (PHE) Model. AB - OBJECTIVE: To identify the variables affecting patients' online health information-seeking behaviours by examining the relationships between patient participation in their healthcare and online health information-seeking behaviours. METHODS: A cross-sectional survey of Italian chronic patients (N=352) was conducted on patient's online health information-seeking behaviours and patient participation-related variables. Structural equation modeling analysis was conducted to test the hypothesis. RESULTS: This study showed how the healthcare professionals' ability to support chronic patients' autonomy affect patients' participation in their healthcare and patient's online health information-seeking behaviours. However, results do not confirm that the frequency of patients' online health-information seeking behavior has an impact on their adherence to medical prescriptions. CONCLUSION: Assuming a psychosocial perspective, we have discussed how patients' engagement - conceived as the level of their emotional elaboration of the health condition - affects the patients' ability to search for and manage online health information. PRACTICE IMPLICATION: To improve the effectiveness of patients' online health information-seeking behaviours and to enhance the effectiveness of technological interventions in this field, healthcare providers should target assessing and improving patient engagement and patient empowerment in their healthcare. It is important that health professionals acknowledge patients' online health information-seeking behaviours that they discuss the information offered by patients and guide them to reliable and accurate web sources. PMID- 28583724 TI - Endovascular treatment of visceral artery aneurysms and pseudoaneurysms with stent-graft: Analysis of immediate and long-term results. AB - INTRODUCTION: The aim of this study is to analyze the safety and efficacy of stent-graft endovascular treatment for visceral artery aneurysms and pseudoaneurysms. METHODS: Multicentric retrospective series of patients with visceral aneurysms and pseudoaneurysms treated by means of stent graft. The following variables were analyzed: Age, sex, type of lesion (aneurysms/pseudoaneurysms), localization, rate of success, intraprocedural and long term complication rate (SIR classification). Follow-up was performed under clinical and radiological assessment. RESULTS: Twenty-five patients (16 men), with a mean age of 59 (range 27-79), were treated. The indication was aneurysm in 19 patients and pseudoaneurysms in 6. The localizations were: splenic artery (12), hepatic artery (5), renal artery (4), celiac trunk (3) and gastroduodenal artery (1). Successful treatment rate was 96% (24/25 patients). Intraprocedural complication rate was 12% (4% major; 8% minor). Complete occlusion was demonstrated during follow up (mean 33 months, range 6-72) in the 24 patients with technical success. Two stent migrations (2/24; 8%) and 4stent thrombosis (4/24; 16%) were detected. Mortality rate was 0%. CONCLUSION: In our study, stent graft endovascular treatment of visceral aneurysmns and pseudoaneurysms has demonstrated to be safe and is effective in the long-term in both elective and emergent cases, with a high rate of successful treatment and a low complication rate. PMID- 28583725 TI - Evolution of laparoscopic surgery in a high volume hepatobiliary unit: 150 consecutive pure laparoscopic hepatectomies. AB - INTRODUCTION: Compared to other surgical areas, laparoscopic liver resection (LLR) has not been widely implemented and currently less than 20% of hepatectomies are performed laparoscopically worldwide. The aim of our study was to evaluate the feasibility, and the ratio of implementation of LLR in our department. METHODS: We analyzed a prospectively maintained database of 749 liver resections performed during the last 10-year period in a single centre. RESULTS: A total of 150 (20%) consecutive pure LLR were performed between 2005 and 2015. In 87% of patients the indication was the presence ofprimary or metastatic liver malignancy. We performed 30 major hepatectomies (20%) and (80%) were minor resections, performed in all liver segments. Twelve patients were operated twice and 2 patients underwent a third LLR. The proportion of LLR increased from 12% in 2011 to 62% in the last year. Conversion rate was 9%. Overall morbidity rate was 36% but only one third were classified as severe. The 90-day mortality rate was 1%. Median hospital stay was 4 days and the rate of readmissions was 6%. CONCLUSIONS: The implementation of LLR has been fast with morbidity and mortality comparable to other published series. In the last 2 years more than half of the hepatectomies are performed laparoscopically in our centre. PMID- 28583726 TI - Results of short term radiotherapy followed by radical surgery for rectal cancer: A long-term unicenter observational study. AB - INTRODUCTION: Short-term radiotherapy (STR) for rectal cancer (RC) has rarely been used in Spain. The aim of the present study is to describe oncological results after RTC and surgery for RC. METHODS: This is a retrospective analysis of a consecutive series of patients treated with STR and surgery for RC (1999 2012). Epidemiological data, staging, complications of STR, STR-surgery interval, surgical approach, rate of anastomotic/perineal wound dehiscence, and pathological data (regression degree and staging) were collected. Global survival, disease free survival, local recurrence rate and incidence of toxicity, response and complications of combined treatment are reported. RESULTS: Of 1229 patients treated, 209 patients received STR and surgery. The median follow-up was 6.2 years. Mean age was 68 years and 66% of the patients were men. A total of 88% were cT3-4 and 44% cN+17 (8.1%) patients had resectable synchronous metastases. Acute and chronic toxicity due to STR was <5%. In 75% of the cases the STR surgery interval was <15 days, and in 9%> 4 weeks. Seven patients (3.3%) presented complete response. Nine (4.3%) patients presented an local recurrence rate. Global survival at 5, 10 and 15 years was 67.8, 49.2 and 37.5%, respectively. Disease free survival at 5, 10 and 15 years was 66.1, 47.1 and 33%, respectively. CONCLUSIONS: The results compare favorably with multicentric historical series. STR offers certain advantages that could be increased by increasing the STR-surgery interval and/or interspersed with sequential chemotherapy. PMID- 28583723 TI - Control of B lymphocyte development and functions by the mTOR signaling pathways. AB - Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development. In this review, we summarize the basic mechanisms of mTOR signaling; describe what is known about the roles of mTORC1, mTORC2, and the Folliculin/Fnip1 pathway in B cell development and functions; and briefly outline current clinical approaches for targeting mTOR in B cell neoplasms. We conclude by highlighting a few salient questions and future perspectives regarding mTOR in B lineage cells. PMID- 28583727 TI - Validating the forgotten joint score-12 in patients after ACL reconstruction. AB - BACKGROUND: The forgotten joint score-12 (FJS-12), used to measure postoperative joint awareness, has been extensively validated to assess outcomes after arthroplasty, however the new score has never been validated in evaluating anterior cruciate ligament (ACL) reconstruction. The purpose of our study was to validate the FJS-12 versus the knee injury and osteoarthritis outcome score (KOOS) for patients who have undergone ACL reconstruction. METHODS: All patients who had undergone ACL reconstruction with the same arthroscopic surgical technique at our institution between 2011 and 2014 (medium-term follow-up group (M-FU)) or between 2000 and 2005 (long-term follow-up group (L-FU)) were considered for inclusion in the study. To analyze unidimensionality of the FJS 12, we calculated Cronbach's alpha, item-total correlations and conducted an exploratory principal component factor analysis. To assess convergent validity, we calculated Spearman correlation coefficients for the FJS-12 and its comparable scales. RESULTS: We analyzed 58 patients of the M-FU (mean follow-up 31.5 (SD13.4) months, range 12-54), and 58 patients of the L-FU (mean follow-up 139 (SD15.2) months, range 120-179). The FJS-12 showed high internal consistency (Cronbach's alpha=0.95). Ceiling effects were considerably lower for the FJS-12 (M-FU 12.1%, L-FU 15.5%) compared with the KOOS subscales (M-FU 5.2-37.9%; L-FU 13.8-55.2%) and WOMAC subscales (M-FU 37.9-62.1%; L-FU 44.8-60.3%). CONCLUSIONS: The FJS-12 is a valid measurement tool to evaluate outcomes of ACL reconstruction. This study extends the possibilities of measuring joint awareness as a patient-reported outcome parameter from joint arthroplasty to ACL reconstruction. PMID- 28583729 TI - Open abdominal surgical training differences experienced by integrated vascular and general surgery residents. AB - BACKGROUND: As the integrated vascular residency program reaches almost a decade of maturity, a common area of concern among trainees is the adequacy of open abdominal surgical training. It is our belief that although their overall exposure to open abdominal procedures has decreased, integrated vascular residents have an adequate and focused exposure to open aortic surgery during training. METHODS: National operative case log data supplied by the Accreditation Council for Graduate Medical Education were compiled for both graduating integrated vascular surgery residents (IVSRs) and graduating categorical general surgery residents (GSRs) for the years 2012 to 2014. Mean total and open abdominal case numbers were compared between the IVSRs and GSRs, with more in depth exploration into open abdominal procedures by organ system. RESULTS: Overall, the mean total 5-year case volume of IVSRs was 1168 compared with 980 for GSRs during the same time frame (P < .0001). IVSRs reported nearly double the number of surgeon-chief cases compared with GSRs (452 vs 239; P < .0001). GSRs reported more than double the number of open abdominal procedures compared with IVSRs (205 vs 83; P < .0001). Sixty-five percent of the open abdominal experience for IVSRs was focused on procedures involving the aorta and its branches, with an average of 54 open aortic cases recorded throughout their training. The largest single contributor to open surgical experience for a GSR was alimentary tract surgery, representing 57% of all open abdominal cases. GSRs completed an average of 116 open alimentary tract surgeries during their training. Open abdominal surgery represented an average of 7.1% of the total vascular case volume for the vascular residents, whereas open abdominal surgery represented 21% of a GSR's total surgical experience. CONCLUSIONS: IVSRs reported almost double the number of total cases during their training, with double chief-level cases. Sixty-five percent of open abdominal surgeries performed by IVSRs involved the aorta or its renovisceral branches. Whereas open abdominal surgery represented 7.1% of an IVSR's surgical training, GSRs had a far broader scope of open abdominal procedures, completing nearly double those of IVSRs. The differences in open abdominal procedures pertain to the differing diseases treated by GSRs and IVSRs. PMID- 28583728 TI - Conical neck is strongly associated with proximal failure in standard endovascular aneurysm repair. AB - OBJECTIVE: Hostile proximal aortic neck (HN) challenges the suitability for standard endovascular aneurysm repair (EVAR) of patients at high risk for "open" repair. However, there has been little if any focus placed on the individual role of the "nonlength" HN features in EVAR outcomes. The aim of this study was to evaluate their individual and potentially predictive role in outcomes of EVAR under HN conditions. METHODS: Data of 156 consecutive EVAR patients with short (<15 mm) HN, treated with the Endurant device (Medtronic Cardiovascular, Santa Rosa, Calif) at three European academic vascular centers between 2007 and 2015, were collected and retrospectively analyzed. All patients had at least one of the four well-known nonlength HN criteria (width >32 mm or bulge, angulation >60 degrees, reverse taper anatomy, and circumferential thrombus or calcification >50%) and underwent standard EVAR without additional techniques, such as use of chimney grafts or endoanchors. Primary end points were absence of type IA endoleak at 1 month and midterm follow-up and aneurysm sac stabilization or shrinkage. Secondary end points were 30-day mortality, overall survival, and secondary interventions related to EVAR. The study cohort was classified in two subgroups related to neck length (length <10 mm and length between 10 and 14 mm) as well as in two subgroups according to on-label or off-label stent graft use. RESULTS: Mean clinical and radiologic follow-up was 41.1 +/- 24.7 and 31.7 +/- 19.0 months, respectively. Overall EVAR-related mortality was 1.9% (n = 3). The total type IA endoleak rate was 5.8% (n = 9). In four patients, the type IA endoleak was detected intraoperatively and solved by endovascular means. A type IA endoleak was detected in three patients at 1 month and in two patients at 2 year follow-up. During follow-up, five patients showed an increase of aneurysm diameter due to type II endoleak and were treated by secondary endovascular reinterventions. The total number of all EVAR-related secondary procedures in the midterm was 12 (7.7%). Univariate analysis showed that the center of treatment and the clinical or anatomic features were not associated with adverse outcomes. Multiple regression and Cox regression analysis of HN features revealed that reverse taper anatomy (conical neck) was the single and significantly associated predictor of proximal EVAR failure (P < .012). Width >32 mm, angulation >60 degrees, and calcification or thrombus were not associated with adverse outcomes. Analysis between HN length cohorts and between on-label and off-label subgroups revealed no difference in outcomes. CONCLUSIONS: A conical neck in hostile anatomies represents the single strongest factor associated with proximal failure of standard EVAR. This finding should be considered and highlighted apart from the length of the infrarenal neck to prevent midterm failure of standard EVAR. PMID- 28583730 TI - Young female vascular surgeons more likely to enter academia. AB - OBJECTIVE: In the last decade, there has been a dramatic increase in the number of women entering vascular surgery. Our goal was to evaluate the differences in career paths based on gender and to determine some of the factors that influence career decisions among young vascular surgeons. METHODS: A 17-item web-based survey focusing on current employment status, reasons for choosing academic vs nonacademic positions, and career satisfaction was distributed to 900 members of the Society for Vascular Surgery who completed vascular surgery training in the past 10 years. RESULTS: A total of 199 individuals responded to the survey (22.1%). The cohort included 49 (24.6%) women and 149 (74.9%) men. The majority of the respondents were non-Hispanic white (66.3%). Sixty-four percent of all respondents were younger than 40 years. Overall, 72.9% of women had applied to academic positions after their training compared with 58.8% of men. Women were more likely to apply for and to work in an academic setting (P = .0266 and P = .0198, respectively) and cited mentorship more frequently (P = .0474) as the reason for choosing an academic practice. Women respondents were less likely to have a spouse or children (P = .0269 and P < .001, respectively). More than 87.4% of all respondents were very satisfied or somewhat satisfied with their careers. However, men were more likely to be very satisfied compared with women (P = .0345). CONCLUSIONS: Career satisfaction remains high among young vascular surgeons. In this cohort of vascular surgery graduates, we found that women were more likely to pursue academic positions than men, with mentorship, ability to teach, and complexity of cases commonly cited as reasons for this career choice. However, whether young women stay in academia and what factors affect academic retention will need further evaluation. PMID- 28583731 TI - Risk factors for postoperative delirium in patients undergoing vascular surgery. AB - OBJECTIVE: Postoperative delirium (PODE) remains a common complication after vascular surgery procedures although the exact pathogenesis remains unclear, mainly because of its multifactorial character. The aim of this systematic review was to evaluate pooled data on potential risk factors for PODE in patients undergoing vascular surgery procedures. METHODS: A systematic literature review was conducted conforming to established criteria to identify eligible articles published from 1990 to 2016. Eligible studies evaluated potential risk factors for PODE after vascular surgery procedures, using both univariate and multivariate analysis. PODE was defined as a disturbance of consciousness with reduced ability to focus, sustain, or shift attention after vascular surgery procedures and was diagnosed in all studies using well-established criteria. Only risk factors reported in at least four studies were included in this review. Pooled results were calculated, and further multivariate regression analysis was conducted. RESULTS: Overall, nine studies (published from 2003 to 2015) including 2388 patients in total were evaluated (457 with and 1931 without PODE). Patients with PODE were older (73.27 vs 69.87 years; P < .0001) and showed a higher male sex rate (78.1% vs 73.5%; P = .043). Open aortic surgery was the most frequent procedure in this analysis, followed by lower limb revascularization. Patients with PODE also showed higher rates of diabetes mellitus, hypertension, cardiac disease, and neurologic disease; lower hemoglobin level; larger duration of surgery; longer hospital and intensive care unit stay; and higher blood loss. Mean age (odds ratio [OR], 3.44; 95% confidence interval [CI], 2.933-4.034; P < .0001), hypertension (OR, 1.94; 95% CI, 1.469-2.554; P < .0001), cardiac disease (OR, 3.16; 95% CI, 2.324-4.284; P < .0001), open aortic surgery (OR, 1.74; 95% CI, 1.421-2.143; P < .0001), blood loss (OR, 1.01; 95% CI, 1.007-1.010; P < .0001), hospital stay (OR, 2.26; 95% CI, 1.953-2.614; P <. 0001), and intensive care unit stay (OR, 6.12; 95% CI, 4.699-7.957; P < .0001) were identified as the strongest risk predictors for PODE, followed by male sex, diabetes mellitus, neurologic disease, and history of smoking. However, body mass index, renal failure, preoperative hemoglobin level, and general anesthesia were not found to be risk factors for PODE in such patients. CONCLUSIONS: This study has confirmed that PODE after vascular surgery procedures is a multifactorial disease, and several independent risk factors have been identified. However, pooled data regarding the effect of PODE on primary outcomes after vascular surgery procedures are still lacking. The results of this review could contribute to the designation of future prediction models and improve prevention of PODE in these patients. PMID- 28583732 TI - Effects of topical negative pressure therapy on tissue oxygenation and wound healing in vascular foot wounds. AB - OBJECTIVE: Topical negative pressure (TNP) therapy is widely used in the treatment of acute wounds in vascular patients on the basis of proposed multifactorial benefits. However, numerous recent systematic reviews have concluded that there is inadequate evidence to support its benefits at a scientific level. This study evaluated the changes in wound volume, surface area, depth, collagen deposition, and tissue oxygenation when using TNP therapy compared with traditional dressings in patients with acute high-risk foot wounds. METHODS: This study was performed with hospitalized vascular patients. Forty eight patients were selected with an acute lower extremity wound after surgical debridement or minor amputation that had an adequate blood supply without requiring further surgical revascularization and were deemed suitable for TNP therapy. The 22 patients who completed the study were randomly allocated to a treatment group receiving TNP or to a control group receiving regular topical dressings. Wound volume and wound oxygenation were analyzed using a modern stereophotographic wound measurement system and a hyperspectral transcutaneous oxygenation measurement system, respectively. Laboratory analysis was conducted on wound biopsy samples to determine hydroxyproline levels, a surrogate marker to collagen. RESULTS: Differences in clinical or demographic characteristics or in the location of the foot wounds were not significant between the two groups. All patients, with the exception of two, had diabetes. The two patients who did not have diabetes had end-stage renal failure. There was no significance in the primary outcome of wound volume reduction between TNP and control patients on day 14 (44.2% and 20.9%, respectively; P = .15). Analyses of secondary outcomes showed a significant result of better healing rates in the TNP group by demonstrating a reduction in maximum wound depth at day 14 (36.0% TNP vs 17.6% control; P = .03). No significant findings were found for the other outcomes of changes in hydroxyproline levels (58.0% TNP vs 94.5% control; P = .32) or tissue perfusion by tissue oxyhemoglobin saturation (19.4% TNP vs 12.0% control; P = .07) at day 14. At 1 year of follow-up, there were no significant outcomes in the analysis of wound failure, major amputation, and overall survival rates between the two groups. CONCLUSIONS: In this pilot study, applying TNP to acute high-risk foot wounds in patients with diabetes or end-stage renal failure improved the wound healing rate in reference to wound depth. This suggests that TNP may play a role in enhancing wound healing. This study sets the foundation for larger studies to evaluate the superiority of TNP over traditional dressings in high risk foot wounds. PMID- 28583733 TI - Treatment strategy based on the natural course of the disease for patients with spontaneous isolated abdominal aortic dissection. AB - OBJECTIVE: This study aimed to determine the natural history of spontaneous isolated abdominal aortic dissection (SIAAD) and to establish an optimal management strategy for patients with SIAAD. METHODS: We searched the database of thoracoabdominal computed tomography (CT) performed at a single institution from January 2003 to July 2016 using the keywords "aortic dissection" and "dissection AND aorta." Once a diagnosis of SIAAD was made, we investigated the initial clinical and morphologic features and aorta-related events for all patients and morphologic changes of the aortic dissection (AD) during the follow-up period for the patients who underwent follow-up CT scans. We compared characteristics of the patients, frequencies of clinical events (aortic rupture, intervention, death), and morphologic changes (false lumen enlargement, progression of AD, remodeling of AD, and involvement of iliac or visceral artery) during the follow-up period according to the location of AD (infrarenal vs suprarenal), symptom status (symptomatic vs asymptomatic), and gender. RESULTS: There were 210 (10.7%) patients (median age, 69.4 years [interquartile range, 61.3-74.7]; male, 73.3%) who were diagnosed with SIAAD among 1958 patients with AD. SIAAD was most frequently located at the infrarenal aorta (86.2%), extended to the iliac (12.4%) or visceral artery (2.9%), and was symptomatic in 13.3% of patients. During the study period, aortic rupture developed in two patients (0.9%), aortic intervention was required in five (2.4%), and aorta-related deaths were identified in three (1.4%). Among 138 (65.7%) patients who underwent follow-up CT scans, 81.9% showed no morphologic change or remodeling during the follow-up period (median, 25 months; range, 1-158 months; interquartile range, 12.3-49.1 months). In the meantime, false lumen enlargement and longitudinal progression of AD developed in 8.7% and 6.5% of patients, respectively. However, newly developed visceral artery extension was not found in any of the patents. When characteristics of the patients and frequencies of clinical events or late morphologic changes of AD were compared on the basis of the location of AD, symptom status, and gender, female gender, presence of symptoms, and suprarenal SIAAD were more frequently associated with aorta-related mortality. False lumen enlargement was more frequent in the suprarenal AD group than in the infrarenal AD group. CONCLUSIONS: Based on our observation, the majority of symptomatic and asymptomatic SIAAD patients can be managed conservatively unless they present with aortic rupture, concomitant large aortic aneurysm, or underlying connective tissue disease. However, a more proactive management strategy may be required for female, symptomatic patients or those with suprarenal SIAAD. PMID- 28583734 TI - Thoracic endovascular aortic repair with branched Inoue Stent Graft for arch aortic aneurysms. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) for thoracic aortic aneurysms (TAAs) is in rapid expansion due to its minimal invasiveness. However, TEVAR for an arch aneurysm with a straight stent graft needs surgical reconstruction for supra-aortic vessels. A branched stent graft pioneered by Inoue (branched Inoue Stent Graft [ISG]) has been expected to resolve this problem, but its utility remains to be established in the real clinical setting. This study evaluated the long-term clinical outcome of branched ISGs for TAAs. METHODS: Among 217 consecutive patients who underwent TEVAR with ISGs between March 2003 and September 2013, 89 patients with TAAs were treated with implantation of the branched ISG (single branch: n = 64; double branch: n = 18; triple branch: n = 7). The primary end point was freedom from aneurysm-related death. Secondary end points included periprocedural adverse events, freedom from all-cause death and major adverse events (composite of aneurysm-related death, surgical conversion, aneurysm rapture, persistent type I or III endoleak, graft infection, graft occlusion, graft migration, and aneurysm expansion), changes of aneurysm diameter, stroke, and any endovascular reintervention during follow-up. RESULTS: All deployments of branched ISGs were successful. The 30-day mortality was 4.5% (single branch, 3.1%; double branch, 0%; triple branch, 29%), and periprocedural stroke was 16% (single branch, 7.8%; double branch, 33%; triple branch, 42%). At 1 and 5 years, freedom from aneurysm-related death was 93% and 93%, respectively, and freedom from all-cause death was 85% and 59%, respectively. Survival free of major adverse events was 76% at 5 years. The cumulative incidence of stroke was 11% at 5 years. Three patients underwent surgical conversion because of persistent type I endoleak. One branch graft occlusion was observed at the left subclavian artery in a patient who received a double-branched graft. CONCLUSIONS: Periprocedural outcome of the single-branched ISG was acceptable, and long-term safety and efficacy were demonstrated. However, the procedural complications of the multibranched ISG leave room for improvement. PMID- 28583735 TI - Electromagnetic tracking of flexible robotic catheters enables "assisted navigation" and brings automation to endovascular navigation in an in vitro study. AB - OBJECTIVE: Combining three-dimensional (3D) catheter control with electromagnetic (EM) tracking-based navigation significantly reduced fluoroscopy time and improved robotic catheter movement quality in a previous in vitro pilot study. The aim of this study was to expound on previous results and to expand the value of EM tracking with a novel feature, assistednavigation, allowing automatic catheter orientation and semiautomatic vessel cannulation. METHODS: Eighteen users navigated a robotic catheter in an aortic aneurysm phantom using an EM guidewire and a modified 9F robotic catheter with EM sensors at the tip of both leader and sheath. All users cannulated two targets, the left renal artery and posterior gate, using four visualization modes: (1) Standard fluoroscopy (control). (2) 2D biplane fluoroscopy showing real-time virtual catheter localization and orientation from EM tracking. (3) 2D biplane fluoroscopy with novel EM assisted navigation allowing the user to define the target vessel. The robotic catheter orients itself automatically toward the target; the user then only needs to advance the guidewire following this predefined optimized path to catheterize the vessel. Then, while advancing the catheter over the wire, the assisted navigation automatically modifies catheter bending and rotation in order to ensure smooth progression, avoiding loss of wire access. (4) Virtual 3D representation of the phantom showing real-time virtual catheter localization and orientation. Standard fluoroscopy was always available; cannulation and fluoroscopy times were noted for every mode and target cannulation. Quality of catheter movement was assessed by measuring the number of submovements of the catheter using the 3D coordinates of the EM sensors. A t-test was used to compare the standard fluoroscopy mode against EM tracking modes. RESULTS: EM tracking significantly reduced the mean fluoroscopy time (P < .001) and the number of submovements (P < .02) for both cannulation tasks. For the posterior gate, mean cannulation time was also significantly reduced when using EM tracking (P < .001). The use of novel EM assisted navigation feature (mode 3) showed further reduced cannulation time for the posterior gate (P = .002) and improved quality of catheter movement for the left renal artery cannulation (P = .021). CONCLUSIONS: These results confirmed the findings of a prior study that highlighted the value of combining 3D robotic catheter control and 3D navigation to improve safety and efficiency of endovascular procedures. The novel EM assisted navigation feature augments the robotic master/slave concept with automated catheter orientation toward the target and shows promising results in reducing procedure time and improving catheter motion quality. PMID- 28583736 TI - Partial distal deployment for precise placement of the GORE Thoracic Endoprosthesis. AB - The GORE TAG Thoracic Endoprosthesis (TAG) device (W. L. Gore & Associates, Flagstaff, Ariz) and the GORE Conformable TAG Thoracic Endoprosthesis (CTAG) are commonly implanted and effective stent grafts for use during thoracic endovascular aortic repair. Precise placement of the endograft is paramount during thoracic endovascular aortic repair, but like all thoracic stent grafts, maldeployment with inaccurate landing has been reported. The partial distal deployment technique describes an alteration of the TAG and CTAG deployment mechanism to allow isolated deployment of the distal half of the graft, which provides stability during deployment. The graft can be safely repositioned after partial distal deployment, thus allowing precise positioning in the proximal landing zone. Similarly, this technique can be used for precision in the distal landing zone, making the TAG and CTAG devices the only thoracic endografts currently available in the United States with a distal-first deployment option. A discussion of the usefulness of this technique and potential pitfalls is included. PMID- 28583737 TI - Development of a validated model to predict 30-day stroke and 1-year survival after carotid endarterectomy for asymptomatic stenosis using the Vascular Quality Initiative. AB - OBJECTIVE: Carotid endarterectomy (CEA) has been shown to be an effective treatment for patients with asymptomatic carotid artery stenosis when perioperative stroke rates are low and patients survive long enough to benefit from the intervention. Our objective was to develop and to validate a simple risk prediction model for 30-day stroke and 1-year mortality to guide optimal selection of patients for CEA. METHODS: Asymptomatic patients undergoing first time elective CEA within the Vascular Quality Initiative (VQI) from 2010 to 2015 were selected. Outcome measures included any 30-day postoperative stroke and 1 year mortality. Patient demographics, comorbidities, carotid artery disease burden, and provider characteristics were evaluated to select a parsimonious clinical model for risk prediction using multivariable logistic regression. Internal validation was performed for stroke and split sample validation was done for 1-year survival to ensure generalizability. RESULTS: We identified 31,939 patients for inclusion in the stroke analysis (2010-2015) and 24,086 patients for the mortality analysis (2010-2014). Both the 30-day stroke rate (0.9%) and 1-year mortality rate (3.4%) varied substantially across 265 VQI centers (range, 0%-8.3% and 0%-20%, respectively). Eleven significant factors were selected for the 30 day stroke risk prediction model (area under the receiver operating characteristic curve [AUC], 0.67). Internal validation demonstrated good discrimination (bias corrected AUC = 0.652; calibration intercept and slope of 0.03 and 1.01, respectively). Similarly, 10 significant factors were selected for the 1-year mortality risk prediction model (AUC, 0.764). External validation demonstrated excellent discrimination and calibration (AUC, 0.764; 95% confidence interval, 0.72-0.80). CONCLUSIONS: Stroke and 1-year mortality rates after CEA for asymptomatic stenosis vary across VQI centers. We have developed a preoperative risk model that can be used to accurately estimate risk of perioperative stroke and 1-year mortality and to assist providers in selecting patients with asymptomatic stenosis who are most likely to benefit from CEA. PMID- 28583738 TI - Predictors of mortality in nursing-home residents with pneumonia: a multicentre study. AB - OBJECTIVES: To evaluate predictors of mortality in patients residing in nursing homes (NHs) or long-term care facilities (LTCFs) with diagnosis of NH-acquired pneumonia (NHAP). METHODS: We conducted an observational, prospective study (December 2013-December 2015) of patients residing in nine NHs/LTCFs of Central and Northern Italy with diagnosis of NHAP. Data on demographics, comorbidities, microbiology, and therapies were entered into an electronic database. To identify risk factors associated with 30-day mortality, we performed univariable and multivariable analyses, and predictors were internally validated using a bootstrap resampling procedure. We derived a prediction rule using the coefficients obtained from the multivariable logistic regression. The model obtained was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Overall, 446 patients with NHAP were included in the final cohort. The median age was 80 (IQR 75-87) years. A definite aetiology was obtained in 120 (26.9%) patients; of these, 66 (55%) had a culture positive for a multidrug-resistant pathogen. The 30-day mortality was 28.7%. On multivariate analysis, malnutrition (OR 7.8; 95% CI 3-20.2, 2 points), bilateral pneumonia (OR 3.7; 95% CI 1.4-9.8, 1 point), acute mental status deterioration (OR 6.2; 95% CI 2.2-17.6, 2 points), hypotension (OR 7.7; 95% CI 2.3-24.9, 2 points), and PaO2/FiO2 ratio <=250 (OR 7.4; 95% CI 2.2-24.2, 2 points) were independently associated with 30-day mortality. The derived prediction rule showed an AUROC of 0.83 (95% CI 0.78-0.87, p <0.001). CONCLUSIONS: NH residents with pneumonia have specific risk factors associated with 30-day mortality. Malnutrition and acute mental change appear as major determinants of death in this population. PMID- 28583739 TI - A new equine and zoonotic threat emerges from an old avian pathogen, Chlamydia psittaci. PMID- 28583740 TI - Diagnosing fungal infections in haematology patients-another case of less is more in the clinical setting? PMID- 28583741 TI - ESCMID-an international Europe-based society committed to fostering cross-border collaboration and education to improve patient care. PMID- 28583743 TI - [Suicidality during perinatal period]. AB - Suicide is one of the leading causes of maternal mortality. Mental disorders, especially mood disorders, have been identified in most perinatal suicide cases. Maternal suicidality has a negative impact on the mother-baby relationship and child development. Systematic screening for psychiatric conditions in the perinatal period is a priority. For women suffering from an acute psychiatric disorder, or a history of mental illness, multidisciplinary management should be implemented. PMID- 28583742 TI - Visual and Motor Deficits in Grown-up Mice with Congenital Zika Virus Infection. AB - Human infants with congenital Zika virus (ZIKV) infection exhibit a range of symptoms including microcephaly, intracranial calcifications, macular atrophy and arthrogryposis. More importantly, prognosis data have lagged far behind the recent outbreak of ZIKV in 2015. In this work, we allow congenitally ZIKV infected mice to grow into puberty. These mice exhibited motor incoordination and visual dysfunctions, which can be accounted by anatomical defects in the retina and cerebellar cortex. In contrary, anxiety level of the ZIKV-infected mice is normal. The spectrum of anatomical and behavioral deficits is consistent across different mice. Our data provided evidence that may help predict the public health burden in terms of prognosis of ZIKV-related congenital brain malformations in an animal model. Our study provided behavioral evaluation for the prognosis of congenital ZIKV infection and provides a platform for screening and evaluation of drugs candidates and treatment aiming at improving regeneration of infected neurons to prevent sequelae caused by ZIKV infection of fetus. PMID- 28583744 TI - [Pulmonary revalvulation and rhythmologenic risks in patients with repaired tetralogy of Fallot]. AB - Tetralogy of Fallot is a frequent congenital heart disease that has been repaired since the mid-1950s. The follow-up after repair is good despite a persistent risk of sudden death. The risk factors in long-term follow-up are advanced age at repair, hemodynamic status of the right ventricle, QRS duration>=180ms, left ventricular dysfunction, and existence of sustained or not ventricular tachycardia. In the presence of significant pulmonary regurgitation, it is necessary to perform revalvulation either by classic surgery or cardiac catheterization. To correct the risk of ventricular arrhythmia, some have proposed radiofrequency ablation of critical isthmus, or cryo-application during surgery. However, the use of implantable cardioverter defibrillator is another therapeutic option that is more and more employed as secondary or primary prevention in patients at risk of sudden death. PMID- 28583745 TI - [Genetics of congenital heart diseases]. AB - Developmental genetics of congenital heart diseases has evolved from analysis of serial slices in embryos towards molecular genetics of cardiac morphogenesis with a dynamic view of cardiac development. Genetics of congenital heart diseases has also changed from formal genetic analysis of familial recurrences or population based analysis to screening for mutations in candidates genes identified in animal models. Close cooperation between molecular embryologists, pathologists involved in heart development and pediatric cardiologists is crucial for further increase of knowledge in the field of cardiac morphogenesis and genetics of cardiac defects. The genetic model for congenital heart disease has to be revised to favor a polygenic origin rather than a monogenic one. The main mechanism is altered genic dosage that can account for heart diseases in chromosomal anomalies as well as in point mutations in syndromic and isolated congenital heart diseases. The use of big data grouping information from cardiac development, interactions between genes and proteins, epigenetic factors such as chromatin remodeling or DNA methylation is the current source for improving our knowledge in the field and to give clues for future therapies. PMID- 28583746 TI - [Health new technology: Uber versus increase]. PMID- 28583747 TI - Targeting DNA damage response systems to impact cancer care. PMID- 28583748 TI - Development of PARP inhibitors in gynecological malignancies. AB - PARP inhibitors demonstrate synthetic lethality in tumors with BRCA1/2 mutations and other homologous recombination repair deficiencies by interfering with DNA repair and causing direct toxicity to DNA through PARP trapping. PARP inhibitors have been shown to be beneficial in the treatment of BRCA1/2-mutated ovarian cancers, which has led to a shift in the treatment paradigm of this disease. Further studies to establish the role of PARP inhibitors during earlier stages of treatment are ongoing. The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including their use in the neoadjuvant and adjuvant settings. PARP inhibitor combination strategies with chemotherapy, targeted agents, radiotherapy, and immunotherapy are also being explored. The role of predictive biomarkers, including molecular signatures and homologous recombination deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to improved patient stratification to enhance the clinical utility of PARP inhibitors. This may also allow the use of PARP inhibitors to be extended beyond tumors with specific homologous recombination DNA repair gene mutations in the future. An improved understanding of the mechanisms underlying PARP inhibitor resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which patients we should be treating with PARP inhibitors and where these agents should come in over the course of treatment. PMID- 28583749 TI - Predictors for early readmission in acute pancreatitis (AP) in the United States (US) - A nationwide population based study. AB - BACKGROUND & AIMS: Population based data on the burden and patterns of acute pancreatitis (AP) early readmissions (<=30-days) are limited. METHODS: 2013 Nationwide Readmission Database (NRD) was queried. AP etiology was determined using associated diagnoses codes. Proportion, reasons for readmission, and associated costs were evaluated. Multivariate logistic regression analysis was performed to identify independent predictors for 30-day readmission. RESULTS: After exclusions, we identified 178,541 patients with primary diagnosis of AP (mean age 53 +/- 17 years, 51% male). 13.7% were readmitted <=30 days [7.1% in acute biliary pancreatitis (ABP) patients with index cholecystectomy (CCY), 16.3% in ABP patients without CCY, and 14.3% in non-biliary AP patients (p < 0.0001)]. Reasons for readmission included AP, chronic pancreatitis, Pseudocyst/walled off necrosis, biliary tract disease, smoldering symptoms and others. On multivariate analysis male gender, comorbidity status (>=3), non-biliary etiology, organ failure, Pseudocyst/walled off necrosis complications, and patients discharged to extended care facilities were associated with increased risk of readmission. ABP patients with index CCY had a significantly lower risk of early unplanned readmission (odds ratio 0.45, p < 0.0001) but ABP patients with index ERCP did not (p = 0.96). CONCLUSIONS: About 1 in 7 AP patients had a 30-day readmission after index hospitalization and about half of these were related to AP. Our data confirms the higher risk of readmission in alcohol and idiopathic AP and a lower risk in ABP. Risk of early unplanned readmission is significantly lower in ABP patients who underwent CCY and not ERCP during index hospitalization. Cholecystectomy should be performed in all ABP patients as per recommended guidelines. PMID- 28583750 TI - Systematic review: Early versus late dangling after free flap reconstruction of the lower limb. AB - INTRODUCTION AND AIMS: Dangling regimes after free flap surgery to the lower limb vary between centres and clinicians. There is currently no accepted gold standard. This review examines the evidence for early versus late post-operative dangling after free flap reconstruction of the lower limb. The secondary aim is to evaluate the regimes used. MATERIAL AND METHODS: Medline, Embase and the Cochrane library were searched for all studies on dangling or rehabilitation after free flap reconstruction in the lower limb (December 2015). All studies outlining a clear dangling regime were included. Data were extracted by two authors independently and analysed using the software package Review Manager (RevMan 5). All authors were contacted for further information. RESULTS: 197 patients were included from 8 studies: 1 randomized, 6 cohort and 1 case-series. Although some studies did not state the aetiology, of those that did; 42% were trauma, 31% oncology, 20% complex wounds and 7% infection. The majority of flaps were latissimus dorsi, 18% parascapular, 15% anterolateral thigh and the remainder was mixed. Forty-eight percent of patients dangled on post-operative day (POD) 7, 29% on day 6, 4% on day 5 and 18% on day 3, with varying regimes. A meta-analysis of comparable studies showed circulatory benefit after 4 days of dangling using tissue oxygen saturation as a measure. Four flap failures (2.0%) were reported. CONCLUSIONS: There is physiological benefit in post-operative dangling. A 3-day flap training regime is sufficient for physiological training. However, the optimal flap training regime remains unclear. It may be appropriate to start dangling as early as POD 3. More research is needed to determine the optimal time to start dangling and the regime. PMID- 28583751 TI - Two-artery replantation for digital tip amputation. PMID- 28583752 TI - Management of knee rheumatoid arthritis and tibia nonunion with one-stage total knee arthroplasty and intramedullary nailing: A report of two cases. AB - Total knee arthroplasty (TKA) is a surgical procedure which is widely used in the treatment of gonarthrosis secondary to rheumatoid arthritis (RA). The incidence of stress fractures in tibia in the patients with RA is higher compared to normal patients. In this study, we report two cases of TKA and intramedullary nailing in RA patients with severe knee arthritis and tibial nonunion. Both patients had a satisfactory clinical outcome with radiological healing of the tibial fracture. PMID- 28583753 TI - Optimal trajectory and insertion accuracy of sacral alar iliac screws. AB - OBJECTIVE: The aim of this study was to analyse the optimal trajectories for sacral alar iliac screws (SAISs) in a Japanese patient population and the clinical assessment of insertion accuracies. METHODS: The ideal trajectories of SAISs, starting from 2 mm medial to the apex of the lateral sacral crest on the midline between S1 and S2 dorsal foramina, were measured in 80 consecutive spinal disease patients (40 males and 40 females; average age: 67.4 +/- 8.1 years) using three-dimensional computed tomographic image software. Following these anatomic analyses, accuracies of 32 inserted SAISs in consecutive patients, who underwent long spinal posterior fusion, were investigated clinically. RESULTS: Lateral angulations of optimal SAIS trajectories in males (left: 37.9; right: 37.7) were significantly larger than those than in females (left: 32.8; right: 32.4). Caudal SAIS angulations for females (left: 33.4; right: 33.9) were significantly larger than those in males (left: 27.5; right: 28.0). The 32 SAISs (100 mm long and 9 mm in diameter) assessed clinically were accurately inserted on optimal trajectories. CONCLUSION: The optimal trajectories of SAISs in a Japanese patient population are more lateral in males and more caudal in females. This study examines the clinical safety and accuracy of SAIS insertion on these optimal trajectories. PMID- 28583754 TI - Bilateral bony increased-offset reverse shoulder arthroplasty in rheumatoid arthritis shoulder with severe glenoid bone defect: A case report. AB - A 53-year-old woman presented with 10-year history of pain and limited range of motion in both shoulders. Radiographs of both shoulders showed severe shoulder osteoarthritis with glenoid bone defect. Very thin rotator cuff and superior migration of the humerus were also observed on computed tomography images. We performed bony increased-offset reverse total shoulder arthroplasty on her both shoulders. The patient had a good clinical outcome without any particular complication. PMID- 28583755 TI - Prognostic significance of an antenatal magnetic resonance imaging staging system on airway outcomes of fetal craniofacial venolymphatic malformations. AB - BACKGROUND: The aim of the article was to determine if anatomical findings on fetal magnetic resonance imaging (MRI) of venolymphatic malformations of the face and neck (VLMFN) can be used to create a staging system predictive of airway outcomes. METHODS: We reviewed 13 fetuses evaluated for VLMFN. Stage was assigned based on anatomical findings on fetal MRI. Stage I: no evidence of polyhydramnios with free egress of amniotic fluid and clear visualization of the aryepiglottic folds and larynx. Stage II: lesions of the tongue or epiglottis but with normal aryepiglottic folds without polyhydramnios. Stage III: lesions of the tongue or larynx; nonvisualization of the aryepiglottic folds without free egress of amniotic fluid along with polyhydramnios. RESULTS: Six met stage I criteria with no airway involvement, nor any subsequent issues. Two met stage II criteria and were managed by ex-utero intrapartum therapy and intubated. One had minimal involvement of the upper airway, was extubated, and had no subsequent issues. Child two had involvement of the tongue and larynx and received a tracheostomy. Five were assigned stage III, delivered by ex-utero intrapartum therapy and intubated. Postnatal evaluation showed involvement of the upper airway by the lesion and was managed with tracheostomy. All treated by tracheostomy remain cannulated because of persistent symptomatic lesions at follow-up (relative risk 4.0; confidence interval 1.2-13.3). Median follow-up was 4 y (range 2-7 y). CONCLUSIONS: Although numbers are small, data suggest anatomical details obtained by antenatal fetal MRI appear to correlate with airway outcomes in children affected by a VLMFN. This information may be useful when counseling expectant families of affected fetuses. PMID- 28583756 TI - Thrombelastography indicates limitations of animal models of trauma-induced coagulopathy. AB - BACKGROUND: Thrombelastography (TEG) has been used to characterize the coagulation changes associated with injury and shock. Animal models developed to investigate trauma-induced coagulopathy (TIC) have failed to produce excessive bleeding. We hypothesize that a native TEG will demonstrate marked differences in humans compared with these experimental models, which explains the difficulties in reproducing a clinically relevant coagulopathy in animal models. METHODS: Whole blood was collected from 138 healthy human volunteers, 25 swine and 66 Sprague-Dawley rats before experimentation. Citrated native TEGs were conducted on each whole blood sample within 2 h of collection. The clot initiation (R-time, minutes), angle (degrees), maximum amplitude (MA; millimeter), and lysis 30 min after MA (LY30; percentage) were analyzed and contrasted between species with data represented as the median and 25th to 75th quartile range. Difference between species was conducted with a Kruskal-Wallis test with alpha adjusted with a Bonferroni correction for multiple comparisons (alpha = 0.016). RESULTS: Median R-time (clot initiation) was 14.65 min (IQR: 13.2-16.3 min) for humans, 5.7 min (4.9-8.8) for pigs, and 5.2 min (4.4-6) for rodents. Humans had longer R-times than both pigs (P < 0.0001) and rats (P < 0.0001); pigs were not different from rats (P = 0.4439). Angle (fibrin cross-linking) was 42.3 degrees (interquartile range [IQR]: 37.5-50.2) for humans, 71.7 degrees (64.3-75.6) for pigs, and 61.8 degrees (56.8-66.7) for rats. Humans had reduced angle compared with both pigs (P < 0.0001) and rats (P < 0.0001); pigs were not different from rats (P = 0.6052). MA (clot strength) was 55.5 mm (IQR: 52.0-59.5) for humans, 72.5 mm (70.4-75.5) for pigs, and 66.5 mm (56.5-68.6) for rats. Humans had reduced MA compared with both pigs (P < 0.0001) and rats (P < 0.0001); pigs were not different from rats (P = 0.0161). LY30 (fibrinolysis) was 1.5% (IQR: 0.975-2.5) for humans, 3.3% (1.9-4.3) for pigs, and 0.5% (0.1-1.2) for rats. Humans had a lesser LY30 than pigs (P = 0.0062) and a greater LY30 than rats (P < 0.0001), and pigs had a greater LY30 than rats (P < 0.0001). CONCLUSIONS: Humans, swine, and rodents have distinctly different coagulation systems, when evaluated by citrated native TEG. Animals are hypercoagulable with rapid clotting times and clots strengths nearly 50% stronger than humans. These coagulation differences indicate the limitations of previous models of trauma-induced coagulopathy in producing coagulation abnormalities associated with increased bleeding. The inherent hypercoagulable baseline tendencies of these animals may result in subclinical biochemical changes that are not detected by conventional TEG and should be taken into consideration when extrapolated to clinical medicine. PMID- 28583757 TI - Intravenous Acetaminophen in Multimodal Pain Management for Patients Undergoing Total Knee Arthroplasty: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Although multimodal pain management including periarticular multidrug injection can provide excellent pain relief in the early postoperative period after total knee arthroplasty (TKA), rebounding pain remains an important challenge. A randomized, double-blind, placebo-controlled trial was performed to investigate the efficacy of adding intravenous acetaminophen to multimodal pain management for TKA. METHODS: We enrolled 67 patients scheduled for unilateral TKA. Patients were randomly assigned to receive either 1000 mg of intravenous acetaminophen at 6-hour intervals or normal saline at the same intervals. All patients were treated with intraoperative periarticular multidrug injection and intravenous and oral nonsteroidal anti-inflammatory drugs. The primary outcome was the postoperative 100-mm visual analog pain scale at the time of administration of study drugs. RESULTS: In the intention-to-treat analysis, the pain score was significantly better in the intravenous acetaminophen group than the placebo group at 17:00 one day after TKA (15.3 +/- 17.0 mm vs 26.8 +/- 19.0 mm; P = .013). There were no significant differences in terms of the rate of complications between groups. CONCLUSION: Even in the setting of multimodal pain management including periarticular multidrug injection, intravenous acetaminophen provided better pain relief for patients undergoing unilateral TKA. PMID- 28583758 TI - Perioperative Complications in Patients With Sleep Apnea Undergoing Total Joint Arthroplasty. AB - BACKGROUND: This study aims to evaluate the effect of sleep apnea (SA) on perioperative complications after total joint arthroplasty (TJA) and whether the type of anesthesia influences these complications. METHODS: Using the ninth and tenth revisions of the International Classification of Diseases, coding systems, we queried our institutional TJA database from January 2005 to June 2016 to identify patients with SA who underwent TJA. These patients were matched in a 1:3 ratio based on age, gender, type of surgery, and comorbidities to patients who underwent TJA but were not coded for SA. Perioperative complications were identified using the same coding systems. Multivariate analysis was used to test if SA is an independent predictor of perioperative complications and if type of anesthesia can affect these complications. RESULTS: A total of 1246 patients with SA were matched to 3738 patients without SA. Pulmonary complications occurred more frequently in patients with SA (1.7% vs 0.6%; P < .001), confirmed using multivariate analysis (odds ratio = 2.91; 95% confidence interval, 1.58-5.36; P = .001). Use of general anesthesia increased risk of all but central nervous system complications and mortality (odds ratio = 15.88; 95% confidence interval, 3.93 64.07; P < .001) regardless of SA status compared with regional anesthesia. Rates of pulmonary and gastrointestinal complications, acute anemia, and mortality were lower in SA patients when regional anesthesia was used (P < .05). CONCLUSION: SA increases risk of postoperative pulmonary complications. The use of regional anesthesia may reduce risk of pulmonary complications and mortality in SA patients undergoing TJA. PMID- 28583759 TI - Morbid Obesity Is a Significant Risk of Failure Following Revision Total Hip Arthroplasty. AB - BACKGROUND: Although it has been shown that morbidly obese patients experience good outcomes following primary total hip arthroplasty (THA), it is unclear whether this also applies to revision surgery. The purpose of this study was to examine the effect of a high body mass index (BMI) on the outcome of revision THA. METHODS: We identified 56 patients with a BMI >40 kg/m2 who had undergone revision THA between 1994 and 2009 at our hospital (group B). Mean age, BMI, and follow-up were 66.4 years, 45.7 kg/m2, and 11.7 years, respectively. This was matched with a second group of patients with a BMI between 30 and 40 kg/m2 according to age, gender, and date of index procedure (group A). Mean age, BMI, and follow-up were 66.6 years, 33.6 kg/m2, and 12 years, respectively. Outcome measures included the rate of subsequent revision, implant survival, and the Harris hip score (HHS). RESULTS: Patients with a BMI >40 kg/m2 had a significantly increased risk of revision surgery (27% vs 12%, P = .036). Cumulative implant survival was 85% (95% CI, 69-92) in group A and 69% (95% CI, 54-80) in group B at 15 years. HHS increased significantly following surgery in both groups (group A: 26.3-79.3) and (group B: 37.6-69.9; P < .001). However, HHS at last follow-up was significantly higher in group A (79.3 vs 69.9, P = .042). CONCLUSION: Morbid obesity appears to be associated with an increased risk of failure and lower functional scores following revision THA. Patients should be well informed of this before surgery. PMID- 28583760 TI - Can Demographic Variables Accurately Predict Component Sizing in Primary Total Knee Arthroplasty? AB - BACKGROUND: As health care reform drives providers to reduce costs and improve efficiencies without compromising patient care, preoperative planning has become imperative. The purpose of this study is to determine whether height, weight, and gender can accurately predict total knee arthroplasty (TKA) sizing. METHODS: A consecutive series of 3491 primary TKAs performed by 2 surgeons was reviewed. Height, weight, gender, implant, preoperative templating sizes, and final implant sizes were collected. Implant-specific dimensions were collected from vendors. Using height, weight, and gender, a multivariate linear regression was performed with and without the inclusion of preoperative templating. Accuracy of the model was reported for commonly used implants. RESULTS: There was a significant linear correlation between height, weight, and gender for femoral (R2 = 0.504; P < .001) and tibial sizes (R2 = 0.610; P < .001). Adding preoperative templating to the regression analysis increased the overall model fit for both the femoral (R2 = 0.756; P < .001) and tibial sizes (R2 = 0.780; P < .001). Femoral and tibial sizes were accurately predicted within 1 size of the final implant 71%-92% and 81%-97% using demographics alone or 85%-99% and 90%-99% using both templating and demographics, respectively. CONCLUSION: This novel TKA templating model allows final implants to be predicted to within 1 size. The model allows for simplified preoperative planning and potential implementation into a cost-savings program that limits inventory and trays required for each case. PMID- 28583761 TI - Bundled Payments for Care Improvement: Boom or Bust? AB - BACKGROUND: As early implementors of the Centers for Medicare and Medicaid Services (CMS) Bundled Payments for Care Improvement (BPCI) initiative, our private practice sought to compare our readmission rates, post-acute care utilization, and length of stay for the first year under BPCI compared to baseline data. METHODS: We used CMS data to compare total expenditures of all diagnosis-related groups (DRGs). Medicare patients who underwent orthopedic surgery between 2009 and 2012 were defined as non-BPCI (n = 8415) and were compared to Medicare BPCI patients (n = 4757) who had surgery in 2015. Ninety-day post-acute events including inpatient rehabilitation facility or subacute nursing facility admission, home health (HH), and readmissions were analyzed. RESULTS: The median expenditure for non-BPCI patients was $22,193 compared to $19,476 for BPCI patients (P < .001). Median post-acute care spend was $6861 for non-BPCI and $5360 for BPCI patients (P < .001). Compared to non-BPCI patients, BPCI patients had a lower rate of subacute nursing facility admissions (non-BPCI 43% vs 37% BPCI; P < .001), inpatient rehabilitation facility admissions (non-BPCI 3% vs 4% BPCI; P = .005), HH (non-BPCI 79% vs 73% BPCI; P < .001), and readmissions (non BPCI 12% vs 10% BPCI; P = .02). Changes in length of stay for post-acute care were only significant for HH with BPCI patients using a median 12 days and non BPCI using 24 days. CONCLUSION: The objective of BPCI was to improve healthcare value. Through substantial efforts both financially and utilization of human resources to contain costs with clinical practice guidelines, patient navigators, and a BPCI management team, the expenditures for CMS were significantly lower for BPCI patients. PMID- 28583762 TI - Puerarin inhibits amyloid beta-induced NLRP3 inflammasome activation in retinal pigment epithelial cells via suppressing ROS-dependent oxidative and endoplasmic reticulum stresses. AB - Amyloid beta (Abeta) is a critical stimulator that promotes the progression of age-related macular degeneration (AMD). NLRP3 inflammasome activation induced by Abeta is estimated to be responsible for retinal pigment epithelium (RPE) dysfunction in such disease. Puerarin, one of the major active constituents of Kudzu root, has been widely used in the clinical treatment of AMD in China for decades; however, the detailed molecular mechanism remains far from clear. In this study, we investigated the protective effect and underlying mechanism of puerarin against Abeta1-40-induced NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. The results showed that Abeta1-40 induced NLRP3 inflammasome activation mainly via triggering ROS-dependent oxidative stress, particularly lipid peroxidation, and endoplasmic reticulum stress in LPS-primed ARPE-19 cells; however, such effect could be significantly reversed by puerarin in a dose dependent manner. Furthermore, the effect of puerarin was potentially mediated through activating Nrf2/HO-1 antioxidant signaling pathway and inhibiting Abeta1 40-induced phosphorylation of IRE1 and PERK as well as nuclear expression of ATF6alpha. Therefore, the significance of the current study is to reveal the novel mechanism of puerarin in the prevention of AMD. PMID- 28583763 TI - Measuring clinically relevant endpoints in a serum-free, three-dimensional, primary cell culture system of human osteoarthritic articular chondrocytes. AB - Osteoarthritis (OA) is characterized by degeneration of articular cartilage within the joint, inflammation and pain. The purpose of this study was to develop a primary, serum free cell culture system of human osteoarthritic articular chondrocytes (HOACs) with which to study manifestations of the disease process. Joint tissues were obtained from OA patients undergoing total knee arthroplasty (TKA). HOACs isolated from the femoral condyles and tibial plateau of the same side were combined, plated in three-dimensional, alginate beads and cultured for five days in serum, hormone and protein free medium. More living cells were obtained from the femoral condyles than the tibial plateau. The optimal plating density was 2.5 * 106 cells/ml of alginate. The amounts of DNA, RNA, proteoglycans and total collagen were similar in cultures prepared from the sides of least and greatest pathology. More type 1 than type 2 collagen was detected in the medium on days 2 and 5. A greater percentage of type 1 than type 2 collagen was degraded. The inflammatory cytokine interleukin-1 beta was present in the medium and alginate associated matrix. Although variation in the metabolic profiles between subjects was observed, HOACs from all patients continued to reflect the OA phenotype for five days in culture. This serum free, three dimensional primary culture system of HOACs provides a platform with which to measure clinically relevant endpoints of OA and screen potential disease modifying OA therapeutics. PMID- 28583764 TI - Proteomic composition and immunomodulatory properties of urinary bladder matrix scaffolds in homeostasis and injury. AB - Urinary bladder matrix (UBM) is used clinically for management of wounds and reinforcement of surgical soft tissue repair, among other applications. UBM consists of the lamina propria and basal lamina of the porcine urinary bladder, and is decellularized as part of the process to manufacture the medical device. UBM is composed mainly of Collagen I, but also contains a wide variety of fibrillar and basement membrane collagens, glycoproteins, proteoglycans and ECM associated factors. Upon application of the biomaterial in a traumatic or non traumatic setting in a mouse model, there is a cascade of immune cells that respond to the damaged tissue and biomaterial. Here, through the use of multicolor flow cytometry, we describe the various cells that infiltrate the UBM scaffold in a subcutaneous and volumetric muscle injury model. A wide variety of immune cells are found in the UBM scaffold immune microenvironment (SIM) including F4/80+ macrophages, CD11c+ dendritic cells, CD3+ T cells and CD19+ B cells. A systemic IL-4 upregulation and a local M2-macrophage response were observed in the proximity of the implanted UBM. The recruitment and activation of these cells is dependent upon signals from the scaffold and communication between the different cell types present. PMID- 28583765 TI - Current role and future perspectives of multivariate (chemometric) methods in NMR spectroscopic analysis of pharmaceutical products. AB - Nuclear magnetic resonance (NMR) is a fast and accurate analytical method. Associated with chemometrics, it gradually becomes more important tool for the pharmaceutical industry. In this review studies dealing with the applications of multivariate analysis to NMR spectroscopic profiles were grouped and discussed according to the analytical problem solved. The following topics were covered: authenticity of medicines according to variety, seasonal and geographical differences of herbal plants; quantitative prediction of pharmacologically relevant parameters; production and batches approval; investigation of drug structure modifications; site-specific natural isotope fractionation (SNIF-NMR) fingerprinting for origin and manufacturer tracking and others. Special focus was put on the heparin authenticity by using 1D and 2D NMR measurements. Finally, further research directions have been outlined. Our review has shown that chemometrics plays an important role for the quality control and authenticity of pharmaceutical products and its role will definitely increase in the future. The discussed approaches are recommended to be implemented during development and production process of pharmaceuticals or in quality control laboratories. PMID- 28583766 TI - Integrating dimensions of biodiversity in choreotrichs and oligotrichs of marine plankton. AB - Choreotrichs and oligotrichs are the main ciliate groups in marine plankton, where they play major roles as trophic intermediaries. We have studied these groups with a variety of approaches to combine the three dimensions of biodiversity-taxonomy, genetics and function. Here we revisit our findings with an integrative perspective, and highlight future directions. In our studies, the correspondence between classical taxonomy (mostly based on morphology) and the increasingly available genetic data (DNA sequences) is examined at the individual, population, species, and assemblage levels. We use a combination of single-cell and environmental sequencing to quantify diversity, track distribution patterns, and explain biogeography processes. Comparativelly, we know little about how the morphological and genetic estimates of diversity relate to function, but we expect to better link these aspects by incorporating modern omics approaches. For example, we have pioneered functional transcriptomic analyses in these groups by contrasting a heterotrophic choreotrich and a mixotrophic oligotrich. These data provide a tremendous resource to start building reference databases needed to measure differential expression of key functional genes, either experimentally or directly in the environment. PMID- 28583767 TI - LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity. AB - Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8. PMID- 28583768 TI - Pancreatic pseudocyst localized in the gastric wall after EUS-guided FNA of type 1 autoimmune pancreatitis. PMID- 28583769 TI - The 5D framework: a clinical primer for fecal microbiota transplantation to treat Clostridium difficile infection. PMID- 28583770 TI - Recent insights into synthetic beta-carbolines with anti-cancer activities. AB - Cancer, an uncontrolled and rapid proliferation of abnormal cells, has become one of the leading cause of death worldwide. The development of resistance among the numerous drugs in clinical use has provided strong impetus for the identification and development of novel cancer therapeutics. beta-carbolines constitute an important class of pharmacologically active scaffolds known to exert their anticancer activities via diverse mechanisms. The purpose of present review article is to update the readers on the current developments in beta-carbolines with an emphasis on synthetic strategies, structure-activity relationships, mechanism of action and in vivo studies wherever possible. PMID- 28583771 TI - Response to - Adverse events associated with the use of cervical spine manipulation or mobilization and patient characteristics: A systematic review. PMID- 28583772 TI - Ultrasound guided trigeminal nerve block as local anaesthetic technique for exenteration and excision of the zygomatic arch with partial caudal maxillectomy in a dog. PMID- 28583774 TI - [Risks of anesthesia in infants]. PMID- 28583773 TI - Anesthetic synergy between two n-alkanes. AB - OBJECTIVE: N-butane and n-pentane can both produce general anesthesia. Both compounds potentiate gamma-aminobutyric acid type A (GABAA) receptor function, but only butane inhibits N-methyl-d-aspartate (NMDA) receptors. It was hypothesized that butane and pentane would exhibit anesthetic synergy due to their different actions on ligand-gated ion channels. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of four Xenopus laevis frogs and 43 Sprague Dawley rats. METHODS: Alkane concentrations for all studies were determined via gas chromatography. Using a Xenopus oocyte expression model, standard two electrode voltage clamp techniques were used to measure NMDA and GABAA receptor responses in vitro as a function of butane and pentane concentrations relevant to anesthesia. The minimum alveolar concentrations (MAC) of butane and pentane were measured separately in rats, and then pentane MAC was measured during coadministration of 0.25, 0.50 or 0.75 times MAC of butane. An isobole with 95% confidence intervals was constructed using regression analysis. A sum of butane and pentane that was statistically less than the lower-end confidence bound isobole indicated a synergistic interaction. RESULTS: Both butane and pentane dose-dependently potentiated GABAA receptor currents over the study concentration range. Butane dose-dependently inhibited NMDA receptor currents, but pentane did not modulate NMDA receptors. Butane and pentane MAC in rats was 39.4+/-0.7 and 13.7+/-0.4 %, respectively. A small but significant (p<0.03) synergistic anesthetic effect with pentane was observed during administration of either 0.50 or 0.75*MAC butane. CONCLUSIONS: Butane and pentane show synergistic anesthetic effects in vivo consistent with their different in vitro receptor effects. CLINICAL RELEVANCE: Findings support the relevance of NMDA receptors in mediating anesthetic actions for some, but not all, inhaled agents. PMID- 28583775 TI - [A lumbar vertebral eosinophilic granuloma with spinal instability in an adolescent]. AB - This is a case report of a rare isolated eosinophilic granuloma of vertebra L3, in a 15-year-old adolescent. Vertebral instability, due to aggravation of the osteolysis, occurred without neurological symptoms despite orthopedic treatment. Surgery was necessary to correct and stabilize the spinal deformation. Postoperative chemotherapy (vinblastine and corticoids) was given as recommended for Langerhans cell histiocytosis (HL2010). No recurrence was observed after 5 years of follow-up. PMID- 28583776 TI - [Neonatal hyperthyroidism: A sometimes challenging diagnosis]. AB - Graves disease complicates two pregnancies out of 1000 and when it is known before pregnancy, it warrants careful monitoring of the fetus and the newborn. We report on a case of neonatal hyperthyroidism, which revealed a previously unknown maternal thyroid disease. In this situation, neonatal signs can be misinterpreted, delaying the diagnosis. Neonatal hyperthyroidism is, however, a therapeutic emergency because of the risk of cardiac and neurological complications. The neonatologist must identify thyroid disease in the absence of a maternal history in order to promptly start therapy. PMID- 28583777 TI - [Isolated gallbladder agenesis mimicking biliary colic: A difficult preoperative diagnosis]. AB - Isolated gallbladder agenesis is a very rare and unrecognized congenital anomaly. Patients are usually asymptomatic, but 23% present with symptoms suggestive of biliary colic. Ultrasound investigation often fails to diagnose this malformation, misinterpreted as scleroatrophic gallbladder, leading to unnecessary and potentially dangerous surgery. We report on a case of a 9-year old child who complained of biliary colic. Ultrasound showed a possible scleroatrophic gallbladder. This diagnosis was in doubt, however, because the patient had no previous history of cholecystitis. Finally, magnetic resonance cholangiopancreatography failed to show any gallbladder. The absence of the visualization of the gallbladder in a context of right upper quadrant pain should suggest gallbladder agenesis. Pain can be explained by the so-called postcholecystectomy syndrome. PMID- 28583778 TI - [Physiopathology and management of cholestatic pruritus in children]. AB - Pruritus is a disabling symptom accompanying chronic cholestasis. In some cases, refractory pruritus may require invasive therapies including liver transplantation. The pathogenesis of pruritus in cholestatic disease is poorly understood. It may involve a specific neural pathway and several pruritogenic substances such as bile acids, opioids, serotonin, and the more recently identified lysophosphatidic acid. While the therapeutic management of cholestatic pruritus is well established in adult patients, there is no consensus in children, given the difficulty in conducting controlled clinical studies. The currently recommended strategy to manage cholestatic pruritus in children is based on several lines of therapy that should always be associated with local cutaneous care and with nonspecific treatment of cholestasis including ursodeoxycholic acid therapy. Pruritus should be assessed as objectively as possible between each therapeutic step. Rifampicin, an enzyme inducer, is the specific first-line treatment of cholestatic pruritus. The second-line therapies require evaluation of the child in an expert center and are discussed on a case by-case basis depending on the underlying disease, the experience of the center and the will of the child and his family. It could be inhibitors of serotonin reuptake (sertraline) or an opioid antagonist (naloxone). Invasive therapies such as biliary diversion or liver transplantation can also be proposed in the most severe cases. PMID- 28583779 TI - [Screening for disturbed eating behavior in adolescents with type 1 diabetes]. PMID- 28583780 TI - [Nephrogenic syndrome of inappropriate antidiuresis: Early diagnosis avoids severe hyponatremia complications]. AB - AIM: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a rare disease characterized by a kidney disability to dilute urine and, as a result, severe recurrent hyponatremia. Due to wide variability in clinical expression, the diagnosis still remains a challenge for clinicians. We report our experience of a case in which NSIAD was diagnosed early. We also stress the importance of early diagnosis and treatment, which protects an infant with NSAID from severe hyponatremia. BACKGROUND: A 1-month-old boy was referred to our hospital for persistent hyponatremia and intense vomiting. He was born full term after a normal pregnancy with a normal birth weight. The parents were healthy, nonconsanguineous, of Moroccan origin. They already had healthy twin girls. The physical examination was normal upon admission with no signs of dehydration and normal weight gain since birth. Plasma sodium was very low (125mmol/L) associated with low plasma urea (5mg/dL), osmolality (258 mOsm/kg) and low natriuresis (59mmol/L). These laboratory results suggested inappropriate antidiuretic hormone secretion (SIAD) and the infant was consequently treated with oral urea (he was already receiving sodium supplements that were later stopped). Due to exclusive breastfeeding, water restriction was impossible. Further biological investigation revealed undetectable plasma arginine vasopressin (AVP), suggesting the diagnosis of NSIAD. This was confirmed by genetic sequencing of the AVP receptor (AVPR2), demonstrating the presence of an R137C mutation. CONCLUSIONS: We herein report a case of a genetic fluid balance disorder due to an activating mutation of AVPR2. NSIAD is an X-linked disease, first described in 2005 by Feldman et al., which involved severe recurrent hyponatremia. The very early diagnosis (at 7 weeks of life) and appropriate treatment with urea prevented seizures and cerebral damage due to severe recurrent hyponatremia. Clinicians should consider the diagnosis of NSIAD in infants with recurrent hyponatremia with hemodilution and low AVP serum level. Genetic analysis of the AVPR2 sequence on the X chromosome will confirm the diagnosis and, given the wide variability of clinical expression, sequencing of the family members should be done. PMID- 28583781 TI - [Macrophage activation syndrome and Kawasaki disease: Four new cases]. AB - Macrophage activation syndrome (MAS) is a rarely reported complication of Kawasaki disease (KD). It must be sought during KD with unusual clinical signs, such as enlargement of the liver or spleen, cytopenia (including thrombocytopenia), and elevated serum triglycerides. Here, we report four cases from a single center. The first is the description of a case of KD occurring in an 11-month-old child 15 days after the occurrence of infectious spondylitis. For the second, acute myocarditis heralded KD in a 5-year-old child. A 15-year-old boy had multiorgan failure with shock. The last case describes an infant with atypical KD. All had hepatosplenomegaly, thrombocytopenia, and increased serum ferritin. For all of them, hemophagocytosis was present on the bone marrow smears. The condition rapidly evolved favorably with intravenous immunoglobulins or steroids. The extensive microbiological work-up was unrevealing. None had any coronary sequelae after the episode. KD should be added to the list of inflammatory conditions that may be complicated by MAS that modifies the presentation mimicking toxic shock or infection-associated activation syndrome and makes the diagnosis difficult. This association does not appear to have a prognostic impact on the course of the disease in the literature, confirmed by the analysis of this small series. PMID- 28583782 TI - [A case of neonatal hypotonia]. PMID- 28583783 TI - Presentaciones poco comunes y peligros de la sifilis secundaria: periosteitis, tenosinovitis y anomalias hepaticas. AB - We herein describe two cases of secondary syphilis in patients with human immunodeficiency virus (HIV) infection with an unusual presentation, a diffuse polyostotic periosteitis. Patients referred mainly intense bone pain. Other relevant aspects of the clinical pictures were flexor tenosynovitis and hepatic abnormalities. Given the persistence of symptoms, the treatment duration performed was different from most described in literature. However, although more slowly than expected, both obtained a favorable clinical response after treatment with benzathine penicillin G. PMID- 28583784 TI - Periodic fever: From Still's disease to Muckle-Wells syndrome. AB - Muckle-Wells syndrome is a systemic autoinflammatory disease included in the group of hereditary periodic febrile syndromes. We report the case of a patient with this rare disease to call the attention to the singularity of this condition, its low incidence, its atypical presentation and the subsequent delay in the diagnosis, which is reached when late and devastating consequences have taken place. In this case, the first-line therapy, anti-interleukin 1 (IL-1), failed to control the disease. Nevertheless, the IL-6 inhibitor, tocilizumab, proved effective, achieving the total remission of nephrotic syndrome associated with AA secondary amyloidosis, changing the bleak prognosis of this disease. PMID- 28583785 TI - Late-onset Cogan's syndrome associated with large-vessel vasculitis. AB - Cogan's syndrome is a rare autoimmune disease that usually affects young Caucasian adults and is classically defined as the combination of nonsyphilitic interstitial keratitis and audiovestibular symptoms resembling Meniere's disease, both of them developed in an interval of less than two years. Nevertheless, cases with atypical ophthalmologic and audiovestibular features, with systemic manifestations or affecting children and older patients have also been reported, expanding the clinical spectrum of Cogan's syndrome. Herein, we present the case of a late-onset Cogan's syndrome associated with a large-vessel vasculitis. PMID- 28583786 TI - Information needs of patients with spondyloarthritis about their disease. AB - OBJECTIVE: 1. To describe the information provided to, or inquired about, by patients with axial spondyloarthritis and psoriatic arthritis. 2. To analyze improvements. METHODS: Analysis of the discourse of focus groups (with patients, some of them from patient associations, and rheumatologists). The discussion included the identification of elements that shape the reality being studied, describing the relationship among them and summarizing the results by: 1)thematic segmentation; 2)categorization according to situations, relationships, opinions, feelings or others; 3)coding of the various categories, and 4)interpretation of results. Representativeness was ensured by using a typological framework. RESULTS: Rheumatologists are the main source of information. Patient associations have a fundamental role and are well-regarded. Internet is used with caution due to its limited reliability. Patients are interested in: disease characteristics and treatments, the course and prognosis, and social, administrative and other kinds of support. More information is needed (objective and constructive, avoiding a catastrophic tone); it should be provided progressively, adjusted to patients features and needs. There are areas for improvement including: the standardization and updating of contents (based on scientific evidence), the optimization of informative materials (written, electronic), and other resources such as nursing and primary care. CONCLUSIONS: Rheumatologists are the main and most reliable source of information for patients with spondyloarthritis and psoriatic arthritis. Patient associations have an important role and are well regarded. Changes in the content, format and sources of information are required. PMID- 28583787 TI - Coatings in food contact materials: Potential source of genotoxic contaminants? AB - Up till now, no harmonized EU regulation exists on chemicals used in coatings for food contact materials (FCM). Therefore, these substances need to comply with the general provisions of EU Regulation 1935/2004 and, if present, with national legislation. Different 'inventory lists' of compounds that might be present in coatings are available, but for hundreds of these substances, the potential human health impact of their use in FCM coatings has not (recently) been evaluated. Since detailed evaluation of all compounds is not feasible, a pragmatic approach was developed to identify substances with a potential concern for human health. First, an inventory was assembled containing all substances potentially used in coatings. Afterwards, the genotoxic potential of the non-evaluated substances was predicted in silico using two structure-activity relationship (SAR) software programs. For substances yielding structural alerts in both models, genotoxicity data were collected from previous European evaluations in a non-FCM context and from the European CHemicals Agency (ECHA) website. In total, 53 substances were identified as genotoxic in both in silico models, of which ten were considered to be of high concern. For most of the substances, additional toxicological information is needed. PMID- 28583788 TI - Thyroid hormone receptor alpha (TRa) tissue expression in ductal invasive breast cancer: A study combining quantitative immunohistochemistry with digital slide image analysis. AB - BACKGROUND: In breast cancer, hormonal receptors hold promise for developing novel targeted therapies. The thyroid exerts its actions via the thyroid hormone receptors alpha and beta. The clinical significance of the expression of thyroid hormone receptors in breast cancer is unclear. MATERIAL AND METHODS: We studied thyroid hormone receptor alpha (TRa) expression in 82 samples from 41 women with ductal invasive breast cancer and no thyroid disease. We performed quantitative immunohistochemistry with digital image analysis and correlated TRa expression with clinicopathological parameters. RESULTS: TRa was expressed in both normal breast epithelium and breast cancer, but expression in breast cancer was significantly lower. TRa was expressed significantly less in larger and grade III tumors. Conversely, breast cancers with lymphovascular invasion showed increased TRa expression compared to cancers without lymphovascular invasion. TRa expression was not significantly different between node-positive and node negative breast cancers, or among different hormonal profiles and intrinsic subtypes. DISCUSSION: This is the first-in-human study to combine quantitative immunohistochemistry with image analysis to study TRa expression in women with ductal invasive breast cancer and no clinical or biochemical evidence of thyroid dysfunction. We confirm that TRa is expressed in both normal and malignant breast epithelium and suggest that TRa expression is downregulated during breast carcinogenesis. Larger and higher grade breast cancers demonstrate partial loss in TRa expression. Alterations in TRa expression take place even in the absence of clinical or biochemical thyroid disease. The underlying mechanism of these findings and their potential significance in survival and relapse mandate further research. PMID- 28583789 TI - Prognostic factors in Merkel cell carcinoma patients undergoing sentinel node biopsy. AB - INTRODUCTION: Debate remains about prognostic factors in primary Merkel cell carcinoma (MCC). We investigated clinicopathological factors as determinants of survival in patients with MCC submitted to sentinel node biopsy. METHODS: Sixty four consecutive patients treated for a primary MCC were identified from a prospectively maintained database at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Time to events outcome were described by product limit estimators and proportional hazards model was used to investigate the association between outcome and potential predictors. RESULTS: The most common site of primary tumor was lower limbs (56.3%). The size of primary lesion was <=2 cm in 67.2% of cases. Presence of residual disease after the diagnostic surgical excision was observed in 28% of cases. All patients received sentinel node biopsy (SNB) and a SN positivity was detected in 26.6%. The median follow up was 78 months. Disease recurrence occurred in 17 patients (26.6%). In the SN negative group 10 recurrences occurred (21.3%), whereas 7 (41.2%) were found in SN positive one. Nine patients SN negative (19.1%) died of disease and 3 (17.6%) among SN positive. SN status was not associated with survival (p = 0.78). Neither age, gender, size and site of primary tumor resulted predictors of patients' outcome. The presence of residual tumor in the specimen of the wide local excision, after the diagnostic surgical excision, was the only variable associated with survival (p = 0.03). CONCLUSIONS: Presence of residual tumor in the specimen of the wide local excision is the main prognostic factor in MCC patients. PMID- 28583790 TI - Transanal endoscopic microsurgery after neoadjuvant radiochemotherapy for locally advanced extraperitoneal rectal cancer. AB - PURPOSE: The aim of this study is to provide a prospective analysis of post operative and oncological outcomes in patients affected by locally advanced rectal cancer (LARC), who obtained a major/complete clinical response after pre operative radio-chemotherapy (RCT) and were treated with local excision (LE) by trans-anal endoscopic microsurgery (TEM) to confirm a pathological complete response (pCR) after to neo-adjuvant RCT. METHODS: All patients with LARC treated by pre-operative RCT and full-thickness LE by TEM (2000-2014) were included in the study. If the pathological analysis confirmed near complete or pCR, intensive follow up was proposed. If the pathological response was incomplete, a radical resection with TME was proposed. Post-operative (according to Clavien's classification), functional and long-term oncological outcome were analyzed. RESULTS: 36 patients were treated by TEM. The median post-operative hospital stay was 5 days. The post-operative morbidity was 41.6% (no grade >=3). At pathological analysis, 23 specimens were ypT0 TRG1, and 4 were ypT1 TRG2. In 9 cases (ypT>1 and/or TRG>2), radical surgery with TME was proposed but 3 refused it. Median follow-up was 68 months. One local recurrence and 4 distant metastases occurred. The 5-yr actuarial local control, overall survival and disease-free survival were 96.0%, 92.0% and 82.8%. CONCLUSIONS: In case of major or complete clinical response of LARC after pre-operative RCT, LE by TEM can be used to confirm the pathological response. This avoids the necessity of radical surgery and, in our experience, this approach seems to guarantee oncological safety with the functional advantages of an organ-sparing procedure. PMID- 28583791 TI - An 18 year population-based study on site of origin and outcome of patients with peritoneal malignancy in Ireland. AB - Peritoneal malignancy (PM) is predominantly metastatic spread from advanced gastrointestinal or gynaecological cancer. PM is generally considered incurable and therefore has rarely been the focus of novel therapeutic strategies. This study assessed patterns and survival outcomes for patients with PM in Ireland. The National Cancer Registry Ireland database was interrogated to identify patients diagnosed with PM during the period 1994-2012. Patient and tumour characteristics were retrieved and survival outcomes calculated. 5791 patients were diagnosed during the study period. Median age at diagnosis was 68 years; females accounted for 62%. The incidence increased annually from 228 in 1994 to 401 in 2012. Primary PM accounted for 3% of cases. Colorectal (22%), ovarian (16%) and gastric (13%) cancers accounted for the majority of cases of secondary PM. Almost 75% of patients had PM at initial presentation. Almost 40% of patients (n = 2274) underwent surgical intervention, while 44% (n = 2560) had tumour directed chemotherapy. The median survival (MS) in patients with secondary PM was 6.6 months, and did not improve significantly during the study period. Outcomes were best in patients with ovarian cancer (MS 15.9 months) and colorectal cancer (MS 14.3 months) and worst in patients with lung (MS 2.4 months) and pancreas (MS 1.9 months) cancers. This is the first population-based study from Ireland to report the incidence and outcomes for PM. PM is more common than previously reported and survival remains poor. These findings highlight the need for greater clinician awareness and the need to focus on new therapeutic approaches to improve patient outcomes. PMID- 28583792 TI - Role of palliative resection of the primary tumour in advanced pancreatic and small intestinal neuroendocrine tumours: A systematic review and meta-analysis. AB - PURPOSE: This study aimed to evaluate the impact on overall survival following palliative surgery to remove the primary lesion in unresectable metastatic small intestinal (SI-NET) and pancreatic neuroendocrine tumours (P-NET). METHODS: A systematic review of the literature and meta-analysis was performed. MEDLINE and Embase databases were searched to identify articles comparing patients undergoing palliative primary tumour resection without metastatectomy vs. no resection. Relevant articles were identified in accordance with PRISMA guidelines. The primary outcome was overall survival. Included studies were evaluated for heterogeneity and publication bias. RESULTS: 13 studies met the inclusion criteria, of which 6 presented data suitable for meta-analysis. No randomised controlled trials were identified. Analysis of pooled multivariate hazard ratios demonstrated significantly longer overall survival in patients undergoing resection of both P-NETs (HR 0.43; 95% CI: 0.34-0.57, p < 0.001) and SI-NETs (HR 0.47; 95% CI: 0.35-0.55, p = 0.007). The increase in median survival in patients treated surgically relative to non-surgically ranged from 14 to 46 months in P NET, and 22-112 months in SI-NET. The number needed to treat in order that one additional patient was alive at five years, ranged from 3.0 to 4.2, and 1.7 to 7.7 respectively. CONCLUSIONS: Meta-analysis demonstrates that palliative resection of primary SI-NETs and P-NETs in the setting of unresectable metastatic disease can increase survival. Although these results should be interpreted with caution due to potential selection and publication bias, the data supports consideration of surgery, particularly in patients with low tumour burdens and good functional status. PMID- 28583793 TI - India's generics-only drug policy could put health at risk. PMID- 28583795 TI - Measuring value and benefit-a matter of perspective. PMID- 28583794 TI - Delivery of meaningful cancer care: a retrospective cohort study assessing cost and benefit with the ASCO and ESMO frameworks. AB - BACKGROUND: The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have developed frameworks that quantify survival gains in light of toxicity and quality of life to assess the benefits of cancer therapies. We applied these frameworks to a cohort of contemporary randomised controlled trials to explore agreement between the two approaches and to assess the relation between treatment benefit and cost. METHODS: We identified all randomised controlled trials of systemic therapies in non-small-cell lung cancer, breast cancer, colorectal cancer, and pancreatic cancer published between Jan 1, 2011, and Dec 31, 2015, and assessed their abstracts and methods. Trials were eligible for inclusion in our cohort if significant differences favouring the experimental group in a prespecified primary or secondary outcome were reported (secondary outcomes were assessed only if primary outcomes were not significant). We assessed trial endpoints with the ASCO and ESMO frameworks at two timepoints 3 months apart to confirm intra-rater reliability. Cohen's kappa statistic was calculated to establish agreement between the two frameworks on the basis of the median ASCO score, which was used as an arbitrary threshold of benefit, and the framework-recommended ESMO threshold. Differences in monthly drug cost between the experimental and control groups of each randomised controlled trial (ie, incremental drug cost) were derived from 2016 average wholesale prices. FINDINGS: 109 randomised controlled trials were eligible for inclusion, 42 (39%) in non-small-cell lung cancer, 36 (33%) in breast cancer, 25 (23%) in colorectal cancer, and six (6%) in pancreatic cancer. ASCO scores ranged from 2 to 77; median score was 25 (IQR 16-35). 41 (38%) trials met the benefit thresholds in the ESMO framework. Agreement between the two frameworks was fair (kappa=0.326). Among the 100 randomised controlled trials for which drug costing data were available, ASCO benefit score and monthly incremental drug costs were negatively correlated (rho=-0.207; p=0.039). Treatments that met ESMO benefit thresholds had a lower median incremental drug cost than did those that did not meet benefit thresholds (US$2981 [IQR 320-9059] vs $8621 [1174-13 930]; p=0.018). INTERPRETATION: There is only fair correlation between these two major value care frameworks, and negative correlations between framework outputs and drug costs. Delivery of optimal cancer care in a sustainable health system will necessitate future oncologists, investigators, and policy makers to reconcile the disconnect between drug cost and clinical benefit. FUNDING: None. PMID- 28583796 TI - New WHO Director-General must address cancer control challenges. PMID- 28583797 TI - Penicillospirone from a marine isolate of Penicillium sp. (SF-5292) with anti inflammatory activity. AB - Chemical investigation of the EtOAc extract of a marine-derived fungal isolate Penicillium sp. SF-5292 yielded a new polyketide-type metabolite, penicillospirone (1). The structure of 1 was determined by analysis of spectroscopic data such as 1D and 2D NMR spectra and MS data, and the final structure including absolute configuration was unambiguously established by single-crystal X-ray diffraction analysis. In the evaluation of its anti inflammatory effects, 1 inhibited the overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and BV2 microglia, and these inhibitory effects were correlated with the suppressive effect of 1 against overexpressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, 1 also inhibited the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta), IL-6, and IL-12. Overall, the anti inflammatory effect of 1 was suggested to be mediated through the negative regulation of NF-kappaB pathway. PMID- 28583798 TI - Thiosemicarbazones as inhibitors of tyrosinase enzyme. AB - In the search for compounds which may inhibit the development of melanomas, a series of thiosemicarbazones has been investigated as possible inhibitors of the tyrosinase enzyme. The results showed that all the thiosemicarbazones tested exhibited significant inhibitory effects on the enzyme. Thiosemicarbazones Thio 1, Thio-2, Thio-3 and Thio-4 substituted with oxygenate moieties, were better inhibitors (IC50 0.42, 0.35, 0.36 and 0.44mM, respectively) than Thio-5, Thio-6, Thio-7 and Thio-8. For the better inhibitors, molecular docking results suggested that the oxygen present in the para position of the aromatic ring is essential for the tyrosinase inhibition, due its high ability for complexation with Cu2+ ions. Inside the active protein pocket, Thio-2 - the best studied inhibitor - is able to interact with the amino acid residues His-155, Gly-170 and Val-172 via hydrogen bonding and hydrophobic force. Thio-2, containing a substituent on the aromatic ring similar to the substrate l-DOPA, showed a competitive inhibition mechanism as viewed in a Lineweaver-Burk plot. The same results were observed in the UV-Vis curves. PMID- 28583799 TI - Ferrocene conjugated oligonucleotide for electrochemical detection of DNA base mismatch. AB - We describe the synthesis, binding, and electrochemical properties of ferrocene conjugated oligonucleotides (Fc-oligos). The key step for the preparation of Fc oligos contains the coupling of vinylferrocene to 5-iododeoxyuridine via Heck reaction. The Fc-conjugated deoxyuridine phosphoramidite was used in the Fc oligonucleotide synthesis. We show that thiol-modified Fc-oligos deposited onto gold electrodes possess potential ability in electrochemical detection of DNA base mismatch. PMID- 28583800 TI - Analysis of natural product regulation of cannabinoid receptors in the treatment of human disease. AB - The organized, tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Delta9-tetrahydrocannabinol (Delta9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Delta9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, alpha,beta-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Delta9-THC and the N-alkylamides that exhibited CB2 selective affinity; the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from commercial markets for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules. PMID- 28583801 TI - Toward Defining "Vocal Constriction": Practitioner Perspectives. AB - OBJECTIVES: This research investigated the terminology used in relation to constriction of the singing voice from a range of practitioner perspectives. It focused on the locality, causes, consequences, management, trends, identification, and vocabulary of constriction. The research aimed to develop a holistic understanding of the term "vocal constriction" from participant experiences and perceptions (N = 10). METHOD: Data collection occurred through in depth, semi-structured interviews with a range of voice care professionals. Participants included three professional groups: (1) Ear, Nose, and Throat medical specialists or laryngologists, (2) speech pathologists or speech therapists, and (3) singing teachers. Purposive sampling was used to ensure that the participants from groups 1 and 2 had extensive experience with singers in their practice. The singing teachers were experienced in either classical or contemporary styles, or both. RESULTS: Participant responses highlighted a discrepancy in preferred terminology, with "constriction" being less favored overall. Several anatomical locations were identified including postural, supraglottic (anteroposterior and false fold), articulatory, and in the intrinsic and extrinsic laryngeal musculature; psychological issues were also identified. Primary causes, secondary causes, and influencing factors were identified. Inefficient technique and poor posture or alignment were considered primary causes; similarly, emotion and anxiety or stress were identified as influencing factors by the majority of participants. There was less uniformity in responses regarding other causes. CONCLUSIONS: The major findings of this research are the respective participant group distinctions, an uncertainty regarding anteroposterior constriction, and that the location and effects of constriction are individual to the singer and must be considered contextually. A definition is offered, and areas for further research are identified. PMID- 28583803 TI - [Admission serum potassium and in-hospital mortality in centenarians]. PMID- 28583804 TI - Refugees and antimicrobial resistance - Response. PMID- 28583802 TI - Cyp1b1 deletion and retinol deficiency coordinately suppress mouse liver lipogenic genes and hepcidin expression during post-natal development. AB - : Cyp1b1 deletion and gestational vitamin A deficiency (GVAD) redirect adult liver gene expression. A matched sufficient pre- and post-natal diet, which has high carbohydrate and normal iron content (LF12), increased inflammatory gene expression markers in adult livers that were suppressed by GVAD and Cyp1b1 deletion. At birth on the LF12 diet, Cyp1b1 deletion and GVAD each suppress liver expression of the iron suppressor, hepcidin (Hepc), while increasing stellate cell activation markers and suppressing post-natal increases in lipogenesis. Hepc was less suppressed in Cyp1b1-/- pups with a standard breeder diet, but was restored by iron supplementation of the LF12 diet. CONCLUSIONS: The LF12 diet delivered low post-natal iron and attenuated Hepc. Hepc decreases in Cyp1b1-/- and GVAD mice resulted in stellate activation and lipogenesis suppression. Endothelial BMP6, a Hepc stimulant, is a potential coordinator and Cyp1b1 target. These neonatal changes in Cyp1b1-/- mice link to diminished adult obesity and liver inflammation. PMID- 28583805 TI - Semisynthesis of autophagy protein LC3 conjugates. AB - Autophagy is a conserved catabolic process involved in the elimination of proteins, organelles and pathogens. Autophagosome formation is the key process in autophagy. Lipidated Atg8/LC3 proteins that are conjugated to phosphatidylethanolamine (PE) play a key role in autophagosome biogenesis. To understand the function of Atg8/LC3-PE in autophagosome formation and host pathogen interaction requires preparation and structural manipulation of lipidated Atg8/LC3 proteins. Herein, we report the semisynthesis of LC3 proteins and mutants with modifications of different PE fragments or lipids using native chemical ligation and aminolysis approaches. PMID- 28583806 TI - The tobacco cembranoid (1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol as a novel angiogenesis inhibitory lead for the control of breast malignancies. AB - (1S,2E,4S,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (1) and its 4-epi-analog (2) are diterpene precursors of the key flavor components in most Nicotiana (tobacco) species that purposely degraded during commercial tobacco fermentation. Angiogenesis, recruitment of new blood vessels, is important for tumor growth, survival and metastasis that can be targeted to control cancer. This study shows evidences and potential of the cembranoid 1 as a potent angiogenesis modulator through targeting VEGFR2. In silico study suggested favorable docking scores and binding affinity of 1 at the ATP binding pocket of VEGFR2. The binding mode of 1 was parallel to the standard FDA-approved antiangiogenic drug sunitinib (4). In vitro, cembranoid 1 significantly reduced the activated VEGFR2 levels in multiple breast cancer cell lines. Intraperitoneal 40mg/kg, 3X/week treatment of 1 significantly reduced the MDA-MB-231 cells breast tumor size in mice. Immunohistochemistry and Western blotting analysis of the treated mice tumors showed significant downregulation of the vasculogenesis marker CD31 and suppressed activated VEGFR2-paxillin-FAK pathway. Matrigel study in Swiss albino mice showed similar trend. The tobacco cembranoid 1 is a potential antiangiogenic lead useful for future use to control breast malignancies. PMID- 28583807 TI - An orthogonally protected CycloTriVeratrylene (CTV) as a highly pre-organized molecular scaffold for subsequent ligation of different cyclic peptides towards protein mimics. AB - The synthesis of a semi-orthogonally protected CycloTriVeratrilene (CTV) scaffold derivative as well as the sequential introduction of three different peptide loops onto this molecular scaffold via Cu(I)-catalyzed azide alkyne cycloaddition towards a medium-sized protein mimic is described. This approach for the construction of medium-sized protein mimics is illustrated by the synthesis of a paratope mimic of the monoclonal antibody Infliximab (Remicade(r)) and provides access to a range of highly pre-organized molecular constructs bearing three different peptide segments. This approach may find wide applications for development of protein-protein interaction disruptors as well as synthetic vaccines. PMID- 28583808 TI - Influence of pH and neutralizing agent on anaerobic succinic acid production by a Corynebacterium crenatum strain. AB - Environmental conditions, particularly pH, have significant effects on the efficiency and final titers of bio-based products. Therefore, these factors need to be identified to ensure the fermentation process is economically attractive. In this study, strategies for controlling pH were optimized to enhance succinic acid production by Corynebacterium crenatum J-2. The results indicate that pH 6.8 is the optimal value for anaerobic succinic acid production by C. crenatum J-2 in terms of productivity and titer. The use of Mg(OH)2 as the neutralizing agent for pH control resulted in the highest levels of succinic acid concentration, yield, and productivity; superior to the levels obtained with Ca(OH)2, KOH, and NaOH. Under conditions of pH 6.8 and Mg(OH)2 as the neutralizing agent, 45.7 g/L succinic acid was produced within 12 h during the prophase of anaerobic fermentation, resulting in a succinic acid productivity of 3.8 g/(L.h). Succinic acid concentration reached 53.8 g/L at 22 h, with a productivity of 2.45 g/(L.h). The results of this study will be useful for the development of highly efficient succinic acid production processes utilizing industrial Corynebacterium spp. strains. PMID- 28583809 TI - An empirical analysis of ontology reuse in BioPortal. AB - Biomedical ontologies often reuse content (i.e., classes and properties) from other ontologies. Content reuse enables a consistent representation of a domain and reusing content can save an ontology author significant time and effort. Prior studies have investigated the existence of reused terms among the ontologies in the NCBO BioPortal, but as of yet there has not been a study investigating how the ontologies in BioPortal utilize reused content in the modeling of their own content. In this study we investigate how 355 ontologies hosted in the NCBO BioPortal reuse content from other ontologies for the purposes of creating new ontology content. We identified 197 ontologies that reuse content. Among these ontologies, 108 utilize reused classes in the modeling of their own classes and 116 utilize reused properties in class restrictions. Current utilization of reuse and quality issues related to reuse are discussed. PMID- 28583811 TI - "You lie": clinical implications of positive impression management in bariatric surgery patients. PMID- 28583810 TI - Antitumor efficacy of Lf modified daunorubicin plus honokiol liposomes in treatment of brain glioma. AB - Malignant brain glioma is the most common and aggressive type of primary intracranial neoplasm. Regular chemotherapy cannot eradicate brain glioma cells and the residual glioma cells could form vasculogenic mimicry (VM) channels under hypoxic conditions to provide nutrients for tumor cell invasion. In addition, the existence of the blood-brain barrier (BBB) restricts most antitumor drugs into brain glioma. In this study, we developed a kind of lactoferrin (Lf) modified daunorubicin plus honokiol liposomes to transport antitumor drugs across BBB, eliminate the VM channels and block tumor cell invasion. The evaluations were performed on BBB model, brain glioma cells and glioma-bearing mice. In vitro results showed that the targeting liposomes with suitable physicochemical property could enhance the drug transportation acrossing the BBB, inhibit C6 cells invasion and destroy VM channels. Action mechanism studies indicated that Lf modified daunorubicin plus honokiol liposomes could activate apoptotic enzymes caspase 3 as well as down-regulate VM protein indicators (PI3K, MMP-2, MMP-9, VE Cadherin and FAK). In vivo results displayed the targeting liposomes improved accumulation in brain tumor tissue and exhibited obvious antitumor efficacy. Therefore, Lf modified daunorubicin plus honokiol liposomes could be used as a potential therapy for treatment of brain glioma. PMID- 28583812 TI - Cost of bariatric surgery and factors associated with increased cost: an analysis of national inpatient sample. AB - BACKGROUND: In the current healthcare environment, bariatric surgery centers need to be cost-effective while maintaining quality. OBJECTIVE: The aim of this study was to evaluate national cost of bariatric surgery to identify the factors associated with a higher cost. SETTING: A retrospective analysis of 2012-2013 Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS). METHOD: We included all patients with a diagnosis of morbid obesity (ICD9 278.01) and a Diagnosis Related Group code related to procedures for obesity, who underwent Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric banding (AGB) as their primary procedure. We converted "hospital charges" to "cost," using hospital specific cost-to-charge ratio. Inflation was adjusted using the annual consumer price index. Increased cost was defined as the top 20th percentile of the expenditure and its associated factors were analyzed using the logistic regression multivariate analysis. RESULTS: A total of 45,219 patients (20,966 RYGBs, 22,380 SGs, and 1,873 AGBs) were included. The median (interquartile range) calculated costs for RYGB, SG, and AGB were $12,543 ($9,970 $15,857), $10,531 ($8,248-$13,527), and $9,219 ($7,545-$12,106), respectively (P<.001). Robotic-assisted procedures had the highest impact on the cost (odds ratio 3.6, 95% confidence interval 3.2-4). Hospital cost of RYGB and SG increased linearly with the length of hospital stay and almost doubled after 7 days. Furthermore, multivariate analysis showed that certain co-morbidities and concurrent procedures were associated with an increased cost. CONCLUSION: Factors contributing to the cost variation of bariatric procedures include co morbidities, robotic platform, complexity of surgery, and hospital length of stay. PMID- 28583813 TI - Laparoscopic approach to a bleeding marginal ulcer fistulized to the gastric remnant in a patient post Roux-en-Y gastric bypass. PMID- 28583814 TI - Prospectively validated preoperative prediction of weight and co-morbidity resolution in individual patients comparing five bariatric operations. AB - BACKGROUND: No method preoperatively predicts the postoperative bariatric surgery outcomes in individual patients. Decisions for or against surgery and operation choice remain subjective. Only 1% of qualifying patients embrace bariatric surgery. OBJECTIVE: To predict preoperatively and validate prospectively the weight and co-morbidity resolution in individual patients after open Roux-en-Y gastric bypass (RYGB) and laparoscopic Roux-en-Y gastric bypass (LRYGB), laparoscopic adjustable gastric band (LAGB), sleeve gastrectomy (SG), and biliopancreatic diversion/duodenal switch (BPD/DS). SETTING: Surgical Review Corporation BOLD database, 2007-2010. METHODS: A total of 166,601 patients who had undergone RYGB (n = 5389), LRYGB (n = 83,059), LAGB (n = 67,514), SG (n = 8966), or BPD/DS (n = 1673) were randomized into modeling (n = 124,053) and validation (n = 42,548) groups. From preoperative data, multivariate linear and logistic regression predicted weight and co-morbidities at 2, 6, 12, 18, and 24 months postoperatively. Model fit was examined by R2 and receiver operating characteristic/area under the curve and predicted versus observed results via Pearson correlation coefficient and sensitivity/specificity. RESULTS: Follow-up at 2/24 months was 120,909/11,014 for the modeling group and 41,528/3703 for validation. Weight models' R2 was .910, .813, .725, .638, and .613 at 2, 6, 12, 18, and 24 months, respectively. The categorical receiver operating characteristic/area under the curve was .617 to .949 for 24-month predictions. Pearson continuous coefficients were .969 and .811 at 2 and 24 months, respectively. The median 24-month sensitivity and specificity of co-morbidity resolution were 79.2% and 97.42%, respectively. CONCLUSIONS: Prospectively validated preoperative models predict, in individual patients, weight and obesity co-morbidities 2 years in advance for RYGB, LRYGB, LAGB, SG, and BPD/DS. This advance knowledge facilitates choosing the operation that is best for each individual and may encourage more patients to choose bariatric surgery. PMID- 28583815 TI - LDL-cholesterol Predicts a First CHD Event in Senior Citizens, Especially So in Those With Elevated Lipoprotein(a): Dubbo Study of the Elderly. AB - OBJECTIVE: The analysis was designed to explore the combined effects of LDL cholesterol and lipoprotein(a) (Lp(a)) in predicting incident coronary heart disease (CHD) in senior citizens without prior CHD. METHODS: This is a prospective cohort study in Dubbo NSW which has followed 2805 men and women 60 years and older for 16 years since 1988-1989. Subjects with prior CHD (n=607) were excluded from this analysis. Incident CHD events were identified by hospital record linkage. The contributions of LDL and Lp(a) to CHD events and their combined effects were evaluated in proportional hazards regression models. RESULTS: There were 689 CHD events over 16 years in a cohort of 2198 men and women without prior CHD. LDL-cholesterol (corrected for cholesterol content of Lp(a)) and Lp(a) modelled in quartile categories each independently predicted CHD, but exclusively in Quartile 4 (Q4) for each parameter. Using the combination of LDL Q1 and Lp(a) Q1 as a reference group, LDL Q4 (>4.90mmol/L) most clearly predicted CHD in combination with Lp(a) Q4 (>276mg/L), hazard ratio 1.95 (95%CI 1.31-2.90). CONCLUSION: The present findings may have important practical implications in clinical management. If Lp(a) is assessed in senior citizens without prior CHD and found to be genuinely low, elevated LDL-cholesterol may not require active intervention. PMID- 28583816 TI - Tert-butylhydroquinone protects PC12 cells against ferrous sulfate-induced oxidative and inflammatory injury via the Nrf2/ARE pathway. AB - Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. This study was aimed to investigate the protective effects of tBHQ on a cellular model of neurodegenerative disease, which was established in PC12 cells by exposure to ferrous sulfate (FS), and elucidate the potential protective mechanisms. The results showed that FS exposure increased lactate dehydrogenase (LDH) release and cell apoptosis in PC12 cells, accompanied by significant increases in the bax/bcl 2 ratio, cytochrome c release, and caspase-3 cleavage. It also enhanced the ROS production, malondialdehyde (MDA) content (lipid peroxidation), gamma-H2A.X formation (DNA damage), and promoted nuclear factor kappa B (NF-kappaB) activation and expressions of cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta). tBHQ pretreatment alleviated FS-induced LDH release, cell apoptosis, oxidative stress and inflammatory response by promoting Nrf2 nuclear translocation and the protein levels of Nrf2 downstream target genes heme oxygenase-1 (Hmox-1), nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 (Nqo1) and glutathione peroxidase-1 (Gpx1). tBHQ alleviated the FS-induced LDH release in control siRNA treated PC12 cells, but failed to alleviate FS-induced LDH release in Nrf2 siRNA treated cells. These findings suggested that pretreatment with tBHQ protected PC12 cells from FS-induced oxidative and inflammatory injury via the Nrf2/ARE pathway. tBHQ was promising as a potential therapeutic agent for neurodegenerative diseases induced by iron toxicity and should be encouraged for further research. PMID- 28583817 TI - Wood Stove Pollution in the Developed World: A Case to Raise Awareness Among Pediatricians. AB - Use of wood for residential heating is regaining popularity in developed countries. Currently, over 11 million US homes are heated with a wood stove. Although wood stoves reduce heating costs, wood smoke may adversely impact child health through the emission of gaseous and particulate air pollutants. Our purpose is to raise awareness of this environmental health issue among pediatricians. To summarize the state of the science, we performed a narrative review of articles published in PubMed and Web of Science. We identified 36 studies in developed countries that reported associations of household wood stove use and/or community wood smoke exposure with pediatric health outcomes. Studies primarily investigated respiratory outcomes, with no evaluation of cardiometabolic or neurocognitive health. Studies found community wood smoke exposure to be consistently associated with adverse pediatric respiratory health. Household wood stove use was less consistently associated with respiratory outcomes. However, studies of household wood stoves always relied on participant self-report of wood stove use, while studies of community wood smoke generally assessed air pollution exposure directly and more precisely in larger study populations. In most studies, important potential confounders, such as markers of socioeconomic status, were unaccounted for and may have biased results. We conclude that studies with improved exposure assessment, that measure and account for confounding, and that consider non-respiratory outcomes are needed. While awaiting additional data, pediatricians can refer patients to precautionary measures recommended by the US Environmental Protection Agency (EPA) to mitigate exposure. These include replacing old appliances with EPA-certified stoves, properly maintaining the stove, and using only dry, well-seasoned wood. In addition, several studies have shown mechanical air filters to effectively reduce wood stove pollution exposure in affected homes and communities. PMID- 28583819 TI - Transcranial Doppler Identification of Neurologic Injury during Pediatric Extracorporeal Membrane Oxygenation Therapy. AB - BACKGROUND: We used transcranial Doppler to examine changes in cerebral blood flow velocity in children treated with extracorporeal membrane oxygenation. We examined the association between those changes and radiologic, electroencephalographic, and clinical evidence of neurologic injury. METHODS: This was a retrospective review and prospective observational study of patients 18 years old and younger at a single university children's hospital. Transcranial Doppler studies were obtained every other day during the first 7 days of extracorporeal membrane oxygenation, and 1 additional study following decannulation, in conjunction with serial neurologic examinations, brain imaging, and 6- to 12-month follow-up. RESULTS: The study included 27 patients, the majority (26) receiving veno-arterial extracorporeal membrane oxygenation. Transcranial Doppler velocities during extracorporeal membrane oxygenation were significantly lower than published values for age-matched healthy and critically ill children across different cerebral arteries. Neonates younger than 10 days had higher velocities than expected. Blood flow velocity increased after extracorporeal membrane oxygenation decannulation and was comparable with age matched critically ill children. There was no significant association between velocity measurements of individual arteries and acute neurologic injury as defined by either abnormal neurologic examination, seizures during admission, or poor pediatric cerebral performance category. However, case analysis identified several patients with regional and global increases in velocities that corresponded to neurologic injury including stroke and seizures. CONCLUSIONS: Cerebral blood flow velocities during extracorporeal membrane oxygenation deviate from age-specific normal values in all major cerebral vessels and across different age groups. Global or regional elevations and asymmetries in flow velocity may suggest impending neurologic injury. PMID- 28583818 TI - A Multicenter Study of 1144 Patients with Cerebral Venous Thrombosis: The VENOST Study. AB - BACKGROUND: Based on a number of small observational studies, cerebral venous sinus thrombosis has diverse clinical and imaging features, risk factors, and variable outcome. In a large, multicenter cerebral venous thrombosis (VENOST) study, we sought to more precisely characterize the clinical characteristics of Caucasian patients. METHODS: All data for the VENOST study were collected between the years 2000 and 2015 from the clinical follow-up files. Clinical and radiological characteristics, risk factors, and outcomes were compared in terms of age and sex distribution. RESULTS: Among 1144 patients 68% were women, and in older age group (>50 years) male patients were more prevalent (16.6% versus 27.8%). The most frequent symptoms were headache (89.4%) and visual field defects (28.9%) in men, and headache (86.1%) and epileptic seizures (26.8%) in women. Gynecological factors comprised the largest group in women, in particular puerperium (18.3%). Prothrombotic conditions (26.4%), mainly methylenetetrahydrofolate reductase mutation (6.3%) and Factor V Leiden mutation (5.1%), were the most common etiologies in both genders. 8.1% of patients had infection-associated and 5.2% had malignancy-related etiology that was significantly higher in men and older age group. Parenchymal involvement constitutively hemorrhagic infarcts, malignancy, and older age was associated with higher Rankin score. Epileptic seizures had no effect on prognosis. CONCLUSIONS: Clinical and radiological findings were consistent with previous larger studies but predisposing factors were different with a higher incidence of puerperium. Oral contraceptive use was not a prevalent risk factor in our cohort. Malignancy, older age, and hemorrhagic infarcts had worse outcome. PMID- 28583821 TI - Cloning and characterization of thermostable GroEL/GroES homologues from Geobacillus thermopakistaniensis and their applications in protein folding. AB - The chaperonin genes encoding GroELGt (ESU72018) and GroESGt (ESU72017), homologues of bacterial GroEL and GroES, from Geobacillus thermopakistaniensis were cloned and expressed in Escherichia coli. The purified gene products possessed the ATPase activity similar to other bacterial and eukaryal counterparts. Recombinant GroELGt and GroESGt were able to refold the denatured insoluble aggregates of alpha-amylase from Bacillus licheniformis into soluble and active form. Furthermore, GroELGt and GroESGt successfully enhanced the thermostability of porcine heart malate dehydrogenase. Expression of GroELGt gene in E. coli cells enhanced the thermotolerance of the host. Furthermore, soluble production of recombinant alcohol dehydrogenase from Bacillus subtilis strain R5 in E. coli, initially produced as insoluble aggregates, was achieved by co expressing the gene with GroELGt. Our results implied that GroELGt could assist folding of nascent protein in E. coli with the help of host co-chaperonin without requiring additional ATP. This system can be used for soluble production of recombinant proteins which otherwise are produced in insoluble form in E. coli. To the best of our knowledge this is the first report on functional characterization and applications of chaperonins from genus Geobacillus. PMID- 28583820 TI - Impact of platelet inhibition level on subsequent no-reflow in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - BACKGROUND: High P2Y12 platelet reactivity (PR) level after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) affects prognosis and may induce the no-reflow phenomenon. AIM: To investigate the role of PR in the genesis of microvascular obstruction. METHODS: Patients with STEMI undergoing PPCI within 12hours of symptoms onset were included prospectively. All patients received a 600mg clopidogrel-loading dose before PPCI and 250mg aspirin. PR was measured thereafter during PPCI while wiring the culprit lesion and before coronary dilatation, using the P2Y12 VerifyNow(r) assay. No-reflow was defined as ST-segment regression<50% observed 90minutes after PPCI. RESULTS: Between January 2014 and November 2015, 140 STEMI patients were included, and divided into two groups: a low PR group (LPR) defined as PR<209P2Y12 reaction units (PRU); and a high PR group (HPR) defined as PR>=209PRU. There were no differences in baseline characteristics between LPR and HPR groups, including age (57.8+/-11.9 vs. 59.4+/-13.2 years, respectively; P=0.44) and weight (76.1+/-15.1 vs. 74.8+/-10.9kg, respectively; P=0.55). Delay to revascularization was 270.1+/-175.5 vs. 295.6+/-206.2minutes (P=0.49) and time between clopidogrel-loading and PR measurement was 53+/-37 vs 65+/-54minutes (P=0.29) in the LPR and HPR groups, respectively. No-reflow was more frequent in the HPR group (44 [47.3%] vs. 9 [19.1%]; P=0.0012). Mean PR was higher in patients with no-reflow: 268.3+/-53 vs. 223.8+/-50.1 PRU (P=0.002). In multivariable analysis, HPR was an independent predictor of no-reflow. Area under the receiver operating characteristic curve was 0.745 (0.654, 0.835); the cut-off value predicting no-reflow was 254PRU. CONCLUSION: High PR level measured at PPCI is independently associated with no-reflow. PMID- 28583822 TI - Practice Patterns for Cholecystectomy After Endoscopic Retrograde Cholangiopancreatography for Patients With Choledocholithiasis. AB - BACKGROUND & AIMS: Cholecystectomy (CCY) after an episode of choledocholithiasis requiring endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction reduces recurrent biliary events compared to expectant management. We studied practice patterns for performance of CCY after ERCP for choledocholithiasis using data from 3 large states and evaluated the effects of delaying CCY. METHODS: We conducted a retrospective cohort study using the ambulatory surgery, inpatient, and emergency department databases from the states of California (years 2009-2011), New York (2011-2013), and Florida (2012-2014). We collected data from 4516 patients hospitalized with choledocholithiasis who underwent ERCP. We compared outcomes of patients who underwent CCY at index admission (early CCY), elective CCY within 60 days of discharge (delayed CCY), or did not undergo CCY (no CCY), calculating rate of recurrent biliary events (defined as an emergency department visit or unplanned hospitalization due to symptomatic cholelithiasis, cholecystitis, choledocholithiasis, cholangitis, or biliary pancreatitis), mortality, and cost by CCY cohort. We also evaluated risk factors for not undergoing CCY. The primary outcome measure was the rate of recurrent biliary events in the 365 days after discharge from index admission. RESULTS: Of the patients who underwent ERCP for choledocholithiasis, 41.2% underwent early CCY, 10.9% underwent delayed CCY, and 48.0% underwent no CCY. Early CCY reduced relative risk of recurrent biliary events within 60 days by 92%, compared with delayed or no CCY (P < .001). After 60 days following discharge from index admission, patients with early CCY had an 87% lower risk of recurrent biliary events than patients with no CCY (P < .001) and patients with delayed CCY had an 88% lower risk of recurrent biliary events than patients with no CCY (P < .001). A strategy of delayed CCY performed on an outpatient basis was least costly. Performance of early CCY was inversely associated with low facility volume. Hispanic race, Asian race, Medicaid insurance, and no insurance associated inversely with performance of delayed CCY. CONCLUSIONS: In a retrospective analysis of >4500 patients hospitalized with choledocholithiasis, we found that CCY was not performed after ERCP for almost half of the cases. Although early and delayed CCY equally reduce the risk of subsequent recurrent biliary events, patients are at 10-fold higher risk of recurrent biliary event while waiting for a delayed CCY compared with patients who underwent early CCY. Delayed CCY is a cost-effective strategy that must be balanced against the risk of loss to follow-up, particularly among patients who are ethnic minorities or have little or no health insurance. PMID- 28583824 TI - A Selection of Best AGA Abstracts of DDW 2017. PMID- 28583823 TI - Regulator of Calcineurin 1 Gene Isoform 4, Down-regulated in Hepatocellular Carcinoma, Prevents Proliferation, Migration, and Invasive Activity of Cancer Cells and Metastasis of Orthotopic Tumors by Inhibiting Nuclear Translocation of NFAT1. AB - BACKGROUND & AIMS: Individuals with Down syndrome have a low risk for many solid tumors, prompting the search for tumor suppressor genes on human chromosome 21 (HSA21). We aimed to identify and explore potential mechanisms of tumor suppressors on HSA21 in hepatocellular carcinoma (HCC). METHODS: We compared expression of HSA21 genes in 14 pairs of primary HCC and adjacent noncancer liver tissues using the Affymetrix HG-U133 Plus 2.0 array (Affymetrix, Santa Clara, CA). HCC tissues and adjacent normal liver tissues were collected from 108 patients at a hospital in China for real-time polymerase chain reaction and immunohistochemical analyses; expression levels of regulator of calcineurin 1 (RCAN1) isoform 4 (RCAN1.4) were associated with clinical features. We overexpressed RCAN1.4 from lentiviral vectors in MHCC97H and HCCLM3 cells and knocked expression down using small interfering RNAs in SMMC7721 and Huh7 cells. Cells were analyzed in proliferation, migration, and invasion assays. HCC cells that overexpressed RCAN1.4 or with RCAN1.4 knockdown were injected into livers or tail veins of nude mice; tumor growth and numbers of lung metastases were quantified. We performed bisulfite pyrosequencing and methylation-specific polymerase chain reaction analyses to analyze CpG island methylation. We measured phosphatase activity of calcineurin in HCC cells. RESULTS: RCAN1.4 mRNA and protein levels were significantly decreased in primary HCC compared with adjacent noncancer liver tissues. Reduced levels of RCAN1.4 mRNA were significantly associated with advanced tumor stages, poor differentiation, larger tumor size, and vascular invasion. Kaplan-Meier survival analysis showed that patients with HCCs with lower levels of RCAN1.4 mRNA had shorter time of overall survival and time to recurrence than patients whose tumors had high levels of RCAN1.4 mRNA. In HCC cell lines, expression of RCAN1.4 significantly reduced proliferation, migration, and invasive activity. HCC cells that overexpressed RCAN1.4 formed smaller xenograft tumors, with fewer metastases and blood vessels, than control HCC cells. In HCC cells, RCAN1.4 inhibited expression of insulin-like growth factor 1 and vascular endothelial growth factor A by reducing calcineurin activity and blocking nuclear translocation of nuclear factor of activated T cells (NFAT1). HCC cells incubated with the calcineurin inhibitor cyclosporin A had decreased nuclear level of NFAT1. HCC cells had hypermethylation of a CpG island in the 5' regulatory region of RCAN1.4, which reduced its expression. CONCLUSIONS: RCAN1.4 is down-regulated in HCC tissues, compared with non-tumor liver tissues. RCAN1.4 prevents cell proliferation, migration, and invasion in vitro; overexpressed RCAN1.4 in HCC cells prevents growth, angiogenesis, and metastases of xenograft tumors by inhibiting calcineurin activity and nuclear translocation of NFAT1. PMID- 28583826 TI - Risk Stratification for Covert Invasive Cancer Among Patients Referred for Colonic Endoscopic Mucosal Resection: A Large Multicenter Cohort. AB - BACKGROUND & AIMS: Among patients with large colorectal sessile polyps or laterally spreading lesions, it is important to identify those at risk for submucosal invasive cancer (SMIC). Lesions with overt endoscopic evidence of SMIC are referred for surgery, although those without these features might still contain SMIC that is not visible on endoscopic inspection (covert SMIC). Lesions with a high covert SMIC risk might be better suited for endoscopic submucosal dissection than for endoscopic mucosal resection (EMR). We analyzed a group of patients with large colon lesions to identify factors associated with SMIC, and examined lesions without overt endoscopic high-risk signs to determine factors associated with covert SMIC. METHODS: We performed a prospective cohort study of consecutive patients referred for EMR of large sessile or flat colorectal polyps or laterally spreading lesions (>=20 mm) at academic hospitals in Australia from September 2008 through September 2016. We collected data on patient and lesion characteristics, outcomes of procedures, and histology findings. We excluded serrated lesions from the analysis of covert SMIC due to their distinct phenotype and biologic features. RESULTS: We analyzed 2277 lesions (mean size, 36.9 mm) from 2106 patients (mean age, 67.7 years; 53.2% male). SMIC was evident in 171 lesions (7.6%). Factors associated with SMIC included Kudo pit pattern V, a depressed component (0-IIc), rectosigmoid location, 0-Is or 0-IIa+Is Paris classification, non-granular surface morphology, and increasing size. After exclusion of lesions that were obviously SMIC or serrated, factors associated with covert SMIC were rectosigmoid location (odds ratio, 1.87; P = .01), combined Paris classification, surface morphology (odds ratios, 3.96-22.5), and increasing size (odds ratio, 1.16/10 mm; P = .012). CONCLUSIONS: In a prospective study of 2106 patients who underwent EMR for large sessile or flat colorectal polyps or laterally spreading lesions, we associated rectosigmoid location, combined Paris classification and surface morphology, and increasing size with increased risk for covert malignancy. Rectosigmoid 0-Is and 0-IIa+Is non-granular lesions have a high risk for malignancy, whereas proximally located 0-Is or 0-IIa granular lesions have a low risk. These findings can be used to inform decisions on which patients should undergo endoscopic submucosal dissection, EMR, or surgery. ClinicalTrials.gov, Number: NCT02000141. PMID- 28583827 TI - Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease. AB - BACKGROUND & AIMS: Proton pump inhibitors (PPI) have been associated with acute kidney injury and recent studies suggest that they may be associated with the risk of chronic kidney disease (CKD). METHODS: We performed a retrospective analysis using the Stockholm creatinine measurements database, which contains information on diagnoses, dispensation claims, and laboratory test results for all citizens in the Stockholm region from 2007 through 2010. We identified new users of PPIs (n = 105,305) and new users of H2 blockers (H2B; n = 9578); data on renal outcomes were collected for a median 2.7 years. The primary outcome was progression CKD, defined as doubling of creatinine or decrease in estimated glomerular filtration rate of 30% or more. Secondary outcomes were end-stage renal disease and acute kidney injury. Complete collection of repeated PPI and H2B dispensations at pharmacies in Sweden allowed modeling the time-dependent risk associated with cumulative PPI exposure. RESULTS: Users of PPIs, compared with users of H2Bs, had an increased risk for doubled levels of creatinine (1985 events; adjusted hazard ratio [HR], 1.26; 95% CI, 1.05-1.51) and decrease in estimated glomerular filtration rate of 30% or more (11,045 events; 1.26; 95% CI, 1.16-1.36). PPI use also associated with development of end-stage renal disease (HR, 2.40; 95% CI, 0.76-7.58) and acute kidney injury (HR, 1.30; 95% CI, 1.00 1.69). There was a graded association between cumulative exposure to PPIs and risk of CKD progression. This was not the case for cumulative H2B use. CONCLUSIONS: Initiation of PPI therapy and cumulative PPI exposure is associate with increased risk of CKD progression in a large, North European healthcare system. Although consistent, the association was modest in magnitude, and cannot exclude residual confounding. PMID- 28583825 TI - A Summary of the 2016 James W. Freston Conference of the American Gastroenterological Association: Intestinal Metaplasia in the Esophagus and Stomach: Origins, Differences, Similarities and Significance. PMID- 28583828 TI - PKM2-mediated inhibition of autophagy facilitates Tat's inducing HIV-1 transactivation. AB - Considerable evidence has shown that autophagy has an important role in HIV-1 infection. However, it is still unknown whether metabolism-regulated autophagy pathway is involved in Tat-mediated HIV-1 transactivation. This study demonstrated that treatment of Tat in TZM-bl cells significantly down-regulated protein levels of Beclin-1, Atg-5, Atg-7, and LC3B-II and up-regulated of p62 levels. Blockage of autophagy enhanced Tat-induced HIV-1 transactivation in TZM bl cells. Moreover, we found that Tat activated the Akt/mTOR and inhibited AMPK signaling pathway that was related to its up-regulation of PKM2 expression. In addition, we showed that PI3K/AKT activation and AMPK inhibtion was required for the PKM2-mediated inhibition of autophagy in Tat-treated TZM-bl cells. In conclusion, our data reveals that PKM2-mediated autophagy inhibition is required for Tat-mediated HIV-1 transactivation. Metabolism-related autophagic pathway may act as a promising diagnostic and therapeutic tool for HIV-1 infection in the future. PMID- 28583829 TI - Interactions between membrane receptors in cellular membranes. PMID- 28583830 TI - Probing the disparate effects of arginine and lysine residues on antimicrobial peptide/bilayer association. AB - Antimicrobial peptides (AMPs) are key components of the innate immune response and represent promising templates for the development of broad-spectrum alternatives to conventional antibiotics. Most AMPs are short, cationic peptides that interact more strongly with negatively charged prokaryotic membranes than net neutral eukaryotic ones. Both AMPs and synthetic analogues with arginine-like side chains are more active against bacteria than those with lysine-like amine groups, though the atomistic mechanism for this increase in potency remains unclear. To examine this, we conducted comparative molecular dynamics simulations of a model negatively-charged membrane system interacting with two mutants of the AMP KR-12: one with lysine residues mutated to arginines (R-KR12) and one with arginine residues mutated to lysine (K-KR12). Simulations show that both partition analogously to the bilayer and display similar preferences for hydrogen bonding with the anionic POPGs. However, R-KR12 binds stronger to the bilayer than K-KR12 and forms significantly more hydrogen bonds, leading to considerably longer interaction times. Additional simulations with methylated R-KR12 and charge-modified K-KR12 mutants show that the extensive interaction seen in the R KR12 system is partly due to arginine's strong atomic charge distribution, rather than being purely an effect of the greater number of hydrogen bond donors. Finally, free energy simulations reveal that both peptides are disordered in solution but form an amphipathic alpha-helix when inserted into the bilayer headgroup region. Overall, these results highlight the role of charge and hydrogen bond strength in peptide bilayer insertion, and offer potential insights for designing more potent analogues in the future. PMID- 28583831 TI - Investigations into the killing activity of an antimicrobial peptide active against extensively antibiotic-resistant K. pneumon iae and P. aeruginosa. AB - SET-M33 is a multimeric antimicrobial peptide active against Gram-negative bacteria in vitro and in vivo. Insights into its killing mechanism could elucidate correlations with selectivity. SET-M33 showed concentration-dependent bactericidal activity against colistin-susceptible and resistant isolates of P. aeruginosa and K. pneumoniae. Scanning and transmission microscopy studies showed that SET-M33 generated cell blisters, blebs, membrane stacks and deep craters in K. pneumoniae and P. aeruginosa cells. NMR analysis and CD spectra in the presence of sodium dodecyl sulfate micelles showed a transition from an unstructured state to a stable alpha-helix, driving the peptide to arrange itself on the surface of micelles. SET-M33 kills Gram-negative bacteria after an initial interaction with bacterial LPS. The molecule becomes then embedded in the outer membrane surface, thereby impairing cell function. This activity of SET-M33, in contrast to other similar antimicrobial peptides such as colistin, does not generate resistant mutants after 24h of exposure, non-specific interactions or toxicity against eukaryotic cell membranes, suggesting that SET-M33 is a promising new option for the treatment of Gram-negative antibiotic-resistant infections. PMID- 28583832 TI - YorkieCA overexpression in the posterior silk gland improves silk yield in Bombyx mori. AB - The traditional hybrid breeding techniques can no longer meet the increasing demands for silk production by the silkworm, Bombyx mori, and further improvement of the silk yield will depend on modern molecular breeding techniques. Here, we report improved silk yield in transgenic silkworms overexpressing the oncogene YorkieCA specifically in the posterior silk gland (PSG). The YorkieCA cDNA was ligated downstream of the hr3 enhancer and the fibroin L-chain (Fil) promoter, then inserted into a piggyBac vector for transgene. Overexpression of YorkieCA in the PSG significantly increased the weight of the PSG, and also increased the weight of the cocoon, larval body, and pupal body to decreasing degrees. Overexpression of YorkieCA up-regulated the Yorkie target genes resulting in increased cell size, endomitosis, the number of protein synthesis organelles, the expression of fibroin genes in the PSG, and eventually silk yield. Additionally, as we reported previously using the binary GAL4/UAS system, transgenic silkworms overexpressing Ras1CA with the hr3 enhancer and the Fil promoter also showed improved silk yield. Unfortunately, the hybrid progeny of YorkieCA-overexpressing silkworms and Ras1CA-overexpressing silkworms did not show overlapping improved silk yield due to the failure to increase expression of both Yorkie and Ras1. PMID- 28583833 TI - Profile and results of frail patient assessed by advanced practice nursing in an Emergency Department. AB - OBJECTIVES: To describe the profile of patients evaluated by Nurse Care Management in an Emergency Department and identify the type of alternative healthcare resource assigned and report the results of clinical practice. MATERIAL AND METHODS: Prospective follow-up, on admission to the Emergency Department in an acute hospital and on discharge from the alternative healthcare resource, of patients assessed by Nurse Care Management, from July to December 2015. The patient characteristics, social environment and results of clinical practice were studied. RESULTS: 190 patients were included of whom 13 were readmitted (6.8%). 122 (59.8%) cases from the Emergency Department were referred to to intermediate care facilities, 71 (34.8%) cases for domiciliary care, 10 (4.9%) cases were referred to an acute care hospital and 1 (0.5%) died. Patients referred to intermediate care were more complex, presented geriatric syndromes as their reason for admission and diagnosed with dementia, while those referred to home care presented more respiratory and cardiovascular illnesses (p <0.05). The mean Barthel Index and polypharmacy before emergency admission were higher than at the time of discharge from the alternative healthcare resource (p <0.05). CONCLUSIONS: Patients presenting with advanced age, complexity, comorbidity, are referred to intermediate care facilities or domiciliary care, they are admitted to acute care hospitasl and are readmitted less than other patients. After being discharged from the alternative resource, they lose functional capacity and present less polypharmacy. PMID- 28583834 TI - Intervention to improve awareness of the risk factors for osteonecrosis of the jaw in patients under treatment with bisphosponates. Randomised clinical trial. AB - PURPOSE: To evaluate the effectiveness of a health education programme on knowledge and reduction of the risk factors for bisphosphonate-related osteonecrosis of the jaw. METHODS: An experimental study control group without intervention was performed with 60 subjects who had started treatment with bisphosphonates in the University Hospital of Leon from October to December 2014. Patients in the experimental group received a structured education intervention in two sessions. The data was collected from a heteroadministered questionnaire at the beginning and at the end of the study period for both groups. RESULTS: The educational intervention designed showed a significantly increased adherence to healthy behaviours related to oral hygiene such as mechanical control of plaque and the use of clorhexidine prior to invasive oral procedures. All subjects reported that they had not been advised to maintain a good level of oral health before starting treatment. After the intervention high percentages of recognition of early diagnostic measures starting from a baseline total ignorance of them were determined. No conclusive information about the use of removable dental prostheses, toxic habits or maintaining proper metabolic control in patients with diabetes mellitus was observed. CONCLUSIONS: Improving adherence to healthy behaviours related to oral health following the intervention, as well as their contribution to the early identification of warning signs of jaw osteonecrosis, stresses the importance of the use of health education as a tool in routine clinical practice. PMID- 28583835 TI - Presentation of a Rare Cystic Mass. PMID- 28583836 TI - Unusual Cause of Hematochezia. PMID- 28583837 TI - When to Search for Occult Infection After Eradication of Hepatitis C? PMID- 28583838 TI - Mimicking Gastric Natural Killer/T-Cell Lymphoma. PMID- 28583839 TI - Undesired Final of a Student's Beer Drinking Duel. PMID- 28583840 TI - Detection of HCV RNA in Sustained Virologic Response to Direct-Acting Antiviral Agents: Occult or Science Fiction? PMID- 28583841 TI - Right Upper Abdominal Distension and Discomfort Caused by a Massive Hepatic Tumor. PMID- 28583842 TI - Febrile Attacks With a Refractory Colonic Lesion. PMID- 28583843 TI - "Errare Humanum Est, Perseverare Autem Diabolicum". PMID- 28583844 TI - Nociceptin/orphanin FQ antagonizes lipopolysaccharide-stimulated proliferation, migration and inflammatory signaling in human glioblastoma U87 cells. AB - Glioblastoma is among the most aggressive brain tumors and has an exceedingly poor prognosis. Recently, the importance of the tumor microenvironment in glioblastoma cell growth and progression has been emphasized. Toll-like receptor 4 (TLR4) recognizes bacterial lipopolysaccharide (LPS) and endogenous ligands originating from dying cells or the extracellular matrix involved in host defense and in inflammation. G-protein coupled receptors (GPCRs) have gained interest in anti-tumor drug discovery due to the role that they directly or indirectly play by transactivating other receptors, causing cell migration and proliferation. A proteomic analysis showed that the nociceptin receptor (NOPr) is among the GPCRs significantly expressed in glioblastoma cells, including U87 cells. We describe a novel role of the peptide nociceptin (N/OFQ), the endogenous ligand of the NOPr that counteracts cell migration, proliferation and increase in IL-1beta mRNA elicited by LPS via TLR4 in U87 glioblastoma cells. Signaling pathways through which N/OFQ inhibits LPS-mediated cell migration and elevation of [Ca2+]i require beta-arrestin 2 and are sensitive to TNFR-associated factor 6, c-Src and protein kinase C (PKC). LPS-induced cell proliferation and increase in IL-1beta mRNA are counteracted by N/OFQ via beta-arrestin 2, PKC and extracellular signal-regulated kinase 1/2; furthermore, the contributions of the transcription factors NF-kB and AP-1 were investigated. Independent of LPS, N/OFQ induces a significant increase in cell apoptosis. Contrary to what was observed in other cell models, a prolonged exposure to this endotoxin did not promote any tolerance of the cellular effects above described, including NOPr down-regulation while N/OFQ loses its inhibitory role. PMID- 28583845 TI - Cav1.2 channel current block by the PKA inhibitor H-89 in rat tail artery myocytes via a PKA-independent mechanism: Electrophysiological, functional, and molecular docking studies. AB - To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca2+ current through Cav1.2 channels [ICa1.2], we have documented a marked capacity of the isoquinoline H-89, widely used as a PKA inhibitor, to reduce current amplitude. We hypothesized that the ICa1.2 inhibitory activity of H-89 was mediated by mechanisms unrelated to PKA inhibition. To support this, an in-depth analysis of H-89 vascular effects on both ICa1.2 and contractility was undertaken by performing whole-cell patch-clamp recordings and functional experiments in rat tail main artery single myocytes and rings, respectively. H-89 inhibited ICa1.2 with a pIC50 (M) value of about 5.5, even under conditions where PKA activity was either abolished by both the PKA antagonists KT5720 and protein kinase inhibitor fragment 6-22 amide or enhanced by the PKA stimulators 6-Bnz cAMP and 8-Br-cAMP. Inhibition of ICa1.2 by H-89 appeared almost irreversible upon washout, was charge carrier- and voltage-dependent, and antagonised by the Cav1.2 channel agonist (S)-(-)-Bay K 8644. H-89 did not alter both potency and efficacy of verapamil, did not affect current kinetics or voltage-dependent activation, while shifting to the left the 50% voltage of inactivation in a concentration-dependent manner. H-89 docked at the alpha1C subunit in a pocket region close to that of (S)-(-)-Bay K 8644 docking, forming a hydrogen bond with the same, key amino acid residue Tyr-1489. Finally, both high K+- and (S)-(-)-Bay K 8644-induced contractions of rings were fully reverted by H-89. In conclusion, these results indicate that H-89 inhibited vascular ICa1.2 and, consequently, the contractile function through a PKA-independent mechanism. Therefore, caution is recommended when interpreting experiments where H-89 is used to inhibit vascular smooth muscle PKA. PMID- 28583846 TI - Epigenetic effects of inhibition of heat shock protein 90 (HSP90) in human pancreatic and colon cancer. AB - Silencing of tumor suppressor and DNA repair genes through methylation plays a role in cancer development, growth and response to therapy in colorectal and pancreatic cancers. Heat shock protein 90 (HSP90) regulates transcription of DNA methyltransferase enzymes (DNMT). In addition, DNMTs are client proteins of HSP90. The aim of this study is to evaluate the effects of HSP90 inhibition on DNA methylation in colorectal and pancreatic cancer cell lines. Our data shows that inhibition of HSP90 using ganetespib resulted in downregulation of mRNA and protein expression of DNMT1, DNMT3A, and DNMT3B in HT-29 and MIA PaCa-2 cell lines. This in turn was associated with a drop in the fraction of methylated cytosine residues and re-expression of silenced genes including MLH-1, P16 and SPARC. These effects were validated in HT-29 tumors implanted subcutaneously in mice following in vivo administration of ganetespib. This work demonstrates the effectiveness of ganetespib, an HSP90 inhibitor in modulating DNA methylation through downregulation of DNMT expression. PMID- 28583848 TI - Psychological effect on single-species population models in a polluted environment. AB - We formulate and investigate the psychological effect of single-species population models in a polluted environment in this paper. For the deterministic single-species population model, the conditions that guarantee the local extinction and persistence in the mean are derived firstly. We then show that, around the pollution-free equilibrium, the stochastic single-species population is weakly persistent in the mean, and is stochastically permanent under some conditions. As a consequence, some numerical simulations demonstrate the efficiency of the main results. PMID- 28583847 TI - TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/beta-catenin signaling pathway and promoting the epithelial mesenchymal transition. AB - This study investigated the expression, clinicopathological significance and mechanism of action of TIMELESS, a mammalian homolog of a Drosophila circadian rhythm gene, in nasopharyngeal carcinoma. Quantitative real-time PCR, western blotting and immunohistochemistry revealed TIMELESS was upregulated in NPC cell lines (n = 8 vs. NP69 cells), and freshly-frozen (n = 6) and paraffin-embedded human NPC specimens (n = 108 vs. normal samples/non-tumor cells). TIMELESS expression was associated with T category (P = 0.002), N category (P = 0.001), clinical stage (P < 0.001), metastasis (P = 0.047), vital status (P = 0.013) and serum Epstein-Barr DNA (P = 0.005). High TIMELESS expression was associated with poorer overall survival (80.7% vs. 95.9%; P = 0.004) and progression free survival (68.1% vs. 88.0%; P = 0.005). Univariate and multivariate analysis revealed TIMELESS was an independent prognostic factor for overall survival and progression free survival. Stable ectopic overexpression of TIMELESS in NPC cell lines conferred resistance to cisplatin-induced apoptosis in vitro and in vivo, promoted an epithelial-to-mesenchymal transition phenotype, and activated the Wnt/beta-catenin pathway and downstream gene transcription; knockdown of TIMELESS had the opposite effects. TIMELESS may play a role in the development of NPC and could represent a valuable prognostic factor and potential therapeutic target. PMID- 28583849 TI - Rapid detection of Lactococcuslactis isolates producing the lantibiotics nisin, lacticin 481 and lacticin 3147 using MALDI-TOF MS. AB - The aim of the study was to evaluate the potential use of Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) for fast and reliable detection of strains producing the lantibiotics nisin, lacticin 481 and lacticin 3147 in a large collection of lactococci. A total of one hundred lactococcal isolates from traditional ewe's and goat's raw milk cheeses were identified to the species level as Lactococcuslactis by MALDI-TOF MS based on comparison with lactococcal entries in the BioTyper database. Mass spectra in the range 2000-4000Da of the identified isolates were compared to reference spectra of three lactococcal strains producing lacticin 481 (IFPL 330), lacticin 3147 (IFPL 105) and nisin (IFPL 503). Only eight isolates had mass spectra with peaks that could be unequivocally identified as lacticin 481 (2900.47Da) or nisin (3330.31Da). None of the assayed isolates matched the mass spectra corresponding to the two-peptide lacticin 3147 (2847.97 and 3306.29Da). The results obtained by MALDI-TOF MS were genetically validated by amplification of the corresponding structural gene coding for lacticin 481, nisin and lacticin 3147. MALDI-TOF MS can be used as a fast and reliable technique to screen a large number of lactococcal isolates for the ability to produce the lantibiotics nisin, lacticin 481 and lacticin 3147. PMID- 28583850 TI - Clinical and electrocardiographic features of complete heart block after blunt cardiac injury: A systematic review of the literature. AB - The underlying mechanisms and temporal course of complete heart block (CHB) after blunt cardiac injuries (BCIs) are poorly understood, and a systematic analysis of available data is lacking. In this systematic review, PubMed was searched for publications of reported cases of CHB-BCI analyzing clinical findings, electrocardiographic features, temporal course, and outcomes. Case reports on CHB BCI were available for 50 patients, mainly secondary to traffic or sport accidents. A fatal outcome occurred in 10 of 50 (20%) of patients, while a structural damage of the atrioventricular (AV) conductive system was evident in 4 of 8 (50%) of necropsy studies. Clinical manifestation of CHB-BCI occurred within 72 hours of injury in 38 of 47 (~80%) of patients, and 1:1 AV conduction was restored within 7-10 days in about half of early survivors. Permanent pacemaker implantation was indicated in 22 of 42 (~50%) of early survivors because of recurrent or permanent CHB. Cardiac troponins, when analyzed, were elevated in 12 of 13 (~90%) of patients, and electrocardiographic features of aberrancy were present in 29 of 40 (>70%) of patients. In conclusion, CHB secondary to BCI is associated with 20% mortality mainly occurring in the early posttraumatic period and most of the deaths are due to or triggered by this malignant arrhythmia. Recurrent or permanent CHB requiring pacemaker implantation occurs in ~50% of survivors. A structural damage of the AV conductive system can be found in 50% of necropsy studies. PMID- 28583851 TI - beta-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-beta-hydroxybutyrylation. AB - Epigenetics regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network. Metabolite changes in vivo after stress contribute to histone modification. Histone3-lysine9-beta-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by beta-hydroxybutyrate, may participate in the development of depression. To examine the role of H3k9bhb in depression, experiments were performed on mice and cells. H3k9bhb were reduced in the brain of depressive mice. Exogenous beta-hydroxybutyrate ameliorated depressive behaviors and reversed the reduction of H3K9bhb and BDNF. We showed that H3k9bhb played a role in depression, and firstly linked BHB and BDNF via H3k9bhb. Our findings emphasized the crucial role of metabolic regulation on epigenetics in depression. PMID- 28583852 TI - B-cell activating factor deficiency suppresses splenomegaly during Leishmania donovani infection. AB - B-cell activating factor (BAFF) is a critical regulator for B-cell development and differentiation. We previously reported elevation of serum BAFF levels in patients with visceral leishmaniasis (VL). In this study, we examined if BAFF is involved in pathologies during infection of Leishmania donovani. BALB/cA mice infected with L. donovani showed significant elevation in serum BAFF and IgG levels as seen in VL patients. In contrast, elevation of serum IgG by L. donovani infection was significantly suppressed in BAFF-deficient mice. The spleen weight of the BAFF-deficient mice after infection was significantly lower than that of the infected wild-type mice, whereas comparable degree of hepatomegaly and anemia were observed in those mice. In the enlarged spleen of L. donovani-infected wild type mice, increase of CD19+ lymphocytes was more prominent than that of CD3+ cells, suggesting the contribution of B cell increase to splenomegaly during VL. Besides, increase of CD19+ lymphocytes was not found in BAFF-deficient mice after L. donovani infection. Taken together, these results suggest that BAFF is involved in strong B cell activation, which has a pathological role in splenomegaly but not in hepatomegaly or anemia, during VL. PMID- 28583853 TI - Lipomyelomeningocele for the urologist: Should we view it the same as myelomeningocele? AB - INTRODUCTION: The primary urologic objectives for lipomyelomeningocele (LMM) and myelomeningocele (MM) are preserving renal integrity and achieving continence. Due to this common ground, LMM and MM are urologically treated the same. However, unlike MM, LMM may present with no evident functional concerns. Indications for and timing of tethered cord release (TCR) in LMM are therefore controversial. Long-term urologic outcomes are not well defined. OBJECTIVE: Expectations for continence and potential for intermittent catheterization (CIC) following TCR in LMM are important for realistically counseling families regarding future needs. The present study aimed to identify prognostic factors for continence and need for CIC in LMM. STUDY DESIGN: The present study retrospectively identified 143 patients from the multidisciplinary clinic who underwent TCR for LMM between 1995 and 2010. Concomitant anorectal/genitourinary anomalies, filar lipoma, fatty filum, previous TCR, and follow-up <1 year were excluded. Analysis was limited to those toilet trained or aged >=6 years at latest follow-up. Lipomyelomeningocele was classified as dorsal, distal, transitional or chaotic. Pre- and post-TCR urologic status was assessed. Ability to achieve urinary continence, with or without CIC, was the primary outcome, and need for CIC was the secondary outcome of interest. RESULTS: A total of 56 patients met inclusion criteria. Median age at TCR was 4.4 months (range 1.0-224.0) with a median follow-up of 10.7 years (range 1.3-19.1); 68% were asymptomatic at presentation. Clinical symptoms were urologic in 7%. At the latest follow-up, 86% of patients were continent spontaneously or with CIC (Summary Fig.). Of the four patients who presented with urologic symptoms, all were continent, but three required CIC. Overall, 23% of patients required CIC. Median age at CIC initiation was 7.6 years (range 1.6 17.4). Long-term continence was not associated with any demographic, anatomic, surgical or functional variable. Need for CIC at latest follow-up was associated with symptomatic presentation, partial TCR, transitional lipoma, and high-risk pre-operative urodynamics. DISCUSSION: In this series of primary TCR for LMM, where 93% of patients were urologically asymptomatic before TCR, prospects for continence were excellent. No studied parameter clearly impacted continence; however, need for CIC was associated with multiple variables. CONCLUSIONS: Clear predictors for continence after TCR will require additional long-term patient outcomes. Families can anticipate 23% likelihood of CIC, which is considerably less than in MM, but long-term urologic follow-up is still strongly recommended. PMID- 28583854 TI - Response to Letter to the Editor re 'Comparison of Variables affecting the surgical outcome of Tubularized and Tubularized Incised Plate Urethroplasty in Adult and Pediatric Hypospadias'. PMID- 28583855 TI - Characterization of aromatase expression in the spinal cord of an animal model of familial ALS. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving motor neurons in the motor cortex, brainstem and spinal cord. ALS leads to progressive, aggravated muscle weakness and paralysis. Although the precise pathogenesis remains unknown, several studies have shown that estrogens exert neuroprotective effects during the course of the disease. Aromatase is the key enzyme in estrogen synthesis. In the present study, we used immunohistochemistry, immunofluorescence and western blotting to observe the characteristics of aromatase expression in the spinal cords of copper-zinc superoxide dismutase-1 (SOD1)-G93A transgenic mice. Under normal and nearly normal (pre-symptomatic stage) conditions, the motor neurons in the spinal anterior horn expressed aromatase. After disease onset, astrocytes began to express aromatase. The total level of aromatase expression decreased with disease progression. These findings may provide the basis for the pathogenesis of ALS through glial aromatization during the progression of this disease. PMID- 28583856 TI - A field based detection method for Rose rosette virus using isothermal probe based Reverse transcription-recombinase polymerase amplification assay. AB - Rose rosette disease, caused by Rose rosette virus (RRV; genus Emaravirus) is a major threat to the rose industry in the U.S. The only strategy currently available for disease management is early detection and eradication of the infected plants, thereby limiting its potential spread. Current RT-PCR based diagnostic methods for RRV are time consuming and are inconsistent in detecting the virus from symptomatic plants. Real-time RT-qPCR assay is highly sensitive for detection of RRV, but it is expensive and requires well-equipped laboratories. Both the RT-PCR and RT-qPCR cannot be used in a field-based testing for RRV. Hence a novel probe based, isothermal reverse transcription-recombinase polymerase amplification (RT-exoRPA) assay, using primer/probe designed based on the nucleocapsid gene of the RRV has been developed. The assay is highly specific and did not give a positive reaction to other viruses infecting roses belonging to both inclusive and exclusive genus. Dilution assays using the in vitro transcript showed that the primer/probe set is highly sensitive, with a detection limit of 1 fg/MUl. In addition, a rapid technique for the extraction of viral RNA (<5min) has been standardized from RRV infected tissue sources, using PBS-T buffer (pH 7.4), which facilitates the virus adsorption onto the PCR tubes at 4 degrees C for 2min, followed by denaturation to release the RNA. RT-exoRPA analysis of the infected plants using the primer/probe indicated that the virus could be detected from leaves, stems, petals, pollen, primary roots and secondary roots. In addition, the assay was efficiently used in the diagnosis of RRV from different rose varieties, collected from different states in the U.S. The entire process, including the extraction can be completed in 25min, with less sophisticated equipments. The developed assay can be used with high efficiency in large scale field testing for rapid detection of RRV in commercial nurseries and landscapes. PMID- 28583857 TI - A novel highly sensitive, rapid and safe Rift Valley fever virus neutralization test. AB - Antibodies specific for Rift Valley fever virus (RVFV) can be detected by diverse methods, including ezyme-linked immunosortbent assay (ELISA) and virus neutralization test (VNT). The VNT is superior in sensitivity and specificity and is therefore considered the gold standard serological assay. Classical VNTs make use of virulent RVFV and therefore have to be performed in biosafety level 3 laboratories. Here, we report the development of a novel VNT that is based on an avirulent RVFV expressing the enhanced green fluorescent protein (eGFP), which can be performed safely outside level 3 biocontainment facilities. Evaluation with a broad panel of experimental sera and field sera demonstrated that this novel VNT is faster and more sensitive than the classical VNT. PMID- 28583858 TI - A rapid silica spin column-based method of RNA extraction from fruit trees for RT PCR detection of viruses. AB - Efficient recovery of high quality RNA is very important for successful RT-PCR detection of plant RNA viruses. High levels of polyphenols and polysaccharides in plant tissues can irreversibly bind to and/or co-precipitate with RNA, which influences RNA isolation. In this study, a silica spin column-based RNA isolation method was developed by using commercially available silica columns combined with the application of a tissue lysis solution, and binding and washing buffers with high concentration guanidinium thiocyanate (GuSCN, 50% w/v), which helps remove plant proteins, polysaccharides and polyphenolic compounds. The method was successfully used to extract high quality RNA from citrus (Citrus aurantifolia), grapevine (Vitis vinifera), peach (Prunus persica), pear (Pyrus spp.), taro (Colocosia esculenta) and tobacco (Nicotiana benthamiana) samples. The method was comparable to conventional CTAB method in RNA isolation efficiency, but it was more sample-adaptable and cost-effective than commercial kits. High quality RNA isolated using silica spin column-based method was successfully used for the RT PCR and/or multiplex RT-PCR amplification of woody fruit tree viruses and a viroid. The study provided a useful tool for the detection and characterization of plant viruses. PMID- 28583859 TI - Detection and quantification of gasping during resuscitation for out-of-hospital cardiac arrest. AB - AIM: To detect and quantify gasping during cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OHCA) patients and to investigate whether gasping is associated with increased return of spontaneous circulation (ROSC). MATERIALS AND METHODS: A prospective observational study in patients resuscitated and mechanically or manually ventilated for OHCA by emergency physicians of Ghent University Hospital. After intubation, pressure catheters were inserted in the endotracheal tube (ETT) and pressures were measured at the proximal and distal ends of the ETT. Gasping was analysed with custom-developed software and volumes were calculated based on pressure differences between the catheters. Data are expressed as median (interquartile range). RESULTS: Data were collected in 292 resuscitated patients of whom 36.2% achieved ROSC. Seventy-six of 292 (26.0%) patients showed gasping on the pressure curves during resuscitation. The median gasping volume was 274ml (196-434). The median gasping rate was 3.7 gasps/min (1.5-7.3). Gasping occurred significantly more in patients displaying ventricular fibrillation as the initial rhythm compared to patients with pulseless electrical activity, pulseless ventricular tachycardia or asystole. The median gasping rate was significantly higher in the ROSC group compared to the non-ROSC group (11.8 gasps/min (95% CI [4.2, 13.9]) and 2.8 gasps/min (95% CI [1.7, 3.9]) respectively (P<0.001)). A gasping rate of >7.3 gasps/min appeared to be the optimal criterion value to herald ROSC. Deeper negative pressures were associated with an increased incidence of ROSC (P=0.011). There was no significant difference in ROSC between patients with gasping and those without. CONCLUSION: The occurrence of gasping during CPR was high. Significant gasping volumes were measured. The presence or absence of gasping was not associated with ROSC, but higher gasping rate and deeper negative pressures were. PMID- 28583860 TI - Effectiveness of different compression-to-ventilation methods for cardiopulmonary resuscitation: A systematic review. AB - AIM: To compare the effectiveness of different compression-to-ventilation methods during cardiopulmonary resuscitation (CPR) in patients with cardiac arrest. METHODS: We searched MEDLINE and Cochrane Central Register of Controlled Trials from inception until January 2016. We included experimental, quasi-experimental, and observational studies that compared different chest compression-to ventilation ratios during CPR for all patients and assessed at least one of the following outcomes: favourable neurological outcomes, survival, return of spontaneous circulation (ROSC), and quality of life. Two reviewers independently screened literature search results, abstracted data, and appraised the risk of bias. Random-effects meta-analyses were conducted separately for randomised and non-randomised studies, as well as study characteristics, such as CPR provider. RESULTS: After screening 5703 titles and abstracts and 229 full-text articles, we included 41 studies, of which 13 were companion reports. For adults receiving bystander or dispatcher-instructed CPR, no significant differences were observed across all comparisons and outcomes. Significantly less adults receiving bystander-initiated or plus dispatcher-instructed compression-only CPR experienced favourable neurological outcomes, survival, and ROSC compared to CPR 30:2 (compression-to-ventilation) in un-adjusted analyses in a large cohort study. Evidence from emergency medical service (EMS) CPR providers showed significantly more adults receiving CPR 30:2 experiencing improved favourable neurological outcomes and survival versus those receiving CPR 15:2. Significantly more children receiving CPR 15:2 or 30:2 experienced favourable neurological outcomes, survival, and greater ROSC compared to compression-only CPR. However, for children <1 years of age, no significant differences were observed between CPR 15:2 or 30:2 and compression-only CPR. CONCLUSIONS: Our results demonstrated that for adults, CPR 30:2 is associated with better survival and favourable neurological outcomes when compared to CPR 15:2. For children, more patients receiving CPR with either 15:2 or 30:2 compression-to ventilation ratio experienced favourable neurological function, survival, and ROSC when compared to CO-CPR for children of all ages, but for children <1years of age, no statistically significant differences were observed. PMID- 28583861 TI - Genetic deletion of GPR52 enhances the locomotor-stimulating effect of an adenosine A2A receptor antagonist in mice: A potential role of GPR52 in the function of striatopallidal neurons. AB - G protein-coupled receptor 52 (GPR52) is largely co-expressed with dopamine D2 receptor (DRD2) in the striatum and nucleus accumbens, and this expression pattern is similar to that of adenosine A2A receptor (ADORA2A). GPR52 has been proposed as a therapeutic target for positive symptoms of schizophrenia, based on observations from pharmacological and transgenic mouse studies. However, the physiological role of GPR52 in dopaminergic functions in the basal ganglia remains unclear. Here, we used GPR52 knockout (KO) mice to examine the role of GPR52 in dopamine receptor-mediated and ADORA2A-mediated locomotor activity and dopamine receptor signaling. High expression of GPR52 protein in the striatum, nucleus accumbens, and lateral globus pallidus of wild type (WT) littermates was confirmed by immunohistochemical analysis. GPR52 KO and WT mice exhibited almost identical locomotor responses to the dopamine releaser methamphetamine and the N methyl-d-aspartate antagonist MK-801. In contrast, the locomotor response to the ADORA2A antagonist istradefylline was significantly augmented in GPR52 KO mice compared to WT mice. Gene expression analysis revealed that striatal expression of DRD2, but not of dopamine D1 receptor and ADORA2A, was significantly decreased in GPR52 KO mice. Moreover, a significant reduction in the mRNA expression of enkephalin, a marker of the activity of striatopallidal neurons, was observed in the striatum of GPR52 KO mice, suggesting that GPR52 deletion could enhance DRD2 signaling. Taken together, these results imply the physiological relevance of GPR52 in modulating the function of striatopallidal neurons, possibly by interaction of GPR52 with ADORA2A and DRD2. PMID- 28583862 TI - Recovery of glomerular morphology in the olfactory bulb of young mice after disruption caused by continuous odorant exposure. AB - Olfactory glomeruli are the first synaptic site of the olfactory system and are formed by the convergence of axons of the same type of sensory neurons onto the olfactory bulbs of the brain. Although the anatomical organization of glomeruli is conserved across species, their particular role in olfactory processing remains uncertain. We studied the composition and maintenance of glomeruli by means of a genetic model, mI7-IRES-tauGFP knock-in young mice, where the cytoskeleton of sensory neurons expressing the mI7 olfactory receptor is tagged with green fluorescent protein. Animals were continuously exposed to heptaldehyde, a cognate ligand of the mI7 receptor, from postnatal days 5-10. We hypothesized that continuous odorant exposure will induce changes in glomerular morphology, and that this can be recovered if the normal odorant environment is reestablished within the early postnatal period. We assessed changes in the distribution of mI7 axons in glomerular morphology, as well as possible changes in the number of the mI7 olfactory sensory neurons. Following odorant exposure the well-defined convergence of mI7 fibers into a single glomerulus was disrupted, producing numerous neighboring glomeruli partially innervated by mI7 fibers. After the normal odor environment was reestablished the number of glomeruli partially innervated by mI7 fibers decreased significantly. Moreover, we found that multiple supernumerary mI7 glomeruli were formed. Our results confirm the significant role of sensory input in glomerular formation and maintenance. Additionally, we show that the developing olfactory system actively maintains glomerular morphology, suggesting the importance of this for olfactory processing. PMID- 28583863 TI - Increasing extracellular Ca2+ sensitizes TNF-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) via a TRPC1/ERK1/2/NFkappaB-dependent pathway in human vascular endothelial cells. AB - Increasing circulating Ca2+ levels within the normal range has been reported to positively correlate with the incidence of fatal cardiovascular diseases (CVDs). However, limited studies have been able to delineate the potential mechanism(s) linking circulating Ca2+ to CVD. In this study, we exposed primary human umbilical vein endothelial cells (HUVECs) and human umbilical vein cell line (EA.hy926) to different extracellular Ca2+ to mimic the physiological state. Our data revealed that increasing extracellular Ca2+ significantly enhanced susceptibility to tumor necrosis factor (TNF)-alpha-stimulated vascular cell adhesion molecule (VCAM)-1 expression and monocytes adhesion. Knocking-down VCAM 1 by siRNA abolished calcium-induced monocytes adhesion on HUVECs. Follow up mechanistic investigations identified that extracellular Ca2+-increased calcium influx contributed to the activation of VCAM-1. This was mediated via upregulation of transient receptor potential channel (TRPC)1 in a nuclear factor (NF)kappaB-dependent manner. Most importantly, we found that a novel TRPC1 regulated extracellular signal-regulated kinase 1/2 (ERK1/2) pathway exclusively contributed to calcium-induced NFkappaB activation. This study provided direct evidence that increasing extracellular Ca2+ enhanced TNF-alpha-induced VCAM-1 activation and monocytes adhesion. Moreover, we identified a novel TRPC1/ERK1/2/NFkappaB signaling pathway mediating VCAM-1 activation and monocyte adhesion in this pathological process. Our studies indicate that blood calcium levels should be strictly monitored to help prevent CVD, and that TRPC1 might act as a potential target for the treatment and prevention against increased circulating calcium-enhanced CVDs. PMID- 28583864 TI - The gut bacterium and pathobiont Bacteroides vulgatus activates NF-kappaB in a human gut epithelial cell line in a strain and growth phase dependent manner. AB - The gut microbiota is increasingly implicated in the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC) although the identity of the bacteria that underpin these diseases has remained elusive. The pathobiont Bacteroides vulgatus has been associated with both diseases although relatively little is known about how its growth and functional activity might drive the host inflammatory response. We identified an ATP Binding Cassette (ABC) export system and lipoprotein in B. vulgatus ATCC 8482 and B. vulgatus PC510 that displayed significant sequence similarity to an NF-kappaB immunomodulatory regulon previously identified on a CD-derived metagenomic fosmid clone. Interestingly, the ABC export system was specifically enriched in CD subjects suggesting that it may be important for colonization and persistence in the CD gut environment. Both B. vulgatus ATCC 8482 and PC510 activated NF-kappaB in a strain and growth phase specific manner in a HT-29/kb-seap-25 enterocyte like cell line. B. vulgatus ATCC 8482 also activated NF-kappaB in a Caco-2-NF-kappaBluc enterocyte like and an LS174T-NF-kappaBluc goblet cell like cell lines, and induced NF-kappaB-p65 subunit nuclear translocation and IL-6, IL-8, CXCL-10 and MCP-1 gene expression. Despite this, NF-kappaB activation was not coincident with maximal expression of the ABC exporter or lipoprotein in B. vulgatus PC510 suggesting that the regulon may be necessary but not sufficient for the immunomodulatory effects. PMID- 28583865 TI - Breast abscess due to Finegoldia magna in a non-puerperal women. AB - Finegoldia magna is a Gram-positive anaerobic coccus involved in a wide variety of infections. We report a unusual case of breast abscess in a non-puerperal patient. A 46-year-old woman presented with pain and a nodular lesion in the left breast. Culture of abscess drainage resulted in isolation of F. magna. Initial treatment with clindamycin was changed to a definitive treatment with amoxicillin clavulanate for 10 days due to resistance to clindamycin, and improvement of this infection was documented. PMID- 28583866 TI - Effects of chronic cocaine, morphine and methamphetamine on the mobility, immobility and stereotyped behaviors in crayfish. AB - The worth of crayfish as a model system for studies of addiction was not previously recognized because a drug-reward phenomenon had not been documented in this model system. In our previous experiments, we demonstrate that the crayfish natural reward pathways are sensitive to human drugs of abuse. This finding supports crayfish as a suitable model to characterize specific behaviors that are relevant in drug addiction research, and the current study builds on our previous findings. The aim of the present study was to investigate unconditioned neurobehavioral effects of repeated treatment regimens using cocaine, morphine, and methamphetamine for three consecutive days. We analyzed mobility, immobility and characterized stereotypic behaviors following intracardial infusions of 2.0MUg/g or 10.0MUg/g doses of cocaine, morphine, and methamphetamine for three days. The results showed that systemic cocaine, morphine, and methamphetamine increased mobility at a low dose of 2.0MUg/g more effectively than a high dose of 10.0MUg/g, while simultaneously showing that the high dose exerted a more prominent effect in increasing immobility. Moreover, systemic cocaine, morphine, and methamphetamine injections have discerning effects towards a group of defined unconditioned stereotyped behavioral patterns associated with each drug, rather than a shared universal behavioral effect. These findings provide insight into the behavioral and pharmacological basis responsible for the unconditioned effects of these drugs in crayfish. PMID- 28583867 TI - Geographical distribution of Toxoplasma gondii genotypes in Asia: A link with neighboring continents. AB - Defining the pattern of genetic diversity of Toxoplasma gondii is important to understand its worldwide distribution. During the last decades, a large number of studies have been published on Toxoplasma genotypes circulating in Europe, in North and South America. Two continents are still largely unexplored, Africa and, to a less extent, Asia. In this last continent, an increasing number of publications reported genotypes circulating in diverse provinces of China, but very few data are available for other Asian countries. After a systematic database search, 47 papers related to T. gondii genotypes in Asia were analyzed. Genetic characterization of DNA was performed by microsatellite markers, or more usually by a multiplex PCR using 11 PCR-RFLP markers, allowing data comparison to draw a first global picture of the population structure of this parasite throughout Asia. Overall, 390 isolates or DNA extracts were completely typed by PCR-RFLP and/or microsatellite marker methods, revealing 36 different PCR-RFLP or equivalent microsatellite genotypes: 15 genotypes identified by a ToxoDB number and 21 atypical or unique genotypes. The most common genotype found in Asia is the genotype ToxoDB#9 (Chinese 1). The clonal types I, II and II variant, and III were also commonly found in Asia. The geographical distribution of these genotypes across Asia may reflect either a continuum with Europe for the western part of Asia (presence of Type II), or the circulation of strains through animal migration or human activities between Africa and the Southwestern part of Asia (Africa 1 genotype in Turkey or ToxoDB#20 both I Sri-Lanka and in Ethiopia or Egypt). Although there are some indications of a genetic population structure in Southeast Asian countries different from the rest of Asia, more studies in this tropical part of Asia will be necessary for a region which represent as well as Africa one of the missing links of the T. gondii genetic diversity. PMID- 28583868 TI - Response to Commentary on "Comparison of intraoperative blood loss between four different surgical procedures in the treatment of bimaxillary protrusion". PMID- 28583869 TI - Total disc replacement versus multidisciplinary rehabilitation in patients with chronic low back pain and degenerative discs: 8-year follow-up of a randomized controlled multicenter trial. AB - BACKGROUND CONTEXT: Lumbar total disc replacement (TDR) is a treatment option for selected patients with chronic low back pain (LBP) that is non-responsive to conservative treatment. The long-term results of disc replacement compared with multidisciplinary rehabilitation (MDR) have not been reported previously. PURPOSE: We aimed to assess the long-term relative efficacy of lumbar TDR compared with MDR. DESIGN: We undertook a multicenter randomized controlled trial at five university hospitals in Norway. PATIENT SAMPLE: The sample consisted of 173 patients aged 25-55 years with chronic LBP and localized degenerative changes in the lumbar intervertebral discs. OUTCOME MEASURES: The primary outcome was self-reported physical function (Oswestry Disability Index [ODI]) at 8-year follow-up in the intention-to-treat population. Secondary outcomes included self reported LBP (visual analogue scale [VAS]), quality of life (EuroQol [EQ-5D]), emotional distress (Hopkins Symptom Checklist [HSCL-25]), occupational status, patient satisfaction, drug use, complications, and additional back surgery. METHODS: Patients were randomly assigned to lumbar TDR or MDR. Self-reported outcome measures were collected 8 years after treatment. The study was powered to detect a difference of 10 ODI points between the groups. The study has not been funded by the industry. RESULTS: A total of 605 patients were screened for eligibility, of whom 173 were randomly assigned treatment. Seventy-seven patients (90%) randomized to surgery and 74 patients (85%) randomized to rehabilitation responded at 8-year follow-up. Mean improvement in the ODI was 20.0 points (95% confidence interval [CI] 16.4-23.6, p<=.0001) in the surgery group and 14.4 points (95% CI 10.7-18.1, p<=.0001) in the rehabilitation group. Mean difference between the groups at 8-year follow-up was 6.1 points (95% CI 1.2-11.0, p=.02). Mean difference in favor of surgery on secondary outcomes were 9.9 points on VAS (95% CI 0.6-19.2, p=.04) and 0.16 points on HSCL-25 (95% CI 0.01-0.32, p=.04). There were 18 patients (24%) in the surgery group and 4 patients (6%) in the rehabilitation group who reported full recovery (p=.002). There were no significant differences between the groups in EQ-5D, occupational status, satisfaction with care, or drug use. In the per protocol analysis, the mean difference between groups was 8.1 ODI points (95% CI 2.3-13.9, p=.01) in favor of surgery. Forty-three of 61 patients (70%) in the surgery group and 26 of 52 patients (50%) in the rehabilitation group had a clinically important improvement (15 ODI points or more) from baseline (p=.03). The proportion of patients with a clinically important deterioration (six ODI points or more) was not significantly different between the groups. Twenty-one patients (24%) randomized to rehabilitation had crossed over and had undergone back surgery since inclusion, whereas 12 patients (14%) randomized to surgery had undergone additional back surgery. One serious adverse event after disc replacement is registered (<1%). CONCLUSIONS: Substantial long-term improvement can be expected after both disc replacement and MDR. The difference between groups is statistically significant in favor of surgery, but smaller than the prespecified clinically important difference of 10 ODI points that the study was designed to detect. Future research should aim to improve selection criteria for disc replacement and MDR. PMID- 28583870 TI - Crystallization behaviours of bacterially synthesized poly(hydroxyalkanoate)s in the presence of oxalamide compounds with different configurations. AB - Bacterially synthesized poly(hydroxyalkanoate)s (PHAs) suffers from low crystallization rate which is enhanced by using tailor-made oxalamide compounds as nucleators. The influence of nucleator configurations on the crystallization behaviour of the PHAs was investigated using differential scanning calorimetry (DSC), polarized optical microscopy (POM) and X-ray diffraction (XRD). The oxalamide compounds with ringy terminal structures (cyclohexyl and phenyl), notably the phenyl group, show higher nucleation efficiency and a better compatibility in the PHAs matrix, while the linear terminal structure (n-hexane) has poor nucleation effect. The crystallization temperature (Tc) and the crystallinity (Xc) of the PHAs are increased from 58 degrees C to 71 degrees C and from 5% to 48%, respectively, after addition of 0.75wt% of the nucleator (phenyl group) upon cooling from the melt. Meanwhile, the half-life isothermal crystallization time (t0.5) of the PHAs at 110 degrees C is decreased by 70%. The oxalamide compounds increases the nuclei density of the PHAs accompanied with a reduction in spherulitic size. In addition, the crystal form and crystallization mechanism of the PHAs are not altered obviously after addition of the nulceators as confirmed by the POM, XRD and Avrami analysis. PMID- 28583871 TI - Studies on glycoxidatively modified human IgG: Implications in immuno-pathology of type 2 diabetes mellitus. AB - Structural rearrangements and condensations of proteins under hyperglycemic stress have been implicated in various pathological disorders. This study aims to probe the role of methylglyoxal (MG) modified human immunoglobulin G (MG-IgG) in immuno-pathology of type 2 diabetes mellitus (T2DM). MG was found to perturb the structural integrity of IgG, affect its aromatic micro-environment and cause the generation of advanced glycation end products (AGEs) and aggregate adducts. It liberated the hydrophobic pockets of the protein, reduced its beta pleated sheet structure and affected its tertiary conformation. Transition from beta sheet to alpha helix and random coil was also observed in IgG upon modification by MG. It acted with strong oxidative potential and caused oligomerisation and disordered or amorphous type aggregation in the modified protein. Modified IgG had a cytotoxic and genotoxic impact. The MG modified IgG presented novel antigenic determinants that lead to an aggressive immune response. The antibodies had high affinity towards the immunogen. Auto-antibodies derived from T2DM patients exhibited strong affinity towards the modified IgG in comparison to the unmodified protein. Specificity of serum antibodies from T2DM patients was further confirmed by competitive-inhibition ELISA. The potential role of MG-IgG in the immunopathogenesis of T2DM has been discussed. PMID- 28583872 TI - Targeted mutations and MD simulations of a methanol-stable lipase YLIP9 from Yarrowia lipolytica MSR80 to develop a biodiesel enzyme. AB - Biodiesel, an environment friendly alternative for fuels, contains methyl esters of long-chain fatty acids. Our group has reported a methanol-stable YLIP9 from Yarrowia lipolytica MSR80 that shows poor catalysis of long-chain fatty acids. To shift its substrate specificity, residues within lid and binding pocket were identified for sequential mutations using YLIP2 as the template. Of the two point mutations (Glu116Leu and Ser119Val) introduced in the lid, the former mutation (YLIP9L1) increased the catalytic rate by ~2-fold without any change in substrate specificity. In this mutant, six binding pocket residues (Bp2-Bp7) were further mutated to obtain six double mutants. YLIP9L1Bp3 showed significant shift in substrate specificity towards long-chain pNPesters with 11-fold increase in catalytic efficiency than YLIP9. Double mutations also led to increased thermostability and lowered activation energy of YLIP9L1Bp3 thereby shifting its optimum temperature from 60 degrees C to 50 degrees C. In silico molecular dynamics simulations revealed improved lid flexibility and increased catalytic triad volume in YLIP9L1Bp3. The enzyme YLIP9L1Bp3 was methanol-stable having selectivity for long-chain fatty acids with improved catalytic efficiency. Its application as a biodiesel enzyme was validated by transesterification of palm oil in presence of methanol, where it showed 8-fold increase in conversion of oil to methyl esters. PMID- 28583873 TI - A trade off between catalytic activity and protein stability determines the clinical manifestations of glucose-6-phosphate dehydrogenase (G6PD) deficiency. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common polymorphism and enzymopathy in humans, affecting approximately 400 million people worldwide. It is responsible for various clinical manifestations, including favism, hemolytic anemia, chronic non-spherocytic hemolytic anemia, spontaneous abortion, and neonatal hyperbilirubinemia. Understanding the molecular mechanisms underlying the severity of G6PD deficiency is of great importance but that of many G6PD variants are still unknown. In this study, we report the construction, expression, purification, and biochemical characterization in terms of kinetic properties and stability of five clinical G6PD variants-G6PD Bangkok, G6PD Bangkok noi, G6PD Songklanagarind, G6PD Canton+Bangkok noi, and G6PD Union+Viangchan. G6PD Bangkok and G6PD Canton+Bangkok noi showed a complete loss of catalytic activity and moderate reduction in thermal stability when compared with the native G6PD. G6PD Bangkok noi and G6PD Union+Viangchan showed a significant reduction in catalytic efficiency, whereas G6PD Songklanagarind showed a catalytic activity comparable to the wild-type enzyme. The Union+Viangchan mutation showed a remarkable effect on the global stability of the enzyme. In addition, our results indicate that the location of mutations in G6PD variants affects their catalytic activity, stability, and structure. Hence, our results provide a molecular explanation for clinical manifestations observed in individuals with G6PD deficiency. PMID- 28583874 TI - Tinidazole functionalized homogeneous electrospun chitosan/poly (epsilon caprolactone) hybrid nanofiber membrane: Development, optimization and its clinical implications. AB - We have prepared tinidazole (TNZ) functionalized biodegradable chitosan (CH)/poly (epsilon-caprolactone) (PCL) mucoadhesive hybrid nanofiber membrane (TNZ-PCHNF) to alleviate existing shortcomings in treatment of periodontitis. Box-Behnken design was employed for evaluating influence of formulation and processing variables on quality of final formulation. Optimized nanofiber membrane was subjected to solid-state and surface characterization studies using FTIR, DSC, XRD, SEM and AFM, which revealed that TNZ was entrapped in an amorphous form inside smooth and uniform cylindrical nanofibers without any physicochemical interaction with excipients. The optimized TNZ-PCHNF membrane had a diameter of 143.55+/-8.5nm and entrapment efficiency of 83.25+/-1.8%. In vitro drug release and antibacterial study demonstrated capability of the developed nanofiber membranes for efficiently delivering TNZ in a sustained manner up to 18days, and its ability to inhibit bacterial growth, respectively. Further, reduction of contact angle (from 123.4+/-2.5 to 27.4+/-2.3) revealed that blending of CH with PCL increases hydrophilicity of the nanofiber membrane. MTT assay and CLSM study suggested that nanofiber membrane was devoid of cytotoxicity on mouse fibroblasts. Moreover, preliminary clinical trials on patients proved therapeutic efficacy of the nanofiber membrane by eliciting a significant (p<0.05) decrease in clinical markers of periodontitis. PMID- 28583875 TI - Quantitative profiling of 19 bile acids in rat plasma, liver, bile and different intestinal section contents to investigate bile acid homeostasis and the application of temporal variation of endogenous bile acids. AB - Bile acid homeostasis is maintained by liver synthesis, bile duct secretion, microbial metabolism and intestinal reabsorption into the blood. When drug insults result in liver damage, the variances of bile acids (BAs) are related to the physiological status of the liver. Here, we established a method to simultaneously quantify 19 BAs in rat plasma, liver, bile and different intestinal section contents (duodenum, jejunum, ileum, cecum and colon) using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to reveal the pattern of bile acid homeostasis in the enterohepatic circulation of bile acids in physiological situations. Dynamic changes in bile acid composition appeared throughout the enterohepatic circulation of the BAs; taurine- and glycine-conjugated BAs and free BAs had different dynamic homeostasis levels in the circulatory system. cholic acid (CA), beta-muricholic acid (beta-MCA), lithocholic acid (LCA), glycocholic acid (GCA) and taurocholic acid (TCA) greatly fluctuated in the bile acid pool under physiological conditions. Taurine- and glycine-conjugated bile acids constituted more than 90% in the bile and liver, whereas GCA and TCA accounted for more than half of the total bile acids and the secretion of bile mainly via conjugating with taurine. While over 80% of BAs in plasma were unconjugated bile acids, CA and HDCA were the most abundant elements. Unconjugated bile acids constituted more than 90% in the intestine, and CA, beta MCA and HDCA were the top three bile acids in the duodenum, jejunum and ileum content, but LCA and HDCA were highest in the cecum and colon content. As the main secondary bile acid converted by microflora in the intestine, LCA was enriched in the cecum and DCA mostly in the colon. As endogenous substances, the concentrations of plasma BAs were closely related to time rhythm and diet. In conclusion, analyzing detailed BA profiles in the enterohepatic circulation of bile acids in a single run is possible using LC-MS/MS. Based on the physiological characteristics of the metabolic profiling of 19 BAs in the total bile acid pool and the time rhythm variation of the endogenous bile acids, this study provided a new valuable method and theoretical basis for the clinical research of bile acid homeostasis. PMID- 28583877 TI - Intrinsic resistance versus intrinsic resistome: are we talking about the same concept? Reply to 'Resistance to polymyxins in Gram-negative organisms'. PMID- 28583876 TI - Enhanced expression of lipase I from Galactomyces geotrichum by codon optimisation in Pichia pastoris. AB - Relatively poor heterologous protein yields have limited the commerical applications of Galactomyces geotrichum lipase I (GGl I) efficacy trials. To address this, we have redesigned the GGl I gene to preferentially match codon frequencies of Pichia pastoris (P. pastoris) while retaining the same amino acid sequence. The wild type and codon optimised GGl I (GGl I-wt and GGl I-op) were synthesised and cloned into pPICZalphaA with an N-terminal 6 * His tag sequence and expressed in P. pastoris X 33. The hydrolytic activity of GGl I-op was 150 U/mL, whereas the activity of the GGl I-wt could not be detected. GGl I-op recombinant proteins were purified by Ni-affinity chromatography and then characterised. The identity and purity of GGl I were confirmed by SDS-PAGE, MALDI TOF mass spectrometry and Western blot analysis. Enzymatic deglycosylation was used to show that the lipase is a glycosylated protein, containing ~10% sugar. The molecular weight (MW) of the GGl I secreted by recombinant P. pastoris was approximated at 63 kDa. The optimum pH and temperature of the recombinant lipase were 8.0 and 35 degrees C, respectively. The enzyme was active over a broad pH range (7.0-9.0) and temperature range (20 degrees C-45 degrees C). The lipase showed high activity toward medium- and long-chain fatty acid methyl esters (C8 C16) and retained much of its activity in the presence of Tween-80 and Trition X 100. Lipase activity was stimulated by Mg2+, Ca2+, Mn2+ and Cu2+ and inhibited by Fe2+, Fe3+, Zn2+ and Co2+. This lipase may prove useful to the detergent industry and in organic synthesis reactions. PMID- 28583878 TI - Variable Resource Utilization in the Prenatal and Postnatal Management of Isolated Hydronephrosis. AB - OBJECTIVE: To characterize contemporary resource utilization and medical outcomes for infants with antenatal hydronephrosis and their mothers from a national claims database. We hypothesize that management of isolated hydronephrosis (IHN) varies widely, with decreased imaging following the 2010 Society for Fetal Urology Consensus Statement. MATERIALS AND METHODS: Using MarketScan claims from 2007 to 2013, we identified infants 0-12 months of age with hydronephrosis and linked mothers. Those with urologic diagnoses more specific than hydronephrosis, additional urologic comorbidities, or postnatal surgeries were excluded. Resource utilization including prenatal and postnatal imaging, laboratory studies, hospital admissions, and medical outcomes within the first year was captured. Demographics, maternal characteristics, utilization measures, and outcomes were compared across imaging intensity groups based on number of postnatal ultrasounds received using bivariate analysis. RESULTS: Among 801,919 mother-child pairs, 8610 infants (1.1%) had hydronephrosis or a related diagnosis. A total of 5876 (68.2%) met inclusion criteria for IHN. Patients underwent a mean 5.3 +/- 3.5 prenatal and 2.1 +/- 1.3 postnatal ultrasounds before age 1. Imaging practices were unchanged following the Society for Fetal Urology consensus statement. CONCLUSION: Antenatal hydronephrosis prevalence in an insured population is consistent with published ranges. Prenatal imaging in IHN is variable and potentially excessive. Future study into the efficacy of evidence-based pathways in reducing excess utilization is warranted. PMID- 28583879 TI - Long-term effects of maternal calcium supplementation on childhood growth differ between males and females in a population accustomed to a low calcium intake. AB - The importance of adequate calcium intakes for healthy growth and bone development has long been recognised. Recent evidence suggests that calcium supplementation may have sex-specific effects on bone growth in childhood. The aim was to describe the long-term effects of calcium supplementation in pregnant Gambian women with a low calcium intake (ISCRTN96502494) on offspring height, weight, bone and body composition in childhood, and whether the effects differ by sex. Children of mothers who participated in the original calcium supplementation trial were measured at age 8-12years using dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Linear models tested for sex*supplement interactions before and after adjusting for current age and size in early life. 447 children, aged 9.2(SD 0.9) years, were measured. Significant sex*supplement interactions (p<0.05) were observed for many of the anthropometric and bone outcomes, Females whose mothers received calcium (F-Ca) were shorter, lighter with smaller bones and less bone mineral than those whose mothers received placebo (F-P), differences (SE) ranged from height=-1.0 (0.5)% to hip BMC -5.5 (2.3)%. Males from mothers in the calcium group (M-Ca) had greater mid upper arm circumference (MUAC) (+2.0 (1.0)%, p=0.05) and fat mass (+11.6 (5.1)%, p=0.02) and tended towards greater BMC and size than those whose mothers were in the placebo group (M-P). The differences in anthropometry and body composition were robust to adjustment for current height and weight, whereas all bone differences became non-significant. F-P were taller with more BMC than M-P, whereas F-Ca had similar sized bones and mineral content to M-Ca. Calcium supplementation of pregnant women with low calcium intakes altered the childhood trajectories of growth and bone and body composition development of their offspring in a sex-specific manner, resulting in slower growth among females compared to placebo and accelerated growth among males by age 8-12years. PMID- 28583880 TI - Slow-5 dynamic functional connectivity reflects the capacity to sustain cognitive performance during pain. AB - Some individuals are more distracted by pain during a cognitive task than others, representing poor pain coping. We have characterized individuals as A-type (attention dominates) or P-type (pain dominates) based on how pain interferes with task speed. The ability to optimize behavior during pain may relate to the flexibility in communication at rest between the dorsolateral prefrontal cortex (DLPFC) of the executive control network, and the anterior mid-cingulate cortex (aMCC) of the salience network (SN) - regions involved in cognitive-interference. The aMCC and aIns (SN hub) also signify pain salience; flexible communication at rest between them possibly allowing prioritizing task performance during pain. We tested the hypotheses that pain-induced changes in task performance are related to resting-state dynamic functional connectivity (dFC) between these region pairs (DLPFC-aMCC; aMCC-aIns). We found that 1) pain reduces task consistency/speed in P-type individuals, but enhances performance in A-type individuals, 2) task consistency is related to the FC dynamics within DLPFC-aMCC and aMCC-aIns pairs, 3) brain-behavior relationships are driven by dFC within the slow-5 (0.01 0.027Hz) frequency band, and 4) dFC across the brain decreases at higher frequencies. Our findings point to neural communication dynamics at rest as being associated with prioritizing task performance over pain. PMID- 28583881 TI - Altered adenosine 2A and dopamine D2 receptor availability in the 6 hydroxydopamine-treated rats with and without levodopa-induced dyskinesia. AB - : Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [11C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [11C]raclopride PET and behavioral tests for motor and cognitive function were performed. METHODS: Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively. All images were anatomically standardized to Paxinos space and analyzed using volume-of-interest (VOI) and voxel-based approaches. The behavioral alternations were assessed with the open field test, Y maze, novel object recognition test, cylinder test, and abnormal involuntary movement (AIM) score. In total, 28 female Wistar rats were included. RESULTS: On the behavioral level, 6-OHDA-lesioned rats showed asymmetry in forepaw use and deficits in spatial memory and explorative behavior as compared to the sham operated animals. 15-Days of levodopa (L-DOPA) treatment induced dyskinesia but did not alleviate motor deficits in PD rats. Intranigral 6-OHDA injection significantly increased D2R binding in the lesioned striatum (BPND: 2.69 +/- 0.40 6-OHDA vs. 2.31 +/- 0.18 sham, + 16.6%; p = 0.03), whereas L-DOPA treatment did not affect the D2R binding in the ipsilateral striatum of the PD rats. In addition, intranigral 6-OHDA injection tended to decrease the A2AR availability in the lesioned striatum. The decrease became significant when data were normalized to the non-affected side (BPND: 4.32 +/- 0.41 6-OHDA vs. 4.58 +/- 0.89 sham; NS, ratio: 0.94 +/- 0.03 6-OHDA vs. 1.00 +/- 0.02 sham; - 6.1%; p = 0.01). L-DOPA treatment significantly increased A2AR binding in the affected striatum (BPND: 6.02 +/- 0.91 L-DOPA vs. 4.90 +/- 0.76 saline; + 23.4%; p = 0.02). In PD rats with LID, positive correlations were found between D2R and A2AR BPND values in the ipsilateral striatum (r = 0.88, ppeak = 8.56.10-4 uncorr), and between AIM score and the D2R BPND in the contralateral striatum (r = 0.98; ppeak = 9.55.10-5 uncorr). CONCLUSION: A2AR availability changed in drug-naive and in L-DOPA treated PD rats. The observed correlations of striatal D2R availability with A2AR availability and with AIM score may provide new knowledge on striatal physiology and new possibilities to further unravel the functions of these targets in the pathophysiology of PD. PMID- 28583882 TI - Numerosity processing in early visual cortex. AB - While parietal cortex is thought to be critical for representing numerical magnitudes, we recently reported an event-related potential (ERP) study demonstrating selective neural sensitivity to numerosity over midline occipital sites very early in the time course, suggesting the involvement of early visual cortex in numerosity processing. However, which specific brain area underlies such early activation is not known. Here, we tested whether numerosity-sensitive neural signatures arise specifically from the initial stages of visual cortex, aiming to localize the generator of these signals by taking advantage of the distinctive folding pattern of early occipital cortices around the calcarine sulcus, which predicts an inversion of polarity of ERPs arising from these areas when stimuli are presented in the upper versus lower visual field. Dot arrays, including 8-32dots constructed systematically across various numerical and non numerical visual attributes, were presented randomly in either the upper or lower visual hemifields. Our results show that neural responses at about 90ms post stimulus were robustly sensitive to numerosity. Moreover, the peculiar pattern of polarity inversion of numerosity-sensitive activity at this stage suggested its generation primarily in V2 and V3. In contrast, numerosity-sensitive ERP activity at occipito-parietal channels later in the time course (210-230ms) did not show polarity inversion, indicating a subsequent processing stage in the dorsal stream. Overall, these results demonstrate that numerosity processing begins in one of the earliest stages of the cortical visual stream. PMID- 28583883 TI - Preferential susceptibility of limbic cortices to microstructural damage in temporal lobe epilepsy: A quantitative T1 mapping study. AB - The majority of MRI studies in temporal lobe epilepsy (TLE) have utilized morphometry to map widespread cortical alterations. Morphological markers, such as cortical thickness or grey matter density, reflect combinations of biological events largely driven by overall cortical geometry rather than intracortical tissue properties. Because of its sensitivity to intracortical myelin, quantitative measurement of longitudinal relaxation time (qT1) provides and an in vivo proxy for cortical microstructure. Here, we mapped the regional distribution of qT1 in a consecutive cohort of 24 TLE patients and 20 healthy controls. Compared to controls, patients presented with a strictly ipsilateral distribution of qT1 increases in temporopolar, parahippocampal and orbitofrontal cortices. Supervised statistical learning applied to qT1 maps could lateralize the seizure focus in 92% of patients. Intracortical profiling of qT1 along streamlines perpendicular to the cortical mantle revealed marked effects in upper levels that tapered off at the white matter interface. Findings remained robust after correction for cortical thickness and interface blurring, suggesting independence from previously reported morphological anomalies in this disorder. Mapping of qT1 along hippocampal subfield surfaces revealed marked increases in anterior portions of the ipsilateral CA1-3 and DG that were also robust against correction for atrophy. Notably, in operated patients, qualitative histopathological analysis of myelin stains in resected hippocampal specimens confirmed disrupted internal architecture and fiber organization. Both hippocampal and neocortical qT1 anomalies were more severe in patients with early disease onset. Finally, analysis of resting-state connectivity from regions of qT1 increases revealed altered intrinsic functional network embedding in patients, particularly to prefrontal networks. Analysis of qT1 suggests a preferential susceptibility of ipsilateral limbic cortices to microstructural damage, possibly related to disrupted myeloarchitecture. These alterations may reflect atypical neurodevelopment and affect the integrity of fronto-limbic functional networks. PMID- 28583884 TI - 28th Conference of the European Network of Teratology Information Services (ENTIS), September 2-5, 2017, Budapest, Hungary. PMID- 28583885 TI - The fourth edition of the head and neck World Health Organization blue book: editors' perspectives. PMID- 28583886 TI - Risk factors and clinical outcomes for carbapenem-resistant Gram-negative late onset sepsis in a neonatal intensive care unit. AB - BACKGROUND: Carbapenem-resistant (CR), Gram-negative (GN), late-onset sepsis (LOS) is a serious threat in the neonatal intensive care unit (NICU). AIM: To assess the prevalence of CR-GN-LOS in NICU patients and to identify the risk factors and outcomes associated with its acquisition. METHODS: Neonates with carbapenem-susceptible (CS)-GN-LOS were compared with those with CR-GN-LOS in a two-year observational study. FINDINGS: A total of 158 patients had GN-LOS; 100 infants had CS-GN-LOS and 58 infants had CR-GN-LOS. The incidence rate of CR-GN LOS was 6.5 cases per 1000 patient-days. The most frequent bacterial strain in both groups was Klebsiella pneumoniae. The duration of total parenteral nutrition (TPN) (P=0.006) and prior carbapenem use (P=0.01) were independent risk factors for CR-GN-LOS acquisition. CR-GN-LOS was associated with higher mortality than CS GN-LOS (P=0.04). Birth weight, small for gestational age, time to start enteral feeding, exclusive formula feeding, previous surgery, previous antifungal use, central venous device before onset, duration of central venous device, and infectious complications were identified as dependent risk factors for overall mortality. However, only male gender (P=0.04) and infectious complications (P < 0.001) were independent risk factors associated with mortality. Infectious complication rates, duration of mechanical ventilation, and length of hospital stay were significantly higher in infants with CR compared to CS-GN-LOS. CONCLUSION: The duration of TPN and carbapenem use were the independent predictors for CR-GN-LOS acquisition. CR-GN-LOS is associated with higher mortality, infectious complication rates, longer mechanical ventilation, and longer hospital stay. Male gender and infectious complications were the independent risk factors for mortality in neonates with GN-LOS. PMID- 28583887 TI - Antimicrobial activity of plant-median synthesized silver nanoparticles against food and agricultural pathogens. AB - The adjuvant applications of silver nanoparticles (AgNPs) in food and agro ecosystems are not completely pursued, which most of the researchers confined to laboratory inventions. AgNPs is gaining a lot of interest among worldwide researcher due to exhibit antimicrobial properties and unique physiochemical properties. In addition, the facile and economically friendly method called biological method to synthesis of AgNPs using Bryophyllum pinnatum leaf extract over other methods and including antimicrobial properties, there is no doubt that AgNPs could be twirled the food and agricultural sector in future. The Ag ion reduced to AgNPs within 5 min. The AgNPs had synthesized in pure state of face centered-cubic nano-crystalline metallic silver with spherical in shape and well dispersed. The AgNPs exhibited against food (Escherichia coli-MTCC-443) and agriculture (Bacillus megaterium-MTCC-2412) pathogens. The synthesized AgNPs are strongly active against microbial associated with food and agriculture pathogens. PMID- 28583888 TI - Extracellular polysaccharide derived from potential probiotic strain with antioxidant and antibacterial activities as a prebiotic agent to control pathogenic bacterial biofilm formation. AB - Because of their functional diversity, bioactive compounds are becoming a new biocontrol agent to limit biofilm formation by pathogens. In this study, the physico-chemical characterization of an exopolysaccharide (EPS) isolated from Lactobacillus plantarum (EPLB) was characterized and its in vitro effect on biofilm formation was studied. The EPS had a molecular weight of 36 kDa and polydispersity index estimated to be 1.2. The tested EPLB had an antibacterial activity, with a Minimal Inhibition Concentration (MIC) values ranging between 1 mg/ml and 10 mg/ml, displayed an antibiofilm effect concentration dependent on Gram positive and negative strains. Among the pathogenic strains, 2 out of 4 appeared to be more than 50% inhibited in their biofilm development by the EPS. The antibiofilm activity can be due to the ability of the EPS to influence the function of biological membranes like hydrophobicity that decreased (P < 0.05) when the EPS was used at a concentration of 512 MUg/ml. This EPS without cytotoxic effect, showed an antioxidant effect on the quenching of DPPH radicals and the inhibition of lipid peroxidation with a percentage of 64% and 66%, respectively. Taken together these biological properties, EPLB can be considered as a potential prebiotic agent in the design of new therapeutic strategies for bacterial biofilm-associated infections. PMID- 28583889 TI - A diet rich in omega-3 fatty acids enhances expression of soluble epoxide hydrolase in murine brain. AB - Several studies suggest that intake of omega-3 polyunsaturated fatty acids (n3 PUFA) beneficially influences cognitive function. However, effects on the adult brain are not clear. Little is known about the impact of dietary intervention on the fatty acid profile in adult brain, the modulation in the expression of enzymes involved in fatty acid biosynthesis and metabolism as well as changes in resulting oxylipins. These questions were addressed in the present study in two independent n3-PUFA feeding experiments in mice. Supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA, 1% each in the diet) for 30days to adult NMRI and C57BL/6 mice led to a distinct shift in the brain PUFA pattern. While n3-PUFAs EPA, n3 docosapentaenoic acid and DHA were elevated, many n6-PUFAs were significantly decreased (except, e.g. C20:3 n6 which was increased). This shift in PUFAs was accompanied by immense differences in concentrations of oxidative metabolites derived from enzymatic conversion of PUFAs, esp. arachidonic acid whose products were uniformly decreased, and a modulation in the activity and expression pattern of delta-5 and delta-6 desaturases. In both mouse strains a remarkable increase in the soluble epoxide hydrolase (sEH) activity (decreased epoxy-FA concentrations and epoxy-FA to dihydroxy-FA-ratios) as well as sEH expression was observed. Taking the high biological activity of epoxy-FA, e.g. on blood flow and nociceptive signaling into account, this finding might be of relevance for the effects of n3-PUFAs in neurodegenerative diseases. On any account, our study suggests a new distinct regulation of brain PUFA and oxylipin pattern by supplementation of n3-PUFAs to adult rodents. PMID- 28583890 TI - CD200 selectively upregulates prostaglandin E2 and D2 synthesis in LPS-treated bone marrow-derived macrophages. AB - The CD200/CD200R signalling pathway downregulates the synthesis of proinflammatory mediators and induces the synthesis of antiinflammatory mediators in macrophages and microglia. However, very little is known about the effect of this immunosuppressive pathway on the synthesis of lipid mediators. Therefore, we determined the synthesis of 35 lipids spanning 5 different lipid families in bone marrow-derived macrophages, which were treated with interleukin (IL) 4, IL10, lipopolysaccharide (LPS), or interferon gamma (IFNgamma) in absence and presence of CD200. Out of these conditions the only significant effect of CD200 was an increased synthesis of prostaglandin (PG) E2 and D2 in the presence of LPS. Accordingly, mRNA levels of cyclooxygenase-2, microsomal PGE2 synthase-1 and hematopoietic PGD synthase were upregulated by CD200 in presence of LPS. During Complete Freund's Adjuvant (CFA-) induced inflammation mPGES-1 was expressed in monocyte-derived macrophages and its expression was stronger in CD200R-positive than in CD200R-negative macrophages. PMID- 28583891 TI - The prognostic value of histologic subtype in node-positive early-stage cervical cancer after hysterectomy and adjuvant radiotherapy. AB - BACKGROUND: To assess the survival outcomes in patients with International Federation of Gynecology and Obstetrics (FIGO) stage I-IIA adenocarcinoma (AC) or squamous cell carcinoma (SCC) of the uterine cervix after hysterectomy and adjuvant radiotherapy (RT). METHODS: Patients with a primary diagnosis of FIGO stage I-IIA AC or SCC of the uterine cervix after hysterectomy and adjuvant RT between 1988 and 2012 were included using data from the Surveillance, Epidemiology, and End Results database. Univariate and multivariate Cox regression analyses were used to analyze the effect of histologic subtype on cause-specific survival (CSS) and overall survival (OS). RESULTS: We included 1171 patients: 919 with cervical SCC and 252 with cervical AC. In multivariate analysis, cervical AC was an independent adverse prognostic factor for survival. Patients with cervical AC had worse CSS (p = 0.001) and OS (p = 0.001) compared to patients with cervical SCC. In the subgroup analysis, patients with cervical SCC in the era of concurrent chemoradiotherapy (CCRT) (2000-2012) had better CSS (p = 0.006) and OS (p = 0.004) compared with the era of RT. However, there was no significant difference in CSS (p = 0.079) and OS (p = 0.053) between the eras of RT (1988-1999) and CCRT for patients with cervical AC. CONCLUSIONS: Survival of cervical AC is significantly worse than that of cervical SCC. As CCRT usage increases, the survival benefit is derived only in cervical SCC, but not in cervical AC. PMID- 28583892 TI - Preoperative chlorhexidine versus povidone-iodine antisepsis for preventing surgical site infection: A meta-analysis and trial sequential analysis of randomized controlled trials. AB - BACKGROUNDS: Updated guidelines for surgical site infections (SSIs) suggested that chlorhexidine (CH) or povidone-iodine (PVI) product was equally appropriate to be applied in preoperative disinfection, but which one was optimal remained ambiguous. Moreover, recent studies reported inconsistent results. Thus, an updated meta-analysis was conducted to clarify the superiority of CH or PVI for prevention of SSIs in clean and clean-contaminated surgery. METHODS: From the inception to November 2016, Pubmed, Embase, and the Cochrane library were systematically searched for randomized controlled trials (RCTs) which explored preoperative antisepsis schemes (CH or PVI) for prevention of SSIs in clean and clean-contaminated surgery. Relative risks (RRs) with 95% confidence interval (CI) were calculated using random effects model. Furthermore, subgroup analysis, sensitive analysis, and trial sequential analysis (TSA) were applied to estimate whether overall pooled effect was enough credible and robust. RESULTS: Thirteen RCTs involving 6997 patients (3352 in CH and 3645 in PVI group) undergoing clean and clean-contaminated surgeries were included in our meta-analysis. Compared with PVI, preoperative CH antisepsis was associated with lower incidence of SSIs (RR, 0.70; 95%CI, 0.60-0.83, I2 = 0). Additionally, subgroup analysis, sensitive analysis, and TSA indicated that the current available evidence was reliable and robust. CONCLUSIONS: CH should be more preferentially recommended for preoperative skin preparation as compared with PVI in clean and clean contaminated surgery. PMID- 28583893 TI - Clinicopathologic features, surgical treatments, and outcomes of small bowel tumors: A retrospective study in China. AB - BACKGROUND: Small bowel tumors are relatively rare. Accumulation of data regarding their clinical presentation, pathologic features, prognostic factors, treatment modalities, and outcome has been an issue. We summarize the clinicopathologic features and evaluate the long-term outcome of patients with small bowel tumors who underwent surgery. METHODS: This is a retrospective study of medical records of 456 patients with small bowel tumors treated surgically at a Cancer Hospital between 1999 and 2016. RESULTS: The study included 275 males (60.3%) and 181 females (39.7%). Small bowel tumors were difficult to diagnose because of non-specific symptoms. The most common symptoms were alimentary symptoms (56.8%) and abdominal pain (37.3%). Final histopathology revealed 241 adenocarcinomas (52.9%), 153 gastrointestinal stromal tumors (GISTs; 33.6%), 16 neuroendocrine tumors (NETs; 3.5%), and 46 other types of tumors (10.1%). The 456 surgeries performed included 153 pancreaticoduodenectomies, 241 limited duodenum resections, 60 palliative bypass surgeries, and 2 abdominal explorations. The 5 year overall survival and progression-free survival rates for patients with small bowel tumor were 57.2% and 44.6%, respectively. Adenocarcinomas resulted in the worst overall survival compared to GISTs or NETs, and tumors with duodenal location resulted in a worse survival compared to those with non-duodenal location. CONCLUSION: Surgery is the mainstay of treatment for small bowel tumors. Adenocarcinomas and duodenal involvement seem to contribute to poor outcomes. PMID- 28583894 TI - Local recurrence after five years is associated with preoperative chemoradiotherapy treatment in patients diagnosed with stage II and III rectal cancer. AB - AIM: To asses the moment of local recurrence and its influence on the appraisal of the results of neoadjuvant chemoradiotherapy (CRT). METHODS: We evaluated 317 patients with a preoperative diagnosis of stage II or III rectal cancer who underwent rectal resection. Gender, age, neoadjuvant treatment, circumferencial resection margin, adjuvant treatment, pretreatment carcinoembryonic antigen level, tumor location, TNM stage, lymph node retrieval, abdominoperineal resection, and lymphatic or vascular infiltration were registered prospectively. Follow-up was performed to detect local or systemic recurrences. Timing of local recurrence (LR) in regard to analyzed variables was performed by using analysis of variance. To evaluate the influence of late local recurrence (LLR) on the results of neoadjuvant CRT, we performed a log-rank test censoring all observations at 60 and at 120 months. RESULTS: After a mean follow-up of 73.6 months (range, 1-171), 68 patients developed a recurrence. Twenty-three patients developed LRs (6.9%), and 5 developed LLRs. The earliest relapse was diagnosed 4 months after rectal surgery, and the latest was diagnosed 120 months after surgery. Patients who underwent neoadjuvant CRT developed LR significantly later than patients without neoadjuvant CRT (51.8 vs 13.5 months; P = 0.002). LR rates in patients who underwent preoperative CRT and those who did not were 9.2% and 3.5% (difference, 5.7%), respectively, after censoring all observations at 60 months and 9.2% and 6.1% (difference, 3.1%) after censoring all observations at 120 months. CONCLUSION: Local recurrence was diagnosed significantly later in patients treated with neoadjuvant CRT. Follow-up longer than 5 years is needed to evaluate definitive results in patients treated with neoadjuvant CRT. PMID- 28583895 TI - The early prevention and treatment of PVST after laparoscopic splenectomy: A prospective cohort study of 130 patients. AB - BACKGROUND: After laparoscopic splenectomy (LS) in patients with cirrhotic and hypersplenism, there is highly risk of suffering from portal vein system thrombosis (PVST) complication. This study is aimed to investigate the risk factors of PVST and study the anticoagulation effect on the prevention of PVST after LS. MATERIALS AND METHODS: We retrospectively observed 130 patients who performed LS from February 2009 to December 2016. Patients were classified into the anticoagulation group (73 patients) and the non-anticoagulation group (57 patients). At the same time, the non-PVST and PVST groups were used to analyze the factors of thrombosis. RESULTS: We analyzed the risk factors of PVST, the mean platelet volume (MPV), platelet count (PLT), plasma d-dimer, thickness of spleen and portal vein diameter were statistically significant (P < 0.05) between PVST group and non-PVST group. Compared with the non-anticoagulant group, anticoagulant group had a lower incidence of PVST (P = 0.044), a significant lower PLT (P = 0.001), a notable lower mean platelet volume (P = 0.006), and an obvious lower d-dimer (P = 0.001) after LS. And prothrombin time (PT) and international normalized ratio (INR) were significant increase after treated with anticoagulant drugs. Multiple logistic regression analysis reported that PLT, d dimer, portal vein diameter and thickness of spleen were the risk factors of PVST, however the anticoagulant drug was an independent protective factor for PVST (P = 0.001). CONCLUSIONS: Anticoagulant drug significantly decreased the incidence rate of PVST in patients with cirrhotic and portal hypertension after LS. PMID- 28583896 TI - A new laparoscopic technique of inguinal ligament suspension for vaginal vault prolapse. AB - INTRODUCTION: The aim of the study was to evaluate the efficacy and safety of laparoscopic inguinal ligament suspension (LILS) as a new surgical technique for the treatment of vaginal vault prolapse. METHODS: From Feb 2014 to Mar 2016, 21 symptomatic women with grades III-IV vaginal vault prolapse were enrolled. All patients underwent LILS procedure in which a bifurcated mesh was used to suspend the vaginal vault to inguinal ligament. The perioperative parameters including surgical time, blood loss, and hospitalization time were recorded. At a minimal 12-month follow-up, the primary outcome measures, such as the anatomical cure rate and patients' satisfaction were respectively evaluated according to Pelvic organ prolapse questionnaire (POP-Q) and Patient Global Impression of Improvement (PGI-I) scale. The secondary outcomes including the impact on symptom severity, quality of life and sexual activity were also recorded. RESULTS: The mean surgical time was 130.71 +/- 16.07 min, the mean estimated blood loss was 53.57 +/- 48.43 ml, and the mean hospital stay was 6 days (range: 5-8 days). After a minimal 12-month follow-up (range: 12-36 months), the rate of anatomical success and the subjective satisfaction were 100% and 90.5%. The symptom severity, quality of life and sexual activity also presented significant improvement. In addition, no serious peri- and postoperative complications occurred. CONCLUSIONS: LILS was a potential method for the treatment of vaginal vault prolapse. The technique could be performed easily and might be an alternative to other POP surgeries. However, further studies were required to focus on its long-term efficacy. PMID- 28583897 TI - Laparoscopic versus open liver resection for colorectal liver metastases: A systematic review and meta-analysis of studies with propensity score-based analysis. AB - BACKGROUND: This meta-analysis collected studies with propensity score matching analysis (PSM) and focused on comparing the short-term and oncological outcomes of patients with colorectal liver metastases (CRLM) who underwent laparoscopic liver resection (LLR) versus open liver resection (OLR), to provide relatively high-level evidence of the additional value of LLR in treating patients with CRLM in comparison with OLR. METHODS: A systematic literature search was performed using the PubMed, Embase and Cochrane Library databases. Bibliographic citation management software (EndNote X7) was used for literature management. Quality assessment was performed based on a modified version of the Newcastle-Ottawa Scale. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by omitting one study in each step. Dichotomous data were calculated by odds ratio (OR) and continuous data were calculated by weighed mean difference (WMD) with 95% confidence intervals (CI). RESULTS: Overall, 10 studies enrolling 2259 patients with CRLM were included in the present meta-analysis. The pooled analysis suggested that LLR was associated with significantly less overall morbidity (OR, 0.57; 95% CI 0.40 to 0.80; I2 = 57%; P < 0.001), reduced blood loss (WMD, -124.68; 95% CI, -177.35 to -72.01; I2 = 83%; P < 0.00001), less transfusion requirement (OR, 0.46; 95% CI 0.35 to 0.62; I2 = 0%; P < 0.00001), shorter length of hospital stay (WMD, -2.13; 95% CI, -2.68 to -1.58; I2 = 0%; P < 0.00001), but longer operative time (WMD, 39.48; 95% CI, 23.68 to 55.27; I2 = 66%; P = 0.04). However, no significant differences were observed in mortality (OR, 0.50; 95% CI 0.21 to 1.2; I2 = 0%; P = 0.12). For oncological outcomes, no significant differences were observed in negative surgical margins (R0 resection), tumor recurrence, 3-year disease-free survival, 5-year disease-free survival, 5-year overall survival between the approaches. Nevertheless, LLR tended to provide higher 3-overall survival rate (OR, 1.37; 95% CI 1.11 to 1.69; I2 = 0%; P = 0.003). The pooled OR for overall morbidity in each subgroup analysis was consistent with the overall pooled OR. Additionally, the pooled OR for overall morbidity varied from (0.63; 95% CI 0.45to 0.88; I2 = 49%; P = 0.007) to (0.51; 95% CI 0.37 to 0.69; I2 = 39%; P < 0.0001) in sensitivity analysis. CONCLUSION: LLR is a beneficial alternative to OLR in select patients, and provides more favorable short-term outcomes such as less overall morbidity, shorter length of hospital stay, less blood loss, lower blood transfusion rate. Simultaneously, LLR does not compromise oncological outcomes including surgical margins R0, tumor recurrence, disease-free survival, 5-overall survival, as well as even yielding better 3-overall survival. Considering unavoidable bias from non randomized trials, high-quality RCTs are badly needed to determine whether LLR can become standard practice for treating patients with CRLM. PMID- 28583898 TI - Associations between proximal tibiofibular joint (PTFJ) types and knee osteoarthritic changes in older adults. AB - PURPOSE: To describe the cross-sectional associations between proximal tibiofibular joint (PTFJ) type configurations and knee joint structural abnormalities in older adults. METHODS: A total of 967 community-based participants were studied. T1-weighted fat-suppressed magnetic resonance image (MRI) with spoiled gradient recalled echo sequence was utilized to assess the PTFJ type configurations. Knee cartilage volume, cartilage defects, bone marrow lesions and osteophytes were measured. Linear regression and binary logistic regression analyses were used to examine the associations between PTFJ type configurations and knee joint cartilage volume as well as knee structural abnormalities, respectively, after adjustment for potential confounders. RESULTS: Seven PTFJ types including plane (49.4%), trochoid (31.9%), double trochoid (4.3%), saddle (5.4%), condylar (5.3%), trochlear (3.5%) and ball & socket (0.2%) were observed. Plane type was used as the comparator. In multivariable analyses, irregular joint types (comprising the five uncommon joint types) were associated negatively with cartilage volume, and positively with knee cartilage defects, bone marrow lesions and osteophytes in the lateral (but not medial) compartments. In contrast, trochoid type was only associated with reduced femoral cartilage volume, but not with knee cartilage defects, bone marrow lesions and osteophytes. CONCLUSIONS: Irregular PTFJ joint shapes are associated with osteoarthritic changes in the lateral, but not medial, tibiofemoral compartment in older adults. The causal relationship needs to be examined in future longitudinal studies. PMID- 28583899 TI - Statins do not inhibit the FGFR signaling in chondrocytes. AB - OBJECTIVE: Statins are widely used drugs for cholesterol lowering, which were recently found to counteract the effects of aberrant fibroblast growth factor receptor (FGFR3) signaling in cell and animal models of FGFR3-related chondrodysplasia. This opened an intriguing therapeutic possibility for human dwarfing conditions caused by gain-of-function mutations in FGFR3, although the mechanism of statin action on FGFR3 remains unclear. Here, we determine the effect of statins on FGFR signaling in chondrocytes. DESIGN: Cultured chondrocyte cell lines, mouse embryonic tibia cultures and limb bud micromasses were treated with FGF2 to activate FGFR signaling. The effects of atorvastatin, fluvastatin, lovastatin and pravastatin on FGFR3 protein stability and on FGFR-mediated chondrocyte growth-arrest, loss of extracellular matrix (ECM), induction of premature senescence and hypertrophic differentiation were evaluated. RESULTS: Statins did not alter the level of FGFR3 protein expression nor produce any effect on FGFR-mediated inhibition of chondrocyte proliferation and hypertrophic differentiation in cultured chondrocyte cell lines, mouse tibia cultures or limb bud micromasses. CONCLUSION: We conclude that statins do not inhibit the FGFR signaling in chondrocytes. Therefore the statin-mediated rescue of FGFR3-related chondrodysplasia, described before, is likely not intrinsic to the growth plate cartilage. PMID- 28583900 TI - pH-responsive unimolecular micelle-gold nanoparticles-drug nanohybrid system for cancer theranostics. AB - : The development of an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging was reported. beta-cyclodextrin-{poly(lactide)-poly(2-(dimethylamino) ethyl methacrylate) poly[oligo(2-ethyl-2-oxazoline)methacrylate]}21 [beta-CD-(PLA-PDMAEMA-PEtOxMA)21] unimolecular micelles served as a template for the in situ formation of gold nanoparticles (GNPs) and the subsequent encapsulation of doxorubicin (DOX). The formation of unimolecular micelles, microstructures and the distributions of GNPs and DOX were investigated through the combination of experiments and dissipative particle dynamics (DPD) simulations. beta-CD-(PLA-PDMAEMA-PEtOxMA)21 formed spherical unimolecular micelles in aqueous solution within a certain range of polymer concentrations. GNPs preferentially distributed in the PDMAEMA area. The maximum wavelength (lambdamax) and the size of GNPs increased with increasing concentration of HAuCl4. DOX preferentially distributed in the PDMAEMA mesosphere, but penetrated the inner PLA core with increasing DOX concentration. DOX-loaded micelles with 41-61% entrapment efficiency showed fast release (88% after 102h) under acidic tumor conditions. Both in vitro and in vivo experiments revealed superior anticancer efficacy and effective CT imaging properties for beta-CD-(PLA-PDMAEMA-PEtOxMA)21/Au/DOX. We conclude that the reported unimolecular micelles represent a class of versatile smart nanocarriers for theranostic application. STATEMENT OF SIGNIFICANCE: Developing polymeric nanoplatforms as integrated theranostic vehicles for improving cancer diagnostics and therapy is an emerging field of much importance. This article aims to develop an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging. Specific emphases is on structure properties relationship. There is a sea of literature on polymeric drug nanocarriers, and a couple of polymer-stabilized gold nanoparticles (GNPs) systems for cancer diagnosis are also known. However, to our knowledge, there has been no report on polymeric unimolecular micelles capable of dual loading of GNPs without external reducing agents and anticancer drugs for cancer diagnosis and treatment. To this end, the target of the current work was to develop an in situ formed nanocarrier, which actively dual wrapped CT contrast agent GNPs and hydrophobic anticancer drug doxorubicin (DOX), achieving high CT imaging and antitumor efficacy under in vitro and in vivo acid tumor condition. Meanwhile, by taking advantage of dissipative particle dynamics (DPD) simulation, we further obtained the formation process and mechanism of unimolecular micelles, and detailed distributions and microstructures of GNPs and DOX on unimolecular micelles. Taken together, our results here provide insight and guidance for the design of more effective nanocarriers for cancer theranostic application. PMID- 28583902 TI - pH-responsive self-healing injectable hydrogel based on N-carboxyethyl chitosan for hepatocellular carcinoma therapy. AB - Injectable hydrogels with pH-responsiveness and self-healing ability have great potential for anti-cancer drug delivery. Herein, we developed a series of polysaccharide-based self-healing hydrogels with pH-sensitivity as drug delivery vehicles for hepatocellular carcinoma therapy. The hydrogels were prepared by using N-carboxyethyl chitosan (CEC) synthesized via Michael reaction in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) (PEGDA). Doxorubicin (Dox), as a model of water-soluble small molecule anti-cancer drug was encapsulated into the hydrogel in situ. Self-healing behavior of the hydrogels was investigated at microscopic and macroscopic levels, and the hydrogels showed rapid self-healing performance without any external stimulus owing to the dynamic covalent Schiff-base linkage between amine groups from CEC and benzaldehyde groups from PEGDA. The chemical structures, rheological property, in vitro gel degradation, morphology, gelation time and in vitro Dox release behavior from the hydrogels were characterized. Injectability was verified by in vitro injection and in vivo subcutaneous injection in a rat. pH-responsive behavior was verified by in vitro Dox release from hydrogels in PBS solutions with different pH values. Furthermore, the activity of Dox released from hydrogel matrix was evaluated by employing human hepatocellular liver carcinoma (HepG2). Cytotoxicity test of the hydrogels using L929 cells confirmed their good cytocompatibility. Together, these pH-responsive self-healing injectable hydrogels are excellent candidates as drug delivery vehicles for liver cancer treatment. STATEMENT OF SIGNIFICANCE: pH responsive drug delivery system could release drug efficiently in targeted acid environment and minimalize the amount of drug release in normal physiological environment. pH-sensitive injectable hydrogels as smart anti-cancer drug delivery carriers show great potential application for cancer therapy. The hydrogels with self-healing property could prolong their lifetime during implantation and provide the advantage of minimally invasive surgery and high drug-loading ratio. This work reported the design of a series of pH-responsive self-healing injectable hydrogels based on N-carboxyethyl chitosan synthesized in aqueous solution and dibenzaldehyde-terminated poly(ethylene glycol) via a green approach, and demonstrated their potential as intelligent delivery vehicle of doxorubicin for hepatocellular carcinoma therapy via the pH-responsive nature of dynamic Schiff base. PMID- 28583903 TI - Interleukin-13 conjugated quantum dots for identification of glioma initiating cells and their extracellular vesicles. AB - : Cadmium selenide (CdSe) based quantum dots modified with polyethylene glycol and chemically linked to interleukin-13 (IL13) were prepared with the aim of identifying the high affinity receptor (IL13Ralpha2) which is expressed in glioma stem cells and exosomes secreted by these cancer stem cells. IL13 conjugated quantum dots (IL13QD) were thoroughly characterized for their physicochemical properties including particle size and surface morphology. Furthermore, the specific binding of the IL13QD to glioma cells and to glioma stem cells (GSC) was verified using a competitive binding study. The exosomes were isolated from the GSC conditioned medium and the expression of IL13Ralpha2 in the GSC and exosomes was verified. The binding property of IL13QD to the tumor associated exosomes was initially confirmed by transmission electron microscopy. The force of attraction between the quantum dots and U251 glioma cells and the exosomes was investigated by atomic force microscopy, which indicated a higher force of binding interaction between the IL13QD and IL13Ralpha2 expressing glioma cells and exosomes secreted by glioma stem cells. Flow cytometry of the IL13QD and exosomes from the culture media and cerebrospinal fluid (CSF) of patients with glioma tumors indicated a distinctly populated complex pattern different from that of non-targeted quantum dots and bovine serum albumin (BSA) conjugated quantum dots confirming specific binding potential of the IL13QD to the tumor associated exosomes. The results of this study demonstrate that IL13QD can serve as an ex vivo marker for glioma stem cells and exosomes that can inform diagnosis and prognosis of patients harboring malignant disease. STATEMENT OF SIGNIFICANCE: Functionalized quantum dots are flexible semiconductor nanomaterials which have an immense application in biomedical research. In particular, when they are functionalized with biomolecules like proteins or antibodies, they have the specialized ability to detect the expression of receptors and antigens in cells and tissues. In this study we designed a cytokine (interleukin-13) functionalized quantum dot to detect a cancer associated receptor expressed in cancer stem cells and the extracellular vesicles (exosomes) secreted by the cancer cells themselves. The binding pattern of these cytokine modified quantum dots to the cancer stem cells and exosomes alters the physical properties of the complex in the fixed and suspended form. This altered binding pattern can be monitored by a variety of techniques, including transmission electron microscopy, atomic force microscopy and flow cytometry, and subsequent characterization of this quantum dot binding profile provides useful data that can be utilized as a fingerprint to detect cancer disease progression. This type of functionalized quantum dot fingerprint is especially useful for invasive cancers including brain and other metastatic cancers and may allow for earlier detection of disease progression or recurrence, thus saving the lives of patients suffering from this devastating disease. PMID- 28583904 TI - A Cloud-Based Virtual Reality App for a Novel Telemindfulness Service: Rationale, Design and Feasibility Evaluation. AB - BACKGROUND: Worldwide, there has been a marked increase in stress and anxiety, also among patients with traumatic brain injury (TBI). Access to psychology services is limited, with some estimates suggesting that over 50% of sufferers are not accessing the existing services available to them for reasons such as inconvenience, embarrassment, or stigmatization concerns around mental health. Health service providers have increasingly been turning to drug-free therapies, such as mindfulness programs, as complementary treatments. OBJECTIVE: Virtual reality (VR) as a new delivery method for meditation-based stress and anxiety reduction therapy offers configurable environments and privacy protection. Our objective was to design a serious learning-meditation environment and to test the feasibility of the developed telemindfulness approach based on cloud technologies. METHODS: We developed a cloud-based system, which consisted of a Web interface for the mindfulness instructor and remote clients, who had 3D VR headsets. The mindfulness instructor could communicate over the Web interface with the participants using the headset. Additionally, the Web app enabled group sessions in virtual rooms, 360-degree videos, and real interactions or standalone meditation. The mindfulness program was designed as an 8-week Mindfulness-Based Stress Reduction course specifically for the developed virtual environments. The program was tested with four employees and four patients with TBI. The effects were measured with psychometric tests, the Mindful Attention Awareness Scale (MAAS) and the Satisfaction With Life Scale (SWLS). Patients also carried out the Mini-Mental State Examination (MMSE). An additional objective evaluation has also been carried out by tracking head motion. Additionally, the power spectrum analyses of similar tasks between sessions were tested. RESULTS: The patients achieved a higher level of life satisfaction during the study (SWLS: mean 23.0, SD 1.8 vs mean 18.3, SD 3.9) and a slight increase of the MAAS score (mean 3.4, SD 0.6 vs mean 3.3, SD 0.4). Particular insight into the MAAS items revealed that one patient had a lower MAAS score (mean 2.3). Employees showed high MAAS scores (mean 4.3, SD 0.7) and although their SWLS dropped to mean 26, their SWLS was still high (mean 27.3, SD 2.8). The power spectrum showed that the employees had a considerable reduction in high-frequency movements less than 0.34 Hz, particularly with the 360-degree video. As expected, the patients demonstrated a gradual decrease of high-frequency movements while sitting during the mindfulness practices in the virtual environment. CONCLUSIONS: With such a small sample size, it is too early to make any specific conclusions, but the presented results may accelerate the use of innovative technologies and challenge new ideas in research and development in the field of mindfulness/telemindfulness. PMID- 28583901 TI - Highly efficient delivery of potent anticancer iminoquinone derivative by multilayer hydrogel cubes. AB - : We report a novel delivery platform for a highly potent anticancer drug, 7 (benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ), using pH- and redox-sensitive poly(methacrylic acid) (PMAA) hydrogel cubes of micrometer size as the encapsulating matrix. The hydrogels are obtained upon cross-linking PMAA with cystamine in PMAA/poly(N-vinylpyrrolidone) multilayers assembled within mesoporous sacrificial templates. The BA-TPQ-loaded hydrogels maintain their cubical shape and pH-sensitivity after lyophilization, which is advantageous for long-term storage. Conversely, the particles degrade in vitro in the presence of glutathione (5mM) providing 80% drug release within 24h. Encapsulating BA-TPQ into hydrogels significantly increases its transport via Caco-2 cell monolayers used as a model for oral delivery where the apparent permeability of BA-TPQ hydrogel cubes was~2-fold higher than that of BA-TPQ. BA-TPQ-hydrogel cubes exhibit better anticancer activity against HepG2 (IC50=0.52ug/mL) and Huh7 (IC50=0.29ug/mL) hepatoma cells with a 40% decrease in the IC50 compared to the non-encapsulated drug. Remarkably, non-malignant liver cells have a lower sensitivity to BA-TPQ-hydrogel cubes with 2-fold increased IC50 values compared to those of cancer cells. In addition, encapsulating BA-TPQ in the hydrogels amplifies the potency of the drug via down-regulation of MDM2 oncogenic protein and upregulation of p53 (a tumor suppressor) and p21 (cell proliferation suppressor) expression in HepG2 liver cancer cells. Moreover, enhanced inhibition of MDM2 protein expression by BA-TPQ-hydrogel cubes is independent of p53 status in Huh7 cells. This drug delivery platform of non-spherical shape provides a facile method for encapsulation of hydrophobic drugs and can facilitate the enhanced efficacy of BA-TPQ for liver cancer therapy. STATEMENT OF SIGNIFICANCE: Many potent anticancer drugs are hydrophobic and lack tumor selectivity, which limits their application in cancer therapy. Although cubical hydrogels of poly(methacrylic acid) exhibit excellent biocompatibility and versatility, they have not been investigated for hydrophobic drug delivery due to poor mechanical stability and incompatibility between hydrophobic drugs and a hydrophilic hydrogel network. In this study, we provide a facile method to prepare a multilayer hydrogel-based platform with controlled nanostructure, cubical shape and redox-responsiveness for delivery of highly potent anticancer therapeutics, hydrophobic BA-TPQ. The BA-TPQ-hydrogel cubes have exceptional structural stability upon lyophilization which is advantageous for a long-term storage. The greatly enhanced trans-epithelial permeability and amplified anti-tumor activity of BA-TPQ are achieved by encapsulation in these hydrogel cubes. Furthermore, the anticancer BA-TPQ-hydrogel platform retains the selective activity of BA-TPQ to hepatocellular carcinoma cells. Overall, the produced BA-TPQ-hydrogel cubes demonstrate a high potential for clinical liver cancer therapy. PMID- 28583905 TI - Health App Possession Among Smartphone or Tablet Owners in Hong Kong: Population Based Survey. AB - BACKGROUND: Health apps are increasingly used with important implications for health. Hong Kong is one of the most technologically advanced and connected cities-smartphone ownership and Internet access rates are among the highest in the world. OBJECTIVE: We investigated the prevalence of health app possession and related sociodemographic factors and health behaviors among smartphone or tablet owners in Hong Kong. METHODS: A territory-wide population-based dual (landline and mobile) telephone survey was conducted in 2016. Respondents were asked whether they had health-related apps on their smartphones or tablets and what functions were available on the apps (eg, tracking physical activity and logging health records). Logistic regression was used to calculate the adjusted odds ratio (aOR) and 95% CI of health app possession for different demographic characteristics, socioeconomic position (education, employment, and income), health behaviors (smoking, alcohol, and physical activity) and health (body mass index and chronic diseases). RESULTS: Of the 4129 smartphone or tablet owners (81.28%, 4129/5080 respondents), 995 (24.10%) had a health app. Tracking physical activity (67.0% of 995) and logging health records (43.0% of 995) were the most common functions of the health apps. Overall, younger age, higher education, and household income were associated with having health apps (all P<.001). Compared with physical inactivity, engaging in moderate physical activity >=1 day/week was associated with having health apps (aOR 1.45 [95% CI 1.20-1.75] for 1-3 days/week, and aOR 1.32 [95% CI 1.07-1.62] for >=4 days/week). Having a history of chronic diseases was associated with having health apps (aOR 1.36 [95% CI 1.11 1.68]). CONCLUSIONS: We have shown a lower prevalence of use of information and communication technologies (ICTs) in respondents with lower education and income in the most developed Chinese city. This could be seen as a confirmation of the "Inverse information law," which suggests that those most in need have less use of services and hence receive less benefits from advancements in medicine and health related ICTs. PMID- 28583906 TI - "You Sort of Go Down a Rabbit Hole...You're Just Going to Keep on Searching": A Qualitative Study of Searching Online for Pregnancy-Related Information During Pregnancy. AB - BACKGROUND: The Web is becoming increasingly popular for gaining information on medical or health issues; with women in particular likely to search online for this type of information and support. Despite the increased use of the Web for health-related information, we need to question whether the Web and the ease of seeking health information that it provides leads to more (patient) empowerment. As well as being a time of joy and expectations, pregnancy can be a worrying time for women, especially first time mums-to-be, with unfamiliar experiences and symptoms and concerns for the baby as well as the self. OBJECTIVE: Our aim was to explore how and why pregnant women use the Web to gain information and support during pregnancy and what they consider a reliable source. METHODS: To meet the objectives of the study, a qualitative approach was required to gather information on the experiences of currently pregnant women who use the Web to gain information and support during their pregnancy. Sixteen pregnant women took part in a semistructured interview, either face-to-face or via telephone. The interviews took place from January to March 2016, all participants were from England, and the health professionals are all employed by the National Health Service (NHS). Qualitative analytical procedures were employed using inductive thematic analysis supported by NVivo software (QSR International). RESULTS: Pregnant women found reassurance from the experiences of others. This reassurance resulted in them feeling less alone, as well as enabling them to normalize any symptoms or experiences they were undergoing. The women understood that caution was needed at times while reading the stories of others, acknowledging the potential for extreme cases or worst case scenarios. This is particularly pertinent to the Web, as this wide range of stories may not be as easily accessible if stories where confined to those in a woman's offline social circle. The interviews provide insights into how and why pregnant women search online for information and perhaps more so, support while pregnant. CONCLUSIONS: Searching for health information and advice online during pregnancy is viewed as quick, easy, and accessible. The affordances of the Web have provided women the opportunity to go online as a first port of call. Knowing they were not alone and reading the experiences or symptoms of other pregnant women enabled women to normalize their experience and was ultimately reassuring for pregnant women. PMID- 28583907 TI - Modern Innovative Solutions in Improving Outcomes in Chronic Obstructive Pulmonary Disease (MISSION COPD): A Comparison of Clinical Outcomes Before and After the MISSION Clinic. AB - BACKGROUND: Chronic obstructive pulmonary disorder (COPD) affects over 1 million people in the United Kingdom, and 1 person dies from COPD every 20 minutes. The cost to people with COPD and the National Health Service is huge - more than 24 million working days lost a year and the annual expenditure on COPD is L810 million and L930 million a year. OBJECTIVE: We aim to identify patients with COPD who are at risk of exacerbations and hospital admissions as well as those who have not been formally diagnosed, yet remain at risk. METHODS: This mixed-methods study will use both data and interviews from patients and health care professionals. The project Modern Innovative SolutionS in Improving Outcomes iN COPD (MISSION COPD) will hold multidisciplinary carousel style clinics to rapidly assess the patients' COPD and related comorbidities, and enhance patient knowledge and skills for self-management. RESULTS: This study is ongoing. CONCLUSIONS: This research will capture quantitative and qualitative outcomes to accompany a program of quality improvement through delivery of novel care models. PMID- 28583908 TI - Emory's Winship Earns Comprehensive Status. AB - Emory University's Winship Cancer Institute in Atlanta, GA, has been granted Comprehensive Cancer Center status, the NCI's highest designation. The center was particularly recognized for its population-based research and extensive clinical trials program. PMID- 28583909 TI - Olaparib Keeps Hereditary Breast Tumors in Check. AB - In the phase III OlympiAD study, tumors shrank in about 60% of women with BRCA mutation-associated metastatic breast cancer who received the PARP inhibitor olaparib compared with 29% who received chemotherapy; the median time to disease progression was 7 months compared with 4.2 months, respectively. These findings are the first to demonstrate that a PARP inhibitor can improve progression-free survival in metastatic, hereditary breast cancer. PMID- 28583910 TI - Dramatic Responses Seen with TRK Inhibitor. AB - Presenting data on 50 of 55 patients with advanced TRK fusion-positive tumors, researchers reported that 76% of patients responded to the selective pan-TRK inhibitor larotrectinib, and 12% of patients experienced complete responses; 93% of responders remain on therapy. The targeted therapy was well tolerated, with just 13% of patients requiring a dose modification. None of the patients discontinued treatment due to adverse events. PMID- 28583911 TI - First Tissue-Agnostic Drug Approval Issued. AB - The PD-1 inhibitor pembrolizumab received accelerated approval for adult and pediatric patients with solid tumors that are mismatch repair-deficient or microsatellite instability-high. This is the first time the FDA has greenlighted a drug based not on tumor type, but on a common biomarker. PMID- 28583913 TI - Patient level cost of diabetes self-management education programmes: an international evaluation. AB - OBJECTIVES: The objective of this study was to examine the value of time-driven activity-based costing (TDABC) in understanding the process and costs of delivering diabetes self-management education (DSME) programmes in a multicountry comparative study. SETTING: Outpatient settings in five European countries (Austria, Denmark, Germany, Ireland, UK) and two countries outside Europe, Taiwan and Israel. PARTICIPANTS: Providers of DSME programmes across participating countries (N=16) including healthcare professionals, administrators and patients taking part in DSME programmes. PRIMARY AND SECONDARY MEASURES: Primary measure: time spent by providers in the delivery of DSME and resources consumed in order to compute programme costs. Secondary measures: self-report measures of behavioural self-management and diabetes disease/health-related outcomes. RESULTS: We found significant variation in costs and the processes of how DSME programmes are provided across and within countries. Variations in costs were driven by a combination of price variances, mix of personnel skill and efficiency variances. Higher cost programmes were not found to have achieved better relative outcomes. The findings highlight the value of TDABC in calculating a patient level cost and potential of the methodology to identify process improvements in guiding the optimal allocation of scarce resources in diabetes care, in particular for DSME that is often underfunded. CONCLUSIONS: This study is the first to measure programme costs using estimates of the actual resources used to educate patients about managing their medical condition and is the first study to map such costs to self-reported behavioural and disease outcomes. The results of this study will inform clinicians, managers and policy makers seeking to enhance the delivery of DSME programmes. The findings highlight the benefits of adopting a TDABC approach to understanding the drivers of the cost of DSME programmes in a multicountry study to reveal opportunities to bend the cost curve for DSME. PMID- 28583912 TI - Noise Trauma-Induced Behavioral Gap Detection Deficits Correlate with Reorganization of Excitatory and Inhibitory Local Circuits in the Inferior Colliculus and Are Prevented by Acoustic Enrichment. AB - Hearing loss leads to a host of cellular and synaptic changes in auditory brain areas that are thought to give rise to auditory perception deficits such as temporal processing impairments, hyperacusis, and tinnitus. However, little is known about possible changes in synaptic circuit connectivity that may underlie these hearing deficits. Here, we show that mild hearing loss as a result of brief noise exposure leads to a pronounced reorganization of local excitatory and inhibitory circuits in the mouse inferior colliculus. The exact nature of these reorganizations correlated with the presence or absence of the animals' impairments in detecting brief sound gaps, a commonly used behavioral sign for tinnitus in animal models. Mice with gap detection deficits (GDDs) showed a shift in the balance of synaptic excitation and inhibition that was present in both glutamatergic and GABAergic neurons, whereas mice without GDDs showed stable excitation-inhibition balances. Acoustic enrichment (AE) with moderate intensity, pulsed white noise immediately after noise trauma prevented both circuit reorganization and GDDs, raising the possibility of using AE immediately after cochlear damage to prevent or alleviate the emergence of central auditory processing deficits.SIGNIFICANCE STATEMENT Noise overexposure is a major cause of central auditory processing disorders, including tinnitus, yet the changes in synaptic connectivity underlying these disorders remain poorly understood. Here, we find that brief noise overexposure leads to distinct reorganizations of excitatory and inhibitory synaptic inputs onto glutamatergic and GABAergic neurons and that the nature of these reorganizations correlates with animals' impairments in detecting brief sound gaps, which is often considered a sign of tinnitus. Acoustic enrichment immediately after noise trauma prevents circuit reorganizations and gap detection deficits, highlighting the potential for using sound therapy soon after cochlear damage to prevent the development of central processing deficits. PMID- 28583914 TI - Association between COL11A1 (rs1337185) and ADAMTS5 (rs162509) gene polymorphisms and lumbar spine pathologies in Chinese Han population: an observational study. AB - OBJECTIVES: A previous study identified a significant association between several single nucleotide polymorphisms (SNPs) and lumbar disc degeneration (LDD) in Indians. To validate the association between these SNPs and specific lumbar spine pathologies, we performed a case-control study in Chinese Han population. DESIGN: An observational study. SETTING: University Hospital in Nanning, China. PARTICIPANTS: This study included 428 patients with LDD and 400 normal controls. OUTCOME MEASURES: Patients with LDD were classified into four subgroups, including disc herniation only (subgroup 1), discopathies or/and osteochondrosis associated with disc herniation (subgroup 2), spinal stenosis or/and spondylolisthesis (subgroup 3) and degenerative scoliosis (subgroup 4). This study was conducted by examining two aspects: environmental factors and SNP genotyping. The environmental factors were evaluated with a questionnaire survey including questions about body mass index, smoking habits, the physical demands of their job and exposure to vibrations. Rs1337185, rs5275, rs5277, rs7575934, rs3213718 and rs162509 were genotyped using a PCR-based invader assay. RESULTS: The physical workload was significantly higher in patients with lumbar spine pathologies than in the normal controls (p=0.035). The genotype and allele frequencies of rs1337185 and rs162509 were significantly different between the patients with LDD and the normal controls. In rs1337185, a significant association was found between the C allele (risk allele) and the presence of disc herniation (OR=1.80; 95% CI 1.21 to 2.68; p=0.003, adjusted p=0.012) and the presence of spinal stenosis and spondylolisthesis (OR=1.92; 95% CI 1.29 to 2.89; p=0.001, adjusted p=0.004). In rs162509, the G allele represented 1.58-fold increased risk to suffer from disc herniation (OR=1.58; 95% CI 1.20 to 2.09; p=0.001, adjusted p=0.004). CONCLUSION: The SNPs rs1337185 in COL11A1 and rs162509 in ADAMTS5 are associated with susceptibility to LDD. The C allele of rs1337185 is risky for patients who are affected by lumbar pathologies such as disc herniation, stenosis and spondylolisthesis. The G allele of rs16250 represents a risk factor for the development of disc herniation. PMID- 28583916 TI - Balancing Anticoagulation Decisions in Patients on Dialysis with Atrial Fibrillation. PMID- 28583917 TI - MDU ceases to cover private spinal surgery. PMID- 28583915 TI - ELABELA and an ELABELA Fragment Protect against AKI. AB - Renal ischemia-reperfusion (I/R) injury is the most common cause of AKI, which associates with high mortality and has no effective therapy. ELABELA (ELA) is a newly identified 32-residue hormone peptide highly expressed in adult kidney. To investigate whether ELA has protective effects on renal I/R injury, we administered the mature peptide (ELA32) or the 11-residue furin-cleaved fragment (ELA11) to hypoxia-reperfusion (H/R)-injured or adriamycin-treated renal tubular cells in vitro ELA32 and ELA11 significantly inhibited the elevation of the DNA damage response, apoptosis, and inflammation in H/R-injured renal tubular cells and suppressed adriamycin-induced DNA damage response. Similarly, overexpression of ELA32 or ELA11 significantly inhibited H/R-induced cell death, DNA damage response, and inflammation. Notably, treatment of mice with ELA32 or ELA11 but not an ELA11 mutant with a cysteine to alanine substitution at the N terminus (AE11C) inhibited I/R injury-induced renal fibrosis, inflammation, apoptosis, and the DNA damage response and markedly reduced the renal tubular lesions and renal dysfunction. Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI. PMID- 28583919 TI - A quarter of Scottish general practices report vacancies. PMID- 28583920 TI - Idiopathic hypogonadotropic hypogonadism reversal after testosterone replacement in a 34-year-old male. AB - A 34-year-old male presented to the endocrinology clinic with the complaint of the absence of facial, axillary and pubic hairs. Further history revealed absent ejaculations and decreased early morning erections. The patient had no history of headaches, visual problems or anosmia. On physical examination, there were sparse facial, axillary and pubic hairs, bilateral gynaecomastia, stretch penile length of 5 cm and bilateral testicular volume of 10 mL. Laboratory investigations showed low luteinising hormone, follicular stimulating hormone and testosterone with normal prolactin and thyroid profile. MRI of the pituitary gland showed no evidence of pituitary microadenoma or macroadenoma. The patient was started on testosterone injections. After 9 months of testosterone replacement, the patient's testicular size increased to 20 mL bilaterally and his penile length increased to the mean adult size for his age with normal testosterone and luteinising hormone. He was, thus, advised to discontinue testosterone therapy. PMID- 28583918 TI - GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy. AB - GPR40 and GPR120 are fatty acid sensors that play important roles in glucose and energy homeostasis. GPR40 potentiates glucose-dependent insulin secretion and demonstrated in clinical studies robust glucose lowering in type 2 diabetes. GPR120 improves insulin sensitivity in rodents, albeit its mechanism of action is not fully understood. Here, we postulated that the antidiabetic efficacy of GPR40 could be enhanced by coactivating GPR120. A combination of GPR40 and GPR120 agonists in db/db mice, as well as a single molecule with dual agonist activities, achieved superior glycemic control compared with either monotherapy. Compared with a GPR40 selective agonist, the dual agonist improved insulin sensitivity in ob/ob mice measured by hyperinsulinemic-euglycemic clamp, preserved islet morphology, and increased expression of several key lipolytic genes in adipose tissue of Zucker diabetic fatty rats. Novel insights into the mechanism of action for GPR120 were obtained. Selective GPR120 activation suppressed lipolysis in primary white adipocytes, although this effect was attenuated in adipocytes from obese rats and obese rhesus, and sensitized the antilipolytic effect of insulin in rat and rhesus primary adipocytes. In conclusion, GPR120 agonism enhances insulin action in adipose tissue and yields a synergistic efficacy when combined with GPR40 agonism. PMID- 28583921 TI - Postmenopausal pregnancy? Evaluation of elevated hCG in a 59-year-old woman. AB - Slightly elevated serum human chorionic gonadotropin (hCG) can be a normal finding in postmenopausal women. We report a case of a 59-year-old woman with a history of abnormal uterine bleeding who presented with a concern for pregnancy after developing nausea and vomiting a few weeks after unprotected intercourse. Although pregnancy was extremely unlikely, hCG was obtained in order to reassure the patient since she reported that her mother conceived at the age of 60. Serum hCG was positive, prompting concern for malignancy versus pregnancy. Stable serum hCG levels, elevated follicle-stimulating hormone and negative transvaginal ultrasound ruled out both malignancy and pregnancy. Positive serum pregnancy test and hCG elevation was attributed to normal postmenopausal state. PMID- 28583922 TI - Modafinil in schizophrenia: is the risk worth taking? AB - Schizophrenia is a severe mental disorder characterised by positive and negative symptoms. Negative symptoms are difficult to treat and there is no specific treatment. In small trials, modafinil has been studied in association with antipsychotic treatment. We present three cases of its use; two have developed positive symptoms and one developed renal impairment. Further studies are needed to assess its usefulness in schizophrenia and safety in this group of patients. PMID- 28583923 TI - Triple synchronous primary malignancies: a rare occurrence. AB - Triple synchronous primary malignant neoplasms are rare. The exact aetiology is unknown; however, risk factors include older age, family history, genetic aberrations, prolonged exposure to carcinogens and smoking. We describe a previously healthy 48-year-old woman who presented with abdominal pain and a palpable abdominal mass. Imaging revealed a complex cystic, solid pelvic mass and another mass in the right upper quadrant. She received an extensive abdominal surgery including exploratory laparotomy, pelvic mass resection, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, omentectomy and right adrenalectomy. During surgery, a mass in the distal sigmoid colon was noted and subsequent sigmoidectomy was performed. The surgical specimen revealed three different primary tumours with three different histologies, a granulosa cell tumour of the ovary, adrenocortical carcinoma and adenocarcinoma of the colon. She received six cycles of adjuvant chemotherapy for colon cancer with 5-fluorourocil, leucovorin and oxaliplatin and is currently living with no recurrence. PMID- 28583924 TI - Congenital hypofibrinogenaemia: a presymptomatic detection of an extremely rare bleeding disorder in preterm twins. AB - Twenty-eight-week-old preterm monochorionic-diamniotic twins were admitted to the neonatal intensive care unit secondary to low birth weight and mild respiratory distress syndrome. A low fibrinogen level of less than 0.5 g/L was detected following an abnormal full blood count. They required fibrinogen transfusions until 32 weeks corrected gestation to maintain adequate fibrinogen levels. Parental screening revealed that their mother had a previously undiagnosed hypofibrinogenaemia. Of note, her only symptom was menorrhagia. This may have implications on further pregnancies as it can be associated with spontaneous miscarriage and post-partum haemorrhage. Congenital hypofibrinogenaemia is a rare disorder and there are no reported cases from Ireland. A higher degree of suspicion for screening is required to detect new cases and demonstrates the benefits of checking parental levels in such situations. PMID- 28583925 TI - Bilateral isolated submandibular gland mumps. AB - Isolated submandibular swellings pose a diagnostic challenge to the practising otolaryngologist. We report an unusual case of mumps isolated to bilateral submandibular glands. We discuss the case and the literature surrounding this condition and remind clinicians that mumps should be considered as a diagnosis in the presence of submandibular gland swelling in the absence of typical parotid swelling associated with mumps. Early consideration of this differential diagnosis, serological testing and a multidisciplinary approach may help to clinch the diagnosis earlier and prevent spread of the virus. PMID- 28583926 TI - Postmating sexual selection and the enigmatic jawed genitalia of Callosobruchus subinnotatus. AB - Insect genitalia exhibit rapid divergent evolution. Truly extraordinary structures have evolved in some groups, presumably as a result of postmating sexual selection. To increase our understanding of this phenomenon, we studied the function of one such structure. The male genitalia of Callosobruchus subinnotatus (Coleoptera: Bruchinae) contain a pair of jaw-like structures with unknown function. Here, we used phenotypic engineering to ablate the teeth on these jaws. We then experimentally assessed the effects of ablation of the genital jaws on mating duration, ejaculate weight, male fertilization success and female fecundity, using a double-mating experimental design. We predicted that copulatory wounding in females should be positively related to male fertilization success; however, we found no significant correlation between genital tract scarring in females and male fertilization success. Male fertilization success was, however, positively related to the amount of ejaculate transferred by males and negatively related to female ejaculate dumping. Ablation of male genital jaws did not affect male relative fertilization success but resulted in a reduction in female egg production. Our results suggest that postmating sexual selection in males indeed favors these genital jaws, not primarily through an elevated relative success in sperm competition but by increasing female egg production. PMID- 28583927 TI - The effects of moderate intensity training in a hypoxic environment on transcriptional responses in Thoroughbred horses. AB - This study investigated the effects of six weeks of normobaric hypoxic training on transcriptional expression of the genes associated with mitochondrial and glycolytic activities in Thoroughbred horses. Eight horses were divided into two groups of four. They completed an identical incremental, moderate intensity training program, except that one group trained in a hypoxic chamber with 15% oxygen for 30 min on alternate days except Sundays (HT), while the other group trained in normal air (NC). Prior to and post training, heart rate and blood lactate were measured during an incremental treadmill test. Muscle biopsy samples were taken prior to and 24 h post the training period for qPCR analysis of mRNA changes in VEGF, PPARgamma, HIF-1alpha, PGC-1alpha, COX4, AK3, LDH, PFK, PKm and SOD-2. No significant differences between the HT and NC were detected by independent-samples t-test with Bonferroni correction for multiple comparisons (P>0.05) in relative changes of mRNA abundance. There were no significant differences between groups for heart rate and blood lactate during the treadmill test. The outcomes indicated that this hypoxia training program did not cause a significant variation in basal level expression of the selected mRNAs in Thoroughbreds as compared with normoxic training. PMID- 28583929 TI - Spotlight on the June 6 issue. PMID- 28583931 TI - Editors' Note. PMID- 28583930 TI - Correlating microscopic findings with B-mode ultrasound in cervical artery dissection. PMID- 28583932 TI - Letter re: Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations. PMID- 28583933 TI - Author response: Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations. PMID- 28583934 TI - Letter re: Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis. PMID- 28583935 TI - Author response: Teaching NeuroImages: Idiopathic hypertrophic pachymeningitis. PMID- 28583936 TI - Teaching NeuroImages: Giant neurocysticercosis with unusual imaging manifestations. PMID- 28583937 TI - Clinical Reasoning: A 10-year-old boy with bilateral vision loss. PMID- 28583938 TI - Clinical Reasoning: A 16-year-old girl with subacute weakness and sensory loss. PMID- 28583939 TI - Pearls & Oy-sters: Symptomatic cerebral vasospasm on conventional angiography following temporal lobe epilepsy surgery. PMID- 28583940 TI - Teaching NeuroImages: Fahr syndrome caused by hypoparathyroidism. PMID- 28583941 TI - Teaching NeuroImages: Giant cystic echinococcosis with unusual imaging manifestations. PMID- 28583942 TI - MANAGEMENT OF ENDOCRINE DISEASE: Risk of overtreatment in patients with adrenal insufficiency: current and emerging aspects. AB - The effects of long-term replacement therapy of adrenal insufficiency (AI) are still a matter of controversy. In fact, the established glucocorticoid replacement regimens do not completely reproduce the endogenous hormonal production and the monitoring of AI treatment may be a challenge for the lack of reliable clinical and biochemical markers. Consequently, several AI patients are frequently exposed to relative glucocorticoid excess potentially leading to develop chronic complications, such as diabetes mellitus, dyslipidemia, hypertension and fragility fractures with consequent impaired QoL and increased mortality risk. This review deals with the pathophysiological and clinical aspects concerning the over-replacement therapy of primary and secondary AI. PMID- 28583943 TI - Impact of travel time and rurality on presentation and outcomes of symptomatic colorectal cancer: a cross-sectional cohort study in primary care. AB - BACKGROUND: Several studies have reported a survival disadvantage for rural dwellers who develop colorectal cancer, but the underlying mechanisms remain obscure. Delayed presentation to GPs may be a contributory factor, but evidence is lacking. AIM: To examine the association between rurality and travel time on diagnosis and survival of colorectal cancer in a cohort from northeast Scotland. DESIGN AND SETTING: The authors used a database linking GP records to routine data for patients diagnosed between 1997 and 1998, and followed up to 2011. METHOD: Primary outcomes were alarm symptoms, emergency admissions, stage, and survival. Travel time in minutes from patients to GP was estimated. Logistic and Cox regression were used to model outcomes. Interaction terms were used to determine if travelling time impacted differently on urban versus rural patients. RESULTS: Rural patients and patients travelling farther to the GP had better 3 year survival. When the travel outcome associations were explored using interaction terms, the associations differed between rural and urban areas. Longer travel in urban areas significantly reduced the odds of emergency admissions (odds ratio [OR] 0.62, P<0.05), and increased survival (hazard ratio 0.75, P<0.05). Longer travel also increased the odds of presenting with alarm symptoms in urban areas; this was nearly significant (OR 1.34, P = 0.06). Presence of alarm symptoms reduced the likelihood of emergency admissions (OR 0.36, P<0.01). CONCLUSION: Living in a rural area, and travelling farther to a GP in urban areas, may reduce the likelihood of emergency admissions and poor survival. This may be related to how patients present with alarm symptoms. PMID- 28583944 TI - Variation in referral and access to new psychological therapy services by age: an empirical quantitative study. AB - BACKGROUND: Older people with common mental health problems (CMHPs) are known to have reduced rates of referral to psychological therapy. AIM: To assess referral rates to the Improving Access to Psychological Therapies (IAPT) services, contact with a therapist, and clinical outcome by age. DESIGN AND SETTING: Empirical research study using patient episodes of care from South West of England IAPT services. METHOD: By analysing 82 513 episodes of care (2010-2011), referral rates and clinical improvement were compared with both total population and estimated prevalence in each age group using IAPT data. Probable recovery of those completing treatment was calculated for each group. RESULTS: Estimated prevalence of CMHPs peaks in 45-49-year-olds (20.59% of population). The proportions of patients identified with CMHPs being referred peaks at 20-24 years (22.95%) and reduces with increase in age thereafter to 6.00% for 70-74-year olds. Once referred, the proportion of those attending first treatment increases with age between 20 years (57.34%) and 64 years (76.97%). In addition, the percentage of those having a clinical improvement gradually increases from the age of 18 years (12.94%) to 69 years (20.74%). CONCLUSION: Younger adults are more readily referred to IAPT services. However, as a proportion of those referred, probabilities of attending once, attending more than once, and clinical improvement increase with age. It is uncertain whether optimum levels of referral have been reached for young adults. It is important to establish whether changes to service configuration, treatment options, and GP behaviour can increase referrals for middle-aged and older adults. PMID- 28583946 TI - Routine blood tests are a basic screening tool for serious pathology. PMID- 28583945 TI - Patients' evaluations of patient safety in English general practices: a cross sectional study. AB - BACKGROUND: Description of safety problems and harm in general practices has previously relied on information from health professionals, with scarce attention paid to experiences of patients. AIM: To examine patient-reported experiences and outcomes of patient safety in primary care. DESIGN AND SETTING: Cross-sectional study in 45 general practices across five regions in the north, centre, and south of England. METHOD: A version of the Patient Reported Experiences and Outcomes of Safety in Primary Care (PREOS-PC) questionnaire was sent to a random sample of 6736 patients. Main outcome measures included 'practice activation' (what a practice does to create a safe environment); 'patient activation' (how proactive are patients in ensuring safe healthcare delivery); 'experiences of safety events' (safety errors); 'outcomes of safety' (harm); and 'overall perception of safety' (how safe patients rate their practice). RESULTS: Questionnaires were returned by 1244 patients (18.4%). Scores were high for 'practice activation' (mean [standard error] = 80.4 out of 100 [2.0]) and low for 'patient activation' (26.3 out of 100 [2.6]). Of the patients, 45% reported experiencing at least one safety problem in the previous 12 months, mostly related to appointments (33%), diagnosis (17%), patient provider communication (15%), and coordination between providers (14%). Twenty-three per cent of the responders reported some degree of harm in the previous 12 months. The overall assessment of level of safety of practices was generally high (86.0 out of 100 [16.8]). CONCLUSION: Priority areas for patient safety improvement in general practices in England include appointments, diagnosis, communication, coordination, and patient activation. PMID- 28583947 TI - Cyclic AMP-Independent Control of Twitching Motility in Pseudomonas aeruginosa. AB - FimV is a Pseudomonas aeruginosa inner membrane hub protein that modulates levels of the second messenger, cyclic AMP (cAMP), through the activation of adenylate cyclase CyaB. Although type IVa pilus (T4aP)-dependent twitching motility is modulated by cAMP levels, mutants lacking FimV are twitching impaired, even when exogenous cAMP is provided. Here we further define FimV's cAMP-dependent and independent regulation of twitching. We confirmed that the response regulator of the T4aP-associated Chp chemotaxis system, PilG, requires both FimV and the CyaB regulator, FimL, to activate CyaB. However, in cAMP-replete backgrounds-lacking the cAMP phosphodiesterase CpdA or the CheY-like protein PilH or expressing constitutively active CyaB-pilG and fimV mutants failed to twitch. Both cytoplasmic and periplasmic domains of FimV were important for its cAMP-dependent and -independent roles, while its septal peptidoglycan-targeting LysM motif was required only for twitching motility. Polar localization of the sensor kinase PilS, a key regulator of transcription of the major pilin, was FimV dependent. However, unlike its homologues in other species that localize flagellar system components, FimV was not required for swimming motility. These data provide further evidence to support FimV's role as a key hub protein that coordinates the polar localization and function of multiple structural and regulatory proteins involved in P. aeruginosa twitching motility.IMPORTANCEPseudomonas aeruginosa is a serious opportunistic pathogen. Type IVa pili (T4aP) are important for its virulence, because they mediate dissemination and invasion via twitching motility and are involved in surface sensing, which modulates pathogenicity via changes in cAMP levels. Here we show that the hub protein FimV and the response regulator of the Chp system, PilG, regulate twitching independently of their roles in the modulation of cAMP synthesis. These functions do not require the putative scaffold protein FimL, proposed to link PilG with FimV. PilG may regulate asymmetric functioning of the T4aP system to allow for directional movement, while FimV appears to localize both structural and regulatory elements-including the PilSR two-component system-to cell poles for optimal function. PMID- 28583948 TI - Lysinibacillus fusiformis M5 Induces Increased Complexity in Bacillus subtilis 168 Colony Biofilms via Hypoxanthine. AB - In recent years, biofilms have become a central subject of research in the fields of microbiology, medicine, agriculture, and systems biology, among others. The sociomicrobiology of multispecies biofilms, however, is still poorly understood. Here, we report a screening system that allowed us to identify soil bacteria which induce architectural changes in biofilm colonies when cocultured with Bacillus subtilis We identified the soil bacterium Lysinibacillus fusiformis M5 as an inducer of wrinkle formation in B. subtilis colonies mediated by a diffusible signaling molecule. This compound was isolated by bioassay-guided chromatographic fractionation. The elicitor was identified to be the purine hypoxanthine using mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy. We show that the induction of wrinkle formation by hypoxanthine is not dependent on signal recognition by the histidine kinases KinA, KinB, KinC, and KinD, which are generally involved in phosphorylation of the master regulator Spo0A. Likewise, we show that hypoxanthine signaling does not induce the expression of biofilm matrix-related operons epsABCDEFGHIJKLMNO and tasA-sipW tapA Finally, we demonstrate that the purine permease PbuO, but not PbuG, is necessary for hypoxanthine to induce an increase in wrinkle formation of B. subtilis biofilm colonies. Our results suggest that hypoxanthine-stimulated wrinkle development is not due to a direct induction of biofilm-related gene expression but rather is caused by the excess of hypoxanthine within B. subtilis cells, which may lead to cell stress and death.IMPORTANCE Biofilms are a bacterial lifestyle with high relevance regarding diverse human activities. Biofilms can be beneficial, for instance, in crop protection. In nature, biofilms are commonly found as multispecies communities displaying complex social behaviors and characteristics. The study of interspecies interactions will thus lead to a better understanding and use of biofilms as they occur outside laboratory conditions. Here, we present a screening method suitable for the identification of multispecies interactions and showcase L. fusiformis as a soil bacterium that is able to live alongside B. subtilis and modify the architecture of its biofilms. PMID- 28583950 TI - The tip of the iceberg in the sub-Saharan Africa: unraveling the real world in the diagnosis and treatment of heart failure. PMID- 28583951 TI - A nationwide contemporary epidemiological portrait of valvular heart diseases. PMID- 28583949 TI - BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi. AB - The ferric uptake regulator (Fur) family of DNA-binding proteins represses and/or activates gene transcription via divalent metal ion-dependent signal sensing. The Borrelia burgdorferi Fur homologue, also known as Borrelia oxidative stress regulator (BosR), promotes spirochetal adaptation to the mammalian host by directly repressing the lipoproteins required for tick colonization and indirectly activating those required for establishing infection in the mammal. Here, we examined whether the DNA-binding activity of BosR was regulated by any of the four most prevalent transition metal ions in B. burgdorferi, Mn, Fe, Cu, and Zn. Our data indicated that in addition to a structural site occupied by Zn(II), BosR had two regulatory sites that could be occupied by Zn(II), Fe(II), or Cu(II) but not by Mn(II). While Fe(II) had no effect, Cu(II) and Zn(II) had a dose-dependent inhibitory effect on the BosR DNA-binding activity. Competition experiments indicated that Cu(II) had a higher affinity for BosR than Zn(II) or Fe(II). A BosR deficiency in B. burgdorferi resulted in a significant increase in the Cu level but no significant change in the levels of Mn, Fe, or Zn. These data suggest that Cu regulates BosR activity, and BosR in turn regulates Cu homeostasis in B. burgdorferi While this regulatory paradigm is characteristic of the Fur family, BosR is the first one shown to be responsive to Cu(II), which may be an adaptation to the potentially high level of Cu present in the Lyme disease spirochete.IMPORTANCE Transition metal ions serve an essential role in the metabolism of all living organisms. Members of the ferric uptake regulator (Fur) family play critical roles in regulating the cellular homeostasis of transition metals in diverse bacteria, and their DNA-binding activity is often regulated by coordination of the cognate divalent metal ions. To date, regulators with metal ion specificity to Fe(II), Mn(II), Zn(II), and Ni(II) have all been described. In this study, we demonstrate that BosR, the sole Fur homologue in Borrelia burgdorferi, is responsive to Cu(II) and regulates Cu homeostasis in this bacterium, which may be an adaption to potentially Cu-rich milieu in the Lyme disease spirochete. This study has expanded the repertoire of the Fur family's metal ion specificity. PMID- 28583952 TI - Pursuing Health Equity. PMID- 28583953 TI - Health Equity. AB - Health disparities-differences in health status, treatment, or outcomes-exist between racial and ethnic minorities; people with low socioeconomic status; lesbian, gay, bisexual, and transgender people; women; people with disabilities; and others, compared with majority populations. Improved insurance coverage and targeted efforts by health care systems have narrowed some disparities, but many gaps remain. There is a growing recognition that interventions outside the health care sector that address social determinants of health such as housing, employment, and education are also needed. The effects of interventions in these areas are of interest to health services researchers. Innovative cross-sector approaches that improve health through medical and nonmedical interventions hold promise for further reducing health disparities. PMID- 28583954 TI - The Health Effects Of Legalizing Same-Sex Marriage. AB - An emerging body of literature suggests a positive association between legal same sex marriage and improved health outcomes. PMID- 28583955 TI - Progress In Achieving Health Equity Requires Attention To Root Causes. AB - Life expectancy and disease rates in the United States differ starkly among Americans depending on their demographic characteristics and where they live. Although health care systems are taking important steps to reduce inequities, meaningful progress requires interventions outside the clinic, in sectors such as employment, housing, transportation, and public safety. Inequities exist in each of these sectors, and barriers to educational attainment, higher-income jobs, and social mobility limit the opportunity of disadvantaged people to improve their circumstances. Financial institutions and other stakeholders are investing in cross-sector collaborations to remove these barriers and thereby strengthen local economies and population health. Meanwhile, recent trends suggest the need to widen the lens on health equity, to include not only the low-income residents of inner-city neighborhoods but also people in economically marginalized rural communities. Widening income inequality and stagnant wages, and their alarming health consequences, underscore the need for policies to help low-income and middle-class families and improve educational opportunities for their children. PMID- 28583956 TI - Emerging Trends Could Exacerbate Health Inequities In The United States. AB - Health inequities among people of different races and ethnicities, geographical locations, and social classes are not a new phenomenon, although the size of the inequities has changed since researchers first began documenting them. While interventions to improve the health of targeted disadvantaged groups may help combat disparities, broader trends that disproportionately benefit privileged groups or harm vulnerable populations can eclipse the progress made through isolated interventions. These trends threaten equity in health and health care in the United States either through direct effects on health or through impacts on the distribution of resources, risks, and power. We highlight trends in four domains: health care technologies, health reform policies, widening socioeconomic inequality, and environmental hazards. We suggest ways of countering the effects of these trends to promote health equity, focusing on strategies that promise co benefits across multiple sectors. PMID- 28583957 TI - Mapping Neighborhood Health Geomarkers To Clinical Care Decisions To Promote Equity In Child Health. AB - Health disparities, which can be understood as disadvantages in health associated with one's social, racial, economic, or physical environment, originate in childhood and persist across an individual's life course. One's neighborhood may drive or influence these disparities. Information on neighborhoods that can characterize their risks-what we call place-based risks-is rarely used in patient care. Community-level data, however, could inform and personalize interventions such as arranging for mold removal from the home of a person with asthma from the moment that person's address is recorded at the site of care. Efficient risk identification could lead to the tailoring of recommendations and targeting of resources, to improve care experiences and clinical outcomes while reducing disparities and costs. In this article we highlight how data on place-based social determinants of health from national and local sources could be incorporated more directly into patient-centered care, adding precision to risk assessment and mitigation. We also discuss how this information could stimulate cross-sector interventions that promote health equity: the attainment of the highest level of health for neighborhoods, patient panels, and individuals. Finally, we draw attention to research questions that focus on the role of geographical place at the bedside. PMID- 28583958 TI - Transitions Clinic Network: Challenges And Lessons In Primary Care For People Released From Prison. AB - Low-income and minority communities are disproportionately affected by incarceration, which exacerbates health disparities. Through enhanced primary care, the Transitions Clinic Network (TCN) seeks to improve the health of people with chronic conditions who return to their communities from prison. Using TCN data, we assessed the impact of early engagement in primary care and referral from correctional systems to TCN on the use of acute care (emergency department visits and hospitalizations) and recidivism. Of 751 patients, 29.8 percent were referred by correctional partners, and 52.7 percent were engaged in TCN care within one month after release. In the twelve months after release, patients referred by correctional partners had fewer acute care visits, compared to those referred by community-based partners, while early engagement was associated with more acute care visits. Neither referral by correctional partners nor early engagement was significantly associated with recidivism. Our findings suggest that health equity for this vulnerable population could be achieved through improved coordination between correctional and community health care systems. PMID- 28583959 TI - HUD Housing Assistance Associated With Lower Uninsurance Rates And Unmet Medical Need. AB - To investigate whether receiving US Department of Housing and Urban Development (HUD) housing assistance is associated with improved access to health care, we analyzed data on nondisabled adults ages 18-64 who responded to the 2004-12 National Health Interview Survey that were linked with administrative data from HUD for the period 2002-14. To account for potential selection bias, we compared access to care between respondents who were receiving HUD housing assistance at the time of the survey interview (current recipients) and those who received HUD assistance within twenty-four months of completing the survey interview (future recipients). Receiving assistance was associated with lower uninsurance rates: 31.8 percent of current recipients were uninsured, compared to 37.2 percent of future recipients. Rates of unmet need for health care due to cost were similarly lower for current recipients than for future recipients. No effect of receiving assistance was observed on having a usual source of care. These findings provide evidence that supports the effectiveness of housing assistance in improving health care access. PMID- 28583960 TI - Simulations Test Impact Of Education, Employment, And Income Improvements On Minority Patients With Mental Illness. AB - Social determinants of health, such as poverty and minority background, severely disadvantage many people with mental disorders. A variety of innovative federal, state, and local programs have combined social services with mental health interventions. To explore the potential effects of such supports for addressing poverty and disadvantage on mental health outcomes, we simulated improvements in three social determinants-education, employment, and income. We used two large data sets: one from the National Institute of Mental Health that contained information about people with common mental disorders such as anxiety and depression, and another from the Social Security Administration that contained information about people who were disabled due to severe mental disorders such as schizophrenia and bipolar disorder. Our simulations showed that increasing employment was significantly correlated with improvements in mental health outcomes, while increasing education and income produced weak or nonsignificant correlations. In general, minority groups as well as the majority group of non Latino whites improved in the desired outcomes. We recommend that health policy leaders, state and federal agencies, and insurers provide evidence-based employment services as a standard treatment for people with mental disorders. PMID- 28583961 TI - The United States Leads Other Nations In Differences By Income In Perceptions Of Health And Health Care. AB - We examined income gaps in the period 2011-13 in self-assessments of personal health and health care across thirty-two middle- and high-income countries. While high-income respondents were generally more positive about their health and health care in most countries, the gap between them and low-income respondents was much bigger in some than in others. The United States has among the largest income-related differences in each of the measures we studied, which assessed both respondents' past experiences and their confidence about accessing needed health care in the future. Relatively low levels of moral discomfort over income based health care disparities despite broad awareness of unmet need indicate more public tolerance for health care inequalities in the United States than elsewhere. Nonetheless, over half of Americans felt that income-based health care inequalities are unfair, and these respondents were significantly more likely than their compatriots to support major health system reform-differences that reflect the country's political divisions. Given the many provisions in the Affordable Care Act that seek to reduce disparities, any replacement would also require attention to disparities or risk taking a step backward in an area where the United States is in sore need of improvement. PMID- 28583962 TI - Challenges To Reducing Discrimination And Health Inequity Through Existing Civil Rights Laws. AB - More than fifty years after the passage of the Civil Rights Act of 1964, health care for racial and ethnic minorities remains in many ways separate and unequal in the United States. Moreover, efforts to improve minority health care face challenges that differ from those confronted during de jure segregation. We review these challenges and examine whether stronger enforcement of existing civil rights legislation could help overcome them. We conclude that stronger enforcement of existing laws-for example, through executive orders to strengthen enforcement of the laws and congressional action to allow private individuals to bring lawsuits against providers who might have engaged in discrimination-would improve minority health care, but this approach is limited in what it can achieve. Complementary approaches outside the legal arena, such as quality improvement efforts and direct transfers of money to minority-serving providers those seeing a disproportionate number of minority patients relative to their share of the population-might prove to be more effective. PMID- 28583963 TI - Identifying Policy Levers And Opportunities For Action Across States To Achieve Health Equity. AB - In the United States, steps to advance health equity often take place at the state and local levels rather than the national level. Using publicly available data sources, we developed a scorecard for all fifty states and the District of Columbia that measures indicators of the use of five evidence-based policies to address domains related to health equity. The indicators are the cigarette excise tax rate, a state's Medicaid expansion status and the size of its coverage gap, percentage of four-year olds enrolled in state-funded pre-kindergarten, minimum wage level, and the presence of state-funded housing subsidy programs and homelessness prevention and rapid rehousing programs. We found that states varied significantly in their implementation of the selected policies and concluded that a variety of approaches to encourage policy changes at the state level will be needed to create healthier and more equitable communities. We describe promising, feasible state-level approaches for states to "do something, do more, do better" when they take action on the five selected policies that can promote health equity. PMID- 28583964 TI - Racial Disparities In Surgical Mortality: The Gap Appears To Have Narrowed. AB - Despite substantial attention to the greater likelihood of poor clinical outcomes among black versus white surgical patients, little is known about whether racial disparities in postoperative mortality in the United States have narrowed over time. Using nationwide Medicare inpatient claims data for the period 2005-14, we examined trends in thirty-day postoperative mortality rates in black and white patients for five high-risk and three low-risk procedures. Overall, national mortality trends improved for both black and white patients, by 0.10 percent per year and 0.07 percent per year, respectively-which significantly narrowed the black-white difference. The reduction occurred primarily within hospitals, rather than between hospitals. Certain subsets of hospitals, such as small hospitals in the Midwest or West that were not minority-serving (that is, not among the top 10 percent of hospitals by volume of black patients served), improved more than others. In spite of concerns that quality improvement efforts may widen disparities, these findings suggest that national racial disparities in surgical mortality are narrowing. PMID- 28583965 TI - For Selected Services, Blacks And Hispanics More Likely To Receive Low-Value Care Than Whites. AB - US minority populations receive fewer effective health services than whites. Using Medicare administrative data for 2006-11, we found no consistent, corresponding protection against the receipt of ineffective health services. Compared with whites, blacks and Hispanics were often more likely to receive the low-value services studied. PMID- 28583966 TI - Impact Of Ambulance Diversion: Black Patients With Acute Myocardial Infarction Had Higher Mortality Than Whites. AB - This study investigated whether emergency department crowding affects blacks more than their white counterparts and the mechanisms behind which this might occur. Using a nonpublic database of patients in California with acute myocardial infarction between 2001 and 2011 and hospital-level data on ambulance diversion, we found that hospitals treating a high share of black patients with acute myocardial infarction were more likely to experience diversion and that black patients fared worse compared to white patients experiencing the same level of emergency department crowding as measured by ambulance diversion. The ninety-day and one-year mortality rates among blacks exposed to high diversion levels were 2.88 and 3.09 percentage points higher, respectively, relative to whites, representing a relative increase of 19 percent and 14 percent for ninety-day and one-year death, respectively. Interventions that decrease the need for diversion in hospitals serving a high volume of blacks could reduce these disparities. PMID- 28583967 TI - New Kidney Allocation System Associated With Increased Rates Of Transplants Among Black And Hispanic Patients. AB - Before the 2014 implementation of a new kidney allocation system by the United Network for Organ Sharing, white patients were more likely than black or Hispanic patients to receive a kidney transplant. To determine the effect of the new allocation system on these disparities, we examined data for 179,071 transplant waiting list events in the period June 2013-September 2016, and we calculated monthly transplantation rates (34,133 patients actually received transplants). Implementation of the new system was associated with a narrowing of the disparities in the average monthly transplantation rates by 0.29 percentage point for blacks compared to whites and by 0.24 percentage point for Hispanics compared to whites, which resulted in both disparities becoming nonsignificant after implementation of the new system. PMID- 28583968 TI - Racial And Ethnic Disparities Persist At Veterans Health Administration Patient Centered Medical Homes. AB - Patient-centered medical homes are widely promoted as a primary care delivery model that achieves better patient outcomes. It is unknown if their benefits extend equally to all racial/ethnic groups. In 2010 the Veterans Health Administration, part of the Department of Veterans Affairs (VA), began implementing patient-centered medical homes nationwide. In 2009 significant disparities in hypertension or diabetes control were present for most racial/ethnic groups, compared with whites. In 2014 hypertension disparities were similar for blacks, had become smaller but remained significant for Hispanics, and were no longer significant for multiracial veterans, whereas disparities had become significant for American Indians/Alaska Natives and Native Hawaiians/other Pacific Islanders. By contrast, in 2014 diabetes disparities were similar for American Indians/Alaska Natives, blacks, and Hispanics, and were no longer significant for Native Hawaiians/other Pacific Islanders. We found that the modest benefits of the VA's implementation of patient-centered medical homes were offset by competing multifactorial external, health system, provider, and patient factors, such as increased patient volume. To promote health equity, health care innovations such as patient-centered medical homes should incorporate tailored strategies that account for determinants of racial/ethnic variations. Evaluations of patient-centered medical homes should monitor outcomes for racial/ethnic groups. PMID- 28583969 TI - Organizational Change Management For Health Equity: Perspectives From The Disparities Leadership Program. AB - Leaders of health care organizations need to be prepared to improve quality and achieve equity in today's health care environment characterized by a focus on achieving value and addressing disparities in a diverse population. To help address this need, the Disparities Solutions Center at Massachusetts General Hospital launched the Disparities Leadership Program in 2007. The leadership program is an ongoing, year-long, executive education initiative that trains leaders from hospitals, health plans, and health centers to improve quality and eliminate racial and ethnic disparities in health care. Feedback from participating organizations demonstrates that health care leaders seem to possess knowledge about what disparities are and about what should be done to eliminate them. Data collection, performance measurement, and multifaceted interventions remain the tools of the trade. However, the barriers to success are lack of leadership buy-in, organizational prioritization, energy, and execution, which can be addressed through organizational change management strategies. PMID- 28583970 TI - The Role Of Nonprofit Hospitals In Identifying And Addressing Health Inequities In Cities. AB - For nonprofit hospitals to maintain their tax-exempt status, the Affordable Care Act requires them to conduct a community health needs assessment, in which they evaluate the health needs of the community they serve, and to create an implementation strategy, in which they propose ways to address these needs. We explored the extent to which nonprofit urban hospitals identified equity among the health needs of their communities and proposed health equity strategies to address this need. We conducted a content analysis of publicly available community health needs assessments and implementation strategies from 179 hospitals in twenty-eight US cities in the period August-December 2016. All of the needs assessments included at least one implicit health equity term (such as disparities, disadvantage, poor, or minorities), while 65 percent included at least one explicit health equity term (equity, health equity, inequity, or health inequity). Thirty-five percent of implementation strategies included one or more explicit health equity terms, but only 9 percent included an explicit activity to promote health equity. While needs assessment reporting requirements have the potential to encourage urban nonprofit hospitals to address health inequities in their communities, hospitals need incentives and additional capacity to invest in strategies that address the underlying structural social and economic conditions that cause health inequities. PMID- 28583971 TI - Trends In Inequalities In Mortality Amenable To Health Care In 17 European Countries. AB - Little is known about the effectiveness of health care in reducing inequalities in health. We assessed trends in inequalities in mortality from conditions amenable to health care in seventeen European countries in the period 1980-2010 and used models that included country fixed effects to study the determinants of these trends. Our findings show remarkable declines over the study period in amenable mortality among people with a low level of education. We also found stable absolute inequalities in amenable mortality over time between people with low and high levels of education, but widening relative inequalities. Higher health care expenditure was associated with lower mortality from amenable causes, but not from nonamenable causes. The effect of health care expenditure on amenable mortality was equally strong, in relative terms, among people with low levels of education and those with high levels. As a result, higher health care expenditure was associated with a narrowing of absolute inequalities in amenable mortality. Our findings suggest that in the European context, more generous health care funding provides some protection against inequalities in amenable mortality. PMID- 28583972 TI - A Black Alzheimer's Patient Wants To Be Part Of The Cure. AB - A daughter gets her mother into a clinical trial for an Alzheimer's drug, with few other black patients enrolled. PMID- 28583973 TI - Solving Disparities Through Payment And Delivery System Reform: A Program To Achieve Health Equity. AB - Payment systems generally do not directly encourage or support the reduction of health disparities. In 2013 the Finding Answers: Solving Disparities through Payment and Delivery System Reform program of the Robert Wood Johnson Foundation sought to understand how alternative payment models might intentionally incorporate a disparities-reduction component to promote health equity. A qualitative analysis of forty proposals to the program revealed that applicants generally did not link payment reform tightly to disparities reduction. Most proposed general pay-for-performance, global payment, or shared savings plans, combined with multicomponent system interventions. None of the applicants proposed making any financial payments contingent on having successfully reduced disparities. Most applicants did not address how they would optimize providers' intrinsic and extrinsic motivation to reduce disparities. A better understanding of how payment and care delivery models might be designed and implemented to reduce health disparities is essential. PMID- 28583977 TI - Mobile Health Applications. PMID- 28583978 TI - Mobile Health Apps: The Authors Reply. PMID- 28583979 TI - Sugar-Sweetened Beverage Tax In Mexico. PMID- 28583980 TI - Sugar-Sweetened Beverage Tax: The Authors Reply. PMID- 28583981 TI - Poverty And Health Care Reform. PMID- 28583982 TI - Errata. PMID- 28583983 TI - Poverty And Health Care Reform: The Author Replies. PMID- 28583985 TI - Preventing Newborn Deaths In Romania And Hungary. PMID- 28583988 TI - Correction: Oncostatin M Suppresses Activation of IL-17/Th17 via SOCS3 Regulation in CD4+ T Cells. PMID- 28583987 TI - New Insights into the Role of IL-1beta in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. AB - Multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis, are neuroinflammatory diseases driven by autoreactive pathogenic TH cells that elicit demyelination and axonal damage. How TH cells acquire pathogenicity and communicate with myeloid cells and cells of the CNS remain unclear. IL-1beta is recognized to play an important role in experimental autoimmune encephalomyelitis (EAE) and perhaps MS. Clinical EAE is significantly attenuated in IL-1R-deficient and IL-1beta-deficient mice, and IL-1beta is found in the blood, cerebrospinal fluid, and CNS lesions of MS patients. In this article, we focus on new reports that elucidate the cellular sources of IL-1beta and its actions during EAE, in both lymphoid tissues and within the CNS. Several immune cell types serve as critical producers of IL-1beta during EAE, with this cytokine inducing response in both hematopoietic and nonhematopoietic cells. These findings from the EAE model should inspire efforts toward investigating the therapeutic potential of IL-1 blockade in MS. PMID- 28583989 TI - Fasting hepatic glucose uptake is higher in men than women. AB - Differences in glucose metabolism between men and women have previously been reported. Our purpose was to determine if there is a gender difference in fasting hepatic glucose uptake (MRglu). Fifty-five patients (44 men, 11 women) referred for routine PET/CT using the glucose tracer 2-deoxy-2-[F-18]fluoro-D-glucose (FDG), mainly for cancer, had dynamic imaging for 30 min immediately following injection. Hepatic FDG clearance (mL/min/100 mL) was measured as gradient divided by intercept from Patlak-Rutland graphical analysis using a volume of interest over the abdominal aorta to record input function. Hepatic MRglu was obtained by multiplication of clearance by blood glucose concentration. Hepatic steatosis was diagnosed as CT density <=40 HU Mean (standard deviation) hepatic MRglu in 44 men was 2.30 (1.14) MUmol/min/100 mL, significantly higher than in 11 women in whom it was 1.07 (1.35) MUmol/min/100 mL (P = 0.003). CT density was 52 (12) HU in women compared with 45 (9) HU in men (P = 0.04), but there was no significant difference in blood glucose, BMI, or prevalence of recent chemotherapy (within 6 months preceding PET/CT). When patients were subdivided into those without hepatic steatosis (31 men/9 women), those without evidence of FDG-avid malignancy on PET/CT (15/6), and those without either (11/5), gender differences in hepatic MRglu remained highly significant, but there were no significant differences in CT density, blood glucose, BMI, or recent chemotherapy history. Despite this being a population of clinically referred patients, the results strongly suggest that fasting hepatic MRglu is higher in men than in women. PMID- 28583990 TI - Docetaxel does not impair skeletal muscle force production in a murine model of cancer chemotherapy. AB - Chemotherapy drugs such as docetaxel are commonly used to treat cancer. Cancer patients treated with chemotherapy experience decreased physical fitness, muscle weakness and fatigue. To date, it is unclear whether these symptoms result only from cancer-derived factors or from the combination of cancer disease and cancer treatments, such as chemotherapy. In this study, we aimed at determining the impact of chemotherapy per se on force production of hind limb muscles from healthy mice treated with docetaxel. We hypothesized that docetaxel will decrease maximal force, exacerbate the force decline during repeated contractions and impair recovery after fatiguing stimulations. We examined the function of soleus and extensor digitorum longus (EDL) muscles 24 h and 72 h after a single injection of docetaxel (acute treatment), and 7 days after the third weekly injection of docetaxel (repeated treatment). Docetaxel was administrated by intravenous injection (20 mg/kg) in female FVB/NRj mice and control mice were injected with saline solution. Our results show that neither acute nor repeated docetaxel treatment significantly alters force production during maximal contractions, repeated contractions or recovery. Only a tendency to decreased peak specific force was observed in soleus muscles 24 h after a single injection of docetaxel (-17%, P = 0.13). In conclusion, docetaxel administered intravenously does not impair force production in hind limb muscles from healthy mice. It remains to be clarified whether docetaxel, or other chemotherapy drugs, affect muscle function in subjects with cancer and whether the side effects associated with chemotherapy (neurotoxicity, central fatigue, decreased physical activity, etc.) are responsible for the experienced muscle weakness and fatigue. PMID- 28583992 TI - The Fat but Fit paradox: what we know and don't know about it. PMID- 28583991 TI - Mutations of PKA cyclic nucleotide-binding domains reveal novel aspects of cyclic nucleotide selectivity. AB - Cyclic AMP and cyclic GMP are ubiquitous second messengers that regulate the activity of effector proteins in all forms of life. The main effector proteins, the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) and the 3',5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), are preferentially activated by cAMP and cGMP, respectively. However, the molecular basis of this cyclic nucleotide selectivity is still not fully understood. Analysis of isolated cyclic nucleotide-binding (CNB) domains of PKA regulatory subunit type Ialpha (RIalpha) reveals that the C-terminal CNB-B has a higher cAMP affinity and selectivity than the N-terminal CNB-A. Here, we show that introducing cGMP-specific residues using site-directed mutagenesis reduces the selectivity of CNB-B, while the combination of two mutations (G316R/A336T) results in a cGMP-selective binding domain. Furthermore, introducing the corresponding mutations (T192R/A212T) into the PKA RIalpha CNB-A turns this domain into a highly cGMP-selective domain, underlining the importance of these contacts for achieving cGMP specificity. Binding data with the generic purine nucleotide 3',5'-cyclic inosine monophosphate (cIMP) reveal that introduced arginine residues interact with the position 6 oxygen of the nucleobase. Co crystal structures of an isolated CNB-B G316R/A336T double mutant with either cAMP or cGMP reveal that the introduced threonine and arginine residues maintain their conserved contacts as seen in PKG I CNB-B. These results improve our understanding of cyclic nucleotide binding and the molecular basis of cyclic nucleotide specificity. PMID- 28583994 TI - Karen Litzy #StrongSmart #DavidButlerSavedmMyLife. PMID- 28583993 TI - New insights into preventing injuries and illnesses among elite athletics athletes. PMID- 28583995 TI - The Students As LifeStyle Activists (SALSA) program. PMID- 28583996 TI - Neurons Over Nephrons: Systematic Review and Meta-Analysis of Contrast-Induced Nephropathy in Patients With Acute Stroke. AB - BACKGROUND AND PURPOSE: Because of the perceived risk of contrast-induced acute kidney injury (AKI), many centers require pre-imaging serum creatinine levels, potentially delaying care. We performed a systematic review and meta-analysis evaluating AKI rates in patients with acute ischemic stroke receiving computed tomographic angiography (CTA) and computed tomographic perfusion (CTP). METHODS: We searched MEDLINE, EMBASE, and the Web of Science through December 2016 for studies reporting on AKI in patients with acute ischemic stroke receiving CTA/CTP. Using a random-effects model, estimates were pooled across studies. Outcomes of interest were (1) the odds of AKI in patients receiving CTA/CTP versus noncontrast computed tomography, (2) overall rate of AKI and hemodialysis in patients with acute ischemic stroke undergoing CTA/CTP, and (3) the odds of CTA/CTP-associated AKI among patients with and without chronic kidney disease. RESULTS: Fourteen studies were included (6 case-control studies and 8 single-arm studies) with 5727 CTA/CTP and 981 noncontrast computed tomography patients. In case-control studies, AKI was significantly lower among CTA/CTP patients compared with noncontrast computed tomography patients (odds ratio=0.47; 95% confidence interval=0.33-0.68; P<0.01). Adjusting for baseline creatinine, there was no difference in AKI rates between groups (odds ratio=0.34; 95% confidence interval=0.10-1.21). The overall rate of AKI in CTA/CTP patients was 3% (95% confidence interval=2%-4%). The overall rate of hemodialysis in the CTA/CTP group was 0.07% (3 of 4373). There was no difference in AKI among CTA/CTP patients with and without chronic kidney disease (odds ratio=0.63; 95% confidence interval=0.34 1.12). CONCLUSIONS: Nonrandomized evidence suggests that CTA/CTP are not associated with statistically significant increase in risk of AKI in patients with stroke, even those with known chronic kidney disease. PMID- 28583997 TI - Response by Pase et al to Letter Regarding Article, "Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study". PMID- 28583998 TI - Letter by Klein Regarding Article, "Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia: A Prospective Cohort Study". PMID- 28583999 TI - Paramedic Initiation of Neuroprotective Agent Infusions: Successful Achievement of Target Blood Levels and Attained Level Effect on Clinical Outcomes in the FAST MAG Pivotal Trial (Field Administration of Stroke Therapy - Magnesium). AB - BACKGROUND AND PURPOSE: Paramedic use of fixed-size lumen, gravity-controlled tubing to initiate intravenous infusions in the field may allow rapid start of neuroprotective therapy for acute stroke. In a large, multicenter trial, we evaluated its efficacy in attaining target serum levels of candidate neuroprotective agent magnesium sulfate and the relation of achieved magnesium levels to outcome. METHODS: The FAST-MAG phase 3 trial (Field Administration of Stroke Therapy - Magnesium) randomized 1700 patients within 2 hours of onset to paramedic-initiated, a 15-minute loading intravenous infusion of magnesium or placebo followed by a 24-hour maintenance dose. The drug delivery strategy included fixed-size lumen, gravity-controlled tubing for field drug administration, and a shrink-wrapped ambulance kit containing both the randomized field loading and hospital maintenance doses for seamless continuation. RESULTS: Among patient randomized to active treatment, magnesium levels in the first 72 hours were assessed 987 times in 572 patients. Mean patient age was 70 years (SD+/-14 years), and 45% were women. During the 24-hour period of active infusion, mean achieved serum level was 3.91 (+/-0.8), consistent with trial target. Mg levels were increased by older age, female sex, lower weight, height, body mass index, and estimated glomerular filtration rate, and higher blood urea nitrogen, hemoglobin, and higher hematocrit. Adjusted odds for clinical outcomes did not differ by achieved Mg level, including disability at 90 days, symptomatic hemorrhage, or death. CONCLUSIONS: Paramedic infusion initiation using gravity controlled tubing permits rapid achievement of target serum levels of potential neuroprotective agents. The absence of association of clinical outcomes with achieved magnesium levels provides further evidence that magnesium is not biologically neuroprotective in acute stroke. PMID- 28584000 TI - Ischemic Amnesia: Causes and Outcome. AB - BACKGROUND AND PURPOSE: We aimed to describe the frequency and characteristics of acute ischemic stroke and transient ischemic attacks presenting predominantly with amnesia (ischemic amnesia) and to identify clinical clues for differentiating them from transient global amnesia (TGA). METHODS: We retrospectively analyzed and described all patients presenting with diffusion weighted imaging magnetic resonance imaging-confirmed acute ischemic stroke/transient ischemic attacks with antero- and retrograde amnesia as the main symptom over a 13.5-year period. We also compared their clinical features and stroke mechanisms with 3804 acute ischemic stroke from our ischemic stroke registry. RESULTS: Thirteen ischemic amnesia patients were identified, representing 0.2% of all patients with acute ischemic stroke/transient ischemic attack. In 69% of ischemic amnesia cases, amnesia was transient with a median duration of 5 hours. Ischemia was not considered in 39% of cases. Fifty-four percent of cases were clinically difficult to distinguish from TGA, including 15% who were indistinguishable from TGA. 1.2% of all presumed TGA patients at our center were later found to have ischemic amnesia. Amnesic strokes were more often cardioembolic, multiterritorial, and typically involved the posterior circulation and limbic system. Clinical clues were minor focal neurological signs, higher age, more risk factors, and stroke favoring circumstances. Although all patients were independent at 3 months, 31% had persistent memory problems. CONCLUSIONS: Amnesia as the main symptom of acute ischemic cerebral events is rare, mostly transient, and easily mistaken for TGA. Although clinical clues are often present, the threshold for performing diffusion-weighted imaging in acute amnesia should be low. PMID- 28584002 TI - Differences in Characteristics and Outcomes Between Asian and Non-Asian Patients in the TIAregistry.org. AB - BACKGROUND AND PURPOSE: This study provides the contemporary causes and prognosis of transient ischemic attack (TIA) and minor stroke in Asians and the direct comparisons with non-Asians. METHODS: The TIAregistry.org enrolled 4789 patients (1149 Asians and 3640 non-Asians) with a TIA or minor ischemic stroke within 7 days of onset. Every participating facility had systems dedicated to urgent intervention of TIA/stroke patients by specialists. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome. RESULTS: Approximately 80% of patients were evaluated within 24 hours of symptom onset. At 1 year, there were no differences in the rates of composite cardiovascular events (6.8% versus 6.0%; P=0.38) and stroke (6.0% versus 4.8%; P=0.11) between Asians and non-Asians. Asians had a lower risk of cerebrovascular disease (stroke or TIA) than non-Asians (adjusted hazard ratio, 0.79; 95% confidence interval, 0.63-0.98; P=0.03); the difference was primarily driven by a lower rate of TIA in Asians (4.2% versus 8.3%; P<0.001). Moderately severe bleeding was more frequent in Asians (0.8% versus 0.3%; P=0.02). In multivariable analysis, multiple acute infarcts (P=0.005) and alcohol consumption (P=0.02) were independent predictors of stroke recurrence in Asians, whereas intracranial stenosis (P<0.001), ABCD2 score (P<0.001), atrial fibrillation (P=0.008), extracranial stenosis (P=0.03), and previous stroke or TIA (P=0.03) were independent predictors in non-Asians. CONCLUSIONS: The short-term stroke risk after a TIA or minor stroke was lower than expected when urgent evidence-based care was delivered, irrespective of race/ethnicity or region. However, the predictors of stroke were different for Asians and non-Asians. PMID- 28584003 TI - Daily Total Physical Activity and Incident Stroke: The Japan Public Health Center Based Prospective Study. AB - BACKGROUND AND PURPOSE: There is limited evidence on the association between total physical activity and stroke in Asian populations experiencing a greater burden of hemorrhagic stroke than Western populations. We aimed to understand their optimal level of physical activity for stroke prevention. METHODS: A total of 74 913 Japanese people 50 to 79 years of age without histories of cardiovascular disease or cancer were followed from 2000 to 2012. RESULTS: During the 698 946 person-years of follow-up, we documented a total of 2738 incident cases of stroke, including 1007 hemorrhagic strokes (747 intraparenchymal and 260 subarachnoid hemorrhages) and 1721 ischemic strokes (1206 nonembolic and 515 embolic infarctions). Individuals in the second or third metabolic equivalents of task-hours per day quartile had the lowest risks of total stroke (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.75-0.93), intraparenchymal hemorrhage (HR, 0.79; 95% CI, 0.64-0.97), subarachnoid hemorrhage (HR, 0.78; CI, 0.55-1.11), and nonembolic infarction (HR, 0.78; CI, 0.67-0.92), whereas those in the fourth quartile had the lowest risk of embolic infarction (HR, 0.76; CI, 0.59-0.97). Cubic spline graphs revealed a steep decrease in stroke risk (30% risk reduction) from the lowest level to a plateau at 5 to 10 metabolic equivalents of task-hours per day (50th percentile). The associations of total physical activity level with hemorrhage stroke showed U or J shape, which were because of vigorous-intensity activities, whereas the association with ischemic stroke showed L shape. CONCLUSIONS: For Japanese people, moderate levels of total physical activity, particularly achieved by moderate-intensity activities, may be optimal for stroke prevention because excessive vigorous-intensity activities might not be beneficial or even disadvantageous for prevention of hemorrhagic stroke. PMID- 28584004 TI - Vaginal birth after two previous caesarean deliveries in a patient with uterus didelphys and an interuterine septal defect. AB - Uterus didelphys is a congenital abnormality characterised by double uteri, double cervices and a double or single vagina that affects 0.3% to 11% of the general female population. A 23-year-old woman, gravida 3 para 3003, with uterus didelphys, acquired an iatrogenic interuterine septal defect during an otherwise routine primary caesarean delivery for fetal malpresentation. The defect was repaired but noted to have dehisced during her second pregnancy. A repeat caesarean section was performed due to fetal malpresentation after an unsuccessful external cephalic version. The dehisced defect was left unrepaired. During her third pregnancy, the placenta implanted in the right uterus, but the fetus migrated to the left uterus at approximately 28 weeks gestation. The umbilical cord traversed the interuterine septal defect. With the fetus in the vertex presentation at term gestation, the patient underwent a vaginal birth after two previous caesarean deliveries without any major perinatal complications. PMID- 28584006 TI - Activated B Cells Participating in the Anti-Myelin Response Are Excluded from the Inflamed Central Nervous System in a Model of Autoimmunity that Allows for B Cell Recognition of Autoantigen. AB - Once activated, T cells gain the ability to access both healthy and inflamed nonlymphoid tissues. They are then reactivated to remain in the tissue and exert their effector function only if they encounter their specific Ag. In this study, we set out to determine if the same is true for B cells using a mouse model of CNS autoimmunity that incorporates both T and B cell recognition of a myelin autoantigen. Both T and B cells were common infiltrates of spinal cords in diseased mice. However, unlike T cells, anti-myelin B cells were excluded from the inflamed tissue. Further, CNS B cells did not have a phenotype consistent with Ag-specific activation as it occurs in lymphatic tissue. Instead, they expressed elevated levels of CD80, indicating that B cells may contribute to local inflammation through nonantigen-specific mechanisms. PMID- 28584005 TI - Neutrophils Slow Disease Progression in Murine Lupus via Modulation of Autoreactive Germinal Centers. AB - Neutrophils are well characterized as mediators of peripheral tissue damage in lupus, but it remains unclear whether they influence loss of self-tolerance in the adaptive immune compartment. Lupus neutrophils produce elevated levels of factors known to fuel autoantibody production, including IL-6 and B cell survival factors, but also reactive oxygen intermediates, which can suppress lymphocyte proliferation. To assess whether neutrophils directly influence the progression of autoreactivity in secondary lymphoid organs (SLOs), we characterized the localization and cell-cell contacts of splenic neutrophils at several stages in the progression of disease in the NZB/W murine model of lupus. Neutrophils accumulate in SLO over the course of lupus progression, preferentially localizing near T lymphocytes early in disease and B cells with advanced disease. RNA sequencing reveals that the splenic neutrophil transcriptional program changes significantly over the course of disease, with neutrophil expression of anti inflammatory mediators peaking during early-stage and midstage disease, and evidence of neutrophil activation with advanced disease. To assess whether neutrophils exert predominantly protective or deleterious effects on loss of B cell self-tolerance in vivo, we depleted neutrophils at different stages of disease. Neutrophil depletion early in lupus resulted in a striking acceleration in the onset of renal disease, SLO germinal center formation, and autoreactive plasma cell production. In contrast, neutrophil depletion with more advanced disease did not alter systemic lupus erythematosus progression. These results demonstrate a surprising temporal and context-dependent role for neutrophils in restraining autoreactive B cell activation in lupus. PMID- 28584007 TI - T Cell-Derived IL-10 Impairs Host Resistance to Mycobacterium tuberculosis Infection. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing ~1.5 million deaths annually. CD4+ T cells and several cytokines, such as the Th1 cytokine IFN-gamma, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C+ monocytes. However, after day 21 postinfection, IL-10-expressing T cells were also highly represented. Notably, mice deficient in T cell-derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL 10-competent mice, indicating a major role for T cell-derived IL-10 in TB susceptibility. IL-10-expressing cells were detected among both CD4+ and CD8+ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN gamma and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4+ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10-induced TB susceptibility. PMID- 28584008 TI - Crucial Role for Immune Complexes but Not FcRn in Immunization against Anti-TNF alpha Antibodies after a Single Injection in Mice. AB - The immunogenicity of infliximab and adalimumab is a major concern because patients may develop Abs also called antidrug Abs (ADA), directed against these anti-TNF-alpha Abs after just a few weeks of treatment. These ADAs can lead to a decrease in biologic concentration, which is associated with lower treatment efficacy. Our aim was to study the involvement of immune complexes and neonatal Fc receptor (FcRn) in the emergence of ADAs in the case of anti-TNF-alpha Abs. Wild type and FcRn knockout mice were injected once with either infliximab or adalimumab, alone or preincubated with TNF-alpha. Adalimumab cross-reacts with murine TNF-alpha whereas infliximab is species specific. When injected alone, only adalimumab elicited a humoral response. By preforming immune complexes with TNF-alpha, an anti-infliximab response was elicited. Surprisingly, both wild type and FcRn knockout mice were able to mount an immune response against anti-TNF alpha Abs, suggesting that immune complexes are a major determinant of this immunization. PMID- 28584009 TI - Nut allergy guidelines discourage complete avoidance. PMID- 28584010 TI - Androstenedione and 17-alpha-Hydroxyprogesterone Are Better Indicators of Adrenal Vein Sampling Selectivity Than Cortisol. AB - For identification of potentially surgically curable primary aldosteronism, guidelines recommend use of adrenal vein sampling (AVS) that requires selective catheterization of both adrenal veins as verified by using the cortisol-derived selectivity index. Unfortunately, bilaterally selective studies are not obtained under unstimulated conditions in a proportion of the cases ranging between 15% and 50% depending on the cutoff used. We therefore investigated whether 17-alpha hydroxyprogesterone and androstenedione, which showed a higher step-up between adrenal vein and inferior vena cava blood than cortisol, can ascertain selectivity when cortisol failed to do so. We prospectively recruited 32 hypertensive patients with confirmed primary aldosteronism, who underwent bilaterally simultaneous sampling without cosyntropin stimulation and with the same predefined AVS protocol. All were consecutively selected because of a cortisol-based selectivity index <2.00 in at least one of the paired adrenal vein blood samples collected as per protocol. Results showed that the values of the selectivity index based on 17-alpha-hydroxyprogesterone and androstenedione were higher (P<0.01) on average by 1.6- and 12-fold, respectively, than those based on cortisol. With use of these steroids, we rescued 43% and 73% of the AVS, respectively, from being judged nonselective. Thus, in challenging patients with primary aldosteronism submitted to AVS use of 17-alpha-hydroxyprogesterone, and even more so of androstenedione, for ascertaining selectivity allows demonstration of correct catheter placement in a proportion of AVS studies better than cortisol. Thus, replacing cortisol measurement with these steroids, and particularly androstenedione, can improve the diagnostic yield of AVS. PMID- 28584011 TI - Regulatory T-Cell Augmentation or Interleukin-17 Inhibition Prevents Calcineurin Inhibitor-Induced Hypertension in Mice. AB - The immunosuppressive calcineurin inhibitors cyclosporine A and tacrolimus alter T-cell subsets and can cause hypertension, vascular dysfunction, and renal toxicity. We and others have reported that cyclosporine A and tacrolimus decrease anti-inflammatory regulatory T cells and increase proinflammatory interleukin-17 producing T cells; therefore, we hypothesized that inhibition of these effects using noncellular therapies would prevent the hypertension, endothelial dysfunction, and renal glomerular injury induced by calcineurin inhibitor therapy. Daily treatment of mice with cyclosporine A or tacrolimus for 1 week significantly decreased CD4+/FoxP3+ regulatory T cells in the spleen and lymph nodes, as well as induced hypertension, vascular injury and dysfunction, and glomerular mesangial expansion in mice. Daily cotreatment with all-trans retinoic acid reported to increase regulatory T cells and decrease interleukin-17 producing T cells, prevented all of the detrimental effects of cyclosporine A and tacrolimus. All-trans retinoic acid also increased regulatory T cells and prevented the hypertension, endothelial dysfunction, and glomerular injury in genetically modified mice that phenocopy calcineurin inhibitor-treated mice (FKBP12-Tie2 knockout). Treatment with an interleukin-17-neutralizing antibody also increased regulatory T-cell levels and prevented the hypertension, endothelial dysfunction, and glomerular injury in cyclosporine A-treated and tacrolimus-treated mice and FKBP12-Tie2 knockout mice, whereas an isotype control had no effect. Augmenting regulatory T cells and inhibiting interleukin-17 signaling using noncellular therapies prevents the cardiovascular and renal toxicity of calcineurin inhibitors in mice. PMID- 28584012 TI - NEFM (Neurofilament Medium) Polypeptide, a Marker for Zona Glomerulosa Cells in Human Adrenal, Inhibits D1R (Dopamine D1 Receptor)-Mediated Secretion of Aldosterone. AB - Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D, ATP1A1, ATP2B3, and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM, encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin. PMID- 28584013 TI - Efficacy and Safety of Quarter-Dose Blood Pressure-Lowering Agents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - There is a critical need for blood pressure-lowering strategies that have greater efficacy and minimal side effects. Low-dose combinations hold promise in this regard, but there are few data on very-low-dose therapy. We, therefore, conducted a systematic review and meta-analysis of randomized controlled trials with at least one quarter-dose and one placebo and standard-dose monotherapy arm. A search was conducted of Medline, Embase, Cochrane Registry, Food and Drug Administration, and European Medicinal Agency websites. Data on blood pressure and adverse events were pooled using a fixed-effect model, and bias was assessed using Cochrane risk of bias. The review included 42 trials involving 20 284 participants. Thirty-six comparisons evaluated quarter-dose with placebo and indicated a blood pressure reduction of -4.7/-2.4 mm Hg (P<0.001). Six comparisons were of dual quarter-dose therapy versus placebo, observing a -6.7/ 4.4 mm Hg (P<0.001) blood pressure reduction. There were no trials of triple quarter-dose combination versus placebo, but one quadruple quarter-dose study observed a blood pressure reduction of -22.4/-13.1 mm Hg versus placebo (P<0.001). Compared with standard-dose monotherapy, the blood pressure differences achieved by single (37 comparisons), dual (7 comparisons), and quadruple (1 trial) quarter-dose combinations were +3.7/+2.6 (P<0.001), +1.3/-0.3 (NS), and -13.1/-7.9 (P<0.001) mm Hg, respectively. In terms of adverse events, single and dual quarter-dose therapy was not significantly different from placebo and had significantly fewer adverse events compared with standard-dose monotherapy. Quarter-dose combinations could provide improvements in efficacy and tolerability of blood pressure-lowering therapy. PMID- 28584014 TI - Prognostic Value of Variability in Systolic Blood Pressure Related to Vascular Events and Premature Death in Type 2 Diabetes Mellitus: The ADVANCE-ON Study. AB - Visit-to-visit variability in systolic blood pressure (SBP) is a risk factor for cardiovascular events. However, whether it provides additional predictive information beyond traditional risk factors, including mean SBP, in the long term is unclear. The ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) was a randomized controlled trial in patients with type 2 diabetes mellitus; ADVANCE-ON (ADVANCE Observational) followed-up patients subsequently. In these analyses, 9114 patients without major macrovascular or renal events or death during the first 24 months were included. Data on SBP from 6 visits during the first 24 months after randomization were used to estimate visit-to-visit variability in several ways: the primary measure was the standard deviation. Events accrued during the following 7.6 years. The primary outcome was a composite of major macrovascular and renal events and all-cause mortality. Standard deviation of SBP was log linearly associated with an increased risk of the primary outcome (P<0.001) after adjustment for mean SBP and other cardiovascular risk factors. The hazard ratio (HR; 95% confidence interval [CI]) in the highest, compared with the lowest, tenth of the standard deviation was 1.39 (1.15-1.69). Results were similar for major macrovascular events alone and all-cause mortality alone (both P<0.01). Addition of standard deviation of SBP significantly improved 8-year risk classification (continuous net reclassification improvement, 5.3%). Results were similar for other measures of visit-to-visit variability, except maximum SBP. Visit-to-visit variability in SBP is an independent predictor of vascular complications and death, which improves risk prediction beyond that provided by traditional risk factors, including mean SBP. PMID- 28584015 TI - Aldosterone-Producing Adenomas: Genotypes and Phenotypes. PMID- 28584017 TI - Quarter Dose Combination Therapy: Good News for Blood Pressure Control. PMID- 28584016 TI - Aldosterone-Producing Adenomas: Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation. AB - Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20*10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3% 0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype. PMID- 28584019 TI - Is It Time to Employ a Measure of Visit-to-Visit Variability in Clinical Practice? PMID- 28584018 TI - Renin-Angiotensin-Aldosterone System Is Not Involved in the Arterial Stiffening Induced by Acute and Prolonged Exposure to High Altitude. AB - : This randomized, double-blind, placebo-controlled study was designed to explore the effects of exposure to very high altitude hypoxia on vascular wall properties and to clarify the role of renin-angiotensin-aldosterone system inhibition on these vascular changes. Forty-seven healthy subjects were included in this study: 22 randomized to telmisartan (age, 40.3+/-10.8 years; 7 women) and 25 to placebo (age, 39.3+/-9.8 years; 7 women). Tests were performed at sea level, pre- and post-treatment, during acute exposure to 3400 and 5400-m altitude (Mt. Everest Base Camp), and after 2 weeks, at 5400 m. The effects of hypobaric hypoxia on mechanical properties of large arteries were assessed by applanation tonometry, measuring carotid-femoral pulse wave velocity, analyzing arterial pulse waveforms, and evaluating subendocardial oxygen supply/demand index. No differences in hemodynamic changes during acute and prolonged exposure to 5400-m altitude were found between telmisartan and placebo groups. Aortic pulse wave velocity significantly increased with altitude (P<0.001) from 7.41+/-1.25 m/s at sea level to 7.70+/-1.13 m/s at 3400 m and to 8.52+/-1.59 m/s at arrival at 5400 m (P<0.0001), remaining elevated during prolonged exposure to this altitude (8.41+/-1.12 m/s; P<0.0001). Subendocardial oxygen supply/demand index significantly decreased with acute exposure to 3400 m: from 1.72+/-0.30 m/s at sea level to 1.41+/-0.27 m/s at 3400 m (P<0.001), remaining significantly although slightly less reduced after reaching 5400 m (1.52+/-0.33) and after prolonged exposure to this altitude (1.53+/-0.25; P<0.001). In conclusion, the acute exposure to hypobaric hypoxia induces aortic stiffening and reduction in subendocardial oxygen supply/demand index. Renin-angiotensin-aldosterone system does not seem to play any significant role in these hemodynamic changes. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/. Unique identifier: 2008-000540-14. PMID- 28584020 TI - KITD816V Induces SRC-Mediated Tyrosine Phosphorylation of MITF and Altered Transcription Program in Melanoma. AB - The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation between KIT, MITF, and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell-cycle progression, suppression of senescence, survival, and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells became hypersensitive to SRC inhibitors. We have therefore delineated a mechanism behind the oncogenic effects of KITD816V in melanoma and provided a rationale for the heightened SRC inhibitor sensitivity in KITD816V transformed cells.Implications: This study demonstrates that an oncogenic tyrosine kinase mutant, KITD816V, can alter the transcriptional program of the transcription factor MITF in melanoma Mol Cancer Res; 15(9); 1265 74. (c)2017 AACR. PMID- 28584021 TI - The Landscape of Isoform Switches in Human Cancers. AB - Alternative usage of transcript isoforms from the same gene has been hypothesized as an important feature in cancers. However, differential usage of gene transcripts between conditions (isoform switching) has not been comprehensively characterized in and across cancer types. To this end, we developed methods for identification and visualization of isoform switches with predicted functional consequences. Using these methods, we characterized isoform switching in RNA-seq data from >5,500 cancer patients covering 12 solid cancer types. Isoform switches with potential functional consequences were common, affecting approximately 19% of multiple transcript genes. Among these, isoform switches leading to loss of DNA sequence encoding protein domains were more frequent than expected, particularly in pancancer switches. We identified several isoform switches as powerful biomarkers: 31 switches were highly predictive of patient survival independent of cancer types. Our data constitute an important resource for cancer researchers, available through interactive web tools. Moreover, our methods, available as an R package, enable systematic analysis of isoform switches from other RNA-seq datasets.Implications: This study indicates that isoform switches with predicted functional consequences are common and important in dysfunctional cells, which in turn means that gene expression should be analyzed at the isoform level. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/9/1206/F1.large.jpg.Mol Cancer Res; 15(9); 1206-20. (c)2017 AACR. PMID- 28584022 TI - IKKbeta-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent. AB - IKKbeta (encoded by IKBKB) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-kappaB pathway. IKKbeta exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that IKBKB gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKbeta in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKbeta in the basal skin layer. IKKbeta overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor-protective role of IKKbeta is independent of p53, but dependent on the activity of the Ink4a/Arf locus. Interestingly, in the absence of p16 and p19, IKKbeta-increased expression favors the appearance of cutaneous spindle cell-like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKbeta activity prevents skin tumor development, and shed light on the complex nature of IKKbeta effects on cancer progression, as IKKbeta can both promote and prevent carcinogenesis depending on the cell type or molecular context.Implications: The ability of IKKbeta to promote or prevent carcinogenesis suggests the need for further evaluation when targeting this protein. Mol Cancer Res; 15(9); 1255-64. (c)2017 AACR. PMID- 28584024 TI - PPARdelta Reprograms Glutamine Metabolism in Sorafenib-Resistant HCC. AB - The tyrosine kinase inhibitor sorafenib is the only therapeutic agent approved for the treatment of advanced hepatocellular carcinoma (HCC), but acquired resistance to sorafenib is high. Here, we report metabolic reprogramming in sorafenib-resistant HCC and identify a regulatory molecule, peroxisome proliferator-activated receptor-delta (PPARdelta), as a potential therapeutic target. Sorafenib-resistant HCC cells showed markedly higher glutamine metabolism and reductive glutamine carboxylation, which was accompanied by increased glucose derived pentose phosphate pathway and glutamine-derived lipid biosynthetic pathways and resistance to oxidative stress. These glutamine-dependent metabolic alterations were attributed to PPARdelta, which was upregulated in sorafenib resistant HCC cells and human HCC tissues. Furthermore, PPARdelta contributed to increased proliferative capacity and redox homeostasis in sorafenib-resistant HCC cells. Accordingly, inhibiting PPARdelta activity reversed compensatory metabolic reprogramming in sorafenib-resistant HCC cells and sensitized them to sorafenib. Therefore, targeting compensatory metabolic reprogramming of glutamine metabolism in sorafenib-resistant HCC by inhibiting PPARdelta constitutes a potential therapeutic strategy for overcoming sorafenib-resistance in HCC.Implications: This study provides novel insight into the mechanism underlying sorafenib resistance and a potential therapeutic strategy targeting PPARdelta in advanced hepatocellular carcinoma. Mol Cancer Res; 15(9); 1230-42. (c)2017 AACR. PMID- 28584023 TI - Notch Represses Transcription by PRC2 Recruitment to the Ternary Complex. AB - It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb Repressor Complex 2 (PRC2) and Lysine Demethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape and repression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis.Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response. Mol Cancer Res; 15(9); 1173-83. (c)2017 AACR. PMID- 28584025 TI - Data sharing statements for clinical trials. PMID- 28584026 TI - Margaret McCartney: Prescribing incentives feel grubby because they are. PMID- 28584027 TI - Caution Regarding Government-Mandated Shared Decision Making for Patients With Atrial Fibrillation. PMID- 28584028 TI - Here Comes Trouble: A Career as a Tobacco Control Activist. AB - Dr Glantz is Professor of Medicine in the Division of Cardiology, the Truth Initiative Distinguished Professor of Tobacco Control, and Director of the Center for Tobacco Control Research and Education at the University of California, San Francisco School of Medicine. He obtained a BSc in aerospace engineering from the University of Cincinnati in 1969 and an MSc and PhD in applied mechanics from Stanford University. He is the author of 4 books, including The Cigarette Papers and Primer of Biostatistics He is also a member of the University of California, San Francisco Cardiovascular Research Institute and Institute for Health Policy Studies and Co-leader of the University of California, San Francisco Comprehensive Cancer Center Tobacco Program. He was elected to the Institute of Medicine in 2005. PMID- 28584029 TI - Real-Life Fractional Flow Reserve. PMID- 28584030 TI - Composite End Points in Clinical Research: A Time for Reappraisal. AB - Advances in cardiovascular medicine fueled by innovative clinical trials have dramatically improved the lives of patients worldwide. Commensurate with this progress has been a decline in morbid and mortal events. Accordingly, an increased propensity to collate patient outcomes in clinical trials has emerged that combines death and nonfatal complications into a single composite event. Despite the acknowledged benefits in trial efficiency from such an approach, this method assumes uniform directionality of each component, does not distinguish the relative clinical significance of each, and counts only the first occurrence of any event in the final tally within a conventional time to first event analysis. In this article, we evaluate the criticisms that have been leveled at this approach and provide an overview of recently published phase III cardiovascular trials using primary composite end points. We then explore what to anticipate from the large cohort of as-yet unpublished clinical trials in this arena. Last, we propose a variety of novel approaches that use composite end points and suggest a path forward to enhancing their use in future clinical trials. PMID- 28584032 TI - Safety of Sports for Athletes With Implantable Cardioverter-Defibrillators: Long Term Results of a Prospective Multinational Registry. PMID- 28584033 TI - Association of Feature-Tracking Cardiac Magnetic Resonance Imaging Left Ventricular Global Longitudinal Strain With All-Cause Mortality in Patients With Reduced Left Ventricular Ejection Fraction. PMID- 28584034 TI - Letter by Moris et al Regarding Article, "Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease". PMID- 28584035 TI - Letter by Siasos et al Regarding Article, "Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease". PMID- 28584036 TI - Response by Jones et al to Letter Regarding Article, "Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease". PMID- 28584037 TI - Letter by Harbaoui et al Regarding Article, "Coronary Artery Calcium to Guide a Personalized Risk-Based Approach to Initiation and Intensification of Antihypertensive Therapy". PMID- 28584038 TI - Response by McEvoy and Blaha to Letter Regarding Article, "Coronary Artery Calcium to Guide a Personalized Risk-Based Approach to Initiation and Intensification of Antihypertensive Therapy". PMID- 28584039 TI - Harms of overoxygenation in patients with exacerbation of chronic obstructive pulmonary disease. PMID- 28584040 TI - Perinatal and maternal morbidity and mortality after attempted operative vaginal delivery at midpelvic station. AB - BACKGROUND: Increased use of operative vaginal delivery (i.e., forceps or vacuum application), of which 20% occurs at midpelvic station, has been advocated to reduce the rate of cesarean delivery. We aimed to quantify severe perinatal and maternal morbidity and mortality associated with attempted midpelvic operative vaginal delivery. METHODS: We studied all term singleton deliveries in Canada between 2003 and 2013, by attempted midpelvic operative vaginal or cesarean delivery with labour (with and without prolonged second stage). The primary outcomes were composite severe perinatal morbidity and mortality (e.g., convulsions, assisted ventilation, severe birth trauma and perinatal death), and composite severe maternal morbidity and mortality (e.g., severe postpartum hemorrhage, shock, sepsis, cardiac complications, acute renal failure and death). RESULTS: The study population included 187 234 deliveries. Among women with dystocia and prolonged second stage of labour, midpelvic operative vaginal delivery was associated with higher rates of severe perinatal morbidity and mortality compared with cesarean delivery (forceps, adjusted odds ratio [AOR] 1.81, 95% confidence interval [CI] 1.24 to 2.64; vacuum, AOR 1.81, 95% CI 1.17 to 2.80; sequential instruments, AOR 3.19, 95% CI 1.73 to 5.88), especially with higher rates of severe birth trauma. Rates of severe maternal morbidity and mortality were not significantly different after operative vaginal delivery, although rates of obstetric trauma were higher (forceps, AOR 4.51, 95% CI 4.04 to 5.02; vacuum, AOR 2.70, 95% CI 2.35 to 3.09; sequential instruments, AOR 4.24, 95% CI 3.46 to 5.19). Among women with fetal distress, similar associations were seen for severe birth trauma and obstetric trauma, although vacuum was associated with lower rates of severe maternal morbidity and mortality (AOR 0.52, 95% CI 0.33 to 0.80). Associations tended to be stronger among women without a prolonged second stage. INTERPRETATION: Midpelvic operative vaginal delivery is associated with higher rates of severe birth trauma and obstetric trauma, whereas overall rates of severe perinatal and maternal morbidity and mortality vary by indication and operative instrument. PMID- 28584042 TI - A 24-year-old woman with heavy menstrual bleeding. PMID- 28584043 TI - Cold agglutinin disease presenting as livedo racemosa. PMID- 28584041 TI - Primary aldosteronism: a common cause of resistant hypertension. PMID- 28584044 TI - A reflection on practising medicine "up North". PMID- 28584045 TI - Mercury poisoning in the Grassy Narrows First Nation: history not completed. PMID- 28584046 TI - Trump travel ban requires balanced discussion. PMID- 28584047 TI - NHS ransomware attack spreads worldwide. PMID- 28584048 TI - The future of legal pot. PMID- 28584049 TI - The future of legal pot. PMID- 28584050 TI - Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization. AB - The human dopamine (DA) transporter (hDAT) is a key regulator of neurotransmission and a target for antidepressants and addictive drugs. Despite the recent resolution of dDAT structures from Drosophila melanogaster, complete understanding of its mechanism of function and even information on its biological assembly is lacking. The resolved dDAT structures are monomeric, but growing evidence suggests that hDAT might function as a multimer, and its oligomerization may be relevant to addictive drug effects. Here, using structure-based computations, we examined the possible mechanisms of hDAT dimerization and its dynamics in a lipid bilayer. Using a combination of site-directed mutagenesis, DA uptake, and cross-linking experiments that exploited the capacity of Cys-306 to form intermonomeric disulfide bridges in the presence of an oxidizing agent, we tested the effects of mutations at transmembrane segment (TM) 6 and 12 helices in HEK293 cells. The most probable structural model for hDAT dimer suggested by computations and experiments differed from the dimeric structure resolved for the bacterial homolog, LeuT, presumably because of a kink at TM12 preventing favorable monomer packing. Instead, TM2, TM6, and TM11 line the dimer interface. Molecular dynamics simulations of the dimeric hDAT indicated that the two subunits tend to undergo cooperative structural changes, both on local (extracellular gate opening/closure) and global (transition between outward facing and inward-facing states) scales. These observations suggest that hDAT transport properties may be allosterically modulated under conditions promoting dimerization. Our study provides critical insights into approaches for examining the oligomerization of neurotransmitter transporters and sheds light on their drug modulation. PMID- 28584051 TI - Ion-pulling simulations provide insights into the mechanisms of channel opening of the skeletal muscle ryanodine receptor. AB - The type 1 ryanodine receptor (RyR1) mediates Ca2+ release from the sarcoplasmic reticulum to initiate skeletal muscle contraction and is associated with muscle diseases, malignant hyperthermia, and central core disease. To better understand RyR1 channel function, we investigated the molecular mechanisms of channel gating and ion permeation. An adequate model of channel gating requires accurate, high resolution models of both open and closed states of the channel. To this end, we generated an open-channel RyR1 model using molecular simulations to pull Ca2+ through the pore constriction site of a closed-channel RyR1 structure determined at 3.8-A resolution. Importantly, we find that our open-channel model is consistent with the RyR1 and cardiac RyR (RyR2) open-channel structures reported while this paper was in preparation. Both our model and the published structures show similar rotation of the upper portion of the pore-lining S6 helix away from the 4-fold channel axis and twisting of Ile-4937 at the channel constriction site out of the channel pore. These motions result in a minimum open-channel pore radius of ~3 A formed by Gln-4933, rather than Ile-4937 in the closed-channel structure. We also present functional support for our model by mutations around the closed- and open-channel constriction sites (Gln-4933 and Ile-4937). Our results indicate that use of ion-pulling simulations produces a RyR1 open-channel model, which can provide insights into the mechanisms of channel opening complementing those from the structural data. PMID- 28584052 TI - Mutations in N-acetylglucosamine (O-GlcNAc) transferase in patients with X-linked intellectual disability. AB - N-Acetylglucosamine (O-GlcNAc) transferase (OGT) regulates protein O GlcNAcylation, an essential and dynamic post-translational modification. The O GlcNAc modification is present on numerous nuclear and cytosolic proteins and has been implicated in essential cellular functions such as signaling and gene expression. Accordingly, altered levels of protein O-GlcNAcylation have been associated with developmental defects and neurodegeneration. However, mutations in the OGT gene have not yet been functionally confirmed in humans. Here, we report on two hemizygous mutations in OGT in individuals with X-linked intellectual disability (XLID) and dysmorphic features: one missense mutation (p.Arg284Pro) and one mutation leading to a splicing defect (c.463-6T>G). Both mutations reside in the tetratricopeptide repeats of OGT that are essential for substrate recognition. We observed slightly reduced levels of OGT protein and reduced levels of its opposing enzyme O-GlcNAcase in both patient-derived fibroblasts, but global O-GlcNAc levels appeared to be unaffected. Our data suggest that mutant cells attempt to maintain global O-GlcNAcylation by down regulating O-GlcNAcase expression. We also found that the c.463-6T>G mutation leads to aberrant mRNA splicing, but no stable truncated protein was detected in the corresponding patient-derived fibroblasts. Recombinant OGT bearing the p.Arg284Pro mutation was prone to unfolding and exhibited reduced glycosylation activity against a complex array of glycosylation substrates and proteolytic processing of the transcription factor host cell factor 1, which is also encoded by an XLID-associated gene. We conclude that defects in O-GlcNAc homeostasis and host cell factor 1 proteolysis may play roles in mediation of XLID in individuals with OGT mutations. PMID- 28584053 TI - NLRC3 protein inhibits inflammation by disrupting NALP3 inflammasome assembly via competition with the adaptor protein ASC for pro-caspase-1 binding. AB - Inflammasomes are multiprotein complexes that sense pathogen-associated and danger-associated molecular patterns and induce inflammation in cells. The NALP3 inflammasome is tightly regulated by recently discovered control mechanisms, but other modulators still remain to be characterized. NLR family CARD-containing 3 (NLRC3) protein, a caspase recruitment domain (CARD)-containing member of the nucleotide oligomerization domain-like receptor (NLR) family, was found to down regulate the NF-kappaB pathway and stimulator of interferon genes (STING) dependent cytokine secretion. However, the effect of NLRC3 on the NALP3 inflammasome or other inflammasomes is still unknown. We hypothesized that NLRC3 might inhibit NALP3 inflammasome complex assembly. Toward this end, we tested whether NLRC3 overexpression or knockdown influences NALP3 activity in human monocyte and HEK293FT cells when the complex is ectopically reconstituted. We found that NLRC3 indeed decreases NALP3-induced IL-1beta maturation and secretion, pro-caspase-1 cleavage, and speck formation by apoptosis-associated speck-like protein containing a CARD (ASC) protein in response to NALP3 activators. We also show that endogenous NLRC3 interacts with both ASC and pro caspase-1 but not with NALP3, disrupts ASC speck formation through its CARD, and impairs the ASC and pro-caspase-1 interaction. Moreover, the NLRC3 CARD alone could dampen IL-1beta secretion and ASC speck formation induced by NALP3 mutants associated with autoinflammatory diseases. In conclusion, we show here that, besides its role in the inhibition of the NF-kappaB pathway, NLRC3 interferes with the assembly and activity of the NALP3 inflammasome complex by competing with ASC for pro-caspase-1 binding. PMID- 28584054 TI - Conformational biosensors reveal allosteric interactions between heterodimeric AT1 angiotensin and prostaglandin F2alpha receptors. AB - G protein-coupled receptors (GPCRs) are conformationally dynamic proteins transmitting ligand-encoded signals in multiple ways. This transmission is highly complex and achieved through induction of distinct GPCR conformations, which preferentially drive specific receptor-mediated signaling events. This conformational capacity can be further enlarged via allosteric effects between dimers, warranting further study of these effects. Using GPCR conformation sensitive biosensors, we investigated allosterically induced conformational changes in the recently reported F prostanoid (FP)/angiotensin II type 1 receptor (AT1R) heterodimer. Ligand occupancy of the AT1R induced distinct conformational changes in FP compared with those driven by PGF2alpha in bioluminescence resonance energy transfer (BRET)-based FP biosensors engineered with Renilla luciferase (RLuc) as an energy donor in the C-tail and fluorescein arsenical hairpin binder (FlAsH)-labeled acceptors at different positions in the intracellular loops. We also found that this allosteric communication is mediated through Galphaq and may also involve proximal (phospholipase C) but not distal (protein kinase C) signaling partners. Interestingly, beta-arrestin-biased AT1R agonists could also transmit a Galphaq-dependent signal to FP without activation of downstream Galphaq signaling. This transmission of information was specific to the AT1R/FP complex, as activation of Galphaq by the oxytocin receptor did not recapitulate the same phenomenon. Finally, information flow was asymmetric in the sense that FP activation had negligible effects on AT1R-based conformational biosensors. The identification of partner-induced GPCR conformations may help identify novel allosteric effects when investigating multiprotein receptor signaling complexes. PMID- 28584055 TI - Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and activation via SIRT3-mediated activation of superoxide dismutase 2. AB - Twenty-four hours of fasting is known to blunt activation of the human NLRP3 inflammasome. This effect might be mediated by SIRT3 activation, controlling mitochondrial reactive oxygen species. To characterize the molecular underpinnings of this fasting effect, we comparatively analyzed the NLRP3 inflammasome response to nutrient deprivation in wild-type and SIRT3 knock-out mice. Consistent with previous findings for human NLRP3, prolonged fasting blunted the inflammasome in wild-type mice but not in SIRT3 knock-out mice. In SIRT3 knock-out bone marrow-derived macrophages, NLRP3 activation promoted excess cytosolic extrusion of mitochondrial DNA along with increased reactive oxygen species and reduced superoxide dismutase 2 (SOD2) activity. Interestingly, the negative regulatory effect of SIRT3 on NLRP3 was not due to transcriptional control or priming of canonical inflammasome components but, rather, occurred via SIRT3-mediated deacetylation of mitochondrial SOD2, leading to SOD2 activation. We also found that siRNA knockdown of SIRT3 or SOD2 increased NLRP3 supercomplex formation and activation. Moreover, overexpression of wild-type and constitutively active SOD2 similarly blunted inflammasome assembly and activation, effects that were abrogated by acetylation mimic-modified SOD2. Finally, in vivo administration of lipopolysaccharide increased liver injury and the levels of peritoneal macrophage cytokines, including IL-1beta, in SIRT3 KO mice. These results support the emerging concept that enhancing mitochondrial resilience against damage-associated molecular patterns may play a pivotal role in preventing inflammation and that the anti-inflammatory effect of fasting mimetic diets may be mediated, in part, through SIRT3-directed blunting of NLRP3 inflammasome assembly and activation. PMID- 28584056 TI - Structural analyses of von Willebrand factor C domains of collagen 2A and CCN3 reveal an alternative mode of binding to bone morphogenetic protein-2. AB - Bone morphogenetic proteins (BMPs) are secreted growth factors that promote differentiation processes in embryogenesis and tissue development. Regulation of BMP signaling involves binding to a variety of extracellular proteins, among which are many von Willebrand factor C (vWC) domain-containing proteins. Although the crystal structure of the complex of crossveinless-2 (CV-2) vWC1 and BMP-2 previously revealed one mode of the vWC/BMP-binding mechanism, other vWC domains may bind to BMP differently. Here, using X-ray crystallography, we present for the first time structures of the vWC domains of two proteins thought to interact with BMP-2: collagen IIA and matricellular protein CCN3. We found that these two vWC domains share a similar N-terminal fold that differs greatly from that in CV 2 vWC, which comprises its BMP-2-binding site. We analyzed the ability of these vWC domains to directly bind to BMP-2 and detected an interaction only between the collagen IIa vWC and BMP-2. Guided by the collagen IIa vWC domain crystal structure and conservation of surface residues among orthologous domains, we mapped the BMP-binding epitope on the subdomain 1 of the vWC domain. This binding site is different from that previously observed in the complex between CV-2 vWC and BMP-2, revealing an alternative mode of interaction between vWC domains and BMPs. PMID- 28584058 TI - Protein kinase A-mediated phosphorylation of the Broad-Complex transcription factor in silkworm suppresses its transcriptional activity. AB - The insect-specific transcription factor Broad-Complex (BR-C) is transcriptionally activated by the steroid 20-hydroxyecdysone (20E) and regulates the expression of many target genes involved in insect growth and development. However, although the transcriptional regulation of BR-C proteins has been well studied, how BR-C is regulated at post-transcription and -translation levels is poorly understood. To this end, using liquid chromatography-tandem mass spectrometry analysis, we identified residue Ser-186 as a phosphorylation site of BR-C in silkworm. Site-directed mutagenesis and treatment with specific kinase activators and inhibitors indicated that the Ser-186 residue in silkworm BR-C is phosphorylated by protein kinase A (PKA). Immunostaining assays disclosed that PKA-mediated phosphorylation of silkworm BR-C has no effect on its nuclear import. However, luciferase reporter analysis, electrophoretic mobility shift assays, and chromatin immunoprecipitation revealed that the PKA phosphorylation event suppresses the transcriptional activation of silkworm BR-C target genes and that this inhibition was caused by repression of BR-C binding to its DNA targets. Of note, both in vitro and ex vivo experiments disclosed that a continuous 20E signal inhibits the PKA-mediated BR-C phosphorylation and also the cAMP/PKA pathway, indicating that 20E's inhibitory effect on PKA-mediated phosphorylation of silkworm BR-C contributes to maintaining BR-C transcriptional activity. In conclusion, our findings indicate that PKA-mediated phosphorylation inhibits silkworm BR-C activity by interfering with its binding to DNA and that 20E signaling relieves PKA-mediated phosphorylation of BR-C, thereby maintaining its transcriptional activity. PMID- 28584060 TI - Test results are meaningless unless we understand their predictive value. PMID- 28584059 TI - Alabama "pill mill" doctors get 20 year prison sentence. PMID- 28584057 TI - An RNAi-based high-throughput screening assay to identify small molecule inhibitors of hepatitis B virus replication. AB - Persistent or chronic infection with the hepatitis B virus (HBV) represents one of the most common viral diseases in humans. The hepatitis B virus deploys the hepatitis B virus X protein (HBx) as a suppressor of host defenses consisting of RNAi-based silencing of viral genes. Because of its critical role in countering host defenses, HBx represents an attractive target for antiviral drugs. Here, we developed and optimized a loss-of-function screening procedure, which identified a potential pharmacophore that abrogated HBx RNAi suppression activity. In a survey of 14,400 compounds in the Maybridge Screening Collection, we prioritized candidate compounds via high-throughput screening based on reversal of green fluorescent protein (GFP)-reported, RNAi-mediated silencing in a HepG2/GFP-shRNA RNAi sensor line. The screening yielded a pharmacologically active compound, N (2,4-difluorophenyl)-N'-[3-(1H-imidazol-1-yl) propyl] thiourea (IR415), which blocked HBx-mediated RNAi suppression indicated by the GFP reporter assay. We also found that IR415 reversed the inhibitory effect of HBx protein on activity of the Dicer endoribonuclease. We further confirmed the results of the primary screen in IR415-treated, HBV-infected HepG2 cells, which exhibited a marked depletion of HBV core protein synthesis and down-regulation of pre-genomic HBV RNA. Using a molecular interaction analysis system, we confirmed that IR415 selectively targets HBx in a concentration-dependent manner. The screening assay presented here allows rapid and improved detection of small-molecule inhibitors of HBx and related viral proteins. The assay may therefore potentiate the development of next-generation RNAi pathway-based therapeutics and promises to accelerate our search for novel and effective drugs in antiviral research. PMID- 28584061 TI - Cuts to addiction services are a false economy. PMID- 28584063 TI - Small Pores with a Big Impact. PMID- 28584064 TI - A Celebration of Fred David Sack. PMID- 28584062 TI - Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling. AB - RATIONALE: Soluble guanylate cyclase (sGC) heme iron, in its oxidized state (Fe3+), is desensitized to NO and limits cGMP production needed for downstream activation of protein kinase G-dependent signaling and blood vessel dilation. OBJECTIVE: Although reactive oxygen species are known to oxidize the sGC heme iron, the basic mechanism(s) governing sGC heme iron recycling to its NO sensitive, reduced state remain poorly understood. METHODS AND RESULTS: Oxidant challenge studies show that vascular smooth muscle cells have an intrinsic ability to reduce oxidized sGC heme iron and form protein-protein complexes between cytochrome b5 reductase 3, also known as methemoglobin reductase, and oxidized sGC. Genetic knockdown and pharmacological inhibition in vascular smooth muscle cells reveal that cytochrome b5 reductase 3 expression and activity is critical for NO-stimulated cGMP production and vasodilation. Mechanistically, we show that cytochrome b5 reductase 3 directly reduces oxidized sGC required for NO sensitization as assessed by biochemical, cellular, and ex vivo assays. CONCLUSIONS: Together, these findings identify new insights into NO-sGC-cGMP signaling and reveal cytochrome b5 reductase 3 as the first identified physiological sGC heme iron reductase in vascular smooth muscle cells, serving as a critical regulator of cGMP production and protein kinase G-dependent signaling. PMID- 28584065 TI - Hornwort Stomata: Architecture and Fate Shared with 400-Million-Year-Old Fossil Plants without Leaves. AB - As one of the earliest plant groups to evolve stomata, hornworts are key to understanding the origin and function of stomata. Hornwort stomata are large and scattered on sporangia that grow from their bases and release spores at their tips. We present data from development and immunocytochemistry that identify a role for hornwort stomata that is correlated with sporangial and spore maturation. We measured guard cells across the genera with stomata to assess developmental changes in size and to analyze any correlation with genome size. Stomata form at the base of the sporophyte in the green region, where they develop differential wall thickenings, form a pore, and die. Guard cells collapse inwardly, increase in surface area, and remain perched over a substomatal cavity and network of intercellular spaces that is initially fluid filled. Following pore formation, the sporophyte dries from the outside inwardly and continues to do so after guard cells die and collapse. Spore tetrads develop in spore mother cell walls within a mucilaginous matrix, both of which progressively dry before sporophyte dehiscence. A lack of correlation between guard cell size and DNA content, lack of arabinans in cell walls, and perpetually open pores are consistent with the inactivity of hornwort stomata. Stomata are expendable in hornworts, as they have been lost twice in derived taxa. Guard cells and epidermal cells of hornworts show striking similarities with the earliest plant fossils. Our findings identify an architecture and fate of stomata in hornworts that is ancient and common to plants without sporophytic leaves. PMID- 28584066 TI - On the Inside. PMID- 28584067 TI - CRISPR-Cas9 Targeted Mutagenesis Leads to Simultaneous Modification of Different Homoeologous Gene Copies in Polyploid Oilseed Rape (Brassica napus). AB - In polyploid species, altering a trait by random mutagenesis is highly inefficient due to gene redundancy. We have stably transformed tetraploid oilseed rape (Brassica napus) with a CRISPR-Cas9 construct targeting two ALCATRAZ (ALC) homoeologs. ALC is involved in valve margin development and, thus, contributes to seed shattering from mature fruits. Knocking out ALC would increase shatter resistance to avoid seed loss during mechanical harvest. We obtained a transgenic T1 plant with four alc mutant alleles by the use of a single target sequence. All mutations were stably inherited to the T2 progeny. The T2 generation was devoid of any wild-type alleles, proving that the underlying T1 was a nonchimeric double heterozygote. T-DNA and ALC loci were not linked, as indicated by random segregation in the T2 generation. Hence, we could select double mutants lacking the T-DNA already in the first offspring generation. However, whole-genome sequencing data revealed at least five independent insertions of vector backbone sequences. We did not detect any off-target effects in two genome regions homologous to the target sequence. The simultaneous alteration of multiple homoeologs by CRISPR-Cas9 mutagenesis without any background mutations will offer new opportunities for using mutant genotypes in rapeseed breeding. PMID- 28584069 TI - Developing guidelines in low-income and middle-income countries: lessons from Kenya. AB - There are few examples of sustained nationally organised, evidence-informed clinical guidelines development processes in Sub-Saharan Africa. We describe the evolution of efforts from 2005 to 2015 to support evidence-informed decision making to guide admission hospital care practices in Kenya. The approach to conduct reviews, present evidence, and structure and promote transparency of consensus-based procedures for making recommendations improved over four distinct rounds of policy making. Efforts to engage important voices extended from government and academia initially to include multiple professional associations, regulators and practitioners. More than 100 people have been engaged in the decision-making process; an increasing number outside the research team has contributed to the conduct of systematic reviews, and 31 clinical policy recommendations has been developed. Recommendations were incorporated into clinical guideline booklets that have been widely disseminated with a popular knowledge and skills training course. Both helped translate evidence into practice. We contend that these efforts have helped improve the use of evidence to inform policy. The systematic reviews, Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approaches and evidence to decision-making process are well understood by clinicians, and the process has helped create a broad community engaged in evidence translation together with a social or professional norm to use evidence in paediatric care in Kenya. Specific sustained efforts should be made to support capacity and evidence-based decision making in other African settings and clinical disciplines. PMID- 28584068 TI - Genomic Insights into the Evolution of the Nicotine Biosynthesis Pathway in Tobacco. AB - In tobacco (Nicotiana tabacum), nicotine is the predominant alkaloid. It is produced in the roots and accumulated mainly in the leaves. Jasmonates play a central signaling role in damage-induced nicotine formation. The genome sequence of tobacco provides us an almost complete inventory of structural and regulatory genes involved in nicotine pathway. Phylogenetic and expression analyses revealed a series of structural genes of the nicotine pathway, forming a regulon, under the control of jasmonate-responsive ETHYLENE RESPONSE FACTOR (ERF) transcription factors. The duplication of NAD and polyamine metabolic pathways and the subsequent recruitment of duplicated primary metabolic genes into the nicotine biosynthesis regulon were suggested to be the drivers for pyridine and pyrrolidine ring formation steps early in the pathway. Transcriptional regulation by ERF and cooperatively acting MYC2 transcription factors are corroborated by the frequent occurrence of cognate cis-regulatory elements of the factors in the promoter regions of the downstream structural genes. The allotetraploid tobacco has homologous clusters of ERF genes on different chromosomes, which are possibly derived from two ancestral diploids and include either nicotine-controlling ERF189 or ERF199 A large chromosomal deletion was found within one allele of the nicotine-controlling NICOTINE2 locus, which is part of one of the ERF gene clusters, and which has been used to breed tobacco cultivars with a low-nicotine content. PMID- 28584070 TI - The natural history of prenatally diagnosed congenital cystic lung lesions: long term follow-up of 119 cases. AB - BACKGROUND: A paucity of evidence regarding the natural history of congenital pulmonary airway malformations (CPAMs) and pulmonary sequestration (PS) has resulted in a divergence in management strategy of asymptomatic cases. METHODS: We describe the long-term clinical course of 119 children diagnosed with these lesions treated at Great Ormond Street Hospital (GOSH). Cases were identified via the GOSH patient database. Study entry required the identification of a cystic lung lesion on prenatal ultrasound and confirmation of CPAM/PS on postnatal CT imaging. Patients followed up for at least 5 years were included. RESULTS: 51 (43%) patients were managed surgically; 8 (6.7%) as an emergency during the neonatal period, 6 (5.1%) electively due to concerning features on CT scan, 20 (17%) following medical advice, 1 (0.8%) following a severe respiratory infection and in 5 (4.2%) the indication was unclear. The indication in 11 (9.2%) was recurrent respiratory infection and median age at surgery was 1.6 years (range 0.4 to 4.6 years). No cases of malignancy were identified on histological examination of resected lesions. 68 (57%) patients were managed conservatively for a median period of 9.9 years (range 5.2 years to 18 years). Seven (10%) were discharged, one was followed-up elsewhere (1.5%) and eight (11%) were lost to follow-up. In four patients (5.9%), the lesion resolved spontaneously. 52 (76%) continue to be followed-up and remain asymptomatic. CONCLUSIONS: This is one of the largest case series documenting the natural history of CPAMs and PS following a prenatal diagnosis and demonstrates that conservative management is a reasonable option in selected cases. PMID- 28584071 TI - SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome. AB - BACKGROUND: Brugada syndrome (BrS) is an inherited primary arrhythmia disorder leading to sudden cardiac arrest. SCN5A, encoding the alpha-subunit of the cardiac sodium channel (Nav1.5), is the most common pathogenic gene of BrS. An implantable cardioverter defibrillator (ICD) is the standard treatment for secondary prevention. This study aimed to evaluate association of the SCN5A variant with this cardiac conduction disturbance and appropriate ICD shock therapy in Thai symptomatic BrS patients with ICD implants. METHODS AND RESULTS: Symptomatic BrS patients diagnosed at university hospital were enrolled from 2008 to 2011. The primary outcome of the study was an appropriate ICD shock defined as having non-pacing-associated ICD shock after the occurrence of ventricular tachycardia or ventricular fibrillation. Associations between SCN5A polymorphisms, cardiac conduction disturbance, and potential confounding factors associated with appropriate ICD shock therapy were analyzed. All 40 symptomatic BrS patients (median age, 43 years) with ICD implantations were followed for 24 months. There were 16 patients (40%) who had the appropriate ICD shock therapy after ICD treatment. An independent factor associated with appropriate ICD shock therapy was SCN5A-R1193Q with an adjusted hazard ratio of 10.550 (95% CI, 1.631 68.232). CONCLUSIONS: SCN5A-R1193Q is associated with cardiac conduction disturbances. It may be a genetic marker associated with ventricular arrhythmia leading to appropriate ICD shock therapy in symptomatic BrS patients with ICD treatment. Because of the small sample size of study population and the appropriate ICD shock outcome, further large studies are needed to confirm the results of this study. PMID- 28584072 TI - Impact of the Publication of Appropriate Use Criteria on Utilization Rates of Myocardial Perfusion Imaging Studies in Ontario, Canada: A Population-Based Study. AB - BACKGROUND: Concern regarding overutilization of cardiac imaging has led to the development of appropriate use criteria (AUC). Myocardial perfusion imaging (MPI) is one of the most commonly used cardiac imaging modalities worldwide. Despite multiple iterations of AUC, there is currently no evidence regarding their real world impact on population-based utilization rates of MPI. Our goal was to assess the impact of the AUC on rates of MPI in Ontario, Canada. We hypothesized that publication of the AUC would be associated with a significant reduction in MPI rates. METHODS AND RESULTS: We conducted a retrospective cohort study of the adult population of Ontario from January 1, 2000, to December 31, 2015. Age- and sex-standardized rates were compared from 4 different periods intersected by 3 published iterations of the AUC. Overall, 3 072 611 MPI scans were performed in Ontario during our study period. The mean monthly rate increased from 14.1/10 000 in the period from January 2000 to October 2005 to 18.2/10 000 between November 2005 and June 2009. After this point in time, there was a reduction in rates, falling to a mean monthly rate of 17.1/10 000 between March 2014 and December 2015. Time series analysis revealed that publication of the 2009 AUC was associated with a significant reduction in MPI rates (P<0.001). This translated into ~88 849 fewer MPI scans at a cost savings of ~72 million Canadian dollars. CONCLUSIONS: Our results reflect a potential real-world impact of the 2009 MPI AUC by demonstrating evidence of a significant effect on population-based rates of MPI. PMID- 28584073 TI - Regions With Low Rates of Bystander Cardiopulmonary Resuscitation (CPR) Have Lower Rates of CPR Training in Victoria, Australia. AB - BACKGROUND: Bystander cardiopulmonary resuscitation (CPR) more than doubles the chance of surviving an out-of-hospital cardiac arrest. Recent data have shown considerable regional variation in bystander CPR rates across the Australian state of Victoria. This study aims to determine whether there is associated regional variation in rates of CPR training and willingness to perform CPR in these communities. METHODS AND RESULTS: We categorized each Victorian postcode as either a low or high bystander CPR region using data on adult, bystander witnessed, out-of-hospital cardiac arrests of presumed cardiac etiology (n=7175) from the Victorian Ambulance Cardiac Arrest Registry. We then surveyed adult Victorians (n=404) and compared CPR training data of the respondents from low and high bystander CPR regions. Of the 404 adults surveyed, 223 (55%) resided in regions with low bystander CPR. Compared with respondents from high bystander CPR regions, respondents residing in regions with low bystander CPR had lower rates of CPR training (62% versus 75%, P=0.009) and lower self-ratings for their overall knowledge of CPR (76% versus 84%, P=0.04). There were no differences between the regions in their reasons for not having undergone CPR training or in their willingness to perform CPR. Rates of survival for bystander-witnessed, out of-hospital cardiac arrests were significantly lower in low bystander CPR regions (15.7% versus 17.0%, P<0.001). CONCLUSIONS: This study found lower rates of CPR training and lower survival in regions with lower rates of bystander CPR in Victoria, Australia. Targeting these regions with CPR training programs may improve bystander CPR rates and out-of-hospital cardiac arrest outcomes. PMID- 28584074 TI - Gut-Derived Serum Lipopolysaccharide is Associated With Enhanced Risk of Major Adverse Cardiovascular Events in Atrial Fibrillation: Effect of Adherence to Mediterranean Diet. AB - BACKGROUND: Gut microbiota is emerging as a novel risk factor for atherothrombosis, but the predictive role of gut-derived lipopolysaccharide (LPS) is unknown. We analyzed (1) the association between LPS and major adverse cardiovascular events (MACE) in atrial fibrillation (AF) and (2) its relationship with adherence to a Mediterranean diet (Med-diet). METHODS AND RESULTS: This was a prospective single-center study including 912 AF patients treated with vitamin K antagonists (3716 patient-years). The primary end point was a composite of MACE. Baseline serum LPS, adherence to Med-diet (n=704), and urinary excretion of 11-dehydro-thromboxane B2 (TxB2, n=852) were investigated. Mean age was 73.5 years; 42.9% were women. A total of 187 MACE (5.0% per year) occurred: 54, 59, and 74 in the first, second, and third tertile of LPS, respectively (log-rank test P=0.004). Log-LPS (hazard ratio 1.194, P=0.009), age (hazard ratio 1.083, P<0.001), and previous cerebrovascular (hazard ratio 1.634, P=0.004) and cardiac events (hazard ratio 1.822, P<0.001) were predictors of MACE. In the whole cohort, AF (versus sinus rhythm) (beta 0.087, P=0.014) and low-density lipoprotein cholesterol (beta 0.069, P=0.049) were associated with circulating LPS. Furthermore, Med-diet score (beta -0.137, P<0.001) was predictive of log LPS, with fruits (beta -0.083, P=0.030) and legumes (beta -0.120, P=0.002) negatively associated with log-LPS levels. Log-LPS and log-TxB2 were highly correlated (r=0.598, P<0.001). Log-LPS (beta 0.574, P<0.001) and Med-diet score (beta -0.218, P<0.001) were significantly associated with baseline urinary excretion of TxB2. CONCLUSIONS: In this cohort of AF patients, LPS levels were predictive of MACE and negatively affected by high adherence to Med-diet. LPS may contribute to MACE incidence in AF by increasing platelet activation. PMID- 28584075 TI - Application of Zone Model Predictive Control Artificial Pancreas During Extended Use of Infusion Set and Sensor: A Randomized Crossover-Controlled Home-Use Trial. AB - OBJECTIVE: As artificial pancreas (AP) becomes standard of care, consideration of extended use of insulin infusion sets (IIS) and continuous glucose monitors (CGMs) becomes vital. We conducted an outpatient randomized crossover study to test the safety and efficacy of a zone model predictive control (zone-MPC)-based AP system versus sensor augmented pump (SAP) therapy in which IIS and CGM failures were provoked via extended wear to 7 and 21 days, respectively. RESEARCH DESIGN AND METHODS: A smartphone-based AP system was used by 19 adults (median age 23 years [IQR 10], mean 8.0 +/- 1.7% HbA1c) over 2 weeks and compared with SAP therapy for 2 weeks in a crossover, unblinded outpatient study with remote monitoring in both study arms. RESULTS: AP improved percent time 70-140 mg/dL (48.1 vs. 39.2%; P = 0.016) and time 70-180 mg/dL (71.6 vs. 65.2%; P = 0.008) and decreased median glucose (141 vs. 153 mg/dL; P = 0.036) and glycemic variability (SD 52 vs. 55 mg/dL; P = 0.044) while decreasing percent time <70 mg/dL (1.3 vs. 2.7%; P = 0.001). AP also improved overnight control, as measured by mean glucose at 0600 h (140 vs. 158 mg/dL; P = 0.02). IIS failures (1.26 +/- 1.44 vs. 0.78 +/- 0.78 events; P = 0.13) and sensor failures (0.84 +/- 0.6 vs. 1.1 +/- 0.73 events; P = 0.25) were similar between AP and SAP arms. Higher percent time in closed loop was associated with better glycemic outcomes. CONCLUSIONS: Zone-MPC significantly and safely improved glycemic control in a home-use environment despite prolonged CGM and IIS wear. This project represents the first home-use AP study attempting to provoke and detect component failure while successfully maintaining safety and effective glucose control. PMID- 28584077 TI - Vascular sprouts induce local attraction of proangiogenic neutrophils. AB - Angiogenesis, the growth of new blood vessels, is a complex process requiring the orchestration of numerous different cell types, growth factors, and chemokines. Some of the recently acknowledged actors in this process are immune cells. They accumulate at hypoxic sites, but the kinetics, dynamics, and regulation of that trafficking are unknown. In this study, we used intravital and live cell imaging to understand how neutrophils and macrophages migrate and behave at angiogenic sites. We developed two reproducible models of angiogenesis: one by transplanting isolated and hypoxic pancreatic islets into the cremaster muscles of mice, and another by in vitro coculturing of mouse aortic rings with neutrophils. In vivo imaging of the hypoxic site revealed recruitment of neutrophils and macrophages, which occurred in parallel, with depletion of one subset not affecting the accumulation of the other. We found, by cell tracking and statistical analyses, that neutrophils migrated in a directional manner to "angiogenic hotspots" around the islet where endothelial sprouting occurs, which was confirmed in the in vitro model of angiogenesis and is dependent on CXCL12 signaling. Intimate interactions between neutrophils and neovessels were prevalent, and neutrophil depletion greatly hampered vessel growth. Macrophages were less motile and attained supportive positions around the neovessels. Here, we present two novel in vivo and in vitro imaging models to study leukocyte behavior and actions during angiogenesis. These models unveiled that neutrophil migration at a hypoxic site was guided by signals emanating from sprouting endothelium where these immune cells gathered at "angiogenic hotspots" at which vascular growth occurred. PMID- 28584076 TI - Frontline Science: Aspirin-triggered resolvin D1 controls herpes simplex virus induced corneal immunopathology. AB - Stromal keratitis (SK) is a chronic immunopathological lesion of the eye, caused by HSV-1 infection, and a common cause of vision impairment in humans. The inflammatory lesions in the cornea are primarily caused by neutrophils with the active participation of CD4+ T cells. Therefore, the targeting of these immune cell types and their products represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin D1 (RvD1) and its epimer aspirin triggered RvD1 (AT-RvD1) are lipid mediators derived from docosahexaenoic acid (DHA) and were shown to promote resolution in several inflammatory disease models. In this report, we examined whether AT-RvD1 administration, begun before infection or at a later stage after ocular infection of mice with HSV-1, could control the severity of SK lesions. Treatment with AT-RvD1 significantly diminished the extent of corneal neovascularization and the severity of SK lesions. AT-RvD1-treated mice had fewer numbers of inflammatory cells that included neutrophils as well as Th1 and Th17 cells in the infected cornea. The mechanisms by which AT-RvD1 acts appear to be multiple. These include inhibitory effects on proinflammatory mediators, such as IL-1beta, IL-6, IL-12, CXCL1, MCP 1, MIP-2, vascular endothelial growth factor (VEGF)-A, matrix metalloproteinase 9 (MMP-9), and proinflammatory miRNA, such as miR-155, miR-132, and miR-223, which are involved in SK pathogenesis and corneal neovascularization. In addition, AT RvD1 attenuated STAT1, which plays an important role in Th1 cell differentiation and IFN-gamma expression. These findings demonstrate that AT-RvD1 treatment could represent a useful strategy for the management of virus-induced immunopathological lesions. PMID- 28584078 TI - Alcohol-induced miR-155 and HDAC11 inhibit negative regulators of the TLR4 pathway and lead to increased LPS responsiveness of Kupffer cells in alcoholic liver disease. AB - Inflammation promotes the progression of alcoholic liver disease. Alcohol sensitizes KCs to gut-derived endotoxin (LPS); however, signaling pathways that perpetuate inflammation in alcoholic liver disease are only partially understood. We found that chronic alcohol feeding in mice induced miR-155, an inflammatory miRNA in isolated KCs. We hypothesized that miR-155 might increase the responsiveness of KCs to LPS via targeting the negative regulators of LPS signaling. Our results revealed that KCs that were isolated from alcohol-fed mice showed a decrease in IRAK-M, SHIP1, and PU.1, and an increase in TNF-alpha levels. This was specific to KCs, as no significant differences were observed in these genes in hepatocytes. We found a causal effect of miR-155 deficiency on LPS responsiveness, as KCs that were isolated from miR-155 KO mice showed a greater induction of IRAK-M, SHIP1, and suppressor of cytokine signaling 1 after LPS treatment. C/EBPbeta, a validated miR-155 target, stimulates IL-10 transcription. We found a higher induction of C/EBPbeta and IL-10 in KCs that were isolated from miR-155 KO mice after LPS treatment. Gain- and loss-of-function studies affirmed that alcohol-induced miR-155 directly regulates IRAK-M, SHIP1, suppressor of cytokine signaling 1, and C/EBPbeta, as miR-155 inhibition increased and miR-155 overexpression decreased these genes in LPS or alcohol-pretreated wild-type KCs. HDAC11, a regulator of IL-10, was significantly increased and IL-10 was decreased in KCs that were isolated from alcohol-fed mice. Functionally, knockdown of HDAC11 with small interfering RNA resulted in an IL-10 increase in LPS or alcohol pretreated Mphi. We found that acetaldehyde and NF-kappaB pathways regulate HDAC11 levels. Collectively, our results indicate that the alcohol-induced responsiveness of KCs to LPS, in part, is governed by miR-155 and HDAC11. PMID- 28584079 TI - Whole-Genome Sequence and Variant Analysis of W303, a Widely-Used Strain of Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has emerged as a superior model organism. Selection of distinct laboratory strains of S. cerevisiae with unique phenotypic properties, such as superior mating or sporulation efficiencies, has facilitated advancements in research. W303 is one such laboratory strain that is closely related to the first completely sequenced yeast strain, S288C. In this work, we provide a high-quality, annotated genome sequence for W303 for utilization in comparative analyses and genome-wide studies. Approximately 9500 variations exist between S288C and W303, affecting the protein sequences of ~700 genes. A listing of the polymorphisms and divergent genes is provided for researchers interested in identifying the genetic basis for phenotypic differences between W303 and S288C. Several divergent functional gene families were identified, including flocculation and sporulation genes, likely representing selection for desirable laboratory phenotypes. Interestingly, remnants of ancestor wine strains were found on several chromosomes. Finally, as a test of the utility of the high quality reference genome, variant mapping revealed more accurate identification of accumulated mutations in passaged mismatch repair-defective strains. PMID- 28584080 TI - Whole Genome Sequencing of the Braconid Parasitoid Wasp Fopius arisanus, an Important Biocontrol Agent of Pest Tepritid Fruit Flies. AB - The braconid wasp Fopius arisanus (Sonan) is an important biological control agent of tropical and subtropical pest fruit flies, including two important global pests, the Mediterranean fruit fly (Ceratitis capitata), and the oriental fruit fly (Bactrocera dorsalis). The goal of this study was to develop foundational genomic resources for this species to provide tools that can be used to answer questions exploring the multitrophic interactions between the host and parasitoid in this important research system. Here, we present a whole genome assembly of F. arisanus, derived from a pool of haploid offspring from a single unmated female. The genome is ~154 Mb in size, with a N50 contig and scaffold size of 51,867 bp and 0.98 Mb, respectively. Utilizing existing RNA-Seq data for this species, as well as publicly available peptide sequences from related Hymenoptera, a high quality gene annotation set, which includes 10,991 protein coding genes, was generated. Prior to this assembly submission, no RefSeq proteins were present for this species. Parasitic wasps play an important role in a diverse ecosystem as well as a role in biological control of agricultural pests. This whole genome assembly and annotation data represents the first genome scale assembly for this species or any closely related Opiine, and are publicly available in the National Center for Biotechnology Information Genome and RefSeq databases, providing a much needed genomic resource for this hymenopteran group. PMID- 28584081 TI - Postglacial response of Arctic Ocean gas hydrates to climatic amelioration. AB - Seafloor methane release due to the thermal dissociation of gas hydrates is pervasive across the continental margins of the Arctic Ocean. Furthermore, there is increasing awareness that shallow hydrate-related methane seeps have appeared due to enhanced warming of Arctic Ocean bottom water during the last century. Although it has been argued that a gas hydrate gun could trigger abrupt climate change, the processes and rates of subsurface/atmospheric natural gas exchange remain uncertain. Here we investigate the dynamics between gas hydrate stability and environmental changes from the height of the last glaciation through to the present day. Using geophysical observations from offshore Svalbard to constrain a coupled ice sheet/gas hydrate model, we identify distinct phases of subglacial methane sequestration and subsequent release on ice sheet retreat that led to the formation of a suite of seafloor domes. Reconstructing the evolution of this dome field, we find that incursions of warm Atlantic bottom water forced rapid gas hydrate dissociation and enhanced methane emissions during the penultimate Heinrich event, the Bolling and Allerod interstadials, and the Holocene optimum. Our results highlight the complex interplay between the cryosphere, geosphere, and atmosphere over the last 30,000 y that led to extensive changes in subseafloor carbon storage that forced distinct episodes of methane release due to natural climate variability well before recent anthropogenic warming. PMID- 28584082 TI - Whole-organism cellular gene-expression atlas reveals conserved cell types in the ventral nerve cord of Platynereis dumerilii. AB - The comparative study of cell types is a powerful approach toward deciphering animal evolution. To avoid selection biases, however, comparisons ideally involve all cell types present in a multicellular organism. Here, we use image registration and a newly developed "Profiling by Signal Probability Mapping" algorithm to generate a cellular resolution 3D expression atlas for an entire animal. We investigate three-segmented young worms of the marine annelid Platynereis dumerilii, with a rich diversity of differentiated cells present in relatively low number. Starting from whole-mount expression images for close to 100 neural specification and differentiation genes, our atlas identifies and molecularly characterizes 605 bilateral pairs of neurons at specific locations in the ventral nerve cord. Among these pairs, we identify sets of neurons expressing similar combinations of transcription factors, located at spatially coherent anterior-posterior, dorsal-ventral, and medial-lateral coordinates that we interpret as cell types. Comparison with motor and interneuron types in the vertebrate neural tube indicates conserved combinations, for example, of cell types cospecified by Gata1/2/3 and Tal transcription factors. These include V2b interneurons and the central spinal fluid-contacting Kolmer-Agduhr cells in the vertebrates, and several neuron types in the intermediate ventral ganglionic mass in the annelid. We propose that Kolmer-Agduhr cell-like mechanosensory neurons formed part of the mucociliary sole in protostome-deuterostome ancestors and diversified independently into several neuron types in annelid and vertebrate descendants. PMID- 28584083 TI - Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle. AB - Skeletal muscle in vertebrates is formed by two major routes, as illustrated by the mouse embryo. Somites give rise to myogenic progenitors that form all of the muscles of the trunk and limbs. The behavior of these cells and their entry into the myogenic program is controlled by gene regulatory networks, where paired box gene 3 (Pax3) plays a predominant role. Head and some neck muscles do not derive from somites, but mainly form from mesoderm in the pharyngeal region. Entry into the myogenic program also depends on the myogenic determination factor (MyoD) family of genes, but Pax3 is not expressed in these myogenic progenitors, where different gene regulatory networks function, with T-box factor 1 (Tbx1) and paired-like homeodomain factor 2 (Pitx2) as key upstream genes. The regulatory genes that underlie the formation of these muscles are also important players in cardiogenesis, expressed in the second heart field, which is a major source of myocardium and of the pharyngeal arch mesoderm that gives rise to skeletal muscles. The demonstration that both types of striated muscle derive from common progenitors comes from clonal analyses that have established a lineage tree for parts of the myocardium and different head and neck muscles. Evolutionary conservation of the two routes to skeletal muscle in vertebrates extends to chordates, to trunk muscles in the cephlochordate Amphioxus and to muscles derived from cardiopharyngeal mesoderm in the urochordate Ciona, where a related gene regulatory network determines cardiac or skeletal muscle cell fates. In conclusion, Eric Davidson's visionary contribution to our understanding of gene regulatory networks and their evolution is acknowledged. PMID- 28584084 TI - Logical modeling of lymphoid and myeloid cell specification and transdifferentiation. AB - Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors, and chromatin remodelers. Using public data and data from our own molecular genetic experiments (quantitative PCR, Western blot, EMSA) or genome-wide assays (RNA-sequencing, ChIP-sequencing), we have assembled a comprehensive regulatory network encompassing the main transcription factors and signaling components involved in myeloid and lymphoid development. Focusing on B-cell and macrophage development, we defined a qualitative dynamical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knockdowns, and the reprogramming of pre-B cells into macrophages induced by the ectopic expression of specific transcription factors. The resulting network model can be used as a template for the integration of new hematopoietic differentiation and transdifferentiation data to foster our understanding of lymphoid/myeloid cell-fate decisions. PMID- 28584085 TI - Language from police body camera footage shows racial disparities in officer respect. AB - Using footage from body-worn cameras, we analyze the respectfulness of police officer language toward white and black community members during routine traffic stops. We develop computational linguistic methods that extract levels of respect automatically from transcripts, informed by a thin-slicing study of participant ratings of officer utterances. We find that officers speak with consistently less respect toward black versus white community members, even after controlling for the race of the officer, the severity of the infraction, the location of the stop, and the outcome of the stop. Such disparities in common, everyday interactions between police and the communities they serve have important implications for procedural justice and the building of police-community trust. PMID- 28584088 TI - Gene regulatory networks and network models in development and evolution. PMID- 28584086 TI - IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors. AB - CD4+CD25+FOXP3+ Tregs constitute a heterogeneous lymphocyte subpopulation essential for curtailing effector T cells and establishing peripheral tolerance. Calcineurin inhibitors (CNIs) are among the most effective agents in controlling effector T-cell responses in humans. However, CNIs also reduce the size of the Treg pool. The functional consequences of this negative effect and the mechanisms responsible remain to be elucidated. We report here that CNIs compromise the overall Treg immunoregulatory capacity to a greater extent than would be predicted by the reduction in the size of the Treg compartment, given that they selectively promote the apoptosis of the resting and activated Treg subsets that are known to display the most powerful suppressive function. These effects are caused by reduced access to IL-2, because Tregs remain capable of translocating NFAT even in the presence of high CNI levels. Exogenous IL-2 restores the phenotypic changes and overall gene-expression effects exerted by CNIs and can even promote Treg expansion by enhancing antiapoptotic Bcl-2 expression. In a skin transplant model, the addition of IL-2 synergizes with CNIs treatment, promoting intragraft accumulation of Tregs and prolonged allograft survival. Hence, the combination of IL-2 and CNIs constitutes an optimal immunomodulatory regimen that enhances the pool of suppressive Treg subsets while effectively controlling cytopathic T cells. PMID- 28584087 TI - Catalytic-site design for inverse heavy-enzyme isotope effects in human purine nucleoside phosphorylase. AB - Heavy-enzyme isotope effects (15N-, 13C-, and 2H-labeled protein) explore mass dependent vibrational modes linked to catalysis. Transition path-sampling (TPS) calculations have predicted femtosecond dynamic coupling at the catalytic site of human purine nucleoside phosphorylase (PNP). Coupling is observed in heavy PNPs, where slowed barrier crossing caused a normal heavy-enzyme isotope effect (kchemlight/kchemheavy > 1.0). We used TPS to design mutant F159Y PNP, predicted to improve barrier crossing for heavy F159Y PNP, an attempt to generate a rare inverse heavy-enzyme isotope effect (kchemlight/kchemheavy < 1.0). Steady-state kinetic comparison of light and heavy native PNPs to light and heavy F159Y PNPs revealed similar kinetic properties. Pre-steady-state chemistry was slowed 32 fold in F159Y PNP. Pre-steady-state chemistry compared heavy and light native and F159Y PNPs and found a normal heavy-enzyme isotope effect of 1.31 for native PNP and an inverse effect of 0.75 for F159Y PNP. Increased isotopic mass in F159Y PNP causes more efficient transition state formation. Independent validation of the inverse isotope effect for heavy F159Y PNP came from commitment to catalysis experiments. Most heavy enzymes demonstrate normal heavy-enzyme isotope effects, and F159Y PNP is a rare example of an inverse effect. Crystal structures and TPS dynamics of native and F159Y PNPs explore the catalytic-site geometry associated with these catalytic changes. Experimental validation of TPS predictions for barrier crossing establishes the connection of rapid protein dynamics and vibrational coupling to enzymatic transition state passage. PMID- 28584089 TI - Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells. AB - Homeobox a1 (Hoxa1) is one of the most rapidly induced genes in ES cell differentiation and it is the earliest expressed Hox gene in the mouse embryo. In this study, we used genomic approaches to identify Hoxa1-bound regions during early stages of ES cell differentiation into the neuro-ectoderm. Within 2 h of retinoic acid treatment, Hoxa1 is rapidly recruited to target sites that are associated with genes involved in regulation of pluripotency, and these genes display early changes in expression. The pattern of occupancy of Hoxa1 is dynamic and changes over time. At 12 h of differentiation, many sites bound at 2 h are lost and a new cohort of bound regions appears. At both time points the genome wide mapping reveals that there is significant co-occupancy of Nanog (Nanog homeobox) and Hoxa1 on many common target sites, and these are linked to genes in the pluripotential regulatory network. In addition to shared target genes, Hoxa1 binds to regulatory regions of Nanog, and conversely Nanog binds to a 3' enhancer of Hoxa1 This finding provides evidence for direct cross-regulatory feedback between Hoxa1 and Nanog through a mechanism of mutual repression. Hoxa1 also binds to regulatory regions of Sox2 (sex-determining region Y box 2), Esrrb (estrogen-related receptor beta), and Myc, which underscores its key input into core components of the pluripotential regulatory network. We propose a model whereby direct inputs of Nanog and Hoxa1 on shared targets and mutual repression between Hoxa1 and the core pluripotency network provides a molecular mechanism that modulates the fine balance between the alternate states of pluripotency and differentiation. PMID- 28584090 TI - Paleogenomics of echinoids reveals an ancient origin for the double-negative specification of micromeres in sea urchins. AB - Establishing a timeline for the evolution of novelties is a common, unifying goal at the intersection of evolutionary and developmental biology. Analyses of gene regulatory networks (GRNs) provide the ability to understand the underlying genetic and developmental mechanisms responsible for the origin of morphological structures both in the development of an individual and across entire evolutionary lineages. Accurately dating GRN novelties, thereby establishing a timeline for GRN evolution, is necessary to answer questions about the rate at which GRNs and their subcircuits evolve, and to tie their evolution to paleoenvironmental and paleoecological changes. Paleogenomics unites the fossil record and all aspects of deep time, with modern genomics and developmental biology to understand the evolution of genomes in evolutionary time. Recent work on the regulatory genomic basis of development in cidaroid echinoids, sand dollars, heart urchins, and other nonmodel echinoderms provides an ideal dataset with which to explore GRN evolution in a comparative framework. Using divergence time estimation and ancestral state reconstructions, we have determined the age of the double-negative gate (DNG), the subcircuit which specifies micromeres and skeletogenic cells in Strongylocentrotus purpuratus We have determined that the DNG has likely been used for euechinoid echinoid micromere specification since at least the Late Triassic. The innovation of the DNG thus predates the burst of post-Paleozoic echinoid morphological diversification that began in the Early Jurassic. Paleogenomics has wide applicability for the integration of deep time and molecular developmental data, and has wide utility in rigorously establishing timelines for GRN evolution. PMID- 28584091 TI - Dissecting BMP signaling input into the gene regulatory networks driving specification of the blood stem cell lineage. AB - Hematopoietic stem cells (HSCs) that sustain lifelong blood production are created during embryogenesis. They emerge from a specialized endothelial population, termed hemogenic endothelium (HE), located in the ventral wall of the dorsal aorta (DA). In Xenopus, we have been studying the gene regulatory networks (GRNs) required for the formation of HSCs, and critically found that the hemogenic potential is defined at an earlier time point when precursors to the DA express hematopoietic as well as endothelial genes, in the definitive hemangioblasts (DHs). The GRN for DH programming has been constructed and, here, we show that bone morphogenetic protein (BMP) signaling is essential for the initiation of this GRN. BMP2, -4, and -7 are the principal ligands expressed in the lineage forming the HE. To investigate the requirement and timing of all BMP signaling in HSC ontogeny, we have used a transgenic line, which inducibly expresses an inhibitor of BMP signaling, Noggin, as well as a chemical inhibitor of BMP receptors, DMH1, and described the inputs from BMP signaling into the DH GRN and the HE, as well as into primitive hematopoiesis. BMP signaling is required in at least three points in DH programming: first to initiate the DH GRN through gata2 expression, then for kdr expression to enable the DH to respond to vascular endothelial growth factor A (VEGFA) ligand from the somites, and finally for gata2 expression in the DA, but is dispensable for HE specification after hemangioblasts have been formed. PMID- 28584092 TI - Secular rise in economically valuable personality traits. AB - Although trends in many physical characteristics and cognitive capabilities of modern humans are well-documented, less is known about how personality traits have evolved over time. We analyze data from a standardized personality test administered to 79% of Finnish men born between 1962 and 1976 (n = 419,523) and find steady increases in personality traits that predict higher income in later life. The magnitudes of these trends are similar to the simultaneous increase in cognitive abilities, at 0.2-0.6 SD during the 15-y window. When anchored to earnings, the change in personality traits amounts to a 12% increase. Both personality and cognitive ability have consistent associations with family background, but the trends are similar across groups defined by parental income, parental education, number of siblings, and rural/urban status. Nevertheless, much of the trends in test scores can be attributed to changes in the family background composition, namely 33% for personality and 64% for cognitive ability. These composition effects are mostly due to improvements in parents' education. We conclude that there is a "Flynn effect" for personality that mirrors the original Flynn effect for cognitive ability in magnitude and practical significance but is less driven by compositional changes in family background. PMID- 28584094 TI - Reconstructing blood stem cell regulatory network models from single-cell molecular profiles. AB - Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all mature cell types for the lifetime of the organism. Differentiation of HSCs toward alternative lineages must be balanced at the population level by the fate decisions made by individual cells. Transcription factors play a key role in regulating these decisions and operate within organized regulatory programs that can be modeled as transcriptional regulatory networks. As dysregulation of single HSC fate decisions is linked to fatal malignancies such as leukemia, it is important to understand how these decisions are controlled on a cell-by-cell basis. Here we developed and applied a network inference method, exploiting the ability to infer dynamic information from single-cell snapshot expression data based on expression profiles of 48 genes in 2,167 blood stem and progenitor cells. This approach allowed us to infer transcriptional regulatory network models that recapitulated differentiation of HSCs into progenitor cell types, focusing on trajectories toward megakaryocyte-erythrocyte progenitors and lymphoid-primed multipotent progenitors. By comparing these two models, we identified and subsequently experimentally validated a difference in the regulation of nuclear factor, erythroid 2 (Nfe2) and core-binding factor, runt domain, alpha subunit 2, translocated to, 3 homolog (Cbfa2t3h) by the transcription factor Gata2. Our approach confirms known aspects of hematopoiesis, provides hypotheses about regulation of HSC differentiation, and is widely applicable to other hierarchical biological systems to uncover regulatory relationships. PMID- 28584093 TI - Treatment with diphenyl-pyrazole compound anle138b/c reveals that alpha-synuclein protects melanoma cells from autophagic cell death. AB - Recent epidemiological and clinical studies have reported a significantly increased risk for melanoma in people with Parkinson's disease. Because no evidence could be obtained that genetic factors are the reason for the association between these two diseases, we hypothesized that of the three major Parkinson's disease-related proteins-alpha-synuclein, LRRK2, and Parkin-alpha synuclein might be a major link. Our data, presented here, demonstrate that alpha synuclein promotes the survival of primary and metastatic melanoma cells, which is the exact opposite of the effect that alpha-synuclein has on dopaminergic neurons, where its accumulation causes neuronal dysfunction and death. Because this detrimental effect of alpha-synuclein on neurons can be rescued by the small molecule anle138b, we explored its effect on melanoma cells. We found that treatment with anle138b leads to massive melanoma cell death due to a major dysregulation of autophagy, suggesting that alpha-synuclein is highly beneficial to advanced melanoma because it ensures that autophagy is maintained at a homeostatic level that promotes and ensures the cell's survival. PMID- 28584095 TI - Sensorimotor integration on a rapid time scale. AB - Sensing is fundamental to the control of movement: From grasping objects to speech production, sensing guides action. So far, most of our knowledge about sensorimotor integration comes from visually guided reaching and oculomotor integration, in which the time course and trajectories of movements can be measured at a high temporal resolution. By contrast, production of vocalizations by humans and animals involves complex and variable actions, and each syllable often lasts a few hundreds of milliseconds, making it difficult to infer underlying neural processes. Here, we measured and modeled the transfer of sensory information into motor commands for vocal amplitude control in response to background noise, also known as the Lombard effect. We exploited the brief vocalizations of echolocating bats to trace the time course of the Lombard effect on a millisecond time scale. Empirical studies revealed that the Lombard effect features a response latency of a mere 30 ms and provided the foundation for the quantitative audiomotor model of the Lombard effect. We show that the Lombard effect operates by continuously integrating the sound pressure level of background noise through temporal summation to guide the extremely rapid vocal motor adjustments. These findings can now be extended to models and measures of audiomotor integration in other animals, including humans. PMID- 28584097 TI - Probabilistic model predicts dynamics of vegetation biomass in a desert ecosystem in NW China. AB - The temporal dynamics of vegetation biomass are of key importance for evaluating the sustainability of arid and semiarid ecosystems. In these ecosystems, biomass and soil moisture are coupled stochastic variables externally driven, mainly, by the rainfall dynamics. Based on long-term field observations in northwestern (NW) China, we test a recently developed analytical scheme for the description of the leaf biomass dynamics undergoing seasonal cycles with different rainfall characteristics. The probabilistic characterization of such dynamics agrees remarkably well with the field measurements, providing a tool to forecast the changes to be expected in biomass for arid and semiarid ecosystems under climate change conditions. These changes will depend-for each season-on the forecasted rate of rainy days, mean depth of rain in a rainy day, and duration of the season. For the site in NW China, the current scenario of an increase of 10% in rate of rainy days, 10% in mean rain depth in a rainy day, and no change in the season duration leads to forecasted increases in mean leaf biomass near 25% in both seasons. PMID- 28584096 TI - Marine reserves can mitigate and promote adaptation to climate change. AB - Strong decreases in greenhouse gas emissions are required to meet the reduction trajectory resolved within the 2015 Paris Agreement. However, even these decreases will not avert serious stress and damage to life on Earth, and additional steps are needed to boost the resilience of ecosystems, safeguard their wildlife, and protect their capacity to supply vital goods and services. We discuss how well-managed marine reserves may help marine ecosystems and people adapt to five prominent impacts of climate change: acidification, sea-level rise, intensification of storms, shifts in species distribution, and decreased productivity and oxygen availability, as well as their cumulative effects. We explore the role of managed ecosystems in mitigating climate change by promoting carbon sequestration and storage and by buffering against uncertainty in management, environmental fluctuations, directional change, and extreme events. We highlight both strengths and limitations and conclude that marine reserves are a viable low-tech, cost-effective adaptation strategy that would yield multiple cobenefits from local to global scales, improving the outlook for the environment and people into the future. PMID- 28584098 TI - Offspring of parents who were separated and not speaking to one another have reduced resistance to the common cold as adults. AB - Exposure to parental separation or divorce during childhood has been associated with an increased risk for physical morbidity during adulthood. Here we tested the hypothesis that this association is primarily attributable to separated parents who do not communicate with each other. We also examined whether early exposure to separated parents in conflict is associated with greater viral induced inflammatory response in adulthood and in turn with increased susceptibility to viral-induced upper respiratory disease. After assessment of their parents' relationship during their childhood, 201 healthy volunteers, age 18-55 y, were quarantined, experimentally exposed to a virus that causes a common cold, and monitored for 5 d for the development of a respiratory illness. Monitoring included daily assessments of viral-specific infection, objective markers of illness, and local production of proinflammatory cytokines. Adults whose parents lived apart and never spoke during their childhood were more than three times as likely to develop a cold when exposed to the upper respiratory virus than adults from intact families. Conversely, individuals whose parents were separated but communicated with each other showed no increase in risk compared with those from intact families. These differences persisted in analyses adjusted for potentially confounding variables (demographics, current socioeconomic status, body mass index, season, baseline immunity to the challenge virus, affectivity, and childhood socioeconomic status). Mediation analyses were consistent with the hypothesis that greater susceptibility to respiratory infectious illness among the offspring of noncommunicating parents was attributable to a greater local proinflammatory response to infection. PMID- 28584099 TI - Genome-wide use of high- and low-affinity Tbrain transcription factor binding sites during echinoderm development. AB - Sea stars and sea urchins are model systems for interrogating the types of deep evolutionary changes that have restructured developmental gene regulatory networks (GRNs). Although cis-regulatory DNA evolution is likely the predominant mechanism of change, it was recently shown that Tbrain, a Tbox transcription factor protein, has evolved a changed preference for a low-affinity, secondary binding motif. The primary, high-affinity motif is conserved. To date, however, no genome-wide comparisons have been performed to provide an unbiased assessment of the evolution of GRNs between these taxa, and no study has attempted to determine the interplay between transcription factor binding motif evolution and GRN topology. The study here measures genome-wide binding of Tbrain orthologs by using ChIP-sequencing and associates these orthologs with putative target genes to assess global function. Targets of both factors are enriched for other regulatory genes, although nonoverlapping sets of functional enrichments in the two datasets suggest a much diverged function. The number of low-affinity binding motifs is significantly depressed in sea urchins compared with sea star, but both motif types are associated with genes from a range of functional categories. Only a small fraction (~10%) of genes are predicted to be orthologous targets. Collectively, these data indicate that Tbr has evolved significantly different developmental roles in these echinoderms and that the targets and the binding motifs in associated cis-regulatory sequences are dispersed throughout the hierarchy of the GRN, rather than being biased toward terminal process or discrete functional blocks, which suggests extensive evolutionary tinkering. PMID- 28584100 TI - Entropy in molecular recognition by proteins. AB - Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein-ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein-ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or "entropy meter" also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water-protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins. PMID- 28584102 TI - Crystal structures of the Burkholderia multivorans hopanoid transporter HpnN. AB - Strains of the Burkholderia cepacia complex (Bcc) are Gram-negative opportunisitic bacteria that are capable of causing serious diseases, mainly in immunocompromised individuals. Bcc pathogens are intrinsically resistant to multiple antibiotics, including beta-lactams, aminoglycosides, fluoroquinolones, and polymyxins. They are major pathogens in patients with cystic fibrosis (CF) and can cause severe necrotizing pneumonia, which is often fatal. Hopanoid biosynthesis is one of the major mechanisms involved in multiple antimicrobial resistance of Bcc pathogens. The hpnN gene of B. multivorans encodes an integral membrane protein of the HpnN family of transporters, which is responsible for shuttling hopanoids to the outer membrane. Here, we report crystal structures of B. multivorans HpnN, revealing a dimeric molecule with an overall butterfly shape. Each subunit of the transporter contains 12 transmembrane helices and two periplasmic loops that suggest a plausible pathway for substrate transport. Further analyses indicate that HpnN is capable of shuttling hopanoid virulence factors from the outer leaflet of the inner membrane to the periplasm. Taken together, our data suggest that the HpnN transporter is critical for multidrug resistance and cell wall remodeling in Burkholderia. PMID- 28584101 TI - Deubiquitinating enzyme VCIP135 dictates the duration of botulinum neurotoxin type A intoxication. AB - Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several months, and exerts its effects by specifically cleaving and inactivating SNAP25. A major factor contributing to the persistence of intoxication is the long half-life of the catalytic light chain, which remains enzymatically active months after entry into cells. Here we report that BoNT/A catalytic light chain binds to, and is a substrate for, the ubiquitin ligase HECTD2. However, the light chain evades proteasomal degradation by the dominant effect of a deubiquitinating enzyme, VCIP135/VCPIP1. This deubiquitinating enzyme binds BoNT/A light chain directly, with the two associating in cells through the C-terminal 77 amino acids of the light chain protease. The development of specific DUB inhibitors, together with inhibitors of BoNT/A proteolytic activity, may be useful for reducing the morbidity and public health costs associated with BoNT/A intoxication and could have potential biodefense implications. PMID- 28584104 TI - Phosphorylation and negative regulation of CONSTITUTIVELY PHOTOMORPHOGENIC 1 by PINOID in Arabidopsis. AB - CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) plays crucial roles in various cellular processes via its E3 ubiquitin ligase activity in organisms, ranging from fungi to humans. As a key component in regulating various biological events, COP1 itself is precisely controlled at multiple layers. Here, we report a negative regulator of COP1, PINOID (PID), which positively mediates photomorphogenic development. Specifically, PID genetically and physically interacts with COP1 and directly phosphorylates COP1 at Ser20. As a result, this posttranslational modification serves to repress COP1 activity and promote photomorphogenesis. Our findings signify a key regulatory mechanism for precisely maintaining COP1 activity, thereby ensuring appropriate development in plants. PMID- 28584103 TI - Neurog2 and Ascl1 together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex. AB - A derepression mode of cell-fate specification involving the transcriptional repressors Tbr1, Fezf2, Satb2, and Ctip2 operates in neocortical projection neurons to specify six layer identities in sequence. Less well understood is how laminar fate transitions are regulated in cortical progenitors. The proneural genes Neurog2 and Ascl1 cooperate in progenitors to control the temporal switch from neurogenesis to gliogenesis. Here we asked whether these proneural genes also regulate laminar fate transitions. Several defects were observed in the derepression circuit in Neurog2-/-;Ascl1-/- mutants: an inability to repress expression of Tbr1 (a deep layer VI marker) during upper-layer neurogenesis, a loss of Fezf2+/Ctip2+ layer V neurons, and precocious differentiation of normally late-born, Satb2+ layer II-IV neurons. Conversely, in stable gain-of-function transgenics, Neurog2 promoted differentiative divisions and extended the period of Tbr1+/Ctip2+ deep-layer neurogenesis while reducing Satb2+ upper-layer neurogenesis. Similarly, acute misexpression of Neurog2 in early cortical progenitors promoted Tbr1 expression, whereas both Neurog2 and Ascl1 induced Ctip2. However, Neurog2 was unable to influence the derepression circuit when misexpressed in late cortical progenitors, and Ascl1 repressed only Satb2. Nevertheless, neurons derived from late misexpression of Neurog2 and, to a lesser extent, Ascl1, extended aberrant subcortical axon projections characteristic of early-born neurons. Finally, Neurog2 and Ascl1 altered the expression of Ikaros and Foxg1, known temporal regulators. Proneural genes thus act in a context dependent fashion as early determinants, promoting deep-layer neurogenesis in early cortical progenitors via input into the derepression circuit while also influencing other temporal regulators. PMID- 28584106 TI - Stability of ferrous-iron-rich bridgmanite under reducing midmantle conditions. AB - Our current understanding of the electronic state of iron in lower-mantle minerals leads to a considerable disagreement in bulk sound speed with seismic measurements if the lower mantle has the same composition as the upper mantle (pyrolite). In the modeling studies, the content and oxidation state of Fe in the minerals have been assumed to be constant throughout the lower mantle. Here, we report high-pressure experimental results in which Fe becomes dominantly Fe2+ in bridgmanite synthesized at 40-70 GPa and 2,000 K, while it is in mixed oxidation state (Fe3+/?Fe = 60%) in the samples synthesized below and above the pressure range. Little Fe3+ in bridgmanite combined with the strong partitioning of Fe2+ into ferropericlase will alter the Fe content for these minerals at 1,100- to 1,700-km depths. Our calculations show that the change in iron content harmonizes the bulk sound speed of pyrolite with the seismic values in this region. Our experiments support no significant changes in bulk composition for most of the mantle, but possible changes in physical properties and processes (such as viscosity and mantle flow patterns) in the midmantle. PMID- 28584107 TI - Adaptive self-organization of Bali's ancient rice terraces. AB - Spatial patterning often occurs in ecosystems as a result of a self-organizing process caused by feedback between organisms and the physical environment. Here, we show that the spatial patterns observable in centuries-old Balinese rice terraces are also created by feedback between farmers' decisions and the ecology of the paddies, which triggers a transition from local to global-scale control of water shortages and rice pests. We propose an evolutionary game, based on local farmers' decisions that predicts specific power laws in spatial patterning that are also seen in a multispectral image analysis of Balinese rice terraces. The model shows how feedbacks between human decisions and ecosystem processes can evolve toward an optimal state in which total harvests are maximized and the system approaches Pareto optimality. It helps explain how multiscale cooperation from the community to the watershed scale could persist for centuries, and why the disruption of this self-organizing system by the Green Revolution caused chaos in irrigation and devastating losses from pests. The model shows that adaptation in a coupled human-natural system can trigger self-organized criticality (SOC). In previous exogenously driven SOC models, adaptation plays no role, and no optimization occurs. In contrast, adaptive SOC is a self-organizing process where local adaptations drive the system toward local and global optima. PMID- 28584105 TI - Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake. AB - The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N-substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC50 = 10 nM) inhibitor N-(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology. PMID- 28584108 TI - Gene regulation during Drosophila eggshell patterning. AB - A common path to the formation of complex 3D structures starts with an epithelial sheet that is patterned by inductive cues that control the spatiotemporal activities of transcription factors. These activities are then interpreted by the cis-regulatory regions of the genes involved in cell differentiation and tissue morphogenesis. Although this general strategy has been documented in multiple developmental contexts, the range of experimental models in which each of the steps can be examined in detail and evaluated in its effect on the final structure remains very limited. Studies of the Drosophila eggshell patterning provide unique insights into the multiscale mechanisms that connect gene regulation and 3D epithelial morphogenesis. Here we review the current understanding of this system, emphasizing how the recent identification of cis regulatory regions of genes within the eggshell patterning network enables mechanistic analysis of its spatiotemporal dynamics and evolutionary diversification. It appears that cis-regulatory changes can account for only some aspects of the morphological diversity of Drosophila eggshells, such as the prominent differences in the number of the respiratory dorsal appendages. Other changes, such as the appearance of the respiratory eggshell ridges, are caused by changes in the spatial distribution of inductive signals. Both types of mechanisms are at play in this rapidly evolving system, which provides an excellent model of developmental patterning and morphogenesis. PMID- 28584109 TI - Dapagliflozin suppresses glucagon signaling in rodent models of diabetes. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of antidiabetic drug used for the treatment of diabetes. These drugs are thought to lower blood glucose by blocking reabsorption of glucose by SGLT2 in the proximal convoluted tubules of the kidney. To investigate the effect of inhibiting SGLT2 on pancreatic hormones, we treated perfused pancreata from rats with chemically induced diabetes with dapagliflozin and measured the response of glucagon secretion by alpha cells in response to elevated glucose. In these type 1 diabetic rats, glucose stimulated glucagon secretion by alpha cells; this was prevented by dapagliflozin. Two models of type 2 diabetes, severely diabetic Zucker rats and db/db mice fed dapagliflozin, showed significant improvement of blood glucose levels and glucose disposal, with reduced evidence of glucagon signaling in the liver, as exemplified by reduced phosphorylation of hepatic cAMP responsive element binding protein, reduced expression of phosphoenolpyruvate carboxykinase 2, increased hepatic glycogen, and reduced hepatic glucose production. Plasma glucagon levels did not change significantly. However, dapagliflozin treatment reduced the expression of the liver glucagon receptor. Dapagliflozin in rodents appears to lower blood glucose levels in part by suppressing hepatic glucagon signaling through down-regulation of the hepatic glucagon receptor. PMID- 28584110 TI - Assessing regulatory information in developmental gene regulatory networks. AB - Gene regulatory networks (GRNs) provide a transformation function between the static genomic sequence and the primary spatial specification processes operating development. The regulatory information encompassed in developmental GRNs thus goes far beyond the control of individual genes. We here address regulatory information at different levels of network organization, from single node to subcircuit to large-scale GRNs and discuss how regulatory design features such as network architecture, hierarchical organization, and cis-regulatory logic contribute to the developmental function of network circuits. Using specific subcircuits from the sea urchin endomesoderm GRN, for which both circuit design and biological function have been described, we evaluate by Boolean modeling and in silico perturbations the import of given circuit features on developmental function. The examples include subcircuits encoding positive feedback, mutual repression, and coherent feedforward, as well as signaling interaction circuitry. Within the hierarchy of the endomesoderm GRN, these subcircuits are organized in an intertwined and overlapping manner. Thus, we begin to see how regulatory information encoded at individual nodes is integrated at all levels of network organization to control developmental process. PMID- 28584111 TI - Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication. AB - The aggregation of the amyloid beta peptide (Abeta) into amyloid fibrils is a defining characteristic of Alzheimer's disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Abeta (Abeta42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Abeta42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Abeta42 fibrils after removal of scFvs that bind Abeta42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Abeta42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril catalyzed secondary nucleation process in Abeta42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer's and related neurodegenerative diseases. PMID- 28584113 TI - Consequences of rapid ice sheet melting on the Sahelian population vulnerability. AB - The acceleration of ice sheet melting has been observed over the last few decades. Recent observations and modeling studies have suggested that the ice sheet contribution to future sea level rise could have been underestimated in the latest Intergovernmental Panel on Climate Change report. The ensuing freshwater discharge coming from ice sheets could have significant impacts on global climate, and especially on the vulnerable tropical areas. During the last glacial/deglacial period, megadrought episodes were observed in the Sahel region at the time of massive iceberg surges, leading to large freshwater discharges. In the future, such episodes have the potential to induce a drastic destabilization of the Sahelian agroecosystem. Using a climate modeling approach, we investigate this issue by superimposing on the Representative Concentration Pathways 8.5 (RCP8.5) baseline experiment a Greenland flash melting scenario corresponding to an additional sea level rise ranging from 0.5 m to 3 m. Our model response to freshwater discharge coming from Greenland melting reveals a significant decrease of the West African monsoon rainfall, leading to changes in agricultural practices. Combined with a strong population increase, described by different demography projections, important human migration flows could be potentially induced. We estimate that, without any adaptation measures, tens to hundreds million people could be forced to leave the Sahel by the end of this century. On top of this quantification, the sea level rise impact over coastal areas has to be superimposed, implying that the Sahel population could be strongly at threat in case of rapid Greenland melting. PMID- 28584112 TI - Causes and evolutionary consequences of primordial germ-cell specification mode in metazoans. AB - In animals, primordial germ cells (PGCs) give rise to the germ lines, the cell lineages that produce sperm and eggs. PGCs form in embryogenesis, typically by one of two modes: a likely ancestral mode wherein germ cells are induced during embryogenesis by cell-cell signaling (induction) or a derived mechanism whereby germ cells are specified by using germ plasm-that is, maternally specified germ line determinants (inheritance). The causes of the shift to germ plasm for PGC specification in some animal clades remain largely unknown, but its repeated convergent evolution raises the question of whether it may result from or confer an innate selective advantage. It has been hypothesized that the acquisition of germ plasm confers enhanced evolvability, resulting from the release of selective constraint on somatic gene networks in embryogenesis, thus leading to acceleration of an organism's protein-sequence evolution, particularly for genes expressed at early developmental stages, and resulting in high speciation rates in germ plasm-containing lineages (denoted herein as the "PGC-specification hypothesis"). Although that hypothesis, if supported, could have major implications for animal evolution, our recent large-scale coding-sequence analyses from vertebrates and invertebrates provided important examples of genera that do not support the hypothesis of liberated constraint under germ plasm. Here, we consider reasons why germ plasm might be neither a direct target of selection nor causally linked to accelerated animal evolution. We explore alternate scenarios that could explain the repeated evolution of germ plasm and propose potential consequences of the inheritance and induction modes to animal evolutionary biology. PMID- 28584115 TI - Asymmetric distribution of type IV pili triggered by directional light in unicellular cyanobacteria. AB - The type IV pili (T4P) system is a supermolecular machine observed in prokaryotes. Cells repeat the cycle of T4P extension, surface attachment, and retraction to drive twitching motility. Although the properties of T4P as a motor have been scrutinized with biophysics techniques, the mechanism of regulation remains unclear. Here we provided the framework of the T4P dynamics at the single cell level in Synechocystis sp. PCC6803, which can recognize light direction. We demonstrated that the dynamics was detected by fluorescent beads under an optical microscope and controlled by blue light that induces negative phototaxis; extension and retraction of T4P was activated at the forward side of lateral illumination to move away from the light source. Additionally, we directly visualized each pilus by fluorescent labeling, allowing us to quantify their asymmetric distribution. Finally, quantitative analyses of cell tracking indicated that T4P was generated uniformly within 0.2 min after blue-light exposure, and within the next 1 min the activation became asymmetric along the light axis to achieve directional cell motility; this process was mediated by the photo-sensing protein, PixD. This sequential process provides clues toward a general regulation mechanism of T4P system, which might be essentially common between archaella and other secretion apparatuses. PMID- 28584118 TI - Correction for Ferrari et al., Hypoxia treatment reverses neurodegenerative disease in a mouse model of Leigh syndrome. PMID- 28584114 TI - Establishment of a vernalization requirement in Brachypodium distachyon requires REPRESSOR OF VERNALIZATION1. AB - A requirement for vernalization, the process by which prolonged cold exposure provides competence to flower, is an important adaptation to temperate climates that ensures flowering does not occur before the onset of winter. In temperate grasses, vernalization results in the up-regulation of VERNALIZATION1 (VRN1) to establish competence to flower; however, little is known about the mechanism underlying repression of VRN1 in the fall season, which is necessary to establish a vernalization requirement. Here, we report that a plant-specific gene containing a bromo-adjacent homology and transcriptional elongation factor S-II domain, which we named REPRESSOR OF VERNALIZATION1 (RVR1), represses VRN1 before vernalization in Brachypodium distachyon That RVR1 is upstream of VRN1 is supported by the observations that VRN1 is precociously elevated in an rvr1 mutant, resulting in rapid flowering without cold exposure, and the rapid flowering rvr1 phenotype is dependent on VRN1 The precocious VRN1 expression in rvr1 is associated with reduced levels of the repressive chromatin modification H3K27me3 at VRN1, which is similar to the reduced VRN1 H3K27me3 in vernalized plants. Furthermore, the transcriptome of vernalized wild-type plants overlaps with that of nonvernalized rvr1 plants, indicating loss of rvr1 is similar to the vernalized state at a molecular level. However, loss of rvr1 results in more differentially expressed genes than does vernalization, indicating that RVR1 may be involved in processes other than vernalization despite a lack of any obvious pleiotropy in the rvr1 mutant. This study provides an example of a role for this class of plant-specific genes. PMID- 28584116 TI - High-mobility group box-1 as an autocrine trophic factor in white matter stroke. AB - Maintenance of white matter integrity in health and disease is critical for a variety of neural functions. Ischemic stroke in the white matter frequently results in degeneration of oligodendrocytes (OLs) and myelin. Previously, we found that toll-like receptor 2 (TLR2) expressed in OLs provides cell-autonomous protective effects on ischemic OL death and demyelination in white matter stroke. Here, we identified high-mobility group box-1 (HMGB1) as an endogenous TLR2 ligand that promotes survival of OLs under ischemic stress. HMGB1 rapidly accumulated in the culture medium of OLs exposed to oxygen-glucose deprivation (OGD). This conditioned medium exhibited a protective activity against ischemic OL death that was completely abolished by immunodepletion of HMGB1. Knockdown of HMGB1 or application of glycyrrhizin, a specific HMGB1 inhibitor, aggravated OGD induced OL death, and recombinant HMGB1 application reduced the extent of OL death in a TLR2-dependent manner. We confirmed that cytosolic translocation of HMGB1 and activation of TLR2-mediated signaling pathways occurred in a focal white matter stroke model induced by endothelin-1 injection. Animals with glycyrrhizin coinjection showed an expansion of the demyelinating lesion in a TLR2-dependent manner, accompanied by aggravation of sensorimotor behavioral deficits. These results indicate that HMGB1/TLR2 activates an autocrine trophic signaling pathways in OLs and myelin to maintain structural and functional integrity of the white matter under ischemic conditions. PMID- 28584117 TI - Histamine modulation of the basal ganglia circuitry in the development of pathological grooming. AB - Aberrant histaminergic function has been proposed as a cause of tic disorders. A rare mutation in the enzyme that produces histamine (HA), histidine decarboxylase (HDC), has been identified in patients with Tourette syndrome (TS). Hdc knockout mice exhibit repetitive behavioral pathology and neurochemical characteristics of TS, establishing them as a plausible model of tic pathophysiology. Where, when, and how HA deficiency produces these effects has remained unclear: whether the contribution of HA deficiency to pathogenesis is acute or developmental, and where in the brain the relevant consequences of HA deficiency occur. Here, we address these key pathophysiological questions, using anatomically and cellularly targeted manipulations in mice. We report that specific ablation or chemogenetic silencing of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus leads to markedly elevated grooming, a form of repetitive behavioral pathology, and to elevated markers of neuronal activity in both dorsal striatum and medial prefrontal cortex. Infusion of HA directly into the striatum reverses this behavioral pathology, confirming that acute HA deficiency mediates the effect. Bidirectional chemogenetic regulation reveals that dorsal striatum neurons activated after TMN silencing are both sufficient to produce repetitive behavioral pathology and necessary for the full expression of the effect. Chemogenetic activation of TMN-regulated medial prefrontal cortex neurons, in contrast, increases locomotion and not grooming. These data confirm the centrality of striatal regulation by neurotransmitter HA in the adult in the production of pathological grooming. PMID- 28584120 TI - Correction for Pearce et al., Variation in the beta-endorphin, oxytocin, and dopamine receptor genes is associated with different dimensions of human sociality. PMID- 28584119 TI - Stratospheric ozone over the United States in summer linked to observations of convection and temperature via chlorine and bromine catalysis. AB - We present observations defining (i) the frequency and depth of convective penetration of water into the stratosphere over the United States in summer using the Next-Generation Radar system; (ii) the altitude-dependent distribution of inorganic chlorine established in the same coordinate system as the radar observations; (iii) the high resolution temperature structure in the stratosphere over the United States in summer that resolves spatial and structural variability, including the impact of gravity waves; and (iv) the resulting amplification in the catalytic loss rates of ozone for the dominant halogen, hydrogen, and nitrogen catalytic cycles. The weather radar observations of ~2,000 storms, on average, each summer that reach the altitude of rapidly increasing available inorganic chlorine, coupled with observed temperatures, portend a risk of initiating rapid heterogeneous catalytic conversion of inorganic chlorine to free radical form on ubiquitous sulfate-water aerosols; this, in turn, engages the element of risk associated with ozone loss in the stratosphere over the central United States in summer based upon the same reaction network that reduces stratospheric ozone over the Arctic. The summertime development of the upper level anticyclonic flow over the United States, driven by the North American Monsoon, provides a means of retaining convectively injected water, thereby extending the time for catalytic ozone loss over the Great Plains. Trusted decadal forecasts of UV dosage over the United States in summer require understanding the response of this dynamical and photochemical system to increased forcing of the climate by increasing levels of CO2 and CH4. PMID- 28584121 TI - Applying gene regulatory network logic to the evolution of social behavior. AB - Animal behavior is ultimately the product of gene regulatory networks (GRNs) for brain development and neural networks for brain function. The GRN approach has advanced the fields of genomics and development, and we identify organizational similarities between networks of genes that build the brain and networks of neurons that encode brain function. In this perspective, we engage the analogy between developmental networks and neural networks, exploring the advantages of using GRN logic to study behavior. Applying the GRN approach to the brain and behavior provides a quantitative and manipulative framework for discovery. We illustrate features of this framework using the example of social behavior and the neural circuitry of aggression. PMID- 28584122 TI - An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence. AB - The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7 trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest. PMID- 28584123 TI - Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants. AB - Enzymes that can catalyze the macrocyclization of linear peptide substrates have long been sought for the production of libraries of structurally diverse scaffolds via combinatorial gene assembly as well as to afford rapid in vivo screening methods. Orbitides are plant ribosomally synthesized and posttranslationally modified peptides (RiPPs) of various sizes and topologies, several of which are shown to be biologically active. The diversity in size and sequence of orbitides suggests that the corresponding macrocyclases may be ideal catalysts for production of cyclic peptides. Here we present the biochemical characterization and crystal structures of the plant enzyme PCY1 involved in orbitide macrocyclization. These studies demonstrate how the PCY1 S9A protease fold has been adapted for transamidation, rather than hydrolysis, of acyl-enzyme intermediates to yield cyclic products. Notably, PCY1 uses an unusual strategy in which the cleaved C-terminal follower peptide from the substrate stabilizes the enzyme in a productive conformation to facilitate macrocyclization of the N terminal fragment. The broad substrate tolerance of PCY1 can be exploited as a biotechnological tool to generate structurally diverse arrays of macrocycles, including those with nonproteinogenic elements. PMID- 28584124 TI - Correction for Ding et al., Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles. PMID- 28584125 TI - Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation. AB - Paired box 6 (Pax6) is considered to be the master control gene for eye development in all seeing animals studied so far. In vertebrates, it is required not only for lens/retina formation but also for the development of the CNS, olfactory system, and pancreas. Although Pax6 plays important roles in cell differentiation, proliferation, and patterning during the development of these systems, the underlying mechanism remains poorly understood. In the fruit fly, Drosophila melanogaster, Pax6 also functions in a range of tissues, including the eye and brain. In this report, we describe the function of Pax6 in Drosophila eye antennal disc development. Previous studies have suggested that the two fly Pax6 genes, eyeless (ey) and twin of eyeless (toy), initiate eye specification, whereas eyegone (eyg) and the Notch (N) pathway independently regulate cell proliferation. Here, we show that Pax6 controls eye progenitor cell survival and proliferation through the activation of teashirt (tsh) and eyg, thereby indicating that Pax6 initiates both eye specification and proliferation. Although simultaneous loss of ey and toy during early eye-antennal disc development disrupts the development of all head structures derived from the eye-antennal disc, overexpression of N or tsh in the absence of Pax6 rescues only antennal and head epidermis development. Furthermore, overexpression of tsh induces a homeotic transformation of the fly head into thoracic structures. Taking these data together, we demonstrate that Pax6 promotes development of the entire eye antennal disc and that the retinal determination network works to repress alternative tissue fates, which ensures proper development of adult head structures. PMID- 28584126 TI - Temperature variability is integrated by a spatially embedded decision-making center to break dormancy in Arabidopsis seeds. AB - Plants perceive and integrate information from the environment to time critical transitions in their life cycle. Some mechanisms underlying this quantitative signal processing have been described, whereas others await discovery. Seeds have evolved a mechanism to integrate environmental information by regulating the abundance of the antagonistically acting hormones abscisic acid (ABA) and gibberellin (GA). Here, we show that hormone metabolic interactions and their feedbacks are sufficient to create a bistable developmental fate switch in Arabidopsis seeds. A digital single-cell atlas mapping the distribution of hormone metabolic and response components revealed their enrichment within the embryonic radicle, identifying the presence of a decision-making center within dormant seeds. The responses to both GA and ABA were found to occur within distinct cell types, suggesting cross-talk occurs at the level of hormone transport between these signaling centers. We describe theoretically, and demonstrate experimentally, that this spatial separation within the decision making center is required to process variable temperature inputs from the environment to promote the breaking of dormancy. In contrast to other noise filtering systems, including human neurons, the functional role of this spatial embedding is to leverage variability in temperature to transduce a fate-switching signal within this biological system. Fluctuating inputs therefore act as an instructive signal for seeds, enhancing the accuracy with which plants are established in ecosystems, and distributed computation within the radicle underlies this signal integration mechanism. PMID- 28584127 TI - Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. AB - Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain microRNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergic-mediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy. PMID- 28584129 TI - Future of fundamental discovery in US biomedical research. AB - Young researchers are crucially important for basic science as they make unexpected, fundamental discoveries. Since 1982, we find a steady drop in the number of grant-eligible basic-science faculty [principal investigators (PIs)] younger than 46. This fall occurred over a 32-y period when inflation-corrected congressional funds for NIH almost tripled. During this time, the PI success ratio (fraction of basic-science PIs who are R01 grantees) dropped for younger PIs (below 46) and increased for older PIs (above 55). This age-related bias seems to have caused the steady drop in the number of young basic-science PIs and could reduce future US discoveries in fundamental biomedical science. The NIH recognized this bias in its 2008 early-stage investigator (ESI) policy to fund young PIs at higher rates. We show this policy is working and recommend that it be enhanced by using better data. Together with the National Institute of General Medical Sciences (NIGMS) Maximizing Investigators' Research Award (MIRA) program to reward senior PIs with research time in exchange for less funding, this may reverse a decades-long trend of more money going to older PIs. To prepare young scientists for increased demand, additional resources should be devoted to transitional postdoctoral fellowships already offered by NIH. PMID- 28584128 TI - Bcl11b and combinatorial resolution of cell fate in the T-cell gene regulatory network. AB - T-cell development from hematopoietic progenitors depends on multiple transcription factors, mobilized and modulated by intrathymic Notch signaling. Key aspects of T-cell specification network architecture have been illuminated through recent reports defining roles of transcription factors PU.1, GATA-3, and E2A, their interactions with Notch signaling, and roles of Runx1, TCF-1, and Hes1, providing bases for a comprehensively updated model of the T-cell specification gene regulatory network presented herein. However, the role of lineage commitment factor Bcl11b has been unclear. We use self-organizing maps on 63 RNA-seq datasets from normal and perturbed T-cell development to identify functional targets of Bcl11b during commitment and relate them to other regulomes. We show that both activation and repression target genes can be bound by Bcl11b in vivo, and that Bcl11b effects overlap with E2A-dependent effects. The newly clarified role of Bcl11b distinguishes discrete components of commitment, resolving how innate lymphoid, myeloid, and dendritic, and B-cell fate alternatives are excluded by different mechanisms. PMID- 28584130 TI - Bam and Otu can regulate stem cell fate by stabilizing cyclin A. PMID- 28584131 TI - Detection of sickness in conspecifics using olfactory and visual cues. PMID- 28584132 TI - Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. AB - Oncogenic RAS mutations are present in 15-30% of thyroid carcinomas. Endogenous expression of mutant Ras is insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. We used Sleeping Beauty (SB) transposon mutagenesis to identify events that cooperate with HrasG12V in thyroid tumor development. Random genomic integration of SB transposons primarily generated loss-of-function events that significantly increased thyroid tumor penetrance in Tpo-Cre/homozygous FR-HrasG12V mice. The thyroid tumors closely phenocopied the histological features of human RAS-driven, poorly differentiated thyroid cancers. Characterization of transposon insertion sites in the SB-induced tumors identified 45 recurrently mutated candidate cancer genes. These mutation profiles were remarkably concordant with mutated cancer genes identified in a large series of human poorly differentiated and anaplastic thyroid cancers screened by next-generation sequencing using the MSK-IMPACT panel of cancer genes, which we modified to include all SB candidates. The disrupted genes primarily clustered in chromatin remodeling functional nodes and in the PI3K pathway. ATXN7, a component of a multiprotein complex with histone acetylase activity, scored as a significant SB hit. It was recurrently mutated in advanced human cancers and significantly co-occurred with RAS or NF1 mutations. Expression of ATXN7 mutants cooperated with oncogenic RAS to induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene. PMID- 28584134 TI - Ancestral gene regulatory networks drive cancer. PMID- 28584133 TI - Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. AB - In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using high-affinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies. PMID- 28584135 TI - Genome-wide association study to identify variants associated with acute severe vaso-occlusive pain in sickle cell anemia. PMID- 28584136 TI - Obinutuzumab: what is there to learn from clinical trials? AB - Obinutuzumab (OBZ) is a recombinant type II anti-CD20 and immunoglobulin G1 Fc optimized monoclonal antibody (mAb), recently approved in chronic lymphocytic leukemia (CLL; B-cell CLL) and follicular lymphoma (FL). Rituximab (RTX) is frequently considered as its "ancestor" and OBZ clinical development was justified by the importance of FcgammaRIIIA-mediated mechanisms in RTX clinical activity. However, RTX differs from OBZ in 2 critical independent properties: being a type I anti-CD20 mAb and not being Fc-optimized. Moreover, the use of a different dosing regimen for RTX and OBZ further complicates any interpretation of clinical results. The results obtained for OBZ in CLL provide new arguments for FcgammaRIIIA-mediated mechanisms when the target antigen is expressed at a low density. Results of OBZ in FL confirm the interest for FcgammaRIIIA-mediated mechanisms, with some limitations, some of them being possibly due to lack of OBZ induced complement activation. The situation in diffuse large B-cell lymphoma is deceiving, as the possible gains of activity of OBZ appear to be annihilated by the lack of complement activation. Although RTX was by chance an anti-CD20 mAb with equilibrated pharmacodynamic properties, the reinforcement of some of these properties, which has been done at the expense of complement activation, has conferred an advantage in some B-cell disorders while restricting OBZ indications. The OBZ story nicely demonstrates that the future of naked mAbs is to design agents with optimized and tailored properties, and that this must be done step by step, with a full clinical validation. PMID- 28584138 TI - Initial Treatment of Cancer Patients with Fluconazole-Susceptible Dose-Dependent Candida glabrata Fungemia: Better Outcome with an Echinocandin or Polyene Compared to an Azole? AB - The 28-day crude mortality rate in 68 cancer patients with fluconazole susceptible dose-dependent Candida glabrata fungemia started on treatment (within 48 h after blood culture collection) with an echinocandin or liposomal amphotericin-B was better (30%) than those treated with azole monotherapy (52%) (P = 0.07). After adjusting for confounders, azole monotherapy also was associated with worse 28-day survival (hazard ratio, 3.8; P = 0.003). PMID- 28584137 TI - Susceptibility of Colistin-Resistant, Gram-Negative Bacteria to Antimicrobial Peptides and Ceragenins. AB - The susceptibility of colistin-resistant clinical isolates of Klebsiella pneumoniae to ceragenins and antimicrobial peptides (AMPs) suggests that there is little to no cross-resistance between colistin and ceragenins/AMPs and that lipid A modifications are found in bacteria with modest changes in susceptibility to ceragenins and with high levels of resistance to colistin. These results suggest that there are differences in the resistance mechanisms to colistin and ceragenins/AMPs. PMID- 28584139 TI - Genomic Analysis of Multidrug-Resistant Escherichia coli from North Carolina Community Hospitals: Ongoing Circulation of CTX-M-Producing ST131-H30Rx and ST131 H30R1 Strains. AB - Escherichia coli sequence type 131 (ST131) predominates globally among multidrug resistant (MDR) E. coli strains. We used whole-genome sequencing (WGS) to investigate 63 MDR E. coli isolates from 7 North Carolina community hospitals (2010 to 2015). Of these, 39 (62%) represented ST131, including 37 (95%) from the ST131-H30R subclone: 10 (27%) from its H30R1 subset and 27 (69%) from its H30Rx subset. ST131 core genomes differed by a median of 15 (range, 0 to 490) single nucleotide variants (SNVs) overall versus only 7 within H30R1 (range, 3 to 12 SNVs) and 11 within H30Rx (range, 0 to 21). The four isolates with identical core genomes were all H30Rx. Epidemiological and clinical characteristics did not vary significantly by strain type, but many patients with MDR E. coli or H30Rx infection were critically ill and had poor outcomes. H30Rx isolates characteristically exhibited fluoroquinolone resistance and CTX-M-15 production, had a high prevalence of trimethoprim-sulfamethoxazole resistance (89%), sul1 (89%), and dfrA17 (85%), and were enriched for specific virulence traits, and all qualified as extraintestinal pathogenic E. coli The high overall prevalence of CTX-M-15 appeared to be possibly attributable to its association with the ST131 H30Rx subclone and IncF[F2:A1:B-] plasmids. Some phylogenetically clustered non ST131 MDR E. coli isolates also had distinctive serotypes/fimH types, fluoroquinolone mutations, CTX-M variants, and IncF types. Thus, WGS analysis of our community hospital source MDR E. coli isolates suggested ongoing circulation and differentiation of E. coli ST131 subclones, with clonal segregation of CTX-M variants, other resistance genes, Inc-type plasmids, and virulence genes. PMID- 28584140 TI - Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study. AB - Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.). PMID- 28584141 TI - Multimechanistic Monoclonal Antibodies (MAbs) Targeting Staphylococcus aureus Alpha-Toxin and Clumping Factor A: Activity and Efficacy Comparisons of a MAb Combination and an Engineered Bispecific Antibody Approach. AB - Secreted alpha-toxin and surface-localized clumping factor A (ClfA) are key virulence determinants in Staphylococcus aureus bloodstream infections. We previously demonstrated that prophylaxis with a multimechanistic monoclonal antibody (MAb) combination against alpha-toxin (MEDI4893*) and ClfA (11H10) provided greater strain coverage and improved efficacy in an S. aureus lethal bacteremia model. Subsequently, 11H10 was found to exhibit reduced affinity and impaired inhibition of fibrinogen binding to ClfA002 expressed by members of a predominant hospital-associated methicillin-resistant S. aureus (MRSA) clone, ST5. Consequently, we identified another anti-ClfA MAb (SAR114) from human tonsillar B cells with >100-fold increased affinity for three prominent ClfA variants, including ClfA002, and potent inhibition of bacterial agglutination by 112 diverse clinical isolates. We next constructed bispecific Abs (BiSAbs) comprised of 11H10 or SAR114 as IgG scaffolds and grafted anti-alpha-toxin (MEDI4893*) single-chain variable fragment to the amino or carboxy terminus of the anti-ClfA heavy chains. Although the BiSAbs exhibited in vitro potencies similar to those of the parental MAbs, only 11H10-BiSAb, but not SAR114-BiSAb, showed protective activity in murine infection models comparable to the respective MAb combination. In vivo activity with SAR114-BiSAb was observed in infection models with S. aureus lacking ClfA. Our data suggest that high-affinity binding to ClfA sequesters the SAR114-BiSAb to the bacterial surface, thereby reducing both alpha-toxin neutralization and protection in vivo These results indicate that a MAb combination targeting ClfA and alpha-toxin is more promising for future development than the corresponding BiSAb. PMID- 28584142 TI - Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients. AB - Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment in an intensive care unit (ICU). These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, to this date there are no data describing the elimination of micafungin during high-dose continuous venovenous hemodiafiltration with modified AN69 membranes. The aim of this prospective open-label pharmacokinetic study was to assess whether micafungin plasma levels are affected by continuous hemodiafiltration in critical ill patients using the commonly employed AN69 membrane. A total of 10 critically ill patients with micafungin treatment due to suspected or proven candidemia were included in this trial. Prefilter/postfilter micafungin clearance was measured to be 46.0 ml/min (+/-21.7 ml/min; n = 75 individual time points), while hemofilter clearance calculated by the sieving coefficient was 0.0038 ml/min (+/-0.002 ml/min; n = 75 individual time points). Total body clearance was measured to be 14.0 ml/min (+/-7.0 ml/min; n = 12). The population area under the curve from 0 to 24 h (AUC0-24) was calculated as 158.5 mg . h/liter (+/-79.5 mg . h/liter; n = 13). In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous hemodiafiltration with AN69 membranes. A dose elevation may, however, be justified in certain cases. (This study has been registered at ClinicalTrials.gov under identifier NCT02651038.). PMID- 28584143 TI - Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis. AB - Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0-24) to MIC. Optimal microbial kill was achieved at an AUC0-24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300 mg/day dose did not achieve AUC0-24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0-24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials. PMID- 28584144 TI - Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA. AB - Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, which is highly prevalent worldwide and has a major impact on reproductive and neonatal health. The superbug status of N. gonorrhoeae necessitates the development of drugs with different mechanisms of action. Here, we focused on targeting the nitrite reductase AniA, which is a pivotal component of N. gonorrhoeae anaerobic respiration and biofilm formation. Our studies showed that gonococci expressing AniA containing the altered catalytic residues D137A and H280A failed to grow under anaerobic conditions, demonstrating that the nitrite reductase function is essential. To facilitate the pharmacological targeting of AniA, new crystal structures of AniA were refined to 1.90-A and 2.35-A resolutions, and a phage display approach with libraries expressing randomized linear dodecameric peptides or heptameric peptides flanked by a pair of cysteine residues was utilized. Biopanning experiments led to the identification of 29 unique peptides, with 1 of them, C7-3, being identified multiple times. Evaluation of their ability to interact with AniA using enzyme-linked immunosorbent assay and computational docking studies revealed that C7-3 was the most promising inhibitor, binding near the type 2 copper site of the enzyme, which is responsible for interaction with nitrite. Subsequent enzymatic assays and biolayer interferometry with a synthetic C7-3 and its derivatives, C7-3m1 and C7-3m2, demonstrated potent inhibition of AniA. Finally, the MIC50 value of C7-3 and C7-3m2 against anaerobically grown N. gonorrhoeae was 0.6 mM. We present the first peptide inhibitors of AniA, an enzyme that should be further exploited for antigonococcal drug development. PMID- 28584146 TI - Targeted Metabolomics Analysis Identifies Intestinal Microbiota-Derived Urinary Biomarkers of Colonization Resistance in Antibiotic-Treated Mice. AB - Antibiotics excreted into the intestinal tract may disrupt the microbiota that provide colonization resistance against enteric pathogens and alter normal metabolic functions of the microbiota. Many of the bacterial metabolites produced in the intestinal tract are absorbed systemically and excreted in urine. Here, we used a mouse model to test the hypothesis that alterations in levels of targeted bacterial metabolites in urine specimens could provide useful biomarkers indicating disrupted or intact colonization resistance. To assess in vivo colonization resistance, mice were challenged with Clostridium difficile spores orally 3, 6, and 11 days after the completion of 2 days of treatment with piperacillin-tazobactam, aztreonam, or saline. For concurrent groups of antibiotic-treated mice, urine samples were analyzed by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify the concentrations of 11 compounds targeted as potential biomarkers of colonization resistance. Aztreonam did not affect colonization resistance, whereas piperacillin-tazobactam disrupted colonization resistance 3 days after piperacillin-tazobactam treatment, with complete recovery by 11 days after treatment. Three of the 11 compounds exhibited a statistically significant and >10-fold increase (the tryptophan metabolite N-acetyltryptophan) or decrease (the plant polyphenyl derivatives cinnamoylglycine and enterodiol) in concentrations in urine 3 days after piperacillin-tazobactam treatment, followed by recovery to baseline that coincided with the restoration of in vivo colonization resistance. These urinary metabolites could provide useful and easily accessible biomarkers indicating intact or disrupted colonization resistance during and after antibiotic treatment. PMID- 28584145 TI - Efficacy of beta-Lactam/beta-Lactamase Inhibitor Combinations for the Treatment of Bloodstream Infection Due to Extended-Spectrum-beta-Lactamase-Producing Enterobacteriaceae in Hematological Patients with Neutropenia. AB - beta-Lactam/beta-lactamase inhibitors (BLBLIs) were compared to carbapenems in two cohorts of hematological neutropenic patients with extended-spectrum-beta lactamase (ESBL) bloodstream infection (BSI): the empirical therapy cohort (174 patients) and the definitive therapy cohort (251 patients). The 30-day case fatality rates and other secondary outcomes were similar in the two therapy groups of the two cohorts and also in the propensity-matched cohorts. BLBLIs might be carbapenem-sparing alternatives for the treatment of BSI due to ESBLs in these patients. PMID- 28584147 TI - Influence of IS256 on Genome Variability and Formation of Small-Colony Variants in Staphylococcus aureus. AB - Staphylococcus aureus has acquired resistance to nearly all antibiotics used in clinical practice. Whereas some resistance mechanisms are conferred by uptake of resistance genes, others evolve by mutation. In this study, IS256 has been shown to play a role, e.g., in S. aureus strains displaying intermediate resistance to vancomycin (VISA). To characterize the IS256 insertion sites in the genomes of two closely related sequence type 247 (ST247) VISA strains, all insertions were mapped in both VISA and a susceptible control strain. The results showed that the three ST247 strains contained the highest number so far of IS256 insertions for all sequenced S. aureus strains. Furthermore, in contrast to the case with the other IS elements in these genomes, the IS256 insertion sites were not identical in the closely related strains, indicating a high transposition frequency of IS256 When IS256 was introduced into a laboratory strain which was then cultured in the presence of antibiotics, it was possible to isolate small-colony variants (SCVs) that possessed IS256 insertions in guaA and hemY that displayed increased resistance to vancomycin and aminoglycosides, respectively. For these clones, a very rapid reversion to the wild type that resembled the fast reversion of clinical SCVs was observed. The reversion was caused by excision of IS256 in a small number of fast-growing clones that quickly outcompeted the SCVs in broth cultures. In conclusion, the presence of IS256 confers a strong genomic plasticity that is useful for adaptation to antibiotic stress. PMID- 28584148 TI - Transcriptional Regulator TetR21 Controls the Expression of the Staphylococcus aureus LmrS Efflux Pump. AB - TetR21 controls the expression of Tet38 and LmrS efflux pumps. A tetR21 mutant, QT21, exhibited a 4-fold increase in the transcription level of lmrSStaphylococcus aureuslmrS overexpressor showed increases of 4-fold and 2 fold, respectively, in the MICs of chloramphenicol and erythromycin, while the MICs of lmrS mutant QT18 and lmrS-tetR21 mutant QT1821 remained similar to those of parental strain RN6390. TetR21 does not bind to the promoter of lmrS, suggesting indirect regulation of lmrS. PMID- 28584149 TI - Different Resistance Mechanisms for Cadazolid and Linezolid in Clostridium difficile Found by Whole-Genome Sequencing Analysis. AB - Cadazolid (CDZ) is a new antibiotic currently in clinical development for the treatment of Clostridium difficile infections. CDZ interferes with the bacterial protein synthesis machinery. The aim of the present study was to identify resistance mechanisms for CDZ and compare the results to those obtained for linezolid (LZD) in C. difficile by whole-genome sequencing (WGS) of strains generated by in vitro passages and to those obtained for LZD-resistant clinical isolates. Clones of C. difficile 630 selected with CDZ during 46 passages had a maximally 4-fold increase in CDZ MIC, while the LZD MIC for clones selected with LZD increased up to 16-fold. CDZ cross-resistance with LZD was maximally 4-fold, and no cross-resistance with other antibiotics tested was observed. Our data suggest that there are different resistance mechanisms for CDZ and LZD in C. difficile Mutations after passages with CDZ were found in rplD (ribosomal protein L4) as well as in tra and rmt, whereas similar experiments with LZD showed mutations in rplC (ribosomal protein L3), reg, and tpr, indicating different resistance mechanisms. Although high degrees of variation between the sequenced genomes of the clinical isolates were observed, the same mutation in rplC was found in two clinical isolates with high LZD MICs. No mutations were found in the 23S rRNA genes, and attempts to isolate the cfr gene from resistant clinical isolates were unsuccessful. Analysis of 50% inhibitory concentrations (IC50s) determined in in vitro transcription/translation assays performed with C. difficile cell extracts from passaged clones correlated well with the MIC values for all antibiotics tested, indicating that the ribosomal mutations are causing the resistant phenotype. PMID- 28584150 TI - Upregulation of Apoptosis Pathway Genes in Peripheral Blood Mononuclear Cells of HIV-Infected Individuals with Antiretroviral Therapy-Associated Mitochondrial Toxicity. AB - A case-control study of the effect of antiretroviral therapy (ART) on apoptosis pathway genes comprising 16 cases (HIV infected with mitochondrial toxicity) and 16 controls (HIV uninfected) was conducted. A total of 26 of 84 genes of the apoptosis pathway were differentially expressed. Two of the upregulated genes, DFFA and TNFRSF1A, classified 75% of study participants correctly as either a case or control. Thus, apoptosis may be in the causal pathway of ART-associated mitochondrial toxicity. These two genes could be markers for detecting and monitoring ART-induced mitochondrial toxicity. PMID- 28584151 TI - Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti HIV Activity. AB - A novel fibronectin-based protein (Adnectin) HIV-1 inhibitor was generated using in vitro selection. This inhibitor binds to human CD4 with a high affinity (3.9 nM) and inhibits viral entry at a step after CD4 engagement and preceding membrane fusion. The progenitor sequence of this novel inhibitor was selected from a library of trillions of Adnectin variants using mRNA display and then further optimized for improved antiviral and physical properties. The final optimized inhibitor exhibited full potency against a panel of 124 envelope (gp160) proteins spanning 11 subtypes, indicating broad-spectrum activity. Resistance profiling studies showed that this inhibitor required 30 passages (151 days) in culture to acquire sufficient resistance to result in viral titer breakthrough. Resistance mapped to the loss of multiple potential N-linked glycosylation sites in gp120, suggesting that inhibition is due to steric hindrance of CD4-binding-induced conformational changes. PMID- 28584152 TI - Pharmacodynamic Optimization for Treatment of Invasive Candida auris Infection. AB - Candida auris is an emerging multidrug-resistant threat. The pharmacodynamics of three antifungal classes against nine C. auris strains was explored using a murine invasive candidiasis model. The total drug median pharmacodynamic (PD) target associated with net stasis was a fluconazole AUC/MIC (the area under the concentration-time curve over 24 h in the steady state divided by the MIC) of 26, an amphotericin B Cmax/MIC (maximum concentration of drug in serum divided by the MIC) of 0.9, and a micafungin AUC/MIC of 54. The micafungin PD targets for C. auris were >=20-fold lower than those of other Candida species in this animal model. Clinically relevant micafungin exposures produced the most killing among the three classes. PMID- 28584153 TI - Use of beta-Lactam/beta-Lactamase Inhibitors for Extended-Spectrum-beta-Lactamase Infections: Defining the Right Patient Population. AB - In a multicenter, multinational observational study that included neutropenic patients with bloodstream infections by extended-spectrum-beta-lactamase producing species, Gudiol et al. (Antimicrob. Agents Chemother. 61:e00164-17, 2017, https://doi.org/10.1128/AAC.00164-17) demonstrated that beta-lactam/beta lactamase inhibitors are effective treatment options. A review of this work, however, reminds us that some lingering questions remain for specific high-risk subgroups. PMID- 28584154 TI - PA3225 Is a Transcriptional Repressor of Antibiotic Resistance Mechanisms in Pseudomonas aeruginosa. AB - The tssABC1 locus is part of the Hcp secretion island I (HSI-I) type VI secretion system (T6SS) in Pseudomonas aeruginosa Previous work implicated the tssC1 gene in P. aeruginosa biofilm-specific antibiotic resistance, and tssC1 is preferentially expressed in biofilms compared to planktonic cells. Using a DNA dependent protein pulldown approach, we discovered that PA3225, an uncharacterized LysR-type transcriptional regulator, specifically bound to the tssABC1 upstream regulatory region. The deletion of PA3225 led to a 2-fold decrease in tssA1 expression levels in planktonic cells compared to the wild type, and tssA1 expression was slightly reduced in DeltaPA3225 biofilms compared to wild-type biofilms. Intriguingly, further investigations revealed that the DeltaPA3225 mutant was less susceptible to multiple, structurally unrelated antibiotics with various mechanisms of action when grown planktonically. The DeltaPA3225 mutant was additionally more resistant to ciprofloxacin when grown in a biofilm. The decreased antibiotic susceptibility of the DeltaPA3225 strain was linked to the transcriptional upregulation of the MexAB-OprM efflux pump. By using transcriptome sequencing (RNA-seq), other PA3225-regulated genes were identified, and the products of these genes, such as the putative ABC transporter PA3228, may also contribute to antibiotic resistance. PMID- 28584155 TI - Capsid Assembly Modulators Have a Dual Mechanism of Action in Primary Human Hepatocytes Infected with Hepatitis B Virus. AB - Hepatitis B virus (HBV) capsid assembly is a critical step in the propagation of the virus and is mediated by the core protein. Due to its multiple functions in the viral life cycle, core became an attractive target for new antiviral therapies. Capsid assembly modulators (CAMs) accelerate the kinetics of capsid assembly and prevent encapsidation of the polymerase-pregenomic RNA (Pol-pgRNA) complex, thereby blocking viral replication. CAM JNJ-632 is a novel and potent inhibitor of HBV replication in vitro across genotypes A to D. It induces the formation of morphologically intact viral capsids, as demonstrated by size exclusion chromatography and electron microscopy studies. Antiviral profiling in primary human hepatocytes revealed that CAMs prevented formation of covalently closed circular DNA in a dose-dependent fashion when the compound was added together with the viral inoculum, whereas nucleos(t)ide analogues (NAs) did not. This protective effect translated into a dose-dependent reduction of intracellular HBV RNA levels as well as reduced HBe/cAg and HBsAg levels in the cell culture supernatant. The same observation was made with another CAM (BAY41 4109), suggesting that mechanistic rather than compound-specific effects play a role. Our data show that CAMs have a dual mechanism of action, inhibiting early and late steps of the viral life cycle. These effects clearly differentiate CAMs from NAs and may translate into higher functional cure rates in a clinical setting when given alone or in combination with the current standard of care. PMID- 28584157 TI - Menoctone Resistance in Malaria Parasites Is Conferred by M133I Mutations in Cytochrome b That Are Transmissible through Mosquitoes. AB - Malaria-related mortality has slowly decreased over the past decade; however, eradication of malaria requires the development of new antimalarial chemotherapies that target liver stages of the parasite and combat the emergence of drug resistance. The diminishing arsenal of anti-liver-stage compounds sparked our interest in reviving the old and previously abandoned compound menoctone. In support of these studies, we developed a new convergent synthesis method that was facile, required fewer steps, produced better yields, and utilized less expensive reagents than the previously published method. Menoctone proved to be highly potent against liver stages of Plasmodium berghei (50 percent inhibitory concentration [IC50] = 0.41 nM) and erythrocytic stages of Plasmodium falciparum (113 nM). We selected for resistance to menoctone and found M133I mutations in cytochrome b of both P. falciparum and P. berghei The same mutation has been observed previously in atovaquone resistance, and we confirmed cross-resistance between menoctone and atovaquone in vitro (for P. falciparum) and in vivo (for P. berghei). Finally, we assessed the transmission potential of menoctone-resistant P. berghei and found that the M133I mutant parasites were readily transmitted from mouse to mosquitoes and back to mice. In each step, the M133I mutation in cytochrome b, inducing menoctone resistance, was confirmed. In summary, this study is the first to show the mechanism of resistance to menoctone and that menoctone and atovaquone resistance is transmissible through mosquitoes. PMID- 28584156 TI - Role of AxyZ Transcriptional Regulator in Overproduction of AxyXY-OprZ Multidrug Efflux System in Achromobacter Species Mutants Selected by Tobramycin. AB - AxyXY-OprZ is an RND-type efflux system that confers innate aminoglycoside resistance to Achromobacter spp. We investigated here a putative TetR family transcriptional regulator encoded by the axyZ gene located upstream of axyXY-oprZ An in-frame axyZ gene deletion assay led to increased MICs of antibiotic substrates of the efflux system, including aminoglycosides, cefepime, fluoroquinolones, tetracyclines, and erythromycin, indicating that the product of axyZ negatively regulates expression of axyXY-oprZ Moreover, we identified an amino acid substitution at position 29 of AxyZ (V29G) in a clinical Achromobacter strain that occurred during the course of chronic respiratory tract colonization in a cystic fibrosis (CF) patient. This substitution, also detected in three other strains exposed in vitro to tobramycin, led to an increase in the axyY transcription level (5- to 17-fold) together with an increase in antibiotic resistance level. This overproduction of AxyXY-OprZ is the first description of antibiotic resistance acquisition due to modification of a chromosomally encoded mechanism in Achromobacter and might have an impact on the management of infected CF patients. Indeed, tobramycin is widely used for aerosol therapy within this population, and we have demonstrated that it easily selects mutants with increased MICs of not only aminoglycosides but also fluoroquinolones, cefepime, and tetracyclines. PMID- 28584158 TI - Identification of Novel Efflux Proteins Rv0191, Rv3756c, Rv3008, and Rv1667c Involved in Pyrazinamide Resistance in Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is a critical drug used for the treatment of tuberculosis (TB). PZA is a prodrug that requires conversion to the active component pyrazinoic acid (POA) by pyrazinamidase (PZase) encoded by the pncA gene. Although resistance to PZA is mostly caused by pncA mutations and less commonly by rpsA, panD, and clpC1 mutations, clinical strains without these mutations are known to exist. While efflux of POA was demonstrated in Mycobacterium tuberculosis previously, the efflux proteins involved have not been identified. Here we performed POA binding studies with an M. tuberculosis proteome microarray and identified four efflux proteins (Rv0191, Rv3756c, Rv3008, and Rv1667c) that bind POA. Overexpression of the four efflux pump genes in M. tuberculosis caused low-level resistance to PZA and POA but not to other drugs. Furthermore, addition of efflux pump inhibitors such as reserpine, piperine, and verapamil caused increased susceptibility to PZA in M. tuberculosis strains overexpressing the efflux proteins Rv0191, Rv3756c, Rv3008, and Rv1667c. Our studies indicate that these four efflux proteins may be responsible for PZA/POA efflux and cause PZA resistance in M. tuberculosis Future studies are needed to assess their roles in PZA resistance in clinical strains. PMID- 28584159 TI - In Vitro Antibiofilm Activity of Eucarobustol E against Candida albicans. AB - Formyl-phloroglucinol meroterpenoids (FPMs) are important types of natural products with various bioactivities. Our antifungal susceptibility assay showed that one of the Eucalyptus robusta-derived FPMs, eucarobustol E (EE), exerted a strong inhibitory effect against Candida albicans biofilms at a concentration of 16 MUg/ml. EE was found to block the yeast-to-hypha transition and reduce the cellular surface hydrophobicity of the biofilm cells. RNA sequencing and real time reverse transcription-PCR analysis showed that exposure to 16 MUg/ml of EE resulted in marked reductions in the levels of expressions of genes involved in hyphal growth (EFG1, CPH1, TEC1, EED1, UME6, and HGC1) and cell surface protein genes (ALS3, HWP1, and SAP5). Interestingly, in response to EE, genes involved in ergosterol biosynthesis were downregulated, while the farnesol-encoding gene (DPP3) was upregulated, and these findings were in agreement with those from the quantification of ergosterol and farnesol. Combined with the obvious elevation of negative regulator genes (TUP1, NRG1), we speculated that EE's inhibition of carbon flow to ergosterol triggered the mechanisms of the negative regulation of hyphal growth and eventually led to biofilm inhibition. PMID- 28584160 TI - Rapid Identification of Different Escherichia coli Sequence Type 131 Clades. AB - Escherichia coli sequence type 131 (ST131) is a pandemic clonal lineage that is responsible for the global increase in fluoroquinolone resistance and extended spectrum-beta-lactamase (ESBL) producers. The members of ST131 clade C, especially subclades C2 and C1-M27, are associated with ESBLs. We developed a multiplex conventional PCR assay with the ability to detect all ST131 clades (A, B, and C), as well as C subclades (C1-M27, C1-nM27 [C1-non-M27], and C2). To validate the assay, we used 80 ST131 global isolates that had been fully sequenced. We then used the assay to define the prevalence of each clade in two Japanese collections consisting of 460 ESBL-producing E. coli ST131 (2001-12) and 329 E. coli isolates from extraintestinal sites (ExPEC) (2014). The assay correctly identified the different clades in all 80 global isolates: clades A (n = 12), B (n = 12), and C, including subclades C1-M27 (n = 16), C1-nM27 (n = 20), C2 (n = 17), and other C (n = 3). The assay also detected all 565 ST131 isolates in both collections without any false positives. Isolates from clades A (n = 54), B (n = 23), and C (n = 483) corresponded to the O serotypes and the fimH types of O16-H41, O25b-H22, and O25b-H30, respectively. Of the 483 clade C isolates, C1 M27 was the most common subclade (36%), followed by C1-nM27 (32%) and C2 (15%). The C1-M27 subclade with blaCTX-M-27 became especially prominent after 2009. Our novel multiplex PCR assay revealed the predominance of the C1-M27 subclade in recent Japanese ESBL-producing E. coli isolates and is a promising tool for epidemiological studies of ST131. PMID- 28584161 TI - Parasitic Protozoa and Interactions with the Host Intestinal Microbiota. AB - Parasitic protozoan infections represent a major health burden in the developing world and contribute significantly to morbidity and mortality. These infections are often associated with considerable variability in clinical presentation. An emerging body of work suggests that the intestinal microbiota may help to explain some of these differences in disease expression. The objective of this minireview is to synthesize recent progress in this rapidly advancing field. Studies of humans and animals and in vitro studies of the contribution of the intestinal microbiota to infectious disease are discussed. We hope to provide an understanding of the human-protozoal pathogen-microbiome interaction and to speculate on how that might be leveraged for treatment. PMID- 28584164 TI - Technology Turbocharges Functional Genomics. PMID- 28584162 TI - Chlamydia muridarum with Mutations in Chromosomal Genes tc0237 and/or tc0668 Is Deficient in Colonizing the Mouse Gastrointestinal Tract. AB - Chlamydiae colonize the gastrointestinal tracts of both animals and humans. However, their medical significance remains unknown. We have previously shown that wild-type Chlamydia muridarum spreads to and establishes stable colonization of the gastrointestinal tract following intravaginal inoculation. In the present study, we found that C. muridarum with mutations in chromosomal genes tc0237 and/or tc0668 was defective in spreading to the mouse gastrointestinal tract, which correlated with its attenuated pathogenicity in the upper genital tract. This correlation was more consistent than that of chlamydial pathogenicity with ascending infection in the genital tract, since attenuated C. muridarum spread significantly less to the gastrointestinal tract but maintained robust ascending infection of the upper genital tract. Transcervical inoculation further confirmed the correlation between C. muridarum spreading to the gastrointestinal tract and its pathogenicity in the upper genital tract. Finally, defective spreading of C. muridarum mutants was due to their inability to colonize the gastrointestinal tract since intragastric inoculation did not rescue the mutants' colonization. Thus, promoting C. muridarum colonization of the gastrointestinal tract may represent a primary function of the TC0237 and TC0668 proteins. Correlation of chlamydial colonization of the gastrointestinal tract with chlamydial pathogenicity in the upper genital tract suggests a potential role for gastrointestinal chlamydiae in genital tract pathogenicity. PMID- 28584163 TI - Protection of Arabidopsis Blunt-Ended Telomeres Is Mediated by a Physical Association with the Ku Heterodimer. AB - Telomeres form specialized chromatin that protects natural chromosome termini from being recognized as DNA double-strand breaks. Plants possess unusual blunt ended telomeres that are unable to form t-loops or complex with single-strand DNA binding proteins, raising the question of the mechanism behind their protection. We have previously suggested that blunt-ended telomeres in Arabidopsis thaliana are protected by Ku, a DNA repair factor with a high affinity for DNA ends. In nonhomologous end joining, Ku loads onto broken DNA via a channel consisting of positively charged amino acids. Here, we demonstrate that while association of Ku with plant telomeres also depends on this channel, Ku's requirements for DNA binding differ between DNA repair and telomere protection. We show that a Ku complex proficient in DNA loading but impaired in translocation along DNA is able to protect blunt-ended telomeres but is deficient in DNA repair. This suggests that Ku physically sequesters blunt-ended telomeres within its DNA binding channel, shielding them from other DNA repair machineries. PMID- 28584167 TI - Severe Cushing's syndrome due to small cell prostate carcinoma: a case and review of literature. AB - Cushing's syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) is associated with a variety of tumours most of which arise in the thorax or abdomen. Prostate carcinoma is a rare but important cause of rapidly progressive CS. To report a case of severe CS due to ACTH production from prostate neuroendocrine carcinoma and summarise previous published cases. A 71-year-old male presented with profound hypokalaemia, oedema and new onset hypertension. The patient reported two weeks of weight gain, muscle weakness, labile mood and insomnia. CS due to ectopic ACTH production was confirmed with failure to suppress cortisol levels following low- and high-dose dexamethasone suppression tests in the presence of a markedly elevated ACTH and a normal pituitary MRI. Computed tomography demonstrated an enlarged prostate with features of malignancy, confirmed by MRI. Subsequent prostatic biopsy confirmed neuroendocrine carcinoma of small cell type and conventional adenocarcinoma of the prostate. Adrenal steroidogenesis blockade was commenced using ketoconazole and metyrapone. Complete biochemical control of CS and evidence of disease regression on imaging occurred after four cycles of chemotherapy with carboplatin and etoposide. By the sixth cycle, the patient demonstrated radiological progression followed by recurrence of CS and died nine months after initial presentation. Prostate neuroendocrine carcinoma is a rare cause of CS that can be rapidly fatal, and early aggressive treatment of the CS is important. In CS where the cause of EAS is unable to be identified, a pelvic source should be considered and imaging of the pelvis carefully reviewed. PMID- 28584165 TI - Phylogenomic Synteny Network Analysis of MADS-Box Transcription Factor Genes Reveals Lineage-Specific Transpositions, Ancient Tandem Duplications, and Deep Positional Conservation. AB - Conserved genomic context provides critical information for comparative evolutionary analysis. With the increase in numbers of sequenced plant genomes, synteny analysis can provide new insights into gene family evolution. Here, we exploit a network analysis approach to organize and interpret massive pairwise syntenic relationships. Specifically, we analyzed synteny networks of the MADS box transcription factor gene family using 51 completed plant genomes. In combination with phylogenetic profiling, several novel evolutionary patterns were inferred and visualized from synteny network clusters. We found lineage-specific clusters that derive from transposition events for the regulators of floral development (APETALA3 and PI) and flowering time (FLC) in the Brassicales and for the regulators of root development (AGL17) in Poales. We also identified two large gene clusters that jointly encompass many key phenotypic regulatory Type II MADS-box gene clades (SEP1, SQUA, TM8, SEP3, FLC, AGL6, and TM3). Gene clustering and gene trees support the idea that these genes are derived from an ancient tandem gene duplication that likely predates the radiation of the seed plants and then expanded by subsequent polyploidy events. We also identified angiosperm-wide conservation of synteny of several other less studied clades. Combined, these findings provide new hypotheses for the genomic origins, biological conservation, and divergence of MADS-box gene family members. PMID- 28584166 TI - SH3 Domain-Containing Protein 2 Plays a Crucial Role at the Step of Membrane Tubulation during Cell Plate Formation. AB - During cytokinesis in plants, trans-Golgi network-derived vesicles accumulate at the center of dividing cells and undergo various structural changes to give rise to the planar cell plate. However, how this conversion occurs at the molecular level remains elusive. In this study, we report that SH3 Domain-Containing Protein 2 (SH3P2) in Arabidopsis thaliana plays a crucial role in converting vesicles to the planar cell plate. SH3P2 RNAi plants showed cytokinesis-defective phenotypes and produced aggregations of vesicles at the leading edge of the cell plate. SH3P2 localized to the leading edge of the cell plate, particularly the constricted or curved regions of the cell plate. The BAR domain of SH3P2 induced tubulation of vesicles. SH3P2 formed a complex with dynamin-related protein 1A (DRP1A) and affected DRP1A accumulation to the cell plate. Based on these results, we propose that SH3P2 functions together with DRP1A to convert the fused vesicles to tubular structures during cytokinesis. PMID- 28584168 TI - Palmitate and oleate exert differential effects on insulin signalling and glucose uptake in human skeletal muscle cells. AB - Saturated fatty acids are implicated in the development of insulin resistance, whereas unsaturated fatty acids may have a protective effect on metabolism. We tested in primary human myotubes if insulin resistance induced by saturated fatty acid palmitate can be ameliorated by concomitant exposure to unsaturated fatty acid oleate. Primary human myotubes were pretreated with palmitate, oleate or their combination for 12 h. Glucose uptake was determined by intracellular accumulation of [3H]-2-deoxy-d-glucose, insulin signalling and activation of endoplasmic reticulum (ER) stress by Western blotting, and mitochondrial reactive oxygen species (ROS) production by fluorescent dye MitoSOX. Exposure of primary human myotubes to palmitate impaired insulin-stimulated Akt-Ser473, AS160 and GSK 3beta phosphorylation, induced ER stress signalling target PERK and stress kinase JNK 54 kDa isoform. These effects were virtually abolished by concomitant exposure of palmitate-treated myotubes to oleate. However, an exposure to palmitate, oleate or their combination reduced insulin-stimulated glucose uptake. This was associated with increased mitochondrial ROS production in palmitate treated myotubes co-incubated with oleate, and was alleviated by antioxidants MitoTempo and Tempol. Thus, metabolic and intracellular signalling events diverge in myotubes treated with palmitate and oleate. Exposure of human myotubes to excess fatty acids increases ROS production and induces insulin resistance. PMID- 28584169 TI - The Effects of Physical Activity and Body Fat Mass on Colorectal Polyp Recurrence in Patients with Previous Colorectal Cancer. AB - We aimed to identify the effects of physical activity and body composition on colorectal polyp recurrence in patients with previous colorectal cancer. A total of 300 patients were selected randomly from the colorectal cancer survivor cohort of Severance Hospital (Seoul, Korea). Patients reported various recreational physical activities and received surveillance colonoscopy. Body composition was measured with a body composition analyzer. We compared patients who exercised for at least 1 hour/week (active) with those who exercised less frequently or not at all (sedentary). The active exercise group (n = 203) had a lower recurrence of advanced adenoma than the sedentary group (n = 97; 6.4% vs. 14.4%, P = 0.023). The prevalence of advanced adenoma recurrence decreased in an exercise dose dependent manner (Ptrend = 0.019). In multivariate logistic analysis, the independent factors associated with advanced polyp recurrence were body fat mass [OR, 7.601; 95% confidence interval (CI), 1.583-36.485; P = 0.011] and active exercise (OR, 0.340; 95% CI, 0.143-0.809; P = 0.015). In Cox proportional hazards models, body fat mass (HR, 5.315; 95% CI, 1.173-24.083; P = 0.030) and active exercise (HR, 0.367; 95% CI, 0.162-0.833; P = 0.017) were the independent factors associated with cumulative advanced adenoma recurrence. In conclusion, exercising for at least 1 hour/week and low body fat mass were found to be related to lower rates of colorectal polyp recurrence in the surveillance of colorectal cancer survivors. Cancer Prev Res; 10(8); 478-84. (c)2017 AACR. PMID- 28584170 TI - One Health for a changing world: new perspectives from Africa. AB - The concept of One Health, which aims to drive improvements in human, animal and ecological health through an holistic approach, has been gaining increasing support and attention in recent years. While this concept has much appeal, there are few examples where it has been successfully put into practice. This Special Issue explores the challenges in African contexts, with papers looking at the complex interactions between ecosystems, diseases and poverty dynamics; at underlying social and political dimensions; at the potentials for integrative modelling; and at the changes in policy and practice required to realise a One Health approach. This introductory paper offers an overview of the 11 papers, coming from diverse disciplinary perspectives, that each explore how a One Health approach can work in a world of social, economic and environmental change. PMID- 28584171 TI - Local disease-ecosystem-livelihood dynamics: reflections from comparative case studies in Africa. AB - This article explores the implications for human health of local interactions between disease, ecosystems and livelihoods. Five interdisciplinary case studies addressed zoonotic diseases in African settings: Rift Valley fever (RVF) in Kenya, human African trypanosomiasis in Zambia and Zimbabwe, Lassa fever in Sierra Leone and henipaviruses in Ghana. Each explored how ecological changes and human-ecosystem interactions affect pathogen dynamics and hence the likelihood of zoonotic spillover and transmission, and how socially differentiated peoples' interactions with ecosystems and animals affect their exposure to disease. Cross case analysis highlights how these dynamics vary by ecosystem type, across a range from humid forest to semi-arid savannah; the significance of interacting temporal and spatial scales; and the importance of mosaic and patch dynamics. Ecosystem interactions and services central to different people's livelihoods and well-being include pastoralism and agro-pastoralism, commercial and subsistence crop farming, hunting, collecting food, fuelwood and medicines, and cultural practices. There are synergies, but also tensions and trade-offs, between ecosystem changes that benefit livelihoods and affect disease. Understanding these can inform 'One Health' approaches towards managing ecosystems in ways that reduce disease risks and burdens.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584172 TI - Integrative modelling for One Health: pattern, process and participation. AB - This paper argues for an integrative modelling approach for understanding zoonoses disease dynamics, combining process, pattern and participatory models. Each type of modelling provides important insights, but all are limited. Combining these in a '3P' approach offers the opportunity for a productive conversation between modelling efforts, contributing to a 'One Health' agenda. The aim is not to come up with a composite model, but seek synergies between perspectives, encouraging cross-disciplinary interactions. We illustrate our argument with cases from Africa, and in particular from our work on Ebola virus and Lassa fever virus. Combining process-based compartmental models with macroecological data offers a spatial perspective on potential disease impacts. However, without insights from the ground, the 'black box' of transmission dynamics, so crucial to model assumptions, may not be fully understood. We show how participatory modelling and ethnographic research of Ebola and Lassa fever can reveal social roles, unsafe practices, mobility and movement and temporal changes in livelihoods. Together with longer-term dynamics of change in societies and ecologies, all can be important in explaining disease transmission, and provide important complementary insights to other modelling efforts. An integrative modelling approach therefore can offer help to improve disease control efforts and public health responses.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well being'. PMID- 28584173 TI - Spatial, seasonal and climatic predictive models of Rift Valley fever disease across Africa. AB - Understanding the emergence and subsequent spread of human infectious diseases is a critical global challenge, especially for high-impact zoonotic and vector-borne diseases. Global climate and land-use change are likely to alter host and vector distributions, but understanding the impact of these changes on the burden of infectious diseases is difficult. Here, we use a Bayesian spatial model to investigate environmental drivers of one of the most important diseases in Africa, Rift Valley fever (RVF). The model uses a hierarchical approach to determine how environmental drivers vary both spatially and seasonally, and incorporates the effects of key climatic oscillations, to produce a continental risk map of RVF in livestock (as a proxy for human RVF risk). We find RVF risk has a distinct seasonal spatial pattern influenced by climatic variation, with the majority of cases occurring in South Africa and Kenya in the first half of an El Nino year. Irrigation, rainfall and human population density were the main drivers of RVF cases, independent of seasonal, climatic or spatial variation. By accounting more subtly for the patterns in RVF data, we better determine the importance of underlying environmental drivers, and also make space- and time sensitive predictions to better direct future surveillance resources.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584174 TI - Poor livestock keepers: ecosystem-poverty-health interactions. AB - Humans have never been healthier, wealthier or more numerous. Yet, present success may be at the cost of future prosperity and in some places, especially in sub-Saharan Africa, poverty persists. Livestock keepers, especially pastoralists, are over-represented among the poor. Poverty has been mainly attributed to a lack of access, whether to goods, education or enabling institutions. More recent insights suggest ecosystems may influence poverty and the self-reinforcing mechanisms that constitute poverty traps in more subtle ways. The plausibility of zoonoses as poverty traps is strengthened by landmark studies on disease burden in recent years. While in theory, endemic zoonoses are best controlled in the animal host, in practice, communities are often left to manage disease themselves, with the focus on treatment rather than prevention. We illustrate this with results from a survey on health costs in a pastoral ecosystem. Epidemic zoonoses are more likely to elicit official responses, but these can have unintended consequences that deepen poverty traps. In this context, a systems understanding of disease control can lead to more effective and pro-poor disease management. We illustrate this with an example of how a system dynamics model can help optimize responses to Rift Valley fever outbreaks in Kenya by giving decision makers real-time access to the costs of the delay in vaccinating. In conclusion, a broader, more ecological understanding of poverty and of the appropriate responses to the diseases of poverty can contribute to improved livelihoods for livestock keepers in Africa.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well being'. PMID- 28584175 TI - One Health, emerging infectious diseases and wildlife: two decades of progress? AB - Infectious diseases affect people, domestic animals and wildlife alike, with many pathogens being able to infect multiple species. Fifty years ago, following the wide-scale manufacture and use of antibiotics and vaccines, it seemed that the battle against infections was being won for the human population. Since then, however, and in addition to increasing antimicrobial resistance among bacterial pathogens, there has been an increase in the emergence of, mostly viral, zoonotic diseases from wildlife, sometimes causing fatal outbreaks of epidemic proportions. Concurrently, infectious disease has been identified as an increasing threat to wildlife conservation. A synthesis published in 2000 showed common anthropogenic drivers of disease threats to biodiversity and human health, including encroachment and destruction of wildlife habitat and the human-assisted spread of pathogens. Almost two decades later, the situation has not changed and, despite improved knowledge of the underlying causes, little has been done at the policy level to address these threats. For the sake of public health and wellbeing, human-kind needs to work better to conserve nature and preserve the ecosystem services, including disease regulation, that biodiversity provides while also understanding and mitigating activities which lead to disease emergence. We consider that holistic, One Health approaches to the management and mitigation of the risks of emerging infectious diseases have the greatest chance of success.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584177 TI - Structural drivers of vulnerability to zoonotic disease in Africa. AB - This paper argues that addressing the underlying structural drivers of disease vulnerability is essential for a 'One Health' approach to tackling zoonotic diseases in Africa. Through three case studies-trypanosomiasis in Zimbabwe, Ebola and Lassa fever in Sierra Leone and Rift Valley fever in Kenya-we show how political interests, commercial investments and conflict and securitization all generate patterns of vulnerability, reshaping the political ecology of disease landscapes, influencing traditional coping mechanisms and affecting health service provision and outbreak responses. A historical, political economy approach reveals patterns of 'structural violence' that reinforce inequalities and marginalization of certain groups, increasing disease risks. Addressing the politics of One Health requires analysing trade-offs and conflicts between interests and visions of the future. For all zoonotic diseases economic and political dimensions are ultimately critical and One Health approaches must engage with these factors, and not just end with an 'anti-political' focus on institutional and disciplinary collaboration.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well being'. PMID- 28584176 TI - One Health contributions towards more effective and equitable approaches to health in low- and middle-income countries. AB - Emerging zoonoses with pandemic potential are a stated priority for the global health security agenda, but endemic zoonoses also have a major societal impact in low-resource settings. Although many endemic zoonoses can be treated, timely diagnosis and appropriate clinical management of human cases is often challenging. Preventive 'One Health' interventions, e.g. interventions in animal populations that generate human health benefits, may provide a useful approach to overcoming some of these challenges. Effective strategies, such as animal vaccination, already exist for the prevention, control and elimination of many endemic zoonoses, including rabies, and several livestock zoonoses (e.g. brucellosis, leptospirosis, Q fever) that are important causes of human febrile illness and livestock productivity losses in low- and middle-income countries. We make the case that, for these diseases, One Health interventions have the potential to be more effective and generate more equitable benefits for human health and livelihoods, particularly in rural areas, than approaches that rely exclusively on treatment of human cases. We hypothesize that applying One Health interventions to tackle these health challenges will help to build trust, community engagement and cross-sectoral collaboration, which will in turn strengthen the capacity of fragile health systems to respond to the threat of emerging zoonoses and other future health challenges. One Health interventions thus have the potential to align the ongoing needs of disadvantaged communities with the concerns of the broader global community, providing a pragmatic and equitable approach to meeting the global goals for sustainable development and supporting the global health security agenda.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well being'. PMID- 28584178 TI - Views from many worlds: unsettling categories in interdisciplinary research on endemic zoonotic diseases. AB - Interdisciplinary research on zoonotic disease has tended to focus on 'risk' of disease transmission as a conceptual common denominator. With reference to endemic zoonoses at the livestock-human interface, we argue for considering a broader sweep of disciplinary insights from anthropology and other social sciences in interdisciplinary dialogue, in particular cross-cultural perspectives on human-animal engagement. We consider diverse worldviews where human-animal encounters are perceived of in terms of the kinds of social relations they generate, and the notion of culture is extended to the 'natural' world. This has implications for how animals are valued, treated and prioritized. Thinking differently with and about animals and about species' boundaries could enable ways of addressing zoonotic diseases which have closer integration with people's own cultural norms. If we can bring this kind of knowledge into One Health debates, we find ourselves with a multiplicity of worldviews, where bounded categories such as human:animal and nature:culture cannot be assumed. This might in turn influence our scientific ways of seeing our own disciplinary cultures, and generate novel ways of understanding zoonoses and constructing solutions.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584179 TI - Zoonoses, One Health and complexity: wicked problems and constructive conflict. AB - Infectious zoonoses emerge from complex interactions among social and ecological systems. Understanding this complexity requires the accommodation of multiple, often conflicting, perspectives and narratives, rooted in different value systems and temporal-spatial scales. Therefore, to be adaptive, successful and sustainable, One Health approaches necessarily entail conflicts among observers, practitioners and scholars. Nevertheless, these integrative approaches have, both implicitly and explicitly, tended to marginalize some perspectives and prioritize others, resulting in a kind of technocratic tyranny. An important function of One Health approaches should be to facilitate and manage those conflicts, rather than to impose solutions.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584180 TI - Engaging research with policy and action: what are the challenges of responding to zoonotic disease in Africa? AB - Zoonotic diseases will maintain a high level of public policy attention in the coming decades. From the spectre of a global pandemic to anxieties over agricultural change, urbanization, social inequality and threats to natural ecosystems, effectively preparing and responding to endemic and emerging diseases will require technological, institutional and social innovation. Much current discussion emphasizes the need for a 'One Health' approach: bridging disciplines and sectors to tackle these complex dynamics. However, as attention has increased, so too has an appreciation of the practical challenges in linking multi-disciplinary, multi-sectoral research with policy, action and impact. In this commentary paper, we reflect on these issues with particular reference to the African sub-continent. We structure the themes of our analysis on the existing literature, expert opinion and 11 interviews with leading One Health scholars and practitioners, conducted at an international symposium in 2016. We highlight a variety of challenges in research and knowledge production, in the difficult terrain of implementation and outreach, and in the politicized nature of decision-making and priority setting. We then turn our attention to a number of strategies that might help reconfigure current pathways and accepted norms of practice. These include: (i) challenging scientific expertise; (ii) strengthening national multi-sectoral coordination; (iii) building on what works; and (iv) re framing policy narratives. We argue that bridging the research-policy-action interface in Africa, and better connecting zoonoses, ecosystems and well-being in the twenty-first century, will ultimately require greater attention to the democratization of science and public policy.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well being'. PMID- 28584181 TI - Facility-based surveillance for emerging infectious diseases; diagnostic practices in rural West African hospital settings: observations from Ghana. AB - The aim of this study was to better understand the effectiveness of Integrated Disease Surveillance and Response (IDSR) facility-based surveillance in detecting newly emerging infectious diseases (EIDs) in rural West African settings. A six month ethnographic study was undertaken in 2012 in the Techiman Municipality of the Brong-Ahafo Region of Ghana, aimed at documenting the trajectories of febrile illness cases of unknown origin occurring within four rural communities. Particular attention was paid to where these trajectories involved the use of formal healthcare facilities and the diagnostic practices that occurred there. Seventy-six participants were enrolled in the study, and 24 complete episodes of illness were documented. While participants routinely used hospital treatment when confronted with enduring or severe illness, the diagnostic process within clinical settings meant that an unusual diagnosis, such as an EID, was unlikely to be considered. Facility-based surveillance is unlikely to be effective in detecting EIDs due to a combination of clinical care practices and the time constraints associated with individual episodes of illness, particularly in the resource-limited settings of rural West Africa, where febrile illness due to malaria is common and specific diagnostic assays are largely unavailable. The success of the 'One Health' approach to EIDs in West Africa is predicated on characterization of accurately diagnosed disease burdens. To this end, we must address inefficiencies in the dominant approaches to EID surveillance and the weaknesses of health systems in the region generally.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'. PMID- 28584182 TI - FOXM1 in Cancer: Interactions and Vulnerabilities. AB - FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as beta-catenin or SMAD3 to induce oncogenic WNT and TGFbeta signaling pathways, respectively. In this review, I will discuss the protein protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs. Cancer Res; 77(12); 3135-9. (c)2017 AACR. PMID- 28584183 TI - Nature and Nurture: What Determines Tumor Metabolic Phenotypes? AB - Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131-4. (c)2017 AACR. PMID- 28584184 TI - Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities. AB - On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data. Cancer Res; 77(12); 3140-3. (c)2017 AACR. PMID- 28584185 TI - TLR-3/9 Agonists Synergize with Anti-ErbB2 mAb-Letter. PMID- 28584186 TI - Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data. AB - OBJECTIVE: To assess the comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in elderly. METHODS: In a retrospective cohort study using 2006-2012 Medicare claims data, we included patients newly treated with allopurinol or febuxostat (baseline period of 183 days without either medication). We used 5:1 propensity-matched Cox regression analyses to compare the HR of incident renal disease with allopurinol use (and dose) versus febuxostat (reference). Sensitivity analyses included multivariable adjusted regression models. RESULTS: There were 31 465 new allopurinol or febuxostat treatment episodes in 26 443 patients; 8570 ended in incident renal disease. Crude rates of incident renal disease per 1000 person-years were 192 with allopurinol versus 338 with febuxostat. Crude rates of incident renal disease per 1000 person-years were lower with higher daily dose: allopurinol <200, 200-299 and >=300 mg/day with 238, 176 and 155; and febuxostat 40 and 80 mg/day with 341 and 326, respectively. In propensity-matched analyses, compared with febuxostat, allopurinol use was associated with lower HR of incident renal disease, 0.61 (95% CI 0.49 to 0.77). Compared with febuxostat 40 mg/day, allopurinol doses <200, 200-299 and >=300 mg/day were associated with lower HR of incident renal disease, 0.75 (95% CI 0.65 to 0.86), 0.61 (95% CI 0.52 to 0.73) and 0.48 (95% CI 0.41 to 0.55), respectively. Sensitivity analyses using multivariable-adjusted regression confirmed these findings. CONCLUSIONS: Allopurinol was associated with a lower risk of incident renal disease in elderly patients than febuxostat. Future studies need to examine the mechanism of this potential renal benefit of allopurinol. PMID- 28584188 TI - How are enthesitis, dactylitis and nail involvement measured and reported in recent clinical trials of psoriatic arthritis? A systematic literature review. PMID- 28584187 TI - Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double blind, phase III equivalence study. AB - OBJECTIVES: ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. METHODS: In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. RESULTS: A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. CONCLUSIONS: Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. TRIAL REGISTRATION NUMBER: NCT01970475; Results. PMID- 28584190 TI - Extracellular polyphosphate signals through Ras and Akt to prime Dictyostelium discoideum cells for development. AB - Linear chains of five to hundreds of phosphates called polyphosphate are found in organisms ranging from bacteria to humans, but their function is poorly understood. In Dictyostelium discoideum, polyphosphate is used as a secreted signal that inhibits cytokinesis in an autocrine negative feedback loop. To elucidate how cells respond to this unusual signal, we undertook a proteomic analysis of cells treated with physiological levels of polyphosphate and observed that polyphosphate causes cells to decrease levels of actin cytoskeleton proteins, possibly explaining how polyphosphate inhibits cytokinesis. Polyphosphate also causes proteasome protein levels to decrease, and in both Dictyostelium and human leukemia cells, decreases proteasome activity and cell proliferation. Polyphosphate also induces Dictyostelium cells to begin development by increasing expression of the cell-cell adhesion molecule CsA (also known as CsaA) and causing aggregation, and this effect, as well as the inhibition of proteasome activity, is mediated by Ras and Akt proteins. Surprisingly, Ras and Akt do not affect the ability of polyphosphate to inhibit proliferation, suggesting that a branching pathway mediates the effects of polyphosphate, with one branch affecting proliferation, and the other branch affecting development. PMID- 28584189 TI - The efficacy of motivational counselling and SMS reminders on daily sitting time in patients with rheumatoid arthritis: a randomised controlled trial. AB - OBJECTIVES: The aim of this report is to investigate the efficacy of an individually tailored, theory-based behavioural intervention for reducing daily sitting time, pain and fatigue, as well as improving health-related quality of life, general self-efficacy, physical function and cardiometabolic biomarkers in patients with rheumatoid arthritis (RA). METHODS: In this randomised controlled trial 150 patients with RA were randomised to an intervention or a no intervention control group. The intervention group received three individual motivational counselling sessions and short message service or text messages aimed at reduction of sedentary behaviour during the 16-week intervention period. Primary outcome was change in daily sitting time measured objectively by ActivPAL. Secondary outcomes included change in pain, fatigue, physical function, general self-efficacy, quality of life, blood pressure, blood lipids, haemoglobin A1c, body weight, body mass index, waist circumference and waist-hip ratio. RESULTS: 75 patients were allocated to each group. Mean reduction in daily sitting time was -1.61 hours/day in the intervention versus 0.59 hours/day increase in the control group between-group difference -2.20 (95% CI -2.72 to 1.69; p<0.0001) hours/day in favour of the intervention group. Most of the secondary outcomes were also in favour of the intervention. CONCLUSION: An individually tailored, behavioural intervention reduced daily sitting time in patients with RA and improved patient-reported outcomes and cholesterol levels. TRIAL REGISTRATION NUMBER: NCT01969604; Results. PMID- 28584191 TI - ARHGAP42 is activated by Src-mediated tyrosine phosphorylation to promote cell motility. AB - The tyrosine kinase Src acts as a key regulator of cell motility by phosphorylating multiple protein substrates that control cytoskeletal and adhesion dynamics. In an earlier phosphotyrosine proteomics study, we identified a novel Rho-GTPase activating protein, now known as ARHGAP42, as a likely biologically relevant Src substrate. ARHGAP42 is a member of a family of RhoGAPs distinguished by tandem BAR-PH domains lying N-terminal to the GAP domain. Like other family members, ARHGAP42 acts preferentially as a GAP for RhoA. We show that Src principally phosphorylates ARHGAP42 on tyrosine 376 (Tyr-376) in the short linker between the BAR-PH and GAP domains. The expression of ARHGAP42 variants in mammalian cells was used to elucidate its regulation. We found that the BAR domain is inhibitory toward the GAP activity of ARHGAP42, such that BAR domain deletion resulted in decreased active GTP-bound RhoA and increased cell motility. With the BAR domain intact, ARHGAP42 GAP activity could be activated by phosphorylation of Tyr-376 to promote motile cell behavior. Thus, phosphorylation of ARHGAP42 Tyr-376 is revealed as a novel regulatory event by which Src can affect actin dynamics through RhoA inhibition. PMID- 28584192 TI - Arf6 and Rab22 mediate T cell conjugate formation by regulating clathrin independent endosomal membrane trafficking. AB - Endosomal trafficking can influence the composition of the plasma membrane and the ability of cells to polarize their membranes. Here, we examined whether trafficking through clathrin-independent endocytosis (CIE) affects the ability of T cells to form a cell-cell conjugate with antigen-presenting cells (APCs). We show that CIE occurs in both the Jurkat T cell line and primary human T cells. In Jurkat cells, the activities of two guanine nucleotide binding proteins, Arf6 and Rab22 (also known as Rab22a), influence CIE and conjugate formation. Expression of the constitutively active form of Arf6, Arf6Q67L, inhibits CIE and conjugate formation, and results in the accumulation of vacuoles containing lymphocyte function-associated antigen 1 (LFA-1) and CD4, molecules important for T cell interaction with the APC. Moreover, expression of the GTP-binding defective mutant of Rab22, Rab22S19N, inhibits CIE and conjugate formation, suggesting that Rab22 function is required for these activities. Furthermore, Jurkat cells expressing Rab22S19N were impaired in spreading onto coverslips coated with T cell receptor-activating antibodies. These observations support a role for CIE, Arf6 and Rab22 in conjugate formation between T cells and APCs. PMID- 28584193 TI - Let-7 contributes to diabetic retinopathy but represses pathological ocular angiogenesis. AB - The in vivo function of microRNAs (miRNAs or miRs) in diabetic retinopathy (DR) and age-related macular degeneration (AMD) remains unclear. Here we report that let-7 family members are expressed in retinal and choroidal endothelial cells (EC). In ECs, overexpression of let-7 by adenovirus represses EC proliferation, migration, and networking in vitro, while inhibition of the let-7 family with a locked nucleic acid (LNA)-anti-miR has the opposite effect. Mechanistically, silencing of the let-7 target gene HMGA2 mimics the phenotype of let-7 overexpression in ECs. Let-7 transgenic (let-7-Tg) mice show features of non proliferative DR, including tortuous retinal vessels and defective pericyte coverage. However, these mice develop significantly less choroidal neovascularization (CNV) compared to wildtype controls after laser injury. Consistently, silencing of let-7 in the eye increased laser-induced CNV in wild type mice. Together, our data establish a causative role of let-7 in non proliferative diabetic retinopathy and a repressive function of let-7 in pathological angiogenesis, suggesting distinct implications of let-7 in the pathogenesis of DR and AMD. PMID- 28584194 TI - Efficient and Accurate Translation Initiation Directed by TISU Involves RPS3 and RPS10e Binding and Differential Eukaryotic Initiation Factor 1A Regulation. AB - Canonical translation initiation involves ribosomal scanning, but short 5' untranslated region (5'UTR) mRNAs are translated in a scanning-independent manner. The extent and mechanism of scanning-independent translation are not fully understood. Here we report that short 5'UTR mRNAs constitute a substantial fraction of the translatome. Short 5'UTR mRNAs are enriched with TISU (translation initiator of short 5'UTR), a 12-nucleotide element directing efficient scanning-independent translation. Comprehensive mutagenesis revealed that each AUG codon-flanking nucleotide of TISU contributes to translational strength, but only a few are important for accuracy. Using site-specific UV cross linking of ribosomal complexes assembled on TISU mRNA, we demonstrate specific binding of TISU to ribosomal proteins at the E and A sites. We identified RPS3 as the major TISU binding protein in the 48S complex A site. Upon 80S complex formation, RPS3 interaction is weakened and switched to RPS10e (formerly called RPS10). We further demonstrate that TISU is particularly dependent on eukaryotic initiation factor 1A (eIF1A) which interacts with both RPS3 and RPS10e. Our findings suggest that the cap-recruited ribosome specifically binds the TISU nucleotides at the A and E sites in cooperation with eIF1A to promote scanning arrest. PMID- 28584197 TI - Extended wavelength anisotropy resolved multidimensional emission spectroscopy (ARMES) measurements: better filters, validation standards, and Rayleigh scatter removal methods. AB - Anisotropy resolved multidimensional emission spectroscopy (ARMES) provides valuable insights into multi-fluorophore proteins (Groza et al 2015 Anal. Chim. Acta 886 133-42). Fluorescence anisotropy adds to the multidimensional fluorescence dataset information about the physical size of the fluorophores and/or the rigidity of the surrounding micro-environment. The first ARMES studies used standard thin film polarizers (TFP) that had negligible transmission between 250 and 290 nm, preventing accurate measurement of intrinsic protein fluorescence from tyrosine and tryptophan. Replacing TFP with pairs of broadband wire grid polarizers enabled standard fluorescence spectrometers to accurately measure anisotropies between 250 and 300 nm, which was validated with solutions of perylene in the UV and Erythrosin B and Phloxine B in the visible. In all cases, anisotropies were accurate to better than +/-1% when compared to literature measurements made with Glan Thompson or TFP polarizers. Better dual wire grid polarizer UV transmittance and the use of excitation-emission matrix measurements for ARMES required complete Rayleigh scatter elimination. This was achieved by chemometric modelling rather than classical interpolation, which enabled the acquisition of pure anisotropy patterns over wider spectral ranges. In combination, these three improvements permit the accurate implementation of ARMES for studying intrinsic protein fluorescence. PMID- 28584196 TI - Atomically dispersed Pd catalysts in graphyne nanopore: formation and reactivity. AB - The formation of single-atom noble metal catalysts on carbon materials remains a challenge due to the weak interaction between metals and pristine carbon. By means of density functional theory (DFT) calculations, it is found that the atomically dispersed Pd in graphyne nanopore is much more stable than that of relative Pd clusters. The large diffusion barrier of Pd from the most stable hollow site to the bridge site confirms the kinetic stability of such structures. While CO adsorption causes the pulling of Pd from graphyne nanopore due to the low diffusion barrier, based on DFT calculations, which can be further confirmed by ab initio molecular dynamic simulations. Finally, CO oxidation on the reconstruction of Pd@graphyne exhibits an energy barrier of 0.62 eV in the rate limiting step through the Langmuir-Hinshelwood mechanism. After the reaction, the catalyst can be restored to the original atomically dispersed state again. This study shows graphyne is an excellent support for an atomically dispersed or single-metal catalyst. PMID- 28584198 TI - Surgical Treatment of Stress Urinary Incontinence in Women in the Mainland of China: Current Status and Outlook. PMID- 28584195 TI - Cyclin-Dependent Kinase-Dependent Phosphorylation of Sox2 at Serine 39 Regulates Neurogenesis. AB - Sox2 is known to be important for neuron formation, but the precise mechanism through which it activates a neurogenic program and how this differs from its well-established function in self-renewal of stem cells remain elusive. In this study, we identified a highly conserved cyclin-dependent kinase (Cdk) phosphorylation site on serine 39 (S39) in Sox2. In neural stem cells (NSCs), phosphorylation of S39 enhances the ability of Sox2 to negatively regulate neuronal differentiation, while loss of phosphorylation is necessary for chromatin retention of a truncated form of Sox2 generated during neurogenesis. We further demonstrated that nonphosphorylated cleaved Sox2 specifically induces the expression of proneural genes and promotes neurogenic commitment in vivo Our present study sheds light on how the level of Cdk kinase activity directly regulates Sox2 to tip the balance between self-renewal and differentiation in NSCs. PMID- 28584199 TI - Prevalence and Factors Associated with Female Sexual Dysfunction in Beijing, China. AB - BACKGROUND: Female sexual dysfunction (FSD) is a highly prevalent and often underestimated problem. However, large-scale, population-based epidemiological surveys of FSD are scarce in China. The present study was conducted to evaluate the prevalence and the potential risk factors of FSD across a selection of social groups in Beijing, China, based on the Female Sexual Function Index (FSFI). METHODS: A cross-sectional study based on the multiple-stage cluster sampling was performed with adult women throughout the Dongcheng and Shunyi districts of Beijing. The Chinese version of FSFI was used, as well as questions on demographic characteristics, the disease-related context, and social relationships. RESULTS: A total of 6000 consecutive women entered this study, with an actual response from 5024 women, corresponding to a response rate of 83.7%. A total of 4697 (78.3%) questionnaires were effective. The prevalence of adult FSD in Beijing was 2973 (63.3%) using a score of 26.55 as the boundary value, whereas the total mean FSFI score was 23.92 +/- 6.37. However, 1423 (30.3%) women did not seek help. By multivariate logistic regression analysis, the possible potential risk factors included age (odds ratio [OR] = 1.051), dissatisfaction with the spouse's sexual ability (OR = 3.520), poor marital affection (OR = 2.087), spouse sexual difficulties (OR = 1.720), dissatisfaction with married life (OR = 1.476), living in a rural area (OR = 1.292), chronic pelvic pain (OR = 1.261), chronic disease (OR = 1.534), previous pelvic surgery (OR = 1.605), vaginal delivery (OR = 2.285), lower education (OR = 3.449) and postmenopausal (OR = 3.183). CONCLUSIONS: As suggested by the FSFI scores, female sexual problems are highly prevalent in Beijing. Dissatisfaction with the spouse's sexual ability, poor marital affection, sexual difficulties of the spouse, dissatisfaction with the marriage, rural life, CPP, and postmenopausal were conceivable risk factors for FSD in Beijing women. PMID- 28584200 TI - Efficacy of Different Treatment Regimens for Antiphospholipid Syndrome-related Recurrent Spontaneous Abortion. AB - BACKGROUND: Antiphospholipid syndrome (APS)-related immune factors are considered as an important cause of recurrent spontaneous abortion (RSA). Anticoagulant and anti-inflammatory treatments are believed to effectively improve adverse pregnancy outcomes by affecting the abnormal autoimmune response of the maternal fetal interface. The aim of this study was to observe the clinical characteristics and treatment outcomes of anticoagulant regimens and anti inflammatory plus anticoagulation regimens for APS-related RSA. METHODS: APS related RSA cases from September 2011 to September 2016 at Peking University Third Hospital were retrospectively analyzed. The patients were assigned to study group (anti-inflammation plus anticoagulation) and control group (simple anticoagulation). The incidence of repeat abortion, the incidence of placental dysfunction, the gestational weeks of pregnancy, and the mean weight of the fetus were observed. RESULTS: The pregnancy and neonatal outcome indicators of the repeat pregnancy loss rate (11.11% vs. 22.70%), placental dysfunction-related diseases (6.35% vs. 15.60%), the mean birth weight of infants born after 24 weeks gestation (3152.41 +/- 844.67 g vs. 2765.76 +/- 816.40 g), full-term delivery weight (3456.28 +/- 419.79 g vs. 3076.18 +/- 518.79 g), the proportions of low birth weight infants (12.70% vs. 21.98%), and small for gestational age (6.35% vs. 14.18%) differed significantly between the study and control groups (all P< 0.05). The incidence of preterm delivery, term delivery, and stillbirth was not significantly different between the two groups, and there was no significant difference between the study and control groups in gestational age at birth (37.6 +/- 3.3 weeks vs. 36.9 +/- 3.2 weeks; P > 0.05). CONCLUSION: The anti inflammatory and anticoagulation regimen is more effective than the simple anticoagulation regimen in the treatment of APS recurrent abortion. PMID- 28584201 TI - Ovarian Damages Produced by Aerosolized Fine Particulate Matter (PM2.5) Pollution in Mice: Possible Protective Medications and Mechanisms. AB - BACKGROUND: Ambient aerosol fine particulate matter (PM2.5) is associated with male reproductive toxicity in experiments and may have adverse effects in the female. However, studies evaluating the protective effects and precise mechanisms of aspirin, Vitamin C, Vitamin E, or ozone against toxic effects of PM2.5are sparse. This study was conducted to investigate the possible protective effects and mechanisms of aspirin, Vitamin C, Vitamin E, or ozone on fertility in female mice treated with PM2.5. METHODS: Eighty-four ICR mice were divided into six groups: control group, PM2.5group, PM2.5 + aspirin group, PM2.5 + Vitamin C group, PM2.5 + Vitamin E group, and PM2.5 + ozone group. PM2.5was given by intratracheal instillation every 2 days for 3 weeks. Aspirin, Vitamin C, and Vitamin E were given once a day by oral gavage for 3 weeks, and ozone was administered by intraperitoneal injection once a day for 3 weeks. The levels of anti-Mullerian hormone (AMH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured using enzyme linked immunosorbent assay. Western blotting analysis was used to analyze the expressions of Bcl-2, Bax, and caspase-3 in ovaries. Changes in histological structure were examined by light microscope and electron microscopy was used to detect ultramicrostructure. RESULTS: The results demonstrated that PM2.5 decreased AMH levels (P < 0.001); however, aspirin (P < 0.001), Vitamin C (P < 0.001), Vitamin E (P = 0.001), and ozone (P = 0.002) alleviated the decrease. Changes of IL-6, TNF-alpha, 8-OHdG, Bax/Bcl-2, and caspase-3 in PM2.5group were increased compared to control group (P < 0.001), while in PM2.5 + aspirin, PM2.5 + Vitamin C, PM2.5 + Vitamin E, and PM2.5 + ozone groups, they were statistically decreased compared to PM2.5group (P < 0.001 or P< 0.05). CONCLUSIONS: PM2.5cause the damage of ovaries, and aspirin, Vitamin C, Vitamin E, and ozone antagonizes the damage. The protective mechanism is probably due to its ability to blunt the inflammatory and oxidative stress caused by PM2.5, which subsequently suppressing the expression of apoptotic regulatory protein and reducing the incidence of ovary apoptosis. PMID- 28584202 TI - Feasibility of Atrial AutoCaptureTM to Detect Atrial Evoked Response: Experience from 102 Patients Implanted with Dual-chamber Pacemakers. AB - BACKGROUND: Atrial AutoCaptureTM (ACapTM) was a new technological development that confirmed atrial capture by analyzing evoked response (ER) with a new method - paced depolarization integral ER detection - and optimized energy output to changes in the stimulation threshold. The purpose of this study was to evaluate the clinical performance of ACapTM function. METHODS: This was a prospective, observational, nonrandomized two-center study. Between November 2008 and August 2014, 102 patients were enrolled from two different institutions. Data were collected by case report forms at enrollment, hospital discharge, and in-office follow-ups scheduled at 1, 2, 3, 6, and 12 months postimplantation. RESULTS: Ambulatory ACapTM function started to become available for 20.6% of patients at 1 day, then progressed to 30.4% at 7 days, 38.6% at 1 month, 41.6% at 2 months, 47.5% at 3 months, 53.5% at 6 months, and 63.4% at 1 year. The cause of the unsuccessful attempts to perform ACapTM threshold was ER/polarization <2:1. Availability for SD, BND, and HOCM indications had shown better results than AVB indication. For SD indication cases, feasibility was significantly better for SD with paroxysmal atrial fibrillation (pAF) than SD without pAF (78.4% vs. 35.0% at 1 year, n = 71, P< 0.001). At each stage of the clinical follow-ups, there had been a strict correlation between ACapTM measurements and those conducted manually with P 0.001 (n = 299). CONCLUSIONS: It has been concluded that ACapTM function was safe and effective to confirm atrial threshold and reduce energy output automatically. ACapTM function is unavailable for some patients at early stages of the implantation; however, availability has been progressively increasing during follow-up. PMID- 28584203 TI - Current Use of Oral Anticoagulants and Prognostic Analysis in Patients with Atrial Fibrillation Undergoing Coronary Stenting. AB - BACKGROUND: It is currently believed that triple oral antithrombotic therapy in patients with atrial fibrillation (AF) after percutaneous coronary intervention (PCI) should be recommended if there are no contraindications. However, selecting triple therapy for AF patients undergoing PCI is still challenging when bleeding risk is considered. This study aimed to investigate the current use of oral anticoagulants (Vitamin K antagonists [VKA]) and perform prognostic analysis in real-world patients with AF undergoing coronary stenting. METHODS: A total of 276 consecutive coronary artery disease (CAD) patients with or without AF undergoing coronary stenting were retrospectively evaluated and analyzed. The univariate and multivariate analyses were conducted to explore the current use of VKA and prognosis of patients with AF undergoing coronary stenting. The primary end-point was composite of all-cause death, nonfatal recurrent myocardial infarction, stroke, serious bleeding events, unplanned repeat revascularization, and worsening heart failure at 12-month follow-up after coronary stenting. RESULTS: AF patients undergoing coronary stenting have more clinical concomitant diseases. Only 9.0% AF patients after coronary stenting received triple antithrombotic therapy (VKA, aspirin, and clopidogrel) at discharge. AF was independently associated with increased risk of the 12-month composite end-points (relative risk = 5.732, 95% confidence interval 1.786-18.396, P = 0.003). CONCLUSIONS: In real-life AF patients undergoing coronary stenting, guideline-recommended VKA was less used. AF patients had adjusted worse prognosis during 12-month follow-up after discharge. It is of utmost importance to improve the current status of oral anticoagulants use. PMID- 28584204 TI - Decision-making Impairments in Primary Angle-closure Glaucoma Patients. AB - BACKGROUND: Primary angle-closure glaucoma (PACG) is a common eye disease and a common cause of blindness. Inappropriate medical decisions severely affect the prognosis. This study investigated decision-making under risk in PACG patients. METHODS: Thirty patients with first acute attack of PACG before surgery and thirty healthy controls were included in the study. Decision-making under risk was evaluated with the game of dice task (GDT). The results of Eysenck Personality Questionnaire (EPQ) and GDT between PACG patients and healthy controls were compared. RESULTS: Risky decisions in PACG patients were more than those in healthy controls as measured by mean score of GDT (12.47 +/- 5.72 vs. 4.33 +/- 3.30, P< 0.001). Higher neuroticism score in EPQ was found in PACG patients compared to healthy controls (14.97 +/- 3.93 vs. 9.90 +/- 4.49, P< 0.001). Neuroticism scores in EPQ were associated with decision-making performance (r = 0.417, P = 0.001). CONCLUSIONS: Neuroticism positively correlated with risky decisions. Decision-making might be influenced by neuroticism. Future studies will show whether therapy compliance will be improved by emotional management and psychological intervention in PACG patients. PMID- 28584205 TI - Effects of Surgical Ventricular Restoration on Left Ventricular Shape, Size, and Function for Left Ventricular Anterior Aneurysm. AB - BACKGROUND: Surgical ventricular restoration (SVR) has been performed to treat left ventricular (LV) aneurysm. However, there is limited analysis of changes in LV shape. This study aimed to evaluate the changes in LV shape induced by SVR and the effects of SVR on LV size and function for LV aneurysm. METHODS: Between April 2006 and March 2015, 18 patients with dyskinetic (dyskinetic group) and 12 patients with akinetic (akinetic group) postinfarction LV anterior aneurysm receiving SVR with the Dor procedure at Chinese People's Liberation Army General Hospital were enrolled in this study. A retrospective analysis was carried out using data from the echocardiography database. LV shape was analyzed by calculating the apical conicity index (ACI). LV end-diastolic volume index, end systolic volume index, and ejection fraction (EF) were measured. One-way analysis of variance was used to compare means at different time points within each group. RESULTS: Within one week after SVR, LV shape became more conical in the two groups (ACI decreased from 0.84 +/- 0.13 to 0.69 +/- 0.11 [t = 5.155, P = 0.000] in dyskinetic group and from 0.73 +/- 0.07 to 0.60 +/- 0.11 [t = 2.701, P = 0.026] in akinetic group; LV volumes were decreased significantly and became closer to normal values and EF was improved significantly in the two groups). On follow-up at least one year, LV shape remained unchanged in dyskinetic group (ACI increased from 0.69 +/- 0.11 to 0.74 +/- 0.12, t = -1.109, P = 0.294), but became more spherical in akinetic group (ACI significantly increased from 0.60 +/- 0.11 to 0.75 +/- 0.11, t = -1.880, P = 0.047); LV volumes remained unchanged in dyskinetic group, but increased significantly in akinetic group and EF remained unchanged in the two groups. CONCLUSIONS: SVR could reshape LV to a more conical shape and a more normal size and improve LV function significantly early after the procedure in patients with dyskinetic or akinetic postinfarction LV anterior aneurysm. However, LV tends to be more spherical and enlarged in the akinetic group on at least 1-year follow-up. PMID- 28584206 TI - Long-term Outcome of Multiple Small-diameter Drilling Decompression Combined with Hip Arthroscopy versus Drilling Alone for Early Avascular Necrosis of the Femoral Head. AB - BACKGROUND: Avascular necrosis of femoral head (AVNFH) typically presents in the young adults and progresses quickly without proper treatments. However, the optimum treatments for early stage of AVNFH are still controversial. This study was conducted to evaluate the therapeutic effects of multiple small-diameter drilling decompression combined with hip arthroscopy for early AVNFH compared to drilling alone. METHODS: This is a nonrandomized retrospective case series study. Between April 2006 and November 2010, 60 patients (98 hips) with early stage AVNFH participated in this study. The patients underwent multiple small-diameter drilling decompression combined with hip arthroscopy in 26 cases/43 hips (Group A) or drilling decompression alone in 34 cases/55 hips (Group B). Patients were followed up at 6, 12, and 24 weeks, and every 6 months thereafter. Radiographs were taken at every follow-up, Harris scores were recorded at the last follow-up, the paired t-test was used to compare the postoperative Harris scores. Surgery effective rate of the two groups was compared using the Chi-square test. RESULTS: All patients were followed up for an average of 57.6 months (range: 17-108 months). Pain relief and improvement of hip function were assessed in all patients at 6 months after the surgery. At the last follow-up, Group A had better outcome with mean Harris' scores improved from 68.23 +/- 11.37 to 82.07 +/- 2.92 (t = -7.21, P = 0.001) than Group B with mean Harris' scores improved from 69.46 +/- 9.71 to 75.79 +/- 4.13 (t = -9.47, P = 0.037) (significantly different: t = 2.54, P = 0.017). The total surgery effective rate was also significantly different between Groups A and B (86.0% vs. 74.5%; chi2 = 3.69, P = 0.02). CONCLUSION: For early stage of AVNFH, multiple small-diameter drilling decompression combined with hip arthroscopy is more effective than drilling decompression alone. PMID- 28584207 TI - A Cross-sectional Survey of Disability Attributed to Mental Disorders and Service Use in China. AB - BACKGROUND: Mental disorders are strongly associated with disabilities. National survey on disability could provide a reliable basis for policymaking in care and rehabilitation of disabled persons. This study aimed to describe the disability prevalence rates attributed to mental disorders, their distribution by sociodemographic factors, and utilizations of service. METHODS: This study is a secondary data analysis of the Second National Sample Survey on Disability in 2006. The disability and severity were assessed using the World Health Organization Disability Assessment Schedule 2.0. Mental disorders were diagnosed according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision Classification of Mental and Behavioral Disorders. Using descriptive and analytic epidemiological methods, prevalence rates of disability attributed to mental disorders and service use were calculated. RESULTS: Data of 2,526,145 respondents were analyzed. The disability prevalence rate attributed to mental disorders in China was 6.30/00, accounting for 9.9% of all disabled people. Regarding disability prevalence attributed to mental disorders, it showed that gender, residential area, marital status, education level, and economic area were related to the prevalence distributions. The proportions of mild disability were highest in the disabled people with onset age of 18-64 years, while the proportion of extremely severe disability was highest in the disabled people with onset age of 65 years and above. Only 58.6% of disabled people attributed to mental disorders used some of the services. CONCLUSIONS: There are statistical differences of disability prevalence attributed to mental disorders by people and region in China. Service use in disabled people with mental disorders is insufficient. PMID- 28584208 TI - Establishment of a Novel Method for Screening Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance Mutations in Lung Cancer. AB - BACKGROUND: Drug resistance to targeted therapies occurs in lung cancer, and resistance mechanisms related to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are continuously being discovered. We aimed to establish a novel method for highly parallel multiplexed detection of genetic mutations related to EGFR TKI-resistant lung cancer using Agena iPLEX chemistry and matrix assisted laser desorption ionization time-of-flight analysis on the MassARRAY mass spectrometry platform. METHODS: A review of the literature revealed 60 mutation hotspots in seven target genes (EGFR, KRAS, PIK3CA, BRAF, ERBB2, NRAS, and BIM) that are closely related to EGFR TKI resistance to lung cancer. A total of 183 primers comprised 61 paired forward and reverse amplification primers, and 61 matched extension primers were designed using Assay Design Software. The detection method was established by analyzing nine cell lines, and by comparison with LungCartaTM kit in ten lung cancer specimens. EGFR, KRAS, and BIM genes in all cell lines and clinical samples were subjected to Sanger sequencing for confirming reproducibility. RESULTS: Our data showed that designed panel was a high-throughput and robust tool, allowing genotyping for sixty hotspots in the same run. Moreover, it made efficient use of patient diagnostic samples for a more accurate EGFR TKIs resistance analysis. The proposed method could accurately detect mutations in lung cancer cell lines and clinical specimens, consistent with those obtained by the LungCartaTM kit and Sanger sequencing. We also established a method for detection of large-fragment deletions based on single base extension technology of MassARRAY platform. CONCLUSIONS: We established an effective method for high-throughput detection of genetic mutations related to EGFR TKI resistance based on the MassARRAY platform, which could provide more accurate information for overcoming cancers with de novo or acquired resistance to EGFR-targeted therapies. PMID- 28584209 TI - Analysis of Closed Claims in the Clinical Management of Rheumatoid Arthritis in Japan. AB - BACKGROUND: Despite an increasing awareness of the risk of medical errors, few data sources are available to highlight the characteristics and patterns of medical errors in the clinical management of rheumatoid arthritis (RA). The present study aimed to evaluate medical malpractice claims associated with the management of RA and other autoimmune connective tissue diseases (ACTDs). METHODS: We analyzed 38 ACTD-associated closed claims extracted from a total of 8530 claims processed between July 2004 and June 2014 by the Tokyo headquarters office of Sompo Japan Nipponkoa Incorporated, a leading malpractice insurer in Japan. RESULTS: RA was the most common ACTD assessed in this study, accounting for 20 cases. Although the male-to-female ratio among these cases was 5:15, in accordance with the general demographic distribution of RA, the proportion of patients older than 60 years (77.8%) was relatively high as the general range of RA susceptibility is 30-50 years. The analysis of allegation types among RA cases revealed statistically significant differences from non-RA cases (Fisher's exact test) as well as the following key findings: diagnosis-related allegations were absent (P < 0.01), whereas medication-related allegations were distinctively common (P = 0.02). Clinical processes related to the assessment process were most vulnerable to breakdown and leading to negligence identified with subsequent medication-related allegations, particularly among RA cases. CONCLUSIONS: The characteristics of malpractice claims associated with RA management, including the high frequency of medication-related allegations, breakdowns in the assessment process, and high claim numbers among patients older than 60 years, suggest the importance of caution exercised by physicians when administering immunosuppressants for the clinical treatment of RA. PMID- 28584210 TI - Atopic Dermatitis-like Graft-versus-host Disease and Lichen Planus-like Graft versus-host Disease: Alterations in Skin Barrier Function and Related Molecules. AB - BACKGROUND: Graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. Skin barrier disruption could induce thymic stromal lymphopoietin (TSLP) expression, and the expression of TSLP was increased in lesions of atopic dermatitis (AD)-like GVHD and lichen planus (LP) like GVHD. This study attempted to investigate the skin barrier function of AD like GVHD and LP-like GVHD and possible mechanisms. METHODS: Eighteen AD-like GVHD patients, 12 LP-like GVHD patients, and 14 healthy volunteers were enrolled in this study. Skin biopsy was done in five AD-like GVHD patients, eight LP-like GVHD patients, and eight healthy volunteers. The intensity of pruritus was assessed by visual analog scale itch score and detailed pruritus score. Transepidermal water loss (TEWL) was measured using Tewameter(r) TM 300. Immunohistochemistry was used to observe the expression of loricrin, involucrin, LL37, and human beta-defensins 2 (hBD2) in skin lesions. Western blot analysis was used for analyzing the protein levels of loricrin and involucrin in skin lesions. Real-time polymerase chain reaction was performed to assess the mRNA levels of LL37 and hBD2 in skin lesions. RESULTS: Pruritus score was higher in patients with AD-like GVHD (11.33 +/- 5.35) than that of patients with LP-like GVHD (2.58 +/- 3.09, P< 0.001). Compared with healthy controls (HCs, 4.52 +/- 1.24 g.m-2.h-1), TEWL was increased in AD-like GVHD (26.72 +/- 9.02 g.m-2.h-1, P < 0.001) and LP-like GVHD patients (18.78 +/- 4.57 g.m-2.h-1, P< 0.001), and expressions of loricrin and involucrin were also increased in skin lesions of AD like GVHD and LP-like GVHD patients (all P< 0.05). LL37 mRNA expression was decreased in lesions of AD-like GVHD and LP-like GVHD patients (P = 0.005 and P = 0.008, vs. HCs, respectively). hBD2 mRNA expression was increased in skin lesions of AD-like GVHD and LP-like GVHD patients (P = 0.002 and P< 0.001, vs. HCs, respectively). CONCLUSIONS: Skin barrier dysfunction is present in AD-like GVHD and LP-like GVHD. The immunoreactions, but not the congenital defect, are considered to be the primary cause of skin barrier impairment in AD-like GVHD and LP-like GVHD. PMID- 28584211 TI - Echocardiographic Evaluation of Coronary Abnormalities and Cardiac Function in a Murine Model of Kawasaki Disease Using High-frequency Ultrasound. AB - BACKGROUND: Murine model of coronary arterial inflammation has been widely accepted as an animal model of and used in Kawasaki disease (KD). This study sought to evaluate the developmental changes of coronary arteries and cardiac function in a murine model of KD with a high-frequency ultrasound system and to provide evidence for the preparation of the model of KD. METHODS: Lactobacillus casei cell wall extract was prepared and injected into C57BL/6 mice intraperitoneally (i.p.) to induce KD. A total of 120 mice were grouped into three groups. The intravenous immunoglobulin (IVIG) treatment group was i.p. injected with IVIG (2 g/kg), while the KD model and normal control groups were i.p. injected with 0.5 ml of phosphate buffered solution on day 5. All high resolution echocardiography detection of mouse heart was performed by the same senior technician. Animal echocardiography was performed by measuring the coronary artery dimensions and cardiac function on days 0, 7, 14, 28, and 56 (high-resolution small animal ultrasound [Vevo770 pattern; VisualSonic, Canada] with broadband probe [RMVTM707B; frequency, 30 mHz; depth of focus, 1.2 cm]) which were measured and analyzed with Vevo770 software. RESULTS: Pathological studies revealed focal inflammatory infiltrate asymmetrically distributed around the coronary artery trunk in the KD model group. Echocardiographic study including coronary dimension and cardiac function measurements was successfully performed in all subjects. The KD model and IVIG treatment groups showed left coronary artery dilation on days 7, 14, 28, and 56. The diameter of left coronary artery in the KD model group (0.53 +/- 0.09 mm; 0.36 +/- 0.07 mm; 0.34 +/- 0.05 mm; 0.34 +/- 0.04 mm) was significantly larger than those of IVIG treatment group (0.22 +/- 0.02 mm; 0.28 +/- 0.03 mm; 0.26 +/- 0.03 mm; 0.27 +/- 0.05 mm; 0.26 +/- 0.03 mm; all P < 0.01) and the normal control group (0.21 +/- 0.02 mm; 0.22 +/- 0.03 mm; 0.22 +/- 0.02 mm; 0.23 +/- 0.02 mm; 0.27 +/- 0.04 mm; all P< 0.01) on days 7, 14, 28, and 56. No significant differences were observed in the measurements of cardiac function among the groups on days 0, 7, 14, 28, and 56 (all P > 0.05). CONCLUSIONS: Echocardiography could identify the consecutive changes of coronary artery in KD mice. Echocardiography is more convenient and direct in evaluating the coronary abnormalities in this animal model. PMID- 28584212 TI - Variations of Postresuscitation Lung Function after Thrombolysis Therapy in a Cardiac Arrest Porcine Model Caused by Pulmonary Thromboembolism. AB - BACKGROUND: Study of lung function in survivor from cardiac arrest (CA) caused by pulmonary thromboembolism (PTE) was rare. The aim of this study was to investigate the variations of postresuscitation lung function after thrombolysis treatment in a CA porcine model caused by PTE. METHODS: After 2 min of untreated CA, pigs of 10-12 weeks with a weight of 30 +/- 2 kg (n = 24) were treated with recombinant human tissue plasminogen activator (50 mg). Cardiopulmonary resuscitation (CPR) and ventilation were initiated after drug administration. Pulmonary function and arterial blood gas parameters were measured at baseline, return of spontaneous circulation (ROSC) immediately, and 1 h, 2 h, 4 h, and 6 h after ROSC. RESULTS: The dynamic lung compliance decreased significantly at ROSC immediately and 1 h after ROSC compared to baseline (21.86 +/- 2.00 vs. 26.72 +/- 2.20 ml/mmHg and 20.38 +/- 1.31 vs. 26.72 +/- 2.20 ml/mmHg, respectively; P < 0.05; 1 mmHg = 0.133 kPa). Compared with baseline, airway resistance increased significantly at ROSC immediately and 1 h after ROSC (P < 0.05). Respiratory index also increased after ROSC and showed significant differences among baseline, ROSC immediately, and 2 h after ROSC (P < 0.05). Oxygen delivery decreased at ROSC immediately compared to baseline (P < 0.05). The oxygenation index decreased significantly at any time after ROSC compared to baseline (P < 0.05). Extravascular lung water index and pulmonary vascular permeability index (PVPI) showed significant differences at ROSC immediately compared to baseline and 1 h after ROSC (P < 0.05); PVPI at ROSC immediately was also different from 6 h after ROSC (P < 0.05). Ventilation/perfusion ratios increased after ROSC (P < 0.05). Histopathology showed fibrin effusion, bleeding in alveoli, and hemagglutination in pulmonary artery. CONCLUSIONS: Lung function remains abnormal even after CPR with thrombolysis therapy; it is essential to continue anticoagulation and symptomatic treatment after ROSC. PMID- 28584213 TI - E-26 Transformation-specific Related Gene Expression and Outcomes in Cytogenetically Normal Acute Myeloid Leukemia: A Meta-analysis. AB - BACKGROUND: The E-26 transformation-specific related gene (ERG) is frequently expressed in cytogenetically normal acute myeloid leukemia (CN-AML). Herein, we performed a meta-analysis to investigate the relationship between the prognostic significance of ERG expression and CN-AML. METHODS: A systematic review of PubMed database and other search engines were used to identify the studies between January 2005 and November 2016. A total of 667 CN-AML patients were collected from seven published studies. Of the 667 patients underwent intensive chemotherapy, 429 had low expression of ERG and 238 had high expression of ERG. Summary odds ratio (OR) and the 95% confidence interval (CI) for the ERG expression and CN-AML were calculated using fixed- or random-effects models. Heterogeneity was assessed using Chi-squared-based Q- statistic test and I2 statistics. All statistical analyses were performed using R.3.3.1 software packages (R Foundation for Statistical Computing, Vienna, Austria) and RevMan5.3 (Cochrane Collaboration, Copenhagen, Denmark). RESULTS: Overall, patients with high ERG expression had a worse relapse (OR = 2.5127, 95% CI: 1.5177-4.1601, P = 0.0003) and lower complete remission (OR = 0. 3495, 95% CI: 0.2418-0.5051, P< 0.0001). With regard to the known molecular markers, both internal tandem duplications of the fms-related tyrosine kinase 3 gene (OR = 3.8634, 95% CI: 1.8285-8.1626, P = 0.004) and brain and acute leukemia, cytoplasmic (OR = 3.1538, 95% CI: 2.0537-4.8432, P< 0.0001) were associated with the ERG expression. In addition, the results showed a statistical significance between French-American British (FAB) classification subtype (minimally differentiated AML and AML without maturation, OR = 4.7902, 95% CI: 2.7772-8.2624, P< 0.0001; acute monocytic leukemia, OR = 0.2324, 95% CI: 0.0899-0.6006, P = 0.0026) and ERG expression. CONCLUSION: High ERG expression might be used as a strong adverse prognostic factor in CN-AML. PMID- 28584215 TI - Active Monitoring of Adverse Drug Reactions with Neural Network Technology. PMID- 28584214 TI - Study on Language Rehabilitation for Aphasia. AB - OBJECTIVE: The aim is to update our clinical recommendations for evidence-based language rehabilitation of people with aphasia, based on a systematic review of the literature from 1999 to 2015. DATA SOURCES: Articles referred to in this systematic review of the Medline and PubMed published in English language literatures were from 1998 to 2015. The terms used in the literature searches were aphasia and evidenced-based. STUDY SELECTION: The task force initially identified citations for 51 published articles. Of the 51 articles, 44 studies were selected after further detailed review. Six articles, which were not written in English, and one study related to laryngectomy rehabilitation interventions, were excluded from the study. This study referred to all the important and English literature in full. RESULTS: Aphasia is the linguistic disability, which usually results from injuries to the dominant hemisphere of the brain. The rehabilitation of aphasia is until in the process of being debated and researched. Evidence-based medicine (EBM), EBM based on the clinical evidence, promotes the practice of combining the clinicians' first-hand experience and the existing objective and scientific evidence encouraging making decisions based on both empirical evidence and the scientific evidence. Currently, EBM is being gradually implemented in the clinical practice as the aim of the development of modern medicine. CONCLUSIONS: At present, the research for the aphasia rehabilitation mainly focuses on the cognitive language rehabilitation and the intensive treatment and the precise treatment, etc. There is now sufficient information to support evidence-based protocols and implement empirically supported treatments for linguistic disability after traumatic brain injury and stroke, which can be used to develop linguistic rehabilitation guidelines for patients with aphasia. PMID- 28584216 TI - The Pillars of Publication Ethics and Research Integrity: Spread the Word. PMID- 28584217 TI - Occult Renal Cell Carcinoma of Eosinophilic Morphology Detected within Renal Angiomyolipoma Mass in a Patient with Tuberous Sclerosis Complex. PMID- 28584218 TI - Renal Artery Pseudoaneurysm Rupturing into the Small Intestine Causing Gastrointestinal Bleeding. PMID- 28584219 TI - Abnormal Origin of the Right Subclavian Artery: A Case Report. PMID- 28584220 TI - Ribs Formed by Prolene Mesh, Bone Cement, and Muscle Flaps Successfully Repair Chest Abdominal Wall Defects after Tumor Resection: A Long-term Study. PMID- 28584221 TI - Establishment and Application of China Pituitary Disease Register Network. PMID- 28584222 TI - Paederus dermatitis. AB - Paederus dermatitis is an irritant dermatitis caused by pederin, a toxin produced by the rove beetle (Paederus). The disease occurs worldwide, but it is often not recognized as a history of contact with the insect is frequently absent. It is commonly seen in the rainy season. Crushing the insect releases pederin, resulting in the characteristic linear lesions with a burning sensation that heal with hyperpigmentation. Treatment comprises immediate washing of the area to eliminate the toxin and topical application of a topical steroid-antibiotic combination. Preventive measures may include reducing the insect population in the surroundings, avoiding contact of insects with the skin, minimizing the lesions after contact. Awareness of the etiology and clinical manifestations makes it easier to suspect this condition even in the absence of a history of exposure to the insect. We present a comprehensive review of the etiopathogenesis, pathology, clinical features, treatment and prevention of Paederus dermatitis and also review the biology of the insect and its behavior. PMID- 28584224 TI - Erratum: Ectodermal dysplasia skin fragility syndrome with a new mutation. AB - [This corrects the article DOI: 10.4103/ijdvl.IJDVL_411_16]. PMID- 28584223 TI - Bullous pemphigoid and antecedent neurological diseases: An association with dementia. AB - BACKGROUND: Bullous pemphigoid is the most common subepidermal immunobullous disorder. Studies have reported the association between bullous pemphigoid and various neurological diseases. AIMS: The aim of this study was to evaluate whether bullous pemphigoid is associated with pre-existent neurological diseases and whether specific diseases exhibit this association. METHODS: All dermatology inpatients from January 2010 to May 2015 were analyzed. Bullous pemphigoid cases were identified based on clinical features and consistent histopathologic and direct immunofluorescence findings. Patients with other autoimmune bullous skin disorders were excluded. An equal number of inpatients with other skin conditions were selected randomly as age- and sex- matched controls. RESULTS: Out of 3015 inpatients, 103 cases of bullous pemphigoid and 103 age- and sex-matched controls were included. Seventy six patients with bullous pemphigoid had a history of at least one neurological disease. After adjusting for age, gender, race, functional status and neuro-psychiatric medications, patients with bullous pemphigoid were found to be approximately thrice as likely to have a history of at least one neurological disease than were controls (odds ratio: 2.88; 95% confidence interval: 1.32-6.26; P = 0.008). Amongst the pre-existing neurological diseases, only dementia was statistically more prevalent in bullous pemphigoid cases compared to controls (adjusted odds ratio: 2.61; 95% confidence interval: 1.19 5.75; P = 0.017). Parkinson disease and psychiatric disorders demonstrated a higher adjusted risk among bullous pemphigoid patients but the difference was not statistically significant. LIMITATIONS: The limitations were potential referral and selection bias, as the patients were inpatients. There is a possible misclassification as the diagnosis of neurological diseases was performed using medical records. The duration from the diagnosis of neurological diseases to bullous pemphigoid could not be accurately determined as it was a retrospective review of records and most neurological diseases have a prolonged course. CONCLUSIONS: Pre-existent neurological disease, specifically dementia, was found to be associated with bullous pemphigoid. PMID- 28584225 TI - Synchronous Gastrointestinal Carcinoid Tumor and Colon Adenocarcinoma: Case Reports and Literature Review. AB - BACKGROUND Coexistence of carcinoid tumor and colorectal adenocarcinoma is rare. In this report, we present two cases and review the current literature for synchronous carcinoid tumor and colorectal carcinoma occurrence. CASE REPORT In both cases, the rectal carcinoid tumors and sigmoid colon adenocarcinomas were detected by colonoscopy. The colon adenocarcinomas were effectively treated with a laparoscopic sigmoidectomy and the carcinoids were successfully removed endoscopically. Our 40-year-old patient was the youngest among 17 reported patient cases. CONCLUSIONS These two cases demonstrate that the diagnosis of gastrointestinal carcinoid requires a complete assessment of the remainder of the colon for another primary cancer to achieve a timely treatment management strategy. PMID- 28584226 TI - Comparison of 3 Times a Week 4- and 5-Hour In-Center Hemodialysis Sessions with Use of Continuous Non-Invasive Hemodynamic Monitoring. AB - BACKGROUND Very aggressive ultrafiltration rate (lasting 3.5-4 h) may result in inadequate hemodialysis (HD). Our aim was to characterize HD-induced cardiovascular adaptation and its links to fluid removal during 4- vs. 5-h HD sessions. MATERIAL AND METHODS The study involved 50 HD patients. A Cardioscreen device (Messtechnik, Ilmenau, Germany) was used to perform non-invasive hemodynamic measurements during mid-week HD sessions. Body fluids and nutritional status were assessed with a Body Composition Monitor (Fresenius Medical Care). Clinical and laboratory data were also analyzed. RESULTS It was shown that when comparing 3 times a week 4- vs. 5-h dialysis sessions, body mass index (BMI [kg/m2]), Kt/V, and ultrafiltration volume (UFV [mL]) were significantly lower in the 4-h dialysis group (23.1+/-3.5 vs. 27.1+/-4.7; 1.36+/-0.28 vs. 1.55+/-0.23; 1770+/-601 vs. 2831+/-836; P<0.05, respectively). Cardiac index (CI [L/min/m2]) and thoracic fluid content (TFC [1/kW]) were significantly reduced in 4-h dialysis sessions (3.1+/-0.6 to 2.7+/-0.7; 35.1+/-8.4 to 32.8+/-6.8; P<0.05, respectively). In patients treated with 5-h dialysis sessions, we found that heart rate (HR [bpm]) was significantly increased (69+/-10 to 74+/-15; P<0.05) and TFC was reduced (34.3+/-8.9 to 31.5+/-8.2; P<0.05). In patients treated with 4-h dialysis sessions, systemic vascular resistance index (SVRI [dyn.s.cm^-5/m2]) increased from 2369+/-799 before HD to 2592+/-735 after HD (P=0.342). CONCLUSIONS The obtained data indicate that in extended (5-h) HD sessions, hemodynamic compensation occurred with increased HR, while in short (4-h) HD sessions, compensation occurred with increased SVRI. Providing longer but less intensive HD is more physiologic than the conventional therapy, and will improve patient tolerability and clinical outcomes. PMID- 28584227 TI - Quantitative Analysis of Lipid-Rich Necrotic Core in Carotid Atherosclerotic Plaques by In Vivo Magnetic Resonance Imaging and Clinical Outcomes. AB - BACKGROUND The aim of this study was to explore the accuracy of in vivo magnetic resonance imaging (MRI) in the quantitative evaluation of lipid-rich necrotic core (LRNC) in carotid atherosclerotic plaques compared with histopathology, and to assess the association of LRNC size with cerebral ischemia symptoms. MATERIAL AND METHODS Thirty patients were enrolled and 19 patients (16 men and 3 women) were analyzed. All the patients were submitted to MRI on a Siemens Avanto (1.5 Tesla) device before carotid endarterectomy (CEA). The scanning protocol included three-dimensional time of flight (3D TOF), T1-weighted image (T1WI), T2-weighted image (T2WI), turbo spin-echo T2-weighted (T2-TSE), and contrast-enhanced T1 weighted image. MRI images were reviewed for quantitative measurements of LRNC areas. LRNC specimens were collected for histology. Percentages of LRNC area to total vessel area were assessed to determine the association of MRI with histological findings. RESULTS There were 151 pairs of matched MRI and pathological sections. LRNC area percentages (LRNC area/vessel area) measured by MRI and histology were 20.6+/-9.0% and 18.7+/-9.5%, respectively (r=0.69, p<0.001). Twelve out of 19 patients had symptoms (S-group; 3 had recent stroke, 3 had a recent stroke and a history of transient ischemic attack (TIA), and 6 had TIA); the remaining 7 subjects showed no symptoms (NS-group). LRNC area percentages in the S- and NS-groups were 22.2+/-5.8% and 12.6+/-10.7%, respectively (p<0.05). CONCLUSIONS MRI can quantitatively measure LRNC in carotid atherosclerotic plaques, and may be useful in predicting the rupture risk of plaques. These findings provide a basis for imaging use in individualized treatment plan. PMID- 28584228 TI - Magnetic character of holmium atom adsorbed on platinum surface. AB - We address a recent controversy concerning the magnetic state of holmium adatom on platinum surface. Within a combination of the density functional theory (DFT) with the exact diagonalization (ED) of Anderson impurity model, the = 0 paramagnetic ground state |J = 8, J z = +/-8> is found. In an external magnetic field, this state is transformed to a spin-polarized state with ~ 6.7. We emphasize the role of 5d-4f interorbital exchange polarization in modification of the 4f shell energy spectrum. PMID- 28584229 TI - Circadian-tunable Perovskite Quantum Dot-based Down-Converted Multi-Package White LED with a Color Fidelity Index over 90. AB - New metrics of the color and circadian performances of down-converted white light emitting diodes (DC-WLEDs) are rapidly becoming popular in smart lighting systems. This is due to the increased desire for accurate analytical methods to measure the effects of newly developed quantum dot (QD)-based lighting on the vision, color, and circadian sensors of retina cells in the human eye. In this regard, a two-measure system known as technical memorandum TM-30-2015 (Illuminating Engineering Society of North America), encompassing the color fidelity index (CFI, R f ) and the color gamut index (CGI, R g ), has been developed as a new metrics of color to replace the currently utilized color rendering index (CRI, R a ). In addition, the tunability of the circadian efficacy of radiation (CER) is now more important due to its effect on the control of melatonin suppression/secretion, resetting of the central/local clocks of individuals given their daily cycles, and benefits to human health. In this paper, we developed and analyzed six-colored perovskite (Pe; cyan, green, yellowish green, amber, orange, and red colors) QDs-based multi-package WLED, and optimized the SPDs of tunable PeQD-based multi-package WLEDs in terms of promising human-centric lighting device, given its optimized visual energy, color qualities and health-promoting effects. PMID- 28584231 TI - Identification of 15 novel risk loci for coronary artery disease and genetic risk of recurrent events, atrial fibrillation and heart failure. AB - Coronary artery disease (CAD) is the major cause of morbidity and mortality in the world. Identification of novel genetic determinants may provide new opportunities for developing innovative strategies to predict, prevent and treat CAD. Therefore, we meta-analyzed independent genetic variants passing P <* 10-5 in CARDIoGRAMplusC4D with novel data made available by UK Biobank. Of the 161 genetic variants studied, 71 reached genome wide significance (p < 5 * 10-8) including 15 novel loci. These novel loci include multiple genes that are involved in angiogenesis (TGFB1, ITGB5, CDH13 and RHOA) and 2 independent variants in the TGFB1 locus. We also identified SGEF as a candidate gene in one of the novel CAD loci. SGEF was previously suggested as a therapeutic target based on mouse studies. The genetic risk score of CAD predicted recurrent CAD events and cardiovascular mortality. We also identified significant genetic correlations between CAD and other cardiovascular conditions, including heart failure and atrial fibrillation. In conclusion, we substantially increased the number of loci convincingly associated with CAD and provide additional biological and clinical insights. PMID- 28584230 TI - Photobiomodulation of human dermal fibroblasts in vitro: decisive role of cell culture conditions and treatment protocols on experimental outcome. AB - Photobiomodulation-based (LLLT) therapies show tantalizing promise for treatment of skin diseases. Confidence in this approach is blighted however by lamentable inconsistency in published experimental designs, and so complicates interpretation. Here we interrogate the appropriateness of a range of previously reported treatment parameters, including light wavelength, irradiance and radiant exposure, as well as cell culture conditions (e.g., serum concentration, cell confluency, medium refreshment, direct/indirect treatment, oxygen concentration, etc.), in primary cultures of normal human dermal fibroblasts exposed to visible and near infra-red (NIR) light. Apart from irradiance, all study parameters impacted significantly on fibroblast metabolic activity. Moreover, when cells were grown at atmospheric O2 levels (i.e. 20%) short wavelength light inhibited cell metabolism, while negligible effects were seen with long visible and NIR wavelength. By contrast, NIR stimulated cells when exposed to dermal tissue oxygen levels (approx. 2%). The impact of culture conditions was further seen when inhibitory effects of short wavelength light were reduced with increasing serum concentration and cell confluency. We conclude that a significant source of problematic interpretations in photobiomodulation reports derives from poor optimization of study design. Further development of this field using in vitro/ex vivo models should embrace significant standardization of study design, ideally within a design-of-experiment setting. PMID- 28584232 TI - Inhibition of Steel Corrosion and Alkaline Zinc Oxide Dissolution by Dicarboxylate Bola-Amphiphiles: Self-Assembly Supersedes Host-Guest Conception. AB - For many decorative applications like industrial and architectural paints, prevention of metal substrates from corrosion is a primary function of organic coatings. Triggered release of inhibitor species is generally accepted as a remedy for starting corrosion in case of coatings damage. A polyurethane based coating, doped with bola-amphiphiles of varying molecular weight but with a common head group motif that stems from ring-opened alkenyl succinic anhydride, enables passivation of the defect and mitigates cathodic delamination, if applied on cold rolled steel. An antagonistic effect results from the intercalation of the bola-amphiphiles into layered double hydroxide Zn2Al(OH)6 and subsequent incorporation of the hybrid phase into the organic matrix. In particular higher molecular weight bola-amphiphiles get immobilized through alkaline degradation of the layered framework in the basic milieu at the cathode. By means of sediments from colloidal states it is demonstrated that in-situ formed zinc oxide encapsulates the hybrid phase, evidenced by impeded dissolution of the ZnO based shell into caustic soda. While inhibition of steel corrosion results from a Donnan barrier layer, impeded zinc oxide dissolution is rooted in zinc catalyzed bola-amphiphile hydrolysis and layered deposition of the crystalline spacer diol hydrogenated bisphenol-A. PMID- 28584233 TI - Single-cell protein-mRNA correlation analysis enabled by multiplexed dual-analyte co-detection. AB - We have investigated the correlation between proteins and mRNAs in single cells employing an integrated workflow for dual-analyte co-detection. This is achieved by combining the oligo extension reaction (OER), which converts protein levels to DNA levels, with reverse transcription for mRNA detection. Unsupervised gene expression profiling analysis, including principal component analysis and hierarchical clustering, revealed different aspects of the protein-mRNA relationship. Violin plot analysis showed that some genes exhibited similar distribution patterns for proteins and mRNAs. We also demonstrate that cells can be separated into subpopulations based on their protein-mRNA expression profiles, and that different subpopulations have distinct correlation coefficient values. Our results demonstrated that integrated investigations of mRNA and protein levels in single cells allows comprehensive analysis not attainable at bulk levels. PMID- 28584234 TI - Stiff, light, strong and ductile: nano-structured High Modulus Steel. AB - Structural material development for lightweight applications aims at improving the key parameters strength, stiffness and ductility at low density, but these properties are typically mutually exclusive. Here we present how we overcome this trade-off with a new class of nano-structured steel - TiB2 composites synthesised in-situ via bulk metallurgical spray-forming. Owing to the nano-sized dispersion of the TiB2 particles of extreme stiffness and low density - obtained by the in situ formation with rapid solidification kinetics - the new material has the mechanical performance of advanced high strength steels, and a 25% higher stiffness/density ratio than any of the currently used high strength steels, aluminium, magnesium and titanium alloys. This renders this High Modulus Steel the first density-reduced, high stiffness, high strength and yet ductile material which can be produced on an industrial scale. Also ideally suited for 3D printing technology, this material addresses all key requirements for high performance and cost effective lightweight design. PMID- 28584235 TI - The Effect of Interleukin 38 on Angiogenesis in a Model of Oxygen-induced Retinopathy. AB - Interleukin 38 (IL-38) is a novel identified cytokine of IL-1 family in which some members are important in inflammation and angiogenesis. However, the role of IL-38 in regulating angiogenesis is unknown. The aim of the present study is to explore the effect of IL-38 on angiogenesis. Oxygen-induced retinopathy (OIR) of C57BL/6 J mice was induced by exposure of hyperoxia (75% oxygen) from postnatal day 7 (P7) to P12 and then returned to room air. The mice were injected with IL 38. At P17, neovascular region (tufts) and avascular area of the retinas were analyzed. The data showed that administration of IL-38 in vivo inhibited retinal angiogenesis significantly. Furthermore, the addition of IL-38 to the cell cultures attenuated the proliferation, scratch wound healing and tube formation of vascular endothelial cells induced by VEGF significantly. Our findings suggest that IL-38 is an antiangiogenic cytokine in pathophysiological settings and may have therapeutic potential for angiogenesis related diseases. PMID- 28584236 TI - Superlattice growth and rearrangement during evaporation-induced nanoparticle self-assembly. AB - Understanding the assembly of nanoparticles into superlattices with well-defined morphology and structure is technologically important but challenging as it requires novel combinations of in-situ methods with suitable spatial and temporal resolution. In this study, we have followed evaporation-induced assembly during drop casting of superparamagnetic, oleate-capped gamma-Fe2O3 nanospheres dispersed in toluene in real time with Grazing Incidence Small Angle X-ray Scattering (GISAXS) in combination with droplet height measurements and direct observation of the dispersion. The scattering data was evaluated with a novel method that yielded time-dependent information of the relative ratio of ordered (coherent) and disordered particles (incoherent scattering intensities), superlattice tilt angles, lattice constants, and lattice constant distributions. We find that the onset of superlattice growth in the drying drop is associated with the movement of a drying front across the surface of the droplet. We couple the rapid formation of large, highly ordered superlattices to the capillary induced fluid flow. Further evaporation of interstitital solvent results in a slow contraction of the superlattice. The distribution of lattice parameters and tilt angles was significantly larger for superlattices prepared by fast evaporation compared to slow evaporation of the solvent. PMID- 28584237 TI - Multiscale characterization of a lithium/sulfur battery by coupling operando X ray tomography and spatially-resolved diffraction. AB - Due to its high theoretical specific capacity, the lithium/sulfur battery is one of the most promising candidates for replacing current lithium-ion batteries. In this work, we investigate both chemical and morphological changes in the electrodes during cycling, by coupling operando spatially resolved X-ray diffraction and absorption tomography to characterize Li/S cells under real working conditions. By combining these tools, the state of the active material in the entire cell was correlated with its electrochemical behavior, leading to a deeper understanding of the performance limiting degradation phenomena in Li/S batteries. Highly heterogeneous behavior of lithium stripping/plating was observed in the anode, while the evolution of sulfur distribution in the cathode depth was followed during cycling. PMID- 28584238 TI - Gold nanozyme-based paper chip for colorimetric detection of mercury ions. AB - In this study, we developed a facile gold nanozyme-based paper chip (AuNZ-PAD) for Hg2+ detection. This device has the advantages of being simple, rapid, cost effective, sensitive, selective, high throughput, and applicable to onsite detection. The colorimetric mercury assay on the AuNZ-PAD is established based on the enzyme-like catalytic activity of gold nanoparticles promoted by the formation of Au-Hg amalgam, which is correlated to the intensity of the colorimetric response resulting from the catalytic reaction of 3,3',5,5' tetramethylbenzidine (TMB) and H2O2. Highly sensitive and selective detection of Hg2+ ions is achieved in both distilled and tap water samples, indicating the feasibility and applicability of our device for the determination of mercury pollution in real samples. Moreover, AuNZ-PAD analysis using a smartphone camera eliminates the need for expensive analytical equipment, thereby increasing the practicality of field monitoring of trace Hg2+ compared with other sensing methods. PMID- 28584239 TI - The effect of the neutral cytidine protonated analogue pseudoisocytidine on the stability of i-motif structures. AB - Incorporation of pseudoisocytidine (psC), a neutral analogue of protonated cytidine, in i-motifs has been studied by spectroscopic methods. Our results show that neutral psC:C base pairs can stabilize i-motifs at neutral pH, but the stabilization only occurs when psC:C base pairs are located at the ends of intercalated C:C+ stacks. When psC occupies central positions, the resulting i motifs are only observed at low pH and psC:C+ or psC:psC+ hemiprotonated base pairs are formed instead of their neutral analogs. Overall, our results suggest that positively charged base pairs are necessary to stabilize this non-canonical DNA structure. PMID- 28584240 TI - Synthetic surfactant- and cross-linker-free preparation of highly stable lipid polymer hybrid nanoparticles as potential oral delivery vehicles. AB - The toxicity associated with concentrated synthetic surfactants and the poor stability at gastrointestinal condition are two major constraints for practical applications of solid lipid nanoparticles (SLN) as oral delivery vehicles. In this study, a synthetic surfactant-free and cross-linker-free method was developed to fabricate effective, safe, and ultra-stable lipid-polymer hybrid nanoparticles (LPN). Bovine serum albumin (BSA) and dextran varying in molecular weights were first conjugated through Maillard reaction and the conjugates were exploited to emulsify solid lipid by a solvent diffusion and sonication method. The multilayer structure was formed by self-assembly of BSA-dextran micelles to envelope solid lipid via a pH- and heating-induced facile process with simultaneous surface deposition of pectin. The efficiency of different BSA dextran conjugates was systematically studied to prepare LPN with the smallest size, the most homogeneous distribution and the greatest stability. The molecular interactions were characterized by Fourier transform infrared and fluorescence spectroscopies. Both nano spray drying and freeze-drying methods were tested to produce spherical and uniform pectin-coated LPN powders that were able to re assemble nanoscale structure when redispersed in water. The results demonstrated the promise of a synthetic surfactant- and cross-linker-free technique to prepare highly stable pectin-coated LPN from all natural biomaterials as potential oral delivery vehicles. PMID- 28584241 TI - E. coli promotes human Vgamma9Vdelta2 T cell transition from cytokine-producing bactericidal effectors to professional phagocytic killers in a TCR-dependent manner. AB - gammadeltaT cells provide immune-surveillance and host defense against infection and cancer. Surprisingly, functional details of gammadeltaT cell antimicrobial immunity to infection remain largely unexplored. Limited data suggests that gammadeltaT cells can phagocytose particles and act as professional antigen presenting cells (pAPC). These potential functions, however, remain controversial. To better understand gammadeltaT cell-bacterial interactions, an ex vivo co-culture model of human peripheral blood mononuclear cell (PBMC) responses to Escherichia coli was employed. Vgamma9Vdelta2 cells underwent rapid T cell receptor (TCR)-dependent proliferation and functional transition from cytotoxic, inflammatory cytokine immunity, to cell expansion with diminished cytokine but increased costimulatory molecule expression, and capacity for professional phagocytosis. Phagocytosis was augmented by IgG opsonization, and inhibited by TCR-blockade, suggesting a licensing interaction involving the TCR and FcgammaR. Vgamma9Vdelta2 cells displayed potent cytotoxicity through TCR dependent and independent mechanisms. We conclude that gammadeltaT cells transition from early inflammatory cytotoxic killers to myeloid-like APC in response to infectious stimuli. PMID- 28584242 TI - Solution-Processed Cu2Se Nanocrystal Films with Bulk-Like Thermoelectric Performance. AB - Thermoelectric power generation can play a key role in a sustainable energy future by converting waste heat from power plants and other industrial processes into usable electrical power. Current thermoelectric devices, however, require energy intensive manufacturing processes such as alloying and spark plasma sintering. Here, we describe the fabrication of a p-type thermoelectric material, copper selenide (Cu2Se), utilizing solution-processing and thermal annealing to produce a thin film that achieves a figure of merit, ZT, which is as high as its traditionally processed counterpart, a value of 0.14 at room temperature. This is the first report of a fully solution-processed nanomaterial achieving performance equivalent to its bulk form and represents a general strategy to reduce the energy required to manufacture advanced energy conversion and harvesting materials. PMID- 28584243 TI - NKX6.3 Regulates Reactive Oxygen Species Production by Suppressing NF-kB and DNMT1 Activities in Gastric Epithelial Cells. AB - NKX6.3 plays an important role in gastric epithelial differentiation and also acts as a gastric tumor suppressor. The specific aim of this study was to determine whether NKX6.3 contributes to gastric mucosal barrier function by regulating reactive oxygen species (ROS) production. NKX6.3 reduced ROS production and regulated expression of anti-oxidant genes, including Hace1. In addition, NKX6.3 reduced DNMT1 expression and activity by down-regulating NF-kB family gene transcription. Silencing of Hace1 recovered ROS production, whereas knock-down of DNMT1 and NF-kB reduced ROS production and induced Hace1 expression by hypomethylating its promoter region. In addition, NKX6.3 inhibited CagA effects on cell growth, ROS production, and NF-kB and DNMT1 activity. In gastric mucosae and cancers, NKX6.3 and Hace1 expression was significantly reduced. The NKX6.3 expression was positively correlated with Hace1 and Nrf2 genes, but negatively correlated with DNMT1. Hypermethylation of Hace1 gene was observed only in gastric mucosae with H. pylori, atrophy and intestinal metaplasia. Thus, these results suggest that NKX6.3 inhibits ROS production by inducing the expression of Hace1 via down-regulating NF-kB and DNMT1 activity in gastric epithelial cells. PMID- 28584244 TI - Earlier flowering did not alter pollen limitation in an early flowering shrub under short-term experimental warming. AB - In animal pollinated plants, phenological shifts caused by climate change may have important ecological consequences. However, no empirical evidence exists at present on the consequences that flowering phenology shifts have on the strength of pollen limitation under experimental warming. Here, we investigated the effects of experimental warming on flowering phenology, flower density, reproductive success, and pollen limitation intensity in Caragana microphylla and evaluated whether earlier flowering phenology affected plant reproduction and the level of pollen limitation using warmed and unwarmed open top chambers in the Horqin Sandy Land of Inner Mongolia, northern China. The results of this study indicated that artificial warming markedly advanced flower phenology rather than extending the duration of the flowering. Additionally, warming was found to significantly reduce flower density which led to seed production reduction, since there were insignificant effects observed on fruit set and seed number per fruit. Experimental floral manipulations showed that warming did not affect pollen limitation. These results revealed the negative effects of advanced phenology induced by warming on flower density and reproductive output, as well as the neutral effects on reproductive success and pollen limitation intensity of long surviving plants. PMID- 28584246 TI - Micro-drive and headgear for chronic implant and recovery of optoelectronic probes. AB - Silicon probes are multisite electrodes used for the electrophysiological recording of large neuronal ensembles. Optoelectronic probes (OEPs) are recent upgrades that allow, in parallel, the delivery of local optical stimuli. The procedures to use these delicate electrodes for chronic experiments in mice are still underdeveloped and typically assume one-time uses. Here, we developed a micro-drive, a support for OEPs optical fibers, and a hat enclosure, which fabrications consist in fitting and fastening together plastic parts made with 3D printers. Excluding two parts, all components and electrodes are relatively simple to recover after the experiments, via the loosening of screws. To prevent the plugging of OEPs laser sources from altering the stability of recordings, the OEPs fibers can be transiently anchored to the hat via the tightening of screws. We test the stability of recordings in the mouse hippocampus under three different conditions: acute head-fixed, chronic head-fixed, and chronic freely moving. Drift in spike waveforms is significantly smaller in chronic compared to acute conditions, with the plugging/unplugging of head-stage and fiber connectors not affecting much the recording stability. Overall, these tools generate stable recordings of place cell in chronic conditions, and make the recovery and reuse of electrode packages relatively simple. PMID- 28584247 TI - See-through optical combiner for augmented reality head-mounted display: index matched anisotropic crystal lens. AB - A novel see-through optical device to combine the real world and the virtual image is proposed which is called an index-matched anisotropic crystal lens (IMACL). The convex lens made of anisotropic crystal is enveloped with the isotropic material having same refractive index with the extraordinary refractive index of the anisotropic crystal. This optical device functions as the transparent glass or lens according to the polarization state of the incident light. With the novel optical property, IMACL can be utilized in the see-through near eye display, or head-mounted display for augmented reality. The optical property of the proposed optical device is analyzed and aberration by the anisotropic property of the index-matched anisotropic crystal lens is described with the simulation. The concept of the head-mounted display using IMACL is introduced and various optical performances such as field of view, form factor and transmittance are analyzed. The prototype is implemented to verify the proposed system and experimental results show the mixture between the virtual image and real world scene. PMID- 28584245 TI - Immune signatures of pathogenesis in the peritoneal compartment during early infection of sheep with Fasciola hepatica. AB - Immune signatures of sheep acutely-infected with Fasciola hepatica, an important pathogen of livestock and humans were analysed within the peritoneal compartment to investigate early infection. Within the peritoneum, F. hepatica antibodies coincided with an intense innate and adaptive cellular immune response, with infiltrating leukocytes and a marked eosinophilia (49%). However, while cytokine qPCR analysis revealed IL-10, IL-12, IL-13, IL-23 and TGFbeta were elevated, these were not statistically different at 18 days post-infection compared to uninfected animals indicating that the immune response is muted and not yet skewed to a Th2 type response that is associated with chronic disease. Proteomic analysis of the peritoneal fluid identified infection-related proteins, including several structural proteins derived from the liver extracellular matrix, connective tissue and epithelium, and proteins related to the immune system. Periostin and vascular cell adhesion protein 1 (VCAM-1), molecules that mediate leukocyte infiltration and are associated with inflammatory disorders involving marked eosinophilia (e.g. asthma), were particularly elevated in the peritoneum. Immuno-histochemical studies indicated that the source of periostin and VCAM-1 was the inflamed sheep liver tissue. This study has revealed previously unknown aspects of the immunology and pathogenesis associated with acute fascioliasis in the peritoneum and liver. PMID- 28584249 TI - Quantum Phase Transition and Entanglement in Topological Quantum Wires. AB - We investigate the quantum phase transition of the Su-Schrieffer-Heeger (SSH) model by inspecting the two-site entanglements in the ground state. It is shown that the topological phase transition of the SSH model is signified by a nonanalyticity of local entanglement, which becomes discontinuous for finite even system sizes, and that this nonanalyticity has a topological origin. Such a peculiar singularity has a universal nature in one-dimensional topological phase transitions of noninteracting fermions. We make this clearer by pointing out that an analogous quantity in the Kitaev chain exhibiting the identical nonanalyticity is the local electron density. As a byproduct, we show that there exists a different type of phase transition, whereby the pattern of the two-site entanglements undergoes a sudden change. This transition is characterised solely by quantum information theory and does not accompany the closure of the spectral gap. We analyse the scaling behaviours of the entanglement in the vicinities of the transition points. PMID- 28584248 TI - Fecal Occult Blood Test Results of the National Colorectal Cancer Screening Program in South Korea (2006-2013). AB - There has been controversy regarding the clinical utility of fecal occult blood test (FOBT) as a screening tool for colorectal cancer (CRC) in the general population. The purpose of this study was to examine the results of Korea national CRC screening using FOBT from 2006 to 2013 and to evaluate the implementation of the program. We analyzed the results of FOBT, colonoscopy, and the side effects during colonoscopy for the subjects (n = 20,609,909) from the Korea National Health Insurance Cancer Screening database. For evaluation of Korea national CRC screening program implementation over the 8-year period, we calculated uptake rate, FOBT positivity rate, and subsequent test compliance rate. The overall uptake rate was 30.1%, with an increasing pattern from 2006 to 2011. A relatively higher FOBT positivity rate (6.4%) and lower subsequent test compliance rate (46.6%) were observed in comparison to the results previously reported in Western countries. Side effects reported within 3 months period after colonoscopy accounted for 0.17% of all procedures, with bleeding being the most prevalent type. Although the implementation of CRC screening program using FOBT in Korea seems successful, trends in key indicators for Korea national CRC screening program should be monitored continuously. PMID- 28584250 TI - The progression pattern of male hyrax songs and the role of climactic ending. AB - The study of animal vocal signals can either focus on the properties of distinct vocal elements or address the signal as a whole. Although some attention has been given to the continuous progression patterns of bird songs, such patterns in mammalian vocalisations have been largely overlooked. We examined temporal changes in structural and acoustic parameters in male rock hyrax songs. We found a gradual increase in call frequency and amplitude towards the song ending, as well as an abrupt increase in bout syntactic complexity, peaking in the last quintile of a song. In musical terms, such a pattern can be described as a crescendo (amplitude increase) with a terminal climax. In Western music, crescendos are used to maintain attention and direct the listeners towards a memorable highpoint of the musical piece. This structure may have an analogous function in animal communication, recruiting audience attention towards the climactic and potentially most informative part of the signal. Our playback experiments revealed that hyrax males tend to reply more to songs with a climactic ending, indicating that this progression pattern is important for hyrax communication. We suggest that animal vocal communication research can benefit from adding musical concepts to the analysis toolbox. PMID- 28584251 TI - The 'obesity paradox' may not be a paradox at all. PMID- 28584252 TI - Long-term outcome of older patients with newly diagnosed de novo acute promyelocytic leukemia treated with ATRA plus anthracycline-based therapy. AB - Treatment outcome in older patients with acute promyelocytic leukemia (APL) is lower compared with younger patients, mainly because of a higher induction death rate and postremission non-relapse mortality (NRM). This prompted us to design a risk- and age-adapted protocol (Programa Espanol de Tratamientos en Hematologia (PETHEMA)/HOVON LPA2005), with dose reduction of consolidation chemotherapy. Patients aged ?60 years reported to the PETHEMA registry and were treated with all-trans retinoic acid (ATRA) plus anthracycline-based regimens according to three consecutive PETHEMA trials that were included. We compared the long-term outcomes of the LPA2005 trial with the preceding PETHEMA trials using non-age adapted schedules (LPA96&LPA99). From 1996 to 2012, 389 older patients were registered, of whom 268 patients (69%) were eligible. Causes of ineligibility were secondary APL (19%), and unfit for chemotherapy (11%). Median age was 67 years, without relevant differences between LPA2005 and LPA96&LPA99 cohorts. Overall, 216 patients (81%) achieved complete remission with no differences between trials. The 5-year NRM, cumulative incidence of relapse, disease-free survival and overall survival in the LPA2005 vs the LPA96&99 were 5 vs 18% (P=0.15), 7 vs 12% (P=0.23), 87 vs 69% (P=0.04) and 74 vs 60% (P=0.06). A less intensive front-line regimen with ATRA and anthracycline monochemotherapy resulted in improved outcomes in older APL patients. PMID- 28584255 TI - Arsenic mobilization in shallow aquifers due to CO2 and brine intrusion from storage reservoirs. AB - We developed an integrated framework of combined batch experiments and reactive transport simulations to quantify water-rock-CO2 interactions and arsenic (As) mobilization responses to CO2 and/or saline water leakage into USDWs. Experimental and simulation results suggest that when CO2 is introduced, pH drops immediately that initiates release of As from clay minerals. Calcite dissolution can increase pH slightly and cause As re-adsorption. Thus, the mineralogy of the USDW is ultimately a determining factor of arsenic fate and transport. Salient results suggest that: (1) As desorption/adsorption from/onto clay minerals is the major reaction controlling its mobilization, and clay minerals could mitigate As mobilization with surface complexation reactions; (2) dissolution of available calcite plays a critical role in buffering pH; (3) high salinity in general hinders As release from minerals; and (4) the magnitude and quantitative uncertainty of As mobilization are predicated on the values of reaction rates and surface area of calcite, adsorption surface areas and equilibrium constants of clay minerals, and cation exchange capacity. Results of this study are intended to improve ability to quantify risks associated with potential leakage of reservoir fluids into shallow aquifers, in particular the possible environmental impacts of As mobilization at carbon sequestration sites. PMID- 28584254 TI - Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups. AB - Chronic lymphocytic leukaemia (CLL) consists of two biologically and clinically distinct subtypes defined by the abundance of somatic hypermutation (SHM) affecting the Ig variable heavy-chain locus (IgHV). The molecular mechanisms underlying these subtypes are incompletely understood. Here, we present a comprehensive whole-genome sequencing analysis of somatically acquired genetic events from 46 CLL patients, including a systematic comparison of coding and non coding single-nucleotide variants, copy number variants and structural variants, regions of kataegis and mutation signatures between IgHVmut and IgHVunmut subtypes. We demonstrate that one-quarter of non-coding mutations in regions of kataegis outside the Ig loci are located in genes relevant to CLL. We show that non-coding mutations in ATM may negatively impact on ATM expression and find non coding and regulatory region mutations in TCL1A, and in IgHVunmut CLL in IKZF3, SAMHD1,PAX5 and BIRC3. Finally, we show that IgHVunmut CLL is dominated by coding mutations in driver genes and an aging signature, whereas IgHVmut CLL has a high incidence of promoter and enhancer mutations caused by aberrant activation induced cytidine deaminase activity. Taken together, our data support the hypothesis that differences in clinical outcome and biological characteristics between the two subgroups might reflect differences in mutation distribution, incidence and distinct underlying mutagenic mechanisms. PMID- 28584253 TI - Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. AB - Robust establishment of survival in multiple myeloma (MM) and its relationship to recurrent genetic aberrations is required as outcomes are variable despite apparent similar staging. We assayed copy number alterations (CNA) and translocations in 1036 patients from the NCRI Myeloma XI trial and linked these to overall survival (OS) and progression-free survival. Through a meta-anlysis of these data with data from MRC Myeloma IX trial, totalling 1905 newly diagnosed MM patients (NDMM), we confirm the association of t(4;14), t(14;16), t(14;20), del(17p) and gain(1q21) with poor prognosis with hazard ratios (HRs) for OS of 1.60 (P=4.77 * 10-7), 1.74 (P=0.0005), 1.90 (P=0.0089), 2.10 (P=8.86 * 10-14) and 1.68 (P=2.18 * 10-14), respectively. Patients with 'double-hit' defined by co occurrence of at least two adverse lesions have an especially poor prognosis with HRs for OS of 2.67 (P=8.13 * 10-27) for all patients and 3.19 (P=1.23 * 10-18) for intensively treated patients. Using comprehensive CNA and translocation profiling in Myeloma XI we also demonstrate a strong association between t(4;14) and BIRC2/BIRC3 deletion (P=8.7 * 10-15), including homozygous deletion. Finally, we define distinct sub-groups of hyperdiploid MM, with either gain(1q21) and CCND2 overexpression (P<0.0001) or gain(11q25) and CCND1 overexpression (P<0.0001). Profiling multiple genetic lesions can identify MM patients likely to relapse early allowing stratification of treatment. PMID- 28584256 TI - Correlations between diffusion tensor imaging and levels of consciousness in patients with traumatic brain injury: a systematic review and meta-analysis. AB - Traumatic brain injury (TBI) often leads to impaired consciousness. Recent diffusion tensor imaging studies associated consciousness with imaging metrics including fractional anisotropy (FA) and apparent diffusion coefficient (ADC). We evaluated their correlations and determined the best index in candidate regions. Six databases were searched, including PubMed and Embase, and 16 studies with 701 participants were included. Data from region-of-interest and whole-brain analysis methods were meta-analysed separately. The FA-consciousness correlation was marginal in the whole-brain white matter (r = 0.63, 95% CI [0.47, 0.79], p = 0.000) and the corpus callosum (CC) (r = 0.60, 95% CI [0.48, 0.71], p = 0.000), and moderate in the internal capsule (r = 0.48, 95% CI [0.24, 0.72], p = 0.000). Correlations with ADC trended negative and lacked significance. Further subgroup analysis revealed that consciousness levels correlated strongly with FA in the CC body (r = 0.66, 95% CI [0.43, 0.89]), moderately in the splenium (r = 0.58, 95% CI [0.38, 0.78]), but insignificantly in the genu. In conclusion, FA correlates better with consciousness levels than ADC in TBI. The degree of correlation varies among brain regions. The CC (especially its splenium and body) is a reliable candidate region to quantitatively reflect consciousness levels. PMID- 28584257 TI - Changes in retinal metabolic profiles associated with form deprivation myopia development in guinea pigs. AB - Retinal metabolic changes have been suggested to be associated with myopia development. However, little is known about either their identity or time dependent behavior during this sight compromising process. To address these questions, gas chromatography time-of-flight mass spectrometry (GC-TOF/MS) was applied to compare guinea pig retinal metabolite levels in form deprivation (FD) eyes at 3 days and 2 weeks post FD with normal control (NC) eyes. Orthogonal partial least squares (OPLS) models discriminated between time dependent retinal metabolic profiles in the presence and absence of FD. Myopia severity was associated with more metabolic pattern differences in the FD than in the NC eyes. After 3 days of FD, 11 metabolite levels changed and after 2 weeks the number of differences increased to 16. Five metabolites continuously decreased during two weeks of FD. Two-way ANOVA of the changes identified by OPLS indicates that 15 out of the 22 metabolites differences were significant. Taken together, these results suggest that myopia progression is associated with an inverse relationship between increases in glucose accumulation and lipid level decreases in form-deprived guinea pig eyes. Such changes indicate that metabolomic studies are an informative approach to identify time dependent retinal metabolic alterations associated with this disease. PMID- 28584258 TI - Cathepsin S inhibition combines control of systemic and peripheral pathomechanisms of autoimmune tissue injury. AB - Cathepsin(Cat)-S processing of the invariant chain-MHC-II complex inside antigen presenting cells is a central pathomechanism of autoimmune-diseases. Additionally, Cat-S is released by activated-myeloid cells and was recently described to activate protease-activated-receptor-(PAR)-2 in extracellular compartments. We hypothesized that Cat-S blockade targets both mechanisms and elicits synergistic therapeutic effects on autoimmune tissue injury. MRL-(Fas)lpr mice with spontaneous autoimmune tissue injury were treated with different doses of Cat-S inhibitor RO5459072, mycophenolate mofetil or vehicle. Further, female MRL-(Fas)lpr mice were injected with recombinant Cat-S with/without concomitant Cat-S or PAR-2 blockade. Cat-S blockade dose-dependently reversed aberrant systemic autoimmunity, e.g. plasma cytokines, activation of myeloid cells and hypergammaglobulinemia. Especially IgG autoantibody production was suppressed. Of note (MHC-II-independent) IgM were unaffected by Cat-S blockade while they were suppressed by MMF. Cat-S blockade dose-dependently suppressed immune-complex glomerulonephritis together with a profound and early effect on proteinuria, which was not shared by MMF. In fact, intravenous Cat-S injection induced severe glomerular endothelial injury and albuminuria, which was entirely prevented by Cat-S or PAR-2 blockade. In-vitro studies confirm that Cat-S induces endothelial activation and injury via PAR-2. Therapeutic Cat-S blockade suppresses systemic and peripheral pathomechanisms of autoimmune tissue injury, hence, Cat-S is a promising therapeutic target in lupus nephritis. PMID- 28584259 TI - Complex beam shaping based on an equivalent q-plate system and analysis of its properties using digital holography polarization imaging. AB - In this study, we generate various complex beams carrying angular momentum (AM) by using a programmable beam shaping system to mimic typical q-plates. When a circularly polarized wave is incident onto the system, the emerging beam reverses its spin handedness and obtains a spatial phase factor. This phase factor can be engineered by designing a computer-generated hologram (CGH) and applying it to a spatial light modulator (SLM) to produce a beam with controllable spatially distributed orbital angular momentum (OAM) density. To determine the properties of the generated fields, we combine digital holography (DH) with the beam shaping system to yield visualizations of the beam intensity, phase, and AM distributions over the transverse plane at different propagation distances. Comparisons of the theoretically and experimentally obtained results show good qualitative agreement. This study advances our understanding and interpretation of AM characteristics produced by a programmable q-plate-like system. PMID- 28584260 TI - Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype. AB - This corrects the article DOI: 10.1038/ijo.2016.228. PMID- 28584261 TI - Health policies for obesity: how to get there! PMID- 28584262 TI - Genome-wide profiling and differential expression of microRNA in rat pluripotent stem cells. AB - MicroRNAs (miRNAs) constitute a class of small noncoding RNAs that plays an important role in the post-transcriptional regulation of gene expression. Much evidence has demonstrated that miRNAs are involved in regulating the human and mouse pluripotency. Nevertheless, to our knowledge, miRNAs in the pluripotent stem cells of one of the most commonly used model organisms - the Rattus norvegicus have not been studied. In the present study, we performed deep sequencing of small RNA molecules in the embryonic fibroblasts, embryonic stem cells, and induced pluripotent stem cells of laboratory rats. Bioinformatics analysis revealed 674 known miRNAs and 394 novel miRNA candidates in all of the samples. Expression of known pluripotency-associated miRNAs, such as the miR-290 295 and miR-183-96-182 clusters as well as members of the miR-200 family, was detected in rat pluripotent stem cells. Analysis of the targets of differentially expressed known and novel miRNAs showed their involvement in the regulation of pluripotency and the reprogramming process in rats. Bioinformatics and systems biology approaches identified potential pathways that are regulated by these miRNAs. This study contributes to our understanding of miRNAs in the regulation of pluripotency and cell reprogramming in the laboratory rat. PMID- 28584263 TI - The evaluation of land consolidation policy in improving agricultural productivity in China. AB - China is presently undergoing rapid economic development and unprecedented urbanization. Concerns over food security have prompted the Chinese government to implement large-scale land consolidation projects. However, no formal evaluation has been conducted on such projects. Thus, effectiveness of land consolidation policy remains uncertain. We obtained detailed geo-spatial information for 5328 land consolidation projects implemented between 2006 and 2010, and used time series MODIS NDVI (2006-2016) data to assess effectiveness of China's land consolidation policy in improving agricultural productivity. Our results show that the overall effectiveness of land consolidation in improving agricultural productivity is low, which lies in contrast to optimistic estimates based on regional statistical analysis and theoretical approaches. For projects (n = 560) implemented in 2006, about 29.5% showed significant (p < 0.05) increasing trends of MODIS NDVI after implementation of land consolidation. For 2007-2010, lower percentages (e.g., 25.9% in 2007 and 13.5% in 2010) of projects showed significant increasing trends. Furthermore, we found effectiveness of land consolidation projects displayed clear regional differences and driving factors are inconsistent with policy design. We anticipate our research to be a starting point for a more comprehensive evaluation involving longer time-series and higher spatial resolution data. PMID- 28584264 TI - Human Chitotriosidase: Catalytic Domain or Carbohydrate Binding Module, Who's Leading HCHT's Biological Function. AB - Chitin is an important structural component of numerous fungal pathogens and parasitic nematodes. The human macrophage chitotriosidase (HCHT) is a chitinase that hydrolyses glycosidic bonds between the N-acetyl-D-glucosamine units of this biopolymer. HCHT belongs to the Glycoside Hydrolase (GH) superfamily and contains a well-characterized catalytic domain appended to a chitin-binding domain (ChBDCHIT1). Although its precise biological function remains unclear, HCHT has been described to be involved in innate immunity. In this study, the molecular basis for interaction with insoluble chitin as well as with soluble chito oligosaccharides has been determined. The results suggest a new mechanism as a common binding mode for many Carbohydrate Binding Modules (CBMs). Furthermore, using a phylogenetic approach, we have analysed the modularity of HCHT and investigated the evolutionary paths of its catalytic and chitin binding domains. The phylogenetic analyses indicate that the ChBDCHIT1 domain dictates the biological function of HCHT and not its appended catalytic domain. This observation may also be a general feature of GHs. Altogether, our data have led us to postulate and discuss that HCHT acts as an immune catalyser. PMID- 28584265 TI - X-ray structures of fructosyl peptide oxidases revealing residues responsible for gating oxygen access in the oxidative half reaction. AB - Current enzymatic systems for quantifying glycated hemoglobin are based on the FAD-containing enzyme fructosyl peptide oxidase (FPOX). FPOX has substrate specificity for fructosyl-alpha N-valyl-histidine derived from proteolytic digestion of the N-terminus of the HbA1c beta-chain. This study reports the X-ray structures of the wild-type and Asn56Ala (N56A) mutant of Phaeosphaeria nodorum fructosyl peptide oxidase (PnFPOX) to elucidate the residues responsible for the oxidative half-reaction. N56A showed decreased oxidase activity compared to the wild -type, while its dye-mediated dehydrogenase activity was higher than that of wild type. In wild-type PnFPOX, Asn56 forms a hydrogen bond with Lys274, thereby preventing it from forming a salt bridge with Asp54. By contrast, Lys274 of PnFPOX N56A moves toward Asp54, and they approach each other to form a salt bridge at a distance of 2.92-3.35 A. Site-directed mutagenesis studies and protein channel analysis suggest that Asp54 assists in accepting oxygen properly at the position of the bound water molecule in the main oxygen channel. These results reveal that Asn56 in PnFPOX is essential for maintaining an effective oxygen accession path, and support the role of Asp54 as a gate keeper that cooperates with Lys274 to enable oxygen to reach the active site properly. PMID- 28584266 TI - Novel rapid-immunohistochemistry using an alternating current electric field for intraoperative diagnosis of sentinel lymph nodes in breast cancer. AB - Axillary lymph node status and pathological diagnosis of sentinel lymph nodes (SLNs) is a prognostic factor that influences management of postoperative therapy. Recent reports indicate that one-step nucleic acid amplification and hematoxylin and eosin (HE)-stained frozen sections are effective for intraoperative diagnosis of SLNs. In the present study, we report a rapid immunohistochemical staining (R-IHC) method that enables intraoperative detection of SLN metastases within 16 min using an anti-cytokeratin antibody. This is the first report on SLN diagnosis using R-IHC in patients with breast cancer. We prospectively examined 160 dissected SLNs from 108 breast cancer patients who underwent surgery at our institute. The dissected SLNs were sectioned and conventionally stained with HE or immunohistochemically labeled with anti cytokeratin antibody using R-IHC procedures. Intraoperative R-IHC analyses were completed within 16 min, after which diagnoses were made by two pathologists. The total time required for intraoperative diagnosis was about 20 min. In this study series, R-IHC detected four metastatic SLNs that were undetected using conventional HE staining (4/20, 20.0%). Compared with subsequent permanent diagnosis, R-IHC offered 95.2% sensitivity and 100% specificity. These findings indicate R-IHC is a clinically applicable technique that enables precise and quick intraoperative detection of micro- and macrometastasis in breast cancer. PMID- 28584267 TI - Application of Box-Behnken designs in parameters optimization of differential pulse anodic stripping voltammetry for lead(II) determination in two electrolytes. AB - Box-Behnken design was advantageous to parameters optimization of differential pulse anodic stripping voltammetry (DPASV) for the analysis of lead(II) with its high efficiency and accuracy. Five Box-Behnken designs were designed and conducted in the electrolyte of 0.1 mol/L acetate buffer and 0.1 mol/L HCl without the removal of oxygen. Significant parameters and interactions in each electrolyte were found (P-value < 0.05) and their quantitative effects on lead(II) determination were classified into two categories, linear and quadratic. Though significant parameters and interactions were not similar in different kinds of electrolytes, characteristic parameters of differential pulse voltammetry, which were pulse amplitude, pulse width and interval time, were found significant in both electrolytes. After optimization, peak currents and relative standard deviation at 20 MUg/L along with detection limits in both electrolytes were superior than before. With the lower detection limit and R.S.D., 0.1 mol/L HCl was a better choice for electrolytes in this work. Meanwhile, with the combination of parameters optimization and background subtraction, the interference of dissolved oxygen for lead(II) determination was eliminated. It was important and necessary to apply Box-Behnken designs in parameters optimization of DPASV for lead(II) determination regardless of the electrolyte kinds. PMID- 28584268 TI - Pulmonary emphysema is a risk factor for radiation pneumonitis in NSCLC patients with squamous cell carcinoma after thoracic radiation therapy. AB - Pulmonary emphysema (PE) has been demonstrated to have a high prevalence in patients with locally advanced non-small cell lung cancer (NSCLC). A total of 153 patients with locally advanced NSCLC were enrolled in this study to investigate the association between PE and radiation pneumonitis (RP) after definitive thoracic radiation therapy (TRT). The incidence of RP in Grade 2, 3 and 5 were 11.1%, 9.8% and 0.7%, respectively. Univariate analysis revealed that age, PE, forced vital capacity (FVC), arterial partial pressure of oxygen (PO2) and mean lung dose (MLD) were significantly associated with the risk of Grade >=2 or Grade >=3 RP in patients with squamous cell carcinoma (SCC, P < 0.05). Logistic analysis demonstrated that PE was an independent risk factor of RP in SCC (P < 0.05). Receiver operating characteristics (ROC) analysis revealed that the combination of age, PE, FVC, PO2 and MLD had a higher value to predict RP in SCC (AUC = 0.856 in Grade >=2 RP and 0.882 in Grade >=3 RP, respectively). Kaplan Meier analysis revealed that the more severe the PE, the higher the incidence of RP in SCC. Our results revealed that PE was a high risk factor for locally advanced NSCLC patients followed definitive TRT, especially for SCC patients. PMID- 28584270 TI - Ambient anthropogenic noise but not light is associated with the ecophysiology of free-living songbird nestlings. AB - Urbanization is associated with dramatic increases in noise and light pollution, which affect animal behaviour, physiology and fitness. However, few studies have examined these stressors simultaneously. Moreover, effects of urbanization during early-life may be detrimental but are largely unknown. In developing great tits (Parus major), a frequently-used model species, we determined important indicators of immunity and physiological condition: plasma haptoglobin (Hp) and nitric oxide (NOx) concentration. We also determined fledging mass, an indicator for current health and survival. Associations of ambient noise and light exposure with these indicators were studied. Anthropogenic noise, light and their interaction were unrelated to fledging mass. Nestlings exposed to more noise showed higher plasma levels of Hp but not of NOx. Light was unrelated to Hp and NOx and did not interact with the effect of noise on nestlings' physiology. Increasing levels of Hp are potentially energy demanding and trade-offs could occur with life-history traits, such as survival. Effects of light pollution on nestlings of a cavity-nesting species appear to be limited. Nonetheless, our results suggest that the urban environment, through noise exposure, may entail important physiological costs for developing organisms. PMID- 28584271 TI - Soil biochemical responses to nitrogen addition in a secondary evergreen broad leaved forest ecosystem. AB - In order to investigate the effects of N deposition on soil biochemistry in secondary forests, one N addition experiment was conducted in a secondary evergreen broad-leaved forest in the western edge of Sichuan Basin, with the highest level of background N deposition (about 95 kg N ha-1 yr-1) in China. Three N treatment levels (+0, +50, +150 kg N ha-1 yr-1) were monthly added to soil surface in this forest beginning in April 2013. Soil biochemistry and root biomass of the 0-10 cm soil horizon were measured from May 2014 to April 2015. Soil respiration was measured for two years (September 2013 to August 2015). It was showed that N additions were correlated to significantly lower soil pH, microbial biomass C (MBC) concentration, MBC/microbial biomass N (MBN) ratio, root biomass, and soil respiration rate, and significantly higher concentrations of ammonium (NH4+) and nitrate (NO3-). These results indicate that N additions had a significant effect on the size of soil microbial community. In addition, soil C storage may potentially increase due to the dropped soil C release under N addition. PMID- 28584269 TI - Time-dependent changes and potential mechanisms of glucose-lipid metabolic disorders associated with chronic clozapine or olanzapine treatment in rats. AB - Chronic treatment with second-generation antipsychotic drugs (SGAs) has been associated with an increased risk of metabolic syndrome. To evaluate the longitudinal changes in glucose-lipid homeostasis after SGA use, we studied the time-dependent effects of olanzapine (OLZ) (3 mg/kg, b.i.d.) or clozapine (CLZ) (20 mg/kg, b.i.d.) treatment on metabolic profiles for 9 weeks in rats. Although only OLZ significantly increased body weight in rats, both OLZ and CLZ elevated blood lipid levels. Chronic OLZ treatment induced significant weight gain leading to a higher fasting insulin level and impaired glucose tolerance, whereas CLZ lowered fasting insulin levels and impaired glucose tolerance independent of weight gain. Treatment with both drugs deranged AKT/GSK phosphorylation and up regulated muscarinic M3 receptors in the rats' livers. Consistent with an elevation in lipid levels, both OLZ and CLZ significantly increased the protein levels of nuclear sterol regulatory element-binding proteins (SREBPs) in the liver, which was associated with improvement in hepatic histamine H1R. However, enhanced carbohydrate response element binding protein (ChREBP) signalling was observed in only CLZ-treated rats. These results suggest that SGA-induced glucose lipid metabolic disturbances could be independent of weight gain, possibly through activation of SREBP/ChREBP in the liver. PMID- 28584272 TI - Solid Conical Cap-closing Hollow Tube Growth by Axial Screw Dislocations. AB - Exploration of the mechanisms for growth of the nanostructures is the key point to achieve nanomaterial syntheses with precisely controlled morphology and structure. Herein, we reported a new mechanism that realized the growth of solid conical cap-closing hollow tube by axial screw dislocations in the formation alpha-Al2O3 nanowires. A hollow tube was firstly grown by axial screw dislocations in the formation alpha-Al2O3 nanowires through vapor-phase synthesis. Afterwards, the hollow tube was closed up by generating a solid conical cap with axial screw dislocations based on the competition between the surface energy and the strain energy of screw dislocation controlled by the growth environment. The solid conical cap-closing hollow tube growth model based on the axial screw dislocations is expected to be a general growth mechanism for nanowires within low supersaturation. This study enriches the fundamental understanding with respective to the kinetics of nanostructured crystal growth and provides guidance to the precise structure control in nanosynthesis and manufacturing. PMID- 28584273 TI - Antennal and abdominal transcriptomes reveal chemosensory gene families in the coconut hispine beetle, Brontispa longissima. AB - Antennal and abdominal transcriptomes of males and females of the coconut hispine beetle Brontispa longissima were sequenced to identify and compare the expression patterns of genes involved in odorant reception and detection. Representative proteins from the chemosensory gene families likely essential for insect olfaction were identified. These include 48 odorant receptors (ORs), 19 ionotropic receptors (IRs), 4 sensory neuron membrane proteins (SNMPs), 34 odorant binding proteins (OBPs) and 16 chemosensory proteins (CSPs). Phylogenetic analysis revealed the evolutionary relationship of these proteins with homologs from Coleopterans or other insects, and led to the identification of putative aggregation pheromone receptors in B. longissima. Comparative expression analysis performed by calculating FPKM values were also validated using quantitative real time-PCR (qPCR). The results revealed that all ORs and antennal IRs, two IR co receptors (BlonIR8a and BlonIR25a) and one SNMP (BlonSNMP1a) were predominantly expressed in antennae when compared to abdomens, and approximately half of the OBPs (19) and CSPs (7) were enriched in antennae. These findings for the first time reveal the identification of key molecular components in B. longissima olfaction and provide a valuable resource for future functional analyses of olfaction, and identification of potential targets to control this quarantine pest. PMID- 28584274 TI - Overexpression of Pea DNA Helicase 45 (PDH45) imparts tolerance to multiple abiotic stresses in chili (Capsicum annuum L.). AB - Imparting tolerance to abiotic stresses is of global importance as they inflict significant yield losses in field as well as in vegetable crops. Transcriptional activators, including helicases are identified to play a pivotal role in stress mitigation. Helicases, also known as molecular motors, are involved in myriad cellular processes that impart intrinsic tolerance to abiotic stresses in plants. Our study demonstrates the potential of a Pea DNA Helicase 45 (PDH45), in combating multiple abiotic stresses in chili. We harnessed Agrobacterium-mediated in planta transformation strategy for the generation of stable, single copy transgenic events. Precise molecular detection of the transgenes by sqRT-PCR coupled with genomic Southern analysis revealed variation in the integration of PDH45 at distinct loci in independent transgenic events. Characterization of five promising transgenic events showed both improved response to an array of simulated abiotic stresses and enhanced expression of several stress-responsive genes. While survival and recovery of transgenic events were significantly higher under gradual moisture stress conditions, under imposition of moderate stress, the transgenic events exhibited invigorated growth and productivity with concomitant improvement in water use efficiency (WUE). Thus, our study, unequivocally demonstrated the cardinal role of PDH45 in alleviating multiple abiotic stresses in chili. PMID- 28584275 TI - Physiological characteristics of Magnetospirillum gryphiswaldense MSR-1 that control cell growth under high-iron and low-oxygen conditions. AB - Magnetosome formation by Magnetospirillum gryphiswaldense MSR-1 is dependent on iron and oxygen levels. We used transcriptome to evaluate transcriptional profiles of magnetic and non-magnetic MSR-1 cells cultured under high-iron and low-iron conditions. A total of 80 differentially expressed genes (DEGs) were identified, including 53 upregulated and 27 downregulated under high-iron condition. These DEGs belonged to the functional categories of biological regulation, oxidation-reduction process, and ion binding and transport, and were involved in sulfur metabolism and cysteine/methionine metabolism. Comparison with our previous results from transcriptome data under oxygen-controlled conditions indicated that transcription of mam or mms was not regulated by oxygen or iron signals. 17 common DEGs in iron- and oxygen-transcriptomes were involved in energy production, iron transport, and iron metabolism. Some unknown-function DEGs participate in iron transport and metabolism, and some are potential biomarkers for identification of Magnetospirillum strains. IrrA and IrrB regulate iron transport in response to low-oxygen and high-iron signals, respectively. Six transcription factors were predicted to regulate DEGs. Fur and Crp particularly co-regulate DEGs in response to changes in iron or oxygen levels, in a proposed joint regulatory network of DEGs. Our findings provide new insights into biomineralization processes under high- vs. low-iron conditions in magnetotactic bacteria. PMID- 28584276 TI - Persistent LHPA Activation in German Individuals Raised in an Overprotective Parental Behavior. AB - Parental upbringing may affect their offspring's mental state across the entire lifespan. Overprotective parental child-rearing style may increase the disease burden in the offspring. Furthermore, this child-rearing style may also play a pathogenetic role by transmitting trauma- and stressor-related disorders (TSRD) across generations. Studies with animals have demonstrated that the mother's immediate and expansive protection of the newborn decreases the limbic hypothalamic-pituitary-adrenal (LHPA) axis activity in the offspring. However, few studies have investigated how stress impact humans raised in an overprotective manner. In a cross-sectional study with 40 healthy students recalling their overprotective upbringing, we show an increase in the dehydroepiandrostendione (DHEA) concentration and a reduction in the cortisol/DHEA-ratio in hair. Additionally, this child rearing style was associated with heightened indications of mental burden, depressiveness, and sense of coherence. Our results provide insight into the roots and consequences of psychological trauma across several generations. Further investigations focusing particularly on multigenerational transmission in extremely burdened families will augment our results. PMID- 28584277 TI - Analysis of aquaporins in Brassicaceae species reveals high-level of conservation and dynamic role against biotic and abiotic stress in canola. AB - Aquaporins (AQPs) are of vital importance in the cellular transport system of all living organisms. In this study, genome-wide identification, distribution, and characterization of AQPs were determined in Arabidopsis lyrata, Capsella grandiflora, C. rubella, Eutrema salsugineum, Brassica rapa, B. oleracea, and B. napus (canola). Classification and phylogeny of AQPs revealed the loss of XIPs and NIP-IIIs in all species. Characterization of distinctive AQP features showed a high level of conservation in spacing between NPA-domains, and selectivity filters. Interestingly, TIP3s were found to be highly expressed in developing seeds, suggesting their role in seed desiccation. Analysis of available RNA-seq data obtained under biotic and abiotic stresses led to the identification of AQPs involved in stress tolerance mechanisms in canola. In addition, analysis of the effect of ploidy level, and resulting gene dose effect performed with the different combinations of Brassica A and C genomes revealed that more than 70% of AQPs expression were dose-independent, thereby supporting their role in stress alleviation. This first in-depth characterization of Brassicaceae AQPs highlights transport mechanisms and related physiological processes that could be exploited in breeding programs of stress-tolerant cultivars. PMID- 28584278 TI - Environmental novelty exacerbates stress hormones and Abeta pathology in an Alzheimer's model. AB - Cognitive stimulation has been proposed as a non-pharmacological intervention to be used in primary, secondary and tertiary prevention approaches for Alzheimer's disease. A common familial Alzheimer's disease transgenic model showed heightened levels of the stress hormone, corticosterone. When exposed to periodic enhanced cognitive stimulation, these animals demonstrated further heightened levels of corticosterone as well as increased Abeta pathology. Hence, Alzheimer's disease may be associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction, causing stimulatory environments to become stress-inducing, leading to a glucocorticoid-pathology cycle contributing to further Abeta release and plaque formation. This finding suggests that stimulation-based interventions and local environments for people with Alzheimer's disease need to be designed to minimise a stress response that may exacerbate brain pathology. PMID- 28584279 TI - Serum hepatitis B core antibody as a biomarker of hepatic inflammation in chronic hepatitis B patients with normal alanine aminotransferase. AB - Our previous studies unexpectedly indicated that the level of serum hepatitis B core antibody (anti-HBc) was positively correlated with the serum alanine aminotransferase (ALT) level. The aim of this study was to determine whether anti HBc could serve as a potential biomarker for the detection of liver inflammation in chronic hepatitis B (CHB) patients, especially in patients with normal ALT levels. Serum anti-HBc levels were quantified in 655 treatment-naive CHB patients, including 45 patients who underwent two liver biopsies (baseline phase and the 78th weeks of antiviral-treatment). Serum anti-HBc levels increased significantly along with the increasing histology activity index (HAI) score. After antiviral-treatment, patients with HAI score reduction had significant decline in serum anti-HBc level. Multivariate analysis showed that anti-HBc was independently associated with moderate-to-severe hepatic inflammation in patients with normal ALT level. Furthermore, serum anti-HBc showed a high diagnostic accuracy for predicting moderate-to-severe inflammation in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB patients with normal ALT levels (area under the curve, AUC = 0.87 and 0.75; respectively). Thus, anti-HBc may be a strong indicator for assessing the hepatic inflammatory degree and used for antiviral treatment decisions in CHB patients with normal ALT levels. PMID- 28584280 TI - Switching of spins and entanglement in surface-supported antiferromagnetic chains. AB - Previous experimental studies discovered universal growth of chains and nanowires of various chemical elements on a corrugated molecular network of Cu3N on the Cu(110). Herein, performing combined ab initio and quantum Hamiltonian studies we demonstrate that such chains can be used for a fast spin switching and entanglement generation by locally applied magnetic pulses. As an example, we show that in antiferromagnetic Co chains a strong entanglement between ends of chains occurs during spin switching. A novel parity effect in spin dynamics is reported. Even-numbered chains are found to exhibit significantly faster spin switching than odd-numbered counterparts. Moreover, at certain parameters of the system the dimerization effect in the spin dynamics of the chains was found. Our studies give a clear evidence that tailoring spin dynamics and entanglement can be achieved by magnetic fields and by tuning exchange interactions in supported chains. PMID- 28584281 TI - Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection. AB - Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169+ sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4+CD25+ T cells and an increased number of B220+CD19+ B cells. The reduction in CD4+CD25+ T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome. PMID- 28584282 TI - Integration of vibrotactile frequency information beyond the mechanoreceptor channel and somatotopy. AB - A wide variety of tactile sensations arise from the activation of several types of mechanoreceptor-afferent channels scattered all over the body, and their projections create a somatotopic map in the somatosensory cortex. Recent findings challenge the traditional view that tactile signals from different mechanoreceptor-channels/locations are independently processed in the brain, though the contribution of signal integration to perception remains obscure. Here we show that vibrotactile frequency perception is functionally enriched by signal integration across different mechanoreceptor channels and separate skin locations. When participants touched two sinusoidal vibrations of far-different frequency, which dominantly activated separate channels with the neighboring fingers or the different hand and judged the frequency of one vibration, the perceived frequency shifted toward the other (assimilation effect). Furthermore, when the participants judged the frequency of the pair as a whole, they consistently reported an intensity-based interpolation of the two vibrations (averaging effect). Both effects were similar in magnitude between the same and different hand conditions and significantly diminished by asynchronous presentation of the vibration pair. These findings indicate that human tactile processing is global and flexible in that it can estimate the ensemble property of a large-scale tactile event sensed by various receptors distributed over the body. PMID- 28584283 TI - Phytohormone ethylene-responsive Arabidopsis organ growth under light is in the fine regulation of Photosystem II deficiency-inducible AKIN10 expression. AB - For photoautotrophic plants, light-dependent photosynthesis plays an important role in organismal growth and development. Under light, Arabidopsis hypocotyl growth is promoted by the phytohormone ethylene. Despite well-characterized ethylene signaling pathways, the functions of light in the hormone-inducible growth response still remain elusive. Our cell-based functional and plant-system based genetic analyses with biophysical and chemical tools showed that a chemical blockade of photosystem (PS) II activity affects ethylene-induced hypocotyl response under light. Interestingly, ethylene responsiveness modulates PSII activity in retrospect. The lack of ethylene responsiveness-inducible PSII inefficiency correlates with the induction of AKIN10 expression. Consistently, overexpression of AKIN10 in transgenic plants suppresses ethylene-inducible hypocotyl growth promotion under illumination as in other ethylene-insensitive mutants. Our findings provide information on how ethylene responsiveness dependent photosynthetic activity controls evolutionarily conserved energy sensor AKIN10 that fine-tunes EIN3-mediated ethylene signaling responses in organ growth under light. PMID- 28584284 TI - Erythropoietin ameliorates diabetes-associated cognitive dysfunction in vitro and in vivo. AB - Several studies indicate that erythropoietin (EPO) has remarkable neuroprotective effects in various central nervous system disorders, while little is known about the effects of EPO in diabetes-associated cognitive dysfunction. Therefore, the present study aimed to investigate whether EPO ameliorates diabetes-associated cognitive dysfunction in vivo and in vitro. We investigated the protective effects of EPO on high-glucose (HG)-induced PC12 cell death and oxidative stress. The effects of EPO (300 U/kg administered three times a week for 4 weeks) on diabetes-associated cognitive decline were investigated in diabetic rats. EPO significantly increased cell viability, increased the activity of superoxide dismutase, decreased the production of malondialdehyde and reactive oxygen species, and decreased the apoptosis rate. Additionally, LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, abolished the protective effects of EPO in HG-treated PC12 cells. In diabetic rats, EPO prevented deficits in spatial learning and memory in the Morris water maze test. The results of real time PCR and Western blotting showed that EPO upregulated EPO receptor, PI3K, and phosphorylated Akt2 relative to unphosphorylated Akt2 (p-Akt2/Akt2) and downregulated glycogen synthase kinase-3beta (GSK-3beta). These studies demonstrate that EPO is an effective neuroprotective agent in the context of diabetes-associated cognitive dysfunction and show that this effect involves the PI3K/Akt/GSK-3beta pathway. PMID- 28584285 TI - Oxygen atoms are critical in rendering THP-1 leukaemia cells susceptible to cold physical plasma-induced apoptosis. AB - Cold physical plasma has been suggested as a powerful new tool in oncology. However, some cancer cells such as THP-1 leukaemia cells have been shown to be resistant towards plasma-induced cell death, thereby serving as a good model for optimizing plasmas in order to foster pro-apoptotic anticancer effects. A helium/oxygen radio frequency driven atmospheric plasma profoundly induced apoptosis in THP-1 cells whereas helium, humidified helium, and humidified helium/oxygen plasmas were inefficient. Hydrogen peroxide - previously shown as central plasma-derived agent - did not participate in the killing reaction but our results suggest hypochlorous acid to be responsible for the effect observed. Proteomic analysis of THP-1 cells exposed to He/O2 plasma emphasized a prominent growth retardation, cell stress, apoptosis, and a pro-immunogenic profile. Altogether, a plasma setting that inactivates previously unresponsive leukaemia cells is presented. Crucial reactive species in the plasma and liquid environment were identified and discussed, deciphering the complexity of plasma from the gas phase into the liquid down to the cellular response mechanism. These results may help tailoring plasmas for clinical applications such as oxidation-insensitive types of cancer. PMID- 28584288 TI - Water remediation: A steam nanogenerator. PMID- 28584286 TI - Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and cognition. AB - We conducted a genome-wide meta-analysis of cognitive empathy using the 'Reading the Mind in the Eyes' Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study. We confirmed a female advantage on the Eyes Test (Cohen's d=0.21, P<2.2 * 10-16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta=1.58 * 10 8). Common single nucleotide polymorphisms explained 5.8% (95% CI: 4.5%-7.2%; P=1.00 * 10-17) of the total trait variance in both sexes, and we identified a twin heritability of 28% (95% CI: 13%-42%). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, openness (NEO Five Factor Inventory), and different measures of educational attainment and cognitive aptitude. PMID- 28584290 TI - More carbon and less salt. PMID- 28584291 TI - Teaching nanosafety. PMID- 28584287 TI - Rescue of impaired sociability and anxiety-like behavior in adult cacna1c deficient mice by pharmacologically targeting eIF2alpha. AB - CACNA1C, encoding the Cav1.2 subunit of L-type Ca2+ channels, has emerged as one of the most prominent and highly replicable susceptibility genes for several neuropsychiatric disorders. Cav1.2 channels play a crucial role in calcium mediated processes involved in brain development and neuronal function. Within the CACNA1C gene, disease-associated single-nucleotide polymorphisms have been associated with impaired social and cognitive processing and altered prefrontal cortical (PFC) structure and activity. These findings suggest that aberrant Cav1.2 signaling may contribute to neuropsychiatric-related disease symptoms via impaired PFC function. Here, we show that mice harboring loss of cacna1c in excitatory glutamatergic neurons of the forebrain (fbKO) that we have previously reported to exhibit anxiety-like behavior, displayed a social behavioral deficit and impaired learning and memory. Furthermore, focal knockdown of cacna1c in the adult PFC recapitulated the social deficit and elevated anxiety-like behavior, but not the deficits in learning and memory. Electrophysiological and molecular studies in the PFC of cacna1c fbKO mice revealed higher E/I ratio in layer 5 pyramidal neurons and lower general protein synthesis. This was concurrent with reduced activity of mTORC1 and its downstream mRNA translation initiation factors eIF4B and 4EBP1, as well as elevated phosphorylation of eIF2alpha, an inhibitor of mRNA translation. Remarkably, systemic treatment with ISRIB, a small molecule inhibitor that suppresses the effects of phosphorylated eIF2alpha on mRNA translation, was sufficient to reverse the social deficit and elevated anxiety like behavior in adult cacna1c fbKO mice. ISRIB additionally normalized the lower protein synthesis and higher E/I ratio in the PFC. Thus this study identifies a novel Cav1.2 mechanism in neuropsychiatric-related endophenotypes and a potential future therapeutic target to explore. PMID- 28584293 TI - Expression and functional analysis of the lysine decarboxylase and copper amine oxidase genes from the endophytic fungus Colletotrichum gloeosporioides ES026. AB - Huperzine A (HupA) isolated from Huperzia serrata is an important compound used to treat Alzheimer's disease (AD). Recently, HupA was reported in various endophytic fungi, with Colletotrichum gloeosporioides ES026 previously isolated from H. serrata shown to produce HupA. In this study, we performed next generation sequencing and de novo RNA sequencing of C. gloeosporioides ES026 to elucidate the molecular functions, biological processes, and biochemical pathways of these unique sequences. Gene ontology and Kyoto Encyclopedia of Genes and Genomes assignments allowed annotation of lysine decarboxylase (LDC) and copper amine oxidase (CAO) for their conversion of L-lysine to 5-aminopentanal during HupA biosynthesis. Additionally, we constructed a stable, high-yielding HupA expression system resulting from the overexpression of CgLDC and CgCAO from the HupA-producing endophytic fungus C. gloeosporioides ES026 in Escherichia coli. Quantitative reverse transcription polymerase chain reaction analysis confirmed CgLDC and CgCAO expression, and quantitative determination of HupA levels was assessed by liquid chromatography high-resolution mass spectrometry, which revealed that elevated expression of CgLDC and CgCAO produced higher yields of HupA than those derived from C. gloeosporioides ES026. These results revealed CgLDC and CgCAO involvement in HupA biosynthesis and their key role in regulating HupA content in C. gloeosporioides ES026. PMID- 28584294 TI - Evaluation of the effects of L-carnitine on medaka (Oryzias latipes) fatty liver. AB - Lifestyle-related diseases have become a major issue in recent years. The increasing incidence of fatty liver underlines the urgency with which the issues of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) need to be addressed. L-carnitine is a compound known to transport fatty acids into the mitochondria to enhance beta-oxidation-mediated metabolism of fats. In this study, the effects of L-carnitine administration on fatty liver of medaka (Oryzias latipes) were analysed, to check for disease improvement and metabolic changes. Additionally, the effects of the concomitant administration of L-carnitine and eicosapentaenoic acid (20:5n-3) (EPA) were investigated. Findings indicated reduced lipid deposition, increase in metabolites associated with beta oxidation, and significant reduction in fatty acid levels in the liver, implying improvement in fatty liver condition. Concomitant administration of L-carnitine and EPA resulted in further benefits, via changes in fatty acid composition in the medaka fatty liver model. PMID- 28584292 TI - Fundamental transport mechanisms, fabrication and potential applications of nanoporous atomically thin membranes. AB - Graphene and other two-dimensional materials offer a new approach to controlling mass transport at the nanoscale. These materials can sustain nanoscale pores in their rigid lattices and due to their minimum possible material thickness, high mechanical strength and chemical robustness, they could be used to address persistent challenges in membrane separations. Here we discuss theoretical and experimental developments in the emerging field of nanoporous atomically thin membranes, focusing on the fundamental mechanisms of gas- and liquid-phase transport, membrane fabrication techniques and advances towards practical application. We highlight potential functional characteristics of the membranes and discuss applications where they are expected to offer advantages. Finally, we outline the major scientific questions and technological challenges that need to be addressed to bridge the gap from theoretical simulations and proof-of-concept experiments to real-world applications. PMID- 28584295 TI - Membrane Ballooning in Aggregated Platelets is Synchronised and Mediates a Surge in Microvesiculation. AB - Human platelet transformation into balloons is part of the haemostatic response and thrombus architecture. Here we reveal that in aggregates of platelets in plasma, ballooning in multiple platelets occurs in a synchronised manner. This suggests a mechanism of coordination between cells, previously unrecognised. We aimed to understand this mechanism, and how it may contribute to thrombus development. Using spinning-disc confocal microscopy we visualised membrane ballooning in human platelet aggregates adherent to collagen-coated surfaces. Within an aggregate, multiple platelets undergo ballooning in a synchronised fashion, dependent upon extracellular calcium, in a manner that followed peak cytosolic calcium levels in the aggregate. Synchrony was observed in platelets within but not between aggregates, suggesting a level of intra-thrombus communication. Blocking phosphatidylserine, inhibiting thrombin or blocking PAR1 receptor, largely prevented synchrony without blocking ballooning itself. In contrast, inhibition of connexins, P2Y12, P2Y1 or thromboxane formation had no effect on synchrony or ballooning. Importantly, synchronised ballooning was closely followed by a surge in microvesicle formation, which was absent when synchrony was blocked. Our data demonstrate that the mechanism underlying synchronised membrane ballooning requires thrombin generation acting effectively in a positive feedback loop, mediating a subsequent surge in procoagulant activity and microvesicle release. PMID- 28584297 TI - Increased risk of influenza among vaccinated adults who are obese. AB - BACKGROUND: Influenza infects 5-15% of the global population each year, and obesity has been shown to be an independent risk factor for increased influenza related complications including hospitalization and death. However, the risk of developing influenza or influenza-like illness (ILI) in a vaccinated obese adult population has not been addressed. OBJECTIVE: This study evaluated whether obesity was associated with increased risk of influenza and ILI among vaccinated adults. SUBJECTS AND METHODS: During the 2013-2014 and 2014-2015 influenza seasons, we recruited 1042 subjects to a prospective observational study of trivalent inactivated influenza vaccine (IIV3) in adults. A total of 1022 subjects completed the study. Assessments of relative risk for laboratory confirmed influenza and ILI were determined based on body mass index. Seroconversion and seroprotection rates were determined using prevaccination and 26-35 days post vaccination serum samples. Recruitment criteria for this study were adults 18 years of age and older receiving the seasonal trivalent inactivated influenza vaccine (IIV3) for the years 2013-2014 and 2014-2015. Exclusion criteria were immunosuppressive diseases, use of immunomodulatory or immunosuppressive drugs, acute febrile illness, history of Guillain-Barre syndrome, use of theophylline preparations or use of warfarin. RESULTS: Among obese, 9.8% had either confirmed influenza or influenza-like-illness compared with 5.1% of healthy weight participants. Compared with vaccinated healthy weight, obese participants had double the risk of developing influenza or ILI (relative risk=2.01, 95% CI 1.12, 3.60, P=0.020). Seroconversion or seroprotection rates were not different between healthy weight and obese adults with influenza or ILI. CONCLUSIONS: Despite robust serological responses, vaccinated obese adults are twice as likely to develop influenza and ILI compared with healthy weight adults. This finding challenges the current standard for correlates of protection, suggesting use of antibody titers to determine vaccine effectiveness in an obese population may provide misleading information. PMID- 28584296 TI - Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations. AB - OBJECTIVES: The development of effective strategies to prevent childhood obesity and its comorbidities requires new, reliable early biomarkers. Here, we aimed to identify in peripheral blood cells potential transcript-based biomarkers of unhealthy metabolic profile associated to overweight/obesity in children. METHODS: We performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between overweight and normal weight children to obtain novel transcript-based biomarkers predictive of metabolic complications. RESULTS: The most significant enriched pathway of differentially expressed genes was related to oxidative phosphorylation, for which most of genes were downregulated in overweight versus normal weight children. Other genes were involved in carbohydrate metabolism/glucose homoeostasis or in lipid metabolism (for example, TCF7L2, ADRB3, LIPE, GIPR), revealing plausible mechanisms according to existing biological knowledge. A set of differentially expressed genes was identified to discriminate in overweight children those with high or low triglyceride levels. CONCLUSIONS: Functional microarray analysis has revealed a set of potential blood-cell transcript-based biomarkers that may be a useful approach for early identification of children with higher predisposition to obesity-related metabolic alterations. PMID- 28584298 TI - Role of aquaporin-7 in ghrelin- and GLP-1-induced improvement of pancreatic beta cell function after sleeve gastrectomy in obese rats. AB - BACKGROUND/OBJECTIVES: Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues as well as for pancreatic insulin secretion. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in beta-cells, and AQP12, an aquaporin related to pancreatic damage, in the improvement of pancreatic function and steatosis after sleeve gastrectomy in diet-induced obese rats. SUBJECTS/METHODS: Male Wistar obese rats (n=125) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by sleeve-gastrectomized animals) interventions. The tissue distribution and expression of AQPs in the rat pancreas were analyzed by real time PCR, western blotting and immunohistochemistry. The effect of ghrelin isoforms and glucagon-like peptide 1 (GLP-1) on insulin secretion, triacylglycerol (TG) accumulation and AQP expression was determined in vitro in RIN-m5F beta-cells. RESULTS: Sleeve gastrectomy reduced pancreatic beta-cell apoptosis, steatosis and insulin secretion. Lower ghrelin and higher GLP-1 concentrations were also found after bariatric surgery. Acylated and desacyl ghrelin increased TG content, whereas GLP-1 increased insulin release in RIN-m5F beta-cells. Sleeve gastrectomy was associated with an upregulation of AQP7 together with a normalization of the increased AQP12 levels in the rat pancreas. Interestingly, ghrelin and GLP-1 repressed AQP7 and AQP12 expression in RIN-m5F beta-cells. AQP7 protein was negatively correlated with intracellular lipid accumulation in acylated ghrelin-treated cells and with insulin release in GLP-1 stimulated beta-cells. CONCLUSIONS: AQP7 upregulation in beta-cells after sleeve gastrectomy contributes, in part, to the improvement of pancreatic steatosis and insulin secretion by increasing intracellular glycerol used for insulin release triggered by GLP-1 rather than for ghrelin-induced TG biosynthesis. PMID- 28584299 TI - Dissociation of body mass index, excess weight loss and body fat percentage trajectories after 3 years of gastric bypass: relationship with metabolic outcomes. AB - BACKGROUND/OBJECTIVES: Body weight, body mass index (BMI) and excess weight loss (EWL) are the most frequently used measures to analyse bariatric surgery outcomes. However, these measurements do not provide accurate information on body composition (BC) with body fat (BF), importantly determining the levels of cardiometabolic risk factors. Our aim was to analyse the evolution of BC after Roux-en-Y Gastric Bypass (RYGB) and its influence on the changes of cardiometabolic risk factors in comparison to BMI and EWL. SUBJECTS/METHODS: A group of 81 obese Caucasian patients (19 males/62 females) aged 44.9+/-1.3 years undergoing RYGB between January 2006 and December 2011 was prospectively followed up for a period of 3 years. BC was determined by air-displacement plethysmography. Visceral adiposity, physical activity and cardiometabolic risk factors were measured. RESULTS: BF was markedly (P<0.001) reduced after the first year, increasing progressively during the second and third years after RYGB, following a different trajectory than body weight, BMI and EWL that decreased up to the second year post surgery. Markers of glucose homeostasis decreased during the first month and continued to decrease during the first year (P<0.05), remaining stabilised or slightly increased between the second and third years following RYGB. However, markers of lipid metabolism decreased (P<0.05) markedly during the first 12 months, increasing thereafter in parallel to the changes observed in BC, with the exception of high-density lipoprotein-cholesterol, which increased progressively throughout the whole period analysed. CONCLUSIONS: The adverse switch in the changes in BC between the first and the second years after RYGB may underlie the changes observed in cardiometabolic risk factors. Tracking of adiposity during the follow-up of bariatric/metabolic surgery yields clinically relevant information to better identify patients in need of increased lifestyle advice or treatment intensification. PMID- 28584300 TI - Duration and degree of adiposity: effect on cardiovascular risk factors at early adulthood. AB - BACKGROUND/OBJECTIVES: The effect of adiposity dynamics throughout adolescence on adult cardiometabolic outcomes is not well known. We aimed to assess the effect of duration and degree of adiposity from adolescence to early adulthood on blood pressure and insulin resistance at 24 years. SUBJECTS/METHODS: We used data from 2253 participants evaluated at 13, 17, 21 and 24 years of age in the EPITeen cohort, Porto, Portugal. The area under the curve of body mass index (BMIAUC) was computed to summarize duration and degree of BMI for the 11-year period. Outcomes were systolic blood pressure (SBP) and insulin resistance at 24 years. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as an indicator of insulin resistance and the variable was log-transformed. Associations between BMIAUC and each outcome were estimated by linear regression models. RESULTS: The median BMIAUC was 243.1 (223.9-268.6) kg m-2 in 11 years, corresponding to 22.1 kg m-2 on average per year. In crude analyses, both BMIAUC and BMI at 24 years were positively associated with SBP (beta=0.096 mm Hg, 95% confidence interval (CI) 0.077; 0.115 for BMIAUC; beta=4.616 mm Hg, 95% CI 3.082; 6.151 for BMI at 24 years) and ln HOMA-IR (beta=0.004, 95% CI 0.003; 0.005 for BMIAUC; beta=0.047, 95% CI 0.036; 0.057 for BMI at 24 years). After adjustment for confounders and for BMI at 24 years, the magnitude of the association of BMIAUC attenuated for both outcomes, mostly for SBP, but the association remained statistically significant. Results using standardized variables confirmed that both outcomes were more strongly associated with BMI at 24 years than with BMIAUC. CONCLUSIONS: In addition to the effect of adult attained BMI, cumulative exposure to higher BMI throughout adolescence, taking into account duration and degree, was also relevant for adult cardiovascular risk factors, mainly for insulin resistance. PMID- 28584301 TI - High resolution profiling of coral-associated bacterial communities using full length 16S rRNA sequence data from PacBio SMRT sequencing system. AB - Coral reefs are a complex ecosystem consisting of coral animals and a vast array of associated symbionts including the dinoflagellate Symbiodinium, fungi, viruses and bacteria. Several studies have highlighted the importance of coral-associated bacteria and their fundamental roles in fitness and survival of the host animal. The scleractinian coral Porites lutea is one of the dominant reef-builders in the Indo-West Pacific. Currently, very little is known about the composition and structure of bacterial communities across P. lutea reefs. The purpose of this study is twofold: to demonstrate the advantages of using PacBio circular consensus sequencing technology in microbial community studies and to investigate the diversity and structure of P. lutea-associated microbiome in the Indo Pacific. This is the first metagenomic study of marine environmental samples that utilises the PacBio sequencing system to capture full-length 16S rRNA sequences. We observed geographically distinct coral-associated microbial profiles between samples from the Gulf of Thailand and Andaman Sea. Despite the geographical and environmental impacts on the coral-host interactions, we identified a conserved community of bacteria that were present consistently across diverse reef habitats. Finally, we demonstrated the superior performance of full-length 16S rRNA sequences in resolving taxonomic uncertainty of coral associates at the species level. PMID- 28584302 TI - CRISPR/Cas9-mediated p53 and Pten dual mutation accelerates hepatocarcinogenesis in adult hepatitis B virus transgenic mice. AB - The p53 mutation and altered Pten expression are two most common genetic events in Hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC). To confirm the causative role of p53 and Pten somatic mutation in HCC development, we established CRISPR/Cas9-mediated somatic gene disruption via hydrodynamic tail vein injection, allowing for in vivo targeting p53 and Pten simultaneously in adult HBV transgenic mice. Here we demonstrated that the utility of this approach resulted in macroscopic liver tumors as early as 4 months' post injection and most tumors harbored both p53 and Pten loss-of-function alterations. Immunohistochemical (IHC) and histopathology analysis demonstrated that the tumors were positive for Glutamine synthetase (GS), a marker of HCC and accompanied with prominent lipid accumulation. The study here indicated that CRISPR/Cas9-mediated p53 and Pten somatic mutation accelerated hepatocarcinogenesis in adult HBV transgenic mice. This method also provides a fast and convenient system for generating mouse model of HCC with HBV infection characteristics. PMID- 28584303 TI - A New Solid Solution Approach for the Study of Self-Irradiating Damage in non Radioactive Materials. AB - A new method to produce a model system for the study of radiation damage in non radioactive materials is presented. The method is based on homogenously dissolving minute amounts of 228Th ions in thin films in a controllable manner using a small volume chemical bath deposition technique. This approach is demonstrated for PbS films. The properties of the PbS (228Th) solid solution film activity were investigated by monitoring the accompanying radioactive processes. Electrical resistivity studies were performed and decay-event damage accumulation was measured, followed by isochronal annealing which presented two annealing stages and another two sub-stages. This is the first report on self-irradiating damage studies in IV-VI semiconductors and the resulting films present a novel method for the analysis of dilute defect systems in semiconductor thin films. PMID- 28584305 TI - Ab-initio study of ReCN in the bulk and as a new two dimensional material. AB - First principles total energy calculations have been applied to describe the ReCN bulk structure and the formation of ReCN monolayers and bilayers. Results demonstrate a strong structural rearrangement in the monolayer due to a reduced dimension effect: an increase in the lattice parameter, accompanied with the contraction of the distance between the C and N planes. On the other hand, a ReCN bilayer has structural parameters similar to those of the bulk. Surface formation energies show that the monolayer is more stable than bilayer geometries. Although bulk ReCN shows a semiconductor behavior, the monolayer ReCN presents a metallic behavior. This metallic character of the ReCN monolayer is mainly due to the d orbitals of Re atoms. PMID- 28584304 TI - Normalization of adiponectin concentrations by leptin replacement in ob/ob mice is accompanied by reductions in systemic oxidative stress and inflammation. AB - The circulating concentrations of adiponectin, an antidiabetic adipokine, have been shown to be reduced in obesity, in relation to an increase in inflammation. The aim of the present work was to assess the effect of leptin replacement on adiponectin levels and expression as well as on markers of oxidative stress and inflammation in leptin-deficient ob/ob mice. Twelve-week-old male mice (n = 7-10 per group) were treated with either saline (wild type and ob/ob mice) or leptin (ob/ob mice) for 18 days. A third group of ob/ob mice was treated with saline and pair-fed to the amount of food consumed by the leptin-treated group. Leptin replacement restored values of adiponectin (P < 0.001), reduced circulating 8 isoprostane and serum amyloid A (SAA) levels (P < 0.05 for both), and significantly downregulated the increased gene expression of osteopontin (Spp1, P < 0.05), Saa3 (P < 0.05), Cd68 (P < 0.01), Il6 (P < 0.01) and NADPH oxidase (Nox1 and Nox2, P < 0.01) in the perirenal WAT and Spp1 (P < 0.05) in the liver of ob/ob mice. In cultured adipocytes from ob/ob mice, leptin increased (P < 0.05) the mRNA expression and secretion of adiponectin. We concluded that circulating concentrations of adiponectin are positively regulated by leptin and ameliorate obesity-associated oxidative stress and inflammation in mice. PMID- 28584306 TI - Downregulation of UHRF1 increases tumor malignancy by activating the CXCR4/AKT JNK/IL-6/Snail signaling axis in hepatocellular carcinoma cells. AB - UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells. PMID- 28584307 TI - Genome-wide identification and characterization of JAZ gene family in upland cotton (Gossypium hirsutum). AB - Plant JAZ (Jasmonate ZIM-domain) proteins play versatile roles in multiple aspects of plant development and defense. However, little is known about the JAZ family in allotetraploid upland cotton (Gossypium hirsutum) so far. In this study, 30 non-redundant JAZ genes were identified in upland cotton through genome wide screening. Phylogenetic analysis revealed that the 30 proteins in cotton JAZ family are further divided into five groups (I - V), and members in the same group share highly conserved motif structures. Subcellular localization assay demonstrated that GhJAZ proteins are localized in the cell nucleus. Quantitative RT-PCR analysis indicated that GhJAZs display different expression patterns in cotton tissues, and most of them could be induced by Jasmonic (JA). Furthermore, some GhJAZ genes are preferentially expressed in cotton ovules and fibers, and showed differential expression in ovules of wild type cotton and fiberless mutant (fl) during fiber initiation. GhJAZ proteins could interact with each other to form homodimer or heterodimer, and they also interacted with some JA signaling regulators and the proteins involved in cotton fiber initiation. Collectively, our data suggested that some GhJAZ proteins may play important roles in cotton fiber initiation and development by regulating JA signaling as well as some fiber related proteins. PMID- 28584308 TI - Cranioplasty as the return-to-work factor - 112 patients with cranial defects treated in the Department of Neurosurgery at the Medical University of Lodz. AB - OBJECTIVES: The number of craniectomies and the consequent reconstructive procedures has grown during the past decades. Cranial defects and methods of their repair could have some influence on work capability of the patients and their employability. MATERIAL AND METHODS: The authors analyzed a group of 112 patients with cranial defects treated in the Department of Neurosurgery at the Medical University of Lodz, Poland, in the course of the katamnestic period longer than 6 months after reconstructive operation, and observed them between February 2008 and February 2015. Their work capability and employment were compared, all the patients were interviewed concerning the reasons for not working according to the Social Insurance Institution predication procedure. RESULTS: Before the cranioplasty, all the patients were capable of working without limitations according to biological criteria and 89 of them were employed. Twenty-three not working people consisted of 6 pupils, 7 retired and 10 not working for other reasons. During the period between the craniectomy and the cranioplasty, 88 patients were capable of working and only 2 were employed. After the reconstruction, 93 were capable of working without limitations and 16 - with limitations. Forty-seven were employed during the period of the follow-up, the rest of patients consisted of 2 pupils, 13 retired and 50 not working for various reasons. CONCLUSIONS: Cranioplasty is a very important factor contributing to return to work. This outcome may be seen as having a great social value and be added to the functions of cranial repair as protective, esthetic and normalizing the intracranial pressure previously described in the literature. Int J Occup Med Environ Health 2017;30(5):803-809. PMID- 28584309 TI - Screening commercial drivers for obstructive sleep apnea: Validation of STOP-Bang questionnaire. AB - OBJECTIVES: The main aim has been to examine psychometric properties of STOP-Bang (snoring, tiredness, observed apnea, high blood pressure, body mass index (BMI), age, neck circumference, male gender) scoring model (Serbian translation), an obstructive sleep apnea (OSA) screening tool, in a sample of commercial drivers. MATERIAL AND METHODS: After formal translation, validation was performed on a sample of bus and truck drivers evaluating test-retest reliability, construct and criterion validity. Overnight polysomnography or cardiorespiratory polygraphy were used for OSA diagnosis purposes. RESULTS: One hundred male participants, 24 62 years old, were included. STOP-Bang classified 69% as potential OSA patients. Polysomnography identified OSA in 57% of the sample. Test-retest reliability (Cohen's kappa = 0.89) was adequate. STOP-Bang score was significantly correlated to apnea-hypopnea index (AHI) and OSA severity. Sensitivity was 100% for AHI >= 15, highest specificity was 53.5% (AHI >= 5). CONCLUSIONS: STOP-Bang showed good measurement properties, supporting its further use in OSA screening of commercial drivers. Int J Occup Med Environ Health 2016;30(5):751-761. PMID- 28584310 TI - Effects of external loading on lumbar extension moment during squat lifting. AB - OBJECTIVES: The main objective of this study has been qualitative investigation of the effects of external loading on the lumbar extension moment during squat lifting. Findings of this study may allow to determine the factor with the most considerable effect on the lumbar extension moment and may help determine the lumbar spine risk factors at temporo-spatial coordination during squat lifting. MATERIAL AND METHODS: Twelve healthy men volunteered to perform slow and fast squat lifting of a box of varied mass (4 kg, 8 kg and 12 kg). The eight-channel electromyography was applied to detect the activities of abdominal (rectus abdominis and external oblique) and lower back muscles (iliocostalis lumborum and multifidus). The lumbar extension moment was calculated using 3D linked segment model. Ground reaction forces and kinematic data were recorded using a Vicon system with 2 parallel Kistler force-plates. RESULTS: Significant increases (both p-values < 0.05) were detected for the peak lumbar extension moment with increases in the lift speed and box weight. Moreover, a significant interaction (p = 0) was detected between the lift speed and box weight. Furthermore, insignificant differences (all p-values > 0.05) were detected between the lumbar angles related to the lower trunk muscles peak activities and lumbar angle related to the peak lumbar extension moment in most of the lifts. CONCLUSIONS: According to the findings, the inertial force of the lifted box is the most important factor that affects the lumbar extension moment during squat lifting. Moreover, critical lumbar angles are seemingly those ones in which the lifted box reaches the peak acceleration. Int J Occup Med Environ Health 2017;30(4):665-679. PMID- 28584311 TI - Takotsubo cardiomyopathy in the case of 72-year-old teacher after work-related psychological stress. Evolution of left ventricular longitudinal strain - Delayed but complete recovery in automated function imaging (AFI). AB - Takotsubo cardiomyopathy (TC) is related to a transient systolic dysfunction of left ventricle (LV), accompanied by clinical and electrocardiographic symptoms of myocardial ischemia in the absence of hemodynamically significant coronary artery disease. Takotsubo cardiomyopathy is usually provoked by a psychologically or/and physically stressful event which may be related to occupational activities. Although visually assessed evolution of LV function is well documented, the data concerning strain changes is sparse and various patterns of deformation abnormalities are suggested. We have described a 72-year-old woman with chest pain related to a lecture given at the meeting of the Senior University, fulfilling all the Mayo Clinic criteria of the TC. The longitudinal strain analysis with automated function imaging (AFI) documented severe impairment and stepwise recovery of regional and global LV contractility. The case described confirms that accurate diagnosis, treatment and documenting of functional improvement in takotsubo cardiomyopathy may enable the return to occupational activities even for elderly persons. Int J Occup Med Environ Health 2017;30(4):681-683. PMID- 28584312 TI - Occupational exposure to radon for underground tourist routes in Poland: Doses to lung and the risk of developing lung cancer. AB - OBJECTIVES: Radon concentrations for 31 Polish underground tourist routes were analyzed. The equivalent dose to the lung, the effective dose and the relative risk were calculated for employees of the analyzed routes on the grounds of information on radon concentrations, work time, etc. MATERIAL AND METHODS: The relative risk for lung cancers was calculated using the Biological Effects of Ionizing Radiation (BEIR) VI Committee model. Equivalent doses to the lungs of workers were determined using the coefficients calculated by the Kendall and Smith. The conversion coefficient proposed by the International Atomic Energy Agency (IAEA) in the report No. 33 was used for estimating the effective doses. RESULTS: In 13 routes, the effective dose was found to be above 1 mSv/year, and in 3 routes, it exceeded 6 mSv/year. For 5 routes, the equivalent dose to lungs was higher than 100 mSv/year, and in 1 case it was as high as 490 mSv/year. In 22.6% of underground workplaces the risk of developing lung cancer among employees was about 2 times higher than that for the general population, and for 1 tourist route it was about 5 times higher. The geometric mean of the relative risk of lung cancer for all workers of underground tourist routes was 1.73 (95% confidence interval (CI): 1.6-1.87). Routes were divided into: caves, mines, post military underground constructions and urban underground constructions. CONCLUSIONS: The difference between levels of the relative risk of developing lung cancer for all types of underground tourist routes was not found to be significant. If we include the professional group of the employees of underground tourist routes into the group of occupational exposure, the number of persons who are included in the Category A due to occupational exposure may increase by about 3/4. The professional group of the employees of underground tourist routes should be monitored for their exposure to radon. Int J Occup Med Environ Health 2017;30(5):687-694. PMID- 28584313 TI - Trends in smoking among secondary school and high school students in Poland, 2009 and 2011. AB - OBJECTIVES: To determine the age and the most common circumstances for smoking initiation along with smoking rates and to evaluate smoking trends for secondary and high school students in Poland during 2009 and 2011. MATERIAL AND METHODS: In 2009, a pilot study was conducted in districts of Poland on high school students and their parents. For statistical analysis, correctly completed questionnaires from 999 students and 667 parents were qualified for use. After the pilot study, a nationwide study of secondary school students and their parents was also conducted in 2009. For statistical analysis, correctly completed questionnaires were used from 9360 students and 6951 from their parents. The research tool was a questionnaire developed by the Chief Sanitary Inspectorate. These studies were then compared to the nationwide research study from 2011. Questionnaires were obtained from a survey of 3548 students from secondary schools and 4423 of those from high schools. RESULTS: Smoking initiation usually begins at ages 12-15 years. Rates of secondary school student smoking at least once in their lifetime were about the same level in the surveyed years (2009 - 9%, 2011 - 11%), whereas rates of high school student smoking increased (2009 - 15%, 2011 - 24%). Moreover, 34% of secondary school student smoked less than once a week, whereas in 2009, only 8% of students had done so. For high school students, a 1/2 smoked every day; similar to 2009. Students usually smoked in parks, on streets or any other open space areas. CONCLUSIONS: From analyzing the smoking trends over the survey period it can be concluded that the problem of smoking increases with respondent age. Int J Occup Med Environ Health 2017;30(5):763-773. PMID- 28584314 TI - Is ulnar nerve entrapment at wrist frequent among patients with carpal tunnel syndrome occupationally exposed to monotype wrist movements? AB - OBJECTIVES: Association between carpal tunnel syndrome (CTS) and ulnar nerve entrapment at wrist remains controversial. The aim of the study has been to investigate the prevalence of Guyon's canal syndrome amongst patients diagnosed with the CTS, occupationally exposed to repetitive wrist movements. MATERIAL AND METHODS: The retrospective analysis of 310 patients (268 females, 42 males) representing the mean age of 52+/-7 years old hospitalized for the suspected occupational CTS was performed. RESULTS: In the analyzed cohort, 4 patients had undergone decompression of the Guyon's canal in the right limbs. Nerve conduction studies (NCS) in the ulnar nerves performed during the hospitalization of those patients did not show any abnormalities. Nerve conduction studies revealed signs of the ulnar neuropathy (UN) at the wrist affecting exclusively sensory fibers for 6 patients. Only those 4 patients who had undergone the operation suffered from clinical symptoms of the UN before the surgery. In the case of the remaining patients, despite the NCS changes, signs suggestive of the UN at the wrist were not detected. In the case of the patients with the occupational CTS, no signs of the ulnar nerve dysfunction were recorded. CONCLUSIONS: The frequency of ulnar nerve entrapment at the wrist among patients with the CTS is lower than that already reported. The low prevalence of ulnar involvement (3.2%) for the CTS patients in our study may be related to the relatively small number of the CTS hands with the severe changes in the NCS and/or other personal factor including anatomical variation of the Guyon's canal borders and its contents. Int J Occup Med Environ Health 2017;30(6):861-874. PMID- 28584315 TI - Social costs of loss in productivity-related absenteeism in Poland. AB - OBJECTIVES: The aim of this study was to estimate indirect costs associated with losses in productivity due to sickness absence among registered workers in Poland. MATERIAL AND METHODS: Data on sick leave durations in 2013 was obtained from the Social Insurance Institution (SII) (Zaklad Ubezpieczen Spolecznych - ZUS). Based on the number of assumptions, this data was used for calculating absence durations. The costs of lost productivity were estimated on the basis of the measure of gross value added. RESULTS: Estimated losses in productivity due to absenteeism in 2013 together accounted for 4.33% of gross domestic product (GDP) (17.09 billion euro). In the female population, the total value of losses amounted to 9.66 billion euro, but excluding the costs of pregnancy, childbirth, and puerperium (2.96 billion euro), it was 6.7 billion euro. In the male population, the loss amounted to 7.43 billion euro. The highest overall costs of sickness absence based on age were found in the age group of 30-39 years (5.14 billion euro, including pregnancy, childbirth, and puerperium - 1.474 billion euro; respiratory diseases - 0.632 billion euro, injuries and poisonings - 0.62 billion euro). In the group of people aged > 40 years, the highest cost was generated by bone-muscular diseases (1.553 billion euro) and injuries and poisoning (1.251 billion euro). Higher losses in the productivity of women in addition to pregnancy, childbirth, and puerperium were due to mental and behavioral disorders (0.71 billion euro), diseases of the genitourinary system (0.38 billion euro), and neoplasms (0.35 billion euro). At the same time, in men, compared to women, we observed higher losses due to injuries and poisoning (1.65 billion euro), and diseases of musculoskeletal (1.26 billion euro), nervous (0.79 billion euro), circulatory (0.65 billion euro), and digestive (0.41 billion euro) systems. CONCLUSIONS: Improvement and further development of effective strategies for prevention of complications of pregnancy and chronic diseases in the workplace are necessary. Policies aimed at reduction of sickness absence could potentially increase prosperity and the socioeconomic situation in Poland. Int J Occup Med Environ Health 2017;30(6):917-932. PMID- 28584316 TI - Stress at the place of work and cognitive functions among women performing intellectual work during peri- and post-menopausal period. AB - OBJECTIVES: The analysis of the relationship between stress at work and results of cognitive functions amongst women, at peri- and post-menopausal age, performing intellectual work. MATERIAL AND METHODS: The study group included women, aged 45-66 years old, employed as intellectual workers. Research instruments were: the Montreal Cognitive Assessment; computer tests of the CNS Vital Signs; the Subjective Work Characteristics Questionnaire, and a questionnaire designed by the author. The results were statistically analyzed. RESULTS: Nearly a half of respondents experienced high stress at the place of work; 1/3 - on the average level, on a low level - every fifth. The largest number of respondents experienced stress caused by social contacts. Among a half of the women, stress was caused by the lack of awards at work, followed by the lack of support. Slightly fewer of them experienced stress caused by the feeling of psychological load related to the complexity of work or the feeling of uncertainty caused by the organization of work. Every third woman experienced stress due to the sense of responsibility or the lack of control. The smallest number experienced stress caused by physical arduousness, the sense of threat and unpleasant working conditions. The examined women obtained the best results with respect to simple attention, the worst results - with respect to the reaction time. The results concerning the remaining 9 cognitive functions were ranked in the middle of the aforementioned results. The intensity of stress at work and factors which caused this stress, negatively correlated with simple attention of women in the early peri-menopausal period, while positively correlating with the psychomotor and processing speed of women in the late peri-menopausal period. Among the post-menopausal women, negative correlations were observed between the majority of cognitive functions and the intensity of stress at work, and the majority of factors which caused this stress. CONCLUSIONS: Cognitive functions of the examined women remained within the range of average evaluations, and were correlated with stress-inducing factors at the place of work. Int J Occup Med Environ Health 2017;30(6):943-961. PMID- 28584317 TI - Exposure to self-reported occupational noise and diabetes - A cross-sectional relationship in 7th European Social Survey (ESS7, 2014). AB - OBJECTIVES: Almost nothing is known about the effect of occupational noise on diabetes, and this is particularly relevant given the wide spread of both noise exposure and diabetes. This study has aimed to determine whether occupational noise exposure is associated with higher risk of diabetes in Europe. MATERIAL AND METHODS: This study is based on 7th European Social Survey (ESS7, 2014) - a multi country population-based questionnaire survey, which covered 28 221 Europeans aged >= 15 years old. Data on self-reported noise exposure, diabetes and other sociodemographic and work-related factors was available. The odds of prevalent diabetes were explored using unconditional logistic regression. RESULTS: In the total sample (N = 23 486), participants ever exposed to very loud noise had no substantive increase in the odds of diabetes (odds ratio (OR) = 1.01, 95% confidence interval (CI): 0.78-1.32). There were subgroups with non-significantly increased odds: men (OR = 1.12, 95% CI: 0.87-1.45), the elderly (OR = 1.09, 95% CI: 0.91-1.31), ethnic minority members (OR = 1.55, 95% CI: 0.91-2.62), those with secondary education (OR = 1.05, 95% CI: 0.78-1.41) and those living in small cities/towns (OR = 1.07, 95% CI: 0.89-1.29). Low-skilled white-collar workers had OR = 1.34 (95% CI: 1.09-1.64). Among participants employed during the preceding 5 years the odds were OR = 1.24 (95% CI: 0.95-1.61). CONCLUSIONS: Self-reported occupational noise was not associated with increased odds of prevalent diabetes in the total sample. Sensitivity analyses revealed some subgroups with non significantly higher odds. Our results suggest that further delve into the relationship between occupational noise and diabetes is feasible and warranted. Int J Occup Med Environ Health 2017;30(4):537-551. PMID- 28584318 TI - Albumin adducts and urinary metabolites resulting from occupational exposure to 1,5-naphthalene diisocyanate. AB - OBJECTIVES: 1,5-Naphthalene diisocyanate (NDI) is used in the plastic industry as a curing agent. 1,5-Naphthalene diisocyanate is classified as a sensitizing agent. The objective of this study has been to develop biomonitoring methods for the evaluation of exposure to NDI. MATERIAL AND METHODS: We obtained blood and urine samples from a group of 20 male workers exposed to NDI. The workers answered a questionnaire about their exposure history, job description, the number of years with the company and the time spent working with NDI over the 10 days of the study. Total plasma, albumin, and urine were analyzed for the presence of 1,5-naphthalenediamine (NDA) after acid hydrolysis using gas chromatography-mass spectrometry (GC-MS). RESULTS: 1,5-Naphthalenediamine was found in about 60% of the samples obtained from the workers. 1,5 Naphthalenediamine was obtained after acid hydrolysis of plasma, albumin, and urine at levels up to 1.5 pmol NDA/mg of plasma proteins, 1.15 pmol NDA/mg of albumin, and 55.3 pmol NDA/ml of urine, respectively. CONCLUSIONS: 1,5 Naphthalenediamine found in urine correlates best with the plasma levels (r = 0.91, p < 0.01). The albumin-adduct levels did not correlate with the NDI specific immunoglobulin E (IgE) or total IgE present in the workers. The adduct and metabolite levels correlate with the air levels of NDI. Int J Occup Med Environ Health 2017;30(4):579-591. PMID- 28584320 TI - Workplace bullying and mental health among teachers in relation to psychosocial job characteristics and burnout. AB - OBJECTIVES: The objective of the study has been to assess the associations between psychological distress and exposure to workplace bullying, taking into account possible influence of adverse psychosocial job characteristics and occupational burnout in a sample of Kaunas (Lithuania) teachers. MATERIAL AND METHODS: The study sample included 517 teachers from 13 secondary schools and was conducted in 2014. The participants filled in the anonymous questionnaire (response rate 71.3%). Twenty-two-item Negative Acts Questionnaire (H. Hoel and S. Einarsen) was used for measuring the exposure to workplace bullying, Goldberg 12-item General Health Questionnaire (GHQ-12) - psychological distress, Maslach Burnout Inventory (MBI) - occupational burnout, Karasek Demand-Control questionnaire - psychosocial job stressors. The IBM SPSS Statistics version 20.0 was used for performing the statistical analysis. Associations between psychological distress, exposure to workplace bullying, psychosocial job characteristics and occupational burnout were analyzed in the logistic regression and expressed in terms of odds ratios (OR). Statistical significance was determined using the 95% confidence interval (CI) level. RESULTS: Workplace bullying was prevalent among Kaunas teachers (occasional - 8.3%, severe - 2.9%). Twenty-five percent of teachers suffered from psychological distress. High emotional exhaustion was found in 25.6% of them, high depersonalization in 10.6% and low personal achievement in 33.7% of cases. Almost a half of respondents (47.4%) reported job strain and 59.6% - low social support at work. Occasional and severe bullying was associated with psychological distress after adjusting to job strain, social support and emotional exhaustion, depersonalization, personal accomplishment (adjusted OR was 3.27, 95% CI: 1.56-6.84 for occasional and 4.98, 95% CI: 1.27-19.62 for severe bullying). CONCLUSIONS: Occasional and severe bullying were strong predictors for psychological distress. Burnout did not mediate those associations. The effect of job strain and low social support decreased to the insignificant level in the final model. Preventive measures are necessary to improve psychosocial working conditions in secondary education institutions. Int J Occup Med Environ Health 2017;30(4):629-640. PMID- 28584319 TI - Identification and characteristics of biological agents in work environment of medical emergency services in selected ambulances. AB - OBJECTIVES: Assessment of microbial air quality and surface contamination in ambulances and administration offices as a control place without occupational exposure to biological agents; based on quantitative and qualitative analysis of bacteria, yeasts and filamentous fungi found in collected samples. MATERIAL AND METHODS: The sampling was done by wet cyclone technology using the Coriolis recon apparatus, imprint and swab methods, respectively. In total, 280 samples from 28 ambulances and 10 offices in Warszawa were tested. Data was analyzed using Shapiro-Wilk normality test, Kruskal-Wallis test with alpha = 0.05. P value <= 0.05 was considered as significant. RESULTS: The levels of air contamination were from 0 to 2.3*101 colony-forming unit (CFU)/m3 for bacteria and for yeast and filamentous fungi were from 0 to 1.8*101 CFU/m3. The assessment of office space air samples has shown the following numbers of microorganisms: bacteria from 3.0*101 to 4.2*101 CFU/m3 and yeast and filamentous fungi from 0 to 1.9*101 CFU/m3. For surface contamination the mean bacterial count in ambulances has been between 1.0*101 and 1.3*102 CFU/25 cm2 and in offices - between 1.1*101 and 8.5*101 CFU/25 cm2. Mean fungal count has reached the level from 2.8*100 to 4.2*101 CFU/25 cm2 in ambulances and 1.3*101 to 5.8*101 CFU/25 cm2 in offices. The qualitative analysis has revealed the presence of Acinetobacter spp. (surfaces), coagulase - negative Staphylococci (air and surfaces), Aspergillus and Penicillium genera (air and surfaces). CONCLUSIONS: The study has revealed a satisfactory microbiological quantity of analyzed air and surface samples in both study and control environments. However, the presence of potentially pathogenic microorganisms in the air and on surfaces in ambulances may endanger the medical emergency staff and patients with infection. Disinfection and cleaning techniques therefore should be constantly developed and implemented. Int J Occup Med Environ Health 2017;30(4):617-627. PMID- 28584321 TI - Occupational exposure to electromagnetic fields in the Polish Armed Forces. AB - OBJECTIVES: Standard devices used by military personnel that may pose electromagnetic hazard include: radars, missile systems, radio navigation systems and radio transceivers. The aim of this study has been to evaluate the exposure of military personnel to electromagnetic fields. MATERIAL AND METHODS: Occupational exposure to electromagnetic fields was analyzed in the work environment of personnel of 204 devices divided into 5 groups (surface-to-air missile system radars, aircraft and helicopters, communication devices, surveillance and height finder radars, airport radars and radio navigation systems). Measurements were carried out at indicators, device terminals, radio panels, above vehicle seats, in vehicle hatches, by cabinets containing high power vacuum tubes and other transmitter components, by transmission lines, connectors, etc. RESULTS: Portable radios emit the electric field strength between 20-80 V/m close to a human head. The manpack radio operator's exposure is 60-120 V/m. Inside vehicles with high frequency/very high frequency (HF/VHF) band radios, the electric field strength is between 7-30 V/m and inside the radar cabin it ranges between 9-20 V/m. Most of the personnel on ships are not exposed to the electromagnetic field from their own radar systems but rather by accidental exposure from the radar systems of other ships. Operators of surface to-air missile systems are exposed to the electric field strength between 7-15 V/m and the personnel of non-directional radio beacons - 100-150 V/m. CONCLUSIONS: In 57% of military devices Polish soldiers work in the occupational protection zones. In 35% of cases, soldiers work in intermediate and hazardous zones and in 22% - only in the intermediate zone. In 43% of devices, military personnel are not exposed to electromagnetic field. Int J Occup Med Environ Health 2017;30(4):565-577. PMID- 28584322 TI - Musculoskeletal symptoms and exposure to whole-body vibration among open-pit mine workers in the Arctic. AB - OBJECTIVES: This cross-sectional questionnaire study was carried out at 4 open pit mines in Finland, Norway, Russia and Sweden as part of the MineHealth project. The aim has been to compare the prevalence of musculoskeletal symptoms between drivers of mining vehicles and non-drivers. MATERIAL AND METHODS: The mine workers were asked whether they had suffered from any musculoskeletal symptoms during the previous 12 months in specified body regions, and to grade the severity of these symptoms during the past month. They were also asked about their daily driving of mining vehicles. RESULTS: The questionnaire was completed by 1323 workers (757 vehicle drivers) and the reported prevalence and severity of symptoms were highest for the lower back, followed by pain in the neck, shoulder and upper back. Drivers in the Nordic mines reported fewer symptoms than non drivers, while for Russian mine workers the results were the opposite of that. The daily driving of mining vehicles had no significant association with the risk of symptoms. Female drivers indicated a higher prevalence of symptoms as compared to male drivers. CONCLUSIONS: The study provided only weak support for the hypothesis that drivers of vehicles reported a higher prevalence of musculoskeletal symptoms than non-vehicle drivers. There were marked differences in the prevalence of symptoms among workers in various enterprises, even though the nature of the job tasks was similar. Int J Occup Med Environ Health 2017;30(4):553-564. PMID- 28584323 TI - Impact of special aviation gymnastics instruments training on selected hormones in cadets' blood serum and plasma. AB - OBJECTIVES: This study has aimed at investigating the impact of the Special Aviation Gymnastics Instruments (SAGI) training scheme on the blood serum cortisol, testosterone, insulin, and plasma adrenaline, noradrenaline, and dopamine in comparison with a control group. MATERIAL AND METHODS: Fifty-five cadets, aged 20 years old, participated in the study. Cadets were divided into 2 groups: A (N = 41) - the SAGI-trained, and B (N = 14) - the control group. In both groups, blood was the examined material, sampled twice: before the training session (BT) and after the training session (AT), at the beginning (training session I), during (training session II), and after completion of the SAGI training session (training session III). Commercially available kits were used for assaying serum cortisol, testosterone, and insulin as well as plasma adrenaline, noradrenaline, and dopamine. Cadets' physical fitness was assessed by means of Aero-Synthetic Efficiency Tests. RESULTS: In group A, a significant decrease in serum cortisol (training session III) and insulin in three training sessions AT in comparison with the values BT was seen. A statistically significant increase in testosterone and catecholamines was noted in all 3 training sessions AT in comparison with the values BT. In group B, a statistically significant increase in cortisol (training session II), testosterone, and catecholamines was observed in all 3 training sessions AT vs. the values in training session BT. In group B, serum levels of all assayed hormones were higher in training session III than those in group A. CONCLUSIONS: In the examined group, the SAGI training produced fewer hormonal changes dependent on the intensity and exercise type and physical efficiency improvement than in the control group. Int J Occup Med Environ Health 2017;30(4):655-664. PMID- 28584324 TI - Absorbed doses for patients undergoing panoramic radiography, cephalometric radiography and CBCT. AB - OBJECTIVES: Contemporary dental radiology offers a wide spectrum of imaging methods but it also contributes to an increase in the participation of dental radiological diagnosis in the patient's exposure to ionizing radiation. The aim of this study is to determine the absorbed doses of the brain, spinal column, thyroid and eye lens for patients during panoramic radiography, cephalometric radiography and cone beam computed tomography (CBCT). MATERIAL AND METHODS: The thermoluminescent dosimetry and anthropomorphic phantom was used for measuring the doses. The 15 panoramic, 4 cephalometric and 4 CBCT exposures were performed by placing high-sensitivity thermoluminescent detectors (TLD) in 18 anatomical points of the phantom. RESULTS: The maximum absorbed dose recorded during performed measurements corresponds to the point representing the brainstem and it is 10 mGy. The dose value recorded by the TLD placed in the thyroid during CBCT imaging in relation to the panoramic radiography differs by a factor of 13.5. CONCLUSIONS: Cone beam computed tomography, in comparison with panoramic or cephalometric imaging technique, provides higher radiation doses to the patients. Int J Occup Med Environ Health 2017;30(5):705-713. PMID- 28584325 TI - Differences in nutritional status of preschool children in the context of the maternal social characteristics. AB - OBJECTIVES: It is generally accepted that maternal factors are important in maintaining the adequate nutritional status of young children. This study was aimed at verifying whether mother's socio-demographic (age and relationship status) and socio-economic features (education and professional status) differentiate the child's nutritional status. MATERIAL AND METHODS: A cross sectional study was conducted between April and October 2013. Five hundred thirty mothers of preschool children from 5 different regions of Poland were interviewed. Mothers were interviewed on their socio-demographic and socio economic status. To assess the child's nutritional status, body mass index (BMI) z-score and the diet indicators were calculated, such as the percentage of the estimated average requirement for energy (%EAR), the percentage of energy coming from carbohydrates (%EC), fat (%ET) and proteins (%EP). Percentage of the estimated average requirement for energy, %EC, %ET and %EP was obtained from 24-h dietary recalls conducted with the mothers. RESULTS: The results showed that mother's education and professional status did not differentiate any of the indices of the child's nutritional status. However, maternal age and her relationship status occurred significant (ANOVA; p < 0.05). Children of younger mothers had higher BMI z-score and higher %EC as compared to children of older mothers. Moreover, %EAR was higher among children of single mothers and it was closer to the recommended nutrition standards as compared to children of mothers with a partner. CONCLUSIONS: When a child is diagnosed with any type of malnutrition, it is worth assessing various factors that might influence the nutritional status, such as child's social background (e.g., maternal factors). Int J Occup Med Environ Health 2017;30(5):811-821. PMID- 28584326 TI - The risk of hearing loss associated with occupational exposure to organic solvents mixture with and without concurrent noise exposure: A systematic review and meta-analysis. AB - This study is a meta-analysis of the previous epidemiological studies which investigated the quantitative estimates of the association between independent or combined exposure to noise and mixed organic solvents and hearing loss until October 2014. Overall, 15 studies with information on 7530 individuals (6% female) were included. Having assessed - by puretone audiometry - the adjusted odds ratio estimates for the association between solvents mixture exposure and the risk of developing hearing loss stood at 2.05 (95% confidence interval (CI): 1.44-2.9). Similarly, for subjects who were concurrently exposed to noise and solvents mixture, an OR of 2.95 (95% CI: 2.1-4.17) was obtained. There was some evidence of heterogeneity within each of the 2 exposure groups (p heterogeneity < 0.001). This heterogeneity was not explained by differences in strength of effect between duration of exposure, the number of solvent and exposure index in subgroups of solvents mixture exposure. Based on the available data, our analysis has provided the evidence of increased risk of developing hearing loss for workers exposed to organic solvents even at quite low concentration. Moreover, if such exposure is accompanied by noise, it will exacerbate the extent of hearing loss. Int J Occup Med Environ Health 2017;30(4):521-535. PMID- 28584327 TI - Mortality for chronic-degenerative diseases in Tuscany: Ecological study comparing neighboring areas with substantial differences in environmental pollution. AB - OBJECTIVES: Environmental pollution is associated with morbidity and mortality for chronic-degenerative diseases. Recent data points out a relationship between proximity to industrial plants and mortality due to neoplasms. The aim of this study has been to compare mortality due to chronic-degenerative diseases in the area of Tuscany (Bassa Val di Cecina), Italy, characterized by the presence of 2 neighboring municipalities similar in terms of size but with substantial differences in industrial activities: Rosignano (the site of chemical, energy production and waste processing industries) and Cecina (with no polluting activity). MATERIAL AND METHODS: Standardized mortality rates for the 2001-2010 decade were calculated; the data of the whole Tuscany was assumed as reference. Environmental levels of pollutants were obtained by databases of the Environmental Protection Agency of Tuscany Region (Agenzia Regionale per la Protezione Ambientale della Toscana - ARPAT). Maximum tolerated pollutant levels set by national laws were assumed as reference. RESULTS: In the whole Bassa Val di Cecina, significantly elevated standardized mortality rates due to mesothelioma, ischemic heart diseases, cerebrovascular diseases and Alzheimer and other degenerative diseases of nervous system were observed. In the municipality of Rosignano, a significant excess of mortality for all these groups of diseases was confirmed. On the contrary, the municipality of Cecina showed only significantly higher mortality rates for ischemic heart diseases. Elevated levels of heavy metals in sea water and of particulate matter which contains particles of diameter <= 10 mm (PM10) and ozone in air were detected in Rosignano. CONCLUSIONS: This study shows an excess of mortality for chronic degenerative diseases in the area with elevated concentration of polluting factories. Proximity to industrial plants seems to represent a risk factor for those diseases. Int J Occup Med Environ Health 2017;30(4):641-653. PMID- 28584328 TI - Spatial and temporal variability of idiopathic pulmonary fibrosis cases in Silesian Voivodeship in years 2006-2010. AB - OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) (J84.1 by the International Statistical Classification of Diseases and Related Health Problems, 10th revision - ICD-10) is a rare disease of unknown cause. Among many risk factors, occupational exposure to metal dust is enumerated. Because of metal industry concentration in the Silesian Voivodeship, Poland, an attempt of spatial and temporal variability of the idiopathic pulmonary fibrosis occurrence evaluation in 2006-2010 is made. MATERIAL AND METHODS: The research is a descriptive analysis. Data of the number of new treated cases and firsttime hospitalization due to idiopathic pulmonary fibrosis in the years 2006-2010 was obtained from the National Health Found (Narodowy Fundusz Zdrowia - NFZ). We also assessed spatial and temporal variability of both rates. Data concerned adults aged >= 19 years old inhabited the Silesian Voivodeship. RESULTS: The standardized incidence rate due to idiopathic pulmonary fibrosis increased in the study period and was in the range of 2.9-3.8/100 000 population. The highest values of incidence were observed in districts localized in the centre of the Silesian Voivodeship. CONCLUSIONS: Incidence of idiopathic pulmonary fibrosis is not so high in the Silesian Voivodeship but the number of newly treated cases slightly increased in 2006-2010. Spatial and temporal variability of incidence rates for treated registered cases of idiopathic pulmonary fibrosis in the Silesian Voivodeship was observed. It could be an effect of occupational exposure to metal dust, however, final conclusions need more precise studies to the extent of analytical epidemiology. Int J Occup Med Environ Health 2017;30(4):593-601. PMID- 28584329 TI - Impact of electromagnetic radiation emitted by monitors on changes in the cellular membrane structure and protective antioxidant effect of vitamin A - In vitro study. AB - OBJECTIVES: The increasing number of devices emitting electromagnetic radiation (EMR) in people's everyday life attracted the attention of researchers because of possible adverse effects of this factor on living organisms. One of the EMR effect may be peroxidation of lipid membranes formed as a result of free radical process. The article presents the results of in vitro studies aimed at identifying changes in malondialdehyde (MDA) concentration - a marker of lipid peroxidation and antioxidant role of vitamin A during the exposure of blood platelets to electromagnetic radiation generated by liquid-crystal-display (LCD) monitors. MATERIAL AND METHODS: Electromagnetic radiation emitted by LCD monitors is characterized by parameters: 1 kHz frequency and 220 V/m intensity (15 cm from display screen). The time of exposure was 30 and 60 min. The study was conducted on porcine blood platelets. The samples were divided into 6 groups: unexposed to radiation, unexposed + vitamin A, exposed for 30 min, exposed for 30 min + vitamin A, exposed for 60 min, exposed for 60 min + vitamin A. RESULTS: The MDA concentration in blood platelets increases significantly as compared to control values after 60 min of exposure to EMR. A significant decrease in MDA concentration after the addition of vitamin A was noticed. In the blood samples exposed to EMR for 30 and 60 min the MDA concentration was significantly increased by addition of vitamin A. CONCLUSIONS: The results show the possibly negative effect of electromagnetic radiation on the cellular membrane structure manifested by changes in malondialdehyde concentration and indicate a possible protective role of vitamin A in this process. Int J Occup Med Environ Health 2017;30(5):695-703. PMID- 28584330 TI - The association between rurality and return to work for workers' compensation claimants with work-related musculoskeletal injuries: An analysis of workers who failed to return to work within typical healing time frames. AB - OBJECTIVES: The objectives of this study have been to: 1) describe and compare urban and rural injured worker populations in Alberta, Canada; 2) identify return to-work outcomes in urban and rural populations; 3) examine the relationship between geographic location of residence and recovery from work-related musculoskeletal injury; and 4) investigate if this relationship is attenuated after controlling for other known risk factors. MATERIAL AND METHODS: This study was a secondary analysis utilizing data of a population of musculoskeletal injury claimants who underwent clinical/RTW (return to work) assessment between December 2009 and January 2011 collected by the Workers' Compensation Board of Alberta. Descriptive statistics were computed for 32 variables and used for comparing urban and rural workers. The logistic regression analysis was performed to test the association between geographic location of residence and likelihood of return to-work. RESULTS: Data on 7843 claimants was included, 70.1% of them being urban and 29.9% - rural. Rural claimants tended to have spent less time in formal education, have a blue-collar job, have no modified work available, have a diagnosed comorbidity, and not been enrolled in a specialized rehabilitation program. They were 1.43 (1.12-1.84) times the odds more likely than urban claimants to be continuing to receive full disability benefits 90 days after their RTW assessment, and 1.68 (1.06-2.67) times the odds as likely to report a recurrence of receiving disability benefits. CONCLUSIONS: Rural residence was associated with prolonged work disability, even after controlling for age, job type, education level, health utilization and other potential confounders. Further research is required to explore why injured workers in rural settings experience prolonged reception of disability benefits and have greater rates of recurrence of receiving disability benefits. Int J Occup Med Environ Health 2017;30(5):715-729. PMID- 28584331 TI - Occupational exposure to bisphenol A (BPA) in a plastic injection molding factory in Malaysia. AB - OBJECTIVES: The purpose of this study has been to assess ambient bisphenol A (BPA) levels in workplaces and urine levels of workers and to establish a BPA database for different populations in Malaysia. MATERIAL AND METHODS: Urine samples were collected from plastic factory workers and from control subjects after their shift. Air samples were collected using gas analyzers from 5 sampling positions in the injection molding unit work area and from ambient air. The level of BPA in airborne and urine samples was quantified by the gas chromatography mass spectrometry - selected ion monitoring (GCMS-SIM) analysis. RESULTS: Bisphenol A was detected in the median range of 8-28.3 ng/m3 and 2.4-3.59 ng/m3 for the 5 sampling points in the plastic molding factory and in the ambient air respectively. The median urinary BPA concentration was significantly higher in the workers (3.81 ng/ml) than in control subjects (0.73 ng/ml). The urinary BPA concentration was significantly associated with airborne BPA levels (rho = 0.55, p < 0.01). CONCLUSIONS: Our findings provide the first evidence that workers in a molding factory in Malaysia are occupationally exposed to BPA. Int J Occup Med Environ Health 2017;30(5):743-750. PMID- 28584332 TI - Immunological and genotoxic effects of occupational exposure to alpha cypermethrin pesticide. AB - OBJECTIVES: The aim of this work has been to find out the occupational oxidative stress, immunological and genotoxic health hazards among alpha-cypermethrin (CYP) pesticide-exposed workers. MATERIAL AND METHODS: A cross-sectional study was performed including 200 workers divided into 3 groups according to the level of exposure: highly exposed group (50 workers), moderately exposed group (50 workers) and unexposed group (100 workers). All workers were subjected to detailed laboratory investigation for gene P53 mutations, immunological parameters as a cluster of differentiation into 3 percentage (CD3%), CD4% and CD8% in addition to peripheral blood total leukocytic and platelet counts that were measured. Spectrophotometer technique was used for detection of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and glutathione peroxidase (GPx). Air samples were collected with a High Volume Small Surface Sampler for measurement of alpha-cypermethrin level. RESULTS: A highly exposed group to the alpha-cypermethrin had lower CD4/CD8 as compared to an unexposed group with statistically significant difference. As regards gene mutation, exons 5a and 6 were more frequent among the highly exposed group as compared to no mutation among moderately exposed and unexposed groups with significant difference. As regards antioxidants; SOD, CAT, GSH and GPx were higher among the unexposed group as compared to the highly and moderately exposed group with statistically significant difference. Significant negative correlation was found between working years and antioxidant parameters. CONCLUSIONS: Repeated exposure to alpha CYP may lead to gene mutations, immunological disturbances and oxidative stress. Strict safety precautions are required not only for workers but also for public users. Int J Occup Med Environ Health 2017;30(4):603-615. PMID- 28584333 TI - Bacteria contamination of touch surfaces in Polish hospital wards. AB - BACKGROUND: The objective of the study has been to evaluate the pathogenic bacteria contamination of touch surfaces in hospital wards. MATERIAL AND METHODS: Samples were taken from frequently touched surfaces in the hospital environment in 13 units of various types. Culturing was carried out on solid blood agar and in growth broth (tryptic soy broth - TSB). Species identification was performed using the analytical profile index (API) biochemical testing and confirmed with matrix assisted laser desorption ionization time-flight mass spectrometry (MALDI TOF-MS) system. RESULTS: The total of 161 samples were taken for the study. Fifty two of them, after 24 h of culture on a solid medium, demonstrated bacterial growth and further 60 samples had growth after prior multiplication in TSB. Overall, 69.6% of samples exhibited growth of 19 bacterial species. Pathogenic species - representing indicator organisms of efficiency of hospital cleaning - was demonstrated by 21.4% of samples. Among them Acinetobacter spp., Enterocococci spp. and Staphylococcus aureus were identified. Coagulase-negative staphylococci (CNS) were predominant. The proportion of various groups of bacteria significantly varied in respective hospitals, and in various types of wards. Disturbing observation is a large proportion of resistance of isolated CNS strains as a potential reservoir of resistance genes. CONCLUSIONS: The results show that touch surfaces in hospital units are contaminated by both potentially pathogenic and pathogenic bacterial species. In connection with the reported, also in Poland, frequent omission or incorrect execution of hand hygiene by hospital staff, and probably patients, touch surfaces still constitute important reservoir of pathogenic bacteria. Improving hand hygiene compliance of health care workers with recommendations is necessary for increasing biological safety of hospital environment. Med Pr 2017;68(3):459-467. PMID- 28584334 TI - [Nanogold - Biological effects and occupational exposure levels]. AB - Nanogold has different properties and biological activity compared to metallic gold. It can be applied in many fields, such as medicine, laboratory diagnostics and electronics. Studies on laboratory animals show that nanogold can be absorbed by inhalation and ingestion. It can penetrate deep into the epidermis and dermis, but there is no evidence that it is absorbed through the skin. Gold nanoobjects accumulate mainly in the liver and spleen, but they can also reach other internal organs. Nanogold can cross the blood-brain and blood-placenta barriers. Toxicokinetics of nanogold depends on the particle size, shape and surface charge. In animals exposure to gold nanoparticles via inhalation induces slight changes in the lungs. Exposure to nanogold by the oral route does not cause adverse health effects in rodents. In animals after injection of gold nanoobjects changes in the liver and lungs were observed. Nanogold induced genotoxic effects in cells, but not in animals. No adverse effects on the fetus or reproduction were found. There are no carcinogenicity studies on gold nanoparticles. The mechanism of toxicity may be related to the interaction of gold nanoobjects with proteins and DNA, and it leads to the induction of oxidative stress and genetic material damage. The impact of nanostructures on human health has not yet been fully understood. The person, who works with nanomaterials should exercise extreme caution and apply existing recommendations on the evaluation of nanoobjects exposure. The risk assessment should be the basis for taking appropriate measures to limit potential exposure to nanometals, including nanogold. Med Pr 2017;68(4):545-556. PMID- 28584335 TI - [Influence of low frequency magnetic field used in magnetotherapy on interleukin 6 (IL-6) contents in rat heart and brain]. AB - BACKGROUND: The human population is exposed ever more frequently to magnetic fields (MF). This is due to both technological progress and development of the economy as well as to advances made in medical science. That is why the thorough understanding and systematized knowledge about mechanisms by which MF exerts its effects on living organisms play such an important role. In this context the health of MF-exposed people is the subject of particular concern. The aim of the study was to evaluate the effect of extremely low frequency magnetic field (ELFMF) used in magnetotherapy on the concentration of interleukin 6 (IL-6) in rat heart and brain. MATERIAL AND METHODS: The male rats were randomly divided into 3 experimental groups: group I - control, without contact with magnetic field; group II - exposed to bipolar, rectangular magnetic field 40 Hz, induction "peak-to-peak" 7 mT 30 min/day for 2 weeks; and group III - exposed to bipolar, rectangular magnetic field 40 Hz, 7 mT 60 min/day for 2 weeks. Concentration of IL-6 in the heart and brain of animals was measured after MF exposure. RESULTS: Exposure to ELFMF: 40 Hz, induction "peak-to-peak" 7 mT 30 min/day for 2 weeks caused a significant IL-6 increase in rat hearts compared to the control group (p < 0.05) and a non-significant IL-6 decrease in rat brain. The magnetic field applied for 60 min resulted in non-significant IL-6 increase in rat hearts compared to the control group and significant IL-6 decrease in rat brain (p < 0.05). CONCLUSIONS: The influence of magnetic field on inflammation in the body varies depending on the MF parameters and the affected tissues or cells. Med Pr 2017;68(4):517-523. PMID- 28584336 TI - [Evaluation of dental X-ray apparatus in terms of patient exposure to ionizing radiation]. AB - BACKGROUND: The use of X-ray in dental procedures causes exposure of the patient to ionizing radiation. This exposure depends primarily on the parameters used in tooth examination. The aim of the study was to determine the patients exposure and to assess the technical condition of X-ray tubes. MATERIAL AND METHODS: Seventeen hundred dental offices were covered by the questionnaire survey and 740 questionnaires were sent back. Direct measurements were performed in 100 units by using the thermoluminescent detectors and X-ray films. RESULTS: The results showed that the most commonly used exposure time is 0.22+/-0.16 s. The average entrance dose for the parameters used most commonly by dentists is 1.7+/-1.4 mGy. The average efficiency of X-ray tube estimated on the basis of exposures is 46.5+/-23.7 MUGy/mAs. CONCLUSIONS: The study results indicate that the vast majority of X-ray tubes meet the requirements specified in the binding regulations. Med Pr 2017;67(4):491-496. PMID- 28584338 TI - First signs of elderly gait for women. AB - BACKGROUND: The aims of this study have been twofold: to attempt to reduce the number of spatiotemporal parameters used for describing gait through the factor analysis and component analysis; and to explore the critical age of decline for other gait parameters for healthy women. MATERIAL AND METHODS: A total of 106 women (aged >= 40 years old (N = 76) and <= 31 years old (N = 30)) were evaluated using a pressure-sensitive mat (Zebris Medical System, Tubingen, Germany) for collecting spatiotemporal gait parameters. RESULTS: The factor analysis identified 2 factors - labelled Time and Rhythm - that accounted for 72% of the variation in significant free-gait parameters; the principal component analysis identified 4 of these parameters that permit full clinical evaluation of gait quality. No difference was found between the groups in terms of the values of parameters reflecting the temporal nature of gait (Rhythm), namely step time, stride time and cadence, whereas significant differences were found for total double support phase (p < 0.001). Next, seeking evidence of a critical decline in gait, we selected 3 parameters: total double support, stride time and velocity. We concluded that the women taking part in the experiment manifested significant signs of senile gait after the age of 60 years old, with the first symptoms thereof already manifesting themselves after 50 years of age. CONCLUSIONS: We show that among 26 spatiotemporal parameters that may be used for characterizing gait, at least a half of them may be omitted in the assessment of gait correctness; a finding that may be useful in clinical practice. The finding that the onset of senile gait occurs in the case of women after the age of 60 years old, in turn, may be useful in evaluating the ability for performing types of physical work that mainly require ambulation. Med Pr 2017;68(4):441-448. PMID- 28584337 TI - [HBV, HCV, and HIV infection prevalence among prison staff in the light of occupational risk factors]. AB - BACKGROUND: Objectives of the study: to assess the occupational risk for blood borne infections (BBIs) among prison staff (number/ circumstances of blood exposures and preventive methods used), and to estimate the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). MATERIAL AND METHODS: The survey, which included serological testing with the use of 3-generation enzyme-linked immunosorbent assays (ELISA) was completed on active staff at a correctional facility in Goleniow, Poland, between June-July 2015. RESULTS: Response rate was 38%, 87 participants (aged 22-64 years, median: 34 years) agreed to participate. There were 88.5% males, correctional officers comprised 87.4% of the participants. Having had >= 1 blood exposure during professional career was reported by 28.7% respondents, 8% - sustained it in the preceding year. For correctional officers the last blood exposure was caused by a hollow-bore needle/razor blade during cell or manual searches. This was not reported by 83.3%. Participation rate in an infection control training was 85.1%. Hepatitis B virus vaccination uptake was 83.9%. Compliance with glove use was 75.9%, with protective eyewear - 28.7%. Regular use of both was reported by 9.2% of participants. The lack of their availability was the most common reason (79.7%) for non-compliance. Anti-HBc (hepatitis B core antigen) total/anti HCV/anti-HIV prevalence was 2.3%, 1.1%, and 0%, respectively. CONCLUSIONS: Prison staff are at risk for occupational exposures to blood. Reporting of such incidents is poor, as well as compliance with personal protective equipment use, which place them at risk for acquiring BBIs. Anti-HCV prevalence is similar to that observed in the general population, anti-HBc total prevalence is lower, possibly due to high vaccination uptake, however, poor response rate limits precise prevalence estimates. Med Pr 2017;68(4):507-516. PMID- 28584339 TI - [A new method for determination of toluene-2,4-diamine and toluene-2,6-diamine in workplace air]. AB - BACKGROUND: Toluenediamines are harmful substances. Toluene-2,4-diamine has been assigned to Carcinogen 1B hazard class, pursuant to Regulation (European Community - EC) No. 1272/2008 of the European Parliament and of the Council, and toluene- 2,6-diamine to Mutagen 2 hazard class. The main routes of exposure to toluene-2,4-diamine and toluene-2,6-diamine are via the respiratory tract and the skin. Toluene-2,4-diamine and toluene-2,6-diamine occur in the work environment in Poland. The aim of this study was to develop and validate a method for the determination of toluene-2,4-diamine and toluene-2,6-diamine that allows the simultaneous determination of their concentrations in the workplace air by personal sampling. MATERIAL AND METHODS: Determination of toluene-2,4-diamine and toluene-2,6-diamine derivatives in acetonitrile were carried out by means of liquid chromatography with a diode assay detector. The method involves passing amine-containing air through sulfuric acidtreated glass fiber filter, washing out the substance settled on the filter, using water and solution of sodium hydroxide, followed by the extraction with toluene, reaction with 3,5 dinitobenzoyl chloride, replacement of dissolvent with acetonitrile and analysis of obtained solution. RESULTS: The method developed in this study enables the researcher to determine the content of toluene-2,4-diamine and toluene-2,6 diamine in the presence of other hazardous substances. In the specified measuring range (2.88-57.6 MUg/ml) calibration curves are linear. Under the optimized conditions of determination, the limit of detection (LOD) values achieved: 51.36 ng/ml for toluene-2,4-diamine and 52.93 ng/ml for toluene-2,6-diamine. CONCLUSIONS: This method makes it possible to determine the concentration of toluene-2,4-diamine and toluene-2,6-diamine in the workplace air within the specified measuring range of 0.004-0.08 mg/m3 (for air sample volume of 720 l). Med Pr 2017;68(4):497-505. PMID- 28584340 TI - How to Produce Translational Research to Guide Arctic Policy. PMID- 28584341 TI - Mapping Conservation Strategies under a Changing Climate. PMID- 28584342 TI - Skills and Knowledge for Data-Intensive Environmental Research. AB - The scale and magnitude of complex and pressing environmental issues lend urgency to the need for integrative and reproducible analysis and synthesis, facilitated by data-intensive research approaches. However, the recent pace of technological change has been such that appropriate skills to accomplish data-intensive research are lacking among environmental scientists, who more than ever need greater access to training and mentorship in computational skills. Here, we provide a roadmap for raising data competencies of current and next-generation environmental researchers by describing the concepts and skills needed for effectively engaging with the heterogeneous, distributed, and rapidly growing volumes of available data. We articulate five key skills: (1) data management and processing, (2) analysis, (3) software skills for science, (4) visualization, and (5) communication methods for collaboration and dissemination. We provide an overview of the current suite of training initiatives available to environmental scientists and models for closing the skill-transfer gap. PMID- 28584343 TI - An improved interfacial bonding model for material interface modeling. AB - An improved interfacial bonding model was proposed from potential function point of view to investigate interfacial interactions in polycrystalline materials. It characterizes both attractive and repulsive interfacial interactions and can be applied to model different material interfaces. The path dependence of work-of separation study indicates that the transformation of separation work is smooth in normal and tangential direction and the proposed model guarantees the consistency of the cohesive constitutive model. The improved interfacial bonding model was verified through a simple compression test in a standard hexagonal structure. The error between analytical solutions and numerical results from the proposed model is reasonable in linear elastic region. Ultimately, we investigated the mechanical behavior of extrafibrillar matrix in bone and the simulation results agreed well with experimental observations of bone fracture. PMID- 28584344 TI - Regional anaesthesia in breast cancer: Benefits beyond pain. PMID- 28584345 TI - Anaesthesia for electroconvulsive therapy: An overview with an update on its role in potentiating electroconvulsive therapy. AB - Despite advances in pharmacotherapy, electroconvulsive therapy (ECT) remains a mainstay treatment option in psychiatry since its introduction in 1930s. It can be used primarily in severe illnesses when there is an urgent need for treatment or secondarily after failure or intolerance to pharmacotherapy. The 'unmodified' technique of ECT was practised initially, with a high incidence of musculoskeletal complications. Several modifications including general anaesthesia and muscle relaxation are used to increase the safety and patient acceptability of ECT. Various anaesthetic techniques including medications are considered to provide adequate therapeutic seizure, simultaneously controlling seizure-induced haemodynamic changes and side effects. A brief review of literature on choice of these anaesthetic techniques is discussed. This article is intended to reinforce the knowledge of clinicians, who may have limited exposure to ECT procedure. Importance is given to the recent updates on the role of induction agents in potentiating therapeutic response to ECT in psychiatric disorders. PMID- 28584346 TI - Analgesic efficacy of ultrasound-guided paravertebral block versus serratus plane block for modified radical mastectomy: A randomised, controlled trial. AB - BACKGROUND AND AIMS: Modified radical mastectomy (MRM) may be associated with severe post-operative pain, leading to chronic pain syndrome. We compared the post-operative analgesic profile of two ultrasound-guided nerve blocks: Paravertebral block (PVB) and serratus plane block (SPB). METHODS: This double blind, randomised study was conducted on fifty adult females, scheduled for MRM with axillary dissection. After inducing general anaesthesia with intravenous midazolam 1 mg, fentanyl 1.5 mcg/kg, propofol 1-2 mg/kg and vecuronium 0.1 mg/kg, patients were administered either ultrasound-guided thoracic PVB at T4 (n = 25) or SPB at 5th rib (n = 25) with 20 ml of 0.5% bupivacaine, both as a single level injection. Time to first rescue analgesia and morphine consumption in 4, 6, 24, 48 and 72 h by PCA pump, visual analogue scale score and any adverse effects were recorded. Quantitative variables were compared using the unpaired t-test or the Mann-Whitney U test between the two groups. Qualitative variables were compared using the Chi-square test or Fisher's exact test. RESULTS: The duration of analgesia (mean +/- Standard deviation [SD]) was significantly longer in the PVB group compared to SPB group (346 +/- 57 min vs. 245.6 +/- 58 min, P < 0.001). The post-operative 24 h morphine consumption (mean +/- SD) was significantly higher in the SPB group (9.7 +/- 2.1 mg) compared to PVB group (6.5 +/- 1.5 mg) (P < 0.001). CONCLUSION: Ultrasound-guided SPB is an alternative analgesic technique to thoracic PVB for MRM although PVB provides a longer duration of analgesia. PMID- 28584347 TI - Anaphylaxis during anaesthesia: Indian scenario. AB - BACKGROUND AND AIMS: Anaphylaxis during anaesthesia is a rare but serious problem. In contrast to the developed countries where databases of perianaesthetic anaphylaxis are preserved, none exist in India. We conducted a survey amongst Indian anaesthesiologists to study the incidence and aetiology of anaphylaxis during anaesthesia in India. METHODS: A written questionnaire comprising 20 items was mailed electronically or distributed personally to 600 randomly selected Indian anaesthesiologists. The responses were compiled and analysed. RESULTS: We received responses from 242 anaesthesiologists. One hundred and sixty-two (67%) anaesthesiologists had encountered anaphylaxis during anaesthesia. Anaesthetic drugs led to 40% of reactions, and 60% of reactions were attributed to non-anaesthetic drugs. Opioids were the most common anaesthetic drugs implicated in anaphylaxis during anaesthesia, and non-depolarising muscle relaxants were the second most commonly implicated agents. Colloids, antibiotics and blood transfusion were the common non-anaesthetic agents thought to be responsible for anaphylactic reactions during anaesthesia. There were five deaths due to anaphylaxis during anaesthesia. Only 10% of anaesthesiologists ordered for allergy testing subsequently though 38% of anaesthesiologists had access to allergy testing facilities. CONCLUSIONS: Our survey reveals that two-thirds of participating Indian anaesthesiologists had witnessed anaphylaxis during anaesthesia. Commonly implicated anaesthetic drugs were opioids and non depolarising muscle relaxants while colloids, antibiotics and blood transfusion were the common non-anaesthetic agents causing anaphylactic reactions during anaesthesia. Further, our survey reveals low utilisation and paucity of referral allergy centres to investigate suspected cases of anaphylaxis during anaesthesia. PMID- 28584348 TI - Difficulty in inserting left double-lumen endobronchial tubes at the cricoid level in small-statured women: A retrospective study. AB - BACKGROUND AND AIMS: Left double-lumen endobronchial tube (DLT) sizes are selected using tracheal diameters and left mainstem bronchial diameters (LMBDs) determined from chest radiographs or computed tomography (CT) scans. In Western women, 35-Fr or 37-Fr DLTs are often selected. However, difficulties can be encountered when inserting 32-Fr or 35-Fr DLTs in Japanese women. We investigated success rates for 32-Fr or 35-Fr DLT insertion in Japanese women and determined the causes of unsuccessful DLT insertion. METHODS: We searched anaesthesia records of Japanese women aged >=20 years who underwent thoracic surgery with 32 Fr or 35-Fr DLTs between April 2010 and March 2015 in our hospital. In the successful group (SG), patients were intubated using the initially selected DLTs. By contrast, in the unsuccessful group (UG), the DLT size had to be changed. The Mann-Whitney U-test and Fisher's exact test were used to compare groups. RESULTS: The SG included 149 (96.1%) of 155 cases of 32-Fr DLT use and 119 (95.2%) of 125 cases of 35-Fr DLT use. Patient height was significantly lower in the UG than in the SG for the 35-Fr DLT (P = 0.0036). In seven of 12 UG patients (three for 32 Fr and four for 35-Fr), the transverse diameters of cricoid cartilages were smaller than the DLTs' tracheal diameters, thereby preventing passage through the cricoid cartilages. CONCLUSION: Along with LMBDs, transverse diameters of cricoid cartilages based on CT scans or ultrasonogram findings may help in selecting the appropriate left DLT size. PMID- 28584349 TI - Comparison of actual and ideal body weight for selection of appropriate size of ProSealTM laryngeal mask airway in overweight and obese patients: A prospective, randomised study. AB - BACKGROUND AND AIMS: The ProSealTM laryngeal mask airway (PLMA) has advantages of providing better cuff seal and the presence of a gastric drain tube. The manufacturer recommends actual body weight (ABW) for size selection. Pharyngeal area reduces with increase in body mass index (BMI); hence, in overweight patients, PLMA selected on ABW may not fit well. We hypothesised that the ideal body weight (IBW) would be more appropriate in size selection of PLMA. METHODS: This randomised, single-blind study included 124 patients of 20-60 years and American Society of Anesthesiologists Class I-II, with BMI >25. Patients were randomly divided into two groups. In Group ABW, PLMA was selected based on ABW (62 patients) and in Group IBW, PLMA was selected based on IBW (62 patients). The primary outcome was the first-attempt insertion success rate. Oropharyngeal air leaks, gastric air leaks, drain tube air leaks, insertion difficulty scores and postoperative complications were assessed. Fibre-optic view (Grade I-IV) was assessed for proper placement by a blinded assessor. Statistical analyses were performed using Chi-square test or Fisher's exact test. RESULTS: First-attempt insertion success rate and overall insertion success rates were similar in both the groups. Group IBW patients had significantly less resistance during insertion, lower peak airway pressures, successful nasogastric tube insertions, better fibre-optic views and less post-operative complications. Oropharyngeal leak pressure and instrumentation used for insertion were comparable. CONCLUSION: IBW is preferable for the size selection of the PLMA in overweight and obese patients compared to the ABW. PMID- 28584350 TI - A randomised comparative study of Miller laryngoscope blade versus Oxiport(r) Miller laryngoscope blade for neonatal and infant intubations. AB - BACKGROUND AND AIMS: Neonates and infants are prone to oxygen desaturation during the induction of general anaesthesia. Pharyngeal oxygen insufflation has been shown to delay the onset of desaturation and hypoxaemia during apnoea. We tested the hypothesis that deep laryngeal oxygenation with Oxiport(r) Miller blade would delay the onset of desaturation compared to laryngoscopy without supplemental oxygen (Miller blade). METHODS: One hundred neonates and infants undergoing general anaesthesia with endotracheal intubation for surgery were recruited and randomly assigned to one of the two groups: Miller or Oxiport group (laryngoscopy performed with Miller or Oxiport(r) blade, respectively). Primary outcome measure was the lowest oxygen saturation (SpO2) attained during intubation. Secondary outcomes were the incidence of severe desaturation (SpO2< 85%), correlation between SpO2and time to intubation in each group. Pearson's correlation coefficient was used to measure the correlation between time to intubation and desaturation in each group. P < 0.05 was considered statistically significant. RESULTS: Data from 95 patients were available for the final analysis: Miller group (n = 48) and Oxiport group (n = 47). Mean lowest SpO2was 95.9% +/- 5.75% in Miller group and 97.55% +/- 2.93% in Oxiport group (P = 0.049). Correlation between time to intubation and SpO2was -0.110; P = 0.459 in Miller group and 0.468; P = 0.001 in Oxiport group. Severe desaturation occurred in 12.5% patients in Miller group and none in Oxiport group. CONCLUSION: Apnoeic laryngeal oxygen insufflation with Oxiport(r) laryngoscope blade decreases the incidence of severe desaturation during neonatal and infant intubations. PMID- 28584351 TI - The effects of dexmedetomidine and magnesium sulphate in adult patients undergoing endoscopic transnasal transsphenoidal resection of pituitary adenoma: A double-blind randomised study. AB - BACKGROUND AND AIM: Transnasal transsphenoidal resection of pituitary tumours is associated with blood loss and wide fluctuations in haemodynamic parameters. The aim of the present study was to compare the effect of dexmedetomidine and magnesium sulphate during the transsphenoidal resection of pituitary tumours. METHODS: The study was a double-blind, randomised study and included 152 patients classified randomly into two groups: Group D: Dexmedetomidine was given as a loading dose 1 MUg/kg over 10 min before induction followed by an infusion at 0.5 MUg/kg/h during the surgery. Group M: Magnesium sulphate was given as loading dose of 50 mg/kg over 10 min followed by an infusion at 15 mg/kg/h during the surgery. The systolic, diastolic and mean arterial blood pressures, in addition to the amount of blood loss were measured at specific timepoints. Data were described in terms of mean +/- standard deviation, median, frequencies, 95% confidence of interval of mean and percentages. RESULTS: Mean bleeding score was lower in Group D than Group M (1.36 +/- 0.48 vs. 3.05 +/- 0.65, respectively; P = 0.002). Mean blood loss was lower in Group D (157.43 +/- 48.79 ml vs.299.47 +/- 77.28 ml in Group M; P < 0.001)Heart rate, mean arterial pressure, fentanyl requirements, end-tidal sevoflurane concentration, and extubation and emergence times were lower, while incidence of bradycardia and hypotension were higher in Group D. CONCLUSIONS: During transsphenoidal pituitary resection, dexmedetomidine, compared to magnesium, is associated with lower blood loss and better operating conditions but with more hypotension and bradycardia. PMID- 28584352 TI - Intravenous clonidine as a part of balanced anaesthesia for controlled hypotension in functional endoscopic sinus surgery: A randomised controled trial. AB - BACKGROUND AND AIMS: Controlled hypotension with balanced anaesthesia minimises blood loss. This study was done to evaluate the effectiveness of intravenous clonidine as a single bolus dose to establish controlled hypotension during functional endoscopic sinus surgery (FESS). METHODS: This randomised, double blind, placebo-controlled study was done in a tertiary hospital in India. Sixty American Society of Anesthesiologists physical status I and II patients (18-65 years) undergoing FESS were randomly allocated to one of the two groups. Placebo group (group A, n = 30) received sterile water whereas the clonidine group (group B, n = 30) received 3MUg/kg of clonidine intravenously, 30 min prior to induction of anaesthesia. The primary outcome was to achieve a target mean arterial blood pressure (MAP) of 55-65 mmHg intraoperatively. The secondary outcomes measured were requirement of additional fentanyl and metoprolol, intra-operative blood loss, surgeon's opinion on the surgical field, pain, sedation score and complications requiring treatment. RESULTS: Target MAP was easily achieved in clonidine group as against the placebo group (P < 0.001). Significant reduction in intra-operative blood loss (P = 0.0449), a better surgical site scoring (P = 0.02), less requirement of additional hypotensive drugs and good analgesia (P = 0.01) were seen in clonidine group. The complication rates were similar in both the groups. CONCLUSION: Clonidine is effective in achieving controlled hypotension in patients undergoing FESS. It reduces intra-operative blood loss, requirement of additional hypotensive drugs, improves the surgical field and offers good analgesia without significant side effects. PMID- 28584353 TI - Lactate/pyruvate monitoring during carotid endarterectomy under general anaesthesia versus cervical plexus block: A randomised controlled study. AB - BACKGROUND AND AIMS: Carotid endarterectomy (CEA) reduces the risk of stroke in patients with significant carotid stenosis and may be performed under general anaesthesia (GA) or regional anaesthesia (RA). This study aimed to compare RA and GA with regard the jugular venous bulb blood lactate and pyruvate levels. METHODS: This randomised-controlled trial was done between October-2013 and September-2015. Thirty-six patients were randomised into either GA or RA groups, with six excluded after randomisation. In the RA group, combined deep and superficial cervical plexus blocks were performed. In the GA group, anaesthesia was induced with propofol and fentanyl. In both groups, monitoring of neurological function was done. Sampling of the contralateral jugular bulb blood was done. The main outcome measures were lactate and pyruvate in the jugular venous blood. For comparing categorical data, Chi-square test was used, and for the numerical variables, t-test was used. RESULTS: Demographics were comparable in the two Groups. Serum lactate and pyruvate levels were higher in the GA group than RA group. At 120 min under anaesthesia, lactate and pyruvate levels under RA vs. GA, respectively were 0.76+/-0.03 mEq/L vs. 1.14+/-0.06, p-0.001 mEq/L, and 0.08+/- 0.00 mEq/L vs. 0.10+/-0.01 mEq/L, p=0.006. Lactate/ pyruvate ratios were normal in both groups. The mean blood pressure was significantly lower in the GA group during anaesthesia. CONCLUSION: In patients undergoing Carotid endarterectomy, serum levels of both lactate and pyruvate were higher under general versus regional anaesthesia. PMID- 28584354 TI - Acute unilateral post-operative submandibular sialadenitis following posterior cranial fossa surgery. AB - Extreme degree of rotation and flexion of the head during posterior fossa surgeries can lead to acute post-operative submandibular sialadenitis that can cause respiratory compromise. Identification of this problem is vital to prevent deterioration in the early post-operative period. This condition responds well to conservative management provided airway obstruction is taken care of. We discuss a case of a 63-year-old female, with a left side vestibular schwannoma who developed airway obstruction in post-operative period due to swelling of right submandibular gland. Various possible mechanisms leading to this condition and related literature are briefy reviewed. PMID- 28584355 TI - Perioperative sublingual levodopa in Parkisnon's Disease: A useful alternative! AB - Timely administration of dopamine agonists is of the essence in Parkinson's disease. The perioperative period especially for abdominal surgeries under general anaesthesia poses a challenge to oral drug administration. Alternatives such as rotigotine patches and subcutaneous apomorphine administration have been described but unavailability restricts their use. Sublingual administration of tablet levodopamine as an alternative worked well in our patients and we would like to describe the same. PMID- 28584356 TI - Role of electromyography endotracheal tube in preventing recurrent laryngeal nerve injury during thyroid surgery: A case reportAirway trauma during difficult intubation... from the frying pan into the fire? PMID- 28584357 TI - Airway trauma during difficult intubation... from the frying pan into the fire? PMID- 28584358 TI - Empagliflozin: Novel antidiabetes and pro-cardiac drug. PMID- 28584359 TI - Regional anaesthesia in a patient with aortic stenosis for bladder tumour resection. PMID- 28584360 TI - Intra-operative carcinoid crisis: Revised anaesthesia management. PMID- 28584361 TI - Knotted epidural catheter in an infant: A case report. PMID- 28584362 TI - Facial skin injury caused by acrylate-based adhesive tapes in a post-menopausal patient: A preventable cause. PMID- 28584363 TI - New anticoagulants and antiplatelet agents in perioperative period: Recommendations and controversies! PMID- 28584364 TI - The Great Indian Epidemic of Superficial Dermatophytosis: An Appraisal. PMID- 28584366 TI - Biostatistics Series Module 9: Survival Analysis. AB - Survival analysis is concerned with "time to event" data. Conventionally, it dealt with cancer death as the event in question, but it can handle any event occurring over a time frame, and this need not be always adverse in nature. When the outcome of a study is the time to an event, it is often not possible to wait until the event in question has happened to all the subjects, for example, until all are dead. In addition, subjects may leave the study prematurely. Such situations lead to what is called censored observations as complete information is not available for these subjects. The data set is thus an assemblage of times to the event in question and times after which no more information on the individual is available. Survival analysis methods are the only techniques capable of handling censored observations without treating them as missing data. They also make no assumption regarding normal distribution of time to event data. Descriptive methods for exploring survival times in a sample include life table and Kaplan-Meier techniques as well as various kinds of distribution fitting as advanced modeling techniques. The Kaplan-Meier cumulative survival probability over time plot has become the signature plot for biomedical survival analysis. Several techniques are available for comparing the survival experience in two or more groups - the log-rank test is popularly used. This test can also be used to produce an odds ratio as an estimate of risk of the event in the test group; this is called hazard ratio (HR). Limitations of the traditional log-rank test have led to various modifications and enhancements. Finally, survival analysis offers different regression models for estimating the impact of multiple predictors on survival. Cox's proportional hazard model is the most general of the regression methods that allows the hazard function to be modeled on a set of explanatory variables without making restrictive assumptions concerning the nature or shape of the underlying survival distribution. It can accommodate any number of covariates, whether they are categorical or continuous. Like the adjusted odds ratios in logistic regression, this multivariate technique produces adjusted HRs for individual factors that may modify survival. PMID- 28584367 TI - Methodology Series Module 9: Designing Questionnaires and Clinical Record Forms - Part II. AB - This article is a continuation of the previous module on designing questionnaires and clinical record form in which we have discussed some basic points about designing the questionnaire and clinical record forms. In this section, we will discuss the reliability and validity of questionnaires. The different types of validity are face validity, content validity, criterion validity, and construct validity. The different types of reliability are test-retest reliability, inter rater reliability, and intra-rater reliability. Some of these parameters are assessed by subject area experts. However, statistical tests should be used for evaluation of other parameters. Once the questionnaire has been designed, the researcher should pilot test the questionnaire. The items in the questionnaire should be changed based on the feedback from the pilot study participants and the researcher's experience. After the basic structure of the questionnaire has been finalized, the researcher should assess the validity and reliability of the questionnaire or the scale. If an existing standard questionnaire is translated in the local language, the researcher should assess the reliability and validity of the translated questionnaire, and these values should be presented in the manuscript. The decision to use a self- or interviewer-administered, paper- or computer-based questionnaire depends on the nature of the questions, literacy levels of the target population, and resources. PMID- 28584365 TI - Use of Topical Corticosteroids in Dermatology: An Evidence-based Approach. AB - Topical corticosteroids (TCs) are the pillars of dermatotherapeutics. These drugs are the "magic molecules," provided they are used judiciously and appropriately, following a rational prescription. On exhaustive literature search in multiple databases, we found a significant evidence favoring the use of TCs in atopic eczema, localized vitiligo, psoriasis, chronic hand eczema, and localized bullous pemphigoid. However, contrary to conventional wisdom, we did not find any high level scientific evidence in support of prescribing TCs in cutaneous lichen planus, sarcoidosis, and seborrhoeic dermatitis. Besides, evidence clearly advocates judicious use of mild-to-moderate corticosteroids (if required) in pregnancy and lactation and there is no risk of any fetal abnormality. PMID- 28584368 TI - Pathophysiology of Autoimmune Bullous Diseases: Nature Versus Nurture. AB - Pemphigus and pemphigoid are the prototypical immunobullous diseases. Although it has been well established that they are caused by deposition of autoreactive antibodies directed against adherence proteins within the skin, the specific genetic and environmental factors leading to development of these diseases continue to be an area of investigation. Herein, we discuss several of the potential environmental triggers that may induce patients to develop immunobullous diseases including medications, viral infections, UV exposure or other radiation injury and dietary factors. In addition, the potential genetic and immunologic mechanisms contributing to the pathogenesis of pemphigus and pemphigoid will be reviewed. The multifactorial nature of these diseases contributes to their complexity and highlights the importance of a detailed personal and family history when caring for these patients. PMID- 28584369 TI - Advanced Diagnostic Techniques in Autoimmune Bullous Diseases. AB - Autoimmune blistering diseases are diverse group of conditions characterized by blisters in the skin with or without mucosal lesions. There may be great degree of clinical and histopathological overlap; hence, advanced immunological tests may be necessary for more precise diagnosis of these conditions. Direct immunofluorescence microscopy is the gold standard tests to demonstrate the tissue-bound antibodies and should be done in all cases. Magnitude of antibody level in patient' serum can be assessed by indirect immunofluorescence and enzyme linked immunosorbent assay. In this article we have reviewed the various techniques that are available in the diagnosis of autoimmune blistering diseases. PMID- 28584370 TI - Counseling in Pemphigus. AB - Pemphigus is a chronic, potentially life threatening, autoimmune intraepidermal blistering disease affecting the skin and the mucous membrane. Pemphigus may have profound impact on the quality of life in the affected patients. Counselling and adjuvant psychotherapy may be beneficial at least in few patients and should be considered as a part of multidisciplinary approach. PMID- 28584371 TI - Shifting Focus in the Therapeutics of Immunobullous Disease. AB - Therapeutics of autoimmune bullous disease has seen a major shift of focus from more global immunosuppression to targeted immunotherapy. Anti CD 20 monoclonal antibody Rituximab revolutionized the therapeutics of autoimmune bullous disease particularly pemphigus. Though it is still being practiced off-label, evidences in the form of RCT and meta analysis are now available. Other novel anti CD 20 monoclonal antibodies like ofatumumab, veltuzumab, and ocrelizumab, tositumomab or obinutuzumab/GA101 may add to the therapeutic options in coming days. Beyond anti CD 20 monoclonal antibodies other options that show promise at least in select scenario are omalizumab, TNF inhibitors plasmapheresis and intravenous immunoglobulin. The present article will discuss the role of rituximab and other newer therapeutics in the treatment of autoimmune blistering disease, especially pemphigus and suggests their positions in the therapeutic ladder. PMID- 28584372 TI - Hypersensitive Reaction to Tattoos: A Growing Menace in Rural India. AB - BACKGROUND: Increased enthusiasm toward newer fashion trends among rural India along with the lack of government regulation has led to increased tattoo reactions. OBJECTIVE: The objective of this study is to describe various clinical manifestations of hypersensitive reactions to tattoo ink reported at a tertiary care hospital in Mandya district. MATERIALS AND METHODS: An observational study was carried out over a period of 1 year from June 2014 to May 2015 at Mandya Institute of Medical Sciences, Mandya. All the patients reporting with allergic reaction due to tattooing were included in the present study after obtaining informed consent. Transient acute inflammatory reaction, infections, and skin diseases localized on tattooed area were excluded from this study. A detailed history regarding the onset, duration and color used for tattooing were collected. Cutaneous examination and biopsy was to done to know the type of reaction. RESULTS: Fifty cutaneous allergic reactions were diagnosed among 39 patients. Mean age of subjects was 22 years and mean duration before the appearance of lesion was 7 months. Common colors associated with reactions were red (53.9%), black (33.3%), green (5.1%), and multicolor (7.7%). Itching was the predominant symptom. Skin lesions mainly consisted of lichenoid papules and plaques, eczematous lesions, and verrucous lesions. Lichenoid histopathology reaction was the most common tissue allergic reaction. CONCLUSION: Increasing popularity of tattooing among young people has predisposed to parallel increase in adverse reactions. Red pigment is most common cause of allergic reaction in the present study, and lichenoid reaction is the most common reaction. PMID- 28584373 TI - Prospective Analysis of Skin Findings in Surgical Critically Ill Patients Intensive Care Unit. AB - BACKGROUND: Intensive Care Units (ICUs) are places where critically ill patients are managed. AIM: We aimed to investigate skin disorders that developed in critically ill surgical patients during their stay in the ICU. METHODS: The prevalence of dermatological disorders and factors affecting their clinical features was prospectively analyzed in surgical ICU patients. We recorded age, sex, type of ICU, comorbidities, skin disorders, time to consultation, duration of ICU stay, and mortality rate. RESULTS: Our study included 605 patients (mean age of 60.1 +/- 20.2 years; 56.4% males). Seventy-three (12.1%) patients were consulted with the Dermatology Department, among which 28.8% had infectious dermatological lesions, 26% dermatoses, and 45.2% drug reactions. The most common infectious dermatological disorder was wound infection (55.6%), the most common drug reaction was maculopapular drug eruption (75.8%), and the most common dermatosis was frictional blisters (47.4%). Multiple comorbidities, hypertension, diabetes mellitus, coronary artery disease, Parkinson disease, and stroke increased dermatological disorders (P < 0.05). The consulted patients had a median ICU stay of 7 days (range 2-53 days); consultation was significantly more common when it exceeded 10 days (74% vs. 26%, P < 0.05). The consulted patients died more commonly (P < 0.05). Infectious dermatological disorders and dermatoses were more common in patients older and younger than 50 years, respectively (P < 0.05). Dermatoses were more common among women (P < 0.05). The median time to consultation was 6 (2-30) days; it was longest for dermatological infections and shortest for dermatoses (P < 0.05). Infectious dermatological disorders were significantly more common among the deceased patients (P < 0.05). CONCLUSION: Multiple factors including multiple comorbidities, duration of ICU stay, time to consultation, and mortality increase dermatological disorders among surgical ICU patients. PMID- 28584374 TI - Demographic Characteristics and Association of Serum Vitamin B12, Ferritin and Thyroid Function with Premature Canities in Indian Patients from an Urban Skin Clinic of North India: A Retrospective Analysis of 71 Cases. AB - BACKGROUND: The incidence of self-reported premature hair graying (PHG) seems to be on the rise. PHG has a profound impact on the patient's quality of life. It remains an incompletely understood etiology with limited and modest treatment options. AIM: The evaluation of the demographic and clinical profile of patients with premature canities, and exploration of the association of this entity with certain systemic disorders suspected to be related to its etiology. METHODS: Seventy-one cases of premature canities (onset noticed by patients before 25 years of age) presenting to an urban skin clinic in Gurugram, India, between September 2012 and September 2015 with this complaint were retrospectively analyzed. The patient records were retrieved that provided details of the onset, duration and pattern of involvement, history, and examination findings (scalp, cutis, and general physical). Since all these patients had been screened for anemia, thyroid disorder, fasting blood glucose, and Vitamin B12 levels at the time of presentation, these parameters were also available for analysis. RESULTS: The mean age at onset of graying was 10.2 +/- 3.6 years (range: 5-19 years), with an almost equal gender distribution. The earliest age of onset recorded was 5 years. A positive family history of PHG (at least one of the biological parents or siblings) was obtained in 64 (90.1%) of the cases. The temporal regions of the scalp (35.2%) were most commonly involved followed by the frontal region (18.3%). Hypovitaminosis B12 and hypothyroidism showed significant association with the disorder, whereas anemia, serum ferritin, and fasting blood glucose did not. CONCLUSION: The age of onset of hair graying can be as low as 5 years. Temporal and frontal areas are the most commonly involved sites. A strong family history, Vitamin B12 deficiency, and hypothyroidism are strongly associated with PHG. Larger case-control studies are mandated for discerning the correlation of these and other risk factors with PHG. PMID- 28584375 TI - Terry's Nails: A Sign of Systemic Disease. AB - Terry's nails are a type of apparent leukonychia, characterized by ground glass opacification of nearly the entire nail, obliteration of the lunula, and a narrow band of normal, pink nail bed at the distal border. The aim of this study is to guide clinical practice by reviewing all of the data concerning Terry's nail that have become available since the original description by Terry in 1954, with particular reference to all clinical features, associated medical conditions, pathogenesis, and necessary workup. PubMed was searched using the keywords "leukonychia" and "Terry nails." Although the abnormality can occur with normal aging, Terry's nails can also be an indication of an underlying medical condition, most notably, cirrhosis, chronic renal failure, and congestive heart failure. A change in nail bed vascularity, secondary to overgrowth of connective tissue, is thought to be responsible, with nail bed biopsy revealing telangiectasias in the distal band. The differential diagnosis for Terry's nails includes half-and-half nails (Lindsay's nails), Muehrcke's nails, and true leukonychia totalis/partialis. Having the ability to delineate these nail findings can be a valuable tool in clinical practice as each entity is associated with a different set of systemic conditions. Terry's nails highlight the intimate connection between nail changes and systemic disease as well as the importance of thorough nail inspection with every physical examination. PMID- 28584376 TI - Solitary Collagenoma of the Labium Majus: A Rare Occurrence. AB - Collagenomas are connective tissue nevi representing hamartomatous proliferation of collagen. Isolated collagenomas are of rare occurrence. They are sporadically acquired, and lesions are often localized to a single body region. We described a case of solitary collagenoma in a 23-year-old woman, confirmed on histopathology and special stains for collagen, involving an uncommon site such as labium majus. A high index of suspicion for a skin-colored circumscribed solitary growth and a low threshold for biopsy often help to arrive at a final diagnosis. PMID- 28584377 TI - Neurolymphomatosis in Primary Cutaneous CD4+ Pleomorphic Small/Medium-sized T cell Lymphoma Mimicking Hansen's Disease. AB - Neurolymphomatosis (NL) refers to nerve infiltration by neurotropic neoplastic cells in the setting of a known or an unknown hematological malignancy. It typically presents as painful or painless peripheral mononeuropathy, mononeuritis multiplex, polyneuropathy, polyradiculopathy, or cranial neuropathy. A 32-year old male presented with a hyperpigmented hypoesthetic plaque over the anterolateral aspect of the right leg with thickening of the right common peroneal nerve and foot drop clinically diagnosed as Hansen's disease. Biopsy taken from skin showed infiltrates of pleomorphic small and medium sized lymphocytes in the dermis and subcutis. On immunohistochemistry, the cells were positive for CD3, CD4 and negative for CD8, CD20, and CD30. Ultrasonography guided fine-needle aspiration of the thickened nerve showed infiltrates of atypical lymphoid cells. Based on these findings, a diagnosis of NL in primary cutaneous CD4+ pleomorphic small/medium-sized T-cell lymphoma was made. The disease responded to systemic chemotherapy and localized radiotherapy with no evidence of relapse during 3 years follow-up. NL in primary cutaneous CD4+ pleomorphic small/medium-sized T-cell lymphoma presenting with manifestations redolent of Hansen's disease is not described in available literature. This case also demonstrates the utility of fine needle aspiration of nerve, a minimally invasive procedure in the diagnosis of NL. PMID- 28584378 TI - Desmoid Tumor of Rectus Abdominis Presenting with Grey-Turner's and Cullen's Sign: A Report of a Rare Case. AB - Desmoid tumor of rectus abdominis presenting with Grey-Turner's and Cullen's sign is rare. Herein, we report desmoid tumor of rectus abdominis in a 64-year-old multiparous female who presented with ecchymosis involving left flank and around the umbilicus. Histopathological examination of biopsy from the tumor confirmed the diagnosis of the desmoid tumor. She was referred to a surgeon for radical resection. PMID- 28584379 TI - Descriptive versus Analytical Studies in a Clinical Setup. PMID- 28584380 TI - Prospective Study Design Conundrum: Disease Registry for Cutaneous Leishmaniasis. PMID- 28584381 TI - Cutaneous Angiosarcoma Mimicking Panniculitis in the Lower Extremities. PMID- 28584382 TI - Widespread Indurated Plaques and Nodules. PMID- 28584383 TI - Spectral dependence of carrier lifetimes in silicon for photovoltaic applications. AB - Charge carrier lifetimes in photovoltaic-grade silicon wafers were measured by a spectral-dependent, quasi-steady-state photoconductance technique. Narrow bandwidth light emitting diodes (LEDs) were used to excite excess charge carriers within the material, and the effective lifetimes of these carriers were measured as a function of wavelength and intensity. The dependence of the effective lifetime on the excitation wavelength was then analyzed within the context of an analytical model relating effective lifetime to the bulk lifetime and surface recombination velocity of the material. The agreement between the model and the experimental data provides validation for this technique to be used at various stages of the solar cell production line to investigate the quality of the passivation layers and the bulk properties of the material. PMID- 28584384 TI - Multigram-scale Synthesis of Enantiopure 3,3-Difluoroproline. AB - An efficient route for the synthesis of enantiopure 3,3-difluoroproline on multigram-scale is described herein. The deoxofluorination can be achieved with DAST on the corresponding racemic pyrrolidinone in good yield. Resolution of the racemate by crystallization with D- and L-tyrosine hydrazide provides both enantiomers of 3,3-difluoroproline in high yield and ee%. PMID- 28584385 TI - Direct Error in Constitutive Equation Formulation for Plane stress Inverse Elasticity Problem. AB - We present a new computational formulation for inverse problems in elasticity with full field data. The formulation is a variant of an error in the constitutive equation formulation, but allows direct solution for the modulus field and accommodates discontinuous strain fields. The development of the formulation is motivated by the relatively poor performance of current direct formulations, reported so far in literature, in dealing with discontinuities in the strain and material property distribution. The formulation relies on minimizing the error in the constitutive equation, and a momentum equation constraint. Numerical results on model problems show that the formulation is capable handling discontinuous, and noisy strain fields, and also converging with mesh refinement for continuous and discontinuous material property distributions. The application to reconstruct the elastic modulus distribution in solid breast tumors is shown. PMID- 28584386 TI - Reference Correlation of the Thermal Conductivity of Cyclohexane from the Triple Point to 640 K and up to 175 MPa. AB - New, wide-range reference equations for the thermal conductivity of cyclohexane as a function of temperature and density are presented. The equations are based in part upon a body of experimental data that has been critically assessed for internal consistency and for agreement with theory whenever possible. We estimate the uncertainty (at the 95% confidence level) for the thermal conductivity of cyclohexane from the triple point (279.86 K) to 650 K at pressures up to 175 MPa to be 4% for the compressed liquid and supercritical phases. For the low-pressure gas phase (up to 0.1 MPa) over the temperature range 280 K to 680 K, the estimated uncertainty is 2.5%. Uncertainties in the critical region are much larger, since the thermal conductivity approaches infinity at the critical point and is very sensitive to small changes in density. PMID- 28584387 TI - Promoting Informal and Professional Help-Seeking for Adolescent Dating Violence. AB - The present study examined factors that differentiate adolescents with varied intentions of informal and professional help-seeking for dating violence. Help seeking intentions among 518 ethnically diverse adolescents from a rural, southern county who participated in a longitudinal study of teen dating violence were categorized into three groups: adolescents unlikely to seek any help, adolescents likely to seek only informal help, and adolescents likely to seek informal and professional help. Multinomial logistic regression found that gender, family functioning, problem-solving competency, dating status, having an adult to talk to about a dating relationship, and acceptability of family violence significantly predicted membership in the help-seeking groups. Implications for promoting informal and professional help-seeking and recommendations for future research are discussed. PMID- 28584388 TI - Relations of Positive and Negative Expressivity and Effortful Control to Kindergarteners' Student-Teacher Relationship, Academic Engagement, and Externalizing Problems at School. AB - The current study examined the role of naturally-occurring negative and positive emotion expressivity in kindergarten and children's effortful control (EC) on their relationships with teachers, academic engagement, and problems behaviors in school. Further, the potential moderating role of EC on these important school outcomes was assessed. Emotion and engagement were observed at school. EC was assessed by multiple methods. Teachers reported on their student-teacher relationships and student's externalizing behaviors. Children's emotion expressivity and EC were related to engagement and relationships with teachers as well as behavioral problems at school. Children low in EC may be particularly vulnerable to the poor outcomes associated with relatively intense emotion expressivity as they struggle to manage their emotions and behaviors in the classroom. PMID- 28584389 TI - Low Temperature Plasma for the Preparation of Crater Walls for Compositional Depth Profiling of Thin Inorganic Multilayers. AB - An indirect, compositional depth profiling of an inorganic multilayer system using a helium low temperature plasma (LTP) containing 0.2% (v/v) SF6 was evaluated. A model multilayer system consisting of four 10 nm layers of silicon separated by four 50 nm layers of tungsten was plasma-etched for (10, 20, and 30) s at substrate temperatures of (50, 75, and 100) degrees C to obtain crater walls with exposed silicon layers that were then visualized using time-of-flight secondary ion mass spectrometry (ToF-SIMS) to determine plasma-etching conditions that produced optimum depth resolutions. At a substrate temperature of 100 degrees C and an etch time of 10 s, the FWHM of the 2nd, 3rd, and 4th Si layers were (6.4, 10.9, and 12.5) nm, respectively, while the 1/e decay lengths were (2.5, 3.7, and 3.9) nm, matching those obtained from a SIMS depth profile. Though artifacts remain that contribute to degraded depth resolutions, a few experimental parameters have been identified that could be used to reduce their contributions. Further studies are needed, but as long as the artifacts can be controlled, plasma etching was found to be an effective method for preparing samples for compositional depth profiling of both organic and inorganic films, which could pave the way for an indirect depth profile analysis of inorganic organic hybrid structures that have recently evolved into innovative next generation materials. PMID- 28584390 TI - Clarity of mind: Structural equation modeling of associations between dispositional mindfulness, self-concept clarity and psychological well-being. PMID- 28584391 TI - Believable Statements of Uncertainty and Believable Science. AB - Nearly fifty years ago, two landmark papers appeared that should have cured the problem of ambiguous uncertainty statements in published data. Eisenhart's paper in Science called for statistically meaningful numbers, and Currie's Analytical Chemistry paper revealed the wide range in common definitions of detection limit. Confusion and worse can result when uncertainties are misinterpreted or ignored. The recent stories of cold fusion, variable radioactive decay, and piezonuclear reactions provide cautionary examples in which prior probability has been neglected. We show examples from our laboratory and others to illustrate the fact that uncertainty depends on both statistical and scientific judgment. PMID- 28584392 TI - Seasonal shifts in sex ratios are mediated by maternal effects and fluctuating incubation temperatures. AB - Sex-specific maternal effects can be adaptive sources of phenotypic plasticity. Reptiles with temperature-dependent sex determination (TSD) are a powerful system to investigate such maternal effects because offspring phenotype, including sex, can be sensitive to maternal influences such as oestrogens and incubation temperatures.In red-eared slider turtles (Trachemys scripta), concentrations of maternally derived oestrogens and incubation temperatures increase across the nesting season; we wanted to determine if sex ratios shift in a seasonally concordant manner, creating the potential for sex-specific maternal effects, and to define the sex ratio reaction norms under fluctuating temperatures across the nesting season.Eggs from early and late season clutches were incubated under a range of thermally fluctuating temperatures, maternally derived oestradiol concentrations were quantified via radioimmunoassay, and hatchling sex was identified. We found that late season eggs had higher maternal oestrogen concentrations and were more likely to produce female hatchlings. The sex ratio reaction norm curves systematically varied with season, such that with even a slight increase in temperature (0.5 degrees C), late season eggs produced up to 49% more females than early season eggs.We found a seasonal shift in sex ratios which creates the potential for sex-specific phenotypic matches across the nesting season driven by maternal effects. We also describe, for the first time, systematic variation in the sex ratio reaction norm curve within a single population in a species with TSD. PMID- 28584393 TI - Adult bacterial exposure increases behavioral variation and drives higher repeatability in field crickets. AB - Among-individual differences in behavior are now a widely studied research-focus within the field of behavioral ecology. Furthermore, elements of an animal's internal state, such as energy or fat reserves, and infection status can have large impacts on behaviors. Despite this, we still know little regarding how state may affect behavioral variation. Recent exposure to pathogens may have a particularly large impact on behavioral expression given that it likely activates costly immune pathways, potentially forcing organism to make behavioral tradeoffs. In this study we investigate how recent exposure to a common bacterial pathogen, Serratia marcescens, affects both the mean behavioral expression and the among-individual differences (i.e. variation) in boldness behavior in the field cricket, Gryllus integer. We find that recent pathogen exposure does not affect mean behavioral expression of the treatment groups, but instead affects behavioral variation and repeatability. Specifically, bacterial exposure drove large among-individual variation, resulting in high levels of repeatability in some aspects of boldness (willingness to emerge into a novel environment), but not others (latency to become active in novel environment), compared to non infected crickets. Interestingly, sham injection resulted in a universal lack of among-individual differences. Our results highlight the sensitivity of among individual variance and repeatability estimates to ecological and environmental factors that individuals face throughout their lives. PMID- 28584394 TI - Letter to the editor comments on Groparu-Cojocaru and Doray (2013). AB - Although estimating the five parameters of an unknown Generalized Normal Laplace (GNL) density by minimizing the distance between the empirical and true characteristic functions seems appealing, the approach cannot be advocated in practice. This conclusion is based on extensive numerical simulations in which a fast minimization procedure delivers deceiving estimators with values that are quite far away from the truth. These findings can be predicted by the very large values obtained for the true asymptotic variances of the estimators of the five parameters of the true GNL density. PMID- 28584395 TI - Effect of amifostine, a radiation-protecting drug, on oxygen concentration in tissue measured by EPR oximetry and imaging. AB - Effect of amifostine, a radiation-protecting drug, on muscle tissue partial pressure of oxygen was investigated by electron paramagnetic resonance spectroscopy and imaging. When amifostine was administered intraperitoneally or intravenously to mice, the linewidth of the electron paramagnetic resonance spectra of the lithium octa-n-butoxy-substituted naphthalocyanine implanted in the mouse leg muscle decreased. Electron paramagnetic resonance oximetry using a lithium octa-n-butoxy-substituted naphthalocyanine probe and electron paramagnetic resonance oxygen mapping using a triarylmethyl radical paramagnetic probe was useful to quantify pressure of oxygen in the tissues of living mice. The result of electron paramagnetic resonance oximetric imaging showed that administration of amifostine could decrease pressure of oxygen in the muscle and also tumor tissues. This finding suggests that lowering pressure of oxygen in tissues might contribute in part to the radioprotection of amifostine. PMID- 28584397 TI - A comparative study of the inhibitory effects by caffeic acid, catechins and their related compounds on the generation of radicals in the reaction mixture of linoleic acid with iron ions. AB - Caffeic acid and (+)-catechin, which are abundantly contained in coffee and tea, are typical polyphenols. In order to know the relative magnitudes of antioxidant activity, effects by caffeic acid, (+)-catechin and their derivatives on the formation of 4-POBN/carbon-centered linoleic acid-derived radical adducts were examined in the control reaction mixture of linoleic acid with FeCl3 at 30 degrees C for 168 h. In the presence of 1.0 mM of the polyphenols, peak to peak heights of the third ESR signal resulted in 7.7 +/- 2.4% (n = 3) (caffeic acid), 145 +/- 13% (n = 3) (quinic acid), 4.4 +/- 0.0% (n = 3) (chlorogenic acid), 104 +/- 4.4% (n = 3) (ferulic acid), 4.3 +/- 0.0% (n = 3) (noradrenaline), 12.5 +/- 10.9% (n = 3) (gallic acid), 38.1 +/- 7.1% (n = 3) [(+)-catechin], 47.9 +/- 11.7% (n = 3) [(-)-epicatechin], 56.5 +/- 1.6% (n = 3) (epigallocatechin), 13.5 +/- 1.7% (n = 3) (catechol) and 83.7 +/- 7.8% (n = 3) (resorcinol) of the control reaction mixture. All the compounds with catechol moiety exerted potent inhibitory effects on the radical formation except for (+)-catechin, (-) epicatechin and epigallocatechin. (+)-Catechin, (-)-epicatechin and epigallocatechin may not exert the inhibitory effect as much possibly because they are less stable compared with caffeic acid. The resorcinol moiety in these molecules may also weaken their antioxidant activity. PMID- 28584396 TI - Protective role of testis-specific peroxiredoxin 4 against cellular oxidative stress. AB - Peroxiredoxin (PRDX), a newly discovered antioxidant enzyme, has an important role in hydrogen peroxide reduction. Among six PRDX genes (PRDX1-6) in mammals, PRDX4 gene is alternatively spliced to produce the somatic cell form (PRDX4) and the testis specific form (PRDX4t). In our previous study, PRDX4 knockout mice displayed testicular atrophy with an increase in cell death due to oxidative stress. However, the antioxidant function of PRDX4t is unknown. In this study, we demonstrate that PRDX4t plays a protective role against oxidative stress in the mammalian cell line HEK293T. The PRDX4t-EGFP plasmid was transferred into HEK293T cells; protein expression was confirmed in the cytoplasm. To determine the protective role of PRDX4t in cells, we performed image-based analysis of PRDX4t EGFP expressed cells exposed to UV irradiation and hydrogen peroxide using fluorescent probe CellROX. Our results suggested that PRDX4t-EGFP expressed cells had reduced levels of oxidative stress compared with cells that express only EGFP. This study highlights that PRDX4t plays an important role in cellular antioxidant defense. PMID- 28584398 TI - Tumor necrosis factor-alpha decreases EC-SOD expression through DNA methylation. AB - Extracellular-superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. EC-SOD expression in cultured cell lines is regulated by various cytokines including tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is a major mediator of pathophysiological conditions and may induce or suppress the generation of various types of mediators. Epigenetics have been defined as mitotically heritable changes in gene expression that do not affect the DNA sequence, and include DNA methylation and histone modifications. The results of the present study demonstrated that TNF-alpha significantly decreased EC-SOD level in fibroblasts with an accompanying increase in methylated DNA. In DNA methylation and demethylation, cytosine is methylated to 5 methylcytosine (5mC) by DNA methyltransferase (DNMT), and 5mC is then converted to 5-hydroxymethylcytosine (5hmC) and cytosine in a stepwise manner by ten-eleven translocation methylcytosine dioxygenases (TETs). However, DNMT did not participate in TNF-alpha-induced DNA methylation within the EC-SOD promoter region. On the other hand, TNF-alpha significantly suppressed TET1 expression and EC-SOD mRNA levels were decreased by the silencing of TET1 in fibroblasts. These results demonstrate that the down-regulation of EC-SOD by TNF-alpha is regulated by DNA methylation through reductions in TET1. PMID- 28584399 TI - Immunonutrition in patients with cyctic fibrosis leads to drop of serum amyloid A and increase of oxidative stress. AB - The aim of the present study is to evaluate of the impact of immunonutrition on parameters of oxidative stress and inflammation in patients with cystic fibrosis and malnutrition. In the 30 patients with cystic fibrosis and long-term enteral nutrition support for malnutrition the effect of standard and immunonutrion sipping on oxidative stress and inflammatory activity parameters was compared. Malonyldialdehyde (MDA) as parameter of oxidative stress and serum amyloid A (SAA), interleukin 1 and 6, hsCRP, IgM, IgA, IgG as parameters of inflammatory activity were examined. Immunonutrition decreased SAA to 17.6 mg/L comparing to 25.6 mg/L when standard nutrition was given (p = 0.014). MDA was 0.66 uM on standard and 0.96 uM on immunonutrition support (p<0.01). The significant negative correlation was recorded between MDA and SAA, hs-CRP, interleukin 6, IgA and IgG. In conclusion, the application of immunonutrition in patients with cystic fibrosis and malnutrition is associated with drop of SAA but with the rise of MDA. PMID- 28584400 TI - Compound 48/80, a mast cell degranulator, causes oxidative damage by enhancing vitamin C synthesis via reduced glutathione depletion and lipid peroxidation through neutrophil infiltration in rat livers. AB - In this study, we examined whether compound 48/80 (C48/80), a mast cell degranulator, causes hepatic oxidative damage in rats. Serum and liver biochemical parameters were determined 0.5, 3 or 6 h after a single treatment with C48/80 (0.75 mg/kg). Serum histamine and serotonin levels increased 0.5 h after C48/80 treatment but diminished thereafter. Increases in serum vitamin C (VC) and transaminases and hepatic hydrogen peroxide, lipid peroxide, and myeloperoxidase levels and a decrease in hepatic reduced glutathione level occurred 0.5 h after C48/80 treatment and further proceeded at 3 h, but these changes diminished at 6 h. Serum lipid peroxide and hepatic VC levels increased 3 h after C48/80 treatment. Hepatic glycogen level decreased 0.5 h after C48/80 treatment and further decreased at 3 h. Pre-administered ketotifen diminished all these changes found at 3 h after treatment, while pre-administered NPC 14686 diminished these changes except changes in serum histamine and serotonin levels. Hepatocellular apoptosis observed at 3 h after C48/80 treatment was attenuated by pre-administered ketotifen and NPC 14686. These results indicate that C48/80 causes oxidative damage by enhancing VC synthesis via reduced glutathione depletion-dependent glycogenolysis and lipid peroxidation through neutrophil infiltration following mast cell degranulation in rat livers. PMID- 28584401 TI - Chemopreventive effects of a low-side-effect antibiotic drug, erythromycin, on mouse intestinal tumors. AB - It is important to establish effective methods for preventing colorectal cancer because the number of colorectal cancer deaths is increasing. Erythromycin one of the macrolide antibiotics, has been shown to exert pleiotropic effects, such as anti-inflammatory and anti-oxidative effects, on mammalian cells. In the present study, we aimed to evaluate the preventive effects of erythromycin on intestinal carcinogenesis. We first confirmed that erythromycin suppresses the transcriptional activity of nuclear factor-kappaB and activator protein-1 and the expression of its downstream targets, interleukin-6 and cyclooxygenase-2 in human colon cancer cells. Next, we fed 5-week-old male Apc mutant Min mice with diets containing 500 ppm erythromycin for 15 weeks. Erythromycin treatment significantly reduced the number of proximal intestinal polyps to 70.9% of the untreated control value. Moreover, erythromycin reduced the levels of interleukin 6 and cyclooxygenase-2 mRNA expression in intestinal polyps. Although the levels of hepatic NADPH oxidase mRNA were decreased, erythromycin treatment did not affect the levels of oxidative stress markers, reactive carbonyl species, in the liver of Min mice. Our results suggest that erythromycin suppresses intestinal polyp development in Min mice, in part by attenuating local inflammation, and indicate that erythromycin is useful as a chemopreventive agent. PMID- 28584402 TI - Effects of patient age and choice of antisecretory agent on success of eradication therapy for Helicobacter pylori infection. AB - The effects of patient age on the efficacy of eradication treatment for Helicobacter pylori (H. pylori) remain unclear. The present study aimed to determine whether age affects eradication therapy involving vonoprazan, a novel potassium-competitive acid blocker (PCAB). We reviewed the cases of 3,261 patients who were administered first-line and second-line H. pylori eradication therapy at Toyoshima Endoscopy Clinic. The first-line treatment was clarithromycin and amoxicillin combined with a proton pump inhibitor (PPI) or a PCAB. The second-line treatment was metronidazole and amoxicillin combined with a PPI or PCAB. The patients were divided into a young to middle-aged group (age <=50 years) and an older group (age >50 years) as well as into PPI and PCAB groups. The PPI-clarithromycin-amoxicillin regimen demonstrated a significantly lower H. pylori eradication rate than the PCAB-clarithromycin-amoxicillin regimen (p<0.001). With the PPI-clarithromycin-amoxicillin regimen, the eradication rate in the young to middle-aged group was significantly lower than that in the older group (p<0.001). Lastly, age had no impact on the eradication rate of PCAB-based therapy or metronidazole-based therapy. In conclusion, with clarithromycin-based triple therapy, PCAB is a better choice of antisecretory agent compared to PPIs, especially in young to middle-aged patients. PMID- 28584403 TI - Increase of transient lower esophageal sphincter relaxation associated with cascade stomach. AB - We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0-60 min), late period (60-120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying. PMID- 28584405 TI - Gastric atrophy prevent from incidence of duodenal tumor? PMID- 28584404 TI - The alpha-glucosidase inhibitor voglibose stimulates delayed gastric emptying in healthy subjects: a crossover study with a 13C breath test. AB - The gastrointestinal effects of alpha-glucosidase inhibitors have not been sufficiently investigated. The aim of this study was to determine whether a single dose of pre-prandial voglibose might affect the rate of gastric emptying, determined using the 13C breath test. Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted overnight and received 0.2 mg voglibose or a placebo 2 h before a test meal. They were then served a liquid test meal consisting of 200 kcal per 200 ml that contained 100 mg 13C-acetate. Breath samples were collected under both conditions until 150 min after the meal. A comparison of the control and voglibose conditions revealed that for gastric emptying rates (with values expressed as median: range), T1/2 [(87.9: 78.0-104.9 min) vs (88.4: 74.3-106.3 min), p = 1], Tlag [(47.1: 39.6-60.1 min) vs (45.4: 31.2-63.3 min), p = 0.432], beta [(1.89: 1.68-2.18) vs (1.90: 1.35 2.15), p = 0.846] and kappa [(0.81: 0.71-0.98) vs (0.81: 0.50-0.94), p = 0.922] did not significantly differ between conditions. A significant difference between the control and voglibose conditions was found for the GEC [(4.28: 4.09-4.44) vs (4.06: 3.69-4.50), p = 0.0138]. In conclusion, this study demonstrated that the ingestion of oral voglibose led to delayed gastric emptying of a liquid meal. PMID- 28584407 TI - Leaching of Conductive Species: Implications to Measurements of Electrical Resistivity. AB - Electrical tests have been used to characterize the microstructure of porous materials, the measured electrical response being determined by the contribution of the microstructure (porosity and tortuosity) and the electrical properties of the solution (conductivity of the pore solution) inside the pores of the material. This study has shown how differences in concentration between the pore solution (i.e., the solution in the pores) and the storage solution surrounding the test specimen leads to significant transport (leaching) of the conductive ionic species between the pore solution and the storage solution. Leaching influences the resistivity of the pore solution, thereby influencing electrical measurements on the bulk material from either a surface or uniaxial bulk resistance test. This paper has three main conclusions: 1.) Leaching of conductive species does occur with concentration gradients and that a diffusion based approach can be used to estimate the time scale associated with this change. 2.) Leaching of ions in the pore solution can influence resistivity measurements, and the ratio of surface to uniaxial resistivity can be used as a method to assess the presence of leaching and 3.) An estimation of the magnitude of leaching for standardized tests of cementitious materials. PMID- 28584406 TI - The Relationship between Psychosocial Factors and Cognition in Multiple Sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a common disorder in some regions of the world, with over 2.3 million people diagnosed worldwide. Cognitive impairment is one of the earliest symptoms to present in the course of the disease and can cause significant morbidity. We proposed a study to explore the psychosocial predictors of cognitive impairment in MS patients in Saudi Arabia, a previously unexplored patient population. METHODS: Demographic data, depression scale (PHQ9), symptom burden (PHQ15), anxiety (GAD7), disease duration, and Montreal Cognitive Assessment (MOCA) scores were collected from 195 patients in a neurology clinic in Ryiadh, Saudi Arabia. Univariate and multiple regression analyses were conducted to identify variables that are significantly associated with cognitive impairment. RESULTS: Variables that were identified to be significantly associated with cognition, p < 0.05, were education level, disease duration, and family history. DISCUSSION: Both education level and disease duration were variables identified in previous studies. We showed family history to be a significant variable, and no association was found with depression or anxiety, which is unique to our study population. CONCLUSIONS: We identified several psychosocial predictors that are associated with cognition in our patient population. It was also noted that a difference exists between patient populations, highlighting the need for further studies in specific geographical regions. PMID- 28584409 TI - Neurological Outcomes Following Suicidal Hanging: A Prospective Study of 101 Patients. AB - CONTEXT: Survivors of suicidal hanging can have variable neurological outcomes - from complete recovery to irreversible brain damage. Literature on the neurological outcomes in these patients is confined to retrospective studies and case series. Hence, this prospective study was carried out. AIMS: The aim is to study the neurological outcomes in suicidal hanging. SETTINGS AND DESIGN: This was a prospective observational study carried out from July 2014 to July 2016. SUBJECTS AND METHODS: Consecutive patients admitted to the emergency and medicine wards were included in the study. Details of the clinical and radiological findings, course in hospital and at 1 month postdischarge were analyzed. STATISTICAL ANALYSIS USED: Statistical analysis was performed using IBM SPSS advanced statistics 20.0 (SPSS Inc., Chicago, USA). Univariate analysis was performed using Chi-square test for significance and Odd's ratio was calculated. RESULTS: Of the 101 patients, 6 died and 4 had residual neuro deficits. Cervical spine injury was seen in 3 patients. Interestingly, 39 patients could not remember the act of hanging (retrograde amnesia). Hypotension, pulmonary edema, Glasgow coma scale (GCS) score <8 at admission, need for mechanical ventilation, and cerebral edema on plain computed tomography were more in those with amnesia as compared to those with normal memory and these findings were statistically significant. CONCLUSIONS: Majority of patients recovered without any sequelae. Routine imaging of cervical spine may not be warranted in all patients, even in those with poor GCS. Retrograde amnesia might be more common than previously believed and further studies are needed to analyze this peculiar feature. PMID- 28584408 TI - Early Life Stress: Effects on the Regulation of Anxiety Expression in Children and Adolescents. AB - This study examined children's (N = 79; 9-10 years) and adolescents' (N = 82; 15 16 years) ability to regulate their emotion expressions of anxiety as they completed a modified version of the Trier Social Stress Test for Children (TSST C). Approximately half in each age group were internationally adopted from institutional care (N = 79) and half were non-adopted, age-matched peers (N = 82). Institutional care was viewed as a form of early life stress. Coders who were reliable and blind to group status watched videos of the session to assess anxiety expressions using the Child and Adolescent Stress and Emotion Scale developed for this study. Children exhibited more expressions of anxiety than adolescents, and youth adopted from institutions showed more expressions of anxiety than their non-adopted counterparts. The role of early life stress on observed anxiety expressions remained significant after controlling for differences in age, physiological stress responses measured through salivary cortisol reactivity, and self-reports of stress during the TSST-C. This suggests possible deficits in the regulation of expressive behavior for youth with early life stress histories, which cannot be explained by experiencing the task as more stressful. PMID- 28584410 TI - Essentials of dental photography. PMID- 28584411 TI - Effectiveness of hyperbaric oxygen therapy in irradiated maxillofacial dental implant patients: A systematic review with meta-analysis. AB - The significantly higher implant failure rates in maxillofacial patients, undergoing radiotherapy, might be caused by the long-term effects of reduced vascularization compromising the implantation site. An extensive preclinical animal literature and a multitude of clinical reports suggest the use of hyperbaric oxygen (HBO) therapy as it can improve the tissue vascularity. Hence, it may increase the implant survival rate by enhancing osseointegration process in such patients. The objective of this systematic review was to investigate the effectiveness of HBO therapy on dental implant survival rate in irradiated maxillofacial patients who require prosthodontic rehabilitation. An electronic search without time restrictions was undertaken in April 2016 using databases: PubMed, Google Scholar, and the Cochrane Oral Health Group Trials Register. We also tried to contact the manufacturers and researchers in the field for necessary details. Clinical human studies, on irradiated maxillofacial dental implant patients, including randomized controlled trials (RCTs), prospective controlled trials, retrospective studies, and preliminary reports were included in the study. Data collection was carried out by two of the authors' independently. The titles and abstracts of all reports were screened for the study design and type of reported intervention; all the duplicates were removed. The data search yielded 62 titles, out of which 14 articles were selected for the study by the article filtration criteria: Title/abstract/full text. Data which were extracted by two authors with any disagreement were resolved by the third author, and a meta-analysis was done using binary random-effect model. The results show decreased implant failure rate in HBO group (9.21%) compared to non HBO group (22.44%). The potential limitations of this study are amount of radiation doses used, period lasting from radiotherapy to the placement of the implants, and follow-up period which varies for every subject of the included study, which can affect the treatment outcome. Although there are many sensitive articles published about HBO, including a number of review papers, RCTs are still lacking. According to the statistical analysis, it can be concluded that preventive HBO therapy can reduce the risk of implant failures in irradiated patients by 1.21 (relative risk) with 95% confidence interval (P < 0.001). Hence, HBO can be the effective treatment protocol for the implant treatment in irradiated maxillofacial patients. PMID- 28584412 TI - Demineralized dentin matrix scaffolds for alveolar bone engineering. AB - From the point of view of implant dentistry, this review discusses the development and clinical use of demineralized dentin matrix (DDM) scaffolds, produced from the patient's own extracted teeth, to repair alveolar bone defects. The structure and the organic and inorganic components of DDM are presented to emphasize the similarities with autogenous bone. Studies of DDM properties, such as osteoinductive and osteoconductive functions as well as efficacy and safety, which are mandatory for its use as a bone graft substitute, are also presented. The clinical applications of powder, block, and moldable DDM are discussed, along with future developments that can support growth factor and stem cell delivery. PMID- 28584414 TI - Impact of interprofessional education module on attitudes of health-care providers involved in maxillofacial rehabilitation: A cross-sectional study. AB - PURPOSE: Rehabilitation of maxillofacial deformities is a challenging task because it involves not only a lot of skills and expertise but also many disciplines working in unison for optimum outcome. However, more often than not a prosthodontist is not a member of tumor board and consulted after surgery which affects the prognosis of the rehabilitation adversely. There was a perceived need to create awareness among referring surgeons and physicians, and interprofessional education (IPE) initiatives were deemed necessary to improve this collaboration. METHODOLOGY: Four-hour IPE module was developed involving residents and faculty from three disciplines. The change in attitudes was evaluated quantitatively using Attitudes toward Health Care Teams questionnaire both before and after the module. Semi-structured interviews with selected participants provided the qualitative feedback. RESULTS: The questionnaire consisted of 14 questions answered on 5-point Likert scale (1-5). The mean score of pretest was 44.2 and of posttest was 49.1. Difference was statistically significant (P < 0.05). Higher score indicates better attitude. CONCLUSION: A brief IPE program can improve interprofessional attitudes and collaborative behavior of health-care professionals involved in maxillofacial rehabilitation. It enables the professionals to understand interact and share viewpoints regarding most critical issues faced by them and find solutions to achieve best possible patient care. PMID- 28584413 TI - Idiopathic condylar resorption: The current understanding in diagnosis and treatment. AB - Idiopathic condylar resorption (ICR) is a condition with no known cause, which manifests as progressive malocclusion, esthetic changes, and often pain. Cone beam computed tomography and magnetic resonance imaging are the most valuable imaging methods for diagnosis and tracking, compared to the less complete and more distorted images provided by panoramic radiographs, and the higher radiation of 99mtechnetium-methylene diphosphonate. ICR has findings that overlap with osteoarthritis, inflammatory arthritis, physiologic resorption/remodeling, congenital disorders affecting the mandible, requiring thorough image analysis, physical examination, and history-taking. Correct diagnosis and determination of whether the ICR is active or inactive are essential when orthodontic or prosthodontic treatment is anticipated as active ICR can undo those treatments. Several treatments for ICR have been reported with the goals of either halting the progression of ICR or correcting the deformities that it caused. These treatments have varying degrees of success and adverse effects, but the rarity of the condition prevents any evidence-based recommendations. PMID- 28584415 TI - A comparison of peri-implant strain generated by different types of implant supported prostheses. AB - AIMS AND OBJECTIVE: To find out and compare peri implant strain developed in four different types of implant supported prostheses i.e., cement retained splinted, cement retained non splinted, screw retained splinted, screw retained non splinted. METHODOLOGY: Four implant analogues were placed in a polyurethane mandibular model at the position of left and right first and second molar. Abutments were fixed to the implant at a torque of 25Ncm. Two such models were made. Four different prostheses were placed on abutment of each model i.e screw retained splinted, screw retained nonsplinted, cement retained splinted, cement retained non splinted. Four strain gauges were attached on the model, two on the buccal and two on the lingual aspect of each implant. Static load of 400N was applied on the prosthesis using universal testing machine. Load application was done ten times for each model and peri implant strain was measured. RESULTS: The mean peri implant strain (+/-SD) generated was found to be highest in non splinted screw retained (1397.70 +/- 44.47 microstrains and 1265.90 +/- 42.76 microstrains) and least in splinted cement retained (630.70 +/- 31.98 microstrains and 519.60 +/- 32.48 microstrains) in both 1st and 2nd molars respectively. CONCLUSIONS: Splinted crowns produce less peri implant strain when compared to non splinted crowns. Cement retained prosthesis produce less peri implant strain when compared to screw retained prosthesis. Least strain was observed in cement retained splinted crowns. PMID- 28584416 TI - Effect of comonomer of methacrylic acid on flexural strength and adhesion of Staphylococcus aureus to heat polymerized poly (methyl methacrylate) resin: An in vitro study. AB - AIMS AND OBJECTIVE: The purpose of the present study was to evaluate and compare flexural strength and Staphylococcus aureus adhesion of heat-activated poly (methyl methacrylate [MMA]) resin modified with a comonomer of methacrylic acid (MAA) and MMA monomer. MATERIALS AND METHODS: Comonomer preparation was done with the addition of varying concentration of MAA (0, 15, 20, and 25 wt %) to the MMA of conventional heat-activated denture base resin to prepare the specimens. Prepared specimens were stored in distilled water at 37 degrees C for 1 day and 1 week before the evaluation of flexural strength and microbial adhesion. Flexural strength was measured using a universal testing machine at a crosshead speed for 2 mm/min (n = 10). Microbial adhesion (colony-forming unit [CFU]) was evaluated against S. aureus using a quadrant streaking method (n = 5). Data were subjected to one-way ANOVA, and the significant differences among the results were subjected to Tukey's HSD test. P < 0.05 was considered statistically significant. RESULTS: Addition of MAA to the MMA monomer was found to significantly reduce the adhesion of S. aureus for all the groups. Reduction of CFU of S. aureus was found be more significant for Group 3 as compared to control, both at 1-day (P < 0.001) and 1-week (P < 0.002) storage in distilled water. However, no statistically significant changes in the flexural strength were observed with the addition of MAA at 1-day (P = 0.52) and 1-week (P = 0.88) time interval. CONCLUSION: Addition of MAA to conventional denture base resin reduced the microbial adhesion without significantly affecting the flexural strength. PMID- 28584417 TI - Effect of smoking status and nicotine dependence on pain intensity and outcome of treatment in Indian patients with temporomandibular disorders: A longitudinal cohort study. AB - PURPOSE: Evidence regarding the association of smoking with various forms of chronic musculoskeletal pain is vast, but that with temporomandibular disorders (TMD) is scarce. AIMS: The aims of this study are to evaluate the effect of smoking status (SS) and nicotine dependence (ND) on TMD pain intensity and treatment outcome in an Indian population with TMD. SUBJECTS AND METHODS: Nine hundred and sixty-two patients with TMD were selected for this longitudinal cohort study. Lifetime SS was evaluated and patients were classified as current smokers (YS), former smokers (FS), or nonsmokers (NS). The Fagerstrom test was used to evaluate the ND of YS. Pain intensity was evaluated using visual analog scale scores. Six months posttreatment, the pain intensity was again recorded. The effect of treatment was evaluated using a global transition outcome measure and categorized as treatment success or failure. A minimum 30% reduction in pain was used as a criterion for categorizing patients as those who had gotten "better." Data obtained from the study were compared using Chi-square tests, paired samples t-tests, and one-way ANOVA tests. The criterion for statistical significance for all analyses was set at P = 0.05. RESULTS: Among groups of SS, YS showed the maximum pain intensity at baseline and posttreatment. The outcome of treatment was most successful in NS and least in FS. The number of patients who had gotten "better" after treatment was significantly highest in NS. There was no significant difference between groups of ND with respect to pain intensity, treatment outcome, or "better" patients. CONCLUSIONS: Among Indian patients with TMD, smokers reported significantly greater pain intensity and poorer response to treatment than NS. Pain intensity or treatment outcome was independent of ND. PMID- 28584418 TI - Comparison of osteogenic potential of poly-ether-ether-ketone with titanium coated poly-ether-ether-ketone and titanium-blended poly-ether-ether-ketone: An in vitro study. AB - STATEMENT OF PROBLEM: Poly-ether-ether-ketone (PEEK), a high-performance semi crystalline thermoplastic polymer, has been employed to replace the metallic implant components in orthopedics. There were various studies performed in accordance to medical grade PEEK, but the relationship between titanium dioxide (TiO2)-coated PEEK, TiO2-blended PEEK, and untreated PEEK still remains complicated, even undefined. PURPOSE: The purpose of this study was to compare and quantify the osteogenic potential of untreated PEEK, TiO2-coated PEEK and TiO2-blended PEEK. MATERIALS AND METHODS: Three groups with ten samples in each group were designed for this study. They were Group 1 - Untreated PEEK, Group 2 - TiO2-coated PEEK, Group 3 - TiO2-blended PEEK. The PEEK samples were prepared according to the ISO standard 15309:2013 and milled to size of 15 mm * 2 mm, and the surfaces were finished with grit-blasted alumina of size 20 MUm. In this 10 samples were chosen for Group 1. Group 2 samples were prepared by coating TiO2 nanoparticles by arc ion plating, and Group 3 samples were prepared by blending TiO2 nanoparticles in HAAKE rheocord with degree of blending analyzed by torque rheometer. These samples were tested for cytotoxicity using human osteosarcoma cells, and alkaline phosphatase (ALP) activity was performed to evaluate and quantify the bone mineralization process. The cross-sectional and the fracture morphology of coatings was observed by a field emission scanning electron microscope (SEM) with the magnification range *20-*200,000. RESULT: Results of cytotoxicity assay and ALP assay of Group 1, Group 2, and Group 3 were statistically analyzed. SEM analysis result clearly showed the difference in the matrix before and after cell adhesion. CONCLUSION: The results made it evident that n-TiO2-coated PEEK was more versatile biomaterial of choice in implant dentistry followed by n-TiO2-blended PEEK and untreated PEEK. PMID- 28584419 TI - A comparative study to correlate between clinically and radiographically determined sagittal condylar guidance in participants with different skeletal relationships. AB - CONTEXT: Many authors have conducted studies that determine horizontal condylar guidance (HCG) using various methods, articulator systems, and recording materials. However, there is a dearth of literature on variability existing in HCG in individuals with different skeletal relationships. This study is an attempt to verify whether such a difference exists or not. AIMS: The aim of this study is to determine and correlate the HCG in individuals with Angle's Class I, Class II, and Class III malocclusion using radiographic and clinical methods. SETTINGS AND DESIGN: HCG was recorded for thirty individuals, ten of each class. For each individual, HCG was recorded clinically as well as radiographically. SUBJECTS AND METHODS: Clinically, HCG was recorded using protrusive check bites and a semi-adjustable articulator. Radiographically, two methods were employed. First, a "tangent method" wherein the angle made by a tangent to the posterior slope of articular eminence with the Frankfurt horizontal (FH) plane was considered as the HCG, and second, a "protrusive method" where the position of the condyle at maximum intercuspation and 6 mm protrusion were traced, and the angle this path made with the FH plane was recorded as the HCG. STATISTICAL ANALYSIS: Descriptive statistical analysis along with Tukey's test and analysis of variance was used to calculate and compare the mean values. Pearson correlation coefficient was used to establish correlation between various means. RESULTS: A significant difference in the HCG of three skeletal relationships was seen, with Class II having a steeper angle than the other two. Among the various methods used, a correlation was found between the clinical and the protrusive method; however, the tangent method yielded greater values of HCG. CONCLUSIONS: The average value of HCG should not be used as it differs according to the skeletal relationship. Radiographic method can be used to yield consistent HCG; however, the protrusive method should be employed. PMID- 28584420 TI - Comparison of temperature change among different adhesive resin cement during polymerization process. AB - PURPOSE: The aim of this study was to assess the intra-pulpal temperature changes in adhesive resin cements during polymerization. MATERIALS AND METHODS: Dentin surface was prepared with extracted human mandibular third molars. Adhesive resin cements (Panavia F 2.0, Panavia SA, and RelyX U200) were applied to the dentin surface and polymerized under IPS e.max Press restoration. K-type thermocouple wire was positioned in the pulpal chamber to measure temperature change (n = 7). The temperature data were recorded (0.0001 sensible) and stored on a computer every 0.1 second for sixteen minutes. Differences between the baseline temperature and temperatures of various time points (2, 4, 6, 8, 10, 12, 14, and 16 minute) were determined and mean temperature changes were calculated. At various time intervals, the differences in temperature values among the adhesive resin cements were analyzed by two-way ANOVA and post-hoc Tukey honestly test (alpha = 0.05). RESULTS: Significant differences were found among the time points and resin cements (P < 0.05). Temperature values of the Pan SA group were significantly higher than Pan F and RelyX (P < 0.05). CONCLUSION: Result of the study on self-adhesive and self-etch adhesive resin cements exhibited a safety intra-pulpal temperature change. PMID- 28584422 TI - An innovative and simple approach to fabricate a hollow ocular prosthesis with functional lubricant reservoir: A solution to artificial eye comfort. AB - The loss of an eye is an emotional and psychological setback to the patient. An ocular prosthesis is created to restore the lost anatomical structure and to correct the cosmetic defect. The tear reflexes do not function at optimal levels in anophthalmic sockets which make prosthesis wear uncomfortable. This case report presents an innovative hollow ocular prosthesis with functional lubricant reservoir which upon normal blinking would draw the lubricant from the reservoir through an exit hole which spreads over the prosthesis allowing a comfortable and long duration of prosthesis wear. PMID- 28584421 TI - Effect of isobutyl methacrylate and methacrylic acid eluted from chairside denture hard reliners on enzymatic cellular antioxidants: An in vitro study in human primary buccal mucosal fibroblasts. AB - AIM: This study was conducted with the objective to evaluate the cytotoxicity of monomers isobutyl methacrylate (IBMA) and methacrylic acid (MA) in human buccal mucosal fibroblast primary cell culture and to study their effect on cellular enzymatic antioxidants-glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). MATERIALS AND METHODS: The tissue for fibroblast cell culture was harvested from oral buccal mucosa of a healthy donor. Fibroblast cells were plated at a density of 1 * 104 cells per well in 96-well tissue culture plates. Cells were exposed to various concentrations of IBMA and MA. The cell viability and various enzyme activities were evaluated 24 h after exposure to the above treatments. All tests were done in triplicate. Cell viability was assessed by trypan blue dye exclusion assay and all enzyme activities were done using assay kits from Cayman Chemicals, Ann Arbor, USA. RESULTS: At all concentrations tested a statistically significant decrease in viability was observed in IBMA- and MA treated cells. Around 42% cells were viable at the highest test concentration of IBMA (80 MUmol/L) and only 20% cells were viable at the highest dose (144 MUmol/L) of MA exposure (P < 0.05). Dose-dependent decrease in the GPx and SOD activities was observed in cells treated with IBMA and MA (P < 0.05). CAT activity was not detectable in the controls. However, a fall in CAT activity was detected in cells exposed to IBMA and MA at all concentrations tested (P < 0.05). CONCLUSION: IBMA and MA leaching out from the chairside denture hard reliners are cytotoxic on human buccal fibroblast primary cell cultures. This could be due to the oxidative stress caused by the generation of reactive oxygen species which is evidenced by the fall in activities of antioxidant enzymes (GPx, SOD, and CAT) and cytotoxicity. PMID- 28584423 TI - Managing maxillary proclination with novel designed angulated implants. AB - Implant-supported removable dental prostheses may be supported by a variety of splinted (bar and clip) attachment systems or nonsplinted abutment-based attachments (ball, magnets, and resilient stud attachments such as locators [Zest Anchors], ERA [Sterngold], and nonresilient-stud attachments such as ANKYLOS SynCone [Dentsply Implants]). Nonsplinted attachments are preferred as they are more economical, less technique sensitive, easier to clean, repair, and maintain than splinted (bar and clip) attachment systems, but they work favorably only when implants in the arch are placed parallel to each other. Often implants in the anterior maxilla have to be placed with a labial inclination (due to the proclination of the premaxilla), resulting in lack of parallelism between the anterior and posterior implants, making it challenging to fabricate a removable dental prostheses supported by nonsplinted attachments, and necessitating the use of angled abutments. Recently, a novel implant design with a 12 degrees restorative platform angulation has been introduced by Southern Implants (Co axis, Keystone Dental, Inc., Burlington, MA, USA). These new angulated implants aid in minimizing the divergence between the anterior and posterior maxillary implants without using angled abutments. The purpose of this article was to report a case utilizing the novel angulated implants (Co-axis, Keystone Dental, Inc., Burlington, MA, USA) in the premaxilla for fabrication of maxillary removable dental prostheses supported and retained by nonsplinted attachments. PMID- 28584424 TI - Two-piece obturator using "lock-and-key" mechanism. AB - This paper describes a method used for the fabrication of a two-piece denture obturator for a patient who had surgical removal of the premaxilla due to squamous cell carcinoma. The patient had been wearing a two-piece obturator but encountered difficulty in inserting the prosthesis. In this case report, a lock and-key mechanism was used to easily assemble the two-piece prosthesis intraorally. A keyhole was designed on the obturator to act as the lock while the denture was used as the key that fitted into the keyhole. This mechanism facilitated insertion and provided retention for the prosthesis. Heat-cured resilient acrylic material (Molloplast B(r)), which was used to fabricate the obturator, was a nonirritant, nontoxic, tissue-compatible material. It also did not contain plasticizers, therefore eliminating the problems associated with leaching out of plasticizers. The use of this flexible and resilient material allowed the obturator to engage in the undercuts without causing trauma and irritation to the soft tissues in the region of the defect. To conclude, the "lock-and-key" mechanism used in the fabrication of the two-piece denture obturator provided the patient with a lightweight, comfortable, and user-friendly form of prostheses. PMID- 28584425 TI - Osseo integrated finger prosthesis with a custom abutment. AB - One of the most regularly encountered forms of partial hand loss causing physical, psychosocial and financial burden to an individual is the finger amputation followed by trauma. The prosthetic rehabilitation of amputated finger is a good treatment option, when compared to all other means of complex and unaffordable options. Osseointegrated implant retained silicone finger prosthesis with innovative prosthetic designs can provide the patient a life changing experience. PMID- 28584426 TI - Use of Nutrition Risk in Critically ill (NUTRIC) Score to Assess Nutritional Risk in Mechanically Ventilated Patients: A Prospective Observational Study. AB - CONTEXT: Nutritional risk assessment must be done on all critically ill patients. Malnutrition in intensive care unit (ICU) patients is associated with adverse clinical outcomes. Traditional scoring systems cannot be used for screening in mechanically ventilated (MV) patients because these patients are unable to provide information on their history of food intake and weight loss. The Nutrition Risk in Critically ill (NUTRIC) score is the appropriate nutritional assessment tool in MV patients. AIMS: This prospective observational study was conducted to identify the nutritional risk in MV patients using modified NUTRIC (mNUTRIC) score (with the exception of interleukin-6). PATIENTS AND METHODS: All adult patients admitted to the ICU and required MV for more than 48 h were included in the study. Data were collected on variables required to calculate mNUTRIC score. Patients with mNUTRIC score >=5 are considered at nutritional risk. Outcome data were collected on ICU length of stay, ventilator-free days, and mortality. RESULTS: A total of 678 MV patients fit into the inclusion criteria. Majority of the patients were male (67%). Mean age of the patients was 55 years. About 288 (42.5%) patients were at high nutritional risk (mNUTRIC score >=5). Patients with high mNUTRIC score >=5 had longer mean ICU average length of stay of 9.0 (+/-4.2) versus 7.8 (+/-5.8) mean (+/- standard deviation) days (P < 0.01) and higher mortality 41.4% versus 26.1% (P < 0.0) compared to patients with low NUTRIC score (<=4). High mNUTRIC score (>=5) predicted mortality with area under the curve of 0.582 (95% confidence interval 0.535-0.628). CONCLUSIONS: Nearly 42.5% of MV patients admitted to ICU were at nutritional risk, and high mNUTRIC score was associated with increased ICU length of stay and higher mortality. PMID- 28584427 TI - Reliability of Ultrasonography in Confirming Endotracheal Tube Placement in an Emergency Setting. AB - BACKGROUND AND OBJECTIVES: Over the past few years, ultrasonography is increasingly being used to confirm the correct placement of endotracheal tube (ETT). In our study, we aimed to compare it with the traditional clinical methods and the gold standard quantitative waveform capnography. Two primary outcomes were measured in our study. First was the sensitivity and specificity of ultrasonography against the other two methods to confirm endotracheal intubation. The second primary outcome assessed was the time taken for each method to confirm tube placement in an emergency setting. METHODS: This is a single-centered, prospective cohort study conducted in an emergency department of a tertiary care hospital. We included 100 patients with indication of emergency intubation by convenient sampling. The intubation was performed as per standard hospital protocol. As part of the study protocol, ultrasonography was used to identify ETT placement simultaneously with the intubation procedure along with quantitative waveform capnography (end-tidal carbon dioxide) and clinical methods. Confirmation of tube placement and time taken for the same were noted by three separate health-care staffs. RESULTS AND DISCUSSION: Out of the 100 intubation attempts, five (5%) had esophageal intubations. The sensitivity and specificity of diagnosis using ultrasonography were 97.89% and 100%, respectively. This was statistically comparable with the other two modalities. The time taken to confirm tube placement with ultrasonography was 8.27 +/- 1.54 s compared to waveform capnography and clinical methods which were 18.06 +/- 2.58 and 20.72 +/- 3.21 s, respectively. The time taken by ultrasonography was significantly less. CONCLUSIONS: Ultrasonography confirmed tube placement with comparable sensitivity and specificity to quantitative waveform capnography and clinical methods. But then, it yielded results considerably faster than the other two modalities. PMID- 28584428 TI - A Pilot Randomized Controlled Trial of Comparison between Extended Daily Hemodialysis and Continuous Veno-venous Hemodialysis in Patients of Acute Kidney Injury with Septic Shock. AB - AIM OF STUDY: Acute kidney injury (AKI) is common in patients of septic shock. There is sparse data comparing sustained low-efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT) in patients with septic shock. MATERIALS AND METHODS: This is a prospective randomized study in a 12-bedded medical intensive care unit. After clearance from institute's ethics committee and obtaining informed consent from the relatives, sixty adult patients with septic shock who were to undergo dialysis for AKI were included in the study. They were randomly assigned to SLED or CRRT group. Hemodynamic instability was defined as in terms of vasopressor dependency (VD). The worst value of VD during the dialysis session was taken into consideration. The primary objective was look at hemodynamic changes and secondarily into the efficacy. RESULTS: The demographic data were comparable between the sixty patients randomized to thirty in each group. Delta VD and delta vasopressor index (DVI) were similar in SLED group compared to the CRRT group. CRRT group had better efficacy in terms of both equivalent renal urea clearance though fluid balance was not significantly better in CRRT group. CONCLUSION: SLED is a viable modality of renal replacement therapy in patients with septic shock as the hemodynamic effects are similar to CRRT. PMID- 28584429 TI - Thromboelastography for Evaluation of Coagulopathy in Nonbleeding Patients with Sepsis at Intensive Care Unit Admission. AB - BACKGROUND: Thromboelastography (TEG) is a global test of coagulation which analyzes the whole coagulation process. TEG is popular in trauma, liver transplant, and cardiac surgeries, but studies in sepsis are limited. We have assessed the utility of TEG for evaluating coagulopathy in nonbleeding patients with sepsis. MATERIALS AND METHODS: A prospective, observational study was done in 12-bedded Intensive Care Unit (ICU) of a tertiary care hospital in North India, during May 2014-November 2014. After ethical clearance, all patients at ICU admission with sepsis were included in the study. Exclusion criteria were age <18 years, plasma/platelet transfusion before admission, patients on oral antiplatelets/anticoagulants, or with underlying hematological disorders. At admission, blood samples for TEG were analyzed by kaolin-based TEG analyzer within an hour of collecting 2.7 ml citrated blood from arterial line. TEG parameters included reaction time (R), K time (K), alpha angle (a), maximum amplitude (MA), coagulation index (CI), and lysis index (LY 30). RESULTS: In TEG, mean values of R, K, a, MA, CI, and LY30 were 6.45 +/- 2.59 (min), 1.67 +/- 0.96 (min), 66.37 +/- 10.44 (0), 67.08 +/- 10.33 (mm), 0.63 +/- 3.46, and 2.23 +/- 4.08 (%), respectively. In conventional coagulation assay (CCA), mean values of international normalized ratio (INR), platelet, and fibrinogen were 1.63 +/- 0.57, 153.96 +/- 99.16 (*103 /mm3), and 301.33 +/- 112.82 (mg/dl), respectively. In those with deranged INR (INR >=1.6), 60% were normocoagulable and 20% were hypercoagulable. Similarly, 81% patients with thrombocytopenia (platelet count <1,00,000/mL) were normocoagulable. CONCLUSION: TEG could differentiate among normocoagulant, hypocoagulant, hypercoagulant states (unlike CCAs). Patients with septic shock had trend toward hypocoagulant state while those without shock had trend toward hypercoagulant state. PMID- 28584430 TI - The Benefit of Benzodiazepine Reduction: Improving Sedation in Surgical Intensive Care. AB - AIMS: Sedation, as it is often required in critical care, is associated with immobilization, prolonged ventilation, and increased morbidity. Most sedation protocols are based on benzodiazepines. The presented study analyzes the benefit of benzodiazepine-free sedation. METHODS: In 2008, 134 patients were treated according to a protocol using benzodiazepine and propofol (Group 1). In 2009, we introduced a new sedation strategy based on sufentanil, nonsteroidal anti inflammatory drugs, neuroleptics, and antidepressants, which was applied in 140 consecutive patients (Group 2). Depth of sedation, duration of mechanical ventilation, duration of Intensive Care Unit, and hospital stay were analyzed. RESULTS: Group 1 had both a longer duration of deep sedation (18.7 +/- 2.5 days vs. 12.6 +/- 1.85 days, P = 0.031) and a longer duration of controlled ventilation (311, 35 +/- 32.69 vs. 143, 96 +/- 20.76 h, P < 0.0001) than Group 2. Ventilator days were more frequent in Group 1 (653, 66 +/- 98.37 h vs. 478, 89 +/ 68.92 h, P = 0.128). CONCLUSIONS: The benzodiazepine-free sedation protocol has been shown to significantly reduce depth of sedation and controlled ventilation. Additional evidence is needed to ascertain reduction of ventilator days which would not only be of benefit for the patient but also for the hospital Management. PMID- 28584431 TI - Hospital-acquired Infection: Prevalence and Outcome in Infants Undergoing Open Heart Surgery in the Present Era. AB - BACKGROUND: The aim of this study is to evaluate the causal relation between hospital-acquired infection (HAI) and clinical outcomes following cardiac surgery in neonates and infants and to identify the risk factors for the development of HAI in this subset of patients. MATERIALS AND METHODS: After Ethics committee approval, one hundred consecutive infants undergoing open heart surgery (OHS) between June 2015 and June 2016 were included in this prospective observational study. Data were prospectively collected. The incidence and distribution of HAI, the microorganisms, their antibiotic resistance and patients' outcome were determined. The Centers for Disease Control and Prevention criteria were used for defining HAIs. Univariate and multivariate risk factor analysis was done using Stata 14. RESULTS: Sixteen infants developed microbiologically documented HAI after cardiac surgery. Neonatal age group was found to be most susceptible. Lower respiratory tract infections accounted for majority of the infections (47.4%) followed by bloodstream infection (31.6%), urinary tract infection (10.5%), and surgical site infection (10.5%). Klebsiella (36.8%) and Acinetobacter (26.3%) were the most frequently isolated pathogens. HAI was associated with prolonged ventilation duration (P = 0.005), Intensive Care Unit stay (P = 0.0004), and hospital stay (P = 0.002). Multivariate risk factor analysis revealed that preoperative hospital stay (odds ratio [OR] 1.22, 95% confidence interval (CI) 1.6-1.39, P = 0.004), and prolonged cardiopulmonary bypass (CPB) (OR 1.03, 95% CI 1.01-1.05, P = 0.001) were associated with the development of HAI. CONCLUSION: HAI still remains a dreaded complication in infants after OHS and contributing to morbidity and mortality. Strategies such as decreasing preoperative hospital stay, CPB time, and early extubation should be encouraged to prevent HAI. PMID- 28584432 TI - The Effect of High-dose Parenteral Sodium Selenite in Critically Ill Patients following Sepsis: A Clinical and Mechanistic Study. AB - INTRODUCTION: Severe sepsis and septic shock is characterized by inflammation and oxidative stress. Selenium levels have been reported to be low due to loss or increased requirements during severe sepsis and septic shock. We investigated the effect of high-dose parenteral selenium administration in septic patients. METHODS: A prospective, randomized control clinical trial was performed in septic patients. After randomization, patients in selenium group received high-dose parenteral sodium selenite (2 mg intravenous [IV] bolus followed by 1.5 mg IV continuous infusion daily for 14 days) plus standard therapy and the control group received standard therapy. The primary endpoint was mortality at 28 days. Changes in the mean levels of high mobility group box-1 (HMGB-1) protein and superoxide dismutase (SOD), duration of vasopressor therapy, incidence of acute renal failure, and 60 days' mortality were secondary endpoints. RESULTS: Fifty four patients were randomized into selenium group (n = 29) and control group (n = 25). There was no significant difference in 28-day mortality. No significant difference between the two groups with respect to the average levels of HMGB-1 protein and SOD at any point in time over the course of 14 days had observed. CONCLUSION: In early administration within the first 6 h of sepsis diagnosis, our study demonstrated that high-dose parenteral selenium administration had no significant effect either on 28-day mortality or the mean levels of HMGB-1 and SOD (Trial Registration: IRCT201212082887N4 at WHO Clinical Trial Registry, August 29, 2014). PMID- 28584433 TI - Critically Ill Obstetric Patients in a General Critical Care Unit: A 5 Years' Retrospective Study in a Public Teaching Hospital of Eastern India. AB - BACKGROUND: Critical care services are essential for the subset of obstetric patients suffering from severe maternal morbidity. Studies on obstetric critical care are important for benchmarking the issues which need to be addressed while managing critically ill obstetric patients. Although there are several published studies on obstetric critical care from India and abroad, studies from Eastern India are limited. The present study was conducted to fill in this lacuna and to audit the obstetric critical care admissions over a 5 years' period. SETTINGS AND DESIGN: Retrospective cohort study conducted in the general critical care unit (CCU) of a government teaching hospital. MATERIALS AND METHODS: The records of all obstetric patients managed in the CCU over a span of 5 years (January 2011 December 2015) were analyzed. RESULTS: During the study, 205 obstetric patients were admitted with a CCU admission rate of 2.1 per 1000 deliveries. Obstetric hemorrhage (34.64%) was the most common primary diagnosis among them followed by pregnancy-induced hypertension (26.83%). Severe hemorrhage leading to organ failure (40.48%) was the main direct indication of admission. Invasive ventilation was needed in 75.61% patients, and overall obstetric mortality rate was 33.66%. The median duration (in days) of invasive ventilation was 2 (interquartile range [IQR] 1-7), and the median length of CCU stay (in days) was 5 (IQR 3-9). CONCLUSIONS: Adequate number of critical care beds, a dedicated obstetric high dependency unit, and effective coordination between critical care and maternity services may prove helpful in high volume obstetric centers. PMID- 28584434 TI - Management of Potential Organ Donor: Indian Society of Critical Care Medicine: Position Statement. PMID- 28584435 TI - A Study of 24 Patients with Colistin-Resistant Gram-negative Isolates in a Tertiary Care Hospital in South India. AB - BACKGROUND: As the use of colistin to treat carbapenem-resistant Gram-negative infections increases, colistin resistance is being increasingly reported in Indian hospitals. MATERIALS AND METHODS: Retrospective chart review of clinical data from patients with colistin-resistant isolates (minimum inhibitory concentration >2 mcg/ml). Clinical profile, outcome, and antibiotics that were used for treatment were analyzed. RESULTS: Twenty-four colistin-resistant isolates were reported over 18 months (January 2014-June 2015). A history of previous hospitalization within 3 months was present in all the patients. An invasive device was used in 22 (91.67%) patients. Urine was the most common source of the isolate, followed by blood and respiratory samples. Klebsiella pneumoniae constituted 87.5% of all isolates. Sixteen (66.6%) were considered to have true infection, whereas eight (33.3%) were considered to represent colonization. Susceptibility of these isolates to other drugs tested was tigecycline in 75%, chloramphenicol 62.5%, amikacin 29.17%, co-trimoxazole 12.5%, and fosfomycin (sensitive in all 4 isolates tested). Antibiotics that were used for treatment were combinations among the following antimicrobials-tigecycline, chloramphenicol, fosfomycin, amikacin, ciprofloxacin, co-trimoxazole, and sulbactam. Among eight patients who were considered to have colonization, there were no deaths. Bacteremic patients had a significantly higher risk of death compared to all nonbacteremic patients (P = 0.014). CONCLUSIONS: Colistin resistance among Gram-negative bacteria, especially K. pneumoniae, is emerging in Indian hospitals. At least one-third of isolates represented colonization only rather than true infection and did not require treatment. Among patients with true infection, only 25% had a satisfactory outcome and survived to discharge. Fosfomycin, tigecycline, and chloramphenicol may be options for combination therapy. PMID- 28584436 TI - Titration of Ideal Positive End-expiratory Pressure in Acute Respiratory Distress Syndrome: Comparison between Lower Inflection Point and Esophageal Pressure Method Using Volumetric Capnography. AB - The tenets of mechanical ventilation in acute respiratory distress syndrome (ARDS) include the utilization of low tidal volume and optimal application of positive end-expiratory pressure (PEEP). Optimal PEEP in ARDS is characterized by reduction in alveolar dead space along with improvement in the lung compliance and resultant betterment in oxygenation. There are various methods of setting PEEP in ARDS. Herein, we report a patient of ARDS, wherein we employed measurement of dead space using volumetric capnography to compare two different PEEP strategies, namely, the lower inflection point and transpulmonary pressure monitoring. PMID- 28584437 TI - Severe Pediatric Acute Respiratory Distress Syndrome Due to Scrub Typhus: Successful Ventilation with Airway Pressure Release Ventilation Mode after Becoming Refractory to Protective Ventilation. AB - Scrub typhus can affect lungs from mild illness like pneumonitis to a severe illness like acute respiratory distress syndrome (ARDS). Such patients may be very challenging to treat when their hypoxemia becomes severe and refractory to treatment. Main treatment is supportive in terms of mechanical ventilation. In adult ARDS, low tidal volume (TV) ventilation has been recommended, but there is no consensus on most effective ventilation mode in children. We present a case of a 12-year-old girl who developed severe ARDS (PO2/FiO2 ratio - 58), refractory to low TV ventilation. There was a rapid improvement in oxygenation on the application of airway pressure release ventilation (APRV) mode within 1/2 h. She was successfully ventilated and weaned off the ventilator over 5 days. This case highlights the utility of APRV mode of ventilation as a rescue therapy for severe refractory ARDS in children. PMID- 28584438 TI - Neurogenic Pulmonary Edema in Traumatic Brain Injury. AB - A 29-year-old male admitted with severe traumatic brain injury following a road traffic accident was sedated and ventilated uneventfully for 72 h. On the fourth posttrauma day, after stopping sedation to assess readiness for extubation, he developed sudden onset desaturation; arterial blood gas showed severe diffusion defect with very low PaO2/FiO2 ratio following an episode of generalized tonic clonic seizure. The differential diagnoses and further management are discussed. PMID- 28584439 TI - Intentional Self-harm Human Poisoning with Agricultural Micronutrient Foliar Spray: From Rural India of Southern Karnataka. PMID- 28584440 TI - Overestimation of Cardiac Output by Bent Pulmonary Artery Catheter. PMID- 28584441 TI - Trouble Shooting a Small Sized IJV. PMID- 28584442 TI - Erratum: Changes in B-type Natriuretic Peptide and Related Hemodynamic Parameters following a Fluid Challenge in Critically ill Patients with Severe Sepsis or Septic Shock. AB - [This corrects the article on p. 117 in vol. 21, PMID: 28400680.]. PMID- 28584443 TI - Annotation of gene sequence and protein structure of brinjal EDS1. AB - Enhanced Disease Susceptibility1 (EDS1) is a nucleo-cytoplasmic protein, known to be a key regulator of plant basal defense and effector-triggered immunity. Sequence of a single copy brinjal EDS1 gene (SmEDS1) was mined from draft brinjal genome assembly. The extracted sequence was found to be incomplete and polished with the help of transcriptome sequence data. Full-length SmEDS1 gene is 4.5kb long having three exons that coded for 1.8kb mRNA. SmEDS1 protein is a 602 amino acid long protein consisting of Lipase3 and EP domain regions. Predicted tertiary structure of SmEDS1 using homology modelling had a mass of 68.8kD and was made of 10 strands, 26 alpha helices, five 310 helices and 43 beta turns. Phylogenetic analysis based on protein sequence grouped the species in clades defined by botanical family suggesting that EDS1 protein has evolved through the speciation process. Phylogenetic tree based on EDS1 structures grouped Solanum species of American origin (tomato, wild tomato and potato) together but brinjal EDS1 (Asiatic origin) occupied a unique position. In silico information generated in this study is expected to be the first step toward cloning and expression analysis of SmEDS1 gene. PMID- 28584444 TI - Quantitative Structure Activity Relationship study of the Anti-Hepatitis Peptides employing Random Forests and Extra-trees regressors. AB - Antimicrobial peptides are host defense peptides being viewed as replacement to broad-spectrum antibiotics due to varied advantages. Hepatitis is the commonest infectious disease of liver, affecting 500 million globally with reported adverse side effects in treatment therapy. Antimicrobial peptides active against hepatitis are called as anti-hepatitis peptides (AHP). In current work, we present Extratrees and Random Forests based Quantitative Structure Activity Relationship (QSAR) regression modeling using extracted sequence based descriptors for prediction of the anti-hepatitis activity. The Extra-trees regression model yielded a very high performance in terms coefficient of determination (R2) as 0.95 for test set and 0.7 for the independent dataset. We hypothesize that the developed model can further be used to identify potentially active anti-hepatitis peptides with a high level of reliability. PMID- 28584445 TI - A comparative molecular docking study of curcumin and methotrexate to dihydrofolate reductase. AB - Interaction of curcumin (CUR) with the enzyme dihydrofolate reductase (DHFR) was studied by molecular docking using AutoDock 4.2 as the docking software application. AutoDock 4.2 software serves as a valid and acceptable docking application to study the interactions of small compounds with proteins. Interactions of curcumin with DHFR were compared to those of methotrexate (MTX), a known inhibitor of the enzyme. The calculated free energy of binding (DeltaG binding) shows that curcumin (DeltaG = -9.02 kcal/mol; Ki = 243 nM) binds with affinity comparable to or better than MTX (DeltaG = -8.78 kcal/mol; Ki = 363 nM). Binding interactions of curcumin with active site residues of the enzyme are also predicted. Curcumin appears to bind in a bent conformation making extensive VDW contacts in the active site of the enzyme. Hydrogen bonding and pi-pi interaction with key active site residues are also observed. Thus, curcumin can be considered as a good lead compound in the development of new inhibitors of DHFR, which is a potential target of anti-cancer drugs. The results of these studies can serve as a starting point for further computational and experimental studies. PMID- 28584446 TI - Antimicrobial activity of various ethanolic plant extracts against pathogenic multi drug resistant Candida spp. AB - A total of 50 Candida isolates were isolated and identified from clinical specimens and these were tested for resistance to various antifungal drugs. It was observed multi-drug resistance in all candida isolates by 84%, 62%, 60%, 76%, 46, 30%, and 22% against fluconazole, clotrimazole, Amphotericin B, itraconazole, ketoconazole, miconazole and nystatin tested respectively. The isolates, which were found to be resistant to antifungal drugs were selected and subjected to antifungal testing against six ethanolic plants, extract namely Azadiracta indica, Allium sativum, Cordia dichotoma Ocimum sanctum, Syzygium cumini and Trigonella foenum grecum. All the plant extracts tested were found to effective against all MDR Candida isolates with inhibition zone ranging from 10- 18mm in diameter. Ethanolic extract of Allium sativum was observed most effective against the isolates among all the plants extracts tested. The minimum inhibitory concentration (MIC) of all ethanolic plant extract was recorded ranging from 1.56 25mg/ml against MDR candida isolates. Phytochemical analysis of the alcoholic plant extracts revealed the presence of alkaloid, flavanoid, glycosoid, phenol; phenol, tannins, saponins in all the plants studied. The present study may be successful in identifying the plants with different antimicrobial activity. These plants containing various phytochemicals may be exploited in the treatment of infectious diseases caused by drug-resistant microorganisms. PMID- 28584447 TI - Analysis of EAWAG-BBD pathway prediction system for the identification of malathion degrading microbes. AB - Insecticides are the toxic substances that are used to kill insects. The use of insecticides is believed to be one of the major factors behind the increase in agricultural productivity in the 20th century. The organophosphates are now the largest and most versatile class of insecticide used and Malathion is the predominant type utilized. The accumulation of Malathion in environment is the biggest threat to the environment because of its toxicity. Malathion is lethal to beneficial insects, snails, micro crustaceans, fish, birds, amphibians, and soil microorganisms. Chronic exposure of non-diabetic farmers to organophosphorus Malathion pesticides may induce insulin resistance, which might ultimately results in diabetes mellitus. Given the potential carcinogenic risk from the pesticides there is serious need to develop remediation processes to eliminate or minimize contamination in the environment. Biodegradation could be a reliable and cost effective technique for pesticide abatement. Since today as there were no metabolic pathway predicted for the degradation of organophosphates pesticide Malathion in KEGG database or in any of the other pathway databases. Thus in the present study, an attempt has been made to predict the microbial biodegradation pathway of Malathion using bioinformatics tools. The present study predicted the degradation pathway for Malathion. The present study also identifies, Streptomyces sp. and E.coli are capable of degrading Malathion through pathway prediction system. PMID- 28584448 TI - Identification and characterization of a cyclosporin binding cyclophilin from Staphylococcus aureus Newman. AB - Cyclophilins, a class of peptidyl-prolyl cis-trans isomerase (PPIase) enzymes, are inhibited by cyclosporin A (CsA), an immunosuppressive drug. Staphylococcus aureus Newman, a pathogenic bacterium, carries a gene for encoding a putative cyclophilin (SaCyp). SaCyp shows significant homology with other cyclophilins at the sequence level. A three-dimensional model structure of SaCyp harbors a binding site for CsA. To verify whether SaCyp possesses both the PPIase activity and the CsA binding ability, we have purified and investigated a recombinant SaCyp (rCyp) using various in vitro tools. Our RNase T1 refolding assay indicates that rCyp has a substantial extent of PPIase activity. rCyp that exists as a monomer in the aqueous solution is truly a cyclophilin as its catalytic activity specifically shows sensitivity to CsA. rCyp appears to bind CsA with a reasonably high affinity. Additional investigations reveal that binding of CsA to rCyp alters its structure and shape to some extent. Both rCyp and rCyp-CsA are unfolded via the formation of at least one intermediate in the presence of guanidine hydrochloride. Unfolding study also indicates that there is substantial extent of thermodynamic stabilization of rCyp in the presence of CsA as well. The data suggest that rCyp may be exploited to screen the new antimicrobial agents in the future. PMID- 28584449 TI - Epitope design of L1 protein for vaccine production against Human Papilloma Virus types 16 and 18. AB - Cervical cancer accounts for about two-thirds of all cancer cases linked etiologically to Human Papilloma Virus (HPV). 15 oncogenic HPV types can cause cervical cancer, of which HPV16 and HPV18 combinedly account for about 70% of it. So, effective epitope design for the clinically relevant HPV types 16 and 18 would be of major medical benefit. Here, a comprehensive analysis is carried out to predict the epitopes against HPV types 16 and 18 through "reverse vaccinology" approach. We attempted to identify the evolutionarily conserved regions of major capsid protein (L1) as well as minor capsid protein (L2) of HPV and designed epitopes within these regions. In this study, we analyzed about 49 and 27 sequences of HPV L2 and L1 proteins respectively. Since we found that the intertype variability of L2 is higher than for L1 proteins, our analysis was emphasized on epitopes of L1 of HPV types 16 and 18. We had selected HLA-A*0201, DRB1*1501, DQB1*0602, DRB1*0401 and DQB1*0301 alleles for the prediction of T cell epitopes of L1 of HPV 16 and 18. Finally, we reported that predicted epitope sequences EEYDLQFIFQLCKITLTA, and RHGEEYDLQFIFQLCKITLTA of L1 protein of HPV 16, and LPDPNKF, PETQRLVWAC, PVPGQYDA, YNPETQRLVWAC, DTGYGAMD, PVPGQYDATK, KQDIPKVSAYQYRVFRV, RDNVSVDYKQTQLCI and YSRHVEEYDLQFIF of L1 protein of HPV 18 could be therapeutic tools for vaccine design against HPV. PMID- 28584450 TI - T-cell epitopes predicted from the Nucleocapsid protein of Sin Nombre virus restricted to 30 HLA alleles common to the North American population. AB - Hantavirus cardiopulmonary syndrome in North America is caused by Sin Nombre virus (SNV) and poses a public health problem. We identified T-cell epitopes restricted to HLA alleles commonly seen in the N. American population. Nucleocapsid (N) protein is 428 aminoacid in length and binds to RNA and functions also as a key molecule between virus and host cell processes. The predicted epitopes from N protein that bind to class I MHC were analyzed for human proteasomes cleavage, TAP efficiency, immunogenicity and antigenicity. We identified 8 epitopes through MHC binding prediction, proteasomal cleavage prediction and TAP efficiency. Epitope VMGVIGFSF had highest Vaxijen score and the epitope, TNRAYFITR had highest immunogenicity score. Epitope AAVSALETK and TIACGLFPA had 100% homology to many HCPS causing viruses. Our study focused on T cell epitope prediction specific to restricted HLA haplotypes of racial groups in North America for the potential vaccine development. Among the candidate epitopes, FLAARCPFL was conserved in SNV, which is suitable for vaccine specific to the virus genotype. Peptide-based vaccines can be designed to include multiple determinants from several hantavirus genotypes, or multiple epitopes from the same genotype. Thereby, immune response will focus solely on relevant epitopes, avoiding non-protective responses or immune evasion. The other advantages include absence of infectious material unlike in live or attenuated vaccines. There is no risk of reversion or formation of adverse reassortants leading to virulence and no risk of genetic integration or recombination forming a rationale for vaccine design including for distinct geographical regions. PMID- 28584451 TI - optCluster: An R Package for Determining the Optimal Clustering Algorithm. AB - : There exist numerous programs and packages that perform validation for a given clustering solution; however, clustering algorithms fare differently as judged by different validation measures. If more than one performance measure is used to evaluate multiple clustering partitions, an optimal result is often difficult to determine by visual inspection alone. This paper introduces optCluster, an R package that uses a single function to simultaneously compare numerous clustering partitions (created by different algorithms and/or numbers of clusters) and obtain a "best" option for a given dataset. The method of weighted rank aggregation is utilized by this package to objectively aggregate various performance measure scores, thereby taking away the guesswork that often follows a visual inspection of cluster results. The optCluster package contains biological validation measures as well as clustering algorithms developed specifically for RNA sequencing data, making it a useful tool for clustering genomic data. AVAILABILITY: This package is available for free through the Comprehensive R Archive Network (CRAN) at http://cran.rproject.org/web/packages/optCluster/. PMID- 28584452 TI - State of the Globe: Hepatitis C - Opportunistic versus Organized Screening. PMID- 28584453 TI - Reflections on the Ebola Public Health Emergency of International Concern, Part 1: Post-Ebola Syndrome: The Silent Outbreak. PMID- 28584454 TI - Reflections on the Ebola Public Health Emergency of International Concern, Part 2: The Unseen Epidemic of Posttraumatic Stress among Health-care Personnel and Survivors of the 2014-2016 Ebola Outbreak. PMID- 28584455 TI - Hepatitis C Virus: Unnoticed and on the Rise in Blood Donor Screening? A 5 Years Cross-sectional Study on Seroprevalence in Voluntary Blood Donors from Central India. AB - CONTEXT: The ultimate goal of a blood transfusion service is the provision of safe and adequate supply free from transfusion-transmitted infections (TTIs). TTIs not only threaten the recipient's safety, but they also increase disease burden. Seroprevalence of TTIs in healthy blood donors indirectly reflects the prevalence of these infections in the general healthy population. AIM AND OBJECTIVES: To study the seroprevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) in healthy donors at a tertiary care hospital-based blood bank. To know the yearly and age-group prevalence of these TTIs as compared with other studies across India. SETTINGS AND DESIGN: This is 5 years observational cross-section study conducted in a tertiary hospital-based teaching institute of Central India (Malwa region). MATERIALS AND METHODS: The results of serological testing of TTIs and donor variables were analyzed during 2011-2015. STATISTICAL ANALYSIS USED: Chi-square test and Chi-square for trend analysis on TTIs prevalence. RESULTS: A total of 58,998 donors were screened for TTIs with dominance of male donation (99.7%). The overall cumulative seroprevalence was 1.14% in our study. The seroprevalence of HIV, HBV, and HCV was 0.09%, 0.98%, and 0.07%, respectively. We found a statistically significant increasing trend for HCV seropositivity during the study. CONCLUSION: Our study reflects an increasing trend of HCV seroprevalence over time. Thus, efforts are needed to increase the awareness and to educate the population in reducing risk factors for HCV infection. PMID- 28584456 TI - Isolation Rate and Clinical Significance of Uropathogens in Positive Urine Cultures of Hemodialysis Patients. AB - BACKGROUND: Hemodialysis (HD) patients are known to be vulnerable to infections. However, there are limited data on the urine microbiology spectrum among patients with end-stage renal disease and on the development of antimicrobial resistance of uropathogens in these patients. MATERIALS AND METHODS: A single-center, retrospective study was conducted to assess the spectrum and antimicrobial resistance profile of microorganisms isolated in urine cultures of HD patients who were hospitalized between September 2008 and August 2015 with an admitting diagnosis of fever, sepsis, or urinary tract infection. Characteristics of patients were recorded, and associations between the aforementioned parameters were assessed with Fisher's exact test. RESULTS: We included 75 HD patients (33 males, mean age 73.6 +/- 16.6 years) with positive urine cultures. Despite urine culture positivity, the urinary tract was the confirmed source of infection in only 31 (41.3%) patients. Among the different pathogens, Escherichia coli was the predominant microorganism. Identification of E. coli as the involved uropathogen was associated neither with a growth of >=105 CFU/ml, presence of fever, sepsis, urinary catheter use nor with higher antimicrobial resistance. E. coli growth, however, was significantly associated with polycystic kidney disease (P = 0.027). Extended antimicrobial resistance was noted in 29 (38.7%) patients but was associated neither with higher incidence of fever or sepsis nor with urinary catheter use. CONCLUSIONS: In our series of HD patients with positive urine cultures, the isolation rates of different uropathogens do not seem to differ from the most commonly encountered ones in nondialysis patients although resistance to antimicrobials may be more frequently observed. PMID- 28584457 TI - Analysis of the Clinical Profile in Patients with Plasmodium falciparum Malaria and Its Association with Parasite Density. AB - BACKGROUND: Malaria remains a major health hazard in the modern world, particularly in developing countries. In Plasmodium falciparum malaria, there is a direct correlation between asexual erythrocytic stage parasite density and disease severity. Accordingly, the correlations between parasite density and various clinical presentations, severity, and outcome were examined in falciparum malaria in India. MATERIALS AND METHODS: The study was conducted in a tertiary health-care center in North India. Of 100 cases of falciparum malaria, 65 patients were male and 35 were female. A total of 54 patients were in the uncomplicated group and 46 patients were in the complicated malaria group. RESULTS: Fever, anemia, icterus, splenomegaly, hepatomegaly, and hepatosplenomegaly were common clinical findings. All clinical findings were significantly more common in the complicated malaria group and patients with a high parasite density than in the uncomplicated group and those with a low parasite density. All patients in the uncomplicated malaria group had a parasite density of <5% while most patients in the complicated malaria group had a parasite density of >5%, and the difference between groups was statistically significant. The incidence of cerebral malaria was significantly higher in cases with a high parasite density; 58.33% mortality was observed in these cases. Cerebral malaria and hyperbilirubinemia was the most frequently encountered combination of complications. CONCLUSIONS: In P. falciparum malaria, parasite density was associated with complications and poor clinical outcomes. These results may inform treatment decisions and suggest that a threshold parasite density of 5% is informative. PMID- 28584458 TI - Epidemiology of Rotavirus in the Iranian Children: A Systematic Review and Meta analysis. AB - Rotavirus is associated with increased risk for severe diarrhea in infants and young children worldwide. This systematic review and meta-analysis was performed to determine the prevalence rate of rotavirus from different parts of Iran and provide an overall relative frequency (RF) for Iran. We performed a systematic literature review from several databases including PubMed, ISI Web of Science, Scopus, OVID, MAG IRAN, IranMedex, and Iranian Scientific Information Database. We searched the following keywords: "rotavirus," "rotavirus infection," "acute gastroenteritis," "diarrhea," "children," "infant," and "Iran." The purpose of this study was to report the prevalence of rotavirus with the application of meta analysis. We selected 43 researches out of 1147 for our study. From all the samples, the pooled estimate of prevalence (95% confidence interval) =39.9% (0.396%-0.409%) were rotavirus positive. It should be noted that rotavirus infection's RF varied from 6.4% to 79.3% in Birjand and Tehran Provinces, respectively. Thereupon, it is divergent in different studies. According to our study result, rotavirus RF has a wide range in Iran and is associated with diarrhea in children. Thus, further researches should be taken to minimize the emergence and transmission of rotavirus. PMID- 28584459 TI - Susceptibility Pattern of Enterococci at Tertiary Care Hospital. AB - The study was aimed to characterize enterococci from various clinical specimens, to determine the antimicrobial susceptibility pattern, and to explore the association between virulence factors and antimicrobial resistance. A total of 283 clinical enterococcal isolates were speciated and subjected to antimicrobial susceptibility testing. Virulence factors (hemolysin, gelatinase, and biofilm production) were detected phenotypically. Of the 283 enterococci isolated, 12 species were identified; predominant species were Enterococcus faecalis (82.33%). High-level gentamicin (HLG) and vancomycin resistance were observed among 55.57% and 6.01% of enteroccal isolates, respectively. All vancomycin-resistant enterococci (VREs) were E. faecalis and had VanA phenotype and genotype. Hemolysin, gelatinase, and biofilm production were seen in 15.90%, 12.36%, and 13.43% of enterococcal isolates, respectively. Vancomycin and HLG resistance were observed in 0.35% and 61.86% of the enterococcal isolates producing virulence factors. Isolates resistant to HLG but susceptible to vancomycin expressed more virulent factors. Further research is required to reveal the complex interplay between drug resistance and virulence factors. PMID- 28584460 TI - Hemophagocytic Lymphohistiocytosis Associated with Anaplasmosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterized by unregulated macrophage and T-lymphocyte activation resulting in cytokine overproduction and subsequent histiocytic phagocytosis. Variant infections, particularly viruses have been postulated as the inciting factor for this potentially fatal disease. Herein, we will report a case of HLH associated with anaplasmosis. PMID- 28584461 TI - Infective Endocarditis Due to Abiotrophia defectiva and Its Feared Complications in an Immunocompetent Person: Rare, But Real. AB - Abiotrophia defectiva is nutritional deficient streptococci that cannot be cultured on routine culture medias. Even though fastidious in growth requirement, it is a virulent bacterium preferentially affecting endovascular structures and is implicated in many culture-negative endocarditis cases. Unlike other organisms, it is known for heart valve destruction leading to heart failure and excessive embolization rates. It's inherent resistance to routinely used antibiotics also contributed to increased mortality and morbidity in affected individuals and warrants timely diagnosis and prompt treatment. Our patient, a previous healthy individual, acquired this rare bacterium from intravenous drug abuse and developed infective endocarditis with valve destruction, heart failure, and distal embolization to multiple organs. He underwent multiple surgeries including mitral valve replacement and embolectomy with clinical improvement. Our case reiterates the possibility of rare cause of common diseases and raises awareness of infective endocarditis caused by A. defectiva among medical professionals. PMID- 28584462 TI - Aeromonas salmonicida Bacteremia Associated with Chronic Well Water Consumption in a Patient with Diabetes. AB - Aeromonas salmonicida is associated with superficial skin infections in fish. Its virulence factors allow colonization of water including surface water such as salt water, beaches, and fresh water wells. Moreover, it is possible for immunocompromised patients to develop invasive disease after chronic exposure to Aeromonas spp. through contaminated water. While there are reports of Aeromonas spp. bacteremia following water ingestion, there have been no reports of A. salmonicida bacteremia from water consumption. We report the first case of A. salmonicida bacteremia in a patient with diabetes due to chronic consumption of well water. PMID- 28584463 TI - Native Valve Endocarditis in a Dialysis Patient by Achromobacter xylosxidans, A Rare Pathogen. PMID- 28584464 TI - Strongyloides stercoralis Infection: A Case Series from a Tertiary Care Center in India. PMID- 28584465 TI - Profile of Helminthic Infections in Patients Attending a Tertiary Care Hospital with Emphasis on Immunocompromised Patients. PMID- 28584466 TI - Morphometric analysis of mandibular ramus for sex determination on digital orthopantomogram. AB - BACKGROUND: Identification of sex from skeletal remains is an important tool in forensic science. Mandibular ramus can be used for sex determination either on dry mandible or through orthopantomogram (OPG). AIM: To determine the sex from mandibular ramus using digital OPG. MATERIALS AND METHODS: The morphometric analysis was conducted on mandibular ramus of 1000 digital OPG using Kodak Master View version 4.3 software. Statistical analysis was performed, and independent t test and discriminant function were applied. RESULTS: The participants' age ranged from 21-60 years with an equal number of males and females. The mean dimensions of all parameters for ramus were higher in males and highly significant (P < 0.001). The total mean length of minimum and maximum ramus breadth was 27.44 +/- 3.41 mm and 32.27 +/- 3.40 mm, respectively. The maximum and projective ramus height was 71.78 +/- 5.98 mm and 65.62 +/- 6.19 mm, respectively. The coronoid height was 59.23 +/- 6.08 mm. The correlation of gender with morphology of mandibular ramus was significant (P < 0.05). The overall accuracy for diagnosing sex was 69%, whereas for diagnosing male and female, the accuracy was 68% and 70%, respectively. CONCLUSION: Measurements of mandibular ramus using OPG are helpful in sex determination. PMID- 28584467 TI - The credibility of dental pulp in human blood group identification. AB - BACKGROUND: The identification of unknown individual has always been of paramount importance to the society. Blood groups are excellent aids to these pursuits. Dental tissue acts beneficial because tooth is the hardest of all human tissues, and they can be preserved intact for a long period of time after the death of the individual. Hence, this study is conducted to evaluate the role of dental pulp in identification of human blood group. AIM: To determine the ABO blood grouping from the pulpal tissue of an extracted tooth and to correlate the same with blood group details obtained from the study subjects. MATERIALS AND METHODS: This is a double-blinded randomized controlled trial conducted on a sample of thirty extracted teeth. The teeth were stored dry for 2 months. An attempt to establish the blood group from pulp was made by absorption-elution method. The collected data were coded, and statistical analysis was carried out using Statistical Package of Social Science (SPSS Version 20). Cronbach's alpha was applied to check the reliability of the absorption-elusion method in the detection of blood group from dental pulp. RESULTS: Blood groups obtained from the pulp were compared with those obtained from the study subjects. Blood group establishment from dental pulp using absorption-elusion method had a good internal consistency in comparison with the conventional Karl Landsteiner's blood typing method. This study showed that pulp tissue is a reliable method to detect blood groups of individuals. CONCLUSION: It can be concluded that dental pulp can be used to establish identity, where teeth happen to be the only remnants available for personal identification. PMID- 28584468 TI - Determination of age, sex, and blood group from a single tooth. AB - BACKGROUND: Human identification is one of the most challenging subjects that human has been confronted with. Through the ages, odontological examinations have been a critical determinant in the search of human identity. Data in the form of age, gender, and blood group might provide vital clues in such investigations. In the recent times, it has been often desirable to preserve tissues for further investigations following the unfolding of certain events or discovery of new data. Hence, it is important to gather as much data as possible using less tissue. AIMS: The purpose of this study was to determine age, sex, and ABO blood group of individual from a single tooth, to determine the effect of different environmental conditions, and to extract maximum information also at the same time preserving some tissue for the further investigation whenever needed. MATERIALS AND METHODS: The study sample consisted of sixty teeth divided into four groups under different environmental conditions and time. The teeth were sectioned longitudinally in the buccolingual plane along the midline. Longitudinal ground sections of each tooth were prepared for age determination from cemental lines. Pulp removed was divided into two halves thereafter sex and blood group was determined. STATISTICAL ANALYSIS: For correlation of age between estimated age and actual age, using cemental lines Pearson's correlation coefficient was applied. Further for determination of both sex and blood group between groups, Chi-square test was applied. RESULTS: A strong positive correlation was found between the estimated age and actual age of the study groups. Moreover, there was no significant difference between the actual and determined sex and blood group of the study groups. CONCLUSION: Although age, sex, and blood group are more reliably determined in freshly extracted teeth, these variables may be of significant help in identification even after a period of 6 weeks postextraction. PMID- 28584469 TI - Pattern self-repetition of fingerprints, lip prints, and palatal rugae among three generations of family: A forensic approach to identify family hierarchy. AB - CONTEXT: The unique pattern and structural diversity of fingerprints, lip prints, palatal rugae, and their occurrence in different patterns among individuals make it questionable whether they are completely unique even in a family hierarchy? Do they have any repetition of the patterns among the generations? Or is this a mere chaos theory? AIMS: The present study aims to assess the pattern self-repetition of fingerprints, lip prints, and palatal rugae among three generations of ten different families. SETTINGS AND DESIGN: The present study was conducted at Rungta College of Dental Science and Research, Bhilai, India. Participants birth by origin of Chhattisgarh were only included in the study. SUBJECTS AND METHODS: Thirty participants from three consecutive generations of ten different families were briefed about the purpose of the study, and their fingerprints, lip prints, and palatal rugae impression were recorded and analyzed for the pattern of self repetition. STATISTICAL ANALYSIS USED: Multiple comparisons among the generations and one-way analysis of variance test were performed using SPSS 20 trial version. RESULTS: Among the pattern of primary palatal rugae, 10% showed repetition in all the three generations. Thirty percent showed repetition of the pattern of thumb fingerprints in all the three generation. The pattern of lip prints in the middle 1/3rd of lower lip, 20% showed repetition in alternative generations. CONCLUSIONS: The evaluations of fingerprints, lip prints, and palatal rugae showed fractal dimensions, occurring variations in dimensions according to the complexity of each structure. Even though a minute self-repetition in the patterns of lip, thumb, and palate among the three consequent generations in a family was observed considering the sample size, these results need to be confirmed in a larger sample, either to establish the role of chaos theory in forensic science or identifying a particular pattern of the individual in his family hierarchy. PMID- 28584470 TI - Denture identification using individual national identification number of Saudi Arabia: An innovative inclusion method of casted metal. AB - CONTEXT: Forensic odontology is one of the branches of dentistry, which played a very important role in identification of individuals in accident, natural and mass disaster, and civil unrest and in genocide crimes. In the absence of natural teeth, marking or labeling of denture plays a vital role in the personal identification. BACKGROUND: Various types of marking or labeling methods are reported. However, many are not according to the criteria put forth by American Dental Association or other professional association. Majority of these techniques may be time consuming and expansive, may not be standardized, long lasting and do not permit the incorporation of a large amount of information. AIM: The aim of this study is to find out a denture identification technique that should be easy, less expensive, long lasting, and standardized. MATERIALS AND METHODS: This article illustrates an inclusion denture casted metal technique of the individual national identification number printed in the patient's residence number or iquama or national identity card issued by the ministry of interior, Kingdom of Saudi Arabia is used as a denture marker in the lingual surface of mandibular denture. RESULTS: The label in this method is durable and can withstand high temperature, less chances of deterioration, visible radiographically, and provide all important information about individual that is standardized, reliable, and also accessible from any remote location. CONCLUSION: Hence, the proposed technique is an easy, less expensive, long lasting, radiographically visible, and standardized method of identification. PMID- 28584471 TI - Child maltreatment: Cross-sectional survey of general dentists. AB - BACKGROUND: Child abuse continues to be a social menace causing both physical and emotional trauma to benevolent children. Census has shown that nearly 50-75% of child abuse include trauma to mouth, face, and head. Thus, dental professionals are in a strategic position to identify physical and emotional manifestations of abuse. AIM: A cross-sectional survey was conducted to assess knowledge and attitude of dental professionals on the exigent issue of child abuse. METHODOLOGY: With prior consent, a 20-question survey including both multiple choice and dichotomous (yes/no) questions was mailed to 120 state-registered general dentists and the data collected were subjected to statistical analysis. STATISTICAL ANALYSIS: The overall response rate to the questionnaires was 97%. Lack of knowledge about dentist role in reporting child abuse accounted to 55% in the reasons for hesitancy to report. Pearson's Chi-square test did not show any significant difference between male and female regarding the reason for hesitancy to report and legal obligation of dentists. RESULTS: Although respondent dentists were aware of the diagnosis of child abuse, they were hesitant and unaware of the appropriate authority to report. CONCLUSION: Increased instruction in the areas of recognition and reporting of child abuse and neglect should be emphasized. PMID- 28584472 TI - Radiographic anthropometric study of frontal sinus for sex determination in Benin city, South-South Nigeria. AB - CONTEXT: The frontal sinuses are situated in the frontal bone between the outer and inner plates of the bone. A good knowledge on dimensions is relevant for successful surgery. AIM: This study was carried out to determine the dimorphic potential of the frontal sinuses and to ascertain the accuracy in sex determination using the logistic regression model among Edo people of Nigeria. MATERIALS AND METHODS: It was a 7 years retrospective study on the Edo, utilizing posterior-anterior radiographs of frontal sinuses in University of Benin Teaching Hospital. The right and left frontal sinus heights and widths were measured in centimeter. STATISTICAL ANALYSIS: The data were analyzed using independent samples t-test and logistic regression with the aid of Statistical Package for the Social Sciences version 20. P <=0.05 was considered statistically significant. RESULTS: All dimensions were higher in males than in females, wherein the the left side height and width were statistically significant (P < 0.05). Left side frontal sinus width gave the highest accuracy of 60% in sex determination using logit regression. CONCLUSION: The dimorphic nature of the left dimensions has implications for human identification. PMID- 28584473 TI - Laser micro-etching of metal prostheses for personal identification. AB - Denture marking techniques play a vital role in establishing personal identification in suitable clinical and forensic situations. The denture marking techniques are categorized broadly into additive and ablative methods. Additive methods involve embedding or impregnation of markers for establishing personal identity. Ablative methods involve partial removal of the denture surface thereby providing a marking for identification. Engraving and etching methods are the commonly used ablative methods. Ablative methods can be of contact and noncontact subtypes. Laser micro-etching is a precise noncontact ablative denture marking technique that could be used for prostheses-guided personal identification. PMID- 28584474 TI - Does the periodontal status of peg-shaped mandibular central incisor affect its prognosis? PMID- 28584475 TI - Virtopsy: Touch-free autopsy. AB - The word "autopsy" denotes "to see with own eyes." Autopsy (postmortem) is a process that includes a thorough examination of a corpse noting everything related to anatomization, surface wounds, histological and culture studies. Virtopsy is a term extracted from two words "virtual" and "autopsy." It employs imaging methods that are routinely used in clinical medicine such as computed tomography and magnetic resonance imaging in the field of autopsy, to find the reason for death. Virtopsy is a multi-disciplinary technology that combines forensic medicine and pathology, roentgenology, computer graphics, biomechanics, and physics. It is rapidly gaining importance in the field of forensics. This approach has been recently used by forensic odontologists, but yet to make its own mark in the field. This article mainly deals with "virtopsy" where in various articles were web searched, relevant data was selected, extracted, and summarized here. PMID- 28584476 TI - Age estimation by dentin translucency measurement using digital method: An institutional study. AB - AIMS: The aims of the present study were to measure translucency on sectioned teeth using available computer hardware and software, to correlate dimensions of root dentin translucency with age, and to assess whether translucency is reliable for age estimation. MATERIALS AND METHODS: A pilot study was done on 62 freshly extracted single-rooted permanent teeth from 62 different individuals (35 males and 27 females) and their 250 MUm thick sections were prepared by micromotor, carborundum disks, and Arkansas stone. Each tooth section was scanned and the images were opened in the Adobe Photoshop software. Measurement of root dentin translucency (TD length) was done on the scanned image by placing two guides (A and B) along the x-axis of ABFO NO. 2 scale. Unpaired t-test, regression analysis, and Pearson correlation coefficient were used as statistical tools. RESULTS: A linear relationship was observed between TD length and age in the regression analysis. The Pearson correlation analysis showed that there was positive correlation (r = 0.52, P = 0.0001) between TD length and age. However, no significant (P > 0.05) difference was observed in the TD length between male (8.44 +/- 2.92 mm) and female (7.80 +/- 2.79 mm) samples. CONCLUSION: Translucency of the root dentin increases with age and it can be used as a reliable parameter for the age estimation. The method used here to digitally select and measure translucent root dentin is more refined, better correlated to age, and produce superior age estimation. PMID- 28584477 TI - Dental sex dimorphism: Using odontometrics and digital jaw radiography. AB - CONTEXT: Estimating the gender from the human skeletal remains can guide the forensic investigator in revealing the missing person's identity. AIMS: (1) To determine the utility of the various parameters taken on the orthopantomographs (mandible) and of odontometrics on tooth remains to estimate the gender. (2) To determine the most dimorphic parameter taken on the radiograph as well as tooth (odontometrics) in the study taken. STUDY AND DESIGN: (1) A retrospective study was planned on 200 subjects (100 males and 100 females) in the age group of 18-30 years and the following parameters (maximum ramus height, bigonion width, and bicondylar breadth) were measured on the orthopantomograph. (2) A prospective clinical study was planned on 200 subjects (100 males and 100 females) in the age group of 18-30 years, to measure the mesio-distal width of permanent maxillary central incisors and canines directly in the patient's mouth, using Digital Vernier calipers. STATISTICAL ANALYSIS USED: The mean, range, and standard deviation were calculated for each variable in the study. The Z-score test was done to find out the magnitude of sexual dimorphism for each parameter in each part of the study. RESULTS: Maximum ramus height proved to be the most dimorphic parameter depicting the utility of mandible for the estimation of gender of the deceased. Permanent maxillary central incisor proved to be more dimorphic than the maxillary canines, depicting it to be population specific. CONCLUSION: Measurements taken on the mandible proved to be useful in the estimation of gender of the deceased. In cases of fragmentary or missing mandible, odontometrics can be used. Hence, teeth proved to be an adjunct tool in the determination of gender of the deceased. PMID- 28584478 TI - Gender determination using barr bodies from teeth exposed to high temperatures. AB - CONTEXT: Gender determination forms a prime step in the forensic identification process. Teeth form a very important identification aid in forensic studies because they are protected by oral tissues and dental pulp is further protected by the mineralized constituents of the teeth. This allows the conservation and sustainable production of dental pulp to help sex determination in circumstances where other tissues cannot be analyzed like victims when exposed to high temperatures during fire accidents, explosions, and other mass disasters. AIM: The present study aimed at gender determination from pulpal tissue extirpated from teeth exposed to high temperatures. MATERIALS AND METHODOLOGY: The study consisted of sixty teeth samples, thirty male and thirty female. The teeth have been subjected to a series of temperatures of 37 degrees C, 100 degrees C, 200 degrees C, 300 degrees C, 400 degrees C, 500 degrees C, 600 degrees C, 800 degrees C, and 1000 degrees C. The dental pulp is then obtained from these teeth, processed, stained, and checked for Barr bodies. STATISTICAL ANALYSIS USED: Descriptive statistical analysis has been used. RESULTS: The results showed that pulp from the female teeth showed the presence of Barr bodies up to a maximum of 400 degrees C, whereas the male pulpal tissue did not show the presence of any Barr bodies. With increase in temperatures, the cellularity of the connective tissue decreased but the average number of Barr body positive cells remained constant within the range of 19-20. CONCLUSIONS: Dental pulp acts as a potential source of gender determination when no other means of identification are available. PMID- 28584479 TI - Gender determination by odontometric method. AB - CONTEXT: Gender determination is central in establishing personal identification from human skeletal remains. The study was conducted to find out the accuracy with which gender can be determined by odontometric methods. AIMS: To investigate the mesiodistal (MD) and buccolingual (BL) dimensions of all the teeth of permanent dentition to find new parameters to differentiate between male and female teeth and to assess whether each type of linear measurement can be used independently in odontometric sex differentiation. MATERIALS AND METHODS: The study was conducted at a dental college on a composite group of 500 individuals comprising 250 males and 250 females. Impressions of upper and lower jaws were made with alginate impression material and casts prepared with dental stone. A digital Vernier calliper was used to measure the BL and MD dimensions of all the upper teeth except the third molars. STATISTICAL ANALYSIS USED: The results were subjected to statistical analysis using univariate analysis and linear stepwise discriminant function analysis to find the variables which discriminate gender significantly. RESULTS: The MD and BL dimensions between males and females were statistically significant. The predicted value for correct classification of gender was also statistically significant. CONCLUSIONS: The ability to differentiate gender in the population using stepwise discriminant functions was found to be very high with 99.8% accuracy with males showing statistically larger teeth than females. This is similar to the near 100% success in gender determination using pelvic and skull bones. PMID- 28584481 TI - Sex determination efficacy of Papanicolaou and acriflavine Schiff stains in buccal smears. AB - BACKGROUND: Barr body is formed from random inactivation and condensation of one of the two female chromosomes in virtually all the somatic cells of female mammals. Buccal smears have been reported to be potential sources of Barr bodies. AIM: This study was done to assess the efficacy of acriflavine (AF) Schiff and Papanicolaou (PAP) stains in sex determination by identifying Barr bodies in buccal smears of both sexes. MATERIALS AND METHODS: Two samples of buccal smears, collected from thirty males and thirty females in the age group of 16-60 years were used to demonstrate Barr bodies using AF Schiff and PAP stains, respectively. Hundred cells were examined for Barr body positive nucleus, and its mean percentage was calculated and statistically analyzed. RESULTS: In females, AF Schiff stained positive cells ranged from 16% to 53% and PAP stained positive cells ranged from 9% to 38%. In males, 0-9% AF positive Barr bodies and 0-5% PAP stained Barr bodies were identified. CONCLUSION: Sex determination using buccal smear is a simple and reliable method. AF Schiff stain is better both qualitatively and quantitatively when compared to PAP stain, thus aids in more accurate sex determination. PMID- 28584480 TI - Assessment of Demirjian's 8-teeth technique of age estimation and Indian-specific formulas in an East Indian population: A cross-sectional study. AB - BACKGROUND: The age of an individual can be assessed by a plethora of widely available tooth-based techniques, among which radiological methods prevail. The Demirjian's technique of age assessment based on tooth development stages has been extensively investigated in different populations of the world. AIM: The present study is to assess the applicability of Demirjian's modified 8-teeth technique in age estimation of population of East India (Odisha), utilizing Acharya's Indian-specific cubic functions. MATERIALS AND METHODS: One hundred and six pretreatment orthodontic radiographs of patients in an age group of 7-23 years with representation from both genders were assessed for eight left mandibular teeth and scored as per the Demirjian's 9-stage criteria for teeth development stages. Age was calculated on the basis of Acharya's Indian formula. Statistical analysis was performed to compare the estimated and actual age. All data were analyzed using SPSS 20.0 (SPSS Inc., Chicago, Illinois, USA) and MS Excel Package. RESULTS: The results revealed that the mean absolute error (MAE) in age estimation of the entire sample was 1.3 years with 50% of the cases having an error rate within +/- 1 year. The MAE in males and females (7-16 years) was 1.8 and 1.5, respectively. Likewise, the MAE in males and females (16.1-23 years) was 1.1 and 1.3, respectively. CONCLUSION: The low error rate in estimating age justifies the application of this modified technique and Acharya's Indian formulas in the present East Indian population. PMID- 28584482 TI - Age and gender assessment through three-dimensional morphometric analysis of maxillary sinus using magnetic resonance imaging. AB - BACKGROUND: Age and sex determinations are important tools in forensic odontology which help in the identification of an individual. Radiographic method of sex and age estimation is a noninvasive simple technique. Measurements of the maxillary sinuses can be used for the estimation of age and gender when other methods are inconclusive. Maxillary sinus dimensions were used as an important tool in the identification of unknown. AIM: This study aims to estimate age and sex using the dimensions and volume of the maxillary sinus in magnetic resonance imaging (MRI). MATERIALS AND METHODS: This study included sixty patients visiting Department of Radiology Mamata General Hospital, Khammam requiring MRI of the brain and paranasal sinuses. Maxillary sinus dimensions were measured using Siemens software, and statistical analysis was done. RESULTS: The volume and dimensions of the maxillary sinus were more in males when compared to the females with a statistically significant difference. The highest percentage of sexual dimorphism was seen in the volume of left maxillary sinus. Age estimated using the volume of maxillary sinus showed no statistically significant difference from the actual age of the subjects. CONCLUSION: The dimensions and volume of the maxillary sinuses were larger in males than in females, in addition to that they tend to be less with the older age. MRI measurements of maxillary sinuses may be useful to support gender and age estimation in forensic radiology. PMID- 28584483 TI - Can dead man tooth do tell tales? Tooth prints in forensic identification. AB - BACKGROUND: We know that teeth trouble us a lot when we are alive, but they last longer for thousands of years even after we are dead. Teeth being the strongest and resistant structure are the most significant tool in forensic investigations. Patterns of enamel rod end on the tooth surface are known as tooth prints. AIM: This study is aimed to know whether these tooth prints can become a forensic tool in personal identification such as finger prints. A study has been targeted toward the same. SETTINGS AND DESIGN: In the present in-vivo study, acetate peel technique has been used to obtain the replica of enamel rod end patterns. MATERIALS AND METHODS: Tooth prints of upper first premolars were recorded from 80 individuals after acid etching using cellulose acetate strips. Then, digital images of the tooth prints obtained at two different intervals were subjected to biometric conversion using Verifinger standard software development kit version 6.5 software followed by the use of Automated Fingerprint Identification System (AFIS) software for comparison of the tooth prints. Similarly, each individual's finger prints were also recorded and were subjected to the same software. STATISTICAL ANALYSIS: Further, recordings of AFIS scores obtained from images were statistically analyzed using Cronbach's test. RESULTS: We observed that comparing two tooth prints taken from an individual at two intervals exhibited similarity in many cases, with wavy pattern tooth print being the predominant type. However, the same prints showed dissimilarity when compared with other individuals. We also found that most of the individuals with whorl pattern finger print showed wavy pattern tooth print and few loop type fingerprints showed linear pattern of tooth prints. CONCLUSIONS: Further more experiments on both tooth prints and finger prints are required in establishing an individual's identity. PMID- 28584484 TI - Dental records of forensic odontological importance: Maintenance pattern among dental practitioners of Pune city. AB - CONTEXT: Forensic odontology plays a pivotal role in the identification of victims in mass disasters with the help of "Preserved dental records" available with the general dental practitioners (GDPs). However, the status of such dental records of forensic importance has not been studied extensively. AIM: To study the current status of awareness and practice of dental record maintenance by GDPs of Pune. MATERIALS AND METHODS: A cross-sectional study was conducted among 100 randomly selected GDPs from Pune. Data was collected in a personalized manner by means of a questionnaire. RESULTS: Six percent of GDPs do not maintain any records of the patient, 11% of them do not record about developmental dental anomalies, and 22% GDPs do not retain radiographs. Sixty-seven percent GDPs mention about the use of abbreviations while recording history. Only 17% of GDPs record denture marking and 11% take conformity certificate for the denture. Thirty percent GDPs do not mention the serial number of an implant whereas 17% of them do not mention about the prescribed medication. Five percent GDPs handover original dental record to the patient and 91% said that they discard casts and models immediately after treatment. CONCLUSION: There was inadequate knowledge and lack of practice regarding proper record maintenance among GDPs. PMID- 28584485 TI - Palatal rugae pattern: An aid for sex identification. AB - BACKGROUND: Palatal rugoscopy, or palatoscopy, is the process by which human identification can be obtained by inspecting the transverse palatal rugae inside the mouth. AIM: The aim of the study is to investigate the potential of using palatal rugae as an aid for sex identification in Bengaluru population. MATERIALS AND METHODS: One hundred plaster casts equally distributed between males and females belonging to age range of 4-16 years were examined for different rugae patterns. Thomas and Kotze classification was adopted for identification of these rugae patterns. STATISTICAL ANALYSIS: The data obtained were subjected to discriminant function analysis to determine the applicability of palatal rugae pattern as an aid for sex identification. RESULTS: Difference in unification patterns among males and females was found to be statistically significant. No significant difference was found between males and females in terms of number of rugae. Overall, wavy and curvy were the most predominant type of rugae seen. Discriminant function analysis enabled sex identification with an accuracy of 80%. CONCLUSION: This preliminary study undertaken showed the existence of a distinct pattern of distribution of palatal rugae between males and females of Bengaluru population. This study opens scope for further research with a larger sample size to establish palatal rugae as a valuable tool for sex identification for forensic purposes. PMID- 28584486 TI - Estimation of Guggulsterone E and Z in the Guggul-based Commercial Formulations Using High-performance Thin-layer Chromatography. AB - BACKGROUND: Guggulsterone (GS) is a plant steroid and bioactive compound present in gum Guggul of Commiphora wightii. An Indian herbal medicine system "Ayurveda" has a long history of use of gum Guggul and plant extract of C. wightii as medicine for the treatment of various illnesses. Complex nature, low availability, and inconsistency of phytoconstituents make its analysis of difficult tasks. AIMS: In this work, six different Guggul-based herbal formulations were examined for estimation of GS and their isomers (E and Z) through high-performance thin-layer chromatography technique. MATERIALS AND METHODS: For that various concentrations of standard E-GS and Z-GS (50 ng-250 ng/spot) with samples (20 MUg/spot) were applied on silica gel coated aluminum plate and developed with the mobile phase of toluene: ethyl acetate: formic acid: methanol (6:2:1:0.5). The scanning was performed at 254 nm wavelength and the absorbance (scan) spectrum of E-GS and Z-GS peak was generated at 200 nm-400 nm wavelength range. RESULTS AND CONCLUSIONS: Rf value and scan spectrum pattern of the samples reveal that they contain either one form of GS (E-GS, Z-GS) or both. The quantity of E-GS and Z-GS within the samples was ranged from 0.230 +/- 0.0040 0.926 +/- 0.0168% to 0.537 +/- 0.0026-0.723 +/- 0.0177%, respectively. PMID- 28584487 TI - Modulatory Effects of Decalepis hamiltonii Extract and Its Compounds on the Antioxidant Status of the Aging Rat Brain. AB - OBJECTIVE: The present study was aimed to investigate the neuroprotective effects of Decalepis hamiltonii (Dh) aqueous root extract and its compounds against age related oxidative stress (OS) in the discrete regions of the rat brain. MATERIALS AND METHODS: Male Wistar albino rats of 4- and 22-month-old were divided into control and six supplemented groups. The supplemented groups were orally administered with ellagic acid (EA), 4-hydroxyisophthalic acid (4-HIA), and Dh extract for 30 days. RESULTS: Age-related decrease in antioxidant enzyme activities was noticed. The hippocampus was found to be more vulnerable to OS as seen by the elevation in the OS markers. Supplementation of the Dh extract, EA, and 4-HIA was found to be effective in up-regulating the antioxidant status. However, the extent of up-regulation was more evident in Dh supplemented animals. CONCLUSION: Our results suggest that Dh extract and its compounds exhibit neuroprotective effects against age-related OS and can be used as a dietary therapeutic intervention for the treatment of neurological disorders. PMID- 28584488 TI - Moisture Sorption-desorption Characteristics and the Corresponding Thermodynamic Properties of Carvedilol Phosphate. AB - AIMS: Carvedilol phosphate (CDP) is a nonselective beta-blocker used for the treatment of heart failures and hypertension. In this work, moisture sorption desorption characteristics and thermodynamic properties of CDP have been investigated. MATERIALS AND METHODS: The isotherms were determined using dynamic vapor sorption analyzer at different humidity conditions (0%-90% relative humidity) and three pharmaceutically relevant temperatures (20 degrees C, 30 degrees C, and 40 degrees C). The experimental sorption data determined were fitted to various models, namely, Brunauer-Emmett-Teller; Guggenheim-Anderson-De Boer (GAB); Peleg; and modified GAB. Isosteric heats of sorption were evaluated through the direct use of sorption isotherms by means of the Clausius-Clapeyron equation. STATISTICAL ANALYSIS USED: The sorption model parameters were determined from the experimental sorption data using nonlinear regression analysis, and mean relative percentage deviation (P), correlation (Correl), root mean square error, and model efficiency were considered as the criteria to select the best fit model. RESULTS: The sorption-desorption isotherms have sigmoidal shape - confirming to Type II isotherms. Based on the statistical data analysis, modified GAB model was found to be more adequate to explain sorption characteristics of CDP. It is noted that the rate of adsorption and desorption is specific to the temperature at which it was being studied. It is observed that isosteric heat of sorption decreased with increasing equilibrium moisture content. CONCLUSIONS: The calculation of the thermodynamic properties was further used to draw an understanding of the properties of water and energy requirements associated with the sorption behavior. The sorption-desorption data and the set of equations are useful in the simulation of processing, handling, and storage of CDP and further behavior during manufacture and storage of CDP formulations. PMID- 28584489 TI - Influence of Milling Process on Efavirenz Solubility. AB - INTRODUCTION: The aim of this study was to investigate the influence of the milling process on the solubility of efavirenz. MATERIALS AND METHODS: Milling process was done using Nanomilling for 30, 60, and 180 min. Intact and milled efavirenz were characterized by powder X-ray diffraction, scanning electron microscopy (SEM), spectroscopy infrared (IR), differential scanning calorimetry (DSC), and solubility test. RESULTS: The X-ray diffractogram showed a decline on peak intensity of milled efavirenz compared to intact efavirenz. The SEM graph depicted the change from crystalline to amorphous habit after milling process. The IR spectrum showed there was no difference between intact and milled efavirenz. Thermal analysis which performed by DSC showed a reduction on endothermic peak after milling process which related to decreasing of crystallinity. Solubility test of intact and milled efavirenz was conducted in distilled water free CO2 with 0.25% sodium lauryl sulfate media and measured using high-performance liquid chromatography method with acetonitrile: distilled water (80:20) as mobile phases. The solubility was significantly increased (P < 0.05) after milling processes, which the intact efavirenz was 27.12 +/- 2.05, while the milled efavirenz for 30, 60, and 180 min were 75.53 +/- 1.59, 82.34 +/- 1.23, and 104.75 +/- 0.96 MUg/mL, respectively. CONCLUSIONS: Based on the results, the solubility of efavirenz improved after milling process. PMID- 28584490 TI - Chromatographic Isolation and Spectroscopic Identification of Phytoconstituents of Jujuba Seeds (Zizyphus jujuba Mill.). AB - BACKGROUND: The seeds of Zizyphus jujuba Mill. (Rhamnaceae) are astringent, aphrodisiac, tonic; used to cure cough, asthma, vomiting, burning sensation, biliousness, leucorrhoea, and eye infections in traditional systems of medicine. MATERIALS AND METHODS: The methanol extract of seeds of Z. jujuba was partitioned into petroleum ether and water soluble fractions. Isolation of compounds was performed by silica gel column chromatography. The structures of isolated compounds were established on the basis of spectral studies and chemical reactions. RESULTS: Chromatographic separation of methanolic extract of seeds yielded three new phyto-constituents characterized as 3, 5, 7-trimethoxy-8, 3', 4', 5'-tetrahydroxy flavone-6-oxy hexahydrobisabolene ether (4), 1, 9-dihydroxy tetrahydrogeranyl-8-oxy-O-beta-D-glucuronopyranoside (5) and terahydrogeranyl-8 oxy-O-beta-D-glucuronopyranosyl (2a->1b)-O-beta-D-glucofuranosyl (2b->1c)-O-beta D-glucofuranosyl (2c->1d)-O-beta-D-glucopyranosyl (2d->1e)-O-beta-D glucopyranosyl (2c->f)-O-beta-D-glucopyranosyl-2f-benzoate (6) along with five known compounds, palmitoyl palmitoleoyl arachidoyl glyceride (1), tetratriacontenoic acid (2), palmitoyl oleoyl linolenoyl glyceride (3), hexanyl tetraglucoside (7) and pentasaccharide (8). CONCLUSION: This is the first report of saturated monoterpene and sesquiterpene derivatives from jujuba seeds. PMID- 28584491 TI - Evaluation of Cassia tora Linn. against Oxidative Stress-induced DNA and Cell Membrane Damage. AB - OBJECTIVE: The present study aims to evaluate antioxidants and protective role of Cassia tora Linn. against oxidative stress-induced DNA and cell membrane damage. MATERIALS AND METHODS: The total and profiles of flavonoids were identified and quantified through reversed-phase high-performance liquid chromatography. In vitro antioxidant activity was determined using standard antioxidant assays. The protective role of C. tora extracts against oxidative stress-induced DNA and cell membrane damage was examined by electrophoretic and scanning electron microscopic studies, respectively. RESULTS: The total flavonoid content of CtEA was 106.8 +/- 2.8 mg/g d.w.QE, CtME was 72.4 +/- 1.12 mg/g d.w.QE, and CtWE was 30.4 +/- 0.8 mg/g d.w.QE. The concentration of flavonoids present in CtEA in decreasing order: quercetin >kaempferol >epicatechin; in CtME: quercetin >rutin >kaempferol; whereas, in CtWE: quercetin >rutin >kaempferol. The CtEA inhibited free radical induced red blood cell hemolysis and cell membrane morphology better than CtME as confirmed by a scanning electron micrograph. CtEA also showed better protection than CtME and CtWE against free radical-induced DNA damage as confirmed by electrophoresis. CONCLUSION: C. tora contains flavonoids and inhibits oxidative stress and can be used for many health benefits and pharmacotherapy. PMID- 28584492 TI - Prevalence of Exposure to Secondhand Smoke among Higher Secondary School Students in Ernakulam District, Kerala, Southern India. AB - INTRODUCTION: The association between secondhand smoke and health outcomes, such as frequent respiratory infections, ischemic heart disease, lung cancer, asthma, and stroke, has long been established. The study aimed to estimate the prevalence of secondhand smoking exposure among higher secondary school students in Ernakulam district, Kerala, Southern India. MATERIALS AND METHODS: A structured questionnaire was administered to all students from four randomly selected higher secondary schools in Ernakulam district. Descriptive statistics was done using frequencies and percentages. Univariate and multivariate analyses were done for factors associated with household exposure to tobacco smoke generating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 629 students participated in the study. The prevalence of ever smokers was 11.9% and of current smokers was 5.2%. Among the study participants, 23.2% were exposed to secondhand smoking from a family member and 18.8% from friends. Lower educational status of father was associated with the household exposure to secondhand smoke (adjusted OR 4.51 [95% CI 1.66-12.22]). More than half of the study participants (56.3%) reported that they were exposed to cigarette smoke in past 1 week in a public place and 10.2% in closed public places. Nearly one-third of the students reported that they have seen somebody smoking inside school campus in the past 30 days. CONCLUSION: Exposure to secondhand smoke at home, schools, and public places was higher among the late adolescent higher secondary school students in Ernakulam district. The findings underscore the urgent need for increased efforts to implement the strategies to reduce secondhand smoke exposure among adolescents. PMID- 28584494 TI - Efficacy and Tolerability of Antihypertensive Drugs in Diabetic and Nondiabetic Patients. AB - OBJECTIVES OF THE STUDY: The aim of the study was to compare the efficacy and tolerability of different classes of antihypertensive drugs in diabetic and nondiabetic patients (NDPs) with essential hypertension. MATERIAL AND METHODS: The study was conducted in Mayo Hospital, Punjab Institute of Cardiology, and National Defence Hospital, Lahore, Pakistan, on 200 hypertensive patients with diabetes and 230 hypertensive patients without (Three hospitals) diabetes. Both male and female patients of age between 30 and 80 years with systolic blood pressure (SBP) above 130 mmHg and diastolic blood pressure (DBP) above 80 mmHg were enrolled in the study. Angiotensin converting enzyme inhibitors (ACEI), beta blocker (betaB), calcium-channel blocker (CCB), diuretics (D), angiotensin receptor blocker (ARB) as well as alpha-blocker classes of antihypertensive drugs were used. These drugs were used as monotherapy as well as combination therapy. The study was conducted for 4 months (July-October). After 4 months, patients were assessed for efficacy by monitoring blood pressure (BP) and tolerability by assessing safety profile on renal function, liver function as well as lipid profile. RESULTS: Significant control in mean BP by all drug groups was observed in "both groups that is patients with diabetes and without diabetes." The efficacy and tolerability data revealed that in diabetic patients with hypertension, the highest decrease in SBP and DBP was observed using monotherapy with ACEI, two-drug combination therapy with ACEI plus diuretic, ARBs plus diuretic, ACEI plus CCBs, three-drug combination therapy with ACEI plus CCBs plus diuretic, and four drug combination therapy with ACEI plus CCBs plus diuretic plus betaBs, ARB's plus CCBs plus diuretic plus betaBs while in NDPs, monotherapy with diuretic, two-drug combination therapy with ACEI plus CCBs, ACEI plus betaBs, three-drug combination therapy with betaBs plus ACEI plus D was found more effective in controlling SBP as well as DBP. Adverse effects observed were dry cough, pedal edema, dizziness, muscular cramps, constipation, palpitations, sweating, vertigo, tinnitus, paresthesia, and sexual dysfunction. CONCLUSION: All classes of antihypertensives were found to control blood pressure significantly in both groups of patients that is diabetic patients with hypertesion and non diabetic patients with hypertension. PMID- 28584493 TI - Assessment of Perception, Experience, and Information-seeking Behavior of the Public of Ras Al-Khaimah, United Arab Emirates, Toward Usage and Safety of Complementary and Alternative Medicine. AB - AIMS AND OBJECTIVES: This study was conducted to identify the different types of complementary and alternative medicine (CAM) used, reasons for the use of CAM, and the perceptions, experience, and information seeking-behavior toward usage and safety of CAM by the general public of Ras Al-Khaimah, UAE. MATERIALS AND METHODS: This was a prospective cross-sectional study. A validated, self administered, or interviewer-assisted survey questionnaire was used to collect the data. Data from 403 respondents satisfying inclusion criteria were collected and were analyzed using the Statistical Package for the Social Sciences version 24.0. RESULTS: A majority of the respondents (218 [54.1%]) were females. The most commonly (210 [52.1%]) used CAM among the study respondents was herbal medicine. A total of 91 (22.6%) of the survey respondents mentioned that they receive conventional medications along with their CAM. Majority (213 [52.9%]) of the survey respondents opted for CAM to prevent illness. Good number (208 [51.6%]) of the survey respondents mentioned that CAM usage was beneficial in improving their health condition, and they (216 [53.6%]) do believe it as safe and effective. However, a small group (26 [6%]) of respondents reported side effects or complications with the use of CAM. CONCLUSION: Widespread use of CAM for different medical problems was evident in our study. Although majority of the CAM users believe it as safe and effective, CAM usage should be discussed with the health-care providers to understand the safety issues involved in the use of majority of CAM. PMID- 28584495 TI - Prevalence, Pattern, and Correlates of Alcohol Misuse among Male Patients Attending Rural Primary Care in India. AB - BACKGROUND: There are limited data available on how the problem of alcohol use is detected in primary care setting in India. Particularly in Odisha, it has not been investigated yet. This study was conducted to determine the prevalence of drinking, drinking patterns, and quitting behavior among the male patients visiting a primary health-care facility in a district of Odisha. METHODOLOGY: A cross-sectional study was conducted among patients attending community health center (CHC), Buguda in the state of Odisha, India, from December 1, 2014, to February 31, 2015. Patients above 18 years of age, conscious, and willing to participate in the study were included in the study, while those with cognitive impairment and critically ill were excluded from the study. All eligible consecutive patients attending outpatient department of CHC were invited to participate while they came out after physician's consultation. A pilot study was conducted prior to the study. Informed verbal consent from each patient was obtained before the interview. The study was approved by the Institutional Ethics Committee of Indian Institute of Public Health, Bhubaneswar. RESULTS: A total of 431 patients were interviewed. Our study showed 38% (95% confidence interval [CI]: 33.5%-42.7%) of respondents were alcoholic and of those 60% (95% CI: 51.4% 66.5%) were hazardous drinkers. One in five patients had a history of alcoholics in their family, and a similar proportion of participants were heavy workers. Smokers were eight times (adjusted odds ratio [AOR] =7.56; 4.03-14.52) more likely to be alcoholics as compared to nonsmokers (P < 0.001), whereas the prevalence of alcohol drinking was four times (AOR = 3.94; 2.25-6.92) higher in smokeless tobacco users compared to nonusers. CONCLUSION: Focusing only on counseling and treatment services will not reduce the piling burden of alcohol use. It is important to target the environment that leads to such habits. PMID- 28584496 TI - Marfan Syndrome. AB - Marfan syndrome (MFS) is the autosomal dominant-inherited multisystem connective tissue disorder, with a reported incidence of 1 in 10,000 individuals and equal distribution in both genders. The main clinical manifestation of this disorder consists of an exaggerated length of the upper and lower limbs, hyperlaxity, scoliosis, alterations in the cardiovascular and pulmonary systems, and atypical bone overgrowth. Orofacial manifestations such as high-arched palate, hypodontia, long narrow teeth, bifid uvula, mandibular prognathism, and temporomandibular disorders are also common. Early diagnosis of MFS is essential to prevent the cardiovascular complications and treatment of orofacial manifestations, thus to increase the quality of life of the patient. PMID- 28584497 TI - Direct Perceptions of Carol Fowler's Theoretical Perspective. AB - Carol Fowler has had a tremendous impact on the field of speech perception, in part by having people disagree with her. The disagreements arise, as they often do, from two incompatible sources: Her positions are often misunderstood and thus "disagreed" with only on the surface, and her positions are rejected because they challenge deeply held, intuitively appealing positions, without being shown to be wrong. The misunderstandings center largely on the assertion that perception is "direct." This is often taken to mean that we have access to the speaker's vocal tract by some means other than the (largely acoustic) speech signal, when, in fact, it asserts that the signal is sufficient to directly specify that production. It is unclear why this misunderstanding persists; while there are still issues to be resolved in this regard, the stance is clear. The challenge to "acoustic" theories of speech perception remains, and thus direct perception is still controversial, as it seems that acoustic theories are held by a majority of researchers. Decades' worth of evidence showing the lack of usefulness of purely acoustic properties and the coherence gained by a production perspective have not changed this situation. Some attempts at combining the two perspectives have emerged, but they largely miss the Gibsonian challenge that Fowler has espoused: Perception of speech is direct. It looks as though it will take some further decades of research and discussion to fully explore her position. PMID- 28584498 TI - Understanding Barriers to Initial Treatment Engagement among Underserved Families Seeking Mental Health Services. AB - This mixed method study examined factors associated with parents not attending their child's mental health treatment after initially seeking help for their 2-5 year old child. It was part of a larger study comparing two evidence-based treatments among low-income racial/ethnic minority families seeking child mental health services. Of 123 parents who initiated mental health treatment (71% African American or multi-racial; 97.6% low-income), 36 (29.3%) never attended their child's first treatment session. Socio-demographic characteristics, parenting stress, depression, severity of child behavior problems, and length of treatment delay from intake to first scheduled treatment session were compared for families who did and did not attend their first treatment session. Parents who never attended their child's first treatment session were more likely to live with more than 4 adults and children (p=.007) and have more depressive symptoms (p=.003). Median length of treatment delay was 80 days (IQR =55) for those who attended and 85 days (IQR =67.5) for those who did not attend their child's first treatment session (p=.142). Three themes emerged from caregiver interviews: (a) expectations about the treatment, (b) delays in getting help, and (c) ambivalence about research participation. Findings suggest the need to develop better strategies for addressing risk factors early in the treatment process and reducing the length of time families with adverse psychosocial circumstances must wait for child mental health treatment. PMID- 28584499 TI - Quantifying Intraoperative Laparoscopic Visual Field Opacity. AB - BACKGROUND AND OBJECTIVES: Laparoscopic surgery can be complicated by condensation and debris on the lens obscuring the visual field, increasing the risk of surgical error and injury to the patient. Despite, development of possible solutions, little is known regarding the quantitative measure of time lost during surgery because of an obscured visual field. Without this knowledge, the cost of laparoscopic lens fogging cannot be quantified and compared to the cost of antifogging devices. In the present study, we investigated the amount of time a laparoscope is withdrawn for cleaning during surgery. METHODS: This was a prospective, observational study of patients (n = 52) who underwent laparoscopic surgery at Florida Hospital Celebration Health. Patient's age, gender, and body mass index, operative time, wound class, estimated blood loss, type of procedure, and complication (if any) were collected. In addition, intraoperative information on the number of times and total amount of time the laparoscope was withdrawn because of obscured visual field were recorded. RESULTS: Eighty-two percent (43) of the procedures required laparoscope withdrawal because of fogging. Increased operative time, increased blood loss, and patient age correlated with the number of times (P < .05) and amount of time (P < .05) the laparoscope was withdrawn. DISCUSSION: There was a significant correlation between increased laparoscope withdrawal because of an obscured visual field with increased EBL, operative time, and patient age. Possible explanations include change in body composition with age, the increased viewing angles required for more complex procedures, and increasing intraoperative effect on the surgeon of the poor visual field caused by fogging and debris. PMID- 28584500 TI - Postablation Endometrial Carcinoma. AB - BACKGROUND: Many women have undergone both resectoscopic and nonresectoscopic (or global) endometrial ablation (EA) during the past 20 years. These women are now approaching their sixth and seventh decades of life, a time frame in which endometrial carcinoma (EC) is most frequently diagnosed. DATABASE: In several reports, surgeons have expressed concern that endometrial ablation may leave a sequestered island of EC that may escape detection, possibly delaying its diagnosis or causing it to appear at an advanced stage. Others suggest that EA artifact does not hinder the evaluation and treatment planning in the presence of EC. Data bases used are from Medline and PubMed. DISCUSSION: We introduce 6 new cases of postablation endometrial carcinoma (PAEC), 4 of which occurred after the introduction of global endometrial ablation (GEA) techniques. In addition, we examine several key questions regarding the impact of EA on the subsequent development of EC, including the manner in which PAEC presents, the efficacy of traditional diagnostic modalities, the ablation-to-cancer interval, and the stage of PAEC at the time of diagnosis. Finally, we explore the use of reoperative hysteroscopic surgery (RHS) as a diagnostic modality and address the possible role ultrasound surveillance as a screening method for women at risk of EC. PMID- 28584501 TI - "Scarless" Inguinal Herniorrhaphy. AB - INTRODUCTION: Laparoscopic inguinal herniorrhaphy is widely accepted. Robotic assisted surgery provides improved 3-dimensional visualization and enhanced dexterity. The purpose of this case series was to demonstrate the feasibility of a modified, robotic, single-site, unilateral inguinal herniorrhaphy. TECHNIQUE: Six patients 18 years of age or older with a body mass index <35 provided informed consent and underwent hernia repair with a modified herniorrhaphy technique from January to July 2014. Eight patients were screened and six case experiences are described in this series. The da Vinci Si robot, gel port, and instruments (Intuitive Surgical, Sunnyvale, California, USA) were used. With the patient in Trendelenburg position, a 25-mm incision was made within the umbilicus. The fascia was incised, and the peritoneal cavity was entered. A robotic cholecystectomy gel port was placed. Robotic instruments were inserted, and the robot was docked. A preperitoneal flap was raised on the affected side with the robotic instruments used interchangeably. The hernia sac was identified and reduced, and the mesh was tacked in place. The preperitoneal flap was tacked back in place. The robot was undocked, the abdomen was desufflated, and the fascia was closed. DISCUSSION: Single-site unilateral inguinal herniorrhaphy was performed for 6 patients. All patients were discharged the same day, had good aesthetic results, and experienced no hernia recurrence. Robotic single-site gel port inguinal herniorrhaphy is feasible and appears as safe and time efficient as laparoscopic herniorrhaphy in this small group. PMID- 28584502 TI - Laparoscopic Splenectomy in Hemodynamically Stable Blunt Trauma. AB - BACKGROUND AND OBJECTIVES: No criteria define indications for laparoscopic splenectomy in trauma. This investigation compared characteristics of trauma patients and outcomes between laparoscopic and open splenectomies. METHODS: Patients were identified retrospectively by using ICD-9 codes. Included patients were 18 or older, with a blunt splenic injury from January 1, 2011, through December 31, 2014, and required splenectomy. Excluded patients had penetrating trauma, successful nonoperative management, or successful embolization. Variables included demographics, presenting characteristics, injury severity scores, abdominal abbreviated injury scores, splenic injury grade, surgical indication and approach (open or laparoscopic), surgery length, intra-operative blood loss, transfusions, length of stay, complications, mortality, and discharge disposition. RESULTS: Forty-one patients underwent open splenectomy, and 11 underwent laparoscopic splenectomy. The mean age was 48.7 years, and men comprised the sample majority (36/52). The groups were well matched for age, abdominal injury scores, and admission vital signs. The open group had a significantly lower level of consciousness and more acidosis compared with the laparoscopic group. Most laparoscopic splenectomies were performed after failed nonoperative management or embolization. The indications for open splenectomy were a positive focused assessment with sonography for trauma and computed tomography results. Laparoscopic patients had significantly longer times between presentation and surgery and longer operations, but had significantly less blood loss and fewer transfusions compared with the open group. There were no differences in mortality, length of stay, complications, or discharge dispositions. CONCLUSION: Laparoscopic splenectomy is useful in patients with blunt trauma in whom conservative management produced no improvement and who do not have other injuries to preclude laparoscopy. PMID- 28584503 TI - Surgical Scales: Primary Closure versus Gastric Resection for Perforated Gastric Ulcer - A Surgical Debate. AB - Perforated gastric ulcer is one of the most life-threatening complications of peptic ulcer disease with high morbidity and mortality rates. The surgical strategy for gastric perforation in contrast with duodenal perforations often requires consilium and intraoperative debates. The subject of the debate is a 59 year-old male patient who presented with perforated giant gastric ulcer complicated by generalized peritonitis and severe sepsis. The debate is based on a systematized table dividing all factors into three groups and putting them on surgical scales. Pathology-related factors influencing the decision-making are size and site of perforation, local tissue inflammation, signs of malignancy, simultaneous complications of peptic ulcer, peritonitis, and sepsis. Besides these factors, patient- and healthcare-related factors should also be considered. PMID- 28584504 TI - Short-term Effect of Tamsulosin and Finasteride Monotherapy and their Combination on Nigerian Men with Benign Prostatic Hyperplasia. AB - OBJECTIVE: The objective of this study was to assess the efficacy of tamsulosin and finasteride monotherapies, and their combination in men with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This is a prospective single-blind randomized study of ninety men with BPH who were managed using drugs. The International Prostate Symptom Score (IPSS), peak urinary flow rate, and prostate volume were measured as parameters for assessment at the beginning, 3 months, and 6 months of the study. RESULTS: The mean age of patients was 61.65 with a range of 44-81 years. There was a progressive and sustained improvement in the IPSS score in all patient groups with mean decrease at 3 months of 7.24 (42.59%), 7.60 (41.85%), and 7.24 (40.61%) and at 6 months of 8.14 (47.88%), 10.33 (56.88%), and 11.1 (62.25%) in the tamsulosin, finasteride, and combination groups, respectively. There was an increase in peak urinary flow rate in all groups with mean increase at 3 months of 0.98, 0.05, and 3.55 (ml/s) and at 6 months of 4.11, 0.87, and 3.74 (ml/s) in the tamsulosin, finasteride, and combination groups, respectively. There was a reduction in the prostate volume in the finasteride and combination groups at 6 months of 6.8 and 6.32 cm3, respectively, while the tamsulosin group recorded an increase. CONCLUSION: At the end of 6 months, tamsulosin monotherapy and combination therapy appear to be equally effective in the treatment of lower urinary tract symptoms BPH while finasteride monotherapy appears to be the least effective. Bothersome, side effects were more in patients taking finasteride alone or as combination therapy. PMID- 28584505 TI - Management and Outcome of Patients with Pancreatic Trauma. AB - INTRODUCTION: Pancreatic trauma is a rare entity occurring in 0.2% of patients with blunt trauma abdomen. Once the diagnosis is made, the management of patients is dependent on multiple variables. Conservative management, suture repair, drainage, and resection have been utilized with varying degree of success. This study is aimed to evaluate the management of patients with pancreatic trauma. MATERIALS AND METHODS: This was a prospective study done in the Department of Surgery in Dayanand Medical College and Hospital where forty hemodynamically stable patients diagnosed to have pancreatic trauma on contrast-enhanced computed tomography abdomen were included in the study. RESULTS: Out of forty patients taken in this study, 38 were male and two were female with age ranging from 3 to 50 years. Road traffic accident was the most common cause of pancreatic injury. Pancreatic injuries were graded according to the American Association for Surgery in Trauma scale. Twelve patients had Grade I and II injuries. Grade III was the most common injury occurring in 14 patients. Twenty-four patients underwent surgical management. Mortality rate was 45% and it was in direct correlation with the severity of injury. CONCLUSION: Grade I and II pancreatic injury can be managed conservatively depending upon the hemodynamic status of the patient. Grade III and IV injuries have a better prognosis if managed surgically. PMID- 28584506 TI - Prognostic Factors and Outcome of Management of Ischemic Priapism in Zaria, Nigeria. AB - OBJECTIVES: The objective of this study was to determine the nuances of management, prognostic factors, and outcome of ischemic priapism in patients seen at Ahmadu Bello University Teaching Hospital, Zaria, Nigeria. PATIENTS AND METHODS: We retrospectively studied the case notes of all patients managed for ischemic priapism in the Ahmadu Bello University Teaching Hospital, Zaria, over a period of 10 years (2006-2015). The data extracted included patients' age, occupation, duration of painful penile erection, and previous episodes. Addition information including precipitating factors, hemoglobin genotype, treatment, and complications was also retrieved. Data obtained were analyzed using SPSS version 20. RESULTS: The records of a total of forty patients managed for priapism over the period under review were retrieved. Thirty-three (82.5%) of these patients had an operative intervention. The mean age was 23.7 years with a range of 8-53 years. Sixty percent of patients were young adults in their third decade of life. The minimum duration of erection at presentation was 18 h and a maximum period of 10 days with a mean of 105.5 h (4 days). Thirty-three patients (82.5%) had sickle cell anemia (HbSS). Erectile dysfunction (ED) accounted for 60% of all forms of postpriapism complications. Five patients (12.5%) had residual tumescence from fibrosis, and three patients had recurrence outside the immediate postoperative period. Duration of symptoms before surgical intervention, SSA and previous episodes were the most important prognostic factors. CONCLUSION: Priapism is a disease of the young, mostly sickle cell anemic patients. Late presentation remains the norm in our environment, hence a higher incidence of ED. The distal penile shunt is an effective means of achieving detumescence even with failed conservative management. Favorable outcome is highly dependent on the duration of erection and early intervention. PMID- 28584507 TI - A Comparative Study of the Use of Harmonic Scalpel versus Unipolar Cautery in Modified Radical Mastectomy. AB - CONTEXT: Oncosurgery is an emerging branch with the set goals of prolonging the life and ensuring the best possible quality of life to the surviving patient. The use of harmonic scalpel has proved to be beneficial in a variety of surgeries but its role in breast surgery is still controversial. AIMS: We conducted this study to compare the intraoperative and postoperative outcomes in modified radical mastectomy using harmonic scalpel versus electrocautery. SUBJECTS AND METHODS: Fifty female patients with confirmed diagnosis of breast carcinoma and planned for modified radical mastectomy were taken up for surgery. Twenty-five patients were operated using harmonic scalpel (Group A) and another 25 were operated using unipolar cautery (Group B). RESULTS: The mean operative time was significantly longer with harmonic scalpel when compared to that with electrocautery (140.40 +/ 29.96 vs. 99.80 +/- 24.00 min, P < 0.001). The smaller amount of drainage content (431.60 +/- 145.94 vs. 594.20 +/- 278.63, P = 0.013) and intraoperative blood loss (426.00 +/- 76.54 vs. 502.00 +/- 104.56, P = 0.005) in the group operated with the ultrasound harmonic scalpel was statistically significant. There was no significant difference between the groups with regard to drain duration (5.24 +/- 0.97, P = 0.127), seroma (12% vs. 16%, P = 0.684), hematoma (4% vs. 4%, P = 1.000), wound infection (24% vs. 32%, P = 0.529), flap necrosis (8% vs. 28%, P = 0.066), pain intensity (measured on visual analog scale) (5.08 +/- 1.29 vs. 5.20 +/- 1.68, P = 0.778), and lymphedema (4% vs. 8%, P = 0.552). The length of hospital stay could not be compared effectively because all the patients were discharged on the 10th or 11th postoperative day. The cost of the equipment used in the electrocautery group was almost negligible as compared to the harmonic group. CONCLUSIONS: The use of harmonic scalpel versus electrocautery is somewhat advantageous but not cost-effective. PMID- 28584508 TI - Childhood Pyogenic Septic Arthritis as Seen in a Teaching Hospital South East Nigeria. AB - BACKGROUND: Childhood pyogenic septic arthritis and its associated musculoskeletal morbidity is an important health concern in developing countries. Its pattern of presentation that varies from and within subregions has implications on the early recognition, treatment, and outcome. The aim of this study was to determine the pattern and outcome of childhood septic arthritis in our environment. MATERIALS AND METHODS: This was a retrospective study of all the children seen with pyogenic septic arthritis in Federal Teaching Hospital Abakaliki between January 2005 and December 2015. RESULTS: Childhood septic arthritis accounted for 44 (83%) of the 53 patients seen with pyogenic septic arthritis. Female to male ratio was 1:1.75 and the mean age was 5.7 +/- 0.73 years. Eight patients (18.2%) had polyarticular involvements. The right shoulder was significantly more involved than the left and the left hip more than right. Overall, there was a preponderance of onset of symptoms in the dry season. Children from the rural areas accounted for 85.7% of those with the onset of symptom in rainy season. Delayed presentation >6 days (in 68.2% of patients) was related to age (P < 0.042), and health seeking behavior (P < 0.036). Staphylococcus aureus was the commonest causative organism. Seventy-seven percent (77%) underwent open arthrotomy. Anemia, septic shock, and joint stiffness were three top complications observed. Mortality rate was 2.3%, and cause of death was overwhelming sepsis. CONCLUSION: In our setting, pyogenic septic arthritis is predominantly a childhood health problem and children under 5 years of age are the most vulnerable. Delayed presentation, an important factor in morbidity and mortality associated with septic arthritis was common among the patients, calls for a public enlightenment program on the importance of early presentation. PMID- 28584509 TI - Prostate Cancer Detected by Screening in a Semi Urban Community in Southeast Nigeria: Correlations and Associations between Anthropometric Measurements and Prostate-specific Antigen. AB - CONTEXT: Prostate cancer (PCa) is frequently diagnosed at advanced stages in Nigeria. AIMS: To determine the screen detected PCa prevalence in a suburban community and explore any relationships between prostate-specific antigen (PSA) and anthropometric measurements. SETTINGS AND DESIGN: Nsukka is a town and local government area (LGA) in Southeast Nigeria in Enugu State. Towns that share a common border with Nsukka are Edem Ani, Alor-uno, Opi, Orba, and Ede-Oballa. Nsukka LGA has an area of 1810 km2 and a population of 309,633 at the 2006 census. All consecutive responders who met the inclusion criteria were recruited. SUBJECTS AND METHODS: A screening outreach was conducted in one location in Nsukka. PSA testing and digital rectal examinations were performed. Height and weight were measured and body mass index (BMI) was calculated. STATISTICAL ANALYSIS USED: Results were subjected to statistical analysis using SPSS 20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, USA). Categorical data were analyzed using the Chi-square test, with significance level set at P < 0.05. Pearson's correlation was conducted for interval data (P < 0.05). RESULTS: One hundred and sixty men met the inclusion criteria and were screened. Age range was 40-81 years; PSA range was 1.20-33.9 ng/ml. Digital rectal examinations (DREs) was abnormal in 17 men. Median BMI was 27.49. A Pearson's correlation coefficient showed a significant correlation between age and PSA, r = 0.127; P <= 0.05, and DRE findings and PSA, r = 0.178; P <= 0.05. There was no significant correlation between height and PSA, r = -0.99; P = 0.211; weight and PSA, r = -0. 81 P = 0.308; and BMI and PSA, r = -0.066; P = 0.407. 8/21 men consented to prostate biopsy with three positive, giving a screen detected PCa prevalence of 1.875%. CONCLUSIONS: Screen detected PCa prevalence in high this population and efforts to improve early detection may be of value in improving treatment outcomes. PMID- 28584510 TI - Evaluation of Mandibular Condylar Changes in Patients Following Orthognathic Surgery: A Retrospective Study. AB - BACKGROUND: Condylar resorption as a cause of relapse after orthognathic surgery is well known. Several authors have presented evidence of the relation between orthognathic surgery and condylar remodeling and resorption. This study was done to appraise the condylar changes along with the form and function following orthognathic surgery, as well as to assess what factors may have contributed to the problems. METHODOLOGY: A diagnosis of progressive condylar resorption (PCR) was made by comparison of preoperative and postoperative radiographs (cephalometric radiograms), as well as clinical evaluations. The radiographs were taken for each patient preoperatively and postoperatively, which include immediately after osteotomy, at 6 months and 24 months. Additional radiographs were taken when required. Then, preoperative and postoperative tracings were compared at 24 months postoperatively. RESULTS AND CONCLUSION: It can be concluded from this study that females of relative low age (<18 years) appeared to be a high-risk factor for the occurrence of condylar alteration including PCR. A steep mandibular plane angle, the low facial height ratio (post/ant), and magnitude of surgery were also significantly related to the occurrence of condylar alteration, but the multivariance regression showed that these parameters had only limited value. PMID- 28584511 TI - An Evaluation of Intra- and Post-operative Blood Loss in Total Hip Arthroplasty at the National Orthopaedic Hospital, Lagos. AB - BACKGROUND: Severe hip pain with associated significant functional limitation is the major indication for total hip replacement, a rewarding and gratifying procedure. However, significant blood loss can occur in the intra- and post operative periods, posing a major challenge and necessitating prompt restoration of circulating blood volume to minimize morbidity and mortality. The aim of this study was to evaluate blood loss after primary total hip replacement, and to determine the effect of surgical time on blood loss. PATIENTS AND METHODS: A prospective study of blood loss after total hip arthroplasty in 41 patients. All cases were primary total hip arthroplasty done by one surgeon. Intra- and post operative blood losses were recorded in two groups of patients (surgical time <2 h and surgical time >2 h), and the effect of these on blood loss was evaluated. RESULTS: The mean intra- and post-operative blood losses were 1222.7 ml and 574.3 ml, respectively. These showed a strong positive correlation with total blood loss (r = 0.790, P < 0.001 and r = 0.517, P < 0.001). Higher intra- and post operative blood losses were recorded in patients with surgical time >2 h, with a significant difference on postoperative days 2 and 3 (P = 0.003 and P = 0.014, respectively). CONCLUSION: Blood loss in total hip replacement is an important factor and may be influenced by a shorter surgical time. PMID- 28584512 TI - Civilian Penetrating Gunshot Injury to the Neurocranium in Enugu. AB - INTRODUCTION: Civilian penetrating gunshot injuries to the neurocranium are no longer uncommon in Nigeria. Such injuries are however poorly reported. They are associated with poor outcome and, at close range, are frequently fatal, especially when inflicted by high-velocity weapons. Prompt transfer to neurosurgical service and urgent intervention may improve outcome in those that are not mortally wounded. MATERIALS AND METHODS: Fifty-two patients with civilian penetrating gunshot wounds seen over a 10-year period (2004-2014) at the University of Nigeria Teaching Hospital and Memfys Hospital for Neurosurgery Enugu were reviewed retrospectively, and their data were analyzed to evaluate factors that impacted on outcome. Only patients with clinical and imaging evidence of cranial gunshot injuries who reached hospital alive were included in the study. The overall mortality and Glasgow outcome score were analyzed. RESULTS: Fifty-two patients with isolated civilian penetrating gunshot wounds were identified (M:F = 7.7:1); mean (standard deviation) age was 32.8 (11.9) years. There was a high correlation (0.983) between the sex of the patients and the outcome. The overall mortality was 30.8%, whereas the mortality for patients with postresuscitation Glasgow coma scale (GCS) score <=8 was 57%, as against 12.9% in those in whom postresuscitation GCS was >8; meaning that 87.1% of patients in whom postresuscitation GCS was >8 survived. Thirty-one patients (59.6%) had papillary abnormalities. Majority of patients with monohemispheric lesions survived while all those with diencephalic, transventricular, and posterior fossa involvement had 100% mortality. CONCLUSIONS: Admitting GCS and bullet trajectory were predictive of outcome. PMID- 28584513 TI - Assessment of PANC3 Score in Predicting Severity of Acute Pancreatitis. AB - INTRODUCTION: Acute pancreatitis is inflammatory process of the pancreas associated with local and systemic complications. At present, there are lots of scores (such as Ransons, APACHE II, bedside index for severity in acute pancreatitis) that help us in predicting severity at the time of admission but these are time consuming or require complex calculation and are costly. MATERIAL AND METHODS: PANC3 Scoring System is one of the better systems because the three criteria used (hematocrit, body mass index, and pleural effusion) are simple, easy to assess, readily available, and economic. In this prospective study, 100 cases were evaluated to see the prospects of PANC3 scoring in predicting the severity of acute pancreatitis as decided by modified Marshals score. RESULTS: The results showed that PANC3 score had a 96.43% specificity, 75% sensitivity, 80% positive predictive value, and 95.29% negative predictive value. CONCLUSION: Hence, the PANC3 score is a cost-effective, promising score that helps in predicting the severity of acute pancreatitis leading to prompt treatment and early referral to higher center. PMID- 28584514 TI - Systemic Assessment of Patients Undergoing Dental Implant Surgeries: A Trans- and Post-operative Analysis. AB - BACKGROUND: Procedure-related and patient-related factors influence the prognosis of dental implants to a major extent. Hence, we aimed to evaluate and analyze various systemic factors in patients receiving dental implants. MATERIALS AND METHODS: Fifty-one patients were included in the study, in which a total of 110 dental implants were placed. Complete examination of the subjects was done before and after placement of dental implants. Implant surgery was planned, and osseointegrated dental implants were placed in the subjects. Postoperative evaluation of the dental implant patients was done after 3 weeks. Anxiety levels were determined using State-Trait Anxiety Inventory (STAI) questionnaire on the surgery day and after 1 week of surgery. The participant describes how they feel at the moment by responding to twenty items as follows: (1) absolutely not, (2) slightly, (3) somewhat, or (4) very much. All the results were recorded and statistical analyzed by SPSS software. RESULTS: Out of 51, 29 patients were males while 22 were females, with ratio of 1.32:1. Female patients' mean age was 50.18 years while male patients' mean age was 52.71 years, with statistically nonsignificant difference between them. Functional rehabilitation was the main purpose of choosing dental implants in more than 90% of the subjects. Diameter of 3.75 mm was the shortest implants to be placed in the present study, whereas in terms of length, 8.5 mm was the shortest length of dental implant used in the present study. Tooth area in which maximum implants were placed in our study was 36 tooth region. Maximum implants were placed in Type II bone quality (n = 38). Implants installed in the mandible were clamped more efficiently than implants placed in the maxilla (P < 0.001). The difference of average STAI-State subscore before and after the surgery was statistically significant (P < 0.05; significant). CONCLUSION: Mandibular dental implants show more clamping (torque) than maxillary dental implants. PMID- 28584515 TI - Circumareolar Incision-subdermal Tunneling Dissection for Excision of Multiple Breast Fibroadenomata. AB - Excision of multiple fibroadenomas (MF) in separate breast quadrants presents difficulties of number and location of incision(s) and extent of tissue dissection and may be associated with more complications and poorer cosmetic outcome. This is a report of excision of MF in multiple quadrants of the breast using a modification of subcutaneous dissection technique dubbed the circumareolar incision and subdermal tunneling (CAST) dissection. After exposure of the superficial fascia with circumareolar incision, subdermal cone-wise dissection was made to allow mobilization of the segment bearing the lump(s). The lump(s) were enucleated and removed. MF were removed from four breasts in three young unmarried females. The first patient had multiple adenomas removed from three quadrants of both breasts: 14 on the right and six on the left. The second patient had excision of three lumps in three separate quadrants, and the third patient had excision of two lumps in two separate quadrants. All patients had edema and bruising. One breast had wound infection and dehiscence. There were no skin necrosis, no nipple loss, and no breast distortion. All ensuing scars were camouflaged. CAST dissection was used for excision of MF in multiple quadrants of the breast with preservation of excellent cosmetic outcome of a single circumareolar incision. PMID- 28584516 TI - Missed Distal Tracheal Foreign Body in Consecutive Bronchoscopies in a 6-year-old Boy. AB - It is unusual but not uncommon for foreign bodies to be missed at bronchoscopy. This case report highlights the importance of the clinical history in the diagnosis of aspirated foreign bodies and the usefulness of chest imaging modalities. A 6-year-old boy presented with recurrent breathlessness and cough of 2 months. He was said to have aspirated the base cap of a pen at about the time symptoms started. He had two sessions of rigid bronchoscopy and a session of flexible bronchoscopy at three different hospitals. He had an initial rigid bronchoscopy which failed to show the foreign body (FB). A chest computerized tomographic scan demonstrated the FB, which was retrieved at combined flexible/rigid bronchoscopy. Although rigid bronchoscopy is the gold standard for managing airway foreign bodies, there remains a false negative rate for this procedure and where necessary, appropriate imaging may compliment rigid bronchoscopy, especially where there is some confusion. PMID- 28584517 TI - A Rare Case of Mesenteric Gastrointestinal Stromal Tumor Presenting as Acute Abdomen. AB - Gastrointestinal stromal tumours (GIST) are rare tumours arising from mesenchyme of gastrointestinal tract and overexpress C-kit protein. Mainly seen in stomach and small bowel. Mesenteric GIST are rarely reported as they constitute less than 1% of total GIST. We here report such a rare case of GIST arising from mesentery of small bowel and presenting as acute abdomen. Good surgical clearance ensures good survival whereas incomplete resection results in a high incidence of recurrences with distant metastasis. PMID- 28584518 TI - An Investigation into a Gear-Based Knee Joint Designed for Lower Limb Prosthesis. AB - A gear-based knee joint is designed to improve the performance of mechanical-type above-knee prostheses. The gear set with the help of some bracing, and bracket arrangement, is used to enable the prosthesis to follow the residual limb movement. The motion analysis and finite-element analysis (FEA) of knee joint components are carried out to assess the feasibility of the design. The maximum stress of 29.74 MPa and maximum strain of 2.393e-004 are obtained in the gear, whereas the maximum displacement of 7.975 mm occurred in the stopper of the knee arrangement. The factor of safety of 3.5 obtained from the FE analysis indicated no possibility of design failure. The results obtained from the FE analysis are then compared with the real data obtained from the literature for a similar subject. The pattern of motion analysis results has shown a great resemblance with the gait cycle of a healthy biological limb. PMID- 28584520 TI - Article Watch: July 2017. AB - This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, MCG-UGA Medical Partnership, 1425 Prince Ave., Athens, GA 30606, USA. Tel: (706) 713 2216; Fax: (706) 713-2221; E-mail: cslaught@uga.edu, or to any member of the editorial board. Article summaries reflect the reviewer's opinions and not necessarily those of the association. PMID- 28584519 TI - Degradation of landfill leachate compounds by persulfate for groundwater remediation. AB - In this study, batch and column experiments were conducted to evaluate the feasibility of using persulfate oxidation to treat groundwater contaminated by landfill leachate (CGW). In batch experiments, persulfate was compared with H2O2, and permanganate for oxidation of organic compounds in CGW. It was also compared with the potential of biodegradation for contaminant removal from CGW. Persulfate was observed to be superior to H2O2 and permanganate for degradation of total organic carbon (TOC) in the CGW. Conversely, biodegradation caused only partial removal of TOC in CGW. In contrast, persulfate caused complete degradation of the TOC in the CGW or aged CGW, showing no selectivity limitation to the contaminants. Magnetite (Fe3O4) enhanced degradation of leachate compounds in both CGW and aged CGW with limited increase in persulfate consumption and sulfate production. Under dynamic flow condition in 1-D column experiments, both biodegradation and persulfate oxidation of TOC were enhanced by Fe3O4. The enhancement, however, was significantly greater for persulfate oxidation. In both batch and column experiments, Fe3O4 by itself caused minimal consumption of persulfate and production of sulfate, indicating that magnetite is a good persulfate activator for treating CGW in heterogeneous systems The results of the study show that the persulfate-based in-situ chemical oxidation (ISCO) method has great potential to treat the groundwater contaminated by landfill leachate. PMID- 28584522 TI - The Relationship Timeline: A Method for the Study of Shared Lived Experiences in Relational Contexts. AB - Lifeline methods-graphic illustrations of the pathways of lived experience traveled by individuals from birth to anticipated death-have been useful in the study of lived experience. Existing lifeline methods and research focus on the individual experience; absent from this literature are the collective experiences of those in intimate relationships. In this paper, based on our research with 120 same-sex couples, we present a method to allow for the joint creation of relationship timelines, which serve as the basis for eliciting dyadic data in multiple forms: graphic representations of relationship development through couples' creation of a timeline of key events and periods; qualitative narratives of couples' shared experiences; and quantitative ratings of significant events and periods in their lives together. Lessons learned from the application of this Relationship Timeline Method are discussed, as are implications for future study of the shared lived experience. PMID- 28584523 TI - Corrigendum: The Involvement of Nitric Oxide in Integration of Plant Physiological and Ultrastructural Adjustments in Response to Arsenic. AB - [This corrects the article on p. 516 in vol. 8, PMID: 28469622.]. PMID- 28584524 TI - Fibroblast Growth Factor 21 Deficiency Attenuates Experimental Colitis-Induced Adipose Tissue Lipolysis. AB - AIMS: Nutrient deficiencies are common in patients with inflammatory bowel disease (IBD). Adipose tissue plays a critical role in regulating energy balance. Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator with emerging beneficial roles in lipid homeostasis. We investigated the impact of FGF21 in experimental colitis-induced epididymal white adipose tissue (eWAT) lipolysis. METHODS: Mice were given 2.5% dextran sulfate sodium (DSS) ad libitum for 7 days to induce colitis. The role of FGF21 was investigated using antibody neutralization or knockout (KO) mice. Lipolysis index and adipose lipolytic enzymes were determined. In addition, 3T3-L1 cells were pretreated with IL-6, followed by recombinant human FGF21 (rhFGF21) treatment; lipolysis was assessed. RESULTS: DSS markedly decreased eWAT/body weight ratio and increased serum concentrations of free fatty acid (FFA) and glycerol, indicating increased adipose tissue lipolysis. eWAT intracellular lipolytic enzyme expression/activation was significantly increased. These alterations were significantly attenuated in FGF21 KO mice and by circulating FGF21 neutralization. Moreover, DSS treatment markedly increased serum IL-6 and FGF21 levels. IL-6 pretreatment was necessary for the stimulatory effect of FGF21 on adipose lipolysis in 3T3-L1 cells. CONCLUSIONS: Our results demonstrate that experimental colitis induces eWAT lipolysis via an IL-6/FGF21-mediated signaling pathway. PMID- 28584526 TI - Analyses of Mineral Content and Heavy Metal of Honey Samples from South and East Region of Turkey by Using ICP-MS. AB - The substantial of mineral ingredients in honey may symbolize the existence of elements in the plants and soil of the vicinity wherein the honey was taken. The aim of this study was to detect the levels of 13 elements (Potassium (K), Sodium (Na), Calcium (Ca), Iron (Fe), Zinc (Zn), Cadmium (Cd), Copper (Cu), Manganese (Mn), Lead (Pb), Nickel (Ni), Chromium (Cr), Aluminum (Al), and Selenium (Se)) in unifloral and multifloral honey samples from south and east regions of Turkey. Survey of 71 honey samples from seven different herbal origins, picked up from the south and east region of Turkey, was carried out to determine their mineral contents during 2015-2016. The mineral contents were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). The most abundant minerals were K, Na, and Ca ranging within 1.18-268 ppm, 0.57-13.1 ppm, and 0.77-4.5 ppm, respectively. Zn and Cu were the most abundant trace element while Pb, Cd, Ni, and Cr were the lowest heavy metals in the honey samples surveyed, with regard to the concentrations of heavy metals such as Zn, Cu, Pb, Cd, Ni, and Cr suggested and influence of the botanical origin of element composition. Geochemical and geographical differences are probably related to the variations of the chemical components of honey samples. PMID- 28584525 TI - Gastrointestinal Motility Disorders and Their Clinical Implications in Cirrhosis. AB - Gastrointestinal motility is impaired in a substantial proportion of patients with cirrhosis. Cirrhosis-related autonomic neuropathy, increased nitric oxide production, and gut hormonal changes have been implicated. Oesophageal dysmotility has been associated with increased frequency of abnormal gastro oesophageal reflux. Impaired gastric emptying and accommodation may result in early satiety and may have an impact on the nutritional status of these patients. Small intestinal dysmotility might be implicated in small intestinal bacterial overgrowth and increased bacterial translocation. The latter has been implicated in the pathophysiology of hepatic encephalopathy and spontaneous bacterial peritonitis. Enhanced colonic motility is usually associated with the use of lactulose. Pharmacological interventions aiming to alter gastrointestinal motility in cirrhosis could potentially have a beneficial effect reducing the risk of hepatic decompensation and improving prognosis. PMID- 28584528 TI - Pigeon Pea and Cowpea-Based Cropping Systems Improve Vesicular Arbuscular Mycorrhizal Fungal Colonisation of Subsequent Maize on the Alfisols in Central Malawi. AB - Mycorrhizal associations contribute to the sustainability of crop production systems through their roles in nutrient cycling and other benefits in the soil plant ecosystems. A two-year study was conducted on the Alfisols of Lilongwe and Dowa districts, Central Malawi, to assess the vesicular-arbuscular mycorrhizal (VAM) fungal colonisation levels in pigeon pea, cowpea, and maize grown in sole cropping, legume-cereal, and legume-legume intercropping systems and in the maize grown in short rotation (year 2) as influenced by the previous cropping systems and N fertilizer application. The gridline intersect method was used to assess the VAM fungal colonisation levels. Results showed that all treatments that included legumes whether grown as sole crop, in legume-cereal or in legume-legume cropping systems in the previous year, had significantly higher (P < 0.05) VAM fungal colonisation of the rotational maize crop roots by a range 39% to 50% and 19% to 47% than those in maize supplied and not supplied with N fertilizer, respectively, in a maize-maize short rotation, at the Lilongwe site. A similar trend was reported for the Dowa site. Furthermore, there were positive correlations between VAM fungal colonisation and the plant P content, dry matter yield, and nodule numbers. Further studies may help to assess the diversity of VAM fungal species in Malawi soils and identify more adaptive ones for inoculation studies. PMID- 28584527 TI - Efficacy and Safety of Manual Partial Red Cell Exchange in the Management of Severe Complications of Sickle Cell Disease in a Developing Country. AB - INTRODUCTION: The realization of red cell exchange (RCE) in Africa faces the lack of blood, transfusion safety, and equipment. We evaluated its efficacy and safety in severe complications of sickle cell disease. PATIENTS AND METHOD: Manual partial RCE was performed among sickle cell patients who had severe complications. Efficacy was evaluated by clinical evolution, blood count, and electrophoresis of hemoglobin. Safety was evaluated on adverse effects, infections, and alloimmunization. RESULTS: We performed 166 partial RCE among 44 patients including 41 homozygous (SS) and 2 heterozygous composites SC and 1 S/beta0-thalassemia. The mean age was 27.9 years. The sex ratio was 1.58. The regression of symptoms was complete in 100% of persistent vasoocclusive crisis and acute chest syndrome, 56.7% of intermittent priapism, and 30% of stroke. It was partial in 100% of leg ulcers and null in acute priapism. The mean variations of hemoglobin and hematocrit rate after one procedure were, respectively, +1.4 g/dL and +4.4%. That of hemoglobin S after 2 consecutive RCE was -60%. Neither alloimmunization nor viral seroconversion was observed. CONCLUSION: This work shows the feasibility of manual partial RCE in a low-resource setting and its efficacy and safety during complications of SCD outside of acute priapism. PMID- 28584529 TI - hTERT-Immortalized Bone Mesenchymal Stromal Cells Expressing Rat Galanin via a Single Tetracycline-Inducible Lentivirus System. AB - The use of human telomerase reverse transcriptase-immortalized bone marrow mesenchymal stromal cells (hTERT-BMSCs) as vehicles to deliver antinociceptive galanin (GAL) molecules into pain-processing centers represents a novel cell therapy strategy for pain management. Here, an hTERT-BMSCs/Tet-on/GAL cell line was constructed using a single Tet-on-inducible lentivirus system, and subsequent experiments demonstrated that the secretion of rat GAL from hTERT-BMSCs/Tet on/GAL was switched on and off under the control of an inducer in a dose dependent manner. The construction of this cell line is the first promising step in the regulation of GAL secretion from hTERT-immortalized BMSCs, and the potential application of this system may provide a stem cell-based research platform for pain. PMID- 28584530 TI - An overview on autologous fibrin glue in bone tissue engineering of maxillofacial surgery. AB - The purpose of this review is to have an overview on the applications on the autologous fibrin glue as a bone graft substitute in maxillofacial injuries and defects. A search was conducted using the databases such as Medline or PubMed and Google Scholar for articles from 1985 to 2016. The criteria were "Autograft," "Fibrin tissue adhesive," "Tissue engineering," "Maxillofacial injury," and "Regenerative medicine." Bone tissue engineering is a new promising approach for bone defect reconstruction. In this technique, cells are combined with three dimensional scaffolds to provide a tissue-like structure to replace lost parts of the tissue. Fibrin as a natural scaffold, because of its biocompatibility and biodegradability, and the initial stability of the grafted stem cells is introduced as an excellent scaffold for tissue engineering. It promotes cell migration, proliferation, and matrix making through acceleration in angiogenesis. Growth factors in fibrin glue can stimulate and promote tissue repair. Autologous fibrin scaffolds are excellent candidates for tissue engineering so that they can be produced faster, cheaper, and in larger quantities. In addition, they are easy to use and the probability of viral or prion transmission may be decreased. Therefore, autologous fibrin glue appears to be promising scaffold in regenerative maxillofacial surgery. PMID- 28584531 TI - Intraoral ancient schwannoma: A systematic review of the case reports. AB - Intraoral ancient schwannoma is a rare type of oral schwannoma, which is encapsulated and well demarcated from the surrounding tissues. Ancient schwannomas are associated with conventional features of neurilemmoma; however, they are distinguished from other types of schwannoma due to factors such as the long history, cellular architecture showing hypocellularity, and hyalinized matrices. This systematic review was performed through searching in databases such as PubMed and Google Scholar using related keywords (intraoral, oral, ancient, schwannoma, and neurilemmoma). Eventually, 26 case reports were systematically reviewed by the researchers. Required data were extracted by one researcher, and all the selected articles were reviewed in full text after screening. This systematic review aimed to determine the most significant influential factors in intraoral ancient schwannoma and evaluate the diagnostic and therapeutic methods in this regard. PMID- 28584532 TI - Histological and histomorphometric evaluation of the synthetic biomaterial Natix(r) in horizontal reconstruction of alveolar ridge. AB - BACKGROUND: Following loss of teeth, atrophy of alveolar ridge of the jaws is a substantial problem and unintended outcome that compels clinicians to perform bone reconstruction ahead of implant placement. Although autogenous bone is recommended as the gold standard in bone reconstruction, aninvasive second surgery harvestinga limited volume of bone (from intraoral source) has led a significant approachingthe use of synthetic bone substitute materials. The aim of this study was to evaluate the histologic and histomorphometric properties of porous titanium granules (Natix(r)) used in horizontal reconstruction of alveolar ridge before implant placement. MATERIALS AND METHODS: In the present quasi experimental clinical trial, four patients (three females and one male) needed horizontal bone augmentation on ten areas of edentulous mandibular ridge before implant treatment. During surgery, the buccal aspect of edentulous ridge was augmented by Natix(r), covered by resorbable membrane (Cytoplast(r)). After 8 months, 10 core biopsies were obtained. RESULTS: In histological study, no foreign body reaction at the site of the newly formed bone or around the biomaterial residue was observed. Newly formed bone was fully vital with large lacunae containing osteocytes. In 60% of cases, connective tissue was observed at the biomaterial - new bone interface. In histomorphometric study, mean percentage of bone formation was 40.56% +/- 19.83% and mean bone trabecular thickness was 39.98 +/- 17.54 MU. CONCLUSION: Despite acceptable histological and histomorphometric bone formation findings, in clinical terms, no increase was created in the horizontal dimension. Thus, it seems that application of this biomaterial in horizontal reconstruction of alveolar ridges with noncontained defects is inappropriate. PMID- 28584533 TI - Salivary oxidative stress in oral lichen planus treated with triamcinolone mouthrinse. AB - BACKGROUND: Total antioxidant capacity (TAC) and malondialdehyde (MDA) levels have not been reported in oral lichen planus (OLP) patients treated with a topical corticosteroid. This study evaluates TAC and MDA levels in unstimulated saliva of OLP patients. Such measurements may need to be supported by clinical observation. MATERIALS AND METHODS: Twenty patients with OLP participated in a study conducted at the Department of Oral Medicine, Tehran University of Medical Sciences. Salivary TAC and MDA were determined by biochemical analyses before and after 5-week triamcinolone acetonide (0.2%) mouthrinse treatment. Subjective symptoms as well as lesion status pre- and post-treatment were measured using visual analog scale (VAS) and clinical scoring system, respectively. Wilcoxon signed rank test was used for the evaluation of MDA and TAC parameters, VASs, and rates of clinical scores. Spearman's rank correlation was used to determine the relationship between different variables. RESULTS: A statistically significant increase in salivary TAC was found after treatment. There was no significant difference in the reduction of salivary MDA levels in OLP patients after treatment. CONCLUSION: Posttreatment analyses revealed a significant degree of recovery and pain relief of OLP lesions. Hence, triamcinolon mouthrinse by reducing oxidative stress is an appropriate treatment in OLP patients. PMID- 28584534 TI - Impact of virtual microscopy with conventional microscopy on student learning in dental histology. AB - BACKGROUND: In dental histology, the assimilation of histological features of different dental hard and soft tissues is done by conventional microscopy. This traditional method of learning prevents the students from screening the entire slide and change of magnification. To address these drawbacks, modification in conventional microscopy has evolved and become motivation for changing the learning tool. Virtual microscopy is the technique in which there is complete digitization of the microscopic glass slide, which can be analyzed on a computer. This research is designed to evaluate the effectiveness of virtual microscopy with conventional microscopy on student learning in dental histology. MATERIALS AND METHODS: A cohort of 105 students were included and randomized into three groups: A, B, and C. Group A students studied the microscopic features of oral histologic lesions by conventional microscopy, Group B by virtual microscopy, and Group C by both conventional and virtual microscopy. The students' understanding of the subject was evaluated by a prepared questionnaire. RESULTS: The effectiveness of the study designs on knowledge gains and satisfaction levels was assessed by statistical assessment of differences in mean test scores. The difference in score between Groups A, B, and C at pre- and post-test was highly significant. This enhanced understanding of the subject may be due to benefits of using virtual microscopy in teaching histology. CONCLUSION: The augmentation of conventional microscopy with virtual microscopy shows enhancement of the understanding of the subject as compared to the use of conventional microscopy and virtual microscopy alone. PMID- 28584535 TI - Stress distribution in maxillary first molar periodontium using straight pull headgear with vertical and horizontal tubes: A finite element analysis. AB - BACKGROUND: One of the most effective ways for distal movement of molars to treat Class II malocclusion is using extraoral force through a headgear device. The purpose of this study was the comparison of stress distribution in maxillary first molar periodontium using straight pull headgear in vertical and horizontal tubes through finite element method. MATERIALS AND METHODS: Based on the real geometry model, a basic model of the first molar and maxillary bone was obtained using three-dimensional imaging of the skull. After the geometric modeling of periodontium components through CATIA software and the definition of mechanical properties and element classification, a force of 150 g for each headgear was defined in ABAQUS software. Consequently, Von Mises and Principal stresses were evaluated. The statistical analysis was performed using T-paired and Wilcoxon nonparametric tests. RESULTS: Extension of areas with Von Mises and Principal stresses utilizing straight pull headgear with a vertical tube was not different from that of using a horizontal tube, but the numerical value of the Von Mises stress in the vertical tube was significantly reduced (P < 0/05). On the other hand, the difference of the principal stress between both tubes was not significant (P > 0/05). CONCLUSION: Based on the results, when force applied to the straight pull headgear with a vertical tube, Von Mises stress was reduced significantly in comparison with the horizontal tube. Therefore, to correct the mesiolingual movement of the maxillary first molar, vertical headgear tube is recommended. PMID- 28584536 TI - Comparative assessment of salivary cotinine level and psychological dependence among tobacco users. AB - BACKGROUND: The aim of the study was to assess the correlation between salivary cotinine level and psychological dependence measured through Fagerstrom test for nicotine dependence (FTND) questionnaire among tobacco users. MATERIALS AND METHODS: This was a cross-sectional study, conducted on tobacco users. Participants with the present habit of tobacco chewing and smoking above the age of 16 years were included in the study. A standard questionnaire form of FTND revised version for smoking and smokeless form of tobacco were given to each participant. Each participant was asked to answer the questions as per their experience of tobacco consumption and calculate the total point score or FTND score. Salivary cotinine level assessment was done using commercial available NicAlert kit. RESULTS: When salivary cotinine level was correlated with different variables of both groups, it was observed that weak correlation between salivary cotinine level and FTND scoring in smokers group (r = 0.083) and also in smokeless group (r = 0.081). When two groups were compared for salivary cotinine level, statistically significant difference (P = 0.021) was observed, with smokeless group showing high level of salivary cotinine level as compared to smokers group. CONCLUSION: Salivary cotinine and psychological dependence through FTND scoring are not strongly correlating with each other. This indicates that dependence over tobacco is a separate phenomenon and cannot be assessed by salivary cotinine level. It is well accepted that salivary cotinine level is influenced by age of individual, duration of habit, and type of tobacco consumption. PMID- 28584537 TI - A comparison of the efficacy of mechanical, chemical, and microwave radiation methods in disinfecting complete dentures. AB - BACKGROUND: Poor denture hygiene can be a potential source of pathogens. The aim of this study was to compare the efficacy of microwave radiation with that of chemical and mechanical techniques in disinfecting complete dentures contaminated with Staphylococcus aureus and Pseudomonas aeruginosa. MATERIALS AND METHODS: Seventy-two sterilized mandibular dentures were separately contaminated with S. aureus (n = 32) and P. aeruginosa (n = 32) and then incubated at 37 degrees C for 48 h. The contaminated dentures were disinfected as follows: chemical disinfection with Corega tablets; chemical disinfection with 2% glutaraldehyde; mechanical disinfection by brushing the denture; and physical disinfection by 650 W microwaves irradiation for 3 min with six samples in each subgroup. Six dentures served as negative control group, and six contaminated dentures with no disinfection served as the positive control group. 10-3-10-6 dilutions were cultured in the nutrient agar, and the colonies were counted after incubation at 37 degrees C for 48 h. To evaluate the lasting time of disinfection, the containers with nutrient agar and dentures were stored for 7 days at 37 degrees C to evaluate turbidity. Data were analyzed using Kruskal-Wallis and Mann-Whitney U test (alpha = 0.05). RESULTS: There was no evidence of bacterial growth in 48 h and turbidity after 7 days of incubation of dentures disinfected by microwaves, glutaraldehyde, and Corega tablets, which was statistically significant compared to the positive controls (P < 0.001). In mechanically disinfected dentures (brushing), bacterial growth was detected after 48 h which was statistically significant compared to the positive controls (P < 0.001) and turbidity was seen in all the nutrient agar plates. CONCLUSION: Microwave iradiation, 2% glutaraldehyde, and Corega tablets disinfected complete dentures contaminated with S. aureus and P. aeruginosa which lasted for a long and a short terms. PMID- 28584538 TI - Pattern of mandibular third molar impaction and its association to caries in mandibular second molar: A clinical variant. AB - BACKGROUND: Caries in second molar is common and prophylactic removal of the impacted teeth may be considered appropriate. Caries detection and restoration can be difficult and a restored second molar can undergo recurrent caries if the third molar is not removed prophylactically. In this study, the clinical findings related to impaction and its association with angular position and depth of impacted third molar were evaluated. MATERIALS AND METHODS: A retrospective descriptive study was carried out among the patients visiting the outpatient, department of Dentistry, RIMS, Ranchi. The clinical examination, periapical radiographs and Pre-op OPG were taken. Teeth positions were analyzed by Pell and Gregory and Winter classification. The angulation and depth of mandibular third molar impaction and caries in the second molar with the eruption status of the mandibular third molar was determined. RESULTS: A total of 200 patients were included in the study between age group 17-45 years. Majority of the Patients reported to the hospital with complaints of decayed tooth (66%) and pain (59%). The most common third molar impaction was mesioangular followed by distoangular. A statistically highly significant difference (P = 0.001) was obtained with the presence of caries in second molar adjacent to mesioangular third molar in class I and level B. CONCLUSION: According to this study, pattern of mandibular third molar impaction is in association to caries in mandibular second molar. More future studies are needed. In addition, the results of the present study can be used to screen and inform the patients about the possibility of caries in relation to third molar mandibular impaction. PMID- 28584539 TI - Correlation between chronological age and third molar developmental stages in an Iranian population (Demirjian method). AB - BACKGROUND: Third molar development is the only available tool for estimating the age of individuals after puberty. Since this tooth has very high interethnic variability, formulas calculated to estimate the age from its development stages cannot be generalized to other populations and should be adjusted for each region. Therefore, this study was conducted to evaluate this method in a sample of Tehran individuals for the first time, and also to compare the development of third molars across sexes and arches, and to estimate cutoff developmental stages for legal minor/major identification. MATERIALS AND METHODS: A total of 150 dental patients aged between 15 and 25 years old were prospectively enrolled, and their Demirjian stages were recorded. The associations between chronological age and Demirjian stages were evaluated. Dental formation was compared between sexes and jaws. Cutoff stages were determined to identify legal minor/major cases (above or below 18 years old). Age estimation formula was found for this population. RESULTS: Of the 150 included patients, 56 were males. The difference between the ages of males and females at each given developmental stage was nonsignificant (P > 0.05), except for the H stage. Age difference between same stage teeth of the maxilla and mandible was nonsignificant. Each of the G and H stages was significantly above 18 years old (P < 0.001). Furthermore, E and F stages were below 18 years old (P < 0.001). All the correlations between Demirjian stages and age were above 90% (all P < 0.001). Third molar development was positively affected by the chronological age (P = 0.000) and being maxillary (P = 0.000) but not sex (P = 0.113). Regression formula for age estimation was: age = 6.52+ (0.64 * sex) + (0.32 * arch) + (1.86 * Demirjian stage). CONCLUSION: Development of third molar might complete after the age 22. Iranian individuals with third molars at the G and H stages are likely above 18 while those at E and F are likely below 18. Pace of molar development differs for jaws, but intergender differences are open to further investigations. PMID- 28584540 TI - Evaluation and comparison of efficacy of three desensitizing dentifrices on dentinal hypersensitivity and salivary biochemical characteristics: A randomized controlled trial. AB - BACKGROUND: This study aimed to evaluate and compare the efficacy of three desensitizing dentifrices on dentinal hypersensitivity (DH) and salivary biochemical characteristics. MATERIALS AND METHODS: A randomized, parallel arm, triple-blinded, clinical trial was conducted over a period of 12 weeks, with a total of three visits: baseline, 6 weeks, and 12 weeks. Calcium sodium phosphosilicate, potassium nitrate and amine fluoride dentifrices were compared. A total of 68 subjects who satisfied the inclusion criteria were included and randomly divided into four groups. Visual analog scale scores for controlled air stimulus were used to assess dentinal sensitivity and salivary pH and buffering capacity were recorded at baseline, 6 and 12 weeks. RESULTS: All groups showed a reduction in sensitivity scores at 6 and 12 weeks. The calcium sodium phosphosilicate group showed a higher degree of effectiveness in reducing DH than potassium nitrate, amine fluoride dentifrices, and placebo for sensitivity measures. Salivary pH of calcium sodium phosphosilicate group was more toward neutral, and the buffering capacity of the same group showed significant changes from baseline to 6 and 12 weeks compared to the other groups. CONCLUSION: The desensitizing toothpaste containing calcium sodium phosphosilicate was found to be more effective in reducing DH and showed improvement in salivary biochemical characteristics over a period of 12 weeks compared to others. PMID- 28584542 TI - Morocco succeeds to eliminate trachoma as a public health problem: World Health Organization. PMID- 28584541 TI - The use of the digital smile design concept as an auxiliary tool in periodontal plastic surgery. AB - Periodontal surgery associated with prior waxing, mock-up, and the use of digital tools to design the smile is the current trend of reverse planning in periodontal plastic surgery. The objective of this study is to report a surgical resolution of the gummy smile using a prior esthetic design with the use of digital tools. A digital smile design and mock-up were used for performing gingival recontouring surgery. The relationship between the facial and dental measures and the incisal plane with the horizontal facial plane of reference were evaluated. The relative dental height x width was measured, and the dental contour drawing was inserted. Complementary lines are drawn such as the gingival zenith, joining lines of the gingival and incisal battlements. The periodontal esthetic was improved according to the established design digital smile pattern. These results demonstrate the importance of surgical techniques and are well accepted by patients and are easy to perform for the professional. When properly planned, they provide the desired expectations. Periodontal Surgical procedures associated with the design digital smile facilitate the communication between the patient and the professional. It is, therefore, essential to demonstrate the reverse planning of the smile and periodontal parameters with approval by the patient to solve the esthetic problem. PMID- 28584543 TI - Comparing the Concept of Caring in Islamic Perspective with Watson and Parse's Nursing Theories. AB - BACKGROUND: In the nursing profession, it is apparent that the definition of caring differs between various perspectives. This article compares the difference of caring in Islamic with the Parse and Watson theories. MATERIALS AND METHODS: In this study, we use concept analyses of Walker-Avants and compare research methods. Material used is all Islamic documents. RESULTS: According to Islamic documents, there are four major types of caring, namely, (1) God taking care of humans, (2) Humans taking care of themselves, (3) Other humans taking care of humans, and (4) The universe taking care of humans and vice versa. God caring for humans affects the three other types of caring. All three definitions of caring have humanistic and holistic view. According to Watson's and Parse's definition, the development of the caring theory is based on the person's experiences that result from human interactions with, and experiences of, their environment. In Islamic definition, although the caring process is affected by environmental experiences and interactions, human not developed only base the effect of environment; rather, it is developed on the basis of human nature and divine commands. God taking care of humans is specific to Islamic perspective and is not found in other definitions. Islamic perspective maintains that God is the creator of humanity and is in charge of guiding humans. A superior form of human can always be discovered. CONCLUSIONS: Thus, nursing implementation in Muslims must be done based on Islamic commands, and Islamic commands are superior to human experiences. However, Islamic commands interpreted with human wisdom and thought can be striving toward excellence. PMID- 28584544 TI - Contextual Facilitators and Maintaining of Compassion-Based Care: An Ethnographic Study. AB - BACKGROUND: Compassion is an important part of nursing. It fosters better relationships between nurses and their patients. Moreover, it gives patients more confidence in the care they receive. Determining facilitators of compassion are essential to holistic care. The purpose of this study was to explore these facilitators. MATERIALS AND METHODS: This ethnographic study was conducted in 2014-2015 with 20 nurses, 12 patients, and 4 family members in the medical and surgical wards. Data collection was done through observations and in-depth semi structured interviews with purposive sampling. The study was carried out in 15 months. Data analysis was performed using constant comparison based on Strauss and Corbin. RESULTS: Data analysis defined three main themes and eight subthemes as the fundamentals of compassion-based care. Nurses' personal factors with subcategories of personality, attitudes, and values and holistic view; and socio cultural factors with subcategories of kindness role model, religious, and cultural values are needed to elicit compassionate behaviors. Initiator factors, with subcategories of patient suffering, patient communication demands, and patient emotional and psychological necessity are also needed to start compassionate behaviors. CONCLUSIONS: The findings of this study showed that nurses' communication with patients is nurse's duty in order to understand and respect the needs of patients. Attention should be paid to issues relating to compassion in nursing and practice educational programs. Indeed, creating a care environment with compassion, regardless of any shortcomings in the work condition, would help in the development of effective nursing. PMID- 28584545 TI - Nonadherence Behaviors and Some Related Factors in Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplantation is the renal replacement therapy of choice for most patients with end-stage renal disease (ESRD), however, adherence to the recommended lifestyle is critical for a positive prognosis. The purpose of this study was to assess adherence to immunosuppressive therapy and lifestyle recommendations along with some related factors among kidney transplant patients. MATERIALS AND METHODS: In this descriptive analytical study, all patients completed a questionnaire regarding medication intake and lifestyle recommendations (preventing of infection, self-monitoring, prevention of cardiovascular disease (CVD), and sun protection). The participants were divided into 4 groups according to the level of adherence (good, partial, poor, and nonadherent) indicated in their responses. RESULTS: Most kidney recipients were adherent to their drug prescriptions, but were partial, poor, or nonadherent regarding lifestyle recommendations. Increased passage of time since transplantation and low family support and educational level resulted in nonadherence. Men showed greater adherence to medication intake than women. Patients with lower number of drugs and reported drug side-effects illustrated better adherence to medication intake. Women adhered to infection protection recommendations more than men, and older and married patients adhered to cardiovascular prevention recommendations more than others. However, younger patients showed greater adherence to self-monitoring recommendations, and singles, young individuals, and women were adherent to sun protection recommendations. CONCLUSIONS: Nonadherence is common among kidney transplant recipients. Thus, it is necessary to determine patients who are at risk of nonadherence and to introduce more educational programs to improve their adherence and their quality of life (QOL). PMID- 28584546 TI - The Effect of Painting on Depression in Children with Cancer Undergoing Chemotherapy. AB - BACKGROUND: Psychological and social health of children with cancer may be severely affected by the disease and its treatment. Successive drawing by children can help them over time in terms of psychological and social adaptation. This study aimed to investigate the effects of drawing on depression in children with cancer undergoing chemotherapy. MATERIALS AND METHODS: This quasi experimental study was conducted on 7-12-year-old children with cancer undergoing chemotherapy. After completing Maria Kovacs' Children's Depression Inventory (CDI), 65 children who had obtained scores higher than 12 were chosen as study participants and were randomly divided into two experimental and control groups. The children in the experimental group were engaged in open painting sessions for 6 weeks. After the intervention, the CDI was completed again in both the groups. The obtained data were analyzed using descriptive and inferential statistical methods, such as independent t-test, paired t-test, and Chi-square and Mann Whitney tests. RESULTS: There was a significant difference between the children's depression scores before and after the intervention in both the two groups (P < 0.001). CONCLUSIONS: The results showed that painting was effective in reducing depression in children with cancer undergoing chemotherapy. Therefore, painting can be used as an easy, cheap, and effective intervention by nurses to help children with cancer undergoing chemotherapy. PMID- 28584547 TI - Validity and Reliability of the Persian Practice Environment Scale of Nursing Work Index. AB - BACKGROUND: The practice environment pivotal role in patients and nurses better outcomes is evident. Practice Environment Scale of Nursing Work Index (PES-NWI) is widely utilized to assess nursing work environments. The present study was conducted to demonstrate the validity and reliability of the Persian version of PES-NWI. MATERIALS AND METHODS: The instrument was translated and its psychometrics were investigated by content, construct validity (factor analysis), and homogeneity (internal consistency and intraclass correlation) on a sample of 350 nurses at educational hospitals in East Azerbaijan, Iran. RESULTS: The 30 items loaded onto 4 factors explained 34.95-50.06% of the variance. The items across the factors differed slightly from those reported by the original author of the PES-NWI. Cronbach's alpha and Pearson coefficient for the entire instrument and also for extracted factors was 0.70-0.96. CONCLUSIONS: The Persian version of PES-NWI has an appropriate level of validity and reliability in the Iranian setting for nurses. The subscale of Nursing Foundations for quality care needs modification. PMID- 28584548 TI - The Effect of Resistance Exercise on Lipid Profile of Coronary Artery Disease Patients: A Randomized Clinical Trial. AB - BACKGROUND: Increased level of blood lipids is one of the risk factors for cardiovascular diseases. Considerable research has done to assess the effects of physical exercises on lipid profile, of which aerobic exercises are the main part of evidence. However, in recent years, resistance exercise has been less investigated. Thus, the present study investigates the effect of resistance exercise on lipid profile in coronary artery disease patients. MATERIALS AND METHODS: This study was a randomized clinical trial. Forty eligible participants were selected through selective sampling and were assigned randomly to either intervention or control groups (20 participants in each group). Fasting blood sample was taken for measurement of lipid profile before, after, and after 4 weeks of the end of intervention. The intervention period lasted 8 weeks and included two exercise sessions of 45-60 minutes per week. Resistance exercise was performed by use of light weights in the range of motion of the elbow, shoulder, and knee joints. The number of repetitions was initially 10 and was gradually increased to 15. Then, the weight was increased by 3-5% and the number of sets too. Data were analyzed on significant level of P < 0.05. RESULTS: In both the groups, the mean and mean changes of lipid profile, before, after. and 4 weeks after the end of the intervention were not significantly different (P < 0.05). CONCLUSIONS: The 8-week of resistance exercise did not lead to a significant decrease in the mean lipid profile. PMID- 28584549 TI - Translation and Psychometric Properties of the Copenhagen Burnout Inventory in Iranian Nurses. AB - BACKGROUND: Burnout has its focus on exhaustion and it includes persistent response to long-lasting job-related stressful events. It has a special relevance in health care area in which staff is under constant psychological, emotional, and physical stress. The results of several studies on burnout prevalence among Iranian nurses indicate its high incidence. Therefore, more accurate researches are required for better preventive interventions, and to do so, a reliable validated scale is required. One of the suitable and new tools for the measurement of burnout is Copenhagen Burnout Inventory (CBI). This study aimed to translate and investigate psychometric properties of CBI in Iranian nurses. MATERIALS AND METHODS: In this methodological study, after the translation process, face and content validities via qualitative and quantitative methods was done. Content validation ratio, scale-level content validated index, item-level content validity index were measured. Then, construct validity was determined through factor analysis. Furthermore, internal consistency reliability and stability were assessed. The questionnaire was sent to 450 nurses who were randomly selected via quota sampling. RESULTS: Face and content validity were acceptable. After translation and cultural adaptation process, exploratory factor analysis suggested a new model based on four factors and fit indices validated this model via confirmatory factor analysis. Internal consistency and stability of CBI were affirmed for each subscale separately. CONCLUSIONS: The four-factor Persian version of the CBI proved to enjoy acceptable psychometric properties. It can be applied to evaluate burnout in Iranian nurses or other health care providers. PMID- 28584550 TI - The Effect of Barkley's Family-Oriented Program on the Burden of Care on Families of Children with Attention Deficit-Hyperactive Disorder. AB - BACKGROUND: Attention deficit-hyperactive disorder (ADHD) is the most common behavioral disorders during childhood whose treatment is greatly dependent on families; therefore, families of such children should improve their relation with them so that they could enjoy their lives. Hence, this study was conducted to evaluate the effect of Barkley's family-oriented program on the burden of care on such families. MATERIALS AND METHODS: This clinical trial was conducted among 64 family care givers for children with ADHD. By simple sampling, samples passing the inclusion criteria were selected and randomly allocated into two groups of control and intervention. The intervention group received Barkley's family education program through 9 sessions; the control group participated in 3 group sessions and expressed their problems and experiences. Data were collected and analyzed using the Zarit Burden Interview. RESULTS: Burden of care was gradually reduced through the study in the intervention group, however, the mean score of burden of care did not have a significant reduction in the control group. CONCLUSIONS: Because Barkley's family-oriented program was able to reduce the burden of care in families of children with ADHD, it is recommended to develop similar programs and evaluate them through various studies. PMID- 28584551 TI - Comparison of the Perceptions of Managers and Nursing Staff Toward Performance Appraisal. AB - BACKGROUND: Performance appraisal is an essential component of health care organizations for the improvement in quality of patients' care. Awareness of managers' and employees' perception of performance appraisal can lead to improved performance appraisal quality. The purpose of this study was to compare the perception of performance appraisal among managers and nursing staff of hospitals affiliated to Isfahan University of Medical Sciences, Isfahan, Iran. MATERIALS AND METHODS: This descriptive-analytical and cross-sectional study was conducted among 75 managers and 313 nurses in 2014. The participants were selected through a two-stage quota-random sampling. Data were collected using two researcher-made questionnaires (nursing managers and nurses' questionnaires). Data were analyzed using descriptive and statistical tests using the Software Package for the Social Sciences software. RESULTS: The mean score of managers' and nurses' perception of the current performance appraisal was 56.8 (14.2) and 51.4 (14.5), respectively. A significant difference was observed between managers' and nurses' perception of performance appraisal (P = 0.004). The participants' perception was examined in terms of performance appraisal method, the consequences of performance appraisal, and the necessity of performance appraisal. In general, perception of managers was more positive than employees. CONCLUSIONS: The evaluation of the perception of nurses revealed deficiencies in the process of performance appraisal. Moreover, managers had a more positive perception than employees toward the current pattern of performance appraisal. The results of this study can be effective on the decisions of authorities in this field. PMID- 28584552 TI - Feeding Behavioral Assessment in Children with Cleft Lip and/or Palate and Parental Responses to Behavior Problems. AB - BACKGROUND: Children with cleft lip and/or palate frequently experience feeding difficulties that may place them at risk of malnutrition. Parents' negative response to these problems is associated with development of problematic behaviors in the child. This study aimed to investigate feeding behavior in children with cleft lip and/or palate and parental responses to these problems. MATERIALS AND METHODS: A total of 120 parents of children (aged 6 months to 6 years) with cleft lip and/or palate were recruited from the Cleft Lip and Palate Clinic in Isfahan University of Medical Sciences, Isfahan, Iran, who gave consent and completed a two-part questionnaire through interviews. Part A of the questionnaire consisted of 25 items that evaluate children's feeding behavior during mealtimes and part B consists of 18 items that assess parental response (strategies, feelings, and anxiety) to these problems. RESULTS: Independent t test showed a significant difference in the mean score of feeding behavior in mothers (P = 0.020) and parental responses in fathers (P = 0.030). The Pearson correlation coefficient showed an inverse correlation between behavioral feeding score and children's interval (P = 0.008, r = -0.381) and direct correlation between parental response and feeding behavioral difficulties (P = 0.003, r = 0.428). CONCLUSIONS: With regards to the results representing appropriate feeding behaviors in children with cleft lip and/or palate, it is suggested that feeding be avioral assessment is an essential nursing and nonmedical intervention for all children. PMID- 28584553 TI - Comparison of the Effect of Acupressure and Pilates-Based Exercises on Sleep Quality of Postmenopausal Women: A Randomized Controlled Trial. AB - BACKGROUND: Postmenopausal women experience a variety of symptoms, among which sleep disorder is one of the most common problems. Acupressure and Pilates exercise programs are effective nonpharmaceutical treatments which can improve sleep quality. In the present study, we aimed to compare the effects of acupressure and Pilates-based exercises on the sleep quality of postmenopausal women referred to medical clinics. MATERIALS AND METHODS: In this single-blinded randomized controlled clinical trial, we recruited 108 women aged 40-60 years who were randomly assigned into one control and two intervention groups using balanced block randomization method (three groups of 36 each). The patients in the Pilates exercise group participated in an exercise training program of three 1-hour sessions per week for 6 consecutive weeks. The participants of acupressure group received acupressure intervention three times a week for 6 weeks. The sleep quality of all participants was assessed and recorded using the Pittsburgh Sleep Quality Index (PSQI) once before and once after the intervention. RESULTS: The results showed no statistically significant difference among the three groups on the total scores of sleep quality after the intervention. The intragroup comparison revealed that the changes in the mean total scores were significant in both the intervention groups (P < 0.001) but not in the control group (P = 0.76). CONCLUSIONS: Pilates-based exercises and acupressure can effectively improve women's sleep quality. Both techniques can be applied as effective alternative and complementary methods for improving sleep quality during the postmenopausal period. PMID- 28584554 TI - Development of a Questionnaire to Measure Attitude Toward Birth Method Selection. AB - BACKGROUND: The rate of mothers undergoing cesarean section in the absence of medical indication is increasing in the world. Women attitude have an essential role in the request or selecting a birth mode. This study aimed to develop a scale for measuring attitude toward birth method selection. MATERIALS AND METHODS: The study was conducted in two qualitative and quantitative parts. Data collection was conducted from June to December 2012 in Ahvaz, Iran. In the qualitative part of the study, 21 interviews were conducted with pregnant or parturient women and key informants. Consequently, content and face validity were performed to provide a pre-final version of the questionnaire. Then, in the quantitative part of the study, validity, exploratory factor analysis, and reliability were performed to assess the psychometric properties of the scale. RESULTS: A 130-item questionnaire was developed through the qualitative phase. It was reduced to an 82-item questionnaire after content and face validity. Exploratory factor analysis loaded a 68-item with an 8-factor solution ("beliefs and attitudes," "sexual and physical attitudes," "fear of childbirth," "preference of convenience, health, and supporting," "socio- cultural norms," "confidence to the birth practitioner," "personal and practical choice," and "sources of motivations," which jointly accounted for 42.97% of the observed variance. Cronbach's alpha coefficient showed excellent internal consistency (alpha = 0.87), and test-retest of the scale with 2-week intervals indicated an appropriate stability for the scale (0.89). CONCLUSIONS: The findings showed that the designed questionnaire was a valid and reliable instrument for indicating the pregnant womens' attitudes to their birth method selection. Also, ATBMS is an easy use questionnaire and contains the most significant factors persuading women to choose vaginal delivery or cesarean section. PMID- 28584555 TI - How to Prevent Workplace Incivility?: Nurses' Perspective. AB - BACKGROUND: Many articles have studied workplace incivility and its influence on outcomes, but very few have been conducted to assess how to prevent this issue. In this study, we aimed to determine how to prevent workplace incivility from the nurses' perspective. MATERIALS AND METHODS: This was a qualitative study which was based on a conventional content analysis approach. Thirty four nurses (25 to 52 years old) from seven training hospitals in Tabriz, Iran were selected through purposive sampling. Thirty six semi-structured interviews and eight field notes were analyzed. RESULTS: The data analysis revealed 417 codes, ten categories, three subthemes and one theme, that is, A Need for a Comprehensive Attempt. Attempt of organization, nurses, and public as subthemes are needed to prevent workplace incivility. CONCLUSIONS: The findings of the study indicated that a comprehensive and systematic attempt was needed to prevent incivility. Nurses should try to improve their skills; officials should try to show the real image and position of nurses and hospitals to the community. PMID- 28584556 TI - The Relationship Between Parental Abuse with Parental and Marital Roles Attitude in Girls. AB - BACKGROUND: Gender role attitude pertains to individuals' attitude toward proper role activities for men and women. Most of the factors relevant to family and society may affect individuals' attitudes toward their role. Meanwhile, parents' behaviors can act as an important factor in formation of different dimensions of children's personality. Accordingly, the present study was aimed to investigate the relationship between maltreatment and girls' attitudes toward parental and marital roles. MATERIALS AND METHODS: This cross-sectional correlational study was conducted in Isfahan University of Medical Sciences in 2013 with 190 female students as the sample. Participants were selected using the random-proportional sampling method. A demographic questionnaire, researcher-made maltreatment questionnaire, and Homami's gender role attitudes questionnaire were used as the data collection instruments. Data were analyzed using Chi-square, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: Results indicated that the feminine attitude was the dominant attitude in gender roles. Findings also revealed no significant correlation between the type of gender role attitude in parental role and maltreatment. However, the correlation was meaningful in marital role of sexual and fertility affairs (P = 0.02). CONCLUSIONS: Results revealed that participants had traditional female attitudes toward their gender roles in two aspects. First, taking the cultural domination on attitudes into account, that type of attitude is appreciated in which the individual feels relaxed and has an acceptable performance in the society. Furthermore, to promote certain types of attitudes, the entire socio-cultural and economic dimensions of the society must be taken into account. Family and social policy makings are regarded as starting points for different attitudes toward maltreatment. PMID- 28584557 TI - Training Midwives and Other Cadre of Health Workers Using a Solar-Charged Device in Ethiopia. PMID- 28584558 TI - Chemical Composition and Hypotensive Effect of Campomanesia xanthocarpa. AB - Campomanesia xanthocarpa is known in Brazil as Guabiroba and is popularly used for various diseases, such as inflammatory, renal, and digestive diseases and dyslipidemia. The aim of the study was to analyze the chemical composition and investigate the effects of aqueous extract of C. xanthocarpa on the blood pressure of normotensive rats, analyzing the possible action mechanism using experimental and in silico procedures. The extract was evaluated for total phenolic compounds and total flavonoid content. The chemical components were determined by HPLC analyses. Systolic and diastolic blood pressure and heart rate were measured with extract and drugs administration. The leaves of C. xanthocarpa presented the relevant content of phenolics and flavonoids, and we suggested the presence of chlorogenic acid, gallic acid, quercetin, and theobromine. The acute administration of aqueous extract of C. xanthocarpa has a dose-dependent hypotensive effect in normotensive rats, suggesting that the action mechanism may be mediated through the renin-angiotensin system by AT1 receptor blockade and sympathetic autonomic response. Docking studies showed models that indicated an interaction between chlorogenic acid and quercetin with the AT1 receptor (AT1R) active site. The findings of these docking studies suggest the potential of C. xanthocarpa constituents for use as preventive agents for blood pressure. PMID- 28584560 TI - Corrigendum to "Anticancer Effects of Salvia miltiorrhiza Alcohol Extract on Oral Squamous Carcinoma Cells". AB - [This corrects the article DOI: 10.1155/2017/5364010.]. PMID- 28584559 TI - Schisandrae Fructus Reduces Symptoms of 4-Vinylcyclohexene Diepoxide-Induced Ovarian Failure in Mice. AB - Menopause is associated with a decrease in the level of sex hormones such as ovarian estradiol and progesterone and can cause various symptoms such as depression, hot flash, fatigue, heart palpitations, and headache. Furthermore, there is a risk of developing complications such as osteoporosis, cardiovascular diseases, Alzheimer's disease, and ovarian cancer. Schisandrae Fructus (SF) is widely used in Korean medicine as a cure for such complications. This study was conducted to evaluate the therapeutic effects of SF against menopause symptoms associated with follicle depletion caused by the industrial chemical 4 vinylcyclohexene diepoxide (VCD) in mice. VCD directly targets the preantral follicles. Mice were injected with VCD (160 mg/kg intraperitoneally) daily for 15 days and then with SF dosage 3 times/week for six weeks. To evaluate the effects of SF, body weight, tail skin temperature, uterine weight, lipid profile, and osteocalcin levels were measured. A decrease in body weight and tail skin temperature and an increase in uterine weight were observed upon SF treatment. Moreover, SF treatment significantly decreased total cholesterol, triglyceride, osteocalcin, and low-density lipoprotein levels and low-density/high-density lipoprotein ratio. These results suggest the potential use of SF in the treatment of menopausal symptoms in women. PMID- 28584561 TI - Active Ingredients of Epimedii Folium and Ligustri Lucidi Fructus Balanced GR/HSP90 to Improve the Sensitivity of Asthmatic Rats to Budesonide. AB - This study aimed to investigate the possible molecular mechanisms of active ingredients of Epimedii Folium (EF) and Ligustri Lucidi Fructus (LLF) combined with Budesonide (Bun) in asthmatic rats. Rats were divided into 5 groups, including normal group, asthma model group, Bun group, group of active ingredients of EL and LLF (EL), and group of coadministration of Bun with EL (Bun&EL). The asthmatic model was prepared by ovalbumin sensitizing and challenging. Lymphocyte apoptosis, GR protein and binding, and the protein and mRNA of GRalpha, GRbeta, and HSP90 were tested. The results showed that Bun&EL 1 markedly increased lymphocyte apoptosis, GR and HSP90 protein, and GR binding in BALF and 2 enhanced the expressions of GRalpha and HSP90 and the ratio of GRalpha to GRbeta or to HSP90 both in protein and in mRNA levels in lung, 3 while decrease occurred in GRbeta mRNA and the mRNA ratio of GRbeta to HSP90 compared with asthma or Bun group. Moreover, there was a significant correlation between GRalpha and GRbeta in protein level, or between GRalpha and HSP90 both in protein and in mRNA levels. EL may effectively enhance the sensitivity of asthmatic rats to Bun via balancing GR/HSP90. And these findings will be beneficial for the treatment of asthma in the future. PMID- 28584562 TI - Ecological Commitments: Why Developmental Science Needs Naturalistic Methods. AB - Much of developmental science aims to explain how or whether children's experiences influence their thoughts and actions. Developmental theories make assumptions and claims-what I call ecological commitments-about events outside research contexts. In this article, I argue that most developmental theories make ecological commitments about children's thoughts, actions, and experiences outside research contexts, and that these commitments sometimes go unstated and untested. I also argue that naturalistic methods can provide evidence for or against ecological commitments, and that naturalistic and experimental studies address unique yet complementary questions. Rather than argue for increasing the ecological validity of experiments or abandoning laboratory research, I propose reconsidering the relations among developmental theories, naturalistic methods, and laboratory experiments. PMID- 28584563 TI - The Relationship of Amount of Resection and Time for Recovery of Bell's Phenomenon after Levator Resection in Congenital Ptosis. AB - BACKGROUND: Recovery of Bell's phenomenon after levator resection is unpredicatable. Delayed recovery can result in vision threatening corneal complications. AIM: To study the variability of Bell's phenomenon and time taken for its recovery following levator resection for blepharoptosis and to correlate it with the amount of resection. METHODS: A prospective observational study was conducted on 32 eyes of 32 patients diagnosed as unilateral simple congenital blepharoptosis who underwent levator resection at a tertiary care center between July 2013 and May 2015. Patients were followed up for 5 months and correction of ptosis, type of Bell's, duration of Bell's recovery and complications were noted. RESULTS: The study group ranged from 16-25 years with 15:17 male: female ratio. There were 9 mild, 16 moderate and 7 severe ptosis. Satisfactory correction was achieved in all cases. Good Bell's recovery occurred in 13 eyes on first post-op day, in 2-14 days in 19 eyes and 28 days in 1 eye. Inverse Bell's was noted along with lid oedema and ecchymosis in 2 patients. Large resections (23-26mm) were associated with poor Bell's on the first postoperative day (p=0.027, Fisher's exact test). However, the duration required for recovery of Bell's phenomenon did not show any significant difference with the amount of resection. (p=0.248, Mann Whitney test). Larger resections resulted in greater lagophthalmos (correlation=0.830, p<0.0001). Patients with recovery of Bell's delayed for more than 7 days were associated with greater number of complications (p=0.001 Fisher's Exact Test). CONCLUSION: Close monitoring for Bell's recovery is required following levator resection. PMID- 28584565 TI - Correction to drug name. AB - [This corrects the article DOI: 10.5489/cuaj.4586.]. PMID- 28584564 TI - Ethical Sensitivity in Nursing Ethical Leadership: A Content Analysis of Iranian Nurses Experiences. AB - BACKGROUND: Considering that many nursing actions affect other people's health and life, sensitivity to ethics in nursing practice is highly important to ethical leaders as a role model. OBJECTIVE: The study aims to explore ethical sensitivity in ethical nursing leaders in Iran. METHOD: This was a qualitative study based on the conventional content analysis in 2015. Data were collected using deep and semi-structured interviews with 20 Iranian nurses. The participants were chosen using purposive sampling. Data were analyzed using conventional content analysis. In order to increase the accuracy and integrity of the data, Lincoln and Guba's criteria were considered. RESULTS: Fourteen sub categories and five main categories emerged. Main categories consisted of sensitivity to care, sensitivity to errors, sensitivity to communication, sensitivity in decision making and sensitivity to ethical practice. CONCLUSION: Ethical sensitivity appears to be a valuable attribute for ethical nurse leaders, having an important effect on various aspects of professional practice and help the development of ethics in nursing practice. PMID- 28584566 TI - Stercoral perforation of the rectum with faecal peritonitis and pneumatosis coli: A case Report. AB - Colonic perforation due to impacted faeces or faecaloma is a relatively uncommon presentation with grave prognosis. If left untreated, it can be life threatening due to complications like faecal peritonitis. Till date, fewer than 150 cases have been reported mostly in the English surgical literature describing constipation as the most common underlying etiology. Involvement of rectum is rare with very limited data published in this context. We present a case of stercoral perforation involving the rectum with associated faecal peritonitis and pneumatosis coli. PMID- 28584567 TI - Radiological Findings in Persistent Mullerian Duct Syndrome: Case Report and Review of Literature. AB - This case involved a 36-year-old adult male who presented with an unusual inguinal hernia in which the uterus and fallopian tubes were identified as contents of the inguinal hernia sac. These findings reflected a rare autosomal recessive developmental syndrome known as PMDS (persistent Mullerian duct syndrome). The diagnosis was established and confirmed via radiological-mainly MRI-investigation. PMID- 28584568 TI - Hypovolemic Shock and Hemoperitoneum from Spontaneous Avulsion of a Large Pedunculated Uterine Leiomyoma. AB - Hemoperitoneum with hypovolemic shock from avulsion of a pedunculated leiomyoma is a rare but highly fatal condition that can occur spontaneously or as a result of trauma. We report a case of hemoperitoneum and hypovolemic shock secondary to a bleeding leiomyoma detected via computed tomography (CT) scan in a 39 year old premenopausal, gravida 0 female that presented with abdominal pain and became hemodynamically unstable in the emergency department. A preoperative bimanual exam revealed a mass consistent with a 20 week gestational uterus. Following fluid resuscitation, the patient underwent emergent myomectomy and ligation of the right uterine artery and was discharged home in good condition. PMID- 28584569 TI - Angiographic diagnosis of Meckel's diverticulum in an adult patient with negative scintigraphy. AB - A Meckel's diverticulum was diagnosed by mesenteric angiography in a 34 year-old patient who presented with hematochezia and dropping hemoglobin. The case demonstrates the challenges often encountered in workup of occult gastrointestinal (GI) bleeding, and shows that angiographic diagnosis of Meckel's diverticulum is possible, even in the absence of angiographic evidence of active extravasation. Our patient had a previous non-diagnostic workup including upper and lower endoscopy, videocapsulography, and Technetium-99m pertechnetate (Tc 99m) scintigraphy. Visceral angiogram demonstrated the presence of a persistent vitelline artery, diagnostic of Meckel's diverticulum. While no active extravasation was seen at the time of the angiogram, operative specimen demonstrated a Meckel's diverticulum with ectopic gastric mucosa and intraluminal hemorrhage. PMID- 28584570 TI - Bone Metastases: An Overview. AB - Bone is a frequent site of metastases and typically indicates a short-term prognosis in cancer patients. Once cancer has spread to the bones it can rarely be cured, but often it can still be treated to slow its growth. The majority of skeletal metastases are due to breast and prostate cancer. Bone metastasis is actually much more common than primary bone cancers, especially in adults. The diagnosis is based on signs, symptoms and imaging. New classes of drugs and new interventions are given a better quality of life to these patients and improved the expectancy of life. It is necessary a multidisciplinary approach to treat patients with bone metastasis. In this paper we review the types, clinical approach and treatment of bone metastases. PMID- 28584571 TI - Novel Strategies to Improve the Endocrine Therapy of Breast Cancer. AB - Endocrine therapy (ET) constitutes the usual first-line of therapy for patients in the treatment of metastatic hormone receptor-positive breast cancer. Unfortunately, not all patients respond to first-line endocrine treatment due to intrinsic resistance, while others may initially respond but eventually progress with secondary acquired resistance leading to disease progression. Mechanisms of resistance to anti-estrogen therapy include, loss of expression for estrogen or progesterone receptor, upregulation of epidermal receptor growth factor 2, increased receptor tyrosine kinase signaling, leading to activation of various intracellular pathways that are involved in signal transduction such as PI3K/AKT/mammalian target of rapamycin, and others. Growing understanding of the signal cascade of estrogen receptors and the signaling pathways that interact with estrogen receptors has revealed the complex role of these receptors in cell growth and proliferation, and on the mechanism in development of resistance. These insights have led to the development of targeted therapies that may prove to be effective options for the treatment of breast cancer and may overcome hormone therapy resistance. In this review we summarize some of the mechanisms of endocrine resistance, selected clinical trials of ET and targeted therapies, which might interfere with estrogen receptor pathways and might reduce or reverse resistance to traditional, sequential, single-agent ET. PMID- 28584573 TI - Inhibitory effect of Gastrodia elata Blume extract on alpha-melanocyte stimulating hormone-induced melanogenesis in murine B16F10 melanoma. AB - BACKGROUND/OBJECTIVES: Gastrodia elata Blume (GEB), a traditional herbal medicine, has been used to treat a wide range of neurological disorders (e.g., paralysis and stroke) and skin problems (e.g., atopic dermatitis and eczema) in oriental medicine. This study was designed to investigate whether GEB extract inhibits melanogenesis activity in murine B16F10 melanoma. MATERIALS/METHOD: Murine B16F10 cells were treated with 0-5 mg/mL of GEB extract or 400 ug/mL arbutin (a positive control) for 72 h after treatment with/without 200 nM alpha melanocyte stimulating hormone (alpha-MSH) for 24 h. Melanin concentration, tyrosinase activity, mRNA levels, and protein expression of microphthalmia associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (Trp)1, and Trp2 were analyzed in alpha-MSH-untreated and alpha-MSH-treated B16F10 cells. RESULTS: Treatment with 200 nM alpha-MSH induced almost 2-fold melanin synthesis and tyrosinase activity along with increased mRNA levels and protein expression of MITF, tyrosinase, Trp1 and Trp2. Irrespective of alpha-MSH stimulation, GEB extract at doses of 0.5-5 mg/mL inhibited all these markers for skin whitening in a dose-dependent manner. While lower doses (0.5-1 mg/mL) of GEB extract generally had a tendency to decrease melanogenesis, tyrosinase activity, and mRNA levels and protein expression of MITF, tyrosinase, Trp1, and Trp2, higher doses (2-5 mg/mL) significantly inhibited all these markers in alpha-MSH treated B16F10 cells in a dose-dependent manner. These inhibitory effects of the GEB extract at higher concentrations were similar to those of 400 ug/mL arbutin, a well-known depigmenting agent. CONCLUSIONS: These results suggest that GEB displays dose-dependent inhibition of melanin synthesis through the suppression of tyrosinase activity as well as molecular levels of MITF, tyrosinase, Trp1, and Trp2 in murine B16F10 melanoma. Therefore, GEB may be an effective and natural skin-whitening agent for application in the cosmetic industry. PMID- 28584574 TI - Increased glucose metabolism and alpha-glucosidase inhibition in Cordyceps militaris water extract-treated HepG2 cells. AB - BACKGROUND/OBJECTIVES: Recent living condition improvements, changes in dietary habits, and reductions in physical activity are contributing to an increase in metabolic syndrome symptoms including diabetes and obesity. Through such societal developments, humankind is continuously exposed to metabolic diseases such as diabetes, and the number of the victims is increasing. This study investigated Cordyceps militaris water extract (CMW)-induced glucose uptake in HepG2 cells and the effect of CMW treatment on glucose metabolism. MATERIALS/METHODS: Colorimetric assay kits were used to determine the glucokinase (GK) and pyruvate dehydrogenase (PDH) activities, glucose uptake, and glycogen content. Either RT PCR or western blot analysis was performed for quantitation of glucose transporter 2 (GLUT2), hepatocyte nuclear factor 1 alpha (HNF-1alpha), phosphatidylinositol 3-kinase (PI3k), protein kinase B (Akt), phosphorylated AMP activated protein kinase (pAMPK), phosphoenolpyruvate carboxykinase, GK, PDH, and glycogen synthase kinase 3 beta (GSK-3beta) expression levels. The alpha glucosidase inhibitory activities of acarbose and CMW were evaluated by absorbance measurement. RESULTS: CMW induced glucose uptake in HepG2 cells by increasing GLUT2 through HNF-1alpha expression stimulation. Glucose in the cells increased the CMW-induced phosphorylation of AMPK. In turn, glycolysis was stimulated, and glyconeogenesis was inhibited. Furthermore, by studying the mechanism of action of PI3k, Akt, and GSK-3beta, and measuring glycogen content, the study confirmed that the glucose was stored in the liver as glycogen. Finally, CMW resulted in a higher level of alpha-glucosidase inhibitory activity than that from acarbose. CONCLUSION: CMW induced the uptake of glucose into HepG2 cells, as well, it induced metabolism of the absorbed glucose. It is concluded that CMW is a candidate or potential use in diabetes prevention and treatment. PMID- 28584572 TI - Journey of TRAIL from Bench to Bedside and its Potential Role in Immuno-Oncology. AB - Induction of apoptosis in cancer cells has increasingly been the focus of many therapeutic approaches in oncology field. Since its identification as a TNF family member, TRAIL (TNF-related apoptosis-inducing ligand) paved a new path in apoptosis inducing cancer therapies. Its selective ability to activate extrinsic and intrinsic cell death pathways in cancer cells only, independently from p53 mutations responsible for conventional therapeutics resistance, spotted TRAIL as a potent cancer apoptotic agent. Many recombinant preparations of TRAIL and death receptor targeting monoclonal antibodies have been developed and being tested pre clinically and clinically both as a single agent and in combinations. Of note, the monoclonal antibodies were not the only type of antibodies developed to target TRAIL receptors. Recent technology has brought forth several single chain variable domains (scFv) designs fused recombinantly to TRAIL as well. Also, it is becoming progressively more understandable that field of nanotechnology has revolutionized cancer diagnosis and therapy. The recent breakthroughs in materials science and protein engineering have helped considerably in strategically loading drugs into nanoparticles or conjugating drugs to their surface. In this review we aim to comprehensively highlight the molecular knowledge of TRAIL in the context of its pathway, receptors and resistance factors. We also aim to review the clinical trials that have been done using TRAIL based therapies and to review various scFv designs, the arsenal of nano carriers and molecules available to selectively target tumor cells with TRAIL. PMID- 28584575 TI - Melanin extract from Gallus gallus domesticus promotes proliferation and differentiation of osteoblastic MG-63 cells via bone morphogenetic protein-2 signaling. AB - BACKGROUND/OBJECTIVES: Gallus gallus domesticus (GD) is a natural mutant breed of chicken in Korea with an atypical characterization of melanin in its tissue. This study investigated the effects of melanin extracts of GD on osteoblast differentiation and inhibition of osteoclast formation. MATERIALS/METHODS: The effects of the melanin extract of GD on human osteoblast MG-63 cell differentiation were examined by evaluating cell viability, osteoblast differentiation, and expression of osteoblast-specific transcription factors such as bone morphogenetic protein 2 (BMP-2), small mothers against decapentaplegic homologs 5 (SMAD5), runt-related transcription factor 2 (RUNX2), osteocalcin and type 1 collagen (COL-1) by reverse transcription-polymerase chain reaction and western blotting analysis. We investigated the inhibitory effect of melanin on the osteoclasts formation through tartrate-resistant acid phosphatase (TRAP) activity and TRAP stains in Raw 264.7 cell. RESULTS: The melanin extract of GD was not cytotoxic to MG-63 cells at concentrations of 50-250 ug/mL. Alkaline phosphatase (ALP) activity and bone mineralization of melanin extract-treated cells increased in a dose-dependent manner from 50 to 250 ug/mL and were 149% and 129% at 250 ug/mL concentration, respectively (P < 0.05). The levels of BMP-2, osteocalcin, and COL-1 gene expression were significantly upregulated by 1.72-, 4.44-, and 2.12-fold in melanin-treated cells than in the control cells (P < 0.05). The levels of RUNX2 and SMAD5 proteins were higher in melanin-treated cells than in control vehicle-treated cells. The melanin extract attenuated the formation of receptor activator of nuclear factor kappa-B ligand-induced TRAP positive multinucleated RAW 264.7 cells by 22%, and was 77% cytotoxic to RAW 264.7 macrophages at a concentration of 500 ug/mL. CONCLUSIONS: This study provides evidence that the melanin extract promoted osteoblast differentiation by activating BMP/SMADs/RUNX2 signaling and regulating transcription of osteogenic genes such as ALP, type I collagen, and osteocalcin. These results suggest that the effective osteoblastic differentiation induced by melanin extract from GD makes it potentially useful in maintaining bone health. PMID- 28584576 TI - Pear pomace ethanol extract improves insulin resistance through enhancement of insulin signaling pathway without lipid accumulation. AB - BACKGROUND/OBJECTIVES: The anti-diabetic activity of pear through inhibition of alpha-glucosidase has been demonstrated. However, little has been reported about the effect of pear on insulin signaling pathway in obesity. The aims of this study are to establish pear pomace 50% ethanol extract (PPE)-induced improvement of insulin sensitivity and characterize its action mechanism in 3T3-L1 cells and high-fat diet (HFD)-fed C57BL/6 mice. MATERIALS/METHODS: Lipid accumulation, monocyte chemoattractant protein-1 (MCP-1) secretion and glucose uptake were measure in 3T3-L1 cells. Mice were fed HFD (60% kcal from fat) and orally ingested PPE once daily for 8 weeks and body weight, homeostasis model assessment of insulin resistance (HOMA-IR), and serum lipids were measured. The expression of proteins involved in insulin signaling pathway was evaluated by western blot assay in 3T3-L1 cells and adipose tissue of mice. RESULTS: In 3T3-L1 cells, without affecting cell viability and lipid accumulation, PPE inhibited MCP-1 secretion, improved glucose uptake, and increased protein expression of phosphorylated insulin receptor substrate 1 [p-IRS-1, (Tyr632)], p-Akt, and glucose transporter type 4 (GLUT4). Additionally, in HFD-fed mice, PPE reduced body weight, HOMA-IR, and serum lipids including triglyceride and LDL cholesterol. Furthermore, in adipose tissue, PPE up-regulated GLUT4 expression and expression ratio of p-IRS-1 (Tyr632)/IRS, whereas, down-regulated p-IRS-1 (Ser307)/IRS. CONCLUSIONS: Our results collectively show that PPE improves glucose uptake in 3T3-L1 cells and insulin sensitivity in mice fed a HFD through stimulation of the insulin signaling pathway. Furthermore, PPE-induced improvement of insulin sensitivity was not accompanied with lipid accumulation. PMID- 28584577 TI - Antioxidant mechanism of black garlic extract involving nuclear factor erythroid 2-like factor 2 pathway. AB - BACKGROUN/OBJECTIVES: Although studies have revealed that black garlic is a potent antioxidant, its antioxidant mechanism remains unclear. The objective of this study was to determine black garlic's antioxidant activities and possible antioxidant mechanisms related to nuclear factor erythroid 2-like factor 2 (Nrf2) Keap1 complex. METHODS/MATERIALS: After four weeks of feeding rats with a normal fat diet (NF), a high-fat diet (HF), a high-fat diet with 0.5% black garlic extract (HF+BGE 0.5), a high-fat diet with 1.0% black garlic extract (HF+BGE 1.0), or a high-fat diet with 1.5% black garlic extract (HF+BGE 1.5), plasma concentrations of glucose, insulin,homeostatic model assessment of insulin resistance (HOMA-IR) were determined. As oxidative stress indices, plasma concentrations of thiobarbituric acid reactive substances (TBARS) and 8 isoprostaglandin F2alpha (8-iso-PGF) were determined. To measure antioxidant capacities, plasma total antioxidant capacity (TAC) and activities of antioxidant enzymes in plasma and liver were determined. The mRNA expression levels of antioxidant related proteins such as Nrf2, NAD(P)H: quinone-oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), glutathione reductase (GR), and glutathione S transferase alpha 2 (GSTA2) were examined. RESULTS: Plasma glucose level, plasma insulin level, and HOMA-IR in black garlic supplemented groups were significantly (P < 0.05) lower than those in the HF group without dose-dependent effect. Plasma TBARS concentration and TAC in the HF+BGE 1.5 group were significantly decreased compared to those of the HF group. The activities of catalase and glutathione peroxidase were significantly (P < 0.05) increased in the HF+BGE 1.0 and HF+BGE 1.5 groups compared to those of the HF group. The mRNA expression levels of hepatic Nrf2, NQO1, HO-1, and GSTA2 were significantly (P < 0.05) increased in the HF with BGE groups compared to those in the HF group. CONCLUSIONS: The improvements of blood glucose homeostasis and antioxidant systems in rats fed with black garlic extract were related to mRNA expression levels of Nrf2 related genes. PMID- 28584578 TI - Lymphocyte DNA damage and plasma antioxidant status in Korean subclinical hypertensive patients by glutathione S-transferase polymorphism. AB - BACKGROUND/OBJECTIVES: Glutathione S-transferase (GST) forms a multigene family of phase II detoxification enzymes which are involved in the detoxification of xenobiotics by conjugating substances with glutathione. The aim of this study is to assess the antioxidative status and the degree of DNA damage in the subclinical hypertensive patients in Korea using glutathione S-transferase polymorphisms. SUBJECTS/METHODS: We examined whether DNA damage and antioxidative status show a difference between GSTM1 or GSTT1 genotype in 227 newly diagnosed, untreated (systolic blood pressure (BP) >= 130 mmHg or diastolic BP >= 85 mmHg) subclinical hypertensive patients and 130 normotensive subjects (systolic BP < 120 mmHg and diastolic BP < 80 mmHg). From the blood of the subjects, the degree of the DNA damage in lymphocyte, the activities of erythrocyte superoxide dismutase, the catalase, and the glutathione peroxidase, the level of glutathione, plasma total radical-trapping antioxidant potential (TRAP), anti oxidative vitamins, as well as plasma lipid profiles and conjugated diene (CD) were analyzed. RESULTS: Of the 227 subjects studied, 68.3% were GSTM1 null genotype and 66.5% were GSTT1 null genotype. GSTM1 null genotype had an increased risk of hypertension (OR: 2.104, CI: 1.38-3.35), but no significant association in GSTT1 null genotype (OR 0.982, CI: 0.62-1.55). No difference in erythrocyte activities of superoxide dismutase, catalase, or glutathione peroxidase, and plasma TRAP, CD, lipid profiles, and GSH levels were observed between GSTM1 or GSTT1 genotype. Plasma levels of alpha-tocopherol increased significantly in GSTT1 wild genotype (P < 0.05); however, plasma level of beta-carotene increased significantly in GSTT1 null genotype (P < 0.01). DNA damage assessed by the Comet assay was significantly higher in GSTM1 null genotype than wild genotype (P < 0.05). CONCLUSIONS: These results confirm the association between GSTM1 null genotype and risk of hypertension as they suggest that GSTM1 null genotype leads to an increased oxidative stress compared with wild genotype. PMID- 28584579 TI - Effect of soy isoflavones supplement on climacteric symptoms, bone biomarkers, and quality of life in Korean postmenopausal women: a randomized clinical trial. AB - BACKGROUND/OBJECTIVES: Soy isoflavones are expected to improve menopausal symptoms and osteoporosis in women. However, their efficacy is still inconclusive, and there was limited data for postmenopausal women in South Korea. We examined the effects of soy isoflavones on climacteric symptoms, bone biomarkers, and quality of life in Korean postmenopausal women. SUBJECTS/METHODS: A randomized, double-blind study design was used. Eighty-seven participants who had undergone natural menopause were randomly administered either 70 mg/day isoflavones (n = 43) or placebo (n = 41) for 12 weeks. We assessed the Kupperman index for climacteric symptoms and the menopause-specific quality of life (MENQOL) questionnaire for quality of the life. Biomarkers of bone metabolism were also measured in serum bone-specific alkaline phosphatase (BALP), osteocalcin (OC), N- and C-terminal cross-linking telopeptides of type I collagen (NTx, CTx), and urine-deoxypyridinolin (u-DPD). RESULTS: Scores of the Kupperman index were decreased in both the isoflavones group (-7.0 +/- 15.8, P = 0.0074) and placebo group (-6.3 +/- 14.6, P = 0.0064) during the intervention, but no significant difference was noted between the groups. Regarding the bone formation markers, the level of serum BALP increased by 6.3 +/- 4.1% (P = 0.004) and OC increased by 9.3 +/- 6.2% (P < 0.001), meanwhile those of the placebo were not changed. For the bone resorption markers, NTx, CTx, and u-DPD were not significantly different in either group. MENQOL was significant decreased in the isoflavone group (-0.6 +/- 0.5) and placebo group (-0.6 +/- 0.4), with a significant difference between groups (P = 0.0228). CONCLUSIONS: Our study suggests that 70 mg isoflavones supplement has beneficial effects on bone formation markers; however, it showed no benefit compared to the placebo on climacteric symptoms or quality of life. PMID- 28584580 TI - Instant noodle consumption is associated with cardiometabolic risk factors among college students in Seoul. AB - BACKGROUND/OBJECTIVES: Increased consumption of instant noodles has recently been reported to be positively associated with obesity and cardiometabolic syndrome in South Korea, which has the highest per capita instant noodle consumption worldwide. This study aimed to investigate the association between instant noodle consumption and cardiometabolic risk factors among college students in Seoul. SUBJECTS/METHODS: The study subjects consisted of 3,397 college students (1,782 male; 1,615 female) aged 18-29 years who participated in a health checkup. Information on instant noodle consumption was obtained from the participants' answers to a question about their average frequency of instant noodle intake over the 1 year period prior to the survey. RESULTS: Statistical analysis using a general linear model that adjusted for age, body mass index, gender, family income, health-related behaviors, and other dietary factors important for cardiometabolic risk, showed a positive association between the frequency of instant noodle consumption and plasma triglyceride levels, diastolic blood pressure, and fasting blood glucose levels in all subjects. Compared to the group with the lowest frequency of instant noodle intake (<= 1/month), the odds ratio for hypertriglyceridemia in the group with an intake of >= 3/week was 2.639 [95% confidence interval (CI), 1.393-5.000] for all subjects, while it was 2.149 (95% CI, 1.045-4.419) and 5.992 (95% CI, 1.859-21.824) for male and female students, respectively. In female students, diastolic blood pressure was also higher among more frequent consumers of instant noodles. CONCLUSIONS: Our results suggest that frequent consumption of instant noodles may be associated with increased cardiometabolic risk factors among apparently healthy college students aged 18-29 years. PMID- 28584581 TI - Preconceptional use of folic acid and knowledge about folic acid among low-income pregnant women in Korea. AB - BACKGROUND/OBJECTIVES: Folic acid supplementation before pregnancy is known to significantly reduce the risk of having a baby with neural tube defects (NTDs). Therefore, it is important for women to be aware of the effects of folic acid supplementation before pregnancy. The purpose of this study was to investigate the awareness and preconceptional use of folic acid and to assess the current knowledge about folic acid among low-income pregnant women in Korea. SUBJECTS/METHODS: A questionnaire survey was conducted in 2012. Five hundred pregnant women were selected from the waiting list for the Nutriplus program implemented in public health centers using a multistage clustered probability sampling design. Data from 439 women were analyzed after excluding ones with incomplete answers. RESULTS: Among women who responded to the questionnaire, 65.6% had heard of folic acid before pregnancy, and 26.4% reported on the preconceptional use of folic acid. Women with a university degree or higher education were more likely to be aware of folic acid and to take folic acid in the preconception period. In a multivariate logistic regression, when age, education level, household income, employment status, gravidity, parity, and folic acid awareness were included in the model, folic acid awareness was a strong predictor of preconceptional folic acid use. As of interview, 85.4% and 77.7% of women were aware of the NTD-preventive role of folic acid and the appropriate time to take folic acid, respectively. The main sources of information on folic acid were healthcare professionals (41.2%), friends and family members (31.2%), and the media (26.5%). CONCLUSIONS: Our results suggest that public health strategies are needed to increase the preconceptional use of folic acid among Korean women. PMID- 28584582 TI - Development of tailored nutrition information messages based on the transtheoretical model for smartphone application of an obesity prevention and management program for elementary-school students. AB - BACKGROUND/OBJECTIVES: Easy access to intervention and support for certain behaviors is important for obesity prevention and management. The available technology such as smartphone applications can be used for intervention regarding healthy food choices for obesity prevention and management in elementary-school students. The transtheoretical model (TTM) is comprised of stages and processes of change and can be adopted to tailored education for behavioral change. This study aims to develop TTM-based nutrition contents for mobile applications intended to change eating behaviors related to weight gain in young children. SUBJECTS/METHODS: A synthesized algorithm for tailored nutrition messages was developed according to the intake status of six food groups (vegetables, fruits, sugar-sweetened beverages, fast food and instant food, snacks, and late-night snacks), decision to make dietary behavioral changes, and self-confidence in dietary behavioral changes. The messages in this study were developed from December 2014 to April 2015. After the validity evaluation of the contents through expert consultation, tailored nutrition information messages and educational contents were developed based on the TTM. RESULTS: Based on the TTM, stages of subjects are determined by their current intake status, decision to make dietary behavioral changes, and self-confidence in dietary behavioral changes. Three versions of tailored nutrition messages at each TTM stage were developed so as to not send the same messages for three weeks at most, and visual materials such as figures and tables were developed to provide additional nutritional information. Finally, 3,276 tailored nutrition messages and 60 nutrition contents for applications were developed. CONCLUSIONS: Smartphone applications may be an innovative medium to deliver interventions for eating behavior changes directly to individuals with favorable cost-effectiveness. In addition, using the TTM for tailored nutrition education for healthy eating is an effective approach. PMID- 28584583 TI - Cardiovascular News. PMID- 28584584 TI - Outcomes of Middle Eastern Patients Undergoing Percutaneous Coronary Intervention: The Primary Analysis of the First Jordanian PCI Registry. AB - AIM: This is a prospective multicenter registry designed to evaluate the incidence of adverse cardiovascular events in Middle Eastern patients undergoing percutaneous coronary interventions (PCI). The registry was also designed to determine the predictors of poor outcomes in such patients. METHODS AND RESULTS: We enrolled 2426 consecutive patients who underwent PCI at 12 tertiary care centers in Jordan between January 2013 and February 2014. A case report form was used to record data prospectively at hospital admission, discharge, and 12 months of follow-up. Mean age was 56 +/- 11 years, females comprised 21% of the study patients, 62% had hypertension, 53% were diabetics, and 57% were cigarette smokers. Most patients (77%) underwent PCI for acute coronary syndrome. In hospital and 1-year mortality rates were 0.78% and 1.94%, respectively. Definite or probable stent thrombosis occurred in 9 patients (0.37%) during hospitalization and in 47 (1.94%) at 1 year. Rates of target vessel repeat PCI and coronary artery bypass graft surgery at 1 year were 3.4% and 0.6%, respectively. The multivariate analysis revealed that cardiogenic shock, congestive heart failure, ST-segment deviation, diabetes, and major bleeding were significantly associated with higher risk of 1-year mortality. CONCLUSIONS: In this first large Jordanian registry of Middle Eastern patients undergoing PCI, patients treated were relatively young age population with low in-hospital and 1 year adverse cardiovascular events. Certain clinical features were associated with worse outcomes and may warrant aggressive therapeutic strategies. PMID- 28584585 TI - An Audit on the Appropriateness of Coronary Computed Tomography Angiography Referrals in a Tertiary Cardiac Center. AB - BACKGROUND: In response to growing concerns regarding the overuse of coronary computed tomography angiography (CCTA) in the clinical setting, multiple societies, including the American College of Cardiology Foundation, have jointly published revised criteria regarding the appropriate use of this imaging modality. However, previous research indicates significant discrepancies in the rate of adherence to these guidelines. AIM: To assess the appropriateness of CCTA referrals in a tertiary cardiac center in Bahrain. METHODS: This retrospective clinical audit examined the records of patients referred to CCTA between the April 1, 2015 and December 31, 2015 in Mohammed bin Khalifa Cardiac Center. Using information from medical records, each case was meticulously audited against guidelines to categorize it as appropriate, inappropriate, or uncertain. RESULTS: Of the 234 records examined, 176 (75.2%) were appropriate, 47 (20.1%) were uncertain, and 11 (4.7%) were inappropriate. About 74.4% of all referrals were to investigate coronary artery disease (CAD). The most common indication that was deemed appropriate was the detection of CAD in the setting of suspected ischemic equivalent in patients with an intermediate pretest probability of CAD (65.9%). Most referrals deemed inappropriate were requested to detect CAD in asymptomatic patients at low or intermediate risk of CAD (63.6%). CONCLUSION: This audit demonstrates a relatively low rate of inappropriate CCTA referrals, indicating the appropriate and efficient use of this resource in the Mohammed bin Khalifa Cardiac Center. Agreement on and reclassification of "uncertain" cases by guideline authorities would facilitate a deeper understanding of referral appropriateness. PMID- 28584586 TI - The Importance of the First Jordanian Percutaneous Coronary Intervention Registry. PMID- 28584587 TI - Anomalous Left-sided Superior Vena Cava with Cephalad Flow. AB - The case of a 24-year-old male with complaints of migraine headaches was referred for echocardiography. The rest of medical history was unremarkable. Agitated saline contrast bubble study showed evidence of a right to left intracardiac shunt, probably secondary to a patent foramen ovale. Results of a transesophageal echocardiogram suggested the possibility of an anomalous venous circulation and eventually identified as anomalous left-sided superior vena cava with cardiac magnetic resonance imaging. PMID- 28584588 TI - Myocardial Cleft in a Patient with Acute Coronary Syndrome Assessed by Multimodal Imaging. AB - Myocardial clefts are rare incidental findings without clinical relevance up to now. The recognition of this imaging entity is of crucial importance to avoid misdiagnosis and even more in the context of coronary artery disease. PMID- 28584589 TI - Computerized Tomography Use in Williams-Beuren Syndrome Aortopathy. AB - Williams-Beuren syndrome is a multisystem genetic disorder caused by hemizygous deletion on chromosome 7q11.23, encompassing about 28 genes including the elastin gene, ELN. Cardiovascular abnormalities are frequent and are related to elastin insufficiency. These abnormalities include supravalvular aortic stenosis (SVAS) in 70% of case, pulmonic valve stenosis, and renal artery stenosis. Definitive therapy for supravalvar aortic stenosis consists of surgical correction of the arteriopathies. Outcomes after surgical correction of SVAS depend on the extent of the arteriopathy and the presence of other associated lesions. We present a case of a 4-year-old boy, with Williams - Beuren syndrome with an SVAS. The patient was assessed with computerized tomography angiography to determine the extent of the aortopathy before surgical intervention. PMID- 28584590 TI - External Compression of Epicardial Coronary Arteries with Partial Calcific Pericarditis. AB - Calcific pericarditis (CP) is a rare disease which results from long-standing pericardial inflammation. Pericardial calcification may completely or partially encase the ventricles, resulting in impaired diastolic filling. We present a case of a 53-year-old male who was incidentally found to have annular CP resulting in external compression of a large territory diagonal branch (D1) reaching the apex with likely chronically occluded left anterior descending artery with collateral circulation from the right coronary artery with hemodynamic compromise on coronary angiography. This was emergently treated with a drug-eluting stent with improved D1 flow and entailed the importance of percutaneous coronary intervention as a viable option in cases of CP resulting in acute hemodynamic compromise. PMID- 28584591 TI - A Case of Left Ventricular False Tendon with Ventricular Tachycardia. PMID- 28584592 TI - The Power of Expectation and Belief. PMID- 28584593 TI - Diabetes as "Coronary Artery Disease Risk Equivalent": A Historical Perspective. PMID- 28584594 TI - Prevalence of Rheumatic Heart Disease. PMID- 28584596 TI - Diabetes Mellitus: A Local and Global Public Health Emergency! PMID- 28584595 TI - Erratum in: Rheumatic Fever and Rheumatic Heart Disease a Historical Perspective. AB - [This corrects the article on p. 120 in vol. 17, PMID: 27867464.]. PMID- 28584597 TI - Writing a Research Proposal to The Research Council of Oman. AB - Writing a research proposal can be a challenging task for young researchers. This article explains how to write a strong research proposal to apply for funding, specifically, a proposal for The Research Council (TRC) of Oman. Three different research proposal application forms are currently used in TRC, including Open Research Grant (ORG), Graduate Research Support Program (GRSP), and Faculty mentored Undergraduate Research Award Program (FURAP). The application forms are filled and submitted electronically on TRC website. Each of the proposals submitted to TRC is selected through a rigorous reviewing and screening process. Novelty and originality of the research idea is the most crucial element in writing a research proposal. Performing an in-depth review of the literature will assist you to compose a good researchable question and generate a strong hypothesis. The development of a good hypothesis will offer insight into the specific objectives of a study. Research objectives should be focused, measurable, and achievable by a specific time using the most appropriate methodology. Moreover, it is essential to select a proper study design in-line with the purpose of the study and the hypothesis. Furthermore, social/economic impact and reasonable budget of proposed research are important criteria in research proposal evaluation by TRC. Finally, ethical principles should be observed before writing a research proposal involving human or animal subjects. PMID- 28584598 TI - Impact of Aberrant Myeloid Antigen Expression on Outcomes of Patients with T-cell Acute Lymphoblastic Leukemia. AB - OBJECTIVES: To evaluate the impact of myeloid antigen expression on complete remission (CR), event-free survival (EFS), and overall survival (OS) in patients with T-cell acute lymphoblastic leukemia (T-ALL) treated with intensive chemotherapy. METHODS: We retrospectively reviewed consecutive patients diagnosed with T-ALL and treated in Sultan Qaboos University Hospital and Royal Hospital in Oman between 2004 and 2010. The diagnosis of T-ALL was established using French American-British classification or World Health Organization criteria. Patients were considered having myeloid antigen expression if they expressed CD13, CD33, or both (My+ and My-). RESULTS: Of the 39 patients, 38 were included in the study (25 patients with My- and median age of 18.4 years, 13 patients with My+ and median age of 22.0 years). Median follow-up was 12 months. Thirty-two out of the total cohort were eligible for response-rate assessment. Twenty-nine patients (90.6%) achieved CR with one or two courses of chemotherapy with similar CR rates between the two groups (p = 0.880). Twenty-five percent (5/20) of the patients with My- required two courses of induction, whereas 58.3% (7/12) of My+ required two courses of induction and the difference was statistically significant (p = 0.040). In the multivariable analysis; age, gender, initial white blood cell count, central nervous system disease, and myeloid antigen expression were not statistically significant predictors of CR. The EFS and OS were similar between the My+ and My- groups p = 0.180 and p = 0.440, respectively. CONCLUSIONS: Patients with T-ALL with myeloid antigen expression need more courses of induction; however, rates of CR, EFS, and OS are not different from those without myeloid antigen expression. Larger prospective studies are required to confirm these findings. PMID- 28584599 TI - The Role of Insulin Therapy in Correcting Hepcidin Levels in Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVES: Iron overload can cause or contribute to the pathogenesis of type 2 diabetes mellitus (T2DM), but how the major parameters of iron metabolism change in different settings of diabetes are still unclear. The aim of this study was to determine the relationship between iron, ferritin, and hepcidin levels in diabetic patients and the effect of insulin treatment. METHODS: The study included 80 subjects, 60 with T2DM and 20 without (control group). Serum hepcidin, insulin, ferritin, and iron levels were determined as well as other clinical parameters. The associations between these parameters were analyzed between both groups. RESULTS: Hepcidin levels expressed as mean+/- standard deviation between groups showed no significant changes (14.4+/-6.7 ng/mL for the control group, and 18.4+/-7.9 ng/mL for patients with diabetes, p = 0.069). Parameters of iron metabolism showed modest correlation with the parameters of glucose metabolism. However, the correlation between ferritin and insulin in both groups was statistically significant (p = 0.032; rho = 0.480 vs. p = 0.011; rho = 0.328). CONCLUSIONS: Our study showed that hepcidin levels in patients with T2DM on insulin therapy do not change, which might be a result of treatment with insulin. In this context, insulin treatment can be used as a novel method for correction of hepcidin levels. By correcting hepcidin levels, we can prevent cellular iron overload and reduce the risk of diabetes. PMID- 28584600 TI - Perception of Preparedness for Clinical Work Among New Residents: A Cross sectional Study from Oman. AB - OBJECTIVES: To evaluate new residents' perceptions of their own preparedness for clinical practice and examine the associated factors. METHODS: This is a cross sectional study conducted on August 20-23, 2016. New residents accepted for postgraduate training by Oman Medical Specialty Board were asked to complete the Preparation for Hospital Practice Questionnaire (PHPQ). Data was analyzed using the Statistical Package for the Social Sciences version 22. RESULTS: A total of 160 residents were invited to participate in this study. Out of 160, 140 residents participated (87.5%), 70.7% were female and 59.3% were graduates from Sultan Qaboos University (SQU). Ninety-nine percent of the graduates were either 'well prepared' or 'fairly well prepared' for hospital practice. Male residents scored higher in the confidence scale, while residents who did a post-internship general practice placement scored higher in understanding science. Graduates from Oman Medical College felt more prepared compared to graduates from SQU. CONCLUSIONS: Most of the new residents were well prepared to clinical work. Factors such as place of undergraduate study, training, and duration of internship significantly influenced the residents' perception of preparedness. Addressing these factors will enhance residents' preparedness for clinical work. PMID- 28584601 TI - Prevalence and Risk Factors for Sulfadoxine Antibody Among Patients Undergoing Treatment for Malaria in Benin City, Nigeria. AB - OBJECTIVES: Because of lack of data on the prevalence of sulfadoxine antibody, this study was conducted to determine the prevalence of sulfadoxine antibodies and its possible risk factors. METHODS: Blood specimens were collected from 500 patients undergoing treatment for malaria at Central Hospital, Benin City, Nigeria. A structured questionnaire was used to collect information and sociodemographic data. Sulfadoxine antibodies were detected by drug absorption (DAT) and immune complex (IMC) methods. ABO, rhesus blood group, and hemoglobin (Hb) phenotype were determined by using standard technique. RESULTS: DAT method had a significantly higher rate of detecting sulfadoxine antibodies compared to IMC method (p = 0.019). Age, gender, and level of education did not affect the prevalence of sulfadoxine antibodies (p > 0.050). Patients that were an artisan (p < 0.001), married (p = 0.025), living in a two-room apartment (p = 0.003), had history of drug reaction, consumed antimalarial drug (maloxine), and consumed sulfadoxine-containing drug within the last month (p < 0.001 each), and significantly affected the prevalence of sulfadoxine antibodies. Individuals with Hb phenotype AA had significantly higher prevalence of sulfadoxine antibodies (p < 0.001), and presence of rhesus D antigen was associated with sulfadoxine antibodies. CONCLUSIONS: An overall prevalence of 22.0% among the tested individuals had sulfadoxine antibodies. Prudent use of sulfadoxine containing drugs is advocated. PMID- 28584602 TI - Gestational Diabetes Mellitus and Metabolic Disorder Among the Different Phenotypes of Polycystic Ovary Syndrome. AB - OBJECTIVES: Polycystic ovary syndrome (PCOS) is a common endocrine disorder related to several metabolic consequences. However, there remains uncertainty regarding the metabolic features of various phenotypes. The aim of this study was to explore the relationship between the prevalence of gestational diabetes mellitus (GDM) and metabolic disorders among the four different phenotypes of PCOS. METHODS: A cross-sectional study was performed in Royan Institute including 208 pregnant women with a history of infertility and PCOS. Using the diagnostic criteria of the American Diabetes Association (ADA), pregnant women with a documented diagnoses of PCOS were further categorized into four different phenotypes (A, B, C, and D) as defined by the Rotterdam criteria. RESULTS: The prevalence of GDM failed to demonstrate a significant relationship among the four phenotypes of PCOS. The mean levels of fasting blood sugar, plasma glucose concentrations at three hours (following the 100 g oral glucose tolerance test) and triglyceride levels were significantly higher in phenotype B compared to the remaining phenotypes (p < 0.050). There was a statistically significant difference between the mean free testosterone level and phenotypes A and C groups (1.8+/-1.6 vs. 1.1+/-1.0, p = 0.003). CONCLUSIONS: Women with a known diagnosis of PCOS who exhibited oligo/anovulation and hyperandrogenism demonstrated an increase of metabolic disorders. These results suggest that metabolic screening, before conception or in the early stages of pregnancy, can be beneficial particularly in women with PCOS phenotypes A and B. Early screening and identification may justify enhanced maternal fetal surveillance to improve maternal and fetal morbidity among women affected with PCOS. PMID- 28584603 TI - A Hypothetical Model to Predict the Potential Impact of Government and Management Support in Implementing Integrated Management of Childhood Illness Practices. AB - OBJECTIVES: Despite broad adoption and implementation of Integrated Management of Childhood Illness (IMCI) in more than 100 countries, childhood mortality and morbidity rates continue to prevail. This calls for further investigation to identify the factors that prevent actual application of IMCI-recommended clinical practices. This study tests a hypothetical structural model to investigate potential role of government and healthcare policymakers on improving implementation and application of IMCI-recommended practices in clinical setting. METHODS: The study was carried out at Sur and Ibra Nursing Institutes in Oman, in June 2016. We used six pre-tested and validated constructs for developing a hypothetical structural model. The constructs were used as underlying variables to examine the probable influence of government and policymakers on actual application of IMCI-recommended practices. Data were collected through structured questionnaires, which designed to measure healthcare professionals' perceptions. Each construct was pre-loaded with three sub-constructs. Cronbach's alpha (CA) was used to calculate the internal consistency and reliability. RESULTS: Factor loadings for each item in the model were >= 0.700. CA values for all the studied constructs were > 0.600. The average variance extracted values for all the constructs were > 0.500. CONCLUSIONS: The findings support the hypothetical structural model and highlights governments could play a significant role in ensuring that IMCI strategy is not only implemented, but also its recommended practices are applied in clinical setting. PMID- 28584604 TI - P53 Protein Expression in Dental Follicle, Dentigerous Cyst, Odontogenic Keratocyst, and Inflammatory Subtypes of Cysts: An Immunohistochemical Study. AB - OBJECTIVES: An odontogenic keratocyst (OKC) is a developmental odontogenic cyst with aggressive clinical behavior. This cyst shows a different growth mechanism from the more common dentigerous cyst and now has been renamed as a keratocystic odontogenic tumor (KCOT). Inflammation can assist tumor growth via different mechanisms including dysregulation of the p53 gene. This study aims to assess and compare the expression of tumor suppressor gene p53 in inflamed and non-inflamed types of OKC and dentigerous cyst. METHODS: Immunohistochemical expression of p53 was assessed in 14 cases of dental follicle, 34 cases of OKC (including 18 inflamed OKCs), and 31 cases of dentigerous cyst (including 16 inflamed cysts). RESULTS: The mean percentage of p53 positive cells was 0.7% in dental follicles, 5.4% in non-inflamed OKCs, 17.3% in inflamed OKCs, 1.2% in non-inflamed dentigerous cysts, and 2.2% in inflamed dentigerous cysts. The differences between the groups were statistically significant (p < 0.050) except for the difference between inflamed and non-inflamed dentigerous cysts, and between dental follicle and non-inflamed dentigerous cyst. CONCLUSIONS: The difference in p53 expression in OKC and dentigerous cyst can explain their different growth mechanism and clinical behavior. Inflammation is responsible for the change in behavior of neoplastic epithelium of OKC via p53 overexpression. PMID- 28584606 TI - Giant Parapharyngeal Space Pleomorphic Adenoma Causing Acute Airway Obstruction. AB - Primary parapharyngeal space (PPS) tumors are rare, representing only 0.5% of all head and neck neoplasms. About 80% of tumors of this space are benign, and 20% are malignant. They often pose therapeutic and diagnostic problems due to variable non-specific symptoms and the complex anatomy of this space. Pleomorphic adenoma is the most common benign tumor of this space. It presents as an asymptomatic mass causing mild bulging in the soft palate or tonsillar region, or fullness near the angle of the mandible in the neck. We report the case of a 60 year-old male admitted to the emergency department with breathing difficulty and acute stridor. He was unable to maintain oxygen saturation, and an emergency tracheostomy was performed. Radiological and cytological evaluation were performed, and the patient was diagnosed as having primary PPS pleomorphic adenoma. The tumor was excised via the transcervical approach. The rarity of tumor in this space and unusual life-threatening presentation prompted the authors to report this case. To our knowledge, this is the third case reported worldwide of a pleomorphic adenoma causing upper airway obstruction and acute respiratory failure. PMID- 28584605 TI - Descriptive Epidemiology of Sitting Time in Omani Men and Women: A Known Risk Factor for Non-Communicable Diseases. AB - OBJECTIVES: Sedentary behaviors (too much sitting as distinct from too little exercise) are associated with increased risk of non-communicable diseases. Identifying the prevalence and sociodemographic correlates of sitting time can inform public health policy and prevention strategies. METHODS: A population based national survey was carried out among Omani adults in 2008 (n = 2 977) using the Global Physical Activity Questionnaire, which included a measure of total sitting time. Bivariate and regression analyses examined the associations of total sitting time with sociodemographic correlates (gender, age, education, work status, marital status, place of residence, and wealth). RESULTS: The proportion who sat for >= 7 hours/day was significantly higher in older than in younger adults (men: 22.0% vs. 14.6%, p < 0.010; women: 26.9% vs. 15.2%, p < 0.001, respectively). The odds ratio (OR) for prolonged sitting was half for men who were not working compared to those who were (p < 0.050). For younger women, the OR for sitting >= 7 hours/day was nearly a third for educated women compared to least educated (p = 0.035). For older women, the OR for prolonged sitting was more than double for married women compared to unmarried (p < 0.001). CONCLUSIONS: One in five Omani adults was identified as sitting for prolonged periods, at levels understood to have deleterious health consequences. Higher risk groups include older adults and working men. With sitting time identified as a key behavioral risk to be targeted for the prevention of non-communicable diseases, further research is needed to understand the factors associated with domain-specific sitting time in order to guide prevention programs and broader public health approaches. PMID- 28584607 TI - Essential Thrombocythemia in a Two-year-old Child, Responsive to Hydroxyurea but Not Aspirin. AB - Essential thrombocythemia (ET) is a myeloproliferative neoplasm that occurs mostly in patients above the age of 50 years. Its incidence in children is very rare, with around 100 cases reported in the literature. High-risk patients are defined by previous life threatening major thrombotic or severe hemorrhagic complication or age > 60. Those patients probably benefit from cytoreductive therapy. On the other hand, antiplatelet drugs are recommended for patients with low risk group. Although rare, ET should be considered in the differential diagnosis of persistent thrombocytosis in children, even at a very young age. A constellation of clinical, pathologic, and molecular testing are essential for diagnosis. Given the rarity of these cases, there is currently no consensus for treatment guidelines in children, especially in asymptomatic patients. We describe a case of a two-year old girl who presented with unexplained, isolated thrombocytosis which persisted for eight years. Bone marrow biopsy demonstrated typical features of ET. Over the course of the disease, hydroxyurea, but not aspirin, showed better control of symptoms and lowered the platelets level. PMID- 28584608 TI - Super Refractory Status Epilepticus in Hashimoto's Encephalopathy. AB - We present a case of a 38-year-old woman who was at eight weeks of gestation and was admitted to Sultan Qaboos University Hospital with refractory status epilepticus (SE). She presented with a two-day history of fever and a depressed level of consciousness that was followed with generalized tonic-clonic seizures. She progressed to refractory SE that required intubation and mechanical ventilation. Autoimmune workup was suggestive of Hashimoto's encephalopathy (HE) as suggested by the high levels of thyroid antibodies. Her magnetic resonance imaging showed bilateral hippocampal and basal ganglia hyperintensities, and electroencephalogram showed bilateral frontal epileptiform discharges. Other autoimmune workup was negative. Intravenous anesthetics were started including propofol, midazolam, ketamine, and thiopentone. She was started on multiple immunosuppressive therapies. Multiple antiepileptics were used including phenytoin, lamotrigine, levetiracetam, sodium valproate, clobazam, phenobarbital, and lacosamide. The outcome was unusual in terms of refractoriness to immunotherapy treatment despite a confirmed diagnosis. We did a literature review of all cases with HE presenting with SE with their clinical characteristics and outcome. PMID- 28584609 TI - Culture-Specific Pathogenicity of Dhat (Semen Loss) Syndrome in an Arab/Islamic Society, Oman. AB - A number of reports from different parts of the world have challenged the assumption that Dhat syndrome is confined to populations in and around the Indian subcontinent. This single case study reports an Omani with features typical of Dhat syndrome. Psychometric measures showed elevated scores on indices of hypochondriasis, psychasthenia, and gender role development as defined in the Minnesota Multiphasic Personality Inventory. He rated adequately in measures assessing cognitive and executive functioning. Implementation of cognitive behavioral therapy, concurrent with a successful marriage proposal, resulted in a gradual resolution of the symptoms. This report concludes with a discussion on whether his Dhat syndrome should be viewed as a culture-reactive or culture specific syndrome. PMID- 28584611 TI - A Vanishing Gastric Submucosal Lesion. PMID- 28584610 TI - The Usefulness of Nap Sleep Recording During Routine Electroencephalography: An Audit Study. AB - OBJECTIVES: A measure to increase the electroencephalogram (EEG) outcome includes a short period of nap sleep during a routine standard EEG with the aim of increasing its sensitivity to interictal abnormalities or provoking seizures. As part of an ongoing auditing of our EEG data, we aimed to investigate the contribution of nap sleep during routine outpatient department based EEGs requested for a variety of reasons. METHODS: EEG data at the Department of Clinical Physiology at Sultan Qaboos University Hospital, Oman, from July 2006 to December 2007 and from January 2009 to December 2010 (total 42 months) were reviewed. The EEGs were for patients older than 13-years referred for possible epilepsy, blackouts, headache, head trauma, and other non-specified attacks. The recording period was between 20 to 40 minutes. Abnormalities were identified during waking and nap sleep periods. RESULTS: A total of 2 547 EEGs were reviewed and 744 were abnormal (29.2%). Of those abnormal EEGs, nap sleep was obtained in 258 (34.7%) EEGs, and 39 (15.1%) showed abnormalities during nap sleep. Nineteen out of the 39 (48.7%) EEGs were abnormal during awake and nap sleep; and 20 (51.3%) were abnormal during nap sleep, which represented only 2.7% of the total abnormal EEGs (n = 744). CONCLUSIONS: The contribution of the short nap sleep to the pickup rate of interictal abnormalities in EEG was minimal. We recommend the EEG service to include one cycle of spontaneous sleep EEG directed at patients with a history suggestive of epilepsy if their awake EEGs are normal. PMID- 28584612 TI - Habitual Sleep Deprivation is Associated with Type 2 Diabetes: What Comes First? PMID- 28584613 TI - Habitual Sleep Deprivation and Type 2 Diabetes: What Actually Comes First? PMID- 28584614 TI - The Importance of a Multidisciplinary Approach or Women with Pelvic Organ Prolapse and Cystocele. PMID- 28584615 TI - Does Alpha-lipoic Acid Supplement Regulate Blood Pressure? A Systematic Review of Randomized, Double-blind Placebo-controlled Clinical Trials. AB - Although several animal and human studies have investigated the effect of alpha lipoic acid (ALA) on blood pressure (BP), these findings are inconsistent. This systematic review of randomized clinical trials was conducted to summarize the evidence on the effect of ALA on BP. PubMed, SCOPUS, and Google Scholar databases were searched based on MESH term ("Thioctic acid" in combination with "Hypertension" and "Blood pressure") to identify related papers published up to December 2015. We summarized the results of the relevant studies in this review. In total, nine studies included in this review, seven parallel-designed trials and two crossover-designed trials. The results of parallel-designed studies are inconsistent. Five studies indicate no significant effects for ALA supplementation on BP, but two trials show effects on BP. Unlike parallel designed trials, two crossover-designed trials have shown similar results and both report no effect for ALA on BP. Several studies investigated the effect of ALA on BP. Most of the papers show no significant effect for supplementation and the studies have shown that associations are limited. However, these findings are limited and there is a need for further and more accurate researches to be clarified. PMID- 28584616 TI - Discouraging the Practice of Tobacco Initiation among Children and Adolescents through Promoting of Smoke-free Films. PMID- 28584617 TI - Tumor Cells Growth and Survival Time with the Ketogenic Diet in Animal Models: A Systematic Review. AB - Recently, interest in targeted cancer therapies via metabolic pathways has been renewed with the discovery that many tumors become dependent on glucose uptake during anaerobic glycolysis. Also the inability of ketone bodies metabolization due to various deficiencies in mitochondrial enzymes is the major metabolic changes discovered in malignant cells. Therefore, administration of a ketogenic diet (KD) which is based on high in fat and low in carbohydrates might inhibit tumor growth and provide a rationale for therapeutic strategies. So, we conducted this systematic review to assess the effects of KD on the tumor cells growth and survival time in animal studies. All databases were searched from inception to November 2015. We systematically searched the PubMed, Scopus, Google Scholars, Science Direct and Cochrane Library according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. To assess the quality of included studies we used SYRCLE's RoB tool. 268 articles were obtained from databases by primary search. Only 13 studies were eligible according to inclusion criteria. From included studies, 9 articles indicate that KD had a beneficial effect on tumor growth and survival time. Tumor types were included pancreatic, prostate, gastric, colon, brain, neuroblastoma and lung cancers. In conclusions, although studies in this field are rare and inconsistence, recent findings have demonstrated that KD can potentially inhibit the malignant cell growth and increase the survival time. Because of differences physiology between animals and humans, future studies in cancer patients treated with a KD are needed. PMID- 28584618 TI - Prevalence and Determinants of Hypertension among Iranian Adults, Birjand, Iran. AB - BACKGROUND: Hypertension (HTN) is a major cause of noncommunicable diseases. In this study, we report the prevalence rate of HTN in Birjand population. METHODS: This cross-sectional study was conducted on 1286 individuals in Birjand in 2014. Individuals with systolic blood pressure (SBP) >=140 mmHg and/or diastolic blood pressure (DBP) >=90 mmHg were considered as hypertensive. Data were analyzed using Chi-square test, independent t-test, and one-way ANOVA. P < 0.05 was considered as statistically significant. RESULTS: Among the 1286 participants, 659 were women (51.2%). Prevalence of HTN was 20.1% (10.3% systolic HTN and 6.9% diastolic HTN). Prevalence self-reported HTN was 12.3%. SBP and DBP means were higher in men (P < 0.001). Mean scores of SBP and DBP increased by aging and body mass index (P < 0.001). Diabetic individuals had higher SBP scores (P < 0.001). Dyslipidemic patients had greater SBP and DBP (P < 0.001). CONCLUSIONS: Prevalence of HTN in our study is high. About one-fifth of the participants had HTN. In addition, BP is higher in men, elderly, and diabetic individual. Therefore, it is necessary to control BP regularly in different groups in society. PMID- 28584619 TI - Clinical Efficacy and Safety of Methotrexate versus Hydroxychloroquine in Preventing Lichen Planopilaris Progress: A Randomized Clinical Trial. AB - BACKGROUND: Lichen planopilaris is an inflammatory cicatricial alopecia, and its management is a challenge for dermatologists. We aimed to compare the efficacy of methotrexate and hydroxychloroquine on refractory lichen planopilaris. METHODS: In a randomized clinical trial, 29 patients were randomly allocated to receive either 15 mg methotrexate/week or 200 mg hydroxychloroquine twice a day for 6 months. Side effects, symptoms/signs, and laboratory tests were assessed periodically. Lichen Planopilaris Activity Index (LPPAI) was measured before intervention and at 2, 4, and 6 months after. The changes from baseline to the end of the study were analyzed within each group and between the two groups by per-protocol and intention-to-treat analysis. RESULTS: After 2 months, mean (standard deviation [SD]) decrease in LPPAI in methotrexate group was significantly more than that in hydroxychloroquine group (1.68 [1.24] vs. 0.8 [0.71], respectively, P = 0.047). Furthermore, after 6 months, mean (SD) decrease in LPPAI in methotrexate group was significantly higher than that in hydroxychloroquine group (3.3 [2.09] vs. 1.51 [0.91], respectively, P = 0.01). The following symptoms/signs showed significant improvements in frequency and/or severity in methotrexate group after intervention: pruritus (P = 0.007), erythema (P = 0.01), perifollicular erythema (P = 0.01), perifollicular scaling (P = 0.08), spreading (P = 0.001), and follicular keratosis (P = 0.04). In hydroxychloroquine group, only erythema (P = 0.004) showed significant improvement. CONCLUSIONS: Methotrexate was more effective than hydroxychloroquine in treating refractory lichen planopilaris. PMID- 28584620 TI - Erratum: Effect of Health Care as the "Home Visiting" on Postpartum Depression: A Controlled Clinical Trial. AB - [This corrects the article on p. 20 in vol. 8, PMID: 28479962.]. PMID- 28584621 TI - Fibroadenoma progress to ductal carcinoma in situ, infiltrating ductal carcinoma and lymph node metastasis? Report an unusual case. AB - Fibroadenoma of the breast is the most common benign neoplasm in young women who present with a palpable, movable mass. Malignancy inside fibroadenomas is rare, with reported rates ranging from 0.002% to 0.125%. Carcinoma in situ inside a fibroadenoma is usually found incidentally when tumours are excised. Whether fibroadenoma is a risk factor for breast cancer remains controversial. Due to the rarity of carcinomas inside fibroadenomas, medical institutes have little experience with this phenomenon. We report an unusual case in which progression occurred from benign fibroadenoma to ductal carcinoma in situ, infiltrating ductal carcinoma and lymph node metastasis. A nipple-areolar complex-preserving mastectomy with immediate breast reconstruction with a gel implant and contralateral augmentation was performed. No local recurrence or metastasis was found during 5 years of follow-up. PMID- 28584622 TI - A rare anatomical variation of the biliary tree. AB - A 31-year-old woman was admitted to our department in order to undergo a laparoscopic cholecystectomy. The operation was converted to open due to cholorrhea during the dissection in the hepatocystic triangle. The cholorrhea came from a transected bile duct, which was 2 mm in diameter, came out of the hepatoduodenal ligament, ran along the common hepatic duct and drained into the cystic duct, in proximity to the neck of the gallbladder. The gallbladder was removed and an intraoperative cholangiography revealed that the aberrant bile duct was originated from the right posterior sectoral duct (RPSD). The RPSD continued its typical course up to its confluence with the right anterior sectoral duct and the formation of the right hepatic duct. This is a rare type of aberrant bile duct, which is added to the long catalogue of the anatomical variations of the biliary tree. PMID- 28584623 TI - Laparoscopic repair of a migrated adjustable gastric band connecting tube with colonic erosion. AB - Laparoscopic adjustable gastric bands are a popular and effective surgical option to treat morbid obesity. The overall complication rate is 10-20% and the most common complication is of 'slippage'. Although other complications such as gastric band migration and erosion have been reported, the phenomenon of a migrated gastric band connecting tube eroding into the colon (after port removal) is seldom reported in the literature. In this article we describe such a case of an incidentally found colonic erosion on colonoscopy and describe the subsequent laparoscopic repair, as well as a review of the literature. PMID- 28584625 TI - Digital pathology imaging as a novel platform for standardization and globalization of quantitative nephropathology. AB - The introduction of digital pathology to nephrology provides a platform for the development of new methodologies and protocols for visual, morphometric and computer-aided assessment of renal biopsies. Application of digital imaging to pathology made substantial progress over the past decade; it is now in use for education, clinical trials and translational research. Digital pathology evolved as a valuable tool to generate comprehensive structural information in digital form, a key prerequisite for achieving precision pathology for computational biology. The application of this new technology on an international scale is driving novel methods for collaborations, providing unique opportunities but also challenges. Standardization of methods needs to be rigorously evaluated and applied at each step, from specimen processing to scanning, uploading into digital repositories, morphologic, morphometric and computer-aided assessment, data collection and analysis. In this review, we discuss the status and opportunities created by the application of digital imaging to precision nephropathology, and present a vision for the near future. PMID- 28584624 TI - The European Renal Association - European Dialysis and Transplant Association Registry Annual Report 2014: a summary. AB - Background: This article summarizes the European Renal Association - European Dialysis and Transplant Association Registry's 2014 annual report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2014 within 35 countries. Methods: In 2016, the ERA-EDTA Registry received data on patients who in 2014 where undergoing RRT for ESRD, from 51 national or regional renal registries. Thirty-two registries provided individual patient level data and 19 provided aggregated patient level data. The incidence, prevalence and survival probabilities of these patients were determined. Results: In 2014, 70 953 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 133 per million population (pmp). The incidence ranged by 10-fold; from 23 pmp in the Ukraine to 237 pmp in Portugal. Of the patients commencing RRT, almost two-thirds were men, over half were aged >=65 years and a quarter had diabetes mellitus as their primary renal diagnosis. By day 91 of commencing RRT, 81% of patients were receiving haemodialysis. On 31 December 2014, 490 743 individuals were receiving RRT for ESRD, equating to an unadjusted prevalence of 924 pmp. This ranged throughout Europe by more than 10 fold, from 157 pmp in the Ukraine to 1794 pmp in Portugal. In 2014, 19 406 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 36 pmp. Again this varied considerably throughout Europe. For patients commencing RRT during 2005-09, the 5-year-adjusted patient survival probabilities on all RRT modalities was 63.3% (95% confidence interval 63.0-63.6). The expected remaining lifetime of a 20- to 24-year-old patient with ESRD receiving dialysis or living with a kidney transplant was 21.9 and 44.0 years, respectively. This was substantially lower than the 61.8 years of expected remaining lifetime of a 20-year-old patient without ESRD. PMID- 28584626 TI - MMP2 and MMP9 associate with crescentic glomerulonephritis. AB - Background: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple organ involvement. Lupus nephritis (LN) is a common manifestation with a wide variety of histological appearances. Matrix metalloproteinases (MMP) 2 and 9 are gelatinases capable of degrading glomerular basement membrane type IV collagen, which have been associated with LN. We examine the expression of MMP2 and MMP9 in different classes of LN. Methods: MMP2 and MMP9 expression was detected by immunohistochemistry in sections from renal biopsy specimens with class III, class IV and class V LN (total n = 31), crescentic immunoglobulin A nephropathy (n = 6), pauci-immune glomerulonephritis (n = 7), minimal change disease (n = 2), mesangiocapillary glomerulonephritis (n = 7), diabetic nephropathy (n = 12) and histologically normal controls (n = 8). Results: MMP2 and MMP9 were not expressed in all classes of LN, but were observed in LN with cellular and fibrocellular crescents. MMP2/MMP9 was expressed in cellular and fibrocellular crescents regardless of glomerulonephritis but not observed in inactive fibrous crescents or with mesangial proliferation. This suggests that MMP2 and MMP9 are involved in the development of extracapillary proliferative lesions. Conclusions: MMP2/MMP9 is expressed with active extracapillary proliferation. Further study is necessary to define whether the expression of MMP2/MMP9 reflects a role in glomerular repair after injury, a role in organ-level immune responses or a role as a marker of epithelialization. PMID- 28584627 TI - Mixed leukocyte cell-derived chemotaxin 2 and amyloid A renal amyloidosis in a Kazakh-German patient. AB - Leukocyte cell-derived chemotaxin 2 (LECT2)-related amyloidosis (ALECT2) constitutes a subtype of systemic amyloidosis affecting the kidney. This is the first case describing mixed ALECT2 and Amyloid A renal amyloidosis in a Kazakh German patient. Genetic analysis shows a polymorphism in the LECT2 gene and a homozygous mutation in the SAA1 gene. Notably, our patient has a body mass index of 61 kg/m2 and a pathological glucose tolerance test. ALECT2 was found in certain ethnic groups with a high incidence of diabetes. In our case, morbid obesity may have played a significant role in clinical manifestation of ALECT2 amyloidosis. PMID- 28584628 TI - Involvement of glycogen debranching enzyme in bladder cancer. AB - Bladder cancer is the most common malignancy of the urinary system, however the molecular pathways underlying this disease are incompletely understood. To understand new regulators of bladder cancer progression, the authors carried out a functional genomic screen which identified glycogen debranching enzyme (AGL) as a novel regulator of bladder cancer growth. Glycogen debranching enzyme is involved in glycogen breakdown and germline loss of function mutation of this gene leads to glycogen storage disease type III. To the best of the authors' knowledge, the present study is the first to demonstrate that loss of AGL leads to aggressive bladder tumor growth. AGL mRNA and protein expression in bladder tumors serve as a prognostic marker for patients. Interestingly, AGL's participation in regulating tumor growth is independent of its enzymatic function and involvement with glycogen metabolism in general. Detailed metabolomics and transcriptomic analysis indicated that increases in glucose metabolism, glycine synthesis driven by serine hydroxymethyltransferase 2 and increases in hyaluronic acid synthase 2-driven HA synthesis are major contributors of aggressive bladder tumor growth with loss of AGL. However, the detailed mechanism of how AGL regulates the above mentioned metabolic and genetic pathways is unknown and is being investigated. The present review focuses on AGL's involvement in bladder cancer. PMID- 28584629 TI - Role of the microRNA-29 family in fibrotic skin diseases. AB - Fibrotic skin diseases are characterized by the accumulation of collagen. The hallmarks of fibrotic skin diseases are unbalanced fibroblast proliferation and differentiation, extracellular matrix production and transforming growth factor beta signalling. Numerous studies have investigated the possibility that microRNAs (miRNAs or miRs) are involved in the pathogenesis of certain fibrotic diseases, including skin, heart, lung and liver diseases. miRNAs are a class of small non-coding RNAs, which modify gene expression by binding to target messenger RNA (mRNA) and blocking the translation or inducing the degradation of target mRNA. The biological relevance of miRNAs has been investigated in physiological and pathological conditions, and there is increasing evidence that the miR-29 family is associated with fibrotic diseases. The aim of the present review is to provide an up-to-date summary of current knowledge on the latest developments associated with the miR-29 family and fibrotic skin diseases. PMID- 28584631 TI - Drug development: Lessons from nature. AB - Natural products have been acknowledged for numerous years as a vital source of active ingredients in therapeutic agents. In particular, the use of active ingredients derived from plants for use in microbial natural products have long been used before the dawn of modern medicine. From ancient times, the efficacy of natural products has been associated with the chemistry, biochemistry and synthetic activities of natural products. Thus, with scientific advancement in modern molecular and cellular biology, analytical chemistry and pharmacology, the unique properties of these natural products are being harnessed in order to exploit the chemical and structural diversity and biodiversity of these types of products in relation to their therapeutic effect. Often, new molecules of interest in drug design units focus on the rearrangement of chemical entities or structural isomers of naturally occurring products in order to generate new molecules; these may be formulated into clinically useful therapies. PMID- 28584630 TI - Connexin 43: Key roles in the skin. AB - Gap junctions are tightly packed intercellular channels that serve a common purpose of allowing the intercellular exchange of small metabolites, second messengers and electrical signals. Connexins (Cxs) are gap junction proteins. Currently, 20 and 21 members of Cxs have been characterized in mice and humans, respectively. Connexin 43 (Cx43) is the most ubiquitously expressed type of Cx in the skin. It is produced by various different types of skin cell, such as keratinocytes, fibroblasts, endothelial and basal cells, melanocytes and dermal papilla cells. At present, more evidence indicates that Cx43 has an important role in skin repair and skin tumor development, as well as in skin cell invasion and metastasis. In this review, current knowledge regarding the regulation and function of Cx43 is summarized and the therapeutic potential of regulating Cx43 activity is discussed. PMID- 28584632 TI - Biochemical and structural features of extracellular vesicle-binding RNA aptamers. AB - Extracellular vesicles are particles in mammalian body fluids that have attracted considerable attention as biomarkers for various diseases. In the present study, the authors isolated RNA aptamers with an affinity for extracellular vesicles from two library pools that encoded randomized sequences of different lengths. After the several rounds of selection, two conserved motifs are identified in the sequences that are obtained by next-generation sequencing. Most of the sequences were predicted to adopt a secondary structure that consisted of a non-conserved stem structure and a conserved loop sequence. Two minimal similar sequences are synthesized and confirmed the ability of these sequences to bind to extracellular vesicles. Circular dichroism spectroscopy and melting temperature analysis demonstrated that the aptamers were able to form a G-quadruplex structure in their loop regions and these structures were stabilized by potassium ions. Consistent with these structural data, the affinity of each aptamer for extracellular vesicles was dependent on potassium ions. The aptamers that were identified may be useful molecular tools for the development of diagnostic methods that utilize body fluids, such as blood, saliva and urine. PMID- 28584633 TI - Construction of a general albumin promoter reporter system for real-time monitoring of the differentiation status of functional hepatocytes from stem cells in mouse, rat and human. AB - Genetic constructs with promoters fused to reporter genes for simultaneous monitoring of cellular events have been the focus of attention in recent years. Adenoviral vectors, which have distinctive characteristics, have been used to monitor the differentiation of stem cells in vitro. In the present study, a modified adenoviral vector was constructed, containing a mouse, rat, and human general albumin promoter sequence fused to a ZsGreen reporter gene, and evaluated its efficiency in different cell types. Two hepatocyte cell lines (Hepa1-6 and HepG2), rat primary hepatocytes, rat bone marrow mesenchymal stem cells (BM-MSCs) and rat BM-MSCs-derived hepatocyte-like cells were transduced with this vector, and the transfection efficiency and functional capabilities of the promoter were evaluated by fluorescent microscopy. The results demonstrated efficient expression of ZsGreen in Hepa1-6 cells, HepG2 cells, rat primary hepatocytes, and rat BM-MSCs-derived hepatocyte-like cells, but not in rat BM-MSCs. In conclusion, the current study demonstrates a simple, high-efficiency, general tool for real time monitoring of the differentiation status of hepatocytes from stem cells in mice, rats, and humans. This tool may be useful for evaluating different protocols to generate functional hepatocytes from stem cells in multiple species. PMID- 28584634 TI - Analysis of the changes in Th9 cells and related cytokines in the peripheral blood of spontaneous urticaria patients. AB - Spontaneous urticaria (SU) is characterized by immune deregulation of mast cells and T helper (Th) cells. Th9 cells, a subset of Th cells, serve a key role in initiating mast cell accumulation and activation. To understand the role of Th9 cells in the pathogenesis of SU, the authors conducted a control study of 28 patients with acute SU (ASU) and chronic SU (CSU) and 28 healthy controls. The percentage of Th9 cells in peripheral blood was assessed using flow cytometry and levels of Th9 related serum cytokines including interleukin (IL)-4, IL-9, IL-17A, IL-33, IL-1beta and transforming growth factor-beta1 (TGF-beta1) using Luminex 200. ASU patients exhibited higher percentages of Th9 cells and increased serum levels of cytokines IL-9, IL-4 and TGF-beta1 compared to healthy controls. In addition, high mRNA expression of the PU.1 transcription factor was observed in ASU patients. However, the percentage of Th9 cells was similar between patients with CSU and healthy controls. Furthermore, the percentage of Th9 cells demonstrated a positive correlation with IL-4 and IL-9 levels in the peripheral blood of ASU patients, but not with disease severity. The current findings suggested that the numbers of Th9 cells increased in ASU patients and indicated its novel role in the pathogenesis of ASU. PMID- 28584635 TI - Interactions between polymorphisms in the 3'untranslated region of the cyclin dependent kinase 6 gene and the human papillomavirus infection, and risk of cervical precancerous lesions. AB - The human papillomavirus (HPV) infection is essential for the development of cervical cancer and its precursor lesions. However, only certain persistently infected individuals develop cervical cancer. Cyclin-dependent kinase 6 (CDK6) is a critical regulatory cancer-associated gene in the cell cycle and in tumorigenesis. Single nucleotide polymorphisms (SNPs) in microRNA sites in the 3' untranslated region (UTR) of target genes may result in target gene expression level changes and susceptibility to diseases, including cancer. Therefore, the aim of the present study was to determine whether SNPs in the 3'UTR of the CDK6 gene may affect susceptibility to cervical precancerous lesions in a Chinese population. Five polymorphisms in the 3'UTR of the CDK6 gene were evaluated in 164 cervical precancerous lesion cases and 296 control subjects. Differences in environmental factors between cases and controls were evaluated using the chi2 test or unpaired t-test. Logistic regression was used to examine the association between the five polymorphisms and cervical precancerous lesions. The model-free multifactor dimensionality reduction (MDR) method was performed to evaluate the interaction effect of environment variables and gene polymorphisms. Interactions on the additive scale are calculated by using the relative excess risk due to interaction (RERI). After controlling for potential confounders, a significantly decreased risk of cervical precancerous lesions for the GA genotype, rs8179, and the AT genotype, rs42033 [GA vs. GA: odds ratio (OR)adjusted=0.17, 95% confidence interval (CI), 0.05-0.57; AT vs. AA: ORadjusted=0.18, 95% CI, 0.05-0.59, respectively] was identified. Furthermore, following MDR analysis, a significant three-locus interaction model was identified, which involved the HPV infection, the number of pregnancies and rs8179. Additionally, a significant antagonistic interaction between the HPV infection and rs8179 was identified on an additive scale. Haplotype AGTA was associated with a decreased risk of developing cervical precancerous lesions (ORadjusted=0.21; 95% CI, 0.06-0.75). Thus, the present results indicated that the rs8179 and rs42033 polymorphisms confer genetic susceptibility to cervical precancerous lesions. Furthermore, the interaction between the rs8179 polymorphism in CDK6 and the HPV infection and haplotype AGTA may be associated with cervical precancerous lesions. PMID- 28584636 TI - ATP serves an anti-inflammatory role by enhancing beta-defensin-2 response in acute pneumonia of rat. AB - The aim of the current study was to evaluate the effect of ATP on the expression of rat beta-defensin-2 (rBD-2) in a time-dependent manner, as well as its therapeutic value in an acute pneumonia rat model. A total of 30 rats as a treatment group and 30 as a control group were treated with the same dose of ATP and normal saline, respectively, lung tissues were isolated from rat and expression of rBD-2 mRNA was assessed with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) at 12, 24 and 36 h following treatment. Rats were divided into five groups: The control group treated with normal saline, the Pseudomonas aeruginosa (PA) infected group, group treated with ATP, group treated with cephalosporins, and the group treated with both ATP and cephalosporins. At 24 h following treatment, rat serum and lung tissues were collected for assessment of histological changes, and alterations to expression of the rBD-2 protein by immunohistochemistry, expression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 proteins by ELISA. RT-qPCR results indicated that the expression of rBD-2 mRNA was upregulated in response to ATP stimulation in lung tissues of rat, reaching its highest peak at 24 h. Immunohistochemistry demonstrated that ATP treatment enhanced the expression of rBD-2 protein in rat lungs. Ceftazidime and ATP protected lungs from infection of PA and reduced the pathological damage of the lung. Overexpression of rBD-2 by ATP led to decreased protein expression of TNF-alpha and IL-6 in lung tissues and serum. ATP upregulates the expression of rBD-2 and serves an anti-inflammatory role in the acute pneumonia of a rat model. PMID- 28584637 TI - Identification of global transcriptome abnormalities and potential biomarkers in eutopic endometria of women with endometriosis: A preliminary study. AB - The etiology and pathophysiology of endometriosis remain unclear. The aim of the current study was to identify a candidate pathogenic gene, as well as potential biomarkers of endometriosis using messenger RNA (mRNA) sequencing (mRNA-seq). Twenty-three eutopic endometria from women with endometriosis and 20 endometria from control subjects were investigated. Eight eutopic endometria and five normal endometria were selected for mRNA-seq. Differentially expressed genes (DEGs) were identified and functional analysis was conducted. Validation of certain DEGs was performed in the remaining cases and control subjects by reverse transcription quantitative polymerase chain reaction (RT-qPCR). A total of 72 DEGs (66 upregulated and 6 downregulated) were identified in samples from women with endometriosis and compared with the control subjects. High DEGs included those involved in various functions, such as extracellular matrix (ECM) remodeling, angiogenesis, cell proliferation and differentiation. Enriched by these DEGs, 100 Gene Ontology terms were identified as significantly important, particularly 'ECM' and 'endogenous stimulus'. Validation using RT-qPCR indicated that matrix metallopeptidase 11, dual specificity phosphatase 1, Fos proto-oncogeneand serpin family E member 1 were significantly upregulated and adenosine deaminase 2 was significantly downregulated in the eutopic endometrium of patients with endometriosis. The identified DEGs may be involved in the pathogenesis of endometriosis and may be potential biomarkers in the eutopic endometrium. The current study provides a comprehensive, but preliminary insight for elucidating the mechanisms of endometriosis, which require further in-depth studies for confirmation. PMID- 28584638 TI - Association between angiotensin-converting enzyme insertion/deletion polymorphisms and intracranial aneurysm susceptibility: A meta-analysis. AB - Various studies have evaluated the association between polymorphisms of angiotensin-converting enzyme (ACE) and intracranial aneurysm (IA) risk; however, the results remain inconsistent. The PubMed, Embase, and Wanfang Data databases were systematically searched until January 6th 2016. Case-control studies investigating the association between the ACE polymorphism and IA risk were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated with the fixed or random-effects model assuming allele, homozygote comparison of codominant, heterozygote comparison of codominant, dominant, and recessive models. Seven studies including 1,074 cases and 1,500 controls were included in the current meta-analysis. The results of the analysis indicated that the ACE polymorphism significantly increased IA risk in the allele, homozygote comparison of codominant and dominant models. According to the further stratified analysis by ethnicity, source of control and sample sizes, a significant association was identified between the ACE variant and IA risk in Asian individuals, hospital based, or large (>300) subgroups in all of the genetic models, not including the recessive model. Furthermore, no significantly increased risk was indicated in Caucasian individuals, population-based, or small (<300) subgroups in the heterozygote comparison of codominant, dominant and recessive models. The available evidence indicates that the ACE polymorphism is associated with an increased risk of IA, particularly in Asian individuals. However, other factors may impact this association. Further large, well-designed multicenter studies are required to validate the findings from the present study. PMID- 28584639 TI - The evaluation of fibrotic effects of the hepatitis B virus pre-core in hepatic stellate cells. AB - The role of the hepatitis B virus (HBV) endogenous pre-core protein in liver fibrosis is controversial. Whether the expression of the pre-core induces the activation of human stellate cells (HSCs) has not yet been reported. Plasmids expressing HBx, or pre-core protein were transfected into LX-2 cells. Subsequently, total RNA extracted and reverse transcription-quantitative polymerase chain reaction was performed to measure the fold change of collagen type I, alpha1 chain, alpha-smooth muscle actin and TIMP metalloproteinase inhibitor-1. Moreover, transforming growth factor (TGF)-beta in the supernatant of HSCs was evaluated by ELISA assay. In addition, a MTT assay was performed to test the cytotoxicity of the endogenous expression in LX-2 cells. None of the plasmids exhibited cytotoxic nor significant proliferative effects on LX-2 cells by MTT assessment. The gene expression analysis of fibrotic genes in LX-2 cells demonstrated that the pre-core protein presented no significant (P>0.05) fibrotic impact when compared to the empty control plasmid and HBx. The data from the TGF beta ELISA was consistent with the mRNA expression as detected with the control plasmid (P>0.05). The endogenous expression of the HBV pre-core exhibited no fibrotic impression in HSCs when compared to HBx. PMID- 28584640 TI - Chlorpheniramine and escitalopram: Similar antidepressant and nitric oxide lowering roles in a mouse model of anxiety. AB - There is a crosstalk between mood disorders and oxidative stress. Chlorpheniramine (CPA), a first generation antihistamine, is hypothesized to have an anxiolytic role at high doses; however, its antidepressant and antioxidant roles have not previously been investigated. The aim of the current study was to evaluate the antidepressant and anxiolytic effects of CPA treatment in association with nitric oxide (NO) and super oxide dismutase (SOD) activity in a mouse model of anxiety. BALB/c mice were divided into unstressed (naive), control, and CPA- (0.5 mg/kg) and escitalopram- (ESC; 10 mg/kg) treated groups for 3 weeks. Subsequently, they were immobilized for 6 h and subjected to behavioural paradigms as follows: The open field test, the elevated plus maze (EPM) and the forced swim test to investigate motor function, anxiety and depression, respectively. The mice were sacrificed and serum was obtained to detect NO and SOD activity. Compared with the control group, the CPA-treated group demonstrated an antidepressant effect similar to that of the ESC-treated group. In addition, CPA prevented stress-induced NO without affecting SOD activity. CPA did not improve anxiety-like behaviour in the EPM, nor did it improve stress-induced locomotion and rearing, as demonstrated by the OFT. Thus, to the best of our knowledge, this is the first study to evaluate the antidepressant role of CPA in association with NO metabolism. However, further studies are required to elucidate the underlying mechanism. PMID- 28584642 TI - Pretreatment with intravenous amiodarone improves the efficacy of ibutilide treatment on cardioversion rate and maintenance time of sinus rhythm in patients with persistent atrial fibrillation. AB - The aim of the present study was to assess the efficacy and safety of the pharmacological conversion of persistent atrial fibrillation (AF) using amiodarone or/and ibutilide. Seventy-nine consecutive patients (48 males and 31 females; mean age, 64.6+/-11.2 years; range, 40-80 years) with non-valvular chronic AF lasting >7 days (range, 7-97 days) that were admitted to hospital for elective pharmacological cardioversion were randomly assigned to receive treatment with intravenous ibutilide (1 mg plus an additional 1 mg if required; n=39) or intravenous amiodarone (300 mg) plus intravenous ibutilide (1 mg; n=40). Success rates of cardioversion were 51.3% (20/39 patients) for ibutilide alone and 71.8% (28/39 patients) for amiodarone + ibutilide (P<0.05). A comparable increase in the QTc interval was observed in the two groups. It was observed that the co-administration of amiodarone and ibutilide was safer than ibutilide alone with regard to the risk of ventricular arrhythmia. Forty-eight patients of successful cardioversion were personally contacted for follow-up. The result indicated that the sinus rhythm maintenance time of the amiodarone + ibutilide group (4.36+/-2.44 months) was significantly higher than that of the ibutilide group (2.34+/-1.75 months; P<0.01). In conclusion, pretreatment with intravenous amiodarone + ibutilide for pharmacological cardioversion of persistent AF is considered to be more effective and safer than treatment with ibutilide alone. PMID- 28584641 TI - Barley grass extract causes apoptosis of cancer cells by increasing intracellular reactive oxygen species production. AB - Cancer remains a leading cause of mortality worldwide, therefore food products are being investigated for potential prevention or treatment strategies. The ingredient, barley grass extract (Hordeum vulgare L.; Bex) is used to prevent or ameliorate various types of disease. In cancer, Bex has been revealed to inhibit tumor growth. However, its effect on cancer cells is yet to be clearly defined. In the present study, the effect of Bex on cancer cell growth was investigated. Bex inhibited the viabilities of breast and prostate cancer cells according to the results of MTT assays. Accordingly, Bex caused apoptosis, which was confirmed by Annexin V staining and western blot analysis for poly (ADP-ribose) polymerase and caspases. Furthermore, Bex increased the intracellular levels of reactive oxygen species (ROS), and N-acetyl-L-cystein blocked Bex-induced apoptosis. Therefore, the study demonstrated that Bex causes apoptosis of breast and prostate cancer cells by increasing intracellular ROS levels. PMID- 28584643 TI - Suppression of inflammation by the rhizome of Anemarrhena asphodeloides via regulation of nuclear factor-kappaB and p38 signal transduction pathways in macrophages. AB - The rhizome of Anemarrhena asphodeloides Bunge (A. asphodeloides) has been used as a traditional East Asian medicine for the treatment of various types of inflammatory disease. However, to the best of our knowledge, there have been no systemic studies regarding the molecular mechanisms of action of the A. asphodeloides rhizome anti-inflammatory effects. The aim of the present study was to elucidate the anti-inflammatory effects and underlying mechanism of action of ethanol extracts of the rhizome of A. asphodeloides (EAA) in murine macrophages. Non-cytotoxic concentrations of EAA (10-100 ug/ml) significantly decreased the production of NO and interleukin (IL)-6 in lipopolysaccharide (LPS)-stimulated macrophages, while the production of tumor necrosis factor-alpha was not regulated by EAA. EAA-mediated reduction of nitric oxide (NO) was due to reduced expression levels of inducible NO synthase (iNOS). Furthermore, protein expression levels of LPS-induced cyclooxygenase-2, another inflammatory enzyme, were alleviated in the presence of EAA. EAA-mediated reduction of those proinflammatory mediators was due to inhibition of nuclear factor-kappaB (NF kappaB) and activator protein 1 transcriptional activities followed by the stabilization of inhibitor of kappa Balpha and inhibition of p38, respectively. These results indicate that EAA suppresses LPS-induced inflammatory responses by negatively regulating p38 and NF-kappaB, indicating that EAA is a candidate treatment for alleviating inflammation. PMID- 28584644 TI - Evaluation of tumor necrosis factor (TNF)-alpha mRNA expression level and the rs1799964 polymorphism of the TNF-alpha gene in peripheral mononuclear cells of patients with inflammatory bowel diseases. AB - Crohn's disease (CD) and ulcerative colitis (UC) are types of chronic inflammatory bowel disease (IBD) of which the actual causes remain unknown. Emerging data indicate that alterations in cytokine synthesis may be involved in IBD pathogenesis. The aim of the present study was to determine whether the tumor necrosis factor (TNF)-alpha mRNA expression level and rs1799964 polymorphism are the genetic susceptibility component of IBD development. The TNF-alpha mRNA expression level of peripheral blood mononuclear cells (PBMCs) was measured using comparative reverse-transcription quantitative polymerase chain reaction (PCR). Genomic DNA from 201 individuals (CD: n=15; UC: n=86; control subjects: n=100) was analyzed for the presence of the TNF-alpha-1031 polymorphism by PCR restriction fragment length polymorphism. An increased TNF-alpha mRNA expression level was additionally observed in the CC genotype of the -1031 TNF-alpha gene polymorphism compared with the TC and TT genotypes (P<0.05). Furthermore, the present results revealed that there was no significant difference in the genotype/allele frequencies of the -1031 TNF-alpha gene polymorphism in Iranian IBD patients. By comparison, the TNF-alpha mRNA expression level was evaluated in patients with a history of taking medications and demonstrated a significant association in the group that received the 5-ASA + Pred + AZA,5. 5-ASA + Pred + AZA + IFX when compared with the other groups (P<0.05). Thus, these results support the hypothesis that overexpression of the TNF-alpha gene, which correlated with the CC genotype, may represent a genetic risk factor for Iranian IBD. PMID- 28584645 TI - Clinical manifestations in two patients with pyruvate dehydrogenase deficiency and long-term survival. AB - Pyruvate dehydrogenase E1-alpha deficiency (PDHAD) results in lactic acidosis and hyperpyruvatemia. Two patients with PDHAD, a man with a p.R263Q mutation, and a girl with a p.C145del mutation in PDHE1alpha, presented with lactic acidosis with neurological disorder. These patients were able to survive for a long period under careful nursing care. Herein, we discuss the factors contributing to their relatively stable clinical course, albeit with intellectual disability. PMID- 28584646 TI - A novel mutation of NFIX causes Sotos-like syndrome (Malan syndrome) complicated with thoracic aortic aneurysm and dissection. AB - Malan syndrome has recently been characterized to present Sotos-like phenotypes, such as intellectual disability and macrocephaly, with mutations in the NFIX gene. Herein, we report a 38-year-old patient with a novel single adenine insertion mutation in exon 2 of the NFIX gene (c.290_291insA). He developed early onset thoracic aortic aneurysm and dissection, which was a rare complication but deserves particular attention in relatively long-lived patients with Sotos-like phenotypes. PMID- 28584647 TI - Big data in mental health research - do the ns justify the means? Using large data-sets of electronic health records for mental health research. AB - Advances in information technology and data storage, so-called 'big data', have the potential to dramatically change the way we do research. We are presented with the possibility of whole-population data, collected over multiple time points and including detailed demographic information usually only available in expensive and labour-intensive surveys, but at a fraction of the cost and effort. Typically, accounts highlight the sheer volume of data available in terms of terabytes (1012) and petabytes (1015) of data while charting the exponential growth in computing power we can use to make sense of this. Presented with resources of such dizzying magnitude it is easy to lose sight of the potential limitations when the amount of data itself appears unlimited. In this short account I look at some recent advances in electronic health data that are relevant for mental health research while highlighting some of the potential pitfalls. PMID- 28584648 TI - Vitamin D deficiency in adolescents in a tier 4 psychiatric unit. AB - Aims and method To review the current clinical practice and guidelines for testing and treating vitamin D deficiency in adolescents admitted to a tier 4 adolescent psychiatric unit in north London. The blood test results of 56 patients admitted between 2012 and 2014 were examined to determine whether vitamin D levels had been tested. For those individuals who were tested for vitamin D, results were analysed by gender and ethnicity. Results Of 56 patients admitted, 48% were tested for vitamin D deficiency and in 81.5% of cases we uncovered deficiency or severe deficiency; 18.5% had the minimum levels of vitamin D for bone health as per our trust guidelines. Clinical implications Adolescents within tier 4 adolescent mental health services may be at higher risk of vitamin D deficiency and so assessment of vitamin D levels should be considered as part of a standard physical health review for this group of young people. PMID- 28584649 TI - Adherence to NICE guidance on lifestyle advice for people with schizophrenia: a survey. AB - Aims and method The STEPWISE trial (STructured lifestyle Education for People WIth SchizophrEnia, schizoaffective disorder and first episode psychosis) is currently evaluating a lifestyle education programme in addition to usual care. However, it is difficult to define what constitutes 'usual care'. We aimed to define 'usual care' for lifestyle management in people with schizophrenia, schizoaffective disorder and first-episode psychosis in STEPWISE study sites. Ten National Health Service (NHS) mental health trusts participated in a bespoke survey based on the National Institute for Health and Care Excellence (NICE) guidance. Results Eight trusts reported offering lifestyle education programmes and nine offered smoking cessation support. Reported recording of biomedical measures varied. Clinical implications Although recommended by NICE, lifestyle education programmes are not consistently offered across UK NHS mental health trusts. This highlights missed opportunities to improve the physical health of people with psychotic illness. Our survey benchmarks 'usual care' for the STEPWISE study, against which changes can be measured. Furthermore, future studies will be able to identify whether any progress in clinical practice has been made towards achieving the NICE recommendations. PMID- 28584651 TI - An analysis of whether a working-age ward-based liaison psychiatry service requires the input of a liaison psychiatrist. AB - Aims and method This article presents a 12-month case series to determine the fraction of ward referrals of adults of working age who needed a liaison psychiatrist in a busy tertiary referral teaching hospital. Results The service received 344 referrals resulting in 1259 face-to-face contacts. Depression accounted for the most face-to-face contacts. We deemed the involvement of a liaison psychiatrist necessary in 241 (70.1%) referrals, with medication management as the most common reason. Clinical implications A substantial amount of liaison ward work involves the treatment and management of severe and complex mental health problems. Our analysis suggests that in the majority of cases the input of a liaison psychiatrist is required. PMID- 28584650 TI - Are men under-treated and women over-treated with antidepressants? Findings from a cross-sectional survey in Sweden. AB - Aims and method To examine gender differences in self-reported depression and prescribed antidepressants (ADs). The Hospital Anxiety and Depression Scale was used to assess depression, and information on prescribed ADs was obtained from the Swedish Prescribed Drug Register. Results Depression was reported by 11.7% of the participants (12.3% men and 11.2% women). ADs were prescribed for 7.6% of the participants (5.3% men, 9.8% women). Among men, 1.8% reported depression and used ADs, 10.5% reported depression but did not use ADs, and 3.6% used ADs but did not report depression. The corresponding figures for women were 2.6%, 8.6% and 7.2%. Clinical implications Men report depression to a greater extent than women but are prescribed ADs to a lesser extent, possibly a sign of under-treatment. Women are prescribed ADs without reporting depression more often than men, possibly a sign of over-treatment. Although the causes remain unclear, diagnostic and treatment guidelines should benefit from considering gender differences in these respects. PMID- 28584652 TI - Civil and forensic patients in secure psychiatric settings: a comparison. AB - Aims and method To evaluate differences between male patients in secure psychiatric settings in the UK based on whether they are detained under civil or forensic sections of the Mental Health Act 1983. A cohort of patients discharged from a secure psychiatric hospital were evaluated for length of stay and frequency of risk-related incidents. Results Overall, 84 patients were included in the study: 52 in the forensic group and 32 in the civil group. Civil patients had more frequent incidents of aggression, sex offending, fire-setting and vulnerability, whereas forensic patients had more frequent episodes of self-harm. Clinical implications Secure hospitals should ensure treatment programmes are tailored to each patient's needs. Civil patients require greater emphasis on treatment of their mental illness, whereas forensic patients have additional offence-related treatment needs. Regular liaison between forensic and general adult services is essential to help ensure patients can return to appropriate settings at the earliest opportunity in their recovery. PMID- 28584653 TI - Known unknowns and unknown unknowns in suicide risk assessment: evidence from meta-analyses of aleatory and epistemic uncertainty. AB - Suicide risk assessment aims to reduce uncertainty in order to focus treatment and supervision on those who are judged to be more likely to die by suicide. In this article we consider recent meta-analytic research that highlights the difference between uncertainty about suicide due to chance factors (aleatory uncertainty) and uncertainty that results from lack of knowledge (epistemic uncertainty). We conclude that much of the uncertainty about suicide is aleatory rather than epistemic, and discuss the implications for clinicians. PMID- 28584654 TI - Drug information update. Unconventional treatment strategies for schizophrenia: polypharmacy and heroic dosing. AB - The majority of patients respond to antipsychotic monotherapy at standard doses, but a subset of patients will require more heroic measures that include antipsychotic polypharmacy and high-dose monotherapy. Indeed, research has shown that roughly 30% of patients with psychosis are prescribed multiple antipsychotic medications. We discuss the potential benefits and challenges of these approaches and provide a rationale for why and when they should be utilised. PMID- 28584655 TI - Should compulsory admission to hospital be part of suicide prevention strategies? AB - The World Health Organization report Preventing Suicide: A Global Imperative provides governments with guidance for comprehensive suicide prevention strategies. However, it does not mention the role that compulsory admission to hospital of psychiatric patients should have in policies for suicide prevention. This was a missed opportunity for international discussion and guidance about a measure that, although widely used, is becoming increasingly controversial in light of the existing evidence and human rights norms. PMID- 28584656 TI - Improving the quality of mental health services using patient outcome data: making the most of HoNOS. AB - Efforts to assess and improve the quality of mental health services are often hampered by a lack of information on patient outcomes. Most mental health services in England have been routinely collecting Health of the Nation Outcome Scales (HoNOS) data for some time. In this article we illustrate how clinical teams have used HoNOS data to identify areas where performance could be improved. HoNOS data have the potential to give clinical teams the information they need to assess the quality of care they deliver, as well as develop and test initiatives aimed at improving the services they provide. PMID- 28584657 TI - Personalisation and social care assessment - the Care Act 2014. AB - The Care Act 2014 represents a significant change in legislation in England. For the first time it brings together various aspects of adult social care into a single statute succeeding earlier acts and policy. Given its importance to the lives of service users and carers, clinicians need to have a clear understanding of its implications. We provide an overview of why it was developed, its underlying principles and international comparisons, as well as implications for assessments, interventions and outcomes. The impact on the lives of patients and carers is discussed, as well as dilemmas and challenges the Act presents. While it addresses other important aspects of social care, including safeguarding, Mental Health Act section 117 aftercare and duty of candour, we focus on personalisation because of the opportunities it provides to enhance management plans for people experiencing mental health problems. PMID- 28584658 TI - Capacity assessments - diagnosis is misleading. PMID- 28584659 TI - Post-flight confusion. PMID- 28584660 TI - Mental capacity to consent to treatment and the association with outcome: a longitudinal study in patients with anorexia nervosa. AB - BACKGROUND: Relevance of diminished mental capacity in anorexia nervosa (AN) to course of disorder is unknown. AIMS: To examine prognostic relevance of diminished mental capacity in AN. METHOD: A longitudinal study was conducted in 70 adult female patients with severe AN. At baseline, mental capacity was assessed by psychiatrists, and clinical and neuropsychological data (decision making) were collected. After 1 and 2 years, clinical and neuropsychological assessments were repeated, and remission and admission rates were calculated. RESULTS: People with AN with diminished mental capacity had a less favourable outcome with regard to remission and were admitted more frequently. Their appreciation of illness remained hampered. Decision-making did not improve, in contrast to people with full mental capacity. CONCLUSIONS: People with AN with diminished mental capacity seem to do less well in treatment and display decision making deficiencies that do not ameliorate with weight improvement. DECLARATION OF INTEREST: None. COPYRIGHT AND USAGE: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 28584661 TI - Evaluation of sexual and fertility dysfunction in spinal cord-injured men in Jamaica. AB - INTRODUCTION: Sexual dysfunction and infertility are common in males with traumatic spinal cord injuries (SCIs). The objective of this study was to determine the prevalence of sexual dysfunction and infertility in males with traumatic SCI managed in Jamaica, as well as the therapeutic options offered. CASE PRESENTATION: A cross-sectional study including males with traumatic SCI managed at the Sir John Golding Rehabilitation Centre, Kingston, Jamaica was carried out between 1 January and 31 December 2015. Sexual function was measured with the International Index of Erectile Function Questionnaire, and further information on social history, fertility desires and treatment options offered were collected. Data were analyzed using Stata 12 for Windows (College Station, TX, USA). The mean age of patients at the time of study was 38.8+/-15.3 years (range 19-71) with a mean duration of injury of 3.7+/-2.4 years (range 1.3-15.6). Of 45 patients with traumatic SCI surveyed, 90.7% had erectile dysfunction, with 62.8% being classified as severe and 73.3% of men were unable to ejaculate. Treatment for erectile and ejaculatory dysfunction was offered in only two patients, respectively. Most (71.1%) patients indicated that they wanted to have children in the future, however, no one had been referred for assisted reproductive techniques. DISCUSSION: Men with traumatic SCI have high rates of severe erectile and ejaculatory dysfunctions, but have preserved interests in maintaining fertility. Adherence to guidelines for sexual education for men with traumatic SCI in Jamaica and the Caribbean is needed. PMID- 28584662 TI - A rare case of acute transverse myelitis associated with Staphylococcusaureus bacteremia and osteomyelitis. AB - INTRODUCTION: Direct intramedullary infections are considered very rare. Only few reports of Staphylococcus aureus myelitis have been published. CASE PRESENTATION: Our patient, a 79-year-old male, presented with a 2-day history of high-grade fever and high inflammatory markers and progressively developed tetraplegia during hospitalization. Lumbar puncture revealed cerebrospinal fluid pleocytosis and a spinal cord MRI revealed transverse myelitis at the level of C3-C5 and possible osteomyelitis of C5-T1. Two blood cultures were positive for methicillin sensitive S. aureus. Despite control of the infection, there was no neurologic improvement. DISCUSSION: The morbidity of infectious myelitis can be severe. Considering the rarity of S. aureus myelitis, experience gained from case reports is important. A brief review of the available literature is provided. PMID- 28584663 TI - Clinical pitfall: false-positive aquaporin-4 IgG leading to misdiagnosis of neuromyelitis optica spectrum disorder in patient with spinal arteriovenous fistula. AB - INTRODUCTION: We report the cases of a 68-year-old male with a filum terminale arteriovenous fistula (AVF) who was initially misdiagnosed with neuromyelitis optica spectrum disorder (NMOSD) based on imaging findings and false-positive aquaporin-4 IgG (AQP4-IgG). CASE PRESENTATION: A 68-year-old male presented with slowly progressive weakness and numbness in his bilateral lower extremities. He was initially diagnosed with NMOSD and treated with immunosuppressive therapy based on findings of extensive spinal cord edema on magnetic resonance imaging (MRI) and initial negative spinal angiography as well as positive AQP4-IgG. Despite immunosuppressive treatment, his symptoms progressed slowly. He repeated MRI that showed persistent abnormal signal within the spinal cord. Second spinal angiography revealed filum terminale dural arteriovenous fistula (AVF). Finally, he underwent surgical disconnection of the fistula. Repeated AQP-IgG was reported negative. DISCUSSION: Although NMOSD and spinal AVFs can share imaging findings on spinal cord MRI, typical clinical features of each disorder are distinct. Identification of AQP4-IgG is the hallmark to confirm a clinical diagnosis of NMOSD; however, different assays can vary in sensitivity and specificity. Although it is rare, false positives can occur especially at low titers. A misdiagnosis of NMOSD and delayed diagnosis of spinal AVF had significant clinical implications because the treatment of spinal AVF is surgical disconnection or endovascular embolization, whereas the treatment for NMOSD includes long-term immunosuppressive therapy. Clinicians should be aware of the potential technical issues in detecting AQP4-IgG especially in the context of patients with atypical presentations for NMOSD. PMID- 28584665 TI - Multimodal Imaging in an Unusual Cluster of Multiple Evanescent White Dot Syndrome. AB - OBJECTIVE: To describe an unusual cluster of multiple evanescent white dot syndrome (MEWDS) encountered within a 3-month period. METHODS: This retrospective observation study is comprised of seven patients who presented with MEWDS in a 3 month period in central Israel. Data were collected from patients' medical records on clinical, multimodal imaging, and viral serology findings. RESULTS: Six women and one man of mean age 31.5 +/- 7.2 years. Three reported a precedent viral infection. All had unilateral decreased vision. Funduscopy revealed foveal granularity. MAIN IMAGING FINDINGS: Hyperfluorescent spots on blue autofluorescence (BAF), hypofluorescent spots on indocyanine green angiography, dark lesions on infrared photos, and ellipsoid zone irregularities on spectral domain optical coherence tomography (SD-OCT). Resolution of the spots on BAF correlated with anatomic (SD-OCT) and visual recovery. OCT angiography performed following the convalescence stage demonstrated intact retinal and choroidal flow. Serologic findings were inconclusive. CONCLUSION: We report a unique cluster of MEWDS patients presented in a short period of time. SD-OCT findings of ellipsoid zone disruption in combination with other multimodal imaging modalities are outlined meticulously. Recognizing these imaging features along with high index of clinical suspicion is important for the diagnosis of MEWDS. Serologic testing might be considered in future patients. PMID- 28584664 TI - A Review of Innovations in Rhegmatogenous Retinal Detachment Surgical Techniques. AB - Rhegmatogenous retinal detachment (RRD) requires surgical intervention for its repair. There are variable techniques used for this purpose, and they are all being continuously refined. In this review, we detail the recent innovations in surgical management of RRD and proliferative vitreoretinopathy (PVR). PMID- 28584666 TI - Short- and Long-Term, 11-22 Years, Results after Laparoscopic Nissen Fundoplication in Obese versus Nonobese Patients. AB - BACKGROUND: Some studies suggest that obesity is associated with a poor outcome after Laparoscopic Nissen Fundoplication (LNF), whereas others have not replicated these findings. The effect of body mass index (BMI) on the short- and long-term results of LNF is investigated. METHODS: Inclusion criteria were only patients who undergone a LNF with at least 11-year follow-up data available, patients with preoperative weight and height data available for calculation of BMI (Kg/m2), and patients with a BMI up to a maximum of 34.9. RESULTS: 201 patients met the inclusion criteria: 43 (21.4%) had a normal BMI, 89 (44.2%) were overweight, and 69 (34.4%) were obese. The operation was significantly longer in obese patients; the use of drains and graft was less in the normal BMI group (p < 0.0001). The hospital stay, conversion (6,4%), and intraoperative and early postoperative complications were not influenced by BMI. CONCLUSIONS: BMI does not influence short-term outcomes following LNF, but long-term control of reflux in obese patients is worse than in normal weight subjects. PMID- 28584667 TI - Melatonin Secretion Pattern in Critically Ill Patients: A Pilot Descriptive Study. AB - Critically ill patients have abnormal circadian and sleep homeostasis. This may be associated with higher morbidity and mortality. The aims of this pilot study were (1) to describe melatonin secretion in conscious critically ill mechanically ventilated patients and (2) to describe whether melatonin secretion and sleep patterns differed in these patients with and without remifentanil infusion. Eight patients were included. Blood-melatonin was taken every 4th hour, and polysomnography was carried out continually during a 48-hour period. American Academy of Sleep Medicine criteria were used for sleep scoring if sleep patterns were identified; otherwise, Watson's classification was applied. As remifentanil was periodically administered during the study, its effect on melatonin and sleep was assessed. Melatonin secretion in these patients followed a phase-delayed diurnal curve. We did not observe any effect of remifentanil on melatonin secretion. We found that the risk of atypical sleep compared to normal sleep was significantly lower (p < 0.001) under remifentanil infusion. Rapid Eye Movement (REM) sleep was only observed during the nonsedation period. We found preserved diurnal pattern of melatonin secretion in these patients. Remifentanil did not affect melatonin secretion but was associated with lower risk of atypical sleep pattern. REM sleep was only registered during the period of nonsedation. PMID- 28584668 TI - Do Successive Preterm Births Increase the Risk of Postpartum Depressive Symptoms? AB - BACKGROUND: Postpartum depression and preterm birth (PTB) are major problems affecting women's health. PTB has been associated with increased risk of postpartum depressive symptoms (PDS). However, it is unclear if PTB in women with a prior history of PTB is associated with an incremental risk of PDS. This study aims to determine if PTB in women with a prior history of PTB is associated with an incremental risk of PDS. METHODS: Data come from the 2009-2011 national Pregnancy Risk Assessment Monitoring System. Study sample included 55,681 multiparous women with singleton live births in the index delivery. Multiple logistic regression was used to examine the association between PTB and PDS. RESULTS: The risk of PDS was 55% higher in women with PTB in both deliveries (aRR = 1.55; 95% CI = 1.28-1.88) and 74% higher in women with PTB in the index delivery only (aRR = 1.74; 95% CI = 1.49-2.05), compared to women with term deliveries. CONCLUSIONS: Preterm birth is a risk factor for PDS. PTB in women with a prior history of PTB is not associated with an incremental risk of PDS. Routine screening for PDS should be conducted for all women and closer monitoring should be done for high risk women with PTB. PMID- 28584669 TI - Freeman-Sheldon Syndrome: First Molecularly Confirmed Case from Sub-Saharan Africa. AB - We report a case of a male baby who has characteristic signs of Freeman-Sheldon syndrome, a rare but recognizable, severe autosomal dominant form of distal arthrogryposis. Diagnosis was based on the distinctive clinical characteristics of the syndrome and confirmed by genetic analysis that showed a de novo missense mutation c.2015G>A (p.Arg672His) of the MYH3 gene. We highlight the different features present in our patient and describe the etiology of the Freeman-Sheldon phenotype and how its clinical complications can be dealt with. To the best of our knowledge, this is the first molecularly confirmed case of Freeman-Sheldon syndrome in sub-Saharan Africa. PMID- 28584670 TI - Solitary Plasmacytoma of the Mesentery: A Systematic Clinician's Diagnosis. AB - INTRODUCTION: Plasmacytoma is an uncommon plasma cell neoplasm and its localized form is solitary plasmacytoma of the bone and solitary extramedullary plasmacytoma. Solitary plasmacytoma of the mesentery is extremely rare, reported only in a handful of cases. CASE PRESENTATION: A 47-year-old man with nonspecific abdominal complains was found to have an ill-defined mass on his mesenteric root. Laparoscopic biopsy and stepwise histopathological examination revealed a mesenteric plasmacytoma, and extensive imaging and laboratory investigations led to the diagnosis of the solitary mesenteric plasmacytoma. The patient underwent definitive radiotherapy and remains under remission one year later. DISCUSSION: Plasma cell dyscrasias include a variant of proliferative disease, characterized by clonal expansion of bone marrow plasma cells, producing a massive quantity of monoclonal immunoglobulin called paraprotein or M-protein. Solitary extramedullary plasmacytoma accounts for only 3-5% of all plasma cell neoplasms. Meticulous adherence to the established diagnostic criteria helps the clinician to set the correct, yet very unusual and unexpected diagnosis. PMID- 28584671 TI - Hybrid Desmoplastic/Follicular Ameloblastoma of the Mandible: A Case Report and Review of the Literature. AB - Desmoplastic ameloblastoma (DA) is one of the 6 histopathological subtypes of ameloblastoma. Hybrid lesions in which histopathologically conventional ameloblastoma coexists with areas of DA are rare. A 40-year-old male was referred to our hospital complaining of a swelling in the right premolar region of the mandible. A panoramic radiograph showed an area of radiolucency with a well defined corticated border, whereas computed tomography revealed a unilocular radiolucent lesion and buccal expansion together with cortical perforation. The lesion was treated via enucleation and curettage of the marginal bone and fenestration. A histopathological examination showed a hybrid ameloblastoma with a pronounced desmoplastic pattern and follicular changes. The patient's postoperative course has been favorable up to now, and no marked changes have been observed. We presented a case of hybrid ameloblastoma and reviewed the 36 reported cases of hybrid ameloblastoma that have been reported in the English literature. PMID- 28584672 TI - Keratoacanthoma of the Nasal Septum Secondary to Ranibizumab Use. AB - Keratoacanthoma (KA) is a benign epithelial tumor that typically presents as a firm, cone-shaped, flesh-colored nodule with a central horn-filled crater. KA is considered to be a low-grade variant of squamous cell carcinoma (SCC). We report a rare case of a 72-year-old male who presented with a KA involving the nasal septum, possibly related to ranibizumab use. A flesh-colored lesion on the right anterior nasal septum lesion was visualized on examination. Histologic examination revealed a well-circumscribed, dome-shaped central crater filled with keratin, well-differentiated squamous epithelium with ground-glass cytoplasm with pushing margins, and intraepithelial microabscesses establishing the diagnosis of KA. KA of the nasal septum has only been reported once in the literature. This case is unusual because it normally presents on sun-exposed areas. Additionally, this patient was taking ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor for macular degeneration. Despite ranibizumab not being directly linked to precancerous and cancerous skin lesions, agents in this medication class have been. Although it is difficult to prove associations in this isolated case, the role of ranibizumab causing cutaneous lesions should be further investigated. PMID- 28584673 TI - Sclerema Neonatorum Treated Successfully with Parenteral Steroids: An Experience from a Resource Poor Country. AB - Sclerema neonatorum is a form of panniculitides characterized by diffuse hardening of subcutaneous tissue with minimal inflammation. It usually affects ill and preterm neonates. Prognosis is usually poor in many cases despite aggressive management. Various treatment modalities (antibiotics, intravenous immunoglobulin, steroids, and exchange transfusion) have been explained in literature. Steroids due to its easy availability and low cost can prove to be lifesaving in such cases, especially in resource poor countries. Here, we report a case of sclerema neonatorum in a one-week preterm baby treated successfully with parenteral steroids and antibiotics. PMID- 28584675 TI - Musculoskeletal neck pain in children and adolescents: Risk factors and complications. AB - BACKGROUND: Neck pain is a major public health concern that has been extensively studied in adults but not in children and adolescents. Therefore, the purpose of this article is to explore musculoskeletal neck pain in children and adolescents, as well as to discuss its possible risk factors and complications. METHODS: Participants were patients under 18 years of age, who had presented to the clinic (Beirut, Lebanon) in 2015, with nonspecific neck pain. They were examined and asked to evaluate and localize the pain. Neck positioning during various activities along with other complications were explored. Patients reporting pain associated with congenital or systemic diseases and fractures were excluded. RESULTS: Two-hundred-and-seven children and adolescents presented with nonspecific neck pain. Musculoskeletal neck pain with spasm was diagnosed in 180 patients (N = 180). Participants did not show any findings on physical examination and radiological studies, and had no comorbidities. More females (57%) than males (43%) and more adolescents (60%) than children (40%) were affected. All the 180 participants (100%) reported flawed flexion of their back and neck while studying and/or using smartphones and tablets. Eye symptoms were reported in 21% of the cases, and parents of most participants (82%) reported a change in the psychological and social behavior of their children. CONCLUSIONS: Musculoskeletal neck pain is an important disease in children and adolescents with numerous risk factors contributing to its development. Increased stresses regarding the cervical spine may lead to cervical degeneration along with other developmental, medical, psychological, and social complications. PMID- 28584676 TI - Transradial approach to treating endovascular cerebral aneurysms: Case series and technical note. AB - BACKGROUND: Several benefits have been described over the years of the transradial versus femoral endovascular approach to cardiac interventions. Consequently, its use has become habitual at most centers that perform cardiac catheterizations. This paper details a right transradial approach, incorporating a variety of coils or flow diverters, which can be utilized for the endovascular treatment of different cerebral aneurysms. METHODS: From 2014 to 2016, we performed 40 endovascular procedures to treat cerebral aneurysms adopting the same right transradial approach. Five aneurysms were treated with flow diverters and 35 were treated with coils. Seven of these aneurisms were asymptomatic, whereas 33 had already ruptured. RESULTS: Satisfactory treatment was achieved in all cases through the same approach in the absence of any complications. CONCLUSIONS: A right transradial approach may be satisfactory for the endovascular treatment of different cerebral aneurysms, including aneurysms in either hemisphere. This is the largest series of cerebral aneurysms treated through a transradial approach. PMID- 28584677 TI - Microvascular decompression for hypoglossal nerve palsy secondary to vertebral artery compression: A case report and review of the literature. AB - BACKGROUND: Neurovascular-compression syndrome (NCS) is described as a prominent pathological contact between cranial nerves and vessels. Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neuralgia are typical clinical entities associated with NCS. On the other hand, the hyoglossal nerve is rarely affected by NCS. CASE DESCRIPTION: We present a case of hypoglossal nerve palsy (HNP) secondary to vertebral artery (VA) compression. A 47-year-old man presented to our hospital with a 1-month history of dysarthria and dysphagia. Neurological examination revealed left HNP, with an intact swallowing reflex and no oropharyngeal or palatal weakness. Magnetic resonance imaging (constructive interference in steady state) revealed left hypoglossal nerve compression by the V4 segment of the left atherosclerotic VA. He underwent microvascular decompression (MVD) surgery. Intraoperatively, the VA was compressing the hypoglossal nerve. The left VA was moved and attached to the dura matter using a polytetrafluoroethylene (Teflon(r)) sheet and fibrin glue. Postoperatively, the patient exhibited gradual recovery of HNP in 3 months without dysfunction of lower cranial nerves. CONCLUSION: In patients with isolated HNP, vascular compression should be considered as a cause of these symptoms, and subsequent MVD can lead to resolution. PMID- 28584678 TI - Preventive effect of tamsulosin on postoperative urinary retention in neurosurgical patients. AB - BACKGROUND: Postoperative urinary retention (POUR) is common in neurosurgical patients. The use of alpha-blockade therapy, such as tamsulosin, has benefited many patients with a history of obstructive uropathy by decreasing lower urinary tract symptoms such as distension, infections, and stricture formation, as well as the incidence of POUR. For this study, we targeted patients who had undergone spinal surgery to examine the prophylactic effects of tamsulosin. Increased understanding of this therapy will assist in minimizing the morbidity of spinal surgery. METHODS: We enrolled 95 male patients undergoing spine surgery in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to receive either preoperative tamsulosin (N = 49) or a placebo (N = 46) and then followed-up prospectively for the development of POUR after removal of an indwelling urinary catheter (IUC). They were also followed-up for the incidence of IUC reinsertions. RESULTS: The rate of developing POUR was similar in both the groups. Of the 49 patients given tamsulosin, 16 (36%) developed POUR compared to 13 (28%) from the control group (P = 0.455). In the control group, 5 (11%) patients had IUC re-inserted postoperatively, whereas 7 (14%) patients in the tamsulosin group had IUC re-inserted postoperatively (P = 0.616). In patients suffering from axial-type symptoms (i.e., mechanical back pain), 63% who received tamsulosin and 18% from the control group (P = 0.048) developed POUR. CONCLUSION: Overall, there was no statistically significant difference in the rates of developing POUR among patients in either group. POUR is caused by a variety of factors, and further studies are needed to shed light on its etiology. PMID- 28584679 TI - Pseudotumoral neuroparacoccidioidomycosis of the posterior fossa: A case report and review of the literature. AB - BACKGROUND: Paracoccidioidomycosis is a systemic mycosis of significant importance in some Latin American countries. The widespread use of neuroimaging methods has shown that involvement of the central nervous system was more frequent than previously reported. The most common form of occurrence of neuroparacoccidioidomycosis is the pseudotumoral one. The authors report a case of pseudotumoral neuroparacoccidioidomycosis localized in the posterior fossa. CASE DESCRIPTION: A 49-year-old single man, rural worker, born and raised in Laranjal Paulista-SP, was admitted to the hospital with 3 months history of bilateral occipital headache every day. Along with a history of active smoking and previous use of alcohol, the patient reported personal history of mild occipitotemporal injury 3 months ago. The patient was submitted to computed tomography in a 16-row multidetector scanner, which revealed a nodular hypodense lesion with a ring-enhancement and associated perilesional edema in the left cerebellar hemisphere. Radiological workup was initiated to investigate the eventual primary neoplastic site. CONCLUSION: The analysis of the lipid peak by spectroscopy of proton magnetic resonance may indicate the neurological involvement by paracoccidioidomycosis, notably in patients with concomitant risk and pulmonary involvement signals. PMID- 28584674 TI - Injectable hydrogels for cartilage and bone tissue engineering. AB - Tissue engineering has become a promising strategy for repairing damaged cartilage and bone tissue. Among the scaffolds for tissue-engineering applications, injectable hydrogels have demonstrated great potential for use as three-dimensional cell culture scaffolds in cartilage and bone tissue engineering, owing to their high water content, similarity to the natural extracellular matrix (ECM), porous framework for cell transplantation and proliferation, minimal invasive properties, and ability to match irregular defects. In this review, we describe the selection of appropriate biomaterials and fabrication methods to prepare novel injectable hydrogels for cartilage and bone tissue engineering. In addition, the biology of cartilage and the bony ECM is also summarized. Finally, future perspectives for injectable hydrogels in cartilage and bone tissue engineering are discussed. PMID- 28584680 TI - Multidisciplinary surgical treatment of presacral meningocele and teratoma in an adult with Currarino triad. AB - BACKGROUND: Currarino syndrome (CS) is a rare genetic condition that presents with the defining triad of anorectal malformations, sacral bone deformations, and presacral masses, which may include teratoma. Neurosurgeons are involved in the surgical treatment of anterior meningoceles, which are often associated with this condition. The accepted surgical treatment is a staged anterior-posterior resection of the presacral mass and obliteration of the anterior meningocele. CASE DESCRIPTION: This case involved a 36-year-old female who presented with late onset of symptoms attributed to CS (e.g., presacral mass, anterior sacral meningocele, and sacral agenesis). She successfully underwent multidisciplinary single-stage approach for treatment of the anterior sacral meningocele and resection of the presacral mass. This required obliteration of the meningocele and closure of the dural defect. One year later, her meningocele had fully resolved. CONCLUSION: While late presentations with CS are rare, early detection and multidisciplinary treatment including single-state anterior may be successful for managing these patients. PMID- 28584681 TI - Abdominal pseudocyst as a complication of ventriculoperitoneal shunt placement: Review of the literature and a proposed algorithm for treatment using 4 illustrative cases. AB - BACKGROUND: Ventriculoperitoneal (VP) shunt placement is one of the most commonly performed procedures in neurosurgery. One rare complication is the formation of an abdominal pseudocyst, which can cause shunt malfunction. CASE DESCRIPTIONS: We present four unique cases of abdominal pseudocyst formation. Our first patient initially presented with a right upper quadrant pseudocyst. Shunt was externalized and the distal end was revised with placement of catheter on the opposite side. He developed another pseudocyst within 5 months of shunt revision and developed another shunt failure. Our second patient had a history of shunt revisions and a known pseudocyst, presented with small bowel obstruction, and underwent laparotomy for the lysis of adhesions with improvement in his symptoms. After multiple readmissions for the same problem, it was thought that the pseudocyst was causing gastric outlet obstruction and his VP shunt was converted into a ventriculopleural shunt followed by percutaneous drainage of his pseudocyst. Our third patient developed hydrocephalus secondary to cryptococcal meningitis. He developed abdominal pain secondary to an abdominal pseudocyst, which was drained percutaneously with relief of symptoms. The fourth patient had a history of multiple shunt revisions and a previous percutaneous pseudocyst drainage that recurred with cellulitis and abscess secondary to hardware infection. CONCLUSION: Abdominal pseudocysts are a rare but important complication of VP shunt placement. Treatment depends on etiology, patient presentation, and clinical manifestations. Techniques for revision include distal repositioning of peritoneal catheter, revision of catheter into pleural space or right atrium, or removal of the shunt completely. PMID- 28584682 TI - Safe time duration for temporary middle cerebral artery occlusion in aneurysm surgery based on motor-evoked potential monitoring. AB - BACKGROUND: Temporary vessel occlusion of the parent artery is an essential technique for aneurysm surgery. Our aim was to clarify the safe time for temporary occlusion for aneurysm surgery, that is the "safe time duration" (STD), in which brain tissue exposed to ischemia will almost never fall into even the ischemic penumbra during temporary occlusion of the middle cerebral artery (MCA), and even transient postoperative motor impairment will be rare using intraoperative motor-evoked potentials (MEP). METHODS: Twenty-four patients underwent MCA aneurysm clipping surgery with MEP monitoring for 13 ruptured aneurysms and 11 unruptured aneurysms. The duration of vessel occlusion in patients without MEP changes was measured as the STD. Average STD was calculated as 95% confidence interval for the population mean using sample data from patients with MEP changes and patients without changes. RESULTS: All 24 patients received proximal flow control only. Five patients (20.8%) developed significant intraoperative MEP changes. Time to MEP change (i.e., STD) in these patients was 4.6 +/- 2.1 min. In patients without MEP changes, STD was 2.7 +/- 1.4 min. Average STD was thus 3.1 +/- 0.7 min. CONCLUSIONS: The 95% lower confidence limit for average STD was 2.4 min when applying temporary occlusion on the proximal side of the MCA. This STD resembled that previously reported for temporary proximal occlusion of the internal carotid artery. PMID- 28584683 TI - Training Nuclei Detection Algorithms with Simple Annotations. AB - BACKGROUND: Generating good training datasets is essential for machine learning based nuclei detection methods. However, creating exhaustive nuclei contour annotations, to derive optimal training data from, is often infeasible. METHODS: We compared different approaches for training nuclei detection methods solely based on nucleus center markers. Such markers contain less accurate information, especially with regard to nuclear boundaries, but can be produced much easier and in greater quantities. The approaches use different automated sample extraction methods to derive image positions and class labels from nucleus center markers. In addition, the approaches use different automated sample selection methods to improve the detection quality of the classification algorithm and reduce the run time of the training process. We evaluated the approaches based on a previously published generic nuclei detection algorithm and a set of Ki-67-stained breast cancer images. RESULTS: A Voronoi tessellation-based sample extraction method produced the best performing training sets. However, subsampling of the extracted training samples was crucial. Even simple class balancing improved the detection quality considerably. The incorporation of active learning led to a further increase in detection quality. CONCLUSIONS: With appropriate sample extraction and selection methods, nuclei detection algorithms trained on the basis of simple center marker annotations can produce comparable quality to algorithms trained on conventionally created training sets. PMID- 28584684 TI - Current State of the Regulatory Trajectory for Whole Slide Imaging Devices in the USA. AB - The regulatory field for digital pathology (DP) has advanced significantly. A major milestone was accomplished when the FDA allowed the first vendor to market their device for primary diagnostic use in the USA and published in the classification order that this device, and substantially equivalent devices of this generic type, should be classified into class II instead of class III as previously proposed. The Digital Pathology Association (DPA) regulatory task force had a major role in the accomplishment of getting the application request for Whole Slide Imaging (WSI) Systems recommended for a de novo. This article reviews the past and emerging regulatory environment of WSI for clinical use in the USA. A WSI system with integrated subsystems is defined in the context of medical device regulations. The FDA technical performance assessment guideline is also discussed as well as parameters involved in analytical testing and clinical studies to demonstrate that WSI devices are safe and effective for clinical use. PMID- 28584685 TI - Renal Epithelioid Angiomyolipoma Associated with Pulmonary Lymphangioleiomyomatosis: Imaging Findings. AB - Renal angiomyolipomas (AMLs) and pulmonary lymphangioleiomyomatosis (LAM) are the most common tumors of the perivascular epithelioid cell (PEComa) family. Both may be associated with tuberous sclerosis (TS) complex. Epithelioid AML (EAML) is a rare variety of AMLs, with a potential aggressive behavior. There are few reports in the English literature addressing on the imaging findings of renal EAMLs, which are considered nonspecific. We present the sonographic, computed tomographic, and magnetic resonance imaging findings of a renal EAML in a pregnant woman with concomitant pulmonary lesions indicative of LAM, without stigmata of TS. We conclude the importance of considering EAML as a possible diagnosis in the presence of a large renal mass with high cellular content and small amounts of fat in the coexistence of pulmonary LAM. PMID- 28584686 TI - Extra-pituitary Cerebral Anomalies in Pediatric Patients of Ectopic Neurohypophysis: An Uncommon Association. AB - CONTEXT: Ectopic neurohypophysis (EN) refers to an interrupted, nonvisualized, and thinned out pituitary stalk with ectopic location of the posterior pituitary gland. Concurrent extra-pituitary cerebral and extra-cranial anomalies have been rarely reported in patients of EN. AIM: The aim of this study was to evaluate the magnetic resonance imaging (MRI) findings of extra-pituitary cerebral anomalies in pediatric patients of EN. SETTINGS AND DESIGN: A hospital-based cross sectional study was conducted in a tertiary care center. SUBJECTS AND METHODS: The study group comprised eight pediatric patients of EN associated with extra pituitary cerebral or vascular anomalies. Clinical and biochemical assessment was done in all patients. RESULTS: Out of the total eight patients with EN, MRI showed interrupted pituitary stalk in five patients (62.5%) and nonvisible pituitary stalk in three patients (37.5%). Ectopic posterior pituitary bright spot was demonstrated in median eminence in six patients (75%), faintly visualized in one patient (12.5%) and nonvisualized in another one patient. Statistical significant association was noted between pituitary gland height and patient's body height with the pituitary gland volume (P < 0.001). Varied extra pituitary cerebral anomalies encountered in our patients ranged from isolated anomalies such as optic nerve hypoplasia in three patients (37.5%), corpus callosum dysplasia in four patients (50%), agyria-pachygyria complex in two patients (25%), and intracranial vascular anomalies in two patients to syndromic association of tuberous sclerosis in one patient. CONCLUSION: Identifying and reporting of associated extra-pituitary cerebral anomalies in patients with EN are crucial in assessing the overall neurological outcome of such patients. PMID- 28584687 TI - Fluorine-18-fluorodihydroxyphenylalanine Positron-emission Tomography Scans of Neuroendocrine Tumors (Carcinoids and Pheochromocytomas). AB - OBJECTIVES: Conventional methods of imaging neuroendocrine tumors with computed tomography, magnetic resonance imaging, indium-111-octreotide, or radiolabeled metaiodobenzilguanidine scintigraphy have limitations. This pilot study tried to improve the localization of these tumors with fluorine-18 fluorodihydroxyphenylalanine (F-DOPA) positron-emission tomography (PET) scanning. MATERIALS AND METHODS: We studied 22 patients, the majority of whom were referred with clinical diagnosis or suspicion of carcinoid (n = 11), neuroendocrine tumors (n = 7) or pheochromocytoma/paraganglioma (PGL) (n = 4). The comparison was made with the prior conventional imaging. RESULTS: The F-DOPA findings were compared with the results of subsequent surgery (2), endoscopy (1), or a long-term follow-up (mean duration, 49 months) for 17 patients. Two patients were lost to follow-up. Foci of F-DOPA deposition were detected in eight patients (final diagnosis of carcinoid in six, of neuroendocrine tumors in one, and of PGL in another). Comparison with the final diagnoses revealed concordance in 16 of the 22 patients. F-DOPA results appeared superior to those obtained with conventional imaging. Despite the small number and diagnostic heterogeneity, in a substantial fraction of patients F-DOPA PET added information relevant to clinical management. CONCLUSION: F-DOPA scanning added prognostic value, particularly when multiple abnormal foci versus a negative examination were considered. PMID- 28584688 TI - Antenatal Umbilical Coiling Index and Newborn Outcomes: Cohort Study. AB - OBJECTIVES: We aimed to test the predictive value of antenatal umbilical coiling index (aUCI) among a prospectively recruited cohort of antenatal women. METHODS: Women with singleton pregnancies were recruited at their second-trimester scan. Images of the umbilical cord were used to calculate the aUCI. Pregnancy and birth outcomes were recorded and statistical associations between aUCI and small for gestational age (SGA) using international standard birth weight centiles and preterm birth were investigated (n = 430). RESULTS: aUCI results were consistent with the literature and showed good reproducibility between observers. Abnormal aUCI was not associated with SGA, but there was a statistical association with preterm birth (odds ratio 3.3 (95% confidence interval 1.4-7.7, P = 0.003). The sensitivity, specificity, and positive and negative predictive values for preterm birth were 47.6%, 76.9%, 9.6%, and 96.6%, respectively. CONCLUSIONS: The coiling index is unlikely to be useful in clinical practice as a screening tool for preterm birth owing to limited predictive value. We exclude a statistically or clinically significant association between abnormal coiling and SGA. PMID- 28584689 TI - An Integrated Interactive-Spaced Education Radiology Curriculum for Preclinical Students. AB - INTRODUCTION: The objective of this study is to determine whether a radiology module, together with online spaced education, helps students of an integrated problem-based learning (PBL) curriculum increase their radiology knowledge and long-term retention. MATERIALS AND METHODS: Second-year students at the American University of Antigua College of Medicine participated in small groups of ten students each into two 2 h of radiology laboratories. The study comprised two cohorts: winter and fall 2013 students (control group) and 2014 students (experimental group). Both groups used face-to-face PBL. The students of the experimental group received additional online-spaced education. The skills were assessed for both groups before the beginning of laboratories and 4 weeks and 7 months after laboratories. RESULTS: There was no significant difference on pretest between the control and experimental groups. On completion of the radiology laboratories, comparison of test results before and after training showed net improvement for both groups. The corresponding difference for the experimental group was higher compared to the one for the control group (7.83 vs. 6.21, P < 0.001). The difference between the scores on delayed test and pretest showed that the students of both groups demonstrated average knowledge improvement even though their level of performance was slightly below the posttest. The corresponding difference for the experimental group did not differ much from the posttest (P > 0.05), and no significant difference of scores was observed 7 months later for either group. Further, a higher percentage of the students in the experimental group strongly agreed that their learning objectives were met (92% vs. 71%, P > 0.001), and this trend persisted throughout the study. CONCLUSION: Online spaced education combined to a face-to-face PBL enhances not only the student's knowledge of basic radiology along with his/her self assessment skills but also the long-term retention of radiology material and satisfaction with the integrated interactive system-based module. Future research is needed to see if medical students in need of additional education support may benefit from spaced education in the field of remediation. PMID- 28584691 TI - Modafinil Augmentation Therapy in Patient with Traumatic Brain Injury. PMID- 28584690 TI - Unusual Patterns of Thoracic Metastasis of Urinary Bladder Carcinoma. AB - Urinary bladder carcinoma (UBC) is the ninth most common malignancy and the second most common urological malignancy after prostate cancer in men. Thoracic metastases occur in more than half of those with muscle-invasive disease, and these generally assume the form of multiple solid parenchymal lesions characteristic of hematogenous seeding of the lung. Unusual patterns of thoracic spread of UBC have also been described albeit sporadically in the form of case reports and series. The aim of our case series is to provide illustrations of several atypical patterns of thoracic involvement by UBC such as isolated mediastinal lymphadenopathy, cavitary lung metastases, malignant pleural effusion, endobronchial disease, and pulmonary tumor embolism. This review is meant to highlight the intersection of the fields of urological oncology and thoracic radiology in the care of patients with UBC. PMID- 28584692 TI - Human Embryonic Stem Cells in the Treatment of Autism: A Case Series. AB - Background: Autism spectrum disorder is a neurodevelopmental disorder accompanied by weak immune system and neuroinflammation. Multiple factors contribute to etiology of autism spectrum disorder including genetic disorders, environmental substances/toxins, imbalanced immune system, encephalitis, and viral infections. Autism spectrum disorder is an incurable disease; however, it can be managed by educational and medical interventions. Human embryonic stem cell therapy has been shown to improve blood perfusion in the brain; thus, this therapy may be effective in improving motor skills, social skills, and cognition in patients with autism spectrum disorder. Method: Three pediatric patients with autism spectrum disorder were administered human embryonic stem cell therapy. Their treatment plan comprised 3 to 4 therapy sessions (T1, T2, T3, T4) that were 4 to 6 weeks in length, with 4- to 8-month gap phases separating each therapy session. Results: The patients showed improvements in eye coordination, writing, balancing, cognition, and speech and showed reduced hypersensitivity to noises and smells. Conclusion: The use of human embryonic stem cell therapy may be a safe and effective treatment for patients with autism spectrum disorder. Studies with larger sample sizes are needed to support the use of human embryonic stem cell therapy in this patient population. PMID- 28584693 TI - Interactive Voice Response and Text-based Self-report Versions of the Electronic Columbia-Suicide Severity Rating Scale Are Equivalent. AB - Objectives: Our study objective was to compare the equivalence of a new version of the electronic Columbia-Suicide Severity Rating Scale that was administered on a tablet device with the existing interactive voice response version in order to support the prospective monitoring of suicidal ideation and behavior in clinical trials and clinical practice. Design: This was a randomized, crossover equivalence study with no treatment intervention. Setting: The study setting was a psychiatric hospital. Participants: Fifty-eight recently admitted psychiatric inpatients and 28 employees of the hospital site were included in the study. Mean age was 41.0 years (standard deviation=12.5), and 59 percent were female. Measurements: Participants completed both tablet and interactive voice response versions in randomized order, with a 25-minute break between administrations. Finally, participants completed a second administration of the first administered version. Intraclass correlation coefficients (ICCs) and Kappa coefficients were used to evaluate agreement across modalities. Results: High levels of agreement were observed for most severe lifetime (ICC=0.88) and recent (ICC=0.79) ideation, occurrence of actual lifetime (Kappa=0.81) and recent (Kappa=0.73) suicide attempts, and occurrence of lifetime interrupted attempts (Kappa=0.78), aborted attempts (Kappa=0.54), and preparatory behaviors (Kappa=0.77), as well as non suicidal self-injurious behavior (Kappa=0.73). Scores from both modes significantly differentiated psychiatric patients and hospital employee controls, and the test-retest reliability of both modes was excellent. Conclusions: These results support the validity and reliability of the new tablet-based electronic Columbia-Suicide Severity Rating Scale. This will allow the inclusion of the electronic Columbia-Suicide Severity Rating Scale in a wider range of clinical studies, particularly where a tablet is also being used to collect other study data. PMID- 28584694 TI - Liothyronine for Depression: A Review and Guidance for Safety Monitoring. AB - Objective: The objective of this review is to discuss triiodothyronine's (T3, liothyronine) mechanism of action, efficacy in enhancement and augmentation trials, and dosing and safety considerations for the treatment of depression. Method: A literature search of PubMed was performed using search terms depression, augmentation, antidepressant, and liothyronine. Only English-language studies of subjects with unipolar depression were included from the past 50 years. Results: Most studies have shown that liothyronine is an efficacious enhancement and augmentation strategy for depression in combination with antidepressants, primarily tricyclic antidepressants and selective serotonin reuptake inhibitors. Conclusion: With appropriate baseline and follow-up safety monitoring, liothyronine augmentation can be a safe and effective treatment for unipolar depression. Larger studies of longer duration assessing liothyronine efficacy with serotonin norepinephrine reuptake inhibitors and multimodal antidepressants are needed. PMID- 28584695 TI - Neuroendocrine, Autonomic, and Metabolic Responses to an Orexin Antagonist, Suvorexant, in Psychiatric Patients with Insomnia. AB - Aim: The aim of this study was to investigate the neuroendocrine, autonomic, and metabolic system responses to suvorexant in psychiatric subjects with insomnia. Design: This prospective study was conducted in Kusatsu Hospital in Hiroshima, Japan and included 40 psychiatric inpatients treated with suvorexant from December 2014 to April 2016. Methods: Questionnaire of Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder-7 (GAD-7), and Patient Health Questionnaire-9 (PHQ-9) scores were checked at baseline, Week 2, and Week 4, and fasting serum levels of prolactin, insulin, cortisol, noradrenaline, white blood cell count, and average pulse rate were measured at baseline and Week 4 and Week 8 after suvorexant initiation. Sequential change of the values were compared against baseline respectively. Results: Subjective sleep quality scores were significantly decreased at Weeks 2 and 4, and sleep duration, habitual sleep efficacy, and global scores were significantly decreased at Week 4 from baseline. Total scores on the Generalized Anxiety Disorder-7 and the Patient Health Questionnaire-9 significantly decreased at Week 4 from baseline. The levels of cortisol and white blood cell count were decreased, significantly at Week 8, and the levels of pulse rate were significantly decreased at Week 4 from baseline. The levels of noradrenaline decreased, although not significantly. The prolactin levels remained unchanged, and no trend was found in the insulin levels. Conclusion: Suvorexant treatment resulted in overall improvement in the quality of sleep and the severity of anxiety and depression. This dual orexin antagonist may be related to autonomic functions and neuroendocrine systems, especially in the hypothalamus-pituitary-adrenal axis in psychiatric subjects. PMID- 28584696 TI - Redefining Acute Relapses in Multiple Sclerosis: Implications for Phase 3 Clinical Trials and Treatment Algorithms. AB - Relapses in multiple sclerosis are defined as periods of clinical worsening and radiological progression. Magnetic resonance imaging data, however, are not always supportive of "clinical worsening," and clinical symptoms of worsening may not always be present in cases of acute relapse. In the pharmaceutical domain, this discordance between "clinical worsening" and "radiological progression" has never been fully elucidated, and no Phase 3 clinical study has addressed this conundrum. Thus, the true number of acute relapse cases enrolled in Phase 3 clinical studies remains unclear. Breach of the blood-brain barrier solely, as determined by magnetic resonance imaging, may be more a more accurate definition of an acute relapse in multiple sclerosis. Increasingly, magnetic resonance imaging data push the boundaries of science and carry significant advantages in sensitivity, data storage, retrieval, and unbiased analyses, if warranted retrospectively. Magnetic resonance imaging data can also be standardized, shared, and exploited by pharmaceutical companies to develop more effective drugs and therapeutic endpoints. Neurology is awakening to big data concepts and how such concepts are evolving the field. Magnetic resonance imaging data is one of the pillars of this evolution. In this commentary, the author reviews the current standard of determining acute relapse in both clinical practice and clinical research, and discusses its limitations. The author then proposes a more modern definition of acute relapse in multiple sclerosis and includes a supportive discussion on the current and emerging roles magnetic resonance imaging and "big data" are playing in the prevention, diagnosis, and treatment of multiple sclerosis. PMID- 28584697 TI - Managing Your Aging Patient Population. AB - This ongoing column is dedicated to providing information to our readers on managing legal risks associated with medical practice. We invite questions from our readers. The answers are provided by PRMS, Inc. (www.prms.com), a manager of medical professional liability insurance programs with services that include risk management consultation, education and onsite risk management audits, and other resources to healthcare providers to help improve patient outcomes and reduce professional liability risk. The answers published in this column represent those of only one risk management consulting company. Other risk management consulting companies or insurance carriers may provide different advice, and readers should take this into consideration. The information in this column does not constitute legal advice. For legal advice, contact your personal attorney. Note: The information and recommendations in this article are applicable to physicians and other healthcare professionals so "clinician" is used to indicate all treatment team members. PMID- 28584698 TI - High or low? Comparing high and low-variability phonetic training in adult and child second language learners. AB - BACKGROUND: High talker variability (i.e., multiple voices in the input) has been found effective in training nonnative phonetic contrasts in adults. A small number of studies suggest that children also benefit from high-variability phonetic training with some evidence that they show greater learning (more plasticity) than adults given matched input, although results are mixed. However, no study has directly compared the effectiveness of high versus low talker variability in children. METHODS: Native Greek-speaking eight-year-olds (N = 52), and adults (N = 41) were exposed to the English /i/-/i/ contrast in 10 training sessions through a computerized word-learning game. Pre- and post-training tests examined discrimination of the contrast as well as lexical learning. Participants were randomly assigned to high (four talkers) or low (one talker) variability training conditions. RESULTS: Both age groups improved during training, and both improved more while trained with a single talker. Results of a three-interval oddity discrimination test did not show the predicted benefit of high-variability training in either age group. Instead, children showed an effect in the reverse direction-i.e., reliably greater improvements in discrimination following single talker training, even for untrained generalization items, although the result is qualified by (accidental) differences between participant groups at pre-test. Adults showed a numeric advantage for high-variability but were inconsistent with respect to voice and word novelty. In addition, no effect of variability was found for lexical learning. There was no evidence of greater plasticity for phonetic learning in child learners. DISCUSSION: This paper adds to the handful of studies demonstrating that, like adults, child learners can improve their discrimination of a phonetic contrast via computerized training. There was no evidence of a benefit of training with multiple talkers, either for discrimination or word learning. The results also do not support the findings of greater plasticity in child learners found in a previous paper (Giannakopoulou, Uther & Ylinen, 2013a). We discuss these results in terms of various differences between training and test tasks used in the current work compared with previous literature. PMID- 28584699 TI - Difference on cone size preferences between two coniferous species by Great Spotted Woodpecker (Dendrocopos major). AB - The number of species that specialize in pre-dispersal seed predation is relatively small. Examples of specialized pre-dispersal seed predators adapted to feeding on closed cones include vertebrate species like Crossbills, Squirrels, Nutcrackers and Woodpeckers. Seed predation selects against certain phenotypic features of cones and favors another phenotypic features. In this study, we document preferences of the Great Spotted Woodpecker (Dendrocopos major) for specific traits in the cones of Norway spruce (Picea abies) and Scots pine (Pinus sylvestris). We found that the Great Spotted Woodpecker prefers to feed on medium sized Norway spruce cones. The results suggest a disruptive selection that favors the extreme cone lengths in Norway spruce. In Scots pine, the woodpeckers avoided cones with large apophyses. Further, the selectivity for the specific characteristics of the cones is probably related to the configuration of the anvil, a place at which woodpeckers extract seeds from the cones. We think that the Great Spotted Woodpecker preferences in relation to the morphological characteristics of cones are a key to the design of the anvil in order to maximize the use of it as a tool for processing cones of both the Norway spruce and the Scots pine. PMID- 28584700 TI - Assessing the utility of an institutional publications officer: a pilot assessment. AB - BACKGROUND: The scholarly publication landscape is changing rapidly. We investigated whether the introduction of an institutional publications officer might help facilitate better knowledge of publication topics and related resources, and effectively support researchers to publish. METHODS: In September 2015, a purpose-built survey about researchers' knowledge and perceptions of publication practices was administered at five Ottawa area research institutions. Subsequently, we publicly announced a newly hired publications officer (KDC) who then began conducting outreach at two of the institutions. Specifically, the publications officer gave presentations, held one-to-one consultations, developed electronic newsletter content, and generated and maintained a webpage of resources. In March 2016, we re-surveyed our participants regarding their knowledge and perceptions of publishing. Mean scores to the perception questions, and the percent of correct responses to the knowledge questions, pre and post survey, were computed for each item. The difference between these means or calculated percentages was then examined across the survey measures. RESULTS: 82 participants completed both surveys. Of this group, 29 indicated that they had exposure to the publications officer, while the remaining 53 indicated they did not. Interaction with the publications officer led to improvements in half of the knowledge items (7/14 variables). While improvements in knowledge of publishing were also found among those who reported not to have interacted with the publications officer (9/14), these effects were often smaller in magnitude. Scores for some publication knowledge variables actually decreased between the pre and post survey (3/14). Effects for researchers' perceptions of publishing increased for 5/6 variables in the group that interacted with the publications officer. DISCUSSION: This pilot provides initial indication that, in a short timeframe, introducing an institutional publications officer may improve knowledge and perceptions surrounding publishing. This study is limited by its modest sample size and temporal relationship between the introduction of the publications officer and changes in knowledge and perceptions. A randomized trial examining the publications officer as an effective intervention is needed. PMID- 28584701 TI - Alien vs. predator: bacterial challenge alters coral microbiomes unless controlled by Halobacteriovorax predators. AB - Coral microbiomes are known to play important roles in organismal health, response to environmental stress, and resistance to disease. The coral microbiome contains diverse assemblages of resident bacteria, ranging from defensive and metabolic symbionts to opportunistic bacteria that may turn harmful in compromised hosts. However, little is known about how these bacterial interactions influence the mechanism and controls of overall structure, stability, and function of the microbiome. We sought to test how coral microbiome dynamics were affected by interactions between two bacteria: Vibrio coralliilyticus, a known temperature-dependent pathogen of some corals, and Halobacteriovorax, a unique bacterial predator of Vibrio and other gram-negative bacteria. We challenged reef-building coral with V. coralliilyticus in the presence or absence of Halobacteriovorax predators, and monitored microbial community dynamics with 16S rRNA gene profiling time-series. Vibrio coralliilyticus inoculation increased the mean relative abundance of Vibrios by greater than 35% from the 4 to 8 hour time point, but not in the 24 & 32 hour time points. However, strong secondary effects of the Vibrio challenge were also observed for the rest of the microbiome such as increased richness (observed species), and reduced stability (increased beta-diversity). Moreover, after the transient increase in Vibrios, two lineages of bacteria (Rhodobacterales and Cytophagales) increased in coral tissues, suggesting that V. coralliilyticus challenge opens niche space for these known opportunists. Rhodobacterales increased from 6.99% (+/-0.05 SEM) to a maximum mean relative abundance of 48.75% (+/-0.14 SEM) in the final time point and Cytophagales from <0.001% to 3.656%. Halobacteriovorax predators are commonly present at low-abundance on coral surfaces. Based on the keystone role of predators in many ecosystems, we hypothesized that Halobacteriovorax predators might help protect corals by consuming foreign or "alien" gram negative bacteria. Halobacteriovorax inoculation also altered the microbiome but to a lesser degree than V. coralliilyticus, and Halobacteriovorax were never detected after inoculation. Simultaneous challenge with both V. coralliilyticus and predatory Halobacteriovorax eliminated the increase in V. coralliilyticus, ameliorated changes to the rest of the coral microbiome, and prevented the secondary blooms of opportunistic Rhodobacterales and Cytophagales seen in the V. coralliilyticus challenge. These data suggest that, under certain circumstances, host-associated bacterial predators may mitigate the ability of other bacteria to destabilize the microbiome. PMID- 28584703 TI - Patterns of bleaching and mortality following widespread warming events in 2014 and 2015 at the Hanauma Bay Nature Preserve, Hawai'i. AB - Drastic increases in global carbon emissions in the past century have led to elevated sea surface temperatures that negatively affect coral reef organisms. Worldwide coral bleaching-related mortality is increasing and data has shown even isolated and protected reefs are vulnerable to the effects of global climate change. In 2014 and 2015, coral reefs in the main Hawaiian Islands (MHI) suffered up to 90% bleaching, with higher than 50% subsequent mortality in some areas. The location and severity of bleaching and mortality was strongly influenced by the spatial and temporal patterns of elevated seawater temperatures. The main objective of this research was to understand the spatial extent of bleaching mortality in Hanauma Bay Nature Preserve (HBNP), O'ahu, Hawai'i to gain a baseline understanding of the physical processes that influence localized bleaching dynamics. Surveys at HBNP in October 2015 and January 2016 revealed extensive bleaching (47%) and high levels of coral mortality (9.8%). Bleaching was highly variable among the four HBNP sectors and ranged from a low of ~31% in the central bay at Channel (CH) to a high of 57% in the area most frequented by visitors (Keyhole; KH). The highest levels of bleaching occurred in two sectors with different circulation patterns: KH experienced comparatively low circulation velocity and a low temperature increase while Witches Brew (WB) and Backdoors (BD) experienced higher circulation velocity and higher temperature increase. Cumulative mortality was highest at WB (5.0%) and at BD (2.9%) although WB circulation velocity is significantly higher. HBNP is minimally impacted by local factors that can lead to decline such as high fishing pressure or sedimentation although human use is high. Despite the lack of these influences, high coral mortality occurred. Visitor impacts are strikingly different in the two sectors that experienced the highest mortality evidenced by the differences in coral cover associated with visitor use however, coral mortality was similar. These results suggest that elevated temperature was more influential in coral bleaching and the associated mortality than high circulation or visitor use. PMID- 28584702 TI - A new view on the morphology and phylogeny of eugregarines suggested by the evidence from the gregarine Ancora sagittata (Leuckart, 1860) Labbe, 1899 (Apicomplexa: Eugregarinida). AB - BACKGROUND: Gregarines are a group of early branching Apicomplexa parasitizing invertebrate animals. Despite their wide distribution and relevance to the understanding the phylogenesis of apicomplexans, gregarines remain understudied: light microscopy data are insufficient for classification, and electron microscopy and molecular data are fragmentary and overlap only partially. METHODS: Scanning and transmission electron microscopy, PCR, DNA cloning and sequencing (Sanger and NGS), molecular phylogenetic analyses using ribosomal RNA genes (18S (SSU), 5.8S, and 28S (LSU) ribosomal DNAs (rDNAs)). RESULTS AND DISCUSSION: We present the results of an ultrastructural and molecular phylogenetic study on the marine gregarine Ancora sagittata from the polychaete Capitella capitata followed by evolutionary and taxonomic synthesis of the morphological and molecular phylogenetic evidence on eugregarines. The ultrastructure of Ancora sagittata generally corresponds to that of other eugregarines, but reveals some differences in epicytic folds (crests) and attachment apparatus to gregarines in the family Lecudinidae, where Ancora sagittata has been classified. Molecular phylogenetic trees based on SSU (18S) rDNA reveal several robust clades (superfamilies) of eugregarines, including Ancoroidea superfam. nov., which comprises two families (Ancoridae fam. nov. and Polyplicariidae) and branches separately from the Lecudinidae; thus, all representatives of Ancoroidea are here officially removed from the Lecudinidae. Analysis of sequence data also points to possible cryptic species within Ancora sagittata and the inclusion of numerous environmental sequences from anoxic habitats within the Ancoroidea. LSU (28S) rDNA phylogenies, unlike the analysis of SSU rDNA alone, recover a well-supported monophyly of the gregarines involved (eugregarines), although this conclusion is currently limited by sparse taxon sampling and the presence of fast-evolving sequences in some species. Comparative morphological analyses of gregarine teguments and attachment organelles lead us to revise their terminology. The terms "longitudinal folds" and "mucron" are restricted to archigregarines, whereas the terms "epicystic crests" and "epimerite" are proposed to describe the candidate synapomorphies of eugregarines, which, consequently, are considered as a monophyletic group. Abolishing the suborders Aseptata and Septata, incorporating neogregarines into the Eugregarinida, and treating the major molecular phylogenetic lineages of eugregarines as superfamilies appear as the best way of reconciling recent morphological and molecular evidence. Accordingly, the diagnosis of the order Eugregarinida Leger, 1900 is updated. PMID- 28584704 TI - Cucurbitacins: elucidation of their interactions with the cytoskeleton. AB - Cucurbitacins, a class of toxic tetracyclic triterpenoids in Cucurbitaceae, modulate many molecular targets. Here we investigated the interactions of cucurbitacin B, E and I with cytoskeletal proteins such as microtubule and actin filaments. The effects of cucurbitacin B, E and I on microtubules and actin filaments were studied in living cells (Hela and U2OS) and in vitro using GFP markers, immunofluorescence staining and in vitro tubulin polymerization assay. Cucurbitacin B, E and I apparently affected microtubule structures in living cells and cucurbitacin E inhibited tubulin polymerization in vitro with IC50 value of 566.91 +/- 113.5 uM. Cucurbitacin E did not affect the nucleation but inhibited the growth phase and steady state during microtubule assembly in vitro. In addition, cucurbitacin B, E and I all altered mitotic spindles and induced the cell cycle arrest at G2/M phase. Moreover, they all showed potent effects on actin cytoskeleton by affecting actin filaments through the depolymerization and aggregation. The interactions of cucubitacin B, E and I with microtubules and actin filaments present new insights into their modes of action. PMID- 28584705 TI - Pond dyes are Culex mosquito oviposition attractants. AB - BACKGROUND: British mosquito population distribution, abundance, species composition and potential for mosquito disease transmission are intimately linked to the physical environment. The presence of ponds and water storage can significantly increase the density of particular mosquito species in the garden. Culex pipiens is the mosquito most commonly found in UK gardens and a potential vector of West Nile Virus WNV, although the current risk of transmission is low. However any factors that significantly change the distribution and population of C. pipiens are likely to impact subsequent risk of disease transmission. Pond dyes are used to control algal growth and improve aesthetics of still water reflecting surrounding planting. However, it is well documented that females of some species of mosquito prefer to lay eggs in dark water and/or containers of different colours and we predict that dyed ponds will be attractive to Culex mosquitoes. METHODS: Black pond dye was used in oviposition choice tests using wild-caught gravid C. pipiens. Larvae from wild-caught C. pipiens were also reared in the pond dye to determine whether it had any impact on survival. An emergence trap caught any adults that emerged from the water. Water butts (80 L) were positioned around university glasshouses and woodland and treated with black pond dye or left undyed. Weekly sampling over a six month period through summer and autumn was performed to quantified numbers of larvae and pupae in each treatment and habitat. RESULTS: Gravid female Culex mosquitoes preferred to lay eggs in dyed water. This was highly significant in tests conducted under laboratory conditions and in a semi-field choice test. Despite this, survivorship in black dyed water was significantly reduced compared to undyed water. Seasonal analysis of wild larval and pupal numbers in two habitats with and without dye showed no impact of dye but a significant impact of season and habitat. Mosquitoes were more successful, with significantly higher numbers of pupae, in the habitat where they had vegetation cover and shade. DISCUSSION: Our study has raised some interesting possibilities; one is that where used, pond dyes may be encouraging mosquitoes to breed in gardens in close proximity to people. Considering the concerns over potential future spread of disease in urban environments, this as well as shading of ponds and water butts, should inform future advice over reducing mosquito breeding and spread. PMID- 28584706 TI - Impact of enzymatic digestion on bacterial community composition in CF airway samples. AB - BACKGROUND: Previous studies have demonstrated the importance of DNA extraction methods for molecular detection of Staphylococcus, an important bacterial group in cystic fibrosis (CF). We sought to evaluate the effect of enzymatic digestion (EnzD) prior to DNA extraction on bacterial communities identified in sputum and oropharyngeal swab (OP) samples from patients with CF. METHODS: DNA from 81 samples (39 sputum and 42 OP) collected from 63 patients with CF was extracted in duplicate with and without EnzD. Bacterial communities were determined by rRNA gene sequencing, and measures of alpha and beta diversity were calculated. Principal Coordinate Analysis (PCoA) was used to assess differences at the community level and Wilcoxon Signed Rank tests were used to compare relative abundance (RA) of individual genera for paired samples with and without EnzD. RESULTS: Shannon Diversity Index (alpha-diversity) decreased in sputum and OP samples with the use of EnzD. Larger shifts in community composition were observed for OP samples (beta-diversity, measured by Morisita-Horn), whereas less change in communities was observed for sputum samples. The use of EnzD with OP swabs resulted in significant increase in RA for the genera Gemella (p < 0.01), Streptococcus (p < 0.01), and Rothia (p < 0.01). Staphylococcus (p < 0.01) was the only genus with a significant increase in RA from sputum, whereas the following genera decreased in RA with EnzD: Veillonella (p < 0.01), Granulicatella (p < 0.01), Prevotella (p < 0.01), and Gemella (p = 0.02). In OP samples, higher RA of Gram-positive taxa was associated with larger changes in microbial community composition. DISCUSSION: We show that the application of EnzD to CF airway samples, particularly OP swabs, results in differences in microbial communities detected by sequencing. Use of EnzD can result in large changes in bacterial community composition, and is particularly useful for detection of Staphylococcus in CF OP samples. The enhanced identification of Staphylococcus aureus is a strong indication to utilize EnzD in studies that use OP swabs to monitor CF airway communities. PMID- 28584707 TI - Rituals decrease the neural response to performance failure. AB - Rituals are found in all types of performance domains, from high-stakes athletics and military to the daily morning preparations of the working family. Yet despite their ubiquity and widespread importance for humans, we know very little of ritual's causal basis and how (if at all) they facilitate goal-directed performance. Here, in a fully pre-registered pre/post experimental design, we examine a candidate proximal mechanism, the error-related negativity (ERN), in testing the prediction that ritual modulates neural performance-monitoring. Participants completed an arbitrary ritual-novel actions repeated at home over one week-followed by an executive function task in the lab during electroencephalographic (EEG) recording. Results revealed that relative to pre rounds, participants showed a reduced ERN in the post rounds, after completing the ritual in the lab. Despite a muted ERN, there was no evidence that the reduction in neural monitoring led to performance deficit (nor a performance improvement). Generally, the findings are consistent with the longstanding view that ritual buffers against uncertainty and anxiety. Our results indicate that ritual guides goal-directed performance by regulating the brain's response to personal failure. PMID- 28584708 TI - Analyses of antioxidant status and nucleotide alterations in genes encoding antioxidant enzymes in patients with benign and malignant thyroid disorders. AB - BACKGROUND: Synthesis of thyroid hormones and regulation of their metabolism involve free radicals that may affect redox balance in the body. Thyroid disorders causing variations in the levels of thyroid hormones may alter cellular oxidative stress. The aim of this study was to measure the antioxidant activities and biomarkers of oxidative stress in serum and red blood cells (RBC) of patients with benign and malignant thyroid disorders and to investigate if changes in the antioxidant activities in these patients were linked to alterations in genes encoding the antioxidant enzymes. METHODS: Forty-one patients with thyroid disorders from University of Malaya Medical Centre were recruited. They were categorised into four groups: multinodular goitre (MNG) (n = 18), follicular thyroid adenoma (FTA) (n = 7), papillary thyroid cancer (PTC) (n = 10), and follicular thyroid cancer (FTC) (n = 6). Serum and RBC of patients were analysed for antioxidant activities, antioxidant enzymes, and biomarkers of oxidative stress. Alterations in genes encoding the antioxidant enzymes were analysed using whole exome sequencing and PCR-DNA sequencing. RESULTS: Patients with thyroid disorders had significantly higher serum superoxide dismutase (SOD) and catalase (CAT) activities compared to control, but had lower activities in RBC. There were no significant changes in serum glutathione peroxidase (GPx) activity. Meanwhile, GPx activity in RBC was reduced in PTC and FTC, compared to control and the respective benign groups. Antioxidant activities in serum were decreased in the thyroid disorder groups when compared to the control group. The levels of malondialdehyde (MDA) were elevated in the serum of FTA group when compared to controls, while in the RBC, only the MNG and PTC groups showed higher MDA equivalents than control. Serum reactive oxygen species (ROS) levels in PTC group of both serum and RBC were significantly higher than control group. Whole exome sequencing has resulted in identification of 49 single nucleotide polymorphisms (SNPs) in MNG and PTC patients and their genotypic and allelic frequencies were calculated. Analyses of the relationship between serum enzyme activities and the total SNPs identified in both groups revealed no correlation. DISCUSSION: Different forms of thyroid disorders influence the levels of antioxidant status in the serum and RBC of these patients, implying varying capability of preventing oxidative stress. A more comprehensive study with a larger target population should be done in order to further evaluate the relationships between antioxidant enzymes gene polymorphisms and thyroid disorders, as well as strengthening the minor evidences provided in literatures. PMID- 28584709 TI - Increasing game prices may alter farmers' behaviours towards leopards (Panthera pardus) and other carnivores in South Africa. AB - Human-carnivore conflict occurs globally, particularly in regions where large carnivores predate livestock. Retaliatory killings do occur, and although predation of livestock by carnivores happens, losses from other factors such as disease or injury can be misattributed because of landowner perceptions. Game farming for both trophy hunting and eco-tourism is becoming increasingly common in South Africa, and there has been a rapid increase in the cost of game animals (in some species as much as five-fold) between 2010 and 2015. This could result in an increase in conflict between commercial game farmers and carnivores. We conducted two questionnaire surveys of farmers in 2010 and 2015 to investigate this. We asked if there had been changes in farming practices, perceived predator activity, perceived amount of livestock and commercial game losses, and actions taken towards carnivores in a South African farming community. We found no significant change in farming types in the area or losses of livestock between the years. However, there was a significant increase in perceived commercial game losses reported, even though protection of game had increased. Actions taken towards carnivores by livestock/game farmers were also significantly more negative in 2015 compared to farmers growing crops, but there was no such difference in 2010. We suggest that these changes could be a result of the increase in game prices over that period, leading to greater financial losses when an animal is predated, which in turn could increase the likelihood of retaliatory killings of carnivores. PMID- 28584710 TI - Proceraea exoryxae sp. nov. (Annelida, Syllidae, Autolytinae), the first known polychaete miner tunneling into the tunic of an ascidian. AB - While studying organisms living in association with the solitary tunicate Phallusia nigra (Ascidiacea, Ascidiidae) from a shallow fringing reef at Zeytouna Beach (Egyptian Red Sea), one of the collected ascidians showed peculiar perforations on its tunic. Once dissected, the perforations revealed to be the openings of a network of galleries excavated in the inner tunic (atrium) by at least six individuals of a polychaetous annelid. The worms belonged to the Autolytinae (Syllidae), a subfamily that is well known to include specialized predators and/or symbionts, mostly associated with cnidarians. The Red Sea worms are here described as Proceraea exoryxae sp. nov., which are anatomically distinguished by the combination of simple chaetae only in anterior chaetigers, and a unique trepan with 33 teeth in one outer ring where one large tooth alternates with one medium-sized tricuspid tooth, and one inner ring with small teeth located just behind the large teeth. Male and female epitokes were found together with atokous individuals within galleries. Proceraea exoryxae sp. nov. constitutes the first known miner in the Autolytinae and the second species in this taxon known to live symbiotically with ascidians. The implications of finding this specialized parasite are discussed considering that Phallusia nigra has been introduced worldwide, in tropical and sub-tropical ecosystems, where it has the potential of becoming invasive. PMID- 28584711 TI - Quercetin reduces hydroxyurea induced cytotoxicity in immortalized mouse aortic endothelial cells. AB - BACKGROUND: Chronic inflammation is a characteristic of sickle cell disease (SCD), and is invariably associated with vascular endothelial injury. Hydroxyurea (HU), a naturally cytotoxic chemotherapeutic agent, is the only FDA drug approved for SCD, and is therefore naturally cytotoxic. Quercetin (QCT) is a dietary flavonoid found ubiquitously in plants and foods that have anti-oxidative and anti-inflammatory characteristics. Our hypothesis is that dietary QCT will decrease cytotoxic effects of lipopolysaccharide (LPS) and HU induced vascular cell damage. METHODS: Lipopolysaccharide (LPS) was used to induce inflammation in immortalized mouse aortic endothelial cells (iMAECs), providing an in vitro model of inflamed endothelial cells. The cells were exposed to LPS throughout the entire experiment. Interventions included treating the LPS exposed cells with QCT, HU, or QCT + HU over 50 hours. The 50-hour period included 24 hours of varying treatments, followed by two hours of hypoxic exposure and then 24 hours under normal aerobic exposure. RESULTS: LDH level was significantly higher for LPS treated versus untreated cells (P = 0.0004). LPS plus 30 micromole QCT reduced the LDH (p = 0.1, trend), whereas LPS plus 100 micromoles HU, significantly increased LDH (p = 0.0004). However, LPS plus treatment with 30 micromoles QCT/100 micromoles HU, significantly reduced LDH, compared with HU alone (p = 0.0002). DISCUSSION: These results suggest that quercetin may be effective against vascular endothelial cell damage for iMAECs in vitro. In particular, it shows promise in preventing HU-induced cytotoxicity, surprisingly found from these results. This latter finding is important, and should be given more consideration, since HU is the only FDA-approved drug for treating sickle cell patients, and its use is rapidly increasing. PMID- 28584712 TI - Prevalence and seroepidemiology of Haemophilus parasuis in Sichuan province, China. AB - Haemophilus parasuis, the causative agent of Glasser's disease, has been reported as widespread, but little is known about its epidemiology in the Sichuan province of China. The goal of our research is to reveal the prevalence and distribution of H. parasuis in this area. Sampling and isolation were performed across Sichuan; isolates were processed using serotyping multiplex PCR (serotyping-mPCR) and agar gel diffusion (AGD) for confirmation of serovar identity. This study was carried out from January 2014 to May 2016 and 254 H. parasuis field strains were isolated from 576 clinical samples collected from pigs displaying clinical symptoms. The isolation frequency was 44.10%. Statistically very significant differences of infection incidence were found in three age groups (P < 0.01) and different seasons (P < 0.01). Serovars 5 (25.98%) and 4 (23.62%) were the most prevalent, however, non-typeable isolates accounted for nearly 7.87%. In terms of geographical distribution, serovars 5 and 4 were mostly prevalent in west and east Sichuan. The results confirmed that the combined approach was dependable and revealed the diversity and distribution of serovars in Sichuan province, which is vital for efforts aimed at developing vaccine candidates allowing for the prevention or control of H. parasuis outbreaks. PMID- 28584713 TI - Transcriptome analysis reveals the regulation of brassinosteroids on petal growth in Gerbera hybrida. AB - Gerbera hybrida is a cut-flower crop of global importance, and an understanding of the mechanisms underlying petal development is vital for the continued commercial development of this plant species. Brassinosteroids (BRs), a class of phytohormones, are known to play a major role in cell expansion, but their effect on petal growth in G. hybrida is largely unexplored. In this study, we found that the brassinolide (BL), the most active BR, promotes petal growth by lengthening cells in the middle and basal regions of petals, and that this effect on petal growth was greater than that of gibberellin (GA). The RNA-seq (high-throughput cDNA sequencing) technique was employed to investigate the regulatory mechanisms by which BRs control petal growth. A global transcriptome analysis of the response to BRs in petals was conducted and target genes regulated by BR were identified. These differentially expressed genes (DEGs) include various transcription factors (TFs) that were activated during the early stage (0.5 h) of BL treatment, as well as cell wall proteins whose expression was regulated at a late stage (10 h). BR-responsive DEGs are involved in multiple plant hormone signal pathways, hormone biosynthesis and biotic and abiotic stress responses, showing that the regulation of petal growth by BRs is a complex network of processes. Thus, our study provides new insights at the transcriptional level into the molecular mechanisms of BR regulation of petal growth in G. hybrida. PMID- 28584714 TI - The development of curvature in the porcine radioulna. AB - Long bone curvature in animal limbs has long been a subject of interest and much work has explored why long bones should be curved. However, the 'when' and 'how' of curvature development is poorly understood. It has been shown that the rat tibia fails to attain its normal curvature if the action of muscles is removed early in life, but it is not clear if this is because the curvature fails to develop or if the bone becomes straighter without the action of muscles. No studies have examined the development of bone curvature in a normally developing quadruped, so this study tracks the course of curvature formation in the radioulna in a series of growing pigs. We also histologically examined the epiphyseal growth plates of these bones to determine if they contribute to the formation of curvature. In all three epiphyseal plates examined, the proliferative zone is thicker and more densely populated with chondrocytes on the cranial (convex) side than the caudal (concave) side. Frost's chondral modelling theory would suggest that the cranial side of the bone is under more compression than the caudal side, and we conclude that this is due to the action of triceps extending the elbow by pulling on the olecranon process. These results support the idea that bone curvature is an adaptation to habitual loading, where longitudinal loads acting on the curved bone cause bending strains that counter the bending resulting from the habitual muscle action. PMID- 28584715 TI - The ratio of serum Angiopoietin-1 to Angiopoietin-2 in patients with cervical cancer is a valuable diagnostic and prognostic biomarker. AB - OBJECTIVES: Angiopoietins have been found to play essential roles in tumor angiogenesis. The present study was aimed at investigating the diagnostic and prognostic values of serum angiopoietin 1 and 2 (sAng-1 and sAng-2) in cervical cancer. METHODS: The sAng-1 and sAng-2 concentrations were analyzed in 77 women with cervical cancer, 44 women with cervical intraepithelial neoplasia (CIN) and 43 women without cervical lesions by enzyme-linked immunosorbent assay. The diagnostic values of sAng-1, sAng-2 and sAng-1/sAng-2 were evaluated by receiver operating characteristic (ROC) curves. The Ang-1 and Ang-2 expression in cervical cancer tissues as well as microvessel density (MVD), were assessed by immunohistochemistry. RESULTS: The concentration of sAng-2 gradually increased and the sAng-1/Ang-2 ratio was gradually decreased from normal control to CIN, then to squamous cell cancer, and the sAng-1/sAng-2 ratio was also significantly decreased in adenocarcinoma. The area under ROC curves of sAng-2 and sAng-1/sAng 2 ratio for discriminating cervical cancer from normal were 0.744 and 0.705, respectively. Decreased sAng-1/sAng-2 was significantly associated with advanced tumor stage, poor differentiation, lymph-vascular space invasion and high MVD. sAng-2 was positively correlated with the Ang-2 expression in cervix epithelia. A high sAng-1/sAng-2 ratio was associated with a longer progression-free survival and a longer overall survival in cervical cancer patients. CONCLUSIONS: These findings suggest that sAng-2 and the sAng-1/sAng-2 ratio may be valuable diagnostic and prognostic biomarkers for cervical cancer. PMID- 28584716 TI - Modeling the cis-regulatory modules of genes expressed in developmental stages of Drosophila melanogaster. AB - Because transcription is the first step in the regulation of gene expression, understanding how transcription factors bind to their DNA binding motifs has become absolutely necessary. It has been shown that the promoters of genes with similar expression profiles share common structural patterns. This paper presents an extensive study of the regulatory regions of genes expressed in 24 developmental stages of Drosophila melanogaster. It proposes the use of a combination of structural features, such as positioning of individual motifs relative to the transcription start site, orientation, pairwise distance between motifs, and presence of motifs anywhere in the promoter for predicting gene expression from structural features of promoter sequences. RNA-sequencing data was utilized to create and validate the 24 models. When genes with high-scoring promoters were compared to those identified by RNA-seq samples, 19 (79.2%) statistically significant models, a number that exceeds previous studies, were obtained. Each model yielded a set of highly informative features, which were used to search for genes with similar biological functions. PMID- 28584717 TI - Calculating site-specific evolutionary rates at the amino-acid or codon level yields similar rate estimates. AB - Site-specific evolutionary rates can be estimated from codon sequences or from amino-acid sequences. For codon sequences, the most popular methods use some variation of the dN/dS ratio. For amino-acid sequences, one widely-used method is called Rate4Site, and it assigns a relative conservation score to each site in an alignment. How site-wise dN/dS values relate to Rate4Site scores is not known. Here we elucidate the relationship between these two rate measurements. We simulate sequences with known dN/dS, using either dN/dS models or mutation selection models for simulation. We then infer Rate4Site scores on the simulated alignments, and we compare those scores to either true or inferred dN/dS values on the same alignments. We find that Rate4Site scores generally correlate well with true dN/dS, and the correlation strengths increase in alignments with greater sequence divergence and more taxa. Moreover, Rate4Site scores correlate very well with inferred (as opposed to true) dN/dS values, even for small alignments with little divergence. Finally, we verify this relationship between Rate4Site and dN/dS in a variety of empirical datasets. We conclude that codon level and amino-acid-level analysis frameworks are directly comparable and yield very similar inferences. PMID- 28584718 TI - The increasing prevalence of HIV/Helicobacter pylori co-infection over time, along with the evolution of antiretroviral therapy (ART). AB - Helicobacter pylori (H. pylori) is one of the most common human bacterial infections with prevalence rates between 10-80% depending upon geographical location, age and socioeconomic status. H. pylori is commonly found in patients complaining of dyspepsia and is a common cause of gastritis. During the course of their infection, people living with HIV (PLHIV) often have a variety of gastrointestinal symptoms including dyspepsia and while previous studies have reported HIV and H. pylori co-infection, there has been little data clarifying the factors influencing this. The aim of this case-control study was to document the prevalence of H. pylori co-infection within the HIV community as well as to describe endoscopic findings, gastritis topography and histology, along with patient demographic characteristics across three different periods of time during which antiretroviral therapy (ART) has evolved, from pre- highly active antiretroviral therapy (HAART) to early and modern HAART eras. These data were compared to well-matched HIV negative controls. Two hundred and twelve PLHIV were compared with 1,617 controls who underwent their first esophagogastroduodenoscopy (EGD) to investigate dyspepsia. The prevalence of H. pylori co-infection among PLHIV was significantly higher in the early (30.2%) and modern HAART period (34.4%) compared with those with coinfection from the pre-HAART period (18.2%). The higher rates seen in patients from the HAART eras were similar to those observed among HIV negative controls (38.5%). This prevalence increase among co infected patients was in contrast to the fall in prevalence observed among controls, from 60.7% in the early period to 52.9% in the second observed period. The three PLHIV co-infected subgroups differed regarding gastritis topography, morphology and pathology. This study suggests that ART has an important impact on the endoscopic and histological features of gastritis among HIV/H. pylori co infected individuals, raising the possibility that H. pylori-induced gastritis could be an immune restoration disease. PMID- 28584719 TI - SIX4 promotes metastasis via activation of the PI3K-AKT pathway in colorectal cancer. AB - BACKGROUND: Several studies report aberrant expression of sine oculis homeobox (SIX) homolog family members during cancer development and progression. SIX4 participates in organ development, such as myogenesis and neurogenesis. However, the expression and clinical implication of SIX4 in colorectal cancer (CRC) remains unclear. METHODS: The SIX4 expression levels in colorectal patients were assessed in nine different human cancer arrays and compared using patient survival data. SIX4 expression was silenced in two cell culture lines for invasion and wound healing assessment. Finally, bioinformatics assessments ascertained the pathways impacted by SIX4. RESULTS: SIX4 was upregulated in The Cancer Genome Atlas CRC cohort and other gene expression omnibus (GEO) cohorts. In addition, SIX4 expression significantly correlated with lymph node metastasis and advanced Tumor Node Metastasis (TNM) stages. Moreover, SIX4 overexpression was related to unfavorable prognosis in CRC patients. Silencing SIX4 inhibited CRC cell metastasis by surpressing AKT phosphorylation. DISCUSSION: SIX4 is upregulated in CRC and can be used as a prognosis biomarker. PMID- 28584720 TI - Clinical impact of human papillomavirus in laryngeal squamous cell carcinoma: a retrospective study. AB - OBJECTIVES: The purpose of this study is to determine the prevalence and clinical impact of human papillomavirus (HPV) related laryngeal squamous cell carcinoma (LSCC). METHODS: A total of 106 LSCC patients who underwent primary surgical resection with or without adjuvant radiotherapy/chemoradiotherapy were enrolled retrospectively. Tumors collected from paraffin-embedded samples were used for HPV detection by polymerase chain reaction and in situ hybridization technique. Clinicopathological parameters were recorded for analysis. RESULTS: The prevalence of HPV in patients with LSCC was 13.2% in our series and 12 out of 14 (85.7%) HPV-positive tumors were HPV-16. The patients with HPV-positive tumors were older (p = 0.042), less local/regional recurrence (p = 0.037) and non-smoker (p = 0.068). There was no significant difference in the 5-year overall survival (OS) (p = 0.8056) between HPV-positive and -negative tumors. The patients with HPV-positive tumors had a better 5-year disease-specific survival (DSS) (100% vs. 84.8%, p = 0.1485), although the difference did not reach statistical significance. However, the local/regional control rate was significantly better in HPV-positive tumors than in HPV-negative tumors (100% vs. 75%, p = 0.0494). CONCLUSIONS: A low prevalence of HPV infection in our series suggests that HPV is not a major cause of LSCC. However, a 100% local/regional control rate and DSS were observed in HPV-positive tumors. This finding suggests a different tumor behavior between HPV-positive and HPV-negative LSCC. Further research with a larger sample size is necessary to confirm our observations. PMID- 28584721 TI - Character strengths, social anxiety, and physiological stress reactivity. AB - In this paper, the effects of character strengths on the physiological reactivity to social anxiety induced by the Trier Social Stress Task were reported. On the basis of their scores in the Chinese Virtues Questionnaire, 30 college students were assigned to either high- (n = 15) or low-character-strength (n = 15) groups. Their psychological stress and physiological data across three laboratory stages (namely, baseline, stress exposure, and post-stress) were collected. Results indicated that individuals with high character strengths exhibited rapid cardiovascular recovery from baseline to post-stress even if high- and low character-strength groups showed similar patterns of cardiovascular arousal in response to the stress at baseline and stress exposure. These results prove that character strengths are stress-defense factors that allow for psychological and physiological adaptation to stress. PMID- 28584722 TI - The shoaling behavior of two cyprinid species in conspecific and heterospecific groups. AB - Mixed-species shoals of fish are frequently found in the field; however, little is known about individual-level interactions within these groups. We examined the collective motion of two cyprinid species (Chinese bream, Parabramis pekinensis, and qingbo, Spinibarbus sinensis) that occupy partially overlapping habitats but differ in social behavior (high vs low aggressiveness) and preferred flow regime (slow vs fast water velocity). We extracted measures of collective motion from video recordings of eight replicate groups of four individuals of either Chinese bream or qingbo (conspecific group) or two Chinese bream plus two qingbo (heterospecific group). Chinese bream in conspecific groups showed lower percent time moving and mean swimming speed but a similar speed while moving as compared to the qingbo conspecific groups. However, the difference in mean swimming speed and percent time moving vanished in the heterospecific group as Chinese bream elevated their swimming activity to coordinate with qingbo. This finding suggests that the two species may share similar interaction rules regarding shoaling behavior. The conspecific groups of qingbo exhibited a greater distance between group members than Chinese bream, suggesting a difference in cohesion. However, the inter-individual distances of all fish were similar in the heterospecific group. Qingbo in the heterospecific group swam more frequently at the front compared to Chinese bream, possibly due to their higher activity level. We also measured the startle response to an artificial stimulus and found that there was no significant difference among groups. In conclusion, the present study demonstrated that in the heterospecific groups, Chinese bream elevated their percent time moving while qingbo decreased their inter-individual distance to achieve consistent collective movement; thus, the two species showed similar behavior in the mixed-species group. PMID- 28584724 TI - Seed morphometric characteristics of European species of Elatine (Elatinaceae). AB - Elatine L. contains ca. 25 small, herbaceous, annual species distributed in ephemeral waters in both hemispheres. All species are amphibious and characterized by a high degree of morphological variability. The importance of seed morphology in Elatine taxonomy has been emphasized by many authors. The degree of seed curvature and seed coat reticulation have been traditionally considered very important in recognizing individual species of this genus. Seed morphometric characteristics of 10 Elatine species, including all European native taxa, are provided on the basis of material from two or three populations of each species. A total of 24-50 seeds were studied from each population, altogether 1,260 images were used for the morphometric study. In total, six parameters were measured from SEM pictures: object surface area, profile specific perimeter (object circuit), rectangle of the object (a) length, rectangle of the object (b) width, angle of the seed curvature, and number of pits in the seed coat counted in the middle row. Our study shows that the range of morphological variation of seeds in European species of Elatine is great, both between the species and the populations. Discrimination analysis showed that all six traits significantly differentiate the populations studied (lambda = 0.001, p < 0.001), and the greatest contributions were "number of pits", "rectangle_a", and "the angle curvature". Multidimensional scaling based on a correlation matrix of Mahalanobis distance of the six features studied revealed the greatest similarity between the three populations of E. alsinastrum, E. macropoda, and E. hexandra. Regarding interspecific differences, a Kruskal-Wallis tests showed that, in many cases, lack of statistically significant differences between species relative to the studied seed traits. If distinction of species is only based on seeds, especially if only a few seeds are evaluated, the following species pairs can be easily confused: E. alsinastrum and E. orthosperma, E. hexandra and E. macropoda, E. campylosperma and E. hydropiper, as well and E. gussonei and E. hungarica. We found no diversity in seed coat micromorphology within pits that could have potential taxonomic importance. An identification key and descriptions of species are provided on the basis of seeds traits. PMID- 28584723 TI - Selection of housekeeping genes as internal controls for quantitative RT-PCR analysis of the veined rapa whelk (Rapana venosa). AB - BACKGROUND: The veined rapa whelk Rapana venosa is an important commercial shellfish in China and quantitative real-time PCR (qRT-PCR) has become the standard method to study gene expression in R. venosa. For accurate and reliable gene expression results, qRT-PCR assays require housekeeping genes as internal controls, which display highly uniform expression in different tissues or stages of development. However, to date no studies have validated housekeeping genes in R. venosa for use as internal controls for qRT-PCR. METHODS: In this study, we selected the following 13 candidate genes for suitability as internal controls: elongation factor-1alpha (EF-1alpha), alpha-actin (ACT), cytochrome c oxidase subunit 1 (COX1), nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1alpha subcomplex subunit 7 (NDUFA7), 60S ribosomal protein L5 (RL5), 60S ribosomal protein L28 (RL28), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), beta-tubulin (TUBB), 40S ribosomal protein S25 (RS25), 40S ribosomal protein S8 (RS8), ubiquitin-conjugating enzyme E2 (UBE2), histone H3 (HH3), and peptidyl prolyl cis-trans isomerase A (PPIA). We measured the expression levels of these 13 candidate internal controls in eight different tissues and twelve larvae developmental stages by qRT-PCR. Further analysis of the expression stability of the tested genes was performed using GeNorm and RefFinder algorithms. RESULTS: Of the 13 candidate genes tested, we found that EF-1alpha was the most stable internal control gene in almost all adult tissue samples investigated with RL5 and RL28 as secondary choices. For the normalization of a single specific tissue, we suggested that EF-1alpha and NDUFA7 are the best combination in gonad, as well as COX1 and RL28 for intestine, EF-1alpha and RL5 for kidney, EF-1alpha and COX1 for gill, EF-1alpha and RL28 for Leiblein and mantle, EF-1alpha, RL5, and NDUFA7 for liver, GAPDH, PPIA, and RL28 for hemocyte. From a developmental perspective, we found that RL28 was the most stable gene in all developmental stages measured, and COX1 and RL5 were appropriate secondary choices. For the specific developmental stage, we recommended the following combination for normalization, PPIA, RS25, and RL28 for stage 1, RL5 and RL28 for stage 2 and 5, RL28 and NDUFA7 for stage 3, and PPIA and TUBB for stage 4. DISCUSSION: Our results are instrumental for the selection of appropriately validated housekeeping genes for use as internal controls for gene expression studies in adult tissues or larval development of R. venosa in the future. PMID- 28584725 TI - Genome-wide analysis suggests high level of microsynteny and purifying selection affect the evolution of EIN3/EIL family in Rosaceae. AB - The ethylene-insensitive3/ethylene-insensitive3-like (EIN3/EIL) proteins are a type of nuclear-localized protein with DNA-binding activity in plants. Although the EIN3/EIL gene family has been studied in several plant species, little is known about comprehensive study of the EIN3/EIL gene family in Rosaceae. In this study, ten, five, four, and five EIN3/EIL genes were identified in the genomes of pear (Pyrus bretschneideri), mei (Prunus mume), peach (Prunus persica) and strawberry (Fragaria vesca), respectively. Twenty-eight chromosomal segments of EIL/EIN3 gene family were found in four Rosaceae species, and these segments could form seven orthologous or paralogous groups based on interspecies or intraspecies gene colinearity (microsynteny) analysis. Moreover, the highly conserved regions of microsynteny were found in four Rosaceae species. Subsequently it was found that both whole genome duplication and tandem duplication events significantly contributed to the EIL/EIN3 gene family expansion. Gene expression analysis of the EIL/EIN3 genes in the pear revealed subfunctionalization for several PbEIL genes derived from whole genome duplication. It is noteworthy that according to environmental selection pressure analysis, the strong purifying selection should dominate the maintenance of the EIL/EIN3 gene family in four Rosaceae species. These results provided useful information on Rosaceae EIL/EIN3 genes, as well as insights into the evolution of this gene family in four Rosaceae species. Furthermore, high level of microsynteny in the four Rosaceae plants suggested that a large-scale genome duplication event in the EIL/EIN3 gene family was predated to speciation. PMID- 28584727 TI - The presumed oldest flying insect: more likely a myriapod? AB - The early fossil record of insects is scarce, with only few finds in the Devonian. All these finds appear problematic and controversial, partly due to incomplete preservation and challenging interpretation of many structures. We provide details of one of these important forms, Rhyniognatha hirsti from the famous Rhynie Chert Lagerstatte with up-to-date 3D imaging techniques. The fossil has been interpreted as the remains of one of the earliest flying insects. The specimen mainly preserves the remains of the head. The structures of the mandibles have been used as a main argument for an interpretation as an insect, but these are in fact less easy to interpret. New observed structures include the remains of a head capsule and an additional pair of mouth parts. Structures formerly suggested to represent remains of the head capsule or apodemes are more likely to be representing glands of ectodermal origin. The newly observed structures do not support an interpretation as an insect. Instead they make the interpretation as a myriapod more likely, possibly as a centipede. Centipede remains from the Rhynie Chert are known from scutigeromorphs. We therefore point out that R. hirsti could be interpreted as an early centipede. PMID- 28584726 TI - The South-American distribution and southernmost record of Biomphalaria peregrina a potential intermediate host of schistosomiasis. AB - Schistosomiasis remains a major parasitic disease, endemic in large parts of South America. Five neotropical species of Biomphalaria have been found to act as intermediate hosts of Schistosoma mansoni in natural populations, while others have been shown to be susceptible in experimental infections, although not found infected in the field. Among these potential intermediate hosts, Biomphalaria peregrina represents the most widespread species in South America, with confirmed occurrence records from Venezuela to northern Patagonia. In this study, we report the southernmost record for the species at the Pinturas River, in southern Patagonia, which finding implies a southward reassessment of the limit for the known species of this genus. The identities of the individuals from this population were confirmed through morphological examination, and by means of two mitochondrial genes, cytochrome oxidase subunit I (COI) and 16S-rRNA. With both markers, phylogenetic analyses were conducted in order to compare the genetic background of individuals from the Pinturas River with previously genetically characterized strains of B. peregrina from various South-American locations. In addition, we produced a potential distribution model of B. peregrina in South America and identified the environmental variables that best predict that distribution. The model was estimated through a maximum entropy algorithm and run with occurrence points obtained from several sources, including the scientific literature and international databases, along with climatic and hydrographic variables. Different phylogenetic analyses with either the COI or 16S-rRNA sequences did not conflict, but rather gave very similar topological organizations. Two major groups were identified, with sequences from the Pinturas River grouping together with haplotypes from subtropical and temperate regions. The model developed had a satisfactory performance for the study area. We observed that the areas with higher habitat suitability were found to be mainly linked to subtropical and temperate regions of South America between 15 degrees and 45 degrees south latitude, with different moderate- and low-suitability areas outside this range. We also identified the coldest temperatures as the main predictors of the potential distribution of this snail. Susceptibility surveys would be required to evaluate if southern populations of B. peregrina still retain their potential as intermediate hosts of S. mansoni. PMID- 28584728 TI - How to be a great dad: parental care in a flock of greater flamingo (Phoenicopterus roseus). AB - In the last years, studies on captive greater flamingos have increased. Research on zoo animals is important to improve the knowledge on these species and to improve their ex-situ and in-situ conservation. The aim of the present study was to investigate the parental behaviour of a captive colony of greater flamingo hosted at Parco Natura Viva, an Italian zoological garden, to improve the knowledge on this species in zoos. In particular, the present study investigated and compared the parental care of females and males in 35 breeding pairs of greater flamingos. For each pair, we collected durations of parental care behaviour of both females and males, recording their position in relation to the nest (near the nest, on the nest, away from the nest) and individual and social behaviours performed. First, both partners were involved in parental care and displayed species-specific behaviours reported in the wild. The main results were that males spent more time than females on the nest (P = 0.010) and near it (P = 0.0001) and were more aggressive toward other flamingos than females, both when sitting on the nest (P = 0.003) and when near the nest (P = 0.0003). Therefore, male flamingos seem to be more involved in incubation duties and nest protection than females. This kind of research is important not only to expand the knowledge on bird species such as flamingos, but also to improve their husbandry and breeding in controlled environment. Indeed, understanding animal behaviour allows us to gain insights into their individual and social needs, addressing potential animal welfare issues. PMID- 28584729 TI - MitoSuite: a graphical tool for human mitochondrial genome profiling in massive parallel sequencing. AB - Recent rapid advances in high-throughput, next-generation sequencing (NGS) technologies have promoted mitochondrial genome studies in the fields of human evolution, medical genetics, and forensic casework. However, scientists unfamiliar with computer programming often find it difficult to handle the massive volumes of data that are generated by NGS. To address this limitation, we developed MitoSuite, a user-friendly graphical tool for analysis of data from high-throughput sequencing of the human mitochondrial genome. MitoSuite generates a visual report on NGS data with simple mouse operations. Moreover, it analyzes high-coverage sequencing data but runs on a stand-alone computer, without the need for file upload. Therefore, MitoSuite offers outstanding usability for handling massive NGS data, and is ideal for evolutionary, clinical, and forensic studies on the human mitochondrial genome variations. It is freely available for download from the website https://mitosuite.com. PMID- 28584730 TI - Comparative transcriptome analysis of isonuclear-alloplasmic lines unmask key transcription factor genes and metabolic pathways involved in sterility of maize CMS-C. AB - Although C-type cytoplasmic male sterility (CMS-C) is one of the most attractive tools for maize hybrid seed production, the detailed regulation network of the male sterility remains unclear. In order to identify the CMS-C sterility associated genes and/or pathways, the comparison of the transcriptomes between the CMS-C line C48-2 and its isonuclear-alloplasmic maintainer line N48-2 at pollen mother cell stage (PS), an early development stage of microspore, and mononuclear stage (MS), an abortive stage of microspore, were analyzed. 2,069 differentially expressed genes (DEGs) between the two stages were detected and thought to be essential for the spikelet development of N48-2. 453 of the 2,069 DEGs were differentially expressed at MS stage between the two lines and thought to be participated in the process or the causes of microspore abortion. Among the 453 DEGs, 385 (84.99%) genes were down-regulated and only 68 (15.01%) genes were up-regulated in C48-2 at MS stage. The dramatic decreased expression of the four DEGs encoding MYB transcription factors and the DEGs involved in "polyamine metabolic process", "Cutin, suberine and wax biosynthesis", "Fatty acid elongation", "Biosynthesis of unsaturated fatty acids" and "Proline metabolism" might play an important role in the sterility of C48-2. This study will point out some directions for detailed molecular analysis and better understanding of sterility of CMS-C in maize. PMID- 28584731 TI - Experience-based human perception of facial expressions in Barbary macaques (Macaca sylvanus). AB - BACKGROUND: Facial expressions convey key cues of human emotions, and may also be important for interspecies interactions. The universality hypothesis suggests that six basic emotions (anger, disgust, fear, happiness, sadness, and surprise) should be expressed by similar facial expressions in close phylogenetic species such as humans and nonhuman primates. However, some facial expressions have been shown to differ in meaning between humans and nonhuman primates like macaques. This ambiguity in signalling emotion can lead to an increased risk of aggression and injuries for both humans and animals. This raises serious concerns for activities such as wildlife tourism where humans closely interact with wild animals. Understanding what factors (i.e., experience and type of emotion) affect ability to recognise emotional state of nonhuman primates, based on their facial expressions, can enable us to test the validity of the universality hypothesis, as well as reduce the risk of aggression and potential injuries in wildlife tourism. METHODS: The present study investigated whether different levels of experience of Barbary macaques, Macaca sylvanus, affect the ability to correctly assess different facial expressions related to aggressive, distressed, friendly or neutral states, using an online questionnaire. Participants' level of experience was defined as either: (1) naive: never worked with nonhuman primates and never or rarely encountered live Barbary macaques; (2) exposed: shown pictures of the different Barbary macaques' facial expressions along with the description and the corresponding emotion prior to undertaking the questionnaire; (3) expert: worked with Barbary macaques for at least two months. RESULTS: Experience with Barbary macaques was associated with better performance in judging their emotional state. Simple exposure to pictures of macaques' facial expressions improved the ability of inexperienced participants to better discriminate neutral and distressed faces, and a trend was found for aggressive faces. However, these participants, even when previously exposed to pictures, had difficulties in recognising aggressive, distressed and friendly faces above chance level. DISCUSSION: These results do not support the universality hypothesis as exposed and naive participants had difficulties in correctly identifying aggressive, distressed and friendly faces. Exposure to facial expressions improved their correct recognition. In addition, the findings suggest that providing simple exposure to 2D pictures (for example, information signs explaining animals' facial signalling in zoos or animal parks) is not a sufficient educational tool to reduce tourists' misinterpretations of macaque emotion. Additional measures, such as keeping a safe distance between tourists and wild animals, as well as reinforcing learning via videos or supervised visits led by expert guides, could reduce such issues and improve both animal welfare and tourist experience. PMID- 28584732 TI - Treatment of HCV in Renal Disease: Subtle Management Considerations in the Era of Direct-acting Antivirals. AB - Chronic hepatitis C virus (HCV) infection is burdensome in patients with chronic kidney disease and contributes to substantial liver-related and all-cause morbidity and mortality. HCV infection itself may cause kidney dysfunction, as exemplified through mixed cryoglobulinemic vasculitis. HCV is more prevalent in patients with significant kidney disease compared to the general population, and recent reports have shown inadvertent HCV transmission in U.S. hemodialysis centers. Further, HCV has been demonstrated to accelerate kidney dysfunction and is associated with worse clinical outcomes in patients with kidney disease. As such, the HCV-infected population with concurrent kidney disease is an important patient subgroup that warrants focused medical care and attention. With the advent of direct-acting antivirals (DAAs), the successful treatment of HCV is now a medical reality for many patients. Nuances in regimen selection and timing need to be considered when treating those with kidney dysfunction, particularly for those considering kidney transplantation. PMID- 28584733 TI - Nosocomial infections and antibiotic resistance pattern in open-heart surgery patients at Imam Ali Hospital in Kermanshah, Iran. AB - Background: Patients undergoing open heart surgery have a relatively high risk of acquiring nosocomial infections. The development of antibiotic-resistant infections is associated with prolonged hospital stays and mortalities. Objectives: The present study was conducted to investigate nosocomial infections and the antibiotic resistance pattern in bacteria causing these infections in open heart surgery patients at Imam Ali Hospital in Kermanshah in the west of Iran over a 4-year period from March 2011 to March 2014. Materials and methods: The present cross-sectional study was conducted on 135 cases of nosocomial infection among open heart surgery patients. The demographic characteristics and the risk factors of each case of infection were recorded. The antibiotic susceptibility test was carried out using the Minimum Inhibitory Concentration (MIC) method based on the Clinical and Laboratory Standards Institute (CLSI) protocol. The data collected were then analyzed in SPSS-16. Results: Out of the 6,000 patients who underwent open heart surgery during this 4-year period at the selected hospital, nosocomial infections developed in 135 patients (2.25%), 59.3% of whom were female and 40.7% male. Surgery site infection (SSI), pneumonia (PNEU), urinary tract infection (UTI) and blood stream infection (BSI) affected 52.6%, 37%, 9.6% and 0.8% of the cases, respectively. E.coli, Klebsiella spp. and S. aureus were the most common bacteria causing the nosocomial infections. E. coli was most frequently resistant to imipenem (23.3%) Klebsiella spp. to gentamicin (38.5%) S. aureus to co-trimoxazole (54.2%). Conclusion: SSI had a high prevalence in this study. Further studies should therefore be conducted to examine the risk factors associated with SSI in open heart surgery. Various studies have shown that antibiotic resistance patterns are different in different regions. Finding a definitive treatment therefore requires an antibiogram. PMID- 28584735 TI - C-reactive Protein: A Prognostic Indicator. PMID- 28584734 TI - Teens Engaged in Collaborative Health: The Feasibility and Acceptability of an Online Skill-Building Intervention for Adolescents at Risk for Depression. AB - BACKGROUND: There is an ongoing need for effective and accessible preventive interventions for adolescent depression and substance abuse. This paper reports on a field trial of an online indicated preventive intervention, ProjectTECH, which is based on cognitive-behavioral therapy (CBT) techniques. The study aims to gather information about the feasibility and acceptability of this program. Secondary aims of this study were to examine the impact of the program on depression symptoms, perceived stress, positive affect, and substance use and to compare differences between groups that were led by a peer versus those that were led by a licensed clinician. METHODS: High school students (n = 39) were recruited primarily through social media advertisements, and assigned to four groups of 8-12 individuals to collaboratively participate in an 8 week peer network-based online preventive intervention which were led by a trained peer guide or a licensed clinician. Participants were provided with didactic lessons, CBT-based mood management tools, and peer networking features, and completed quantitative and qualitative feedback at baseline, midpoint, end of intervention, and 1 month follow up. RESULTS: The program attracted and retained users primarily from social media and was used frequently by many of the participants (system login M = 25.62, SD = 16.58). Participants rated the program as usable, and offered several suggestions for improving the program, including allowing for further personalization by the individual user, and including more prompts to engage with the social network. From baseline to end of intervention, significant decreases were observed in depressive symptoms and perceived stress (p's < .05). Significant increases in positive affect were observed from baseline to midpoint (p < .05) and no changes were observed in substance use, although the rate of substance use was low in this sample. While this study had low power to detect group differences, no consistent differences were observed between participants in a peer-led group and those in a clinician-led group. CONCLUSIONS: Results of this study indicates that ProjectTECH, an indicated preventive intervention for high school-aged adolescents, demonstrates both feasibility, acceptability, and short-term, longitudinal psychological benefits for participants. Future iterations of the program may benefit from close attention to user interface design and the continued use of trained peer support guides. PMID- 28584736 TI - Maternal Near-Miss Audit: Lessons to Be Learnt. AB - Mother and child constitute a large, vulnerable, and a priority group as the risk is involved with childbearing in women and of growth and development in children. For every woman who dies from pregnancy or childbirth-related causes, it is estimated that twenty more suffer from pregnancy-related illness or experience other severe complications. These women who nearly escape death are categorized under "near miss" which has been defined as "a woman who nearly died but survived a complication that occurred during pregnancy, childbirth or within 42 days of termination of pregnancy." Maternal near-miss audits give us an opportunity to study the cases which were almost similar to those where maternal deaths happened; thus, their review may give concrete evidence of reasons/deficiencies in health care leading to severe complications and even grave consequences as maternal deaths. Near-miss audits will allow the care of critically ill women to be analyzed, deficiencies in the provision of care to be identified, and comparison within and between institutions and, ultimately, improve the quality of obstetric care and further reduce maternal morbidity and mortality. PMID- 28584737 TI - Study of Lipid Peroxidation, Nitric Oxide End Product, and Trace Element Status in Type 2 Diabetes Mellitus with and without Complications. AB - BACKGROUND: Oxidative stress has become a real entity in etiopathogenesis of Type 2 diabetes mellitus (DM). It may result from steady flux of free radicals and lipid peroxides in vivo. Malondialdehyde (MDA) is a stable end product of lipid peroxidation. Accumulative evidences suggest that hyperglycemia in Type 2 DM can produce major changes in nitric oxide (NO) production as well as in its action. Alteration in metabolism of trace elements is also observed in DM. OBJECTIVE: To evaluate oxidative stress, status of NO, and trace elements zinc (Zn) and magnesium (Mg) in type 2 DM and to correlate these parameters with disease process. MATERIALS AND METHODS: Ninety-two cases with diabetes were included in the study, out of which 51 were type 2 DM without any complication and 41 were type 2 DM with complications. Fifty-one nondiabetic healthy controls from hospital staff were selected for the study. Blood samples were collected after an overnight fast for estimation of fasting plasma glucose, postprandial glucose, glycated hemoglobin (HbA1c), lipid profile, trace element status, MDA, and NO. RESULTS: Study revealed a rise in MDA levels in both uncomplicated and complicated cases with diabetes (2.47 +/- 0.53, 3.98 +/- 0.42 nmol/ml, respectively) as compared to controls (1.43 +/- 0.23 nmol/ml), which was statistically significant (P < 0.05). The mean levels of NO, Zn, and Mg were significantly lower in both the diabetic groups than the control group (P < 0.05). MDA showed a significant positive correlation with plasma glucose, lipid profile parameters (except high-density lipoprotein cholesterol), and significant negative correlation with Zn (r = -0.44, P < 0.05) and Mg (r = -0.31, P < 0.05). NO levels were correlated significantly with plasma glucose, dyslipidemia, and HbA1c (P < 0.05). The effects of glycemic status on trace element concentrations were evident from a significant negative correlation between Zn and Mg with fasting plasma glucose and HbA1c. CONCLUSION: Findings of the present study may establish the role of hyperglycemia, oxidative stress, impaired NO, and trace elements in pathogenesis and long-term vascular complications of type 2 DM. PMID- 28584739 TI - Profile of Lymphadenopathy: An Institutional Based Cytomorphological Study. AB - INTRODUCTION: Lymphadenopathy is one of the most common clinical presentations of patients attending the outdoor department of a hospital. Lymph node aspiration is of great value for the diagnosis of lymphadenitis, lymphomas, and metastatic carcinoma. MATERIALS AND METHODS: In this study, we have reported the pattern of cytological diagnosis on fine-needle aspiration cytology (FNAC) of lymphadenopathy cases in Jammu region of Jammu and Kashmir state of India. The mean age of all the patients in this study was 21.67 years. The most common site of lymphadenopathy was cervical region (71.79%) followed by axillary region (11.11%). RESULTS: Tubercular lymphadenitis (44.02%) was the single most common cause of lymphadenopathy followed by reactive lymphadenitis (42.64%), metastatic lesions (9.40%), and malignant lymphoma (4.70%). The sensitivity of 94.49%, positive predictive value of 96.26%, and diagnostic accuracy of 91.15% was achieved in our study. CONCLUSION: This study highlights the role of FNAC as a simple, inexpensive, relatively painless, rapid, repeatable, and reliable method of investigation for lymphadenopathy, especially in outpatient departments, peripheral hospitals, and dispensaries. PMID- 28584738 TI - Performance Characteristics of Kidney Injury Molecule-1 In Relation to Creatinine, Urea, and Microalbuminuria in the Diagnosis of Kidney Disease. AB - CONTEXT: The diagnosis and evaluation of impaired renal function remains a challenge owing to lack of reliable biomarker for assessment of kidney function. The existing panel of biomarkers currently displays several limitations, and recently kidney injury molecule-1 (KIM-1) has been suggested as a sensitive biomarker of renal function and proposed to enter clinical practice. AIMS: This study was conducted to determine the diagnostic value of serum creatinine, urea, and microalbuminuria (MAU) in relation to the novel biomarker, KIM-1. MATERIALS AND METHODS: Serum creatinine, urea, MAU, and KIM-1 were measured in forty individuals with and forty without kidney disease. Data were analyzed using multivariate methods of assessing diagnostic efficiency, test agreement, condition effects, and variability. RESULTS: The area under the receiver-operator characteristic curve revealed a diagnostic advantage of creatinine (0.924 +/- 0.0066) and urea (0.925 +/- 0.0068) over MAU (0.880 +/- 0.078) and KIM-1 (0.35 +/ 0.124). Overall diagnostic efficiency was higher for creatinine and urea (89.5% and 90.9%, respectively), followed by MAU (85.7%) and then KIM-1 (56.3%). Logistic regression analysis showed that creatinine and urea (R2 = 0.75 and R2 = 0.72, respectively, P < 0.001 for both) were better predictors of kidney disease than MAU (R2 = 0.64, P < 0.001) and KIM-1 (R2 = 0.046, P = 0.116). Further analysis of agreement showed that urea had an excellent agreement with creatinine (kappa r = 0.835, P < 0.001), with KIM-1 (kappa r = -0.198, P = 0.087) showing a poor agreement with creatinine. CONCLUSION: Our results indicate that elevated serum creatinine and urea above specific cutoff points reliably identifies patients with acute kidney injury or chronic kidney disease. However, more researches are warranted to further validate the diagnostic efficiency and application of MAU and for KIM-1 before its implementation in clinical practice. PMID- 28584740 TI - Impact of Preoperative Echocardiography on Perioperative Management in Geriatric Hip Trauma: A Retrospective Observational Study. AB - BACKGROUND AND AIM: Hip fractures are associated with a significant risk of morbidity and mortality in the elderly population. Current guidelines propose that these patients should be operated as early as possible. Preoperative cardiac investigations, especially echocardiography, have been considered to delay surgery with few changes in the patient management. The present study has been conducted to evaluate whether preoperative echocardiography improve or worsen the prognosis in such hip trauma surgery. MATERIALS AND METHODS: In this retrospective study, we reviewed the records of elderly patients with hip trauma operated in the tertiary care trauma center of our institute over a period of 1 year. Out of 120 patients, preoperative echocardiography was done in 30 patients. We compared the patients for whom echocardiography was done with the patients who did not undergo echocardiography. Descriptive statistical methods were used to analyze the results and observations. RESULTS: We observed that preoperative transthoracic echocardiography led to an escalation in cardiac medication in 53% patients when compared with 23.3% in patients who did not undergo echocardiography. No preoperative cardiac intervention was done in any patient. However, there was a delay of 2.5 days in surgery in the echocardiography group as compared to the patients of nonechocardiography group. Rate of regional anesthesia was comparable in both the groups (54% vs. 56.6%). CONCLUSIONS: In the present study, it was observed that echocardiography significantly delays surgery without a significant change in preoperative cardiac medication or anesthesia technique. This may have a potential possible adverse effect on the outcome in geriatric hip trauma which was not observed to a significant limit in the present study as the study was not a longitudinal study. For "fast tracking" of geriatric hip trauma, institutional guidelines should be developed depending on the resources available. PMID- 28584741 TI - Adverse Drug Events in Patients with Mental Disorder in an Ambulatory Setting. AB - BACKGROUND: Although adverse drug events (ADEs) among inpatients occur frequently and are widely studied, few data are available on ADEs among outpatients with mental disorders. AIMS: To determine the rates, types, and severity of ADEs in patients with mental disorder. MATERIALS AND METHODS: Cross-sectional survey of patients with mental disorder attending outpatient department. Data were collected over a period of 6 months. RESULTS: A total of 400 patients (217 schizophrenia patients, 127 bipolar affective disorder patients, and 56 patients of depression) with a mean age of 32.1 +/- 9.7(+/-standard deviation) participated in the study. Patients suffering from schizophrenia and all nonadherent patients reported significantly more ADEs (P < 0.05). Out of 343 patients (86%) who reported at least one ADE, majority (87%) reported central nervous system ADEs followed by weight gain (48%), gastro-intestinal (28%), skin (4%), cardiovascular (1%), and sexual dysfunctions (0.3%). Out of 673 ADEs reported, sedation (41%) and weight gain (25%) were reported most commonly. Most ADEs reported (76%) were mild; however, there were no life-threatening, fatal, or serious ADEs. The medication classes most frequently involved in ADEs were antipsychotics (72%) followed by sedatives (44%), antimanic drugs (32%), and antidepressants (27%). Patients on atypical antipsychotic drugs reported significantly more body weight gain (P < 0.05). More than three drugs were prescribed in 49% of patients who reported ADEs. CONCLUSION: The study data indicate high prevalence of ADEs in the outpatients on psychotropic medications. PMID- 28584742 TI - Antepartum Hemorrhage: A Retrospective Analysis from a Northern Nigerian Teaching Hospital. AB - BACKGROUND: Antepartum hemorrhage (APH) contributes significantly to maternal and perinatal morbidity and mortality globally, particularly in the developing world like ours. Prevention, early detection, and prompt management cannot be overemphasized to significantly reduce the morbidity and mortality associated with this condition. OBJECTIVES: The study is aimed at determining the prevalence, etiology, sociodemographic characteristics, and the fetomaternal outcome of pregnancies complicated by APH in Aminu Kano Teaching Hospital, Kano. MATERIALS AND METHODS: A 5 years retrospective study of all pregnancies complicated by APH at Aminu Kano Teaching Hospital, Kano, Nigeria, between January 1, 2009, and December 31, 2013, was conducted. RESULTS: A total of 224 cases of APH were recorded out of the 18,273 cases admitted for delivery during the study period, giving an institutional prevalence rate of 1.2%. Two hundred and eighteen folders were retrieved and analyzed giving a retrieval rate of 97.3%. The mean gestational age at presentation was 35.3 +/- 2 weeks and the most common causes were abruptio placenta and placenta previa constituting 68.3% and 30.0%, respectively. Sociodemographic characteristics associated with the occurrence of APH included age, booking status, parity, and socioeconomic status. The peak prevalence of APH was observed in the 35-39 year age group accounting for 33.0%. There were 123 live births and 92 stillbirths. The cesarean section rate was 53.5%. Major complications were intrauterine fetal deaths in 42.8%, postpartum hemorrhage in 24.2% of cases, and anemia necessitating blood transfusion in 61.5%. There were three maternal deaths all due to abruptio placentae during the study period giving a case specific fatality rate of 2%. CONCLUSION: The prevalence of APH in our setting is high. The major causes were abruptio placenta and placenta previa. The major fetal complication was intrauterine fetal death, and the major maternal complications were postpartum hemorrhage and anemia with consequent high blood transfusion rate. Early detection, provision of antenatal care, and emergency obstetric care services can reduce the negative effects of APH. PMID- 28584743 TI - Benign and Malignant Thyroid Gland Diseases in the Patients with Primary Hyperparathyroidism. AB - INTRODUCTION: This study aimed to evaluate concurrently detected thyroid pathologies in the patients who underwent surgery for primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: In this study, we retrospectively analyzed the files of the patients who underwent surgery for PHPT between 2012 and 2015. Pre- and post-operative laboratory examination results and preoperative radiological and nuclear medicine findings of the patients were retrospectively recorded. RESULTS: A total number of 41 patients with PHPT were divided into two groups as the Group 1 with PHPT and benign thyroid pathology (21 patients) and the Group 2 with PHPT and malignant thyroid pathology (20 patients). In Group 1, 18 and 3 of 21 patients were females and males, respectively. Group 2 included 15 male and 5 female patients. The mean age of the patients was found to be 55.6 and 53.9 years in Group 1 and Group 2, respectively. Both groups were matched for age and gender. In terms of thyroid pathology, 20 of 41 patients (48.7%) who underwent total thyroidectomy for PHPT were found to have thyroid papillary carcinoma while benign pathologic conditions were detected in 21 (51.3%) individuals. CONCLUSIONS: Cooccurrence of thyroid diseases and PHPT is common. Therefore, all the patients should preoperatively be evaluated for the presence of thyroid pathology to determine the technique of parathyroid surgery. PMID- 28584744 TI - Evaluation of Serum C-reactive Protein Levels in Subjects with Aggressive and Chronic Periodontitis in Comparison with Healthy Controls: A Clinico-biochemical Study. AB - AIM: Evaluation and comparison of serum C-reactive protein (CRP) levels in subjects with chronic and aggressive periodontitis. MATERIALS AND METHODS: Based on the periodontal status, 45 subjects were selected and divided into three groups. Group I - subjects with clinically healthy periodontium, Group II - generalized aggressive periodontitis (GAP), and Group III - chronic periodontitis (CP). Blood samples were collected from subjects for measurement of CRP. Periodontal parameters include plaque index (PI), gingival index, bleeding index (BI), probing pocket depth (PPD), and clinical attachment loss (CAL) were assessed. CRP levels were assessed by means of a commercially available high sensitivity-CRP enzyme immunoassay kit. RESULTS: CRP levels were increased in Group III (6.0671 +/- 3.15639 mg/L) and Group II subjects (4.5453 +/- 2.88116 mg/L) compared to the Group I (1.0180 +/- 0.94069 mg/L). CRP levels showed a positive correlation with all clinical parameters in Group I subjects. BI (r = 0.073), PI (r = 0.120) showed a positive correlation with CRP level in Group II and a positive correlation was also seen for PI (r = 0.492), PPD (r = 0.340), CAL (r = 0.160), and CRP level in Group III subjects. CONCLUSION: The mean CRP levels were found to be greater in CP compared to GAP subjects, but there was no statistically significant difference. PMID- 28584745 TI - Autologous Platelet-rich Plasma versus Corticosteroid in the Management of Elbow Epicondylitis: A Randomized Study. AB - INTRODUCTION: Elbow epicondylar tendinitis is a common problem for patients whose activities require strong gripping or repetitive wrist movements in the day-to day activities of life. Histologic specimens from chronic cases confirm that tendinitis is not an acute inflammatory condition but rather a failure of the normal tendon repair mechanism associated with angiofibroblastic degeneration. Tendon regeneration may be improved by injecting autologous growth factors obtained from the patient's own blood. Autologous growth factors can be injected with autologous whole blood or platelet-rich plasma (PRP). MATERIALS AND METHODS: A randomized study with 83 patients was done. The study population comprised two groups. Group A (n = 50) treated with local steroid injection and Group B (n = 33) treated with autologous PRP. Patients were allocated randomly using computer generated random number table. The base-line evaluation was done using visual analog score (VAS) and modified Mayo performance index for elbow (MAYO). Re evaluation was after 1, 2, and 6 months of the procedure. Statistical analysis was done using independent t-test. RESULTS: Six months after treatment with PRP, patient's with elbow epicondylitis had a significant improvement in their VAS (P < 0.05) and MAYO (P < 0.05) in contrast to steroid, whereas no statistical difference was found between the two groups at 1 and 2 months after intervention. CONCLUSION: Treatment of patients with epicondylitis with PRP reduces pain and significantly increases function, exceeding the effect of corticosteroid injection. PMID- 28584746 TI - Screening of Patients with Chronic Medical Disorders in the Outpatient Department for Depression Using Handheld Computers as Interface and Patient Health Questionnaire-9 as a Tool. AB - BACKGROUND AND OBJECTIVES: Depression, especially in concurrence with chronic medical disorders, is highly prevalent worldwide. An average between 9.3% and 23% of patients with one or more chronic disease have co-morbid depression. This comorbid depression has the worst health scores of all the disease states. Despite this, patients with chronic medical disorders are not commonly screened for depression. Lack of objective screening by health-care providers as well as lack of infrastructure (time/space/personnel) probably contributes to gross underdiagnosis of depression. This issue can be addressed using short objective depression screening score (Patient Health Questionnaire-9 [PHQ-9]) (validated in native languages, e.g., Hindi) and paperless self-administered interface on handheld computer (tablet), which is the objective of the study. SUBJECTS AND METHODS: One hundred consecutive patients with chronic medical disorders visiting our medicine outpatient department were screened for depression using tablets with PHQ-9 Hindi on a self-administered interface. RESULTS: The overall prevalence of depression was found to be 25% (95% confidence interval 16.6-34.8). Nearly half of the patients with depression had moderate depression (PHQ-9 score 10-14) while rest had moderately severe or very severe depression (PHQ-9 score >14). Association of depression was not found to be statistically significant with age, duration of disease, gender, the type of disease, or the number of disease. Majority of patients rated ease of the use of tablet interface (on a visual analog scale) as very easy (approx 95%). All the patients were able to complete the tablet screener without assistance, answering all of the questions. The median time of completion with interquartile range was 4 (3-5) min. Majority of the patients (63%) completed the questionnaire within 5 min while rest completed it in 5-10 min. CONCLUSIONS: It is feasible to use tablets with PHQ-9 questionnaire in native language for screening depression in chronic medical disorders. With high prevalence of comorbid depression, any comprehensive care of patients with chronic medical disorders will not be possible, unless such patients are screened and treated for depression. A self-administered screening questionnaire for depression on handheld tablets can prove to be a handy tool to achieve above aim. PMID- 28584747 TI - Expression of Human Papillomavirus DNA and p53 Polymorphisms through Polymerase Chain Reaction in Normal Mucosa and Oral Leukoplakia Individuals with Deleterious Oral Habits. AB - CONTEXT: Oral leukoplakia (OL) is a well-recognized precancerous lesion with various etiological factors. Most commonly deleterious oral habits such as tobacco smoking and viral etiologies mainly human papillomavirus (HPV) play an important role. p53 polymorphisms mostly homozygous Arginine (Arg) allele has a greater risk of degradation by HPV. Hence, HPV infection and p53 polymorphisms may act as synergistic factors for increased the risk of malignant transformation in oral precancerous lesions. AIMS: The aim of this study is to evaluate the risk of OL and its malignant transformation due to infection by HPV and p53 polymorphisms in the oral biopsy samples through polymerase chain reaction (PCR). SUBJECTS AND METHODS: A total of 40 individuals were involved- 10 individuals were controls without deleterious habits, 15 were controls with deleterious habits, and 15 were with histologically confirmed OL individuals with deleterious habits. PCR and restriction fragment length polymorphism using sma1 enzyme were carried out to evaluate the expression of HPV and p53 polymorphisms. STATISTICAL ANALYSIS USED: Chi-square test, Fischer's exact t-test, and odds ratio. RESULTS: (1) HPV DNA expression was higher in Leukoplakia individuals than controls. (2) p53 genotype with homozygous Arg was more in HPV-infected individuals. CONCLUSIONS: To conclude HPV infected OL cases were mostly with Arg/Arg type of p53 polymorphism. PMID- 28584748 TI - Papilliferous Keratoameloblastoma: A Rare Case Report. AB - Ameloblastoma is true odontogenic tumor of epithelial origin, which is described as locally aggressive with varying chances of recurrence. It is believed to derive from enamel organ, remnants of dental lamina, lining of odontogenic cysts, or basal cells of oral epithelium. Radiologically, it may present as unilocular or multilocular radiolucency commonly. Although conventional ameloblastoma presents typical histological features as described by Vickers and Gorlin, few unusual variants have been reported with different histological patterns. However, the clinical and biological behavior of these lesser known variants has not been established yet due to the scarcity of cases reported. Here, we report an extremely rare case of papilliferous ameloblastoma in a young male patient with 2-year follow-up and presenting with unusual histological presentation than conventional ameloblastoma. PMID- 28584749 TI - Accessory Flexor Carpi Ulnaris and Bilaterally Variant Vascular Anatomy of Upper Limb: An Unusual Presentation. AB - We report a rare combination of variations in the upper limb of a human cadaver. Accessory flexor carpi ulnaris with absent palmaris longus was observed in the left forearm during routine dissection of a male cadaver. Variant vascular pattern was observed bilaterally. Brachial artery bifurcated at a higher level. Ulnar artery gave rise to persistent median artery (PMA) which pierced the median nerve and accompanied it deep into flexor retinaculum to terminate as two common palmar digital arteries. Superficial palmar arch was not formed as the PMA did not anastomose with either the radial or ulnar artery. Radial artery was small and deep palmar arch was mainly contributed by the deep branch of ulnar artery. Awareness of these coexistent variations in the forearm and hand is anatomically as well as clinically important in reconstructive hand surgeries. PMID- 28584750 TI - Rupture of Noncommunicating Rudimentary Horn of Uterus. AB - Rudimentary horn pregnancy though an extremely rare condition can be associated with high morbidity. We report a case of ruptured noncommunicating rudimentary horn with unicornuate uterus. PMID- 28584751 TI - A Conjecture as to the Physiological Origins of Yawning. PMID- 28584752 TI - Body to Scalp: Evolving Trends in Body Hair Transplantation. AB - Follicular unit extraction (FUE) is becoming an increasingly popular method for hair restoration. As FUE leaves behind no linear scars, it is more suitable to harvest from various body areas including beard, chest, and extremities in hirsute individuals. Body hair characteristics such as thickness, length, and hair cycle may not completely match to that of the scalp hair. The techniques of harvesting body hairs are more time consuming, requiring higher degree of skill than regular scalp FUE. Body hair transplantation can be successfully used either alone or in combination with scalp hair in advanced grades of baldness, for improving the cosmetic appearance of hairlines and in scarring alopecia when there is paucity of donor scalp hair. Harvesting of body hairs opens up a new viable donor source for hair restoration surgeons, especially in cases of advanced Norwood grades five and above of androgenetic alopecia. PMID- 28584754 TI - Occupational Dermatoses among Cottage Industry Workers of Kashmir Valley in North India. AB - INTRODUCTION: Cottage industry is usually a small-scale industry operated from home by family members using their own equipment. Kashmir has a unique cottage industry of its own which deals with production of many handicrafts, which may lead to a peculiar pattern of skin diseases in these artisans. Aim: The aim of this study was to find out the pattern of skin disorders in the cottage industry workers of Kashmir valley, with primary focus on the occupation-related dermatoses and to identify the most common cutaneous manifestation in these workers. MATERIALS AND METHODS: This was a cross-sectional descriptive study in which 1062 cottage industry workers engaged in different crafts were screened. A detailed history taking and examination was carried out in each worker and the diagnosis was made on clinical grounds. Wherever deemed necessary, relevant investigations were done to establish the nature of the disease. RESULTS: A total of 1062 workers were evaluated for the presence of skin disorders. The male-to female ratio was 1:1.5. The mean age of the study group was 30.3 years +/- 10.79 years, with maximum number of workers (164) belonging to the crewel embroidery industry. The mean duration of work was 6.4 +/- 2.08 hours/day. A total of 953 workers (89.7%) had cutaneous manifestations, with callosities being the most common finding seen in 371 workers (35%), followed by cumulative insult dermatitis seen in 201 workers (19%). CONCLUSION: Cottage industry of Kashmir valley is a unique occupational group where a high percentage of workers had cutaneous manifestations related to their occupation, with callosities being the most common finding. Information and better knowledge regarding these dermatoses are important in devising strategies to improve the health scenario of these workers. Simple measures such as proper use of instruments, use of protective gloves, guarded use of chemicals, and hand washing may be very beneficial in reducing the burden of health problems in these workers. PMID- 28584753 TI - A Pilot Study for the Evaluation of PCR as a Diagnostic Tool in Patients with Suspected Dermatophytoses. AB - CONTEXT: The conventional diagnostic tools for dermatophytoses suffer from several limitations including low sensitivity, specificity, and long turn-around time. AIMS: The present study was, therefore, performed to evaluate the performance of a polymerase chain reaction (PCR)-based method for the diagnosis of this condition. SETTINGS AND DESIGN: The study was conducted in the Dermatology outpatient department of a tertiary care teaching hospital in central India over a period of 3 months from July to September 2015. MATERIALS AND METHODS: Forty participants, including 25 cases and 15 controls, were recruited in this observational study. Direct microscopy and fungal culture were performed from skin scrapings and nail clippings collected from the participants. PCR was also performed to amplify the chitin synthase 1 and internal transcribed spacer 2 genes from DNA samples extracted from the same clinical materials, using the method reported by Brillowska-Dabrowska et al. The diagnostic performance of fungal culture and PCR was compared using OpenEpi software. RESULTS: We observed a significant male predominance among patients with dermatophytoses. The sensitivity of fungal culture and dermatophyte PCR to diagnose dermatophytoses was 24% and 48%, respectively, whereas the specificity of the two assays was 100% and 93.3%, respectively. The likelihood ratio of a positive PCR assay was 7.2 and the negative likelihood ratio was 0.5. PCR assay also delivered a significant shortening of the time-to-diagnosis, with the mean turn-around-time being 8 hours and 14 days for PCR and culture, respectively. CONCLUSION: This study, thus, highlights the potential merits of the dermatophyte PCR assay in achieving a rapid diagnosis of dermatophytoses and underscores its utility as a complementary test to improve the sensitivity of the conventional diagnostic tools for this condition, as well as to reliably differentiate this condition from other similar skin conditions. PMID- 28584755 TI - Misuse of Topical Corticosteroids over Face: A Clinical Study. AB - INTRODUCTION: Topical corticosteroids (TCS) have been widely used in various dermatological diseases. However, because of inadvertent use, TCS misuse has become a common problem faced by dermatologists in various parts of the world. Prolonged use over the face can cause various side effects such as steroid rosacea, acneiform eruptions, and hypertrichosis. AIM: To study the effects of TCS misuse and analyze various factors promoting its use on face. MATERIALS AND METHODS: A total of 100 patients presenting with various facial dermatoses following the misuse of TCS on the face were studied. Detailed history was noted and the various side effects were recorded. RESULTS: Majority of the patients (70%) were females with maximum number of patients belonging to the age group of 11-20 years. Eighty-five percent of the patients were applying TCS for medical conditions, with acne being the most common indication, and the rest were applying as a general face cream. Pruritus and acneiform eruptions were the most common side effects observed and the other reported were erythema, photosensitivity, steroid dependent face, and telangiectasia. CONCLUSION: TCS misuse especially over the face can lead to a multitude of side effects. It is high time to create awareness among the patients as well as doctors regarding the proper usage of this wonder drug. PMID- 28584756 TI - Disseminated Cutaneous Trichosporonosis in an Adult Bone Marrow Transplant Patient. AB - The Trichosporon species are yeast-like opportunistic pathogens in immunocompromised patients. Trichosporon asahii infections have been reported in pediatric bone marrow transplant (BMT) patients. However, its incidence is low in the adult literature. A 52-year-old Chinese woman who was diagnosed with acute myeloid leukemia received induction chemotherapy and underwent allogenic bone marrow transplant, which was complicated by a relapse and required salvage chemotherapy. She developed persistent non-neutropenic fever secondary to presumed hepatosplenic candidiasis. Antifungal therapy with fluconazole and anidulafungin was administered. She remained febrile and tender dusky nodules appeared over all the four limbs. Histopathological examination and fungal culture identified T. asahii. Oral voriconazole was initiated with complete resolution of her lesions. The Trichosporon species is a frequently isolated yeast species from cancer patients. Voriconazole has become the first choice agent against Trichosporon. We highlight the increased awareness and clinical suspicion required for diagnosis and subsequent management in similar adult patients. PMID- 28584757 TI - Dermatofibrosarcoma Protuberans in a 9-Year-Old Child. AB - Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue neoplasm of low to-intermediate grade malignant potential. Childhood onset of DFSP is rare. It is most commonly seen on the trunk and proximal extremities. In children, a high index of suspicion is necessary to avoid delays in diagnosis that can lead to further morbidity. Here, we report a case of DFSP in a 9-year-old female child. Excision biopsy of lesion was performed with 1 cm margin. After confirmation of the diagnosis by histopathology, the patient was observed for recurrence, but there was no recurrence after 1 and half years of follow up. PMID- 28584758 TI - Atypical Lichen Myxedematosus: A Case with Remarkable Response to Low Dose Melphalan. AB - A 41-year-old man was referred to our outpatient department with a diagnosis of urticaria with angioedema of 3 months duration. On examination, he had generalized coalescent waxy papules and diffuse periorbital swelling. Systemic examination was unremarkable except for limited finger flexion. Serum electrophoresis and thyroid function tests were normal. Histopathological examination showed normal epidermis and intradermal mucin deposition, which was diagnostic of lichen myxedematosus (LM). The patient showed prompt response to melphalan. Here, we report this case of atypical LM because the patient had generalized eruption with normal thyroid function along with the absence of monoclonal gammopathy. PMID- 28584759 TI - Cutaneous Meningioma: A Cytomorphological Diagnosis. AB - Cutaneous meningiomas are rare tumors. These are ectopic meningothelial cells located in the dermis and subcutis, and are usually seen on the scalp. Here, we report the case of a 40-year-old woman who presented with a slowly growing asymptomatic mass over the scalp in the right parieto-occipital region. The lesion was firm, adherent to underlying structures, and covered by normal appearing skin. The cytomorphological features along with histological and immunohistochemical studies showing positivity for epithelial membrane antigen, Vimentin, and S100 helped in making a definitive diagnosis of cutaneous meningioma. No evidence of intracranial meningioma was noted in contrast-enhanced computed tomography of the brain. PMID- 28584761 TI - A Case of Peeling Skin Syndrome. AB - Peeling skin syndrome is a very rare autosomal recessive disease characterized by widespread painless peeling of the skin in superficial sheets. Etiology is still unknown with an autosomal recessive inheritance. Less than 100 cases have been reported in the medical literature. We present a 32-year-old man having asymptomatic peeling of skin since birth. Sheets of skin were peeling from his neck, trunk, and extremities, following friction or rubbing especially if pre soaked in water but sparing palm and soles. Histologically, there was epidermal separation at the level of stratum corneum, just above the stratum granulosum. This case is being presented due to its rarity. PMID- 28584760 TI - Mucocele on Lower Lip: A Case Series. AB - Mucocele is a common salivary gland disorder that can appear in the lacrimal sac, paranasal sinuses, oral cavity, appendix, or gall bladder. These lesions occur due to mucous accumulation resulting from the alteration of minor salivary glands. Lower lip is the most common site of occurrence of these lesions in the oral cavity and most probable cause is trauma or habit of lip biting. Diagnosis is mainly clinical due to its pathognomonic presentation. We report a case series of mucocele in children treated by conventional surgical excision of the lesion. PMID- 28584762 TI - Curbside (Corridor to the E-corridor) Consultations and the Dermatologists. PMID- 28584763 TI - Rapp Hodgkin Syndrome. PMID- 28584764 TI - Persistent and Generalized Purpuric Lesions in an Adolescent: A Rare Atypical Form of Pityriasis Rosea. PMID- 28584765 TI - Successful Treatment of Generalized Granuloma Annulare with Pentoxifylline. PMID- 28584766 TI - Pedunculated Hemorrhagic Cystic Swelling: An Unusual Presentation of Polydactyly. PMID- 28584767 TI - Trastuzumab-Docetaxel Combination Chemotherapy Induced Severe Onychopathy. PMID- 28584768 TI - Zinc Responsive Acrodermatitis in Nephrotic Syndrome. PMID- 28584769 TI - Sturge-Weber Syndrome with Choroidal Hemangioma. PMID- 28584770 TI - SkIndia Quiz 37: A Persistent Plaque in the Pubic Region. PMID- 28584771 TI - SkIndia Quiz 38: Subcutaneous Thumb Tumor. PMID- 28584772 TI - Kaposi's Varicelliform Eruption in Phenytoin-Induced Erythroderma. PMID- 28584773 TI - Dermatoscopy Image Characteristics and Differences among Commonly Used Standard Dermatoscopes. PMID- 28584774 TI - Nonthermal Plasma in Dentistry: An Update. AB - The recent enormous progress in understanding of plasma physics and development of plasma jet has attracted focus on the application of plasma in medicine and dentistry. Active plasma ions, electrons, and photons have the ability to activate and control various biochemical procedures. Nonthermal plasma (NTP) is widely used for various therapeutic applications in health care. Particularly in dentistry, NTP holds big potential such as for bacterial inactivation, efficient sterilization, and treatment of dental caries. This review intends to provide information on potential NTP applications in dentistry. PMID- 28584775 TI - Evaluation of Periodontal Status and Treatment Needs of Institutionalized Intellectually Disabled Individuals in Lebanon. AB - AIMS AND OBJECTIVES: No reported data is available on the periodontal health and treatment needs of the intellectually disabled in Lebanon. To evaluate the periodontal condition and treatment needs of institutionalized intellectually disabled individuals in Lebanon. MATERIALS AND METHODS: A total of 272 individuals (141 males and 131 females) aged 15 years and 35-44 years were examined. Periodontal health was recorded following the community periodontal index of treatment needs (CPITN), and treatment need was assigned accordingly. The IBM(r) SPSS(r) statistics 20.0 and Stata/SE 11.1 statistical packages were used to carry out all statistical analyses. Statistical analysis was performed using linear regression (P <= 0.05). RESULTS: Healthy periodontium was recorded in 26.1%, bleeding on probing in 27.9%, supra-/sub-gingival calculus in 31.3%, pockets of 4-5 mm in 11% and >=6 mm in 3.7%. The largest proportion of the sample was in need for oral hygiene instruction and calculus removal (42.3%). Age, geographical location, consumption of carbohydrate-rich meals and sweets between meals were significantly associated with CPITN score severity in multivariate analysis (P < 0.05). Gender, severity of disability, frequency of tooth brushing, and caretaker characteristics were not significant predictors of CPITN (P > 0.05). CONCLUSION: The predominantly poor periodontal health and social inequalities warrant nationwide preventive oral health programs in addition to planning the provision of treatment services to meet existing treatment needs. PMID- 28584776 TI - Cross-Cultural Validation of the Scale of Oral Health-Related Outcomes for 5-Year Old-Children with a Low-Income Sample from the Dominican Republic. AB - AIMS AND OBJECTIVES: To conduct a thorough psychometric assessment and validation of a Spanish-adapted version of the Scale of Oral Health-Related Outcomes for 5 Year-Old-Children (SOHO-5). MATERIALS AND METHODS: The sample consisted of 69 children aged 6 and 7 years attending a public school from a low-income community in the Dominican Republic. Outcomes consisted of SOHO-5 test scores and caries lesion severity scores, with the latter measured according to the International Caries Detection and Assessment System criteria. The IBM SPSS Statistics 20 and Mplus 7.4 programs were used for the statistical analyses. RESULTS: A confirmatory factor analysis revealed an excellent fit for the theoretical one factor structure of the SOHO-5, with all the items having high loadings on this latent factor. In addition, the SOHO-5 was able to significantly explain a large amount of variance (37%) in caries lesion severity (P < 0.001), while its scale scores had good internal consistency reliability (Cronbach's alpha [alpha] = 0.85, 95% confidence interval [CI] 0.79-0.90). Further, the SOHO-5 could identify children with moderate and extensive caries lesions (area under the receiver operating characteristic curve = 0.82, 95% CI 0.70-0.94, P < 0.001). CONCLUSIONS: The current findings highlight the good psychometric properties and criterion related validity of the Spanish-adapted SOHO-5 for young children who come from impoverished backgrounds. PMID- 28584777 TI - Dental and Skeletal Age Estimations in Lebanese Children: A Retrospective Cross sectional Study. AB - AIMS AND OBJECTIVES: Assessing dental and bone ages is frequently required in a wide range of fields such as odontology, forensic science, as well as orthopedics. The aim of this study was to evaluate applicability of two methods of bone age assessment and two methods of dental age (DA) assessment for Lebanese children. MATERIALS AND METHODS: Skeletal age (SA) of 260 orthodontic patients (124 males, 136 females divided into four groups each) was consecutively assessed using Greulich and Pyle and Fishman's SMI methods. DA was evaluated using both Demirjian's and Willem's methods. Mean age was 11.89 +/- 1.38 years for males and 11.75 +/- 1.58 years for females. Data were collected and statistically analyzed using the SPSS software (IBM SPSS Statistics, version 21, USA). The differences between estimated DA, estimated SA, and chronological age (CA) were compared by gender and age group. RESULTS: Greulich and Pyle method showed nonsignificant difference with CA in male sample, while in both assessment methods, the difference between skeletal and CAs is significant in female sample. Results of Willem's method in the whole sample suggested a statistically nonsignificant difference, when compared to CA. Demirjian's method delivered higher mean value than Willem's assessment in both genders. CONCLUSIONS: Greulich and Pyle method is accurate for SA assessment in males and only in one group of females, while it significantly overestimates age in all other female groups. Willem's method is more suitable to assess DA in both genders. A strong correlation exists between both dental and skeletal assessment methods and CA. PMID- 28584778 TI - Temporomandibular Joint Pain: Clinical Presentations and Response to Conservative Treatments in a Nigerian Tertiary Hospital. AB - AIMS AND OBJECTIVES: The aims of this study are to determine the prevalence, pattern of presentation, and response to conservative (medical) interventions among patients who presented with temporomandibular joint (TMJ) pain in a Nigerian teaching hospital. MATERIAL AND METHODS: Consecutive patients who presented in Oral Medicine and Periodontology Clinic of Obafemi Awolowo University Teaching Hospitals' Complex on account of TMJ pain from January 2015 to December 2015 were recruited for the study. They were all interviewed and examined. The severity of pain was recorded using visual analog scale (VAS). Patients were treated with medications and physiotherapy. They were reviewed at 2, 4, and 6 weeks. Those who could not make the appointment were contacted through phone. The findings were recorded and analyzed using STATA version 11. RESULTS: A total of 401 participants were seen, 55 presented on account of TMJ pain. The mean age of patients with TMJ pain was 54 +/- 16.9 with 60% being female. Pain was present in all participants; other signs include clicking joint sound (85%), jaw deviation (64%), attrition (24%), and reduced mouth opening (23%). The left joint was more frequently affected (75%). Following 6 weeks of conservative treatments, none of the respondents had VAS score of more than 3. CONCLUSION: The prevalence of TMJ pain was 13%. TMJ was found to be more common in participants above 50 years with female predilection. Pain was most common symptom seen, and response to conservative treatments as assessed using VAS following 6-week of treatment showed complete remission of the pain. PMID- 28584779 TI - Evaluation of Surface Roughness of Different Direct Resin-based Composites. AB - AIMS AND OBJECTIVE: To evaluate surface roughness of different resin-based composites. MATERIALS AND METHODS: Three resin composites, one nanohybrid, one nanoceramic, and one bulk-fill resin-based composite, were used in this study. Cylindrical Teflon mold and 8 mm in diameter and 2 mm in thickness disc specimens were prepared. For each composite material, 15 discs were fabricated, with a total of sixty discs were obtained (n = 60). A glass slide 1-2 mm thick was placed over the strip before curing with the light-curing unit to flatten the surfaces. The specimens were then cured for 40 s through the Mylar strip and the glass slide. Five specimens per each material received no finishing treatment after being cured under Mylar strips; these specimens served as a control. Ten specimens from each composite material were finished/polished with Eve discs at coarse, medium, fine, and superfine grits for 30 s (using stopwatch) each on the specimens. After polishing, the composite surfaces were assessed quantitatively by profilometry and qualitatively by scanning electron microscopy. Data were analyzed using SPSS software. RESULTS: Tetric Evo Ceram and Tetric Evo Ceram Bulk Fill specimens polished with Eve revealed slightly the same surface appearance as the Mylar strip. Eve discs scratched and exposed fillers of Ceram-x. Eve discs for Z250 surfaces exposed and scratched the filler particles but less than occurred with Ceram-x. CONCLUSION: Bulk-Fill and nanohybrid resin composites exhibit smoothest surfaces compared with nanoceramic and microhybrid resin composites after polishing. PMID- 28584780 TI - Comparison of the Effectiveness of a Mobile Phone-based Education Program in Educating Mothers as Oral Health Providers in Two Regions of Saudi Arabia. AB - AIMS AND OBJECTIVES: The penetration of mobile phone devices is widespread across the Kingdom of Saudi Arabia. Recently, there has been evidence of the success of phone-based applications in the provision of preventive oral health care to children and their parents. The aim of this study was to compare the effectiveness of a mobile phone-based application in educating mothers of children aged below 6 years of age in preventive dental care. MATERIALS AND METHODS: A mobile phone-based application (iTeetheyTM) was developed for iPhone and Android and made freely available on Google Play and App Store. The application was then distributed to 3879 mothers of children below 6 years of age (1989 in Riyadh Region and 1890 in Najran region). The mothers were subjected to a standardized knowledge attitude and practice of oral hygiene questionnaire before being asked to download the application. A total of 1055 mothers who downloaded the application completed 3-month recall process. RESULTS: Significant improvement in the knowledge of the mothers was reported after the use of the application from both regions. The mothers from Najran showed significantly greater improvement in knowledge when compared to the mothers from Riyadh region. The application was also more effective in mothers with more than one child when compared to first-time mothers. CONCLUSION: Within the limitations of this study, we can state that the mobile phone application used in this study significantly improves the knowledge of mothers toward their child's oral health. PMID- 28584782 TI - Quantification and Measurement of Changes in Anxiety Level in Preschool Children and Their Mothers through Multiple-visit Dental Treatment. AB - AIM: The aims of the present study were to quantify anxiety and find the level of anxiety in the very 1st day of dental treatment and the pattern of change in the following visits and to find possible impact of maternal anxiety during dental treatment of their wards. MATERIALS AND METHODS: The study was conducted on 297 children aged 3-6 years visiting the Department of Pedodontics and Preventive Dentistry of Dr. R. Ahmed Dental College and Hospital for treatment. In addition, accompanying parents were also included in the study. The blood pressure and heart rate of the participants were recorded at three visits with a digital blood pressure and heart rate monitor with wrist cuff (Omron; Japan). The same instrument and the same procedure were employed for the mothers also. Blood pressures and pulse rates so recorded were tabulated according to age and were made ready for statistical analysis using the SPSS version 12 (Statistical Package for Social Sciences, SPSS Inc., Chicago, Illinosis, USA) software. RESULTS: There was a significant difference in blood pressure and heart rate of children in the subsequent visits. CONCLUSION: The majority of the children suffered from anxiety on the 1st day of treatment which gradually diminished in the subsequent visits. Maternal anxiety was also highest in the initial visit which gradually came down in the subsequent visits. PMID- 28584783 TI - Association between Nutritional Status and Early Childhood Caries in Indian Children. AB - AIMS AND OBJECTIVES: To assess the body mass index (BMI) status and to correlate between nutritional status and early childhood caries among 3-6-year-old children in Vikarabad, Telangana, India. MATERIALS AND METHODS: A cross-sectional study was conducted among 350 children attending the outpatient department of Pedodontia in Sri Sai College of Dental Surgery, Vikarabad. Caries experience was recorded using dmft index (WHO 1997); various anthropometric measures, such as weight, BMI, and height, were recorded as per the standard guidelines. Pearson correlation coefficient and chi square test were used to determine significant differences. Data were analyzed using the statistical analysis software (SPSS version 17.0 Chicago IL, USA). RESULTS: Maximum number of participants (69%) were with normal BMI- for-age followed by underweight, overweight, and obese categories. The mean dmft values for each BMI category among the underweight, normal, overweight, and obese children were 4.9 +/- 4.0, 4.6 +/- 3.3, 2.7 +/- 1.9, and 4.4 +/- 3.0, respectively, which was statistically not significant. CONCLUSION: No significant association was found between dmft and BMI-for-age, rather a negative correlation existed between dmft and BMI-for-age (r = -0.023), which was not statistically significant (P = 0.66). PMID- 28584781 TI - Clinicopathological Profile and Malignant Transformation in Oral Lichen Planus: A Retrospective Study. AB - OBJECTIVES: The aim of this study was to analyze the histopathologically diagnosed cases of oral lichen planus (OLP) in terms of age, gender, clinical variant, site, hyperpigmentation, systemic illness, grade of dysplasia, and associated malignant transformation. This study also intended to do a review of reported cases of OLP with malignant transformation. MATERIALS AND METHODS: One hundred and forty-three cases of histopathologically diagnosed OLP between 2010 and 2016 were retrospectively reviewed. Demographic and clinicopathological data including malignant transformation were obtained. The data obtained were analyzed using the Statistical Package for the Social Sciences (SPSS) software for Windows version 20.0 (IBM SPSS, SPSS Inc., Chicago, IL, USA). A review of published literature on OLP with malignant transformation was also done from 1988 to 2017 and tabulated. RESULTS: OLP in this study showed a male predilection with most of the patients in the third decade. The buccal mucosa (bilateral presentation) was the most common site (79.72%), and reticular type was the most common clinical type (79.02%) followed by erosive type (20.98%). The majority (92.31%) of cases were diagnosed with OLP without dysplasia. The rest (7.69%) of dysplastic cases were predominantly seen in the buccal mucosa of 58 years and above, female patients manifesting mainly as erosive type. Two patients (1.4%) previously diagnosed clinically and histopathologically as OLP developed oral squamous cell carcinoma. CONCLUSION: The present investigation revealed the predominance of OLP among middle-aged male population and the prevalence of bilateral involvement of buccal mucosa. Two of our cases showed malignant transformation over an average period of 3.5 years. The outcome of this study emphasizes the role of clinical follow-up of patients with OLP. PMID- 28584784 TI - Could Salivary Cyclosporine Dosage Replace the Whole Blood Cyclosporine Measurements in Renal Transplant Patients? AB - BACKGROUND: Cyclosporin (CsA) has been extensively used as the immunosuppressant of choice in renal transplantation. Currently available approaches to assess CsA levels, both in serum and blood, fail to accurately reflect the concentration of the pharmacologically active drug fraction. Free CsA levels in biological fluids (blood or saliva) have been advocated to play an important role. Traditional salivary CsA monitoring tests are based on available archaic salivary techniques that are nonspecific and require large amounts of saliva. The aim of this study was to assess salivary CsA correlation using a novel and more accurate technique and to correlate with CsA levels in blood. MATERIAL AND METHODS: Patients provided blood samples of 2 ml and 2 ml of unstimulated saliva on the same day 2 h after the morning CsA dose (C2). Whole blood levels of CsA were determined using the monoclonal fluorescent polarization immunoassay (FPIA) kit. The FPIA kit was adapted to salivary testing by using a novel extraction method developed and patented under the name of Middle East Research Institute (MERI). Wilcoxon signed rank test compared the differences in blood and salivary CsA. Pearson's correlation coefficient assessed the linear association between blood and salivary CsA concentrations. All analyses were performed using IBM-SPSS version 23 (IBM Corp, Armonk, NY, USA). RESULTS: No significant correlation was observed between blood and salivary CsA levels. CONCLUSION: Salivary CsA concentrations at C2 cannot adequately replace C2 blood levels as an indicator of CsA bioavailability despite improved performance of monoclonal FPIA and application of the MERI technique. More studies may be warranted to design more reliable and less invasive procedures for therapeutic drug monitoring. PMID- 28584785 TI - Cytomorphometric Analysis on the Effects of Components of Orthodontic Appliances on the Epithelial Cells of the Buccal Mucosa. AB - AIM: The aim of the present study was to evaluate the effect of fixed orthodontic appliances on the epithelial cells of buccal mucosa in patients undergoing orthodontic treatment. MATERIALS AND METHODS: The study group included 30 healthy patients who were advised orthodontic treatment. Applying sterile cement spatula, scrapping of exfoliated buccal epithelial cells was performed from the middle part of the inner cheeks before starting the orthodontic treatment and at 1st week, 2nd week, 1 month, and 45 days after the treatment, followed by smearing and staining with Papanicolaou stain. Light microscope was used to score micronuclei, and independent two-tailed t-test was used for statistical analysis. RESULTS: Micronuclei were assessed during the various stages of treatment and were recorded accordingly. At 1 week, there was increase in micronuclei number compared to before starting the treatment (day 0) and at 15th day; 30th day showed decrease in number compared to 1 week but increase compared to day 0. The results of day 45 were almost equal to day 0 with a significant P value (P < 0.001). CONCLUSION: Fixed orthodontic appliances induce increased micronuclei frequency, especially in the first weeks of treatment, however, these genotoxic effects tend to approach baseline levels in later period. PMID- 28584786 TI - NIRF Heptamethine Cyanine Dye Nanocomplexes for Multi Modal Theranosis of Tumors. AB - Heptamethine cyanine dyes are categorized as a class of near infrared fluorescent (NIRF) dyes which have been discovered to have tumor targeting and accumulation capability. This unique feature of NIRF dye makes it a promising candidate for imaging, targeted therapy and also as a drug delivery vehicle for various types of cancers. The favored uptake of dyes only in cancer cells is facilitated by several factors which include organic anion-transporting polypeptides, high mitochondrial membrane potential and tumor hypoxia in cancer cells. Currently nanotechnology has opened possibilities for multimodal or multifunctional strategies for cancer treatment. Including heptamethine cyanine dyes in nanoparticle based delivery systems have generally improved its theranostic ability by several fold owing to the multiple functionalities and structural features of heptamethine dyes. For this reason, nanocomplexes with NIRF heptamethine cyanine dye probe are preferred over non-targeting dyes such as indo cyanine green (ICG). This review sums up current trends and progress in NIRF heptamethine cyanine dye, including dye properties, multifunctional imaging and therapeutic applications in cancer. PMID- 28584787 TI - Structure-Inherent Targeting of Near-Infrared Fluorophores for Image-Guided Surgery. AB - Although various clinical imaging modalities have been developed to visualize internal body structures and detect abnormal tissues prior to surgical procedures, most medical imaging modalities do not provide disease-specific images in real-time. Optical imaging can provide the surgeon with real-time visualization of the surgical field for intraoperative image-guided surgery. Imaging in the near-infrared (NIR) window (650-900 nm), also known as the "therapeutic window" has high potential by offering low absorbance and scattering in tissues resulting in minimized background autofluorescence. Clinically, optical fluorescence imaging with the targeted contrast agents provides opportunities for significant advances in intraoperative image-guided surgery. There are only two clinically available NIR fluorophores, indocyanine green (ICG) and methylene blue (MB), that support the image-guided surgery. However, neither of them perform in vivo by providing optimum specificity and stability for targeted image guidance. Therefore, it is of paramount importance to develop targeted NIR fluorophores for unmet clinical needs. Using the right combination of an NIR fluorescence imaging system and a targeted fluorophore, the desired target tissues can be imaged to provide real-time fluorescence guidance without changing the field-of-view during surgery. Thus, in a clinical discipline, the development of NIR fluorophores for 'structure-inherent targeting' is an unmet need for early phase diagnostics with accurate targeting. PMID- 28584788 TI - Clinical Implications of New Drugs and Regimens for the Treatment of Drug resistant Tuberculosis. AB - The emergence of drug-resistant tuberculosis (TB) is a growing problem worldwide. The lack of safe and effective drugs, together with the frequent development of adverse drug reactions can result in worse outcomes. Therefore, new TB drugs able to bolster the current TB treatment regimen are urgently required. Novel drugs that are effective and safe against Mycobacterium tuberculosis are required to reduce the number of drugs and the duration of treatment in both drug-susceptible TB and multi-drug-resistant (MDR)-TB. This review covers promising novel TB drugs and regimens that are currently under development. Bedaquiline and delamanid are the most promising novel drugs for the treatment of MDR-TB, each having a high efficacy and tolerability. However, the best regimen for achieving better outcomes and reducing adverse drug reactions remains yet to be determined, with safety concerns regarding cardiac events due to QT prolongation still to be addressed. Pretomanid is a novel drug that potentially shortens the duration of treatment in both drug-susceptible and drug-resistant TB. Many regimens consisting of injection free drugs with shorter treatment duration compared to the conventional treatment are now undergoing clinical trials. Therefore a simple and short treatment with higher efficacy, and lesser adverse drug reactions and drug-drug interaction is expected for patients with MDR-TB. PMID- 28584789 TI - Anticoagulation Therapy during Extracorporeal Membrane Oxygenator Support in Pediatric Patients. AB - Extracorporeal membrane oxygenation (ECMO) is a salvage therapy for critically ill patients. Although ECMO is becoming more common, hemorrhagic and thromboembolic complications remain the major causes of death in patients undergoing ECMO treatments. These complications commence upon blood contact with artificial surfaces of the circuit, blood pump, and oxygenator system. Therefore, anticoagulation therapy is required in most cases to prevent these problems. Anticoagulation is more complicated in pediatric patients than in adults, and the foreign surface of ECMO only increases the complexity of systemic anticoagulation. In this review, we discuss the pathophysiology of coagulation, anticoagulants, and monitoring tools in pediatric patients receiving ECMO. PMID- 28584790 TI - Ameliorative Effects of Nilotinib on CCl4 Induced Liver Fibrosis Via Attenuation of RAGE/HMGB1 Gene Expression and Oxidative Stress in Rat. AB - Nilotinib as a tyrosine kinase inhibitor has been recently used to improve the liver fibrosis process, but the exact mechanisms still require further clarification. In this study, we investigated the anti-fibrotic effects of Nilotinib via RAGE/HMGB1axis and antioxidant mechanisms. This experimental study was performed in the Hamadan University of Medical Sciences, Iran, from May 2015 to December 2016. Liver fibrosis was induced in Wistar male rats by CCL4. Rats were gavaged daily with Nilotinib (10 mg/kg). RAGE, HMGB1, TNF-alpha and TGF-beta mRNA expression were evaluated by quantitative RT-PCR. TNF-alpha protein levels were measured using the immunoassay method. Thiol groups, carbonyl groups, nitric oxide levels and glutathione peroxidase activity were measured by spectrophotometric methods.The results showed that Nilotinib decreased TNF-alpha, TGF-beta, RAGE and HMGB1 mRNA expression (p<0.001) in the liver tissues of the fibrosis group. Nilotinib also decreased carbonyl groups and nitric oxide levels and increased thiol groups and glutathione peroxidase activity in the fibrosis groups. The histopathological changes were found to be attenuated by Nilotinib. In conclusion, Nilotinib can improve liver fibrosis and open new mechanisms of the anti-fibrotic properties of Nilotinib. PMID- 28584791 TI - The Effect of Perineural Administration of Dexmedetomidine on Narcotic Consumption and Pain Intensity in Patients Undergoing Femoral Shaft Fracture Surgery; A Randomized Single-Blind Clinical Trial. AB - Dexmedetomidine is a selective alpha-2 adrenoceptor agonist with anxiolytic, sedative, and analgesic properties that prolongs analgesia and decreases opioid related side effects when used in neuraxial and perineural areas as a local anesthetics adjuvant. The current study was designed to evaluate the effects of a single perineural administration of dexmedetomidine without local anesthetics on narcotic consumption and pain intensity in patients with femoral shaft fractures undergoing surgery. This prospective randomized single-blind clinical trial was conducted in patients undergoing femoral fracture shaft surgery. Based on block permuted randomization, the patients were randomly divided into intervention and control groups. The intervention group received 100ug dexmedetomidine, for a femoral nerve block without any local anesthetics. Total intraoperative opioid consumption, postoperative opioid consumption, visual analogue score (VAS) for pain, and hemodynamic parameters were recorded and compared. Finally the data from 60 patients with a mean age of 30.4+/-12.3 were analyzed (90% male). There were no significant differences between the baseline characteristics of the two groups (p>0.05). The mean total consumption of narcotics was reduced during induction and maintenance of anesthesia in the intervention group (p<0.05). The amount of postoperative narcotics required showed a significant difference in the intervention group compared with the control group (p<0.05). It is likely that perineural administration of dexmedetomidine significantly not only reduced intra and postoperative narcotic requirement but also decreased postoperative pain intensity in patients undergoing femoral shaft surgery. Femoral blockade by dexmedetomidine can provide excellent analgesia while minimizing the side-effects of opioids. PMID- 28584792 TI - Correlation of Prognostic Factors of Invasive Lobular Carcinoma with ADC Value of DWI and SUVMax of FDG-PET. AB - Invasive lobular carcinoma (ILC) is the second most common kind of breast cancer. Diffusion weighted imaging (DWI) and positron emission tomography/computed tomography (PET/CT) are functional modalities for presenting the biological characteristics of breast cancer. The purpose of this article is to study the relationship between DWI or PET/CT and ILC's prognostic factors. The relationship between the apparent diffusion coefficient (ADC) values, standard uptake value (SUV)max and prognostic factors of ILC were statistically evaluated. The ADC values were lower in mass types of ILC. SUVmax was statistically higher in grade 3 and 4 background parenchymal enhancement and positive lymph node metastasis. ADC values of DWI and SUVmax of PET/CT can be helpful in the prediction of the prognosis of ILC. PMID- 28584794 TI - Correlations between High Platelet Reactivity, Extent of Coronary Artery Disease, and Periprocedural Myonecrosis in Patients with Acute Coronary Syndrome. AB - The purpose of the present study was to evaluate the correlations between high platelet reactivity (HPR) and the extent of coronary atherosclerosis and periprocedural myonecrosis in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). A total of 485 patients who underwent PCI for ACS was studied. HPR was defined as >=230 platelet reactivity units (PRU) in point-of-care P2Y12 tested by the VerifyNow assay. The incidence of multi-vessel disease (MVD) was higher in patients with HPR than those with no HPR (56.2% vs 45.8%, p=0.023). PRU values progressively increased with the number of diseased coronary arteries (1-vessel disease 221.8+/-86.7; 2-vessel disease 239.3+/-90.1; 3-vessel disease 243.4+/-84.5; p=0.038 by ANOVA). Multivariate analysis revealed that HPR was independently associated with MVD (Odds ratio 1.48, 95% confidence interval 1.01-2.25, p=0.048). Patients with periprocedural myonecrosis showed significantly higher PRU values compared with those without myonecrosis (258.6+/-94.5 vs. 228.5+/-85.6, p=0.013). Multivariate analysis revealed that HPR was an independent predictor for periprocedural myonecrosis as defined as any creatine kinase-myocardial band isoenzyme elevation or troponin T elevation. In conclusion, HPR is associated with MVD and periprocedural myonecrosis in patients with ACS and PCI. Thus, platelet reactivity after treatment with clopidogrel might be associated not only with blood clot formation but also with increased coronary atherosclerotic burden. PMID- 28584793 TI - Clinical Significance of p53 Protein Expression, Beta-catenin Expression and HER2 Expression for Epstein-Barr Virus-associated Gastric Cancer. AB - This study assessed the expression of the p53 protein, beta-catenin, and HER2 and their prognostic implications in patients with EBV-associated gastric cancer (EBVaGC). After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The immunohistochemistry results were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result, strong beta-catenin expression in at least 10% of cytoplasmic nuclei was interpreted as a positive result, and moderate or strong complete or basolateral membrane staining in 10% of tumor cells was interpreted as a positive result for HER2. Immunohistochemical staining for p53 was performed on tumor tissue from 105 patients, among whom 25 (23.8%) tested positive. Meanwhile, beta-catenin expression was positive in 10 patients (17.5%) and HER2 expression was positive in 8 patients (6.8%). The positive expression of p53 was significantly associated with a high T stage (p=0.006). More patients with lymph node metastasis were p53 positive (p=0.013). In the univariate analysis, the p53-positive patients showed significantly decreased disease-free survival (DFS) when compared with the p53 negative patients (p=0.022), although the p53 status was only marginally associated with overall survival (OS) (p=0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Moreover, beta catenin and HER2 showed no association with DFS and OS in the survival analysis. The current study found a significant correlation between p53 expression and tumor progression and lymph node metastases in patients with EBVaGC. PMID- 28584795 TI - Carotid Atherosclerosis and Electrocardiographic Left Ventricular Hypertrophy in the General Population: The Namwon Study. AB - This study aimed to investigate the relationship between carotid atherosclerosis and left ventricular hypertrophy on electrocardiogram (ECG-LVH) on adults living in the community. A total of 9,266 adults who participated in the Namwon Study were included in this analysis. Carotid atherosclerosis, including intima-media thickness (IMT) and plaques, were assessed using high-resolution B-mode ultrasound. ECG-LVH was determined using the Sokolow-Lyon voltage (SokV) and Cornell voltage (CorV) criteria. The prevalence of ECG-LVH was 12.7% using the SokV criteria and 9.7% using the CorV criteria. After full adjustment, compared to the lowest quartile of common carotid artery IMT (CCA-IMT), the odds ratios and 95% confidence intervals for ECG-LVH of the carotid IMT quartiles 2, 3, and 4 increased linearly as follows: 1.54 (1.24-1.90), 1.62 (1.31-2.02), and 1.91 (1.54 2.38), respectively, for the SokV criteria (p<0.001); and 1.33 (1.05-1.68), 1.41 (1.11-1.78), and 1.48 (1.16-1.88), respectively, for the CorV criteria (p=0.003). Positive associations between the carotid bulb IMT (CB-IMT) quartiles and the ECG LVH were also observed, although the magnitudes of association between CB-IMT and ECG-LVH were slightly lower than those of CCA-IMT. However, no significant association between carotid plaques and ECG-LVH as defined by the SokV or CorV criteria was found. The present study demonstrated that increased carotid IMT, but not carotid plaques, is significantly associated with LVH defined by various ECG criteria in a large population. PMID- 28584796 TI - MicroRNA-29 Family Suppresses the Invasion of HT1080 Human Fibrosarcoma Cells by Regulating Matrix Metalloproteinase 2 Expression. AB - Matrix metalloproteinase 2 (MMP2) is a potent protumorigenic, proangiogenic, and prometastatic enzyme that is overexpressed in metastatic cancer. Although there have been various studies on the MMP2 gene, further studies of regulatory factors are required to achieve inhibition of MMP2 enzyme activities. MicroRNAs (miRNAs) play key roles in tumor metastasis. However, the specific functions of miRNAs in metastasis are unclear. In this study, we assessed the function of the microRNA 29 family (miR-29s) in HT1080 human fibrosarcoma cells and examined the regulatory mechanisms of these miRNAs on MMP2 activation. Using miRanda, TargetScan, and PicTar databases, miR-29s were identified as candidate miRNAs targeting MMP2. Gain-of-function studies showed that overexpression of miR-29s could inhibit the invasion of HT1080 cells, suggesting their tumor-suppressive roles in HT1080 cells. In addition, dual luciferase reporter assays indicated that miR-29s could inhibit the expression of the luciferase gene containing the 3'-untranslated region of MMP2 mRNA. Ectopic expression of miR-29s down-regulated the expression of MMP2. Moreover, ectopic expression of miR-29s reduced MMP2 enzyme activity. These results suggested that miR-29s could decrease the invasiveness of HT1080 cells by modulating MMP2 signaling. Taken together, our results demonstrated that miR-29s may serve as therapeutic targets to control tumor metastasis. PMID- 28584797 TI - Panax Ginseng Induces Toxic Hepatitis and Acute Kidney Injury. PMID- 28584798 TI - Bile Cast Nephropathy Associated with Acute Hepatitis A. PMID- 28584799 TI - Transcatheter Occlusion of a Giant Pulmonary Arteriovenous Malformation in a 1 year-old Child Using Amplatzer Vascular Plugs and Interlocking Detachable Coils. PMID- 28584800 TI - Medical education. PMID- 28584801 TI - Infective endocarditis: a history of the development of its understanding. AB - Inflammation of the inner layer of the heart, especially the valvular endothelium, chordae tendinae and mural endocardium was first recognized almost 350 years ago. Over the years it has had many names, but is now generally designated infective endocarditis (IE) and has an associated infectious agent. A sterile vegetative process can also affect the valves and is usually referred to as Libman-Sacks endocarditis. The developments of medical science that allowed for our understanding of this entity included refinement of the autopsy, medical microscopy, microbiology, and in recent years, molecular studies. Some observations were misleading but clarification particularly followed the reports of Morgagni, Osler and Libman. As understanding of the pathobiology of infective endocarditis grew so did the effectiveness of therapy. This paper provides a detailed history of the development of the concept of Infective endocarditis citing many key morphological observations and concludes with brief comments about current concepts of pathogenesis as well as a few remarks about therapy. PMID- 28584802 TI - Infective endocarditis with left to right intracardiac fistula due to Streptococcus anginosus - a rare complication caused by an even rarer bacterium. AB - Although infective endocarditis (IE) has been described in reports dating from the Renaissance, the diagnosis still challenges and the outcome often surprises. In the course of time, diagnostic criteria have been updated and validated to reduce misdiagnosis. Some risk factors and epidemiology have shown dynamic changes since degenerative valvular disease became more predominant in developed countries, and the mean age of the affected population increased. Despite streptococci have been being well known as etiologic agents, some groups, although rare, have been increasingly reported (e.g., Streptococcus milleri.) Intracardiac complications of IE are common and have a worse prognosis, frequently requiring surgical treatment. We report a case of a middle-aged diabetic man who presented with prolonged fever, weight loss, and ultimately severe dyspnea. IE was diagnosed based on a new valvular regurgitation murmur, a positive blood culture for Streptococcus anginosus, an echocardiographic finding of an aortic valve vegetation, fever, and pulmonary thromboembolism. Despite an appropriate antibiotic regimen, the patient died. Autopsy findings showed vegetation attached to a bicuspid aortic valve with an associated septal abscess and left ventricle and aortic root fistula connecting with the pulmonary artery. A large thrombus was adherent to the pulmonary artery trunk and a pulmonary septic thromboemboli were also identified. PMID- 28584803 TI - Intracardiac metastasis of squamous cell carcinoma of the penis. AB - Penile cancer shows variable incidence in different countries with a higher prevalence in developing countries. Squamous cell carcinoma represents the most common histologic type. The seventh decade of life corresponds to the mean age at diagnosis, but it is not an unusual diagnosis among young adults. Most cases present as "in situ" neoplasia or loco regional disease; however, systemic disseminated disease occurs via lymphatic and/or hematogeneous routes. The lymph nodes, liver, and lungs are the most frequently involved sites whereas the heart constitutes an exceptional and atypical site for penile cancer metastases. We report a case of a 79-year-old patient who presented a metastatic squamous cell carcinoma of the penis with intracardiac dissemination. The patient had a past history of cardiomyopathy, which required an artificial cardiac pacemaker implantation. He had been treated 1 year before with a partial penectomy but was admitted for emasculation due to the cancer relapse. During the postoperative period, he experienced sudden respiratory distress and died. The autopsy findings showed metastatic disease into the cardiac right chambers, pulmonary tumoral thrombi, and pulmonary hilar involvement. The authors call attention to the possibility of the presence of pacing leads, cardiomyopathy and the altered low blood flow in the right chambers, as predisposing factors for the tumoral seeding in this case. PMID- 28584804 TI - Primary diffuse large B-cell lymphoma or lymphomatoid granulomatosis grade 3: a still-puzzling diagnosis in autopsy. AB - Primary lung lymphoma is a rare entity accounting for approximately 0.3% of all primary neoplasia of the lung and includes diffuse large B-cell lymphoma (DLBL) and lymphomatoid granulomatosis (LYG). Considering that clinical features may be similar, whereas epidemiology, morphology, and radiological features are different, the authors report a case of a middle-aged man who presented multiple pulmonary nodules in the lower lobes and ground-glass opacities scattered bilaterally on computed tomography. Clinically, he presented a consumptive syndrome with respiratory failure and pleurisy, which progressed until death. The autopsy findings were consistent with lymphomatoid granulomatosis (LYG) grade 3/ diffuse large B-cell lymphoma (DLBL). The authors call attention to the difficulty of establishing an accurate diagnosis, mainly when the demonstration of EBV-infected atypical B-cells fails. PMID- 28584805 TI - Primary sclerosing cholangitis associated with severe ulcerative colitis in a young man. AB - Primary sclerosing cholangitis, a chronic progressive cholestatic liver disease, is the most serious hepatobiliary complication of ulcerative colitis (UC). The authors present the case of a severe and intractable form of UC associated with primary sclerosing cholangitis, in which the diagnosis of this hepatobiliary complication was made during the postmortem examination. A 19-year-old man, with an 8-month diagnosis of UC, was non-responsive to any therapeutic approach. He presented at the emergency care unit severely ill and with cachexia, and subsequently died of septic shock. The postmortem examination confirmed the clinical diagnosis of severe UC and disclosed the presence of primary sclerosing cholangitis. Although laboratory tests have shown a typical cholestatic profile with elevated alkaline phosphatase and gamma-glutamyl transferase levels, hepatic dysfunction was related to sepsis. This report highlights how challenging the diagnosis of primary sclerosing cholangitis can be and shows the value of the postmortem examination to add important information to a medical diagnosis. PMID- 28584806 TI - Wharton's jelly absence: a possible cause of stillbirth. AB - The umbilical cord is a structure that provides vascular flow between the fetus and the placenta. It contains two arteries and one vein, which are surrounded and supported by gelatinous tissue known as Wharton's jelly. There are many umbilical cord abnormalities that are related to the prognosis of fetus survival and birth weight. The authors report a case of umbilical cord constriction due to the localized absence of Wharton's jelly, which was undiagnosed antenatally and had a fatal outcome. A review of the association between the absence of Wharton's jelly and an unfavorable pregnancy outcome was undertaken. PMID- 28584807 TI - Pyloric Brunner's gland hamartoma with atypical hyperplasia. AB - Brunner's gland hamartoma (BGH) is an extremely rare benign digestive tumor, generally located in the duodenal bulb. We report the case of a 51-year-old asymptomatic man with a large pedunculated BGH arising from the pylorus. It was successfully removed en bloc by endoscopic resection. PMID- 28584809 TI - Unusual tomographic findings of complicated necrotizing pancreatitis. AB - Acute pancreatitis (AP) is a potential life-threatening disease, which originates from inflammatory involvement of the pancreas and surrounding tissues. Serious complications eventuate and treatment is difficult. AP is classified in both interstitial edematous pancreatitis, which occurs in 70-80% of patients, and necrotizing pancreatitis, which occurs in 20-30% of patients. Diagnosis is based on the presence of two of the following criteria: abdominal pain, increased serum determination of amylase and/or lipase more than three times the reference value, and characteristic tomographic findings. Among the latter, there is the pancreatic and surrounding tissue damage as well as that related to distant organ involvement. This case report shows the fatal case of a male patient with a history of heavy alcoholic abuse admitted with the diagnosis of necrotizing pancreatitis. The authors call attention to the unusual tomographic findings; namely, a huge duodenal hematoma and a large hemoperitoneum, ischemic involvement of the spleen and kidneys, as well as pancreatic and peripancreatic necrosis. PMID- 28584808 TI - Unilateral giant renal angiomyolipoma and pulmonary lymphangioleiomyomatosis. AB - Angiomyolipomas (AMLs) are mesenchymal neoplasms, named so because of the complex tissue composition represented by variable proportions of mature adipose tissue, smooth muscle cells, and dysmorphic blood vessels. Although AMLs may rise in different sites of the body, they are mostly observed in the kidney and liver. In the case of renal AMLs, they are described in two types: isolated AMLs and AMLs associated with tuberous sclerosis (TS). While most cases of AMLs are found incidentally during imaging examinations and are asymptomatic, others may reach huge proportions causing symptoms. Pulmonary lymphangioleiomyomatosis (LAM) is a rare benign disease characterized by cystic changes in the pulmonary parenchyma and smooth muscle proliferation, leading to a mixed picture of interstitial and obstructive disease. AML and LAM constitute major features of tuberous sclerosis complex (TSC), a multisystem autosomal dominant tumor-suppressor gene complex diagnosis. The authors report the case of a young female patient who presented a huge abdominal tumor, which at computed tomography (CT) show a fat predominance. The tumor displaced the right kidney and remaining abdominal viscera to the left. Chest CT also disclosed pulmonary lesions compatible with lymphangioleiomyomatosis. Because of sudden abdominal pain accompanied by a fall in the hemoglobin level, the patient underwent an urgent laparotomy. The excised tumor was shown to be a giant renal AML with signs of bleeding in its interior. The authors call attention to the diagnosis of AML and the huge proportions that the tumor can reach, as well as for ruling out the TSC diagnosis, once it may impose genetic counseling implications.. PMID- 28584810 TI - Renal papillary necrosis. PMID- 28584811 TI - Erratum: Assessment of a 2D Electronic Portal Imaging Devices-based Dosimetry Algorithm for Pretreatment and In-vivo Midplane Dose Verification. AB - [This corrects the article on p. 171 in vol. 5, PMID: 28028511.]. PMID- 28584812 TI - Upper Eyelid Silicone Oil Migration after Sutureless 23-gauge Vitrectomy. AB - To report a case of upper eyelid swelling and ptosis caused by silicone oil migration in a patient after sutureless 23-gauge pars plana vitrectomy and silicone oil injection. A 36-year-old female was referred to eye clinic with total retinal detachment (RD) and superotemporal giant dialysis secondary to trauma in the left eye. Transconjunctival sutureless 23-gauge pars plana vitrectomy and intraocular silicone oil (1300 centistokes) injection were performed. After about 5 months, she came back with the left upper eyelid and periorbital swelling. Palpation of the eyelid revealed soft and mobile subcutaneous small lumps that were not attached to the skin. Computed tomography scan of the orbit showed an 11 mm * 8 mm soft tissue density mass in lateral aspect of the left orbit. Transcutaneously surgical exploration was performed. The patient was seen after 1 week postoperatively and there was a significant improvement of the ptosis. Eyelid swelling and ptosis caused by silicone oil migration after RD surgery are very rare and this is one of the few reports in literature. PMID- 28584814 TI - Predictors of Extracorporeal Membrane Oxygenation Support for Children with Acute Myocarditis. AB - The clinical presentation of acute myocarditis in children may range from asymptomatic to sudden cardiac arrest. This study analyzed the clinical spectrum of acute myocarditis in children to identify factors that could aid primary care physicians to predict the need for extracorporeal membrane oxygenation (ECMO) earlier and consult the pediatric cardiologist promptly. Between October 2011 and September 2016, we retrospectively analyzed 60 patients aged 18 years or younger who were admitted to our pediatric emergency department with a definite diagnosis of acute myocarditis. Data on demographics, presentation, laboratory tests, electrocardiogram and echocardiography findings, treatment modalities, complications, and long-term outcomes were obtained. During the study period, 60 patients (32 male, 28 female; mean age, 8.8 +/- 6.32 years) were diagnosed with acute myocarditis. Fever, cough, and chest pain were the most common symptoms (68.3%, 56.7%, and 53.3%, resp.). Arrhythmia and left ventricular ejection fraction (LVEF) < 60%, vomiting, weakness, and seizure were more common in the ECMO group than in the non-ECMO group, with statistical significance (P < 0.05). Female sex, vomiting, weakness, seizure, arrhythmia, and echocardiography showing LVEF < 60% may predict the need for ECMO. Initial serum troponin-I cutoff values greater than 14.21 ng/mL may also indicate the need for ECMO support for children with acute myocarditis. PMID- 28584815 TI - From Human Mesenchymal Stem Cells to Insulin-Producing Cells: Comparison between Bone Marrow- and Adipose Tissue-Derived Cells. AB - The aim of this study is to compare human bone marrow-derived mesenchymal stem cells (BM-MSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs), for their differentiation potentials to form insulin-producing cells. BM-MSCs were obtained during elective orthotopic surgery and AT-MSCs from fatty aspirates during elective cosmetics procedures. Following their expansion, cells were characterized by phenotyping, trilineage differentiation ability, and basal gene expression of pluripotency genes and for their metabolic characteristics. Cells were differentiated according to a Trichostatin-A based protocol. The differentiated cells were evaluated by immunocytochemistry staining for insulin and c-peptide. In addition the expression of relevant pancreatic endocrine genes was determined. The release of insulin and c-peptide in response to a glucose challenge was also quantitated. There were some differences in basal gene expression and metabolic characteristics. After differentiation the proportion of the resulting insulin-producing cells (IPCs), was comparable among both cell sources. Again, there were no differences neither in the levels of gene expression nor in the amounts of insulin and c-peptide release as a function of glucose challenge. The properties, availability, and abundance of AT-MSCs render them well-suited for applications in regenerative medicine. Conclusion. BM-MSCs and AT-MSCs are comparable regarding their differential potential to form IPCs. The availability and properties of AT-MSCs render them well-suited for applications in regenerative medicine. PMID- 28584813 TI - Contribution of Brain Tissue Oxidative Damage in Hypothyroidism-associated Learning and Memory Impairments. AB - The brain is a critical target organ for thyroid hormones, and modifications in memory and cognition happen with thyroid dysfunction. The exact mechanisms underlying learning and memory impairments due to hypothyroidism have not been understood yet. Therefore, this review was aimed to compress the results of previous studies which have examined the contribution of brain tissues oxidative damage in hypothyroidism-associated learning and memory impairments. PMID- 28584816 TI - The Lumbodorsal Fascia as a Potential Source of Low Back Pain: A Narrative Review. AB - The lumbodorsal fascia (LF) has been proposed to represent a possible source of idiopathic low back pain. In fact, histological studies have demonstrated the presence of nociceptive free nerve endings within the LF, which, furthermore, appear to exhibit morphological changes in patients with chronic low back pain. However, it is unclear how these characteristics relate to the aetiology of the pain. In vivo elicitation of back pain via experimental stimulation of the LF suggests that dorsal horn neurons react by increasing their excitability. Such sensitization of fascia-related dorsal horn neurons, in turn, could be related to microinjuries and/or inflammation in the LF. Despite available data point towards a significant role of the LF in low back pain, further studies are needed to better understand the involved neurophysiological dynamics. PMID- 28584817 TI - Molecular Cloning, Expression Profiling, and Marker Validation of the Chicken Myoz3 Gene. AB - Myozenin3 (Myoz3) has been reported to bind multiple Z-disc proteins and hence play a key role in signal transduction and muscle fiber type differentiation. The purpose of current study is to better understand the basic characteristics of Myoz3. Firstly, we cloned the ORF (open reading frame) of the Myoz3 gene. AA (amino acid) sequence analysis revealed that the Myoz3 gene encodes a 26 kDa protein which have 97% identities with that of turkey. Expression profiling showed that Myoz3 mRNA is mainly expressed in leg muscle and breast muscle. Furthermore, we investigated Myoz3 gene polymorphisms in two broiler breeds, the Yellow Bantam (YB) and the Avian. Five SNPs (single nucleotide polymorphisms) were identified in the YB breed and 3 were identified in the Avian breed. Genotypes and haplotype were constructed and their associations with carcass traits were analyzed. In the YB breed, c.516 C>T had a strong effect on both shank bone length and the [Formula: see text] value of breast muscle, and the H1H3 diplotype had the highest FC compared to other diplotypes. The markers identified in this study may serve as useful targets for the marker-assisted selection (MAS) of growth and meat quality traits in chickens. PMID- 28584819 TI - Comment on "Controversies about Interspinous Process Devices in the Treatment of Degenerative Lumbar Spine Diseases: Past, Present, and Future". PMID- 28584818 TI - Effects of Pirfenidone and Collagen-Polyvinylpyrrolidone on Macroscopic and Microscopic Changes, TGF-beta1 Expression, and Collagen Deposition in an Experimental Model of Tracheal Wound Healing. AB - Tracheal stenosis (TS) is a fibrosis originated by prolonged inflammation and increased transforming growth factor beta 1 (TGF-beta1) expression and collagen deposition (CD) in the tracheal wound. Several wound-healing modulators (WHMs) have been used to modulate the tracheal healing process and prevent TS, but they have failed, justifying the need to evaluate alternative WHM. The pirfenidone (PFD) and collagen-polyvinylpyrrolidone (Collagen-PVP) decrease inflammation and fibrosis. This study assessed the effect of PFD administration and Collagen-PVP topical application on macroscopic and microscopic changes, TGF-beta1 expression, and CD in an experimental model of tracheal wound healing. Forty Wistar rats underwent cervical tracheoplasty, were divided into 4 groups (n = 10), and were treated with different WHM: group I, saline solution (SS); group II, Collagen PVP; group III, mitomycin C (MMC); and group IV, 40 mg/kg PFD. Four weeks after surgery, the macroscopic and microscopic changes, in situ TGF-beta1 expression, and CD in posttracheoplasty scars were evaluated. The animals treated with Collagen-PVP and PFD developed less inflammation and fibrosis than animals in the other study groups (p < 0.05, Kruskal-Wallis) and, moreover, showed lower TGF beta1 expression and CD than animals in group I (p < 0.05, ANOVA and Tukey's test). In conclusion, PFD and Collagen-PVP decrease inflammation, fibrosis, TGFbeta-1 expression, and CD in the posttracheoplasty rats' scar. PMID- 28584821 TI - Th1/Th2 Balance and Th17/Treg-Mediated Immunity in relation to Murine Resistance to Dextran Sulfate-Induced Colitis. AB - BACKGROUND: The role of the Th17/Treg balance in the development of experimental colitis remains poorly understood. METHODS: We exploited the differential response of BALB/c mice and C57BL/6 mice towards drinking water mediated by dextran sulfate sodium (DSS) challenge. RESULTS: DSS-resistant BALB/c mice were characterized by low levels of IFN-gamma and TNF-alpha but high levels of IL-4, IL-6, IL-10, IL-17A, IL-17F, and colon lamina propria and mesenteric lymph node (MLN) CD4+CD25+FoxP3+ T cells when compared to C57BL/6 mice. Collectively, these data indicate the propensity of BALB/c mice towards a Th2/Th17/Treg-polarized immunity protecting these animals against DSS challenge, whereas Th1-polarization of C57BL/6 mice confers sensitivity to DSS-induced colitis. CONCLUSIONS: The intrinsic congenital capacity of mouse strains with respect to T cell proliferation determines sensitivity to experimental colitis. PMID- 28584822 TI - Diabetes management with a care coordinator improves glucose control in African Americans and Hispanics. AB - BACKGROUND: The purpose of this study was to evaluate diabetes control, as measured by hemoglobin A1c (HbA1c) improvements among African American and Hispanic patients receiving conventional clinical treatment combined with a bilingual diabetes educator using culturally and linguistically appropriate educational materials. This study also sought to estimate the healthcare cost savings resulting from any A1c improvements and assess the cost-effectiveness of this approach. MATERIALS AND METHODS: This was a multistage, face-to-face observational study undertaken in Texas, United States and focused on 153 African American and Hispanic patients with poor blood glucose control (baseline A1c >8.0%). For two years, a bilingual care coordinator motivated patient behavior changes that could lead to improvements in glucose control. The primary evaluation measure was change in %HbA1c, with secondary measures being change in blood pressure (BP) and low-density lipoprotein (LDL). We also sought to gauge the program's potential cost-effectiveness. RESULTS: Within the study group, A1c levels decreased over the study period from a mean of 10.0% to 8.4%. The same group saw no statistically significant improvement (reduction) in blood concentrations of LDL. The African American subgroup had a small reduction in systolic BP while changes for non-White Hispanics were not statistically significant. The average A1c reduction realized in this observational study provided estimated cost savings that are nearly twice pilot expenditures. CONCLUSIONS: Combining standard diabetes care with a bilingual educational care coordinator results in significant reductions in mean A1c (-1.6% HbA1c) in patients with poorly controlled blood glucose and African American/non-White Hispanic heritage, an intervention that also was shown to be cost-effective. This may be an effective model for improving diabetes care in provider practices. PMID- 28584823 TI - Awareness of health warnings and factors predicting awareness and perceived effectiveness of pictorial health warnings on tobacco products among adults in rural Puducherry, India. AB - BACKGROUND: Limited information exists in India about the awareness and perception of the people regarding pictorial health warnings (PHWs) and text warnings on tobacco products, more so from rural areas. Objectives were to report the awareness of these warnings, factors predicting awareness and perceived effectiveness of PHWs, and understanding of their content in a rural population. MATERIALS AND METHODS: A community-based cross-sectional study was conducted in two villages (chosen randomly out of total four) in the rural field practice area of a tertiary care teaching hospital in Puducherry. Households were selected by systematic random sampling. All persons >=18 years and residing in the area for at least 6 months were included. Data regarding awareness and perception of participants was collected through a semi-structured interview schedule. RESULTS: A total of 428 participants were recruited; 197 (46%) were male, and 231 (54%) were female. The mean age of the participants was 38.9 (standard deviation 15.0) years. Awareness of PHWs and text warnings was 39.5% (169/428) and 21% (90/428), respectively. Only 11.2% participants perceived PHWs as effective. Most (45%) of the participants had a vague understanding of the content of PHWs. On multivariate logistic regression, male gender, current tobacco use, and better education emerged as predictors of greater awareness of PHWs. Extended family predicted greater perceived effectiveness of PHWs, whereas, high socioeconomic class and middle school completion predicted lower perceived effectiveness of PHWs. CONCLUSION: Awareness and perceived effectiveness of adults in rural Puducherry regarding PHWs were low. There is a need to create awareness through education and using meaningful, larger pictures. PMID- 28584820 TI - The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling. AB - The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes. PMID- 28584824 TI - Smoking history and Alzheimer's disease risk in a community-based clinic population. AB - BACKGROUND: The relationship between cigarette smoking and development of Alzheimer's disease (AD) is not fully determined, and previous reports disagree, with some studies suggesting an increased relative risk and others a decreased odds ratio. Consequently, we wanted to determine if the prevalence of past cigarette smoking observed in a community-based clinic sample of patients with AD would be more consistent with the expected value obtained from a model using either an increased relative risk or a decreased odds ratio to estimate the effect of smoking on development of AD. MATERIALS AND METHODS: Retrospective cross-sectional analysis of all patients treated for AD in a community-based Neurology Clinic during a 2-year period. Estimates of expected past smoking prevalence were calculated based on published values for either an increased relative risk or a decreased odds ratio and compared to the past smoking prevalence observed in the clinic sample. RESULTS: The observed past smoking prevalence in the clinic population was 29.17%. The expected past smoking prevalence calculated using the increased relative risk was 30.07% (95% confidence interval [CI] = 27.67-32.32%), and using the decreased odds ratio was 12.54% (95% CI = 6.32-24.81%). CONCLUSION: The observed past smoking prevalence among the patients being treated for AD in a community-based clinic falls within the expected 95% CI for the increased relative risk model and outside of the expected 95% CI for the decreased odds ratio model. These results support the contention that the relationship between cigarette smoking and development of AD is the best characterized by an increased relative risk. PMID- 28584825 TI - Sexual function and quality of life in diabetic women referring to health care centers in Mashhad. AB - CONTEXT: Quality of life (QOL) is one of the important indexes of health and well being promotion in the diabetic patients. Based on numerous studies, these patients have a lower QOL, compared to nondiabetic individuals. In addition, a higher prevalence of sexual function disorder has been reported in their population that can have a negative effect on their QOL. AIMS: This study aimed to investigate the association between sexual function and QOL in diabetic women referring to health care centers in Mashhad during 2013-2014. SETTINGS AND DESIGNS: In this correlational study, the association between sexual function and QOL in 90 diabetic women with type two diabetes referring to health care centers in Mashhad during 2013-2014 was investigated. SUBJECTS AND METHODS: Data were collected by Rosen female sexual function index and short form-36 questionnaires. STATISTICAL ANALYSIS USED: Data were analyzed by mean comparison and Spearman correlation coefficient statistical test through SPSS 16. RESULTS: Subjects' mean sexual function score was 21.7 +/- 6.30. Based on the finding, 25.6% of the subjects suffered from sexual function disorder. Subjects' mean score of QOL was 58.75 +/- 1616.24. There was a significant association between an overall score of sexual function and its subscales, with their QOL and two dimensions of overall physical and psychological and mental health scores (P < 0.005). CONCLUSIONS: Sexual function is one of the important and associated aspects of QOL in diabetic patients. Designing and evaluation of the interventions with the goal of an improvement in this variable plays a notable role in the promotion of these patients' QOL. However, with regard to limited research in this field, further studies on this association are suggested. PMID- 28584827 TI - Effect of health education on awareness about oral cancer and oral self examination. AB - CONTEXT: Oral cancer is preceded by visible changes in the oral mucosa. These lesions can be detected by oral self-examination, but awareness about oral cancer is still low in developing countries. AIM: To evaluate the effect of health education on awareness about oral cancer and oral self-examination. SETTINGS AND DESIGN: Quasi-experimental trial was conducted in an urban resettlement colony of Chandigarh, India. MATERIALS AND METHODS: A brochure having information and pictorials on oral lesions was used for conducting health education sessions on a one-to-one basis in the household setting among 85 males in age group 15-59 years during 2013, and each participant was encouraged to perform an oral self examination. Study participants were interviewed about their awareness on oral cancer and oral self-examination before- and after-health education using a pretested interview schedule. STATISTICAL ANALYSIS: Awareness items were scored, and mean change in awareness score was computed. Paired t-test was used for testing statistical significance. RESULTS: Thirty-three percent of the study participants were current smokers, 25% consumed alcohol, and 9.4% chewed tobacco. The awareness scores after health education increased significantly from 5.3 to 6.7 (P < 0.05), and 34% of the tobacco or alcohol users expressed their intention to quit these habits, and two persons actually quit tobacco chewing. Out of the 77 study participants who performed oral self-examination, nine were able to detect lesions, and one was found to have submucous fibrosis. CONCLUSIONS: Health education intervention was able to initiate a favorable behavior change in the community. Hence, oral self-examination programs should be promoted. PMID- 28584826 TI - Determinants of physical activity in middle-aged woman in Isfahan using the health belief model. AB - INTRODUCTION: Nowadays with respect to the automation of the lifestyle, immobility statistics in middle-aged women has increased and they are at risk for complications of immobility. One of the models used to identify factors associated with physical activity is Health Belief Model utilized in different age and different cultural backgrounds and different results have been obtained from those studies. The purpose of this study was to investigate the factors affecting on physical activity in middle-aged women using Health Belief Model. MATERIALS AND METHODS: This descriptive-correlation study was conducted on 224 middle-aged women referring to health centers in Isfahan. Health Belief Model structures including perceived susceptibility and severity, perceived barriers and benefits, and self-efficacy were measured by questionnaire and physical activity was assessed using the international physical activity questionnaire. Collected data were analyzed using descriptive statistics and Pearson correlation coefficient test and regression analysis. RESULTS: There wasn't significant correlation between perceived susceptibility (P = 0.263, r = 0.075) and perceived severity with physical activity duration (P = 0.127, r = 0.058) but there was positive and weak correlation between physical activity duration with perceived benefits (P = 0.001 and r = 0.26) and perceived self-efficacy (P = 0.001, r = 0.54) and had weak and inverse correlation with perceived barriers (P = 0.001, r = -0.25). Regression analysis also showed that from among all the Health Belief Model structures just self-efficacy structure has influenced on behavior independently and other structures are affected by it. CONCLUSION: The obtained results implied on a correlation between benefits, barriers and perceived self efficacy with and moderate physical activity. Therefore it is necessary to develop appropriate educational programs with emphasis on structures of Health Belief Model that has the maximum impact on physical activity in middle-aged women. PMID- 28584829 TI - Comparing two instructional methods of role playing and lecture on primigravida females, decision about type of delivery. AB - INTRODUCTION: Each mother has the legal right to decide about her delivery, but this decision should be made based on scientific knowledge. Instructions during pregnancy help to choose the proper type of delivery. This study conducted aimed to compare two instructional methods of role playing and lecture on primigravida decision about type of delivery. SUBJECTS AND METHODS: In this single-blind clinical trial 67 primigravida, 34-36 week were selected using multi-stage sampling and assigned into two groups randomly. Decision-making (before, 2-week after, and at admission in maternity department) was tested by a questionnaire. In role-playing group, advantages and disadvantages of two type delivery were presented by role-playing in 90-min by three scenarios. In lecture group, it was also presented in a 90-min lecture. Data were analyzed by mean difference test, Fisher test, independent and paired t-test. RESULTS: Two groups showed a significant difference in terms of decision at admission to maternity department (P = 0.000). 75% of lecture group and 100% of role-playing group selected normal delivery. Postintervention knowledge score in lecture group was 18 +/- 5.3 and in role-playing group 17.1 +/- 4.0. Percent of change in knowledge scores in two groups was significant (P = 0.001). Participants' attitude, before and after the intervention, in both groups was significant (P < 0.05). Mean difference of pre- and post-test in relation to two groups' knowledge and attitude scores was not significant (P > 0.05). CONCLUSION: In this research, lecture was more effective in raising knowledge level, and role playing was more effective in raising decision to vaginal delivery and reducing elective caesarean section. It is therefore suggested to use both teaching methods altogether for pregnant women to decrease the rate of unnecessary cesarean. PMID- 28584828 TI - Measurement of the levels anxiety, self-perception of preparation and expectations for success using an objective structured clinical examination, a written examination, and a preclinical preparation test in Kerman dental students. AB - STATEMENT OF THE PROBLEM: Examinations have an important role in evaluating students' learning outcomes and their mastery of a subject. Passing or failing an examination can have far-reaching consequences for the students. Therefore, it is not surprising that international studies consistently show that dental students report examinations and grades among the highest ranking stressors in dental schools. PURPOSE: The aim of this research was to measure the levels of anxiety, self-perception of preparation and expectations for success using an objective structured clinical examination (OSCE), a written examination and a preclinical preparation test, and to examine the effects of the three predictive variables on the outcomes of assessments. MATERIALS AND METHODS: The present research is a cross-sectional study. The population under consideration was students of Kerman Dental School in 2013. Examination anxiety was measured with Spielberger's state anxiety inventory. Preparation for the assessment (I am fully prepared = 4, I am prepared = 3, I'm not prepared = 2, I'm not fully prepared = 1) and expectation to succeed (I am quite successful = 4, I am successful = 3, I'm not successful = 2, I'm not quite successful = 1) were quantified with Likert scale. The questionnaire was completed during an OSCE, a written examination, a preclinical crown and bridge preparation test and a nonexamination situation. RESULTS: The study population consisted of 138 4th, 5th, and 6th year Kerman dental students (65 males and 73 females). The results showed that all the assessment methods induced a significant increase in state anxiety compared to baseline levels with the highest anxiety levels reported during an OSCE (62.4 +/- 8.1, P = 0.04) and a written examination (48.8 +/- 9.2, P = 0.04). The preparation levels in females were significantly higher than those in males in OSCE (P = 0.03) and written (P = 0.04). CONCLUSION: State anxiety was high in all the three assessment methods. OSCE induced more anxiety than other assessment formats. However, anxiety was not predictive of performance outcomes in contrast to preparation and expectation to succeed, which were good predictors of the outcome scores. Also, this study showed that despite a better answer to the assessment of (I prepared myself well for the test), the students showed high levels of state anxiety. PMID- 28584830 TI - Digital games as an effective approach for cancer management: Opportunities and challenges. AB - OBJECTIVE: Cancer is one of the most preventable and common chronic diseases that have economic, social and psychological burden for patients, families, and the society. Cancer can be monitored by new information technology. Digital games as a uniquely powerful interaction tool support optimal care management program operation in all dimensions. The aim of this review article is to describe opportunities and challenges of this new modern technology on the delivery of cancer care services in cancer management domains for cancer care improvement. METHODS: This study was un-systematic (narrative) review article. In this research, 50 full-text papers and reports had been retrieved, studied exactly, and arranged based on study aims. We searched papers based on specific and relevant keywords in research databases including PubMed, ScienceDirect, Scopus, and Google scholar. CONCLUSION: In cancer management domain, digital games are as an effective medium for health education and intervention, disease self management training, attention distraction to relieve pain, enhance clinical outcomes, improvements in lifestyles, and physical and psychosocial activity promotion when active participation and behavior rehearsal are required for cancer patient. In spite of potential benefits of new technology, sometimes people confront various challenges such as social isolation, unusual anxiety, and disorder in physiological times of body, low physical activities, decrease academic performance, increase aggressive behavior, and physical pain. These problems can be partly overcome by proper planning, good design, and usage of suitable and continuous monitoring. PMID- 28584831 TI - The effect of bibliotherapy on the psychological capital of the staff of the School of Management and Medical Informatics of Isfahan University of Medical Science. AB - BACKGROUND: Bibliotherapy is defined as using dynamic interaction along with reading a book in order to help the people to increase their cognitive understanding. This study aims to investigate the effect of bibliotherapy on the psychological capital of the employees of the Department of Management and Medical Informatics of Isfahan University of Medical Science. MATERIALS AND METHODS: This is an applied study using a semi-empirical method. The statistical population consists of all nonfaculty employees of the target department (70 people). Twenty eight people were randomly selected and divided into experiment and control groups and answered the psychological capital questionnaire. The data gathering tool was the psychological capital questionnaire of Luthans. The experiment group underwent six 2-h sessions of bibliotherapy where the control group underwent no interference. Both groups answered the questionnaire again 1 month after the final bibliotherapy session. The information was analyzed using descriptive (average and frequency distribution) and analytical (independent t test, paired t-test, Chi-square test, and Mann-Whitney U-test) with the help of SPSS 20 software. RESULTS: The findings showed no meaningful distinction average scores of the physiological capital of both groups before interference. However, the average physiological capital score and an average score of each factor in the experiment group was meaningfully higher than that of the control group after the bibliotherapy sections. CONCLUSION: The results showed that bibliotherapy is a suitable method for increasing the psychological capital of the employees of different organizations which will in turn provide both the employees themselves and the organization with material and spiritual gains. PMID- 28584832 TI - The proportion of unmet costs considering inpatients billing of selected hospitals, after 2014 Health System reform implementation in Isfahan Province. AB - INTRODUCTION: Since 2013, in Iran's health care, the contribution of direct payments for health-care services was estimated more than 50 % of all expenditures. In May 2014, Iran's health-care reform was established to improve health services quality and reduce patients' out-of-pocket payments <10% in urban and 5% in rural areas. Therefore, the purpose of this study is to investigate unmet costs (those which are not covered either by the insurance companies nor the recent reform coverage mentioned in Sections 1.2.2 and 1.2.1, Article 6 of the Health Minister Reform Guideline) in the inpatient billings within the first 5 months from the reform implementation. METHODS: This study was conducted as a cross-sectional research in the second half of 2014 on the selected hospitals in Isfahan Province. Data were collected by investigating 97,000 inpatients' billing records issued by 28 hospitals affiliated to Isfahan University of Medical Sciences using census method. RESULTS: Findings of the study showed that the average of unmet costs paid by the inpatients constituted 21.8% of the total billing costs in 28 hospitals, and the average unmet costs paid by each patient was 1,903,832 Rials. CONCLUSION: Considering the definition of unmet cost in the context of health-care reform guideline and hospitals' problems in providing some costly services, drugs, and medical equipment (that were not covered by insurance organizations and the reform scheme) within the obligations of the reform, it is necessary to review these obligations and further interact with insurance companies about expanding the coverage to some costly services required by the patients. PMID- 28584833 TI - Empowerment in breastfeeding as viewed by women: A qualitative study. AB - BACKGROUND: The positive effect of breastfeeding on health is globally accepted. However, breastfeeding has not yet practiced at a favorite level. Empowerment of mothers is an important factor for continuing breastfeeding. This study was conducted to explore women's perception of empowerment in breastfeeding. METHODS: The present qualitative study was conducted in conventional content analysis method. Thirty-four semi-structured deep interviews were conducted with 18 mothers, four key family members, and 12 other personnel involved in breastfeeding counseling services. RESULTS: Analysis of participants' descriptions led to the emergence of five main categories: Enough knowledge and skill for breastfeeding, feeling adequacy in breastfeeding, overcoming breastfeeding problems, informed belief in the value of breastfeeding, and perceiving comprehensive support for breastfeeding. CONCLUSION: In participants' point of view, empowerment in breastfeeding can be formed through an acquisition of "Enough knowledge and skill for breastfeeding" as well as assurance about the proper quality and quantity of mother's milk. As well as overcoming breastfeeding problems will lead to stabilization empowerment in breastfeeding. In addition, data analysis showed that informed belief in the value of breastfeeding strengthens the empowerment in breastfeeding and presence of perceived comprehensive support for breastfeeding facilitates empowerment in breastfeeding continuance. Thus, comprehensive plans should be designing for promoting breastfeeding. PMID- 28584834 TI - Effectiveness of a program on evidence-based dentistry in dental students. AB - INTRODUCTION: Evidence-based dentistry (EBD) is an approach to oral healthcare by combining the best scientific evidence and clinical diagnostics, clinical expertise of the dentist, and the patient's treatment needs and preferences. The aim of the present study is to evaluate the effectiveness of an education program on EBD offered in a community-dentistry course in improving knowledge and attitudes of students in this regard. STUDY METHODS: By a quasi-experimental study design, 64 senior dental students of Islamic Azad University of Khorasgan recruited in a controlled trial. All of the students were randomized as intervention (32) and control (32) groups. A course-based educational program on EBD was randomly assigned to one group. Actual knowledge, self-assessed knowledge, and attitudes, before and after education, were measured in both groups. A questionnaire consisted of 40 items developed by the researcher was used after confirming its validity and reliability. The difference between mean scores at two timelines were measured and compared in three fields by paired t test and independent t-test analysis via SPSS version 20 software. RESULTS: While the mean scores of actual and self-assessed knowledge and attitude were not significantly different between two groups at the beginning of the program (P > 0.05), the mean scores of all fields in the intervention group were significantly more than those of the control group after education (P < 0.001). The effect size of intervention was 86%, 62%, and 57% in three fields, respectively. There was not a significant difference between mean scores of three fields in the control group, after the intervention. CONCLUSION: Due to the poor knowledge and attitudes of students and improved knowledge and attitudes of the intervention group after education, the education program seems to be effective. Durability of educational impact and evaluating evidence-based performance can be studied in the future. PMID- 28584835 TI - Knowledge, attitude, and practice of urban Gujarati type 2 diabetics: Prevalence and impact on disease control. AB - CONTEXT: Type 2 diabetes is the modern epidemic wherein patient care needs multiple approaches, education, and self-awareness being one of them. There are some knowledge, attitude, and practice (KAP) studies from India but very few relating it with disease control. AIMS: We tried to study KAP of treated type 2 diabetics and its correlation with glycemic control. SETTINGS AND DESIGN: Cross sectional KAP study. SUBJECTS AND METHODS: We formulated KAP questionnaires in the form of KAP - 10 points for each and total 30. We recruited 200 type 2 diabetics (96 males, 104 females) treated by MD physicians with known current glycemic status. They were asked KAP questionnaires one to one by a direct interview in local language and results were associated with various factors and glycemic control. RESULTS: KAP score on was average 19 out of 30 in type 2 diabetics having mean age 58 years, mean duration 9 years. KAP score was unaffected by gender, occupation, duration of disease but significantly affected by current age, and education level. Only 40% patients had good glycemic control who scored better KAP than poor glycemic. There was positive correlation between KAP score and glycemic control, with significance for only glycosylated hemoglobin and not fasting blood sugar, postprandial blood sugar. CONCLUSIONS: Physician treated type 2 diabetics of our region had moderate KAP score, affected by age, education which suggested to affect glycemic control. Lacunae in knowledge regarding incurability of disease, attitudes toward complication, self care, and good practices like walking, enriching knowledge need improvement so as an optimum glycemic control. PMID- 28584836 TI - Effect of green tea on metabolic and hormonal aspect of polycystic ovarian syndrome in overweight and obese women suffering from polycystic ovarian syndrome: A clinical trial. AB - BACKGROUND AND OBJECTIVE: Polycystic ovarian syndrome (PCOS) is the common cause of Oligo-ovulation. This syndrome causes long-term metabolic issues as well as increase the risk of diabetes type 2, hypertension, dyslipidemia, and cardiovascular disease. The current research aimed to study the effect of green tea on weight and hormonal changes of women suffering from PCOS. METHODS: This two group, double-blind, randomized clinical trial was conducted in Isfahan city. Overweight women suffering from PCOS (n = 60) were randomly divided into two groups. Green tea was prescribed to the experimental group, and placebo was prescribed to the control group. Free testosterone hormones and fasting insulin were compared in both groups at the beginning and 12 weeks after the study commencement. The weight of participants of both groups was also measured before and after the study. The statistical data were analyzed by SPSS software and paired t-test. RESULTS: The paired t-test showed that there was no significant difference in the mean weight of both groups before the intervention (P = 0.812), but the difference was significant after the intervention (P = 0.031). There was no significant difference in the mean fasting insulin of both groups before the intervention (P = 0.352), but the difference was significant after the intervention (P < 0.0001). Moreover, there was no significant difference in the mean free testosterone level of both groups before the intervention (P = 0.638), but the difference was significant after the intervention (P < 0.0001). CONCLUSION: The consumption of green tea by overweight and obese women suffering from PCOS leads to weight loss, a decrease in fasting insulin, and a decrease in the level of free testosterone. PMID- 28584837 TI - Hospital managers' attitude and commitment toward electronic medical records system in Isfahan hospitals 2014. AB - INTRODUCTION: Electronic medical record system (EMRS) is a valuable system for safe access to the patient's data and increases health care quality. Manpower is one of the requirements for EMRS, among which manager is the most important person in any hospital. Taking into account manager's positive attitude and good commitments, EMRS will be implemented successfully. As such, we decided to assess manager's attitude and commitment toward EMRS in Isfahan hospitals in the year of 2014. AIM: This article aimed to determine the hospital managers' attitude and commitment toward the implementation of EMRS. MATERIALS AND METHODS: The present article is an applied analytic study. Research society consisted of the managers of all the hospitals in Isfahan that include hospitals affiliated to Isfahan University of Medical Sciences, private, and social security hospitals. This study was done in 2014. Data collection tools included a questionnaire for which reliability and validity were determined. Data were analyzed by means of SPSS 20. RESULTS: Average score for the managers' attitude toward EMRS in the city of Isfahan was 77.5 out of 100 and their average score for commitment was 74.7. Manager's attitude in social security hospitals was more positive than the private and governmental ones (83.3%). In addition, the amount of commitment by the managers in social security hospitals was higher than the same in private and governmental hospitals (86.6%). CONCLUSION: At present, managers' attitude and commitment in Isfahan hospitals toward EMRS are very high and social security hospitals show more readiness in this respect. PMID- 28584838 TI - Evaluating combined effect of noise and heat on blood pressure changes among males in climatic chamber. AB - INTRODUCTION: Exposure to noise and heat causes individuals to experience some changes in the function of cardiovascular system in workplaces. This study aimed to find the combined effect of heat and noise on systolic and diastolic types of blood pressure in experimentally controlled conditions. METHODS: This quasi experimental study was performed with 12 male students in a climatic chamber in 2014. Blood pressure including systolic and diastolic was measured in the following conditions: 15 min after rest in exposure to heat (40 degrees C, relative humidity [RH]: 30%), exposure to noise with 75, 85, and 95 dB rates in thermal comfort condition (22.1 +/- 0.9 wet-bulb globe temperature), and combined exposure to heat (40 degrees C, RH: 30%) and noise with 75, 85, and 95 dB. Friedman test was used to analyze the data. RESULTS: The mean change of systolic blood pressure was different significantly before and after exposure to heat and noise levels including 75, 85, and 95 dB (P = 0.015, P = 0.001, P > 0.001, P = 0.027, respectively). Although systolic and diastolic blood pressures changed drastically, it was not significantly different in simultaneous exposure to heat and noise. CONCLUSION: Both systolic and diastolic blood pressures decreased in exposure to heat, while exposure to different levels of noise elevates systolic and diastolic blood pressures. However, when exposed to a combination of heat and noise, subtle changes of blood pressure were traced, which can be characterized as average, considering heat-only and noise-only tension situations. PMID- 28584839 TI - A randomized trial to promote physical activity during pregnancy based on health belief model. AB - BACKGROUND: The positive effects of physical activities during pregnancy are totally recognized but due to lack of knowledge and negative aspect toward it, physical activities decrease throughout the pregnancy period. To find the appropriate model to enhance physical activity during pregnancy, the education that are focused on health belief constructs about physical activity during pregnancy, were assessed. MATERIALS AND METHODS: This was a semi-experimental study conducted on 90 pregnant women in their first trimester that were divided into two groups of control and intervention. After assessing health belief model (HBM) constructs and measuring the duration of severe/moderate-intensity) physical activity through a questionnaire, participants were divided into two groups of 45. The intervention group received education about physical activity based on HBM and the control group received dental health education. In the second trimester again, the constructs of HBM and the duration of physical activities were evaluated. Significant level was set at P < 0.05. RESULTS: Data analysis showed that level of perceived susceptibility/severity and perceived benefits and also the level of appealing physical activity (P < 0.05), had a significant increase in the intervention group after the education, but the mean of the severe/moderate-intensity physical activity with did not rise to 150 min/week. CONCLUSION: Study results showed that education based on HBM could lead to an increase in physical activity during pregnancy by increasing the level of health beliefs in pregnant women, but this increase does not reach the adequate level. PMID- 28584840 TI - Reported influences of backpack loads on postural deviation among school children: A systematic review. AB - BACKGROUND: Nowadays, a large number of students experience spinal pain quite early in life due to heavy school bag loads. Moreover, external forces in the form of school bags may influence the normal growth, development of children and adolescents, and also maintenance of alignment of their bodies, which can pose a huge threat to postural integrity under external load. Awareness about the appropriate load and placement of backpack is thought to be important in reducing musculoskeletal complications among children's. METHODS: A systematic review of randomized controlled trials (RCTs) was conducted to determine the influence of postural deviations due to backpack load among school children's. Electronic databases were searched, and a reference list of retrieved articles were relevant to postural changes among school children with the backpack were screened. Reviewers graded the papers according to Lloyd-Smith's hierarchy of evidence scale. Papers were quality appraised using a modified Crombie tool. RESULTS: Twelve papers were identified for inclusion in this review. Methodological difference limited our ability to collate evidence. CONCLUSION: Most of the articles recommended that backpack load limit for school children should be 10 15% of body weight. However, the appropriate load limit for school children is limited due to lack of articles, the low hierarchy of evidence, and small sample size. This review constrains the use of published literature to inform good load limit of school pack among the school children. PMID- 28584842 TI - Diffuse Large B-Cell Lymphoma with Secondary Hemophagocytic Lymphohistiocytosis Presenting as Acute Liver Failure. AB - Hemophagocytic lymphohistiocytosis (HLH) and newly diagnosed malignant infiltration of liver are rare presentations of acute liver failure associated with poor prognosis. We report a case of a patient with acute liver failure caused by malignant infiltration by diffuse large B-cell lymphoma and secondary HLH. PMID- 28584843 TI - Ruptured Dissecting Intramural Duodenal Hematoma Following Endoscopic Retrograde Cholangiopancreatography. AB - A 34-year-old woman with schizophrenia developed abdominal pain. Ultrasound demonstrated cholelithiasis and a dilated biliary tree. The patient underwent endoscopic retrograde cholangiopancreatography (ERCP), sphincterotomy, and extraction of gallstones from the common bile duct. She developed post-procedure fever, tachycardia, and abdominal pain and was taken to the operating room for urgent cholecystectomy with intraoperative cholangiogram. At laparotomy, an intramural dissecting duodenal hematoma was discovered, which extended the length of the duodenum and ruptured. She underwent gastric pyloric exclusion, gastrojejunostomy, and healed uneventfully. ERCP is not without risks, and a degree of vigilance should be maintained in patients who develop new symptomatology following the procedure. PMID- 28584841 TI - Assessment of Iranian orthodontists' practice with regard to the prevention and treatment of white spot lesions. AB - INTRODUCTION: White spot lesions (WSLs) are common adverse effect of orthodontic treatment, which can be prevented and treated by orthodontists. This study was conducted to assess Iranian orthodontists' practice regarding the prevention and treatment of WSLs in their patients. METHODS: In this cross-sectional study, 109 Iranian orthodontists were selected from the Iranian Association of Orthodontists' directory by cluster sampling. For data collection, a questionnaire was designed and its validity and reliability was confirmed (Cronbach's alpha =0.85). The questionnaire included eight general questions and eight questions about practice with regard to the prevention and treatment of WSL. Data were analyzed by descriptive tests, ANOVA test, and t-test in SPSS 20 software. P < 0.05 was considered statistically significant. RESULTS: The mean score of orthodontists' practice was 7.62 (range: 0-8), and 94.4% of the participants were rated as good, while 3.7% and 1.9% were rated as moderate and weak, respectively. Women's score was significantly higher than that of men (P = 0.001). With increasing participants' age, their practice has been improved (P = 0.001), but there was no significant relation between years of experience and their practice (P = 0.230). Nearly 94.4% of the orthodontists prescribed fluoride products. Toothpastes and fluoride mouth rinses were the most common prescribed products (34%). CONCLUSIONS: With regard to Iranian orthodontists' practice, it was fortunate to note that majority of the respondents were taking care of their patients with regarding to the prevention and treatment of WSLs. For enhancing their competencies, it is recommended to plan educational courses which are useful for promoting their knowledge and practice about new products and procedures used for the prevention and treatment of WSLs. PMID- 28584844 TI - Castleman Disease Presenting as an Abdominal Mass. AB - Unicentric Castleman disease is a rare condition of lymphoid hyperplasia, of which only 15% of cases occur in the abdomen. We report a 66-year-old man who presented with complaints of abdominal pain. Computed tomography scans revealed nephrolithiasis and a homogeneous calcified mass between the pancreas and stomach and several para-pancreatic nodes. Direct visualization during exploratory laparotomy revealed a mass on the lesser curvature of the stomach. Pyloromyotomy and mass resection were performed. Biopsy showed reactive lymphoid hyperplasia consistent with the hyaline vascular variant of Castleman disease. PMID- 28584845 TI - Shoulder Mass as the Initial Presentation of Metastatic Hepatocellular Carcinoma. PMID- 28584846 TI - Rare Esophageal Migration of AXIOS Stent Used for Walled-off Pancreatic Necrosis Drainage. AB - The AXIOS stent (Boston Scientific, Marlborough, MA) is a novel lumen-apposing self-expandable metallic stent designed for enteric drainage of nonadherent lumens. Efficacy and safety of using the AXIOS stent for pancreatic fluid drainage have been consistently shown in several studies. Although it is less common with this novel stent, stent migration still may happen. We present a case of AXIOS stent migration into the esophagus. PMID- 28584847 TI - Acute Appendicitis Caused by an Echinococcal Brood Capsule Unmasks an Asymptomatic Hepatic Hydatid Cyst. AB - Hydatidosis is an endemic helminthic disease in the cattle-grazing regions of Asia. It is usually caused by the cestode Echinococcus granulosus. Internal organs, particularly the liver and lungs, are predominantly affected, but the appendix is only rarely involved with the formation of characteristic hydatid cyst. We present a unique case of appendiceal hydatidosis in an 18-year-old woman with acute appendicitis. Her preoperative abdominal ultrasound revealed an asymptomatic hydatid cyst in the liver. An echinococcal brood capsule was detected postoperatively within the appendicular lumen under microscope. PMID- 28584848 TI - Acute Shunt Failure Due to Perforation of Ventriculoperitoneal Shunt Tubing during Percutaneous Gastrostomy. AB - The placement of a percutaneous endoscopic gastrostomy (PEG) in a patient with a pre-existing ventriculoperitoneal shunt is generally regarded as safe. A critical but often overlooked technical consideration is confirmation of the course of the distal shunt tube prior to PEG insertion. We present the case of a 4-month-old male infant with shunted hydrocephalus who experienced shunt malfunction due to perforation of the distal shunt tubing after PEG placement. PMID- 28584849 TI - Carbapenem-Resistant Enterobacteriaceae Infections: Results From a Retrospective Series and Implications for the Design of Prospective Clinical Trials. AB - BACKGROUND: The increasing incidence of multidrug-resistant Gram negatives, such as carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a critical need for new antimicrobials. Most studies of new antimicrobials have been performed in patients with nondrug-resistant pathogens. We performed a retrospective analysis of patients with CRE infections to inform the design of phase 3 clinical trials. METHODS: This was a retrospective study at 22 centers in 4 countries. Baseline data, treatment, and outcomes were collected in patients with complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), ventilator-associated bacterial pneumonia (VABP), and bacteremia due to CRE. RESULTS: Two hundred fifty-six cases of CRE infection were identified: 75 cUTI/AP, 21 HABP, 20 VABP, and 140 bacteremia. The patient population had significant comorbidities: 32.8% had chronic renal insufficiency, and 26.2% were immunocompromised. Illness severity at presentation was high: 29.3% presented with septic shock. Treatment regimens varied widely; however, a majority of patients received combination therapy. Outcomes were universally poor (28-day mortality was 28.1%) across all sites of infection, particularly in dialysis patients and those with sepsis. CONCLUSIONS: The CRE infections occured in patients with substantial comorbidities and were associated with high mortality and low rates of clinical cure with available antibiotics. Patients with these comorbidities are often excluded from enrollment in clinical trials for registration of new drugs. These results led to changes in the inclusion/exclusion criteria of a phase 3 trial to better represent the patient population with CRE infections and enable enrollment. Observational studies may become increasingly important to guide clinical trial design, inform on the existing standard of care, and provide an external control for subsequent trials. PMID- 28584850 TI - A Subset of Extreme Human Immunodeficiency Virus (HIV) Controllers Is Characterized by a Small HIV Blood Reservoir and a Weak T-Cell Activation Level. AB - BACKGROUND: Human immunodeficiency virus controllers (HICs) form a heterogeneous group of patients with regard to formal definitions, immunologic characteristics, and changes over time in viral load. PATIENTS AND METHODS: The HICs with undetectable viral load ([uHICs] ie, for whom a viral load had never been detected with routine assays; n = 52) were compared with 178 HICs with blips during the follow up (bHICs). Clinical characteristics, ultrasensitive HIV ribonucleic acid (RNA) and HIV-deoxyribonucleic acid (DNA) loads, HIV1-Western blot profiles, and immune parameters were analyzed. RESULTS: Relative to bHICs, uHICs had significantly lower ultrasensitive plasma HIV-RNA loads (P < .0001) and HIV-DNA levels in peripheral blood mononuclear cells (P = .0004), higher CD4+ T cell count (P = .04) at enrollment, and lower T-cell activation levels. Between diagnosis and inclusion in the cohort, the CD4+ T-cell count had not changed in uHICs but had significantly decreased in bHICs. Twenty-one percent of the uHICs lacked specific anti-HIV immunoglobulin G antibodies, and these individuals also had very low levels of HIV-DNA. Half of the uHICs had a protective human leukocyte antigen (HLA) allele (-B57/58/B27), a weak CD8+ T-cell response, and very small HIV-DNA reservoir. CONCLUSIONS: We suggest that an interesting HIC phenotype combines protective HLA alleles, low level of HIV blood reservoirs, and reduced immune activation. Prospective studies aimed at evaluating the benefit of combined antiretroviral therapy in HICs might take into account the identification of uHICs and bHICs. PMID- 28584851 TI - Successful Pre- and Posttransplant Sofosbuvir-Based Anti-Hepatitis C Virus Treatment in Persons Living With Human Immunodeficiency Virus Infection. AB - This retrospective study reports the data of sofosbuvir-based anti-hepatitis C virus treatment in 24 candidates and 24 recipients of liver transplantation coinfected with human immunodeficiency virus. Sustained virologic response was cumulatively 85% (90% and 100% in those treated with optimal schedules pre- and posttransplant, respectively). PMID- 28584852 TI - Immunological Predictors of Nonresponse to Directly Acting Antiviral Therapy in Patients With Chronic Hepatitis C and Decompensated Cirrhosis. AB - BACKGROUND: Sustained virological response rates (SVRs) to directly acting antiviral (DAA) therapy for hepatitis C virus (HCV) are lower in decompensated cirrhosis. Markers of innate immunity predict nonresponse to interferon-based HCV treatment; however, whether they are associated with the response to DAAs in patients with decompensation is not known. METHODS: Information on demographics, adherence, viral kinetics, and resistance were gathered prospectively from a cohort with decompensated cirrhosis treated with 12 weeks of DAAs. C-X-C motif chemokine-10 (CXCL-10) level and T-cell and natural killer (NK) cell phenotype were analyzed pretreatment and at 4 and 12 weeks of treatment. RESULTS: Of 32 patients, 24 of 32 (75%) achieved SVR (responders). Eight of 32 (25%) experienced relapse after the end of treatment (nonresponders). There were no differences in demographics or adherence between groups. Nonresponders had higher CXCL-10; 320 pg/mL (179461) vs 109 pg/mL (88170) in responders (P < .001) and differential CXCL-10 dynamics. Nonresponders had lower NK cell frequency, higher expression of activation receptor NKp30, and lower frequency of the NK subset CD56-CD16+. CONCLUSIONS: Nonresponders to DAAs displayed a different NK phenotype and CXCL-10 profile to responders. Nonresponders did not have poorer adherence or baseline virological resistance, and this shows that immunological parameters are associated with treatment response to interferon-free treatment for HCV in individuals with decompensated cirrhosis. PMID- 28584854 TI - Lysinibacillus massiliensis Panniculitis Masquerading as Erythema Nodosum: A Case Report. AB - Lysinibacillus massiliensis, formerly Bacillus massiliensis, is an environmental Gram-positive bacillus that is generally non-pathogenic. Rare case reports in immunosuppressed patients have described sepsis with this organism. In this study, we report a case of L massiliensis as a cause of infectious panniculitis mimicking erythema nodosum after infusion of autologous adipose-derived stem cells in an immunosuppressed patient with refractory Crohn's disease. This case highlights the importance of care providers to consider exposures and host factors when interpreting culture results with otherwise benign organisms. PMID- 28584853 TI - The Presence of Human Immunodeficiency Virus-Associated Neurocognitive Disorders Is Associated With a Lower Adherence to Combined Antiretroviral Treatment. AB - BACKGROUND: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are defined according to their diagnostic degrees as follows: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV associated dementia. Because high adherence to combined antiretroviral therapy (cART) is required to maintain viral suppression among HIV-infected patients, it is important to investigate the impact of HAND on medication adherence. Our study hypothesis was that patients with HAND had a lower medication adherence than patients who did not have HAND. METHODS: This was an observational, exploratory, 2-center pilot study of patients who had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015 while also being followed at their respective adherence clinics. Adherence was measured with electronic monitors. Patients' sociodemographic characteristics, HIV viral load, and CD4 counts were retrieved from the Swiss HIV Cohort Study database. At each time t, adherence was computed as the proportion of patients taking medication as prescribed at that time. RESULTS: We included 59 patients, with a median (Q1, Q3) age of 53 years (47-58) and 39 (66%) were male participants. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit (implementation stayed 90% during follow-up). CONCLUSIONS: Our findings support the hypothesis that HAND is associated with reduced cART adherence. PMID- 28584856 TI - Impact of an Electronic Medical Record-Based System to Promote Human Immunodeficiency Virus/Hepatitis C Virus Screening in Public Hospital Primary Care Clinics. AB - BACKGROUND: United States guidelines recommend that all adolescents and adults be tested for human immunodeficiency virus (HIV) and that persons born between 1945 and 1965 be tested for hepatitis C virus (HCV). METHODS: We used electronic medical record (EMR) data to identify patients in 3 primary care clinics in Seattle, Washington who met national criteria for routine HCV or HIV testing and had no documented history of prior testing. Clinic staff received daily lists of untested patients with scheduled appointments. We used generalized linear models to compare the percentage of patients tested and newly diagnosed with HIV and HCV in the 18 months before and during the intervention. RESULTS: A total of 16784 patients aged 18-64 and 9370 patients born between 1945 and 1965 received care from January 2011 to December 2015. Comparing the preintervention and intervention periods, the percentage of previously untested patients tested for HIV and HCV increased from 14.9% to 30.8% and from 18.0% to 35.5%, respectively (P < .0001 for both). Despite this increase in testing, there was no change in the percentage of patients newly diagnosed with HIV (0.7% in both periods, P = .96) or HCV (3.6% vs 3.7%, P = .81). We estimate that 1.2%-15% of HCV-infected primary care patients in our medical center are undiagnosed. CONCLUSIONS: EMR based HCV/HIV testing promotion increased testing but not case finding among primary care patients in our medical center. In our institution, most HCV infected patients are already diagnosed, primarily through risk-based and clinical screening, highlighting the need to concentrate future efforts on increasing HCV treatment. PMID- 28584855 TI - Febrile Rhinovirus Illness During Pregnancy Is Associated With Low Birth Weight in Nepal. AB - BACKGROUND: Adverse birth outcomes, including low birth weight (LBW), defined as <2500 grams, small-for-gestational-age (SGA), and prematurity, contribute to 60% 80% of infant mortality worldwide and may be related to infections during pregnancy. The aim of this study was to assess whether febrile human rhinovirus (HRV) illness is associated with adverse birth outcomes. METHODS: Active household-based weekly surveillance was performed for respiratory illness episodes in pregnant women as part of a community-based, prospective, randomized trial of maternal influenza immunization in rural Nepal. Rhinovirus (HRV) febrile illness episodes were defined as fever plus cough, sore throat, runny nose, and/or myalgia with HRV detected on mid-nasal swab. Multivariate regression analysis evaluated the association between febrile HRV respiratory illness and adverse birth outcomes. RESULTS: Overall, 96 (3%) of 3693 pregnant women had HRV positive febrile respiratory illnesses. Infants born to pregnant women with HRV febrile illness had a 1.6-fold increased risk of being LBW compared with those with non-HRV febrile illness (28 of 96 [38%] vs 109 of 458 [24%]; relative risk [RR], 1.6; 95% confidence interval [CI], 1.1-2.3). No difference in risk of LBW was observed between infants born to mothers with non-HRV febrile respiratory illness and those without respiratory illness during pregnancy (109 of 458 [24%] vs 552 of 2220 [25%], respectively; RR, 1.0; 95% CI, 0.8-1.2). CONCLUSIONS: Febrile illness due to rhinovirus during pregnancy was associated with increased risk of LBW in a rural South Asian population. Interventions to reduce the burden of febrile respiratory illness due to rhinovirus during pregnancy may have a significant impact on LBW and subsequent infant mortality. PMID- 28584857 TI - Evolving Failures in the Delivery of Human Immunodeficiency Virus Care: Lessons From a Ugandan Meningitis Cohort 2006-2016. AB - BACKGROUND: Because of investments in human immunodeficiency virus (HIV) care in sub-Saharan Africa, the number of people aware of their status and receiving antiretroviral therapy (ART) has increased; however, HIV/acquired immune deficiency syndrome (AIDS) mortality still remains high. METHODS: We performed retrospective analysis of 3 sequential prospective cohorts of HIV-infected Ugandan adults presenting with AIDS and meningitis from 2006 to 2009, 2010 to 2012, and 2013 to 2016. Participants were categorized as follows: (1) unknown HIV status; (2) known HIV+ without ART; (3) known HIV+ with previous ART. We further categorized 2006 and 2013 cohort participants by duration of HIV-status knowledge and of ART receipt. RESULTS: We screened 1353 persons with suspected meningitis. Cryptococcus was the most common pathogen (63%). Over the decade, we observed an absolute increase of 37% in HIV status knowledge and 59% in antecedent ART receipt at screening. The 2006 cohort participants were new/recent HIV diagnoses (65%) or known HIV+ but not receiving ART (35%). Many 2013 cohort participants were new/recent HIV diagnoses (34%) and known HIV+ with <1 month ART (20%), but a significant proportion were receiving ART 1-4 months (11%) and >4 months (30%). Four percent of participants discontinued ART. From 2010 to 2016, meningitis cases per month increased by 33%. CONCLUSIONS: Although improved HIV screening and ART access remain much-needed interventions in resource-limited settings, greater investment in viral suppression and opportunistic infection care among the growing HIV-infected population receiving ART is essential to reducing ongoing AIDS mortality. PMID- 28584858 TI - A longitudinal population study of the impact of cataract extraction on sleep quality. AB - PURPOSE: To investigate the longitudinal effects of cataract extraction on sleep quality in two discrete population cohorts. METHODS: 301 participants who had senile cataract in both eyes at the baseline examination were selected from two large longitudinal epidemiologic studies of age-related eye disease, hearing, olfaction, and cognition. The participants were divided into two groups: one had cataract surgery (CS) in both eyes, and the other had no cataract surgery (NCS) in either eye by the follow up examination. Cataract was graded from photos or digital images using a standardized protocol. The quality of sleep was assessed using a modified Wisconsin Sleep Cohort Study Questionnaire. The NCS and CS groups were compared as to the change in the number of sleep problems reported from the baseline to the follow-up examination. Systemic co-morbidity data were included as potential confounders, including diabetes mellitus, obesity, hypertension, cerebrovascular disease, thyroid disease, tobacco and alcohol use, and the SF-12 physical component and mental component summary scores. RESULTS: The average (mean+/-SD) age was 71.0+/-8.8 years in the NCS (n=237) group and 73.4+/-9.1 years (n=64) in the CS group. There was no statistically significant difference in the change in the number of sleep problems reported between the NCS and CS groups (mean: -0.068 for NCS and 0.016 for CS, p=0.57). The multivariable linear regression models, when adjusted for confounders, yielded similar results. CONCLUSION: In this longitudinal, community-based population study, we found no significant impact of cataract extraction on sleep quality. Studies of the effect of cataract extraction on sleep should allow a longer follow up to demonstrate sustainability. PMID- 28584859 TI - Efficient fiber-coupled single-photon source based on quantum dots in a photonic crystal waveguide. AB - Many photonic quantum information processing applications would benefit from a high brightness, fiber-coupled source of triggered single photons. Here, we present a fiber-coupled photonic-crystal waveguide single-photon source relying on evanescent coupling of the light field from a tapered out-coupler to an optical fiber. A two-step approach is taken where the performance of the tapered out-coupler is recorded first on an independent device containing an on-chip reflector. Reflection measurements establish that the chip-to-fiber coupling efficiency exceeds 80 %. The detailed characterization of a high-efficiency photonic-crystal waveguide extended with a tapered out-coupling section is then performed. The corresponding overall single-photon source efficiency is 10.9 % +/ 2.3 %, which quantifies the success probability to prepare an exciton in the quantum dot, couple it out as a photon in the waveguide, and subsequently transfer it to the fiber. The applied out-coupling method is robust, stable over time, and broadband over several tens of nanometers, which makes it a highly promising pathway to increase the efficiency and reliability of planar chip-based single-photon sources. PMID- 28584860 TI - Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes. AB - In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest-particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N methyl-D-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies. PMID- 28584861 TI - Childhood family wealth and mental health in a national cohort of young adults. AB - PURPOSE: Mental health is critical to young adult health, as the onset of 75% of psychiatric disorders occurs by age 24 and psychiatric disorders early in life predict later behavioral health problems. Wealth may serve as a buffer against economic stressors. Family wealth may be particularly relevant for young adults by providing them with economic resources as they make educational decisions and move towards financial and social independence. METHODS: We used prospectively collected data from 2060 young adults aged 18-27 in 2005-2011 from the Panel Study of Income Dynamics, a national cohort of US families. We examined associations between nonspecific psychological distress (measured with the K-6 scale) and childhood average household wealth during ages 0-18 years (net worth in 2010 dollars). RESULTS: In demographics-adjusted generalized estimating equation models, higher childhood wealth percentile was related to a lower prevalence of serious psychological distress: compared to below-median wealth, prevalence ratio (PR) = 0.56 (0.36-0.87) for 3rd quartile and PR = 0.46 (0.29 0.73) for 4th quartile. The associations were attenuated slightly by adjustment for parent education and more so by adjustment for childhood household income percentile. CONCLUSIONS: Understanding the lifelong processes through which distinct aspects of socioeconomic status affect mental health can help us identify high-risk populations and take steps to minimize future disparities in mental illness. PMID- 28584862 TI - Corrigendum to "Comparative Study on the Efficacy of Anorganic Bovine Bone (Bio Oss) and Nanocrystalline Hydroxyapatite (Ostim) in Maxillary Sinus Floor Augmentation". AB - [This corrects the article DOI: 10.1155/2014/967091.]. PMID- 28584863 TI - Reply to the letter to the editor by J. Hissbach, S. Zimmermann & W. Hampe. PMID- 28584864 TI - Student selection cannot resolve the lack of general practitioners and country doctors. PMID- 28584865 TI - The Gender Lens: Development of a learning aid to introduce gender medicine. AB - Background and aim: Gender medicine takes into account biological and social differences between men and women in terms of prevalence and course of disease, diagnosis and therapy. Medical students should be made aware of this in the early stages of medical education. However, there is hardly any teaching material currently available. This article presents the adaption and first use of the German "Gender Lens," a tool to introduce gender medicine to medical students. Method: The original Canadian "Gender Lens Tool" was translated into German, tested by (n=5) teachers and adapted based on current scientific concepts. The instrument was applied and evaluated using qualitative methods in a student focus group (n=4). It was then piloted in a cohort of fourth-semester students (n=247) in a seminar addressing gender medicine. These experiences were evaluated using quantitative methods. Results: The German translation of the Gender Lens offers students a framework with which to analyze sex and gender differences in terms of the "prevalence, diagnosis, course, therapy and prevention" of a specific disease. Furthermore, it enables a refined search for causes such as "biological disposition, attitudes and behaviors, family and social networks, occupational and material circumstances and experiences with the health care system." Recommendations were received from the student groups regarding teaching methods. Male and female fourth-semester students agreed that the Gender Lens is useful as an introduction to gender medicine. Discussion: Initial experiences with the Gender Lens adapted for the German curriculum suggest that such a learning aid can contribute to raising awareness of gender medicine in medical students. PMID- 28584866 TI - The prescription talk - an approach to teach patient-physician conversation about drug prescription to medical students. AB - Background: Medication communication from physicians to patients often is poor, by this among others enhancing the risk of non-adherence. In this context, a neglect regarding the prescription talk has been complained. Aim of the project: In a newly developed elective medical students work on physician-patient conversations dealing with drug prescription. Essential aspects related to an effective and safe drug treatment are combined with steps of shared decision making. Together with a tutor, students develop a (model) conversation guide that might be tailored according to individual needs and views. Description/Methods: In a one-week course 3rd-5th year medical students treat a paper case according to problem-based learning. This is accompanied by a one-hour lecture and literature provided on an online learning platform (ILIAS). During a workshop, aspects of drug treatment and patient participation are integrated into a guide for a prescription talk. At the end of the week the students are invited to apply the (if need be individualized) guide in a simulated physician-patient communication with an actor. The conversation is evaluated using a checklist based upon the (model) conversation guide. Results: Informal and formalized feedback indicate high acceptance and satisfaction of participants with this elective. The checklist turned out to be of acceptable to good reliability with mostly selective items. Portfolio entries and written evaluation suggest that participants' positions and attitudes are influenced. PMID- 28584867 TI - Utilization and acceptance of virtual patients in veterinary basic sciences - the vetVIP-project. AB - Context: In medical and veterinary medical education the use of problem-based and cased-based learning has steadily increased over time. At veterinary faculties, this development has mainly been evident in the clinical phase of the veterinary education. Therefore, a consortium of teachers of biochemistry and physiology together with technical and didactical experts launched the EU-funded project "vetVIP", to create and implement veterinary virtual patients and problems for basic science instruction. In this study the implementation and utilization of virtual patients occurred at the veterinary faculties in Budapest, Hannover and Lublin. Methods: This report describes the investigation of the utilization and acceptance of students studying veterinary basic sciences using optional online learning material concurrently to regular biochemistry and physiology didactic instruction. The reaction of students towards this offer of clinical case-based learning in basic sciences was analysed using quantitative and qualitative data. Quantitative data were collected automatically within the chosen software-system CASUS as user-log-files. Responses regarding the quality of the virtual patients were obtained using an online questionnaire. Furthermore, subjective evaluation by authors was performed using a focus group discussion and an online questionnaire. Results: Implementation as well as usage and acceptance varied between the three participating locations. High approval was documented in Hannover and Lublin based upon the high proportion of voluntary students (>70%) using optional virtual patients. However, in Budapest the participation rate was below 1%. Due to utilization, students seem to prefer virtual patients and problems created in their native language and developed at their own university. In addition, the statement that assessment drives learning was supported by the observation that peak utilization was just prior to summative examinations. Conclusion: Veterinary virtual patients in basic sciences can be introduced and used for the presentation of integrative clinical case scenarios. Student post course comments also supported the conclusion that overall the virtual cases increased their motivation for learning veterinary basic sciences. PMID- 28584868 TI - FAMULATUR PLUS - A successful model for improving students' physical examination skills? AB - Introduction/Project description: Several studies have revealed insufficient physical examination skills among medical students, both with regard to the completeness of the physical examination and the accuracy of the techniques used. FAMULATUR PLUS was developed in response to these findings. As part of this practice-oriented instructional intervention, physical examination skills should be taught through examination seminars and problem-oriented learning approaches. In order to ensure practical relevance, all courses are integrated into a 30-day clinical traineeship in the surgery or internal medicine department of a hospital (FAMULATUR PLUS). Research question: Does participation in the FAMULATUR PLUS project lead to a more optimistic self-assessment of examination skills and/or improved performance of the physical examination? Methodology: A total of 49 medical students participated in the study. The inclusion criteria were as follows: enrollment in the clinical studies element of their degree program at the University of Ulm and completion of the university course in internal medicine examinations. Based on their personal preferences, students were assigned to either the intervention (surgery/internal medicine; n=24) or the control group (internal medicine; n=25). All students completed a self-assessment of their physical examination skills in the form of a questionnaire. However, practical examination skills were only assessed in the students in the intervention group. These students were asked to carry out a general physical examination of the simulation patient, which was recorded and evaluated in a standardized manner. In both instances, data collection was carried out prior to and after the intervention. Results: The scores arising from the student self assessment in the intervention (IG) and control groups (CG) improves significantly in the pre-post comparison, with average scores increasing from 3.83 (+/-0.72; IG) and 3.54 (+/-0.37; CG) to 1.92 (+/-0.65; IG) and 3.23 (+/ 0.73; CG). The general physical examination, which was only assessed among the students in the intervention group, was performed more completely after the instructional intervention than prior to it. Discussion: On the basis of the data collected, it can be deduced that the FAMULATUR PLUS course has a positive effect on the self-assessment of medical students with regard to their physical examination skills. The validity of this conclusion is limited by the small sample size. In addition, it remains unclear whether a more positive self assessment correlates with an objective improvement in physical examination skills. PMID- 28584869 TI - Development of the competency-based medical curriculum for the new Augsburg University Medical School. AB - Aim: With the resolution from April 28, 2014, the Bavarian state government in Germany decided to found a new medical school at Augsburg University, thereby requiring the development of a competency-based medical curriculum. Methods: Two interdisciplinary groups developed a spiral curriculum (following Harden) employing the model of Thumser-Dauth & Ochsner. The curriculum focuses on specifically defined competencies: medical expertise, independent scientific reasoning, argumentation and scholarship, as well as communication skills. Results: The spiral curriculum was developed as a hybrid curriculum. Its modular structure incorporates the mandatory subjects required by the German regulations for medical licensure (Approbationsordnung) into organ- and system-centered blocks which are integrated both horizontally and vertically. Basic preclinical sciences are covered in the blocks "Movement," "Balance" and "Contact." The clinical sciences are organized according to six pillars (conservative medicine, surgical medicine, men's-women's-children's medicine, the senses, the nervous system and the mind, and general medicine) which students revisit three times each over the course of the program. A longitudinal clinical course incorporates interdisciplinary education. A particular focus is on scientific education encompassing a longitudinal course in the sciences (including interdisciplinary classes with other university departments), block practicums, and two scientific projects. Conclusion: It is not only the degree of integration und intensity of the Augsburg University undergraduate medical degree program, but also its targeted advancement of academic, social and communication skills that have not yet been realized to such an extent elsewhere in Germany. On July 8, 2016, the German Council of Science and Humanities unanimously gave this concept a positive evaluation. Future research will examine and evaluate the Augsburg medical curriculum and the impact of the new medical school on the hospital and university in Augsburg. PMID- 28584870 TI - The inventory as a core element in the further development of the science curriculum in the Mannheim Reformed Curriculum of Medicine. AB - Introduction: The German Council of Science and Humanities as well as a number of medical professional associations support the strengthening of scientific competences by developing longitudinal curricula for teaching scientific competences in the undergraduate medical education. The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) has also defined medical scientific skills as learning objectives in addition to the role of the scholar. The development of the Mannheim science curriculum started with a systematic inventory of the teaching of scientific competences in the Mannheim Reformed Curriculum of Medicine (MaReCuM). Methods: The inventory is based on the analysis of module profiles, teaching materials, surveys among experts, and verbatims from memory. Furthermore, science learning objectives were defined and prioritized, thus enabling the contents of the various courses to be assigned to the top three learning objectives. Results: The learning objectives systematic collection of information regarding the current state of research, critical assessment of scientific information and data sources, as well as presentation and discussion of the results of scientific studies are facilitated by various teaching courses from the first to the fifth year of undergraduate training. The review reveals a longitudinal science curriculum that has emerged implicitly. Future efforts must aim at eliminating redundancies and closing gaps; in addition, courses must be more closely aligned with each other, regarding both their contents and their timing, by means of a central coordination unit. Conclusion: The teaching of scientific thinking and working is a central component in the MaReCuM. The inventory and prioritization of science learning objectives form the basis for a structured ongoing development of the curriculum. An essential aspect here is the establishment of a central project team responsible for the planning, coordination, and review of these measures. PMID- 28584871 TI - "History, Theory and Ethics of Medicine": The Last Ten Years. A Survey of Course Content, Methods and Structural Preconditions at Twenty-nine German Medical Faculties. AB - Objective: "History, Theory, Ethics of Medicine" (German: "Geschichte, Theorie, Ethik der Medizin", abbreviation: GTE) forms part of the obligatory curriculum for medical students in Germany since the winter semester 2003/2004. This paper presents the results of a national survey on the contents, methods and framework of GTE teaching. Methods: Semi-structured questionnaire dispatched in July 2014 to 38 institutions responsible for GTE teaching. Descriptive analysis of quantitative data and content analysis of free-text answers. Results: It was possible to collect data from 29 institutes responsible for GTE teaching (response: 76%). There is at least one professorial chair for GTE in 19 faculties; two professorial chairs or professorships remained vacant at the time of the survey. The number of students taught per academic year ranges from <100 to >350. Teaching in GTE comprises an average of 2.18 hours per week per semester (min: 1, max: 6). Teaching in GTE is proportionally distributed according to an arithmetic average as follows: history: 35.4%, theory 14.7% and ethics 49.9%. Written learning objectives were formulated for GTE in 24 faculties. The preferred themes of teaching in history, theory or ethics which according to respondents should be taught comprise a broad spectrum and vary. Teaching in ethics (79 from a max. of 81 possible points) is, when compared to history (61/81) and theory (53/81), attributed the most significance for the training of medical doctors. Conclusion: 10 years after the introduction of GTE the number of students and the personnel resources available at the institutions vary considerably. In light of the differences regarding the content elicited in this study the pros and cons of heterogeneity in GTE should be discussed. PMID- 28584872 TI - A multi-centre student survey on weighing disciplines in medical curricula - a pilot study. AB - Aim: Initiated by students, this pilot study examines how obtaining medical students' perspectives via a structured online survey may prove useful for curriculum deliberation. Methods: In 2012, 747 students of 32 medical faculties in Germany assessed disciplines specified in the Medical Licensure Act (AApprO) thereby concerning the allocation of teaching time, perceived usefulness regarding preparation for state examination and medical practice, their interest and motivation for studying as well as consideration for future work. Results: Internal medicine, surgery, paediatrics, gynaecology/obstetrics and general medicine rank amongst the upper third regarding allocation of teaching time and perceived usefulness for future medical practice. Concerning both preparation for state examination and medical practice internal medicine ranks second, while surgery only 22nd and 28th of 32, respectively. Some clinical-theoretical disciplines (e.g. pharmacology) are in the top ten regarding perceived preparation for state examination, too. Students who consider choosing internal medicine for future work rate associated disciplines significantly higher regarding usefulness for clinical practice (e.g. pharmacology) or motivation for studying (e.g. microbiology) than other students do. Conclusion: A simple survey reveals interesting data on students' perceptions and ideas of medical studies. Though the data are plausible, interpretations should be done with caution. Nonetheless, data like these should give rise to further questions and discussions, e.g. as part of curriculum deliberation. PMID- 28584873 TI - Visions and reality: the idea of competence-oriented assessment for German medical students is not yet realised in licensing examinations. AB - Objective: Competence orientation, often based on the CanMEDS model, has become an important goal for modern curricula in medical education. The National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education (NKLM) has been adopted in Germany. However, it is currently unknown whether the vision of competence orientation has also reached the licensing examination procedures. Methods: Therefore, a prospective, descriptive, single centre, exemplary study design was applied to evaluate 4051 questions/tasks (from 28 examiners at 7 two-day licensing oral-practical exams) for undergraduate medical students at the University of Ulm. The oral and practical questions/tasks as well as the real bedside assessment were assigned to specific competence roles (NKLM section I), categories (NKLM section II) and taxonomy levels of learning domains. Results: Numerous questions/tasks were set per candidate (day 1/2: 70+/ 24/86+/-19 questions) in the licensing oral-practical exam. Competence roles beyond the "medical expert" were scarcely considered. Furthermore, practical and communication skills at the bedside were hardly addressed (less than 3/15 min). Strikingly, there was a significant predominance of questions with a low-level taxonomy. Conclusions: The data indicate a misalignment of competence-oriented frameworks and the "real world" licensing practical-oral medical exam, which needs improvement in both evaluation and education processes. PMID- 28584875 TI - Beyond the Impact Factor - What do alternative metrics have to offer? PMID- 28584874 TI - Cluster-randomized Studies in Educational Research: Principles and Methodological Aspects. AB - An increasing number of studies are being performed in educational research to evaluate new teaching methods and approaches. These studies could be performed more efficiently and deliver more convincing results if they more strictly applied and complied with recognized standards of scientific studies. Such an approach could substantially increase the quality in particular of prospective, two-arm (intervention) studies that aim to compare two different teaching methods. A key standard in such studies is randomization, which can minimize systematic bias in study findings; such bias may result if the two study arms are not structurally equivalent. If possible, educational research studies should also achieve this standard, although this is not yet generally the case. Some difficulties and concerns exist, particularly regarding organizational and methodological aspects. An important point to consider in educational research studies is that usually individuals cannot be randomized, because of the teaching situation, and instead whole groups have to be randomized (so-called "cluster randomization"). Compared with studies with individual randomization, studies with cluster randomization normally require (significantly) larger sample sizes and more complex methods for calculating sample size. Furthermore, cluster randomized studies require more complex methods for statistical analysis. The consequence of the above is that a competent expert with respective special knowledge needs to be involved in all phases of cluster-randomized studies. Studies to evaluate new teaching methods need to make greater use of randomization in order to achieve scientifically convincing results. Therefore, in this article we describe the general principles of cluster randomization and how to implement these principles, and we also outline practical aspects of using cluster randomization in prospective, two-arm comparative educational research studies. PMID- 28584876 TI - On the nature of directed behavior to drug-associated light cues in rhesus monkeys (Macaca mulatta). AB - The present study investigated the role of drug-paired stimuli in controlling the behavior of rhesus monkeys. Systematic observations were made with nine monkeys who had a history of drug self-administration; they had been lever pressing to produce intravenous infusions of various drugs. These observations revealed that the stimulus light co-occurring with drug infusion produced robust and cue directed behavior such as orienting, touching and biting. Experiment 1 showed that this light-directed behavior would occur in naive monkeys exposed to a Pavlovian pairing procedure. Four monkeys were given response-independent injections of cocaine. In two monkeys, a red light preceded cocaine injections by 5 s, and a green light co-occurred with the 5-s cocaine injections. In the other two monkeys, the light presentations and cocaine injections occurred independently. Light-directed behavior occurred in all four monkeys within the first couple of trials and at high levels but decreased across sessions. The cocaine-paired stimulus maintained behavior longer and at higher levels than the uncorrelated stimuli. Furthermore, light-directed behavior was not maintained when cocaine was replaced with saline. Light-directed behavior did not occur in the absence of the lights. When these monkeys were subsequently trained to lever press for cocaine, light-directed behavior increased to levels higher than previously observed. Behavior directed towards drug-paired stimuli is robust, reliable and multiply determined; the mechanisms underlying this activity likely include Pavlovian conditioning, stimulus novelty, habituation and operant conditioning. PMID- 28584877 TI - Neocortical Chandelier Cells Developmentally Shape Axonal Arbors through Reorganization but Establish Subcellular Synapse Specificity without Refinement. AB - Diverse types of cortical interneurons (INs) mediate various kinds of inhibitory control mechanisms to balance and shape network activity. Distinct IN subtypes develop uniquely organized axonal arbors that innervate different subcellular compartments of excitatory principal neurons (PNs), which critically contribute to determining their output properties. However, it remains poorly understood how they establish this peculiar axonal organization and synaptic connectivity during development. Here, taking advantage of genetic labeling of IN progenitors, we examined developmental processes of axonal arbors and synaptic connections formed by murine chandelier cells (ChCs), which innervate axon initial segments (AISs) of PNs and thus powerfully regulate their spike generation. Our quantitative analysis by light microscopy revealed that ChCs overgrow and subsequently refine axonal branches as well as varicosities. Interestingly, we found that although a significant number of axonal varicosities are formed off AISs in addition to on AISs, presynaptic markers are predominantly colocalized with those on AISs throughout development. Immunoelectron microscopic (IEM) analysis also demonstrated that only varicosities apposed to AISs contain presynaptic profiles. These results suggest that subcellular synapse specificity of ChCs is genetically predetermined while axonal geometry is shaped through remodeling. Molecular cues localized at AISs may regulate target recognition and synapse formation by ChCs. PMID- 28584878 TI - A Population-Based Digital Reference Object (DRO) for Optimizing Dynamic Susceptibility Contrast (DSC)-MRI Methods for Clinical Trials. AB - The standardization and broad-scale integration of dynamic susceptibility contrast (DSC)-magnetic resonance imaging (MRI) have been confounded by a lack of consensus on DSC-MRI methodology for preventing potential relative cerebral blood volume inaccuracies, including the choice of acquisition protocols and postprocessing algorithms. Therefore, we developed a digital reference object (DRO), using physiological and kinetic parameters derived from in vivo data, unique voxel-wise 3-dimensional tissue structures, and a validated MRI signal computational approach, aimed at validating image acquisition and analysis methods for accurately measuring relative cerebral blood volume in glioblastomas. To achieve DSC-MRI signals representative of the temporal characteristics, magnitude, and distribution of contrast agent-induced T1 and changes observed across multiple glioblastomas, the DRO's input parameters were trained using DSC MRI data from 23 glioblastomas (>40 000 voxels). The DRO's ability to produce reliable signals for combinations of pulse sequence parameters and contrast agent dosing schemes unlike those in the training data set was validated by comparison with in vivo dual-echo DSC-MRI data acquired in a separate cohort of patients with glioblastomas. Representative applications of the DRO are presented, including the selection of DSC-MRI acquisition and postprocessing methods that optimize CBV accuracy, determination of the impact of DSC-MRI methodology choices on sample size requirements, and the assessment of treatment response in clinical glioblastoma trials. PMID- 28584879 TI - Synthetic nanoscale electrostatic particles as growth factor carriers for cartilage repair. AB - The efficient transport of biological therapeutic materials to target tissues within the body is critical to their efficacy. In cartilage tissue, the lack of blood vessels prevents the entry of systemically administered drugs at therapeutic levels. Within the articulating joint complex, the dense and highly charged extracellular matrix (ECM) hinders the transport of locally administered therapeutic molecules. Consequently, cartilage injury is difficult to treat and frequently results in debilitating osteoarthritis. Here we show a generalizable approach in which the electrostatic assembly of synthetic polypeptides and a protein, insulin-like growth factor-1 (IGF-1), can be used as an early interventional therapy to treat injury to the cartilage. We demonstrated that poly(glutamic acid) and poly(arginine) associated with the IGF-1 via electrostatic interactions, forming a net charged nanoscale polyelectrolyte complex (nanoplex). We observed that the nanoplex diffused into cartilage plugs in vitro and stimulated ECM production. In vivo, we monitored the transport, retention and therapeutic efficacy of the nanoplex in an established rat model of cartilage injury. A single therapeutic dose, when administered within 48 hours of the injury, conferred protection against cartilage degradation and controlled interleukin-1 (IL-1) mediated inflammation. IGF-1 contained in the nanoplex was detected in the joint space for up to 4 weeks following administration and retained bioactivity. The results indicate the potential of this approach as an early intervention therapy following joint injury to delay or even entirely prevent the onset of osteoarthritis. PMID- 28584880 TI - Sulfate radicals enable a non-enzymatic Krebs cycle precursor. AB - The evolutionary origins of the tricarboxylic acid cycle (TCA), or Krebs cycle, are so far unclear. Despite a few years ago, the existence of a simple non enzymatic Krebs-cycle catalyst has been dismissed 'as an appeal to magic', citrate and other intermediates have meanwhile been discovered on a carbonaceous meteorite and do interconvert non-enzymatically. To identify the non-enzymatic Krebs cycle catalyst, we used combinatorial, quantitative high-throughput metabolomics to systematically screen iron and sulfate reaction milieus that orient on Archean sediment constituents. TCA cycle intermediates are found stable in water and in the presence of most iron and sulfate species, including simple iron-sulfate minerals. However, we report that TCA intermediates undergo 24 interconversion reactions in the presence of sulfate radicals that form from peroxydisulfate. The non-enzymatic reactions critically cover a topology as present in the Krebs cycle, the glyoxylate shunt and the succinic semialdehyde pathways. Assembled in a chemical network, the reactions achieve more than ninety percent carbon recovery. Our results show that a non-enzymatic precursor for the Krebs cycle is biologically sensible, efficient, and forms spontaneously in the presence of sulfate radicals. PMID- 28584881 TI - Thalamocortical dysconnectivity in autism spectrum disorder: An analysis of the Autism Brain Imaging Data Exchange. AB - BACKGROUND: Individuals with autism spectrum disorder (ASD) exhibit differences in basic sensorimotor processing as well as general cortical excitability. These observations converge to implicate thalamocortical connectivity as a potential unifying neural mechanism. The goal of this study was to clarify mixed findings on thalamocortical functional connectivity in a large sample of individuals with ASD. METHODS: Using the Autism Brain Imaging Data Exchange (ABIDE), we examined thalamocortical functional connectivity in 228 individuals with ASD and a matched comparison group of 228 typically developing individuals. In order to fully characterize thalamocortical functional networks, we employed complementary seed based approaches that examined connectivity of major cortical divisions (e.g. prefrontal cortex, temporal lobe) with the thalamus and whole-brain connectivity of specific thalamic sub-regions. RESULTS: Prefrontal cortex, temporal lobe, and sensorimotor cortex exhibited hyper-connectivity with the thalamus in ASD. In the whole-brain analysis, hyper-connectivity of several thalamic seeds included multiple cortical areas, but tended to converge in temporal cortical areas, including the temporoparietal junction. Follow-up analyses of age effects revealed that the connectivity abnormalities in ASD were more pronounced in adolescents compared to children and adults. CONCLUSIONS: These results confirm previous findings of temporal and motor thalamocortical hyper-connectivity in ASD, and extend them to include somatosensory and prefrontal cortex. While not directly addressable with the data available in ABIDE, this widespread hyper connectivity could theoretically account for sensorimotor symptoms and general cortical excitability in ASD. Future studies should target comprehensive clinical and behavioral characterization in combination with functional connectivity in order to explore this possibility. PMID- 28584884 TI - Population splitting of rodlike swimmers in Couette flow. AB - We present a quantitative analysis on the response of a dilute active suspension of self-propelled rods (swimmers) in a planar channel subjected to an imposed shear flow. To best capture the salient features of the shear-induced effects, we consider the case of an imposed Couette flow, providing a constant shear rate across the channel. We argue that the steady-state behavior of swimmers can be understood in the light of a population splitting phenomenon, occurring as the shear rate exceeds a certain threshold, initiating the reversal of the swimming direction for a finite fraction of swimmers from down- to upstream or vice versa, depending on the swimmer position within the channel. Swimmers thus split into two distinct, statistically significant and oppositely swimming majority and minority populations. The onset of population splitting translates into a transition from a self-propulsion-dominated regime to a shear-dominated regime, corresponding to a unimodal-to-bimodal change in the probability distribution function of the swimmer orientation. We present a phase diagram in terms of the swim and flow Peclet numbers showing the separation of these two regimes by a discontinuous transition line. Our results shed further light on the behavior of swimmers in a shear flow and provide an explanation for the previously reported non-monotonic behavior of the mean, near-wall, parallel-to-flow orientation of swimmers with increasing shear strength. PMID- 28584882 TI - Increases in Intrinsic Thalamocortical Connectivity and Overall Cognition Following Cognitive Remediation in Chronic Schizophrenia. AB - BACKGROUND: Thalamic projections to the prefrontal cortex (PFC) are critical for cognition, and disruptions in these circuits are thought to underlie the pathophysiology of schizophrenia. Cognitive remediation (REM) is a behavioral intervention that holds promise for improving cognition and functioning in schizophrenia, however the extent to which it affects thalamo-prefrontal connections has not been researched. This study sought to determine whether patients with schizophrenia who undergo a placebo-controlled trial of REM show increased functional connectivity between the thalamus and PFC, and whether these changes correspond to improvements in cognition. METHODS: Twenty-six patients with chronic schizophrenia were randomized to either 48 hours (over 16 weeks) of a drill-and-practice working memory-focused REM or an active placebo condition. All participants underwent cognitive assessment (MATRICS Consensus Cognitive Battery), as well as both resting and task-based fMRI before and after their respective intervention. All clinicians, technicians, and raters were blind to participant condition. RESULTS: We observed changes in resting-state connectivity in the PFC for the REM group but not the placebo group. Increased intrinsic connectivity between the thalamus and right middle frontal gyrus correlated with improvements in overall cognition. Additionally, lower baseline cognition correlated with greater increases in connectivity between the thalamus and PFC. Similar findings were observed when patients were scanned during a working memory task. CONCLUSIONS: These results suggest that increases in thalamo-prefrontal circuitry correspond with training-related improvements of the cognitive deficits associated with schizophrenia. PMID- 28584883 TI - Projection artifact removal improves visualization and quantitation of macular neovascularization imaged by optical coherence tomography angiography. AB - PURPOSE: To visualize and quantify the size and vessel density of macular neovascularization (MNV) using optical coherence tomography angiography (OCTA) with a projection artifact removal algorithm. DESIGN: Multicenter, observational study. PARTICIPANTS: Subjects with MNV in at least one eye. METHODS: Patients were imaged using either a swept-source OCT angiography (SS-OCTA) prototype system or a spectral-domain OCT angiography (SD-OCTA) prototype system. The optical microangiography (OMAG) algorithm was used to generate the OCTA images. Projection artifacts from the overlying retinal circulation were removed from the OMAG OCTA images using a novel algorithm. Following removal of the projection artifacts from the OCTA images, we assessed the size and vascularity of the MNV. Concurrent fluorescein angiography (FA) and indocyanine green angiography (ICGA) images were used to validate the artifact-free OMAG images whenever available. MAIN OUTCOME MEASURES: Size and vascularity of MNV imaged with OCTA before and after the use of a projection-artifact removal algorithm. RESULTS: A total of 30 subjects (40 eyes) diagnosed with MNV were imaged. Five patients were imaged before and after intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. Following the use of the projection artifact removal algorithm, we found improved visualization of the MNV. Lesion sizes and vascular densities were more easily measured on all the artifact-free OMAG images. In eyes treated with vascular endothelial growth factor inhibitors, vascular density was reduced in all five eyes after treatment, and in four eyes, the size of the MNV decreased. One of five patients showed a slight increase in lesion size, but a decrease in vascular density. CONCLUSIONS: OCTA imaging of MNV using the OMAG algorithm combined with removal of projection artifacts resulted in improved visualization and measurements of the neovascular lesions. OMAG with projection artifact removal should be useful for assessing the response of MNV to treatment using OCTA imaging. PMID- 28584885 TI - Viscoelastic hydrogels for 3D cell culture. AB - In tissues, many cells are surrounded by and interact with a three-dimensional soft extracellular matrix (ECM). Both the physical and biochemical properties of the ECM play a major role in regulating cell behaviours. To better understand the impact of ECM properties on cell behaviours, natural and synthetic hydrogels have been developed for use as synthetic ECMs for 3D cell culture. It has long been known that ECM and tissues are viscoelastic, or display a time-dependent response to deformation or mechanical loading, exhibiting stress relaxation and creep. However, only recently have there been efforts made to understand the role of the time-dependent aspects of the ECM mechanics on regulating cell behaviours using hydrogels for 3D culture. Here we review the characterization and molecular basis of hydrogel viscoelasticity and plasticity, and describe newly developed approaches to tuning viscoelasticity in hydrogels for 2D and 3D culture. Then we highlight several recent studies finding a potent impact of hydrogel stress relaxation or creep on cell behaviours such as cell spreading, proliferation, and differentiation of mesenchymal stem cells. The role of time-dependent mechanics on cell biology remains largely unclear, and ripe for further exploration. Further elucidation of this topic may substantially advance our understanding of cell-matrix interactions during development, homeostasis, wound healing, and disease, and guide the design of biomaterials for regenerative medicine. PMID- 28584886 TI - UV-responsive amphiphilic graft copolymers based on coumarin and polyoxazoline. AB - A series of amphiphilic photo-responsive heterografted copolymers have been successfully synthesized. The random copolymers were composed of a methacrylate backbone, with various compositions of hydrophilic oligomeric 2-methyl-2 oxazoline side chains (OMOx) and hydrophobic long alkyl chains terminated by a coumarin moiety (Cm). Using dynamic (DLS) and static light scattering (SLS), and transmission electron microscopy (TEM), their self-assembling behavior was studied in water using the nanoprecipitation method. Depending on the system, one, two or three particle size distributions co-exist in solution. However, DLS measurements showed that monomodal and slightly polydisperse self-assemblies were obtained with the more hydrophobic copolymers (i.e., 85% of hydrophobic monomers with a long alkyl chain terminated by a coumarin moiety (MCm) per molecule) with hydrodynamic diameters ranging from ca. 130 to 300 nm. Morphological information on these self-assembly structures was obtained using SLS: a Gaussian behavior has thus been evidenced. Finally, these heterografted copolymers were illuminated using UV light at lambda = 350 nm inducing photo-crosslinking of the coumarin units. The influence of UV illumination on the thus-formed nanoparticles was investigated by carrying out complementarily DLS-measurements and UV spectroscopy. PMID- 28584887 TI - Intramedullary tibial nailing of distal tibiofibular fractures: additional fibular fixation or not? AB - INTRODUCTION: The anatomy of the distal tibia accounts for reduced biomechanical stability and higher complication rates when treating distal tibiofibular fractures with an intramedullary tibia nail (IMTN). The goal of this study was to identify variables that affect the stability of IMTN. We assessed the value of additional fibular fixation, angular stable interlocking screws (ASLS) and multiplanar screw configuration in IMTN. PATIENTS AND METHODS: A retrospective cohort study was performed including 184 distal tibial fractures and associated fibula fracture treated with IMTN. Relevant demographic, fracture-related (type and level of the tibia and fibula fracture) and operative variables (depth of the nail, screw type and configuration, use of polar screws, fibular fixation) were studied. Coronal and sagittal alignment was assessed directly and 3-6 months after IMTN. Loss of reduction (LOR) was classified as 5-9 degrees or >=10 degrees . RESULTS: 48.4% of the patients showed >=5 degrees LOR in one or both planes. Coronal LOR 5 degrees -9 degrees significantly correlated with low tibial fractures (p = 0.034), AO/OTA type 43 distal tibial fractures (p = 0.049), and sagittal LOR 5 degrees -9 degrees (p = 0.015). Although sagittal LOR 5 degrees -9 degrees was associated with fibular fractures (non-fixated suprasyndesmotic, p = 0.011), conversely we could not demonstrate the added value of (suprasyndesmotic) fibula fixation in IMTN. Coronal LOR >=10 degrees significantly correlated with AO/OTA type 43 distal tibial fractures (p = 0.009). In contrast to multiplanar configuration, we found a clear benefit of ASLS in distal IMTN locking. CONCLUSIONS: The level of the tibial fracture (AO/OTA type) and (suprasyndesmotic) fibular fractures were the main determinants of LOR after IMTN. ASLS was found to increase the stability of IMTN. Due to heterogeneity, however, we could not demonstrate the value of fibular fixation in IMTN. Therefore, a future prospective study with uniform treatment strategy for IMTN of distal tibiofibular fractures, with or without fixation of the fibula, is mandatory. PMID- 28584889 TI - Associations between early tumor shrinkage and depth of response and clinical outcomes in patients treated with 1st-line chemotherapy for advanced gastric cancer. AB - BACKGROUND: Although early tumor shrinkage (ETS) predictions of the efficacy and depth of response (DpR) reflects clinical outcomes in chemotherapy with epidermal growth factor receptor inhibitor regimens to treat metastatic colorectal cancer, their value in assessing treatments for advanced gastric cancer (AGC) is unclear. Here we evaluated relationships between ETS and DpR and clinical outcomes in AGC patients treated with first-line chemotherapy. METHODS: We retrospectively enrolled 612 consecutive patients treated with first-line chemotherapy for AGC between January 2010 and June 2016. ETS and DpR were defined as changes from baseline in summed longest diameters in target lesions at 8 (+/-4) weeks for ETS and at the smallest observed volume for DpR. RESULTS: Eligible patients were sorted into HER2+ (n = 100) and HER2- (n = 186) groups. Median follow-up was 14.8 months. The overall response rate and disease control rates were 64 and 87% in the HER2+ group and 53.2 and 86.0% in the HER2- group. Respective median PFS and OS were HER2+: 7.9 and 20.8 months and HER2-: 6.6 and 13.8 months. The respective ETS rate and median DpR were HER2+: 70 and 44% and HER2-: 57.5 and 24%. Clinical outcomes and ETS/DpR were correlated, especially in the HER2+ group (OS: P < 0.0001; PFS: P < 0.0001). In multivariate analysis, ETS was an independent predictor for OS in the HER2+ group and for PFS in both groups. CONCLUSION: These results indicate that ETS may be an early-on treatment predictor of the efficacy of HER2+ advanced gastric cancer treated with first-line chemotherapy that includes trastuzumab. PMID- 28584890 TI - Survival benefit of "D2-plus" gastrectomy in gastric cancer patients with duodenal invasion. AB - BACKGROUND: The optimal extent of lymph node (LN) dissection for gastric cancer with duodenal invasion is yet to be clarified. This study sought to evaluate the significance of gastrectomy with D2-plus lymphadenectomy including posterior LNs along the common hepatic artery (no. 8p), hepatoduodenal ligament LNs along the bile duct (no. 12b) and those behind the portal vein (no. 12p), LNs on the posterior surface of the pancreatic head (no. 13), LNs along the superior mesenteric vein (no. 14v) and para-aortic LNs around the left renal vein (nos. 16a2 and 16b1) dissection. METHODS: Patients with gastric cancer with duodenal invasion undergoing R0 gastrectomy from January 2000 to December 2015 were enrolled. The therapeutic value index (TVI) of each LN dissection was calculated by multiplying the incidence of metastasis to each LN station by the 5-year overall survival (OS) rate of the patients with metastasis to the station. RESULTS: In total, 117 patients were eligible. The 5-year OS rates (and TVI) of the patients with metastasis to LNs were 40.4% (7.4) in no. 12b, 25.4% (6.8) in no. 13, 32.0% (6.1) in no. 14v, 50.0% (13.0) in no. 16a2 and 40.0% (10.0) in no. 16b1. None of the patients with metastasis in no. 8p or no. 12p survived 5 years or longer. CONCLUSION: In a potentially curative gastrectomy for gastric cancer with duodenal invasion, there may be some survival benefit in dissection of nos. 12b, 13, 14v, 16a2 and 16b1 LNs, while no benefit was seen in dissection of nos. 8p or 12p LNs. PMID- 28584891 TI - Gratitude mediates quality of life differences between fibromyalgia patients and healthy controls. AB - PURPOSE: Despite a growing literature on the benefits of gratitude for adjustment to chronic illness, little is known about gratitude in medical populations compared to healthy populations, or the degree to which potential deficits in gratitude might impact quality of life. The purpose of the present study was to (1) examine levels of gratitude and quality of life in fibromyalgia patients and healthy controls and (2) consider the role of gratitude in explaining quality of life differences between fibromyalgia patients and healthy controls. METHODS: Participants were 173 fibromyalgia patients and 81 healthy controls. All participants completed measures of gratitude, quality of life, and socio demographics. RESULTS: Although gratitude was positively associated with quality of life, levels of gratitude and quality of life were lower in the fibromyalgia sample relative to the healthy controls. This difference in gratitude partially mediated differences in quality of life between the two groups after controlling for socio-demographic variables. CONCLUSIONS: Our findings suggest that gratitude is a valuable positive psychological trait for quality of life in people with fibromyalgia. Interventions to improve gratitude in this patient population may also bring enhancement in quality of life. PMID- 28584894 TI - Erratum to: Identification of a restriction point at the M/G1 transition in CHO cells. PMID- 28584892 TI - Coping profiles and subjective well-being among people living with HIV: less intensive coping corresponds with better well-being. AB - PURPOSE: The aim of this study was to investigate the relationship between coping strategies and subjective well-being (SWB) among people living with HIV (PLWH) using the latent profile analysis (LPA) with control for socio-medical covariates. METHODS: The sample comprised five hundred and thirty people (N = 530) with a confirmed diagnosis of HIV+. The study was cross-sectional with SWB operationalized by satisfaction with life (Satisfaction with Life Scale) and positive and negative affect (PANAS-X). Coping with stress was measured by the Brief COPE Inventory, enriched by several items that assessed rumination and enhancement of positive emotional states. Additionally, the relevant socio medical variables were collected. RESULTS: The one-step model of LPA revealed the following: (1) a solution with five different coping profiles suited the data best; (2) socio-medical covariates, except for education, were not related to the profiles' membership. Further analysis with SWB as a distal outcome showed that higher intensity coping profiles have significantly worse SWB when compared with lower intensity coping profiles. However, the lowest SWB was noted for mixed intensity coping profile (high adaptive/low maladaptive). CONCLUSIONS: The person centered approach adopted in this study informs about the heterogeneity of disease-related coping among PLWH and its possible reactive character, as the highest SWB was observed among participants with the lowest intensity of coping. PMID- 28584893 TI - Development of Novel Monoclonal Antibodies for Evaluation of Transmembrane Prostate Androgen-Induced Protein 1 (TMEPAI) Expression Patterns in Gastric Cancer. AB - Transmembrane prostate androgen-induced protein 1 (TMEPAI) is a single-span membrane protein, functionally involved in transforming growth factor beta signaling pathway. The particular protein presented in cells in three isoforms, which differs in the length of the soluble N-terminal extracellular domain, making it challenging for the immunochemical recognition. By using quantitative real-time polymerase chain reaction, we identified significant upregulation of PMEPA1 gene expression in malignant tissues of patients with gastric adenocarcinoma. The main part of commercially available anti-TMEPAI antibodies are having polyclonal nature or not suitable for immunocytochemical localization of target protein in tissue specimens. Hence, we decide to generate a set of novel rat monoclonal antibodies (mAb) directed against conservative C-terminal cytoplasmic epitope. Immunoblotting analysis showed that monoclonal antibodies, 2E1, 6C6, and 10A7 were able to recognize specifically target protein in transiently transfected HEK293T and CHO-K1 cells. Especially established mAb, named 10A7, showed the excellent binding ability to target protein in immunohistochemistry. By using developed antibodies, we observed pronounced expression of TMEPAI in normal gastric epithelial cells while tumor cells from gastric adenomas, and adenocarcinoma samples were mostly negative for target protein expression. Also, we found that gastric epithelium cells lose the TMEPAI expression concurrently with severe dysplasia progression, which probably caused by a mechanism involving specific microRNA. PMID- 28584895 TI - Effect of olive cultivar on bioaccessibility and antioxidant activity of phenolic fraction of virgin olive oil. AB - AIM: This study aims to characterize the phenolic profile and antioxidant capacity of seven monovarietal virgin olive oils (VOOs) and evaluate their in vitro gastrointestinal stability. METHODS: 'Picual', 'Blanqueta', 'Sevillana', 'Habichuelero', and 'Chetoui' olive cultivars were selected for VOO extraction. The oils were subjected to in vitro digestion. The recovery index (RI) of phenolic compounds after each digestion step and the bioaccessibility index (BI) were evaluated. In addition, the antioxidant activity of the bioaccessible fraction (BF) of VOOs was determined by DPPH, ABTS, and ORAC assays, as well as by studying the intracellular reactive oxygen species in Caco-2 cells. RESULTS: Differences were found in the composition of phenolic compounds in VOOs depending on cultivars. During the digestive process, important losses of phenolic compounds were observed between the buccal and duodenal steps, unlike HTy and Ty, which presented increased recovery due to the hydrolysis of secoiridoid derivatives. Differences in the bioaccessibility of phenolic compounds were found between varieties of VOOs. 'Sevillana' VOO had the highest total bioaccessibility (36%), followed by the 'Picual' (19%), 'Chetoui' (17%), 'Habichuelero' (10%), and 'Blanqueta' (8%) varieties. The BF of all the varieties of VOO showed similar radical ABTS scavenging capacity, 'Chetoui', and 'Blanqueta'-BF having the highest radical DPPH scavenging capacity, and 'Habichuelero' and 'Picual'-BF showing protective effects against the peroxyl radical measured by ORACFL assay. All VOO-BFs presented decreases in ROS levels in Caco-2 cells. CONCLUSIONS: Our results suggest differences in the bioaccessibility of phenolics from diverse VOO varieties, which could lead to different biological properties. Therefore, this study represents a first step toward the development of novel dietary strategies focusing on the phenolic supplementation of different VOOs to preserve human health. PMID- 28584888 TI - Autism spectrum disorder: neuropathology and animal models. AB - Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11 13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments. PMID- 28584896 TI - Importance of tissue sampling, laboratory methods, and patient characteristics for detection of Pneumocystis in autopsied lungs of non-immunosuppressed individuals. AB - To understand the epidemiological significance of Pneumocystis detection in a lung tissue sample of non-immunosuppressed individuals, we examined sampling procedures, laboratory methodology, and patient characteristics of autopsy series reported in the literature. Number of tissue specimens, DNA-extraction procedures, age and underlying diagnosis highly influence yield and are critical to understand yield differences of Pneumocystis among reports of pulmonary colonization in immunocompetent individuals. PMID- 28584897 TI - Effects of Juice Processing on Oxalate Contents in Carambola Juice Products. AB - Effects of processing methods including pressing, enzyme-assisted extraction, lactic acid fermentation by Lactobacillus acidophilus, and alcohol fermentation by Saccharomyces cerevisiae on total and soluble oxalate contents of carambola juices were studied. In comparison with pressing, the use of enzyme increased juice yields (15.89-17.29%), but resulted in higher total oxalate (1.60-1.73 times) and soluble oxalate contents (1.16-1.49 times). In addition, extension of enzyme incubation periods led to an increase in soluble oxalate contents in the products (p < 0.05). On the other hand, alcohol fermentation with Saccharomyces cerevisiae from 1 to 5 weeks reduced 37-58% of total oxalate and 39-59% of soluble oxalate contents. Prolonged fermentation also demonstrated better reduction of oxalate contents. Meanwhile, lactic acid fermentation using Lactobacillus acidophilus had no effects on total and soluble oxalate contents in carambola juices. These results suggested that carambola juice products should only be consumed moderately, and that alcohol fermentation could be a potential method to reduce oxalate contents in foods in order to prevent the risks of forming kidney stones. PMID- 28584898 TI - Factors Affecting the Dissolution of Indomethacin Solid Dispersions. AB - The aim of this study was to investigate the influence of factors such as carrier type, drug/carrier ratio, binary carriers, and preparation method on the dissolution of an insoluble drug, indomethacin (IM), under supersaturation conditions. Using a solvent evaporation (SE) method, poloxamer 188 and PVP K30 showed better dissolution among the selected carriers. Furthermore, as the ratio of carriers increased (drug/carrier ratio from 1:0.5 to 1:2), the dissolution rate increased especially in almost two times poloxamer 188 solid dispersions (SDs), while the reverse results were observed for PVP K30 SDs. For the binary carrier SD, a lower dissolution was found. Under hot melt extrusion (HME), the dissolution of poloxamer 188 SD and PVP K30 SD was 0.83- and 0.94-folds lower than that using SE, respectively, while the binary carrier SD showed the best dissolution. For poloxamer 188 SDs, the drug's crystal form changed when using SE, while no crystal form change was observed using HME. IM was amorphous in PVP K30 SDs prepared by both methods. For binary carrier systems, amorphous and crystalline drugs coexisted in SD using SE, and negligible amorphous IM was in SD using HME. This study indicated that a higher amorphous proportion in SD did not correlate with higher dissolution rate, and other factors, such as carrier type, particle size, and density, were also critical. PMID- 28584899 TI - Development of Aerosol Phospholipid Microparticles for the Treatment of Pulmonary Hypertension. AB - Pulmonary arterial hypertension (PAH) is an incurable cardiovascular disease characterized by high blood pressure in the arteries leading from the heart to the lungs. Over two million people in the USA are diagnosed with PAH annually and the typical survival rate is only 3 years after diagnosis. Current treatments are insufficient because of limited bioavailability, toxicity, and costs associated with approved therapeutics. Aerosol delivery of drugs is an attractive approach to treat respiratory diseases because it increases localized drug concentration while reducing systemic side effects. In this study, we developed phospholipid based aerosol microparticles via spray drying consisting of the drug tacrolimus and the excipients dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol. The phospholipid-based spray-dried aerosol microparticles were shown to be smooth and spherical in size, ranging from 1 to 3 MUm in diameter. The microparticles exhibited thermal stability and were amorphous after spray drying. Water content in the microparticles was under 10%, which will allow successful aerosol dispersion and long-term storage stability. In vitro aerosol dispersion showed that the microparticles could successfully deposit in the deep lung, as they exhibited favorable aerodynamic diameters and high fine particle fractions. In vitro dose-response analysis showed that TAC is nontoxic in the low concentrations that would be delivered to the lungs. Overall, this work shows that tacrolimus-loaded phospholipid-based microparticles can be successfully created with optimal physicochemical and toxicological characteristics. PMID- 28584900 TI - Nanosuspension-Based Aloe vera Gel of Silver Sulfadiazine with Improved Wound Healing Activity. AB - The present study focuses on the development and characterization of nanosuspension of a poorly soluble drug, silver sulfadiazine (SSD) incorporated in Aloe vera gel (AV-gel) for improving its therapeutic efficacy. The SSD solution in ammonia was subjected to nanoprecipitation in surfactant solution and particle size was optimized by varying concentration of surfactant. Optimized formulation constituted of 5.5% (w/v) Span 20 and 5.5% (w/v) Tween 80 as a dispersing agent and 0.5% (w/v) Poloxamer 188 as a co-surfactant. The prepared nanosuspension was evaluated for particle size, polydispersity index, surface morphology, and x-ray diffraction study. The optimized nanosuspension was incorporated into nanogel formulation with the addition of 1% AV-gel and 0.5% Carbopol 940 for topical delivery of nanosized SSD. Evaluation of in vitro drug release exhibited a significant enhancement in release rate of the drug from developed nanogel formulation (77.16 +/- 3.241%) in comparison to marketed formulation (42.81 +/- 1.452%) after 48 h. In vivo histopathological studies in rats for 14 days of application of prepared nanogel showed improvement in the wound healing potential as compared to marketed formulation. PMID- 28584901 TI - Endovascular treatment of diabetic peripheral arterial disease in older and oldest old patients: a retrospective study. AB - BACKGROUND: Peripheral arterial disease (PAD) is frequent among older diabetic patients, but the evidence about endovascular revascularization is very limited. METHOD: We retrospectively analyzed data collected from 120 diabetic patients consecutively admitted to a Diabetic Foot Clinic, including 64 patients aged 65 79 years and 56 patients aged 80 or more. RESULTS: Percutaneous transluminal angioplasty (PTA) was followed by technical success in 82.5% of older patients and 62.5% of oldest old ones (p = 0.05). No significant difference was observed in regards to complete re-epithelization (76.6 vs 76.8%, p = 0.820), recurrent stenosis (26.6 vs 19.6%, p = 0.371), intra- or post-procedure complications (21.9 vs 10.7%, p = 0.102), and amputations (12.5 vs 5.4%, p = 0.176). DISCUSSION: Our findings suggest that older and oldest old patients with diabetic foot and critical ischemia could be effectively and safely treated with PTA. PMID- 28584902 TI - Quantitative trait loci analysis of melon (Cucumis melo L.) domestication-related traits. AB - KEY MESSAGE: Loci on LGIV, VI, and VIII of melon genome are involved in the control of fruit domestication-related traits and they are candidate to have played a role in the domestication of the crop. The fruit of wild melons is very small (20-50 g) without edible pulp, contrasting with the large size and high pulp content of cultivated melon fruits. An analysis of quantitative trait loci (QTL) controlling fruit morphology domestication-related traits was carried out using an in vitro maintained F2 population from the cross between the Indian wild melon "Trigonus" and the western elite cultivar 'Piel de Sapo'. Twenty-seven QTL were identified in at least two out of the three field trials. Six of them were also being detected in BC1 and BC3 populations derived from the same cross. Ten of them were related to fruit morphological traits, 12 to fruit size characters, and 5 to pulp content. The Trigonus alleles decreased the value of the characters, except for the QTL at andromonoecious gene at linkage group (LG) II, and the QTL for pulp content at LGV. QTL genotypes accounted for a considerable degree of the total phenotypic variation, reaching up to 46%. Around 66% of the QTL showed additive gene action, 19% exhibited dominance, and 25% consisted of overdominance. The regions on LGIV, VI, and VIII included the QTL with more consistent and strong effects on domestication-related traits. QTLs on those regions were validated in BC2S1, BC2S2, and BC3 families, with "Trigonus" allele decreasing the fruit morphological traits in all cases. The validated QTL could represent loci involved in melon domestication, although further experiments as genomic variation studies across wild and cultivated genotypes would be necessary to confirm this hypothesis. PMID- 28584903 TI - Incidence and outcome of retained Port-A-Cath fragments during removal. AB - PURPOSE: Port-A-Cath devices are frequently used for long-term venous access. We postulate that long-term use predisposes them to getting stuck and retained in a central vein at the time of removal. We aim to report the incidence and outcome of this complication. METHODS: Between January 2006 and July 2016, a retrospective review of all Port-A-Cath removals that were performed at our centre was conducted. At the time of removal, catheters that could not be removed from the vein were considered retained. RESULTS: During the study period, 107 children had 174 episodes of silicone Sitimplant (Vygon, Ecouen, France) Port-A Cath insertions. These children required 135 removal episodes and there were 3 (2.2%) instances whereby the catheter fragment was retained. These episodes of retained catheters only occurred in children with factor VIII deficiency (4.1% incidence in this cohort). For each episode of catheter insertion and removal, the catheters had been left in situ for a mean duration of 43 months in children with factor deficiency and no retained fragments, and the mean duration was 91 months in children with factor deficiency and retained catheter fragments (p = 0.0011). CONCLUSIONS: Port-A-Caths that are retained after attempted removal is a complication encountered predominantly in catheters that have been in use for a prolonged duration. Furthermore, factor replacement therapy in haemophiliacs may be a risk factor for this complication. PMID- 28584904 TI - Posterior sagittal anorectoplasty in vestibular fistula: with or without colostomy. AB - PURPOSE: The aim of this study is to compare the results and complications of one and three-stage repairs in females with vestibular fistula (VF) and make contribution to the discussion of whether the disadvantages outweigh the protective effect of a colostomy from wound infection and wound dehiscence following posterior sagittal anorectoplasty (PSARP). METHODS: Patients with a diagnosis of VF who underwent PSARP between October 2009 and November 2015 were retrospectively reviewed. The patients were divided into two groups: Group 1 patients treated by one-stage procedure (n = 30); Group 2-patients treated by three-stage procedure (n = 16). RESULTS: There were no statistically significant differences between the groups with respect to wound infection, recurrence of fistula and rectal mucosal prolapse. Minor wound dehiscence occurred slightly more common in Group 1, even if p value is not significant. No wound dehiscence has been observed since we switched to the protocol of keeping the child nil per oral for 5 postoperative days and loperamide (0.1 mg/kg) administration for 7 postoperative days. The mean time before resuming oral intake was 2.87 +/- 1.7 and 1.19 +/- 0.4 days in Group 1 and Group 2, respectively (p = 0.001). None developed major wound disruption or anal stenosis in either group. There were no statistical differences between the groups in terms of voluntary bowel movements, soiling and constipation. CONCLUSIONS: PSARP performed without a protective colostomy in patients with VF has low morbidity, good continence rates and obvious advantages for both the patients and their parents. PMID- 28584905 TI - Clinical characteristics of intussusception secondary to pathologic lead points in children: a single-center experience with 65 cases. AB - OBJECTIVE: Intussusception secondary to pathologic lead points (PLPs) is a challenging condition for pediatric surgeons, and few studies have been published on this subject. The aim of this study was to review and analyze clinical data on the diagnosis and management of intussusception secondary to PLPs in children. METHODS: Between 2002 and 2016, a total of 65 pediatric patients with a diagnosis of intussusception secondary to PLPs were retrospectively reviewed. RESULTS: The series comprised 47 males and 18 females. The average age of the patients was 4.9 years old. All patients had typical clinical manifestations, and intussusception was proven by ultrasound. Fifty-one patients had recurrent intussusception, of whom 21 had one, 14 had two, 10 had three, and 6 had more than three. There were 20 episodes of recurrence within 24 h (39.2%), 15 episodes were found between 24 and 72 h (29.4%), and the remaining 31.4% (16/51) of recurrences occurred after 72 h. All patients received surgical intussusception reduction. Meanwhile, enterectomy was the procedure of choice in 55 patients, polypectomy in 5 patients, and cystectomy in 3 patients. The types of intussusception secondary to PLPs included small intestinal (n = 25), ileocolic (n = 19), ileocecal (n = 11), ileo-ileocolic (n = 9) and cecalcolic (n = 1). The types of PLPs included Meckel diverticulum (n = 32), intestinal duplication (n = 14), benign polyps (n = 5), malignant lymphoma (n = 4), Peutz-Jeghers syndrome (n = 3), mesenteric cyst (n = 3), intestinal wall hematoma of hemophilia (n = 2), allergic purpura (n = 1), and hamartoma (n = 1). All patients recovered well with no relapse during follow-up, except for one patient who had an intestinal obstruction from adhesions that occurred approximately 3 months after discharge and who was curable after conservative treatment. CONCLUSIONS: Intussusception secondary to PLPs tends to exhibit recurrence. There are various types of intussusception secondary to PLPs. It is necessary to improve auxiliary examinations to identify the etiology and avoid intraoperative omission. Surgical reduction of intussusception secondary to PLPs is the preferred clinical management. PMID- 28584906 TI - Music intervention efficacy in elderly: a promising non-pharmacological approach to cognitive dysfunctions. PMID- 28584907 TI - Acute psychoactive and toxic effects of D. metel on mice explained by 1H NMR based metabolomics approach. AB - Datura metel L. (D. metel) is one well-known folk medical herb with wide application and also the most abused plants all over the world, mainly for spiritual or religious purpose, over-dosing of which often produces poisonous effects. In this study, mice were orally administered with the extract of D. metel once a day at doses for 10 mg/kg and 40 mg/kg for consecutive 4 days, 1H NMR based metabolomics approach aided with histopathological inspection and biochemical assays were used for the first time to study the psychoactive and toxic effects of D. metel. Histopathological inspection revealed obvious hypertrophy of hepatocytes, karyolysis and karyorrhexis in livers as well as distinct nerve cell edema, chromatolysis and lower nuclear density in brains. The increased tissue level of methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD), decreased tissue level of glutathione (GSH) along with increased serum level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) suggested brain and liver injury induced by D. metel. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis revealed significant altered metabolites and related pathway that contributed to oxidative stress, energy metabolism disturbances, neurotransmitter imbalance and amino acid metabolism disorders. PMID- 28584908 TI - The EP3 Receptor/Gz Signaling Axis as a Therapeutic Target for Diabetes and Cardiovascular Disease. AB - Cardiovascular disease is a common co-morbidity found with obesity-linked type 2 diabetes. Current pharmaceuticals for these two diseases treat each of them separately. Yet, diabetes and cardiovascular disease share molecular signaling pathways that are increasingly being understood to contribute to disease pathophysiology, particularly in pre-clinical models. This review will focus on one such signaling pathway: that mediated by the G protein-coupled receptor, Prostaglandin E2 Receptor 3 (EP3), and its associated G protein in the insulin secreting beta-cell and potentially the platelet, Gz. The EP3/Gz signaling axis may hold promise as a dual target for type 2 diabetes and cardiovascular disease. PMID- 28584910 TI - Factors that influence lower urinary tract symptom (LUTS)-related quality of life (QoL) in a healthy population. AB - OBJECTIVES: The aim of this study was to evaluate the factors affecting the lower urinary tract symptoms (LUTS) related quality of life (QoL) score. METHODS: This retrospective study analyzed 29,123 men who underwent health check-ups from January 2007 to July 2011 at a single institution. Those patients who completed the American urologic association symptom index (AUA-SI) with QoL, beck depression inventory (BDI) and state-trait anxiety inventory questionnaires were included in the study. Men with a history of medication for LUTS were excluded from the study. Men who submitted QoL scores of 3 or higher in spite of mild LUTS (total AUA-SI score <8) were defined as having a relatively worse QoL. RESULTS: Mean age of 21,390 men was 48.4 +/- 9.5 years. Mean total AUA-SI score was 6.4 +/ 5.9 points. The QoL score was well correlated with the total AUA-SI score (r = 0.705, p < 0.001). Among all AUA-SI items, AUA-SI item 1 (incomplete emptying, r = 0.600, p < 0.001) had the strongest correlation with QoL scores. On the multivariate analysis, hypertension, total AUA-SI score, BDI score, and trait anxiety score were found to be independent factors that influenced the QoL scores. A lower age, a higher PSA, a higher AUA-SI score and a higher BDI score were risk factors for relatively worse QoL scores in spite of mild LUTS. CONCLUSIONS: Among the seven items of AUA-SI, AUA-SI item 1 has the strongest correlation with a worse LUTS-related QoL. Psychological status also influences the QoL scores. PMID- 28584911 TI - Bioprospecting for beta-lactam resistance genes using a metagenomics-guided strategy. AB - Emergence of new antibiotic resistance bacteria poses a serious threat to human health, which is largely attributed to the evolution and spread of antibiotic resistance genes (ARGs). In this work, a metagenomics-guided strategy consisting of metagenomic analysis and function validation was proposed for rapidly identifying novel ARGs from hot spots of ARG dissemination, such as wastewater treatment plants (WWTPs) and animal feces. We used an antibiotic resistance gene database to annotate 76 putative beta-lactam resistance genes from the metagenomes of sludge and chicken feces. Among these 76 candidate genes, 25 target genes that shared 40~70% amino acid identity to known beta-lactamases were cloned by PCR from the metagenomes. Their resistances to four beta-lactam antibiotics were further demonstrated. Furthermore, the validated ARGs were used as the reference sequences to identify novel ARGs in eight environmental samples, suggesting the necessity of re-examining the profiles of ARGs in environmental samples using the validated novel ARG sequences. This metagenomics-guided pipeline does not rely on the activity of ARGs during the initial screening process and may specifically select novel ARG sequences for function validation, which make it suitable for the high-throughput screening of novel ARGs from environmental metagenomes. PMID- 28584913 TI - Effects of different doses of triazolam in the middle-of-the-night insomnia: a double-blind, randomized, parallel group study. AB - It has been reported that insomnia characterized by difficulty returning to sleep following a nocturnal awakening, otherwise defined as the middle-of-the-night (MOTN) insomnia, is a common form of insomnia in adults with growing prevalence by increasing age. The aim of this study is to evaluate the efficacy and safety of different dosages of triazolam in insomnia patients when taken after a MOTN awakening with difficulty returning to sleep. In this double-blind, randomized, parallel group study, 24 patients (mean age 41.00 +/- 10.40, 10 female and 14 male) affected by MOTN insomnia were enrolled and randomized into three groups according to different dosages of triazolam: group A (0.0625 mg), group B (0.125 mg), and group C (0.250 mg). A significant increment of total sleep time, sleep efficiency and a reduction of wake after sleep onset, number of awakening and non REM sleep stage 1 was observed in T1 (triazolam) in comparison to T0 (placebo) by means of polysomnographic recording, irrespective of dosage. After 2 weeks of the treatment, insomnia severity significantly improved in all three groups in comparison to baseline without diurnal residual effects. This study demonstrates that low dose of triazolam objectively and subjectively improves the sleep of patients having MOTN insomnia. PMID- 28584912 TI - New cryptotanshinone derivatives with anti-influenza A virus activities obtained via biotransformation by Mucor rouxii. AB - This paper provides an efficient platform to diversify the structure and pharmaceutical potentials of known natural products. Seven metabolites were obtained via the biotransformation of cryptotanshinone by the fungus Mucor rouxii AS 3.3447, and assigned as 13R-14R-hydroxy-anhydride of 16R-cryptotanshinone (1), 1S-hydroxy-anhydride of 16R-cryptotanshinone (2), 1R-hydroxy-anhydride of 16R cryptotanshinone (3), 3S-hydroxy-epicryptoacetalide (4), 3S-hydroxy cryptoacetalide (5), epicryptoacetalide (6), and cryptoacetalide (7). Among these compounds, 1-5 are novel. The ortho-naphthoquinone chromophore of cryptotanshinone was degraded and rearranged by M. rouxii. 1 and 3 showed good anti-influenza A virus activities with the reduced cytotoxic activities compared to the parent substrate cryptotanshinone (8). The structures of all the new compounds were determined on the basis of HRESIMS (high-resolution electrospray ionization mass spectroscopy) spectrometry, NMR (nuclear magnetic resonance) spectroscopy, ECD (electronic circular dichroism) calculations, and the CD (circular dichroism) of "in situ" method with [Rh2(OCOCF3)4]. PMID- 28584914 TI - Optical coherence tomography for the diagnosis and monitoring of idiopathic intracranial hypertension. AB - The objectives of the study were to investigate the value of optical coherence tomography in detecting papilledema in patients with idiopathic intracranial hypertension (IIH), a disease which is difficult to monitor and which can lead to permanent visual deficits; to analyze retinal changes over time. In this non interventional case-control study, spectral-domain optical coherence tomography (SD-OCT) was used to analyze the retinal and optic nerve head (ONH) morphology of 21 patients with IIH and 27 age- and sex-matched healthy controls over time. We analyzed the ONH volume using a custom-made algorithm and employed semi-automated segmentation of macular volume scans to assess the macular retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer complex as well as the total macular volume. In IIH patients, the ONH volume was increased and correlated with cerebrospinal fluid (CSF) pressure. The ONH volume decreased after the initiation of treatment with acetazolamide. The macular RNFL volume decreased by 5% in 3.5 months, and a stepwise multivariate regression analysis identified CSF pressure as the main influence on macular RNFL volume at diagnosis. The only factor predicting macular RNFL volume loss over time was ONH volume. SD-OCT can non-invasively monitor changes in retinal and ONH morphology in patients with IIH. Increased ONH volume leads to retinal atrophy in the form of macular RNFL volume loss, presumably due to mechanic jamming of the optic nerve at the disc and subsequent axonal loss. PMID- 28584909 TI - A Review of Phosphate Binders in Chronic Kidney Disease: Incremental Progress or Just Higher Costs? AB - As kidney disease progresses, phosphorus retention also increases, and phosphate binders are used to treat hyperphosphatemia. Clinicians prescribe phosphate binders thinking that reducing total body burden of phosphorus may decrease risks of mineral and bone disorder, fractures, cardiovascular disease, progression of kidney disease, and mortality. Recent meta-analyses suggest that sevelamer use results in lower mortality than use of calcium-containing phosphate binders. However, studies included in meta-analyses show significant heterogeneity, and exclusion or inclusion of specific studies alters results. Since no long-term studies have been conducted to determine whether treatment with any phosphate binder is better than placebo on any hard clinical endpoint (including mortality), it is unclear whether possible benefit with sevelamer represents net benefit of sevelamer, net harm with calcium-containing phosphate binders, or both. Although one meta-analysis suggested that calcium acetate may be more efficacious gram for gram than calcium carbonate as a binder, calcium acetate did not reduce hypercalcemia, and gastrointestinal intolerance was higher. Data are insufficient to determine whether calcium acetate provides lower risk of vascular calcification than calcium carbonate. Fears of lanthanum accumulation in the central nervous system or bone with long-term treatment do not appear to be warranted. Newer iron-containing phosphate binders have potential benefits, such as lower pill burden (sucroferric oxyhydroxide) and improved iron parameters (ferric citrate). The biggest challenge to phosphate binder efficacy is non adherence. This article reviews the current knowledge regarding safety, effectiveness, and adherence with currently marketed phosphate binders and those in development. PMID- 28584915 TI - Understanding Lennox-Gastaut syndrome: insights from focal epilepsy patients with Lennox-Gastaut features. AB - To delineate the clinical and EEG features of adults with focal epilepsy associated with a generalized paroxysmal fast activity (GPFA) pattern on EEG who developed refractory seizures, notably drop attacks, but do not fulfill the classical triad for the diagnosis of Lennox-Gastaut syndrome (LGS) and provide further insight into LGS mechanisms. Among 957 patients admitted to video-EEG monitoring between 2002 and 2015, we retrospectively research adult patients with refractory focal epilepsy, drop attacks and GPFA on EEG. We collected demographic, anamnestic, and clinical data from medical records. We reviewed for all patients the interictal and ictal video-EEG recordings. We identified ten patients with focal epilepsy and electro-clinical features of LGS. As compared to classical LGS patients, our patients: (1) began epilepsy later (15.4 +/- 8 years); (2) exhibited exclusively focal onset seizures, including drop attacks seizures linked to focal asymmetrical tonic posturing seizures; (3) had a stable cognition over time and (4) evolved favourably with a good secondary response to treatments in 80% of cases. Interestingly, all patients exhibited apparent diffuse interictal and ictal EEG abnormalities but a detailed analysis revealed that 50% had asymmetrical GPFA and 70% secondary bilateral synchrony processes. We may hypothesize here that a process of "secondary LGS" occurred which produced a worsening of seizures with the apparition of drop attacks and GPFA on EEG. This study brings arguments to consider that some cases of LGS could be linked to the development of a "secondary epileptic network" driven by a primary focal epileptic zone. PMID- 28584916 TI - Hypoesthesia associated with mandibular movement after sagittal split ramus osteotomy. AB - PURPOSE: This retrospective study investigated the relationship between the degree of neurosensory disturbance (NSD) and mandibular movement distance after sagittal split ramus osteotomy (SSRO) and assessed sensory recovery. METHODS: Lower lip hypoesthesia was evaluated at 1 week, 1 month, and 2 months after SSRO in 38 patients categorized according to the distance of mandibular movement: S group (0-7 mm; n = 17, 4 males and 13 females) and L group (7-14 mm; n = 21, 7 males, 14 females). Symptoms were evaluated by visual analog scale (VAS), tactile threshold (SW) test, static 2-point discrimination (s-2PD) test, and current perception threshold (CPT) test. RESULTS: The two groups did not differ significantly in gender and age. The Abeta fiber results of the CPT test differed significantly between the groups at 1 week and 1 month postsurgery (P < 0.05). There were no significant differences between the groups throughout the period in terms of VAS, SW, s-2PD, Adelta fiber, and C fiber of CPT. CONCLUSIONS: Post SSRO, the incidence of NSD in terms of tactile sensation may be greater in the L group early postoperatively. This may assist surgeons in explaining postoperative hypoesthesia to patients preoperatively. PMID- 28584917 TI - Morphometry and microsurgical anatomy of Bochdalek's flower basket and the related structures of the cerebellopontine angle. AB - BACKGROUND: Bochdalek's flower basket (Bfb) is the distal part of the horizontal segment of the fourth ventricle's choroid plexus protruding through the lateral aperture (foramen of Luschka). The microsurgical anatomy of the cerebellopontine angle, fourth ventricle and its inner choroid plexus is well described in the literature, but only one radiological study has investigated the Bfb so far. The goal of the present study was to give an extensive morphometric analysis of the Bfb for the first time and discuss the surgically relevant anatomical aspects. METHOD: Forty-two formalin-fixed human brains (84 cerebellopontine angles) were involved in this study. Photomicrographs with scale bars were taken in every step of dissection to perform further measurements with Fiji software. The lengths and widths of the Bfb, rhomboid lip and lateral aperture of the fourth ventricle as well as the related neurovascular and arachnoid structures were measured. The areas of two sides were compared with paired t-tests using R software. Significance level was set at p < 0.05. RESULTS: Protruding choroid plexus was present in 77 cases (91.66%). In 6 cases (7.14%), the Bfb was totally covered by the rhomboid lip, and in one case (1.19%), it was absent. The mean width of the Bfb was 6.618 mm (2-14 mm), the mean height 5.658 mm (1.5-14 mm) and mean area 25.80 mm2 (3.07-109.83 mm2). There was no statistically significant difference between the two sides (p = 0.1744). The Bfb was in contact with 20 AICAs (23.80%), 6 PICAs (7.14%) and 39 vestibulocochlear nerves (46.42%). Arachnoid trabecules, connecting the lower cranial nerves to the Bfb or rhomboid lip, were found in 57 cases (67.85%). CONCLUSIONS: The Bfb is an important landmark during various surgical procedures. Detailed morphology, dimensions and relations to the surrounding neurovascular structures are described in this study. These data are essential for surgeons operating in this region. PMID- 28584918 TI - Association between telomere length and PIK3CA amplification in gastric cancer. PMID- 28584919 TI - Incidental finding in a young man. PMID- 28584921 TI - Patterns of Bullying and Sexual Harassment: Connections with Parents and Teachers as Direct Protective Factors. AB - Involvement in bullying and sexual harassment in adolescence is associated with a variety of internalizing, externalizing, and health-risk behaviors. Yet, the two behaviors are often studied independently. The current study examined how bullying and sexual harassment co-occur and whether social connections protected youth from risk patterns. The data for this study come from the 2013 Minnesota Student Survey (N = 121,311; 50% female, 74% White, 26% received free or reduced price lunch; M age = 14.9, SD = 1.3). Students reported on bullying and sexual harassment victimization and perpetration. Using latent class analysis, youth were classified into five patterns: High-Risk of All Forms of Victimization and Perpetration (7%), Relational and Cyberbullying Victimization (17%), Sexual Harassment Victimization and Perpetration (8%), Physical Bullying Perpetration (6%), and Low-Risk (62%). Compared to the low-risk class, the four other classes had lower levels of social connections, particularly with teachers and parents. Older youth (9th and 11th grade students) were at greater risk for the sexual harassment pattern, while younger youth (8th grade students) were at greater risk for bullying patterns. The results indicate that efforts to reduce bullying should also address sexual harassment and social connections with adults. PMID- 28584920 TI - Co-culture of dedifferentiated and primary human chondrocytes obtained from cadaveric donor enhance the histological quality of repair tissue: an in-vivo animal study. AB - To compare the quality of the repair tissue in three-dimensional co-culture of human chondrocytes implanted in an in vivo model. Six cadaveric and five live human donors were included. Osteochondral biopsies from the donor knees were harvested for chondrocyte isolation. Fifty percent of cadaveric chondrocytes were expanded until passage-2 (P2) while the remaining cells were cryopreserved in passage-0 (P0). Fresh primary chondrocytes (P0f) obtained from live human donors were co-cultured. Three-dimensional constructs were prepared with a monolayer of passage-2 chondrocytes, collagen membrane (Geistlich Bio-Gide(r)), and pellet of non-co-cultured (P2) or co-cultured chondrocytes (P2 + P0c, P2 + P0f). Constructs were implanted in the subcutaneous tissue of athymic mice and left for 3 months growth. Safranin-O and Alcian blue staining were used to glycosaminoglycan content assessment. Aggrecan and type-II collagen were evaluated by immunohistochemistry. New-formed tissue quality was evaluated with an adaptation of the modified O'Driscoll score. Histological quality of non-co-cultured group was 4.37 (SD +/-4.71), while co-cultured groups had a mean score of 8.71 (SD +/ 3.98) for the fresh primary chondrocytes and 9.57 (SD +/-1.27) in the cryopreserved chondrocytes. In immunohistochemistry, Co-culture groups were strongly stained for type-II and aggrecan not seen in the non-co-cultured group. It is possible to isolate viable chondrocytes from cadaveric human donors in samples processed in the first 48-h of dead. There is non-significant difference between the numbers of chondrocytes isolated from live or cadaveric donors. Cryopreservation of cadaveric primary chondrocytes does not alter the capability to form cartilage like tissue. Co-culture of primary and passaged chondrocytes enhances the histological quality of new-formed tissue compared to non-co cultured cells. PMID- 28584923 TI - Arabidopsis FRIGIDA stimulates EFS histone H3 Lys36 methyltransferase activity. PMID- 28584922 TI - Deletion of a target gene in Indica rice via CRISPR/Cas9. AB - KEY MESSAGE: Using CRISPR/Cas9, we successfully deleted large fragments of the yield-related gene DENSE AND ERECT PANICLE1 in Indica rice at relatively high frequency and generated gain-of-function dep1 mutants. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 is a rapidly developing technology used to produce gene-specific modifications in both mammalian and plant systems. Most CRISPR-induced modifications in plants reported to date have been small insertions or deletions. Few large target gene deletions have thus far been reported, especially for Indica rice. In this study, we designed multiple CRISPR sgRNAs and successfully deleted DNA fragments in the gene DENSE AND ERECT PANICLE1 (DEP1) in the elite Indica rice line IR58025B. We achieved deletion frequencies of up to 21% for a 430 bp target and 9% for a 10 kb target among T0 events. Constructs with four sgRNAs did not generate higher full-length deletion frequencies than constructs with two sgRNAs. The multiple mutagenesis frequency reached 93% for four targets, and the homozygous mutation frequency reached 21% at the T0 stage. Important yield-related trait characteristics, such as dense and erect panicles and reduced plant height, were observed in dep1 homozygous T0 mutant plants produced by CRISPR/Cas9. Therefore, we successfully obtained deletions in DEP1 in the Indica background using the CRISPR/Cas9 editing tool at relatively high frequency. PMID- 28584924 TI - Echography of pneumatosis intestinalis and hepatic portal venous gas in a patient with septic shock. PMID- 28584926 TI - Theory of mind performance in Parkinson's disease is associated with motor and cognitive functions, but not with symptom lateralization. AB - Next to the typical motor signs, Parkinson's disease (PD) goes along with neuropsychiatric symptoms, amongst others affecting social cognition. Particularly, Theory of Mind (ToM) impairments have mostly been associated with right hemispherical brain dysfunction, so that it might prevail in patients with left dominant PD. Fourty-four PD patients, twenty-four with left and twenty with right dominant motor symptoms, engaged in the Reading the Mind in the Eyes (RME) and the Faux Pas Detection Test (FPD) to assess affective and cognitive ToM. The results were correlated with performance in further cognitive tests, and analyzed with respect to associations with the side of motor symptom dominance and severity of motor symptoms. No association of ToM performance with right hemispheric dysfunction was found. RME results were inversely correlated with motor symptom severity, while FPD performance was found to correlate with the performance in verbal fluency tasks and the overall cognitive evaluation. Affective ToM was found associated with motor symptom severity and cognitive ToM predominantly with executive function, but no effect of PD lateralization on this was identified. The results suggest that deficits in social cognition occur as a sequel of the general corticobasal pathology in PD, rather than as a result of hemisphere-specific dysfunction. PMID- 28584927 TI - CORR Insights(r): Rotational Laxity Control by the Anterolateral Ligament and the Lateral Meniscus Is Dependent on Knee Flexion Angle: A Cadaveric Biomechanical Study. PMID- 28584925 TI - Peripherally inserted central catheters are associated with lower risk of bloodstream infection compared with central venous catheters in paediatric intensive care patients: a propensity-adjusted analysis. AB - PURPOSE: Central line-associated bloodstream infection (CLABSI) is an important cause of complications in paediatric intensive care units (PICUs). Peripherally inserted central catheters (PICCs) could be an alternative to central venous catheters (CVCs) and the effect of PICCs compared with CVCs on CLABSI prevention is unknown in PICUs. Therefore, we aimed to evaluate whether PICCs were associated with a protective effect for CLABSI when compared to CVCs in critically ill children. METHODS: We have carried out a retrospective multicentre study in four PICUs in Sao Paulo, Brazil. We included patients aged 0-14 years, who needed a CVC or PICC during a PICU stay from January 2013 to December 2015. Our primary endpoint was CLABSI up to 30 days after catheter placement. We defined CLABSI based on the Center for Disease Control and Prevention's National Healthcare Safety Networks (NHSN) 2015 surveillance definitions. To account for potential confounders, we used propensity scores with inverse probability weighting. RESULTS: A total of 1660 devices (922 PICCs and 738 CVCs) in 1255 children were included. The overall CLABSI incidence was 2.28 (95% CI 1.70 3.07)/1000 catheter-days. After covariate adjustment using propensity scores, CVCs were associated with higher risk of CLABSI (adjHR 2.20, 95% CI 1.05-4.61; p = 0.037) compared with PICCs. In a sensitivity analysis, CVCs remained associated with higher risk of CLABSI (adjHR 2.18, 95% CI 1.02-4.64; p = 0.044) after adding place of insertion and use of parenteral nutrition to the model as a time dependent variable. CONCLUSIONS: PICC should be an alternative to CVC in the paediatric intensive care setting for CLABSI prevention. PMID- 28584930 TI - The reality of scientific research in Latin America; an insider's perspective. AB - There is tremendous disparity in scientific productivity among nations, particularly in Latin America. At first sight, this could be linked to the relative economic health of the different countries of the region, but even large and relatively rich Latin American countries do not produce a good level of science. Although Latin America has increased the number of its scientists and research institutions in recent years, the gap between developed countries and Latin American countries is startling. The prime importance of science and technology to the development of a nation remains unacknowledged. The major factors contributing to low scientific productivity are the limited access to grant opportunities, inadequate budgets, substandard levels of laboratory infrastructure and equipment, the high cost and limited supply of reagents, and inadequate salaries and personal insecurity of scientists. The political and economic instability in several Latin America countries results in a lack of long term goals that are essential to the development of science. In Latin America, science is not an engine of the economy. Most equipment and supplies are imported, and national industries are not given the incentives to produce these goods at home. It is a pity that Latin American society has become accustomed to expect new science and technological developments to come from developed countries rather than from their own scientists. In this article, we present a critical view of the Latin American investigator's daily life, particularly in the area of biomedicine. Too many bright young minds continue to leave Latin America for developed countries, where they are very successful. However, we still have many enthusiastic young graduates who want to make a career in science and contribute to society. Governments need to improve the status of science for the sake of these young graduates who represent the intellectual and economic future of their countries. PMID- 28584928 TI - Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys. AB - RATIONALE: Accumulating evidence shows that the serotonergic system plays a major role in psychostimulant abuse through its interactions with the dopaminergic system. Studies indicate that serotonin 5-HT2C receptors are one of the main classes of receptors involved in mediating the influence of serotonin in drug abuse. OBJECTIVE: The aim of the present study was to evaluate the effects of the selective serotonin 5-HT2C receptor agonist WAY163909 on the behavioral neuropharmacology of cocaine and methamphetamine in adult rhesus macaques. METHODS: Cocaine or methamphetamine self-administration and reinstatement were evaluated under second-order and fixed-ratio schedules of reinforcement, respectively. Cocaine- and methamphetamine-induced increases in dopamine were assessed through in vivo microdialysis targeting the nucleus accumbens. RESULTS: Pretreatment with WAY163909 dose-dependently attenuated cocaine and methamphetamine self-administration and drug-induced reinstatement of extinguished behavior previously maintained by cocaine or methamphetamine delivery. In an additional experiment, WAY163909 induced a dose-dependent attenuation of cocaine- or methamphetamine-induced dopamine overflow in the nucleus accumbens. CONCLUSIONS: Our data indicate that selective 5-HT2C receptor activation decreases drug intake and drug-seeking behavior in nonhuman primate models of psychostimulant abuse through neurochemical mechanisms involved in the modulation of mesolimbic dopamine. PMID- 28584929 TI - Steep effort discounting of a preferred reward over a freely-available option in prolonged methamphetamine withdrawal in male rats. AB - RATIONALE: Drug addiction can be described as aberrant allocation of effort toward acquiring drug, despite associated costs. It is unclear if this behavioral pattern results from an overvaluation of reward or to an altered sensitivity to costs. OBJECTIVE: Present experiments assessed reward sensitivity and effortful choice in rats following 1 week of withdrawal from methamphetamine (mAMPH). METHODS: Rats were treated with either saline or an escalating dose mAMPH regimen, then tested after a week without the drug. In experiment 1, rats were given a free choice between water and various concentrations of sucrose solution to assess general reward sensitivity. In experiment 2, rats were presented with a choice between lever-pressing for sucrose pellets on a progressive ratio schedule or consuming freely-available chow. RESULTS: In experiment 1, we found no differences in sucrose preference between mAMPH- and saline-pretreated rats. In experiment 2, when selecting between two options, mAMPH-pretreated rats engaged in less lever-pressing for sucrose pellets (p < 0.01) and switched from this preferred reward to the chow sooner than saline-pretreated rats (p < 0.05). This effect was not consistent with general reward devaluation or loss of motivation. CONCLUSIONS: These findings demonstrate that mAMPH exposure and withdrawal lead to steeper discounting of reward value by effort, an effect that is consistent with the effect of mAMPH on discounting by delay, and which may reflect an underlying shared mechanism. PMID- 28584931 TI - Pacing strategy during the final stage of a self-paced VO2max (SPV) test does not affect maximal oxygen uptake. AB - PURPOSE: Self-paced [Formula: see text] tests (SPVs) have shown to produce maximal oxygen consumption values similar to those from traditional protocols. These tests involve perceptually regulated stages in which subjects are asked to maintain rating of perceived exertion values of 11, 13, 15, 17 and 20 for 2 min each. What is not clear is how the last stage should be paced. The purpose of this study was to compare two different pacing strategies during the final stage. METHODS: Fourteen healthy, recreationally active individuals (11 men, 3 women) participated in a familiarization and two experimental laboratory visits. For both lab visits, a treadmill-based SPV was performed. In one of these SPVs, an aggressive pacing strategy was used; in the other, a conservative strategy was implemented. [Formula: see text], HR, [Formula: see text], [Formula: see text] and RER were recorded and compared between conditions. RESULTS: There were no differences in [Formula: see text] between the conditions [aggressive 58.8 +/- 8.8 ml kg-1 min-1 (mean +/- SD), conservative 58.3 +/- 7.9 ml kg-1 min-1; p = 0.548]. There were also no differences in HR, [Formula: see text], or [Formula: see text] between the pacing strategies. There was a significantly higher RER found in the aggressive (1.25 +/- 0.09) compared to the conservative (1.18 +/- 0.07) strategy (p = 0.040). CONCLUSIONS: The pacing strategy that is implemented in the last 2 min of an SPV on a treadmill does not affect the maximal oxygen consumption that is elicited during that test. Either pacing strategy can be used for this protocol without compromising the results, when [Formula: see text] is the variable of interest. PMID- 28584932 TI - Modifications of a signal sequence for antibody secretion from insect cells. AB - Monoclonal antibodies and antibody fragments have recently been developed for use in diverse diagnostic and therapeutic applications. Insect cells can efficiently secrete recombinant proteins such as antibody molecules through post translational processing and modifications that are similar to those performed in mammalian cells. In eukaryotic cells, the signal sequence in a nascent polypeptide is recognized by the signal recognition particle, and the polypeptide is then folded and modified in the endoplasmic reticulum. The signal sequence consists of three regions, a positively charged N-terminus, a hydrophobic core, and a polar C-terminus. In the present study, we examined the substitutions of the characteristic amino acids of a Drosophila immunoglobulin heavy chain binding protein signal sequence, and investigated the effect on the secretory production of an antibody Fab fragment from lepidopteran insect cells in transient expression. A modification of the signal sequence for the heavy chain resulted in a twofold increase in the secreted Fab fragment, while the modification for the light chain led to a more than 3.6-fold increase. PMID- 28584933 TI - Reply to: MASCC/ESMO consensus recommendations for the management of nausea and vomiting in advanced cancer. PMID- 28584934 TI - Management of infection during chemotherapy for acute leukemia in Japan: a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group. AB - PURPOSE: We performed a nationwide questionnaire-based survey to evaluate the current clinical practices of infectious complications during chemotherapy for acute leukemia in Japan. METHODS: We e-mailed a questionnaire to member institutions of the Japan Adult Leukemia Study Group in September, 2013. The questionnaire consisted of 50 multiple-choice questions covering therapeutic environment, antimicrobial prophylaxis, screening test during neutropenia, empirical therapy for febrile neutropenia, and the use of granulocyte-colony stimulating factor. The results were compared to those of previous surveys conducted in 2001 and 2007, and also to the recommendations described in the guidelines. RESULTS: Usable responses were received from 141 out of 222 (63.5%) institutions. Chemotherapy for acute myeloid leukemia was performed in protective environment in 90% of the institutions, which increased compared to previous survey (76%). Fluoroquinolones and fluconazole were the most commonly used antimicrobial agents for antibacterial and antifungal prophylaxis, followed by sulfamethoxazole-trimethoprim and itraconazole, respectively. In empirical therapy for febrile neutropenia, monotherapy with beta-lactum antibiotics was the first-line therapy in most of the institutions. While empirical antifungal therapy was adopted for persistent fever in more than half of the institutions, preemptive/presumptive therapy was also used in approximately 40% of the institutions. Most of the clinicians were reluctant to use granulocyte-colony stimulating factor routinely in chemotherapy for acute myeloid leukemia. CONCLUSIONS: This study clarified the current clinical practices of infectious complications during chemotherapy for acute leukemia and would provide important information for the development of a suitable guideline in Japan. PMID- 28584935 TI - Evaluation of Optic Nerve Head Parameters and Retinal Nerve Fiber Layer Thickness in Axial Myopia Using SD OCT. AB - INTRODUCTION: The purpose of this research was to study the effect of increased axial myopia, in non-glaucomatous eyes, and its correlation with ONH parameters, and RNFL thickness, using Cirrus HD 4000 SD-OCT. METHODS: The myopia group included 86 eyes of 86 patients, while the control group involved 92 eyes of 92 patients, attending the Ophthalmology Outpatient Clinic in Minia University Hospital, between November 2013 and March 2015. ONH parameters and peripapillary RNFL thickness measurement were evaluated by using SD-OCT, selecting the standard optic disc cube 200 * 200. RESULTS: The mean age of the myopia group was (36.55 +/- 9.44), the mean spherical equivalent was (-12.70 +/- 3.87 D), and the mean axial length was (27.88 +/- 1.92 mm). The control group had mean age of (34.82 +/ 8.87), mean spherical equivalent of -0.65 +/- 0.41 D, and mean AL of (22.16 +/- 0.82). A significant difference was reported between the two groups, regarding disc area (p = 0.01), rim area (p = 0.001), vertical C/D (p = 0.01), average C/D ratio (p = 0.001), average and temporal RNFL thickness (p = 0.0001, p = 0.001, respectively). CONCLUSION: A significant difference was found between highly myopic non-glaucomatous eyes and the control group, regarding ONH parameters and RNFL thickness as measured by SD-OCT. As OCT magnification adjusted ONH parameters were larger, global and the temporal RNEL were thicker in the myopia group, those magnification adjusted parameters helped in an accurate evaluation of ONH and RNFL in highly myopic eyes, in order to avoid misdiagnosis of glaucoma in such eyes. PMID- 28584937 TI - A Single-Port Robotic Platform for Laparoscopic Surgery with a Large Central Channel for Additional Instrument. AB - A new approach to a surgical robotic platform for single incision laparoscopic or natural orifice transluminal endoscopic surgery is presented in this paper This platform allows insertion of up to four instruments including the robotic arms and the camera through a single cannula at the same footprint. After insertion of all instruments, a large central channel of 15 mm diameter is kept clear for the passage of additional laparoscopic instruments, such as passage or retrieval of suture needles, and/or suction irrigators which greatly facilitates the performance of complex surgical procedures. Phantom and animal trials have been performed to evaluate the insertion and retrieval sequences. These important features were made possible by internally-motorized robotic arms with 7 degrees of freedom and with no external mechanical device connections. The whole platform, together with the 3 degrees of freedom from the swivel system that support the cannula, has altogether 10 degrees of freedom to allow the operation of complex surgeries and access to all quadrants of the abdominal cavity. This new single-port robotic platform paves a new development direction for future non invasive surgery. PMID- 28584936 TI - A Review of Nitric Oxide for the Treatment of Glaucomatous Disease. AB - Glaucoma is the leading cause of irreversible blindness worldwide, affecting 64.3 million people. An estimated 60.5 million people are affected by primary open angle glaucoma globally, and this will increase to 111.8 million by 2040. The definition of glaucoma has evolved greatly over time. Although multiple risk factors such as ischemia, inflammation, myopia, race, age and low ocular perfusion pressure may play a role, intraocular pressure (IOP) is still the main risk factor we can easily identify and modify. Currently, both medical and surgical interventions aim to reduce IOP. Effective IOP reduction controls and prevents the progression in many cases of glaucoma. Although this multifactorial disease's true pathophysiology is difficult to elucidate, physiologic mediators including nitric oxide (NO) are being evaluated as novel ways to impact progression by both lowering IOP and improving optic nerve head perfusion. Latanoprostene bunod 0.024% is an emerging therapeutic agent that has shown promise in clinical trials. As a nitric oxide-donating prostaglandin F2-alpha receptor agonist, it has proven to effectively, and with good tolerability, reduce IOP in glaucoma and ocular hypertensive patients. Latanoprostene bunod capitalizes on NO's ability to modulate the conventional aqueous humor outflow system, directly improving outflow through the trabecular meshwork, Schlemm's canal and distal scleral vessels. Importantly, targeting the conventional outflow tissues with NO-donating drugs represents an opportunity to restore outflow function, which will most likely have a beneficial consequence of additional IOP lowering effects with dampening of diurnal and other IOP fluctuations, the benefit of a healthy trabecular meshwork. PMID- 28584938 TI - The effect of sleep duration on exhaled nitric oxide levels in U.S. adults. AB - PURPOSE: Poor sleep quality and duration are associated with systemic endothelial dysfunction. However, an association between poor sleep and pulmonary endothelial dysfunction has not been elucidated. We sought to determine if there is a relationship between sleep duration and fractional exhaled nitric oxide (FeNO) concentrations as a surrogate for pulmonary endothelial function. METHODS: We used three National Health and Nutrition Examination Survey (NHANES) cycles (2007 2012). Linear regression models were built with and without adjustment for age, sex, race, BMI, asthma/bronchitis, CRP, smoking, folate, renal function, respiratory infections, and steroid use. To examine a non-linear relationship, we introduced a spline, with single knot at mean sleep duration (7 h). RESULTS: Of 13,173 participants (50.8% male, 44.2% Caucasian), 78% slept 6-8 hours (h). FeNO was significantly higher in the group sleeping 6-8 h (17.3 +/- 14.9 ppb) than in the other two groups (16.0 +/- 13.0 ppb, 15.9 +/- 12.7 ppb for <6 and >8 h respectively; P < 0.001). In unadjusted linear regression, FeNO increased by 1.1 ppb for each hour increase in sleep up to 7 h (P < 0.001). Increased sleep duration beyond 7 h saw a 0.96 ppb decrease in FeNO (P < 0.001). After adjustment for confounders, FeNO increased by 1.09 ppb for each hour of sleep up to 7 h (P = 0.001) and decreased by 0.71 ppb for each hour after (P = 0.02). CONCLUSION: Sleeping less or more than 7 h is associated with pulmonary endothelial dysfunction as measured by FeNO. Further study is needed to evaluate mechanism(s) of this association and validity of FeNO as a marker of endothelial function. PMID- 28584939 TI - Severity of desaturation events differs between hypopnea and obstructive apnea events and is modulated by their duration in obstructive sleep apnea. AB - PURPOSE: Frequency of apnea and hypopnea events is used to estimate the severity of obstructive sleep apnea (OSA). However, comprehensive information on whether apneas and hypopneas cause an equal biological effect is not available. The purpose of the present work was to evaluate the effect of the breathing cessation event type (i.e., obstructive apnea or hypopnea) and duration on the severity of related SpO2 desaturation events. METHODS: Type 1 polysomnographies of 395 patients (220 males and 175 females) examined for suspected OSA were analyzed. Desaturation severity related to hypopnea and obstructive apnea events were compared and comparison was controlled for gender, sleep stage, sleeping position, age, and body mass index. Hypopneas and obstructive apneas were further divided into eight different durational categories and related desaturation event characteristics were compared between the categories. RESULTS: SpO2 desaturation events caused by obstructive apneas were statistically significantly (p <= 0.004) longer, greater in area, and deeper compared to the SpO2 desaturations caused by hypopneas. The increase in the duration of hypopnea and obstructive apnea events led to increase in the duration and area of related SpO2 desaturations. The increase in the obstructive apnea event duration also led to increase in the depth of related desaturation event. CONCLUSIONS: Obstructive apneas led to more severe SpO2 desaturation compared to hypopneas. Increased event duration led to increase in the severity of the related SpO2 desaturation. In addition to considering event duration, obstructive apneas should have more weight than hypopneas when estimating severity of OSA and associated long-term cardiovascular risk. PMID- 28584940 TI - Drug-induced sedation endoscopy (DISE) classification systems: a systematic review and meta-analysis. AB - PURPOSE: Drug-induced sedation endoscopy (DISE) classification systems have been used to assess anatomical findings on upper airway obstruction, and decide and plan surgical treatments and act as a predictor for surgical treatment outcome for obstructive sleep apnoea management. The first objective is to identify if there is a universally accepted DISE grading and classification system for analysing DISE findings. The second objective is to identify if there is one DISE grading and classification treatment planning framework for deciding appropriate surgical treatment for obstructive sleep apnoea (OSA). The third objective is to identify if there is one DISE grading and classification treatment outcome framework for determining the likelihood of success for a given OSA surgical intervention. METHODS: A systematic review was performed to identify new and significantly modified DISE classification systems: concept, advantages and disadvantages. RESULTS: Fourteen studies proposing a new DISE classification system and three studies proposing a significantly modified DISE classification were identified. None of the studies were based on randomised control trials. CONCLUSION: DISE is an objective method for visualising upper airway obstruction. The classification and assessment of clinical findings based on DISE is highly subjective due to the increasing number of DISE classification systems. Hence, this creates a growing divergence in surgical treatment planning and treatment outcome. Further research on a universally accepted objective DISE assessment is critically needed. PMID- 28584941 TI - 'Trophic' and 'source' amino acids in trophic estimation: a likely metabolic explanation. AB - Amino acid nitrogen isotopic analysis is a relatively new method for estimating trophic position. It uses the isotopic difference between an individual's 'trophic' and 'source' amino acids to determine its trophic position. So far, there is no accepted explanation for the mechanism by which the isotopic signals in 'trophic' and 'source' amino acids arise. Yet without a metabolic understanding, the utility of nitrogen isotopic analyses as a method for probing trophic relations, at either bulk tissue or amino acid level, is limited. I draw on isotopic tracer studies of protein metabolism, together with a consideration of amino acid metabolic pathways, to suggest that the 'trophic'/'source' groupings have a fundamental metabolic origin, to do with the cycling of amino nitrogen between amino acids. 'Trophic' amino acids are those whose amino nitrogens are interchangeable, part of a metabolic amino-nitrogen pool, and 'source' amino acids are those whose amino-nitrogens are not interchangeable with the metabolic pool. Nitrogen isotopic values of 'trophic' amino acids will reflect an averaged isotopic signal of all such dietary amino acids, offset by the integrated effect of isotopic fractionation from nitrogen cycling, and modulated by metabolic and physiological effects. Isotopic values of 'source' amino acids will be more closely linked to those of equivalent dietary amino acids, but also modulated by metabolism and physiology. The complexity of nitrogen cycling suggests that a single identifiable value for 'trophic discrimination factors' is unlikely to exist. Greater consideration of physiology and metabolism should help in better understanding observed patterns in nitrogen isotopic values. PMID- 28584942 TI - Combined CT, Fluoroscopic and IVUS Guidance for Percutaneous Treatment of a Postsurgical Pseudoaneurysm Following Repair of Ascending Thoracic Aortic Aneurysm. AB - Thoracic aortic pseudoaneurysms are a recognized complication following aortic arch replacement. The established first line treatment is surgical repair; however, this may not be feasible in all patients. Percutaneous treatment of ascending thoracic pseudoaneurysms has been described as an alternative for nonsurgical candidates. Utilization of multimodality imaging can prove invaluable in minimizing the risk of potentially fatal intra-procedural complications. We present a case of successful embolization using computer tomography-guided direct percutaneous puncture of the pseudoaneurysm, with concomitant endovascular treatment under fluoroscopic and intravascular ultrasound guidance in a patient with challenging vascular anatomy. PMID- 28584943 TI - Compartment Syndrome after Embolization of Arteriovenous Malformation. AB - Management of arteriovenous malformations (AVMs) remains challenging because of their unpredictable course and high morbidity rate. In this case report, we present a patient with a huge AVM on the right calf who suffered complications of compartment syndrome, rhabdomyolysis, skin necrosis, and nerve damage after sclerotherapy. Limb salvage was achieved in spite of these devastating complications. A multidisciplinary team approach is important especially when making decisions for the management of a complicated AVM. PMID- 28584944 TI - Psoas Abscess and Spondylodiscitis Following Radiofrequency Ablation of a Renal Tumour: Unexpected Complications. PMID- 28584945 TI - Cirse Quality Assurance Document and Standards for Classification of Complications: The Cirse Classification System. AB - Interventional radiology provides a wide variety of vascular, nonvascular, musculoskeletal, and oncologic minimally invasive techniques aimed at therapy or palliation of a broad spectrum of pathologic conditions. Outcome data for these techniques are globally evaluated by hospitals, insurance companies, and government agencies targeting in a high-quality health care policy, including reimbursement strategies. To analyze effectively the outcome of a technique, accurate reporting of complications is necessary. Throughout the literature, numerous classification systems for complications grading and classification have been reported. Until now, there has been no method for uniform reporting of complications both in terms of definition and grading. The purpose of this CIRSE guideline is to provide a classification system of complications based on combining outcome and severity of sequelae. The ultimate challenge will be the adoption of this system by practitioners in different countries and health economies within the European Union and beyond. PMID- 28584946 TI - Post-procedural Care in Interventional Radiology: What Every Interventional Radiologist Should Know-Part II: Catheter Care and Management of Common Systemic Post-procedural Complications. AB - Interventional radiology (IR) has evolved into a full-fledged clinical specialty with attendant comprehensive patient care responsibilities. Providing excellent and thorough clinical care is as essential to the practice of IR as achieving technical success in procedures. Basic clinical skills that every interventional radiologist should learn include routine management of percutaneously inserted drainage and vascular catheters and rapid effective management of common systemic post-procedural complications. A structured approach to post-procedural care, including routine follow-up and early identification and management of complications, facilitates efficient and thorough management with an emphasis on quality and patient safety. The aim of this second part, in conjunction with part 1, is to complete the comprehensive review of post-procedural care in patients undergoing interventional radiology procedures. We discuss common problems encountered after insertion of drainage and vascular catheters and describe effective methods of troubleshooting these problems. Commonly encountered systemic complications in IR are described, and ways for immediate identification and management of these complications are provided. PMID- 28584947 TI - Mechanical Recanalization Using Solitaire AB Device for Severe Thromboembolic Events in Endovascular Treatment of Intracranial Aneurysms. AB - INTRODUCTION: Severe thromboembolism with complete occlusion of the proximal arteries during or after coil embolization can cause serious neurologic deficits. The study aimed to assess the effectiveness and safety of Solitaire AB device as a rescue therapy for severe thromboembolic complications in the endovascular treatment of intracranial aneurysms. MATERIALS AND METHODS: Between February 2013 and April 2016, 1047 intracranial aneurysms treated with endovascular procedures were retrospectively reviewed in our center. Severe thromboembolisms occurred in ten patients and were treated by Solitaire AB device including clot retriever and permanent stent deployment. RESULTS: The location of arterial occlusion was distal to the aneurysm rather than the coil/parent artery interface or in-stent area. Four patients had distal thromboembolic events before coil embolization, and six patients had it after coiling. The complete arterial recanalization (TICI 3) was achieved in all patients, and no cerebral hemorrhage was related to the procedure after the rescue therapy. Among these patients with the aforementioned neurovascular procedures, the mean Glasgow Outcome Scale (GOS) score was 4.5 (ranging 3-5) and eight cases had good outcome with a score of GOS 4-5 at discharge, while eight patients presented mRS <=2 at 3-month follow-up. CONCLUSIONS: These results demonstrate that mechanical recanalization using Solitaire AB device seems to be effective and safe as a rescue therapy for severe thromboembolic events during cerebral aneurysm embolization. PMID- 28584948 TI - Evaluation of Visualization Using a 50/50 (Contrast Media/Glucose 5% Solution) Technique for Radioembolization as an Alternative to a Standard Sandwich Technique. AB - BACKGROUND: Radioembolization (RE) with 90yttrium (90Y) resin microspheres generally employs a sandwich technique with separate sequential administration of contrast medium (CM), followed by vehicle (e.g., glucose 5% [G5] solution), then 90Y resin microspheres (in G5), then G5, and then CM again to avoid contact of CM and microspheres under fluoroscopic guidance. This study evaluates the visualization quality and safety of a modified sandwich technique with a 50/50 mixture of CM (Imeron 300) and G5 for administration of 90Y resin microspheres. MATERIALS AND METHODS: A retrospective analysis of 81 RE procedures in patients with primary or secondary liver tumors was performed. The quality of angiographic visualization of the hepatic vessels was assessed before the first injection and immediately before the whole dose has been injected. Visualization and flow rate were graded on a 5-point scale: 1 = very good to 5 = not visible/no antegrade flow. Univariate logistic regression models and multiple linear regression models were used to evaluate the prognostic variables associated with visualization and flow scores. RESULTS: Visualization quality was inversely related to flow rate, the lower the flow rate the better the grade of the visualization. Visualization quality was also inversely related to body-mass-index (BMI). Performing RE with the 50/50-CM/G5 mixture resulted in a mean injection time for 1 GBq of 15 min. No clinically significant adverse events, including radiation-induced liver disease were reported. CONCLUSION: RE with a 50/50-mixture of CM and G5 for administration of 90Y resin microspheres in a modified sandwich technique is a safe administration alternative and provides good visualization of hepatic vessels, which is inversely dependent on flow rate and BMI. Injection time was reduced compared with our experience with the standard sandwich technique. PMID- 28584952 TI - Identity and semantic negative priming in rapid serial visual presentation streams. AB - In selective attention tasks, the efficiency of processing concurrently presented target and distractor stimuli in a given display is often influenced by the relationship these stimuli have with those in the previous display. When a to-be attended target on a current trial (the probe trial) matches the ignored, non target distractor on a previous trial (the prime trial), a response to the target is typically delayed compared with when the two stimuli are not associated. This negative priming (NP) phenomenon has been observed in numerous studies with traditional NP tasks presenting the target and distractor simultaneously in both the prime and probe trial couplets. Here, however, in four experiments using a mixture of stimulus types (letters, digits, English number words, and logographic Chinese number words), target and distractor stimuli were temporally separated in two rapid serial visual presentation (RSVP) streams instead of concurrently presented. The findings provide a conceptual replication and substantial extension of a recent study by Wong (Plos One, 7, e37023, 2012), and suggest that active suppression of irrelevant distracting information is a more ubiquitous form of cognitive control than previously thought. PMID- 28584954 TI - The impact of category structure and training methodology on learning and generalizing within-category representations. AB - When interacting with categories, representations focused on within-category relationships are often learned, but the conditions promoting within-category representations and their generalizability are unclear. We report the results of three experiments investigating the impact of category structure and training methodology on the learning and generalization of within-category representations (i.e., correlational structure). Participants were trained on either rule-based or information-integration structures using classification (Is the stimulus a member of Category A or Category B?), concept (e.g., Is the stimulus a member of Category A, Yes or No?), or inference (infer the missing component of the stimulus from a given category) and then tested on either an inference task (Experiments 1 and 2) or a classification task (Experiment 3). For the information-integration structure, within-category representations were consistently learned, could be generalized to novel stimuli, and could be generalized to support inference at test. For the rule-based structure, extended inference training resulted in generalization to novel stimuli (Experiment 2) and inference training resulted in generalization to classification (Experiment 3). These data help to clarify the conditions under which within-category representations can be learned. Moreover, these results make an important contribution in highlighting the impact of category structure and training methodology on the generalization of categorical knowledge. PMID- 28584953 TI - Studying visual attention using the multiple object tracking paradigm: A tutorial review. AB - Human observers are capable of tracking multiple objects among identical distractors based only on their spatiotemporal information. Since the first report of this ability in the seminal work of Pylyshyn and Storm (1988, Spatial Vision, 3, 179-197), multiple object tracking has attracted many researchers. A reason for this is that it is commonly argued that the attentional processes studied with the multiple object paradigm apparently match the attentional processing during real-world tasks such as driving or team sports. We argue that multiple object tracking provides a good mean to study the broader topic of continuous and dynamic visual attention. Indeed, several (partially contradicting) theories of attentive tracking have been proposed within the almost 30 years since its first report, and a large body of research has been conducted to test these theories. With regard to the richness and diversity of this literature, the aim of this tutorial review is to provide researchers who are new in the field of multiple object tracking with an overview over the multiple object tracking paradigm, its basic manipulations, as well as links to other paradigms investigating visual attention and working memory. Further, we aim at reviewing current theories of tracking as well as their empirical evidence. Finally, we review the state of the art in the most prominent research fields of multiple object tracking and how this research has helped to understand visual attention in dynamic settings. PMID- 28584951 TI - An Integrative Eco-Epidemiological Analysis of West Nile Virus Transmission. AB - West Nile disease, caused by the West Nile virus (WNV), is a mosquito-borne zoonotic disease affecting humans and horses that involves wild birds as amplifying hosts. The mechanisms of WNV transmission remain unclear in Europe where the occurrence of outbreaks has dramatically increased in recent years. We used a dataset on the competence, distribution, abundance, diversity and dispersal of wild bird hosts and mosquito vectors to test alternative hypotheses concerning the transmission of WNV in Southern France. We modelled the successive processes of introduction, amplification, dispersal and spillover of WNV to incidental hosts based on host-vector contact rates on various land cover types and over four seasons. We evaluated the relative importance of the mechanisms tested using two independent serological datasets of WNV antibodies collected in wild birds and horses. We found that the same transmission processes (seasonal virus introduction by migratory birds, Culex modestus mosquitoes as amplifying vectors, heterogeneity in avian host competence, absence of 'dilution effect') best explain the spatial variations in WNV seroprevalence in the two serological datasets. Our results provide new insights on the pathways of WNV introduction, amplification and spillover and the contribution of bird and mosquito species to WNV transmission in Southern France. PMID- 28584955 TI - Miss it and miss out: Counterproductive nonspatial attentional capture by task irrelevant, value-related stimuli. AB - Recent studies of visual search suggest that learning about valued outcomes (rewards and punishments) influences the likelihood that distractors will capture spatial attention and slow search for a target, even when those value-related distractors have never themselves been the targets of search. In the present study, we demonstrated a related effect in the context of temporal, rather than spatial, selection. Participants were presented with a temporal stream of pictures in a fixed central location and had to identify the orientation of a rotated target picture. Response accuracy was reduced if the rotated target was preceded by a "valued" distractor picture that signaled that a correct response to the target would be rewarded (and an incorrect response punished), relative to a distractor picture that did not signal reward or punishment. This effect of signal value on response accuracy was short-lived, being most prominent with a short lag between distractor and target. Impairment caused by a valued distractor was observed if participants were explicitly instructed regarding its relation to reward/punishment (Exps. 1, 3, and 4), or if they could learn this relationship only via trial-by-trial experience (Exp. 2). These findings show that the influence of signal value on attentional capture extends to temporal selection, and also demonstrate that value-related distractors can interfere with the conscious perception of subsequent target information. PMID- 28584956 TI - Natural scenes can be identified as rapidly as individual features. AB - Can observers determine the gist of a natural scene in a purely feedforward manner, or does this process require deliberation and feedback? Observers can recognise images that are presented for very brief periods of time before being masked. It is unclear whether this recognition process occurs in a purely feedforward manner or whether feedback from higher cortical areas to lower cortical areas is necessary. The current study revealed that the minimum presentation time required to identify or to determine the gist of a natural scene was no different from that required to determine the orientation or colour of an isolated line. Conversely, a visual task that would be expected to necessitate feedback (determining whether an image contained exactly six lines) required a significantly greater minimum presentation time. Assuming that the orientation or colour of an isolated line can be determined in a purely feedforward manner, these results indicate that the identification and the determination of the gist of a natural scene can also be performed in a purely feedforward manner. These results challenge a number of theories of visual recognition that require feedback. PMID- 28584957 TI - Binding object features to locations: Does the "spatial congruency bias" update with object movement? AB - One of the fundamental challenges of visual cognition is how our visual systems combine information about an object's features with its spatial location. A recent phenomenon related to object-location binding, the "spatial congruency bias," revealed that two objects are more likely to be perceived as having the same identity or features if they appear in the same spatial location, versus if the second object appears in a different location. The spatial congruency bias suggests that irrelevant location information is automatically encoded with and bound to other object properties, biasing perceptual judgments. Here we further explored this new phenomenon and its role in object-location binding by asking what happens when an object moves to a new location: Is the spatial congruency bias sensitive to spatiotemporal contiguity cues, or does it remain linked to the original object location? Across four experiments, we found that the spatial congruency bias remained strongly linked to the original object location. However, under certain circumstances-for instance, when the first object paused and remained visible for a brief time after the movement-the congruency bias was found at both the original location and the updated location. These data suggest that the spatial congruency bias is based more on low-level visual information than on spatiotemporal contiguity cues, and reflects a type of object-location binding that is primarily tied to the original object location and that may only update to the object's new location if there is time for the features to be re encoded and rebound following the movement. PMID- 28584959 TI - Preventing Tuberculosis in a Low Incidence Setting: Evaluation of a Multi lingual, Online, Educational Video on Latent Tuberculosis. AB - Treating latent tuberculosis infection (LTBI) in those at risk is an important yet challenging cornerstone of TB elimination. We evaluated a culturally tailored, multi-lingual, 4.5-min, health promotional video on LTBI. Mixed methods study assessed use of the video with web-analytics, acceptability of content through interviews and survey questions, and compared knowledge scores in viewers and non-viewers using a survey. The video was viewed 6999 times in six languages over 1 year. Of 1598 survey respondents, 193 viewers had a mean knowledge score of 59%, compared to 38% in non-viewers. Eighty-four percent of viewers rated the video as helpful. When controlling for other factors, viewing the video was associated with a 1.04 (95% CI 0.85-1.26) or a 21% increase in a knowledge score. Qualitative data suggested the video was acceptable and may facilitate behavior change. This online, educational video shows promise as a tool to supplement clinical care. PMID- 28584958 TI - A predictive diagnostic model using multiparametric MRI for differentiating uterine carcinosarcoma from carcinoma of the uterine corpus. AB - PURPOSE: To construct a diagnostic model for differentiating carcinosarcoma from carcinoma of the uterus. MATERIALS AND METHODS: Twenty-six patients with carcinosarcomas and 26 with uterine corpus carcinomas constituted a derivation cohort. The following nine MRI features of the tumors were evaluated: inhomogeneity, predominant signal intensity, presence of hyper- and hypointense areas, conspicuity of tumor margin, cervical canal extension on T2WI, presence of hyperintense areas on T1WI, contrast defect area volume percentage, and degree of enhancement. Two predictive models-with and without contrast-were constructed using multivariate logistic regression analysis. Fifteen other patients with carcinosarcomas and 30 patients with carcinomas constituted a validation cohort. The sensitivity and specificity of each model for the validation cohort were calculated. RESULTS: Inhomogeneity, predominant signal intensity on T2WI, and presence of hyperintense areas on T1WI were significant predictors in the unenhanced-MRI-based model. Presence of hyperintensity on T1WI, contrast defect area volume percentage, and degree of enhancement were significant predictors in the enhanced-MRI-based model. The sensitivity/specificity of unenhanced MRI were 87/73 and 87/70% according to reviewer 1 and 2, respectively. The sensitivity/specificity of the enhanced-MRI-based model were 87/70% according to both reviewers. CONCLUSIONS: Our diagnostic models can differentiate carcinosarcoma from carcinoma of the uterus with high sensitivity and moderate specificity. PMID- 28584960 TI - Qualitative Study of Latino Cancer Patient Perspectives on Care Access and Continuity in a Rural, U.S.-Mexico Border Region. AB - Access to quality cancer care for cancer patients living in the rural U.S.-Mexico border region is complex due to common binational health care-seeking behaviors and regional socio-economic and cultural characteristics. But little is known about the challenges border dwelling residents face when navigating their cancer care systems. In-depth interviews were conducted with 22 cancer patients in Southern California. Thematic analysis was applied to identify patterns of meaning in the data. Emerging themes were: (1) delays in cancer care coordination: (a) poor coordination of cancer care (b) U.S. and cross-border discordance in cancer diagnosis; (2) regional shortage of cancer specialists; and (3) financial hardship. Findings revealed that care needs distinctly involved care coordination in/outside of the patient's community and bi-national care coordination. In addition to local solutions to improve cancer coordination through community-based partnerships, efforts to bridge care in a two-nation context are also imperative. PMID- 28584961 TI - Health of International Marriage Immigrant Women in South Korea: A Systematic Review. AB - International marriage migration is now one of the most prominent forms of migration in Asia, and the number of women migrating to South Korea for marriage has increased dramatically in the last two decades. In this article, we provide a systematic review regarding the health status and health-related issues of international marriage immigrant women. The literature search identified 620 articles, of which 53 studies are presented in the article. Three overarching categories including six subcategories were identified according to the research focus; 'Environmental factors of health' including social support and barriers, 'Health status' including physical, psychological and social health, and quality of life as 'Outcome of health'. Overall women immigrants by marriage showed relatively poor health outcomes. Social support was an important factor affecting the health status and quality of life in this population. We offer recommendations to develop and implement culturally and linguistically appropriate health promoting programs for international marriage immigrant women in South Korea. PMID- 28584963 TI - Steroid-resistant autoimmune myelofibrosis in a patient with autoimmune hepatitis and Evans syndrome complicated with increased expression of TGF-beta in the bone marrow: a case report. AB - We here report a 47-year-old female with autoimmune myelofibrosis (AIMF) associated with liver damage caused by autoimmune hepatitis and Evans syndrome. Bone marrow biopsy revealed hypocellular marrow with grade 2 reticulin fibrosis and increased levels of B lymphocytes (CD20+), T lymphocytes (CD3+, CD8+), and plasma cells (CD138+). Immunohistochemical analysis revealed increased expression of transforming growth factor-beta (TGF-beta) in infiltrating lymphocytes and macrophages in the bone marrow. She was initially treated with oral prednisolone (PSL) for 2 months, which had a limited effect. However, after treatment with rituximab, the patient's pancytopenia showed improvement, allowing us to rapidly reduce the PSL dosage. The present case suggests the possibility that increased expression of TGF-beta in infiltrating lymphocytes and macrophages of bone marrow may contribute to the pathogenesis of AIMF. Prednisolone combined with rituximab may thus be an effective option for steroid-refractory cases. PMID- 28584964 TI - Antifungal activity of the pygidial gland secretion of Laemostenus punctatus (Coleoptera: Carabidae) against cave-dwelling micromycetes. AB - The antifungal potential of the pygidial gland secretion of the troglophilic ground beetle Laemostenus punctatus from a cave in Southeastern Serbia against cave-dwelling micromycetes, isolated from the same habitat, has been investigated. Eleven collected samples were analyzed and 32 isolates of cave dwelling fungi were documented. A total of 14 fungal species were identified as members of the genera Aspergillus, Penicillium, Alternaria, Cladosporium, Rhizopus, Trichoderma, Arthrinium, Aureobasidium, Epicoccum, Talaromyces, and Fusarium. Five isolates were selected for testing the antifungal activity of the pygidial gland secretion: Talaromyces duclauxi, Aspergillus brunneouniseriatus, Penicillium sp., Rhizopus stolonifer, and Trichoderma viride. The microdilution method has been applied to detect minimal inhibitory concentrations (MICs) and minimal fungicidal concentrations (MFCs). The most sensitive isolate was Penicillium sp., while the other isolates demonstrated a high level of resistance to the tested agent. L. punctatus has developed a special mechanism of producing specific compounds that act synergistically within the secretion mixture, which are responsible for the antifungal action against pathogens from the cave. The results open opportunities for further research in the field of ground beetle defense against pathogens, which could have an important application in human medicine, in addition to the environmental impact, primarily. PMID- 28584965 TI - Enzymatic Hydrolysis of Agavins to Generate Branched Fructooligosaccharides (a FOS). AB - Recently, agavins (branched neo-fructans) of short degree of polymerization have shown beneficial effects on the health of both healthy and overweight individuals. Therefore, the aim of the present work was to investigate the potential use of Agave angustifolia agavins on the generation of branched fructooligosacharides (a-FOS). A. angustifolia agavins were hydrolyzed using exo , endo-inulinase, and a mixture of both (25 and 75%, respectively). Exo- and the inulinase mixture degraded quickly the agavins in relation to endo-inulinase treatment. Only endo-inulinase and the inulinase mixture generated a-FOS formation. Endo-inulinase degraded 31% of agavins, yielding approximately 20% of a-FOS after 48 h, whereas the inulinase mixture hydrolyzed 33% of agavins in just 90 min, but only yielded 10% of a-FOS. These results suggest that agave plants could be an abundant raw material for a-FOS production, which might have a huge prebiotic potential as new branched fructooligosaccharides with many applications in the alimentary and pharmaceutical industry. PMID- 28584966 TI - Relations Between Moso Bamboo Surface Properties Pretreated by Kraft Cooking and Dilute Acid with Enzymatic Digestibility. AB - Lignocellulosics pretreatment is intended to dismantle biomass' natural recalcitrance. Chemical and morphological changes of lignocellulosic materials would occur through varying pretreatment processes. In order to figure out why the acid-pretreated and Kraft-cooked bamboo residues showed very different enzymatic digestibility, the surface properties of pretreated bamboo residues were characterized in this work. It was found that analyzed surface properties were considered to be associating with each corresponding enzymatic digestibility of the pretreated samples. The zeta potentials of pretreated bamboo residues have a negative correlation with enzymatic efficiency. Kraft-cooked substrates were found to posse a less hydrophobic nature and demonstrated higher enzymatic conversion than substrates that were dilute sulfuric acid pretreated. The surface accessibility analysis (BET and Direct Red staining) revealed that the higher enzymatic efficiency of Kraft-cooked materials was mostly due to the larger cellulosic surface area than that in acid-pretreated materials. The results re affirm that different pretreatments create a variety of surface characteristics, leading to the idea that pretreatment and enzymatic hydrolysis can be favorably turned to maximize carbohydrate recovery from bamboo residues. PMID- 28584967 TI - Effect of UV-B Radiation and Desiccation Stress on Photoprotective Compounds Accumulation in Marine Leptolyngbya sp. AB - Increased awareness regarding the harmful effects of ultraviolet (UV)-B radiation has led to the search for new sources of natural UV-B protecting compounds. Mycosporine-like amino acids are one of such promising compounds found in several organisms. Cyanobacteria are ideal organisms for isolation of these compounds due to their compatibility and adaptability to thrive under harsh environmental conditions. In the following investigation, we report the production of shinorine in Leptolyngbya sp. isolated from the intertidal region. Based on the spectral characteristics and liquid chromatography-mass spectrometry analysis, the UV absorbing compound was identified as shinorine. To the best of our knowledge, this is the first report on the occurrence of shinorine in Leptolyngbya sp. We also investigated the effect of artificial UV-B radiation and periodic desiccation on chlorophyll-a, total carotenoids, and mycosporine-like amino acids (MAAs) production. The UV-B radiation had a negative effect on growth and chlorophyll concentration, whereas it showed an inductive effect on the production of total carotenoids and MAAs. Desiccation along with UV-B radiation led to an increase in the concentration of photoprotective compounds. These results indicate that carotenoids and MAAs thus facilitate cyanobacteria to avoid and protect themselves from the deleterious effects of UV-B and desiccation. PMID- 28584968 TI - Informing Environmental Water Management Decisions: Using Conditional Probability Networks to Address the Information Needs of Planning and Implementation Cycles. AB - One important aspect of adaptive management is the clear and transparent documentation of hypotheses, together with the use of predictive models (complete with any assumptions) to test those hypotheses. Documentation of such models can improve the ability to learn from management decisions and supports dialog between stakeholders. A key challenge is how best to represent the existing scientific knowledge to support decision-making. Such challenges are currently emerging in the field of environmental water management in Australia, where managers are required to prioritize the delivery of environmental water on an annual basis, using a transparent and evidence-based decision framework. We argue that the development of models of ecological responses to environmental water use needs to support both the planning and implementation cycles of adaptive management. Here we demonstrate an approach based on the use of Conditional Probability Networks to translate existing ecological knowledge into quantitative models that include temporal dynamics to support adaptive environmental flow management. It equally extends to other applications where knowledge is incomplete, but decisions must still be made. PMID- 28584969 TI - The effect of melatonin on gene expression of calcitonin gene-related peptide and some proinflammatory mediators in patients with pure menstrual migraine. AB - The neuropeptide calcitonin gene-related peptide (CGRP), a potent vasoactive and a marker of trigeminal inflammation, has been considered as an important mediator in various types of migraine such as pure menstrual migraine. Earlier studies have shown that CGRP can modulate the synthesis and release of other inflammatory factor including nitric oxide (NO) and interleukin-1beta (IL-1beta) from trigeminal ganglion glial cells. Exogenous melatonin protects the tissues from inflammatory damages. The goal of this study was to determine the anti inflammatory effects of melatonin on the CGRP expression, inducible nitric oxide synthase (iNOS) activity, NO, and IL-1beta release in cultured peripheral blood mononuclear cells (PBMCs) from pure menstrual migraine patients and healthy subjects. This study was performed on 12 pure menstrual migraine patients and 12 age-and sex-matched healthy subjects. PBMCs were isolated and treated with melatonin for 12 h at pharmacological dose. Gene expression was evaluated by real time PCR. CGRP and IL-1beta proteins in culture supernatant were determined by ELISA method. iNOS activity in PBMCs was determined by colorimetric assays. Total nitrite as an indicator of NO concentrations in the culture supernatants was measured using Griess method. We found that melatonin treatment significantly decreases mRNA expression of CGRP release, NO production, and iNOS activity in the patient groups. Taken together, it appears that melatonin reduces inflammation through decreasing CGRP level and iNOS activity in the patients with migraine; however, further studies are needed in this regard. PMID- 28584970 TI - Morphometric evaluation of facial and vestibulocochlear nerves using magnetic resonance imaging: comparison of Meniere's disease ears with normal hearing ears. AB - Loss of neural structures (such as hair cells or neurones within the spiral ganglion) has been proposed to be involved in Meniere's disease (MD) (Spoendlin et al. Acta oto-laryngologica Supplementum 499:1-21, 1; Merchant et al. Eur Arch Oto-Rhino-Laryngol Off J Eur Feder Oto-Rhino-Laryngol Soc (EUFOS) Affil German Soc Oto-Rhino-Laryngol Head Neck Surg 252(2):63-75, 2; Tsuji et al. Ann Otol Rhinol Laryngol Suppl 81:26-31, 3; Kariya, Otol Neurotol Off Publ Am Otol Soc Am Neurotol Soc Eur Acad Otol Neurotol 28(8):1063-1068, 4; Megerian Laryngoscope 115(9):1525-1535, 5) but this has yet to be confirmed. Therefore, the aim of this study was to investigate morphometric changes of VIIth and VIIIth cranial nerve in MD. MD is characterized by episodic vertigo, tinnitus, fluctuating hearing loss, and aural fullness. The exact pathophysiological mechanisms involved such as viral infections, autoimmune processes, genetic predisposition, cellular apoptosis, and oxidative stress are still not clear. Using a T2-weighted 3D-GE "constructive interference in steady state" (CISS) 3T magnetic resonance imaging (MRI) sequence, we evaluated the properties of the VIIth and VIIIth cranial nerves as they passed from the cerebellopontine angle to the inner ear modiolus. 21 patients with MD were examined along with 39 normal controls. Bidirectional nerve diameters and cross-sectional areas (CSA) were measured in a transverse plane. The comparison of study and control group showed statistically significant (P < 0.000595 after Bonferroni correction) differences between the CSA measurements. The facial, cochlear, superior vestibular, and inferior vestibular nerves (FN, CN, SVN, IVN) of MD patients were significantly larger than those of the control group, both on the MD-affected side and on the healthy side. Thus for example, the cochlear nerve CSA measurements were 0.69 +/- 0.14 mm2 (P < 0.0001) in the affected ears of the unilateral MD group, 0.70 +/- 0.12 mm2 (P < 0.0001) in the affected ears of the cohort including the bilateral MD group, 0.71 +/- 0.13 mm2 (P < 0.0001) in the non-affected ears of the MD patients, as compared to 0.46 +/- 0.14 mm2 in the control group. The perpendicular nerve diameters were found to vary according to site of measurement and type of measurement used. For example a statistically significant enlargement of the short diameter measurements of the SVN at the level of the meatus was found, but not of long diameter measurements at the same site. Although cellular death would theoretically be expected to lead to a decreased nerve thickness, our data showed a swelling of cranial nerves VII and VIII within the study group compared to our normal hearing control group. The similar reaction of the facial nerve supports mediator-based theories of MD pathophysiology. PMID- 28584971 TI - F-18 FDG and F-18 Tau PET in posterior cortical atrophy. PMID- 28584973 TI - From single muscle fiber to whole muscle mechanics: a finite element model of a muscle bundle with fast and slow fibers. AB - Muscles exhibit highly complex, multi-scale architecture with thousands of muscle fibers, each with different properties, interacting with each other and surrounding connective structures. Consequently, the results of single-fiber experiments are scarcely linked to the macroscopic or whole muscle behavior. This is especially true for human muscles where it would be important to understand of how skeletal muscles disorders affect patients' life. In this work, we developed a mathematical model to study how fast and slow muscle fibers, well characterized in single-fiber experiments, work and generate together force and displacement in muscle bundles. We characterized the parameters of a Hill-type model, using experimental data on fast and slow single human muscle fibers, and comparing experimental data with numerical simulations obtained from finite element (FE) models of single fibers. Then, we developed a FE model of a bundle of 19 fibers, based on an immunohistochemically stained cross section of human diaphragm and including the corresponding properties of each slow or fast fiber. Simulations of isotonic contractions of the bundle model allowed the generation of its apparent force-velocity relationship. Although close to the average of the force-velocity curves of fast and slow fibers, the bundle curve deviates substantially toward the fast fibers at low loads. We believe that the present model and the characterization of the force-velocity curve of a fiber bundle represents the starting point to link the single-fiber properties to those of whole muscle with FE application in phenomenological models of human muscles. PMID- 28584972 TI - Relation between thoracic aortic inflammation and features of plaque vulnerability in the coronary tree in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention. An FDG positron emission tomography and optical coherence tomography study. AB - PURPOSE: To evaluate the relationship between aortic inflammation as assessed by 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) and features of plaque vulnerability as assessed by frequency domain-optical coherence tomography (FD-OCT). METHODS: We enrolled 30 consecutive non-ST-segment elevation acute coronary syndrome patients undergoing percutaneous coronary intervention. All patients underwent three-vessel OCT before intervention and 18F-FDG-PET before discharge. Univariable and C-reactive protein (CRP)-adjusted linear regression analyses were performed between features of vulnerability [namely:lipid-rich plaques with and without macrophages and thin cap fibroatheromas (TCFA)] and 18F FDG uptake in both ascending (AA) and descending aorta (DA) [measured either as averaged mean and maximum target-to-blood ratio (TBR) or as active slices (TBRmax >= 1.6)]. RESULTS: Mean age was 62 years, and 26 patients were male. On univariable linear regression analysis TBRmean and TBRmax in DA was associated with the number of lipid-rich plaques (beta = 4.22; 95%CI 0.05-8.39; p = 0.047 and beta = 3.72; 95%CI 1.14-6.30; p = 0.006, respectively). TBRmax in DA was also associated with the number of lipid-rich plaques containing macrophages (beta = 2.40; 95%CI 0.07-4.72; p = 0.044). A significant CRP adjusted linear association between the TBRmax in DA and the number of lipid-rich plaques was observed (CRP adjusted beta = 3.58; 95%CI -0.91-6.25; p = 0.01). TBRmax in DA showed a trend towards significant CRP-adjusted association with number of lipid-rich plaques with macrophages (CRP-adjusted beta = 2.30; 95%CI -0.11-4.71; p = 0.06). We also observed a CRP-adjusted (beta = 2.34; 95%CI 0.22-4.47; p = 0.031) linear association between the number of active slices in DA and the number of lipid rich plaques. No relation was found between FDG uptake in the aorta and the number of TCFAs. CONCLUSIONS: In patients with first NSTEACS, 18F-FDG uptake in DA is correlated with the number of OCT detected lipid-rich plaques with or without macrophages. This association may be independent from CRP values. PMID- 28584974 TI - High Resolution Mapping of QTLs for Heat Tolerance in Rice Using a 5K SNP Array. AB - BACKGROUND: Heat stress is one of the major abiotic threats to rice production, next to drought and salinity stress. Incidence of heat stress at reproductive phase of the crop results in abnormal pollination leading to floret sterility, low seed set and poor grain quality. Identification of QTLs and causal genes for heat stress tolerance at flowering will facilitate breeding for improved heat tolerance in rice. In the present study, we used 272 F8 recombinant inbred lines derived from a cross between Nagina22, a well-known heat tolerant Aus cultivar and IR64, a heat sensitive popular Indica rice variety to map the QTLs for heat tolerance. RESULTS: To enable precise phenotyping for heat stress tolerance, we used a controlled phenotyping facility available at ICAR-Indian Institute of Wheat and Barley Research, Karnal, India. Based on 'days to 50% flowering' data of the RILs, we followed staggered sowing to synchronize flowering to impose heat stress at uniform stage. Using the Illumina infinium 5K SNP array for genotyping the parents and the RILs, and stress susceptibility and stress tolerance indices (SSI and STI) of percent spikelet sterility and yield per plant (g), we identified five QTLs on chromosomes 3, 5, 9 and 12. The identified QTLs explained phenotypic variation in the range of 6.27 to 21. 29%. Of these five QTLs, two high effect QTLs, one novel (qSTIPSS9.1) and one known (qSTIY5.1/qSSIY5.2), were mapped in less than 400 Kbp genomic regions, comprising of 65 and 54 genes, respectively. CONCLUSIONS: The present study identified two major QTLs for heat tolerance in rice in narrow physical intervals, which can be employed for crop improvement by marker assisted selection (MAS) after development of suitable scorable markers for breeding of high yielding heat tolerant rice varieties. This is the first report of a major QTL for heat tolerance on chromosome 9 of rice. Further, a known QTL for heat tolerance on chromosome 5 was narrowed down from 23 Mb to 331 Kbp in this study. PMID- 28584975 TI - Crystal structure and functional analysis of Leishmania major pseudoperoxidase. AB - Leishmania major pseudoperoxidase (LmPP) is a recently discovered heme protein expressed by the human pathogen. Previous in vivo and in vitro studies suggest that LmPP is a crucial element of the pathogen's defense mechanism against the reactive nitrogen species peroxynitrite produced during the host immune response. To shed light on the potential mechanism of peroxynitrite detoxification, we have determined the 1.76-A X-ray crystal structure of LmPP, revealing a striking degree of homology with heme peroxidases. The most outstanding structural feature is a Cys/His heme coordination, which corroborates previous spectroscopic and mutagenesis studies. We also used a combination of stopped-flow and electron paramagnetic spectroscopies that together suggest that peroxynitrite is not a substrate for LmPP catalysis, leaving the function of LmPP an open question. PMID- 28584976 TI - Sparse Reconstruction of Fluorescence Molecular Tomography Using Variable Splitting and Alternating Direction Scheme. AB - PURPOSE: Fluorescence molecular tomography (FMT) is a novel imaging modality for three-dimensional preclinical research and has many potential applications for drug therapy evaluation and tumor diagnosis. However, FMT presents an ill conditioned and ill-posed inverse problem, which is a challenge for its tomography reconstruction. Due to the importance of FMT reconstruction, it is valuable and necessary to develop further practical reconstruction methods for FMT. PROCEDURES: In this study, an efficient method using variable splitting strategy as well as alternating direction strategy (VSAD) was proposed for FMT reconstruction. In this method, the variable splitting strategy and the augmented Lagrangian function were first introduced to obtain an equivalent optimization formulation of the original problem. Then, the alternating direction scheme was used to solve the optimization problem and to accelerate its convergence. To examine the property of the VSAD method, three numerical simulation experiments (accuracy assessment experiment, robustness assessment experiment, and reconstruction speed assessment experiment) were performed and analyzed. RESULTS: The results indicated that the reconstruction accuracy, the reconstruction robustness, and the reconstruction speed of FMT were satisfactory by using the proposed VSAD method. Two in vivo studies, which were conducted by using two nude mouse models, further confirmed the advantages of the proposed method. CONCLUSIONS: The results indicated that the proposed VSAD algorithm is effective for FMT reconstruction. It was accurate, robust, and efficient for FMT imaging and was feasibly applied for in vivo FMT applications. PMID- 28584977 TI - Andrographolide Benefits Rheumatoid Arthritis via Inhibiting MAPK Pathways. AB - Andrographolide (AD) is the main compound distributed in medicinal herb Andrographis paniculata and exhibits anti-inflammatory activity. AD has been used for the treatment of multiple inflammatory diseases. However, the therapeutic value of AD on human rheumatoid arthritis (RA) remains unclear. In this study, we investigated the effects of AD on collagen-induced arthritis (CIA) and human RA synovial fibroblasts (RA-SFs). CIA mice were treated with AD (dissolved in 0.5% CMC-Na, 100 mg/kg per day) or vehicle (0.5% CMC-Na) daily by oral gavage for 2 weeks. The arthritis severity and joint destruction were assessed. Serum anti collagen II antibody (anti-CII Abs) and cytokines were determined by ELISA. TNFalpha-stimulated human RA-SFs were treated with varying doses of AD for in vitro investigation. Results showed that AD significantly attenuated the arthritis severity and joint damage. AD treatment significantly reduced the production of serum anti-CII, TNFalpha, IL-1beta, and IL-6. In vitro, AD decreased the secretion of IL-1beta and IL-6 from TNFalpha-stimulated RA-SFs in a dose-dependent manner. AD treatment reduced the TNFalpha-induced phosphorylation of p38 MAPK and ERK1/2 in a dose-dependent manner. Thus, our findings suggest that AD confers protective effects on autoimmune arthritis through inhibiting MAPK pathways. PMID- 28584978 TI - Review of total suspended particles (TSP) and PM2.5 concentration variations in Asia during the years of 1998-2015. AB - In Asian countries such as China, Malaysia, Pakistan, India, Taiwan, Korea, Japan and Hong Kong, ambient air total suspended particulates and PM2.5 concentration data were collected and discussed during the years of 1998-2015 in this study. The aim of the present study was to (1) investigate and collect ambient air total suspended particulates (TSP) and PM2.5 concentrations for Asian countries during the past two decades. (2) Discuss, analyze and compare those particulates (TSP and PM2.5) annual concentration distribution trends among those Asian countries during the past two decades. (3) Test the mean concentration differences in TSP and PM2.5 among the Asian countries during the past decades. The results indicated that the mean TSP concentration order was shown as China > Malaysia > Pakistan > India > Taiwan > Korea > Japan. In addition, the mean PM2.5 concentration order was shown as Vietnam > India > China > Hong Kong > Mongolia > Korea > Taiwan > Japan and the average percentages of PM2.5 concentrations for Taiwan, China, Japan, Korea, Hong Kong, Mongolia and Other (India and Vietnam) were 8, 21, 6, 8, 14, 13 and 30%, respectively, during the past two decades. Moreover, t test results revealed that there were significant mean TSP and PM2.5 concentration differences for either China or India to any of the countries such as Taiwan, Korea and Japan in Asia during the past two decades for this study. Noteworthy, China and India are both occupied more than 60% of the TSP and PM2.5 particulates concentrations out of all the Asia countries. As for Taiwan, the average PM2.5 concentration displayed increasing trend in the years of 1998-1999. However, it showed decreasing trend in the years of 2000-2010. As for Korea, the average PM2.5 concentrations showed decreasing trend during the years of 2001 2013. Finally, the average PM2.5 concentrations for Mongolia displayed increasing trend in the years of 2004-2013. PMID- 28584979 TI - Mouse Immunization with Radioattenuated Yeast Cells of Paracoccidioides brasiliensis. AB - Paracoccidioides brasiliensis is the agent of paracoccidioidomycosis, the most prevalent mycosis in Latin America, and currently there is no effective vaccine. The present chapter describes the methodology to obtain radioattenuated yeast cells of P. brasiliensis and a protocol to evaluate protective response elicited by this immunogen in experimental paracoccidioidomycosis. The radioattenuated yeast provides a valuable tool for immunological studies in experimental paracoccidioidomycosis and vaccine research. PMID- 28584980 TI - Heat-Killed Yeast as a Pan-Fungal Vaccine. AB - Fungal infections continue to rise worldwide. Antifungal therapy has long been a mainstay for the treatment of these infections, but often can fail for a number of reasons. These include acquired or innate drug resistance of the causative agent, poor drug penetration into the affected tissues, lack of cidal activity of the drug and drug toxicities that limit therapy. In some instances, such as coccidioidal meningitis, therapy is life-long. In addition, few new antifungal drugs are under development. In light of this information a preventative vaccine is highly desirable. Although numerous investigators have worked toward the development of fungal vaccines, none have become commercially available for use in humans. In the course of our studies, we have discovered that heat-killed yeast (HKY) of Saccharomyces cerevisiae can be used as a vaccine and have shown that it has efficacy in the prevention and reduction of five different fungal infections when used experimentally in mice, which raises the possibility of a pan-fungal vaccine preparation. In our studies we grow S. cerevisiae in broth and heat-kill the organism at 70 degrees C for 3 h. The number of dead yeast cells is adjusted and mice are vaccinated subcutaneously beginning 3-7 weeks prior to infection. After infection, efficacy is assessed on the basis of survival and residual burden of the fungus in the target organs. Alternatively, efficacy can be assessed solely on fungal burden at a predetermined time postinfection. Although itself it is unlikely to be moved toward commercialization, HKY can be used a positive control vaccine for studies on specific molecular entities as vaccines, and as a guidepost for the key elements of potential, more purified, pan-fungal vaccine preparations. PMID- 28584981 TI - Immunoinformatics as a Tool for New Antifungal Vaccines. AB - Immunoinformatics aids in screening for vaccine candidates, which can be experimentally tested for their efficacy. This chapter describes methods to use immunoinformatics to screen fungal vaccines candidates. Surface-localized molecules called adhesins could elicit immune response and serve as efficient vaccine candidates. The screening process is patterned on two steps, namely, a First Layer screen mostly used for value addition and prioritization based on characteristics of known antigens and a Second Layer highly focussed on core immunoinformatics analysis involving the binding and interactions of the molecules of the immune system. Together they offer a comprehensive objective evaluation of vaccine candidates selection in silico for fungal pathogens. PMID- 28584982 TI - Rational Design of T Lymphocyte Epitope-Based Vaccines Against Coccidioides Infection. AB - Coccidioidomycosis is a potentially life-threatening mycosis endemic to the Southwestern USA and some arid regions of Central and South America. A vaccine against Coccidioides infection would benefit over 30-million people who reside in or visit the endemic regions. Vaccine candidates against systemic fungal infections come in many forms. Live attenuated vaccines are derived from disease causing pathogens and generally stimulate excellent protective immunity. Since attenuated vaccines contain living microbes, there is a degree of unpredictability raising concerns regarding safety and stability. Generation of a subunit vaccine has initiated efforts to design a safe reagent suitable for administration to humans at risk of coccidioidomycosis. Epitope-based vaccines allow for eliciting specific protective immune responses and removal of potentially detrimental sequences to improve safety. This chapter describes methods for the identification of T cell epitopes derived from Coccidioides antigens, design, and production of a recombinant vaccine containing multiple T cell epitopes, and evaluation of its protective efficacy and vaccine immunity against pulmonary Coccidioides infection using a strain of transgenic mice that express a human MHC II molecule. PMID- 28584983 TI - Identification of Fungal T Cell Epitopes by Mass Spectrometry-Based Proteomics. AB - CD4+ T cells play a key role in host defense against many fungal infections. T cells are also implicated in vaccine immunity to fungi. To date, only a small number of fungal antigens have been identified. Knowing the antigenic determinants of fungi-specific T cells greatly facilitates the detection, enumeration and characterizes the antifungal T cells and it constitutes an important step toward the design and development of vaccination strategies. This chapter describes a method of MHC-II ligand elution and mass spectrometric analysis to identify naturally processed and presented fungal peptide epitopes. PMID- 28584984 TI - Intranasal Antifungal Vaccination Using DNA-Transfected Dendritic Cells. AB - Dendritic cells are the most potent antigen-presenting cells, and are critical for the generation of an antigen-specific immune response and protective immunity. These unique features have been applied to dendritic cell-based immunization in a number of disease conditions. Our published results have demonstrated that the immunity induced by intranasal immunization with DNA transfected dendritic cells results in reduced fungal burden, and alleviated lung tissue damage in a mouse model of pulmonary fungal infection. In this article, approaches for the preparation and characterization of DNA-transfected dendritic cells and intranasal immunization in mice are described. PMID- 28584985 TI - DNAhsp65 Vaccine as Therapy against Paracoccidioidomycosis. AB - The conventional treatment for fungal diseases usually shows long periods of therapy and the high frequency of relapses and sequels. New strategies of the treatment are necessary. We have shown that the Mycobacterium leprae HSP65 gene can be successfully used as therapy against murine Paracoccidioidomycosis (PCM). Here, we described the methodology of DNAhsp65 immunotherapy in mice infected with the dimorphic fungus Paracoccidioides brasiliensis, one of PCM agent, evaluating cytokines levels, fungal burden, and lung injury. Our results provide a new prospective on the immunotherapy of mycosis. PMID- 28584986 TI - Idiotypic Antifungal Vaccination: Immunoprotection by Antiidiotypic Antibiotic Antibodies. AB - As implied by the idiotypic network theory, the interaction between the functional epitope of a microbicidal molecule (X) and its specific cell-wall receptor (RX) on sensitive microorganisms may be imaged by the bond between the idiotype (Id) of a neutralizing monoclonal antibody (anti-X Ab) and its anti idiotype (anti-Id) X-like Ab (anti-anti-X Ab). Consequently, anti-X Ab Id may mimic RX acting as a vaccine (idiotypic vaccination) for the elicitation of protective anti-Id Abs with antibiotic activity (antibiobodies). PMID- 28584987 TI - Peptide Vaccine Against Paracoccidioidomycosis. AB - The chapter reviews methods utilized for the isolation and characterization of a promising immunogen candidate, aiming at a human vaccine against paracoccidioidomycosis. Peptide P10 carries a T-CD4+ epitope and was identified as an internal sequence of the major diagnostic antigen known as gp43 glycoprotein. It successfully treated massive intratracheal infections by virulent Paracoccidioides brasiliensis in combination with chemotherapy.An introduction about the systemic mycosis was found essential to understand the various options that were considered to design prophylactic and therapeutic vaccine protocols using peptide P10. PMID- 28584988 TI - Methodology for Anti-Cryptococcal Vaccine Development. AB - Cryptococcus neoformans and Cryptococcus gattii, the predominant etiological agents of cryptococcosis, are fungal pathogens that cause disease ranging from a mild pneumonia to life-threatening infections of the central nervous system (CNS). C. neoformans is widely considered an opportunistic fungal pathogen which targets individuals with impaired immune systems, while C. gattii is predominantly associated with fungal infections in immunocompetent individuals. However, C. neoformans and C. gattii have certainly been identified as the causative agent of cryptococcosis in both immune compromised and immune competent individuals. Cell-mediated immunity (CMI) by T-helper (Th) 1-type CD4+ T cells is the predominant host defense mechanism against cryptococcosis. Consequently, there has been great interest in identifying cryptococcal antigens that elicit protective CMI against Cryptococcus infection. Although many different cryptococcal proteins have been shown to stimulate potent cellular responses, there remains no standardized vaccine available for the prevention of cryptococcal infections in humans. Several studies have identified immunodominant antigens that may serve as attractive candidates for the development of novel subunit vaccines for the treatment and/or the prevention of cryptococcosis. The purpose of this chapter is to describe one methodology to screen and isolate cryptocococcal proteins that induce protective immune responses against cryptococossis. PMID- 28584989 TI - Beta-Glucan Particles as Vaccine Adjuvant Carriers. AB - Glucan particles (GPs) are spherical hollow particles derived from Saccharomyces cerevisiae cell walls and mainly consist of beta-1, 3-D-glucans. The inner hollow cavity of glucan particles can be loaded with different compounds, including protein antigens, and delivered to macrophages and dendritic cells. Moreover, the GP delivery system possesses beta-glucan's intrinsic immunostimulatory properties. Therefore, GPs serve as both an antigen-presenting cell-targeted delivery system and an adjuvant.Here, we describe the production of GPs from S. cerevisiae using hot alkaline and solvent extraction and characterization of these particles for morphology, particle density, and hydrodynamic volume. A detailed protocol for loading and entrapping a model antigen, ovalbumin (OVA), into these particles using yeast RNA is presented. Similar methods are used to load pathogen-specific antigens (peptides, proteins, soluble extracts) which then can be tested in in vivo vaccination models. PMID- 28584990 TI - Th1-Inducing Agents in Prophylaxis and Therapy for Paracoccidioidomycosis. AB - Adjuvants and immunomodulatory molecules could be included in the treatment of P. brasiliensis infection. In this context, we reported that the therapeutic and/or prophylactic administration of Th1-inducing agents, such as immunomodulatory lectins and adjuvants, was able to provide protection against experimental paracoccidioidomycosis. Then, we described the protocols to investigate the effect of immunomodulatory agents on the course of P. brasiliensis infection. In this sense, we detailed the measurement of fungal burden and cytokine production, and the histopathological analysis used to evaluate the most effective administration regime. PMID- 28584991 TI - Nanoparticle-Based Mycosis Vaccine. AB - Many diseases that were considered major affliction of mankind in the past have been successfully eradicated with introduction of appropriate vaccine strategies. In order to expedite new challenges coming up to deal with various infectious diseases, nano-particulate-based subunit vaccines seem to be the demand of ordeal. The nano-vaccines can find better scope for the diseases that were not rampant in the semi-advanced world few years back. For example in present-day circumstances that corroborate with advancement in the field of medical sciences in terms of cancer chemotherapy, organ transplantation, therapy of autoimmune diseases, etc.; along with prevalence of altogether unheard diseases such as HIV infection, people are at risk of infliction with many more pathogens. In this regard, development of an effective prophylactic strategy against many opportunistic infections primarily caused by fungal pathogens needs better understanding of host pathogen relation and role of active immunity against pathogenic fungi. In the present study, we have tried to decipher effectiveness of a nano-sized vaccine delivery system in imparting protection against fungal pathogens. PMID- 28584992 TI - Yeast Expressing Gp43 Protein as a Vaccine Against Paracoccidioides brasiliensis Infection. AB - Paracoccidioidomycosis (PCM) represents the most frequent systemic mycosis in Latin American. The disease is caused by the pathogenic thermally dimorphic fungus Paracoccidioides brasiliensis, and is initially characterized by pulmonary lesions, which can subsequently disseminate to other organs, resulting in secondary injuries. Although its high incidence, there is no commercially available vaccine against fungal diseases. A novel strategy, using Saccharomyces cerevisiae yeast as a vehicle for immunization against PCM, was recently successfully described. Herein, we describe strategies for the construction of the suitable S. cerevisiae vaccine, and protocols of administration and evaluation of the efficacy of the vaccine against experimental PCM. PMID- 28584993 TI - Vaccination with Phage-Displayed Antigenic Epitope. AB - Phage-displayed antigenic epitope is able to induce both humoral and cell mediated immune responses, which could be used as an delivery system to design vaccines without compromising safety and tolerability. Here, we describe the vaccination with phage-displayed antigenic epitope (M13 phage-displayed SLAQVKYTSASSI) against Candida albicans infection in BALB/c mice by this method. PMID- 28584994 TI - Preparation of an Oral Vaccine by Proteome Analysis and Molecular Display Technology. AB - In recent years, genetic engineering and protein expression technologies have promoted the development of recombinant protein vaccines. To accelerate the development of efficient vaccines for mycosis, screening candidate antigens, and determining the optimal route of administration are indispensable steps. Two methods for identifying novel antigens and producing antigens specific to Candida albicans, as a model causative pathogen of mycosis, are discussed in this chapter. Specifically, the application of liquid chromatography/tandem mass spectrometry using a long monolithic column for proteome analysis to identify virulence factors of C. albicans, followed by molecular display technology to produce an oral vaccine using antigens found by the proteomic study, is described. PMID- 28584995 TI - Precise and Efficient In-Frame Integration of an Exogenous GFP Tag in Aspergillus fumigatus by a CRISPR System. AB - As one of the most common airborne fungal pathogenic species, Aspergillus fumigatus infection is the increasingly fatal threat to immunocompromised patients worldwide. Setting up an efficient live-cell pathogen-labeling system will give insight into the dynamic process of the pathogen invasion in host, which offers us opportunities to explore the pathogenesis of A. fumigatus. In this chapter, we have described an efficient CRISPR-Cas9 system, which enables a precise in situ tag-insertion of an exogenous GFP tag at the predicted site with or without marker insertion in A. fumigatus. According to the detectable proportional fluorescence intensity, it is possible to in vivo track the A. fumigatus infection and to assess the fungal burden in relative organs. PMID- 28584996 TI - Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis. AB - Multiple animal models have been developed to study the pathogenesis of invasive pulmonary aspergillosis, as well as to evaluate the efficacy, pharmacokinetics, and pharmacodynamics of various antifungal agents and vaccines. Each model is beneficial depending on the questions that are asked. In this chapter, we will discuss the endpoints assessment of the persistently neutropenic rabbit models of invasive pulmonary aspergillosis and invasive pulmonary mucormycosis. PMID- 28584997 TI - CD4+ T Cells Mediate Aspergillosis Vaccine Protection. AB - Adaptive effector CD4+ T cells play essential roles in the defense against fungal infections, especially against invasive aspergillosis (IA). Such protective CD4+ T cells can be generated through immunization with specialized antifungal vaccines, as has been demonstrated for pulmonary Aspergillus fumigatus infections in mouse experiments. Adaptive transfer of fungal antigen-specific CD4+ T cells conferred protection onto non-immunized naive mice, an experimental approach that could potentially become a future treatment option for immunosuppressed IA patients, focusing on the ultimate goal to improve their otherwise dim chances for survival. Here, we describe the different techniques to analyze CD4+ T cell immune responses after immunization with a recombinant fungal protein. We present three major methods that are used to analyze the role of CD4+ T cells in protection against A. fumigatus challenge. They include (1) transplantation of CD4+ T cells from vaccinated mice into immunosuppressed naive mice, observing increasing protection of the cell recipients, (2) depletion of CD4+ T cells from vaccinated mice, which abolishes vaccine protection, and (3) T cell proliferation studies following stimulation with overlapping synthetic peptides or an intact protein vaccine. The latter can be used to validate immunization status and to identify protective T cell epitopes in vaccine antigens. In the methods detailed here, we used versions of the well-studied Asp f3 protein expressed in a bacterial host, either as the intact full length protein or its N-terminally truncated version, comprised of residues 15-168. However, these methods are generally applicable and can well be adapted to study other protein-based subunit vaccines. PMID- 28584998 TI - T-Cell-Mediated Cross-Protective Immunity. AB - Human invasive fungal infections are caused by different mold and yeast species. Hence, cross-reactive T cells that recognize conserved epitopes of various fungal pathogens are of special interest for vaccination protocols or adoptive T cell transfer. Here, we describe an ELISpot-based method to test cross-reactivity of T cell lines or clones to different molds and yeasts. PMID- 28584999 TI - Assessment of Post-Vaccination Phagocytic Activation Using Candida albicans Killing Assays. AB - Candida albicans is an important opportunistic fungal pathogen. It is now the fourth leading cause of nosocomial bloodstream infections and a great threat to the immuncompromised patients attributed to the disseminated candidiasis with the mortality up to 40%. Phagocytic cells are the first line of defense against Candida infections. Antibodies induced by vaccination can effectively enhance the capacities of phagocytosis and killing of neutrophils and macrophages. In this chapter, flow cytometric analysis (FACS) and killing assay by plate culture methods are introduced to evaluate the phagocytosis and killing of strains of Candida albicans opsonized with immune serum obtained from mice vaccinated with yeast and recombinant enolase. PMID- 28585000 TI - Immunization with Antigen-Pulsed Dendritic Cells Against Highly Virulent Cryptococcus gattii Infection: Analysis of Cytokine-Producing T Cells. AB - Cryptococcosis caused by highly virulent Cryptococcus gattii (Hv-Cg) is an emerging infectious disease that affects immunocompetent individuals. The Hv-Cg outbreak began in 1999, but the mechanisms responsible for its hyper-virulence as well as protective immunity against Hv-Cg infection remain to be elucidated. To better understand the protective immunity against Hv-Cg infection, we developed a novel immunization method using antigen-pulsed dendritic cells (DCs). We constructed a capsule-deficient Cg strain (?cap60) and used it as a vaccine antigen. Mouse bone marrow-derived DCs were pulsed with ?cap60 and transferred into mice twice before pulmonary infection with Hv-Cg strain R265. This DC-based immunization strongly induced cell-mediated immunity, including Th1 cells, Th17 cells, and multinucleated giant cells enclosing fungal cells in lungs. This vaccination significantly ameliorated the fungal burden and the survival rate after pulmonary infection with R265. The efficacy of DC-based immunization was significantly but partially reduced in IFNgamma-deficient mice, thereby suggesting that the Th1 and Th17 responses play roles in vaccine-induced protection against Hv-Cg infection. This approach might provide new insights into overcoming Hv-Cg infections in immunocompetent subjects. In this chapter, we describe the procedures for DC-vaccine preparation and the analysis of cytokine producing CD4+ T cells. PMID- 28585001 TI - Testing Antifungal Vaccines in an Animal Model of Invasive Candidiasis and in Human Mucosal Candidiasis. AB - The following article will concentrate on the NDV-3 anti-Candida and Staphylococcus vaccine. The vaccine is composed of the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) and aluminum hydroxide as adjuvant. The vaccine conferred protection to mice against experimental vaginal, oral, and intravenous challenge with C. albicans. Due to the sequence and structural homology of the Als3p with Staphylococcus aureus surface proteins, the vaccine also protected against experimental skin and IV infection with S. aureus. The vaccine has reached the stage of human trials: phase 1 clinical studies have shown that the vaccine is safe and immunogenic. The latest brief conference abstract reports of vaccination in women suffering from recurrent vaginal candidiasis, indicating that the recurrence rates were lower in the women receiving the vaccine. PMID- 28585002 TI - Post-mastectomy radiation therapy in breast cancer with 1-3 involved lymph nodes: the Pros. AB - In 2014, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reported that post-mastectomy radiation therapy (PMRT) for breast cancer patients with 1-3 cancer-positive lymph nodes is associated with a survival benefit. However, it is not known whether this applies to Japanese patients in daily clinical practice, because this conclusion was based on the results of older, western trials. Therefore, we studied the differences between PMRT results in western breast cancer patients and current practice in Japanese patients. Although we identified three differences, they do not appear to strongly impact the results of EBCTCG. We conclude that Japanese breast cancer patients with 1-3 positive lymph nodes should receive PMRT in daily clinical practice. PMID- 28585003 TI - Secondary breast carcinoma after completely remitted chronic myeloid leukemia following targeted tyrosine kinase inhibitor therapy. AB - We describe a rare case of secondary breast carcinoma after chronic myeloid leukemia (CML) in a 56-year-old woman. The patient was treated with hydroxyurea and imatinib for CML and achieved complete remission (she has since been taking imatinib as the maintenance therapy). Four years later, the patient noticed a firm and painless lump in the left breast, which was diagnosed as ductal carcinoma in situ based on a percutaneous biopsy of the mass. Simple resection and sentinel lymph node biopsy of the left breast were then performed. Pathological studies revealed a medium-grade intraductal carcinoma, with local infiltration associated with invasive micropapillary carcinoma. She received adjuvant endocrine therapy with imatinib after surgery. Breast cancer secondary to CML (treated with imatinib and completely remitted) is extremely rare. This report provides evidence to assist in the diagnosis and treatment for this rare manifestation. PMID- 28585004 TI - Metallothionein: a Potential Link in the Regulation of Zinc in Nutritional Immunity. AB - Nutritional immunity describes mechanisms for withholding essential transition metals as well as directing the toxicity of these metals against infectious agents. Zinc is one of these transition elements that are essential for both humans and microbial pathogens. At the same time, Zn can be toxic both for man and microbes if its concentration is higher than the tolerance limit. Therefore a "delicate" balance of Zn must be maintained to keep the immune cells surveilling while making the level of Zn either to starve or to intoxicate the pathogens. On the other hand, the invading pathogens will exploit the host Zn pool for its survival and replication. Apparently, different sets of protein in human and bacteria are involved to maintain their Zn need. Metallothionein (MT)-a group of low molecular weight proteins, is well known for its Zn-binding ability and is expected to play an important role in that Zn balance at the time of active infection. However, the differences in structural, functional, and molecular control of biosynthesis between human and bacterial MT might play an important role to determine the proper use of Zn and the winning side. The current review explains the possible involvement of human and bacterial MT at the time of infection to control and exploit Zn for their need. PMID- 28585005 TI - Wind farm topology-finding algorithm considering performance, costs, and environmental impacts. AB - Optimal power in wind farms turns to be a modern problem for investors and decision makers; onshore wind farms are subject to performance and economic and environmental constraints. The aim of this work is to define the best installed capacity (best topology) with maximum performance and profits and consider environmental impacts as well. In this article, we continue the work recently done on wind farm topology-finding algorithm. The proposed resolution technique is based on finding the best topology of the system that maximizes the wind farm performance (availability) under the constraints of costs and capital investments. Global warming potential of wind farm is calculated and taken into account in the results. A case study is done using data and constraints similar to those collected from wind farm constructors, managers, and maintainers. Multi state systems (MSS), universal generating function (UGF), wind, and load charge functions are applied. An economic study was conducted to assess the wind farm investment. Net present value (NPV) and levelized cost of energy (LCOE) were calculated for best topologies found. PMID- 28585006 TI - Studies on piston bowl geometries using single blend ratio of various non-edible oils. AB - The depletion of fossil fuels and hike in crude oil prices were some of the main reasons to explore new alternatives from renewable source of energy. This work presents the impact of various bowl geometries on diesel engine with diesel and biodiesel samples. Three non-edible oils were selected, namely pumpkin seed oil, orange oil and neem oil. These oils were converted into respective biodiesel using transesterification process in the presence of catalyst and alcohol. After transesterification process, the oils were termed as pumpkin seed oil methyl ester (PSOME), orange oil methyl ester (OME) and neem oil methyl ester (NOME), respectively. The engine used for experimentation was a single-cylinder four stroke water-cooled direct-injection diesel engine and loads were applied to the engine using eddy current dynamometer. Two bowl geometries were developed, namely toroidal combustion chamber (TCC) and trapezoidal combustion chamber (TRCC). Also, the engine was inbuilt with hemispherical combustion chamber (HCC). The base line readings were recorded using neat diesel fuel with HCC for various loads. Followed by 20% of biodiesel mixed with 80% neat diesel for all prepared methyl esters and termed as B1 (20% PSOME with 80% diesel), B2 (20% OME with 80% diesel) and B3 (20% NOME with 80% diesel). All fuel samples were tested in HCC, TCC and TRCC bowl geometries under standard injection timing and with compression ratio of 18. Increased brake thermal efficiency and reduced brake specific fuel consumption were observed with diesel in TCC geometry. Also, higher heat release and cylinder pressures with lower ignition delay were recorded with TCC bowl geometry. TCC bowl geometry showed lower CO, HC and smoke emissions with B2 fuel sample than diesel and other biodiesel samples. But, higher NOx emission was observed in HCC and TCC than that in TRCC bowl geometry. Graphical abstract ?. PMID- 28585007 TI - CeO2 nanoparticle fate in environmental conditions and toxicity on a freshwater predator species: a microcosm study. AB - We studied the fate and toxicity of two types of CeO2 NPs (bare or citrate coated) in environmentally relevant conditions, using large indoor microcosms. Long-term exposure was carried out on a three-leveled freshwater trophic chain, comprising microbial communities as primary producers, chironomid larvae as primary consumers, and amphibian larvae as secondary consumers. Whereas coated NPs preferentially sedimented, bare NPs were mainly found in the water column. However, mass balance indicated low recovery (51.5%) for bare NPs, indicating possible NP loss, against 98.8% of recovery for coated NPs. NPs were rather chemically stable, with less than 4% of dissolution. Chironomid larvae ingested large amounts of NPs and were vectors of contamination for amphibian larvae. Although bioaccumulation in amphibian larvae was important (9.47 and 9.74 mg/kg for bare and coated NPs, respectively), no biomagnification occurred through the trophic chain. Finally, significant genotoxicity was observed in amphibian larvae, bare CeO2 NPs being more toxic than citrate-coated NPs. ?. PMID- 28585009 TI - A bibliometric analysis of eutrophication literatures: an expanding and shifting focus. AB - This paper examined the eutrophication literatures from 1998 to 2015 using bibliometric techniques basing on the database of Science Citation Index. Bibliometric techniques, social network analysis, and mapping knowledge domains in this paper were used. The results revealed that article was the most used document type accounting for 94.79% (14,006) of the records. With the rapid development of eutrophication domain after 2004, the annual article publishing amount also grew notably in each country, with the list of US tops. International cooperation was not enough to compare with that between institutions. An author keyword analysis showed that "phosphorus," "nutrients," "nitrogen," "water quality," "phytoplankton," and "sediment" were the most popular keywords. And it was also found that climate change, life cycle assessment, and chlorophyll a appear with high frequency in recent years, indicating that the eutrophication mechanism analysis might turn from uni-factor microresearch to multi-factor macroresearch, and the eutrophication management research tends to be whole process management research. In addition, the future focuses of research directions, including (1) eutrophication and its ecosystem response, (2) eutrophication management, (3) eutrophication and climate change interactions, (4) eutrophication monitoring and forecast, and (5) ecological restoration of eutrophication. These findings are useful for the future endeavor of eutrophication academic research. PMID- 28585008 TI - Characteristics, source, and potential ecological risk assessment of polycyclic aromatic hydrocarbons (PAHs) in the Songhua River Basin, Northeast China. AB - The concentration characteristics, sources, and potential ecological risk assessment of 16 PAHs were investigated in the surface water from the Songhua River Basin, Northeast China. A total of 48 river water samples, including 16 from the main streams and 32 from the tributaries, were collected. Samples were separated into dissolved phases and suspended particle matter (SPM) via filtration with 0.47 MUm glass fiber filters. Each phase was analyzed for PAHs. The total PAH concentration in the dissolved phase in the water ranged from 32.5 to 108 ng L-1 and from 0.3 to 62.3 MUg g-1 (dry weight) in the suspended particle matter (SPM). The total PAH concentration in the main stream was lower than in the tributaries; the volume of annual runoff of rivers had a significant effect on the ?PAH in the rivers. The 2- and 3-ring PAHs dominated in both the dissolved phase and SPM, indicating a relatively recent local source of PAHs in the study area. The concentrations of PAHs in the Songhua River Basin are lower when compared with the values previously reported in the literature from other rivers around the world. The sources of PAHs were assessed by diagnostic ratios and principal component analysis (PCA), and the ecological risk of the PAHs was assessed based on the risk quotient (RQ). The diagnostic ratios and PCA indicated that the main sources of PAHs originated from pyrogenic and petrogenic sources, and pyrogenic sources had a greater impact. The ecological risk assessment indicated that the PAHs presented low ecosystem risk in the Songhua River Basin. PMID- 28585010 TI - High level leaching of heavy metals from colorful ceramic foodwares: a potential risk to human. AB - Ceramic foodwares are among the products used by people on daily basis without being cautious of exposures to heavy metals through possible leaching from the glaze ceramics. This study investigated the levels of heavy metals found in some commonly used ceramic foodwares in Nigeria with the aim of determining levels of human exposures through the use of the ceramics. To achieve this, acid digestion was carried out for the total metal concentrations and leaching tests were done using 4% acetic acid as a leaching agent. Metal concentrations were quantified using flame atomic absorption spectrometry (FAAS) and particle-induced X-ray emission spectrometry (PIXES) analysis. All the ceramic foodwares studied were found to contain varied amounts of heavy metals in their glazes, with concentrations in the range of 26.45-2071.46, 5.20-547.00, 1.24-2681.02, 2590.00 8848.40, 6.42-654.66, 112.69-649.95, 63.38-2518.51, and 3786.51-8249.44 MUg g-1 for Pb, Cd, Zn, As, Cu, Cr, Mn, and Fe, respectively. Concentrations of the metals leached from the ceramics were in the range of 0.11-0.97, 0.01-0.28, 0.00 4.19, 1.93-15.00, 0.01-0.41, 0.09-0.60, 0.01-2.14, and 0.01-11.53 mgL-1 for Pb, Cd, Zn, As, Cu, Cr, Mn, and Fe, respectively. Comparing the ratio of the metals leached from the ceramic wares with those of the metal oxides in the ceramics, it was noticeable that not all the metals detected in the ceramic samples were domiciled in the glaze but in the clay materials used for the ceramics. PMID- 28585011 TI - Preparation of La-modified magnetic composite for enhanced adsorptive removal of tetracycline. AB - Composite adsorbents usually outperform single component adsorbents as they could combine the properties and advantages of each component. In this research, rare earth element Lanthanum was introduced into magnetic substrate by a method of chemical co-precipitation to enhance its adsorption capability. It was found that the La-modified magnetic composite with a presumed La and Fe3O4 molar ratio at 1:50 had a better adsorption performance for tetracycline than the magnetic adsorbents at other molar ratios. The La-modified magnetic composite was characterized by scanning electron microscope, X-ray diffractometer, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The results showed that the magnetic adsorbent was nano-sized, and the introduction of La did not change the crystal structure of magnetic substrate. The adsorptive removal of tetracycline was favorable at neutral pH conditions. Kinetic experiments indicated that most of the uptake occurred within the initial 120 min. Chemisorption occurred in the process while rate-determining step might be diffusive in nature. An empirical model (Langmuir model) was applied in this paper, and fitting result indicates that the q max value of the magnetic composite reached as much as 145.9 mg/g for the uptake of tetracycline at 298 K. The above indicates that method of La doping could significantly enhance the adsorption capability of an intentionally designed composite adsorbent. PMID- 28585012 TI - Variability of zinc, copper and lead contents in sludge of the municipal stormwater treatment plant. AB - Several years of observations enabled us to assess the extent and variability of heavy metal contamination (Zn, Cu and Pb) of the sludge of the municipal stormwater treatment plant (the town of Pulawy, Poland). In terms of size (high capacity) and innovation, it is the only facility of this kind in the country. It collects rainwater run-offs from two catchments (separate inlets) with a total area of about 500 ha. The concentration of the analysed metals is characterised by a large spatial and temporal diversity. The reason for this may be differences in the manner and intensity of use of drained surfaces and different hydraulic conditions (of sedimentation) prevailing in the particular treatment devices. The highest pollution was found in sediments in the grit chamber and in the part of the settler from the side of the interceptor supplying sewage, i.e. from the main traffic route of the town (heavy traffic and developed technical infrastructure). The best-quality sludge was retained in the pond for treated wastewater. In the pool of analysed components, the largest share is Zn, which amounts to about 85%. The content of heavy metals limits the possibility of the natural use of sludge from the municipal stormwater treatment plant. In chemical terms, they should be seen as a potentially dangerous waste and undergo remediation. PMID- 28585013 TI - Association of atmospheric concentrations of polycyclic aromatic hydrocarbons with their urinary metabolites in children and adolescents. AB - This study aims to determine the atmospheric concentrations of particulate matter 2.5 (PM2.5)-bounded polycyclic aromatic hydrocarbons (PAHs) and their association with their urinary metabolites in children and adolescents. This study was conducted from October 2014 to March 2016 in Isfahan, Iran. We measured 16 species of PAHs bounded to PM2.5 by gas chromatography mass spectrometry (GC/MS) from 7 parts of the city. Moreover, PAH urinary metabolites were measured in 186 children and adolescents, randomly selected from households. Urinary metabolites consisted of 1-hydroxy naphthalene (1-naphthol), 2-hydroxy naphthalene (2 naphthol), 9-hydroxy phenanthrene (9-phenanthrol), and 1-hydroxy pyrene using GC/MS. Considering the short half-lives of PAHs, we measured the metabolites twice with 4 to 6 months of time interval. We found that the ambient concentrations of PAHs were significantly associated with their urinary metabolites. 1-hydroxy naphthalene and 2-hydroxy naphthalene concentrations showed an increase of 1.049 (95% CI: 1.030, 1.069) and 1.047 (95% CI: 1.025, 1.066) for each unit increase (1 ng/m3) in ambient naphthalene. Similarly, 1 hydroxy pyrene showed an increase of 1.009 (95% CI: 1.006-1.011) for each unit increase (1 ng/m3) in ambient pyrene concentration after adjustment for body mass index, physical activity level, urinary creatinine, age, and sex. The association of urinary 9-hydroxyphenanthrene and ambient phenantherene was significant in the crude model; however after adjustment for the abovementioned covariates, it was no more significant. We found significant correlations between exposure to ambient PM2.5-bounded PAHs and their urinary excretion. Considering the adverse health effects of PAHs in the pediatric age group, biomonitoring of PAHs should be underscored; preventive measures need to be intensified. PMID- 28585015 TI - Long-term dynamic characterization of aeolian desertification in northwest Shanxi, China. AB - Northwest Shanxi is located on the farming-pastoral ecotone of northern China, where aeolian desertification is one of the most serious environmental and socioeconomic issues. The remote sensing image and geostatistical approach were implemented to estimate aeolian desertified land (ADL) dynamic variations from 1975 to 2015. Results showed that the ADL covered 11,685.21 km2 (82.29%) of the study area in 2015, the majority of which was classified as a light or moderate degree. The area of ADL gradually expanded at an increasing rate of 87.37 km2 a-1 during the 1975-2000 periods. More specifically, the area of ADL has increased by 1259.23 km2 from 1975 to 1990 and by 924.96 km2 from 1990 to 2000, respectively. In contrast, spatial transfer of ADL areas has dwindled by 2365.85 km2 with a net decrease of 157.72 km2 a-1, and the mitigated areas of aeolian desertification were 10,602.24 km2 between 2000 and 2015. During the past 40 years, the gravity center of ADL migrated to southeast until 2000 and moved northwest in 2000-2015. From 1975 to 2000, the migration distance of severe ADL was the largest, migrated toward the northwest by 19.03 km in 1975-1990 and by 20.16 km in 1990-2000, respectively. From 2000 to 2015, the migration distance of light ADL was the largest, 27.54 km migrated to the northwest. Aeolian desertification rapidly expanded from 1975 to 2000 under the combination of climate change and intensive human activities. Since the year of 2000, ecological engineering strategy initiated by the governments has been the dominant contributor to the aeolian desertification severity reversal. Aeolian desertification prevention is a complicated process. Both the central and local government should play a critical role in the rehabilitation of ADL in the long term. PMID- 28585014 TI - Distribution, sources, and ecological risk assessment of polycyclic aromatic hydrocarbons in surface sediments from the Haihe River, a typical polluted urban river in Northern China. AB - The distribution, sources, and ecological risk of polycyclic aromatic hydrocarbons (PAHs) were investigated in surface sediments from the Haihe River. Total PAH concentrations varied from 171.4 to 9511.2 ng g-1 with an average of 2125.4 ng g-1, suggesting serious pollution of the Haihe River in comparison with other reported rivers worldwide. PAH contaminants differed significantly among 17 sampling locations with high values occurring in industrial areas and densely populated areas. The composition of PAHs was characterized by high abundance of 4 ring and 5-ring PAHs, and benzo[a]anthracene, chrysene, and benzo[a]pyrene were the predominant components. Molecular diagnostic ratios have confirmed that PAHs in Haihe River sediments resulted from mixed sources, primarily including various combustion processes. Ecological risk assessment using the Sediments Quality Guidelines indicated that PAHs in sediments could cause certain negative effects on aquatic organisms in most survey regions. PMID- 28585016 TI - Ecotoxicological assessment of pesticides and their combination on rhizospheric microbial community structure and function of Vigna radiata. AB - India is one of the leading countries in production and indiscriminate consumption of pesticides. Owing to their xenobiotic nature, pesticides affect soil microorganisms that serve as mediators in plant growth promotion. Our study aimed to deliver a comprehensive picture, by comparing the effects of synthetic pesticides (chlorpyriphos, cypermethrin, and a combination of both) with a biopesticide (azadirachtin) at their recommended field application level (L), and three times the recommended dosage (H) on structure and function of microbial community in rhizosphere of Vigna radiata. Effect on culturable fraction was assessed by enumeration on selective media, while PCR-denaturing gradient gel electrophoresis (DGGE) was employed to capture total bacterial community diversity. This was followed by a metabolic sketch using community-level physiological profiling (CLPP), to obtain a broader picture of the non-target effects on rhizospheric microbial community. Although plant parameters were not significantly affected by pesticide application, the microbial community structure experienced an undesirable impact as compared to control devoid of pesticide treatment. Examination of DGGE banding patterns through cluster analysis revealed that microbial community structure of pesticide-treated soils had only 70% resemblance to control rhizospheric soil even at 45 days post application. Drastic changes in the metabolic profiles of pesticide-treated soils were also detected in terms of substrate utilization, rhizospheric diversity, and evenness. It is noteworthy that the effects exacerbated by biopesticide were comparable to that of synthetic pesticides, thus emphasizing the significance of ecotoxicological assessments before tagging biopesticides as "safe alternatives." PMID- 28585017 TI - Laboratory-induced learned helplessness attenuates approach motivation as indexed by posterior versus frontal theta activity. AB - Research suggests that midline posterior versus frontal electroencephalographic (EEG) theta activity (PFTA) may reflect a novel neurophysiological index of approach motivation. Elevated PFTA has been associated with approach-related tendencies both at rest and during laboratory tasks designed to enhance approach motivation. PFTA is sensitive to changes in dopamine signaling within the fronto striatal neural circuit, which is centrally involved in approach motivation, reward processing, and goal-directed behavior. To date, however, no studies have examined PFTA during a laboratory task designed to reduce approach motivation or goal-directed behavior. Considerable animal and human research supports the hypothesis put forth by the learned helplessness theory that exposure to uncontrollable aversive stimuli decreases approach motivation by inducing a state of perceived uncontrollability. Accordingly, the present study examined the effect of perceived uncontrollability (i.e., learned helplessness) on PFTA. EEG data were collected from 74 participants (mean age = 19.21 years; 40 females) exposed to either Controllable (n = 26) or Uncontrollable (n = 25) aversive noise bursts, or a No-Noise Condition (n = 23). In line with prediction, individuals exposed to uncontrollable aversive noise bursts displayed a significant decrease in PFTA, reflecting reduced approach motivation, relative to both individuals exposed to controllable noise bursts or the No-Noise Condition. There was no relationship between perceived uncontrollability and frontal EEG alpha asymmetry, another commonly used neurophysiological index of approach motivation. Results have implications for understanding the neurophysiology of approach motivation and establishing PFTA as a neurophysiological index of approach-related tendencies. PMID- 28585018 TI - Resting-state theta/beta EEG ratio is associated with reward- and punishment related reversal learning. AB - Prior research has shown that the ratio between resting-state theta (4-7 Hz)-beta (13-30 Hz) oscillations in the electroencephalogram (EEG) is associated with reward- and punishment-related feedback learning and risky decision making. However, it remains unclear whether the theta/beta EEG ratio is also an electrophysiological index for poorer behavioral adaptation when reward and punishment contingencies change over time. The aim of the present study was to investigate whether resting-state theta (4-7 Hz)-beta (13-30 Hz) EEG ratio correlated with reversal learning. A 4-min resting-state EEG was recorded and a gambling task with changing reward-punishment contingencies was administered in 128 healthy volunteers. Results showed an inverse relationship between theta/beta EEG ratio and reversal learning. Our findings replicate and extend previous findings by showing that higher midfrontal theta/beta EEG ratios are associated with poorer reversal learning and behavioral adaptive responses under changing environmental demands. PMID- 28585019 TI - Women in the midluteal phase of the menstrual cycle have difficulty suppressing the processing of negative emotional stimuli: An event-related potential study. AB - Emotion regulation deficits have been implicated in anxiety and depressive disorders, and these internalising disorders are more prevalent in women than men. Few electrophysiological studies have investigated sex differences in emotional reactivity and emotion regulation controlling for menstrual phase. Event-related potentials (ERPs) were recorded from 28 early follicular women, 29 midluteal women, and 27 men who completed an emotion regulation task. A novel finding of increased N2 amplitude during suppression was found for midluteal women compared with men. These findings suggest midluteal women may be significantly less able to suppress cortical processing of negative stimuli compared to men. This ERP finding was complemented by behavioral ratings data which revealed that while both early follicular and midluteal women reported more distress than men, midluteal women also reported greater effort when suppressing their responses than men. P1 and N1 components were increased in midluteal women compared to men regardless of instructional set, suggesting greater early attentional processing. No sex or menstrual phase differences were apparent in P3 or LPP. This study underscores the importance of considering menstrual phase when examining sex differences in the cortical processing of emotion regulation and demonstrates that midluteal women may have deficits in down-regulating their neural and behavioural responses. PMID- 28585020 TI - Experimental manipulation of infant temperament affects amygdala functional connectivity. AB - In this functional magnetic resonance imaging (fMRI) study we examined neural processing of infant faces associated with a happy or a sad temperament in nulliparous women. We experimentally manipulated adult perception of infant temperament in a probabilistic learning task. In this task, participants learned about an infant's temperament through repeated pairing of the infant face with positive or negative facial expressions and vocalizations. At the end of the task, participants were able to differentiate between "mostly sad" infants who cried often and "mostly happy" infants who laughed often. Afterwards, brain responses to neutral faces of infants with a happy or a sad temperament were measured with fMRI and compared to brain responses to neutral infants with no temperament association. Our findings show that a brief experimental manipulation of temperament can change brain responses to infant signals. We found increased amygdala connectivity with frontal regions and the visual cortex, including the occipital fusiform gyrus, during the perception of infants with a happy temperament. In addition, amygdala connectivity was positively related to the post-manipulation ratings of infant temperament, indicating that amygdala connectivity is involved in the encoding of the rewarding value of an infant with a happy temperament. PMID- 28585022 TI - Erratum to: Relationship between individual and group learning in a marine teleost: A case study with sea bass under self-feeding conditions. PMID- 28585023 TI - Dynamic radiostereometric analysis for evaluation of hip joint pathomechanics. AB - BACKGROUND: Dynamic RSA (dRSA) enables non-invasive 3D motion-tracking of bones and may be used to evaluate in-vivo hip joint kinematics including hip pathomechanics such as femoroacetabular impingement (FAI) and the biomechanical effects of arthroscopic cheilectomy and -rim trimming (ACH). The study aim was to evaluate the kinematic changes in the hip joint after ACH. METHODS: Seven non-FAI affected human cadaveric hips were CT-scanned and CT-bone models were created. dRSA recordings of the hip joints were acquired at five frames/s during passive flexion, adduction to stop, and internal rotation to stop (FADIR). ACH was performed and dRSA was repeated. dRSA images were analyzed using model-based RSA. Hip joint kinematics before and after ACH were compared pairwise. The volume of removed bone was quantified and compared to the postoperative range of motion (ROM). RESULTS: Mean hip internal rotation increased from 19.1 to 21.9 degrees (p = 0.04, Delta2.8 degrees , SD 2.7) after ACH surgery. Mean adduction of 3.9 degrees before and 2.7 degrees after ACH surgery was unchanged (p = 0.48, Delta 1.2 degrees ; SD 4.3). Mean flexion angles during dRSA tests were 82.4 degrees before and 80.8 degrees after ACH surgery, which were similar (p = 0.18, Delta 1.6 degrees , SD = 2.7). No correlation between volume of removed bone and ROM was observed. CONCLUSIONS: A small increase in internal rotation, but not in adduction, was observed after arthroscopic cheilectomy and -rim trimming in cadaver hips. The hip flexion angle of the FADIR test was reproducible. dRSA kinematic analysis is a new and clinically applicable method with good potential to evaluate hip joint kinematics and to test FAI pathomechanics and other surgical corrections of the hip. PMID- 28585025 TI - Our trainees, our future. PMID- 28585021 TI - The relationship between hyperthyrotropinemia and metabolic and cardiovascular risk factors in a large group of overweight and obese children and adolescents. AB - PURPOSE: Mild TSH elevations are frequently observed in obese patients, in the absence of any detectable thyroid disease. Our objective is to evaluate the relationship between the raised TSH levels and the biochemical and clinical consequences of obesity. METHODS: This is a retrospective cross-sectional study of a large population of obese children and adolescents. We evaluated 833 subjects (340 m, 493 f), aged 14.4 +/- 2.5 (range 5.2-18.5) years, height SDS 0.27 +/- 1.04 (-3.49-4.35), and BMI SDS 2.94 +/- 0.59 (1.60-4.68). Body composition, free T4, TSH, anti-TPO antibodies, anti-TG antibodies, inflammation markers (total WBC and the subtypes, ultrasensitive C-reactive protein), and metabolic parameters [AST, ALT, gammaGT, ALP, glycaemia, insulin, total cholesterol (TC), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C), triglycerides (TG)] were measured, and oral disposition index (ODI) and cardiovascular risk factors (TC/HDL-C and TG/HDL-C) were calculated. After exclusion of the subjects showing anti-thyroid antibodies, the remaining 779 (325 m, 454 f) were then subdivided into two subgroups according to a TSH value below (group A) or above (group B) 4.5 mU/L. RESULTS: Clinical characteristics and hematological markers of patients with and without positive anti-thyroid antibodies were similar, with the exception of higher TSH levels in the latter group. Using analysis of covariance, the subjects of group B had significantly higher values of TC (170.3 +/- 28.7 vs 163.3 +/- 32.9 mg/dL; p < 0.05), systolic (125.8 +/- 13.5 vs 124.5 +/- 13.1 mm/Hg), and diastolic blood pressure (79.2 +/- 8.0 vs 77.9 +/- 8.2 mm/Hg) than subjects of group A. No difference was observed in body composition, ODI, and the cardiovascular risk factors between these two groups. CONCLUSION: TSH elevation in overweight and obese children and adolescents, being associated with a higher TC and blood pressure, might negatively influence the cardiac status. Longitudinal studies are requested, however, to confirm this hypothesis and, therefore, to conclude whether a substitutive treatment with l-thyroxine is really needed in these patients. PMID- 28585024 TI - Job Displacement and First Birth Over the Business Cycle. AB - In this article, we investigate the impact of job displacement on women's first birth rates as well as the variation in this effect over the business cycle. We use mass layoffs to estimate the causal effects of involuntary job loss on fertility in the short and medium term, up to five years after displacement. Our analysis is based on rich administrative data from Germany, with an observation period spanning more than 20 years. We apply inverse probability weighting (IPW) to flexibly control for the observed differences between women who were and were not displaced. To account for the differences in the composition of the women who were displaced in a downturn and the women who were displaced in an upswing, we use a double weighting estimator. Results show that the extent to which job displacement has adverse effects on fertility depends on the business cycle. The first-birth rates were much lower for women who were displaced in an economic downturn than for those who lost a job in an economic upturn. This result cannot be explained by changes in the observed characteristics of the displaced women over the business cycle. PMID- 28585026 TI - Standardized uptake values in FDG PET/CT for prosthetic heart valve endocarditis: a call for standardization. AB - BACKGROUND: The significance of and threshold values for the standardized uptake value (SUV) in FDG PET/CT to diagnose prosthetic heart valve (PHV) endocarditis (PVE) are unclear at present. METHODS: A literature search was performed in the PubMed and EMBASE medical databases, comprising the following terms: (FDG OR *fluorode* OR *fluoro-de*) AND (endocarditis OR prosthetic heart valve OR valve replacement). Studies reporting SUVs correlated to the diagnosis of PVE were selected for analysis. RESULTS: 8 studies were included, with a total of 330 PHVs assessed. SUVs for PVE varied substantially across studies due to differences in acquisition, reconstruction, and measurement protocols, with median SUVmax values for rejected PVE ranging from 0.5 to 4.9 and for definite PVE ranging from 4.2 to 7.4. CONCLUSION: Reported SUV values for PVE are not interchangeable between sites, and further standardization of quantification is desirable. To this end, optimal protocols for patient preparation, image acquisition, and reconstruction and measurement methods need to be standardized across centers. PMID- 28585028 TI - Nuclear cardiology in the literature: A selection of recent, original research papers. PMID- 28585027 TI - Myocardial ischemia without obstructive CAD: there is more than meets the eye! PMID- 28585029 TI - Another potential step to improve prosthetic heart valve endocarditis imaging with 18F-FDG PET/CT. PMID- 28585030 TI - Assessment of myocardial viability of a patient with old myocardial infarction by 18F-fluorodeoxyglucose PET/MRI. PMID- 28585031 TI - 18F-FDG-PET in Finnish patients with clinical suspicion of cardiac sarcoidosis: Female sex and history of atrioventricular block increase the prevalence of positive PET findings. AB - INTRODUCTION: Fluorodeoxyglucose positron emission tomography (FDG-PET) is a non invasive imaging modality that has been shown to be a feasible method to demonstrate myocardial inflammation. The aim of this study was to identify the patients suspected of having cardiac sarcoidosis (CS), who are most likely to benefit from PET imaging. MATERIALS AND METHODS: 137 patients suspected of having CS underwent a dedicated cardiac FDG-PET examination at Tampere University Hospital between August 2012 and September 2015. These examinations were retrospectively analyzed. RESULTS: 33 and 12 of the 137 patients had abnormal left and right ventricular (LV and RV) FDG-uptake, respectively. Abnormal LV uptake and RV-uptake were significantly associated with female sex and a history of advanced AV-block (P < 0.05). Abnormal RV-uptake was also associated with ventricular tachycardia and atrial fibrillation (P < 0.05). 56% of the 27 female patients with a history of AV-block had a pathological PET finding compared to only 6% of the 49 male patients without a history of AV-block. There were 17 female patients with history of both AV-block and ventricular tachycardia, 71% of them had abnormal PET finding. CONCLUSIONS: Abnormal FDG-PET findings were associated with female sex, AV-block, and arrhythmias in this clinical cohort. PMID- 28585032 TI - Emerging role of echocardiography, cardiac magnetic resonance imaging and 99mTc labeled bone tracer scintigraphy for the diagnosis of cardiac amyloidosis. PMID- 28585033 TI - Screening pre-renal transplant: Risk factors appear key but important questions remain. PMID- 28585035 TI - UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis. AB - Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD = 0.11, P < 0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD = 0.09, P < 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD = 0.18, P < 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD = 0.08, P = 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD = 0.15, P = 0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment. PMID- 28585036 TI - Differential expression pattern of protein markers for predicting chemosensitivity of dexamethasone-based chemotherapy of B cell acute lymphoblastic leukemia. AB - Dexamethasone is considered as a direct chemotherapeutic agent in the treatment of pediatric acute lymphoblastic leukemia (ALL). Beside the advantages of the drug, some problems arising from the dose-related side effects are challenging issues during the treatment. Accordingly, the classification of patients to dexamethasone sensitive and resistance groups can help to select optimizing the therapeutic dose with the lowest adverse effects particularly in sensitive cases. For this purpose, we investigated inhibited proliferation and induced cytotoxicity in NALM-6 cells, as sensitive cells, after dexamethasone treatment. In addition, comparative protein expression analysis using the 2DE-MALDI-TOF MS technique was performed to identify the specific altered proteins. In addition, we evaluated mRNA expression levels of the identified proteins in bone-marrow samples from pediatric ALL patients using the real-time q-PCR method. Eventually, proteomic analysis revealed a combination of biomarkers, including capping proteins (CAPZA1 and CAPZB), chloride channel (CLIC1), purine nucleoside phosphorylase (PNP), and proteasome activator (PSME1), in response to the dexamethasone treatment. In addition, our results indicated low expression of identified proteins at both the mRNA and protein expression levels after drug treatment. Moreover, quantitative real-time PCR data analysis indicated that independent of the molecular subtypes of the leukemia, CAPZA1, CAPZB, CLIC1, and PNP expression levels were lower in ALL samples than normal samples, although PSME1 expression level was higher in ALL samples than normal samples. Furthermore, the expression level of all proteins (except PSME1) was different between high-risk and standard-risk patients that suggesting the prognostic value of them. In conclusion, our study suggests a panel of biomarkers comprising CAPZA1, CAPZB, CLIC1, PNP, and PSME1 as early diagnosis and treatment evaluation markers that may differentiate cancer cells which are presumably to benefit from dexamethasone-based chemotherapy and may facilitate the prediction of clinical outcome. PMID- 28585037 TI - A review of diazinon use, contamination in surface waters, and regulatory actions in California across water years 1992-2014. AB - Diazinon is an organophosphorus insecticide that has been widely used in the USA and in California resulting in contamination of surface waters. Several federal and state regulations have been implemented with the aim of reducing its impact to human health and the environment, e.g., the cancellation of residential use products by the USEPA and dormant spray regulations by the California Department of Pesticide Regulation. This study reviewed the change in diazinon use and surface water contamination in accordance with the regulatory actions implemented in California over water years 1992-2014. We observed that use amounts began declining when agencies announced the intention to regulate certain use patterns and continued to decline after the implementation of those programs and regulations. The reduction in use amounts led to a downward trend in concentration data and exceedance frequencies in surface waters. Moreover, we concluded that diazinon concentrations in California's surface waters in recent years (i.e., water years 2012-2014) posed a de minimis risk to aquatic organisms. PMID- 28585034 TI - Myocardial perfusion imaging in women for the evaluation of stable ischemic heart disease-state-of-the-evidence and clinical recommendations. AB - This document from the American Society of Nuclear Cardiology represents an updated consensus statement on the evidence base of stress myocardial perfusion imaging (MPI), emphasizing new developments in single-photon emission tomography (SPECT) and positron emission tomography (PET) in the clinical evaluation of women presenting with symptoms of stable ischemic heart disease (SIHD). The clinical evaluation of symptomatic women is challenging due to their varying clinical presentation, clinical risk factor burden, high degree of comorbidity, and increased risk of major ischemic heart disease events. Evidence is substantial that both SPECT and PET MPI effectively risk stratify women with SIHD. The addition of coronary flow reserve (CFR) with PET improves risk detection, including for women with nonobstructive coronary artery disease and coronary microvascular dysfunction. With the advent of PET with computed tomography (CT), multiparametric imaging approaches may enable integration of MPI and CFR with CT visualization of anatomical atherosclerotic plaque to uniquely identify at-risk women. Radiation dose-reduction strategies, including the use of ultra-low-dose protocols involving stress-only imaging, solid-state detector SPECT, and PET, should be uniformly applied whenever possible to all women undergoing MPI. Appropriate candidate selection for stress MPI and for post-MPI indications for guideline-directed medical therapy and/or invasive coronary angiography are discussed in this statement. The critical need for randomized and comparative trial data in female patients is also emphasized. PMID- 28585038 TI - Power analysis as a tool to identify statistically informative indicators for monitoring coral reef disturbances. AB - Extensive biological field surveys are costly and time consuming. To optimize sampling and ensure regular monitoring on the long term, identifying informative indicators of anthropogenic disturbances is a priority. In this study, we used 1800 candidate indicators by combining metrics measured from coral, fish, and macro-invertebrate assemblages surveyed from 2006 to 2012 in the vicinity of an ongoing mining project in the Voh-Kone-Pouembout lagoon, New Caledonia. We performed a power analysis to identify a subset of indicators which would best discriminate temporal changes due to a simulated chronic anthropogenic impact. Only 4% of tested indicators were likely to detect a 10% annual decrease of values with sufficient power (>0.80). Corals generally exerted higher statistical power than macro-invertebrates and fishes because of lower natural variability and higher occurrence. For the same reasons, higher taxonomic ranks provided higher power than lower taxonomic ranks. Nevertheless, a number of families of common sedentary or sessile macro-invertebrates and fishes also performed well in detecting changes: Echinometridae, Isognomidae, Muricidae, Tridacninae, Arcidae, and Turbinidae for macro-invertebrates and Pomacentridae, Labridae, and Chaetodontidae for fishes. Interestingly, these families did not provide high power in all geomorphological strata, suggesting that the ability of indicators in detecting anthropogenic impacts was closely linked to reef geomorphology. This study provides a first operational step toward identifying statistically relevant indicators of anthropogenic disturbances in New Caledonia's coral reefs, which can be useful in similar tropical reef ecosystems where little information is available regarding the responses of ecological indicators to anthropogenic disturbances. PMID- 28585039 TI - Total mercury in muscles and liver of Mugil spp. from three coastal lagoons of NW Mexico: concentrations and risk assessment. AB - Total mercury (Hg) concentrations were determined by atomic absorption spectrophotometry in muscles and liver of composite samples of Mugil cephalus and M. curema collected during November 2013 and in January, April, and July 2014 from the coastal lagoons Altata-Ensenada del Pabellon (AEP), Ceuta (CEU), and Teacapan-Agua Brava (TAG) of Sinaloa State. The mean Hg contents and information on local consumption were used to assess the possible risk caused by fish ingestion. Mean total mercury levels in the muscles ranged from 0.11 to 0.39 MUg/g, while the range for liver was 0.12-3.91 MUg/g. The mean Hg content of the liver was significantly (p < 0.001) higher than that of the muscles only in samples collected from AEP. Although total Hg levels in the muscles were lower than the official permissible limit, the HQ values for methyl mercury calculated for the younger age classes of one fishing community were >1, indicating a possible risk for some fishing communities of the Mexican Pacific coast. PMID- 28585040 TI - Water demand forecasting: review of soft computing methods. AB - Demand forecasting plays a vital role in resource management for governments and private companies. Considering the scarcity of water and its inherent constraints, demand management and forecasting in this domain are critically important. Several soft computing techniques have been developed over the last few decades for water demand forecasting. This study focuses on soft computing methods of water consumption forecasting published between 2005 and 2015. These methods include artificial neural networks (ANNs), fuzzy and neuro-fuzzy models, support vector machines, metaheuristics, and system dynamics. Furthermore, it was discussed that while in short-term forecasting, ANNs have been superior in many cases, but it is still very difficult to pick a single method as the overall best. According to the literature, various methods and their hybrids are applied to water demand forecasting. However, it seems soft computing has a lot more to contribute to water demand forecasting. These contribution areas include, but are not limited, to various ANN architectures, unsupervised methods, deep learning, various metaheuristics, and ensemble methods. Moreover, it is found that soft computing methods are mainly used for short-term demand forecasting. PMID- 28585041 TI - Clinical Impact of Mismatch Repair Protein Testing on Outcome of Early Staged Colorectal Carcinomas. AB - INTRODUCTION: Colorectal cancer is the third most common cancer in men and second most common in women globally. In the present study, we aimed to analyse the proportion of patients with loss of immunostaining for mismatch repair (MMR) proteins in all newly diagnosed stage II cases of colorectal cancer for the purpose of prognostication, for determination of further chemotherapeutic strategy and for familial screening. METHOD: From January 2014 to December 2015, 62 consecutive newly diagnosed cases of stage II colorectal cancer were included in the study. Details of each patient related to their demographic profile and tumour profile were recorded. All the cases were grossed and staged according to College of American Pathologist (CAP) guidelines. The expression of MMR proteins (which was earlier validated on normal as well as tumour tissue) in FFPE tumour tissue using IHC for mut L homologue 1 (MLH1), mut S homologue 2 (MSH2), mut S homologue 6 (MSH6) and post-meiotic segregation increased 2 (PMS2) was studied. Information regarding stage, treatment, clinical outcome and overall survival was retrieved when available. RESULTS: Out of a total of 371 cases, 62 (16.7%) cases were of stage II CRC, out of which 43 (12%) were treatment naive. Among the selected 62 cases, 26 (41.9%) demonstrated loss of MMR proteins and 36 (58.0%) cases had intact nuclear expression. Out of the cases with MMR loss, 38.4% showed loss of MLH1 and PMS2, 30.7% showed loss of MSH2 and MSH6, 26.9% showed isolated loss of PMS2 and 3.8% showed isolated loss of MSH6. Right-sided location (57.6%) was more common than left-sided (19.2%) and transverse colon (23.0%). Majority of the cases were moderately differentiated (65.3%) in morphology. There was no intratumoural infiltrate in most of the cases (53.8%), and only 3.8% cases showed marked intratumoural infiltrate. Also, peritumoural lymphocytic infiltrate was mild to moderate in most of the cases (26.9%) and marked Crohn's-like infiltrate was seen in only 7.6% cases. CONCLUSION: Our study shows that the routine evaluation of MMR proteins is achievable and essential for the purpose of prognostication, planning of treatment strategies and ascertaining a hereditary basis of CRC. The incidence of MMR protein loss was quite high in our study compared to other studies probably due to a difference in ethnicity. Though a right-sided predominance was supported, none of the typical morphological features of microsatellite instability (MSI) tumours were substantiated by our study, highlighting the lack of importance of histology for predicting MSI, and emphasising the point that MSI testing should be done as a routine procedure in all stage II CRC. A short follow-up was done for all our cases and comparison between the survival of the chemotherapy treated MSI cases versus those which were treatment naive was performed and revealed that chemotherapy (CT) did not provide additional benefit to survival; MSI tumours in general are a better prognostic category and do not require additional chemotherapy. PMID- 28585042 TI - Characterizing the interactions of two lipid modifications with lipid rafts: farnesyl anchors vs. palmitoyl anchors. AB - Farnesyl (Far) and palmitoyl (Pal) anchors play important roles in the traffic of many lipidated proteins. Herein, we show the distinctive interactions and influences of the two lipid modifications on lipid rafts (LRs) and non-raft-like membranes using molecular dynamics simulations. Palmitoyl anchors behave in a more ordered fashion, pack tighter with the lipids of LRs and diffuse at a slower rate than farnesyl anchors in LRs. When interacting with non-raft-like membranes these two types of anchors become less ordered, pack more loosely with lipids, and diffuse at a higher rate. By calculating both the number of contacts per chain and the number of contact atoms per carbon of the two anchors with the lipid components, we found that the palmitoyl chains preferred to associate with the saturated chains of lipids and cholesterol molecules in LRs, while farnesyl chains favored association with saturated chains and unsaturated chains. For non raft-like membranes, these two lipid anchors had roughly the same preference for the three types of contact lipid chains. Additionally, palmitoyl anchors caused cholesterol to orient more perpendicular to the membrane surface, surrounding lipids to become more ordered, and lipid lateral fluidity to reduce significantly, compared to farnesyl anchors in LRs. By contrast, the POPE and DSPC became much less ordered, cholesterol became more tilted, and lipids became more fluid, when the two types lipid anchors were inserted in non-raft-like membranes. These findings are useful for understanding the traffic mechanisms of lipidated proteins with farnesyl and palmitoyl modifications in cell membranes. PMID- 28585043 TI - Candidate genes for migration do not distinguish migratory and non-migratory birds. AB - Migratory traits in birds have been shown to have a strong heritable component and several candidate genes have been suggested to control these migratory traits. To investigate if the genetic makeup of one or a set of these candidate genes can be used to identify a general pattern between migratory and non migratory birds, we extracted genomic sequence data for 25 hypothesised candidate genes for migration from 70 available genomes across all orders of Aves and characterised sequence divergence between migratory and non-migratory phenotypes. When examining each gene separately across all species, we did not identify any genetic variants in candidate genes that distinguished migrants from non migrants; any resulting pattern was driven by the phylogenetic signal. This was true for each gene analysed independently, but also for concatenated sequence alignments of all candidate genes combined. We also attempted to distinguish between migrant and non-migrants using structural features at four candidate genes that have previously been reported to show associated with migratory behaviour but did not pick up a signal for migratory phenotype here either. Finally, a screen for dN/dS ratio across all focal candidate genes to probe for putative features of selection did not uncover a pattern, though this might not be expected given the broad phylogenetic scale used here. Our study demonstrates the potential of public genomic data to test for general patterns of migratory gene candidates in a cross-species comparative context, and raise questions on the applicability of candidate gene approaches in a macro-evolutionary context to understand the genetic architecture of migratory behaviour. PMID- 28585044 TI - Lifestyle-tailored interventions for South Asians with type 2 diabetes living in high-income countries: a systematic review. AB - AIM: To summarize evidence on the effectiveness of educational interventions for type 2 diabetes control in South Asians living in high-income countries. METHODS: We systematically searched PubMed, EMBASE, Cinahl and the Cochrane Library, using Medical Subject Heading and free-text terms. The considered outcomes were: mortality, morbidity, glycaemic control, blood pressure, practice (diet, physical activity and self-care), attitudes/awareness and knowledge. Papers published up to July 2015 were considered. Two reviewers independently screened the title and abstract and then read the full text of selected papers. RESULTS: Nine studies were included, four non-randomized studies of interventions and five randomized controlled trials. All studies except one were conducted in the UK. Target population ranged from 39 to 1486 individuals; the follow-up ranged from 1 to 24 months. The interventions were mostly based on a tailored educational package, individually or group administered, conducted by lay link workers, health professionals or both. No study measured mortality or morbidity. An effect on glycaemic control was observed only in before/after studies, while a randomized study showed a non-significant improvement (percentage of glycated haemoglobin 0.15, P = 0.11). Two randomized studies found a reduction in blood pressure. Changes in practice and attitudes showed heterogeneous results, mostly favouring intervention. CONCLUSIONS: There was weak evidence that interventions using link workers and tailored education can modify attitudes, self-care skills and blood pressure in South Asian migrants to industrialized countries. Only one larger trial, with adequate follow-up, showed a small non-significant improvement of glycaemic control. PMID- 28585045 TI - Vaginal repair of a vesicocervical fistula after labored-cesarean delivery without concomitant hysterectomy. PMID- 28585046 TI - Gene Overexpression in Streptomyces hygroscopicus Associated with DNA Amplification. AB - The genetics of the Streptomyces hygroscopicus strain 10-22 is of interest due to the ability of this strain to produce antifungal compounds. Strain T110 was obtained through insertional mutagenesis of strain 10-22 and was found to have undergone DNA amplification, as determined by both conventional and pulsed-field gel electrophoresis (PFGE). pIJ702, the vector used for insertional mutagenesis, was shown to have integrated into and co-amplified with the chromosomal DNA sequence of T110, as pIJ702 hybridized predominantly with two of the three amplified BamHI fragments. The amplified DNA sequence in T110 is 10.8 kb in length and consists of 5.18 kb of Streptomyces chromosomal DNA and the entire 5.62 kb pIJ702 sequence. Sequence analysis of the 5.18 kb chromosomal sequence revealed two open reading frames, one encoding a putative IS5 family transposase and the other encoding a putative dihydroxy-acid dehydratase. Real-time PCR analysis showed that expression of the putative dehydratase gene in T110 is about 50 times greater than in the wild-type strain, consistent with the high level of amplification of this DNA region, and therefore this system has the potential for producing economically or clinically important molecules. PMID- 28585047 TI - Aquichromatium aeriopus gen. nov., sp. nov., A Non-phototrophic Aerobic Chemoheterotrophic Bacterium, and Proposal of Aquichromatiaceae fam. nov. in the Order Chromatiales. AB - A gram-staining negative, non-motile, aerobic chemoheterotrophic, ovoid or short rod-shaped bacterium, designated as J89T, was isolated from a seawater sample collected from the coast of Yellow Sea in Qingdao, China. The strain grew at salinities of 1.0-6.0% (w/v) NaCl (optimum, 3.0%). Growth occurred at pH 6.0-9.0 (optimum, pH 7.0) and at 10-35 degrees C (optimum, 25-30 degrees C). The genomic DNA G+C content was determined to be 59.3 mol%. Q-8 was detected as the respiratory quinone. The major fatty acids (>10%) were summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), summed feature 8 (C18:1 omega7c and/or C18:1 omega6c), and C16:0. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, two unidentified phospholipids, and an unidentified polar lipid. Comparison of the 16S rRNA gene sequence indicated that the strain was most closely related (<91%) to members of the order Chromatiales in the class Gammaproteobacteria. Phylogenetic analyses showed that this strain represented a distinct phylogenetic lineage in the order Chromatiales and could not be assigned to any of the defined families in the order. On the basis of low sequence similarities and differential characteristics of strain J89T from the genera of neighboring families, the strain is proposed to be a representative of a novel genus Aquichromatium gen. nov. A new family Aquichromatiaceae with the type genus Aquichromatium is proposed. Strain J89T (=MCCC 1K03281T=CMRC C2017206T) is the type strain of the type species Aquichromatium aeriopus sp. nov. PMID- 28585049 TI - Characteristics and in-hospital outcomes in young patients presenting with acute coronary syndrome treated by percutaneous coronary intervention. AB - There is a growing interest in the optimizing care of acute coronary syndrome (ACS) in young patients, largely owing to their potential for longer life expectancy. Herein, we aimed to investigate the clinical characteristics and outcome of young ACS patients (e.g. under 60 year old) from a Japanese multicenter percutaneous coronary intervention (PCI) registry (KiCS-PCI). KiCS PCI registered consecutive ACS patients from 15 institutions, and 1560 (24.0%) out of 6499 ACS-related PCI involved patients aged <60 years. In this group, prevalence of dyslipidemia, smoking and family history of premature coronary artery disease (CAD) was higher, while the other classical risk factors were lower when compared to the old patients. After adjustment for known confounders, presentation with cardiogenic shock (CS) before PCI (OR 32.57, 95% CI 12.06 87.97), culprit lesion of LMT (OR 7.53, 95% CI 1.26-44.98), multi-vessel disease (OR 3.82, 95% CI 1.37-10.63) and higher body mass index (OR 1.12, 95% CI 1.00 1.24) showed association with higher in-hospital mortality in young patients. Multi-vessel disease (OR 4.1, 95% CI 1.9-8.9) and chronic kidney disease (OR 3.56, 95% CI 2.26-5.68) were associated with CS presentation. CS presentation was inversely associated with classical risk factors such as hypertension (OR 0.61, 95% CI 0.38-0.96), family history of CAD (OR 0.49, 95% CI 0.25-0.96), and dyslipidemia (OR 0.45, 95% CI 0.29-0.71) and culprit lesion of RCA (OR 0.60, 95% CI 0.37-0.94). Overall, ACS in the younger population was observed frequently, accounting for a quarter of ACS-related PCI. CS was a harbinger for in-hospital mortality in these patients. PMID- 28585048 TI - Diminished femoral head-neck offset and the restricted hip range of motion suggesting a possible role in ACL injuries. AB - PURPOSE: Femoroacetabular impingement may be associated with anterior cruciate ligament (ACL) injuries. The purpose of this study was to determine the head-neck offset, as measured by 45 degrees Dunn's view alpha angles, in patients with ACL injuries compared to control subjects. METHODS: In this retrospective study, 140 consecutive non-professional athletes with primary ACL ruptures confirmed with knee arthroscopy and 100 consecutive patients with non-ACL injury were enrolled. Hip range of motion was assessed in lower extremities in all participants, and alpha angle was calculated according to 45 degrees Dunn's view radiographs. RESULTS: There is not any difference in age, gender distribution, height, weight, and BMI between groups. Internal rotation, abduction, and adduction of the hip were significantly decreased in ACL-injured patients comparing with control subjects (p < 0.001). ACL-injured patients had also a significantly higher alpha angle comparing to the control individuals (p < 0.001). The mean of alpha angle in the ACL-injured patients was 56.1 (SD 10.1) and in the non-ACL-injured group was 49.3 (SD 9.4). CONCLUSIONS: The patients in ACL-injured group showed a significant restriction in hip range of motion and also a diminished femoral head neck offset suggesting a possible role of these findings in the outcome assessed. LEVEL OF EVIDENCE: III. PMID- 28585050 TI - Exact analytical results for integrate-and-fire neurons driven by excitatory shot noise. AB - A neuron receives input from other neurons via electrical pulses, so-called spikes. The pulse-like nature of the input is frequently neglected in analytical studies; instead, the input is usually approximated to be Gaussian. Recent experimental studies have shown, however, that an assumption underlying this approximation is often not met: Individual presynaptic spikes can have a significant effect on a neuron's dynamics. It is thus desirable to explicitly account for the pulse-like nature of neural input, i.e. consider neurons driven by a shot noise - a long-standing problem that is mathematically challenging. In this work, we exploit the fact that excitatory shot noise with exponentially distributed weights can be obtained as a limit case of dichotomous noise, a Markovian two-state process. This allows us to obtain novel exact expressions for the stationary voltage density and the moments of the interspike-interval density of general integrate-and-fire neurons driven by such an input. For the special case of leaky integrate-and-fire neurons, we also give expressions for the power spectrum and the linear response to a signal. We verify and illustrate our expressions by comparison to simulations of leaky-, quadratic- and exponential integrate-and-fire neurons. PMID- 28585051 TI - The role of the putamen in language: a meta-analytic connectivity modeling study. AB - The putamen is a subcortical structure that forms part of the dorsal striatum of basal ganglia, and has traditionally been associated with reinforcement learning and motor control, including speech articulation. However, recent studies have shown involvement of the left putamen in other language functions such as bilingual language processing (Abutalebi et al. 2012) and production, with some authors arguing for functional segregation of anterior and posterior putamen (Oberhuber et al. 2013). A further step in exploring the role of putamen in language would involve identifying the network of coactivations of not only the left, but also the right putamen, given the involvement of right hemisphere in high order language functions (Vigneau et al. 2011). Here, a meta-analytic connectivity modeling technique was used to determine the patterns of coactivation of anterior and bilateral putamen in the language domain. Based on previous evidence, we hypothesized that left putamen coactivations would include brain regions directly associated with language processing, whereas right putamen coactivations would encompass regions involved in broader semantic processes, such as memory and visual imagery. The results showed that left anterior putamen coactivated with clusters predominantly in left hemisphere, encompassing regions directly associated with language processing, a left posterior putamen network spanning both hemispheres, and cerebellum. In right hemisphere, coactivations were in both hemispheres, in regions associated with visual and orthographic processing. These results confirm the differential involvement of right and left putamen in different language components, thus highlighting the need for further research into the role of putamen in language. PMID- 28585052 TI - Measurement of total CO2 in microliter samples of urine and other biological fluids using infrared detection of CO2. AB - The purpose of this study is to describe a low-cost and simply made instrument capable of measuring the total CO2 content of microliter volumes of biological fluids utilizing a commercially available CO2 sensor based on a NDIR detector. The described instrument is based on transformation of dissolved HCO3- to CO2 by acidification and subsequent measurement of the produced CO2. The instrument has a linear response in the range 0.025-10 MUmol HCO3-, which enables measurements in fresh urine and plasma samples down to 5 MUl. The values from plasma were compared to measurements made on 65 MUl whole blood in an automatic blood gas analyzer and found not to differ significantly. Compared to currently commercially available instruments applying the same principles to measure total CO2, this study provides a simple and robust alternative which even can be used on smaller sample volumes. PMID- 28585053 TI - Circulating levels of dickkopf-1, osteoprotegerin and sclerostin are higher in old compared with young men and women and positively associated with whole-body bone mineral density in older adults. AB - : Bone mineral density declines with increasing older age. We examined the levels of circulating factors known to regulate bone metabolism in healthy young and older adults. The circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin were positively associated with whole-body bone mineral density (WBMD) in older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young. INTRODUCTION: This study aims to investigate the relationship between whole-body bone mineral density (WBMD) and levels of circulating factors with known roles in bone remodelling during 'healthy' ageing. METHODS: WBMD and fasting plasma concentrations of dickkopf-1, fibroblast growth factor-23, osteocalcin, osteoprotegerin, osteopontin and sclerostin were measured in 272 older subjects (69 to 81 years; 52% female) and 171 younger subjects (18-30 years; 53% female). RESULTS: WBMD was lower in old than young. Circulating osteocalcin was lower in old compared with young, while dickkopf-1, osteoprotegerin and sclerostin were higher in old compared with young. These circulating factors were each positively associated with WBMD in the older adults and the relationships remained after adjustment for covariates (r values ranging from 0.174 to 0.254, all p < 0.01). In multivariate regression, the body mass index, circulating sclerostin and whole body lean mass together accounted for 13.8% of the variation with WBMD in the older adults. In young adults, dickkopf-1 and body mass index together accounted for 7.7% of variation in WBMD. CONCLUSION: Circulating levels of dickkopf-1, osteocalcin, osteoprotegerin and sclerostin are positively associated with WBMD in community-dwelling older adults, despite the average WBMD being lower and circulating dickkopf-1, osteoprotegerin and sclerostin being higher in old than young. PMID- 28585055 TI - Forgetting from lapses of sustained attention. AB - When performing any task for an extended period of time, attention fluctuates between good and bad states. These fluctuations affect performance in the moment, but may also have lasting consequences for what gets encoded into memory. Experiment 1 establishes this relationship between attentional states and memory, by showing that subsequent memory for an item was predicted by a response time index of sustained attention (average response time during the three trials prior to stimulus onset). Experiment 2 strengthens the causal interpretation of this predictive relationship by treating the sustained attention index as an independent variable to trigger the appearance of an encoding trial. Subsequent memory was better when items were triggered from good versus bad attentional states. Together, these findings suggest that sustained attention can have downstream consequences for what we remember, and they highlight the inferential utility of adaptive experimental designs. By continuously monitoring attention, we can influence what will later be remembered. PMID- 28585054 TI - The effects of person-centered or other supportive interventions in older women with osteoporotic vertebral compression fractures-a systematic review of the literature. AB - Vertebral compression fracture (VCF) is a common fragility fracture and the starting point of a lasting, painful, disabling condition. The aim was to summarize evidence of person-centered/non-medical interventions supporting women with VCF. Results show small numbers of studies with only probable effect on function, pain, QoL, fear of falling, and psychological symptoms. The vertebral compression fracture (VCF) caused by osteoporosis is the third most common fragility fracture worldwide. Previously, it was believed that the pain caused by VCF was self-subsiding within weeks or a few months post-fracture. However, this positive prognosis has been refuted by studies showing that, for the great majority of patients, the VCF was the starting point of a long-lasting, severely painful, and disabling condition. The low number of studies focusing on the experience of the natural course of VCF, and what support is available and how it is perceived by those affected, calls for further investigation. Strengthening older patients' sense of security and increasing confidence in their own abilities are of great importance for successful rehabilitation following VCF. More research is needed to identify resources, possibilities, and strategies that can assist older patients to reach their goals to improve well-being. The purpose of this systematic review was to identify and summarize the current evidence of person-centered or other structured non-medical/non-surgical interventions supporting older women after experiencing an osteoporotic VCF. A systematic literature search was conducted on the MeSH terms encompassing osteoporosis and vertebral compression fractures in the PubMed-MEDLINE and Cumulative Index for Nursing and Allied Health Literature (CINAHL) databases during March through June 2015. The initial search identified 8789 articles, but only seven articles (six randomized controlled trials and one observational study with a control group) met the inclusion criteria. It became evident from the current study that the availability of evidence on the effects of non-medical interventions aiming to support older women with VCF is limited, to say the least. The trials included in this review have few limitations and were mainly considered to be of moderate quality. This systematic literature review suggests that non-medical interventions aiming to support older women with VCF might decrease levels of pain and use of analgesic as well as promote improved physical mobility and function. These interventions would probably result in an improved difference in experiences of fear of falling and perceived psychological symptoms, but would only slightly improve quality of life. However, given the nature of the seven studies, potential biases in patient selection, issues around precision with small cohorts, and failure to control for confounders, makes it difficult to draw a definitive conclusion about the significant effects of non-medical interventions. Incurring a VCF is a complex and diverse event, necessitating equally complex interventions to identify new ways forward. However, to date, interventions struggle with a risk of selection bias in that only the needs of the healthiest of the population are addressed and the voices of the remaining majority of the people affected by VCF are unheard. PMID- 28585056 TI - Time course of syllabic and sub-syllabic processing in Mandarin word production: Evidence from the picture-word interference paradigm. AB - The time course of phonological encoding in Mandarin monosyllabic word production was investigated by using the picture-word interference paradigm. Participants were asked to name pictures in Mandarin while visual distractor words were presented before, at, or after picture onset (i.e., stimulus-onset asynchrony/SOA = -100, 0, or +100 ms, respectively). Compared with the unrelated control, the distractors sharing atonal syllables with the picture names significantly facilitated the naming responses at -100- and 0-ms SOAs. In addition, the facilitation effect of sharing word-initial segments only appeared at 0-ms SOA, and null effects were found for sharing word-final segments. These results indicate that both syllables and subsyllabic units play important roles in Mandarin spoken word production and more critically that syllabic processing precedes subsyllabic processing. The current results lend strong support to the proximate units principle (O'Seaghdha, Chen, & Chen, 2010), which holds that the phonological structure of spoken word production is language-specific and that atonal syllables are the proximate phonological units in Mandarin Chinese. On the other hand, the significance of word-initial segments over word-final segments suggests that serial processing of segmental information seems to be universal across Germanic languages and Chinese, which remains to be verified in future studies. PMID- 28585058 TI - Pictorial review of 18F-FDG PET/CT findings in musculoskeletal lesions. AB - We herein reviewed 18F-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) findings in a number of musculoskeletal lesions including malignant tumors, benign tumors, and tumor-like lesions with correlations to other radiographic imaging modalities, and described the diversity of the 18F-FDG PET/CT findings of this entity. Malignant primary musculoskeletal tumors are typically 18F-FDG avid, whereas low-grade malignant tumors show mild uptake. Benign musculoskeletal tumors generally show a faint uptake of 18F-FDG, and tumor-like conditions also display various uptake patterns of 18F-FDG. Although musculoskeletal tumors show various uptakes of 18F-FDG on PET/CT, its addition to morphological imaging modalities such as CT and MRI is useful for the characterization and differentiation of musculoskeletal lesions. PMID- 28585059 TI - Erratum to: Association between serum and synovial fluid Dickkopf-1 levels with radiographic severity in primary knee osteoarthritis patients. PMID- 28585057 TI - A dual memory theory of the testing effect. AB - A new theoretical framework for the testing effect-the finding that retrieval practice is usually more effective for learning than are other strategies-is proposed, the empirically supported tenet of which is that separate memories form as a consequence of study and test events. A simplest case quantitative model is derived from that framework for the case of cued recall. With no free parameters, that model predicts both proportion correct in the test condition and the magnitude of the testing effect across 10 experiments conducted in our laboratory, experiments that varied with respect to material type, retention interval, and performance in the restudy condition. The model also provides the first quantitative accounts of (a) the testing effect as a function of performance in the restudy condition, (b) the upper bound magnitude of the testing effect, (c) the effect of correct answer feedback, (d) the testing effect as a function of retention interval for the cases of feedback and no feedback, and (e) the effect of prior learning method on subsequent learning through testing. Candidate accounts of several other core phenomena in the literature, including test-potentiated learning, recognition versus cued recall training effects, cued versus free recall final test effects, and other select transfer effects, are also proposed. Future prospects and relations to other theories are discussed. PMID- 28585060 TI - Rheumatoid arthritis-related interstitial lung disease (RA-ILD): methotrexate and the severity of lung disease are associated to prognosis. AB - Interstitial lung disease (ILD) is a severe rheumatoid arthritis (RA) manifestation. The worst survival has been associated with usual interstitial pneumonia (UIP) definitive pattern in high-resolution chest tomography (HRCT) scans. Moreover, the use of methotrexate in RA-ILD is controversial. Our aim was to evaluate prognostic factors including methotrexate in an RA-ILD cohort and their association with survival. RA-ILD patients referred for medical evaluation and treatment at a single center were included. At the baseline, pulmonary function tests were carried out and a HRCT was obtained. A radiologist evaluated the ILD tomographic pattern and the extent of lung disease. Patients were considered as receiving methotrexate therapy if this drug was specifically prescribed for the treatment of RA-ILD at the beginning of follow up. Seventy eight patients were included. UIP definite pattern in HRCT was not associated to worse survival. Variables associated with mortality reflected the severity of lung disease. Treatment with methotrexate was associated with survival (HR 0.13, 95% CI 0.02-0.64); older patients had worse prognosis (HR 1.04, 95% CI 1.003 1.09). After adjusting for confounding variables, methotrexate was strongly associated with survival. Methotrexate treatment during follow up was associated with survival. The severity of lung disease and not the tomographic pattern is associated with mortality; older patients had worse prognosis. PMID- 28585061 TI - Quality of life correlates with muscle strength in patients with dermato- or polymyositis. AB - The aim of this study was to compare health-related quality of life (HQoL) in adults with dermatomyositis (DM) or polymyositis (PM) with a healthy control group and to assess whether muscle strength was associated with HQoL in patients with DM or PM. A cross-sectional study was performed and included 75 patients with DM or PM and 48 healthy controls. HQoL was assessed by the Short Form 36 questionnaire (SF-36). Muscle strength of the patients was assessed using the Manual Muscle Test-8 (MMT8). Covariables and possible confounding factors were collected by validated tools. Associations were determined in multiple linear regression models. The patients had significantly lower HQoL than the control group in both the physical component summary score (PCS) and the mental component summary score (MCS). Thus, the PCS-difference between groups was 32% (p < 0.001), whereas the MCS-difference was 14% (p < 0.001). Muscle strength was associated with one domain in the patients; Physical Function (beta = 1.2; 95% confidence interval 0.37 to 2.1). No statistically significant associations were found between muscle strength and HQoL in the remaining domains. Patients with DM or PM have reduced HQoL compared to healthy controls. Notably, muscle strength was associated with scores of the domain reflecting perceived physical function in patients. These findings corroborate the validity of including selected patient reported outcomes in the evaluation and monitoring of patients with DM or PM. PMID- 28585062 TI - Comparison of the social systems of primates and feral horses: data from a newly established horse research site on Serra D'Arga, northern Portugal. AB - Horses are phylogenetically distant from primates, but considerable behavioral links exist between the two. The sociality of horses, characterized by group stability, is similar to that of primates, but different from that of many other ungulates. Although horses and primates are good models for exploring the evolution of societies in human and non-human animals, fewer studies have been conducted on the social system of horses than primates. Here, we investigated the social system of feral horses, particularly the determinant factors of single male/multi-male group dichotomy, in light of hypotheses derived from studies of primate societies. Socioecological data from 26 groups comprising 208 feral horses on Serra D'Arga, northern Portugal suggest that these primate-based hypotheses cannot adequately explain the social system of horses. In view of the sympatric existence of multi- and single-male groups, and the frequent intergroup transfers and promiscuous mating of females with males of different groups, male female relationships of horses appear to differ from those of polygynous primates. PMID- 28585063 TI - Enabling Real-Time Volume Rendering of Functional Magnetic Resonance Imaging on an iOS Device. AB - Powerful non-invasive imaging technologies like computed tomography (CT), ultrasound, and magnetic resonance imaging (MRI) are used daily by medical professionals to diagnose and treat patients. While 2D slice viewers have long been the standard, many tools allowing 3D representations of digital medical data are now available. The newest imaging advancement, functional MRI (fMRI) technology, has changed medical imaging from viewing static to dynamic physiology (4D) over time, particularly to study brain activity. Add this to the rapid adoption of mobile devices for everyday work and the need to visualize fMRI data on tablets or smartphones arises. However, there are few mobile tools available to visualize 3D MRI data, let alone 4D fMRI data. Building volume rendering tools on mobile devices to visualize 3D and 4D medical data is challenging given the limited computational power of the devices. This paper describes research that explored the feasibility of performing real-time 3D and 4D volume raycasting on a tablet device. The prototype application was tested on a 9.7" iPad Pro using two different fMRI datasets of brain activity. The results show that mobile raycasting is able to achieve between 20 and 40 frames per second for traditional 3D datasets, depending on the sampling interval, and up to 9 frames per second for 4D data. While the prototype application did not always achieve true real time interaction, these results clearly demonstrated that visualizing 3D and 4D digital medical data is feasible with a properly constructed software framework. PMID- 28585064 TI - Revised editorial guidelines for manuscripts on the pharmacology of plant extracts. PMID- 28585065 TI - The right vertebral artery originating from the right occipital artery and the absence of the transverse foramen: a rare anatomical variation. AB - Variations in the origin of the vertebral artery (VA) is a congenital anomaly that occurs during embryological development. Multiple variations related to VA origin have been reported in the literature. Abnormal VA origin is usually determined as incidental findings during angiographic or postmortem anatomical studies. Although most of the cases are asymptomatic, in patients with VA anomaly symptoms such as dizziness have been described. The anomalous variation in the origin of the right VA is rare and separated into three categories: (1) originating from the aorta, (2) originating from the carotid arteries, (3) duplicated origin. In this case, we aimed to present the right VA originating from the right occipital artery and concomitant anomalies of the transverse foramen that have not been reported previously according to our knowledge in literature. In a 32-year-old female patient referred to our hospital because of dizziness, the right VA was not observed on magnetic resonance imaging and computed tomography angiography (CTA) examination was performed. CTA showed hypoplasia of the right transverse foramen at the levels of the C1, C5 and C6 vertebrae and aplasia of the right transverse foramen at the levels of the C2, C3 and C4 vertebrae. The right VA originating from the right occipital artery continues to its normal course by entering the cranium through the foramen magnum at the level of the atlantooccipital junction. PMID- 28585066 TI - Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation. AB - Although the immune response is often regarded as acting to suppress tumor growth, it is now clear that it can be both stimulatory and inhibitory. The interplay between these competing influences has complex implications for tumor development, cancer dormancy, and immunotherapies. In fact, early immunotherapy failures were partly due to a lack in understanding of the nonlinear growth dynamics these competing immune actions may cause. To study this biological phenomenon theoretically, we construct a minimally parameterized framework that incorporates all aspects of the immune response. We combine the effects of all immune cell types, general principles of self-limited logistic growth, and the physical process of inflammation into one quantitative setting. Simulations suggest that while there are pro-tumor or antitumor immunogenic responses characterized by larger or smaller final tumor volumes, respectively, each response involves an initial period where tumor growth is stimulated beyond that of growth without an immune response. The mathematical description is non identifiable which allows an ensemble of parameter sets to capture inherent biological variability in tumor growth that can significantly alter tumor-immune dynamics and thus treatment success rates. The ability of this model to predict non-intuitive yet clinically observed patterns of immunomodulated tumor growth suggests that it may provide a means to help classify patient response dynamics to aid identification of appropriate treatments exploiting immune response to improve tumor suppression, including the potential attainment of an immune induced dormant state. PMID- 28585067 TI - Modelling accidental hypothermia effects on a human body under different pathophysiological conditions. AB - Accidental exposure to cold water environment is one of the most challenging situations in which hypothermia occurs. In the present work, we aim to characterise the energy balance of a human body subjected to such extreme environmental conditions. This study is carried out using a recently developed computational model and by setting boundary conditions needed to simulate the effect of cold surrounding environment. A major finding is the capacity of the body core regions to maintain their temperature high for a substantial amount of time, even under the most extreme environmental conditions. We also considered two disease states that highlight the spectrum of possible pathologies implicated in thermal regulation of the human body. These states are (i) cardiomyopathy, which affects the operating capacity of the heart, and (ii) malnutrition, which directly impairs the body's ability to regulate heat exchange with the environment. We have found that cardiomyopathy has little influence on the thermal balance of the human body, whereas malnutrition has a profound negative effect on the thermal balance and leads to dramatic reduction in core temperature. PMID- 28585068 TI - A novel nitrilase from Ralstonia eutropha H16 and its application to nicotinic acid production. AB - A novel aliphatic nitrilase, REH16, was found in Ralstonia eutropha H16 and overexpressed in Escherichia coli BL21(DE3), and its enzymatic properties were studied. The temperature and pH optima were 37 degrees C and 6.6, respectively, and the best thermostability of the nitrilase was observed at 25 degrees C, which preserved 95% of activity after 120 h of incubation. REH16 has a broad hydrolytic activity toward aliphatic and heterocyclic nitriles and showed high tolerance of 3-cyanopyridine; this enzyme could hydrolyze as high as 100 mM 3 cyanopyridine completely. To improve the 3-cyanopyridine conversion efficiency in an aqueous reaction system, water-miscible organic solvents were tested, and ethanol (10% v/v) was chosen as the optimal co-solvent. Finally, under optimized conditions, using the fed-batch reaction mode, total of 1050 mM 3-cyanopyridine was hydrolyzed completely in 20.8 h with eight substrate feedings, yielding 129.2 g/L production of nicotinic acid and thus showing a potential for industrial application. PMID- 28585069 TI - Special issue on titin and its binding proteins in striated muscle. PMID- 28585070 TI - Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. AB - The most common causes of morbidity and mortality in myeloproliferative neoplasms (MPN) are thrombotic and hemorrhagic complications. The JAK2V617F mutation, commonly found in MPN, correlates with several clinical and laboratory characteristics even if the relevance of JAK2V617F allele burden in the natural history of these diseases is unclear. In this study we searched, a relation between thrombotic and hemorrhagic complications and JAK2V617F allele burden level in MPN patients. We evaluated 253 consecutive MPN [121 essential thrombocythemia (ET), 124 polycythemia vera (PV), and 8 primary myelofibrosis (PMF)] patients in whom the JAK2V617F allele burden was available, all studied and followed (median 8.8 years) in our department. Patients were stratified accordingly to their JAK2V617F allele burden, into four quartiles (1st <25%, 2nd 26-50%, 3rd 51-75%, and 4th >75%). Significantly higher incidence of thromboses (p = 0.001) and hemorrhages (p < 0.001) during follow-up has been observed in higher quartiles when compared to lower ones. Thrombosis- and hemorrhage-free survivals were poorer in patients belonging to the highest quartile. Our data suggest that MPN patients with JAK2V617F allele burden higher than 75% have to be considered as high risk patients, being prone to develop thrombo-hemorrhagic complications during the disease course. PMID- 28585071 TI - Impact of non-transferrin-bound iron (NTBI) in comparison to serum ferritin on outcome after allogeneic stem cell transplantation (ASCT). AB - The optimal parameters and time points for the measurement of iron overload (IO) in allogeneic stem cell transplantation (ASCT) patients are still under discussion. Hyperferritinemia and IO are poor prognostic factors in ASCT. We hypothesize that non-transferrin-bound iron (NBTI) is possibly a better marker to predict the effect of IO on the outcome than serum ferritin (SF), which however is not specific for IO. The aim of this prospective observational trial was to evaluate the influence of NBTI in comparison to SF on the outcome of ASCT patients [overall survival, bloodstream infections (BSIs), and invasive fungal infections (IFIs)]. We analyzed daily transferrin saturation (TSAT), SF, and NTBI (if TSAT exceeded 70%) in 100 patients who received ASCT during conditioning, and on day 0, +7, and +14 post-ASCT. After a median NTBI level of 0 MUmol/l at baseline, the median of the area under the curve (AUC) of NTBI between conditioning and ASCT (d0) increased to 17 MUmol*d/l, and between ASCT and day +14 to 56.3 MUmol*d/l. Higher NTBI-AUC d0 resulted in a higher risk of BSI (HR 1.042, p = 0.009) and IFI (HR 1.070, p = 0.001) and showed a trend of inferior 1 year survival (65 vs. 76%, p = 0.09). Baseline SF did not influence BSI, but higher levels resulted in more IFI (HR 1.26, p < 0.001). In conclusion, NTBI possibly better predict for a higher risk of bloodstream infections than SF and needs further investigation. PMID- 28585072 TI - Maternal Health: a Qualitative Study of Male Partners' Participation in Lagos, Nigeria. AB - PURPOSE: Male involvement in maternal healthcare has been described as a key factor to reducing maternal mortality globally. Hence, this study investigated the choice of facility to be used during pregnancy and examined factors that influence male participation in maternal healthcare issues of their spouses as these factors may sometimes influence the choice of health care services for pregnant women. METHOD: The study was cross-sectional in design; the setting was at Badagry, Lagos, Nigeria. Thirty married men with at least the experience of birth of baby, who consented to participate, were purposively recruited for the study. Data were transcribed and content analysed using free narrative. RESULT: The results show that orthodox health care, traditional birth attendance (TBA), and faith healing were utilised by the respondents. The majority of the participants identified cost of health care services, economic recession, and their job demand as the reasons for their non-active participation in accompanying their spouses for antenatal clinic visit. CONCLUSION: However, to increase the level of men's participation in maternal healthcare, especially visiting antenatal clinic with spouses, antenatal services should be free of any monetary charges so as to encourage men to be involved and not look for excuses of financial needs. Utilisation of skilled birth attendance should be reinvigorated. PMID- 28585073 TI - Exploring the Social Needs and Challenges of Chinese American Immigrant Breast Cancer Survivors: a Qualitative Study Using an Expressive Writing Approach. AB - PURPOSE: Little is known about the psychological well-being and social barriers among immigrant Chinese American breast cancer survivors. The aim of the present study was to explore the social needs and challenges of Chinese American immigrant breast cancer survivors. METHOD: This study used the expressive writing approach to explore the experiences among 27 Chinese American breast cancer survivors. The participants were recruited through community-based organizations in Southern California, most of whom were diagnosed at stages I and II (33 and 48%, respectively). Participants, on average, had been living in the USA for 19 years. Participants were asked to write three 20-min essays related to their experience with breast cancer (in 3 weeks). Participants' writings were coded with line-by-line analysis, and categories and themes were generated. RESULTS: Emotion suppression, self-stigma, and perceived stigma about being a breast cancer survivor were reflected in the writings. Interpersonally, participants indicated their reluctance to disclose cancer diagnosis to family and friends and concerns about fulfilling multiple roles. Some of them also mentioned barriers of communicating with their husbands. Related to life in the USA, participants felt unfamiliar with the healthcare system and encountered language barriers. CONCLUSION: Counseling services addressing concerns about stigma and communication among family members may benefit patients' adjustments. Tailor-made information in Chinese about diagnosis and treatment for breast cancer and health insurance in the USA may also help patients go through the course of recovery. PMID- 28585074 TI - Subtype-specific prognostic impact of different immune signatures in node negative breast cancer. AB - BACKGROUND: The role of different subtypes of immune cells is still a matter of debate. METHODS: We compared the prognostic relevance for metastasis-free survival (MFS) of a B-cell signature (BS), a T-cell signature (TS), and an immune checkpoint signature (CPS) in node-negative breast cancer (BC) using mRNA expression. Microarray-based gene-expression data were analyzed in six previously published cohorts of node-negative breast cancer patients not treated with adjuvant therapy (n = 824). The prognostic relevance of the individual immune markers was assessed using univariate analysis. The amount of independent prognostic information provided by each immune signature was then compared using a likelihood ratio statistic in the whole cohort as well as in different molecular subtypes. RESULTS: Univariate Cox regression in the whole cohort revealed prognostic significance of CD4 (HR 0.66, CI 0.50-0.87, p = 0.004), CXCL13 (HR 0.86, CI 0.81-0.92, p < 0.001), CD20 (HR 0.76, CI 0.64-0.89, p = 0.001), IgkappaC (HR 0.81, CI 0.75-0.88, p < 0.001), and CTLA-4 (HR 0.67, CI 0.46 0.97, p = 0.032). Multivariate analyses of the immune signatures showed that both TS (p < 0.001) and BS (p < 0.001) showed a significant prognostic information in the whole cohort. After accounting for clinical-pathological variables, TS (p < 0.001), BS (p < 0.05), and CPS (p < 0.05) had an independent effect for MFS. In subgroup analyses, the prognostic effect of immune cells was most pronounced in HER2+ BC: BS as well as TS showed a strong association with MFS when included first in the model (p < 0.001). CONCLUSION: Immune signatures provide subtype specific additional prognostic information over clinical-pathological variables in node-negative breast cancer. PMID- 28585075 TI - Disease Progression in Papillary Thyroid Cancer with Biochemical Incomplete Response to Initial Therapy. AB - BACKGROUND: Dynamic risk stratification is utilized in the follow-up of patients with papillary thyroid carcinoma (PTC). Analysis of outcomes after biochemical incomplete response (BIR) to initial therapy will allow better individualization of care. METHODS: A total of 494 patients with PTC were followed prospectively. Immunohistochemistry (IHC) for BRAFV600E mutation was completed on all surgical specimens. After exclusion of patients with inadequate data, 353 patients were stratified into four categories of response to initial therapy: excellent, biochemical incomplete, structural incomplete, or indeterminate. Patients with BIR, defined as elevated stimulated thyroglobulin >2 ug/L with negative imaging, were analysed for progression of disease. The primary outcome measure was development of structural recurrence. RESULTS: Forty-nine of 353 (13.9%) patients had BIR. BRAFV600E mutation was present in 32 of 49 (65.3%) with BIR. Progression to structural recurrence occurred in 8 of 49 (16.3%) with BIR, all of whom were positive for the BRAFV600E mutation (p = 0.02). Nine patients (18%) with BIR remitted during follow-up to no evidence of disease (6 had additional RAI therapy). After mean follow-up of 35 months, 12 patients with BIR (24%) remained biochemically abnormal with no structural evidence of disease. CONCLUSIONS: Patients with BIR following initial treatment for PTC have generally favorable outcomes. Positive IHC for BRAFV600E identifies patients at risk of structural disease recurrence. PMID- 28585076 TI - Redefining anterior shoulder impingement: a literature review. AB - Many different types of impingements have been described in the shoulder. Inasmuch as the term 'shoulder impingement' usually refers to subacromial impingement, anterior impingement usually refers to subcoracoid impingement. However, there are many different subtypes of anterior impingements in the shoulder, and awareness of their existence is critical as they vary in their nature and treatment. Recent advances in biomechanical research and arthroscopic exploration of the anterior structures of the shoulder have brought new insights on the various potential impingements, warranting a revision and update of the current definitions of anterior shoulder impingement. The purpose of this article is to propose a comprehensive review and classification of all different subtypes of anterior impingement in the shoulder, including newly described entities. PMID- 28585077 TI - A new species of Moniliformis from a Sigmodontinae rodent in Patagonia (Argentina). AB - The majority of species of Acanthocephala known thus far from South America have been recorded mostly in fish and wild birds. In particular, rodents in Argentina have been poorly studied for acanthocephalans. The genus Abrothrix (Sigmodontinae Cricetidae) ranges from the Altiplano of southern Peru through the highlands of Bolivia, northern Chile, and Argentina south through Tierra del Fuego. The purpose of this paper was to study Acanthocephala species parasitizing different populations of Abrothrix from Santa Cruz province (Patagonia Argentina). Specimens of Acanthocephala were found in the small intestine of Abrothrix olivaceus, showing values of P 14.7%, IM = 2.8, and AM = 0.41. All the rodents parasitized were collected in Punta Quilla, Santa Cruz, Argentina. The specimens of Abrothrix longipilis were not parasitized. Moniliformis amini n. sp. is described with features such as the long, cylindrical, and pseudo-segmented body; proboscis receptacle double walled, outer wall with muscle fibers usually arranged spirally, and a combination of several morphometric characters, mainly the very small size of the proboscis receptacle and length of the testes and lemnisci. A marked proportion of arthropods was found in the diet of A. olivaceus, characterizing it as arthropodivorous. Possibly, a larger sampling effort and specific projects dealing with the study of acanthocephalans will shed light on several questions of the rodent-Moniliformis relationship. PMID- 28585079 TI - New Mammalian Expression Systems. AB - There are an increasing number of recombinant antibodies and proteins in preclinical and clinical development for therapeutic applications. Mammalian expression systems are key to enabling the production of these molecules, and Chinese hamster ovary (CHO) cell platforms continue to be central to delivery of the stable cell lines required for large-scale production. Increasing pressure on timelines and efficiency, further innovation of molecular formats and the shift to new production systems are driving developments of these CHO cell line platforms. The availability of genome and transcriptome data coupled with advancing gene editing tools are increasing the ability to design and engineer CHO cell lines to meet these challenges. This chapter aims to give an overview of the developments in CHO expression systems and some of the associated technologies over the past few years. PMID- 28585078 TI - Associations between fasciolosis and milk production, and the impact of anthelmintic treatment in dairy herds. AB - Liver fluke is a ubiquitous parasite that causes extensive production losses in cattle and is a zoonosis. The aims of this study were to determine the prevalence of fasciolosis in 178 dairy cattle herds in Styria (federal state of Austria) and its influence on production, to detect the risk factors for infection, and to explore effective strategies in management and control. A questionnaire on farm management, prophylaxis, and therapy was developed and applied. Furthermore, production parameters (milk yield, milk protein content, butter fat content, non return rate 90, calving to conception interval, service period) were recorded for 2014 and 2015, and a commercial ELISA for detection of Fasciola hepatica antibodies was applied in bulk tank milk in March 2014 and March 2015. Analysis of bulk tank milk samples showed a prevalence of 61.3% in 2014 and 45.5% in 2015. No associations could be found between F. hepatica exposure and farm structure or pasture management. Farms with highly positive (optical density ratio (ODR) >= 0.6 and lying above the upper interquartile range) antibody levels had a significantly lower annual milk yield of 438 kg per cow per year (p = 0.045), butterfat content of 0.091% (p = 0.004), and milk protein content of 0.046% (p = 0.024). However, fertility parameters were not significantly associated with liver fluke exposure. Anthelmintic treatment led to significantly lower antibody levels in the subsequent year (p = 0.042) and had a significant influence on protein content in milk (p = 0.003). This study highlighted the importance of fasciolosis in Austria and its influence on milk production and the need for veterinary advice regarding prophylactic measures to reduce economic losses. PMID- 28585080 TI - Visuo-locomotor control in persons with spinal cord injury in a manual or power wheelchair for direction change and obstacle circumvention. AB - Many individuals, such as persons with spinal cord injury (SCI), rely on wheeled locomotion involving manual (MWC) or power (PWC) wheelchairs to navigate their environments. Yet, visuo-locomotor control underlying WC navigation in experienced users is not well understood. The objective of this study was to compare the visuo-locomotor control between MWC and PWC in individuals with SCI while changing direction and circumventing an obstacle. Participants with SCI using a MWC (n = 12, 38.5 +/- 10.7 years) or a PWC (n = 10, 47.8 +/- 8.6 years) were asked to maneuver their chair straight ahead, while changing direction 45 degrees to the right, and while circumventing an obstacle to the right, all at self-selected speeds. Speed, minimal clearance, point of deviation, temporal body and WC coordination, relative timing of segment rotations and visual behavior were analyzed. There was no main effect of group for speed, clearance and point of deviation. During direction change, the head always led body and wheelchair reorientation while an "en bloc" strategy was used for circumventing obstacle for both groups. In straight-ahead locomotion, participants predominantly fixed their gaze on the end target. During direction change and obstacle circumvention, participants fixated more on the future path and the obstacle for both WC modes. Overall, specific gaze behavior depended on environmental demands. While MWC and PWC users adopt similar navigational strategies and visuo-locomotor coordination while changing direction and circumventing obstacle, there were some differences in the amount of head rotation that could be related to a counter-movement used more by PWC users. PMID- 28585081 TI - Mental health assessed by the Strengths and Difficulties Questionnaire for children born extremely preterm without severe disabilities at 11 years of age: a Norwegian, national population-based study. AB - The aims were to investigate mental health problems with the Strength and Difficulties Questionnaire (SDQ) in children born extremely preterm/extremely low birth weight (EP/ELBW) without severe disabilities compared to controls, and to identify peri-, or neonatal factors possibly predicting later mental health problems. A national Norwegian cohort of 11-year-old EP/ELBW children, excluding those with intellectual disabilities, non-ambulatory cerebral palsy, blindness and/or deafness, was assessed. Parents and teachers completed the SDQ. Mean scores and scores >=90th percentile for the control group, combined (parent and/or teacher reporting the child >=90th percentile), and pervasive ratings (both parent and teacher reporting the child >=90th percentile) were presented. The controls consisted of an unselected population of all 11-year-old children born in 1995 who attended public or private schools in Bergen. Of the eligible children, 216 (64%) EP/ELBW and 1882 (61%) control children participated. The EP/ELBW children had significantly higher scores and/or increased risk of parent, teacher, combined, and pervasive rated hyperactivity/inattention, emotional-, and peer problems (OR 2.1-6.3). Only parents reported the EP/ELBW children to be at an increased risk of conduct problems (OR 1.6, 95% CI 1.1-2.6). Only low maternal education at birth was significantly associated with mental health problems at 11 years of age (OR 2.5, 95% CI 1.2-5.4). EP/ELBW children without severe disabilities had increased risk of symptoms of hyperactivity/inattention, emotional-, and peer problems. None of the peri- or neonatal factors were significantly associated with later mental health problems, except for low maternal education. PMID- 28585082 TI - Magnetic resonance imaging perfusion is associated with disease severity and activity in multiple sclerosis. AB - PURPOSE: The utility of perfusion-weighted imaging in multiple sclerosis (MS) is not well investigated. The purpose of this study was to compare baseline normalized perfusion measures in subgroups of newly diagnosed MS patients. We wanted to test the hypothesis that this method can differentiate between groups defined according to disease severity and disease activity at 1 year follow-up. METHODS: Baseline magnetic resonance imaging (MRI) including a dynamic susceptibility contrast perfusion sequence was performed on a 1.5-T scanner in 66 patients newly diagnosed with relapsing-remitting MS. From the baseline MRI, cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were generated. Normalized (n) perfusion values were calculated by dividing each perfusion parameter obtained in white matter lesions by the same parameter obtained in normal-appearing white matter. Neurological examination was performed at baseline and at follow-up approximately 1 year later to establish the multiple sclerosis severity score (MSSS) and evidence of disease activity (EDA). RESULTS: Baseline normalized mean transit time (nMTT) was lower in patients with MSSS >3.79 (p = 0.016), in patients with EDA (p = 0.041), and in patients with both MSSS >3.79 and EDA (p = 0.032) at 1-year follow-up. Baseline normalized cerebral blood flow and normalized cerebral blood volume did not differ between these groups. CONCLUSION: Lower baseline nMTT was associated with higher disease severity and with presence of disease activity 1 year later in newly diagnosed MS patients. Further longitudinal studies are needed to confirm whether baseline-normalized perfusion measures can differentiate between disease severity and disease activity subgroups over time. PMID- 28585083 TI - Multiclass analytical method for the determination of natural/synthetic steroid hormones, phytoestrogens, and mycoestrogens in milk and yogurt. AB - Within this study, a new method enabling monitoring of various estrogenic substances potentially occurring in milk and dairy products was proposed. Groups of compounds fairly differing in physico-chemical properties and biological activity were analyzed: four natural estrogens, four synthetic estrogens, five mycoestrogens, and nine phytoestrogens. Since they may pass into milk mainly in glucuronated and sulfated forms, an enzymatic hydrolysis was involved prior to the extraction based on the QuEChERS methodology. For the purification of the organic extract, a dispersive solid-phase extraction (d-SPE) with sorbent C18 was applied. The final analysis was performed by ultra-high-performance liquid chromatography (UHPLC) coupled with triple quadrupole tandem mass spectrometry (MS/MS). Method recovery ranged from 70 to 120% with a relative standard deviation (RSD) value lower than 20% and limits of quantification (LOQs) in the range of 0.02-0.60 MUg/L (0.2-6.0 MUg/kg dry weight) and 0.02-0.90 MUg/kg (0.2 6.0 MUg/kg dry weight) for milk and yogurt, respectively. The new procedure was applied for the investigation of estrogenic compounds in 11 milk samples and 13 yogurt samples from a Czech retail market. Mainly phytoestrogens were found in the studied samples. The most abundant compounds were equol and enterolactone representing 40-90% of all estrogens. The total content of phytoestrogens (free and bound) was in the range of 149-3870 MUg/kg dry weight. This amount is approximately 20 times higher compared to non-bound estrogens. PMID- 28585085 TI - Surface-enhanced Raman scattering (SERS) imaging-guided real-time photothermal ablation of target cancer cells using polydopamine-encapsulated gold nanorods as multifunctional agents. AB - In this study, we developed a novel "see-and-treat" theranostic system named "surface-enhanced Raman scattering (SERS) imaging-guided real-time photothermal therapy" for accurate cancer detection and real-time cancer cell ablation using the same Raman laser. Facilely synthesized polydopamine-encapsulated gold nanorods (AuNRs), which possess excellent biocompatibility and enhanced stability, were used as multifunctional agents. Under near-infrared (NIR) laser irradiation, polydopamine-encapsulated AuNRs show strong SERS effect and high photothermal conversion efficiency simultaneously. After immobilization of antibodies (anti-EpCAM), polydopamine-encapsulated gold nanorods show high specificity to target cancer cells. Tumor margins could be distinguished facilely by a quick SERS imaging process, which was confirmed by H&E staining results. By focusing the exciting light on detected cancer cells for a prolonged time, cancer cells could be ablated immediately without the need of other procedure. This "see and-treat" theranostic strategy combining SERS imaging and real-time photothermal therapy using the same Raman laser is proposed for the first time. Experimental results confirmed the feasibility of our "SERS imaging-guided real-time photothermal therapy system." This novel theranostic strategy can significantly improve the efficiency of cancer therapy in clinical application, allowing the effective ablation of cancer cells with no effects on surrounding healthy tissues. Graphical abstract ?. PMID- 28585086 TI - A mechanistic study of geminal dicationic ionic liquids as mobile phase additives for improving the separation performance of high-performance liquid chromatography. AB - Due to the acidity and strong polarity of auxinic herbicides, separation of these compounds in food and environmental samples is a great challenge. In this study, 12 geminal dicationic ionic liquids (GDILs) were synthesized and used as mobile phase additives to separate six auxinic herbicides. The effects of the kind of dication, the length of linkage chain, the kind of anion, the concentration of GDILs, and the pH of mobile phase for the separation were investigated in detail. Compared with [C4MIm][BF4], GDILs ([C8(MIm)2][BF4]2) showed higher resolution, better peak shape, and lower retention factor. The separation performance of additives was in the order of [C8(MIm)2][BF4]2 > [C8(MPy)2][BF4]2, [(C4)2MPiz][BF4]2, [C8(MMo)2][BF4]2, [C4MIm][BF4], [C8(MPid)2][BF4]2 > [C8(HBOc)2][BF4]2 > TBAB. GDILs showed the best separation under the following conditions: cation: imidazolium; length of linkage chain: 8; anion: BF4-; mobile phase pH: 3; concentration: 5 mmol L-1. The separation mechanism of GDILs may mainly be due to their symmetric structure and the abundance of positive charge sites which could help GDILs shield the residual silanol and interact with analytes more efficiently to improve the peak shapes, resolution, and retention. In addition, the GDILs in the mobile phase and anions adsorbed on the stationary phase also greatly affected the separation. GDILs used as mobile phase additives to separate auxinic herbicides showed high efficiency separation and low damage to HPLC columns, and the developed chromatographic method had excellent linearity, accuracy, precision, and repeatability. The application and mechanism study of GDILs in HPLC would be instructive to determine and separate acid herbicides in food and environmental samples. Graphical abstract As HPLC mobile phase additives, GDILs show high separation performance due to their unique symmetric structures. PMID- 28585087 TI - Corticosteroids and aldose reductase inhibitor Epalrestat modulates cardiac action potential via Kvbeta1.1 (AKR6A8) subunit of voltage-gated potassium channel. AB - We previously demonstrated the role of Kvbeta1.1 subunit of voltage-activated potassium channel in heart for its sensory roles in detecting changes in NADH/NAD and modulation of ion channel. However, the pharmacological role for the association of Kvbeta1 via its binding to ligands such as cortisone and its analogs remains unknown. Therefore, we investigated the significance of Kvbeta1.1 binding to cortisone analogs and AR inhibitor epalrestat. In addition, the aldose reductase (AR) inhibitor epalrestat was identified as a pharmacological target and modulator of cardiac activity via binding to the Kvbeta1 subunit. Using a combination of ex vivo cardiac electrophysiology and in silico binding, we identified that Kvbeta1 subunit binds and interacts with epalrestat. To identify the specificity of the action potential changes, we studied the sensitivity of the action potential prolongation by probing the electrical changes in the presence of 4-aminopyridine and evaluated the specificity of pharmacological effects in the hearts from Kvbeta1.1 knock out mouse. Our results show that pharmacological modulation of cardiac electrical activity by cortisone analogs and epalrestat is mediated by Kvbeta1.1. PMID- 28585084 TI - Glycomic and glycoproteomic analysis of glycoproteins-a tutorial. AB - The structural analysis of glycoproteins is a challenging endeavor and is under steadily increasing demand, but only a very limited number of labs have the expertise required to accomplish this task. This tutorial is aimed at researchers from the fields of molecular biology and biochemistry that have discovered that glycoproteins are important in their biological research and are looking for the tools to elucidate their structure. It provides brief descriptions of the major and most common analytical techniques used in glycomics and glycoproteomics analysis, including explanations of the rationales for individual steps and references to published literature containing the experimental details necessary to carry out the analyses. Glycomics includes the comprehensive study of the structure and function of the glycans expressed in a given cell or organism along with identification of all the genes that encode glycoproteins and glycosyltransferases. Glycoproteomics which is subset of both glycomics and proteomics is the identification and characterization of proteins bearing carbohydrates as posttranslational modification. This tutorial is designed to ease entry into the glycomics and glycoproteomics field for those without prior carbohydrate analysis experience. PMID- 28585088 TI - Allyl isothiocyanate, a potent chemopreventive agent targets AhR/Nrf2 signaling pathway in chemically induced mammary carcinogenesis. AB - In the present study, we investigated the effect of allyl isothiocyanate (AITC) on liver detoxification signaling pathway in 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinogenesis. Mammary tumor was induced by a single dose of DMBA (25 mg/rat) injected subcutaneously near the mammary gland in Sprague Dawley rats. DMBA-alone-treated rats show an increased synthesis of phase I detoxification enzymes, lipid peroxidative markers, liver marker enzymes, and lipid profiles whereas, depletion of phase II detoxification enzymes and antioxidants in rat liver tissues. Oral administration of AITC restored the levels of biochemical markers in DMBA-treated rats. Furthermore, histopathological results also confirmed that AITC protects DMBA-mediated hepatocellular damage. We also observed that AITC treatment significantly downregulates AhR and upregulates the expression of Nrf2 in DMBA-treated rats. The binding efficacy of AITC with AhR and Nrf2 analysis by molecular docking studies reveals that AITC has strong interaction with AhR and Nrf2 proteins through hydrogen and hydrophobic interactions. Thus, AITC prevents DMBA-induced mammary carcinogenesis via inhibition of phase I and induction of phase II detoxification enzymes by modulating AhR/Nrf2 signaling pathway. PMID- 28585089 TI - Combination of cationic dexamethasone derivative and STAT3 inhibitor (WP1066) for aggressive melanoma: a strategy for repurposing a phase I clinical trial drug. AB - Glucocorticoid, such as dexamethasone (Dex) is often used along with chemotherapy to antagonize side effects of chemotherapy. However, sustained use of Dex frequently develops drug resistance in patients. As a strategy to re-induce drug sensitivity, we planned to modify Dex by chemically conjugating it with twin ten carbon aliphatic chain containing cationic lipid. The resultant molecule, DX10, inhibited STAT3 activation through lowering the production of IL-6. To enhance the STAT3 inhibitory effect of DX10, we used WP (a commercially available STAT3 inhibitor) along with DX10. Combination treatment of both significantly inhibited STAT3 activation when compared to either of the individual treatment. The effect of DX10, either in combination or alone, was mediated through glucocorticoid receptor (GR), thereby repurposing the role of GR in the context of p-STAT3 inhibition-mediated cancer treatment. Cellular viability study proved the synergistic effect of WP and DX10. Further, combination treatment led to induction of early stage of apoptosis and cell cycle arrest. In vivo melanoma tumor regression study confirmed the enhanced anti-tumor activity of co-treatment over individual treatment of DX10 or WP. Thus, together our result demonstrates that DX10 may be used in combination therapy with STAT3 inhibitor like WP for combating cancer with constitutively active STAT3. PMID- 28585090 TI - Intuitive control of mobile robots: an architecture for autonomous adaptive dynamic behaviour integration. AB - In this paper, we present a novel approach to human-robot control. Taking inspiration from behaviour-based robotics and self-organisation principles, we present an interfacing mechanism, with the ability to adapt both towards the user and the robotic morphology. The aim is for a transparent mechanism connecting user and robot, allowing for a seamless integration of control signals and robot behaviours. Instead of the user adapting to the interface and control paradigm, the proposed architecture allows the user to shape the control motifs in their way of preference, moving away from the case where the user has to read and understand an operation manual, or it has to learn to operate a specific device. Starting from a tabula rasa basis, the architecture is able to identify control patterns (behaviours) for the given robotic morphology and successfully merge them with control signals from the user, regardless of the input device used. The structural components of the interface are presented and assessed both individually and as a whole. Inherent properties of the architecture are presented and explained. At the same time, emergent properties are presented and investigated. As a whole, this paradigm of control is found to highlight the potential for a change in the paradigm of robotic control, and a new level in the taxonomy of human in the loop systems. PMID- 28585091 TI - A Generalist Herbivore Copes with Specialized Plant Defence: the Effects of Induction and Feeding by Helicoverpa armigera (Lepidoptera: Noctuidae) Larvae on Intact Arabidopsis thaliana (Brassicales) Plants. AB - Plants of the Brassicaceae are defended from feeding by generalist insects by constitutively-expressed and herbivory-induced glucosinolates (GS). We induced Arabidopsis plants 1, 16 and 24 h prior to allowing neonate larvae of the generalist Helicoverpa armigera to feed on whole plants for 72 h. These plants were subsequently retested with another group of neonates for a further 72 h. We used wild-type A. thaliana Col-0, and mutant lines lacking indolic GS, aliphatic GS or all GS. We hypothesized that larvae would not grow well on defended plants (WT) compared to those lacking GS, and would not grow well if plants had been primed or fed on for longer, due to the expected induced GS. There was survivorship on all lines suggesting H. armigera is a suitable generalist for these experiments. Larvae performed less well on wild-type and no indolic lines than on no aliphatic and no GS lines. Larvae distributed feeding damage extensively in all lines, more so on wild type and no-indolic lines. Contrary to expectations, larvae grew better on plants that had been induced for 1 to 16 h than on un-induced plants suggesting they moved to and selected less toxic plant parts within a heterogeneously defended plant. Performance declined on all lines if plants had been induced for 24 h, or had been fed upon for a further 72 h. However, contrary to expectation, individual and total GS did not increase after these two treatments. This suggests that Arabidopsis plants induce additional (not GS) defenses after longer induction periods. PMID- 28585092 TI - Rhizophagus irregularis MUCL 41833 transitorily reduces tomato bacterial wilt incidence caused by Ralstonia solanacearum under in vitro conditions. AB - Bacterial wilt caused by Ralstonia solanacearum is one of the world's most important soil-borne plant diseases. In Martinique, French West Indies, a highly virulent new pathogenic variant of this bacterium (phylotype IIB/4NPB) severely impacts tomato production. Here we report on the effect of R. solanacearum CFBP 6783, classified in phytotype IIB/4NPB, on tomato plantlets grown under strict in vitro culture conditions in the presence or absence of the arbuscular mycorrhizal fungus Rhizophagus irregularis MUCL 41833. A mycelium donor plant (i.e. Crotalaria spectabilis) was used for rapid, uniform mycorrhization of tomato plantlets that were subsequently infected by the bacterium. Bacterial wilt was significantly delayed and the incidence of the disease consequently reduced in the mycorrhizal tomato plantlets. Conversely, R. solanacearum did not affect root colonization by the AMF within the 16 days of the experiment. These results suggested that the mycorrhizal fungus was able to reduce bacterial wilt symptoms, probably by eliciting defence mechanisms in the plant. PMID- 28585093 TI - Serum fatty acid profile in psoriasis and its comorbidity. AB - Psoriasis is a chronic inflammatory skin disease that is accompanied by metabolic disturbances and cardio-metabolic disorders. Fatty acids (FAs) might be a link between psoriasis and its comorbidity. The aim of the study was to evaluate serum concentrations of FAs and to investigate their association with the disease activity, markers of inflammation and possible involvement in psoriatic comorbidity: obesity, type 2 diabetes and hypertension. We measured 14 total serum fatty acids content and composition by gas-liquid chromatography and flame ionization detector after direct in situ transesterification in 85 patients with exacerbated plaque psoriasis and in 32 healthy controls. FAs were grouped according to their biologic properties to saturated FA (SFA), unsaturated FA (UFA), monounsaturated FA (MUFA), n-3 polyunsaturated FA (n-3 PUFA) and n-6 PUFA. Generally, patients characteristic included: Psoriasis Area and Severity Index (PASI), Body Mass Index, inflammatory and biochemical markers, lipid profile and presence of psoriatic comorbidity. We have observed highly abnormal FAs pattern in psoriatic patients both with and without obesity compared to the control group. We have demonstrated association of PASI with low levels of circulating DHA, n-3 PUFA (p = 0.044 and p = 0.048, respectively) and high percent of MUFA (p = 0.024) in the non-obese psoriatic group. The SFA/UFA ratio increased with the duration of the disease (p = 0.03) in all psoriatic patients. These findings indicate abnormal FAs profile in psoriasis which may reflect metabolic disturbances and might play a role in the psoriatic comorbidity. PMID- 28585094 TI - A retrospective review comparing two-year patient-reported outcomes, costs, and healthcare resource utilization for TLIF vs. PLF for single-level degenerative spondylolisthesis. AB - PURPOSE: The purpose of this study was to compare patient-reported outcomes (PROs), morbidity, and costs of TLIF vs PLF to determine whether one treatment was superior in the setting of single-level degenerative spondylolisthesis. METHODS: Patients undergoing TLIF or PLF for single-level spondylolisthesis were included for retrospective analysis. EQ-5D, ODI, SF-12 MCS/PCS, NRS-BP/LP scores were collected at baseline and 24 months after surgery. 90-day post-operative complications, revision surgery rates, and satisfaction scores were also collected. Two-year resource use was multiplied by unit costs based on Medicare payment amounts (direct cost). Patient and caregiver workday losses were multiplied by the self-reported gross-of-tax wage rate (indirect cost). Total cost was used to assess mean total 2-year cost per QALYs gained after surgery. RESULTS: 62 and 37 patients underwent TLIF and PLF, respectively. Patients in the PLF group were older (p < 0.01). No significant differences were seen in baseline or 24-month PROs between the two groups. There was a significant improvement in all PROs from baseline to 24 months after surgery (p < 0.001). Both groups had similar rates of 90-day complications, revision surgery, satisfaction, and similar gain in QALYs and cost per QALYs gained. There was no significant difference in 24-month direct, indirect, and total cost. CONCLUSIONS: Overall costs and health care utilization were similar in both the groups. Both TLIF and PLF for single-level degenerative spondylolisthesis provide improvement in disability, pain, quality of life, and general health. PMID- 28585098 TI - Impact of Coordinated Behavioral Health Management on Quality Measures of Antipsychotic Use. AB - A state Care Management Entity (CME) using the wraparound practice model provided intensive care coordination for youth with severe mental illness, those most likely to receive antipsychotics. The model has led to improved clinical/functional outcomes, but little is known about the impact on antipsychotic prescribing and safety monitoring. A pre-post study was conducted to evaluate antipsychotic dosing, concomitant antipsychotic use, and metabolic monitoring among CME-enrolled and non-CME-enrolled comparison groups. CME enrolled youth had greater decrease in concomitant antipsychotic use than non-CME enrolled youth, but no difference in dosing or metabolic monitoring. More education of prescribing antipsychotics and team-based engagement in care coordination are needed. PMID- 28585097 TI - Coordination of Self- and Parental-Regulation Surrounding Type I Diabetes Management in Late Adolescence. AB - Background: Type 1 diabetes management involves self- and social-regulation, with past research examining components through individual differences unable to capture daily processes. Purpose: Dynamical systems modeling was used to examine the coordinative structure of self- and social-regulation (operationalized as parental-regulation) related to daily diabetes management during late adolescence. Methods: Two hundred and thirty-six late adolescents with type 1 diabetes (M age = 17.77 years, SD = .39) completed a 14-day diary reporting aspects of self- (e.g., adherence behaviors, cognitive self-regulation failures, and positive and negative affect) and parental-regulation (disclosure to parents, knowledge parents have, and help parents provide). Results: Self-regulation functioned as one coordinative structure that was separate from parental regulation, where mothers and fathers were coordinated separately from each other. Mothers' perceived helpfulness served as a driver of returning adolescents back to homeostasis. Conclusions: The results illustrate a dynamic process whereby numerous facets of self- and social-regulation are coordinated in order to return diabetes management to a stable state. PMID- 28585096 TI - Cellular citrate levels establish a regulatory link between energy metabolism and the hepatic iron hormone hepcidin. AB - : Expression of the hepatic peptide hormone hepcidin responds to iron levels via BMP/SMAD signaling, to inflammatory cues via JAK/STAT signaling, to the nutrient sensing mTOR pathway, as well as to proliferative signals and gluconeogenesis. Here, we asked the question whether hepcidin expression is altered by metabolites generated by intermediary metabolism. To identify such metabolites, we took advantage of a comprehensive RNAi screen, which revealed effectors involved in citrate metabolism. We show that the inhibition of citrate-consuming enzymes increases hepcidin mRNA expression in primary murine hepatocytes. Consistently, citrate treatment of primary murine hepatocytes or intravenous injection of citrate in mice increases cellular citrate concentrations and hepcidin expression. We further demonstrate that the hepcidin response to citrate involves the SMAD signaling pathway. These results reveal links between iron homeostasis and energy metabolism that may help to explain why iron levels are frequently altered in metabolic disorders. KEY MESSAGES: * Elevated citrate levels increase hepcidin mRNA expression in primary hepatocytes. * Citrate treatment in primary hepatocytes activates hepcidin expression. * Intravenous injection of citrate in mice increases hepcidin mRNA levels. * The hepcidin response to citrate involves the BMP/SMAD signaling pathway. PMID- 28585095 TI - A clinical review of inhalation anesthesia with sevoflurane: from early research to emerging topics. AB - A large number of studies during the past two decades have demonstrated the efficacy and safety of sevoflurane across patient populations. Clinical researchers have also investigated the effects of sevoflurane, its hemodynamic characteristics, its potential protective effects on several organ systems, and the incidence of delirium and cognitive deficiency. This review examines the clinical profiles of sevoflurane and other anesthetic agents, and focuses upon emerging topics such as organ protection, postoperative cognitive deficiency and delirium, and novel ways to improve postanesthesia outcomes. PMID- 28585099 TI - Recent advances in targeting DNA-repair pathways for the treatment of ovarian cancer: introduction. PMID- 28585101 TI - Effectiveness of a Brief Multi-Component Intervention to HIV Prevention Among Spanish Youth. AB - The greater rate of HIV infection occurs before age 30 in Spain. Our aim was to evaluate the long-term impact of a brief HIV preventive intervention on key sexual risk behavior components in Spanish young population. Participants were 467 young people aged 18-25 years who participated in B-PAPY intervention. They were evaluated at four times: a week, a month, three months and one year after intervention. A self-administered instrument was used. It was found a significant increase from pre-test to follow-ups in HIV knowledge, HIV susceptibility perception, confidence in condom and use of condoms. There were decreases statistically significant in the perceived severity of AIDS. The HIV intervention showed effectiveness over time in the main risk variables for HIV infection. Brief multi-component HIV interventions would be a useful resource to generalize HIV prevention. PMID- 28585100 TI - How Do We Get Partners to Test for HIV?: Predictors of Uptake of Partner HIV Testing Following Individual Outpatient Provider Initiated HIV Testing in Rural Uganda. AB - In a sample of outpatients (152 females, 152 males) receiving individual provider initiated HIV testing and counselling (PITC) we aimed to identify factors associated with subsequent uptake of partner HIV testing. Purposively sampled outpatients receiving PITC at a Ugandan hospital completed a questionnaire immediately prior to testing for HIV, and then at 3 and 6 months post-test. By 6 month follow-up 96% of participants reported disclosing their HIV test results to their partner and 96.4% reported asking their partner to test. 38.8% of women and 78.9% of men reported that their partner tested and they knew their results. Recent (men AOR 5.84, 95.0% CI 1.90-17.99; women AOR 6.19, 95.0% CI 2.74-13.59) or any previous testing by the partner (women AOR 4.01, 95% CI 1.06-15.10) predicted uptake of partner testing by the 6-month follow-up. Among women, perceiving greater social support from their partner, which perhaps reflects better relationship quality, was predictive of their male partner testing for HIV (AOR 2.37, 95% CI 1.22-4.58). Notably intimate partner violence showed no negative association with partner testing. Our findings demonstrate that women are at a disadvantage compared to men in their ability to influence their partner to test for HIV, and that improving social support in intimate relationships should be a focus of HIV partner testing interventions. However, more research on interventions to improve partner testing is needed, particularly in identifying effective ways to support women in engaging their partners to test. PMID- 28585102 TI - The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach. AB - PURPOSE: Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. METHODS: We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. RESULTS: While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. CONCLUSIONS: Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes. PMID- 28585103 TI - A review of fur-mites of the genus Dubininetta Fain & Lukoschus, 1978 (Acariformes: Listrophoridae), ectoparasites of moles (Soricomorpha: Talpidae). AB - The fur mite genus Dubininetta Fain & Lukoschus, 1978 (Acariformes: Listrophoridae) represented by ectoparasites of moles (Soricomorpha: Talpidae) is revised. An amended diagnosis of this genus is provided. Two new species are described from moles in Vietnam: Dubininetta euroscaptor n. sp. from Euroscaptor parvidens (Miller) and Dubininetta abramovi n. sp. from Euroscaptor subanura Kawada, Son & Can. The insufficiently described D. taiwanensis (Fain & Lukoschus, 1978) from Mogera insularis (Swinhoe) (type-host) is redescribed based on the type-specimens and numerous newly collected in the Russian Far East specimens from Mogera robusta Nehring. The host ranges are considered for all species of Dubininetta. A key to the five species presently known in this genus is provided. PMID- 28585104 TI - Can teenage novel users perform as well as General Surgery residents upon initial exposure to a robotic surgical system simulator? AB - New techniques in minimally invasive and robotic surgical platforms require staged curricula to insure proficiency. Scant literature exists as to how much simulation should play a role in training those who have skills in advanced surgical technology. The abilities of novel users may help discriminate if surgically experienced users should start at a higher simulation level or if the tasks are too rudimentary. The study's purpose is to explore the ability of General Surgery residents to gain proficiency on the dVSS as compared to novel users. The hypothesis is that Surgery residents will have increased proficiency in skills acquisition as compared to naive users. Six General Surgery residents at a single institution were compared with six teenagers using metrics measured by the dVSS. Participants were given two 1-h sessions to achieve an MScoreTM in the 90th percentile on each of the five simulations. MScoreTM software compiles a variety of metrics including total time, number of attempts, and high score. Statistical analysis was run using Student's t test. Significance was set at p value <0.05. Total time, attempts, and high score were compared between the two groups. The General Surgery residents took significantly less Total Time to complete Pegboard 1 (PB1) (p = 0.043). No significant difference was evident between the two groups in the other four simulations across the same MScoreTM metrics. A focused look at the energy dissection task revealed that overall score might not be discriminant enough. Our findings indicate that prior medical knowledge or surgical experience does not significantly impact one's ability to acquire new skills on the dVSS. It is recommended that residency-training programs begin to include exposure to robotic technology. PMID- 28585105 TI - Physical, Complementary, and Alternative Medicine in the Treatment of Pelvic Floor Disorders. AB - PURPOSE OF REVIEW: The purpose of the study was to catalog the most recent available literature regarding the use of conservative measures in treatment of pelvic floor disorders. RECENT FINDINGS: Pelvic floor disorders encompass abnormalities of urination, defecation, sexual function, pelvic organ prolapse, and chronic pain, and can have significant quality of life implications for patients. Current guidelines recommend behavioral modifications and conservative treatments as first-line therapy for pelvic floor disorders. We have reviewed the literature for articles published on physical, complementary, and alternative treatments for pelvic floor disorders over the past 5 years. Review of pelvic floor muscle physiotherapy (PFMT) and biofeedback (BF) shows a benefit for patients suffering from bladder dysfunction (incontinence, overactive bladder), bowel dysfunction (constipation, fecal incontinence), pelvic organ prolapse, and sexual dysfunction (pelvic pain). Combination of PFMT and BF has shown improved results compared to PFMT alone, and some studies find that electrical stimulation can augment the benefit of BF and PFMT. Additionally, acupuncture and cognitive behavioral therapy has shown to be an effective treatment for pelvic floor disorders, particularly with respect to pelvic pain. This update highlights beneficial conservative treatments available for pelvic floor dysfunction, and supplements the current literature on treatment options for patients suffering from these disorders. PMID- 28585106 TI - Portal Vein Embolization Reduces Postoperative Hepatic Insufficiency Associated with Postchemotherapy Hepatic Atrophy. AB - BACKGROUND: The risk of postoperative hepatic insufficiency (PHI) is increased among patients with significant postchemotherapy hepatic atrophy. The primary aim of this study was to evaluate whether the liver regeneration stimulated by portal vein embolization (PVE) can protect against PHI. METHODS: Clinicopathological features of 177 patients treated with preoperative chemotherapy followed by PVE and hepatectomy were reviewed. Degree of atrophy was defined as the ratio of percentage difference in total liver volume (estimated by manual volumetry) to standardized liver volume. Kinetic growth rate (KGR, degree of hypertrophy [absolute % change in future liver remnant volume] divided by the number of weeks after PVE) and PHI events were compared between patients with degree of atrophy <10 vs >=10%. Risk factors for the PHI were assessed using logistic regression. RESULTS: Seventy patients (40%) experienced significant hepatic atrophy >=10% following preoperative chemotherapy. PHI rates were not significantly increased in patients who experienced significant hepatic atrophy (5.6 vs 8.6%, P = 0.443). KGR <2%/week (odds ratio, 8.10, P = 0.037) was the sole independent preoperative predictor of PHI. KGR >=2% was associated with decreased PHI in both patients with <10% atrophy (0 vs 9.5%, P = 0.035) and >=10% atrophy (2.6 vs 16.0%, P = 0.044). CONCLUSIONS: Even in high-risk patients with >=10% degree of atrophy from preoperative chemotherapy, KGR >=2% mitigates the deleterious effects of hepatic atrophy and significantly reduces PHI to almost zero. In these high-risk patients, PVE with KGR calculation remains the most important preoperative technique to reduce liver failure after major hepatectomy. PMID- 28585107 TI - A Technique to Define Extrahepatic Biliary Anatomy Using Robotic Near-Infrared Fluorescent Cholangiography. AB - BACKGROUND: Bile duct injury is a rare but serious complication of minimally invasive cholecystectomy. Traditionally, intraoperative cholangiogram has been used in difficult cases to help delineate anatomical structures, however, new imaging modalities are currently available to aid in the identification of extrahepatic biliary anatomy, including near-infrared fluorescent cholangiography (NIFC) using indocyanine green (ICG).1-5 The objective of the study was to evaluate if this technique may aid in safe dissection to obtain the critical view. METHODS: Thirty-five consecutive multiport robotic cholecystectomies using NIFC with ICG were performed using the da Vinci Firefly Fluorescence Imaging System. All patients received 2.5 mg ICG intravenously at the time of intubation, followed by patient positioning, draping, and establishment of pneumoperitoneum. No structures were divided until the critical view of safety was achieved. Real time toggling between NIFC and bright-light illumination was utilized throughout the case to define the extrahepatic biliary anatomy. RESULTS: ICG was successfully administered to all patients without complication, and in all cases the extrahepatic biliary anatomy was able to be identified in real-time 3D. All procedures were completed without biliary injury, conversion to an open procedure, or need for traditional cholangiography to obtain the critical view. Specific examples of cases where x-ray cholangiography or conversion to open was avoided and NIFC aided in safe dissection leading to the critical view are demonstrated, including (1) evaluation for aberrant biliary anatomy, (2) confirmation of non-biliary structures, and (3) use in cases where the infundibulum is fused to the common bile duct. CONCLUSION: NIFC using ICG is demonstrated as a useful technique to rapidly identify and aid in the visualization of extrahepatic biliary anatomy. Techniques that selectively utilize this technology specifically in difficult cases where the anatomy is unclear are demonstrated in order to obtain the critical view of safety. PMID- 28585108 TI - Contribution of Malabsorption to Weight Loss After Roux-en-Y Gastric Bypass: a Systematic Review. AB - Roux-en-Y gastric bypass (RYGB) is traditionally classified as a combined restrictive and malabsorptive operation. This notion of the operation influences its technical variations and revisions for patients who do not achieve significant weight loss after this surgery. There is an increasing body of literature suggesting a role for appetite suppression mediated by neuro-hormonal signals after RYGB. The purpose of this paper was to systematically review published English language scientific literature to determine the role of malabsorption towards weight loss achieved with RYGB. This review finds that there is little or no malabsorption of carbohydrates or protein after RYGB but there is some fat malabsorption. Overall, malabsorption makes a little (approximately 11.0% in the early period) overall contribution to weight loss after RYGB. PMID- 28585109 TI - Efficacy and Tolerability of Peritendinous Hyaluronic Acid in Patients with Supraspinatus Tendinopathy: a Multicenter, Randomized, Controlled Trial. AB - BACKGROUND: Physical therapy and peritendinous hyaluronic acid (HA) injections have both shown promising results in the treatment of shoulder tendinopathies. However, the superiority of treatment combining physical therapy and HA is unclear. METHODS: Patients with ultrasound-confirmed supraspinatus tendinopathy were randomized to receive either physical therapy + subacromial HA injections or physical therapy only. Treatment efficacy was assessed using a Visual Analog Scale (VAS) for pain and an Activities of Daily Living (ADL) scale. Other measures were the number of rehabilitation sessions and days needed for recovery, the Tampa Scale for Kinesiophobia (TSK), and the physician and patient's perception of efficacy and tolerability. Patients were followed up for 90 days. RESULTS: Overall, VAS and ADL scores showed a progressive decrease during the follow-up (P < 0.01 at all visits for both groups), without significant differences between groups. The TSK score decreased significantly more in the HA group than in the control group (3.6 vs. 2.4; P < 0.001). Patients in the control group needed more rehabilitation sessions (28 vs. 22 in the HA group; P = 0.006) and more days for returning to their pre-injury activity (32 vs. 20 in the HA group; P = 0.013). Both patients and investigators perceived higher efficacy in the HA group than in the control group (P = 0.034). Both treatments were safe and well tolerated. CONCLUSIONS: Subacromial HA injections combined with physical therapy have high efficacy in the treatment of supraspinatus tendinopathy, leading to an earlier return to pre-injury activity and the need for fewer rehabilitation sessions, which may benefit both patients and the healthcare system. PMID- 28585110 TI - Survey on health care transition services in pediatric nephrology. PMID- 28585112 TI - Fine mapping of chromosome 9 locus associated with congenital cataract. AB - PURPOSE: The purpose of this study was to study the molecular basis of inherited autosomal recessive cataracts in Pakistan population and to identify the molecular defect segregating with the disease phenotype. METHODS: Families having two or more affected individuals were identified through hospital, blood samples were collected and DNA was extracted. We employed the traditional strategy of linkage analysis using M13-labeled primers to map the already known genes for autosomal recessive cataract. Statistically, the data were evaluated through LOD score. RESULTS: Ten families affected with autosomal receive congenital cataract were enrolled for this study. Overall, three families were linked to reported loci for autosomal recessive congenital cataract. Out of these, one family Bl05 was linked to a cataract locus at 9q13. Fine mapping of the chromosome 9 locus considerably delimited the previously reported linkage interval from 13.99 to 7.99 cM in this study. CONCLUSION: Our results reduced the linkage interval of previously reported cataract locus on chromosome 9, thus considerably reducing the number of candidate genes. PMID- 28585111 TI - Morphometric features on enhanced depth imaging optical coherence tomography scans in idiopathic posterior uveitis or panuveitis. AB - PURPOSE: Enhanced depth imaging (EDI) optical coherence tomography (OCT) has emerged as a novel tool for qualitative and quantitative choroidal assessment in posterior uveitis. The objective of this study was to investigate the role of EDI OCT to assess the choroidal and retinal changes in posterior uveitis. METHODS: In this retrospective study, EDI-OCT scans of patients with idiopathic posterior uveitis or panuveitis were reviewed. Morphological features from retina and choroid from the OCT scans were assessed and compared to the fellow normal eyes. Follow-up assessment was performed at 6-month follow-up. RESULTS: Nineteen patients with idiopathic posterior or panuveitis were included in the study. Choroidal examination using EDI-OCT scans showed areas of focal hypo-reflective and discrete hyper-reflective foci in one-third patients. Macular edema, disruption of the ellipsoid zone (generalized and discrete), outer retinal hyper reflective foci, and intraretinal and subretinal fluid were observed. CONCLUSIONS: The index study reports qualitative OCT-derived parameters as possible tools in monitoring disease progression in uveitis. PMID- 28585113 TI - Sex-Dependent Glial Signaling in Pathological Pain: Distinct Roles of Spinal Microglia and Astrocytes. AB - Increasing evidence suggests that spinal microglia regulate pathological pain in males. In this study, we investigated the effects of several microglial and astroglial modulators on inflammatory and neuropathic pain following intrathecal injection in male and female mice. These modulators were the microglial inhibitors minocycline and ZVEID (a caspase-6 inhibitor) and the astroglial inhibitors L-alpha-aminoadipate (L-AA, an astroglial toxin) and carbenoxolone (a connexin 43 inhibitor), as well as U0126 (an ERK kinase inhibitor) and D-JNKI-1 (a c-Jun N-terminal kinase inhibitor). We found that spinal administration of minocycline or ZVEID, or Caspase6 deletion, reduced formalin-induced inflammatory and nerve injury-induced neuropathic pain primarily in male mice. In contrast, intrathecal L-AA reduced neuropathic pain but not inflammatory pain in both sexes. Intrathecal U0126 and D-JNKI-1 reduced neuropathic pain in both sexes. Nerve injury caused spinal upregulation of the astroglial markers GFAP and Connexin 43 in both sexes. Collectively, our data confirmed male-dominant microglial signaling but also revealed sex-independent astroglial signaling in the spinal cord in inflammatory and neuropathic pain. PMID- 28585114 TI - Distinct Roles of Dopamine Receptors in the Lateral Thalamus in a Rat Model of Decisional Impulsivity. AB - The thalamus and central dopamine signaling have been shown to play important roles in high-level cognitive processes including impulsivity. However, little is known about the role of dopamine receptors in the thalamus in decisional impulsivity. In the present study, rats were tested using a delay discounting task and divided into three groups: high impulsivity (HI), medium impulsivity (MI), and low impulsivity (LI). Subsequent in vivo voxel-based magnetic resonance imaging revealed that the HI rats displayed a markedly reduced density of gray matter in the lateral thalamus compared with the LI rats. In the MI rats, the dopamine D1 receptor antagonist SCH23390 or the D2 receptor antagonist eticlopride was microinjected into the lateral thalamus. SCH23390 significantly decreased their choice of a large, delayed reward and increased their omission of lever presses. In contrast, eticlopride increased the choice of a large, delayed reward but had no effect on the omissions. Together, our results indicate that the lateral thalamus is involved in decisional impulsivity, and dopamine D1 and D2 receptors in the lateral thalamus have distinct effects on decisional impulsive behaviors in rats. These results provide a new insight into the dopamine signaling in the lateral thalamus in decisional impulsivity. PMID- 28585115 TI - Cyanobacterial Neurotoxins: Their Occurrence and Mechanisms of Toxicity. AB - Cyanobacteria are some of the oldest organisms on earth, and have evolved to produce a battery of toxic metabolites, including hepatotoxins, dermatoxins, and neurotoxins. In this review, we focus on the occurrence and mechanisms of toxicity of a number of neurotoxins synthesised by these ancient photosynthetic prokaryotes. We discuss the evidence linking beta-methylamino-L-alanine (BMAA), a non-protein amino acid, to an unusual neurological disease complex reported on the island of Guam in the 1950s, and how 60 years later, the role that BMAA plays in human disease is still unclear. There is now evidence that BMAA is also produced by some eukaryotes, and can bioaccumulate in food chains; this combined with higher frequency of cyanobacterial blooms globally, increases the potential for human exposure. Three BMAA isomers that often co-occur with BMAA have been identified, and the current knowledge on the toxicity of these molecules is presented. The acute alkaloid toxins; anatoxin-a, homoanatoxin-a and the saxitoxins, and the organophosphate neurotoxin anatoxin-a(S) are also discussed. In many cases, human exposure to a cocktail of cyanobacterial neurotoxins is likely; however, the implications of combined exposure to these toxins have not been fully explored. Increased understanding of the combined effects of cyanobacterial neurotoxins is required to fully understand how these molecules impact on human health. PMID- 28585117 TI - Driving Behaviour Profile of Drivers with Autism Spectrum Disorder (ASD). AB - The symptomatology of autism spectrum disorder (ASD) can make driving risky, but little is known about the on-road driving behaviour of individuals with ASD. This study assessed and compared the on-road driving performance of drivers with and without ASD, and explored how the symptomatology of ASD hinders or facilitates on road driving performance. Sixteen drivers with ASD and 21 typically-developed drivers participated in the study. Drivers with ASD underperformed in vehicle manoeuvring, especially at left-turns, right-turns and pedestrian crossings. However, drivers with ASD outperformed the TD group in aspects related to rule following such as using the indicator at roundabouts and checking for cross traffic when approaching intersections. Drivers with ASD in the current study presented with a range of capabilities and weaknesses during driving. PMID- 28585116 TI - Charge Mediated Compaction and Rearrangement of Gas-Phase Proteins: A Case Study Considering Two Proteins at Opposing Ends of the Structure-Disorder Continuum. AB - Charge reduction in the gas phase provides a direct means of manipulating protein charge state, and when coupled to ion mobility mass spectrometry (IM-MS), it is possible to monitor the effect of charge on protein conformation in the absence of solution. Use of the electron transfer reagent 1,3-dicyanobenzene, coupled with IM-MS, allows us to monitor the effect of charge reduction on the conformation of two proteins deliberately chosen from opposite sides of the order to disorder continuum: bovine pancreatic trypsin inhibitor (BPTI) and beta casein. The ordered BPTI presents compact conformers for each of three charge states accompanied by narrow collision cross-section distributions (TWCCSDN2 >He). Upon reduction of BPTI, irrespective of precursor charge state, the TWCCSN2 >He decreases to a similar distribution as found for the nESI generated ion of identical charge. The behavior of beta casein upon charge reduction is more complex. It presents over a wide charge state range (9-28), and intermediate charge states (13-18) have broad TWCCSDN2->He with multiple conformations, where both compaction and rearrangement are seen. Further, we see that the TWCCSDN2->He of the latter charge states are even affected by the presence of radical anions. Overall, we conclude that the flexible nature of some proteins result in broad conformational distributions comprised of many families, even for single charge states, and the barrier between different states can be easily overcome by an alteration of the net charge. Graphical Abstract ?. PMID- 28585118 TI - Analysis of Promoters of Arabidopsis thaliana Divergent Gene Pair SERAT3;2 and IDH-III Shows SERAT3;2 Promoter is Nested Within the IDH-III Promoter. AB - Intergenic regions of divergent gene pairs show bidirectional promoter activity but whether regulatory sequences for gene expression in opposite directions are shared is not established. In this study, promoters of divergently arranged gene pair At4g35640-At4g35650 (SERAT3;2-IDH-III) of Arabidopsis thaliana were analyzed to identify overlapping regulatory regions. Both genes showed the highest expression in flower buds and flowers. 5' RACE experiments extended the intergenic region from 161 bp shown in TAIR annotation to 512 bp. GUS analysis of transgenic A. thaliana plants carrying the 691 bp fragment (512 bp intergenic region plus 5' UTR of both the genes) linked to uidA gene revealed that SERAT3;2 promoter drives gene expression in the tapetum, whereas IDH-III promoter functions specifically in microspores/pollen. Serial 5' deletion of the 691 bp fragment showed SERAT3;2 promoter extends up to -355 position, whereas IDH-III promoter encompasses the 512 bp intergenic region. In transgenics, uidA transcript levels were lower than native SERAT3;2 and IDH-III transcripts indicating presence of additional cis regulatory elements beyond the 691 bp fragment. The present study demonstrated for the first time occurrence of a nested promoter in plants and identified a novel bidirectional promoter capable of driving gene expression in tapetum and microspores/pollen. PMID- 28585119 TI - The effectiveness of hybrid treatment for sever multiple trauma: a case of multiple trauma for damage control laparotomy and thoracic endovascular repair. AB - BACKGROUND: Time is a crucial factor for the successful early management of the multi-trauma patient. Hybrid operating theaters, which support the integration of surgical treatment and interventional radiology, provide opportunities to reduce the time-to-surgery for life threatening conditions. CASE PRESENTATION: We describe the early successful treatment of a 54-year-old male who sustained multiple injuries when he was hit by a 1000 kg bale of wheat that fell from a height. He was admitted with hemorrhagic shock due to intra-abdominal bleeding, an unstable fracture of the pelvis, and blunt aortic injury, which was considered to be at high risk of rupture. External fixation was applied to the pelvis in the resuscitation bay, and the patient was transferred to a hybrid operating theater for treatment of both the intra-abdominal hemorrhage and blunt aortic injury. Damage control laparotomy and thoracic endovascular aortic repair were performed uneventfully. CONCLUSIONS: Hybrid treatment, which combines emergency surgery and intraoperative interventional radiology, provides a prompt and appropriate management approach for the treatment of patients with severe multiple trauma and may improve patient outcomes. PMID- 28585120 TI - Occupational formaldehyde and amyotrophic lateral sclerosis. AB - Prior studies have yielded inconsistent evidence regarding the association between formaldehyde exposure and amyotrophic lateral sclerosis (ALS). We conducted a population case-control study in the Danish National Registries on the relationship between occupationally-derived formaldehyde exposure and ALS. Occupational history was obtained from a comprehensive and prospectively recorded pension database of all paid work in Denmark since 1964, and was linked to a job exposure matrix to derive individual exposure estimates. Each case was matched to 4 age- and sex-matched population controls alive on the date of the case diagnosis via risk set sampling, and odds ratios and confidence intervals (CI) were calculated via conditional logistic regression, adjusting for potential confounders. There were 3650 incident cases of ALS in the Danish National Patient Register from 1982 to 2009. Among controls, 25% were ever employed in jobs with a positive prevalence of formaldehyde exposure. Exposure to formaldehyde was associated with a 1.3-fold increased rate of ALS (95% CI 1.2-1.4). This study suggests that formaldehyde exposure, or employment in formaldehyde-exposed occupations, is related to the risk of ALS. PMID- 28585121 TI - Ultra-sensitive troponin I is an independent predictor of incident coronary heart disease in the general population. AB - Troponins are sensitive markers of myocardial injury and predictive of cardiovascular events, but conventional assays fail to detect slightly elevated troponins in a considerable proportion of the general population. Using a novel ultrasensitive assay, we explored the relationship of troponin levels with the incidence of coronary heart disease (CHD) in a case-cohort sample (mean age 52.5 +/- 0.2 years, 51.5% women) comprising 803 CHD cases and 1942 non-cases. Ultrasensitive troponin I was detectable in 99.9% of available case-cohort samples. In an age- and sex-adjusted model, individuals in the highest quartile of the troponin distribution had a more than threefold increased risk for CHD events compared to those in the bottom quartile [hazard ratio, HR, 3.11; 95% confidence interval (CI) 2.15-4.49]. In a model adjusting for cardiovascular risk factors including C-reactive protein, cystatin C and N-terminal pro brain natriuretic peptide, individuals in the highest troponin I quartile still showed a hazard ratio of 2.58 (95% CI 1.66-4.00) for incident CHD as compared to those in the lowest quartile. Ultrasensitive troponin I was detectable in almost all individuals of a study sample reflecting middle-aged to elderly European general population. Ultrasensitive troponin concentrations exhibit an independent, graded, positive relation with incident CHD. PMID- 28585122 TI - Long-term a posteriori dietary patterns and risk of hip fractures in a cohort of women. AB - Dietary pattern analysis is a useful tool to study the importance of food components in the context of a diet and how they relate to health and disease. The association between dietary patterns and fractures is at present uncertain. We aimed to study associations between dietary patterns and risk of hip fracture in the Swedish Mammography Cohort, including 56,736 women (median baseline age 52 years). Diet data was collected in food frequency questionnaires at two investigations and dietary patterns were defined by principal component analysis using 31 food groups. Information on hip fractures was collected from the Swedish National Patient Register. Multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated in Cox proportional hazards regression analysis. The two patterns identified-the healthy and Western/convenience dietary patterns-were time-updated and analysed. During a median follow-up time of 25.5 years, 4997 women experienced a hip fracture. Hip fracture rate was 31% lower in the highest compared to the lowest quartile of the healthy dietary pattern [HR (95% CI) 0.69 (0.64; 0.75)]. In contrast, women in the highest compared to the lowest quartile of the Western/convenience dietary pattern had a 50% higher [HR (95% CI) 1.50 (1.38; 1.62)] hip fracture rate. Further, in each stratum of a Western/convenience dietary pattern a higher adherence to a healthy dietary pattern was associated with less hip fractures. The present results suggest that a varied healthy diet may be beneficial for the prevention of fragility fractures in women. PMID- 28585124 TI - Premature Mortality Among People with Mental Illness: Advocacy in Academic Psychiatry. PMID- 28585123 TI - Occupational exposure to diesel motor exhaust and risk of lung cancer by histological subtype: a population-based case-control study in Swedish men. AB - We investigated occupational exposure to diesel motor exhaust (DME) and the risk of lung cancer by histological subtype among men, using elemental carbon (EC) as a marker of DME exposure. 993 cases and 2359 controls frequency-matched on age and year of study inclusion were analyzed by unconditional logistic regression in this Swedish case-control study. Work and smoking histories were collected by a questionnaire and telephone interviews. DME was assessed by a job-exposure matrix. We adjusted for age, year of study inclusion, smoking, occupational exposure to asbestos and combustion products (other than motor exhaust), residential exposure to radon and exposure to air pollution from road traffic. The OR for lung cancer for ever vs. never exposure to DME was 1.15 (95% CI 0.94 1.41). The risk was higher for squamous and large cell, anaplastic or mixed cell carcinoma than for alveolar cell cancer, adenocarcinoma and small cell carcinoma. The OR in the highest quartile of exposure duration (>=34 years) vs. never exposed was 1.66 (95% CI 1.08-2.56; p for trend over all quartiles: 0.027) for lung cancer overall, 1.73 (95% CI 1.00-3.00; p: 0.040) for squamous cell carcinoma and 2.89 (95% CI 1.37-6.11; p: 0.005) for the group of undifferentiated, large cell, anaplastic and mixed cell carcinomas. We found no convincing association between exposure intensity and lung cancer risk. Long-term DME exposure was associated with an increased risk of lung cancer, particularly to squamous cell carcinoma and the group of undifferentiated, large cell, anaplastic or mixed carcinomas. PMID- 28585125 TI - Role of microtubule-associated protein tau phosphorylation in Alzheimer's disease. AB - As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer's disease (AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3beta (GSK-3beta) and protein phosphatase 2A (PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3beta or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity. PMID- 28585126 TI - Long-term trends and predictors of smoking behaviors among men following first ever ischemic stroke. AB - Continued smoking following stroke is associated with adverse outcomes including increased risk of mortality and secondary stroke. The aim of this study was to examine the long-term trends in smoking behaviors and factors associated with smoking relapse among men who survived their first-ever stroke. Data collection for this longitudinal study was conducted at baseline through face-to-face interviews and follow-up was completed every 3 months via telephone, beginning in 2010 and continuing through 2014. Cox proportional hazard regression models were used to identify predictors of smoking relapse behavior. At baseline, 372 male patients were recruited into the study. Totally, 155 (41.7%) of these patients stopped smoking for stroke, and 61 (39.3%) began smoking again within 57 months after discharge with an increasing trend in the number of cigarettes smoked per day. Exposure to environmental tobacco smoke at places outside of home and work (such as bars, restaurants) (HR, 2.34; 95% CI, 1.04-5.29, P=0.04), not having a spouse (HR, 0.12; 95% CI, 0.04-0.36; P=0.0002) and smoking at least 20 cigarettes per day before stroke (HR, 2.42; 95% CI, 1.14-5.14, P=0.02) were predictors of smoking relapse. It was concluded that environmental tobacco smoke is an important determinant of smoking relapse among men who survive their first stroke. Environmental tobacco smoke should be addressed by smoke-free policies in public places. PMID- 28585127 TI - Neuropsychological functioning after adenotonsillectomy in children with obstructive sleep apnea: A meta-analysis. AB - The present study aimed to investigate the efficacy of adenotonsillectomy (AT) for children with obstructive sleep apnea syndrome (OSAS) and the improvement of their cognitive function. Studies on cognitive performance of OSAS children treated with or without AT were identified by searching the Pubmed, EMBASE and Cochrane library. A meta-analysis was conducted to analyze the literature. The random-effects model was used to evaluate 11 eligible studies using an inverse- variance method. The neuropsychological test results of 4 cognitive domains (general intelligence, memory, attention-executive function and verbal ability) were obtained and analyzed. By comparison of cognitive function between OSAS children and healthy controls, the effect sizes of each domain were achieved as follows: general intelligence,-0.5 (P<0.0001); memory,-0.18 (P=0.02); attention executive function,-0.21 (P=0.002); and verbal ability,-0.48 (P=0.0006). The effect sizes of general intelligence, memory, attention-executive function, and verbal ability after AT compared to baseline level were-0.37 (P=0.008),-0.36 (P=0.0005),-0.02 (P=0.88), and-0.45 (P=0.009), respectively. Comparing the cognitive ability between OSAS children after AT and healthy controls showed that the effect sizes were-0.54 (P=0.0009),-0.24 (P=0.12),-0.17 (P=0.35), and-0.45 (P=0.009) in general intelligence, memory, attention-executive function, and verbal ability, respectively. Our results confirmed that OSAS children performed worse than healthy children in terms of the 4 cognitive domains investigated. After 6-12 months of observation, significant improvement in attention-executive function and verbal ability were found in OSAS children treated with AT compared to their baseline level; restoration of attention-executive function and memory were observed in OSAS children after AT in comparison to healthy controls. Further rigorous randomized controlled trials should be conducted to obtain definitive conclusions. PMID- 28585128 TI - Expression of IL-17 and syndecan-1 in nasal polyps and their correlation with nasal polyps. AB - Nasal polyp (NP) is a common chronic inflammatory disease of the nasal cavity and sinuses. Although some authors have suggested that NP is related to inflammatory factors such as interleukin (IL)-1beta, IL-5, IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, and IL-17, the mechanisms underlying the pathogenesis and progression of NP remain obscure. This study investigated the expression and distribution of IL-17 and syndecan-1 in NP, and explored the roles of these two molecules in the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) and non-Eos CRSwNP. Real time PCR and immunohistochemistry were used to detect the expression of IL-17 and syndecan-1 in samples [NP, unciform process (UP) from patients with CRS, and middle turbinate (MT) from healthy controls undergoing pituitary tumor surgery]. The results showed that the expression levels of IL-17 and syndecan-1 were upregulated in both NP and UP tissues, but both factors were higher in NP tissues than in UP tissues. There was no significant difference in IL-17 levels between the Eos CRSwNP and non-Eos CRSwNP samples, and syndecan-1 levels were increased in the non-Eos CRSwNP tissues as compared with those in Eos CRSwNP tissues. In all of the groups, there was a close correlation between the expression of IL-17 and syndecan-1 in nasal mucosa epithelial cells, glandular epithelial cells, and inflammatory cells, suggesting that IL-17 and syndecan-1 may play a role, and interact with each other, in the pathogenesis of non-Eos CRSwNP. PMID- 28585129 TI - Enhanced biocompatibility and osseointegration of calcium titanate coating on titanium screws in rabbit femur. AB - This study aimed to examine the biocompatibility of calcium titanate (CaTiO3) coating prepared by a simplified technique in an attempt to assess the potential of CaTiO3 coating as an alternative to current implant coating materials. CaTiO3 coated titanium screws were implanted with hydroxyapatite (HA)-coated or uncoated titanium screws into medial and lateral femoral condyles of 48 New Zealand white rabbits. Imaging, histomorphometric and biomechanical analyses were employed to evaluate the osseointegration and biocompatibility 12 weeks after the implantation. Histology and scanning electron microscopy revealed that bone tissues surrounding the screws coated with CaTiO3 were fully regenerated and they were also well integrated with the screws. An interfacial fibrous membrane layer, which was found in the HA coating group, was not noticeable between the bone tissues and CaTiO3-coated screws. X-ray imaging analysis showed in the CaTiO3 coating group, there was a dense and tight binding between implants and the bone tissues; no radiation translucent zone was found surrounding the implants as well as no detachment of the coating and femoral condyle fracture. In contrast, uncoated screws exhibited a fibrous membrane layer, as evidenced by the detection of a radiation translucent zone between the implants and the bone tissues. Additionally, biomechanical testing revealed that the binding strength of CaTiO3 coating with bone tissues was significantly higher than that of uncoated titanium screws, and was comparable to that of HA coating. The study demonstrated that CaTiO3 coating in situ to titanium screws possesses great biocompatibility and osseointegration comparable to HA coating. PMID- 28585131 TI - Predictive value of initial serum human chorionic gonadotropin levels for pregnancies after single fresh and frozen blastocyst transfer. AB - As one of the earliest markers for predicting pregnancy outcomes, human chorionic gonadotropin (hCG) values have been inconclusive on reliability of the prediction after frozen and fresh embryo transfer (ET). In this retrospective study, patients with positive hCG (day 12 after transfer) were included to examine the hCG levels and their predictive value for pregnancy outcomes following 214 fresh and 1513 vitrified-warmed single-blastocyst transfer cycles. For patients who got clinical pregnancy, the mean initial hCG value was significantly higher after frozen cycles than fresh cycles, and the similar result was demonstrated for patients with live births (LB). The difference in hCG value existed even after adjusting for the potential covariates. The area under curves (AUC) and threshold values calculated by receiver operator characteristic curves were 0.944 and 213.05 mIU/mL for clinical pregnancy after fresh ET, 0.894 and 399.50 mIU/mL for clinical pregnancy after frozen ET, 0.812 and 222.86 mIU/mL for LB after fresh ET, and 0.808 and 410.80 mIU/mL for LB after frozen ET with acceptable sensitivity and specificity, respectively. In conclusion, single frozen blastocyst transfer leads to higher initial hCG values than single fresh blastocyst transfer, and the initial hCG level is a reliable predictive factor for predicting IVF outcomes. PMID- 28585130 TI - Factors associated with peripheral neuropathy in type 2 diabetes: Subclinical versus confirmed neuropathy. AB - This study determined the prevalence of diabetic peripheral neuropathy (DPN) and subclinical DPN (sDPN) in patients with type 2 diabetes mellitus (T2DM) using nerve conduction study (NCS) as a diagnostic tool. We also investigated the factors associated with the development of sDPN and compared factors between the sDPN and confirmed DPN (cDPN). This cross-sectional study involved 240 T2DM patients who were successively admitted to the endocrinology wards of Wuhan Union Hospital over the period of January to December 2014. Data on the medical history, physical and laboratory examinations were collected. DPN was diagnosed using NCS. One-way ANOVA with least significant difference (LSD) analysis or chi square tests was used to compare parameters among DNP-free, sDPN and cDPN patients. Independent factors associated with sDPN were determined using logistic regression. The results showed that 50.8% of the participants had DPN, and among them, 17.1% had sDPN. sDPN showed significant independent associations with age, height, HbA1c, presence of atherosclerosis and diabetic retinopathy. Patients with DPN differed significantly from those without DPN with respect to age, duration of disease (DOD), HbA1c, presence of atherosclerosis, diabetic retinopathy, nephropathy and hypertension. Patients with cDPN, relative to those with sDPN, had significantly longer DOD and higher prevalence of peripheral artery disease (PAD) and coronary artery disease (CAD). Our study suggests that a significant number of T2DM patients are affected by sDPN, and the development of this condition is associated with advanced age, tall stature, poor glycaemic control, presence of diabetic retinopathy and atherosclerosis. On the other hand, patients with cDPN tend to have a longer DOD and are more likely to suffer from PAD and CAD. PMID- 28585132 TI - No significant association between PIK3CA mutation and survival of esophageal squamous cell carcinoma: A meta-analysis. AB - The prognostic value of phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) in patients with esophageal squamous cell carcinoma (ESCC) is controversial. We aimed to investigate the prognostic significance of PIK3CA mutation in patients with ESCC. EMBASE, PubMed, and Web of Science databases were systematically searched from inception through Oct. 3, 2016. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using a random effects model for overall survival (OS) and disease-free survival (DFS). Seven studies enrolling 1505 patients were eligible for inclusion of the current meta-analysis. Results revealed that PIK3CA mutation was not significantly associated with OS (HR: 0.90, 95% CI: 0.63-1.30, P=0.591), with a significant heterogeneity (I 2=65.7%, P=0.012). Additionally, subgroup analyses were further conducted according to various variables, such as types of specimen, the sample size, technique and statistical methodology. All results suggested that no significant relationship was found between PIK3CA mutation and OS in patients with ESCC. For DFS, there was no significant association between PIK3CA mutation and DFS in patients with ESCC (HR: 1.00, 95% CI=0.47-2.11, P=0.993, I 2=73.7%). Publication bias was not present and the results of sensitivity analysis were very stable in the current meta-analysis. Our findings suggest that PIK3CA mutation has no significant effects on OS and DFS in ESCC patients. More well-designed prospective studies with better methodology for PIK3CA assessment are required to clarify the prognostic significance of PIK3CA mutation in ESCC patients. PMID- 28585133 TI - Therapeutic effects of curcumin nanoemulsions on prostate cancer. AB - The therapeutic potential of curcumin (Cur) is hampered by its poor aqueous solubility and low bioavailability. The aim of this study was to determine whether Cur nanoemulsions enhance the efficacy of Cur against prostate cancer cells and increase the oral absorption of Cur. Cur nanoemulsions were developed using the self-microemulsifying method and characterized by their morphology, droplet size and zeta potential. The results showed that the cytotoxicity and cell uptake were considerably increased with Cur nanoemulsions compared to free Cur. Cur nanoemulsions exhibited a significantly prolonged biological activity and demonstrated better therapeutic efficacy than free Cur, as assessed by apoptosis and cell cycle studies. In situ single-pass perfusion studies demonstrated higher effective permeability coefficient and absorption rate constant for Cur nanoemulsions than for free Cur. Our study suggested that Cur nanoemulsions can be used as an effective drug delivery system to enhance the anticancer effect and oral bioavailability of Cur. PMID- 28585134 TI - CENP-A regulates chromosome segregation during the first meiosis of mouse oocytes. AB - Proper chromosome separation in both mitosis and meiosis depends on the correct connection between kinetochores of chromosomes and spindle microtubules. Kinetochore dysfunction can lead to unequal distribution of chromosomes during cell division and result in aneuploidy, thus kinetochores are critical for faithful segregation of chromosomes. Centromere protein A (CENP-A) is an important component of the inner kinetochore plate. Multiple studies in mitosis have found that deficiencies in CENP-A could result in structural and functional changes of kinetochores, leading to abnormal chromosome segregation, aneuploidy and apoptosis in cells. Here we report the expression and function of CENP-A during mouse oocyte meiosis. Our study found that microinjection of CENP-A blocking antibody resulted in errors of homologous chromosome segregation and caused aneuploidy in eggs. Thus, our findings provide evidence that CENP-A is critical for the faithful chromosome segregation during mammalian oocyte meiosis. PMID- 28585135 TI - Motivations, challenges and coping strategies for smoking cessation: Based on multi-ethnic pregnant couples in far western China. AB - The present study aimed to clarify the smoking cessation motivations, challenges and coping strategies among pregnant couples. A qualitative design using a grounded theory approach was applied. Data were collected by individual semi structured interviews with 39 married individuals (21 non-smoking pregnant women and 18 smoking or ever-smoking men with a pregnant wife) and 3 imams in an ethnically diverse region of far western China. The most common theme for smoking cessation motivation was "embryo quality" (i.e., a healthier baby), followed by family's health. Most interviewees reported that husband's withdrawal symptoms were the greatest challenge to smoking cessation, followed by the Chinese tobacco culture. Coping strategies given by the pregnant women typically involved combining emotional, behavioral and social interventions. Social interventions showed advantages in helping to quit smoking. Pregnancy appears to be a positive stimulus for pregnant couples' smoking cessation. Our results suggest that pregnancy, a highly important life event, may help to reduce barriers to smoking cessation at the social level (e.g., limiting access to cigarettes, avoiding temptation to smoke), but does little to help with the withdrawal symptoms. Professional guidance for smoking cessation is still necessary. PMID- 28585136 TI - Effect and underlying mechanism of Bu-Shen-An-Tai recipe on ovarian apoptosis in mice with controlled ovarian hyperstimulation implantation dysfunction. AB - The effect and underlying mechanism of Bu-Shen-An-Tai recipe on ovarian apoptosis in mice with controlled ovarian hyperstimulation (COH) implantation dysfunction were studied. The COH implantation dysfunction model in mice was established by intraperitoneal injection of 7.5 IU pregnant mare's serum gonadotrophin (PMSG), followed by 7.5 IU human chorionic gonadotrophin (HCG) 48 h later. Then the female mice were mated with male at a ratio of 2:1 in the same cage at 6:00 p.m. The female mice from normal group were injected intraperitoneally with normal saline and mated at the corresponding time. Day 1 of pregnancy was recorded by examining its vaginal smears at 8:00 a.m. of the next day. Fifty successfully pregnant mice were equally randomly divided into 5 groups: normal control pregnant group (NC), COH implantation dysfunction model group (COH), low dosage of Bu-Shen-An-Tai recipe group (LOW), middle dosage of Bu-Shen-An-Tai recipe group (MID) and high dosage of Bu-Shen-An-Tai recipe group (HIGH). Then from day 1, the mice in different groups were respectively intragastrically given corresponding treatments at 9:00 a.m. for 5 consecutive days. The concentrations of 17beta-estradiol (E2) and progesterone (P4) were determined by radioimmunoassay (RIA). The ultrastructural changes of ovarian tissues were observed by transmission electron microscope (TEM). The histopathological changes of ovarian tissues were observed by HE staining. The number of atretic follicles and pregnant corpus luteum were also recorded. TUNEL was applied to measure apoptotic cells of ovarian tissues. Western blotting was used to detect the protein expression of apoptosis- related factors like Bax, Bcl-2 and cleaved caspase-3 in ovarian tissue of mice. The results showed that ovarian weight, the concentrations of E2 and P4, the number of atretic follicles and pregnant corpus luteum, as well as the apoptosis of granulosa cells were significantly increased in the COH group. The ultrastructures of ovarian tissues in the COH group showed that chromatin in granulosa cells was increased, agglutinated, aggregated or crescent-shaped. The focal cavitation and the typical apoptotic bodies could be seen in granulosa cells in the late stage of apoptosis. After the treatment with different doses of Bu-Shen-An-Tai recipe, the ultrastructural changes of ovarian granulosa cells apoptosis were dramatically improved and even disappeared under TEM. Visible mitochondria and mitochondrial cristae were increased and vacuoles were significantly reduced. The lipid dropltes were shown in a circluar or oval shape. The protein expression levels of Bax and cleaved-caspase-3 were decreased, and the expression of Bcl-2 protein was increased after treatment. It was concluded that Bu-Shen-An-Tai recipe can inhibit the apoptosis of ovarian granulosa cells, probably by up-regulating the protein expression of Bcl-2 and down-regulating Bax and cleaved-caspase-3, which contributes to the formation and maintenance of ovarian corpus luteum. It's helpful to promote the embryonic implantation, to reduce embryo loss and ultimately to improve the success rate of pregnancy. PMID- 28585137 TI - Risk factors of perioperative complications in patients undergoing radical retropubic prostatectomy: A ten-year experience. AB - Radical retropubic prostatectomy (RRP) has been one of the most effective treatments for prostate cancer. This study is designed to identify the related predictive risk factors for complications in patients following RRP. Between 2000 and 2012 in Department of Urology, Fudan University Shanghai Cancer Center, 421 cases undergoing RRP for localized prostate cancer by one surgeon were included in this retrospective analysis. We reviewed various risk factors that were correlated with perioperative complications, including patient characteristics [age, body mass index (BMI), co-morbidities], clinical findings (preoperative PSA level, Gleason score, clinical stage, pathological grade), and surgeon's own clinical practice. Charlson comorbidity index (CCI) was used to explain comorbidities. The total rate of perioperative complications was 23.2% (98/421). There were 45/421 (10.7%), 28/421 (6.6%), 24/421 (5.7%) and 1/421 (0.2%) in grade I, II, III, IV respectively, and 323/421 (76.8%) cases had none of these complications. Statistical analysis of multiple potential risk factors revealed that BMI >30 (P=0.014), Charlson score >=1 (P<0.001) and surgical experience (P=0.0252) were predictors of perioperative complications. Age, PSA level, Gleason score, TNM stage, operation time, blood loss, and blood transfusion were not correlated with perioperative complications (P>0.05). It was concluded that patients' own factors and surgeons' technical factors are related with an increased risk of development of perioperative complications following radical prostatectomy. Knowing these predictors can both favor risk stratification of patients undergoing RRP and help surgeons make treatment decisions. PMID- 28585138 TI - Assessment of complications after liver surgery: Two novel grading systems applied to patients undergoing hepatectomy. AB - Although quality assessment is gaining increasing attention, there is still no consensus on how to define and grade postoperative complications. The absence of a definition and a widely accepted ranking system to classify surgical complications has hampered proper interpretation of the surgical outcome. This study aimed to define and search the simple and reproducible classification of complications following hepatectomy based on two therapy-oriented severity grading system: Clavien-Dindo classification of surgical complications and Accordion severity grading of postoperative complications. Two classifications were tested in a cohort of 2008 patients who underwent elective liver surgery at our institution between January 1986 and December 2005. Univariate and multivariate analyses were performed to link respective complications with perioperative parameters, length of hospital stay and the quality of life. A total of 1716 (85.46%) patients did not develop any complication, while 292 (14.54%) patients had at least one complication. According to Clavien-Dindo classification of surgical complications system, grade I complications occurred in 150 patients (7.47%), grade II in 47 patients (2.34%), grade IIIa in 59 patients (2.94%), grade IIIb in 13 patients (0.65%), grade IVa in 7 patients (0.35%), grade IVb in 1 patient (0.05%), and grade V in 15 patients (0.75%). According to Accordion severity grading of postoperative complications system, mild complications occurred in 160 patients (7.97%), moderate complications in 48 patients (2.39%), severe complications (invasive procedure/no general anesthesia) in 48 patients (2.39%), severe complications (invasive procedure under general anesthesia or single organ system failure) in 20 patients (1.00%), severe complications (organ system failure and invasive procedure under general anesthesia or multisystem organ failure) in 1 patient (0.05%), and mortality was 0.75% (n=15). Complication severity of Clavien-Dindo system and Accordion system were all correlated with the length of hospital stay, the number of hepatic segments resected, the blood transfusion and the Hospital Anxiety and Depression Scale-Anxiety (HADS-A). The Clavien-Dindo classification system and Accordion classification system are the simple ways of reporting all complications following the liver surgery. PMID- 28585139 TI - Relationship between placenta location and resolution of second trimester placenta previa. AB - This prospective study was conducted to assess the rate of resolution of second trimester placenta previa in women with anterior placenta and posterior placenta, and that in women with and without previous cesarean section. In this study, placenta previa was defined as a placenta lying within 20 mm of the internal cervical os or overlapping it. We recruited 183 women diagnosed with previa between 20+0 weeks and 25+6 weeks. They were grouped according to their placenta location (anterior or posterior) and history of cesarean section. Comparative analysis was performed on demographic data, resolution rate of previa and pregnancy outcomes between anterior group and posterior group, and on those between cesarean section group and non-cesarean section group. Women with an anterior placenta tended to be advanced in parity (P=0.040) and have increased number of dilatation and curettage (P=0.044). The women in cesarean section group were significantly older (P=0.000) and had more parity (P=0.000), gravidity (P=0.000), and dilatation and curettage (P=0.048) than in non-cesarean section group. Resolution of previa at delivery occurred in 87.43% women in this study. Women with a posterior placenta had a higher rate of resolution (P=0.030), while history of cesarean section made no difference. Gestational age at resolution was earlier in posterior group (P=0.002) and non-cesarean section group (P=0.008) than in anterior group and cesarean section group correspondingly. Placenta location and prior cesarean section did not influence obstetric outcomes and neonatal outcomes. This study indicates that it is more likely to have subsequent resolution of the previa when the placenta is posteriorly located for women who are diagnosed with placenta previa in the second trimester. PMID- 28585140 TI - Effects of meglumine cyclic adenylate pretreatment on systemic inflammatory response syndrome induced by lipopolysaccharide in rats. AB - Studies showed that the use of cyclic adenosine monophosphate (cAMP) substitutes or intracellular cAMP activators increased intracellular cAMP level, causing anti inflammatory effects. This study was to investigate the effects of pretreatment with meglumine cyclic adenylate (MCA), a compound of meglumine and cAMP, on systemic inflammation induced by lipopolysaccharide (LPS) in rats. Eighteen adult male Sprague-Dawley rats were randomly divided into 3 groups (n=6 each): control group (NS group), LPS group (LPS group) and LPS with MCA pretreatment group (MCA group). Systemic inflammation was induced with LPS 10 mg/kg injected via the femoral vein in LPS and MCA groups. In MCA group, MCA 2 mg/kg was injected via the femoral vein 20 min before LPS injection, and the equal volume of normal saline was given in NS and LPS groups at the same time. Three hours after LPS injection, the blood samples were taken from the abdominal aorta for determination of plasma concentrations of TNF-alpha, IL-1, IL-6, IL-10, cAMP by ELISA and NF-kappaBp65 expression by Western blotting. The experimental results showed that inflammatory and antiinflammatory indices were increased in LPS group compared to NS group; inflammatory indices were declined and anti-inflammatory indices were increased in MCA group relative to LPS group. Our study suggested that MCA pretreatment may attenuate LPS-induced systemic inflammation. PMID- 28585141 TI - Protective effects of hydrogen sulfide on portal hypertensive vasculopathy in rabbits by activating AKT-NF-kappaB pathway. AB - The role of hydrogen sulfide (H2S) in portal hypertension (PH)-induced esophagus gastric junction vascular lesions in rabbits was observed. The rabbit PH models were established. The animals were randomly divided into the following groups: normal, PH, PH+sodium hydrosulfide (PH+S), PH+propargylglycine (PH+PPG). The plasma H2S levels, apoptosis of esophageal-gastric junction vascular smooth muscle cells, and the expression of nuclear transcription factor-kappaB (NF kappaB), p-AKT, IkappaBa and Bcl-2 were detected. The cystathionine gamma lyase (cystathionine-gamma-splitting enzyme, CSE) in the junction vascular tissue was measured. The results showed that the plasma H2S levels and the CSE expression levels had statistically significant difference among different groups (P<0.05). As compared with PH group, plasma H2S levels were declined obviously (11.9+/-4.2 vs. 20.6+/-4.5, P<0.05), and CSE expression levels in the junction vascular tissue were notably reduced (1.7+/-0.6 vs. 2.8+/-0.8, P<0.05), apoptosis rate of vascular smooth muscle cells per unit area was significantly decreased (0.10+/ 0.15 vs. 0.24+/-0.07, P<0.05), and the expression levels of p-AKT and NF-kappaB were significantly decreased (2.31+/-0.33 vs. 3.04+/-0.38, P<0.05; 0.33+/-0.17 vs. 0.51+/-0.23, P<0.05), however, IkappaBa and Bcl-2 expression increased obviously (5.57+/-0.17 vs. 3.67+/-0.13, P<0.05; 0.79+/-0.29 vs. 0.44+/-0.36, P<0.05) in PH+PPG group. As compared with PH group, H2S levels were notably increased (32.7+/-7.3 vs. 20.6+/-4.5, P<0.05), the CSE levels in the junction vascular tissue were significantly increased (6.3+/-0.7 vs. 2.8+/-0.8, P<0.05), apoptosis rate of vascular smooth muscle cells per unit area was significantly increased (0.35+/-0.14 vs. 0.24+/-0.07, P<0.05), and the expression levels of p AKT and NF-kappaB were significantly increased (4.29+/-0.49 vs. 3.04+/-0.38, P<0.05; 0.77+/-0.27 vs. 0.51+/-0.23, P<0.05), yet IkappaBa and Bcl-2 expression decreased significantly (3.23+/-0.24 vs. 3.67+/-0.13, P<0.05; 0.31+/-0.23 vs. 0.48+/-0.34, P<0.05) in PH+S group. It is concluded that esophagus-gastric junction vascular lesions happen under PH, and apoptosis of smooth muscle cells is declined. H2S can activate NF-kappaB by the p-AKT pathway, leading to the down regulation of Bcl-2, eventually stimulating apoptosis of vascular smooth muscle cells, easing PH. H2S/CSE system may play an important role in remission of PH via the AKT-NF-kappaB pathway. PMID- 28585143 TI - Single-allergen sublingual immunotherapy versus multi-allergen subcutaneous immunotherapy for children with allergic rhinitis. AB - It has always been controversial whether a single allergen performs better than multiple allergens in polysensitized patients during the allergen-specific immunotherapy. This study aimed to examine the clinical efficacy of single allergen sublingual immunotherapy (SLIT) versus multi-allergen subcutaneous immunotherapy (SCIT) and to discover the change of the biomarker IL-4 after 1 year immunotherapy in polysensitized children aged 6-13 years with allergic rhinitis (AR) induced by house dust mites (HDMs). The AR polysensitized children (n=78) were randomly divided into two groups: SLIT group and SCIT group. Patients in the SLIT group sublingually received a single HDM extract and those in the SCIT group were subcutaneously given multiple-allergen extracts (HDM in combination with other clinically relevant allergen extracts). Before and 1 year after the allergen-specific immunotherapy (ASIT), the total nasal symptom scores (TNSS), total medication scores (TMS) and IL-4 levels in peripheral blood mononuclear cells (PBMCs) were compared respectively between the two groups. The results showed that the TNSS were greatly improved, and the TMS and IL-4 levels were significantly decreased after 1-year ASIT in both groups (SLIT group: P<0.001; SCIT group: P<0.001). There were no significant differences in any outcome measures between the two groups (for TNSS: P>0.05; for TMS: P>0.05; for IL-4 levels: P>0.05). It was concluded that the clinical efficacy of single allergen SLIT is comparable with that of multi-allergen SCIT in 6-13-year-old children with HDM-induced AR. PMID- 28585142 TI - New mini dental implant attachments versus O-ring attachment after cyclic aging: Analysis of retention strength and gap space. AB - Overdenture as a treatment modality for both partially and fully edentulous patients is costeffective and less expensive. The purpose of the present study was to examine the newly fabricated attachments by comparing them with conventional O-ring attachment in vitro in terms of retention force and cyclic aging resistance. A total of 150 samples were prepared and divided into five groups according to the materials used (O-ring attachment, Deflex M10 XR, Deflex Classic SR, Deflex Acrilato FD, and flexible acrylic resin). The retention force of different attachments was measured by a mini dental implant after three subsequent aging (0, 63, and 126) cycles in the circumstances similar to the oral environment. The gap space between the head of the implant and the inner surface of the attachments was detected. Two-way analysis of variance (ANOVA) analysis with multiple comparisons test was applied for statistical analysis. The results showed that Deflex M10 XR had the highest retention force and the lowest gap space after cyclic aging; in addition, by comparing the relative force reduction, the lowest values were obtained in the O-ring attachment and the highest values in the flexible acrylic resin attachment. The retention force measured after cyclic aging for the Deflex M10 XR attachment was greatly improved when compared with the O-ring attachment and other types of attachment materials; in addition, the Deflex M10 XR attachment exhibited the minimum gap space between the inner surface and the mini dental implant head. In conclusion, Deflex M10 XR has the ability to withstand weathering conditions and retains its durable and retentive properties after aging when compared with other attachments. PMID- 28585144 TI - Weighted gene co-expression network analysis of gene modules for the prognosis of esophageal cancer. AB - Esophageal cancer is a common malignant tumor, whose pathogenesis and prognosis factors are not fully understood. This study aimed to discover the gene clusters that have similar functions and can be used to predict the prognosis of esophageal cancer. The matched microarray and RNA sequencing data of 185 patients with esophageal cancer were downloaded from The Cancer Genome Atlas (TCGA), and gene co-expression networks were built without distinguishing between squamous carcinoma and adenocarcinoma. The result showed that 12 modules were associated with one or more survival data such as recurrence status, recurrence time, vital status or vital time. Furthermore, survival analysis showed that 5 out of the 12 modules were related to progression-free survival (PFS) or overall survival (OS). As the most important module, the midnight blue module with 82 genes was related to PFS, apart from the patient age, tumor grade, primary treatment success, and duration of smoking and tumor histological type. Gene ontology enrichment analysis revealed that "glycoprotein binding" was the top enriched function of midnight blue module genes. Additionally, the blue module was the exclusive gene clusters related to OS. Platelet activating factor receptor (PTAFR) and feline Gardner-Rasheed (FGR) were the top hub genes in both modeling datasets and the STRING protein interaction database. In conclusion, our study provides novel insights into the prognosis-associated genes and screens out candidate biomarkers for esophageal cancer. PMID- 28585145 TI - Correlation of enhancement degree on contrast-enhanced ultrasound with histopathology of carotid plaques and serum high sensitive C-reactive protein levels in patients undergoing carotid endarterectomy. AB - This study was undertaken to investigate the correlation of the enhancement degree on contrast-enhanced ultrasound (CEUS) with the histopathology of carotid plaques and the serum high sensitive C-reactive protein (hs-CRP) levels in patients undergoing carotid endarterectomy (CEA). Carotid CEUS was performed preoperatively in 115 patients who would undergo CEA, and the enhancement degree of the carotid plaques was evaluated by both the visual semiquantitative analysis and the quantitative time-intensity curve analysis. Serum hs-CRP levels were detected using the particle-enhanced immunoturbidimetric assay also before the operation. Additionally, the carotid plaque samples were subjected to histopathological examination postoperatively. The density of neovessels and the number of macrophages in the plaques were assessed by immunohistochemistry. The results showed that among the 115 patients, grade 0 plaque contrast enhancement was noted in 35 patients, grade 1 in 48 patients and grade 2 in 32 patients. The degree of plaque enhancement, the density of neovessels, the number of macrophages, and the hs-CRP levels were highest in the grade 2 patients. Correlation analysis showed that the enhancement degree of the carotid plaques was closely related to the immunohistochemical parameters of the plaques and the serum hs-CRP levels. It was suggested that the carotid plaque enhancement on CEUS can be used to evaluate the vulnerability of carotid plaques. PMID- 28585146 TI - Deceleration capacity-a novel measure for autonomic nervous system in patients with vasovagal syncope on tilt-table testing. AB - This study was to investigate the changes of autonomic nerve function and hemodynamics in patients with vasovagal syncope (VVS) during head-up tilt-table testing (HUT). HUT was performed in 68 patients with unexplained syncope and 18 healthy subjects served as control group. According to whether bradycardia, hypotension or both took place during the onset of syncope, the patients were divided during the test into three subgroups: vasodepressor syncope (VD), cardioinhibitory syncope (CI) and mixed syncope (MX) subgroups. Heart rate, blood pressure, heart rate variability (HRV), and deceleration capacity (DC) were continuously analyzed during HUT. For all the subjects with positive responses, the normalized low frequency (LFn) and the LF/HF ratio markedly decreased whereas normalized high frequency (HFn) increased when syncope occurred. Syncopal period also caused more significant increase in the power of the DC in positive groups. These changes were more exaggerated compared to controls. All the patients were indicative of a sympathetic surge in the presence of withdrawal vagal activity before syncope and a sympathetic inhibition with a vagal predominance at the syncopal stage by the frequency-domain analysis of HRV. With the measurements of DC, a decreased vagal tone before syncope stage and a vagal activation at the syncopal stage were observed. The vagal tone was higher in subjects showing cardioinhibitory responses at the syncopal stage. DC may provide an alternative method to understand the autonomic profile of VVS patients. PMID- 28585147 TI - Optimal threshold of stimulated serum thyroglobulin level for 18F-FDG PET/CT imaging in patients with thyroid cancer. AB - This study was to explore the optimal threshold of thyroid-stimulating hormone (TSH)-stimulated serum thyroglobulin (s-Tg) for patients who were to receive 18F fluorodeoxyglucose (18F-FDG) PET/CT scan owing to clinical suspicion of differentiated thyroid cancer (DTC) recurrence but negative post-therapeutic 131I whole-body scan (131I-WBS). A total of 60 qualified patients underwent PET/CT scanning from October 2010 to July 2014. The receiver operating characteristic (ROC) curve analyses showed that s-Tg levels over 49 MUg/L led to the highest diagnostic accuracy of PET/CT to detect recurrence, with a sensitivity of 89.5% and a specificity of 90.9%. Besides, bivariate correlation analysis showed positive correlation between s-Tg levels and the maximum standardized uptake values (SUVmax) of 18F-FDG in patients with positive PET/CT scanning, suggesting a significant influence of TSH both on Tg release and uptake of 18F-FDG. So, positive PET/CT imaging is expected when patients have negative 131I-WBS but s-Tg levels over 49 MUg/L. PMID- 28585148 TI - Combined use of single-balloon enteroscope and colonoscope for self-expandable metal stent placement in patients with malignant small intestinal obstruction: a single-center comparative clinical observation. AB - Small intestinal obstruction is a common complication of primary gastrointestinal cancer or metastatic cancers. Patients with this condition are often poor candidates for surgical bypasses, and placement of self-expanding metal stent (SEMS) can be technically challenging. In this study, we examined the feasibility of combined application of single-balloon enteroscope (SBE) and colonoscope for SEMS placement in patients with malignant small intestinal obstruction. Thirty four patients were enrolled in this study, among which 22 patients received SEMS placement by using SBE and colonoscope, while the other 12 patients received conservative medical treatment. The patients were followed up for one year. Stent placement was technically feasible in 95.5% (21/22). Clinical improvement was achieved in 86.4% (19/22). For the 19 clinical success cases, the average time of benefits from a gastric outlet obstruction scoring system (GOOSS) increase >=1 was 111.9+/-89.5 days. For the 12 patients receiving conservative medical treatment, no significant improvement in GOOSS score was observed. Moreover, a significant increase of Short-Form-36 health survey score was observed in the 19 patients at time of 30 days after stent placement. By Kaplan-Meier analysis, a significant survival improvement was observed in patients with successful SEMS placement, compared with patients receiving conservative medical treatment. Taken together, combined use of SBE and colonoscope makes endoscopic stent placement feasible in patients with malignant small intestinal obstruction, and patients can benefit from it in terms of prolonged survival and improved quality of life. PMID- 28585149 TI - Inhibition of adhesion and metastasis of HepG2 hepatocellular carcinoma cells in vitro by DNA aptamer against sialyl Lewis X. AB - The sialyl Lewis X (SLex) antigen encoded by the FUT7 gene is the ligand of endotheliam-selectin (E-selectin). The combination of SLex antigen and E-selectin represents an important way for malignant tumor metastasis. In the present study, the effect of the SLex-binding DNA aptamer on the adhesion and metastasis of hepatocellular carcinoma HepG2 cells in vitro was investigated. Reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence staining were conducted to detect the expression of FUT7 at both transcriptional and translational levels. The SLex expression in HepG2 cells treated with different concentrations of SLex-binding DNA aptamer was detected by flow cytometry. Besides, the adhesion, migration, and invasion of HepG2 cells were measured by cell adhesion assay, and the Transwell migration and invasion assay. The results showed that the FUT7 expression was up-regulated at both mRNA and protein levels in HepG2 cells. SLex-binding DNA aptamer could significantly decrease the expression of SLex in HepG2 cells. The cell adhesion assay revealed that the SLex binding DNA aptamer could effectively inhibit the interactions between E-selectin and SLex in the HepG2 cells. Additionally, SLex-binding DNA aptamers at 20 nmol/L were found to have the similar effect to the monoclonal antibody CSLEX-1. The Transwell migration and invasion assay revealed that the number of penetrating cells on the down-side of Transwell membrane was significantly less in cells treated with 5, 10, 20 nmol/L SLex-binding DNA aptamer than those in the negative control group (P<0.01). Our study demonstrated that the SLex-binding DNA aptamer could significantly inhibit the in vitro adhesion, migration, and invasion of HepG2 cells, suggesting that the SLex-binding DNA aptamer may be used as a potential molecular targeted drug against metastatic hepatocellular carcinoma. PMID- 28585150 TI - Mild encephalopathy/encephalitis with a reversible splenial lesion (MERS): A report of five neonatal cases. AB - Mild encephalopathy/encephalitis with a reversible splenial (MERS) lesion is a clinic-radiological entity. The clinical features of MERS in neonates are still not systemically reported. This paper presents five cases of MERS, and the up-to date reviews of previously reported cases were collected and analyzed in the literature. Here we describe five cases clinically diagnosed with MERS. All of them were neonates and the average age was about 4 days. They were admitted for the common neurological symptoms such as hyperspasmia, poor reactivity and delirium. Auxiliary examinations during hospitalization also exhibited features in common. In this report, we reached following conclusions. Firstly, magnetic resonance imaging revealed solitary or comprehensive lesions in the splenium of corpus callosum, some of them extending to almost the whole corpus callosum. The lesions showed low intensity signal on T1-weighted images, homogeneously hyperintense signal on T2-weighted images, fluid-attenuated inversion recovery and diffusion-weighted images, and exhibited an obvious reduced diffusion on apparent diffusion coefficient map. Moreover, the lesions in the magnetic resonance imaging disappeared very quickly even prior to the clinical recovery. Secondly, all the cases depicted here suffered electrolyte disturbances especially hyponatremia which could be easily corrected. Lastly, all of the cases recovered quickly over one week to one month and majority of them exhibited signs of infections and normal electroencephalography. PMID- 28585151 TI - Microstructure study of normal lunates with micro-computed tomography. AB - In order to study the microstructure characteristics of normal lunate bones, eight fresh cadaver normal lunates were scanned with micro-computed tomography. High-resolution images of the micro-structure of normal lunates were obtained and we analyzed the nutrient foramina. Then nine regions of interest (ROI) were chosen in the central sagittal plane so that we could obtain the parameters of trabecular bones of ROIs. The distal lamellar-like compact structure had statistically significant differences when it was compared with the ROIs in the volar and dorsal ends of the distal cortex. The difference of diameter between the volar and dorsal foramina was significant (P<0.05). However, there was no significant difference regarding the number. The trabecular bones of the volar and dorsal distal ends had lower intensity than those of the distal central subchondral bone plate. The diameters of the nutrient foramina on the volar cortex were larger than those on the dorsal. This research provided more detailed information about microstructure of normal lunate and the nutrient foramina on cortex, and a reference for further study about diseased lunate. PMID- 28585152 TI - Overview of the Safety of Anti-VEGF Drugs: Analysis of the Italian Spontaneous Reporting System. AB - INTRODUCTION: Anti-vascular endothelial growth factor (anti-VEGF) drugs are widely used for the treatment of several cancers and retinal diseases. The systemic use of anti-VEGF drugs has been associated with an increased risk of serious adverse reactions. Whether this risk is also related to intravitreal administration of anti-VEGF drugs is unclear. OBJECTIVE: The aim of this study was to provide an overview of the safety of anti-VEGF drugs in oncology and ophthalmology settings using the Italian Spontaneous Reporting System (SRS). METHODS: We selected all suspected adverse drug reaction (ADR) reports attributed to anti-VEGF drugs and conducted descriptive frequency analyses stratified by indication of use. As a measure of disproportionality, we calculated the proportional reporting ratio with 95% confidence intervals at the level of standardized Medical Dictionary for Regulatory Activities (MedDRA(r)) queries (SMQs). RESULTS: Of a total of 2472 anti-VEGF drug-related reports, 2173 (87.9%) and 299 (12.1%) were attributed to systemic and intravitreal use of these drugs, respectively. The frequency of serious ADRs reported was higher for intravitreal administration of anti-VEGF drugs than for systemic use in patients with cancer (58.9 vs. 34.1%) (p < 0.001) and were disproportionally associated with ischemic heart disease and thromboembolic and cerebrovascular events. Most serious ADRs related to anti-VEGF drugs in patients with cancer are known and clinically relevant (e.g., gastrointestinal and vascular disorders). CONCLUSIONS: This study documented that serious ADRs and systemic toxicity may occur not only with systemic use of anti-VEGF drugs in patients with cancer but also with intravitreal administration. Close monitoring of cardio/cerebrovascular adverse events should be considered during treatment with all anti-VEGF drugs. PMID- 28585153 TI - Second-Generation Antipsychotics and Metabolic Side Effects: A Systematic Review of Population-Based Studies. AB - INTRODUCTION: There is strong evidence from randomized controlled trials (RCTs) that second-generation antipsychotic (SGA) medications are associated with metabolic adverse events. However, with the recent increases in the use of SGAs worldwide and frequent off-label use, it is unclear whether these associations are generalizable to populations beyond those included in RCTs. OBJECTIVES: This review aims to characterize the impact of SGAs on the population through a systematic review of population-based studies of SGA users. Studies could examine the use of any SGA medication and any comparator group. Studies also needed to include at least one metabolic outcome such as type 2 diabetes mellitus, dyslipidemia, obesity, hypertension, or metabolic syndrome. METHODS: A systematic search process was used to identify studies for inclusion in this review. Included studies had to be population-based studies of users of any SGA medication with at least one reported metabolic outcome. Study quality was also assessed using the AMSTAR tool, and evidence was synthesized by both metabolic outcome and specific SGA medication. RESULTS: In total, 15 studies were included in this review. Type 2 diabetes mellitus was the most frequently reported outcome; clozapine and olanzapine were most strongly associated with type 2 diabetes mellitus. Evidence was mixed for a moderate association between type 2 diabetes mellitus and risperidone or quetiapine. Few studies examined other metabolic outcomes, and therefore it is difficult to estimate the true effect in the population. DISCUSSION: Population-based evidence for other SGAs and metabolic outcomes was limited. However, clozapine and olanzapine were consistently more strongly associated with metabolic adverse events than were other SGAs currently available. PMID- 28585155 TI - Latino Sexual Beliefs Scale: An Exploratory Factor Analysis of Latino Men Who Have Sex With Men. AB - The catalyzing forces behind risky sexual behavior are a rich area of interest for public health researchers concerned with reducing HIV risk. Social cognitive theory would suggest that sexual beliefs are a viable example of one such influential agent. Recognizing that culture plays an important role in forming such sexual beliefs, and seeking to understand the unique HIV risks present for Latino men who have sex with men (MSM), this article presents an exploratory factor analysis of the 13-item Latino Sexual Beliefs Scale (LSBS) created as part of a larger study to investigate predictors of condom use among a sample of 482 MSM born in Brazil, Colombia, and the Dominican Republic and living in the U.S. The current analysis identified two psychometric factors in the LSBS as Romantic Exigency (containing six items with a mean loading of .62) and Sexual Acquiescence (containing seven items with a mean loading of .57). This is the first factor analysis conducted on the 13-item LSBS and represents the first known quantitative measure of Latino cultural sexual beliefs related to condom use for Latino MSM. Implications for future research include further validation, use in studies exploring the role of sexual beliefs on condom use, and possible thematic targets in HIV risk reduction interventions. PMID- 28585156 TI - Sex Work Criminalization Is Barking Up the Wrong Tree. AB - There is a notable shift toward more repression and criminalization in sex work policies, in Europe and elsewhere. So-called neo-abolitionism reduces sex work to trafficking, with increased policing and persecution as a result. Punitive "demand reduction" strategies are progressively more popular. These developments call for a review of what we know about the effects of punishing and repressive regimes vis-a-vis sex work. From the evidence presented, sex work repression and criminalization are branded as "waterbed politics" that push and shove sex workers around with an overload of controls and regulations that in the end only make things worse. It is illustrated how criminalization and repression make it less likely that commercial sex is worker-controlled, non-abusive, and non exploitative. Criminalization is seriously at odds with human rights and public health principles. It is concluded that sex work criminalization is barking up the wrong tree because it is fighting sex instead of crime and it is not offering any solution for the structural conditions that sex work (its ugly sides included) is rooted in. Sex work repression travels a dead-end street and holds no promises whatsoever for a better future. To fight poverty and gendered inequalities, the criminal justice system simply is not the right instrument. The reasons for the persistent stigma on sex work as well as for its present revival are considered. PMID- 28585154 TI - Systematic reviews of diagnostic tests in endocrinology: an audit of methods, reporting, and performance. AB - BACKGROUND: Systematic reviews provide clinicians and policymakers estimates of diagnostic test accuracy and their usefulness in clinical practice. We identified all available systematic reviews of diagnosis in endocrinology, summarized the diagnostic accuracy of the tests included, and assessed the credibility and clinical usefulness of the methods and reporting. METHODS: We searched Ovid MEDLINE, EMBASE, and Cochrane CENTRAL from inception to December 2015 for systematic reviews and meta-analyses reporting accuracy measures of diagnostic tests in endocrinology. Experienced reviewers independently screened for eligible studies and collected data. We summarized the results, methods, and reporting of the reviews. We performed subgroup analyses to categorize diagnostic tests as most useful based on their accuracy. RESULTS: We identified 84 systematic reviews; half of the tests included were classified as helpful when positive, one fourth as helpful when negative. Most authors adequately reported how studies were identified and selected and how their trustworthiness (risk of bias) was judged. Only one in three reviews, however, reported an overall judgment about trustworthiness and one in five reported using adequate meta-analytic methods. One in four reported contacting authors for further information and about half included only patients with diagnostic uncertainty. CONCLUSION: Up to half of the diagnostic endocrine tests in which the likelihood ratio was calculated or provided are likely to be helpful in practice when positive as are one-quarter when negative. Most diagnostic systematic reviews in endocrine lack methodological rigor, protection against bias, and offer limited credibility. Substantial efforts, therefore, seem necessary to improve the quality of diagnostic systematic reviews in endocrinology. PMID- 28585157 TI - Gay Men's Health and Identity: Social Change and the Life Course. AB - Due to significant historical change in the late 20th and early 21st century related to both health and cultural attitudes toward homosexuality, gay men of distinct birth cohorts may diverge considerably in their health and identity development. We argue that research on gay men's health has not adequately considered the significance of membership in distinct generation-cohorts, and we present a life course paradigm to address this problem. Focusing on the U.S. as an exemplar that can be adapted to other cultural contexts, we identify five generations of gay men alive today and review unique issues related to health and identity development for each. Implications for research, practice, and advocacy on gay men's health and development are discussed. PMID- 28585158 TI - Properties of Probiotics Kocuria SM1 and Rhodococcus SM2 Isolated from Fish Guts. AB - This study characterized probiotics Kocuria SM1 and Rhodococcus SM2, which were recovered from the intestinal microbiota of rainbow trout (Oncorhynchus mykiss, Walbaum). The cultures were Gram-positive, non-motile, catalase-positive and oxidase-negative cocci or rods. Cell multiplication of SM1 and SM2 was observed at 4-37 degrees C (45 degrees C for SM1), in 0-20% (w/v) NaCl and at pH 2-11. The viability was not affected when exposed to pepsin at pH 2.0 and 3.0, and pancreatin at pH 8.0. Neither isolates were chrome azurol S-positive for siderophore production. Of the 19 common enzymes analysed using the API-ZYM system, only 8 were evident in the culture of SM1 compared to 11 enzymes for SM2. The secondary metabolites of both probiotics were inhibitory to Acinetobacter baumannii, Vibrio anguillarum and V. ordalii; SM2 inhibited Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. SM2 was resistant to penicillin and sulphatriad, out of six antimicrobial agents; SM1 was resistant to sulphatriad. These results suggest that Kocuria SM1 and Rhodococcus SM2 are able to grow over a wide range of temperature, salinity and pH, including in conditions that mimic the gastrointestinal environment of fish and produce extracellular enzymes that may have a role in the host digestive processes. Importantly, Rhodococcus SM2 displays a high degree of bacteriocinogenic potential against multi-drug-resistant human pathogens that have never been documented among the gut microbiota of fish. PMID- 28585159 TI - Need for closure is associated with urgency in perceptual decision-making. AB - Constant decision-making underpins much of daily life, from simple perceptual decisions about navigation through to more complex decisions about important life events. At many scales, a fundamental task of the decision-maker is to balance competing needs for caution and urgency: fast decisions can be more efficient, but also more often wrong. We show how a single mathematical framework for decision-making explains the urgency/caution balance across decision-making at two very different scales. This explanation has been applied at the level of neuronal circuits (on a time scale of hundreds of milliseconds) through to the level of stable personality traits (time scale of years). PMID- 28585160 TI - Relative speed of processing determines color-word contingency learning. AB - In three experiments, we tested a relative-speed-of-processing account of color word contingency learning, a phenomenon in which color identification responses to high-contingency stimuli (words that appear most often in particular colors) are faster than those to low-contingency stimuli. Experiment 1 showed equally large contingency-learning effects whether responding was to the colors or to the words, likely due to slow responding to both dimensions because of the unfamiliar mapping required by the key press responses. For Experiment 2, participants switched to vocal responding, in which reading words is considerably faster than naming colors, and we obtained a contingency-learning effect only for color naming, the slower dimension. In Experiment 3, previewing the color information resulted in a reduced contingency-learning effect for color naming, but it enhanced the contingency-learning effect for word reading. These results are all consistent with contingency learning influencing performance only when the nominally irrelevant feature is faster to process than the relevant feature, and therefore are entirely in accord with a relative-speed-of-processing explanation. PMID- 28585161 TI - Is 18F-FDG-PET useful for predicting R0 resection after induction therapy for initially unresectable locally advanced esophageal carcinoma? AB - OBJECTIVE: Induction therapy followed by surgery is a promising strategy for esophageal cancer patients with invasion of the trachea/bronchus or aorta. However, no diagnostic criteria have been established to diagnose whether R0 resection can be performed. We investigated whether 18F-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) and other modalities are useful for predicting R0 resection. METHODS: Fifty-seven patients with esophageal cancer invading the trachea/bronchus or aorta who underwent induction therapy followed by surgery were enrolled. We divided the participants into two groups, an R0 resection group (n = 43) and a non-R0 resection group (n = 14), and then compared the between-group results of three modalities, including computed tomography (CT), endoscopy and 18F-FDG-PET, before and after induction therapy. RESULTS: The post-maximal standardized uptake value (SUVmax) after induction therapy in the R0 resection group was significantly lower than that in the non-R0 resection group (4.4 vs. 6.6, p = 0.005). The receiver operating characteristic curve analysis showed that the cut-off value for the post-SUVmax based on 18F-FDG-PET prediction of R0 resection was 4.7. Furthermore, a tumor reduction rate of >=44% on CT, no residual stenosis, and no deep ulcer on endoscopy were associated with R0 resection after induction therapy (p = 0.002, p = 0.091, and p = 0.059, respectively). Multivariate logistic analyses revealed that the tumor reduction rate on CT and post-SUVmax <4.7 in 18F-FDG-PET were independent factors for R0 resection. CONCLUSIONS: The post-SUVmax determined by 18F-FDG-PET and the volume reduction rate based on CT scans were useful for predicting R0 resection after induction therapy for initially unresectable locally advanced esophageal carcinoma. PMID- 28585162 TI - Omega-3 supplementation in patients with sepsis: a systematic review and meta analysis of randomized trials. AB - BACKGROUND: Nutritional supplementation of omega-3 fatty acids has been proposed to modulate the balance of pro- and anti-inflammatory mediators in sepsis. If proved to improve clinical outcomes in critically ill patients with sepsis, this intervention would be easy to implement. However, the cumulative evidence from several randomized clinical trials (RCTs) remains unclear. METHODS: We searched the Cochrane Library, MEDLINE, and EMBASE through December 2016 for RCTs on parenteral or enteral omega-3 supplementation in adult critically ill patients diagnosed with sepsis or septic shock. We analysed the included studies for mortality, intensive care unit (ICU) length of stay, and duration of mechanical ventilation, and used the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of the evidence for each outcome. RESULTS: A total of 17 RCTs enrolling 1239 patients met our inclusion criteria. Omega-3 supplementation compared to no supplementation or placebo had no significant effect on mortality [relative risk (RR) 0.85; 95% confidence interval (CI) 0.71, 1.03; P = 0.10; I 2 = 0%; moderate quality], but significantly reduced ICU length of stay [mean difference (MD) -3.79 days; 95% CI -5.49, -2.09; P < 0.0001, I 2 = 82%; very low quality] and duration of mechanical ventilation (MD 2.27 days; 95% CI -4.27, -0.27; P = 0.03, I 2 = 60%; very low quality). However, sensitivity analyses challenged the robustness of these results. CONCLUSION: Omega-3 nutritional supplementation may reduce ICU length of stay and duration of mechanical ventilation without significantly affecting mortality, but the very low quality of overall evidence is insufficient to justify the routine use of omega-3 fatty acids in the management of sepsis. PMID- 28585164 TI - Implementation of the REACH model of dementia caregiver support in American Indian and Alaska Native communities. AB - The Resources for Enhancing Alzheimer's Caregivers Health in the VA (REACH VA) dementia caregiving intervention has been implemented in the VA, in community agencies, and internationally. As identified in the 2013 and 2015 National Plan to Address Alzheimer's Disease, REACH is being made available to American Indian and Alaska Native communities. Implementation activities are carried out by local Public Health Nursing programs operated by Indian Health Service and Tribal Health programs, and Administration for Community Living/Administration on Aging funded Tribal Aging program staff already working in each community. The implementation is described using the Fixsen and Blase implementation process model. Cultural, community, health system, and tribe-specific adaptations occur during the six implementation stages of exploration and adoption, program installation, initial implementation, full operation, innovation, and sustainability. Adaptations are made by local staff delivering the program. Implementation challenges in serving AI/AN dementia caregivers include the need to adapt the program to fit the unique communities and the cultural perceptions of dementia and caregiving. Lessons learned highlight the importance of using a clinically successful intervention, the need for support and buy-in from leadership and staff, the fit of the intervention into ongoing routines and practices, the critical role of modifications based on caregiver, staff, and organization needs and feedback, the need for a simple and easily learned intervention, and the critical importance of community receptivity to the services offered. PMID- 28585163 TI - Engaging multilevel stakeholders in an implementation trial of evidence-based quality improvement in VA women's health primary care. AB - The Veterans Health Administration (VHA) has undertaken primary care transformation based on patient-centered medical home (PCMH) tenets. VHA PCMH models are designed for the predominantly male Veteran population, and require tailoring to meet women Veterans' needs. We used evidence-based quality improvement (EBQI), a stakeholder-driven implementation strategy, in a cluster randomized controlled trial across 12 sites (eight EBQI, four control) that are members of a Practice-Based Research Network. EBQI involves engaging multilevel, inter-professional leaders and staff as stakeholders in reviewing evidence and setting QI priorities. The goal of this analysis was to examine processes of engaging stakeholders in early implementation of EBQI to tailor VHA's medical home for women. Four inter-professional regional stakeholder planning meetings were conducted; these meetings engaged stakeholders by providing regional data about gender disparities in Veterans' care experiences. Subsequent to each meeting, qualitative interviews were conducted with 87 key stakeholders (leaders and staff). Stakeholders were asked to describe QI efforts and the use of data to change aspects of care, including women's health care. Interview transcripts were summarized and coded using a hybrid deductive/inductive analytic approach. The presentation of regional-level data about gender disparities resulted in heightened awareness and stakeholder buy-in and decision-making related to women's health-focused QI. Interviews revealed that stakeholders were familiar with QI, with regional and facility leaders aware of inter-disciplinary committees and efforts to foster organizational change, including PCMH transformation. These efforts did not typically focus on women's health, though some informal efforts had been undertaken. Barriers to engaging in QI included lack of communication across clinical service lines, fluidity in staffing, and lack of protected time. Inter-professional, multilevel stakeholders need to be engaged in implementation early, with data and discussion that convey the importance and relevance of a new initiative. Stakeholder perspectives on institutional norms (e.g., gender norms) and readiness for population-specific QI are useful drivers of clinical initiatives designed to transform care for clinical subpopulations. PMID- 28585165 TI - Biodiversity in targeted metabolomics analysis of filamentous fungal pathogens by 1H NMR-based studies. AB - The taxonomical classification among fungi kingdom in the last decades was evolved. In this work the targeted metabolomics study based on 1H NMR spectroscopy combined with chemometrics tools was reported to be useful for differentiation of three model of fungal strains, which represent various genus of Ascomycota (Aspergillus pallidofulvus, Fusarium oxysporum, Geotrichum candidum) were selected in order to perform metabolomics studies. Each tested species, revealed specific metabolic profile of primary endo-metabolites. The species of A. pallidofulvus is represented by the highest concentration of glycerol, glucitol and Unk5. While, F. oxysporum species is characterised by increased level of propylene glycol, ethanol, 4-aminobutyrate, succinate, xylose, Unk1 and Unk4. In G. candidum, 3-methyl-2-oxovalerate, glutamate, pyruvate, glutamine and citrate were elevated. Additionally, a detailed analysis of metabolic changes among A. pallidofulvus, F. oxysporum and G. candidum showed that A. pallidofulvus seems to be the most pathogenic fungi. The obtained results demonstrated that targeted metabolomics analysis could be utilized in the future as a supporting taxonomical tool for currently methods. PMID- 28585166 TI - Development of media to accelerate the isolation of indigo-reducing bacteria, which are difficult to isolate using conventional media. AB - Indigo-reducing bacteria perform natural fermentation in indigo fermentation fluid. Owing to the stochastic nature of the process, the constituent in indigo fermentation fluid differ depending on the prepared batch and fermentation period. To identify new indigo-reducing bacteria, isolation of the bacteria is indispensable. However, isolation of indigo-reducing bacteria is difficult because conventional media are often unsuitable to isolate these slow-growing bacteria that also exist in low numbers. Hydrolysates of polysaccharides and mixtures of plant base constituents are candidates to accelerate the isolation of indigo-reducing bacteria that cannot be isolated using conventional media. In this current study, wheat bran hydrolysate and composted indigo leaves (sukumo) were used as ingredients in the fermentation fluid in the selective medium for indigo-reducing bacteria in anaerobic culture. The results suggested that obligate and oxygen-non-metabolizing facultative anaerobes are difficult to isolate using conventional media, whereas oxygen-metabolizing facultative anaerobes, relatively rapid-growing and major bacterial strains are relatively easy to isolate. Media containing sukumo hydrolysate facilitated the isolation of novel species of Bacillus pseudofirmus-related strains, whereas media containing wheat bran hydrolysate facilitated the isolation of Amphibacillus spp. (including new species). Seven species (including two new species) of indigo-reducing bacteria were isolated using wheat bran hydrolysate-containing media, whereas six species (including three new species) of indigo-reducing bacteria were isolated using media containing both wheat bran and sukumo hydrolysates. These newly developed culture media will facilitate the isolation of unknown bacteria in indigo fermentation and in environments similar to indigo fermentation fluid. PMID- 28585167 TI - Analysis of bacterial communities in rhizosphere soil of continuously cropped healthy and diseased konjac. AB - The bacterial community and diversity in healthy and diseased konjac rhizosphere soils with different ages of continuous cropping were investigated using next generation sequencing. The results demonstrated that the number of years of continuous cropping significantly altered soil bacterial community and diversity. Soil bacterial Shannon diversity index and Chao 1 index decreased with the increasing cropping years of konjac. After 1 year of cropping, the soil exhibited the highest bacterial relative abundance and diversity. Of the 44 bacterial genera (relative abundance ratio of genera greater than 0.3%), 14 were significantly affected by the duration of continuous cropping and plant status. With increasing continuous cropping, Alicyclobacillus decreased, while Achromobacter, Lactobacillus, Kaistobacter, Rhodoplanes increased after 3 years continuous cropping. Continuous cropping altered the structure and composition of the soil bacterial community, which led to the reduction in the beneficial bacteria and multiplication of harmful bacteria. These results will improve our understanding of soil microbial community regulation and soil health maintenance in konjac farm systems. PMID- 28585168 TI - Production of macrolide antibiotics from a cytotoxic soil Streptomyces sp. strain ZDB. AB - Crude extract from a culture of a soil Streptomyces sp. strain ZDB showed toxicity towards Artemia salina and antimicrobial activity against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Chlorella vulgaris, and Chlorella sorokiniana. Large scale fermentation of the strain led to the isolation of the macrolide antibiotics, bafilomycins A1 (1), B1 (2), and D (3) together with nonactic acid (4) and bostrycoidin-9-methyl ether (5). Structures of the antibiotics were determined based on spectral data analysis. We describe the isolation of the compounds and characterization of the producing strain. PMID- 28585169 TI - Evaluating fermentation characteristics of Kazachstania spp. and their potential influence on wine quality. AB - The current study is the first one to demonstrate the wine fermentation potential of members of several species of the genus Kazachstania including strains derived from grape must. The fermentation characteristics were evaluated in synthetic grape juice medium and in Sauvignon blanc. Our data show that none of the species evaluated could ferment to dryness in monoculture fermentations. However, at least 75% of the sugar was consumed before the fermentations got stuck. In mixed culture fermentations with Saccharomyces cerevisiae diverse aroma profiles were evident especially in Sauvignon blanc fermentations. Four distinct potential aroma associations were identified: (i) Kazachstania solicola-vinegar and solvent like, (ii) Kazachstania hellenica-spirituous, cheesy, (iii) Kazachstania aerobia CBS-fruity, floral (iv) K. aerobia IWBT, Kazachstania unispora and Kazachstania servazii-rancid, harsh. Furthermore, strain variation was apparent as the two K. aerobia strains displayed distinct karyotypes and aroma potential. Our data show that although members of the genus Kazachstania are typically encountered at low frequency in grape must, some of the species have positive aroma attributes that should be explored further. PMID- 28585171 TI - Assessing the biodegradation of polycyclic aromatic hydrocarbons and laccase production by new fungus Trematophoma sp. UTMC 5003. AB - Environmental pollution caused by petroleum compounds has become a global concern. The aim of this study was to evaluate the indigenous fungal isolates in Iran for biodegradation of crude oil pollutants. In order to isolate fungal strains, the soil samples were enriched in minimal salts medium (MSM) with 1% crude oil and then the crude oil degradation was measured by total petroleum hydrocarbon (TPH) assay. The degradation of hydrocarbons compounds was also analysed by FT-IR and HPLC, and the activity of peroxidase enzyme and biosurfactant production were also measured. We isolated 40 fungal strains and selected the isolate G-05 with 70% degradation ability of petroleum hydrocarbons as a premium isolate after 15 days. Residual crude oil analysis with FT-IR spectrophotometry and HPLC showed that G-05 is able to degrade 90 and 100% of aliphatic compounds and some polycyclic aromatic hydrocarbons (PAH), respectively. Evaluation of enzymatic activity showed that this isolate can produce 4 U L-1 of Laccase enzyme for oil removal; it is capable of producing biosurfactant and reducing the surface tension of the medium to 25.95 +/- 0.1 m Nm-1. This strain was identified as a member of Trematophoma genus and the obtained results showed that this strain is a highly potent strain in bioremediation of soils contaminated by crude oil. PMID- 28585172 TI - Identification and physiological properties of a Nigerian strain of Volvariella sp. isolated from oil palm waste. AB - Over the years several species of edible mushrooms have been collected for consumption from different agro-wastes in Nigeria. Identification of most of these mushrooms was often by morphological descriptive methods. This study reports the morphological study, physiological study and identification of a Nigerian wild strain of Volvariella sp. (VNW) isolated from discarded oil palm waste and three Indian commercial strains V11, V245 and V247 of V. volvacea. Effect of incubation temperatures and medium pH was investigated. Molecular characterization of the strains was carried out using ITS-1 and ITS-4 primers. Results obtained showed close similarities of the Nigerian strain to the Indian strains with few morphological variations in colour, shape and appearance. Growth was observed at temperature range of 20-40 degrees C and pH range of 4.0-8.0 for all strains with optimum mycelia extension at 35 degrees C and pH 6.0. VNW recorded a significantly higher (p <= 0.05) mycelia extension rate at 35 degrees C (25.20 +/- 1.80 mm/day) and pH 6.0 (40.20 +/- 0.34 mm/day). Highest biomass yield was observed at pH 6.0 with V11 recording a significantly (p <= 0.05) higher yield (1.74 +/- 0.07 g/100 mL). Increasing percentage (w/v) of CaSO4.H2O increased biomass yield of all the strains. NJ phylogenetic tree showed the Nigerian and Indian strains in the same cluster indicating evolutionary closeness than with other species of Volvariella from GenBank in a separate cluster even though they share a common ancestor. This successfully proves the identity of a Nigerian strain of Volvariella sp. VNW from oil palm waste as V. volvacea with GenBank accession number KC894923. PMID- 28585170 TI - Rapid and simple identification of carbapenemase genes, bla NDM, bla OXA-48, bla VIM, bla IMP-14 and bla KPC groups, in Gram-negative bacilli by in-house loop mediated isothermal amplification with hydroxynaphthol blue dye. AB - Carbapenem-resistant Enterobacteriaceae isolates by carbapenemase production are being reported globally with increasing frequency, leading to limited therapeutic options. We therefore developed a loop-mediated isothermal amplification method with hydroxynaphthol blue dye (LAMP-HNB) for rapid confirmation of bla NDM, bla OXA-48, bla VIM, bla IMP-14 and bla KPC groups. Sixty-two Enterobacteriaceae and Pseudomonas spp. isolates carrying various carbapenemase genes (28 bla NDM-1, 9 bla IMP-14a, 2 bla IMP-48, 1 bla IMP-1, 1 bla IMP-4, 1 bla IMP-9, 1 bla IMP-15, 4 bla VIM-2, 1 bla VIM-1, 1 bla IMP-14a & bla VIM-2, 7 bla KPC-2, 3 bla OXA-48 and 3 bla OXA-181) and 37 non-carbapenemase-producing Enterobacteriaceae isolates as confirmed by the PCR methods were included. Bacterial DNA was extracted by a simple boiling method. The LAMP-HNB method for each target gene was carried out using a set of six primers under isothermal condition at 65 degrees C in an ordinary water bath within 60 min and visual measurement of reaction by the change from violet to sky blue. This method had high efficiency (100% sensitivity and specificity) for identifying the bla NDM, bla OXA-48, bla VIM, bla IMP-14 and bla KPC groups compared with the PCR method. The HNB is easy to prepare, inexpensive and provides reliable results. Therefore, this method could be used as a confirmatory carbapenemase test in routine laboratory or for epidemiological purposes. PMID- 28585173 TI - Isolation and characterisation of the epothilone gene cluster with flanks from high alkalotolerant strain Sorangium cellulosum (So0157-2). AB - Epothilones are cytotoxic macrolactones having auspicious anti-tumorous activities, but merely produced by rare Sorangium strains. Here, we have focused on the epothilone gene cluster from special niche bacterial strain, S. cellulosum So0157-2. Therefore, we have isolated a high pH tolerant S. cellulosum strain So0157-2 and characterized the epothilones gene cluster and its flanks by cosmid/fosmid libraries preparation and sequencing. The assembly spanned 94,459 bp and consisted of 56,019 bp core region. Remarkably, the core as well as upstream 420 bp and downstream 315 bp were highly conserved, while further neighboring regions varied extremely. Transposase traces were identified near the core of clusters, supporting that the transposon-mediated transgenesis is a naturally evolved strategy for the cluster's dissemination. A predicted neighboring esterase gene was identified as a potential epothilone-resistance gene preventing self-toxicity. Novel modification or regulatory genes, a multi position-cyclo releasing gene and their relationship with corresponding analogs were identified in strain So0157-2. These findings open the door to discover additional, naturally evolved epothilone-related genes for significant applications in industrial as well as clinical sector. PMID- 28585174 TI - A patent landscape on application of microorganisms in construction industry. AB - Construction biotechnology includes research and development of construction materials and processes that make use of various microbes. The present technology landscape gives a perspective on how microbes have been used in construction industry as cement and concrete additives by analyzing patents filed in this technology arena. All patents related to the technology of interest published globally to date have been reviewed. The earliest patent filing in this technology domain was recorded in the year 1958 and the patenting activity reached its peak around mid to late 1990s. The early technology was mainly focused on microbial polysaccharides and other metabolic products as additives. Year 2002 onwards, biomineralization has taken precedence over the other technologies with consistent patent filings indicating a shift in innovation focus. Japan has been the global leader with highest number of patents filed on application of microbes in construction industry. Southeast University, China has topped the patent assignee list with maximum number of filings followed by Kajima Corp. and Shin-Etsu Chemical Co., Ltd. Most patent applications have claimed microbe based bio-products. Construction-related microbial technologies are mainly based on activity of different microorganisms such as urease-producing, acidogenic, halophilic, alkaliphilic, nitrate and iron-reducing bacteria. Sporosarcina pasteurii has been the most widely used microbe for biomineralization. PMID- 28585175 TI - Nematicidal effect of rhizobacteria on plant-parasitic nematodes associated with vineyards. AB - The action of metabolites and exoenzymes from rhizobacteria on different plant parasitic nematodes has an influence on the nematicidal efficacy of the microbe. Seven rhizobacteria, divided into two bacterial groups, were evaluated in vitro for nematicidal activity on Meloidogyne ethiopica and Xiphinema index. The direct effect of their filtrates on egg hatching and juveniles of M. ethiopica as well as mobile stages of X. index was evaluated during a 72-h period. The production of four exoenzymes and two metabolites associated with nematode mortality was investigated. Molecular characterization of three isolates was performed, and the physiological profiles and lipase activity of all isolates were obtained using the BIOLOG EcoPlate system. While chitinase and collagenase were measured using the BIOLOG MT2 plate system, protease, hydrogen cyanide and hydrogen sulphide were directly determined in Petri dishes. Nematode mobile stages exposure to the bacterial filtrate revealed a nematicidal effect up to 93.7% on X. Index and up to 83.3% on M. ethiopica. The control of egg hatching varied between 35 and 85%. A positive correlation was found between the mortality of both nematode mobile stages and the concerted activities of the bacterial enzymes as well as the level of the volatile metabolites. The nematicidal effect of rhizobacteria strains varies by nematode genera and among the developmental stages evaluated. PMID- 28585176 TI - The crystal structure of Ac-AChBP in complex with alpha-conotoxin LvIA reveals the mechanism of its selectivity towards different nAChR subtypes. AB - The alpha3* nAChRs, which are considered to be promising drug targets for problems such as pain, addiction, cardiovascular function, cognitive disorders etc., are found throughout the central and peripheral nervous system. The alpha conotoxin (alpha-CTx) LvIA has been identified as the most selective inhibitor of alpha3beta2 nAChRs known to date, and it can distinguish the alpha3beta2 nAChR subtype from the alpha6/alpha3beta2beta3 and alpha3beta4 nAChR subtypes. However, the mechanism of its selectivity towards alpha3beta2, alpha6/alpha3beta2beta3, and alpha3beta4 nAChRs remains elusive. Here we report the co-crystal structure of LvIA in complex with Aplysia californica acetylcholine binding protein (Ac AChBP) at a resolution of 3.4 A. Based on the structure of this complex, together with homology modeling based on other nAChR subtypes and binding affinity assays, we conclude that Asp-11 of LvIA plays an important role in the selectivity of LvIA towards alpha3beta2 and alpha3/alpha6beta2beta3 nAChRs by making a salt bridge with Lys-155 of the rat alpha3 subunit. Asn-9 lies within a hydrophobic pocket that is formed by Met-36, Thr-59, and Phe-119 of the rat beta2 subunit in the alpha3beta2 nAChR model, revealing the reason for its more potent selectivity towards the alpha3beta2 nAChR subtype. These results provide molecular insights that can be used to design ligands that selectively target alpha3beta2 nAChRs, with significant implications for the design of new therapeutic alpha-CTxs. PMID- 28585178 TI - Editing base in mouse model. PMID- 28585177 TI - Potent and conditional redirected T cell killing of tumor cells using Half DVD Ig. AB - Novel biologics that redirect cytotoxic T lymphocytes (CTLs) to kill tumor cells bearing a tumor associated antigen hold great promise in the clinic. However, the ability to safely and potently target CD3 on CTL toward tumor associated antigens (TAA) expressed on tumor cells remains a challenge of both technology and biology. Herein we describe the use of a Half DVD-Ig format that can redirect CTL to kill tumor cells. Notably, Half DVD-Ig molecules that are monovalent for each specificity demonstrated reduced non-specific CTL activation and conditional CTL activation upon binding to TAA compared to intact tetravalent DVD-Ig molecules that are bivalent for each specificity, while maintaining good drug like properties and appropriate PK properties. PMID- 28585179 TI - Effective gene editing by high-fidelity base editor 2 in mouse zygotes. AB - Targeted point mutagenesis through homologous recombination has been widely used in genetic studies and holds considerable promise for repairing disease-causing mutations in patients. However, problems such as mosaicism and low mutagenesis efficiency continue to pose challenges to clinical application of such approaches. Recently, a base editor (BE) system built on cytidine (C) deaminase and CRISPR/Cas9 technology was developed as an alternative method for targeted point mutagenesis in plant, yeast, and human cells. Base editors convert C in the deamination window to thymidine (T) efficiently, however, it remains unclear whether targeted base editing in mouse embryos is feasible. In this report, we generated a modified high-fidelity version of base editor 2 (HF2-BE2), and investigated its base editing efficacy in mouse embryos. We found that HF2-BE2 could convert C to T efficiently, with up to 100% biallelic mutation efficiency in mouse embryos. Unlike BE3, HF2-BE2 could convert C to T on both the target and non-target strand, expanding the editing scope of base editors. Surprisingly, we found HF2-BE2 could also deaminate C that was proximal to the gRNA-binding region. Taken together, our work demonstrates the feasibility of generating point mutations in mouse by base editing, and underscores the need to carefully optimize base editing systems in order to eliminate proximal-site deamination. PMID- 28585180 TI - Efficacy and Safety of Insulin Degludec for Hyperglycemia Management in Noncritical Hospitalized Patients with Diabetes: An Observational Study. AB - INTRODUCTION: To assess the efficacy and safety of insulin degludec administered in a basal-bolus regimen according to the GesTIO protocol in noncritical hospitalized patients with T1DM and T2DM. METHODS: Mean blood glucose levels (BG) and their standard deviations (SD) at admission vs. discharge were compared in 52 subjects (48.1% >=75 years) managed through a basal-bolus scheme including degludec. The percentages of patients with BG at target (140-180 mg/dl) or below at discharge and the incidence rate (and the 95% confidence interval for it) of hypoglycemia were assessed. RESULTS: From admission to discharge, fasting BG decreased from 237 to 153 mg/dl (p < 0.0001) and SD dropped from 125 to 38 mg/dl (p < 0.0001); average BG decreased from 189 to 145 mg/dl (SD dropped from 57 to 32 mg/dl). At discharge, 28.9% had BG at target, while 50.0% had lower levels (average 119.0 +/- 14.4 mg/dl). The incidence rate of hypoglycemia was 0.07 (0.05; 0.11) episodes per person-day; 1 out of 27 episodes occurred during the night. CONCLUSIONS: Degludec in hospitalized, mainly elderly patients is effective and minimizes glucose variability and nocturnal hypoglycemia. PMID- 28585181 TI - Which way is best for stone fragments and dust extraction during percutaneous nephrolithotomy. AB - Percutaneous nephrolithotomy (PCNL) is a commonly used type of minimally invasive treatment in kidney stone surgeries. Surgical success is assessed according to residual stone amount after surgery. The purpose of this study is to compare the two methods' success and practicality that are applied after the fracture of the stone in the patients who applied PCNL and which enable the removal of the residual stones. Among 102 patients who underwent a single-session of PCNL at our department between June 2015 and November 2016 were evaluated. Previously identified irrigation method and our aspiration method which described used in post-operative patients divided into two groups of residual fragments was assessed by computed tomography. The results were evaluated in statistical analyses. Significant p was accepted as p < 0.05. The age and gender distribution of patients in the irrigation and aspiration groups did not differ significantly (p > 0.05). In irrigation and aspiration groups, stone size did not differ significantly (p > 0.05). The amount of residue stones and dust remaining in the irrigation group was significantly higher (p < 0.05) than the aspiration group. Although many methods have been tried before, we think that the aspiration method we have described is a cheaper, more effective and feasible option. PMID- 28585182 TI - Lime powder treatment reduces urinary excretion of total protein and transferrin but increases uromodulin excretion in patients with urolithiasis. AB - Our previous study has shown that lime powder (LP) had an inhibitory effect against calcium oxalate stone formation. However, the precise mechanisms underlying such beneficial effect remained unclear. Our present study thus aimed to address the effect of LP on excretory level and compositions of urinary proteins using a proteomics approach. From a total of 80 calcium oxalate stone formers recruited into our 2-year randomized clinical trial of LP effect, 10 patients with comparable age and clinical parameters were selected for this proteomic study. 24-h urine specimens were collected from all subjects, at baseline (before) and after LP treatment for 6 months, and then subjected to quantitative proteomics analysis and subsequent validation by ELISA. Total urinary protein excretion was significantly decreased by LP treatment, but unaffected by placebo. Nanoflow liquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS) followed by quantitative analysis revealed 17 proteins whose levels were significantly altered (16 decreased and 1 increased) exclusively by LP treatment. Among these, the decrease of transferrin and increase of uromodulin were validated by ELISA. Moreover, there was a significant correlation between microalbuminuria and urinary transferrin level by Pearson's correlation test. In summary, LP treatment caused significant reduction in total urinary protein excretion and changes in urinary protein compositions that could be linked to stone inhibitory effects and might be relevant mechanisms responsible for the beneficial effects of LP to prevent kidney stone formation and recurrence. PMID- 28585183 TI - Precision Medicine for Heart Failure with Preserved Ejection Fraction: An Overview. AB - There are few proven therapies for heart failure with preserved ejection fraction (HFpEF). The lack of therapies, along with increased recognition of the disorder and its underlying pathophysiology, has led to the acknowledgement that HFpEF is heterogeneous and is not likely to respond to a one-size-fits-all approach. Thus, HFpEF is a prime candidate to benefit from a precision medicine approach. For this reason, we have assembled a compendium of papers on the topic of precision medicine in HFpEF in the Journal of Cardiovascular Translational Research. These papers cover a variety of topics relevant to precision medicine in HFpEF, including automated identification of HFpEF patients; machine learning, novel molecular approaches, genomics, and deep phenotyping of HFpEF; and clinical trial designs that can be used to advance precision medicine in HFpEF. In this introductory article, we provide an overview of precision medicine in HFpEF with the hope that the work described here and in the other papers in this special theme issue will stimulate investigators and clinicians to advance a more targeted approach to HFpEF classification and treatment. PMID- 28585184 TI - Text Mining of the Electronic Health Record: An Information Extraction Approach for Automated Identification and Subphenotyping of HFpEF Patients for Clinical Trials. AB - Precision medicine requires clinical trials that are able to efficiently enroll subtypes of patients in whom targeted therapies can be tested. To reduce the large amount of time spent screening, identifying, and recruiting patients with specific subtypes of heterogeneous clinical syndromes (such as heart failure with preserved ejection fraction [HFpEF]), we need prescreening systems that are able to automate data extraction and decision-making tasks. However, a major obstacle is the vast amount of unstructured free-form text in medical records. Here we describe an information extraction-based approach that automatically converts unstructured text into structured data, which is cross-referenced against eligibility criteria using a rule-based system to determine which patients qualify for a major HFpEF clinical trial (PARAGON). We show that we can achieve a sensitivity and positive predictive value of 0.95 and 0.86, respectively. Our open-source algorithm could be used to efficiently identify and subphenotype patients with HFpEF and other disorders. PMID- 28585185 TI - Intercalary reconstructions after bone tumor resections: a review of treatments. AB - An intercalary reconstruction is defined as replacement of the diaphyseal portion of a long bone after segmental skeletal resection (diaphysectomy). Intercalary reconstructions typically result in superior function compared to other limb sparing procedures as the patient's native joints above and below the reconstruction are left undisturbed. The most popular reconstructive options after segmental resection of a bone sarcoma include allografts, vascularized fibula graft, combined allograft and vascularized fibula, segmental endoprostheses, extracorporeal devitalized autograft, and segmental transport using the principles of distraction osteogenesis. This article aims to review the indications, techniques, limitations, pros and cons, and complications of the aforementioned methods of intercalary bone tumor resections and reconstructions in the context of the ever-growing, brave new field of limb-salvage surgery. PMID- 28585187 TI - A BRCA1-Dependent DNA Damage Response in the Regenerating Adult Peripheral Nerve Milieu. AB - It is not generally appreciated that DNA repair machinery has a critical role in the remodeling of neurons that adopt a regenerative phenotype. We identified that breast cancer 1 (BRCA1)-dependent DNA activity, previously well known to repair cancer cells, is active in adult peripheral neurons and Schwann cells during their injury and regeneration response. Temporary or partial loss of BRCA1 or blockade of its intraneuronal nuclear entry impaired outgrowth in neurons in vitro and impacted nerve regeneration and functional recovery in vivo. We found that distal axonal injury triggered a BRCA1-dependent DNA damage response (DDR) signal in neuronal soma. BRCA1 also supported an enabling transcriptional program of injured neurons and supporting Schwann cells. Our findings indicate that BRCA1 offers prominent functional roles in neurons and glial cells including key support for their physical and molecular integrity. Since BRCA1 mutations are common in humans, this function of BRCA1 in peripheral neurons and their glial partners warrants attention. PMID- 28585186 TI - Tumors of the hand. AB - Tumors of the hand comprise a vast array of lesions involving skin, soft tissue and bone. The majority of tumors in the hand are benign. Malignant tumors, although rare, do occur and frequently have unique characteristics in this specific anatomic location. Careful staging, histological diagnosis and treatment are essential to optimize clinical outcome. However, straightforward most of the time, hand tumor management does have pitfalls; caution is advised, as a missed or delayed diagnosis or an improperly executed biopsy may have devastating consequences. This article reviews the clinical spectrum of the most common benign and malignant bone and soft tissue tumors of the hand and discusses the clinicopathological findings, imaging features and current concepts in treatment for these tumors. PMID- 28585188 TI - A Possible Anti-Inflammatory Effect of Proline in the Brain Cortex and Cerebellum of Rats. AB - Although many studies show the toxic effects of proline, recently it has been reported some anti-inflammatory effect of this amino acid. Our principal objective was to investigate the effects of proline on the alterations caused by LPS (lipopolysaccharide) administration in the cerebral cortex and cerebellum of young Wistar rats. The animals were divided into four groups: control (0.85% saline); proline, (12.8 MUmol of proline/g body weight from day 7 to 13; 14.6 MUmol of proline/g body weight from day 14 to 17 and 16.4 MUmol of proline/g body weight from day 18 to 21); LPS (1 mg/g body weight); LPS plus proline. The animals were killed at 22 days of age, 12 h after the last injection, by decapitation without anesthesia. The brain cortex and cerebellum were separated for chemical determinations. The effects of proline and LPS in the cerebral cortex and cerebellum on the expression of S100B and GFAP, oxidative stress parameters, enzymes of phosphoryl transfer network activity, and mitochondrial respiration chain complexes were investigated. Two-way ANOVA showed that the administration of proline did not alter the analyzed parameter in cerebral cortex and cerebellum. On the other hand, LPS administration caused a change in these parameters. Besides, the co-administration of proline and LPS showed the ability of Pro in preventing the effects of LPS. These results indicated that LPS induces inflammation, oxidative stress, and alters energy parameters in cerebral cortex and cerebellum of the rats. Moreover, co-administration of Pro was able to prevent these harmful effects of LPS. PMID- 28585189 TI - Modulatory Role of Nurr1 Activation and Thrombin Inhibition in the Neuroprotective Effects of Dabigatran Etexilate in Rotenone-Induced Parkinson's Disease in Rats. AB - Recently, it has been shown that both decreased nuclear receptor-related 1 (Nurr1) expression and thrombin accumulation are involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). The new anticoagulant dabigatran etexilate (DE) is a direct thrombin inhibitor that owns benzimidazole group, which has been proposed to activate Nurr1. In the present study, we examined the neuroprotective effects of DE in rotenone model of PD. Rotenone was injected subcutaneously at a dose of 1.5 mg/kg every other day for 21 days. An oral regimen of DE (15 mg/kg) was started after the 5th rotenone injection following the manifestations of PD. Treatment of PD rats with DE mitigated rotenone-induced neuronal degeneration and restored striatal dopamine level with motor recovery. As well, DE enhanced Nurr1 expression in substantia nigra along with increasing transcriptional activation of Nurr1-controlled genes namely tyrosine hydroxylase, vascular monoamine transporter, glial cell line-derived neurotrophic factor, and its receptor gene c-Ret, which are critical for development and maintenance of dopaminergic neurons. DE also suppressed thrombin accumulation in substantia nigra. Both effects probably contributed to repressing neurotoxic proinflammatory cytokines, which was manifested by decreased level of nuclear factor kappa beta and tumor necrosis factor alpha. In conclusion, the present results suggest that DE could possess significant neuroprotective and regenerative effects in a rotenone-induced PD animal model as consequence of Nurr1 activation and thrombin inhibition. PMID- 28585190 TI - Spinal AMPA Receptor GluA1 Ser831 Phosphorylation Controls Chronic Alcohol Consumption-Produced Prolongation of Postsurgical Pain. AB - Previous studies have shown that excessive alcohol drinking is associated with chronic pain development; however, the molecular mechanism underlying this association is poorly understood. In this study, we investigated the effect of chronic alcohol consumption on plantar incision-induced postsurgical pain. We observed that 4-week ethanol drinking significantly prolonged plantar incision induced mechanical pain, but not thermal pain. The chronic alcohol consumption enhanced plantar incision-produced alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor GluA1 phosphorylation at the Ser831 site in the spinal cord. The targeted mutation of the GluA1 phosphorylation site in GluA1 S831A mutant mice significantly inhibited the incisional pain prolongation produced by chronic alcohol consumption. Moreover, chronic alcohol consumption combined with plantar incision markedly increased AMPA receptor-mediated miniature excitatory postsynaptic currents in the spinal dorsal horn neurons, and this effect was diminished significantly in the GluA1 S831A mutant mice. Our results suggest that chronic alcohol consumption may promote the development of persistent postsurgical pain by enhancing AMPA receptor GluA1 Ser831 phosphorylation. We identified chronic alcohol consumption as a risk factor for pain chronification after surgery. PMID- 28585191 TI - Why Topical Retinoids Are Mainstay of Therapy for Acne. AB - : Acne-focused dermatology expert groups have consistently recommended that most patients with acne be treated with a combination of topical retinoid and antimicrobial therapy. This is based on clinical data as well as evidence that these drug classes have different and complementary mechanisms of action that target multiple aspects of acne's complex pathophysiology. Recent evidence-based guidelines for acne, including those from the American Academy of Dermatology (AAD) and the European Dermatology Forum (EDF), have agreed that retinoids have an essential role in this widespread disease. The AAD states "retinoids are the core of topical therapy for acne because they are comedolytic, resolve the precursor microcomedone lesion, and are anti-inflammatory;" further, they "allow for maintenance of clearance." Despite uniform recommendation for use of topical retinoids, a recent study of prescribing practices from 2012 to 2014 indicated that dermatologists prescribed retinoids just 58.8% of the time while non dermatologists prescribed them for only 32.4% of cases. In this article, we review the reasons supporting retinoids as the mainstay of acne therapy and discuss some of the perceived barriers that may be limiting use of this important drug class. Further, we discuss how and when titrating retinoid concentrations may be utilized in clinical practice. FUNDING: Galderma International. PMID- 28585192 TI - Rsk2 Knockout Affects Emotional Behavior in the IntelliCage. AB - Ribosomal s6 kinase 2 is a growth factor activated serine/threonine kinase and member of the ERK signaling pathway. Mutations in the Rsk2 gene cause Coffin Lowry syndrome, a rare syndromic form of intellectual disability. The Rsk2 KO mouse model was shown to have learning and memory defects. We focused on the investigation of the emotional behavioral phenotype of Rsk2 KO mice mainly in the IntelliCage. They exhibited an anti-depressive, sucrose reward seeking phenotype and showed reduced anxiety. Spontaneous activity was increased in some conventional tests. However, KO mice did not show defects in place learning, working memory and motor impulsivity. In addition, we found changes of the monoaminergic system in HPLC and qRT-PCR experiments. Taken together, RSK2 not only plays a role in cognitive processes but also in emotional and reward-related behaviors. PMID- 28585193 TI - The Definition and Prevalence of Obesity and Metabolic Syndrome. AB - Increase in prevalence of obesity has become a worldwide major health problem in adults, as well as among children and adolescents. Furthermore, total adiposity and truncal subcutaneous fat accumulation during adolescence are positively and independently associated with atherosclerosis at adult ages. Centrally accumulation of body fat is associated with insulin resistance, whereas distribution of body fat in a peripheral pattern is metabolically less important. Obesity is associated with a large decrease in life expectancy. The effect of extreme obesity on mortality is greater among younger than older adults. In this respect, obesity is also associated with increased risk of several cancer types. However, up to 30% of obese patients are metabolically healthy with insulin sensitivity similar to healthy normal weight individuals, lower visceral fat content, and lower intima media thickness of the carotid artery than the majority of metabolically "unhealthy" obese patients.Abdominal obesity is the most frequently observed component of metabolic syndrome. The metabolic syndrome; clustering of abdominal obesity, dyslipidemia, hyperglycemia and hypertension, is a major public health challenge. The average prevalence of metabolic syndrome is 31%, and is associated with a two-fold increase in the risk of coronary heart disease, cerebrovascular disease, and a 1.5-fold increase in the risk of all cause mortality. PMID- 28585194 TI - Circadian Rhythms in Diet-Induced Obesity. AB - The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronizes these with daily cycles, feeding patterns also regulates circadian clocks. The clock genes and adipocytokines show circadian rhythmicity. Dysfunction of these genes are involved in the alteration of these adipokines during the development of obesity. Food availability promotes the stimuli associated with food intake which is a circadian oscillator outside of the suprachiasmatic nucleus (SCN). Its circadian rhythm is arranged with the predictable daily mealtimes. Food anticipatory activity is mediated by a self sustained circadian timing and its principal component is food entrained oscillator. However, the hypothalamus has a crucial role in the regulation of energy balance rather than food intake. Fatty acids or their metabolites can modulate neuronal activity by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. The timing of three-meal schedules indicates close association with the plasma levels of insulin and preceding food availability. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition can lead to uncoupling of peripheral clocks from the central pacemaker and to the development of metabolic disorders. Metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, eventual disruption of circadian clock functioning can lead to obesity. While CLOCK expression levels are increased with high fat diet-induced obesity, peroxisome proliferator-activated receptor (PPAR) alpha increases the transcriptional level of brain and muscle ARNT-like 1 (BMAL1) in obese subjects. Consequently, disruption of clock genes results in dyslipidemia, insulin resistance and obesity. Modifying the time of feeding alone can greatly affect body weight. Changes in the circadian clock are associated with temporal alterations in feeding behavior and increased weight gain. Thus, shift work is associated with increased risk for obesity, diabetes and cardio vascular diseases as a result of unusual eating time and disruption of circadian rhythm. PMID- 28585195 TI - Eat and Death: Chronic Over-Eating. AB - Obesity-related co-morbidities decrease life quality, reduce working ability and lead to early death. The total amount of dietary fat consumption may be the most potent food-related risk factor for weight gain. In this respect, dietary intake of high-caloric, high-fat diets due to chronic over-eating and sedentary lifestyle lead to increased storage of triglycerides not only in adipose tissue but also ectopically in other tissues . Increased plasma concentrations of non esterified free fatty acids and lipid-overloaded hypertrophic adipocytes may cause insulin resistance in an inflammation-independent manner. Even in the absence of metabolic disorders, mismatch between fatty acid uptake and utilization leads to the accumulation of toxic lipid species resulting in organ dysfunction. Lipid-induced apoptosis, ceramide accumulation, reactive oxygen species overproduction, endoplasmic reticulum stress, and mitochondrial dysfunction may play role in the pathogenesis of lipotoxicity. The hypothalamus senses availability of circulating levels of glucose, lipids and amino acids, thereby modifies feeding according to the levels of those molecules. However, the hypothalamus is also similarly vulnerable to lipotoxicity as the other ectopic lipid accumulated tissues. Chronic overnutrition most likely provides repetitive and persistent signals that up-regulate inhibitor of nuclear factor kappa B kinase beta subunit/nuclear factor kappa B (IKKbeta/NF-kappaB) in the hypothalamus before the onset of obesity. However, the mechanisms by which high fat diet induced peripheral signals affect the hypothalamic arcuate nucleus remain largely unknown. In this chapter, besides lipids and leptin, the role of glucose and insulin on specialized fuel-sensing neurons of hypothalamic neuronal circuits has been debated. PMID- 28585196 TI - Obesity, Persistent Organic Pollutants and Related Health Problems. AB - The present review aims to delve into persistent organic pollutants (POPs) , as xenobiotics, in correlation to human health. POPs exhibit a group of common characteristics, including lipophilicity, persistence to decomposition and bioaccumulation in tissues. POPs have been thoroughly studied by former researchers, as they offer a particular interest in the elucidation of metabolic, endocrine and immune perturbation caused by their synergy with intracellular mechanisms. Herein particular focus is attributed to the relationship of POPs with obesity provocation. Obesity nowadays receives epidemic dimensions, as its prevalence elevates in an exponential degree. POPs-induced obesity rotates around interfering in metabolic and endocrinal procedures and interacting with peroxisome-proliferator and retinoic receptors. Moreover, polymorphisms in CYP gene families exert a negative result, as they incapacitate detoxification of POPs. Obesity could be deemed as a multidimensional condition, as various factors interact to lead to an obesogenic result. Therefore, concomitant disorders may occur, from mild to lethal, and get intensified due to POPs exposure. POPs exact function mechanisms remain rather enigmatic, thus further investigation should be prospectively performed, for a more lucid picture of this issue, and, consequently for the establishment of alternative solutions. PMID- 28585197 TI - Human Protein Kinases and Obesity. AB - The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity, and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified by the target amino acid in their substrates. Some protein kinases can phosphorylate both serine/threonine, as well as tyrosine residues. This group of kinases has been known as dual specificity kinases. Unlike the dual specificity kinases, a heterogeneous group of protein phosphatases are known as dual-specificity phosphatases. These phosphatases remove phosphate groups from tyrosine and serine/threonine residues on their substrate. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases. The protein kinase-phosphoproteins interactions play an important role in obesity . In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signaling pathways mainly involve the nuclear factor kappa B (NF-kappaB) and the c-Jun N-terminal kinase (JNK) systems as well as the inhibitor of kappaB-kinase beta (IKK beta). Impairment of insulin signaling in obesity is largely mediated by the activation of the IKKbeta and the JNK. Furthermore, oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Additionally, obesity activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2alpha kinase (PERK) and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. Increase in intracellular oxidative stress can promote PKC-beta activation. Activated PKC-beta induces growth factor adapter Shc phosphorylation. Shc generated peroxides reduce mitochondrial oxygen consumption and enhances triglyceride accumulation. Obesity is fundamentally caused by cellular energy imbalance and dysregulation. Like adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), N-terminal Per-ARNT-Sim (PAS) kinase are nutrient responsive protein kinases and important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular level. Defective responses of AMPK to leptin may contribute to resistance to leptin action on food intake and energy expenditure in obese states. PMID- 28585198 TI - Fat Cell and Fatty Acid Turnover in Obesity. AB - The ratio of free fatty acid (FFA) turnover decreases significantly with the expansion of white adipose tissue. Adipose tissue and dietary saturated fatty acid levels significantly correlate with an increase in fat cell size and number. Inhibition of adipose triglyceride lipase leads to an accumulation of triglyceride, whereas inhibition of hormone-sensitive lipase leads to the accumulation of diacylglycerol. The G0/G1 switch gene 2 increases lipid content in adipocytes and promotes adipocyte hypertrophy through the restriction of triglyceride turnover. Excess triacylglycerols (TAGs), sterols and sterol esters are surrounded by the phospholipid monolayer surface and form lipid droplets. Following the release of lipid droplets from endoplasmic reticulum, cytoplasmic lipid droplets increase their volume either by local TAG synthesis or by homotypic fusion. The number and the size of lipid droplet distribution is correlated with obesity. Obesity-associated adipocyte death exhibits feature of necrosis-like programmed cell death. NOD-like receptors family pyrin domain containing 3 (NLRP3) inflammasome-dependent caspase-1 activation in hypertrophic adipocytes induces obese adipocyte death by pyroptosis. Actually adipocyte death may be a prerequisite for the transition from hypertrophic to hyperplastic obesity. Major transcriptional factors, CCAAT/enhancer-binding proteins beta and delta, play a central role in the subsequent induction of critical regulators, peroxisome-proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha and sterol regulatory element-binding protein 1, in the transcriptional control of adipogenesis in obesity.Collectively, in this chapter the concept of adipose tissue remodeling in response to adipocyte death or adipogenesis, and the complexity of lipid droplet interactions with the other cellular organelles are reviewed. Furthermore, in addition to lipid droplet growth, the functional link between the adipocyte-specific lipid droplet-associated protein and fatty acid turn-over is also debated. PMID- 28585200 TI - What Is Lipotoxicity? AB - Enlarged fat cells in obese adipose tissue diminish capacity to store fat and are resistant to the anti-lipolytic effect of insulin. Insulin resistance (IR) associated S-nitrosylation of insulin-signaling proteins increases in obesity. In accordance with the inhibition of insulin-mediated anti-lipolytic action, plasma free fatty acid (FFA) levels increase. Additionally, endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in adipocytes. Failure of packaging of excess lipid into lipid droplets causes chronic elevation of circulating fatty acids, which can reach to toxic levels within non-adipose tissues. Deleterious effects of lipid accumulation in non-adipose tissues are known as lipotoxicity. In fact, triglycerides may also serve a storage function for long-chain non-esterified fatty acids and their products such as ceramides and diacylglycerols (DAGs). Thus, excess DAG, ceramide and saturated fatty acids in obesity can induce chronic inflammation and have harmful effect on multiple organs and systems. In this context, chronic adipose tissue inflammation, mitochondrial dysfunction and IR have been discussed within the scope of lipotoxicity. PMID- 28585199 TI - Adipose Tissue Function and Expandability as Determinants of Lipotoxicity and the Metabolic Syndrome. AB - The adipose tissue organ is organised as distinct anatomical depots located all along the body axis and it is constituted of three different types of adipocytes : white, beige and brown which are integrated with vascular, immune, neural and extracellular stroma cells. These distinct adipocytes serve different specialised functions. The main function of white adipocytes is to ensure healthy storage of excess nutrients/energy and its rapid mobilisation to supply the demand of energy imposed by physiological cues in other organs, whereas brown and beige adipocytes are designed for heat production through uncoupling lipid oxidation from energy production. The concert action of the three type of adipocytes/tissues has been reported to ensure an optimal metabolic status in rodents. However, when one or multiple of these adipose depots become dysfunctional as a consequence of sustained lipid/nutrient overload, then insulin resistance and associated metabolic complications ensue. These metabolic alterations negatively affects the adipose tissue functionality and compromises global metabolic homeostasis. Optimising white adipose tissue expandability and its functional metabolic flexibility and/or promoting brown/beige mediated thermogenic activity counteracts obesity and its associated lipotoxic metabolic effects. The development of these therapeutic approaches requires a deep understanding of adipose tissue in all broad aspects. In this chapter we will discuss the characteristics of the different adipose tissue depots with respect to origins and precursors recruitment, plasticity, cellular composition and expandability capacity as well as molecular and metabolic signatures in both physiological and pathophysiological conditions. PMID- 28585201 TI - The Pathogenesis of Obesity-Associated Adipose Tissue Inflammation. AB - Obesity is characterized by a state of chronic, low-grade inflammation. However, excessive fatty acid release may worsen adipose tissue inflammation and contributes to insulin resistance. In this case, several novel and highly active molecules are released abundantly by adipocytes like leptin, resistin, adiponectin or visfatin, as well as some more classical cytokines. Most likely cytokines that are released by inflammatory cells infiltrating obese adipose tissue are such as tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) (CCL-2) and IL-1. All of those molecules may act on immune cells leading to local and generalized inflammation. In this process, toll-like receptor 4 (TLR4)/phosphatidylinositol-3'-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, the unfolded protein response (UPR) due to endoplasmic reticulum (ER) stress through hyperactivation of c-Jun N terminal Kinase (JNK) -Activator Protein 1 (AP1) and inhibitor of nuclear factor kappa-B kinase beta (IKKbeta)-nuclear factor kappa B (NF-kappaB) pathways play an important role, and may also affect vascular endothelial function by modulating vascular nitric oxide and superoxide release. Additionally, systemic oxidative stress, macrophage recruitment, increase in the expression of NOD-like receptor (NLR) family protein (NLRP3) inflammasone and adipocyte death are predominant determinants in the pathogenesis of obesity-associated adipose tissue inflammation. In this chapter potential involvement of these factors that contribute to the adverse effects of obesity are reviewed. PMID- 28585202 TI - Microbiota and Lipotoxicity. AB - Obesity and metabolic syndrome is a multisystemic disorder, that is characterized by excess caloric intake and spillover lipotoxicity caused by ectopic lipid accumulation in non-adipose tissues. Low grade chronic inflammation and insulin resistance are the hallmarks of the disorder, which further aggravate the condition. Gut microbiota constitutes an indispensible part of human superorganism's energy harvesting apparatus. The dynamic composition of microbiota changes with age, life style and host metabolic background. The wealth of genetic repertoire provided by these microorganism enables to extend host's substrate processing and harvesting capability. Some of these compounds including short chain fatty acids and indole act as signalling molecules on mammalian cells and modulate their behaviour. Nonetheless, this symbiotic style of interaction is restrained by immune system. The role of chronic low grade inflammation in metabolic syndrome is well established. Treg cells are the key players that sense and reshape the composition of microbiota. In this regard, any disturbance in Treg functionality may aggravate the inflammation and shift the symbiotic balance towards dysbiosis, which is characterized by autoimmunity and insulin resistance. Thus, immune system is responsible for the modulation of host and microbiota metabolisms and Treg cells act as a bridge in between. PMID- 28585203 TI - Endoplasmic Reticulum Stress and Obesity. AB - In recent years, the world has seen an alarming increase in obesity and closely associated with insulin resistance which is a state of low-grade inflammation, the latter characterized by elevated levels of proinflammatory cytokines in blood and tissues. A shift in energy balance alters systemic metabolic regulation and the important role that chronic inflammation, endoplasmic reticulum (ER) dysfunction, and activation of the unfolded protein response (UPR) play in this process.Why obesity is so closely associated with insulin resistance and inflammation is not understood well. This suggests that there are probably other causes for obesity-related insulin resistance and inflammation. One of these appears to be endoplasmic reticulum (ER) stress.The ER is a vast membranous network responsible for the trafficking of a wide range of proteins and plays a central role in integrating multiple metabolic signals critical in cellular homeostasis. Conditions that may trigger unfolded protein response activation include increased protein synthesis, the presence of mutant or misfolded proteins, inhibition of protein glycosylation, imbalance of ER calcium levels, glucose and energy deprivation, hypoxia, pathogens or pathogen-associated components and toxins. Thus, characterizing the mechanisms contributing to obesity and identifying potential targets for its prevention and treatment will have a great impact on the control of associated conditions, particularly T2D. PMID- 28585204 TI - Insulin Resistance, Obesity and Lipotoxicity. AB - Lipotoxicity , originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas and muscle. Lipotoxicity has roles in insulin resistance and pancreatic beta cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling, have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk and lipotoxicity seems to play a crucial role in the pathophysiology of these associations. PMID- 28585205 TI - Adipose Tissue Hypoxia in Obesity and Its Impact on Preadipocytes and Macrophages: Hypoxia Hypothesis. AB - Obese subjects exhibit lower adipose tissue oxygen consumption in accordance with the lower adipose tissue blood flow. Thus, compared with lean subjects, obese subjects have 44% lower capillary density and 58% lower vascular endothelial growth factor (VEGF). The VEGF expression together with hypoxia-inducible transcription factor-1 (HIF-1) activity also requires phosphatidylinositol 3 kinase (PI3K)- and target of rapamycin (TOR)-mediated signaling. HIF-1alpha is an important signaling molecule for hypoxia to induce the inflammatory responses. Hypoxia affects a number of biological functions, such as angiogenesis, cell proliferation, apoptosis, inflammation and insulin resistance. Additionally, reactive oxygen radical (ROS) generation at mitochondria is responsible for propagation of the hypoxic signal. Actually mitochondrial ROS (mtROS) production, but not oxygen consumption is required for hypoxic HIF-1alpha protein stabilization. Adipocyte mitochondrial oxidative capacity is reduced in obese compared with non-obese adults. In this respect, mitochondrial dysfunction of adipocyte is associated with the overall adiposity. Furthermore, hypoxia also inhibits macrophage migration from the hypoxic adipose tissue. Alterations in oxygen availability of adipose tissue directly affect the macrophage polarization and are responsible from dysregulated adipocytokines production in obesity. Hypoxia also inhibits adipocyte differentiation from preadipocytes. In addition to stressed adipocytes, hypoxia contributes to immune cell immigration and activation which further aggravates adipose tissue fibrosis. Fibrosis is initiated in response to adipocyte hypertrophy in obesity. PMID- 28585206 TI - Adipocyte-Macrophage Cross-Talk in Obesity. AB - Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte macrophage interaction has a primary importance in obesity. Large amounts of macrophages are accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway also promotes more macrophage accumulation into the obese adipose tissue. However, increased local extracellular lipid concentrations is a final mechanism for adipose tissue macrophage accumulation. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation; free fatty acid induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro inflammatory pathways in CD11c+ immune cells; are effective in macrophage accumulation and in the development of adipose tissue inflammation. Old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. The obesity-induced changes in adipose tissue macrophage numbers are mainly due to increases in the triple-positive CD11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2 macrophages is increased in obesity. Furthermore, hypoxia along with higher concentrations of free fatty acids exacerbates macrophage-mediated inflammation in obesity. The metabolic status of adipocytes is a major determinant of macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding proteins act at the interface of metabolic and inflammatory pathways. Both macrophages and adipocytes are the sites for active lipid metabolism and signaling. PMID- 28585207 TI - Endothelial Dysfunction in Obesity. AB - Chronic inflammatory state in obesity causes dysregulation of the endocrine and paracrine actions of adipocyte-derived factors, which disrupt vascular homeostasis and contribute to endothelial vasodilator dysfunction and subsequent hypertension. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Adipose tissue inflammation, nitric oxide (NO)-bioavailability, insulin resistance and oxidized low-density lipoprotein (oxLDL) are main participating factors in endothelial dysfunction of obesity. In this chapter, disruption of inter-endothelial junctions between endothelial cells, significant increase in the production of reactive oxygen species (ROS), inflammation mediators, which are originated from inflamed endothelial cells, the balance between NO synthesis and ROS , insulin signaling and NO production, and decrease in L arginine/endogenous asymmetric dimethyl-L-arginine (ADMA) ratio are discussed in connection with endothelial dysfunction in obesity. PMID- 28585208 TI - Diet-Induced Obesity and the Mechanism of Leptin Resistance. AB - Leptin signaling blockade by chronic overstimulation of the leptin receptor or hypothalamic pro-inflammatory responses due to elevated levels of saturated fatty acid can induce leptin resistance by activating negative feedback pathways. Although, long form leptin receptor (Ob-Rb) initiates leptin signaling through more than seven different signal transduction pathways, excessive suppressor of cytokine signaling-3 (SOCS-3) activity is a potential mechanism for the leptin resistance that characterizes human obesity. Because the leptin-responsive metabolic pathways broadly integrate with other neurons to control energy balance, the methods used to counteract the leptin resistance has extremely limited effect. In this chapter, besides the impairment of central and peripheral leptin signaling pathways, limited access of leptin to central nervous system (CNS) through blood-brain barrier, mismatch between high leptin and the amount of leptin receptor expression, contradictory effects of cellular and circulating molecules on leptin signaling, the connection between leptin signaling and endoplasmic reticulum (ER) stress and self-regulation of leptin signaling has been discussed in terms of leptin resistance. PMID- 28585209 TI - Influence of Antioxidants on Leptin Metabolism and its Role in the Pathogenesis of Obesity. AB - Obesity is associated with low-grade inflammation. Leptin, a hormone made by fat cells regulates appetite and hunger and thus food intake behavior. Interestingly, , food preservatives like sodium sulfite and sodium benzoate and also natural colorant and spice compounds such as curcumin were found to decrease the release of leptin in murine 3T3-L1 adipocytes, after co-incubation with LPS, which was added to mimic the pro-inflammatory status in obesity. Several of these compounds are well known food antioxidants.Whilst reducing oxidation events is beneficial in states of elevated oxidative stress, overexposure to food antioxidant can lead to adverse effects. There are hints from in vivo data, that antioxidant stress in younger age plays a role in the development of adiposity in later life. The insufficient exposure to oxidizing compounds like reactive oxygen species (ROS) cannot only cause an insufficient burning of calories but there is also a link to the regulation of food intake behavior. If the in vitro findings can be extrapolated to the in vivo situation, consumption of antioxidant supplemented food could lead to decreased leptin release and contribute to an obesogenic environment. This aspect sheds some new critical light on the potential role of an antioxidant-enriched nutrition in the obesity epidemic during the past few centuries. Doing sports could represent not only a proper strategy to initiate physiological ROS production and burning of calories, but also may shift the hormone milieu towards a reduction of hunger feelings and thus reduce appetite and food intake. PMID- 28585210 TI - Adiponectin-Resistance in Obesity. AB - The decrease in adiponectin levels are negatively correlated with chronic subclinical inflammation markers in obesity. The hypertrophic adipocytes cause obesity-linked insulin resistance and metabolic syndrome. Furthermore, macrophage polarization is a key determinant regulating adiponectin receptor (AdipoR1/R2) expression and differential adiponectin-mediated macrophage inflammatory responses in obese individuals. In addition to decrease in adiponectin concentrations, the decline in AdipoR1/R2 mRNA expression leads to a decrement in adiponectin binding to cell membrane, and this turns into attenuation in the adiponectin effects. Within the receptor complex, adaptor protein-containing pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is the intracellular binding partner of AdipoR1 and AdipoR2. The expression levels of APPL1 or APPL2 lead to an altered adiponectin activity. Despite normal or high adiponectin levels, an impaired post receptor signaling due to APPL1/APPL2 may alter adiponectin efficiency and activity. However, APPL2 blocks adiponectin signaling through AdipoR1 and AdipoR2 by competitive inhibition of APPL1. APPL1 is also an important mediator of adiponectin dependent insulin sensitization. In this context, adiponectin resistance is associated with insulin resistance and is thought to be partly due to the down-regulation of the AdipoRs in high-fat diet fed subjects. Actually, adiponectin resistance occurs very rapidly after saturated fatty acid feeding, this metabolic disturbance is not due to a decrease in AdipoR1 protein content. Intra-abdominal adipose tissue AdipoR2 expression is reduced in obesity, whereas AdipoR1 expression is not changed. Adiponectin resistance together with insulin resistance forms a vicious cycle. The elevated adiponectin levels with adiponectin resistance is a compensatory response in the condition of an unusual discordance between insulin resistance and adiponectin unresponsiveness.Additionally, different mechanisms are involved in vascular adiponectin resistance at different stages of obesity. Nevertheless, diet-induced hyperlipidemia is the leading cause of vascular adiponectin resistance. Leptin/adiponectin imbalance may also be an important marker of the elevated risk of developing abdominal obesity-associated cardiovascular diseases. PMID- 28585211 TI - Non-Alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic and it is the most common cause of liver diseases. The development of hepatic steatosis in majority of patients is linked to dietary fat ingestion. NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to both increased inflow of free fatty acids and de novo hepatic lipogenesis. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2) associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol, fatty acyl CoA or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/Non-alcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with rising saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in liver tissue of patients with NASH. Furthermore, hepatocyte lipoapoptosis is a critical feature of NASH. In "second hit" reduced glutathione levels due to oxidative stress lead to overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused by the ineffectual cycling of the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and Kelch like-ECH-associated protein 1 (Keap1)- Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. PMID- 28585212 TI - Lipotoxicity-Related Hematological Disorders in Obesity. AB - Lipotoxicity can mediate endothelial dysfunction in obesity. Altered endothelial cell phenotype during the pathobiological course of the lipotoxicity may lead to the hemostatic abnormalities, which is a hallmark of several hematological disorders. Impaired hemostasis could also be directly related to the numerous metabolic diseases such as hypertension, diabetes and atherosclerosis. On the other hand, local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) contributes to the development of atherosclerosis via acting on the lipotoxicity processes. Local BM RAS, principally an autocrine/ paracrine/ intracrinehematological system, is located at the crossroads of cellular regulation, molecular interactions and the lipotoxicity-mediated vascular endothelial dysfunction. The positive regulatory role of plasma LDL on AT1 receptor-mediated hematopoietic stem cell (HSC) differentiation and the production of pro-atherogenic monocytes had been described. LDL-regulated HSC function may explain in part hypercholesterolemia-induced inflammation as well as the anti-inflammatory and anti-atherosclerotic effects of AT1 receptor blockers. The role of local adipose tissue RAS is directly related to the pathogenesis of metabolic derangements in obesity. There may be a crosstalk between local BM RAS and local adipose tissue RAS at the genomics and transcriptomics levels. The aim of this chapter is to review hematological alterations propagating the pathological influences of lipotoxicity on the vascular endothelium. PMID- 28585213 TI - MicroRNA and Adipogenesis. AB - In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte selective microRNAs (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block expression of master regulators of adipogenesis. Additionally, specific miRNAs have been implicated in adipocyte differentiation and mature adipocyte functions. While, each miRNA targets multiple mRNAs, which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. In this respect, development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor associated factor 6 activity, lipolysis, lipotoxicity and insulin resistance are effectively controlled by miRNAs. PMID- 28585214 TI - The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity. AB - Obesity activates both innate and adaptive immune responses in adipose tissue. Elevated levels of eosinophils with depression of monocyte and neutrophil indicate the deficiencies in the immune system of morbidly obese individuals. Actually, adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-gamma)-producing CD4+ T cells in adipose tissue of obese subjects. Eventually, diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in visceral adipose tissue. Activity of inducible indoleamine 2,3-dioxygenase-1 (IDO-1) plays a major role under pro-inflammatory, IFN-gamma dominated settings. One of the two rate-limiting enzymes which can metabolize tryptophan to kynurenine is IDO-1. Tumor necrosis factor-alpha (TNF alpha) correlates with IDO-1 in adipose compartments. Actually, IDO-1-mediated tryptophan catabolism due to chronic immune activation is the cause of reduced tryptophan plasma levels and be considered as the driving force for food intake in morbidly obese patients. Thus, decrease in plasma tryptophan levels and subsequent reduction in serotonin (5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. However, after bariatric surgery, weight reduction does not lead to normalization of IDO-1 activity. Furthermore, there is a connection between arginine and tryptophan metabolic pathways in the generation of reactive nitrogen intermediates. Hence, abdominal obesity is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) availability. IFN-gamma-induced activation of the inducible nitric oxide synthase (iNOS) and dissociation of endothelial adenosine monophosphate activated protein kinase (AMPK)- phosphoinositide 3-kinase (PI3K) protein kinase B (Akt)- endothelial NO synthase (eNOS) pathway enhances oxidative stress production secondary to high-fat diet. Thus, reduced endothelial NO availability correlates with the increase in plasma non-esterified fatty acids and triglycerides levels. Additionally, in obese patients, folate-deficiency leads to hyperhomocysteinemia. Folic acid confers protection against hyperhomocysteinemia-induced oxidative stress. PMID- 28585215 TI - Eligibility and Success Criteria for Bariatric/Metabolic Surgery. AB - Obesity is a worldwide main health concern, with a high treatment failure. This chapter focuses on the definition of obesity, based on excessive fat accumulation and thus underscores the importance of body composition, and the clinical tools currently used to diagnose it, mainly body mass index that is only a proxy measure of body composition. It also highlights the importance of the personal commitment to comply to a healthy diet and physical activity recommendations since surgery is most effective when accompanied by lifestyle modifications. Additionally, it addresses the description of types of patients who could benefit most from surgical management of excessive body fat percentage and metabolic derangements, as well as on the indications for surgery that are currently valid. PMID- 28585216 TI - Does Bariatric Surgery Improve Obesity Associated Comorbid Conditions. AB - Obesity is a constantly growing health problem which reduces quality of life and life expectancy. Bariatric surgery for obesity is taken into account when all other conservative treatment modalities have failed. Comparison of the multidisciplinary programs with bariatric surgery regarding to weight loss showed that substantial and durable weight reduction have been achieved only with bariatric surgical treatments. However, the benefits of weight loss following bariatric procedures are still debated regarding the pro-inflammatory and metabolic profile of obesity. PMID- 28585217 TI - Obesity-associated Breast Cancer: Analysis of risk factors. AB - Several studies show that a significantly stronger association is obvious between increased body mass index (BMI) and higher breast cancer incidence. Furthermore, obese women are at higher risk of all-cause and breast cancer specific mortality when compared to non-obese women with breast cancer. In this context, increased levels of estrogens due to excessive aromatization activity of the adipose tissue, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factors (IGFs) pathways, adipocyte-derived adipokines, hypercholesterolemia and excessive oxidative stress contribute to the development of breast cancer in obese women. While higher breast cancer risk with hormone replacement therapy is particularly evident among lean women, in postmenopausal women who are not taking exogenous hormones, general obesity is a significant predictor for breast cancer. Moreover, increased plasma cholesterol leads to accelerated tumor formation and exacerbates their aggressiveness. In contrast to postmenopausal women, premenopausal women with high BMI are inversely associated with breast cancer risk. Nevertheless, life-style of women for breast cancer risk is regulated by avoiding the overweight and a high-fat diet. Estrogen plus-progestin hormone therapy users for more than 5 years have elevated risks of both invasive ductal and lobular breast cancer. Additionally, these cases are more commonly node-positive and have a higher cancer-related mortality. Collectively, in this chapter, the impacts of obesity-related estrogen, cholesterol, saturated fatty acid, leptin and adiponectin concentrations, aromatase activity, leptin and insulin resistance on breast cancer patients are evaluated. Obesity-related prognostic factors of breast cancer also are discussed at molecular basis. PMID- 28585218 TI - Lipotoxicity in Obesity: Benefit of Olive Oil. AB - The clinical implication of Lipotoxicity in obesity derives primarily from its potential to progress to insulin resistance, endothelial dysfunction and atherosclerosis. Olive oil rich diet decrease accumulation of triglyceride in the liver, improved postprandial triglyceride levels, improve glucose and GLP-1 response in insulin resistant subjects, and up regulate GLUT-2 expression in the liver. The exact molecular mechanism is unknown but, decreasing NFkB activation, decreasing LDL oxidation and improving insulin resistance by less production of inflammatory cytokines (TNF-a, IL-6) and improvement of kinases JNK-mediated phosphorylation of IRS-1 are the principle mechanisms. The beneficial effect of the Mediterranean diet derived from monounsaturated fatty acids (MUFA), mainly from olive oil. In this review we document lipotoxicity in obesity and the benefit of olive oil. PMID- 28585219 TI - PET/CT scanning with 3D acquisition is feasible for quantifying myocardial blood flow when diagnosing coronary artery disease. AB - BACKGROUND: The quantification of myocardial blood flow (MBF) and coronary flow reserve (CFR) are useful approaches for evaluating the functional severity of coronary artery disease (CAD). 15O-water positron emission tomography (PET) is considered the gold standard method for MBF quantification. However, MBF measurements in 15O-water PET with three-dimensional (3D) data acquisition, attenuation correction using computed tomography (CT), and time of flight have not been investigated in detail or validated. We conducted this study to evaluate the diagnostic potential of MBF measurements using PET/CT for a comparison of a control group and patients suspected of having CAD. RESULTS: Twenty-four patients with known or suspected CAD and eight age-matched healthy volunteers underwent rest and pharmacological stress perfusion studies with 15O-water PET/CT. The whole and three regional (left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA) territory) MBF values were estimated. The CFR was computed as the ratio of the MBF during adenosine triphosphate-induced stress to the MBF at rest. The inter-observer variability was assessed by two independent observers. PET/CT using a 15O-water dose of 500 MBq and 3D data acquisition showed good image quality. A strong inter-observer correlation was detected in both the whole MBF analysis and the regional analysis with high intra-class correlation coefficients (r > 0.90, p < 0.001). Regional MBF at rest (LAD, 0.82 +/- 0.15 ml/min/g; LCX, 0.83 +/- 0.17 ml/min/g; RCA, 0.71 +/- 0.20 ml/min/g; p = 0.74), MBF at stress (LAD, 3.77 +/- 1.00 ml/min/g; LCX, 3.56 +/- 1.01 ml/min/g; RCA, 3.27 +/- 1.04 ml/min/g; p = 0.62), and CFR (LAD, 4.64 +/- 0.90; LCX, 4.30 +/ 0.64; RCA, 4.64 +/- 0.96; p = 0.66) of the healthy volunteers showed no significant difference among the three regions. The global CFR of the patients was significantly lower than that of the volunteers (2.75 +/- 0.81 vs. 4.54 +/- 0.66, p = 0.0002). The regional analysis of the patients demonstrated that the CFR tended to be lower in the stenotic region compared to the non-stenotic region (2.43 +/- 0.81 vs. 2.95 +/- 0.92, p = 0.052). CONCLUSIONS: 15O-water PET/CT with 3D data acquisition can be reliably used for the quantification of functional MBF and CFR in CAD patients. PMID- 28585221 TI - Vagal Nerve Stimulation for Treatment-Resistant Depression. AB - Major depressive disorder (MDD) is prevalent. Although standards antidepressants are more effective than placebo, up to 35% of patients do not respond to 4 or more conventional treatments and are considered to have treatment-resistant depression (TRD). Considerable effort has been devoted to trying to find effective treatments for TRD. This review focuses on vagus nerve stimulation (VNS), approved for TRD in 2005 by the Food and Drugs Administration. Stimulation is carried by bipolar electrodes on the left cervical vagus nerve, which are attached to an implanted stimulator generator. The vagus bundle contains about 80% of afferent fibers terminating in the medulla, from which there are projections to many areas of brain, including the limbic forebrain. Various types of brain imaging studies reveal widespread functional effects in brain after either acute or chronic VNS. Although more randomized control trials of VNS need to be carried out before a definitive conclusion can be reached about its efficacy, the results of open studies, carried out over period of 1 to 2 years, show much more efficacy when compared with results from treatment as usual studies. There is an increase in clinical response to VNS between 3 and 12 months, which is quite different from that seen with standard antidepressant treatment of MDD. Preclinically, VNS affects many of the same brain areas, neurotransmitters (serotonin, norepinephrine) and signal transduction mechanisms (brain-derived neurotrophic factor-tropomyosin receptor kinase B) as those found with traditional antidepressants. Nevertheless, the mechanisms by which VNS benefits patients nonresponsive to conventional antidepressants is unclear, with further research needed to clarify this. PMID- 28585224 TI - Experimental setup for transfer function measurement to assess RF heating of medical leads in MRI: Validation in the case of a single wire. AB - PURPOSE: The measurement of the transfer function is a good tool to evaluate the radiofrequency heating of complex conductive wires, such as pacemaker leads. The aim is to describe precisely the design of a transfer function bench and compare the measurements to simulations. METHODS: The transfer function was measured by mean of an excitation probe and a receiving probe, both connected to a two-port vector network analyzer. The experimental results were compared with the simulated results, reproducing the excitation scheme. This procedure was applied to two different cables with different geometrical and insulation properties to test the robustness of the setup. RESULTS: It is possible to touch the cable electrode with the excitation probe without inducing an error in the measured transfer function, which solves the direct coupling problem. There is a good agreement between the measured and simulated transfer function for both tested cables. CONCLUSIONS: A valid transfer function measurement bench is described. Magn Reson Med 79:1766-1772, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28585222 TI - Potential Therapeutic Effects of Psilocybin. AB - Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. A small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms. PMID- 28585220 TI - Inherited Arterial Calcification Syndromes: Etiologies and Treatment Concepts. AB - PURPOSE OF REVIEW: We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS: Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes. PMID- 28585226 TI - Transient sex differences during adolescence on auditory perceptual tasks. AB - Many perceptual abilities differ between the sexes. Because these sex differences have been documented almost exclusively in adults, they have been attributed to sex-specific neural circuitry that emerges during development and is maintained in the mature perceptual system. To investigate whether behavioral sex differences in perception can also have other origins, we compared performance between males and females ranging in age from 8 to 30 years on auditory temporal interval discrimination and tone-in-noise detection tasks on which there are no sex differences in adults. If sex differences in perception arise only from the establishment and subsequent maintenance of sex-specific neural circuitry, there should be no sex differences during development on these tasks. In contrast, sex differences emerged in adolescence but resolved by adulthood on two of the six conditions, with signs of a similar pattern on a third condition. In each case, males reached mature performance earlier than females, resulting in a sex difference in the interim. These results suggest that sex differences in perception may arise from differences in the maturational timing of common circuitry used by both sexes. They also imply that sex differences in perceptual abilities may be more prevalent than previously thought based on adult data alone. PMID- 28585223 TI - A Molecular Tweezer Ameliorates Motor Deficits in Mice Overexpressing alpha Synuclein. AB - Aberrant accumulation and self-assembly of alpha-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar alpha-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble alpha-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic alpha-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type alpha-synuclein under control of the Thy 1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and alpha synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble alpha-synuclein in the striatum. Proteinase-K-resistant, insoluble alpha-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic alpha-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies. PMID- 28585225 TI - Ultrafast Growth of High-Quality Monolayer WSe2 on Au. AB - The ultrafast growth of high-quality uniform monolayer WSe2 is reported with a growth rate of ~26 um s-1 by chemical vapor deposition on reusable Au substrate, which is ~2-3 orders of magnitude faster than those of most 2D transition metal dichalcogenides grown on nonmetal substrates. Such ultrafast growth allows for the fabrication of millimeter-size single-crystal WSe2 domains in ~30 s and large area continuous films in ~60 s. Importantly, the ultrafast grown WSe2 shows excellent crystal quality and extraordinary electrical performance comparable to those of the mechanically exfoliated samples, with a high mobility up to ~143 cm2 V-1 s-1 and ON/OFF ratio up to 9 * 106 at room temperature. Density functional theory calculations reveal that the ultrafast growth of WSe2 is due to the small energy barriers and exothermic characteristic for the diffusion and attachment of W and Se on the edges of WSe2 on Au substrate. PMID- 28585227 TI - Developing guinea pig brain as a model for cortical folding. AB - The cerebral cortex in mammals, the neocortex specifically, is highly diverse among species with respect to its size and morphology, likely reflecting the immense adaptiveness of this lineage. In particular, the pattern and number of convoluted ridges and fissures, called gyri and sulci, respectively, on the surface of the cortex are variable among species and even individuals. However, little is known about the mechanism of cortical folding, although there have been several hypotheses proposed. Recent studies on embryonic neurogenesis revealed the differences in cortical progenitors as a critical factor of the process of gyrification. Here, we investigated the gyrification processes using developing guinea pig brains that form a simple but fundamental pattern of gyri. In addition, we established an electroporation-mediated gene transfer method for guinea pig embryos. We introduce the guinea pig brain as a useful model system to understand the mechanisms and basic principle of cortical folding. PMID- 28585228 TI - Development and testing of a stepwise thaw and dilute protocol for cryopreserved umbilical cord blood units. AB - BACKGROUND: It is clinically important to maintain high viability and potency of umbilical cord blood units (CBUs) for transplantation during thawing. In the absence of a standard thawing protocol, this study was designed to develop one based on the consensus practice of transplant centers and address the shortage of dextran 40 thawing solution. STUDY DESIGN AND METHODS: Frozen CBU aliquots were thawed using dextran 40 thawing solution while manipulating temperature and volume of diluent and mode of dilution. The effects of these on CD45+ and CD34+ cell viability were measured through annexin V and SYTOX green staining. The developed protocol was then used to compare dextran 40 and PLASMA-LYTE A thawing solutions and finally tested on whole CBUs. RESULTS: Step-by-step investigations resulted in the development of a protocol that thaws and dilutes CBUs with room temperature diluent to five times the original volume using two sequential dilutions separated by equilibration times. PLASMA-LYTE A diluent provided superior viability of CD45+ and CD34+ cells than dextran 40 and recovered more colony-forming units. However, both diluents were equally effective in maintaining stability of the thawed CBU for 4 hours. Moreover, the stem cell enriched CD34+CD38- subpopulations appeared more resistant to cryoinjuries than their CD34+CD38+ counterpart. CONCLUSION: The developed thawing protocol recovers viable CD45+ and CD34+ cells above the standard thresholds and maintains CBU potency. PLASMA-LYTE A for thawing solution proved to be an efficient alternative to dextran 40. Finally, greater dilution should be avoided to maintain the viability of CD45+ cells and maximize graft cell dose. PMID- 28585229 TI - Tomoelastography of the prostate using multifrequency MR elastography and externally placed pressurized-air drivers. AB - PURPOSE: To demonstrate the feasibility of in vivo multifrequency magnetic resonance elastography (MRE) of the prostate using externally placed drivers. METHODS: Three pressurized-air drivers were used to excite shear waves within the prostate at vibration frequencies of 60, 70, and 80 Hz. Full 3D wave fields were acquired by multislice spin-echo echo-planar imaging in conjunction with tomoelastography wave speed recovery for generating full field-of-view stiffness maps. Twelve healthy volunteers were repeatedly scanned to analyze test-retest reproducibility. Five patients with suspected prostate cancer were investigated to demonstrate the clinical feasibility of the method. RESULTS: In healthy volunteers, the shear wave speed of the entire prostate was 2.24 +/- 0.20 m/s with a repeatability coefficient of 0.14 m/s and 88% intraclass correlation coefficient. No significant difference between the peripheral zone (2.27 +/- 0.20 m/s) and the central gland (2.22 +/- 0.23 m/s) was observed. In patients, wave speed maps displayed stiff regions consistent with the localization of suspicious masses detected by other imaging markers. CONCLUSIONS: The proposed method provides reproducible quantitative maps of tissue stiffness throughout the pelvic region and can easily be integrated into clinical imaging protocols. Clinical stiffness maps display many details of potential interest for cancer diagnosis. Magn Reson Med 79:1325-1333, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28585230 TI - A Molecular Polycrystalline Ferroelectric with Record-High Phase Transition Temperature. AB - An outstanding advantage of inorganic ceramic ferroelectrics is their usability in the polycrystalline ceramic or thin film forms, which has dominated applications in the ferroelectric, dielectric, and piezoelectric fields. Although the history of ferroelectrics began with the molecular ferroelectric Rochelle salt in 1921, so far there have been very few molecular ferroelectrics, with lightweight, flexible, low-cost, and biocompatible superior properties compared to inorganic ceramic ferroelectrics, that can be applied in the polycrystalline form. Here, a multiaxial molecular ferroelectric, guanidinium perchlorate ([C(NH2 )3 ]ClO4 ), with a record-high phase transition temperature of 454 K is presented. It is the rectangular polarization-electric field (P-E) hysteresis loops recorded on the powder and thin film samples (with respective large Pr of 5.1 and 8.1 uC cm-2 ) that confirm the ferroelectricity of [C(NH2 )3 ]ClO4 in the polycrystalline states. Intriguingly, after poling, the piezoelectric coefficient (d33 ) of the powder sample shows a significant increase from 0 to 10 pC N-1 , comparable to that of LiNbO3 single crystal (8 pC N-1 ). This is the first time that such a phenomenon has been observed in molecular ferroelectrics, indicating the great potential of molecular ferroelectrics being used in the polycrystalline form like inorganic ferroelectrics, as well as being viable alternatives or supplements to conventional ceramic ferroelectrics. PMID- 28585231 TI - The Employers' perspective on barriers and facilitators to employment of people with intellectual disability: A differential mixed-method approach. AB - BACKGROUND: Obtaining employment is among the most important ambitions of people with intellectual disability. Progress towards comprehensive inclusive employment is hampered by numerous barriers. Limited research is available on these barriers and strategies to overcome them. METHOD: A mixed method approach in a sample of 30 HR-managers was used to assess (i) differences in perceived barriers for employment of people with specific disabilities and mental disorders; (ii) barriers specific to employing people with intellectual disability; (iii) strategies to overcome these barriers. RESULTS: Employers perceive more barriers for hiring people with intellectual disability and mental disorders than for physical disabilities. Employment for this population is hampered by a perceived lack of skills and legal issues. Strategies perceived as beneficial are supplying information, changes in organizational strategies and legal changes. CONCLUSIONS: Employers' differentiated expectations and reservations towards hiring individuals with specific disabilities need to be taken into account to increase employment for people with intellectual disability. PMID- 28585233 TI - Progress in the blood supply of Afghanistan. AB - BACKGROUND: The blood supply system in Afghanistan was badly damaged by years of conflict. In 2009, the Afghanistan National Blood Safety and Transfusion Service (ANBSTS) was established. STUDY DESIGN AND METHODS: For 6 years, we collaborated to assist with policy and infrastructure development; blood bank operations; blood collection, testing, and component production; transfusion practices; and training of technicians, nurses, midwives, and physicians. RESULTS: Policies were established, infrastructure was strengthened, and capable staff was acquired and trained. Standard operating procedures were developed, testing was improved, and quality systems were established. Thirty trainings were held for blood center staff. Four additional formal trainings were held for 39 physicians, 36 nurses and/or midwives, and 38 laboratory technicians. During 5 years of this project, blood collection increased by 40%. CONCLUSION: The ANBSTS has made impressive progress developing infrastructure, personnel, procedures, quality systems, and training programs and increasing blood collection. Knowledge of transfusion medicine was improved through structured training. PMID- 28585234 TI - Interpulse phase corrections for unbalanced pseudo-continuous arterial spin labeling at high magnetic field. AB - PURPOSE: To evaluate a prescan-based radiofrequency phase-correction strategy for unbalanced pseudo-continuous arterial spin labeling (pCASL) at 9.4 T in vivo and to test its robustness toward suboptimal shim conditions. METHODS: Label and control interpulse phases were optimized separately by means of two prescans in rats. The mean perfusion as well as the interhemispherical symmetry were measured for several phase combinations (optimized versus theoretical phases) to evaluate the correction quality. Interpulse phases were also optimized under degraded shim conditions (i.e., up to four times the study shim values) to test the strategy's robustness. RESULTS: For all tested shim conditions, the full arterial spin labeling (ASL) signal could be restored. Without any correction, the relative ASL signal was 1.4 +/- 1.7%. It increased to 3.6 +/- 1.4% with an optimized label phase and to 5.3 +/- 1.2% with optimized label and control phases. Moreover, asymmetry between brain hemispheres, which could be as high as 100% without phase optimization, was dramatically reduced to 1 +/- 3% when applying optimized label and control phases. CONCLUSIONS: Pseudo-continuous ASL at high magnetic field is very sensitive to shim conditions. Label and control radiofrequency phase optimization based on prescans robustly maximizes the ASL signal obtained with unbalanced pCASL and minimizes the asymmetry between hemispheres. Magn Reson Med 79:1314-1324, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28585232 TI - In vitro-in silico-based analysis of the dose-dependent in vivo oestrogenicity of the soy phytoestrogen genistein in humans. AB - BACKGROUND AND PURPOSE: The in vivo oestrogenicity of genistein and its glycoside genistin is still under debate. The present study aimed to develop a physiologically based kinetic (PBK) model that provides insight in dose-dependent plasma concentrations of genistein aglycone and its metabolites and enables prediction of in vivo oestrogenic effective dose levels of genistein and genistin in humans. EXPERIMENTAL APPROACH: A PBK model for genistein and genistin in humans was developed based on in vitro metabolic parameters. The model obtained was used to translate in vitro oestrogenic concentration-response curves of genistein to in vivo oestrogenic dose-response curves for intake of genistein and genistin. KEY RESULTS: The model predicted that genistein-7-O-glucuronide was the major circulating metabolite and that levels of the free aglycone were generally low [0.5-17% of total plasma genistein at oral doses from 0.01 to 50 mg (kg.bw)-1 ]. The predicted in vivo benchmark dose for 5% response values for oestrogenicity varied between 0.06 and 4.39 mg kg-1 genistein. For genistin, these values were 1.3-fold higher. These values are in line with reported human data and show that oestrogenic responses can be expected at an Asian dietary and a supplementary intake, while intake resulting from a Western diet may not be effective. CONCLUSIONS AND IMPLICATIONS: The present study shows how plasma concentrations of genistein and its metabolites and oestrogenic dose levels of genistein in humans can be predicted by combining in vitro oestrogenicity with PBK model-based reverse dosimetry, eliminating the need for human intervention studies. PMID- 28585235 TI - Synthesis of Ultrathin PdCu Alloy Nanosheets Used as a Highly Efficient Electrocatalyst for Formic Acid Oxidation. AB - Inspired by the unique properties of ultrathin 2D nanomaterials and excellent catalytic activities of noble metal nanostructures for renewable fuel cells, a facile method is reported for the high-yield synthesis of ultrathin 2D PdCu alloy nanosheets under mild conditions. Impressively, the obtained PdCu alloy nanosheet after being treated with ethylenediamine can be used as a highly efficient electrocatalyst for formic acid oxidation. The study implicates that the rational design and controlled synthesis of an ultrathin 2D noble metal alloy may open up new opportunities for enhancing catalytic activities of noble metal nanostructures. PMID- 28585237 TI - Role of tree size in moist tropical forest carbon cycling and water deficit responses. AB - Drought disproportionately affects larger trees in tropical forests, but implications for forest composition and carbon (C) cycling in relation to dry season intensity remain poorly understood. In order to characterize how C cycling is shaped by tree size and drought adaptations and how these patterns relate to spatial and temporal variation in water deficit, we analyze data from three forest dynamics plots spanning a moisture gradient in Panama that have experienced El Nino droughts. At all sites, aboveground C cycle contributions peaked below 50-cm stem diameter, with stems >= 50 cm accounting for on average 59% of live aboveground biomass, 45% of woody productivity and 49% of woody mortality. The dominance of drought-avoidance strategies increased interactively with stem diameter and dry season intensity. Although size-related C cycle contributions did not vary systematically across the moisture gradient under nondrought conditions, woody mortality of larger trees was disproportionately elevated under El Nino drought stress. Thus, large (> 50 cm) stems, which strongly mediate but do not necessarily dominate C cycling, have drought adaptations that compensate for their more challenging hydraulic environment, particularly in drier climates. However, these adaptations do not fully buffer the effects of severe drought, and increased large tree mortality dominates ecosystem-level drought responses. PMID- 28585236 TI - Melatonin in regulation of inflammatory pathways in rheumatoid arthritis and osteoarthritis: involvement of circadian clock genes. AB - Rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most prevalent joint diseases. A such, they are important causes of pain and disability in a substantial proportion of the human population. A common characteristic of these diseases is the erosion of articular cartilage and consequently joint dysfunction. Melatonin has been proposed as a link between circadian rhythms and joint diseases including RA and OA. This hormone exerts a diversity of regulatory actions through binding to specific receptors and intracellular targets as well as having receptor-independent actions as a free radical scavenger. Cytoprotective effects of melatonin involve a myriad of prominent receptor mediated pathways/molecules associated with inflammation, of which the role of omnipresent NF-kappaB signalling is crucial. Likewise, disturbance of circadian timekeeping is closely involved in the aetiology of inflammatory arthritis. Melatonin is shown to stimulate cartilage destruction/regeneration through direct/indirect modulation of the expression of the main circadian clock genes, such as BMAL, CRY and/or DEC2. In the current article, we review the effects of melatonin on RA and OA, focusing on its ability to regulate inflammatory pathways and circadian rhythms. We also review the possible protective effects of melatonin on RA and OA pathogenesis. PMID- 28585238 TI - Three-dimensional mapping of brain venous oxygenation using R2* oximetry. AB - PURPOSE: Cerebral venous oxygenation (Yv ) is an important biomarker for brain diseases. This study aims to develop an R2*-based MR oximetry that can measure cerebral Yv in 3D. METHODS: This technique separates blood signal from tissue by velocity-encoding phase contrast and measures the R2* of pure blood by multi gradient-echo acquisition. The blood R2* was converted to Yv using an R2*-versus oxygenation (Y) calibration curve, which was obtained by in vitro bovine blood experiments. Reproducibility, sensitivity, validity, and resolution dependence of the technique were evaluated. RESULTS: In vitro R2*-Y calibration plot revealed a strong dependence of blood R2* on oxygenation, with additional dependence on hematocrit. In vivo results demonstrated that the technique can provide a 3D venous oxygenation map that depicts both large sinuses and smaller cortical veins, with venous oxygenation ranging from 57 to 72%. Intrasession coefficient of variation of the measurement was 3.0%. The technique detected an average Yv increase of 10.8% as a result of hyperoxia, which was validated by global oxygenation measurement from T2 -Relaxation-Under-Spin-Tagging (TRUST) MRI. Two spatial resolutions, one with an isotropic voxel dimension and the other with a nonisotropic dimension, were tested for full brain coverage. CONCLUSIONS: This study demonstrated the feasibility of 3D brain oxygenation mapping without using contrast agent. Magn Reson Med 79:1304-1313, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28585239 TI - Modulation of Metal and Insulator States in 2D Ferromagnetic VS2 by van der Waals Interaction Engineering. AB - 2D transition-metal dichalcogenides (TMDCs) are currently the key to the development of nanoelectronics. However, TMDCs are predominantly nonmagnetic, greatly hindering the advancement of their spintronic applications. Here, an experimental realization of intrinsic magnetic ordering in a pristine TMDC lattice is reported, bringing a new class of ferromagnetic semiconductors among TMDCs. Through van der Waals (vdW) interaction engineering of 2D vanadium disulfide (VS2 ), dual regulation of spin properties and bandgap brings about intrinsic ferromagnetism along with a small bandgap, unravelling the decisive role of vdW gaps in determining the electronic states in 2D VS2 . An overall control of the electronic states of VS2 is also demonstrated: bond-enlarging triggering a metal-to-semiconductor electronic transition and bond-compression inducing metallization in 2D VS2 . The pristine VS2 lattice thus provides a new platform for precise manipulation of both charge and spin degrees of freedom in 2D TMDCs availing spintronic applications. PMID- 28585240 TI - Agency, social and healthcare supports for adults with intellectual disability at the end of life in out-of-home, non-institutional community residences in Western nations: A literature review. AB - BACKGROUND: The nature and quality of end-of-life care received by adults with intellectual disabilities in out-of-home, non-institutional community agency residences in Western nations is not well understood. METHOD: A range of databases and search engines were used to locate conceptual, clinical and research articles from relevant peer-reviewed journals. RESULTS: The present authors present a literature review of the agency, social and healthcare supports that impact end-of-life care for adults with intellectual disabilities. More information is needed about where people with intellectual disabilities are living at the very end of life and where they die. CONCLUSIONS: The support needs for adults with intellectual disabilities will change over time, particularly at the end of life. There are some areas, such as removing barriers to providing services, staff training, partnerships between agencies and palliative care providers, and advocacy, where further research may help to improve the end-of life care for adults with intellectual disabilities. PMID- 28585241 TI - Reduced alpha4 subunit expression in alpha4+- and alpha4+- /beta2+- nicotinic acetylcholine receptors alters alpha4beta2 subtype up-regulation following chronic nicotine treatment. AB - BACKGROUND AND PURPOSE: Genomic analysis has shown many variants in both CHRNA4 and CHRNB2, genes which encode the alpha4 and beta2 subunits of nicotinic ACh receptors (nAChR) respectively. Some variants influence receptor expression, raising the possibility that CHRNA4 variants may affect response to tobacco use in humans. Chronic exposure to nicotine increases expression of nAChRs, particularly alpha4beta2-nAChRs, in humans and laboratory animals. Here, we have evaluated whether the initial level of receptor expression affects the increase in expression. EXPERIMENTAL APPROACH: Mice differing in expression of alpha4 and/or beta2 nAChR subunits were chronically treated with saline, 0.25, 1.0 or 4.0 mg.kg-1 .h-1 nicotine. Brain preparations were analysed autoradiographically by [125 I]-epibatidine binding, immunoprecipitation and Western blotting. KEY RESULTS: Immunochemical studies confirmed that most of the [3 H]-epibatidine binding corresponds to alpha4beta2*-nAChR and that increases in binding correspond to increases in alpha4 and beta2 proteins. Consistent with previous reports, the dose-dependent increase in nAChR in wild-type mice following chronic nicotine treatment, measured with any of the methods, reached a maximum. Although receptor expression was reduced by approximately 50% in beta2+- mice, the pattern of response to chronic treatment resembled that of wild-type mice. In contrast, both alpha4+- and alpha4+- /beta2+- exhibited relatively greater up-regulation. Consistent with previous reports, alpha4beta2alpha5-nAChR did not increase in response to nicotine. CONCLUSIONS AND IMPLICATIONS: These results indicate that mice with reduced expression of the alpha4 nAChR subunit have a more robust response to chronic nicotine than mice with normal expression of this subunit. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc. PMID- 28585243 TI - Root apical meristem diversity in extant lycophytes and implications for root origins. AB - Root apical meristem (RAM) organization in lycophytes could be a key to understanding the early evolution of roots, but this topic has been insufficiently explored. We examined the RAM organization of lycophytes in terms of cell division activities and anatomies, and compared RAMs among vascular plants. RAMs of 13 species of lycophytes were semi-thin-sectioned and observed under a light microscope. Furthermore, the frequency of cell division in the RAM of species was analyzed using thymidine analogs. RAMs of lycophytes exhibited four organization types: type I (Lycopodium and Diphasiastrum), II (Huperzia and Lycopodiella), III (Isoetes) and RAM with apical cell (Selaginella). The type I RAM found in Lycopodium had a region with a very low cell division frequency, reminiscent of the quiescent center (QC) in angiosperm roots. This is the first clear indication that a QC-like region is present in nonseed plants. At least four types of RAM are present in extant lycophytes, suggesting that RAM organization is more diverse than expected. Our results support the paleobotanical hypothesis that roots evolved several times in lycophytes, as well as in euphyllophytes. PMID- 28585242 TI - Addressing unmet needs of patients with chronic diseases: Impact of the VISIT website during consultations. AB - RATIONALE, AIMS, AND OBJECTIVES: Patient concerns are often neglected in consultations, especially for chronic diseases where patients and providers fall into the routine of chronic disease management in consultations. One strategy to elicit patient concerns has been to ask patients to complete agenda lists before the consultation. This study aimed to explore the impact of a preconsultation agenda website in addressing patients' unmet needs during chronic disease consultations. METHODS: Patients entered their concerns into a website (Values In Shared Interactions Tool (VISIT)). Doctors accessed this information via the electronic medical records before consultations. Individual in-depth interviews were then conducted with patients and doctors on the website's impact on consultations. Interviews were transcribed verbatim and analysed thematically. RESULTS: The average age (years) was 65.7 for patients (n = 8) and 35.7 for doctors (n = 7). Patients in the study entered between 1 to 6 items in the website. From postconsultation interviews, we found that the website impacted the consultation in 5 ways: (1) It facilitated patients to communicate their full agenda to doctors; (2) it helped address unmet patient needs as it gave them opportunity to raise other issues besides their chronic condition; (3) it facilitated rapport between doctor and patient; (4) it facilitated doctors to organize their consultation around the concerns the patient had listed; and (5) it disrupted the doctor's usual consultation style if the list of concerns was lengthy. CONCLUSIONS: Integrating patient concerns into electronic health records helped to facilitate patient-centred consultations. Doctors found this information useful but felt uneasy if the agenda list was too long or too complex. Areas for future studies include training doctors to manage complex agendas and formal evaluation of the VISIT tool. PMID- 28585244 TI - Characterization of phenolic composition in Carignan noir grapes (Vitis vinifera L.) from six wine-growing sites in Maule Valley, Chile. AB - BACKGROUND: Among Chilean varieties, Carignan noir has had a major resurgence due to its rediscovered wine quality potential. For this, the aim of this study was to characterize phenolic composition of grapes grown in six sites from the Maule Valley. RESULTS: The data showed that myricetin-3-glc and catechin were the most important flavonol and flavanol, respectively. Anthocyanin and flavonol composition was correlated with biologically effective degree days, exhibiting a relationship with grape maturity. Flavanol and hydroxycinnamic acid composition was inversely correlated to the average maximum temperature of the warmest month, showing that their synthesis is favored by cooler temperatures during the warmest month. CONCLUSION: These results have enological and viticultural interest for grape growers as vineyard site selection for this cultivar can confer differentiable attributes in terms of grape composition and quality. On the other hand, understanding the effects of climate on the synthesis of phenolic compounds may be useful for managing the vineyards with the aim of improving grape quality. (c) 2017 Society of Chemical Industry. PMID- 28585245 TI - Improved confidence interval for average annual percent change in trend analysis. AB - This paper considers an improved confidence interval for the average annual percent change in trend analysis, which is based on a weighted average of the regression slopes in the segmented line regression model with unknown change points. The performance of the improved confidence interval proposed by Muggeo is examined for various distribution settings, and two new methods are proposed for further improvement. The first method is practically equivalent to the one proposed by Muggeo, but its construction is simpler, and it is modified to use the t-distribution instead of the standard normal distribution. The second method is based on the empirical distribution of the residuals and the resampling using a uniform random sample, and its satisfactory performance is indicated by a simulation study. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585246 TI - Confining the Nucleation of Pt to In Situ Form (Pt-Enriched Cage)@CeO2 Core@Shell Nanostructure as Excellent Catalysts for Hydrogenation Reactions. AB - Ultrathin (Pt-enriched cage)@CeO2 core@shell nanostructures are successfully fabricated via a facile hard-template method. It is found that the usage of Pd@Ag@CeO2 bi-metallic core@shell nanostructure as the hard template plays an important role in avoiding the independent nucleation of Pt metal during the galvanic replacement process between K2 PtCl4 and Ag components. This unique core@shell samples show extraordinary activity and selectivity for the cinnamaldehyde hydrogenation reaction. It can achieve over 95% conversion with 87% selectivity of hydrocinnamaldehyde in 5 h under 1 atm H2 pressure. It is considered that such high catalytic performance could be attributed to the densely CeO2 -coated core@shell hybrid form as well as the ultrathin nature of the Pt-enriched cage. PMID- 28585248 TI - Specific PCR detection of Fusarium oxysporum f. sp. raphani: a causal agent of Fusarium wilt on radish plants. AB - : Fusarium oxysporum, a causal agent of Fusarium wilt, is one of the most important fungal pathogens worldwide, and detection of F. oxysporum DNA at the forma specialis level is crucial for disease diagnosis and control. In this study, two novel F. oxysporum f. sp. raphani (For)-specific primer sets were designed, FOR1-F/FOR1-R and FOR2-F/FOR2-R, to target FOQG_17868 and FOQG_17869 ORFs, respectively, which were selected based on the genome comparison of other formae speciales of F. oxysporum including conglutinans, cubense, lycopersici, melonis, and pisi. The primer sets FOR1-F/FOR1-R and FOR2-F/FOR2-R that amplified a 610- and 425-bp DNA fragment, respectively, were specific to For isolates which was confirmed using a total of 40 F. oxysporum isolates. From infected plants, the FOR2-F/FOR2-R primer set directly detected the DNA fragment of For isolates even when the radish plants were collected in their early stage of disease development. Although the loci targeted by the For-specific primer sets were not likely involved in the pathogenesis, the primer set FOR2-F/FOR2-R is available for the determination of pathogenicity of radish-infecting F. oxysporum isolates. This study is the first report providing novel primer sets to detect F. oxysporum f. sp. raphani. SIGNIFICANCE AND IMPACT OF THE STUDY: Because plant pathogenic Fusarium oxysporum has been classified into special forms based on its host specificity, identification of F. oxysporum usually requires a pathogenicity assay as well as knowledge of the morphological characteristics. For rapid and reliable diagnosis, this study provides PCR primer sets that specifically detect Fusarium oxysporum f. sp. raphani (For) which is a devastating pathogen of radish plants. Because one of the primer sets directly detected the DNA fragment of For isolates from infected plants, the specific PCR method demonstrated in this study will provide a foundation for integrated disease management practices in commodity crops. PMID- 28585247 TI - Tunable Photocontrolled Motions Using Stored Strain Energy in Malleable Azobenzene Liquid Crystalline Polymer Actuators. AB - A new strategy for enhancing the photoinduced mechanical force is demonstrated using a reprocessable azobenzene-containing liquid crystalline network (LCN). The basic idea is to store mechanical strain energy in the polymer beforehand so that UV light can then be used to generate a mechanical force not only from the direct light to mechanical energy conversion upon the trans-cis photoisomerization of azobenzene mesogens but also from the light-triggered release of the prestored strain energy. It is shown that the two mechanisms can add up to result in unprecedented photoindued mechanical force. Together with the malleability of the polymer stemming from the use of dynamic covalent bonds for chain crosslinking, large-size polymer photoactuators in the form of wheels or spring-like "motors" can be constructed, and, by adjusting the amount of prestored strain energy in the polymer, a variety of robust, light-driven motions with tunable rolling or moving direction and speed can be achieved. The approach of prestoring a controllable amount of strain energy to obtain a strong and tunable photoinduced mechanical force in azobenzene LCN can be further explored for applications of light-driven polymer actuators. PMID- 28585249 TI - Closure of the vertebral canal in human embryos and fetuses. AB - The vertebral column is the paradigm of the metameric architecture of the vertebrate body. Because the number of somites is a convenient parameter to stage early human embryos, we explored whether the closure of the vertebral canal could be used similarly for staging embryos between 7 and 10 weeks of development. Human embryos (5-10 weeks of development) were visualized using Amira 3D(r) reconstruction and Cinema 4D(r) remodelling software. Vertebral bodies were identifiable as loose mesenchymal structures between the dense mesenchymal intervertebral discs up to 6 weeks and then differentiated into cartilaginous structures in the 7th week. In this week, the dense mesenchymal neural processes also differentiated into cartilaginous structures. Transverse processes became identifiable at 6 weeks. The growth rate of all vertebral bodies was exponential and similar between 6 and 10 weeks, whereas the intervertebral discs hardly increased in size between 6 and 8 weeks and then followed vertebral growth between 8 and 10 weeks. The neural processes extended dorsolaterally (6th week), dorsally (7th week) and finally dorsomedially (8th and 9th weeks) to fuse at the midthoracic level at 9 weeks. From there, fusion extended cranially and caudally in the 10th week. Closure of the foramen magnum required the development of the supraoccipital bone as a craniomedial extension of the exoccipitals (neural processes of occipital vertebra 4), whereas a growth burst of sacral vertebra 1 delayed closure until 15 weeks. Both the cranial- and caudal-most vertebral bodies fused to form the basioccipital (occipital vertebrae 1-4) and sacrum (sacral vertebrae 1-5). In the sacrum, fusion of its so-called alar processes preceded that of the bodies by at least 6 weeks. In conclusion, the highly ordered and substantial changes in shape of the vertebral bodies leading to the formation of the vertebral canal make the development of the spine an excellent, continuous staging system for the (human) embryo between 6 and 10 weeks of development. PMID- 28585251 TI - TFE3-rearranged hepatic epithelioid hemangioendothelioma-a case report with immunohistochemical and molecular study. AB - A recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1-negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver. We present the first case of TFE3-rearranged hepatic epithelioid hemangioendothelioma in a 39-year-old Taiwanese woman. Computed tomography scan revealed multifocal, ill-defined nodules involving both hepatic lobes. She then underwent deceased donor liver transplantation. Histologically, the tumors in the liver explant showed a biphasic growth pattern. One component was composed of dilated and well-formed blood vessels lined by epithelioid cells with abundant eosinophilic cytoplasm, mimicking an alveolar pattern, whereas the other component was composed of cords and single cells, featuring intracytoplasmic vacuoles, separated by a myxoid stroma. The tumor cells showed vesicular nuclei and small indistinct nucleoli with mild to moderate cytologic atypia. Most tumor cells showed factor VIII, CD34, CD31, and TFE3 positivity in immunohistochemical study. Fluorescence in situ hybridization analysis for the tumor cells exhibited TFE3 gene rearrangement. The patient is currently alive, and no post-operative tumor recurrence developed during a 13-year follow-up. Awareness of this rare vasoformative variant and identification of the gene rearrangement would be helpful on differential diagnosis with other high-grade carcinoma and angiosarcoma of liver. PMID- 28585252 TI - Polysaccharides, oligosaccharides and nitrogenous compounds change during the ageing of Tempranillo and Verdejo sparkling wines. AB - BACKGROUND: Verdejo and Tempranillo are traditional varieties for producing still wines; however, they could provide an alternative for the manufacturing of sparkling wines. Sparkling wines were elaborated by the traditional method, followed by ageing on lees for 9 months. A study on the changes that take place in polysaccharides, oligosaccharides and nitrogenous compounds during the ageing on lees of Tempranillo and Verdejo sparkling wines has been undertaken. RESULTS: Mannoproteins and the glucose residue of oligosaccharides were the major carbohydrates detected in all vinification stages. Yeast polysaccharides and glucan-like structures of the oligosaccharides increased after 3 months of ageing. The evolution of yeast polysaccharides and the composition of PRAG-like structure were different among grape varieties. A decrease in amino acids and biogenic amines was observed during the ageing. The contents of polysaccharides, oligosaccharides and nitrogenous compound were significantly higher in Tempranillo than in Verdejo sparkling wines at the end of the ageing period. CONCLUSION: Polysaccharides and oligosaccharides from yeast were more significant autolysis markers of sparkling wines than the nitrogenous compounds. Our data suggest a potential cultivar effect on the evolution of yeast polysaccharides and on the composition of PRAG, which may influence the physico-chemical and sensory properties of sparkling wines. (c) 2017 Society of Chemical Industry. PMID- 28585250 TI - Deletion of ghrelin prevents aging-associated obesity and muscle dysfunction without affecting longevity. AB - During aging, decreases in energy expenditure and locomotor activity lead to body weight and fat gain. Aging is also associated with decreases in muscle strength and endurance leading to functional decline. Here, we show that lifelong deletion of ghrelin prevents development of obesity associated with aging by modulating food intake and energy expenditure. Ghrelin deletion also attenuated the decrease in phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) and downstream mediators in muscle, and increased the number of type IIa (fatigue resistant, oxidative) muscle fibers, preventing the decline in muscle strength and endurance seen with aging. Longevity was not affected by ghrelin deletion. Treatment of old mice with pharmacologic doses of ghrelin increased food intake, body weight, and muscle strength in both ghrelin wild-type and knockout mice. These findings highlight the relevance of ghrelin during aging and identify a novel AMPK-dependent mechanism for ghrelin action in muscle. PMID- 28585253 TI - Prediction of canned black bean texture (Phaseolus vulgaris L.) from intact dry seeds using visible/near infrared spectroscopy and hyperspectral imaging data. AB - BACKGROUND: Texture is a major quality parameter for the acceptability of canned whole beans. Prior knowledge of this quality trait before processing would be useful to guide variety development by bean breeders and optimize handling protocols by processors. The objective of this study was to evaluate and compare the predictive power of visible and near infrared reflectance spectroscopy (visible/NIRS, 400-2498 nm) and hyperspectral imaging (HYPERS, 400-1000 nm) techniques for predicting texture of canned black beans from intact dry seeds. Black beans were grown in Michigan (USA) over three field seasons. The samples exhibited phenotypic variability for canned bean texture due to genetic variability and processing practice. Spectral preprocessing methods (i.e. smoothing, first and second derivatives, continuous wavelet transform, and two band ratios), coupled with a feature selection method, were tested for optimizing the prediction accuracy in both techniques based on partial least squares regression (PLSR) models. RESULTS: Visible/NIRS and HYPERS were effective in predicting texture of canned beans using intact dry seeds, as indicated by their correlation coefficients for prediction (Rpred ) and standard errors of prediction (SEP). Visible/NIRS was superior (Rpred = 0.546-0.923, SEP = 7.5-1.9 kg 100 g-1 ) to HYPERS (Rpred = 0.401-0.883, SEP = 7.6-2.4 kg 100 g-1 ), which is likely due to the wider wavelength range collected in visible/NIRS. However, a significant improvement was reached in both techniques when the two-band ratios preprocessing method was applied to the data, reducing SEP by at least 10.4% and 16.2% for visible/NIRS and HYPERS, respectively. Moreover, results from using the combination of the three-season data sets based on the two-band ratios showed that visible/NIRS (Rpred = 0.886, SEP = 4.0 kg 100 g-1 ) and HYPERS (Rpred = 0.844, SEP = 4.6 kg 100 g-1 ) models were consistently successful in predicting texture over a wide range of measurements. CONCLUSION: Visible/NIRS and HYPERS have great potential for predicting the texture of canned beans; the robustness of the models is impacted by genotypic diversity, planting year and phenotypic variability for canned bean texture used for model building, and hence, robust models can be built based on data sets with high phenotypic diversity in textural properties, and periodically maintained and updated with new data. (c) 2017 Society of Chemical Industry. PMID- 28585254 TI - Use of clinical guidelines in cardiology practice in Sudan. AB - RATIONALE, AIMS, AND OBJECTIVE: The aim of this study was to explore the views of prescribers in cardiology in Sudan about the use of guidelines in clinical practice and the extent to which guidelines whether national or international can be adopted in clinical practice in Sudan. METHODS: Interviews were conducted with the consultants in 2 of the main cardiac hospitals in Sudan. This was followed by a survey amongst the doctors in the hospitals to examine the views of a larger population of prescribers about the matter investigated. RESULTS: Twelve consultants were interviewed, and 47 prescribers (60%) replied to the questionnaire that followed. Most doctors relied on foreign guidelines to prescribe for their patients. The doctors acknowledged the limitation of using foreign guidelines in Sudan. A number of doctors were not in favour of following any guidelines, as they perceived that the practice in Sudan does not allow implementation of guidelines. CONCLUSION: The prescribers in Sudan had to rely on guidelines made in foreign countries if they want to get the benefit of evidence based medicine to their patients, but they had to find a way to adapt these guidelines to their patients and to the health care system they are working within. However, it is not known if this adaptation of foreign guidelines is providing the benefits intended or is risking evidence-based medicine. PMID- 28585255 TI - Life years lost among patients with a given disease. AB - A number of suggested measures of life years lost among patients with a given disease are reviewed, and some new ones are proposed. The methods are all phrased in the framework of a (Markov or non-Markov) illness-death model in combination with a population life table. The methods are illustrated using data on Danish male patients with bipolar disorder, and some recommendations are given. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585256 TI - Information-adaptive clinical trials with selective recruitment and binary outcomes. AB - Selective recruitment designs preferentially recruit individuals who are estimated to be statistically informative onto a clinical trial. Individuals who are expected to contribute less information have a lower probability of recruitment. Furthermore, in an information-adaptive design, recruits are allocated to treatment arms in a manner that maximises information gain. The informativeness of an individual depends on their covariate (or biomarker) values, and how information is defined is a critical element of information adaptive designs. In this paper, we define and evaluate four different methods for quantifying statistical information. Using both experimental data and numerical simulations, we show that selective recruitment designs can offer a substantial increase in statistical power compared with randomised designs. In trials without selective recruitment, we find that allocating individuals to treatment arms according to information-adaptive protocols also leads to an increase in statistical power. Consequently, selective recruitment designs can potentially achieve successful trials using fewer recruits thereby offering economic and ethical advantages. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585257 TI - Paule-Mandel estimators for network meta-analysis with random inconsistency effects. AB - Network meta-analysis is used to simultaneously compare multiple treatments in a single analysis. However, network meta-analyses may exhibit inconsistency, where direct and different forms of indirect evidence are not in agreement with each other, even after allowing for between-study heterogeneity. Models for network meta-analysis with random inconsistency effects have the dual aim of allowing for inconsistencies and estimating average treatment effects across the whole network. To date, two classical estimation methods for fitting this type of model have been developed: a method of moments that extends DerSimonian and Laird's univariate method and maximum likelihood estimation. However, the Paule and Mandel estimator is another recommended classical estimation method for univariate meta-analysis. In this paper, we extend the Paule and Mandel method so that it can be used to fit models for network meta-analysis with random inconsistency effects. We apply all three estimation methods to a variety of examples that have been used previously and we also examine a challenging new dataset that is highly heterogenous. We perform a simulation study based on this new example. We find that the proposed Paule and Mandel method performs satisfactorily and generally better than the previously proposed method of moments because it provides more accurate inferences. Furthermore, the Paule and Mandel method possesses some advantages over likelihood-based methods because it is both semiparametric and requires no convergence diagnostics. Although restricted maximum likelihood estimation remains the gold standard, the proposed methodology is a fully viable alternative to this and other estimation methods. PMID- 28585258 TI - Masticatory muscle architecture in a water-rat from Australasia (Murinae, Hydromys) and its implication for the evolution of carnivory in rodents. AB - Murines are well known for their generalist diet, but several of them display specializations towards a carnivorous diet such as the amphibious Indo-Pacific water-rats. Despite the fact that carnivory evolved repeatedly in this group, few studies have investigated associated changes in jaw muscle anatomy and biomechanics. Here, we describe the jaw muscles and cranial anatomy of a carnivorous water-rat, Hydromys chrysogaster. The architecture of the jaw musculature of six specimens captured both on Obi and Papua were studied and described using dissections. We identified the origin and insertions of the jaw muscles, and quantified muscle mass, fiber length, physiological cross-sectional area, and muscle vectors for each muscle. Using a biomechanical model, we estimated maximum incisor and molar bite force at different gape angles. Finally, we conducted a 2D geometric morphometric analyses to compare jaw shape, mechanical potential, and diversity in lever-arm ratios for a set of 238 specimens, representative of Australo-Papuan carnivorous and omnivorous murids. Our study reveals major changes in the muscle proportions among Hydromys and its omnivorous close relative, Melomys. Hydromys was found to have large superficial masseter and temporalis muscles as well as a reduced deep masseter and zygomatico mandibularis, highlighting major functional divergence among omnivorous and carnivorous murines. Changes in these muscles are also accompanied by changes in jaw shape and the lines of action of the muscles. A more vertically oriented masseter, reduced masseteric muscles, as well as an elongated jaw with proodont lower incisors are key features indicative of a reduced propalinality in carnivorous Hydromys. Differences in the fiber length of the masseteric muscles were also detected between Hydromys and Melomys, which highlight potential adaptations to a wide gape in Hydromys, allowing it to prey on larger animals. Using a biomechanical model, we inferred a greater bite force in Hydromys than in Melomys, implying a functional shift between omnivory and carnivory. However, Melomys has an unexpected greater bite force at large gape compared with Hydromys. Compared with omnivorous Melomys, Hydromys have a very distinctive low mandible with a well-developed coronoid process, and a reduced angular process that projects posteriorly to the ascending rami. This jaw shape, along with our mechanical potential and jaw lever ratio estimates, suggests that Hydromys has a faster jaw closing at the incisor, with a higher bite force at the level of the molars. The narrowing of the Hydromys jaw explains this higher lever advantage at the molars, which constitutes a good compromise between a wide gape, a reduced anterior masseteric mass, and long fiber lengths. Lever arms of the superficial and deep masseter are less favourable to force output of the mandible in Hydromys but more favourable to speed. Compared with the small input lever arm defined between the condyle and the angular process, the relatively longer mandible of Hydromys increases the speed at the expense of the output force. This unique combination of morphological features of the masticatory apparatus possibly has permitted Hydromys to become a highly successful amphibious predator in the Indo Pacific region. PMID- 28585259 TI - Antibiotic complications during the treatment of Mycobacterium ulcerans disease in Australian patients. AB - BACKGROUND: Antibiotics are the recommended first-line treatment for Mycobacterium ulcerans disease. Antibiotic toxicity is common in Australian patients, yet antibiotic complication rates and their risk factors have not been determined. AIM: To determine the incidence rate and risk factors for antibiotic toxicity in Australian patients treated for M. ulcerans disease. METHODS: An analysis of severe antibiotic complications was performed using data from a prospective cohort of M. ulcerans cases managed at Barwon Health from 1 January 1998 to 30 June 2016. A severe antibiotic complication was defined as an antibiotic adverse event that required its cessation. Antibiotic complication rates and their associations were assessed using a Poisson regression model. RESULTS: A total of 337 patients was included; 184 (54.6%) males and median age 57 years (interquartile range (IQR) 36-73 years). Median antibiotic treatment duration was 56 days (IQR 49-76 days). Seventy-five (22.2%) patients experienced severe antibiotic complications after a median 28 days (IQR 17-45 days) at a rate of 141.53 per 100 person-years (95% confidence interval (CI) 112.86-177.47). Eleven (14.7%) patients required hospitalisation. Compared with rifampicin/clarithromycin combinations, severe complication rates were not increased for rifampicin/ciprofloxacin (rate ratio (RR) 1.49, 95% CI 0.89-2.50, P = 0.13) or rifampicin/moxifloxacin (RR 2.54, 95% CI 0.76-8.50, P = 0.13) combinations, but were significantly increased for 'other' combinations (RR 2.53, 95% CI 1.13-5.68, P = 0.03). In a multivariable analysis, severe complication rates were significantly increased with reduced estimated glomerular filtration rates (EGFR) (adjusted rate ratio (aRR) 2.65, 95% CI 1.24-5.65 for EGFR 60-89 mL/min and aRR 1.31, 95% CI 0.49-3.53 for EGFR 0-59 mL/min compared with EGFR >=90 mL/min, P < 0.01) and female gender (aRR 2.15, 95% CI 1.38-3.30, P < 0.01). CONCLUSIONS: Severe antibiotic complications during M. ulcerans treatment are high with increased rates independently associated with reduced renal function and female gender. PMID- 28585260 TI - Randomised controlled trial of topical antibacterial Manuka (Leptospermum species) honey for evaporative dry eye due to meibomian gland dysfunction. AB - BACKGROUND: The aim was to evaluate the efficacy of standardised Manuka (Leptospermum species) antibacterial honey as adjunctive twice daily treatment to conventional therapy (warm compresses, lid massage and preservative-free lubricant), in participants with evaporative dry eye due to moderate to advanced meibomian gland dysfunction. METHODS: This prospective, open-label study involved 114 participants. After two weeks of conventional therapy participants were randomised to one of three treatment groups: Optimel Antibacterial Manuka Eye Gel (98 per cent Leptospermum species honey) plus conventional therapy (n = 37), Optimel Manuka plus Lubricant Eye Drops (16 per cent Leptospermum species honey) plus conventional therapy (n = 37) and a control (conventional therapy) (n = 40). Clinical evaluations performed at baseline and Week 8 included: symptom scores (Ocular Surface Disease Index, Ocular Comfort Index), daily lubricant use, tear assessments (break-up time, secretion, osmolarity and InflammaDry), corneal sensation, ocular surface staining, meibomian gland secretion quality and expressibility, bulbar conjunctival, limbal and lid marginal redness and eyelid marginal bacterial cultures and colony counts. RESULTS: Significant improvements (p <= 0.05) occurred at Week 8 in symptoms, tear break-up time, staining, tear osmolarity, meibum quality and bulbar, limbal and lid margin redness for all treatments. Improvement in staining was significantly greater with Optimel 16 per cent drops (p = 0.035). Significant improvements (p < 0.05) in meibomian gland expressibility and InflammaDry occurred for both Optimel treatments. Optimel 98 per cent gel was significantly more effective in improving meibum quality (p = 0.005) and gland expressibility (p = 0.042). Total eyelid marginal bacterial colony counts reduced significantly with Optimel 16 per cent drops (p = 0.03) but not the other treatments. Staphylococcus epidermidis counts reduced significantly with Optimel 16 per cent drops (p = 0.041) and Optimel 98 per cent gel (p = 0.027). Both Optimel treatments significantly reduced the need for lubricants, with Optimel 16 per cent drops decreasing lubricant use most (p = 0.001). Temporary redness and stinging were the only adverse effects of Optimel use. CONCLUSIONS: Optimel antibacterial honey treatments are effective as adjunctive therapies for meibomian gland dysfunction. PMID- 28585261 TI - Discovery of Rapid and Reversible Water Insertion in Rare Earth Sulfates: A New Process for Thermochemical Heat Storage. AB - Thermal energy storage based on chemical reactions is a prospective technology for the reduction of fossil-fuel consumption by storing and using waste heat. For widespread application, a critical challenge is to identify appropriate reversible reactions that occur below 250 degrees C, where abundant low-grade waste heat and solar energy might be available. Here, it is shown that lanthanum sulfate monohydrate La2 (SO4 )3 ?H2 O undergoes rapid and reversible dehydration/hydration reactions in the temperature range from 50 to 250 degrees C upon heating/cooling with remarkably small thermal hysteresis (<50 degrees C), and thus it emerges as a new candidate system for thermal energy storage. Thermogravimetry and X-ray diffraction analyses reveal that the reactions proceed through an unusual mechanism for sulfates: water is removed from, or inserted in La2 (SO4 )3 ?H2 O with progressive change in hydration number x without phase change. It is also revealed that only a specific structural modification of La2 (SO4 )3 exhibits this reversible dehydration/hydration behavior. PMID- 28585262 TI - Reliable Piezoelectricity in Bilayer WSe2 for Piezoelectric Nanogenerators. AB - Recently, piezoelectricity has been observed in 2D atomically thin materials, such as hexagonal-boron nitride, graphene, and transition metal dichalcogenides (TMDs). Specifically, exfoliated monolayer MoS2 exhibits a high piezoelectricity that is comparable to that of traditional piezoelectric materials. However, monolayer TMD materials are not regarded as suitable for actual piezoelectric devices due to their insufficient mechanical durability for sustained operation while Bernal-stacked bilayer TMD materials lose noncentrosymmetry and consequently piezoelectricity. Here, it is shown that WSe2 bilayers fabricated via turbostratic stacking have reliable piezoelectric properties that cannot be obtained from a mechanically exfoliated WSe2 bilayer with Bernal stacking. Turbostratic stacking refers to the transfer of each chemical vapor deposition (CVD)-grown WSe2 monolayer to allow for an increase in degrees of freedom in the bilayer symmetry, leading to noncentrosymmetry in the bilayers. In contrast, CVD grown WSe2 bilayers exhibit very weak piezoelectricity because of the energetics and crystallographic orientation. The flexible piezoelectric WSe2 bilayers exhibit a prominent mechanical durability of up to 0.95% of strain as well as reliable energy harvesting performance, which is adequate to drive a small liquid crystal display without external energy sources, in contrast to monolayer WSe2 for which the device performance becomes degraded above a strain of 0.63%. PMID- 28585263 TI - Combined interventional sialendoscopy and intraductal steroid therapy for recurrent sialadenitis in Sjogren's syndrome: Results of a pilot monocentric trial. AB - OBJECTIVES: To evaluate the effectiveness of interventional sialendoscopy alone or combined with outpatient intraductal steroid irrigations in patients with sialadenitis due to Sjogren's syndrome (SS). DESIGN: A pilot therapeutic study. SETTING: ENT Clinics, Universities of Milan and Pavia. STUDY POPULATION: We included 22 patients with SS of whom 12 underwent interventional sialendoscopy followed by intraductal steroid irrigations (group A), and 10 interventional sialendoscopy alone (group B). OUTCOMES MEASURES: The following outcome measures were considered and recorded before and after the therapeutic intervention: (i) number of episodes of glandular swelling, (ii) cumulative prevalence of patients with glandular swelling assessed by the specific domain, the EULAR SS Disease Activity Index (ESSDAI), (iii) severity of pain by means of a 0-10 pain visual analogue scale (VAS), (iv) severity of xerostomia and other disease symptoms assessed by the EULAR SS Patient Reported Index (ESSPRI) and the Xerostomia Inventory questionnaire. RESULTS: The postoperative reduction in the mean number of episodes of glandular swelling was 87% (95% CI: 77-93) and 75% (95% CI: 47% 88%) in the groups A and B, respectively. The percentage of patients with glandular swelling decreased from 41.7% to 0.0% in the group A and from 30.0% to 0.0% in the group B, respectively. Most of the patients experienced a subjective clinical improvement documented by the statistically significant reductions in the postoperative mean pain VAS (group A P<.001; group B P=.004), Xerostomia Inventory (P<.001 and P=.003) and ESSPRI scores (P<.001 and P=.008). Interventional sialendoscopy followed by outpatient intraductal steroid irrigations was more effective than interventional sialendoscopy alone, when pain VAS, Xerostomia Inventory and ESSPRI scores before and after treatment were analysed together using the multivariate Hotelling T2 test (P=.0173). CONCLUSIONS: This pilot study confirms that interventional sialendoscopy with steroid duct irrigation significantly reduces the number of painful episodes of sialadenitis and improves the subjective sensation of oral dryness and other disease symptoms in patients with SS. The study results also suggest that the improvement is greater when interventional sialendoscopy is combined with a cycle of outpatient steroid ductal irrigations. Larger controlled randomised studies are certainly needed to confirm these preliminary data. PMID- 28585264 TI - Metasurfaces and Colloidal Suspensions Composed of 3D Chiral Si Nanoresonators. AB - High-refractive-index silicon nanoresonators are promising low-loss alternatives to plasmonic particles in CMOS-compatible nanophotonics applications. However, complex 3D particle morphologies are challenging to realize in practice, thus limiting the range of achievable optical functionalities. Using 3D film structuring and a novel gradient mask transfer technique, the first intrinsically chiral dielectric metasurface is fabricated in the form of a monolayer of twisted silicon nanocrescents that can be easily detached and dissolved into colloidal suspension. The metasurfaces exhibit selective handedness and a circular dichroism as large as 160 degrees um-1 due to pronounced differences in induced current loops for left-handed and right-handed polarization. The detailed morphology of the detached particles is analyzed using high-resolution transmission electron microscopy. Furthermore, it is shown that the particles can be manipulated in solution using optical tweezers. The fabrication and detachment method can be extended to different nanoparticle geometries and paves the way for a wide range of novel nanophotonic experiments and applications of high-index dielectrics. PMID- 28585265 TI - Past, present and future of epigenetics in brain sexual differentiation. AB - Sexual differentiation has long been considered "epigenetic", although the meaning of that word has shifted over time. Here, we track the evolution of ideas about epigenetics in sexual differentiation, and identify principles that have emerged from recent studies. Experiments manipulating a particular epigenetic mechanism during neonatal life demonstrate a role for both histone acetylation and DNA methylation in the development of sex differences in the brain and behaviour of rodents. In addition, hormone-dependent sex differences in the number of neurones of a particular phenotype may be programmed by differences in DNA methylation early in life. Genome-wide studies suggest that many effects of neonatal testosterone on the brain methylome do not emerge until adulthood, and there may be sex biases in the use of epigenetic marks that do not correlate with differences in gene expression. In other words, even when the transcription of a gene does not differ between males and females, the epigenetic underpinnings of that expression may differ. Finally, recent evidence suggests that sex differences in epigenetic marks may primarily serve to make gene expression more similar in males and females. We discuss the implications of these findings for understanding sex differences in susceptibility to disease, and point to recent conceptual and technical advances likely to influence the field going forward. PMID- 28585266 TI - An evaluation of the feasibility and validity of a patient-administered malnutrition universal screening tool ('MUST') compared to healthcare professional screening in an inflammatory bowel disease (IBD) outpatient clinic. AB - BACKGROUND: Malnutrition is common in inflammatory bowel disease (IBD) and is associated with poor health outcomes. Despite this, screening for malnutrition in the outpatient-setting is not routine and research in the area is limited. The present study aimed to evaluate whether agreement between malnutrition screening completed by patients and healthcare professionals (HCPs) could be achieved by comparing patient self-administered 'MUST' ('MUST'-P) with HCP administered 'MUST' ('MUST'-HCP) in a single tertiary IBD outpatient clinic. METHODS: We conducted a feasibility and validity study on adult outpatients with IBD. We collected anthropometric, nutritional and clinical data from patients. All patients completed 'MUST'-P using a self-administered questionnaire, followed by 'MUST'-HCP. 'MUST'-P was timed and feedback on ease-of-use was obtained. The risk of malnutrition was classified as low (score = 0), medium (score = 1) and high (score >= 2) and agreement was tested using kappa statistics (kappa). RESULTS: Eighty patients were recruited (Crohn's disease: n = 49, ulcerative colitis: n = 29, unclassified: n = 2), with a mean (SD) age of 39.9 (15.1) years (51.2% were males). Seventy-one (92%) of patients found 'MUST'-P either easy or very easy. The mean (SD) time to complete 'MUST'-P was 3.1 (1.8) min (range 1-10 min). Sixty-eight (85%) of patients were at low risk of malnutrition when screened by the HCP. There was moderate agreement (kappa = 0.486, P < 0.001) between 'MUST'-P and 'MUST'-HCP, with 100% agreement in scoring for medium- and high-risk categories. CONCLUSIONS: The results of the present study suggests that self screening using 'MUST' could be effectively used in an IBD outpatient clinic to identify those at medium and high risk of malnutrition. The patient friendly version of 'MUST' ('MUST'-P) was considered quick and easy to use by patients. Implementation of self-screening with 'MUST' could improve the nutritional management of IBD patients. PMID- 28585267 TI - Intense pulsed light treatment and meibomian gland expression for moderate to advanced meibomian gland dysfunction. AB - BACKGROUND: The aim was to evaluate the efficacy of periocular intense pulsed light therapy combined with meibomian gland expression for chronic dry eye due to moderate to advanced meibomian gland dysfunction. METHODS: This single institution, open-label prospective study involved 26 participants who received bilateral treatments using a proprietary intense pulsed light device (E > Eye, E Swin, Paris, France) combined with therapeutic meibomian gland expression at baseline, Week 2 and Week 6. Clinical evaluations performed at baseline, Week 4, Week 8 and Week 12 were symptom scores (Ocular Surface Disease Index [OSDI], Ocular Comfort Index [OCI], daily lubricant use, tear break-up time and ocular surface staining). Tear secretion, tear osmolarity, InflammaDry tear immunoassay, corneal sensation, meibomian secretion quality and expressibility, bulbar conjunctival, limbal and lid margin redness and eyelid margin bacterial swab for cultures and colony counts were performed at baseline and Week 8 only. RESULTS: Significant improvements occurred at Week 8 in meibomian gland expressibility (p = 0.002), meibum quality (p = 0.006), tear break-up time (p = 0.002), corneal staining (p = 0.001), lid margin redness (p = 0.001), bulbar redness (p = 0.05) and limbal redness (p = 0.001). Symptom survey outcomes, eyelid margin bacteria colony counts, Schirmer I test, tear osmolarity, corneal sensitivity and daily lubricant use were unchanged. At Week 12, significant improvements in symptoms (OSDI p = 0.025; OCI p = 0.003), tear break-up time (p = 0.001) and corneal staining (p = 0.001) occurred. Improvement in OSDI score was correlated to the improvement in ocular surface staining (R = 0.43, p = 0.03) and associated with baseline meibomian gland expressibility (Kendall tau: the distributions are ordered the same, p = 0.1). There were no adverse effects of treatment. CONCLUSIONS: Serial intense pulsed light therapy combined with meibomian gland expression significantly improved dry eye symptoms and clinical signs, including meibomian gland secretion quality and expressibility and ocular surface inflammation. Treatment effects were cumulative and sustained for at least six weeks after the final treatment. PMID- 28585268 TI - Pilot-scale radiofrequency blanching of potato cuboids: heating uniformity. AB - BACKGROUND: Traditional hot water blanching has a slow heat transfer rate, whereas radiofrequency (RF) heating has the advantages of a much faster heating rate and a higher penetration depth. In the present study, RF heating was applied to improve heating uniformity for subsequent blanching experiments involving potato cuboids. Potato cuboids were treated in a pilot-scale, RF heating system (27.12 MHz, 6 kW) under different operating conditions. RESULTS: The dielectric constant increased first and then decreased with temperature, whereas the loss factor increased as the temperature increased. The results of the present study reveal that the electrode gap, sample height and NaCl solution had significant effects (P < 0.05) on the temperature distribution and heating uniformity of the sample after RF heating. The optimum RF heating uniformity was obtained at an electrode gap of 120 mm, a sample height of 60 mm and when immersed in NaCl solution of 0.5 s m-1 . The central heating pattern was presented in a sample. Cold spots were located at the edge of the top surface of the sample. CONCLUSION: The present study shows the great potential of RF heating for the blanching of vegetables. Future studies should aim to determine changes in the texture and nutrient contents of vegetables during RF heating. (c) 2017 Society of Chemical Industry. PMID- 28585269 TI - Piezo-Phototronic Effect on Selective Electron or Hole Transport through Depletion Region of Vis-NIR Broadband Photodiode. AB - Silicon underpins nearly all microelectronics today and will continue to do so for some decades to come. However, for silicon photonics, the indirect band gap of silicon and lack of adjustability severely limit its use in applications such as broadband photodiodes. Here, a high-performance p-Si/n-ZnO broadband photodiode working in a wide wavelength range from visible to near-infrared light with high sensitivity, fast response, and good stability is reported. The absorption of near-infrared wavelength light is significantly enhanced due to the nanostructured/textured top surface. The general performance of the broadband photodiodes can be further improved by the piezo-phototronic effect. The enhancement of responsivity can reach a maximum of 78% to 442 nm illumination, the linearity and saturation limit to 1060 nm light are also significantly increased by applying external strains. The photodiode is illuminated with different wavelength lights to selectively choose the photogenerated charge carriers (either electrons or holes) passing through the depletion region, to investigate the piezo-phototronic effect on electron or hole transport separately for the first time. This is essential for studying the basic principles in order to develop a full understanding about piezotronics and it also enables the development of the better performance of optoelectronics. PMID- 28585270 TI - Intra- and interrater reliability of the Chicago Classification of achalasia subtypes in pediatric high-resolution esophageal manometry (HRM) recordings. AB - BACKGROUND: Subtyping achalasia by high-resolution manometry (HRM) is clinically relevant as response to therapy and prognosis have shown to vary accordingly. The aim of this study was to assess inter- and intrarater reliability of diagnosing achalasia and achalasia subtyping in children using the Chicago Classification (CC) V3.0. METHODS: Six observers analyzed 40 pediatric HRM recordings (22 achalasia and 18 non-achalasia) twice by using dedicated analysis software (ManoView 3.0, Given Imaging, Los Angeles, CA, USA). Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), intrabolus pressurization pattern (IBP), and distal latency (DL) were extracted and analyzed hierarchically. Cohen's kappa (2 raters) and Fleiss' kappa (>2 raters) and the intraclass correlation coefficient (ICC) were used for categorical and ordinal data, respectively. RESULTS: Based on the results of dedicated analysis software only, intra- and interrater reliability was excellent and moderate (kappa=0.89 and kappa=0.52, respectively) for differentiating achalasia from non-achalasia. For subtyping achalasia, reliability decreased to substantial and fair (kappa=0.72 and kappa=0.28, respectively). When observers were allowed to change the software-driven diagnosis according to their own interpretation of the manometric patterns, intra- and interrater reliability increased for diagnosing achalasia (kappa=0.98 and kappa=0.92, respectively) and for subtyping achalasia (kappa=0.79 and kappa=0.58, respectively). CONCLUSIONS: Intra- and interrater agreement for diagnosing achalasia when using HRM and the CC was very good to excellent when results of automated analysis software were interpreted by experienced observers. More variability was seen when relying solely on the software-driven diagnosis and for subtyping achalasia. Therefore, diagnosing and subtyping achalasia should be performed in pediatric motility centers with significant expertise. PMID- 28585271 TI - Partial-mouth periodontal examination protocols for the determination of the prevalence and extent of gingival bleeding in adolescents. AB - OBJECTIVE: To compare the performance of partial-mouth periodontal examination (PMPE) protocols with different cut-off points to the full-mouth examination (FME) in the assessment of the prevalence and extent of gingival bleeding in adolescents. METHODS: A cross-sectional study was conducted involving 12-year-old adolescents. Following a systematic two-stage cluster sampling process, 1134 individuals were evaluated. Different PMPE protocols were compared to the FME with six sites per tooth. Sensitivity, specificity, area under the ROC curve (AUC), intraclass correlation coefficient (ICC), relative and absolute biases and the inflation factor were assessed for each PMPE protocol with different cut-off points for the severity of gingival bleeding. RESULTS: The highest AUC values were found for the six-site two-diagonal quadrant (2-4) (0.97), six-site random half-mouth (0.95) and Community Periodontal Index (0.95) protocols. The assessment of three sites [mesiobuccal (MB), buccal (B) and distolingual (DL)] in two diagonal quadrants and the random half-mouth protocol had higher sensitivity and lower specificity than the same protocols with distobuccal (DB) sites. However, the use of DB sites led to better specificity and improved the balance between sensitivity and specificity, except for the two-diagonal quadrant (1-3) protocol. The >=1 cut-off point led to the most discrepant results from the FME. CONCLUSION: Six-site two-diagonal quadrant (2-4) and random half-mouth assessments perform better in the evaluation of gingival bleeding in adolescents. However, when a faster protocol is needed, a two-diagonal quadrant assessment using only MB, B and DL sites can be used with no important loss of information. PMID- 28585272 TI - Homogeneous 2D MoTe2 p-n Junctions and CMOS Inverters formed by Atomic-Layer Deposition-Induced Doping. AB - Recently, alpha-MoTe2 , a 2D transition-metal dichalcogenide (TMD), has shown outstanding properties, aiming at future electronic devices. Such TMD structures without surface dangling bonds make the 2D alpha-MoTe2 a more favorable candidate than conventional 3D Si on the scale of a few nanometers. The bandgap of thin alpha-MoTe2 appears close to that of Si and is quite smaller than those of other typical TMD semiconductors. Even though there have been a few attempts to control the charge-carrier polarity of MoTe2 , functional devices such as p-n junction or complementary metal-oxide-semiconductor (CMOS) inverters have not been reported. Here, we demonstrate a 2D CMOS inverter and p-n junction diode in a single alpha MoTe2 nanosheet by a straightforward selective doping technique. In a single alpha-MoTe2 flake, an initially p-doped channel is selectively converted to an n doped region with high electron mobility of 18 cm2 V-1 s-1 by atomic-layer deposition-induced H-doping. The ultrathin CMOS inverter exhibits a high DC voltage gain of 29, an AC gain of 18 at 1 kHz, and a low static power consumption of a few nanowatts. The results show a great potential of alpha-MoTe2 for future electronic devices based on 2D semiconducting materials. PMID- 28585273 TI - Direct access colonoscopy: impact of intervention on time to colorectal cancer diagnosis and treatment in North West Tasmania. AB - BACKGROUND: Direct access colonoscopy (DAC) allows general practitioners to refer directly for colonoscopy, without specialist review. Research suggests DAC reduces times to diagnosis and treatment of colorectal cancer. However, there is no information about outcomes of DAC in Australia. AIM: To determine if DAC in North West Tasmania expedited colorectal diagnosis and treatment. METHODS: Pre post intervention study evaluating time from referral to diagnosis and definitive treatment. Patient demographic characteristics, referral, colonoscopy and treatment information was retrieved from hospital records. Timelines were investigated in standard referrals (SR), emergency department/inpatient referrals and DAC using survival analysis. RESULTS: Two hundred and six colorectal cancer cases were identified (117 SR, 26 DAC, 48 emergency department/inpatient and 15 unknown pathways). Median time to colonoscopy/diagnosis (DAC 6 weeks vs SR 7 weeks, P = 0.55) or definitive treatment (surgery/chemoradiation) (DAC 8 weeks vs SR 9 weeks, P = 0.81) was not significantly improved with DAC. Among SR only, time to diagnosis was 9 weeks pre-intervention versus 5 weeks post-intervention (P = 0.13), and time to treatment was 11 weeks pre-intervention versus 6 weeks post-intervention (P = 0.07). CONCLUSION: There was no statistically significant improvement in time to colorectal cancer diagnosis or treatment among patients referred through DAC compared to SR. There was a trend towards improved waiting times for SR concurrent with the introduction of the DAC pathway, indicating improvement of all referral processes. DAC may not be effective at expediting colorectal cancer diagnosis if it is not accompanied by strict referral guidelines. Larger evaluations of DAC are required in the Australian context. PMID- 28585274 TI - Junior doctors' attitudes to opioids for refractory breathlessness in patients with advanced chronic obstructive pulmonary disease. AB - BACKGROUND: Refractory breathlessness is a common, distressing symptom in patients with advanced chronic obstructive pulmonary disease (COPD). The judicious, off-licence prescription of opioids, together with other management strategies, can improve breathlessness, however, internationally there is profound reluctance to prescribe opioids for breathlessness in COPD. AIMS: To understand Australian junior doctors' knowledge and attitudes regarding the management of refractory breathlessness and the role of opioids in COPD. METHODS: All junior doctors undertaking basic training in internal medicine in Victoria were invited to complete an online survey. Knowledge, willingness, and experience prescribing opioids to COPD patients with refractory breathlessness, were examined. RESULTS: Of the 243 responses received, most trainees (193, 86.5%) believed opioids have a role in treating refractory breathlessness in stable COPD outpatients, with 143 (64.1%) recommending morphine as first-line treatment for refractory breathlessness. One quarter (55, 24.7%) reported having themselves initiated an opioid and 102 (45.7%) had prescribed an opioid under senior supervision for management of breathlessness in COPD. Concern regarding adverse opioid effects was low, with 58 (26.0%) having no concerns prescribing an opioid to COPD patients. CONCLUSION: This is the first study of doctors to demonstrate high awareness, confidence, willingness and experience in prescribing opioids for the off-licence indication of refractory breathlessness in COPD. These findings differ significantly from attitudes reported overseas and are unexpected given the doctors surveyed were recently qualified. The low awareness of possible adverse events and limited insight regarding knowledge gaps is concerning and highlights the significant need for greater education in palliative care. PMID- 28585275 TI - Postsynthetic Doping of MnCl2 Molecules into Preformed CsPbBr3 Perovskite Nanocrystals via a Halide Exchange-Driven Cation Exchange. AB - Unlike widely used postsynthetic halide exchange for CsPbX3 (X is halide) perovskite nanocrystals (NCs), cation exchange of Pb is of a great challenge due to the rigid nature of the Pb cationic sublattice. Actually, cation exchange has more potential for rendering NCs with peculiar properties. Herein, a novel halide exchange-driven cation exchange (HEDCE) strategy is developed to prepare dually emitting Mn-doped CsPb(Cl/Br)3 NCs via postsynthetic replacement of partial Pb in preformed perovskite NCs. The basic idea for HEDCE is that the partial cation exchange of Pb by Mn has a large probability to occur as a concomitant result for opening the rigid halide octahedron structure around Pb during halide exchange. Compared to traditional ionic exchange, HEDCE is featured by proceeding of halide exchange and cation exchange at the same time and lattice site. The time and space requirements make only MnCl2 molecules (rather than mixture of Mn and Cl ions) capable of doping into perovskite NCs. This special molecular doping nature results in a series of unusual phenomenon, including long reaction time, core shell structured mid states with triple emission bands, and dopant molecules composition-dependent doping process. As-prepared dual-emitting Mn-doped CsPb(Cl/Br)3 NCs are available for ratiometric temperature sensing. PMID- 28585276 TI - Hypertrophic cardiomyopathy in mitochondrial disorders: description of an uncommon clinical case. PMID- 28585278 TI - Abstract Proceedings of the 2017 Annual Meeting of the International Society for Laboratory Hematology, 4-6 May 2017, Honolulu, Hawaii. PMID- 28585277 TI - Technical Note: Monte Carlo calculations of the AAPM TG-43 brachytherapy dosimetry parameters for a new titanium-encapsulated Yb-169 source. AB - Due to a number of distinct advantages resulting from the relatively low energy gamma ray spectrum of Yb-169, various designs of Yb-169 sources have been developed over the years for brachytherapy applications. Lately, Yb-169 has also been suggested as an effective and practical radioisotope option for a novel radiation treatment approach often known as gold nanoparticle-aided radiation therapy (GNRT). In a recently published study, the current investigators used the Monte Carlo N-Particle Version 5 (MCNP5) code to design a novel titanium encapsulated Yb-169 source optimized for GNRT applications. In this study, the original MC source model was modified to accurately match the specifications of the manufactured Yb-169 source. The modified MC model was then used to obtain a complete set of the AAPM TG-43 parameters for the new titanium-encapsulated Yb 169 source. The MC-calculated dose rate constant for this titanium-encapsulated Yb-169 source was 1.19 +/- 0.03 cGy.h-1.U-1, indicating no significant change from the values reported for stainless steel-encapsulated Yb-169 sources. The source anisotropy and radial dose function for the new source were also found similar to those reported for the stainless steel-encapsulated Yb-169 sources. The current results suggest that the use of titanium, instead of stainless steel, to encapsulate the Yb-169 core would not lead to any major change in the dosimetric characteristics of the Yb-169 source. The results also show that the titanium encapsulation of the Yb-169 source could be accomplished while meeting the design goals as described in the current investigators' published MC optimization study for GNRT applications. PMID- 28585279 TI - Serum bile acid level and fatty acid composition in Chinese children with non alcoholic fatty liver disease. AB - OBJECTIVE: To determine serum bile acid (BA) and fatty acid (FA) profiles in Chinese children with non-alcoholic fatty liver disease (NAFLD). METHODS: A total 76 children aged 4-17 years were categorized into three groups according to the presence and absence of as well as the severity of NAFLD, that is, non-NAFLD (control), mild and moderate to severe NAFLD groups, respectively, based on their liver ultrasonography findings. Serum BA and FA profiles were quantified separately by mass spectrometry and gas chromatography. General linear models were performed to assess the differences among the groups. RESULTS: After adjusted for potential confounders, children with NAFLD had higher levels of chenodeoxycholic acid (CDCA), unconjugated primary BAs (CDCA + cholic acid) but lower levels of deoxycholic acid (DCA), taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), total DCA (DCA + TDCA + GDCA), glycolithocholic acid (GLCA) and total lithocholic acid (GLCA + taurolithocholic acid) than children without NAFLD. As for FAs, children with mild and moderate to severe NAFLD had higher levels of n-7 monounsaturated FA. CONCLUSIONS: Circulating BA and FA profiles may change in children with NAFLD. Further studies are needed to determine their associations and to understand the underlying mechanism of action. PMID- 28585280 TI - Meta-analysis combining parallel and crossover trials using generalised estimating equation method. AB - Clinical trials have different designs: In late stage drug development, the parallel trial design is the most frequent one; however, the crossover design is not rare; different techniques are used to analyse their results. Although both designs measure the same treatment effect, combining parallel and crossover trials in a meta-analysis is not straightforward. We present here a meta-analysis method based on generalised estimating equation (GEE) regression to combine aggregated results of crossover and parallel trials using a marginal estimation approach. This method is based on the fixed effects meta-analytic model; it allows combining average outcomes belonging to the exponential distributions obtained from trials of different designs and in particular from crossover trials with more than 2 periods and 2 treatments. By extending the methods proposed so far to combine the 2 trial designs, the GEE regression allows for adjusting for bias, such as a carry-over effect typical in crossover trials. In this paper, the GEE meta-analysis method is compared to the classical weighted average method with examples of published and simulated meta-analyses. Although the GEE can account for crossover specificities, it is limited by the availability of detailed trial information often encountered with reports of these trials. PMID- 28585281 TI - The deep fascia and retinacula of the equine forelimb - structure and innervation. AB - Recent advances in human fascia research have shed new light on the role of the fascial network in movement perception and coordination, transmission of muscle force, and integrative function in body biomechanics. Evolutionary adaptations of equine musculoskeletal apparatus that assure effective terrestrial locomotion are employed in equestrianism, resulting in the wide variety of movements in performing horses, from sophisticated dressage to jumping and high-speed racing. The high importance of horse motion efficiency in the present-day equine industry indicates the significance of scientific knowledge of the structure and physiology of equine fasciae. In this study, we investigated the structure and innervation of the deep fascia of the equine forelimb by means of anatomical dissection, histology and immunohistochemistry. Macroscopically, the deep fascia appears as a dense, glossy and whitish lamina of connective tissue continuous with its fibrous reinforcements represented by extensor and flexor retinacula. According to the results of our histological examination, the general structure of the equine forelimb fascia corresponds to the characteristics of the human deep fasciae of the limbs. Although we did find specific features in all sample types, the general composition of all examined fascial tissues follows roughly the same scheme. It is composed of dense, closely packed collagen fibers organized in layers of thick fibrous bundles with sparse elastic fibers. This compact tissue is covered from both internal and external sides by loosely woven laminae of areolar connective tissue where elastic fibers are mixed with collagen. Numerous blood vessels running within the loose connective tissue contribute to the formation of regular vascular network throughout the compact layer of the deep fascia and retinacula. We found nerve fibers of different calibers in all samples analyzed. The fibers are numerous in the areolar connective tissue and near the blood vessels but scarce in the compact layers of collagen. We did not observe any Ruffini, Pacini or Golgi-Mazzoni corpuscles. In conclusion, the multilayered composition of compact bundles of collagen, sparse elastic fibers in the deep fascia and continuous transition into retinacula probably facilitate resistance to gravitational forces and volume changes during muscle contraction as well as transmission of muscle force during movement. However, further research focused on innervation is needed to clarify whether the deep fascia of the equine forelimb plays a role in proprioception and movement coordination. PMID- 28585283 TI - Enhanced crude oil biodegradative potential of natural phytoplankton-associated hydrocarbonoclastic bacteria. AB - Phytoplankton have been shown to harbour a diversity of hydrocarbonoclastic bacteria (HCB), yet it is not understood how these phytoplankton-associated HCB would respond in the event of an oil spill at sea. Here, we assess the diversity and dynamics of the bacterial community associated with a natural population of marine phytoplankton under oil spill-simulated conditions, and compare it to that of the free-living (non phytoplankton-associated) bacterial community. While the crude oil severely impacted the phytoplankton population and was likely conducive to marine oil snow formation, analysis of the MiSeq-derived 16S rRNA data revealed dramatic and differential shifts in the oil-amended communities that included blooms of recognized HCB (e.g., Thalassospira, Cycloclasticus), including putative novel phyla, as well as other groups with previously unqualified oil-degrading potential (Olleya, Winogradskyella, and members of the inconspicuous BD7-3 phylum). Notably, the oil biodegradation potential of the phytoplankton-associated community exceeded that of the free-living community, and it showed a preference to degrade substituted and non-substituted polycyclic aromatic hydrocarbons. Our study provides evidence of compartmentalization of hydrocarbon-degrading capacity in the marine water column, wherein HCB associated with phytoplankton are better tuned to degrading crude oil hydrocarbons than that by the community of planktonic free-living bacteria. PMID- 28585284 TI - Predictive factors of depressive symptoms of elderly patients with cancer: A critical comment. PMID- 28585282 TI - Models to define the stages of articular cartilage degradation in osteoarthritis development. AB - Osteoarthritis (OA) is a common chronic disorder that affects an increasing number of the ageing population. Despite the prevalence, there are currently no therapies. Defining new therapies that target specific pathogenic phases of disease development relies on the effective separation of the different stages of OA. This manuscript reviews the tissues and models that are being used to separate these stages of disease, in particular initiation and early and late progression. These models include human tissues with known initiating factors, the use of anatomical locations with defined relationships to the primary cartilage lesion area, timing of OA development in well-described animal models and the versatility of a non-invasive model of murine knee joint trauma. PMID- 28585285 TI - The synergistic potential of various teas, herbs and therapeutic drugs in health improvement: a review. AB - Tea is one of the most widely consumed non-alcoholic beverages in the world next to water. It is classified as Camellia sinensis and non-Camellia sinensis (herbal teas). The common bioactive compounds found mainly in green teas are flavan-3-ols (catechins) (also called flavanols), proanthocyanidins (tannins) and flavonols. Black tea contains theaflavins and thearubigins and white tea contains l-theanine and gamma-aminobutyric acid (GABA), while herbal teas contain diverse polyphenols. Phytochemicals in tea exhibit antimicrobial, anti-diabetic and anti cancer activities that are perceived to be helpful in managing chronic diseases linked to lifestyle. Many of these phytochemicals are reported to be biologically active when combined. Knowledge of the synergistic interactions of tea with other teas or herbs in terms of biological activities will be of benefit for therapeutic enhancement. There is evidence that various types of teas act synergistically in exhibiting health benefits to humans, improving consumer acceptance and economic value. Similar observations have been made when teas and herbs or medicinal drugs were combined. The aim of this review is to highlight potential beneficial synergies between combinations of different types of teas, tea and herbs, and tea and medicinal drugs. (c) 2017 Society of Chemical Industry. PMID- 28585286 TI - Improved sample preparation for direct quantitative detection of Escherichia coli O157 in soil using qPCR without pre-enrichment. AB - The prominence of fresh produce as a vehicle for foodborne pathogens such as enterohaemorrhagic Escherichia coli (EHEC) O157 is rising, where disease cases can cause hospitalization and in some cases death. This rise emphasises the necessity for accurate and sensitive methods for detection of pathogens in soil, potential sources of contamination of fresh produce. The complexity of the soil matrix has previously proven prohibitive to pathogen detection via molecular methods without the use of a culture enrichment step, thereby excluding the detection of viable but non-culturable cells. Here, a sample preparation procedure to facilitate a direct qPCR assay is developed for the detection of E. coli O157 in soil, bypassing culture steps in favour of sample separation through pulsification release and filtration. In sand and peat-based compost, the method is sensitive to 10 CFU g-1 soil. When testing soils from agricultural sites, it was found that several were qPCR positive for E. coli O157 while being culture negative, with peat-based compost possessing a concentration of 200 tir gene copies per gram. This procedure offers a rapid, quantitative assessment of the potential presence of E. coli O157 in soils which can act as a prescreen of their suitability to grow fresh produce safely. PMID- 28585287 TI - Effect of VERO pan-tilt motion on the dose distribution. AB - Tumor tracking is an option for intra-fractional motion management in radiotherapy. The VERO gimbal tracking system creates a unique beam geometry and understanding the effect of the gimbal motion in terms of dose distribution is important to assess the dose deviation from the reference conditions. Beam profiles, output factors (OF) and percentage depth doses (PDD) were measured and evaluated to investigate this effect. In order to find regions affected by the pan-tilt motion, synthesized 2D dose distributions were generated. An evaluation of the 2D dose distribution with the reference position was done using dose difference criteria 1%-4%. The OF and point dose at central axis were measured and compared with the reference position. Furthermore, the PDDs were measured using a special monitoring approach to filtering inaccurate points during the acquisition. Beam profiles evaluation showed that the effect of pan-tilt at inline direction was stronger than at the crossline direction. The maximum average deviation of the full width half maximum (FWHM), flatness, symmetry, penumbra left and right were 0.39 +/- 0.25 mm, 0.62 +/- 0.50%, 0.76 +/- 0.59%, 0.22 +/- 0.16 mm, and 0.19 +/- 0.15 mm respectively. The OF and the measured dose average deviation were <0.5%. The mechanical accuracies during the PDD measurements were 0.28 +/- 0.09 mm and 0.21 +/- 0.09 mm for pan and tilt and pan or tilt position. The PDD average deviations were 0.58 +/- 0.26 % and 0.54 +/- 0.25 % for pan-or-tilt and pan-and-tilt position respectively. All the results showed that the deviation at pan and tilt position are higher than pan or tilt. The most influences were observed for the penumbra region and the shift of radiation beam path. PMID- 28585288 TI - Incentives for preventing smoking in children and adolescents. AB - BACKGROUND: Adult smoking usually has its roots in adolescence. If individuals do not take up smoking during this period it is unlikely that they ever will. Further, once smoking becomes established, cessation is challenging; the probability of subsequently quitting is inversely proportional to the age of initiation. One novel approach to reducing the prevalence of youth smoking is the use of incentives. OBJECTIVES: To assess the effect of incentives on preventing children and adolescents (aged 5 to 18 years) from starting to smoke. It was also our intention to assess, where possible, the dose-response of incentives, the costs of incentive programmes, whether incentives are more or less effective in combination with other interventions to prevent smoking initiation, and any unintended consequences arising from the use of incentives. SEARCH METHODS: For the original review (published 2012) we searched the Cochrane Tobacco Addiction Group Specialized Register, with additional searches of MEDLINE, Embase, CINAHL, CSA databases and PsycINFO for terms relating to incentives, in combination with terms for smoking and tobacco use, and children and adolescents. The most recent searches were of the Cochrane Tobacco Addiction Group Specialized Register, and were carried out in December 2016. SELECTION CRITERIA: We considered randomized controlled trials (RCTs) allocating children and adolescents (aged 5 to 18 years) as individuals, groups or communities to intervention or control conditions, where the intervention included an incentive aimed at preventing smoking uptake. We also considered controlled trials (CTs) with baseline measures and post intervention outcomes. DATA COLLECTION AND ANALYSIS: Two review authors extracted and independently assessed the data. The primary outcome was the smoking status of children or adolescents at follow-up who reported no smoking at baseline. We required a minimum follow-up of six months from baseline and assessed each included study for risks of bias. We used the most rigorous definition of abstinence in each trial; we did not require biochemical validation of self reported tobacco use for study inclusion. Where possible we combined eligible studies to calculate pooled estimates at the longest follow-up, using the Mantel Haenszel fixed-effect method, grouping studies by study design. MAIN RESULTS: We identified three eligible RCTs and five CTs, including participants aged 11 to 14 years, who were non-smokers at baseline. Of the eight trials identified, six had analyzable data relevant for this review, which contributed to meta-analyses (7275 participants in total: 4003 intervention; 3272 control; 2484 participants after adjusting for clustering). All except one of the studies tested the 'Smokefree Class Competition' (SFC), which has been widely implemented throughout Europe. In this competition, classes with youth generally between the ages of 11 and 14 years commit to being smoke-free for a six-month period, and report their smoking status regularly. If 90% or more of the class are non-smokers at the end of the six months, the class goes into a competition to win prizes. The one study that was not a trial of the SFC was a controlled trial in which schools in two communities were assigned to the intervention, with schools in a third community acting as controls. Students in the intervention community with lower smoking rates at the end of the project (one school year) received rewards.Most studies resulted in statistically non-significant results. Only one study of the SFC reported a significant effect of the competition on the prevention of smoking at the longest follow-up. However, this study was at risk of multiple biases, and when we calculated the adjusted risk ratio (RR) we no longer detected a statistically significant difference. The pooled RR for the more robust RCTs (3 studies, n = 3056 participants/1107 adjusted for clustering) suggests that there is no statistically significant effect of incentives, in the form of the SFC, to prevent smoking initiation among children and adolescents in the long term (RR 1.00, 95% confidence interval (CI) 0.84 to 1.19). Pooled results from the non randomized trials also did not detect a significant effect of the SFC, and we were unable to extract data on our outcome of interest from the one trial that did not study the SFC. There is little robust evidence to suggest that unintended consequences (such as making false claims about their smoking status and bullying of smoking students) are consistently associated with such interventions, although this has not been the focus of much research. There was insufficient information to assess the dose-response relationship or to report costs of incentives for preventing smoking uptake.We judged the included RCTs to be at unclear risk of bias, and the non-RCTs to be at high risk of bias. Using GRADE, we rated the overall quality of the evidence for our primary outcome as 'low' (for RCTs) and 'very low' (for non-RCTs), because of imprecision (all studies had wide confidence intervals), and for the risks of bias identified. We further downgraded the non-RCT evidence, due to issues with the non-RCT study design, likely to introduce further bias. AUTHORS' CONCLUSIONS: The very limited evidence currently available suggests that incentive programmes do not prevent smoking initiation among youth. However, there are relatively few published studies and these are of variable quality. In addition, trials included in the meta-analyses were all studies of the SFC, which distributed small to moderately-sized prizes to whole classes, usually through a lottery system. It is therefore possible that other incentive programmes could be more successful at preventing smoking uptake in young people.Future studies might investigate the efficacy of a wider range of incentives, including those given to individual participants to prevent smoking uptake, whilst considering both the effect of incentives on smoking initiation and the progression to smoking. It would be useful if incentives were evaluated in varying populations from different socioeconomic and ethnic backgrounds, and if intervention components were described in detail. PMID- 28585289 TI - Effects of weak/non-complement-binding HLA antibodies on C1q-binding. AB - It is unknown under what conditions and to what extent weak/non-complement (C) binding IgG subclasses (IgG2/IgG4) can block C1q-binding triggered by C-binding IgG subclasses (IgG1/IgG3). Therefore, we investigated in vitro C1q-binding induced by IgG subclass mixtures targeting the same HLA epitope. Various mixtures of HLA class II specific monoclonal antibodies of different IgG subclasses but identical V-region were incubated with HLA DRB1*07:01 beads and monitored for C1q binding. The lowest concentration to achieve maximum C1q-binding was measured for IgG3, followed by IgG1, while IgG2 and IgG4 did not show appreciable C1q-binding. C1q-binding occurred only after a critical amount of IgG1/3 has bound and sharply increased thereafter. When both, C-binding and weak/non-C-binding IgG subclasses were mixed, C1q-binding was diminished proportionally to the fraction of IgG2/4. A 2- to 4-fold excess of IgG2/4 inhibited C1q-binding by 50%. Very high levels (10-fold excess) almost completely abrogated C1q-binding even in the presence of significant IgG1/3 levels that would usually lead to strong C1q-binding. In sensitized renal allograft recipients, IgG subclass constellations with >= 2-fold excess of IgG2/4 over IgG1/3 were present in 23/66 patients (34.8%) and overall revealed slightly decreased C1q signals. However, spiking of patient sera with IgG2 targeting a different epitope than the patient's IgG1/3 synergistically increased C1q-binding. In conclusion, if targeting the same epitope, an excess of IgG2/4 is repressing the extent of IgG1/3 triggered C1q-binding in vitro. Such IgG subclass constellations are present in about a third of sensitized patients and their net effect on C1q-binding is slightly inhibitory. PMID- 28585291 TI - Reviving Lithium-Metal Anodes for Next-Generation High-Energy Batteries. AB - Lithium-metal batteries (LMBs), as one of the most promising next-generation high energy-density storage devices, are able to meet the rigid demands of new industries. However, the direct utilization of metallic lithium can induce harsh safety issues, inferior rate and cycle performance, or anode pulverization inside the cells. These drawbacks severely hinder the commercialization of LMBs. Here, an up-to-date review of the behavior of lithium ions upon deposition/dissolution, and the failure mechanisms of lithium-metal anodes is presented. It has been shown that the primary causes consist of the growth of lithium dendrites due to large polarization and a strong electric field at the vicinity of the anode, the hyperactivity of metallic lithium, and hostless infinite volume changes upon cycling. The recent advances in liquid organic electrolyte (LOE) systems through modulating the local current density, anion depletion, lithium flux, the anode electrolyte interface, or the mechanical strength of the interlayers are highlighted. Concrete strategies including tailoring the anode structures, optimizing the electrolytes, building artificial anode-electrolyte interfaces, and functionalizing the protective interlayers are summarized in detail. Furthermore, the challenges remaining in LOE systems are outlined, and the future perspectives of introducing solid-state electrolytes to radically address safety issues are presented. PMID- 28585290 TI - CSF biomarkers in delirium: a systematic review. AB - OBJECTIVE: In recent years, there has been a blossoming of studies examining cerebrospinal fluid (CSF) as a method of studying the pathophysiology of delirium. We systematically reviewed the literature for CSF studies in delirium and provide here a summary of the implications for our understanding of delirium pathophysiology. We also summarise the methods used for CSF analysis and discuss challenges and implications for future studies. METHODS: In this systematic review, we screened MEDLINE, EMBASE, PsycINFO, Web of Science, PubMed and the Cochrane Library for articles on CSF biomarkers in delirium, published on 3 September 2016. Studies were required to use Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases criteria for delirium or a validated tool. We excluded case reports. There were no other restrictions on study type. RESULTS: We identified 3280 articles from our initial search, and 22 articles were included in this review. All studies were prospective, including over 400 patients with delirium and 700 controls. More than 70 different biomarkers were studied. Studies could not be compared with each other for meta-analysis because of their heterogeneity and varied widely in their risk of bias and quality assessments. CONCLUSIONS: The 22 studies identified in this review reveal a small but growing literature, in which many of the important hypotheses in delirium pathogenesis have been examined, but from which few firm conclusions can currently be drawn. Nevertheless, the overall interpretation of the literature supports the vulnerable brain concept, that is, that biomarker evidence of, for example, Alzheimer's disease pathology and/or neuroinflammation, is associated with delirium. PMID- 28585292 TI - Taking a sympathetic approach to post-traumatic stress disorder. PMID- 28585293 TI - Electric-Field-Controlled Dopant Distribution in Organic Semiconductors. AB - Stable electrical doping of organic semiconductors is fundamental for the functionality of high performance devices. It is known that dopants can be subjected to strong diffusion in certain organic semiconductors. This work studies the impact of operating conditions on thin films of the polymer poly(3 hexylthiophene) (P3HT) and the small molecule Spiro-MeOTAD, doped with two differently sized p-type dopants. The negatively charged dopants can drift upon application of an electric field in thin films of doped P3HT over surprisingly large distances. This drift is not observed in the small molecule Spiro-MeOTAD. Upon the dopants' directional movement in P3HT, a dedoped region forms at the negatively biased electrode, increasing the overall resistance of the thin film. In addition to electrical measurements, optical microscopy, spatially resolved infrared spectroscopy, and scanning Kelvin probe microscopy are used to investigate the drift of dopants. Dopant mobilities of 10-9 to 10-8 cm2 V-1 s-1 are estimated. This drift over several micrometers is reversible and can be controlled. Furthermore, this study presents a novel memory device to illustrate the applicability of this effect. The results emphasize the importance of dynamic processes under operating conditions that must be considered even for single doped layers. PMID- 28585294 TI - Ichthyosis fetalis in a cross-bred lamb. AB - BACKGROUND: Ichthyosis is a dermatological disease characterized by varying degrees of generalized hyperkeratosis and alopecia. Two congenital forms of ichthyosis are recognized in animals: fetalis (IF) and congenita. The disease occurs rarely in cattle, swine, dogs, chickens and a goat; it has not been reported in sheep. HYPOTHESIS/OBJECTIVES: To provide clinical, laboratory and pathological assessments of a case of IF in a cross-bred lamb. ANIMALS: A male cross-bred lamb. RESULTS: Physical examination revealed apathy, fever, ectropion and eclabium. Generalized thickening and scaling of the skin was noted; this was most severe on the face, ears, inner thighs, limbs and perineum. Deep fissures and wounds were present on the hind limbs and forelimbs. The lamb was monitored for 75 days. During this period, lesions progressed and occasionally obstructed the nostrils and increasingly made it difficult for the lamb to flex major limb joints. Postmortem findings included severe epidermal thickening, multiple subcutaneous abscesses, ectropion and corneal scars. Histological findings revealed diffuse orthokeratotic hyperkeratosis, follicular keratosis, irregular epidermal hyperplasia and atrophy of the sebaceous glands. Serum vitamin A concentration was within the normal range for the species. CONCLUSIONS AND CLINICAL IMPORTANCE: This case report describes a case of presumptive ichthyosis fetalis in a lamb. Greater awareness by practitioners is required for this disease to be included in the differential diagnosis of dermatopathies in this species. PMID- 28585296 TI - Satisfaction and difficulties of French professional home caregivers in supporting older people with Alzheimer's disease or alcohol misuse. AB - In France, few studies have examined home care when it comes to ageing support and even fewer have considered alcohol misuse in this context. The studies also show that being old and having alcohol use disorders are two unfavourable conditions for receiving help, whereas for the Alzheimer's disease, there is a clear need for optimal care. In this article, we study professional home caregiver's perceptions of their job along with their difficulties and satisfactions in supporting older people with Alzheimer's disease or alcohol misuse. Out of the 23 professionals approached, 17 took part in a research interview from October 2013 to January 2014. All interviews were recorded, fully transcribed and lexically analysed with Alceste(r) software. Among the five classes that were identified from 63% of the initial data, the main themes that emerged illustrate the nature of the associated pathologies, the perceptions and satisfactions related to the profession, their adaptive skills, the difficulties related to the life context of the older person, and the wine consumption of the latter. The lexical discourse analysis shows that the professional home caregivers are involved in looking after not only people with Alzheimer's disease but also those with alcohol misuse. However, despite the difficulties and satisfactions encountered, adaptation to the older people seems to be their priority and one of the many skills that they have acquired during their professionalisation. Most of the older people who are helped are women and the difficulties mentioned by their caregivers usually arise at the time of their death. Lastly, when caring for alcohol misusers, they describe negative attitudes in their support. Although research in this area is rare while home care for the older person, whatever the pathology, is increasing, professionals need to be supported by the associations or companies that employ them and should be trained to help them provide the appropriate care. PMID- 28585297 TI - Principles of proportional recovery after stroke generalize to neglect and aphasia. AB - BACKGROUND AND PURPOSE: Motor recovery after stroke can be characterized into two different patterns. A majority of patients recover about 70% of initial impairment, whereas some patients with severe initial deficits show little or no improvement. Here, we investigated whether recovery from visuospatial neglect and aphasia is also separated into two different groups and whether similar proportions of recovery can be expected for the two cognitive functions. METHODS: We assessed 35 patients with neglect and 14 patients with aphasia at 3 weeks and 3 months after stroke using standardized tests. Recovery patterns were classified with hierarchical clustering and the proportion of recovery was estimated from initial impairment using a linear regression analysis. RESULTS: Patients were reliably clustered into two different groups. For patients in the first cluster (n = 40), recovery followed a linear model where improvement was proportional to initial impairment and achieved 71% of maximal possible recovery for both cognitive deficits. Patients in the second cluster (n = 9) exhibited poor recovery (<25% of initial impairment). CONCLUSIONS: Our findings indicate that improvement from neglect or aphasia after stroke shows the same dichotomy and proportionality as observed in motor recovery. This is suggestive of common underlying principles of plasticity, which apply to motor and cognitive functions. PMID- 28585295 TI - Bioinspired Collagen Scaffolds in Cranial Bone Regeneration: From Bedside to Bench. AB - Calvarial defects are common reconstructive dilemmas secondary to a variety of etiologies including traumatic brain injury, cerebrovascular disease, oncologic resection, and congenital anomalies. Reconstruction of the calvarium is generally undertaken for the purposes of cerebral protection, contour restoration for psychosocial well-being, and normalization of neurological dysfunction frequently found in patients with massive cranial defects. Current methods for reconstruction using autologous grafts, allogeneic grafts, or alloplastic materials have significant drawbacks that are unique to each material. The combination of wide medical relevance and the need for a better clinical solution render defects of the cranial skeleton an ideal target for development of regenerative strategies focused on calvarial bone. With the improved understanding of the instructive properties of tissue-specific extracellular matrices and the advent of precise nanoscale modulation in materials science, strategies in regenerative medicine have shifted in paradigm. Previously considered to be simple carriers of stem cells and growth factors, increasing evidence exists for differential materials directing lineage specific differentiation of progenitor cells and tissue regeneration. In this work, we review the clinical challenges for calvarial reconstruction, the anatomy and physiology of bone, and extracellular matrix-inspired, collagen-based materials that have been tested for in vivo cranial defect healing. PMID- 28585298 TI - Severe erythematotelangiectatic rosacea with cold wave-induced epidermal necrosis treated with carvedilol combined with brimonidine gel. PMID- 28585299 TI - Mycobacterium bovis hosted by free-living-amoebae permits their long-term persistence survival outside of host mammalian cells and remain capable of transmitting disease to mice. AB - Bovine tuberculosis (TB) is a zoonotic disease caused by Mycobacterium bovis. Despite intensive TB control campaigns, there are sporadic outbreaks of bovine TB in regions declared TB free. It is unclear how M. bovis is able to survive in the environment for long periods of time. We hypothesized that Free-living amoebae (FLA), as ubiquitous inhabitants of soil and water, may act as long-term reservoirs of M. bovis in the environment. In our model, M. bovis would be taken up by amoebal trophozoites, which are the actively feeding, replicating and mobile form of FLA. Upon exposure to hostile environmental conditions, infected FLA will encyst and provide an intracellular niche allowing their M. bovis cargo to persist for extended periods of time. Here, we show that five FLA species (Acanthamoeba polyphaga, Acanthamoeba castellanii, Acanthamoeba lenticulata, Vermamoeba vermiformis and Dictyostellium discoideum) are permissive to M. bovis infection and that the M. bovis bacilli may survive within the cysts of four of these species for over 60 days. We further show that exposure of M. bovis infected trophozoites and cysts to Balb/c mice leads to pulmonary TB. This work describes for the first time that FLA carrying M. bovis can transmit TB. PMID- 28585300 TI - Investigation of error detection capabilities of phantom, EPID and MLC log file based IMRT QA methods. AB - A patient specific quality assurance (QA) should detect errors that originate anywhere in the treatment planning process. However, the increasing complexity of treatment plans has increased the need for improvements in the accuracy of the patient specific pretreatment verification process. This has led to the utilization of higher resolution QA methods such as the electronic portal imaging device (EPID) as well as MLC log files and it is important to know the types of errors that can be detected with these methods. In this study, we will compare the ability of three QA methods (Delta4 (r), MU-EPID, Dynalog QA) to detect specific errors. Multileaf collimator (MLC) errors, gantry angle, and dose errors were introduced into five volumetric modulated arc therapy (VMAT) plans for a total of 30 plans containing errors. The original plans (without errors) were measured five times with each method to set a threshold for detectability using two standard deviations from the mean and receiver operating characteristic (ROC) derived limits. Gamma passing percentages as well as percentage error of planning target volume (PTV) were used for passing determination. When applying the standard 95% pass rate at 3%/3 mm gamma analysis errors were detected at a rate of 47, 70, and 27% for the Delta4 , MU-EPID and Dynalog QA respectively. When using thresholds set at 2 standard deviations from our base line measurements errors were detected at a rate of 60, 30, and 47% for the Delta4 , MU-EPID and Dynalog QA respectively. When using ROC derived thresholds errors were detected at a rate of 60, 27, and 47% for the Delta4 , MU-EPID and Dynalog QA respectively. When using dose to the PTV and the Dynalog method 11 of the 15 small MLC errors were detected while none were caught using gamma analysis. A combination of the EPID and Dynalog QA methods (scaling Dynalog doses using EPID images) matches the detection capabilities of the Delta4 by adding additional comparison metrics. These additional metrics are vital in relating the QA measurement to the dose received by the patient which is ultimately what is being confirmed. PMID- 28585302 TI - Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis. AB - Mammalian target of rapamycin (mTOR) signalling controls many essential cellular functions. However, the role of Rictor/mTOR complex 2 (mTORC2) in regulating macrophage activation and kidney fibrosis remains largely unknown. We report here that Rictor/mTORC2 was activated in macrophages from the fibrotic kidneys of mice. Ablation of Rictor in macrophages reduced kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction or ischaemia/reperfusion injury. In bone marrow-derived macrophages (BMMs), deletion of Rictor or blockade of protein kinase Calpha inhibited cell migration. Additionally, deletion of Rictor or blockade of Akt abolished interleukin-4-stimulated or transforming growth factor (TGF)-beta1 stimulated macrophage M2 polarization. Furthermore, deletion of Rictor downregulated TGF-beta1-stimulated upregulation of multiple profibrotic cytokines, including platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor, in BMMs. Conditioned medium from TGF beta1-pretreated Rictor-/- macrophages stimulated fibroblast activation less efficiently than that from TGF-beta1-pretreated Rictor+/+ macrophages. These results demonstrate that Rictor/mTORC2 signalling can promote macrophage activation and kidney fibrosis. Targeting this signalling pathway in macrophages may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 28585304 TI - An analysis of the delivery of anaesthetic training sessions in the United Kingdom. AB - We analysed data from the electronic rota system CLWRota, covering 2,689,962 anaesthetic sessions between 01/01/2014 and 31/12/2015, in 91 UK Trusts, in order to investigate trainees' supervision. There were 8209 trainee attachments analysed, during which 618,695 sessions were undertaken by trainees. The number of supervised sessions per week that trainees worked varied considerably (median (IQR [range]) 2.6 (1.6-3.6 [0-10]) for all grades combined), with senior trainees more likely than junior trainees to be supervised for fewer than the three sessions per week mandated by the Royal College of Anaesthetists. The number of supervised sessions was unrelated to Trusts' size, suggesting that trainees in smaller hospitals receive the same level of supervision as in larger teaching hospitals. Analysis of a dataset of this size should be a good reflection of the delivery of anaesthesia training in the UK. PMID- 28585303 TI - Different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. AB - Celiac disease is associated with the HLA-DR3-DQA1*05:01-DQB1*02:01 and DR4 DQA1*03:01-DQB1*03:02 haplotypes. In addition, there are currently over 40 non HLA loci associated with celiac disease. This study extends previous analyses on different HLA haplotypes in celiac disease using next generation targeted sequencing. Included were 143 patients with celiac disease and 135 non-celiac disease controls investigated at median 9.8 years (1.4-18.3 years). PCR-based amplification of HLA and sequencing with Illumina MiSeq technology were used for extended sequencing of the HLA class II haplotypes HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1, respectively. Odds ratios were computed marginally for every allele and haplotype as the ratio of allelic frequency in patients and controls as ratio of exposure rates (RR), when comparing a null reference with equal exposure rates in cases and controls. Among the extended HLA haplotypes, the strongest risk haplotype for celiac disease was shown for DRB3*01:01:02 in linkage with DQA1*05:01-DQB1*02:01 (RR = 6.34; P-value < .0001). In a subpopulation analysis, DRB3*01:01:02-DQA1*05:01-DQB1*02:01 remained the most significant in patients with Scandinavian ethnicity (RR = 4.63; P < .0001) whereas DRB1*07:01:01-DRB4*01:03:01-DQA1*02:01-DQB1*02:02:01 presented the highest risk of celiac disease among non-Scandinavians (RR = 7.94; P = .011). The data also revealed 2 distinct celiac disease risk DR3-DQA1*05:01-DQB*02:01 haplotypes distinguished by either the DRB3*01:01:02 or DRB3*02:02:01 alleles, indicating that different DRB1*03:01-DQB1*02:01 haplotypes confer different risk for celiac disease. The associated risk of celiac disease for DR3-DRB3*01:01:02 DQA1*05:01-DQB1*02:01 is predominant among patients of Scandinavian ethnicity. PMID- 28585305 TI - The universal light coupler. PMID- 28585306 TI - Circulation and diagnostics of Puumala virus in Norway: nephropatia epidemica incidence and rodent population dynamics. AB - Hantaviruses pose a public health concern worldwide causing haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Puumala virus (PUUV) is the most prevalent hantavirus in Central and Northern Europe, and causes a mild form of HFRS, also known as nephropathia epidemica (NE). In nature, the main host of PUUV is the bank vole (Myodes glareolus), and transmission to humans occurs through inhalation of aerosols from rodent excreta. Nephropathia epidemica is particularly prevalent in Nordic countries, however, few studies of PUUV have been performed in Norway. The aim of this study was to analyse the dynamics of PUUV in Norway and compare with bank vole population dynamics, and also to complement the current diagnostic methodology of NE in Norway. Our results showed a significant seasonal and geographical variation of NE, and a general parallel peak trend between bank vole population densities and human NE incidence. A real-time and a nested PCR were successfully established as an invaluable diagnostic tool, with detection and sequencing of PUUV in a human serum sample for the first time in Norway. Phylogenetic analysis showed clustering of the obtained human sample with previous Norwegian bank vole isolates. PMID- 28585307 TI - Maternal antibodies against tetanus toxoid do not inhibit potency of antibody responses to autologous antigen in newborn rhesus monkeys. AB - BACKGROUND: Our previous study suggested newborns have competent immune systems with the potential to respond to foreign antigens and vaccines. In this study, we examined infant immune responses to tetanus toxoid (TT) vaccination in the presence of maternal antibody to TT. METHODS: We examined changes in plasma levels of tetanus toxoid-specific IgG1 (anti-TT IgG1) in a total of eight infant rhesus macaques from birth through 6 months of age using a commercial Monkey Anti TT IgG1 ELISA kit. RESULTS: A significant correlation between anti-TT IgG1 levels in vaccinated dams and their paired newborn infants was detected in control (non vaccinated) infants as previously reported. Maternal anti-TT IgG1 levels declined rapidly within 1 month of birth in non-vaccinated infants (n=4). In four infants vaccinated with TT at birth, we found two had rapid and robust antibody responses to vaccination. Interestingly, the other two first showed declining TT antibody levels for 2 weeks followed by increasing levels without additional vaccine boosts, indicating all four had good antibody responses to primary TT vaccination at birth, despite the presence of high levels of maternal antibodies to TT in all four infants. CONCLUSIONS: Our data indicate that newborn macaques have competent immune systems that are capable of generating their own primary antibody responses to vaccination, at least to tetanus antigens. Maternal antibodies thus do not significantly impair antibody response to the vaccination, even when received on the day of birth in infant rhesus macaques. PMID- 28585301 TI - Analysis of complete genome sequence and major surface antigens of Neorickettsia helminthoeca, causative agent of salmon poisoning disease. AB - Neorickettsia helminthoeca, a type species of the genus Neorickettsia, is an endosymbiont of digenetic trematodes of veterinary importance. Upon ingestion of salmonid fish parasitized with infected trematodes, canids develop salmon poisoning disease (SPD), an acute febrile illness that is particularly severe and often fatal in dogs without adequate treatment. We determined and analysed the complete genome sequence of N. helminthoeca: a single small circular chromosome of 884 232 bp encoding 774 potential proteins. N. helminthoeca is unable to synthesize lipopolysaccharides and most amino acids, but is capable of synthesizing vitamins, cofactors, nucleotides and bacterioferritin. N. helminthoeca is, however, distinct from majority of the family Anaplasmataceae to which it belongs, as it encodes nearly all enzymes required for peptidoglycan biosynthesis, suggesting its structural hardiness and inflammatory potential. Using sera from dogs that were experimentally infected by feeding with parasitized fish or naturally infected in southern California, Western blot analysis revealed that among five predicted N. helminthoeca outer membrane proteins, P51 and strain-variable surface antigen were uniformly recognized. Our finding will help understanding pathogenesis, prevalence of N. helminthoeca infection among trematodes, canids and potentially other animals in nature to develop effective SPD diagnostic and preventive measures. Recent progresses in large-scale genome sequencing have been uncovering broad distribution of Neorickettsia spp., the comparative genomics will facilitate understanding of biology and the natural history of these elusive environmental bacteria. PMID- 28585308 TI - Immunosurveillance profile of oral squamous cell carcinoma and oral epithelial dysplasia through dendritic and T-cell analysis. AB - : Oral squamous cell carcinomas (OSCCs) can arise from potentially malignant disorders, such as leukoplakia. The immune system plays an important role recognizing tumour precursor cells. However, due to immuno-editing mechanisms cancer cells are able to escape immune system surveillance. OBJECTIVE: To evaluate the profile of dendritic (Langerhans and plasmacytoid) and T cells in OSCC and oral epithelial dysplasia (OED) and correlate these findings with clinical data. MATERIALS AND METHODS: Fifty cases of OSCC and 48 of OED were immunostained for CD1a and CD83 dendritic Langerhans cells (DLC), CD303 plasmacytoid dendritic cells (pDC) and CD8 followed by quantitative analysis. RESULTS: Analysis revealed a significant decrease in the number of mature CD83 DLC in OSCC compared with OED. CD303 positivity was significantly increased in the OSCC group when compared to OED. CD8-positive lymphocytes were significantly decreased in OSCC compared with OED lesions. No statistical correlation was found with clinical data. CONCLUSION: The number of mature dendritic cells (DC) was decreased in OSCC compared with OED lesions suggesting that either these cells might have migrated to lymph nodes to present the tumour antigens and activate the immune system or cytokines secreted by the tumour microenvironment are inhibiting the adequate maturation of DLC. The numbers of pDC were significantly increased in the OSCC group compared with the OED group. This suggests they may play an important role in the defence against tumours although it is not clear whether this is promoting or inhibiting malignant progression. PMID- 28585309 TI - A High-Performance Li-O2 Battery with a Strongly Solvating Hexamethylphosphoramide Electrolyte and a LiPON-Protected Lithium Anode. AB - The aprotic Li-O2 battery has attracted a great deal of interest because theoretically it can store more energy than today's Li-ion batteries. However, current Li-O2 batteries suffer from passivation/clogging of the cathode by discharged Li2 O2 , high charging voltage for its subsequent oxidation, and accumulation of side reaction products (particularly Li2 CO3 and LiOH) upon cycling. Here, an advanced Li-O2 battery with a hexamethylphosphoramide (HMPA) electrolyte is reported that can dissolve Li2 O2 , Li2 CO3 , and LiOH up to 0.35, 0.36, and 1.11 * 10-3 m, respectively, and a LiPON-protected lithium anode that can be reversibly cycled in the HMPA electrolyte. Compared to the benchmark of ether-based Li-O2 batteries, improved capacity, rate capability, voltaic efficiency, and cycle life are achieved for the HMPA-based Li-O2 cells. More importantly, a combination of advanced research techniques provide compelling evidence that operation of the HMPA-based Li-O2 battery is backed by nearly reversible formation/decomposition of Li2 O2 with negligible side reactions. PMID- 28585310 TI - Direct-acting antivirals for chronic hepatitis C. AB - BACKGROUND: Millions of people worldwide suffer from hepatitis C, which can lead to severe liver disease, liver cancer, and death. Direct-acting antivirals (DAAs) are relatively new and expensive interventions for chronic hepatitis C, and preliminary results suggest that DAAs may eradicate hepatitis C virus (HCV) from the blood (sustained virological response). However, it is still questionable if eradication of hepatitis C virus in the blood eliminates hepatitis C in the body, and improves survival and leads to fewer complications. OBJECTIVES: To assess the benefits and harms of DAAs in people with chronic HCV. SEARCH METHODS: We searched for all published and unpublished trials in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, LILACS, and BIOSIS; the Chinese Biomedical Literature Database (CBM), China Network Knowledge Information (CNKI), the Chinese Science Journal Database (VIP), Google Scholar, The Turning Research into Practice (TRIP) Database, ClinicalTrials.gov, European Medicines Agency (EMA) (www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp), the Food and Drug Administration (FDA) (www.fda.gov), and pharmaceutical company sources for ongoing or unpublished trials. Searches were last run in October 2016. SELECTION CRITERIA: Randomised clinical trials comparing DAAs versus no intervention or placebo, alone or with co-interventions, in adults with chronic HCV. We included trials irrespective of publication type, publication status, and language. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were hepatitis C-related morbidity, serious adverse events, and quality of life. Our secondary outcomes were all-cause mortality, ascites, variceal bleeding, hepato renal syndrome, hepatic encephalopathy, hepatocellular carcinoma, non-serious adverse events (each reported separately), and sustained virological response. We systematically assessed risks of bias, performed Trial Sequential Analysis, and followed an eight-step procedure to assess thresholds for statistical and clinical significance. The overall quality of the evidence was evaluated using GRADE. MAIN RESULTS: We included a total of 138 trials randomising a total of 25,232 participants. The 138 trials assessed the effects of 51 different DAAs. Of these, 128 trials employed matching placebo in the control group. All included trials were at high risk of bias. Eighty-four trials involved DAAs on the market or under development (13,466 participants). Fifty-seven trials administered withdrawn or discontinued DAAs. Trial participants were treatment-naive (95 trials), treatment-experienced (17 trials), or both treatment-naive and treatment experienced (24 trials). The HCV genotypes were genotype 1 (119 trials), genotype 2 (eight trials), genotype 3 (six trials), genotype 4 (nine trials), and genotype 6 (one trial). We identified two ongoing trials.Meta-analysis of the effects of all DAAs on the market or under development showed no evidence of a difference when assessing hepatitis C-related morbidity or all-cause mortality (OR 3.72, 95% CI 0.53 to 26.18, P = 0.19, I2 = 0%, 2,996 participants, 11 trials, very low quality evidence). As there were no data on hepatitis C-related morbidity and very few data on mortality (DAA 15/2377 (0.63%) versus control 1/617 (0.16%)), it was not possible to perform Trial Sequential Analysis on hepatitis C-related morbidity or all-cause mortality.Meta-analysis of all DAAs on the market or under development showed no evidence of a difference when assessing serious adverse events (OR 0.93, 95% CI 0.75 to 1.15, P = 0.52, I2 = 0%, 15,817 participants, 43 trials, very low-quality evidence). The Trial Sequential Analysis showed that the cumulative Z-score crossed the trial sequential boundary for futility, showing that there was sufficient information to rule out that DAAs compared with placebo reduced the relative risk of a serious adverse event by 20%. The only DAA that showed a significant difference on risk of serious adverse events when meta analysed separately was simeprevir (OR 0.62, 95% CI 0.45 to 0.86). However, Trial Sequential Analysis showed that there was not enough information to confirm or reject a relative risk reduction of 20%, and when one trial with an extreme result was excluded, then the meta-analysis result showed no evidence of a difference.DAAs on the market or under development seemed to reduce the risk of no sustained virological response (RR 0.44, 95% CI 0.37 to 0.52, P < 0.00001, I2 = 77%, 6886 participants, 32 trials, very low-quality evidence) and Trial Sequential Analysis confirmed this meta-analysis result.Only 1/84 trials on the market or under development assessed the effects of DAAs on health-related quality of life (SF-36 mental score and SF-36 physical score).Withdrawn or discontinued DAAs had no evidence of a difference when assessing hepatitis C related morbidity and all-cause mortality (OR 0.64, 95% CI 0.23 to 1.79, P = 0.40, I2 = 0%; 5 trials, very low-quality evidence). However, withdrawn DAAs seemed to increase the risk of serious adverse events (OR 1.45, 95% CI 1.22 to 1.73, P = 0.001, I2 = 0%, 29 trials, very low-quality evidence), and Trial Sequential Analysis confirmed this meta-analysis result.Most of all outcome results were short-term results; therefore, we could neither confirm nor reject any long-term effects of DAAs. None of the 138 trials provided useful data to assess the effects of DAAs on the remaining secondary outcomes (ascites, variceal bleeding, hepato-renal syndrome, hepatic encephalopathy, and hepatocellular carcinoma). AUTHORS' CONCLUSIONS: Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low. PMID- 28585311 TI - Real-Time Observation of Carbon Nanotube Etching Process Using Polarized Optical Microscope. AB - Controllable synthesis of carbon nanotubes (CNTs) is of great importance in its further application, which attracts broad attention. As growth and etching are the two sides in the process of material crystallography and the control of the competition between them forms the foundation for modern technology of materials design and manufacture, the understanding on etching process of carbon nanotubes is still very unclear because technically it is of great challenge to characterize the dynamics in such small one-dimensional (1D) scale. Here the real time investigation on the etching process of CNTs is reported, by the hot-wall chemical reactor equipped with a polarized optical microscope. It is discovered that the CNT etching behavior in air is totally of random, including the etching sites, termination sites, and structure dependence. Combining with the dynamic simulation, it is revealed that the random behavior reflects the unique "self termination" phenomenon. A structure-independent etching propagation barrier of 2.4 eV is also obtained, which indicates that the etching propagation process still follows the conventional Kinetic Wulff construction theory. The results represent the new knowledge on the etching process in carbon nanotube and can contribute to its selective enrichment. Furthermore, the "self-termination" phenomenon may be a universal behavior in 1D process. PMID- 28585312 TI - Manganese-Based Layered Double Hydroxide Nanoparticles as a T1 -MRI Contrast Agent with Ultrasensitive pH Response and High Relaxivity. AB - Recently, Mn(II)-containing nanoparticles have been explored widely as an attractive alternative to Gd(III)-based T1 -weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn-based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5-7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH-ultrasensitive Mn-based layered double hydroxide (Mn-LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm-1 s-1 at pH 5.0 and 6.82 mm-1 s-1 at pH 7.0 vs 1.16 mm-1 s-1 at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn-LDH, as demonstrated by extended X-ray absorption fine structure. Further in vivo imaging reveals that Mn-LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment. PMID- 28585313 TI - Ultrastiff Hydrogels Prepared by Schiff's Base Reaction of Bis(p-Formylphenyl) Sebacate and Pillar[5]arene Appended with Multiple Hydrazides. AB - Herein a facile method is reported to prepare polymer gels based on the formation of acylhydrazone bond under mild conditions. A pillar[5]arene derivative appended with ten hydrazide groups provides multiple sites for the reaction with the aldehyde groups of bis(p-formylphenyl) sebacate in the presence of a small amount of HCl as the catalyst in dimethyl sulfoxide (DMSO), producing transparent polymer organogels. The mechanical properties of gels can be easily tuned by the molar ratio of the reactant compounds. After solvent exchange from DMSO to water, translucent polymer hydrogels with dramatically enhanced strength and stiffness are obtained. The tensile breaking stress and Young's modulus of hydrogels are 20 60 and 1.2-2.7 MPa, respectively, 100 and 20 times those of the corresponding organogels. These robust hydrogels with ultrahigh stiffness should find applications such as in load-bearing artificial organs. This work should merit designing functional materials using other macrocycles. PMID- 28585314 TI - Yield, quality and biochemical properties of various strawberry cultivars under water stress. AB - BACKGROUND: Although strawberry (Fragaria x ananassa Duch.) species are sensitive to abiotic stress conditions, some cultivars are known to be tolerant to different environmental conditions. We examined the response of different strawberry cultivars to water stress conditions in terms of yield, quality and biochemical features. The trial was conducted under two different irrigation regimes: in grow bags containing cocopeat (control, 30%; water stress, 15% drainage) with four different cultivars (Camarosa, Albion, Amiga and Rubygem). RESULTS: Fruit weight declined by 59.72% and the yield per unit area by 63.62% under water stress conditions as compared to control. Albion and Rubygem were found to be more tolerant and Amiga the most sensitive in terms of yield under stress conditions. Water stress increased all biochemical features in fruits such as total phenol, total anthocyanin, antioxidant activity and sugar contents. Among the cultivars, glucose and fructose was higher in Albion. CONCLUSION: Considering the rise in global warming, identification of resistant and tolerant cultivars to stress conditions are crucial for future breeding programmes. Our results showed that some of the fruit's physical features were affected negatively by stress conditions whereas many of the biochemical features such as total anthocyanin content, total phenolic content and antioxidant activity were positively modulated. (c) 2017 Society of Chemical Industry. PMID- 28585315 TI - Heparin-binding protein as a biomarker of acute kidney injury in critical illness. AB - BACKGROUND: There is no biomarker with high sensitivity and specificity for the development of acute kidney injury (AKI) in a mixed intensive care unit (ICU) population. Heparin-binding protein (HBP) is released from granulocytes and causes increased vascular permeability which plays a role in the development of AKI in sepsis and ischemia. The aim of this study was to investigate whether plasma levels of HBP on admission can predict the development of AKI in a mixed ICU population and in the subgroup with sepsis. METHODS: Longitudinal observational study with plasma HBP levels from 245 patients taken on admission to ICU. Presence and severity of AKI was scored daily for 1 week. RESULTS: Mean (95% CI) plasma concentrations of log HBP (ng/ml) in the groups developing different stages of AKI were: stage 0 (n = 175), 3.5 (3.4-3.7); stage 1 (n = 33), 3.7 (3.5-4.0), stage 2 (n = 20), 4.4 (3.5-4.8); and stage 3 (n = 17), 4.6 (3.8 5.2). HBP levels were significantly higher in patients developing AKI stage 3 (P < 0.01) compared to AKI stage 0 and 1. The area under the curve (AUC) for HBP to discriminate the group developing AKI stage 2-3 was 0.70 (CI: 0.58-0.82) and in the subgroup with severe sepsis 0.88 (CI: 0.77-0.99). CONCLUSION: Heparin-binding protein levels on admission to ICU are associated with the development of severe kidney injury. The relationship between HBP and AKI needs to be further validated in larger studies. PMID- 28585316 TI - Patterns of antiepileptic drug prescription in Sweden: A register-based approach. AB - OBJECTIVES: To determine drug utilization pathways from the incident healthcare visit due to epilepsy and three years onward. MATERIAL AND METHODS: Anti epileptic drug utilization was calculated using individual information on inpatient- and outpatient care utilization and drug sales. Throughout, we used national register information pertaining to pharmaceutical sales linked to diagnosis-related healthcare utilization. Information on pharmaceutical sales was collected for the 2007-2013 period. RESULTS: For the entire studied period, a majority of new patients with epilepsy were initiated on anti-epileptic drug treatment with a monotherapy (98%); most of these patients remained on that first treatment (64%). The three most frequently prescribed drugs accounted for 72% of the initiated AED treatments. Patients with epilepsy (ICD-10: G40/41) were most commonly prescribed carbamazepine, lamotrigine and valproate. The most common second-line monotherapy was levetiracetam. About 12% of new patients with epilepsy who were initiated on AED treatment during the period eventually switched to an add-on therapy. The proportion of patients who were initiated on treatment with carbamazepine or valproate decreased, and the proportion of patients who remained on their initial monotherapy increased between 2007 and 2013. CONCLUSIONS: A limited number of anti-epileptic drugs accounted for the treatment of a majority of new patients with epilepsy (carbamazepine, lamotrigine and valproate accounted for more than 70%). Add-on therapies showed the same pattern, as the most frequently prescribed add-on regimens were the same ones that accounted for most of the monotherapies. There was a tendency towards fewer patients being initiated on AED treatment with either carbamazepine or valproate. PMID- 28585317 TI - Modified posterior pelvic exenteration for advanced ovarian malignancies: a single-institution study of 35 cases. AB - INTRODUCTION: This study aimed to investigate the possible benefits of a complete cytoreduction in patients with advanced ovarian cancer and concomitant rectal invasion. Furthermore, we evaluated the morbidity associated with radical surgery. MATERIAL AND METHODS: A retrospective analysis examined 35 women who underwent radical surgery in the form of modified posterior pelvic exenteration. Descriptive statistics, Kaplan-Meier survival curves and log-rank test were used for statistical estimations. Surgical complications were analyzed using the Clavien-Dindo classification. RESULTS: The analysis of survival in relation to residual disease assessed according to Sugarbaker confirmed an optimistic prognosis in patients with optimal debulking with a mean disease-free survival period of 33.6 months in R0 patients, 19.6 months in R1 patients, and 14.3 months in R2 patients. A statistically significant difference in disease-free survival (p = 0.023) was observed between the R0 (without residual disease) and R1+2 (with residual disease) groups. Surgical complications occurred in 83% of patients, with early postoperative complications being most frequent (65.7%). While grade III-IV complications occurred in 37.7% of all patients, no cases of surgery associated mortality occurred. CONCLUSIONS: Modified posterior pelvic exenteration is a highly effective method for achieving optimal debulking in cases of advanced ovarian cancer with the direct invasion of the rectum. Modified posterior pelvic exenteration does not delay the beginning of complementary chemotherapy. However, it is necessary to take into account surgery-related morbidity. As modified posterior pelvic exenteration represents an extremely invasive technique, the surgical plan and perioperative care should be personalized to address the individual medical and surgical conditions of each patient. PMID- 28585318 TI - Hermansky-Pudlak syndrome type 2: Aberrant pre-mRNA splicing and mislocalization of granule proteins in neutrophils. AB - Hermansky-Pudlak syndrome type 2 (HPS2) is a syndrome caused by mutations in the beta-3A subunit of the adaptor protein (AP)-3 complex (AP3B1 gene). We describe five unreported cases with four novel mutations, one of which caused aberrant pre mRNA splicing. A point mutation c.2702C>G in exon 23 of the AP3B1 gene caused deletion of 112 bp in the mRNA in two siblings. This mutation activates a cryptic donor splice site that overrules the wild-type donor splice site of this exon. Three other novel mutations in AP3B1 were identified, that is, a nonsense mutation c.716G>A (p.Trp239Ter), a 1-bp and a 4-bp deletion c.177delA and c.1839_1842delTAGA, respectively, both causing frameshift and premature termination of translation. Mass spectrometry in four of these HPS2 patients demonstrated the (near) absence of all AP-3 complex subunits. Immunoelectron microscopy on the neutrophils of two of these patients showed abnormal granule formation. We found clear mislocalization of myeloperoxidase in the neutrophils even though the content of this protein but not the activity seemed to be present at normal levels. In sum, HPS2 is the result of the absence of the entire AP-3 complex, which results in severe neutropenia with a defect in granule formation as the major hematological finding. PMID- 28585319 TI - Structurally and Functionally Optimized Silk-Fibroin-Gelatin Scaffold Using 3D Printing to Repair Cartilage Injury In Vitro and In Vivo. AB - Articular cartilage repair remains a great challenge for clinicians and researchers. Recently, there emerges a promising way to achieve one-step cartilage repair in situ by combining endogenic bone marrow stem cells (BMSCs) with suitable biomaterials using a tissue engineering technique. To meet the increasing demand for cartilage tissue engineering, a structurally and functionally optimized scaffold is designed, by integrating silk fibroin with gelatin in combination with BMSC-specific-affinity peptide using 3D printing (3DP) technology. The combination ratio of silk fibroin and gelatin greatly balances the mechanical properties and degradation rate to match the newly formed cartilage. This dually optimized scaffold has shown superior performance for cartilage repair in a knee joint because it not only retains adequate BMSCs, due to efficient recruiting ability, and acts as a physical barrier for blood clots, but also provides a mechanical protection before neocartilage formation and a suitable 3D microenvironment for BMSC proliferation, differentiation, and extracellular matrix production. It appears to be a promising biomaterial for knee cartilage repair and is worthy of further investigation in large animal studies and preclinical applications. Beyond knee cartilage, this dually optimized scaffold may also serve as an ideal biomaterial for the regeneration of other joint cartilages. PMID- 28585321 TI - Delayed onset filler complication: Two case reports and literature review. AB - Soft tissue augmentation by fillers has become a popular cosmetic tool to offer rejuvenation and aesthetic improvement. Its results are comparable to those previously achieved only by plastic surgery. However, marked increase of filler procedures is associated with a great number of complications. Complications associated with filler injection might have early onset (within days) or late onset (after weeks to years). Delayed complications include infections, foreign body granulomatous reaction, migration of filler material, persistent discoloration, and scarring. Here we report two cases of delayed complications: one case of foreign body granuloma with migration and one case of acute inflammation involving a quiescent granuloma. PMID- 28585322 TI - Semiparametric regression analysis of failure time data with dependent interval censoring. AB - Interval-censored failure-time data arise when subjects are examined or observed periodically such that the failure time of interest is not examined exactly but only known to be bracketed between two adjacent observation times. The commonly used approaches assume that the examination times and the failure time are independent or conditionally independent given covariates. In many practical applications, patients who are already in poor health or have a weak immune system before treatment usually tend to visit physicians more often after treatment than those with better health or immune system. In this situation, the visiting rate is positively correlated with the risk of failure due to the health status, which results in dependent interval-censored data. While some measurable factors affecting health status such as age, gender, and physical symptom can be included in the covariates, some health-related latent variables cannot be observed or measured. To deal with dependent interval censoring involving unobserved latent variable, we characterize the visiting/examination process as recurrent event process and propose a joint frailty model to account for the association of the failure time and visiting process. A shared gamma frailty is incorporated into the Cox model and proportional intensity model for the failure time and visiting process, respectively, in a multiplicative way. We propose a semiparametric maximum likelihood approach for estimating model parameters and show the asymptotic properties, including consistency and weak convergence. Extensive simulation studies are conducted and a data set of bladder cancer is analyzed for illustrative purposes. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585323 TI - Racial differences in periodontal disease and 10-year self-reported tooth loss among late middle-aged and older adults: the dental ARIC study. AB - OBJECTIVE: To investigate racial differences in the associations between periodontitis and 10-year self-reported incident tooth loss in a biracial, community-based cohort of US late middle-aged and older adults. METHODS: Subjects were 3,466 dentate men and women aged 53-74 who underwent dental examinations from 1996 to1998. In 2012-2013, telephone interviewers asked participants about tooth loss in the preceding 10 years. Separate multivariable ordinal logistic regression models were used to calculate proportional odds ratios (OR) and 95% confidence intervals (CI) as estimates of association between periodontitis and tooth loss for Whites and African-Americans (AAs). RESULTS: The majority of participants were White (85 percent) and female (57 percent) with 23 teeth on average at enrollment. Approximately half the Whites (56 percent) and AAs (49 percent) had periodontitis. At follow-up, approximately 44 percent of AAs and 38 percent of Whites reported having lost >=1 tooth. In multivariable models, severe periodontitis (OR = 3.03; 95% CI = 2.42-3.80) and moderate periodontitis (OR = 1.64; 95% CI= 1.39-1.94) were significant risk factors of incident tooth loss among Whites. For AAs, severe but not moderate periodontitis increased the odds of incident tooth loss (OR = 2.22; 95% CI = 1.37-3.59). In the final model, education was inversely associated with incident tooth loss among AAs, while lower income was associated with greater odds of tooth loss among Whites. CONCLUSIONS: In this population-based cohort, there is racial heterogeneity in the association between periodontitis and tooth loss. Interventions to reduce the impact of periodontitis on tooth loss need to consider these differences. PMID- 28585325 TI - Synaptic distribution of individually labeled mitral cells in the external plexiform layer of the mouse olfactory bulb. PMID- 28585320 TI - Blockade of the 5-HT transporter contributes to the behavioural, neuronal and molecular effects of cocaine. AB - BACKGROUND AND PURPOSE: The psychostimulant cocaine induces complex molecular, cellular and behavioural responses as a consequence of inhibiting presynaptic dopamine, noradrenaline and 5-HT transporters. To elucidate 5-HT transporter (SERT)-specific contributions to cocaine action, we evaluated cocaine effects in the SERT Met172 knock-in mouse, which expresses a SERT coding substitution that eliminates high-affinity cocaine recognition. EXPERIMENTAL APPROACH: We measured the effects of SERT Met172 on cocaine antagonism of 5-HT re-uptake using ex vivo synaptosome preparations and in vivo microdialysis. We assessed SERT dependence of cocaine actions behaviourally through acute and chronic locomotor activation, sensitization, conditioned place preference (CPP) and oral cocaine consumption. We used c-Fos, quantitative RT-PCR and RNA sequencing methods for insights into cellular and molecular networks supporting SERT-dependent cocaine actions. KEY RESULTS: SERT Met172 mice demonstrated functional insensitivity for cocaine at SERT. Although they displayed wild-type levels of acute cocaine-induced hyperactivity or chronic sensitization, the pattern of acute motor activation was different, with a bias toward thigmotaxis. CPP was increased, and a time dependent elevation in oral cocaine consumption was observed. SERT Met172 mice displayed relatively higher levels of neuronal activation in the hippocampus, piriform cortex and prelimbic cortex (PrL), accompanied by region-dependent changes in immediate early gene expression. Distinct SERT-dependent gene expression networks triggered by acute and chronic cocaine administration were identified, including PrL Akt and nucleus accumbens ERK1/2 signalling. CONCLUSION AND IMPLICATIONS: Our studies reveal distinct SERT contributions to cocaine action, reinforcing the possibility of targeting specific aspects of cocaine addiction by modulation of 5-HT signalling. PMID- 28585324 TI - Identification of major loci and genomic regions controlling acid and volatile content in tomato fruit: implications for flavor improvement. AB - Plant metabolites are important to world food security due to their roles in crop yield and nutritional quality. Here we report the metabolic profile of 300 tomato accessions (Solanum lycopersicum and related wild species) by quantifying 60 primary and secondary metabolites, including volatile organic compounds, over a period of 2 yr. Metabolite content and genetic inheritance of metabolites varied broadly, both within and between different genetic groups. Using genotype information gained from 10 000 single nucleotide polymorphism markers, we performed a metabolite genome-wide association mapping (GWAS) study. We identified 79 associations influencing 13 primary and 19 secondary metabolites with large effects at high resolution. Four genome regions were detected, highlighting clusters of associations controlling the variation of several metabolites. Local linkage disequilibrium analysis and allele mining identified possible candidate genes which may modulate the content of metabolites that are of significant importance for human diet and fruit consumption. We precisely characterized two associations involved in fruit acidity and phenylpropanoid volatile production. Taken together, this study reveals complex and distinct metabolite regulation in tomato subspecies and demonstrates that GWAS is a powerful tool for gene-metabolite annotation and identification, pathways elucidation, and further crop improvement. PMID- 28585326 TI - Chicken feather hydrolysate as an inexpensive complex nitrogen source for PHA production by Cupriavidus necator on waste frying oils. AB - : The chicken feather hydrolysate (FH) has been tested as a potential complex nitrogen source for the production of polyhydroxyalkanoates by Cupriavidus necator H16 when waste frying oil was used as a carbon source. The addition of FH into the mineral salt media with decreased inorganic nitrogen source concentration improved the yields of biomass and polyhydrohyalkanoates. The highest yields were achieved when 10 vol.% of FH prepared by microwave-assisted alkaline hydrolysis of 60 g l-1 feather was added. In this case, the poly(3 hydroxybutyrate) (PHB) yields were improved by more than about 50% as compared with control cultivation. A positive impact of FH was also observed for accumulation of copolymer poly(3-hydroxybutyrate-co-3-hydroxyvalerate) when sodium propionate was used as a precursor. The copolymer has superior processing and mechanical properties in comparison with PHB homopolymer. The application of FH eliminated the inhibitory effect of propionate and resulted in altered content of 3-hydroxyvalerate (3HV) in copolymer. Therefore, the hydrolysed feather can serve as an excellent complex source of nitrogen for the polyhydroxyalkanoates (PHA) production. Moreover, by the combination of two inexpensive types of waste, such as waste frying oil and feather hydrolysate, it is possible to produce PHA with substantially improved efficiency and sustainability. SIGNIFICANCE AND IMPACT THE STUDY: Millions of tons of feathers, important waste product of poultry-processing industry, are disposed off annually without any further benefits. Thus, there is an inevitable need for new technologies that enable ecologically and economically sensible processing of this waste. Herein, we report that alkali-hydrolysed feathers can be used as a complex nitrogen source considerably improving polyhydroxyalkanoates production on waste frying oil employing Cupriavidus necator. PMID- 28585328 TI - The recommended dose of idarucizumab may not always be sufficient for sustained reversal of dabigatran: comment. PMID- 28585327 TI - Arabinoxylan activates lipid catabolism and alleviates liver damage in rats induced by high-fat diet. AB - BACKGROUND: Arabinoxylan was thought to have the potential to change lipid metabolism and redox homeostasis in human and animal. However, the effect of arabinoxylan on the liver damage induced by high-fat diet needs further exploiting. RESULTS: Six-weeks-old 30 male Sprague-Dawley Rats were assigned randomly to three groups (n = 10 per group), i.e. a control diet (CON) group, a high-fat diet (HF) group and a high-fat diet supplemented with arabinoxylan (6% AX, HF-AX) group. Results showed that final body weight and liver weight were similar in CON group and HF-AX group, but higher in the HF group. In serum, the HF-AX group showed lower triglyceride concentrations than did the HF group. In liver, higher lipoprotein lipase, hepatic lipase, total lipase, and acyl-CoA oxidase activities and lower triglyceride and cholesterol level were observed in the HF-AX group than in the HF group. For the redox homeostasis, arabinoxylan supplemented in HF increased T-SOD activity and GSH-PX activity and reduced MDA + 4-HNE level in liver and/or compared with those in the HF group. Lipid droplets and liver cell damage were observed in the HF group compared with the CON and HF AX groups. CONCLUSION: Arabinoxylan could improve lipid metabolic disorder and alleviate liver damage in rats induced by high-fat diet via activating lipid catabolism and suppressing lipid peroxidation. (c) 2017 Society of Chemical Industry. PMID- 28585329 TI - Effect of linseed supplementation and slaughter age on meat quality of grazing cross-bred Galician x Burguete foals. AB - BACKGROUND: The aim of this study was to assess the effect of finishing diet (control concentrate vs. linseed concentrate) and slaughter age (13 vs. 26 months) on meat and nutritional quality of foal meat. For this study, 46 foals from crossing Galicia Mountain x Burguete breeds were used. RESULTS: The obtained results showed that slaughter age had an influence on chemical composition and colour parameters. Foals slaughtered at the age of 13 months had lower content of intramuscular fat and higher cholesterol contents than those slaughtered at 26 months of age. Regarding colour parameters, older foals showed the highest values of redness and lowest myoglobin contents. Finishing diet had a low effect on the majority of parameters evaluated. Foals fed with linseed presented lower shear force values than those fed with control concentrate. Fatty acid and amino acid contents were hardly influenced by finishing diet, whereas slaughter age effect had a high impact on fatty acid profile. Older animals showed lowest SFA values and n-6/n-3 ratio. CONCLUSION: Older animals presented the best meat quality. Diet had low effect in meat quality and could be related to the short time during finishing diet was administered and the low amount of linseed in the experimental diet. (c) 2017 Society of Chemical Industry. PMID- 28585330 TI - The Optical Janus Effect: Asymmetric Structural Color Reflection Materials. AB - Structurally colored materials are often used for their resistance to photobleaching and their complex viewing-direction-dependent optical properties. Frequently, absorption has been added to these types of materials in order to improve the color saturation by mitigating the effects of nonspecific scattering that is present in most samples due to imperfect manufacturing procedures. The combination of absorbing elements and structural coloration often yields emergent optical properties. Here, a new hybrid architecture is introduced that leads to an interesting, highly directional optical effect. By localizing absorption in a thin layer within a transparent, structurally colored multilayer material, an optical Janus effect is created, wherein the observed reflected color is different on one side of the sample than on the other. A systematic characterization of the optical properties of these structures as a function of their geometry and composition is performed. The experimental studies are coupled with a theoretical analysis that enables a precise, rational design of various optical Janus structures with highly controlled color, pattern, and fabrication approaches. These asymmetrically colored materials will open applications in art, architecture, semitransparent solar cells, and security features in anticounterfeiting materials. PMID- 28585331 TI - The length of Y-chromosomal sequence reads in noninvasive prenatal testing reflect allogeneic bone marrow transplant. PMID- 28585332 TI - Inadequate adherence to Swedish guidelines for uncomplicated lower urinary tract infections among adults in general practice. AB - In a primary care study of urinary tract infections (UTIs) performed 2008 in Uppsala County, Sweden, 43% of the patients were culture negative. In order to investigate the background to the observed overdiagnosis of UTI, study invitations were sent to the previously included patients. A total of 256 patients (88% women) approved to participate. Patient charts and recorded laboratory data were reviewed. Two or more of the cardinal symptoms were reported in 53% of the women and in 19% of the men. A dipstick test was performed in 93% of the consultations. The highest positive predicted values in women had a positive nitrite test (95%, 95% CI 87; 99) and dysuria in combination with urgency (81%, 95% CI 72; 88). Seventy-one percent of the women who fulfilled the symptom criteria received an antibiotic prescription directly, 87% of these had a positive culture. The drug of choice was pivmecillinam for women (51%) and quinolones (50%) for men. The treatment duration was too long for the women; 68% were treated for >=7 days. In conclusion, the adherence to national guidelines/recommendations was inadequate. To reduce the selection of multiresistant bacteria, an improvement of the use of diagnostic criteria/tools and antibiotic drugs in primary care is necessary. PMID- 28585333 TI - Prospective cohort study: Cinacalcet-mediated lowering of PTH level and cardiovascular disease mortality in younger Korean patients with stage 5 CKD at a Korean secondary hospital. AB - WHAT IS KNOWN AND OBJECTIVES: Cinacalcet may reduce cardiovascular disease (CVD) mortality in elderly patients with chronic kidney disease (CKD). However, previous studies of the clinical responses to cinacalcet have exhibited discrepancies due to highly variable baseline levels of parathyroid hormone (PTH), kidney function and age. Little is known about the true effect of cinacalcet on stage 5 CKD. The objective of the current observational study was to evaluate whether cinacalcet-mediated lowering of PTH levels improves all-cause mortality and cardiovascular disease mortality in younger stage 5 CKD patients (mean age <55 years). METHODS: This prospective, cohort study reviewed the electronic medical records (EMRs) of CKD patients (n=540) with secondary hyperparathyroidism (SHPT) for a period of 36 months. Of 540 patients, 104 subjects met the inclusion criteria and were included in the final evaluation (mean serum iPTH 688.7 pg/mL). Patients were divided into a cinacalcet group (n=43) and a non-cinacalcet group (n=61). RESULTS AND DISCUSSION: Comparing the cinacalcet group to the non-cinacalcet group, Cox proportional hazard modelling found that all-cause mortality was five (31.3%) in the cinacalcet group and three (15.8%) in the non-cinacalcet group for patients with serum levels of PTH>600 pg/mL [P=.277, hazard ratio 2.213, 95% confidence interval (CI): 0.529-9.262]. Cardiovascular disease mortality (CVD: heart disease) occurred in two (5.3%) in the cinacalcet group and one (2.1%) in the non-cinacalcet group [P=.425, HR 2.611, 95% CI: 0.228-9.939]. Overall, there were no significant differences in CVD mortality between the two groups. WHAT IS NEW AND CONCLUSION: Cinacalcet was not associated with decreases in all-cause mortality or CVD mortality in younger stage 5 CKD patients with high PTH levels (>600 pg/mL). This could be explained by the diversity of the population in terms of the patient's age, health insurance policies, target serum level of biochemical and PTH, and glomerular filtration rate (GFR) at admission. These data, although based on an observational study, indicate that adding cinacalcet to the current standard care for younger stage 5 CKD patients should be re-evaluated. PMID- 28585334 TI - Low eddy current RF shielding enclosure designs for 3T MR applications. AB - PURPOSE: Magnetic resonance-compatible medical devices operate within the MR environment while benefitting from the superior anatomic information of MRI. Avoiding electromagnetic interference between such instrumentation and the MR system is crucial. In this work, various shielding configurations for positron emission tomography (PET) detectors were studied and analyzed regarding radiofrequency (RF) shielding effectiveness and gradient-induced eddy current performances. However, the results of this work apply to shielding considerations for any MR-compatible devices. METHODS: Six shielding enclosure configurations with various thicknesses, patterns, and materials were designed: solid and segmented copper, phosphor bronze mesh (PBM), and carbon fiber composite (CFC). A series of tests was performed on RF shielding effectiveness and the gradient induced eddy current. RESULTS: For the shielding effectiveness, the solid copper with various thickness and PBM configurations yield significantly better shielding effectiveness (>15 dB) compared with CFC and segmented configurations. For the gradient-induced eddy current performance, the solid copper shielding configurations with different thicknesses showed significantly worse results, up to a factor of 3.89 dB, compared with the segmented copper, PBM, and the CFC configurations. CONCLUSIONS: We evaluated the RF shielding effectiveness and the gradient-induced eddy current artifacts of several shielding designs, and only the PBM showed positive outcomes for both aspects. Magn Reson Med 79:1745-1752, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28585335 TI - Comparison of two skin imaging analysis instruments: The VISIA(r) from Canfield vs the ANTERA 3D(r) CS from Miravex. AB - BACKGROUND: The skin imaging analysis instruments are widely used to record and measure the surface and subsurface skin conditions. The main aim of this study is to reveal the differences and correlations in measuring wrinkle, skin texture, coloration/evenness, vascular features, and pore between two commercially available instruments. METHODS: Twenty-eight subjects were enrolled in the study. A 2*2 cm cardboard was used to make sure the two instruments analyze the same area. Pictures were taken and analyzed by the VISIA(r) from Canfield and the ANTERA 3D(r) CS from Miravex, in sequence. RESULTS: The spot, ultraviolet spot, brown spot, red area, texture values measured with VISIA(r) were positively correlated with age, while the pore and wrinkle values showed no significance. The wrinkle, texture, melanin, hemoglobin, pore index, pore volume values measured with ANTERA 3D(r) had a significantly positive correlation with age. The spot, brown spot values from VISIA(r) were positively correlated with the melanin value from ANTERA 3D(r) . Texture value measured with the two instruments revealed positive linear correlation. Strong correlation was found between the red area value from VISIA(r) and the hemoglobin value from ANTERA 3D(r) . Ultraviolet spot from VISIA(r) showed no linear correlation with the melanin value from ANTERA 3D(r) . Neither of the wrinkle and pore measured with the two instruments showed linear correlation. CONCLUSIONS: ANTERA 3D(r) relies on multidirectional illumination obtained by LEDs of different wavelengths from different directions which make it advanced at the qualitative evaluation of various dermatologic conditions. Compared with VISIA(r) , ANTERA 3D(r) is more sensitive in the assessment of wrinkle and it may also be available to evaluate the aging-related enlarged pore. PMID- 28585336 TI - Liver-Directed Human Amniotic Epithelial Cell Transplantation Improves Systemic Disease Phenotype in Hurler Syndrome Mouse Model. AB - Mucopolysaccharidosis type 1 (MPS1) is an inherited lysosomal storage disorder caused by a deficiency in the glycosaminoglycan (GAG)-degrading enzyme alpha-l iduronidase (IDUA). In affected patients, the systemic accumulation of GAGs results in skeletal dysplasia, neurological degeneration, multiple organ dysfunction, and early death. Current therapies, including enzyme replacement and bone marrow transplant, improve life expectancy but the benefits to skeletal and neurological phenotypes are limited. In this study, we tested the therapeutic efficacy of liver-directed transplantation of a placental stem cell, which possesses multilineage differentiation potential, low immunogenicity, and high lysosomal enzyme activity. Unfractionated human amniotic epithelial cells (hAECs) were transplanted directly into the liver of immunodeficient Idua knockout mouse neonates. The hAECs engraftment was immunohistochemically confirmed with anti human mitochondria staining. Enzyme activity assays indicated that hAECs transplantation restored IDUA function in the liver and significantly decreased urinary GAG excretion. Histochemical and micro-computed tomography analyses revealed reduced GAG deposition in the phalanges joints and composition/morphology improvement of cranial and facial bones. Neurological assessment in the hAEC treated mice showed significant improvement of sensorimotor coordination in the hAEC treated mice compared to untreated mice. Results confirm that partial liver cell replacement with placental stem cells can provide long-term (>20 weeks) and systemic restoration of enzyme function, and lead to significant phenotypic improvement in the MPS1 mouse model. This preclinical data indicate that liver-directed placental stem cell transplantation may improve skeletal and neurological phenotypes of MPS1 patients. Stem Cells Translational Medicine 2017;6:1583-1594. PMID- 28585338 TI - Research priorities for conservation and natural resource management in Oceania's small-island developing states. AB - For conservation science to effectively inform management, research must focus on creating the scientific knowledge required to solve conservation problems. We identified research questions that, if answered, would increase the effectiveness of conservation and natural resource management practice and policy in Oceania's small-island developing states. We asked conservation professionals from academia, governmental, and nongovernmental organizations across the region to propose such questions and then identify which were of high priority in an online survey. We compared the high-priority questions with research questions identified globally and for other regions. Of 270 questions proposed by respondents, 38 were considered high priority, including: What are the highest priority areas for conservation in the face of increasing resource demand and climate change? How should marine protected areas be networked to account for connectivity and climate change? What are the most effective fisheries management policies that contribute to sustainable coral reef fisheries? High-priority questions related to the particular challenges of undertaking conservation on small-island developing states and the need for a research agenda that is responsive to the sociocultural context of Oceania. Research priorities for Oceania relative to elsewhere were broadly similar but differed in specific issues relevant to particular conservation contexts. These differences emphasize the importance of involving local practitioners in the identification of research priorities. Priorities were reasonably well aligned among sectoral groups. Only a few questions were widely considered answered, which may indicate a smaller-than expected knowledge-action gap. We believe these questions can be used to strengthen research collaborations between scientists and practitioners working to further conservation and natural resource management in this region. PMID- 28585337 TI - Ultramicronized palmitoylethanolamide counteracts the effects of compound 48/80 in a canine skin organ culture model. AB - BACKGROUND: Ultramicronized palmitoylethanolamide (PEA-um) has been reported to reduce pruritus and skin lesions in dogs with moderate atopic dermatitis and pruritus. HYPOTHESIS/OBJECTIVES: A canine ex vivo skin model was used to investigate the ability of PEA-um to counteract changes induced by compound 48/80, a well-known secretagogue that causes mast cell degranulation. ANIMALS: Normal skin was obtained from three donor dogs subjected to surgery for reasons unrelated to the study. METHODS: Cultured skin biopsy samples in triplicate were treated with 10 and 100 MUg/mL compound 48/80, without or with 30 MUM PEA-um. Mast cell (MC) degranulation, histamine release into the culture medium, local microvascular dilatation, epidermal thickness, keratinocyte proliferation and epidermal differentiation markers were evaluated. RESULTS: Exposure of the skin organ culture to PEA-um 24 h before and 72 h concomitantly to compound 48/80 resulted in a significant decrease of degranulating MCs. PEA-um also reduced the histamine content in the culture medium by half, although the effect did not reach statistical significance. PEA-um significantly counteracted vasodilation induced by 100 MUg/mL compound 48/80. Finally, PEA-um alone did not induce changes in epidermal thickness, differentiation markers, keratinocyte proliferation, MC density and/or degranulation. CONCLUSIONS AND CLINICAL IMPORTANCE: Collectively, these results support the protective action PEA-um on the skin of dogs undergoing allergic changes. PMID- 28585339 TI - Graphitized Carbon Fibers as Multifunctional 3D Current Collectors for High Areal Capacity Li Anodes. AB - The Li metal anode has long been considered as one of the most ideal anodes due to its high energy density. However, safety concerns, low efficiency, and huge volume change are severe hurdles to the practical application of Li metal anodes, especially in the case of high areal capacity. Here it is shown that that graphitized carbon fibers (GCF) electrode can serve as a multifunctional 3D current collector to enhance the Li storage capacity. The GCF electrode can store a huge amount of Li via intercalation and electrodeposition reactions. The as obtained anode can deliver an areal capacity as high as 8 mA h cm-2 and exhibits no obvious dendritic formation. In addition, the enlarged surface area and porous framework of the GCF electrode result in lower local current density and mitigate high volume change during cycling. Thus, the Li composite anode displays low voltage hysteresis, high plating/stripping efficiency, and long lifespan. The multifunctional 3D current collector promisingly provides a new strategy for promoting the cycling lifespan of high areal capacity Li anodes. PMID- 28585340 TI - A Supramolecular Artificial Light-Harvesting System with an Ultrahigh Antenna Effect. AB - An efficient artificial light-harvesting system is fabricated from a cyclic polysaccharide, sulfato-beta-cyclodextrin (SCD); an aggregation-induced emission molecule, an oligo(phenylenevinylene) derivative (OPV-I); and a fluorescent dye, nile red (NiR), via noncovalent interactions in an aqueous solution. In this system, the OPV-I/SCD supramolecular assembly acts as a donor, and NiR that is loaded into the OPV-I/SCD assembly acts as an acceptor. Significantly, an efficient energy-transfer process occurs between the OPV-I/SCD assembly and the loaded NiR, leading to an extremely high antenna effect. PMID- 28585341 TI - Investigation of a correlation between taxane-based chemotherapy and the ultrasonic time-of-flight of human fingernails. AB - BACKGROUND: Medical practitioners have long associated the physical appearance of human fingernails with certain underlying health conditions due to their direct connection to the vascular system. The objective of this study was to demonstrate how human fingernails can potentially be used as a biomarker to determine the severity of a patient's reaction to chemotherapy. METHODS: Quantitative investigation of fingernails in patients undergoing taxane-based chemotherapy was conducted using a high-frequency 50 MHz ultrasound device in B-mode in the form of a pilot study. Time-of-Flight (TOF) ultrasonic signal measurements were recorded longitudinally across fingernails over three time intervals; (before treatment, in the middle of treatment, and on the last day of treatment); a neuropathy assessment and photographs were also taken for comparison. RESULTS: A total of 17 patients were examined in this study with ages ranging from 35-69 years old with both weekly and biweekly chemotherapy regimens. Onycholysis and fingernail discoloration were observed in 8 of the 17 patients. White transverse lines and white lunula were observed on 4 of the 17 patients. Quantitative assessment revealed a TOF median decrease in fingernails during the first half of chemotherapy treatment; conversely, TOF median was found to have increased during the second half. Median TOF measurements at the end of treatment were found to return to approximately that of the baseline value. CONCLUSION: This was a novel application of ultrasound in fingernails as chemotherapy biomarkers and further studies should be considered to verify and expand on the results obtained in this study. PMID- 28585343 TI - Effects of four short-chain fatty acids or salts on fermentation characteristics and aerobic stability of alfalfa (Medicago sativa L.) silage. AB - BACKGROUND: The objective of the present study was to evaluate the effects of four chemicals on the fermentation quality and aerobic stability of alfalfa (Medicago sativa L.) silage. Wilted alfalfa was ensiled without additive (control), or with formic acid (FA), potassium diformate (KDF), sodium diacetate (SDA) or calcium propionate (CAP). RESULTS: After 60 days of ensiling, the pH values in FA, KDF and SDA silages were lower (P < 0.05) compared to that of control and CAP silages, and chemicals (P < 0.05) decreased butyric acid and ammonia N concentrations and populations of aerobic bacteria and yeasts compared to the control. The SDA and CAP silages had a higher (P < 0.05) lactic acid bacteria content compared to the FA and KDF silages. The SDA and CAP silages had higher (P < 0.05) acetic and propionic acid contents compared to the other silages, respectively. The ammonia N concentrations in the FA and KDF silages were lower compared to the other silages during the first 5 days of aerobic exposure, and then increased sharply to 105 and 100 g kg-1 total N, respectively, which was higher (P < 0.05) than that of the SDA and CAP silages on day 9 of aerobic exposure. Yeasts and aerobic bacteria counts in SDA silage slowly increased and remained at lower levels compared to the other silages after 7 days of aerobic exposure. CONCLUSION: Additives prolonged the aerobic stability duration compared to the control, and the SDA and CAP silages remained stable for more than 216 h, followed by the KDF and FA silages (202 and 196 h, respectively). (c) 2017 Society of Chemical Industry. PMID- 28585342 TI - European consensus statement on phenotypes of pustular psoriasis. AB - Pustular psoriasis (PP) is a group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis to such an extent that clinically visible sterile pustules develop. Because of clinical co incidence, PP is currently grouped with psoriasis vulgaris (PV). However, PP and PV are phenotypically different, respond differently to treatments and seem to be distinct on the genetic level. In contrast to PV, the phenotypes of PP are not well defined. Descriptions of each form of PP are discordant among standard dermatology textbooks [Saurat Dermatologie 2016, Rook's Dermatology 2016, Fitzpatrick's 2012 and Braun-Falco 2012], encumbering the collection of phenotypically well-matched groups of patients as well as clinical trials. The European Rare and Severe Psoriasis Expert Network (ERASPEN) was founded to define consensus criteria for diagnosis, deeply phenotype large groups of PP patients, analyse the genetics and pathophysiology and prepare for prospective clinical trials. This work reviews historical aspects of these conditions, new genetic findings and presents our initial considerations on the phenotypes of PP and a consensus classification of clinical phenotypes that will be used as a baseline for further, prospective studies of PP. Generalized pustular psoriasis (GPP) is defined as primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques). GPP can occur with or without systemic inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition. Acrodermatitis continua of Hallopeau (ACH) is characterized by primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus. Palmoplantar pustulosis (PPP) has primary, persistent (>3 months), sterile, macroscopically visible pustules on palms and/or soles and can occur with or without PV. PMID- 28585344 TI - A Game Changer: A Multifunctional Perovskite Exhibiting Giant Ferroelectricity and Narrow Bandgap with Potential Application in a Truly Monolithic Multienergy Harvester or Sensor. AB - An ABO3 -type perovskite solid-solution, (K0.5 Na0.5 )NbO3 (KNN) doped with 2 mol% Ba(Ni0.5 Nb0.5 )O3-delta (BNNO) is reported. Such a composition yields a much narrower bandgap (~1.6 eV) compared to the parental composition-pure KNN-and other widely used piezoelectric and pyroelectric materials (e.g., Pb(Zr,Ti)O3 , BaTiO3 ). Meanwhile, it exhibits the same large piezoelectric coefficient as that of KNN (~100 pC N-1 ) and a much larger pyroelectric coefficient (~130 uC m-2 K-1 ) compared to the previously reported narrow-bandgap material (KNbO3 )1-x -BNNOx . The unique combination of these excellent ferroelectric and optical properties opens the door to the development of multisource energy harvesting or multifunctional sensing devices for the simultaneous and efficient conversion of solar, thermal, and kinetic energies into electricity in a single material. Individual and comprehensive characterizations of the optical, ferroelectric, piezoelectric, pyroelectric, and photovoltaic properties are investigated with single and coexisting energy sources. No degrading interaction between ferroelectric and photovoltaic behaviors is observed. This composition may fundamentally change the working principles of state-of-the-art hybrid energy harvesters and sensors, and thus significantly increases the unit-volume energy conversion efficiency and reliability of energy harvesters in ambient environments. PMID- 28585345 TI - Genetic screening of FecB, FecXG and FecXI mutations and their linkage with litter size in Barki and Rahmani sheep breeds. AB - Characterization of fecundity genes offers the opportunity to improve production efficiency, and the consequent increase in litter size in livestock industry, through utilizing them in breeding programs. The main objective of this study was to detect the BMPR-IB, BMP15 and GDF9 gene mutations and to investigate whether these mutations are associated with litter size in Egyptian sheep breeds. To achieve this goal, 73 adult ewes representing Barki (n = 33) and Rahmani (n = 40) breeds were used. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) screening approach was used to detect the presence of FecB, FecXG and FecXI mutations in the two selected breeds. Results of this study showed that the three different candidate gene mutations, namely FecB, FecXG and FecXI are not present among these selected populations of the Egyptian breeds. Further studies regarding other mutations and/or other genes, which may influence ovulation rate, should be carried out to determine the type and mode of inheritance of such genes in Egyptian sheep breeds. PMID- 28585346 TI - Ablation of Tacr2 in mice leads to gastric emptying disturbance. AB - BACKGROUND: Tacr2 is one of the G protein-coupled receptors(GPCRs) that mediate the biological actions of tachykinins. It is abundantly expressed in the gastrointestinal (GI) system and is thought to play an important role in GI motility, secretion, and visceral sensitivity. Previously, the physiological and pathophysiological functions of Tacr2 were mainly studied using Tacr2 selective agonists or antagonists. Here, we seek to investigate the effect of Tacr2 disruption in mice to provide further insights. METHODS: The Tacr2 knockout mice were generated by homologous recombination and the phenotypic changes of the Tacr2-null mice were analyzed and compared with their wild type (wt) littermates. KEY RESULTS: Increased food retention was detected in Tacr2-/- mice. The stomach of Tacr2-/- mice had thinner muscularis externa and less neurons in the myenteric plexus. The stomach and small intestine exhibited longer duration of electrical field stimulation (EFS)-induced inhibition in the gastric fundus and decreased frequency of migrating motor complex (MMC), respectively. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were significantly up regulated due to Tarc2 deficiency, contributing to enhanced nitric oxide (NO) signaling in the stomach of Tacr2-/- mice. Intraperitoneal application of 7 nitroindazole (7-NI) to Tacr2-/- mice effectively relieved the gastric emptying disturbance. Moreover, Creb and NF-kappaB signalings were involved in the regulation of these physiological changes initiated by Tacr2 deficiency. CONCLUSIONS & INFERENCES: Tacr2 negatively regulated the expression of nNOS and VIP both in vivo and in vitro. Its ablation in mice elevated the expression of nNOS and VIP, enhanced NO signaling and changed the Creb and NF-kappaB signalings, finally leading to the gastric emptying disturbance of Tacr2-/- mice. PMID- 28585347 TI - Giant Ferroelectric Polarization in Ultrathin Ferroelectrics via Boundary Condition Engineering. AB - Tailoring and enhancing the functional properties of materials at reduced dimension is critical for continuous advancement of modern electronic devices. Here, the discovery of local surface induced giant spontaneous polarization in ultrathin BiFeO3 ferroelectric films is reported. Using aberration-corrected scanning transmission electron microscopy, it is found that the spontaneous polarization in a 2 nm-thick ultrathin BiFeO3 film is abnormally increased up to ~90-100 uC cm-2 in the out-of-plane direction and a peculiar rumpled nanodomain structure with very large variation in c/a ratios, which is analogous to morphotropic phase boundaries (MPBs), is formed. By a combination of density functional theory and phase-field calculations, it is shown that it is the unique single atomic Bi2 O3-x layer at the surface that leads to the enhanced polarization and appearance of the MPB-like nanodomain structure. This finding clearly demonstrates a novel route to the enhanced functional properties in the material system with reduced dimension via engineering the surface boundary conditions. PMID- 28585348 TI - Synthesis of Magnetic-Nanoparticle/Ansamitocin Conjugates-Inductive Heating Leads to Decreased Cell Proliferation In Vitro and Attenuation Of Tumour Growth In Vivo. AB - Conjugates based on nanostructured, superparamagnetic particles, a thermolabile linker and a cytotoxic maytansinoid were developed to serve as a model for tumour selective drug delivery and release. It combines chemo- with thermal therapy. The linker-modified toxin was prepared by a combination of biotechnology and semisynthesis. Drug release was achieved by hyperthermia through an external oscillating electromagnetic field that induces heat inside the particles. Efficacy of this release concept was demonstrated both for cancer cell proliferation in vitro, and for tumour growth in vivo, in a xenograft mouse model. Biocompatibility studies for these magnetic-nanoparticle/ansamitocin conjugates complement this work. PMID- 28585349 TI - CSNK2B splice site mutations in patients cause intellectual disability with or without myoclonic epilepsy. AB - De novo mutations are a frequent cause of disorders related to brain development. We report the results from the screening of two patients diagnosed with intellectual disability (ID) using exome sequencing to identify new causative de novo mutations. Exome sequencing was conducted in two patient-parent trios to identify de novo variants. In silico and expression studies were also performed to evaluate the functional consequences of these variants. The two patients presented developmental delay with minor facial dysmorphy. One of them presented pharmacoresistant myoclonic epilepsy. We identified two de novo splice variants (c.175+2T>G; c.367+2T>C) in the CSNK2B gene encoding the beta subunit of the Caseine kinase 2 (CK2). CK2 is a ubiquitously expressed kinase that is present in high levels in brain and it appears to be constitutively active. The mRNA transcripts were abnormal and significantly reduced in affected fibroblasts and most likely produced truncated proteins. Taking into account that mutations in CSNK2A1, encoding the alpha subunit of CK2, were previously identified in patients with neurodevelopmental disorders and dysmorphic features, our study confirmed that the protein kinase CK2 plays a major role in brain, and showed that CSNK2, encoding the beta subunit, is a novel ID gene. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy, and highlights CSNK2B as a new gene for neurodevelopmental disorders. PMID- 28585350 TI - A DNA-Based Label-Free Artificial Tongue for Pattern Recognition of Metal Ions. AB - An array-based sensing method offers several advantages for detecting various analytes. DNA molecules as sensor elements have attracted considerable interest owing to their unique properties. Here, a label-free sensor array using DNA and commercially available dyes to differentiate metal ions is reported. Based on the different interactions between dye-bound DNA and metal ions, the fluorescence intensities of the sensor elements are changed to different degrees. In this way, fourteen metal ions can be efficiently distinguished by principal component analysis (PCA) and hierarchical cluster analysis (HCA). A highly sensitive discrimination of metal ions with 92.8 % identification accuracy can be achieved. The present work provides a simple and convenient method for the construction of a DNA-based sensor array. PMID- 28585351 TI - Representation scaffolds improve diagnostic efficiency in medical students. AB - CONTEXT: Diagnostic efficiency is important in daily clinical practice as doctors have to face problems within a limited time frame. To foster the clinical reasoning of students is a major challenge in medical education research. Little is known about students' diagnostic efficiency. On the basis of current theories, scaffolds for case representation (statement of the case as far as it is summarised in the mind) could be a promising approach to make the diagnostic reasoning of intermediate medical students more efficient. METHODS: Clinical case processing of 88 medical students in their fourth and fifth years was analysed in a randomised, controlled laboratory study. Cases dealing with dyspnoea were provided in an electronic learning environment (CASUS). Students could freely choose the time, amount and sequence of clinical information. During the learning phase the intervention group was asked to write down case representation summaries while working on the cases. In the assessment phase diagnostic efficiency was operationalised as the number of correct diagnoses divided by the time spent on diagnosing. RESULTS: Diagnostic efficiency was significantly improved by the representation scaffolding (M = 0.12 [SD = 0.07], M = 0.09 [SD = 0.06] correct cases/time, p = 0.045), whereas accuracy remained unchanged (M = 2.28 [SD = 1.10], M = 2.09 [SD = 1.08], p = 0.52). Both groups screened the same amount of clinical information, but the scaffolding group did this faster (M = 20.8 minutes [SD = 7.15], M = 24.6 minutes [SD = 7.42], p = 0.01; Cohen's d = 0.5). CONCLUSION: Diagnostic efficiency is an important outcome variable in clinical reasoning research as it corresponds to workplace challenges. Scaffolding for case representations significantly improved the diagnostic efficiency of fourth and fifth-year medical students, most likely because of a more targeted screening of the available information. PMID- 28585352 TI - A RAB27A duplication in several cases of Griscelli syndrome type 2: An explanation for cases lacking a genetic diagnosis. AB - Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss-of-function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2-5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism. PMID- 28585353 TI - VapC toxins drive cellular dormancy under uranium stress for the extreme thermoacidophile Metallosphaera prunae. AB - When abruptly exposed to toxic levels of hexavalent uranium, the extremely thermoacidophilic archaeon Metallosphaera prunae, originally isolated from an abandoned uranium mine, ceased to grow, and concomitantly exhibited heightened levels of cytosolic ribonuclease activity that corresponded to substantial degradation of cellular RNA. The M. prunae transcriptome during 'uranium-shock' implicated VapC toxins as possible causative agents of the observed RNA degradation. Identifiable VapC toxins and PIN-domain proteins encoded in the M. prunae genome were produced and characterized, three of which (VapC4, VapC7, VapC8) substantially degraded M. prunae rRNA in vitro. RNA cleavage specificity for these VapCs mapped to motifs within M. prunae rRNA. Furthermore, based on frequency of cleavage sequences, putative target mRNAs for these VapCs were identified; these were closely associated with translation, transcription, and replication. It is interesting to note that Metallosphaera sedula, a member of the same genus and which has a nearly identical genome sequence but not isolated from a uranium-rich biotope, showed no evidence of dormancy when exposed to this metal. M. prunae utilizes VapC toxins for post-transcriptional regulation under uranium stress to enter a cellular dormant state, thereby providing an adaptive response to what would otherwise be a deleterious environmental perturbation. PMID- 28585354 TI - "Real-world" pediatric endocrine practice; how much is it influenced by physician's gender and region of practice. Results of an international survey. AB - OBJECTIVE: To determine whether hormonal treatments for frequent clinical cases (short stature, delayed and precocious puberty) are prescribed strictly according to clinical guidelines or based on personal tendencies, and whether the decisions correlate with physician's personal demographics (age, sex, and place of practice). METHODS: Cross-sectional survey, with made-up clinical cases, distributed to pediatric endocrinologists using 2 web-based professional forums, Israeli and an international. The questionnaire included 8 clinical cases and 5 demographic questions regarding the physician. Differences in practice between Israeli and international endocrinologists were assessed, and correlation between the physician's gender and their decisions regarding treatment. RESULTS: One hundred fifty-five physicians responded, 28% Israeli and 72% international. In girls with early puberty, 60% of international and 26% of Israeli physicians chose not to treat with a gonadotropin-releasing hormone agonist. In girls with short stature, 79% of Israeli and 34% of international physicians offered growth hormone treatment. In girls with early puberty, both male and female physicians responded similarly in the international group, but in the Israeli group 47% of male and 15% of female doctors would not treat. In girls with constitutional growth delay, 67% of Israeli male doctors would not treat with growth hormone compared to 30% of Israeli female physicians. CONCLUSIONS: Our study demonstrated significant practice differences between Israeli and international pediatric endocrinologists. Within the Israeli group, significant practice differences were seen between male and female physicians. Given that Israeli physicians follow the same clinical guidelines it is clear that a large "grey zone" of clinical cases exist and much of the decisions on treatment are personal and influenced by personal beliefs or gender. PMID- 28585355 TI - Improving Care of Transgender Patients. PMID- 28585356 TI - Decreased plant productivity resulting from plant group removal experiment constrains soil microbial functional diversity. AB - Anthropogenic environmental changes are accelerating the rate of biodiversity loss on Earth. Plant diversity loss is predicted to reduce soil microbial diversity primarily due to the decreased variety of carbon/energy resources. However, this intuitive hypothesis is supported by sparse empirical evidence, and most underlying mechanisms remain underexplored or obscure altogether. We constructed four diversity gradients (0-3) in a five-year plant functional group removal experiment in a steppe ecosystem in Inner Mongolia, China, and quantified microbial taxonomic and functional diversity with shotgun metagenome sequencing. The treatments had little effect on microbial taxonomic diversity, but were found to decrease functional gene diversity. However, the observed decrease in functional gene diversity was more attributable to a loss in plant productivity, rather than to the loss of any individual plant functional group per se. Reduced productivity limited fresh plant resources supplied to microorganisms, and thus, intensified the pressure of ecological filtering, favoring genes responsible for energy production/conversion, material transport/metabolism and amino acid recycling, and accordingly disfavored many genes with other functions. Furthermore, microbial respiration was correlated with the variation in functional composition but not taxonomic composition. Overall, the amount of carbon/energy resources driving microbial gene diversity was identified to be the critical linkage between above- and belowground communities, contrary to the traditional framework of linking plant clade/taxonomic diversity to microbial taxonomic diversity. PMID- 28585357 TI - Hierarchical Co(OH)F Superstructure Built by Low-Dimensional Substructures for Electrocatalytic Water Oxidation. AB - The development of new materials/structures for efficient electrocatalytic water oxidation, which is a key reaction in realizing artificial photosynthesis, is an ongoing challenge. Herein, a Co(OH)F material as a new electrocatalyst for the oxygen evolution reaction (OER) is reported. The as-prepared 3D Co(OH)F microspheres are built by 2D nanoflake building blocks, which are further woven by 1D nanorod foundations. Weaving and building the substructures (1D nanorods and 2D nanoflakes) provides high structural void porosity with sufficient interior space in the resulting 3D material. The hierarchical structure of this Co(OH)F material combines the merits of all material dimensions in heterogeneous catalysis. The anisotropic low-dimensional (1D and 2D) substructures possess the advantages of a high surface-to-volume ratio and fast charge transport. The interconnectivity of the nanorods is also beneficial for charge transport. The high-dimensional (3D) architecture results in sufficient active sites per the projected electrode surface area and is favorable for efficient mass diffusion during catalysis. A low overpotential of 313 mV is required to drive an OER current density of 10 mA cm-2 on a simple glassy carbon (GC) working electrode in a 1.0 m KOH aqueous solution. PMID- 28585358 TI - Muscle microcirculation alterations and relation to dipping status in newly diagnosed untreated patients with arterial hypertension-A pilot study. AB - OBJECTIVE: The importance of abnormalities observed in the microcirculation of patients with arterial hypertension (AH) is being increasingly recognized. The authors aimed to evaluate skeletal muscle microcirculation in untreated, newly diagnosed hypertensive patients with NIRS, a noninvasive method that evaluates microcirculation. METHODS: We evaluated 34 subjects, 17 patients with AH (13 males, 49+/-13 years, BMI: 26+/-2 kg/m2 ) and 17 healthy controls (12 males, 49+/ 15 years, BMI: 25+/-3 kg/m2 ). The thenar muscle StO2 (%) was measured by NIRS before, during and after 3-minutes vascular occlusion to calculate OCR (%/min), EF (%/min), and RHT (minute). The dipping status of hypertensive patients was assessed. RESULTS: The RHT differed between AH patients and healthy subjects (2.6+/-0.3 vs 2.1+/-0.3 minutes, P<.001). Dippers had higher EF than nondippers (939+/-280 vs 710+/-164%/min, P=.05). CONCLUSIONS: The study suggests an impaired muscle microcirculation in newly diagnosed, untreated AH patients. PMID- 28585359 TI - "They just said inappropriate contact." What do service users hear when staff talk about sex and relationships? AB - BACKGROUND: Research into how people with intellectual disabilities (ID) pursue intimate relationships in care settings presents some contradictory findings; despite increasingly liberal staff views, service users experience significant restrictions. This study attempts to explore this gap within a secure hospital, examining service user's representations of staff discourses about sexuality and intimate relationships. METHOD: Semi-structured interviews with eight service users with intellectual disability were analysed using critical discourse analysis. RESULTS: Analysis enabled construction of 11 themes falling into three categories. Dominant discourses appeared to maintain the integrity of the institution, enable staff to occupy a position of power and demonstrate service users' responses to perceived control. CONCLUSIONS: Discourses around sex appear to serve the interests of staff and the hospital, while being restrictive and often incomprehensible to service users. Implications for service development, and future research directions, are considered in the context of "Transforming Care." PMID- 28585360 TI - Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria. AB - BACKGROUND: Chronic urticaria (CU) is a frequent skin disease characterized by relapsing appearance of pruritic hives. While clinical symptoms are due to the release of histamine by cutaneous mast cells, the underlying pathophysiology is still unknown. However, previous studies indicate that basophils might be of relevance. Besides, the occurrence of autoantibodies against IgE or its receptor, FcepsilonRI, and the therapeutic efficacy of anti-IgE antibodies imply that IgE mediated mechanisms also play an important role in CU. METHODS: Reactivity of CU patients' peripheral blood basophils (n=60) to specific anti-FcepsilonRI and IgE independent fMLP stimulation was determined by basophil activation test in comparison with patients suffering from IgE-mediated allergic rhinitis (n=10) and healthy controls (n=10). In addition, immunoglobulin receptor (FcepsilonRI, FcgammaRII) expression and surface bound antibodies (IgE, IgG) were quantified on basophils. Furthermore, the autoreactive capacity of CU sera was evaluated and urticaria-related symptoms were assessed by both UCT and CU-Q2 oL. RESULTS: Stimulating CU patients' basophils via FcepsilonRI, we identified three distinct immunologic phenotypes. One subgroup of patients' basophils reacted to FcepsilonRI stimulation, whereas the others had anti-FcepsilonRI nonreactive basophils. Among the latter, a subgroup with pronounced basopenia was identified. Of note, this group was characterized by augmented serum-induced basophil activation, increased levels of autoantibodies against thyroid peroxidase, and also exhibited the strongest disease impact on their quality of life. CONCLUSIONS: Patients with CU can be categorized into three immunologic subgroups based on their basophil reactivity and frequency. These phenotypes are associated with different clinical characteristics, pointing to basophils as important players in CU pathophysiology. PMID- 28585361 TI - Prevalence of HIV-1 transmitted drug resistance in the incarcerated population. AB - OBJECTIVES: The aim of the study was to determine the prevalence of transmitted drug resistance (TDR)-associated mutations among treatment-naive, incarcerated individuals with HIV-1 infection in the USA as well as the class TDR and antiretroviral (ARV) mutations present at baseline. METHODS: Patients over the age of 18 years were included in the study if they had been diagnosed with HIV infection, if their HIV infection was managed through telemedicine and if they were incarcerated in the State of Illinois Department of Corrections between 10 July 2010 and 29 April 2016. Additionally, the patients were required to have a documented genotype and be ARV-naive. A medical chart review was conducted to assess demographic information, disease burden, and risk factors for acquiring the virus. RESULTS: The inclusion criteria were met for 105 patients. A total of 24 patients (23%) had a clinically significant mutation associated with resistance to any drug class. The prevalence of mutations conferring clinically significant resistance was 19% for nonnucleoside reverse transcriptase inhibitors (NNRTIs), 18% for nucleoside reverse transcriptase inhibitors (NRTIs), and 4% for protease inhibitors (PIs). Five per cent of patients had dual-class TDR to both NRTI and NNRTI drug classes and 2% of patients had mutations to both NNRTI and PI drug classes. There was no significant increase in the prevalence of clinically relevant drug resistance mutations based on demographics, burden of disease, or risk factors for acquiring the virus. CONCLUSIONS: A high prevalence of TDR was identified in the ARV-naive incarcerated population. The results of this study indicate an increased prevalence of TDR in a largely unstudied incarcerated population, demonstrating the need for increased monitoring of resistance in HIV infected patients world-wide. PMID- 28585363 TI - Response to letter to the editor by Professor Tomoyuki Kawada regarding the article "Oral health-related quality of life in patients with temporomandibular disorders: A case-control study considering psychological aspects". PMID- 28585362 TI - Tailor-made PAT platform for safe syngas fermentations in batch, fed-batch and chemostat mode with Rhodospirillum rubrum. AB - Recently, syngas has gained significant interest as renewable and sustainable feedstock, in particular for the biotechnological production of poly([R]-3 hydroxybutyrate) (PHB). PHB is a biodegradable, biocompatible polyester produced by some bacteria growing on the principal component of syngas, CO. However, working with syngas is challenging because of the CO toxicity and the explosion danger of H2 , another main component of syngas. In addition, the bioprocess control needs specific monitoring tools and analytical methods that differ from standard fermentations. Here, we present a syngas fermentation platform with a focus on safety installations and process analytical technology (PAT) that serves as a basis to assess the physiology of the PHB-producing bacterium Rhodospirillum rubrum. The platform includes (i) off-gas analysis with an online quadrupole mass spectrometer to measure CO consumption and production rates of H2 and CO2 , (ii) an at-line flow cytometer to determine the total cell count and the intracellular PHB content and (iii) different online sensors, notably a redox sensor that is important to confirm that the culture conditions are suitable for the CO metabolization of R. rubrum. Furthermore, we present as first applications of the platform a fed-batch and a chemostat process with R. rubrum for PHB production from syngas. PMID- 28585364 TI - Supercharging Proteins: How Many Charges Can a Protein Carry? AB - Very highly charged proteins, so-called "supercharged" ions, can lose (excess) protons to background gases like N2 . It is remarkable that such extremely acidic species can be generated in electrospray ionization, in the presence of not just N2 but also much higher-basicity solvents. What mechanism(s) can explain such high charging, and what is the ultimate limit? PMID- 28585365 TI - Tracking a century of changes in microbial eukaryotic diversity in lakes driven by nutrient enrichment and climate warming. AB - High-throughput sequencing of sedimentary DNA (sed-DNA) was utilized to reconstruct the temporal dynamics of microbial eukaryotic communities (MECs) at a centennial scale in two re-oligotrophicated lakes that were exposed to different levels of phosphorus enrichment. The temporal changes within the MECs were expressed in terms of richness, composition and community structure to investigate their relationships with two key forcing factors (i.e., nutrient enrichment and climate warming). Various groups, including Apicomplexa, Cercozoa, Chrysophyceae, Ciliophora, Chlorophyceae and Dinophyceae, responded to phosphorus enrichment levels with either positive or negative impacts on their richness and relative abundance. For both lakes, statistical modelling demonstrated that phosphorus concentration ([P]) was a dominant contributor to MECs modifications before the 1980s; after the mid-80s, the contribution of air temperature changes increased and potentially surpassed the contribution of [P]. Co-occurrence network analysis revealed that some clusters of taxa (i.e., modules) composed mainly of Dinophyceae and unclassified Alveolata were strongly correlated to air temperature in both lakes. Overall, our data showed that sed-DNA constitutes a precious archive of information on past biodiversity changes, allowing the study of the dynamics of numerous eukaryotic groups that were not traditionally considered in paleo-reconstructions. PMID- 28585366 TI - Advances in Therapeutic Approaches to Extend Healthspan: a perspective from the 2nd Scripps Symposium on the Biology of Aging. AB - The 2nd Scripps Florida Symposium on The Biology of Aging entitled 'Advances in Therapeutic Approaches to Extend Healthspan' was held on January 22nd -25th , 2017 at The Scripps Research Institute in Jupiter, Florida. The meeting highlighted a variety of therapeutic approaches in animal models of aging that either are or soon will be in clinic trials. For example, drugs targeting senescent cells, metformin, rapalogs, NAD precursors, young plasma, mitochondrial targeted free radical scavengers, stem cells, and stem cell factors all have shown significant preclinical efficacy. This perspective, based on presentations and discussions at the symposium, outlines the current and future state of development of therapeutic approaches to extend human healthspan. PMID- 28585367 TI - Bioinspired Ultrastrong Solid Electrolytes with Fast Proton Conduction along 2D Channels. AB - Solid electrolytes have attracted much attention due to their great prospects in a number of energy- and environment-related applications including fuel cells. Fast ion transport and superior mechanical properties of solid electrolytes are both of critical significance for these devices to operate with high efficiency and long-term stability. To address a common tradeoff relationship between ionic conductivity and mechanical properties, electrolyte membranes with proton conducting 2D channels and nacre-inspired architecture are reported. An unprecedented combination of high proton conductivity (326 mS cm-1 at 80 degrees C) and superior mechanical properties (tensile strength of 250 MPa) are achieved due to the integration of exceptionally continuous 2D channels and nacre-inspired brick-and-mortar architecture into one materials system. Moreover, the membrane exhibits higher power density than Nafion 212 membrane, but with a comparative weight of only ~0.1, indicating potential savings in system weight and cost. Considering the extraordinary properties and independent tunability of ion conduction and mechanical properties, this bioinspired approach may pave the way for the design of next-generation high-performance solid electrolytes with nacre like architecture. PMID- 28585368 TI - Psychometric evaluation of a 6-item Chinese version of the Hamilton Depression Rating Scale: Mokken scaling and item analysis. AB - BACKGROUND: It is unclear whether the 6-item Melancholia subscale of the Hamilton Depression Rating Scale (HAM-D6 ) has better psychometric properties than the parental 17-item version (HAM-D17 ) in the Chinese populations. METHODS: The study was to check the Chinese HAM-D17 and HAM-D6 for reliability and validity with Mokken scale analysis and item analysis. We reanalyzed a clinical sample of adult psychiatric outpatients (N = 214; age, mean (SD) = 38.3 (10.5) years; 63.1% female) in Taiwan. RESULTS: Our Mokken scale analysis showed that the HAM-D6 was a moderate unidimensional scale (Hs = 0.44) while the HAM-D17 was not (Hs = 0.26). The 5 items of the HAM-D6 had strong invariant item ordering (HT = 0.58). The HAM-D17 and HAM-D6 had comparable reliability (alpha = 0.79) and validity (r = 0.91), and the HAM-D6 was more homogenous than the HAM-D17 . To predict depression in remission (HAM-D17 <= 7), the best cutoff of the HAM-D6 was 4 (specificity, 87.5%; sensitivity, 100%; positive predictive value, 56.0%; negative predictive value, 100%). DISCUSSION: The Chinese HAM-D6 was a reliable, valid, and unidimensional scale of depression. PMID- 28585369 TI - Chemical composition and antibacterial, antifungal, allelopathic and acetylcholinesterase inhibitory activities of cassumunar-ginger. AB - BACKGROUND: Zingiber montanum (J.Koenig) Link ex A.Dietr. (Zingiberaceae), commonly known as cassumunar-ginger, is a folk remedy for the treatment of inflammations, sprains, rheumatism and asthma. The aim of the present study was to assess the chemical composition, and antibacterial, antifungal, allelopathic and acetylcholinesterase inhibitory activities of the essential oil of Z. montanum originating from India. RESULTS: The hydrodistilled essential oil of Z. montanum rhizome was analyzed using gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. A total of 49 constituents, forming 98.7-99.9% of the total oil compositions, was identified. The essential oil was characterized by higher amount of monoterpene hydrocarbons (32.6-43.5%), phenylbutanoids (27.5-41.2%) and oxygenated monoterpenes (11.4-34.1%). Major constituents of the oil were sabinene (13.5-38.0%), (E)-1-(3',4' dimethoxyphenyl)buta-1,3-diene (DMPBD) (20.6-35.3%), terpinen-4-ol (9.0-31.3%), gamma-terpinene (1.1-4.8%) and beta-phellandrene (1.0-4.4%). The oil was evaluated against eight pathogenic bacteria and two fungal strains. It exhibited low to good antibacterial activity (minimum inhibitory concentration: 125-500 ug mL-1 ) and moderate antifungal activity (250 ug mL-1 ) against the tested strains. The oil reduced germination (69.8%) and inhibited the root and shoot growth of lettuce significantly (LD50 : 3.58 uL plate-1 ). However, it did not demonstrate acetylcholinesterase inhibitory activity up to a concentration of 10 mg mL-1 . CONCLUSIONS: The essential oil of Z. montanum can be used as a potential source of DMPBD, terpinen-4-ol and sabinene for pharmaceutical products. The results of the present study add significant information to the pharmacological activity of Z. montanum native to India. (c) 2017 Society of Chemical Industry. PMID- 28585370 TI - Gout: an Asia-Pacific update. AB - Even though, Hippocrates recognized gout as an affection of older men and a product of high living long back in 5th century BC, this painful condition promises to accompany humanity to the 21st century. The incidence is progressively rising and females are also affected in the modern era. There are also regional and ethnic variations in the incidence, the genetics of which is being studied. The recommended best therapy for the acute attacks and long term prophylaxis has improved remarkably in the recent years. However, patients are often treated inadequately and risk factors for their disease are not well explored in daily practice. Although well designed long term studies of current and newer treatment are welcomed, educating doctors especially the primary care physicians who manage majority of gout cases, in optimizing the currently available management options would improve the present care. PMID- 28585372 TI - Widespread production of nonmicrobial greenhouse gases in soils. AB - Carbon dioxide (CO2 ), methane (CH4 ), and nitrous oxide (N2 O) are the three most important greenhouse gases (GHGs), and all show large uncertainties in their atmospheric budgets. Soils of natural and managed ecosystems play an extremely important role in modulating their atmospheric abundance. Mechanisms underlying the exchange of these GHGs at the soil-atmosphere interface are often assumed to be exclusively microbe-mediated (M-GHGs). We argue that it is a widespread phenomenon for soil systems to produce GHGs through nonmicrobial pathways (NM GHGs) based on a review of the available evidence accumulated over the past half century. We find that five categories of mechanistic process, including photodegradation, thermal degradation, reactive oxidative species (ROS) oxidation, extracellular oxidative metabolism (EXOMET), and inorganic chemical reactions, can be identified as accounting for their production. These pathways are intricately coupled among themselves and with M-GHGs production and are subject to strong influences from regional and global change agents including, among others, climate warming, solar radiation, and alterations of atmospheric components. Preliminary estimates have suggested that NM-GHGs could play key roles in contributing to budgets of GHGs in the arid regions, whereas their global importance would be enhanced with accelerated global environmental changes. Therefore, more research should be undertaken, with a differentiation between NM-GHGs and M-GHGs, to further elucidate the underlying mechanisms, to investigate the impacts of various global change agents, and to quantify their contributions to regional and global GHGs budgets. These efforts will contribute to a more complete understanding of global carbon and nitrogen cycling and a reduction in the uncertainty of carbon-climate feedbacks in the Earth system. PMID- 28585371 TI - Influences of early child nutritional status and home learning environment on child development in Vietnam. AB - Early childhood development plays a key role in a child's future health, educational success, and economic status. However, suboptimal early development remains a global challenge. This study examines the influences of quality of the home learning environment (HOME) and child stunting in the first year of life on child development. We used data collected from a randomized controlled trial of preconceptional micronutrient supplementation in Vietnam (n = 1,458). The Bayley Scales of Infant Development-III were used to assess cognition, language, and motor development domains at 2 years. At 1 year, 14% of children were stunted, and 15%, 58%, and 28% of children lived in poor, medium, and high HOME environments, respectively. In multivariate generalized linear regression models, living in a high HOME environment was significantly associated with higher scores (0.10 to 0.13 SD) in each of the developmental domains. Stunted children scored significantly lower for cognitive, language, and motor development (-0.11 to 0.18), compared to nonstunted children. The negative associations between stunting on development were modified by HOME; the associations were strong among children living in homes with a poor learning environment whereas they were nonsignificant for those living in high-quality learning environments. In conclusion, child stunting the first year of life was negatively associated with child development at 2 years among children in Vietnam, but a high-quality HOME appeared to attenuate these associations. Early interventions aimed at improving early child growth as well as providing a stimulating home environment are critical to ensure optimal child development. PMID- 28585374 TI - SVMDLF: A novel R-based Web application for prediction of dipeptidyl peptidase 4 inhibitors. AB - Dipeptidyl peptidase 4 (DPP4) is a well-known target for the antidiabetic drugs. However, currently available DPP4 inhibitor screening assays are costly and labor intensive. It is important to create a robust in silico method to predict the activity of DPP4 inhibitor for the new lead finding. Here, we introduce an R based Web application SVMDLF (SVM-based DPP4 Lead Finder) to predict the inhibitor of DPP4, based on support vector machine (SVM) model, predictions of which are confirmed by in vitro biological evaluation. The best model generated by MACCS structure fingerprint gave the Matthews correlation coefficient of 0.87 for the test set and 0.883 for the external test set. We screened Maybridge database consisting approximately 53,000 compounds. For further bioactivity assay, six compounds were shortlisted, and of six hits, three compounds showed significant DPP4 inhibitory activities with IC50 values ranging from 8.01 to 10.73 MUm. This application is an OpenCPU server app which is a novel single-page R-based Web application for the DPP4 inhibitor prediction. The SVMDLF is freely available and open to all users at http://svmdlf.net/ocpu/library/dlfsvm/www/ and http://www.cdri.res.in/svmdlf/. PMID- 28585373 TI - 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. AB - OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (>=3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies. PMID- 28585376 TI - Reduce pests, enhance production: benefits of intercropping at high densities for okra farmers in Cameroon. AB - BACKGROUND: Intercropping can help reduce insect pest populations. However, the results of intercropping can be pest- and crop-species specific, with varying effects on crop yield, and pest suppression success. In Cameroon, okra vegetable is often grown in intercropped fields and sown with large distances between planting rows (~ 2 m). Dominant okra pests include cotton aphids, leaf beetles and whiteflies. In a field experiment, we intercropped okra with maize and bean in different combinations (okra monoculture, okra-bean, okra-maize and okra-bean maize) and altered plant densities (high and low) to test for the effects of diversity, crop identity and planting distances on okra pests, their predators and yield. RESULTS: We found crop identity and plant density, but not crop diversity to influence okra pests, their predators and okra yield. Only leaf beetles decreased okra yield and their abundance reduced at high plant density. Overall, okra grown with bean at high density was the most economically profitable combination. CONCLUSIONS: We suggest that when okra is grown at higher densities, legumes (e.g. beans) should be included as an additional crop. Intercropping with a leguminous crop can enhance nitrogen in the soil, benefiting other crops, while also being harvested and sold at market for additional profit. Manipulating planting distances and selecting plants based on their beneficial traits may thus help to eliminate yield gaps in sustainable agriculture. (c) 2017 Society of Chemical Industry. PMID- 28585375 TI - Intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion in patients with lung cancer: Influences of the size and inner-air density of tumors. AB - BACKGROUND: This study was conducted to assess intra-observer and inter-observer agreements for the measurement of dual-input whole tumor computed tomography perfusion (DCTP) in patients with lung cancer. METHODS: A total of 88 patients who had undergone DCTP, which had proved a diagnosis of primary lung cancer, were divided into two groups: (i) nodules (diameter <=3 cm) and masses (diameter >3 cm) by size, and (ii) tumors with and without air density. Pulmonary flow, bronchial flow, and pulmonary index were measured in each group. Intra-observer and inter-observer agreements for measurement were assessed using intraclass correlation coefficient, within-subject coefficient of variation, and Bland Altman analysis. RESULTS: In all lung cancers, the reproducibility coefficient for intra-observer agreement (range 26.1-38.3%) was superior to inter-observer agreement (range 38.1-81.2%). Further analysis revealed lower agreements for nodules compared to masses. Additionally, inner-air density reduced both agreements for lung cancer. CONCLUSION: The intra-observer agreement for measuring lung cancer DCTP was satisfied, while the inter-observer agreement was limited. The effects of tumoral size and inner-air density to agreements, especially between two observers, should be emphasized. In future, an automatic computer-aided segment of perfusion value of the tumor should be developed. PMID- 28585377 TI - Approaching Intra- and Interchain Charge Transport of Conjugated Polymers Facilely by Topochemical Polymerized Single Crystals. AB - Charge transport of small molecules is measured well with scanning tunneling microscopy, conducting atomic force microscopy, break junction, nanopore, and covalently bridging gaps. However, the manipulation and measurement of polymer chains remain a long-standing fundamental issue in conjugated polymers and full of challenge since conjugated polymers are naturally disordered materials. Here, a fundamental breakthrough in generating high-quality conjugated-polymer nanocrystals with extended conjugation and exceptionally high degrees of order using a surface-supported topochemical polymerization method is demonstrated. In the crystal the conjugated-polymer chains are extended along the long axis of the crystal with the side chains perpendicular to the long axis. Devices with conducting channels along the polymer chains show efficient charge transport, nearly two orders of magnitude greater than the interchain charge transport along the pi-pi stacking direction. This is the first example to clarify intra- and interchain charge transport based on an individual single crystal of conjugated polymers, and demonstrate the importance of intrachain charge transport in plastic electronics. PMID- 28585379 TI - groEL is a suitable genetic marker for detecting Vibrio parahaemolyticus by loop mediated isothermal amplification assay. AB - : A groEL gene-based loop-mediated isothermal amplification (LAMP) assay was developed to detect Vibrio parahaemolyticus in contaminated seafood and water. The assay was optimized and conducted at 63 degrees C for 40 min using Bacillus stearothermophilus (Bst) DNA polymerase, large fragment. Amplification was analysed via multiple detection methods, including opacity, formation of white precipitate, DNA intercalating dyes (ethidium bromide and SYBR Green I), metal ion-binding indicator dye, calcein, and 2% agarose gel electrophoresis. A characteristic ladder-like band pattern on agarose gel and the desired colour changes when using different dyes were observed in positive cases, and these were species-specific for V. parahaemolyticus when compared with other closely related Vibrio spp. The limit of detection (LoD) of this assay was 100 fg per reaction, 100-fold higher than that for conventional polymerase chain reaction (PCR). When tested on artificially contaminated seafood and seawater, the LoDs of the LAMP assay were 120 and 150 fg per reaction respectively, and those of conventional PCR were 120 and 150 pg per reaction respectively. Based on our results, the groEL gene-based LAMP assay is rapid, specific, sensitive, and reliable for detecting V. parahaemolyticus, and it could be used in field diagnosis. SIGNIFICANCE AND IMPACT OF THE STUDY: The loop-mediated isothermal amplification (LAMP) assay using groEL gene (an abundant, highly conserved gene and member of the groESL chaperone gene family) provided rapid, species-specific and highly sensitive method for detecting Vibrio parahaemolyticus, the leading causal agent of seafood-borne diseases worldwide. Moreover, groEL LAMP revealed high efficiency than conventional PCR assay for V. parahaemolyticus using template both from pure culture and artificially contaminated seafood and water, which indicated the applicability in the field and environmental screening purpose for the organism. PMID- 28585378 TI - 4beta-Hydroxycholesterol level significantly correlates with steady-state serum concentration of the CYP3A4 substrate quetiapine in psychiatric patients. AB - AIM: 4beta-Hydroxycholesterol (4betaOHC) is sensitive towards induction or inhibition of CYP3A4, but its potential usefulness as a dosing biomarker remains to be demonstrated. The aim of this study was to investigate the correlation between 4betaOHC levels and steady-state concentrations (Css) of quetiapine, a CYP3A4 substrate with high presystemic metabolism, in psychiatric patients. METHODS: Serum samples from 151 patients treated with quetiapine as immediate release (IR; n = 98) or slow release (XR; n = 53) tablets were included for analysis of 4betaOHC. In all patients, Css of quetiapine had been measured at trough level, i.e. 10-14 and 17-25 h post-dosing for IR and XR tablets, respectively. Correlations between 4betaOHC levels and dose-adjusted Css (C/D ratios) of quetiapine were tested by univariate (Spearman's) and multivariate (multiple linear regression) analyses. Gender, age (>=60 vs. <60 years) and tablet formulation were included as potential covariates in the multivariate analysis. RESULTS: Correlations between 4betaOHC levels and quetiapine C/D ratios were highly significant both for IR- and XR-treated patients (P < 0.0001). Estimated Spearman r values were -0.47 (95% confidence interval -0.62, -0.30) and -0.56 (-0.72, -0.33), respectively. The relationship between 4betaOHC level and quetiapine C/D ratio was also significant in the multiple linear regression analysis (P < 0.001), including gender (P = 0.023) and age (P = 0.003) as significant covariates. CONCLUSIONS: The present study shows that 4betaOHC level is significantly correlated with steady-state concentration of quetiapine. This supports the potential usefulness of 4betaOHC as a phenotype biomarker for individualized dosing of quetiapine and other drugs where systemic exposure is mainly determined by CYP3A4 metabolism. PMID- 28585380 TI - Astrocytes in a dish: Using pluripotent stem cells to model neurodegenerative and neurodevelopmental disorders. AB - Neuroscience and Neurobiology have historically been neuron biased, yet up to 40% of the cells in the brain are astrocytes. These cells are heterogeneous and regionally diverse but universally essential for brain homeostasis. Astrocytes regulate synaptic transmission as part of the tripartite synapse, provide metabolic and neurotrophic support, recycle neurotransmitters, modulate blood flow and brain blood barrier permeability and are implicated in the mechanisms of neurodegeneration. Using pluripotent stem cells (PSC), it is now possible to study regionalised human astrocytes in a dish and to model their contribution to neurodevelopmental and neurodegenerative disorders. The evidence challenging the traditional neuron-centric view of degeneration within the CNS is reviewed here, with focus on recent findings and disease phenotypes from human PSC-derived astrocytes. In addition we compare current protocols for the generation of regionalised astrocytes and how these can be further refined by our growing knowledge of neurodevelopment. We conclude by proposing a functional and phenotypical characterisation of PSC-derived astrocytic cultures that is critical for reproducible and robust disease modelling. PMID- 28585381 TI - Modeling Parkinson's disease with induced pluripotent stem cells harboring alpha synuclein mutations. AB - Parkinson's disease (PD) is a common neurodegenerative condition affecting more than 8 million people worldwide. Although, the majority of PD cases are sporadic in nature, there are a growing number of monogenic mutations identified to cause PD in a highly penetrant manner. Many of these familial mutations give rise to a condition that is clinically and neuropathologically similar, if not identical, to sporadic PD. Mutations in genes such as SNCA cause PD in an autosomal dominant manner and patients have motor and non-motor symptoms that are typical for sporadic PD. With the advent of reprogramming technology it is now possible to capture these mutations in induced pluripotent stem cells (iPSCs) to establish models of PD in a dish. There are multiple neuronal subtypes affected in PD including the midbrain dopaminergic (mDA) neurons of the substantia nigra. Robust neuronal differentiation into mDA or other relevant neural cell types are critical to accurately model the disease and ensure the findings are relevant to understanding the disease process. Another challenge for establishing accurate models of PD is being met by the generation of isogenic control iPSC lines with precise correction of mutations using advanced gene editing technology. The contributions of ageing and environmental factors present further challenges to this field, but significant progress is being made in these areas to establish highly relevant and robust models of PD. These human neuronal models, used in conjunction with other model systems, will vastly improve our understanding of the early stages of the PD, which will be key to identifying disease-modifying and preventative treatments. PMID- 28585382 TI - Modeling tau pathology in human stem cell derived neurons. AB - Tau pathology is a defining characteristic of multiple neurodegenerative disorders including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) with tau pathology. There is strong evidence from genetics and experimental models to support a central role for tau dysfunction in neuronal death, suggesting tau is a promising therapeutic target for AD and FTD. However, the development of tau pathology can precede symptom onset by several years, so understanding the earliest molecular events in tauopathy is a priority area of research. Induced pluripotent stem cells (iPSC) derived from patients with genetic causes of tauopathy provide an opportunity to derive limitless numbers of human neurons with physiologically appropriate expression levels of mutated genes for in vitro studies into disease mechanisms. This review discusses the progress made to date using this approach and highlights some of the challenges and unanswered questions this technology has the potential to address. PMID- 28585383 TI - 19-Year-Old Male with Headaches and a Possible Seizure. PMID- 28585384 TI - Modeling the C9ORF72 repeat expansion mutation using human induced pluripotent stem cells. AB - C9ORF72 repeat expansion is the most frequent causal genetic mutation giving rise to amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). The relatively recent discovery of the C9ORF72 repeat expansion in 2011 and the complexity of the mutation have meant that animal models that successfully recapitulate human C9ORF72 repeat expansion-mediated disease are only now emerging. Concurrent advances in the use of patient-derived induced pluripotent stem cells (iPSCs) to model aspects of neurological disease offers an additional approach for the study of C9ORF72 mutation. This review focuses on the opportunities of human C9ORF72 iPSC platforms to model pathological aspects of disease and how findings compare with other existing models of disease and post mortem data. PMID- 28585386 TI - Understanding neurodevelopmental disorders using human pluripotent stem cell derived neurons. AB - Research into psychiatric disorders has long been hindered by the lack of appropriate models. Induced pluripotent stem cells (iPSCs) offer an unlimited source of patient-specific cells, which in principle can be differentiated into all disease-relevant somatic cell types to create in vitro models of the disorder of interest. Here, neuronal differentiation protocols available for this purpose and the current progress on iPSCs-based models of schizophrenia, autism spectrum disorders and bipolar disorder were reviewed. We also discuss the impact of the recently developed CRISPR/Cas9 genome editing tool in the disease modeling field. Genetically engineered mutation of disease risk alleles in well characterized reference "control" hPSCs or correction of disease risk variants in patient iPSCs has been used as a powerful means to establish causality of the identified cellular pathology. Together, iPSC reprogramming and CRISPR/CAS9 genome editing technology have already significantly contributed to our understanding of the developmental origin of some major psychiatric disorders. The challenge ahead is the identification of shared mechanisms in their etiology, which will ultimately be relevant to the development of new treatments. PMID- 28585387 TI - A 53-Year-Old Woman with a Subfascial Mass of the Back that Lasted for Years. PMID- 28585388 TI - A 32-Year-Old Man with Headache and Visual Loss. PMID- 28585389 TI - AN 11-Year-Old Boy with a Leptomeningeal Tumor. PMID- 28585390 TI - Type 4 pili are dispensable for biofilm development in the cyanobacterium Synechococcus elongatus. AB - The hair-like cell appendages denoted as type IV pili are crucial for biofilm formation in diverse eubacteria. The protein complex responsible for type IV pilus assembly is homologous with the type II protein secretion complex. In the cyanobacterium Synechococcus elongatus PCC 7942, the gene Synpcc7942_2071 encodes an ATPase homologue of type II/type IV systems. Here, we report that inactivation of Synpcc7942_2071 strongly affected the suite of proteins present in the extracellular milieu (exo-proteome) and eliminated pili observable by electron microscopy. These results support a role for this gene product in protein secretion as well as in pili formation. As we previously reported, inactivation of Synpcc7942_2071 enables biofilm formation and suppresses the planktonic growth of S. elongatus. Thus, pili are dispensable for biofilm development in this cyanobacterium, in contrast to their biofilm-promoting function in type IV pili producing heterotrophic bacteria. Nevertheless, pili removal is not required for biofilm formation as evident by a piliated mutant of S. elongatus that develops biofilms. We show that adhesion and timing of biofilm development differ between the piliated and non-piliated strains. The study demonstrates key differences in the process of biofilm formation between cyanobacteria and well-studied type IV pili-producing heterotrophic bacteria. PMID- 28585391 TI - Understanding mortality rates after hip fracture repair using ASA physical status in the National Hip Fracture Database. AB - Hip fracture is the most common reason for older patients to need emergency anaesthesia and surgery. Up to one-third of patients die in the year after hip fracture, but this view of outcome may encourage therapeutic nihilism in peri operative decisions and discussions. We used a multicentre national dataset to examine relative and absolute mortality rates for patients presenting with hip fracture, stratified by ASA physical status. We analysed ASA physical status, dates of surgery, death and hospital discharge for 59,369 out of 64,864 patients in the 2015 National Hip Fracture Database; 3914 (6.6%) of whom died in hospital. Rates of death in hospital were 1.8% in ASA 1-2 patients compared with 16.5% in ASA 4 patients. Survival rates for ASA 4 patients on each of the first three postoperative days were: 98.8%, 99.1% and 99.1% (compared with figures of > 99.9% in ASA 1-2 patients over these days). Survival on postoperative day 6 was 99.4% for ASA 4 patients. Nearly half (48.6%) of the 1427 patients who did not have surgery died in hospital. Although technically sound, a focus on cumulative and relative risk of mortality may frame discussions in an unduly negative fashion, discouraging surgeons and anaesthetists from offering an operation, and deterring patients and their loved ones from agreeing to it. A more optimistic and pragmatic explanation that over 98% of ASA 4 patients survive both the day of surgery and the day after it, may be more appropriate. PMID- 28585393 TI - Orientational Coupling Locally Orchestrates a Cell Migration Pattern for Re Epithelialization. AB - Re-epithelialization by collective migration of epithelial cells over a heterogeneous environment to restore tissue integrity and functions is critical for development and regeneration. Here, it is reported that the spatial organization of adjacent adherent paths within sparsely distributed extracellular matrix (ECM) has a significant impact on the orientational coupling between cell polarization and collective cell migration. This coupling effect determines the migration pattern for human keratinocytes to regain their cohesion, which impacts the occupancy of epithelial bridge and the migration velocity in wound repair. Statistical studies suggest the converging organization of ECM, in which adjacent paths become closer to each other and finally converge to a junctional point, facilitating collective cell migration mostly within variable ECM organization, as the polarization of the advancing cell sheet is remodeled to align along the direction of cell migration. The findings may help to design implantable ECM to optimize efficient skin regeneration. PMID- 28585392 TI - Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775). AB - Lysergic acid diethylamide (LSD) is perhaps one of the best-known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as 'research chemicals' or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM-775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM-775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM-775. A powdered sample of LSM-775 was characterized by X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC MS), high mass accuracy electrospray MS/MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM-775 acts as a nonselective agonist at 5-HT1A and 5-HT2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM-775 activates 5-HT2A receptors and produces hallucinogen-like effects in vivo. LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by pretreatment with the antagonist WAY-100,635 (1 mg/kg, subcutaneous). These findings suggest that 5-HT1A activation by LSM-775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM-775 is only capable of producing weak LSD-like effects in humans. PMID- 28585394 TI - Wii-based exercise program to improve physical fitness, motor proficiency and functional mobility in adults with Down syndrome. AB - BACKGROUND: People with Down syndrome (DS) usually display reduced physical fitness (aerobic capacity, muscle strength and abnormal body composition), motor proficiency impairments (balance and postural control) and physical functional limitations. Exergames can be an appealing alternative to enhance exercise engagement and compliance, whilst improving physical fitness and motor function. This study aims to analyse the effects of a Wii-based exercise program on physical fitness, functional mobility and motor proficiency of adults with DS. METHODS: Twenty-seven adults with DS were randomly allocated to an experimental group (Wii; n = 14) or control group (n = 13). Participants in the experimental group completed a 2-month Wii-based exercise program, with three 1-h sessions per week that included training games for aerobic endurance, balance and isometric strength. Participants completed assessments regarding anthropometric measures, physical fitness, functional mobility and motor proficiency. RESULTS: Mixed ANOVA analysis showed a significant group by time interaction for aerobic endurance, explosive leg power and flexibility. Independent samples t-test for change scores indicated significant between-group differences favouring the experimental group regarding speed of limb movement, trunk strength and functional mobility, as well as a trend towards significance on body weight. Mann-Whitney's U test for change scores demonstrated between-group differences favouring the experimental group for visceral fat as well as running speed and agility. Large within-group effect sizes were observed for explosive leg power (d = 1.691), body weight (d = 1.281), functional mobility (d = 1.218), aerobic endurance (d = 1.020), speed of limb movement (d = 0.867) and flexibility (d = 0.818) in the experimental group. CONCLUSIONS: Our findings suggest that Wii-based exercise can be an effective tool to improve physical fitness, functional mobility and motor proficiency of adults with DS, including crucial measures such as aerobic capacity and lower limb strength. Exergames using Wii Fit or other equipment can be appealing alternatives for adults with DS to engage in regular physical activity, preventing sedentary behaviour and decreasing the risk to develop cardiovascular diseases. PMID- 28585396 TI - Climate change does not impacts on Coffea arabica yield in Brazil. AB - BACKGROUND: Brazil is the largest producer of coffee in the world. Studies on climate change estimate large impacts on production of Coffea arabica (C. arabica). In this context, it is necessary to know the quantitative production values to provide evidence for policy makers to target the prompt answer. RESULTS: Using data from 18 municipalities located in five Brazilian States that produce more coffee in Brazil, in an unprecedented way, in this work it is shown that although the minimum temperature is the most important climatic variable for the production, its effect, although positive, and its degree of explanation, were technically too small to explain the volume of production in Brazilian conditions. According to the model of non-stationary time series ARIMA (1, 1, 0) the coffee production in the future may reach almost four million tons, and the productivity almost 2,500 kg ha-1 on average, being the advancement of technology the main factor that should promote the simultaneous increases in production and productivity. However, despite the natural climate variations, which make it the most responsible for the variability of annual coffee production, the producer must increase the use of the technologies to support the Brazilian coffee agribusiness. CONCLUSIONS: The results of this study reveal that the coffee production in Brazil is much more due to productivity than to the minimum ambient temperature change over the long term, despite this climate variable be considered the most influential on the production and productivity of coffee. PMID- 28585395 TI - Epithelial-mesenchymal transition markers in malignant ovarian germ cell tumors. AB - The purpose of this study was to determine the expression and potential clinical role of epithelial-to-mesenchymal transition (EMT)-related factors in malignant ovarian germ cell tumors (MOGCT). Protein expression of E-cadherin, N-cadherin, P cadherin, Zeb1, HMGA2, and vimentin by immunohistochemistry was analyzed in 42 MOGCT from patients treated in Norway during the period 1981-2001. Expression was analyzed for association with clinicopathologic parameters. E-cadherin (p = 0.016) and HMGA2 (p = 0.002) expression was significantly higher in immature teratomas and yolk sac tumors compared with dysgerminomas. Vimentin (p < 0.001) and Zeb1 (p = 0.029) staining was significantly higher in immature teratomas compared with yolk sac tumors and dysgerminomas, whereas no significant differences were observed for N-cadherin and P-cadherin. EMT-associated markers were not significantly related to clinicopathologic parameters including age, tumor diameter, and FIGO stage. In conclusion, based on this limited series, EMT associated markers are not associated with clinical parameters in MOGCT, in contrast to ovarian carcinoma. EMT-related proteins are differentially expressed among various MOGCT subtypes, suggesting differences in biological characteristics associated with invasion and metastasis. PMID- 28585397 TI - Curcumin for the treatment of tumor-stage mycosis fungoides. PMID- 28585399 TI - Current evidence for the use of sugammadex in children. PMID- 28585398 TI - Genetic status determines 18 F-FDG uptake in pheochromocytoma/paraganglioma. AB - INTRODUCTION: Although few studies have demonstrated utility of 18 F- fluoro-2 deoxy-d-glucose positron emission tomography/computerised tomography (18 F-FDG PET/CT) in benign pheochromocytoma/paragangliomas (PCC/PGLs), there limited data on factors predicting the FDG uptake in PCC/PGL. METHODS: The study was conducted at a tertiary health care centre. In addition to the routine investigations, all patients (n = 96) with PCC/PGL were evaluated with 18 F-FDGPET/CT and majority (n = 78) underwent 131 I-metaiodobenzyl guanidine (131 I-MIBG) scintigraphy. Forty three patients also underwent testing for germline mutations in five PCC/PGL susceptibility genes (VHL, RET, SDHB, SDHC and SDHD) and all patients were evaluated clinically for neurofibromatosis-1. RESULTS: The study included 96 patients with PCC/PGL(82 benign and 14 malignant). FDGSUVmax was significantly higher for malignant than benign PCC/PGL(P = 0.009) and for extra-adrenal PGL than adrenal PCC (P = 0.017). In subgroup analysis, metanephrine-secreting PCC and non-secretory PCC had significantly lower FDG SUVmax than normetanephrine secreting PCC (P = 0.017, P = 0.038 respectively), normetanephrine-secreting sympathetic PGL (P = 0.008, P = 0.019 respectively) and non-secretory sympathetic PGL (P = 0.003, P = 0.009 respectively). Patients with mutations in cluster 1 genes (n = 14) had significantly higher FDG SUVmax than those with mutations in cluster 2 genes (n = 4) (P = 0.04). Sensitivities of 131 I-MIBG and 18 F-FDG PET/CTwere 77.78% and 100% for cluster 1 genes-related PCC/PGL whereas they were 100% and 50% for cluster 2 genes-related PCC/PGL, respectively. Multivariate regression analysis of mutation positive patients identified genetic status as the only independent predictor of FDG SUVmax. CONCLUSION: The study suggests that the underlying genetic status determines FDG uptake in PCC/PGL and not location, secretory status or malignancy. PMID- 28585400 TI - Managing the marginally raised aPTT-looking beyond the absolute number. PMID- 28585403 TI - Reducing risk in pediatric anesthesia: What are the implications from the APRICOT study? PMID- 28585401 TI - Caudal analgesia, hypospadias, and urethrocutaneous fistula: Does association mean causality? PMID- 28585404 TI - Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis C patients treated with all-oral direct-acting antivirals: Analysis of a Japanese prospective cohort. AB - AIM: Several case reports have shown that hepatitis B virus (HBV) reactivation developed in hepatitis C patients with a current or previous HBV infection during direct-acting antiviral (DAA) treatment, which led to severe hepatitis or death in some cases. However, its precise frequency and risk factors are not entirely clear. We analyzed a prospective cohort. METHODS: We analyzed HBV reactivation in 461 consecutive hepatitis C patients who received 12 weeks of ledipasvir/sofosbuvir for genotype 1 or sofosbuvir plus ribavirin for genotype 2 at multiple centers. RESULTS: By the examination of the preserved sera at baseline, 159 patients (34%) were identified as seropositive for HBV core antibody (anti-HBc) and were included in the subsequent analysis; 4 patients were positive for HBV surface antigen (HBsAg), and the others were negative. Serum HBV DNA was undetectable or was detectable but <20 IU/mL at baseline for all patients. Serial measurement of HBV DNA at 4 weeks and 12 weeks in the preserved serum samples was available in 147 patients and identified HBV reactivation (defined as the appearance of serum HBV DNA >=20 IU/mL) in 2 HBsAg-positive and 3 HBsAg-negative patients. No patient developed HBV-associated hepatitis. Patients who developed HBV reactivation had significantly lower anti-HBs titers and higher serum alanine transferase levels before treatment. CONCLUSION: Hepatitis B virus reactivation during direct-acting antiviral therapies occurs in 3.4% (5/147) of patients who are positive for anti-HBc. A low titer of anti-HBs and a high serum alanine transferase level prior to treatment are associated with reactivation in this patient group. PMID- 28585405 TI - Type of oral solid medication packaging and medication preparation time in nursing homes: A direct observation study. AB - WHAT IS KNOWN AND OBJECTIVE: Medication administration is a substantial portion of the workday in nursing homes, with the medication preparation step being the most time-consuming. However, little is known about how medication preparation time is affected by the type of packaging used for oral solid medications (ie, tablets/capsules). We examined the effects of two types of packaging. As fewer steps are associated with strip packaging compared to bingo card packaging, we hypothesized that the increase in medication preparation seconds per resident with each additional oral solid medication would be smaller when strip packaging was used. METHODS: A total of 430 medication preparations conducted by eight nurses during the regularly scheduled morning medication administration period in two nursing homes-using strip packaging and bingo card packaging, respectively were observed. Each medication preparation observation was matched to its corresponding medication administration record and observations averaged across resident. Using the resident sample (N=149), we estimated three regression models (adjusting the standard errors for the clustering of resident by nurse). The first model regressed medication preparation seconds on the number of oral solid medications. The second model added the type of packaging used and the control variables (type of unit [long-term care, post-acute care], the number of one-half pills and the dosage form diversity in the preparation). To test our hypothesis, the third model added an interaction term between the number of oral solid medications and the type of packaging used. RESULTS AND DISCUSSION: As hypothesized, all else equal, the number of oral solid medications tended to increase medication preparation time per resident in both nursing homes, but the increase was smaller in the strip packaging nursing home (P<.05). Each additional oral solid medication in the bingo card packaging nursing home increased medication preparation by an average of 13 seconds (b=13.077), whereas each oral solid medication administered in the strip packaging nursing home increased medication preparation by an average of only 8 seconds (13.077-5.092=7.985). This is a difference on average of about 5 seconds per oral solid medication. WHAT IS NEW AND CONCLUSION: To our knowledge, we were the first to examine the effect of type of oral solid medication packaging on medication preparation time in nursing homes. Type of packaging matters. The time saved using strip packaging (vs bingo card packaging) has implications for quality of care and the movement towards person-centred care in the nursing home sector. Nurses (or other staff tasked with medication preparation) in nursing homes using strip packaging potentially have more time to devote to nurturing a relationship with the resident. However, time saved in medication preparation by strip packaging is counterproductive if a serious error results. Thus, future studies should investigate the effects of type of packaging on medication preparation errors. PMID- 28585406 TI - MR-safe personal radiation dosimeters. AB - Magnetic resonance imaging (MRI) is being rapidly integrated for cancer treatments-such systems are referred to as MRI-guided radiation therapy (MRIgRT). As the magnet of an MRI scanner is always on, the presence of a strong static magnetic field from the MRI scanner during radiotherapy delivery presents new challenges. One of the challenges is that a personal radiation dosimeter used to estimate the radiation dose deposited in an individual wearing the device must be MR-safe. No such devices, however, are currently available. In this work we first modified an existing personal dosimeter (by removing a metal clip) to make it MR safe and then investigated potential effects of magnetic field on dosimeter readings, i.e., optically stimulated luminescent dosimeter (OSLD) readings. We found that the effect of magnetic field on OSLD sensitivity was within radiation protection tolerance levels. OSLD personal dosimeters can be directly used in conjunction with MRIgRT radiation protection purposes. PMID- 28585407 TI - Carbon Nanotubes as an Ultrafast Emitter with a Narrow Energy Spread at Optical Frequency. AB - Ultrafast electron pulses, combined with laser-pump and electron-probe technologies, allow ultrafast dynamics to be characterized in materials. However, the pursuit of simultaneous ultimate spatial and temporal resolution of microscopy and spectroscopy is largely subdued by the low monochromaticity of the electron pulses and their poor phase synchronization to the optical excitation pulses. Field-driven photoemission from metal tips provides high light-phase synchronization, but suffers large electron energy spreads (3-100 eV) as driven by a long wavelength laser (>800 nm). Here, ultrafast electron emission from carbon nanotubes (~1 nm radius) excited by a 410 nm femtosecond laser is realized in the field-driven regime. In addition, the emitted electrons have great monochromaticity with energy spread as low as 0.25 eV. This great performance benefits from the extraordinarily high field enhancement and great stability of carbon nanotubes, superior to metal tips. The new nanotube-based ultrafast electron source opens exciting prospects for extending current characterization to sub-femtosecond temporal resolution as well as sub-nanometer spatial resolution. PMID- 28585408 TI - Increased risk of infection-associated death with incompatible kidney transplantations. PMID- 28585409 TI - A population-based study of risk perceptions of paracetamol use among Swedes-with a special focus on young adults. AB - PURPOSE: The purpose of this study was to investigate risk perceptions of paracetamol use, with a special focus on young adults. METHODS: A web survey was sent to a representative sample (n = 5838) of the Swedish adult population. Altogether, 3120 persons answered the full questionnaire. Risk perceptions of paracetamol use in relation to sex, age, and education were determined using logistic regression. RESULTS: Most respondents (70.5%) reported use of paracetamol in the 3 months prior to the study; the highest proportion was found among those aged 18 to 25 years (75.8%). Nine in 10 were over-the-counter (OTC) paracetamol users. A total of 14.2% thought paracetamol is completely harmless to use while 54.3% indicated risks associated with use even when following the dosing instructions. One third disagreed that it is less risky to use paracetamol compared with nonsteroidal antiinflammatory drugs. Three-quarters identified liver damage as a potential consequence of exceeding the recommended maximum daily dose. The likelihood of a high-risk perception was higher in women compared with men, and increased with age. No association was found between risk perception and educational status. Participants aged 18 to 25 years had the same ability to identify risks of overdose as did those aged 26 to 65, but expressed more careless attitudes towards use. CONCLUSIONS: Although the study population purchased paracetamol primarily OTC, they demonstrated basic awareness of paracetamol use including the potential consequences of overdosing. Young adults (18-25 y), who were the most frequent users of OTC paracetamol, perceived less risk associated with use compared with older participants. PMID- 28585411 TI - Ultra-fast LC-MS/MS in therapeutic drug monitoring: Quantification of clozapine and norclozapine in human plasma. AB - A novel approach to high-throughput, targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed. A single chromatographic system can be used for the analysis of a range of 20 drugs and metabolites with a total analysis time of 36 s (one 96-well plate of prepared samples per hour). To demonstrate the applicability of this approach to quantitative analysis, a method has been validated for the therapeutic drug monitoring of clozapine and norclozapine following automated extraction from human plasma. Chromatographic retention times were 11.4 and 12.4 s for norclozapine and clozapine, respectively (for both analytes the chromatographic peak width was less than 1 s). Comparison with a conventional LC-MS/MS method (5 min analysis time) showed excellent agreement. This new approach offers analysis times more akin to flow-injection analysis, but is likely to be more widely applicable because of chromatographic resolution from residual matrix components and isobaric interferences. PMID- 28585410 TI - 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. AB - OBJECTIVE: To develop recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP). METHODS: We conducted a systematic review to synthesize the evidence for the benefits and harms of GIOP prevention and treatment options. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of evidence. We used a group consensus process to determine the final recommendations and grade their strength. The guideline addresses initial assessment and reassessment in patients beginning or continuing long-term (>=3 months) glucocorticoid (GC) treatment, as well as the relative benefits and harms of lifestyle modification and of calcium, vitamin D, bisphosphonate, raloxifene, teriparatide, and denosumab treatment in the general adult population receiving long-term GC treatment, as well as in special populations of long-term GC users. RESULTS: Because of limited evidence regarding the benefits and harms of interventions in GC users, most recommendations in this guideline are conditional (uncertain balance between benefits and harms). Recommendations include treating only with calcium and vitamin D in adults at low fracture risk, treating with calcium and vitamin D plus an additional osteoporosis medication (oral bisphosphonate preferred) in adults at moderate-to-high fracture risk, continuing calcium plus vitamin D but switching from an oral bisphosphonate to another antifracture medication in adults in whom oral bisphosphonate treatment is not appropriate, and continuing oral bisphosphonate treatment or switching to another antifracture medication in adults who complete a planned oral bisphosphonate regimen but continue to receive GC treatment. Recommendations for special populations, including children, people with organ transplants, women of childbearing potential, and people receiving very high-dose GC treatment, are also made. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions. Clinicians and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies. PMID- 28585412 TI - Correction. PMID- 28585413 TI - Correction. PMID- 28585414 TI - Tissue factor variants induce monocyte transformation and transdifferentiation into endothelial cell-like cells. AB - : Essentials Monocytes (Mo) transdifferentiate into endothelial cell-like (ECL) cells. Mo induce tissue factor (TF) expression and secretion in microvascular endothelial cells (mECs). TF interacts with Mo in a paracrine fashion, inducing their transdifferentiation into ECL cells. TF generates a positive feedback crosstalk between Mo and mECs that promotes angiogenesis. SUMMARY: Background Monocytes (Mo) increase neovascularization by releasing proangiogenic mediators and/or transdifferentiating into endothelial cell-like (ECL) cells. Recently, we have reported that Mo-microvascular endothelial cells (mECs) crosstalk induces mEC-tissue factor (TF) expression and promotes angiogenesis. However, the effect of TF on Mo remains unknown. Objective Here, we analyzed whether TF might exert angiogenic effects by inducing transdifferentiation of Mo. Methods Full-length TF (flTF) and alternatively spliced TF (asTF) were overexpressed in mECs, and their supernatants were added to Mo cultures. CD16 positivity and expression of vascular endothelial cell (VEC) markers in Mo were analyzed by fluorescence activated cell sorting. The capacity to form tube-like structures were visualized in three-dimensional cultures. Results In mECs flTF and asTF expression and release were increased in cultures with Mo-conditioned media. TF variants induced expansion of a CD16+ Mo subset and Mo transdifferentiation into ECL-cells expressing VEC markers that can form new microvessels. CD16+ Mo exposed to TF showed an increased expression of VE-cadherin, von Willebrand factor (VWF) and eNOS. Mo cultured with supernatants obtained from TF-silenced mECs did not transdifferentiate to ECL-cells or expressed VEC markers. Blocking beta1-integrin in Mo significantly blocked the effects of the TF variants. Conclusions Mo induce mECs to express and release TF, which drives CD16- Mo to transform into CD16+ Mo and to transdifferentiate into ECL-cells that can form new microvessels. Our results reveal a TF-mediated positive feedback between mECs and Mo that stimulates Mo differentiation and induces angiogenesis. PMID- 28585415 TI - Methodologies for Quantitative Systems Pharmacology (QSP) Models: Design and Estimation. AB - With the increased interest in the application of quantitative systems pharmacology (QSP) models within medicine research and development, there is an increasing need to formalize model development and verification aspects. In February 2016, a workshop was held at Roche Pharma Research and Early Development to focus discussions on two critical methodological aspects of QSP model development: optimal structural granularity and parameter estimation. We here report in a perspective article a summary of presentations and discussions. PMID- 28585416 TI - Implications of HCV RNA level at week 4 of direct antiviral treatments for hepatitis C. AB - We aimed to determine whether the HCV viral load after four weeks of treatment (W4VL) with direct-acting antiviral agents (DAAs) predicts sustained virologic response (SVR) in a real-world clinical setting. We identified 21 095 patients who initiated DAA-based antiviral treatment in the national Veterans Affairs (VA) healthcare system from 01/01/2014 to 06/30/2015. Week 4 viral load was categorized as undetectable, detectable below quantification (DBQ), detectable above quantification (DAQ) with viral load <=42 IU/mL and DAQ with viral load >42 IU/mL. Week 4 viral load was undetectable in 36.1%, detectable below quantification in 45.6%, DAQ <=42 in 9.3%, DAQ >42 in 9.1%. Detectable above quantification was much more common and undetectable week 4 viral load much less common when tested with the Abbott RealTime HCV assay vs the Roche COBAS AmpliPrep/COBAS TaqMan Version 2 assay. Compared to patients with undetectable week 4 viral load (SVR=93.5%), those with detectable below quantification (SVR=91.8%, adjusted odds ratio [AOR] 0.79, P-value=.001), DAQ <=42 (SVR=90.0%, AOR 0.63, P-value<.001) and DAQ >42 (SVR=86.2%, AOR 0.52, P-value<.001) had progressively lower likelihood of achieving SVR after adjusting for baseline characteristics and treatment duration. Among genotype 1-infected patients who were potentially eligible for 8-week sofosbuvir/ledipasvir monotherapy, we did not find evidence that treatment for 12 weeks instead of 8 weeks was associated with higher SVR, even among those with detectable above quantification. In summary, DBQ and DAQ W4VL are very common in real-world practice, contrary to what was reported in clinical trials, and strongly predict reduced SVR across genotypes and clinically relevant patient subgroups. Whether and how week 4 viral load results should influence treatment decisions requires further study. PMID- 28585418 TI - One Model, Two Enzymes: Activation of Hydrogen and Carbon Monoxide. AB - The ability to catalyze the oxidation of both H2 and CO in one reaction pot would be a major boon to hydrogen technology since CO is a consistent contaminant of H2 supplies. Here, we report just such a catalyst, with the ability to catalyze the oxidation of either or both H2 and CO, based on the pH value. This catalyst is based on a NiIr core that mimics the chemical function of [NiFe]hydrogenase in acidic media (pH 4-7) and carbon monoxide dehydrogenase in basic media (pH 7-10). We have applied this catalyst in a demonstration fuel cell using H2 , CO, and H2 /CO (1/1) feeds as fuels for oxidation at the anode. The power density of the fuel cell depends on the pH value in the media of the fuel cell and shows a similar pH dependence in a flask. We have isolated and characterized all intermediates in our proposed catalytic cycles. PMID- 28585417 TI - Cyanobacterial peptides as a prototype for the design of cathepsin D inhibitors. AB - Cathepsin D (Cath D) is overexpressed and secreted in a number of solid tumors and involved in the progress of tumor invasion, proliferation, metastasis, and apoptosis. Inhibition of Cath D is regarded as an attractive pathway for the development of novel anticancer drugs. Our previous studies revealed that tasiamide B, a cyanobacterial peptide that contained a statine-like unit, exhibited good inhibition against Cath D and other aspartic proteases. Using this natural product as prototype, we designed and synthesized three new analogs, which bear isophthalic acid fragment at the N-terminus and isobutyl amine (1), cyclopropyl amine (2), or 3-methoxybenzyl amine (3) moiety at the C-terminus. Enzymatic assays revealed that all these three compounds showed moderate-to-good inhibition against Cath D, with IC50 s of 15, 884, and 353 nM, respectively. Notably, compound 1 showed extreme selectivity for Cath D with 576-fold over Cath E and 554-fold over BACE1, which could be a valuable template for the design of highly potent and selective Cath D inhibitors. Additionally, compound 1 showed moderated activity against HeLa cell lines with IC50 of 41.8 MUM. Copyright (c) 2017 European Peptide Society and John Wiley & Sons, Ltd. PMID- 28585419 TI - Synthesis and biological evaluation of 2-acylbenzofuranes as novel alpha glucosidase inhibitors with hypoglycemic activity. AB - A series of benzofuran derivatives was synthesized as analogues of known natural alpha-glucosidase inhibitors. Their activity was evaluated in enzymatic assay and in rat model of diabetes mellitus. Newly identified inhibitors demonstrate significant potency with IC50 values ranging from 6.50 to 722.2 MUm, as well as hypoglycemic activity exceeding the reference drug acarbose. Docking simulations provided insight into structure-activity relationships to direct further development of these novel hypoglycemic agents. PMID- 28585420 TI - Quantitative biogeography of picoprasinophytes establishes ecotype distributions and significant contributions to marine phytoplankton. AB - Bathycoccus and Ostreococcus are broadly distributed marine picoprasinophyte algae. We enumerated small phytoplankton using flow cytometry and qPCR assays for phylogenetically distinct Bathycoccus clades BI and BII and Ostreococcus clades OI and OII. Among 259 photic-zone samples from transects and time-series, Ostreococcus maxima occurred in the North Pacific coastal upwelling for OI (36 713 +/- 1485 copies ml-1 ) and the Kuroshio Front for OII (50 189 +/- 561 copies ml-1 ) and the two overlapped only in frontal regions. The Bathycoccus overlapped more often with maxima along Line-P for BI (10 667 +/- 1299 copies ml-1 ) and the tropical Atlantic for BII (4125 +/- 339 copies ml-1 ). Only BII and OII were detected at warm oligotrophic sites, accounting for 34 +/- 13% of 1589 +/- 448 eukaryotic phytoplankton cells ml-1 (annual average) at Station ALOHA's deep chlorophyll maximum. Significant distributional and molecular differences lead us to propose that Bathycoccus clade BII represents a separate species which tolerates higher temperature oceanic conditions than Bathycoccus prasinos (BI). Morphological differences were not evident, but quick-freeze deep-etch electron microscopy provided insight into Bathycoccus scale formation. Our results highlight the importance of quantitative seasonal abundance data for inferring ecological distributions and demonstrate significant, differential picoprasinophyte contributions in mesotrophic and open-ocean waters. PMID- 28585421 TI - Evaluation of potential anti-toxoplasmosis efficiency of combined traditional herbs in a mouse model. AB - Toxoplasma gondii is a worldwide spread protozoan and is able to infect almost all warm-blood animals. No effective drugs are available clinically on toxoplasmosis. Chinese traditional herbal medicines have provided remedies for many health problems. There exists a possibility that Chinese herbs may provide protection against T. gondii. This work aims to assess the protective efficacy of combined Chinese herbs against T. gondii. We screened five herbal medicines that have different pharmacological effects and combined them into a prescription according to the traditional Chinese medicine compatibility principle. The drug potential and protective efficacy were evaluated through a mouse model by determining the survival time, the parasite load in blood and tissues, the change of cell proportions in blood and histological detection. The results showed that the survival time of mice in the 500 mg Chinese herbs group and sulfadiazine group was significantly longer than that of the PBS control group. Also the parasite load in blood and tissues of 500 mg Chinese herbs and sulfadiazine groups was significantly lower than that of PBS group at 7 days post infection (dpi), which was in accordance with the result of histological detection. Monocyte and neutrophil of infected mice were remarkably increased while lymphocyte was dramatically decreased compared to that of blank group at 7 dpi. The results demonstrated that the 500 mg dosage of our Chinese herbs could slow down the replication of T. gondii and prolong the survival time of mice and could be considered as possible candidate drug against toxoplasmosis. PMID- 28585422 TI - Menaquinone-7 production from maize meal hydrolysate by Bacillus isolates with diphenylamine and analogue resistance. AB - A menaquinone-7 (MK-7) high-producing strain needs to be isolated to increase MK 7 production, in order to meet a requirement of MK-7 given the low MK-7 content in food products. This article focuses on developing MK-7 high-producing strains via screening and mutagenesis by an atmospheric and room temperature plasma (ARTP) mutation breeding system. We isolated an MK-7-producing strain Y-2 and identified it as Bacillus amyloliquefaciens, which produced (7.1+/-0.5) mg/L of MK-7 with maize meal hydrolysate as carbon source. Then, an MK-7 high-producing strain B. amyloliquefaciens H.beta.D.R.-5 with resistance to 1-hydroxy-2 naphthoic acid, beta-2-thienylalanine, and diphenylamine was obtained from the mutation of the strain Y-2 using an ARTP mutation breeding system. Using strain H.beta.D.R.-5, efficient production of MK-7 was achieved ((30.2+/-2.7) mg/L). In addition, the effects of nitrogen sources, prenyl alcohols, and MgSO4 on MK-7 production were investigated, suggesting that soymeal extract combined with yeast extract, isopentenol, and MgSO4 was beneficial. Under the optimized condition, the MK-7 production and biomass-specific yield reached (61.3+/-5.2) mg/L and 2.59 mg/L per OD600 unit respectively in a 7-L fermenter. These results demonstrated that strain H.beta.D.R.-5 has the capacity to produce MK-7 from maize meal hydrolysate, which could reduce the substrate cost. PMID- 28585423 TI - Copper-modified palygorskite is effective in preventing and treating diarrhea caused by Salmonella typhimurium. AB - The aim of this research was to develop effective alternative therapies to reduce antibiotic use in animal agriculture. In this study, the efficacy of copper modified palygorskite (CM-Pal) in preventing diarrhea caused by Salmonella was specifically examined both in vitro and in vivo. The CM-Pal was prepared with palygorskite (Pal) and copper nitrate. The antibacterial activity of the CM-Pal was detected by comparing the differences in cell numbers on plate count agar before and after adding the CM-Pal to Salmonella typhimurium cultures. Seventy ICR mice were then allocated into seven groups. Five groups (the treatment groups) were infected with S. typhimurium by intraperitoneal (i.p.) injection and were given Pal, CM-Pal, montmorillonite powder, gentamicin, and physiological saline, respectively. One group (the prevention group) was given CM-Pal before infection with S. typhimurium. Another group (the uninfected group) was not infected with S. typhimurium. The effects of Pal, CM-Pal, montmorillonite powder, and gentamicin on the treatment or prevention of diarrhea in the mice were examined by stool studies, fecal scoring, and assessment of growth performance and villus height. The CM-Pal had satisfactory anti-bacterial properties in vitro: the antibacterial rate was 100% after 2 h incubation with S. typhimurium NJS1 cultures (1*106 colony-forming units (CFU)/ml). In the in vivo experiment, the CM-Pal exerted superior effects in the treatment and prevention of diarrhea in mice compared with Pal, montmorillonite powder, and gentamicin. In the CM-Pal group, no mice showed signs of diarrhea at 24 h post infection (p.i.), and all mice fully recovered from infection. However, the Pal group, montmorillonite group, and gentamicin group only recovered after 48, 48, and 96 h, respectively. The villus height level in the CM-Pal treatment group recovered at 3 d p.i. However, the recovery time of the other groups was longer (at least 5 d). The CM Pal prevention group had a better effect on weight gain than the other groups. This study suggested that CM-Pal may be an effective alternative to conventional antibiotics for the treatment and prevention of animal diarrhea caused by Salmonella. PMID- 28585424 TI - Punicalagin protects bovine endometrial epithelial cells against lipopolysaccharide-induced inflammatory injury. AB - OBJECTIVE: Bovine endometritis is one of the most common reproductive disorders in cattle. The aim of this study was to investigate the anti-inflammation potential of punicalagin in lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and to uncover the underlying mechanisms. METHODS: bEECs were stimulated with different concentrations (1, 10, 30, 50, and 100 MUg/ml) of LPS for 3, 6, 9, 12, and 18 h. MTT assay was used to assess cell viability and to identify the conditions for inflammatory injury and effective concentrations of punicalagin. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression of pro-inflammatory cytokines. Western blotting was used to assess levels of inflammation-related proteins. RESULTS: Treatment of bEECs with 30 ug/ml LPS for 12 h induced cell injury and reduced cell viability. Punicalagin (5, 10, or 20 ug/ml) pretreatment significantly decreased LPS-induced productions of interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) in bEECs. Molecular research showed that punicalagin inhibited the activation of the upstream mediator nuclear factor-kappaB (NF-kappaB) by suppressing the production of inhibitor kappaBalpha (IkappaBalpha) and phosphorylation of p65. Results also indicated that punicalagin can suppress the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). CONCLUSIONS: Punicalagin may attenuate LPS-induced inflammatory injury and provide a potential option for the treatment of dairy cows with Escherichia coli endometritis. PMID- 28585425 TI - CIDE gene expression in adipose tissue, liver, and skeletal muscle from obese and lean pigs. AB - The expression of the cell death-inducing DNA fragmentation factor alpha-like effector (CIDE) family including Cidea, Cideb, and Cidec was significantly increased in mouse and human models of obesity. However, there was less information on these genes' expression in pigs. Here, we hypothesized that different fat accumulation between lean (Duroc*Landrace*Yorkshire gilts, DLY) and obese (Lantang) pigs was attributed to porcine CIDE-modulating lipid metabolism. Our data showed that Cidea and Cidec were expressed at a high level in adipose tissue, and at a relatively high level in skeletal muscle, whereas Cideb was mainly expressed in the liver in both breeds of pig. Lantang pigs had higher white adipose and skeletal muscle Cidea and Cidec mRNA abundance, and hepatic and muscle Cideb mRNA than DLY pigs. Lipid metabolism-related genes including sterol regulatory element binding protein 1c (SREBP-1c), hepatocyte nuclear factor 4alpha (HNF-4alpha), peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), fatty acid synthase (FASN), diacylglycerol O-acyltransferase 1 (DGAT1), and DGAT2 showed a higher expression level in adipose tissue from obese pigs than in that from lean pigs. Lantang pigs exhibited higher mRNA abundance for liver SREBP-1c, HNF-4alpha, and PGC-1alpha, and higher skeletal muscle SREBP-1c, HNF-4alpha, PGC-1alpha, and DGAT2 expression, as compared with DLY pigs. However, the perlipin2 mRNA levels in adipose tissues, liver, and skeletal muscle were significantly lower in obese pigs than in their lean counterparts. Furthermore, plasma non-esterified fatty acid (NEFA), glucose, and triacylglycerol (TAG) levels were greater in obese pigs than in lean pigs. Finally, data from correlation analysis further found that CIDE mRNA expression was positively correlated with back fat thickness (BFT), abdominal fat mass (AFM), and the levels of NEFA, TAG, and glucose in the two breeds. Collectively, these data revealed that the porcine CIDEs possibly modulated lipid metabolism and contributed to the development of fat deposition and obesity in Lantang pigs. PMID- 28585426 TI - Effect of Helichrysum plicatum DC. subsp. plicatum ethanol extract on gentamicin induced nephrotoxicity in rats. AB - The aim of this study was to evaluate the possible therapeutic or protective effects of Helichrysum plicatum DC. subsp. plicatum ethanol extract (HPE) against gentamicin-induced nephrotoxicity. Thirty-six Sprague Dawley male rats weighing between 200 and 250 g were used as live material. They were formed into six groups containing 6 rats each and were allowed to adapt to laboratory conditions for 7 d. Group I: control, 5% DMSO intraperitoneal (i.p.); Group II: HPE 100 mg/(kg.d) i.p.; Group III: HPE 200 mg/(kg.d) i.p.; Group IV: gentamicin as 80 mg/(kg.d) i.p.; Group V: gentamicin as 80 mg/(kg.d) i.p.+HPE 100 mg/(kg.d) i.p.; and Group VI: gentamicin as 80 mg/(kg.d) i.p.+HPE 200 mg/(kg.d) i.p. for 8 d. Following treatment, serum, liver, and kidney tissues were used to assess blood urea nitrogen (BUN), creatinine, enzymatic and non-enzymatic antioxidants, and lipid peroxidation. Gentamicin significantly increased serum BUN, creatinin, and liver and kidney levels of malondialdehyde (MDA). It also decreased the activity of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD). Treatment with the HPE 100 mg/kg reversed gentamicin-induced alterations as evidenced by decreased serum BUN and creatinin, liver and kidney oxidant marker, and tubular necrosis as well as by an increase in antioxidant enzymes. It was found that HPE 200 mg/kg significantly increased liver and kidney tissue MDA levels in nephrotoxicity in rats. As a result, these findings support the proposition that HPE in 100 mg/kg dose demonstrates in the kidney and liver as free radicals and scavenger to prevent the toxic effects of gentamicin in both the biochemical and histopathology parameters. PMID- 28585427 TI - Uptake, transport and distribution of molybdenum in two oilseed rape (Brassica napus L.) cultivars under different nitrate/ammonium ratios. AB - OBJECTIVES: To investigate the effects of different nitrate sources on the uptake, transport, and distribution of molybdenum (Mo) between two oilseed rape (Brassica napus L.) cultivars, L0917 and ZS11. METHODS: A hydroponic culture experiment was conducted with four nitrate/ammonium (NO3-:NH4+) ratios (14:1, 9:6, 7.5:7.5, and 1:14) at a constant nitrogen concentration of 15 mmol/L. We examined Mo concentrations in roots, shoots, xylem and phloem sap, and subcellular fractions of leaves to contrast Mo uptake, transport, and subcellular distribution between ZS11 and L0917. RESULTS: Both the cultivars showed maximum biomass and Mo accumulation at the 7.5:7.5 ratio of NO3-:NH4+ while those were decreased by the 14:1 and 1:14 treatments. However, the percentages of root Mo (14.8% and 15.0% for L0917 and ZS11, respectively) were low under the 7.5:7.5 treatment, suggesting that the equal NO3-:NH4+ ratio promoted Mo transportation from root to shoot. The xylem sap Mo concentration and phloem sap Mo accumulation of L0917 were lower than those of ZS11 under the 1:14 treatment, which suggests that higher NO3-:NH4+ ratio was more beneficial for L0917. On the contrary, a lower NO3-:NH4+ ratio was more beneficial for ZS11 to transport and remobilize Mo. Furthermore, the Mo concentrations of both the cultivars' leaf organelles were increased but the Mo accumulations of the cell wall and soluble fraction were reduced significantly under the 14:1 treatment, meaning that more Mo was accumulated in organelles under the highest NO3-:NH4+ ratio. CONCLUSIONS: This investigation demonstrated that the capacities of Mo absorption, transportation and subcellular distribution play an important role in genotype-dependent differences in Mo accumulation under low or high NO3-:NH4+ ratio conditions. PMID- 28585428 TI - Anti-hepatocarcinoma activity of TT-1, an analog of melittin, combined with interferon-alpha via promoting the interaction of NKG2D and MICA. AB - Hepatocarcinoma is one of the malignant cancers with significant morbidity and mortality. Immunotherapy has emerged in clinical treatment, owing to the limitation and severe side effects of chemotherapy. In the immune system, natural killer (NK) cells are important effectors required to eliminate malignant tumor cells without the limitation of major histocompatibility complex (MHC) molecule issues. Hence, treatment which could stimulate NK cells is of great interest. Here, we investigated the efficacy of the combined therapy of TT-1 (a mutant of melittin) and interferon-alpha (IFN-alpha) on NK cells and human liver cancer HepG-2/Huh7 cells in vitro and in vivo, as well as the mechanism involved. The combination therapy significantly inhibited the growth of HepG-2/Huh7 cells in vivo, but this effect was impaired after depleting NK cells. TT-1 not only up regulated MHC class I-related chain molecules A (MICA) expression, but also prevented the secretion of soluble MICA (sMICA). Both the mRNA and protein of a disintegrin and metallopeptidase 10 (ADAM 10) in HepG-2/Huh7 cells were decreased after TT-1 treatment. The combined therapy of TT-1 and IFN-alpha could suppress the growth of HepG-2/Huh7 xenografted tumor effectively via promoting the interaction of NK group 2, member D (NKG2D) and MICA, indicating that TT-1+IFN alpha would be a potential approach in treating liver cancer. PMID- 28585429 TI - Laparoscopic versus open distal pancreatectomy for pancreatic ductal adenocarcinoma: a single-center experience. AB - OBJECTIVE: The aim of this study was to compare complications and oncologic outcomes of patients undergoing laparoscopic distal pancreatectomy (LDP) and open distal pancreatectomy (ODP) at a single center. METHODS: Distal pancreatectomies performed for pancreatic ductal adenocarcinoma during a 4-year period were included in this study. A retrospective analysis of a database of this cohort was conducted. RESULTS: Twenty-two patients underwent LDP for pancreatic ductal adenocarcinoma, in comparison to seventy-six patients with comparable tumor characteristics treated by ODP. No patients with locally advanced lesions were included in this study. Comparing LDP group to ODP group, there were no significant differences in operation time (P=0.06) or blood loss (P=0.24). Complications (pancreatic fistula, P=0.62; intra-abdominal abscess, P=0.44; postpancreatectomy hemorrhage, P=0.34) were similar. There were no significant differences in the number of lymph nodes harvested (11.2+/-4.6 in LDP group vs. 14.4+/-5.5 in ODP group, P=0.44) nor the rate of patients with positive lymph nodes (36% in LDP group vs. 41% in ODP group, P=0.71). Incidence of positive margins was similar (9% in LDP group vs. 13% in ODP group, P=0.61). The mean overall survival time was (29.6+/-3.7) months for the LDP group and (27.6+/-2.1) months for ODP group. There was no difference in overall survival between the two groups (P=0.34). CONCLUSIONS: LDP is a safe and effective treatment for selected patients with pancreatic ductal adenocarcinoma. A slow-compression of pancreas tissue with the GIA stapler is effective in preventing postoperative pancreatic fistula. The oncologic outcome is comparable with the conventional open approach. Laparoscopic radical antegrade modular pancreatosplenectomy contributed to oncological clearance. PMID- 28585430 TI - Satisfactory clinical outcome following delayed repositioning of a traumatic post LASIK flap with dislocation and shrinkage managed by irrigation, stretching, and debridement. AB - OBJECTIVE: To report surgical management and favorable outcome in a case with delayed repair of traumatic laser in situ keratomileusis (LASIK) flap dislocation with shrinkage and folds. METHODS: A 30-year-old man with a five-year history of bilateral LASIK experienced blunt trauma to his right eye followed by decreased vision for 5 weeks. The surgical management included initially softening the flap by irrigation with balanced salt solution (BSS). The shrinkage folds were carefully and gently stretched by scraping with a 26-gauge cannula accompanied by BSS irrigation. All of the epithelial ingrowth on the flap inner surface and on the bed was thoroughly debrided by scraping and irrigation. After the flap was repositioned to match its original margin, a soft bandage contact lens was placed. RESULTS: At his initial visit, slit-lamp microscopy and optical coherence tomography (OCT) showed shrinkage of the LASIK flap with an elevated margin approximately 3 mm above the original position. The flap covered half of the pupil and had multiple horizontal folds. Two months after surgery, the flap remained well positioned with only faint streaks in the anterior stroma. The uncorrected visual acuity of the right eye was 20/20 with a manifest refraction of Plano. CONCLUSIONS: For delayed repair of traumatically dislocated LASIK flaps, sufficient softening by BSS, stretching the shrinkage folds, and thorough debridement of ingrowth epithelium enable resetting the flap and provide satisfactory results. PMID- 28585431 TI - Sensory quality evaluation for appearance of needle-shaped green tea based on computer vision and nonlinear tools. AB - Tea is one of the three greatest beverages in the world. In China, green tea has the largest consumption, and needle-shaped green tea, such as Maofeng tea and Sparrow Tongue tea, accounts for more than 40% of green tea (Zhu et al., 2017). The appearance of green tea is one of the important indexes during the evaluation of green tea quality. Especially in market transactions, the price of tea is usually determined by its appearance (Zhou et al., 2012). Human sensory evaluation is usually conducted by experts, and is also easily affected by various factors such as light, experience, psychological and visual factors. In the meantime, people may distinguish the slight differences between similar colors or textures, but the specific levels of the tea are hard to determine (Chen et al., 2008). As human description of color and texture is qualitative, it is hard to evaluate the sensory quality accurately, in a standard manner, and objectively. Color is an important visual property of a computer image (Xie et al., 2014; Khulal et al., 2016); texture is a visual performance of image grayscale and color changing with spatial positions, which can be used to describe the roughness and directivity of the surface of an object (Sanaeifar et al., 2016). There are already researchers who have used computer visual image technologies to identify the varieties, levels, and origins of tea (Chen et al., 2008; Xie et al., 2014; Zhu et al., 2017). Most of their research targets are crush, tear, and curl (CTC) red (green) broken tea, curly green tea (Bilochun tea), and flat-typed green tea (West Lake Dragon-well green tea) as the information sources. However, the target of the above research is to establish a qualitative evaluation method on tea quality (Fu et al., 2013). There is little literature on the sensory evaluation of the appearance quality of needle-shaped green tea, especially research on a quantitative evaluation model (Zhou et al., 2012; Zhu et al., 2017). PMID- 28585432 TI - Full genome analysis of swine genotype 3 hepatitis E virus isolated from eastern China. AB - Hepatitis E is believed to occur in both endemic and sporadic forms in developing countries, which causes a major public health problem in Asia and Africa (Meng, 2010; Wang et al., 2016a). Recent studies have documented that the disease is also endemic in many industrialized countries (Wenzel et al., 2011). The causative agent, hepatitis E virus (HEV), belonging to the genus Orthohepevirus, is a non-enveloped RNA virus with a single-stranded, positive-sense genome of approximately 7.2 kb (Smith et al., 2014). The genome consists of a short 5' un translated region (UTR), three open reading frames (ORFs), and a 3' UTR containing a poly(A) tail (Meng, 2011). Four recognized major genotypes of HEV are identified: genotype 1 (Asian and African strains), genotype 2 (a Mexican strain), genotype 3 (primarily from America and Europe, and some Asian countries), and genotype 4 (mainly Asian strains) (Smith et al., 2016). Previous study revealed that HEV genotype 4 is the dominant zoonotic HEV genotype in China (Wang et al., 2016a). However, infections with HEV 3 have been found more commonly in recent years in China (Liu et al., 2012; Zhang et al., 2013). To date, only one full genome of Chinese swine genotype 3 HEV strain from Shanghai has been documented (Si et al., 2009). We report here the first full genome sequence of a genotype 3 swine HEV strain from Zhejiang, China. PMID- 28585434 TI - Genes for the high life: New genetic variants point to positive selection for high altitude hypoxia in Tibetans. PMID- 28585435 TI - Creating animal models, why not use the Chinese tree shrew (Tupaia belangeri chinensis)? AB - The Chinese tree shrew (Tupaia belangeri chinensis), a squirrel-like and rat sized mammal, has a wide distribution in Southeast Asia, South and Southwest China and has many unique characteristics that make it suitable for use as an experimental animal. There have been many studies using the tree shrew (Tupaia belangeri) aimed at increasing our understanding of fundamental biological mechanisms and for the modeling of human diseases and therapeutic responses. The recent release of a publicly available annotated genome sequence of the Chinese tree shrew and its genome database (www.treeshrewdb.org) has offered a solid base from which it is possible to elucidate the basic biological properties and create animal models using this species. The extensive characterization of key factors and signaling pathways in the immune and nervous systems has shown that tree shrews possess both conserved and unique features relative to primates. Hitherto, the tree shrew has been successfully used to create animal models for myopia, depression, breast cancer, alcohol-induced or non-alcoholic fatty liver diseases, herpes simplex virus type 1 (HSV-1) and hepatitis C virus (HCV) infections, to name a few. The recent successful genetic manipulation of the tree shrew has opened a new avenue for the wider usage of this animal in biomedical research. In this opinion paper, I attempt to summarize the recent research advances that have used the Chinese tree shrew, with a focus on the new knowledge obtained by using the biological properties identified using the tree shrew genome, a proposal for the genome-based approach for creating animal models, and the genetic manipulation of the tree shrew. With more studies using this species and the application of cutting-edge gene editing techniques, the tree shrew will continue to be under the spot light as a viable animal model for investigating the basis of many different human diseases. PMID- 28585437 TI - A new species of the genus Amolops (Anura: Ranidae) from high-altitude Sichuan, southwestern China, with a discussion on the taxonomic status of Amolops kangtingensis. AB - A new species of the genus Amolops Cope, 1865 is described from Xinduqiao, Kangding, Sichuan. It was previously identified as Amolops kangtingensis, which is synonymized to Amolops mantzorum in this study. The new species, Amolops xinduqiao sp. nov., is distinguished from all other congeners by the following combination of characters: (1) medium body size, adult males SVL 41.2-47.5 mm ( n=15, average 43.9 mm), adult females SVL 48.5-56.6 mm ( n=15, average 52.5 mm); (2) head length equal to width or slightly wider than long; (3) tympanum small, but distinct; (4) vomerine teeth in two tiny rows, separated by a space about one vomerine teeth row; (5) bony projections on lower jaw absent; (6) dorsolateral folds usually absent; (7) tarsal folds or glands on tarsus absent; (8) circummarginal groove on disc of finger I absent; (9) tibiotarsal articulation reaching nostril or beyond; (10) webs of toe IV reaching to distal articulation, other toes fully webbed to disc; and (11) vocal sac absent in males. PMID- 28585438 TI - Pulmonary immune cells and inflammatory cytokine dysregulation are associated with mortality of IL-1R1 -/-mice infected with influenza virus (H1N1). AB - Respirovirus infection can cause viral pneumonia and acute lung injury (ALI). The interleukin-1 (IL-1) family consists of proinflammatory cytokines that play essential roles in regulating immune and inflammatory responses in vivo. IL-1 signaling is associated with protection against respiratory influenza virus infection by mediation of the pulmonary anti-viral immune response and inflammation. We analyzed the infiltration lung immune leukocytes and cytokines that contribute to inflammatory lung pathology and mortality of fatal H1N1 virus infected IL-1 receptor 1 (IL-1R1) deficient mice. Results showed that early innate immune cells and cytokine/chemokine dysregulation were observed with significantly decreased neutrophil infiltration and IL-6, TNF-alpha, G-CSF, KC, and MIP-2 cytokine levels in the bronchoalveolar lavage fluid of infected IL-1R1 /- mice in comparison with that of wild type infected mice. The adaptive immune response against the H1N1 virus in IL-1R1 -/- mice was impaired with downregulated anti-viral Th1 cell, CD8+ cell, and antibody functions, which contributes to attenuated viral clearance. Histological analysis revealed reduced lung inflammation during early infection but severe lung pathology in late infection in IL-1R1 -/- mice compared with that in WT infected mice. Moreover, the infected IL-1R1 -/- mice showed markedly reduced neutrophil generation in bone marrow and neutrophil recruitment to the inflamed lung. Together, these results suggest that IL-1 signaling is associated with pulmonary anti-influenza immune response and inflammatory lung injury, particularly via the influence on neutrophil mobilization and inflammatory cytokine/chemokine production. PMID- 28585436 TI - Tree shrew (Tupaia belangeri) as a novel laboratory disease animal model. AB - The tree shrew (Tupaia belangeri) is a promising laboratory animal that possesses a closer genetic relationship to primates than to rodents. In addition, advantages such as small size, easy breeding, and rapid reproduction make the tree shrew an ideal subject for the study of human disease. Numerous tree shrew disease models have been generated in biological and medical studies in recent years. Here we summarize current tree shrew disease models, including models of infectious diseases, cancers, depressive disorders, drug addiction, myopia, metabolic diseases, and immune-related diseases. With the success of tree shrew transgenic technology, this species will be increasingly used in biological and medical studies in the future. PMID- 28585441 TI - Skeletal Rearrangement of Twisted Polycyclic Aromatic Hydrocarbons under Scholl Reaction Conditions. AB - Treatment of a twisted polycyclic aromatic hydrocarbon containing cyclooctatetraene fused by two 9,9'-bifluorenylidene units under the Scholl reaction conditions (FeCl3 or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and scandium trifluoromethanesulfonate) led to stepwise skeletal rearrangements to afford initially a hydrocarbon with a seven-membered ring and then tetrabenzo[a,d,j,m]coronene with all six-membered rings. The course of the rearrangement was interpreted in terms of the acid-catalyzed isomerization of 9,9'-bifluorenylidene into dibenzo[g,p]chrysene moieties on the basis of theoretical investigations. PMID- 28585440 TI - EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production. AB - The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high altitude adaptation through regulating NO production. PMID- 28585442 TI - Social dominance in children with cerebral palsy during a problem-solving task with peers. AB - PURPOSE: Children with cerebral palsy tend to have poorer social competence outcomes than their peers without a disability in mainstream school settings. To understand their social competence, this study compared children with cerebral palsy with paired children without cerebral palsy with respect to their ability to access resources, defined here as "social dominance", in a problem-solving situation. METHOD: Children with cerebral palsy were randomly paired to a peer (teammate) and put in a competitive context where each team of two children was instructed to solve an impossible problem. To control for social status, a sociometric measure was administered previously in the classroom (Social Preference score). Behaviors related to social dominance (prosocial and coercive behaviors) were coded using an observation scale validated for this study. RESULTS: The results showed that regardless of social status, children with cerebral palsy were less socially dominant than controls without cerebral palsy. Furthermore, their teams seemed to be less dominant than teams composed of two controls. CONCLUSIONS: The lower social competence in children with cerebral palsy could be partly explained by their reduced social dominance behavior in activities requiring speed and fluidity as an expression of executive functions. This might be viewed as a marker for social risks in the integration process at school. Implications for rehabilitation Gross Motor Function Classification System level I or II cerebral palsy is a condition that affects not only motor abilities but also social competence in children. Lower social competence in children with cerebral palsy could be partly explained by reduced social dominance behavior in activities such as problem solving with peers. To improve social competence, rehabilitation interventions should include social participation opportunities in which children with cerebral palsy are encouraged to take an active role in the activity. PMID- 28585443 TI - Corrigendum. PMID- 28585439 TI - GCH1 plays a role in the high-altitude adaptation of Tibetans. AB - Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene ( GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia. PMID- 28585444 TI - Artificial cultivation of true morels: current state, issues and perspectives. AB - Morels (Morchella, Ascomycota), which are some of the most highly prized edible and medicinal mushrooms, are of great economic and scientific value. Morel cultivation has been a research focus worldwide for more than 100 years, and the outdoor cultivation of morels has succeeded and expanded to a large scale in China in recent years. In this study, we review the progress in recent research regarding the life cycle and reproductive systems in the genus Morchella and the current state of outdoor cultivation. Sclerotia formation and conidia production are two important phases during the life cycle. The morel species cultivated commercially in America is M. rufobrunnea based on molecular phylogenetic analysis. The species currently cultivated in China are black morels, including M. importuna, M. sextalata and M. eximia. The field cultivation of morels expanded in the majority of the provinces in China with a yield of fresh morels of 0-7620 kg per ha. The key techniques include spawn production, land preparation and spawning, the addition of exogenous nutrition, fruiting management and harvesting. The application of exogenous nutrition is the most important breakthrough in the field of morel cultivation, but the mechanism remains unclear. It was estimated that the total amount of field cultivated fresh morels was ~500 t in 2015-2016. We also discuss the potential issues remaining in the current literature and suggest directions for future studies. PMID- 28585445 TI - Lactose esters: synthesis and biotechnological applications. AB - Biodegradable nonionic sugar esters-based surfactants have been gaining more and more attention in recent years due to their chemical plasticity that enables the various applications of these molecules. In this review, various synthesis methods and biotechnological implications of lactose esters (LEs) uses are considered. Several chemical and enzymatic approaches are described for the synthesis of LEs, together with their applications, i.e. function in detergents formulation and as additives that not only stabilize food products but also protect food from undesired microbial contamination. Further, this article discusses medical applications of LEs in cancer treatment, especially their uses as biosensors, halogenated anticancer drugs, and photosensitizing agents for photodynamic therapy of cancer and photodynamic inactivation of microorganisms. PMID- 28585446 TI - Pharmacological management of acute severe behavioural disturbance: a survey of current protocols. AB - OBJECTIVES: The investigators reviewed protocols for the pharmacological management of acute severe behavioural disturbance (ASBD) used in Australasian psychiatric settings. Relevant literature was also examined, with a focus on Australian research. METHODS: All Fellows of the RANZCP were emailed on two occasions in 2014 requesting a copy of the guidelines for pharmacological management of the ASBD patient used in their workplace. A literature search was also undertaken. RESULTS: Thirty-six pharmacological management protocols for the ASBD patient were received. Twenty-six of these referred to patients aged 18-65 years and were selected for analysis. A number of recent publications provided new evidence in relation to the safe and effective management of patients with ASBD. CONCLUSIONS: ASBD is a heterogeneous, transnosological set of presentations requiring careful assessment and rational clinical decision making. Treatment protocols arising from an evolving evidence base provide safe and effective pathways for the majority of patients. However, sound clinical knowledge and a careful assessment of each presentation is required to enable the clinician to tailor treatment individually. PMID- 28585447 TI - Anticonvulsant Effects of Aerial Parts of Verbena officinalis Extract in Mice: Involvement of Benzodiazepine and Opioid Receptors. AB - To evaluate the anticonvulsant activity of the aerial parts of Verbena officinalis used traditionally by local Iranians for the treatment of convulsion. The anticonvulsant activity of the extract was assessed in pentylenetetrazole (PTZ) and maximal electroshock (MES) induced seizures in mice. Diazepam was used as reference drug. In addition, for investigating the mechanism of V officinalis in PTZ model, flumazenil and naloxone were injected before V officinalis. The extract showed no toxicity and significantly increased the period taken before the onset and decreased the duration of the seizures induced by PTZ. In the MES test, V officinalis displayed significant reduction in hind limb tonic extension duration in a dose-dependent manner. The results propose that V officinalis ethanolic extract has anticonvulsant activity against seizure. It seems that these effects may be related to potentiating of GABAergic system. Moreover, this study supports the use of this plant by local Iranians in order to treat convulsion. PMID- 28585448 TI - Embedding exercise interventions as routine mental health care: implementation strategies in residential, inpatient and community settings. AB - OBJECTIVES: Evaluation of physical activity (PA) programs among populations with severe mental illness (SMI) has predominately focused on efficacy and therapeutic benefits. There is now strong evidence to support the benefits of PA in people with SMI. What remains is a gap in the implementation of pragmatic and sustainable PA interventions in mental-health settings. The current paper provides examples of interventions that have been successfully implemented in Australian settings, identifies key components of successful PA interventions and outlines practical strategies that can assist with widespread implementation of PA interventions in mental-health settings. CONCLUSIONS: There is an emergence of PA interventions being imbedded within a variety of mental-health settings. These interventions vary in terms of mode and intensity of service delivery. Yet, all aim to increase PA and reduce sedentary behaviour. Adopting the identified strategies may help facilitate successful implementation and increase access to PA interventions for mental-health service users. PMID- 28585449 TI - Go baby go cafe: a case study on an immersive rehabilitation environment to improve functional outcomes and quality of life. AB - PURPOSE: To determine the effectiveness of involving traumatic brain injury survivors in a novel "enriched rehabilitation environment" in which physical, cognitive, social and speech impairments are simultaneously addressed during training within a functioning business. METHOD: Participant was a 34-year old with a history of a severe head injury 17 years ago due to a motor vehicle accident. A novel intervention was provided within the Go Baby Go Cafe at the University of Delaware during her two hour shifts, three times a week for 2 months. RESULTS: The participant showed improvement in hand function, dynamic mobility, gait speed and cognitive ability. Additionally, changes were also noted across different domains like social activities, feeling of well-being, gross motor function and quality of life. CONCLUSIONS: The Cafe may be a viable environment for comprehensive intervention. Participation in the Cafe was associated with wide spread gains in scores on a variety of physical, cognitive, quality-of-life outcomes. Implications for rehabilitation Long-term impairments after traumatic brain injury often impairs activities of daily living, community integration and return to work. The Go Baby Go Cafe, installed with an overhead harness system serves as an "Immersive Environment" to address various impairments all at once in a real-world setting. Individuals with impairments can benefit from this rehabilitation technique, which is structured to improve changes across the International Classification of Functioning Disability and Health spectrum. PMID- 28585450 TI - Volatile Organic Compounds in the Breath of Oral Squamous Cell Carcinoma Patients: A Pilot Study. AB - Objective To assess the feasibility of detecting signature volatile organic compounds in the breath of patients with oral squamous cell carcinoma. Study Design Prospective cohort pilot study. Setting University hospital. Subjects and Methods Using gas chromatography and mass spectrometry, emitted volatile organic compounds in the breath of patients before and after curative surgery (n = 10) were compared with those of healthy subjects (n = 4). It was hypothesized that certain volatile organic compounds disappear after surgical therapy. A characteristic signature of these compounds for diseased patients was compiled and validated. Results Breath analyses revealed 125 volatile organic compounds in patients with oral cancer. A signature of 8 compounds that were characteristic for patients with oral cancer could be detected: 3 from this group presented were absent after surgery. Conclusion The presented results confirmed the hypothesis of an absence of cancer-associated volatile organic compounds in the breath after therapy. In this pilot study, we proved the feasibility of this test approach. Further studies should be initiated to establish protocols for usage in a clinical setting. PMID- 28585452 TI - How scenes containing visual errors affect speech fluency in young and older adults. AB - We compared young and older adults' speech during an error detection task, with some pictures containing visual errors and anomalies and other pictures error free. We analyzed three disfluency types: mid-phrase speech fillers (e.g., It's a little, um, girl), repetitions (e.g., He's trying to catch the- the birds), and repairs (e.g., She- you can see her legs). Older adults produced more mid-phrase fillers than young adults only when describing pictures containing errors. These often reflect word retrieval problems and represent clear disruptions to fluency, so this interaction indicates that the need to form and maintain representations of novel information can specifically compromise older adults' speech fluency. Overall, older adults produced more repetitions and repairs than young adults, regardless of picture type, indicating general age-related increases in these disfluencies. The obtained patterns are discussed in the context of the Transmission Deficit Hypothesis and other approaches to age-related changes in speech fluency. PMID- 28585451 TI - A Three-Way Transcriptomic Interaction Study of a Biocontrol Agent (Clonostachys rosea), a Fungal Pathogen (Helminthosporium solani), and a Potato Host (Solanum tuberosum). AB - Helminthosporium solani causes silver scurf, which affects the quality of potato. The biocontrol agent Clonostachys rosea greatly limited the severity of silver scurf symptoms and amount of H. solani genomic DNA in laboratory experiments. Transcriptomic analysis during interaction showed that H. solani gene expression was highly reduced when coinoculated with the biocontrol agent C. rosea, whereas gene expression of C. rosea was clearly boosted as a response to the pathogen. The most notable upregulated C. rosea genes were those encoding proteins involved in cellular response to oxidative stress, proteases, G-protein signaling, and the methyltransferase LaeA. The most notable potato response to both fungi was downregulation of defense-related genes and mitogen-activated protein kinase kinase kinases. At a later stage, this shifted, and most potato defense genes were turned on, especially those involved in terpenoid biosynthesis when H. solani was present. Some biocontrol-activated defense-related genes in potato were upregulated during early interaction with C. rosea alone that were not triggered by H. solani alone. Our results indicate that the reductions of silver scurf using C. rosea are probably due to a combination of mechanisms, including mycoparasitism, biocontrol-activated stimulation of plant defense mechanisms, microbial competition for nutrients, space, and antibiosis. PMID- 28585453 TI - Cognitive outcomes following anti-N-methyl-D-aspartate receptor encephalitis: A systematic review. AB - INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an immune-mediated neurological disorder that (among other severe neuropsychiatric symptoms) affects cognition. This study aimed to summarize current knowledge regarding the rates, nature, and predictors of neuropsychological dysfunction in patients recovering from anti-NMDAR encephalitis. METHOD: A systematic review of studies describing neuropsychological outcomes following anti-NMDAR encephalitis was conducted. Electronic databases Medline, PsycINFO, EMBASE, and CINAHL were searched from inception to September 2016. Results were summarized using descriptive statistics and a series of chi-square analyses. RESULTS: Of 4030 identified studies, 44 were included. These reported neuropsychological outcomes for 109 treated patients (83.5% female, Mage = 22.5 years, range = 2-67) recovering from anti-NMDAR encephalitis. High rates of neuropsychological dysfunction were identified, with diverse impairments of variable severity documented in >75% of patients at assessments conducted during acute, subacute, and longer term recovery periods. Despite this, cognitive outcomes were ultimately considered favorable in most cases (74.3%). This estimate does not account for the potential impact of relapses. The frequency of impairments in overall intellectual functioning, language, attention, working memory, and visuospatial functions were significantly higher within the acute recovery period than in later phases of convalescence. However, rates of impaired processing speed, episodic memory, and aspects of executive functioning were consistent across time points. Adverse neuropsychological outcomes occurred at significantly higher frequency in patients where immunotherapy was delayed, chi2(1, N = 66) = 10.84, p < .003. CONCLUSIONS: Neuropsychological deficits are prevalent at all points of recovery from anti-NMDAR encephalitis, although improvement in cognitive outcomes can be expected as patients recover. Some cognitive deficits may be less likely than others to resolve. Close neuropsychological monitoring is warranted in this population. Longitudinal studies of neuropsychological functioning of patients with anti-NMDAR encephalitis are needed to accurately inform prognosis. PMID- 28585454 TI - Trainee perspectives on postdoctoral recruitment in clinical neuropsychology: reflections on commentaries by Bodin and Grote (2016) and Nelson et al. (2016). AB - OBJECTIVE: The aim of the current invited paper is to provide the trainees' perspective on recent commentaries on recruitment for postdoctoral fellowship in clinical neuropsychology. The current system of recruitment includes both a match and non-match process and has been problematic for trainees and training programs alike. METHOD: The author team completed a non-systematic review of previously published commentaries on the current state of postdoctoral fellowship recruitment, which are briefly summarized in the current paper. The trainee perspective is addressed using both survey data and anecdotal experiences of the authors. RESULT: Trainees report high levels of dissatisfaction with the current dual recruitment system; however, there is no clear preference from trainees for either a match or non-match system. Trainees from both recruitment systems report high levels of satisfaction with their training experience. CONCLUSION: It seems that either a match or non-match approach, if it led to a unified system, would improve trainee satisfaction. PMID- 28585455 TI - Examination of the Modified Somatic Perception Questionnaire (MSPQ) in a large sample of credible and noncredible patients referred for neuropsychological testing. AB - OBJECTIVE: The current study evaluated MSPQ sensitivity to noncredible PVT performance in the context of external incentive, and examined MSPQ false positive rates in noncompensation-seeking neuropsychology patients; and investigated effects of ethnicity/culture, gender, and somatoform diagnosis on MSPQ scores, and relationships with PVT and MMPI-2-RF data. METHOD: MSPQ scores were compared in credible (n = 110) and noncredible (n = 153) neuropsychology referrals. RESULTS: Noncredible patients scored higher than credible patients. When the credible group was divided into those with somatoform orientation (n = 39) versus those without (n = 71), the credible nonsomatoform group scored lower than the other two groups, who did not differ from each other. MSPQ elevations were found in ethnic minorities, and in individuals who learned English as a second language or concurrently with another language. MSPQ elevations were also associated with chronic systemic diseases, neurologic illness, and substance abuse. Women scored higher than men, but men and women were equally represented among those patients scoring beyond cut-offs. MSPQ scores were minimally related to PVT data but were more strongly correlated with MMPI-2-RF scales, particularly over-report validity scales, RC1, and Somatic/Cognitive scales, with more widespread relationships observed in noncredible patients. CONCLUSIONS: A cut-off of 18 resulted in few false positives in credible nonsomatoform patients, and appears appropriate for identifying physical symptom over-report (due to malingering or somatoform orientations), with associated sensitivity of 29%. However, clinicians are cautioned regarding using the MSPQ in patients with systemic, neurologic, and substance abuse conditions, and in ethnic minorities and non-monolingual English-speakers. PMID- 28585456 TI - Potential conflicts in midwifery practice regarding conscientious objection to abortions in Scotland. AB - BACKGROUND: This study was developed as a result of a court case involving conflicts between midwives' professional practice and their faith when caring for women undergoing abortions in Scotland. RESEARCH QUESTIONS: What are practising Roman Catholics' perspectives of potential conflicts between midwives' professional practice in Scotland with regard to involvement in abortions and their faith? How relevant is the 'conscience clause' to midwifery practice today? and What are participants' understandings of Canon 1398 in relation to midwifery practice? RESEARCH DESIGN: The theoretical underpinning of this study was Gadamer's hermeneutic out of which the method developed by Fleming et al. involving a five-stage approach was utilised. Participants and research context: The research was conducted in the south of Scotland. A purposive sampling method was used. Eight participants who were practising Roman Catholics familiar with the subject of conscientious objection who were either midwives, lawyers (civil, canon or both) or priests contributed. Ethical considerations: The major ethical issues related to respect for autonomy, maintaining confidentiality and obtaining voluntary informed consent. Parish priests agreed to act as gatekeepers to prospective participants. All legal requirements were addressed regarding data collection and storage. Approval was given by the ethics committee of the university with which one of the researchers were associated. FINDINGS: Three key themes provide an understanding of the situation in which midwives find themselves when considering the care for a woman admitted for an abortion: competing legal systems, competing views of conscience and limits of participation. CONCLUSION: Clear guidelines for practice should be developed by a multi-professional and consumer group based on an update of the abortion law to reflect the change from a surgical to medical procedure. Clarification of Canon 1398 in relation to what is and is not participation in the procurement of abortion would be of benefit to midwives with a conscientious objection. PMID- 28585457 TI - Effect of geometric parameters in the design of customized hip implants. AB - In this paper, the effects of geometric parameters on the development of stress in custom cementless hip implant have been studied. Taguchi methods and analysis of variance (ANOVA) were used to find out which geometric parameters are statistically significant for the maximum von Mises stresses in the hip implant. The multiple regression analysis was also performed, to replace the FE solver and accurately and quickly predict the stress values for new patients. Three parameters horizontal offset (HO), vertical offset and neck shaft angle (NSA), with three levels have been selected. Based on L9 orthogonal array, nine hip implant shapes with three different geometric parameters were modelled. Stress analysis was carried out by using finite element analysis. ANOVA results showed that HO has the maximum impact on von Mises stresses followed by the NSA. It is shown that as the HO increases, the stress at the given region increases, however, as the neck shaft (NSA) increases the stress at the given region decreases. Good agreement is found between von Mises stresses, calculated from multiple regression analysis and obtained from FE analysis. To redesign customised hip implant for the minimum stresses, the results of this work will be important. PMID- 28585458 TI - Safety of cesarean myomectomy in women with single anterior wall and lower uterine segment myomas. AB - OBJECTIVE: Cesarean myomectomy (CM) is a safe procedure in selected cases. Nevertheless, literature lacks clear guidelines on patient selection. We aimed to evaluate CM safety in patients with single anterior wall and lower uterine segment (LUS) myomas. METHODS: The authors selected pregnants at term, scheduled for CSs, with single anterior wall or LUS myomas. All their clinical, demographic, obstetric, and surgical parameters were recorded. RESULTS: Thirty six women had a CM (study group), and 17 had a CS without myoma removal (control group). No significant differences were detected in the socio-demographic and clinical findings between the groups. The average size of myomas in the study and control group (p = .873), was 55.44 mm and 47.25 mm, respectively. The average surgery duration was 62.5 min in the study and 53.82 in the control group (p = .058). Intraoperative hemorrhage was more frequent in the study group (p = .045). Nevertheless, neither the number nor the volume of intraoperative transfusions was significantly different. None of the major CM complications were recorded, and the duration of hospitalization was similar in both groups. CONCLUSIONS: CM in patients with single anterior wall and LUS myomas does not cause increased perioperative morbidity, and, therefore, can be considered safe in such cases. PMID- 28585459 TI - Standardisation of bioelectrical impedance analysis for the estimation of body composition in healthy paediatric populations: a systematic review. AB - BACKGROUND: Bioelectrical impedance analysis (BIA) requires a high degree of standardisation in order to ensure valid and reproducible impedance measurements. The overall aim of this review was to study the degree to which BIA papers conducted in healthy paediatric populations (aged 0-17 years) were standardised. METHODS: Literature was identified on the basis of a systematic search of internationally-recognised electronic databases and hand searching of the reference lists of the included papers in order to identify additional relevant papers. The review was limited to lead-type BIA devices for whole-body, segmental and focal impedance measurements. In total, 71 papers published between 1988 and 2016 were included. To evaluate the degree of standardisation of the papers, a recently published review detailing critical factors that may impact on BIA measurements in children was used as a model for structuring and extracting data. RESULTS: There was a general lack of BIA standardisation, or its reporting, in the papers under review, which hinders comparison of data between studies and could potentially lead to erroneous measurements. CONCLUSIONS: If the BIA technique should be accepted clinically for routine use in paediatric populations, there is a need for an increased focus on the importance of improved standardisation and its reporting in future studies. Consequently, this review contains recommendations for performing and reporting BIA measurements in a standardised manner. PMID- 28585460 TI - Assessment of knee alignment with varus and valgus force through the range of flexion with non-invasive navigation. AB - In image-free total knee arthroplasty (TKA) navigation, infra-red markers are attached to bony landmarks to provide kinematic data intra-operatively, with the aim of improving the precision of implant placement. In non-invasive navigation, infra-red markers are attached to the skin surface, with recent evidence suggesting that this can give repeatable measurements of lower limb mechanical alignment. The aim of our study was to evaluate the use of a non-invasive navigation system in the assessment of mechanical alignment with applied coronal force through the range of flexion. A previously validated non-invasive system (PhysiopilotTM) was tested on 23 volunteers with healthy knees. Two users performed two registrations of the software workflow on each participant's right and left knees. A force was manually applied to the end-point of varus and valgus knee laxity and the measured change in mechanical alignment was recorded. Force was applied with the knee positioned in increments of flexion from 0 to 90 degrees . In keeping with previous studies, satisfactory values of coefficient of repeatability (CR) of 1.55 and 1.33 were found for intra-observer repeatability in measurement of supine mechanical femoro-tibial angle (MFTA) in extension, with a good inter-observer correlation of intraclass correlation coefficient (ICC) .72. However, when flexion was introduced, intra-observer and inter-observer reliability fell out with acceptable limits. Therefore, the trial did not support use of the PhysiopilotTM system as a measure of MFTA when flexion is introduced. It was felt that learning-curve, soft tissue artefacts and lack of force standardisation equipment may have accounted for significant levels of error, with further studies required to address these issues. PMID- 28585461 TI - Age differences in autobiographical memory across the adult lifespan: older adults report stronger phenomenology. AB - As an individual's life story evolves across adulthood, the subjective experience (phenomenology) of autobiographical memory likely changes. In addition to age at retrieval, both the recency of the memory and the age when a memory is formed may be particularly important to its phenomenology. The present work examines the effect of three temporal factors on phenomenology ratings: (a) age of the participant, (b) age at the event reported in the memory, and (c) memory age (recency). A large sample of Americans (N = 1120), stratified by chronological age, recalled and rated two meaningful memories, a Turning Point and an Early Childhood Memory. Ratings of phenomenology (e.g., vividness of turning points) were higher among older adults compared to younger adults. Memories of events from the reminiscence bump were more positive in valence than events from other time periods but did not differ on other phenomenological dimensions; recent memories had stronger phenomenology than remote memories. In contrast to phenomenology, narrative content was generally unrelated to participant age, age at the event, or memory age. Overall, the findings indicate age-related differences in how meaningful memories are re-experienced. PMID- 28585462 TI - Medical Malpractice Implications of Clinical Practice Guidelines. AB - Clinical practice guidelines aim to improve medical care by clarifying and making useful recommendations to providers. Although providers should account for patients' unique characteristics when determining a treatment plan, it is generally perceived as good practice to follow guidelines when applicable. This is of interest in malpractice litigation, where it is essential to establish a standard of care to evaluate the performances of providers. Although the opinions of expert witnesses are used to determine standards of care, guidelines are expected to play a leading role. Guidelines alone should not establish a legal standard but may help inform this discussion in the courtroom. Therefore, it is incumbent that excellent, practical, and timely guidelines are continually created and updated in a transparent way. These guidelines must be very clear and underscore the various strengths of recommendation based on the quality of available evidence. PMID- 28585463 TI - Endoscopic Lateral Cartilage Graft Tympanoplasty. AB - Objective To describe a novel technique for lateral graft tympanoplasty. Study Design Case series with chart review. Setting Tertiary care university hospital. Subjects and Methods Pediatric and adult patients with tympanic membrane perforations deemed unfavorable for a medial graft technique due to the perforation characteristics or myringitis. Results Between 2014 and 2016, 34 ears from 31 patients underwent a transcanal endoscopic lateral cartilage graft tympanoplasty. The mean age was 24.4 years (range, 6-71 years), and 22 patients (65%) were younger than 18 years. All patients had tympanic membrane perforations. Eighteen patients (53%) had total or near-total perforations, leaving a minimal anterior remnant, and 16 patients (47%) had extensive myringitis. A bisected tragal cartilage-perichondrium shield graft was used in 33 patients (97%). The mean (SD) follow-up length was 9.8 (5.7) months. Initial perforation closure rate was 88.2% (30/34). Three of the persistent perforations underwent a revision endoscopic medial graft tympanoplasty with successful closure, leaving a final closure rate of 97.1% (33/34). Five patients (15%) required topical therapy for postoperative myringitis. Mean (SD) pure-tone average and air-bone gap significantly improved by 11.5 (10.7) dB ( P < .001) and 11.4 (10.6) dB ( P < .001), respectively. Twenty-seven patients (79%) closed their air-bone gap within 20 dB. Conclusion Transcanal endoscopic lateral cartilage graft tympanoplasty is feasible, and initial data support favorable outcomes. Further data are necessary for evaluation of long-term results and efficacy comparisons. PMID- 28585464 TI - The contribution of aromatic components in Katsuobushi to preference formation and reinforcement effect. AB - Katsuodashi, a dried bonito broth, is very basic and indispensable in Japanese cuisine and contains taste-exhibiting components and unique aroma. We previously reported that its unique aroma contributes to the preference and reinforcement effect associated with dried bonito. This study aims to elucidate the contribution of aromatic components in Katsuobushi to preference formation and reinforcement effect. Volatile components obtained from dried bonito were fractionated and the fractions were subjected to two-bottle choice test. The fractionation test suggested that the component responsible for the preference is not one but comprises multiple components. In the GC-MS analysis/reconstruction test, solution with aromatic flavor narrowed down to 125 compounds had preference, and also had reinforcement effect. Moreover, GC-MS-olfactometry analysis narrowed down the candidate components to 28 out of 125. Mice showed preference for the test solution with aromatic flavor reconstructed with 28 components but did not show reinforcement behavior. PMID- 28585465 TI - Chitosan signaling in guard cells requires endogenous salicylic acid. AB - An elicitor chitosan (CHT) induces stomatal closure but the mechanism remains to be clarified. A phytohormone salicylic acid (SA) is crucial for elicitor-induced defense signaling in plants. Here we investigated whether endogenous SA is required for CHT signaling in guard cells. In the SA-deficient nahG mutant, treatment of CHT did not induce either apoplastic reactive oxygen species (ROS) production or stomatal closure but co-treatment of CHT and SA induced both apoplastic ROS production and stomatal closure, indicating the involvement of endogenous SA in CHT-induced apoplastic ROS production and CHT-induced stomatal closure. Furthermore, CHT induced transient cytosolic free calcium concentration increments in the nahG mutant in the presence of exogenous SA but not in the absence of exogenous SA. These results provide evidence that endogenous SA is a crucial element in CHT-induced stomatal closure. PMID- 28585467 TI - Do players and staff sleep more during the pre- or competitive season of elite rugby league? AB - This study establishes the sleep behaviour of players and staff during the pre- and competitive seasons of elite rugby league. For seven days during both the pre and competitive seasons, seven rugby league players and nine full-time staff from one professional Australian rugby league club had their sleep monitored via wrist actigraphy and self-report sleep diaries. Two-way repeated measures analysis of variance determined differences between the pre- and competitive season in players and staff, with effect sizes (ES) used to interpret the practical magnitude of differences. Findings show an earlier bed time and wake time for players (-34 min, ES = 1.5; +/-0.5 and -39 min, 2.1; +/-0.5 respectively) and staff (-29 min, ES = 0.8; +/-0.3 and -35 min, ES = 1.7; +/-0.4 respectively) during pre-season when compared to the competitive season. Despite this, no differences were seen when considering the amount of time in bed, sleep duration or sleep efficiency obtained between the pre- and competitive seasons. Our results suggest that early morning training sessions scheduled during pre season advances wake time in elite rugby league. However, both players and staff can aim to avoid reductions in sleep duration and sleep efficiency with subsequent adjustment of night time sleep patterns. This may be particularly pertinent for staff, who wake earlier than players during both the pre- and competitive seasons. PMID- 28585466 TI - Reformulation of Traditional Chamomile Oil: Quality Controls and Fingerprint Presentation Based on Cluster Analysis of Attenuated Total Reflectance-Infrared Spectral Data. AB - Herbal oils have been widely used in Iran as medicinal compounds dating back to thousands of years in Iran. Chamomile oil is widely used as an example of traditional oil. We remade chamomile oils and tried to modify it with current knowledge and facilities. Six types of oil (traditional and modified) were prepared. Microbial limit tests and physicochemical tests were performed on them. Also, principal component analysis, hierarchical cluster analysis, and partial least squares discriminant analysis were done on the spectral data of attenuated total reflectance-infrared in order to obtain insight based on classification pattern of the samples. The results show that we can use modified versions of the chamomile oils (modified Clevenger-type apparatus method and microwave method) with the same content of traditional ones and with less microbial contaminations and better physicochemical properties. PMID- 28585468 TI - Sesquiterpene glucosides from Shenzhou honey peach fruit showed the anti-aging activity in the evaluation system using yeasts. AB - One new (1, SZMT01) and one known (2) anti-aging substances were isolated from Shenzhou honey peach fruit. Their structures were elucidated by spectroscopic methods and chemical derivatization, and the result reveals that these two compounds are sesquiterpene glucosides. SZMT01 possesses a new glycosylation with an ester linkage at one terminal in an acyclic sesquiterpenoid which is the end of a double bond at another terminal. Both compounds extend the replicative lifespan of K6001 yeast strain at doses of 7.5 and 25 MUM. Then, to understand the action mechanism involved, we performed an anti-oxidative experiment on SZMT01. The result revealed that treatment with SZMT01 increased the survival rate of yeast under oxidative stress. Moreover, the lifespans of sod1 and sod2 mutant yeast strains with a K6001 background were not affected by SZMT01. These results demonstrate that anti-oxidative stress performs important roles in anti aging effects of SZMT01. PMID- 28585469 TI - Heterologous expression of the Pleurotus ostreatus MnP3 gene by the laccase gene promoter in Lentinula edodes. AB - Lentinula edodes (shiitake), which have a powerful ligninolytic system, is one of the most important edible mushrooms in Asia. In this study, we introduced the manganese peroxidase (MnP, EC 1.11.1.13) gene from Pleurotus ostreatus driven by L. edodes laccase 1 gene promoter into L. edodes for expression. The resulting transformant expressed the recombinant gene and showed a higher level of MnP activity than that of the wild-type strain. PMID- 28585470 TI - Property of filler-loaded magnetic ferrite from plastic waste bottle used to treat municipal domestic sewage. AB - The present work investigates the properties of self-made magnetic filler from plastic waste bottle and explores a new technology approach of waste plastic resource utilization. The magnetic filler was prepared by air plasma modification and loading magnetic ferrite on the plastic strip from waste plastic bottle. The surface properties of magnetic filler were characterized by Atomic Force Microscope (AFM), contact angle system and Fourier Transform Infrared (FTIR). AFM images of original and modified plastic strip showed that low-temperature plasma treatment markedly increased the surface roughness of plastic strip. The mean roughness (Ra) of plastic strip rose from 1.116 to 5.024 nm. FTIR spectra indicated that a lot of polar oxygenic groups were introduced onto the surface of plastic by plasma modification. Modification by low-temperature plasma increased the hydrophilicity of plastic strip surface. When treatment time is 40 s, water contact angle of plastic strip surface reduced from 78.2 degrees of original plastic strip to 25.3 degrees . When used in bioreactor, magnetic filler had very favorable microenvironment for microorganism growth. Magnetic filler was more efficient for removing chemical oxygen demand (COD) and [Formula: see text] in sewage than nonmagnetic filler. The resource utilization of plastic wastes will become reality if the magnetic filler is applied widely. PMID- 28585471 TI - The transmission and stability of cultural life scripts: a cross-cultural study. AB - Cultural life scripts are shared knowledge about the timing of important life events. In the present study, we examined whether cultural life scripts are transmitted through traditions and whether there are additional ways through which they can be attained by asking Australian and Malaysian participants which information sources they had used to generate the life script of their culture. Participants hardly reported that they had used cultural and religious traditions. They more often reported that they had used their own experiences and experiences of relatives and friends. They also reported the use of comments of relatives and friends and the use of newspapers, books, movies and television programmes. Furthermore, we examined the stability of life scripts and similarities and differences across cultures. We found that life scripts are stable cognitive structures and that there are, besides cross-cultural differences in the content, small cross-cultural differences in the valence and distribution of life script events, with the Australian life script containing more positive events and more events expected to occur before the age of 16. PMID- 28585472 TI - Home care organization impacts patient management and survival in ALS. AB - OBJECTIVE: Progression of amyotrophic lateral sclerosis (ALS) depends on several factors linked to the disease. However, both the patient's living place and care organization role need to be evaluated. METHODS: We analysed the effect on survival of factors linked to ALS or the socio-geographical context in a prospective cohort of 203 patients followed between 2003 and 2011. RESULTS: Patients were 97 females and 106 males with a mean age of 65.5 years. Survival was longer in younger patients, in case of upper limb involvement, longer time to diagnosis, and initially higher forced vital capacity. Non-invasive positive pressure ventilation (NIPPV) and percutaneous gastrostomy (PEG) failed to demonstrate benefit. Patients who lived at home had longer survival. The nature of non-medical organization at home statistically influenced survival, which was longer with an organized network than with an unorganized one and shorter in absence of non-medical organization. In patients with indication of PEG and NIPPV, the proposition was statistically different according to the care givers. CONCLUSIONS: Besides the natural history of ALS, survival depended on home organization and the presence or the nature of a home-care system. Home organization was an important factor of decision for NIPPV and PEG proposals. PMID- 28585473 TI - Computer-aided generation and lung deposition modeling of nano-scale particle aggregates. AB - The study sets its main focus on the introduction of a random-walk-based model for the generation of variably shaped particle aggregates consisting of a predefined number of spherical components. With the help of a well-defined algorithm, the user is enabled to select between isodimensional, chain-like and platelet-like aggregates, for which related aerodynamic parameters (dynamic shape factors, volume-equivalent diameters, aerodynamic diameters) are determined automatically. The theoretical approach for random aggregate construction is directly connected with the previously developed stochastic particle transport and deposition model. Thereby, individually shaped aggregates may be provided for each random-walk scenario taking place in the almost realistic lung structure. Preliminary application of the aggregate generation model was carried out by assuming single components with a constant diameter of 1 nm and unit-density (1 g cm-3) and variably shaped aggregates consisting of 10, 100 and 1000 components. Inhalation of the aggregate-loaded aerosol into lungs of average size (FRC = 3300 mL) was supposed to take place under sitting, light-exercise and heavy-exercise conditions. Results obtained from deposition modeling clearly show that, independent of aggregate geometry, total deposition declines with increasing number of components included in the particulate construct, but experiences a continuous enhancement with rising inhalation flow rate. Among the predefined geometric categories, platelet-like aggregates are distinguished by lowest deposition and isodimensional clusters by highest. While isodimensional aggregates preferentially deposit in the extrathoracic and bronchial airways, chain-like and platelet-like aggregates exhibit a significantly increased tendency to hit the alveolar walls. PMID- 28585474 TI - Family experience with osteogenesis imperfecta type 1: the most distressing situations. AB - BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by decreased bone mass and increased bone fragility. Despite increasing research on the biomedical aspects of the disease, only a few studies focus on the psychosocial implications of living with OI. This study aimed to explore the situations that are perceived by OI type-1 children, their parents and siblings, as being the most distressing and stressful in their experience with the disease. METHODS: Seven families of children diagnosed with OI type 1 for longer than four years participated. An in-depth semistructured interview with open-ended questions was used to separately collect each participant's (mother, father, patient and sibling) subjective report of their experience. Interviews were audiotaped and a qualitative discourse analysis was performed. RESULTS: Pain and fractures, hospitalization, home recovery, back to school and time of diagnosis emerged as the most challenging situations. Time of diagnosis was only mentioned by parents. Some commonalities but also relevant differences in the subjective experience of the same situations, depending on the family role, were found. CONCLUSIONS: Our results reinforce the assumption that OI is a family matter and point to the importance of providing comprehensive and family-centered health and educational services tailored to each family member and to the different situations faced by these families. Implications for rehabilitation Osteogenesis imperfecta is a chronic rare disease that impacts severely the patient's life and the life of all family members. The most distressing situations are related to fractures and pain, hospitalization, recovery from fractures while being at home and preparing for school reentry. All family members participate in the rehabilitation process, each one accomplishing different tasks. Rehabilitation should include educational and psychological intervention to enhance family strengths and support all family members. Tailored and effective communication from health providers may play a critical role in the rehabilitation process. PMID- 28585475 TI - Virilization and Enlarged Ovaries in a Postmenopausal Woman. AB - A patient with postmenopausal bleeding and virilization was found to have bilaterally enlarged ovaries with a yellow cut surface. Histology revealed cortical stromal hyperplasia with stromal hyperthecosis. This hyperplastic condition should not be mistaken for an ovarian neoplasm. PMID- 28585476 TI - Harmonic analysis of peripheral pulse for screening subjects at high risk of diabetes. AB - Power spectral density (PSD) of peripheral pulses in human has been investigated in the past for its clinical applications. Continuing the efforts, data acquired using Peripheral Pulse Analyser in research projects sponsored by Board of Research in Nuclear Sciences in 207 control subjects, 18 descendants of diabetic patients and 22 patients with systemic hypertension have been subjected to PSD analysis for its study of harmonics. Application software, named Pulse Harmonic Analyser specifically developed for this work, selected 131,072 samples from each data file, obtained PSD, derived 52 PHA parameters and saved them in an Excel sheet. Coefficient of variation in control data was reduced significantly by application of Central Limit Theorem, which enabled use of parametric methods for statistical analysis of the observations. Data in hypertensive patients have shown significant difference in comparison to that of controls in eight parameters at low values of alpha and beta. Data in offspring of diabetic patients also have shown significant difference in one parameter indicating its usefulness in screening subjects with genetic disposition of acquiring Type-II Diabetes. PHA analysis has also yielded sub-harmonic components, which are related to combined variability in the heart rate, pulse volume and pulse morphology and has a potential to become method of choice for real time variability monitoring. PMID- 28585477 TI - The trends and constructive ambiguity in international agreements on intellectual property and pharmaceutical affairs: Implications for domestic legislations in low- and middle-income countries. AB - The purpose of this study is to analyse the trends in international agreements including Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), Korea-United States Free Trade Agreements, and Trans-Pacific Partnership Agreements on intellectual property and pharmaceutical affairs with the updated framework. The study also assesses constructive ambiguity in international agreements, which might affect the implementation process through interpretation and domestic legislations. Five flexibility clauses and three TRIPS-plus provisions were selected, and presence of constructive ambiguity in the agreements was analysed to draw actual trends in international agreements. Flexibility provisions excluding compulsory licensing were not noticeably changed, and TRIPS-plus provisions including data exclusivity and patent linkage were expanded in scope or newly appeared, respectively. The clause regarding compulsory licensing, extension of the patent term, data exclusivity, and patent linkage showed unclear definitions or the lack of adequate explanations. With constructive ambiguity in those clauses, a country who wants to join international agreements in the near future could amend domestic legislations to minimise the detrimental effect of international agreements on access to medicines. PMID- 28585478 TI - Succession, Humility, and Fidelity to a Vision. PMID- 28585479 TI - The Art of Health Promotion ideas for improving health outcomes. PMID- 28585482 TI - Clinical Assessment of Cognitive Function in Patients with Head and Neck Cancer: Prevalence and Correlates. AB - Objective Identify the prevalence and clinical correlates of cognitive impairment in patients presenting for treatment of head and neck cancer (HNC) using brief screening within a multidisciplinary care team. Study Design A case series with planned data collection of cognitive function, quality of life (QoL), and psychosocial variables. Setting Urban Midwest academic medical center. Subjects and Methods In total, 209 consecutive patients with a diagnosis of HNC between August 2015 and September 2016 who had a pretreatment assessment with a clinical health psychologist. At pretreatment assessment, the Montreal Cognitive Assessment (MoCA), a brief screening tool for cognitive function, was administered along with a semistructured interview to gather information on psychiatric symptoms, social support, and substance use. Patient information, including demographics, clinical variables, and psychosocial variables, was extracted via chart review. A subset of patients with HNC completed the Functional Assessment of Cancer Therapy-Head and Neck Cancer at pretreatment assessment and was included in the QoL analyses. Results Cognitive impairment was associated with current alcohol use, past tobacco use and number of pack years, time in radiotherapy, and adherence to treatment recommendations. Social, emotional, and functional QoL scales were associated with cognitive impairment, including executive function, language, and memory. Conclusion Cognitive impairment is common in patients with HNC, and there are important associations between cognitive impairment and psychosocial, QoL, and treatment adherence variables. The results argue for the incorporation of cognitive screening as part of pretreatment assessment for patients, as well as further research into more direct, causal relationships via longitudinal, prospective studies. PMID- 28585481 TI - Novel approaches to develop community-built biological network models for potential drug discovery. AB - INTRODUCTION: Hundreds of thousands of data points are now routinely generated in clinical trials by molecular profiling and NGS technologies. A true translation of this data into knowledge is not possible without analysis and interpretation in a well-defined biology context. Currently, there are many public and commercial pathway tools and network models that can facilitate such analysis. At the same time, insights and knowledge that can be gained is highly dependent on the underlying biological content of these resources. Crowdsourcing can be employed to guarantee the accuracy and transparency of the biological content underlining the tools used to interpret rich molecular data. Areas covered: In this review, the authors describe crowdsourcing in drug discovery. The focal point is the efforts that have successfully used the crowdsourcing approach to verify and augment pathway tools and biological network models. Technologies that enable the building of biological networks with the community are also described. Expert opinion: A crowd of experts can be leveraged for the entire development process of biological network models, from ontologies to the evaluation of their mechanistic completeness. The ultimate goal is to facilitate biomarker discovery and personalized medicine by mechanistically explaining patients' differences with respect to disease prevention, diagnosis, and therapy outcome. PMID- 28585484 TI - The effect of a foot gymnastic exercise programme on gait performance in older adults: A randomised controlled trial. AB - BACKGROUND: Aged-related loss of ankle dorsiflexion range of motion (ROM) and toe plantarflexor strength play an important role in gait performance. Further, conventional strength, balance and gait training can significantly improve the lower extremity muscle power and functional abilities of older individuals. It remains unclear, however, whether training effects can be enhanced by augmenting ankle ROM and toe plantarflexor strength complementary to training. OBJECTIVE: This study investigated the effect of physical exercise combined with foot gymnastics on the gait performance in older adults. METHODS: Fifty-six independent living, older adults aged 66-91 years were randomly assigned to either foot gymnastics group (FG;n - 28) or training group (TG;n = 28). Further, 14 subjects were integrated as a control group (CG;n = 14) (no exercise). The FG and TG completed the same training program consisting of aerobic exercises, progressive resistance strength training and stretching exercises twice per week for 12 weeks, whereas the FG performed additional foot gymnastic exercises at the end of the training session and a 10-min foot gymnastics home-program daily. Assessments included the Falls Efficacy Scale - International (FES-I), Expanded Timed Get-up-and-Go test (ETGUG), gait analysis and muscle power measurements of the knee and ankle joint at pre- and post-training. RESULTS: No significant change in FES-I score occurred in either group. The FG showed a significant improvement of ankle ROM. There were significant time x group interactions in walking speed, step length, in several muscle power measurements and in ETGUG. The positive effects of gait parameters ranged between 1 and 11% and between 2 and 12%, of muscle power between 14 and 34% and 14 and 46% and of ETGUG were 10 and 8% for the FG and TG, respectively. The FG and TG did not differ significantly in their improvements. The CG showed a trend to deteriorations between 0 and -6% for gait parameters, between -4 and - 14% for muscle power and 0% for ETGUG. CONCLUSIONS: The results of this study provide evidence of significant improvements in gait performance, muscle power and ETGUG after a conventional training program in independent living, older adults. However, there is no additional effect on physical performance after foot gymnastic exercises. PMID- 28585483 TI - What undermines healthy habits with regard to physical activity and food? Voices of adolescents in a disadvantaged community. AB - This study aimed to illuminate factors that undermine the healthy habits of adolescents from a multicultural community with low socioeconomic status (S.E.S.) in Sweden with regard to physical activity (P.A.) and food, as stated in their own voices. Adolescents (n = 53, 12-13 y/o) were recruited from one school situated in a multicultural community characterized by low S.E.S. Embracing an interpretive approach, 10 focus-group interviews were conducted to produce data for the study. The focus-group interviews were audio recorded, transcribed verbatim, and analysed using qualitative content analysis. The analysis resulted in two major themes: (1) the availability of temptations is large, and support from the surroundings is limited; and (2) norms and demands set the agenda. The adolescents' voices illuminate a profound awareness and the magnitude of tempting screen-based activities as undermining their P.A. and healthy food habits. Moreover, several gender boundaries were highlighted as undermining girls' P.A. and healthy food habits. The adolescents' stories illuminated that it is difficult for them, within their environment, to establish healthy habits with regard to P.A. and food. To facilitate the adolescents' healthy habits, we suggest that support from family, friends, the school, and society at large is essential. PMID- 28585486 TI - Narrative literature review: Health, activity and participation issues for women following traumatic brain injury. AB - OBJECTIVE: This narrative review will draw attention to the current limitations within the literature related to women following traumatic brain injury in order to stimulate discussion and inform future directions for research. BACKGROUND: There is a wide-ranging body of research about traumatic brain injury with the higher incidence of brain injury among males reflected in this body of work. As a result, the specific gendered issues facing women with traumatic brain injury are not as well understood. METHOD: A search of electronic databases was conducted using the terms "traumatic brain injury", "brain injury", "women", "participation", "concussion" and "outcomes". RESULTS: The 36 papers revealed the following five themes (1) Relationships and life satisfaction; (2) Perception of self and body image; (3) Meaningful occupation; (4) Sexuality and sexual health; and (5) Physical function. CONCLUSIONS: Without research, which focuses specifically on the experience of women and girls with traumatic brain injury there is a risk that clinical care, policy development and advocacy services will not effectively accommodate them. Implications for rehabilitation Exploring the gendered issues women may experience following traumatic brain injury will enhance clinicians understanding of the unique challenges they face. Such information has the potential to guide future directions for research, policy, and practice. Screening women for hormonal imbalances such as hypopituitarism following traumatic brain injury is recommended as this may assist clinicians in addressing the far reaching implications in regard to disability, quality of life and mood. The growing literature regarding the cumulative effect of repeat concussions following domestic violence and women's increased risk of sport related concussion may assist clinicians in advocating for appropriate rehabilitation and community support services. PMID- 28585487 TI - Improvement of nonalcoholic fatty liver disease in morbidly obese patients after sleeve gastrectomy: association of ultrasonographic findings with lipid profile and liver enzymes. AB - BACKGROUND: After bariatric surgery an improvement or even complete resolution of nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients is achieved, but little is known about the effect of laparoscopic sleeve gastrectomy (LSG). PATIENTS AND METHODS: A prospective observational study of patients undergoing LSG was performed. An abdominal ultrasonography and blood sample extraction (investigating liver enzymes and lipid profile) were performed preoperatively and 12 months after surgery. RESULTS: Fifty patients were included in the study. Preoperatively, 84% of the patients presented liver steatosis. A significant reduction of steatosis could be observed 12 months after surgery (p < .001). Preoperative degree of steatosis showed a direct correlation with AST (p = .008) and ALT (p = .007) and an inverse correlation with HDL-cholesterol (p = .019). The reduction of liver steatosis showed an inverse correlation with the increase of HDL-cholesterol between pre- and postoperative determinations (p = .008). CONCLUSIONS: Liver steatosis, as measured by ultrasonography, improves after sleeve gastrectomy, achieving a complete resolution in 90% of the cases. Preoperative steatosis correlates directly with AST and ALT levels and inversely with HDL-cholesterol. The postoperative increase of HDL-cholesterol shows an inverse correlation with liver steatosis improvement, suggesting that it could be a good marker for monitoring the postoperative liver status. PMID- 28585488 TI - Is Pepsin a Reliable Marker of Laryngopharyngeal Reflux? A Systematic Review. AB - Objective Laryngopharyngeal reflux (LPR) is a common illness of otolaryngology visits. Over the past few years, pepsin has become a promising marker of LPR. The objective of the present research is to analyze the existing literature using pepsin as a diagnostic tool of LPR through a systematic review. Data Sources PubMed (Medline), Trip Database, Cochrane Library, EMBASE, SUMsearch, and Web of Science. Review Methods The outcome assessed was the presence of pepsin in LPR patients. We included articles in which pepsin was studied in LPR patients (clinically suspected or with confirmed diagnosis). Studies with no control group, comparison group, and/or a sample size lower than 20 patients were excluded. Results Twelve studies were included. All included studies, with the exception of 2, found statistically significant differences for pepsin in cases compared with healthy controls. Conclusion Pepsin might be a reliable marker in LPR patients, although questions remain about optimal timing, location, nature, and threshold values for pepsin testing. Future investigations are necessary to clarify the best method to use pepsin in the diagnostic process of LPR. PMID- 28585489 TI - Evaluation of the Radiation Dose-Volume Effects of Optic Nerves and Chiasm by Psychophysical, Electrophysiologic Tests, and Optical Coherence Tomography in Nasopharyngeal Carcinoma. AB - PURPOSE: To evaluate the radiation dose-volume effects of optic nerves and chiasm by visual psychophysical, electrophysiologic tests, and optical coherence tomography in patients with locally advanced nasopharyngeal carcinoma. MATERIALS AND METHODS: A series of visual tests including visual acuity, visual field, contrast sensitivity, visual evoked potential, and optical coherence tomography were administered to 20 patients with locally advanced (T3-T4) nasopharyngeal carcinoma who were treated with definitive chemoradiotherapy. Volume that received 55 Gy (V55), mean dose ( Dmean), highest dose to 5% of the volume (D5), and maximum dose (Dmax) for optic nerves and chiasm were evaluated for each patient. Cutoff values were identified as V55: 50%, Dmean: 50 Gy, D5: 55 Gy, and Dmax: 60 Gy. The effects of radiation dose-volume on ophthalmologic tests were evaluated. RESULTS: Ophthalmological evaluation revealed optic neuropathy with simultaneous retinopathy in 6 eyes of 4 patients and radiation retinopathy alone in both eyes of 1 patient. Regarding radiation dose-volume effects of the optic nerve, significant detrimental effect of all parameters was observed on visual acuity. Visual field and contrast sensitivity were affected significantly with V55 >= 50% and Dmean >= 50 Gy. Visual evoked potential latency was affected significantly with Dmean >= 50 Gy, D5 >= 55 Gy, and Dmax >= 60 Gy. For the chiasm, significant detrimental effect of all parameters was observed on visual acuity as well. Retinal nerve fiber layer thickness and visual evoked potential amplitude were not affected by any of the dose-volume parameters neither optic nerves nor chiasm. CONCLUSION: The volume receiving the threshold dose, mean dose, and 5% of the volume receiving the maximum dose are important parameters besides maximum dose to optic nerves and chiasm. A comprehensive ophthalmological evaluation including visual field, contrast sensitivity, visual evoked potential latency, and amplitude should be performed for these patients. Visual evoked potential latency is an objective predictor of vision loss before the onset of clinical signs. PMID- 28585490 TI - In vivo Portal Imaging Dosimetry Identifies Delivery Errors in Rectal Cancer Radiotherapy on the Belly Board Device. AB - PURPOSE: We recently developed a novel, open-source in vivo dosimetry that uses the electronic portal imaging device to detect dose delivery discrepancies. We applied our method on patients with rectal cancer treated on a belly board device. METHODS: In vivo dosimetry was performed on 10 patients with rectal cancer treated prone on the belly board with a 4-field box arrangement. Portal images were acquired approximately once per week from each treatment beam. Our dosimetry method used these images along with the planning CT to reconstruct patient planar dose at isocenter depth. RESULTS: Our algorithm proved sensitive to dose discrepancies and detected discordances in 7 patients. The majority of these were due to soft tissue differences between planning and treatment, present despite matching to bony anatomy. As a result of this work, quality assurance procedures have been implemented for our immobilization devices. CONCLUSION: In vivo dosimetry is a powerful quality assurance tool that can detect delivery discrepancies, including changes in patient setup and position. The added information on actual dose delivery may be used to evaluate equipment and process quality and to guide for adaptive radiotherapy. PMID- 28585491 TI - A Simple Method for 2-D In Vivo Dosimetry by Portal Imaging. AB - PURPOSE: To improve patient safety and treatment quality, verification of dose delivery in radiotherapy is desirable. We present a simple, easy-to-implement, open-source method for in vivo planar dosimetry of conformal radiotherapy by electronic portal imaging device (EPID). METHODS: Correlation ratios, which relate dose in the mid-depth of slab phantoms to transit EPID signal, were determined for multiple phantom thicknesses and field sizes. Off-axis dose is corrected for by means of model-based convolution. We tested efficacy of dose reconstruction through measurements with off-reference values of attenuator thickness, field size, and monitor units. We quantified the dose calculation error in the presence of thickness changes to simulate anatomical or setup variations. An example of dose calculation on patient data is provided. RESULTS: With varying phantom thickness, field size, and monitor units, dose reconstruction was almost always within 3% of planned dose. In the presence of thickness changes from planning CT, the dose discrepancy is exaggerated by up to approximately 1.5% for 1 cm changes upstream of the isocenter plane and 4% for 1 cm changes downstream. CONCLUSION: Our novel electronic portal imaging device in vivo dosimetry allows clinically accurate 2-dimensional reconstruction of dose inside a phantom/patient at isocenter depth. Due to its simplicity, commissioning can be performed in a few hours per energy and may be modified to the user's needs. It may provide useful dose delivery information to detect harmful errors, guide adaptive radiotherapy, and assure quality of treatment. PMID- 28585493 TI - Combination of Permanent Interstitial 125I-Seed Brachytherapy and Surgery for the Treatment of Large Hepatocellular Carcinoma. AB - The treatment methods available for large primary hepatocellular carcinomas (diameter >5 cm) are inadequate. Here, we report the successful management of 80 cases of large hepatocellular carcinoma, using a combination of custom-designed permanent interstitial iodine-125 seed brachytherapy and palliative surgery. Patients were enrolled in the study between 2011 and 2014. All patients underwent surgical treatment along with permanent interstitial iodine-125 seed brachytherapy; for the latter, patients received minimum doses covering 90% of the target (D90 s) of iodine-125 seeds ranging from 100 to 160 Gy (median: 110 Gy). All patients received 6 cycles of chemotherapy and were followed up at 6, 12, 24, and 36 months postoperatively. The clinical symptom remission rate was 95.3% (61 of 64). Alanine aminotransferase and aspartate aminotransferase levels decreased to normal in 80% (50 of 60) and 75% of the patients (45 of 60), respectively. The posttreatment alpha-fetoprotein levels decreased by 50% in 80% of the patients (40 of 50). The effective therapy rates were 80% (76 of 95) for 95 tumor nodules (diameters 5-10 cm) and 78.6% (33 of 42) for 42 tumor nodules (diameters >10 cm). The 3-year disease-free survival rate was 66.6%. Palliative surgery plus permanent interstitial iodine-125 seed brachytherapy appears to be a reasonable therapeutic alternative for large hepatocellular carcinoma. PMID- 28585492 TI - Electrosensitization Increases Antitumor Effectiveness of Nanosecond Pulsed Electric Fields In Vivo. AB - Nanosecond pulsed electric fields are emerging as a new modality for tissue and tumor ablation. We previously reported that cells exposed to pulsed electric fields develop hypersensitivity to subsequent pulsed electric field applications. This phenomenon, named electrosensitization, is evoked by splitting the pulsed electric field treatment in fractions (split-dose treatments) and causes in vitro a 2- to 3-fold increase in cytotoxicity. The aim of this study was to show the benefit of split-dose treatments for in vivo tumor ablation by nanosecond pulsed electric field. KLN 205 squamous carcinoma cells were embedded in an agarose gel or grown subcutaneously as tumors in mice. Nanosecond pulsed electric field ablations were produced using a 2-needle probe with a 6.5-mm interelectrode distance. In agarose gel, splitting a pulsed electric field dose of 300, 300-ns pulses (20 Hz, 4.4-6.4 kV) in 2 equal fractions increased cell death up to 3-fold compared to single-train treatments. We then compared the antitumor effectiveness of these treatments in vivo. At 24 hours after treatment, sensitizing tumors by a split-dose pulsed electric field exposure (150 + 150, 300-ns pulses, 20 Hz, 6.4 kV) caused a 4- and 2-fold tumor volume reduction as compared to sham and single train treatments, respectively. Tumor volume reduction that exceeds 75% was 43% for split-dose-treated animals compared to only 12% for single-dose treatments. The difference between the 2 experimental groups remained statistically significant for at least 1 week after the treatment. The results show that electrosensitization occurs in vivo and can be exploited to assist in vivo cancer ablation. PMID- 28585495 TI - Tympanostomy Tube Placement in Children Using a Single-Pass Tool with Moderate Sedation. AB - Insertion of tympanostomy tubes is a common elective pediatric surgical procedure and is typically performed under general anesthesia. The potential to reduce general anesthetic requirements for young children has led to increased interest in alternatives for tympanostomy tube placement. A tympanostomy tube system, developed to enable tympanostomy tube placement in a single pass on conscious patients under moderate sedation, was evaluated. A prospective study on 128 children and 253 tympanostomy tube placements conducted at 4 centers in the United States demonstrated an 88.3% success rate in performing the procedure under moderate sedation with adverse events within normal rates reported in the literature. The feasibility of completing tympanostomy tube placement under moderate sedation enables avoidance of general anesthesia and provides additional choices to physicians and parents. PMID- 28585494 TI - Recombinant protein expression of Moringa oleifera lectin in methylotrophic yeast as active coagulant for sustainable high turbid water treatment. AB - The natural coagulant Moringa oleifera lectin (MoL) as cationic protein is a promising candidate in coagulation process of water treatment plant. Introducing the gene encoding MoL into a host, Pichia pastoris, to secrete soluble recombinant protein is assessed in this study. Initial screening using PCR confirmed the insertion of MoL gene, and SDS-PAGE analysis detected the MoL protein at 8 kDa. Cultured optimization showed the highest MoL protein at 520 mg/L was observed at 28 degrees C for 144 h of culturing by induction in 1% methanol. Approximately, 0.40 mg/mL of recombinant MoL protein showed 95 +/- 2% turbidity removal of 1% kaolin suspension. In 0.1% kaolin suspension, the concentration of MoL at 10 MUg/mL exhibits the highest turbidity reduction at 68 +/- 1%. Thus, recombinant MoL protein from P. pastoris is an effective coagulant for water treatment. PMID- 28585497 TI - [Looking into international journals]. PMID- 28585498 TI - ? PMID- 28585496 TI - Preoperative Tracheostomy Is Associated with Poor Disease-Free Survival in Recurrent Laryngeal Cancer. AB - Objectives It is unknown if preoperative tracheostomy for persistent/recurrent laryngeal squamous cell carcinoma (LSCC) plays a role in unrecognized local disease spread and disease recurrence after salvage laryngectomy. The goals of this study were to determine the effect of preoperative tracheostomy on disease free survival (DFS) in patients with recurrent/persistent LSCC undergoing salvage laryngectomy. Study Design Retrospective case series derived from prospectively maintained database. Setting Tertiary care academic center. Subjects Patients with recurrent/persistent LSCC after radiation/chemoradiation (RT/CRT) who underwent salvage laryngectomy at the University of Michigan from 1997 to 2015. Methods Demographic, clinical, pathologic, and survival data were collected. Kaplan-Meier survival estimates were performed. Results DFS was worse for patients with tracheostomy prior to laryngectomy than patients without a tracheostomy (5 year: 39% vs 67%; P < .001). Patients with tracheostomy prior to RT/CRT compared to patients with tracheostomy after RT/CRT or patients without a tracheostomy had worse DFS (5-year: 25%, 49%, and 67%, respectively; P < .001). In bivariable analyses controlling for T classification, N classification, or overall stage, preoperative tracheostomy was associated with worse DFS. In multivariable analysis, presence of a preoperative tracheostomy had a worse DFS (hazard ratio, 1.63; 95% confidence interval, 1.00-2.67; P = .048). Conclusion Preoperative tracheostomy is associated with disease recurrence in patients with persistent/recurrent LSCC undergoing salvage laryngectomy, particularly in patients who had tracheostomy prior to completion of initial RT/CRT. Notably, preoperative tracheostomy as a causal factor vs marker for disease recurrence is difficult to ascertain. Nevertheless, clinicians should be aware of the increased risk of locoregional recurrence in patients with preoperative tracheostomy when counseling on surgical salvage and when considering the role of additional therapy. PMID- 28585499 TI - ? PMID- 28585500 TI - [The authors in this issue]. PMID- 28585501 TI - [News]. PMID- 28585502 TI - [Frequency of somatic syndromes in primary care]. PMID- 28585503 TI - Admission Exam at a Medical School: Correlation Between Symptoms of Somatization and Performance. PMID- 28585504 TI - [Congress dates]. PMID- 28585505 TI - [Manualized psychotherapy for the optimization of immunosuppressant adherence following kidney transplantation: Results of a feasibility study]. PMID- 28585506 TI - [Psychotherapeutic care of women in pregnancy and peripartum: Evaluation and treatment utilization]. PMID- 28585507 TI - The Influence of Doctor-Patient Communication on Health Outcomes: A Systematic Review. PMID- 28585508 TI - [Activity trails in the therapy of clinical depression: A randomized controlled equivalence trial]. PMID- 28585509 TI - [Conflict dynamics in chronic depression - Results of the conflict and structure axis using the OPD in the LAC Study]. PMID- 28585510 TI - Reemergence of the Natural History of Otolaryngologic Infections: Lessons Learned from 2 American Presidents. AB - Presidents George Washington and Theodore Roosevelt suffered complications of epiglottitis and otomastoiditis, respectively. The introduction of antibiotics and vaccinations against Haemophilus influenzae and Streptococcus pneumoniae has significantly reduced the incidence of these otolaryngologic infections, such that the natural history of the disease is rarely encountered. However, antibiotic resistance and pathogenic evolution has raised concern about increased virulence of these common organisms. A retrospective evaluation of the complications suffered by Washington and Roosevelt provides valuable insight to the natural history of common otolaryngologic infections that may reemerge as a result of organism evolution in response to antibiotics and vaccines. PMID- 28585512 TI - Auditory-visual speech perception in three- and four-year-olds and its relationship to perceptual attunement and receptive vocabulary. AB - Despite the body of research on auditory-visual speech perception in infants and schoolchildren, development in the early childhood period remains relatively uncharted. In this study, English-speaking children between three and four years of age were investigated for: (i) the development of visual speech perception - lip-reading and visual influence in auditory-visual integration; (ii) the development of auditory speech perception and native language perceptual attunement; and (iii) the relationship between these and a language skill relevant at this age, receptive vocabulary. Visual speech perception skills improved even over this relatively short time period. However, regression analyses revealed that vocabulary was predicted by auditory-only speech perception, and native language attunement, but not by visual speech perception ability. The results suggest that, in contrast to infants and schoolchildren, in three- to four-year-olds the relationship between speech perception and language ability is based on auditory and not visual or auditory-visual speech perception ability. Adding these results to existing findings allows elaboration of a more complete account of the developmental course of auditory-visual speech perception. PMID- 28585511 TI - Three-dimensional Ultrasound Elasticity Imaging on an Automated Breast Volume Scanning System. AB - Ultrasound elasticity imaging has demonstrated utility in breast imaging, but it is typically performed with handheld transducers and two-dimensional imaging. Two dimensional (2D) elastography images tissue stiffness of only a plane and hence suffers from errors due to out-of-plane motion, whereas three-dimensional (3D) data acquisition and motion tracking can be used to track out-of-plane motion that is lost in 2D elastography systems. A commercially available automated breast volume scanning system that acquires 3D ultrasound data with precisely controlled elevational movement of the 1D array ultrasound transducer was employed in this study. A hybrid guided 3D motion-tracking algorithm was developed that first estimated the displacements in one plane using a modified quality-guided search method, and then performed an elevational guided-search for displacement estimation in adjacent planes. To assess the performance of the method, 3D radiofrequency echo data were acquired with this system from a phantom and from an in vivo human breast. For both experiments, the axial displacement fields were smooth and high cross-correlation coefficients were obtained in most of the tracking region. The motion-tracking performance of the new method was compared with a correlation-based exhaustive-search method. For all motion tracking volume pairs, the average motion-compensated cross-correlation values obtained by the guided-search motion-tracking method were equivalent to those by the exhaustive-search method, and the computation time was about a factor of 10 lesser. Therefore, the proposed 3D ultrasound elasticity imaging method was a more efficient approach to produce a high quality of 3D ultrasound strain image. PMID- 28585513 TI - Meta-analysis of longitudinal studies of cognition in bipolar disorder: comparison with healthy controls and schizophrenia. AB - BACKGROUND: Bipolar disorder (BP) is associated with significant cognitive impairment. Recent evidence suggests that cognitive deficits are already evident after first-episode mania. However, it is not clear whether BP is associated with further decline in cognitive functions in individuals with established illness. Aim of this meta-analytic review was to examine longitudinal neurocognitive changes in BP and to compare trajectory of cognitive deficits in BP with schizophrenia and healthy controls. METHODS: Electronic databases were searched for the studies published between January 1987 and November 2016. In total 22 reports were included in the current meta-analysis. The main analysis assessed the longitudinal change in cognition in 643 patients with BP. Further analyses were conducted in studies investigating cognitive changes in BP along with healthy controls (459 BP and 367 healthy controls) and schizophrenia (172 BP and 168 schizophrenia). RESULTS: There was no cognitive decline overtime neither in short-term (mean duration = 1.5 years) nor in long-term (mean duration = 5.5 years) follow-up studies in BP. In contrast, there was evidence for modest improvements in task performance in memory and working memory at follow-up. The trajectory of cognitive functioning in BP was not significantly different from changes in schizophrenia and healthy controls. CONCLUSIONS: Together with the findings in early BP and individuals at genetic risk for BP, current findings suggest that neurodevelopmental factors might play a significant role in cognitive deficits in BP and do not support the notion of progressive cognitive decline in most patients with BP. PMID- 28585514 TI - CONSANGUINEOUS MARRIAGES AMONG IRANIAN MANDAEANS LIVING IN SOUTH-WEST IRAN. AB - SummarySeveral studies have indicated that consanguineous marriages (unions between biologically related persons) are associated with increased risk of autosomal recessive diseases and several multifactorial traits. Mandaeans are a closed ethno-religious community living in areas of southern Iraq and Iran (Khuzestan Province). There are currently no data on the prevalence of consanguineous marriages among Mandaeans. The present study was carried out in 2016 to determine the prevalence of consanguinity among Iranian Mandaeans living in Khuzestan Province, south-west Iran. A total of 137 couples (urban areas: 79 couples; rural areas: 58 couples) were included in the study. Information on the consanguineous marriages of the subjects was collected through direct interviews. Marriages were classified by the degree of relationship between couples as double first cousins, first cousins, first cousin once removed, second cousins and unrelated marriages. The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (alpha) estimated for the population, stratified by rural and urban areas. The overall frequency of consanguinity was found to be 50.7% in urban and 86.2% in rural areas. There was a significant difference between rural and urban areas in types of marriages (chi 2=24.8, df=4, p<0.001) and first cousin marriages (51.8%) were the most common type. The overall alpha-value was estimated to be 0.0363 for the Iranian Mandaean population. PMID- 28585515 TI - Cost Savings and Burden of an Intravascular Line Tip Culture Screening Policy. PMID- 28585516 TI - The Biomarker Salivary SP-D May Indicate Small Airway Inflammation and Asthma Exacerbation. AB - BACKGROUND: Noninvasive and child-friendly biomarkers are important tools for understanding the various phenotypes of childhood asthma. Objective: The aim of this study was to examine the usefulness of salivary surfactant protein (SP) D in assessing the pathophysiology of childhood asthma. METHODS: We measured salivary concentrations of SP-D and forced oscillation technique (FOT) indexes in 19 healthy controls and 21 asthmatic children. Regression equations for the predictive values of FOT indexes were generated from healthy controls. We analyzed the correlations between salivary SP-D concentration and percentages of the predictive values of FOT indexes, as well as the severity of exacerbation. RESULTS: We found that salivary SP-D levels were higher in asthmatic children than in healthy controls. In the asthmatic children, salivary SP-D levels correlated with the percentages of predicted differences in resistance between 5 Hz and 20 Hz (%R5-R20), which represented the resistance of peripheral airways, and with the severity of asthma exacerbation. CONCLUSIONS: Salivary SP-D may reflect asthmatic inflammation in peripheral small airways and may be a useful marker for monitoring the degree of exacerbation in childhood asthma. PMID- 28585517 TI - Quantitative atomic force microscopy. AB - A variety of atomic force microscopy (AFM) modes is employed in the field of surface science. The most prominent AFM modes include the amplitude modulation (AM) and the frequency modulation (FM) mode. Over the years, different ways for analyzing data acquired with different AFM modes have been developed, where each analysis is usually based on mode-specific assumptions and approximations. Checking the validity of the seemingly different approximations employed in the various analysis methods can be a tedious task. Moreover, a straightforward comparison of data analyzed with different methods can, therefore, be challenging. Here, we combine the existing evaluation methods which have been separately developed for the different AFM modes and present a unifying set of three equations. These three AFM equations allow for a straightforward analysis of AFM data within the harmonic approximation, regardless of the AFM mode. The three AFM equations provide the three and only pieces of information about the tip-sample force available within the harmonic approximation. We demonstrate the generality of our approach by quantitatively analyzing three-dimensional AFM data obtained in both the AM and FM mode. PMID- 28585518 TI - The synergistic effect of micro/nano-structured and Cu2+-doped hydroxyapatite particles to promote osteoblast viability and antibacterial activity. AB - Microstructure and chemical constitution are important factors affecting the biological activity of biomaterials. This study aimed to fabricate hydroxyapatite (HAp) particles with both micro/nanohybrid structure and Cu2+ doping to promote osteogenic differentiation and antibacterial property. In the presence of inositol hexakisphosphate (IP6), micro/nano-structured and Cu2+-doped HAp (HAp IP6-Cu) microspheres were successfully fabricated via hydrothermal method. Morphological observation showed that HAp-IP6-Cu microspheres with a diameter of 3.1-4.1 MUm were chrysanthemum-like and composed of nano-flakes approximately 50 nm in thickness. Compared with the HAp micro-rods or IP6 modified HAp (HAp-IP6) microspheres, HAp-IP6-Cu microspheres had a larger specific surface area, better hydrophilicity and stronger ability to adsorb bovine serum albumin. To evaluate the synergistic effects of micro/nanohybrid structure and Cu2+ on cell behavior, rat calvarial osteoblasts (RCOs) were cultured on HAp-IP6-Cu, HAp-IP6 and HAp layers as well as their extracts, respectively. Results demonstrated that HAp-IP6 Cu layer promoted the adhesion, proliferation and osteogenic differentiation of RCOs. The cells grew on HAp-IP6-Cu and HAp-IP6 layers exhibited greater spreading than those on HAp layer. In addition, quantitative test by the agar disk diffusion technique found that HAp-IP6-Cu microspheres were effectively against S taphylococcus aureus and E scherichia coli. These results demonstrated that HAp IP6-Cu microspheres may be a potential candidate as a bioactive and anti infective biomaterial for bone regeneration. PMID- 28585519 TI - Tailoring graphene layer-to-layer growth. AB - A layered material grown between a substrate and the upper layer involves complex interactions and a confined reaction space, representing an unusual growth mode. Here, we show multi-layer graphene domains grown on liquid or solid Cu by the chemical vapor deposition method via this 'double-substrate' mode. We demonstrate the interlayer-induced coupling effect on the twist angle in bi- and multi-layer graphene. We discover dramatic growth disunity for different graphene layers, which is explained by the ideas of a chemical 'gate' and a material transport process within a confined space. These key results lead to a consistent framework for understanding the dynamic evolution of multi-layered graphene flakes and tailoring the layer-to-layer growth for practical applications. PMID- 28585520 TI - Iterative image-domain ring artifact removal in cone-beam CT. AB - Ring artifacts in cone beam computed tomography (CBCT) images are caused by pixel gain variations using flat-panel detectors, and may lead to structured non uniformities and deterioration of image quality. The purpose of this study is to propose a method of general ring artifact removal in CBCT images. This method is based on the polar coordinate system, where the ring artifacts manifest as stripe artifacts. Using relative total variation, the CBCT images are first smoothed to generate template images with fewer image details and ring artifacts. By subtracting the template images from the CBCT images, residual images with image details and ring artifacts are generated. As the ring artifact manifests as a stripe artifact in a polar coordinate system, the artifact image can be extracted by mean value from the residual image; the image details are generated by subtracting the artifact image from the residual image. Finally, the image details are compensated to the template image to generate the corrected images. The proposed framework is iterated until the differences in the extracted ring artifacts are minimized. We use a 3D Shepp-Logan phantom, Catphan(c)504 phantom, uniform acrylic cylinder, and images from a head patient to evaluate the proposed method. In the experiments using simulated data, the spatial uniformity is increased by 1.68 times and the structural similarity index is increased from 87.12% to 95.50% using the proposed method. In the experiment using clinical data, our method shows high efficiency in ring artifact removal while preserving the image structure and detail. The iterative approach we propose for ring artifact removal in cone-beam CT is practical and attractive for CBCT guided radiation therapy. PMID- 28585521 TI - Structural evaluation of an amyloid fibril model using small-angle x-ray scattering. AB - Amyloid fibrils are highly structured protein aggregates associated with a wide range of diseases including Alzheimer's and Parkinson's. We report a structural investigation of an amyloid fibril model prepared from a commonly used plasma protein (bovine serum albumin (BSA)) using small-angle x-ray scattering (SAXS) technique. As a reference, the size estimates from SAXS are compared to dynamic light scattering (DLS) data and the presence of amyloid-like fibrils is confirmed using Congo red absorbance assay. Our SAXS results consistently show the structural transformation of BSA from spheroid to rod-like elongated structures during the fibril formation process. We observe the elongation of fibrils over two months with fibril length growing from 35.9 +/- 3.0 nm to 51.5 +/- 2.1 nm. Structurally metastable fibrils with distinct SAXS profiles have been identified. As proof of concept, we demonstrate the use of such distinct SAXS profiles to detect fibrils in the mixture solutions of two species by estimating their volume fractions. This easily detectable and well-characterized amyloid fibril model from BSA can be readily used as a control or standard reference to further investigate SAXS applications in the detection of structurally diverse amyloid fibrils associated with protein aggregation diseases. PMID- 28585522 TI - Structural and photoluminescence properties of silicon nanowires extracted by means of a centrifugation process from plasma torch synthesized silicon nanopowder. AB - We report on a method for the extraction of silicon nanowires (SiNWs) from the by product of a plasma torch based spheroidization process of silicon. This by product is a nanopowder which consists of a mixture of SiNWs and silicon particles. By optimizing a centrifugation based process, we were able to extract substantial amounts of highly pure Si nanomaterials (mainly SiNWs and Si nanospheres (SiNSs)). While the purified SiNWs were found to have typical outer diameters in the 10-15 nm range and lengths of up to several MUm, the SiNSs have external diameters in the 10-100 nm range. Interestingly, the SiNWs are found to have a thinner Si core (2-5 nm diam.) and an outer silicon oxide shell (with a typical thickness of ~5-10 nm). High resolution transmission electron microscopy (HRTEM) observations revealed that many SiNWs have a continuous cylindrical core, whereas others feature a discontinuous core consisting of a chain of Si nanocrystals forming a sort of 'chaplet-like' structures. These plasma-torch produced SiNWs are highly pure with no trace of any metal catalyst, suggesting that they mostly form through SiO-catalyzed growth scheme rather than from metal catalyzed path. The extracted Si nanostructures are shown to exhibit a strong photoluminescence (PL) which is found to blue-shift from 950 to 680 nm as the core size of the Si nanostructures decreases from ~5 to ~3 nm. This near IR visible PL is shown to originate from quantum confinement (QC) in Si nanostructures. Consistently, the sizes of the Si nanocrystals directly determined from HRTEM images corroborate well with those expected by QC theory. PMID- 28585523 TI - Fusion of P300 and eye-tracker data for spelling using BCI2000. AB - OBJECTIVE: Various augmentative and alternative communication (AAC) devices have been developed in order to aid communication for individuals with communication disorders. Recently, there has been interest in combining EEG data and eye-gaze data with the goal of developing a hybrid (or 'fused') BCI (hBCI) AAC system. This work explores the effectiveness of a speller that fuses data from an eye tracker and the P300 speller in order to create a hybrid P300 speller. APPROACH: This hybrid speller collects both eye-tracking and EEG data in parallel, and the user spells characters on the screen in the same way that they would if they were only using the P300 speller. Online and offline experiments were performed. The online experiments measured the performance of the speller for sixteen non disabled participants, while the offline simulations were used to assess the robustness of the hybrid system. MAIN RESULTS: Online results showed that for fifteen non-disabled participants, using eye-gaze in a Bayesian framework with EEG data from the P300 speller improved accuracy ([Formula: see text], [Formula: see text], [Formula: see text] for estimated, medium and high variance configurations) and reduced the average number of flashes required to spell a character compared to the standard P300 speller that relies solely on EEG data ([Formula: see text], [Formula: see text], [Formula: see text] for estimated, medium and high variance configurations). Offline simulations indicate that the system provides more robust performance than a standalone eye gaze system. SIGNIFICANCE: The results of this work on non-disabled participants shows the potential efficacy of hybrid P300 and eye-tracker speller. Further validation on the amyotrophic lateral sceloris population is needed to assess the benefit of this hybrid system. PMID- 28585524 TI - Theoretical modeling of charge trapping in crystalline and amorphous Al2O3. AB - The characteristics of intrinsic electron and hole trapping in crystalline and amorphous Al2O3 have been studied using density functional theory (DFT). Special attention was paid to enforcing the piece-wise linearity of the total energy with respect to electron number through the use of a range separated, hybrid functional PBE0-TC-LRC (Guidon et al 2009 J. Chem. Theory Comput. 5 3010) in order to accurately model the behaviour of localized states. The tuned functional is shown to reproduce the geometric and electronic structures of the perfect crystal as well as the spectroscopic characteristics of MgAl hole centre in corundum alpha-Al2O3. An ensemble of ten amorphous Al2O3 structures was generated using classical molecular dynamics and a melt and quench method and their structural characteristics compared with the experimental data. The electronic structure of amorphous systems was characterized using the inverse participation ratio method. Electrons and holes were then introduced into both crystalline and amorphous alumina structures and their properties calculated. Holes are shown to trap spontaneously in both crystalline and amorphous alumina. In the crystalline phase they localize on single O ion with the trapping energy of 0.38 eV. In amorphous phase, holes localize on two nearest neighbour oxygen sites with an average trapping energy of 1.26 eV, with hole trapping sites separated on average by about 8.0 A. No electron trapping is observed in the material. Our results suggest that trapping of positive charge can be much more severe and stable in amorphous alumina rather than in crystalline samples. PMID- 28585525 TI - Near transferable phenomenological n-body potentials for noble metals. AB - We present a semi-empirical model of cohesion in noble metals with suitable parameters reproducing a selected set of experimental properties of perfect and defective lattices in noble metals. It consists of two short-range, n-body terms accounting respectively for attractive and repulsive interactions, the former deriving from the second moment approximation of the tight-binding scheme and the latter from the gas approximation of the kinetic energy of electrons. The stability of the face centred cubic versus the hexagonal compact stacking is obtained via a long-range, pairwise function of customary use with ionic pseudo potentials. Lattice dynamics, molecular statics, molecular dynamics and nudged elastic band calculations show that, unlike previous potentials, this cohesion model reproduces and predicts quite accurately thermodynamic properties in noble metals. In particular, computed surface energies, largely underestimated by existing empirical cohesion models, compare favourably with measured values, whereas predicted unstable stacking-fault energy profiles fit almost perfectly ab initio evaluations from the literature. All together the results suggest that this semi-empirical model is nearly transferable. PMID- 28585526 TI - Quantum-trajectory analysis for charge transfer in solid materials induced by strong laser fields. AB - We investigate the dependence of charge transfer on the intensity of driving laser field when SiO2 crystal is irradiated by an 800 nm laser. It is surprising that the direction of charge transfer undergoes a sudden reversal when the driving laser intensity exceeds critical values with different carrier-envelope phases. By applying quantum-trajectory analysis, we find that the Bloch oscillation plays an important role in charge transfer in solids. Also, we study the interaction of a strong laser with gallium nitride (GaN), which is widely used in optoelectronics. A pump-probe scheme is applied to control the quantum trajectories of the electrons in the conduction band. The signal of charge transfer is controlled successfully by means of a theoretically proposed approach. PMID- 28585527 TI - Organic hydrogen peroxide-driven low charge potentials for high-performance lithium-oxygen batteries with carbon cathodes. AB - Reducing the high charge potential is a crucial concern in advancing the performance of lithium-oxygen batteries. Here, for water-containing lithium oxygen batteries with lithium hydroxide products, we find that a hydrogen peroxide aqueous solution added in the electrolyte can effectively promote the decomposition of lithium hydroxide compounds at the ultralow charge potential on a catalyst-free Ketjen Black-based cathode. Furthermore, for non-aqueous lithium oxygen batteries with lithium peroxide products, we introduce a urea hydrogen peroxide, chelating hydrogen peroxide without any water in the organic, as an electrolyte additive in lithium-oxygen batteries with a lithium metal anode and succeed in the realization of the low charge potential of ~3.26 V, which is among the best levels reported. In addition, the undesired water generally accompanying hydrogen peroxide solutions is circumvented to protect the lithium metal anode and ensure good battery cycling stability. Our results should provide illuminating insights into approaches to enhancing lithium-oxygen batteries. PMID- 28585528 TI - Tailoring protein nanomechanics with chemical reactivity. AB - The nanomechanical properties of elastomeric proteins determine the elasticity of a variety of tissues. A widespread natural tactic to regulate protein extensibility lies in the presence of covalent disulfide bonds, which significantly enhance protein stiffness. The prevalent in vivo strategy to form disulfide bonds requires the presence of dedicated enzymes. Here we propose an alternative chemical route to promote non-enzymatic oxidative protein folding via disulfide isomerization based on naturally occurring small molecules. Using single-molecule force-clamp spectroscopy, supported by DFT calculations and mass spectrometry measurements, we demonstrate that subtle changes in the chemical structure of a transient mixed-disulfide intermediate adduct between a protein cysteine and an attacking low molecular-weight thiol have a dramatic effect on the protein's mechanical stability. This approach provides a general tool to rationalize the dynamics of S-thiolation and its role in modulating protein nanomechanics, offering molecular insights on how chemical reactivity regulates protein elasticity. PMID- 28585530 TI - Multimode entanglement in reconfigurable graph states using optical frequency combs. AB - Multimode entanglement is an essential resource for quantum information processing and quantum metrology. However, multimode entangled states are generally constructed by targeting a specific graph configuration. This yields to a fixed experimental setup that therefore exhibits reduced versatility and scalability. Here we demonstrate an optical on-demand, reconfigurable multimode entangled state, using an intrinsically multimode quantum resource and a homodyne detection apparatus. Without altering either the initial squeezing source or experimental architecture, we realize the construction of thirteen cluster states of various sizes and connectivities as well as the implementation of a secret sharing protocol. In particular, this system enables the interrogation of quantum correlations and fluctuations for any multimode Gaussian state. This initiates an avenue for implementing on-demand quantum information processing by only adapting the measurement process and not the experimental layout. PMID- 28585529 TI - Crop wild relative populations of Beta vulgaris allow direct mapping of agronomically important genes. AB - Rapid identification of agronomically important genes is of pivotal interest for crop breeding. One source of such genes are crop wild relative (CWR) populations. Here we used a CWR population of <200 wild beets (B. vulgaris ssp. maritima), sampled in their natural habitat, to identify the sugar beet (Beta vulgaris ssp. vulgaris) resistance gene Rz2 with a modified version of mapping-by-sequencing (MBS). For that, we generated a draft genome sequence of the wild beet. Our results show the importance of preserving CWR in situ and demonstrate the great potential of CWR for rapid discovery of causal genes relevant for crop improvement. The candidate gene for Rz2 was identified by MBS and subsequently corroborated via RNA interference (RNAi). Rz2 encodes a CC-NB-LRR protein. Access to the DNA sequence of Rz2 opens the path to improvement of resistance towards rhizomania not only by marker-assisted breeding but also by genome editing. PMID- 28585532 TI - Mechanism of microtubule stabilization by taccalonolide AJ. AB - As a major component of the cytoskeleton, microtubules consist of alphabeta tubulin heterodimers and have been recognized as attractive targets for cancer chemotherapy. Microtubule-stabilizing agents (MSAs) promote polymerization of tubulin and stabilize the polymer, preventing depolymerization. The molecular mechanisms by which MSAs stabilize microtubules remain elusive. Here we report a 2.05 A crystal structure of tubulin complexed with taccalonolide AJ, a newly identified taxane-site MSA. Taccalonolide AJ covalently binds to beta-tubulin D226. On AJ binding, the M-loop undergoes a conformational shift to facilitate tubulin polymerization. In this tubulin-AJ complex, the E-site of tubulin is occupied by GTP rather than GDP. Biochemical analyses confirm that AJ inhibits the hydrolysis of the E-site GTP. Thus, we propose that the beta-tubulin E-site is locked into a GTP-preferred status by AJ binding. Our results provide experimental evidence for the connection between MSA binding and tubulin nucleotide state, and will help design new MSAs to overcome taxane resistance. PMID- 28585531 TI - Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. AB - Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. However, the altered secretome of senescent cells can promote the growth of the surrounding cancer cells. Although extracellular vesicles (EVs) have emerged as new players in intercellular communication, their role in the function of senescent cell secretome has been largely unexplored. Here, we show that exosome-like small EVs (sEVs) are important mediators of the pro-tumorigenic function of senescent cells. sEV-associated EphA2 secreted from senescent cells binds to ephrin-A1, that is, highly expressed in several types of cancer cells and promotes cell proliferation through EphA2/ephrin-A1 reverse signalling. sEV sorting of EphA2 is increased in senescent cells because of its enhanced phosphorylation resulting from oxidative inactivation of PTP1B phosphatase. Our results demonstrate a novel mechanism of reactive oxygen species (ROS)-regulated cargo sorting into sEVs, which is critical for the potentially deleterious growth promoting effect of the senescent cell secretome. PMID- 28585533 TI - Correspondence: Reply to 'Analytical flaws in a continental-scale forest soil microbial diversity study'. PMID- 28585534 TI - One-step generation of complete gene knockout mice and monkeys by CRISPR/Cas9 mediated gene editing with multiple sgRNAs. AB - The CRISPR/Cas9 system is an efficient gene-editing method, but the majority of gene-edited animals showed mosaicism, with editing occurring only in a portion of cells. Here we show that single gene or multiple genes can be completely knocked out in mouse and monkey embryos by zygotic injection of Cas9 mRNA and multiple adjacent single-guide RNAs (spaced 10-200 bp apart) that target only a single key exon of each gene. Phenotypic analysis of F0 mice following targeted deletion of eight genes on the Y chromosome individually demonstrated the robustness of this approach in generating knockout mice. Importantly, this approach delivers complete gene knockout at high efficiencies (100% on Arntl and 91% on Prrt2) in monkey embryos. Finally, we could generate a complete Prrt2 knockout monkey in a single step, demonstrating the usefulness of this approach in rapidly establishing gene-edited monkey models. PMID- 28585536 TI - Erratum: Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations. AB - This corrects the article DOI: 10.1038/ncomms14944. PMID- 28585535 TI - Blood-brain-barrier spheroids as an in vitro screening platform for brain penetrating agents. AB - Culture-based blood-brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB regulatory proteins, and is unable to discriminate between the transport of angiopep-2 and a control peptide. Finally, we have utilized the BBB spheroids to screen and identify BBB-penetrant cell-penetrating peptides (CPPs). This robust in vitro BBB model could serve as a valuable next-generation platform for expediting the development of CNS therapeutics. PMID- 28585537 TI - Single-mutation fitness landscapes for an enzyme on multiple substrates reveal specificity is globally encoded. AB - Our lack of total understanding of the intricacies of how enzymes behave has constrained our ability to robustly engineer substrate specificity. Furthermore, the mechanisms of natural evolution leading to improved or novel substrate specificities are not wholly defined. Here we generate near-comprehensive single mutation fitness landscapes comprising >96.3% of all possible single nonsynonymous mutations for hydrolysis activity of an amidase expressed in E. coli with three different substrates. For all three selections, we find that the distribution of beneficial mutations can be described as exponential, supporting a current hypothesis for adaptive molecular evolution. Beneficial mutations in one selection have essentially no correlation with fitness for other selections and are dispersed throughout the protein sequence and structure. Our results further demonstrate the dependence of local fitness landscapes on substrate identity and provide an example of globally distributed sequence-specificity determinants for an enzyme. PMID- 28585538 TI - Chirality and energy transfer amplified circularly polarized luminescence in composite nanohelix. AB - Transfer of both chirality and energy information plays an important role in biological systems. Here we show a chiral donor pi-gelator and assembled it with an achiral pi-acceptor to see how chirality and energy can be transferred in a composite donor-acceptor system. It is found that the individual chiral gelator can self-assemble into nanohelix. In the presence of the achiral acceptor, the self-assembly can also proceed and lead to the formation of the composite nanohelix. In the composite nanohelix, an energy transfer is realized. Interestingly, in the composite nanohelix, the achiral acceptor can both capture the supramolecular chirality and collect the circularly polarized energy from the chiral donor, showing both supramolecular chirality and energy transfer amplified circularly polarized luminescence (ETACPL). PMID- 28585540 TI - Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase. AB - Transcription in all living organisms is accomplished by multi-subunit RNA polymerases (msRNAPs). msRNAPs are highly conserved in evolution and invariably share a ~400 kDa five-subunit catalytic core. Here we characterize a hypothetical ~100 kDa single-chain protein, YonO, encoded by the SPbeta prophage of Bacillus subtilis. YonO shares very distant homology with msRNAPs, but no homology with single-subunit polymerases. We show that despite homology to only a few amino acids of msRNAP, and the absence of most of the conserved domains, YonO is a highly processive DNA-dependent RNA polymerase. We demonstrate that YonO is a bona fide RNAP of the SPbeta bacteriophage that specifically transcribes its late genes, and thus represents a novel type of bacteriophage RNAPs. YonO and related proteins present in various bacteria and bacteriophages have diverged from msRNAPs before the Last Universal Common Ancestor, and, thus, may resemble the single-subunit ancestor of all msRNAPs. PMID- 28585541 TI - The social dimensions of invasive plants. AB - Invasive plants pose a major environmental management issue. Research into the social dimensions of this issue has flourished over the past decade, as part of the critical examination of relations between human and nonhuman worlds. The social sciences and humanities have made substantial contributions to conceptualizing invasiveness and nativeness; understanding the perceptions, attitudes and values of diverse stakeholders; and analysing the politics and practices of invasive plant management. Cultural analysis allows areas of conflict and commonality to be identified. Social complexity must be added to ecological complexity to understand the causal relationships underlying invasions; and linear understandings of science-policy relationships are too simplistic. Productive connections have been established between recent social and natural science approaches in the context of rapid environmental change and unpredictable futures. Nonetheless, the prevalence of human exceptionalism in the ecological sciences constitutes a major point of divergence between social and natural science perspectives. PMID- 28585539 TI - IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours. AB - During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy. PMID- 28585542 TI - Loss of function CHCHD10 mutations in cytoplasmic TDP-43 accumulation and synaptic integrity. AB - Although multiple CHCHD10 mutations are associated with the spectrum of familial and sporadic frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) diseases, neither the normal function of endogenous CHCHD10 nor its role in the pathological milieu (that is, TDP-43 pathology) of FTD/ALS have been investigated. In this study, we made a series of observations utilizing Caenorhabditis elegans models, mammalian cell lines, primary neurons and mouse brains, demonstrating that CHCHD10 normally exerts a protective role in mitochondrial and synaptic integrity as well as in the retention of nuclear TDP 43, whereas FTD/ALS-associated mutations (R15L and S59L) exhibit loss of function phenotypes in C. elegans genetic complementation assays and dominant negative activities in mammalian systems, resulting in mitochondrial/synaptic damage and cytoplasmic TDP-43 accumulation. As such, our results provide a pathological link between CHCHD10-associated mitochondrial/synaptic dysfunction and cytoplasmic TDP 43 inclusions. PMID- 28585543 TI - Correspondence: Analytical flaws in a continental-scale forest soil microbial diversity study. PMID- 28585544 TI - Serotonin modulates a depression-like state in Drosophila responsive to lithium treatment. AB - Major depressive disorder (MDD) affects millions of patients; however, the pathophysiology is poorly understood. Rodent models have been developed using chronic mild stress or unavoidable punishment (learned helplessness) to induce features of depression, like general inactivity and anhedonia. Here we report a three-day vibration-stress protocol for Drosophila that reduces voluntary behavioural activity. As in many MDD patients, lithium-chloride treatment can suppress this depression-like state in flies. The behavioural changes correlate with reduced serotonin (5-HT) release at the mushroom body (MB) and can be relieved by feeding the antidepressant 5-hydroxy-L-tryptophan or sucrose, which results in elevated 5-HT levels in the brain. This relief is mediated by 5-HT-1A receptors in the alpha-/beta-lobes of the MB, whereas 5-HT-1B receptors in the gamma-lobes control behavioural inactivity. The central role of serotonin in modulating stress responses in flies and mammals indicates evolutionary conserved pathways that can provide targets for treatment and strategies to induce resilience. PMID- 28585546 TI - A molecular portrait of microsatellite instability across multiple cancers. AB - Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ~8,000 exomes and ~1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy. PMID- 28585545 TI - Sox5 regulates beta-cell phenotype and is reduced in type 2 diabetes. AB - Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion, but the mechanisms underlying insulin secretion failure are not completely understood. Here, we show that a set of co-expressed genes, which is enriched for genes with islet-selective open chromatin, is associated with T2D. These genes are perturbed in T2D and have a similar expression pattern to that of dedifferentiated islets. We identify Sox5 as a regulator of the module. Sox5 knockdown induces gene expression changes similar to those observed in T2D and diabetic animals and has profound effects on insulin secretion, including reduced depolarization-evoked Ca2+-influx and beta-cell exocytosis. SOX5 overexpression reverses the expression perturbations observed in a mouse model of T2D, increases the expression of key beta-cell genes and improves glucose-stimulated insulin secretion in human islets from donors with T2D. We suggest that human islets in T2D display changes reminiscent of dedifferentiation and highlight SOX5 as a regulator of beta-cell phenotype and function. PMID- 28585547 TI - Split-BioID a conditional proteomics approach to monitor the composition of spatiotemporally defined protein complexes. AB - Understanding the function of the thousands of cellular proteins is a central question in molecular cell biology. As proteins are typically part of multiple dynamic and often overlapping macromolecular complexes exerting distinct functions, the identification of protein-protein interactions (PPI) and their assignment to specific complexes is a crucial but challenging task. We present a protein fragments complementation assay integrated with the proximity-dependent biotinylation technique BioID. Activated on the interaction of two proteins, split-BioID is a conditional proteomics approach that allows in a single and simple assay to both experimentally validate binary PPI and to unbiasedly identify additional interacting factors. Applying our method to the miRNA mediated silencing pathway, we can probe the proteomes of two distinct functional complexes containing the Ago2 protein and uncover the protein GIGYF2 as a regulator of miRNA-mediated translation repression. Hence, we provide a novel tool to study dynamic spatiotemporally defined protein complexes in their native cellular environment. PMID- 28585548 TI - Possible absence of critical thickness and size effect in ultrathin perovskite ferroelectric films. AB - Although the size effect in ferroelectric thin films has been known for long time, the underlying mechanism is not yet fully understood and whether or not there is a critical thickness below which the ferroelectricity vanishes is still under debate. Here, we directly measure the thickness-dependent polarization in ultrathin PbZr0.2Ti0.8O3 films via quantitative annular bright field imaging. We find that the polarization is significantly suppressed for films <10-unit cells thick (~4 nm). However, approximately the polarization never vanishes. The residual polarization is ~16 MUCcm-2 (~17%) at 1.5-unit cells (~0.6 nm) thick film on bare SrTiO3 and ~22 MUCcm-2 at 2-unit cells thick film on SrTiO3 with SrRuO3 electrode. The residual polarization in these ultrathin films is mainly attributed to the robust covalent Pb-O bond. Our atomic study provides new insights into mechanistic understanding of nanoscale ferroelectricity and the size effects. PMID- 28585549 TI - Improving the DNA specificity and applicability of base editing through protein engineering and protein delivery. AB - We recently developed base editing, a genome-editing approach that enables the programmable conversion of one base pair into another without double-stranded DNA cleavage, excess stochastic insertions and deletions, or dependence on homology directed repair. The application of base editing is limited by off-target activity and reliance on intracellular DNA delivery. Here we describe two advances that address these limitations. First, we greatly reduce off-target base editing by installing mutations into our third-generation base editor (BE3) to generate a high-fidelity base editor (HF-BE3). Next, we purify and deliver BE3 and HF-BE3 as ribonucleoprotein (RNP) complexes into mammalian cells, establishing DNA-free base editing. RNP delivery of BE3 confers higher specificity even than plasmid transfection of HF-BE3, while maintaining comparable on-target editing levels. Finally, we apply these advances to deliver BE3 RNPs into both zebrafish embryos and the inner ear of live mice to achieve specific, DNA-free base editing in vivo. PMID- 28585550 TI - Compaction of quasi-one-dimensional elastoplastic materials. AB - Insight into crumpling or compaction of one-dimensional objects is important for understanding biopolymer packaging and designing innovative technological devices. By compacting various types of wires in rigid confinements and characterizing the morphology of the resulting crumpled structures, here, we report how friction, plasticity and torsion enhance disorder, leading to a transition from coiled to folded morphologies. In the latter case, where folding dominates the crumpling process, we find that reducing the relative wire thickness counter-intuitively causes the maximum packing density to decrease. The segment size distribution gradually becomes more asymmetric during compaction, reflecting an increase of spatial correlations. We introduce a self-avoiding random walk model and verify that the cumulative injected wire length follows a universal dependence on segment size, allowing for the prediction of the efficiency of compaction as a function of material properties, container size and injection force. PMID- 28585552 TI - Rice domestication: An imperfect African solution. PMID- 28585551 TI - Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis. AB - Diverticular disease is characterized by pouches (that is, diverticulae) due to weakness in the bowel wall, which can become infected and inflamed causing diverticulitis, with potentially severe complications. Here, we test 32.4 million sequence variants identified through whole-genome sequencing (WGS) of 15,220 Icelanders for association with diverticular disease (5,426 cases) and its more severe form diverticulitis (2,764 cases). Subsequently, 16 sequence variants are followed up in a diverticular disease sample from Denmark (5,970 cases, 3,020 controls). In the combined Icelandic and Danish data sets we observe significant association of intronic variants in ARHGAP15 (Rho GTPase-activating protein 15; rs4662344-T: P=1.9 * 10-18, odds ratio (OR)=1.23) and COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase; rs7609897-T: P=1.5 * 10-10, OR=0.87) with diverticular disease and in FAM155A (family with sequence similarity 155A; rs67153654-A: P=3.0 * 10-11, OR=0.82) with diverticulitis. These are the first loci shown to associate with diverticular disease in a genome-wide study. PMID- 28585553 TI - NEDD4 controls spermatogonial stem cell homeostasis and stress response by regulating messenger ribonucleoprotein complexes. AB - P bodies (PBs) and stress granules (SGs) are conserved cytoplasmic aggregates of cellular messenger ribonucleoprotein complexes (mRNPs) that are implicated in mRNA metabolism and play crucial roles in adult stem cell homeostasis and stress responses. However, the mechanisms underlying the dynamics of mRNP granules are poorly understood. Here, we report NEDD4, an E3 ubiquitin ligase, as a key regulator of mRNP dynamics that controls the size of the spermatogonial progenitor cell (SPC) pool. We find that NEDD4 targets an RNA-binding protein, NANOS2, in spermatogonia to destabilize it, leading to cell differentiation. In addition, NEDD4 is required for SG clearance. NEDD4 targets SGs and facilitates their rapid clearance through the endosomal-lysosomal pathway during the recovery period. Therefore, NEDD4 controls the turnover of mRNP components and inhibits pathological SG accumulation. Accordingly, we propose that a NEDD4-mediated mechanism regulates mRNP dynamics, and facilitates SPC homeostasis and viability under normal and stress conditions. PMID- 28585555 TI - Predicting the Future Burden of Esophageal Cancer by Histological Subtype: International Trends in Incidence up to 2030. AB - OBJECTIVES: Rapid increases in the incidence of esophageal adenocarcinoma (EAC) in high-income countries in the past decades have raised public health concerns. This study is the first to predict the future burden of esophageal cancer by histological subtype using international incidence data. METHODS: Data on esophageal cancer incidence by year of diagnosis, sex, histology, and age group were extracted from 42 registries in 12 countries included in the last three volumes (VIII-X) of Cancer Incidence in Five Continents, contributing at least 15 years of consecutive data. Numbers of new cases and incidence rates were predicted up to 2030 by fitting and extrapolating age-period-cohort models; the differential impact of demographic vs. risk changes on future cases were examined. RESULTS: The number of new AC cases is expected to increase rapidly 2005-2030 in all studied countries as a combined result of increasing risk and changing demographics. In contrast, the incidence of esophageal squamous cell carcinoma (ESCC) is predicted to continue decreasing in most countries. By 2030, 1 in 100 men in the Netherlands and the United Kingdom are predicted to be diagnosed with EAC during their lifetime. CONCLUSIONS: The burden from EAC is expected to rise dramatically across high-income countries and has already or will surpass ESCC incidence in the coming years, especially among men. Notwithstanding the inherent uncertainties in trend-based predictions and in subtype misclassification, these findings highlight an ongoing transition in the epidemiology of esophageal cancer that is highly relevant to future cancer control planning and clinical practice. PMID- 28585556 TI - Beneficial Effects of Statins on the Rates of Hepatic Fibrosis, Hepatic Decompensation, and Mortality in Chronic Liver Disease: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Statins may improve outcomes in patients with chronic liver disease (CLD). We conducted a systematic review and meta-analysis to evaluate the impact of statins in the setting of CLD. METHODS: We searched several databases from inception to 17 October 2016 to identify comparative studies evaluating the role of statins in CLD. Outcomes of interest were the associations between statin use and progression of fibrosis, development of hepatic decompensation in cirrhosis, and mortality in CLD. Adjusted hazard ratios (HRs) were pooled and analyzed using a random effects model. Subgroup analyses were performed based on the method of detection for progression of hepatic fibrosis and quality of studies. RESULTS: We included 10 studies (1 randomized controlled trial and 9 observational) with 259,453 patients (54,441 statin users and 205,012 nonusers). For progression of hepatic fibrosis, pooled HR (95% confidence interval) was 0.49 (0.39-0.62). On subgroup analysis of studies using ICD-9 (The International Classification of Diseases, Ninth Revision) coding and a second method to detect cirrhosis, pooled HR was 0.58 (0.51-0.65); pooled HR for studies using ICD-9 coding only was 0.36 (0.29-0.44). For progression of fibrosis in patients with hepatitis C virus (HCV) infection, pooled HR was 0.52 (0.37-0.73). For hepatic decompensation in cirrhosis, pooled HR was 0.54 (0.46-0.65). For mortality, pooled HR based on observational studies was 0.67 (0.46-0.98); in the randomized controlled trial, HR was 0.39 (0.15-0.99). However, the quality of evidence for these associations is low as most included studies were retrospective in nature and limited by residual confounding. CONCLUSIONS: Statins may retard the progression of hepatic fibrosis, may prevent hepatic decompensation in cirrhosis, and may reduce all cause mortality in patients with CLD. As the quality (certainty) of evidence is low, further studies are needed before statins can be routinely recommended. PMID- 28585554 TI - Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease. AB - OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged >=65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65 74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged >=80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin <=3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age >=75 years (2.59 (1.16-5.83); P =0.02) and albumin <=3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (<=3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (>=75 years) or those with advanced liver disease (albumin <=3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended. PMID- 28585557 TI - Pharmacodynamics and effectiveness of topical nitroglycerin at lowering blood pressure during autonomic dysreflexia. AB - STUDY DESIGN: Secondary analysis of prospectively collected observational data assessing the safety of an autonomic dysreflexia (AD) management protocol. OBJECTIVES: To estimate the time to onset of action, time to full clinical effect (sustained systolic blood pressure (SBP) <160 mm Hg) and effectiveness of nitroglycerin ointment at lowering blood pressure for patients with spinal cord injuries experiencing AD. SETTING: US Veterans Affairs inpatient spinal cord injury (SCI) unit. METHODS: Episodes of AD recalcitrant to nonpharmacologic interventions that were given one to two inches of 2% topical nitroglycerin ointment were recorded. Pharmacodynamics as above and predictive characteristics (through a mixed multivariate logistic regression model) were calculated. RESULTS: A total of 260 episodes of pharmacologically managed AD were recorded in 56 individuals. Time to onset of action for nitroglycerin ointment was 9-11 min. Time to full clinical effect was 14-20 min. Topical nitroglycerin controlled SBP <160 mm Hg in 77.3% of pharmacologically treated AD episodes with the remainder requiring additional antihypertensive medications. A multivariate logistic regression model was unable to identify statistically significant factors to predict which patients would respond to nitroglycerin ointment (odds ratios 95% confidence intervals 0.29-4.93). The adverse event rate, entirely attributed to hypotension, was 3.6% with seven of the eight events resolving with close observation alone and one episode requiring normal saline. CONCLUSIONS: Nitroglycerin ointment has a rapid onset of action and time to full clinical effect with high efficacy and relatively low adverse event rate for patients with SCI experiencing AD. PMID- 28585559 TI - Prostate cancer: Escaping enzalutamide: Malat1 contributes to resistance. PMID- 28585560 TI - Surgery: First penis transplant in the USA. PMID- 28585558 TI - Correlates of self-reported physical function in individuals with spinal cord injuries and disorders: does self-efficacy matter? AB - STUDY DESIGN: Data were collected via a cross-sectional mailed survey with Veterans with spinal cord injury and disorders (SCI/D). OBJECTIVES: To examine self-efficacy in Veterans with SCI/D reporting high versus low perceptions of physical function. SETTING: Department of Veterans Affairs (VA) Spinal Cord Injury System of Care-nation-wide, 24 Spinal Cord Injury (SCI) Centers. METHODS: The survey provided patient-reported data on demographic and injury characteristics, basic mobility and fine motor function, and perceived self efficacy. Bivariate comparisons were conducted to compare perceptions of self efficacy between Veterans with SCI/D reporting perceptions of 'high' versus 'low' basic mobility and fine motor function. A multivariate logistic regression was conducted to identify factors independently associated with high physical function when controlling for covariates. RESULTS: Response rate (896/1452=61.7%). Multivariate analysis showed that age (odds ratio (OR)=0.98, 95% confidence interval (CI): 0.96-1.00, P=0.03), tetraplegia (OR=0.20, 95% CI: 0.13-0.32, P?0.0001), diabetes (OR=0.53, 95% CI: 0.31-0.91, P=0.02), depression (OR=0.62, 95% CI: 0.39-0.98, P=0.04) and pressure ulcers (OR=0.42, 95% CI: 0.25 0.72, P=0.001) were all independently associated with lower odds of high physical function. When controlling for covariates, persons with high self-efficacy were nearly two times more likely to have high physical function (OR=1.98, 95% CI: 1.22-3.22, P=0.01). CONCLUSION: Lower perceptions of basic mobility and fine motor function among individuals with SCI/D were correlated with lower self efficacy, even when controlling for other covariates. The relationship between physical function and self-efficacy suggests that interventions focused on improving self-efficacy or physical function may also see improvements in the other. Further, studies exploring the impact of interventions on the relationship between self-efficacy and physical function are needed to understand the relationship between the two. PMID- 28585561 TI - Nitrogen transformations in modern agriculture and the role of biological nitrification inhibition. AB - The nitrogen (N)-use efficiency of agricultural plants is notoriously poor. Globally, about 50% of the N fertilizer applied to cropping systems is not absorbed by plants, but lost to the environment as ammonia (NH3), nitrate (NO3-), and nitrous oxide (N2O, a greenhouse gas with 300 times the heat-trapping capacity of carbon dioxide), raising agricultural production costs and contributing to pollution and climate change. These losses are driven by volatilization of NH3 and by a matrix of nitrification and denitrification reactions catalysed by soil microorganisms (chiefly bacteria and archaea). Here, we discuss mitigation of the harmful and wasteful process of agricultural N loss via biological nitrification inhibitors (BNIs) exuded by plant roots. We examine key recent discoveries in the emerging field of BNI research, focusing on BNI compounds and their specificity and transport, and discuss prospects for their role in improving agriculture while reducing its environmental impact. PMID- 28585562 TI - Sperm cells are passive cargo of the pollen tube in plant fertilization. AB - Sperm cells of seed plants have lost their motility and are transported by the vegetative pollen tube cell for fertilization, but the extent to which they regulate their own transportation is a long-standing debate. Here we show that Arabidopsis lacking two bHLH transcription factors produces pollen without sperm cells. This abnormal pollen mostly behaves like the wild type and demonstrates that sperm cells are dispensable for normal pollen tube development. PMID- 28585563 TI - Global metabolic interaction network of the human gut microbiota for context specific community-scale analysis. AB - A system-level framework of complex microbe-microbe and host-microbe chemical cross-talk would help elucidate the role of our gut microbiota in health and disease. Here we report a literature-curated interspecies network of the human gut microbiota, called NJS16. This is an extensive data resource composed of ~570 microbial species and 3 human cell types metabolically interacting through >4,400 small-molecule transport and macromolecule degradation events. Based on the contents of our network, we develop a mathematical approach to elucidate representative microbial and metabolic features of the gut microbial community in a given population, such as a disease cohort. Applying this strategy to microbiome data from type 2 diabetes patients reveals a context-specific infrastructure of the gut microbial ecosystem, core microbial entities with large metabolic influence, and frequently produced metabolic compounds that might indicate relevant community metabolic processes. Our network presents a foundation towards integrative investigations of community-scale microbial activities within the human gut. PMID- 28585564 TI - Sara phosphorylation state controls the dispatch of endosomes from the central spindle during asymmetric division. AB - During asymmetric division, fate assignation in daughter cells is mediated by the partition of determinants from the mother. In the fly sensory organ precursor cell, Notch signalling partitions into the pIIa daughter. Notch and its ligand Delta are endocytosed into Sara endosomes in the mother cell and they are first targeted to the central spindle, where they get distributed asymmetrically to finally be dispatched to pIIa. While the processes of endosomal targeting and asymmetry are starting to be understood, the machineries implicated in the final dispatch to pIIa are unknown. We show that Sara binds the PP1c phosphatase and its regulator Sds22. Sara phosphorylation on three specific sites functions as a switch for the dispatch: if not phosphorylated, endosomes are targeted to the spindle and upon phosphorylation of Sara, endosomes detach from the spindle during pIIa targeting. PMID- 28585569 TI - Political potholes in the roadmap for research. PMID- 28585565 TI - Architecture of the RNA polymerase II-Paf1C-TFIIS transcription elongation complex. AB - The conserved polymerase-associated factor 1 complex (Paf1C) plays multiple roles in chromatin transcription and genomic regulation. Paf1C comprises the five subunits Paf1, Leo1, Ctr9, Cdc73 and Rtf1, and binds to the RNA polymerase II (Pol II) transcription elongation complex (EC). Here we report the reconstitution of Paf1C from Saccharomyces cerevisiae, and a structural analysis of Paf1C bound to a Pol II EC containing the elongation factor TFIIS. Cryo-electron microscopy and crosslinking data reveal that Paf1C is highly mobile and extends over the outer Pol II surface from the Rpb2 to the Rpb3 subunit. The Paf1-Leo1 heterodimer and Cdc73 form opposite ends of Paf1C, whereas Ctr9 bridges between them. Consistent with the structural observations, the initiation factor TFIIF impairs Paf1C binding to Pol II, whereas the elongation factor TFIIS enhances it. We further show that Paf1C is globally required for normal mRNA transcription in yeast. These results provide a three-dimensional framework for further analysis of Paf1C function in transcription through chromatin. PMID- 28585566 TI - Analysis of LINE-1 Elements in DNA from Postmortem Brains of Individuals with Schizophrenia. AB - Whereas some rare genetic variants convey high risk for schizophrenia (SZ), common alleles conveying even moderate risk remain elusive. Long interspersed element-1s (L1) are mobile retrotransposons comprising ~17% of the human genome. L1 retrotransposition can cause somatic mosaicism during neurodevelopment by insertional mutagenesis. We hypothesized that, compared to controls, patients diagnosed with schizophrenia (PDS) may have increased numbers of deleterious L1 insertions, perhaps occurring de novo, in brain-expressed genes of dorsolateral prefrontal cortex (DLPFC) neurons. Neuronal and non-neuronal nuclei were separated by fluorescence-activated cell sorting from postmortem DLPFC of 36 PDS and 26 age-matched controls. Genomic sequences flanking the 3'-side of L1s were amplified from neuronal DNA, and neuronal L1 libraries were sequenced. Aligned sequences were analyzed for L1 insertions using custom bioinformatics programs. Ontology and pathway analyses were done on lists of genes putatively disrupted by L1s in PDS and controls. Cellular or population allele frequencies of L1s were assessed by droplet digital PCR or Taqman genotyping. We observed a statistically significant increase in the proportion of intragenic novel L1s in DLPFC of PDS. We found over-representation of L1 insertions within the gene ontologies 'cell projection' and 'postsynaptic membrane' in the gene lists derived from PDS samples, but not from controls. Cellular allele frequencies of examined L1 insertions indicated heterozygosity in genomes of DLPFC cells. An L1 within ERI1 exoribonuclease family member 3 (ERI3) was found to associate with SZ. These results extend prior work documenting increased L1 genetic burden in the brains of PDS and also identify unique genes that may provide new insight into the pathophysiology of schizophrenia. PMID- 28585570 TI - Data management and best practice for plant science. PMID- 28585567 TI - Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex. AB - Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration (SA) underlie reinstatement of drug seeking. Dysregulation of the pathway from the prelimbic (PrL) cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the PrL cortex following a final cocaine SA session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking. Src family kinases (SFKs) are involved in both NMDA-mediated activation of TrkB- and TrkB mediated tyrosine phosphorylation of NMDA receptors. We hypothesized that infusion of the SFK inhibitor, PP2, into the PrL cortex prior to a BDNF infusion, immediately after the end of the last cocaine SA session, would block BDNF's ability to suppress reinstatement of cocaine-seeking in rats with a cocaine SA history. PP2, but not the negative control, PP3, blocked BDNF's suppressive effect on context-induced relapse after 1 week of abstinence and cue-induced reinstatement after extinction. As previously reported, infusion of BDNF into the PrL cortex blocked cocaine SA-induced dephosphorylation of ERK, GluN2A, and GluN2B-containing receptors. Inhibition of SFKs using PP2 blocked BDNF-mediated phosphorylation of GluN2A, GluN2B, and ERK. These data indicate that SFK activity is necessary for BDNF-mediated suppression of cocaine-seeking and reversal of cocaine-induced dephosphorylation of key phosphoproteins in the prefrontal cortex related to synaptic plasticity. PMID- 28585568 TI - Brain Tissue Pulsatility is Increased in Midlife Depression: a Comparative Study Using Ultrasound Tissue Pulsatility Imaging. AB - Cerebrovascular disease (CVD) is consistently associated with late-life depression but poorly documented in midlife depression. It can be hypothesized that the relatively low sensitivity of conventional neuroimaging techniques does not allow the detection of subtle CVD in midlife depression. We used tissue pulsatility imaging (TPI), a novel ultrasound (US) neuroimaging technique that has demonstrated good sensitivity to detect changes in the pulsatility of small brain volumes, to identify early and subtle changes in brain vascular function in midlife depression. We compared the maximum and mean brain tissue pulsatility (MaxBTP and MeanBTP), as identified by TPI, between three groups of middle-aged females matched for age: patients with depression (n=25), patients with remitted depression (n=24) and community controls (n=25). MRI arterial spin labeling, white matter hyperintensities (WMHs) and transcranial doppler (TCD) were used as control conventional markers for CVD. We found no difference in the MRI and TCD measures among the three groups. In contrast, depressive patients showed an increased BTP related to the mean global brain pulsatility (MeanBTP) and no change related to large vessels (MaxBTP) in comparison with the remitted and control groups. US neuroimaging is a highly accurate method to detect brain pulsatility changes related to cerebrovascular functioning, and TPI identified an increased BTP in midlife depressed patients, suggesting early and subtle vascular impairments in this population at risk for CVD such as stroke or WMHs. Because high pulsatility could represent prodromal cerebrovascular changes that damage the brain over time, this paper provides a potential target for blocking the progression of CVD. PMID- 28585571 TI - Lithospheric foundering and underthrusting imaged beneath Tibet. AB - Long-standing debates exist over the timing and mechanism of uplift of the Tibetan Plateau and, more specifically, over the connection between lithospheric evolution and surface expressions of plateau uplift and volcanism. Here we show a T-shaped high wave speed structure in our new tomographic model beneath South Central Tibet, interpreted as an upper-mantle remnant from earlier lithospheric foundering. Its spatial correlation with ultrapotassic and adakitic magmatism supports the hypothesis of convective removal of thickened Tibetan lithosphere causing major uplift of Southern Tibet during the Oligocene. Lithospheric foundering induces an asthenospheric drag force, which drives continued underthrusting of the Indian continental lithosphere and shortening and thickening of the Northern Tibetan lithosphere. Surface uplift of Northern Tibet is subject to more recent asthenospheric upwelling and thermal erosion of thickened lithosphere, which is spatially consistent with recent potassic volcanism and an imaged narrow low wave speed zone in the uppermost mantle. PMID- 28585572 TI - The combination of histological prostate atrophy and inflammation is associated with lower risk of prostate cancer in biopsy specimens. AB - BACKGROUND: To evaluate whether the presence of both prostate atrophy (PA) and chronic prostate inflammation (CPI) in the same biopsy and in the same biopsy core are associated with prostate cancer (PCa) risk and grade in repeat biopsies. METHODS: Retrospective analyses of 6132 men who were 50-75 years old undergoing 2 year repeat prostate biopsy after a negative baseline biopsy for PCa in the REduction by DUtasteride of prostate Cancer Events (REDUCE) study. PA, CPI and PCa were determined by central pathology. The association of baseline PA and CPI with 2-year repeat biopsy cancer status and grade was evaluated with chi2 test and logistic regression controlling clinicopathological features. RESULTS: PA, CPI and both were detected in 583 (9.5%), 1063 (17.4%) and 3675 (59.9%) baseline biopsies, respectively. Compared with biopsies with neither PA nor CPI, the presence of PA (odds ratio (OR)=0.73, 95% confidence interval (CI)=0.57-0.93), CPI (OR=0.72, 95% CI=0.58-0.88) and both (OR=0.54, 95% CI=0.45-0.64) were associated with lower PCa risk in the 2-year repeat prostate biopsy. Results were similar in multivariable analysis. Among subjects with both PA and CPI, those with both findings in the same core had even lower PCa risk compared with PA and CPI in different cores (univariable OR=0.68, 95% CI=0.51-0.91; multivariable OR=0.73, 95% CI=0.54-0.99). Combination of PA and CPI was associated with lower risk of high-grade PCa. CONCLUSIONS: The presence of both PA and CPI in baseline biopsies, especially in the same core, was associated with lower PCa risk and grade. The presence and topographical distribution of PA and CPI may be used in PCa risk stratification. PMID- 28585573 TI - Tools for predicting patient-reported outcomes in prostate cancer patients undergoing radical prostatectomy: a systematic review of prognostic accuracy and validity. AB - BACKGROUND: Radical prostatectomy is a common surgical procedure performed to treat prostate cancer. Patient-reported outcomes after surgery include urinary incontinence, erectile dysfunction, decreased quality of life and psychological effects. Predictive tools to assess the likelihood of an individual experiencing various patient-reported outcomes have been developed to aid decision-making when selecting treatment. METHODS: A systematic review was undertaken to identify all papers describing tools for the prediction of patient-reported outcome measures in men with prostate cancer treated with radical prostatectomy. To be eligible for inclusion, papers had to provide a summary measure of accuracy. PubMed and EMBASE were searched from July 2007. Title/abstract screening, and full-text review were undertaken by two reviewers, while data extraction and critical appraisal was performed by a single reviewer. RESULTS: The search strategy identified 3217 potential studies, of which 191 progressed to full-text review and 14 were included. From these studies, 27 tools in total were identified, of which 18 predicted urinary symptoms, six predicted erectile function and one predicted freedom from a group of three outcomes ('trifecta') (biochemical recurrence, incontinence and erectile dysfunction). On the basis of tool accuracy (>70%) and external validation, two tools predicting incontinence and two tools predicting erectile dysfunction are ready for implementation. CONCLUSIONS: A small number of tools for the prediction of patient-reported outcomes following radical prostatectomy have been developed. Four tools were found to have adequate accuracy and validation and are ready for implementation for the prediction of urinary incontinence and erectile dysfunction. PMID- 28585576 TI - Research publications and education in Pakistani medical universities: Avoiding predatory journals and improving the quality of research. PMID- 28585575 TI - Human Cytomegalovirus: a neglected public health area of significant relevance to women, the foetus and new born. Time for action! PMID- 28585577 TI - Clinicopathological profile of gastric cancers in Al-Madinah, Saudi Arabia. AB - OBJECTIVE: To characterise the clinicopathological features of gastric cancer. METHODS: This retrospective study was conducted at the histopathology laboratory of King Fahad Hospital, Madinah, Saudi Arabia, and comprised record of gastric cancer patients from January 2006 to September 2015. Data of all patients who had undergone gastrectomy was included. SPSS 19 was used for data analysis. RESULTS: Of the 63 patients, 42(66.7%) were males while 21(33.3%) were females. The overall mean age was 58.5+/-14.6years (range: 23-95 years). The mean age of males at diagnosis was greater than the mean ages of females (60.4 +/- 15.1vs. 54.5 +/- 13.6 years). Adenocarcinoma was the most common histologic type, occurring in 49(77.8%) patients. There were 30(47.6%) cases of intestinal subtype and 19(30.2%) cases of diffuse subtypes of adenocarcinoma. The mean age of patients with intestinal subtype was greater than those with diffuse type (60.2 +/- 14.9 vs. 56.8+/-14.2 years). Younger patients mainly presented with poorly differentiated tumours as compared to elder patients. The most common site of gastric cancer was body 28(44.5%), followed by antrum 12(30.1%). . CONCLUSIONS: Gastric cancer was diagnosed in advanced stages and in young females. Younger patients were more frequently affected by poorly differentiated and diffuse adenocarcinoma. PMID- 28585574 TI - Structural basis of HypK regulating N-terminal acetylation by the NatA complex. AB - In eukaryotes, N-terminal acetylation is one of the most common protein modifications involved in a wide range of biological processes. Most N acetyltransferase complexes (NATs) act co-translationally, with the heterodimeric NatA complex modifying the majority of substrate proteins. Here we show that the Huntingtin yeast two-hybrid protein K (HypK) binds tightly to the NatA complex comprising the auxiliary subunit Naa15 and the catalytic subunit Naa10. The crystal structures of NatA bound to HypK or to a N-terminal deletion variant of HypK were determined without or with a bi-substrate analogue, respectively. The HypK C-terminal region is responsible for high-affinity interaction with the C terminal part of Naa15. In combination with acetylation assays, the HypK N terminal region is identified as a negative regulator of the NatA acetylation activity. Our study provides mechanistic insights into the regulation of this pivotal protein modification. PMID- 28585578 TI - Comparison of position-related changes on uroflowmetric parameters in healthy young men. AB - OBJECTIVE: To determine the mean difference in maximum urine flow rate and post void residual urine volume in sitting as well as standing voiding position in healthy males. METHODS: This descriptive, cross-sectional study was conducted at the Department of Urology, Indus Hospital, Karachi, from October 2013 to March 2014, and comprised healthy volunteers enrolled using non-probability, consecutive sampling technique. Each volunteer was asked to perform uroflowmetry in sitting and standing positions on two separate days, and a post-void residual volume was assessed after each test. The values of maximum flow rate, average flow rate, voiding volume, and post-void residue were compared between the different voiding positions. RESULTS: A total of 50 volunteers were inducted. In standing position the maximum flow rate was 32.4+/-9.6 ml/sec, average flow rate 8.8+/-16.9 ml/sec, and post-void residue was 8.8+/-16.9ml. Similarly, in sitting position, the maximum flow rate was 14.8+/-5.4 ml/sec, average flow rate 14.8+/ 5.4 ml/sec, and post-void residue was 6.6+/-9.4ml. A significant difference in both voiding positions was observed regarding the maximum flow rate, and average flow rate (p=0.001; p=0.003). However, the difference was not significant for voided volume (p=0.676), or post-void residual volume (p=0.771) in either position. Age-wise stratification of data showed significant difference in both younger and older age groups in terms of maximum flow rate (p=00.19). However, the average flow rate was only significantly different in younger age group (p=0.00). There was no difference in voided volume or post-void residue in either age group (p>0.05). CONCLUSIONS: The standing voiding position in healthy people influenced uroflowmetry findings, and was associated with higher flow rates. PMID- 28585579 TI - Classification of normal and arrhythmic ECG using wavelet transform based template-matching technique. AB - OBJECTIVE: To propose a wavelet-based template matching technique to extract features for automatic classification of electrocardiogram signals of normal and arrhythmic individuals. METHODS: The study was conducted from December 2014 to December 2015 at the Department of Electrical Engineering, Institute of Space Technology, Islamabad, Pakistan. Electrocardiogram signals analysed in this study were taken from the freely available database www.physionet.org. The data for normal subjects was taken from the Massachusetts Institute of Technology-Beth Israel Hospital's normal sinus rhythm database and data for diseased subjects was taken from the arrhythmia database. RESULTS: Of the 30 subjects, there were 15(50%) normal and 15(50%) diseased subjects. The group-averaged phase difference indices of arrhythmic subjects were significantly larger than that of normal individuals (p<0.05) within the frequency range of 0.9-1.1 Hz. Moreover, the scatter plot between the phase difference index and magnitude of wavelet cross spectrum for frequency range of 0.9-1.1 Hz demonstrated a satisfactory delineation between normal and arrhythmic individuals. CONCLUSIONS: Wavelet decomposition-based template matching technique achieved satisfactory delineation of normal and arrhythmic electrocardiogram dynamics. PMID- 28585580 TI - Stages of chronic kidney disease and soluble Transferrin Receptor (sTfR), Ferritin, ratio. AB - OBJECTIVE: To assess the ratio of soluble transferrin receptor to ferritin in different stages of chronic kidney disease. METHODS: This case-control study was conducted at the Aga Khan University Hospital and the Jinnah Postgraduate Medical Centre, Karachi, from January to September 2014, and comprised chronic kidney disease patients and healthy controls. Group 1 comprised controls, whereas groups 2, 3 and 4 had patients based on their mean glomerular filtration rate. SPSS 19 was used for data analysis. RESULTS: Of the 170 participants, 126(74.1%) were cases and 44(25.9%) were controls. The overall mean age was 55.87+/-3.48 years and the mean body mass index was 24.25+/-2.9 kg/m2. Decreased levels of iron and haemoglobin were observed in cases compared to controls (p<0.001), while high serum ferritin was seen in cases compared to the controls (p<0.001). Correspondingly, the soluble transferrin receptor-to-ferritin ratio was significantly decreased in groups 2, 3 and 4 (p<0.001). CONCLUSIONS: The ratio of soluble transferrin receptor to ferritin was lower in higher stages of chronic kidney disease. PMID- 28585581 TI - Serum APOE, leptin, CFH and HTRA1 levels in Pakistani age related macular degeneration patients. AB - OBJECTIVE: To determine the association between serum levels of apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 in patients with age-related macular degeneration. METHODS: This case-control study was conducted at the Quaid-i-Azam University, Islamabad, Pakistan, from May to October 2013, and comprised patients with age-related macular degeneration and matching controls. The confirmation of age-related macular degeneration was carried out through slit lamp examination, fundoscopy and ocular coherence tomography. The selected subjects were not suffering with any other systemic or ophthalmic complication(s). Serum apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 were estimated in serum samples of all subjects. SPSS 18 was used for data analysis. RESULTS: Of the 190 participants, 90(47.4%) were patients with age-related macular degeneration and 100(52.6%) were controls. Significantly elevated serum apolipoprotein E (p<0.0024) and high temperature requirement A-1 (p<0.0001) levels were observed in the patients, while serum leptin (p<0.008) and complimentary factor H (p<0.0001) levels were significantly reduced. Logistic regression showed that lower leptin (p<0.026) and elevated high temperature requirement A-1 (p<0.0001) were the relevant risk factors. CONCLUSIONS: Serum apolipoprotein E, leptin, complimentary factor H and high temperature requirement A-1 levels were altered in age-related macular degeneration patients. PMID- 28585582 TI - Factors associated with mortality to drug-resistant tuberculosis and their programmatic management in treatment centres of Punjab, Pakistan. AB - OBJECTIVE: To describe the characteristics and assess the factors of mortality in drug-resistant tuberculosis patients. METHODS: This retrospective study was conducted at 11 programmatic management of drug-resistant tuberculosis centres located in different cities of the Punjab province of Pakistan, and comprised record of patients with drug-resistant tuberculosis from January 2010 to September 2015. Data was retrieved from patient medical records using electronic nominal review system of the provincial tuberculosis control programme. Cox's proportional hazards model was performed to identify the factors for death. SPSS 17 was used for data analysis. RESULTS: Of the 1,136 patients, 472(41.5%) died during treatment and 664(58.5%) were declared cured or their treatment was completed. Of those who expired, 97(20.6%) expired within 3 months of the start of the treatment. Men had higher rates of death which was not significantly associated with the drug-resistant tuberculosis mortality (p>0.05). CONCLUSIONS: The number of patients who died from drug-resistant tuberculosis treatment was relatively high. PMID- 28585583 TI - PhD programs in nursing in Iran and Canada: A qualitative study. AB - OBJECTIVE: To compare doctoral programmes of nursing in Iran and Canada. METHODS: This qualitative study was conducted in Mashhad, Iran, in April 2014. It was based on Beredy's model, including description, interpretation, juxtaposition and comparison. The validity of the related documents was assessed by internal validity, importance and accuracy of documents. Critique on the external validity and core of documents were reviewed. Then, they were interpreted, juxtaposed and compared. RESULTS: Both the countries had significant differences in fundamental elements of their curricula, including mission, vision, aim, objectives, roles and tasks of graduates. Consequently, academic units, final comprehensive exam, and research courses were also different. CONCLUSIONS: Doctoral programmes in Canada focussed on competency-based, community-based, task-based and student centred approaches. These approaches were ignored in the Iranian curriculum. PMID- 28585584 TI - Dietary practices and severity of depression. Comparative study among housewives and working women in Karachi. AB - OBJECTIVE: To compare levels of depression and locate difference in effects of dietary practices on depression severity in housewives and working women. METHODS: This comparative, cross-sectional study was conducted at the University of Karachi and the Dow University of Health Sciences, Karachi, from January to April 2015. Convenient sampling method was used. Participants included educated women, comprising housewives and working women aged 35-45 years. A structured questionnaire was used to collect data about participants' dietary habits. Depression levels were recorded through Patient Health Questionnaire-9 questionnaire. SPSS 21 was used for data analysis. RESULTS: Of the 600 participants, 300(50%) were housewives and 300(50%) were working women. The mean age of housewives was 35.56+/-7.53 years and that of working women was 35.44+/ 6.65 years (p=0.827). Study outcomes revealed that dietary habits influenced severity of depression. In none/minimal category, most women in both study groups were those who were taking 3 meals [18(14.5%) housewives and 114(52.8%) working women], 8 or more glasses of water [16(16%) housewives and 94(48%) working women]and fast food rarely[20(12%) housewives and76(44.7%) working women]. A high number of women with minimal depression were witnessed among participants who rarely consumed vegetables [16(13.1%) housewives and 50(42.4%) working women]. Considering overall depression, a large number of housewives showed moderate depression, i.e. 156(52%). On the contrary, the number of working women showing minimal depression was 142(47.3%) compared to 30(17.4%) housewives (p<0.001). CONCLUSIONS: Although housewives were more depressed than working women, the highest number of participants with none or minimal depression in both study groups were those who had better dietary practices. PMID- 28585585 TI - Comparing the effectiveness of Betamethasone Gel with Lidocaine Gel local application on endotracheal tube in preventing post-operative sore throat (POST). AB - OBJECTIVE: To see whether betamethasone gel or lidocaine gel is superior in reducing the incidence of post-operative sore throat after tracheal extubation. METHODS: This clinical study was conducted at the Nishtar Hospital and Medical College, Multan, Pakistan, from July to December 2015, and comprised patients who were set to undergo elective surgery under general anaesthesia. The patients were divided into two equal groups. In group 1, endotracheal tube was lubricated with betamethasone gel (0.05%). In group 2, endotracheal tube was lubricated with 4.0% lidocaine gel. SPSS 20 was used for data analysis. Generalised estimating equation was used to see the association between the treatment methods and severity of sore throat over time. RESULTS: Of the 120 patients, there were 60(50%) each in the two groups. The mean intubation time was 5.58+/-1.31 hours in group 1and 5.43+/-1.21 hours in group 2. Besides, 7(11.7%) patients developed mild sore throat and 3(5.0%) moderate sore throat in group 1,whereas 13(21.7%) patients developed mild sore throat, 7(11.6%) moderate and 2(3.3%) severe sore throat after one hour of extubation (p=0.04). After 6 hours, there were 2(3.3%) patients with moderate and 1(1.7%) with severe sore throat in group 1 compared to 8(13.3%) with moderate and 4(6.7%) with severe sore throat in group 2. After 24 hours,5(8.3%) patients developed mild and 2(3.3%) moderate sore throat in group 1 compared to 14(23.7%) patients with mild sore throat, 5(8.5%) with moderate and 1(1.7%) with severe throat in group 2. Generalised estimating equation analysis showed a significant positive association between application of lidocaine gel on endotracheal tube and severity of sore throat (p<0.001). CONCLUSIONS: Local application of betamethasone gel was associated with reduced risk of post operative sore throat as compared to local application of lidocaine gel on the endotracheal tube. PMID- 28585586 TI - Effects of sevoflurane on female reproductive functions in Wistar rats. AB - OBJECTIVE: To determine the effects of sevoflurane by inhalation on female reproductive hormones and ovarian tissues. METHODS: This experimental study was conducted at the Gaziosmanpasa University, Tokat, Turkey, and comprised Wistar Albino female rats. The rats were divided into six groups; one control and five study groups. The control group (C) received 2 L/min O2 in 18 min/day for seven days; the first study group (S1) received 1 minimum alveolar concentration sevoflurane + 2 L/min O2 in 18 min/day for seven days; the second group (S2) received 1 minimum alveolar concentration sevoflurane + 2 L/min O2 in 18 min/day for seven days and no treatment for the following seven days; the third group (S3) received 1 minimum alveolar concentration sevoflurane + 2 L/min O2 in 18 min/day for 14 days; the fourth group (S4) received 1 minimum alveolar concentration sevoflurane + 2 L/min O2 in 18 min/day for 14 days and no treatment for the following seven days; and the fifth group (S5) received 1 minimum alveolar concentration sevoflurane + 2 L/min O2 in 18 min/day for 14 days and no treatment for the following 14 days. The duration of the study was 28 days in February 2015. Reproductive system hormone levels were analysed and histological assessment of the ovaries was performed. SPSS 20 was used for data analysis. RESULTS: Of the 30 rats, there were 5(16.7%) in each group. Histological injury scores in S2, S3, S4, and S5 were significantly higher than in C (p=0.016, p=0.008, p=0.016 and p=0.032, respectively). The hormone levels belonging to follicle stimulating hormone, luteinising hormone, estradiol and progesterone revealed significant alterations in all groups (p<0.05). CONCLUSIONS: Chronic exposure to sevoflurane negatively affected the histological structure of the ovary and hormonal regulation. PMID- 28585587 TI - Depression and anxiety in patients undergoing elective and emergency surgery: Cross-sectional study from Allama Iqbal Memorial Teaching Hospital, Sialkot. AB - OBJECTIVE: To determine the frequency of depression and anxiety in post-operative patients undergoing elective and emergency surgery. METHODS: The cross-sectional analytical study was conducted at the Department of Surgery and Department of Psychiatry of the Allama Iqbal Memorial Teaching Hospital, Sialkot, Pakistan, from September 2013 to April 2016, and comprised patients due for elective or emergency surgery. Patients admitted to the surgical wards, including general surgical, neurosurgical, urological and orthopaedic wards, undergoing major surgical procedures were enrolled. The patients were divided into elective surgery group 1 and emergency surgery group 2. The hospital anxiety and depression scale was used to screen for symptoms of anxiety and depression. SPSS 22 was used for data analysis. RESULTS: Of the 6,624 patients, 4,635(69.97%) were in group 1 and 1,989(30.03%) in group 2.The mean age of patients was 36.75+/ 10.3years in group 1 and 39.11+/-11.4 years in group 2. There were 1,715(37%) males and 2,920(63%) females in group 1, while 518(26%) males and 1,471(74%) females were in group 2. Anxiety was present in 914(45.95%) and 656(32%) patients at 0 and 3 weeks in patients undergoing emergency surgery, while in elective surgery patients it was noted in 509(10.93%) and 1,390(29.87%) subjects, respectively. Depression was present in 218(10.96%) and 616(30.97%) patients at 0 and 3 weeks in patients undergoing emergency surgery, while in elective surgery it was noted in 463(9.98%) and 1,488(32.1%) respectively. CONCLUSIONS: Depression and anxiety were quite frequent in patients undergoing major surgeries. Anxiety was more common in patients who underwent emergency surgeries. PMID- 28585588 TI - Non-pharmacological strategies used to reduce procedural pain in infants by nurses at family health centres. AB - OBJECTIVE: To determine the methods used by nurses working in family health centres to decrease pain during medical procedures in infants. METHODS: This descriptive, cross-sectional study was conducted at family health centres in the county town of Bandirma, and city centres of Karaman and Gaziantep, Turkey, in September and October 2015, and comprised nurses. Data was collected through face to-face interviews using a questionnaire. SPSS 15 was used for data analysis. RESULTS: Of the 144 participants, 71(49.3%) were aged 31-40 years, 74(51.4%) had a bachelor's degree, and 76(52.8%) had worked in a family health centre for 1-5 years. It was observed that 91(63.3%) nurses used contact/massage for decreasing the pain during vaccinations and 72(50.3%) used skin-to-skin contact during heel lance. A statistically significant difference was found between the level of education and use of non-pharmacological methods (p<0.05). CONCLUSIONS: Nurses used different non-pharmacologic methods during invasive procedures. PMID- 28585589 TI - Use of polypharmacy and herbal medication on quality of life in elderly patients at Okmeydani hospital's polyclinics in Istanbul, Turkey. AB - OBJECTIVE: To determine what should be done as a preventive medicine physician by analysing the effect of polypharmacy and herbal treatment. METHODS: This survey based, cross-sectional study was carried out at Istanbul Okmeydani Training and Research Hospital, Istanbul, Turkey, from February to May 2015, and comprised patients using two or more medicines at full strength for at least 240 days. The patients were classified into two groups. Group A comprised those who were using less than 4 medications (at least 2), while group B comprised patients using more than 4 medications. The short version of World Health Organisation's quality-of life questionnaire was applied. SPSS 22 was used for data analysis. RESULTS: Of the 350 participants, 106(30.3%) were receiving herbal treatment while 244(69.7%) had no such treatment. Group B patients had meaningfully lower scores for body, spiritual, social and external environment (p=0.001). Moreover, the patients having no herbal or supportive treatment scored significantly higher in the physical, spiritual, social relations and external environment (p=0.001). In group A, patients receiving no herbal treatment scored meaningfully higher in all fields, including physical (p=0.009), social relations (p=0.043) and external environment (p=0.001). CONCLUSIONS: Old age, living alone, level of education, having a regular monthly income, the number of drugs used, chronic diseases and herbal treatments affected the life quality. PMID- 28585591 TI - Current status of Helicobacter pylori association with haematological and cardiovascular diseases: A mini review. AB - Helicobacter pylori infection is considered the most commonly prevalent gastrointestinal pathogen where it manages to survive despite the hostile environment of human stomach, leading to various gastric diseases including gastric cancer. Due to the chronic inflammatory state induced by H. pylori and its interaction with host immune system have diverted researchers to investigate its correlation with systemic diseases outside of the gastrointestinal tract. This literature review was done to explore the association of H. pylori infection with haematological and cardiovascular diseases. We used medical subject heading (MeSH) terms "Helicobacter pylori" with "inflammation," "haematological diseases," "coronary heart diseases" or "vascular diseases" to search PubMed database. All relevant studies identified from 2005 to 2015 were included. As many of the studies are small-scale or showed weak association, further studies are needed to address the role of H. pylori in pathogenesis of haematological and cardiovascular diseases. PMID- 28585590 TI - Isolation of potentially pathogenic fungi from selected pigeons' feeding sites in Karachi: A new dimension to health hazard. AB - OBJECTIVE: To determine the presence of pathogenic fungal strains in areas where pigeons are present in a large number. METHODS: This study was conducted at the Federal Urdu University of Arts, Science and Technology, Karachi, from February 2015 to March2016, and comprised samples of soil contaminated with pigeons' excreta. The samples were collected from 20 different pigeon-feeding places in the city. These samples were processed for the isolation and identification of fungi by using standard conventional methods. The fungal strains isolated were also tested for their susceptibility to commonly used antifungal agents by disc diffusion technique. RESULTS: There were 105 samples. A wide variety of fungal strains belonging to different genera of Aspergillus, Rhizopus, Penicillium, Fusarium and Candida were isolated and identified by using conventional methods. The antifungal resistance pattern of these strains also depicts emergence of resistance against commonly used antifungal agents such as amphotericin B and fluconazole. CONCLUSIONS: The soil and air of places densely populated with pigeons were found to be loaded with fungal spores and many of them were potential pathogens. PMID- 28585592 TI - Magnetic resonance spectroscopy and magnetic resonance spectroscopic imaging in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy: A literature review. AB - This review focuses on the current literature directed towards the brain metabolite findings in Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) disease using magnetic resonance spectroscopy (MRS) and magnetic resonance spectroscopic imaging (MRSI). Using search terms "metabolites", "spectroscopy", and "CADASIL", six articles were found on PubMed database, Scopus and Google Scholar. Changes in metabolites concentrations and relative ratios (RR) were found not only in abnormal but also in normal-appearing brain regions. PMID- 28585593 TI - Incidentaloma: from general practice to specific endocrine frame. AB - Incidentaloma, a modern concept connected to technology progress, represents an accidentally discovered tumour, usually used for hypophysis and adrenals, and rarely for thyroid, parathyroids, and ovaries. This is a narrative review based on PubMed research, between 2012 and 2016 focusing on general and endocrine approach and current controversies. Main dilemma is the terminology itself: randomly imagery finding is enough or non-functioning profile and low-growth rate (not requiring surgery) should be mandatory? The controversies refers to best time framing of re-scanning pituitary and adrenal incidentaloma and setting of clear criteria for subclinical Cushing's syndrome. The need for general practical guidelines is imperative so clinicians from different areas of medicine touse the same definition and protocols. Currently, the widely accepted part is represented by incidental finding. For restricted defined incidentaloma the best intervention is no intervention, while some cases may require surgery depending on tumours features, patient's age and preference. PMID- 28585594 TI - Role of early contrast enhanced CT scan in severity prediction of acute pancreatitis. AB - Severe pancreatitis occurs in approximately 15-25% of patients with acute pancreatitis. The objective of our study was to compare the CT Severity Index (CTSI) with a clinical score (BISAP score) to predict severity of acute pancreatitis. Forty-eight consecutive patients with acute pancreatitis who underwent contrast enhanced CT scan within 72 hours of presentation were included. Results of our study showed that both CTSI and BISAP score were reliable predictors of mortality (p value = 0.019 and <0.001 respectively) and need for mechanical ventilation (p value = .002 and .006 respectively). Positive predictive value of CTSI to predict recovery without intervention was 91.4% as compared to 78% for that of BISAP score. Receiver Operating Characteristics (ROC) Curves showed CT scan was superior to BISAP Score in predicting need of percutaneous or surgical intervention. Early CT scan may be utilized for prediction of clinical course of patients with acute pancreatitis. PMID- 28585595 TI - Treatment of chronic Hepatitis C in Thalassemia major patients. AB - Treatment of chronic hepatitis C (HCV) is difficult in thalassemics due to the haemolytic side effects of therapy. This study evaluated the treatment response to conventional interferon and ribavirin in HCV patients with thalassemia major. It was conducted at PMRC Research Centre, Jinnah Postgraduate Medical Centre (JPMC) Karachi. At baseline complete blood count, liver function tests, serum protein/ albumin, random blood glucose, serum ferritin, TSH, HCV RNA (quantitative) and genotyping were done. Conventional interferon 3 MIU thrice weekly and ribavirin 400 mg daily was given for 24 or 48 weeks. HCV RNA was done at 1st month (RVR), 3rd month (EVR), 6th month (ETR) and six months post treatment sustained virological response (SVR). A total of 17 Anti HCV positive patients, age range 7-28 years were included.HCV RNA was found in 12. Treatment was completed in 8 patients. Genotype 3(87.5%) was found in 7 patients, 1 had genotype 1. RVR was achieved in 5 (62.5%) cases, negative PCR at 3 and 6 months of treatment (EVR) in 7 (87.5%) patients, one patient was non responder. SVR was achieved in 2(25%) patients. Anaemia was the most common side effect due to which transfusion requirements increased in 4(50%) patients. PMID- 28585596 TI - Sexual self-esteem in mothers of normal and mentally-retarded children. AB - Sexual self-esteem is negatively influenced by the stressful experiences in lifetime. This study compared the sexual self-esteem and its components in mothers with normal and mentally-retarded children in Qaen city, in 2014. A total of 120 mothers were selected and assigned into two groups of 60 samples based on convenient sampling method and randomized multiple stage sampling. Both groups completed sexual self-esteem questionnaire. The data were analyzed employing t test through SPSS software version15. The results showed that the rate of sexual self-esteem in mothers of mentally-retarded children decreased significantly compared with that of mothers with normal children (p<0.05). Moreover, the mean scores of all components of sexual self-esteem including skill and experience, attractiveness, control, moral judgment, and adaptiveness in mothers of mentally retarded children were significantly less than those of mothers with normal children (p <0.05). Therefore, it is recommended that self-esteem, especially the sexual one, be taught to mothers of mentally-retarded children by specialists. PMID- 28585597 TI - Effects of chronic exposure to Formaldehyde on micronucleus rate of bone marrow cells in male mice. AB - Formaldehyde (FA) is the major volatile organic chemical (VOC) present in indoor air, and a constituent known to be associated with sick building syndrome. In the present study, mice were exposed to different concentrations of FA (0, 1, 10 mg/ m3) through static inhalation for 2 hours per day for 20 weeks. The polychromatic erythrocytes/ normochromatic erythrocyte (PCE/NCE) ratio and the micronucleus rates in bone marrow cells were detected. Data indicated that the PCE/NCE ratio in two FA exposure groups were statistically significant lower than the negative control group (P <0.05), and the micronucleus rate in two FA exposure groups were not significantly higher than the control group (P>0.05). These results suggest that chronic static inhalation of FA can reduce the ratio of PCE/NCE in the mice bone marrow, but the effects to the mice bone micronucleus rate are not sure. PMID- 28585598 TI - Pulmonary hypertensive crisis and its efficient management. A Case report and literature review. AB - Perioperative anaesthetic management of patients with pulmonary hypertensive crisis is complex and challenging because of limited window period and treatment options. This case report describes the successful management of a patient with severe valvular heart disease superimposed by severe pulmonary hypertension, who developed pulmonary hypertensive crisis soon after induction of general anaesthesia for cardiac surgery. Pulmonary hypertensive crisis is not a usual phenomenon in these patients, but if it occurs it can be fatal. Anticipatory care of the patient to prevent crisis is the mainstay of treatment, otherwise it adds additional morbidity to such patients. Fortunately our patient survived the crisis without causing any additional morbidity during his hospital stay. PMID- 28585599 TI - Discordant disease expression of neonatal lupus erythematosus in twins. AB - Neonatal lupus erythematosus is an autoimmune disease resulting from the trans placental passage of maternal anti-SSA/Ro, anti-SSB/La, and less frequently anti RNP antibodies to the foetus. At the time of diagnosis 50% of mothers are asymptomatic. Neonatal manifestations of this multisystem disease may include congenital heart block, cutaneous lesions and haematological abnormalities. We present the case of congenital neonatal lupus erythematosus in non-identical twins, showing variability in clinical manifestation of this disease,despite receiving the same level of antibodies from the mother. This case adds to the growing body of evidence about the role of genetics and other feto-maternal contributing factors in addition to the presence of auto antibodies. It raises interesting questions about discordant disease expression in offspring's of the same mother. PMID- 28585600 TI - Perforation of Meckel's diverticulum with a foreign body mimicking acute appendicitis: A rare complication. AB - Meckel's diverticulum mimicking acute appendicitis is a very rare condition encountered in practice. MD is asymptomatic in most of cases and only about 4 to16% of cases develop complications. Perforation of MD by a foreign body is even rarer being only reported in few cases in the literature. The surgical management might be wedge resection or segmental resection and primary anastomoses depending on the intra operative findings. We report a case with foreign body impaction in MD with perforation mimicking acute appendicitis. PMID- 28585601 TI - Canakinumab treatment in four children with colchicine resistant familial mediterranean fever. AB - Familial Mediterranean Fever (FMF) is an autosomal recessive and autoinflammatory disease, characterized with inflammation of serous membranes such as peritoneum, pleura, synovium with fever and pain. Colchicine is the main treatment of FMF, but 5-10 % of patients are unresponsive to colchicine. We report using anti interleukin-1 agents anakinra and canakinumab in four colchicine-resistant patients who were successfully treated. Three of the patients were siblings. PMID- 28585602 TI - Manual Vacuum Aspiration (MVA) - A safe option for evacuation of first trimester miscarriage in cardiac patients. AB - This case series was done at Armed Forces Institute of Cardiology, National Institute of Heart Disease, Rawalpindi, to observe safety and efficacy of manual vacuum aspiration and frequency of complications in cardiac patients with missed abortion. All cardiac patients presenting in first trimester with diagnosed early foetal demise (missed miscarriage) or incomplete miscarriage were included. Manual vacuum aspiration was done as an outpatient procedure. Cardiac and procedure related complications including arrhythmias, thromboembolism, heart failure and ischaemia were noted. A total of 34 patients were enrolled. Mean age and parity was 25.9+/-2.25 years and 1.18+/-1.02. Mitral valve was the dominant valve involved in 20(58.8%) followed by double valve replacement in 5(14.7%), dilated cardiomyopathy 4(11.76%), aortic valve involvement in 3(8.8%) and supra ventricular tachycardia in 2(5.9%) patients. Complete evacuation was achieved in 100% patients and there were no major cardiac or gynaecological complications except arrhythmia in 1(2.9%) patient. MVA seems to be a safe and cost effective intervention compared to other modalities of miscarriage management even in high risk cardiac patients. PMID- 28585603 TI - Etiological and epidemiological factors in hearing-impaired students in Van, East of Turkey: A case series. AB - The aim of the present case series was to investigate the causes of hearing loss in the children studying at a primary School for the deaf in Van Province, Turkey. The present series included 95 children with sensorineural hearing loss. Otoscopic and ophthalmological examinations, pure-tone audiometry, and tympanometry were performed for each patient. Measles IgG, rubella IgG, cytomegalovirus (CMV) IgG, toxoplasma IgG, herpes simplex virus (HSV) Type I (HSV I) IgG, HSV Type II (HSV-II) IgG, and Mycoplasma pneumonia IgG were evaluated in serum samples. Temporal bone anomalies were analyzed on temporal bone computed tomography (CT). A total of 7 radiologically distinct inner ear malformations were detected in 19 children. Twelve children were detected with various fundus pathologies. The most common cause of hearing loss was family-related factors (52%). In conclusion, the etiological and epidemiological factors were consistent with those reported in the literature. PMID- 28585604 TI - Drug addiction and diabetes: South Asian action. AB - Both diabetes and drug addiction are common phenomena across the world. Drug abuse impacts glycaemic control in multiple ways. It becomes imperative, therefore, to share guidance on drug deaddiction in persons with diabetes. The South Asian subcontinent is home to specific forms and patterns of drug abuse. Detailed study is needed to ensure good clinical practice regarding the same. This communication provides a simple and pragmatic framework to address this issue, while calling for concerted action on drug deaddiction in South Asia. PMID- 28585605 TI - Pragmatic selection of cooking oils. AB - Fats and oils are one of the very important components of diet. However excess of either overall fat or certain kind of fats in the diet may result in negative health impacts including risk of obesity, dyslipidaemia, cardiovascular diseases and certain malignancies. It is thus important to have an optimum amount of fat in the diet, and also important to choose appropriate sources of fat in the diet. In this mini review we suggest pragmatic selection of cooking oils for optimum health benefits. PMID- 28585606 TI - Extent of resection and timing of surgery in adult low grade glioma. AB - Low grade glioma is a group of WHO grade II tumours including diffuse astrocytoma, oligodendroglioma, and oligoastrocytoma. Strong evidence exists in literature now to support early surgery and higher extent of safe resection in improving outcomes. In this review, we are highlighting some of the important studies done in the last few years specifically addressing timing of surgery and extent of resection. PMID- 28585607 TI - Microangiopathic haemolytic anaemia (maha) caused by non O157:H7 E-coli. PMID- 28585608 TI - Hysteroscopic Myomectomy can lead to intrauterine adhesions and infertility. PMID- 28585609 TI - Comment on Ahsan Ali Syed et al (J Pak Med Assoc 2017; 67: 400-404) Frequency of worsening liver function in severe dengue hepatitis patients receiving paracetamol: A retrospective analysis of hospital data. PMID- 28585610 TI - Response to comment on Ahsan Ali Syed et al (J Pak Med Assoc 2017; 67: 400-404 Frequency of worsening liver function in severe dengue hepatitis patients receiving paracetamol: A retrospective analysis of hospital data. PMID- 28585611 TI - Knowledge and attitude of physicians about antimicrobial resistance and their prescribing practices in Services hospital, Lahore, Pakistan. AB - A cross sectional study was conducted in Services Hospital, Lahore using a self administered questionnaire to test the knowledge, attitude and prescribing practices of residents and attending physicians using non-probability convenience sampling. A total of 116 questionnaires were filled (Response rate=77.3%). Knowledge was below average (mean score of 3.66+/-1.1). Only 18 physicians (16%) could correctly estimate the rates of resistance of Klebsiella pneumoniae and pseudomonas aeruginosa to cephalosporin. Mostly physicians reviewed their decisions to prescribe an antibiotic by discussing with a senior colleague (n=93; 80%). When they did, the senior colleague sometimes recommended a different antibiotic (n=106; 91%). Seventy seven physicians (66%) reported that they prescribed more than one antibiotic per day. Physicians also stated that their decision of antimicrobial prescription was influenced by patient's socioeconomic status (n=108; 93.1%) and patients' demands (n=24; 20.7%). This study highlighted the importance of Antimicrobial stewardship and revealed topics to address during future antimicrobial prescribing interventions such as dissemination of information about local resistance rates and encouraging knowledge about antimicrobials. PMID- 28585612 TI - [Recent advances of immunooncology in the treatment of solid tumours and haematological malignancies: the immune checkpoint inhibitors]. AB - Cancer immunotherapy is coming of age, as outstanding results can be achieved in the therapy of cancer with poor prognosis by altering the patients' immune system and by promoting the immune response against tumours. Amongst immunotherapies, the immune checkpoint inhibitors (ICI) proved to be the most effective, primarily in the treatment of solid tumours, including melanoma, non-small cell lung carcinoma, and classical Hodgkin's lymphoma. The reason for this efficacy is the immunosuppressive microenvironment typical for many cancer types, directly and indirectly inhibiting effector T-cell responses. To date, three cytotoxic T lymphocyte antigen 4 (CTLA-4) or programmed cell death protein 1 (PD-1) checkpoint inhibitors have been approved in Europe, and six in the USA. Furthermore, an increasing number of these drugs is available in the setting of clinical trials. For the optimal use of the numerous different ICIs there is an ever increasing need to identify reliable predictive biomarkers and to explore therapy-associated resistance mechanisms, which will represent the main challenge of the next years. PMID- 28585613 TI - [Immunotherapy of renal cell cancer]. AB - The authors briefly highlight the results of targeted therapy and present new solutions in kidney cancer immunotherapy. The important checkpoint inhibitors (anti-CTLA-4, -PD-1 and -PD-L1/2) and their combinations, together with the combinations of targeted drugs and immunotherapy are discussed. The newest checkpoint agents, vaccination and pegylated interleukin-2 are also presented. The most promising clinical trials (CheckMate-025, AGS-003, IMA 901) and the on going first line phase III trials are shown in metastatic clear cell renal carcinoma. PMID- 28585614 TI - [Advances in immunotherapy for metastatic melanoma]. AB - Improved understanding of melanoma genetics and immune regulatory pathways have culminated in the development of targeted and immunotherapies of the patients with metastatic melanoma. Recent advances in these oncological modalities have dramatically shifted this landscape with highly increased survival rates. Cytotoxic T-lymphocyte antigen-4 and programmed death-1 based treatments (ipilimumab, nivolumab and pembrolizumab) have been an integral part of this therapeutic success. Nowadays the combined immune checkpoint inhibitor therapies have demonstrated a significant improvement in overall survival of patients with advanced melanoma. This review summarizes briefly the most important updated principals of this field in dermato-oncology. PMID- 28585615 TI - [The role of immunotherapy in the modern treatment of urothelial carcinoma]. AB - By the emergence of modern immunotherapies with active agents like PD-1 (nivolumab, pembrolizumab) and PD-L1 immune checkpoint blockers (atezolizumab, avelumab, durvalumab), new therapeutic options have become available for the treatment of patients with locally advanced and metastatic urothelial carcinoma. According to the recent publications, they have been effective in case of progression after platinum therapy, in or after second-line and in firstline therapies for cisplatin ineligible patients, respectively. Patient survival and tumor response data are very promising; in particular stages, they seem to be more effective than the previously administered chemotherapies. Their toxicity profiles also appear to be more favorable. Immunological side effects are rare; their identification and management require preparedness and multidisciplinary thinking. Current and ongoing trials are investigating the combinations of new remedies with other immunotherapeutic agents (e.g., CTLA-4 inhibitor ipilimumab, tremelimumab) or chemotherapies as well as trying to identify biomarkers in order to further increase effectiveness. In our review, we summarize the recently published data about urothelial carcinoma therapy and give a brief overview of the ongoing clinical trials. PMID- 28585616 TI - [Role of immunotherapy in the management of colorectal cancer]. AB - Immunotherapy proved to be effective in various forms of cancer but it is in its infancy in colorectal cancer, although the Immunoscore was developed to classify this tumor immunologically. Various forms of immunotherapy were tested in early clinical trials but anti-PD-1 antibodies seem the most promising so far. These studies also revealed that one particular molecular subgroup of colorectal cancer, the microsatellite instable variant, is extremely sensitive for such modality. PMID- 28585617 TI - [Immunotherapy for lung cancer]. AB - Similarly to other malignancies, immune checkpoint inhibitor therapy is a revolutionary, effective new treatment possibility for lung cancer. In lung cancer carcinogenesis is related mainly to tobacco smoking with high somatic mutation rate and immunogenicity. The PD-1 inhibitor nivolumab and pembrolizumab and the PD-L1 inhibitor atezolizumab is a labelled indication in second line setting in advanced nonsmall cell lung cancer (NSCLC). Avelumab and durvalumab have promising activity as well. Based on the data of KEYNOTE 024 trial, pembrolizumab is approved in first line setting for cases with >=50% PD-L1 expression. In this selected patient population, progression-free survival has doubled, and overall survival was significantly better in pembrolizumab-treated patients compared to those receiving standard of care. Pembrolizumab treatment became a new first line standard of care in advanced NSCLC. There are numerous ongoing clinical trials in lung cancer with immune checkpoint inhibitors in combination with cytotoxic chemotherapy, targeted agents, or in adjuvant setting. PMID- 28585618 TI - [Predictive markers of immunotherapy of cancer, practical issues of PD-L1 testing]. AB - Pathologists have detected signs of antitumor immune reactions for a long time but only in case of a few cancer types became this part of the report. The advent of immunotherapy of cancers, however, radically alters this routine and promotes the development of clinically valid prognostic and predictive immunological makers. The most advanced immunological markers are the Immunoscore (density of T cell subpopulations), and PD-L1 protein expression on tumor or immune cells. PD L1 testing of cancers raises new issues since almost all novel therapies developed its own in vitro diagnostics. Due to the incompatibility of these assays it is suggested to use the companion diagnostic of the given immunotherapeutic drug defined in its label. PMID- 28585619 TI - [Palbociclib combinations as new therapeutic strategies in the treatment of HR+/HER2- advanced breast cancer]. AB - Until recently, the only endocrine agents used to treat HR+/HER2- advanced breast cancers were tamoxifen, aromatase inhibitors and fulvestrant, although a substantial proportion of patients relapse on these standard therapies. Intensive research has been conducted to develop new strategies to overcome endocrine resistance and to enhance the efficacy of endocrine treatments by combining hormone therapy with other targeted treatment approaches. The development of selective CDK4/6 inhibitors and the introduction of palbociclib, the first molecule in this class in clinical practice, represent an important step in the treatment of HR+ advanced breast cancer. High level evidence supports the use of palbociclib plus letrozole in the treatment of endocrine sensitive breast cancers, or palbociclib plus fulvestrant in tumors that develop acquired resistance to endocrine therapy. These combinations are effective and well tolerated therapeutic modalities. The new combination regimens with palbociclib represent an important addition to the therapeutic armamentarium in locally advanced and metastatic ER+/HER2- breast cancer. The article reviews the current role of palbociclib in combination with endocrine therapy in the therapy of HR+/HER2- advanced breast cancer. PMID- 28585620 TI - [Treatment of bone metastases: bisphosphonates and denosumab]. AB - Some disseminated tumor cells (as "seeds") feel well in the skeletal tissue, as a "soil", but the humoral crosstalk between tumor cells and bone cells disrupts the normal bone homeostasis (remodeling), which leads to a vicious circle, the multiple bone metastatic disease. The tumor cells could stimulate bone resorption, bone neo-formation or both, characteristic of the primary tumor. This usually incurable condition involves serious consequences, as fractures, pain, surgeries, irradiations, plegias, hypercalcemia, etc. (skeletal-related events, SREs), which destroy the quality of life. Targeting bone resorption with bisphosphonates or RANK ligand dependent mechanism could improve the rate of serious SREs and disease-free survival. PMID- 28585621 TI - Specific dsDNA recognition by a mimic of the DNA binding domain of the c-Myc/Max transcription factor. AB - We here report on the synthesis of the first mimic of the DNA binding domain of the c-Myc/Max-bHLH-ZIP transcription factor able to selectively recognize its cognate E-box sequence 5'-CACGTG-3' through the major groove of the double stranded DNA. The designed peptidosteroid conjugate was shown to be effective as DNA binder in the presence of excess competitor DNA. PMID- 28585622 TI - Enantioselective synthesis of pyrazolone alpha-aminonitrile derivatives via an organocatalytic Strecker reaction. AB - A new organocatalytic enantioselective Strecker reaction of pyrazolone-derived ketimine electrophiles has been developed. Using pseudo-enantiomeric squaramide catalysts the nucleophilic 1,2-addition of trimethylsilyl cyanide to the ketimines efficiently provides a direct entry to both enantiomers of pyrazolone alpha-aminonitrile derivatives at will in good yields and high enantioselectivities for a wide variety of substrates. PMID- 28585623 TI - Photocatalyzed cascade oxidative annulation of propargylamines and phosphine oxides. AB - On account of the broad utilities of organophosphorus compounds, the development of highly efficient and concise phosphination methods is significantly important and urgent. Herein, we disclose a novel method for the synthesis of phosphorylated heterocycles: versatile intermediate propargylamines serving as a new type of radical acceptors incorporated in P-radicals via a photocatalytic strategy. This reaction proceeds through a cascade phosphinoylation/cyclization/oxidation/aromatization pathway using readily available starting materials under mild conditions of light with excellent atom economy, catalyzed by AgOAc or fac-Ir(ppy)3. One of the phosphorylated quinolines was selected, as an example, as an electron-transporting material for fabricating phosphorescence organic light-emitting diodes displaying excellent electroluminescence performances with a maximum external quantum efficiency of 21.9% with negligible efficiency roll-off ratios. PMID- 28585624 TI - Exploiting the biomimetic and luminescence properties of multivalent dendrimer semiconductor nanohybrid materials in the ultra-low level determination of folic acid. AB - In view of the enhanced generation of folate receptors in cancerous cells and diseases linked to the deficiency of folic acid, such as anemia, mental devolution, congenital malformation, etc., the development of a simple method for the ultra-sensitive determination of folic acid remains a long-standing issue for practical applications in medicine and biotechnology. Thus, the proposed luminescence based strategy involving multifunctional poly(amidoamine) (PAMAM) dendrimer encapsulated quantum dots (QDs) as a probe provides a simple, fast and efficient method for the selective determination of folic acid at the nano-molar level. Absorption and Fourier transform infra-red (FTIR) spectroscopy provide evidence of the binding of folic acid with dendrimer amine groups. The emission quenching of dendrimer encapsulated CdS QDs follows a linear Stern-Volmer plot with an exceedingly high value of the Stern-Volmer constant (KSV = 8.4 * 106 M-1) facilitating a higher detection efficiency. Similar quenching analysis with dendrimer-ZnS QDs showed a slightly lower Stern-Volmer constant (KSV = 2.29 * 106 M-1). The lower probing efficiency of the protein or amino acid capping of QDs has been explained through zeta potential measurements. The solvent polarity dependence suggests a charge transfer process responsible for the emission quenching of CdS QDs, which is static in nature as revealed by lifetime measurements. The determination of folic acid at this low level is not affected by possible interfering molecules, such as vitamin C, vitamin B12 and uric acid. Calorimetric measurements showed that the exothermic binding of folic acid with a dendrimer follows enthalpy-entropy compensation. The detailed mechanistic aspect of interactions of folic acid with the QD probe helps in a better understanding of the detection process, which in turn can assist in developing a dendrimer based material for image analysis and drug delivery in folate receptor rich cells. PMID- 28585625 TI - Synthesis of CaCO3 nano- and micro-particles by dry ice carbonation. AB - Here we report a new low temperature dry ice carbonation approach for the synthesis of carbonate-based nano- and micro-particulate materials, which enables the preparation of monodispersed calcium carbonate nanoparticles and microspheres with very high purity phases. PMID- 28585626 TI - Modulation of the catalytic activity of Pt nanoparticles through charge-transfer interactions with metal-organic frameworks. AB - We employed metal-organic framework (MOF) supports to modulate the electronic states of loaded Pt nanoparticles (NPs) in their composite catalysts (Pt/MOFs). Pt NPs were homogenously deposited on four MOFs characterized with different electronic states (Zn-MOF-74, Mg-MOF-74, HKUST-1, and UiO-66-NH2). Theoretical and experimental studies demonstrated that a charge-transfer interaction between Pt NPs and MOFs is a critical factor for controlling the catalytic activity of Pt NPs supported on MOFs. PMID- 28585627 TI - Guided protein/cell patterning on superhydrophilic polymer brushes functionalized with mussel-inspired polydopamine coatings. AB - A simple approach for preparing bicomponent polymer patterns was developed by coating polydopamine (PDA) on superhydrophilic poly(2-acryl-amido-2-methylpropane sulfonic acid) (PAMPS) brushes. Well-defined and versatile arrays of proteins and cells were achieved without harm to proteins and cells. PMID- 28585628 TI - Intracellular delivery of a catalytic organometallic complex. AB - A homogeneous carbene-based palladium catalyst was conjugated to a cell penetrating peptide, allowing intracellular delivery of catalytically active Pd complexes that demonstrated bioorthogonal activation of a profluorophore within prostate cancer cells. PMID- 28585629 TI - A thermodynamic model to predict electron mobility in superfluid helium. AB - Electron mobility in superfluid helium is modeled between 0.1 and 2.2 K by a van der Waals-type thermodynamic equation of state, which relates the free volume of solvated electrons to temperature, density, and phase dependent internal pressure. The model is first calibrated against known electron mobility reference data along the saturated vapor pressure line and then validated to reproduce the existing mobility literature values as a function of pressure and temperature with at least 10% accuracy. Four different electron mobility regimes are identified: (1) Landau critical velocity limit (T ~ 0), (2) mobility limited by thermal phonons (T < 0.6 K), (3) thermal phonon and discrete roton scattering ("roton gas") limited mobility (0.6 K < T < 1.2 K), and (4) the viscous liquid ("roton continuum") limit (T > 1.2 K) where the ion solvation structure directly determines the mobility. In the latter regime, the Stokes equation can be used to estimate the hydrodynamic radius of the solvated electron based on its mobility and fluid viscosity. To account for the non-continuum behavior appearing below 1.2 K, the temperature and density dependent Millikan-Cunningham factor is introduced. The hydrodynamic electron bubble radii predicted by the present model appear generally larger than the solvation cavity interface barycenter values obtained from density functional theory (DFT) calculations. Based on the classical Stokes law, this difference can arise from the variation of viscosity and flow characteristics around the electron. The calculated DFT liquid density profiles show distinct oscillations at the vacuum/liquid interface, which increase the interface rigidity. PMID- 28585633 TI - Can time-dependent density functional theory predict intersystem crossing in organic chromophores? A case study on benzo(bis)-X-diazole based donor-acceptor donor type molecules. AB - Here we utilized new diagnostic tools in time-dependent density functional theory to explain the trend of intersystem crossing in benzo(bis)-X-diazole based donor acceptor-donor type molecules. These molecules display a wide range of fluorescence quantum yields and triplet yields, making them excellent candidates for testing the validity of these diagnostic tools. We believe that these tools are cost-effective and can be applied to structurally similar organic chromophores to predict/explain the trends of intersystem crossing, and thus fluorescence quantum yields and triplet yields without the use of complex and expensive multireference configuration interaction or multireference pertubation theory methods. PMID- 28585634 TI - Dual external field-responsive polyaniline-coated magnetite/silica nanoparticles for smart fluid applications. AB - In this communication, an electromagnetorheological fluid containing Fe3O4/SiO2/PANI nanoparticles is reported to demonstrate its controllable rheological properties under electric and magnetic fields. The EMR performance was significantly enhanced under the dual fields in the parallel direction. PMID- 28585637 TI - Post-digestion stabilization of osmium enables quantification by ICP-MS in cell culture and tissue. AB - An orally active osmium anticancer compound was reliably quantified in the organs of treated mice by inductively coupled plasma-mass spectrometry (ICP-MS) by adding a stabilizing solution consisting of ascorbic acid, thiourea and EDTA during sample preparation and avoiding oxidizing conditions. The limits of detection (LOD) and quantification (LOQ) of 189Os were determined in liver tissue to be 0.02 and 0.075 MUg kg-1, respectively. In spiked liver tissue, the internal precision showed a relative standard deviation (RSD) of 4%, a matrix recovery of 92% and a digestion recovery of 99%. A similar quantification protocol was developed for cellular accumulation studies in vitro. The cells were lysed with a non-oxidizing lysis buffer consisting of 150 mmol L-1 NaCl, 1.0% Triton X-100, 0.1% SDS, and 50 mmol L-1 Tris at pH 8.0 before adding the stabilizing solution. The osmium compound was compared with an isosteric ruthenium analogue and they displayed similar cellular accumulation and organ distribution profiles. PMID- 28585639 TI - Hyperpolarized 133Cs is a sensitive probe for real-time monitoring of biophysical environments. AB - 133Cs NMR is a valuable tool for non-invasive analysis of biological systems, where chemical shift and relaxation properties report on changes in the physical environment. Hyperpolarization can increase the liquid-state 133Cs NMR signal by several orders of magnitude and allow real-time monitoring of physical changes in cell based systems. PMID- 28585640 TI - Naphtho[b]-fused BODIPYs: one pot Suzuki-Miyaura-Knoevenagel synthesis and photophysical properties. AB - Naphtho[b]-fused BODIPYs have been facilely synthesized via Suzuki-Miyaura Knoevenagel reaction between mono-iodo-BODIPY or 2,6-diiodo-BODIPY with (2 formylphenyl)boronic acid. This one-pot reaction represents a very straightforward approach for tuning the absorption and emission of BODIPYs in the red visible/NIR range. PMID- 28585641 TI - A facile strategy for the fast construction of porous graphene frameworks and their enhanced electrosorption performance. AB - Porous graphene frameworks were originally and rapidly constructed via a facile photochemical strategy, and feature 3D interconnected porous structures, highly graphitic shells comprised of three-six graphene layers, high available surface area, tunable pore size and superior electrical conductivity. They achieved an enhanced electrosorption capacity and excellent regeneration performance for removal of NaCl from saltwater. PMID- 28585642 TI - Aromatic and antiaromatic spherical structures: use of long-range magnetic behavior as an aromatic indicator for bare icosahedral [Al@Al12]- and [Si12]2- clusters. AB - The long-range characteristics of the induced magnetic field in the bare icosahedral [Al@Al12]- and [Si12]2- clusters reveal inherent characteristics for spherical aromatic and antiaromatic systems. Here, we extend the shielding cone property to these highly symmetrical inorganic examples to achieve a suitable indicator for aromaticity as a reliable method for evaluating the aromaticity of clusters containing interstitial atoms. PMID- 28585644 TI - Current-voltage characteristics influenced by the nanochannel diameter and surface charge density in a fluidic field-effect-transistor. AB - The nanochannel diameter and surface charge density have a significant impact on current-voltage characteristics in a nanofluidic transistor. We have simulated the effect of the channel diameter and surface charge density on current-voltage characteristics of a fluidic nanochannel with positive surface charge on its walls and a gate electrode on its surface. Anion depletion/enrichment leads to a decrease/increase in ion current with gate potential. The ion current tends to increase linearly with gate potential for narrow channels at high surface charge densities and narrow channels are more effective to control the ion current at high surface charge densities. The current-voltage characteristics are highly nonlinear for wide channels at low surface charge densities and they show different regions of current change with gate potential. The ion current decreases with gate potential after attaining a peak value for wide channels at low values of surface charge densities. At low surface charge densities, the ion current can be controlled by a narrow range of gate potentials for wide channels. The current change with source drain voltage shows ohmic, limiting and overlimiting regions. PMID- 28585647 TI - Extra electronic outer-shell peculiarities accessible under a joint XPS and DFT study. AB - Electronic configuration of chemically bound atoms at the surface, including adsorbed species, or in the bulk of a solid contains a set of natural traps for energy absorption provided by valence band transitions or plasmon oscillations. The core level excitation of any origin is generally coupled with those traps, forming a multichannel route for nonradiative energy dissipation. Using an example of Pt and graphite-based materials, the study shows experimental tracing over these channels by means of elastic electron scattering and X-ray photoelectron spectroscopy. As a complement to the experimental data, calculations of the density of states provide information on chemical behavior and local geometry of the atoms in a sample. PMID- 28585649 TI - A polymer and graphene layer to increase dye regeneration and suppress back electron transfer in dye sensitized solar cells. AB - Dye regeneration was improved by using an optimum quantity of graphene, which was dispersed in a polymer that suppresses back electron transfer. Using this approach, DSSCs with an efficiency of 10.4% have been fabricated. PMID- 28585648 TI - The controlled synthesis of pillar[6]arene-based hexagonal cylindrical structures on an electrode surface via electrochemical oxidation. AB - Electrochemical oxidation of pillar[6]arene containing six hydroquinones resulted in the formation of hexagonal cylindrical structures on an electrode surface driven by charge transfer interaction. The electrochemical approach successfully controlled the size and shape of the structures. PMID- 28585650 TI - Targeted cancer imaging and photothermal therapy via monosaccharide-imprinted gold nanorods. AB - Plasmonic nanomaterials have been widely used for photothermal therapy (PTT) of cancer, but their recognition specificity remains challenging. We prepared monosaccharide-imprinted gold nanorods (AuNRs) for targeted cancer PTT, using sialic acid (SA) as a representative monosaccharide. The SA-imprinted AuNRs exhibited good specificity, enabling the killing of cancer cells without damaging healthy cells. PMID- 28585651 TI - Lewis acid catalyzed cascade annulation of alkynols with alpha-ketoesters: a facile access to gamma-spiroketal-gamma-lactones. AB - A novel Lewis acid catalyzed intermolecular cascade annulation of alkynols with alpha-ketoesters has been developed. This simple and efficient cascade annulation proceeds through a 5-exo-dig cyclization of alkynols followed by annulation with alpha-ketoester to provide a wide variety of unsaturated gamma-spiroketal-gamma lactones (1,6-dioxaspiro[4.4]non-3-en-2-ones) related to many natural products. PMID- 28585652 TI - A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets. AB - We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 MUL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD. PMID- 28585653 TI - Chemically tunable photoresponse of ultrathin polypyrrole. AB - Building a complex structure system of conductive polymers without a complicated fabricating process is a long-awaited goal to improving the functional photoresponse properties of conductive polymers. In this study, we demonstrate that the photoresponse of polypyrrole (PPy)-based photodetector devices with an ultrathin polymer layer can be chemically modulated by simply immersing the devices into an alkaline solution. After alkaline treatment, the pyrrole unit transforms into a quinoid structure. Characteristics of current-voltage reveal an increased photosensitivity with several orders of magnitude when decreasing the applied bias voltage. Furthermore, ultrathin PPy belts with a width of 100 nm exhibit ultra-high photosensitivites of roughly 1000 (unit) and photoresponsivities of 54.3 A W-1 due to the high surface area ratio of the nanobelts. PMID- 28585654 TI - Correction: An updated roadmap for the integration of metal-organic frameworks with electronic devices and chemical sensors. AB - Correction for 'An updated roadmap for the integration of metal-organic frameworks with electronic devices and chemical sensors' by Ivo Stassen et al., Chem. Soc. Rev., 2017, DOI: 10.1039/c7cs00122c. PMID- 28585655 TI - Growth of low doped monolayer graphene on SiC(0001) via sublimation at low argon pressure. AB - Silicon carbide (SiC) sublimation is the most promising option to achieve transfer-free graphene at the wafer-scale. We investigated the initial growth stages from the buffer layer to monolayer graphene on SiC(0001) as a function of annealing temperature at low argon pressure (10 mbar). A buffer layer, fully covering the SiC substrate, forms when the substrate is annealed at 1600 degrees C. Graphene formation starts from the step edges of the SiC substrate at higher temperature (1700 degrees C). The spatial homogeneity of the monolayer graphene was observed at 1750 degrees C, as characterized by Raman spectroscopy and magneto-transport. Raman spectroscopy mapping indicated an AG-graphene/AG-HOPG ratio of around 3.3%, which is very close to the experimental value reported for a graphene monolayer. Transport measurements from room temperature down to 1.7 K indicated slightly p-doped samples (p ? 1010 cm-2) and confirmed both continuity and thickness of the monolayer graphene film. Successive growth processes have confirmed the reproducibility and homogeneity of these monolayer films. PMID- 28585656 TI - Polydopamine nanocoated whole-cell asymmetric biocatalysts. AB - Our whole-cell biocatalyst with a polydopamine nanocoating shows high catalytic activity (5 times better productivity than the native cell) and reusability (84% of the initial yield after 5 batches, 8 times higher than the native cell) in asymmetric reduction. It also integrates with titania, silica, and magnetic nanoparticles for multi-functionalization. PMID- 28585657 TI - A rare case of monozygotic iniodymic diprosopiasis in a German Holstein calf. AB - Craniofacial duplication abnormity is a rare phenomenon in buiatric practice. This report attends to a male German Holstein calf which could be classified as a diprosopic iniodymus. A fetus exhibiting a doubled face was delivered after fetotomy. To our knowledge, this is the first description of diprosopiasis with two cranial cavities as well as two separate encephala in a calf showing the potential extent of duplication. Throughout this work also the question is answered of whether this malformation in a bovine species arose from one embryo or rather, there is a dizygotic background by genotyping of tissue samples from both parts of the diprosopus. Regarding etiology, not only hereditary dispositions including among others a failed function of the signaling molecule Sonic hedgehog mediating regulation of craniofacial morphogenesis, but also incompletely separated monozygotic twins are discussed. PMID- 28585659 TI - Errata for "Genetic Testing for Psychopharmacology: Is It Ready for Prime Time?" PMID- 28585660 TI - Becoming a Public Thought Leader in 140 Characters or Less: How Nurses Can Use Social Media as a Platform. PMID- 28585661 TI - Drugs to Treat Bipolar Disorders. PMID- 28585658 TI - [Cystinuria caused by a SLC7A9 missense mutation in Siamese-crossbred littermates in Germany]. AB - Cystinuria is caused by defective proximal renal tubular reabsorption of the amino acids cystine, ornithine, lysine, and arginine (COLA). The low solubility of cystine in mildly acidic urine may lead to the formation of urinary cystine crystals and uroliths. Much progress has been made recently in the diagnosis and understanding of cystinuria in companion animals. In cats, cystinuria affects equally both genders independent of neutering status and, despite being rare, already more cystinuria-causing mutations have been detected in cats compared to dogs. In this study a litter of Siamese-crossbred cats in Germany was assessed clinically for cystinuria and screened for mutations known to cause cystinuria in cats. An adult male castrated cat was presented with cystine crystalluria and calculi-related urinary obstruction and treated with perineal urethrostomy, cystotomy, and medical management. This cat and a neutered male littermate without evidence of urinary tract disease were found to be positive for cystine by urinary nitroprusside test, to have increased urinary COLA values and to be homozygous for the p.Val294Glu mutation in the SLC7A9 gene coding for b0,+AT subunit of the b0,+ renal COLA transporter. Another littermate was non-cystinuric and did not carry this mutation. The same SLC7A9 mutation was previously found in a Maine coon, a Sphinx and a medium-haired cat in North America suggesting a common ancestor and likely first widespread SLC7A9 mutation causing cystinuria in cats. Genetic screening for this mutation may offer a simple and precise mean to diagnose other cats for cystinuria and offer specific management. PMID- 28585662 TI - Medication Safety: What Nurses Should Know About Black Box Warnings. AB - "Safety first" has always been a nursing priority-just as medication education has been an essential nursing function. Approximately 79 million individuals of all ages, birth-to-death, were prescribed psychotropic medications in 2013. Nurses of all disciplines and who work in all practice settings must be aware of the potential safety concerns related to medications patients may be taking. Black Box Warnings (BBWs) are the strictest labeling requirements that the U.S. Food and Drug Administration can mandate. Risks of increased suicidality, mortality in older adults, potential for abuse and drug dependence, and life threatening hepatic failure are among the most significant BBWs attributed to psychotropic medications. As such, nurses must be aware of not only how medications will benefit patients in relieving symptoms of or preventing their disease but also the potential risks, adverse reactions, and BBWs. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 11-15.]. PMID- 28585663 TI - A Primer on Heroin and Fentanyl. AB - Heroin and fentanyl use have reached epidemic proportions in the United States and are now blamed for the majority of drug-related overdose deaths. Both drugs are produced primarily in South America and Asia and enter the United States illegally. One result of smoking or injecting heroin or fentanyl is the development of a substance use disorder (SUD), which causes changes in brain chemistry and function. These changes result in negative behaviors and an inability to stop use. Yet, treatments are available and recovery is possible. Nurses have the potential to impact the heroin and fentanyl epidemic through developing therapeutic relationships with patients who are at risk or already have a SUD. Strategies for effective communication include maintaining a supportive, nonjudgmental attitude and incorporating motivational interviewing. All patients should be screened for opioid use and referred for treatment if indicated. It is important for nurses to be knowledgeable about heroin and fentanyl and available treatments. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 16-20.]. PMID- 28585664 TI - Identification and Treatment of Adolescents With Perinatal Anxiety and Depression. AB - Perinatal mood and anxiety disorders (PMAD) are the most common, yet under diagnosed and undertreated complication of pregnancy, affecting up to 50% of pregnant and parenting teens. PMAD are a global health issue that can have devastating effects on the mental, physical, emotional, developmental health, and social life of the mother, infant, and family. Adolescents present with similar symptoms of PMAD as their adult counterparts, but also experience isolation from their peer group and lack of resources and coping strategies, as well as difficulty sleeping and lack of concentration and ability to focus. Nurses and nurse practitioners are in an ideal position to assess preexisting risk factors for PMAD. The current applied evidence-based article addresses the diagnosis of PMAD, provides a conceptual framework for understanding the intra- and interpersonal dynamics affecting teens with PMAD, and suggests a new screening tool to guide diagnosis. An easy to recall mnemonic for diagnosis and referral (SAIL AHEAD) is proposed. By using the SAIL AHEAD mnemonic, providers will impact adolescents' parenting success and resiliency, thereby enhancing their future success in life. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 23-29.]. PMID- 28585665 TI - Perceived Stress in Family Caregivers of Individuals With Mental Illness. AB - The current study aimed to measure the stress levels of family caregivers of individuals with mental illness and compare their stress levels according to the diagnosis and other sociodemographic characteristics. The sample comprised 310 family caregivers of individuals with mental illness in Jordan. Family caregivers completed a demographic checklist and the Arabic version of the Perceived Stress Scale 10-Item (PSS-10) questionnaire. A significant difference was found in PSS 10 levels among family caregivers according to gender, diagnosis of their family member, and time since diagnosis. Female caregivers reported significantly higher stress levels than male caregivers. Family members of individuals with schizophrenia reported the highest stress levels (p < 0.001). Results also indicated that there was a significant negative correlation between PSS-10 levels of family caregivers and time since diagnosis. Investigating stress levels in family members of individuals with mental illness may be helpful when designing interventions to reduce such stress. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 30-35.]. PMID- 28585666 TI - Public Stigma Toward Mental Illness in Jordan: A Cross-Sectional Survey of Family Members of Individuals With Schizophrenia, Depression, and Anxiety. AB - Stigma affects family members of individuals with mental illness. A survey of 640 family members of individuals with mental illness was conducted. Three factors were found to influence stigma regarding schizophrenia, depression, and anxiety: (a) preconceived stereotypes, (b) a sense of personal responsibility or blame for the condition, and (c) perceptions of the patient's inability to recover from the condition. A stronger association between negative stereotypes and inability to recover was found with schizophrenia than depression or anxiety. Conversely, depression and anxiety were found to be correlated with personal responsibility or blame for the condition. The public perception of mental health conditions (e.g., depression, anxiety, schizophrenia) has a crucial role in deriving programs for reducing stigma and raising awareness. Personalized and efficacious treatment regimens may be facilitated by understanding these perceptions and the underlying explanations for why they exist. [Journal of Psychosocial Nursing and Mental Health Services, 55(6), 36-43.]. PMID- 28585668 TI - "English Garden" by Gustave Alhadeff. PMID- 28585669 TI - Effectiveness of Traumatic Brain Injury Management Guideline Introduction in Hungary. AB - AIM: To describe the impact of the Traumatic Brain Injury management guideline introduction in Hungary. MATERIAL AND METHODS: Hospital discharge records (HDR) including age, gender, codes of interventions applied, ICD codes of diagnosed disorders of patients admitted between 01/01/2004 and 31/12/2010 with the diagnosis of intracranial injury (S06 by ICD10) from every inpatient institution in Hungary were collected from the database of National Health Insurance Fund (NHIF). The Case Fatality Ratios (CFR) for one week, one month and six months were calculated for the periods before and after the guideline introduction. The change of CFRs was applied as indicators for change of clinical quality elicited by the guideline. RESULTS: The centers together at one week, one month and six months had pre-guideline introduction CFRs of 23.4%, 37.7% and 47.5% and post guideline introduction CFRs of 22.1%, 39.1%, and 50.0% respectively. The secondary institutions together at one week, one month and six months had pre guideline introduction CFRs of 21.5%, 34.8% and 46.3% and post-guideline introduction CFRs of 21.9%, 37.0%, and 48.9% respectively. None of the CFRs showed significant change. CONCLUSION: The effectiveness of TBI management guideline adaptation in Hungary is poor. Without supportive financing and external auditing system, guideline introduction alone cannot achieve standard clinical practice and a reduction in CFR. PMID- 28585670 TI - Association of two primitive carotid-basilar anastomoses and cerebrovascular abnormalities on the brain base: a case report. AB - Simultaneous presence of the persistent primitive trigeminal artery and so-called intermediate communicating artery in a 77-years-old cadaver autopsied due to the myocardial infarction was discovered. Many vascular variants and abnormalities such as an aplasia of the right vertebral artery (VA), a presence of two right posterior cerebral arteries (PCAs), partial duplication of the right superior cerebellar artery, hypoplasia of the pre-communicating part (A1) of the right anterior cerebral artery and the right PCA of basilar origin, a special configuration of the anterior communicating artery (ACoA), and a small aneurysm at the right A1-ACoA junction were associated. The finding of an incipient cerebral aneurysm at the junction of the hypoplastic A1 and embryonal configuration of the ACoA in eight decade of life indicates that its development was caused by long-term pressure of blood flow at branching points of this artery independent from its caliber. However, it is not yet clear whether the persistence of the first and/or the second carotid-basilar anastomoses in this case was the condition for an aplasia of one VA or vice versa. PMID- 28585671 TI - Effects of Intrathecal Caffeic Acid Phenethyl Ester (CAPE) on IL-6 and TNF-alpha Levels and Local Inflammatory Responses in Spinal Cord Injuries. AB - AIM: To investigate the effects of intrathecal caffeic acid phenethyl ester (CAPE) on tissue and serum IL-6 and TNF-alpha levels following spinal cord injury (SCI) as well as its effects on edema and microhemorrage. MATERIAL AND METHODS: Forty rats were divided into four groups. The sham group underwent single-level laminectomy and then received an intrathecal injection of isotonic saline. The control group received an intrathecal injection of isotonic saline following SCI induction. The methylprednisolone (MP) group received a single dose of MP intrathecally following SCI. The CAPE group received a single dose of CAPE intrathecally following SCI. IL-6 and TNF-alpha levels were determined using the ELISA method. Spinal cord samples were evaluated histopathologically. RESULTS: The decrease in IL-6 levels in the CAPE group was significantly higher than that in the sham and control groups. However, this decrease wasn't as significant as that in the MP group. No significant decrease was identified in TNF-alpha levels. A significant decrease was observed in spinal cord edema and microhemorrage in the CAPE group. A decrease in edema was observed in the MP group, but no effect was observed on microhemorrage. CONCLUSION: Intrathecal CAPE administration following SCI decreases tissue and serum IL-6 levels as well as decreases spinal cord edema and microhemorrage. PMID- 28585672 TI - A trial for an evaluation of perianeurysmal arterial pressure change during carotid artery stenting in patients with concomitant severe extracranial carotid artery stenosis and ipsilateral intracranial aneurysm. AB - Concomitant occurrence of severe extracranial large vessel stenosis and an ipsilateral intracranial aneurysm is often detected incidentally, but the optimal therapeutic strategy is not clear. Several reports have investigated whether simultaneous carotid artery stenting and coil embolization, or multi-stage therapy is better. These treatment strategies are still controversial because simultaneous therapy will decrease the risk of aneurysm rupture, but may also increase the risk of thromboembolic complications. For multi-stage therapy, the interval between CAS and coil embolization for the ipsilateral intracranial aneurysm remains obscure. We experienced a case of severe extracranial internal carotid artery stenosis, ipsilateral intracranial aneurysm. Multi-stage therapy was chosen, and perianeurysmal arterial pressure did not increase over 100 mmHg after CAS. Subsequent ipsilateral coil embolization was performed 3 weeks later with careful blood pressure control to prevent aneurysmal rupture and with the expectation of stable neointimal formation over the stent strut to prevent thrombotic complications during coil embolization. All procedures were performed without any complications. We suggest that evaluation of perianeurysmal arterial pressure may be helpful for selecting a treatment strategy in patients with multiple ipsilateral lesions to prevent thromboembolic and hemorrhagic complications. PMID- 28585673 TI - Can Hypo/Hypernatremic Conditions be a Factor for Na Ion Channel Kinetics: Model Study. AB - AIM: Dysnatremic cases are frequently faced in clinical practice. Its macroscopic effects and consequences are well known, but microscopic effects are not well defined. The aim of this study was to reveal the effects of dysnatremia at the cellular level. MATERIAL AND METHODS: By using an action potential simulation, the effects of extracellular sodium (Na) concentration on the Na ion channel kinetics were studied. The experimental sets were chosen to mimic hypo/hypernatremic conditions and, in both cases, the degree of the severity was varied. RESULTS: Hyponatremic situations through modifying the axonal Na+ channels kinetics result in the rundown of the sodium current (INa). The degree of the hyponatremia-dependent effect seen in the Na ion channel is severity dependent, which is more effective in the recovery phase of the ion channel. Hypernatremic conditions, on the other hand, have also affected the Na ion channel activity through modifying the kinetics of the channel. Unlike hyponatremia, the effect seen in hypernatremic conditions was through decreasing the response time of the channel. The degree of the significance of the effect seen on the Na ion channel in the case of the hypernatremia was found to be less destructive compared to the hyponatremic condition. CONCLUSION: The Na channels are susceptible to the changes of the extracellular Na concentrations. Thus, the underestimation of hypo/hypernatremic conditions can put patients in danger and close monitoring of serum Na level might be required. PMID- 28585674 TI - Real-time Video-Streaming to Surgical Loupe Mounted Head-Up Display for Navigated Meningioma Resection. AB - AIM: Wearable technology interfaces with normal human movement and function, thereby enabling more efficient and adaptable use.We developed a wearable display system for use with intra-operative neuronavigation for brain tumor surgery. MATERIAL AND METHODS: The Google glass head-up display system was adapted to surgical loupes with a video-streaming integrated hardware and software device for display of the Stealth S7 navigation screen. Phantom trials of surface ventriculostomy were performed. The device was utilized as an alternative display screen during cranial surgery. RESULTS: Image-guided brain tumor resection was accomplished using Google Glass head-up display of Stealth S7 navigation images. Visual display consists of navigation video-streaming over a wireless network. The integrated system developed for video-streaming permits video data display to the operating surgeon without requiring movement of the head away from the operative field. CONCLUSION: Google Glass head-up display can be used for intra operative neuronavigation in the setting of intracranial tumor resection. PMID- 28585675 TI - A Modified Jaslow-Transforaminal Lumbar Interbody Fusion for the Treatment of Isthmic Spondylolisthesis. AB - AIM: To describe a modified Jaslow-transforaminal lumbar interbody fusion (TLIF) technique for the treatment of single-level, isthmic spondylolisthesis (IS). MATERIAL AND METHODS: Between April 2011 and September 2012, 32 patients with IS undergoing a modified Jaslow-TLIF were retrospectively reviewed. The intervertebral space height (IH), vertebral slippage ratio, lordotic angles of the treated segments (SA) and lumbar lordotic angles (LA) were measured and the scores by Visual Analogue Scale (VAS), Oswestry Disability Index (ODI) and Japanese Orthopaedic Association (JOA) were recorded. RESULTS: An average follow up duration of over 2 years was available. The average slippage percentage was 17.8+/-4.3% preoperatively, 5.3+/-2.4% postoperatively, and 5.4+/-2.5% at the last follow-up. The average IH was 7.7+/-1.9 mm preoperatively, 10.3+/-1.6 mm postoperatively, and 10.2+/-1.5 mm at the final follow-up. The average SA and LA were, respectively, 11.7+/-5.8 degrees and 49.1+/-13.9 degrees preoperatively, 13.5+/-5.7 degrees and 48.3+/-9.4 degrees postoperatively, and 13.2+/-5.3 degrees and 47.7+/-8.8 degrees at the last follow-up. The mean VAS was ameliorated from 7.7+/-0.6 to 2.4+/-0.5, ODI from 49.6+/-1.6% to 10.5+/-1.3%, and JOA from 10.8+/-1.3 to 26.6+/-1.0, at the last follow-up. All patients had clinical and radiographic evidence of solid fusion without any need for revision. CONCLUSION: The modified Jaslow-TLIF technique for the treatment of IS was advantageous for greater safety and efficacy. PMID- 28585676 TI - Evaluation of Apparent Diffusion Coefficients in the Cerebellar Tonsils and Bulbus in Chiari Type I Malformations: Comparison Before and After Surgery. AB - AIM: To evaluate the preoperative and postoperative 6th month mean apparent diffusion coefficient (ADC) values of the cerebellar tonsils and bulbus in patients with Chiari Malformation Type I (CMI), and to compare the results with healthy controls. MATERIAL AND METHODS: We included 15 patients with CMI who underwent suboccipital decompression, upper cervical laminectomy, and duraplasty surgery, and compared them with 10 healthy individuals. Three regions of interest were placed, one each in the cerebellar tonsils and one in the bulbus. The mean ADC values were measured separately in each region. RESULTS: Among the patients, mean ADC values were significantly decreased after surgery compared with before surgery. The mean ADC values before surgery were significantly higher for patients than for controls; however, although mean ADC values were slightly higher after surgery for patients than for controls, the differences were not significant. Thus, after surgical intervention, ADC values in patients with CMI became close to those of normal individuals. CONCLUSION: The increased ADC values in patients with CMI before surgery implied that not only morphologic changes but also increased diffusivity may play a key role in the pathophysiology and clinical presentation of the disease. We conclude that decompression surgery can produce favorable diffusional alterations. PMID- 28585677 TI - Sciatic Nerve Injuries from Gluteal Intramuscular Injection According to Records of the High Health Council. AB - AIM: To analyze the cases discussed at the High Health Council (HHC) and to determine the solutions for problems related to gluteal intramuscular injection (IMI) applications. MATERIAL AND METHODS: In a 10-year period, the cases of IMI related sciatic nerve injury (SNI) referred for an opinion from the HHC of Turkey were reviewed. The cases were analyzed based on demographic features, degree of nerve damage, side of gluteal injection, injected drugs, primary disease, appropriateness of parenteral therapy indications, and management. RESULTS: There were 107 SNIs from gluteal IMI during the 103 months. Eight of the 107 cases were male and 99 female. The mean age was 28 years. The left sciatic nerve was more commonly injured (41 right, 65 left side). SNI was partial in 48.5% of the cases. The most commonly injected drug was diclofenac sodium (29.9%), and 23.3% of cases were injected more than one drug together. Conservative management was performed in all cases, except one. CONCLUSION: Based on our findings, indications of parenteral therapies were exaggerated and nurses injected the drug while the patient"s position was inappropriate for IMI. However, an IMI into the gluteal region is potentially devastating. For those reasons, we conclude that physicians should be restricted in their indications for IMI, and continuous education courses should be organized for nurses. Injured patients should be managed according to their neurological damage. PMID- 28585678 TI - Human sperm motility, capacitation and acrosome reaction are impaired by 2 arachidonoylglycerol endocannabinoid. AB - The endocannabinoids are cannabinoids synthesized by mammalian tissues. These compounds are closely related to the regulation of the male reproductive system. However, little is known about the effects produced by 2-arachidonoylglycerol (2AG) on in vitro human sperm functions. This study was undertaken to determine the effects produced by 2AG on fresh human sperm and in the capacitation technique. Semen samples from healthy young men were exposed to different concentrations of 2AG before and during capacitation technique. In this work, we have demonstrated that 2AG induces the spontaneous acrosome reaction and reduces progressive motility in fresh human sperm. During the capacitation technique, sperm becomes more sensitive to low concentrations of 2AG, triggering the acrosome reaction and inhibiting protein phosphorylation. In summary, 2AG affects the in vitro functionality of human sperm by reducing motility, inhibiting capacitation and triggering the acrosome reaction. PMID- 28585679 TI - Diagnostic value of selected biochemical markers in the detection of recurrence of medullary thyroid cancer - comparison of calcitonin, procalcitonin, chromogranin A, and carcinoembryonic antigen. AB - INTRODUCTION: Medullary thyroid cancer (MTC) is a malignancy of the thyroid gland, which derives from parafollicular C cells. Periodic measurement of biochemical markers of MTC remains a crucial part of patient follow-up and disease monitoring. The aim of the study was to compare the diagnostic value of four selected markers - calcitonin (Ct), procalcitonin (PCT), chromogranin A (CgA), and carcinoembryonic antigen (CEA). MATERIAL AND METHODS: Patients with histopathologically confirmed MTC hospitalised in a single department between January 2015 and December 2015 were included in the study. Patients were subdivided into two groups: a remission group and an active disease group, based upon serum markers of MTC and imaging. Levels of Ct, PCT, CgA, and CEA were compared between the groups. RESULTS: Forty-four patients were included; 20 patients presented active disease and 24 were in remission. All patients with active disease had Ct exceeding the upper limit of normal range (10 pg/mL) - for that threshold the sensitivity was 100.0% and the specificity was 73.9%; for the best-fit threshold of 121.0 pg/mL the specificity was 95.8% with sensitivity 100.0%. There was significant correlation between Ct and PCT - p < 0.000001, r = 0.93. All patients with active disease exceeded the upper limit of the normal range (0.5 ng/mL) - for that threshold the sensitivity was 100.0% and the specificity was 83.3%; for the best-fit threshold of 0.95 ng/mL the specificity was 95.8% with sensitivity 100.0%. In case of CEA for the best-fit threshold of 12.66 ng/mL the specificity was 100.0% with sensitivity 57.9%; for CgA the best fit threshold was 75.66 ng/mL with specificity 83.3% and sensitivity 75.0%. CONCLUSIONS: Our study confirms that PCT can be considered as an equivalent alternative for measurement of calcitonin. On the other hand, it is also worth noting that MTC can be a rare cause of very high levels of PTC not resulting from infectious diseases. The diagnostic value of CEA and chromogranin A is much lower and can be within the normal range even in patients with advanced, metastatic MTC. They should be used only as accessory markers. PMID- 28585680 TI - Thyroid cancer post radioactive iodine treatment for hyperthyroidism - case series and review of the literature. AB - INTRODUCTION: To assess the rate of thyroid cancer and mortality rate in a cohort of patients who received RAI131 treatment for hyperthyroidism and to report the index cases' characteristics and management MATERIAL AND METHODS: A cohort of 264 patients who received RAI131 treatment for different causes of thyrotoxicosis were followed up over a period of 18 years (1996-2014) by physical exam, radiological evaluation and serial thyroid function tests. RESULTS: During the follow up period, three cases of thyroid cancer were identified. The prevalence of thyroid cancer was 1.136% of cases who received RAI131. The relative risk was 378.79 (95% CI: 76.8 < RR < 1868.23). The P value was < 0.0000004 and the SMR is 1.99/1000. CONCLUSIONS: The prevalence of thyroid cancer was 1.136% in the cohort of patients treated with RAI131. Despite the fact that no direct cause-effect relationship between RAI and thyroid cancer could be established, these cases highlights the importance of life-long surveillance of patients who receive RAI131. PMID- 28585681 TI - Glucose metabolism disorders in patients with non-functioning adrenal adenomas - single-centre experience. AB - INTRODUCTION: The presence of glucose metabolism disorders and their possible correlation with degree of cortisol secretion were evaluated in patients with non functioning adrenal incidentalomas (NFAIs). MATERIAL AND METHODS: The study group consisted of 131 patients with hormonally inactive adrenal incidentalomas. In each patient, besides hormonal and radiological evaluation, was assessed for fasting glucose and insulin concentrations, and the oral glucose tolerance test (OGTT) was performed in all participants without previous history of glucose disturbances. The HOMA-IR, QUICKI, and TyG indices were calculated. RESULTS: Diabetes was diagnosed in 30.5% of the studied group. Among glucose tolerance abnormalities, impaired fasting glucose (IFG) was found in 23.7%, impaired glucose tolerance (IGT) in 4.6%, and combined IFG and IGT in 11.5%. Normoglycaemia was recognised in 29.8% of NFAIs patients. The occurrence rate of glucose aberrations increased with age. There was a significant difference in all insulin resistance indices shown between normoglycaemic patients and those with impairments in glucose tolerance. There was no significant correlation between fasting glucose, insulin resistance indices, and adrenal tumour size or degree of cortisol secretion. CONCLUSIONS: The prevalence of diabetes and impaired fasting glucose among NFAIs patients is much higher than in the general population. Therefore, patients with incidentally discovered adrenal tumours should be tested for glucose tolerance. PMID- 28585683 TI - The age of developing diabetes and FTO polymorphisms (rs9939609, rs1421085, and rs9930506). AB - INTRODUCTION: Type 2 diabetes (T2DM) is a common complex metabolic disorder that has a strong genetic predisposition. Fat mass and obesity-associated protein (FTO) is one of the genes of interest to us. Hypomethylation of a CpG site in the FTO gene was significantly associated with the risk of T2DM. The aim of the study was to find the answer to the question of whether the polymorphism changes of the FTO gene in the pathogenesis of type 2 diabetes are comparable in young, middle aged, and elderly people. MATERIAL AND METHODS: The study involved 282 consecutive patients with type 2 diabetes, who attended a primary healthcare clinic in Southern Poland. The study subjects were divided into three groups according to the age at which type 2 diabetes mellitus was diagnosed (> 40 years old, 40-60 years old, and > 60 years old). The genotyping of rs9939609, rs1421085, and rs9930506 FTO polymorphisms was conducted using TaqManPre-designed SNP Genotyping Assay. RESULTS: No statistically significant difference was shown between the examined FTO polymorphism (rs9939609, rs1421085, and rs9930506) distribution between the subjects diagnosed with diabetes < 40 years , 40-60 years, and > 60 years old. CONCLUSIONS: There were no statistically significant relationships between the different analysed anthropometric and other parameters and distribution of examined FTO polymorphisms (rs9939609 , rs1421085, and rs9930506). The age of diabetes was not affect by the tested FTO polymorphisms (rs9939609 , rs1421085, and rs9930506). PMID- 28585684 TI - Novel multipolar mapping system identifying coexistence of multiple conduction patterns in persistent AF: A case report. PMID- 28585682 TI - The usefulness of laparoscopic adrenalectomy in the treatment of adrenal neoplasms - a single-centre experience. AB - INTRODUCTION: Adrenal neoplasms comprise about 10% of all tumours affecting this organ and constitute a significant, at first diagnostic and subsequently therapeutic, problem, especially since a relatively high proportion of neoplastic lesions are asymptomatic. The number of diagnosed metastases to adrenal glands is increasing. Surgical treatment involves both open surgery as well as laparoscopy. MATERIAL AND METHODS: There were 245 adrenalectomies performed at our centre due to various indications over the past four years. In 27 (11.5%) cases neoplasms were diagnosed in the final histopahtological examination. In 11 (40.7%) cases primary adrenal cortex tumours were diagnosed, metastases from other solid organ tumours were identified in another 12 (44.4%) patients, and rarer neoplasms were diagnosed in the remaning 4 (14.8%) subjects. Cases of malignant pheochromocytoma were not included in this report. RESULTS: Laparoscopic adrenalectomy was performed in 23 (85.2%) subjects, while the ramaining 4 (12.9%) patients were subject to open adrenalectomy (conversion to open procedure in one case). There were no deaths or significant complications in the perioperative period. Comparing mean duration of open (140 minutes) and laparoscopic (190 minutes) procedures yielded a statistically significant difference (p = 0.02). There was no statistically significant difference found in the duration of operation with regard to laparoscopic adrenalectomies of tumours less than 50 mm and over 55 mm in diameter (p = 0.16). CONCLUSIONS: Laparoscopic adrenalectomy is a safe and effective method of treatment of adrenal tumours. Its oncological completeness is comparable (to open surgery) when performed by experienced surgical teams. Laparoscopy is the reason for the smooth postoperative course observed in most patients. PMID- 28585685 TI - Pulmonary artery: A pivotal site for catheter ablation in idiopathic RVOT ventricular arrhythmias. AB - In patients without associated myocardial diseases, characterized by left bundle branch block and inferior axis morphologies, repetitive idiopathic right ventricular tachycardias and ventricular premature contractions typically arise from right ventricular outflow tract (RVOT). Accumulated evidences have shown that radiofrequency catheter ablation is a useful treatment for patients with RVOT ventricular arrhythmias (VAs). Interestingly, several medical centers have shown that pulmonary artery (PA) is a potential novel site for catheter ablation in RVOT-like VAs, particularly in patients where termination of RVOT VAs at the usual site fails. In this review, we comprehensively demonstrated that RVOT VAs were successfully terminated at the site of PA, analyzed the characteristics of surface electrocardiogram and endocardial potentials, and explored the underlying mechanisms for these cases. PMID- 28585686 TI - Neutralization of Lipopolysaccharide by Heat Shock Protein in Pediococcus pentosaceus AK-23. AB - About 1000 species of bacteria are present in the human intestine. Some Gram negative bacteria such as Escherichia coli or Salmonella spp. among intestinal bacteria have lipopolysaccharide (LPS), which might induce inflammation of human intestines. Actually, LPS, especially its lipid A constituent, is toxic. Small amounts of LPS in bacteria cause inflammation of mucosa and other tissues in humans. Such bacteria may be regulated by beneficial lactic acid bacteria to maintain human health. Many lactic acid bacteria show cancer prevention activity and anti-inflammatory activity in intestines. Recently, Pediococcus pentosaceus AK-23 was isolated from fermentative vegetable pickles for neutralization of LPS. For this study, a protein for LPS neutralization was purified partly from P. pentosaceus AK-23. For this study, a protein for LPS neutralization was purified partly from P. pentosaceus AK-23, by ultrafiltration using a 300 kDa membrane and a 100 kDa membrane after cell wall digestion by lysozyme. Gel running blue native electrophoresis revealed the existence of a 217 kDa protein. The band of the protein having the ability to bind LPS on the gel was analyzed for amino acid homology. As the result, it is revealed as part of a subunit of heat shock protein (HSP). Furthermore, it displayed LPS binding or hydrophobic motifs. The protein neutralized LPS to release fatty acid as myristic acid and glucose from polysaccharide. These findings suggest that HSP in P. pentosaceus AK-23 neutralizes LPS to decompose it compising fatty acid and polysaccharide. PMID- 28585687 TI - Analytical Fingerprint of Wolframite Ore Concentrates. AB - Ongoing violent conflicts in Central Africa are fueled by illegal mining and trading of tantalum, tin, and tungsten ores. The credibility of document-based traceability systems can be improved by an analytical fingerprint applied as an independent method to confirm or doubt the documented origin of ore minerals. Wolframite (Fe,Mn)WO4 is the most important ore mineral for tungsten and is subject to artisanal mining in Central Africa. Element concentrations of wolframite grains analyzed by laser ablation-inductively coupled plasma-mass spectrometry are used to establish the analytical fingerprint. The data from ore concentrate samples are multivariate, not normal or log-normal distributed. The samples cannot be regarded as representative aliquots of a population. Based on the Kolmogorov-Smirnov distance, a measure of similarity between a sample in question and reference samples from a database is determined. A decision criterion is deduced to recognize samples which do not originate from the declared mine site. PMID- 28585688 TI - Preliminary Study on Determining the Sequence of Intersecting Lines by Fluorescence Technique. AB - The determination of the sequence of intersecting lines is an important part of questioned document examinations. A fluorescence technique was used to determine the sequence of heterogeneous intersecting lines produced using inkpad ink, stamp pad ink, ballpoint pens, gel pens, fountain pens, colorants of carbon paper, photocopiers, laser printers, and inkjet printers. A SteREO Discovery.V20 equipped with the ZEN Blue Lite software was chosen to perform the tests.As the results obtained from the study were positive under most conditions, the fluorescence technique was found to be very successful in determining the sequence of intersecting lines from ballpoint pen, gel pen, fountain pen, photocopier, laser and inkjet printers, and inkpad inks. The method was also successful in determining the sequence of intersecting lines from ballpoint pen, photocopier, laser printer, and stamp-pad inks under most conditions. The technique was not successful in determining the order of crossing lines blending together. PMID- 28585689 TI - Fibroblasts take the centre stage in human skeletal muscle regeneration. PMID- 28585690 TI - Satisfying America's Fruit Gap: Summary of an Expert Roundtable on the Role of 100% Fruit Juice. AB - The 2015 to 2020 Dietary Guidelines for Americans (DGAs) recognize the role of 100% fruit juice in health and in helping people meet daily fruit recommendations and state that 100% fruit juice is a nutrient-dense beverage that should be a primary choice, along with water and low-fat/fat-free milk. The DGAs note that children are consuming 100% fruit juice within recommendations (that is, 120 to 180 mL/d for children aged 1 to 6 y and 236 to 355 mL/d for children aged 7 to 18 y). Evidence shows that compared to nonconsumers, those who consume 100% fruit juice come closer to meeting daily fruit needs and have better diet quality. In children, 100% fruit juice is associated with increased intakes of nutrients such as vitamin C, folate, and potassium. When consumed within the DGA recommendations, 100% fruit juice is not associated with overweight/obesity or childhood dental caries and does not compromise fiber intake. Preliminary data suggest that polyphenols in some 100% fruit juices may inhibit absorption of naturally occurring sugars. Given its role in promoting health and in helping people meet fruit needs, experts participating in a roundtable discussion agreed that there is no science-based reason to restrict access to 100% fruit juice in public health nutrition policy and programs such as the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC). Reducing or eliminating 100% fruit juice could lead to unintended consequences such as reduced daily fruit intake and increased consumption of less nutritious beverages (for example, sugar-sweetened beverages). PMID- 28585691 TI - Facial Age Synthesis Using Sparse Partial Least Squares (The Case of Ben Needham). AB - Automatic facial age progression (AFAP) has been an active area of research in recent years. This is due to its numerous applications which include searching for missing. This study presents a new method of AFAP. Here, we use an active appearance model (AAM) to extract facial features from available images. An aging function is then modelled using sparse partial least squares regression (sPLS). Thereafter, the aging function is used to render new faces at different ages. To test the accuracy of our algorithm, extensive evaluation is conducted using a database of 500 face images with known ages. Furthermore, the algorithm is used to progress Ben Needham's facial image that was taken when he was 21 months old to the ages of 6, 14, and 22 years. The algorithm presented in this study could potentially be used to enhance the search for missing people worldwide. PMID- 28585692 TI - OsGCD1 is essential for rice fertility and required for embryo dorsal-ventral pattern formation and endosperm development. AB - Rice fertility is critical for rice reproduction and is thus a focus of interest. Most studies have addressed male sterility and its relation to rice production. The mechanisms of regulation of embryogenesis and endosperm development are essential for rice reproduction, but remain largely unknown. Here, we report a functional analysis of the rice gene OsGCD1, which encodes a highly conserved homolog of Arabidopsis GCD1 (GAMETE CELLS DEFECTIVE1). OsGCD1 mutants were generated using the CRISPR/Cas9 system and subjected to functional analysis. The homozygote mutants cannot be obtained, whereas heterozygotes showed altered phenotypes. In the majority of aborted seeds, the endosperm nucleus divided a limited number of times. The free nuclei were distributed only at the micropylar end of embryo sacs, and their oriented positioning was blocked. In addition, aleurone differentiation was interrupted. The embryo developed slowly, and pattern formation, particularly the dorsal-ventral pattern and symmetry establishment, of embryos was disturbed. Thus, the embryos showed various morphological and structural dysplasias. Our findings reveal that OsGCD1 is essential for rice fertility and is required for dorsal-ventral pattern formation and endosperm free nucleus positioning, suggesting a critical role in sexual reproduction of both monocotyledon and dicotyledon plants. PMID- 28585693 TI - Influences of Soaking Temperature and Storage Conditions on Hardening of Soybeans (Glycine max) and Red Kidney Beans (Phaseolus vulgaris). AB - The influences of soaking treatment and storage conditions on the softening of cooked beans, namely, soybeans and red kidney beans, were investigated. It was revealed that the softening of fresh soybeans and fresh red kidney beans was suppressed during subsequent boiling after soaking treatment at 50 and 60 degrees C. Furthermore, in treated aged soybeans and red kidney beans that were subjected to storage at 30 degrees C/75% relative humidity for 6 mo and soaking treatment at 50 to 60 degrees C, the hardness during cooking was further amplified. This suggested that the mechanism of softening suppression differs depending on the influences of soaking and storage. Analysis of the pectin fraction in alcohol insoluble solid showed insolubilization of metal ions upon storage at high temperature and high humidity in both soybeans and red kidney beans, which suggests interaction between Ca ions and hemicellulose or cellulose as cell wall polysaccharides. The results of differential scanning calorimetry (DSC) showed that aged soybeans exhibited a shift in the thermal transition temperature of glycinin-based protein to a higher temperature compared with fresh soybeans. From the results of DSC and scanning electron microscopy for aged red kidney beans, damaged starch is not conspicuous in the raw state after storage but is abundant upon soaking treatment. As for the influence of soaking at 60 degrees C, it can be suggested that its influence on cell wall crosslinking was large in soybeans and red kidney beans in both a fresh state and an aged state. PMID- 28585694 TI - The Abrams geriatric self-neglect scale: introduction, validation and psychometric properties. AB - OBJECTIVE: Self-neglect is an imprecisely defined entity with multiple clinical expressions and adverse health consequences, especially in the elderly. However, research has been limited by the absence of a measurement instrument that is both inclusive and specific. Our goal was to establish the psychometric properties of a quantitative instrument, the Abrams Geriatric Self-Neglect Scale (AGSS). METHODS: We analyzed data from a 2007 case-control study of 71 cognitively intact community-dwelling older self-neglectors that had used the AGSS. The AGSS was validated against two "gold standards": a categorical definition of self-neglect developed by expert consensus; and the clinical judgment of a geriatric psychiatrist using chart review. Frequencies were examined for the six scale domains by source (Subject, Observer, and Overall Impression). Internal consistency was estimated for each source, and associations among the sources were evaluated. RESULTS: Internal consistency estimates for the AGSS were rated as "good," with the Subject responses having the lowest alpha and omega (0.681 and 0.692) and the Observer responses the highest (0.758 and 0.765). Subject and Observer scores had the lowest association (0.578, p < 0.001). Using expert consensus criteria as the primary "gold standard," the Observer and Overall Impression subscales were "good" at classifying self-neglect, while the Subject subscale was "fair." CONCLUSIONS: The AGSS correctly classified and quantified self-neglect against two "gold standards." Sufficient correlations among multiple sources of information allow investigators and clinicians to choose flexibly from Subject, Observer, or Overall Impression. The lower internal consistency estimates for Subject responses are consistent with self-neglectors' propensity to disavow symptoms. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585695 TI - The RhoGAP Myo9b Promotes Bone Growth by Mediating Osteoblastic Responsiveness to IGF-1. AB - The Ras homolog A (RhoA) subfamily of Rho guanosine triphosphatases (GTPases) regulates actin-based cellular functions in bone such as differentiation, migration, and mechanotransduction. Polymorphisms or genetic ablation of RHOA and some of its regulatory guanine exchange factors (GEFs) have been linked to poor bone health in humans and mice, but the effects of RhoA-specific GTPase activating proteins (GAPs) on bone quality have not yet been identified. Therefore, we examined the consequences of RhoGAP Myo9b gene knockout on bone growth, phenotype, and cellular activity. Male and female mice lacking both alleles demonstrated growth retardation and decreased bone formation rates during early puberty. These mice had smaller, weaker bones by 4 weeks of age, but only female KOs had altered cellular numbers, with fewer osteoblasts and more osteoclasts. By 12 weeks of age, bone quality in KOs worsened. In contrast, 4 week-old heterozygotes demonstrated bone defects that resolved by 12 weeks of age. Throughout, Myo9b ablation affected females more than males. Osteoclast activity appeared unaffected. In primary osteogenic cells, Myo9b was distributed in stress fibers and focal adhesions, and its absence resulted in poor spreading and eventual detachment from culture dishes. Similarly, MC3T3-E1 preosteoblasts with transiently suppressed Myo9b levels spread poorly and contained decreased numbers of focal adhesions. These cells also demonstrated reduced ability to undergo IGF-1-induced spreading or chemotaxis toward IGF-1, though responses to PDGF and BMP-2 were unaffected. IGF-1 receptor (IGF1R) activation was normal in cells with diminished Myo9b levels, but the activated receptor was redistributed from stress fibers and focal adhesions into nuclei, potentially affecting receptor accessibility and gene expression. These results demonstrate that Myo9b regulates a subset of RhoA-activated processes necessary for IGF-1 responsiveness in osteogenic cells, and is critical for normal bone formation in growing mice. (c) 2017 American Society for Bone and Mineral Research. PMID- 28585697 TI - Concerns on "Dissection of Regulatory Elements During Direct Conversion of Somatic Cells Into Neurons" Paper. PMID- 28585696 TI - Occurrence and human dietary assessment of fluoroquinolones antibiotics in cultured fish around tai lake, China. AB - Fluoroquinolone antibiotics are widely used in the production of aquatic products and considered to be a significant contributing factor to the burden of both natural and aquaculture environments. However, the main types of fluoroquinolones present in aquaculture systems have not been determined. The objectives of the present study were to explore the occurrence of residual fluoroquinolone antibiotics in fish muscle tissues sampled from across the entire aquaculture season in the Tai Lake basin in China and to assess the dietary risks associated with the upcoming vendible fish in the last month of the aquaculture season. Fluoroquinolones were detected in 95.69% of all fish samples, and the concentrations ranged from the limit of quantification (LOQ) to 47 108.00 MUg . kg-1 . Enrofloxacin contributed the most among the 9 fluoroquinolone antibiotics tested. Of the 4 fish species studied, enrofloxacin was present in bream at significant (p < 0.05) concentrations in August, with an average value of 321.45 MUg . kg-1 , while enrofloxacin concentrations peaked in crab and shrimp in September, with average values of 6949.60 and 460.82 MUg . kg-1 , respectively. However, different patterns were observed in perch, suggesting that other categories of antibiotics may be used in the production of this fish. Dietary risk assessment showed that the residual levels and estimated daily intake in bream, perch, and shrimp were far below the maximum residual level and acceptable daily intake. However, the average residual level in crab exceeded the maximum residual level, and the estimated daily intake value accounted for 78.49% of the acceptable daily intake, indicating potential consumption risk. In summary, the present study aims to guide the production and consumption of aquatic products. Environ Toxicol Chem 2017;36:2899-2905. (c) 2017 SETAC. PMID- 28585698 TI - Lycopene Protects Keratinocytes Against UVB Radiation-Induced Carcinogenesis via Negative Regulation of FOXO3a Through the mTORC2/AKT Signaling Pathway. AB - Lycopene, one of the most potent anti-oxidants, has been reported to exhibit potent anti-proliferative properties in a wide range of cancer cells through modulation of the cell cycle and apoptosis. Forkhead box O3 (FOXO3a) plays a pivotal role in modulating the expression of genes involved in cell death. Herein, we investigated the role of FOXO3a signaling in the anti-cancer effects of lycopene. Results showed that lycopene pretreatment attenuated UVB-induced cell hyper-proliferation and promoted apoptosis, accompanied by decreased cyclin dependent kinase 2 (CDK2) and CDK4 complex in both human keratinocytes and SKH-1 hairless mice. FOXO3a is phosphorylated in response to UVB irradiation and sequestered in the cytoplasm, while lycopene pretreatment rescued this sensitization. Gene ablation of FOXO3a attenuated lycopene-induced decrease in cell hyper-proliferation, CDK2, and CDK4 complex, indicating a critical role of FOXO3a in the lycopene-induced anti-proliferative effect of keratinocytes during UVB irradiation. Transfection with FOXO3a siRNA inhibited the lycopene-induced increase in cell apoptosis, BAX and cleaved PARP expression. Moreover, loss of AKT induced further accelerated lycopene-induced FOXO3a dephosphorylation, while loss of mechanistic target of rapamycin complex 2 (mTORC2) by transfection with RICTOR siRNA induced levels of AKT phosphorylation comparable to those obtained with lycopene. In contrast, overexpression of AKT or mTORC2 decreased the effects of lycopene on the expression of FOXO3a as well as AKT phosphorylation, suggesting that lycopene depends on the negative modulation of mTORC2/AKT signaling. Taken together, our findings demonstrate that the mTORC2/AKT/FOXO3a axis plays a critical role in the anti-proliferative and pro-apoptotic effects of lycopene in UVB-induced photocarcinogenesis. J. Cell. Biochem. 119: 366-377, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28585699 TI - Impact of ageing on postsynaptic neuronal nicotinic neurotransmission in auditory thalamus. AB - KEY POINTS: Neuronal nicotinic acetylcholine receptors (nAChRs) play a fundamental role in the attentional circuitry throughout the mammalian CNS. In the present study, we report a novel finding that ageing negatively impacts nAChR efficacy in auditory thalamus, and this is probably the result of a loss of nAChR density (Bmax ) and changes in the subunit composition of nAChRs. Our data support the hypothesis that age-related maladaptive changes involving nAChRs within thalamocortical circuits partially underpin the difficulty that elderly adults experience with respect to attending to speech and other salient acoustic signals. ABSTRACT: The flow of auditory information through the medial geniculate body (MGB) is regulated, in part, by cholinergic projections from the pontomesencephalic tegmentum. The functional significance of these projections is not fully established, although they have been strongly implicated in the allocation of auditory attention. Using in vitro slice recordings, we have analysed postsynaptic function and pharmacology of neuronal nicotinic ACh receptors (nAChRs) in young adult and the aged rat MGB. We find that ACh produces significant excitatory postsynaptic actions on young MGB neurons, probably mediated by beta2-containing heteromeric nAChRs. Radioligand binding studies show a significant age-related loss of heteromeric nAChR receptor number, which supports patch clamp data showing an age-related loss in ACh efficacy in evoking postsynaptic responses. Use of the beta2-selective nAChR antagonist, dihydro-beta erythroidine, suggests that loss of cholinergic efficacy may also be the result of an age-related subunit switch from high affinity beta2-containing nAChRs to low affinity beta4-containing nAChRs, in addition to the loss of total nAChR number. This age-related nAChR dysfunction may partially underpin the attentional deficits that contribute to the loss of speech understanding in the elderly. PMID- 28585700 TI - Evaluation of the Treatment Strategies for Medication-Related Osteonecrosis of the Jaws (MRONJ) and the Factors Affecting Treatment Outcome: A Multicenter Retrospective Study with Propensity Score Matching Analysis. AB - Medication-related osteonecrosis of the jaw (MRONJ) is an adverse event that may inhibit the treatment of primary disease and remarkably influence the patient's quality of life. The treatment methods for MRONJ, nonsurgical and surgical, are controversial, with no agreement as to which method provides the best outcome and should therefore be recommended. This multicenter retrospective study aimed to investigate the treatment methods and outcome in a large number of patients with MRONJ in Japan, utilizing propensity score matching analysis. A total of 361 patients with MRONJ, at eight hospitals, were registered in this study retrospectively. Various demographic and treatment-related variables were examined and analyzed to determine their correlation with the treatment outcome. After propensity score matching for treatment methods (nonsurgical versus surgical treatment), 176 patients were analyzed by logistic regression. It was shown that those with low-dose administration of an antiresorptive agent and surgical treatment had better outcomes. Furthermore, in 159 patients who underwent surgical treatment, those who underwent extensive surgery experienced significantly better treatment outcomes than those who underwent conservative surgery. This is the first study to compare treatment methods for MRONJ using propensity score matching analysis. The results indicated that extensive surgical treatment should be performed as first-choice therapy for patients with MRONJ. (c) 2017 American Society for Bone and Mineral Research. PMID- 28585701 TI - Giant primary pleomorphic dermal liposarcoma. PMID- 28585702 TI - Consistent Belief in a Good True Self in Misanthropes and Three Interdependent Cultures. AB - People sometimes explain behavior by appealing to an essentialist concept of the self, often referred to as the true self. Existing studies suggest that people tend to believe that the true self is morally virtuous; that is deep inside, every person is motivated to behave in morally good ways. Is this belief particular to individuals with optimistic beliefs or people from Western cultures, or does it reflect a widely held cognitive bias in how people understand the self? To address this question, we tested the good true self theory against two potential boundary conditions that are known to elicit different beliefs about the self as a whole. Study 1 tested whether individual differences in misanthropy-the tendency to view humans negatively-predict beliefs about the good true self in an American sample. The results indicate a consistent belief in a good true self, even among individuals who have an explicitly pessimistic view of others. Study 2 compared true self-attributions across cultural groups, by comparing samples from an independent country (USA) and a diverse set of interdependent countries (Russia, Singapore, and Colombia). Results indicated that the direction and magnitude of the effect are comparable across all groups we tested. The belief in a good true self appears robust across groups varying in cultural orientation or misanthropy, suggesting a consistent psychological tendency to view the true self as morally good. PMID- 28585703 TI - Husk Tomato (Physalis ixocarpa Brot.) Waste as a Promising Source of Pectin: Extraction and Physicochemical Characterization. AB - Husk tomato (Physalis ixocarpa Brot. var. Rendidora) waste was evaluated as a source of specialized pectin, and pectin extracted from this waste was characterized physicochemically. Fruit was blanched for 10 or 15 min and extracted in 0.1 N HCl for 15 to 25 min. Extracted pectin was subjected to physicochemical analysis. For all extraction conditions, the percentage of anhydrogalacturonic acid exceeded 60%, indicating that husk tomato was a good source of pectin. The degree of esterification of pectin molecules was 63% to 91%. The amount of extracted pectin decreased with increasing extraction time. The apparent viscosity of husk tomato pectin showed the characteristic behavior of pseudoplastic fluids. Neutral sugars were identified, and the amounts of 6 sugars (fucose, rhamnose, arabinose, galactose, glucose, and xylose) were quantified. Sugars identified in husk tomato pectin and present in the Rhamnogalacturonan I region, arabinose, galactose, and rhamnose suggest a highly branched structure, which will influence its future applications. Molecular weight values were 542 to 699 kDa, exceeding molecular weight values reported for commercial citrus pectins from 134 to 480 kDa. The extraction process significantly (P < 0.05) influenced the physicochemical properties of pectin. Up to 19.8% from the total amount of pectin in the husk tomato was extracted by 10 min of blanching and 20 min of a more heat treatment. Our findings indicate that husk tomato can be a good alternative source of pectin having highly distinctive physicochemical characteristics. PMID- 28585704 TI - The regulations and role of circadian clock and melatonin in uterine receptivity and pregnancy-An immunological perspective. AB - During normal pregnancy, the mechanism by which the fetus escapes immunological rejection by the maternal womb remains elusive. Given the biological complexities, the immunological mechanism is unlikely to be simply an allograft response in acceptance or rejection of the early pregnancy. Circadian clock responsible for the mammalian circadian rhythm is an endogenously generated rhythm associated with almost all physiological processes including reproduction. There is now growing evidence to suggest that the circadian clocks are intricately linked to the immune system and pregnancy. When perturbed, the role of immune cells can be affected on maintaining the enriched vascular system needed for placentation. This alteration can be triggered by the irregular production of maternal and placental melatonin. Hence, the role of circadian rhythm modulators such as melatonin offers intriguing opportunities for therapy. In this review, we evaluate the complex interaction between the circadian clock and melatonin within the immune system and their roles in the circadian regulation and maintenance of normal pregnancy. PMID- 28585705 TI - Ganglioside GM3 induces cumulus cell apoptosis through inhibition of epidermal growth factor receptor-mediated PI3K/AKT signaling pathways during in vitro maturation of pig oocytes. AB - Gangliosides are components of the mammalian plasma membrane that help regulate receptor signaling. Ganglioside GM3, for example, plays an important role in initiating apoptosis in cancer cells; however, physiological roles for GM3 in normal processes, such as during pig oocyte maturation, are not clear. The aim of this study was to investigate the functional link between GM3 and cellular apoptosis in porcine cumulus-oocyte-complexes (COCs) during in vitro maturation. Our results indicated that denuded oocytes possess less ST3GAL5, a GM3 synthesizing enzyme, than cumulus cells or COCs after 44 hr of in vitro maturation. GM3 also affected the meiotic maturation of cultured pig oocytes, as evaluated by orcein staining. In vitro treatment of COCs with exogenous GM3 also reduced cumulus cell expansion, the proportion of meiotic maturation, and increased cumulus cell transcription of PTX3, TNFAIP6, and HAS2. Interestingly, GM3 treatment reduced the expression of Epidermal growth factor receptor (EGFR) mediated Phosphoinositide 3-kinase/AKT signaling proteins in COCs in a concentration-dependent manner, instead increasing the abundance of pro-apoptotic factors such as AIF, activated Caspase 9, cleaved PARP1, and Caspase 3 were. Thus, GM3 might affect porcine oocyte maturation via suppression of EGFR-mediated PI3K/AKT signaling and/or induction of apoptosis during in vitro maturation. PMID- 28585706 TI - Delivery of dsRNA through topical feeding for RNA interference in the citrus sap piercing-sucking hemipteran, Diaphorina citri. AB - RNA interference (RNAi) is a powerful means to study functional genomics in insects. The delivery of dsRNA is a challenging step in the development of RNAi assay. Here, we describe a new delivery method to increase the effectiveness of RNAi in the Asian citrus psyllid Diaphorina citri. Bromophenol blue droplets were topically applied to fifth instar nymphs and adults on the ventral side of the thorax between the three pairs of legs. In addition to video recordings that showed sucking of the bromophenol blue by the stylets, dissected guts turned blue indicating that the uptake was through feeding. Thus, we called the method topical feeding. We targeted the abnormal wing disc gene (awd), also called nucleoside diphosphate kinase (NDPK), as a reporter gene to prove the uptake of dsRNA via this method of delivery. Our results showed that dsRNA-awd caused reduction of awd expression and nymph mortality. Survival and lifespan of adults emerged from treated nymphs and treated adults were affected. Silencing awd caused wing malformation in the adults emerged from treated nymphs. Topical feeding as a delivery of dsRNA is highly efficient for both nymphs and adults. The described method could be used to increase the efficiency of RNAi in D. citri and other sap piercing-sucking hemipterans. PMID- 28585707 TI - Early relapse of psoriasis after stopping brodalumab: a retrospective cohort study in 77 patients. AB - BACKGROUND: Biological agents targeting IL-17 are very effective for clearing moderate to severe psoriasis. There is limited information regarding the frequency and pattern of psoriasis relapse upon treatment cessation. OBJECTIVE: To investigate the pattern of psoriasis recurrence in patients who were treated with brodalumab following Amgen's decision to stop the clinical programme in June 2015. MATERIALS AND METHODS: Between June 2015 and March 2016, we constructed a retrospective multicenter cohort study including patients who were treated with brodalumab in Amgen's protocols after the abrupt interruption of the drug development programme. The relapse was defined as the request of patient to initiate a new treatment after brodalumab withdrawal. RESULTS: Seventy-seven patients were followed up. At the time brodalumab treatment was stopped, 67 (87%) patients had reached PASI 90. After brodalumab discontinuation, all 77 patients relapsed after a follow-up of 9 months. The median time to relapse was 46 days (range 7-224 days). Concerning the type of relapse, 73 patients presented with plaque psoriasis, one patient presented with erythrodermic psoriasis, and three patients experienced pustular psoriasis. In seven patients who had no previous history of psoriatic arthritis (PsA), the relapse of psoriasis was associated with inflammatory joint pain suggestive of PsA. At week 36, eight patients who had a limited relapse were controlled with topical treatment, 43 patients received a biological agent, two patients were included in a clinical trial with an investigational drug and 15 patients were treated with conventional systemic agents. CONCLUSION: Abrupt cessation of brodalumab is associated with a rapid relapse of psoriasis with some patients experiencing a rebound. It seems not advisable to stop treatment with IL-17 receptor antagonists abruptly even in patients who experience complete clearance of psoriasis. PMID- 28585709 TI - Do they practice what we preach: Findings from over a decade of breast imaging CME. PMID- 28585710 TI - Comparison of complications associated with induction by misoprostol versus dilation and evacuation for second-trimester abortion. AB - OBJECTIVE: To compare the frequency of complications between medical induction with misoprostol and dilation and evacuation (D&E) for second-trimester uterine evacuation. METHODS: In a retrospective cohort study, records were reviewed from all women who underwent second-trimester uterine evacuation between 14 and 24 weeks of pregnancy at an academic hospital in the USA from January 2007 to December 2008. Total complications and serious complications were compared between medical induction and D&E, and clinical covariates associated with complications were assessed. RESULTS: Overall, 465 women were included. At least one complication occurred in 28 (23.0%) of 122 women in the medical induction group, and 24 (7.0%) of 343 women in the D&E group (P<0.001). One or more serious complications occurred in 4 (3.3%) women undergoing medical induction and 5 (1.5%) undergoing D&E (P=0.251). Logistic regression analysis demonstrated that increasing pregnancy length (P=0.003) and medical induction (as compared with D&E; P=0.004) were associated with complications. CONCLUSION: Although D&E resulted in fewer overall complications as compared with medical induction, the rate of serious complications did not differ between the two procedures. PMID- 28585711 TI - Sudden rhythm change in dual-chamber pacemaker: Is the device working properly? PMID- 28585712 TI - A Novel Non-Apoptotic Role of Procaspase-3 in the Regulation of Mitochondrial Biogenesis Activators. AB - The executioner caspase-3 has been proposed as a pharmacological intervention target to preserve degenerating dopaminergic (DA) neurons because apoptotic mechanisms involving caspase-3 contribute, at least in part, to the loss of DA neurons in patients and experimental models of Parkinson's disease (PD). Here, we determined that genetic intervention of caspase-3 was sufficient to prevent cell death against oxidative stress (OS), accompanied by unexpected severe mitochondrial dysfunction. Specifically, as we expected, caspase-3-deficient DA neuronal cells were very significantly resistant to OS-induced cell death, while the activation of the initiator caspase-9 by OS was preserved. Moreover, detailed phenotypic characterization of caspase-3-deficient DA cells revealed severe mitochondrial dysfunction, including an accumulation of damaged mitochondria with a characteristic swollen structure and broken cristae, reduced membrane potential, increased levels of reactive oxygen species (ROS), and deficits in mitochondrial oxidative phosphorylation (OXPHOS) enzymes. Of great interest, we found that mitochondrial biogenesis was dramatically decreased in caspase-3 deficient DA cells, whereas their capability of mitophagy was normal. In accordance with this observation, caspase-3 gene knock down (KD) resulted in dramatically decreased expression of the key transcriptional activators of mitochondrial biogenesis, such as Tfam and Nrf-1, implicating a non-apoptotic role of procaspase-3 in mitochondrial biogenesis. Therefore, a prolonged anti apoptotic intervention targeting caspase-3 should be considered with caution due to the potential adverse effects in mitochondria dynamics resulting from a novel potential functional role of procaspase-3 in mitochondrial biogenesis via regulating the expression of mitochondrial biogenesis activators. J. Cell. Biochem. 119: 347-357, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28585713 TI - Nitrous gas analgesia and sedation for lumbar punctures in children: Has the time for practice change come? PMID- 28585714 TI - Use of Standing Gold Nanorods for Detection of Malachite Green and Crystal Violet in Fish by SERS. AB - With growing consumption of aquaculture products, there is increasing demand on rapid and sensitive techniques that can detect prohibited substances in the seafood products. This study aimed to develop a novel surface-enhanced Raman spectroscopy (SERS) method coupled with simplified extraction protocol and novel gold nanorod (AuNR) substrates to detect banned aquaculture substances (malachite green [MG] and crystal violet [CV]) and their mixture (1:1) in aqueous solution and fish samples. Multivariate statistical tools such as principal component analysis (PCA) and partial least squares regression (PLSR) were used in data analysis. PCA results demonstrate that SERS can distinguish MG, CV and their mixture (1:1) in aqueous solution and in fish samples. The detection limit of SERS coupled with standing AuNR substrates is 1 ppb for both MG and CV in fish samples. A good linear relationship between the actual concentration and predicted concentration of analytes based on PLSR models with R2 values from 0.87 to 0.99 were obtained, indicating satisfactory quantification results of this method. These results demonstrate that the SERS method coupled with AuNR substrates can be used for rapid and accurate detection of MG and CV in fish samples. PMID- 28585708 TI - The cytokine network in women with an asymptomatic short cervix and the risk of preterm delivery. AB - PROBLEM: To characterize the amniotic fluid (AF) inflammatory-related protein (IRP) network in patients with a sonographic short cervix (SCx) and to determine its relation to early preterm delivery (ePTD). METHOD OF STUDY: A retrospective cohort study included women with a SCx (<=25 mm; n=223) who had amniocentesis and were classified according to gestational age (GA) at diagnosis and delivery (ePTD <32 weeks of gestation). RESULTS: (i) In women with a SCx <= 22 1/7 weeks, the concentration of most IRPs increased as the cervix shortened; those with ePTD had a higher rate of increase in MIP-1alpha, MCP-1, and IL-6 concentrations than those delivering later; and (ii) the concentration of most IRPs and the correlation between several IRP pairs were higher in the ePTD group than for those delivering later. CONCLUSION: Women with a SCx at 16-22 1/7 weeks have a unique AF cytokine network that correlates with cervical length at diagnosis and GA at delivery. This network may aid in predicting ePTD. PMID- 28585715 TI - Does liver resection/transplantation affect respiratory induced liver motion in patients with hepatocellular carcinoma? AB - The purpose of this study was to evaluate the changes in magnitude of three dimensional (3D) liver motion after liver resection/transplantation in patients with hepatocellular carcinoma (HCC) using four-dimensional (4D)-computed tomography (CT) images. From January 2012 to April 2016, 74 HCC patients underwent 4D-CT scans under a free-breathing state to assess respiratory liver motion. Of the 74 patients, 40 did not have a liver resection/transplantation (Group A), 34 with liver resection/transplantation. 15 underwent major or minor resection in the right liver lobe (Group B), 14 underwent major or minor resection in the left liver lobe (Group C), and five underwent liver transplantation (Group D). The 4D-CT images were sorted into 10 image series according to the respiratory phase from the end inspiration to the end expiration, and then transferred to treatment planning software. All liver contours were drawn by a single physician and confirmed by a second. Liver relative coordinates were automatically generated to calculate liver respiratory motion in different axial directions and compiled into a single composite image. Differences in respiratory liver motion were assessed using one-way ANOVA. The average liver respiratory motion in the cranial-caudal direction and 3D magnitude were 10.46 +/- 2.78 mm (range, 5.60-18.80 mm) and 11.74 +/- 2.65 mm (range, 7.45 20.79 mm) for patients without liver resection/transplantation, and 7.74 +/- 2.79 mm (range, 2.20-12.90 mm) and 9.07 +/- 2.38 mm (range, 4.79-14.08 mm) for posthepatectomy/post-transplant patients respectively. There were significant differences between Group A and B, Group A and C, Group A and D. However, there were no significant differences among Group B, C, and D. Liver resection/transplantation greatly affected respiratory-induced liver motion in patients with HCC. We, therefore, recommend discriminatory internal target volume (ITV) determination for patients with or without liver resection/transplantation undergoing external radiotherapy for hepatic tumors while respiratory motion management is unavailable. PMID- 28585717 TI - A meta-analysis of intraoperative neuromonitoring of recurrent laryngeal nerve palsy during thyroid reoperations. AB - BACKGROUND: The rate of recurrent laryngeal nerve (RLN) palsy, a common complication of thyroid surgery, is especially high in thyroid reoperations. The present meta-analysis assesses whether intraoperative neuromonitoring (IONM) reduces the prevalence of RLN palsy in thyroid reoperations. DESIGN AND METHODS: A systematic literature search was conducted in the PubMed, SCIE and Wan Fang databases for studies published up to 31 August 2016. All data were analysed using STATA (version 11) software. Publication bias was assessed using Begg's funnel plot and Egger's test, and sensitivity analysis was performed. RESULTS: Nine studies including 2436 at-risk nerves met the inclusion criteria. The results were presented as pooled relative risks (RRs) with 95% confidence intervals (CI). The overall RLN palsy rate was significantly lower in reoperations conducted with IONM than in those conducted without IONM (RR=0.434, 95% CI=0.206-0.916, P=.029). High heterogeneity was found (I2 =70.2%, P=.001). The rates of transient RLN palsy with and without IONM did not differ significantly (RR=0.607, 95% CI=0.270-1.366, P=.227). The heterogeneity was high (I2 =67.4%, P=.005). However, IONM was significantly associated with a reduction in permanent RLN palsy (RR=0.426, 95% CI=0.196-0.925, P=.031). No significant heterogeneity was found (I2 =13.7%, P=.325). Funnel plots for overall and transient RLN palsy showed a possible publication bias. CONCLUSIONS: Intraoperative neuromonitoring (IONM) is associated with a reduction in overall and permanent RLN palsy in thyroid reoperations. However, given the limited sample size and heterogeneity in this meta-analysis, further studies are required to confirm our preliminary findings. PMID- 28585716 TI - Detection of dendritic cells and related cytokines in follicular fluid of patients with polycystic ovary syndrome. AB - PROBLEM: The presence of dendritic cells (DCs) and associated cytokines in follicular fluid (FF) from patients with polycystic ovary syndrome (PCOS) remains unknown. METHODS OF STUDY: FF was collected from PCOS patients and patients with severe male factor infertility (control) at the day of transvaginal oocyte retrieval. Phenotypes of DC were detected by flow cytometry, and TNF-alpha, IL-6, IL-10, and IL-23 were assessed by ELISA. RESULTS: A significant decrease in the percentage of DC was found in patients with PCOS (16.22+/-5.5%) compared with control (21.27+/-5.5%, P<.01). E2 on the day of hCG administration was correlated positively with the mean fluorescence intensity of HLA-DR (r=.75, P<.01) and reversely correlated with the concentration of TNF-alpha in FF (r=-.69, P<.01). The level of TNF-alpha, IL-6, and IL-10 increased significantly but IL-23 decreased in FF from patients with PCOS. CONCLUSION: The decrease of DC and disturbance of associated cytokines in FF from PCOS patients indicates a disorder of immunological microenvironment of the ovarian follicle, which might be involved in the dysfunction of folliculogenesis. PMID- 28585718 TI - Emotion dysregulation, symptoms, and interpersonal problems as independent predictors of a broad range of personality disorders in an outpatient sample. AB - : Emotion dysregulation (ED) is considered a hallmark of borderline personality disorder and is prominent in other personality disorders (PDs). Its presence and contribution to personality pathology need to be explored in the whole range of PDs. In this study, we investigated the association of ED with the whole range of PD traits, symptoms, and interpersonal problems and then investigated whether ED had a unique contribution in predicting the different PDs. A sample of 478 treatment-seeking outpatients was interviewed with the SCID-II. The patients were then tested for symptoms (SCL-90-R), interpersonal problems (IIP-32), and ED (DERS). RESULTS: ED correlated with the large majority of PDs and with symptoms and interpersonal problems. Regression showed how ED explained a unique part of the variance for many PDs. ED appears to be a relevant feature of pathology in many PDs; with replication, it can be considered a treatment target in this population. PRACTITIONER POINTS: Emotion dysregulation is present in many personality disorders. Emotion dysregulation is not just explained by heightened symptoms and interpersonal problems in personality disorders. Emotion dysregulation could be considered a treatment target in personality disorders other than borderline. PMID- 28585719 TI - Toward a community ecology of landscapes: predicting multiple predator-prey interactions across geographic space. AB - Community ecology was traditionally an integrative science devoted to studying interactions between species and their abiotic environments in order to predict species' geographic distributions and abundances. Yet for philosophical and methodological reasons, it has become divided into two enterprises: one devoted to local experimentation on species interactions to predict community dynamics; the other devoted to statistical analyses of abiotic and biotic information to describe geographic distribution. Our goal here is to instigate thinking about ways to reconnect the two enterprises and thereby return to a tradition to do integrative science. We focus specifically on the community ecology of predators and prey, which is ripe for integration. This is because there is active, simultaneous interest in experimentally resolving the nature and strength of predator-prey interactions as well as explaining patterns across landscapes and seascapes. We begin by describing a conceptual theory rooted in classical analyses of non-spatial food web modules used to predict species interactions. We show how such modules can be extended to consideration of spatial context using the concept of habitat domain. Habitat domain describes the spatial extent of habitat space that predators and prey use while foraging, which differs from home range, the spatial extent used by an animal to meet all of its daily needs. This conceptual theory can be used to predict how different spatial relations of predators and prey could lead to different emergent multiple predator-prey interactions such as whether predator consumptive or non-consumptive effects should dominate, and whether intraguild predation, predator interference or predator complementarity are expected. We then review the literature on studies of large predator-prey interactions that make conclusions about the nature of multiple predator-prey interactions. This analysis reveals that while many studies provide sufficient information about predator or prey spatial locations, and thus meet necessary conditions of the habitat domain conceptual theory for drawing conclusions about the nature of the predator-prey interactions, several studies do not. We therefore elaborate how modern technology and statistical approaches for animal movement analysis could be used to test the conceptual theory, using experimental or quasi-experimental analyses at landscape scales. PMID- 28585720 TI - Optimizing Specialty Drug Use. PMID- 28585721 TI - "Let him speak:" a descriptive qualitative study of the roles and behaviors of family companions in primary care visits among older adults with cognitive impairment. AB - OBJECTIVE: Cognitive impairment poses communication challenges in primary care. Although family "companions" commonly attend primary care visits of older adults with cognitive impairment, little is known about how their involvement affects communication. Therefore, we sought to understand how companion involvement affects the quality of primary care visit communication for older adults with cognitive impairment. METHODS: Cross-sectional, descriptive qualitative study participants were as follows: (1) English-speaking adults age 65 or older with mild, moderate, or severe cognitive impairment; (2) family members or other unpaid companions who accompany older adults to primary care visits; and (3) primary care clinicians. Twenty semi-structured and in-depth qualitative interviews of older adults and their companions (N = 20 dyads) and two focus groups (N = 10 primary care clinicians) were conducted. Interviews and focus groups were transcribed and analyzed thematically. RESULTS: Family companions commonly facilitate communication by advocating for patients, ensuring the accuracy of information exchange and understanding, and preserving rapport. Significant communication challenges were also identified, including patient and companion role ambiguity, competing visit agendas, and primary care clinician confusion regarding the most accurate source of information. Patients, companions, and clinicians each identified strategies to improve communication, chief among them being to identify, differentiate, and respect both patient and companion priorities and perspectives. CONCLUSIONS: Family companions actively participate in primary care visits of older adults with cognitive impairment in ways that promote and inhibit effective communication. Findings suggest the need for strategies that more effectively and purposefully involve family in the care of primary care patients with cognitive impairment. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585722 TI - The association between question type and the outcomes of a Dermatology eConsult service. AB - BACKGROUND: eConsult is a web based service that facilitates communication between primary care providers (PCPs) and specialists, which can reduce the need for face-to-face consultations with specialists. One example is the Champlain BASE (Building Access to Specialist through eConsultation) service with dermatology being the largest specialty consulted. METHODS: Dermatology eConsults submitted from July 2011 to January 2015 were reviewed. Post eConsult surveys for PCPs were analyzed to determine the number of traditional consults avoided and perceived value of eConsults. The time it took the PCP to receive a reply and the amount of time reported by the specialist to answer eConsult were proactively recorded and analyzed. A subset of 154 most recent eConsults was categorized for dermatology content and question type (e.g. diagnosis or management) using a validated taxonomy. RESULTS: A total of 965 eConsults were directed to dermatology from 217 unique PCPs. The majority of eConsults (64%) took the specialist between 10 and 15 minutes to answer. The overall value of this service to the provider was rated as very good or excellent in 95% of cases. In 49%, traditional in-person assessments were avoided. In the subset of the most recent cases, diagnosis was the most common question type asked (65.2%) followed by management (29%) and drug treatment (10.6%). The top five subject areas (40%) were: Dermatitis, Infections, Neoplasm, Nevi, and Pruritus. CONCLUSION: eConsults was feasible and well received by PCPs, which improves access to dermatology care with a potential to reduce wait times for traditional consultation. PMID- 28585724 TI - Assessment of volumetric absorbed dose for mobile fluoroscopic 3D image acquisition. AB - Mobile fluoroscopy (c-arm) units offering 3D image reconstruction are becoming more common in surgical settings. Although these images are "CT-like" and sometimes replace the postoperative CT, the acquisition is technically very different from a traditional CT acquisition. Dose assessment is complicated by a large beam width, automatic exposure rate control, and a rotation of less than 360 degrees . The purpose of this work was to explore the impact of these factors on the volumetric dose calculation and to provide practical recommendations for clinical physicists assessing dose from these units using commonly available equipment. CTDIW was calculated using the IAEA method for dosimetry of wide beams and compared to scans of the 32-cm CTDI phantom using the full beam width and a 20-mm collimated beam width. The impact of the partial rotation on the CTDIW calculation was assessed by acquiring measurements at four and twelve positions on the phantom periphery. For the system tested, the CTDIW was calculated to be 16.1 mGy using the IAEA method with default clinical protocol. Results showed that measuring CTDIW with the full beam width or a collimated beam width alone resulted in CTDI values of 19.0 mGy and 19.5 mGy, respectively. Using four peripheral measurements instead of 12 resulted in a difference of 4% for a collimated beam and 6% for an open beam. Variations in positioning on the order of a few centimeters resulted in a variation of only 4% with an open beam. The excellent reproducibility of the measurements using the full beam width suggests that this simple method is adequate for year-to-year comparisons. In contrast, the IAEA method is difficult to employ, particularly with 180 degrees acquisitions. Use of peripheral measurements in excess of the usual four is time consuming and not necessary for most applications obtained with the geometry specific to this system. PMID- 28585725 TI - Laboratory parameter-based machine learning model for excluding non-alcoholic fatty liver disease (NAFLD) in the general population. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects 20%-40% of the general population in developed countries and is an increasingly important cause of hepatocellular carcinoma. Electronic medical records facilitate large-scale epidemiological studies, existing NAFLD scores often require clinical and anthropometric parameters that may not be captured in those databases. AIM: To develop and validate a laboratory parameter-based machine learning model to detect NAFLD for the general population. METHODS: We randomly divided 922 subjects from a population screening study into training and validation groups; NAFLD was diagnosed by proton-magnetic resonance spectroscopy. On the basis of machine learning from 23 routine clinical and laboratory parameters after elastic net regulation, we evaluated the logistic regression, ridge regression, AdaBoost and decision tree models. The areas under receiver-operating characteristic curve (AUROC) of models in validation group were compared. RESULTS: Six predictors including alanine aminotransferase, high-density lipoprotein cholesterol, triglyceride, haemoglobin A1c , white blood cell count and the presence of hypertension were selected. The NAFLD ridge score achieved AUROC of 0.87 (95% CI 0.83-0.90) and 0.88 (0.84-0.91) in the training and validation groups respectively. Using dual cut-offs of 0.24 and 0.44, NAFLD ridge score achieved 92% (86%-96%) sensitivity and 90% (86%-93%) specificity with corresponding negative and positive predictive values of 96% (91%-98%) and 69% (59%-78%), and 87% of overall accuracy among 70% of classifiable subjects in the validation group; 30% of subjects remained indeterminate. CONCLUSIONS: NAFLD ridge score is a simple and robust reference comparable to existing NAFLD scores to exclude NAFLD patients in epidemiological studies. PMID- 28585727 TI - Atopic dermatitis characteristics and medication-use patterns in school-age children with AD and asthma symptoms. AB - BACKGROUND: Atopic dermatitis (AD) and asthma often coexist. Both diseases can have a major impact on the lives of children with AD and their caregivers. AIM: To investigate the association of patient characteristics, comorbidities and impact of AD on children who have both asthma and AD. METHODS: Children with AD (n = 140) were selected from a larger cohort of children with a reported use of asthma medication. The Children's Dermatology Life Quality Index (CDLQI) was used to assess Quality of Life (QoL), and the Self-Assessed Eczema Area and Severity Index (SA-EASI) was used to measure AD severity. Characteristics assessed included: age, sex, and the number and type of atopic comorbidities. Medication use for AD was defined using the total number of AD prescriptions, the number of different topical AD prescriptions and the highest potency topical corticosteroid (TCS) used. Determinants of AD severity and QoL were evaluated using Spearman rank tests. RESULTS: The following factors were most strongly associated with a lower QoL: characteristics of AD lesions (Spearman Rs = 0.61-0.69, P < 0.01), a higher SA-EASI score (Rs = 0.54, P < 0.01) and a larger number of different topical AD prescriptions (Rs = 0.38, P < 0.01). The following factors were correlated with more severe AD: age (Rs = -0.36, P < 0.01), larger number of different TCS preparations used (Rs = 0.27, P < 0.05) and larger number of TCS prescriptions (Rs = 0.25, P < 0.05). CONCLUSION: In children with asthma and AD, the number of TCS preparations used is associated with lower QoL and increased AD severity. PMID- 28585728 TI - Gallic Acid Grafted Chitosan Has Enhanced Oxidative Stability in Bulk Oils. AB - Gallic acid (GA) was grafted in chitosan and the effects of GA grafted chitosan (GA-g-CS) on the oxidative stability in bulk oil was tested at 60 and 140 degrees C. To text oxidative stability in oils, headspace oxygen content, conjugated dienoic acid (CDA) value, p-anisidine value (p-AV), and acid value were determined. Chitosan itself did not show antioxidative or prooxidative effects in oils at 60 degrees C. However, GA-g-CS and GA acted as antioxidants at 60 degrees C. At 140 degrees C heating with moisture supplied condition, different results were observed. GA-g-CS acted as antioxidants based on the results of CDA and p-AV. However, chitosan showed the highest oxidative stability based on results of acid value and brown color formation at 140 degrees C. This could be due to reduction of moisture content by chitosan. GA was continuously released from GA-g-CS in bulk oil. This might have provided extra antioxidant activities to oils. PMID- 28585726 TI - Later life swimming performance and persistent heart damage following subteratogenic PAH mixture exposure in the Atlantic killifish (Fundulus heteroclitus). AB - High-level, acute exposures to individual polycyclic aromatic hydrocarbons (PAHs) and complex PAH mixtures result in cardiac abnormalities in developing fish embryos. Whereas acute PAH exposures can be developmentally lethal, little is known about the later life consequences of early life, lower level PAH exposures in survivors. A population of PAH-adapted Fundulus heteroclitus from the PAH contaminated Superfund site, Atlantic Wood Industries, Elizabeth River, Portsmouth, Virginia, United States, is highly resistant to acute PAH cardiac teratogenicity. We sought to determine and characterize long-term swimming performance and cardiac histological alterations of a subteratogenic PAH mixture exposure in both reference killifish and PAH-adapted Atlantic Wood killifish embryos. Killifish from a relatively uncontaminated reference site, King's Creek, Virginia, United States, and Atlantic Wood killifish were treated with dilutions of Elizabeth River sediment extract at 24 h post fertilization (hpf). Two proven subteratogenic dilutions, 0.1 and 1.0% Elizabeth River sediment extract (total PAH 5.04 and 50.4 ug/L, respectively), were used for embryo exposures. Then, at 5 mo post hatching, killifish were subjected to a swim performance test. A separate subset of these individuals was processed for cardiac histological analysis. Unexposed King's Creek killifish significantly outperformed the unexposed Atlantic Wood killifish in swimming performance as measured by Ucrit (i.e., critical swimming speed). However, King's Creek killifish exposed to Elizabeth River sediment extract (both 0.1 and 1.0%) showed significant declines in Ucrit. Histological analysis revealed the presence of blood in the pericardium of King's Creek killifish. Although Atlantic Wood killifish showed baseline performance deficits relative to King's Creek killifish, their pericardial cavities were nearly free of blood and atrial and ventricular alterations. These findings may explain, in part, the diminished swimming performance of King's Creek fish. Environ Toxicol Chem 2017;36:3246-3253. (c) 2017 SETAC. PMID- 28585729 TI - Diastereoselective Total Synthesis of the Euphorbia Diterpenoid Pepluanol A: A Reductive Annulation Approach. AB - A new titanium(III)-catalyzed reductive annulation constructed a series of diversely functionalized 1,5-diols in good to excellent yields with respect to a wide scope of vinyl epoxide-aldehyde substrates. Taken together with a Diels Alder reaction and a substrate-controlled diastereoselective cyclopropanation as additional key steps, the synthetic utility of this novel method has been preliminarily explored by the first and concise total synthesis of the Euphorbia diterpenoid (+/-)-pepluanol A. PMID- 28585723 TI - Therapeutic Potential of Matrix Metalloproteinase Inhibition in Breast Cancer. AB - Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that cleave nearly all components of the extracellular matrix as well as many other soluble and cell-associated proteins. MMPs have been implicated in normal physiological processes, including development, and in the acquisition and progression of the malignant phenotype. Disappointing results from a series of clinical trials testing small molecule, broad spectrum MMP inhibitors as cancer therapeutics led to a re-evaluation of how MMPs function in the tumor microenvironment, and ongoing research continues to reveal that these proteins play complex roles in cancer development and progression. It is now clear that effective targeting of MMPs for therapeutic benefit will require selective inhibition of specific MMPs. Here, we provide an overview of the MMP family and its biological regulators, the tissue inhibitors of metalloproteinases (TIMPs). We then summarize recent research from model systems that elucidate how specific MMPs drive the malignant phenotype of breast cancer cells, including acquisition of cancer stem cell features and induction of the epithelial-mesenchymal transition, and we also outline clinical studies that implicate specific MMPs in breast cancer outcomes. We conclude by discussing ongoing strategies for development of inhibitors with therapeutic potential that are capable of selectively targeting the MMPs most responsible for tumor promotion, with special consideration of the potential of biologics including antibodies and engineered proteins based on the TIMP scaffold. J. Cell. Biochem. 118: 3531-3548, 2017. (c) 2017 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals, Inc. PMID- 28585730 TI - Recommendations for the derivation and use of biota-sediment bioaccumulation models for carcinogenic polycyclic aromatic hydrocarbons. AB - Carcinogenic polycyclic aromatic hydrocarbons (cPAHs) are important sediment contaminants that can pose health risks to people who eat shellfish from contaminated sites. Biota-sediment accumulation factors (BSAFs) are quotients of colocated lipid-normalized tissue concentrations and organic carbon (OC) normalized sediment concentrations, whereas biota-sediment accumulation regressions (BSARs) are models describing the relationships between these tissue and sediment concentrations. BSAR/Fs (BSARs and/or BSAFs) are commonly used to back-calculate sediment preliminary remediation goals (PRGs) from target tissue concentrations; the PRGs are then used to set target action levels (i.e., sediment concentrations above which remedial actions will be prescribed). The cPAH BSAR/Fs reported across sites and species are highly variable due to both site- and species-specific differences and inconsistent BSAR/F calculation methods and assumptions. We reviewed past studies, identified best practices for developing BSAR/Fs, and compiled publicly available colocated tissue and sediment data for 7 cPAHs from 13 sites across the United States. Of the 249 unique cPAH data sets compiled for various species, only 17 yielded acceptable BSAR/Fs, 16 of which were for clams. The influence of BSAR/Fs on sediment remedial action decisions and costs can be disproportionate to the quality of the statistical models from which they are derived. Therefore, it is important to establish and follow best practices for deriving BSAR/Fs and for deciding whether and how BSAR/Fs should be used. Based on our review and analysis, we highlight the advantages of relying on BSARs and propose a consistent method for deriving and judging the reliability of these relationships. We also offer guidance for evaluating the ramifications of BSAR uncertainty on remedial decision making at contaminated sediment sites, and we discuss alternative ways to make risk management decisions in the absence of a reliable site-specific BSAR. Integr Environ Assess Manag 2017;13:1060-1071. (c) 2017 SETAC. PMID- 28585731 TI - Intracellular determinants of hippocampal cell assembly formation during associative learning. PMID- 28585733 TI - Life Threat and Sleep Disturbances in Adolescents: A Two-Year Follow-Up of Survivors From the 2011 Utoya, Norway, Terror Attack. AB - A significant number of adolescents have been exposed to traumatic life events. However, knowledge about the specific sleep disturbance that occurs in individuals after trauma exposure is predominantly based on studies of adults. This study reports specific sleep disturbance in 42 survivors of the 2011 mass shooting at a youth summer camp on the Norwegian island Utoya, mean age = 20.91 years, SD = 2.32, 62.5% females. When compared with matched controls, significantly more survivors reported having sleep disturbances, 52.4% versus 13.6%, d = 0.93, of which onset began at the time of the shooting, chi2 = 14.9, p < .001. The prevalence of insomnia, 56.3% versus 11.0%, d = 0.73; excessive daytime sleepiness, 34.4% versus 13.6%, d = 0.61; symptoms of obstructive sleep apnea, 18.8% versus 0%, d = 0.70; and frequent nightmares, 37.5% versus 2.3%, d = 0.90, were all higher in the survivors than in the controls. In a subgroup of survivors (n = 20) with psychiatric diagnoses, sleep disturbances were more prevalent than in survivors without psychiatric diagnosis. Actigraphy data revealed delayed bedtime, sleep onset, and rise time in survivors compared with controls, ts > 1.7, ps = .044 to .028. These results corroborate the effects of a life threat on the range and extent of sleep disturbances, and emphasize the need to better assess and treat sleep disorders in adolescents exposed to trauma. PMID- 28585732 TI - Cost-effective immobilization for whole brain radiation therapy. AB - To investigate the inter- and intra-fraction motion associated with the use of a low-cost tape immobilization technique as an alternative to thermoplastic immobilization masks for whole-brain treatments. The results of this study may be of interest to clinical staff with severely limited resources (e.g., in low income countries) and also when treating patients who cannot tolerate standard immobilization masks. Setup reproducibility of eight healthy volunteers was assessed for two different immobilization techniques. (a) One strip of tape was placed across the volunteer's forehead and attached to the sides of the treatment table. (b) A second strip was added to the first, under the chin, and secured to the table above the volunteer's head. After initial positioning, anterior and lateral photographs were acquired. Volunteers were positioned five times with each technique to allow calculation of inter-fraction reproducibility measurements. To estimate intra-fraction reproducibility, 5-minute anterior and lateral videos were taken for each technique per volunteer. An in-house software was used to analyze the photos and videos to assess setup reproducibility. The maximum intra-fraction displacement for all volunteers was 2.8 mm. Intra-fraction motion increased with time on table. The maximum inter-fraction range of positions for all volunteers was 5.4 mm. The magnitude of inter-fraction and intra-fraction motion found using the "1-strip" and "2-strip" tape immobilization techniques was comparable to motion restrictions provided by a thermoplastic mask for whole-brain radiotherapy. The results suggest that tape-based immobilization techniques represent an economical and useful alternative to the thermoplastic mask. PMID- 28585734 TI - Immunological function of vitamin D during human pregnancy. AB - The well-established classic role of vitamin D is implicated in the regulation of the balance between calcium and phosphorus. Furthermore, vitamin D is also involved in many non-classic physiological processes, mainly including the regulation of cell proliferation, differentiation, apoptosis and immune function, participation in the inflammatory response and maintenance of genome stability function. During pregnancy, vitamin D receptor and its metabolic enzymes are expressed at the placenta and decidua, indicating the potential role in the mechanism of immunomodulation at the maternal-fetal interface. The insufficiency or deficiency of vitamin D may affect the mother directly and is related to specific pregnancy outcomes, such as preeclampsia, gestational diabetes, and recurrent miscarriage. This article reviews the effects of vitamin D on immune regulation during pregnancy. PMID- 28585735 TI - A Randomized, Double-blind, Placebo-controlled Clinical Trial Examining the Effects of Green Tea Extract on Systemic Lupus Erythematosus Disease Activity and Quality of Life. AB - Antiinflammatory and immunomodulatory benefit of green tea (Camellia sinensis) in autoimmune disease has been proven in recent studies. The objective of this study was to assess the effects of green tea on disease activity and quality of life in systemic lupus erythematosus patients. A randomized controlled trial on subjects with lupus was conducted, and 68 patients in the age range of 39.1 +/- 10.3 years and body mass index of 25.7 +/- 5.21 kg/m2 completed the 12-week study. Patients were randomly divided into two groups of intervention (1000 mg green tea extract, two capsules/day) and control (1000 mg of starch, two capsules/day). Main outcome measure, systemic lupus erythematosus disease activity, was assessed by the systemic lupus erythematosus disease activity index at the first and after 3 months of intervention. In addition, patient's quality of life was evaluated by short form of quality-of-life questionnaire at baseline and after 3 months. Green tea extract supplementation significantly reduced disease activity in lupus patients (p < 0.004); in addition, it significantly increased the vitality (p < 0.006) and general health (p < 0.01). This study showed that daily consumption of green tea extracts for 12 weeks improves the systemic lupus erythematosus disease activity as well as some aspects of quality of life. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585736 TI - Genotoxic effects of old landfill leachate on HepG2 cells after nitration/ultrafiltration/reverse osmosis membrane treatment process. AB - Toxicity assessment of nitration/ultrafiltration/reverse osmosis (nitration/UF/RO) project, which has recently been widely used as an efficient process with applications in practical leachate treatment, was very limited. In the present study, DNA damage of leachates was investigated before and after the nitration/UF/RO process by a battery of assays with human hepatoma cells. Methyletrazolium assay showed a high cytotoxicity of 97.1% after being exposed to the highest concentration of raw leachate for 24 h, and a cytotoxicity of 26% in effluent at a concentration of 30% (v/v). Both comet assay (24 h) and gammaH2AX flow cytometer assay (3 h) showed increased levels of DNA damage in cells exposed to raw leachate and after nitration/UF-treated leachate followed by a significant increase of 7-ethoxyresorufin-O-deethylase activity. However, the effluent after nitration/UF/RO treatment showed no significant difference compared to negative control for gammaH2AX flow cytometer assay but slight DNA damage at concentrations of 20% and 30% (v/v) as well as increase of 7-ethoxyresorufin-O deethylase. Analysis showed that nitration/UF/RO process exhibited high removal of physicochemical indexes and significant reduction of toxic and genotoxic effects of leachate, but still demands an improvement to reduce all possible negative risks to the environment and humans. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585737 TI - A New Measure of Hallucinatory States and a Discussion of REM Sleep Dreaming as a Virtual Laboratory for the Rehearsal of Embodied Cognition. AB - Hallucinatory states are experienced not only in connection with drugs and psychopathologies but occur naturally and spontaneously across the human circadian cycle: Our nightly dreams bring multimodal experiences in the absence of adequate external stimuli. The current study proposes a new, tighter measure of these hallucinatory states: Sleep onset, REM sleep, and non-REM sleep are shown to differ with regard to (a) motor imagery indicating interactions with a rich imaginative world, and (b) cognitive agency that could enable sleepers to recognize their hallucinatory state. Mentation reports from the different states were analysed quantitatively with regard to two grammatical-semantic constructs, motor agency and cognitive agency. The present results support earlier physiological and psychological evidence in revealing a decline in cognitive functions and an increase in simulated interactions with a hallucinatory world, en route to normal REM sleep. This leads us to introduce the hypothesis that REM sleep, which exhibits remarkably high levels of (simulated) sensorimotor processes, may have evolved to serve as a virtual laboratory for the development and rehearsal of embodied cognition. The new measure of hallucinatory states presented here may also hold implications for the study of executive functions and (meta-)cognitions, which might be interesting, for example, for the investigation of lucid dreaming. PMID- 28585738 TI - Dispersion Stability of O/W Emulsions with Different Oil Contents Under Various Freezing and Thawing Conditions. AB - Freezing and thawing of oil-in-water (O/W) emulsion-type foods bring about oil water separation and deterioration; hence, the effects of freezing and thawing conditions on the destabilization of O/W emulsions were examined. The freezing rate and thawing temperature hardly affected the stability of the O/W emulsion. O/W emulsions having different oil fractions were stored at temperatures ranging from -30 to -20 degrees C and then thawed. The stability after thawing depended on the storage temperature, irrespective of the oil fraction of the emulsion. A good correlation was found between the time at which the stability began to decrease and the time taken for the oil to crystalize. These results indicated that the dominant cause for the destabilization of the O/W emulsion during freezing and thawing is the crystallization of the oil phase and that the effects of the freezing and thawing rates on the stability are insignificant. PMID- 28585739 TI - Iron oxide nanoparticles induced cytotoxicity, oxidative stress and DNA damage in lymphocytes. AB - Over the past few decades nanotechnology and material science has progressed extremely rapidly. Iron oxide nanoparticles (IONPs) owing to their unique magnetic properties have a great potential for their biomedical and bioengineering applications. However, there is an inevitable need to address the issue of safety and health effects of these nanoparticles. Hence, the present study was aimed to assess the cytotoxic effects of IONPs on rats' lymphocytes. Using different assays, we studied diverse parameters including mitochondrial membrane potential, intracellular accumulation of reactive oxygen species (ROS), lactate dehydrogenase activity, antioxidant enzymes activity and DNA damage measurements. Intracellular metal uptake and ultrastructure analysis were also carried out through inductively coupled plasma atomic emission spectroscopy, transmission electron microscopy respectively. The results show that the IONP induced oxidative stress was concentration-dependent in nature, with significant (P < 0.05) increase in ROS levels, lipid peroxidation level as well as depletion of antioxidant enzymes and glutathione. Moreover, we observed morphological changes in the cell after intracellular uptake and localization of nanoparticles in cells. From the findings of the study, it may be concluded that IONPs induce ROS-mediated cytotoxicity in lymphocytes. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585741 TI - Synthesis and Reactivity of Fluoroalkyl Copper Complexes by the Oxycupration of Tetrafluoroethylene. AB - The copper(I)-mediated generation of -OCF2 CF2 - moieties by the oxycupration of tetrafluoroethylene (TFE) using either copper aryloxides or alkoxides is disclosed. The key intermediates, 2-aryloxy-1,1,2,2-tetrafluoroethyl and 2-alkoxy 1,1,2,2-tetrafluoroethyl copper complexes, were obtained from the reaction of the corresponding aryloxy and alkoxy copper complexes with TFE, and their structures in solution and in the solid state were unambiguously determined by multinuclear NMR spectroscopy and X-ray diffraction analysis. These copper complexes subsequently reacted with aryl iodides (ArI) to afford ROCF2 CF2 Ar (R=aryl or alkyl) in high yields. PMID- 28585742 TI - Initiator-Loaded Gold Nanocages as a Light-Induced Free-Radical Generator for Cancer Therapy. AB - Tumor hypoxia greatly suppresses the therapeutic efficacy of photodynamic therapy (PDT), mainly because the generation of toxic reactive oxygen species (ROS) in PDT is highly oxygen-dependent. In contrast to ROS, the generation of oxygen irrelevant free radicals is oxygen-independent. A new therapeutic strategy based on the light-induced generation of free radicals for cancer therapy is reported. Initiator-loaded gold nanocages (AuNCs) as the free-radical generator were synthesized. Under near-infrared light (NIR) irradiation, the plasmonic heating effect of AuNCs can induce the decomposition of the initiator to generate alkyl radicals (R. ), which can elevate oxidative-stress (OS) and cause DNA damages in cancer cells, and finally lead to apoptotic cell death under different oxygen tensions. As a proof of concept, this research opens up a new field to use various free radicals for cancer therapy. PMID- 28585740 TI - Comparing Trauma Exposure, Mental Health Needs, and Service Utilization Across Clinical Samples of Refugee, Immigrant, and U.S.-Origin Children. AB - Most mental health services for trauma-exposed children and adolescents were not originally developed for refugees. Information is needed to help clinicians design services to address the consequences of trauma in refugee populations. We compared trauma exposure, psychological distress, and mental health service utilization among children and adolescents of refugee-origin, immigrant-origin, and U.S.-origin referred for assessment and treatment by U.S. providers in the National Child Traumatic Stress Network (NCTSN). We used propensity score matching to compare trauma profiles, mental health needs, and service use across three groups. Our sample comprised refugee-origin youth (n = 60, 48.3% female, mean age = 13.07 years) and propensity-matched samples of immigrant-origin youth (n = 143, 60.8% female, mean age = 13.26 years), and U.S.-origin youth (n = 140, 56.1% female, mean age = 12.11 years). On average, there were significantly more types of trauma exposure among refugee youth than either U.S.-origin youth (p < .001) or immigrant youth (p <= .001). Compared with U.S.-origin youth, refugee youth had higher rates of community violence exposure, dissociative symptoms, traumatic grief, somatization, and phobic disorder. In contrast, the refugee group had comparably lower rates of substance abuse and oppositional defiant disorder (ps ranging from .030 to < .001).This clinic-referred sample of refugee origin youth presented with distinct patterns of trauma exposure, distress symptoms, and service needs that merit consideration in services planning. PMID- 28585743 TI - Intraspecific variation shapes community-level behavioral responses to urbanization in spiders. AB - Urban areas are an extreme example of human-changed environments, exposing organisms to multiple and strong selection pressures. Adaptive behavioral responses are thought to play a major role in animals' success or failure in such new environments. Approaches based on functional traits have proven especially valuable to understand how species communities respond to environmental gradients. Until recently, they have, however, often ignored the potential consequences of intraspecific trait variation (ITV). When ITV is prevalent, it may highly impact ecological processes and resilience against stressors. This may be especially relevant in animals, in which behavioral traits can be altered very flexibly at the individual level to track environmental changes. We investigated how species turnover and ITV influenced community-level behavioral responses in a set of 62 sites of varying levels of urbanization, using orb web spiders and their webs as models of foraging behavior. ITV alone explained around one-third of the total trait variation observed among communities. Spider web structure changed according to urbanization, in ways that increase the capture efficiency of webs in a context of smaller urban prey. These trait shifts were partly mediated by species turnover, but ITV increased their magnitude, potentially helping to buffer the effects of environmental changes on communities. The importance of ITV varied depending on traits and on the spatial scale at which urbanization was considered. Despite being neglected from community-level analyses in animals, our results highlight the importance of accounting for intraspecific trait variation to fully understand trait responses to (human induced) environmental changes and their impact on ecosystem functioning. PMID- 28585744 TI - Glomangioma of the male breast. PMID- 28585745 TI - Sentinel node biopsy for early breast cancer in Queensland, Australia, during 2008-2012. AB - BACKGROUND: Sentinel node biopsy (SNB) is now the standard of care for women with early-stage breast cancer. Despite lower morbidity than axillary lymph node dissection, widespread variation in SNB rates by non-clinical factors persists. We explored the factors associated with SNB usage and changes in those associations over time for recently diagnosed women. METHODS: We report here on a linked population-based cancer registry and hospital inpatient admission data set for 5577 women aged at least 20 years diagnosed with a first primary invasive early-stage node-negative breast cancer from July 2008 to 2012 in Queensland, Australia, who underwent breast cancer-related surgery within 2 years of diagnosis. Multivariate logistic regression was used to model predictors of SNB separately for 5172 women with <=30 mm tumours and 405 with 31 to <=50 mm tumours. RESULTS: Overall, 3972 (77%) women with <=30 mm tumours and 221 (55%) of those with larger tumours underwent SNB. Usage increased over time for both cohorts but was consistently lower among those with larger tumours. A more recent diagnosis, having breast-conserving surgery, living in more accessible areas and attending a private or high-volume hospital independently increased the odds of SNB for both cohorts. There was no evidence that the geographical disparity had reduced over the study period for either cohort. CONCLUSION: Geographical disparities to accessing SNB persist. Efforts to promote multidisciplinary care and facilitate education in healthcare changes through innovative solutions using emerging technologies as well as targeted research to identify the barriers to equitable access remain critical. PMID- 28585746 TI - Randomized Clinical Trial Investigating the Effects of an Anxiety Sensitivity Intervention on Posttraumatic Stress Symptoms: A Replication and Extension. AB - A growing body of research suggests the importance of anxiety sensitivity (AS) in the development and maintenance of posttraumatic stress symptoms (PTSS). Specifically, AS cognitive concerns (fears of cognitive dyscontrol) may be particularly relevant for those with elevated PTSS. Preliminary research has suggested that interventions targeting AS may be beneficial in decreasing PTSS, but to date there has been no randomized controlled trial testing the direct and indirect effects of an AS cognitive concerns intervention among a clinical sample of trauma-exposed individuals. The current study tested these effects among a sample 63 trauma-exposed participants who were randomized to either an AS cognitive concerns intervention or a repeated contact control. Results indicated a direct effect of the intervention on PTSS 1 month postintervention, and that this effect was mediated by changes in AS, specifically AS cognitive concerns, during the intervention period. Effect sizes were in the small-to-medium range (variance accounted for ranged from .05 to .15; odds ratio for diagnostic change = .06). These findings provide further evidence that targeting AS may be beneficial in the treatment of PTSS, and expansion upon this area of research by demonstrating these effects may be specific to AS cognitive concerns and can be achieved within a mixed clinical sample. PMID- 28585747 TI - A Biologically Plausible Action Selection System for Cognitive Architectures: Implications of Basal Ganglia Anatomy for Learning and Decision-Making Models. AB - Several attempts have been made previously to provide a biological grounding for cognitive architectures by relating their components to the computations of specific brain circuits. Often, the architecture's action selection system is identified with the basal ganglia. However, this identification overlooks one of the most important features of the basal ganglia-the existence of a direct and an indirect pathway that compete against each other. This characteristic has important consequences in decision-making tasks, which are brought to light by Parkinson's disease as well as genetic differences in dopamine receptors. This paper shows that a standard model of action selection in a cognitive architecture (ACT-R) cannot replicate any of these findings, details an alternative solution that reconciles action selection in the architecture with the physiology of the basal ganglia, and extends the domain of application of cognitive architectures. The implication of this solution for other architectures and existing models are discussed. PMID- 28585748 TI - Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo. AB - Tobacco smoke is a major risk factor for hepatic cancer. Epithelial-mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585749 TI - Glycan profiling using formalin-fixed, paraffin-embedded tissues: Hippeastrum hybrid lectin is a sensitive biomarker for squamous cell carcinoma of the uterine cervix. AB - AIM: Glycosylation of proteins is altered in cancer cells and distinctive glycan structures are associated with specific cancers, but little is known about the complete glycan profile of particular tumors. In this study, glycomic analysis of squamous cell carcinoma (SCC) of the uterine cervix was performed to search for useful markers. METHODS: A lectin microarray containing 45 lectins with different binding preferences that covered N- and O-linked glycans was coupled with evanescent field-activated fluorescent detection for glycomic analysis of SCC and normal squamous epithelium (NSE) of the cervix. Formalin-fixed, paraffin-embedded tissue specimens were obtained from 16 patients with uterine cervical cancer. Sections that included both tumor and non-tumor tissues were examined to detect alterations of glycans based on the lectin-binding pattern. RESULTS: Hippeastrum hybrid lectin was found to be a sensitive marker for distinguishing SCC of the cervix from NSE. It was the best lectin for discriminating SCC from other tissues according to receiver-operator curve analysis, as it showed a high sensitivity (81.8%), a high specificity (70.1%), and a large area under the curve (0.8182). Histochemistry confirmed specific cytoplasmic staining of SCC cells by Hippeastrum hybrid lectin, while there was little staining of cervical intraepithelial neoplasia and no staining of NSE. CONCLUSION: The present lectin microarray technique could be applied for tissue-based glycomic analysis of various tumors and for discovery of glycan-related biomarkers. PMID- 28585751 TI - Surgical research in the public hospital. PMID- 28585750 TI - Effects of intraoperative liberal fluid therapy on postoperative nausea and vomiting in children-A randomized controlled trial. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the most distressing complications following surgery. Supplemental perioperative fluid therapy might be an effective strategy to reduce PONV in children. OBJECTIVES: The study was conducted to evaluate the effects of intraoperative liberal fluid therapy with crystalloids on PONV in children. METHODS: In this randomized trial, a total of 150 children of 3-7 years undergoing lower abdominal and penile surgery under general anesthesia were randomly assigned into two groups. "Restricted group" received 10 mL kg-1 h-1 and "Liberal group" received 30 mL kg 1 h-1 infusion of Ringer's lactate solution intraoperatively. All patients received a caudal block and intravenous paracetamol for analgesia. No opioids and muscle relaxants were used. All episodes of nausea-vomiting and the requirement of rescue antiemetic were assessed during 24 hours postoperatively. RESULTS: The incidence of PONV was significantly less in the liberal group patients as compared to the restricted group; 33 (45.8%) patients in the restricted group had vomiting as compared to 20 (27.4%) patients in the liberal group (RR 0.59, 95% CI: 0.38-0.93, P=.021). The adjusted odds ratio of PONV for the liberal group vs restricted group was 2.24 (95% CI: 1.12-4.48, P=.022). The incidence of fluid intake during the first 6 postoperative hours was significantly higher in the restricted group patients; 60 (83%) children in the restricted group complained of thirst as compared to 12 (17%) children in the liberal group (RR 0.19, 95% CI: 0.18-0.33, P=.0001). The parents of the liberal group were more satisfied as compared to the restricted group (mean difference -0.9, 95% CI: -1.8, -0.1, P=.04). None of the children had any complication attributed to the liberal fluid therapy. CONCLUSION: Liberal intraoperative fluid therapy was found to be effective in reducing PONV in children undergoing lower abdominal surgery. PMID- 28585754 TI - Management of patients with polyposis. PMID- 28585753 TI - Response to Re: Interns' perceptions of exposure to urology during medical school education in Victoria, Australia. PMID- 28585755 TI - Capacity building in Timor Leste: a work in progress. PMID- 28585756 TI - Enhancing surgical research at the hospital level: a new model. PMID- 28585757 TI - Medicine in small doses. PMID- 28585758 TI - Challenges and next steps in teaching professionalism in surgical training. PMID- 28585759 TI - Tablespoons and corkscrew: a culinary solution for retrieval of a rectal foreign body. PMID- 28585760 TI - Re: Interns' perceptions of exposure to urology during medical school education in Victoria, Australia. PMID- 28585762 TI - Upregulation of the long non-coding RNA FALEC promotes proliferation and migration of prostate cancer cell lines and predicts prognosis of PCa patients. AB - BACKGROUND: LncRNAs are aberrantly expressed in various cancer types and were found to be a responsible prognosis biomarker and therapeutic target of many human cancers. METHODS: In this study, we characterized the expression profile of FALEC in prostate cancer and paired histologically normal tissues. Additionally, biological function of FALEC in prostate cancer cell lines was determined by in vitro and in vivo assays. RESULTS: In a total of 85 patients, FALEC expression was significantly increased in clinical PCa tissues compared to adjacent normal tissues, and can be considered as an independent prognostic factor in patients with PCa. Downregulation of FALEC could inhibit cell proliferation, migration and invasion in vitro. In vivo tumorigenesis study and orthotopic bioluminescence image also support the evidence that FALEC may promote the progression of prostate cancer. We also find FALEC is a potential hypoxia induced lncRNA and can be induced by the hypoxia master regulator HIF-1alpha. CONCLUSIONS: These findings suggested that FALEC may be a potential diagnostic and therapeutic target in patients with prostate cancer. PMID- 28585763 TI - A combinatorial strategy of alternative promoter use during differentiation of a heterocystous cyanobacterium. AB - Heterocystous cyanobacteria such as Nostoc sp. are filamentous photosynthetic organisms that, in response to nitrogen deficiency, undergo a differentiation process transforming certain, semi-regularly spaced cells into heterocysts, devoted to nitrogen fixation. During transition to a nitrogen-fixing regime, growth of most vegetative cells in the filament is temporarily arrested due to nutritional deprivation, but developing heterocysts require intense transcriptional activity. Therefore, the coexistence of arrested vegetative cells and actively developing prospective heterocysts relies on the simultaneous operation of somewhat opposite transcriptional programs. We have identified genes with multiple nitrogen-responsive transcriptional starts appearing in seemingly paradoxical combinations. For instance, sigA, encoding the RNA polymerase housekeeping sigma factor, is transcribed from one major nitrogen stress repressed promoter and from a second, nitrogen stress-induced promoter. Here, we show that both promoters are expressed with complementary temporal dynamics. Using a gfp reporter we also show that transcription from the inducible promoter takes place exclusively in differentiating heterocysts and is already detected before any morphological or fluorescence signature of differentiation is observed. Tandem promoters with opposite dynamics could operate a compensatory mechanism in which repression of transcription from the major promoter operative in vegetative cells is offset by transcription from a new promoter only in developing heterocyst. PMID- 28585761 TI - Somatic Experiencing for Posttraumatic Stress Disorder: A Randomized Controlled Outcome Study. AB - This study presents the first known randomized controlled study evaluating the effectiveness of somatic experiencing (SE), an integrative body-focused therapy for treating people with posttraumatic stress disorder (PTSD). There were 63 participants meeting DSM-IV-TR full criteria for PTSD included. Baseline clinical interviews and self-report measures were completed by all participants, who were then randomly assigned to study (n = 33) or waitlist (n = 30) groups. Study participants began 15 weekly SE sessions, whereas waitlist participants waited the same period, after which the second evaluation was conducted. All participants were evaluated a third time after an additional 15 weeks, during which time the waitlist group received SE therapy. Pretreatment evaluation showed no significant differences between groups. Mixed model linear regression analysis showed significant intervention effects for posttraumatic symptoms severity (Cohen's d = 0.94 to 1.26) and depression (Cohen's d = 0.7 to 1.08) both pre-post and pre-follow-up. This randomized controlled study of SE shows positive results indicating SE may be an effective therapy method for PTSD. Further research is needed to understand who shall benefit most from this treatment modality. PMID- 28585764 TI - Evaluation of Commercial-off-the-Shelf Materials for the Preservation of Bacillus anthracis Vegetative Cells for Forensic Analysis. AB - Environmental surface sampling is crucial in determining the zones of contamination and overall threat assessment. Viability retention of sampled material is central to such assessments. A systematic study was completed to determine viability of vegetative cells under nonpermissive storage conditions. Despite major gains in nucleic acid sequencing technologies, initial positive identification of threats must be made through direct culture of the sampled material using classical microbiological methods. Solutions have been developed to preserve the viability of pathogens contained within clinical samples, but many have not been examined for their ability to preserve biological agents. The purpose of this study was to systematically examine existing preservation materials that can retain the viability of Bacillus anthracis vegetative cells stored under nonpermissive temperatures. The results show effectiveness of five of seventeen solutions, which are capable of retaining viability of a sporulation deficient strain of B. anthracis Sterne when stored under nonrefrigerated conditions. PMID- 28585765 TI - Tree-ring analysis and modeling approaches yield contrary response of circumboreal forest productivity to climate change. AB - Circumboreal forest ecosystems are exposed to a larger magnitude of warming in comparison with the global average, as a result of warming-induced environmental changes. However, it is not clear how tree growth in these ecosystems responds to these changes. In this study, we investigated the sensitivity of forest productivity to climate change using ring width indices (RWI) from a tree-ring width dataset accessed from the International Tree-Ring Data Bank and gridded climate datasets from the Climate Research Unit. A negative relationship of RWI with summer temperature and recent reductions in RWI were typically observed in continental dry regions, such as inner Alaska and Canada, southern Europe, and the southern part of eastern Siberia. We then developed a multiple regression model with regional meteorological parameters to predict RWI, and then applied to these models to predict how tree growth will respond to twenty-first-century climate change (RCP8.5 scenario). The projections showed a spatial variation and future continuous reduction in tree growth in those continental dry regions. The spatial variation, however, could not be reproduced by a dynamic global vegetation model (DGVM). The DGVM projected a generally positive trend in future tree growth all over the circumboreal region. These results indicate that DGVMs may overestimate future wood net primary productivity (NPP) in continental dry regions such as these; this seems to be common feature of current DGVMs. DGVMs should be able to express the negative effect of warming on tree growth, so that they simulate the observed recent reduction in tree growth in continental dry regions. PMID- 28585766 TI - One minute static stretch of plantar flexors transiently increases H reflex excitability and exerts no effect on corticospinal pathways. AB - NEW FINDINGS: What is the central question of this study? What mediates neural responses following static stretching, and how long do these influences last? What is the main finding and its importance? This study shows that 1 min of static stretching inhibits the tendon tap reflex and facilitates the H reflex without influencing motor-evoked potentials. The results indicate that at least two different mechanisms mediate neural responses after static stretching. The purpose of this study was to determine whether the neural responses observed after static stretching are mediated by sensitivity of muscle spindles, spinal excitability or cortical excitability and how long these influences last. Nineteen volunteers (25.7 +/- 5.6 years old) were tested for the tendon tap reflex (T-reflex), H reflex and motor-evoked potentials on ankle flexors and extensors immediately, 5 and 10 min after 1 min static stretching applied at individual maximal ankle dorsiflexion, as well as immediately, 5 and 10 min after a control period of the same duration. Comparison of measurements collected immediately after stretching or control conditions revealed that the T-reflex was weaker after stretching than after control (-59.2% P = 0.000). The T-reflex showed a slow recovery rate within the first 150 s after stretching, but 5 min after the inhibition had disappeared. The H reflex increased immediately after stretching (+18.3%, P = 0.036), showed a quick tendency to recover and returned to control values within 5 min from stretching. Motor-evoked potentials were not affected by the procedure. These results suggest that 1 min of static stretching primarily decreases muscle spindle sensitivity and facilitates the H reflex, whereas effects on the motor cortex can be excluded. PMID- 28585767 TI - Computational Insights into the CH3 Cl+OH Chemical Reaction Dynamics at the Air Water Interface. AB - The reaction of methyl chloride with the hydroxyl radical OH is an important process in the troposphere. The kinetics of this reaction has been thoroughly studied in the gas phase, both experimentally and theoretically, but little is known about the effect of water on this reaction. In particular, investigating the reaction mechanism at the air-water interface is key in order to better understand the role of cloud water droplets and aerosols on the overall oxidation capacity of the troposphere. In this work, we have implemented a "rare event" approach combined to QM/MM (quantum mechanics and molecular mechanics) molecular dynamics simulations to investigate the dynamics of the H-abstraction reaction CH3 Cl+OH->CH2 Cl+H2 O at the air-water interface. For comparison, high-level ab initio calculations for the reaction mechanism in the gas phase are also reported and accurate kinetic constants at different temperatures are provided. PMID- 28585768 TI - Allergic rhinitis, rather than asthma, is a risk factor for dental caries. AB - OBJECTIVES: The association between AS (asthma) and dental caries is controversial, while that between allergic rhinitis (AR) and caries has not been established. This study aimed to verify the relationship among AR, AS and dental caries. DESIGN: Retrospective cohort study. SETTING: Data from Health Insurance Database of the Taiwan's National Health Insurance Research Database. PARTICIPANTS: Nine thousand and thirty-eight children born in 2004 were obtained. Their claims data were evaluated from birth to the age of 9 years. MAIN OUTCOME MEASURES: The frequencies of clinical visits for dental caries were calculated for primary teeth (age 1-5) and for dental transitional period (age 6-9). Differences in the frequencies of clinical visits for caries in AR vs non-AR and AS vs non-AS children were compared. Correlation between AR, AS and caries frequencies was studied, and the influences of AR drugs on the development of caries were evaluated. RESULTS: After adjusting for confounding factors and AS case, the frequencies of clinical visits for caries were higher in AR (increased by 13%-25% and P<.001 at different age periods). The AR frequencies significantly correlated with caries frequencies in children with AR. Different AR drugs also correlated with caries formation. After adjusting for confounding factors and AR case, there was no relationship between AS and caries in children. CONCLUSION: Asthma is not associated with dental caries, but AR can increase the frequency of clinical visits for caries. Medications for AR may also play a role in caries formation. Thus, AR may be a risk factor for childhood dental caries. PMID- 28585769 TI - Effects of transforming growth factor-beta1 treatment on muscle regeneration and adipogenesis in glycerol-injured muscle. AB - Transforming growth factor (TGF)-beta1 is associated with fibrosis in many organs. Recent studies demonstrated that delivery of TGF-beta1 into chemically injured muscle enhances fibrosis. In this study, we investigated the effects of exogenous TGF-beta1 on muscle regeneration and adipogenesis in glycerol-injured muscle of normal mice. Tibialis anterior (TA) muscles were injured by glycerol injection. TGF-beta1 was either co-injected with glycerol, as an 'early treatment' group, or injected at day 4 after glycerol, as a 'late treatment' group and the TA muscles were collected at day 7 after initial injury. Myotube density was significantly lower in the early treatment group than in the glycerol injured group (without TGF-beta1 treatment). Moreover, the Oil red O-positive area was significantly smaller in the early treatment group than in the late treatment group and glycerol-injured group. Furthermore, TGF-beta1 treatment increased endomysial fibrosis and induced immunostaining of alpha-smooth muscle actin. The greater inhibitory effects of early TGF-beta1 treatment than that of late TGF-beta1 treatment during regeneration in glycerol-injured muscle suggest a more potent effect of TGF-beta1 on the initial stage of muscle regeneration and adipogenesis. Combination of TGF-beta1 with glycerol might be an alternative to enhance muscle fibrosis for future studies. PMID- 28585770 TI - Mining the Proteome of Leishmania donovani for the Development of Novel MHC Class I Restricted Epitope for the Control of Visceral Leishmaniasis. AB - Although, the precise host defence mechanism(s) is not completely understood, T cell-mediated immune responses is believed to play a pivotal role in controlling parasite infection. Here we target the stage dependent over expressed gene. Here, the consensus based computational approach was adopted for the screening of potential major histocompatibility complex class I restricted epitopes. Based on the computational analysis and previously published report, a set 19 antigenic proteins derived from Leishmania donovani were screened for further characterization as vaccine candidates. A total of 49 epitopes were predicted, which revealed a comprehensive binding affinity to the 40 different MHC class I supertypes. Based on the population coverage and HLA cross presentation, nine highly promiscuous epitopes such as LTYDDVWTV (P1), FLFPQRTAL(P2), FLFSNGAVV (P3), YIYNFGIRV (P4), YMTAAFAAL (P5), KLLRPFAPL (P6), FMLGWIVTI (P7), SLFERNKRV (P8), and SVWNRIFTL (P9) which have either a high or an intermediate TAP binding affinity were selected for further analysis. Theoretical population coverage analysis of polytope vaccine (P1-P9) revealed more than 92% population. Stimulation with the cocktail of peptide revealed a proliferative CD8+ T cell response and increased IFN-gamma production. An upregulated NF-kappaB activity is thought to be play a pivotal role in T cell proliferation against the selected peptide. The Th1-type cytokine profile (presence of IFN-gamma and absence of IL 10) suggests the potentiality of the cocktail of epitope as a subunit vaccine against leishmaniasis. However, the efficiency of these epitopes to trigger other Th1 cytokines and chemokines in a humanized mice model could explore its plausibility as a vaccine candidate. J. Cell. Biochem. 119: 378-391, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28585771 TI - Thermal sensitivity of bacteriocytes constrains the persistence of intracellular bacteria in whitefly symbiosis under heat stress. AB - Temperature affects the persistence of diverse symbionts of insects. Our previous study indicates that the whitefly symbionts confined within bacteriocytes or scattered throughout the body cavity outside bacteriocytes may have differential thermal sensitivity. However, the underlying mechanisms remain largely unknown. Here, we report that following continuous heat stress, Portiera and Hamiltonella were almost completely depleted in two species of Middle East-Asia Minor 1 (MEAM1) and Mediterranean (MED) of the Bemisia tabaci whitefly cryptic species complex. Meanwhile, proliferation of bacteriocytes was severely inhibited and approximately 50% of the nymphs had lost one of the two bacteriomes. While cell size of bacteriocytes was increased, cell number was severely decreased leading to reduction of total volume of bacteriocytes. Moreover, bacteriocyte organelles and associated symbionts were lysed, and huge amount of electron-dense inclusions accumulated. Eventually, Portiera and Hamiltonella failed to be transmitted to the next generation. In contrast, Rickettsia could be detected although at a reduced level, and successfully transmitted to eggs. The results suggest that the thermal sensitivity of bacteriocytes may limit thermal tolerance and vertical transmission of the associated symbionts, and consequently different patterns of distribution of symbionts may affect their capacity to tolerate unfavourable temperatures and persistence in the host. PMID- 28585772 TI - Adolescent perfectionism: Structural features of the Frost Multidimensional Perfectionism Scale and correlates with attachment and psychopathology. AB - OBJECTIVES: Perfectionism is recognized as a significant risk factor for psychopathology. Emerging research links attachment to perfectionism in adult and college-age samples. The Frost Multidimensional Perfectionism Scale (FMPS) has been used in adults and adolescents with a variety of factor structures found. This study sought to establish the factor structure in a general adolescent sample prior to testing for associations between perfectionism, attachment, and psychopathology in the same sample. DESIGN: A cross-sectional survey design was used. Confirmatory factor analysis, and correlational and regression analyses were employed. METHODS: A total of 290 adolescents, aged 12-18 years, were recruited from a state secondary school. All completed the FMPS along with brief measures of attachment and psychopathology. RESULT: Exploratory and confirmatory factor analyses failed to replicate previously published models, and a new six item, 1-factor model representing perfectionism was found instead. This new variable was then used to establish a role for perfectionism and attachment anxiety in predicting internalizing problems. Perfectionism also correlated with conduct problems and hyperactivity. CONCLUSION: This study established a novel factor structure for the FMPS, allowing proof of principle of the role of perfectionism in a relationship with attachment and psychopathology, which after replication, may inform new interventions for perfectionism. Caution is noted about the use of extant perfectionism measures that are not properly developmentally informed and which do not capture the dynamic nature of adolescence and adolescent perfectionism. PRACTITIONER POINTS: Perfectionism is a feature of adolescent psychopathology, including internalizing and externalizing problems. Perfectionism is associated with attachment anxiety and together contributes to internalizing problems. Current conceptualizations of perfectionism may not capture the specific developmental and dynamic aspects of adolescence and should not be regarded as a stable personality trait. PMID- 28585773 TI - Electrically Activated Conductivity and White Light Emission of a Hydrocarbon Nanoring-Iodine Assembly. AB - Numerous otherwise difficult applications have been realized with materials, the chemical/physical properties of which can be controlled by external stimuli such as heat, pressure, photo-irradiation, and voltage bias. However, the complexity of design and the lack of easy-to-conduct synthetic methods make the creation of on-demand stimuli responsive materials a formidable task. Here we report an electric-stimuli-responsive multifunctional material, [10]CPP-I: crystalline assembly of a hydrocarbon nanoring ([10]cycloparaphenylene: [10]CPP) as an "electro-responsive porous host" and iodine as a "potentially functional molecule". Through applying electric stimulus, [10]CPP-I turned to exhibit two attractive properties: electronic conductivity and white light emission. We revealed that electric stimuli trigger the cascade formation of polyiodide chains inside the [10]CPP assembly through charge transfer, leading to the emergence of these properties. This "responsive porous host" approach is expected to be applicable for different stimuli, and opens the path for devising a generic strategy to the development of stimuli-responsive materials. PMID- 28585775 TI - The roles of the PD-1/PD-L1 pathway at immunologically privileged sites. AB - The PD-1/PD-L1 pathway plays a vital role in the maintenance of peripheral tolerance, promoting the development and function of regulatory T cells, and maintaining the quiescence of autoreactive T cells. Abnormalities in this inhibitory pathway are involved in the pathogenesis of some disorders such as tumours, autoimmune diseases, pregnancy complications, and transplantation rejection. Immune privilege represents a special immunological condition, where foreign antigens can be tolerated and do not elicit an immune response. The anterior chamber of the eye, central nervous system, testis, pregnant uterus, and hair follicles are all regarded as immune-privileged sites in humans. Numerous studies show that the PD-1/PD-L1 pathway contributes to the maintenance of the immune-privileged microenvironment. In this review, we will mainly focus on the roles of the PD-1/PD-L1 pathway in the anterior chamber of the eye, brain and testis, as well as further investigations in testis. PMID- 28585776 TI - Comparison of adverse events following pentavalent and diphtheria-tetanus pertussis vaccines among Nigerian children. AB - INTRODUCTION: Adverse events following immunization (AEFI) may follow the use of any vaccine. There is thus a need for documentation of the types and prevalence of AEFIs for each vaccine and early identification of new events or those occurring at rates higher than expected. When one vaccine replaces another, it is important to document the safety of the new vaccine as well as compare to that of the old. In this study, we aimed to document the AEFIs following the use of pentavalent vaccine recently introduced into the National Programme on Immunization and compare with those of diphtheria-tetanus-pertussis (DTwP) vaccine which it replaced. METHODS: This was a retrospective cohort study on infants with at least 2 immunization visits who commenced immunization between June 2011 and May 2013 at the Child Welfare Clinic of Institute of Child Health, University of Benin, Nigeria. At every visit for immunization, the caregiver is asked about any reaction that followed the previous immunization, and this is documented in immunization registers which data were reviewed for this study. RESULTS: There were 2475 doses of DTwP and pentavalent vaccines administered to 946 children. Adverse events following immunizations were reported following 487 (19.7%) doses. The prevalence of AEFIs following pentavalent vaccine (22.1%) was significantly higher than that following DTwP (13.5%) P < .0001. Significantly more AEFIs followed the first dose of either vaccine compared to subsequent doses P < .0001. The commonest AEFI reported for either vaccine was fever. CONCLUSION: Adverse events following immunization following pentavalent vaccine although higher than that following DTwP was within expected levels. PMID- 28585774 TI - A physiologically based pharmacokinetic model of vitamin D. AB - Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 MUg and 10 MUg) supplementation of vitamin D over the course of 28 days in the absence of sunlight. Vitamin D and its metabolites are highly lipophilic and binding assays of these compounds in serum may not account for binding by lipids and additional proteins. To compensate for the additional bound amounts, this study allowed the effective adipose-plasma partition coefficient to vary dynamically with the concentration of each compound in serum utilizing the Hill equation for binding. Through incorporating the optimized parameters with the adipose partition coefficient adaptation to the PBPK model, this study was able to fit serum concentration data for circulating vitamin D at all three supplementation concentrations within confidence intervals of the data. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28585777 TI - Natural Course of Co-Occurring PTSD and Alcohol Use Disorder Among Recent Combat Veterans. AB - Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) commonly co occur in veterans, yet little is known about the longitudinal course of PTSD and drinking in comorbid populations. This study assessed the natural course of daily alcohol consumption and weekly changes in PTSD symptoms in 112 recent combat veterans over the course of 11 months. Latent class growth mixture modeling was used to classify individuals into distinct classes with similar PTSD symptom and alcohol use growth trajectories. We then investigated theorized predictors of class membership including sociodemographics; pre-, peri-, and postdeployment factors; coping; symptom severity; and number of mental health/substance use appointments attended. Results revealed that most participants had severe and nonremitting PTSD. Trajectories for alcohol use included gradual and drastic declines, and chronic low-level drinking. The use of behavioral health services (odds ratio = 2.47) and fewer current stressors (odds ratio = 0.42) predicted AUD remission. Because little variation was observed in the PTSD course, our study did not observe coordinated fluctuations of PTSD symptoms and heavy drinking. Our findings suggest that treatment impacts the course of AUD and that recent combat veterans who do not seek PTSD treatment may have chronic and severe PTSD symptoms. PMID- 28585778 TI - Intensified Biobutanol Recovery by using Zeolites with Complementary Selectivity. AB - A vapor-phase adsorptive recovery process is proposed as an alternative way to isolate biobutanol from acetone-butanol-ethanol (ABE) fermentation media, offering several advantages compared to liquid phase separation. The effect of water, which is still present in large quantities in the vapor phase, on the adsorption of the organics could be minimized by using hydrophobic zeolites. Shape-selective all-silica zeolites CHA and LTA were prepared and evaluated with single-component isotherms and breakthrough experiments. These zeolites show opposite selectivities; adsorption of ethanol is favorable on all-silica CHA, whereas the LTA topology has a clear preference for butanol. The molecular sieving properties of both zeolites allow easy elimination of acetone from the mixture. The molecular interaction mechanisms are studied by density functional theory (DFT) simulations. The effects of mixture composition, humidity and total pressure of the vapor stream on the selectivity and separation behavior are investigated. Desorption profiles are studied to maximize butanol purity and recovery. The combination of LTA with CHA-type zeolites (Si-CHA or SAPO-34) in sequential adsorption columns with alternating adsorption and desorption steps allows butanol to be recovered in unpreceded purity and yield. A butanol purity of 99.7 mol % could be obtained at nearly complete butanol recovery, demonstrating the effectiveness of this technique for biobutanol separation processes. PMID- 28585780 TI - The effects of l-DOPA and sulpiride on growth hormone secretion at different injection times in Holstein steers. AB - The effects of l-DOPA, a precursor of dopamine (DA), and sulpiride, a D2 -type DA receptor blocker, on growth hormone (GH) and prolactin (PRL) secretion were investigated in steers. Eight Holstein steers (212.8 +/- 7.8 kg body weight) were used. Lighting conditions were 12:12 L:D (lights on: 06.00-18.00 hours). Blood samplings were performed during the daytime (11.00-15.00 hours) and nighttime (23.00-03.00 hours). Intravenous injections of drugs or saline were performed at 12.00 hour for the daytime and 00.00 hour for the nighttime, respectively. Plasma GH and PRL concentrations were determined by radioimmunoassay. l-DOPA did not alter the GH secretion when it was injected at 12.00 hour (spontaneous GH level at its peak). On the other hand, l-DOPA increased GH secretion at 00.00 hour (GH level at its trough). Injection of sulpiride suppressed GH secretion at 12.00 hour but did not affect GH levels at 00.00 hour. l-DOPA inhibited and sulpiride stimulated PRL release during both periods. These results suggest that dopaminergic neurons have stimulatory action on GH secretion and inhibitory action on PRL secretion in cattle. In addition, injection time should be considered to evaluate the exact effects on GH secretion due to its ultradian rhythm of GH secretion in cattle. PMID- 28585782 TI - [Pediatric Surgery in the European Reference Networks: look after, share, treat]. PMID- 28585779 TI - The impact of initial cancer stage on the incidence of venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) Cohort. AB - : Essentials Impact of cancer stage on venous thromboembolism (VTE) risk is not well-known in all cancers. The Scandinavian Thrombosis and Cancer Cohort provides person-time data and validated VTEs. Impact of cancer stage on VTE incidence tended to vary with cancer type. Cancer stage may not per se be a risk factor for VTE in all cancer types. SUMMARY: Background Absolute measures of the impact of cancer stage on the incidence of venous thromboembolism (VTE) in patients with distinct cancer types have not been investigated in a large population-based cohort study. Objectives To investigate differences in the incidence rates of objectively confirmed VTE according to the development of cancer in a large population-based cohort study. Cancer type and stage at the time of diagnosis were taken into account. Patients and Methods The Scandinavian Thrombosis and Cancer Cohort includes data regarding cancer types, stages and objectively confirmed VTE diagnoses among 144 952 participants followed from 1993 to 2012. We studied stage-specific incidence rates of VTE, and calculated incidence rate differences (IRDs) for VTE according to stages in patients with 10 types of solid cancer. Results During the entire follow-up, 335 VTEs occurred, of which 293 occurred within 5 years. The IRD of VTE in patients with distant metastasis as compared with those with localized disease indicated large variation depending on cancer type. The highest IRD was observed for pancreatic cancer (IRD of 187.0 * 10-3 person-years [p-y]; 95% confidence interval [CI] - 6.7 to 380.8), and the lowest IRD was observed for prostate cancer (IRD of 3.7 * 10-3 p-y; 95% CI - 7 to 15.2). Regional spread as compared with localized disease also indicated large variation depending on cancer type; the highest IRD was observed for uterine cancer (IRD of 37.6 * 10-3 p-y; 95% CI - 23.7 to 99), and the IRDs for breast and prostate cancer were close to zero. Conclusion More advanced cancer at the time of diagnosis was associated with a higher risk of VTE, but the strength of the associations differed substantially between cancer types. PMID- 28585781 TI - Interspecies cross-talk between co-cultured Pseudomonas putida and Escherichia coli. AB - Pseudomonas putida and Escherichia coli are ubiquitous microorganisms that can be isolated from soil rhizosphere, the surface of vegetables, fresh waters and wastewaters - environments in which they likely co-exist. Despite this, the potential interactions between these microbes have not been studied in detail. To analyse these interactions, we carried out RNA-seq transcriptomic analysis of these microbes as monocultures and as co-cultures. Our results show that co culture of these microbes significantly alters transcriptional profiles. The most dramatic transcriptional changes in both microorganisms were involved in central carbon metabolism, as well as adhesion to surfaces and the activation of drug efflux pumps. We also found that acetate production was one of the mechanisms used by E. coli K-12 MG1655 in response to the presence of P. putida DOT-T1E. PMID- 28585783 TI - [More than three hours, less than three years. Safety of anesthetic procedures in children under three years, subject to surgeries of more than three hours]. AB - The Food and Drug Administration (USA) warning (December 2016) on the safety of general anesthesia and sedation in patients younger that 3 years and pregnant women has raised many questions about the attitude that should be taken by professionals involved in the treatment of these patients. In view of this situation, the following Medical Scientific Societies: SEDAR, SECP, SECIP and SENeo have constituted a working group to analyze and clarify the safety of these techniques. In the present article, we conclude that at present both general anesthesia and deep sedation should continue to be considered safe techniques because there is no sufficient opposing evidence in clinical studies with humans. Despite this, we should not ignore the problem which must be followed carefully mainly in patients under three years of age undergoing anesthetic procedures longer than three hours or prolonged sedation in Neonatal or Pediatric Intensive Care Units. PMID- 28585785 TI - [Should the laparoscopic approach be avoided in a Nissen fundoplication procedure?] AB - OBJECTIVE: A recently published trial concludes that the recurrence of GER by laparoscopic fundoplication (LF) is higher than by open surgery (OF) modifying their informed consent and the surgery approach. Objective: To analyze our results to assess changing clinical practice where the laparoscopy is the approach of choice. MATERIAL AND METHODS: Retrospective study of patients undergoing laparoscopic fundoplication between 2010-2015. The same criteria of the reference clinical trial were applied in the collected data and recurrence criteria. RESULTS: 56 patients were operated. Our patients were comparable on sex and neurological injury to those of the study. Our average follow-up was 2.6 years (0.07-6.3). During the monitoring period there were five recurrences. The relative risk (RR) of failure in the LF group was 4 times higher than ours (RR 4.19; 95% CI, 1.66-10.5). Our survival was 90% per year. Multivariate analysis was performed (Cox regression controlling neurological injury, esophageal atresia and after gastrostomy). Neurological injury (p= 0.01) was the only risk factor for recurrence. CONCLUSION: A clinical trial is not enough to change clinical practice, but it motivates further studies. According to our review, the results suggest no increased risk of recurrence with laparoscopy but long-term monitoring is necessary. PMID- 28585784 TI - [Use of ultrasound for placement of central venous catheters in pediatrics: results of a national survey]. AB - OBJECTIVES: To study the variability of techniques used for vascular access of central venous devices, totally implanted and external tunneled, as well as polling the use of ultrasound by pediatric surgeons in Spain. MATERIAL AND METHODS: Descriptive study of a survey results, conducted by phone, email and online, about 20 items related to the placement of these devices in children and the use of ultrasound in this procedure. RESULTS: We analyzed 71 surveys from 31 national hospitals. The response rate was 54%. In 66% of the cases the pediatric surgeon is the one who carries out the vascular access. 75% of the respondents place less than 25 catheters/year. Only 28% have attended to an ultrasound-guided vascular puncture course. The vein used more often is the internal jugular (55%), followed by the subclavian (17.4%), with preference for the right side in most of the cases (87%). 64% perform the ultrasound-guided technique, 29% the venous cutdown and 7% the landmark approach. There is no significant association between the technique chosen (landmark vs ultrasound-guided) and the vein used (p= 0,062). The majority of the respondents does not modify the usual approach in case of coagulopathy. We describe the complications associated with the three techniques. CONCLUSIONS: The preferred via for the vascular access by pediatric surgeons is the internal jugular vein, being this access ultrasound-guided in most of the cases. 91.5% consider the use of ultrasound decreases the number of associated complications. Nevertheless, just a minority has attended to a training course. PMID- 28585787 TI - [Home training as a treatment of faecal incontinence and sphincter dyssynergia]. AB - OBJECTIVE: The defecation disorders represents the 3% of consultations in pediatrics patients. Our goal was to demonstrate the effectiveness and efficiency of the reeducation of the defecation maneuver through home training in patients with encopresis and sphincter dyssynergia. MATERIAL AND METHODS: Study of patients with fecal incontinence treated with home training at our center between 2014-2015. Anorectal manometry was performed and was valued defecation maneuver by expulsion of rectal probe with or without the ball. Daily sessions were performed using a Foley catheter (18-20Fr.) with progressive filling of the balloon, maximum 20cc. The response to the treatment was assessed in terms of episodes of soiling. RESULTS: Seven patients (6 males and 1 female) with a mean age of 9.7 years (range, 5-15) were included; two patients with anorectal malformation history, 1 Hirschsprung disease, 1 sacrococcygeal teratoma and 3 functional encopresis. Three patients had soiling episodes daily and 4 patients frequently. The mean basal pressure of anal channel was 32.34mmHg (range, 11.74 50.75) with negative defecation maneuver in 2 cases, deficient in 3 and dyssynergic in 2 patients. The mean time of biofeedback therapy to be asymptomatic was 5.14 months (range, 2-11), with a mean of 16.14 months (range, 3 24), with the 7 patients currently maintained clean. CONCLUSIONS: The present study suggests that re-education of defecation maneuver through home training, seems to be an effective and efficient therapy, achieving excellent results in medium term. PMID- 28585786 TI - [Results of the mesoportal bypass (Rex shunt) in the treatment of idiopathic extrahepatic portal vein obstruction in children]. AB - BACKGROUND: Extrahepatic portal vein obstruction (EPVO) is the principal cause of portal hypertension in children. The objective of this study was to analyze the capacity of the surgical technique that creates a mesoportal shunt to treat changes caused by EPVO. METHODS: Retrospective review of patients with idiopathic EPVO who underwent a mesoportal shunt and analysis of the changes in the number of leucocytes, platelets, prothrombin time and spleen size one year after the surgery. RESULTS: Twelve patients underwent surgery, out of which 10 had prior leukopenia, 11 thrombopenia, 9 longer prothrombin times and all had hypersplenism. One patient suffered a postoperative shunt thrombosis, was reoperated and underwent a change in the operative technique. The remaining patients (92%) have functioning shunts 4.3 +/- 2.5 years after surgery, and none have suffered any episode of gastrointestinal bleeding. One year after surgery, there were significant changes in the number of platelets, prothrombin time and spleen size, with no significant changes in the number of leukocytes. However, the number of patients who went from a leukopenic to a normal state was significant, as happened with changes in prothrombin time. CONCLUSIONS: Mesoportal Rex shunt improves some of the disorders caused by portal hypertension in children suffering EPVO, with a high rate of surgical success. This technique should be of first choice in these patients. PMID- 28585788 TI - [Intestinal complications in twin-to-twin transfusion syndrome (TTTS) treated by laser coagulation (LC)]. AB - AIM OF THE STUDY: The hemodynamic imbalance due to placental vascular anastomoses in TTTS but also vascular changes generated after intrauterine treatment may lead to hypoxic-ischemic complications. Different intestinal complications in TTTS are reviewed in this paper. METHODS: Retrospective review of TTTS cases treated by laser coagulation (LC) from 2012-2015. Demographic data, fetal therapy, prenatal diagnosis (US, MRI) and perinatal outcome were recorded. We describe cases with intestinal complications and their postnatal management. Results are expressed by median and range. RESULTS: 29 monochorionic pregnancies with TTTS were treated (23 LC, 4 cord occlusions and 2 cord occlusions after LC). The diagnosis was made at 19 (16-26) weeks and 86% presented stage of Quintero >= II. In 70% of mothers survived at least one fetus with a median of 31 (24-37) weeks at birth. Four patients had intestinal complications (1 jejunal atresia, 2 ileal atresia, 1 perforated necrotizing enterocolitis), half of them had prenatal diagnosis. Postnatal resections of the affected segments and ostomies were performed. Intestinal transit was restored and there were no severe digestive sequelae after 21 (8-38) months of follow up. CONCLUSIONS: Different types of intestinal complications were associated with TTTS and LC. US and MRI enable prenatal diagnosis of these complications and this allows prompt decisions after birth. PMID- 28585789 TI - [Management protocol in gastroschisis]. AB - AIM: There are two classical managements in gastroschisis: primary or delayed closure. From 2007 on, a multidisciplinary approach protocol based in preterm caesarean delivery at 34-35th gestational age (in order to minimize peel injury) plus primary closure is followed in our institution. Prior to this, term delivery, either by caesarean section or not, was the rule. METHODS: Retrospective study of gastroschisis's patients before (1978-2006) and after (2007-2016) protocol approval. Complex gastroschisis frequency, peel's presence, primary or delayed closure, complications, re-interventions, neonatal intensive care unit (NICU) length of stay, age at onset of enteral nutrition, total parenteral nutrition's length and length of stay were compared. MAIN RESULTS: Study groups: before (12 patients) and after (13 newborns) the protocol implantation (pre/post). Nine complex gastroschisis were observed in the pre protocol period, compared to one in the post-protocol era (p= 0.001). The re interventions also decreased: 58.33% in the pre-protocol vs. 15.38% in the post protocol group (p= 0.025). Complications rate were 66.67% before protocol vs. 23.07% after protocol (p= 0.028). NICU length of stay decreased from 40 +/- 32 to 17 +/- 12 days (p= 0.025). Parenteral total nutrition length was 61 +/- 36 in the pre-protocol vs. 15 +/- 6 in the port-protocol eras, respectively (p= 0.043). The age at onset of enteral nutrition was 34 +/- 26 vs. 9 +/- 5 days (p= 0.004) and hospitalization length was 98 +/- 81 days pre vs. 35 +/- 15 days post protocol implantation (p= 0.011). CONCLUSIONS: The protocol implantation has allowed primary closure, decreased hospitalization; reduced complications and mortality rate as well. PMID- 28585790 TI - [The diagnosis of pilomatrixoma in children is not as easy as it may seem. A review of 126 cases]. AB - OBJECTIVE: To describe our experience with pilomatrixomas, clinical presentation, clinical accuracy, associated diseases, and surgical treatment. METHODS: A retrospective review of patients with a pathology report of an excised pilomatrixoma between 2011 and 2014. Data regarding gender, age of intervention, number of masses, size, location, and preoperative clinical diagnosis, pathology report, recurrences, and associated diseases were collected. Statistical analysis was performed using EPIinfo 7.1.5. RESULTS: A total of 151 tumors in 138 patients were removed, 25 were excluded for having a clinical diagnosis of pilomatrixoma without confirmation of the pathology report. The remaining 126 cases have an average age of 8.26 years (range 1-14 years) and 50.72% are males. The tumors were located above the umbilicus in 97% of the cases, with a higher concentration of 50.72% in the head and neck. The clinical diagnosis corresponds with the pathology report in 69.05% of cases. Out of these confirmed cases the most frequent differential diagnosis is cystic lesion (11.90%) and dermoid cyst (10.22%). There were no cases of malignant degeneration. The average diameter is 1.13 cm, there were no recurrences, but there were 11 cases of a new lesion in a different location. There is no statistical association with other pathologies. The most frequent diseases found were obesity (3.62%) and attention deficit syndrome (3.62%). CONCLUSION: The pilomatrixoma is a tumor that appears predominantly in the head and neck, and has a difficult clinical diagnosis. Complete removal is curative, although it does not prevent the appearance of new lesions. PMID- 28585791 TI - [Pediatric traumatic brain injury due to civil gunshot wounds at a General Hospital in Cali, Colombia]. AB - OBJECTIVES: Traumatic brain injury (TBI) due to gunshot-wounds (GSW) is a critical situation in the pediatric population. The aim of this study is to characterize TBI in this population since there are few reports that describe it especially in Colombia where its incidence is high, also to determine which were the main mortality predictor within our population. MATERIAL AND METHODS: We conducted a retrospective cross-sectional study in which we reviewed pediatric medical records of patients that had consulted at the Fundacion Valle del Lili pediatric Emergency Room between January of 2011 and December of 2015 because of TBI due to GSW. A descriptive statistical analysis was performed. RESULTS: In our sample of 32 patients the average age was of 13.3 (SD +/- 5.4) and with 75% male patients. In our sample the Glasgow Coma Scale (GCS) at entry was less than 8 in 59.38%, a 15.6% needed craniotomy and 81.2% were admitted to the Intensive Care Unit (ICU). Death occurred in 43.75% of cases. The following mortality predictors were obtained: GCS at entry, pupillary exam and light reflexes, ISS, Marshal Score, absence of basal cisterns and presence of subarachnoid hemorrhage in CT scan, and APACHE II. CONCLUSIONS: TBI due to GSW is a devastating entity, especially in the pediatric population, they are responsible of high mortality and disability rates. There were no significant findings regarding infection rates and the use of surgery as a preventive method, therefore there's a chance it might not be indicated. PMID- 28585792 TI - [Endovascular embolization in the treatment of the pulmonary intralobar sequestration]. AB - INTRODUCTION: Up to date the classical therapeutic approach for intralobar sequestrations (IS) has been surgical excision. However, systemic arteries embolization is presented as an alternative, and even constitutes the first line of treatment in some centers. We summarize our experience in selected cases with the aim of preserving the maximum lung parenchyma. MATERIAL AND METHODS: Retrospective study of IS who underwent endovascular embolization at our institution between 2013 and 2014. RESULTS: Three patients of 12, 14 and 21 months old were treated. Two patients had unilateral IS, one in the left lower lobe (LLL) and the other in the right lower lobe (RLL); the third one had bilateral lesions (a CAM-S complex in the RLL and a IS in the LII). The embolization of the four lesions was performed via right femoral artery. The case with bilateral lesions underwent thoracoscopic lobectomy of the CAM-S 7 months after embolization, finding adherences to the diaphragm. None of the patients had immediate complications and were discharged within 48 hours after embolization. In successive ultrasound and plain radiographs controls, with a follow-up of 6, 18 and 30 months, no complications were found. CONCLUSIONS: Systemic vessels embolization is a treatment option for the treatment of IS that avoids surgery, preserves lung parenchyma and does not preclude surgical resection in case of treatment failure or presence of parenchymal lesions. Longer follow-up is needed to determine long-term effectiveness. PMID- 28585793 TI - Prevalence and Factors Associated With Second Eye Cataract Surgery and the Trend in the Time Interval Between the Two Eye Surgeries Based on the Malaysian National Eye Database. AB - PURPOSE: To study the prevalence of second eye cataract surgery (SECS), trend in time interval between subsequent surgeries over the years, and factors associated with SECS utilization among patients who underwent cataract surgeries in the Ministry of Health (MOH), Malaysia. DESIGN: Secondary cross-sectional analysis of the Malaysian National Eye Database (NED) data. METHODS: The Malaysian Cataract Surgery Registry collected data on patients who had cataract surgery from 2002 2004 and 2007-2012. Data collected included demography, operative events, time interval between 2 surgeries, and postoperative visual outcomes. Descriptive analysis was performed. RESULTS: Total surgeries increased from 11,954 in 2002 to 30,265 in 2012 with a proportionate increase in SECS (30.7% in 2002 to 34.3% in 2012). Poor vision (<6/12) was reduced from 81.1% to 14.2% after surgery. With improved data capturing, missing data reduced from 29.22% to 1.05%. The time interval between surgeries was 10.58 months in 2002 and 14.49 months in 2012. Malays (40.2%) and those aged 61-70 years (38.1%) had the highest number of SECS. Those aged 40-50 years (10.96 months) and with poorer vision (9.97 months) had the shortest time interval between the 2 surgeries. The commonest surgical method was phacoemulsification (72.3%). Negeri Sembilan State had the highest SECS rate (35.91%) and Melaka had the shortest interval between surgeries (10.15 months). CONCLUSIONS: Despite an increase in the number of SECS, the time interval is still long. Poor presenting second eye vision and disparity among different states warrants the health authority's attention and intervention. PMID- 28585794 TI - [Is hepatic cirrhosis a predisposing factor for Burkholderia cepacia pneumonia?] PMID- 28585796 TI - Impact of 13-valent pneumococal conjugate polysaccharide vaccination in exacerbations rate of COPD patients with moderate to severe obstruction. AB - OBJECTIVE: One of the major microorganisms described as the cause of exacerbations of chronic obstructive pulmonary disease (COPD) is Streptococcus pneumoniae. The aim of this study is to evaluate the impact of 13-valent pneumococcal conjugate polysaccharide vaccine (PCV13) on COPD patients with regard to the development of exacerbations and the possible differential effect according to the patient's phenotype. METHODS: Prospective observational study of patients with COPD and FEV1 <= 65% and 18-month follow-up. Main variables: vaccination status with PCV13, phenotype "exacerbator" or "non-exacerbator", number of exacerbations, hospitalization and deaths. A descriptive statistical analysis was performed according to the nature of the variable and an inferential analysis with CI95%, bivariate contrasts, and multivariate analysis. Significance level 5%. The statistical packages EPIDAT 3.0 and SPSS version 21.0 were used. RESULTS: 121 patients were included. Twenty-four percent were labeled as phenotype exacerbator. 36% were vaccinated with PCV13. During follow-up, 68% of patients had at least one exacerbation and 27% required hospitalization. We observed similarity (p> 0.05) in the number of exacerbations and deaths; however, the percentage of hospitalization in the vaccinated was 18%, compared to 32% in the non-vaccinated group. In the multivariate adjustment (controlling for the phenotype), an adjusted OR of 2.77 risk of hospitalization was observed in the non-vaccinated group (p = 0.044). CONCLUSIONS: Non-vaccination with PCV13 almost triples the risk of hospitalization in patients with COPD. PMID- 28585795 TI - [Decolonization for Staphylococcus aureus carriers in arthroplasty surgery after hip fracture]. AB - OBJECTIVE: Staphylococcus aureus is the main causative agent of joint prosthesis infections. The decolonization of the carriers is effective in the prevention of the infections of the elective arthroplasties. The aim of this study is to evaluate if it is also in arthroplasties after hip fracture. METHODS: Study in patients with hip fracture who underwent joint prosthesis from January 2011 to December 2015 with a protocol of S. aureus detection-decolonization with intranasal mupirocin and chlorhexidine baths. Patients between January 2009 and December 2010 were the comparison group. RESULTS: In the intervention period, the study of colonization of S. aureus was performed in 307 patients, of whom 87 were positive (28.3%). The study period was completed by 267 patients, of whom two developed S. aureus infection, compared to six of 138 in the control group (0.7% vs 4.3%, RR 0.1, p = 0.03). CONCLUSIONS: In our study, S. aureus decolonization in patients with hip fracture decreased the incidence of joint prosthesis infection by this microorganism. PMID- 28585797 TI - Outpatient parenteral antimicrobial therapy for infective endocarditis in patients over 80 years. AB - OBJECTIVE: The incidence of infective endocarditis is progressively increasing, especially in elderly patients. Outpatient parenteral antibiotic therapy (OPAT) is being an excellent alternative for treatment, but advanced age is one of the relative contraindications. The aim of this study is to compare the characteristics and prognosis of patients less or more than 80 years, treated with OPAT. METHODS: One hundred and ninety four patients were included between 1996 and 2015, 31 of them older than 80 years. RESULTS: The most frequently affected valve is the aortic one, mainly native valves. Most used antibiotics are ceftriaxone, ampicillin, cloxacillin and daptomycin. Differences in surgery (39.9% vs 9.7%, p=0.001) and use of infusion pump (55.2% vs 35.5%; p= 0.044) were observed, under 80 years and older respectively. No differences in readmissions and mortality were observed. CONCLUSIONS: OPAT could be considered an effective alternative for appropriately-selected elderly patients with infective endocarditis. PMID- 28585798 TI - ? PMID- 28585799 TI - Composites Formed from Thermoresponsive Polymers and Conductive Nanowires for Transient Electronic Systems. AB - The disintegration of transient electronic systems after a preprogrammed time or a particular stimulus (e.g., water, light, or temperature) is fundamentally linked to the properties and behavior of the materials used for their construction. Herein, we demonstrate that polymers exhibiting lower critical solution temperature (LCST) behavior can work as thermoresponsive substrates for circuitry and that these materials can be coupled with conductive nanowires to form a transient electronics platform with unique, irreversible temperature responsive behavior. The transient systems formed from composites of LCST polymers and conductive nanowires exhibit stable electrical performance in solution (Tsolution > LCST) for over 24 h until a cooling stimulus triggers a rapid (within 5 min) and gigantic (3-4 orders of magnitude) transition in electrical conductance due to polymer dissolution. Using a parylene mask, we are able to fabricate thermoresponsive electrical components, such as conductive traces and parallel-plate capacitors, demonstrating the versatility of this material and patterning technique. With this unique stimulus-responsive transient system and polymers with LCSTs above room temperature (e.g., poly(N isopropylacrylamide), methyl cellulose), we have developed a platform in which a circuit requires a source of heat to remain viable and is destroyed and vanishes once this heat source is lost. PMID- 28585800 TI - Self-Assembled 3D Hierarchical Porous Bi2MoO6 Microspheres toward High Capacity and Ultra-Long-Life Anode Material for Li-Ion Batteries. AB - Three-dimensional (3D) hierarchical porous Bi2MoO6 microspheres (HPBMs) were successfully prepared and used as the anode material in Li-ion batteries (LIBs) for the first time. The HPBMs showed a high capacity (>830 mAh.g-1, 734.5 mAh.cm 2), high rate capability (20 A.g-1, 177.7 mAh.g-1), and superior long cycle life (>2700 cycles) in the temperature range 5-55 degrees C without adding any other conductive carbon materials, such as graphene and carbon nanotubes. This can be reasonably attributed to their substantially high surface area, 3D hierarchical porous structure, and homogeneous conductive matrix composed of metallic nanoparticles. HPBMs surprisingly showed a high reversible discharge capacity of 537.2 mAh.g-1 (475.4 mAh.cm-2) and an average discharge voltage >3.0 V even when coupled with LiCoO2 in a full cell. The results highlight the feasibility of HPBMs as anode material for LIBs. PMID- 28585801 TI - Microneedle pH Sensor: Direct, Label-Free, Real-Time Detection of Cerebrospinal Fluid and Bladder pH. AB - Acid-base homeostasis (body pH) inside the body is precisely controlled by the kidneys and lungs and buffer systems, such that even a minor pH change could severely affect many organs. Blood and urine pH tests are common in day-to-day clinical trials and require little effort for diagnosis. There is always a great demand for in vivo testing to understand more about body metabolism and to provide effective diagnosis and therapy. In this article, we report the simple fabrication of microneedle-based direct, label-free, and real-time pH sensors. The reference and working electrodes were Ag/AgCl thick films and ZnO thin films on tungsten (W) microneedles, respectively. The morphological and structural characteristics of microneedles were carefully investigated through various analytical methods. The developed sensor exhibited a Nernstian response of -46 mV/pH. Different conditions were used to test the sensor to confirm their accuracy and stability, such as various buffer solutions, with respect to time, and we compared the reading with commercial pH electrodes. Besides that, the fabricated microneedle sensor ability is proven by in vivo testing in mouse cerebrospinal fluid (CSF) and bladders. The pH sensor procedure reported here is totally reversible, and results were reproducible after several rounds of testing. PMID- 28585802 TI - Cu/Zn Superoxide Dismutase Forms Amyloid Fibrils under Near-Physiological Quiescent Conditions: The Roles of Disulfide Bonds and Effects of Denaturant. AB - Cu/Zn superoxide dismutase (SOD1) forms intracellular aggregates that are pathological indicators of amyotrophic lateral sclerosis. A large body of research indicates that the entry point to aggregate formation is a monomeric, metal-ion free (apo), and disulfide-reduced species. Fibril formation by SOD1 in vitro has typically been reported only for harsh solvent conditions or mechanical agitation. Here we show that monomeric apo-SOD1 in the disulfide-reduced state forms fibrillar aggregates under near-physiological quiescent conditions. Monomeric apo-SOD1 with an intact intramolecular disulfide bond is highly resistant to aggregation under the same conditions. A cysteine-free variant of SOD1 exhibits fibrillization behavior and fibril morphology identical to those of disulfide-reduced SOD1, firmly establishing that intermolecular disulfide bonds or intramolecular disulfide shuffling are not required for aggregation and fibril formation. The decreased lag time for fibril formation resulting from reduction of the intramolecular disulfide bond thus primarily reflects the decreased stability of the folded state relative to partially unfolded states, rather than an active role of free sulfhydryl groups in mediating aggregation. Addition of urea to increase the amount of fully unfolded SOD1 increases the lag time for fibril formation, indicating that the population of this species does not dominate over other factors in determining the onset of aggregation. Our results contrast with previous results obtained for agitated samples, in which case amyloid formation was accelerated by denaturant. We reconcile these observations by suggesting that denaturants destabilize monomeric and aggregated species to different extents and thus affect nucleation and growth. PMID- 28585804 TI - Membrane Interactions of hIAPP Monomer and Oligomer with Lipid Membranes by Molecular Dynamics Simulations. AB - Interaction of human islet amyloid polypeptide (hIAPP) peptides with cell membrane is crucial for the understanding of amyloid toxicity associated with Type II diabetes (T2D). While it is known that the hIAPP-membrane interactions are considered to promote hIAPP aggregation into fibrils and induce membrane disruption, the membrane-induced conformation, orientation, aggregation, and adsorption behaviors of hIAPP peptides have not been well understood at the atomic level. Herein, we perform all-atom explicit-water molecular dynamics (MD) simulations to study the adsorption, orientation, and surface interaction of hIAPP aggregates with different sizes (monomer to tetramer) and conformations (monomer with alpha-helix and tetramer with beta-sheet-rich U-turn) upon adsorption on the lipid bilayers composed of both pure zwitterionic POPC (1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and mixed anionic POPC/POPE (1 palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine) (3:1) lipids. MD simulation results show that hIAPP monomer with alpha-helical conformation and hIAPP pentamer with beta-sheet conformation can adsorb on both POPC and POPC/POPE bilayers via a preferential orientation of N-terminal residues facing toward the bilayer surface. The hIAPP aggregates show stronger interactions with mixed POPC/POPE lipids than pure POPC lipids, consistent with experimental observation that hIAPP adsorption and fibrililation are enhanced on mixed lipid bilayers. While electrostatic interactions are main attractive forces to drive the hIAPP aggregates to adsorb on both bilayers, the introduction of the more hydrophilic head groups of POPE lipids further promote the formation of the interfacial hydrogen bonds. Complement to our previous studies of hIAPP aggregates in bulk solution, this computational work increases our knowledge about the mechanism of amyloid peptide-membrane interactions that is central to the understanding the progression of all amyloid diseases. PMID- 28585803 TI - Low Work Function Lacunary Polyoxometalates as Electron Transport Interlayers for Inverted Polymer Solar Cells of Improved Efficiency and Stability. AB - Effective interface engineering has been shown to play a vital role in facilitating efficient charge-carrier transport, thus boosting the performance of organic photovoltaic devices. Herein, we employ water-soluble lacunary polyoxometalates (POMs) as multifunctional interlayers between the titanium dioxide (TiO2) electron extraction/transport layer and the organic photoactive film to simultaneously enhance the efficiency, lifetime, and photostability of polymer solar cells (PSCs). A significant reduction in the work function (WF) of TiO2 upon POM utilization was observed, with the magnitude being controlled by the negative charge of the anion and the selection of the addenda atom (W or Mo). By inserting a POM interlayer with ~10 nm thickness into the device structure, a significant improvement in the power conversion efficiency was obtained; the optimized POM-modified poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5 b']dithiophene-2,6-diyl][3-fluoro-2-[(2- 33 ethylhexyl)carbonyl]thieno[3,4 b]thiophenediyl]]:[6,6]-phenyl-C70 butyric acid methyl ester (PTB7:PC70BM)-based PSCs exhibited an efficiency of 8.07%, which represents a 21% efficiency enhancement compared to the reference TiO2 cell. Similar results were obtained in POM-modified devices based on poly(3-hexylthiophene) (P3HT) with electron acceptors of different energy levels, such as PC70BM or indene-C60 bisadduct (IC60BA), which enhanced their efficiency up to 4.34 and 6.21%, respectively, when using POM interlayers; this represents a 25-33% improvement as compared to the reference cells. Moreover, increased lifetime under ambient air and improved photostability under constant illumination were observed in POM-modified devices. Detailed analysis shows that the improvements in efficiency and stability synergistically stem from the reduced work function of TiO2 upon POM coverage, the improved nanomorphology of the photoactive blend, the reduced interfacial recombination losses, the superior electron transfer, and the more effective exciton dissociation at the photoactive layer/POM/TiO2 interfaces. PMID- 28585806 TI - Sodium-Selective Fluoroionophore-Based Optodes for Seawater Salinity Measurement. AB - A new fluorescent sensor for Na+ is presented. The sensor relies on a Na+ selective fluoroionophore based on a bright red-emitting BODIPY chromophore. The fluorescence of the fluoroionophore is enhanced upon binding of Na+-ions to the highly selective aza-crown ether receptor due to reduction of the photoinduced electron transfer (PET) quenching. Solid state sensing materials were prepared by physically embedding the fluoroionophore into water-swellable biocompatible polymer matrices (polyurethane hydrogels), thus enabling continuous measurements of aqueous samples. Despite the simple design, the sensor showed no leaching of the indicator and featured fast and reversible response. Among different polyurethane hydrogels investigated, the hydrogel D1 featuring the highest water uptake was found to be the most suitable due to the highest dynamics between "off" and "on" states. Due to little or no cross sensitivity to other ions (e.g., Mg2+, Ca2+, K+) and its insensitivity to potential changes in pH, this sensor is promising for use in clinical diagnostics and for biological and marine applications. Fiber-optic sensors based on referenced read-out with a compact phase fluorimeter were prepared. To demonstrate their practical applicability, the sensors were used to determine the salinity in the seawater and brackish water of the Baltic Sea. PMID- 28585805 TI - Ligand-Specific Restriction of Extracellular Conformational Dynamics Constrains Signaling of the M2 Muscarinic Receptor. AB - G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and beta-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands. Using the muscarinic M2 receptor as a model system, we have analyzed the relationship between ligand-dependent conformational changes as revealed in all-atom MD simulations and the activation of specific G proteins. We find that the extent of closure of the extracellular, allosteric binding site interferes with the activation of certain G proteins. Our data allow the rational design of Gi-biased agonists at the M2 receptor and delineate a simple principle which may be translated to other GPRCs. PMID- 28585807 TI - Isotope Tracing of Long-Term Cadmium Fluxes in an Agricultural Soil. AB - Globally widespread phosphate fertilizer applications have resulted in long-term increases in the concentration of cadmium (Cd) in soils. The accumulation of this biotoxic, and bioaccumulative metal presents problems for the management of soil plant-animal systems, because the magnitude and direction of removal fluxes (e.g., crop uptake, leaching) have been difficult to estimate. Here, Cd isotopic compositions (delta114/110Cd) of archived fertilizer and soil samples from a 66 year-long agricultural field trial in Winchmore, New Zealand, were used to constrain the Cd soil mass balance between 1959 and 2015 AD, informing future soil Cd accumulation trajectories. The isotopic partitioning of soil Cd sources in this system was aided by a change in phosphate source rocks in 1998 AD, and a corresponding shift in fertilizer isotope composition. The dominant influence of mixing between isotopically distinct Cd end-members was confirmed by a Bayesian modeling approach. Furthermore, isotope mass balance modeling revealed that Cd removal processes most likely increased in magnitude substantially between 2000 and 2015 AD, implying an increase in Cd bioaccumulation and/or leaching over that interval. Natural-abundance stable isotopes are introduced here as a powerful tool for tracing the fate of Cd in agricultural soils, and potentially the wider environment. PMID- 28585808 TI - Evidence for Improved Encapsulated Pathway Behavior in a Bacterial Microcompartment through Shell Protein Engineering. AB - Bacterial microcompartments are a class of proteinaceous organelles comprising a characteristic protein shell enclosing a set of enzymes. Compartmentalization can prevent escape of volatile or toxic intermediates, prevent off-pathway reactions, and create private cofactor pools. Encapsulation in synthetic microcompartment organelles will enhance the function of heterologous pathways, but to do so, it is critical to understand how to control diffusion in and out of the microcompartment organelle. To this end, we explored how small differences in the shell protein structure result in changes in the diffusion of metabolites through the shell. We found that the ethanolamine utilization (Eut) protein EutM properly incorporates into the 1,2-propanediol utilization (Pdu) microcompartment, altering native metabolite accumulation and the resulting growth on 1,2 propanediol as the sole carbon source. Further, we identified a single pore lining residue mutation that confers the same phenotype as substitution of the full EutM protein, indicating that small molecule diffusion through the shell is the cause of growth enhancement. Finally, we show that the hydropathy index and charge of pore amino acids are important indicators to predict how pore mutations will affect growth on 1,2-propanediol, likely by controlling diffusion of one or more metabolites. This study highlights the use of two strategies to engineer microcompartments to control metabolite transport: altering the existing shell protein pore via mutation of the pore-lining residues, and generating chimeras using shell proteins with the desired pores. PMID- 28585809 TI - BSim 2.0: An Advanced Agent-Based Cell Simulator. AB - Agent-based models (ABMs) provide a number of advantages relative to traditional continuum modeling approaches, permitting incorporation of great detail and realism into simulations, allowing in silico tracking of single-cell behaviors and correlation of these with emergent effects at the macroscopic level. In this study we present BSim 2.0, a radically new version of BSim, a computational ABM framework for modeling dynamics of bacteria in typical experimental environments including microfluidic chemostats. This is facilitated through the implementation of new methods including cells with capsular geometry that are able to physically and chemically interact with one another, a realistic model of cellular growth, a delay differential equation solver, and realistic environmental geometries. PMID- 28585810 TI - Structure-Based Correlation of Light-Induced Histidine Reactivity in A Model Protein. AB - Light is known to induce covalently linked aggregates in proteins. These aggregates can be immunogenic and are of concern for drug product development in the biotechnology industry. Histidine (His) is proposed to be a key residue in cross-link generation ( Pattison , D. I. Photochem. Photobiol. Sci. 2012 , 11 , 38 - 53 ). However, the factors that influence the reactivity of His in proteins, especially the intrinsic factors are little known. Here, we used rhDNase, which only forms His-His covalent dimers after light treatment to determine the factors that influence the light-induced reactivity of His. This system allowed us to fully characterize the light-induced covalent dimer and rank the reactivities of the His residues in this protein. The reactivities of these His residues were correlated with solvent accessibility-related parameters both by crystal structure-based calculations of solvent-accessible surface area and by hydrogen deuterium exchange (HDX) experiments. Through this correlation, we demonstrate that the photoreactivity of His is determined by both solvent accessibility and structural flexibility. This new insight can explain the highly complex chemistry of light-induced aggregation and help predict the aggregation propensity of protein under light treatment. PMID- 28585812 TI - Flexible Transparent Conductive Films with High Performance and Reliability Using Hybrid Structures of Continuous Metal Nanofiber Networks for Flexible Optoelectronics. AB - We report an Ag nanofiber-embedded glass-fabric reinforced hybrimer (AgNF GFRHybrimer) composite film as a reliable and high-performance flexible transparent conducting film. The continuous AgNF network provides superior optoelectronic properties of the composite film by minimizing transmission loss and junction resistance. In addition, the excellent thermal/chemical stability and mechanical durability of the GFRHybrimer matrix provides enhanced mechanical durability and reliability of the final AgNF-GFRHybrimer composite film. To demonstrate the availability of our AgNF-GFRHybrimer composite as a transparent conducting film, we fabricated a flexible organic light-emitting diode (OLED) device on the AgNF-GFRHybrimer film; the OLED showed stable operation during a flexing. PMID- 28585811 TI - Dinuclear RuII(bipy)2 Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation. AB - Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)2}2(MU-L)][CF3SO3]4 (L = bptz, 1a) and [{Ru(bipy)2}2(MU-L)][CF3SO3]2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)2Cl2. The complexes were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (~2 MUM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells. PMID- 28585813 TI - Green Synthesis of Nanosilica from Coal Fly Ash and Its Stabilizing Effect on CaO Sorbents for CO2 Capture. AB - High-temperature sorption of CO2 via calcium looping has wide applications in postcombustion carbon capture, sorption-enhanced hydrogen production, and inherent energy storage. However, fast deactivations of CaO sorbents and low CO2 uptake in the fast carbonation stage are major drawbacks of this technology. For the first time, we developed a green approach through the reuse of nanosilica derived from coal fly ash (CFA) to enhance both the cyclic CO2 uptakes and the sorption kinetics of CaO sorbents. The as-synthesized nanosilica-supported CaO sorbent showed superior cyclic stability even under realistic carbonation/calcination conditions, and maintained a final CO2 uptake of 0.20 g(CO2) g(sorbent)-1 within short carbonation time, markedly increased by 155% over conventional CaO sorbent. Significantly, it also exhibited very fast sorption rate and could achieve almost 90% of the total CO2 uptake within ~20 s after the second cycle, which is critical for practical applications. These positive effects were attributed to the formation of larnite (Ca2SiO4) and the physical nanostructure of silica, which could yield and keep abundant reactive small pores directly exposed to CO2 throughout multiple cycles. The proposed strategy, integrating the on-site recycling of CFA, appears to be promising for CO2 abatement from coal-fired power plants. PMID- 28585814 TI - Carbazolic Porous Framework with Tetrahedral Core for Gas Uptake and Tandem Detection of Iodide and Mercury. AB - A multifunctional carbazolic porous framework (Cz-TPM), with a tetrahedral core, has been synthesized by FeCl3 oxidative coupling polymerization. The Brunauer Emmett-Teller surface area of the obtained polymers reaches 713.2 m2 g-1. Gas adsorption isotherms show that Cz-TPM exhibits large carbon dioxide (97.9 mg g-1, 9.8 wt %, 273 K, and 1 bar) and hydrogen uptake capacities (149.3 cm3 g-1, 1.34 wt %, 77 K, and 1 bar). Furthermore, Cz-TPM has been found to display tandem visual detection of iodide and mercury, respectively. The Cz-TPM dispersion turns to yellow in the presence of iodide salts and subsequently changes to nearly colorless on addition of Hg2+ salts that could be easily observed by the naked eye. Cz-TPM can detect I- via "turn off" fluorescence quenching, and then the in situ generated Cz-TPM@I complexes can recognize Hg2+ ions via "turn on" fluorescence recovery. More importantly, Cz-TPM is stable over common solvents and can be easily recovered by excessive water washing and centrifugation for further repeated use. As far as we know, carbazolic porous organic frameworks enabling detection of I- and Hg2+ have not been reported. PMID- 28585816 TI - Single-Molecule Detection of Polynucleotide Kinase Based on Phosphorylation Directed Recovery of Fluorescence Quenched by Au Nanoparticles. AB - 5'-Polynucleotide kinase such as T4 polynucleotide kinase (T4 PNK) may catalyze the phosphorylation of 5'-hydroxyl termini in nucleic acids, playing a crucial role in DNA replication, DNA recombination, and DNA damage repair. Here, we demonstrate for the first time single-molecule detection of PNK based on phosphorylation-directed recovery of fluorescence quenched by Au nanoparticle (AuNP) in combination with lambda exonuclease-mediated cleavage reaction. In the presence of PNK, the gamma-phosphate group from adenosine triphosphate (ATP) is transferred to 5'-hydroxyl terminus, resulting in 5'-phosphorylation of the hairpin probe. The phosphorylated hairpin probes may function as the substrates of lambda exonuclease and enable the removal of 5' mononucleotides from the stem, leading to the unfolding of hairpin structure and the formation of binding probes. The resultant binding probes may specifically hybridize with the AuNP modified capture probes, forming double-strand DNA (dsDNA) duplexes with 5' phosphate groups as the substrates of lambda exonuclease and subsequently leading to the cleavage of capture probes and the liberation of Cy5 molecules and the binding probes. The released binding probes may further hybridize with new capture probes, inducing cycles of digestion-release-hybridization and consequently the release of numerous Cy5 molecules. Through simply monitoring Cy5 molecules with total internal reflection fluorescence (TIRF)-based imaging, PNK activity can be quantitatively measured. This assay is very sensitive with a limit of detection of 9.77 * 10-8 U/MUL, and it may be further used to screen the PNK inhibitors and measure PNK in cancer cell extracts. PMID- 28585817 TI - Production of Medium Chain Fatty Acids by Yarrowia lipolytica: Combining Molecular Design and TALEN to Engineer the Fatty Acid Synthase. AB - Yarrowia lipolytica is a promising organism for the production of lipids of biotechnological interest and particularly for biofuel. In this study, we engineered the key enzyme involved in lipid biosynthesis, the giant multifunctional fatty acid synthase (FAS), to shorten chain length of the synthesized fatty acids. Taking as starting point that the ketoacyl synthase (KS) domain of Yarrowia lipolytica FAS is directly involved in chain length specificity, we used molecular modeling to investigate molecular recognition of palmitic acid (C16 fatty acid) by the KS. This enabled to point out the key role of an isoleucine residue, I1220, from the fatty acid binding site, which could be targeted by mutagenesis. To address this challenge, TALEN (transcription activator-like effector nucleases)-based genome editing technology was applied for the first time to Yarrowia lipolytica and proved to be very efficient for inducing targeted genome modifications. Among the generated FAS mutants, those having a bulky aromatic amino acid residue in place of the native isoleucine at position 1220 led to a significant increase of myristic acid (C14) production compared to parental wild-type KS. Particularly, the best performing mutant, I1220W, accumulates C14 at a level of 11.6% total fatty acids. Overall, this work illustrates how a combination of molecular modeling and genome-editing technology can offer novel opportunities to rationally engineer complex systems for synthetic biology. PMID- 28585815 TI - Neisseria gonorrhoeae Lytic Transglycosylases LtgA and LtgD Reduce Host Innate Immune Signaling through TLR2 and NOD2. AB - Neisseria gonorrhoeae releases anhydro peptidoglycan monomers during growth through the action of two lytic transglycosylases encoded in the N. gonorrhoeae genome, LtgA and LtgD. Because peptidoglycan and peptidoglycan components activate innate immune signaling, we hypothesized that the activity of LtgA and LtgD would influence the host responses to gonococcal infection. N. gonorrhoeae lacking LtgA and LtgD caused increased host production of inflammatory cytokines IL-1beta and TNF-alpha. Culture supernatants from DeltaltgA/DeltaltgD N. gonorrhoeae contain more shed outer membrane-associated proteins and multimeric peptidoglycan fragments rather than monomers. These culture supernatants were more potent activators of host TLR2 and NOD2 signaling when compared to supernatants from the isogenic parental N. gonorrhoeae strain. Purified peptidoglycan monomers containing anhydro muramic acid produced by LtgA were poor stimulators of NOD2, whereas peptidoglycan monomers containing reducing muramic acid produced by host lysozyme were potent stimulators of NOD2. These data indicate that LtgA and LtgD reduce recognition of N. gonorrhoeae by TLR2 and NOD2. PMID- 28585818 TI - Oxidation of Secondary Methyl Ethers to Ketones. AB - We present a mild way of converting secondary methyl ethers into ketones using calcium hypochlorite in aqueous acetonitrile with acetic acid as activator. The reaction is compatible with various oxygen- and nitrogen-containing functional groups and afforded the corresponding ketones in up to 98% yield. The use of this methodology could expand the application of the methyl group as a useful protecting group. PMID- 28585820 TI - Water Vapor Sorption in Hybrid Pillared Square Grid Materials. AB - We report water vapor sorption studies on four primitive cubic, pcu, pillared square grid materials: SIFSIX-1-Cu, SIFSIX-2-Cu-i, SIFSIX-3-Ni, and SIFSIX-14-Cu i. SIFSIX-1-Cu, SIFSIX-3-Ni, and SIFSIX-14-Cu-i were observed to exhibit negative water vapor adsorption at ca. 40-50% relative humidity (RH). The negative adsorption is attributed to a water-induced phase transformation from a porous pcu topology to nonporous sql and sql-c* topologies. Whereas the phase transformation of SIFSIX-1-Cu was found to be irreversible, SIFSIX-3-Ni could be regenerated by heating and can therefore be recycled. In contrast, SIFSIX-2-Cu-i, which is isostructural with SIFSIX-14-Cu-i, exhibited a type V isotherm and no phase change. SIFSIX-2-Cu-i was observed to retain both structure and gas sorption properties after prolonged exposure to heat and humidity. The hydrolytic stability of SIFSIX-2-Cu-i in comparison to its structural counterparts is attributed to structural features and therefore offers insight into the design of hydrolytically stable porous materials. PMID- 28585819 TI - Wettability of Complex Fluids and Surfactant Capped Nanoparticle-Induced Quasi Universal Wetting Behavior. AB - Even though there are quite large studies on wettability of aqueous surfactants and a few studies on effects of nanoparticles on wettability of colloids, to the best of authors' knowledge, there is no study reported on the combined effect of surfactant and nanoparticles in altering the wettability. The present study, for the first time, reports an extensive experimental and theoretical study on the combined effect of surfactants and nanoparticles on the wettability of complex fluids such as nanocolloids on different substrates, ranging from hydrophilic with a predominantly polar surface energy component (silicon wafer and glass) to near hydrophobic range with a predominantly dispersive component of surface energy (aluminum and copper substrates). Systematically planned experiments are carried out to segregate the contributing effects of surfactants, particles, and combined particle and surfactants in modulating the wettability. The mechanisms and the governing parameters behind the interactions of nanocolloids alone and of surfactant capped nanocolloids with different surfaces are found to be grossly different. The article, for the first time, also analyzes the interplay of the nature of surfaces, surfactant and particle concentrations on contact angle, and contact angle hysteresis (CAH) of particle and surfactant impregnated colloidal suspensions. In the case of nanoparticle suspensions, the contact angle is observed to decrease for the hydrophobic system and increase for the hydrophilic systems considered. On the contrary, the combined particle and surfactant colloidal system shows a quasi-unique wetting behavior of decreasing contact angle with particle concentration on all substrates. Also interestingly, the combined particle surfactant system at all particle concentrations shows a wetting angle much lower than that of the only-surfactant case at the same surfactant concentration. Such counterintuitive observations have been explained based on the near-surface interactivity of the particle, fluid, and surfactant molecules based on effective slip length considerations. The CAH analyses of colloidal suspensions at varying surfactant and particle concentrations reveal in depth physical insight into contact line pinning, and a unique novel relationship is established between the contact angle and differential energy for distorting the instantaneous contact angle for a pinned sessile droplet. A detailed theoretical analysis of the governing parameters influencing the wettability has been presented invoking the principles of DLVO (Derjaguin-Landau-Verwey Overbeek), surface energy and interaction parameters influencing at the molecular scale, and the theoretical framework is found to support the experimental observations. PMID- 28585821 TI - Polarized Raman and Infrared Spectroscopy and ab Initio Calculation of Palmitic and Stearic Acids in the Bm and C Forms. AB - A complete experimental study on the vibrational properties of palmitic and stearic acids crystallized in the Bm and C forms, both belonging to the monoclinic system with the P21/a (C2h5) space group, through polarized Raman and infrared spectroscopy, is reported in this paper. Density functional theory calculations were also performed to assign the normal modes and to help in the interpretation of the experimental data. The different polarizations were compared and their influence on the spectral profiles, in both the lattice and the internal mode regions, was discussed. In general, the Raman and infrared spectra exhibit accentuated differences among the polymorphic forms, which are associated with the different molecular modifications, defined as gauche and all trans conformations. Insights about interaction among different groups are also furnished. PMID- 28585822 TI - Size, Shape, and Phase Control in Ultrathin CdSe Nanosheets. AB - Ultrathin two-dimensional nanosheets raise a rapidly increasing interest due to their unique dimensionality-dependent properties. Most of the two-dimensional materials are obtained by exfoliation of layered bulk materials or are grown on substrates by vapor deposition methods. To produce free-standing nanosheets, solution-based colloidal methods are emerging as promising routes. In this work, we demonstrate ultrathin CdSe nanosheets with controllable size, shape, and phase. The key of our approach is the use of halogenated alkanes as additives in a hot-injection synthesis. Increasing concentrations of bromoalkanes can tune the shape from sexangular to quadrangular to triangular and the phase from zinc blende to wurtzite. Geometry and crystal structure evolution of the nanosheets take place in the presence of halide ions, acting as cadmium complexing agents and as surface X-type ligands, according to mass spectrometry and X-ray photoelectron spectroscopies. Our experimental findings show that the degree of these changes depends on the molecular structure of the halogen alkanes and the type of halogen atom. PMID- 28585823 TI - Copper-Catalyzed Radical Cascade Difluoromethylation/Cyclization of 2-(3 Arylpropioloyl)benzaldehydes: A Route to Difluoromethylated Naphthoquinones. AB - A novel copper-catalyzed cascade difluoromethylation/cyclization of 2-(3 arylpropioloyl)benzaldehydes has been developed. This method affords an efficient and straightforward access to structurally diverse difluoromethylated naphthoquinones in one pot, starting from readily available starting materials. The reaction represents the first trans-acyldifluoromethylation of internal alkynes, which features aldehydes as acceptors for the addition of alkenyl radicals. Furthermore, this protocol can also access to monofluoromethylated naphthoquinone and difluoromethylated indanones in the same reaction condition. PMID- 28585824 TI - Effect of Bisulfate, Ammonia, and Ammonium on the Clustering of Organic Acids and Sulfuric Acid. AB - We investigate the effect of the bisulfate anion HSO4-, ammonium cation NH4+, and ammonia NH3 on the clustering of sulfuric acid and pinic acid or 3-methyl-1,2,3 butanetricarboxylic acid (MBTCA). The systems were chosen based on their expected relevance in atmospheric new particle formation. Using quantum chemical methods together with kinetic calculations, we study the ability of these compounds to enhance cluster formation and growth. The cluster structures are obtained and frequencies are calculated using three different DFT functionals (M06-2X, PW91, and omegaB97X-D) with the 6-31++G(d,p) basis set. The electronic energies are corrected using an accurate DLPNO-CCSD(T)/def2-QZVPP level of theory. The evaporation rates are evaluated based on the calculated Gibbs free energies. The interaction between the ions and sulfuric acid or carboxylic acid group is strong, and thereby small two-component ionic clusters are found to be very stable against evaporation. The presence of bisulfate stimulates the cluster formation through addition of the sulfuric acid, whereas the presence of ammonium favors the addition of organic acids. Bisulfate and ammonium enhance the first steps of cluster formation; however, at atmospheric conditions further cluster growth is limited due to the weak interaction and fast evaporation of the larger three-component clusters. On the basis of our results it is therefore unlikely that the studied organic acids and sulfuric acid, even together with bisulfate, ammonia, or ammonium can drive new-particle formation via clustering mechanisms. Other mechanisms such as chemical reactions are needed to explain observed new particle formation events in the presence of oxidized organic compounds resembling the acids studied here. PMID- 28585825 TI - Plasmon-Mediated Surface Engineering of Silver Nanowires for Surface-Enhanced Raman Scattering. AB - We reveal nanoscale morphological changes on the surface of a silver nanowire (AgNW) in the conventional surface-enhanced Raman scattering (SERS) measurement condition. The surface morphology changes are due to the surface plasmon-mediated photochemical etching of silver in the presence of certain Raman probes, resulting in a dramatic increase of Raman scattering intensity. This observation indicates that the measured SERS enhancement does not always originate from the as-designed/fabricated structures themselves, but sometimes with contribution from the morphological changes by plasmon-mediated photochemical reactions. Our work provides a guideline for more reliable SERS measurements and demonstrates a novel method for simple and site-specific engineering of SERS substrate and AgNW probes for designing and fabricating new SERS systems, stable and efficient TERS mapping, and single-cell SERS endoscopy. PMID- 28585826 TI - Field-Effect Tuned Adsorption Dynamics of VSe2 Nanosheets for Enhanced Hydrogen Evolution Reaction. AB - Transition metal dichalcogenides, such as MoS2 and VSe2 have emerged as promising catalysts for the hydrogen evolution reaction (HER). Substantial work has been devoted to optimizing the catalytic performance by constructing materials with specific phases and morphologies. However, the optimization of adsorption/desorption process in HER is rare. Herein, we concentrate on tuning the dynamics of the adsorption process in HER by applying a back gate voltage to the pristine VSe2 nanosheet. The back gate voltage induces the redistribution of the ions at the electrolyte-VSe2 nanosheet interface, which realizes the enhanced electron transport process and facilitates the rate-limiting step (discharge process) under HER conditions. A considerable low onset overpotential of 70 mV is achieved in VSe2 nanosheets without any chemical treatment. Such unexpected improvement is attributed to the field tuned adsorption-dynamics of VSe2 nanosheet, which is demonstrated by the greatly optimized charge transfer resistance (from 1.03 to 0.15 MOmega) and time constant of the adsorption process (from 2.5 * 10-3 to 5.0 * 10-4 s). Our results demonstrate enhanced catalysis performance in the VSe2 nanosheet by tuning the adsorption dynamics with a back gate, which provides new directions for improving the catalytic activity of non noble materials. PMID- 28585827 TI - Relating Ultrastable Glass Formation to Enhanced Surface Diffusion via the Johari Goldstein beta-Relaxation in Molecular Glasses. AB - Glasses are materials essential for modern technology; they are usually prepared by cooling liquids. Recently, novel ultrastable glasses (SGs) with extraordinary thermodynamic and kinetic stability have been created by vapor deposition at appropriate substrate temperatures. However, the underlying mechanism for the formation of SGs is still not established. For most of the molecular SGs created so far, we demonstrate that the formation of SGs is closely related to the Johari Goldstein beta-relaxation from the fact that the lowest substrate temperatures possible for the formation of SGs match the secondary glass-transition temperatures, where the beta-relaxation time reaches 103 s. Theoretically the beta-relaxation time via the primitive relaxation time of the coupling model has proven capable of accounting for the enhancement of molecular mobility at the surface. Thus our findings provide evidence to support that the immense enhancement of molecular diffusion at the surface is critical for the formation of SGs. The result has implications in the design and fabrication of SGs. PMID- 28585828 TI - Computational Dissection of Two-Dimensional Rectangular Titanium Mononitride TiN: Auxetics and Promises for Photocatalysis. AB - Recently, two-dimensional (2D) transition-metal nitrides have triggered an enormous interest for their tunable mechanical, optoelectronic, and magnetic properties, significantly enriching the family of 2D materials. Here, by using a broad range of first-principles calculations, we report a systematic study of 2D rectangular materials of titanium mononitride (TiN), exhibiting high energetic and thermal stability due to in-plane d-p orbital hybridization and synergetic out-of-plane electronic delocalization. The rectangular TiN monolayer also possesses enhanced auxeticity and ferroelasticity with an alternating order of Possion's Ratios, stemming from the competitive interactions of intra- and inter- Ti-N chains. Such TiN nanosystem is a n-type metallic conductor with specific tunable pseudogaps. Halogenation of TiN monolayer downshifts the Fermi level, achieving the optical energy gap up to 1.85 eV for TiNCl(Br) sheet. Overall, observed electronic features suggest that the two materials are potential photocatalysts for water splitting application. These results extend emerging phenomena in a rich family 2D transition-metal-based materials and hint for a new platform for the next-generation functional nanomaterials. PMID- 28585829 TI - Role of Spatial Constraints of Bronsted Acid Sites for Adsorption and Surface Reactions of Linear Pentenes. AB - The Bronsted acid sites of H-ZSM-5 and ferrierite reversibly adsborb linear pentenes via hydrogen bonding, rapidly isomerizing the double bond. On H-ZSM-5, dimerization of adsorbed pentenes occurs at a slower rate and leads to pentyl ester covalently bound to the surface. Pentene adsorbed on zeolites with narrower pores, such as ferrierite, remained stable in a hydrogen-bonded state even up to 423 K. Comparing the differential heat of adsorption of 2-pentene on silicalite and ferrierite allowed for the determination of the enthalpy difference between physically adsorbed pentene in ZSM-5 and the localized hydrogen-bonded pi-complex at Bronsted acid sites, -36 kJ/mol. The activation energy (35 kJ/mol) for dimerization is almost identical to this enthalpy difference, suggesting that the rate-determining step is associated either with the mobilization of pi-bonded 2 pentene or with the equally large activation barrier to form an alkoxy group via a carbenium-ion transition state. In a closed system, the dimerization rate is first order in the concentration of the pi-complex that is both in equilibrium with the mobile pentene phase and in production of the carbenium ion that reacts with the mobile pentene. Overall, the alkoxy group is -41 +/- 7 kJ/mol more stable than physisorbed pentene, establishing a series of energetically well separated groups of reactive surface species. PMID- 28585830 TI - Excitonic and Vibrational Coherence in the Excitation Relaxation Process of Two LH1 Complexes as Revealed by Two-Dimensional Electronic Spectroscopy. AB - Ultrafast excitation relaxation within a manifold exciton state and long-lived vibrational coherence are two universal characteristics of photosynthetic antenna complexes. In this work, we studied the two-dimensional electronic spectra of two core light-harvesting (LH1) complexes of Thermochromatium (Tch.) tepidum, native Ca2+-LH1 and modified Ba2+-LH1. The role of the vibrational coherence in the exciton relaxation was revealed by comparing the two LH1 with similar structures but different electronic properties and by the evolution of the exciton and vibrational coherence as a function of temperature. PMID- 28585831 TI - Characterization of Self-Assembled Monolayers on a Ruthenium Surface. AB - We have modified and stabilized the ruthenium surface by depositing a self assembled monolayer (SAM) of 1-hexadecanethiol on a polycrystalline ruthenium thin film. The growth mechanism, dynamics, and stability of these monolayers were studied. SAMs, deposited under ambient conditions, on piranha-cleaned and piranha + H2SO4 cleaned substrates were compared to monolayers formed on H-radical cleaned Ru surfaces. We found that alkanethiols on H-radical-cleaned Ru formed densely packed monolayers that remained stable when kept in a nitrogen atmosphere. X-ray photoelectron spectroscopy (XPS) shows a distinct sulfur peak (BE = 162.3 eV), corresponding to metal-sulfur bonding. When exposed to ambient conditions, the SAM decayed over a period of hours. PMID- 28585832 TI - Polymer-Chlorosome Nanocomposites Consisting of Non-Native Combinations of Self Assembling Bacteriochlorophylls. AB - Chlorosomes are one of the characteristic light-harvesting antennas from green sulfur bacteria. These complexes represent a unique paradigm: self-assembly of bacteriochlorophyll pigments within a lipid monolayer without the influence of protein. Because of their large size and reduced complexity, they have been targeted as models for the development of bioinspired light-harvesting arrays. We report the production of biohybrid light-harvesting nanocomposites mimicking chlorosomes, composed of amphiphilic diblock copolymer membrane bodies that incorporate thousands of natural self-assembling bacteriochlorophyll molecules derived from green sulfur bacteria. The driving force behind the assembly of these polymer-chlorosome nanocomposites is the transfer of the mixed raw materials from the organic to the aqueous phase. We incorporated up to five different self-assembling pigment types into single nanocomposites that mimic chlorosome morphology. We establish that the copolymer-BChl self-assembly process works smoothly even when non-native combinations of BChl homologues are included. Spectroscopic characterization revealed that the different types of self assembling pigments participate in ultrafast energy transfer, expanding beyond single chromophore constraints of the natural chlorosome system. This study further demonstrates the utility of flexible short-chain, diblock copolymers for building scalable, tunable light-harvesting arrays for technological use and allows for an in vitro analysis of the flexibility of natural self-assembling chromophores in unique and controlled combinations. PMID- 28585833 TI - Energetic Basis for Inhibition of Calcium Phosphate Biomineralization by Osteopontin. AB - Calcium oxalate kidney stones form attached to Randall's plaques (RP), calcium phosphate (Ca-P) deposits on the renal papillary surface. Osteopontin (OPN) suppresses crystal growth in the complex process of urinary stone formation, but the inhibitory role of active domains of OPN involved in the initial formation of the RPs attached to epithelial cells has yet to be clarified. Here we demonstrate the thermodynamic basis for how OPN sequences regulate the onset of Ca-P mineral formation on lipid rafts as a model membrane. We first quantify the kinetics of hydroxyapatite (HAP) nucleation on membrane substrates having liquid-condensed (LC) and liquid-expanded (LE) phases using in situ atomic force microscopy (AFM). We find that rates are sequence-dependent, and the thermodynamic barrier to nucleation is reduced by minimizing the interfacial free energy gamma. Combined with single-molecule determination of the binding energy (DeltaGB) of the OPN peptide segments adsorbed to the HAP (100) face, we show a linear relationship of gamma and DeltaGB, suggesting that the increase in the nucleation barriers correlates with strong peptide-crystal nuclei binding. These findings reveal fundamental energetic clues for inhibition of membrane-mediated nucleation by sequence motifs and subdomains within the OPN protein through spatial location of charged moieties and provide insight connecting peripheral cell membranes to pathological mineralization. PMID- 28585835 TI - General Synthetic Route toward Highly Dispersed Metal Clusters Enabled by Poly(ionic liquid)s. AB - The ability to synthesize a broad spectrum of metal clusters (MCs) with their size controllable on a subnanometer scale presents an enticing prospect for exploring nanosize-dependent properties. Here we report an innovative design of a capping agent from a polytriazolium poly(ionic liquid) (PIL) in a vesicular form in solution that allows for crafting a variety of MCs including transition metals, noble metals, and their bimetallic alloy with precisely controlled sizes (~1 nm) and record-high catalytic performance. The ultrastrong stabilization power is a result of an unusual synergy between the conventional binding sites in the heterocyclic cations in PIL and an in situ generated polycarbene structure induced simultaneously to the reduction reaction. PMID- 28585834 TI - Acute Consumption of Flavan-3-ol-Enriched Dark Chocolate Affects Human Endogenous Metabolism. AB - Flavan-3-ols and methylxanthines have potential beneficial effects on human health including reducing cardiovascular risk. We performed a randomized controlled crossover intervention trial to assess the acute effects of consumption of flavan-3-ol-enriched dark chocolate, compared with standard dark chocolate and white chocolate, on the human metabolome. We assessed the metabolome in urine and blood plasma samples collected before and at 2 and 6 h after consumption of chocolates in 42 healthy volunteers using a nontargeted metabolomics approach. Plasma samples were assessed and showed differentiation between time points with no further separation among the three chocolate treatments. Multivariate statistics applied to urine samples could readily separate the postprandial time points and distinguish between the treatments. Most of the markers responsible for the multivariate discrimination between the chocolates were of dietary origin. Interestingly, small but significant level changes were also observed for a subset of endogenous metabolites. 1H NMR revealed that flavan-3-ol-enriched dark chocolate and standard dark chocolate reduced urinary levels of creatinine, lactate, some amino acids, and related degradation products and increased the levels of pyruvate and 4 hydroxyphenylacetate, a phenolic compound of bacterial origin. This study demonstrates that an acute chocolate intervention can significantly affect human metabolism. PMID- 28585837 TI - Postsynthetic Approach for the Rational Design of Chiral Ferroelectric Metal Organic Frameworks. AB - Ferroelectrics (FEs) are materials of paramount importance with a wide diversity of applications. Herein, we propose a postsynthetic methodology for the smart implementation of ferroelectricity in chiral metal-organic frameworks (MOFs): following a single-crystal to single-crystal cation metathesis, the Ca2+ counterions of a preformed chiral MOF of formula Ca6II{CuII24[(S,S) hismox]12(OH2)3}.212H2O (1), where hismox is a chiral ligand derived from the natural amino acid l-histidine, are replaced by CH3NH3+. The resulting compound, (CH3NH3)12{CuII24[(S,S)-hismox]12(OH2)3}.178H2O (2), retains the polar space group of 1 and is ferroelectric below 260 K. These results open a new synthetic avenue to enlarge the limited number of FE MOFs. PMID- 28585839 TI - Solid-Phase Synthesis of Oxetane Modified Peptides. AB - Solid-phase peptide synthesis (SPPS) is used to create peptidomimetics in which one of the backbone amide C?O bonds is replaced by a four-membered oxetane ring. The oxetane containing dipeptide building blocks are made in three steps in solution, then integrated into peptide chains by conventional Fmoc SPPS. This methodology is used to make a range of peptides in high purity including backbone modified derivatives of the nonapeptide bradykinin and Met- and Leu-enkephalin. PMID- 28585836 TI - Artificial Base zT as Functional "Element" for Constructing Photoresponsive DNA Nanomolecules. AB - In contrast to small molecules, DNA and RNA macromolecules can be accurately formulated with base "elements" abbreviated as A, T, U, C, and G. However, the development of functionally artificial bases can result in the generation of new biomaterials with unique properties and applications. Therefore, we herein report the design and synthesis of a photoresponsive base as a new functional or molecular "element" for constructing DNA nanomolecules. The new base is made by fusion of an azobenzene with a natural T base (zT). zT, a new molecular element, is not only the most size-expanded T analogue but also a photoresponsive base capable of specific self-assembly through hydrogen bonding. Our results showed that stable and selective self-assembly of double-stranded DNAs occurred through zT-A base pairing, but it could still be efficiently dissociated by light irradiation. The photoresponsive DNA bases will provide the versatility required for constructing desired DNA nanomolecules and nanodevices. PMID- 28585840 TI - [Postoperative administration of octreotide to reduce lymphorrhea, lymphocele, lymphedema and lymphatic ascites after lymphadenectomy in gynecological malignancies]. AB - INTRODUCTION: Octreotide is a synthetic analogue of natural somatostatin. Octreotide effect on lymphorrhea reduction in gynecological malignancies has only been assessed in case studies. DESIGN: Original work. SETTING: Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Masaryk University and University Hospital Brno. METHODS: In 2014 there was a prospective, randomized, one-institution study. Patients underwent surgery including pelvic or pelvic and paraaortic lymphadenectomy for cervical, uterine and ovarian cancer. The informed consent was signed. Octreotide was evaluated in relation to diagnosis, surgery (laparoscopy versus laparotomy), pelvic and/or paraaortic lymphadenectomy, number of removed lymph nodes and their positivity, neoadjuvant chemotherapy, adjuvant chemotherapy, adjuvant radiotherapy, albumin, BMI, number of days with drains postoperatively, number of days in hospital, blood loss during surgery, time of surgery, total number of drains placed into abdominal cavity. In follow up period, within 1 year after surgery, we searched for lymphocele, lymph-edema of lower extremities and lymphatic ascites in relation to lymphorrhea. RESULTS: 44 patients (9 cervical, 19 endometrial and 16 ovarian cancer) were enrolled in two statistically comparable randomized groups. "Octreotide group", which paradoxically showed lymphorrhea of 4082 ml on average, (without 1992 ml, p = 0.001), needed drainage for more days (p = 0.001). The diagnosis had no influence on lymphorrhea in both groups (p = 0.966). The neoadjuvant chemotherapy was administered (p = 0.026), the more lymph nodes were removed (p = 0.018), the more days the drainage was in place (p < 0.001), the bigger the lymphorrhea; no relationship between lymphorrhea and age (p = 0.631), albumin level (p = 0.584), BMI ( p= 0.966) or number of positive nodes (p = 0.259), length of surgery (p = 0.206), blood loss (p = 0.494). Nor lymphedema (p = 0.404), nor lymphocele (p = 0.086), correlated with postoperative lymphorrhea. Lymphatic ascites was associated with lymphorrhea (p = 0.048). CONCLUSION: Octreotide did not reduce lymphorrhea and the incidence of lymphocele, lymphedema of lower extremities and lymphatic ascites within one year of follow-up period after surgery. According to our results, we do not recommend to administer the octreotide in oncogynecological patients after pelvic and/or paraaortic lymphadenectomy. PMID- 28585841 TI - [Vascular anatomy and abnormalities of retroperitoneal pelvic and paraaortic area in relation to the radical oncogynecological surgery - individual experiences]. AB - OBJECTIVE: The overview of vascular anatomy and abnormalities of retroperitoneal pelvic and paraaortic area in relation to the radical oncogynecological surgery. DESIGN: Retrospective study. SETTING: Gynecologic Oncology Center, Department of Obstetrics and Gynecology, Faculty of Medicine, Masaryk University and University Hospital Brno. MATERIAL AND METHODS: The overview of visualized vascular anatomy of retroperitoneal pelvic, infrarenal suprapelvic and subhepatic area in relation to the radical oncogynecological surgery. Presentation of physiological vascular anatomy. Summary of the most common abnormalities and potential complications in terms of vascular injury. Basic management of these complications from the viewpoint of oncogynecologist. CONCLUSION: The perfect knowledge of vascular anatomy and its possible abnormalities has represented an absolute necessity for uncomplicated course and sufficient extent of radical surgery. PMID- 28585842 TI - [Inflammatory bowel disease during pregnancy and childbirth]. AB - OBJECTIVE: The aim is to give basic information about inflammatory bowel disease (IBD) during pregnancy, to highlight the importance of treatment in pregnancy and also show our own experience with the issue. DESIGN: Original work - a retrospective study. SETTING: Department of Obstetrics and Gynecology, Hospital Horovice. RESULTS: We provide basic overview information about inheritance, fertility, mutual influence of IBD and pregnancy therapy in pregnancy and childbirth options for patients with IBD. We present also the results of the group of 17 patients with varying degrees of disability IBD (including patients after previous surgeries - bowel resection, hemicolectomy, ileostomy or with a pouch) that gave birth to our workplace. CONCLUSION: A crucial factor for good results is the degree of inflammation at the time of conception and during pregnancy. If the disease is inactive and nutrition of the diseased sufficient, there is no decrease in fertility, course of pregnancy is seamless, there is no greater risk of deterioration of disease in pregnancy and pregnancy do not differ from the normal population. The opposite situation occurs if there is a pregnancy at the time of disease activity. Then up to 75% pregnancy courses with big problems, fertility is declining, inflammation is also worsening and the risk of exacerbations increases during pregnancy, which aggravates the course of pregnancy and childbirth and has a negative effect on the fetus. Pregnancy is therefore necessary to plan for a longer period of disease stabilization and continue chronic medication and not discontinue drugs for fear of negative impact of medications on fetal development. On the contrary, active inflammation of the mother during pregnancy poses a greater risk to the fetus than adequate treatment. Commonly used drugs-aminosalicylates, corticosteroids, immunosuppressants and biological therapy appears to be safe and well tolerated during pregnancy. Method of delivery is individual and depends on the form and location of the inflammation and the preceding operations. PMID- 28585844 TI - [Abdominal pregnancy at a patient after cesarean section, bilateral salpingectomy and embryotransfer]. AB - OBJECTIVE: Presentation of rare complication following the assisted reproduction at a patient after cesarean section and bilateral salpingectomy. DESIGN: Case report. SETTINGS: Department of Obstetrics and Gynaecology, Regional Hospital Liberec, a. s.; Department of Obstetrics and Gynaecology, Palacky University Hospital, Olomouc. OBSERVATION: Pregnant woman, 26-years old, primiparous, with history of cesarean section and bilateral salpingectomy, was referred from the assisted reproduction centre to solve suspicion of molar intrauterine pregnancy. This diagnosis was settled on the basis of ultrasound scan of uterine cavity and high level of human choriogonadotropine. Instrumental revision of uterine cavity was performed, however there was not consequently demonstrated any histological prove of the pregnancy tissue in uterine cavity and decrease of human choriogonadotropine values. The verifying ultrasound examination was made and then the suspicion of ectopic pregnancy on the right side of the uterus was expressed. Laparoscopy diagnosed ectopic pregnancy localized in the right broad ligament. It was treated by exstirpation of the pregnancy tissue. CONCLUSION: The diagnosis of ectopic pregnancy should be based on personal history, human choriogonadotropine level assessment and pelvic ultrasound examination. Although it's important to evaluate all the components globally, ultrasound examination is in a majority of cases the most important part for setting the right diagnosis. PMID- 28585843 TI - Triple pregnancy with mixed chorionicity following in vitro fertilization: is fetal reduction neccesary? AB - OBJECTIVE: The increasing incidence and management of monozygotic twinning in patients undergoing in vitro fertilization (IVF) has been the subject of much debate. Here, we describe the management and outcome of two triple pregnancies with mixed chorionicity with a monochorionic-diamniotic twin pair and a singleton following the transfer of two embryos during IVF treatment. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Palacky University Hospital, Olomouc, Czech Republic. METHODS: This study involved Patient A (30 years of age; 0 para) and Patient B (32 years of age; I Para), both with triplets of mixed chorionicity following the transfer of two embryos during IVF treatment, and treated in The Fetal Medicine Centre, Palacky University Olomouc. Detailed counselling led to the deployment of different management strategies for each case. RESULTS: The monochorionic twin component of Patient A was terminated by fetal reduction in the 15th week of gestation, while the remaining single pregnancy was delivered at term without complication. Patient B opted for expectant management. However, the pregnancy was complicated by severe maternal morbidity and was terminated in the 28th week of gestation following the death of one fetus. CONCLUSION: Fetal reduction should be offered as a management tool to patients carrying triplets in order to improve perinatal survival. In triplets with mixed chorionicity, the reduction of monochorionic twins is particularly advisable in preventing the additional risk posed by a shared placenta. PMID- 28585845 TI - [Carcinoid of the appendix during pregnancy]. AB - OBJECTIVE: Early diagnosis of the appendiceal carcinoid during first trimester of pregnancy. DESIGN: Case report. SETTING: Department of Obstetrics and Gynaecology, Merciful Brothers Hospital, Brno. METHODS: Own observation, review of literature. CONCLUSION: In case of unclear clinical or intraoperative finding, the appendectomy may reveal a serious disease. Thorough examination of the appendix should be a part of every gynaecological operation. PMID- 28585846 TI - [Czech linguistic validation of the Pelvic Organ Prolapse/ Urinary Incontinence Sexual Questionnaire - IUGA revised]. AB - OBJECTIVE: To produce a Czech version of a validated tool for sexual quality of life assessment among women with pelvic floor disorders; PISQ-IR (Pelvic organ prolapse/Incontinence Sexual Questionnaire - Internationally Revised). DESIGN: Original study. SETTING: Department of Obstetrics and Gynecology, University Hospital and Faculty of Medicine, Charles University in Pilsen. METHODS: The whole process of translation and linguistic validation of the questionnaire followed the protocol of the International Urogynecology Association developed for this purpose. The original translation was repeatedly discussed with patients with incontinence or prolapse in order to preserve the meaning and comprehensibility of the items. The resulting questionnaire was reversely translated into English by an independent translator and sent to IUGA translation working group for validation. The translation was finalized based on recommendations from the group. RESULTS: PISQ-IR is a self-administered questionnaire improved from the previous and short versions. It contains 20 questions, the first question determines whether section 1 for sexually inactive or section 2 for sexually active women is to be completed. The first section for sexually inactive women contains five questions with 12 items. The second section comprises of 14 questions with 22 items for sexually active women with a partner or 12 questions with 19 items for those without a partner. The questionnaire is evaluated separately for individual sub-scales. Compared to former PISQ-12, the PISQ-IR was improved to enable separate assessment of individual domains and its subscales, and to be useful also in non-sexually active women and women with anal incontinence. At the same time it can be also utilized in case of incompletely filled-in questionnaire. A certain disadvantage for clinical practice is its more complex evaluation. CONCLUSION: Linguistic validation of a PISQ-IR questionnaire was performed and the questionnaire is presented. We present a Czech translation of a validated tool for assessment of quality of sexual life in women with prolapse or urinary/anal incontinence. Psychometric evaluation remains yet to be performed. PMID- 28585847 TI - [Uterine inversion]. AB - AIM: Summarize the literature on the inversion of the uterus. DESIGN: A review article. SETTING: Department of Obstetrics and Gynecology, SZZ Krnov, Department of Obstetrics and Gynecology, University Hospital, Palacky University, Olomouc. METHOD: Literature review was conducted using the following key words. There were included articles published in English since 1980, from which relevant data were obtained. RESULTS: In the literature the general occurrence is broad, ranging from 1:27 000 in the UK to 1:1739 in the US, where it varies greatly according to geographic location. The uterine inversion can be generally classified according to the period from birth to diagnosis, in relation to pregnancy or by anatomical degree of prolapse. From 1887 to 2006 there were only 150 cases of uterine inversion in non puerperal women recorded. In the vast majority the incidence was observed in women older than 45 years. 85% of uterine inversion was caused by benign pathology, only 15% was associated with cancer. Treatment consists of repositioning of the uterus, to which can be used in noninvasive and invasive techniques. CONCLUSION: Inversion of the uterus is a very serious and fortunately relatively rare complication in the third stage of labor, but also in non puerperal women. This is the situation with high maternal morbidity and mortality rates, at which it can easily cause life-threatening hemorrhage, disseminated intravascular coagulation and the development of hemorrhagic and neurogenic shock. In most of cases there are no risk factor. PMID- 28585848 TI - [Ultrasound diagnosis of fetal inflammatory response syndrome in women with preterm premature rupture of membrane]. AB - OBJECTIVE: The aim of this review is to analyze the existing possibilities of using ultrasound in the diagnosis of the fetal inflammatory response. DESIGN: Review. SETTINGS: Gynekologicko-porodnicka klinika, Fakultni nemocnice Ostrava. METHODS: Preterm delivery is defined as a delivery before completed 37 weeks of gestation. Approximately one-thirdof these cases is associated with preterm premature rupture of membranes. About forty percent of preterm premature rupture of membranes is complicated by the fetal inflammatory response syndrome, which is associated with the development of severe perinatal morbidity. Recent prenatal diagnosis of the fetal inflammatory response syndrome is based on the invasive methods (amniocentesis, cordocentesis), which are limited by several risk factors accompanying these procedures and technical difficulties. Therefore, there is an effort to replace them by non-invasive approach. The development of ultrasound, as a diagnostic method through the last decade, and knowledge of pathophysiological and morphological changes in fetal organs associated with the fetal inflammatory response may lead to more specific diagnosis in the future and improvement of neonatal outcome. CONCLUSION: Early identification of fetuses affected by FIRS in pregnancies with PPROM is necessary for right management of these pregnancy pathology. At this moment, ultrasonography examination of fetal lineal vein and fetal echocardiography, seems to be suitable for diagnosing FIRS. PMID- 28585849 TI - [Contemporary technicqes in diagnostic patients with vaginal microbiota]. AB - OBJECTIVE: Review of literature dealing with the specificity of the vagina from the standpoint of microbial colonization. DESIGN: Literature review. SETTING: Department of Obstetrics and Gynecology, Department of Clinical Microbiology, University Hospital and Medical Faculty in Hradec Kralove, Charles University Prague. METHODS: Analysis of the literature review and personal experience dealing with vaginal microbiota. PMID- 28585850 TI - ? PMID- 28585851 TI - Update on chronic complex patient malnutrition AB - The Scientific Committee of the Sociedad Espanola de Nutricion Parenteral y Enteral (SENPE) and the Nutricia Advanced Medical Nutrition company began this Course some years ago, and now, it is a referent course in the multidisciplinary training of Clinical Nutrition.With this issue we review the advances in Clinical Nutrition in different situations and, this year, the topic is the malnutrition in chronic complex patients. PMID- 28585853 TI - Is the integration of nutritional care in the different assistance levels possible? The Catalan experience. Clinical perspective AB - Disease-related malnutrition is highly prevalent in pathologies commonly integrating care complexity. Healthcare models for complexity must include malnutrition detection and approaches, since it is a key factor which has great impact on the patient's evolution and the consumption of healthcare resources. Malnourished patients present higher hospitalization, complication and mortality rates, higher demand of post-discharge social resources and higher hospital readmission frequency. Detecting malnutrition is necessary to implement a nutritional care program which might be used in any assistance level. The integration of health and social care and the development of information tools which are shared by the different assistance agents has allowed the development of a program for the management of disease-related malnutrition in patients with clinical complexity in Catalonia. PMID- 28585852 TI - Is the integration of nutritional care in the different assistance levels possible? Refl ections from the perspective of chronicity and clinical complexity AB - Nowadays, chronicity is the leitmotiv in all healthcare systems. Consequently, multimorbidity and the management of complex care needs become a critical challenge in modern welfare societies.Professionals and other agents' difficulties to identify and satisfy healthcare related needs of these patients is especially signifi cant in a 5% of the population. This has an enormous impact not only from a clinical perspective, but also in terms of the resilience of public health care systems. In this context, nutritional status plays an outstanding role as a health indicator and also as a determinant vector of morbidity and mortality. However, improvement possibilities regarding the evolution of epidemiological knowledge and the implementation of person-centered attention models are still vast.The management of malnutrition related to complex chronic conditions is not limited to the profi le of the patient's conditions, since the explanatory role of social factors, which become key to clinical management, is crucial.As a result of the above, integrated and person-centered approaches, where nutritional factors often play an important role, are required to provide care to the most vulnerable patients within our settings. Therefore, collaborative work appears as one of the keys to success. PMID- 28585854 TI - Nutritional approach of the patient with diabetes mellitus and chronic kidney disease. A case report AB - The prevention and treatment of chronic kidney disease (CKD) in diabetes through diet and lifestyle have been a topic of much interest over the years. Consideration of the type and amount of carbohydrate, protein and fat is required for optimal blood glucose control, for clinical outcomes related to renal function and for consideration of risk reduction for cardiovascular disease. Depending on the CKD stage different dietary changes should be considered protein calorie malnutrition is common in chronic kidney disease patients and is a powerful predictor of morbidity and mortality. We review the nutritional management of a diabetic patient throughout the progression of their CKD. PMID- 28585855 TI - Our great forgotten, chronic respiratory sufferers AB - Lung's own properties make that nutritional support, besides covering the requirements can modulate its infl ammatory response.Lung tissue has a low glucose stock. Fatty acids are the main energy producer of type II pneumocytes, which use them in order to form phospholipids, essential for surfactant whose creation and release decrease in acute lung injury (ALI). Glutamine is a good substratum for endocrine cells and type II pneumocytes. Due to high nutritional risk, it is important its assessments in disorders as COPD and acute respiratory distress syndrome (ADRS). Indirect calorimetry values the effect of ventilation and nutritional support, avoiding overfeeding. Hypophosphatemia and refeeding syndrome are frequent and need to be avoided because of their morbidity.In critically ill patients, malnutrition can lead to respiratory failure and increasing mechanical ventilation time. To avoid hypercapnia in weaning, glucose levels should be controlled.High lipids/carbohydrates ratio do not show usefulness in COPD neither mechanical ventilation removal. ALI patients beneficiate from an early start and the volume administered. Enteral nutrition with high fatty acids ratio (EPA, DHA and gamma-linolenic acid) and antioxidants do not show any superiority. Omega-3 fatty acid in parenteral nutrition could modulate infl ammation and immunosuppression in a positive manner. The use of glutamine, vitamins or antioxidants in these patients could be justified. PMID- 28585856 TI - How is the patient's nutrition after a stroke? AB - Neurological conditions usually cause altered levels of consciousness or swallowing mechanisms which make artificial nutritional support necessary. International guidelines recommend nutritional screening to detect malnutrition in patients with neurological diseases. Dysphagia is a common problem after a stroke, however, it is a treatable pathology, and swallowing rehabilitation allows for improving patients' nutritional status.Awareness of this problem is required among healthcare professionals both for its diagnosis and for the implementation of nutritional intervention measures. Patients should be tested for dysphagia within the first 24 hours of the stroke onset; this swallowing assessment as well as malnutrition screening should never be delayed by more than 72 hours. The present study addresses diagnostic and therapeutic approaches, the indications of the different nutritional treatments available and the transition to oral feeding in patients who have had a stroke episode. PMID- 28585857 TI - Polypharmacy and enteral nutrition in patients with complex chronic diseases AB - Oral medications are often administered through enteral feeding tubes in patients with complex chronic diseases. It is important to consider possible interactions between drugs and enteral nutrition that might lead to unsuccessful treatment or tube occlusion. These patients become subjects for higher risk of problems and errors such as drug incompatibility with enteral nutrition and inappropriate dosage form selection. It is possible to minimize the risk of tube occlusion and incompatibilities problems by recognizing potential medication errors, selecting the most appropriate drug and dosage form and using appropriate administration techniques. In this context, high-alert medications for patients with chronic diseases deserve special attention. Furthermore, risk exposure should be considered among healthcare professionals and patient caregivers handling hazardous drugs. Therefore, main incompatibility problems between drugs and enteral nutrition have been reviewed, including general recommendations for administration of oral medications through enteral feeding tubes and safe handling of hazardous drugs. Specific recommendations for administration of high alert medications for patients with chronic diseases are also included. PMID- 28585858 TI - Talking with the chronic patient about malnutrition AB - We talk with Alejandro Toledo, the President of the Fundacion Renal ALCER and Vicepresident of the First Platform of Patients Organizations. PMID- 28585860 TI - Frailty and cardiac rehabilitation: A long-neglected connection. PMID- 28585859 TI - Evaluation of the Potential for Drug Interactions With Patiromer in Healthy Volunteers. AB - INTRODUCTION: Patiromer is a potassium-binding polymer that is not systemically absorbed; however, it may bind coadministered oral drugs in the gastrointestinal tract, potentially reducing their absorption. METHODS: Twelve randomized, open label, 3-period, 3-sequence crossover studies were conducted in healthy volunteers to evaluate the effect of patiromer (perpetrator drug) on absorption and single-dose pharmacokinetics (PK) of drugs (victims) that might be commonly used with patiromer. Subjects received victim drug alone, victim drug administered together with patiromer 25.2 g (highest approved dose), and victim drug administered 3 hours before patiromer 25.2 g. The primary PK endpoints were area under the curve (AUC), extrapolated to infinity (AUC0-infinity), and maximum concentration ( Cmax). Results were reported as 90% confidence intervals (CIs) about the geometric mean AUC0-infinity and Cmax ratios with prespecified equivalence limits of 80% to 125%. RESULTS: Overall, 370 subjects were enrolled, with 365 receiving >=1 dose of patiromer; 351 subjects completed the studies and all required treatments. When coadministered with patiromer, the 90% CIs for AUC0 infinity remained within 80% to 125% for 9 drugs (amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil, and warfarin). The AUC0-infinity point estimate ratios for levothyroxine and metformin with patiromer coadministration were >=80%, with the lower bounds of the 90% CIs at 76.8% and 72.8%, respectively. For ciprofloxacin, the point estimate for AUC0-infinity was 71.5% (90% CI: 65.3-78.4). For 8 of 12 drugs, point estimates for Cmax were >=80% with patiromer coadministration; for ciprofloxacin, clopidogrel, metformin, and metoprolol, the point estimates were <80%. When patiromer was administered 3 hours after each victim drug, the 90% CIs for AUC0-infinity and Cmax for each drug were within the prespecified 80% to 125% limits. CONCLUSION: For 9 of the 12 drugs coadministered with patiromer, there were no clinically significant drug-drug interactions. For 3 drugs (ciprofloxacin, levothyroxine, and metformin), a 3-hour separation between patiromer and their administration resulted in no clinically significant drug drug interactions. PMID- 28585861 TI - Alternative measures reveal different but low estimates of labour market attachment after severe traumatic brain injury: A nationwide cohort study. AB - OBJECTIVE: To explore if the definition of labour market attachment (LMA) changes LMA proportions after severe traumatic brain injury (TBI). DESIGN: Cohort study with 5-year follow-up. PARTICIPANTS: Patients aged 18-64 years with severe TBI from 2004 to 2012 (n = 637) and matched controls (n = 2497). METHODS: LMA was defined in three ways. All definitions included patients working with no government benefits. Definition 2 included patients receiving unemployment benefits (LMA-unemployment benefits). Definition 3 included patients receiving supplemental benefits/services such as patients involved in work-activation schemes (LMA supplementary benefits). First week of return to work (RTW), stable LMA first year after RTW and weekly LMA prevalence were calculated. Patients and controls were compared using multivariable conditional logistic regression. RESULTS: LMA unemployment benefits had similar proportions to LMA with no benefits. These estimates were lower than LMA supplemental benefits where 52% attempted to RTW and 31% achieved stable LMA within 2 years. The maximal LMA prevalence (LMA supplementary benefits) decreased from 33 to 30% from years 2 to 5. Adjusted odds ratios were 0.05 and 0.06 for years 1 and 2, and 0.07 for stable LMA in patients compared to controls. CONCLUSION: LMA proportions differed depending on the definition. Regardless of definition, LMA proportions following severe TBI were low in Denmark. PMID- 28585862 TI - Preference-based care and research. PMID- 28585863 TI - Contamination of Carcasses and Utensils in Small Swine Slaughterhouses by Salmonella in the Northwestern Region of the State of Rio de Janeiro, Brazil. AB - Salmonella is a major foodborne pathogen that constantly threatens food safety in developed countries and underdeveloped countries such as Brazil, where it is responsible for 38% of notified cases of foodborne illness. Swine are one of the main meat-producing species that may asymptomatically carry Salmonella, periodically shedding the bacteria through feces. The state of Rio de Janeiro is not a major producer of swine meat, but small slaughterhouses are operational and produce meat for consumption within the state, although few studies have been conducted in the region. In this context, this study was designed to evaluate Salmonella contamination in carcasses, lymph nodes, feces, utensils, and the environment of three small slaughterhouses in the state of Rio de Janeiro. A total of 344 samples from carcasses, utensils, equipment, water, and the environment were collected from these slaughterhouses in the northwestern region of Rio de Janeiro. Salmonella was isolated from 36 (10.5%) samples: 10 of 48 carcasses, 19 of 96 lymph nodes, 4 of 48 fecal samples, 2 of 6 water samples, and 1 of 6 bleeding knives; 55 isolates were recovered. Serotyping revealed the predominance of Salmonella Typhimurium (20 isolates) followed by Salmonella Abony (10 isolates), Salmonella Give (7 isolates), Salmonella Heidelberg (4 isolates), and Salmonella Infantis (1 isolate). Ten isolates were only partially typeable, with only their O antigen identified, and three isolates had rough, nontypeable colonies. Despite the overall low prevalence of Salmonella in this study, all three slaughterhouses had poor hygienic and sanitary conditions, providing easy routes for carcass and, consequently, meat contamination. Thus, it is imperative to enforce sanitary inspections in these establishments and to apply good manufacture practices to assure the safety of the produced pork. PMID- 28585864 TI - Sustained release effects of berberine-loaded chitosan microspheres on in vitro chondrocyte culture. AB - The low bioavailability and short biological half-life of berberine chloride (BBR) negatively affect the protective role of this compound against osteoarthritis (OA). The present study was performed to evaluate the effectiveness of sustained BBR release system. Novel BBR-loaded chitosan microspheres (BBR-loaded CMs) were successfully synthesized using an ionic cross linking method for sustained release. The basic characteristics of the prepared microspheres were subsequently evaluated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) techniques, encapsulation efficiency (EE), and in vitro release experiments. BBR loaded CMs displayed spherical forms to encapsulate a considerable quantity of BBR (100.8 +/- 2.7 mg/g); these microspheres also exhibited an ideal releasing profile. The FT-IR spectra and XRD results revealed that BBR-loaded CMs were successfully synthesized via electrostatic interaction. In vitro experiments further showed that BBR-loaded CMs significantly inhibited sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis as well as cytoskeletal remodeling, and led to increasing mitochondrial membrane potential and maintaining the nuclear morphology. BBR-loaded CMs exerted markedly higher anti-apoptotic activity in the treatment of OA, and markedly inhibited the protein expression levels of caspase 3, a disintegrin, and metalloproteinase with thrombospondin motifs (ADAMTS)-5 and matrix metalloproteinase (MMP)-13 induced by SNP in rat articular chondrocytes, compared with free BBR at equivalent concentration. Therefore, novel BBR-loaded CMs may offer potential for application in the treatment of OA. PMID- 28585867 TI - Characterization of transgene expression and pDNA distribution of the suctioned kidney in mice. AB - We have previously developed an efficient and safe transfection method for the kidney in mice: renal suction-mediated transfection. In this study, we verified the detailed characteristics of transgene expression and plasmid DNA (pDNA) in mice to develop therapeutic strategies and application to gene function analysis in the kidney. After naked pDNA was administered intravenously, the right kidney was immediately suctioned by a tissue suction device. We examined the spatial distribution of transgene expression and pDNA in the suctioned kidney using tissue clearing by CUBIC, ClearT2, and Scale SQ reagents. Spatial distribution analysis showed that pDNA was transfected into extravascular cells and sufficiently delivered to the deep renal cortex. In addition, we revealed that transgene expression occurred mainly in peritubular fibroblasts of the suctioned kidney by tissue clearing and immunohistochemistry. Next, we confirmed the periods of pDNA uptake and activation of transcription factors nuclear factor kappaB and activator protein 1 by luciferase assays. Moreover, the use of a pCpG free plasmid enabled sustained transgene expression in the suctioned kidney. In conclusion, analyses of the spatial distribution and immunostaining of the section suggest that pDNA and transgene expression occurs mainly in peritubular fibroblasts of the suctioned kidney. In addition, we clarified some factors for efficient and/or sustained transgene expression in the suctioned kidney. PMID- 28585865 TI - Protein kinase C epsilon delays latency until anoxic depolarization through arc expression and GluR2 internalization. AB - Global cerebral ischemia is a debilitating injury that damages the CA1 region of the hippocampus, an area important for learning and memory. Protein kinase C epsilon (PKCE) activation is a critical component of many neuroprotective treatments. The ability of PKCE activation to regulate AMPA receptors (AMPARs) remains unexplored despite the role of AMPARs in excitotoxicity after brain ischemia. We determined that PKCE activation increased expression of a protein linked to learning and memory, activity-regulated cytoskeleton-associated protein (arc). Also, arc is necessary for neuroprotection and confers protection through decreasing AMPAR currents via GluR2 internalization. In vivo, activation of PKCE increased arc expression through a BDNF/TrkB pathway, and decreased GluR2 mRNA levels. In hippocampal cultured slices, PKCE activation decreased AMPAR current amplitudes in an arc- and GluR2-dependent manner. Additionally, PKCE activation triggered an arc- and GluR2 internalization-dependent delay in latency until anoxic depolarization. Inhibiting arc also blocked PKCE-mediated neuroprotection against lethal oxygen and glucose deprivation. These data characterize a novel PKCE-dependent mechanism that for the first time defines a role for arc and AMPAR internalization in conferring neuroprotection. PMID- 28585866 TI - Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer's disease. AB - A novel family of cinnamic acid derivatives has been developed to be multifunctional cholinesterase inhibitors against AD by fusing N-benzyl pyridinium moiety and different substituted cinnamic acids. In vitro studies showed that most compounds were endowed with a noteworthy ability to inhibit cholinesterase, self-induced Abeta (1-42) aggregation, and to chelate metal ions. Especially, compound 5l showed potent cholinesterase inhibitory activity (IC50, 12.1 nM for eeAChE, 8.6 nM for hAChE, 2.6 MUM for eqBuChE and 4.4 MUM for hBuChE) and the highest selectivity toward AChE over BuChE. It also showed good inhibition of Abeta (1-42) aggregation (64.7% at 20 MUM) and good neuroprotection on PC12 cells against amyloid-induced cell toxicity. Finally, compound 5l could penetrate the BBB, as forecasted by the PAMPA-BBB assay and proved in OF1 mice by ex vivo experiments. Overall, compound 5l seems to be a promising lead compound for the treatment of Alzheimer's diseases. PMID- 28585868 TI - Long-term effects of Internet-delivered cognitive behavioral therapy for depression in primary care - the PRIM-NET controlled trial. AB - OBJECTIVE: Internet-delivered cognitive behavioral therapy (ICBT) is recommended as an efficient treatment alternative for depression in primary care. However, only few previous studies have been conducted at primary care centers (PCCs). We evaluated long-term effects of ICBT treatment for depression compared to treatment as usual (TAU) in primary care settings. DESIGN: Randomized controlled trial. SETTING: Patients were enrolled at16 PCCs in south-west Sweden. PARTICIPANTS: Patients attending PCCs and diagnosed with depression (n = 90). INTERVENTIONS: Patients were assessed by a primary care psychologist/psychotherapist and randomized to ICBT or TAU. The ICBT included an ICBT program consisting of seven modules and weekly therapist e-mail or telephone support during the 3-month treatment period. MAIN OUTCOME MEASURES: Questionnaires on depressive symptoms (BDI-II), quality of life (EQ-5D) and psychological distress (GHQ-12) were administered at baseline, with follow-ups at 3, 6 and 12 months. Antidepressants and sedatives use, sick leave and PCC contacts were registered. RESULTS: Intra-individual change in depressive symptoms did not differ between the ICBT group and the TAU group during the treatment period or across the follow-up periods. At 3-month follow-up, significantly fewer patients in ICBT were on antidepressants. However, the difference leveled out at later follow-ups. There were no differences between the groups concerning psychological distress, sick leave or quality of life, except for a larger improvement in quality of life in the TAU group during the 0- to 6-month period. CONCLUSIONS: ICBT with weekly minimal therapist support in primary care can be equally effective as TAU among depressed patients also over a 12-month period. CLINICAL TRIAL REGISTRATION: The trial was registered in the Swedish Registry, researchweb.org, ID number 30511. PMID- 28585869 TI - Postmarketing surveillance evaluating the safety and effectiveness of golimumab in Japanese patients with rheumatoid arthritis. AB - OBJECTIVES: The purpose of this study was to evaluate the real-world safety and effectiveness of golimumab (GLM) in Japanese patients with rheumatoid arthritis. METHODS: A postmarketing surveillance of 5154 patients was conducted with a follow-up duration of at least 24 weeks. Patients were divided into four groups based on the initial treatment: 50 mg or 100 mg of GLM with concomitant use of methotrexate (MTX) and 50 mg or 100 mg of GLM monotherapy. Patient characteristics at baseline, safety and effectiveness were assessed for each group. RESULTS: Over 70% of patients received 50 mg of GLM with concomitant MTX, and approximately, 20% received monotherapy. The incidence rate of adverse events was 45.40 per 100 patient-years. The incidence of adverse events including serious adverse events was comparable across all groups. The proportion of patients showing remission or low disease activity increased from 13.69% to 46.21% at the final evaluation, and no differences were observed in the percentage of remission across the four groups. Concomitant MTX use was associated with higher probability of continuing therapy. CONCLUSIONS: GLM showed effectiveness in Japanese rheumatoid arthritis patients with an acceptable safety profile. PMID- 28585871 TI - Continuous Glucose Monitoring and Global Reimbursement: An Update. AB - Real-time continuous glucose monitoring has been available for a decade and reimbursement for the technology has been slowly growing. Reasons for the various rates of reimbursement and adoption are explored in this article and the status of country-wide reimbursement is discussed. PMID- 28585870 TI - Accuracy of diagnosis and counseling of fetal brain anomalies prior to 24 weeks of gestational age. AB - OBJECTIVE: To evaluate the accuracy of prenatal neurosonography in diagnosing underlying causes of fetal ventriculomegaly, posterior fossa anomalies and microcephaly before 24 weeks' gestational age (GA) and to study the accuracy of prenatal counseling on postnatal prognosis. METHODS: A retrospective cohort study based on 146 cases of these fetal brain anomalies before 24 weeks' GA. Counseling on prognosis was compared with postnatal outcome. Data on genetic testing was analyzed. RESULTS: Out of 146 cases, 135 (92%) were diagnosed correctly before 24 weeks' GA. Accuracy was 98% (97/99) in cases with multiple anomalies and 81% (38/47) in cases with an isolated abnormality. Counseling on prognosis was correct in 143 out of 146 cases (98%). Prenatal genetic diagnostics detected an anomaly in 51/113 (45%) of cases. In 14/62 (23%) cases prenatal karyotyping was normal, but postnatal array-CGH detected a pathogenic anomaly. CONCLUSIONS: Despite the challenges of early gestation, accuracy in diagnosing and counseling fetal brain anomalies before 24 weeks' GA was high. Prenatal genetic testing is a valuable diagnostic tool and should be offered to all women with fetal brain anomalies. Considering the many different types of anomalies and diverse etiologies, a multidisciplinary approach is essential for counseling on postnatal outcome. PMID- 28585872 TI - The Future of Continuous Glucose Monitoring. PMID- 28585873 TI - A Simple Composite Metric for the Assessment of Glycemic Status from Continuous Glucose Monitoring Data: Implications for Clinical Practice and the Artificial Pancreas. AB - BACKGROUND: The potential clinical benefits of continuous glucose monitoring (CGM) have been recognized for many years, but CGM is used by a small fraction of patients with diabetes. One obstacle to greater use of the technology is the lack of simplified tools for assessing glycemic control from CGM data without complicated visual displays of data. METHODS: We developed a simple new metric, the personal glycemic state (PGS), to assess glycemic control solely from continuous glucose monitoring data. PGS is a composite index that assesses four domains of glycemic control: mean glucose, glycemic variability, time in range and frequency and severity of hypoglycemia. The metric was applied to data from six clinical studies for the G4 Platinum continuous glucose monitoring system (Dexcom, San Diego, CA). The PGS was also applied to data from a study of artificial pancreas comparing results from open loop and closed loop in adolescents and in adults. RESULTS: The new metric for glycemic control, PGS, was able to characterize the quality of glycemic control in a wide range of study subjects with various mean glucose, minimal, moderate, and excessive glycemic variability and subjects on open loop versus closed loop control. CONCLUSION: A new composite metric for the assessment of glycemic control based on CGM data has been defined for use in assessing glycemic control in clinical practice and research settings. The new metric may help rapidly identify problems in glycemic control and may assist with optimizing diabetes therapy during time-constrained physician office visits. PMID- 28585874 TI - Stability, Accuracy, and Risk Assessment of a Novel Subcutaneous Glucose Sensor. AB - BACKGROUND: Users of continuous glucose monitoring (CGM) systems are concerned with the frequency of inserting and calibrating new sensors, with sensor accuracy and reliability throughout the sensor's functional life, and with the risks associated with inaccurate sensor readings. METHODS: A sensor for our next generation CGM system was tested for accuracy by comparison with self-monitored blood glucose (SMBG) values throughout 10 days of wear. Fifty subjects (49 with type 1 diabetes, 1 with type 2 diabetes, 20 male, mean +/- standard deviation [SD] age 32.5 +/- 18.7 years) enrolled. Subjects wore one sensor each, calibrated it once per day, and obtained multiple daily SMBG values for comparison. A total of 2739 paired CGM-SMBG values were analyzed to arrive at standard accuracy statistics and plotted on the surveillance error grid (SEG) to estimate the risk of SMBG-CGM discrepancies. RESULTS: The overall mean and median absolute relative difference (ARD) values were 9.6% and 7.2%, respectively. The median ARD values ranged from 8.9% on Day 1 to 6.5% on Day 10. SEG analysis categorized 2727 points (99.6%) as "no" or "slight" risk and 12 points (0.4%) as "moderate" or "great" risk. Thirty-nine (79.6%) of the 49 systems worked through the end of Day 10. Sensors and adhesives were well tolerated, with minimal erythema and induration. CONCLUSIONS: This new CGM system's accuracy throughout its 10-day functional life, the convenience associated with once-daily calibrations, and the high proportion of measurements in the "no risk" zone of the SEG support its nonadjunctive use in diabetes management and closed-loop insulin delivery systems. PMID- 28585875 TI - Continuous Glucose Monitoring with Multiple Daily Insulin Treatment: Outcome Studies. AB - Continuous glucose monitoring (CGM) is developing into an increasingly useful tool for glucose monitoring and therapeutic guidance in the treatment of diabetes. Multiple daily doses of insulin (MDI) is the most common method for intensive insulin treatment of type 1 diabetes and is also becoming more common in the treatment of type 2 diabetes as an increasing population with type 2 diabetes experiences progressive beta cell loss. The clinical evidence demonstrating the benefit of CGM in the outcomes of patients treated with MDI is becoming clearer, particularly with the recent completion of several randomized clinical trials addressing both type 1 and 2 diabetes. This evidence is reviewed. PMID- 28585876 TI - CGM, Pregnancy, and Remote Monitoring. AB - The glycemic goals of pregnancy are very narrow to reduce excess risks for numerous maternal and fetal complications. Continuous glucose monitors (CGMs) may help women achieve glucose goals and reduce hypoglycemia. CGM use has been found to be safe and effective in pregnancies associated with diabetes. CGM use can accurately identify glycemic patterns among women with and without diabetes in pregnancy. The data on the effects of CGM use on maternal and fetal outcomes are conflicting. Using CGMs in conjunction with continuous subcutaneous insulin infusion therapy in pregnancies complicated by diabetes may improve outcomes. There are limitations of CGM use that affect patients in and outside of pregnancy, as well as specific barriers that only affect pregnant women. Of importance, CGM use does not replace standard clinical care, but may be used an adjunctive tool in pregnancy. CGM remote monitoring in pregnancy is an understudied field. In this study, we review the studies on CGM use in pregnancy. PMID- 28585877 TI - Future of Automated Insulin Delivery Systems. AB - Advances in continuous glucose monitoring (CGM) have brought on a paradigm shift in the management of type 1 diabetes. These advances have enabled the automation of insulin delivery, where an algorithm determines the insulin delivery rate in response to the CGM values. There are multiple automated insulin delivery (AID) systems in development. A system that automates basal insulin delivery has already received Food and Drug Administration approval, and more systems are likely to follow. As the field of AID matures, future systems may incorporate additional hormones and/or multiple inputs, such as activity level. All AID systems are impacted by CGM accuracy and future CGM devices must be shown to be sufficiently accurate to be safely incorporated into AID. In this article, we summarize recent achievements in AID development, with a special emphasis on CGM sensor performance, and discuss the future of AID systems from the point of view of their input-output characteristics, form factor, and adaptability. PMID- 28585878 TI - Practical Considerations on the Use of Continuous Glucose Monitoring in Pediatrics and Older Adults and Nonadjunctive Use. AB - Clinical use of continuous glucose monitoring (CGM) devices has grown over the past 15 years from a niche concept to becoming standard of care for patients with type 1 diabetes (T1D). With the December 2016 Food and Drug Administration approval for diabetes treatment decisions directly from CGM values (nonadjunctive use) without finger-stick confirmation, the uptake and scope of CGM use will likely further expand. With this expansion, it is important to consider the role and impact of CGM technology in specific settings and high-risk populations, such as the young and the elderly. In pediatric patients, CGM concerns include limited body surface area, difficulty keeping sensors adhered, and the role of nonadjunctive use in the school setting. In older adults, Medicare did not, until very recently, cover CGM devices and as such, their use had been limited by lack of reimbursement. As CGM use will likely expand in clinical practice given the nonadjunctive indication, guidelines and recommendations for clinical practice are warranted. In this article, we discuss recent research on CGM use in the special populations of children and older adults and provide initial guidelines for nonadjunctive use in clinical practice. PMID- 28585880 TI - Service needs and barriers to care five or more years after moderate to severe TBI among Veterans. AB - PRIMARY OBJECTIVE: The objective of this paper is to identify the most frequent service needs, factors associated with needs, and barriers to care among Veterans and service members five or more years after moderate to severe traumatic brain injury (TBI). RESEARCH DESIGN: Survey administered via telephone 5-16 years after injury (median eight years) and subsequent acute inpatient rehabilitation at a regional Veterans Affairs (VA) medical centre. METHODS AND PROCEDURES: Participants were 119 Veterans and military personnel, aged 23-70 (median 35), 90% male. Demographics, injury characteristics, service needs, whether needs were addressed, barriers to care, health and general functioning were assessed. MAIN OUTCOMES AND RESULTS: The most frequent needs were for help with memory, information about available services and managing stress. Obtaining information about services was the most consistently un-addressed need; managing stress was the most consistently addressed need. Cognitive and psychiatric symptoms and alienation from community were associated with needs going un-addressed. Participants treated after an expansion of TBI services at the study site reported fewer un-addressed needs. Not knowing where to get help was the most common barrier to care. CONCLUSION: Repeated outreach, assessment of needs and education about available services are needed throughout Veterans' lifespan after moderate to severe TBI. PMID- 28585882 TI - Increased astroglial activity and reduced neuronal function across brain in AbetaPP-PS1 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease associated with progressive loss of cognitive function, personality, and behavior. The present study evaluates neuronal and astroglial metabolic activity, and neurotransmitter cycle fluxes in AbetaPP-PS1 mouse model of AD by using 1H-[13C] nuclear magnetic resonance (NMR) spectroscopy together with an infusion of either [1,6-13C2]glucose or [2-13C]acetate. The levels of N-acetyl-aspartate (NAA) and glutamate were found to be decreased in the cerebral cortex and hippocampus in AbetaPP-PS1 mice, when compared with wild type controls. The cerebral metabolic rate of acetate oxidation was increased in the hippocampus and cerebral cortex of AbetaPP-PS1 mice suggesting enhanced astroglial activity in AD. AbetaPP-PS1 mice exhibit severe reduction in glutamatergic and gamma-amino butyric acid (GABA)ergic neuronal metabolic activity and neurotransmitter cycling fluxes in the hippocampus, cerebral cortex, and striatum as compared with controls. These data suggest that metabolic activity of excitatory and inhibitory neurons is compromised across brain in AbetaPP-PS1 mouse model of AD. PMID- 28585881 TI - Factors related to poor asthma control in Latvian asthma patients between 2013 and 2015. AB - OBJECTIVES: To investigate whether beliefs about asthma medication, cognitive and emotional factors are related to poor asthma control in a sample of Latvian asthma patients in 2015. DESIGN: Cross-sectional, self-administered survey. SUBJECTS: Three hundred and fifty two asthma patients (mean age 57.5 years) attending outpatient pulmonologist consultations in Riga, Latvia during September 2013 to December 2015. The sample size was calculated to detect a prevalence of poor asthma control of 50% with a margin of error of 5% and a power of 95%. MAIN OUTCOME MEASURES: The validated Beliefs about Medication Questionnaire (BMQ) and the Brief Illness Perception Questionnaire (brief IPQ) were used. Good asthma control was assessed using the asthma control test (ACT), a validated five-item scale that reliably assesses asthma control over a recall period of four weeks. Logistic regression models were used to predict poor asthma control. RESULTS: Patients who had a good control of asthma medication (OR 0.70; 95% CI 0.61-0.79) or were confident that their asthma medication improves illness (OR 0.84; 95% CI 0.74-0.95) had a reduced risk of poor asthma control. The more symptoms (OR 1.63; 95% CI 1.44-1.84) the asthma patients perceived or the more their illness affects their life, the higher the probability of poor asthma control (OR 1.47; 95% CI 1.31-1.65). Some beliefs of necessity and concerns of asthma medication were also statistically significantly related to poor asthma control. CONCLUSIONS: Beliefs of necessity of asthma medication, cognitive and emotional illness perception factors correlate well with poor asthma control in Latvian patients. PMID- 28585883 TI - Dissimulation strategies on standard neuropsychological tests: A qualitative investigation. AB - OBJECTIVE: Most previous studies in the area of malingering neuropsychological deficits have focused on the development and validation of measures to detect falsification of symptoms or suboptimal performance. The present study employs qualitative methods to investigate strategies employed by individuals attempting to feign cognitive impairment. This study aims to achieve a richer and more detailed understanding of the phenomenon of feigning. METHOD: Detailed semi structured interviews were administered to 15 non-neurological individuals instructed to feign cognitive impairment on a standard neuropsychological test battery. The interviews, which considered the strategies used and the thinking underlying participants' choices, were subjected to Thematic Analysis. RESULTS: Thematic Analysis revealed three main organising themes. Participants described Using Strategies, on specific tests and generally across the battery, Having a Rationale for their decisions and spontaneously commented on their Experience of the Task. CONCLUSION: The findings of the present study reveal numerous potentially useful identifiers of feigning strategies, including many not previously reported. The resulting themes point to the development of more effective methods for detecting feigned cognitive impairments and could have a significant impact on the way that neuropsychological testing sessions are conducted. PMID- 28585879 TI - Continuous Glucose Monitoring: A Review of Recent Studies Demonstrating Improved Glycemic Outcomes. AB - Continuous Glucose Monitoring (CGM) has been demonstrated to be clinically valuable, reducing risks of hypoglycemia and hyperglycemia, glycemic variability (GV), and improving patient quality of life for a wide range of patient populations and clinical indications. Use of CGM can help reduce HbA1c and mean glucose. One CGM device, with accuracy (%MARD) of approximately 10%, has recently been approved for self-adjustment of insulin dosages (nonadjuvant use) and approved for reimbursement for therapeutic use in the United States. CGM had previously been used off-label for that purpose. CGM has been demonstrated to be clinically useful in both type 1 and type 2 diabetes for patients receiving a wide variety of treatment regimens. CGM is beneficial for people using either multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). CGM is used both in retrospective (professional, masked) and real-time (personal, unmasked) modes: both approaches can be beneficial. When CGM is used to suspend insulin infusion when hypoglycemia is detected until glucose returns to a safe level (low-glucose suspend), there are benefits beyond sensor-augmented pump (SAP), with greater reduction in the risk of hypoglycemia. Predictive low glucose suspend provides greater benefits in this regard. Closed-loop control with insulin provides further improvement in quality of glycemic control. A hybrid closed-loop system has recently been approved by the U.S. FDA. Closed-loop control using both insulin and glucagon can reduce risk of hypoglycemia even more. CGM facilitates rigorous evaluation of new forms of therapy, characterizing pharmacodynamics, assessing frequency and severity of hypo- and hyperglycemia, and characterizing several aspects of GV. PMID- 28585884 TI - Conveying hope in consultations with patients with life-threatening diseases: the balance between supporting and challenging the patient. AB - OBJECTIVE: There is limited knowledge about the communication of hope and denial in consultations with patients with life-threatening diseases on a practical level. In this study, we explored a real-life medical consultation between a doctor and a patient with incurable cancer, focusing on conveying hope. DESIGN AND METHODS: We found one consultation especially suited for illustrating how a physician can convey and reinforce hope without attaching it to curative treatment. The consultation was analysed using a method for discourse analysis, where we took as a point of departure that discourse means language in use. RESULTS: The doctor communicated in a recognising manner, expressing respect for the patient as a subject and an authority of his own experiences. The doctor and patient succeeded in creating a good working alliance characterised by warmth and trust. Within this context, there was room for the doctor to challenge the patient's views and communicate disagreement. CONCLUSIONS: The doctor succeeds in conveying and maintaining hope. Within a good working alliance with the patient the doctor can convey hope by balancing between supporting and challenging him. Exploring and grasping the patient's real concerns is essential for being able to relieve and comfort him and convey hope. PMID- 28585885 TI - Validity of Danish Breast Cancer Group (DBCG) registry data used in the predictors of breast cancer recurrence (ProBeCaRe) premenopausal breast cancer cohort study. AB - BACKGROUND: Validation studies of the Danish Breast Cancer Group (DBCG) registry show good agreement with medical records for adjuvant treatment data, but inconsistent recurrence information. No studies have validated changes in menopausal status or endocrine therapy during follow-up. In a longitudinal study, we validated DBCG data using medical records as the gold standard. MATERIAL AND METHODS: From a cohort of 5959 premenopausal women diagnosed during 2002-2010 with stage I-III breast cancer, we selected 151 patients - 77 estrogen-receptor positive and 74 estrogen-receptor-negative - from three hospitals. We assessed the validity of DBCG registry data on patient, tumor, and treatment factors, and follow-up information on menopausal transition, changes in endocrine therapy, and recurrence. We computed positive predictive values (PPVs) with 95% confidence intervals (95%CI). RESULTS: Agreement was near perfect for tumor size, lymph node involvement, receptor status, surgery type, and receipt of radiotherapy, chemotherapy, or tamoxifen treatment. The PPV for a change in endocrine therapy in the DBCG was 96% (95%CI = 83, 100). The PPV for menopausal transition was 61% (95%CI = 42, 77). The PPV for DBCG-recorded recurrence was 100%. However, of 19 patients who had a recurrence documented in their medical record, 13 had the recurrence registered in DBCG. CONCLUSIONS: DBCG data are valid for most epidemiological studies of breast cancer treatment. Data on menopausal transition may be less valid, though this interpretation depends on the suitability of medical records for making this assessment. Although recurrence is missing for some, this would not bias most ratio measures of association. PMID- 28585887 TI - Symptomatic ptosis cerebelli after suboccipital craniectomy in a patient with severe brain trauma. AB - PRIMARY OBJECTIVE: To report the first case of symptomatic cerebellar ptosis after a large suboccipital craniectomy in a patient with severe brain trauma and a review of the literature. PATIENT AND METHODS: A 36-year-old man suffered severe traumatic brain injury after a four-metre fall. He underwent a large suboccipital craniectomy because his computed tomography scan revealed a posterior fossa subdural haematoma and cerebellar swelling. Four weeks after admission, he developed communicating hydrocephalus, and a ventriculoperitoneal shunt was placed. Although he experienced good recovery, seven months after the trauma he complained of cephalea, dizziness, recurrent vomiting and diplopia. Magnetic resonance imaging (MRI) showed descent of the cerebellum through a wide bone defect. RESULTS: We performed a posterior fossa cranioplasty after other causes of delayed worsening were ruled out, such as shunt malfunction, overdrainage and ischaemic lesions. The patient improved, and a post-operative MRI confirmed the upward migration of the cerebellum. CONCLUSIONS: Cerebellar ptosis must be considered in cases of delayed symptoms after large suboccipital craniectomy regardless of pathology. Posterior fossa cranioplasty to provide structural support to slumped cerebellum can improve or resolve symptoms. PMID- 28585886 TI - Clinical indications for antibiotic use in Danish general practice: results from a nationwide electronic prescription database. AB - OBJECTIVE: To assess the availability and applicability of clinical indications from electronic prescriptions on antibiotic use in Danish general practice. DESIGN: Retrospective cohort register-based study including the Danish National Prescription Register. SETTING: Population-based study of routine electronic antibiotic prescriptions from Danish general practice. SUBJECTS: All 975,626 patients who redeemed an antibiotic prescription at outpatient pharmacies during the 1-year study period (July 2012 to June 2013). MAIN OUTCOME MEASURES: Number of prescriptions per clinical indication. Number of antibiotic prescriptions per 1000 inhabitants by age and gender. Logistic regression analysis estimated the association between patient and provider factors and missing clinical indications on antibiotic prescriptions. RESULTS: A total of 2.381.083 systemic antibiotic prescriptions were issued by Danish general practitioners in the study period. We identified three main clinical entities: urinary tract infections (n = 506.634), respiratory tract infections (n = 456.354) and unspecified infections (n = 416.354). Women were more exposed to antibiotics than men. Antibiotic use was high in children under 5 years and even higher in elderly people. In 32% of the issued prescriptions, the clinical indication was missing. This was mainly associated with antibiotic types. We found that a prescription for a urinary tract agent without a specific clinical indication was uncommon. CONCLUSION: Clinical indications from electronic prescriptions are accessible and available to provide an overview of drug use, in casu antibiotic prescriptions, in Danish general practice. These clinical indications may be further explored in detail to assess rational drug use and congruence with guidelines, but validation and optimisation of the system is preferable. PMID- 28585888 TI - Predictive genetic testing for amyotrophic lateral sclerosis and frontotemporal dementia: genetic counselling considerations. AB - Once a gene mutation that is causal of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) is identified in a family, relatives may decide to undergo predictive genetic testing to determine whether they are at risk of developing disease. Recent advances in gene discovery have led to a pressing need to better understand the implications of predictive genetic testing. Here we review the uptake of genetic counselling, predictive and reproductive testing, and the factors that impact the decision to undergo testing, for consideration in clinical practice. The literature suggests that the factors impacting the decision to undergo testing are complex due to the nature of these diseases, absence of available preventative medical treatment and variable age of onset in mutation carriers. Gaining further insight into the decision-making process and the impact of testing is critical as we seek to develop best-practice guidelines for predictive testing for familial ALS and FTD. PMID- 28585889 TI - Influence of the microbiological component of Cariogram(r) for evaluating the risk of caries in children. AB - OBJECTIVE: To compare the risk for caries in children as determined by Cariogram(r) software (CS; Stockholm, Sweden) with and without its microbiological component and by a form based on Cariogram(r) (FBC). METHODS: Children (n = 28) aged 3-9 years were included. Data were collected clinically and from anamnesis. The salivary levels of Streptococcus mutans (SM) were evaluated. A linear regression model was used to determine which variables were predictive for each type of risk analysis. Caries risk was the dependent variable and the independent variables were caries experience, related disease, plaque amount, diet frequency, salivary levels of SM, fluoride sources and clinical judgment. A paired Student t-test was used for the following comparisons: (a) CS with and without SM; (b) CS without SM and FBC; (c) CS with SM and FBC. RESULTS: The mean dmft/DMFT was 5.56 +/- 2.51. There was no difference between the methods (p < .05). Regardless of caries risk, the children presented the same levels of SM (p = .889). Caries experience, plaque amount, diet frequency and fluoride sources were predictors of caries risk in all assessment methods. Clinical judgment was a significant predictor in CS. CONCLUSIONS: Caries experience, plaque amount, diet frequency and fluoride sources are valuable predictors of caries risk; microbiological tests are not necessary for evaluating caries risk in children, which can be assessed similarly by CS without SM and FBC. PMID- 28585890 TI - Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries? AB - Central nervous system diseases are among the most disabling in the world. Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation as pharmacology treatments are often insufficiently effective. Conditioning the central nervous system has been proposed as a potential non-pharmacological neuro-therapeutic. Conditioning refers to a procedure by which a potentially deleterious stimulus is applied near to but below the threshold of damage to the organism to increase resistance to the same or even different noxious stimuli given above the threshold of damage. Hypoxic conditioning has been investigated in several cellular and preclinical models and is now recognized as inducing endogenous mechanisms of neuroprotection. Ischemic, traumatic, or chronic neurodegenerative diseases can benefit from hypoxic conditioning strategies aiming at preventing the deleterious consequences or reducing the severity of the pathological condition (preconditioning) or aiming at inducing neuroplasticity and recovery (postconditioning) following central nervous system injury. Hypoxic conditioning can consist in single (sustained) or cyclical (intermittent, interspersed by short period of normoxia) hypoxia stimuli which duration range from few minutes to several hours and that can be repeated over several days or weeks. This mini review addresses the existing evidence regarding the use of hypoxic conditioning as a potential innovating neuro-therapeutic modality to induce neuroprotection, neuroplasticity and brain recovery. This mini-review also emphasizes issues which remain to be clarified and future researches to be performed in the field. Impact statement Neuroprotection and brain recovery from either acute or chronic neurodegeneration still represent a challenge in neurology and neurorehabilitation. Hypoxic conditioning may represent a harmless and efficient non-pharmacological new therapeutic modality in the field of neuroprotection and neuroplasticity, as supported by many preclinical data. Animal studies provide clear evidence for neuroprotection and neuroplasticity induced by hypoxic conditioning in several models of neurological disorders. These studies show improved functional outcomes when hypoxic conditioning is applied and provides important information to translate this intervention to clinical practice. Some studies in humans provide encouraging data regarding the tolerance and therapeutic effects of hypoxic conditioning strategies. The main issues to address in future research include the definition of the appropriate hypoxic dose and pattern of exposure, the determination of relevant physiological biomarkers to assess the effects of the treatment and the evaluation of combined strategies involving hypoxic conditioning and other pharmacological or non-pharmacological treatments. PMID- 28585892 TI - Blood glucose monitoring in type 2 diabetes - Nepalese patients' opinions and experiences. AB - BACKGROUND: Blood glucose monitoring forms a vital component of diabetes care. Monitoring conducted at home using glucometers, and in laboratories by professionals, are two common methods of blood glucose monitoring in clinical practice. OBJECTIVE: To investigate Nepalese patients' perceptions and practices of blood glucose monitoring in diabetes. METHODS: In-depth interviews were conducted with 48 Nepalese participants with type 2 diabetes in Sydney and Kathmandu. The interviews were audio-recorded, transcribed verbatim and thematically analysed. RESULTS: In Australia, most participants perceived home monitoring as useful; and both home and laboratory monitoring were conducted at fairly regular intervals. In Nepal, only a small number conducted home monitoring and the laboratory method formed the primary method of day-to-day monitoring. The laboratory method was preferred due to easy access to laboratories, lack of faith in glucometers and perceptions that home monitoring is costlier. However, overall monitoring was irregular in Nepal. In addition to the healthcare system which enabled cheaper self-monitoring in Australia, Nepalese in Australia also tended to have a better understanding about the purpose of home monitoring. CONCLUSIONS: This study has highlighted the disparity in perceptions and practices related to blood glucose monitoring. Understanding the importance of blood glucose monitoring and access to affordable resources are critical facilitators for conducting regular monitoring. Both patient and health-system factors play a key role in ensuring continued diabetes monitoring and management. PMID- 28585893 TI - Performance of two respiratory protective devices used by home-attending health care workers (a pilot study). AB - OBJECTIVES: This pilot study aimed at determining the Workplace Protection Factor (WPF) for respiratory protective devices widely used by health care workers to reduce exposure to potentially hazardous aerosols when attending patients in their homes. Two devices were tested, an N95 filtering facepiece respirator (FFR) and a surgical mask (SM). METHODS: Three home-attending health care workers were recruited, medically cleared and fit tested. At the workplace, the aerosol concentrations outside (Cout) and inside (Cin) of the tested respiratory protective device worn by a subject were measured using two simultaneously operating P-Trak condensation particle counters within the particle size range of approximately 20-1,000 nm. Real-time and integrated (time-weighted average, TWA) values of WPF = Cout/Cin were determined. RESULTS: This pilot study demonstrated that the WPF of the tested N95 FFR consistently exceeded that of the SM. The WPFTWA(C) values calculated for the entire test time (based on the TWA aerosol concentration values) ranged from 29 to 40 and 2 to 9, respectively. In all cases, the N95 FFR provided protection above the Occupational Safety and Health Administration's (OSHA) assigned protection factor of 10, whereas the SM often offered little or essentially no protection against the measured sub-micrometer aerosol particles. For both devices, the protection level was found to depend on activity. For example, the WPFTWA(C) for one subject wearing the N95 FFR was 56 during normal activity but fell almost 70% during tracheal suctioning. It is explicable considering that different procedures implemented by health care workers in homes generate particles of different sizes and require different body movements; both factors are anticipated to affect the WPF. CONCLUSIONS: Wearing an N95-certified respirator helps significantly reduce the aerosol inhalation exposure of home-attending health care workers. An SM offers much lower protection. The WPF depends on several factors, including, but not limited to, the health care worker's activity and/or body movements; the WPF varies from one worker to another. PMID- 28585891 TI - In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research. AB - Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis skin or the disease pathology. This work provides a complete overview of the different available in vitro psoriasis models and suggests improvements for future models. Moreover, a focus was given to psoriatic skin equivalent models, as they offer several advantages over the other models, including commercial availability and validity. The potential and reported applicability of these models in psoriasis pre clinical research is extensively discussed. As such, this work offers a guide to researchers in their choice of pre-clinical psoriasis model depending on their type of research question. PMID- 28585894 TI - Attenuated Total Reflection Surface-Enhanced Infrared Absorption (ATR SEIRA) Spectroscopy for the Analysis of Fatty Acids on Silver Nanoparticles. AB - The application of attenuated total reflection surface-enhanced infrared absorption spectroscopy (ATR SEIRA) to the analysis of fatty acids on silver nanoparticles was investigated. Attenuated total reflection measurements using four types of internal reflection elements (IREs)-zinc selenide, diamond, silicon, and germanium-were performed for silver nanoparticles modified with fatty acids, and germanium IRE was shown to be suitable for the analysis of silver nanoparticles, even when the sample had a high refractive index. Fatty acids coating the silver nanoparticles could be directly identified by SEIRA enhancement, because both symmetric carboxylate stretching vibration and methylene wagging vibration were strongly detected. Furthermore, the peak positions for methylene wagging vibration differed depending on the carbon number of the fatty acid, so that information from the ATR SEIRA spectra makes it possible to identify substances coating silver nanoparticles. Therefore, ATR SEIRA would appear to have significant potential as a technique for the identification of substances coated on metal nanoparticle surfaces. PMID- 28585895 TI - An examination of MCE filter morphology and implications on preparation and analysis of air samples for asbestos. AB - Morphological imperfections of mixed-cellulose ester filters and their possible influence on sample preparation and analysis of asbestos were examined. Filters were identified with large regions of non-porous "dead zones" which could negatively affect fiber deposition and, therefore, fiber recovery and analysis by Transmission Electron Microscopy (TEM). As these imperfections are effectively erased during the preparation of the sample, they may not be readily observed by TEM. Un-collapsed filters as well as those collapsed using dimethylformamide (DMF) and two acetone techniques were examined. In order to minimize negative sampling and analytical bias, it is suggested that MCE samples be collapsed utilizing a 35% DMF solution, etched with a correctly calibrated low-temperature etcher, carbon coated using a rotating and tilted stage, and analyzed with a strong analyst-independent grid square opening randomization scheme. PMID- 28585896 TI - Multiple struggles in fighting violence against women: implications among Romani women leaders in Spain. AB - BACKGROUND: Violence against women (VAW) is a central issue in gender studies and one that has united feminist activists from around the world. But this does not mean that this struggle is singular: indeed, one can say that there are many, diverse and sometimes even contradictory struggles occurring throughout the world. OBJECTIVES: To identify and analyze the different struggles faced by women from Roma organizations in Spain in relation to VAW and their work with affected women. METHODS: Twelve semi-structured interviews were conducted among women actively involved in Roma associations in different Spanish cities, in 2015. An inductive thematic analysis was used to analyze the empirical materials. RESULTS: Our analysis resulted in three themes that captured different struggles that women from Roma organizations have faced: 'between persistence and rupture of restrictive gender norms', 'invisibility and normalization of violence against women' and 'willingness and trust in daily work with women'. The activities related to VAW carried out by the interviewed women were more related to their personal initiatives and abilities than to strategies proposed by the organizations they work for. CONCLUSIONS: The results show the need to support the initiatives of Romani women and their own struggles related to identity. This is what makes them true promoters of social change and, more specifically, change related to gender relations both within and outside of their communities. PMID- 28585897 TI - Interrelationships of Dictyocaulus spp. in Wild Ruminants with Morphological Description of Dictyocaulus cervi n. sp. (Nematoda: Trichostrongyloidea) from Red Deer, Cervus elaphus. AB - Lungworms from the genus Dictyocaulus cause parasitic bronchitis (dictyocaulosis) characterized by coughing and severe lung pathology in both domestic and wild ruminants. In this study we investigated the interrelationships of Dictyocaulus spp. from European bison (Bison bonasus L.), roe deer (Capreolus capreolus), and red deer (Cervus elaphus) by nucleotide sequence analysis spanning the 18S RNA gene (small subunit [SSU]) and internal transcribed spacer 2 (ITS2) regions of the ribosomal gene array as well as the mitochondrial cytochrome c oxidase subunit 1 (cox1). Molecular analyses of sequence data obtained partly with novel primers from between 10 and 50 specimens from each host were carried out. Bayesian inference analysis revealed that each host species was infected with different genotypes. Analysis of cox1 sequence data showed a diverse genetic background and high evolutionary potential of Dictyocaulus taxa. Data from lungworms of European bison revealed a distinct genotype of Dictyocaulus viviparus, whereas Dictyocaulus capreolus was only found in roe deer. In contrast, red deer were infected with a taxon with unique SSU, ITS2, and cox1 sequences. These results indicate the occurrence of a novel genotype from red deer, which differs significantly from the National Center for Biotechnology Information reference sequence of Dictyocaulus eckerti. The molecular evidence was consistent with a morphological study with description and imaging of Dictyocaulus cervi n. sp. recovered from red deer. Dictyocaulus cervi n. sp. can be distinguished from D. eckerti on the basis of the absence of cervical papillae, the occurrence of a single ring of 4 symmetrical submedian cephalic papillae, length of the tail in females, morphometry of the female reproductive system, and measurements of gubernacula in males. In conclusion, our findings further strengthen the idea that the genetic complexity and diversity among Dictyocaulus lungworms infecting wildlife ruminants is larger than previously believed and warrants further investigation. PMID- 28585898 TI - Circulating extracellular DNA levels are acutely elevated in ischaemic stroke and associated with innate immune system activation. AB - OBJECTIVE: The objective of this work was to assess the ability of peripheral blood cell-free DNA (cfDNA) levels to identify ischaemic stroke early in the acute phase of care, as well as to examine the relationship between peripheral blood cfDNA levels and stroke-induced innate immune system activation. METHODS: Upon emergency department admission, peripheral blood samples were obtained from 43 patients experiencing acute ischaemic stroke and 20 patients identified as stroke mimics. Plasma cfDNA levels were measured using quantitative polymerase chain reaction (qPCR), infarct volume and NIH stroke scale (NIHSS) were used to assess injury severity, and peripheral blood neutrophil count was used as a measure of innate immune system status. RESULTS: Peripheral blood cfDNA levels were significantly elevated in patients suffering stroke relative to those diagnosed as stroke mimics, and could differentiate between groups with 86% (95% CI = 72-95%) sensitivity and 75% (95% CI = 51-91%) specificity. Furthermore, cfDNA levels displayed significant positive associations between both infarct volume and peripheral blood neutrophil count within the stroke group. CONCLUSIONS: These findings suggest that assessment of peripheral blood cfDNA levels may be useful for the identification of ischaemic stroke in the acute care setting, and provide associative evidence that cfDNA is a potential activator of the peripheral innate immune system in response to cerebral ischaemia. PMID- 28585901 TI - Correction to: Biomechanical Response of the Infant Head to Shaking: An Experimental Investigation; DOI: 10.1089/neu.2016.4687. PMID- 28585900 TI - Strategies for the screening of antibiotic residues in eggs: comparison of the validation of the classical microbiological method with an immunobiosensor method. AB - Efficient screening methods are needed to control antibiotic residues in eggs. A microbiological kit (Explorer(r) 2.0 test (Zeu Inmunotech, Spain)) and an immunobiosensor kit (Microarray II (AM(r) II) on Evidence InvestigatorTM system (Randox, UK)) have been evaluated and validated for screening of antibiotic residues in eggs, according to the European decision EC/2002/657 and to the European guideline for the validation of screening methods. The e-readerTM system, a new automatic incubator/reading system, was coupled to the Explorer 2.0 test. The AM II kit can detect residues of six different families of antibiotics in different matrices including eggs. For both tests, a different liquid/liquid extraction of eggs had to be developed. Specificities of the Explorer 2.0 and AM II kit were equal to 8% and 0% respectively. The detection capabilities were determined for 19 antibiotics, with representatives from different families, for Explorer 2.0 and 12 antibiotics for the AM II kit. For the nine antibiotics having a maximum residue limit (MRL) in eggs, the detection capabilities CCbeta of Explorer 2.0 were below the MRL for four antibiotics, equal to the MRL for two antibiotics and between 1 and 1.5 MRLs for the three remaining antibiotics (tetracyclines). For the antibiotics from other families, the detection capabilities were low for beta-lactams and sulfonamides and satisfactory for dihydrostreptomycin (DHS) and fluoroquinolones, which are usually difficult to detect with microbiological tests. The CCbeta values of the AM II kit were much lower than the respective MRLs for three detected antibiotics (tetracycline, oxytetracycline, tylosin). Concerning the nine other antibiotics, the detection capabilities determined were low. The highest CCbeta was obtained for streptomycin (100 ug kg-1). PMID- 28585899 TI - Cognitive functions: evaluation and changes after transcatheter aortic valve implantation in elderly patients. AB - AIM: To assess the prevalence and postprocedural evolution of cognitive impairment (CI) in patients undergoing transcatheter aortic valve implantation. METHODS: 62 patients were enrolled. Mini Mental state examination (MMSE), verbal memory test (VMT), visual search test (VST) and phonemic verbal fluency (PVF) were used to evaluate the cognitive status. CI was considered when a pathological result of MMSE was confirmed by VMT, VST and PVF. RESULTS: A total of 26.2% patients had CI at baseline. MMSE, VMT, VST and PVF were pathologic in 39, 16.1, 8.1 and 22.6% of the patients, respectively. Overall, no significant differences in cognitive function in any dimension were observed from baseline up to 1-year follow-up. CONCLUSION: CI is frequent in patients undergoing transcatheter aortic valve implantation, though the procedure does not forge cognitive status. PMID- 28585902 TI - Negotiating between individual and joint goals in ensemble musical performance. AB - Successful joint action requires negotiation, especially in the event of goal incongruence. This article addresses goal incongruence in joint musical performance by manipulating the congruence of score instructions (congruent/incongruent) regarding tempo (speed) and dynamics (sound intensity) given to piano duos. The aim is to investigate how co-performers negotiate incongruent instructions for tempo and dynamics by balancing the prioritisation of individual goals versus the joint outcome and how this negotiation is modulated by musical expertise and personality (locus of control). In total, 14 pairs of pianists, who were not informed of the congruence manipulation, were placed back-to-back and were directed to achieve a successful performance over four repeated performances without verbal communication. Interpersonal coordination generally improved from the first to final performance in the congruent and incongruent conditions for both the tempo and dynamics tasks. Furthermore, in incongruent conditions, results suggest that performers prioritise the joint performance in the tempo task, but prioritise their own performance in the dynamics task. Although individual performance appears to be modulated by musical expertise, the balance of individual/joint performance across the duo is not influenced by musical part (melody vs accompaniment), expressive instruction, musical expertise or locus of control. PMID- 28585904 TI - Egyptian experience in increasing utilization of reperfusion therapies in acute ischemic stroke. AB - Background The rate of alteplase (tPA) thrombolysis utilization in acute stroke in Egypt is <1%. We report on the causes of this low rate of reperfusion therapies and take corrective action to improve it. Methods Two prospective observational studies were conducted at Ain Shams University hospitals. The first included 269 acute stroke patients admitted to the hospital over a six-month period. Obstacles to reperfusion therapy were identified, and based on the results, a corrective action plan was implemented including making alteplase(tPA) available, training, and establishing a standardized local protocol for reperfusion therapy. A second study was then conducted that included 284 acute ischemic stroke patients over another six-month period. Results In the first study, 53/269 patients (19.7%) arrived at hospital within 4.5 h and were eligible for reperfusion therapy. Of those, seven (13.2%) received alteplase(tPA), representing 2.6% of the total ischemic stroke patients admitted. The main causes for not giving thrombolytic therapy was unavailability of alteplase(tPA) (56.5%), wrong treatment decision (17.4%), missed window while performing brain imaging (15%), and unavailability of intermediate care bed (10.9%). The second study showed that out of 284 cases admitted with acute ischemic stroke, 37 were eligible for thrombolysis and 35 received alteplase(tPA) (94.3%), representing 12.3% of the total ischemic stroke admissions. Conclusion A comprehensive action plan that centers around making the drug available and training resulted in a significant improvement of reperfusion therapy utilization in Egypt. PMID- 28585903 TI - Dabigatran following acute transient ischemic attack and minor stroke II (DATAS II). AB - Rationale Patients with transient ischemic attack or minor stroke are at high risk of early recurrent cerebrovascular events. Anticoagulation with heparin or warfarin acutely after ischemic stroke is at least as efficacious as aspirin for preventing recurrent events but is associated with an increased risk of clinical worsening due to hemorrhagic transformation. Aim and hypothesis We aim to demonstrate the safety of early anticoagulation with dabigatran, an oral direct thrombin inhibitor, in acute cerebrovascular syndrome patients. The primary hypothesis is that symptomatic hemorrhagic transformation rates in dabigatran and aspirin-treated patients will be similar. Sample size estimates At least 136 participants in two groups required to demonstrate an absolute between-group difference in the rate of hemorrhagic transformation of 5.6% with 80% power, assuming alpha = 5%. Methods and design A randomized, multicenter open-label clinical trial (NCT02295826). Three-hundred participants with a transient ischemic attack/ischemic stroke (National Institutes of Health Stroke Scale <= 9) will undergo magnetic resonance imaging within 72 h of symptom onset and will be randomized to aspirin 81 mg daily or dabigatran 150 mg twice daily for 30 days. Participants undergo repeat magnetic resonance imaging at 30 days and clinical assessment to 90 days. Study outcomes The primary outcome is the symptomatic hemorrhagic transformation rate. Secondary outcomes include recurrent stroke and new ischemic lesions on repeat magnetic resonance imaging. Discussion This study will determine the safety of early anticoagulation with dabigatran in patients with acute transient ischemic attack/ischemic stroke and will inform the design of a phase III randomized trial aimed at demonstrating reduced recurrent early ischemic events after acute transient ischemic attack/stroke. PMID- 28585905 TI - Polyphenols from flowers of Magnolia coco and their anti-glycation effects. AB - We investigated the inhibitory effects of several plant extracts on advanced glycation end-products (AGEs) formation. Among tested samples, the flower extract of Magnolia coco showed significant inhibition of AGE formation. We isolated and characterized procyanidin oligomer and four other compounds from the flowers, and evaluated their inhibitory effects on AGE formation and the AGE-derived crosslink cleaving activity of the isolated compounds. PMID- 28585907 TI - Correction to: J Endourol 2017;31:461-467. PMID- 28585906 TI - Elevation of plasma oncostatin M in heart failure. AB - AIM: Oncostatin M (OSM) is an inflammatory cytokine of the gp130 family. OSM could participate in adverse cardiovascular remodeling through regulation of FGF23. MATERIALS & METHODS: OSM levels were determined in 80 heart failure patients with reduced left ventricular ejection fraction (HFrEF). RESULTS: OSM levels are significantly increased in HFrEF patients compared with healthy subjects. We have also demonstrated that, in HFrEF patients, plasma OSM levels are correlated to parathyroid hormone PTH(1-84) and 1,25(OH)2D, two other biomarkers related to bone and mineral metabolism and associated to adverse cardiovascular outcomes. CONCLUSION: OSM concentrations are elevated in HFrEF patients and could interplay with parathyroid hormone and vitamin D impacting cardiovascular function. Nevertheless, the prognostic value of OSM testing appears limited. PMID- 28585909 TI - Agreement analysis comparing iPad LCVA and Sloan testing in multiple sclerosis patients. AB - BACKGROUND: Visual symptoms are common in multiple sclerosis (MS). Low-contrast visual acuity (LCVA) testing using Sloan charts has demonstrated increased sensitivity for visual deficits compared to high-contrast acuity testing. Computerized testing of visual acuity may facilitate use in the clinic setting. OBJECTIVES: To evaluate the agreement between an iPad-based and Sloan testing of LCVA in a cohort of MS patients. METHODS: A total of 38 patients with relapsing remitting MS were enrolled after providing informed written consent at Partners MS Center, Brigham and Women's hospital. Monocular LCVA was measured using retroilluminated Sloan chart and iPad-based LogMAR chart. Number of correct letters and agreement between two measurements were assessed for each eye using Bland-Altman analysis and paired t-test. RESULTS: For both eyes, there was no significant difference in number correct between the two measurements using a paired t-test, and there was high correlation between two measurements (oculus dextrus (OD) r = 0.89, p < 0.001; oculus sinister (OS) r = 0.78, p < 0.001). The limits of agreement were -7.9 to +8.5 letters for the right eye and -10.9 to +11.2 letters for the left eye. CONCLUSION: An iPad-based LCVA test shows good agreement with Sloan testing in MS patients. PMID- 28585908 TI - Tuning the specificity of a Two-in-One Fab against three angiogenic antigens by fully utilizing the information of deep mutational scanning. AB - Monoclonal antibodies developed for therapeutic or diagnostic purposes need to demonstrate highly defined binding specificity profiles. Engineering of an antibody to enhance or reduce binding to related antigens is often needed to achieve the desired biologic activity without safety concern. Here, we describe a deep sequencing-aided engineering strategy to fine-tune the specificity of an angiopoietin-2 (Ang2)/vascular endothelial growth factor (VEGF) dual action Fab, 5A12.1 for the treatment of age-related macular degeneration. This antibody utilizes overlapping complementarity-determining region (CDR) sites for dual Ang2/VEGF interaction with KD in the sub-nanomolar range. However, it also exhibits significant (KD of 4 nM) binding to angiopoietin-1, which has high sequence identity with Ang2. We generated a large phage-displayed library of 5A12.1 Fab variants with all possible single mutations in the 6 CDRs. By tracking the change of prevalence of each mutation during various selection conditions, we identified 35 mutations predicted to decrease the affinity for Ang1 while maintaining the affinity for Ang2 and VEGF. We confirmed the specificity profiles for 25 of these single mutations as Fab protein. Structural analysis showed that some of the Fab mutations cluster near a potential Ang1/2 epitope residue that differs in the 2 proteins, while others are up to 15 A away from the antigen binding site and likely influence the binding interaction remotely. The approach presented here provides a robust and efficient method for specificity engineering that does not require prior knowledge of the antigen antibody interaction and can be broadly applied to antibody specificity engineering projects. PMID- 28585910 TI - CXC Chemokine Receptor Type 4 Antagonism Ameliorated Allograft Fibrosis in Rat Kidney Transplant Model. AB - OBJECTIVES: In this study, we evaluated the effects of CXC chemokine receptor type 4 and stromal cell-derived factor 1 signaling in the progression of chronic allograft nephropathy in a rat model. MATERIALS AND METHODS: Experimental rats were divided into 3 groups: Lewis-to-Lewis isograft transplant (group A), Fisher 344 rat-to-Lewis allograft transplant with immunosuppressant cyclosporine (group B), and Fisher 344 rat-to-Lewis allograft transplant treated with cyclosporine and the CXC chemokine receptor type 4 antagonist AMD3100 (1 mg/kg/d) (group C). On day 90 after the operation, renal graft function, proteinuria, and histologic Banff score were measured. The expression levels of transforming growth factor beta1 and collagen IV were determined by quantitative real-time polymerase chain reaction. RESULTS: Renal function and urinary protein were increased in allografts of groups B and C compared with isografts of group A. The Banff score was significantly decreased in the AMD3100-treated animals (group C), with renal fibrosis being reduced. In addition, overexpressed levels of transforming growth factor beta1 and collagen IV in group B allografts were significantly reduced versus that shown with treatment with the CXC chemokine receptor type 4 antagonist in group C. CONCLUSIONS: Together, these data strongly implicate that CXC chemokine receptor type 4 antagonism alleviated renal interstitial fibrosis in long-term surviving allografts by down-regulating expression of transforming growth factor beta1. PMID- 28585911 TI - Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study. AB - OBJECTIVES: Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. MATERIALS AND METHODS: Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. RESULTS: Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. CONCLUSIONS: Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group. PMID- 28585913 TI - A Case of Recurrent Pneumoperitoneum and Pneumatosis Intestinalis After Bilateral Lung Transplant. AB - We report a case of a 60-year-old male patient with recurrent episodes of free gas in the peritoneal and the retroperitoneal cavities as well as pneumatosis intestinalis 3 months after bilateral lung transplant. Interestingly, despite staged laparotomy within the scope of the first episode, no cause for free gas could be found. In a second episode of symptomatically pneumatosis, a conservative treatment with metro_nidazole was performed successfully. Despite several case reports on patients with pneumatosis intestinalis after lung transplant, an effective treatment strategy has not yet been proposed. PMID- 28585912 TI - Anti-HLA Antibodies Testing on Solid Phase: Comparative Evaluation of Different Kit Vendors Through Luminex Technology. AB - OBJECTIVES: For decades, the detection of anti-HLA antibodies in candidates for solid-organ transplant has been performed with the traditional complement dependent cytotoxicity method; this assay has been then integrated with the introduction of solid-phase assays. Over the past 20 years, the Luminex assay has become the most widely used in clinical laboratories due to both increased sensitivity and specificity versus enzyme-linked immunosorbent assay. However, even the Luminex technique has shown some critical issues, and choosing the most reliable method still remains challenging. In this study, we verified the concordance of the results obtained in detecting anti-HLA antibodies with 2 kit vendors that provide reagents for the Luminex platform. MATERIALS AND METHODS: We used 314 serum samples from patients on wait lists for solid-organ transplant. Sera were tested with LABScreen Mixed-LSM12 (One Lambda-Thermo Fisher, Canoga Park, CA, USA) and LIFECODES LifeScreen Deluxe-LMX (Gen-Probe-Immucor, Stanford, CT, USA),which we indicated as vendor A and vendor B, respectively. Anti-HLA class I and class II antibody analyses were conducted by verifying the concordance of the results with Cohen kappa coefficient statistics and confidence interval. RESULTS: The kappa coefficient statistics showed "substantial" reliability for class I (0.61; confidence interval, 0.50-0.73) and "moderate" reliability for class II (0.56; confidence interval, 0.43-0.69). There were no considerable differences in results between the 2 kits regarding overall assignment of negativity or positivity of a sample. Discordant data between positive values for a test and negative for the other were found for samples with weak antibody positivity. CONCLUSIONS: Some discordant data were probably attributable to several factors such as the composition of the kits, the antibody titer in the serum, whether sera were diluted, different washing methods, and type of plate used. PMID- 28585914 TI - Glutathione S-Transferase Gene Polymorphisms and the Development of New-Onset Diabetes After Liver Transplant. AB - OBJECTIVES: The association between the glutathione S-transferase polymorphisms and the development of new-onset diabetes mellitus after liver transplant was studied. MATERIALS AND METHODS: Peripheral blood samples were collected from 106 liver transplant patients divided into 2 groups: 52 with new-onset diabetes mellitus and 54 without new-onset diabetes mellitus; 169 healthy individuals with no clinical evidence of diabetes mellitus were selected as a control group. The multiplex polymerase chain reaction technique was used for genotyping GSTM1 and GSTT1 genes, using the cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) gene as an internal control. The genotype of GSTP1 was determined using the restriction fragment length polymorphism-polymerase chain reaction technique. RESULTS: The frequency of both GSTM1 null and GSTT1 null genotypes was not significantly different in liver transplant patients with new-onset diabetes mellitus compared with the control group (P = .11 for GSTM1; P = .71 for GSTT1). Also, there was no statistically significant association between the frequency of the GSTP1 genotypes in the liver transplant patients with new-onset diabetes mellitus compared with controls. Neither GSTM1 nor GSTT1 null genotypes were associated with the risk of developing new-onset diabetes mellitus (P = .22 for GSTM1; P = .56 for GSTT1). However, the frequency of the heterozygous mutation (AG) in the A313G GSTP1 polymorphism in patients with new-onset diabetes mellitus was significantly higher than in patients without new-onset diabetes mellitus (55.8% vs 7.4%; P = .00). Thus, the risk of developing new-onset diabetes mellitus was significantly higher in patients presenting with heterozygous GSTP1 genotypes (odds ratio = 15.76; 95% confidence interval = 4.53-60.28; P = .00). CONCLUSIONS: The GSTP1 AG genotype was associated with an increased susceptibility to the development of new-onset diabetes mellitus after liver transplant. PMID- 28585915 TI - Hemodynamic Changes Are Predictive of Coagulopathic Hemorrhage After Living Donor Liver Transplant. AB - OBJECTIVES: Our goal was to evaluate the predictors of coagulopathic hemorrhage after living-donor liver transplant. MATERIALS AND METHODS: We retrospectively evaluated 161 patients who had undergone living-donor liver transplant from July 2005 to April 2014 at a single medical institution. Of these patients, 32 developed hemorrhage after transplant. Patients were separated into those with coagulopathy-related hemorrhage (n=15) or noncoagulopathy-related hemorrhage (n=17) based on the results of computed tomography images. Predictors of hemorrhage after living-donor liver transplant evaluated in this study included preoperative, perioperative, and posttransplant factors and hemodynamic status. RESULTS: Patients who developed coagulopathy-related hemorrhage had significantly lower pretransplant platelet counts (P = .040), a longer cold-ischemia time (P = .045), more blood loss (P = .040), and earlier onset of hemorrhage (P = .048) than patients who had noncoagulopathy-related hemorrhage after transplant. Results of the generalized estimating equation analysis showed that heart rate and central venous pressure differed significantly between the 2 groups of patients. Heart rates increased significantly during hemorrhage (P < .010). Central venous pressure was higher in the coagulopathic group (P = .005) than in the noncoagulopathic group. CONCLUSIONS: Lower pretransplant platelet counts, longer cold ischemia time, more blood loss, earlier onset of hemorrhage, and higher central venous pressure level are indicators of coagulopathic hemorrhage after living-donor liver transplant. PMID- 28585916 TI - MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015. AB - We investigated the kinetics of the Middle East respiratory syndrome coronavirus (MERS-CoV) neutralizing and spike protein antibody titers over the course of 1 year in 11 patients who were confirmed by reverse transcription PCR to have been infected during the outbreak in South Korea in 2015. Robust antibody responses were detected in all survivors who had severe disease; responses remained detectable, albeit with some waning, for <1 year. The duration of viral RNA detection (but not viral load) in sputum significantly correlated with the antibody response magnitude. The MERS S1 ELISA antibody titers correlated well with the neutralizing antibody response. Antibody titers in 4 of 6 patients who had mild illness were undetectable even though most had evidence of pneumonia. This finding implies that MERS-CoV seroepidemiologic studies markedly underestimate the extent of mild and asymptomatic infection. Obtaining convalescent-phase plasma with high antibody titers to treat MERS will be challenging. PMID- 28585917 TI - Recombinant GII.P16-GII.2 Norovirus, Taiwan, 2016. AB - In Taiwan, acute gastroenteritis outbreaks caused by a new norovirus genotype GII.2 increased sharply toward the end of 2016. Unlike previous outbreaks, which often involved restaurants, GII.2 outbreaks mainly occurred in schools. Phylogenetic analysis indicates that these noroviruses are recombinant GII.P16 GII.2 strains. PMID- 28585918 TI - Crosstalk within a functional INO80 complex dimer regulates nucleosome sliding. AB - Several chromatin remodellers have the ability to space nucleosomes on DNA. For ISWI remodellers, this involves an interplay between H4 histone tails, the AutoN and NegC motifs of the motor domains that together regulate ATPase activity and sense the length of DNA flanking the nucleosome. By contrast, the INO80 complex also spaces nucleosomes but is not regulated by H4 tails and lacks the AutoN and NegC motifs. Instead nucleosome sliding requires cooperativity between two INO80 complexes that monitor DNA length simultaneously on either side of the nucleosome during sliding. The C-terminal domain of the human Ino80 subunit (Ino80CTD) binds cooperatively to DNA and dimerisation of these domains provides crosstalk between complexes. ATPase activity, rather than being regulated, instead gradually becomes uncoupled as nucleosome sliding reaches an end point and this is controlled by the Ino80CTD. A single active ATPase motor within the dimer is sufficient for sliding. PMID- 28585921 TI - Detection of lung cancer in exhaled breath with an electronic nose using support vector machine analysis. AB - Lung cancer is one of the most common malignancies and has a low 5-year survival rate. There are no cheap, simple and widely available screening methods for the early diagnostics of lung cancer. The aim of this study was to determine whether analysis of exhaled breath with an artificial olfactory sensor using support vector analysis can differentiate patients with lung cancer from healthy individuals and patients with other lung diseases, regardless of the stage of lung cancer and the most common comorbidities. Patients with histologically or cytologically verified lung cancer, healthy volunteers and patients with other lung diseases (e.g. chronic obstructive pulmonary disease (COPD), asthma, pneumonia, pulmonary embolism, benign lung tumors) were enrolled in the study. Breath sample collection and analysis with a Cyranose 320 sensor device was performed and data were further analyzed using a support vector machine (SVM). The SVM correctly differentiated between cancer patients and healthy volunteers in 98.8% of cases. The cancer versus non-cancer group patients (healthy volunteers and patients with other lung diseases) were classified correctly by SVM in 87.3% of cases. In the mixed diagnosis groups (only cancer, only COPD, cancer + COPD and control) all 79 out of 79 patients were predicted correctly in the cancer + COPD group, with the rate of correct prognosis in other patient groups being lower. Exhaled breath analysis by electronic nose using a SVM is able to discriminate patients with lung cancer from healthy subjects and mixed groups of patients with different lung diseases. It can also provide a certain level of discrimination between lung cancer patients, lung cancer patients with concomitant COPD, COPD alone and a healthy control group. PMID- 28585919 TI - Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells. AB - Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFkappaB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli. PMID- 28585922 TI - Information loss. AB - The complete gravitational collapse of a body in general relativity will result in the formation of a black hole. Although the black hole is classically stable, quantum particle creation processes will result in the emission of Hawking radiation to infinity and corresponding mass loss of the black hole, eventually resulting in the complete evaporation of the black hole. Semiclassical arguments strongly suggest that, in the process of black hole formation and evaporation, a pure quantum state will evolve to a mixed state, i.e. there will be 'information loss'. There has been considerable controversy over this issue for more than 40 years. In this review, we present the arguments in favor of information loss, and analyze some of the counter-arguments and alternative possibilities. PMID- 28585920 TI - Palaeogenomes of Eurasian straight-tusked elephants challenge the current view of elephant evolution. AB - The straight-tusked elephants Palaeoloxodon spp. were widespread across Eurasia during the Pleistocene. Phylogenetic reconstructions using morphological traits have grouped them with Asian elephants (Elephas maximus), and many paleontologists place Palaeoloxodon within Elephas. Here, we report the recovery of full mitochondrial genomes from four and partial nuclear genomes from two P. antiquus fossils. These fossils were collected at two sites in Germany, Neumark Nord and Weimar-Ehringsdorf, and likely date to interglacial periods ~120 and ~244 thousand years ago, respectively. Unexpectedly, nuclear and mitochondrial DNA analyses suggest that P. antiquus was a close relative of extant African forest elephants (Loxodonta cyclotis). Species previously referred to Palaeoloxodon are thus most parsimoniously explained as having diverged from the lineage of Loxodonta, indicating that Loxodonta has not been constrained to Africa. Our results demonstrate that the current picture of elephant evolution is in need of substantial revision. PMID- 28585923 TI - DATS, the data tag suite to enable discoverability of datasets. AB - Today's science increasingly requires effective ways to find and access existing datasets that are distributed across a range of repositories. For researchers in the life sciences, discoverability of datasets may soon become as essential as identifying the latest publications via PubMed. Through an international collaborative effort funded by the National Institutes of Health (NIH)'s Big Data to Knowledge (BD2K) initiative, we have designed and implemented the DAta Tag Suite (DATS) model to support the DataMed data discovery index. DataMed's goal is to be for data what PubMed has been for the scientific literature. Akin to the Journal Article Tag Suite (JATS) used in PubMed, the DATS model enables submission of metadata on datasets to DataMed. DATS has a core set of elements, which are generic and applicable to any type of dataset, and an extended set that can accommodate more specialized data types. DATS is a platform-independent model also available as an annotated serialization in schema.org, which in turn is widely used by major search engines like Google, Microsoft, Yahoo and Yandex. PMID- 28585924 TI - Understanding the origin of Paris Agreement emission uncertainties. AB - The UN Paris Agreement puts in place a legally binding mechanism to increase mitigation action over time. Countries put forward pledges called nationally determined contributions (NDC) whose impact is assessed in global stocktaking exercises. Subsequently, actions can then be strengthened in light of the Paris climate objective: limiting global mean temperature increase to well below 2 degrees C and pursuing efforts to limit it further to 1.5 degrees C. However, pledged actions are currently described ambiguously and this complicates the global stocktaking exercise. Here, we systematically explore possible interpretations of NDC assumptions, and show that this results in estimated emissions for 2030 ranging from 47 to 63 GtCO2e yr-1. We show that this uncertainty has critical implications for the feasibility and cost to limit warming well below 2 degrees C and further to 1.5 degrees C. Countries are currently working towards clarifying the modalities of future NDCs. We identify salient avenues to reduce the overall uncertainty by about 10 percentage points through simple, technical clarifications regarding energy accounting rules. Remaining uncertainties depend to a large extent on politically valid choices about how NDCs are expressed, and therefore raise the importance of a thorough and robust process that keeps track of where emissions are heading over time. PMID- 28585926 TI - A monthly global paleo-reanalysis of the atmosphere from 1600 to 2005 for studying past climatic variations. AB - Climatic variations at decadal scales such as phases of accelerated warming or weak monsoons have profound effects on society and economy. Studying these variations requires insights from the past. However, most current reconstructions provide either time series or fields of regional surface climate, which limit our understanding of the underlying dynamics. Here, we present the first monthly paleo-reanalysis covering the period 1600 to 2005. Over land, instrumental temperature and surface pressure observations, temperature indices derived from historical documents and climate sensitive tree-ring measurements were assimilated into an atmospheric general circulation model ensemble using a Kalman filtering technique. This data set combines the advantage of traditional reconstruction methods of being as close as possible to observations with the advantage of climate models of being physically consistent and having 3 dimensional information about the state of the atmosphere for various variables and at all points in time. In contrast to most statistical reconstructions, centennial variability stems from the climate model and its forcings, no stationarity assumptions are made and error estimates are provided. PMID- 28585925 TI - Conserved linear dynamics of single-molecule Brownian motion. AB - Macromolecular diffusion in homogeneous fluid at length scales greater than the size of the molecule is regarded as a random process. The mean-squared displacement (MSD) of molecules in this regime increases linearly with time. Here we show that non-random motion of DNA molecules in this regime that is undetectable by the MSD analysis can be quantified by characterizing the molecular motion relative to a latticed frame of reference. Our lattice occupancy analysis reveals unexpected sub-modes of motion of DNA that deviate from expected random motion in the linear, diffusive regime. We demonstrate that a subtle interplay between these sub-modes causes the overall diffusive motion of DNA to appear to conform to the linear regime. Our results show that apparently random motion of macromolecules could be governed by non-random dynamics that are detectable only by their relative motion. Our analytical approach should advance broad understanding of diffusion processes of fundamental relevance. PMID- 28585927 TI - Extreme temperatures in Southeast Asia caused by El Nino and worsened by global warming. AB - In April 2016, southeast Asia experienced surface air temperatures (SATs) that surpassed national records, exacerbated energy consumption, disrupted agriculture and caused severe human discomfort. Here we show using observations and an ensemble of global warming simulations the combined impact of the El Nino/Southern Oscillation (ENSO) phenomenon and long-term warming on regional SAT extremes. We find a robust relationship between ENSO and southeast Asian SATs wherein virtually all April extremes occur during El Nino years. We then quantify the relative contributions of long-term warming and the 2015-16 El Nino to the extreme April 2016 SATs. The results indicate that global warming increases the likelihood of record-breaking April extremes where we estimate that 29% of the 2016 anomaly was caused by warming and 49% by El Nino. These post-Nino Aprils can potentially be anticipated a few months in advance, and thus, help societies prepare for the projected continued increases in extremes. PMID- 28585929 TI - Association between the serotonin transporter gene polymorphism and verbal learning in older adults is moderated by gender. AB - The S allele of the functional 5-HTTLPR polymorphism has previously been associated with reductions in memory function. Given the change in function of the serotonergic system in older adults, and the functional consequences of memory decline in this age group, further investigation into the impact of 5 HTTLPR in healthy older adults is required. This investigation examined the effect of 5-HTTLPR variants (S carriers versus L/L homozygotes) on verbal and visual episodic memory in 438 healthy older adults participating in the Tasmanian Healthy Brain Project (age range 50-79 years, M=60.35, s.d.=6.75). Direct effects of 5-HTTLPR on memory processes, in addition to indirect effects through interaction with age and gender, were assessed. Although no direct effects of 5 HTTLPR on memory processes were identified, our results indicated that gender significantly moderated the impact that 5-HTTLPR variants exerted on the relationship between age and verbal episodic memory function as assessed by the Rey Auditory Verbal Learning Test. No significant direct or indirect effects were identified in relation to visual memory performance. Overall, this investigation found evidence to suggest that 5-HTTLPR genotype affects the association of age and verbal episodic memory for males and females differently, with the predicted negative effect of S carriage present in males but not females. Such findings indicate a gender-dependent role for 5-HTTLPR in the verbal episodic memory system of healthy older adults. PMID- 28585928 TI - Predicting attention-deficit/hyperactivity disorder severity from psychosocial stress and stress-response genes: a random forest regression approach. AB - Identifying genetic variants contributing to attention-deficit/hyperactivity disorder (ADHD) is complicated by the involvement of numerous common genetic variants with small effects, interacting with each other as well as with environmental factors, such as stress exposure. Random forest regression is well suited to explore this complexity, as it allows for the analysis of many predictors simultaneously, taking into account any higher-order interactions among them. Using random forest regression, we predicted ADHD severity, measured by Conners' Parent Rating Scales, from 686 adolescents and young adults (of which 281 were diagnosed with ADHD). The analysis included 17 374 single-nucleotide polymorphisms (SNPs) across 29 genes previously linked to hypothalamic-pituitary adrenal (HPA) axis activity, together with information on exposure to 24 individual long-term difficulties or stressful life events. The model explained 12.5% of variance in ADHD severity. The most important SNP, which also showed the strongest interaction with stress exposure, was located in a region regulating the expression of telomerase reverse transcriptase (TERT). Other high-ranking SNPs were found in or near NPSR1, ESR1, GABRA6, PER3, NR3C2 and DRD4. Chronic stressors were more influential than single, severe, life events. Top hits were partly shared with conduct problems. We conclude that random forest regression may be used to investigate how multiple genetic and environmental factors jointly contribute to ADHD. It is able to implicate novel SNPs of interest, interacting with stress exposure, and may explain inconsistent findings in ADHD genetics. This exploratory approach may be best combined with more hypothesis-driven research; top predictors and their interactions with one another should be replicated in independent samples. PMID- 28585930 TI - Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression. AB - Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine-adenine-guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR in two well-characterized Dutch cohorts-the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons including 2165 depressed and 1058 non-depressed individuals-aged 18-93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with <=10, CAG repeats in both ATXN7 alleles (OR=1.90, confidence interval (CI) 1.26-2.85). For TBP we found a similar association: A CAG repeat length exceeding the median in both alleles was associated with an increased risk for lifetime depression (OR=1.33, CI 1.00-1.76). In conclusion, we observed that carriers of either ATXN7 or TBP alleles with relatively large CAG repeat sizes in both alleles had a substantially increased risk of lifetime depression. Our findings provide critical evidence for the notion that repeat polymorphisms can act as complex genetic modifiers of depression. PMID- 28585931 TI - The modulation of adult neuroplasticity is involved in the mood-improving actions of atypical antipsychotics in an animal model of depression. AB - Depression is a prevalent psychiatric disorder with an increasing impact in global public health. However, a large proportion of patients treated with currently available antidepressant drugs fail to achieve remission. Recently, antipsychotic drugs have received approval for the treatment of antidepressant resistant forms of major depression. The modulation of adult neuroplasticity, namely hippocampal neurogenesis and neuronal remodeling, has been considered to have a key role in the therapeutic effects of antidepressants. However, the impact of antipsychotic drugs on these neuroplastic mechanisms remains largely unexplored. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 3 weeks of stress exposure, animals were treated with two different antipsychotics: haloperidol (a classical antipsychotic) and clozapine (an atypical antipsychotic). We demonstrated that clozapine improved both measures of depressive-like behavior (behavior despair and anhedonia), whereas haloperidol aggravated learned helplessness in the forced-swimming test and behavior flexibility in a cognitive task. Importantly, an upregulation of adult neurogenesis and neuronal survival was observed in animals treated with clozapine, whereas haloperidol promoted a downregulation of these processes. Furthermore, clozapine was able to re establish the stress-induced impairments in neuronal structure and gene expression in the hippocampus and prefrontal cortex. These results demonstrate the modulation of adult neuroplasticity by antipsychotics in an animal model of depression, revealing that the atypical antipsychotic drug clozapine reverts the behavioral effects of chronic stress by improving adult neurogenesis, cell survival and neuronal reorganization. PMID- 28585932 TI - Plasma REST: a novel candidate biomarker of Alzheimer's disease is modified by psychological intervention in an at-risk population. AB - The repressor element 1-silencing transcription (REST) factor is a key regulator of the aging brain's stress response. It is reduced in conditions of stress and Alzheimer's disease (AD), which suggests that increasing REST may be neuroprotective. REST can be measured peripherally in blood plasma. Our study aimed to (1) examine plasma REST levels in relation to clinical and biological markers of neurodegeneration and (2) alter plasma REST levels through a stress reduction intervention-mindfulness training. In study 1, REST levels were compared across the following four well-characterized groups: healthy elderly (n=65), mild cognitive impairment who remained stable (stable MCI, n=36), MCI who later converted to dementia (converter MCI, n=29) and AD (n=65) from the AddNeuroMed cohort. REST levels declined with increasing severity of risk and impairment (healthy elderly>stable MCI>converter MCI>AD, F=6.35, P<0.001). REST levels were also positively associated with magnetic resonance imaging-based hippocampal and entorhinal atrophy and other putative blood-based biomarkers of AD (Ps<0.05). In study 2, REST was measured in 81 older adults with psychiatric risk factors for AD before and after a mindfulness-based stress reduction intervention or an education-based placebo intervention. Mindfulness-based training caused an increase in REST compared with the placebo intervention (F=8.57, P=0.006), and increased REST was associated with a reduction in psychiatric symptoms associated with stress and AD risk (Ps<0.02). Our data confirm plasma REST associations with clinical severity and neurodegeneration, and originally, that REST is modifiable by a psychological intervention with clinical benefit. PMID- 28585933 TI - Neuroimaging studies of GABA in schizophrenia: a systematic review with meta analysis. AB - Data from animal models and from postmortem studies suggest that schizophrenia is associated with brain GABAergic dysfunction. The extent to which this is reflected in data from in vivo studies of GABA function in schizophrenia is unclear. The Medline database was searched to identify articles published until 21 October 2016. The search terms included GABA, proton magnetic resonance spectroscopy (1H-MRS), positron emission tomography (PET), single photon emission computed tomography (SPECT), schizophrenia and psychosis. Sixteen GABA 1H-MRS studies (538 controls, 526 patients) and seven PET/SPECT studies of GABAA/benzodiazepine receptor (GABAA/BZR) availability (118 controls, 113 patients) were identified. Meta-analyses of 1H-MRS GABA in the medial prefrontal cortex (mPFC), parietal/occipital cortex (POC) and striatum did not show significant group differences (mFC: g=-0.3, 409 patients, 495 controls, 95% confidence interval (CI): -0.6 to 0.1; POC: g=-0.3, 139 patients, 111 controls, 95% CI: -0.9 to 0.3; striatum: g=-0.004, 123 patients, 95 controls, 95% CI: -0.7 to 0.7). Heterogeneity across studies was high (I2>50%), and this was not explained by subsequent moderator or meta-regression analyses. There were insufficient PET/SPECT receptor availability studies for meta-analyses, but a systematic review did not suggest replicable group differences in regional GABAA/BZR availability. The current literature does not reveal consistent alterations in in vivo GABA neuroimaging measures in schizophrenia, as might be hypothesized from animal models and postmortem data. The analysis highlights the need for further GABA neuroimaging studies with improved methodology and addressing potential sources of heterogeneity. PMID- 28585934 TI - Crenothrix are major methane consumers in stratified lakes. AB - Methane-oxidizing bacteria represent a major biological sink for methane and are thus Earth's natural protection against this potent greenhouse gas. Here we show that in two stratified freshwater lakes a substantial part of upward-diffusing methane was oxidized by filamentous gamma-proteobacteria related to Crenothrix polyspora. These filamentous bacteria have been known as contaminants of drinking water supplies since 1870, but their role in the environmental methane removal has remained unclear. While oxidizing methane, these organisms were assigned an 'unusual' methane monooxygenase (MMO), which was only distantly related to 'classical' MMO of gamma-proteobacterial methanotrophs. We now correct this assignment and show that Crenothrix encode a typical gamma-proteobacterial PmoA. Stable isotope labeling in combination swith single-cell imaging mass spectrometry revealed methane-dependent growth of the lacustrine Crenothrix with oxygen as well as under oxygen-deficient conditions. Crenothrix genomes encoded pathways for the respiration of oxygen as well as for the reduction of nitrate to N2O. The observed abundance and planktonic growth of Crenothrix suggest that these methanotrophs can act as a relevant biological sink for methane in stratified lakes and should be considered in the context of environmental removal of methane. PMID- 28585936 TI - Letting go: bacterial genome reduction solves the dilemma of adapting to predation mortality in a substrate-restricted environment. AB - Resource limitation and predation mortality are major determinants of microbial population dynamics, and optimization for either aspect is considered to imply a trade-off with respect to the other. Adaptation to these selective factors may, moreover, lead to disadvantages at rich growth conditions. We present an example of a concomitant evolutionary optimization to both, substrate limitation and predation in an aggregate-forming freshwater bacterial isolate, and we elucidate an underlying genomic mechanism. Bacteria were propagated in serial batch culture in a nutrient-restricted environment either with or without a bacterivorous flagellate. Strains isolated after 26 growth cycles of the predator-prey co cultures formed as much total biomass as the ancestor at ancestral growth conditions, albeit largely reallocated to cell aggregates. A ~273 kbp genome fragment was lost in three strains that had independently evolved with predators. These strains had significantly higher growth yield on substrate-restricted media than others that were isolated from the same treatment before the excision event. Under predation pressure, the isolates with the deletion outcompeted both, the ancestor and the strains evolved without predators even at rich growth conditions. At the same time, genome reduction led to a growth disadvantage in the presence of benzoate due to the loss of the respective degradation pathway, suggesting that niche constriction might be the price for the bidirectional optimization. PMID- 28585935 TI - Shifts in rhizosphere fungal community during secondary succession following abandonment from agriculture. AB - Activities of rhizosphere microbes are key to the functioning of terrestrial ecosystems. It is commonly believed that bacteria are the major consumers of root exudates and that the role of fungi in the rhizosphere is mostly limited to plant associated taxa, such as mycorrhizal fungi, pathogens and endophytes, whereas less is known about the role of saprotrophs. In order to test the hypothesis that the role of saprotrophic fungi in rhizosphere processes increases with increased time after abandonment from agriculture, we determined the composition of fungi that are active in the rhizosphere along a chronosequence of ex-arable fields in the Netherlands. Intact soil cores were collected from nine fields that represent three stages of land abandonment and pulse labeled with 13CO2. The fungal contribution to metabolization of plant-derived carbon was evaluated using phospholipid analysis combined with stable isotope probing (SIP), whereas fungal diversity was analyzed using DNA-SIP combined with 454-sequencing. We show that in recently abandoned fields most of the root-derived 13C was taken up by bacteria but that in long-term abandoned fields most of the root-derived 13C was found in fungal biomass. Furthermore, the composition of the active functional fungal community changed from one composed of fast-growing and pathogenic fungal species to one consisting of beneficial and slower-growing fungal species, which may have essential consequences for the carbon flow through the soil food web and consequently nutrient cycling and plant succession. PMID- 28585937 TI - Nitrogen cost minimization is promoted by structural changes in the transcriptome of N-deprived Prochlorococcus cells. AB - Prochlorococcus is a globally abundant marine cyanobacterium with many adaptations that reduce cellular nutrient requirements, facilitating growth in its nutrient-poor environment. One such genomic adaptation is the preferential utilization of amino acids containing fewer N-atoms, which minimizes cellular nitrogen requirements. We predicted that transcriptional regulation might further reduce cellular N budgets during transient N limitation. To explore this, we compared transcription start sites (TSSs) in Prochlorococcus MED4 under N deprived and N-replete conditions. Of 64 genes with primary and internal TSSs in both conditions, N-deprived cells initiated transcription downstream of primary TSSs more frequently than N-replete cells. Additionally, 117 genes with only an internal TSS demonstrated increased internal transcription under N-deprivation. These shortened transcripts encode predicted proteins with an average of 21% less N content compared to full-length transcripts. We hypothesized that low translation rates, which afford greater control over protein abundances, would be beneficial to relatively slow-growing organisms like Prochlorococcus. Consistent with this idea, we found that Prochlorococcus exhibits greater usage of glycine glycine motifs, which causes translational pausing, when compared to faster growing microbes. Our findings indicate that structural changes occur within the Prochlorococcus MED4 transcriptome during N-deprivation, potentially altering the size and structure of proteins expressed under nutrient limitation. PMID- 28585938 TI - Genomics and metagenomics of trimethylamine-utilizing Archaea in the human gut microbiome. AB - The biological significance of Archaea in the human gut microbiota is largely unclear. We recently reported genomic and biochemical analyses of the Methanomassiliicoccales, a novel order of methanogenic Archaea dwelling in soil and the animal digestive tract. We now show that these Methanomassiliicoccales are present in published microbiome data sets from eight countries. They are represented by five Operational Taxonomic Units present in at least four cohorts and phylogenetically distributed into two clades. Genes for utilizing trimethylamine (TMA), a bacterial precursor to an atherosclerogenic human metabolite, were present in four of the six novel Methanomassiliicoccales genomes assembled from ELDERMET metagenomes. In addition to increased microbiota TMA production capacity in long-term residential care subjects, abundance of TMA utilizing Methanomassiliicoccales correlated positively with bacterial gene count for TMA production and negatively with fecal TMA concentrations. The two large Methanomassiliicoccales clades have opposite correlations with host health status in the ELDERMET cohort and putative distinct genomic signatures for gut adaptation. PMID- 28585940 TI - Identifying the core seed bank of a complex boreal bacterial metacommunity. AB - Seed banks are believed to contribute to compositional changes within and across microbial assemblages, but the application of this concept to natural communities remains challenging. Here we describe the core seed bank of a bacterial metacommunity from a boreal watershed, using the spatial distribution of bacterial operational taxonomic units (OTUs) across 223 heterogeneous terrestrial, aquatic and phyllosphere bacterial assemblages. Taxa were considered potential seeds if they transitioned from rare to abundant somewhere within the metacommunity and if they were ubiquitous and able to persist under unfavorable conditions, the latter assessed by checking their presence in three deeply sequenced samples (one soil, one river and one lake, 2.2-3 million reads per sample). We show that only a small fraction (13%) of all detected OTUs constitute a metacommunity seed bank that is shared between all terrestrial and aquatic communities, but not by phyllosphere assemblages, which seem to recruit from a different taxa pool. Our results suggest directional recruitment driven by the flow of water in the landscape, since most aquatic sequences were associated to OTUs found in a single deeply-sequenced soil sample, but only 45% of terrestrial sequences belonged to OTUs found in the two deeply-sequenced aquatic communities. Finally, we hypothesize that extreme rarity, and its interplay with water residence time and growth rates, may further constrain the size of the potential seed bank. PMID- 28585939 TI - Linking rhizosphere microbiome composition of wild and domesticated Phaseolus vulgaris to genotypic and root phenotypic traits. AB - Plant domestication was a pivotal accomplishment in human history, but also led to a reduction in genetic diversity of crop species compared to their wild ancestors. How this reduced genetic diversity affected plant-microbe interactions belowground is largely unknown. Here, we investigated the genetic relatedness, root phenotypic traits and rhizobacterial community composition of modern and wild accessions of common bean (Phaseolus vulgaris) grown in agricultural soil from the highlands of Colombia, one of the centers of common bean diversification. Diversity Array Technology-based genotyping and phenotyping of local common bean accessions showed significant genetic and root architectural differences between wild and modern accessions, with a higher specific root length for the wild accessions. Canonical Correspondence Analysis indicated that the divergence in rhizobacterial community composition between wild and modern bean accessions is associated with differences in specific root length. Along the bean genotypic trajectory, going from wild to modern, we observed a gradual decrease in relative abundance of Bacteroidetes, mainly Chitinophagaceae and Cytophagaceae, and an increase in relative abundance of Actinobacteria and Proteobacteria, in particular Nocardioidaceae and Rhizobiaceae, respectively. Collectively, these results establish a link between common bean domestication, specific root morphological traits and rhizobacterial community assembly. PMID- 28585942 TI - Progress of crystallization in microfluidic devices. AB - Microfluidic technology provides a unique environment for the investigation of crystallization processes at the nano or meso scale. The convenient operation and precise control of process parameters, at these scales of operation enabled by microfluidic devices, are attracting significant and increasing attention in the field of crystallization. In this paper, developments and applications of microfluidics in crystallization research including: crystal nucleation and growth, polymorph and cocrystal screening, preparation of nanocrystals, solubility and metastable zone determination, are summarized and discussed. The materials used in the construction and the structure of these microfluidic devices are also summarized and methods for measuring and modelling crystal nucleation and growth process as well as the enabling analytical methods are also briefly introduced. The low material consumption, high efficiency and precision of microfluidic crystallizations are of particular significance for active pharmaceutical ingredients, proteins, fine chemicals, and nanocrystals. Therefore, it is increasingly adopted as a mainstream technology in crystallization research and development. PMID- 28585943 TI - Covalent-reaction-induced interfacial assembly to transform doxorubicin into nanophotomedicine with highly enhanced anticancer efficiency. AB - Herein, we show that a molecular assembly offers tremendous opportunities of affording existing building units with new physicochemical properties, holding promise in wide applications. Herein, we develop a facile covalent assembly using a natural occurring linker, genipin, to efficiently transform a traditional chemo drug, doxorubicin, into a nanophotomedicine. A possible mechanism is proposed, in which doxorubicin reacts with genipin through covalent bonding to produce poorly soluble units, which further form nuclei and mediate the interfacial assembly to generate uniform nanoparticles. Such assembled nanophotomedicine shows remarkably enhanced singlet oxygen generation ability (about 1000 folds), leading to a much higher photodynamic activity. Moreover, this self-carried nanodrug exhibits adjustable size, excellent colloidal stability, high capacity and preferable endocytosis. These favorable features lead to greatly improved anticancer efficiency under light at the same dosage, compared to that of pure doxorubin. We believe this study brings a new dimension to develop advanced drug delivery systems by molecular assembly. PMID- 28585941 TI - Ubiquity and quantitative significance of bacterioplankton lineages inhabiting the oxygenated hypolimnion of deep freshwater lakes. AB - The oxygenated hypolimnion accounts for a volumetrically significant part of the global freshwater systems. Previous studies have proposed the presence of hypolimnion-specific bacterioplankton lineages that are distinct from those inhabiting the epilimnion. To date, however, no consensus exists regarding their ubiquity and abundance, which is necessary to evaluate their ecological importance. The present study investigated the bacterioplankton community in the oxygenated hypolimnia of 10 deep freshwater lakes. Despite the broad geochemical characteristics of the lakes, 16S rRNA gene sequencing demonstrated that the communities in the oxygenated hypolimnia were distinct from those in the epilimnia and identified several predominant lineages inhabiting multiple lakes. Catalyzed reporter deposition fluorescence in situ hybridization revealed that abundant hypolimnion-specific lineages, CL500-11 (Chloroflexi), CL500-3, CL500 37, CL500-15 (Planctomycetes) and Marine Group I (Thaumarchaeota), together accounted for 1.5-32.9% of all bacterioplankton in the hypolimnion of the lakes. Furthermore, an analysis of single-nucleotide variation in the partial 16S rRNA gene sequence (oligotyping) suggested the presence of different sub-populations between lakes and water layers among the lineages occurring in the entire water layer (for example, acI-B1 and acI-A7). Collectively, these results provide the first comprehensive overview of the bacterioplankton community in the oxygenated hypolimnion of deep freshwater lakes. PMID- 28585945 TI - Enhanced photochromic modulation efficiency: a novel plasmonic molybdenum oxide hybrid. AB - Plasmonic materials have drawn emerging interest with their high charge carrier density and solar harvesting ability, resulting in tunable enhanced absorption and scattering resonances. Herein, a novel plasmonic MoO3-x hybrid comprising orthorhombic MoO3-x nanorod and hexagonal MoO3 nanograin was obtained using a simple hydrothermal method. An excellent photochromic property with up to 40% solar modulation efficiency at 600-1000 nm was achieved, which was mainly attributed to the localized surface plasmon resonance (LSPR) absorption at around 900 nm and the polaron absorption at 650 nm with a synergistic effect. In comparison to the limited near-infrared absorption of conventional crystalline MoO3, a distinct modulation range in the critical range between visible and near infrared was rationalized by a size effect deduced from Mie scattering theory. Our research provided a novel plasmonic molybdenum oxide hybrid to realize an optical modulation function with a tunable wavelength range for energy saving. PMID- 28585946 TI - Simultaneous spectrum fitting and baseline correction using sparse representation. AB - Sparse representation has been applied in many domains, such as signal processing, image processing and machine learning. In this paper, a redundant dictionary with each column composed of a Voigt-like lineshape is constructed to represent the pure spectrum of the sample. With the prior knowledge that the baseline is smooth and sparse representation coefficient for a pure spectrum, a method simultaneously fitting the pure spectrum and baseline is proposed. Since the pure spectrum is nonnegative, the representation coefficients are also made to be nonnegative. Then through alternating optimization, a surrogate function based algorithm is used to obtain the sparse coefficients. Finally, we adopt one simulated data set and two real data sets to evaluate our method. The results of quantitative analysis show that our method successfully estimates the baseline and pure spectrum and is superior compared to other baseline correction and preprocessing methods. PMID- 28585948 TI - Radical cascade cyclization of 1,n-enynes and diynes for the synthesis of carbocycles and heterocycles. AB - Carbo- and heterocycles are widely found in natural products, biologically active structures, medicinally relevant compounds, and in many other fine chemicals. The development of novel, general and efficient methods for their construction has therefore gained great interest in synthetic organic chemistry. Recently, radical chemistry has become a heavily investigated research field (a renaissance!). Along these lines, radical cascade cyclization of 1,n-enynes and diynes has emerged as a powerful strategy for the preparation of carbo- and heterocycles. In this review, we highlight recent advances in this rapidly growing area also focusing on reaction mechanisms. PMID- 28585947 TI - Selectively switching on europium emission in drug site one of human serum albumin. AB - A luminescent europium probe has been discovered that binds selectively to drug site I in human serum albumin, signalled by a 'switching on' of europium emission, and accompanied by strong induced circularly polarised luminescence. PMID- 28585950 TI - Electrochemical CO2 reduction on Au surfaces: mechanistic aspects regarding the formation of major and minor products. AB - In the future, industrial CO2 electroreduction using renewable energy sources could be a sustainable means to convert CO2 and water into commodity chemicals at room temperature and atmospheric pressure. This study focuses on the electrocatalytic reduction of CO2 on polycrystalline Au surfaces, which have high activity and selectivity for CO evolution. We explore the catalytic behavior of polycrystalline Au surfaces by coupling potentiostatic CO2 electrolysis experiments in an aqueous bicarbonate solution with high sensitivity product detection methods. We observed the production of methanol, in addition to detecting the known products of CO2 electroreduction on Au: CO, H2 and formate. We suggest a mechanism that explains Au's evolution of methanol. Specifically, the Au surface does not favor C-O scission, and thus is more selective towards methanol than methane. These insights could aid in the design of electrocatalysts that are selective for CO2 electroreduction to oxygenates over hydrocarbons. PMID- 28585952 TI - The influence of hydrogen bonds on NIAD-4 for use in the optical imaging of amyloid fibrils. AB - The fast and accurate detection of amyloid fibrils, which are associated with many neurodegenerative diseases, is important for their early diagnosis. {[50-(p Hydroxyphenyl)-2,20-bithienyl-5-yl]-methylidene}-propanedinitrile (NIAD-4) is a new promising fluorescent marker for amyloid fibrils, and the photophysical behaviour of NIAD-4 is controversial. Nonadiabatic dynamic simulations, density functional theory (DFT) and time-dependent density functional theory (TDDFT) calculations were performed to determine the influence of the environment on NIAD 4 and the photophysical behaviour of NIAD-4. The results indicate that NIAD-4 is in the NIAD-4.3H2O compound form in the ground state in water. The torsion process of NIAD-4 proposed by Hu et al. (Phys. Chem. Chem. Phys. 2016, 18, 28) does not occur in the excited state. In addition, the fluorescence behaviour of NIAD-4 is sensitive to a hydrogen bonding environment, the maximum fluorescence wavelengths of NIAD-4 show considerable red-shifts, and the fluorescence intensity of NIAD-4 increases significantly in a hydrogen bonding environment. Intermolecular hydrogen bonds are vital for the phenomenon observed in the experiment because the fluorescence intensity of NIAD-4 becomes unusually high with increasing solvent polarities. Therefore, the influence of the intermolecular hydrogen bond should be carefully taken into consideration when NIAD-4 is used to probe the amyloid fibrils in hydrogen-bonding surroundings, especially in complex bioenvironments. PMID- 28585944 TI - Cellular uptake of nanoparticles: journey inside the cell. AB - Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell-cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano-bio interface. Recent advances in chemical synthesis have yielded new nanoscale materials with precisely defined biochemical features, and emerging analytical techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available analytical techniques to follow and track these processes. PMID- 28585955 TI - A precisely positioned chiral center in an i, i + 7 tether modulates the helicity of the backbone peptide. AB - In some cases, helical peptides stabilized by an i, i + 7 tether exhibit better target binding and cellular functions compared to their i, i + 4 analogues. Herein, we carried out a systematic study of the effects of an in-tether chiral center on the i, i + 7 system. We screened the optimal cross linking mode, tether length, in-tether chiral center positions, and absolute configurations. From these studies, we determined that a chiral center of R absolute configuration at the gamma-position to the C-terminal of a 10-membered tether could function to efficiently induce helicity of the backbone peptides. This is an important addition to the current i, i + 4 in-tether chiral center induced helicity strategy (CIH strategy), and could have broad biological applications. PMID- 28585956 TI - Engineering the exchange bias and bias temperature by modulating the spin glassy state in single phase Bi9Fe5Ti3O27. AB - Exchange anisotropy is normally observed at ferromagnetic (FM)/anti-ferromagnetic (AFM) interfaces and also usually at low temperatures. An effective way to find new single-phase materials with strong exchange bias (EB) and high operation temperatures is required for making them useful in practical applications of future spintronic devices. In this work, the exchange bias behaviors of single phase Bi9Fe5Ti3O27 (BFT) were found able to be manipulated by altering its spin glassy state, when the material was intentionally prepared in the nanobelt format. A core-shell model has been proposed to explain the controllable behavior of both exchange bias and bias temperature, in which the AFM domain could be effectively reduced within the nanobelts when changing their particle sizes. A direct observation of two spin glassy behaviors corresponding to two distinct peaks in the zero field cooling (ZFC) curves manifests the validity of the proposed core-shell model. PMID- 28585953 TI - A facile strategy for fine-tuning the stability and drug release of stimuli responsive cross-linked micellar nanoparticles towards precision drug delivery. AB - Precision drug delivery has a great impact on the application of precision oncology for better patient care. Here we report a facile strategy for fine tuning the stability, drug release and responsiveness of stimuli-responsive cross linked nanoparticles towards precision drug delivery. A series of micellar nanoparticles with different levels of intramicellar disulfide crosslinkages could be conveniently produced with a mixed micelle approach. These micellar nanoparticles were all within a size range of 25-40 nm so that they could take full advantage of the enhanced permeability and retention (EPR) effect for tumor targeted drug delivery. The properties of these nanoparticles such as critical micelle concentration (CMC), stability, drug release and responsiveness to a reductive environment could be well correlated with the levels of crosslinking (LOC). Compared to the micellar nanoparticles with a LOC at 0% that caused the death of animals of two species (mouse and rat) due to the acute toxicity such as hemolysis, the nanoparticles at all other levels of crosslinking were much safer to be administered into animals. The in vitro antitumor efficacy of micellar nanoparticles crosslinked at lower levels (20% & 50%) were much more effective than that of 100% crosslinked micellar nanoparticles in SKOV-3 ovarian cancer cells. PMID- 28585957 TI - Heterogeneously Nd3+ doped single nanoparticles for NIR-induced heat conversion, luminescence, and thermometry. AB - The current frontier in nanomaterials engineering is to intentionally design and fabricate heterogeneous nanoparticles with desirable morphology and composition, and to integrate multiple functionalities through highly controlled epitaxial growth. Here we show that heterogeneous doping of Nd3+ ions following a core shell design already allows three optical functions, namely efficient (eta > 72%) light-to-heat conversion, bright NIR emission, and sensitive (SR > 0.1% K-1) localized temperature quantification, to be built within a single ca. 25 nm nanoparticle. Importantly, all these optical functions operate within the transparent biological window of the NIR spectral region (lambdaexc ~ 800 nm, lambdaemi ~ 860 nm), in which light scattering and absorption by tissues and water are minimal. We find NaNdF4 as a core is efficient in absorbing and converting 808 nm light to heat, while NaYF4:1%Nd3+ as a shell is a temperature sensor based on the ratio-metric luminescence reading but an intermediate inert spacer shell, e.g. NaYF4, is necessary to insulate the heat convertor and thermometer by preventing the possible Nd-Nd energy relaxation. Moreover, we notice that while temperature sensitivity and luminescence intensity are optically stable, increased excitation intensity to generate heat above room temperature may saturate the sensing capacity of temperature feedback. We therefore propose a dual beam photoexcitation scheme as a solution for possible light-induced hyperthermia treatment. PMID- 28585959 TI - Functionalized self-assembly of colloidal CdX (X = S, Se) nanorods on solid substrates for device applications. AB - In comparison to randomly oriented nanorods (NRs), self-assembly of the colloidal CdX (X = S, Se) NRs into well-organized large-scale structures results in unique collective properties. Moreover, the anisotropic structural features of self assemblies preserved from colloidal CdX (X = S, Se) NRs have opened up exciting opportunities in the field of nanotechnology applications. We present the latest strategies for the self-assembly of colloidal NRs on solid substrates, and further focus on the self-assembled NRs for applications in devices. Advanced progress in the preparation of NR building blocks on the basis of nanofabrication techniques and comprehensive studies on the interactions of NRs with substrates will remarkably expand the application of colloidal semiconductor NRs. Understanding and mastering the driving forces behind the assembly of the NRs is the key goal of engineering future functional structures based on NRs. PMID- 28585960 TI - Thermal conductivity of suspended single crystal CH3NH3PbI3 platelets at room temperature. AB - Recently, organic-inorganic lead halide perovskites have gained great attention for their breakthrough in photovoltaic and optoelectronics. However, their thermal transport properties that affect the device lifetime and stability are still rarely explored. In this work, the thermal conductivity properties of single crystal CH3NH3PbI3 platelets grown by chemical vapor deposition are studied via non-contact micro-photoluminescence (PL) spectroscopy. We developed a measurement methodology and derived expressions suitable for the thermal conductivity extraction for micro-sized perovskites. The room temperature thermal conductivity of ~0.14 +/- 0.02 W m-1 K-1 is extracted from the dependence of the PL peak energy on the excitation laser power. On changing the film thickness from 80 to 400 nm, the thermal conductivity does not show noticeable variations, indicating the minimal substrate effects due to the advantage of the suspended configuration. The ultra-low thermal conductivity of perovskites, especially thin films, suggests their promising applications for thermal isolation, such as thermal insulation and thermo-electricity. PMID- 28585961 TI - Multi-responsive actuators based on a graphene oxide composite: intelligent robot and bioinspired applications. AB - Carbon-based electrothermal or photothermal actuators have attracted intense attention recently. They can directly convert electrical or light energy into thermal energy and exhibit obvious deformations. However, if the actuation mechanism is only limited to thermal expansion, the deformation amplitude is difficult to increase further. Moreover, complex shape-deformation is still challenging. Although a few materials were reported to realize twisting or untwisting actuation by cutting the samples into strips along different orientations, each single strip could perform only one shape-deformation mode. In this work, we propose multi-responsive actuators based on a graphene oxide (GO) and biaxially oriented polypropylene (BOPP) composite, which are designed with different shapes (strip-shape and helical-shape). The strip-shape GO/BOPP actuator shows great bending actuations when driven by humidity (curvature of up to 3.1 cm-1). Due to a developed dual-mode actuation mechanism, the actuator shows a bending curvature of 2.8 cm-1 when driven by near infrared (NIR) light. The great actuation outperforms most other carbon-based actuators. Then, an intelligent robot based on the GO/BOPP composite is fabricated, which can switch between the protection mode and weightlifting mode with different external stimuli. Inspired from plant tendrils, a bioinspired helical GO/BOPP actuator is further realized to show both twisting and untwisting actuations in a single actuator, fully mimicking the deformation of plant tendrils. Finally, a robot arm consisting of strip-shape and helical GO/BOPP actuators can grasp an object that is 2.9 times heavier than itself, demonstrating promising bioinspired applications. PMID- 28585963 TI - Self-adapted and tunable graphene strain sensors for detecting both subtle and large human motions. AB - Conventional strain sensors rarely have both a high gauge factor and a large strain range simultaneously, so they can only be used in specific situations where only a high sensitivity or a large strain range is required. However, for detecting human motions that include both subtle and large motions, these strain sensors can't meet the diverse demands simultaneously. Here, we come up with laser patterned graphene strain sensors with self-adapted and tunable performance for the first time. A series of strain sensors with either an ultrahigh gauge factor or a preferable strain range can be fabricated simultaneously via one-step laser patterning, and are suitable for detecting all human motions. The strain sensors have a GF of up to 457 with a strain range of 35%, or have a strain range of up to 100% with a GF of 268. Most importantly, the performance of the strain sensors can be easily tuned by adjusting the patterns of the graphene, so that the sensors can meet diverse demands in both subtle and large motion situations. The graphene strain sensors show significant potential in applications such as wearable electronics, health monitoring and intelligent robots. Furthermore, the facile, fast and low-cost fabrication method will make them possible and practical to be used for commercial applications in the future. PMID- 28585962 TI - Deterministic trapping, encapsulation and retrieval of single-cells. AB - We present a novel method for conducting true single-cell encapsulation at very high efficiency for the manipulation of precious samples. Our unique strategy is based on the sequential capture and original encapsulation of single-cells into a series of hydrodynamic traps. We identified two distinct modes of encapsulation and we established their associated design rules. We improved the trapping scheme to reach a near perfect capture efficiency and make it compatible with the encapsulation process. Finally, we developed the complete device operation that permits highly efficient single-cell encapsulation and droplet retrieval. This platform provides the foundation to a fully integrated multiparameter platform that will impact the analysis of tissues at single-cell resolution. PMID- 28585964 TI - Thermal transport at a solid-nanofluid interface: from increase of thermal resistance towards a shift of rapid boiling. AB - We use molecular dynamics simulations to investigate interfacial thermal transport between an ethanol suspension containing gold atomic clusters and a gold surface, using both realistic and simplified molecular models of nanoparticles. The interfacial thermal conductance was determined via a thermal relaxation method for a variety of nanoparticle-nanoparticle and nanoparticle surface interaction strengths. The Kapitza resistance is found to increase due to the presence of nanoparticles in the vicinity of the solid-liquid interface. The heat flow from the solid to the nanoparticles is separated from its counterpart from the solid to the liquid to discriminate their respective contribution to the total heat current. A per-vibrational-mode analysis highlights a shift of major heat carriers from low frequencies towards higher frequencies due to the coupling of the internal nanoparticle dynamics to the gold surface, in addition to stronger particle-surface interactions. Finally, we demonstrate that the increase of the Kapitza resistance significantly shifts the nanofluid/solid surface explosive boiling temperature to higher temperatures compared to pure ethanol. PMID- 28585965 TI - A journey through ternary lead chlorido tungstates by thermal scanning. AB - The reduction of tungsten hexachloride with lead powder was investigated by differential scanning calorimetry (DSC) combined with X-ray diffraction (XRD) studies. Intermediate compounds along the way of the reduction of W6+ to W2+ were detected, prepared by solid-state synthesis, and structurally characterized by X ray diffraction techniques. Five new compounds, namely Pb0.5WCl6, PbW2Cl10, Pb1.5[W3Cl13], Pb2Cl[W3Cl13], and Pb[W6Cl14] are discovered to be formed with increasing temperature, and structurally characterized within this study. The analysis of the reduction pathway is meant to gain a better understanding of the metallothermic reduction process and intercalation chemistry in the solid state. PMID- 28585966 TI - Photoinduced electron transfer across an organic molecular wall: octa acid encapsulated ESIPT dyes as electron donors. AB - Efficient photoinduced electron transfer from proton transfer dyes encapsulated within water soluble supramolecular host octa acid to electron acceptors present outside the capsule was observed in aqueous solution. N-Methylpyridinium iodide was found to be the best acceptor compared to 4,4'-dimethylviologen dichloride, most likely due to its better binding with the exterior of the host octa acid walls. PMID- 28585967 TI - A simple and highly sensitive spectroscopic fluorescence-detection system for multi-channel plastic-microchip electrophoresis based on side-entry laser-beam zigzag irradiation. AB - A five-color fluorescence-detection system for eight-channel plastic-microchip electrophoresis was developed. In the eight channels (with effective electrophoretic lengths of 10 cm), single-stranded DNA fragments were separated (with single-base resolution up to 300 bases within 10 min), and seventeen-loci STR genotyping for forensic human identification was successfully demonstrated. In the system, a side-entry laser beam is passed through the eight channels (eight A channels), with alternately arrayed seven sacrificial channels (seven B channels), by a technique called "side-entry laser-beam zigzag irradiation." Laser-induced fluorescence from the eight A channels and Raman-scattered light from the seven B channels are then simultaneously, uniformly, and spectroscopically detected, in the direction perpendicular to the channel array plane, through a transmission grating and a CCD camera. The system is therefore simple and highly sensitive. Because the microchip is fabricated by plastic injection molding, it is inexpensive and disposable and thus suitable for actual use in various fields. PMID- 28585968 TI - Isonucleotide incorporation into middle and terminal siRNA duplexes exhibits high gene silencing efficacy and nuclease resistance. AB - In this study, we introduced a pair of nucleotide enantiomers, d-/l isonucleotides (d-/l-isoNA), to examine the interactions between siRNAs and their related proteins. The serum stability and gene-silencing activity of the modified siRNAs were systematically evaluated. Gene-silencing activity had a site-specific effect, and the incorporation of a single d-isoNA at the 8th position (counting from the 5'-terminus) in the antisense strand improved the gene-silencing activity by improving RISC loading and affecting the movement of the PIWI domain. d-isoNA incorporated at the terminus of siRNA including the 2nd position in the antisense strand and 3'-overhangs in the sense strand, especially the latter, enhanced nuclease resistance and prolonged the silencing retention time. In addition, l-isoNA incorporation into the middle of the sense strand enhanced activity. These results provide a chemical strategy for the modulation of siRNA gene-silencing activity and nuclease resistance. PMID- 28585969 TI - Air and thermally stable perovskite solar cells with CVD-graphene as the blocking layer. AB - The poor air and thermal stability of organic-inorganic halide perovskite solar cells have hindered their real applications. Here we report the insertion of a chemical vapor deposited graphene between the Au electrode and spiro-OMeTAD in planar perovskite solar cells to block the diffusion of air and Au into the perovskite layer, where the single layer graphene is transferred into the devices by a simple laminated process. After ageing in 45% humidity air for 96 h or thermal annealing at 80 degrees C for 12 h, more than 94% PCE of the devices with graphene can be maintained, which is much better than that of devices without graphene (~57%). The improved stability of devices with the graphene layer is attributed to the reduction of carrier recombination from decomposition of the perovskite layer in air or Au doping into the perovskite layer under annealing treatment. Therefore, graphene is a promising ultra-thin barrier against air and metal diffusion, and has potential applications in photovoltaic devices, integrated circuit chips and light emitting diodes. PMID- 28585970 TI - Mesoporous silica nanoparticles in injectable hydrogels: factors influencing cellular uptake and viability. AB - The incorporation of nanoparticles as drug vectors into 3D scaffolds has attracted a lot of recent interest. In particular, tissue engineering applications would benefit from a spatially and temporally regulated release of biological cues, which act on precursor/stem cells in a three-dimensional growth environment. Injectable cell- and nanoparticle-containing scaffolds are especially interesting in this respect, but require matrix self-assembly and coordinated interactions between cells, matrices, and nanoparticles, which are largely uncharacterized yet. In this proof of concept study we combined the matrix-forming self-assembling peptide RADA16-I, different mesoporous silica nanoparticles (MSN) as potential drug carriers, and MC3T3-E1 osteoblast precursor cells. When injected to physiological media, the mixtures rapidly formed hybrid peptide-silica hydrogels containing RADA16-I nanofiber scaffolds with uniform spatial distribution of viable cells and MSN. MSN surface chemistry was critical for interactions within the hydrogel and for RADA16-I adsorption, thereby dominantly influencing cellular uptake and cell viability, whereas the impact of serum protein was minor. Thus, important parameters which allow tuning of nanoparticulate drug vector interactions with cells in injectable 3D scaffolds are identified, which are of importance for the future design of smart scaffolds for advanced tissue engineering in vivo. PMID- 28585972 TI - Plasmonic nanohole array biosensor for label-free and real-time analysis of live cell secretion. AB - Cell secretion dynamics plays a central role in physiological and disease processes. Due to its various temporal profiles, it is essential to implement a precise detection scheme for continuous monitoring of secretion in real time. The current fluorescent and colorimetric approaches hinder such applications due to their multiple time-consuming steps, molecular labeling, and especially the 'snapshot' endpoint readouts. Here, we develop a nanoplasmonic biosensor for real time monitoring of live cell cytokine secretion in a label-free configuration. Our nanoplasmonic biosensor is composed of gold nanohole arrays supporting extraordinary optical transmission (EOT), which enables sensitive and high throughput analysis of biomolecules. The nanobiosensor is integrated with an adjustable microfluidic cell module for the analysis of live cells under well controlled culture conditions. We achieved an outstanding sensitivity for the detection of vascular endothelial growth factor (VEGF) directly in complex cell media. Significantly, the secretion dynamics from live cancer cells were monitored and quantified for 10 hours while preserving good cell viability. This novel approach of probing cytokine secretion activity is compatible with conventional inverted microscopes found in a common biology laboratory. With its simple optical set-up and label-free detection configuration, we anticipate our nanoplasmonic biosensor to be a powerful tool as a lab-on-chip device to analyze cellular activities for fundamental cell research and biotechnologies. PMID- 28585973 TI - Impact on short-lived climate forcers (SLCFs) from a realistic land-use change scenario via changes in biogenic emissions. AB - More than one quarter of natural forests have been cleared by humans to make way for other land-uses, with changes to forest cover projected to continue. The climate impact of land-use change (LUC) is dependent upon the relative strength of several biogeophysical and biogeochemical effects. In addition to affecting the surface albedo and exchanging carbon dioxide (CO2) and moisture with the atmosphere, vegetation emits biogenic volatile organic compounds (BVOCs), altering the formation of short-lived climate forcers (SLCFs) including aerosol, ozone (O3) and methane (CH4). Once emitted, BVOCs are rapidly oxidised by O3, and the hydroxyl (OH) and nitrate (NO3) radicals. These oxidation reactions yield secondary organic products which are implicated in the formation and growth of aerosol particles and are estimated to have a negative radiative effect on the climate (i.e. a cooling). These reactions also deplete OH, increasing the atmospheric lifetime of CH4, and directly affect concentrations of O3; the latter two being greenhouse gases which impose a positive radiative effect (i.e. a warming) on the climate. Our previous work assessing idealised deforestation scenarios found a positive radiative effect due to changes in SLCFs; however, since the radiative effects associated with changes to SLCFs result from a combination of non-linear processes it may not be appropriate to scale radiative effects from complete deforestation scenarios according to the deforestation extent. Here we combine a land-surface model, a chemical transport model, a global aerosol model, and a radiative transfer model to assess the net radiative effect of changes in SLCFs due to historical LUC between the years 1850 and 2000. PMID- 28585974 TI - Roles of nitrogen functionalities in enhancing the excitation-independent green color photoluminescence of graphene oxide dots. AB - Fluorescent graphene oxide dots (GODs) are environmentally friendly and biocompatible materials for photoluminescence (PL) applications. In this study, we employed annealing and hydrothermal ammonia treatments at 500 and 140 degrees C, respectively, to introduce nitrogen functionalities into GODs for enhancing their green-color PL emissions. The hydrothermal treatment preferentially produces pyridinic and amino groups, whereas the annealing treatment produces pyrrolic and amide groups. The hydrothermally treated GODs (A-GODs) present a high conjugation of the nonbonding electrons of nitrogen in pyridinic and amino groups with the aromatic pi orbital. This conjugation introduces a nitrogen nonbonding (nN 2p) state 0.3 eV above the oxygen nonbonding state (nO 2p state; the valence band maximum of the GODs). The GODs exhibit excitation-independent green-PL emissions at 530 nm with a maximum quantum yield (QY) of 12% at 470 nm excitation, whereas the A-GODs exhibit a maximum QY of 63%. The transformation of the solvent relaxation-governed pi* -> nO 2p transition in the GODs to the direct pi* -> nN 2p transition in the A-GODs possibly accounts for the substantial QY enhancement in the PL emissions. This study elucidates the role of nitrogen functionalities in the PL emissions of graphitic materials and proposes a strategy for designing the electronic structure to promote the PL performance. PMID- 28585975 TI - Synthesis and electronic investigation of mono- and di-substituted 4-nitro- and 4 amino-pyrazol-1-yl bis(pyrazol-1-yl)pyridine-type ligands and luminescent Eu(iii) derivatives. AB - Four new disubstituted and monosubstituted nitro- and amino- bis(pyrazol-1 yl)pyridine (bppy) ligands, substituted at the pyrazole 4-position (1, 2, 5, 6) have been synthesized, along with two luminescent Eu(iii) tris-beta-diketonate derivatives of the amino substituted ligands (7, 8). The compounds have been studied using UV-Vis absorbance spectroscopy and cyclic voltammetry which has allowed for characterization of the electronic environments of these ligands. The calculated HOMO-LUMO gap values (1: 3.54 eV; 2: 3.53 eV; 5: 3.01 eV; 6: 3.66 eV) differ from that of bppy (3.86 eV) and the range is indicative that tuning of the ligand electronic environment is possible. Additionally, fluorescence spectroscopy studies were employed to determine ligand T1 energy levels of the amine-bearing ligands 2 and 6, yielding values of T1 of 25 381 cm-1 and 26 201 cm 1, respectively. These ligands were employed in the synthesis of Eu(iii) complexes 7 and 8, for which the absolute and intrinsic quantum yields, lifetimes and ligand sensitization efficiencies were determined. PMID- 28585976 TI - Dynamic glycosylation of liposomes by thioester exchange. AB - The interplay of dynamic functionalization and specific molecular recognition on biological membranes is key to numerous physiological processes. In this work we present a simple glycocalyx model based on the covalent yet reversible glycosylation of liposomes and subsequent recognition by a lectin. Reversible thioester exchange of membrane embedded amphiphilic thioesters with thiol-tagged d-mannose in solution is performed at physiologically relevant conditions. Recognition with the lectin concanavalin A is possible directly from this reaction mixture, leading to liposome agglutination. To the best of our knowledge, the dynamic covalent glycosylation of liposomes is so far unprecedented. PMID- 28585978 TI - Outside the Hospital Walls: Social Determinants and Population Health. PMID- 28585977 TI - Dynamic effects and adhesion of water droplet impact on hydrophobic surfaces: bouncing or sticking. AB - This work reported the dynamic effects of water droplet impact on flat, porous and pincushion structure films of star shaped polyhedral oligomeric silsesquioxane (POSS) fluorinated acrylates, POSS-poly(trifluoroethyl methacrylate)8 (POSS-(PTFEMA)8) and POSS-(poly(trifluoroethyl methacrylate)-b poly(methyl methacrylate))8 (POSS-(PTFEMA-b-PMMA)8), using the breath figure method. The porous and pincushion structure films with different surface chemical compositions were obtained by controlling the copolymer structure and temperature and by stripping of the surface. The water contact angles on the different films were measured, and the water droplets on the pincushion structure films when reversed at 45 degrees , 90 degrees , 135 degrees and 180 degrees were also studied. It was found that the pincushion structure films revealed a water adhesion ability. Furthermore, the water droplet impact behavior on these films was investigated. The morphology variations of water droplets, spreading diameter of the droplets, energy conversion, restitution coefficient and adhesion force were examined. Finally, the schematic illustration of water droplets under the static and dynamic states in contact with the pincushion and porous structure surfaces was proposed. It is critical to materialize various applications such as microdroplet transportation, soil erosion, spray painting, anti-icing surface and antifouling agents for textiles. PMID- 28585979 TI - Impact of Interprofessional Simulation on Nursing Students' Attitudes Toward Teamwork and Collaboration. AB - BACKGROUND: The purpose of this study was to examine the influence of a multipatient, interprofessional simulation session on nursing students' attitudes toward nurse-physician collaboration using the Jefferson Scale of Attitudes Toward Physician-Nurse Collaboration. METHOD: Final-semester nursing students, along with medical resident and students from other health programs, participated in a simulation exercise that included a period of prebriefing, simulation, and debriefing. Participants completed pre- and postsimulation surveys to assess the impact on collaboration. RESULTS: In total, 268 nursing students completed the survey. Participants had a more positive attitude toward nurse-physician collaboration following the simulation event, compared with prior to it. Significant differences between male and female nursing students were found on mean postsimulation scores and for three of the four subscales of the tool. CONCLUSION: Interprofessional simulation may be an effective way to enhance collaborative relationships, which ultimately may influence patient safety and quality of care. [J Nurs Educ. 2017;56(6):321-327.]. PMID- 28585980 TI - Flipped Learning With Simulation in Undergraduate Nursing Education. AB - BACKGROUND: Flipped learning has proliferated in various educational environments. This study aimed to verify the effects of flipped learning on the academic achievement, teamwork skills, and satisfaction levels of undergraduate nursing students. METHOD: For the flipped learning group, simulation-based education via the flipped learning method was provided, whereas traditional, simulation-based education was provided for the control group. After completion of the program, academic achievement, teamwork skills, and satisfaction levels were assessed and analyzed. RESULTS: The flipped learning group received higher scores on academic achievement, teamwork skills, and satisfaction levels than the control group, including the areas of content knowledge and clinical nursing practice competency. In addition, this difference gradually increased between the two groups throughout the trial. CONCLUSION: The results of this study demonstrated the positive, statistically significant effects of the flipped learning method on simulation-based nursing education. [J Nurs Educ. 2017;56(6):329-336.]. PMID- 28585982 TI - The Experience of Teaching Online in Nursing Education. AB - BACKGROUND: Online education has become a key instructional delivery method in nursing education; however, limited understanding exists about what it is like to teach online. The aim of this study was to uncover the experience of teaching online in nursing education. METHOD: The sample for this phenomenological study included 14 nursing faculty who completed at least 50% of their teaching workload assignment in fully online courses in baccalaureate, master's, or doctoral nursing programs. Data were collected through the use of a demographic questionnaire and personal interviews. RESULTS: Four themes emerged from the data: (a) Looking at a Lot of Moving Parts, (b) Always Learning New Things, (c) Going Back and Forth, and (d) Time Is a Blessing and a Curse. CONCLUSION: Online teaching in nursing education differs from traditional classroom teaching in a variety of ways. Policies and guidelines that govern faculty teaching should encompass the identified intricacies of online teaching. [J Nurs Educ. 2017;56(6):343-349.]. PMID- 28585981 TI - Curriculum Revision: Student Stress and Lessons Learned. AB - BACKGROUND: Curricular revision and engaging students in learning are important aspects of preparing students for a complex health care environment. The purpose of this study was to identify student perceptions of active learning practices incorporated into the junior year of a new curriculum. METHOD: A descriptive qualitative design using focus group interviews for data collection was used to explore student perceptions of stress, engagement, and self-directed learning in an active learning environment. RESULTS: Three themes emerged from the data, including Feeling Stressed and Overwhelmed, Coping With Stress, and Being Prepared. CONCLUSION: The results of this study highlight how students responded to the increased stress of junior-year nursing courses and the lessons learned by both the students and the faculty teaching junior-year nursing students after a curricular revision and subsequent change in teaching strategies. [J Nurs Educ. 2017;56(6):337-342.]. PMID- 28585983 TI - Exploring the Correlation Between Nontraditional Variables and Student Success: A Longitudinal Study. AB - BACKGROUND: The purpose of this project was to determine whether a correlation exists between the traditional admission criteria of grade point averages with the potential admission criteria of emotional intelligence (EI) scores or critical thinking (CT) scores to predict upper division student outcomes. METHOD: A quantitative, longitudinal design was selected to examine the identified variables to predict undergraduate student success. The recruiting sample included a convenience sample drawn from 112 junior-level undergraduate nursing students beginning their first of a five-semester nursing program. RESULTS: EI and HESI(r) CT scores did not significantly correlate with main analysis variables. CONCLUSION: Although EI and CT scores were not significant in this study, it remains vital to incorporate EI and CT activities throughout the curriculum to develop students' ability to think like a nurse and, therefore, be successful in nursing practice. [J Nurs Educ. 2017;56(6):351-355.]. PMID- 28585985 TI - Investigating Interrater Reliability in an Online RN-to-BSN Program: Disparate Conclusions. AB - BACKGROUND: Interrater reliability of student-written assignments within a nursing education program is a desirable characteristic to ensure uniform quality of academic work. As online programs that advance RNs to baccalaureate-prepared nurses (i.e., RN-to-BSN programs) grow in popularity, the challenges of quality control increase. METHOD: Grading data representing mean, median, mode, and range from 19 course sections in an online RN-to-BSN program were submitted. Data were analyzed for measures of central tendency with a query of interrater reliability. RESULTS: The data indicate that instructors assess student performance at a uniformly high level. CONCLUSION: The data lead to two disparate conclusions: student performance is high and is reliably assessed as such, or the online program suffers from grade inflation. Such disparate conclusions are uniquely endemic to any program that serves the RN-to-BSN population, typically high performing students who have established prior mastery on licensure examinations. [J Nurs Educ. 2017;56(6):360-363.]. PMID- 28585984 TI - Faculty Attitudes and Adoption of Simulation: Pilot Testing of a New Instrument. AB - BACKGROUND: This study evaluated the reliability and validity of a new instrument, the Faculty Attitudes and Adoption of Simulation (FAAS). The FAAS was designed to identify faculty attitudes toward and levels of perceived knowledge and adoption of simulation. The instrument was developed based on a comprehensive literature review. METHOD: A convenience sample of 47 faculty members was used. Content validity, internal consistency reliability, and convergent construct validity were evaluated. RESULTS: Content validity, measured through a content validity index, was found to be .91. Pilot testing of the FAAS demonstrated a Cronbach's alpha of .83. Construct validity was evaluated by comparing the FAAS with a related tool called the Faculty Attitudes and Intent to Use Related to the Human Patient Simulator instrument (r = .64, p < .001). CONCLUSION: Pilot testing of the FAAS demonstrated initial reliability and validity for measuring faculty attitudes toward and perceived knowledge and adoption of simulation. [J Nurs Educ. 2017;56(6):356-359.]. PMID- 28585986 TI - Evaluation of Doctor of Nursing Practice Students' Competencies in an Online Informatics Course. AB - BACKGROUND: Doctor of Nursing Practice (DNP) programs have experienced rapid growth across the United States. With the expansion of electronic health records, DNP students are expected to acquire the knowledge and skills needed to manage data and apply informatics concepts. However, little information exists to help faculty evaluate student competency in these areas. METHOD: This retrospective analysis evaluated the competencies of a convenience sample of DNP students enrolled in an online informatics course. Two areas were assessed in this study: acquisition of informatics skills, and analysis or application of informatics concepts. RESULTS: Regarding informatics skills, postbaccalaureate students performed better than post-master's students. In analysis and application of informatics concepts, post-master's students performed better than postbaccalaureate students. CONCLUSION: Different educational strategies may need to be created to meet the varying needs of postbaccalaureate and post-master's students in DNP programs. [J Nurs Educ. 2017;56(6):364-367.]. PMID- 28585987 TI - Online or In-Class: Evaluating an Alternative Online Pedagogy for Teaching Transcultural Nursing. AB - BACKGROUND: Online learning formats are prevalent in current higher education. Given the changing student demographics and the drive for creativity in educating a technology-savvy student, it is imperative to incorporate innovative and alternative learning modalities to engage these students. METHOD: This pilot study was designed as a quality improvement program evaluation comparing the effects of an online learning module with traditional classroom delivery of transcultural nursing content using a posttest two-group survey design in associate degree nursing students. The students' perceived knowledge and confidence were investigated after receiving the lecture for both the online and in-class groups. RESULTS: Data analysis revealed the online cohort perceived themselves as more knowledgeable concerning the ways that cultural factors influence nursing care, but not more confident in providing culturally competent care. CONCLUSION: Due to the students' perceived knowledge gain, this pilot study supports the use of online learning modules as being more effective than the traditional classroom delivery of transcultural nursing content. [J Nurs Educ. 2017;56(6):368-372.]. PMID- 28585988 TI - An Academic-Service Partnership: A System-Wide Approach and Case Report. AB - BACKGROUND: An academic-service partnership was formed to increase educational capacity, improve evidence-based nursing at the point of care, and engage staff nurses, clinical faculty, and students in patient and family care. METHOD: This case report reflects an overview of the first year of full implementation, and survey results from nurse leaders and faculty at the 3-year time point. RESULTS: Following its third year of an academic-service partnership, the shared mission, vision, and values have resulted in stronger NCLEX-RN results, improved quality initiatives, and trends for improvements in patient outcomes. Alignment with faculty and mentors surrounding student expectations has improved, as well as shared evidence-based practices. CONCLUSION: Sustaining an academic-service partnership requires dedicated leaders, faculty, and mentors. This partnership continues to thrive and move toward excellence in patient- and family-centered outcomes and undergraduate clinical education. [J Nurs Educ. 2017;56(6):373 377.]. PMID- 28585989 TI - Contemplative Activities in Undergraduate Nursing Courses. AB - BACKGROUND: Affective learning is valued in nursing, but it is often difficult to plan and evaluate learning activities in this domain. Contemplative activities can promote learning and are relatively easy to implement. These activities can promote deep, reflective thinking. METHOD: A variety of contemplative activities were used in undergraduate nursing courses. Students participated in and reflected on a vigil promoting domestic violence awareness. They attended two different art exhibits and related these exhibits to nursing. The students used journals and eportfolios to reflect on the entire nursing program. They participated in breathing exercises and guided imagery meditations. RESULTS: Students evaluated the activities positively, and their reflections were thoughtful. CONCLUSION: Contemplative activities can be useful to develop affective competencies. [J Nurs Educ. 2017;56(6):378-382.]. PMID- 28585990 TI - Romantic Song Lyrics Used to Facilitate Nursing Students' Comprehension of Qualitative Data Analysis. PMID- 28585991 TI - Student Moderator Teaching-Learning Strategy. PMID- 28585992 TI - Complex Lumbar Spine Fusion for an Elderly Patient Under Spinal Anesthesia. AB - Spinal anesthesia for spine surgery is an emerging technique. Because of their lack of physiologic reserve, elderly patients are an appealing population for this technique. Unfortunately, the safe limits of spine surgery using spinal anesthesia for the geriatric population are not well defined. The authors describe an elderly patient with severe spine degeneration who elected for a 5 level lumbar spine fusion with spinal anesthesia. Adequate anesthesia was maintained throughout the procedure, which lasted 3 hours and 24 minutes. The patient experienced no perioperative complications. To the authors' knowledge, this is one of the longest spine surgeries using spinal anesthesia. Also, the fusion procedure spans more vertebral levels than previously reported. Further investigation is needed to determine the safety of this technique. [Orthopedics. 2017; 40(5):e915-e917.]. PMID- 28585993 TI - A Modified Lateral Approach for Total Knee Replacement in Type 2 Valgus Deformity. AB - Total knee replacement for patients with osteoarthritis and valgus deformity remains challenging, with soft tissue balance often difficult to achieve. Most orthopedic surgeons use the medial parapatellar approach for total knee replacement. However, the lateral approach described in this case allows direct access to the pathology. The valgus deformity is corrected by using a modified lateral parapatellar arthrotomy with a staged and gradual release of the contracted lateral capsuloligamentous structures and the iliotibial tract. A Z shaped dissection of the lateral retinaculum and careful dissection and preservation of the infrapatellar fat pad is performed. The creation of this laterally based vascularized flap provides the necessary tissue to cover the soft tissue gap resulting on the lateral aspect of the knee after valgus correction. The lateral approach has advantages, including ligament balancing and preservation of the medial retinaculum and the medial neurovascular structures for the supply of the patella. However, this approach should be used with caution by experienced surgeons. [Orthopedics. 2017; 40(5):313-316.]. PMID- 28585994 TI - New Technique for Removal of Screws With Damaged Heads. AB - Removal of orthopedic implants may sometimes be difficult because of ongrowth of new bone. Titanium screws can become encased or stripped during the process of initial open reduction and internal fixation or at the time of hardware removal. Difficulty in removing screws from a locking plate is particularly well-known. Two patients with tibial and femoral diaphyseal fractures were treated using a locking plate or an intramedullary nail. However, after fracture healing, it was difficult to remove the locking screw or reconstruction screws because of damage to the heads. The stripped reconstruction screw was successfully removed employing the authors' so-called parallel planes technique. In this method, a high-speed diamond-tipped burr is applied to opposite sides of the screw head to form 2 parallel faces located slightly away from the recess of the screw head. The 2 faces can then be grasped solidly with locking pliers, allowing removal of the implant by unscrewing it with a gentle upward pulling action. The locking plate was cut from the plate edge to the edge of the screw hole. While making these radial cuts in the plates, the authors were careful not to extend the blade into the screw head. After removal of the locking plate from the screw, the authors were able to extract the jammed screw uneventfully using this technique. This technique can be performed without difficulty and does not require a special device. It is a useful option for extraction of damaged screws. [Orthopedics. 2017; 40(5):e911-e914.]. PMID- 28585995 TI - Outcomes of Primary Total Knee Arthroplasty in Patients With Hematopoietic Stem Cell Transplantation. AB - Patients who have undergone hematopoietic stem cell transplantation to treat underlying bone marrow pathology represent a unique and potentially high-risk patient population for total knee arthroplasty (TKA). This study retrospectively reviewed 15 TKA procedures performed on 11 patients with a history of hematopoietic stem cell transplantation. The authors analyzed patient survivorship; clinical outcomes, including complications; and implant survivorship. Mean follow-up was 5 years (range, 2-10 years). Patient survivorship free from mortality was 91% (95% confidence interval, 76%-100%) and 55% (95% confidence interval, 25%-85%) at 2 and 5 years, respectively. Patients who underwent hematopoietic stem cell transplantation for multiple myeloma had a significantly higher 5-year mortality rate (100%) compared with patients who had an underlying diagnosis of non-Hodgkin's lymphoma (0%) (P=.008). Mean Knee Society Score improved to 83 postoperatively (P<.001). Two patients (13%) had postoperative wound healing complications that did not lead to periprosthetic joint infection; however, an additional patient (7%) underwent revision surgery at 5 years for periprosthetic joint infection. Estimated implant survivorship without revision was 80% (95% confidence interval, 60%-100%) at 5 years. Elective primary TKA does not appear to affect survivorship in patients with a history of hematopoietic stem cell transplantation. These patients have modest clinical outcomes, higher complication rates as a result of delayed wound healing, and poorer implant survivorship compared with historical control subjects. [Orthopedics. 2017; 40(5):e774-e778.]. PMID- 28585996 TI - Posterior Percutaneous Endoscopic Cervical Foraminotomy and Diskectomy With Unilateral Biportal Endoscopy. AB - This report describes a new, minimally invasive procedure, posterior percutaneous endoscopic cervical diskectomy, performed with a unilateral biportal endoscopic approach. The procedure is used to treat cervical foraminal soft disk protrusion. This report also describes the short-term results with this procedure. In 2015, 14 patients underwent this new, minimally invasive procedure. The technique was applied with a standard arthroscopy device and conventional spine instruments. The Neck Disability Index and visual analog scale scores for the neck and upper arm were evaluated, and 13 consecutive patients were included in the analysis. Mean follow-up was 14.8 months (range, 12-18 months). The Neck Disability Index decreased from 27.0+/-2.5 to 6.8+/-1.4 at the last follow-up (P<.05). Visual analog scale scores for the neck and upper arm also decreased significantly (neck, 6.2+/-0.8 to 2.4+/-0.9; upper arm, 7.0+/-1.1 to 2.2+/-0.6). Posterior percutaneous endoscopic cervical diskectomy with a uniportal endoscope provides a clear operative field because of continuous endoscopic saline irrigation and requires only a short hospitalization and no postoperative rehabilitation. Posterior percutaneous endoscopic cervical diskectomy with a unilateral biportal endoscopic approach also can be performed efficiently because of the wide field of visualization and familiar surgical field. Thus, posterior percutaneous endoscopic cervical diskectomy with the unilateral biportal endoscopic approach may be an alternative procedure for cervical foraminal soft disk protrusion. [Orthopedics. 2017; 40(5):e779-e783.]. PMID- 28585997 TI - Diagnosis and Management of Traumatic Patellar Instability in the Pediatric Patient. AB - Instability of the patella is a common cause of knee pain and dysfunction in pediatric and adolescent patients and can be due to several factors. Although some patients will recall a specific traumatic event others may not, requiring the diagnosis to be made on the basis of physical examination and imaging. Congenital dislocation and connective tissue disorders should also be considered, even in the setting of trauma. There are radiographic parameters that may identify causes of instability such as trochlear and patellar abnormalities, and magnetic resonance imaging can identify signs of trauma such as bony edema, loose osteochondral fragments, and increased tibial tubercle-trochlear groove distance. The first line of treatment for instability is most commonly nonoperative in nature; however, there are many options for operative management in the event of severe chondral injury or recurrent dislocation. Surgical management to best restore stability of the patellofemoral joint varies depending on the skeletal maturity of the patient and the source of instability (ligamentous, osteocartilaginous, or both). A combination of soft tissue, bony, and anatomic ligamentous repair or reconstruction is used to best augment patellar tracking and optimize patient outcome. [Orthopedics. 2017; 40(5):e749-e757.]. PMID- 28585998 TI - Correlation of the Features of the Lumbar Multifidus Muscle With Facet Joint Osteoarthritis. AB - Facet joint osteoarthritis is considered a consequence of the aging process; however, there is evidence that it may be associated with degenerative changes of other structures. The goal of this study was to investigate the correlation between lumbar multifidus muscle features and facet joint osteoarthritis. This retrospective study included 160 patients who had acute or chronic low back pain and were diagnosed with facet joint osteoarthritis on computed tomography scan. Morphometric parameters, including cross-sectional area, muscle-fat index, and percentage of bilateral multifidus asymmetry at L3-L4, L4-L5, and L5-S1, were evaluated with T2-weighted magnetic resonance imaging. Patients with facet joint osteoarthritis had a smaller cross-sectional area and a higher muscle-fat index than those without facet joint osteoarthritis (P<.001). In multivariate regression analysis, older age and higher muscle-fat index were independently associated with facet joint osteoarthritis at all 3 spinal levels (P<.001). Smaller cross-sectional area was independently associated with facet joint osteoarthritis only at L4-L5 (P=.005). Asymmetry of the bilateral multifidus cross-sectional area was independently associated with facet joint osteoarthritis at L5-S1 (P=.009), but did not seem to be responsible for asymmetric degeneration of the bilateral facet joints. A higher multifidus muscle-fat index was independently associated with facet joint osteoarthritis, and bilateral multifidus size asymmetry was associated with the development of facet joint osteoarthritis at L5-S1. It seems more accurate to consider facet joint osteoarthritis a failure of the whole joint structure, including the paraspinal musculature, rather than simply a failure of the facet joint cartilage. [Orthopedics. 2017; 40(5):e793-e800.]. PMID- 28585999 TI - Treatment of a Pediatric T-type Intercondylar Humerus Fracture With Hybrid Percutaneous Pinning and External Fixation. AB - T-type intercondylar fractures of the distal humerus are rare injuries in skeletally immature patients. Few studies are available to guide the treatment of these injuries. Small case series and expert recommendations suggest superiority of the open approach for direct reduction of the articular surface. This approach poses risks of vascular compromise and elbow stiffness. However, success with percutaneous intercondylar screw fixation has been described for simple split patterns. The authors present a case that illustrates a novel percutaneous technique to treat this fracture type. A healthy 8-year-old boy sustained a T type intercondylar fracture of the distal humerus (AO 13-C1). Excellent reduction was noted after closed reduction and crossed percutaneous pinning. Compression was applied across the pins through a small external fixator bar to address the intercondylar split component. At the 6-week postoperative clinic visit, the pins and fixator were removed uneventfully, and normal healing with full range of elbow motion was noted. This case report describes a simple, minimally invasive technique to treat uncomplicated T-type intercondylar fractures of the distal humerus in skeletally immature patients. Practitioners familiar with percutaneous fixation of supracondylar fractures can easily perform this technique. The described technique spares an open dissection and avoids permanent implants around the joint. Further multicenter research is warranted to determine the long term outcomes and safety of the described technique. [Orthopedics. 2017; 40(6):e1096-e1098.]. PMID- 28586000 TI - Underlying mechanism of Sirt1 on apoptosis and extracellular matrix degradation of osteoarthritis chondrocytes. AB - The study investigated the effects and underlying mechanisms of silent information regulation of transcription 1 (Sirt1) action on apoptosis in chondrocytes and degradation of the extracellular matrix. Cartilage tissue samples were derived from knee arthroplasty of patients with osteoarthritis (OA). The three groups were as follows: Control, resveratrol (Res) and Res+small interfering (si)RNA (Res+siRNA Sirt1). The level of Sirt1 protein expression significantly increased in the Res group (1.03+/-0.10) compared with the control (0.22+/-0.03) and Res+siRNA (0.18+/-0.01) groups (both P<0.05). Early and late stage cell apoptosis rates decreased in the Res group and increased in the Res+siRNA group (both P<0.05). B-cell lymphoma 2 (Bcl-2) expression levels were upregulated and Bcl-2-associated X protein (Bax) expression levels were downregulated in the Res group compared with the control group. Protein expression levels of MMP1 and MMP13 and the phosphorylation levels of extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 were downregulated in the Res group and upregulated in the Res+siRNA group. In conclusion, upregulation of Sirt1 expression may inhibit OA chondrocyte apoptosis and extracellular matrix degradation by increasing Bcl-2 expression and decreasing Bax, MMP1 and MMP13 expression, via downregulation of p38, JNK and ERK phosphorylation. PMID- 28586001 TI - Apoptosis is induced by docosahexaenoic acid in breast cancer cells via death receptor and mitochondria-mediated pathways. AB - In the present study, the antitumor effect of n-3 fatty acid was evaluated, and the effect of docosahexaenoic acid (DHA) on the induction of apoptosis and its underlying mechanism were examined. Flow cytometry and western blot analysis were performed to analyze apoptosis and the expression of protein factors in human breast cancer cells. The data revealed that DHA inhibited the viability of MCF-7 breast cancer cells in vitro, and promoted cell death by the induction of apoptosis. DHA decreased the expression of B-cell lymphoma 2 (Bcl-2), whereas the expression of Bcl-2-associated X protein was increased. DHA was also shown to promote the release of Smac/Diablo and cytochrome c from the mitochondria. DHA increased the levels of cleaved caspase-8, -9 and -3. Additionally, the protein expression of tumor necrosis factor-related apoptosis-inducing ligand, death receptor 4 and Fas were increased following DHA treatment. In conclusion, DHA caused apoptosis of the human breast cancer cells in vitro through the death receptor and mitochondria-mediated pathways. The results of this study encourage further investigation of the effect of fish oil on the prevention and treatment of human breast cancer. PMID- 28586002 TI - Effect of Sorbus commixta on the invasion and migration of human hepatocellular carcinoma Hep3B cells. AB - Tumor metastasis is a main cause of cancer-related morbidity and mortality. Thus, a number of medicinal herbs and phytochemicals have been investigated as possible candidates for the inhibition of cancer metastasis. Sorbus commixta Hedl. (SC) is a traditional medicinal plant used in the treatment of inflammatory diseases, as it has antioxidant, anti-inflammatory, anti-atherosclerotic and anti-hepatotoxic activities. In this study, we demonstrate that the water extract of SC exerts inhibitory effect on the invasion and migration of hepatocellular carcinoma Hep3B cells. The activity and expression of matrix metalloproteinase (MMP)-9, which is responsible for the invasion of cancer cells, was decreased by SC treatment. The invasive and migratory potentials of the Hep3B cells were also decreased, as evidence by in vitro assay using the Boyden chamber system. In addition, the expression of the chemokine receptors, C-X-C chemokine receptor type 4 (CXCR)4 and C-X-C chemokine receptor type 6 (CXCR6), were inhibited by SC in Hep3B cells. Furthermore, actin fiber organization was markedly suppressed by SC treatment. Taken together, the findings of this study suggest for the first time, to the best of our knowledge, that SC suppresses the invasion and migration of highly metastatic Hep3B cells. PMID- 28586003 TI - Lymphotoxin beta receptor activation promotes mRNA expression of RelA and pro inflammatory cytokines TNFalpha and IL-1beta in bladder cancer cells. AB - The role of inflammation in tumorigenesis and development is currently well established. Lymphotoxin beta receptor (LTbetaR) activation induces canonical and noncanonical nuclear factor (NF)-kappaB signaling pathways, which are linked to inflammation-induced carcinogenesis. In the present study, 5,637 bladder cancer cells were cultured and the activation of LTbetaR was induced by functional ligand, lymphotoxin (LT) alpha1beta2, and silencing with shRNA. Reverse transcription-quantitative polymerase chain reaction was utilized to detect the mRNA expression levels of NF-kappaB family members RelA and RelB, cytokines including LTalpha, LTbeta, tumor necrosis factor (TNF)alpha, TNF superfamily member 14, interleukin (IL)-6 and IL-1beta, and proliferation-related genes including CyclinD1 and Survivin. The expression of phospho-p65 was determined by western blotting. Activation of LTbetaR on bladder cancer 5,637 cells was demonstrated to upregulate the mRNA expression levels of the RELA proto-oncogene, RelA, by 2.5-fold compared with unstimulated cells, while no significant change was observed in the RELB proto-oncogene NF-kappaB member mRNA levels. Expression of pro-inflammatory cytokines tumor necrosis factor (TNF)alpha and interleukin (IL)-1beta mRNA levels were significantly increased nearly 5-fold and 1.5-fold, respectively, following LTbetaR activation compared with unstimulated cells. The LTbetaR-induced upregulation of RelA, TNFalpha and IL-1beta was decreased by ~33, 27, and 26% respectively when LTbetaR was silenced via short hairpin RNA. Activation of LTbetaR had no effect on 5,637 cell growth, despite CyclinD1 and Survivin mRNA levels increasing by ~2.7 and 1.3-fold, respectively, compared with unstimulated cells. In conclusion, activation of LTbetaR induced the expression of RelA mRNA levels. LTbetaR activation might be an important mediator in promoting an inflammatory microenvironment in bladder cancer, via the upregulation of TNFalpha and IL-1beta mRNA levels. LTbetaR may be a potential therapeutic target for bladder cancer. PMID- 28586004 TI - COX-2 regulates Snail expression in gastric cancer via the Notch1 signaling pathway. AB - The conversion of arachidonic acid into prostaglandins by cyclooxygenase (COX)-2 contributes to the biological properties of malignant tumours. During the initiation and development of various tumours, the Notch family plays a key role. However, the association between COX-2 and the Notch family in gastric cancer (GC) remains unclear. The present study aimed to clarify the mechanisms through which COX-2 participates in the pathogenesis of GC. Quantitative PCR and western blot analysis were used to detect the expression of Notch family members and COX 2 in human GC and paracancerous tissues, GES-1 cells and GC cell lines (AGS, SGC 7901, BGC-823, and MGC-803) treated with or without celecoxib, prostaglandin E2 and small interfering RNA (siRNA). A CCK-8 assay was performed to detect the proliferation of GC cells transfected with siRNA against COX-2 (si-COX-2). A high mRNA expression of Notch1 and a decreased expression of Notch-1 intracellular active domain (N1IC) in GC were found to be related to the depth of invasion and TNM staging. The mRNA levels of Notch2, Notch3, Jagged1 and N2IC were found to be high in GC. A High expression of COX-2 was associated with poorly differentiated and deeply invasive GC. COX-2 and Notch1 exhibited an inverse expression pattern in the GES-1 cells and different GC cell lines; the inhibition of COX-2 increased Notch1 expression and activated the GC cells, whereas Notch1 downregulation had the opposite effect. Notch1 exhibited varying effects on Snail in the GC cell lines. The downregulation of COX-2 expression significantly inhibited the proliferation of GC cells. On the whole, the expression of Notch signalling molecules differed in GC. COX-2 inversely regulated Notch1 in GC and partially depended on the Notch1 signalling pathway in altering the expression of Snail. PMID- 28586006 TI - Butein inhibits NF-kappaB, AP-1 and Akt activation in adult T-cell leukemia/lymphoma. AB - Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia/lymphoma (ATLL) but there is no effective treatment for HTLV-1 associated diseases. Herein, we determined the effect of butein, a bioactive plant polyphenol, on cell growth, apoptosis and signaling pathways in HTLV-1 infected T-cell lines and on tumor growth in SCID mice. Treatment with butein caused a decrease in viability of HTLV-1-infected T-cell lines. T cells cultured with butein showed obvious apoptosis morphology, and cleavage of poly(ADP-ribose) polymerase with activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor partially blocked butein-induced inhibition of cell viability. Butein also resulted in cell cycle arrest at G1 phase. Butein markedly downregulated the protein expression levels of CDK4, CDK6, cyclin D1, cyclin D2, cyclin E, survivin, XIAP, c-IAP2 and phospho-pRb. Butein also inhibited i) total and phospho-protein levels of IkappaB kinase (IKK)alpha and IKKbeta, ii) degradation and phosphorylation of IkappaBalpha, iii) JunB and JunD, iv) total and phospho-protein levels of Akt, v) phosphorylation of RelA, vi) heat shock protein 90, and vii) DNA-binding activity of NF-kappaB and AP-1. In mice harboring ATLL xenograft tumors, butein caused a significant inhibition of tumor growth and reduced serum levels of soluble interleukin-2 receptor alpha chain and soluble cluster of differentiation 30. Considered together, the results indicated that butein has antiproliferative and proapoptotic properties through the suppression of NF-kappaB, AP-1 and Akt signaling in HTLV-1-infected T cells, both in vitro and in vivo, suggesting its therapeutic potential against HTLV-1 associated diseases including ATLL. PMID- 28586005 TI - Clinical significance and prognostic value of SOX7 expression in liver and pancreatic carcinoma. AB - Sex determining region Y-box 7 (SOX7) is known to function as a tumor suppressor in a number of types of cancer; however, its role in liver and pancreatic carcinoma remains unclear. The present study investigated the association between SOX7 expression and the clinical pathology of these carcinomas, in particular if SOX7 expression may be used to predict recurrence and patient prognosis following radical resection of liver and pancreatic carcinoma. SOX7 expression in human liver and pancreatic carcinoma was detected by immunohistochemical analyses and validated using mRNA data from a high-throughput sequencing dataset from The Cancer Genome Atlas (TCGA). SOX7 expression was significantly downregulated in liver and pancreatic carcinoma relative to the adjacent benign tissues [immunoreactivity scores: Liver carcinoma (3.53+/-1.57) vs. benign (7.00+/-0.00), P<0.001; and pancreatic carcinoma (2.39+/-1.88) vs. benign (4.80+/-0.45), P=0.005]. In addition, downregulation of SOX7 was significantly associated with advanced stage liver carcinoma, and the primary pathological tumor stage and regional lymph node stages. These findings were further validated in the TCGA dataset. However, SOX7 down regulation was closely associated with the only pathological grade in pancreatic patients. Kaplan-Meier analyses revealed significant differences in overall and disease-free survival between patients with high and low levels of SOX7 expression. In addition, a multivariate analysis with Cox regression indicated that SOX7 may be an independent predictor of disease-free survival. The results indicate that SOX7 may inhibit the progression of liver carcinoma and that SOX7 downregulation may accurately predict poor prognosis in liver carcinoma patients. PMID- 28586007 TI - APG-1252-12A induces mitochondria-dependent apoptosis through inhibiting the antiapoptotic proteins Bcl-2/Bcl-xl in HL-60 cells. AB - Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Despite improved remission rates, current treatment regimens for AML are often associated with a very poor prognosis and adverse effects, necessitating more effective and safer agents. B-cell leukemia/lymphoma 2 (Bcl-2) family proteins regulate apoptotic pathway that can be targeted with small molecule inhibitors. APG-1252 12A is a Bcl-2 homology (BH)-3 mimetic that specifically binds to Bcl-2 and Bcl xl, which has shown efficacy in some Bcl-2 dependent hematological cancers. In this study, we investigated whether APG-1252-12A inhibits the growth of five leukemia cell lines in a concentration- or time-dependent manner by MTS assay. Following treatment of AML cell line HL-60 with this compound, cell apoptosis was detected using flow cytometry and nuclear condensation was observed after Hoechst 33258 dye. Immunoblotting for cytochrome c, cleaved caspase-3 and PARP-1 cleavage was used to demonstrate the mechanism of inducing mitochondria-dependent apoptosis by APG-1252-12A. Our findings showed that this new compound inhibited cell proliferation in five leukemia cell lines and induced apoptotic death. There was a link between the level of Bcl-2 protein and IC50. APG-1252-12A targeted mitochondria and induced caspase-dependent apoptosis by inducing the HL-60 cell cytochrome c released, PARP cleavage and caspase activation. These data suggested that APG-1252-12A is a candidate drug for the in vivo analysis and clinical evaluation in AML. PMID- 28586008 TI - A nanobody targeting carcinoembryonic antigen as a promising molecular probe for non-small cell lung cancer. AB - Carcinoembryonic antigen (CEA) is a biomarker and therapy target for non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Nanobodies with high target specificity are promising candidates to function as anti-CEA probes. In the present study, the targeting effects of an anti-CEA nanobody obtained from phage display were investigated using technetium-99 m (99mTc) and fluorescence labeling. In vitro binding and immunofluorescent staining assays, as well as in vivo blood clearance and biodistribution assays were performed. High specificity and affinity of the nanobody for CEA-positive H460 cells was observed in vitro. The pharmacokinetics assay of the 99mTc nanobody in Wistar rats demonstrated that the nanobody had appropriate T1/2alpha and T1/2beta, which were 20.2 and 143.5 min, respectively. The biodistribution assay using H460 xenograft-bearing nude mice demonstrated a high ratio of signal in tumor compared with background, which confirmed that the nanobody may be useful as a molecular probe for CEA-positive cancer, particularly in NSCLC. PMID- 28586009 TI - Fli-1 overexpression in erythroleukemic cells promotes erythroid de differentiation while Spi-1/PU.1 exerts the opposite effect. AB - The ETS transcription factors play a critical role during hematopoiesis. In F MuLV-induced erythroleukemia, Fli-1 insertional activation producing high expression of this transcription factor required to promote proliferation. How deregulated Fli-1 expression alters the balance between erythroid differentiation and proliferation is unknown. To address this issue, we exogenously overexpressed Fli-1 in an erythroleukemic cell harboring activation of spi-1/PU.1, another ETS gene involved in erythroleukemogenesis. While the proliferation in culture remains unaffected, Fli-1 overexpression imparts morphological and immunohistochemical characteristics of immature erythroid progenitors. Fli-1 overexpression in erythroleukemic cells increased the numbers of erythroid colonies on methylcellulose and reduced tumorigenicity as evidenced by increase latency of erythroleukemogenesis in mice inoculated with these cells. Although all transplanted mice developed enlargement of the spleen and liver due to leukemic infiltration, Fli-1 overexpression altered the hematopoietic phenotype, significantly increasing the expression of regulatory hematopoietic genes cKIT, SCA-1, CD41 and CD71. In contrast, expression of Spi-1/PU.1 in a Fli-1 producing erythroleukemia cell line in which fli-1 is activated, resulted in increased proliferation through activation of growth promoting proteins MAPK, AKT, cMYC and JAK2. Importantly, these progenitors express high levels of markers such as CD71 and TER119 associated with more mature erythroid cells. Thus, Fli-1 overexpression induces a de-differentiation program by reverting CFU-E to BFU-E erythroid progenitor activity, while Spi-1/PU.1 promoting maturation from BFU-E to CFU-E. PMID- 28586010 TI - Resveratrol protects against L-arginine-induced acute necrotizing pancreatitis in mice by enhancing SIRT1-mediated deacetylation of p53 and heat shock factor 1. AB - Acute necrotizing pancreatitis (ANP) is a common severe critical illness with a high mortality rate. Resveratrol, a polyphenol compound derived from various plants such as grape skin, peanut, berry and veratrum, exhibits multiple biological activities, especially potent anti-inflammatory activity, but its effect on ANP has not yet been fully elucidated. The present study aimed to investigate the effects of resveratrol on L-arginine-induced ANP and the possible mechanisms. A mouse model of ANP was established by 2 hourly intraperitoneal injections of 8% L-arginine (4 g/kg). Then the mice were treated by intragastric administration of resveratrol (80 mg/kg) every 12 h immediately after the second injection of L-arginine. Mice with ANP showed increased apoptosis of pancreatic acinar cells, pancreatic myeloperoxidase activity, serum lactate dehydrogenase activity, amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) levels as well as decreased serum IL-10 level, pancreatic expression of heat shock factor 1 (HSF1), sirtuin 1 (SIRT1) and p53, but the ratio of acetylated HSF1 and p53 was markedly increased. Resveratrol enhanced the survival rate of mice with ANP from 47.8 to 71.4% and obviously restored the changes in mice with ANP as mentioned above. Additionally, interactions between SIRT1 and p53 and between SIRT1 and HSF1 in the pancreas of the mice were confirmed by co immunoprecipitation. These data suggest that resveratrol protects against L arginine-induced ANP, which may be related to the enhancement of SIRT1-mediated deacetylation of p53 and HSF1. PMID- 28586011 TI - Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60. AB - Reactive microglia are present in lesions of myelin-associated white matter disorders resulting in injuries to oligodendrocyte precursor cells (OPCs). Therefore, protection of OPCs from injury due to excessive activation of microglia is important in treating these diseases. Heat shock protein 60 (HSP60) has been demonstrated to be released extracellularly in the failing heart upon stress or injury. However, the role of HSP60 in the central nervous system and whether it participates in the toxic effects of microglia on OPCs remains unclear. The present study used the co-culture, cell death assays, binding assays, immunochemistry, western blot and ELISA. HSP60 was demonstrated to be released extracellularly by LPS-activated microglia and to bind to OPCs, triggering OPC apoptosis. When pretreated with toll-like receptor (TLR) 4 blocking antibody, the viability of OPCs increased, while the expression of nuclear factor kappaB (NFkappaB), caspase 3 and the release of proinflammatory cytokines triggered by HSP60 decreased. These results suggest that HSP60 released by microglia may mediate OPC apoptosis through binding to TLR4 on the surface of OPCs and subsequently activating the TLR4-NFkappaB signaling pathway. HSP60 may, therefore, serve as a potential target for treatment of myelin-associated neurodegenerative diseases that are accompanied by microglia activation. PMID- 28586013 TI - Immunogenicity and immunoreactivity of Tp0821 recombinant protein from Treponema pallidum. AB - Treponema pallidum (Tp) is responsible for invading reproductive organs and the skin in early stages, and involves almost all organs/systems at advanced stages. In the present study, screening of the dominant epitope fragment of the Tp outer membrane protein, Tp0821, was performed and the prokaryotic expression vector pQE32/Tp0821 was constructed. The denaturation and dialysis of rTp0821 were achieved through ultrasound, inclusion body washing and dissolution. Experiments in purified rTp0821-immune New Zealand rabbits indicated that the recombinant proteins were of high immunogenicity, and the irritation led a marked humoral immune response in the New Zealand rabbits. Western blot analysis showed that the purified recombinant proteins reacted with the Tp-positive infected serum, confirming the high level of immunoreactivity. The delayed type hypersensitivity of rTp0821 recombinant proteins was positive, indicating that rTp0821 induced a specific cell immune response and was selected as a Tp vaccine candidate protein. The findings of the present study provided novel evidence, which provided information for further investigations on the pathogenic mechanism of Tp and the development of diagnostic reagents. PMID- 28586012 TI - Methylated +322-327 CpG site decreases hOGG1 mRNA expression in non-small cell lung cancer. AB - hOGG1 plays a role in several disease pathways, including various cancers. Despite such functional importance, how hOGG1 is regulated at the transcriptional level in human non-small cell lung cancer (NSCLC) remains unknown, particularly via DNA methylation changes. We obtained NSCLC tissues and adjacent non-cancerous tissues and examined hOGG1 mRNA expression levels. NSCLC cells were treated with 5-Aza to test whether DNA methylation can influence the expression of hOGG1. The MassARRAY EpiTYPER and luciferase reporter gene assays were used to define the functional region of the hOGG1 gene (including CpG sites). Finally, ChIP assay was utilized to verify transcription factor binding to the hOGG1 5'-UTR region. Our previous studies supported the idea that the methylation of the hOGG1 gene promoter region occurs frequently in NSCLC. Treatment with 5-Aza, a demethylating agent, led to a significant restoration of hOGG1 expression in NSCLC cell lines. Quantitative PCR and MassARRAY EpiTYPER assays demonstrated that methylation of the +322-327 CpG site in the 5'-UTR region of hOGG1 was higher in NSCLC tissues compared with adjacent non-cancerous tissues. Notably, the methylation level of +322-327 site (T/N) was inversely correlated with that of hOGG1 mRNA level (T/N) in 25 NSCLC tissues. ChIP assay and in silico prediction showed an association between the +322-327 CpG site and Sp1, which has been reported to be an activator of transcription. Importantly, luciferase reporter gene and ChIP assays showed that +322-327 CpG site methylation particularly reduced the recruitment of Sp1 to the 5'-UTR sequence in hOGG1 and reduced transcriptional activity ~50%. In summary, we have demonstrated that hOGG1 mRNA is downregulated in NSCLC tissues. Moreover, we identified that the methylated +322-327 CpG site in the hOGG1 5'-UTR is associated with reduced expression of hOGG1 by decreasing the recruitment of Sp1 to the 5'-UTR of hOGG1. PMID- 28586015 TI - Evaluation of the anti-inflammatory actions of various functional food materials including glucosamine on synovial cells. AB - The anti-inflammatory actions of glucosamine (GlcN) on arthritic disorders involve the suppression of inflammatory mediator production from synovial cells. GlcN has also been reported to inhibit the activation of the p38 mitogen activated protein kinase (MAPK) pathway. The present study aimed to determine the cooperative and anti-inflammatory actions of functional food materials and evaluated the production of interleukin (IL)-8 and phosphorylation of p38 MAPK in IL-1beta-activated synovial cells, incubated with the combination of GlcN and various functional food materials containing L-methionine (Met), undenatured type II collagen (UC-II), chondroitin sulfate (CS), methylsulfonylmethane (MSM) and agaro-oligosaccharide (AO). The results indicated that Met, UC-II, CS, MSM and AO slightly or moderately suppressed the IL-1beta-stimulated IL-8 production by human synovial MH7A cells. The same compounds further decreased the IL-8 level lowered by GlcN. Similarly, they slightly suppressed the phosphorylation level of p38 MAPK and further reduced the phosphorylation level lowered by GlcN. These observations suggest a possibility that these functional food materials exert an anti-inflammatory action (inhibition of IL-8 production) in combination with GlcN by cooperatively suppressing the p38 MAPK signaling (phosphorylation). PMID- 28586014 TI - Lewis(y) antigen promotes the progression of epithelial ovarian cancer by stimulating MUC1 expression. AB - MUC1 is a type I transmembrane glycoprotein and is overexpressed in various epithelial tumor tissues. Some researchers have demonstrated that the glycosylation status of MUC1 can affect MUC1-mediated tumor growth and cell differentiation. In our previous study, we proved that the abilities of cell proliferation, adhesion, invasion and metastasis, and drug resistance were enhanced in ovarian cancer cells stably expressing Lewis(y). Therefore, we hypothesized that Lewis(y) antigen may play a central role in regulating MUC1 expression, and MUC1-mediated cell growth and differentiation may be closely associated with Lewis(y) antigen. This study aimed to examine the correlation between MUC1 expression and Lewis(y) antigen levels in ovarian cancer cell lines and tissue samples. A series of techniques, including RT-qPCR, western blot anlaysis, immunoprecipitation, immunohistochemistry and double-labeling immunofluorescence were applied to detect the expression of Lewis(y) and MUC1. In malignant epithelial ovarian tumors, the positive expression rates of Lewis(y) antigen and MUC1 were 88.33 and 86.67%, respectively, which were markedly higher than those in borderline (60.00 and 53.33%, P<0.05), benign (33.33 and 30%, P<0.01) and normal (0 and 25%, P<0.01) ovarian samples. There was no correlation between the positive expression rates of Lewis(y) or MUC1 and clinicopathological parameters in ovarian cancers (P>0.05). The expression levels of Lewis(y) and MUC1 correlated with the clinical FIGO stage (P<0.05). Both MUC1 and Lewis(y) were highly expressed in ovarian cancer tissues, and their expression levels were positively correlated (P<0.01). In alpha1,2-fucosyltransferase (alpha1,2-FT) transfected cells, the gene and protein expression levels of MUC1 were significantly upregulated compared with the cells that did not overexpress alpha1,2-FT (P<0.05). The ratio of Lewis(y) immunoprecipitated with MUC1 to total MUC1 increased 1.55-fold in alpha1,2-FT-overexpressing cells (P<0.05). The overexpression of Lewis(y) resulted in the upregulation of MUC1. On the whole, our data indicate that both MUC1 and Lewis(y) are associated with the occurrence and development of ovarian cancers. PMID- 28586016 TI - Protective effects of asiatic acid in a spontaneous type 2 diabetic mouse model. AB - Asiatic acid (AA) has been demonstrated to exhibit anti-diabetic activity. However, the mechanisms and underlying signaling pathways remain to be elucidated. The present study was performed to confirm the protective effect of AA and demonstrate its ability to regulate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway in db/db mice. Db/db mice fed on a high-fat diet were used to model diabetes mellitus. Modeled mice were divided randomly into the model control, pioglitazone hydrochloride tablet (PH) and AA groups. Age-matched C57 BL/6J mice served as normal controls. Lipid and glucose levels, and glycogen synthesis rates were assessed following treatment. Pathological changes were detected using hematoxylin and eosin staining. Expression of the PI3K/AKT/GSK 3beta signaling pathway at the mRNA level was measured using quantitative polymerase chain reaction analysis. The model control group revealed typical characteristics of obesity and diabetes, including high glucose and lipid levels, and decreased glycogen synthesis. Four weeks of treatment with AA or PH ameliorated these abnormalities. AA and PH treatments mitigated the upregulation of PI3K, AKT, insulin receptor, and insulin receptor substrate-1 mRNA expression in modeled mice. Furthermore, AA and PH treatments decreased GSK-3beta and glucose-6-phosphatase mRNA expression compared with the normal control group. The results of the present study confirmed that AA possesses anti-diabetic activity in db/db mice. The PI3K/AKT/GSK-3beta signaling pathway may mediate this protective effect. PMID- 28586017 TI - KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells. AB - KML001 (NaAsO2, sodium metaarsenite, KOMINOX), a kind of arsenic compound, that has shown promising efficacy in non-Hodgkin's lymphoma (NHL) both in vitro and in vivo. In our study, the antileukemic effect of KML001 on acute lymphoid leukemia (ALL) and its mechanism of action were investigated. The results showed that KML001 inhibited cell proliferation in two types of ALL cell lines, CCRF-CEM and Molt-4. Exposure of ALL cells to KML001 induced apoptosis in a time-dependent manner. KML001 caused cell cycle arrest at G2/M phase instead of G0/G1 phase shown in other leukemia cells. In addition, we also tested the possibility of synergy of KML001 with doxercalciferol, a vitamin D2 derivative. Also, we found that a combination of KML001 with doxercalciferol showed a synergistic effect on ALL cell lines and this could be due to its different mechanism of action. Overall, our findings demonstrated KML001 could be a promising antileukemic agent especially when it is combined with doxercalciferol in ALL treatment. PMID- 28586018 TI - Transient cerebral ischemia induces albumin expression in microglia only in the CA1 region of the gerbil hippocampus. AB - Albumin, the most abundant plasma protein, is known to exhibit a neuroprotective effect in animal models of focal and global cerebral ischemia. In the present study, the expression and immunoreactivity of albumin was examined in the hippocampus following 5 min of transient cerebral ischemia in gerbils. Albumin immunoreactivity was observed in microglia of the CA1 hippocampal region 2 days post-ischemic insult, and it was significantly increased at 4 days following ischemia-reperfusion. In addition, at 4 days post-ischemic insult, albumin immunoreactive microglia were abundant in the stratum pyramidale of the CA1 region. The present results demonstrated that albumin was newly expressed post injury in microglia in the CA1 region, suggesting ischemia-induced neuronal loss. Albumin expression may therefore be associated with ischemia-induced delayed neuronal death in the CA1 region following transient cerebral ischemia. PMID- 28586020 TI - Altered expression of epithelial mesenchymal transition and pluripotent associated markers by sex steroid hormones in human embryonic stem cells. AB - Embryonic stem (ES) cells are pluripotent stem cells derived from a developmental stage of pre-implanted embryos. The present study investigated the effect of female sex steroid hormones on the characteristics of human ES cells by using a feeder-free culture protocol. In a feeder-free condition without sex hormones, human ES cells assumed the form of tightly packed cells that grow in a monolayer. The cells had clean and defined edges with no evidence of differentiation and expressed several markers specific for undifferentiated ES cells including POU class 5 homeobox 1 (POU5F1), sex determining region Y-box 2 (SOX2) and NANOG homeobox (NANOG). It was then investigated if female sex steroid hormones including 17beta-estradiol (E2) and progesterone (P4) altered the protein expression of epithelial-mesenchymal transition (EMT) associated markers in addition to pluripotency markers including POU5F1, SOX2 and NANOG in human ES cells. The protein expression levels of N-cadherin, Snail and Slug were increased while E-cadherin expression was decreased by treatment of E2 or P4, and the expression levels of POU5F1, SOX2 and NANOG were decreased by the treatment of E2 or P4. When E2 and P4 were treated in combination with an estrogen receptor inhibitor (ICI 182,780) and progesterone receptor inhibitor (RU486) respectively, their effects on EMT and pluripotency of ES cells were restored to control levels. The results suggested that E2 and P4 may regulate EMT and pluripotency of human ES cells by mediating their receptors. The present study may aid in the understanding of the role of sex steroid hormones in the cellular biology of human ES cells. PMID- 28586019 TI - Protective effects of astragaloside IV against ovalbumin-induced allergic rhinitis are mediated by T-box protein expressed in T cells/GATA-3 and forkhead box protein 3/retinoic acid-related orphan nuclear receptor gammat. AB - 3-O-beta-D-xylopyranosyl-6-O-beta-D-glucopyranosyl-cycloastragenol, or Astragaloside IV (AST), is one of the major active ingredients isolated from Astragalus membranaceous with distinct pharmacological effects, and possesses anti-inflammatory, immunoregulatory and antifibrotic properties. However, the effects of AST on allergic rhinitis remain to be elucidated. The present study aimed to examine the effects of AST on immunoglobulin (Ig) E-mediated allergic reactions in vivo, by using a mouse model of allergic rhinitis established via repetitive sensitization and intranasal challenge with ovalbumin (OVA). Intragastric administration of AST (25 mg/kg or 50 mg/kg) or dexamethasone (DEX; 3 mg/kg) significantly alleviated the inflammatory response, nasal symptoms and mucosa remodeling, and decreased the serum levels of OVA-specific IgE in allergic mice. Furthermore, treatment with AST or DEX significantly suppressed the mRNA and protein expression levels of the transcription factor GATA-3 and retinoic acid receptor-related orphan nuclear receptor (ROR)gammat in tissue samples isolated from the spleen and nasal mucosa of mice with allergic rhinitis. Conversely, mRNA and protein expression levels of T-box protein expressed in T cells (T-bet) and forkhead box protein 3 (Foxp3) were upregulated in the spleen and nasal mucosa of mice with allergic rhinitis following treatment with AST or DEX, and spleen protein levels of signal transducer and activator of transcription 3 followed a similar trend. In addition, treatment with AST was associated with fewer adverse events compared with treatment with DEX. The present results suggested that treatment with AST may attenuate OVA-induced allergic rhinitis via regulating the expression of the transcription factors GATA 3, RORgammat, T-bet and Foxp3, which commit T helper cells to the Th1 phenotype. Therefore, AST may represent an alternative therapeutic approach for the treatment of patients with allergic rhinitis. PMID- 28586021 TI - Construction and characterization of a transmembrane eukaryotic expression vector based on the membrane domain structure of TNF-alpha. AB - The aim of the present study was to construct a fast-acting, eukaryotic expression vector in eukaryotic cells based on transmembrane-tumor necrosis factor-alpha (TM-TNF-alpha) structure. Two types of recombinant eukaryotic expression vectors were constructed, pcDNA3.1-TM-enterokinase-TNF-alpha and pcDNA3.1-TM-Factor Xa-TNF-alpha, according to the TNF-alpha transmembrane segments. Following the generation of these vectors, mouse embryonic 3T3 fibroblasts were transfected and reverse transcription-polymerase chain reaction and western blotting analyses were used to analyze mTNF-alpha mRNA and protein expression levels, respectively, in total cellular protein extracts and extracellular fluid. The biological activity of TNF-alpha in the extracellular fluid was then measured using an MTT assay. The vectors were successfully constructed, and mRNA and fusion proteins were detected in the 3T3 cells. Among the fusion proteins, the one observed in pcDNA3.1-TM-FactorXa-TNF-alpha transfected 3T3 cells remained as a transmembrane protein. In addition, treatment of L929 cells with TNF-alpha derived extracellular fluid samples from pcDNA3.1-TM FactorXa-TNF-alpha-transfected 3T3 cells was associated with a dose-dependent reduction in in cell-specific activity. The results indicate that proteins expressed using pcDNA3.1-TM-FactorXa-TNF-alpha vectors form transmembrane proteins. In addition, the results indicate that, only when coupled with FactorXa activity, the extracellular region of TM-TNF-alpha forms s-TNF-alpha, and the controlled expression of the fusion protein is initiated. PMID- 28586022 TI - Small protein A and phospholipase D immunization serves a protective role in a mouse pneumonia model of Acinetobacter baumannii infection. AB - Acinetobacter baumannii is an important pathogen that primarily causes hospital acquired pneumonia. The present study sought to investigate whether small protein A (SmpA) and phospholipase D (PLD) are potential candidates for protective immunity against infection with A. baumannii. Mice immunized with the fusion proteins histidine (His)-SmpA and His-PLD exhibited a specific immunoglobulin G response. In a pneumonia model, active and passive immunization against SmpA and PLD protected mice from A. baumannii infection. The protection was demonstrated by a markedly improved survival rate, and reduced pulmonary bacterial load, infiltration and cytokine levels in the broncho-alveolar lavage fluid and the serum, although a combination of the two antigens did not provide improved protection compared with immunization with the individual antigens alone. In conclusion, it was identified that SmpA and PLD are highly immunogenic proteins, and potential antigen candidates for the development of effective vaccines or to prepare antisera to mitigate A. baumannii infection. PMID- 28586023 TI - Genetic testing and counseling of a recipient after bone marrow transplant from a sibling harboring a germline BRCA1 pathogenic mutation. AB - Allogenic bone marrow transplant recipients represent a unique challenge, when they are referred for genetic testing and counseling. When performing genetic testing, it is extremely important to ensure that the detected DNA mutations originate from the patients own DNA, and therefore the most appropriate and reliable biological sample for DNA isolation must be obtained. The aim of the present study was to present the germline testing and counseling approach utilized in a rare case of a chimeric woman who received an allogenic bone marrow transplant from a sibling with a germline BRCA1 pathogenic mutation. According to our results, hairs with follicles are a reliable and ready source of DNA in a patient whose blood is of allogenic bone marrow transplant donor origin. Compared with a fibroblast culture, which is more difficult to obtain, the hair follicles are much more accessible and hair sampling is less invasive for the patient. Genetic testing based on the other sources of DNA, such as buccal swabs, is questionable due to the known risk of donor DNA contamination. PMID- 28586024 TI - Quercetin protects neuronal cells from oxidative stress and cognitive degradation induced by amyloid beta-peptide treatment. AB - The present study aimed to investigate the effect of quercetin on cytotoxicity and cognitive degradation induced by amyloid beta(Abeta)-peptide in mice. Using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) method and a Y-maze assay, the radical quenching ability and effect on working memory were determined, respectively, of quercetin treatment following 4 days of Abeta administration. The acute oral toxicity was assessed used to determine the concentration of quercetin at which 50% lethality of the neuronal cells was induced. For determination of the effect of quercetin on degradation of learning and memory loss induced by Abeta, a passive avoidance test was used. The results revealed that quercetin was involved in the inhibition of DPPH radical activity and was found to reduce radical activity by 76.5%. Quercetin significantly protected PC12 neuronal cells from death induced by Abeta treatment. Treatment of mice with daily doses of 100 mg/kg body weight quercetin for 30 days significantly improved the degradation of learning and memory loss induced by Abeta. The acute oral dose of quercetin in mice was determined to be 575 mg/kg body weight. Therefore, quercetin was found to be of therapeutic value for the treatment of neurological disorders, including AD, although further investigations are required. PMID- 28586026 TI - Effects of galectin-9 on apoptosis, cell cycle and autophagy in human esophageal adenocarcinoma cells. AB - The incidence of esophageal adenocarcinoma (EAC) is rapidly increasing in western countries. The overall mortality of this disease remains high with a 5-year survival rate of less than 20%, despite remarkable advances in the care of patients with EAC. Galectin-9 (Gal-9) is a tandem-repeat type galectin that exerts anti-proliferative effects on various cancer cell types. The aim of the present study was to evaluate the effects of Gal-9 on human EAC cells and to assess the expression of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. Gal-9 suppressed the proliferation of the EAC cell lines OE19, OE33, SK-GT4, and OACM 5.1C. Additionally, Gal-9 treatment induced apoptosis and increased the expression levels of caspase-cleaved cytokeratin 18, activated caspase-3 and activated caspase-9. However, it did not promote cell cycle arrest by reducing cell cycle-related protein levels. Furthermore, Gal-9 increased the level of the angiogenesis-related protein interleukin-8 (IL-8) and markedly altered miRNA expression. Based on these findings, Gal-9 may be of clinical use for the treatment of EAC. PMID- 28586025 TI - Protective role of 17beta-estradiol on tumor necrosis factor-alpha-induced apoptosis in human nucleus pulposus cells. AB - The molecular mechanisms underlying protection and pathogenesis in spinal degenerative diseases remain unclear. Tumor necrosis factor-alpha (TNF-alpha) has been demonstrated to induce apoptosis of inte rvertebral disc (IVD) cells during IVD degeneration, and 17beta-estradiol (17beta-E2) has a protective effect against IVD cell apoptosis. However, the underlying molecular mechanism by which 17beta-E2 protects nucleus pulposus (NP) cells remains to be investigated. The aim of the present study was to evaluate whether 17beta-E2 modulates apoptosis of human NP cells induced by TNF-alpha. In addition, the concentration-response effect of 17beta-E2 on human NP cells was investigated. Human NP cells were cultured in complete medium, which was replaced every three days until the culture was ~80% confluent. Cells were treated with 100 ng/ml TNF-alpha for 48 h, with or without pretreatment with various concentrations of 17beta-E2, and ICI 182,780, for 30 min. Morphologic alterations characteristic of apoptosis were observed by inverted phase-contrast microscopy and Hoechst 33258 staining; the apoptosis rate was analyzed by flow cytometry. A Cell Counting kit-8 assay was used to assess cell proliferation. Furthermore, caspase-3 activity was determined and proteins associated with apoptosis were analyzed by western blotting. The level of apoptosis and caspase-3 activity in human NP cells increased, whereas proliferation and the expression of poly ADP-ribose polymerase decreased following TNF-alpha treatment. These effects of TNF-alpha were abolished by pretreatment with 17beta-E2 in a concentration-dependent manner. The results of the present study indicated that 17beta-E2 serves a critical role in the survival of degenerative human NP cells. PMID- 28586027 TI - Inhibitory effects of Stichopus japonicus extract on melanogenesis of mouse cells via ERK phosphorylation. AB - Stichopus japonicus has been used as a folk medicine and as an ingredient in traditional food in East Asian countries. In recent years, the bioactive compounds found in S. japonicus have been reported to possess efficacy in wound healing and may be of potential use in the cosmeceutical, pharmaceutical and biomedical industries. Although the components and their functions require further investigation, S. japonicus extracts exhibit anti-inflammatory properties, and may be used for cancer prevention and treatment. Although several reports have examined different aspects of S. japo-nicus, the effects of S. japonicus extract on melanogenesis in the skin has not been reported to date. Therefore the present study aimed to investigate the effects of S. japonicus extract on melanogenesis. Treatment with a mixture of S. japonicus extracts (MSCE) reduced melanin synthesis and tyrosinase (TYR) activity in mouse melanocyte cells lines, B16F10 and Melan-A. In addition, MSCE treatment reduced the protein expression levels of TYR, tyrosinase-related protein-1 and tyrosinase related protein-2. The reduced protein levels may be the result of decreased microphthalmia-associated transcription factor (MITF) expression, which is an important regulator of melanogenesis. The reduced expression level of MITF was associated with delayed phosphorylation of extracellular signal-regulated kinase (ERK) induced by MSCE treatment. A specific MEK inhibitor, PD98059, significantly blocked MSCE-mediated inhibition of melanin synthesis. In conclusion, these results indicate that MSCE may be useful as a potential skin-whitening compound in the skin medical industry. PMID- 28586028 TI - ATM mediates DAB2IP-deficient bladder cancer cell resistance to ionizing radiation through the p38MAPK and NF-kappaB signaling pathway. AB - Although surgery remains the standard therapy for the treatment of bladder cancer (BCa), the data from previous clinical studies suggest that there is an increase in the number of patients with a preference for bladder preservation strategies, including radiotherapy, to improve their life quality. Our preliminary results showed that disabled homolog 2 interactive protein (DAB2IP), a putative tumor suppressor gene, is often downregulated in BCa with a radioresistant phenotype. Subsequent investigations revealed that elevated expression of ataxia telangiectasia mutated (ATM) induced by DAB2IP-knockdown may be the key event in BCa cell resistance to ionizing radiation (IR). However, how ATM is involved in the survival of DAB2IP-deficient cells exposed to IR remains to be fully elucidated. The present study knocked down the expression of ATM in DAB2IP deficient BCa cells using RNA interference technology. Activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways were detected by western blot analysis and immunofluorescence assay, respectively. It was demonstrated that knockdown of ATM enhanced the response of DAB2IP-deficient BCa cells to IR, which may have resulted from delayed DNA double strand break repair kinetics, compromised nuclear factor-kappaB translocation, inhibited phosphorylation of p38 and the induced activation of c-Jun N-terminal kinase. Taken together, these findings suggested that ATM may be an effective target in the radiotherapy of patients with DAB2IP-deficient BCa. PMID- 28586029 TI - Fangchinoline suppresses the proliferation, invasion and tumorigenesis of human osteosarcoma cells through the inhibition of PI3K and downstream signaling pathways. AB - Osteosarcoma is the most common malignant bone tumor. Most patients diagnosed with osteosarcoma are less than 20 years of age. Osteosarcoma cells proliferate rapidly and invade other tissues. At present, neoadjuvant chemotherapy is the primary pharmacodynamic strategy to prevent the progression of osteosarcoma. However, adverse effects of this strategy limit its long-term application. Previous research has shown that fangchinoline exerts antitumor effects on several types of tumor cells; however, its effect on osteosarcoma cells remains unknown. The present study evaluated the effects of fangchinoline on the proliferation, apoptosis, migration and invasion of osteosarcoma cells in vitro and on their tumorigenesis in vivo and determined the possible underlying mechanism of action. Fangchinoline-treated MG63 and U20S cells showed significantly decreased proliferation and significantly increased apoptosis. Fangchinoline markedly suppressed the migration and invasion of the MG63 cells. Fangchinoline-treated MG63 cells showed significantly decreased expression of phosphoinositide 3-kinase (PI3K) and Aktp-Thr308. Moreover, fangchinoline-treated MG63 cells showed downregulated expression of cyclin D1 and matrix metalloproteinase 2 and 9, which act downstream of PI3K, and upregulated expression of caspase-3 and caspase-8. Furthermore, fangchinoline suppressed the growth of subcutaneous osteosarcoma tumors in Balb/c mice subcutaneously injected with osteosarcoma cells. These findings suggest that fangchinoline inhibits the progression of osteosarcoma by suppressing the proliferation, migration and invasion and by accelerating the apoptosis of osteosarcoma cells. In addition, our results suggest that the mechanism underlying the antitumor effects of fangchinoline involve the inhibition of PI3K and its downstream signaling pathways. PMID- 28586030 TI - Expression of the EP300, TP53 and BAX genes in colorectal cancer: Correlations with clinicopathological parameters and survival. AB - E1A binding protein P300 (EP300), tumor protein P53 (TP53) and BCL2 associated X, apoptosis regulator (BAX) genes encode proteins which cooperate to regulate important cellular processes. The present study aimed to determine the expression levels of EP300, TP53 and BAX in colorectal cancer (CRC) and to investigate their prognostic value and association with the progression of CRC. Tumor and matched unchanged colorectal tissues were collected from 121 CRC patients. Quantitative polymerase chain reaction and immunohistochemistry were used to assess the mRNA and protein levels of the studied genes. Altered expression of the studied genes in CRC tissues was observed at both the mRNA and protein levels. The depth of invasion was associated with TP53 mRNA levels and was correlated negatively with BAX mRNA expression. Moreover, a relationship between tumor location and BAX mRNA content was noted. BAX immunoreactivity was correlated positively with the intensity of p300 immunostaining and was associated with lymph node involvement and tumor-node-metastasis (TNM) disease stage. Univariate regression analysis revealed that overexpression of p53 and BAX in CRC tissues was associated with poor patient outcome. In conclusion, dysregulation of the expression of the studied genes was found to contribute to CRC pathogenesis. The association between p300 and BAX levels suggests the existence of an interdependent regulatory mechanism of their expression. Moreover, BAX expression may be regulated alternatively, in a p53-independent manner, since the lack of correlations between expression of these factors was observed. PMID- 28586031 TI - Punicalagin suppresses the proliferation and invasion of cervical cancer cells through inhibition of the beta-catenin pathway. AB - Natural botanical drugs have attracted attention due to their cancer chemopreventive and chemotherapeutic properties in cancer. Punicalagin (PUN) is the major bioactive component of pomegranate peel, and has been shown to have antioxidant, anti-inflammatory, antiviral, antiproliferation and anticancer properties. PUN has been shown to induce apoptosis in several cancer cell lines. The aim of the present study was to investigate the effect of PUN on HeLa human cervical cancer cells in vitro. The viability of the HeLa cells was assessed following treatment with PUN (0, 12.5, 25, 50, 100 and 200 uM) for 24, 36 and 48 h using a Cell Counting Kit-8 assay. In addition, the cell cycle distribution, protein expression levels of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-3 and the beta catenin pathway, and the activities of matrix metalloproteinase (MMP)-2 and MMP-9 were analyzed following treatment with PUN (0, 25, 50 and 100 uM) for 36 h using cell cycle analysis, western blot analysis and gelatin zymography, respectively. In addition, a wound-healing assay was used to detect cell migration. PUN led to a number of effects on the HeLa cells, including the inhibition of cell proliferation and cell migration, downregulation of MMP-2 and MMP-9, upregulation of TIMP-2 and TIMP-3, cell-cycle arrest in the G1 phase, induction of apoptosis via alterations of Bcl-2 and Bax, and downregulation of beta-catenin and its downstream proteins, cyclin D1 and c-myc. These results suggested that PUN may have chemopreventive and chemotherapeutic effects against cervical cancer in humans through inhibition of the beta-catenin signaling pathway. PMID- 28586033 TI - Sufentanil attenuates oxaliplatin cytotoxicity via inhibiting connexin 43 composed gap junction function. AB - Comprehensive strategies for the treatment of colorectal cancer (CRC) have become increasingly important. One of the most important factors is pain relief. Therefore, patients with CRC are concurrently treated with analgesics and chemotherapeutic agents; however, the effects of analgesics on the therapeutic activity of chemotherapeutic agents remain largely unknown. The present study investigated the effects of three widely used analgesics in clinics: Fentanyl, remifentanil and sufentanil, on the cytotoxicity of oxaliplatin, a commonly used chemotherapeutic agent for CRC. Furthermore, the underlying mechanisms of those effects in association with connexin 43 (Cx43)-composed gap junction (GJ) function were analyzed. The Lovo, Colo320, HCT116 and HT29 human CRC cell lines, with or without Cx43 expression, were used to examine the effects of the three analgesics on the cytotoxicity of oxaliplatin. The results demonstrated that in the cell lines expressing Cx43 (Lovo and Colo320), the cytotoxicity of oxaliplatin was attenuated and Cx43 GJ function was inhibited. Sufentanil, not fentanyl or remifentanil, inhibited Cx43 GJ function effectively, and reduced the cytotoxicity of oxaliplatin. In contrast, these effects were not observed in the other two colon cancer cell lines not expressing Cx43 (HCT116 and HT29). These results suggested that alternation of Cx43 GJ function may regulate the cytotoxicity of oxaliplatin in regard to CRC. Furthermore, sufentanil, not fentanyl or remifentanil, suppressed the cytotoxicity of oxaliplatin through inhibition of Cx43 GJ function. These results may be beneficial for the treatment of CRC and reduction of treatment resistance. PMID- 28586032 TI - A sketch of known and novel MYCN-associated miRNA networks in neuroblastoma. AB - Neuroblastoma (NB) originates from neural crest-derived precursors and represents the most common childhood extracranial solid tumour. MicroRNAs (miRNAs), a class of small non-coding RNAs that participate in a wide variety of biological processes by regulating gene expression, appear to play an essential role within the NB context. High-throughput next generation sequencing (NGS) was applied to study the miRNA transcriptome in a cohort of NB tumours with and without MYCN amplification (MNA and MNnA, respectively) and in dorsal root ganglia (DRG), as a control. Out of the 128 miRNAs differentially expressed in the NB vs. DRG comparison, 47 were expressed at higher levels, while 81 were expressed at lower levels in the NB tumours. We also found that 23 miRNAs were differentially expressed in NB with or without MYCN-amplification, with 17 miRNAs being upregulated and 6 being downregulated in the MNA subtypes. Functional annotation analysis of the target genes of these differentially expressed miRNAs demonstrated that many mRNAs were involved in cancer-related pathways, such as DNA-repair and apoptosis as well as FGFR and EGFR signalling. In particular, we found that miR-628-3p negatively affects MYCN gene expression. Furthermore, we identified a novel miRNA candidate with variable expression in MNA vs. MNnA tumours, whose putative target genes are implicated in the mTOR pathway. The present study provides further insight into the molecular mechanisms that correlate miRNA dysregulation to NB development and progression. PMID- 28586035 TI - DOC-2/DAB2 interactive protein regulates proliferation and mobility of nasopharyngeal carcinoma cells by targeting PI3K/Akt pathway. AB - Tumor suppressors are a group of important inverse regulators for carcinogenesis in human cancers including nasopharyngeal carcinoma (NPC). DOC-2/DAB2 interactive protein (DAB2IP) has been found to be a novel tumor suppressor in malignancies. However, the expression and biological function of DAB2IP in NPC have not been previously reported. This study found that the levels of DAB2IP were decreased in NPC tissues compared to non-cancerous nasopharyngeal epithelium tissues. In addition, downregulation of DAB2IP mRNA was confirmed by qRT-PCR in NPC cell lines as compared with a human immortalized nasopharyngeal epithelial cell line NP69. The reduced expression of DAB2IP was significantly correlated with lymph node metastasis and advanced clinical stage. DAB2IP low expressing NPC patients showed a notable reduced overall survival and disease-free survival. Functionally, DAB2IP restoration prohibited cell proliferation, colony formation, migration and invasion in both 5-8F and CNE-2 cells. Moreover, DAB2IP overexpression restrained the subcutaneous growth and lung metastasis of NPC cells in nude mice. Mechanically, DAB2IP overexpression repressed the activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and subsequently reduced the expression of its downstream targets including cyclin D1 and matrix metallopeptidase 7 (MMP7), which were identified as critical regulators for growth and metastasis of NPC. The Akt inhibitor MK-2206 showed similar effects to DAB2IP overexpression on growth and metastasis of 5-8F cells. Thus, DAB2IP suppresses growth and metastasis of NPC probably by targeting PI3K/Akt pathway, and may act as a hopeful therapeutic target for NPC. PMID- 28586034 TI - Acerogenin C from Acer nikoense exhibits a neuroprotective effect in mouse hippocampal HT22 cell lines through the upregulation of Nrf-2/HO-1 signaling pathways. AB - Oxidative stress contributes to neuronal death in the brain, and neuronal death can cause aging or neurodegenerative disease. Heme oxygenase 1 (HO-1) serves a vital role in the regulation of biological reactions, including oxidative stress associated with reactive oxygen species. In the present study, acerogenin C isolated from the Aceraceae plant Acer nikoense, which is used as a Japanese folk medicine for hepatic disorders and eye diseases. However, there have been no studies on the mechanisms underlying the antineurodegenerative biological activities of acerogenin C. In the present study, acerogenin C demonstrated neuroprotective action against glutamate-induced cell death in hippocampal HT22 cells through the upregulation of HO-1 expression. These effects were also associated with nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activation of phosphoinositide 3-kinase/protein kinase B. Taken together of the efficacy researches, this study determines that the Nrf2/HO 1 pathways denotes a biological mark and that acerogenin C might contribute to prevention of neurodegenerative disorders. PMID- 28586037 TI - Transcriptional co-regulator RIP140: An important mediator of the inflammatory response and its associated diseases (Review). AB - The inflammatory response is a physiological process that is essential for maintaining homeostasis of the immune system. Inflammation is classified into acute inflammation and chronic inflammation, both of which pose a risk to human health. However, specific regulatory mechanisms of the inflammatory response remain to be elucidated. Receptor interacting protein (RIP) 140 is a nuclear receptor that affects an extensive array of biological and pathological processes in the body, including energy metabolism, inflammation and tumorigenesis. RIP140 mediated macrophage polarization is important in regulating the inflammatory response. Overexpression of RIP140 in macrophages results in M1-like polarization and expansion during the inflammatory response. Conversely, decreased expression of RIP140 in macrophages reduces the number of M1-like macrophages and increases the number of alternatively polarized cells, which collectively promote endotoxin tolerance (ET) and relieve inflammation. This review summarizes the role of RIP140 in acute and chronic inflammatory diseases, with a focus on insulin resistance, atherosclerosis, sepsis and ET. PMID- 28586036 TI - Epigenetically silenced PTPRO functions as a prognostic marker and tumor suppressor in human lung squamous cell carcinoma. AB - Protein tyrosine phosphatase receptor-type O (PTPRO), a member of the PTP family, has been frequently reported as potential tumor suppressor in many types of cancer. However, the exact function of PTPRO in lung squamous cell carcinoma (LSCC) remains unclear. Bisulfite sequencing and methylation specific polymerase chain reaction (PCR) were used to identify the methylation status of PTPRO in LSCC cells, and quantitative methylation specific PCR was used to evaluate the methylation levels of PTPRO in LSCC patients. Stably expressing PTPRO vectors were constructed and transfected into H520 and SK-MES-1 cells, followed by MTT and colony formation assays, and analysis of tumor weight and volume in in vivo mouse xenograft models. The present study demonstrated that the CpG island of PTPRO exon 1 was obviously hypermethylated in LSCC cells and tissues. The mRNA expression of PTPRO could be restored by treatment with a demethylation agent. Increased methylation and decreased mRNA levels of PTPRO were observed in LSCC samples compared with adjacent healthy tissues, and were associated with poor prognosis of patients. The mRNA expression of PTPRO was negatively correlated with its methylation level in tumors. Functionally, ectopic PTPRO expression in LSCC cells significantly inhibited the proliferation rates, and colony formation, in comparison with control and non-transfected cells. In vivo assays confirmed the inhibitory effect of PTPRO on LSCC cell growth. In conclusion, these data provided evidence that epigenetic regulation of PTPRO impairs its tumor suppressor role in LSCC, and restoration of PTPRO may be a potential therapeutic strategy. PMID- 28586039 TI - Exosomes derived from hypoxic epithelial ovarian cancer deliver microRNA-940 to induce macrophage M2 polarization. AB - Hypoxia is a common feature of solid tumors. It is closely related to tumor progression. Exosomal microRNAs derived from cancers are considered to be mediators between cancer cells and the tumor microenvironment. In addition, the number of tumor-associated macrophages (TAMs) in the tumor microenvironment has also been demonstrated to correlate with tumor development. However, the relationship between tumor-secreted exosomes and TAM polarization under hypoxic conditions during tumor progression is not clear. Herein, we demonstrated that hypoxia induces the high expression of microRNA-940 (miR-940) in exosomes derived from epithelial ovarian cancer (EOC). We also found that miR-940 is highly expressed in exosomes isolated from ascites of EOC patients. Moreover, the overexpression of miR-940 in macrophages delivered by exosomes stimulated M2 phenotype polarization, while the M2 subtype macrophages promoted EOC proliferation and migration. These results highlight the function of hypoxia in enhancing the high level of expression of miR-940 in tumor exosomes taken up by macrophages. We also showed that the tumor-promoting function of miR-940 is mediated by TAM polarization in EOC. These findings show that tumor-derived exosomal miR-940 induced by hypoxia plays an important role in stimulating TAM polarization in the progression of EOC. PMID- 28586038 TI - miR-1247-5p functions as a tumor suppressor in human hepatocellular carcinoma by targeting Wnt3. AB - Increasing evidence suggests that aberrant expression of certain microRNAs (miRNAs) may participate in the genesis and progression of tumors. Several studies have indicated that miR-1247-5p plays different roles in various types of cancer cells. The effects of miR-1247-5p on human hepatocellular carcinoma (HCC) cells are elusive. In the present study, we investigated the effects of miR-1247 5p on the progression of HCC. The transcript of miR-1247-5p was markedly downregulated in clinical samples of patients with HCC and HCC cell lines, and ectopic overexpression of miR-1247-5p markedly inhibited the proliferation and invasion of HepG2 cells, induced cell apoptosis in vitro, and suppressed the growth of transplanted tumors in vivo. Wnt3 was found to be a potential target of miR-1247-5p and overexpression of miR-1247-5p was able to significantly downregulate the expression of Wnt3 by directly targeting the 3'UTR of this gene, which was verified by luciferase reporter assay and western blotting. Furthermore, we found that the miR-1247-5p gene was hypermethylated in HepG2 cells, and the transcript of miR-1247-5p was increased significantly after treatment with the demethylation drug 5-azacytidine. These findings demonstrated that miR-1247-5p functions as a tumor suppressor in human HCC by targeting Wnt3 and that the expression of miR-1247-5p can be regulated by DNA methylation, which indicates that miR-1247-5p has the potential to be a therapeutic target as well as a diagnostic marker of HCC. PMID- 28586040 TI - Low expression of PinX1 is associated with malignant behavior in basal-like breast cancer. AB - Human Pinx1 protein, associated with shelterin proteins, is widely revealed as a haploinsufficient tumor suppressor. Growing evidence has manifested the deregulation of PinX1 in distinct cancers. Nonetheless, the loss status of PinX1 and its diagnostic, prognostic and clinicopathological significance in Basal-like breast cancer are still unclear. In the present study, the PinX1 expression levels of breast cancer tissues were investigated by qRT-PCR and immunoblotting assays. Then immunohistochemistry (IHC) was performed to detect PinX1 expression on a tissue microarray. The optimal threshold for PinX1 positivity was determined by receiver operating characteristic (ROC) curve analysis. To clarify the probable role of PinX1 in BLBC, the PinX1 knockout and stably over-expressed MDA MB-231 cell lines were constructed by the CRISPR-Cas9 system and gene transfection. The association of PinX1 expression with cell proliferation, migration and apoptosis of MDA-MB-231 cells were observed by CCK-8 assay, wound healing assay, transwell assay, flow cytometric analysis and immunoblotting of the cleaved caspase-3 protein level. Our results showed that both PinX1 mRNA and protein expression were downregulated in breast cancer tissues (P<0.05). In IHC analysis, the optimal cut-off parameter for PinX1 positive expression was 62.5% (the AUC was 0.749, P<0.01). PinX1 positivity was 76.9% (10/14) in luminal subtypes, 50% (5/10) in Her2-enriched breast cancer and 27.3% (9/33) in basal like subtypes. Besides, in 59 invasive ductal breast carcinomas, PinX1 expression was inversely related to histology grade (P<0.05) while it was positively associated with PR status (P<0.05) and ER status (P<0.05). These results indicated that low expression of PinX1 correlated with aggressive clinicopathological significance of breast cancer, especially in the basal-like subtype. Besides, we identified that overexpression of PinX1 inhibited the proliferation rates and migration ability and increased the apoptosis rates of BLBC. Our findings demonstrated that low expression of PinX1 was associated with malignant behaviors in basal-like subtype of breast cancer. PinX1 is likely a feasible biomarker and molecular target of BLBC. PMID- 28586041 TI - Effects of demethoxycurcumin on the viability and apoptosis of skin cancer cells. AB - The present study investigated the effects and mechanisms of demethoxycurcumin (DMC) on a human skin squamous cell carcinoma cell line, A431, and a human keratinocyte cell line, HaCaT. A431 and HaCaT cells were cultured in vitro. The effects of DMC treatment on cell viability were analyzed using the Cell Counting kit-8 (CCK-8) assay; cell cycle distribution was analyzed by flow cytometry; apoptosis was assessed by flow cytometry and Hoechst 33258 staining; and the protein expression levels of cytochrome c, B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (BAX), caspase-9 and caspase-3 were evaluated by western blotting. CCK-8 assay results demonstrated that DMC treatment significantly inhibited viability of A431 and HaCaT cells in a dose-dependent manner. Flow cytometric analysis confirmed that DMC treatment induced apoptosis in a dose dependent manner, and significantly increased the proportion of cells in G2/M phase. Western blot analysis indicated that the protein expression levels of Bcl 2 were decreased, whereas the expression levels of BAX, caspase-9, caspase-3 and cytochrome c were increased following DMC treatment compared with in untreated cells. In conclusion, DMC treatment significantly inhibited viability of A431 and HaCaT cells, and induced cell cycle arrest in G2/M phase. The present study indicated that DMC may induce apoptosis of skin cancer cells through a caspase dependent pathway. PMID- 28586042 TI - Effects of cryopreservation on excretory function, cellular adhesion molecules and vessel lumen formation in human umbilical vein endothelial cells. AB - Cryopreservation is widely used in regenerative medicine for tissue preservation. In the present study, the effects of cryopreservation on excretory function, cellular adhesion molecules and vessel lumen formation in human umbilical vein endothelial cells (HUVECs) were investigated. After 0, 4, 8, 12 or 24 weeks of cryopreservation in liquid nitrogen, the HUVECs were thawed. The excretory functions markers (endothelin-1, prostaglandin E1, von Willebrand factor and nitric oxide) of HUVECs were measured by ELISA assay. The expression of intercellular adhesion molecule-1 (ICAM-1) in HUVECs was analyzed using flow cytometry. An angiogenesis assay was used to determine the angiogeneic capabilities of the thawed HUVECs. The results demonstrated that cryopreserved/thawed and recultivated HUVECs were unsuitable for tissue engineered microvascular construction. Specifically, the excretory function of the cells was significantly decreased in the post-cryopreserved HUVECs at 24 weeks. In addition, the level of ICAM-1 in HUVECs was significantly upregulated from the fourth week of cryopreservation. Furthermore, the tube-like structure forming potential was weakened with increasing cryopreservation duration, and the numbers of lumen and the length of the pipeline were decreased in the thawed HUVECs, in a time-dependent manner. In conclusion, the results of the present study revealed that prolonged cryopreservation may lead to HUVEC dysfunction and did not create stable cell lines for tissue-engineered microvascular construction. PMID- 28586043 TI - GRP78 silencing enhances hyperoxia-induced alveolar epithelial cell apoptosis via CHOP pathway. AB - Hyperoxia is one of the primary causes of bronchopulmonary dysplasia, which may occur in premature infants following supplemental oxygen therapy. Glucose regulated protein 78 (GRP78), which is a molecular chaperone located in the lumen of the endoplasmic reticulum (ER), has been reported to regulate hyperoxia associated ER stress. The role of GRP78 in lung epithelial cells during hyperoxia remains to be elucidated. In the present study, the A549 cultured human lung epithelial cell line was exposed to hyperoxic conditions, and then transfected with short interfering (si)RNA targeted to GRP78. siRNA or pEGFP-N1 plasmid were used to knockdown or overexpress specific genes, reverse transcription quantitative polymerase chain reaction and western blot analysis were used to detect RNA and protein levels of gene expression, and flow cytometry was used to detect apoptosis. The expression levels of ER stress-associated genes were determined, and a significant increase in C/EBP homologous protein (CHOP) expression and apoptosis of A549 cells was observed, following GRP78 knockdown. The overexpression of CHOP downregulated B-cell lymphoma (Bcl)-2 expression levels, upregulated BCL2 associated X (Bax), and increased apoptosis of A549 cells under conditions of hyperoxia. CHOP knockdown demonstrated the opposite effect on Bcl-2 and Bax expression levels. These results suggested that GRP78 silencing promoted lung epithelial cell apoptosis during hyperoxia, via regulation of the CHOP pathway. PMID- 28586044 TI - Noninvasive detection of acute renal allograft rejection by measurement of soluble Tim-3 in urine. AB - The purpose of the present study was to assess whether urinary soluble T-cell immunoglobulin and mucin domain-containing protein 3 (sTim-3) could be adopted as a novel non-invasive biomarker for acute rejection (AR) following renal transplantation. A total of 156 patients were enrolled between January 2006 and December 2009, comprising 49 patients with biopsy-proven AR, 58 patients with stable grafts and no abnormal histological findings (NO-AR), 10 patients with subclinical rejection (SCR) in protocol biopsies, 10 patients with acute tubular necrosis (ATN) and 29 patients with chronic allograft nephropathy (CAN). Additionally, urine samples from 40 healthy individuals were also collected as controls. The urinary concentration of sTim-3 was determined by ELISA in the 156 renal allograft recipients and 40 healthy controls. Compared with NO-AR and healthy controls, patients with AR excreted urinary sTim-3 at a significantly higher level (4,356+/-440.4, 95% CI: 3,473-5,242 ng/mmol creatinine). Likewise, patients with ATN exhibited a significantly lower level of urinary sTim-3 (2,060+/-217, 95% CI: 1,679-2,680 ng/mmol creatinine) than patients with AR. The discriminatory value was measured by the area under the receiver operating characteristic curve (ROC), which had a value of 0.88 (95% CI: 0.809-0.951), demonstrating that sTim-3 was a suitable marker for the diagnosis of AR. At a cut off point of 1,836 ng/mmol creatinine, the sensitivity was 89.8% and the specificity was 82.8% (P<0.001). Amongst the patients with AR, patients with steroid-resistant acute rejection (n=31) had significantly higher urinary sTim-3 concentrations than patients with steroid-sensitive acute rejection (n=18; 5,548+/-613.5, 95%CI: 4,287-6,809 ng/mmol creatinine vs. 2,653+/-391.7, 95% CI: 1,830-3,476 ng/mmol creatinine; P=0.0002). No significant difference in urinary sTim-3 was found between patients with AR and CAN (3,920+/-543.5, 95% CI: 3,473 5,242 ng/mmol creatinine), and a significantly higher level of Tim-3 was excreted by patients with CAN compared with patients with NO-AR and healthy controls (P<0.001). The present study, therefore, suggests that urinary sTim-3 may be used as a valuable non-invasive biomarker for the detection of AR. In addition, urinary sTim-3 levels were demonstrated to be associated with the response to anti-rejection therapy. The results of the present study may provide support future research into the screening of novel immune suppressants. PMID- 28586045 TI - Low HtrA1 expression in patients with long-standing ulcerative colitis and colorectal cancer. AB - The association between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is being increasingly investigated. HtrA1 overexpression inhibits cell growth and proliferation by influencing apoptosis, invasiveness and migration of tumour cells. In the present study, HtrA1 expression was analysed in 228 colon tissue samples from patients with CRC, adenoma with high-grade dysplasia (AHD), adenoma with low-grade dysplasia (ALD), ulcerative colitis of >10 year duration (UCL), ulcerative colitis of <5 year duration (UCS) and colonic diverticulitis (D), and was compared with its expression in normal colon tissues (NCTs) collected 5 cm from the CRC lesion and in healthy colon mucosa (HC), to establish whether HtrA1 can serve as a biomarker for these conditions. All tissue specimens came from Italian Caucasian subjects. The main finding of the present study was that HtrA1 expression was significantly reduced in CRC and UCL tissues compared with that observed in both NCT and HC samples and with tissues from the other patients. In particular, a similar HtrA1 expression was detected in the stromal compartment of UCL and CRC samples. In contrast, the HtrA1 level was significantly lower (p=0.0008) in UCL compared with UCS tissues, suggesting an inverse relationship between HtrA1 expression and ulcerative colitis duration. HtrA1 immunostaining in the stromal compartment of AHD and ALD tissues showed no differences compared with the HC tissues. No data are available on the immunohistochemical localization of HtrA1 in CRC or IBD. The present findings suggest that HtrA1 could serve as a marker to identify UCL patients at high risk of developing CRC. PMID- 28586046 TI - Enhanced effect of nuclear localization signal peptide during ultrasound-targeted microbubble destruction-mediated gene transfection. AB - Ultrasound-targeted microbubble destruction (UTMD) can promote the entry of plasmid DNA (pDNA) into the cell cytoplasm, by increasing the permeability of the cell membrane. But the transfection efficiency remains low due to inability of the pDNA to enter the nucleus. Various methods have been explored to improve the UTMD transfection efficiency, but with little success. In cells, the classic nuclear localization signal (cNLS) peptide is an amino acid sequence that signals proteins that are due for nuclear transport. The present study aimed to investigate whether binding of a cNLS peptide to the pDNA may improve the transfection efficiency of UTMD. Four experimental groups were analyzed: Control group (UTMD + pDNA), group with cNLS (UTMD + pDNA + cNLS), group with mutated NLS (mNLS; UTMD + pDNA + mNLS), and group with cNLS and the nuclear import blocker, wheat germ agglutinin (WGA; UTMD + pDNA + cNLS + WGA). The NLS was labeled by fluorescein isothiocyanate, whereas pDNA was labeled with Cy3. Different molar ratios were tested for the NLS and pDNA combination in order to achieve optimal binding of the two molecules. Human umbilical vein endothelial cells were then transfected using the optimum ultrasonic irradiation parameters and NLS/pDNA molar ratio. At 6 h post-transfection, the rates of Cy3-labeled pDNA inside the cells and their nuclei were detected by flow cytometry and laser confocal microscopy, and the cellular vs. nuclear uptake of pDNA was calculated. In order to further evaluate the effect of NLS on UTMD-mediated gene transfection, the transfection efficiency and relative expression levels of mRNA and protein were detected at 48 h post-transfection. The results demonstrated that the optimal molar ratio of NLS with pDNA was 104:1. The rates of pDNA successful entry into the cell and nucleus were significantly higher in the cNLS group compared with the control group. The transfection efficiency, and relative expression levels of mRNA and protein from the plasmid were significantly increased in the cNLS group compared with the control group. The mNLS group displayed no significant difference compared with the control group, while the WGA group exhibited significant inhibition in most indicators of transfection efficiency compared to the cNLS group. These results suggest that combining a cNLS peptide with pDNA during UTMD-mediated transfection significantly improved transfection efficiency. Thus, a cNLS peptide may be an important mediator and a new strategy in enhancing the efficiency of UTMD-mediated gene transfection. PMID- 28586048 TI - Modeling osteosarcoma progression by measuring the connectivity dynamics using an inference of multiple differential modules algorithm. AB - Understanding the dynamic changes in connectivity of molecular pathways is important for determining disease prognosis. Thus, the current study used an inference of multiple differential modules (iMDM) algorithm to identify the connectivity changes of sub-network to predict the progression of osteosarcoma (OS) based on the microarray data of OS at four Huvos grades. Initially, multiple differential co-expression networks (M-DCNs) were constructed, and weight values were assigned for each edge, followed by detection of seed genes in M-DCNs according to the topological properties. Using these seed gene as a start, an iMDM algorithm was utilized to identify the multiple candidate modules. The statistical significance was determined to select multiple differential modules (M-DMs) based on the null score distribution of candidate modules generated using randomized networks. Additionally, the significance of Module Connectivity Dynamic Score (MCDS) to quantify the dynamic change of M-DMs connectivity. Further, DAVID was employed for KEGG pathway enrichment analysis of genes in dynamic modules. In addition to the basal condition, four conditions, OS grade 1 4, were also included (M=4). In total, 4 DCNs were constructed, and each of them included 2,138 edges and 272 nodes. A total of 13 genes were identified and termed 'seed genes' based on the z-score distribution of 272 nodes in DCNs. Following the module search, module refinement and statistical significance analysis, a total of four 4-DMs (modules 1, 2, 3 and 4) were identified. Only one significant 4-DM (module 3 in the DCNs of grade 1, 2, 3 and 4 OS) with dynamic changes was detected when the MCDS of real 4-DMs were compared to a null distribution of MCDS of random 4-DMs. Notably, the genes of the dynamic module (module 3) were enriched in two significant pathway terms, ubiquitin-mediated proteolysis and ribosome. The seed genes with the highest degrees included protein phosphatase 1 regulatory subunit 12A (PPP1R12A), UTP3, small subunit processome component homolog (UTP3), prostaglandin E synthase 3 (PTGES3). Thus, pathway functions (ubiquitin-mediated proteolysis and ribosome) and several seed genes (PPP1R12A, UTP3, and PTGES3) in the dynamic module 3 may be associated with the progression of OS and may serve as potential therapeutic targets in OS. PMID- 28586047 TI - Identification and functional analysis of the risk microRNAs associated with cerebral low-grade glioma prognosis. AB - Low-grade gliomas (LGGs) are associated with neurological disability. The present study used microRNA (miRNA) expression profiles to identify risk miRNAs for potential prognosis of cerebral LGGs. miRNA expression profiles and clinical data from 408 patients with cerebral LGGs were obtained from the Cancer Genome Atlas database. Risk miRNAs were identified by plotting Kaplan-Meier curves and Cox proportional hazard regression analysis with the survival and KMsurv packages in R. A regulatory network of miRNA-targets was constructed, followed by gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network of miRNA targets was built using Search Tool for the Retrieval of Interacting Genes software, and sub-pathway identification was performed using the iSubpathwayMiner package in R. In total, 39 miRNAs had significant effect on survival curves. Following the Cox analysis and construction of miRNA-targets regulatory network, hsa-miRNA (miR)-326 was identified to regulate 397 target genes. Additionally, targets of miR-326 were primarily enriched in the GO terms of cell proliferation, epithelial growth factor receptor and nerve growth factor signaling pathways. Additionally, son of sevenless homolog 1 (SOS1), neuroblastoma RAS viral oncogene homolog (NRAS), vitamin D receptor (VDR) and mothers against decapentaplegic family member 3 (SMAD3) were most enriched in the PPI network. Targets of miR-326 were primarily enriched in sub-pathways including sphingolipid metabolism and arachidonic acid metabolism, in which sphingomyelin synthase 1 (SGMS1) and hematopoietic prostaglandin D synthase (HPGDS) were screened out. Hsa-miR-326 was identified as a risk miRNA for prognosis and may improve the outcome prediction of patients with cerebral LGG. This miRNA may regulate cancer cell proliferation by targeting SOS1, NRAS, VDR, SMAD3, SGMS1 and HPGDS. PMID- 28586049 TI - A novel missense mutation in the ALPL gene causes dysfunction of the protein. AB - Hypophosphatasia (HP) is a rare genetic disease caused by mutation in the alkaline phosphatase, liver/bone/kidney (ALPL) gene with highly variable clinical manifestations. Efforts have been made to collect cases with novel mutations and to examine how a missense mutation affects ALPL protein function, which remains difficult to predict. The present study investigated the underlying mechanism of ALPL dysfunction in a patient diagnosed with HP. Bidirectional sequencing of the ALPL gene was conducted in a 5-year-old Chinese girl preliminary diagnosed with childhood HP. Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping v2 (PolyPhen-2) tools were used to forecast the impact of the mutation on protein function. Site-directed mutagenesis was performed and transfected into cells to verify the role of the specific mutation. Furthermore, the mechanism of the impact was investigated via all-atom molecular dynamics (MD) simulation. The patient demonstrated a compound heterozygote with two missense mutations in the ALPL gene, p.Trp29Arg and p.Ile395Val. Trp29 and Ile395 were determined to be 'tolerable' by SIFT, whereas they were 'possibly damaging' by PolyPhen-2 in terms of conservation. Additionally, HEK293 cells were transfected with plasmids expressing wild type and/or mutated ALPL. Only 4.1% of ALP activity remained when Trp29 was substituted by Arg, whereas 19.1, 33.7, 50.1 and 7.6% ALP activity remained in cells expressing p.Ile395Val, wild type+p.Trp29Arg, wild type+p.Ile395Val and p.Trp29Arg+p.Ile395Val substitutions, respectively. All-atom MD simulation demonstrated that the N-terminal helix of mutated ALPL, where Trp29 is located, separated from the main body of the protein after 30 nsec, and moved freely. These results demonstrated that p.Trp29Arg, as a novel missense mutation in the ALPL gene, reduced the enzymatic activity of ALPL. This effect may be associated with an uncontrolled N-terminal helix. These results provide novel information about the genetic basis of HP, and may facilitate the development of future therapies. PMID- 28586050 TI - Inhibitory capacity of Rhus coriaria L. extract and its major component methyl gallate on Streptococcus mutans biofilm formation by optical profilometry: Potential applications for oral health. AB - Streptococcus mutans (S. mutans) bacterium is the most well recognized pathogen involved in pathogenesis of dental caries. Its virulence arises from its ability to produce a biofilm and acidogenicity, causing tooth decay. Discovery of natural products capable to inhibit biofilm formation is of high importance for developing health care products. To the best of our knowledge, in all previous scientific reports, a colorimetric assay was applied to test the effect of sumac and methyl gallate (MG) on S. mutans adherence. Quantitative assessment of the developed biofilm should be further performed by applying an optical profilometry assay, and by testing the effect on both surface roughness and thickness parameters of the biofilm. To the best of our knowledge, this is the first study to report the effect of sumac extract and its constituent MG on biofilm formation using an optical profilometry assay. Testing antibacterial activity of the sumac extract and its fractions revealed that MG is the most bioactive component against S. mutans bacteria. It reduced S. mutans biofilm biomass on the polystyrene surface by 68-93%, whereas 1 mg/ml MG was able to decrease the biofilm roughness and thickness on the glass surface by 99%. MG also prevented a decrease in pH level by 97%. These bioactivities of MG occurred in a dose dependent manner and were significant vs. untreated bacteria. The findings are important for the development of novel pharmaceuticals and formulations of natural products and extracts that possess anti-biofilm activities with primary applications for oral health, and in a broader context, for the treatment of various bacterial infections. PMID- 28586051 TI - Overexpression of microRNA-133b is associated with the increased survival of patients with hepatocellular carcinoma after curative hepatectomy: Involvement of the EGFR/PI3K/Akt/mTOR signaling pathway. AB - The aim of the present study was carried out to investigate the association of microRNA-133b (miRNA-133b) expression with the prognosis of patients with hepatocellular carcinoma (HCC) after curative hepatectomy. In the present study, the expression of miRNA-133b in HCC tissues was determined to be lower than that noted in the adjacent normal tissues. Overall and disease-free survival of the HCC patients with high miRNA-133b expression was observably extended, compared with the HCC patients with low miRNA-133b expression. Moreover, the overexpression of miRNA-133b inhibited cell proliferation, increased lactate dehydrogenase (LDH) activity, induced apoptosis and promoted caspase-3/-8 activities and Bax/Bcl-2 protein expression in HCC cells, whereas the protein expression of epidermal growth factor receptor (EGFR) was significantly decreased. The overexpression of miRNA-133b significantly suppressed PI3K, phosphorylated (p)-Akt and p-mTOR protein expression in HCC cells. GW2974, an EGFR inhibitor, suppressed the protein expression of EGFR, inhibited cell proliferation, increased LDH activity, induced apoptosis and promoted caspase-3/ 8 activities and Bax/Bcl-2 protein expression, downregulated PI3K, p-Akt and p mTOR protein expression in the transfected HCC cells overexpressing miRNA-133b. Taken together, our results indicate that the overexpression of miRNA-133b is associated with the increased survival of HCC patients after curative hepatectomy. The effects of miRNA-133b in HCC are mediated through the EGFR/PI3K/Akt/mTOR signaling pathway. PMID- 28586052 TI - A novel approach to select differential pathways associated with hypertrophic cardiomyopathy based on gene co-expression analysis. AB - The present study was designed to develop a novel method for identifying significant pathways associated with human hypertrophic cardiomyopathy (HCM), based on gene co-expression analysis. The microarray dataset associated with HCM (E-GEOD-36961) was obtained from the European Molecular Biology Laboratory European Bioinformatics Institute database. Informative pathways were selected based on the Reactome pathway database and screening treatments. An empirical Bayes method was utilized to construct co-expression networks for informative pathways, and a weight value was assigned to each pathway. Differential pathways were extracted based on weight threshold, which was calculated using a random model. In order to assess whether the co-expression method was feasible, it was compared with traditional pathway enrichment analysis of differentially expressed genes, which were identified using the significance analysis of microarrays package. A total of 1,074 informative pathways were screened out for subsequent investigations and their weight values were also obtained. According to the threshold of weight value of 0.01057, 447 differential pathways, including folding of actin by chaperonin containing T-complex protein 1 (CCT)/T-complex protein 1 ring complex (TRiC), purine ribonucleoside monophosphate biosynthesis and ubiquinol biosynthesis, were obtained. Compared with traditional pathway enrichment analysis, the number of pathways obtained from the co-expression approach was increased. The results of the present study demonstrated that this method may be useful to predict marker pathways for HCM. The pathways of folding of actin by CCT/TRiC and purine ribonucleoside monophosphate biosynthesis may provide evidence of the underlying molecular mechanisms of HCM, and offer novel therapeutic directions for HCM. PMID- 28586053 TI - HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia. AB - Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6. Cell viability test and Transwell assay were applied to evaluate the effects of malignant biological properties. Primary cilia staining and related proteins were detected. The abnormal expression of HDAC6 and cilia intraflagellar transport protein 88 (IFT88) was found in chondrosarcoma tissues. The inhibition of HDAC6 could downregulate the proliferation of chondrosarcoma cells in a concentration- and time-dependent manner and suppress the invasion capacity of tumor cells. Besides, the downregulation of HDAC6 exhibited a negative effect on the proliferation of relevant proteins but a positive effect on the primary cilia related expression of IFT88 and acetylated alpha-tubulin. Primary cilia restoration could be observed after HDAC6 siRNA transfection. The Aurora A-HDAC6 cascade was involved in regulating primary cilia resorption by affecting alpha tubulin deacetylation and Tubastatin A could inhibit chondrosarcoma cell growth in vivo. These results indicate that restricting HDAC6 can restore primary cilia assembly accompanied with suppressed chondrosarcoma cell proliferation and invasion capacities. Thus, promoting primary cilia restoration by targeting HDAC6 may be a feasible potential therapeutic method for chondro-sarcoma treatment. PMID- 28586054 TI - Propofol reduces hypoxia-induced autophagic cell death through downregulating HIF 1alpha in alveolar epithelial type II cells of rats. AB - Propofol (2,6-diisopropylphenol) exerts protective effects on alveolar epithelial type II (ATII) cells, partly through attenuating hypoxia-induced apoptosis. Autophagy is involved in the activation of apoptosis. Therefore, the present study investigated the modulating effect of propofol against autophagy in ATII cells under hypoxia. Western blot analysis was performed to detect the protein expression of the autophagy molecular marker, microtubule-associated protein 1 light chain 3 (LC3)-II, under various conditions. The effects of propofol on the accumulation of other autophagy-associated proteins and apoptosis-associated proteins were also determined using western blot analysis. The interactions between proteins were determined by co-immunoprecipitation. Apoptosis of the ATII cells was monitored using FITC-conjugated AV/PI staining. Furthermore, hypoxia inducible factor 1alpha (HIF 1alpha) small interfering (si) RNA was designed to construct si-HIF 1alpha ATII cells. The efficiency of interference was measured using reverse transcription-quantitative polymerase chain reaction and western blot analyses. Following pre-treatment with propofol, the hypoxia-induced accumulation of LC3-II, HIF 1alpha and B-cell lymphoma-2 interacting protein 3 (Bnip3) were markedly decreased, accompanied with the activation of mammalian target of rapamycin. In addition, cleaved-poly ADP-ribose polymerase was suppressed, and hypoxia-induced autophagic cell death was inhibited by propofol pre-treatment. HIF 1alpha was inhibited by si-HIF 1alpha, which simultaneously suppressed Bnip3 and LC3-II under hypoxia. Taken together, propofol reduced hypoxia-induced autophagic cell death through reducing the expression of HIF 1alpha in ATII cells, indicating a novel strategy for modulating autophagy via propofol in hypoxic ATII cells. PMID- 28586055 TI - Differential expression of miRNAs in Osborne's ligament of cubital tunnel syndrome. AB - Cubital tunnel syndrome (CuTS) is the second most common peripheral nerve compression disease, however, the pathogenesis and pathology of CuTS remain to be fully elucidated. The aim of the present study was to compare the expression pattern of microRNAs (miRNAs) in pachyntic Osborne's ligament with that in control tendinous tissue, and select meaningful miRNAs for further investigation of the clinical pathological mechanism underlying CuTS. A microarray assay was performed to examine the expression profiles of miRNAs in the Osborne's ligament and control tendinous tissues. An online bioinformatics algorithms tool (miRWalk) was used to predict putative target genes for the deregulated miRNAs, and functional annotation was performed by Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the results of microarray were partially validated using reverse transcription-quantitative polymerase chain reaction analysis. The expression of total of 60 miRNAs were found to be significantly different between the pachyntic Osborne's ligament and control tendinous tissues. MiRWalk2.0 predicted 1,804 target genes for these miRNAs, and the GO functional analysis of the predicted genes suggested cellular mechanisms, including metabolic process, regulation of cell growth, cell cycle processes, cell division regulation, cellular metabolic process and signal transmission, were involved. Furthermore, KEGG pathway analysis revealed important pathways, including adherent junction, focal adhesion, lysine degradation, cell adhesion molecules and mitogen-activated protein kinase. Compared with the heathy tissue, Osborne's ligament tissue from patients with CuTS showed a markedly different miRNA expression profile, which suggested that miRNAs may be involved in the pathogenesis of CuTS. PMID- 28586056 TI - MicroRNA-497 acts as a tumor suppressor in gastric cancer and is downregulated by DNA methylation. AB - Gastric cancer (GC) is one of the most common malignant tumors in the world and microRNAs (miRNAs) play an important role in GC. In this study, we found miR-497 played an important role and served as a novel biomarker in GC. Quantitative real time PCR (qRT-PCR) was used to measure the miR-497 expression in GC cell lines and 86 paired GC samples and we also analyzed its correlation with GC clinicopathological parameters. A series of cellular function experiments were applied to validate the effects of miR-497 on GC. In addition, methylation specific PCR (MSP) was applied to detect the gene methylation status. Finally, the correlation between miR-497 and the target gene was analyzed by western blotting assay. miR-497 was reduced obviously in GC cells and tissues and significantly associated with the pathologic stage. Low expression of miR-497 significantly inhibited the proliferation, invasion and migration of GC cell lines and accelerated apoptosis. Moreover, we found that the aberrant expression of miR-497 may be ascribed to DNA methylation. microRNA.org and luciferase reporter assay suggested that RAF1 was a direct target of miR-497 in GC. This study suggested that miR-497 could serve as a tumor suppressor and a potential early diagnostic marker of GC by targeting Raf-1 proto-oncogene, serine/threonine kinase (RAF1). PMID- 28586057 TI - MicroRNA-296-5p downregulated AKT2 to inhibit hepatocellular carcinoma cell proliferation, migration and invasion. AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy in men, and the seventh in women worldwide. Despite development in the therapy of HCC, the prognosis of HCC patients remains poor. Therefore, it is of great significance to explore the molecular mechanism underlying HCC progression, and investigate novel therapeutic strategies for the treatments of HCC. MicroRNAs (miRs) are known to be involved in the pathogenesis of HCC. The present study aimed to investigate the expression patterns and potential roles of miR-296-5p in HCC. Results revealed that miR-296-5p was frequently downregulated in HCC tissue samples and cell lines. Additionally, reduced miR-296-5p expression levels were correlated with tumor size, TNM stage and metastasis in HCC. Gain-of-function demonstrated that miR-296-5p inhibited HCC cell proliferation, migration and invasion in vitro. Furthermore, AKT2 was identified as a novel direct and functional target of miR-296-5p in HCC. These findings indicated that miR-296-5p/AKT2 axis serves important roles in HCC carcinogenesis and progression, and miR-296-5p/AKT2 based target therapy hampers HCC tumor growth and metastasis. PMID- 28586058 TI - 3,3'-diindolylmethane downregulates cyclin D1 through triggering endoplasmic reticulum stress in colorectal cancer cells. AB - As a major in vivo condensation product of indole-3-carbinol, which is mostly present in cruciferous vegetables, 3,3'-diindolylmethane (DIM) has been previously reported with anti-proliferative action in different types of cancer by our group and others. To further elucidate these underlying mechanisms, we examined the effect of DIM on cyclin D1, which was aberrantly overexpressed in various cancer cells and tumors. Herein, we found that DIM downregulated cyclin D1 expression in colorectal cancer cells (CRC), which was independent of PPARgamma expression and protease activity. Furthermore, DIM did not affect cyclin D1 mRNA expression, suggesting DIM modulated cyclin D1 expression at the translational level. Subsequently, blocking eIF2alpha phosphorylation resulted from endoplasmic reticulum (ER) stress restored cyclin D1 in the presence of DIM. Thus, the present study demonstrates that DIM downregulates cyclin D1 through triggering ER stress in human colorectal cancer cells. PMID- 28586059 TI - Identification of critical genes in nucleus pulposus cells isolated from degenerated intervertebral discs using bioinformatics analysis. AB - Intervertebral disc (IVD) degeneration is a pathological process, which may lead to lower back pain. The present study aimed to investigate the pathogenesis of IVD degeneration. GSE42611 was downloaded from Gene Expression Omnibus, including 4 nucleus pulposus samples isolated from degenerated IVDs and 4 nucleus pulposus samples separated from normal IVDs. The differentially expressed genes (DEGs) between the degenerated and normal samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted separately for the upregulated and downregulated genes, using Database for Annotation, Visualization and Integrated Discovery software. In addition, protein-protein interaction (PPI) networks were constructed using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. Finally, module analyses were conducted for the PPI networks using the MCODE plug-in in Cytoscape. A total of 558 DEGs were identified in the degenerated nucleus pulposus cells: 253 upregulated and 305 downregulated. Pathway enrichment analysis revealed that downregulated thrombospondin 1 (THBS1) was enriched in extracellular matrix-receptor interaction. Interleukin (IL)-6 in the PPI network for the upregulated genes and vascular endothelial growth factor A (VEGFA) in the PPI network for the downregulated genes had higher degrees. Additionally, four modules (uM1, uM2, uM3 and uM4) were identified from the PPI network for the upregulated genes. Four modules (dM1, dM2, dM3 and dM4) were identified from the PPI network for the downregulated genes. In the dM2 module, collagen genes and integrin subunit alpha4 (ITGA4) may interact with each other. Additionally, functional enrichment indicated that collagen genes were enriched in extracellular matrix organization. In conclusion, IL-6, VEGFA, THBS1, ITGA4 and collagen genes may contribute to the progression of IVD degeneration. These results suggested that the manipulation of these genes and their products may have potential as a novel therapeutic strategy for the treatment of patients with IVD. PMID- 28586060 TI - Potential role of autophagy in T-cell survival in polymyositis and dermatomyositis. AB - Peripheral blood T lymphocytopenia has previously been identified in polymyositis/dermatomyositis (PM/DM) patients. Therefore, the present study aimed to examine the potential role of autophagy in peripheral blood T cell survival in PM/DM patients. Transmission electron microscopy was used to detect the formation of autophagosomes of peripheral blood cluster of differentiation (CD)3+ T cells obtained from 24 patients with PM/DM and 21 healthy controls. Protein and mRNA expression levels of autophagy-related molecules were examined by western blot analysis and reverse transcription-quantitative polymerase chain reaction, respectively. The number of peripheral blood CD3+ T cells decreased significantly in PM/DM patients. The median percentage of apoptosis of CD3+ T cells in PM/DM patients was significantly increased compared with healthy controls. Furthermore, the number of autophagosomes and the expression of the autophagy markers microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin-1 were significantly reduced in the circulating CD3+ T cells of PM/DM patients compared with those of healthy controls. LC3 and Beclin-1 protein levels correlated negatively with apoptosis rates in circulating CD3+ T cells in patients with PM/DM. CD3+ T cells from PM/DM patients treated with rapamycin increased autophagy and decreased apoptosis compared with untreated cells (P<0.05). In conclusion, these results suggested that autophagy may serve a potential protective role in the peripheral blood T cells of patients with PM/DM. PMID- 28586061 TI - Chlorogenic acid prevents inflammatory responses in IL-1beta-stimulated human SW 1353 chondrocytes, a model for osteoarthritis. AB - Chlorogenic acid (CGA), which is a natural compound found in various plants, has been reported to exert notable anti-inflammatory activities. The present study investigated the effects and underlying mechanism of CGA on interleukin (IL) 1beta-induced osteoarthritis (OA) chondrocytes. An in vitro OA-like chondrocyte model was established using IL-1beta-stimulated human SW-1353 chondrocytes. Cell viability was assessed using an MTT assay. Nitric oxide (NO) and IL-6 production were evaluated by Griess reaction and ELISA, respectively. The expression levels of inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), collagen II, matrix metalloproteinase (MMP)-13, p65 nuclear factor (NF)-kappaB and inhibitor-kappaBalpha were detected by western blot analysis. The results indicated that CGA reversed IL-1beta-induced increases in iNOS/NO, IL-6, MMP-13 and COX-2/PGE2 production, and reversed the IL-1beta mediated downregulation of collagen II. In addition, the data suggested that CGA was capable of inhibiting the IL-1beta-induced inflammatory response, at least partially via the NF-kappaB signaling pathway. In conclusion, CGA may be considered a suitable candidate agent in the treatment of OA. PMID- 28586062 TI - Therapy-relevant aberrant expression of MRP3 and BCRP mRNA in TCC-/SCC-bladder cancer tissue of untreated patients. AB - Multidrug resistance (MDR) is a critical factor, which results in suboptimal outcomes in cancer chemotherapy. One principal mechanism of MDR is the increased expression of ATP-binding cassette (ABC) transporters. Of these, multidrug resistance-associated protein 3 (MRP3) and breast cancer resistance protein (BCRP) confer MDR when overexpressed in cancer cell lines. We measured the mRNA expression of MRP3 and BCRP in primary untreated bladder cancer specimens using reverse transcription-quantitative PCR (RT-qPCR) in comparison to normal bladder tissue. The MRP3 and BCRP expression in the two major histotypes of bladder cancer; transitional cell carcinoma (TCC; urothelial type of bladder cancer) and squamous cell carcinoma (SCC; 'Schistosoma-induced' bladder cancer) were compared. Furthermore, the association between MRP3 and BCRP expression and tumor grade and stage were investigated. MRP3 mRNA expression in bladder cancer specimens was increased ~13-fold on average compared to normal bladder tissue (n=36, P<0.0001). BCRP mRNA expression was decreased in bladder cancer specimens to ~1/5 on average, compared to normal bladder tissue (n=38, P<0.0001). TCC showed significantly increased MRP3 mRNA expression compared to SCC of the bladder (P<0.0001). BCRP mRNA expression was similar in TCC and SCC of the bladder (P=0.1072). The increased MRP3 mRNA expression was not related to bladder tumor grade (P=0.3465) but was, however, significantly higher in superficial than in invasive bladder tumors (P=0.0173). The decreased expression of BCRP was not related to bladder tumor grade (P=0.1808) or stage (P=0.8016). The current data show that bladder cancer is associated with perturbed expression of MRP3 and BCRP. Representing drug resistance factors, determining the expression of these transporters in native tumors may be predictive of the outcome of chemotherapy based-treatment of bladder cancer. PMID- 28586063 TI - MYC and hsa-miRNA-423-5p as biomarkers in nasopharyngeal carcinoma revealed by miRNA-mRNA-pathway network integrated analysis. AB - The present study was performed to identify the dysregulated microRNAs (miRNAs/miRs) and mRNAs, and enriched pathways involved in nasopharyngeal carcinoma (NPC) through the establishment of an miRNA-mRNA-pathways network. mRNA and miRNA expression profiles were collected from the European Molecular Biology Laboratory-European Bioinformatics Institute. Differentially expressed genes and differentially expressed miRNA were selectively screened using the metaDE package. Following prediction of the risk genes and pathway pairs involved in NPC, an miRNA-mRNA-pathway network was constructed by merging the miRNA-mRNA pairs, the mRNA-pathway pairs and the mRNA-mRNA pairs. The miRNA and mRNA biomarkers, as well as the functional pathway pairs, were identified in the network analysis, based on the topological properties of nodes in the network. Additionally, 10-fold cross-validation was performed to evaluate the performance of the selected risk genes and their corresponding miRNA in NPC by calculating the area under the curve (AUC). In total, 99 upregulated and 841 downregulated genes, and 192 upregulated and 26 downregulated miRNAs were identified. The miRNA mRNA-pathway network was established using 403 miRNA-mRNA pairs, including 40 miRNAs and 302 risk genes, as well as 22 prominent pathway pairs. Network analysis demonstrated that v-myc avian myelocytomatosis viral oncogene homolog (MYC) and hsa-miR-423-5p were the mRNA and miRNA signatures for NPC, respectively. The AUC of these biomarkers for NPC was 0.7568 and 0.7798, respectively. Additionally, the focal adhesion pair pathway in cancer was identified to be associated with NPC. MYC and hsa-miR-423-5p have been identified to be critical biomarkers in NPC as revealed by miRNA-mRNA-pathway network integrated analysis, suggesting a direction for further research into the diagnosis and treatment of NPC. PMID- 28586064 TI - MicroRNA-210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells. AB - Radiotherapy is one of the primary methods of treatment of malignant tumors, however, resistance to radiation is a major problem. The reasons for the radioresistance are still poorly understood. However, it is generally accepted that microRNAs (miRNAs or miRs) can regulate the radiosensitivity of tumors. The present study therefore aimed to identify specific miRNAs and their effects on radioresistant cells. More specifically, the aim was to investigate specific miRNAs and their effects on radioresistant tumor cells. The radioresistant tumor cells (CNE-2R) were established using a dose gradient method, and the miRNA expression profiles of CNE-2R cells and the parental cells (CNE-2) were determined. The expression of miR-210 in CNE-2R cells was significantly higher than in CNE-2 cells. CNE-2R cells were transfected with LV-hsa-miR-210-inhibitor, and CNE-2 cells were transfected with LV-hsa-miR-210. The expression of miR-210 was confirmed by reverse transcription quantitative-polymerase chain reaction. The percentages of CNE-2R-miR-210-inhibitor and CNE-2 cells in the G2/M phase were higher than in the CNE-2R and CNE-2-miR-210 cells, and the percentages of cells in S phase were lower than in the CNE-2R and CNE-2-miR-210 cells. Following 4 Gy of radiation, CNE-2R-miR-210-inhibitor and CNE-2 cells, which express low levels of miR-210, had a higher apoptosis rate than CNE-2R and CNE-2-miR-210 cells. Following 4, 8 and 12 Gy of radiation, cell viability and survival fraction of CNE-2R-miR-210-inhibitor cells were lower than those of CNE-2R and CNE-2-miR-210 cells, and similar to those of CNE-2 cells. Together, these findings strongly suggest that miR-210 negatively regulates the radiosensitivity of tumor cells, and may therefore have therapeutic potential for the treatment of radiation resistance. PMID- 28586065 TI - Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents. AB - It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)-induced PH in rats and chronic hypoxia-induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c-Jun N-terminal kinase 1/2 and extracellular signal-regulated kinase 1/2 signaling pathways and significantly reduced MCT-induced upregulation of pulmonary matrix metalloproteinases-2 and -9, and transforming growth factor-beta1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH. PMID- 28586066 TI - MicroRNA-148a suppresses epithelial-mesenchymal transition and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/beta-catenin signaling pathway. AB - Epithelial-mesenchymal transition (EMT) plays a critical role in the process of cancer invasion and metastasis. The Wnt/beta-catenin signaling pathway is known as a stimulative factor, which may trigger EMT and metastasis of cancer cells. In addition, several microRNAs (miRNAs) have been proven to regulate the EMT process. Recent research revealed that miR-148a is downregulated in pancreatic cancer. However, the definite role of miR-148a in EMT and invasion of pancreatic cancer is still unknown. The present study attempted to demonstrate the underlying mechanism of miR-148a in the regulation of EMT and invasion of pancreatic cancer cells. Our data revealed that the expression of miR-148a was markedly downregulated in human pancreatic ductal adenocarcinoma (PDAC) cell lines and tissues. In addition, the downregulation of miR-148a was associated with poor prognosis and EMT phenotype. Furthermore, restoration of miR-148a expression inhibited the EMT process, as well as the migration and invasion of BxPC-3 pancreatic cancer cells. Wnt10b, a promoting molecule of the Wnt/beta catenin signaling pathway, was demonstrated by dual-luciferase reporter assay to be a direct target of miR-148a. Subsequently, we found that miR-148a negatively regulated the protein expression of beta-catenin, cyclin D1 and MMP-9, which were important components of the Wnt/beta-catenin signaling pathway. In conclusion, these findings revealed that miR-148a suppresses EMT and invasion of pancreatic cancer cells by targeting Wnt10b and inhibiting the Wnt/beta-catenin signaling pathway, and thus, miR-148a may serve as a novel therapeutic target for pancreatic cancer. PMID- 28586067 TI - Prognosis genes in gastric adenocarcinoma identified by cross talk genes in disease-related pathways. AB - The aim of the present study was to investigate the prognostic value of genes that participate in the development of gastric adenocarcinoma, via exploring gene cross talk in disease-related pathways. Differentially expressed genes (DEGs) in the gastric samples were identified by analyzing the expression data downloaded from the GEO database. The DEGs were subjected to the human protein-protein interaction (PPI) network to construct the PPI network of DEGs, which was then used for the identification of key genes in cancer samples via the expression deviation score and degree in the network. A total of 635 DEGs, including 432 downregulated and 203 upregulated ones were screened in the gastric adenocarcinomas samples. The PPI network of DEGs comprised 590 DEGs and 4,299 interaction pairs. A total of 200 key genes were obtained, which were significantly enriched in six downregulated and six upregulated pathways. Cross talk genes in the connected pathways were analyzed, and the Kyoto Encyclopedia of Genes and Genomes pathways hsa00980 (Metabolism of xenobiotics by cytochrome P450) and hsa00982 (Drug metabolism) were reported to share 8 cross talk genes: ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B and CYP2C18. Among all cross talk genes, ADH7, ALDH3A1 and CLDN3 were the most specific genes. The high- and low-risk samples identified by the prognosis model presented a remarkable difference in total survival time, indicating its robustness and sensitivity as the prognosis genes for gastric adenocarcinoma. ADH7, ALDH3A1, GSTA1, GSTA2, UGT2B17, UGT2B10, ADH1B, CYP2C18ADH7, ALDH3A1 and CLDN3 may be used as the prognosis markers and target biomarkers for chemotherapies in gastric adenocarcinoma. PMID- 28586068 TI - Sulforaphane increases Nrf2 expression and protects alveolar epithelial cells against injury caused by cigarette smoke extract. AB - Cigarette smoking is a primary risk factor for chronic obstructive pulmonary disease (COPD), as it damages epithelial cells through a variety of mechanisms. Sulforaphane (SFN) is an antioxidant agent, which exerts protective effects against cell damage by activating the nuclear factor erythroid 2 like 2 (NFE2L2; Nrf2). The present study was undertaken to investigate the effects and underlying mechanisms of SFN in preventing cigarette smoke extract (CSE)-induced oxidative damage to RLE-6TN rat lung epithelial cells. MTT assay was used to determine the cytotoxicity of SFN and CSE. The effect of SFN and CSE on cell cycle progression, apoptosis and intracellular reactive oxygen species (ROS) levels were analyzed using flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to quantify mRNA and protein expression levels of Nrf2 respectively. SFN protected RLE-6TN cells from oxidative damage, potentially via increasing Nrf2 expression and reducing ROS levels. In addition, SFN attenuated G1 phase cell cycle arrest and abrogated apoptosis. Therefore, SFN protected alveolar epithelial cells against CSE-induced oxidative injury by upregulating Nrf2 expression. The results of the present study may provide theoretical support for the clinical use of SFN in patients with COPD. PMID- 28586069 TI - miR-203 inhibits the expression of collagen-related genes and the proliferation of hepatic stellate cells through a SMAD3-dependent mechanism. AB - Activation of hepatic stellate cells (HSCs) is a pivotal event during hepatic fibrogenesis. Activated HSCs are the main source of collagen and other extracellular matrix (ECM) components, and emerging antifibrotic therapies are aimed at preventing ECM synthesis and deposition. MicroRNAs (miRNAs) have been demonstrated to exert regulatory effects on HSC activation and ECM synthesis. In the present study, the HSC-T6 rat hepatic stellate cell line was transiently transfected with a miRNA (miR)-203 mimic, which is an artificial miRNA that enhances the function of miR-203, with a miR-203 inhibitor or with a scramble miRNA negative control. mRNA and protein expression levels of collagen (COL) 1A1, COL3A1, alpha-smooth muscle actin (alpha-SMA) and mothers against decapentaplegic homolog 3 (SMAD3) were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The interaction between miR-203 and the 3'-untranslated region (UTR) of SMAD3 mRNA was examined using a dual-luciferase reporter assay. The proliferative capabilities of activated HSCs were measured using an MTT assay. The present results demonstrated that the mRNA and protein expression levels of COL1A1, COL3A1, alpha-SMA and SMAD3 were significantly upregulated following transfection of HSC-T6 cells with the miR-203 inhibitor. Conversely, COL1A1, COL3A1, alpha SMA, and SMAD3 mRNA and protein expression appeared to be downregulated in rat HSCs transfected with miR-203 mimics. Notably, the inhibition of miR-203 expression was revealed to promote HSC proliferation, whereas increased miR-203 expression suppressed the proliferative capabilities of HSC-T6 cells. Furthermore, SMAD3 was revealed to be a direct target of miR-203. The present study suggested that miR-203 may function to prevent the synthesis and deposition of ECM components, including COL1A1, COL3A1 and alpha-SMA, and to inhibit the proliferation of HSCs through a SMAD3-dependent mechanism. Therefore, it may be hypothesized that miR-203 has potential as a novel target for the development of alternative therapeutic strategies for the treatment of patients with hepatic fibrosis in clinical practice. PMID- 28586070 TI - Protective effect of diethylcarbamazine inhibits NF-kappaB activation in isoproterenol-induced acute myocardial infarction rat model through the PARP pathway. AB - The present study investigated the protective effect of diethylcarbamazine in inhibiting nuclear factor (NF)-kappaB activation in isoproterenol-induced acute myocardial infarction (AMI) rats through the poly ADP ribose polymerase (PARP) pathway. Male albino Wistar rats were injected subcutaneously with isoproterenol (100 mg/kg/day) for 2 days to induce an AMI model. Diethylcarbamazine (50 mg/kg) was administered by gavage for 12 days prior to the isoproterenol-induced AMI. It was noted that diethylcarbamazine significantly inhibited AMI-induced casein kinase and lactate dehydrogenase levels, and reduced the AMI-induced wet heart weight to body weight ratio in AMI rats. Diethylcarbamazine treatment significantly weakened reactive oxygen species production and reduced the levels of tumor necrosis factor (TNF)-alpha, interleukin-6 and NF-kappaB/p65 in AMI rats. Western blotting demonstrated that diethylcarbamazine significantly suppressed the AMI-induced inducible nitric oxide synthase (iNOS), transforming growth factor (TGF)-beta1, cyclooxygenase-2 (COX-2) and PARP protein expression in AMI rats. The results demonstrated that the protective effect of diethylcarbamazine inhibited isoproterenol-induced AMI through the suppression of inflammation, iNOS, TGF-beta1, COX-2 and the PARP pathway, and revealed the clinical potential of diethylcarbamazine for therapeutic and clinical applications. PMID- 28586072 TI - Treatment of colon cancer cells with 5-fluorouracil can improve the effectiveness of RNA-transfected antitumor dendritic cell vaccine. AB - Non-cytotoxic concentrations of selected chemotherapeutic agents amplify the antigen presentation capacity of dendritic cells (DCs) and are able to increase the immunogenicity of the colon cancer cell lineage HCT-116, as previously demonstrated by our group. Since this functional alteration was associated with changes in gene expression, we aimed to evaluate whether transcriptional changes of tumor cells can be transferred to DCs, increasing their ability to induce a specific antitumor response. Therefore, HCT-116 cells were treated with two different concentrations of 5-fluorouracil (5-FU), and their total RNA was transfected into human monocyte-derived DC, which function was evaluated through their ability to stimulate the proliferation of normal allogeneic T lymphocytes (MLR), and to generate cytolytic T cells. The transfected DCs demonstrated an increased percentage of CD83+, HLA-DR+, CD80+ and CD86+ cells. These phenotypical changes were followed by functional improvement demonstrated by the increased capacity of these DC to induce allogeneic T cell proliferation and to generate specific anti-HCT-116 cytolytic T cells, as demonstrated by IFN-gamma production following in vitro challenge with tumor cells. Our results allow us to conclude that treatment of tumor cells with a non-toxic concentration of 5-FU induces immunogenic changes that are transferred to DC by transfection of total RNA. PMID- 28586071 TI - A comparative study of the influence of two types of PHEMA stents on the differentiation of ASCs to myocardial cells. AB - In the present study, subcutaneous fat was obtained from adult women that had undergone conventional liposuction surgery. A comparative study was performed to investigate the effect of transparent and white poly-beta-hydroxyethyl methacrylate (PHEMA) stents, which have different surface and cross-sectional morphological characteristics, on the differentiation of adipose-derived stem cells (ASCs) into myocardial cells. The cell counting kit-8 assay revealed that cell growth increased at varying rates among the different treatment groups. The absorbance of the experimental transparent PHEMA treated group increased in a time-dependent manner with the duration of incubation. The highest levels of proliferation were observed in the transparent PHEMA group. In addition, the transparent PHEMA treated group exhibited the strongest cell adhesion ability, which was significantly different to that of the white PHEMA group (P<0.01 and P<0.05 for Matrigel and fibronectin assay, respectively). Comparisons between the two stent materials with the inducer control group revealed statistically significant differences in the rate of ASC differentiation (P<0.05). The level of differentiation was the greatest in the transparent PHEMA group, and was significantly different to the white PHEMA group (P<0.05) and the blank control group (P<0.01). The results suggest that the inducers 5-aza-2-deoxycytidin and laminin, and material microstructure stents effectively promote the proliferation, growth and adhesion of ASCs. However, the transparent material microstructure may be a more suitable candidate for ASC-associated injections. The present study provides further evidence that a PHEMA stent structure, comprised of a high number of matrixes and a low water content, induces a high level of ASC differentiation to myocardial cells. PMID- 28586074 TI - Microarray expression profile of long non-coding RNAs in paclitaxel-resistant human lung adenocarcinoma cells. AB - Paclitaxel (PTX)-based chemotherapy is a standard treatment for human lung adenocarcinoma, but treatment often fails since resistance develops. Recent studies have described the activity of long non-coding RNAs (lncRNAs) in many biological processes and human diseases. Chemotherapy resistance is one of these areas, but the role of lncRNAs in paclitaxel resistance of human lung adenocarcinoma cells has not been reported. A paclitaxel resistance model was established using A549 human lung adenocarcinoma cells. lncRNAs and mRNAs were profiled in parental A549 and paclitaxel-resistant A549/PTX cells by microarray analysis. Real-time quantitative PCR (RT-qPCR) was used to validate the results of the microarray. Chromosomal distribution patterns of differentially expressed lncRNAs and mRNAs were assessed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using gene set enrichment. We screened 1,154 lncRNAs and 1,733 mRNAs that had a >3-fold difference in expression in A549/PTX cells compared with A549 cells, most of which were downregulated. Nine lncRNAs and six mRNAs were randomly selected and validated by RT-qPCR. Most aberrantly expressed lncRNAs and mRNAs were located on chromosomes 1, 2, 6, 12 and 17, particularly on chromosome 1. Bioinformatics, GO and KEGG pathway analyses, revealed that some differentially expressed genes regulated classical functions and pathways such as cytosol components, protein binding, gene expression and metabolic pathways. Differential expression of lncRNAs and mRNAs in A549/PTX and A549 cells indicates that various lncRNAs may be useful diagnostic or prognostic markers of resistance to treatment, or future targets for paclitaxel-based chemotherapy, providing a novel rationale for clinical treatment. PMID- 28586073 TI - Effects of the Tangningtongluo formula as an alternative strategy for diabetics via upregulation of insulin receptor substrate-1. AB - Tangningtongluo (TNTL), a traditional Chinese medicine, has been widely used in clinics for decades in southwest China. Its pharmacological properties and underlying molecular mechanisms remain unclear. The main goal of ethnopharmacology is to identify novel bioactive compounds derived from plants for use in indigenous medical practice. This knowledge can be used to develop novel pharmaceuticals. In the present study, hyperglycemic C57BL/KsJ-db/db (db/db) mice were used to test the effect of TNTL on microvasculature of the retina and hypoglycemia. Metformin (Met) was selected as a positive control. 26 week-old mice were randomly assigned to receive either the anti-diabetic agent Met [140 mg/kg body weight (BW)], 1.8, 0.9 or 0.45 g/kg BW TNTL, or a placebo. The fasting blood glucose, serum insulin and glycated hemoglobin levels were measured. Histopathologic examination of the pancreas was performed to confirm the hypoglycemic effect. Fluorescein angiography was applied to detect diabetes induced retinal angioma in the db/db mice. TNTL intake significantly decreased the fasting blood glucose level in a dose-dependent manner. Additionally, TNTL intervention resulted in a significant decrease in the insulin resistance index. Notably, TNTL treatment markedly reduced the speed of retinal degeneration and mildly reversed microvascular caliber degeneration. Western blot analysis indicated that upregulation of phosphorylated insulin receptor substrate-1 (p-IRS 1) by the administration of TNTL may be strongly involved in the improvement of insulin resistance. In conclusion, TNTL exerted a strong hypoglycemic effect and reversed retinal degeneration via upregulation of ISR-1. The present findings provide important scientific evidence supporting TNTL as an effective alternative approach for the management of Type 2 diabetes mellitus. PMID- 28586075 TI - [The mountain of waste in Swedish surgery]. PMID- 28586076 TI - ? PMID- 28586078 TI - ? PMID- 28586079 TI - [Health care must be recognized as a universal human right]. PMID- 28586077 TI - [Organ donation - follow France!]. PMID- 28586080 TI - [Place pediatrics and child psychiatry at "the same table"]. PMID- 28586081 TI - ? AB - Assessment of neurologic prognosis after cardiac arrest. Updated recommendations from the Swedish CPR Council Expert Group European Resuscitation Council (ERC) issued updated guidelines for postresuscitation care in 2015. This paper provides updated Swedish recommendations for neurological prognostication of patients remaining unconscious after cardiac arrest (CA). The prognostication should be based on independent methods; clinical and neurophysiological examinations, imaging and biomarkers. It should not be performed earlier than three days after CA and any influence from sedatives must be negligible. Bilateral absence of both corneal and pupillary reflexes and bilaterally absent Somatosensory Evoked N20 Potentials (SSEP) at 72 hours are reliable predictors of poor outcome but the ocular reflexes have limited sensitivity and SSEP has limited availability. Hence, further delay of at least 24 hours and combinations of findings from multiple methods are often needed for reliable prognostication. If firm evidence of a poor prognosis is lacking four days after CA, further expectation with repeated examinations is recommended. PMID- 28586082 TI - ? AB - Sex chromosome abnormalities are among the most common genetic changes. The manifestations vary and may include growth abnormalities, specific appearance features, and other endocrinological and physical disorders, but also delayed psychomotor development, learning disabilities, and psychiatric conditions including ADHD and autism spectrum disorders. Increased knowledge about the relationship between sex chromosome abnormalities, development and psychiatric conditions would enable improved care of these patients. PMID- 28586083 TI - [Active follow-up after suicide attempts has a preventive effect]. PMID- 28586084 TI - The iterative process in the development of a parent-reported questionnaire for children with unilateral paresis. PMID- 28586086 TI - Young Children's Moral Judgments, Justifications, and Emotion Attributions in Peer Relationship Contexts. AB - Children (n = 160, 4- to 9-year-olds; Mage = 6.23 years, SD = 1.46) judged, justified, attributed emotions, and rated intent for hypothetical physical harm, psychological harm, and resource distribution transgressions against close friends, acquaintances, disliked peers, or bullies. Transgressions against bullies were judged more acceptable than against friends and disliked peers and less deserving of punishment than against acquaintances and disliked peers. Transgressions against friends were judged least intended and resulting in more negative emotions for transgressors; actors transgressing against disliked peers, as compared to bullies or acquaintances, were happy victimizers. Across relationships, children viewed moral transgressions as wrong independent of rules and authority, based primarily on welfare and fairness justifications. Peer context colors but does not fundamentally change moral evaluations. PMID- 28586085 TI - Enrichment of IL-17A+ IFN-gamma+ and IL-22+ IFN-gamma+ T cell subsets is associated with reduction of NKp44+ ILC3s in the terminal ileum of Crohn's disease patients. AB - Crohn's disease (CD) is a chronic inflammatory condition of the human gastrointestinal tract whose aetiology remains largely unknown. Dysregulated adaptive immune responses and defective innate immunity both contribute to this process. In this study, we demonstrated that the interleukin (IL)-17A+ interferon (IFN)-gamma+ and IL-22+ IFN-gamma+ T cell subsets accumulated specifically in the inflamed terminal ileum of CD patients. These cells had higher expression of Ki 67 and were active cytokine producers. In addition, their proportions within both the IL-17A-producer and IL-22-producer populations were increased significantly. These data suggest that IL-17A+ IFN-gamma+ and IL-22+ IFN-gamma+ T cell subsets might represent the pathogenic T helper type 17 (Th17) population in the context of intestinal inflammation for CD patients. In the innate immunity compartment we detected a dramatic alteration of both phenotype and function of the intestinal innate lymphoid cells (ILCs), that play an important role in the maintenance of mucosal homeostasis. In the inflamed gut the frequency of the NKp44- CD117- ILC1s subset was increased significantly, while the frequency of NKp44+ ILC3s was reduced. Furthermore, the frequency of human leucocyte antigen D-related (HLA-DR) expressing-NKp44+ ILC3s was also reduced significantly. Interestingly, the decrease in the NKp44+ ILC3s population was associated with an increase of pathogenic IL-17A+ IFN-gamma+ and IL-22+ IFN-gamma+ T cell subsets in the adaptive compartment. This might suggest a potential link between NKp44+ ILC3s and the IL-17A+ IFN-gamma+ and IL-22+ IFN-gamma+ T cell subsets in the terminal ileum of CD patients. PMID- 28586087 TI - Waiting for the Second Treat: Developing Culture-Specific Modes of Self Regulation. AB - The development of self-regulation has been studied primarily in Western middle class contexts and has, therefore, neglected what is known about culturally varying self-concepts and socialization strategies. The research reported here compared the self-regulatory competencies of German middle-class (N = 125) and rural Cameroonian Nso preschoolers (N = 76) using the Marshmallow test (Mischel, 2014). Study 1 revealed that 4-year-old Nso children showed better delay-of gratification performance than their German peers. Study 2 revealed that culture specific maternal socialization goals and interaction behaviors were related to delay-of-gratification performance. Nso mothers' focus on hierarchical relational socialization goals and responsive control seems to support children's delay-of gratification performance more than German middle-class mothers' emphasis on psychological autonomous socialization goals and sensitive, child-centered parenting. PMID- 28586088 TI - Optimal timing for hepatitis C antiviral therapy in the peritransplant period? PMID- 28586089 TI - Reply. PMID- 28586091 TI - Mutant PNPLA3 I148M protein as pharmacological target for liver disease. PMID- 28586092 TI - Quantitative skin assessment using spatial frequency domain imaging (SFDI) in patients with or at high risk for pressure ulcers. AB - BACKGROUND AND OBJECTIVE: Pressure ulcers (PU) are a significant problem facing the health system in the United States. Here, we present preliminary case studies demonstrating feasibility of Spatial Frequency Domain Imaging (SFDI) to assess skin status in high-risk populations and pre-existing wounds. SFDI is a wide field non-contact optical imaging technology that uses structured light to obtain tissue optical properties and of tissue constituents. This study aims to determine the fit of SFDI for PU care and determine the next steps. STUDY DESIGN/MATERIALS AND METHODS: Patients at risk for pressure ulcers were imaged using a near-infrared SFDI system. SFDI-derived images of tissue function (tissue hemoglobin, tissue oxygen saturation) and structure (tissue scattering) were then compared to each other as well as a blinded dermatologist's clinical impressions. RESULTS: Four case series were chosen to demonstrate the imaging capability of this technology. The first scenario demonstrates normal skin of three patients without skin breakdown with spatially uniform measures of tissue oxygen saturation, scattering, and blood volume. The second scenario demonstrates a stage II PU; the third case shows non-blanchable erythema of an unstageable PU; a fourth scenario is a clinically indistinguishable skin rash versus early stages of a PU. In all these cases, we observe spatial changes in tissue constituents (decrease in tissue oxygen saturation, increased blood pooling, decreased scattering). CONCLUSION: We have presented the first use of SFDI for pressure ulcer imaging and staging. This preliminary study demonstrates the feasibility of this optical technology to assess tissue oxygen saturation and blood volume status in a quantitative manner. With the proposed improvements in modeling and hardware, SFDI has potential to provide a means for pressure ulcer risk stratification, healing and staging. Lasers Surg. Med. 49:827-834, 2017 (c) 2017 Wiley Periodicals, Inc. PMID- 28586090 TI - The association of QRS duration with atrial fibrillation in a heart failure with preserved ejection fraction population: a pilot study. AB - BACKGROUND: Heart failure is a significant cause of morbidity and mortality, yet patient risk stratification may be difficult. Prevention or treatment of atrial fibrillation (AF) may be an important strategy in these patients that could positively affect their outcome. It has been demonstrated that in patients with systolic dysfunction, prolonged QRS duration (QRSd), an easily measured electrocardiographic parameter, is associated with AF. HYPOTHESIS: Prolonged QRSd is associated with an increase in prevalence of AF in patients with heart failure with preserved ejection fraction(HFPEF). METHODS: Between February 2006 and February 2009, 718 patients were discharged with a diagnosis of HF from the Dartmouth-Hitchcock Medical Center. Of these, 206 had EF >=50% by echocardiography performed within 72 hours of admission. After exclusions, 82 patients remained, of which 25 had AF and 57 had sinus rhythm. Characteristics of the AF and sinus-rhythm patients were compared in this pilot study. RESULTS: After adjustment for age, prior diagnosis of HF, and left atrial area, there was a nonsignificant trend (odds ratio: 2.2, 95% CI of 0.3-17.2) for a QRSd >120 ms to be associated with AF. CONCLUSIONS: Similar to results in patients with systolic dysfunction, patients with preserved EF may have an association between a prolonged QRSd and AF. PMID- 28586093 TI - Agreement between jaw-muscle activity measurement with portable single-channel electromyography and polysomnography in children. AB - BACKGROUND: Polysomnography (PSG) is the gold standard for sleep bruxism (SB) assessment. High economical costs, complex technical equipment, and unfamiliar laboratory setting limit its use in children. AIM: To determine the night-to night variability of electromyography (EMG) episodes during a five-night recording with the GrindCare Measure (GCM), and the agreement in the assessment of masticatory muscle activity (MMA) between GCM and PSG in children. DESIGN: Forty-seven children from clinics of Universidad CES participated. Each participant was assessed with GCM for five consecutive nights. The last night, children underwent a single-night PSG study, together with the GCM. Spearman correlation coefficients were used to analyze data. RESULTS: The frequency of SB occurrence was 'sometimes' in 12 (25.5%) and 'usually' in 19 (40.4%) children. Simultaneous measurements with GCM and PSG obtained during the fifth night of measurement were not significantly correlated. Correlation between GCM total EMG episodes and EMG episodes/h and PSG total SB episodes, SB episodes/h, total bursts and burst/h measured with PSG was also not significant. CONCLUSION: EMG measurement with GCM was not accurate to detect PSG/SB in children. There was not advantage of multiple assessment for five nights with GCM, reducing the impact of night-to-night EMG episodes' variability on the GCM/PSG correlation. PMID- 28586094 TI - Disparities in liver cancer occurrence in the United States by race/ethnicity and state. AB - Liver cancer is highly fatal, and death rates in the United States are increasing faster than for any other cancer, having doubled since the mid-1980s. In 2017, it is estimated that the disease will account for about 41,000 new cancer cases and 29,000 cancer deaths in the United States. In this article, data from the Surveillance, Epidemiology, and End Results (SEER) Program and the National Center for Health Statistics are used to provide an overview of liver cancer incidence, mortality, and survival rates and trends, including data by race/ethnicity and state. The prevalence of major risk factors for liver cancer is also reported based on national survey data from the Centers for Disease Control and Prevention. Despite the improvement in liver cancer survival in recent decades, only 1 in 5 patients survives 5 years after diagnosis. There is substantial disparity in liver cancer death rates by race/ethnicity (from 5.5 per 100,000 in non-Hispanic whites to 11.9 per 100,000 in American Indians/Alaska Natives) and state (from 3.8 per 100,000 in North Dakota to 9.6 per 100,000 in the District of Columbia) and by race/ethnicity within states. Differences in risk factor prevalence account for much of the observed variation in liver cancer rates. Thus, in contrast to the growing burden, a substantial proportion of liver cancer deaths could be averted, and existing disparities could be dramatically reduced, through the targeted application of existing knowledge in prevention, early detection, and treatment, including improvements in vaccination against hepatitis B virus, screening and treatment for chronic hepatitis C virus infections, maintaining a healthy body weight, access to high-quality diabetes care, preventing excessive alcohol drinking, and tobacco control, at both the state and national levels. CA Cancer J Clin 2017;67:273-289. (c) 2017 American Cancer Society. PMID- 28586096 TI - Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted. PMID- 28586095 TI - CMV drives the expansion of highly functional memory T cells expressing NK-cell receptors in renal transplant recipients. AB - Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post-transplant. We describe how active and latent CMV affect T-cell subsets in RTRs who are stable on maintenance therapy. T-cell responses to CMV were assessed in RTRs (n = 54) >2 years post-transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8+ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T-cell (TEM ), terminally differentiated T-cell (TEMRA ) and CD57+ TEMRA cell populations. Expression of NK-cell receptors, LIR-1 and KLRG1 on CD4+ and CD8+ CD57+ TEM and TEMRA cells correlated with elevated interferon-gamma and cytotoxic responses to anti-CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8+ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) 1 peptides. The data show that latent and active CMV infection can alter T-cell subsets in RTRs many years after transplantation, and up-regulate T-cell expression of NK-cell receptors. This may enhance effector responses of CD4+ and CD8+ T cells against CMV. PMID- 28586097 TI - Genome-wide analysis of specific alterations in transcript structure and accumulation caused by nutrient deficiencies in Arabidopsis thaliana. AB - The alteration of transcript structure contributes to transcriptome plasticity. In this study, we analyzed the genome-wide response of exon combination patterns to deficiencies in 12 different nutrients in Arabidopsis thaliana roots. RNA sequencing analysis and bioinformatics using a simulation survey revealed more than 600 genes showing varying exon combinations. The overlap between genes showing differential expression (DE) and genes showing differential exon combination (DC) was notably low. Additionally, gene ontology analysis showed that gene functions were not shared between the DE and DC genes, suggesting that the genes showing DC had different roles than those showing DE. Most of the DC genes were nutrient specific. For example, two homologs of the MYB transcription factor genes MYB48 and MYB59 showed differential alternative splicing only in response to low levels of potassium. Alternative splicing of those MYB genes modulated DNA-binding motifs, and MYB59 is reportedly involved in the inhibition of root elongation. Therefore, the increased abundance of MYB isoforms with an intact DNA-binding motif under low potassium may be involved in the active inhibition of root elongation. Overall, we provide global and comprehensive data for DC genes affected by nutritional deficiencies, which contribute to elucidating an unknown mechanism involved in adaptation to nutrient deficiency. PMID- 28586099 TI - Benchmarking Discount Rate in Natural Resource Damage Assessment with Risk Aversion. AB - Benchmarking a credible discount rate is of crucial importance in natural resource damage assessment (NRDA) and restoration evaluation. This article integrates a holistic framework of NRDA with prevailing low discount rate theory, and proposes a discount rate benchmarking decision support system based on service-specific risk aversion. The proposed approach has the flexibility of choosing appropriate discount rates for gauging long-term services, as opposed to decisions based simply on duration. It improves injury identification in NRDA since potential damages and side-effects to ecosystem services are revealed within the service-specific framework. A real embankment case study demonstrates valid implementation of the method. PMID- 28586098 TI - Diastolic Dysfunction of Hypertrophic Cardiomyopathy Genotype-Positive Subjects Without Hypertrophy Is Detected by Tissue Doppler Imaging: A Systematic Review and Meta-analysis. AB - OBJECTIVES: To evaluate whether diastolic dysfunction derived by tissue Doppler imaging (TDI) would be an earlier manifestation in genotype-positive hypertrophic cardiomyopathy (HCM) subjects without left ventricular hypertrophy (LVH). METHODS: We systematically searched Pubmed, Medline, and Web of Science with an upper date limit of June 2016 for studies evaluating the diastolic function of HCM genotype-positive subjects without hypertrophy (G+/LVH-). Based on the inclusion criteria, eligible studies were selected. The quality of selected studies was assessed by the Newcastle-Ottawa Scale before being included in the meta-analysis. The statistic data such as weighted mean difference (WMD) and 95% confidence interval (CI) were calculated by Stata 12.0 software. RESULTS: Seventeen studies were included in the systematic review, and 12 were finally involved in the meta-analysis. The G+/LVH- subjects showed decreased Ea derived by TDI on both the interventricular septum (WMD [95% CI] = -1.822 [-3.104, 0.541]) and lateral wall (WMD [95% CI] = -2.269 [-3.820, -0.719]), and increased E/Ea on both interventricular septum (WMD [95% CI] = 1.363 [0.552, 2.174]) and lateral (WMD [95% CI] = 1.339 [0.386, 2.293]) wall. CONCLUSIONS: Tissue Doppler imaging-derived diastolic dysfunction can be found in HCM genotype-positive subjects without hypertrophy. PMID- 28586100 TI - Obstructive sleep apnea is associated with increased readmission in heart failure patients. AB - BACKGROUND: Heart failure (HF) readmission rates have become an increasingly important quality metric since the advent of the Hospital Readmissions Reduction Program. Despite many well-intentioned efforts to reduce readmissions, clinicians continue to struggle with the problem of high HF readmission rates. HYPOTHESIS: HF patients with obstructive sleep apnea (OSA) will have higher burden of rehospitalization and mortality than HF patients without OSA. METHODS: Our study included 344 patient encounters (among 271 unique patients) with a diagnosis of HF from September 2014 through September 2015. Our primary endpoints were all cause readmission within 30 and 90 days. Multivariate logistic regression was used to assess the relationship between OSA and readmission when accounting for potential confounders. RESULTS: The patients' were 72 +/- 10 years old, and predominantly white (76.2%) and male (99.4%). Among the 344 patient encounters, 247 (71.8%) had diagnosed coronary artery disease, 159 (46.2%) had atrial fibrillation, and 99 (28%) had obstructive sleep apnea (OSA). Notably, patients with OSA had an elevated rate of readmission within 30 days (OSA: 30.3% vs no OSA: 19.6%, P = 0.037) and within 90 days (OSA: 57.6% vs no OSA: 36.3P < 0.01). Patients with OSA had increased risk of readmission within 90 days (odds ratio: 2.38, 95% confidence interval: 1.47-3.83, P < 0.01) even after adjustment for potential confounders of age, race, obesity, diabetes, and chronic obstructive pulmonary disease. CONCLUSIONS: HF patients with OSA have an elevated rate of readmission compared to the general HF population, particularly within the first 90 days after discharge. PMID- 28586101 TI - Functional role of glycosphingolipids in contact inhibition of growth in a human mammary epithelial cell line. AB - We have demonstrated previously the involvement of certain glycosphingolipids (GSLs) in 'contact inhibition' (dependent on cell-to-cell contact) of cell growth. Here, we examined the roles of specific GSLs in contact inhibition of the human epithelial cell line MCF10A. Contact-inhibited cells show increased expression of the ganglioside GD3 and the globo-series GSL Gb3, and of the mRNAs for the corresponding sialyltransferases ST8SIA1 (GD3 synthase) and galactosyltransferase A4GALT (Gb3 synthase). siRNA knockdown (KD) of ST8SIA1 and/or A4GALT significantly suppresses contact inhibition. Exogenous addition of GD3 or Gb3 inhibits proliferation of low-density cells. Our findings suggest that GSLs play functional roles in contact inhibition of these cells and that Merlin/NF2, a tumor suppressor protein, is involved in the GSL function. PMID- 28586103 TI - Minimal configuration of body surface potential mapping for discrimination of left versus right dominant frequencies during atrial fibrillation. AB - BACKGROUND: Ablation of drivers maintaining atrial fibrillation (AF) has been demonstrated as an effective therapy. Drivers in the form of rapidly activated atrial regions can be noninvasively localized to either left or right atria (LA, RA) with body surface potential mapping (BSPM) systems. This study quantifies the accuracy of dominant frequency (DF) measurements from reduced-leads BSPM systems and assesses the minimal configuration required for ablation guidance. METHODS: Nine uniformly distributed lead sets of eight to 66 electrodes were evaluated. BSPM signals were registered simultaneously with intracardiac electrocardiograms (EGMs) in 16 AF patients. DF activity was analyzed on the surface potentials for the nine leads configurations, and the noninvasive measures were compared with the EGM recordings. RESULTS: Surface DF measurements presented similar values than panoramic invasive EGM recordings, showing the highest DF regions in corresponding locations. The noninvasive DFs measures had a high correlation with the invasive discrete recordings; they presented a deviation of <0.5 Hz for the highest DF and a correlation coefficient of >0.8 for leads configurations with 12 or more electrodes. CONCLUSIONS: Reduced-leads BSPM systems enable noninvasive discrimination between LA versus RA DFs with similar results as higher-resolution 66-leads system. Our findings demonstrate the possible incorporation of simplified BSPM systems into clinical planning procedures for AF ablation. PMID- 28586102 TI - Enhancing Photodynamic Therapy through Resonance Energy Transfer Constructed Near Infrared Photosensitized Nanoparticles. AB - Photodynamic therapy (PDT) is an important cancer treatment modality due to its minimally invasive nature. However, the efficiency of existing PDT drug molecules in the deep-tissue-penetrable near-infrared (NIR) region has been the major hurdle that has hindered further development and clinical usage of PDT. Thus, herein a strategy is presented to utilize a resonance energy transfer (RET) mechanism to construct a novel dyad photosensitizer which is able to dramatically boost NIR photon utility and enhance singlet oxygen generation. In this work, the energy donor moiety (distyryl-BODIPY) is connected to a photosensitizer (i.e., diiodo-distyryl-BODIPY) to form a dyad molecule (RET-BDP). The resulting RET-BDP shows significantly enhanced absorption and singlet oxygen efficiency relative to that of the acceptor moiety of the photosensitizer alone in the NIR range. After being encapsulated with biodegradable copolymer pluronic F-127-folic acid (F-127 FA), RET-BDP molecules can form uniform and small organic nanoparticles that are water soluble and tumor targetable. Used in conjunction with an exceptionally low power NIR LED light irradiation (10 mW cm-2 ), these nanoparticles show superior tumor-targeted therapeutic PDT effects against cancer cells both in vitro and in vivo relative to unmodified photosensitizers. This study offers a new method to expand the options for designing NIR-absorbing photosensitizers for future clinical cancer treatments. PMID- 28586105 TI - Seventeen Hours. PMID- 28586104 TI - Reply to: Estimating the Full Value of High-Dose Influenza Vaccine. PMID- 28586106 TI - Sonographic Measurement of Cervical Volume in Pregnant Women at High Risk of Preterm Birth Using a Geometric Formula for a Frustum Versus 3-Dimensional Automated Virtual Organ Computer-Aided Analysis. AB - OBJECTIVES: To compare cervical volume measurements by 3-dimensional (3D) sonography using Virtual Organ computer-aided analysis (VOCAL; GE Healthcare, Milwaukee, WI) versus a manual method using a geometric formula for a frustum. METHODS: We included 142 asymptomatic pregnant women at 16 to 24 weeks gestation at high risk for preterm birth. With a Voluson 730 Expert system (GE Healthcare), they underwent 2-dimensional (2D) transvaginal sonographic cervical length measurements and 3D cervical volume acquisition. The stored volumes were processed by VOCAL on a surface tablet. Cervical volume was manually calculated from the 2D images by using the formula V = 1/3 * pi * h * (r12 + r22 + r1 * r2), where V represents cervical volume; pi was approximated as 3.14159; h, cervical length; r1, radius at the internal os; and r2, radius at the external os. RESULTS: Cervical volume was lower when obtained manually than by VOCAL, with a coefficient of variation of 30%, a mean difference of 10.1 +/- 14.9 cm3 (P < .0001), and a poor interclass correlation coefficient of 0.62 (95% confidence interval [CI], 0.31 to 0.78). Both methods had good reproducibility; however, VOCAL had wider limits of agreement. A positive correlation was found between both methods (r = 0.63; P < .0001). No correlation was found between cervical length by 2D transvaginal ultrasound and cervical volume by the VOCAL technique (r = 0.06; 95% CI, -0.10 to 0.22) or cervical volume by the manual method (r = 0.2; 95% CI, 0.08 to 0.39). CONCLUSIONS: The cervix represents a frustum (truncated cone, r1 is not equal to r2) in shape rather than a cylinder. Both methods are reproducible; VOCAL is less reliable but provides higher values of cervical volume. PMID- 28586107 TI - Are energy and protein requirements met in hospital? AB - BACKGROUND: Malnutrition is a problem within hospitals, which impacts upon clinical outcomes. The present audit assesses whether a hospital menu meets the energy and protein standards recommended by the British Dietetic Association's (BDA) Nutrition and Hydration Digest and determines the contribution of oral nutrition supplements (ONS) and additional snacks. METHODS: Patients in a UK South West hospital were categorised as 'nutritionally well' or 'nutritionally vulnerable' in accordance with their Malnutrition Universal Screening Tool score. Energy and protein content of food selected from the menu ('menu choice'), menu food consumed ('hospital intake') and total food consumed including snacks ('overall intake') were calculated and compared with the standards. RESULTS: In total, 93 patients were included. For 'nutritionally well' patients (n = 81), energy and protein standards were met by 11.1% and 33.3% ('menu choice'); 7.4% and 22.2% ('hospital intake'); and 14.8% and 28.4% ('overall intake'). For 'nutritionally vulnerable' patients (n = 12), energy and protein standards were met by 0% and 8.3% ('menu choice'); 0% and 8.3% ('hospital intake'); and 8.3% and 16.7% ('overall intake'). Ten percent of patients consumed ONS. Patients who consumed hospital snacks (34%) were more likely to meet the nutrient standards (P <= 0.001). CONCLUSIONS: The present audit demonstrated that most patients are not meeting the nutrient standards recommended by the BDA Nutrition and Hydration Digest. Recommendations include the provision of energy/protein-dense snacks, as well as menu, offering ONS where clinically indicated, in addition to training for staff. A food services dietitian is ideally placed to lead this, forming a vital link between patients, caterers and clinical teams. PMID- 28586109 TI - Fyn kinase mediates cortical actin ring depolymerization required for mast cell migration in response to TGF-beta in mice. AB - Transforming growth factor-beta (TGF-beta) is a potent mast cell (MC) chemoattractant able to modulate local inflammatory reactions. The molecular mechanism leading to TGF-beta-directed MC migration is not fully described. Here we analyzed the role of the Src family protein kinase Fyn on the main TGF-beta induced cytoskeletal changes leading to MC migration. Utilizing bone marrow derived mast cells (BMMCs) from WT and Fyn-deficient mice we found that BMMC migration to TGF-beta was impaired in the absence of the kinase. TGF-beta caused depolymerization of the cortical actin ring and changes on the phosphorylation of cofilin, LIMK and CAMKII only in WT cells. Defective cofilin activation and phosphorylation of regulatory proteins was detected in Fyn-deficient BMMCs and this finding correlated with a lower activity of the catalytic subunit of the phosphatase PP2A. Diminished TGF-beta-induced chemotaxis of Fyn-deficient cells was also observed in an in vivo model of MC migration (bleomycin-induced scleroderma). Our results show that Fyn kinase is an important positive effector of TGF-beta-induced chemotaxis through the control of PP2A activity and this is relevant to pathological processes that are related to TGF-beta-dependent mast cell migration. PMID- 28586108 TI - Bcl6 promotes follicular helper T-cell differentiation and PD-1 expression in a Blimp1-independent manner in mice. AB - The transcription factors Bcl6 and Blimp1 have opposing roles in the development of the follicular helper T (TFH ) cells: Bcl6 promotes and Blimp1 inhibits TFH cell differentiation. Similarly, Bcl6 activates, while Blimp1 represses, expression of the TFH -cell marker PD-1. However, Bcl6 and Blimp1 repress each other's expression, complicating the interpretation of the regulatory network. Here we sought to clarify the extent to which Bcl6 and Blimp1 independently control TFH -cell differentiation by generating mice with T-cell specific deletion of both Bcl6 and Blimp1 (double conditional KO [dcKO] mice). Our data indicate that Blimp1 does not control TFH -cell differentiation independently of Bcl6. However, a population of T follicular regulatory (TFR ) cells developed independently of Bcl6 in dcKO mice. We have also analyzed regulation of IL-10 and PD-1, two genes controlled by both Bcl6 and Blimp1, and observed that Bcl6 regulates both genes independently of Blimp1. We found that Bcl6 positively regulates PD-1 expression by inhibiting the ability of T-bet/Tbx21 to repress Pdcd1 transcription. Our data provide a novel mechanism for positive control of gene expression by Bcl6, and illuminate how Bcl6 and Blimp1 control TFH -cell differentiation. PMID- 28586111 TI - Estimating the Full Value of High-Dose Influenza Vaccine. PMID- 28586112 TI - Conservative management of cervical ectopic pregnancy: Single-center experience. AB - AIM: The aim of this study was to assess the results of conservative treatment of cervical ectopic pregnancy (CEP). METHODS: We retrospectively reviewed all cervical ectopic pregnancies diagnosed at the present department between January 2010 and July 2015. Patients with CEP who were treated with either systemic or intra-amniotic methotrexate (MTX) injection were included in the study. RESULTS: Ten CEP patients were identified. Median maternal age was 33 years (range, 23-40 years). Median gestational age at diagnosis was 47 days (range, 44-58 days). Before treatment, overall mean serum beta-human chorionic gonadotrophin (beta hCG) was 29 706.9 +/- 19 695.2 mIU/mL. Mean gestational sac size was 29.0 +/- 6.24 mm. Eight patients had viable fetuses with detected cardiac activity. Six patients were treated primarily with systemic MTX, and four were treated with local MTX injection. One patient in the systemic MTX injection group was switched to local MTX treatment due to severe oral ulceration and increasing beta-hCG titers after the fourth dose. One patient in the local treatment group had severe hemorrhage 7 days after local MTX. Three of six women achieved spontaneous pregnancy and gave birth to term, healthy infants after treatment. CONCLUSION: Conservative treatment of CEP with both systemic and local MTX is generally successful with regard to maternal morbidity and reproductive function, but these patients must be closely followed due to the small but real risk of late hemorrhage. PMID- 28586113 TI - Lung Consolidation Locations for Optimal Lung Ultrasound Scanning in Diagnosing Pediatric Pneumonia. AB - OBJECTIVES: Lung ultrasound (US) has been shown to be accurate in diagnosing pneumonia in children. Evidence to inform an optimal scanning protocol is limited. Our objective is to describe an optimized lung US scanning protocol for pediatric pneumonia based on the anatomic location and transducer orientation. METHODS: We performed a secondary analysis of data and images from 2 prospective lung US studies for the emergency department diagnosis of pneumonia in children (0-21 years). The anatomic location of each lung consolidation was mapped to 1 or more of 6 anatomic zones on the chest, noting the transducer orientation (sagittal or transverse) in which it was identified. RESULTS: Seventy-eight patients were included; 51% were female, and the median age was 3 years (interquartile range, 1-7 years). Overall, 46.5% (95% CI confidence interval [CI], 37.9%-55.1%) of lung zones with a visible consolidation were posterior; 31.0% (95% CI, 23.0%-39.0%) were anterior; and 22.5% (95% CI, 15.3%-29.1%) were axillary. A total of 54.3% (95% CI, 45.7%-62.9%) of affected lung zones were in the lower lung compared to the upper lung (8.5%; 95% CI, 3.7%-13.3%) and middle lung (37.2%; 95% CI, 28.9%-45.5%). Most lung consolidations were seen in both transducer orientations: 96.2% (95% CI, 92.0%-100%) of patients had a visible consolidation on the transverse view, whereas 85.9% (95% CI, 78.2%-93.6% had a consolidation on the sagittal view. CONCLUSIONS: Efficient lung US scanning may start with the posterior, anterior, and then lateral chest zones if no pneumonia is identified. A transverse transducer orientation detects more pneumonia than a sagittal orientation. Omission of either orientation or any lung zone may miss pneumonia. PMID- 28586110 TI - Molecular Containers Bind Drugs of Abuse in Vitro and Reverse the Hyperlocomotive Effect of Methamphetamine in Rats. AB - We measured the affinity of five molecular container compounds (calabadions 1 and 2, CB[7], sulfocalix[4]arene, and HP-beta-CD) toward seven drugs of abuse in homogenous aqueous solution at physiological pH by various methods (1 H NMR, UV/Vis, isothermal titration calorimetry [ITC]) and found binding constants (Ka values) spanning from <102 to >108 m-1 . We also report X-ray crystal structures of CB[7]?methamphetamine and 1?methamphetamine. We found that 2, but not CB[7], was able to ameliorate the hyperlocomotive activity of rats treated with methamphetamine. The bioavailability of the calabadions and their convergent building block synthesis suggest potential for further structural optimization as reversal agents for intoxication with nonopioid drugs of abuse for which no treatments are currently available. PMID- 28586114 TI - A phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of nononcogenic receptor tyrosine kinases. AB - : Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to nononcogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that in the liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26Met ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated that liver tumorigenesis modeled by Alb-R26Met mice corresponds to a subset of hepatocellular carcinoma (HCC) patients, thus establishing the clinical relevance of this HCC mouse model. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb-R26Met HCC versus control livers to design an "educated guess" drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report synergistic effects of mitogen-activated protein kinase kinase, ribosomal S6 kinase, and cyclin-dependent kinase 1/2 in combination with Bcl-XL inhibition on a panel of liver cancer cells. Focusing on mitogen-activated protein kinase kinase and Bcl-XL targeting, we mechanistically demonstrated concomitant down-regulation of phosphorylated extracellular signal-regulated kinase and myeloid cell leukemia 1 levels. Of note, a phosphorylated extracellular signal-regulated kinase+/BCL-XL+ /myeloid cell leukemia 1+ signature, deregulated in Alb-R26Met tumors, characterizes a subgroup of HCC patients with poor prognosis. CONCLUSION: Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in nononcogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program; furthermore, our outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients. (Hepatology 2017;66:1644-1661). PMID- 28586115 TI - Early Detection of Postoperative Acute Kidney Injury in Acute Stanford Type A Aortic Dissection With Doppler Renal Resistive Index. AB - OBJECTIVES: This study aimed to evaluate the early efficiency of Doppler renal resistive index (DRRI) in prediction of acute kidney injury (AKI) after surgery in acute Stanford Type A aortic dissection (AAAD) patients. METHODS: Sixty-one AAAD patients who planned to receive Sun's surgical management were prospectively enrolled. The DRRI was measured by ultrasonography Doppler on the day before surgery (DRRIpre ), on admission to the intensive care unit (DRRIT0 ), 6 hours after surgery (DRRIT6 ), 24 hours after surgery (DRRIT24 ), and 48 hours after surgery (DRRIT48 ). The maximum DRRI value (DRRImax ) was recorded. The AKI was evaluated according to the classifications of the Acute Kidney Injury Network. The DRRI and serum creatinine (sCr) were compared between the pre- and postoperative time stations, as well as between the AKI and no-AKI groups. RESULTS: Thirty-nine (63.9%) patients suffered from AKI, and 12 (19.6%) patients received dialysis. No significant difference was found in DRRIpre (0.63 +/- 0.04 versus 0.65 +/- 0.06, P = .059) and sCrpre (84.13 +/- 23.77 versus 94.29 +/- 51.11, P = .383) between the two groups with and without AKI. Both the DRRI and sCr increased significantly after surgery in the AKI groups (P < .001). However, the DRRI reached its maximum 6 hours after surgery, whereas the sCr reached its maximum after 24 hours. Both the DRRI and sCr improved 48 hours after surgery. The area under the receiver operating characteristic curve for DRRImax (0.864, 95% confidence interval: 0.770-0.957) and DRRIT6 (0.861, 95% confidence interval: 0.766-0.957) was larger than the other three DRRIs measured at different time points. The cutoff value of DRRImax was 0.71, a sensitivity of 76.9% and specificity of 95.5%. CONCLUSIONS: Postoperative DRRI predicts the AKI earlier than sCr after AAAD surgery. The best time to detect DRRI was 6 hours after surgery. PMID- 28586117 TI - Male Centenarians: How and Why Are They Different from Their Female Counterparts? PMID- 28586116 TI - Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial. AB - : Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5-month follow-up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5 days of broad-spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End-Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post-FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. CONCLUSION: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727-1738). PMID- 28586118 TI - A DNA hypermethylation profile reveals new potential biomarkers for the evaluation of prognosis in urothelial bladder cancer. AB - DNA hypermethylation has emerged as a molecular biomarker for the evaluation of cancer diagnosis and prognosis. We define a methylation signature of bladder cancer and evaluate whether this profile assesses prognosis of patients. Genome wide methylation analysis was performed on 70 tumor and 10 normal bladder samples. Hypermethylation status of 1505 CpGs present in the promoter region of 807 genes was studied. Thirty-three genes were significantly hypermethylated in >=10% of the tumors. Three clusters of patients were characterized by their DNA methylation profile, one at higher risk of dead of disease (p = 0.0012). Association between cluster distribution and stage (p = 0.02) or grade (p = 0.02) was demonstrated. Hypermethylation of JAK3 and absence of hypermethylation of EYA4, GAT6, and SOX1 were associated with low-grade non-invasive disease. On the other hand, in high-grade invasive disease hypermethylation of CSPG2, HOXA11, HOXA9, HS3ST2, SOX1, and TWIST1 was associated with muscle invasiveness. A panel of hypermethylated genes including APC, CSPG2, EPHA5, EYA4, HOXA9, IPF1, ISL1, JAK3, PITX2, SOX1, and TWIST1 predicted cancer-specific survival and SOX1 (HR = 3.46), PITX2 (HR = 4.17), CSPG2 (HR = 5.35), and JAK3 hypermethylation (HR = 0.19) did so independently. Silencing of genes by hypermethylation is a common event in bladder cancer and could be used to develop diagnostic and prognostic markers. Combined hypermethylation of SOX1, PITX2, or CSPG2 signals patients at higher risk of death from bladder cancer. PMID- 28586119 TI - DMclust, a Density-based Modularity Method for Accurate OTU Picking of 16S rRNA Sequences. AB - Clustering 16S rRNA sequences into operational taxonomic units (OTUs) is a crucial step in analyzing metagenomic data. Although many methods have been developed, how to obtain an appropriate balance between clustering accuracy and computational efficiency is still a major challenge. A novel density-based modularity clustering method, called DMclust, is proposed in this paper to bin 16S rRNA sequences into OTUs with high clustering accuracy. The DMclust algorithm consists of four main phases. It first searches for the sequence dense group defined as n-sequence community, in which the distance between any two sequences is less than a threshold. Then these dense groups are used to construct a weighted network, where dense groups are viewed as nodes, each pair of dense groups is connected by an edge, and the distance of pairwise groups represents the weight of the edge. Then, a modularity-based community detection method is employed to generate the preclusters. Finally, the remaining sequences are assigned to their nearest preclusters to form OTUs. Compared with existing widely used methods, the experimental results on several metagenomic datasets show that DMclust has higher accurate clustering performance with acceptable memory usage. PMID- 28586121 TI - Chronic myeloid leukemia: Global impact from a local laboratory. PMID- 28586122 TI - The Geriatrics 5M's: A New Way of Communicating What We Do. PMID- 28586120 TI - Chaperone-Polymer-Assisted, Photodriven DNA Strand Displacement. AB - Photodriven DNA strand displacement by using a 2',6'-dimethylazobenzene-tethered strand and poly(l-lysine)-graft-dextran (PLL-g-Dex) as a chaperone is reported. Rapid strand displacement was reversibly induced by UV and visible-light irradiation without any toehold portion. To further improve the method, the concentration of PLL-g-Dex and the number of equivalents of the photoresponsive strand were optimised. Optimally, 64 % strand displacement was reversibly induced by alternating UV and visible-light irradiation. PMID- 28586123 TI - Boosting the Supercapacitance of Nitrogen-Doped Carbon by Tuning Surface Functionalities. AB - The specific capacitance of a highly porous, nitrogen-doped carbon is nearly tripled by orthogonal optimization of the microstructure and surface chemistry. First, the carbons' hierarchical pore structure and specific surface area were tweaked by controlling the temperature and sequence of the thermal treatments. The best process (pyrolysis at 900 degrees C, washing, and subsequent annealing at 1000 degrees C) yielded a carbon with a specific capacitance of 117 F g-1 nearly double that of a carbon made by a typical single-step synthesis at 700 degrees C. Following the structural optimization, the surface chemistry of the carbons was enriched by applying an oxidation routine based on a mixture of nitric and sulfuric acid in a 1:4 ratio at two different treatment temperatures (0 and 20 degrees C) and different treatment times. The optimal treatment times were 4 h at 0 degrees C and only 1 h at 20 degrees C. Overall, the specific capacitance nearly tripled relative to the original carbon, reaching 168 F g-1 . The inherent nitrogen doping of the carbon comes into interplay with the acid induced surface functionalization, creating a mixture of oxygen- and nitrogen oxygen functionalities. The evolution of the surface chemistry was carefully followed by X-ray photoelectron spectroscopy and by N2 sorption porosimetry, revealing stepwise surface functionalization and simultaneous carbon etching. Overall, these processes are responsible for the peak-shaped capacitance trends in the carbons. PMID- 28586125 TI - Sperm motility initiating substance may be insufficient to induce forward motility of Cynops ensicauda sperm. AB - Sperm motility-initiating substance (SMIS) is a key protein for internal fertilization of the newt, Cynops pyrrhogaster, and commonly enhances forward sperm motility in some amphibian species, including external fertilizers. SMIS action varies among different species in correlation with a species-specific reproductive environment. In the present study, we identified the gene of C. ensicauda SMIS (CeSMIS) and examined the mechanism of SMIS action with reference to that of the closely related Cynops species. The CeSMIS was identified by a 176 amino acid sequence including seven amino acids critical for the initiation of sperm motility. The amino acid sequence showed 91% homology to the whole sequence of C. pyrrhogaster SMIS (CpSMIS). By immunostaining with an anti-CpSMIS antibody, CeSMIS was shown to be localized in the outer layer of the egg jelly. A peptide presenting the active site of SMIS was observed to bind to the axial rod of the midpiece in C. ensicauda sperm. The localization and binding patterns of CeSMIS were fundamentally similar to those of CpSMIS. However, the SMIS peptide did not induce forward motility of C. ensicauda sperm, although it induced a fast wave of the undulating membrane. Forward sperm motility was induced in the egg jelly extract containing CeSMIS. These results suggest that the mechanism of initiation of sperm motility is differentiated between C. ensicauda and C. pyrrhogaster. PMID- 28586124 TI - Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice. AB - : Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are important regulators of bile acid, lipid, and glucose homeostasis. Here, we show that global Fxr -/- Shp-/- double knockout (DKO) mice are refractory to weight gain, glucose intolerance, and hepatic steatosis when challenged with high-fat diet. DKO mice display an inherently increased capacity to burn fat and suppress de novo hepatic lipid synthesis. Moreover, DKO mice were also very active and that correlated well with the observed increase in phosphoenolpyruvate carboxykinase expression, type IA fibers, and mitochondrial function in skeletal muscle. Mechanistically, we demonstrate that liver-specific Shp deletion protects against fatty liver development by suppressing expression of peroxisome proliferator-activated receptor gamma 2 and lipid-droplet protein fat-specific protein 27 beta. CONCLUSION: These data suggest that Fxr and Shp inactivation may be beneficial to combat diet-induced obesity and uncover that hepatic SHP is necessary to promote fatty liver disease. (Hepatology 2017;66:1854 1865). PMID- 28586126 TI - Significance of oliguria in critically ill patients with chronic liver disease. AB - : Clinical guidelines recommend using Kidney Disease Improving Global Outcomes (KDIGO) criteria for the diagnosis and classification of acute kidney injury (AKI) in patients with chronic liver disease (CLD). Concerns have been raised about the use of urine output (UO) criteria in CLD. We examined the significance of oliguria meeting the urine output criteria for AKI (AKI-UO) and examined its association with clinical outcomes in CLD patients. Using an 8-year clinical database from a large university medical center, 3458 patients with CLD were identified. AKI occurred in 2854 (82.5%) patients when they fulfilled any KDIGO criteria. When serum creatinine (SC) and UO criteria were used, 604 patients (17.5%) had no evidence of AKI and had the lowest hospital mortality rate (5%). Using AKI-UO criteria alone, 2103 patients (60.8%) were classified as stage 2-3 AKI. When only SC criteria were applied, 1281 (61%) of those patients with stage 2-3 AKI-UO were misclassified as either no AKI or AKI stage 1. Patients reclassified with AKI according to UO criteria (AKI-UO) had nearly a 3-fold increased rate of hospital mortality compared with patients without any AKI (14.6% versus 5%; P < 0.001) and more than a 50% increased mortality compared with stage 1 AKI-SC (14.6% versus 9%; P < 0.001). Patients with transient oliguria (AKI-UO stage 1) had increased mortality rates compared with patients without oliguria (14.9% versus 6.9%; P < 0.001). CONCLUSION: CLD patients have a high incidence of AKI. Compared with creatinine criteria alone, incorporating UO into the diagnostic criteria increased the measured incidence of AKI. Stage 2-3 AKI-UO has a high negative impact on hospital mortality. (Hepatology 2017;66:1592 1600). PMID- 28586127 TI - Cervical stitch (cerclage) for preventing preterm birth in singleton pregnancy. AB - BACKGROUND: Cervical cerclage is a well-known surgical procedure carried out during pregnancy. It involves positioning of a suture (stitch) around the neck of the womb (cervix), aiming to give mechanical support to the cervix and thereby reduce risk of preterm birth. The effectiveness and safety of this procedure remains controversial. This is an update of a review last published in 2012. OBJECTIVES: To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on woman's history and/or ultrasound finding of 'short cervix' and/or physical exam improves subsequent obstetric care and fetal outcome. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (30 June 2016) and reference lists of identified studies. SELECTION CRITERIA: We included all randomised trials of cervical suturing in singleton pregnancies. Cervical stitch was carried out when the pregnancy was considered to be of sufficiently high risk due to a woman's history, a finding of short cervix on ultrasound or other indication determined by physical exam. We included any study that compared cerclage with either no treatment or any alternative intervention. We planned to include cluster-randomised studies but not cross-over trials. We excluded quasi-randomised studies. We included studies reported in abstract form only. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion. Two review authors independently assessed risk of bias and extracted data. We resolved discrepancies by discussion. Data were checked for accuracy. The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: This updated review includes a total of 15 trials (3490 women); three trials were added for this update (152 women). Cerclage versus no cerclageOverall, cerclage probably leads to a reduced risk of perinatal death when compared with no cerclage, although the confidence interval (CI) crosses the line of no effect (RR 0.82, 95% CI 0.65 to 1.04; 10 studies, 2927 women; moderate quality evidence). Considering stillbirths and neonatal deaths separately reduced the numbers of events and sample size. Although the relative effect of cerclage is similar, estimates were less reliable with fewer data and assessed as of low quality (stillbirths RR 0.89, 95% CI 0.45 to 1.75; 5 studies, 1803 women; low quality evidence; neonatal deaths before discharge RR 0.85, 95% CI 0.53 to 1.39; 6 studies, 1714 women; low quality evidence). Serious neonatal morbidity was similar with and without cerclage (RR 0.80, 95% CI 0.55 to 1.18; 6 studies, 883 women; low-quality evidence). Pregnant women with and without cerclage were equally likely to have a baby discharged home healthy (RR 1.02, 95% CI 0.97 to 1.06; 4 studies, 657 women; moderate quality evidence).Pregnant women with cerclage were less likely to have preterm births compared to controls before 37, 34 (average RR 0.77, 95% CI 0.66 to 0.89; 9 studies, 2415 women; high quality evidence) and 28 completed weeks of gestation.Five subgroups based on clinical indication provided data for analysis (history-indicated; short cervix based on one-off ultrasound in high risk women; short cervix found by serial scans in high risk women; physical exam-indicated; and short cervix found on scan in low risk or mixed populations). There were too few trials in these clinical subgroups to make meaningful conclusions and no evidence of differential effects. Cerclage versus progesteroneTwo trials (129 women) compared cerclage to prevention with vaginal progesterone in high risk women with short cervix on ultrasound; these trials were too small to detect reliable, clinically important differences for any review outcome. One included trial compared cerclage with intramuscular progesterone (75 women) which lacked power to detect group differences. History indicated cerclage versus ultrasound indicated cerclageEvidence from two trials (344 women) was too limited to establish differences for clinically important outcomes. AUTHORS' CONCLUSIONS: Cervical cerclage reduces the risk of preterm birth in women at high-risk of preterm birth and probably reduces risk of perinatal deaths. There was no evidence of any differential effect of cerclage based on previous obstetric history or short cervix indications, but data were limited for all clinical groups. The question of whether cerclage is more or less effective than other preventative treatments, particularly vaginal progesterone, remains unanswered. PMID- 28586128 TI - Capturing Elusive Cobaltacycle Intermediates: A Real-Time Snapshot of the Cp*CoIII -Catalyzed Oxidative Alkyne Annulation. AB - Despite Cp*CoIII catalysts having emerged as a very attractive alternative to noble transition metals for the construction of heterocyclic scaffolds through C H activation, the structure of the reactive species remains uncertain. Herein, we report the identification and unambiguous characterization of two long-sought cyclometalated Cp*CoIII complexes that have been proposed as key intermediates in C-H functionalization reactions. The addition of MeCN as a stabilizing ligand plays a crucial role, allowing the access to otherwise highly reactive species. Mechanistic investigations demonstrate the intermediacy of these species in oxidative annulations with alkynes, including the direct observation, under catalytic conditions, of a previously elusive post-migratory insertion seven membered cobaltacycle. PMID- 28586129 TI - Psychometric validation of the Chinese version of the Illness Perception Questionnaire-Revised for women with stress urinary incontinence. AB - AIM: The aim of this study was to examine the reliability and validity of the Illness Perception Questionnaire-Revised (IPQ-R) in patients with stress urinary incontinence (SUI). METHODS: A total of 256 patients with SUI and 76 patients with myoma of the uterus were recruited to complete the Chinese IPQ-R. For the reliability, the key tests included Cronbach's alpha coefficient and intraclass correlation coefficients. For the validity, the key tests included factor analysis, Spearman's correlation coefficient, and the Student's t-test. RESULTS: Cronbach's alpha values ranged from 0.68 to 0.90 for each subscale and the intraclass correlation coefficients ranged from 0.80 to 0.94. The results of the confirmatory factor analysis showed that the seven-factor structure as proposed by the original IPQ-R fit the data poorly. Although removal of three items improved the model's fit, the goodness-of-fit statistics were still below acceptable standards. We identified an acceptable seven-factor solution from the 38 items on Illness Beliefs using an exploratory factor analysis (EFA), which accounted for 68.12% of the variance. For the concurrent validity, Consequences and Emotional Representation both had good correlations with anxiety and depression (r = 0.52-0.62) and better quality of life (r = 0.58-0.73). The inter correlation coefficient of the seven factors ranged from 0.05 to 0.59, suggesting acceptable discriminant validity. There were significant differences on the scale scores of Disease Identity (t = 9.39, P < 0.01), Timeline-Acute/Chronic (t = 3.69, P < 0.01), Consequences (t = 4.53, P < 0.01), Illness Coherence (t = 7.73, P < 0.01), Timeline-Cyclical (t = 6.48, P < 0.01), Emotional Representation (t = 6.40, P < 0.01), and Cause (t = 4.29, P < 0.01) between the patients with SUI and with myoma of the uterus, which also indicated acceptable discriminant validity. CONCLUSION: The findings of this study supported the Chinese IPQ-R as being a reliable and valid tool for measuring illness perception among patients with SUI. PMID- 28586130 TI - Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases. AB - Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation. Copyright (c) 2017 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 28586132 TI - Strongly Luminescent Cyclometalated Gold(III) Complexes Supported by Bidentate Ligands Displaying Intermolecular Interactions and Tunable Emission Energy. AB - A series of charge-neutral AuIII complexes, which comprise a dicarbanionic C deprotonated biphenyl ligand and bidentate ancillary ligands ([Au(C^C)(L^X)]; L^X=beta-diketonate and relatives (O^O), quinolinolate and relatives (N^O), and diphosphino (P^P) ligands), were prepared. All the complexes are emissive in degassed CH2 Cl2 solutions and in thin-film samples with Phiem up to 18 and 35 %, respectively, except for 5 and 6, which bear (N^O)-type ancillary ligands. Variation of the electronic characteristics of the beta-diketonate ancillary ligand was demonstrated to be a viable route for tuning the emission color from blue-green (peak lambdaem at ca. 466 nm for 1 and 2; 501 nm for 4 a and 4 b) to orange (peak lambdaem at 585 nm for 3), in contrast to the common observations that the ancillary ligand has a negligible effect on the excited-state energy of the AuIII complexes reported in the literature. DFT/time-dependent (TD) DFT calculations revealed that the energies of the 3 pipi*(C^C) and the 3 ILCT(O^O) excited states (ILCT=intraligand charge transfer) switch in order on going from O^O=acetylacetonate (acac) to aryl-substituted beta-diketonate ligands. Solution processed and vacuum-deposited organic light-emitting diode (OLED) devices of selected complexes were prepared. The vacuum-deposited OLED fabricated with 2 displays a sky-blue emission with a maximum external quantum efficiency (EQE) of 6.71 % and CIE coordinates of (0.22, 0.40). The crystal structures of 7 and 9 reveal short intermolecular AuIII ???AuIII contacts, with intermetal distances of 3.408 and 3.453 A, respectively. DFT/TDDFT calculations were performed on 7 and 9 to account for the noncovalent interactions. Solid samples of 1, 3, and 9 exhibit excimeric emission at room temperature, which is rarely reported in AuIII complexes. PMID- 28586133 TI - Noncovalent Immobilization of Molecular Electrocatalysts for Chemical Synthesis: Efficient Electrochemical Alcohol Oxidation with a Pyrene-TEMPO Conjugate. AB - Electrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene-tethered TEMPO derivative (TEMPO=2,2,6,6-tetramethylpiperidinyl-N oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4-acetamido-TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h-1 , respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin. PMID- 28586131 TI - Mechanisms underlying vestibulo-cerebellar motor learning in mice depend on movement direction. AB - KEY POINTS: Directionality, inherent to movements, has behavioural and neuronal correlates. Direction of vestibular stimulation determines motor learning efficiency. Vestibulo-ocular reflex gain-increase correlates with Purkinje cell simple spike potentiation. The locus of neural correlates for vestibulo-ocular reflex adaptation is paradigm specific. ABSTRACT: Compensatory eye movements elicited by head rotation, also known as vestibulo-ocular reflex (VOR), can be adapted with the use of visual feedback. The cerebellum is essential for this type of movement adaptation, although its neuronal correlates remain to be clarified. In the present study, we show that the direction of vestibular input determines the magnitude of eye movement adaptation induced by mismatched visual input in mice, with larger changes during contraversive head rotation. Moreover, the location of the neural correlate of this changed behaviour depends on the type of paradigm. Gain-increase paradigms induce increased simple spike (SS) activity in ipsilateral cerebellar Purkinje cells (PC), which is in line with eye movements triggered by optogenetic PC activation. By contrast, gain-decrease paradigms do not induce changes in SS activity, indicating that the murine vestibulo-cerebellar cortical circuitry is optimally designed to enhance ipsiversive eye movements. PMID- 28586134 TI - Associations between psychological stress and smoking, drinking, obesity, and high blood pressure in an upper middle-income country in the African region. AB - The direction and magnitude of the associations between cardiovascular risk factors (CVRFs) and psychological stress continue to be debated, and no data are available from surveys in the African region. In this study, we examine the associations between CVRFs and psychological stress in the Seychelles, a rapidly developing small island state in the African region. A survey was conducted in 1,240 adults aged 25-64 years representative of the Seychelles. Participants were asked to rank psychological stress that they had experienced during the past 12 months in four domains: work, social life, financial situation, and environment around home. CVRFs (high blood pressure, tobacco use, alcohol drinking, and obesity) were assessed using standard procedures. Psychological stress was associated with age, sex, and socioeconomic status. Overall, there were only few consistent associations between psychological stress and CVRFs, adjusting for age, sex, and socioeconomic status. Social stress was associated with smoking, drinking, and obesity, and there were marginal associations between stress at work and drinking, and between financial stress, and smoking and drinking. Psychological stress was not associated with high blood pressure. These findings suggest that psychological stress should be considered in cardiovascular disease prevention and control strategies. PMID- 28586135 TI - Changes in temperature sensitivity of spring phenology with recent climate warming in Switzerland are related to shifts of the preseason. AB - The spring phenology of plants in temperate regions strongly responds to spring temperatures. Climate warming has caused substantial phenological advances in the past, but trends to be expected in the future are uncertain. A simple indicator is temperature sensitivity, the phenological advance statistically associated with a 1 degrees C warmer mean temperature during the "preseason", defined as the most temperature-sensitive period preceding the phenological event. Recent analyses of phenological records have shown a decline in temperature sensitivity of leaf unfolding, but underlying mechanisms were not clear. Here, we propose that climate warming can reduce temperature sensitivity simply by reducing the length of the preseason due to faster bud development during this time period, unless the entire preseason shifts forward so that its temperature does not change. We derive these predictions theoretically from the widely used "thermal time model" for bud development and test them using data for 19 phenological events recorded in 1970-2012 at 108 stations spanning a 1600 m altitudinal range in Switzerland. We consider how temperature sensitivity, preseason start, preseason length and preseason temperature change (i) with altitude, (ii) between the periods 1970-1987 and 1995-2012, which differed mainly in spring temperatures, and (iii) between two non-consecutive sets of 18 years that differed mainly in winter temperatures. On average, temperature sensitivity increased with altitude (colder climate) and was reduced in years with warmer springs, but not in years with warmer winters. These trends also varied among species. Decreasing temperature sensitivity in warmer springs was associated with a limited forward shift of preseason start, higher temperatures during the preseason and reduced preseason length, but not with reduced winter chilling. Our results imply that declining temperature sensitivity can result directly from spring warming and does not necessarily indicate altered physiological responses or stronger constraints such as reduced winter chilling. PMID- 28586136 TI - Benchmarking Geant4 hadronic models for prompt-gamma monitoring in carbon ion therapy. AB - PURPOSE: The real-time monitoring of the spread-out Bragg peak would allow the planned dose delivered during treatment to be directly verified, but this poses a major challenge in modern ion beam therapy. A possible method to achieve this goal is to exploit the production of secondary particles by the nuclear reactions of the beam with the patient and correlate their emission profile to the planned target volume position. In this study, we present both the production rate and energy spectra of the prompt-gamma produced by the interactions of the 12 C ion beam with a polymethyl methacrylate (PMMA) target. We also assess three different Monte Carlo models for prompt-gamma simulation based on our experimental data. METHODS: The experiment was carried out at the GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany with a 220 MeV/u 12 C ions beam impinging on a 5* 5* 20 cm3 polymethyl methacrylate beam stopping target, with the prompt-gamma being detected by a hexagonally-shaped barium fluoride scintillator with a circumscribed radius of 5.4 cm and a length of 14 cm, placed at 60 degrees and 90 degrees with respect to the beam direction. Monte Carlo simulations were carried out with three different hadronic models from the Geant4 code: binary ion cascade (BIC), quantum molecular dynamics (QMD), and Liege intranuclear cascade (INCL++ ). RESULTS: An experimental prompt-gamma yield of 1.06 * 10-2 sr-1 was measured at 90 degrees . A good agreement was observed between the shapes of the experimental and simulated energy spectra, especially with the INCL++ physics list. The prompt-gamma yield obtained with this physics list was compatible with the measurement within 2sigma, with a relative difference of 26% on average. BIC and QMD physics lists proved to be less accurate than INCL++ , with the difference between the measured and simulated yields exceeding 100%. The differences between the three physics lists were ascribed to important discrepancies between the models of the physical processes producing prompt-gamma emissions. CONCLUSION: In conclusion, this study provides prompt-gamma yield values in agreement with previously published results for different carbon ions energies. This work demonstrates that the INCL++ physics list from Geant4 is more accurate than BIC and QMD to reproduce prompt-gamma emission properties. PMID- 28586137 TI - Adaptive root foraging strategies along a boreal-temperate forest gradient. AB - The tree root-mycorhizosphere plays a key role in resource uptake, but also in the adaptation of forests to changing environments. The adaptive foraging mechanisms of ectomycorrhizal (EcM) and fine roots of Picea abies, Pinus sylvestris and Betula pendula were evaluated along a gradient from temperate to subarctic boreal forest (38 sites between latitudes 48 degrees N and 69 degrees N) in Europe. Variables describing tree resource uptake structures and processes (absorptive fine root biomass and morphology, nitrogen (N) concentration in absorptive roots, extramatrical mycelium (EMM) biomass, community structure of root-associated EcM fungi, soil and rhizosphere bacteria) were used to analyse relationships between root system functional traits and climate, soil and stand characteristics. Absorptive fine root biomass per stand basal area increased significantly from temperate to boreal forests, coinciding with longer and thinner root tips with higher tissue density, smaller EMM biomass per root length and a shift in soil microbial community structure. The soil carbon (C) : N ratio was found to explain most of the variability in absorptive fine root and EMM biomass, root tissue density, N concentration and rhizosphere bacterial community structure. We suggest a concept of absorptive fine root foraging strategies involving both qualitative and quantitative changes in the root-mycorrhiza bacteria continuum along climate and soil C : N gradients. PMID- 28586138 TI - Postoperative radiotherapy dose requirement in standard combined-modality practice for head and neck squamous cell carcinoma: Analysis of salient surgical and radiotherapy parameters in 2 cohorts. AB - BACKGROUND: This study compared 2 sequential cohorts to identify the postoperative radiotherapy (PORT) dose requirement for head and neck squamous cell carcinoma (HNSCC). METHODS: Two distinct PORT dose regimens were prescribed over 11 years; group 1 received 56 Gy or less, and group 2 received 60 Gy or more. The 2D and 3D techniques were used. RESULTS: Two sequential cohorts consisted of 478 patients, with mean and median follow-up for group 1 and 2 as: 37.0 versus 28.5 months and 13.8 versus 13.1 months, respectively. Grades 3-4 mucosal toxicities (11.4% vs 28.3%), hospitalization (3.2% vs 17.4%), and nasogastric feeding (11.9% vs 29.7%) were higher in group 2. The 2-year disease free survival (DFS) was higher with PORT >60 Gy for the following factors: age <= 50 years (P = .041); >= 4 positive nodes (P = .029); and overall treatment time (OTT) >= 100 days (P = .042). CONCLUSION: Except for the benefit of doses >60 Gy for limited parameters, a lower PORT dose did not compromise the results and can potentially reduce the morbidities and healthcare costs. PMID- 28586139 TI - Silicon Photoanodes Partially Covered by Ni@Ni(OH)2 Core-Shell Particles for Photoelectrochemical Water Oxidation. AB - Two obstacles hindering solar energy conversion by photoelectrochemical (PEC) water-splitting devices are the charge separation and the transport efficiency at the photoanode-electrolyte interface region. Herein, core-shell-structured Ni@Ni(OH)2 nanoparticles were electrodeposited on the surface of an n-type Si photoanode. The Schottky barrier between Ni and Si is sensitive to the thickness of the Ni(OH)2 shell. The photovoltage output of the photoanode increases with increasing thickness of the Ni(OH)2 shell, and is influenced by interactions between Ni and Ni(OH)2 , the electrolyte screening effect, and the p-type nature of the Ni(OH)2 layer. Ni@Ni(OH)2 core-shell nanoparticles with appropriate shell thicknesses coupled to n-type Si photoanodes promote the separation of photogenerated carriers and improve the charge-injection efficiency to nearly 100 %. An onset potential of 1.03 V versus reversible hydrogen electrode (RHE) and a saturated current density of 36.4 mA cm-2 was obtained for the assembly. PMID- 28586140 TI - Automated Quantum Mechanical Predictions of Enantioselectivity in a Rhodium Catalyzed Asymmetric Hydrogenation. AB - A computational toolkit (AARON: An automated reaction optimizer for new catalysts) is described that automates the density functional theory (DFT) based screening of chiral ligands for transition-metal-catalyzed reactions with well defined reaction mechanisms but multiple stereocontrolling transition states. This is demonstrated for the Rh-catalyzed asymmetric hydrogenation of (E)-beta aryl-N-acetyl enamides, for which a new C2 -symmetric phosphorus ligand is designed. PMID- 28586141 TI - Connectivity Predicts deep brain stimulation outcome in Parkinson disease. AB - OBJECTIVE: The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort. METHODS: A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of the Unified Parkinson Disease Rating Scale [UPDRS]). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center. RESULTS: In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p < 0.001). This same connectivity profile predicted response in an independent patient cohort (p < 0.01). Structural and functional connectivity were independent predictors of clinical improvement (p < 0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease matched to our DBS patients. INTERPRETATION: Effective STN DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. Ann Neurol 2017;82:67-78. PMID- 28586142 TI - Experimental hybridization and reproductive isolation between two sympatric species of tephritid fruit flies in the Anastrepha fraterculus species group. AB - Among tephritid fruit flies, hybridization has been found to produce local adaptation and speciation, and in the case of pest species, induce behavioral and ecological alterations that can adversely impact efficient pest management. The fraterculus species group within Anastrepha (Diptera: Tephritidae), is a rapidly radiating aggregate, which includes cryptic species complexes, numerous sister species, and several pest species. Molecular studies have highlighted the possibility of introgression between A. fraterculus and A. obliqua. Reproductive isolation has been studied among morphotypes of the A. fraterculus species complex as a tool for species delimitation. Here we examined the existence and strength of prezygotic and postzygotic isolation between sympatric populations of two closely related species within the highly derived fraterculus group (A. fraterculus and A. obliqua), coexisting in nature. Although adults of both species showed a strong tendency for assortative mating, a small proportion of hybrid pairings in both directions were observed. We also observed asymmetric postzygotic isolation, with one hybrid cross displaying a strong reduction in fecundity and F1 egg fertility. Survival was greater for the progeny of homotypic and hybrid crosses in the maternal host. There was a marked female biased sex ratio distortion for both F1 hybrid adults. Hybridization between A. fraterculus and A. obliqua in nature may be difficult but possible; these two species display stronger reproductive isolation than all pairs of species previously examined in the A. fraterculus species complex. Asymmetric postzygotic isolation is suggestive of Wolbachia mediated cytoplasmic incompatibilities that may be exploited in area-wide pest management. PMID- 28586144 TI - Co-occurrence of Jalili syndrome and muscular overgrowth. AB - Jalili syndrome is a rare disorder inherited in an autosomal recessive pattern manifesting as a combination of cone-rod dystrophy including progressive loss of visual acuity, color blindness, photophobia, and amelogenesis imperfecta with hypoplastic, immature, or hypocalcified dental enamel. It is caused by mutations in CNNM4, which encodes the ancient conserved domain protein 4. Here we report three brothers with Jalili syndrome and muscle overgrowth of the legs. Myopathic changes were found in needle electromyography. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant. In order to exclude other causative variants that could modify the patients' phenotype we performed exome sequencing and MLPA analysis of the DMD gene in Patient 1. These analyses did not identify any additional variants. Our results expand the mutational spectrum associated with Jalili syndrome and suggest that mild myopathy with muscle overgrowth of the legs could be a newly identified manifestation of the disorder. PMID- 28586143 TI - Current status of non-invasive prenatal testing in Japan. AB - AIM: The purpose of this study was to report the 3-year experience of a nationwide demonstration project to introduce non-invasive prenatal testing (NIPT) of maternal plasma for aneuploidy, and review the current status of NIPT in Japan. METHODS: Tests were conducted to detect aneuploidy in high-risk pregnant women, and adequate genetic counseling was provided. The clinical data, test results, and pregnancy outcomes were recorded. We discuss the problems of NIPT on the basis of published reports and meta-analyses. RESULTS: From April 2013 to March 2016, 30 613 tests were conducted at 55 medical sites participating in a multicenter clinical study. Among the 30 613 women tested, 554 were positive (1.81%) and 30 021 were negative (98.1%) for aneuploidy. Of the 289, 128, and 44 women who tested positive for trisomies 21, 18, and 13, respectively, and underwent definitive testing, 279 (96.5%), 106 (82.8%), and 28 (63.6%) were determined to have a true-positive result. For the 13 481 women with negative result and whose progress could be traced, two had a false-negative result (0.02%). The tests were performed on the condition that a standard level of genetic counseling be provided at hospitals. CONCLUSION: Here, we report on the 3 year nationwide experience with NIPT in Japan. It is important to establish a genetic counseling system to enable women to make informed decisions regarding prenatal testing. Moreover, a welfare system is warranted to support women who decide to give birth to and raise children with chromosomal diseases. PMID- 28586145 TI - CT colonography practice at a university teaching hospital: improving standards. PMID- 28586146 TI - Locating the Level and Extent of Congenital High Airway Obstruction: Fluid in the Airway Tract as Reference Points. AB - Described here are a series of four cases of congenital high airway obstruction in the fetus. All of the patients presented in the second trimester and all had hydrops fetalis. Three cases had bilateral hyperinflated lungs, midline shift of heart, flattening or inversion of the diaphragm, and fetal ascites. Autopsy was performed in one of these three and showed laryngeal atresia. In one fetus, there was only a unilateral huge enlargement of the lung with mediastinal shift. On autopsy, this fetus had atresia of right main bronchus. All parents had terminated the pregnancy following the prenatal diagnosis. Laryngeal atresia is an extremely rare fetal anomaly with dismal prognosis. It is important to differentiate the condition from other lesions with a more favorable prognosis, such as congenital adenomatoid malformation of the lung. Much research is needed in the future to explore the therapeutic options, including fetoscopic intervention or transplantation of stem cell-derived airways. PMID- 28586147 TI - Epileptic networks in action: Synchrony between distant hemodynamic responses. AB - OBJECTIVE: Structural and functional imaging studies in focal epilepsy often reveal distributed regions of abnormality. These are interpreted as representing the existence of epileptic networks, but the presence of actual neuronal interactions between these regions has not been demonstrated. We sought to determine whether the distributed hemodynamic responses often seen in functional magnetic resonance imaging (fMRI) studies of scalp interictal epileptic discharges (IEDs) actually correspond to synchronized neuronal activities when examining the intracerebral electroencephalogram (iEEG) at distant nodes of the network. METHODS: We studied 28 patients who underwent first EEG-fMRI and then iEEG, and had significant hemodynamic responses in the gray matter. We coregistered the hemodynamic responses to the iEEG electrode contact positions and analyzed synchrony, measured by correlation, between IEDs recorded by iEEG in regions with and without hemodynamic responses. RESULTS: The synchrony of intracerebral IED activity between pairs of regions showing a hemodynamic response was higher compared to that between pairs of regions without (p < 0.0001) and between pairs of regions, one with and one without hemodynamic response (p < 0.0001). These differences were found during the interictal periods with IEDs but were absent during the interictal periods without IEDs. Higher synchrony was also observed between regions involved at seizure onset (p < 0.0001). INTERPRETATION: EEG-fMRI studies are unique in their ability to reveal hemodynamic concomitants of IEDs anywhere in the brain. This study proves that iEEG activity is synchronized between these regions of hemodynamic response, thus demonstrating the existence of an actual neuronally based interictal epileptic network. This also validates the EEG-fMRI approach to reveal this network noninvasively. Ann Neurol 2017;82:57-66. PMID- 28586148 TI - Use of the optical disector in canine mammary simple and complex carcinomas. AB - Grading of canine mammary carcinomas (CMC) is associated to subjective assessments made by the pathologists. Due to its unbiased nature, stereology can be used to objectively quantify morphological parameters associated with grading and malignancy. However, the use of stereology in CMC has not been fully disclosed. The nuclear numerical density [NV (nuclei, tumor)] is a cellularity associated parameter that can be estimated by the optical disector. Herein, it was estimated in 44 CMC and its association with clinicopathologic factors - such as tumor size, histological subtype and grade, vascular/lymph node invasion, nuclear pleomorphism, and survival - was evaluated. Considering all the cases, the mean NV (nuclei, tumor) was 1.6 * 106 +/- 0.5 * 106 nuclei/mm3 . Lower values were attained in complex carcinomas, comparing to simple carcinomas, in tumors smaller than 5 cm, with low mitotic activity and in those with high nuclear pleomorphism. No statistically significant association with grade or vascular/lymph node invasion was observed, but tumors with disease progression had lower nuclear densities. The NV (nuclei, tumor) and the correlated parameters mirror to some extension those in human breast cancer, suggesting an interesting interspecies agreement. This first estimation of the nuclear numerical density in CMC highlights the feasibility of the optical disector and their utility for objective morphological assessments in CMC. The association between nuclear numerical density and disease progression warrants future studies. PMID- 28586149 TI - Comparative analysis of von Willebrand factor profiles after implantation of left ventricular assist device and total artificial heart. AB - : Essentials Bleeding is a major source of morbidity during mechanical circulatory support. von Willebrand factor (VWF) multimer loss may contribute to bleeding. Different patterns of VWF multimer loss were seen with the two device types. This is the first report of total artificial heart associated VWF multimer loss. SUMMARY: Background Bleeding remains a challenge during mechanical circulatory support and underlying mechanisms are incompletely understood. Functional von Willebrand factor (VWF) impairment because of loss of high molecular-weight multimers (MWMs) produces acquired von Willebrand disease (VWD) after left ventricular assist device (LVAD). Little is known about VWF multimers with total artificial hearts (TAHs). Here, VWF profiles with LVADs and TAHs are compared using a VWD panel. Methods VWD evaluations for patients with LVAD or TAH (2013-14) were retrospectively analyzed and included: VWF activity (ristocetin cofactor, VWF:RCo), VWF antigen (VWF:Ag), ratio of VWF:RCo to VWF:Ag, and quantitative VWF multimeric analysis. Results Twelve patients with LVADs and 12 with TAHs underwent VWD evaluation. All had either normal (47.8%) or elevated (52.2%) VWF:RCo, normal (26.1%) or elevated (73.9%) VWF:Ag and 50.0% were disproportional (ratio <= 0.7). Multimeric analysis showed abnormal patterns in all patients with LVADs: seven with high MWM loss; five with highest MWM loss. With TAH, 10/12 patients had abnormal patterns: all with highest MWM loss. High MWM loss correlated with presence of LVAD and highest MWM loss with TAH. Increased low MWMs were detected in 22/24. Conclusion Using VWF multimeric analysis, abnormalities after LVAD or TAH were detected that would be missed with measurements of VWF level alone: loss of high MWM predominantly in LVAD, loss of highest MWM in TAH, and elevated levels of low MWM in both. This is the first study to describe TAH-associated highest MWM loss, which may contribute to bleeding. PMID- 28586150 TI - Analysis of viral infection and biomarkers in patients with acute exacerbation of chronic obstructive pulmonary disease. AB - OBJECTIVE: To investigate viral infection in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Shanghai, and to analyze the clinical characteristics and biomarkers in viral infection. METHODS: This study included all consecutive patients who were admitted for a diagnosis of AECOPD during June 2013 to May 2015. Thirty-one stable COPD patients and 31 healthy controls were also recruited. Oropharyngeal samples were assessed, PCR for respiratory viruses were performed. Patients were divided into AECOPD virus positive (+) group and AECOPD virus-negative (-) group according to viral detection. Luminex was used to detect the concentrations of inflammatory cytokines in the serum. RESULTS: A total of 264 patients were included with a mean age of 75 +/- 0.5 years. There were 72 patients (27.3%) identified with viral positive, of whom two patients were detected with double viral infections (FluA + FluB and RSVA + HRV, respectively). The rate of viral detection was associated with season, highest in winter. Comparisons of clinical characteristics showed no significant differences between AECOPD virus+ group and AECOPD virus- group. However, serum concentrations of interferon-inducible protein-10 (IP-10) and interferon-gamma (IFN-gamma) in virus+ AECOPD patients were significantly higher than those in the virus- AECOPD, stable COPD and healthy control groups (P < .05). CONCLUSION: Viral infection was an important pathogen in AECOPD patients; the most common viruses included FluA, HRV and FluB. It was very difficult to diagnose the viral infection according to clinical characteristics. The increased of serum IP-10 and IFN-gamma levels might be value to indicate viral infection in AECOPD. PMID- 28586151 TI - A heterozygous microdeletion of 20p12.2-3 encompassing PROKR2 and BMP2 in a patient with congenital hypopituitarism and growth hormone deficiency. AB - Congenital growth hormone deficiency is a rare disorder with an incidence of approximately 1 in 4,000 live births. Pituitary development is under the control of a multitude of spatiotemporally regulated signaling molecules and transcription factors. Mutations in the genes encoding these molecules can result in hypopituitarism but for the majority of children with congenital hypopituitarism, the aetiology of their disease remains unknown. The proband is a 5-year-old girl who presented with neonatal hypoglycaemia and prolonged jaundice. No definitive endocrine cause of hypoglycaemia was identified in the neonatal period. She was born of normal size at 42 weeks but demonstrated growth failure with a progressive reduction in height to -3.2 SD by age 4.5 years and failed a growth hormone stimulation test with a peak growth hormone of 4.2 mcg/L. MRI of the pituitary gland demonstrated a hypoplastic anterior lobe and ectopic posterior lobe. Array CGH demonstrated an inherited 0.2 Mb gain at 1q21.1 and a de novo 4.8 Mb heterozygous deletion at 20p12.2-3. The deletion contained 17 protein coding genes including PROKR2 and BMP2, both of which are expressed during embryological development of the pituitary gland. PROKR2 mutations have been associated with hypopituitarism but a heterozygous deletion of this gene with hypopituitarism is a novel observation. In conclusion, congenital hypopituitarism can be present in individuals with a 20p12.3 deletion, observed with incomplete penetrance. Array CGH may be a useful investigation in select cases of early onset growth hormone deficiency, and patients with deletions within this region should be evaluated for pituitary hormone deficiencies. PMID- 28586152 TI - Right Upper Quadrant Pain: Ultrasound First! AB - Acute right upper quadrant (RUQ) pain is a common presenting symptom in emergency departments and outpatient medical practices, and is most commonly attributable to biliary and hepatic pathology. Ultrasound should be used as a first-line imaging modality for the diagnosis of gallstones and cholecystitis, as it allows the differentiation of medical and surgical causes of upper abdominal pathology, and in many circumstances is sufficient to guide patient management. Knowledge of strengths and limitations of ultrasound in the evaluation of RUQ is paramount in correct diagnosis. A spectrum of RUQ pathology for which a RUQ ultrasound examination should reasonably be considered as the initial imaging modality of choice will be reviewed. PMID- 28586153 TI - MiR-19a Affects Hepatocyte Autophagy via Regulating lncRNA NBR2 and AMPK/PPARalpha in D-GalN/Lipopolysaccharide-Stimulated Hepatocytes. AB - This study aims to evaluate the potential involvement and regulatory mechanism of miR-19a in hepatocytes autophagy of acute liver failure (ALF). The in vitro hepatocytes injury model of primary hepatocyte and hepatocytes line HL-7702 was established by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) co treatment. Relative expression level of miR-19a and NBR2 was determined by qRT PCR. Protein expression of AMPK/PPARalpha and autophagy-related gene was determined by Western blot. In hepatic tissue of 20 ALF patients and D-GalN/LPS stimulated hepatocytes, miR-19a was upregulated and NBR2 was downregulated. D GalN/LPS stimulation caused the inactivation of AMPK/PPARalpha signaling and the decrease of autophagy-related LC3-II/LC3-I ratio and beclin-1 expression in hepatocytes. The expression of both AMPK/PPARalpha and NBR2 were negatively controlled by miR-19a overexpression or knockdown. Moreover, both NBR2 and PPARalpha were targeted regulated by miR-19a according to luciferase reporter assay. In D-GalN/LPS-stimulated hepatocytes, AMPK activation promoted PPARalpha expression. AMPK inactivation inhibited the pro-autophagy effect of miR-19a and caused the decrease of LC3-II/LC3-I ratio and beclin-1 expression. PPARalpha activation abrogated the anti-autophagy effect of miR-19a mimic and caused the increase of LC3-II/LC3-I ratio and beclin-1 expression. NBR2 knockdown reversed the anti-autophagy impact of miR-19a inhibitor and caused the decrease of LC3 II/LC3-I ratio and beclin-1 expression. In summary, our data suggested that miR 19a negatively controlled the autophagy of hepatocytes attenuated in D-GalN/LPS stimulated hepatocytes via regulating NBR2 and AMPK/PPARalpha signaling. J. Cell. Biochem. 119: 358-365, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28586154 TI - 1,4-Diphosphinines from Imidazole-2-thiones. AB - 1,4-Diphosphinines that are fused to two thiourea units were synthesized from the corresponding tricyclic 1,4-dichloro-1,4-dihydro-1,4-diphosphinines, and their structures and spectroscopic features are described. Electrochemical studies revealed very low oxidation potentials, which are due to the effective pi interaction between the 1,4-diphosphinine ring and the orbitals of the two ylidic C=S bonds. In accordance with the low-lying LUMO, which is largely localized at the two phosphorus centers, dianion formation is strongly preferred. Despite the small HOMO-LUMO gap, which is in accordance with the red color of the title compounds, theoretical calculations suggest considerable aromaticity for the 1,4 diphosphinine ring. PMID- 28586155 TI - One-pot preparation of an organic polymer monolith by thiol-ene click chemistry for capillary electrochromatography. AB - A novel organic monolith was successfully fabricated by a one-pot thiol-ene click reaction of triallyl isocyanurate with pentaerythritol tetrakis-(2 mercaptoacetate) and mercaptopropionic acid in the presence of porogens. We investigated the effects of the ratio of monomer and cross-linking agent, the type and ratio of porogen, and click reaction temperature on the permeability and morphology of the prepared poly triallyl isocyanurate-co-pentaerythritol tetrakis (2-mercaptoacetate) monoliths. The monolith was also characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The results indicated that the monoliths had continuous porous framework, good permeability, and high mechanical stability. A series of analytes with different properties such as alkylbenzenes, polycyclic aromatic hydrocarbons, anilines, and phenols were used to evaluate the electrochromatographic performance of the prepared monoliths in pressurized capillary electrochromatography. The prepared polymer monolith showed typical reversed-phase electrochromatographic behavior for hydrophobic substances. Moreover, the prepared monolith showed a mix of reversed phase and cation exchange interaction modes for basic aniline compounds. The minimum plate height of the monolith was 8.76 MUm (132 100 plates/m) for propylbenzene. These results demonstrated that one-pot thiol-ene click chemistry can provide a simple and reliable method for the preparation of organic monoliths. PMID- 28586156 TI - Thermal adaptation and phenotypic plasticity in a warming world: Insights from common garden experiments on Alaskan sockeye salmon. AB - An important unresolved question is how populations of coldwater-dependent fishes will respond to rapidly warming water temperatures. For example, the culturally and economically important group, Pacific salmon (Oncorhynchus spp.), experience site-specific thermal regimes during early development that could be disrupted by warming. To test for thermal local adaptation and heritable phenotypic plasticity in Pacific salmon embryos, we measured the developmental rate, survival, and body size at hatching in two populations of sockeye salmon (Oncorhynchus nerka) that overlap in timing of spawning but incubate in contrasting natural thermal regimes. Using a split half-sibling design, we exposed embryos of 10 families from each of two populations to variable and constant thermal regimes. These represented both experienced temperatures by each population, and predicted temperatures under plausible future conditions based on a warming scenario from the downscaled global climate model (MIROC A1B scenario). We did not find evidence of thermal local adaptation during the embryonic stage for developmental rate or survival. Within treatments, populations hatched within 1 day of each other, on average, and among treatments, did not differ in survival in response to temperature. We did detect plasticity to temperature; embryos developed 2.5 times longer (189 days) in the coolest regime compared to the warmest regime (74 days). We also detected variation in developmental rates among families within and among temperature regimes, indicating heritable plasticity. Families exhibited a strong positive relationship between thermal variability and phenotypic variability in developmental rate but body length and mass at hatching were largely insensitive to temperature. Overall, our results indicated a lack of thermal local adaptation, but a presence of plasticity in populations experiencing contrasting conditions, as well as family-specific heritable plasticity that could facilitate adaptive change. PMID- 28586157 TI - Role of Point Shear Wave Elastography in the Determination of the Severity of Fibrosis in Pediatric Liver Diseases With Pathologic Correlations. AB - OBJECTIVES: Our aims in this study were as follows: (1) to determine the cutoff value that can distinguish between advanced liver fibrosis and normal liver tissue for two different elastographic techniques; (2) to determine the cutoff value that can distinguish mild liver fibrosis from normal liver tissue for the techniques; and (3) to assess tissue stiffness in nonalcoholic fatty liver disease (NAFLD). METHODS: Seventy-five patients assessed for liver biopsy on the same day were evaluated by point shear wave elastography. Thirty-one healthy children and 11 children with NAFLD were also evaluated. A 9L4 transducer with Virtual Touch quantification (VTQ) and Virtual Touch imaging and quantification (VTIQ) modes (Siemens Medical Solutions, Mountain View, CA) was used for quantification. RESULTS: The shear wave speed of the patients with NAFLD was higher than that of the control group. The only predictive factor for VTQ and VTIQ was the histologic fibrosis score (model-adjusted R2 = 0.56 for VTQ and 0.75 for VTIQ). Shear wave speed cutoffs were 1.67 m/s for VTQ and 1.56 m/s for VTIQ in detecting fibrosis or inflammation and 2.09 m/s for VTQ and 2.17 m/s for VTIQ in discriminating children with low and high histologic liver fibrosis scores. CONCLUSIONS: The VTQ and VTIQ values reveal high-grade histopathologic fibrosis and have high success rates when distinguishing high- from low-grade fibrosis. However, they have limited success rates when differentiating low-grade fibrosis from normal liver tissue. PMID- 28586158 TI - Quantitative assessment of fascia preservation improves the prediction of membranous urethral length and inner levator distance on continence outcome after robot-assisted radical prostatectomy. AB - AIMS: To determine whether preoperative prostate/pelvic anatomical structures and intraoperative fascia preservation (FP) predict continence recovery after robot assisted radical prostatectomy (RARP). METHODS: Between January 2012 and March 2016, 439 prostate cancer (PCa) patients with normal preoperative continence were retrospectively included. FP score was defined as the extent of FP from base to apex of the prostate, quantitatively assessed by the surgeon. Anatomical prostate structures were measured on endorectal preoperative Magnetic Resonance Imaging. The International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) was used to assess urinary incontinence (UI). Cox analysis was used to determine predictive factors for early continence recovery. Finally a binary logistic regression analysis was performed to develop a risk calculator. RESULTS: At a median follow up of 12.1 months 50.8% of men reported UI. In the Cox multivariate analysis longer membranous urethral length (MUL; P < 0.0001; OR 1.309; CI 1.211, 1.415) and shorter inner levator distance (ILD; P < 0.0001; OR 0.904; CI 0.85, 0.961) were predictors of earlier continence recovery. In the multivariate binary logistic regression analysis longer MUL (P < 0.0001; OR 1.565, CI 1.362, 1.798), shorter ILD (P < 0.0001; OR 0.819, CI 0.742, 0.904) and higher FP score (P = 0.024; OR 1.089, CI 1.011, 1.172) were independent predictors of continence outcome. The risk calculator predicted continence recovery between 1.3% and 99%. CONCLUSIONS: Preoperative longer MUL and shorter ILD, but also intraoperative FP independently improve continence recovery after RARP. The risk calculator could be used to identify patients at high risk of UI. PMID- 28586159 TI - Reply to Emile et al. PMID- 28586160 TI - Preparation of Solid Polyfunctional Alkynylzinc Pivalates with Enhanced Air and Moisture Stability for Organic Synthesis. AB - We report the preparation of solid and air-stable polyfunctionalized alkynylzinc pivalates from the corresponding alkynes using TMPZnOPiv (TMP=2,2,6,6 tetramethylpiperidyl) as base. These organozinc pivalates are obtained as powders under mild conditions in excellent yields and can be manipulated in air for several hours without significant decomposition. These zinc reagents show an excellent reactivity in various carbon-carbon bond- forming reactions and 1,3 dipolar cycloadditions. An alkynylzinc pivalate has been used to prepare a carboxyamidotriazole with potential antineoplastic activity in eight steps and 38 % overall yield. PMID- 28586161 TI - Alkyltin Keggin Clusters Templated by Sodium. AB - Dodecameric (Sn12 ) and hexameric topologies dominate monoalkyltin-oxo cluster chemistry. Their condensation, triggered by radiation exposure, recently produced unprecedented patterning performance in EUV lithography. A new cluster topology was crystallized from industrial n-BuSnOOH, and additional characterization techniques indicate other clusters are present. Single-crystal X-ray analysis reveals a beta-Keggin cluster, which is known but less common than other Keggin isomers in polyoxometalate and polyoxocation chemistry. The structure is formulated [NaO4 (BuSn)12 (OH)3 (O)9 (OCH3 )12 (Sn(H2 O)2 )] (beta-NaSn13 ). SAXS, NMR, and ESI MS differentiate beta-NaSn13 , Sn12 , and other clusters present in crude "n-BuSnOOH" and highlight the role of Na as a template for alkyltin Keggin clusters. Unlike other alkyltin clusters that are cationic, beta NaSn13 is neutral. Consequently, it stands as a unique model system, absent of counterions, to study the transformation of clusters to films and nanopatterns. PMID- 28586163 TI - A Dysprosium Metallocene Single-Molecule Magnet Functioning at the Axial Limit. AB - Abstraction of a chloride ligand from the dysprosium metallocene [(Cpttt )2 DyCl] (1Dy Cpttt =1,2,4-tri(tert-butyl)cyclopentadienide) by the triethylsilylium cation produces the first base-free rare-earth metallocenium cation [(Cpttt )2 Dy]+ (2Dy ) as a salt of the non-coordinating [B(C6 F5 )4 ]- anion. Magnetic measurements reveal that [2Dy ][B(C6 F5 )4 ] is an SMM with a record anisotropy barrier up to 1277 cm-1 (1837 K) in zero field and a record magnetic blocking temperature of 60 K, including hysteresis with coercivity. The exceptional magnetic axiality of 2Dy is further highlighted by computational studies, which reveal this system to be the first lanthanide SMM in which all low-lying Kramers doublets correspond to a well-defined MJ value, with no significant mixing even in the higher doublets. PMID- 28586162 TI - Chain length-dependent effects of inulin-type fructan dietary fiber on human systemic immune responses against hepatitis-B. AB - SCOPE: In vivo studies demonstrating that only specific dietary-fibers contribute to immunity are still inconclusive, as measuring immune effects in healthy humans remains difficult. We applied a relatively inefficacious vaccination-challenge to study chain length-dependent effects of inulin-type fructan (ITF) dietary fibers on human immunity. METHODS AND RESULTS: ITFs with two different 'degree of polymerization-' (DP)-profiles were tested in vitro for effects on PBMC-cytokines and TLR2 activation. In a double-blind placebo-controlled trial, 40 healthy volunteers (18-29 years) were divided into three groups and supplemented from day 1 to day 14 with DP10-60 ITF, DP2-25 ITF (both n = 13), or fructose placebo (n = 14), 8 g/day. On day 7, all volunteers were vaccinated against hepatitis B. Anti HbsAg-titer development and lymphocyte subsets were studied. In vitro, DP10-60 ITFs stimulated a Th1-like cytokine profile and stimulated TLR2 more strongly than DP2-25 ITFs. In vivo, DP10-60 increased anti-HBsAg titers, Th1-cells, and transitional B-cells. Both ITFs increased CD45ROhi CTLs at day 35, and CD161+ cytokine producing NK-cells at day 21 and 35. CONCLUSION: Support of immunity is determined by the chain length of ITFs. Only long-chain ITFs support immunity against pathogenic hepB-epitopes introduced by vaccination. Our findings demonstrate that specific dietary fibers need to be selected for immunity support. PMID- 28586166 TI - Differentiating Psoriatic Arthritis From Psoriasis Without Psoriatic Arthritis Using Novel Serum Biomarkers. AB - OBJECTIVE: There is a high prevalence of undiagnosed psoriatic arthritis (PsA) in patients with psoriasis. Identifying soluble biomarkers for PsA will help in screening psoriasis patients for appropriate rheumatology referral. We therefore aimed to investigate whether serum levels of novel markers previously discovered by quantitative mass spectrometric analysis of synovial fluid and skin biopsies performs better than the C-reactive protein (CRP) level in differentiating PsA patients from those with psoriasis without PsA (PsC). METHODS: In this case control study, serum samples were obtained from 100 subjects with PsA, 100 with PsC, and 100 healthy controls. Patients with PsA and PsC were group matched for age, sex, psoriasis duration, and Psoriasis Area and Severity Index and were not currently receiving biologic treatment. Using enzyme-linked immunosorbent assay, 4 high-priority markers (Mac-2-binding protein [M2BP], CD5-like protein [CD5L], myeloperoxidase [MPO], and integrin beta5 [ITGbeta5]), as well as previously established markers (matrix metalloproteinase 3 [MMP-3] and CRP level) were assayed. Data were analyzed using logistic regression. Receiver operating characteristic (ROC) curves were plotted. RESULTS: In comparisons to controls, CD5L, ITGbeta5, M2BP, MPO, MMP-3, and CRP level were independently associated with PsA, while only CD5L, M2BP, and MPO were independently associated with PsC alone. In comparisons to PsC, ITGbeta5, M2BP, and CRP level were independently associated with PsA. ROC analysis of this model shows an area under the curve (AUC) of 0.85 (95% confidence interval [95% CI] 0.80-0.90). The model that included CRP level alone had an AUC of 0.71 (95% CI 0.64-0.78). CONCLUSION: CD5L, ITGbeta5, M2BP, MPO, MMP-3, and CRP level are markers for PsA. The combination of ITGbeta5, M2BP, and CRP level differentiates PsA from PsC, and performs better than CRP level alone. PMID- 28586164 TI - Synthesis of [5,6]-Bicyclic Heterocycles with a Ring-Junction Nitrogen Atom: Rhodium(III)-Catalyzed C-H Functionalization of Alkenyl Azoles. AB - The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C-H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C-H functionalization for the rapid synthesis of a patented drug candidate. PMID- 28586165 TI - 3,3'-Diindolylmethane suppresses high-fat diet-induced obesity through inhibiting adipogenesis of pre-adipocytes by targeting USP2 activity. AB - SCOPE: Indole-3-carbinol (I3C), a derivative abundant in cruciferous vegetables such as cabbage, is well known for its various health benefits such as chemo preventive and anti-obesity effects. I3C is easily metabolized to 3,3' diindolylmethane (DIM), a more stable form, in acidic conditions of the stomach. However, the anti-obesity effect of DIM has not been investigated clearly. We sought to investigate the effect of DIM on diet-induced obesity and to elucidate its underlying mechanisms. METHODS AND RESULTS: High-fat diet (HFD)-fed obese mouse and MDI-induced 3T3-L1 adipogenesis models were used to study the effect of DIM. We observed that the administration of DIM (50 mg/kg BW) significantly suppressed HFD-induced obesity, associated with a decrease in adipose tissue. Additionally, we observed that DIM treatment (40 and 60 MUM), but not I3C treatment, significantly inhibited MDI-induced adipogenesis by reducing the levels of several adipogenic proteins such as PPAR-gamma and C/EBPalpha. DIM, but not I3C, suppressed cell cycle progression in the G1 phase, which occurred in the early stage of adipogenesis, inducing post-translational degradation of cyclin D1 by inhibiting ubiquitin specific peptidase 2 (USP2) activities. CONCLUSION: Our findings indicate that cruciferous vegetables, which can produce DIM as a metabolite, have the potential to prevent or treat chronic obesity. PMID- 28586168 TI - Synthesis and Characterization of a Metallacyclic Framework with Three Fused Five membered Rings. AB - Polycyclic complexes containing a bridgehead transition metal are interesting species because the transition metal is shared by all the rings simultaneously. In this study, we present a novel osmium-bridgehead system with three fused five membered rings. This novel framework can be viewed as a 10-atom carbon chain coordinating to the osmium center. In sharp contrast to the nonplanar organic analogue, this unique metallacycle exhibits good planarity, which was unambiguously verified by means of X-ray diffraction. Interestingly, preliminary DFT calculations show that the aromaticity in the three 5MRs of these osmatricycles can be easily tuned by the ligand substitution. Finally, the broad UV/Vis absorption spectra of these novel polycyclic complexes were also reported. PMID- 28586167 TI - Card9-dependent IL-1beta regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer. AB - Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell-specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL 1beta production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis-associated cancer (CAC) model. Card9-/- mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL-1beta generation and defective IL-1beta controlled IL-22 production from group 3 innate lymphoid cells. Consistent with the key role of immune-derived IL-22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9-/- mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9-controlled, ILC3-mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9-mediated innate immunity in inflammation-associated carcinogenesis. PMID- 28586171 TI - Predictors of oral health-related quality of life in patients with temporomandibular disorders. PMID- 28586169 TI - Metabolomic-based identification of clusters that reflect dietary patterns. AB - SCOPE: Classification of subjects into dietary patterns generally relies on self reporting dietary data which are prone to error. The aim of the present study was to develop a model for objective classification of people into dietary patterns based on metabolomic data. METHODS AND RESULTS: Dietary and urinary metabolomic data from the National Adult Nutrition Survey (NANS) was used in the analysis (n = 567). Two-step cluster analysis was applied to the urinary data to identify clusters. The subsequent model was used in an independent cohort to classify people into dietary patterns. Two distinct dietary patterns were identified. Cluster 1 was characterized by significantly higher intakes of breakfast cereals, low fat and skimmed milks, potatoes, fruit, fish and fish dishes (p < 0.05) representing a "healthy" cluster. Cluster 2 had significantly higher intakes of chips/processed potatoes, meat products, savory snacks and high-energy beverages (p < 0.05) representing an "unhealthy cluster". Classification was supported by significant differences in nutrient status (p < 0.05). Validation in an independent group revealed that 94% of subjects were correctly classified. CONCLUSION: The model developed was capable of classifying individuals into dietary patterns based on metabolomics data. Future applications of this approach could be developed for rapid and objective assignment of subjects into dietary patterns. PMID- 28586170 TI - Pru p 3-Epitope-based sublingual immunotherapy in a murine model for the treatment of peach allergy. AB - SCOPE: Food-specific immunotherapy (SIT) is a promising treatment for lipid transfer protein (LTP)-syndrome. We propose a novel sublingual-SIT (SLIT) that combines a Pru p 3 T-cell peptide and an oligodeoxyribonucleotide (ODN) with CpG motifs (ODN-CpG) as adjuvants to induce a specific Th1/Treg response. METHODS AND RESULTS: LTP-peach allergic mice were treated sublingually with a combination of a CpG sequence and mono- or tetravalent systems including a Pru p 3 peptide, D1 (Prup3) or D4 (Prup3). Mice were challenged intraperitoneally with Pru p 3 one or three weeks after SLIT and tolerance was assessed. Mice treated with D1 (Prup3)+CpG were protected from anaphylaxis after Pru p 3 challenge. They showed no change in body temperature, lower levels of Pru p 3-specific IgE and IgG1 antibodies and higher levels of sIgG2a compared to the untreated group. They had fewer IgE and IgG1 secreting cells and more sIgG2a secreting cells. Moreover, a significantly lower number of Pru p 3-specific CD4+ T cells and a higher number of Treg cells were found, alongside a Th1 cytokine pattern. These changes were maintained for three weeks after stopping treatment. CONCLUSION: D1 Prup3+CpG represents a promising SIT for food allergy. It is easily synthesized and induces protection from anaphylaxis to Pru p 3 that is maintained for at least three weeks. PMID- 28586172 TI - Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta analysis. AB - : Many noninvasive methods for diagnosing liver fibrosis (LF) have been proposed. To determine the best method for diagnosing LF in nonalcoholic fatty liver disease (NAFLD), we conducted a systemic review and meta-analysis to compare the performance of aspartate aminotransferase to platelets ratio index (APRI), fibrosis-4 index (FIB-4), BARD score, NAFLD fibrosis score (NFS), FibroScan, shear wave elastography (SWE), and magnetic resonance elastography (MRE) for diagnosing LF in NAFLD. We compared the sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve (AUROC) of these noninvasive methods for detecting significant fibrosis (SF), advanced fibrosis (AF), and cirrhosis. Heterogeneity was explored using meta-regression. Sixty-four articles with a total of 13,046 NAFLD subjects were included. The overall mean prevalence of SF, AF, and cirrhosis was 45.0%, 24.0%, and 9.4% in NAFLD patients, respectively. With an APRI threshold of 1.0 and 1.5, the sensitivities and specificities were 50.0% and 84.0% and 18.3% and 96.1%, respectively, for AF. With a FIB-4 threshold of 2.67 and 3.25, the sensitivities and specificities were 26.6% and 96.5% and 31.8% and 96.0%, respectively, for AF. The summary sensitivities and specificities of BARD score (threshold of 2), NFS (threshold of -1.455), FibroScan M (threshold of 8.7 9), SWE, and MRE for detecting AF were 0.76 and 0.61, 0.72 and 0.70, 0.87 and 0.79, 0.90 and 0.93, and 0.84 and 0.90, respectively. The summary AUROC values using APRI, FIB-4, BARD score, NFS, FibroScan M probe, XL probe, SWE, and MRE for diagnosing AF were 0.77, 0.84, 0.76, 0.84, 0.88, 0.85, 0.95, and 0.96, respectively. CONCLUSION: MRE and SWE may have the highest diagnostic accuracy for staging fibrosis in NAFLD patients. Among the four noninvasive simple indexes, NFS and FIB-4 probably offer the best diagnostic performance for detecting AF. (Hepatology 2017;66:1486-1501). PMID- 28586173 TI - Xanthophyll esters are found in human colostrum. AB - SCOPE: Carotenoids in human milk are associated with other lipid counterparts in several metabolic processes. One interesting association that has not been demonstrated to date is the presence of xanthophyll esters. Colostrum and mature milk samples were analyzed to determine the occurrence of xanthophyll esters and identify the compounds. Thus, the association of the amounts of these compounds with lactation and whether they are significant contributors to the carotenoid profile of human milk was assessed. METHODS AND RESULTS: Pre-term and term delivering mothers were included in the study to donate colostrum at 3-5 days postpartum and mature milk at 15 days postpartum. Carotenoids extracts were subjected to a clean-up procedure to remove the triacylglycerol fraction and then analyzed by HPLC-MSn . Identification of xanthophyll esters was achieved by considering their chromatographic behaviour, UV-visible characteristics and MSn features. CONCLUSION: Xanthophyll esters are significant contributors to the carotenoid profile in the colostrum, while mature milk does not contain these compounds. Therefore, fatty acid acylation to xanthophylls is activated during the accumulation of carotenoids in the human mammary gland. The sharp decline in the amount of xanthophyll esters in mature milk indicates that the lipophilic components are those recently incorporated in the mammary epithelium. PMID- 28586174 TI - 2,6-Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure-Activity Relationships. AB - A wide variety of drug-resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic-resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature-sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic beta-tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin resistant Staphylococcus aureus, as well as vancomycin-resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure-activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6-difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials. PMID- 28586175 TI - Adaptation of gut microbiome to different dietary nonstarch polysaccharide fractions in a porcine model. AB - SCOPE: Dietary fibers, consisting of nonstarch polysaccharides (NSPs) were found to modulate the gut microbiota. However, little is known about the role of a separated fiber fraction. Here, we describe a response in gut microbiome to different fiber fractions using a porcine model. METHODS AND RESULTS: Ileal and cecal digesta were collected from pigs fed with fiber-free diet (FFD) or diet containing 5% cellulose (CEL), xylan (XYL) or beta-glucan (GLU). We observed an elevated 16S rRNA gene copies in ileum and cecum digesta after NSP ingestion. Interestingly, we found that cecum digesta contained higher bacterial diversity than ileum digesta. Moreover, NSPs had no significant influence on overall diversity, but acutely altered the abundance of specific bacteria. Importantly, NSPs decreased the abundance of phylum Firmicutes, but increased the phylum Proteobacteria in ileal samples. Among the NSP-treated groups, pigs on CEL containing diet had exclusively higher abundance of Lactobacillus spp. in the ileum. Whereas, the GLU-treated samples had more Clostridium spp. CONCLUSION: This study not only indicated how the gut microbiome adapts to the three major NSP fractions, but the results also contribute to our understanding of the role of dietary fibers in modulating gut microbiota and health. PMID- 28586176 TI - Visible-Light Photoreduction of CO2 to CH4 over ZnTe-Modified TiO2 Coral-Like Nanostructures. AB - Rapidly depleting fossil fuels and the related environmental issues are two alarming global concerns the world is facing today. To address these issues efficiently, future energy requirements need to be fulfilled by renewable and environmentally friendly resources. In this context, we report the ZnTe-modified TiO2 photocatalysts with varying amounts of ZnTe (1.96, 16, and 65 %) for the photoreduction of carbon dioxide into methane under visible light. The hydrothermally synthesized photocatalysts have been characterized by using various techniques, such as X-ray diffraction, scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy, transmission electron microscopy, UV/Vis spectroscopy, X-ray photoelectron spectroscopy and Brunauer Emmett-Teller (BET) analysis for surface-area measurements. The photocatalyst with 1.96 % ZnTe shows the best results, which are attributed to its high BET specific surface area and the formation of a heterojunction at the interface, which can facilitate efficient charge transfer. PMID- 28586177 TI - Teaching laboratory management and quality assurance/quality improvement skills in a cytopathology fellowship program. PMID- 28586178 TI - Outcomes in Duchenne muscular dystrophy: nature, nurture, culture-or all three? PMID- 28586180 TI - VSPrep: A General KNIME Workflow for the Preparation of Molecules for Virtual Screening. AB - Over the past decades, virtual screening has proved itself to be a valuable asset to identify new bioactive compounds. The vast majority of commonly used techniques can be described in three steps: pre-processing the dataset i. e. small (ligands) and eventually larger (receptors) molecules, execute the method and finally analyse the results. Hence, the preparation of ligands is a critical step for success of commonly used virtual screening approaches such as protein ligand docking, similarity or pharmacophore search. We present here a new workflow, VSPrep, for the pre-processing of small molecules; it is based on freely accessible tools for academics and is integrated within the KNIME platform. It can be used to perform several chemoinformatics tasks such as molecular database cleaning, tautomer and stereoisomer enumeration, focused library design and conformer generation. Additionally, graphical reports of the results are provided to the user as a convenient analysis tool. PMID- 28586181 TI - ? PMID- 28586182 TI - Single Port Laparoscopic Gastrostomy: description of a technique and initial experience. AB - INTRODUCTION: Since the first classic descriptions of surgicalgastrostomies for feeding by supra-umbilical medialincisions, patients were operated under general anesthesia,with prolonged time of surgery; these were patients in poorhealth status, undernourished due to inadequate intake orto neurological or tumor involvement, with prolonged hospitalization,both for the recovery of the intestinal motilityas well as for the recovery of post-surgical wounds. Therefore,we describe a new minimally invasive technique as an alternativeto the percutaneous or endoscopic gastrostomy, inpatients where we are not allowed to place a nasogastric tubeto insufflate the stomach. This is mostly seen in patients withtumors, which cause obstruction. MATERIAL AND METHODS: Between July 2012 and June 2013, 8 patients underwenta single port laparoscopic gastrostomy. Five were females,mean age: 77 years (range: 67-87). In all the patients, itwas impossible to place a nasogastric tube, due to obstructivetumor. RESULTS: The mean time of the procedure was45 minutes. Seven patients underwent tolerance of dextrose10% through the catheter after 12 hours and one 24 hoursafter the procedures. Enteral feeding was indicated after thedextrose 10% tolerance was performed. No complications relatedto the procedure were observed. DISCUSSION: Currently,the gold standard technique to perform a gastrostomy is thepercutaneous or endoscopic approach. In patients with headand neck tumors, when it is not possible to insert a nasogastrictube to insufflate the stomach, a laparoscopic gastrostomywould be indicated. We describe a new technique, step bystep, to perform less invasive laparoscopic surgery by a singleport laparoscopic gastrostomy. CONCLUSION: The diametercreated is the same as the one performed with an open technique,but in this case, with a minimally invasive approach,that allows us to start feeding the patient with a high qualityof feeding, because of the wider lumen. PMID- 28586179 TI - Improved posttransplant mortality after share 35 for liver transplantation. AB - : The Share 35 policy was implemented in June 2013 to improve equity in access to liver transplantation (LT) between patients with fulminant liver failure and those with cirrhosis and severe hepatic decompensation. The aim of this study was to assess post-LT outcomes after Share 35. Relevant donor, procurement, and recipient data were extracted from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. All adult deceased donor LTs from January 1, 2010, to March 31, 2016, were included in the analysis. One-year patient survival before and after Share 35 was assessed by multivariable Cox proportional hazards analysis, with adjustment for variables known to affect graft survival. Of 34,975 adult LT recipients, 16,472 (47.1%) were transplanted after the implementation of Share 35, of whom 4,599 (27.9%) had a Model for End Stage Liver Disease (MELD) score >=35. One-year patient survival improved from 83.9% to 88.4% after Share 35 (P < 0.01) for patients with MELD >=35. There was no significant impact on survival of patients with MELD <35 (P = 0.69). Quality of donor organs, as measured by a donor risk index without the regional share component, improved for patients with MELD >=35 (P < 0.01) and worsened for patients with lower MELD (P < 0.01). In multivariable Cox regression analysis, Share 35 was associated with improved 1-year patient survival (hazard ratio, 0.69; 95% confidence interval, 0.60-0.80) in recipients with MELD >=35. CONCLUSION: Share 35 has had a positive impact on survival after transplantation in patients with MELD >=35, without a reciprocal detriment in patients with lower acuity; this was in part a result of more favorable donor-recipient matching. (Hepatology 2018;67:273-281). PMID- 28586183 TI - ? AB - : Infection by Helicobacter pylori affects over half of theworld's population and is a public health issue. Its prevalenceis significantly higher in developing countries such as Brazil.It has been suggested that infection by H pylori can impactcalorie intake and homeostasis. AIM: Analyze the influenceof infection by H pylori and of its eradication on nutritionalstatus and dietary intake. MATERIAL AND METHODS: The studyincluded 124 patients (48 of whom H pylori positive, 45 Hpylori negative, and 31 eradicated). Weight and height weremeasured to calculate the body mass index (BMI). Dietaryintake was assessed using a 24-hour diet recall (24hR) intwo occasions. RESULTS: Pre-obesity was the highest among theeradicated patients (p = 0.011). Homogenicity was foundin the dietary intake for the nutrients studied, except forsaccharose, whose intake was the lowest among the eradicatedgroup (p < 0.001). CONCLUSIONS: Patients eradicatedfor H pylori had a higher rate of pre-obesity. The dietaryintake was similar among the groups for nearly all nutrientsassessed, except for saccharose, whose intake by eradicatedpatients was lower. This entails discussions about possiblyincluding the investigation of nutritional status and diet inthe routine procedures towards those who seek a diagnosis ofinfection by H pylori. PMID- 28586185 TI - ? AB - : In Argentina there are no multicenter studies evaluating themanagement of patients with acute pancreatitis (AP) nationwide. OBJECTIVES: The main objective of this study is toknow how the patients with AP are treated in Argentina.The secondary objective is to assess whether the results complywith the recommendation of the American College of GastroenterologyGuide. MATERIAL AND METHODS: Twenty threecenter participated in the study. They include in a databasehosted online consecutive patients with acute pancreatitisfrom june 2010 to june 2013. RESULTS: 854 patients enteredthe study. The average age was 46.6 years and 495(58%) belonged to the female sex. The most common cause(88.2%) of AP was biliary. Some prognostic system wasused in 99 % of patients and the most used was Ranson(74.5%). Were classified as mild 714 (83.6%) patientsand severe 140 (16.4%). Systemic complications occurredin 43 patients and local complications in 21. 86 patientsunderwent dynamic CT scans and 73 patients had pancreaticand / or peripancreatic necrosis. Mortality was1.5%. There was no difference in mortality in relation tothe size, complexity or affiliation of the center. The comply of key recommendations of the American College of GastroenterologyGuide was over 80%. CONCLUSIONS: Thediagnosis and treatment of patients with AP in 23 healthcenters located throughout the country was optimal. Themanagement complied with most of the recommendationsof the American College of Gastroenterology Guide. PMID- 28586191 TI - Reduced Graphene Oxide/Alumina, A Good Accelerant for Cellulose-Based Artificial Nacre with Excellent Mechanical, Barrier, and Conductive Properties. AB - In this article, a simple strategy was employed to fabricate bioinspired hybrid composite with carboxymethyl cellulose (CMC), graphene oxide, and reduced graphene oxide/alumina (rGO/Al) by a facile solution casting method. The tensile strength and toughness of rGO/Al-CMC-GO can reach 586.6 +/- 12 MPa, 12.1 +/- 0.44 MJm-3, respectively, due to the interface strengthening of alumina, which is 1.43 and 12 times higher than steel and about 4.3 and 6.7 times that of nature nacre. The artificial nacre hybrid composite is conductive due to the introduction of rGO/Al on the surface. Interestingly this structure can also be coated on the surface of cotton thread to give the thread good mechanical performance and conductivity. Additionally, the artificial nacre has better fire shielding and gas barrier properties. The oxygen permeability (OP) for 1% rGO/Al-CMC decreased from 0.0265 to 0.003 mLMUm m-2 day-1 kpa-1, the water vapor permeability (WVP) decreased from 0.363 to 0.205 gmmm-2 day-1 kpa-1 when the concentration increased from 1% rGO/Al to 6% rGO/Al. It is believed this work provided a simple and feasible strategy to fabricate ultrastrong and ultratough graphene-based artificial nacre multifunctional materials. PMID- 28586190 TI - Elemental Precursor Solution Processed (Cu1-xAgx)2ZnSn(S,Se)4 Photovoltaic Devices with over 10% Efficiency. AB - The partial substitution of Cu+ with Ag+ into the host lattice of Cu2ZnSn(S,Se)4 thin films can reduce the open-circuit voltage deficit (Voc,deficit) of Cu2ZnSn(S,Se)4 (CZTSSe) solar cells. In this paper, elemental Cu, Ag, Zn, Sn, S, and Se powders were dissolved in solvent mixture of 1,2-ethanedithiol (edtH2) and 1,2-ethylenediamine (en) and used for the formation of (Cu1-xAgx)2ZnSn(S,Se)4 (CAZTSSe) thin films with different Ag/(Ag + Cu) ratios. The key feature of this approach is that the impurity atoms can be absolutely excluded. Further results indicate that the variations of grain size, band gap, and depletion width of the CAZTSSe layer are generally determined by Ag substitution content. Benefiting from the Voc enhancement (~50 mV), the power conversion efficiency is successfully increased from 7.39% (x = 0) to 10.36% (x = 3%), which is the highest efficiency of Ag substituted devices so far. PMID- 28586192 TI - Selenium-Functionalized Graphene Oxide That Can Modulate the Balance of Reactive Oxygen Species. AB - Graphene oxide (GO) is an important two-dimensional material since it is water soluble and can be functionalized to adapt to different applications. However, the current covalent functionalization methods usually require hash conditions, long duration, and sometimes even multiple steps, while noncovalent functionalization is inevitably unstable, especially under a physiological environment where competing species exist. Diselenide bond is a dynamic covalent bond and can respond to both redox conditions and visible light irradiation in a sensitive manner. Thus, in this work by combining the stimuli response of diselenide bond and the oxidative/radical attackable nature of GO, we achieved the in situ covalent functionalization of GO simply by stirring GO with diselenide-containing molecules in aqueous solution. The covalent functionalization was proved by Fourier transform infrared, time-of-flight secondary ion mass spectrometry, atomic force microscopy, thermogravimetric analysis, and so forth, and the functionalization mechanism was deduced to involve both redox reaction and radical addition reaction according to the X-ray photoelectron spectrscopy, atomic emission spectroscopy, and Raman spectroscopy. Moreover, we modified GO with a biocompatible diselenide-containing polymer (mPEGSe)2 and found selenium-functionalized GO could modulate the balance of reactive oxygen species (ROS). GOSe could decrease ROS level by accelerating the reduction of peroxides when the ROS concentration is high while boosting the ROS level by in situ generating ROS when its concentration is relatively low. PMID- 28586193 TI - Controllable Fabrication of Two-Dimensional Patterned VO2 Nanoparticle, Nanodome, and Nanonet Arrays with Tunable Temperature-Dependent Localized Surface Plasmon Resonance. AB - A universal approach to develop various two-dimensional ordered nanostructures, namely nanoparticle, nanonet and nanodome arrays with controllable periodicity, ranging from 100 nm to 1 MUm, has been developed in centimeter-scale by nanosphere lithography technique. Hexagonally patterned vanadium dioxide (VO2) nanoparticle array with average diameter down to sub-100 nm as well as 160 nm of periodicity is fabricated, exhibiting distinct size-, media-, and temperature dependent localized surface plasmon resonance switching behaviors, which fits well with the predication of simulations. We specifically explore their decent thermochromic performance in an energy saving smart window and develop a proof-of concept demo which proves the effectiveness of patterned VO2 film to serve as a smart thermal radiation control. This versatile and facile approach to fabricate various ordered nanostructures integrated with attractive phase change characteristics of VO2 may inspire the study of temperature-dependent physical responses and the development of smart devices in extensive areas. PMID- 28586194 TI - Two-Dimensional 1T-Phase Transition Metal Dichalcogenides as Nanocarriers To Enhance and Stabilize Enzyme Activity for Electrochemical Pesticide Detection. AB - Single or few layers lithium-exfoliated transition metal dichalcogenides (TMDs) are found to exist predominantly in the conducting metallic 1T-polymorph, which makes it desirable for numerous applications due to its large surface area, good electrical conductivity, and enhanced electrocatalytic capabilities. We demonstrated the use of tert-butyllithium exfoliated TMDs (MoS2, MoSe2, WS2, WSe2) as a platform for the indirect electrochemical detection of an organophosphate pesticide, fenitrothion, via enzymatic inhibition pathway. All four reported materials enhanced the response of the enzymatic biosensor in comparison to the corresponding biosensor in the absence of TMDs. 1T-Phase WS2 outperforms all other TMD materials, and we proved that it serves as an excellent transducer for enhancing electron transfer in a robust model enzyme-based inhibition assay system using cross-linking immobilization with glutaraldehyde. The reported system showed a broad fenitrothion concentration range (1-1000 nM) with an excellent linearity (r = 0.987). Moreover, the system displayed high sensitivity with low limit of detection (2.86 nM) obtained, which far exceeds the required limit set by Food and Agriculture Organisation (FAO) of the United Nations (UN). The feasibility of the proposed system in real samples was demonstrated in apple juice samples with good recoveries of 80.2% and 80.3% obtained at 10 and 1000 nM fenitrothion, respectively. PMID- 28586195 TI - Ex Vivo Cell-Based Screening Platform for Modulators of Hepatosteatosis. AB - Nonalcoholic fatty liver disease (NAFLD) is the result of the ectopic accumulation of lipids in hepatic cells and is the early stage of liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma. While some mechanisms of aberrant lipid storage are understood, unbiased phenotypic drug screening holds the potential to identify new therapeutic small molecule mechanisms that reverse lipid accumulation in hepatic cells and prevent disease progression. Immortalized hepatocyte cell lines are often used as in vitro models of hepatocyte function, including in the study of lipid accumulation. However, mechanisms and therapeutic agents studied in these systems suffer from poor translation to primary cells and animal models of disease. Herein, we report an ex vivo high-throughput screening platform using primary mouse hepatocytes with a physiologically relevant lipid-laden phenotype isolated from mice that are administered a choline-methionine deficient diet. This screening platform using primary diseased hepatocytes may help to overcome a major hurdle in liver disease drug discovery and could lead to the development of new therapeutics for hepatosteatosis. PMID- 28586196 TI - Real-Time Imaging of Endocytosis and Intracellular Trafficking of Semiconducting Polymer Dots. AB - Semiconducting polymer dots (Pdots) have shown great promise in biomedical applications, including biosensing, drug delivery, and live imaging of cells and biomolecules. Insight into the mechanism and regulation of cellular uptake and intracellular metabolism of Pdots is important for the development of superior Pdots-based theranostic nanoconjugates. Herein, we performed real-time imaging of endocytosis and intracellular trafficking of a type of fluorescent Pdots that showed excellent biocompatibility in various types of cells. The endocytic routes and kinetics of Pdots were differently regulated in distinct cell types. Following endocytosis, Pdots were transported in vesicles along microtubule and destined for lysosomes. Furthermore, our results revealed exosome-mediated extracellular release of Pdots and have tracked the dynamic process at the single particle level. These results provide new insight into the design of more effective and selective imaging probes as well as drug carriers. PMID- 28586197 TI - A Potential Red-Emitting Phosphor BaZrGe3O9:Eu3+ for WLED and FED Applications: Synthesis, Structure, and Luminescence Properties. AB - A variety of Eu3+-activated BaZrGe3O9 phosphors was synthesized via solid-state reaction. The phase formation of BaZrGe3O9:Eu3+ samples was verified by powder X ray diffraction analysis, while Rietveld refinement method was used to confirm the crystal structure. The electronic structure and characteristic photoluminescence as well as cathodoluminescence properties were researched in detail. The samples show strong absorption at 394 nm, which matches well with the commercial near-ultraviolet chips. Under 394 nm excitation, the phosphors exhibit the characteristic emissions of Eu3+ ions consistent with the 5D0-7FJ transitions. Then we investigated the thermal stability detailedly. The temperature-dependent photoluminescence emission spectra suggest that the obtained phosphors have favorable thermal stability. A white light-emitting diode (WLED) lamp with low correlated color temperature and good color render index was fabricated with blue-emitting BaMgAl10O17:Eu2+, green-emitting Sr2SiO4:Eu2+ (commercial), and red-emitting BaZrGe3O9:Eu3+ phosphors in near-ultraviolet light emitting diodes (lambdamax = 395 nm) as well. Furthermore, the phosphor also exhibits red emission with high resistance and high current saturation under low voltage electron bombardment. It has better degradation resistance than the commercial Y2O3:Eu phosphor. All the results manifest that the Ba0.88Eu0.08ZrGe3O9 phosphor can be an eligible red-emitting phosphor candidate for WLEDs and field-emission displays. PMID- 28586198 TI - Electronic Spectra of Tris(2,2'-bipyridine)-M(II) Complex Ions in Vacuo (M = Fe and Os). AB - We measured the electronic spectra of mass-selected [M(bpy)3]2+ (M = Fe and Os, bpy = 2,2'-bipyridine) ions in vacuo by photodissociation spectroscopy of their N2 adducts, [M(bpy)3]2+.N2. Extensive band systems in the visible (predominantly charge transfer) and near-ultraviolet (pipi*) spectral regions are reported. The [M(bpy)3]2+.N2 target ions were prepared by condensing N2 onto electrosprayed ions in a cryogenic ion trap at ca. 25 K and then mass-selected by time-of-flight mass spectrometry. The electronic photodissociation spectra of the cold, gas phase ions closely reflect their intrinsic properties, i.e., without perturbation by solvent effects. The spectra are interpreted using time-dependent density functional theory calculations both with and without accounting for relativistic effects. PMID- 28586199 TI - Uptake, Distribution, and Transformation of CuO NPs in a Floating Plant Eichhornia crassipes and Related Stomatal Responses. AB - Engineered nanoparticles (NPs) are being released into aquatic environments with their increasing applications. In this work, we investigated the interaction of CuO NPs with a floating plant, water hyacinth (Eichhornia crassipes). CuO NPs (50 mg/L) showed significant growth inhibition on both roots and shoots of E. crassipes after 8-day exposure, much higher than that of the bulk CuO particles (50 mg/L) and their corresponding dissolved Cu2+ ions (0.30 mg/L). Scanning electron and light microscopic observations showed that the root caps and meristematic zone of E. Crassipes were severely damaged after CuO NP exposure, with disordered cell arrangement and a destroyed elongation zone of root tips. It is confirmed that CuO NPs could be translocated to shoot from both roots and submerged leaves. As detected by X-ray absorption near-edge spectroscopy analysis (XANES), CuO NPs were observed in roots, submerged leaves, and emerged leaves. Cu2S and other Cu species were also detected in these tissues, providing solid evidence of the transformation of CuO NPs. In addition, stomatal closure was observed during CuO NPs-leaf contact, which was induced by the production of H2O2 and increased Ca level in leaf guard cells. These findings are helpful for better understanding the fate of NPs in aquatic plants and related biological responses. PMID- 28586200 TI - Oligothiophene-Bridged Conjugated Covalent Organic Frameworks. AB - Two-dimensional covalent organic frameworks (2D-COFs) are crystalline, porous materials comprising aligned columns of pi-stacked building blocks. With a view toward the application of these materials in organic electronics and optoelectronics, the construction of oligothiophene-based COFs would be highly desirable. The realization of such materials, however, has remained a challenge, in particular with respect to laterally conjugated imine-linked COFs. We have developed a new building block design employing an asymmetric modification on an otherwise symmetric backbone that allows us to construct a series of highly crystalline quaterthiophene-derived COFs with tunable electronic properties. Studying the optical response of these materials, we have observed for the first time the formation of a charge transfer state between the COF subunits across the imine bond. We believe that our new building block design provides a general strategy for the construction of well-ordered COFs from various extended building blocks, thus greatly expanding the range of applicable molecules. PMID- 28586201 TI - Ruthenium(II) Bipyridyl Complexes with Cyclometalated NHC Ligands. AB - We present the synthesis and characterization of novel cyclometalated ruthenium N heterocyclic carbene (NHC) complexes of the general formula [Ru(C^C*)(bpy)2]PF6 (bpy = 2,2'-bipyridine), with the C^C* ligand being based on different 1 phenylimidazoles. They were synthesized in a one-pot procedure starting from the corresponding p-cymene NHC complexes [Ru(C^C*)(p-cymene)Cl]. Their structural, spectroscopic, and electrochemical properties were investigated by NMR, X-ray, UV/vis, and CV, as well as density functional theory methods. Because of the stronger electron-donating carbene ligands, these complexes represent a new class of bisheteroleptic dyes with improved photophysical and electrochemical properties. PMID- 28586202 TI - Cytosine Iminyl Radical (cytN*) Formation via Electron-Induced Debromination of 5 Bromocytosine: A DFT and Gaussian 4 Study. AB - Halogen-substituted pyrimidines, such as 5-bromouracil and 5-iodouracil, have been used as radio therapeutic (RT) agents in cancer treatment. The radiosensitizing activity of 5-bromouracil is attributed to its reaction with electron which produce the highly reactive uracil-5-yl radical by dissociating the C5-Br bond. Using density functional methods and highly accurate Gaussian 4 (G4) theory, herein, we show that 5-bromocytosine (5-Brcyt) after reaction with electron, also, leads to the formation of cytosine-5-yl radical. However, our results show that this species can subsequently undergo a base-catalyzed tautomerization reaction to form the pi-aminyl radical followed by a second tautomerization to the thermodynamically most stable sigma-iminyl radical (cytN*). From the present theoretical calculations, we infer that the mechanism of the formation of cytN* by one-electron reduction of 5-Brcyt is straightforward and may take place in 5-Brcyt-labeled DNA in competition with the usual reactions expected for the cytosine-5-yl radical such as abstraction and water addition. PMID- 28586203 TI - Why Is Research on Amyloid-beta Failing to Give New Drugs for Alzheimer's Disease? AB - The two hallmarks of Alzheimer's disease (AD) are the presence of neurofibrillary tangles (NFT) made of aggregates of the hyperphosphorylated tau protein and of amyloid plaques composed of amyloid-beta (Abeta) peptides, primarily Abeta1-40 and Abeta1-42. Targeting the production, aggregation, and toxicity of Abeta with small molecule drugs or antibodies is an active area of AD research due to the general acceptance of the amyloid cascade hypothesis, but thus far all drugs targeting Abeta have failed. From a review of the recent literature and our own experience based on in vitro, in silico, and in vivo studies, we present some reasons to explain this repetitive failure. PMID- 28586204 TI - Ce-Doped La3Si6.5Al1.5N9.5O5.5, a Rare Highly Efficient Blue-Emitting Phosphor at Short Wavelength toward High Color Rendering White LED Application. AB - Phase pure nondoped and Ce doped La3Si6.5Al1.5N9.5O5.5 (Al containing La N-phase) samples have been obtained by solid-state reaction synthesis for the first time. 1% Ce-doped La3Si6.5Al1.5N9.5O5.5 phosphor displays a broad excitation band ranging from UV to 410 nm, with a maximum at 355 nm. UV light excitation results in a narrow Ce3+ 5d-4f emission band (fwhm = 68 nm) centered at 418 nm. The emission can be tuned from 417 nm at 0.5% Ce to 450 nm at 50% Ce. A high internal quantum efficiency up to 84% is achieved for a 1% Ce doped sample, which has CIE chromaticity coordinates of x = 0.157 and y = 0.069, close to the NTSC blue standard (x = 0.155; y = 0.070). Compared to La3Si8O4N11:Ce phosphor, the quantum efficiency and thermal stability have been enhanced for La3Si6.5Al1.5N9.5O5.5:Ce phosphor without shifting the emission peak wavelength. La3Si6.5Al1.5N9.5O5.5:Ce shows less thermal quenching than La3Si8O4N11:Ce and no shift or change in the shape of emission spectra with increasing the temperature from 4 to 573 K. These results show that La3Si6.5Al1.5N9.5O5.5:Ce is more efficient than any other (oxy )nitride phosphor with an emission in the short wavelength blue region (400-450 nm). A white LED was fabricated using the La3Si6.5Al1.5N9.5O5.5:5%Ce as a blue phosphor. The high color rendering index (Ra = 93.2, R9 = 91.4, and R12 = 89.5) obtained shows that the phosphor is a very promising conversion phosphor for white LEDs. PMID- 28586205 TI - Black Anatase Formation by Annealing of Amorphous Nanoparticles and the Role of the Ti2O3 Shell in Self-Organized Crystallization by Particle Attachment. AB - We use amorphous titania nanoparticle networks produced by pulsed laser vaporization at room temperature as a model system for understanding the mechanism of formation of black titania. Here, we characterize the transformation of amorphous nanoparticles by annealing in pure Ar at 400 degrees C, the lowest temperature at which black titania was observed. Atomic resolution electron microscopy methods and electron energy loss spectroscopy show that the onset of crystallization occurs by nucleation of an anatase core that is surrounded by an amorphous Ti2O3 shell. The formation of the metastable anatase core before the thermodynamically stable rutile phase occurs according to the Ostwald phase rule. In the second stage the particle size increases by coalescence of already crystallized particles by a self-organized mechanism of crystallization by particle attachment. We show that the Ti2O3 shell plays a critical role in both black titania transformation and functionality. At 400 degrees C, Ti2O3 hinders the agglomeration of neighboring particles to maintain a high surface-to-volume ratio that is beneficial for enhanced photocatalytic activity. In agreement with previous results, the thin Ti2O3 surface layer acts as a narrow bandgap semiconductor in concert with surface defects to enhance the photocatalytic activity. Our results demonstrate that crystallization by particle attachment can be a highly effective mechanism for optimizing photocatalytic efficiency by controlling the phase, composition, and particle size distribution in a wide range of self-doped defective TiO2 architectures simply by varying the annealing conditions of amorphous nanoparticles. PMID- 28586206 TI - Functionalized Fullerene Targeting Human Voltage-Gated Sodium Channel, hNav1.7. AB - Mutations of hNav1.7 that cause its activities to be enhanced contribute to severe neuropathic pain. Only a small number of hNav1.7 specific inhibitors have been identified, most of which interact with the voltage-sensing domain of the voltage-activated sodium ion channel. In our previous computational study, we demonstrated that a [Lys6]-C84 fullerene binds tightly (affinity of 46 nM) to NavAb, the voltage-gated sodium channel from the bacterium Arcobacter butzleri. Here, we extend this work and, using molecular dynamics simulations, demonstrate that the same [Lys6]-C84 fullerene binds strongly (2.7 nM) to the pore of a modeled human sodium ion channel hNav1.7. In contrast, the fullerene binds only weakly to a mutated model of hNav1.7 (I1399D) (14.5 mM) and a model of the skeletal muscle hNav1.4 (3.7 mM). Comparison of one representative sequence from each of the nine human sodium channel isoforms shows that only hNav1.7 possesses residues that are critical for binding the fullerene derivative and blocking the channel pore. PMID- 28586207 TI - PrimaDORAC: A Free Web Interface for the Assignment of Partial Charges, Chemical Topology, and Bonded Parameters in Organic or Drug Molecules. AB - : We present PrimaDORAC, a simple and freely accessible web interface for generating the topology and the parameter files of organic or drug molecules to be used in molecular mechanics or molecular dynamics calculations. The interface relies on our in-house FORTRAN90 parser, working on the recently released Generalized Amber Force Field parameter set (GAFF2). AM1/BCC charges are computed using the Public Domain MOPAC7 program and the bond charge corrections (BCC) reported in Jakalian, A.; Jack, D. B.; Bayly, C. I.; J. Comp. Chem., 2002, 23, 1623-1641. The interface has been tested on about 52,000 compounds (identified with a CAS registry number) taken from the National Cancer Institute (NCI) Open Database. PrimaDORAC has been found to be very reliable, producing GAFF2 minimized structures bearing a mean root square displacement of about 0.01-0.02 nm with respect to the original CORINA-generated 3D NCI structures. As a demonstrative example, we release the full topology and parameter files, along with the AM1/BCC-GAFF2 computed in vacuo IR spectrum, for some recently discovered PARP/MCL1 inhibitors. The web interface and parser, including the sources, are part of the ORAC code (Procacci, P.; J. Chem. Inf. MODEL: , 2016, 56, 1117-1121), distributed under the General Public License at www.chim.unifi.it/orac. PMID- 28586208 TI - Measurement and Modeling of Setschenow Constants for Selected Hydrophilic Compounds in NaCl and CaCl2 Simulated Carbon Storage Brines. AB - Carbon capture, utilization, and storage (CCUS), a climate change mitigation strategy, along with unconventional oil and gas extraction, generates enormous volumes of produced water containing high salt concentrations and a litany of organic compounds. Understanding the aqueous solubility of organic compounds related to these operations is important for water treatment and reuse alternatives, as well as risk assessment purposes. The well-established Setschenow equation can be used to determine the effect of salts on aqueous solubility. However, there is a lack of reported Setschenow constants, especially for polar organic compounds. In this study, the Setschenow constants for selected hydrophilic organic compounds were experimentally determined, and linear free energy models for predicting the Setschenow constant of organic chemicals in concentrated brines were developed. Solid phase microextraction was employed to measure the salting-out behavior of six selected hydrophilic compounds up to 5 M NaCl and 2 M CaCl2 and in Na-Ca-Cl brines. All compounds, which include phenol, p cresol, hydroquinone, pyrrole, hexanoic acid, and 9-hydroxyfluorene, exhibited log-linear behavior up to these concentrations, meaning Setschenow constants previously measured at low salt concentrations can be extrapolated up to high salt concentrations for hydrophilic compounds. Setschenow constants measured in NaCl and CaCl2 brines are additive for the compounds measured here; meaning Setschenow constants measured in single salt solutions can be used in multiple salt solutions. The hydrophilic compounds in this study were selected to elucidate differences in salting-out behavior based on their chemical structure. Using data from this study, as well as literature data, linear free energy relationships (LFERs) for prediction of NaCl, CaCl2, LiCl, and NaBr Setschenow constants were developed and validated. Two LFERs were improved. One LFER uses the Abraham solvation parameters, which include the index of refraction of the organic compound, organic compound's polarizability, hydrogen bonding acidity and basicity of the organic compound, and the molar volume of the compound. The other uses an octanol-water partitioning coefficient to predict NaCl Setschenow constants. Improved models from this study now include organic compounds that are structurally and chemically more diverse than the previous models. The CaCl2, LiCl, and NaBr single parameter LFERs use concepts from the Hofmeister series to predict new, respective Setschenow constants from NaCl Setschenow constants. The Setschenow constants determined here, as well as the LFERs developed, can be incorporated into CCUS reactive transport models to predict aqueous solubility and partitioning coefficients of organic compounds. This work also has implications for beneficial reuse of water from CCUS; this can aide in determining treatment technologies for produced waters. PMID- 28586209 TI - Ab Initio Prediction of Adsorption Isotherms for Gas Mixtures by Grand Canonical Monte Carlo Simulations on a Lattice of Sites. AB - Gibbs free energies of adsorption on individual sites and the lateral (adsorbate adsorbate) interaction energies are obtained from quantum chemical ab initio methods and molecular statistics. They define a Grand Canonical Monte Carlo (GCMC) Hamiltonian for simulations of gas mixtures on a lattice of adsorption sites. Coadsorption of CO2 and CH4 at Mg2+ sites in the pores of the metal organic framework CPO-27-Mg (Mg-MOF-74) is studied as an example. Simulations with different approximations as made in widely used coadsorption models such as the ideal adsorbed solution theory (IAST) show their limitations in describing adsorption selectivities for binary mixtures. PMID- 28586210 TI - QTAIM and Stress Tensor Characterization of Intramolecular Interactions Along Dynamics Trajectories of a Light-Driven Rotary Molecular Motor. AB - A quantum theory of atoms in molecules (QTAIM) and stress tensor analysis was applied to analyze intramolecular interactions influencing the photoisomerization dynamics of a light-driven rotary molecular motor. For selected nonadiabatic molecular dynamics trajectories characterized by markedly different S1 state lifetimes, the electron densities were obtained using the ensemble density functional theory method. The analysis revealed that torsional motion of the molecular motor blades from the Franck-Condon point to the S1 energy minimum and the S1/S0 conical intersection is controlled by two factors: greater numbers of intramolecular bonds before the hop-time and unusually strongly coupled bonds between the atoms of the rotor and the stator blades. This results in the effective stalling of the progress along the torsional path for an extended period of time. This finding suggests a possibility of chemical tuning of the speed of photoisomerization of molecular motors and related molecular switches by reshaping their molecular backbones to decrease or increase the degree of coupling and numbers of intramolecular bond critical points as revealed by the QTAIM/stress tensor analysis of the electron density. Additionally, the stress tensor scalar and vector analysis was found to provide new methods to follow the trajectories, and from this, new insight was gained into the behavior of the S1 state in the vicinity of the conical intersection. PMID- 28586211 TI - Structure Based Design of N-(3-((1H-Pyrazolo[3,4-b]pyridin-5 yl)ethynyl)benzenesulfonamides as Selective Leucine-Zipper and Sterile-alpha Motif Kinase (ZAK) Inhibitors. AB - A series of N-(3-((1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl)benzenesulfonamides were designed as the first class of highly selective ZAK inhibitors. The representative compound 3h strongly inhibits the kinase activity of ZAK with an IC50 of 3.3 nM and dose-dependently suppresses the activation of ZAK downstream signals in vitro and in vivo, while it is significantly less potent for the majority of 403 nonmutated kinases evaluated. Compound 3h also exhibits orally therapeutic effects on cardiac hypertrophy in a spontaneous hypertensive rat model. PMID- 28586212 TI - Species Identification of Necrophagous Insect Eggs Based on Amino Acid Profile Differences Revealed by Direct Analysis in Real Time-High Resolution Mass Spectrometry. AB - The colonization of decomposing remains by necrophagous insects such as blow flies is of forensic importance because the progression through the various stages of insect development can be correlated to time of death. The ability to infer this information hinges on accurate determination of the fly species that are associated with the entomological evidence collected. This evidence can include eggs, larvae, pupae, and puparial casings. Determination of the egg's identity is particularly challenging because the eggs of multiple species are morphologically very similar. We report here that the species identity of fly eggs can be determined from their chemical fingerprint signatures acquired by direct analysis in real time high-resolution mass spectrometry (DART-HRMS). Thus, freshly laid eggs were collected and readily distinguished from multiple necrophagous fly species in the Manhattan area of New York City. These species included representatives from the blow fly family (Calliphoridae), specifically Calliphora vicina, Lucilia sericata, L. coeruleiviridis, and Phormia regina species as well as the Phoridae and Sarcophagidae families. Multivariate statistical analysis of their observed DART-HRMS spectra revealed intraspecies similarities and interspecies differences that were the basis of species differentiation. The chemical basis of discrimination was differences in amino acid profiles. This represents the first chemically based fly egg identification approach with applications to forensic entomology. The rapidity of the method makes feasible the generation of a fly egg chemical profile database against which the DART-HRMS spectra of unknown eggs can be screened to rapidly assess species identity without needing to rear the eggs to adulthood. PMID- 28586213 TI - Atomically Precise Clusters of Noble Metals: Emerging Link between Atoms and Nanoparticles. AB - Atomically precise pieces of matter of nanometer dimensions composed of noble metals are new categories of materials with many unusual properties. Over 100 molecules of this kind with formulas such as Au25(SR)18, Au38(SR)24, and Au102(SR)44 as well as Ag25(SR)18, Ag29(S2R)12, and Ag44(SR)30 (often with a few counterions to compensate charges) are known now. They can be made reproducibly with robust synthetic protocols, resulting in colored solutions, yielding powders or diffractable crystals. They are distinctly different from nanoparticles in their spectroscopic properties such as optical absorption and emission, showing well-defined features, just like molecules. They show isotopically resolved molecular ion peaks in mass spectra and provide diverse information when examined through multiple instrumental methods. Most important of these properties is luminescence, often in the visible-near-infrared window, useful in biological applications. Luminescence in the visible region, especially by clusters protected with proteins, with a large Stokes shift, has been used for various sensing applications, down to a few tens of molecules/ions, in air and water. Catalytic properties of clusters, especially oxidation of organic substrates, have been examined. Materials science of these systems presents numerous possibilities and is fast evolving. Computational insights have given reasons for their stability and unusual properties. The molecular nature of these materials is unequivocally manifested in a few recent studies such as intercluster reactions forming precise clusters. These systems manifest properties of the core, of the ligand shell, as well as that of the integrated system. They are better described as protected molecules or aspicules, where aspis means shield and cules refers to molecules, implying that they are "shielded molecules". In order to understand their diverse properties, a nomenclature has been introduced with which it is possible to draw their structures with positional labels on paper, with some training. Research in this area is captured here, based on the publications available up to December 2016. PMID- 28586215 TI - Experimental and Theoretical Investigation of the Anti-Ferromagnetic Coupling of CrIII Ions through Diamagnetic -O-NbV-O- Bridges. AB - The synthesis and properties of a novel hetero-tetranuclear compound [Cr2(bpy)4(MU-O)4Nb2(C2O4)4].3H2O (1; bpy = 2,2'-bipyridine), investigated by single-crystal X-ray diffraction, magnetization measurements, IR, UV/visible spectroscopy, electron paramagnetic resonance (EPR; X- and Q-bands and high field), and density functional theory (DFT) calculations, are reported. Crystal structure of 1 (orthorhombic Pcab space group) consists of a square-shaped macrocyclic {Cr2(MU-O)4Nb2} core in which CrIII and NbV ions are alternately bridged by oxo ions and three uncoordinated water molecules. The intramolecular CrIII...CrIII distances through the -O-NbV-O- bridges are 7.410(2) and 7.419(2) A, while diagonal separation is 5.406(2) A. The temperature dependence of magnetization M(T) evidences an anti-ferromagnetic ground state, which originates from a magnetic interaction between two CrIII ions of spin 3/2 through two triatomic -O-NbV-O- diamagnetic bridges. A spin Hamiltonian appropriate for polynuclear isolated magnetic units was used. The best-fitting curve for this model is obtained with the parameters gCr = 1.992(3), J = -12.77(5) cm-1, and |D| = 0.17(4) cm-1. The CrIII...CrIII dimer model is confirmed by EPR spectra, which exhibit a pronounced change of their shape around the temperature corresponding to the intradimer coupling J. The EPR spectra simulations and DFT calculations reveal the presence of a single-ion anisotropy that is close to being uniaxial, D = -0.31 cm-1 and E = 0.024 cm-1. PMID- 28586216 TI - Catalytic Formylation of Primary and Secondary Amines with CO2 and H2 Using Abundant-Metal Catalysts. AB - Catalytic hydrogenation of CO2 is an efficient and selective way to prepare formic acid derivatives, but most of the highly active catalysts used for this purpose require precious metals. In this study, in situ abundant-metal complexes have been evaluated as potential catalysts for CO2 hydrogenation to prepare formamides, including N-formylmorpholine, 2-ethylhexylformamide, and dimethylformamide, from the corresponding amines. From these initial screening results, the most active catalysts for these reactions were found to be MX2/dmpe in situ catalysts (M = Fe(II), Ni(II); X = Cl-, CH3CO2-, acac-; dmpe = 1,2 bis(dimethylphosphino)ethane) in DMSO. The optimal reaction conditions were found to be 100-135 degrees C and a total pressure of 100 bar. Morpholine was formylated with a TON value of up to 18000, which is the highest TON for the hydrogenation of CO2 to formamides using any abundant-metal-phosphine complex. With an appropriate selection of catalyst and reaction conditions, >90-98% conversion of amine to formamide could be achieved. PMID- 28586214 TI - Establishing an Artificial Pathway for De Novo Biosynthesis of Vanillyl Alcohol in Escherichia coli. AB - Vanillyl alcohol is a phenolic alcohol and is used as a flavoring agent in foods and beverages. In this paper, we propose a novel artificial pathway for microbial production of vanillyl alcohol from simple carbon sources. The pathway extends from 4-hydroxybenzoic acid (4-HBA), and needs only three heterologous enzymes, p hydroxybenzoate hydroxylase (PobA), carboxylic acid reductase (CAR) and caffeate O-methyltransferase (COMT). First, we examined the promiscuous activity of COMT toward 3,4-dihydroxybenzyl alcohol and found a kcat value of 0.097 s-1. Meanwhile, 499.36 mg/L vanillyl alcohol was produced by COMT in vivo catalysis when fed with 1000 mg/L 3,4-dihydroxybenzyl alcohol. In the following experiment, de novo biosynthesis of vanillyl alcohol was carried out and 240.69 mg/L vanillyl alcohol was produced via modular optimization of pathway genes. This work was to date the first achievement for microbial production of vanillyl alcohol. Additionally, the present study demonstrates the application of enzyme promiscuity of COMT in the design of an artificial pathway for the production of high-value methylated aromatic compounds. PMID- 28586217 TI - Integrated Hierarchical Cobalt Sulfide/Nickel Selenide Hybrid Nanosheets as an Efficient Three-dimensional Electrode for Electrochemical and Photoelectrochemical Water Splitting. AB - Developing highly active electrocatalysts for photoelectrochemical water splitting is critical to bring solar/electrical-to-hydrogen energy conversion processes into reality. Herein, we report a three-dimensional (3D) hybrid electrocatalyst that is constructed through in situ anchoring of Co9S8 nanosheets onto the surface of Ni3Se2 nanosheets vertically aligned on an electrochemically exfoliated graphene foil. Benefiting from the synergistic effects between Ni3Se2 and Co9S8, the highly conductive graphene support, and large surface area, the novel 3D hybrid electrode delivers superior electrocatalytic activity toward water reduction in alkaline media, featuring overpotentials of -0.17 and -0.23 V to achieve current densities of 20 and 50 mA cm-2, respectively, demonstrating an electrocatalytic performance on the top of the Ni3Se2- and Co9S8-based electrocatalysts as reported in literature. Experimental investigations and theoretical calculations confirm that the remarkable activity of the obtained material results from the unique 3D hierarchical architecture and interface reconstruction between Ni3Se2 and Co9S8 through Ni-S bonding, which leads to charge redistribution and thus lowers the energy barrier of hydrogen desorption in the water splitting process. Further integration of the 3D hybrid electrode with a macroporous silicon photocathode enables highly active and sustainable sunlight-driven water splitting in both basic media and real river water. The overall water splitting with 10 mA cm-2 at a low voltage of 1.62 V is achieved using our hybrid as both anode and cathode catalysts, which surpasses that of the Ir/C-Pt/C couple (1.60 V) for sufficiently high overpotentials. PMID- 28586218 TI - Alkoxy Radical Bond Scissions Explain the Anomalously Low Secondary Organic Aerosol and Organonitrate Yields From alpha-Pinene + NO3. AB - Oxidation of monoterpenes (C10H16) by nitrate radicals (NO3) constitutes an important source of atmospheric secondary organic aerosol (SOA) and organonitrates. However, knowledge of the mechanisms of their formation is incomplete and differences in yields between similar monoterpenes are poorly understood. In particular, yields of SOA and organonitrates from alpha-pinene + NO3 are low, while those from Delta3-carene + NO3 are high. Using computational methods, we suggest that bond scission of the nitrooxy alkoxy radicals from Delta3-carene lead to the formation of reactive keto-nitrooxy-alkyl radicals, which retain the nitrooxy moiety and can undergo further reactions to form SOA. By contrast, bond scissions of the nitrooxy alkoxy radicals from alpha-pinene lead almost exclusively to the formation of the relatively unreactive and volatile product pinonaldehyde (C10H16O2), thereby limiting organonitrate and SOA formation. This hypothesis is supported by laboratory experiments that quantify products of the reaction of alpha-pinene + NO3 under atmospherically relevant conditions. PMID- 28586219 TI - Stable, Yet Highly Reactive Nonclassical Iron(II) Polyhydride Pincer Complexes: Z Selective Dimerization and Hydroboration of Terminal Alkynes. AB - The synthesis, characterization, and catalytic activity of nonclassical iron(II) polyhydride complexes containing tridentate PNP pincer-type ligands is described. These compounds of the general formula [Fe(PNP)(H)2(eta2-H2)] exhibit remarkable reactivity toward terminal alkynes. They efficiently promote the catalytic dimerization of aryl acetylenes giving the corresponding conjugated 1,3-enynes in excellent yields with low catalyst loadings. When the reaction is carried out in the presence of pinacolborane, vinyl boronates are obtained. Both reactions take place under mild conditions and are highly chemo-, regio-, and stereoselective with up to 99% Z-selectivity. PMID- 28586220 TI - Discovery of Allosteric Inhibitors Targeting the Spliceosomal RNA Helicase Brr2. AB - Brr2 is an RNA helicase belonging to the Ski2-like subfamily and an essential component of spliceosome. Brr2 catalyzes an ATP-dependent unwinding of the U4/U6 RNA duplex, which is a critical step for spliceosomal activation. An HTS campaign using an RNA-dependent ATPase assay and initial SAR study identified two different Brr2 inhibitors, 3 and 12. Cocrystal structures revealed 3 binds to an unexpected allosteric site between the C-terminal and the N-terminal helicase cassettes, while 12 binds an RNA-binding site inside the N-terminal cassette. Selectivity profiling indicated the allosteric inhibitor 3 is more Brr2-selective than the RNA site binder 12. Chemical optimization of 3 using SBDD culminated in the discovery of the potent and selective Brr2 inhibitor 9 with helicase inhibitory activity. Our findings demonstrate an effective strategy to explore selective inhibitors for helicases, and 9 could be a promising starting point for exploring molecular probes to elucidate biological functions and the therapeutic relevance of Brr2. PMID- 28586222 TI - Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study. AB - Histatin 5 (Hst5) is a naturally occurring antimicrobial peptide that acts as the first line of defense against oral candidiasis. It has been shown that conjugation of the active Hst5 fragment, Hst54-15, and the polyamine spermidine (Spd) improves the candidacidal effect. Knowledge about the structure of these conjugates is, however, very limited. Thus, the aim of this study was to characterize the structural properties of the Hst54-15-Spd conjugates by performing atomistic molecular dynamics simulations in combination with small angle X-ray scattering. It was shown that the Hst54-15-Spd conjugates adopt extended and slightly rigid random coil conformations without any secondary structure in aqueous solution. It is hypothesized that the increased fungal killing potential of Hst54-15-Spd, in comparison with the Spd-Hst54-15 conjugate, is due to the more extended conformations of the former, which cause the bonded Spd molecule to be more accessible for recognition by polyamine transporters in the cell. PMID- 28586224 TI - Au22Ir3(PET)18: An Unusual Alloy Cluster through Intercluster Reaction. AB - An intercluster reaction between Au25(PET)18 and Ir9(PET)6 producing the alloy cluster, Au22Ir3(PET)18 exclusively, is demonstrated where the ligand PET is 2 phenylethanethiol. Typical reactions of this kind between Au25(PET)18 and Ag25(SR)18, and other clusters reported previously, produce mixed cluster products. The cluster composition was confirmed by detailed high-resolution electrospray ionization mass spectrometry (ESI MS) and other spectroscopic techniques. This is the first example of Ir metal incorporation in a monolayer protected noble metal cluster. The formation of a single product was confirmed by thin layer chromatography (TLC). Density functional theory (DFT) calculations suggest that the most favorable geometry of the Au22Ir3(PET)18 cluster is one wherein the three Ir atoms are arranged triangularly with one Ir atom at the icosahedral core and the other two on the icosahedral shell. Significant contraction of the metal core was observed due to strong Ir-Ir interactions. PMID- 28586225 TI - In Situ Determination of the Water Condensation Mechanisms on Superhydrophobic and Superhydrophilic Titanium Dioxide Nanotubes. AB - One-dimensional (1D) nanostructured surfaces based on high-density arrays of nanowires and nanotubes of photoactive titanium dioxide (TiO2) present a tunable wetting behavior from superhydrophobic to superhydrophilic states. These situations are depicted in a reversible way by simply irradiating with ultraviolet light (superhydrophobic to superhydrophilic) and storage in dark. In this article, we combine in situ environmental scanning electron microscopy (ESEM) and near ambient pressure photoemission analysis (NAPP) to understand this transition. These experiments reveal complementary information at microscopic and atomic level reflecting the surface wettability and chemical state modifications experienced by these 1D surfaces upon irradiation. We pay special attention to the role of the water condensation mechanisms and try to elucidate the relationship between apparent water contact angles of sessile drops under ambient conditions at the macroscale with the formation of droplets by water condensation at low temperature and increasing humidity on the nanotubes' surfaces. Thus, for the as-grown nanotubes, we reveal a metastable and superhydrophobic Cassie state for sessile drops that tunes toward water dropwise condensation at the microscale compatible with a partial hydrophobic Wenzel state. For the UV-irradiated surfaces, a filmwise wetting behavior is observed for both condensed water and sessile droplets. NAPP analyses show a hydroxyl accumulation on the as-grown nanotubes surfaces during the exposure to water condensation conditions, whereas the water filmwise condensation on a previously hydroxyl enriched surface is proved for the superhydrophilic counterpart. PMID- 28586223 TI - In Situ Neutron Diffraction Studies of the Ion Exchange Synthesis Mechanism of Li2Mg2P3O9N: Evidence for a Hidden Phase Transition. AB - Motivated by predictions made using a bond valence sum difference map (BVS-DM) analysis, the novel Li-ion conductor Li2Mg2P3O9N was synthesized by ion exchange from a Na2Mg2P3O9N precursor. Impedance spectroscopy measurements indicate that Li2Mg2P3O9N has a room temperature Li-ion conductivity of about 10-6 S/cm (comparable to LiPON), which is 6 orders of magnitude higher than the extrapolated Na-ion conductivity of Na2Mg2P3O9N at this temperature. The structure of Li2Mg2P3O9N was determined from ex situ synchrotron and time-of flight neutron diffraction data to retain the P213 space group, though with a cubic lattice parameter of a = 9.11176(8) A that is significantly smaller than the a = 9.2439(1) A of Na2Mg2P3O9N. The two Li-ion sites are found to be very substantially displaced (~0.5 A) relative to the analogous Na sites in the precursor phase. The non-molten salt ion exchange method used to prepare Li2Mg2P3O9N produces a minimal background in powder diffraction experiments, and was therefore exploited for the first time to follow a Li+/Na+ ion exchange reaction using in situ powder neutron diffraction. Lattice parameter changes during ion exchange suggest that the reaction proceeds through a Na2-xLixMg2P3O9N solid solution (stage 1) followed by a two-phase reaction (stage 2) to form Li2Mg2P3O9N. However, full Rietveld refinements of the in situ neutron diffraction data indicate that the actual transformation mechanism is more complex and instead involves two thermodynamically distinct solid solutions in which the Li exclusively occupies the Li1 site at low Li contents (stage 1a) and then migrates to the Li3 site at higher Li contents (stage 1b), a crossover driven by the different signs of the local volume change at these sites. In addition to highlighting the importance of obtaining full structural data in situ throughout the ion exchange process, these results provide insights into the general question of what constitutes a thermodynamic phase. PMID- 28586226 TI - Elucidation of CuWO4 Surface States During Photoelectrochemical Water Oxidation. AB - Electrochemical, photoelectrochemical, and impedance spectroscopy measurements were performed to investigate the role of CuWO4 surface states during water oxidation. We found that a capacitive feature related to a surface state is clearly observable under water oxidation conditions. The magnitude of the surface state capacitance is light intensity-dependent, with a peak potential that coincides with the water oxidation onset potential region. The surface state is not observed in the dark nor in contact with nonaqueous solvents. These results strongly support our assignment of this surface state as the buildup of water oxidation intermediate species at the surface of CuWO4 photoanodes, not a permanent or intrinsic state as previously reported. We suggest this is a general feature that controls the behavior and efficiency of solar water splitting reactions. PMID- 28586221 TI - The Structure-Activity Relationship of a Tetrahydroisoquinoline Class of N-Methyl d-Aspartate Receptor Modulators that Potentiates GluN2B-Containing N-Methyl-d Aspartate Receptors. AB - We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist. Multiple compounds potentiate the response of NMDARs with submicromolar EC50 values. Analysis of enantiomeric pairs revealed that the S-(-) enantiomer is active at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the R-(+) enantiomer is only active at GluN2C/D subunits. These results provide a starting point for the development of selective positive allosteric modulators for GluN2B-containing receptors. PMID- 28586227 TI - Synthesis of Core@Shell Nanostructures in a Continuous Flow Droplet Reactor: Controlling Structure through Relative Flow Rates. AB - Bimetallic nanostructures are primarily synthesized in small volume batches. However, droplet-based reactors are receiving attention due to their ability to maintain thermal and compositional equilibrium within and between droplets, enabling flow operations for inline analyses and the scale-up of nanomaterial syntheses. Here, the syntheses of shape-controlled core@shell Au@Pd nanostructures with variable shell thicknesses are reported through control of the relative flow rates of reagents within the microreactor. Specifically, Pd shells were grown on cubic or octahedral Au seeds, selected as a model system. In batch reactions, shell thickness is determined by precursor concentration; however, as shown here, precursor feedstock concentration can be held constant, with the precursor concentration within the droplets being controlled through relative flow rates. This approach allows process conditions to be modified inline rather than from batch to batch to achieve particles with different shell thicknesses, and this procedure should be applicable to other multicomponent systems. PMID- 28586228 TI - Retained Carrier-Mobility and Enhanced Plasmonic-Photovoltaics of Graphene via ring-centered eta6 Functionalization and Nanointerfacing. AB - Binding graphene with auxiliary nanoparticles for plasmonics, photovoltaics, and/or optoelectronics, while retaining the trigonal-planar bonding of sp2 hybridized carbons to maintain its carrier-mobility, has remained a challenge. The conventional nanoparticle-incorporation route for graphene is to create nucleation/attachment sites via "carbon-centered" covalent functionalization, which changes the local hybridization of carbon atoms from trigonal-planar sp2 to tetrahedral sp3. This disrupts the lattice planarity of graphene, thus dramatically deteriorating its mobility and innate superior properties. Here, we show large-area, vapor-phase, "ring-centered" hexahapto (eta6) functionalization of graphene to create nucleation-sites for silver nanoparticles (AgNPs) without disrupting its sp2 character. This is achieved by the grafting of chromium tricarbonyl [Cr(CO)3] with all six carbon atoms (sigma-bonding) in the benzenoid ring on graphene to form an (eta6-graphene)Cr(CO)3 complex. This nondestructive functionalization preserves the lattice continuum with a retention in charge carrier mobility (9% increase at 10 K); with AgNPs attached on graphene/n-Si solar cells, we report an ~11-fold plasmonic-enhancement in the power conversion efficiency (1.24%). PMID- 28586229 TI - The Interplay between Trap Density and Hysteresis in Planar Heterojunction Perovskite Solar Cells. AB - Anomalous current-voltage (J-V) hysteresis in perovskite (PSK) solar cell is open to dispute, where hysteresis is argued to be due to electrode polarization, dipolar polarization, and/or native defects. However, a correlation between those factors and J-V hysteresis is hard to be directly evaluated because they usually coexist and are significantly varied depending on morphology and crystallinity of the PSK layer, selective contacts, and device architecture. In this study, without changing morphology and crystallinity of PSK layer in a planar heterojunction structure employing FA0.9Cs0.1PbI3, a correlation between J-V hysteresis and trap density is directly evaluated by means of thermally induced PbI2 regulating trap density. Increase in thermal annealing time at a given temperature of 150 degrees C induces growth of PbI2 on the PSK grain surface, which results in significant reduction of nonradiative recombination. Hysteresis index is reduced from 0.384 to 0.146 as the annealing time is increased from 5 to 100 min due to decrease in the amplitude of trap-mediated recombination. Reduction of hysteresis by minimizing trap density via controlling thermal annealing time leads to the stabilized PCE of 18.84% from the normal planar structured FA0.9Cs0.1PbI3 PSK solar cell. PMID- 28586230 TI - Weak Donor-Acceptor Interaction and Interface Polarization Define Photoexcitation Dynamics in the MoS2/TiO2 Composite: Time-Domain Ab Initio Simulation. AB - To realize the full potential of transition metal dichalcogenides interfaced with bulk semiconductors for solar energy applications, fast photoinduced charge separation, and slow electron-hole recombination are needed. Using a combination of time-domain density functional theory with nonadiabatic molecular dynamics, we demonstrate that the key features of the electron transfer (ET), energy relaxation and electron-hole recombination in a MoS2-TiO2 system are governed by the weak van der Waals interfacial interaction and interface polarization. Electric fields formed at the interface allow charge separation to happen already during the photoexcitation process. Those electrons that still reside inside MoS2, transfer into TiO2 slowly and by the nonadiabatic mechanism, due to weak donor-acceptor coupling. The ET time depends on excitation energy, because the TiO2 state density grows with energy, increasing the nonadiabatic transfer rate, and because MoS2 sulfur atoms start to contribute to the photoexcited state at higher energies, increasing the coupling. The ET is slower than electron-phonon energy relaxation because the donor-acceptor coupling is weak, rationalizing the experimentally observed injection of primarily hot electrons. The weak van der Waals MoS2-TiO2 interaction ensures a long-lived charge separated state and a short electron-hole coherence time. The injection is promoted primarily by phonons within the 200-800 cm-1 range. Higher frequency modes are particularly important for the electron-hole recombinations, because they are able to accept large amounts of electronic energy. The predicted time scales for the forward and backward ET, and energy relaxation can be measured by time-resolved spectroscopies. The reported simulations generate a detailed time-domain atomistic description of the complex interplay of the charge and energy transfer processes at the MoS2/TiO2 interface that are of fundamental importance to photovoltaic and photocatalytic applications. The results suggest that even though the photogenerated charge-separated state is long-lived, the slower charge separation, compared to the electron-phonon energy relaxation, can present problems in practical applications. PMID- 28586231 TI - Silicon Nanowire/Polymer Hybrid Solar Cell-Supercapacitor: A Self-Charging Power Unit with a Total Efficiency of 10.5. AB - An integrated self-charging power unit, combining a hybrid silicon nanowire/polymer heterojunction solar cell with a polypyrrole-based supercapacitor, has been demonstrated to simultaneously harvest solar energy and store it. By efficiency enhancement of the hybrid nanowire solar cells and a dual functional titanium film serving as conjunct electrode of the solar cell and supercapacitor, the integrated system is able to yield a total photoelectric conversion to storage efficiency of 10.5%, which is the record value in all the integrated solar energy conversion and storage system. This system may not only serve as a buffer that diminishes the solar power fluctuations from light intensity, but also pave its way toward cost-effective high efficiency self charging power unit. Finally, an integrated device based on ultrathin Si substrate is demonstrated to expand its feasibility and potential application in flexible energy conversion and storage devices. PMID- 28586233 TI - A Vibration Device to Control Injection Discomfort. AB - Pain from local anesthesia injections can be reduced by distraction and counter stimulation techniques. This study investigated the DentalVibe(r) Injection Comfort System (third-generation, DV3), developed to lessen anesthesia pain through pulsed vibration, a form of counter-stimulation. The aim of the study was to evaluate both the efficacy of DV3 in reducing pain and discomfort from intraoral long buccal (LB) and inferior alveolar nerve (IAN) injections and the time needed to achieve complete anesthesia during an IAN block. The study enrolled 60 subjects, 30 men and 30 women, aged 21 to 32 years, who rated both injection pain on a visual analog scale and discomfort, unpleasantness, and difficulty in enduring the injection on a modified symptom severity index. Each subject received bilateral LB injections and an IAN block. Using block design, the third-generation DV (DV3) was randomly assigned to either the first or second LB injection and to 30 subjects on their third injection, the IAN block. No topical anesthesia was applied. Subjects receiving DV3 reported significantly less pain, discomfort, unpleasantness, and difficulty in enduring LB and IAN injections (P < .05), regardless of whether DV3 was used on the first or second LB injection. Time to complete anesthesia was not significantly different (P > .05) when DV3 was used on IAN block injections. The DV3 significantly (P < .02) reduced pain/discomfort from anesthetic injections in this pilot study, in which many subjects were either dental or medical students familiar with performing and enduring injections. More studies are warranted on layperson populations. PMID- 28586232 TI - Does 6 Hours of Contact With Alginate Impression Material Affect Dental Cast Properties? AB - Alginate impression (irreversible hydrocolloid) material is commonly used in dental practice because it is easy to mix, low in cost, and well tolerated by patients. The material is not dimensionally stable, however; thus, it is necessary to pour the impression immediately after the molding is accomplished, or within 60 minutes if the impression is kept in 100% humidity. Excessive contact of the alginate impression with the cast model over time may affect the model's properties. In this study, the authors tested the effect of contact time between an alginate impression and type III dental stone on cast model properties. Sixty-seven cast models were obtained from a stainless steel cylinder by using irreversible hydrocolloid impression material and type III dental stone. Thirty-seven cast models were separated from the impression after 1 hour (control group) and 30 cast models were separated after 6 hours (study group). The samples were evaluated under light microscope for surface details and measured by digital caliper for dimensional stability. An indentation on the cast was made and the depth of the indentation was then measured with a digital caliper to measure hardness. The dimensional stability of the cast models was not affected when contact time was increased from 1 hour to 6 hours (P = .507). Surface details did not deteriorate when contact time was increased, as all of the samples could reproduce all details after the 1-hour and 6-hour interval periods. However, hardness was greater after 1 hour of contact time (P = .001) than after 6 hours of contact time. In conclusion, contact between alginate impression material and type III dental stone up to 6 hours did not affect the dimensional stability and richness of the surface; hardness, though, was significantly affected. PMID- 28586234 TI - The Direct-Indirect Technique for Composite Restorations Revisited. AB - In the direct-indirect composite technique, composite is applied to a nonretentive tooth preparation (eg, a noncarious cervical lesion or a veneer/inlay/onlay preparation) without any bonding agent, sculpted to a primary anatomic form, and light-cured. The partially polymerized restoration is then removed from the preparation and finished and tempered extraorally chairside. The finished inlay is bonded to the preparation using a resin-based luting agent. Advantages of this technique include enhanced physical and mechanical properties afforded by the extraoral chairside tempering process because of increased monomer conversion, and greater operator control over the final marginal adaptation, surface finishing and polishing, and anatomy of the restoration, given that these elements are defined outside of the patient's mouth. The direct indirect approach also affords enhanced gingival health and patient comfort. This article presents a clinical case in which the direct-indirect composite technique was used to restore three noncarious cervical lesions on the same quadrant on an adult patient. Clinical steps and tips for success are offered. The authors also present scanning electron microscope and atomic force microscope images showing the excellent marginal fit obtained with the direct-indirect composite technique. PMID- 28586235 TI - New High-Translucent Cubic-Phase-Containing Zirconia: Clinical and Laboratory Considerations and the Effect of Air Abrasion on Strength. AB - Fabricating all-ceramic restorations with minimal or no application of a secondary phase while maintaining esthetics has been a sought-after goal of the dental profession. The objective has been development of a monolithic material with optical properties similar to the natural tooth without the need for layering porcelain. This article examines some of the newer cubic zirconia materials used in a monolithic form. The authors discuss laboratory-processing issues that affect esthetics, including evaluation of colorizing, sintering, finishing, and polishing, and assess initial translucency testing of several materials while evaluating the effect of air abrasion on flexural strength of these cubic zirconias. Lastly, the article demonstrates an anterior single-unit monolithic case with several of the newer materials. PMID- 28586236 TI - Inspecting Targeted Deep Sequencing of Whole Genome Amplified DNA Versus Fresh DNA for Somatic Mutation Detection: A Genetic Study in Myelodysplastic Syndrome Patients. AB - Whole genome amplification (WGA) has become an invaluable method for preserving limited samples of precious stock material and has been used during the past years as an alternative tool to increase the amount of DNA before library preparation for next-generation sequencing. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by presenting somatic mutations in several myeloid-related genes. In this work, targeted deep sequencing has been performed on four paired fresh DNA and WGA DNA samples from bone marrow of MDS patients, to assess the feasibility of using WGA DNA for detecting somatic mutations. The results of this study highlighted that, in general, the sequencing and alignment statistics of fresh DNA and WGA DNA samples were similar. However, after variant calling and when considering variants detected at all frequencies, there was a high level of discordance between fresh DNA and WGA DNA (overall, a higher number of variants was detected in WGA DNA). After proper filtering, a total of three somatic mutations were detected in the cohort. All somatic mutations detected in fresh DNA were also identified in WGA DNA and validated by whole exome sequencing. PMID- 28586237 TI - A Unique Second-Generation Recombinant Form of HIV-1 Identified Among Men Who Have Sex with Men Population in Beijing, China. AB - In China, CRF01_AE and CRF07_BC are the most circulating strains of HIV-1, more and more second-generation recombinant forms have been isolated around the two strains. The same situation happened in Beijing in recent years. In our study, we have isolated a new second-generation recombinant form of HIV-1 from a male patient who was infected by homosexual behavior. Polygenetic analysis revealed that the sequence includes five CRF01_AE fragments and four CRF07_BC fragments. CRF01_AE is the skeleton of the recombinant which was inserted with four CRF07_BC fragments. The emergency of such second-generation recombinant forms manifests the diversity of the HIV-1 epidemic. Consequently, further investigation of molecular epidemiology is needed to track the genetic evolution of HIV-1. PMID- 28586238 TI - Toward Accountable Discrimination-Aware Data Mining: The Importance of Keeping the Human in the Loop-and Under the Looking Glass. AB - "Big Data" and data-mined inferences are affecting more and more of our lives, and concerns about their possible discriminatory effects are growing. Methods for discrimination-aware data mining and fairness-aware data mining aim at keeping decision processes supported by information technology free from unjust grounds. However, these formal approaches alone are not sufficient to solve the problem. In the present article, we describe reasons why discrimination with data can and typically does arise through the combined effects of human and machine-based reasoning, and argue that this requires a deeper understanding of the human side of decision-making with data mining. We describe results from a large-scale human subjects experiment that investigated such decision-making, analyzing the reasoning that participants reported during their task to assess whether a loan request should or would be granted. We derive data protection by design strategies for making decision-making discrimination-aware in an accountable way, grounding these requirements in the accountability principle of the European Union General Data Protection Regulation, and outline how their implementations can integrate algorithmic, behavioral, and user interface factors. PMID- 28586239 TI - Entertainment-Education Videos as a Persuasive Tool in the Substance Use Prevention Intervention "keepin' it REAL". AB - Based on social cognitive theory and narrative engagement theory, the current study examined hypothesized indirect effects of engagement with keepin' it REAL (kiR) curriculum entertainment-education (E-E) videos on youth alcohol use via youth drug offer refusal efficacy. Students in 7th grade (N = 1,464) at 25 public schools in two Midwestern states were randomly assigned to one of the two versions of the kiR curriculum, the kiR urban version and the kiR rural version. Each version had their own set of five culturally-grounded E-E videos depicting communicative skills to refuse drug offers. Differential effects for engagement components were expected depending on the degree of cultural matching. Pre/post surveys were administered at the beginning and the end of 7th grade. Structural equation modeling analysis resulted in partial support for the research hypotheses. Rural youth receiving the urban curriculum who reported higher interest in the E-E videos were more likely to report having higher refusal efficacy, and in turn, less likely to use alcohol. Rural youth receiving the rural curriculum who identified with the E-E video main characters were more likely to report having higher refusal efficacy, and in turn, less likely to use alcohol. Implications for E-E health promotion are discussed. PMID- 28586240 TI - The March for Effectiveness Science. PMID- 28586241 TI - Unbiased Quantitation of Alveolar Type II to Alveolar Type I Cell Transdifferentiation during Repair after Lung Injury in Mice. AB - The alveolar epithelium consists of squamous alveolar type (AT) I and cuboidal ATII cells. ATI cells cover 95-98% of the alveolar surface, thereby playing a critical role in barrier integrity, and are extremely thin, thus permitting efficient gas exchange. During lung injury, ATI cells die, resulting in increased epithelial permeability. ATII cells re-epithelialize the alveolar surface via proliferation and transdifferentiation into ATI cells. Transdifferentiation is characterized by down-regulation of ATII cell markers, up-regulation of ATI cell markers, and cell spreading, resulting in a change in morphology from cuboidal to squamous, thus restoring normal alveolar architecture and function. The mechanisms underlying ATII to ATI cell transdifferentiation have not been well studied in vivo. A prerequisite for mechanistic investigation is a rigorous, unbiased method to quantitate this process. Here, we used SPCCreERT2;mTmG mice, in which ATII cells and their progeny express green fluorescent protein (GFP), and applied stereologic techniques to measure transdifferentiation during repair after injury induced by LPS. Transdifferentiation was quantitated as the percent of alveolar surface area covered by ATII-derived (GFP+) cells expressing ATI, but not ATII, cell markers. Using this methodology, the time course and magnitude of transdifferentiation during repair was determined. We found that ATI cell loss and epithelial permeability occurred by Day 4, and ATII to ATI cell transdifferentiation began by Day 7 and continued until Day 16. Notably, transdifferentiation and barrier restoration are temporally correlated. This methodology can be applied to investigate the molecular mechanisms underlying transdifferentiation, ultimately revealing novel therapeutic targets to accelerate repair after lung injury. PMID- 28586242 TI - Tyrosine kinase inhibitor (TKI) therapy for newly-diagnosed patients with chronic myeloid leukemia: focusing on TKI discontinuation due to adverse events - is better always good? PMID- 28586244 TI - Converging on the Value of Value Frameworks. PMID- 28586243 TI - Falls, Functioning, and Disability Among Women With Persistent Symptoms of Chemotherapy-Induced Peripheral Neuropathy. AB - Purpose Chemotherapy-induced peripheral neuropathy (CIPN) may persist after treatment ends and may lead to functional decline and falls. This study compared objective and self-report measures of physical function, gait patterns, and falls between women cancer survivors with and without symptoms of CIPN to identify targets for functional rehabilitation. Methods A secondary data analysis of 512 women cancer survivors (age, 62 +/- 6 years; time since diagnosis, 5.8 +/- 4.1 years) categorized and compared women self-reporting symptoms of CIPN (CIPN+) with asymptomatic women (CIPN-) on the following: maximal leg strength, timed chair stand, physical function battery, gait characteristics (speed; step number, rate, and length; base of support), self-report physical function and disability, and falls in the past year. Results After an average of 6 years after treatment, 47% of women still reported symptoms of CIPN. CIPN+ had significantly worse self report and objectively measured function than did CIPN-, with the exception of maximal leg strength and base of support during a usual walk. Gait was slower among CIPN+, with those women taking significantly more, but slower and shorter, steps than did CIPN- (all P < .05). CIPN+ reported significantly more disability and 1.8 times the risk of falls compared with CIPN- ( P < .0001). Increasing symptom severity was linearly associated with worsening function, increasing disability, and higher fall risk (all P < .05). Conclusion This work makes a significant contribution toward understanding the functional impact of CIPN symptoms on cancer survivors. Remarkably, 47% of women in our sample had CIPN symptoms many years after treatment, together with worse function, greater disability, and more falls. CIPN must be assessed earlier in the clinical pathway, and strategies to limit symptom progression and to improve function must be included in clinical and survivorship care plans. PMID- 28586245 TI - Expanding the Perspective on Chemotherapy-Induced Peripheral Neuropathy Management. PMID- 28586246 TI - Characterization of a New HIV-1 CRF01_AE/CRF07_BC Recombinant Virus in Guangxi, China. AB - Currently, more and more kinds of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) were identified in China. A novel second-generation CCR5 tropic HIV-1 recombinant virus (GX2016EU09) was identified here, which was isolated from a HIV-1-infected man who had sex with men (MSM) in Guangxi, China. Phylogenetic analysis of near full-length genome (NFLG) showed that the novel HIV 1 recombinant GX2016EU09 clustered with CRF01_AE reference sequences, but set up a distinct branch. Recombinant analysis showed that the NFLG of GX2016EU09 composed of CRF01_AE (as the backbone) and CRF07_BC, with nine recombination break points observed in the gag, pol, vif, vpr, tat, rev, vpu, env, and nef regions. To our knowledge, this HIV-1 URF differs from previously documented CRF01_AE/CRF07_BC forms. The emergence of a novel CRF01_AE/CRF07_BC recombinant strain indicates the increasing complexity of the HIV-1 epidemic among the MSM group in Guangxi, China. PMID- 28586247 TI - Holmium Laser Enucleation of the Prostate After Prostatic Urethral Lift Surgery: Feasibility and Technical Considerations from a Multi-Institutional Case Series. AB - INTRODUCTION AND OBJECTIVE: Ten percent of patients undergoing prostatic urethral lift (PUL) require repeat surgical treatment within 3 years. We describe the feasibility and considerations of performing holmium laser enucleation of the prostate (HoLEP) as a salvage therapy after previous PUL. METHODS: Men who had undergone HoLEP after PUL were retrospectively identified from three institutions with surgeons experienced in HoLEP. Subjects were characterized by age, time from PUL procedure (months) to HoLEP surgery, indication for retreatment, and pre operative prostate volume by ultrasound. Outcomes of interest included enucleation time, morcellation time, morcellator type, weight of tissue resected, and Clavien complications. We also summarize findings related to the location of PUL device implants, and the effect of the implants on the enucleation and morcellation portions of the procedure. RESULTS: From December 15, 2015 to October 31, 2016, seven men aged 51-78 years underwent HoLEP at a median of 8.6 months (range 3-18) after PUL. The median prostate volume by transrectal ultrasound was 80 cm3 (range 56-160 cm3). For the 7 patients, 6 out of the 22 device implants were found in aberrant locations. Auxiliary maneuvers were required in five cases. Morcellation devices tended to jam with each implant, requiring a pause for withdrawal of the morcellator and manual removal from the blade or requiring grasper retrieval of device components. There were no Clavien complications. CONCLUSIONS: HoLEP can be performed safely and effectively post PUL; however, device implants may be found in areas other than the intended location, and morcellation of the adenoma tissue is complicated by metallic implants of the PUL device. PMID- 28586249 TI - Friends Don't Let Friends Smoke: How Storytelling and Social Distance Influence Nonsmokers' Responses to Antismoking Messages. AB - This study examines nonsmokers' responses to antismoking messages. Informed by construal-level theory (CLT), it investigates whether and how evidence type (narrative vs. non-narrative) and social distance might interact to influence nonsmokers' attitudes toward others' quitting smoking and intentions to persuade others to quit smoking. Results of a controlled experiment (N = 281) revealed an approximately significant two-way interaction pertaining to attitudes. Simple effects analyses revealed that narratives produced less-favorable attitudes toward others' quitting smoking than nonnarratives when participants thought about their best friend. Yet, there was no difference in attitudes between narratives and nonnarratives when participants thought about socially distant others. The results also indicated that nonnarratives overpowered narratives to influence participants' attitudes toward others' quitting smoking. Moreover, social distance had a consistent impact on their risk beliefs, such that they perceive fewer health risks of their close friends than an average college student. Theoretical and practical implications of the results are discussed. PMID- 28586248 TI - Side effects and potential risk factors of botulinum toxin type A intramuscular injections in knee flexion contractures of hemophiliacs. AB - INTRODUCTION: Knee flexion contracture (KFC) is a common complication of recurrent hemarthrosis in children and young adults with hemophilia. If the KFC is not prevented (by means of primary prophylaxis) and treated properly and early (be means of physical medicine and rehabilitation), it will become fixed. Areas covered: The aim of this article is to review the potential role of botulinum toxin type A (BTX-A) intramuscular injections for the treatment of KFC in people with hemophilia (PWH). Expert commentary: Although two recent reports have mentioned the benefits of intramuscular injections of BTX-A in PWH with KFC, the data are still scant and too preliminary. The use of intramuscular injections of BTX-A in PWH today should not be recommended until more case studies/small series (ideally well-designed clinical trials) fully demonstrate that this is safe and effective. The risks of intramuscular injections to a hemophilia patient cannot be underestimated (iatrogenic muscle hematomas and pseudotumors). This paper calls the attention of hemophilia treaters on the potential risks of this apparently interesting technique. The current use of BTX-A intramuscular injections in KFC of PWH could make no sense. Raising false expectations in these patients should be avoided. PMID- 28586250 TI - Pain After Percutaneous Irreversible Electroporation of Renal Tumors Is Not Dependent on Tumor Location. AB - INTRODUCTION: Irreversible electroporation (IRE) is a non-thermal minimally invasive technique that is used to treat small renal masses (SRMs). Prior work has demonstrated greater narcotic requirements after radiofrequency ablation (RFA) for tumors that are closer to body-wall musculature. We hypothesized that pain after IRE is not dependent on tumor location due to the athermal mechanistic action. MATERIALS AND METHODS: A retrospective review of 50 consecutive percutaneous IRE and RFA cases was performed from 2013 to 2014. Eight patients were excluded from analysis due to incomplete anesthesia record and/or multiple ablations per session, leaving 21 patients in each group. Data collected included patient age, sex, body mass index, nephrometry score, shortest distance to the closest body-wall muscle, perioperative narcotic use, and patient-reported pain score. Pearson correlation test and multivariable linear regression were used to identify predictors of postoperative pain, with significance set at p = 0.05. RESULTS: There was no difference in the mean distance from tumor edge to the nearest body-wall muscle between IRE and RFA (2.6 cm vs 2.4 cm, p = 0.729, respectively). Total mean perioperative narcotic usage was 20.4 mg after IRE and 26.7 mg after RFA (p = 0.096). Mean postoperative pain score (scale 0-10) was slightly higher after RFA (4.3) compared with IRE (2.4), but this was not statistically significant (p = 0.088). Pearson correlation test identified tumor proximity to be significiantly associated with both pain score (p = 0.011) and postoperative narcotic use (p = 0.049) after RFA but not after IRE. On multivariable analysis, only tumor proximity to the body wall was significantly correlated to pain score (-1.4, p = 0.041) after RFA but was not found to be a factor for pain after IRE. CONCLUSIONS: Patients whose tumors lie close to their body-wall musculature do not have greater narcotic requirements or higher pain scores in the perioperative period after IRE. Percutaneous IRE may be preferred over RFA for SRMs that are close to the body wall to minimize pain. PMID- 28586251 TI - The relationship between idiopathic cytopenias/dysplasias of uncertain significance (ICUS/IDUS) and autoimmunity. AB - INTRODUCTION: This review examines the several lines of evidence that support the relationship between myelodysplasia and autoimmunity, i.e. their epidemiologic association, the existence of common immune-mediated physiopathologic mechanisms, and the response to similar immunosuppressive therapies. The same relationship is reviewed here considering idiopathic cytopenia of uncertain significance (ICUS) and idiopathic dysplasia of uncertain significance (IDUS), two recently recognized provisional conditions characterized by isolated/unexplained cytopenia and/or dysplasia in <10% bone marrow cells. Areas covered: The review focuses on alterations of cytokine profiles, telomere/telomerase and toll-like receptors, and on increased myelosuppressive mediators and apoptotic markers in both myelodysplasia and autoimmunity. In addition, the presence of an autoimmune reaction directed against marrow precursors is described in refractory/relapsing autoimmune cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia, chronic idiopathic neutropenia), possibly contributing to their evolution to ICUS/IDUS/bone marrow failure syndromes. Expert commentary: The increasing availability of omics methods has fuelled the discussion on the role of somatic mutations in the pathogenesis of IDUS/ICUS, clonal hematopoiesis of indeterminate potential, and clonal cytopenias of undetermined significance, and in their possible evolution. Even more attracting is the involvement of the genetic background/accumulating somatic mutations in cytopenias with autoimmune alterations. PMID- 28586252 TI - Lapachol and lapachone analogs: a journey of two decades of patent research(1997 2016). AB - INTRODUCTION: Lapachol (1), beta-lapachone (2) and alpha-lapachone (3) are three well-studied natural products isolated from Tabebuia impetiginosa having most interesting chemodiversity and demonstrating diverse biological effects. Areas covered: The current review summarizes the recent and past discovery of chemotherapeutic agents based on the compounds 1-3. This review presents an overview of patents filed over the past two decades (1997 to 2016) mostly relating to the anticancer effects of these lapachol and lapachone analogues. Expert opinion: The large number of interesting patents published on the therapeutic potential of quinones 1-3 and their synthetic derivatives lends credence to the importance of these molecules. Moreover, these quinones demonstrated potent anticancer effects towards various cancer cell lines and chemical modification of these quinones have led to products displaying enhanced anticancer effects. It is noteworthy that the majority of patents published are on the anticancer effects of quinones 1-3 and their synthetic derivatives along with a limited number of additional biological effects. It is our opinion that in order to get lead compounds, there needs to be a greater focus on the elucidation of the precise mechanism of action of these compounds including SAR and in vivo studies. PMID- 28586253 TI - Characterization of recombinant Trypanosoma brucei gambiense Translationally Controlled Tumor Protein (rTbgTCTP) and its interaction with Glossina midgut bacteria. AB - In humans, sleeping sickness (i.e. Human African Trypanosomiasis) is caused by the protozoan parasites Trypanosoma brucei gambiense (Tbg) in West and Central Africa, and T. b. rhodesiense in East Africa. We previously showed in vitro that Tbg is able to excrete/secrete a large number of proteins, including Translationally Controlled Tumor Protein (TCTP). Moreover, the tctp gene was described previously to be expressed in Tbg-infected flies. Aside from its involvement in diverse cellular processes, we have investigated a possible alternative role within the interactions occurring between the trypanosome parasite, its tsetse fly vector, and the associated midgut bacteria. In this context, the Tbg tctp gene was synthesized and cloned into the baculovirus vector pAcGHLT-A, and the corresponding protein was produced using the baculovirus Spodoptera frugicola (strain 9) / insect cell system. The purified recombinant protein rTbgTCTP was incubated together with bacteria isolated from the gut of tsetse flies, and was shown to bind to 24 out of the 39 tested bacteria strains belonging to several genera. Furthermore, it was shown to affect the growth of the majority of these bacteria, especially when cultivated under microaerobiosis and anaerobiosis. Finally, we discuss the potential for TCTP to modulate the fly microbiome composition toward favoring trypanosome survival. PMID- 28586254 TI - Hospitalizations for asthma among adults exposed to the September 11, 2001 World Trade Center terrorist attack. AB - OBJECTIVE: We described the patterns of asthma hospitalization among persons exposed to the 2001 World Trade Center (WTC) attacks, and assessed whether 9/11 related exposures or comorbidities, including posttraumatic stress disorder (PTSD) and gastroesophageal reflux symptoms (GERS), were associated with an increased rate of hospitalization. METHODS: Data for adult enrollees in the WTC Health Registry, a prospective cohort study, with self-reported physician diagnosed asthma who resided in New York State on 9/11 were linked to administrative hospitalization data to identify asthma hospitalizations during September 11, 2001-December 31, 2010. Multivariable zero-inflated Poisson regression was used to examine associations among 9/11 exposures, comorbid conditions, and asthma hospitalizations. RESULTS: Of 11 471 enrollees with asthma, 406 (3.5%) had >=1 asthma hospitalization during the study period (721 total hospitalizations). Among enrollees diagnosed before 9/11 (n = 6319), those with PTSD or GERS had over twice the rate of hospitalization (adjusted rate ratio (ARR) = 2.5, 95% CI = 1.4-4.1; ARR = 2.1, 95% CI = 1.3-3.2, respectively) compared to those without. This association was not statistically significant in enrollees diagnosed after 9/11. Compared to higher educational attainment, completing less than college was associated with an increased hospitalization rate among participants with both pre-9/11- and post-9/11-onset asthma (ARR = 1.9, 95% CI = 1.2-2.9; ARR = 2.6, 95% CI = 1.6-4.1, respectively). Sinus symptoms, exposure to the dust cloud, and having been a WTC responder were not associated with asthma hospitalization. CONCLUSIONS: Among enrollees with pre 9/11 asthma, comorbid PTSD and GERS were associated with an increase in asthma hospitalizations. Management of these comorbidities may be an important factor in preventing hospitalization. PMID- 28586255 TI - Disparities in Assisted Reproductive Technology Utilization by Race and Ethnicity, United States, 2014: A Commentary. AB - Disparities in infertility and access to infertility treatments, such as assisted reproductive technology (ART), by race/ethnicity, have been reported. However, identifying disparities in ART usage may have been hampered by missing race/ethnicity information in ART surveillance. We review infertility prevalence and treatment disparities, use recent data to examine ART use in the United States by race/ethnicity and residency in states with mandated insurance coverage for in vitro fertilization (IVF), and discuss approaches for reducing disparities. We used 2014 National ART Surveillance System (NASS) data to calculate rates of ART procedures per million women 15-44 years of age, a proxy measure of ART utilization, for Census-defined racial/ethnic groups in the United States; rates were further stratified by the presence of insurance mandates for IVF treatment. Missing race/ethnicity data (35.6% of cycles) were imputed. Asian/Pacific Islander (A/PI) women had the highest rates of ART utilization at 5883 ART procedures per million women 15-44 years of age in 2014, whereas American Indian/Alaska Native non-Hispanic women had the lowest rates at 807 per million, compared with other racial/ethnic groups. In each racial/ethnic category, ART utilization rates were higher for women in states with an insurance mandate for IVF treatment versus those without. In 2014, A/PI women had the highest rates of ART utilization. ART utilization for all racial/ethnic groups was higher in states with insurance mandates for IVF than those without, although disparities were still evident. Although mandates may increase access to infertility treatments, they are not sufficient to eliminate these disparities. PMID- 28586256 TI - Pediatric Palliative Care: A Five-Year Retrospective Chart Review Study. AB - BACKGROUND: More children are living with serious illness. However, survival and complexity of illnesses have not been described. OBJECTIVE: To describe types of illnesses, timing of referral, and time to death following referral to palliative care; to examine the associations between demographics and clinical characteristics and patient survival; and to examine whether average daily pain decreases after referral. DESIGN: Retrospective chart review of all children ages 2-16 years referred to palliative care at one large children's hospital during the five-year study period from January 1, 2009, through December 31, 2013. MEASUREMENTS: The primary outcome was patient survival and the main independent predictor was type of illness. Kaplan-Meier estimation was used to estimate patient survival time following referral, Cox proportional hazards regression was used to build predictive models based on gender, age, race, religion, and types of illnesses, and paired t-test compared the assessment of pain before and after referral. RESULTS: The cohort consisted of 256 children. Survival experience did not differ significantly based on gender, age, race, or religion (p >= 0.05); however, survival did vary based on referring diagnosis (chi2 = 40.3, df = 4, p < 0.001), particularly cancer. Forty-eight children with three days of pain assessments pre- and postreferral had significantly decreased pain postreferral (t(47) = 1.816, p < 0.05 one tailed), supporting our hypothesis. DISCUSSION: Results provide important information on the complexity of disease processes for children referred to palliative care, types of illnesses referred, survival, and pain levels. Results reflect earlier referral to palliative care for most children and highlight the medical complexity especially for children with congenital and genetic diagnoses. PMID- 28586257 TI - The Impact of Specialized Telephonic Guides on Employee Engagement in Corporate Well-Being Programs. AB - Employer-sponsored well-being programs have been growing in popularity as a means to control rising health care costs and increase workplace productivity. Engagement by employees is necessary for these programs to achieve their desired effects. Extrinsic motivators in the form of incentives and surcharges are commonly introduced by employer program sponsors to promote meaningful engagement. Although these may be successful in achieving a degree of engagement, individuals benefit by being intrinsically motivated as they modify behaviors and improve short- and long-term well-being. Telephonic guides equipped with motivational interviewing and other behavioral strategies to improve engagement may bridge the gap between extrinsic and intrinsic motivation. The objectives of this study are to determine characteristics associated with employee utilization of these guides when offered and to compare subsequent program engagement rates between utilizers to a propensity score matched group of employees who were not offered the service. The data were retrieved from a well-being program provider's database. The study examined 166,258 employees across 35 employers. It found utilizers were older, proportionally more female, in the manufacturing industry, incented to use the guide service, offered a larger incentive for program participation, had healthier self-reported behaviors, and had a higher perception of their employer's focus on well-being. The study found that guide utilizers were significantly more likely to engage in telephonic coaching, digital coaching, and activity tracking up to 6 months. The study's findings suggest telephonic guides using a range of behavioral techniques are an effective strategy to drive well-being program engagement. PMID- 28586259 TI - Implementation of Advance Care Planning in Oncology: A Review of the Literature. AB - Advance care planning (ACP) should be initiated early and be readdressed often for patients with cancer. This directive is expressed in the Institute of Medicine's report, "Dying in America," and is a component of several quality metrics, including ASCO's Quality Oncology Practice Initiative and the Centers for Medicare & Medicaid Services Oncology Care Model. Although simple in concept, implementation in practice is challenging. A variety of patient education tools exist in several different forms, including pamphlets, guidebooks, and question prompt lists, with the strongest data supporting the use of video decision aids that depict cardiopulmonary resuscitation. These educational tools should address topics that include anticancer treatment, cardiopulmonary resuscitation, and health care surrogates. Physician prompts in the electronic health record to discuss ACP should be considered. Health care provider training should be offered to meet the needs and comfort level of the practitioners who conduct the intervention. Intervention studies that assessed ACP documentation rates as the primary end point increased documentation from 15% to 30% to 40%. Additional well conducted randomized studies are needed to understand the intervention characteristics that can further improve the completion and documentation of ACP. Further research is needed to determine if there is a difference in outcome based on which provider conducts ACP as well as how to maximize the benefits of the electronic health record, such as prompts to readdress ACP. PMID- 28586258 TI - Reactance and Coping Responses to Tobacco Counter-Advertisements. AB - Tobacco prevention messages generally take one of three tactics: They can be educational, attack the tobacco industry, or attack particular brands. Being a smoker and smoking a particular brand may form an essential part of a person's self-identity. As such, reactance theory suggests that attack messages can unintentionally attack smokers' self-image. A 2 * 2 * 2 * 2 experiment using six different messages and 260 respondents tested whether smokers have different reactions to tobacco counter-advertisements than nonsmokers. It also examined whether attacking a smoker's brand leads to greater reactance and other maladaptive responses compared to attacking other brands. Consistent with predictions, smokers reported more maladaptive coping responses and fewer adaptive coping responses to tobacco counter-ads than nonsmokers. The study also reveals differences attributable to brand identification. These findings suggest that interventions should consider different counter-advertising tactics for smokers and nonsmokers. Similar admonitions may apply to counter-advertising strategies on other health issues. PMID- 28586260 TI - Laparoscopic Ventral Rectopexy Versus Laparoscopic Wells Rectopexy for Complete Rectal Prolapse: Long-Term Results. AB - BACKGROUND: There is no agreement about which laparoscopic rectopexy technique is best for treating complete rectal prolapse. Purpose was to compare functional outcome, the recurrence rate, and quality of life in patients treated with laparoscopic ventral rectopexy (LVR) versus the laparoscopic Wells rectopexy (LWR) for complete rectal prolapse. MATERIALS AND METHODS: A retrospective review of a prospectively maintained database of consecutive patients who presented with complete rectal prolapse. Patients were divided into two cohorts: first one had LVR and the other one had LWR. Exclusion criteria were previous major abdominal surgery, slow transit constipation, Hirschsprung's disease, inflammatory bowel disease, pregnancy, and patients on drugs that cause constipation. Patients were assessed preoperatively by clinical examination to evaluate constipation using the Wexner constipation scale (WCS), incontinence using the Wexner incontinence score (WIS), and quality of life using the gastrointestinal quality of life index (GIQOL). The primary outcome measures were disappearance of prolapse and recurrences. Secondary outcome parameters were operative time, complications, length of hospital stay, effect on perineal descent, functional outcome (constipation and continence), and quality of life. RESULTS: A total of 74 patients (mean age of 55 years) with complete rectal prolapse had LVR (n = 41) and LWR (n = 33). Sixty (81%) patients were females. Operative time was significantly longer in LVR (122 minutes versus 105 minutes; P = .001). Also, length of stay was significantly longer in LVR (4.5 days versus 3.7 days; P = .04). Recurrences were reported in 1 patient in each group. Perineal descent improved >50% in defecogram 6 months postoperatively in 79% in LVR versus 21% in LWR. In LVR, mean WCS decreased from 11.3 to 5.1 postoperatively (P < .0001), while in LWR it decreased from 8.9 to 6.9 (P = .11). Mean WIS decreased in LVR from 5.9 to 3.8, P = .01, while in LWR, it decreased from 6.6 to 2.8; P = .001. GIQOL improved from 74.4 to 124.9 in LVR and from 79.3 to 112.6 in LWR. The change in both groups was statistically significant (P = .0001). CONCLUSIONS: In this study, both LVR and LWR successfully and safely corrected the prolapse and prevented recurrence in patients after long-term follow-up. Operative time and hospital length of stay are significantly shorter in LWR. High incontinence scores and age >70 are potential predictors of bad continence postoperatively. LVR appears to be more suitable for patients with a high constipation score and abnormal perineal descent. PMID- 28586261 TI - Modulation of reward in a live social context as revealed through interactive social neuroscience. AB - Social neuroscience research investigating autism spectrum disorder (ASD) has yielded inconsistent findings, despite ASD being well-characterized by difficulties in social interaction and communication through behavioral observation. In particular, specific etiologies and functional and structural assays of the brain in autism have not been consistently identified. To date, most social neuroscience research has focused on a single person viewing static images. Research utilizing interactive social neuroscience featuring dual-brain recording offers great promise for the study of neurodevelopmental disabilities. Reward processing has been implicated in the pathology of ASD, yet mixed findings have brought uncertainty about the role reward processing deficits may play in ASD. The current study employed dual-brain EEG recording to examine reward processing during live interaction and its relation to autistic traits. Sixteen typically developing (TD) adults played a competitive treasure-hunt game against a computer and against a human partner. EEG results revealed enhanced neural sensitivity to reward outcome during live interaction with a human competitor. Further, individuals with higher levels of autistic traits demonstrated reduced sensitivity to reward outcome during live interaction. These findings provide novel insight into reward processing mechanisms associated with autistic traits, as well as support the necessary utility of interactive social neuroscience techniques to study developmental disorders. PMID- 28586262 TI - Effect of Laparoscopic Peritoneal Lavage and Drainage and Continuous Venovenous Diahemofiltration on Severe Acute Pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP), one severe and fatal disease, the therapy of which is pretty hard. This study aimed to study the effect of laparoscopic peritoneal lavage and drainage (LPLD) and continuous venovenous diahemofiltration (CVVDH) on SAP. MATERIALS AND METHODS: Two hundred forty-five patients with SAP in total were randomly assigned into four groups according to the therapeutic plan: basic treatment; LPLD; CVVDH; or LPLD+CVVDH. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, the ratios of multiple organ dysfunction syndrome (MODS), mortality, hospitalization time, hospitalization cost, ratios of complications, the abdominal distention relief time, abdominal pain relief time, plasma concentration of endotoxin, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-8 were evaluated. RESULTS: Ratios of MODS, mortality, hospitalization time, hospitalization cost, the abdominal distention relief time, abdominal pain relief time, concentration of endotoxin, TNF-alpha, IL-6, IL-8, and APACHE II scores were significantly decreased in the CVVDH, LPLD, and CVVDH+LPLD groups, while ratios of recovery were significantly increased in the CVVDH, LPLD, and CVVDH+LPLD groups, especially in the CVVDH+LPLD group. CONCLUSIONS: LPLD and CVVDH are effective in the treatment of SAP by eliminating endotoxin, TNF-alpha, IL-6, and IL-8. The combination of CVVDH and LPLD can further improve the treatment effect. PMID- 28586263 TI - The Interplay Between Fat Mass and Fat Distribution as Determinants of the Metabolic Syndrome Is Sex-Dependent. AB - BACKGROUND: Fat mass and fat distribution are major determinants of the metabolic syndrome (MetS), but the interplay between them has not been thoroughly investigated. In addition, fat mass and fat distribution are generally different in men than in women. We aimed to determine whether the interplay between fat mass and fat distribution regarding MetS and its components is sex-dependent using data from the large-scale population-based sample EpiHealth. METHODS: Occurrence of MetS and its components was determined together with fat mass by bioimpedance in 19,094 participants in the EpiHealth sample [mean age 61 years (SD 8.5), 56% females]. MetS was defined by the NCEP/ATPIII-criteria. RESULTS: MetS prevalence was 23.0%. Fat mass (percent of body weight) was more strongly related to MetS (and the number of MetS components) in men than in women (P < 0.0001 for interaction term) and in those with a high compared with those with a low waist/hip ratio (WHR). This modulating effect of WHR on the fat mass versus MetS-relationship was more pronounced in women than in men (P < 0.0001 for interaction term). When analyzing the MetS components one by one, fat mass was more closely related to all the individual MetS criteria in men than in women, except for the glucose criteria. CONCLUSIONS: Fat mass is more closely related to prevalent MetS in men than in women, but the modulating effect of an abdominal type of fat distribution on the fat mass versus MetS-relationship is stronger in women. PMID- 28586264 TI - Practical considerations for chimeric antigen receptor design and delivery. AB - INTRODUCTION: The development of chimeric antigen receptor (CAR)-modified immune cells has become a highly active field of research since the introduction of this approach in 1989. New ideas are constantly being proposed and tested, resulting in CARs that are more effective and specialized. Areas covered: Many aspects of CAR design and administration can be varied in order to achieve the best possible outcomes; optimization of this therapeutic schema is an active area of research. Here, the authors summarize the work that has been carried out thus far to assess different adaptations for each portion of the CAR itself. They also discuss the various methods used for CAR transgene transfer into effector cells. Expert opinion: While the field has made significant advancements in terms of expansion and testing of the variations available for CAR therapy, it remains difficult to ascertain which options are truly superior and under what conditions. Continued research in this area, as well as in aspects such as improving the safety profile and the anti-tumor potency of CARs, will be required to bring this therapy from early-phase clinical trials to standard of care as an effective treatment for a broad range of tumor types. PMID- 28586265 TI - The Roles of Prevention Messages, Risk Perception, and Benefit Perception in Predicting Binge Drinking among College Students. AB - To account for the effect of prevention-message exposure on binge drinking among college students, I hypothesized a conceptual model outlining potential mechanisms including perceived probability of negative consequences (PPNC), perceived severity of negative consequences (PSNC), perceived probability of positive consequences (PPPC), and perceived beneficiality of positive consequences (PBPC) from binge drinking, based on the two-step process model. I conducted an online survey at a public university in the US (N = 278). Findings suggested only PBPC was significantly related to binge drinking and the relationship was positive; prevention-message exposure was not directly associated with binge drinking, but was positively associated with PPNC, PSNC, PPPC, and PBPC; none of the mediational paths was significant; higher risk perception (interaction between PPNC and PSNC) was significantly related to less binge drinking, while benefit perception (interaction between PPPC and PBPC) was not predictive of binge drinking. Implications of findings were discussed. PMID- 28586266 TI - iTeos Therapeutics. PMID- 28586267 TI - Content Design and System Implementation of a Teleophthalmology System for Eye Disease Diagnosis and Treatment and Its Preliminary Practice in Guangdong, China. AB - BACKGROUND: We have developed a new telemedicine system for comprehensive eye examination, diabetic retinopathy (DR) screening, and eye disease diagnosis and treatment. The novel points of the system include a tablet application for facilitating doctor's examination and diagnosis process, a comprehensive eye examination component, and integrated treatment planning and recording. METHODS: The system provided a new service model through one ophthalmological center linking with multiple remote and rural hospitals for eye care in Guangdong province, China. RESULTS: The early stage of the project study also undertook the responsibility of educations for remote-area doctors and image graders for DR grading and glaucoma grading and research on the effectiveness of short message service (SMS) reminder for patient revisit. Some other research, such as the comparison of the accuracy of graders' DR grading with the gold standard, and doctor's tentative diagnosis with final diagnosis and related statistical information, has been implemented in the system. In the preliminary practice, we summarized the outcomes related to presenting system performance and made an initial analysis. CONCLUSION: From the practice, the project has shown the telemedicine system and associated contents have satisfied our initial goal and demonstrated their effectiveness and efficiency. PMID- 28586268 TI - Biopolitics and Boundary Work in South Africa's Sutherlandia Clinical Trial. AB - Between 2008 and 2011, South African and American investigators carried out a randomized controlled trial to assess the safety and efficacy of an African traditional medicine in South Africans who were HIV-seropositive but asymptomatic. The medicine was derived from Sutherlandia frutescens, a plant endemic to and widely used to stimulate immune function by people across southern Africa. In this article, I report on the cross-cultural challenges generated by trial investigators' transformation of Sutherlandia into a clinical trial substance and a potential "treatment gap" therapy for persons with HIV. While Sutherlandia is in many respects an unusual addition to evidence-based medicine, it is also familiar in this context-especially in the manner the therapy was biopolitically imagined by trial investigators, and in terms of the indeterminacy the therapy produced. PMID- 28586269 TI - The meaning of menarche: A cross-cultural semantic network analysis. AB - The psychological meaning of menarche was explored in 102 college students from Mexico and the United States. The Natural Semantic Networks Technique was used and participants were asked to respond to the prompt "My first period was ..." The strongest components of the Mexican women's semantic network were scary, confusing, and unexpected; the strongest components of the American women's semantic network were unexpected, annoying, and painful. Only the Americans listed positive words (i.e., nice). The Mexicans' network contained the most negative words (i.e., dirty). The results suggest a need for better education and greater social support, especially in Mexico. PMID- 28586270 TI - IRB Problems and Solutions in Health Communication Research. AB - In this article, we contribute to the current literature on the difficulties that social scientists encounter with IRBs, but with a focus on the distinct challenges that health communication scholars face in dealing with IRBs at their own institutions and elsewhere. Although health communication researchers, like other communication researchers, can expect to face many of the same challenges that their social science colleagues face during the IRB process, the researcher narratives we present in this article suggest that health communication research presents some distinct challenges because the communication interactions that we investigate occur in highly protected, private spaces, including the medical exam room, online patient forums, and electronic health records. To that end, we present a series of examples in which health communication researchers were able to find solutions or workarounds to the challenges they faced in gaining IRB approval for their research. In every case that we present, the researcher had to revise her initial study design to get around the constraints imposed by IRB requirements, and in every case, the researcher reports having experienced points of incommensurability similar to those reported by many other social scientists. In some situations, investigators even express frustration that the IRB's needs and demands superseded those of healthcare professionals and the patients whom they serve. Additionally, in some situations, investigators' understandings of human subjects' protection actually go further to protect patients' privacy and confidentiality than the IRB required. But, in all four cases that we present, the health communication research was ultimately successful. PMID- 28586271 TI - "Before the war we had it all": Family planning among couples in a post-conflict setting. AB - There is little evidence about family planning knowledge, attitudes, and use among couples in post-conflict Democratic Republic of the Congo. We used qualitative descriptions to analyze data from 75 participants. Intimate partner violence (IPV) was common among participants. They were aware of family planning methods; however, IPV and fears of side effects were barriers to use. Although participants were concerned about the cost of large families, had positive attitudes toward family planning, and intended to use it, actual use was uncommon. The need for family planning was acute because of war-related poverty. Couples negotiated, but men had strong influence over family planning decisions. Couples saw health workers as a valuable resource. Interventions in this setting should include a couple-based approach that addresses IPV as well as family planning content. PMID- 28586272 TI - Pharmacological treatment options for cryopyrin-associated periodic syndromes. AB - INTRODUCTION: Cryopyrin-associated periodic syndromes (CAPS) are rare monogenic autoinflammatory diseases, comprising a spectrum of phenotypes of varying severity. CAPS are associated with gain-of-function mutations in the NLRP3 inflammasome, a multiprotein complex critical for the activation of IL-1beta, and are characterized by episodes of fever, urticaria-like rash, musculoskeletal, ocular, and neurological symptoms. Areas covered: Accounting for the pivotal role of IL-1beta in the pathogenesis of CAPS, three therapeutic options, all blocking the action of IL-1beta, are currently approved: anakinra, a recombinant IL-1 receptor antagonist, the IL-1 trap rilonacept and canakinumab, a monoclonal anti IL-1beta antibody. All agents reduce or even resolve clinical symptoms, biochemical activity markers and improve quality of life in CAPS. This review also covers pharmacokinetic, pharmacodynamic and safety aspects of the approved drugs and the potential utility of IL-1beta blockers in a wide range of other conditions with an autoinflammatory component. Expert commentary: Due to the success story of current pharmaceutics, the therapeutic options in CAPS are not expected to expand in the near future. Prospective observational studies are needed to confirm long-term efficacy and sustained benefit. New IL-1beta blockers will likely address unmet clinical needs in other autoinflammatory conditions. PMID- 28586273 TI - Food insecurity, sexual risk behavior, and adherence to antiretroviral therapy among women living with HIV: A systematic review. AB - Gender inequalities shape the experience of food insecurity among women living with HIV (WLHIV). We systematically reviewed the impact of food insecurity on sexual risk behaviors and antiretroviral therapy (ART) adherence among WLHIV. We included qualitative or quantitative peer-reviewed articles, extracted data in duplicate, and assessed rigor. Seven studies, from sub-Saharan Africa, North America, and Europe, met inclusion criteria. Food insecurity was associated with increased sexual risk through transactional sex and inability to negotiate safer sex. Hunger and food insecurity were barriers to ART initiation/adherence. Multidimensional programming and policies should simultaneously address poverty, gender inequality, food insecurity, and HIV. PMID- 28586274 TI - Famine exposure during early life and risk of hypertension in adulthood: A meta analysis. AB - BACKGROUND: Many epidemiologic studies have explored the association between famine exposure and the risk of hypertension, but the results remain controversial. OBJECTIVE: A meta-analysis was performed to determine the association between early life famine exposure, fetal famine exposure, and childhood famine exposure and risk of hypertension. METHODS: A literature search was performed in PubMed, Web of science, Embase, and China National Knowledge Infrastructure for relevant articles published up to October 2016. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Sixteen studies from 14 articles for early life famine exposure, 11 studies from 10 articles for fetal famine exposure, and 10 studies from 8 articles for childhood famine exposure were included in our meta analysis. Compared with unexposed group, the pooled RRs were (1.26; 95% CI, 1.11 1.44), (1.27; 95% CI, 1.08-1.49), and (1.32; 95% CI, 1.15-1.52) for early life famine exposure, fetal famine exposure, and childhood famine exposure, respectively. In subgroup analyses, the above-mentioned associations were consistent in cohort studies, and studies conducted in Asia. CONCLUSION: This meta-analysis confirmed the association between exposure to famine in early life and increased risk of hypertension in adulthood. Prevention of malnutrition during early life is an appropriate recommendation to prevent hypertension. PMID- 28586275 TI - Good Food, Bad Food, and White Rice: Understanding Child Feeding Using Visual Narrative Elicitation. AB - Visual-narrative elicitation, a process combining photo elicitation and pile sorting in applied medical anthropology, sheds light on food consumption patterns in urban areas of Vanuatu where childhood malnutrition is a persistent problem. Groups of participants took photographs of the foods they feed their children, and the resources and barriers they encounter in accessing foodstuffs. This revealed how imported and local foods are assigned value as "good" or "bad" foods when contributing to dietary diversity and creating appropriate meals for children, particularly in the context of consuming white rice. The process of gathering and working with photographs illuminated the complex negotiations in which caregivers engaged when making food and nutritional choices for their children. At the nexus of visual and medical anthropology, the visual-narrative elicitation process yielded nuanced, comprehensive understandings of how caregivers value the various foods they feed their children. PMID- 28586277 TI - Pilot-scale biopesticide production by Bacillus thuringiensis subsp. kurstaki using starch industry wastewater as raw material. AB - Pilot-scale Bacillus thuringiensis based biopesticide production (2000 L bioreactor) was conducted using starch industry wastewater (SIW) as a raw material using optimized operational parameters obtained in 15 L and 150 L fermenters. In pilot scale fermentation process the oxygen transfer rate is a major limiting factor for high product yield. Thus, the volumetric mass transfer coefficient (KLa) remains a tool to determine the oxygen transfer capacity [oxygen utilization rate (OUR) and oxygen transfer rate (OTR)] to obtain better bacterial growth rate and entomotoxicity in new bioreactor process optimization and scale-up. This study results demonstrated that the oxygen transfer rate in 2000 L bioreactor was better than 15 L and 150 L fermenters. The better oxygen transfer in 2000 L bioreactor augmented the bacterial growth [total cell (TC) and viable spore count (SC)] and delta-endotoxin yield. Prepared a stable biopesticide formulation for field use and its entomotoxicity was also evaluated. This study result corroborates the feasibility of industrial scale operation of biopesticide production using starch industry wastewater as raw material. PMID- 28586276 TI - Dendritic Cell Trafficking and Function in Rare Lung Diseases. AB - Dendritic cells (DCs) are highly specialized immune cells that capture antigens and then migrate to lymphoid tissue and present antigen to T cells. This critical function of DCs is well defined, and recent studies further demonstrate that DCs are also key regulators of several innate immune responses. Studies focused on the roles of DCs in the pathogenesis of common lung diseases, such as asthma, infection, and cancer, have traditionally driven our mechanistic understanding of pulmonary DC biology. The emerging development of novel DC reagents, techniques, and genetically modified animal models has provided abundant data revealing distinct populations of DCs in the lung, and allow us to examine mechanisms of DC development, migration, and function in pulmonary disease with unprecedented detail. This enhanced understanding of DCs permits the examination of the potential role of DCs in diseases with known or suspected immunological underpinnings. Recent advances in the study of rare lung diseases, including pulmonary Langerhans cell histiocytosis, sarcoidosis, hypersensitivity pneumonitis, and pulmonary fibrosis, reveal expanding potential pathogenic roles for DCs. Here, we provide a review of DC development, trafficking, and effector functions in the lung, and discuss how alterations in these DC pathways contribute to the pathogenesis of rare lung diseases. PMID- 28586278 TI - The immunogenicity of GSK's recombinant hepatitis B vaccine in children: a systematic review of 30 years of experience. AB - INTRODUCTION: The World Health Organization recommends hepatitis B virus (HBV) vaccines to be included in national immunization schedules everywhere, and has adopted the strategic goal of halting viral hepatitis as a major public health threat by 2030, under which vaccination plays a major role. EngerixTM B (GSK HepB, GSK, Belgium) was the first recombinant HBV vaccine to be licensed, and marked its 30th anniversary in 2016. Areas covered: We conducted a systematic review of the literature summarizing 30 years of immunogenicity and safety data for GSK HepB in children and adolescents. Expert commentary: Primary 3-dose vaccination of healthy infants and children, including infants born to HBsAg positive mothers, using the standard 0, 1, 6 month schedule was associated with seroprotection rates >=96.0%. In high-risk infants, vaccine efficacy at year 5 was 96.0% after 3-dose priming in infancy and immunoglobulin at birth. Lower seroprotection rates were observed in children with severe underlying disease including human immunodeficiency virus infection and cancer. GSK HepB had a clinically acceptable safety profile in all of the populations studied. HBV vaccines have demonstrated long-term impacts on rates of fulminant hepatitis, chronic liver disease and hepatocellular carcinoma. GSK HepB will continue to contribute to global HBV control for the foreseeable future. PMID- 28586280 TI - A decade of proteomics accomplished! Central and Eastern European Proteomic Conference (CEEPC) celebrates its 10th Anniversary in Budapest, Hungary. AB - The Central and Eastern European Proteomic Conference (CEEPC) proudly celebrated its 10th Anniversary with an exciting scientific program inclusive of proteome, proteomics and systems biology in Budapest, Hungary. Since 2007, CEEPC has represented 'state-of the-art' proteomics in and around Central and Eastern Europe and these series of conferences have become a well-recognized event in the proteomic calendar. Fresher challenges and global healthcare issues such as ageing and chronic diseases are driving clinical and scientific research towards regenerative, reparative and personalized medicine. To this end, proteomics may enable diverse intertwining research fields to reach their end goals. CEEPC will endeavor to facilitate these goals. PMID- 28586281 TI - Opioid vs nonopioid prescribers: Variations in care for a standardized acute back pain case. AB - BACKGROUND: Opioid analgesics are effective and appropriate therapy for many types of acute pain. Epidemiologic evidence supports a direct relationship between increased opioid prescribing and increases in opioid use disorders and overdoses. OBJECTIVE: To tailor our residency curriculum, we designed and fielded an unannounced standardized patient (USP) case involving a patient with acute back pain who is requesting Vicodin (5/325 mg). We describe residents' case management and examine whether their management decisions, including opioid prescribing, were related to their core clinical skills. METHODS: Results are based on 50 (USP) visits with residents in 2 urban primary care clinics. Highly trained USPs portrayed a patient with acute lower back pain who was taking leftover Vicodin with effective pain relief but was running out. We describe how residents managed this case, using both USP report and chart review data, and compare summary clinical skills scores between those who prescribed Vicodin and those who did not. RESULTS: Of the 50 residents, 18 prescribed Vicodin (10-60 pills). Among those who did not prescribe (32/50), most (50%) prescribed ibuprofen. Eighty-three percent of the prescribers and 72% of nonprescribers ordered physical therapy (nonsignificant). Of the 18 prescribers, 13 documented checking the prescription monitoring database. Prescribers had significantly better communication scores than nonprescribers (relationship development: 80% vs. 58% well done, P = .029; patient education: 59% vs. 31% well done, P = .018). Assessment summary scores were also higher (60% vs. 46%) but not significantly (P = .060). Patient satisfaction and activation scores were higher in the prescribers than nonprescribers (71% vs. 39%, P = .004 and 48% vs. 26%, P = .034, respectively). CONCLUSIONS: Most Vicodin prescribers did not follow prescribing guidelines, and they demonstrated better communication and assessment skills than the nonprescribers. Results suggest the need to guide residents in using a systematic approach to prescribing opioids safely and to develop an acceptable alternative pain management plan when they decide against prescribing. PMID- 28586282 TI - Remediation capacity of Cd and Pb ions by mycelia of Imleria badia, Laetiporus sulphureus, and Agaricus bisporus in vitro cultures. AB - The goal of this study was to evaluate cadmium and lead accumulation ability of in vitro cultures biomass containing selected edible mushroom species derived from the environment (Laetiporus sulphureus, Imleria badia) and those of commercial origin (Agaricus bisporus). Atomic absorption spectrometry was used to evaluate the content of Cd(II) and Pb(II) on the medium supplemented with Cd(II) or Pb(II), each of them at the same concentration of 5.10-5 M. The highest concentration of Cd(II) ions was determined in the biomass from L. sulphureus in vitro cultures, while the highest concentration of Pb(II) ions was found in the biomass from A. bisporus in vitro cultures. The greatest Cd(II) and Pb(II) accumulation ability in mycelium per dry weight was shown for L. sulphureus. Among the test species, biomass of A. bisporus showed the lowest ability for the bioaccumulation of Cd(II); however, comparable ability for the remediation of Pb(II) was provided by the biomasses from A. bisporus and I. badia in vitro cultures. The results confirm the possibility of using these mushroom species for remediation and indicate the relationship between bioaccumulation of heavy metals and the test species. PMID- 28586283 TI - Mkl1-dependent gene activation is sufficient to induce actin cap assembly. AB - Actin-dependent forces mechanically control both the position and shape of the nucleus. While the mechanisms that establish nuclear position are well defined, less understood is how actin filaments determine nuclear shape. We recently showed that nuclear envelope-spanning LINC complexes promote stress fiber assembly by activating the small GTPase RhoA and Mkl1-dependent gene activation. We now report that a subset of these stress fibers associate with the apical face of the nuclear envelope through LINC complexes that contain the inner nuclear membrane protein Sun2. Apical stress fibers have previously been shown to specifically couple cell and nuclear morphology, suggesting that LINC complexes influence nuclear shape in part by regulating the small GTPase RhoA. PMID- 28586284 TI - A patent review of the therapeutic potential of isoflavones (2012-2016). AB - INTRODUCTION: Isoflavones are well-studied natural products isolated from natural sources with interesting chemodiversity and possess a wide variety of biological effects. Moreover, chemical modifications based on the isoflavone scaffold, has generated synthetic chemodiversity to enhance the bioactivities of isoflavones. Areas covered: The current review summarizes the discovery of new chemotherapeutic agents possessing the isoflavone skeleton. This review incorporates patents filed between 2012 and 2016 mostly related to anticancer, antidiabetic, antimicrobial, anti-HIV, anti-gastric ulcer, anti-gastritis, antiparasitic and some other biological effects demonstrated by isoflavone analogs. Expert opinion: The number of interesting patents published during the five year period (2012-2016) on the therapeutic potential of isoflavones indicated the importance of this molecule. Natural isoflavones possess potent anticancer, anti-HIV and antidiabetic activities and chemical analogs of natural isoflavones increase the abovementioned biological effects. Additionally isoflavones have only been tested for a limited number of biological activities and thus future research should focus on additional biological activities viz., anti-inflammatory, antimalarial, and anti-leishmanial effects. However, the absence of SAR studies and in vivo data restricted the rational design of more potent isoflavone analogs and we believe that in order to get lead compounds, there needs to be a greater focus on SAR and in vivo studies. PMID- 28586285 TI - Improving the Health of Rural America's Chronically Ill: A Case Study of a Patient-Centered Medical Home Clinic in Mississippi. PMID- 28586286 TI - Optimization of a methodology for the simultaneous determination of deltamethrin, permethrin and malathion in stored wheat samples using dispersive liquid-liquid microextraction with solidification of floating organic drop and HPLC-UV. AB - The purpose of this study was to investigate common pesticides in stored wheat at Kermanshah province's silos in Iran. A simple, inexpensive, reliable and environmentally friendly method based on dispersive liquid-liquid microextraction with solidification of floating organic drop was developed. The analytical characteristics of the method were determined. Also, various parameters such as the materials of the silos, types of ownerships of the silos, geographic orientation of silo locations and climatic conditions of silo locations on pesticide residues in studied wheat samples were investigated. Among all the studied parameters, the climatic conditions of silo locations showed the highest influence on pesticide residues in wheat samples. Generally, 61.2% of the samples had pesticide levels below the method detection limits and 38.8% of the total samples had at least one of the understudied pesticides. Also, 13.9% of the samples had deltamethrin residues, 16.7% of the samples had permethrin, 22.2% of the samples had malathion, 11.1% of the samples had both permethrin and malathion and 2.8% of the samples had both deltamethrin and malathion. The results revealed that the residues of deltamethrin and malathion were lower than the standard level announced by European Union regulation and only three samples contained permethrin higher than Europe standard level. PMID- 28586287 TI - Esophageal Penetration of the Magnetic Sphincter Augmentation Device: History Repeats Itself. AB - BACKGROUND: An alternative approach to the treatment of gastroesophageal reflux disease (GERD) has recently been introduced in clinical practice, involving the implantation of a magnetic sphincter augmentation device (MSAD). This "magnetic ring" is implanted laparoscopically around the lower esophageal sphincter to improve its barrier function. The literature is still limited on the midterm results achieved in controlling reflux because the MSAD is a very new procedure. So far, only a few cases of the MSAD causing erosion of the esophagus have been reported. METHODS: We report on two cases of progressive and severe dysphagia after the implantation of an MSAD elsewhere. In both cases, the symptoms were caused by the migration of the device into the esophagus. RESULTS: The devices were removed endoscopically in a single step in both cases, using the Olympus cutter. After 3 months, the first patient had a laparoscopic Nissen fundoplication without any complications and with a good final reflux control. The second only underwent removal of the device, using the same endoscopic approach and again without any complications. CONCLUSIONS: Judging from the literature, MSAD implantation may be an effective way to control GERD, but the method can carry major complications, such as migration of the device into the esophagus (as in the two cases reported here). Endoscopic removal of a device possibly penetrating inside the esophagus is feasible and safe, and may later be followed up with a laparoscopic antireflux procedure without any particular difficulty. PMID- 28586289 TI - "PAL-LIFE Project: International Advisory Working Group on Diffusion and Development of Palliative Care in the World": First Meeting Report. PMID- 28586279 TI - Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. AB - BACKGROUND: Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non-small-cell lung cancer (NSCLC). We investigated alectinib as compared with crizotinib in patients with previously untreated, advanced ALK-positive NSCLC, including those with asymptomatic CNS disease. METHODS: In a randomized, open-label, phase 3 trial, we randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily). The primary end point was investigator-assessed progression-free survival. Secondary end points were independent review committee-assessed progression-free survival, time to CNS progression, objective response rate, and overall survival. RESULTS: During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group. The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached. The results for independent review committee-assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28; P<0.001). A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09). Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib). CONCLUSIONS: As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC. (Funded by F. Hoffmann-La Roche; ALEX ClinicalTrials.gov number, NCT02075840 .). PMID- 28586290 TI - Non-contraceptive benefits of intrauterine levonorgestrel administration: why not? AB - Levonorgestrel intrauterine systems (LNG-IUS) represent a modern therapy for an array of preexisting gynecological conditions, though they were first marketed in Finland in 1990. However, there are countries in which their use is extremely limited by social and cultural factors. This manuscript describes the possible reasons for this misuse, taking in consideration the clinical noncontraceptive benefits of intrauterine levonorgestrel in routinary practice. Medical diseases in which LNG-IUS represent a treatment include abnormal uterine bleeding, iron deficiency anemia, endometrial hyperplasia, uterine fibroids, adenomyosis, endometriosis, and coagulopathies. The advantage of reducing the need for more radical treatments such as surgery or hysterectomy is well demonstrated, with remarkable benefits for patients. However, in many countries, surgery is still used as a first-line treatment and there is a need to define who could benefit from a less invasive option. It seems clear that such a reduced use of LNG-IUS depends on factors that imply both patients and practitioners, and that the role of counseling is becoming a key component in the decision-making process to reach the ultimate goal of compliance. PMID- 28586288 TI - Genomic signatures of local adaptation in the Drosophila immune response. AB - As environments and pathogen landscapes shift, host defenses must evolve to remain effective. Due to this selection pressure, among-species comparisons of genetic sequence data often find immune genes to be among the fastest evolving genes across the genome. The full extent and nature of these immune adaptations, however, remain largely unexplored. In a recent study, we analyzed patterns of selection within distinct components of the Drosophila melanogaster immune pathway. While we found evidence of positive selection within some immune processes, immune genes were not universally characterized by signatures of strong selection. On the contrary, we even found that some immune functions show greater than expected constraint. Overall these results highlight 2 major factors that appear to play an outsize role in determining a gene's evolutionary rate: the type of pathogen the gene targets and the gene's position within the immune network. These results join a growing body of literature that highlight the complexity of immune adaptation. Rather than there being uniformly strong selection across all immune genes, a combination of pathogen-specificity and host genetic constraints appear to play key roles in determining each immune gene's individual evolutionary trajectory. PMID- 28586291 TI - Evaluation of the Utility of Screening Mammography for High-Risk Women Undergoing Screening Breast MR Imaging. AB - Purpose To evaluate the value of mammography in detecting breast cancer in high risk women undergoing screening breast magnetic resonance (MR) imaging. Materials and Methods An ethics-approved, retrospective review of prospective databases was performed to identify outcomes of 3934 screening studies (1977 screening MR imaging examinations and 1957 screening mammograms) performed between January 2012 and July 2014 in 1249 high-risk women. Performance measures including recall and cancer detection rates, sensitivity, specificity, and positive predictive values were calculated for both mammography and MR imaging. Results A total of 45 cancers (33 invasive and 12 ductal carcinomas in situ) were diagnosed, 43 were seen with MR imaging and 14 with both mammography and MR imaging. Additional tests (further imaging and/or biopsy) were recommended in 461 screening MR imaging studies (recall rate, 23.3%; 95% confidence interval [CI]: 21.5%, 25.2%), and mammography recalled 217 (recall rate, 11.1%; 95% CI: 9.7%, 12.6%). The cancer detection rate for MR imaging was 21.8 cancers per 1000 examinations (95% CI: 15.78, 29.19) and that for mammography was 7.2 cancers per 1000 examinations (95% CI: 3.92, 11.97; P < .001). Sensitivity and specificity of MR imaging were 96% and 78% respectively, and those of mammography were 31% and 89%, respectively (P < .001). Positive predictive value for MR imaging recalls was 9.3% (95% CI: 6.83%, 12.36%) and that for mammography recalls was 6.5% (95% CI: 3.57%, 10.59%). Conclusion Contemporaneous screening mammography did not have added value in detection of breast cancer for women who undergo screening MR imaging. Routine use of screening mammography in women undergoing screening breast MR imaging warrants reconsideration. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 28586293 TI - Parental Support and Objectively Measured Physical Activity in Children: A Yearlong Cluster-Randomized Controlled Efficacy Trial. AB - PURPOSE: We studied whether physical activity (PA) counseling for parents influenced the level of parental support of children's PA and leisure-time PA in children of different levels of initial parental support. We hypothesized that the initial level of parental support would moderate the intervention efficacy. METHOD: Children (n = 44, Mage = 6.09 +/- 1.17 years) and their parents (n = 61) randomly assigned to an intervention group received counseling for 6 months. Children in the control group (n = 47, Mage = 6.12 +/- 1.11 years) and their parents (n = 63) did not receive any counseling. Parental support was assessed using the Family Physical Activity Environment Questionnaire, and children's leisure-time PA was recorded using triaxial accelerometers at baseline, at 6 months, and at 12 months. The efficacy of the intervention was tested by linear mixed-effects modeling adjusted for confounding variables (Model 1) and additionally for children's participation in organized PA or sports (Model 2). RESULTS: Parents within the lowest initial parental support intervention tertile significantly increased their support, and their children's mean level of leisure time PA significantly improved compared with the corresponding controls during the counseling period. On the other hand, intervention was found to have an unfavorable influence especially in the PA of children of initially highly supportive parents. CONCLUSION: Targeting PA counseling for parents with low support of their children's PA could contribute to better family-based PA counseling efficacy. PMID- 28586292 TI - A Systematic Evaluation of Factors Affecting Extracellular Vesicle Uptake by Breast Cancer Cells. AB - Extracellular vesicles (EVs) are nanometer-scale particles that are secreted by cells and mediate intercellular communication by transferring biomolecules between cells. Harnessing this mechanism for therapeutic biomolecule delivery represents a promising frontier for regenerative medicine and other clinical applications. One challenge to realizing this goal is that to date, our understanding of which factors affect EV uptake by recipient cells remains incomplete. In this study, we systematically investigated such delivery questions in the context of breast cancer cells, which are one of the most well-studied cell types with respect to EV delivery and therefore comprise a facile model system for this investigation. By displaying various targeting peptides on the EV surface, we observed that although displaying GE11 on EVs modestly increased uptake by MCF-7 cells, neuropeptide Y (NPY) display had no effect on uptake by the same cells. In contrast, neurotensin (NTS) and urokinase plasminogen activator (uPA) display reduced EV uptake by MDA-MB-231 cells. Interestingly, EV uptake rate did not depend on the source of the EVs; breast cancer cells demonstrated no increase in uptake on administration of breast cancer-derived EVs in comparison to HEK293FT-derived EVs. Moreover, EV uptake was greatly enhanced by delivery in the presence of polybrene and spinoculation, suggesting that maximal EV uptake rates are much greater than those observed under basal conditions in cell culture. By investigating how the cell's environment might provide cues that impact EV uptake, we also observed that culturing cells on soft matrices significantly enhanced EV uptake, compared to culturing on stiff tissue culture polystyrene. Each of these observations provides insights into the factors impacting EV uptake by breast cancer cells, while also providing a basis of comparison for systematically evaluating and perhaps enhancing EV uptake by various cell types. PMID- 28586294 TI - Determinants of mammography adoption among iranian women: What are the differences in the cognitive factors by the stages of test adoption? AB - Our aim in this cross-sectional study was to investigate the predictors of the stages of change in mammography adoption (MA) based on Health Belief Model among Iranian women. Through multistage cluster sampling, we recruited and interviewed 1131 women older than 40. After statistical adjustment for other risk factors, perceived barriers (OR D 0.84, 95% CI D .81-.87) and benefits (OR D 1.17, 95% CI D 1.11-1.24) were significant predictors for MA. Majority of the women were in the pre-contemplation and contemplation stages of change for MA. Our findings are informative for the development of targeted interventions to foster MA among women. PMID- 28586296 TI - Asthma control and disease burden in patients with asthma and allergic comorbidities. AB - OBJECTIVE: To assess asthma control and associations with health-related quality of life (HRQoL) and economic outcomes among patients with asthma and allergic comorbidities treated with inhaled corticosteroids (ICS) and long-acting beta agonists (LABA) combination therapy. METHODS: Data from the 2011-2013 US National Health and Wellness Survey were used to identify patients with asthma currently treated with ICS and LABA combination therapy (N = 1923). Patients were included if they self-reported a physician diagnosis of asthma and at least one allergic/asthma-related comorbid condition (e.g., nasal allergies, atopic dermatitis). Asthma Control Test scores categorized patients as very poorly (scores <= 15; 29.3%), not well (16-19; 25.1%), or well controlled (20-25; 45.7%). Outcomes included HRQoL (SF-36v2; SF-12v2), work productivity and activity impairment, healthcare utilization (HRU), and annual indirect and direct costs. Generalized linear models, controlling for covariates, examined whether outcomes differed by asthma control. RESULTS: Over half of the patients had very poorly or not well-controlled asthma (54.4%). Patients with very poorly controlled versus well-controlled asthma reported significantly greater decreases in HRQoL, greater overall work impairment, and higher HRU (all, p < 0.05). Very poorly controlled patients incurred over double the indirect costs and nearly one and a half times the direct and total costs of well-controlled patients. CONCLUSIONS: Increasing level of asthma control was related to improved HRQoL and lower costs. The considerably high prevalence of uncontrolled asthma among patients on ICS and LABA suggests poor treatment adherence or unmet needs in current treatment and may require step-up therapy in appropriate patients according to clinical guidelines. PMID- 28586295 TI - Temperature Management in Neurological and Neurosurgical Intensive Care Unit. PMID- 28586297 TI - Fecal microbiota variation across the lifespan of the healthy laboratory rat. AB - Laboratory rats are commonly used in life science research as a model for human biology and disease, but the composition and development of their gut microbiota during life is poorly understood. We determined the fecal microbiota composition of healthy Sprague Dawley laboratory rats from 3 weeks to 2 y of age, kept under controlled environmental and dietary conditions. Additionally, we determined fecal short-chain fatty acid profiles, and we compared the rat fecal microbiota with that of mice and humans. Gut microbiota and to a lesser extent SCFAs profiles separated rats into 3 different clusters according to age: before weaning, first year of life (12- to 26-week-old animals) and second year of life (52- to 104-week-old). A core of 46 bacterial species was present in all rats but its members' relative abundance progressively decreased with age. This was accompanied by an increase of microbiota alpha-diversity, likely due to the acquisition of environmental microorganisms during the lifespan. Contrastingly, the functional profile of the microbiota across animal species became more similar upon aging. Lastly, the microbiota of rats and mice were most similar to each other but at the same time the microbiota profile of rats was more similar to that of humans than was the microbiota profile of mice. These data offer an explanation as to why germ-free rats are more efficient recipients and retainers of human microbiota than mice. Furthermore, experimental design should take into account dynamic changes in the microbiota of model animals considering that their changing gut microbiota interacts with their physiology. PMID- 28586300 TI - Assessment of the clinical utility of adding common single nucleotide polymorphism genetic scores to classical risk factor algorithms in coronary heart disease risk prediction in UK men. AB - BACKGROUND: Risk prediction algorithms for coronary heart disease (CHD) are recommended for clinical use. However, their predictive ability remains modest and the inclusion of genetic risk may improve their performance. METHODS: QRISK2 was used to assess CHD risk using conventional risk factors (CRFs). The performance of a 19 single nucleotide polymorphism (SNP) gene score (GS) for CHD including variants identified by genome-wide association study and candidate gene studies (weighted using the results from the CARDIoGRAMplusC4D meta-analysis) was assessed using the second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases). To improve the GS, five SNPs with weak evidence of an association with CHD were removed and replaced with seven robustly associated SNPs - giving a 21-SNP GS. RESULTS: The weighted 19 SNP GS was associated with lipid traits (p<0.05) and CHD after adjustment for CRFs, (OR=1.31 per standard deviation, p=0.03). Addition of the 19 SNP GS to QRISK2 showed improved discrimination (area under the receiver operator characteristic curve 0.68 vs. 0.70 p=0.02), a positive net reclassification index (0.07, p=0.04) compared to QRISK2 alone and maintained good calibration (p=0.17). The 21-SNP GS was also associated with CHD after adjustment for CRFs (OR=1.39 per standard deviation, 1.42*10-3), but the combined QRISK2 plus GS score was poorly calibrated (p=0.03) and showed no improvement in discrimination (p=0.55) or reclassification (p=0.10) compared to QRISK2 alone. CONCLUSIONS: The 19-SNP GS is robustly associated with CHD and showed potential clinical utility in the UK population. PMID- 28586299 TI - Inter-Fork Strand Annealing causes genomic deletions during the termination of DNA replication. AB - Problems that arise during DNA replication can drive genomic alterations that are instrumental in the development of cancers and many human genetic disorders. Replication fork barriers are a commonly encountered problem, which can cause fork collapse and act as hotspots for replication termination. Collapsed forks can be rescued by homologous recombination, which restarts replication. However, replication restart is relatively slow and, therefore, replication termination may frequently occur by an active fork converging on a collapsed fork. We find that this type of non-canonical fork convergence in fission yeast is prone to trigger deletions between repetitive DNA sequences via a mechanism we call Inter Fork Strand Annealing (IFSA) that depends on the recombination proteins Rad52, Exo1 and Mus81, and is countered by the FANCM-related DNA helicase Fml1. Based on our findings, we propose that IFSA is a potential threat to genomic stability in eukaryotes. PMID- 28586301 TI - Definition of the upper reference limit of glycated albumin in blood donors from Italy. AB - BACKGROUND: Glycated Albumin (GA) has been proposed as a short-term indicator of glycemic homeostasis. The aim of this study is to describe the distribution of GA in a large sample of blood donors from Italy to evaluate whether demographic features, namely age and sex, could influence GA levels and define specific reference limits. METHODS: The study included 1334 Italian blood donors. GA was measured using an enzymatic method (quantILab Glycated Albumin, IL Werfen, Germany). The upper reference limit (URL) was calculated using the non-parametric percentile method. RESULTS: A modest, although significant, increase of GA was observed in relation to age (p<0.001), especially in males, where the differences were more pronounced (p<0.001 in males, p=0.003 in females). Slight differences were documented based on sex (12% [11.3-12.8] in males; 12.2% [11.4-13.1] in females; p=0.01). After excluding individuals with fasting plasma glucose >=7 mmol/L, the calculated GA URL was 14.5% (95% CI: 14.3-14.7). Subjects with GA>14.5% presented a mean age of 48.4+/-12.2 years, 66.7% were males and the mean glucose was 6.88+/-2.5 mmol/L. CONCLUSIONS: GA in Caucasians shows a similar increasing trend at older ages documented in other ethnicities. The definition of the URL in this population could be useful for both clinical studies, which will clarify the role of GA for diagnosing and monitoring diabetes, and will encourage the introduction of GA in clinical practice. PMID- 28586303 TI - Craving for cigarette smoking among male adolescents in Isfahan based on mindfulness and emotional self-regulation. AB - Background Cigarette smoking among adolescents and its consequences are categorized as serious health problems. Cigarette craving is influenced by various psycho-social factors. Objective This study aimed to investigate desire and intention to smoke based on mindfulness and emotional self-regulation in adolescents. Methods In this correlational study conducted based on structural equation modeling, a sample of 350 male students was randomly selected from different schools of education districts in Isfahan. Three questionnaires, including Hooked on Nicotine Checklist, emotional regulation inventory, and Mindful Attention Awareness Scale were employed. Data were analyzed using chi2, correlation coefficient and structural modeling tests. In this regard, SPSS and AMOS software were used. Results The results showed that 62% of male students had experienced cigarette smoking at least once. There was a significant inverse correlation between cigarette craving and emotional reappraisal (r = -0.48), expressive suppression (r = -0.58) and mindfulness (r = -0.55), respectively (p < 0.01). In addition to the direct effect, mindfulness through emotional self regulation had indirect effects on nicotine craving. A total of 58% of the variance in nicotine craving was explained by the study variables. Conclusion The results showed that the high percentage of male students hooked on smoking is an important issue. In this regard, students' psychological issues such as efficient mechanisms of emotional regulation and their knowledge of the risks of smoking must be addressed by authorities and families. PMID- 28586302 TI - Comparison of 25-hydroxyvitamin D and metabolic parameters between women with and without polycystic ovarian syndrome. AB - Background There is increasing evidence that supports the contribution of vitamin D deficiency in metabolic disturbances among women with polycystic ovarian syndrome (PCOS). The aim of this study was to compare 25-hydroxyvitamin D level and the prevalence of metabolic syndrome in the PCOS and normal women. Materials and methods A case-controlled study was conducted in a teaching hospital over a 6 month duration from June 2015 to January 2016. A total of 90 women, who consisted of 45 women with PCOS (study group) and 45 women without PCOS (control group), were recruited. Results The final analysis was of 80 women only and the prevalence of vitamin D deficiency (<20 ng/mL) was high between both groups, i.e. 93.7% but there was no significant difference (p = 0.874). Nevertheless, the prevalence of metabolic syndrome was significantly higher in the study group as compared to the control group (27.5% vs. 5.0%, p = 0.013). There was no statistically significant correlation between vitamin D level with clinical [age, weight, body mass index (BMI), waist and hip circumference, systolic and diastolic blood pressure (SBP and DPB, respectively)] and metabolic parameters (fasting glucose, triglycerides, cholesterol, high-density lipoprotein and low density lipoprotein) among women with PCOS. However, height was positively correlated (r = 0.338, p = 0.033) and the contrary waist-hip ratio was negatively correlated with vitamin D level (r = -0.605, p = 0.048). Conclusion The prevalence of vitamin D deficiency was high in our study population. Nevertheless, the prevalence of metabolic syndrome was higher among women with PCOS as compared to women without PCOS. PMID- 28586304 TI - Identification of common words to improve self-confidence in Japanese students with subthreshold depression. AB - Background Subthreshold depression (StD) is more common than major depressive disorder. Objective The study aimed to identify common words to improve self confidence in Japanese university students with StD for developing a smartphone application to help those with StD. Methods In this cross-sectional study, words participants used to improve their self-confidence were gathered using self report questionnaires in 154 university students in Japan. The words used to improve self-confidence were categorized using a computerized text analysis method based on the frequency of appearance. Results Participants were 154 male and females [StD group (n = 82) and healthy control (HC) group (n = 72); median age = 20 years]. A total of 290 words for improving self-confidence were identified. In the StD group, the keywords that appeared with the highest frequencies were "can", "let's try", "good luck", "able", and "don't worry". The keywords that occurred with the highest frequencies (the top eight) were common across both groups. The keywords were grouped into eight categories. The "encouragement" and "praise" categories were found in the responses of more than 80% of participants in both groups. Frequencies of the "determination" and "trust" categories were significantly higher in the StD group than in the HC group. Conclusions We conclude that "can", "let's try", and "good luck" are the most common words that Japanese students with StD use when describing how they improve their self-confidence. Future work will use these common words to develop a smartphone application to help those suffering from StD. PMID- 28586305 TI - A combined approach to generate laboratory reference intervals using unbalanced longitudinal data. AB - BACKGROUND: The interpretation of individual laboratory test results requires the availability of population-based reference intervals. In children, reference interval estimation has to consider frequently the strong age-dependency. Generally, for the construction of reference intervals, a sufficiently large number of independent measurement values is required. Data selections from hospitals or cohort studies often comprise dependencies violating the independence assumption. METHODS: In this article, we propose a combination of LMS-like (mean, M; coefficient of variation, S; skewness, lambda or L) and resampling methods to overcome this drawback. The former is recommended by the World Health Organization (WHO) for the construction of continuous reference intervals of anthropometric measurements in children. The approach allows the inclusion of dependent measurements, for example, repeated measurements per subject. It also provides pointwise confidence envelopes as a measure of reliability. RESULTS AND CONCLUSIONS: The combination of LMS-type methods and resampling provides a feasible approach to estimate age-dependent percentiles and reference intervals using unbalanced longitudinal data. PMID- 28586306 TI - Revisiting nicotine's role in the ageing brain and cognitive impairment. AB - Brain ageing is a complex process which in its pathologic form is associated with learning and memory dysfunction or cognitive impairment. During ageing, changes in cholinergic innervations and reduced acetylcholinergic tonus may trigger a series of molecular pathways participating in oxidative stress, excitotoxicity, amyloid-beta toxicity, apoptosis, neuroinflammation, and perturb neurotrophic factors in the brain. Nicotine is an exogenous agonist of nicotinic acetylcholine receptors (nAChRs) and acts as a pharmacological chaperone in the regulation of nAChR expression, potentially intervening in age-related changes in diverse molecular pathways leading to pathology. Although nicotine has therapeutic potential, paradoxical effects have been reported, possibly due to its inverted U shape dose-response effects or pharmacokinetic factors. Additionally, nicotine administration should result in optimum therapeutic effects without imparting abuse potential or toxicity. Overall, this review aims to compile the previous and most recent data on nicotine and its effects on cognition-related mechanisms and age-related cognitive impairment. PMID- 28586312 TI - Assessing the reliability of dose coefficients for exposure to radioiodine by members of the public, accounting for dosimetric and risk model uncertainties. AB - Assessments of risk to a specific population group resulting from internal exposure to a particular radionuclide can be used to assess the reliability of the appropriate International Commission on Radiological Protection (ICRP) dose coefficients used as a radiation protection device for the specified exposure pathway. An estimate of the uncertainty on the associated risk is important for informing judgments on reliability; a derived uncertainty factor, UF, is an estimate of the 95% probable geometric difference between the best risk estimate and the nominal risk and is a useful tool for making this assessment. This paper describes the application of parameter uncertainty analysis to quantify uncertainties resulting from internal exposures to radioiodine by members of the public, specifically 1, 10 and 20-year old females from the population of England and Wales. Best estimates of thyroid cancer incidence risk (lifetime attributable risk) are calculated for ingestion or inhalation of 129I and 131I, accounting for uncertainties in biokinetic model and cancer risk model parameter values. These estimates are compared with the equivalent ICRP derived nominal age-, sex- and population-averaged estimates of excess thyroid cancer incidence to obtain UFs. Derived UF values for ingestion or inhalation of 131I for 1 year, 10-year and 20 year olds are around 28, 12 and 6, respectively, when compared with ICRP Publication 103 nominal values, and 9, 7 and 14, respectively, when compared with ICRP Publication 60 values. Broadly similar results were obtained for 129I. The uncertainties on risk estimates are largely determined by uncertainties on risk model parameters rather than uncertainties on biokinetic model parameters. An examination of the sensitivity of the results to the risk models and populations used in the calculations show variations in the central estimates of risk of a factor of around 2-3. It is assumed that the direct proportionality of excess thyroid cancer risk and dose observed at low to moderate acute doses and incorporated in the risk models also applies to very small doses received at very low dose rates; the uncertainty in this assumption is considerable, but largely unquantifiable. The UF values illustrate the need for an informed approach to the use of ICRP dose and risk coefficients. PMID- 28586313 TI - Physical insights into the blood-brain barrier translocation mechanisms. AB - The number of individuals suffering from diseases of the central nervous system (CNS) is growing with an aging population. While candidate drugs for many of these diseases are available, most of these pharmaceutical agents cannot reach the brain rendering most of the drug therapies that target the CNS inefficient. The reason is the blood-brain barrier (BBB), a complex and dynamic interface that controls the influx and efflux of substances through a number of different translocation mechanisms. Here, we present these mechanisms providing, also, the necessary background related to the morphology and various characteristics of the BBB. Moreover, we discuss various numerical and simulation approaches used to study the BBB, and possible future directions based on multi-scale methods. We anticipate that this review will motivate multi-disciplinary research on the BBB aiming at the design of effective drug therapies. PMID- 28586314 TI - MicroRNA-mediated regulatory circuits: outlook and perspectives. AB - MicroRNAs have been found to be necessary for regulating genes implicated in almost all signaling pathways, and consequently their dysfunction influences many diseases, including cancer. Understanding of the complexity of the microRNA mediated regulatory network has grown in terms of size, connectivity and dynamics with the development of computational and, more recently, experimental high throughput approaches for microRNA target identification. Newly developed studies on recurrent microRNA-mediated circuits in regulatory networks, also known as network motifs, have substantially contributed to addressing this complexity, and therefore to helping understand the ways by which microRNAs achieve their regulatory role. This review provides a summarizing view of the state-of-the-art, and perspectives of research efforts on microRNA-mediated regulatory motifs. In this review, we discuss the topological properties characterizing different types of circuits, and the regulatory features theoretically enabled by such properties, with a special emphasis on examples of circuits typifying their biological significance in experimentally validated contexts. Finally, we will consider possible future developments, in particular regarding microRNA-mediated circuits involving long non-coding RNAs and epigenetic regulators. PMID- 28586315 TI - Report of IRPA task group on the impact of the eye lens dose limits. AB - In 2012 IRPA established a task group (TG) to identify key issues in the implementation of the revised eye lens dose limit. The TG reported its conclusions in 2013. In January 2015, IRPA asked the TG to review progress with the implementation of the recommendations from the early report and to collate current practitioner experience. This report presents the results of a survey on the view of the IRPA professionals on the new limit to the lens of the eye and on the wider issue of tissue reactions. Recommendations derived from the survey are presented. This report was approved by IRPA Executive Council on 31 January 2017. PMID- 28586316 TI - Direct 3D cell-printing of human skin with functional transwell system. AB - Three-dimensional (3D) cell-printing has been emerging as a promising technology with which to build up human skin models by enabling rapid and versatile design. Despite the technological advances, challenges remain in the development of fully functional models that recapitulate complexities in the native tissue. Moreover, although several approaches have been explored for the development of biomimetic human skin models, the present skin models based on multistep fabrication methods using polydimethylsiloxane chips and commercial transwell inserts could be tackled by leveraging 3D cell-printing technology. In this paper, we present a new 3D cell-printing strategy for engineering a 3D human skin model with a functional transwell system in a single-step process. A hybrid 3D cell-printing system was developed, allowing for the use of extrusion and inkjet modules at the same time. We began by revealing the significance of each module in engineering human skin models; by using the extrusion-dispensing module, we engineered a collagen-based construct with polycaprolactone (PCL) mesh that prevented the contraction of collagen during tissue maturation; the inkjet-based dispensing module was used to uniformly distribute keratinocytes. Taking these features together, we engineered a human skin model with a functional transwell system; the transwell system and fibroblast-populated dermis were consecutively fabricated by using the extrusion modules. Following this process, keratinocytes were uniformly distributed onto the engineered dermis by the inkjet module. Our transwell system indicates a supportive 3D construct composed of PCL, enabling the maturation of a skin model without the aid of commercial transwell inserts. This skin model revealed favorable biological characteristics that included a stabilized fibroblast-stretched dermis and stratified epidermis layers after 14 days. It was also observed that a 50 times reduction in cost was achieved and 10 times less medium was used than in a conventional culture. Collectively, because this single-step process opens up chances for versatile designs, we envision that our cell-printing strategy could provide an attractive platform in engineering various human skin models. PMID- 28586318 TI - Modelling of induced electric fields based on incompletely known magnetic fields. AB - Determining the induced electric fields in the human body is a fundamental problem in bioelectromagnetics that is important for both evaluation of safety of electromagnetic fields and medical applications. However, existing techniques for numerical modelling of induced electric fields require detailed information about the sources of the magnetic field, which may be unknown or difficult to model in realistic scenarios. Here, we show how induced electric fields can accurately be determined in the case where the magnetic fields are known only approximately, e.g. based on field measurements. The robustness of our approach is shown in numerical simulations for both idealized and realistic scenarios featuring a personalized MRI-based head model. The approach allows for modelling of the induced electric fields in biological bodies directly based on real-world magnetic field measurements. PMID- 28586317 TI - Right lateral versus left lateral view for forearm coronary angiography. An operator radiation exposure and image quality study. AB - OBJECTIVES: The aim of this study was to analyze the operator radiation exposure (ORE) and the image quality in a coronary angiography (CA) of the standard left lateral view (LLV) and compare it with an alternative right lateral view (RLV). BACKGROUND: Interventional cardiologists are exposed to high doses of scatter radiation, especially in angulated projections. METHODS: We prospectively included consecutive patients who underwent diagnostic CA. A standard +90 degrees LLV and an alternative RLV (-90 degrees ) were done in each patient with the same protocol. The operator effective dose rate (mSv/h) was determined for each projection with digital dosimeters located in the collar, waist and knee. The image quality of both the LLV and RLV was analyzed and compared to a standard projection. RESULTS: 116 patients were enrolled; left coronary artery (LCA) was assessed in 52 patients and right coronary artery (RCA) in 64 patients. The ORE was significantly lower with the RLV compared to the conventional LLV with a maximum ORE reduction of 91.5% in the operator waist (LLV: 6.84 mSv h-1 versus RLV: 0.58 mSv h-1, p < 0.001). No significant differences in image quality were observed for the RCA in both projections. For the LCA, a slight loss of quality was observed with the RLV. CONCLUSIONS: -90 degrees RLV is associated with a significant decrease in ORE compared to the conventional +90 degrees LLV without losing image resolution for the RCA and resulting in a slight quality loss for the LCA evaluation. The RLV should be the first choice for RCA evaluation. For the LCA, the RLV loss of resolution should be balanced with the benefit of minimizing ORE, mainly in cases with long fluoroscopy times, such as complex percutaneous coronary interventional procedures. PMID- 28586319 TI - REV-ERB and ROR: therapeutic targets for treating myopathies. AB - Muscle is primarily known for its mechanical roles in locomotion, maintenance of posture, and regulation of cardiac and respiratory function. There are numerous medical conditions that adversely affect muscle, myopathies that disrupt muscle development, regeneration and protein turnover to detrimental effect. Skeletal muscle is also a vital secretory organ that regulates thermogenesis, inflammatory signaling and directs context specific global metabolic changes in energy substrate preference on a daily basis. Myopathies differ in the causative factors that drive them but share common features including severe reduction in quality of life and significantly increased mortality all due irrefutably to the loss of muscle mass. Thus far clinically viable approaches for preserving muscle proteins and stimulating new muscle growth without unwanted side effects or limited efficacy has been elusive. Over the last few decades, evidence has emerged through in vitro and in vivo studies that suggest the nuclear receptors REV-ERB and ROR might modulate pathways involved in myogenesis and mitochondrial biogenesis. Hinting that REV-ERB and ROR might be targeted to treat myopathies. However there is still a need for substantial investigation into the roles of these nuclear receptors in in vivo rodent models of degenerative muscle diseases and acute injury. Although exciting, REV-ERB and ROR have somewhat confounding roles in muscle physiology and therefore more studies utilizing in vivo models of skeletal muscle myopathies are needed. In this review we highlight the molecular forces driving some of the major degenerative muscular diseases and showcase two promising molecular targets that may have the potential to treat myopathies: ROR and REV-ERB. PMID- 28586320 TI - Comparative analyses of studies of childhood leukemia and magnetic fields, radon and gamma radiation. AB - In this paper we compare the findings of epidemiologic studies of childhood leukemia that examined at least two of ELF magnetic fields and/or distance to power lines, and exposure to radon and gamma radiation or distance to nuclear plants. Many of the methodologic aspects are common to studies of non-ionising (i.e. ELF-MF) and ionising radiation. A systematic search and review of studies with more than one exposure under study identified 33 key and 35 supplementary papers from ten countries that have been included in this review. Examining studies that have looked at several radiation exposures, and comparing similarities and differences for the different types of radiation, through the use of directed acyclic graphs, we evaluate to what extent bias, confounding and other methodological issues might be operating in these studies. We found some indication of bias, although results are not clear cut. There is little evidence that confounding has had a substantial influence on results. Influence of the residential mobility on the study conduct and interpretation is complex and can manifest as a selection bias, confounding, increased measurement error or could also be a potential risk factor. Other factors associated with distance to power lines and to nuclear power plants should be investigated. A more complete and consistent reporting of results in the future studies will allow for a more informative comparison across studies and integration of results. PMID- 28586321 TI - Treatment of Ischemia-Reperfusion Injury of the Skin Flap Using Human Umbilical Cord Mesenchymal Stem Cells (hUC-MSCs) Transfected with "F-5" Gene. AB - BACKGROUND Recent studies have shown that skin flap transplantation technique plays an important role in surgical procedures. However, there are many problems in the process of skin flap transplantation surgeries, especially ischemia reperfusion injury, which directly affects the survival rate of the skin flap and patient prognosis after surgeries. MATERIAL AND METHODS In this study, we used a new method of the "stem cells-gene" combination therapy. The "F-5" gene fragment of heat shock protein 90-alpha (Hsp90-alpha) was transfected into human umbilical cord mesenchymal stem cells (hUC-MSCs) by genetic engineering technique. RESULTS The synergistic effects of "F-5" gene and hUC-MSCs in the treatment of ischemia reperfusion injury of the skin flap were confirmed by histochemical and immunohistochemical methods. CONCLUSIONS This study showed that the hUC-MSCs transfected with "F-5" gene can effectively improve the repair of ischemia reperfusion injury. PMID- 28586323 TI - Corrigendum: Quaternary contact in the initial interaction of CD4 with the HIV-1 envelope trimer. PMID- 28586322 TI - DNA N6-methyladenine in metazoans: functional epigenetic mark or bystander? AB - The DNA-adenine modification N6-methyladenine (6mA), initially thought to be mainly restricted to prokaryotes and certain unicellular eukaryotes, has recently been found in metazoans. Proposed functions vary from gene activation to transposon suppression. However, since most metazoan genomes possess 5 methylcytosine (5mC) as a dominant epigenetic mark, it raises the question of why 6mA is required. This Perspective summarizes the latest discoveries and suggests potential functional roles for 6mA in metazoan genomes. PMID- 28586324 TI - Frozen in action: cryo-EM structure of a GPCR-G-protein complex. PMID- 28586326 TI - Erratum: Molecular basis of telomere dysfunction in human genetic diseases. PMID- 28586325 TI - Distinct mechanisms obviate the potentially toxic effects of inverted-repeat Alu elements on cellular RNA metabolism. PMID- 28586328 TI - Promoter interactions direct chromatin folding in embryonic stem cells. PMID- 28586329 TI - RNA base-pairing drives phase transitions. PMID- 28586327 TI - A glimpse into chromatin remodeling. PMID- 28586330 TI - Gathering by the Red Sea highlights links between environment and epigenetics. PMID- 28586331 TI - Viral vanguard: Designing cancer-killing viruses to chase metastatic tumors. PMID- 28586332 TI - Source code: Putting metagenomics to the test in the clinic. PMID- 28586333 TI - The cannabis paradox: when age matters. PMID- 28586334 TI - Biased for benefit: Stimulating the world's most popular drug targets with more nuance. PMID- 28586336 TI - Erratum: PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer. PMID- 28586337 TI - Corrigendum: SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. PMID- 28586338 TI - Understanding cancer from the stem cells up. PMID- 28586339 TI - Erratum: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. PMID- 28586340 TI - Patrolling monocytes sense peripheral infection and induce cytokine-mediated neuronal dysfunction. PMID- 28586335 TI - Biology and evolution of poorly differentiated neuroendocrine tumors. AB - Neuroendocrine (NE) cancers are a diverse group of neoplasms typically diagnosed and treated on the basis of their site of origin. This Perspective focuses on advances in our understanding of the tumorigenesis and treatment of poorly differentiated neuroendocrine tumors. Recent evidence from sequencing indicates that, although neuroendocrine tumors can arise de novo, they can also develop as a result of lineage plasticity in response to pressure from targeted therapies. We discuss the shared genomic alterations of these tumors independently of their site of origin, and we explore potential therapeutic strategies on the basis of recent biological findings. PMID- 28586341 TI - Erratum: Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. PMID- 28586342 TI - A role for neutrophils in asthma exacerbations. PMID- 28586344 TI - A generalized right truncated bivariate Poisson regression model with applications to health data. AB - A generalized right truncated bivariate Poisson regression model is proposed in this paper. Estimation and tests for goodness of fit and over or under dispersion are illustrated for both untruncated and right truncated bivariate Poisson regression models using marginal-conditional approach. Estimation and test procedures are illustrated for bivariate Poisson regression models with applications to Health and Retirement Study data on number of health conditions and the number of health care services utilized. The proposed test statistics are easy to compute and it is evident from the results that the models fit the data very well. A comparison between the right truncated and untruncated bivariate Poisson regression models using the test for nonnested models clearly shows that the truncated model performs significantly better than the untruncated model. PMID- 28586343 TI - Production of transgenic pig as an Alzheimer's disease model using a multi cistronic vector system. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with memory loss and cognitive impairments. An AD transgenic (Tg) pig model would be useful for preclinical testing of therapeutic agents. We generated an AD Tg pig by somatic cell nuclear transfer (SCNT) using a multi-cistronic vector that harbored three AD-related genes with a total of six well-characterized mutations: hAPP (K670N/M671L, I716V, and V717I), hTau (P301L), and hPS1 (M146V and L286P). Four AD Tg cell lines were established from Jeju black pig ear fibroblasts (JB PEFs); the resultant JB-PEFAD cells harbored transgene integration, expressed transgene mRNAs, and had normal karyotypes. Tg line #2-1, which expressed high levels of the transgenes, was used for SCNT; cleavage and blastocyst rates of embryos derived from this line were lower than those of Non-Tg. These embryos yielded three piglets (Jeju National University AD-Tg pigs, JNUPIGs) revealed by microsatellite testing to be genetically identical to JB-PEFAD. Transgenes were expressed in multiple tissues, and at especially high levels in brain, and Abeta 40/42, total Tau, and GFAP levels were high in brains of the Tg animals. Five or more copies of transgenes were inserted into chromosome X. This is the first report of an AD Tg pig derived from a multi-cistronic vector. PMID- 28586345 TI - Delivery of the autofluorescent protein R-phycoerythrin by calcium phosphate nanoparticles into four different eukaryotic cell lines (HeLa, HEK293T, MG-63, MC3T3): Highly efficient, but leading to endolysosomal proteolysis in HeLa and MC3T3 cells. AB - Nanoparticles can be used as carriers to transport biomolecules like proteins and synthetic molecules across the cell membrane because many molecules are not able to cross the cell membrane on their own. The uptake of nanoparticles together with their cargo typically occurs via endocytosis, raising concerns about the possible degradation of the cargo in the endolysosomal system. As the tracking of a dye-labelled protein during cellular uptake and processing is not indicative of the presence of the protein itself but only for the fluorescent label, a label free tracking was performed with the red-fluorescing model protein R phycoerythrin (R-PE). Four different eukaryotic cell lines were investigated: HeLa, HEK293T, MG-63, and MC3T3. Alone, the protein was not taken up by any cell line; only with the help of calcium phosphate nanoparticles, an efficient uptake occurred. After the uptake into HeLa cells, the protein was found in early endosomes (shown by the marker EEA1) and lysosomes (shown by the marker Lamp1). There, it was still intact and functional (i.e. properly folded) as its red fluorescence was detected. However, a few hours after the uptake, proteolysis started as indicated by the decreasing red fluorescence intensity in the case of HeLa and MC3T3 cells. 12 h after the uptake, the protein was almost completely degraded in HeLa cells and MC3T3 cells. In HEK293T cells and MG-63 cells, no degradation of the protein was observed. In the presence of Bafilomycin A1, an inhibitor of acidification and protein degradation in lysosomes, the fluorescence of R-PE remained intact over the whole observation period in the four cell lines. These results indicate that despite an efficient nanoparticle-mediated uptake of proteins by cells, a rapid endolysosomal degradation may prevent the desired (e.g. therapeutic) effect of a protein inside a cell. PMID- 28586346 TI - 3D bioprinting of methacrylated hyaluronic acid (MeHA) hydrogel with intrinsic osteogenicity. AB - In bone regenerative medicine there is a need for suitable bone substitutes. Hydrogels have excellent biocompatible and biodegradable characteristics, but their visco-elastic properties limit their applicability, especially with respect to 3D bioprinting. In this study, we modified the naturally occurring extracellular matrix glycosaminoglycan hyaluronic acid (HA), in order to yield photo-crosslinkable hydrogels with increased mechanical stiffness and long-term stability, and with minimal decrease in cytocompatibility. Application of these tailor-made methacrylated hyaluronic acid (MeHA) gels for bone tissue engineering and 3D bioprinting was the subject of investigation. Visco-elastic properties of MeHA gels, measured by rheology and dynamic mechanical analysis, showed that irradiation of the hydrogels with UV light led to increased storage moduli and elastic moduli, indicating increasing gel rigidity. Subsequently, human bone marrow derived mesenchymal stromal cells (MSCs) were incorporated into MeHA hydrogels, and cell viability remained 64.4% after 21 days of culture. Osteogenic differentiation of MSCs occurred spontaneously in hydrogels with high concentrations of MeHA polymer, in absence of additional osteogenic stimuli. Addition of bone morphogenetic protein-2 (BMP-2) to the culture medium further increased osteogenic differentiation, as evidenced by increased matrix mineralisation. MeHA hydrogels demonstrated to be suitable for 3D bioprinting, and were printed into porous and anatomically shaped scaffolds. Taken together, photosensitive MeHA-based hydrogels fulfilled our criteria for cellular bioprinted bone constructs within a narrow window of concentration. PMID- 28586347 TI - What makes a reach movement effortful? Physical effort discounting supports common minimization principles in decision making and motor control. AB - When deciding between alternative options, a rational agent chooses on the basis of the desirability of each outcome, including associated costs. As different options typically result in different actions, the effort associated with each action is an essential cost parameter. How do humans discount physical effort when deciding between movements? We used an action-selection task to characterize how subjective effort depends on the parameters of arm transport movements and controlled for potential confounding factors such as delay discounting and performance. First, by repeatedly asking subjects to choose between 2 arm movements of different amplitudes or durations, performed against different levels of force, we identified parameter combinations that subjects experienced as identical in effort (isoeffort curves). Movements with a long duration were judged more effortful than short-duration movements against the same force, while movement amplitudes did not influence effort. Biomechanics of the movements also affected effort, as movements towards the body midline were preferred to movements away from it. Second, by introducing movement repetitions, we further determined that the cost function for choosing between effortful movements had a quadratic relationship with force, while choices were made on the basis of the logarithm of these costs. Our results show that effort-based action selection during reaching cannot easily be explained by metabolic costs. Instead, force loaded reaches, a widely occurring natural behavior, imposed an effort cost for decision making similar to cost functions in motor control. Our results thereby support the idea that motor control and economic choice are governed by partly overlapping optimization principles. PMID- 28586348 TI - Primary multidrug-resistant tuberculosis versus drug-sensitive tuberculosis in non-HIV-infected patients: Comparisons of CT findings. AB - BACKGROUND: Multidrug-resistant tuberculosis has emerged as a global threat. The aim of this work was to compare the CT findings of primary multidrug-resistant tuberculosis and drug-sensitive tuberculosis in non-AIDS adults. MATERIAL AND METHODS: From January 2012 to February 2016, 89 patients with primary multidrug resistant tuberculosis were retrospectively reviewed, and 89 consecutive drug sensitive TB patients with no history of anti-tuberculous chemotherapy from January 2014 to November 2014 were enrolled as control group. All patients were seronegative for HIV. The patients' demographic data and the locations, frequency and patterns of lung lesions on chest CT were compared. RESULTS: Gender and frequency of diabetes were similar between the two groups. The mean age of primary multidrug-resistant tuberculosis patients was younger than that of drug sensitive tuberculosis (39.0 vs 47.5, P = 0.005). Lung cavitary nodules or masses were more frequently observed and also showed greater extent in primary multidrug resistant tuberculosis compared with drug-sensitive tuberculosis. The extent of bronchiectasis was significantly greater in primary multidrug-resistant tuberculosis than in drug-sensitive tuberculosis. Calcification, large nodules and calcified lymph nodes were more frequent in drug-sensitive tuberculosis. CONCLUSION: Characteristic chest CT findings may help differentiate between primary multi-drug resistant tuberculosis and drug-sensitive tuberculosis in patients without HIV infection. PMID- 28586349 TI - Comparison of the induced fields using different coil configurations during deep transcranial magnetic stimulation. AB - Stimulation of deeper brain structures by transcranial magnetic stimulation (TMS) plays a role in the study of reward and motivation mechanisms, which may be beneficial in the treatment of several neurological and psychiatric disorders. However, electric field distributions induced in the brain by deep transcranial magnetic stimulation (dTMS) are still unknown. In this paper, the double cone coil, H-coil and Halo-circular assembly (HCA) coil which have been proposed for dTMS have been numerically designed. The distributions of magnetic flux density, induced electric field in an anatomically based realistic head model by applying the dTMS coils were numerically calculated by the impedance method. Results were compared with that of standard figure-of-eight (Fo8) coil. Simulation results show that double cone, H- and HCA coils have significantly deep field penetration compared to the conventional Fo8 coil, at the expense of induced higher and wider spread electrical fields in superficial cortical regions. Double cone and HCA coils have better ability to stimulate deep brain subregions compared to that of the H-coil. In the mean time, both double cone and HCA coils increase risk for optical nerve excitation. Our results suggest although the dTMS coils offer new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions, the selection of the most suitable coil settings for a specific clinical application should be based on a balanced evaluation between stimulation depth and focality. PMID- 28586350 TI - A conserved role for the ESCRT membrane budding complex in LINE retrotransposition. AB - Long interspersed nuclear element-1s (LINE-1s, or L1s) are an active family of retrotransposable elements that continue to mutate mammalian genomes. Despite the large contribution of L1 to mammalian genome evolution, we do not know where active L1 particles (particles in the process of retrotransposition) are located in the cell, or how they move towards the nucleus, the site of L1 reverse transcription. Using a yeast model of LINE retrotransposition, we identified ESCRT (endosomal sorting complex required for transport) as a critical complex for LINE retrotransposition, and verified that this interaction is conserved for human L1. ESCRT interacts with L1 via a late domain motif, and this interaction facilitates L1 replication. Loss of the L1/ESCRT interaction does not impair RNP formation or enzymatic activity, but leads to loss of retrotransposition and reduced L1 endonuclease activity in the nucleus. This study highlights the importance of the ESCRT complex in the L1 life cycle and suggests an unusual mode for L1 RNP trafficking. PMID- 28586351 TI - Reducing US cardiovascular disease burden and disparities through national and targeted dietary policies: A modelling study. AB - BACKGROUND: Large socio-economic disparities exist in US dietary habits and cardiovascular disease (CVD) mortality. While economic incentives have demonstrated success in improving dietary choices, the quantitative impact of different dietary policies on CVD disparities is not well established. We aimed to quantify and compare the potential effects on total CVD mortality and disparities of specific dietary policies to increase fruit and vegetable (F&V) consumption and reduce sugar-sweetened beverage (SSB) consumption in the US. METHODS AND FINDINGS: Using the US IMPACT Food Policy Model and probabilistic sensitivity analyses, we estimated and compared the reductions in CVD mortality and socio-economic disparities in the US population potentially achievable from 2015 to 2030 with specific dietary policy scenarios: (a) a national mass media campaign (MMC) aimed to increase consumption of F&Vs and reduce consumption of SSBs, (b) a national fiscal policy to tax SSBs to increase prices by 10%, (c) a national fiscal policy to subsidise F&Vs to reduce prices by 10%, and (d) a targeted policy to subsidise F&Vs to reduce prices by 30% among Supplemental Nutrition Assistance Program (SNAP) participants only. We also evaluated a combined policy approach, combining all of the above policies. Data sources included the Surveillance, Epidemiology, and End Results Program, National Vital Statistics System, National Health and Nutrition Examination Survey, and published meta-analyses. Among the individual policy scenarios, a national 10% F&V subsidy was projected to be most beneficial, potentially resulting in approximately 150,500 (95% uncertainty interval [UI] 141,400-158,500) CVD deaths prevented or postponed (DPPs) by 2030 in the US. This far exceeds the approximately 35,100 (95% UI 31,700-37,500) DPPs potentially attributable to a 30% F&V subsidy targeting SNAP participants, the approximately 25,800 (95% UI 24,300-28,500) DPPs for a 1-y MMC, or the approximately 31,000 (95% UI 26,800 35,300) DPPs for a 10% SSB tax. Neither the MMC nor the individual national economic policies would significantly reduce CVD socio-economic disparities. However, the SNAP-targeted intervention might potentially reduce CVD disparities between SNAP participants and SNAP-ineligible individuals, by approximately 8% (10 DPPs per 100,000 population). The combined policy approach might save more lives than any single policy studied (approximately 230,000 DPPs by 2030) while also significantly reducing disparities, by approximately 6% (7 DPPs per 100,000 population). Limitations include our effect estimates in the model; these estimates use interventional and prospective observational studies (not exclusively randomised controlled trials). They are thus imperfect and should be interpreted as the best available evidence. Another key limitation is that we considered only CVD outcomes; the policies we explored would undoubtedly have additional beneficial effects upon other diseases. Further, we did not model or compare the cost-effectiveness of each proposed policy. CONCLUSIONS: Fiscal strategies targeting diet might substantially reduce CVD burdens. A national 10% F&V subsidy would save by far the most lives, while a 30% F&V subsidy targeting SNAP participants would most reduce socio-economic disparities. A combined policy would have the greatest overall impact on both mortality and socio-economic disparities. PMID- 28586353 TI - Lack of robustness of textural measures obtained from 3D brain tumor MRIs impose a need for standardization. AB - PURPOSE: Textural measures have been widely explored as imaging biomarkers in cancer. However, their robustness under dynamic range and spatial resolution changes in brain 3D magnetic resonance images (MRI) has not been assessed. The aim of this work was to study potential variations of textural measures due to changes in MRI protocols. MATERIALS AND METHODS: Twenty patients harboring glioblastoma with pretreatment 3D T1-weighted MRIs were included in the study. Four different spatial resolution combinations and three dynamic ranges were studied for each patient. Sixteen three-dimensional textural heterogeneity measures were computed for each patient and configuration including co-occurrence matrices (CM) features and run-length matrices (RLM) features. The coefficient of variation was used to assess the robustness of the measures in two series of experiments corresponding to (i) changing the dynamic range and (ii) changing the matrix size. RESULTS: No textural measures were robust under dynamic range changes. Entropy was the only textural feature robust under spatial resolution changes (coefficient of variation under 10% in all cases). CONCLUSION: Textural measures of three-dimensional brain tumor images are not robust neither under dynamic range nor under matrix size changes. Standards should be harmonized to use textural features as imaging biomarkers in radiomic-based studies. The implications of this work go beyond the specific tumor type studied here and pose the need for standardization in textural feature calculation of oncological images. PMID- 28586352 TI - The specific host plant DNA detection suggests a potential migration of Apolygus lucorum from cotton to mungbean fields. AB - The polyphagous mirid bug Apolygus lucorum (Heteroptera: Miridae) has more than 200 species of host plants and is an insect pest of important agricultural crops, including cotton (Gossypium hirsutum) and mungbean (Vigna radiata). Previous field trials have shown that A. lucorum adults prefer mungbean to cotton plants, indicating the considerable potential of mungbean as a trap crop in cotton fields. However, direct evidence supporting the migration of A. lucorum adults from cotton to mungbean is lacking. We developed a DNA-based polymerase chain reaction (PCR) approach to reveal the movement of A. lucorum between neighboring mungbean and cotton fields. Two pairs of PCR primers specific to cotton or mungbean were designed to target the trnL-trnF region of chloroplast DNA. Significant differences in the detectability half-life (DS50) were observed between these two host plants, and the mean for cotton (8.26 h) was approximately two times longer than that of mungbean (4.38 h), requiring weighted mean calculations to compare the detectability of plant DNA in the guts of field collected bugs. In field trials, cotton DNA was detected in the guts of the adult A. lucorum individuals collected in mungbean plots, and the cotton DNA detection rate decreased successively from 5 to 15 m away from the mungbean-cotton midline. In addition to the specific detection of cotton- and mungbean-fed bugs, both cotton and mungbean DNA were simultaneously detected within the guts of single individuals caught from mungbean fields. This study successfully established a tool for molecular gut-content analyses and clearly demonstrated the movement of A. lucorum adults from cotton to neighboring mungbean fields, providing new insights into understanding the feeding characteristics and landscape-level ecology of A. lucorum under natural conditions. PMID- 28586354 TI - Contextual diversity facilitates learning new words in the classroom. AB - In the field of word recognition and reading, it is commonly assumed that frequently repeated words create more accessible memory traces than infrequently repeated words, thus capturing the word-frequency effect. Nevertheless, recent research has shown that a seemingly related factor, contextual diversity (defined as the number of different contexts [e.g., films] in which a word appears), is a better predictor than word-frequency in word recognition and sentence reading experiments. Recent research has shown that contextual diversity plays an important role when learning new words in a laboratory setting with adult readers. In the current experiment, we directly manipulated contextual diversity in a very ecological scenario: at school, when Grade 3 children were learning words in the classroom. The new words appeared in different contexts/topics (high contextual diversity) or only in one of them (low-contextual diversity). Results showed that words encountered in different contexts were learned and remembered more effectively than those presented in redundant contexts. We discuss the practical (educational [e.g., curriculum design]) and theoretical (models of word recognition) implications of these findings. PMID- 28586355 TI - Incidence and causes of maternal near-miss in selected hospitals of Addis Ababa, Ethiopia. AB - BACKGROUND: Because maternal mortality is a rare event, it is important to study maternal near-miss as a complement to evaluate and improve the quality of obstetric care. Thus, the study was conducted with the aim of assessing the incidence and causes of maternal near-miss. METHODS: A facility-based cross sectional study was conducted in five selected public hospitals of Addis Ababa, Ethiopia from May 1, 2015 to April 30, 2016. All maternal near-miss cases admitted to the selected hospitals during the study period were prospectively recruited. World Health Organization criteria were used to identify maternal near miss cases. The number of maternal near-miss cases over one year per 1000 live births occurring during the same year was calculated to determine the incidence of maternal near-miss. Underlying and contributing causes of maternal near-miss were documented from each participant's record. RESULTS: During the one-year period, there were a total of 238 maternal near-miss cases and 29,697 live births in all participating hospitals, which provides a maternal near-miss incidence ratio of 8.01 per 1000 live births. The underlying causes of the majority of maternal near-miss cases were hypertensive disorders and obstetric hemorrhage. Anemia was the major contributing cause reported for maternal near-miss. Most of the maternal near-miss cases occurred before the women's arrival at the participating hospitals. CONCLUSION: The study demonstrated a lower maternal near miss incidence ratio compared to previous country-level studies. The majority of the near-miss cases occurred before the women's arrival at the participating hospitals, which underscores the importance of improving pre-hospital barriers. Efforts made toward improvement in the management of life-threatening obstetric complications could reduce the occurrence of maternal near-miss problems that occur during hospitalization. PMID- 28586356 TI - Bidirectional relationships between retention and health-related quality of life in Chinese mainland patients receiving methadone maintenance treatment. AB - This study aimed to explore the bidirectional relationships between retention and health-related quality of life (HRQoL) in patients from mainland China receiving methadone maintenance treatment (MMT). This prospective cohort study recruited 1,212 eligible MMT patients from the two largest MMT clinics (one privately and another publicly funded) in Xi'an. This study started in March 2012 with a 2-year follow-up until March 2014. Retention was assessed by repeated terminations, past treatment duration, premature terminations, and follow-up treatment duration. HRQoL was evaluated using the Chinese (simple) short-form 36 health survey version 2 (SF-36v2) and the quality of life scale for drug addicts (QOL-DAv2.0). Linear and Cox regression analyses were used to explore relationships between retention and HRQoL. A general linear model was used to further examine the global effect of past treatment duration on HRQoL. Multivariate analyses showed that repeated terminations had no significant impact on HRQoL scores in MMT patients; however, past treatment time (year) influenced the SF-36v2PCS (P = 0.004): treatment for >=4 years showed a lower SF-36v2PCS score (regression coefficient: -2.39; 95% confidence interval [CI]: -3.80, -0.97; P = 0.001) than treatment for <1 year. In addition, patients with an SF-36v2PCS score > 49 (hazard ratio: 0.83; 95% CI: 0.69, 0.98; P = 0.03) were 17% less likely to terminate MMT than those with scores of <=49. In conclusion, retention and HRQoL tended to have a bidirectional relationship, which should be considered in the development of retention and health-management programs for patients with MMT. PMID- 28586357 TI - Satellite data based estimation of methane emissions from rice paddies in the Sanjiang Plain in northeast China. AB - The Sanjiang Plain (SJP), one of the major rice producing regions in China, is an important source of methane (CH4) emissions. However, there have been large uncertainties in the estimates of CH4 emissions from this area during the past few years. In this study, we estimated CH4 emissions using a process-based model derived by rice area, CH4 flux, land surface temperature (LST), and the ratio of precipitation (P) and evapotranspiration (ET) in rice paddies in the SJP during the rice growing seasons in 2000, 2006, and 2010, respectively. The results showed that the total area of rice fields was 1.64 million ha in 2010, which was approximately 35 and 13% higher than in 2000 and 2006, respectively. The average LST was 22.1 degrees C in 2000 which was higher than in 2006 (21.6 degrees C) and 2010 (21.5 degrees C). Monthly ET and P displayed similar seasonal and annual variability. The monthly ET was 61.7, 66.5, and 63.0 mm month-1 and P was 85.1, 80.6 and 85.9 mm month-1 during the rice growing seasons in 2000, 2006, and 2010, respectively. The averaged CH4 flux rates were 24.83, 24.63, and 24.59 ton km-2, and the estimated mean annual CH4 emissions from rice paddies were 0.30, 0.36, and 0. 40 Tg yr-1 in 2000, 2006, and 2010, respectively. The CH4 emissions displayed obvious spatial variations that decreased from east to west in the SJP, and were mainly affected by temperature. The results will improve our understanding of the inter-annual and spatial variations of CH4 emissions and provide a more accurate regional budget of CH4 emissions from rice paddies in the Sanjiang Plain. PMID- 28586359 TI - Genome-wide analysis of DWD proteins in soybean (Glycine max): Significance of Gm08DWD and GmMYB176 interaction in isoflavonoid biosynthesis. AB - A subset of WD40 proteins with DWD motif has been proposed to serve as substrate receptor of DDB-CUL4-ROC1 complex, thereby getting involved in protein degradation via ubiquitination pathway. Here, we identified a total of 161 potential DWD proteins in soybean (Glycine max) by searching DWD motif against the genome-wide WD40 repeats, and classified them into 20 groups on the basis of their functional domains and annotations. These putative DWD genes in soybean displayed tissue-specific expression patterns, and their genome localization and analysis of evolutionary relationship identified 48 duplicated gene pairs within 161 GmDWDs. Among the 161 soybean DWD proteins, Gm08DWD was previously found to interact with an isoflavonoid regulator, GmMYB176. Therefore, Gm08DWD and its homologue Gm05DWD were further investigated. Expression profile of both genes in different soybean tissues revealed that Gm08DWD was expressed higher in embryo, while Gm05DWD exhibited maximum transcript accumulation in leaf. Our protein protein interaction studies demonstrated that Gm08DWD interacts with GmMYB176. Although Gm08DWD was localized both in nucleus and cytoplasm, the resulting complex of Gm08DWD and GmMYB176 was mainly observed in the nucleus. This finding is consistent with the functional localization of CUL4-E3 ligase complex. In conclusion, the survey on soybean potential DWD protein is useful reference for the further functional investigation of their DDB1-binding ability. Based on the functional investigation of Gm08DWD, we speculate that protein-protein interaction between Gm08DWD and GmMYB176 may lead to the degradation of GmMYB176 through CUL4-DDB1complex. PMID- 28586360 TI - Comparative proteomic analysis of eggplant (Solanum melongena L.) heterostylous pistil development. AB - Heterostyly is a common floral polymorphism, but the proteomic basis of this trait is still largely unexplored. In this study, self- and cross-pollination of L-morph and S-morph flowers and comparison of embryo sac development in eggplant (Solanum melongena L.) suggested that lower fruit set from S-morph flowers results from stigma-pollen incompatibility. To explore the molecular mechanism underlying heterostyly development, we conducted isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis of eggplant pistils for L- and S-morph flowers. A total of 5,259 distinct proteins were identified during heterostyly development. Compared S-morph flowers with L-morph, we discovered 57 and 184 differentially expressed proteins (DEPs) during flower development and maturity, respectively. Quantitative real time polymerase chain reactions were used for nine genes to verify DEPs from the iTRAQ approach. During flower development, DEPs were mainly involved in morphogenesis, biosynthetic processes, and metabolic pathways. At flower maturity, DEPs primarily participated in biosynthetic processes, metabolic pathways, and the formation of ribosomes and proteasomes. Additionally, some proteins associated with senescence and programmed cell death were found to be upregulated in S-morph pistils, which may lead to the lower fruit set in S-morph flowers. Although the exact roles of these related proteins are not yet known, this was the first attempt to use an iTRAQ approach to analyze proteomes of heterostylous eggplant flowers, and these results will provide insights into biochemical events taking place during the development of heterostyly. PMID- 28586358 TI - Parental alcohol use and risk of behavioral and emotional problems in offspring. AB - OBJECTIVE: The majority of studies that have examined parental alcohol use and offspring outcomes have either focused on exposure in the antenatal period or from clinical populations. This study sought to examine proximal and distal associations between parental alcohol use and offspring conduct problems and depressive symptoms in a population birth cohort. METHODS: We used prospective data from a large UK based population cohort (ALSPAC) to investigate the association between parental alcohol use, measured in units, (assessed at ages 4 and 12 years) with childhood conduct trajectories, (assessed on six occasions from 4 to 13.5 years, n = 6,927), and adolescent depressive symptoms (assessed on four occasions from ~13 to ~18 years, n = 5,539). Heavy drinking was defined as >=21 units per week in mothers and partners who drank 4+ units daily. RESULTS: We found little evidence to support a dose response association between parental alcohol use and offspring outcomes. For example, we found insufficient evidence to support an association between maternal alcohol use at age 4 years and childhood conduct problems (childhood limited: OR = 1.00, 95% CI = .99, 1.01; adolescent onset: OR = 0.99, 95% CI = .98, 1.00; and early-onset persistent: OR = 0.99, 95% CI = .98, 1.00) per 1-unit change in maternal alcohol use compared to those with low levels of conduct problems. We also found insufficient evidence to support an association between maternal alcohol use at age 4 years and adolescent depressive symptoms (intercept: b = .001, 95% CI = -.01, .01, and slope: b = .003, 95% CI = -.03, .03) per 1-unit change in maternal alcohol use. Results remained consistent across amount of alcohol consumed (i.e., number of alcohol units or heavy alcohol use), parent (maternal self-reports or maternal reports of partner's alcohol use), and timing of alcohol use (assessed at age 4 or age 12 years). CONCLUSIONS: There is no support for an association between parental alcohol use during childhood and conduct and emotional problems during childhood or adolescence. PMID- 28586361 TI - Parents' experience of perinatal post-mortem following stillbirth: A mixed methods study. AB - OBJECTIVES: To analyse quantitative and qualitative data, to describe the experience of parents in relation to post-mortem following stillbirth, looking at offer and uptake of post-mortem, information-giving, the type of post-mortem carried out, receiving the results and any sociodemographic differences in care practices in relation to post-mortem. DESIGN: Secondary analysis of a postal survey which included both open and closed questions allowing for a mixed methods study design. POPULATION: Random sample of women who experienced a stillbirth in 2013. METHODS: A sample of women who experienced a stillbirth in 2013 were selected by staff at the Office for National Statistics and sent a letter and information leaflet about the study followed by a postal questionnaire. The questionnaire included questions about pregnancy, labour and birth, the postnatal period, the time at which the baby died, and also asked about the post-mortem process. RESULTS: Completed questionnaires were received from 477 women. Overall, 95% of women were asked for consent to a post-mortem, almost half prior to birth, and half by a consultant. The majority of women received written information and felt sufficiently informed, and agreed to a full post-mortem. A third of women had to wait longer than 12 weeks for the post-mortem result and this was the most common theme in the free text comments. Women also commented on the manner of being asked for consent, and wrote about issues related to communication and support. There were significant differences between sociodemographic groups in many of these factors. CONCLUSIONS: The inconsistencies in offer and consent to post-mortem following stillbirth suggest inequality in this area. The amount of time that many parents have to wait for post-mortem results is unacceptable and should be prioritised for improvement. PMID- 28586362 TI - Fast and general tests of genetic interaction for genome-wide association studies. AB - A complex disease has, by definition, multiple genetic causes. In theory, these causes could be identified individually, but their identification will likely benefit from informed use of anticipated interactions between causes. In addition, characterizing and understanding interactions must be considered key to revealing the etiology of any complex disease. Large-scale collaborative efforts are now paving the way for comprehensive studies of interaction. As a consequence, there is a need for methods with a computational efficiency sufficient for modern data sets as well as for improvements of statistical accuracy and power. Another issue is that, currently, the relation between different methods for interaction inference is in many cases not transparent, complicating the comparison and interpretation of results between different interaction studies. In this paper we present computationally efficient tests of interaction for the complete family of generalized linear models (GLMs). The tests can be applied for inference of single or multiple interaction parameters, but we show, by simulation, that jointly testing the full set of interaction parameters yields superior power and control of false positive rate. Based on these tests we also describe how to combine results from multiple independent studies of interaction in a meta-analysis. We investigate the impact of several assumptions commonly made when modeling interactions. We also show that, across the important class of models with a full set of interaction parameters, jointly testing the interaction parameters yields identical results. Further, we apply our method to genetic data for cardiovascular disease. This allowed us to identify a putative interaction involved in Lp(a) plasma levels between two 'tag' variants in the LPA locus (p = 2.42 ? 10-09) as well as replicate the interaction (p = 6.97 ? 10-07). Finally, our meta-analysis method is used in a small (N = 16,181) study of interactions in myocardial infarction. PMID- 28586364 TI - Intracellular zinc flux causes reactive oxygen species mediated mitochondrial dysfunction leading to cell death in Leishmania donovani. AB - Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection. Zinc is crucial for cellular growth and disruption in its homeostasis hinders growth and survival in many cells. However, little is known about the role of zinc in Leishmania growth and survival. In this study, the effect of zinc on the growth and survival of L.donovani was analyzed by both Zinc depletion and Zinc-supplementation using Zinc-specific chelator N, N, N', N' tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) and Zinc Sulfate (ZnSO4). Treatment of parasites with TPEN rather than ZnSO4 had significantly affected the growth in a dose- and time-dependent manner. The pre-treatment of promastigotes with TPEN resulted into reduced host-parasite interaction as indicated by decreased association index. Zn depletion resulted into flux in intracellular labile Zn pool and increased in ROS generation correlated with decreased intracellular total thiol and retention of plasma membrane integrity without phosphatidylserine exposure in TPEN treated promastigotes. We also observed that TPEN-induced Zn depletion resulted into collapse of mitochondrial membrane potential which is associated with increase in cytosolic calcium and cytochrome c. DNA fragmentation analysis showed increased DNA fragments in Zn-depleted cells. In summary, intracellular Zn depletion in the L. donovani promastigotes led to ROS-mediated caspase-independent mitochondrial dysfunction resulting into apoptosis-like cell death. Therefore, cellular zinc homeostasis in Leishmania can be explored for new drug targets and chemotherapeutics to control Leishmanial growth and disease progression. PMID- 28586365 TI - Trait variation and genetic diversity in a banana genomic selection training population. AB - Banana (Musa spp.) is an important crop in the African Great Lakes region in terms of income and food security, with the highest per capita consumption worldwide. Pests, diseases and climate change hamper sustainable production of bananas. New breeding tools with increased crossbreeding efficiency are being investigated to breed for resistant, high yielding hybrids of East African Highland banana (EAHB). These include genomic selection (GS), which will benefit breeding through increased genetic gain per unit time. Understanding trait variation and the correlation among economically important traits is an essential first step in the development and selection of suitable GS models for banana. In this study, we tested the hypothesis that trait variations in bananas are not affected by cross combination, cycle, field management and their interaction with genotype. A training population created using EAHB breeding material and its progeny was phenotyped in two contrasting conditions. A high level of correlation among vegetative and yield related traits was observed. Therefore, genomic selection models could be developed for traits that are easily measured. It is likely that the predictive ability of traits that are difficult to phenotype will be similar to less difficult traits they are highly correlated with. Genotype response to cycle and field management practices varied greatly with respect to traits. Yield related traits accounted for 31-35% of principal component variation under low and high input field management conditions. Resistance to Black Sigatoka was stable across cycles but varied under different field management depending on the genotype. The best cross combination was 1201K 1xSH3217 based on selection response (R) of hybrids. Genotyping using simple sequence repeat (SSR) markers revealed that the training population was genetically diverse, reflecting a complex pedigree background, which was mostly influenced by the male parents. PMID- 28586363 TI - Preoperative serum cystatin-C as a potential biomarker for prognosis of renal cell carcinoma. AB - PURPOSE: The prognostic value of serum cystatin-C (Cys-C) in renal cell carcinoma (RCC) remains unknown. The purpose of this study is to explore the prognostic value of Cys-C for RCC patients. PATIENTS AND METHODS: The levels of preoperative Cys-C, creatinine (CRE) and estimated glomerular filtration rate (e-GFR) were retrospectively collected in 325 RCC patients undergoing surgery. The cutoff values of Cys-C, CRE and e-GFR were determined by the standardized Cutoff Finder algorithm. The receiver operating characteristic (ROC) curve and pairwise comparison were performed to compare the three variables. Univariate and multivariate Cox regression analyses were performed to investigate the prognostic value of serum Cys-C in RCC. RESULTS: Based on the analysis of Cutoff Finder algorithm, ROC curve and pairwise comparison, the preoperative Cys-C was superior to CRE and e-GFR as a predictive factor in RCC. Multivariate Cox regression analyses showed that high preoperative Cys-C (>1.09 mg/L) was significantly associated with shorter overall survival (OS) in all RCC patients (hazard ratio [HR], 1.59; P = 0.012), patients at pT1-2 (P<0.001), pN0 (P<0.001) and pM0 stages (P<0.001). Moreover, Multivariate Cox regression analyses also showed that in the 306 patients without metastasis, high preoperative Cys-C was also associated with shorter disease-free survival (DFS) (HR, 3.50; P = 0.013). CONCLUSIONS: An elevated preoperative Cys-C level was demonstrated to be related with worse survival in patients with RCC. Measuring preoperative serum Cys-C might be a simple way for finding poor prognostic patients and patients with elevated preoperative Cys-C level should be more closely followed up. PMID- 28586367 TI - Maternal region of birth and stillbirth in Victoria, Australia 2000-2011: A retrospective cohort study of Victorian perinatal data. AB - BACKGROUND: There is growing evidence from high-income countries that maternal country of birth is a risk factor for stillbirth. We aimed to examine the association between maternal region of birth and stillbirth between 2000 and 2011 inclusive in Victoria, Australia. METHODS: Retrospective population based cohort study of all singleton births at 24 or more weeks gestational age from 2000-2011 in Victoria, Australia. Stillbirths due to termination of pregnancy, babies with congenital anomalies and Indigenous mothers were excluded. Main Outcome Measure: Stillbirth. RESULTS: Over the 12-year period there were 685,869 singleton births and 2299 stillbirths, giving an overall stillbirth rate of 3.4 per 1000 births. After adjustment for risk factors, compared to women born in Australia/New Zealand, women born in South Asia (aOR 1.27, 95% CI 1.01-1.53, p = 0.01), were more likely to have a stillbirth whereas women born in South East and East Asia were (aOR 0.60, (95% CI 0.49-0.72, p<0.001) less likely to have a stillbirth. Additionally, the increasing rate of stillbirth as gestation length progressed began to rise earlier and more steeply in the South Asian compared to Australian/New Zealand born women. The following risk factors were also significantly associated with an increased odds of stillbirth in multivariate analyses: maternal age <20 and 35 years and more, nulliparity, low socio-economic status, previous stillbirth, no ultrasound reported in 1st trimester, pre existing hypertension, antepartum haemorrhage and failure to detect growth restriction antenatally. CONCLUSION: Maternal region of birth is an independent risk factor for stillbirth. Improvements in the rate of stillbirth, particularly late pregnancy stillbirth, are likely to be gained in high-income settings where clinical care is informed by maternal region of birth. PMID- 28586366 TI - Sagittal spino-pelvic alignment in adults: The Wakayama Spine Study. AB - OBJECTIVES: To establish the normal values of spino-pelvic alignment and to clarify the effect of age-related changes using large, community-based cohorts. METHODS: In this study, data from 1461 participants (466 men, 995 women) were analyzed. On lateral standing radiographs, the following parameters were measured: thoracic kyphosis (TK), lumbar lordosis (LL), pelvic tilt (PT), pelvic incidence (PI), and C7 sagittal vertical axis (SVA). All values are expressed as the mean+/-standard deviation. The Spearman rank correlation coefficient was used to examine correlations between variables of spino-pelvic parameters. Finally, we analyzed the relationship between age and spino-pelvic parameters. Therefore, we entered values for the body mass index (BMI), SVA, TK, and PI-LL into a multiple regression model to adjust for potential confounding factors. RESULTS: The SVA, TK, and PT increased with age, and LL decreased with age. Regarding sex differences, the TK was statistically significantly larger in men than in women, and LL, PT, and PI were statistically significantly smaller in men than in women. Correlation coefficients between the SVA and TK, between the SVA and PI-LL, and between TK and PI-LL were none, strong, and weak, respectively. Results of multiple regression analysis between age and spino-pelvic parameters showed that the standardized partial regression coefficients for the SVA, TK, and PI-LL were 0.17, 0.30, and 0.23, respectively, in men and 0.29, 0.32, and 0.23, respectively, in women. CONCLUSIONS: We found that all parameters were significantly associated with age in men and women. The SVA, TK, and PT increased with age, and LL decreased with age. Results of multiple regression analysis also demonstrated that the SVA, TK, and PI-LL are related to age. Indeed, the PI-LL value increased with age. In this study, a more excessive PI-LL mismatch was shown, indicating an increased risk of spinal malalignment. Differences in the absolute values of spino-pelvic parameters in each sex were small yet statistically significant. Thus, further study should be performed to corroborate this finding. PMID- 28586368 TI - Stabilization of lead in incineration fly ash by moderate thermal treatment with sodium hydroxide addition. AB - Municipal solid waste (MSW) incineration fly ash (IFA) can be potentially reused as a substitute for some raw materials, but treatment for detoxification is indispensable owing to high contents of heavy metals in fly ash. In the present work, due to excessive leaching concentration of lead (Pb), a moderate thermal treatment with sodium hydroxide (NaOH) addition was employed to stabilize Pb in IFA. The moderate thermal treatment was performed under relatively low temperature ranging from 300 to 500 degrees C and at retention time from 1 to 3 h with NaOH addition in a range of 1 to 9%. Leaching results showed that leaching concentrations of Pb in IFA leachates decreased below the standard for hazardous waste identification (5 mg/L) in China under all treatment scenarios. With the increase of temperature, retention time and the amount of NaOH, the concentration of Pb were further suppressed in IFA leachates. Especially, at 500 degrees C for 3 h with 9% NaOH addition, the concentration of Pb dropped to 0.18 mg/L, which was below the standard for sanitary landfill (0.25 mg/L) in China. In thermal process, needle-like crystallites melted to form granules and clumps with compacter structure and less pores. After the thermal treatment, water-soluble and exchangeable fractions of Pb significantly decreased. Therefore, the thermal treatment coupled with NaOH could be applied to realize the environmentally sound management of MSW IFA. PMID- 28586369 TI - Synthesis and biochemical characterization of EGF receptor in a water-soluble membrane model system. AB - ErbB (Erythroblastic Leukemia Viral Oncogene Homolog) receptor tyrosine kinases are critical for tissue development and maintenance, and frequently become oncogenic when mutated or overexpressed. In vitro analysis of ErbB receptor kinases can be difficult because of their large size and poor water solubility. Here we report improved production and assembly of the correctly folded full length EGF receptor (EGFR) into nanolipoprotein particles (NLPs). NLPs are ~10 nm in diameter discoidal cell membrane mimics composed of apolipoproteins surrounding a lipid bilayer. NLPs containing EGFR were synthesized via incubation of baculovirus-produced recombinant EGFR with apolipoprotein and phosphoplipids under conditions that favor self-assembly. The resulting EGFR-NLPs were the correct size, formed dimers and multimers, had intrinsic autophosphorylation activity, and retained the ability to interact with EGFR-targeted ligands and inhibitors consistent with previously-published in vitro binding affinities. We anticipate rapid adoption of EGFR-NLPs for structural studies of full-length receptors and drug screening, as well as for the in vitro characterization of ErbB heterodimers and disease-relevant mutants. PMID- 28586370 TI - Long-term tremor therapy for Parkinson and essential tremor with sensor-guided botulinum toxin type A injections. AB - OBJECTIVE: Current pharmacological agents used to treat Parkinson disease (PD) tremor and essential tremor (ET) provide suboptimal benefit and are commonly associated with significant adverse effects. Botulinum toxin type A (BoNT-A) has been shown to be effective for wrist tremor though functionally bothersome muscle weakness frequently occurs. This is the longest study to date demonstrating that BoNT-A therapy coupled with kinematic guidance can provide efficacious outcomes for upper limb tremor with minimized unwanted weakness. METHODS: A total of 28 PD and 24 ET participants with bothersome, disabling tremor, received six serial BoNT-A treatments every 16 weeks starting at week 0 with a follow-up visit 6 weeks following a treatment, totaling 96 weeks. Clinical scales, including Fahn Tolosa-Marin tremor rating scale (FTM), and sensor-based tremor assessments were conducted at each visit. Kinematics was utilized to identify which arm muscles contributed to the tremulous movements and the experienced injector used clinical expertise in determining BoNT-A dosages. RESULTS: Following BoNT-A treatment, clinical ratings of tremor severity and functional ability (FTM) showed significant improvements following the first treatment which was maintained up to week 96 in PD and ET. Kinematics detected a significant reduction in PD and ET tremor amplitudes by 70% and 76% over the treatment course, respectively. By objectively distinguishing tremulous muscles and tremor severity, adverse effects were limited to mild perceived weakness by participants in injected muscles during follow-ups. Following the fourth treatment, BoNT-A dosages in flexor and extensor wrist muscles and biceps were reduced for those experiencing residual weakness which ultimately did not interfere with tremor relief or arm function. CONCLUSIONS: Kinematics is an objective method that can aid clinicians in assessing and determining optimal BoNT-A parameters to alleviate both PD and ET tremor. BoNT-A injections are tolerable and effective when focal therapy regimens are determined and optimized kinematically over a long-term. PMID- 28586372 TI - A novel tri-band T-junction impedance-transforming power divider with independent power division ratios. AB - In this paper, a novel L network (LN) is presented, which is composed of a frequency-selected section (FSS) and a middle stub (MS). Based on the proposed LN, a tri-band T-junction power divider (TTPD) with impedance transformation and independent power division ratios is designed. Moreover, the closed-form design theory of the TTPD is derived based on the transmission line theory and circuit theory. Finally, a microstrip prototype of the TTPD is simulated, fabricated, and measured. The design is for three arbitrarily chosen frequencies, 1 GHz, 1.6 GHz, and 2.35 GHz with the independent power division ratios of 0.5, 0.7, and 0.9. The measured results show that the fabricated prototype is consistent with the simulation, which demonstrates the effectiveness of this proposed design. PMID- 28586371 TI - Opium and bladder cancer: A systematic review and meta-analysis of the odds ratios for opium use and the risk of bladder cancer. AB - OBJECTIVE: The association between opium use and bladder cancer has been investigated in many studies, with varying reporting results reported. This study aims to estimate the total odds ratio for the association between bladder cancer and opium consumption using meta-analysis. METHODS: The study was designed according to PRISMA guidelines. Two independent researchers searched for the relevant studies using PubMed, Web of Science, Scopus, OVID, Embase, and Google Scholar. After systematic screening of the studies identified during the first step, Cochrane risk of bias tool was determined for the selected studies. The case-control and the cohort studies were investigated to assess risk of bladder cancer due to opium use. In addition, the cross-sectional studies were analysed separately to assess frequency of opium consumption. These estimates were combined using the inverse variance method. Fixed or random effect models were applied to combine the point odds ratios. The heterogeneity between the primary results was assessed using the Cochran test and I-square index. The suspected factors for heterogeneity were investigated using meta-regression models. An Egger test was conducted to identify any probable publication bias. Forest plots illustrated the point and pooled estimates. All analyses were performed using Stata version 14 software and RevMan version 5.3. RESULTS: We included 17 primary studies (11 case-control, one cohort and five cross-sectional) in the final meta analysis. The total odds ratios (95% confidence intervals) for developing bladder cancer by opium use alone, and concurrent use of opium and cigarettes were estimated as 3.85 (3.05-4.87) and 5.7 (1.9-16.3) respectively. The odds ratio (95% confidence interval) for opium use with or without cigarette smoking was estimated as 5.3 (3.6-7.7). CONCLUSION: This meta-analysis showed that opium use similar to cigarette smoking and maybe with similar mechanisms can be a risk factor for bladder cancer. It is therefore expected to be a risk factor for other cancers. PMID- 28586374 TI - Nocturnal leg cramps: Prevalence and associations with demographics, sleep disturbance symptoms, medical conditions, and cardiometabolic risk factors. AB - BACKGROUND: Nocturnal leg cramps (NLC) are common and poorly understood. OBJECTIVE: To determine the prevalence of NLC and associations with cardiometabolic, sleep, and behavioral risk factors in the US population. DESIGN: Cross-sectional epidemiology. PARTICIPANTS: National Health and Nutrition Examination Survey, 2005-2006 and 2007-2008 waves. MAIN OUTCOME(S) AND MEASURE(S): NLC were assessed with, "In the past month, how often did you have leg cramps while trying to sleep?" Responses were categorized as None, Mild, or Moderate-Severe. Demographics, medical history, sleep disturbances, and cardiometabolic risk factors were evaluated using the 2005-2006 dataset. Variables that demonstrated significant relationships to NLC after adjusting for age, sex, education, and BMI were assessed in the 2007-2008 dataset. Variables that were still significant were entered into a forward stepwise regression model combining both waves, to determine which variables best explained the variance in NLC. RESULTS: Prevalence was 24-25% reporting mild and 6% reporting moderate severe NLC. NLC increased with age, lower education, unemployment, shorter sleep duration, all assessed sleep symptoms (nocturnal "leg jerks", snoring, snorting/gasping, difficulty falling asleep, difficulty maintaining sleep, non restorative sleep, sleepiness, use of sleep medications), higher BMI, smoking, medical history (hypertension, heart failure, angina, stroke, arthritis, respiratory disease, and cancer), depression symptoms, and biomarkers (CRP, HbA1c, calcium, cadmium, red blood cells). Stepwise analysis showed that moderate severe nocturnal leg cramps were associated with (in decreasing order of partial R2): leg jerks, poor overall health, arthritis, difficulty falling asleep, age, nonrestorative sleep, red blood cell count, lower education, angina, and difficulty maintaining sleep. CONCLUSIONS AND RELEVANCE: Based on this first large, representative study, NLC occurring >5x per month are reported by 6% of the adult US population. Sleep disturbance symptoms and health conditions are associated with higher frequency of NLC, suggesting that NLC is a marker, and possibly contributor, to poor sleep and general health. PMID- 28586373 TI - Age and preoperative pain are major confounders for sex differences in postoperative pain outcome: A prospective database analysis. AB - OBJECTIVES: Current literature is in disagreement regarding female sex as a risk factor for pain after surgery. We hypothesized, that sex differences exist but that they are influenced by certain factors. Here, we investigated the influence of sex for different clinically relevant postoperative pain (POP) outcome parameters and evaluated the role of assumed confounders for sex differences. METHODS: From 1372 screened patients undergoing orthopedic surgery at the university hospital of Muenster between March 2010 and June 2011, 890 patients were included. The validated International Pain Outcomes questionnaire was used to assess the role of sex for several aspects of POP including pain severity, physical and emotional functional interference as well as the patient's perceptions of the care they received on the first day after surgery. Assessed confounders were age, preoperative chronic pain, anesthetic technique employed and surgical procedure. All statistical analyses were performed with SPSS Statistics Software 22. RESULTS: Linear regression analysis demonstrated that sex was a statistically significant risk factor for "worst pain since surgery". Additionally, significant sex differences in "time spent in severe pain", "feeling anxious due to pain", "feeling helpless due to pain" and "opioid consumption since surgery" could be identified. An univariate general linear model showed that "age" and "preoperative pain" were significant confounders for sex differences. Further descriptive subgroup analysis revealed consistent sex differences for several POP outcome variables especially in patients older than 50 years or patients with preoperative chronic pain. However, sex differences disappeared in younger patients and in patients without preoperative pain. DISCUSSION: Our data confirmed that sex differences exist in pain intensity and frequency, pain interference with feelings and opioid consumption during the first 24 hours postoperatively. However, sex differences were significantly influenced by the factors "age" and "preoperative pain". These findings may in part explain why clinical studies get different results related to sex differences and renders specific awareness in older women and female patients with preoperative chronic pain. PMID- 28586375 TI - Performance analysis of a new hypersonic vitrector system. AB - PURPOSE: To evaluate porcine vitreous flow and water flow rates in a new prototype hypersonic vitrectomy system compared to currently available pneumatic guillotine vitrectors (GVs) systems. METHODS: Two vitrectors were tested, a prototype, ultrasound-powered, hypersonic vitrector (HV) and a GV. Porcine vitreous was obtained within 12 to 24 h of sacrifice and kept at 4 degrees C. A vial of vitreous or water was placed on a precision balance and its weight measured before and after the use of each vitrector. Test parameters included changes in aspiration levels, vitrector gauge, cut rates for GVs, % ultrasound (US) power for HVs, and port size for HVs. Data was analysed using linear regression and t-tests. RESULTS: There was no difference in the total average mean water flow between the 25-gauge GV and the 25-gauge HV (t-test: P = 0.363); however, 25-gauge GV was superior (t-test: P < 0.001) in vitreous flow. The 23 gauge GV was only more efficient in water and vitreous removal than 23-gauge HV needle-1 (Port 0.0055) (t-test: P < 0.001). For HV, wall thickness and gauge had no effect on flow rates. Water and vitreous flows showed a direct correlation with increasing aspiration levels and % US power (p<0.05). CONCLUSIONS: The HV produced consistent water and vitreous flow rates across the range of US power and aspiration levels tested. Hypersonic vitrectomy may be a promising new alternative to the currently available guillotine-based technologies. PMID- 28586376 TI - Oncologic and surgical outcomes in colorectal cancer patients with liver cirrhosis: A propensity-matched study. AB - The management of colorectal cancer in patients with liver cirrhosis requires a thorough understanding of both diseases. This study evaluated the effect of liver cirrhosis on oncologic and surgical outcomes and prognostic factors in colorectal cancer patients. Fifty-five consecutive colorectal cancer patients with liver cirrhosis underwent colorectal resection (LC group). Using a prospectively maintained database, these patients were matched 1:4 using propensity scoring with R programming language, package "MatchIt" and "optmatch" by sex, age, cancer location, and tumor stage with 220 patients without liver cirrhosis (non-LC group), resulting in 275 patients. The 5-year overall survival (OS) was significantly worse in the LC group than in the non-LC group (46.7% vs. 76.2% respectively, P < 0.001); however, the 5-year proportion of recurrence free (PRF) rates were similar (73.1% vs. 84.5% respectively, P = 0.094). On multivariate analysis of the LC group, tumor-node-metastasis (TNM) stage >=III disease, venous invasion, and a model for end-stage liver disease plus serum sodium (MELD-Na) score >10 were prognostic factors for OS. However, the OS was not different between the LC group with MELD-Na score <=10 and the non-LC group (5-year OS rate, TNM stage <=II, 85.7 vs 89.5%, p = 0.356; TNM stage >=III, 41.1 vs 66.2%, p = 0.061). Colorectal cancer patients with liver cirrhosis have poorer OS compared to those without liver cirrhosis; however, the PRF rates are similar. It might be due to the mortality from the liver, and surgical treatment should be actively considered for patients with MELD-Na score <10. PMID- 28586377 TI - Psychometric properties of a Power Mobility Caregiver Assistive Technology Outcome Measure. AB - Caregiver burnout is a serious concern among informal caregivers, especially for those who provide care to individuals with more severe limitations such as power mobility users. The Power Wheelchair Caregiver Assistive Technology Outcome Measure tool measures device specific and overall burden experienced by informal caregivers of power mobility users. A one-month, test-retest study was conducted to examine the reliability, internal consistency, and construct validity of the Power Wheelchair Caregiver Assistive Technology Outcome Measure. Two construct validity measures were administered: the Hospital Anxiety and Depression Scale and the Late Life Disability Index. The test-retest-reliabilities of part 1 (power wheelchair specific burden) and part 2 (general caregiving burden) were 0.769 and 0.843 respectively. Scores on part 1 were moderately and positively correlated with part 2 and with frequency of participation. Scores on part 2 were moderately and negatively correlated with anxiety, depression, and positively with perceived limitation of participation. The strength and direction of these correlations provide support for the construct validity of the measure and suggest part 1 and part 2 provide complementary information. Further testing is needed to assess the clinical utility and responsiveness of the measure. PMID- 28586378 TI - Quantification of gammadelta T cells and HLA-DR+ NK cells does not predict emergence of new contrast enhancing lesions in MS patients suspending natalizumab treatment. AB - BACKGROUND: Natalizumab (NTZ) is a drug that has been widely used in the treatment of multiple sclerosis (MS). NTZ is very effective in suppressing inflammation, but if treatment is suspended many patients will experience relapses. OBJECTIVE: To investigate if quantification of gammadelta T cells and HLA-DR+ NK cells could predict early disease reactivation after NTZ suspension. METHODS: Absolute counts of gammadelta T cells and HLA-DR+ NK cells in whole blood were determined with flow cytometry in fifteen patients treated with NTZ. NTZ treatment was then withdrawn and patients were followed with clinical visits and MR investigations. RESULTS: Patients with recurrent disease had higher absolute counts of gammadelta T cells 129 (+/-156) cells/MUl in comparison to patients with stable disease 50.0 (+/-51.0) cells/MUl but the difference was not statistically significant and largely driven by outliers. Patients with recurrent and stable disease had similar absolute counts of HLA-DR+ NK cells. CONCLUSION: Quantification of gammadelta T cells and HLA-DR+ NK cells could not predict active disease after NTZ suspension. PMID- 28586380 TI - Correction: Micro-level explanations for emergent patterns of self-governance arrangements in small-scale fisheries-A modeling approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0175532.]. PMID- 28586379 TI - LAMP-2 absence interferes with plasma membrane repair and decreases T. cruzi host cell invasion. AB - Trypanosoma cruzi enters host cells by subverting the mechanism of cell membrane repair. In this process, the parasite induces small injuries in the host cell membrane leading to calcium entry and lysosomal exocytosis, which are followed by compensatory endocytosis events that drive parasites into host cells. We have previously shown that absence of both LAMP-1 and 2, major components of lysosomal membranes, decreases invasion of T. cruzi into host cells, but the mechanism by which they interfere with parasite invasion has not been described. Here we investigated the role of these proteins in parasitophorous vacuole morphology, host cell lysosomal exocytosis, and membrane repair ability. First, we showed that cells lacking only LAMP-2 present the same invasion phenotype as LAMP1/2-/- cells, indicating that LAMP-2 is an important player during T. cruzi invasion process. Second, neither vacuole morphology nor lysosomal exocytosis was altered in LAMP-2 lacking cells (LAMP2-/- and LAMP1/2-/- cells). We then investigated the ability of LAMP-2 deficient cells to perform compensatory endocytosis upon lysosomal secretion, the mechanism by which cells repair their membrane and T. cruzi ultimately enters cells. We observed that these cells perform less endocytosis upon injury when compared to WT cells. This was a consequence of impaired cholesterol traffic in cells lacking LAMP-2 and its influence in the distribution of caveolin-1 at the cell plasma membrane, which is crucial for plasma membrane repair. The results presented here show the major role of LAMP-2 in caveolin traffic and membrane repair and consequently in T. cruzi invasion. PMID- 28586381 TI - Correction: Return Customers: Foraging Site Fidelity and the Effect of Environmental Variability in Wide-Ranging Antarctic Fur Seals. AB - [This corrects the article DOI: 10.1371/journal.pone.0120888.]. PMID- 28586382 TI - Vibrio cholerae ensures function of host proteins required for virulence through consumption of luminal methionine sulfoxide. AB - Vibrio cholerae is a diarrheal pathogen that induces accumulation of lipid droplets in enterocytes, leading to lethal infection of the model host Drosophila melanogaster. Through untargeted lipidomics, we provide evidence that this process is the product of a host phospholipid degradation cascade that induces lipid droplet coalescence in enterocytes. This infection-induced cascade is inhibited by mutation of the V. cholerae glycine cleavage system due to intestinal accumulation of methionine sulfoxide (MetO), and both dietary supplementation with MetO and enterocyte knock-down of host methionine sulfoxide reductase A (MsrA) yield increased resistance to infection. MsrA converts both free and protein-associated MetO to methionine. These findings support a model in which dietary MetO competitively inhibits repair of host proteins by MsrA. Bacterial virulence strategies depend on functional host proteins. We propose a novel virulence paradigm in which an intestinal pathogen ensures the repair of host proteins essential for pathogenesis through consumption of dietary MetO. PMID- 28586383 TI - At-risk and intervention thresholds of occupational stress using a visual analogue scale. AB - BACKGROUND: The visual analogue scale (VAS) is widely used in clinical practice by occupational physicians to assess perceived stress in workers. However, a single cut-off (black-or-white decision) inadequately discriminates between workers with and without stress. We explored an innovative statistical approach to distinguish an at-risk population among stressed workers, and to establish a threshold over which an action is urgently required, via the use of two cut-offs. METHODS: Participants were recruited during annual work medical examinations by a random sample of workers from five occupational health centres. We previously proposed a single cut-off of VAS stress in comparison with the Perceived Stress Scale (PSS14). Similar methodology was used in the current study, along with a gray zone approach. The lower limit of the gray zone supports sensitivity ("at risk" threshold; interpreted as requiring closer surveillance) and the upper limit supports specificity (i.e. "intervention" threshold-emergency action required). RESULTS: We included 500 workers (49.6% males), aged 40+/-11 years, with a PSS14 score of 3.8+/-1.4 and a VAS score of 4.0+/-2.4. Using a receiver operating characteristic curve and the PSS cut-off score of 7.2, the optimal VAS threshold was 6.8 (sensitivity = 0.89, specificity = 0.87). The lower and upper thresholds of the gray zone were 5 and 8.2, respectively. CONCLUSIONS: We identified two clinically relevant cut-offs on the VAS of stress: a first cut-off of 5.0 for an at-risk population, and a second cut-off of 8.2 over which an action is urgently required. Future investigations into the relationships between this upper threshold and deleterious events are required. PMID- 28586384 TI - Multi-level characterization of balanced inhibitory-excitatory cortical neuron network derived from human pluripotent stem cells. AB - Generation of neuronal cultures from induced pluripotent stem cells (hiPSCs) serve the studies of human brain disorders. However we lack neuronal networks with balanced excitatory-inhibitory activities, which are suitable for single cell analysis. We generated low-density networks of hPSC-derived GABAergic and glutamatergic cortical neurons. We used two different co-culture models with astrocytes. We show that these cultures have balanced excitatory-inhibitory synaptic identities using confocal microscopy, electrophysiological recordings, calcium imaging and mRNA analysis. These simple and robust protocols offer the opportunity for single-cell to multi-level analysis of patient hiPSC-derived cortical excitatory-inhibitory networks; thereby creating advanced tools to study disease mechanisms underlying neurodevelopmental disorders. PMID- 28586385 TI - Receptor-transporting protein (RTP) family members play divergent roles in the functional expression of odorant receptors. AB - Receptor transporting protein (RTP) family members, RTP1S and RTP2, are accessory proteins to mammalian odorant receptors (ORs). They are expressed in the olfactory sensory neurons and facilitate OR trafficking to the cell-surface membrane and ligand-induced responses in heterologous cells. We previously identified different domains in RTP1S that are important for different stages of OR trafficking, odorant-mediated responses, and interaction with ORs. However, the exact roles of RTP2 and the significance of the requirement of the seemingly redundant co-expression of the two RTP proteins in vivo have received less attention in the past. Here we attempted to dissect the functional differences between RTP1S and RTP2 using a HEK293T cell-based OR heterologous expression system. When a set of 24 ORs were tested against 28 cognate ligands, unlike RTP1S, which always showed a robust ability to support odorant-mediated responses, RTP2 had little or no effect on OR responses and exhibited a suppressive effect over that of RTP1S for a subset of the ORs tested. RTP1S and RTP2 showed no significant difference in OR ligand selectivity and co transfection with RTP2 increased the detection threshold for some ORs. A protein protein interaction analysis showed positive interactions among OR, RTP1S, and RTP2, corroborating the functional linkages among the three molecules. Finally, further cell-surface and permeabilized immunocytochemical studies revealed that OR and the co-expressed RTP1S proteins were retained in the Golgi when co transfected with RTP2, indicating that RTP1S and RTP2 could play different roles in the OR trafficking process. By examining the functional differentiations between the two RTP family members, we provided a molecular level explanation to the suppressive effect exerted by RTP2, shedding light on the divergent mechanisms underlying the RTP proteins in regulating the functional expression of ORs. PMID- 28586386 TI - Differential Th17 response induced by the two clades of the pandemic ST258 Klebsiella pneumoniae clonal lineages producing KPC-type carbapenemase. AB - The spread of KPC-type carbapenemases is mainly attributed to the global dissemination of Klebsiella pneumoniae (KP) strains belonging to the clonal group (CG) 258, including sequence type (ST) 258 and other related STs. Two distinct clades of CG258-KP have evolved, which differ mainly for the composition of their capsular polysaccharides, and recent studies indicate that clade 1 evolved from an ancestor of clade 2 by recombination of a genomic fragment carrying the capsular polysaccharide (cps) locus. In this paper, we investigated the ability of two ST258-KP strains, KKBO-1 and KK207-1, selected as representatives of ST258 KP clade 2 and clade 1, respectively, to activate an adaptive immune response using ex vivo-stimulation of PBMC from normal donors as an experimental model. Our data showed that KKBO-1 (clade 2) induces a Th17 response more efficiently than KK207-1 (clade 1): the percentage of CD4+IL17+ cells and the production of IL-17A were significantly higher in cultures with KKBO-1 compared to cultures with KK207-1. While no differences in the rate of bacterial internalization or in the bacteria-induced expression of CD86 and HLA-DR by monocytes and myeloid dendritic cells were revealed, we found that the two strains significantly differ in inducing the production of cytokines involved in the adaptive immune response, as IL-1beta, IL-23 and TNF-alpha, by antigen-presenting cells, with KKBO-1 being a more efficient inducer than KK207-1. The immune responses elicited by KK207-1 were comparable to those elicited by CIP 52.145, a highly virulent K. pneumoniae reference strain known to escape immune-inflammatory responses. Altogether, present results suggest that CG258-KP of the two clades are capable of inducing a different response of adaptive immunity in the human host. PMID- 28586387 TI - Salsalate ameliorates metabolic disturbances by reducing inflammation in spontaneously hypertensive rats expressing human C-reactive protein and by activating brown adipose tissue in nontransgenic controls. AB - Chronic low-grade inflammation plays an important role in the pathogenesis of insulin resistance. In the current study, we tested the effects of salsalate, a non-steroidal anti-inflammatory drug, in an animal model of inflammation and metabolic syndrome using spontaneously hypertensive rats (SHR) that transgenically express human C-reactive protein (SHR-CRP rats). We treated 15 month-old male transgenic SHR-CRP rats and nontransgenic SHR with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP and SHR rats were fed a standard diet without salsalate. In the SHR-CRP transgenic strain, salsalate treatment decreased circulating concentrations of the inflammatory markers TNF alpha and MCP-1, reduced oxidative stress in the liver and kidney, increased sensitivity of skeletal muscles to insulin action and improved tolerance to glucose. In SHR controls with no CRP-induced inflammation, salsalate treatment reduced body weight, decreased concentrations of serum free fatty acids and total and HDL cholesterol and increased palmitate oxidation and incorporation in brown adipose tissue. Salsalate regulated inflammation by affecting the expression of genes from MAPK signalling and NOD-like receptor signalling pathways and lipid metabolism by affecting hepatic expression of genes that favour lipid oxidation from PPAR-alpha signalling pathways. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation. PMID- 28586388 TI - A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy. AB - BACKGROUND: Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. METHODS: Twelve patients with SCLC were enrolled after failing platinum based chemotherapy. Following informed consent, genome-wide exome and RNA sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. RESULTS: The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. CONCLUSIONS: Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes. PMID- 28586390 TI - Detection of genome-edited mutant clones by a simple competition-based PCR method. AB - Genome editing by the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats / CRISPR-associated protein 9) system is a revolutionary strategy to study gene functions. Since the efficiency of gene disruption in cell culture does not reach 100% typically, cloning of mutant cells is often performed to obtain fully mutated cells. Therefore, a method to discriminate accurately mutated clones easily and quickly is crucial to accelerate the research using CRISPR/Cas9. Here, we show that knockout cells can be discriminated by a competition-based PCR, using a mixture of three primers, among which one primer overlaps with the Cas9 cleavage site. Together, we show how to optimize primer design in order to improve the effectiveness of the discrimination. Finally, we applied this method to show that mutations conferring drug resistance can be detected with high accuracy. The provided method is easy to perform and requires only basic laboratory equipment, making it suitable for almost all laboratories. PMID- 28586389 TI - Characterization of the species Malassezia pachydermatis and re-evaluation of its lipid dependence using a synthetic agar medium. AB - The genus Malassezia includes lipophilic yeasts, which are part of the skin microbiota of various mammals and birds. Unlike the rest of Malassezia species, M. pachydermatis is described as non-lipid-dependent, as it is able to grow on Sabouraud glucose agar (SGA) without lipid supplementation. In this study we have examined the phenotypic variability within M. pachydermatis and confirmed its lipid-dependent nature using a synthetic agar medium. We used a selection of representative non-lipid-dependent strains from different animal species and three atypical lipid-dependent strains of this species, which were not able to grow after multiple passages on SGA. More than 400 lipid-dependent Malassezia isolates from animals were studied in order to detect the three lipid-dependent strains of M. pachydermatis. The identity of the atypical strains was confirmed by DNA sequencing. On the other hand, we have modified the Tween diffusion test, which is widely used in the characterization of these yeasts, by using a synthetic agar-based medium instead of SGA. This modification has proved to be useful for differentiation of M. pachydermatis strains, providing reproducible results and a straightforward interpretation. The finding of these peculiar lipid dependent strains exemplifies the large variability within the species M. pachydermatis, which involves rare atypical strains with particular growth requirements. PMID- 28586391 TI - Affective temperament, job stress and professional burnout in nurses and civil servants. AB - INTRODUCTION: The risk of professional burnout is constituted by job-related as well as individual factors. The latter involve affective temperament, which influences the perception of job-related stress. The aim of the present study was to assess the affective temperament, the level of job stress and professional burnout, as well as the relationships between these variables, in public servants and nurses. MATERIAL AND METHODS: 100 civil servants and 100 nurses were enrolled in the study. Affective temperament and burnout were assessed by means of TEMPS-A and MBI questionnaires, respectively. To measure the level of job-related stress, we have designed a 6-item self-reported questionnaire, which considered stressors common for both professions. RESULTS: Compared to the civil servants, nurses showed higher rate of anxious temperament and experienced greater intensity of job-related stress. The groups did not differ in the intensity of burnout symptoms. The rates of cyclothymic and anxious temperaments correlated with the intensity of stress, and burnout symptoms in the group of nurses. Within the civil servants group, the level of stress correlated with intensity of burnout, however no correlations with affective temperament were observed. The regression analysis performed in both groups revealed the significant effect of stress and cyclothymic temperament on burnout, while the effect of anxious temperament was not significant. CONCLUSIONS: Cyclothymic and anxious temperaments are related to the level of experienced job stress and the risk of burnout. In professions like nursing, where employees show elevated rates of these temperaments, burnout prevention and stress management education is of particular importance. PMID- 28586392 TI - Desire for a child and eating disorders in women seeking infertility treatment. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence of EDs in women seeking treatment for infertility, and to better characterize their clinical profile. STUDY DESIGN: Sixty participants completed self-report measures that assessed EDs, desire for a child, body preoccupations, quality of life, anxiety and depression. RESULTS: Ten patients (17%) met criteria for a past or current ED. We showed a significant association between greater body dissatisfaction and a more ambivalent desire for a child. Furthermore, an ED was associated with (i) a lower quality of life, and (ii) more anxiety disorders. CONCLUSION: Screening for a history of ED in infertile women is recommended to plan for adapted care regarding infertility but also regarding ED and psychiatric comorbidities. Therefore, the assessment has to take into account the desire for a child and the body satisfaction, that are essential parts of the ED process on the one hand and infertility process on the other. This could help with the infertility treatment and the prevention of negative maternal and fetal outcomes. PMID- 28586393 TI - A numerical framework for interstitial fluid pressure imaging in poroelastic MRE. AB - A numerical framework for interstitial fluid pressure imaging (IFPI) in biphasic materials is investigated based on three-dimensional nonlinear finite element poroelastic inversion. The objective is to reconstruct the time-harmonic pore pressure field from tissue excitation in addition to the elastic parameters commonly associated with magnetic resonance elastography (MRE). The unknown pressure boundary conditions (PBCs) are estimated using the available full-volume displacement data from MRE. A subzone-based nonlinear inversion (NLI) technique is then used to update mechanical and hydrodynamical properties, given the appropriate subzone PBCs, by solving a pressure forward problem (PFP). The algorithm was evaluated on a single-inclusion phantom in which the elastic property and hydraulic conductivity images were recovered. Pressure field and material property estimates had spatial distributions reflecting their true counterparts in the phantom geometry with RMS errors around 20% for cases with 5% noise, but degraded significantly in both spatial distribution and property values for noise levels > 10%. When both shear moduli and hydraulic conductivity were estimated along with the pressure field, property value error rates were as high as 58%, 85% and 32% for the three quantities, respectively, and their spatial distributions were more distorted. Opportunities for improving the algorithm are discussed. PMID- 28586394 TI - Polyamine transporter potABCD is required for virulence of encapsulated but not nonencapsulated Streptococcus pneumoniae. AB - Streptococcus pneumoniae is commonly found in the human nasopharynx and is the causative agent of multiple diseases. Since invasive pneumococcal infections are associated with encapsulated pneumococci, the capsular polysaccharide is the target of licensed pneumococcal vaccines. However, there is an increasing distribution of non-vaccine serotypes, as well as nonencapsulated S. pneumoniae (NESp). Both encapsulated and nonencapsulated pneumococci possess the polyamine oligo-transport operon (potABCD). Previous research has shown inactivation of the pot operon in encapsulated pneumococci alters protein expression and leads to a significant reduction in pneumococcal murine colonization, but the role of the pot operon in NESp is unknown. Here, we demonstrate deletion of potD from the NESp NCC1 strain MNZ67 does impact expression of the key proteins pneumolysin and PspK, but it does not inhibit murine colonization. Additionally, we show the absence of potD significantly increases biofilm production, both in vitro and in vivo. In a chinchilla model of otitis media (OM), the absence of potD does not significantly affect MNZ67 virulence, but it does significantly reduce the pathogenesis of the virulent encapsulated strain TIGR4 (serotype 4). Deletion of potD also significantly reduced persistence of TIGR4 in the lungs but increased persistence of PIP01 in the lungs. We conclude the pot operon is important for the regulation of protein expression and biofilm formation in both encapsulated and NCC1 nonencapsulated Streptococcus pneumoniae. However, in contrast to encapsulated pneumococcal strains, polyamine acquisition via the pot operon is not required for MNZ67 murine colonization, persistence in the lungs, or full virulence in a model of OM. Therefore, NESp virulence regulation needs to be further established to identify potential NESp therapeutic targets. PMID- 28586395 TI - The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: A translational research project of a prospective randomized phase III trial. AB - BACKGROUND: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy. METHODS: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining. RESULTS: 258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC. CONCLUSION: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance. PMID- 28586396 TI - Prevalence, incidence and correlates of HSV-2 infection in an HIV incidence adolescent and adult cohort study in western Kenya. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) infections are associated with increased risk of HIV transmission. We determined HSV-2 prevalence, incidence and associated risk factors, incidence among persons with indeterminate results, and prevalence of HSV-2/HIV co-infection among young adults (18-34 years) and adolescents (16-17 years) enrolled in an HIV incidence cohort study in western Kenya. METHODS: Participants (n = 1106; 846 adults) were screened and those HIV-1 negative were enrolled and followed-up quarterly for one year. HSV-2 was assessed using the Kalon enzyme immunoassay. HSV-2 incidence was calculated separately among HSV-2 seronegative participants and those indeterminate at baseline. Logistic regression was used to estimate the odds of HSV-2 infection and Poisson regression was used to assess HSV-2 incidence and associated factors. RESULTS: Overall, HSV-2 prevalence was 26.6% [95% confidence interval (CI): 23.9-29.4] and was higher in adults (31.5% [95% CI: 28.3-34.9]) than adolescents (10.7% [95% CI: 7.1-15.3]). Factors associated with prevalent HSV-2 included female gender, increasing age, HIV infection, history of sexually transmitted infection, low level of education, multiple sexual partners, and being married, divorced, separated or widowed. Overall HSV-2 incidence was 4.0 per 100 person-years (/100PY) 95% CI: 2.7-6.1 and was higher in adults (4.5/100PY) and females (5.1/100PY). In multivariable analysis only marital status was associated with HSV-2 incidence. Among 45 participants with indeterminate HSV-2 results at baseline, 22 seroconverted, resulting in an incidence rate of 53.2 /100PY [95% CI: 35.1-80.9]. Inclusion of indeterminate results almost doubled the overall incidence rate to 7.8 /100 PY [95% CI: 5.9-10.5]. Prevalence of HIV/HSV-2 co infection was higher in female adults than female adolescents (17.1 [95% CI: 13.6 21.0] versus 3.4 [95% CI: 1.1-7.8]). CONCLUSION: The high incidence rate among persons with indeterminate results underscores the public health concerns for HSV 2 spread and underreporting of the HSV-2 burden. Careful consideration is needed when interpreting HSV-2 serology results in these settings. PMID- 28586397 TI - Serum from dengue virus-infected patients with and without plasma leakage differentially affects endothelial cells barrier function in vitro. AB - BACKGROUND: Although most of cases of dengue infections are asymptomatic or mild symptomatic some individuals present warning signs progressing to severe dengue in which plasma leakage is a hallmark. METHODOLOGY/PRINCIPAL FINDINGS: The present study used Electric Cell-substrate Impedance Sensing (ECIS(r)) which allows for electrical monitoring of cellular barrier function measuring changes in Transendothelial Electric Resistance (TEER) to investigate the parameters associated with dengue induced leakage. Three groups of individuals were tested: dengue-positives with plasma leakage (leakage), dengue-positives without plasma leakage (no leakage), and dengue-negatives (control). Data show that TEER values of human umbilical vein endothelial cells (HUVECs) was significantly lower after incubation with serum from subjects of the leakage group in comparison to the no leakage or control groups. The serum levels of CXCL1, EGF, eotaxin, IFN-gamma, sCD40L, and platelets were significantly decreased in the leakage group, while IL 10, IL-6, and IP-10 levels were significantly increased. We also found a strong correlation between TEER values and augmented levels of IP-10, GM-CSF, IL-1alpha, and IL-8, as well as decreased levels of CXCL1 and platelets. CONCLUSIONS/SIGNIFICANCE: The present work shows that the magnitude of the immune response contributes to the adverse plasma leakage outcomes in patients and that serum components are important mediators of changes in endothelial homeostasis during dengue infections. In particular, the increased levels of IP-10 and the decreased levels of CXCL1 and platelets seem to play a significant role in the disruption of vascular endothelium associated with leakage outcomes after DENV infection. These findings may have important implications for both diagnostic and therapeutic approaches to predict and mitigate vascular permeabilization in those experiencing the most severe clinical disease outcomes after dengue infection. PMID- 28586398 TI - The protective effects of Zhen-Wu-Tang against cisplatin-induced acute kidney injury in rats. AB - Acute kidney injury (AKI) is a common clinical condition that confers a risk of progression of chronic kidney disease and a high risk of death. The purpose of the current study is to investigate the anti-apoptotic and anti-fibrotic effects of Zhen-Wu-Tang (ZWT) on cisplatin (CIS)-induced renal injury and elucidate the involvement of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the PI3K/Akt signaling pathway, transforming growth factor (TGF)-beta and the Wnt/beta-catenin signaling pathway in the positive effects of Zhen-Wu-Tang on the kidneys. Wistar rats were randomly assigned into six groups of 6 rats each as follows: normal control 1; normal control 2; CIS 1 and CIS 2, which received single intraperitoneal injections of CIS (6 mg/kg); CIS+ZWT 4 and CIS+ZWT 10, which received ZWT (1 ml/100 g/day, ig) starting days after the CIS injection for 4 and 10 days, respectively. Hematoxylin-eosin (H&E) staining was performed to identify the amelioration of histopathological changes in the kidneys and apoptosis of the renal proximal tubular cells. Picrosirius red staining was used to evaluate renal fibrosis after ZWT treatment. The relationship between ZWT and the upregulation of Nrf2, phosphorylation of Akt, and the downregulation of TGF-beta and WNT/beta catenin were determined by Western blotting. At the end of the experiment, serum was isolated from the orbital blood of rats, and blood urea nitrogen (BUN) and creatinine (Cr) levels were measured. The results showed that ZWT restored the histological alterations, aberrant collagen deposition in the kidneys and the BUN and Cr levels that were increased by CIS. Treatment with ZWT reduced the expression levels of TGF-beta and Wnt and increased the expression levels of Nrf2, PI3K and Akt in the CIS-exposed kidney tissues. Furthermore, ZWT downregulated apoptosis and fibrosis by modulating the expression levels of caspase-3, Bax and alpha-smooth muscle actin (alpha-SMA). In conclusion, this study provides evidence for the anti-fibrotic and anti-apoptotic roles of ZWT in CIS-induced experimental kidney injury. PMID- 28586399 TI - The relationship between the Early Childhood Environment Rating Scale and its revised form and child outcomes: A systematic review and meta-analysis. AB - The Early Childhood Environment Rating Scale (ECERS) and its revised version (ECERS-R) were designed as global measures of quality that assess structural and process aspects of Early Childhood Education and Care (ECEC) programs. Despite frequent use of the ECERS/ECERS-R in research and applied settings, associations between it and child outcomes have not been systematically reviewed. The objective of this research was to evaluate the association between the ECERS/ECERS-R and children's wellbeing. Searches of Medline, PsycINFO, ERIC, websites of large datasets and reference sections of all retrieved articles were completed up to July 3, 2015. Eligible studies provided a statistical link between the ECERS/ECERS-R and child outcomes for preschool-aged children in ECEC programs. Of the 823 studies selected for full review, 73 were included in the systematic review and 16 were meta-analyzed. The combined sample across all eligible studies consisted of 33, 318 preschool-aged children. Qualitative systematic review results revealed that ECERS/ECERS-R total scores were more generally associated with positive outcomes than subscales or factors. Seventeen separate meta-analyses were conducted to assess the strength of association between the ECERS/ECERS-R and measures that assessed children's language, math and social-emotional outcomes. Meta-analyses revealed a small number of weak effects (in the expected direction) between the ECERS/ECERS-R total score and children's language and positive behavior outcomes. The Language-Reasoning subscale was weakly related to a language outcome. The enormous heterogeneity in how studies operationalized the ECERS/ECERS-R, the outcomes measured and statistics reported limited our ability to meta-analyze many studies. Greater consistency in study methodology is needed in this area of research. Despite these methodological challenges, the ECERS/ECERS-R does appear to capture aspects of quality that are important for children's wellbeing; however, the strength of association is weak. PMID- 28586400 TI - Patients with schizophrenia activate behavioural intentions facilitated by counterfactual reasoning. AB - METHOD: The main variables assessed were: answer to complete a target task (wrong or correctly), and percentage gain in the reaction time (RT) to complete a target task correctly depending on whether the prime was a counterfactual or a neutral control cue. These variables were assessed in 37 patients with schizophrenia and 37 healthy controls. Potential associations with clinical status and socio demographic characteristics were also explored. RESULTS: When a counterfactual prime was presented, the probability of giving an incorrect answer was lower for the entire sample than when a neutral prime was presented (OR 0.58; CI 95% 0.42 to 0.79), but the schizophrenia patients showed a higher probability than the controls of giving an incorrect answer (OR 3.89; CI 95% 2.0 to 7.6). Both the schizophrenia patients and the controls showed a similar percentage gain in RT to a correct answer of 8%. CONCLUSIONS: Challenging the results of previous research, our findings suggest a normal activation of behavioural intentions facilitated by CFT in schizophrenia. Nevertheless, the patients showed more difficulty than the controls with the task, adding support to the concept of CFT as a potential new target for consideration in future therapeutic approaches for this illness. PMID- 28586401 TI - 3D printing and milling a real-time PCR device for infectious disease diagnostics. AB - Diagnosing infectious diseases using quantitative polymerase chain reaction (qPCR) offers a conclusive result in determining the infection, the strain or type of pathogen, and the level of infection. However, due to the high-cost instrumentation involved and the complexity in maintenance, it is rarely used in the field to make a quick turnaround diagnosis. In order to provide a higher level of accessibility than current qPCR devices, a set of 3D manufacturing methods is explored as a possible option to fabricate a low-cost and portable qPCR device. The key advantage of this approach is the ability to upload the digital format of the design files on the internet for wide distribution so that people at any location can simply download and feed into their 3D printers for quick manufacturing. The material and design are carefully selected to minimize the number of custom parts that depend on advanced manufacturing processes which lower accessibility. The presented 3D manufactured qPCR device is tested with 20 MUL samples that contain various concentrations of lentivirus, the same type as HIV. A reverse-transcription step is a part of the device's operation, which takes place prior to the qPCR step to reverse transcribe the target RNA from the lentivirus into complementary DNA (cDNA). This is immediately followed by qPCR which quantifies the target sequence molecules in the sample during the PCR amplification process. The entire process of thermal control and time-coordinated fluorescence reading is automated by closed-loop feedback and a microcontroller. The resulting device is portable and battery-operated, with a size of 12 * 7 * 6 cm3 and mass of only 214 g. By uploading and sharing the design files online, the presented low-cost qPCR device may provide easier access to a robust diagnosis protocol for various infectious diseases, such as HIV and malaria. PMID- 28586402 TI - Effect of food intake on 92 biomarkers for cardiovascular disease. AB - OBJECTIVE: The present study evaluates the effect of food intake on 92 biomarkers for cardiovascular disease (CVD). METHODS: Twenty two healthy subjects (11 male and 11 female aged 25.9+/-4.2 years) were investigated. A total of 92 biomarkers were measured before a standardized meal as well as 30 and 120 minutes afterwards with the Proseek Multiplex CVD III kit. RESULTS: The levels for eight biomarkers decreased significantly (P<0.05) 30 minutes after food intake. The levels for seven biomarkers remained significantly decreased 120 minutes after food intake. Nine biomarker decreased significantly at 120 minutes after food intake. The changes were between 4-30%, most commonly around 5%. Only six biomarkers showed a difference of 10% or more due to food intake. The biggest differences were observed for Insulin-like growth factor-binding protein 1 (30%); Azurocidin, Cystatin-B, and Myeloperoxidase (13%); Monocyte chemotactic protein 1 (11%); and Myeloblastin (10%), all 120 minutes after food intake. CONCLUSIONS: This study shows that food intake affects several different CVD biomarkers, but the effect is predominantly modest. Timing of blood sampling in relation to food intake, therefore, appears not to be a major concern. Further studies are warranted in older healthy subjects and in patients with various cardiac diseases to determine whether the findings are reproducible. PMID- 28586403 TI - Evolution of class 1 integrons: Mobilization and dispersal via food-borne bacteria. AB - Class 1 integrons have played a major role in the global dissemination of antibiotic resistance. Reconstructing the history of class 1 integrons might help us control further spread of antibiotic resistance by understanding how human activities influence microbial evolution. Here we describe a class 1 integron that represents an intermediate stage in the evolutionary history of clinical integrons. It was embedded in a series of nested transposons, carried on an IncP plasmid resident in Enterobacter, isolated from the surface of baby spinach leaves. Based on the structure of this integron, we present a modified hypothesis for integron assembly, where the ancestral clinical class 1 integron was captured from a betaproteobacterial chromosome to form a Tn402-like transposon. This transposon then inserted into a plasmid-borne Tn21-like ancestor while in an environmental setting, possibly a bacterium resident in the phyllosphere. We suggest that the qacE gene cassette, conferring resistance to biocides, together with the mercury resistance operon carried by Tn21, provided a selective advantage when this bacterium made its way into the human commensal flora via food. The integron characterized here was located in Tn6007, which along with Tn6008, forms part of the larger Tn6006 transposon, itself inserted into another transposable element to form the Tn21-like transposon, Tn6005. This element has previously been described from the human microbiota, but with a promoter mutation that upregulates integron cassette expression. This element we describe here is from an environmental bacterium, and supports the hypothesis that the ancestral class 1 integron migrated into anthropogenic settings via foodstuffs. Selection pressures brought about by early antimicrobial agents, including mercury, arsenic and disinfectants, promoted its initial fixation, the acquisition of promoter mutations, and subsequent dissemination into various species and pathogens. PMID- 28586404 TI - Left ventricular thrombus or pseudothrombus? A rare cardiac CT artifact. PMID- 28586405 TI - The trapped mitral regurgitation. PMID- 28586406 TI - A solitary cardiac plasmacytoma: features in multimodality imaging. PMID- 28586407 TI - A Bayesian hierarchical model for network meta-analysis of multiple diagnostic tests. AB - To compare the accuracy of multiple diagnostic tests in a single study, three designs are commonly used (i) the multiple test comparison design; (ii) the randomized design, and (iii) the non-comparative design. Existing meta-analysis methods of diagnostic tests (MA-DT) have been focused on evaluating the performance of a single test by comparing it with a reference test. The increasing number of available diagnostic instruments for a disease condition and the different study designs being used have generated the need to develop efficient and flexible meta-analysis framework to combine all designs for simultaneous inference. In this article, we develop a missing data framework and a Bayesian hierarchical model for network MA-DT (NMA-DT) and offer important promises over traditional MA-DT: (i) It combines studies using all three designs; (ii) It pools both studies with or without a gold standard; (iii) it combines studies with different sets of candidate tests; and (iv) it accounts for heterogeneity across studies and complex correlation structure among multiple tests. We illustrate our method through a case study: network meta-analysis of deep vein thrombosis tests. PMID- 28586409 TI - Retirement Sequences of Older Americans: Moderately Destandardized and Highly Stratified Across Gender, Class, and Race. AB - Purpose of the Study: A destandardization of labor-force patterns revolving around retirement has been observed in recent literature. It is unclear, however, to which degree and of which kind. This study looked at sequences rather than individual statuses or transitions and argued that differentiating older Americans' retirement sequences by type, order, and timing and considering gender, class, and race differences yields a less destandardized picture. Design and Methods: Sequence analysis was employed to analyze panel data from the Health and Retirement Study (HRS) for 7,881 individuals observed 6 consecutive times between ages 60-61 and 70-71. Results: As expected, types of retirement sequences were identified that cannot be subsumed under the conventional model of complete retirement from full-time employment around age 65. However, these retirement sequences were not entirely destandardized, as some irreversibility and age grading persisted. Further, the degree of destandardization varied along gender, class, and race. Unconventional sequences were archetypal for middle-level educated individuals and Blacks. Also, sequences for women and individuals with lower education showed more unemployment and part-time jobs, and less age grading. Implications: A sequence-analytic approach that models group differences uncovers misjudgments about the degree of destandardization of retirement sequences. When a continuous process is represented as individual transitions, the overall pattern of retirement sequences gets lost and appears destandardized. These patterns get further complicated by differences in social structures by gender, class, and race in ways that seem to reproduce advantages that men, more highly educated individuals, and Whites enjoy in numerous areas over the life course. PMID- 28586410 TI - A newborn intracardiac mass after coronary stenting: a case of left atrial intramural haematoma. PMID- 28586411 TI - Incidence and treatment of heavy menstrual bleeding in general practice. AB - Background: Heavy menstrual bleeding (HMB) is a common problem in women of reproductive age. In 2008, the Dutch guideline for general practitioners (GPs) was revised to recommend the levonorgestrel intrauterine system (LNG-IUS) as a first-choice treatment for HMB. However, GP prescribing practices have not been studied in depth. Objectives: To investigate the incidence and initial treatment of HMB in general practice, and to identify if there were changes in prescribing practices after the revision of the national guideline in 2008. Methods: Retrospective analysis of data from the Registration Network Groningen, the Netherlands. We selected data for prescriptions and referrals related to women consulting their GP for HMB between 2004 and 2013. We calculated the incidence rates and investigated potential trends in prescribing over time, with particular attention to the prescribing of LNG-IUS. Results: Over 10 years, 881 women consulted their GP for HMB, with a mean annual incidence of 9.3 per 1000 person years (95% confidence interval: 8.5-10.2). Most women received hormonal treatment (406/881; 46%) within three months of diagnosis, but many (387/881; 44%) received no medication. The LNG-IUS was prescribed for 2.4%, but there was no significant increase in the number of prescriptions over time. Conclusion: In this cohort, most women with HMB were treated with oral hormone therapy, and few received the LNG-IUS. If patients are to benefit from the LNG-IUS, further research is needed into the reasons for this lack of change in prescribing practices. PMID- 28586412 TI - High-Fat Diet and Female Fertility. AB - The prevalence of obesity is high among reproductive-age women and is associated with impaired reproductive function. Obesity is multifactorial in origin, yet many cases of obesity result from overconsumption of a diet high in fat. Excess dietary fat increases both adipose and nonadipose tissue lipid content and, through lipotoxicity, leads to cell dysfunction and death. High dietary fat intake, with or without the development of obesity, impairs female hypothalamic pituitary-ovarian (HPO) axis functionality and fertility. Based on the current evidence, it appears the reproductive dysfunction involves increased leptin and insulin signaling at the various levels of the HPO axis, as well as changes in peroxisome proliferator-activated receptor gamma actions and increased inflammation, yet other mechanisms may also be involved. This review summarizes the current body of knowledge on impaired female reproductive function after high fat diet exposure, as well as discusses proposed mechanisms through which this may occur. PMID- 28586413 TI - Role of the tricuspid regurgitation after mitraclip and transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - Aims: Treatment of tricuspid regurgitation (TR) is common after surgery for mitral and/or aortic valves. The prognostic role of moderate to severe TR in patients undergoing mitraclip or transcatheter aortic valve implantation (TAVI) is not well-defined. Thus, the aim of this article is to perform a systematic review and meta-analysis of articles valuing the prognostic role of TR for patients undergoing mitraclip and TAVI. Methods and results: Articles were searched in Pubmed, Cochrane Library, Google Scholar and Biomed Central in September 2016. Inclusion criteria: observational or randomized clinical trials with data on the prognostic role of TR in patients undergoing mitraclip or TAVI. Primary outcome was all-cause mortality expressed as hazard ratio (HR). Six articles fulfilled inclusion criteria, three were on mitraclip and three on TAVI. A total of 2329 patients were analysed (mean age was 78.38 (3.09), 63% male): 1328 treated with TAVI and 1001 with mitraclip. The HR for all-cause mortality of moderate to severe TR was 2.0 (95% CI 1.57-2.55, I2 = 0%). Data were confirmed also after subgroup analysis for mitraclip vs. TAVI. None of the factor considered in meta-regression analyses was affecting the primary outcome. Conclusions: The current meta-analysis suggests that the presence of moderate to severe TR in patients undergoing mitraclip or TAVI might be a major determinant of all-cause mortality. New studies are needed to confirm it and to plan possible intervention in order to reduce its impact. PMID- 28586415 TI - A Technique Using the Suction-Assisted Endoscope Sheath to Transfer SMAS for Lip Augmentation. PMID- 28586414 TI - Adverse events related to hospital care: a retrospective medical records review in a Swiss hospital. AB - Objective: Retrospective records reviews carried out in several countries have shown substantial rates of adverse events (AE) among hospitalized patients, preventable in half the cases. As no such data have been recorded in Switzerland, we estimated the incidence of AE in one acute care hospital as a basis for a safety improvement program. Design: A two steps retrospective records review (screening criteria and full review of positively screened records). Setting: A medium size community hospital. Participants: A stratified sample of 400 surgical and 600 medical hospitalizations whose records fulfilled a set of information quality criteria. Intervention(s): Not applicable. Main outcome measure(s): Adverse events, preventable adverse events and extent of resulting harm. Results: The proportion of hospitalizations with at least one AE was 12.3% (95% CI: 10.4 14.1) whereas the overall hospital incidence rate was 14.1% (95% CI: 12.0-16.2). Nearly half of AE were judged preventable, corresponding to one or more preventable AE in 6.4% of hospitalizations (95% CI: 5.0-7.8). Sixty percent of AE resulted in no or minor impairment at discharge whereas 23% resulted in severe disability. AE were twice more frequent in surgical patients, and preventable AE resulted more often in severe impairment than unpreventable AE. No death was attributed to an AE. The proportion of stays with an AE increased with age and length of stay. Conclusions: The incidence of preventable AE in patients hospitalized in one Swiss hospital is comparable to previously reported rates. Further, patient safety improvement is needed, especially among older patients, and for surgical procedures. PMID- 28586416 TI - Bridging the Gap between Reproducibility and Translation: Data Resources and Approaches. AB - Animal research has constituted a fundamental means to achieve groundbreaking therapies for human disease. However, for complex diseases, promising preclinical results have failed to translate to the clinic. Reasons for this disparity are multifactorial. These include the challenges inherent in modeling complex disease in animals, as well issues of study design, reproducibility and operational norms within the biomedical research enterprise. In this issue, we explore the range of information resources available for the comparative study of disease, as well as challenges to the ultimate translation of preclinical findings. Genomics resources in support of translational research are described for zebrafish, mice, rats and non-human primates. The utility of transcriptomics to explore the temporal basis of lesion development in toxicologic pathology is reviewed. Integration of the ever-increasing volume of text-based and bioinformatics data is a significant challenge, and in this issue, informatics resources and general text mining methodologies to explore and aggregate text data are described. Finally, factors contributing to both reproducibility and translatability are examined. Guidelines designed to address reproducibility are essential to improving individual studies. To this end, a viewpoint from the National Institutes of Health on measures needed to enhance rigor and reproducibility is given, as well as an overview of the role of the Institutional Animal Care and Use Committee in this regard. The challenge of improving generalizability of animal experiments so that their findings can be more frequently extended to the intended human population remains. Reasons why models that replicate key aspects of human disease fail to be predictive in humans are explored in two fields in which translation has been a challenge: sepsis and neurodegeneration. PMID- 28586408 TI - Engineering tolerance to industrially relevant stress factors in yeast cell factories. AB - The main focus in development of yeast cell factories has generally been on establishing optimal activity of heterologous pathways and further metabolic engineering of the host strain to maximize product yield and titer. Adequate stress tolerance of the host strain has turned out to be another major challenge for obtaining economically viable performance in industrial production. Although general robustness is a universal requirement for industrial microorganisms, production of novel compounds using artificial metabolic pathways presents additional challenges. Many of the bio-based compounds desirable for production by cell factories are highly toxic to the host cells in the titers required for economic viability. Artificial metabolic pathways also turn out to be much more sensitive to stress factors than endogenous pathways, likely because regulation of the latter has been optimized in evolution in myriads of environmental conditions. We discuss different environmental and metabolic stress factors with high relevance for industrial utilization of yeast cell factories and the experimental approaches used to engineer higher stress tolerance. Improving stress tolerance in a predictable manner in yeast cell factories should facilitate their widespread utilization in the bio-based economy and extend the range of products successfully produced in large scale in a sustainable and economically profitable way. PMID- 28586417 TI - Development and validation study of a non-alcoholic fatty liver disease risk scoring model among adults in China. AB - Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in China. It is usually asymptomatic and transabdominal ultrasound (USS) is the usual means for diagnosis, but it may not be feasible to have USS screening of the whole population. Objective: To develop a risk scoring model for predicting the presence of NAFLD using parameters that can be easily obtain in clinical settings. Methods: A retrospective study on the data of 672 adults who had general health check including a transabdominal ultrasound. Fractional polynomial and multivariable logistic regressions of sociodemographic and biochemical variables on NAFLD were used to identify the predictors. A risk score was assigned to each predictor using the scaled standardized beta-coefficient to create a risk prediction algorithm. The accuracy for NAFLD detection by each cut off score in the risk algorithm was evaluated. Results: The prevalence of NAFLD in our study population was 33.0% (222/672). Six significant factors were selected in the final prediction model. The areas under the curve (AUC) was 0.82 (95% CI: 0.78-0.85). The optimal cut-off score, based on the ROC was 35, with a sensitivity of 76.58% (95% CI: 70.44-81.98%) and specificity of 74.89% (95% CI: 70.62-78.83%). Conclusion: A NAFLD risk scoring model can be used to identify asymptomatic Chinese people who are at risk of NAFLD for further USS investigation. PMID- 28586419 TI - Evaluating quality improvement methods and economics of preventable adverse events in the healthcare: From Africa to Europe. PMID- 28586418 TI - Nocturnal but not Diurnal Hypertension Is Associated to Insulin Resistance Markers in Subjects With Normal or Mildly Elevated Office Blood Pressure. AB - OBJECTIVE: The aim was to evaluate the relationships among insulin resistance markers and nocturnal and diurnal hypertension in normotensive or mildly untreated hypertensive adults. METHODS: The study was performed in both female and male adults referred to the Cardiometabolic Unit of the Hospital San Martin, La Plata, Argentina, in order to perform an ambulatory blood pressure measurement (ABPM) for the evaluation of a possible hypertensive disorder. The population was stratified according to their ABPM in: 1-presence or absence of diurnal hypertension and 2-presence or absence of nocturnal hypertension; both conditions were analyzed separately. Fasting plasma insulin (FPI), homeostasis model assessment of insulin resistance (HOMA-IR), and triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C) ratio were used as surrogate markers of insulin resistance and compared among subjects with vs. without diurnal or nocturnal hypertension. RESULTS: One hundred and five patients, 55 women, 47 (11) years old, and 50 men, 44 (16) years old, were included. Diurnal and nocturnal hypertension were found in 60% and 64% of the sample, respectively. There were no significant differences among the levels of insulin resistance markers between individuals with or without diurnal hypertension. In contrast, individuals with nocturnal hypertension were more insulin resistant irrespectively of whether they were evaluated using FPI (P = 0.016), HOMA-IR (P = 0.019), or TG/HDL-C ratio (P = 0.011); FPI differences remained significant after adjustment for sex, age, and obesity indicators (P = 0.032). CONCLUSIONS: Nocturnal but not diurnal hypertension was related to higher levels of 3 insulin resistance markers in normotensive and untreated mildly hypertensive adults; this relationship seems partially independent of obesity. PMID- 28586420 TI - Appropriateness criteria for the use of cardiovascular imaging in heart valve disease in adults: a European Association of Cardiovascular Imaging report of literature review and current practice. AB - Heart valve disease is common and a major indication for imaging. Echocardiography is the first-line imaging technique for diagnosis, assessment, and serial surveillance. However, other modalities, notably cardiac magnetic resonance imaging and computerized tomography, are used if echocardiographic imaging is suboptimal or to obtain complementary information, particularly to aid risk assessment in individual patients. This review is a summary of current evidence for state-of-the-art clinical practice to inform appropriateness criteria for heart valve disease. It is divided according to common clinical scenarios: detection of valve disease, assessment of the valve and other cardiac structures, risk assessment, screening, and intervention. PMID- 28586421 TI - FRUITFULL controls SAUR10 expression and regulates Arabidopsis growth and architecture. AB - MADS-domain transcription factors are well known for their roles in plant development and regulate sets of downstream genes that have been uncovered by high-throughput analyses. A considerable number of these targets are predicted to function in hormone responses or responses to environmental stimuli, suggesting that there is a close link between developmental and environmental regulators of plant growth and development. Here, we show that the Arabidopsis MADS-domain factor FRUITFULL (FUL) executes several functions in addition to its noted role in fruit development. Among the direct targets of FUL, we identified SMALL AUXIN UPREGULATED RNA 10 (SAUR10), a growth regulator that is highly induced by a combination of auxin and brassinosteroids and in response to reduced R:FR light. Interestingly, we discovered that SAUR10 is repressed by FUL in stems and inflorescence branches. SAUR10 is specifically expressed at the abaxial side of these branches and this localized activity is influenced by hormones, light conditions and by FUL, which has an effect on branch angle. Furthermore, we identified a number of other genes involved in hormone pathways and light signalling as direct targets of FUL in the stem, demonstrating a connection between developmentally and environmentally regulated growth programs. PMID- 28586423 TI - The transcriptome of human oocytes is related to age and ovarian reserve. AB - STUDY QUESTION: How does the human oocyte transcriptome change with age and ovarian reserve? SUMMARY ANSWER: Specific sets of human oocyte messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs) are affected independently by age and ovarian reserve. WHAT IS KNOWN ALREADY: Although it is well established that the ovarian reserve diminishes with increasing age, and that a woman's age is correlated with lower oocyte quality, the interplay of a diminished reserve and age on oocyte developmental competence is not clear. After maturation, oocytes are mostly transcriptionally quiescent, and developmental competence prior to embryonic genome activationrelies on maternal RNA and proteins. STUDY DESIGN, SIZE, DURATION: A total of 36 vitrified/warmed MII oocytes from 30 women undergoing oocyte donation were included in this study, processed and analyzed individually. PARTICIPANTS/MATERIALS, SETTING, METHODS: Total RNA from each oocyte was independently isolated, amplified, labeled, and hybridized on HTA 2.0 arrays (Affymetrix). Data were analyzed using TAC software, in four groups, each including nine oocytes, according to the woman's age and antral follicular count (AFC) (mean +/- SD): Young with High AFC (YH; age 21 +/- 1 years and 24 +/- 3 follicles); Old with High AFC (OH; age 32 +/- 2 years and 29 +/- 7 follicles); Young with Low AFC (YL; age 24 +/- 2 years and 8 +/- 2 follicles); Old with Low AFC (OL; age 34 +/- 1 years and 7 +/- 1 follicles). qPCR was performed to validate arrays. MAIN RESULTS AND THE ROLE OF CHANCE: We identified a set of 30 differentially expressed mRNAs when comparing oocytes from women with different ages and AFC. In addition, 168 non-coding RNAs (ncRNAs) were differentially expressed in relation to age and/or AFC. Few mRNAs have been identified as differentially expressed transcripts, and among ncRNAs, a set of Piwi-interacting RNAs clusters (piRNAs-c) and precursor microRNAs (pre-miRNAs) were identified as increased in high AFC and old groups, respectively. Our results indicate that age and ovarian reserve are associated with specific ncRNA profiles, suggesting that oocyte quality might be mediated by ncRNA pathways. LARGE SCALE DATA: Data can be found via GEO accession number GSE87201. LIMITATIONS, REASONS FOR CAUTION: The oldest woman included in the study was 35 years old, thus our results cannot readily be extrapolated to women older than 35 or infertile women. WIDER IMPLICATIONS OF THE FINDINGS: We show, for the first time, that several non coding RNAs, usually regulating DNA transcription, are differentially expressed in relation to age and/or ovarian reserve. Interestingly, the mRNA transcriptome of in vivo matured oocytes remains remarkably stable across ages and ovarian reserve, suggesting the possibility that changes in the non-coding transcriptome might regulate some post-transcriptional/translational mechanisms which might, in turn, affect oocyte developmental competence. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by intramural funding of Clinica EUGIN and by the Secretary for Universities and Research of the Ministry of Economy and Knowledge of the Government of Catalonia. J.H. and A.S. are employees of Affymetrix, otherwise there are no competing interests. PMID- 28586422 TI - Tomato ethylene sensitivity determines interaction with plant growth-promoting bacteria. AB - Background and Aims: Plant growth-promoting bacteria (PGPB) are soil micro organisms able to interact with plants and stimulate their growth, positively affecting plant physiology and development. Although ethylene plays a key role in plant growth, little is known about the involvement of ethylene sensitivity in bacterial inoculation effects on plant physiology. Thus, the present study was pursued to establish whether ethylene perception is critical for plant-bacteria interaction and growth induction by two different PGPB strains, and to assess the physiological effects of these strains in juvenile and mature tomato ( Solanum lycopersicum ) plants. Methods: An experiment was performed with the ethylene insensitive tomato never ripe and its isogenic wild-type line in which these two strains were inoculated with either Bacillus megaterium or Enterobacter sp. C7. Plants were grown until juvenile and mature stages, when biomass, stomatal conductance, photosynthesis as well as nutritional, hormonal and metabolic statuses were analysed. Key Results: Bacillus megaterium promoted growth only in mature wild type plants. However, Enterobacter C7 PGPB activity affected both wild-type and never ripe plants. Furthermore, PGPB inoculation affected physiological parameters and root metabolite levels in juvenile plants; meanwhile plant nutrition was highly dependent on ethylene sensitivity and was altered at the mature stage. Bacillus megaterium inoculation improved carbon assimilation in wild-type plants. However, insensitivity to ethylene compromised B. megaterium PGPB activity, affecting photosynthetic efficiency, plant nutrition and the root sugar content. Nevertheless, Enterobacter C7 inoculation modified the root amino acid content in addition to stomatal conductance and plant nutrition. Conclusions: Insensitivity to ethylene severely impaired B. megaterium interaction with tomato plants, resulting in physiological modifications and loss of PGPB activity. In contrast, Enterobacter C7 inoculation stimulated growth independently of ethylene perception and improved nitrogen assimilation in ethylene-insensitive plants. Thus, ethylene sensitivity is a determinant for B. megaterium , but is not involved in Enterobacter C7 PGPB activity. PMID- 28586424 TI - Role of ERalpha in Mediating Female Uterine Transcriptional Responses to IGF1. AB - Estrogen (E2) signaling through its nuclear receptor, E2 receptor alpha (ERalpha) increases insulinlike growth factor 1 (IGF1) in the rodent uterus, which then initiates further signals via the IGF1 receptor. Directly administering IGF1 results in similar biological and transcriptional uterine responses. Our studies using global ERalpha-null mice demonstrated a loss of uterine biological responses of the uterus to E2 or IGF1 treatment, while maintaining transcriptional responses to IGF1. To address this discrepancy in the need for uterine ERalpha in mediating the IGF1 transcriptional vs growth responses, we assessed the IGF1 transcriptional responses in PgrCre+Esr1f/f (called ERalphaUtcKO) mice, which selectively lack ERalpha in progesterone receptor (PGR) expressing cells, including all uterine cells, while maintaining ERalpha expression in other tissues and cells that do not express Pgr. Additionally, we profiled IGF1-induced ERalpha binding sites in uterine chromatin using chromatin immunoprecipitation sequencing. Herein, we explore the transcriptional and molecular signaling that underlies our findings to refine our understanding of uterine IGF1 signaling and identify ERalpha-mediated and ERalpha-independent uterine transcriptional responses. Defining these mechanisms in vivo in whole tissue and animal contexts provides details of nuclear receptor mediated mechanisms that impact biological systems and have potential applicability to reproductive processes of humans, livestock and wildlife. PMID- 28586425 TI - Mothers of Deaf Children in the 21st Century. Dynamic Positioning Between the Medical and Cultural-Linguistic Discourses. AB - Traditional research examining the communicational choices made by families with deaf children tends to emanate from the premise that families engage with either of the two grand discourses on deafness (i.e., the medical or cultural-linguistic perspective). This study investigated hearing mother's engagement with the educational options for their child from a dynamic, poststructural perspective. Three Flemish mothers were interviewed in-depth at the child's ages of 6, 9, 12, 18, and 24 months. The data were analyzed within a theoretical model that describes the positioning process of the mothers. This method yielded alternative explanations for former findings concerning mothers' decision-making processes, especially the difficulty of learning sign language as a second language in an effort to provide a bilingual-bicultural education, and highlighted the importance of having rich experiences. It further showed that a bilingual bicultural position was scarcely available and poorly supported for these mothers. These findings are discussed in relation to recent international consensus statements on best practices in early intervention. PMID- 28586428 TI - Valvular heart disease: new risk factors and new challenges. PMID- 28586426 TI - A Sensitive Method for Detecting Zika Virus Antigen in Patients' Whole-Blood Specimens as an Alternative Diagnostic Approach. AB - Background: Epidemics caused by the reemergence of Zika virus (ZIKV) warrant the need to develop new diagnostic measures to complement currently used detection methods. In this study, we explored the detection of ZIKV antigen in a defined leukocyte subset from patients' whole-blood specimens. Methods: Whole-blood samples were obtained at the acute and early convalescent phases from ZIKV infected patients during the Singapore outbreak in August-September 2016. Presence of ZIKV antigen was determined by flow cytometry staining for intracellular ZIKV NS3, using a ZIKV-specific polyclonal antibody. The presence of ZIKV antigen was determined in CD45+CD14+ monocytes. Results: Data showed that ZIKV NS3 antigen could be detected in CD45+CD14+ monocytes. The levels of detection were further categorized into 3 groups: high (positivity among >40% of monocytes), moderate (positivity among 10%-40%), and low (positivity among <10%). While a majority of patients showed a decrease in the amount of ZIKV antigen detected at later time points, some patients displayed higher levels as the disease progressed. Conclusions: Our data highlights an alternative approach in using flow cytometry as a sensitive method for detecting ZIKV antigen in whole blood. Importantly, it further confirms the role of CD14+ monocytes as an important cellular target for ZIKV infection during the viremic phase. PMID- 28586427 TI - Benefits of flooding-induced aquatic adventitious roots depend on the duration of submergence: linking plant performance to root functioning. AB - Background and Aims: Temporal flooding is a common environmental stress for terrestrial plants. Aquatic adventitious roots (aquatic roots) are commonly formed in flooding-tolerant plant species and are generally assumed to be beneficial for plant growth by supporting water and nutrient uptake during partial flooding. However, the actual contribution of these roots to plant performance under flooding has hardly been quantified. As the investment into aquatic root development in terms of carbohydrates may be costly, these costs may - depending on the specific environmental conditions - offset the beneficial effects of aquatic roots. This study tested the hypothesis that the balance between potential costs and benefits depends on the duration of flooding, as the benefits are expected to outweigh the costs in long-term but not in short-term flooding. Methods: The contribution of aquatic roots to plant performance was tested in Solanum dulcamara during 1-4 weeks of partial submergence and by experimentally manipulating root production. Nutrient uptake by aquatic roots, transpiration and photosynthesis were measured in plants differing in aquatic root development to assess the specific function of these roots. Key Results: As predicted, flooded plants benefited from the presence of aquatic roots. The results showed that this was probably due to the contribution of roots to resource uptake. However, these beneficial effects were only present in long-term but not in short-term flooding. This relationship could be explained by the correlation between nutrient uptake and the flooding duration-dependent size of the aquatic root system. Conclusions: The results indicate that aquatic root formation is likely to be selected for in habitats characterized by long-term flooding. This study also revealed only limited costs associated with adventitious root formation, which may explain the maintenance of the ability to produce aquatic roots in habitats characterized by very rare or short flooding events. PMID- 28586429 TI - Hafnia, an enterobacterial genus naturally resistant to colistin revealed by three susceptibility testing methods. AB - Objectives: To determine the susceptibility to colistin of Hafnia alvei and Hafnia paralvei, and to compare methods for colistin resistance detection in the Hafnia genus. Methods: A collection of 25 Hafnia isolates was studied. Species were identified by using 16S rRNA gene sequencing with subsequent phylogeny analysis. Susceptibility to colistin was determined using the broth microdilution (BMD) reference method, the Phoenix automated system, the Rapid Polymyxin NP test, the Etest system and the disc diffusion method. Results: The collection consisted of 15 H. alvei and 10 H. paralvei isolates. Based on the 16S rRNA analysis, a close relationship of the Hafnia genus with naturally colistin resistant enterobacterial genera (Proteus, Morganella, Providencia and Serratia) was identified. Susceptibility testing performed using the BMD method, the Phoenix automated system and the Rapid Polymyxin NP test revealed a high rate of colistin resistance (96%). Underestimation of colistin resistance using Etest strips (72%) and the disc diffusion method (0%) was observed. Conclusions: The high rate of colistin resistance observed within the Hafnia genus and its close phylogenetic relationship with naturally colistin-resistant genera suggest that Hafnia is a naturally colistin-resistant enterobacterial genus. PMID- 28586430 TI - National Study of Excellence and Innovation in Physical Therapist Education: Part 1-Design, Method, and Results. AB - Background: The Carnegie Foundation for the Advancement of Teaching commissioned the Preparation for the Professions Program, a qualitative study of professional education in 5 professions: medicine, nursing, law, engineering, and clergy. These studies identified curricular structures, instructional practices, assessment approaches, and environmental characteristics that support the preparation of professionals and led to educational reforms. The physical therapy profession has not had any in-depth, national investigation of physical therapist education since the Catherine Worthingham studies conducted more than 50 years ago. Objectives: This research was a Carnegie-type study, investigating elements of excellence and innovation in academic and clinical physical therapist education in the United States. Design: Five physical therapist education researchers from across the United States used a qualitative multiple-case study design. Methods: Six academic and 5 clinical programs were selected for the study. The academic institutions and clinical agencies studied were diverse in size, institutional setting, geography, and role in residency education. Qualitative case studies were generated from review of artifacts, field observations, and interviews (individual and focus group), and they provided the data for the study. Results: A conceptual framework grounded in 3 major dimensions was generated, with 8 supporting elements: (1) culture of excellence (shared beliefs and values, leadership and vision, drive for excellence, and partnerships), (2) praxis of learning (signature pedagogy, practice-based learning, creating adaptive learners, and professional formation), and (3) organizational structures and resources. Conclusion: Building on the work of the Carnegie Foundation's Preparation for the Professions Program, a conceptual model was developed, representing the dimensions and elements of excellence in physical therapist education that is centered on the foundational importance of a nexus of linked and highly valued aims of being learner centered and patient centered in all learning environments, both academic and clinical. PMID- 28586431 TI - Proteomic Analysis of Calcium Effects on Soybean Root Tip under Flooding and Drought Stresses. AB - Flooding and drought are disadvantageous environmental conditions that induce cytosolic calcium in soybean. To explore the effects of flooding- and drought induced increases in calcium, a gel-free/label-free proteomic analysis was performed. Cytosolic calcium was decreased by blocking calcium channels in the endoplasmic reticulum (ER) and plasma membrane under both stresses. Calnexin, protein disulfide isomerase, heat shock proteins and thioredoxin were predominantly affected as the ER proteins in response to calcium, and ER associated degradation-related proteins of HCP-like superfamily protein were up regulated under stress exposure and then down-regulated. Glycolysis, fermentation, the tricarboxylic acid cycle and amino acid metabolism were mainly induced as the types of cellular metabolism in response to calcium under both stresses. Pyruvate decarboxylase was increased and decreased under flooding and drought, respectively, and was further decreased by the reduction of cytosolic calcium; however, it was recovered by exogenous calcium under both stresses. Furthermore, pyruvate decarboxylase activity was increased under flooding, but decreased under drought. These results suggest that calcium is involved in protein folding in the ER, and ER-associated degradation might alleviate ER stress during the early stage of both stresses. Furthermore, calcium appears to modify energy metabolism, and pyruvate decarboxylase may be a key enzyme in this process under flooding and drought. PMID- 28586432 TI - Locus-specific ChIP combined with NGS analysis reveals genomic regulatory regions that physically interact with the Pax5 promoter in a chicken B cell line. AB - Chromosomal interactions regulate genome functions, such as transcription, via dynamic chromosomal organization in the nucleus. In this study, we attempted to identify genomic regions that physically bind to the promoter region of the Pax5 gene, which encodes a master regulator for B cell lineage commitment, in a chicken B cell line, DT40, with the goal of obtaining mechanistic insight into transcriptional regulation through chromosomal interaction. We found that the Pax5 promoter bound to multiple genomic regions using locus-specific chromatin immunoprecipitation (locus-specific ChIP), a method for locus-specific isolation of target genomic regions, in combination with next-generation sequencing (NGS). Comparing chromosomal interactions in wild-type DT40 with those in a macrophage like counterpart, we found that some of the identified chromosomal interactions were organized in a B cell-specific manner. In addition, deletion of a B cell specific interacting genomic region in chromosome 11, which was marked by active enhancer histone modifications, resulted in moderate but significant down regulation of Pax5 transcription. Together, these results suggested that Pax5 transcription in DT40 is regulated by B cell-specific inter-chromosomal interactions. Moreover, these analyses showed that locus-specific ChIP combined with NGS analysis is useful for non-biased identification of functional genomic regions that physically interact with a locus of interest. PMID- 28586433 TI - Speech Intelligibility and Psychosocial Functioning in Deaf Children and Teens with Cochlear Implants. AB - Deaf children with cochlear implants (CIs) are at risk for psychosocial adjustment problems, possibly due to delayed speech-language skills. This study investigated associations between a core component of spoken-language ability speech intelligibility-and the psychosocial development of prelingually deaf CI users. Audio-transcription measures of speech intelligibility and parent reports of psychosocial behaviors were obtained for two age groups (preschool, school age/teen). CI users in both age groups scored more poorly than typically hearing peers on speech intelligibility and several psychosocial scales. Among preschool CI users, five scales were correlated with speech intelligibility: functional communication, attention problems, atypicality, withdrawal, and adaptability. These scales and four additional scales were correlated with speech intelligibility among school-age/teen CI users: leadership, activities of daily living, anxiety, and depression. Results suggest that speech intelligibility may be an important contributing factor underlying several domains of psychosocial functioning in children and teens with CIs, particularly involving socialization, communication, and emotional adjustment. PMID- 28586436 TI - Response to the letter regarding the impact of psychogenic nonepileptic seizures and our seizure assessment tool. PMID- 28586434 TI - The Arabidopsis Cys2/His2 zinc finger transcription factor ZAT18 is a positive regulator of plant tolerance to drought stress. AB - Environmental stress poses a global threat to plant growth and reproduction, especially drought stress. Zinc finger proteins comprise a family of transcription factors that play essential roles in response to various abiotic stresses. Here, we found that ZAT18 (At3g53600), a nuclear C2H2 zinc finger protein, was transcriptionally induced by dehydration stress. Overexpression (OE) of ZAT18 in Arabidopsis improved drought tolerance while mutation of ZAT18 resulted in decreased plant tolerance to drought stress. ZAT18 was preferentially expressed in stems, siliques, and vegetative rosette leaves. Subcellular location results revealed that ZAT18 protein was predominantly localized in the nucleus. ZAT18 OE plants exhibited less leaf water loss, lower content of reactive oxygen species (ROS), higher leaf water content, and higher antioxidant enzyme activities after drought treatment when compared with the wild type (WT). RNA sequencing analysis showed that 423 and 561 genes were transcriptionally modulated by the ZAT18 transgene before and after drought treatment, respectively. Pathway enrichment analysis indicated that hormone metabolism, stress, and signaling were over-represented in ZAT18 OE lines. Several stress responsive genes including COR47, ERD7, LEA6, and RAS1, and hormone signaling transduction-related genes including JAZ7 and PYL5 were identified as putative target genes of ZAT18. Taken together, ZAT18 functions as a positive regulator and plays a crucial role in the plant response to drought stress. PMID- 28586435 TI - Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice. AB - Context: Fetuses exposed to the high thyroid hormone (TH) levels of mothers with resistance to thyroid hormone beta (RTH-beta), due to mutations in the THRB gene, have low birth weight and suppressed TSH. Objective: Determine if such exposure to high TH levels in embryonic life has a long-term effect into adulthood. Design: Observations in humans with a parallel design on animals to obtain a preliminary information regarding mechanism. Setting: University research centers. Patients or other participants: Humans and mice with no RTH-beta exposed during intrauterine life to high TH levels from mothers who were euthyroid due to RTH-beta. Controls were humans and mice of the same genotype but born to fathers with RTH-beta and mothers without RTH-beta and thus, with normal serum TH levels. Interventions: TSH responses to stimulation with thyrotropin-releasing hormone (TRH) during adult life in humans and male mice before and after treatment with triiodothyronine (T3). We also measured gene expression in anterior pituitaries, hypothalami, and cerebral cortices of mice. Results: Adult humans and mice without RTH-beta, exposed to high maternal TH in utero, showed persistent central resistance to TH, as evidenced by reduced responses of serum TSH to TRH when treated with T3. In mice, anterior pituitary TSH-beta and deiodinase 3 (D3) mRNAs, but not hypothalamic and cerebral cortex D3, were increased. Conclusions: Adult humans and mice without RTH-beta exposed in utero to high maternal TH levels have persistent central resistance to TH. This is likely mediated by the increased expression of D3 in the anterior pituitary, enhancing local T3 degradation. PMID- 28586437 TI - Psychological issues and cognitive impairment in adults with familial hypercholesterolemia. AB - A literature review about depression, anxiety, illness perception and neurocognitive impairment in adults with familial hypercholesterolemia (FH) was performed. Through PubMed and PsycINFO published studies from 1980 until March 2017 were searched. Two papers assessed depression and anxiety. Four papers explored illness perception. Five studies assessed cognitive impairment. Mean depression and anxiety scores were within normal range. From the reviewed research, it can be concluded that deficits in executive functioning and memory appear in FH patients between 18 and 40 years old, and mild cognitive impairment in older than 50. The research in the field of the present review is relatively recent: all the studies have been published in the current century. Further research should be done using complete standardized neuropsychological assessment and brain imaging techniques. Studies exploring the possible influence of cognitive deficits on adherence should be conducted also. PMID- 28586438 TI - COSINE: non-seeding method for mapping long noisy sequences. AB - Third generation sequencing (TGS) are highly promising technologies but the long and noisy reads from TGS are difficult to align using existing algorithms. Here, we present COSINE, a conceptually new method designed specifically for aligning long reads contaminated by a high level of errors. COSINE computes the context similarity of two stretches of nucleobases given the similarity over distributions of their short k-mers (k = 3-4) along the sequences. The results on simulated and real data show that COSINE achieves high sensitivity and specificity under a wide range of read accuracies. When the error rate is high, COSINE can offer substantial advantages over existing alignment methods. PMID- 28586440 TI - Circumferential Wall Enhancement on Magnetic Resonance Imaging is Useful to Identify Rupture Site in Patients with Multiple Cerebral Aneurysms. AB - BACKGROUND: Identification of rupture sites in patients with multiple intracranial aneurysms is largely based on aneurysm size, location, and shape. Finding circumferential enhancement along the aneurysm wall (CEAW) on magnetic resonance (MR) vessel wall imaging was recently shown to be indicative of ruptured aneurysm. OBJECTIVE: To investigate the hypothesis that a higher degree of CEAW would identify the site of rupture in patients with multiple aneurysms. METHODS: We prospectively performed quantitative analysis of CEAW in consecutive patients with both aneurysmal subarachnoid hemorrhage and multiple aneurysms (26 patients with a total of 62 aneurysms), using MR vessel wall imaging. Three dimensional T1-weighted fast spin-echo sequences were obtained before and after injection of contrast media, and the wall enhancement index (WEI) was calculated. Aneurysm characteristics (size, location, irregular shape, aspect ratio [neck-to dome length/neck width], and WEI) were compared between ruptured and unruptured aneurysms. Odds ratios with 95% confidence intervals for ruptures were calculated with conditional univariable logistic regression analysis. Analyses were repeated after adjustment for aneurysm size. RESULTS: Large aneurysm size, high aspect ratio, WEI (above the median values), and irregular shape were significantly associated with aneurysm rupture. After adjustment for aneurysm size, WEI (adjusted odds ratio: 8.8; 95% confidence interval, 1.1-72.6) as well as irregular shape and aspect ratio showed a strong association with rupture. CONCLUSION: CEAW is associated with rupture of intracranial aneurysm independent of aneurysm size and patient characteristics. Contrast-enhanced MR vessel wall imaging helps to identify the site of rupture in patients with multiple aneurysms. PMID- 28586439 TI - RAMP2 Influences Glucagon Receptor Pharmacology via Trafficking and Signaling. AB - Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we investigated the interaction of the GCGR with receptor activity modifying protein (RAMP)2, a member of the family of receptor activity modifying proteins. We used a combination of competition binding experiments, cell surface enzyme-linked immunosorbent assay, functional assays assessing the Galphas and Galphaq pathways and beta-arrestin recruitment, and small interfering RNA knockdown to examine the effect of RAMP2 on the GCGR. Ligands tested were glucagon; glucagonlike peptide-1 (GLP-1); oxyntomodulin; and analog G(X), a GLP-1/glucagon coagonist developed in house. Confocal microscopy was used to assess whether RAMP2 affects the subcellular distribution of GCGR. Here we demonstrate that coexpression of RAMP2 and the GCGR results in reduced cell surface expression of the GCGR. This was confirmed by confocal microscopy, which demonstrated that RAMP2 colocalizes with the GCGR and causes significant GCGR cellular redistribution. Furthermore, the presence of RAMP2 influences signaling through the Galphas and Galphaq pathways, as well as recruitment of beta-arrestin. This work suggests that RAMP2 may modify the agonist activity and trafficking of the GCGR, with potential relevance to production of new peptide analogs with selective agonist activities. PMID- 28586441 TI - The development and testing of the Person-centred Practice Inventory - Staff (PCPI-S). AB - Objective: The aim of the study was to develop and test an instrument, underpinned by a recognized theoretical framework, that examines how staff perceive person-centred practice, using proven methods of instrument design and psychometric analysis. Design: The study used a mixed method multiphase research design involving: two Delphi studies to agree definitions and items to measure the constructs aligned to the person-centred practice theoretical framework (Phase 1); and a large-scale quantitative cross-sectional survey (Phase 2). Setting: Phase 1 was an international study involving representatives from seven countries across Europe and Australia, with Phase 2 conducted in one country across five organizations. Participants: Two international panels of experts (n = 33) in person-centred practice took part in the Delphi study and a randomly selected sample of registered nurses (n = 703, 23.8%) drawn from across a wide range of clinical settings completed the Person-centred Practice Inventory - Staff (PCPI-S). Main Outcome Measures: The main outcome is to establish a measure of staff perceptions of person-centred Practice. Results: Broad consensus on definitions relating to 17 constructs drawn from a person-centred practice framework was achieved after two rounds; likewise with the generation of 108 items to measure the constructs; a final instrument comprising 59 items with proven psychometric properties was achieved. Conclusions: The PCPI-S is psychometrically acceptable instrument validated by an international expert panel that maps specifically to a theoretical framework for person-centred practice and provides a generic measure of person-centredness. PMID- 28586442 TI - The relationship between shared decision-making and health-related quality of life among patients in Hong Kong SAR, China. AB - Objective: To elucidate the association between health-related quality of life and shared decision-making among patients in Hong Kong after adjustment for potential confounding variables. Design: A telephone survey was conducted with patients attending all public specialist outpatient clinics in Hong Kong between July and December 2014. The Specialist Outpatient Patient Experience Questionnaire and EQ-5D questionnaire were used to evaluate shared decision making and quality of life, respectively. We performed a Tobit regression analysis to examine the associations between shared decision-making and quality of life after adjustment for known social, economic and health-related factors. Setting: Twenty-six of the Hospital Authority's specialist outpatient clinics. Participants: Patients aged 18 years or older who attended one of the Hospital Authority's specialist outpatient clinics between July and November 2014. Main Outcome Measure(s): Shared decision-making and quality of life score. Results: Overall, 13 966 patients completed the study. The group reporting partial involvement in decision-making had slightly higher EQ-5D scores than the 'not involved' group and the 'fully involved' group. EQ-5D scores were higher among subjects who were younger, male, and had a higher level of education. Respondents living alone and living in institutions scored lower on the EQ-5D than patients living with families. Conclusions: Important differences in the relationship between the attitudes towards shared decision-making and quality of life were identified among patients. These associations should be taken into consideration when promoting patient-centred care and improving health professional-patient communication. PMID- 28586443 TI - Deconstructing One Medical School's Pain Curriculum: II. Partnering with Medical Students on an Evidence-Guided Redesign. AB - Objective: To reshape medical education about pain to present it as a population based public health process as well as a neuron-centered phenomenon. Design: Collaborate with students to apply a recent inventory of pain-related preclinical curricular content and clinical training in order to modify the current multiyear presentation and offer a broadened social perspective on pain. Appraise fourth year medical students' pain-related educational needs by surveying their knowledge, attitudes, experience with the curriculum, and self-reported assessment of pain-related competencies. Setting and subjects: University affiliated medical school and its fourth-year medical students. Methods: Analysis of a detailed inventory of first- and second-year curricula. Survey of graduating medical students assessing attitudes, skills, and confidence. Construction of a fourth-year pain education elective and collaboration with enrollees to better integrate pain throughout the four-year curriculum. Results: This student-faculty collaboration produced an evidence-guided proposal to reorganize pain-related content across the longitudinal medical curriculum. An attitudes/skills/confidence survey of graduating medical students (104 respondents of 200 polled) found that 70% believed chances for successful outcomes treating chronic pain were low. Self-evaluated competency was high for evaluating (82%) and managing (69%) acute pain; for chronic pain, both were lower (evaluating = 38%; managing = 6%). Self-evaluated knowledge of pain physiology and neurobiology was poor (14%), fair (54%), or good (30%), but rarely excellent (2%). Conclusions: To meet graduating students' desire for increased competency in pain, pain-related curricula can and should be reorganized to include pain as a disease state and a widespread public health burden, not merely a symptom. PMID- 28586444 TI - Technical Communication: Admixture of Bupivacaine-Clonidine-Buprenorphine Dexamethasone at the Bedside in a Tertiary Care Hospital Block Room Is Not Associated with Any Apparent Burdens of Endotoxin or Microbial Growth. PMID- 28586446 TI - Erratum. PMID- 28586445 TI - Relative Conspicuity of Gadolinium-Based Contrast Agents in Interventional Pain Procedures. AB - Objective: To assess the relative radiographic conspicuity of gadolinium-based contrast agents (GBCAs) that may be used in spinal injection procedures when iodine-based contrast agents are contraindicated. Methods: Eight GBCAs and three iodinated agents of varying iodine concentrations were radiographed under conditions representative of lumbar spinal injections at four kilovoltage peak (kVp) values. Radiographic contrast of each agent was measured as the percent pixel value difference with respect to background. Results: Gadobutrol (Gadovist, 1 mM/mL) had the highest radiographic contrast among the gadolinium agents tested. Measured radiographic contrast correlated with the molar concentration of gadolinium. Gadobutrol radiographic contrast lies between the contrast of iohexol concentrations of 240 and 140 mgI/mL. All agents have decreasing contrast as kVp increases, but GBCAs decrease less than iodine-based agents. Conclusions: Gadobutrol is the GBCA with the greatest conspicuity for use in spinal injection procedures. It also has the highest molar concentration of gadolinium, and potential neural toxicity from intrathecal delivery must be considered. PMID- 28586447 TI - Seizure control as a new metric in assessing efficacy of tumor treatment in low grade glioma trials-impact of psychogenic non-epileptic seizures. PMID- 28586448 TI - Letter to the Editor: "Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss". PMID- 28586449 TI - Response to Letter: "Characteristics of Men Who Report Persistent Sexual Symptoms After Finasteride Use for Hair Loss". PMID- 28586450 TI - Letter to the Editor: What Is the Role of Serum Thyroglobulin Measurement in Patients With Differentiated Thyroid Cancer Treated Without Radioactive Iodine? PMID- 28586451 TI - Letter to the Editor: Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation. PMID- 28586452 TI - Letter to the Editor: "Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline". PMID- 28586453 TI - Response to Letter: "Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline". PMID- 28586455 TI - Erratum for "IGSF1 Deficiency: Lessons From an Extensive Case Series and Recommendations for Clinical Management". PMID- 28586454 TI - Erratum for "Everolimus in Patients With Advanced Follicular-Derived Thyroid Cancer: Results of a Phase II Clinical Trial". PMID- 28586456 TI - Response to Letter: Severe Rebound-Associated Vertebral Fractures After Denosumab Discontinuation. PMID- 28586457 TI - Response to Letter: What Is the Role of Serum Thyroglobulin Measurement in Patients With Differentiated Thyroid Cancer Treated Without Radioactive Iodine? PMID- 28586458 TI - Disease Stabilization of DYT1-Positive Primary Generalized Dystonia With Deep Brain Stimulation of the Globus Pallidus Interna: A 15-Year Follow-up. AB - BACKGROUND AND IMPORTANCE: Primary generalized dystonia (PGD) is a genetic form of dystonia that frequently displays pharmacological resistance and progresses quickly after onset. Deep brain stimulation (DBS) has been used successfully to treat refractory dystonia, specifically globus pallidus interna (GPi) DBS for DYT1-positive PGD patients. Long-term follow-up of the safety and efficacy falls short of the longevity seen in other diseases treated with DBS. CASE PRESENTATION: A male patient presented for neurosurgical evaluation with scapular winging, hand contractures, and violent truncal spasms, which forced him to be bedridden. After failing conservative therapy, the 18-yr-old patient was implanted with bilateral GPi-DBS. DBS parameter adjustments were made primarily within the first 3 yr after implantation, with nominal changes thereafter. Initial settings were contact of 3 + 0-, amplitude of 4.9 V, frequency of 185 Hz, and pulse width of 270 MUsec on the left and 3 + 0-, 2.8 V, 185 Hz, and 120 MUsec on the right. Current settings are 3 + 2 + 1-, 5.2 V, 130 Hz, 330 MUsec on the left and 3 + 0-, 3.5 V, 185 Hz, and 180 MUsec on the right and have been relatively unchanged in the past 4 yr. Unified dystonia rating scale scores reveal a significant decrease in dystonic symptoms. CONCLUSION: While prior reports have shown that GPi-DBS is effective for dystonia, this is the first with 15 yr of long-term follow-up showing disease stabilization, suggesting that stimulation is efficacious and can potentially prevent disease progression. This report reaffirms previous reports that recommend early surgical intervention before the onset of permanent musculoskeletal deficits. PMID- 28586460 TI - A pre-in vitro maturation medium containing cumulus oocyte complex ligand receptor signaling molecules maintains meiotic arrest, supports the cumulus oocyte complex and improves oocyte developmental competence. AB - STUDY QUESTION: Can a pre-in vitro maturation (pre-IVM) medium containing signaling molecules rather than chemical/pharmaceutical agents, sustain meiotic arrest and improve developmental competence of in vitro matured oocytes in CF1 outbred mice? SUMMARY ANSWER: A short 2 h period of pre-IVM prevents spontaneous meiotic resumption, improves mitochondria activity in subsequently matured oocytes, and increases developmental competence, pregnancy rate and implantation of resulting embryos. WHAT IS KNOWN ALREADY: Spontaneous resumption of meiosis in vitro is detrimental for oocyte developmental competence. Pre-IVM systems that prevent spontaneous meiotic resumption with chemical/pharmaceutical agents are a promising approach to improving IVM oocyte competence; however, the success of these methods has proven to be inconsistent. STUDY DESIGN, SIZE, DURATION: This study consisted of a series of experiments using cumulus oocyte complexes (COC) derived from outbred mice following ovarian stimulation. The study was designed to examine if a novel, ligand/receptor-based pre-IVM treatment could sustain meiotic arrest in vitro and improve oocyte developmental competence, compared to control IVM. Two pre-IVM durations (2 h and 24 h) were evaluated, and the effect of the mitochondrial stimulator PQQ during 24 h pre-IVM was studied. PARTICIPANTS/MATERIALS, SETTING, METHODS: Murine (outbred CF1) immature COC were cultured in vitro in the presence of C-type natriuretic peptide (CNP) (30 nM), estradiol (100 nM), FSH (1 * 10-4 IU/ml) and bone morphogenic protein 15 (BMP15) (100 ng/ml) for 2 h or 24 h prior to IVM. Meiotic status during pre-IVM and IVM was analyzed using orcein staining, and functionality of gap junction communication was confirmed using the functional gap junction inhibitor carbenoxolone (CBX). Oocytes exposed to pre-IVM treatment were compared to control oocytes collected on the same day from the same females and undergoing standard IVM. Developmental competence and embryo viability was assessed by oocyte mitochondrial activity and ATP concentration, in vitro embryo development following IVF and in vitro culture, blastocyst cell number and allocation, embryo morphokinetics, and embryo transfer. Differences were determined to be significant when P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Both a short (2 h) and long (24 h) pre-IVM period successfully prevented spontaneous resumption of meiosis. Moreover, gap junctions remained open during the pre-IVM period, as shown by the resumption of meiosis (95.9 +/- 2.1%) in the presence of CBX during pre-IVM. A 2 h pre-IVM treatment improved blastocyst development after 96 h of culture per cleaved embryo compared to control (71.9 +/- 7.4% versus 53.3 +/- 6.2%, respectively), whereas a longer 24 h pre-IVM had no effect on development. A short 2 h period of pre-IVM increased mitochondrial activity in mature oocytes. On the contrary, mitochondrial activity was reduced in mature oocytes following 24 h of arrest and IVM. Treatment of arrested COC with pyrroloquinoline quinone (PQQ) during the 24 h pre-IVM period successfully maintained mitochondrial activity equal to control. However, PQQ was not able to improve blastocyst development compared to pre-IVM 24 h without PQQ. Moreover, ATP concentration in mature oocytes following pre-IVM and/or IVM, did not differ between treatments. A 2 h pre-IVM period prior to IVM improved pregnancy rate following transfer to recipient females. Implantation was also improved after transfer of embryos derived from oocytes arrested for either 2 h or 24 h prior to IVM, compared to control IVM derived embryos (41.9 +/- 9%, 37.2 +/- 9.5% and 17.2 +/- 8.3%, respectively), although fetal development did not differ. LIMITATIONS, REASONS FOR CAUTION: Slower meiotic resumption and enhanced mitochondrial activity likely contribute to improved developmental competence of oocytes exposed to pre-IVM for 2 h, but further experiments are required to identify specific mechanisms. Maintaining oocytes in meiotic arrest for 24 h with this approach could be a potential window to improve oocyte quality. However, an initial attempt to utilize this period of arrest to manipulate quality with PQQ, a mitochondrial stimulator, did not improve oocyte competence. WIDER IMPLICATIONS OF THE FINDINGS: IVM could be an attractive clinical alternative to conventional IVF, with reduced time, cost and reliance on high doses of exogenous hormones to stimulate follicle growth, thus eliminating ovarian hyperstimulation syndrome (OHSS). Currently IVM is not widely used as it results in reduced embryo development and lower pregnancy outcomes compared to embryos produced from in vivo matured oocytes. Our approach to IVM, incorporating a ligand/receptor pre IVM period, could improve human oocyte quality following IVM leading to routine adoption of this patient friendly technology. In addition, our methodology of pre IVM containing signaling molecules rather than chemical/pharmaceutical agents may prove to be more consistent at improving oocyte quality than those focusing only on cAMP modulation with pharmacological agents. Finally, a reliable method of maintaining oocytes in meiotic arrest in vitro provides a novel window of opportunity in which the oocyte may be manipulated to address specific physiological deficiencies prior to meiotic resumption. LARGE SCALE DATA: N/A. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Colorado Center for Reproductive Medicine (CCRM, Lone Tree, Colorado USA). We declare no conflict of interest. PMID- 28586459 TI - FASTmiR: an RNA-based sensor for in vitro quantification and live-cell localization of small RNAs. AB - Small RNAs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs), play a variety of important regulatory roles in many eukaryotes. Their small size has made it challenging to study them directly in live cells. Here we describe an RNA-based fluorescent sensor for small RNA detection both in vitro and in vivo, adaptable for any small RNA. It utilizes an sxRNA switch for detection of miRNA mRNA interactions combined with a fluorophore-binding sequence 'Spinach', a GFP like RNA aptamer for which the RNA-fluorophore complex exhibits strong and consistent fluorescence under an excitation wavelength. Two example sensors, FASTmiR171 and FASTmiR122, can rapidly detect and quantify the levels of miR171 and miR122 in vitro. The sensors can determine relative levels of miRNAs in total RNA extracts with sensitivity similar to small RNA sequencing and northern blots. FASTmiR sensors were also used to estimate the copy number range of miRNAs in total RNA extracts. To localize and analyze the spatial distribution of small RNAs in live, single cells, tandem copies of FASTmiR122 were expressed in different cell lines. FASTmiR122 was able to quantitatively detect the differences in miR122 levels in Huh7 and HEK293T cells demonstrating its potential for tracking miRNA expression and localization in vivo. PMID- 28586461 TI - Genetically low vitamin D concentrations and myopic refractive error: a Mendelian randomization study. AB - Background: Myopia prevalence has increased in the past 20 years, with many studies linking the increase to reduced time spent outdoors. A number of recent observational studies have shown an inverse association between vitamin D [25(OH)D] serum levels and myopia. However, in such studies it is difficult to separate the effects of time outdoors and vitamin D levels. In this work we use Mendelian randomization (MR) to assess if genetically determined 25(OH)D levels contribute to the degree of myopia. Methods: We performed MR using results from a meta-analysis of refractive error (RE) genome-wide association study (GWAS) that included 37 382 and 8 376 adult participants of European and Asian ancestry, respectively, published by the Consortium for Refractive Error And Myopia (CREAM). We used single nucleotide polymorphisms (SNPs) in the DHCR7, CYP2R1, GC and CYP24A1 genes with known effects on 25(OH)D concentration as instrumental variables (IV). We estimated the effect of 25(OH)D on myopia level using a Wald type ratio estimator based on the effect estimates from the CREAM GWAS. Results: Using the combined effect attributed to the four SNPs, the estimate for the effect of 25(OH)D on refractive error was -0.02 [95% confidence interval (CI) 0.09, 0.04] dioptres (D) per 10 nmol/l increase in 25(OH)D concentration in Caucasians and 0.01 (95% CI -0.17, 0.19) D per 10 nmol/l increase in Asians. Conclusions: The tight confidence intervals on our estimates suggest the true contribution of vitamin D levels to degree of myopia is very small and indistinguishable from zero. Previous findings from observational studies linking vitamin D levels to myopia were likely attributable to the effects of confounding by time spent outdoors. PMID- 28586462 TI - Preclinical Models to Investigate Mechanisms of Negative Symptoms in Schizophrenia. PMID- 28586463 TI - Crowding-induced transcriptional bursts dictate polymerase and nucleosome density profiles along genes. AB - During eukaryotic transcription, RNA polymerase (RNAP) translocates along DNA molecules covered with nucleosomes and other DNA binding proteins. Though the interactions between a single nucleosome and RNAP are by now fairly well understood, this understanding has not been synthesized into a description of transcription on crowded genes, where multiple RNAP transcribe through nucleosomes while preserving the nucleosome coverage. We here take a deductive modeling approach to establish the consequences of RNAP-nucleosome interactions for transcription in crowded environments. We show that under physiologically crowded conditions, the interactions of RNAP with nucleosomes induce a strong kinetic attraction between RNAP molecules, causing them to self-organize into stable and moving pelotons. The peloton formation quantitatively explains the observed nucleosome and RNAP depletion close to the initiation site on heavily transcribed genes. Pelotons further translate into short-timescale transcriptional bursts at termination, resulting in burst characteristics consistent with instances of bursty transcription observed in vivo. To facilitate experimental testing of our proposed mechanism, we present several analytic relations that make testable quantitative predictions. PMID- 28586464 TI - Does unmeasured confounding influence associations between the retail food environment and body mass index over time? The Coronary Artery Risk Development in Young Adults (CARDIA) study. AB - Background: Findings in the observational retail food environment and obesity literature are inconsistent, potentially due to a lack of adjustment for residual confounding. Methods: Using data from the CARDIA study (n = 12 174 person observations; 6 examinations; 1985-2011) across four US cities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA), we used instrumental-variables (IV) regression to obtain causal estimates of the longitudinal associations between the percentage of neighbourhood food stores or restaurants (per total food outlets within 1 km network distance of respondent residence) with body mass index (BMI), adjusting for individual-level socio-demographics, health behaviours, city, year, total food outlets and market-level prices. To determine the presence and extent of bias, we compared the magnitude and direction of results with ordinary least squares (OLS) and random effects (RE) regression, which do not control for residual confounding, and with fixed effects (FE) regression, which does not control for time-varying residual confounding. Results: Relative to neighbourhood supermarkets (which tend to be larger and have healthier options than grocery stores), a higher percentage of grocery stores [mean = 53.4%; standard deviation (SD) = 31.8%] was positively associated with BMI [beta = 0.05; 95% confidence interval (CI) = 0.01, 0.10] using IV regression. However, associations were negligible or null using OLS (beta = -0.001; 95% CI = 0.01, 0.01), RE (beta = -0.003; 95% CI = -0.01, 0.0001) and FE (beta = -0.003; 95% CI = -0.01, 0.0002) regression. Neighbourhood convenience stores and fast food restaurants were not associated with BMI in any model. Conclusions: Longitudinal associations between neighbourhood food outlets and BMI were greater in magnitude using a causal model, suggesting that weak findings in the literature may be due to residual confounding. PMID- 28586465 TI - ROS Induces Anthocyanin Production Via Late Biosynthetic Genes and Anthocyanin Deficiency Confers the Hypersensitivity to ROS-Generating Stresses in Arabidopsis. AB - Anthocyanins are known to have antioxidant activities. Their accumulation can be triggered by many chemical and environmental factors, including reactive oxygen species (ROS). However, the mechanism of ROS-induced anthocyanin accumulation and the role of anthocyanins in the response of Arabidopsis (Arabidopsis thaliana) to different stresses are largely unknown. Here, we study the cross-regulation between ROS and anthocyanin production. Ten Arabidopsis mutants covering the main anthocyanin regulatory and biosynthetic genes are systematically analyzed under ROS-generating stresses. We find that ROS triggers anthocyanin accumulation by up regulating the anthocyanin late biosynthetic and the corresponding regulatory genes. The anthocyanin-deficient mutants have more endogenous ROS and are more sensitive to ROS-generating stresses while having decreased antioxidant capacity. Supplementation with cyanidin makes them less susceptible to ROS, with increased anthocyanin and reduced ROS accumulation. In contrast, pap1-D, which overaccumulates anthocyanins, shows the opposite responses. Gene expression analysis reveals that photosynthetic capacity is more impaired in anthocyanin deficient mutants under high-light stress. Expression levels of ROS-scavenging enzyme genes are not correlated with the radical-scavenging activity in different mutants. We conclude that ROS are an important source signal to induce anthocyanin accumulation by up-regulating late biosynthetic and the corresponding regulatory genes and, as a feed-back regulation, anthocyanins modulate the ROS level and the sensitivity to ROS-generating stresses in maintaining photosynthetic capacity. PMID- 28586466 TI - Health and Economic Impact of a Tender-Based, Sex-Neutral Human Papillomavirus 16/18 Vaccination Program in the Netherlands. AB - Background: Uptake of human papillomavirus (HPV) vaccine among girls in the Dutch immunization program has plateaued at around 60%. Vaccinating boys may be an appealing complementary strategy for the prevention of HPV-related diseases, especially since tender negotiations and reduced dosing schemes have driven down the cost of vaccination. Methods: We expanded a previously published Bayesian synthesis framework to account for all vaccine type-related cancers and herd immunity effects from vaccinating girls and boys. We evaluated the efficiency of vaccinating boys relative to increasing vaccine uptake among girls and assessed the cost-effectiveness of a sex-neutral program. Results: Vaccinating 40% of boys along with 60% of girls yielded the same gain in life-years (LYs) as increasing the uptake in girls from 60% to 80%. The incremental cost-effectiveness ratio (ICER) of vaccinating boys was ?9134/LY (95% credible interval [CrI], ?7323/LY ?11231/LY) under 3% discounting. The ceiling vaccination costs at which the ICER remained below the per capita gross domestic product threshold was ?240 (95% CrI, ?200-?280) per vaccinated boy. If girls' uptake increased to 90%, the ceiling costs decreased to ?70 (95% CrI, ?40-?100) per vaccinated boy. Conclusions: Vaccinating boys along with girls is only modestly less efficient than increasing uptake among girls and highly likely to be cost-effective under current vaccine costs and uptake in the Netherlands. PMID- 28586468 TI - National Study of Excellence and Innovation in Physical Therapist Education: Part 2-A Call to Reform. AB - This perspective shares recommendations that draw from (1) the National Study of Excellence and Innovation in Physical Therapist Education research findings and a conceptual model of excellence in physical therapist education, (2) the Carnegie Foundation's Preparation for the Professions Program (PPP), and (3) research in the learning sciences. The 30 recommendations are linked to the dimensions described in the conceptual model for excellence in physical therapist education: Culture of Excellence, Praxis of Learning, and Organizational Structures and Resources. This perspective proposes a transformative call for reform framed across 3 core categories: (1) creating a culture of excellence, leadership, and partnership, (2) advancing the learning sciences and understanding and enacting the social contract, and (3) implementing organizational imperatives. Similar to the Carnegie studies, this perspective identifies action items (9) that should be initiated immediately in a strategic and systematic way by the major organizational stakeholders in physical therapist education. These recommendations and action items provide a transformative agenda for physical therapist education, and thus the profession, in meeting the changing needs of society through higher levels of excellence. PMID- 28586467 TI - Plastidial Folate Prevents Starch Biosynthesis Triggered by Sugar Influx into Non Photosynthetic Plastids of Arabidopsis. AB - Regulation of sucrose-starch interconversion in plants is important to maintain energy supplies necessary for viability and growth. Arabidopsis mutants were screened for aberrant responses to sucrose to identify candidates with a defect in the regulation of starch biosynthesis. One such mutant, fpgs1-4, accumulated substantial amounts of starch in non-photosynthetic cells. Dark-grown mutant seedlings exhibited shortened hypocotyls and accumulated starch in etioplasts when supplied with exogenous sucrose/glucose. Similar starch accumulation from exogenous sucrose was observed in mutant chloroplasts, when photosynthesis was prevented by organ culture in darkness. Molecular genetic analyses revealed that the mutant was defective in plastidial folylpolyglutamate synthetase, one of the enzymes engaged in folate biosynthesis. Active folate derivatives are important biomolecules that function as cofactors for a variety of enzymes. Exogenously supplied 5-formyl-tetrahydrofolate abrogated the mutant phenotypes, indicating that the fpgs1-4 mutant produced insufficient folate derivative levels. In addition, the antifolate agents methotrexate and 5-fluorouracil induced starch accumulation from exogenously supplied sucrose in dark-grown seedlings of wild type Arabidopsis. These results indicate that plastidial folate suppresses starch biosynthesis triggered by sugar influx into non-photosynthetic cells, demonstrating a hitherto unsuspected link between plastidial folate and starch metabolism. PMID- 28586469 TI - Dormancy-Associated MADS-Box (DAM) and the Abscisic Acid Pathway Regulate Pear Endodormancy Through a Feedback Mechanism. AB - In the pear 'Kosui' (Pyrus pyrifolia Nakai), the dormancy-associated MADS-box (PpDAM1 = PpMADS13-1) gene has been reported to play an essential role in bud endodormancy. Here, we found that PpDAM1 up-regulated expression of 9-cis epoxycarotenoid dioxygenase (PpNCED3), which is a rate-limiting gene for ABA biosynthesis. Transient assays with a dual luciferase reporter system (LUC assay) and electrophoretic mobility shift assay (EMSA) showed that PpDAM1 activated PpNCED3 expression by binding to the CArG motif in the PpNCED3 promoter. PpNCED3 expression was increased toward endodormancy release in lateral flower buds of 'Kosui', which is consistent with the induced levels of ABA, its catabolism (ABA 8'-hydroxylase) and signaling genes (type 2C protein phosphatase genes and SNF1 related protein kinase 2 genes). In addition, we found that an ABA response element (ABRE)-binding transcription factor, PpAREB1, exhibiting high expression concomitant with endodormancy release, bound to three ABRE motifs in the promoter region of PpDAM1 and negatively regulated its activity. Taken together, our results suggested a feedback regulation between PpDAM1 and the ABA metabolism and signaling pathway during endodormancy of pear. This first evidence of an interaction between a DAM and ABA biosynthesis in vitro will provide further insights into bud endodormancy regulatory mechanisms of deciduous trees including pear. PMID- 28586470 TI - The IDA-LIKE peptides IDL6 and IDL7 are negative modulators of stress responses in Arabidopsis thaliana. AB - Small signalling peptides have emerged as important cell to cell messengers in plant development and stress responses. However, only a few of the predicted peptides have been functionally characterized. Here, we present functional characterization of two members of the IDA-LIKE (IDL) peptide family in Arabidopsis thaliana, IDL6 and IDL7. Localization studies suggest that the peptides require a signal peptide and C-terminal processing to be correctly transported out of the cell. Both IDL6 and IDL7 appear to be unstable transcripts under post-transcriptional regulation. Treatment of plants with synthetic IDL6 and IDL7 peptides resulted in down-regulation of a broad range of stress responsive genes, including early stress-responsive transcripts, dominated by a large group of ZINC FINGER PROTEIN (ZFP) genes, WRKY genes, and genes encoding calcium-dependent proteins. IDL7 expression was rapidly induced by hydrogen peroxide, and idl7 and idl6 idl7 double mutants displayed reduced cell death upon exposure to extracellular reactive oxygen species (ROS). Co-treatment of the bacterial elicitor flg22 with IDL7 peptide attenuated the rapid ROS burst induced by treatment with flg22 alone. Taken together, our results suggest that IDL7, and possibly IDL6, act as negative modulators of stress-induced ROS signalling in Arabidopsis. PMID- 28586473 TI - Exome Sequencing Identifies Two Variants of the Alkylglycerol Monooxygenase Gene as a Cause of Relapses in Visceral Leishmaniasis in Children, in Sudan. AB - Background: Visceral leishmaniasis (kala-azar, KA) is the most severe form of leishmaniasis, characterized by fever, weight loss, hepatosplenomegaly, and lymphadenopathy. During an outbreak of KA in Babar El Fugara (Sudan), 5.7% of cured patients displayed relapses, with familial clustering in half the cases. Methods: We performed whole-exome sequencing on 10 relapsing individuals and 11 controls from 5 nuclear families. Results: Rare homozygous and compound heterozygous nonsense (c.1213C > T, rs139309795, p.Arg405*) and missense (c.701A > G, rs143439626, p.Lys234Arg) mutations of the alkylglycerol monooxygenase (AGMO) gene were associated with KA relapse in 3 families. Sequencing in additional family members confirmed the segregation of these mutations with relapse and revealed an autosomal dominant mode of transmission. These mutations were detected heterozygous in 2 subjects among 100 unrelated individuals with KA who never relapsed after cure, suggesting incomplete penetrance of AGMO deficiency. AGMO is expressed in hematopoietic cells, and is strongly expressed in the liver. AGMO modulates PAF production by mouse macrophages, suggesting that it may act through the PAF/PAF receptor pathway previously shown to have anti Leishmania activity. Conclusions: This is the first demonstration that relapses after a first episode of KA are due to differences in human genetic susceptibility and not to modifications of parasite pathogenicity. PMID- 28586472 TI - Maternal consumption of artificially sweetened beverages during pregnancy, and offspring growth through 7 years of age: a prospective cohort study. AB - Background: Artificial sweeteners are widely replacing caloric sweeteners. Data on long-term impact of artificially sweetened beverage (ASB) consumption during pregnancy on offspring obesity risk are lacking. We prospectively investigated intake of ASBs and sugar-sweetened beverages (SSBs) during pregnancy in relation to offspring growth through age 7 years among high-risk children born to women with gestational diabetes. Methods: In a prospective study of 918 mother singleton child dyads from the Danish National Birth Cohort, maternal dietary intake was assessed by a food frequency questionnaire during pregnancy. Offspring body mass index z-scores (BMIZ) and overweight/obesity status were derived using weight and length/height at birth, 5 and 12 months and 7 years. Linear regression and Poisson regression with robust standard errors were used, adjusting for major risk factors. Results: Approximately half of women reported consuming ASBs during pregnancy and 9% consumed daily. Compared to never consumption, daily ASB intake during pregnancy was positively associated with offspring large-for-gestational age [adjusted relative risk (aRR) 1.57; 95% CI: 1.05, 2.35 at birth], BMIZ (adjusted beta 0.59; 95% CI: 0.23, 0.96) and overweight/obesity (aRR 1.93; 95% CI; 1.24, 3.01) at 7 years. Per-serving-per-day substitution of ASBs with water during pregnancy was related to a lower overweight/obesity risk at 7 years (aRR 0.83; 95% CI: 0.76, 0.91), whereas SSB substitution with ASBs was not related to a lower risk (aRR 1.14; 95% CI: 1.00, 1.31). Conclusions: Our findings illustrated positive associations between intrauterine exposure to ASBs and birth size and risk of overweight/obesity at 7 years. Data with longer follow-up are warranted. PMID- 28586474 TI - Epidemiology in the age of sustainable development. PMID- 28586476 TI - Development and Validation of a Novel Adult Spinal Deformity Surgical Invasiveness Score: Analysis of 464 Patients. AB - BACKGROUND: A surgical invasiveness index (SII) has been validated in general spine procedures but not adult spinal deformity (ASD). OBJECTIVE: To assess the ability of the SII to determine the invasiveness of ASD surgery and to create and validate a novel ASD index incorporating deformity-specific factors, which could serve as a standardized metric to compare outcomes and risk stratification of different ASD procedures for a given deformity. METHODS: Four hundred sixty-four patients who underwent ASD surgery between 2009 and 2012 were identified in 2 multicenter prospective registries. Multivariable models of estimated blood loss (EBL) and operative time were created using deformity-specific factors. Beta coefficients derived from these models were used to attribute points to each component. Scoring was iteratively refined to determine the R2 value of multivariate models of EBL and operative time using adult spinal deformity surgical (ASD-S) as an independent variable. Similarly, we determined weighting of postoperative changes in radiographical parameters, which were incorporated into another index (adult spinal deformity-surgical and radiographical [ASD-SR]). The ability of these models to predict surgical invasiveness was assessed in a validation cohort. RESULTS: Each index was a significant, independent predictor of EBL and operative time (P < .001). On multivariate analysis, ASD-S and ASD-SR explained more variability in EBL and operative time than did the SII (P < .001). The ASD-SR explained 21% of the variation in EBL and 10% of the variation in operative time, whereas the SII explained 17% and 3.2%, respectively. CONCLUSION: The ASD-SR, which incorporates deformity-specific components, more accurately predicts the magnitude of ASD surgery than does the SII. PMID- 28586471 TI - Intranasal Oxytocin May Improve High-Level Social Cognition in Schizophrenia, But Not Social Cognition or Neurocognition in General: A Multilevel Bayesian Meta analysis. AB - While there is growing interest in the potential for intranasal oxytocin (IN-OT) to improve social cognition and neurocognition (ie, nonsocial cognition) in schizophrenia, the extant literature has been mixed. Here, we perform a Bayesian meta-analysis of the efficacy of IN-OT to improve areas of social and neurocognition in schizophrenia. A systematic search of original research publications identified randomized controlled trials (RCTs) of IN-OT as a treatment for social and neurocognitive deficits in schizophrenia for inclusion. Standardized mean differences (SMD) and corresponding variances were used in multilevel Bayesian models to obtain meta-analytic effect-size estimates. Across a total of 12 studies (N = 273), IN-OT did not improve social cognition (SMD = 0.07, 95% credible interval [CI] = [-0.06, 0.17]) or neurocognition (SMD = 0.12, 95% CI = [-0.12, 0.34]). There was moderate between study heterogeneity for social cognition outcomes (taus= 0.12). Moderator analyses revealed that IN-OT had a significantly larger effect on high-level social cognition (ie, mentalizing and theory of mind) compared to low-level social cognition (ie, social cue perception) (b = 0.19, 95% CI = [0.05, 0.33]). When restricting our analysis to outcomes for high-level social cognition, there was a significant effect of IN-OT (SMD = 0.20, 95 % CI = [0.05, 0.33]) but the effect was not robust to sensitivity analyses. The present analysis indicates that IN-OT may have selective effects on high-level social cognition, which provides a more focused target for future studies of IN-OT. PMID- 28586475 TI - Aging in Activity Space: Results From Smartphone-Based GPS-Tracking of Urban Seniors. AB - Objectives: Prior research emphasizes the importance of the residential neighborhood context during later life but little attention has been afforded to other areas that older adults encounter as they move beyond their residential environments for daily activities and social interactions. This study examines the predominance of the residential context within older adults' everyday lives. Method: We provided 60 older adults in four New York City neighborhoods with iPhones, which captured Global Positioning Systems (GPS) locations at 5-min intervals over 1 week (n = 55,561) and 17 ecological momentary assessments (EMAs) over 4 days (n = 757) to assess real-time activities. Results: Older adults in our sample spent nearly 40% of their time outside of their residential tracts and they visited 28 other tracts, on average. Exercising, shopping, socializing, and social activities were especially likely to take place outside of residential tracts. Differences in residential and nonresidential poverty exposure vary across gender, race/ethnicity, education, car ownership, and residential areas. Discussion: Measuring activity space, rather than relying on residential tracts, allows examination of the social environments that are relevant for older adults' everyday lives. Variation in characteristics of activity spaces may be an underexplored source of differences in health and well-being during later life. PMID- 28586477 TI - Affinity purification with metabolomic and proteomic analysis unravels diverse roles of nucleoside diphosphate kinases. AB - Interactions between metabolites and proteins play an integral role in all cellular functions. Here we describe an affinity purification (AP) approach in combination with LC/MS-based metabolomics and proteomics that allows, to our knowledge for the first time, analysis of protein-metabolite and protein-protein interactions simultaneously in plant systems. More specifically, we examined protein and small-molecule partners of the three (of five) nucleoside diphosphate kinases present in the Arabidopsis genome (NDPK1-NDPK3). The bona fide role of NDPKs is the exchange of terminal phosphate groups between nucleoside diphosphates (NDPs) and triphosphates (NTPs). However, other functions have been reported, which probably depend on both the proteins and small molecules specifically interacting with the NDPK. Using our approach we identified 23, 17, and 8 novel protein partners of NDPK1, NDPK2, and NDPK3, respectively, with nucleotide-dependent proteins such as actin and adenosine kinase 2 being enriched. Particularly interesting, however, was the co-elution of glutathione S transferases (GSTs) and reduced glutathione (GSH) with the affinity-purified NDPK1 complexes. Following up on this finding, we could demonstrate that NDPK1 undergoes glutathionylation, opening a new paradigm of NDPK regulation in plants. The described results extend our knowledge of NDPKs, the key enzymes regulating NDP/NTP homeostasis. PMID- 28586478 TI - Autoregulation of RBM10 and cross-regulation of RBM10/RBM5 via alternative splicing-coupled nonsense-mediated decay. AB - Mutations in the spliceosomal RNA binding protein RBM10 cause TARP syndrome and are frequently observed in lung adenocarcinoma (LUAD). We have previously shown that RBM10 enhances exon skipping of its target genes, including its paralog RBM5. Here, we report that RBM10 negatively regulates its own mRNA and protein expression and that of RBM5 by promoting alternative splicing-coupled nonsense mediated mRNA decay (AS-NMD). Through computational analysis and experimental validation, we identified RBM10-promoted skipping of exon 6 or 12 in RBM10 and exon 6 or 16 in RBM5 as the underlying AS-NMD events. Importantly, we showed that LUAD-associated mutations affecting splice sites of RBM10 exons 6 or 12 abolished exon inclusion and correlated with reduced expression of RBM10 RNA. Together, our investigations have revealed novel molecular mechanisms underlying RBM10 autoregulation and cross-regulation of RBM5, thereby providing insights concerning the functions of RBM10 under various physiological and pathological conditions. Our combined computational and experimental approach should be useful for elucidating the role of AS-NMD in auto- and cross-regulation by other splicing regulators. PMID- 28586479 TI - Advanced multi-loop algorithms for RNA secondary structure prediction reveal that the simplest model is best. AB - Algorithmic prediction of RNA secondary structure has been an area of active inquiry since the 1970s. Despite many innovations since then, our best techniques are not yet perfect. The workhorses of the RNA secondary structure prediction engine are recursions first described by Zuker and Stiegler in 1981. These have well understood caveats; a notable flaw is the ad-hoc treatment of multi-loops, also called helical-junctions, that persists today. While several advanced models for multi-loops have been proposed, it seems to have been assumed that incorporating them into the recursions would lead to intractability, and so no algorithms for these models exist. Some of these models include the classical model based on Jacobson-Stockmayer polymer theory, and another by Aalberts and Nadagopal that incorporates two-length-scale polymer physics. We have realized practical, tractable algorithms for each of these models. However, after implementing these algorithms, we found that no advanced model was better than the original, ad-hoc model used for multi-loops. While this is unexpected, it supports the praxis of the current model. PMID- 28586481 TI - Dietary fiber and digestive health in children. AB - Digestive health is an expanding area in nutrition research due to the interest in how food components such as fiber affect gastrointestinal tolerance, stool form, defecation frequency, transit time, and gut microbial composition and metabolic activity. In children, however, digestive health studies that intervene with dietary fiber are limited due to legal and ethical concerns. To better understand if fiber improves digestive health in children, a literature review was conducted to answer the following research question: What are the effect(s) of fiber-containing foods and/or supplements on digestive health outcomes in children? A search of the PubMed database identified a total of 12 studies that fit the inclusion criteria established for this review. Most of the evidence in children shows beneficial effects of partially hydrolyzed guar gum, glucomannan, and bran on digestive health outcomes; however, the existing evidence is not conclusive. Furthermore, limited data exists on the effect of whole-grain sources of dietary fiber, such as oats. Additional well-designed intervention trials are needed to determine whether outcomes of digestive health such as stool form, gastrointestinal tolerance, and stool frequency are improved by increasing the fiber content of children's diets with whole-grain sources. PMID- 28586480 TI - Lifetime Prevalence and Correlates of Schizophrenia-Spectrum, Affective, and Other Non-affective Psychotic Disorders in the Chinese Adult Population. AB - Lifetime prevalence of psychotic disorders varies widely across studies. Epidemiological surveys have rarely examined prevalences of specific psychotic disorders other than schizophrenia, and the majority used a single-phase design without employing clinical reappraisal interview for diagnostic verification. The current study investigated lifetime prevalence, correlates and service utilization of schizophrenia-spectrum, affective, and other non-affective psychotic disorders in a representative sample of community-dwelling Chinese adult population aged 16-75 years (N = 5719) based on a territory-wide, population-based household survey for mental disorders in Hong Kong. The survey adopted a 2-phase design comprising first-phase psychosis screening and second phase diagnostic verification incorporating clinical information from psychiatrist-administered semi-structured interview and medical record review to ascertain DSM-IV lifetime diagnosis for psychotic disorders. Data on sociodemographics, psychosocial characteristics and service utilization were collected. Our results showed that lifetime prevalence was 2.47% for psychotic disorder overall, 1.25% for schizophrenia, 0.15% for delusional disorder, 0.38% for psychotic disorder not otherwise specified, 0.31% for bipolar disorder with psychosis, and 0.33% for depressive disorder with psychosis. Schizophrenia spectrum disorder was associated with family history of psychosis, cigarette smoking and variables indicating socioeconomic disadvantage. Victimization experiences were significantly related to affective psychoses and other non affective psychoses. Around 80% of participants with any psychotic disorder sought some kind of professional help for mental health problems in the past year. Using comprehensive diagnostic assessment involving interview and record data, our results indicate that approximately 2.5% of Chinese adult population had lifetime psychotic disorder which represents a major public health concern. PMID- 28586482 TI - Determination of tRNA aminoacylation levels by high-throughput sequencing. AB - Transfer RNA (tRNA) decodes mRNA codons when aminoacylated (charged) with an amino acid at its 3' end. Charged tRNAs turn over rapidly in cells, and variations in charged tRNA fractions are known to be a useful parameter in cellular responses to stress. tRNA charging fractions can be measured for individual tRNA species using acid denaturing gels, or comparatively at the genome level using microarrays. These hybridization-based approaches cannot be used for high resolution analysis of mammalian tRNAs due to their large sequence diversity. Here we develop a high-throughput sequencing method that enables accurate determination of charged tRNA fractions at single-base resolution (Charged DM-tRNA-seq). Our method takes advantage of the recently developed DM tRNA-seq method, but includes additional chemical steps that specifically remove the 3'A residue in uncharged tRNA. Charging fraction is obtained by counting the fraction of A-ending reads versus A+C-ending reads for each tRNA species in the same sequencing reaction. In HEK293T cells, most cytosolic tRNAs are charged at >80% levels, whereas tRNASer and tRNAThr are charged at lower levels. These low charging levels were validated using acid denaturing gels. Our method should be widely applicable for investigations of tRNA charging as a parameter in biological regulation. PMID- 28586485 TI - Development of a Clinically Useful Algorithm for Tractography-Based Ventral Intermediate Nucleus Targeting. PMID- 28586484 TI - Can Electroencephalogram Detect Vasospasm Before We Do? PMID- 28586483 TI - Isolated Mitochondria Transfer Improves Neuronal Differentiation of Schizophrenia Derived Induced Pluripotent Stem Cells and Rescues Deficits in a Rat Model of the Disorder. AB - Dysfunction of mitochondria, key players in various essential cell processes, has been repeatedly reported in schizophrenia (SZ). Recently, several studies have reported functional recovery and cellular viability following mitochondrial transplantation, mostly in ischemia experimental models. Here, we aimed to demonstrate beneficial effects of isolated active normal mitochondria (IAN-MIT) transfer in vitro and in vivo, using SZ-derived induced pluripotent stem cells (iPSCs) differentiating into glutamatergic neuron, as well as a rodent model of SZ. First, we show that IAN-MIT enter various cell types without manipulation. Next, we show that IAN-MIT transfer into SZ-derived lymphoblasts induces long lasting improvement in various mitochondrial functions including cellular oxygen consumption and mitochondrial membrane potential (Delta psi m). We also demonstrate improved differentiation of SZ-derived iPSCs into neurons, by increased expression of neuronal and glutamatergic markers beta3-tubulin, synapsin1, and Tbr1 and by an activation of the glutamate-glutamine cycle. In the animal model, we show that intra-prefrontal cortex injection of IAN-MIT in adolescent rats exposed prenatally to a viral mimic prevents mitochondrial Delta psi m and attentional deficit at adulthood. Our results provide evidence for a direct link between mitochondrial function and SZ-related deficits both in vitro and in vivo and suggest a therapeutic potential for IAN-MIT transfer in diseases with bioenergetic and neurodevelopmental abnormalities such as SZ. PMID- 28586486 TI - Fasudil Slows Development of Cavernous Malformations. PMID- 28586487 TI - Intraventricular Thrombolytics in Intraventricular Hemorrhage: Their Role is not so Clear. PMID- 28586488 TI - Use of Chimeric Antigen Receptor T Cells as a Potential Therapeutic for Glioblastoma. PMID- 28586489 TI - BRCA1-Regulated RRM2 Expression Protects Glioblastoma Cells from Endogenous Replication Stress and Promotes Tumorigenicity. PMID- 28586490 TI - A Decline in Cognitive Decline: The Brain's Modifiable Fate. PMID- 28586491 TI - Intracortical Microstimulation of Human Somatosensory Cortex Reproduces Touch in Spinal Cord Injury Patient. PMID- 28586492 TI - Advances in Implanted Brain-Computer Interfaces Allow for Independent Communication in a Locked-In Patient. PMID- 28586494 TI - Global Brain Initiatives. PMID- 28586493 TI - A Randomized Clinical Trial of Conscious Sedation vs General Anesthesia on Outcomes in Patients Receiving Thrombectomy for Ischemic Stroke. PMID- 28586496 TI - Small Incision Lenticule Extraction (SMILE) for Hyperopia: Optical Zone Diameter and Spherical Aberration Induction. AB - PURPOSE: To evaluate optical zone diameter efficacy and spherical aberration change in hyperopic small incision lenticule extraction (SMILE). METHODS: Prospective study of 60 consecutive hyperopic SMILE procedures using the VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany) and matched LASIK procedures with the VisuMax and MEL 80 excimer (Carl Zeiss Meditec) lasers. Inclusion criteria were maximum attempted hyperopic meridian of between +1.00 and +7.00 diopters (D). For SMILE, the transition zone was 2 mm and the mean optical programmed zone was 6.37 mm (range: 6.3 to 6.7 mm). Two LASIK control groups (6.5 and 7-mm optical zone) matched for spherical equivalent treated were generated. Both tangential and axial curvature difference maps were generated for each eye at 3 months. A fixed grid and set of concentric circles were superimposed on the difference map to measure the achieved optical zone diameter. RESULTS: Mean attempted spherical equivalent refraction was +5.58 +/- 0.95 D (range: +3.20 to +6.50 D) in the SMILE group. By tangential mapping, SMILE programmed at a mean optical zone of 6.37 mm achieved a diameter of 5.03 +/- 0.30 mm, similar to 7-mm LASIK (4.96 +/- 0.25 mm, P = 0.33) but larger than 6.5-mm LASIK (4.53 +/- 0.25 mm, P < .001). By axial mapping, the achieved optical zone diameter was 6.75 +/- 0.31 mm for 6.37-mm SMILE, larger than for both 6.5-mm (6.61 +/- 0.21 mm) and 7 mm (6.92 +/- 0.14 mm) LASIK (P < .01). Spherical aberration changed on average by -0.45 +/- 0.22 MUm for 6.37-mm SMILE, similar to 7-mm LASIK (-0.50 +/- 0.21 MUm, P = .29) and less than for 6.5-mm LASIK (-0.69 +/- 0.22 MUm, P < .001). CONCLUSIONS: The mean achieved optical zone diameter of hyperopic SMILE was found to be larger than the mean achieved optical zone diameter of hyperopic LASIK. Consequently, spherical aberration induction was similar for 6.37-mm SMILE and 7 mm LASIK. [J Refract Surg. 2017;33(6):370-376.]. PMID- 28586495 TI - Meta-analysis of the FDA Reports on Patient-Reported Outcomes Using the Three Latest Platforms for LASIK. AB - PURPOSE: To analyze the impact of the three latest U.S. Food and Drug Administration (FDA)-approved lasers on patient-reported outcomes after LASIK. METHODS: In this meta-analysis of patient-reported FDA data, an aggregated total of 718 eyes undergoing LASIK using VISX iDesign (Abbott Medical Optics Manufacturing, Milpitas, CA), Alcon Contoura (Alcon Research, Ltd., Fort Worth, TX), and Nidek CATz (Nidek Co. Ltd., Gamagori, Japan) lasers were evaluated for overall changes in visual symptoms postoperatively. Statistical significance was calculated when appropriate to assess changes. A P value of less than .05 was considered statistically significant. RESULTS: At 12 months following LASIK, there was a decrease in the postoperative difficulty driving at night (29%) with respect to preoperative values. There was a significant postoperative reduction in prior moderate to severe symptoms for light sensitivity (9%), difficulty driving at night (22%), reading difficulty (8%), double vision (2%), glare (12%), and halos (6%) at 12 months following LASIK. CONCLUSIONS: Analysis of the FDA data shows that modern lasers have significantly improved patient-reported visual outcomes after LASIK. [J Refract Surg. 2017;33(6):362-368.]. PMID- 28586497 TI - A Three-Year Observation of Corneal Backscatter After Small Incision Lenticule Extraction (SMILE). AB - PURPOSE: To investigate changes in corneal backscatter after small incision lenticule extraction (SMILE). METHODS: One eye was randomly selected from 34 patients who underwent SMILE procedures. Corneal backscatter was analyzed using Scheimpflug technology before surgery and at postoperative 1 day, 1 week, 1 month, 3, 6, and 12 months, and 3 years. Three different corneal depths (the anterior 120 um, the center, and the posterior 60 um) and three concentric radial zones (0 to 2, 2 to 6, and 6 to 10 mm) were analyzed. Another 40 eyes of 40 patients who underwent femtosecond laser-assisted LASIK (FS-LASIK) were examined before surgery and at postoperative 1 day and 3 years as the control group. RESULTS: At postoperative day 1, a significant increase in corneal backscatter was detected in the SMILE group compared to preoperative values in the central 0 to 6 mm zone of the anterior layer and the 0 to 2 mm zone of the central layer (all P < .01). This increase was higher than the increase in the FS-LASIK group in the central 0 to 6 mm zone of the anterior and central layers (all P < .01). No significant differences in corneal backscatter were detected between preoperative values and the 1-week, and 1-, 3-, 6-, and 12-month follow-up visits in the SMILE group (all P > .05). Moreover, a significant decrease in corneal backscatter was detected in the three zones of all three layers in the two groups at 3 years postoperatively compared to preoperative values (all P < .001) and no significant difference was found between the two groups (all P < .05). CONCLUSIONS: Corneal backscatter peaks and declines to the baseline in the early period after SMILE and corneal transparency achieves an improvement within 3 years postoperatively. [J Refract Surg. 2017;33(6):377-382.]. PMID- 28586498 TI - Increased Hair Cortisol Concentrations in Patients With Progressive Keratoconus. AB - PURPOSE: To investigate hair cortisol concentration (HCC), a biochemical correlate of chronic psychological stress, and its relationship to the progression of keratoconus. METHODS: Eighty-six participants were included in this prospective observational study (32 patients with progressive keratoconus, 32 patients with stable keratoconus, and 22 healthy controls). Hair cortisol concentrations were determined from 3-cm hair strands collected near the scalp from patients and controls as an index of cumulative cortisol secretion during the 3-month period prior to hair sampling. In addition, self-reported chronic stress was assessed using the Trier Inventory for the Assessment of Chronic Stress screening scale. RESULTS: Patients with progressive keratoconus exhibited higher hair cortisol concentrations (mean value: 29.11 pg/mg; 95% confidence interval [CI]: 22.13 to 38.28) than patients with stable keratoconus (mean value: 15.88 pg/mg; 95% CI: 12.25 to 20.65; P = .007) and healthy controls (mean value: 16.98 pg/mg; 95% CI: 12.30 to 23.44; P = .049). There were no significant differences in hair cortisol concentrations between healthy controls and patients with stable keratoconus (P = .991). Group differences were not affected by relevant covariates (body mass index, age, or sex). CONCLUSIONS: This study shows that increased hair cortisol concentration seems to be associated with the progression of keratoconus. There are a variety of causes of increased hair cortisol concentration. [J Refract Surg. 2017;33(6):383-388.]. PMID- 28586499 TI - A New Extended Depth of Focus Intraocular Lens Based on Spherical Aberration. AB - PURPOSE: To describe a new extended depth of focus intraocular lens (IOL) design offering multifocality by the variation of spherical aberration in the central optical zone. METHODS: The new IOL (Mini WELL; SIFI, Catania, Italy) is an aspheric IOL with positive spherical aberration in the central 2-mm zone and negative spherical aberration in the pericentral 1-mm annulus, the amount of which was determined by specific optic calculation. The new IOL design was tested at the optical bench to investigate depth of focus and sensitivity to tilt, decentration, and angle Kappa. Visual acuity simulations were obtained from distance (4 m) to near (0.5 m). RESULTS: Modulation transfer function (MTF) for a 3-mm pupil was 0.35 to 0.40 for distance vision and 0.25 to 0.30 for intermediate and near vision. MTF for a 4.5-mm pupil was 0.40 to 0.55 and 0.10 to 0.20, respectively. These values were not influenced by tilt up to +/-2.5 degrees , by decentration up to +/-0.5 mm, or by angle Kappa up to 9 degrees . Visual acuity simulations indicated good visual acuity up to 2.00 D of pseudoaccommodation. CONCLUSIONS: The new IOL with double spherical aberration in the central 3-mm zone offered good MTF over a wide dioptric interval, suggesting good visual acuity between 4 m and 50 cm. This extended depth of focus IOL with no diffractive rings is expected to produce lower unwanted optical phenomena than current multifocal IOLs. [J Refract Surg. 2017;33(6):389-394.]. PMID- 28586500 TI - Implantation of Implantable Collamer Lenses After Radial Keratotomy. AB - PURPOSE: To assess the predictability, efficacy, and safety of posterior chamber phakic implantable collamer lens (ICL) implantation after radial keratotomy. METHODS: In a retrospective non-comparative interventional case series, outcomes in 6 consecutive eyes of 4 patients with residual refraction after radial keratotomy were analyzed after the implantation of ICLs. All of the lenses were implanted to correct the residual refractive error, ranging from -12.00 to +3.50 diopters (D) for sphere and from -0.75 to -3.75 D for cylinder. RESULTS: The mean uncorrected distance visual acuity after ICL implantation was 0.31 +/- 0.36 logMAR and the corrected distance visual acuity was 0.12 +/- 0.10 logMAR. The mean efficacy index was 0.86. No eyes lost lines of visual acuity, two eyes did not change after surgery, two eyes gained one line, and two eyes gained two lines. The mean safety index was 1.17. No intraoperative complications were found and ICL explantation or repositioning was not required during the follow-up. No cases of cataract, pigment dispersion glaucoma, pupillary block, or other vision threatening complications were found. CONCLUSIONS: ICL implantation may be considered a reasonable surgical procedure for correcting residual refractive errors after radial keratotomy. [J Refract Surg. 2017;33(6):395-398.]. PMID- 28586501 TI - Biomechanical Characterization of Subclinical Keratoconus Without Topographic or Tomographic Abnormalities. AB - PURPOSE: To present a case series of patients with subclinical keratoconus with normal topometric (anterior curvature) and tomographic findings in one eye who showed abnormalities detected by Corvis ST (Oculus Optikgerate GmbH, Wetzlar, Germany) in vivo biomechanical assessment. METHODS: All patients had a complete ophthalmic examination, including the Corvis ST biomechanical measurements, optical tomography, and pachymetry with Pentacam (Oculus Optikgerate GmbH), and Placido-based topography with either the Nidek (OPD III Nidek, Gamagori, Japan) or CSO platform (Costruzione Strumenti Oftalmici, Florence, Italy). Inclusion criteria were a clinical diagnosis of ectasia in one eye and normal topometric and tomographic findings in the fellow eye (subclinical keratoconus), including a Belin/Ambrosio Enhanced Ectasia total deviation index from the Pentacam with less than 1.6 standard deviations from normative values and a Corvis Biomechanical Index score of greater than 0.5 in both eyes. RESULTS: Tomographic and topographic analysis was normal in one eye and abnormal in the fellow eye in 12 patients. The biomechanical results with the Corvis Biomechanical Index were shown to be abnormal in both eyes of all patients and aided the diagnosis. CONCLUSIONS: Biomechanical analysis showed abnormalities, whereas tomography and topography were normal. Basing on these findings, the authors suggest the use of biomechanics as an additional diagnostic tool. [J Refract Surg. 2017;33(6):399 407.]. PMID- 28586502 TI - Biomechanical Changes After LASIK Flap Creation Combined With Rapid Cross-Linking Measured With Brillouin Microscopy. AB - PURPOSE: To evaluate the biomechanical changes occurring after LASIK flap creation and rapid corneal cross-linking (CXL) measured with Brillouin light microscopy. METHODS: Porcine eyes (n = 11) were evaluated by Brillouin light microscopy sequentially in the following order: virgin state, after LASIK flap creation, and after rapid CXL. Each eye served as its own control. Depth profile of the Brillouin frequency shift was computed to reveal the depth-dependent changes in corneal stiffness. RESULTS: There was a statistically significant reduction of Brillouin shift (reduced corneal stiffness) after LASIK flap creation compared to virgin corneas across total corneal thickness (-0.035 GHz, P = .0195) and within the anterior stromal region (-0.104 GHz, P = .0039). Changes in the central (-0.029 GHz, P = .0391) and posterior (-0.005 GHz, P = .99) stromal regions were not significant. There was a small increase in Brillouin shift after rapid cross-linking that was not statistically or clinically significant across total corneal thickness (0.006 GHz, P = .4688 for any specific stromal region; 0.002 to 0.009 GHz, P > .46 for all). CONCLUSIONS: LASIK flap creation significantly reduced Brillouin shift in the anterior third of the stroma in porcine eyes. Rapid corneal cross-linking had no significant effect on Brillouin shift after LASIK flap creation in porcine eyes. With further validation, non-contact, non-perturbative Brillouin microscopy could become a useful monitoring tool to evaluate the biomechanical impact of corneal refractive procedures and corneal cross-linking protocols. [J Refract Surg. 2017;33(6):408 414.]. PMID- 28586503 TI - Questionnaires for Measuring Refractive Surgery Outcomes. AB - PURPOSE: To identify the questionnaires used to assess refractive surgery outcomes, assess the available questionnaires in regard to their psychometric properties, validity, and reliability, and evaluate the performance of the available questionnaires in measuring refractive surgery outcomes. METHODS: An extensive literature search was done on PubMed, MEDLINE, Scopus, CINAHL, Cochrane, and Web of Science databases to identify articles that described or used at least one questionnaire to assess refractive surgery outcomes. The information on content quality, validity, reliability, responsiveness, and psychometric properties was extracted and analyzed based on an extensive set of quality criteria. RESULTS: Eighty-one articles describing 27 questionnaires (12 refractive error-specific, including 4 refractive surgery-specific, 7 vision-but non-refractive, and 8 generic) were included in the review. Most articles (56, 69.1%) described refractive error-specific questionnaires. The Quality of Life Impact of Refractive Correction (QIRC), the Quality of Vision (QoV), and the Near Activity Visual Questionnaire (NAVQ) were originally constructed using Rasch analysis; others were developed using the Classical Test Theory. The National Eye Institute Refractive Quality of Life questionnaire was the most frequently used questionnaire, but it does not provide a valid measurement. The QoV, QIRC, and NAVQ are the three best existing questionnaires to assess visual symptoms, quality of life, and activity limitations, respectively. CONCLUSIONS: This review identified three superior quality questionnaires for measuring different aspects of quality of life in refractive surgery. Clinicians and researchers should choose a questionnaire based on the concept being measured with superior psychometric properties. [J Refract Surg. 2017;33(6):416-424.]. PMID- 28586504 TI - Removal of Persistent Cellular Deposits After Foldable Iris-Fixated Phakic IOL Implantation. AB - PURPOSE: To report a case of severe recurrent cellular deposits after Artiflex intraocular lens (Ophtec B. V., Groningen, The Netherlands) implantation. METHODS: Case report. RESULTS: A 25-year-old woman underwent uneventful Artiflex intraocular lens implantation in both eyes. After 3 months, severe cellular deposits were seen in the posterior surface of the lens in one eye. Topical steroids were administered, with temporary improvement. Four months later, the deposits recurred and did not respond to topical steroids. Corrected distance visual acuity lost five lines. Treatment by polishing the posterior surface of the lens 10 months after the initial implantation was performed and resulted in complete visual recovery. No recurrence of the deposits were observed after 2 years of follow-up. CONCLUSIONS: Persistent cellular deposits after Artiflex intraocular lens implantation may cause severe visual loss and may need surgical intervention. Polishing the posterior surface of the lens to mechanically remove the deposits was an effective long-term solution. [J Refract Surg. 2017;33(6):426 428.]. PMID- 28586505 TI - Cellular stress response mechanisms as therapeutic targets of ginsenosides. AB - Ginseng, one of the most widely used traditional herbal medicines and dietary supplements, has historically been recognized as a tonic herb and adaptogen that can enhance the body's tolerance to various adversities. Ginsenosides are a diverse group of steroidal saponins that comprise the major secondary metabolites of ginseng and are responsible for its multiple pharmacological effects. Emerging evidence suggests that hormetic phytochemicals produced by environmentally stressed plants can activate the moderate cellular stress response mechanisms at a subtoxic level in humans, which may enhance tolerance against severe dysfunction or disease. In this review, we initially describe the role of ginsenosides in the chemical defense of plants from the genus Panax suffering from biotic and abiotic stress. Next, we summarize the diverse evolutionarily conserved cellular stress response pathways regulated by ginsenosides and the subsequent stress tolerance against various dysfunctions or diseases. Finally, the structure-activity relationship involved in the effect of ginsenosides is also analyzed. The evidence presented in this review implicates that ginseng as "the King of all herbs" could be regarded as a well-characterized example of the critical role of cellular stress response mechanisms in understanding the health benefits provided by herbal medicines from an evolutionary and ecological perspective. PMID- 28586506 TI - Second-Trimester Uterine Model for Teaching Ultrasound-Guided Obstetric Procedures. AB - The declining number of ultrasound-guided obstetric procedures in clinical practice mandates a shift toward simulation-based teaching. Current uterine simulation aids are animal tissue-sourced or expensive, and improvement is needed. We describe a low-cost reusable uterine model with "fetus," cord and skin, constructed from synthetic gel and silicone rubber. Ultrasound appearance and tactile feedback approximate clinical use, and all parts of the model are portable, durable, and shelf-stable. Those made of ballistics gel can be recycled numerous times without noticeable effect. This appears to be ideal for proctored learning and independent practice within an ultrasound procedural curriculum. PMID- 28586507 TI - Patterns of glucose-lowering therapies and neonatal outcomes in the treatment of gestational diabetes in Canada, 2009-2014. AB - AIM: To examine patterns of use of different glycaemic control agents for treating gestational diabetes mellitus. METHODS: This was a large, retrospective, population-based cohort study of pregnant women with gestational diabetes from Alberta, Canada. We linked data from the Alberta Vital Statistics - Birth database with administrative claims data. Alberta Vital Statistics - Birth data were used to identify births that occurred between 1 January 2009 and 31 December 2014. We used International Classification of Diseases version 9/10 codes to identify women with gestational diabetes, and we excluded women with pre-existing diabetes. RESULTS: Our cohort consisted of 16 857 women with gestational diabetes, with a total of 18 761 birth events between 2009 and 2014. Over the study period, the proportion of women with gestational diabetes who were treated with glycaemic control therapies increased from 25.0% to 31.4% (P<0.0001). The number of pregnancies treated with insulin only increased (from 23.6% to 28.3%; P<0.0001), as did the number treated with metformin, +/- insulin (from 1.4% to 3.2%; P<0.0001). Rates of large-for-gestational-age infants were significantly higher among pregnancies treated with insulin only (17%) or metformin (16.5%) than among pregnancies that did not receive any pharmacological treatment (12.8%). CONCLUSIONS: Our findings show increasing use of insulin and metformin in women with gestational diabetes. Rates of large-for-gestational-age infants were similar among pregnant women receiving either pharmacological treatment, and higher than among pregnant women who did not receive any pharmacological treatment. Future research should explore the long-term outcomes and safety of metformin as an alternative for treating gestational diabetes. PMID- 28586509 TI - Association between neoadjuvant chemoradiation and survival for patients with locally advanced rectal cancer. AB - AIM: To examine the overall survival differences for the following neoadjuvant therapy modalities - no therapy, chemotherapy alone, radiation alone and chemoradiation - in a large cohort of patients with locally advanced rectal cancer. METHOD: Adults with clinical Stage II and III rectal adenocarcinoma were selected from the National Cancer Database and grouped by type of neoadjuvant therapy received: no therapy, chemotherapy only, radiotherapy only or chemoradiation. Multivariable regression methods were used to compare adjusted differences in perioperative outcomes and overall survival. RESULTS: Among 32 978 patients included, 9714 (29.5%) received no neoadjuvant therapy, 890 (2.7%) chemotherapy only, 1170 (3.5%) radiotherapy only and 21 204 (64.3%) chemoradiation. Compared with no therapy, chemotherapy or radiotherapy alone were not associated with any adjusted differences in surgical margin positivity, permanent colostomy rate or overall survival (all P > 0.05). With adjustment, neoadjuvant chemoradiation vs no therapy was associated with a lower likelihood of surgical margin positivity (OR 0.74, P < 0.001), decreased rate of permanent colostomy (OR 0.77, P < 0.001) and overall survival [hazard ratio (HR) 0.79, P < 0.001]. When compared with chemotherapy or radiotherapy alone, chemoradiation remained associated with improved overall survival (vs chemotherapy alone HR 0.83, P = 0.04; vs radiotherapy alone HR 0.83, P < 0.019). CONCLUSION: Neoadjuvant chemoradiation, not chemotherapy or radiotherapy alone, is important for sphincter preservation, R0 resection and survival for patients with locally advanced rectal cancer. Despite this finding, one-third of patients in the United States with locally advanced rectal cancer fail to receive stage-appropriate chemoradiation. PMID- 28586510 TI - A 10-second sprint does not blunt hormonal counter-regulation to subsequent hypoglycaemia. AB - AIM: To investigate whether a 10-second (s) sprint impairs the counter-regulatory response to subsequent hypoglycaemia. METHODS: Nine people (five male, four female) with Type 1 diabetes, aged 21.1 +/- 4.5 years, performed a 10-s rest or a 10-s maximum-effort sprint in random order on different days, while subjected to an euinsulinaemic-euglycaemic clamp. This was followed by a hyperinsulinaemic hypoglycaemic glucose clamp 2.5 h later to induce hypoglycaemia for 40 min. At timed intervals, the counter-regulatory hormonal responses to hypoglycaemia were measured. Blood pressure, heart rate and hypoglycaemic symptoms were also assessed. RESULTS: During the hypoglycaemic clamp, epinephrine, norepinephrine, growth hormone and cortisol levels increased significantly from baseline, and their responses were similar after both rest and sprint conditions. In particular, plasma epinephrine rose eightfold, from 197 +/- 103 pmol/l to 1582 +/ 1118 pmol/l after the rest condition, and from 219 +/- 119 pmol/l to 1900 +/- 898 pmol/l after the sprint condition. CONCLUSION: A 10-s sprint is unlikely to blunt the subsequent hormonal counter-regulation to hypoglycaemia in individuals with Type 1 diabetes. PMID- 28586508 TI - Overexpressing wild-type gamma2 subunits rescued the seizure phenotype in Gabrg2+/Q390X Dravet syndrome mice. AB - OBJECTIVE: The mutant gamma-aminobutyric acid type A (GABAA ) receptor gamma2(Q390X) subunit (Q351X in the mature peptide) has been associated with the epileptic encephalopathy, Dravet syndrome, and the epilepsy syndrome genetic epilepsy with febrile seizures plus (GEFS+). The mutation generates a premature stop codon that results in translation of a stable truncated and misfolded gamma2 subunit that accumulates in neurons, forms intracellular aggregates, disrupts incorporation of gamma2 subunits into GABAA receptors, and affects trafficking of partnering alpha and beta subunits. Heterozygous Gabrg2+/Q390X knock-in (KI) mice had reduced cortical inhibition, spike wave discharges on electroencephalography (EEG), a lower seizure threshold to the convulsant drug pentylenetetrazol (PTZ), and spontaneous generalized tonic-clonic seizures. In this proof-of-principal study, we attempted to rescue these deficits in KI mice using a gamma2 subunit gene (GABRG2) replacement therapy. METHODS: We introduced the GABRG2 allele by crossing Gabrg2+/Q390X KI mice with bacterial artificial chromosome (BAC) transgenic mice overexpressing HA (hemagglutinin)-tagged human gamma2HA subunits, and compared GABAA receptor subunit expression by Western blot and immunohistochemical staining, seizure threshold by monitoring mouse behavior after PTZ-injection, and thalamocortical inhibition and network oscillation by slice recording. RESULTS: Compared to KI mice, adult mice carrying both mutant allele and transgene had increased wild-type gamma2 and partnering alpha1 and beta2/3 subunits, increased miniature inhibitory postsynaptic current (mIPSC) amplitudes recorded from layer VI cortical neurons, reduced thalamocortical network oscillations, and higher PTZ seizure threshold. SIGNIFICANCE: Based on these results we suggest that seizures in a genetic epilepsy syndrome caused by epilepsy mutant gamma2(Q390X) subunits with dominant negative effects could be rescued potentially by overexpression of wild-type gamma2 subunits. PMID- 28586511 TI - Factors affecting dance exercise performance in students at a special needs school. AB - BACKGROUND: In Japan, dance exercise has been introduced as a compulsory element of health and physical education, but there is a considerable discrepancy in the levels of performance among students with intellectual disability (ID) at special needs schools. The aim of this study was therefore to identify the factors affecting the performance of dance exercise in students with ID. METHODS: A 4 month dance exercise program was implemented for junior high school students at a special needs school, and the performance of 32 students at 22 sessions was assessed quantitatively according to calorie use during exercise and performance proficiency score. The measures were compared according to gender, age, body mass index, diagnosis, and development quotient (DQ) score. RESULTS: Performance in many students improved with repetition and reached the highest attainment level at around the third month. Male gender and older age had a significant positive impact on calorie use, whereas diagnosis of Down syndrome and higher DQ score had a significant positive impact on proficiency score. Four students with poor performance were all female students with autism. CONCLUSION: This study provides some possible explanations for differences in the levels of dance performance among students with ID. PMID- 28586512 TI - Ellagic acid and rosmarinic acid attenuate doxorubicin-induced testicular injury in rats. AB - The anticancer drug doxorubicin causes testicular toxicity as an undesirable effect. The present study was undertaken to investigate the possible protection of ellagic acid and rosmarinic acid during doxorubicin administration. For this purpose eight groups of male Sprague-Dawley rats were used (n = 10), one group received vehicle served as control, and other groups received 5 mg/kg doxorubicin twice a week for 2 weeks for a cumulative dose of 20 mg/kg, ellagic acid (10 mg/kg/day, 14 consecutive days p.o.), rosmarinic acid (75 mg/kg/day, 14 consecutive days p.o.), ellagic acid and rosmarinic acid. The latter three regimens were given to control and doxorubicin-received rats. Doxorubicin decreased testicular relative weight, sperm count, motility, serum testosterone, testicular glycogen, and sialic acid with increased incidence of histopathological changes, oxidative stress, tumor necrosis factor-alpha, as well as cholinesterase activity. Conversely, ellagic and rosmarinic acid treatment ameliorated such damage, thus showing the possibility to use as an adjuvant during doxorubicin treatment. PMID- 28586513 TI - The association between the physical environment and the well-being of older people in residential care facilities: A multilevel analysis. AB - AIMS: To investigate the associations between the quality of the physical environment and the psychological and social well-being of older people living in residential care facilities. BACKGROUND: Many older people in care facilities have cognitive and physical frailties and are at risk of experiencing low levels of well-being. High-quality physical environments can support older people as frailty increases and promote their well-being. Although the importance of the physical environment for residents' well-being is recognized, more research is needed. DESIGN: A cross-sectional survey of 20 care facilities from each of which 10 residents were sampled. As the individual resident data were nested in the facilities, a multilevel analysis was conducted. METHODS: Data were collected during 2013 and 2014. The care facilities were purposely sampled to ensure a high level of variation in their physical characteristics. Residents' demographic and health data were collected via medical records and interviews. Residents' well being and perceived quality of care were assessed via questionnaires and interviews. Environmental quality was assessed with a structured observational instrument. RESULTS: Multilevel analysis indicated that cognitive support in the physical environment was associated with residents' social well-being, after controlling for independence and perceived care quality. However, no significant association was found between the physical environment and residents' psychological well-being. CONCLUSION: Our study demonstrates the role of the physical environment for enhancing the social well-being of frail older people. Professionals and practitioners involved in the design of care facilities have a responsibility to ensure that such facilities meet high-quality specifications. PMID- 28586515 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 25/2017. PMID- 28586514 TI - >Corrigendum: Type III Polyketide Synthases: Functional Classification and Phylogenomics. PMID- 28586516 TI - Corrigendum: Acid-Mediated Formation of Radicals or Baeyer-Villiger Oxidation from Criegee Adducts. PMID- 28586517 TI - Extracellular vesicles in the tumor microenvironment: Therapeutic resistance, clinical biomarkers, and targeting strategies. AB - Numerous studies have proved that cell-nonautonomous regulation of neoplastic cells is a distinctive and essential characteristic of tumorigenesis. Two way communications between the tumor and the stroma, or within the tumor significantly influence disease progression and modify treatment responses. In the tumor microenvironment (TME), malignant cells utilize paracrine signaling initiated by adjacent stromal cells to acquire resistance against multiple types of anticancer therapies, wherein extracellular vesicles (EVs) substantially promote such events. EVs are nanoscaled particles enclosed by phospholipid bilayers, and can mediate intercellular communications between cancerous cells and the adjacent microenvironment to accelerate pathological proceeding. Here we review the most recent studies of EV biology and focus on key cell lineages of the TME and their EV cargoes that are biologically active and responsible for cancer resistance, including proteins, RNAs, and other potentially essential components. Since EVs are emerging as novel but critical elements in establishing and maintaining hallmarks of human cancer, timely and insightful understanding of their molecular properties and functional mechanisms would pave the road for clinical diagnosis, prognosis, and effective targeting in the global landscape of precision medicine. Further, we address the potential of EVs as promising biomarkers in cancer clinics and summarize the technical improvements in EV preparation, analysis, and imaging. We highlight the practical issues that should be exercised with caution to guide the development of targeting agents and therapeutic methodologies to minimize cancer resistance driven by EVs, thereby allowing to effectively control the early steps of disease exacerbation. PMID- 28586519 TI - [2.2]Paracyclophane-Bis(triazole) Systems: Synthesis and Photochemical Behavior. AB - Mono-, pseudo-gem, and pseudo-para ethynylcyclophanes and bis(azides) have been employed as addition partners in CuAAC reactions to design and build complex extended molecular scaffolds. The reactivity of the resulting triazoles was investigated under photochemical conditions. A variety of newly substituted [2.2]paracyclophanes were identified; deazotization of pseudo-gem and pseudo-para adducts provided indolophane derivatives. An intramolecular stabilization effect was observed in the case of pseudo-gem derivatives. A photochemical rearrangement from a pseudo-para adduct to a pseudo-ortho product was identified. PMID- 28586518 TI - Combination therapy with multiple oral hypoglycaemic agents together with short term basal insulin in new-onset Type 2 diabetes mellitus with marked hyperglycaemia. PMID- 28586520 TI - Registered Nurses' and nurse assistants' responses to older persons' expressions of emotional needs in home care. AB - AIM: This study aims to explore nurse assistants' and Registered Nurses' responses to older persons' expressions of emotional needs during home care visits. BACKGROUND: Communication is a central aspect of care. Older persons might express different emotions and needs during home care visits and such expressions can be challenging to respond to. Little is known about communication in home care or nursing staff responses to older persons' expressed emotional needs. DESIGN: Descriptive, cross-sectional design on nursing staff responses to older persons' negative emotions in home care. METHODS: Collected data consisted of audio recordings of home care visits between older persons and nursing staff. Data were collected between August 2014-November 2015. The nursing staff responses to older persons' negative emotions in the communication were analysed with the Verona Coding Definitions of Emotional Sequences (VR-CoDES). RESULTS: The nursing staff most often give non-explicit responses, providing space for further disclosure of older persons' expressed negative emotions. Such responses were more frequent if the nursing staff had elicited the older persons' expressions of a negative emotion than if such expressions were elicited by the older persons themselves. Most frequent types of responses were backchannel, active invitation or information advice. CONCLUSION: The nursing staff responses were mainly non-explicit responses providing space for older persons to tell more about their experiences. Such responses can be discussed in terms of person centred communication and is important for the comfort of emotional concerns. PMID- 28586521 TI - An Auto-Inductive Cascade for the Optical Sensing of Thiols in Aqueous Media: Application in the Detection of a VX Nerve Agent Mimic. AB - A new auto-inductive protocol employs a Meldrum's-acid-based conjugate acceptor (1) as a latent source of thiol for signal amplification, as well as optical detection of thiols. The auto-induction is initiated by a thiol-disulfide exchange that leads to the generation of beta-mercaptoethanol, which in turn decouples the conjugate acceptor to release more thiols, resulting in a self propagating cycle that continues until all the conjugate acceptor is consumed. Using 1 in a two-step integrated protocol yields a rapid, sensitive, and precise diagnostic assay for the ultratrace quantitation of a thiophosphate nerve agent surrogate. PMID- 28586523 TI - Increased Arctic sea ice drift alters adult female polar bear movements and energetics. AB - Recent reductions in thickness and extent have increased drift rates of Arctic sea ice. Increased ice drift could significantly affect the movements and the energy balance of polar bears (Ursus maritimus) which forage, nearly exclusively, on this substrate. We used radio-tracking and ice drift data to quantify the influence of increased drift on bear movements, and we modeled the consequences for energy demands of adult females in the Beaufort and Chukchi seas during two periods with different sea ice characteristics. Westward and northward drift of the sea ice used by polar bears in both regions increased between 1987-1998 and 1999-2013. To remain within their home ranges, polar bears responded to the higher westward ice drift with greater eastward movements, while their movements north in the spring and south in fall were frequently aided by ice motion. To compensate for more rapid westward ice drift in recent years, polar bears covered greater daily distances either by increasing their time spent active (7.6%-9.6%) or by increasing their travel speed (8.5%-8.9%). This increased their calculated annual energy expenditure by 1.8%-3.6% (depending on region and reproductive status), a cost that could be met by capturing an additional 1-3 seals/year. Polar bears selected similar habitats in both periods, indicating that faster drift did not alter habitat preferences. Compounding reduced foraging opportunities that result from habitat loss; changes in ice drift, and associated activity increases, likely exacerbate the physiological stress experienced by polar bears in a warming Arctic. PMID- 28586522 TI - Is sweat chloride predictive of severity of cystic fibrosis lung disease assessed by chest computed tomography? AB - BACKGROUND: Cystic Fibrosis (CF) lung disease is characterized by a marked heterogeneity. Sweat chloride-level is a functional marker of the CF Transmembrane Regulator (CFTR) protein and could be an important predictor of later disease severity. METHODS: In this retrospective analysis children from the Rotterdam CF clinic with available sweat chloride level at diagnosis and at least one routine spirometry-controlled volumetric chest CT scan in follow-up were included. CT scans were scored using the CF-CT scoring system (% of maximum). Associations between sweat chloride-levels and CF-CT scores were calculated using linear regression models, adjusting for age at sweat test and age at follow-up. Because structural lung damage develops over the course of many years, effect modification by the age at follow-up CT-scan was tested for by age stratification. RESULTS: In 59 children (30 male) sweat chloride was measured at diagnosis (median age 0.5 years, range 0-13) and later chest CT performed (median age 14 years, range 6-18). Sweat chloride was associated with significantly higher CT-CT total score, bronchiectasis score, and mucus plugging score. Stratification for age at follow-up in tertiles showed this association remained only in the oldest age group (range 15-18 years). In that subgroup associations were found with all but one of the CF-CT subscores, as well as with all tested lung functions parameters. CONCLUSION: Sweat chloride-level is a significant predictor of CF lung disease severity as determined by chest CT and lung function. This association could only be demonstrated in children with follow-up to age 15 years and above. PMID- 28586524 TI - Experiential Self-Focus in Social Anxiety Disorder: Is it Beneficial? AB - OBJECTIVE: Self-focused processing is a significant maintaining factor in cognitive models of social anxiety disorder (SAD), but it may also be analytic (detached, evaluative, maladaptive) or experiential (concrete, nonevaluative, adaptive). The current study aimed to investigate the effect of self-focus modes in a sample meeting criteria for SAD as previous studies have yielded mixed results. METHOD: Individuals meeting criteria for SAD and nonanxious controls (N = 80, 77.5% female; mean age = 19.46) were randomly allocated to complete a task inducing analytic or experiential self-focused processing, followed by a social interaction task, including measurement of affective and cognitive variables. RESULTS: Controls demonstrated the expected benefits of experiential compared to analytic self-focus on social anxiety, negative affect, and self-beliefs. Unexpectedly, SAD participants reported no difference between self-focus conditions. CONCLUSION: Results suggest that experiential processing may have no benefit for SAD individuals proximal to a social threat. Implications of these findings are discussed. PMID- 28586525 TI - Novel therapeutic clues in thyroid carcinomas: The role of targeting cancer stem cells. AB - Thyroid carcinomas (TCs), the most common endocrine tumors, represent the eighth most common cancer diagnosed worldwide in both women and men. To treat these malignancies, several drugs are now available and a number of novel ones have been enrolling in clinical trials, addressing both oncogenic pathways in cancer cells and angiogenic pathways in tumor endothelial cells. However, their use is not devoid of serious toxicities and their efficacy is limited, being dependent on carcinoma typology and the occurrence of acquired resistance. Accordingly, it is time to recast therapeutic strategies against these types of tumors to get to newer and fully effective drugs. In this perspective, latest findings demonstrate that cancer stem cells (CSCs) represent a challenging target to strike. They possess core traits of self-renewal and differentiation, being resistant to the effects of chemotherapy and radiation and playing a key role in mediating metastasis. Therefore, basic molecular elements sustaining both development of thyroid cancer stem cells and their residence in the stemness condition represent a set of innovative and still unexplored targets to address. In this review, a thorough literature survey has been accomplished, to take stock of mechanisms governing thyroid carcinomas and to point out both their currently available treatments and the novel forthcoming ones. Pubmed, Scifinder and ClinicalTrials.gov were exploited as research applications and registry database, respectively. Original articles, reviews, and editorials published within the last ten years, as well as open clinical investigations in the field, were analyzed to suggest new exciting therapeutic opportunities for people affected by TCs. PMID- 28586526 TI - Weaning attempts, cough strength and albumin are independent risk factors of reintubation in medical patients. AB - BACKGROUND: Reintubation is associated with increased hospital mortality. It is necessary to identify risk factors associated with reintubation. METHODS: A prospective observational study was performed in a respiratory intensive care unit. Medical patients who successfully completed a spontaneous breathing trial (SBT) were enrolled. Before extubation, age, gender, vital signs, acute physiology and chronic health evaluation II score, SBT attempts, cough peak flow, arterial blood gas tests and albumin were recorded. RESULTS: We enrolled 139 patients. Of these, 22 (15.8%) patients experienced reintubation within 72 hours after extubation. SBT attempts (odds ratio [OR] = 1.446, 95% confidence interval [CI]: 1.095-1.910), cough peak flow (OR = 0.975, 95% CI: 0.956-0.994) and albumin (OR = 0.847, 95% CI: 0.752-0.954) were independent risk factors for reintubation. In patients with 1, 2 and >=3 SBT attempts, reintubation rates were 7.3%, 21.1% and 45.8%, respectively (P < .01). In patients with cough peak flow <=60, 61-89 and >=90 L/min, reintubation rates were 29.4%, 16.7% and 1.9%, respectively (P < .01). In patients with albumin <=25, 26-30 and >=31 g/L, reintubation rates were 32.4%, 11.1% and 9.8%, respectively (P = .01). CONCLUSIONS: Multiple SBT attempts, weak cough and low albumin were associated with increased reintubation in medical patients. This study provides information for clinical practitioners in the consideration of patient extubation. PMID- 28586527 TI - Generation of the membrane potential and its impact on the motility, ATP production and growth in Campylobacter jejuni. AB - The generation of a membrane potential (Deltapsi), the major constituent of the proton motive force (pmf), is crucial for ATP synthesis, transport of nutrients and flagellar rotation. Campylobacter jejuni harbors a branched electron transport chain, enabling respiration with different electron donors and acceptors. Here, we demonstrate that a relatively high Deltapsi is only generated in the presence of either formate as electron donor or oxygen as electron acceptor, in combination with an acceptor/donor respectively. We show the necessity of the pmf for motility and growth of C. jejuni. ATP generation is not only accomplished by oxidative phosphorylation via the pmf, but also by substrate level phosphorylation via the enzyme AckA. In response to a low oxygen tension, C. jejuni increases the transcription and activity of the donor complexes formate dehydrogenase (FdhABC) and hydrogenase (HydABCD) as well as the transcription of the alternative respiratory acceptor complexes. Our findings suggest that in the gut of warm-blooded animals, C. jejuni depends on at least formate or hydrogen as donor (in the anaerobic lumen) or oxygen as acceptor (near the epithelial cells) to generate a pmf that sustains efficient motility and growth for colonization and pathogenesis. PMID- 28586528 TI - Coping and Psychopathological Profile in Nonsuicidal Self-Injurious Chilean Adolescents. AB - OBJECTIVE: The aims of this study were to establish the roles of coping typologies and the psychological problems associated with nonsuicidal self-injury (NSSI) and to identify adolescents who are at greater risk of engaging in this practice. METHOD: The total sample comprised 965 adolescents (57% girls, aged 12 18 years) from several Chilean schools who answered the Inventory of Statements About Self-Injury questionnaire. RESULTS: Young people with and without NSSI present different coping patterns, especially when compared by gender. Adolescents with repetitive NSSI (R-NSSI) report using escape, search for friendship, and venting feelings as coping strategies as well as a more avoidant style and less search for family support than those adolescents without NSSI. Adolescents who present avoidance coping typology are three times more likely (relative risk = 3.5) to engage in NSSI than adolescents who present approach coping typology. R-NSSI adolescents present higher scores on psychological symptomatology (within clinical ranges) than their N-NSSI counterparts. Girls were more likely to present psychological symptoms than boys. CONCLUSION: The authors highlight the usefulness of coping typologies for the detection of high risk populations for NSSI as well as the need to consider the gender variable. Professionals who detect clinical levels of symptomatology should also assess the presence of NSSI. PMID- 28586529 TI - Reproducibility of the plasma glucose response to moderate-intensity exercise in adolescents with Type 1 diabetes. AB - AIMS: The aim of the study was to evaluate the reproducibility of the plasma glucose response to moderate-intensity exercise performed on different days under controlled conditions in adolescents with Type 1 diabetes. METHODS: Eight adolescents with Type 1 diabetes on continuous subcutaneous insulin infusion completed two exercise sessions, each on two separate days, under basal insulin and fasting conditions. On each day, participants cycled twice for 30 min at 55% of their peak rate of oxygen consumption, with each exercise session separated by a 30-min rest. RESULTS: Plasma insulin levels were similar between testing days and exercise sessions. The mean absolute drop in plasma glucose from the commencement to the end of exercise was 1.6 +/- 0.5 mmol/l on day 1 and 1.9 +/- 0.7 mmol/l on day 2 (P = 0.3). In response to the first exercise session, plasma glucose levels relative to baseline did not change significantly (0.2 +/- 0.6 and -0.2 +/- 0.5 mmol/l on days 1 and 2). By contrast, the change in plasma glucose during the second exercise session was -1.1 +/- 0.7 and -1.3 +/- 0.7mmol/l on days 1 and 2, respectively. The mean absolute intra-individual difference in the change in plasma glucose between testing days were 0.7 +/- 0.5 [95% confidence interval (CI) 0.4-1.0] and 0.7 +/- 0.4 (95% CI 0.4-1.0) mmol/l, at the end of the first and second exercise sessions respectively. CONCLUSIONS: The plasma glucose response to moderate-intensity exercise under similar glycaemic and basal insulin conditions can be reproducible in adolescents with Type 1 diabetes. PMID- 28586530 TI - Increase in the incidence of severe hypoglycaemia in people with Type 2 diabetes in spite of new drugs: analysis based on health insurance data from Germany. AB - AIM: To evaluate the use of new anti-hyperglycaemic agents that offer effective glycaemic control while reducing risk of hypoglycaemia, by analysing the incidence rates of severe hypoglycaemia in 2006 vs 2011 in relation to the medication. METHODS: This cross-sectional, population-based study used German health insurance data. All adults diagnosed with Type 2 diabetes mellitus (extrapolated to the German population: 6.35 million in 2006 and 7.52 million in 2011) were screened for severe hypoglycaemia. Anti-hyperglycaemic agents were identified by their Anatomical Therapeutic Chemical code, and defined daily doses of each medication were calculated. RESULTS: The severe hypoglycaemic event rate was 460 per 100,000 people/year in 2006 and 490 per 100,000 people/year in 2011. In 2006 and 2011, 10.9% and 7.3%, respectively, of all people with severe hypoglycaemia were on sulfonylureas, while 12.7% and 9.3%, respectively, were on a combination therapy of metformin and sulfonylureas. Among those with severe hypoglycaemia, there were no prescriptions of dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 receptor agonists in 2006, but in 2011, 1.55% and 0.17%, of those with severe hypoglycaemia were receiving the respective treatments. In 2006 vs 2011, human insulin was prescribed for 11.3% vs 10.3% of people with severe hypoglycaemia, while insulin analogues were prescribed for 5.4% vs 8.1%, and mixed human insulins for 19.7% vs 14.0% of patients with severe hypoglycaemia. People receiving insulin analogue therapy had a higher risk of severe hypoglycaemia than those receiving metformin, after adjusting for age, gender, nephropathy diagnosis and year of survey (odds ratio 14.6; CI 13.3-15.9). CONCLUSION: The incidence of severe hypoglycaemic events in Germany increased between 2006 and 2011, despite increased use of newer anti-hyperglycaemic agents and decreased use of insulins. PMID- 28586531 TI - Anion Exchange Renders Hydrophobic Capsules and Cargoes Water-Soluble. AB - Control over the solubility properties of container molecules is a central challenge in host-guest chemistry. Herein we present a simple anion-exchange protocol that allows the dissolution in water of various hydrophobic metal organic container molecules prepared by iron(II)-templated subcomponent self assembly. Our process involved the exchange of less hydrophilic trifluoromethanesulfonate anions for hydrophilic sulfate; the resulting water soluble cages could be rendered water-insoluble through reverse anion exchange. Notably, this strategy allowed cargoes within capsules, including polycyclic aromatic compounds and complex organic drugs, to be brought into water. Hydrophobic effects appeared to enhance binding, as many of these cargoes were not bound in non-aqueous media. Studies of the scope of this method revealed that cages containing tetratopic and tritopic ligands were more stable in water, whereas cages with ditopic ligands disassembled. PMID- 28586532 TI - Periodontal status and serum biomarker levels in HFE haemochromatosis patients. A case-series study. AB - AIM: To investigate the association between periodontal status and serum biomarkers in patients with HFE haemochromatosis. MATERIAL AND METHODS: This clinical case series included 84 HFE-C282Y homozygous patients. Periodontal evaluation was performed using clinical attachment level, probing depth, gingival bleeding index, visible plaque index and gingival index. Serum markers of iron metabolism were collected from medical records. The relationship between serum biomarkers of iron burden and the severity of periodontitis was investigated. RESULTS: The study population consisted of 47 men and 37 women, routinely treated in the Unit of Hepatology, University Hospital, Rennes. All patients presented with periodontitis (mild: n = 1, moderate: n = 37 and severe: n = 46). There was a positive association between transferrin saturation >45% and the severity of periodontitis (adjusted odds ratio = 5.49, p = .002). CONCLUSION: Severe periodontitis is associated with the severity of iron burden in patients with HFE related hereditary haemochromatosis. Dental examination should be included in the initial assessment of all these patients. PMID- 28586534 TI - Working Alliance, Interpersonal Problems, and Depressive Symptoms in Tele Interpersonal Psychotherapy for HIV-infected Rural Persons: Evidence for Indirect Effects. AB - OBJECTIVE: Interpersonal psychotherapy (IPT) has demonstrated efficacy for the treatment of depression, yet little is known about its therapeutic mechanisms. As a specific treatment, IPT has been shown to directly reduce depressive symptoms, although it is unclear whether these reductions occur via interpersonal changes. Within IPT, the potential role of the working alliance, a common factor, as a predictor of depression and interpersonal changes is also unclear. METHOD: Participants were 147 depressed persons living with HIV in rural communities of 28 U.S. states enrolled in a randomized clinical trial. Seventy-five patients received up to 9 sessions of telephone-administered IPT (tele-IPT) plus standard care and 72 patients received standard care only. Two models were tested; one included treatment condition (tele-IPT vs. control) and another included the working alliance as independent variables. RESULTS: The first model found an indirect effect whereby tele-IPT reduced depression via decreased social avoidance. There was a direct effect between tele-IPT and reduced depression. In the second model, the working alliance influenced depressive symptom relief via reductions in social avoidance. Both goal and task working alliance subscales were indirectly associated with reductions in depressive symptoms, also through reductions in social avoidance. There were no direct effects involving the working alliance. Tele-IPT's influence on depressive symptom reduction was primarily through a direct effect, whereas the influence of working alliance depression was almost entirely via an indirect effect through interpersonal problems. CONCLUSION: Study findings have implications for IPT when intervening with depressed rural people living with HIV/AIDS over the telephone. PMID- 28586535 TI - Ultrafast Excited-State Deactivation Dynamics of Cyclotrisazobenzene-A Novel Type of UV-B Absorber. AB - Azobenzenes are widely utilized as molecular photoswitches for control of nanoscale processes. Their photoisomerization reaction is highly robust and is retained even in extremely rigid systems. Currently, it is not clear what geometric restrictions are required to block this isomerization successfully. We present here a combined experimental and theoretical study on the ultrafast dynamics of cyclotrisazobenzene (CTA) and demonstrate that the structural constraints in CTA prevent isomerization of the photoswitch units. In the developed molecular picture, the N=N bonds respond elastically to the motion along the isomerization coordinates, which leads to ultrafast and complete dissipation of the UV excitation as heat. Based on this property, CTA and possibly other similarly designed molecules can be utilized as UV absorbers, for example in sunscreens; other potential applications are also envisioned. PMID- 28586533 TI - Characterization of rapid extraction protocols for high-throughput metabolomics. AB - RATIONALE: In the last five years, high-throughput metabolomics has significantly advanced scientific research and holds the potential to promote strides in the fields of clinical metabolomics and personalized medicine. While innovations in the field of flow-injection mass spectrometry and three-minute metabolomics methods now allow investigators to process hundreds to thousands of samples per day, time-sensitive clinical applications, particularly in the emergency department, are limited by a lack of rapid extraction methods. METHODS: Here we characterized the efficacy of fast liquid-liquid extractions for characterization of hydrophilic compounds through ultra-high-pressure liquid chromatography/mass spectrometry. Internal stable-isotope-labeled standards were used to quantitatively characterize markers of energy and oxidative metabolism in human whole blood, plasma and red blood cells - three common matrices of clinical relevance. RESULTS: For all the tested matrices, vortexing time (4-60 min) did not significantly affect extraction yields for the tested hydrophilic metabolites. Coefficients of variations <<20% for all tested compounds, except for the redox-sensitive metabolite cystine (accumulating over time). Internal standards and second extractions confirmed recoveries >80% for all tested metabolites, except for basic amino acids and polyamines, which showed reproducible yields ranging from 50 to 75%. Global profiling and absolute quantitation of 24 metabolites revealed similarities between the plasma and red blood cell metabolomes. CONCLUSIONS: Rapid extraction (~4 min) of hydrophilic compounds is a viable and potentially automatable strategy to perform quantitative analysis of whole blood, plasma and red blood cells for research or clinical applications. PMID- 28586536 TI - Should recommendations for clinical use be restricted to patients who were enrolled in a pivotal clinical trial? PMID- 28586538 TI - Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. PMID- 28586537 TI - Patient-reported outcomes in the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED ejection fraction (SOCRATES-PRESERVED) study. AB - AIMS: Exploratory assessment of the potential benefits of the novel soluble guanylate cyclase stimulator vericiguat on health status in patients with heart failure (HF) with preserved ejection fraction. METHODS AND RESULTS: The SOCRATES PRESERVED trial randomized patients with chronic HF and ejection fraction >= 45% within 4 weeks of decompensation to 12 weeks of treatment with titrated doses of vericiguat (1.25, 2.5, 5, and 10 mg once daily) or placebo. Health status was assessed with the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) and the generic health-related quality of life measure EQ-5D. In total, 477 patients were randomized 12.9 +/- 9.0 days after hospitalization or if requiring outpatient treatment with intravenous diuretics for HF. Baseline KCCQ clinical summary score (CSS), a combination of symptom and physical function domains, was 52.3 +/- 20.4 in the 10 mg arm and 54.1 +/- 23.0 in placebo, and EQ 5D US index score was 0.74 +/- 0.2 and 0.73 +/- 0.2, respectively. A larger proportion of patients treated with vericiguat in the 10 mg arm, compared with placebo, achieved clinically meaningful improvements in KCCQ-CSS (82.0% vs. 59.0%, number needed to treat = 4.35, P = 0.0052). Important domains of the KCCQ as well as EQ-5D scores demonstrated a dose-dependent relationship with vericiguat. In the 10 mg arm, the mean physical limitations domain increased by +17.2 +/- 19.1 at 12 weeks, compared with +4.5 +/- 21.6 in placebo (P = 0.0009). The EQ-5D US index score increased by +0.064 +/- 0.167 in the 10 mg arm, compared with a decrease of -0.009 +/- 0.195 in placebo (P = 0.0461). Improvements in KCCQ and EQ-5D scores paralleled physician-assessed NYHA class and clinical congestion. CONCLUSION: Vericiguat, in exploratory hypothesis-generating analyses, was associated with clinically important improvements in patients' health status, as assessed by the KCCQ and EQ-5D. Further studies should be conducted to test the hypothesis that vericiguat improves physical functioning and health-related quality of life in patients with HF with preserved ejection fraction. PMID- 28586539 TI - June 2017 at a glance: biomarkers and medical treatment. PMID- 28586540 TI - Quantification and risk assessment of organic products resulting from non-thermal plasma removal of toluene in nitrogen. AB - RATIONALE: Non-thermal plasma (NTP) has proven to be an effective approach for the removal of volatile organic compounds (VOCs). However, harmful organic by products, produced during NTP-mediated removal of VOCs, hinder practical applications of this technology. It is necessary to characterize the organic by products to assess their health risks. METHODS: A method is proposed for analyzing and evaluating organic by-products for NTP-mediated removal of VOCs in this work. NTP generated by a coaxial dielectric barrier discharge (DBD) reactor was used for the removal of a model VOC, toluene, in nitrogen. Organic products were characterized using a real-time proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) apparatus. RESULTS: The PTR-TOF-MS apparatus has been shown to be effective for real-time high-sensitivity detection of trace VOCs. The main observed organic compounds, with concentrations on the order of ppb/ppm, were hydrogen cyanide, acetonitrile, propanenitrile, benzene, benzonitrile, and benzyl nitrile, etc. CONCLUSIONS: A health-related index (HRI) was introduced to assess the health risks associated with these organic products. The HRI was not correlated with the removal efficiency (eta), with higher eta possibly yielding higher HRI, associated with higher health risks. Specific input energy (SIE) was a key factor affecting the formation of the observed organic products and their HRI values. We conclude that in practical applications, SIE, HRI, and eta must be balanced. PMID- 28586541 TI - Sex differences in telomeres and lifespan in Soay sheep: From the beginning to the end. AB - There is tremendous diversity in ageing rates and lifespan not only among taxa but within species, and particularly between the sexes. Women often live longer than men, and considerable research on this topic has revealed some of the potential biological, psychological and cultural causes of sex differences in human ageing and lifespan. However, sex differences in lifespan are widespread in nonhuman animals suggesting biology plays a prominent role in variation in ageing and lifespan. Recently, evolutionary biologists have borrowed techniques from biomedicine to identify whether similar mechanisms causing or contributing to variation in ageing and lifespan in humans and laboratory animals also operate in wild animals. Telomeres are repetitive noncoding DNA sequences capping the ends of chromosomes that are important for chromosomal stability but that can shorten during normal cell division and exposure to stress. Telomere shortening is hypothesized to directly contribute to the ageing process as once telomeres shorten to some length, the cells stop dividing and die. Men tend to have shorter telomeres and faster rates of telomere attrition with age than women, suggesting one possible biological cause of sex differences in lifespan. In this issue of Molecular Ecology, Watson et al. () show that telomere lengths in wild Soay sheep are similar between females and males near the beginning of life but quickly diverge with age because males but not females showed reduced telomere lengths at older ages. The authors further show that some of the observed sex difference in telomere lengths in old age may be due to male investment in horn growth earlier in life, suggesting that sexually dimorphic allocation to traits involved in sexual selection might underlie sex differences in telomere attrition. This study provides a rare example of how biological mechanisms potentially contributing to sex differences in lifespan in humans may also operate in free-living animals. However, future studies using a longitudinal approach are necessary to confirm these observations and identify the ultimate and proximate causes of any sex differences in telomere lengths. Collaborations between evolutionary biologists and gerontologists are especially needed to identify whether telomere lengths have a causal role in ageing, particularly in natural conditions, and whether this directly contributes to sex differences in lifespan. PMID- 28586542 TI - Terra incognita of soil biodiversity: unseen invasions under our feet. AB - Whilst cartographers of the 19th century endeavoured to chart the last unknown lands, the great challenge for biologists in the 21st century is to fill the gaps on the biodiversity map of the Earth. And one of the largest gaps concerns the biodiversity of soils, a terra incognita right under our feet. The study of soil biodiversity, and particularly the complex communities of small invertebrates, has suffered from a severe 'taxonomic impediment' (Decaens ) leading to great uncertainties about total species richness, phylogenetic diversity, geographical structure, temporal dynamics of soil organisms, and consequently about their role on ecosystem function (Bardgett & van der Putten ). However, the revolution in high-throughput sequencing is now revealing the hidden biodiversity of the soil with unprecedented detail (e.g. Arribas et al. ). In a noteworthy from the Cover article in this issue of Molecular Ecology, Cicconardi et al. () apply these new tools to study soil communities of Collembola in three distant oceanic islands of volcanic origin, obtaining a striking result: only 38 of 70 species (54%) are exclusively found in a single island, with the remaining shared among islands or with other distant regions, suggesting a massive recent introduction of soil species, whose impact is entirely unknown. PMID- 28586543 TI - Acute fatigue predicts sickness absence in the workplace: A 1-year retrospective cohort study in paediatric nurses. AB - AIMS: To examine the relationship between fatigue and sickness absence in nurses from a paediatric hospital over 12 months of follow-up. A secondary aim was to identify other work and personal factors that predict sickness absence. BACKGROUND: Sickness absence is often related to worker-fatigue, yet few studies have explored this relationship in nurses despite documented high fatigue levels. DESIGN: The study used retrospective cohort design. METHODS: Baseline data on 40 nurses from an intervention study were linked to absence data using the hospital's attendance records (2012-2013). A total of 6,057 work shifts were studied of which 5.2% were absence episodes. Fatigue was measured by the Occupational Fatigue Exhaustion Recovery scale. The questionnaire included instruments assessing sleep disturbances, workload and personal characteristics. Generalized linear mixed models were used to test the associations between fatigue, work, personal factors and sickness absence, while accounting for non independency of repeated measures. RESULTS: With 1SD increase in acute fatigue scores, nurses were 1.29 times more likely to be absent from work. Factors such as intershift recovery, perceived workload, obstructive sleep apnoea and marital status also predicted sickness absence, that is, with 1SD increase in workload scores, nurses were 1.23 times more likely to be absent from work. Nurses with obstructive sleep apnoea had two times higher odds of sickness absence. CONCLUSION: Sickness absence is related to acute fatigue in paediatric nurses and to workload. Nursing leaders can monitor these factors to reduce sickness absence and screen for sleep apnoea and assist nurses in receiving the appropriate treatments. PMID- 28586544 TI - Segmental and regional quantification of 3D cellular density of human meniscus from osteoarthritic knee. AB - The knee menisci have important roles in the knee joint. Complete healing of the meniscus remains a challenge in the clinics. Cellularity is one of the most important biological parameters that must be taken into account in regenerative strategies. However, knowledge on the 3D cellularity of the human meniscus is lacking in the literature. The aim of this study was to quantify the 3D cellular density of human meniscus from the osteoarthritic knee in a segmental and regional manner with respect to laterality. Human lateral menisci were histologically processed and stained with Giemsa for histomorphometric analysis. The cells were counted in an in-depth fashion. 3D cellular density in the vascular region (27 199 cells/mm3 ) was significantly higher than in the avascular region (12 820 cells/mm3 ). The cells were observed to possess two distinct morphologies, roundish or flattened. The 3D density of cells with fibrochondrocyte morphology (14 705 cells/mm3 ) was significantly greater than the 3D density of the cells with fibroblast-like cell morphology (5539 cells/mm3 ). The best-fit equation for prediction of the 3D density of cells with fibrochondrocyte morphology was found to be: Density of cells with fibrochondrocyte morphology = 1.22 * density of cells withfibroblast-like cell morphology + 7750. The present study revealed the segmental and regional 3D cellular density of human lateral meniscus from osteoarthritic knee with respect to laterality. This crucial but so far missing information will empower cellular strategies aiming at meniscus tissue regeneration. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28586545 TI - Multifaceted therapeutic benefits of factors derived from stem cells from human exfoliated deciduous teeth for acute liver failure in rats. AB - In acute liver failure (ALF), a poorly controlled innate immune response causes massive hepatic destruction, which elicits a systemic inflammatory response, progressive multiple organ failure and ultimate sudden death. Although the liver has inherent tissue-repairing activities, its regeneration during ALF fails, and orthotopic liver transplantation is the only curative approach. Here we show that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED CM) into the d-galactosamine-induced rat model of ALF markedly improved the condition of the injured liver and the animals' survival rate. The engraftment of infused SHEDs was very low, and both SHEDs and SHED-CM exerted similar levels of therapeutic effect, suggesting that the SHEDs reversed ALF by paracrine mechanisms. Importantly, SHED-CM attenuated the ALF-induced pro-inflammatory response and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like hepatic macrophages. Secretome analysis by cytokine antibody array revealed that the SHED CM contained multiple tissue-regenerating factors with known roles in anti apoptosis/hepatocyte protection, angiogenesis, macrophage differentiation and the proliferation/differentiation of liver progenitor cells. Taken together, our findings suggest that SHEDs produce factors that provide multifaceted therapeutic benefits for AFL. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28586546 TI - A bioartificial environment for kidney epithelial cells based on a supramolecular polymer basement membrane mimic and an organotypical culture system. AB - Renal applications in healthcare, such as renal replacement therapies and nephrotoxicity tests, could potentially benefit from bioartificial kidney membranes with fully differentiated and functional human tubular epithelial cells. A replacement of the natural environment of these cells is required to maintain and study cell functionality cell differentiation in vitro. Our approach was based on synthetic supramolecular biomaterials to mimic the natural basement membrane (BM) on which these cells grow and a bioreactor to provide the desired organotypical culture parameters. The BM mimics were constructed from ureidopyrimidinone (UPy)-functionalized polymer and bioactive peptides by electrospinning. The resultant membranes were shown to have a hierarchical fibrous BM-like structure consisting of self-assembled nanofibres within the electrospun microfibres. Human kidney-2 (HK-2) epithelial cells were cultured on the BM mimics under organotypical conditions in a custom-built bioreactor. The bioreactor facilitated in situ monitoring and functionality testing of the cultures. Cell viability and the integrity of the epithelial cell barrier were demonstrated inside the bioreactor by microscopy and transmembrane leakage of fluorescently labelled inulin, respectively. Furthermore, HK-2 cells maintained a polarized cell layer and showed modulation of both gene expression of membrane transporter proteins and metabolic activity of brush border enzymes when subjected to a continuous flow of culture medium inside the new bioreactor for 21 days. These results demonstrated that both the culture and study of renal epithelial cells was facilitated by the bioartificial in vitro environment that is formed by synthetic supramolecular BM mimics in our custom-built bioreactor. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28586548 TI - Frontal Fibrosing Alopecia Severity Index (FFASI): a call for a more inclusive and globally relevant severity index for frontal fibrosing alopecia. PMID- 28586547 TI - PCL-HA microscaffolds for in vitro modular bone tissue engineering. AB - The evolution of microscaffolds and bone-bioactive surfaces is a pivotal point in modular bone tissue engineering. In this study, the design and fabrication of porous polycaprolactone (PCL) microscaffolds functionalized with hydroxyapatite (HA) nanoparticles by means of a bio-safe and versatile thermally-induced phase separation process is reported. The ability of the as-prepared nanocomposite microscaffolds to support the adhesion, growth and osteogenic differentiation of human mesenchymal stem cells (hMSCs) in standard and osteogenic media and using dynamic seeding/culture conditions was investigated. The obtained results demonstrated that the PCL-HA nanocomposite microparticles had an enhanced interaction with hMSCs and induced their osteogenic differentiation, even without the exogenous addition of osteogenic factors. In particular, calcium deposition, alizarin red assay, histological analysis, osteogenic gene expression and collagen I secretion were assessed. The results of these tests demonstrated the formation of bone microtissue precursors after 28 days of dynamic culture. These findings suggest that PCL-HA nanocomposite microparticles represent an excellent platform for in vitro modular bone tissue engineering. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 28586550 TI - Commentary on Ostergaard et al. (2017): Evidence of an association between cannabis use and suicide in subjects with bipolar disorder. PMID- 28586552 TI - Corrigendum. PMID- 28586551 TI - New developments and opportunities for preventing hepatitis C virus (HCV) among people who use and inject drugs-announcing an Addiction series. PMID- 28586549 TI - Effect of pregnancy planning on maternal and neonatal outcomes in women with Type 1 diabetes. AB - AIMS: To assess the effect of pregnancy planning on maternal and neonatal outcomes in women with Type 1 diabetes. METHODS: Pregnancy planning was assessed retrospectively in a cohort of women who participated in the Diabetes and Pre eclampsia Intervention Trial (DAPIT). Pregnancy planning was determined based on self-report as to whether pregnancy was planned or unplanned. The effect of pregnancy planning on maternal and neonatal outcomes was examined, controlling for confounding variables. RESULTS: A total of 747 women were included in the study, of whom 39% considered their pregnancy unplanned. Characteristics associated with unplanned pregnancy included being younger (P<0.001), being a current smoker (P<0.001), being from a lower social class (P<0.001) and having higher HbA1c values prior to and throughout pregnancy (P<=0.005). Significantly fewer women with unplanned vs planned pregnancies received pre-pregnancy counselling (24% vs 64%; P<0.001). Infants of women with unplanned pregnancies were more likely to be small for gestational age (<5th centile; P=0.004), to be admitted to the neonatal care unit (P=0.001) and to have a longer stay in hospital (P=0.01). Outcomes did not differ between the groups in relation to pre eclampsia, congenital malformations or a composite adverse outcome. CONCLUSIONS: Risks associated with diabetes in pregnancy need to be highlighted to all women, their partners and families, and healthcare professionals. Further research is required to determine if these groups are fully aware of the risks associated with diabetes in pregnancy. PMID- 28586553 TI - Commentary on Halonen et al. (2017): Pondering the latent class trajectories of retiring older adults. PMID- 28586555 TI - Commentary on Gountas et al. (2017): Time to focus on empirical evidence for HCV treatment as prevention. PMID- 28586556 TI - Corrigendum. PMID- 28586557 TI - Opiod Misuse, Abuse and Addiction Part 2: Opiod Prescriber Responsibilities and Resources. PMID- 28586558 TI - Announcing the 2017 Edward J. Ill Excellence in Medicine Awards. PMID- 28586559 TI - Legislative Update. PMID- 28586560 TI - New Jersey Combats rise in Sexually Transmitted Disease. PMID- 28586561 TI - Infantile Paralysis: The Newark Polio Epidemic of 1916. PMID- 28586562 TI - The Dangers of Concussions in Young Athletes: An interview with John Shumko, MD. PMID- 28586564 TI - Advocating for Cultural Competency n the Medical Profession. PMID- 28586563 TI - Top Tips For Physicians: Understand the Importance of Coding and Billing Accuracy. PMID- 28586565 TI - POV: The Effect of Hospital Mergers on Healthcare. PMID- 28586566 TI - New Jersey's Opiod Addiction Health Crisis. PMID- 28586567 TI - Ending the HIV epidemic with the Help of biomedical Prevention Interventions. PMID- 28586568 TI - Perspectives on Healthcare from the 2017 Edward J. Ill Excellence in Medicine Honorees. PMID- 28586570 TI - Frederick Douglass Memorial Hospital and Training School: A Historical Persepctive. PMID- 28586569 TI - Spring Legistlative. PMID- 28586571 TI - Promoting the Vitality of Faculty to Combat Burnout. PMID- 28586572 TI - Igniting Passion in Your People. PMID- 28586573 TI - The Value of Mentorship. PMID- 28586574 TI - Bundled Payment for Physician Group Practices and Organized Delivery Systems. PMID- 28586575 TI - And Yet One More Adds To The Sorrow. AB - Chikungunya is one of the vector borne diseases. It is caused by Chikungunya virus, an alpha virus, spread by the bite of female Aedes mosquito. Chikungunya is a non-fatal, self-limiting Dengue like illness which is characterized by high grade fever, headache, skin rash, and prolong debilitating arthralgia mostly affecting peripheral small joints. Treatment is usually supportive for the symptoms which includes antipyretic, analgesics and anti-inflammatory drugs. Current outbreak in Karachi is the first declared outbreak in Pakistan. To control the current outbreak, integrated vector management approach must be used to control Aedes not only to combat the current outbreak but also to reduce the endemicity and to prevent introduction of other Aedes borne diseases. PMID- 28586576 TI - Non arteritic anterior ischemic optic neuropathy; does Anticoagulation help? AB - BACKGROUND: Non Arteritic Anterior Ischemic Optic Neuropathy (NAION) is the most common acute optic neuropathy in patients over 50 years of age. This study was conducted to determine the beneficial effects of anticoagulation with Heparin and Warfarin in patients with NAION presenting within 4 weeks of onset of symptoms. METHODS: A prospective, interventional, pilot study was conducted in Eye- A unit of Khyber Teaching Hospital from July 2010 onwards on patients with NAION presenting within 4 weeks of onset of symptoms. Patients underwent complete ophthalmological examination including Snellen's visual acuity (latter converted to Log MAR), pupil examination, fundus examination and automated Humphrey visual field analysis. Hematologic tests, Thrombophilia screening, Echocardiography and carotid Doppler ultrasound were carried on patients. All patients were anticoagulated with Heparin and Warfarin after obtaining informed written consent. Patients were examined at 1 Month, 3 months and 6 months' time period. Primary parameter measured was improvement in visual acuity. RESULTS: Total number of patients in our study was 24. Regarding visual outcome total number of patients having significant improvement of visual acuity in our study was 16 (66.6%), while 4 (16.7%) patients had marginal improvement of visual acuity. Three (12.5%) patients maintained stable visual acuity of 6/6 throughout the study period in presence of thrombophilic disorders. One patient (4.1%) suffered a decline in visual acuity compared to VA at baseline presentation. CONCLUSIONS: Anticoagulation using heparin and warfarin does benefit patients with NAION presenting within 4 weeks of onset of symptoms. In our study a higher proportion of patients experienced significant improvement of visual acuity following anticoagulation as compared to the highest reported spontaneous improvement in such patients. PMID- 28586577 TI - Pattern and profile of electric burn injury cases at a Burn centre. AB - BACKGROUND: Electrical burns are quite different from thermal and chemical burns. This study is from a centre which deals with job related electric burn injuries alone and thus can give a pure account of the electric burns and discuss the related peculiarities. Study aims to highlight the differences in the mechanism of electric burn injury, its mode of presentation, morbidity, complications and thus the treatment strategies as compared to rest of the burn injuries. METHODS: This is a descriptive case series study of first consecutive 61 electric burn victims treated at a Burn Unit and Plastic Surgery centre. Cases were admitted and resuscitated at the emergency, and further treated at burn unit. Thorough history, examination findings and operative procedures were recorded. Patients were photographed for record as well. Emergency operative procedures, wound management, soft tissue coverage procedures and complications during the hospital stay were recorded and studied. RESULTS: Twenty cases (33%) were in the fifth decade of life. High voltage electric burn injury was seen in 42 (69%) of the cases. Whereas only 9 cases were treated conservatively, other 52 cases had 24 fasciotomies and 71 debridements. Series witnessed 10 expiries, and 22 amputations and all these were result of high voltage electric burns. Twenty eight soft tissue coverage procedures were carried out. CONCLUSIONS: Electric burn injuries are altogether different from rest of the burn injuries and must be treated accordingly. These injuries are peculiar for ongoing damage, extensive trauma, complications and prolonged morbidity. Treatment requires a high degree of suspicion, more aggressive management to unfold and minimize the deep seated insult. PMID- 28586578 TI - Electrophysiological changes in patients with liver cirrhosis in a tertiary care hospital in Karachi, Pakistan. AB - BACKGROUND: Electrophysiological changes in cirrhosis are well known but least investigated especially in our country hence we wanted to see electrophysiological changes especially QT interval in cirrhotic patients. METHODS: A cross-sectional study was conducted at Aga Khan University Hospital Karachi (AKUH) in which medical records (duration 2008-2010) of cirrhotic patients were reviewed. RESULTS: Three hundred and eighty cirrhotic patients' charts were studied, 227 (59.7 %) were male and mean age of this cohort was 52.8+/-12.6 years. The most common cause for CLD was Hepatitis C (CHC) in 260 (68.4%), NBNC in 56(14.7%) and HBV in 51 (13.4%). Only 225 had complete ECG workup, the mean corrected QT interval was 0.44+/-0.067sec. Among the electrophysiological abnormalities, 79 (35%) had a prolonged corrected QT interval, 7 (3.1%) had a prolonged PR interval (>0.22s) and prolonged QRS duration was seen in 23 (10.4%) patients. QT prolongation was seen in 1 of the 5 patients with Child Class A (20%), 22 of the 73 patients with Child Class B (30.1%), and 25 of the 61 patients with Child Class C (41%). However, this difference however was not statistically significant. (p-value=.331). CONCLUSIONS: We conclude that QT prolongation is more frequent in patients with liver cirrhosis especially when the disease is more advanced like in Child C hence these patients are more prone to sudden cardiac death. Moreover, this study shows that the risk associated with QT prolongation is present through all classes of liver cirrhosis. We recommend that routine cardiac screening with ECG of all cirrhotic patients be performed. PMID- 28586580 TI - Impact of antenatal corticosteroids on frequency and mortality due to respiratory distress syndrome in preterm neonates. AB - BACKGROUND: Prematurity is still a major problem for health care services throughout the world. Before the late 1980s, respiratory distress syndrome (RDS) was the primary cause of morbidity and mortality in preterm new-borns. Frequency of RDS and ensuing mortality in infants treated with antenatal steroid is less than those delivered without this therapy. Many pregnant females deliver before term or 37 weeks, hence may be advised this prophylactic therapy without creating significant maternal or foetal side effects. METHODS: It was a descriptive case series conducted in the department of obstetrics and gynaecology, unit II of Jinnah Hospital Lahore for a period of 6 months. RESULTS: The study sample of 230 was divided into two groups on the basis of exposure to dexamethasone. RDS was reported 76 (33.0%) cases (preterm neonates) in the study, out of these 26 (22.4%) cases belonged to exposed group and 50 (43.9%) cases belonged to non exposed group. Mortality due to RDS among all preterm neonates with RDS occurred in total 29 (12.6%) preterm neonates in the study, out of these 5 (4.3%) cases belonged to exposed group and 24 (21.1%) belonged to non-exposed group. CONCLUSIONS: Frequency of RDS and mortality due to this disease in group of infants treated with antenatal steroid is far less than the group of preterm new borns delivered without this therapy. PMID- 28586579 TI - Exploration of variations in positions of upper and Lower incisors, overjet, overbite, and irregularity Index in orthodontic patients with dissimilar depths of Curve of spee. AB - BACKGROUND: The position and arrangement of teeth as well as the entire scheme of occlusion differs from one individual to the other .The purpose of this study was to examine differences in position and inclination of incisors, overjet, overbite and lower arch crowding in subjects with different depths of curve of Spee and to determine correlations between depth of curve of Spee and these variables. METHODS: The sample comprised of 114 patients (55 females and 59 males) with fully erupted permanent second molars (age 12-25 years), having no history of previous orthodontic treatment, no craniofacial anomalies, and no missing permanent teeth. Study parameters were assessed by using pretreatment lateral cephalograms and dental casts of orthodontic patients. The entire sample was divided into three groups according to depth of curve of Spee (mild Spee=38, moderate Spee=38, severe Spee=38). Descriptive statistics were calculated. Differences between the Spee groups were assessed by analysis of variance. In addition, correlation coefficients were calculated between curve of Spee and other parameters. RESULTS: Statistically significant differences were found in upper incisor inclination (p=0.000), lower incisor inclination (p=0.003), Steiner's mandibular plane angle (p=0.000), overjet (p=0.001), overbite (p=0.000) and irregularity index (p=0.008) among the Spee groups. Moreover, statistically significant positive correlations were found between curve of Spee and overjet, overbite and irregularity index. Upper and lower incisor inclinations as well as mandibular plane angle were found to have statistically significant but negative correlations with curve of Spee. CONCLUSIONS: Overjet and overbite in severe Spee group are larger than in mild and moderate Spee groups. There is negative correlation between curve of Spee depth and inclinations of upper and lower incisors. There is positive correlation between curve of Spee depth and severity of lower anterior crowding and Steiner's mandibular plane angle. PMID- 28586581 TI - Difficulties in laparoscopic cholecystectomy: Conversion versus surgeon's failure. AB - BACKGROUND: Laparoscopic cholecystectomy is considered to be gold standard treatment for symptomatic gall stones. Despite several benefits there are still disadvantages of laparoscopic cholecystectomy in difficult cases where anatomy is disturbed even in experienced hand. Aim of this study is to identify advantages of early conversion to open cholecystectomy in difficult cases and how it should not be associated with surgeon's failure. METHODS: Observational study was conducted at tertiary care hospital of Karachi, Pakistan from January 2012 till June 2015. All patients who presented to general surgery department with symptomatic gall stones and planned for laparoscopic cholecystectomy was included in the study. Demographic data was collected. Preoperative workup includes baselines investigations with liver profile test and imaging study (ultrasound scan). All patient underwent laparoscopic cholecystectomy at first. Operative difficulties, incidence of conversion, reason for conversion and complication intra-operative or postoperative were recorded. Data was analyzed using SPSS 20. RESULTS: Out of 1026 patients, 78.26% (803) were female. Mean age of patients were 41.30+/-8.43 years (range 26-68 years). Common presenting symptoms were pain at upper abdomen and dyspepsia. Most of the patients had multiple gall stones (93.85%). Nine hundred and ninety-two patients (96.68%) of patients underwent successful laparoscopic cholecystectomy. This includes patients in whom dissections were difficult because of disturbed anatomy of calots triangle. Only 3.13% of patients were converted to open cholecystectomy. There was a significant difference (<0.05) in complications observed between completed and converted cholecystectomies. CONCLUSIONS: Conversion from laparoscopic to open procedure should be done in cases of technically difficult situations to avoid significant mortality and morbidity. Surgeons experience had a pivotal role in determining its need and justification. PMID- 28586582 TI - Isolated Gastric Tuberculosis Mimicking Malignancy. AB - Isolated tuberculosis of upper gastrointestinal tract is a rare pathology, often mimicking malignancy in clinical presentation and radiological features. We present a case of middle aged gentleman with isolated tuberculosis of stomach, proven on histopathology and showing remarkable improvement on follow up. PMID- 28586583 TI - Eales Disease. AB - Eales disease is an eponym after a British ophthalmologist Henry Eales. The aetiology behind Eales disease is ill-understood and stands controversial. Various systemic diseases associated with peripheral retinal revascularization and Retinal vasculitis could imitate the proliferative and inflammatory phases of Eales' disease, respectively. We present a case of a 30 years old female patient with Eales disease and discuss the clinical features, treatment plan and its outcome in our patient. Tuberculosis appears to be the cause of Eales disease but the relation is yet to be established and clinically proven. Steroid therapy is usually the main stay of treatment with tapering doses of systemic corticosteroids. Other interventions are vitrectomy, photocogulation or cryotherapy. PMID- 28586584 TI - Hypothyroidism In Hepatitis C Patients On Pegylated Interferon Therapy. AB - BACKGROUND: Chronic hepatitis has become a major health problem all over the world especially in the third world countries. The most common cause of chronic hepatitis in Pakistan is hepatitis C which can lead Toliver cirrhosis and hepatocellular carcinoma. In Pakistan Pegylated Interferon Alpha is still corner stone of therapy for chronic hepatitis C. One of the major side effects of this therapy is the development of thyroid dysfunction, i.e., hypothyroidism and hyperthyroidism. This study was done to assess the frequency of hypothyroidism in hepatitis C patients after three months of pegylated interferon therapy. METHODS: This study was conducted from 1st October 2013 to 31st march 2014 at outpatients department (OPD) of Gastroenterology and Hepatology, Lahore General Hospital Lahore. Descriptive case series study design was used. The sample of 200 patients was taken from the patients who visited OPD and fulfil the inclusion criteria of the study. Serum thyroid stimulating hormone level (TSH) was done before and after completion of three months therapy at centre for Nuclear Medicine (CENUM) laboratory, Mayo Hospital, Lahore by immune-radiometric assay (IRMA) and patients having TSH>4.0 mIU/L (normal range: 0.2-4.0 mIU/L) were considered hypothyroid. RESULTS: The mean age of the patients was 36.29+/-8.5 years. One hundred and twenty-three (61.5%) were male and 77 (38.5%) were female. After 3 months of interferon therapy, 163 (81.5%) patients were euthyroid and 37(18.5%) patients were having thyroid dysfunction. There were total 29 (14.5%) hypothyroid patients; 8 (27.6%) were male and 21 (72.4%) female. CONCLUSIONS: It is concluded from this study that frequency of hypothyroidism in patients with chronic hepatitis C was 14.5% after treatment with pegylated interferon therapy for 3 months. Female patients were more prone to develop hypothyroidism as compared to male patients. PMID- 28586585 TI - Efficacy Of Local Anaesthesia In Repair Of Inguinal Hernia. AB - BACKGROUND: Local anaesthesia has been identified as the most favourable anaesthesia for elective inguinal hernia repair with respect to complication rate, cost effectiveness and overall patients' satisfaction. This study was conducted to determine the efficacy of local anaesthesia in inguinal hernia in terms of pain relief, wound infection and hospital stay. METHODS: In this randomized controlled trial (RCT), 60 patients with inguinal hernia were included at the General Surgical 'B' Unit, Ayub Teaching Hospital Abbottabad. RESULTS: The day-case rates were significantly higher when patients underwent surgery under LA compared to GA (82.6% versus 42.6%). The incidence of urinary retention was higher in the GA group (p<0.05). There were 17 (2.9%) re-admissions overall. The reasons for readmission included haematoma (n=6), severe pain (n=4), infection (n=3), fainting (n=2) and urinary retention (n=2). CONCLUSIONS: This study demonstrates that local anaesthesia for inguinal hernia repair has better efficacy as compared to general anaesthesia. PMID- 28586586 TI - Comparative Analysis Of Anterior Knee Pain In Transpatellar And Medial Parapatellar Tendon Approaches In Tibial Interlocking Nailing. AB - BACKGROUND: Anterior knee pain is the most common complaint after intramedullary nail of the tibia. The incidence of anterior knee pain ranges from 10-86% and the exact ethology is unclear. Transpatellar tendon approach is commonly used for tibial intramedullary interlocking nailing but it can also be done through medial parapatellar tendon approach. The objective of the study was to compare post operative anterior knee pain after intramedullary nailing technique by transpatellar approach compared to medial parapatellar approach. METHODS: This randomized controlled trial was carried out in Department of Orthopaedic and Spine Surgery, Ghurki trust teaching hospital, Lahore from 20th February to 19th Nov 2015. Sixty patients who presented at emergency department for the treatment of simple tibial shaft fractures were included in the study. They were divided into two groups with 30 patients in each group, Group A containing patients operated through transpatellar tendon approach while group B containing patients operated through medial parapatellar tendon approach. RESULTS: In Group A, 27 patients were male and 3 patients were female with a mean age of 28.667+/-9.63 while in Group B, 28 were male and 2 were female with a mean age of 34.63+/ 15.82. The main causes of tibial shaft fractures were RTA followed by fall. In Group A mean anterior knee pain was 4.4 while in Group B, it was was 2.5 with a p value of .000. CONCLUSIONS: This study shows that medial parapatellar tendon approach causes less pain as compared to transpatellar approach. PMID- 28586587 TI - Laser Myringotomy Versus Ventilation Tubes In Otitis Media With Effusion. AB - BACKGROUND: Otitis media with effusion (OME) is a leading cause of difficulty in hearing in paediatric population. Otitis media with effusion must be detected and managed early to prevent conductive hearing loss in children. It was aimed to compare results of laser myringotomy and ventilation tube insertion, in terms of hearing improvement and recurrence of Middle ear effusion (MEE). METHODS: This randomized controlled trial was conducted from February 2012 to January 2015. Children of 4- 12 years of age with decreased hearing due to OME were included in the study. These children were investigated with pure tone audiometry (PTA) and tympanometry to confirm conductive hearing loss. Patients were put in 2 groups, group one comprised of patients treated with laser myringotomy and group 2, treated with ventilation tube insertion. The objective was to evaluate and compare results of the two procedures in terms of resolution of middle ear effusion (MEE) and improvement of hearing. The two procedures were also compared in terms of complications like otorrhea, persistence of perforation, hypertrophic scar and thinning of tympanic membrane (TM). RESULTS: Middle ear effusion cleared in 35 out of 68 ears with laser myringotomy (LM) as compared to 52 out of 62 ears with ventilation tubes (VT). The myringotomy was still patent in 21 ears treated with LM while tube was in site in 50 years with VT after 3 months. The hearing level improved with LM by 10-15 dB after first 3 months. CONCLUSIONS: The aim in Otitis media with effusion is ventilation of tympanic cavity. Laser myringotomy can be substitute to ventilation tube insertion (VT). But it remains patent for shorter time and less effective than VT. The ears with refractory or recurrent MEE should have VT insertion. PMID- 28586588 TI - Outcome Analysis Of Two Different Injection Solutions For Epidural Injection In Radicular Lumbar Backache Syndromes. AB - BACKGROUND: Backache is a significant source of disability and suffering in our society. The treatment modalities need continued enhancement in order to achieve the desired goals of lowering morbidity and financial losses while improving the response of the patient. METHODS: This prospective comparative study was conducted at the department of Orthopaedics and Spine Surgery, Khyber Teaching Hospital Peshawar from July 2013 to June 2015. Two interventional groups were designated; Group 1 was comprised of 54 patients who were injected with epidural bupivacaine plus methylprednisolone while Group 2 included 55 patients who were injected with bupivacaine only. Outcome was assessed using the visual analogue scale and Oswestry disability index (ODI). RESULTS: Fifty-five female and 54 male patients with mean age 49.37 years+/-10.46 SD, Mean symptoms duration was 15.01 months+/-9.32 SD. Common presenting symptoms were backache (77.1%), lower limbs pain (66.1%), dermatomal paresthesias (54.1%) and neurogenic claudication in 57.8% patients. The mean visual analogue score (VAS) after injection was 3.18+/ 1.29 while mean ODI after injection was 23.615. There was a statistically significant reduction in VAS scores (2-sided p=0.003, OR =4.03, 95% CI: 1.535 10.60) following the injection. CONCLUSIONS: An epidural spinal injection is a viable option for achieving relief of pain & improves functioning in individuals with radicular backache. However, further research is advised in order to clarify the role of ESI for long-term relief. PMID- 28586589 TI - Cephalic Tetanus: A Case Report In 68-Year-Old Man. AB - Cephalic tetanus is an emergency condition, which is commonly observed in child age group here we report a case of 68-year-old man with the complain of right sided weakness for one day, associated with difficulty in breathing and speech, history of fall also present, case was diagnosed as cephalic tetanus. Here we report a case of cephalic tetanus in an elderly patient. PMID- 28586590 TI - Diagnostic Dilemma Of Biotinidase Deficiency: Case Of A Child From Pakistan. AB - Biotinidase deficiency is an autosomal recessive in born error of metabolism which is characterized by the lack of cleavage of biotin. This disease has been reported very rarely with the incidence found to be 1 per 60,089 and 1 per 112,271 of live births, respectively. This condition has profound effects on the neurological system, various neurocutaneous manifestations and metabolic derangements. We report a case of 3-year-old male child who presented in ER with severe respiratory distress for 1 day in a tertiary care set up. He had been referred from multiple peripheral centres. His associated complaints included severe rash, restlessness and progressive mental deterioration for 2 years. He was managed on symptomatically initially, later a diagnosis of Biotinidase deficiency was made, he responded well on supplemental biotin. Our intention to document this case was for sake of its uniqueness with very common symptoms, varied presentation and rarity of the disease which makes it a diagnostic dilemma. PMID- 28586591 TI - Celiac Crisis: A Rare Or Rarely Recognized Disease. AB - BACKGROUND: Celiac crisis is a serious life threatening complication of celiac disease characterized by profuse diarrhoea, severe dehydration and metabolic disturbances leading to neuromuscular weakness, cardiac arrhythmias and sudden death. It has been described as rare condition and not well documented in the literature. To improve awareness and facilitate diagnosis of this condition, we studied risk factors, pattern of presentation and management plans of celiac crisis. METHODS: It was a descriptive cross sectional study. Patients presenting in emergency room(ER) with profuse diarrhoea leading to severe dehydration, neuromuscular weakness, and metabolic acidosis and electrolyte abnormalities enrolled in the studies after positive serology and small bowel biopsy suggestive of celiac disease. RESULTS: Total 126 patients out of 350 fulfilled the criteria including 54 (42.8%) male and 71 (56.3%) female. The mean age at presentation was 5.25+/-1.18 years. Risk factors were poor social status (97.60%), consanguinity (96.77%), early weaning with gluten contained diet (93.54%), and Presenting complaints were loose motion (100%), loss of neck holding (96.77%), dehydration (96.77%), polyuria (95.96%), inability to walk (67.74%), abdominal distension (85.86%). Electrolytes imbalances were hypokalaemia (2.4+/-0.55), hypocalcaemia (7.29+/-0.66), hypomagnesaemia (1.89+/-0.50), hypophosphatemia (2.8+/-0.68), hypoalbuminemia (3.05+/-0.48) and metabolic acidosis (96%). One hundred & twenty patients were stabilized with GFD and correction of dehydration, acidosis and electrolyte imbalance. Six patients needed parenteral steroids ant total parenteral nutrition (TPN). Recovery time from crisis was mean 5.4+/-2.73 days (range 3-20 days). CONCLUSIONS: Celiac crisis is a common but under recognized problem in developing countries. Commonest presenting feature is neuromuscular paralysis and biochemical abnormality is hypokalaemia. PMID- 28586592 TI - Ultrasound Assistance In Differentiating Malignant Thyroid Nodules From Benign Ones. AB - BACKGROUND: The search is ongoing for simple, effective ways to identify and differentiate thyroid nodules in order to avoid invasive procedures. This study aims to perform an ultrasound assessment of clinically suspected patients with malignant nodules, to perform a fine needle biopsy on them, and to compare the results obtained. METHODS: In total, 135 patients with thyroid nodules suspected to be malignant in the ultrasound underwent ultrasound-guided fine needle biopsies. The patients' gender, age, ultrasound views (echogenicity, shape, and calcification type), nodule size, number of nodules, and needle biopsy results were retrospectively evaluated. RESULTS: Of the 135 patients, 117 (86.7%) were female and 18 (13.3%) were male. In terms of age, 67 (49.16%) were younger than 40 and the rest were older. According to the Chi-square test, a significant relationship was found between the type of nodule and calcification found in the ultrasound views (p=0.001). The nodule type was not significantly related to gender (p=0.563) or to the number of nodules (p=0.128); however, there was a significant relationship between nodule size and type (p=0.001). Ultrasound specificity, sensitivity, positive and negative predictive values, and accuracy for differentiating benign from malignant nodules were 93.2%, 93.8%, 81.1%, 98%, and 93.3%, respectively. CONCLUSIONS: Ultrasound views (comet tail artefact and linear echogenic foci) were better predictors of benign nodules than of malignant ones, while round, echogenic foci, brighter and larger than typical micro calcifications without any visible echoes and multiple punctuate round echogenic foci were better predicted malignancy. PMID- 28586593 TI - Immune Response And Anamnestic Immune Response In Children After A 3-Dose Primary Hepatitis B Vaccination. AB - BACKGROUND: Diseases caused by Hepatitis B virus (HBV) have a worldwide distribution. Pakistan adopted the recommendations of World Health Organization (WHO) for routine universal infant vaccination against hepatitis B in 2002, currently being administered at 6, 10, and 14 weeks of age in a combination vaccine. This study was conducted to determine the immune response & anamnestic immune response in children, 9 months-10 years of age, after a 3dose primary Hepatitis B vaccination. METHODS: This cross sectional study was conducted in the Department of Paediatrics, King Edward Medical University/Mayo Hospital, Lahore, Pakistan, from January to June, 2014. A total of 200 children of either sex between the ages of 9 months to 10 years, documented to have received 3 doses of hepatitis B vaccines according to Expanded Program of Immunization (6,10,14 weeks) schedule in infancy, were recruited by consecutive sampling. The level of serum antiHBsAb by ELIZA was measured. Children with antiHBs titers >=10 mIU/mL were considered to be immune. Those with anti HBsAb levels <10 mIU/mL were offered a booster dose of infant recombinant hepatitis B vaccine. The second serum sample was obtained 21-28 days following the administration of the booster dose and the anamnestic immune response was measured. Data was analysed using SPSS 17 to determine the relation between time interval since last vaccination and antibody titer. Chi square test was applied. RESULTS: Of the 200 children, protective antibody response was found in 58%. Median serological response was 18.60 (range 2.82 - 65.15). Antibody levels were found to have a statistically significant ( pvalue 0.019) negative correlation with the time since last administration of vaccine. A booster dose of Hepatitis B vacci ne was administered to all nonresponders, with each registering a statistically significant (pvalue 0.00) anamnestic response. CONCLUSIONS: The vaccination schedule with short dosage interval was unable to provide protection to 42% of the study population. Introduction of birth dose of Hepatitis B vaccine to the existing schedule is recommended. PMID- 28586594 TI - Risk Factors For Necrotizing Fasciitis And Its Outcome At A Tertiary Care Centre. AB - BACKGROUND: Necrotizing fasciitis (NF) is a serious and potentially fatal condition where there is rapid progression of inflammation of skin, subcutaneous tissue, and superficial fascia and can be mono-microbial or poly-microbial. The disease is rapidly progressive in nature and if not promptly treated leads to significant morbidity or even mortality. This study was designed to explore the various risk factors commonly present and study the outcome of the disease. METHODS: This was a cross sectional study done in tertiary centre over period of one year from April 2014 to March 2015. Patient admitted with soft tissue infection were presumptively made diagnosis of NF based on clinical features and final diagnosis was made after pre-operative surgical findings. RESULTS: Forty two (40.38%) patients had final diagnosis of NF out of 102 soft tissue infections. Twentynine (69%) of 42 patients with NF fully recovered with surgical and medical management. Eleven (26.2%) of these patients succumbed to their illness and two (4.8%) needed amputation of limb to control the infection. The most common co-morbid condition was alcoholism, followed by diabetes mellitus. CONCLUSIONS: The incidence of necrotizing fasciitis in patients admitted with soft tissue infection was 40.38%. Mortality and morbidity due to this condition was found to be high. PMID- 28586595 TI - Patterns And Determinants Of Breast Feeding Among Mother Infant Pairs In Dera Ghazi Khan, Pakistan. AB - BACKGROUND: Proper breastfeeding practices are effective ways for reducing childhood morbidity and mortality. The objective of the present study was to determine the patterns and explore the determinants associated with breast feeding practices among the nursing women in Dera Ghazi Khan. METHODS: A cross sectional study was conducted on randomly selected lactating mother infant pairs in Dera Ghazi Khan. Structured questionnaire was used for data collection. Analysis was done by using SPSS, chi square test was applied to see the association between breast feeding practices and its determinants such as knowledge of breast feeding practices. RESULTS: Majority 372 (93%) of mothers mentioned that they had ever breastfed the youngest child. About 292 (73%) mothers gave colostrum to the child, and 48 (12%) exclusively breastfed. Weaning babies before four month of age was practiced by 84 (21%) of the mothers, 120 (55%) mothers started weaning at 4-6 months of child age, while 72 (18%) started to give additional food after baby turned six months old. Out of total 276 (69%) mothers reported that they had knowledge regarding breast feeding. Significant association was found between knowledge of breastfeeding and initiation and Exclusive Breast Feeding (EBF) practices (p-values <0.05). Income, family type, mode of delivery and assistance for child were significantly associated with initiation of breastfeeding within one hour after birth (p-value <0.001). CONCLUSIONS: Breast feeding practices in the studied area were not up to the mark. There is a strong need to improve the breastfeeding practices by Behavior Change Communication. PMID- 28586596 TI - Histological Pattern Of Endometrial Samples In Postmenopausal Women With Abnormal Uterine Bleeding. AB - BACKGROUND: Abnormal uterine bleeding is one of the most common clinical problems in gynaecological practice and is an indicator of various underlying disorders. An endometrial biopsy should be done in all women over 35 years with AUB to rule out endometrial cancer or pre-malignant lesion and to initiate treatment. However, wide range of histological patterns on endometrial biopsy offer a diagnostic challenge to practicing pathologists. The objective of this study was to determine histological patterns of endometrium in postmenopausal women with abnormal uterine bleeding. METHODS: This cross-sectional study was conducted in the department of obstetrics and gynaecology, Benazir Bhutto Shaheed women and children teaching hospital, Abbottabad from 15/11/2014 to 14/05/2015. This study involved 110 postmenopausal women presenting with abnormal uterine bleeding. A written informed consent was obtained from every patient. RESULTS: The mean age of the patients was 61.60+/-6.17 years and the mean duration of AUB was 5.20+/ 2.80 years. Most of the patients were para 6 (28.2%) and para 5 (28.2%) followed by para 4 (18.2%) and para 3 (17.3%) while only 8.2% were para 1. The most common histological pattern observed was complex hyperplasia without atypia (30.9%) followed by atrophic endometrium (24.5%), simple hyperplasia (23.6%), malignancy (12.7%), complex hyperplasia with atypia (4.5%) and benign endometrial polyp (3.6%). When stratified the data, there was no significant difference of histological patterns across various age groups (p=.673), duration of AUB (p=.064) and parity (p=.242). CONCLUSIONS: The most common histological pattern observed in postmenopausal women with AUB was complex hyperplasia without atypia (30.9%) followed by atrophic endometrium (24.5%), simple hyperplasia (23.6%), malignancy (12.7%), complex hyperplasia with atypia (4.5%) and benign endometrial polyp (3.6%). PMID- 28586597 TI - Identification Of Mutation Sites In Hepatitis C Virus Genotype 3a In Non Responders To Combination Therapy With Interferon- Alphalfa And Ribavirin In Residents Of Khyber Pakhtunkhwa Province Pakistan. AB - BACKGROUND: This study was carried out to search for mutations in the gene encoding for Non- Structural Protein 5A, specifically in the interferon sensitivity determining region of hepatitis C virus (HCV) genotype 3a, isolated from serum samples of patients not responding to treatment with oral Ribavirin and Interferon alpha injections. METHODS: This descriptive case series was conducted on HCV patients reporting in the attached teaching hospitals of Peshawar Medical College selected by consecutive sampling technique from 1st July to 31st December 2012. Amino acid sequencing was performed at the Centre of Applied Molecular Biology Lahore. Patients showing no clinical response after 6 months of combination therapy with Injection Interferon alpha + Ribavirin and still having positive polymerase chain reaction (Declared Non-Responders) were included in this study. RESULTS: Amino acid sequencing was performed on HCV isolates from twenty non-responder and five responder patients. All these sequences were compared with Newzealand1 (NZL1) sequence from the gene bank for mutations; 0-7 mutations were observed in responders as compared to 10-27 mutations in non-responder patients (p value <0.005). CONCLUSIONS: We were able to determine that there is a positive correlation between the number of mutations in NS5A ISDR and non-response to combination therapy. Synonymous mutations >10 and non-synonymous mutations >7 in this region suggest poor response to treatment. PMID- 28586598 TI - An Unusual Pathogen Causing Native Valve Endocarditis. AB - We present the case of a gentleman who was being evaluated for restrictive lung disease and was incidentally found to have mitral valve stenosis on an HRCT. During the surgical procedure for valve replacement, he was found to have an abscess around the native mitral valve which was drained. Pus from the abscess as well as the valve tissue grew Propionibacterium acnes after holding the cultures long. The patient was treated with IV ceftriaxone with good response to therapy. While Propionibacterium acnes is known to cause prosthetic valve infections there are rare case reports with native valves. This is the first case to be reported from our country. PMID- 28586600 TI - Liddle's Syndrome. AB - Hypertension in paediatric age group is commonly secondary to a known cause. It is crucial to identify the cause of hypertension and treat it before development of any associated complications to prevent morbidity and mortality. Paediatric Hypertension is one of the important clinical finding in a child with certain clinical syndrome. We are presenting a case of a 10 month old child presenting with hypertension and hypokalaemia, after excluding all identifiable causes and her positive response to therapy, that is amiloride, along with supportive biochemical data she was diagnosed as a case of monogenic type of hypertension known as Liddle's syndrome. PMID- 28586599 TI - C-Reactive Protein Level In Coronary Artery Disease And Its Correlation With Serum D-Dimer. AB - BACKGROUND: C-reactive protein concentration has continuous associations with risk of coronary artery disease, ischemic stroke and death from several cancers. In addition, several studies have shown that CRP could be used to predict first ever myocardial infarction and stroke in healthy subjects, as well as outcome in acute setting. High levels of another biomarker, D-dimer, have been found to be independently associated with occurrence of coronary events. METHODS: This correlational study was carried out at the Department of Cardiology, Ayub Teaching Hospital Abbottabad, in collaboration with the department of Biochemistry Postgraduate Medical Institute Lahore from 15th July 2013 to 15th May 2014. Patients aged 30 years or more of either gender having coronary artery disease was included in the study. Their serum D-dimer levels and Creactive protein levels were measured for correlation with coronary artery disease. RESULTS: A total of 50 patients of CAD were included in this study. Out of these 30 (60%) were males and 20 (40%) were females. Elevated CRP levels and D-dimer levels were noted in all of these patients. Pearson correlation coefficient test was performed on both CRP and D-dimer levels. Pearson correlation coefficient was calculated to be r= -0.1522 and when a p value was calculated, it was found to be 0.292 which implied that the results were not significant. CONCLUSIONS: This study showed that there is no correlation between CRP levels and D-dimer levels in patients with Coronary Artery Disease. PMID- 28586601 TI - Outcome Of Two Column Acetabular Fractures Treated Operatively Through Single Posterior Approach. AB - BACKGROUND: Involvement of both columns in acetabular fractures is a common presentation; these fractures create a challenging situation for the surgeons in terms of understanding the dimensions of osseous injury and selection of surgical approach. The study was done with an objective to evaluate the efficacy of single posterior approach for acetabular fractures involving both columns directly reducing the posterior wall and column and indirectly reducing the anterior column. METHODS: An evaluation of 25 adult patients 18 male and 7 female presenting in the accident and emergency department of Khyber Teaching Hospital from December 2013 to June 2015 having acetabular fracture involving both the anterior and posterior column were included in this case series study. All patients were operated within 8 days of injury by a single operating team. Exposing and reducing the posterior acetabular column through kockerlengenbeck approach did open reduction and internal fixation with reconstruction plate and cortical screws. Additional lag screw was used to stabilize anterior column after indirect reduction with confirmation through C- arm and digital palpation through the greater sciatic notch. Patients were followed up for 6 months and Harris Hip score was evaluated after the end of the follow up period and the result was analysed. RESULTS: Majority of the patients 20 out of 25 had haris hip score more than 90 after 6 months of the operative management. CONCLUSIONS: It is suggested that acetabular that fractures involving both the acetabular columns in certain situations, may be managed by a single posterior approach as it is associated with good clinical outcome and involves lesser soft tissue complications. PMID- 28586602 TI - Frequency Of Metabolic Syndrome In Asthmatic Patients Of Hazara Division. AB - BACKGROUND: Bronchial asthma is a common disease and most asthmatics are obese. Both asthma and obesity are showing parallel trends in their increasing prevalence. Obesity is also the main component of metabolic syndrome and several studies have shown metabolic syndrome to be associated with bronchial asthma. The present study was, therefore, designed to determine the frequency of metabolic syndrome among patients with chronic asthma in our setup. METHODS: This cross sectional study was conducted in Department of Medicine, Ayub Teaching Hospital, Abbottabad from May to November, 2014. One hundred and fifty-four asthmatic patients were enrolled in this study. Samples for blood glucose, triglycerides and HDL Cholesterol were taken after an overnight fast. Sitting blood pressure was measured with mercury sphygmomanometer after 10 minutes of rest. Waist circumference was measured at the level of the midpoint between the high point of the iliac crest and the last rib. RESULTS: Out of 154 patients, 80 were males and 74 were females. Metabolic syndrome was diagnosed in 46 (29.87%) patients. When metabolic syndrome was stratified according to age, sex and duration of asthma, the results were found to be insignificant (p-0.89, 0.30 and 0.85). CONCLUSIONS: This study showed that metabolic syndrome was present in almost one third of study population. PMID- 28586603 TI - Evaluating The Risk Of Osteoporosis Through Bone Mass Density. AB - BACKGROUND: Osteoporosis is a bone disorder, characterized by loss of bone mass density. Osteoporosis affects more than 30% of post-menopausal women. Osteoporosis is often associated with restricted body movement, pain and joint deformities. Early identification and early intervention can help in reducing these complications. The primary objective of this study was to estimate the burden of Osteoporosis in Urban setting of Sindh among women of different age groups and to access the effect of different protective measures that can reduce the risk of Osteoporosis. METHODS: In this study, 500 women's of 3 major cities of Sindh were approached by non-probability convenience sampling technique. Women bearing age 20 years or more were included. Women who fall under inclusion criteria were screened for BMD (Bone mineral density) test and were classified as Healthy, Osteopenic and Osteoporotic based on their T-score. The association of different protective measures and risk of osteoporosis was assessed by prevalence relative risk (PRR). RESULTS: The result of this study indicate that the burden of Osteoporosis is very high among the women of Sindh, only 17.4% (84) women were found to have normal BMD score. The life style of majority of women was sedentary. The PRR calculated for Exposure to sunlight, regular exercise, and use of nutritional supplement was 12.5, 5.19 and 2.72 folds respectively. CONCLUSIONS: The results of study reveal that exposure to sunlight, regular physical exercise and use of nutritional supplements found to be effective in reducing the risk of osteoporosis among women of all age group. Health education and promotion toward osteoporosis prevention can significantly contribute in reducing the morbidity of osteoporosis. PMID- 28586604 TI - Orbital Involvement In Sinonasal Diseases. AB - BACKGROUND: Orbital involvement in sinonasal diseases can present as proptosis, ophthalmoplegia or even as blindness due to optic nerve damage. There are a number of sinonasal diseases which can involve eyes. The purpose of this study was to enlist diagnoses of all the patients with sinonasal disease, in which orbit was also involved unilaterally or bilaterally and to analyse the management strategy and final outcome in all the cases. METHODS: Hundred consecutive patients having orbital symptoms along with sinonasal complaints that presented in ENT department of Shaikh Zayed federal postgraduate medical institute were included in our prospective study. CT scan and/or MRI were done in all the cases and ophthalmological consultation was done. Patients with sinonasal complaints without clinical involvement of orbit and those with primary orbital pathology were excluded from our study. Final diagnosis was made after histopathological confirmation. RESULTS: A total of 37% of the patients were diagnosed to be having "Allergic fungal rhinosinusitis" 17% had "mucormycosis", 16% had "chronic invasive fungal sinusitis". Other pathologies identified were Nasopharyngeal CA (4%), Squamous cell Ca (4%), cavernous sinus thrombosis (3%), Adenocarcinoma (3%), Angiofibroma (2%) fibrous dysplasia (2%) and Acute complicated Rhinosinusitis (2%) Following rare pathologies were identified in only one patient each. These included Lymphoma, Osteoma, and Rhabdomyosarcoma, Transitional cell carcinoma arising from inverted papilloma, Hemangiopericytoma, Spindle cell sarcoma, Pituitary adenoma, Giant cell sarcoma, malignant undifferentiated tumour, plexiform neurofibroma and sinonasal tuberculosis. Most common orbital symptom was proptosis. Eighty-one patients had proptosis followed by 23 patients with diplopia, 22 patients with ophthalmoplegia, 16 patients with visual loss and 15 patients with ptosis. CONCLUSIONS: Orbital involvement in most of the sinonasal diseases indicate extensive and aggressive nature of the pathology and many of these, even if they are not malignancies are difficult to treat. This is especially true for acute fulminant and chronic invasive fungal rhinosinusitis. PMID- 28586605 TI - Burden Of Atherosclerosis Risk Among Different Ethinicity: A Hidden Health Challenge. AB - BACKGROUND: Atherosclerosis risk and incidence of developing chronic cardiovascular conditions vary greatly between ethnic groups in South Asian population. To evaluate different ethnic groups in Pakistan, population based study was conducted at Karachi, the largest metropolitan city of Pakistan; to assess ten years and lifetime estimated cardiovascular disease risks without preexisting cardiovascular disease in Pakistani subjects by using Pooled Cohort Risk equation (calculator) as per American College of Cardiology (ACC) and the American Heart Association (AHA) 2013 guidelines. METHODS: For the study, consecutive subjects (n=437) with multi-ethnic background, aged 20-79 years and having non-atherosclerotic disease were enrolled at site of National Institute of Cardio-Vascular Diseases (NICVD), Karachi, Pakistan. RESULTS: Within each ethnic group and overall, the risk of developing atherosclerosis was common in all ethnic groups especially Urdu speaking are mostly at the high with all the factors above the borderline values, followed by Punjabis and Pathans that may point toward associated higher risk for prevalence of cardiovascular disease. These ethnic groups showed increased prevalence of dyslipidemia, obesity, and much greater abnormalities asunique risk. Although there are differences in these altered factors but the changes in lifestyle, urbanization, genetic profile and physiological makeup are the main reasons that could be a trigger to increase cardiovascular events. CONCLUSIONS: The present study provides the first evidence and may serve as useful guidance to calculate the estimated risk both 10 years and lifetime in the non-atherosclerotic Pakistani population with different ethnic background. PMID- 28586606 TI - Varicocele Embolization Following Failure Of Varicocelectomy: A Case Series And Review Of Literature. AB - Varicocelectomy remains the same mainstay of treatment for varicoceles. However, with growing focus on minimally invasive techniques, recent literature has investigated the use of venous embolization for the treatment of varicoceles in patients with recurrence after surgical treatment. Embolization has many advantages, including use of local anaesthesia, lower operating time, decreased risk of hydrocele and faster recovery times. In addition to this direct visualization of the vasculature during embolization allows for identification of any anatomic variants or collateral vessel accounting for the recurrence. This permits more definitive treatment in case of prior surgical failure. We present a case series where venous embolization is successfully done following failure of varicocelectomy. For patients who experience recurrence after a varicocelectomy, we recommend consideration for varicocele embolization. PMID- 28586607 TI - Role Of Symptomatic Treatment In Comparison To Antibiotics In Uncomplicated Urinary Tract Infections. AB - BACKGROUND: Uncomplicated urinary tract infections (UTIs) are the most common bacterial infections among women presenting to primary care causing rapidly increasing strains of resistant bacteria to the growing antibiotic industry. Restricting antibiotics to necessary indications is the only solution. The objectives of the study were to compare the efficacy of symptomatic treatment vs antibiotic in patients with uncomplicated UTI, in terms of individual symptom score, i.e., frequency, urgency, dysuria, supra pubic pain scores and total symptoms scores. METHODS: A randomized control trial (RCT) in 100 women (15-50 years) with symptoms of urinary frequency, urgency, dysuria and pain supra pubic region, associated with uncomplicated UTI, at Urology department, AMI, Abbottabad. Two treatment strategies were compared in uncomplicated UTI patient). Patients were randomized to antibiotic or symptomatic treatment groups on consecutive non-probability basis (50 in each group) given for 05 days. Efficacy of medications was assessed by comparing pre and post treatment symptom scores along with the post treatment scores of both groups compared to see statistical significance of difference by independent samples t-test. RESULTS: There was a statistically significant difference in symptoms improvement in both treatment arms of all scores, i.e., p-value=0.000. Whereas only dysuria score was able to show a statistically significance of difference in post Rx scores comparison of both groups, p-value=0.004. CONCLUSIONS: Symptomatic treatment is not inferior to antibiotic treatment when proper patient selection is undertaken, resulting in decreased need for unnecessary antibiotics use. PMID- 28586608 TI - Adherence To Diabetes Mellitus Treatment Guidelines From Theory To Practice: The Missing Link. AB - Diabetes mellitus is a complex multisystem disease that requires high quality care. Clinical practice guidelines help physicians and patients make the best possible health care decisions and improve health care management of diabetic patients. These guidelines provide the norms for clinical management as well as monitoring of diabetes care. They are not simple algorithms but are based on structured evidence based diabetic management protocols developed from randomized controlled trials. Despite the widespread availability of this diabetic guideline, their use is suboptimal at best. There are several factors blamed for contributing to this missing link from available theoretical guideline recommendations to practical applications of these guidelines. We present a brief review based on available literature review for an ongoing interventional study being done by authors in two tertiary care hospital in Lahore Pakistan for improving adherence to diabetes guidelines. We will discuss guideline implementation cycle and also present a framework encompassing various factors involved in adherence to guidelines. Until recently the emphasis to improve the guideline adherence targeted the factors relating to individual health care professionals in reference to their knowledge, attitude practice of the guidelines. However, we will discuss that broader range of health care systems, organizational factors, and factors relating to patients which may also significantly impact the adherence to the guidelines. The framework emphasises that it is important to understand the factors that act as barriers and contribute to the missing link between theory and practice of diabetic guidelines. This will help plan appropriate strategies in the pre-implementation stage for effective and improved diabetes guidelines adherence and management. PMID- 28586609 TI - Comparison Of Ultrasound Evaluation Of Patients Of Obstructive Jaundice With Endoscopic Retrograde Cholangio-Pancreatography Findings. AB - BACKGROUND: Ultrasonography has proven to be quite effective in differentiating hepatocellular from obstructive cause of jaundice in various studies. This study was conducted with the aim to determine the efficacy of ultrasonography and Endoscopic Retrograde Cholangio-Pancreatography (ERCP) in the diagnosis of obstructive reason of jaundice. METHODS: In this descriptive case series, 200 patients with >15 years age of either gender with cholestatic liver enzymes were included, i.e., those patients who had an ultrasound prior to ERCP at the department of gastroenterology of Patel Hospital, Karachi. Patients known to have liver disease with cholestatic jaundice had imaging other than ultrasound were excluded. The results of ultrasonography and ERCPs were compared in particularly looking for the cause of obstruction. RESULTS: Out of total 200 patients, mean age was 41.22+/-12.46 years with 107 (53.5%) females. Ability of ultrasound in correctly diagnosing obstructive reason for stone CBD was found to be 72.5%, dilated CBD without reason 41.7%, proximal obstruction, 63.15%, distal CBD obstruction 60%, and sludge 66.7%. Overall ability of ultrasound in correctly diagnosing the cause of obstruction was 64.17%. CONCLUSIONS: Ultrasound is recommended as the initial examination, which provides a guide to choose patients for either a more advanced noninvasive imaging like MRCP or to an invasive procedure like ERCP. PMID- 28586610 TI - Weight Changes In Patients With Hodgkin Lymphoma Following Treatment: Experience From A Cancer Hospital. AB - BACKGROUND: Some recent studies have suggested that patients with Hodgkin lymphoma who undergo remission following treatment are likely to experience significant weight gain and may become overweight or obese. The association between treatment for Hodgkin lymphoma and subsequent weight gain has not been explored in Pakistan. We undertook a review of weight changes in adult Hodgkin lymphoma patients who received treatment at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore. METHODS: In this longitudinal study, we collected and analysed secondary data including adult patients who received treatment for Hodgkin lymphoma at our institute from January 2010 till December 2013. We retrospectively noted baseline demographic, clinical characteristics, details about treatment received and change in weight from baseline at start of treatment to 6, 12, and 18 months after start of treatment. RESULTS: A total of 470 patients registered for Hodgkin lymphoma at our centre. Data were available for 402 patients who were included in this study. Progressive increase in weight was observed in patients after treatment. The mean weight gain from the start of treatment to 6, 12, and 18 months was 3.1 kg, 7.1 kg, and 9.5 kg, respectively. Weight gain was not significantly associated with age or sex of patients. Weight gain was significantly associated with higher stages of cancer, response to treatment and B symptoms. CONCLUSIONS: The evaluation of Hodgkin lymphoma patients after treatment demonstrated considerable tendency for weight gain. Further work is warranted to explore this association and its impact on HL survivors. PMID- 28586611 TI - Occlusal Outcome Of Non-Extraction And All First Premolars Extraction Treatment In Patients With Class-I Malocclusion. AB - BACKGROUND: Class-1 malocclusion commonly presents with crowding and poses an aesthetic concern to patients. An orthodontist may encounter a variety of dental problems and must handle them strategically to establish adequate occlusal relationships. Hence, this study was conducted to evaluate the occlusal characteristics of patients who have undergone non-extraction or all first premolars extraction treatment for class I malocclusion using the peer assessment rating (PAR) index. METHODS: The pre-treatment and post treatment dental casts of 94 subjects with class-I malocclusion were retrospectively screened. The sample was distributed into two groups, i.e., nonextraction and all first premolars extraction groups. The Mann Whitney-U test was used to compare the mean percentage improvement in the PAR scores between the two groups. A p-value of <=0.05 was considered statistically significant. RESULTS: The mean percentage improvement in the non-extraction group was 74.28% in the non-extraction group and 74.5% in the all first premolars extraction group. A significant difference (p=0.04) was found between the pretreatment PAR scores for the two treatment modalities. There was no significant difference between the post treatment PAR scores (p=0.45) and the mean percentage improvement in PAR scores (p=0.41) between the treatment groups. CONCLUSIONS: The improvement in occlusal characteristics in patients who underwent non-extraction treatment and all first premolar extraction treatment was comparable as assessed through mean percentage improvement in PAR scores. PMID- 28586612 TI - Comparison Of Bipolar And Monopolar Cautry Use In Turp For Treatment Of Enlarged Prostate. AB - BACKGROUND: In recent years, bipolar Transurethral resection of prostate (TURP) has been increasingly being used by urologist instead of conventional monopolar TURP for the treatment of enlarge prostate. Bipolar TURP is considered to be more efficacious and has better clinical outcome in comparison with monopolar TURP. We compared both procedures to assess their clinical out-comes and efficacy by comparing their different parameters. METHODS: This randomized control trial was conducted in the Institute of Kidney Diseases and Transplant Peshawar over 220 consecutive patients from Sep 2013 to Dec 2014. Patients were randomly divided in two groups. Maximum flow rate (Q max), duration of resection, weight of tissue resected, TUR syndrome, blood transfusion and duration of hospital stay and catheterization were compared in both groups. RESULTS: There were 110 patients in both groups each. Post-operative Q max, duration of resection, weight of tissue resected, duration of hospital stay, duration of catheterization was statistically insignificant. While statistically significant difference was found only the duration of procedure. CONCLUSIONS: Bipolar and monopolar have the same clinical out-come and complication rates, yet the monopolar TURP requires significantly less operating time in comparison to bipolar TURP efficacy. Both procedures can be used for the treatment equally however if urologist want to save the time he should use monopolar TURP. PMID- 28586613 TI - Hyperlactetemia And Its Trends In Critically Ill Children Admitted In Pediatric Intensive Care Unit Of A Developing Country. AB - BACKGROUND: There is increasing evidence that in setting of critical ailments clinical signs lag biomarkers like Lactate and hyperlactetemia can be the only marker for this disorder. This study was conducted to describe the incidence of hyperlactatemia in critically ill children and its association with outcome. METHODS: Retrospective review of medical records of all children who had their lactic acid (LA) levels measured during their admission in PICU from January 2014 to December 2015 was done. Demographic and clinical variables were recorded along with PICU therapies, outcome (Survived or expired) and development of multi-organ dysfunction. Results are presented as frequency with percentages and mean with standard deviation. Appropriate statistical tests were applied and p-value of <0.05 was taken as significant. RESULTS: Total 300 patients had their LA measured and 202 were included in the study. Males were 130 (64%) and mean age was 5.7+/ 4.6 years. Hyperlactatemia was found in 68 (33%) patients and another 75 (37%) had a second LA level >4 mmol/L. Increasing LA trend was found in 79 (39%) patients. Diagnostic categories included cardiovascular diseases (45, 22%), central nervous system diseases (40, 20%), respiratory diseases (31, 15%), sepsis (28, 14%), and gastrointestinal diseases14 (7%). 168 (83%) needed mechanical ventilation. Mean pH was 7.31+/-0.15 and metabolic acidosis was observed in 91 patients (45%). Mean LA levels in survivors and non survivors were 3.3+/-3.12 and 5.35+/-5.47 respectively. Hyperlactatemia was associated with death (p=0.01) and development of MODS (p=0.03) on univariate analysis. On multivariate logistic regression rising lactate and development of MODS were significantly associated with death (p=<0.05, odds ratio (OR) 9.24 (95% confidence interval 1.55-55.20). CONCLUSIONS: Hyperlactatemia and increasing LA trend in critically ill children are associated with worse outcome in PICU. PMID- 28586614 TI - Frequency, Indications And Complications Of Pulmonary Artery Catheter Insertion In Adult Open-Heart Surgery Patients Of A Tertiary Care Hospital. AB - BACKGROUND: Patients presenting for cardiac surgery have unstable cardiovascular disease and haemodynamics with multiple coexisting diseases. Optimal monitoring in the perioperative period is very important for best perioperative outcome. The introduction of the flow-directed pulmonary artery catheter (PAC) into clinical practice is one of the most important and popular advances in the field of cardiac anaesthesia. The objective of the study was to determine the frequency, indications and complications of pulmonary artery catheter insertion in adult open-heart surgery patients. METHODS: A Prospective observational study was conducted at cardiac operating rooms and Cardiac Intensive care unit (CICU) of Aga Khan University Hospital for a period of six months from Nov 2015 to April 2016.Two hundred and seven patients were included in this study. PAC was inserted through right/left internal jugular vein or subclavian vein. Complications noted were arrhythmias (atrial and ventricular), right bundle branch block, coiling and knotting, pulmonary artery rupture, and infection up to 72 hours of PAC insertion. Frequency and percentage were computed for gender, comorbids (Hypertension, Diabetes, Chronic kidney disease, Chronic Obstructive Pulmonary Disease) and PAC frequency of insertion, indications and complications were noted. RESULTS: The frequency of PAC insertion was 47.83%. Major indications for PAC insertion were poor left ventricular function, acute coronary syndrome, cardiogenic shock, significant left main disease and valvular heart disease patients. Minor complications were found in 23.22% cases, which included arrhythmia in 19.2% cases and coiling in 4.02%. CONCLUSIONS: TPulmonary artery catheter insertion is a safe technique with useful clinical application in the management of high-risk cardiac surgical patients. The PAC insertion rationale must be standardized to confirm the judicious use. PMID- 28586615 TI - Association Of Smoking With Recurrence Of Pulmonary Kochs; After Completion Of Antituberculous Treatment. AB - BACKGROUND: Smoking is one of the most important yet modifiable risk factors for incidence, morbidity, recurrence and mortality from Pulmonary Koch's or tuberculosis. This study attempted to demonstrate the association between smoking and recurrence risk of Pulmonary Koch's in Pakistani male population. METHODS: This case control study was conducted at Federal Government Tuberculosis Hospital, Rawalpindi from 2015 to 2016. It included 332 study participants; 166 recurrent cases of Pulmonary Tuberculosis within two years of completion of Anti tuberculous therapy (ATT) and 166 non-recurrent controls. Smoking status of all study participants was assessed. RESULTS: Amongst 166 cases of recurrence, 75 (63.6%) had continued smoking after ATT compared to 43 (36.4%) controls who continued smoking (p-value 0.00, OR=2.35, 95% CI=1.48 to 3.74, NNH=4.75). Highly statistically significant associations of recurrence were observed with smoking>10 years (p-value 0.00, OR=3.67, CI=1.55-8.71 NNH=4.75) and if ever smoked in life (p-value 0.00, OR=2.05, CI=1.32-3.19, NNH=5.61). Mean duration of smoking in cases (12.37+/-8.72 years) was statistically different from controls (9.54+/-7.01 years), with p-value of 0.04. CONCLUSIONS: There is strong association of recurrence of Pulmonary Kochs with continuation of smoking within 2 years of completion of ATT, with ever smoking in life and smoking >10 years in life. PMID- 28586616 TI - Why should the faculty adopt reciprocal teaching as part of the medical curriculum? AB - Understanding the text is crucial to achieve depth in understanding of complex concepts for students at all levels of education for whom English is not their first language. Reciprocal teaching is an instructional activity that stimulate learning through a dialogue between teachers and students regarding segments of text. The process of summarizing, question-generating, clarifying and predicting allows the gaps to be recognised and filled by the student, who is in control of the learning process and able to analyse and reflect upon the reading material. Whereas reciprocal teaching has been applied at school and college level, little is known about its effectiveness in medical education. Incorporating reciprocal teaching in early years of medical education such as reading the literature and summarizing the flow of information in the study of integrated body systems could be an area to explore. Feasibility exercises and systematic validation studies are required to confirm authors' assertion. PMID- 28586617 TI - Effect Of Non- Surgical Periodontal Treatment On Glycemic Control Among Type 2 Diabetes Mellitus Patients With Periodontitis. AB - BACKGROUND: Periodontitis and Diabetes Mellitus are two closely, bidirectional linked disease where periodontitis is a well-known complication of diabetes it is also considered to be a cause for poor glycaemic control. The present study objective was to evaluate the glycaemic control in patients suffering from both Diabetes Mellitus and Periodontitis after non-surgical periodontal treatment. METHODS: A comparative cross-sectional study was conducted with two groups of patients attending Diabetic Clinic, Jinnah Hospital, Lahore, during six months from September 2013 to February 2014. Forty-six diabetes mellitus subjects who were undergoing non-surgical treatment of periodontal disease that includes mechanical removal of supra- and sub gingival bacterial plaque with scalers, antibiotics and or root canal if required while 46 subjects with diabetic mellitus having periodontal disease did not had treatment for periodontal disease. HbA1c was compared at base line and at three months. Data was compiled and analysed through SPSS version 16. Quantitative variables like HbA1c was presented as mean+/-SD. Qualitative variables like gender, education status, economic status, treatment for diabetes mellitus and periodontal disease were described by using frequency percentages. The t-test was applied to assess statistical significance in mean difference HbA1c between two groups. p-value <0.05 was considered significant. RESULTS: Forty-six subjects who received non surgical treatment for periodontitis 43 (93.5%) received scaling only while 3 (6.5%) received scaling plus antibiotics. Fall in the level of HbA1c was observed among subjects with treatment of periodontal disease indicating a good control of diabetes while in group without treatment there was either no change or increase in HbA1c. Mean HbA1c at baseline in group with treatment of periodontitis at baseline was 7.672+/-.6414 and without treatment was 6.957+/-.3494. (t= -1.008, p<.279). Mean HbA1c after 3 months in group with treatment of periodontitis was 6.867+/-.6168, and in group without treatment was 6.983+/-.3678. (t=6.641, p<.000). CONCLUSIONS: Non-surgical periodontal treatment is associated with improved glycaemic control (reduced HbA1c level) in type 2 diabetic patients. PMID- 28586618 TI - Non-steroidal anti-inflammatory drugs vs. Paracetamol: drug availability, patients' preference and knowledge of toxicity. AB - BACKGROUND: Self-medication is a common practice which is influenced by level of education, society factors and health care facilities availability. In our region, Pakistan, it is very common and awareness regarding prescription implementation needs to be ensured. Hence the current study highlights the preference, availability and knowledge of toxicity of non-steroidal antiinflammatory medications and paracetamol in Pakistan. METHODS: It was a Descriptive, cross sectional, conducted in Rawalpindi and Islamabad, Pakistan from May to august 2012. A total of 1000 questionnaires comprising of 21 questions were distributed to the persons with age groups from 18 years to 40 years. Non-probability convenience sampling technique was used for results deduction. Data was analysed using descriptive statistics. RESULTS: The most commonly used medicine was Mefenamic acid (n=191, 40.8%). Paracetamol was second on the priority list (n=146, 31.3%). About 178 out of 467(38.1%) used these medications for headache. Very few responders knew about the toxic doses of the medicines they used. Only 52 (11%) were aware of the raised bleeding tendency being the most common side effect of acetylsalicylic acid and 129 (28%) were aware of liver damage by paracetamol toxicity. CONCLUSIONS: In Pakistan, common people take NSAIDs and Paracetamol without prescription and majority of them are unaware of the side effects of these medicines. This is the reason it is important to make the general public aware of the problems they may face if they misuse or over use the drugs without the prescription. PMID- 28586619 TI - Role Of Stretching Exercises In The Management Of Constipation In Spastic Cerebral Palsy. AB - BACKGROUND: Constipation is considered as one of the most common non-motor manifestations in cerebral palsy (CP). Along with other reasons, spasticity also contributes in developing constipation in CP, by decreasing mobility of trunk and lower extremities and abdominal viscera. Stretching exercises of upper extremities, trunk and lower extremities are routine management of spasticity in CP children. The objective of the study was to determine the role of stretching exercises in improving constipation symptoms in children with spastic cerebral palsy and to explore the association between spasticity and constipation among cerebral palsy children. METHODS: Single-group Pretest-Posttest Design (Quasi Experimental Study Design). The study was conducted at Physiotherapy Department of National Institute of Rehabilitation Medicine (NIRM) Islamabad. Thirty spastic CP children - both male and female - with complaints of constipation were recruited through non-probability, convenience sampling. The mean age of the children was 7.55+/-1.33 years. Each child was assessed for defecation frequency (DF), constipation severity by constipation assessment scale (CAS) and level of spasticity by modified ash worth scale for spasticity (MASS) at baseline. Stretching exercises were performed for 30 seconds with five repetitions and at least once a day for six week, followed by positioning of patients in reflex inhibiting posture. Final data was collected using the same tools as done at the baseline. Paired samples t-test was used to analyse the rehabilitation-induced changes after 6 weeks. To determine association between spasticity and constipation Pearson product-moment correlation coefficient was used. The data was analysed through SPSS 20. RESULTS: Significant changes, compared to the baseline scores, were observed after 6 weeks of stretching exercises in MASS (2.53+/-0.62 Vs 1.53+/-0.77), DF (2.43+/-0.67 Vs 3.70+/-1.02) and CAS (7.23+/ 1.50 Vs 5.43+/-1.73) with p<=0.05. The results also showed significant correlation between changes in levels of spasticity and severity of constipation (r = 0.37; p=0.04). Finally, significant correlation was present between improvement in spasticity and defecation frequency (r =-0.39; p=0.02). CONCLUSIONS: Stretching exercises administered for the management of spasticity in CP can significantly improve the symptoms of constipation in such children. The results of the study showed that constipation is strongly associated with level of spasticity in CP children. PMID- 28586620 TI - Density Functional Study of Neutral and Charged Silver Clusters Agn with n = 2 22. Evolution of Properties and Structure. AB - Geometries and electronic properties of neutral Agn, cationic Agn+, and anionic Agn- silver clusters with n = 2-22 were investigated by density functional theory (DFT) with M06 functional. For neutral clusters, transition from planar to "empty cage" structure occurs at n = 7, "empty cage" to "cage with one Ag atom" at n = 18, and to "cage with two Ag atoms" at n = 22. For lowest-energy Agn clusters, Ag8 and Ag18 show lowest polarizability due to closed-shell valence electron configurations 1S2/1P6 and 1S2/1P6/1D10. High stability of Ag8 is manifested in small dissociation energies of Ag9 to Ag8 plus Ag1 and Ag10 cluster to Ag8 plus Ag2. Cluster Ag20 with configuration 1S2/1P6/1D10/2S2 is stable due to low dissociation energy of Ag21 to Ag1 and Ag22 to Ag2. Cationic clusters with even n namely Ag10+ (9 valence electrons), Ag16+ (15 valence electrons), and Ag22+ (21 valence electrons) dissociate to Ag1 and closed-shell Ag9+ (1S2/1P6), Ag15+ (1S2/1D10/2S2) and Ag21+ (1S2/1P6/1D10/2S2). For odd n, Ag11+ and Ag17+ dissociate to Ag2 and closed-shell Ag9+ and Ag15+. For anionic clusters Agn-, cohesion energy Ecoh and binding energy (BE) show maxima at n = 7 and n = 17 due to stable Ag7- and Ag17- clusters. Small Agn- clusters (n = 4-11) with even n (except n = 8) have lower dissociation energy for loss of Ag1 while those with odd n have lower dissociation energy for loss of Ag2. For n = 12-22, all clusters have lower dissociation energy for loss of Ag1. PMID- 28586622 TI - Atelocollagen Enhances the Healing of Rotator Cuff Tendon in Rabbit Model. AB - BACKGROUND: Failure of rotator cuff healing is a common complication despite the rapid development of surgical repair techniques for the torn rotator cuff. PURPOSE: To verify the effect of atelocollagen on tendon-to-bone healing in the rabbit supraspinatus tendon compared with conventional cuff repair. STUDY DESIGN: Controlled laboratory study. METHODS: A tear of the supraspinatus tendon was created and repaired in 46 New Zealand White rabbits. They were then randomly allocated into 2 groups (23 rabbits per group; 15 for histological and 8 for biomechanical test). In the experimental group, patch-type atelocollagen was implanted between bone and tendon during repair; in the control group, the torn tendon was repaired without atelocollagen. Each opposite shoulder served as a sham (tendon was exposed only). Histological evaluation was performed at 4, 8, and 12 weeks. Biomechanical tensile strength was tested 12 weeks after surgery. RESULTS: Histological evaluation scores of the experimental group (4.0 +/- 1.0) were significantly superior to those of the control group (7.7 +/- 2.7) at 12 weeks ( P = .005). The load to failure was significantly higher in the experimental group (51.4 +/- 3.9 N) than in the control group (36.4 +/- 5.9 N) ( P = .001). CONCLUSION: Histological and biomechanical studies demonstrated better results in the experimental group using atelocollagen in a rabbit model of the supraspinatus tendon tear. CLINICAL RELEVANCE: Atelocollagen patch could be used in the cuff repair site to enhance healing. PMID- 28586623 TI - Longitudinal Trends in Vaccine Hesitancy in a Cohort of Mothers Surveyed in Washington State, 2013-2015. AB - Parents who refuse or delay vaccines because of vaccine hesitancy place children at increased risk for vaccine-preventable disease. How parental vaccine hesitancy changes as their children age is not known. In 2015, we conducted a follow-up survey of 237 mothers enrolled in a 2-arm clinic-level cluster randomized trial (n = 488) in Washington State that was completed in 2013. We surveyed mothers at their baby's birth, age 6 months, and age 24 months using a validated measure of vaccine hesitancy. Both mean hesitancy scores (mean 4.1-point reduction; 95% CI, 2.5-5.6; P = .01) and the proportion of mothers who were vaccine hesitant (9.7% at baseline vs 5.9% at 24 months; P = .01) decreased significantly from child's birth to age 24 months. Changes from baseline were similar for first-time mothers and experienced mothers. Individual item analysis suggested that the decrease may have been driven by increases in maternal confidence about the safety and efficacy of vaccines. Our results suggest that hesitancy is a dynamic measure that may peak around childbirth and may remit as experience with vaccines accumulates. PMID- 28586625 TI - Advocacy: IBCLCs Advocating for Global Breastfeeding Through Skilled Lactation Support. PMID- 28586624 TI - Does Participation in Sports Affect Osteoarthritic Progression After Periacetabular Osteotomy? AB - BACKGROUND: Periacetabular osteotomy (PAO) is an effective treatment for symptomatic acetabular dysplasia. However, whether postoperative participation in sports leads to progression of the Kellgren-Lawrence (KL) grade of osteoarthritis (OA) in these patients is unclear. PURPOSE: To investigate (1) participation in sports before and after PAO and (2) whether postoperative participation in sports leads to progression of the KL grade. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: The authors retrospectively reviewed data on 161 patients (183 hips) who underwent PAO for symptomatic acetabular dysplasia with preoperative KL grade 1 or 2 between 1998 and 2011. The mean age at the time of surgery was 42.0 +/- 10.9 years (range, 12-64 years), and the mean follow-up duration was 100 months (range, 13-180 months). Data included participation in sports, the University of California, Los Angeles (UCLA) activity scale score, age at the time of surgery, body mass index, follow-up duration, history of treatment for developmental hip dislocations, Merle d'Aubigne-Postel score, Oxford Hip Score, center-edge angle, and KL grade. Univariate and multivariate analyses were applied to determine which factors were associated with progression to KL grade 3 or 4 after PAO. RESULTS: The number of patients who participated in sports significantly increased from 50 (31.1%) preoperatively to 89 (55.3%) postoperatively. The mean UCLA score significantly increased from 4.7 +/- 2.1 preoperatively to 5.5 +/- 2.0 postoperatively. The KL grade progressed to grade 3 or 4 in 16 hips, including 4 hips that underwent conversion to total hip arthroplasty. No significant differences were found in postoperative participation in sports (89 hips [53.3%] vs 11 hips [68.8%], respectively; P = .24) and the UCLA score (5.6 +/- 2.0 vs 5.1 +/- 2.0, respectively; P = .30) between hips with KL grade 1 or 2 and KL grade 3 or 4. A multivariate analysis revealed that no factors, including postoperative participation in sports, were significantly associated with progression to KL grade 3 or 4. CONCLUSION: Postoperative participation in sports after PAO did not significantly and negatively influence progression of the KL grade at midterm follow-up. PMID- 28586621 TI - Evaluating the Use of Electronic Health Records for Type 2 Diabetes Surveillance in 2 California Counties, 2010-2014. AB - OBJECTIVES: Electronic health records (EHRs) and electronic laboratory records (ELRs) are increasingly seen as a rich source of data for performing public health surveillance activities and monitoring community health status. Their potential for surveillance of chronic illness, however, may be underused. Our objectives were to (1) evaluate the use of EHRs and ELRs for diabetes surveillance in 2 California counties and (2) examine disparities in diabetes prevalence by geography, income, and race/ethnicity. METHODS: We obtained data on a clinical diagnosis of diabetes and hemoglobin A1c (HbA1c) test results for adult members of Kaiser Permanente Northern California living in Contra Costa County or Solano County at any time during 2010-2014. We evaluated the validity of using HbA1c test results to determine diabetes prevalence, using clinical diagnoses as a gold standard. We estimated disparities in diabetes prevalence by combining HbA1c test results with US Census data on income, race, and ethnicity. RESULTS: When compared with a clinical diagnosis of diabetes, data on a patient's 5-year maximum HbA1c value >=6.5% yielded the best combination of sensitivity (87.4%) and specificity (99.2%). The prevalence of 5-year maximum HbA1c >=6.5% decreased with increasing median family income and increased with greater proportions of residents who were either non-Hispanic black or Hispanic. CONCLUSIONS: Timely diabetes surveillance data from ELRs can be used to document disparities, target interventions, and evaluate changes in population health. ELR data may be easier to access than a patient's entire EHR, but outcome metric validation with diabetes diagnoses would need to be ongoing. Future research should validate ELR and EHR data across multiple providers. PMID- 28586626 TI - Delayed and Unreported Drug-Susceptibility Testing Results in the US National Tuberculosis Surveillance System, 1993-2014. AB - OBJECTIVES: Drug-susceptibility testing (DST) of Mycobacterium tuberculosis is necessary for identifying drug-resistant tuberculosis, administering effective treatment regimens, and preventing the spread of drug-resistant tuberculosis. DST is recommended for all culture-confirmed cases of tuberculosis. We examined trends in delayed and unreported DST results in the Centers for Disease Control and Prevention's National Tuberculosis Surveillance System. METHODS: We analyzed culture-confirmed tuberculosis cases reported to the National Tuberculosis Surveillance System during 1993-2014 for annual trends in initial DST reporting for first-line antituberculosis drugs and trends in on-time, delayed, and unreported results. We defined on-time reporting as DST results received during the same calendar year in which the patient's case was reported or <=4 months after the calendar year ended and delayed reporting as DST results received after the calendar year. We compared cases with on-time, delayed, and unreported DST results by patient and tuberculosis program characteristics. RESULTS: The proportion of cases with reported results for all first-line antituberculosis drugs increased during 1993-2011. Reporting of pyrazinamide results was lower than reporting of other drugs. However, during 2000-2012, of 134 787 tuberculosis cases reported to the National Tuberculosis Surveillance System, reporting was on time for 125 855 (93.4%) cases, delayed for 5332 (4.0%) cases, and unreported for 3600 (2.7%) cases. CONCLUSIONS: Despite increases in the proportion of cases with on-time DST results, delayed and unreported results persisted. Carefully assessing causes for delayed and unreported DST results should lead to more timely reporting of drug-resistant tuberculosis. PMID- 28586627 TI - Validation of a Syndromic Case Definition for Detecting Emergency Department Visits Potentially Related to Marijuana. AB - OBJECTIVES: Reliable methods are needed to monitor the public health impact of changing laws and perceptions about marijuana. Structured and free-text emergency department (ED) visit data offer an opportunity to monitor the impact of these changes in near-real time. Our objectives were to (1) generate and validate a syndromic case definition for ED visits potentially related to marijuana and (2) describe a method for doing so that was less resource intensive than traditional methods. METHODS: We developed a syndromic case definition for ED visits potentially related to marijuana, applied it to BioSense 2.0 data from 15 hospitals in the Denver, Colorado, metropolitan area for the period September through October 2015, and manually reviewed each case to determine true positives and false positives. We used the number of visits identified by and the positive predictive value (PPV) for each search term and field to refine the definition for the second round of validation on data from February through March 2016. RESULTS: Of 126 646 ED visits during the first period, terms in 524 ED visit records matched >=1 search term in the initial case definition (PPV, 92.7%). Of 140 932 ED visits during the second period, terms in 698 ED visit records matched >=1 search term in the revised case definition (PPV, 95.7%). After another revision, the final case definition contained 6 keywords for marijuana or derivatives and 5 diagnosis codes for cannabis use, abuse, dependence, poisoning, and lung disease. CONCLUSIONS: Our syndromic case definition and validation method for ED visits potentially related to marijuana could be used by other public health jurisdictions to monitor local trends and for other emerging concerns. PMID- 28586628 TI - Effectiveness of Radial Extracorporeal Shock Wave Therapy (rESWT) When Combined With Supervised Exercises in Patients With Subacromial Shoulder Pain: A Double Masked, Randomized, Sham-Controlled Trial. AB - BACKGROUND: Subacromial shoulder pain is a common complaint, and radial extracorporeal shock wave therapy (rESWT) is increasingly used to treat this condition. Although many therapists use rESWT in combination with supervised exercises, no studies have evaluated the additional effect of rESWT with supervised exercises for subacromial shoulder pain. PURPOSE: To assess whether rESWT is more effective than sham rESWT when combined with supervised exercises for improving pain and function in patients with subacromial shoulder pain. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Patients between 25 and 70 years of age with subacromial shoulder pain with and without calcification in the rotator cuff lasting at least 3 months were assessed for eligibility; 143 patients were recruited. Participants were allocated (1:1) by computer-generated randomization in blocks of 20 to receive either rESWT or sham rESWT in addition to supervised exercises. The rESWT and sham rESWT were performed once a week with additional supervised exercises once a week for the first 4 weeks. The following 8 weeks, the patients received supervised exercises twice a week. The primary outcome was change in the Shoulder Pain and Disability Index (SPADI) after 24 weeks. Patients and outcome assessors were masked to group assignment. RESULTS: At 24 weeks, participants in both the sham group and the rESWT group had improved ( P < .001) in SPADI score compared with baseline (-23.9 points [SD, 23.8 points] and -23.3 points [SD, 25.0 points], respectively), but there were no differences between the groups (mean difference 0.7; 95% CI, -6.9 to 8.3; P = .76). Prespecified subgroup analysis of patients with calcification in rotator cuff showed that the rESWT group had a greater improvement in SPADI score after 24 weeks (mean difference -12.8; 95% CI, -24.8 to -0.8; P = .018). CONCLUSION: Radial ESWT offered no additional benefit to supervised exercises in the treatment of subacromial shoulder pain after 24 weeks, except in the subgroup of patients with calcification in the rotator cuff. Registration: NCT01441830 ( ClinicalTrials.gov identifier). PMID- 28586629 TI - Case Finding Using Syndromic Surveillance Data During an Outbreak of Shiga Toxin Producing Escherichia coli O26 Infections, Oregon, 2015. AB - Shiga toxin-producing Escherichia coli (STEC) causes an estimated 265 000 infections in the United States annually. Of emerging non-O157:H7 STEC serotypes, O26 is the most commonly recognized. During an outbreak of STEC O26 in Oregon in 2015, we used syndromic surveillance data to supplement case finding by laboratory reporting. From 157 records retrieved by querying syndromic surveillance data, we detected 4 confirmed and 5 suspected cases. However, none of the suspected cases were confirmed by stool culture, and by the time that the data were being analyzed, the confirmed cases were already known to investigators. Syndromic surveillance data can potentially supplement case finding during outbreaks of foodborne disease. To be an effective case-finding strategy, timely completion of all steps, including collecting specimens from suspected cases, should be performed in real time. PMID- 28586630 TI - Engaging Community and Faith-Based Organizations in the Zika Response, United States, 2016. PMID- 28586631 TI - TGF-beta1 Improves Biomechanical Strength by Extracellular Matrix Accumulation Without Increasing the Number of Tenogenic Lineage Cells in a Rat Rotator Cuff Repair Model. AB - BACKGROUND: Transforming growth factor beta1 (TGF-beta1) positively regulates the tenogenic marker genes scleraxis ( Scx) and tenomodulin ( Tnmd) in mesenchymal progenitors in vitro. However, little is known about the effect of TGF-beta1 on the expression of tenogenic markers during rotator cuff (RC) healing in rats. HYPOTHESIS: TGF-beta1 improves the biomechanical properties and histological maturity of reparative tissue in a rat RC repair model by stimulating the growth of tenogenic cells. STUDY DESIGN: Controlled laboratory study. METHODS: Adult male Sprague-Dawley rats (N = 180) underwent unilateral supraspinatus tendon-to bone surgical repair and were randomly treated with a gelatin hydrogel presoaked in TGF-beta1 (100 ng) or phosphate-buffered saline. The effects of TGF-beta1 on RC healing were investigated at 2, 4, 6, 8, and 12 weeks postoperatively by immunostaining for proliferating cell nuclear antigen, by real-time reverse transcription polymerase chain reaction and in situ hybridization or immunostaining for enthesis-related markers (SRY-box containing gene 9 [ Sox9], Scx, and Tnmd), and by real-time reverse transcription polymerase chain reaction and immunostaining for type I and III collagen. At 6 and 12 weeks postoperatively, biomechanical testing, micro-computed tomography, and biochemical analysis were also performed. At 2 and 4 weeks postoperatively, mesenchymal stem cell-related markers, phospho-Smad2, and matrix metalloproteinase 9 (MMP-9) and MMP-13 were assessed by immunostaining. RESULTS: The TGF-beta1-treated group had significantly higher ultimate load to failure and tissue volume at 6 and 12 weeks postoperatively and a higher collagen content at 12 weeks compared with the saline group. Tendon-related gene expression, histological maturity, cell proliferation, and mesenchymal stem cell-related marker immunoreactivity were not affected by exogenously administrated TGF-beta1 at all time points. In the TGF-beta1-treated group, the percentage of phospho Smad2-positive cells within the healing tissue increased, whereas the expression of MMP-9 and MMP-13 significantly decreased at 2 and 4 weeks postoperatively. CONCLUSION: TGF-beta1 enhances formation of tough fibrous tissues at the healing site by inhibiting MMP-9 and MMP-13 expression to increase collagen accumulation but without the growth of tenogenic lineage cells. CLINICAL RELEVANCE: These findings suggest that TGF-beta1 could be used for enhancing biomechanical strength after RC surgical repair. PMID- 28586632 TI - Antibody Profile of Colostrum and the Effect of Processing in Human Milk Banks: Implications in Immunoregulatory Properties. AB - BACKGROUND: When feeding preterm infants, donor milk is preferred if the mother's own milk is unavailable. Pasteurization may have detrimental effects on bioactivity, but more information is needed about its effects on the immunological compounds. Research aim: This work has two main aims: evaluate the antibody profile of colostrum and study the quantitative variations in the antibodies' level and specific reactivity after undergoing Holder pasteurization. The authors focused on immunoregulatory components of colostrum (antidietary antibodies and TGF-beta2) in the neonatal gut. METHODS: This is a descriptive cross-sectional study of a convenience sample of 67 donated colostrum samples at different days after delivery, both raw and pasteurized. Antibody profiles were analyzed at different times during breastfeeding, and total and specific antibodies (IgM, IgA, and IgG subclasses) were compared with tetanus toxoid and ovalbumin using enzyme-linked immunosorbent assay. The processing effect on total and specific antibodies, as well as TGF-beta2, was evaluated by paired analyses. RESULTS: No variations in immunological compounds were observed throughout the colostrum stage. The TGF-beta2, antibodies' concentrations, and antibodies' specific reactivity after pasteurization did not vary significantly as days of lactation varied. Changes in antibody levels were dependent on isotype and IgG subclass, and IgG4 showed remarkable resistance to heating. Moreover, the effect of the pasteurization on specific reactivity was antigen dependent. CONCLUSION: The supply of relevant immunological components is stable throughout the colostrum stage. The effects of pasteurization on antibodies depend on isotype, subclass, and specificity. This information is relevant to improving the immunological quality of colostrum, especially for preterm newborns. PMID- 28586633 TI - Aqueous Solubility Enhancement for Bioassays of Insoluble Inhibitors and QSPR Analysis: A TNF-alpha Study. AB - The aim of this study is to improve the aqueous solubility of a group of compounds without interfering with their bioassay as well as to create a relevant prediction model. A series of 55 potential small-molecule inhibitors of tumor necrosis factor-alpha (TNF-alpha; SPD304 and 54 analogues), many of which cannot be bioassayed because of their poor solubility, was used for this purpose. The solubility of many of the compounds was sufficiently improved to allow measurement of their respective dissociation constants (Kd). Parameters such as dissolution time, initial state of the solute (solid/liquid), co-solvent addition (DMSO and PEG3350), and sample filtration were evaluated. Except for filtration, the remaining parameters affected aqueous solubility, and a solubilization protocol was established according to these. The aqueous solubility of the 55 compounds in 5% DMSO was measured with this protocol, and a predictive quantitative structure property relationship model was developed and fully validated based on these data. This classification model separates the insoluble from the soluble compounds and predicts the solubility of potential small molecule inhibitors of TNF-alpha in aqueous solution (containing 5% DMSO as co solvent) with an accuracy of 81.2%. The domain of applicability of the model indicates the type of compounds for which estimation of aqueous solubility can be confidently predicted. PMID- 28586634 TI - Where do hypotheses come from? AB - Why are human inferences sometimes remarkably close to the Bayesian ideal and other times systematically biased? In particular, why do humans make near rational inferences in some natural domains where the candidate hypotheses are explicitly available, whereas tasks in similar domains requiring the self generation of hypotheses produce systematic deviations from rational inference. We propose that these deviations arise from algorithmic processes approximating Bayes' rule. Specifically in our account, hypotheses are generated stochastically from a sampling process, such that the sampled hypotheses form a Monte Carlo approximation of the posterior. While this approximation will converge to the true posterior in the limit of infinite samples, we take a small number of samples as we expect that the number of samples humans take is limited. We show that this model recreates several well-documented experimental findings such as anchoring and adjustment, subadditivity, superadditivity, the crowd within as well as the self-generation effect, the weak evidence, and the dud alternative effects. We confirm the model's prediction that superadditivity and subadditivity can be induced within the same paradigm by manipulating the unpacking and typicality of hypotheses. We also partially confirm our model's prediction about the effect of time pressure and cognitive load on these effects. PMID- 28586635 TI - Tin protoporphyrin activates the oxidant-dependent NRF2-cytoprotective pathway and mitigates acute kidney injury. AB - Tin protoporphyrin (SnPP), a heme oxygenase (HO) inhibitor, can paradoxically protect against diverse forms of acute kidney injury (AKI). This study sought potential underlying mechanisms. CD-1 mice received intravenous SnPP, followed 4 18 hours later by a variety of renal biochemical, histologic, and genomic assessments. Renal resistance to ischemic-reperfusion injury (IRI) was also sought. SnPP was rapidly taken up by kidney and was confined to proximal tubules. Transient suppression of renal heme synthesis (decreased delta aminolevulinic acid synthase expression), a 2.5-fold increase in "catalytic" Fe levels and oxidant stress resulted (decreased glutathione; increased malondialdehyde, and protein carbonyl content). Nrf2 nuclear translocation (~2x Nrf2 increase; detected by enzyme-linked immunosorbent assay, Western blotting), with corresponding activation of ~20 Nrf2-sensitive genes (RNA-Seq) were observed. By 18 hours after SnPP injection, marked protection against IRI emerged. This represented "preconditioning", not a direct SnPP effect, given that SnPP administered at the time of IRI exerted no protective effect. The importance of transient oxidant stress in SnPP "preconditioning" was exemplified by the following: (1) oxidant stress induced by a different mechanism (myoglobin injection) recapitulated SnPP's protective action; (2) GSH treatment blunted SnPP's protective influence; (3) SnPP raised cytoprotective heavy chain ferritin (Fhc), a response enhanced by exogenous Fe injection; and (4) SnCl2, a ~35- to 50 fold HO-1 inducer (not inhibitor) evoked neither oxidant stress nor mitigated IRI (seemingly excluding HO-1 activity in SnPP's protective effect). SnPP specifically accumulates within proximal tubule cells; transient "catalytic" Fe overload and oxidative stress result; Nrf2-cytoprotective pathways are upregulated; and these changes help protect against ischemic AKI. PMID- 28586636 TI - Effectiveness of an Online Natural Family Planning Program for Breastfeeding Women. AB - OBJECTIVE: To analyze the effectiveness of an online, nurse-managed natural family planning (NFP) program among breastfeeding women and subgroups of these women. DESIGN: Longitudinal comparative cohort study. SETTING: A university-based online NFP education program and menstrual cycle charting system. PARTICIPANTS: Women (N = 816) with a mean age of 30.3 years (standard deviation = 4.5) who registered to use the online NFP system and indicated they were breastfeeding. METHODS: Participants tracked their fertile times with an electronic hormone fertility monitor (EHFM), cervical mucus monitoring, or both. All unintended pregnancies were evaluated by professional nurses. RESULTS: The correct use pregnancy rates were 3 per 100 users over 12 cycles of use, and typical rates were 14 per 100 at 12 cycles of use. At 12 cycles of use, total pregnancy rates were 16 per 100 for electronic hormone fertility monitor users (n = 380), 81 per 100 among mucus-only users (n = 45), and 14 per 100 for electronic hormone fertility monitor plus mucus users (n = 391). CONCLUSION: Use of a nurse-managed online NFP program for women can be effective to help women avoid pregnancy while breastfeeding, especially with correct and consistent use. PMID- 28586637 TI - Association Between Severe Dental Caries and Child Abuse and Neglect. AB - PURPOSE: In their maxillofacial practice, the authors have encountered some children with severe dental caries whose teeth had to be removed; many later appeared to be abused children. The authors hypothesized that in the group of children who underwent multiple tooth extractions for caries under general anesthesia, a larger percentage would be found to be abused compared with the normal population. PATIENTS AND METHODS: The authors identified children who underwent multiple tooth extractions under general anesthesia in a well-defined region in the Netherlands in 2005 and 2006. Subsequently, they sought these children in the database of the Dutch national organization against domestic violence and child abuse (Veilig Thuis) in 2015. RESULTS: Of the total group of 376 children, 205 (55%) underwent the procedure because of caries during this period. Child abuse and neglect was established by Veilig Thuis in 47 of these children (23%; 95% confidence interval, 20-26), whereas the procedure occurred before the child abuse was established in 27. CONCLUSION: There appears to be a strong association between severe dental caries and child abuse and neglect. Hence, severe dental caries could be regarded as an early symptom of child abuse and neglect. PMID- 28586638 TI - Efficacy of Codeine When Added to Paracetamol (Acetaminophen) and Ibuprofen for Relief of Postoperative Pain After Surgical Removal of Impacted Third Molars: A Double-Blinded Randomized Control Trial. AB - PURPOSE: The use of opioids in combination with nonopioids is common practice for acute pain management after third molar surgery. One such combination is paracetamol, ibuprofen, and codeine. The authors assessed the efficacy of codeine when added to a regimen of paracetamol and ibuprofen for pain relief after third molar surgery. MATERIALS AND METHODS: This study was a randomized, double blinded, placebo-controlled trial conducted in patients undergoing the surgical removal of at least 1 impacted mandibular third molar requiring bone removal. Participants were randomly allocated to a control group (paracetamol 1,000 mg and ibuprofen 400 mg) or an intervention group (paracetamol 1,000 mg, ibuprofen 400 mg, and codeine 60 mg). All participants were treated under intravenous sedation and using identical surgical conditions and technique. Postoperative pain was assessed using the visual analog scale (VAS) every 3 hours (while awake) for the first 48 hours after surgery. Pain was globally assessed using a questionnaire on day 3 after surgery. RESULTS: There were 131 participants (36% men; control group, n = 67; intervention group, n = 64). Baseline characteristics were similar for the 2 groups. Data were analyzed using a modified intention-to-treat analysis and, for this, a linear mixed model was used. The model showed that the baseline VAS score was associated with subsequent VAS scores and that, with each 3-hour period, the VAS score increased by an average of 0.08. The treatment effect was not statistically meaningful, indicating there was no difference in recorded pain levels between the 2 groups during the first 48 hours after mandibular third molar surgery. Similarly, the 2 groups did not differ in their global ratings of postoperative pain. CONCLUSION: Codeine 60 mg added to a regimen of paracetamol 1,000 mg and ibuprofen 400 mg does not improve analgesia after third molar surgery. PMID- 28586639 TI - The Bony Side of Endothelial Cells in Prostate Cancer. AB - Prostate cancer bone metastases are primarily osteoblastic, but the source of bone-forming cells in these lesions remains poorly defined. In this issue of Developmental Cell, Lin et al. (2017) demonstrate that tumor-associated endothelial cells can give rise to osteoblasts in prostate cancer through endothelial-to-osteoblast (EC-to-OSB) conversion. PMID- 28586640 TI - At the Crossroads between Cell Polarity and Adhesion in Neocortical Development. AB - In this issue of Developmental Cell, Jossin et al. (2017) show that the tumor suppressor protein Lgl1 interacts with N-cadherin to stabilize apical junctions in brain stem cells. Neural progenitors lacking Lgl1 had decreased N-cadherin internalization and abnormal cell junctions, generating an ectopic neuronal layer that resembles cerebral cortex abnormalities in humans. PMID- 28586641 TI - Tregs Expand the Skin Stem Cell Niche. AB - Regulatory T cells (Tregs) are emerging as an essential stem cell niche component that promotes wound repair in adipose, muscle, and lung tissues. Recently in Cell, Ali et al. (2017) report that skin resident Tregs facilitate the proliferation and differentiation of hair follicle stem cells through Notch signaling. PMID- 28586642 TI - R-spondin Is More Than Just Wnt's Sidekick. AB - The intestinal crypt and its stem cells are dependent on the Wnt pathway. Reporting in Nature, Yan et al. (2017) show that Wnts and Wnt signaling potentiator R-spondins have non-interchangeable roles. Both are necessary for intestinal stem cell (ISC) maintenance, and R-spondins are the limiting factor that defines ISC number. PMID- 28586643 TI - On the Formation of Digits and Joints during Limb Development. AB - Critical steps in forming the vertebrate limb include the positioning of digits and the positioning of joints within each digit. Recent studies have proposed that the iterative series of digits is established by a Turing-like mechanism generating stripes of chondrogenic domains. However, re-examination of available data suggest that digits are actually patterned as evenly spaced spots, not stripes, which then elongate into rod-shaped digit rays by incorporating new cells at their tips. Moreover, extension of the digit rays and the patterning of the joints occur simultaneously at the distal tip, implying that an integrated model is required to fully understand these processes. PMID- 28586645 TI - The Protein Phosphatase 4 and SMEK1 Complex Dephosphorylates HYL1 to Promote miRNA Biogenesis by Antagonizing the MAPK Cascade in Arabidopsis. AB - Phosphorylation plays an essential role in microRNA (miRNA) processing by regulating co-factors of the miRNA biogenesis machinery. HYL1 (Hyponastic Leaves 1), a core co-factor in plant miRNA biogenesis, is a short-lived phosphoprotein. However, the precise balance and regulatory mechanism of the stability and phosphorylation of HYL1 remain unclear. Here, we show that a highly conserved PP4 (Protein Phosphatase 4) and SMEK1 (Suppressor of MEK 1) complex dephosphorylates HYL1 to promote miRNA biogenesis, by antagonizing the MAPK cascade in Arabidopsis. The smek1 mutants exhibit defective miRNA biogenesis due to accelerated degradation of HYL1. SMEK1 stabilizes HYL1 in a dual manner: SMEK1, as a suppressor, inhibits MAPK activation to attenuate HYL1 phosphorylation; SMEK1 assembles a functional PP4 to target HYL1 for dephosphorylation. Moreover, the protein level of SMEK1 is increased in response to abscisic acid. Our results provide insights into the delicate balance between a protein kinase and a phosphatase during miRNA biogenesis. PMID- 28586644 TI - Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer. AB - Prostate cancer (PCa) bone metastasis is frequently associated with bone-forming lesions, but the source of the osteoblastic lesions remains unclear. We show that the tumor-induced bone derives partly from tumor-associated endothelial cells that have undergone endothelial-to-osteoblast (EC-to-OSB) conversion. The tumor associated osteoblasts in PCa bone metastasis specimens and patient-derived xenografts (PDXs) were found to co-express endothelial marker Tie-2. BMP4, identified in PDX-conditioned medium, promoted EC-to-OSB conversion of 2H11 endothelial cells. BMP4 overexpression in non-osteogenic C4-2b PCa cells led to ectopic bone formation under subcutaneous implantation. Tumor-induced bone was reduced in trigenic mice (Tie2cre/Osxf/f/SCID) with endothelial-specific deletion of osteoblast cell-fate determinant OSX compared with bigenic mice (Osxf/f/SCID). Thus, tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa. PMID- 28586646 TI - Nuclear Pores Regulate Muscle Development and Maintenance by Assembling a Localized Mef2C Complex. AB - Nuclear pore complexes (NPCs) are multiprotein channels connecting the nucleus with the cytoplasm. NPCs have been shown to have tissue-specific composition, suggesting that their function can be specialized. However, the physiological roles of NPC composition changes and their impacts on cellular processes remain unclear. Here we show that the addition of the Nup210 nucleoporin to NPCs during myoblast differentiation results in assembly of an Mef2C transcriptional complex required for efficient expression of muscle structural genes and microRNAs. We show that this NPC-localized complex is essential for muscle growth, myofiber maturation, and muscle cell survival and that alterations in its activity result in muscle degeneration. Our findings suggest that NPCs regulate the activity of functional gene groups by acting as scaffolds that promote the local assembly of tissue-specific transcription complexes and show how nuclear pore composition changes can be exploited to regulate gene expression at the nuclear periphery. PMID- 28586647 TI - Phosphate Starvation-Dependent Iron Mobilization Induces CLE14 Expression to Trigger Root Meristem Differentiation through CLV2/PEPR2 Signaling. AB - Low inorganic phosphate (Pi) availability causes terminal differentiation of the root apical meristem (RAM), a phenomenon known as root meristem exhaustion or determined growth. Here, we report that the CLE14 peptide acts as a key player in this process. Low Pi stress induces iron mobilization in the RAM through the action of LPR1/LPR2, causing expression of CLE14 in the proximal meristem region. CLV2 and PEPR2 receptors perceive CLE14 and trigger RAM differentiation, with concomitant downregulation of SHR/SCR and PIN/AUXIN pathway. Our results reveal multiple steps of the molecular mechanism of one of the most physiologically important root nutrient responses. PMID- 28586649 TI - Altered Bowel Habits and Pelvic Fullness in a 75-Year-Old Woman. PMID- 28586650 TI - E6 proteins of alpha and beta cutaneous HPV types differ in their ability to potentiate Wnt signaling. AB - We recently showed that E6 protein of human papillomavirus (HPV) 16, a mucosal high-risk alpha-PV type, can potentiate Wnt/beta-catenin/TCF signaling. Here we investigated the transcriptional activities of E6 proteins of cutaneous HPV types from the beta and alpha genera. Results from reporter-gene assays showed that similar to HPV16 E6, E6 of HPV10, a cutaneous alpha-HPV type that is prevalent in skin warts, efficiently enhances and stimulates Wnt/beta-catenin/TCF transcription. HPV10 E6 also effectively elevated the expression levels of beta catenin and promoted its nuclear accumulation. E6 proteins of beta-HPV types 8, 24, 38 and 49, which are prevalent in skin cancer, exhibited lower activities in all tested functions. The differences in activity correlated with E6's competence to interact with the ubiquitin ligase E6AP. This study reveals a role for E6 proteins of diverse cutaneous HPV types in potentiation of Wnt/beta-catenin signaling, irrespective of their carcinogenic potential. PMID- 28586648 TI - Objective features of subjective cognitive decline in a United States national database. AB - INTRODUCTION: Functional and cognitive features of subjective cognitive decline (SCD) were identified in a longitudinal database from the National Alzheimer's Coordinating Center. METHODS: Cognitively normal older adults with (SCD+) and without (SCD-) self-reported memory complaints (N = 3915) were compared on (1) baseline Functional Assessment Questionnaire ratings, (2) baseline scores and longitudinal rate of change estimates from nine neuropsychological tests, and (3) final clinical diagnoses. RESULTS: SCD+ had higher baseline ratings of functional impairment, reduced episodic memory practice effects and poorer performance on neuropsychological tests of psychomotor speed and language, and higher frequencies of mild cognitive impairment and dementia diagnoses at the end of follow-up compared with the SCD-group. DISCUSSION: Subtle clinical features of SCD identified in this large cohort are difficult to detect at the individual level. More sensitive tests are needed to identify those with SCD who are vulnerable to cognitive decline and dementia. PMID- 28586651 TI - Optimization of degradation of Reactive Black 5 (RB5) and electricity generation in solar photocatalytic fuel cell system. AB - The photocatalytic fuel cell (PFC) system was developed in order to study the effect of several operating parameters in degradation of Reactive Black 5 (RB5) and its electricity generation. Light irradiation, initial dye concentration, aeration, pH and cathode electrode are the operating parameters that might give contribution in the efficiency of PFC system. The degradation of RB5 depends on the presence of light irradiation and solar light gives better performance to degrade the azo dye. The azo dye with low initial concentration decolorizes faster compared to higher initial concentration and presence of aeration in PFC system would enhance its performance. Reactive Black 5 rapidly decreased at higher pH due to the higher amount of OH generated at higher pH and Pt-loaded carbon (Pt/C) was more suitable to be used as cathode in PFC system compared to Cu foil and Fe foil. The rapid decolorization of RB5 would increase their voltage output and in addition, it would also increase their Voc, Jsc and Pmax. The breakage of azo bond and aromatic rings was confirmed through UV-Vis spectrum and COD analysis. PMID- 28586652 TI - Accelerated biodegradation of BPA in water-sediment microcosms with Bacillus sp. GZB and the associated bacterial community structure. AB - Bisphenol A (BPA) is a synthetic chemical primarily used to produce polycarbonate plastics and epoxy resins. Significant industrial and consumer's consumption of BPA-containing products has contributed to extensive contamination in different environmental matrices. In this study, microcosms bioaugmented with Bacillus sp. GZB were constructed to investigate BPA biodegradation, identify the main bacterial community, and evaluate bacterial community responses in the microcosms. Under aerobic conditions, BPA was quickly depleted as a result of bioaugmentation with Bacillus sp. GZB in water-sediment contaminated with pollutants. The pollutants used were generally associated with the electronic wastes (mobile phones, computers, televisions) dismantling process. Adding BPA affected the bacterial community composition in the water-sediment. Furthermore, BPA biodegradation was enhanced by adding electron donors/co-substrates: humic acid, NaCl, glucose, and yeast extract. Metagenomic analysis of the total 16S rRNA genes from the BPA-degrading microcosms with bioaugmentation illustrated that the genera Bacillus, Thiobacillus, Phenylobacterium, and Cloacibacterium were dominant after a 7-week incubation period. A consortium of microorganisms from different bacterial genera may be involved in BPA biodegradation in electronic waste contaminated water-sediment. This study provides new insights about BPA bioaugmentation and bacterial ecology in the BPA-degrading environment. PMID- 28586653 TI - Interactions of carbon nanotubes and/or graphene with manganese peroxidase during biodegradation of endocrine disruptors and triclosan. AB - Molecular-level biodegradation processes of bisphenol A (BPA), nonylphenol (NP) and triclosan (TCS) mediated by manganese peroxidase (MnP) were investigated with and without single-walled carbon nanotube (SWCNT) and/or graphene (GRA). Although the incorporation of SWCNT, GRA or their combination (SWCNT+GRA) did not break up the complexes composed of manganese peroxidase (MnP) and these substrates, they had different effects on the native contacts between the substrates and MnP. GRA tended to decrease the overall stability of the binding between MnP and its substrates. SWCNT or SWCNT+GRA generally had a minor impact on the mean binding energy between MnP and its substrates. We detected some sensitive residues from MnP that were dramatically disturbed by the GRA, SWCNT or SWCNT+GRA. Nanomaterials changed the number and behavior of water molecules adjacent to both MnP and its substrates, which was not due to the destruction of H-bond network formed by sensitive regions and water molecules. The present results are useful for understanding the molecular basis of pollutant biodegradation affected by the nanomaterials in the environment, and are also helpful in assessing the risks of these materials to the environment. PMID- 28586654 TI - Occurrence, distribution, and risk assessment of antibiotics in the surface water of Poyang Lake, the largest freshwater lake in China. AB - SPE-UPLC-MS/MS was used to investigate the occurrence of 18 target antibiotics in the surface water of Poyang Lake over different seasons of 2014-2015. The maximum concentrations of sulfadiazine, oxytetracycline, and doxycycline were 56.2, 48.7, and 39.7 ng/L, respectively. Compared with those in the other lakes or surface waters, the surface water of Poyang Lake contained moderate or below-average levels of antibiotics. The significantly lower concentrations (P < 0.01) of roxithromycin in June 2015 likely resulted from the dilution effect of water flow during the flood season. Antibiotic concentrations were higher in site P3-1 than in other sites (P < 0.01), whereas those in other sites (P1-1, P2-1, P5-1, P6-1, P7-1, P13-1, P16-1, P17-1, P18-1) were not significantly different (P > 0.05). Given that tetracyclines and sulfonamides are common veterinary medicines, the high concentrations of oxytetracycline, doxycycline, and sulfadiazine in site P3 1 might be closely related to agricultural production in the surrounding areas. The risk assessment of the main antibiotic contaminants revealed that the majority of the risk quotients of the target antibiotics were below 0.01, thereby indicating the minimal risk of these antibiotics to organisms at three different trophic levels. Sulfadimidine and sulfadiazine were identified as the main antibiotics that contribute to ecological risk in Poyang Lake, and that the daphnid is the main model organism exposed to these risks. This study provides important data for antibiotic pollution control and environmental protection in the study area and enriches environmental monitoring data on a global scale. PMID- 28586655 TI - Short-term social memory deficits in adult female mice exposed to tannery effluent and possible mechanism of action. AB - The accumulated organic residues in tannery-plant courtyards are an eating attraction to small rodents; however, the contact of these animals with these residues may change their social behavior. Thus, the aim of the present study is to investigate whether the exposure to tannery effluent (TE) can damage the social recognition memory of female Swiss mice, as well as to assess whether vitamin C supplementation could provide information about how TE constituents can damage these animals' memory. We have observed that resident females exposed to TE (without vitamin supplementation) did not explore the anogenital region, their body or chased intruding females for shorter time or with lower frequency during the retest session of the social recognition test, fact that indicates social recognition memory deficit in these animals. Such finding is reinforced by the confirmation that there was no change in the animals' olfactory function during the buried food test, or locomotor changes in females exposed to the pollutant. Since no behavioral change was observed in the females exposed to TE and treated with vitamin C (before or after the exposure), it is possible saying that these social cognitive impairments seem to be directly related to the imbalance between the cellular production of reactive oxygen species and the counteracting antioxidant mechanisms (oxidative stress) in female mice exposed to the pollutant (without vitamin supplementation). Therefore, the present study evidences that the direct contact with tannery effluent, even for a short period-of-time, may cause short-term social memory deficits in adult female Swiss mice. PMID- 28586656 TI - Heterologous expression of mlrA gene originated from Novosphingobium sp. THN1 to degrade microcystin-RR and identify the first step involved in degradation pathway. AB - Information on the catalytic role of mlrA gene-encoded enzyme (MlrA) in microcystin-RR (MC-RR) biodegradation was limited. This study succeeded in expressing mlrA homolog of Novosphingobium sp. THN1 in heterologous host for the first time, by constructing a recombinant bacterium. Mass spectrometric analysis showed that the recombinant MlrA hydrolyzed MC-RR into linear intermediate product by cleaving the peptide bond between Adda and arginine residue, greatly detoxifying MC-RR. This finding clearly manifested that the MlrA homolog of THN1 strain possesses its original catalytic function, and ring-opening constituted the first step in MC-RR biodegradation pathway of THN1 strain. Moreover, MC-RR degradation by intact recombinant cells and cell-free crude enzyme (CE) from recombinant was compared. Results exhibited that intact recombinant was able to degrade 20 MUg mL-1 MC-RR more quickly than CE, with the maximum rate of 9.22 MUg mL-1 h-1 in the first 8 h. Thus, this study provided new insights on the catalytic activity and roles of MlrA originated from THN1 strain in MC-RR biodegradation process, which lay a foundation for efficiently removing and detoxifying MC-RR, and exploring downstream steps in MC-RR biodegradation pathway of THN1 strain. PMID- 28586657 TI - The use of carbon adsorbents for the removal of perfluoroalkyl acids from potable reuse systems. AB - Bench- and pilot-scale sorption tests were used to probe the performance of several biochars at removing perfluoroalkyl acids (PFAA) from field waters, compared to granular activated carbon (GAC). Screening tests using organic matter free water resulted in hardwood (HWC) (Kd = 41 L g-1) and pinewood (PWC) (Kd = 49 L g-1) biochars having the highest perfluorooctanoic acid (PFOA) removal performance that was comparable to bituminous coal GAC (Kd = 41 L g-1). PWC and HWC had a stronger affinity for PFOA sorbed in Lake Mead surface water (KF = 11 mg(1-n) Ln g-1) containing a lower (2 mg L-1) dissolved organic carbon (DOC) concentration than in a tertiary-filtered wastewater (KF = 8 mg(1-n) Ln g-1) with DOC of 4.9 mg L-1. A pilot-scale study was performed using three parallel adsorbers (GAC, anthracite, and HWC biochar) treating the same tertiary-filtered wastewater. Compared to HWC, and anthracite, GAC was the most effective in mitigating perfluoropentanoic acid (PFPnA), perfluorohexanoic acid (PHxA), PFOA, perfluorooctane sulfonic acid (PFOS), and DOC (45-67% removed at 4354 bed volumes) followed by HWC, and then anthracite. Based on bench- and pilot-scale results, shorter-chain PFAA [perfluorobutanoic acid (PFBA), PFPnA, or PFHxA] were more difficult to remove with both biochar and GAC than the longer-chain, PFOS and PFOA. PMID- 28586658 TI - Beauty Requires Thought. PMID- 28586659 TI - A Simple Computational Model of the Bee Mushroom Body Can Explain Seemingly Complex Forms of Olfactory Learning and Memory. PMID- 28586660 TI - Seminal fluid. AB - Seminal fluid does more than transport sperm. Hopkins et al., describe the diverse features and functions of seminal fluid, and its role in evolution and medicine. PMID- 28586661 TI - Mucus-secreting lips offer protection to suction-feeding corallivorous fishes. AB - Of the 6,000 reef fish species, only 128 feed on corals [1,2]. Despite being widely available on tropical reefs, corals appear to represent a particularly challenging trophic resource, with mucus- and nematocyst-laden tissues spread over a sharp coral skeleton. Here we report that coral-feeding tubelip wrasses use highly modified lips to suck material from the coral surface. These lips have a specialized mushroom-like lamellar epithelium that secretes mucus. This mucus may facilitate suction and reduce damage by nematocysts in a manner akin to anemonefishes. The remarkable lip specializations observed in tubelip wrasses highlight the potential role of soft tissues in shaping the trophic ability of fishes. PMID- 28586662 TI - Evolution: Of X-Cells and X-Men. AB - Humans are obsessed with labels, constantly seeking to name and categorise unknowns, or 'X-things'. DNA sequencing has finally solved the identity of mysterious X-cells associated with tumours in marine fish, but how should we approach X in people? PMID- 28586663 TI - Neural Coding: Bumps on the Move. AB - By meticulously deconstructing the Drosophila head-direction neural circuit, two recent studies have revealed the mechanism of how the fly's body rotations are translated into a continuously updated internal compass representation. PMID- 28586664 TI - Flagellum Length Control: How Long Is Long Enough? AB - The bacterial flagellum is an organelle that self-assembles outside the cell body. Recent work has uncovered the mechanism for length control of this self assembly process. PMID- 28586665 TI - Cerebellar Granule Cells: Dense, Rich and Evolving Representations. AB - For half a century it was assumed that granule cells use ultra-sparse encoding, but now in vivo calcium-imaging studies have shown that large ensembles of granule cells provide dense signals, which themselves evolve and adapt during training. PMID- 28586666 TI - Prefrontal Cortex: A Mystery of Belated Memories. AB - A recent study suggests that the prefrontal cortex gradually becomes critical as a storage site for remotely acquired memories. How do we interpret this observation in light of the well-known functional role of the prefrontal cortex in cognition and memory? PMID- 28586667 TI - Cell Biology: Control of Partner Lifetime in a Plant-Fungus Relationship. AB - Arbuscules are tree-shaped fungal structures inside plant root cells that facilitate the exchange of nutrients delivered by the fungus with carbon sources from the host. To maintain symbiotic efficiency, plant cells can trigger degeneration of underperforming arbuscules. A recent study reveals the first transcription factor, which induces genes encoding hydrolytic enzymes, to mediate arbuscule degeneration. PMID- 28586668 TI - Neuroscience: Formation of a Percept in the Rat Cortex. AB - It has long been known that we subjectively experience longer stimuli as being more intense. A recent study sheds light on the neural mechanisms underlying this bias by tracking the formation of a percept of intensity in the rat brain. PMID- 28586669 TI - Evolution: Contingent Predictability in Mammalian Evolution. AB - Convergence of distantly related species to similar forms speaks to the predictability of evolution, but we still lack general insights into whether convergence is more common or rare than we would expect. Using a global dataset of mammalian species, Mazel and colleagues find that both convergence and divergence occur more often than expected. Convergence was especially common at broad scales that involved Australia, speaking to the extraordinary replicate mammalian communities found there. PMID- 28586670 TI - Hippocampus: Activity-Driven Maturation of Neural Circuits for Navigation. AB - New research reveals that neural activity is required for post-natal maturation of hippocampal neural circuits underlying memory and navigation; this activity dependent maturation occurs sequentially along the classic 'tri-synaptic' pathway, following the direction of information flow found in the adult hippocampus. PMID- 28586671 TI - Trends and frontiers for the science and management of the oceans. AB - People have an enduring fascination with the biology of the oceans. When the BBC's 'Blue Planet' series first aired on British television almost a quarter of the nation tuned in. As the diversity of science in this special issue of Current Biology attests, the ocean presents a challenging environment for study while also exhibiting some of the most profound and disruptive symptoms of global change. Marine science has made major advances in the past few decades, which were primarily made possible through important technological innovations. This progress notwithstanding, there are persistent challenges in achieving an understanding of marine processes at appropriate scales and delivering meaningful insights to guide ocean policy and management. Naturally, the examples chosen below betray my ecological leanings, but I hope that many of the issues raised resonate with readers in many different disciplines. PMID- 28586672 TI - Seagrass meadows. AB - Seagrass meadows are an important and threatened ecosystem. PMID- 28586673 TI - Marine microplastics. AB - Galloway and Lewis discuss marine microplastics and their devastating effects on ocean ecosystems. PMID- 28586674 TI - Prochlorococcus. AB - Move over plants-make way for tiny Prochlorococcus, the smallest and most abundant photosynthetic cell on earth! Penny Chisholm tells us all about this powerhouse marine bacterium. PMID- 28586675 TI - Seabirds. AB - In this Quick Guide, Votier and Sherley explain how diverse seabirds play important roles in ecosystem functioning, global nutrient cycling and climate regulation, but are declining in the face of multiple threats. PMID- 28586676 TI - Hydrothermal vents. AB - William Brazelton introduces deep sea hydrothermal vents and the unusual life forms they host. PMID- 28586677 TI - Cryptobenthic reef fishes. AB - Christopher Goatley and Simon Bran introduce the 'hidden' small fishes found on coral reefs. PMID- 28586678 TI - Polar oceans in a changing climate. AB - Most of Earth's surface is blue or white, but how much of each would depend on the time of observation. Our planet has been through phases of snowball (all frozen), greenhouse (all liquid seas) and icehouse (frozen and liquid). Even during current icehouse conditions, the extent of ice versus water has changed considerably between ice ages and interglacial periods. Water has been vital for life on Earth and has driven and been influenced by transitions between greenhouse and icehouse. However, neither the possession of water nor having liquid and frozen seas are unique to Earth (Figure 1). Frozen water oceans on the moons Enceladus and Europa (and possibly others) and the liquid and frozen hydrocarbon oceans on Titan probably represent the most likely areas to find extraterrestrial life. We know very little about life in Earth's polar oceans, yet they are the engine of the thermohaline 'conveyor-belt', driving global circulation of heat, oxygen, carbon and nutrients as well as setting sea level through change in ice-mass balance. In regions of polar seas, where surface water is particularly cold and dense, it sinks to generate a tropic-ward flow on the ocean floor of the Pacific, Atlantic and Indian Oceans. Cold water holds more gas, so this sinking water exports O2 and nutrients, thereby supporting life in the deep sea, as well as soaking up CO2 from the atmosphere. Water from mid depths at lower latitudes flows in to replace the sinking polar surface water. This brings heat. The poles are cold because they receive the least energy from the sun, and this extreme light climate varies on many different time scales. To us, the current warm, interglacial conditions seem normal, yet such phases have represented only ~10% of Homo sapiens' existence. Variations in Earth's orbit (so called 'Milankovitch cycles') have driven cyclical alternation of glaciations (ice ages) and warmer interglacials. Despite this, Earth's polar regions have been our planet's most environmentally constant surface regions for several millions of years, with most land ice-covered and much of the ocean seasonally freezing. The two poles have much in common, such as light climate, temperature and water viscosity, winter calm and summer (iceberg and storm) disturbance and resources. However, they are also regions of striking contrasts: the Arctic Ocean is near surrounded by land compared with the Antarctic continent, which is surrounded by the Southern Ocean. Polar oceans contrast in size, age, isolation, depth, oceanography, biology and human factors, such as governance and human habitation. The simplest foodwebs with the smallest residents live on the 1% of Antarctica that is ice free, whilst the largest animals that have ever lived on Earth (Blue and Fin whales) feed in the Arctic and Southern Oceans. PMID- 28586679 TI - The deep-sea under global change. AB - The deep ocean encompasses 95% of the oceans' volume and is the largest and least explored biome of Earth's Biosphere. New life forms are continuously being discovered. The physiological mechanisms allowing organisms to adapt to extreme conditions of the deep ocean (high pressures, from very low to very high temperatures, food shortage, lack of solar light) are still largely unknown. Some deep-sea species have very long life-spans, whereas others can tolerate toxic compounds at high concentrations; these characteristics offer an opportunity to explore the specialized biochemical and physiological mechanisms associated with these responses. Widespread symbiotic relationships play fundamental roles in driving host functions, nutrition, health, and evolution. Deep-sea organisms communicate and interact through sound emissions, chemical signals and bioluminescence. Several giants of the oceans hunt exclusively at depth, and new studies reveal a tight connection between processes in the shallow water and some deep-sea species. Limited biological knowledge of the deep-sea limits our capacity to predict future response of deep-sea organisms subject to increasing human pressure and changing global environmental conditions. Molecular tools, sensor-tagged animals, in situ and laboratory experiments, and new technologies can enable unprecedented advancement of deep-sea biology, and facilitate the sustainable management of deep ocean use under global change. PMID- 28586680 TI - Emergence of modern marine ecosystems. AB - The structure and function of marine ecosystems are not fixed. Instead, major innovations - from the origin of oxygenic photosynthesis, to the evolution of reefs or of deep bioturbation, to the rise of pelagic calcifiers - have changed biogeochemical cycles and ecosystem dynamics. As a result, modern marine ecosystems are fundamentally different from those in the distant past. PMID- 28586681 TI - Ocean currents and marine life. AB - Ocean currents have many profound impacts on marine life, moving not only animals and plants around the ocean but also redistributing heat and nutrients. While some of these impacts have been well known for many decades, there have been major recent developments in this area. Biologists are increasingly collaborating with physical oceanographers. At the same time, methods to accurately predict ocean currents and their variability have improved over a broad range of spatial and temporal scales. Emerging from these initiatives is an understanding of how currents impact the connectivity of marine populations, how they influence the migration of strong swimmers, including whales and turtles, and how changing currents, as part of global climate change, may re-shape entire communities. PMID- 28586683 TI - Plankton. AB - Plankton comprises unicellular plants - phytoplankton - and generally small (millimetres or less) animals - zooplankton - that are adrift on the currents. Phytoplankton are responsible for about 45% of global annual primary production and are grazed by zooplankton, which in turn are suitably sized food items for predators including commercially important fish and great whales. Plankton are vital components of marine and freshwater water-column ecosystems. They also make major contributions to global biogeochemical cycling, and ameliorate atmospheric accumulation of carbon dioxide by 'pumping' carbon to the deep sea. The integrity of these roles is under threat from climate-related physiological impacts on individual organisms and on the wide-scale distribution of plankton communities. PMID- 28586682 TI - Nutrients that limit growth in the ocean. AB - Phytoplankton form the basis of the marine food web and are responsible for approximately half of global carbon dioxide (CO2) fixation (~ 50 Pg of carbon per year). Thus, these microscopic, photosynthetic organisms are vital in controlling the atmospheric CO2 concentration and Earth's climate. Phytoplankton are dependent on sunlight and their CO2-fixation activity is therefore restricted to the upper, sunlit surface ocean (that is, the euphotic zone). CO2 usually does not limit phytoplankton growth due to its high concentration in seawater. However, the vast majority of oceanic surface waters are depleted in inorganic nitrogen, phosphorus, iron and/or silica; nutrients that limit primary production in the ocean (Figure 1). Phytoplankton growth is mainly supported by either the recycling of nutrients or by reintroduction of nutrients from deeper waters by mixing. A small percentage of primary production, though, is fueled by 'external' or 'new' nutrients and it is these nutrients that determine the amount of carbon that can be sequestered long term in the deep ocean. For most nutrients such as phosphorus, iron, and silica, the external supply is limited to atmospheric deposition and/or coastal and riverine inputs, whereas their main sink is the sedimentation of particulate matter. Nitrogen, however, has an additional, biological source, the fixation of N2 gas, as well as biological sinks via the processes of denitrification and anammox. Despite the comparatively small contributions to the overall turnover of nutrients in the ocean, it is these biological processes that determine the ocean's capacity to sequester CO2 from the atmosphere on time scales of ocean circulation (~ 1000 years). This primer will highlight shifts in the traditional paradigms of nutrient limitation in the ocean, with a focus on the uniqueness of the nitrogen cycling and its biological sources and sinks. PMID- 28586685 TI - Marine microbial diversity. AB - Invisible to the naked eye, yet dominating life with some 1030 cells, bacteria and archaea (referred to herein as 'microbes') play key roles in the global cycling of nutrients, matter and energy in our oceans. Having experimented for over 3.5 billion years since their first appearance, they are true master chemists that are capable of carrying out the most diverse and complex of chemical reactions. One of the most abundant groups, cyanobacteria, converts light into chemical energy by fixing carbon dioxide into organic matter. Part of this fixed carbon is consumed by higher trophic levels, while another fraction sinks to the deep sediments where, over geological time scales, it fossilizes into the natural resources that we tap into for our everyday lives. Despite our knowledge of their global importance and significant recent advances in marine microbiome research (Figure 1), some of the most fundamental questions still remain unanswered, and serve as active drivers of current research in this field: How many microbes are out there, and how many different types? What are they? What are their functional roles? How are they globally distributed? How do they adapt to varying environmental conditions and how will they respond to future environmental changes? This Primer provides a brief overview on how these questions have been addressed in the context of developing technologies. We discuss new insights, as well as new concepts and more refined questions, and we highlight some of the future promises and challenges that lie ahead. PMID- 28586684 TI - Herbivory in the marine realm. AB - Herbivory occurs when animals consume plants; but the term hides two fundamentally different processes. One relates to the animal's nutrition, the other to the plant's survival and abundance. Both are central to the ecological process called herbivory. Evolutionary innovations in herbivore function have shaped shallow marine ecosystems from kelp forests to coral reefs. PMID- 28586686 TI - Vision and lack of vision in the ocean. AB - As land-locked animals, when we visualise the ocean our mind's eye may see crashing waves or a vast blue expanse stretching to the horizon, a raft of torpedoing penguins, a glimpse of colourful coral reef fish from the shark-free safety of a sandy beach. Underwater, the crystal-clear, and in fact not at all silent, world of Jacques Cousteau, or more recently David Attenborough, is a wonderland that some cannot wait to witness first hand as divers, while others are content to see it on a screen. Spend a bit of time underwater, in the English Channel for example, and a few facts emerge. Most obviously, much of this underwater realm is visually very different to land and indeed to the cherry picked clear waters of documentaries. It may be disappointingly murky and monochromatic. Perhaps surprisingly, therefore, on close inspection the diversity of eye designs and light sensing mechanisms that evolved in the ocean are more varied than on land, reflecting the greater range of light environments and lifestyles of the marine world. Particularly in the last ten years, the destructive influence we are having on the oceans has become visibly obvious, not just to fisheries biologists and ecologists, but to anyone returning to a favourite dive spot or reef resort. Climate change, as a result of burning fossil fuels, human greed and carelessness with plastic disposal, are rapidly degrading entire oceanic ecosystems. PMID- 28586687 TI - Marine bioacoustics. AB - The marine environment is the planet's largest, yet in many respects the least accessible. Our human sensory repertoire, with its emphasis on vision and air adapted hearing, does not serve us well underwater. Underwater vision is often limited and as divers we find hearing of little, or no, use. Yet we know from the physics that underwater sound has properties well suited to serve as sensory and communication channels for suitably-adapted marine animals. The rapidly developing area of marine bioacoustics seeks to characterise underwater sound in relation to the acoustic capability of particular species (acoustic habitat), and discover the role of acoustics in the lives of marine animals (acoustic ecology) (Clarke et al., 2011). PMID- 28586688 TI - Marine ecosystem services. AB - Coastal and marine environments can begin up to 100 kilometers inland, extend to the continental shelf, and include ocean systems with waters up to 50 meters in depth. The distinct marine ecosystems found in these environments include estuarine and coastal wetlands, such as marshes and mangroves, sand beaches and dunes, seagrass beds, and coral and oyster reefs. PMID- 28586689 TI - Marine Biodiversity, Biogeography, Deep-Sea Gradients, and Conservation. AB - The oceans appear ideal for biodiversity - they have unlimited water, a large area, are well connected, have less extreme temperatures than on land, and contain more phyla and classes than land and fresh waters. Yet only 16% of all named species on Earth are marine. Species richness decreases with depth in the ocean, reflecting wider geographic ranges of deep sea than coastal species. Here, we assess how many marine species are named and estimated to exist, paying particular regard to whether discoveries of deep-sea organisms, microbes and parasites will change the proportion of terrestrial to marine species. We then review what factors have led to species diversification, and how this knowledge informs conservation priorities. The implications of this understanding for marine conservation are that the species most vulnerable to extinction will be large and endemic. Unfortunately, these species are also the most threatened by human impacts. Such threats now extend globally, and thus the only refuges for these species will be large, permanent, fully protected marine reserves. PMID- 28586690 TI - The Vulnerability and Resilience of Reef-Building Corals. AB - Reef-building corals provide the foundation for the structural and biological diversity of coral-reef ecosystems. These massive biological structures, which can be seen from space, are the culmination of complex interactions between the tiny polyps of the coral animal in concert with its unicellular symbiotic algae and a wide diversity of closely associated microorganisms (bacteria, archaea, fungi, and viruses). While reef-building corals have persisted in various forms for over 200 million years, human-induced conditions threaten their function and persistence. The scope for loss associated with the destruction of coral reef systems is economically, biologically, physically and culturally immense. Here, we provide a micro-to-macro perspective on the biology of scleractinian corals and discuss how cellular processes of the host and symbionts potentially affect the response of these reef builders to the wide variety of both natural and anthropogenic stressors encountered by corals in the Anthropocene. We argue that the internal physicochemical settings matter to both the performance of the host and microbiome, as bio-physical feedbacks may enhance stress tolerance through environmentally mediated host priming and effects on microbiome ecological and evolutionary dynamics. PMID- 28586691 TI - Marine Protists Are Not Just Big Bacteria. AB - The study of marine microbial ecology has been completely transformed by molecular and genomic data: after centuries of relative neglect, genomics has revealed the surprising extent of microbial diversity and how microbial processes transform ocean and global ecosystems. But the revolution is not complete: major gaps in our understanding remain, and one obvious example is that microbial eukaryotes, or protists, are still largely neglected. Here we examine various ways in which protists might be better integrated into models of marine microbial ecology, what challenges this will present, and why understanding the limitations of our tools is a significant concern. In part this is a technical challenge - eukaryotic genomes are more difficult to characterize - but eukaryotic adaptations are also more dependent on morphology and behaviour than they are on the metabolic diversity that typifies bacteria, and these cannot be inferred from genomic data as readily as metabolism can be. We therefore cannot simply follow in the methodological footsteps of bacterial ecology and hope for similar success. Understanding microbial eukaryotes will require different approaches, including greater emphasis on taxonomically and trophically diverse model systems. Molecular sequencing will continue to play a role, and advances in environmental sequence tag studies and single-cell methods for genomic and transcriptomics offer particular promise. PMID- 28586692 TI - Functional Innovations and the Conquest of the Oceans by Acanthomorph Fishes. AB - The world's oceans are home to many fantastic creatures, including about 16,000 species of actinopterygian, or ray-finned, fishes. Notably, 85% of marine fish species come from a single actinopterygian subgroup, the acanthomorph or spiny rayed fishes. Here, we review eight functional innovations found in marine acanthomorphs that have been instrumental in the adaptive radiation of this group in the marine realm. Jaw protrusion substantially enhances the suction feeding mechanism found in all fish. Fin spines serve as a major deterrent to predators and enhance the locomotor function of fins. Pharyngognathy, a specialization of the second pair of jaws in the pharynx, enhances the ability of fishes to process hard and tough prey. Endothermy allows fishes to function at high levels of physiological performance in cold waters and facilitates frequent movement across strong thermal gradients found in the open ocean. Intramandibular joints enhance feeding for fishes that bite and scrape prey attached to hard surfaces. Antifreeze proteins prevent ice crystal growth in extracellular fluids, allowing fish to function in cold waters that would otherwise freeze them. Air-breathing allowed fishes at the water's edge to exploit terrestrial habitats. Finally, bioluminescence functions in communication, attracting prey and in hiding from predators, particularly for fishes of the deep ocean. All of these innovations have evolved multiple times in fishes. The frequent occurrence of convergent evolution of these complex functional novelties speaks to the persistence and potency of the selective forces in marine environments that challenge fishes and stimulate innovation. PMID- 28586693 TI - The Ecological Rise of Whales Chronicled by the Fossil Record. AB - The evolution of cetaceans is one of the best examples of macroevolution documented from the fossil record. While ecological transitions dominate each phase of cetacean history, this context is rarely stated explicitly. The first major ecological phase involves a transition from riverine and deltaic environments to marine ones, concomitant with dramatic evolutionary transformations documented in their early fossil record. The second major phase involves ecological shifts associated with evolutionary innovations: echolocation (facilitating hunting prey at depth) and filter-feeding (enhancing foraging efficiency on small prey). This latter phase involves body size shifts, attributable to changes in foraging depth and environmental forcing, as well as re-invasions of freshwater systems on continental basins by multiple lineages. Modern phenomena driving cetacean ecology, such as trophic dynamics and arms races, have an evolutionary basis that remains mostly unexamined. The fossil record of cetaceans provides an historical basis for understanding current ecological mechanisms and consequences, especially as global climate change rapidly alters ocean and river ecosystems at rates and scales comparable to those over geologic time. PMID- 28586694 TI - Challenges and Priorities in Shark and Ray Conservation. AB - Sharks, rays, and chimaeras (Class Chondrichthyes; herein 'sharks') are the earliest extant jawed vertebrates and exhibit some of the greatest functional diversity of all vertebrates. Ecologically, they influence energy transfer vertically through trophic levels and sometimes trophic cascades via direct consumption and predation risk. Through movements and migrations, they connect horizontally and temporally across habitats and ecosystems, integrating energy flows at large spatial scales and across time. This connectivity flows from ontogenetic growth in size and spatial movements, which in turn underpins their relatively low reproductive rates compared with other exploited ocean fishes. Sharks are also ecologically and demographically diverse and are taken in a wide variety of fisheries for multiple products (e.g. meat, fins, teeth, and gills). Consequently, a range of fisheries management measures are generally preferable to 'silver bullet' and 'one size fits all' conservation actions. Some species with extremely low annual reproductive output can easily become endangered and hence require strict protections to minimize mortality. Other, more prolific species can withstand fishing over the long term if catches are subject to effective catch limits throughout the species' range. We identify, based on the IUCN Red List status, 64 endangered species in particular need of new or stricter protections and 514 species in need of improvements to fisheries management. We designate priority countries for such actions, recognizing the widely differing fishing pressures and conservation capacity. We hope that this analysis assists efforts to ensure this group of ecologically important and evolutionarily distinct animals can support both ocean ecosystems and human activities in the future. PMID- 28586695 TI - Brief note: Applying developmental intergroup perspectives to the social ecologies of bullying: Lessons from developmental social psychology. AB - Over the past decades, the field of bullying research has seen dramatic growth, notably with the integration of the social-ecological approach to understanding bullying. Recently, researchers (Hymel et al., 2015; Hawley & Williford, 2015) have called for further extension of the field by incorporating constructs of group processes into our investigation of the social ecologies of bullying. This brief note details the critical connections between power, social identity, group norms, social and moral reasoning about discrimination and victimization, and experiences of, evaluations of, and responses to bullying. The authors highlight a parallel development in the bridging of developmental social-ecological and social psychological perspectives utilized in the field of social exclusion that provides a roadmap for extending the larger field of bullying research. This article is part of a Special Issue entitled [VSI: Bullying] IG000050. PMID- 28586696 TI - Precision and accuracy of the new XPrecia Stride mobile coagulometer. AB - INTRODUCTION: Oral anticoagulation therapy (OAT) with coumarins (vitamin K antagonist) is the most used against thromboembolism. Prothrombin time (PT) International Normalized Ratio (INR) monitoring is fundamental to establish coumarins dosage and prevent bleeding complications or thrombotic events. In this contest, the method and apparatus used for providing the INR measurements are crucial. Several studies have been published regarding the precision and accuracy of mobile coagulometers with different conclusions. No studies have been published regarding the new XPrecia Stride Mobile Coagulometer (Siemens). The aim of this work is to analyze precision and accuracy of the new XPrecia Stride mobile coagulometer to provide recommendations for clinical use and quality control. MATERIALS AND METHODS: A total of 163 patients (mean age=77.4years old) under Warfarin OAT for whom the INR was assessed by both the traditional cs 2100i Sysmex and the new Xprecia Stride Mobile Coagulometer were included in this pilot study. RESULTS AND CONCLUSIONS: The precision of the new mobile coagulometer resulted very good (CV<3%). The analytical accuracy was also within the acceptable ranges of reliability (Lin's concordance=0.962). Finally, the clinical accuracy was also acceptable (deviation>15% from the true value in 20% of cases). Considering the overall results obtained by the new Xprecia Stride in comparison to that ones obtained from the other commercial devices, we can conclude that the new coagulometer is enough reliable for clinical settings. However, a larger trial to confirm these data is needed. PMID- 28586697 TI - The diagnostic management of upper extremity deep vein thrombosis: A review of the literature. AB - Upper extremity deep vein thrombosis (UEDVT) accounts for 4% to 10% of all cases of deep vein thrombosis. UEDVT may present with localized pain, erythema, and swelling of the arm, but may also be detected incidentally by diagnostic imaging tests performed for other reasons. Prompt and accurate diagnosis is crucial to prevent pulmonary embolism and long-term complications as the post-thrombotic syndrome of the arm. Unlike the diagnostic management of deep vein thrombosis (DVT) of the lower extremities, which is well established, the work-up of patients with clinically suspected UEDVT remains uncertain with limited evidence from studies of small size and poor methodological quality. Currently, only one prospective study evaluated the use of an algorithm, similar to the one used for DVT of the lower extremities, for the diagnostic workup of clinically suspected UEDVT. The algorithm combined clinical probability assessment, D-dimer testing and ultrasonography and appeared to safely and effectively exclude UEDVT. However, before recommending its use in routine clinical practice, external validation of this strategy and improvements of the efficiency are needed, especially in high-risk subgroups in whom the performance of the algorithm appeared to be suboptimal, such as hospitalized or cancer patients. In this review, we critically assess the accuracy and efficacy of current diagnostic tools and provide clinical guidance for the diagnostic management of clinically suspected UEDVT. PMID- 28586698 TI - Multiscale characterization of the hierarchical structure of Dynastes hercules elytra. AB - Beetle elytra are thickened forewings, they are lightweight and tough to protect the hindwings without hindering flight capacities. Dynastes hercules elytra are known for their hygrochromic properties. However, the whole structure of the elytron remains to be characterized. Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and to our knowledge for the first time X Ray tomography were undertaken on adult male Dynastes hercules to characterize their multi-scale structure. Trabeculae present a periodic arrangement over a short distance. Two inferred models describe the heights of plies in endocuticles of dorsal and ventral cuticles. We hypothesize that this study could provide inspiration for biomimetic materials. PMID- 28586699 TI - Measuring anxiety in depressed patients: A comparison of the Hamilton anxiety rating scale and the DSM-5 Anxious Distress Specifier Interview. AB - DSM-5 included criteria for an anxious distress specifier for major depressive disorder (MDD). In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project we examined whether a measure of the specifier, the DSM-5 Anxious Distress Specifier Interview (DADSI), was as valid as the Hamilton Anxiety Scale (HAMA) as a measure of the severity of anxiety in depressed patients. Two hundred three psychiatric patients with MDD were interviewed by trained diagnostic raters who administered the Structured Clinical Interview for DSM-IV (SCID) supplemented with questions to rate the DADSI, HAMA, and Hamilton Depression Rating Scale (HAMD). The patients completed self-report measures of depression, anxiety, and irritability. Sensitivity to change was examined in 30 patients. The DADSI and HAMA were significantly correlated (r = 0.60, p < 0.001). Both the DADSI and HAMA were more highly correlated with measures of anxiety than with measures of the other symptom domains. The HAMD was significantly more highly correlated with the HAMA than with the DADSI. For each anxiety disorder, patients with the disorder scored significantly higher on both the DADSI and HAMA than did patients with no current anxiety disorder. A large effect size of treatment was found for both measures (DADSI: d = 1.48; HAMA: d = 1.37). Both the DADSI and HAMA were valid measures of anxiety severity in depressed patients, though the HAMA was more highly confounded with measures of depression than the DADSI. The DADSI is briefer than the HAMA, and may be more feasible to use in clinical practice. PMID- 28586700 TI - Injection into the jugular vein among people who inject drugs in the United Kingdom: Prevalence, associated factors and harms. AB - BACKGROUND: While people who inject drugs (PWID) typically use peripheral veins, some inject into their central veins, including the femoral and jugular veins. Injection into the jugular vein can have serious adverse health consequences, including jugular vein thrombosis, deep neck infections, pneumothorax, endocarditis and sepsis. This study examined the prevalence of, and factors associated with, jugular vein injection among a large sample of PWID in the United Kingdom. METHOD: Unlinked anonymous surveys (2011-14) recruited PWID from agencies providing services to this population. Self-reported demographic and injection-related data were collected from consenting respondents using a brief questionnaire and dried blood spot samples were tested for exposure to HIV, hepatitis C virus (HCV) and hepatitis B virus (HBV). Univariate and multivariable logistic regression were used to examine factors associated with jugular vein injection. RESULTS: Among 5261 PWID, one third had injected into a central vein in the previous 28 days, including 6% (n=339) who had injected into their jugular vein and 1% (n=52) who had used this site exclusively for recent injections. Factors independently associated with recent jugular vein injection in multivariable analysis included female gender, a lifetime history of imprisonment, sharing needles and syringes, poly-drug injection and injection into multiple body sites. Jugular vein injection was also associated with experiencing injection-related injuries, although no associations were identified with respect to exposure to blood borne viral infections. CONCLUSION: A significant minority of PWID inject into the jugular vein in the United Kingdom. Public health responses should investigate ways to support and promote good injection site management in order to minimise vascular damage and reduce problems with peripheral venous access. Women who inject drugs, PWID with a history of imprisonment and those people who are experiencing early signs of injection-related skin and soft tissue injuries are priority sub-populations for interventions. PMID- 28586702 TI - First principle electron transport modeling of Be-doped organic molecular junctions. AB - The transport properties of beryllium doped anthracene molecular junction are investigated using density functional non-equillibrium Green's function method. The equilibrium conductance of anthracene Metal-molecule-Metal (MmM) junction increases by approximately 77% by adding beryllium impurity to it. The electronic transport characteristics under both zero bias as well as finite bias are explored of such molecular junction. We observe novel attributes such as molecular rectification and NDR behavior for the molecular junction under consideration. It is found that the doping effect of Be- atom significantly changes the transport properties of aromatic molecular junction. Our findings shed light on the electron transport metrics that affect the conductance of MmM junctions within appreciable transmission limits. We firmly believe that the results deduced in this paper can be generalized for other aromatic molecular junctions as well. PMID- 28586703 TI - Exploring the potential of boron-doped nanographene as efficient charge transport and nonlinear optical material: A first-principles study. AB - Owing to their excellent electrochemical properties, graphenes found applications in several fields ranging from semiconductors, solar cells, field effect transistors, and nanoscale electronic devices as well as in nonlinear optical (NLO) applications. The structural features, electro-optical, charge transport and nonlinear optical properties of the boron-doped graphene (BG) compound 1 were studied using density functional theory methods The BG compound comprises a central electron deficient site of boron atoms, which can serve as electron acceptor while terminal alkoxy groups as donors leading to powerful donor-pi acceptor (D-pi-A) configuration. The experimental crystal structure was successfully reproduced by optimized ground state geometry at PBE0/6-311G* level of theory for isolated molecule. The experimental lattice parameters, geometries, crystal presentation and alignment of molecules in the unit cells as well as their packing orientation of BG compound 1 was also efficiently reproduced by applying periodic boundary conditions (PBC) at PBE level. The comprehensive intramolecular charge transfer (CT) was realized from terminal rings of the HOMO to the electron deficient sites of boron atoms of the LUMO. The nature of BG compound 1 might be more towards hole transport even though its hole reorganization energy is twice than that of the electron one due to the significant higher hole transfer integral values. The superior hole transfer integrals and intrinsic mobility values of the BG compound 1 might lead remarkable hole transport contender as compared to many other organic materials. The narrow band gap, density of states profile, dielectric function, uniform conductivity functions and noteworthy electronic as well as CT properties revealed that the BG compound 1 might be proficient optoelectronic contestant having intermolecular CT as well as intramolecular CT with optimal stability. A comparison of static third-order polarizability of BG compound 1, as calculated in present investigation, was also performed with some standard NLO molecules as well as graphene nanoflakes. Moreover, longitudinal component gammazzzz of parent compound has been found 12 and 4 times larger than those of previously reported open-shell poly aromatic hydrocarbons (PAH). Interestingly, by increasing the donor ability, i.e., introduction of C2H2PhNH2 groups in place of OC4H9 groups (BG compound 3) at terminal positions boosts the amplitude~8 times than that of its parent BG compound 1. PMID- 28586701 TI - The extent of and factors associated with self-reported overdose and self reported receipt of naloxone among people who inject drugs (PWID) in England, Wales and Northern Ireland. AB - BACKGROUND: Overdose is a major cause of death among PWID, and for opioid overdoses naloxone administration can reduce harm. However, globally there is limited national level data on the extent of non-fatal overdose and naloxone uptake. The first national level data on the extent of self-reported overdose and self-reported receipt of naloxone among UK PWID, providing a baseline to monitor the impact of the recent policy change regarding naloxone availability, is presented. METHODS: Data on self-reported overdose and receipt of naloxone during the preceding year for 2013-2014 from a national survey of PWID was analysed. Participants who reported injecting during the preceding year were included. RESULTS: Participants (3850) were predominantly male (75%); mean age was 36 years. The most commonly injected drugs were: heroin (91%), crack (45%) and amphetamine (29%). 15% (591) reported overdosing during the preceding year. There were no differences in the proportion reporting overdose by age or gender, but overdose was more common among those who: injected multiple drugs; recently ceased addiction treatment; injected with used needles/syringes; ever had transactional sex; had used a sexual health clinic or emergency department and lived in Wales or Northern Ireland. Among those reporting an overdose during the preceding year, a third reported two to four overdoses and 7.5% five or more overdoses; half reported receiving naloxone. Those reporting naloxone receipt in the preceding year were more likely to: live in Wales or Northern Ireland; ever received used needles/syringes; ever been imprisoned; and less likely to have injected two drug types. CONCLUSION: These data provide a baseline for monitoring the impact of the 2015 UK policy change to improve take-home naloxone access. Interventions tackling overdose should promote naloxone awareness and access, and target those who; are poly-drug injectors, have ceased treatment, share needles/syringes and whose drug use links to sexual activity. PMID- 28586704 TI - Study of inactive layer uniformity and charge collection efficiency of a p-type point-contact germanium detector. AB - The characteristics of the surface inactive layer of a 1-kg-mass p-type point contact germanium detector were studied. The thickness of the inactive layer and its uniformity on the top and lateral surfaces were measured. A charge collection efficiency function was developed according to the Monte Carlo simulation to describe the charge collection capacity along the depth within this inactive layer. In the energy range below 18keV, the surface, bulk, and total spectra of 57Co, 133Ba, 137Cs, and 60Co from simulations based on the charge collection efficiency function were well consistent with those from experiments. PMID- 28586705 TI - Late-onset seizures, underlying etiology and antiepileptic drugs: A gordian knot? PMID- 28586706 TI - LGI1-antibody encephalitis is characterised by frequent, multifocal clinical and subclinical seizures. AB - PURPOSE: To describe clinical and electrographic characteristics of seizures LGI1 antibody encephalitis, and their correlations with two-year outcomes. METHODS: Video-electroencephalography recordings were performed on a cohort of 16 consecutive patients with LGI1-antibodies from two UK neuroscience-centers over five-years. RESULTS: From 14 of 16 patients (13 males; age-range 53-92years), 86 faciobrachial dystonic seizures were recorded at a median frequency of 0.4 per hour (range 0.1-9.8), and ictal EEG changes accompanied 5/86 events. In addition, 11/16 patients showed 53 other seizures - subclinical (n=18), motor (n=16), or sensory (n=19) - at a median of 0.1 per hour (range 0.1-2) associated with temporal and frontal discharges. The sensory events were most commonly thermal sensations or body-shuddering, and the motor events were frequently automatisms or vocalisations. Furthermore, multifocal interictal epileptiform discharges, from temporal, frontal and parietal regions, and interictal slow-wave activity were observed in 25% and 69% of patients, respectively. Higher observed seizure frequency correlated with poorer functional recovery at two-years (p=0.001). CONCLUSIONS: Multiple frequent seizure semiologies, in addition to numerous subclinical seizures and interictal epileptiform discharges, are hallmarks of LGI1-antibody encephalitis. High overall seizure frequency may predict more limited long-term recovery. These observations should encourage closer monitoring and proactive treatment of seizure activity in these patients. PMID- 28586708 TI - Impact of comorbidity on survival by tumour location: Breast, colorectal and lung cancer (2000-2014). AB - BACKGROUND: To assess the impact of comorbidity, measured by the Charlson Comorbidity Index (CCI), on survival in breast, colorectal and lung cancer. METHODS: We identified 3455 breast cancer, 3336 colorectal cancer and 2654 lung cancer patients through the Hospital del Mar cancer registry. The prevalence of comorbidities according to the CCI was calculated. Kaplan-Meier curves and the log-rank test were used to compare survival curves for each cancer location. Cox regression was used to calculate survival hazard ratios and 1-, 3- and 5-year mortality rate ratios adjusted by age, sex, CCI, place of first consultation, stage, treatment and period of diagnosis. RESULTS: The overall unadjusted 5-year follow-up survival proportion was 82.6% for breast cancer, 55.7% for colorectal cancer, and 16.3% for lung cancer. Overall survival was associated with CCI>=3 in breast cancer (HR: 2.33 95%CI: 1.76-3.08), colorectal cancer (HR: 1.39; 95%CI: 1.13-1.70) and lung cancer (HR: 1.22; 95%CI: 1.06-1.40). In breast cancer, the higher the CCI, the higher the adjusted mortality rate ratio and differences were greater in 5-year than in 1-year follow-up survival. CONCLUSIONS: Comorbidity is a significant predictor of overall survival in cancer patients; however, it has a stronger impact on survival in breast cancer than in colorectal and lung cancer. PMID- 28586707 TI - Consensus-based guidelines for Video EEG monitoring in the pre-surgical evaluation of children with epilepsy in the UK. AB - PURPOSE: Paediatric Epilepsy surgery in the UK has recently been centralised in order to improve expertise and quality of service available to children. Video EEG monitoring or telemetry is a highly specialised and a crucial component of the pre-surgical evaluation. Although many Epilepsy Monitoring Units work to certain standards, there is no national or international guideline for paediatric video telemetry. METHODS: Due to lack of evidence we used a modified Delphi process utilizing the clinical and academic expertise of the clinical neurophysiology sub-specialty group of Children's Epilepsy Surgical Service (CESS) centres in England and Wales. This process consisted of the following stages I: Identification of the consensus working group, II: Identification of key areas for guidelines, III: Consensus practice points and IV: Final review. Statements that gained consensus (median score of either 4 or 5 using a five point Likerttype scale) were included in the guideline. RESULTS: Two rounds of feedback and amendments were undertaken. The consensus guidelines includes the following topics: referral pathways, neurophysiological equipment standards, standards of recording techniques, with specific emphasis on safety of video EEG monitoring both with and without drug withdrawal, a protocol for testing patient's behaviours, data storage and guidelines for writing factual reports and conclusions. All statements developed received a median score of 5 and were adopted by the group. CONCLUSION: Using a modified Delphi process we were able to develop universally-accepted video EEG guidelines for the UK CESS. Although these recommendations have been specifically developed for the pre-surgical evaluation of children with epilepsy, it is assumed that most components are transferable to any paediatric video EEG monitoring setting. PMID- 28586709 TI - The motor repertoire in 3- to 5-month old infants with Down syndrome. AB - BACKGROUND: Even though Down syndrome is the most common chromosomal cause of intellectual disability, studies on early development are scarce. AIM: To describe movements and postures in 3- to 5-month-old infants with Down syndrome and assess the relation between pre- and perinatal risk factors and the eventual motor performance. METHODS AND PROCEDURES: Exploratory study; 47 infants with Down syndrome (26 males, 27 infants born preterm, 22 infants with congenital heart disease) were videoed at 10-19 weeks post-term (median=14 weeks). We assessed their Motor Optimality Score (MOS) based on postures and movements (including fidgety movements) and compared it to that of 47 infants later diagnosed with cerebral palsy and 47 infants with a normal neurological outcome, matched for gestational and recording ages. OUTCOMES AND RESULTS: The MOS (median=13, range 10-28) was significantly lower than in infants with a normal neurological outcome (median=26), but higher than in infants later diagnosed with cerebral palsy (median=6). Fourteen infants with Down syndrome showed normal fidgety movements, 13 no fidgety movements, and 20 exaggerated, too fast or too slow fidgety movements. A lack of movements to the midline and several atypical postures were observed. Neither preterm birth nor congenital heart disease was related to aberrant fidgety movements or reduced MOS. CONCLUSIONS AND IMPLICATIONS: The heterogeneity in fidgety movements and MOS add to an understanding of the large variability of the early phenotype of Down syndrome. Studies on the predictive values of the early spontaneous motor repertoire, especially for the cognitive outcome, are warranted. WHAT THIS PAPER ADDS: The significance of this exploratory study lies in its minute description of the motor repertoire of infants with Down syndrome aged 3-5 months. Thirty percent of infants with Down syndrome showed age-specific normal fidgety movements. The rate of abnormal fidgety movements (large amplitude, high/slow speed) or a lack of fidgety movements was exceedingly high. The motor optimality score of infants with Down syndrome was lower than in infants with normal neurological outcome but higher than in infants who were later diagnosed with cerebral palsy. Neither preterm birth nor congenital heart disease were related to the motor performance at 3-5 months. PMID- 28586710 TI - Regulation of gastrulation movements by emergent cell and tissue interactions. AB - It is during gastrulation that the primordial germ layers are specified, embryonic axes become morphologically manifest, and the embryonic body plan begins to take shape. As morphogenetic movements push and pull nascent tissues into position within the gastrula, new interactions are established between neighboring cells and tissues. These interactions represent an emergent property within gastrulating embryos, and serve to regulate and promote ensuing morphogenesis that establishes the next set of cell/tissue contacts, and so on. Several recent studies demonstrate the critical roles of such interactions during gastrulation, including those between germ layers, along embryonic axes, and at tissue boundaries. Emergent tissue interactions result from - and result in - morphogen signaling, cell contacts, and mechanical forces within the gastrula. Together, these comprise a dynamic and complex regulatory cascade that drives gastrulation morphogenesis. PMID- 28586711 TI - An eye tracking system for monitoring face scanning patterns reveals the enhancing effect of oxytocin on eye contact in common marmosets. AB - Eye tracking systems are used to investigate eyes position and gaze patterns presumed as eye contact in humans. Eye contact is a useful biomarker of social communication and known to be deficient in patients with autism spectrum disorders (ASDs). Interestingly, the same eye tracking systems have been used to directly compare face scanning patterns in some non-human primates to those in human. Thus, eye tracking is expected to be a useful translational technique for investigating not only social attention and visual interest, but also the effects of psychiatric drugs, such as oxytocin, a neuropeptide that regulates social behavior. In this study, we report on a newly established method for eye tracking in common marmosets as unique New World primates that, like humans, use eye contact as a mean of communication. Our investigation was aimed at characterizing these primates face scanning patterns and evaluating the effects of oxytocin on their eye contact behavior. We found that normal common marmosets spend more time viewing the eyes region in common marmoset's picture than the mouth region or a scrambled picture. In oxytocin experiment, the change in eyes/face ratio was significantly greater in the oxytocin group than in the vehicle group. Moreover, oxytocin-induced increase in the change in eyes/face ratio was completely blocked by the oxytocin receptor antagonist L-368,899. These results indicate that eye tracking in common marmosets may be useful for evaluating drug candidates targeting psychiatric conditions, especially ASDs. PMID- 28586712 TI - Ultrasound shear wave elastography in the assessment of passive biceps brachii muscle stiffness: influences of sex and elbow position. AB - OBJECTIVE: To assess differences in biceps brachii muscle (BBM) stiffness as evaluated by ultrasound shear wave elastography (SWE). METHODS: The passive stiffness of the BBM was quantified with shear wave velocity (SWV) measurements obtained from 10 healthy volunteers (5 men and 5 women, mean age 50years, age range 42-63 years) with the elbow at full extension and 30 degrees flexion in this IRB-approved study. Potential differences between two depths within the muscle, two elbow positions, the two arms, and sexes were assessed by using two tailed t-test. The reproducibility of SWV measurements was tested by using intraclass correlation coefficient (ICC). RESULTS: Significantly higher passive BBM stiffness was found at full elbow extension compared to 30 degrees of flexion (p<=0.00006 for both arms). Significantly higher passive stiffness in women was seen for the right arm (p=0.04 for both elbow positions). Good correlation of shear wave velocity measured at the different depths. The ICC for interobserver and intraobserver variation was high. CONCLUSIONS: SWE is a reliable quantitative tool for assessing BBM stiffness, with differences in stiffness based on elbow position demonstrated and based on sex suggested. PMID- 28586713 TI - A randomized controlled trial of Internet-Based Cognitive Behavior Therapy for perfectionism including an investigation of outcome predictors. AB - Being highly attentive to details can be a positive feature. However, for some individuals, perfectionism can lead to distress and is associated with many psychiatric disorders. Cognitive behavior therapy has been shown to yield many benefits for those experiencing problems with perfectionism, but the access to evidence-based care is limited. The current study investigated the efficacy of guided Internet-based Cognitive Behavior Therapy (ICBT) and predictors of treatment outcome. In total, 156 individuals were included and randomized to an eight-week treatment or wait-list control. Self-report measures of perfectionism, depression, anxiety, self-criticism, self-compassion, and quality of life were distributed during screening and at post-treatment. Intention-to-treat were used for all statistical analyses. Moderate to large between-group effect sizes were obtained for the primary outcome measures, Frost Multidimensional Perfectionism Scale, subscales Concerns over Mistakes and Personal Standards, Cohen's d = 0.68 1.00, 95% Confidence Interval (CI) [0.36-1.33], with 35 (44.9%) of the patients in treatment being improved. Predictors were also explored, but none were related to treatment outcome. In sum, guided ICBT can be helpful for addressing problems with clinical perfectionism, but research of its long-term benefits is warranted. PMID- 28586714 TI - Towards a taxonomy of conjugative plasmids. AB - Conjugative plasmids are the keystone of horizontal gene transfer. Metagenomic research and clinical understanding of plasmid transmission beg for a taxonomical approach to conjugative plasmid classification. Up to now, a meaningful classification was difficult to achieve for lack of appropriate analytical tools. The advent of the genomic era revolutionized the landscape, offering a plethora of plasmid sequences as well as bioinformatic analytical tools. Given the need and the opportunity, in view of the available evidence, a taxonomy of conjugative plasmids is proposed in the hope that it will leverage plasmid studies. PMID- 28586715 TI - Hostility predicts alcohol consumption over a 21-year follow-up in the Gazel cohort. AB - BACKGROUND: Hostility has been found to be positively associated with alcohol intake in cross-sectional studies. Our aim was to examine prospectively the long lasting association of hostility with alcohol consumption. METHODS: We included 10,612 men and 3834 women from the French Gazel cohort with mean ages in 1993 of 48.6 (SD=2.9) and 45.7(SD=4.2), respectively. Hostility (i.e., total, cognitive and behavioral) was assessed in 1993 with the Buss and Durkee Hostility Inventory. Alcohol consumption was self-reported annually from 1994 to 2014. Hostility scores were introduced successively in general linear mixed models with annual alcohol consumption in drinks per week as dependent variable. Multivariable analyses were adjusted for age, occupational status, marital status, retirement status and depression score. All the analyses were stratified by sex. RESULTS: Among men (women), 83.0% (76.2%) completed at least 75% of all annual assessment of alcohol consumption over a 21-year follow-up. In univariate analysis, alcohol consumption was associated with total and behavioral hostility in both sex (all p<0.001). In multivariable analyses, these associations remained significant with a greater size effect for behavioral hostility. Estimated means of alcohol consumptions ranged from 10.50 [95CI%: 10.01-10.92] drinks per week to 13.32 [95%CI: 12.90-13.74] in men and from 4.09 [95%CI: 3.71-4.46] to 5.78 [95%CI: 5.39-6.17] in women, for the first and last quartiles respectively (p trends<0.001 and all pairwise comparisons<0.01). Similar effects were observed among participants with at-risk alcohol consumption at baseline. CONCLUSIONS: In both men and women, behavioral hostility predicted alcohol consumption over a 21 year follow-up. Interventions aiming at modulating behavioral hostility may help reducing its long-lasting influence on alcohol consumption. PMID- 28586716 TI - Design, synthesis and characterization of novel quinacrine analogs that preferentially kill cancer over non-cancer cells through the down-regulation of Bcl-2 and up-regulation of Bax and Bad. AB - Both quinacrine, which contains a 9-aminoacridine scaffold, and thiazolidin-4-one are promising anticancer leads. In an attempt to develop effective and potentially safe anticancer agents, we synthesized 23 novel hybrid compounds by linking the main structural unit of the 9-aminoacridine ring with the thiazolidin 4-one ring system, followed by examination of their anticancer effects against three human breast tumor cell lines and matching non-cancer cells. Most of the hybrid compounds showed good activities, and many of them possessed the preferential killing property against cancer over non-cancer cells. In particular, 3-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-2-(2,6-difluoro phenyl)-thiazolidin-4-one (11; VR118) effectively killed/inhibited proliferation of cancer cells at IC50 values in the range of 1.2-2.4 MUM. Furthermore, unlike quinacrine or cisplatin, compound 11 showed strong selectivity for cancer cell killing, as it could kill cancer cells 7.6-fold (MDA-MB231 vs MCF10A) to 14.7 fold (MCF7 vs MCF10A) more effectively than matching non-cancer cells. Data from flow cytometry, TUNEL and Western blot assays showed that compound 11 kills cancer cells by apoptosis through the down-regulation of Bcl-2 (but not Bcl-XL) survival protein and up-regulation of Bad and Bax pro-apoptotic proteins. Thus, compound 11 is a highly promising lead for an effective and potentially anticancer therapy. PMID- 28586717 TI - Conjugation of platinum(IV) complexes with chlorambucil to overcome cisplatin resistance via a "joint action" mode toward DNA. AB - Two platinum(IV) complexes were designed and prepared by conjugation of cisplatin and oxaliplatin units with a DNA-damaging agent, chlorambucil, respectively. By taking a joint action to enhance the damage of DNA, the conjugates displayed potent antitumor activity against all the tested cancer cell lines comparable to cisplatin and oxaliplatin, and notably could overcome cisplatin resistance at certain degree. Complex 4, a hybrid of cisplatin and chlorambucil, arrested the cell cycle at the S and G2 phases, distinctive from those of cisplatin and oxaliplatin. Apoptosis studies revealed that complex 4 could induce cell apoptosis significantly in both SGC7901 and SGC7901/CDDP cells. Moreover, further investigation indicated that complex 4 suppressed the drug resistance by the improvement of the platinum uptake and the inhibition of PRAP-1 protein. These results show that the "joint action" on DNA is an effective strategy to overcome cisplatin resistance. PMID- 28586718 TI - Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor. AB - Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC50 values of 0.025 MUM and 0.13 MUM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1H)-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 MUM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model. PMID- 28586719 TI - A heparin conjugate, LHbisD4, inhibits lymphangiogenesis and attenuates lymph node metastasis by blocking VEGF-C signaling pathway. AB - Clinical studies have found that the incidence of cancer metastasis through the lymphatic vessels are 3-5 times higher than that through the blood vessels. These findings suggest the potency of anti-lymphangiogenic therapy in reducing the incidence of cancer metastasis. Previously, we reported LHbisD4, which is the conjugate of low molecular weight heparin (LMWH) and four bis-deoxycholates as a potent anti-angiogenic drug with less toxicity and orally active property. Here, we show that LHbisD4 could also suppress the formation of new lymphatic vessels and attenuate the incidence of metastasis by blocking VEGF-C signaling pathway. LHbisD4 significantly enhanced binding affinity with VEGF-C when compared with LMWH, which enables LHbisD4 to suppress the proliferation, migration and formation of tubular structures of human dermal lymphatic endothelial cells(HDLECs) in in vitro condition even in the presence of excessive amounts of VEGF-C. Similarly, we found that the density of lymphatic vessels in the primary tumor tissue in breast cancer bearing mice was significantly diminished when LHbisD4 was administered compared with the control group. Also, the incidence of axillary lymph nodes and distant organ metastasis was significantly reduced in the LHbisD4 administered group, which demonstrates that LHbisD4 could successfully lower the incidence of metastasis through blocking VEGF-C induced lymphangiogenesis. Based on these results, we propose LHbisD4 as a potent anti cancer drug that can reduce the incidence of metastasis by suppressing lymphangiogenesis through blocking VEGF-C signaling pathway. PMID- 28586720 TI - Study of Galfenol direct cytotoxicity and remote microactuation in cells. AB - Remote microactuators are of great interest in biology and medicine as minimally invasive tools for cellular stimulation. Remote actuation can be achieved by active magnetostrictive transducers which are capable of changing shape in response to external magnetic fields thereby creating controlled displacements. Among the magnetostrictive materials, Galfenol, the multifaceted iron-based smart material, offers high magnetostriction with robust mechanical properties. In order to explore these capabilities for biomedical applications, it is necessary to study the feasibility of material miniaturization in standard fabrication processes as well as evaluate the biocompatibility. Here we develop a technology to fabricate, release, and suspend Galfenol-based microparticles, without affecting the integrity of the material. The morphology, composition and magnetic properties of the material itself are characterized. The direct cytotoxicity of Galfenol is evaluated in vitro using human macrophages, osteoblast and osteosarcoma cells. In addition, cytotoxicity and actuation of Galfenol microparticles in suspension are evaluated using human macrophages. The biological parameters analyzed indicate that Galfenol is not cytotoxic, even after internalization of some of the particles by macrophages. The microparticles were remotely actuated forming intra- and extracellular chains that did not impact the integrity of the cells. The results propose Galfenol as a suitable material to develop remote microactuators for cell biology studies and intracellular applications. PMID- 28586721 TI - Antibacterial and antibiofilm activities of the metabolites isolated from the culture of the mangrove-derived endophytic fungus Eurotium chevalieri KUFA 0006. AB - Five previously undescribed metabolites, including acetylquestinol, two prenylated indole 3-carbaldehyde derivatives, an anthranilic acid derivative and an isochromone derivative, were isolated, in addition to eleven known compounds: palmitic acid, ergosterol 5,8-endoperoxide, emodin, physcion, questin, questinol, (11S, 14R)-cyclo(tryptophylvalyl), preechinulin, neoechinulin E, echinulin and eurocristatine, from the culture of the endophytic fungus Eurotium chevalieri KUFA 0006. The structures of the previously undescribed compounds were established based on an extensive 1D and 2D NMR spectral analysis as well as HRMS and IR data. In case of 2-(2, 2-dimethylcyclopropyl)-1H-indole-3-carbaldehyde and 6, 8-dihydroxy-3-(2S-hydroxypropyl)-7-methylisochromone, the absolute configurations of their stereogenic carbons were established based on comparison of their experimental and calculated ECD spectra. All the compounds, except for palmitic acid and ergosterol 5, 8-endoperoxide, were evaluated for their antibacterial and antibiofilm activities against two Gram-positive and two Gram negative bacteria, as well as multidrug-resistant isolates from the environment. Emodin not only exhibited moderate antibacterial activity against the Gram positive bacteria but also showed strong synergistic association with oxacillin against MRSA Staphylococcus aureus. PMID- 28586722 TI - Childhood obesity and maternal education in Ireland. AB - This paper analyses the socioeconomic gradient of childhood obesity in Ireland using the Growing Up in Ireland data with three innovations compared to previous work in the area. A different measure of socioeconomic status, maternal education, is employed. In addition, the depth and severity of obesity are examined as well as the incidence. Finally, the use of two waves of longitudinal data permits the analysis of the persistence of obesity. Results show that overall childhood obesity stabilised between the two waves. However the socioeconomic gradient becomes steeper in wave 2 for girls and in particular when depth, severity and persistence of obesity are accounted for. Girls whose mothers fail to complete secondary education are shown to be at a particular disadvantage. PMID- 28586724 TI - Sub-1min separation in sequential injection chromatography for determination of synthetic water-soluble dyes in pharmaceutical formulation. AB - Sequential Injection Chromatography (SIC) evolved from fast and automated non separation Sequential Injection Analysis (SIA) into chromatographic separation method for multi-element analysis. However, the speed of the measurement (sample throughput) is due to chromatography significantly reduced. In this paper, a sub 1min separation using medium polar cyano monolithic column (5mm*4.6mm) resulted in fast and green separation with sample throughput comparable with non separation flow methods The separation of three synthetic water-soluble dyes (sunset yellow FCF, carmoisine and green S) was in a gradient elution mode (0.02% ammonium acetate, pH 6.7 - water) with flow rate of 3.0mLmin-1 corresponding with sample throughput of 30h-1. Spectrophotometric detection wavelengths were set to 480, 516 and 630nm and 10Hz data collection rate. The performance of the separation was described and discussed (peak capacities 3.48-7.67, peak symmetries 1.72-1.84 and resolutions 1.42-1.88). The method was represented by validation parameters: LODs of 0.15-0.35mgL-1, LOQs of 0.50-1.25mgL-1, calibration ranges 0.50-150.00mgL-1 (r>0.998) and repeatability at 10.0mgL-1 of RSD<=0.98% (n=6). The method was used for determination of the dyes in "forest berries" colored pharmaceutical cough-cold formulation. The sample matrix - pharmaceuticals and excipients were not interfering with vis determination because of no retention in the separation column and colorless nature. The results proved the concept of fast and green chromatography approach using very short medium polar monolithic column in SIC. PMID- 28586723 TI - Validation of liquid and gaseous calibration techniques for quantification of propofol in breath with sorbent tube Thermal Desorption System GC-MS. AB - Plasma concentrations of intravenous drugs cannot currently be evaluated in real time to guide clinical dosing. However, a system for estimating plasma concentration of the anesthetic propofol from exhaled breath may soon be available. Developing reliable calibration and analytical validation techniques is thus necessary. We therefore compared the established sorbent tube liquid injection technique with a gas injection procedure using a reference gas generator. We then quantified propofol with Tenax sorbent tubes in combination with gas-chromatography coupled mass spectrometry in the breath of 15 patients (101 measurements). Over the clinically relevant concentration range from 10 to 50 ppbv, coefficient of determination was 0.995 for gas calibration; and over the range from 10 to 100ng, coefficient of determination was 0.996 for liquid calibration. A regression comparing gas to liquid calibration had a coefficient of determination of 0.89; slope 1.05+/-0.01 (standard deviation). The limit of detection was 0.74ng and the lower limit of quantification was 1.12ng for liquid; the limit of detection was 0.90 ppbv and the lower limit of quantification was 1.36 ppbv for gas. Loaded sorbent tubes were stable for at least 14days without significant propofol loss as determined with either method. Measurements from liquid or gas samples were comparably suitable for evaluation of patient breath samples. PMID- 28586725 TI - Cadmium, arsenic, selenium and iron- Implications for tumor progression in breast cancer. AB - The aim of this study was to determine Cd (cadmium) and As (arsenic) contents in human breast cancer tissues, investigate their interactions with Se (selenium) and Fe (iron), and assess their further implications for tumor progression. Metal contents were determined in 42 tissue sets (tumor and adjacent tissue) collected from 42 women diagnosed with primary breast cancer. Analytical methods included AAS and ICP-MS techniques. Significantly higher contents of Cd (p=0.0003), Se (p<0.0001) and Fe (p=0.0441) whereas significantly lower content of As (p<0.0001) were observed in tumors as compared to adjacent tissues. There was a significant positive correlation between Cd and As contents in tumor tissue. However, only Cd was significantly associated with histological type of tumor, its size, grading and progesterone receptor status. This study support the role of Cd in breast cancer risk and progression. The possible link between As exposure and breast cancer is still not clear. PMID- 28586726 TI - Evaluation of cytotoxicity of hematite nanoparticles in bacteria and human cell lines. AB - Metal nanoparticles have a great impact and even change the composition of soil microbial communities. This poses the risk of their accumulation in the ecosystem, which may call on health hazard. Statistical techniques such as Plackett-Burman design, Response Surface Methodology were used for optimizing medium constituents for Bacillus cereus SVK1 and other critical variables responsible for the production of biomolecules and biosynthesis of hematite nanoparticles. The effect of hematite nanoparticles on the growth of soil bacteria were tested by agar-well diffusion method and dynamic growth curve techniques. Bacterial growth inhibition was not observed with hematite nanoparticle concentration of up to 25mg/mL. In addition, hematite nanoparticles enhanced the growth of the soil bacteria. The results show that hematite nanoparticles were non-toxic to soil bacteria indicating their scope for wide range of applications. The effective cytotoxic concentration (CTC50) of hematite nanoparticles against MCF-7, A549, Hep3B and Vero cell lines was found to be 207.58, 224.69, 193.26 and 2530MUg/mL respectively. Hematite nanoparticles didn't cause lysis of red blood cells. PMID- 28586729 TI - Biocompatible zwitterionic phosphorylcholine polymers with aggregation-induced emission feature. AB - Two novel zwitterionic phosphorylcholine polymers (MTP1 and MTP2) with aggregation-induced emission (AIE) feature were prepared through reversible addition fragmentation chain transfer polymerization between an AIE monomer with vinyl end group and a zwitterionic phosphorylcholine monomer. The synthesized copolymers were characterized and confirmed by 1H NMR, FT-IR, and X-ray photoelectron spectra. By introduction of the zwitterionic phosphorylcholine component, the synthesized copolymers showed amphiphilic properties and tended to self-assemble into fluorescent polymeric nanoparticles (FPNs) in water. The dynamic light scattering results indicated the size distribution of the MTP1 FPNs was 345+/-22nm, and that of the MTP2 FPNs was 147+/-36nm. The transmission electron microscopy results demonstrated spherical nanoparticle morphology for the FPNs. The high dispersibility of the FPNs in water was proved by the UV-vis absorption study with high transmittance of the solution. Fluorescent spectra of the prepared FPNs revealed bright green fluorescence with high fluorescence quantum yield of 45% for MTP1 and 34% for MTP2. More importantly, the FPNs showed excellent particle stability with low critical micelle concentration of 0.008mgmL 1 for MTP1 and 0.007mgmL-1 for MTP2. The cytotoxicity evaluation confirmed high cytocompatibility of the prepared FPNs at different concentrations, and demonstrated excellent biocompatibility for cell imaging. In virtue of the high performance MTP1 and MTP2 FPNs, including high water dispersion, good particle stability, and excellent cytocompatibility, this work would inspire more researches about high-performance biocompatible fluorescent polymers for biomedical application. PMID- 28586730 TI - A multifunctional organosilica cross-linker for the bio-conjugation of gold nanorods. AB - We report on the use of organosilica shells to couple gold nanorods to functional peptides and modulate their physiochemical and biological profiles. In particular, we focus on the case of cell penetrating peptides, which are used to load tumor-tropic macrophages and implement an innovative drug delivery system for photothermal and photoacoustic applications. The presence of organosilica exerts subtle effects on multiple parameters of the particles, including their size, shape, electrokinetic potential, photostability, kinetics of endocytic uptake and cytotoxicity, which are investigated by the interplay of colorimetric methods and digital holographic microscopy. As a rule of thumb, as the thickness of organosilica increases from none to ~30nm, we find an improvement of the photophysical performances at the expense of a deterioration of the biological parameters. Therefore, detailed engineering of the particles for a certain application will require a careful trade-off between photophysical and biological specifications. PMID- 28586727 TI - Cobalt and titanium nanoparticles influence on mesenchymal stem cell elasticity and turgidity. AB - Bone cells are damaged by wear particles originating from total joint replacement implants. We investigated Mesenchymal stem cells (MSCs) nanomechanical properties when exposed to cobalt and titanium nanoparticles (resembling wear debris) of different sizes for up to 3days using AFM nanoindentation; along with flow cytometry and MTT assay. The results demonstrated that cells exposed to increasing concentrations of nanoparticles had a lower value of elasticity and spring constant without significant effect on cell metabolic activity and viability but some morphological alteration (bleeping). Cobalt induced greater effects than titanium and this is consistent with the general knowledge of cyto compatibility of the later. This work demonstrates for the first time that metal nanoparticles do not only influence MSCs enzymes activity but also cell structure; however, they do not result in full membrane damage. Furthermore, the mechanical changes are concentration and particles composition dependent but little influenced by the particle size. PMID- 28586728 TI - Adhesion of Bacillus subtilis and Pseudoalteromonas lipolytica to steel in a seawater environment and their effects on corrosion. AB - In a marine environment, Bacillus subtilis and Pseudoalteromonas lipolytica are commonly found in the biofilms adherent to low-alloy engineering steel, and they have distinct effects on corrosion. In the present work, this phenomenon was investigated through the study of various materials characterization methods, electrochemical techniques, and contact angle measurements. It was found that the surface film formed on the steel in the presence of B. subtilis was compact, uniform, free of cracks, and hydrophobic. However, the film formed in the presence of P. lipolytica was loose, rough, heterogeneous, and hydrophilic. The main components of the films formed in the presence of B. subtilis and P. lipolytica were polysaccharides/TasA amyloid fibers and proteins/carboxylic acid, respectively. The composition, structure, and properties of the surface films formed on the steel were associated with different effects on corrosion. The presence of B. subtilis enhances the steel's resistance to corrosion, whereas corrosion was increased by the presence of P. lipolytica. In short, the compact and hydrophobic biofilm of B. subtilis appears to inhibit the corrosion of steel, while the loose, hydrophilic film of P. lipolytica tends to induce pitting corrosion. PMID- 28586731 TI - Cellular interactions of zinc oxide nanoparticles with human embryonic kidney (HEK 293) cells. AB - Zinc oxide nanoparticles (ZnO NPs) have potential biomedical, industrial and commercial applications. So they constantly come into contact with the body parts during applications. Safety concerns about ZnO NPs are increasing today and yet only few reports are available about their toxicity in kidney cells. It is very essential to analyze the toxicity on kidney because kidney plays a decisive role in nanoparticles excretion. Therefore, the present study focuses on the interaction of ZnO NPs with human embryonic kidney 293 (HEK 293) cells in vitro. The results showed that the cellular viability was much affected by ZnO NPs in a dose and time dependent manner. Oxidative stress increased the formation of reactive oxygen species (ROS), was found to be the prime mechanism of cytotoxicity. Formation of ROS eventually induced loss of mitochondrial membrane potential, lysosomal activity and nuclear condensation, which ultimately leads to apoptosis. PMID- 28586733 TI - The influence of vegetation, mesoclimate and meteorology on urban atmospheric microclimates across a coastal to desert climate gradient. AB - Many cities are increasing vegetation in part due to the potential for microclimate cooling. However, the magnitude of vegetation cooling and sensitivity to mesoclimate and meteorology are uncertain. To improve understanding of the variation in vegetation's influence on urban microclimates we asked: how do meso- and regional-scale drivers influence the magnitude and timing of vegetation-based moderation on summertime air temperature (Ta), relative humidity (RH) and heat index (HI) across dryland cities? To answer this question we deployed a network of 180 temperature sensors in summer 2015 over 30 high- and 30 low-vegetated plots in three cities across a coastal to inland to desert climate gradient in southern California, USA. In a followup study, we deployed a network of temperature and humidity sensors in the inland city. We found negative Ta and HI and positive RH correlations with vegetation intensity. Furthermore, vegetation effects were highest in evening hours, increasing across the climate gradient, with reductions in Ta and increases in RH in low-vegetated plots. Vegetation increased temporal variability of Ta, which corresponds with increased nighttime cooling. Increasing mean Ta was associated with higher spatial variation in Ta in coastal cities and lower variation in inland and desert cities, suggesting a climate dependent switch in vegetation sensitivity. These results show that urban vegetation increases spatiotemporal patterns of microclimate with greater cooling in warmer environments and during nighttime hours. Understanding urban microclimate variation will help city planners identify potential risk reductions associated with vegetation and develop effective strategies ameliorating urban microclimate. PMID- 28586732 TI - The virtual approach to the assessment of skeletal injuries in human skeletal remains of forensic importance. AB - While assessing skeletal injuries in human skeletal remains, forensic anthropologists are frequently presented with fractured, fragmented, or otherwise modified skeletal remains. The examination of evidence and the mechanisms of skeletal injuries often require that separate osseous elements be permanently or temporarily reassembled or reconstructed. If not dealt with properly, such reconstructions may impede accurate interpretation of the evidence. Nowadays, routine forensic examinations increasingly incorporate digital imaging technologies. As a result, a variety of PC-assisted imaging techniques, collectively referred to as the virtual approach, have been made available to treat fragmentary skeletal remains. The present study employs a 3D virtual approach to assess mechanisms of skeletal injuries, and provides an expert opinion of causative tools in three forensic cases involving human skeletal remains where integrity was compromised by multiple peri- or postmortem alterations resulting in fragmentation and/or incompleteness. Three fragmentary skulls and an incomplete set of foot bones with evidence of perimortem fractures (gunshot wounds) and sharp force trauma (saw marks) were digitized using a desktop laser scanner. The digitized skeletal elements were reassembled in the virtual workspace using functionalities incorporated in AMIRA(r) version 5.0 software, and simultaneously in real physical space by traditional reconstructive approaches. For this study, the original skeletal fragments were substituted by replicas built by 3D printing. Inter-method differences were quantified by mesh based comparison after the physically reassembled elements had been re-digitized. Observed differences were further reinforced by visualizing local variations using colormaps and other advanced 3D visualization techniques. In addition, intra-operator and inter-operator error was computed. The results demonstrate that the importance of incorporating the virtual approach into the assessment of skeletal injuries increases with the complexity and state of preservation of a forensic case. While in relatively simple cases the virtual approach is a welcome extension to a traditional approach, which merely facilitates the analysis, in more complex and extensively fragmentary cases such as multiple gunshot wounds or dismemberment, the virtual approach can be a crucial step in applying the principles of gunshot wounds or sharp force traumatic mechanisms. The unrestricted manipulation with digital elements enabling limitless repairs and adjustments to a "best-case scenario" also produced smaller inter-operator variation in comparison to the traditional approach. PMID- 28586734 TI - Sorption of Cu by humic acid from the decomposition of rice straw in the absence and presence of clay minerals. AB - The sorption of Cu on humic acid (HA) from the decomposition of rice straw in the absence (Ck-HA) and presence of montmorillonite (M-HA), kaolinite (K-HA), gibbsite (Gi-HA) and goethite (Go-HA) was investigated at pH 5.0 by using batch studies combined with isothermal titration calorimetry (ITC) and atomic force microscopy (AFM). Characterization by elemental analysis and potentiometric titration showed the composition difference among these five HA. The sorption capacity and rate increased in the order: M-HA < K-HA < Gi-HA < Ck-HA < Go-HA. ITC results revealed that the sorption process was spontaneous and endothermic. The aggregation of HA particles after sorption were observed by AFM images. The influence of pH and positive correlations between the sorption capacity and the content of acidic functional groups of HA indicated that the dissociated acidic functional groups, especially the dissociation of carboxylic groups in HA played an important role in Cu sorption. Sequential desorption of sorbed Cu showed that the surface bonded fraction (97.6-99.0%) was significantly higher than the ion exchanged fraction (1.0-2.4%). Markedly positive entropies (DeltaS, 94.4-104.3 J mol-1 K-1) further demonstrated that Cu binding to HA by forming inner-sphere complexes. The findings of this study would promote the understanding on the environmental impact of the decomposition of organic waste from agricultural production. PMID- 28586735 TI - Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer - Results from the prospective German TMK cohort study. AB - Data on treatment and outcome of advanced breast cancer in routine practice are rare, especially concerning recurrent disease, but important to complement the results from clinical trials and to improve the standard of care. We present data on choice of systemic first-line treatment, number of treatment lines, and survival of patients treated by medical oncologists in Germany. 1395 patients recruited by 124 sites at start of first-line therapy into the ongoing, prospective German clinical cohort study TMK (Tumour Registry Breast Cancer) between February 2007 and October 2015 were analysed. The median OS was 33.8 months (95% CI 30.2-40.2) for HR-positive/HER2-negative, 38.2 months (95% CI 31.3 43.0) for HER2-positive and 16.8 months (95% CI 11.5-22.0) for triple negative breast cancer. Patients with triple negative tumours more often died before start of a third-line therapy than patients with HR-positive or HER2-positive tumours (44% vs. 25%). Use of taxane-based chemotherapies has increased since 2007, with 65% of all first-line chemotherapy-treatments containing taxanes in 2013-15 (60% HR-positive/HER2-negative, 75% HER2-positive, 56% triple negative). 52% of the patients with HR-positive/HER2-negative tumours received first-line endocrine therapy in 2013-15; when restricted to patients with only non-visceral metastases this percentage increased to 63%. To our knowledge, this is the first cohort study showing systemic first-line therapy for all subtypes of advanced breast cancer. Overall survival in the TMK is comparable to that reported by clinical trials despite the inclusion of older and comorbid patients. PMID- 28586737 TI - Efficient reductive elimination of bromate in water using zero-valent zinc prepared by acid-washing treatments. AB - Although zero valent zinc (ZVZ) is a strong reductant, studies using ZVZ for bromate reduction are rare. In this study, ZVZ is prepared by acid-washing zinc powder with HCl and used to reduce bromate. The effect of acid-washing on the morphology of zinc powder is also examined. Zinc powder inefficiently reduces bromate, but ZVZ obtained by acid-washing zinc powder eliminates bromate and converts it to bromide. A higher dose of ZVZ enhances elimination efficiency perhaps because the formation of a passivation layer of zinc oxide could be scattered on the large surface of ZVZ. Elevated temperature also substantially improves both elimination efficiency and kinetics. The effect of pH is shown to have the most significant impact on the bromate elimination; elimination efficiency and kinetics are tremendously bolstered at pH = 3, whereas the elimination of bromate is completely suppressed under alkaline conditions. ZVZ can reduce bromate to bromide even in the presence of other anions and also be reused multiple times. Thus, ZVZ can be easily prepared and used to efficiently reduce bromate to bromide. The findings presented here are essential to the design and implementation of bromate elimination in water using zero-valent metals. PMID- 28586738 TI - Fast MinMax energy-based phase correction method for NMR spectra with linear phase distortion. AB - This paper addresses the problem of phase correction of dense NMR spectra on the example of the etoxy derivative of the fused heterocyclic system 5,6,10b triazaacephenanthrylene (TAAP-OEt). A new estimation method for the linear phase correction coefficients is proposed that successfully extends the min-max (minimization of maximum errors) approach of Siegel (1981). Distinctive to the Siegel method, the smallest values of the real part of the discrete Fourier transform (DFT) spectrum are maximized, not for the whole spectrum but only for DFT bins near the peaks selected by anew energy-based criterion. Additionally, the method makes use of two one-parameter optimizations for finding the phase correction line coefficients and not the single two-parameter search. The new method is demonstrated to be precise, fast and robust against additive noise. The method's properties are verified in comparison with the state-of-the-art algorithms of Chen et al. (2002) and Bao et al. (2013) for laboratory recorded TAAP-OEt FID data and for simulated TAAP-OEt signal consisting of the sum of more than 100 complex damped exponentials. Extensive simulations were also conducted on the set of test signals derived from the TAAP-OEt signal by deterministic and pseudorandom manipulation of its content. The components of the signal model were identified by the Bertocco-Yoshida Interpolated DFT (IpDFT) algorithm with a spectral leakage correction. Simulated signals were embedded in the additive Gaussian noise, and the noise-robustness of all of the algorithms was evaluated. The obtained results demonstrate that the proposed method outperforms the Chen and the Bao algorithms, being more than 100 times faster than the Bao method (for a signal having 216 samples). PMID- 28586736 TI - Mixed surfactant systems of sucrose esters and lecithin as a synergistic approach for oil structuring. AB - In order to modify the self-assembly of sucrose esters (SEs) in sunflower oil, we added sunflower lecithin (SFL) as co-surfactant. It is hypothesized that SFL modifies the self-assembly of SEs by interrupting the extensive hydrogen bonding between SEs monomers. The addition of SFL into SEs induced gelation of the mixed surfactant system oleogels at all studied ratios. The 7:3 SEs:SFL combination showed enhanced rheological properties compared to the other studied ratios, which suggests better molecular ordering induced by SFL. The modifications might have been caused by interference in the hydrogen bonding, connecting the polar heads of SEs molecules in the presence of SFL. This effect was confirmed by thermal behavior and small angle X-ray diffraction (SAXD) analysis. From the crystallization and melting analyses, it was shown that the peak temperature, shape and enthalpy decreased as the SFL ratio increases. Meanwhile, the bi component oleogels exhibited new peaks in the SAXD profile, which imply a self assembly modification. The microscopic study through polarized and electrons revealed a change in the structure. Therefore, it can be concluded that a synergistic effect between SEs and SFL, more particularly at 7:3 ratio, towards sunflower oil structuring could be obtained. These findings shed light for greater applications of SEs as structuring and carrier agent in foods and pharmaceutical. PMID- 28586739 TI - A method for longitudinal relaxation time measurement in inhomogeneous fields. AB - The spin-lattice relaxation time (T1) plays a crucial role in the study of spin dynamics, signal optimization and data quantification. However, the measurement of chemical shift-specific T1 constants is hampered by the magnetic field inhomogeneity due to poorly shimmed external magnetic fields or intrinsic magnetic susceptibility heterogeneity in samples. In this study, we present a new protocol to determine chemical shift-specific T1 constants in inhomogeneous fields. Based on intermolecular double-quantum coherences, the new method can resolve overlapped peaks in inhomogeneous fields. The measurement results are in consistent with the measurements in homogeneous fields using the conventional method. Since spatial encoding technique is involved, the experimental time for the new method is very close to that for the conventional method. With the aid of T1 knowledge, some concealed information can be exploited by T1 weighting experiments. PMID- 28586740 TI - Umbelliferone arrest cell cycle at G0/G1 phase and induces apoptosis in human oral carcinoma (KB) cells possibly via oxidative DNA damage. AB - Umbelliferone (UMB) has widespread pharmacological activity, comprising anti inflammatory, anti-oxidant, anti-genotoxic and anti-immunomodulatory but the anticancer activity remains unknown in human oral carcinoma (HOC) KB cells. MTT assay determinations was revealed that treatment of KB cells with UMB, prevent and reduce the cell proliferation with the IC50 - 200MUM as well as induces loss of cell viability, morphology change and internucleosomal DNA fragmentation in a concentration dependent manner. Acridine orange and ethidium bromide dual staining assay established that UMB induced apoptosis in KB cells in a dose dependent manner. Alkaline comet assay determination revealed UMB has the potential to increase oxidative DNA damage in KB cells through DNA tail formation significantly (p<0.05). Furthermore, UMB brought a dose-dependent elevation of reactive oxygen species (ROS), which is evidenced by the DCF fluorescence, altered the mitochondrial membrane potential in KB cells. Similarly, we observed increased DNA damage stimulated apoptotic morphological changes in UMB treated cells. Taken together, the present study suggests that UMB exhibits anticancer effect on KB cell line with the increased generation of intracellular ROS, triggered oxidative stress mediated depolarization of mitochondria, which contributes cell death via DNA damage as well as cell cycle arrest at G0/G1 phase. The results have also provided us insight in the pharmacological backgrounds for the potential use of UMB, to target divergent pathways of cell survival and cell death. To conclude UMB could develop as a novel candidate for cancer chemoprevention and therapy, which is our future focus and to develop a connectivity map between in vivo and in vitro activity. PMID- 28586741 TI - Libidibia ferrea presents antiproliferative, apoptotic and antioxidant effects in a colorectal cancer cell line. AB - Colorectal cancer is noted for being one of the most frequent of tumors, with expressive morbidity and mortality rates. In new drug discovery, plants stand out as a source capable of yielding safe and high-efficiency products. Well known in Brazilian popular medicine, Libidibia ferrea (Mart. Ex Tul.) L.P. Queiroz var. ferrea (better known as "ironwood" or "juca"), has been used to treat a wide spectrum of conditions and to prevent cancer. Using methodologies that involved flow cytometry, spectrophotometry and RT-qPCR assays, crude extracts of the fruits of L. ferrea (20T, 40T, 60T and 80T) were evaluated at 24h and/or 48h for: their ability to inhibit cell proliferation; induce apoptosis through Bcl-2, caspase-3 and Apaf-1; their antioxidant activity and effects on important targets related to cell proliferation (EGFR and AKT) in the HT-29 human colorectal cancer lineage. The results revealed high antiproliferative potential as compared to the controls, induction of apoptosis through the intrinsic pathway, and probable tumor inhibition activity under the mediation of important targets in tumorigenesis. In addition, L. ferrea revealed antioxidant, lipid peroxidation and chemoprotective effects in healthy cells. Thus, L. ferrea derivatives have important anticancer effects, and may be considered promising candidate for colorectal cancer therapy. PMID- 28586742 TI - A network meta-analysis for efficacy and safety of seven regimens in the treatment of type II diabetes. AB - The efficacy and safety of seven regimens based on metformin (placebo plus metformin, dapagliflozin plus metformin, vildagliptin plus metformin, saxagliptin plus metformin, empagliflozin plus metformin, exenatide plus metformin and sitagliptin plus metformin) on type 2 diabetes (T2D) were compared based on network meta-analysis. PubMed, Embase and Cochrane Library were applied in the computer-based retrieval process. Randomized controlled trials (RCTs) which were related with the above seven regimens based on metformin in the treatment of T2D were included in this study. Network meta-analysis merged the direct and indirect comparison evidence for the estimation of the weighted mean difference (WMD), odd ratios (ORs) and surface under the cumulative sequencing ranking curve (SUCRA) values. Eight eligible RCTs were applied in this network meta-analysis. The results demonstrated that: in terms of efficacy, the glycated hemoglobin (HbA1c) levels of T2D patients receiving vildagliptin plus metformin were relatively lower when compared with placebo plus metformin (WMD=-1.95, 95%CI=-3.70--0.23); in comparison with exenatide plus metformin, the triglyceride level in T2D patients taking vildagliptin plus metformin remained relatively lower (WMD=-1.36, 95%CI=-2.64--0.01). In terms of safety, the rate of adverse events in patients with T2D who received empagliflozin plus metformin was relatively lower when compared with saxagliptin plus metformin (OR=0.37, 95%CI=0.14-0.98). Furthermore, the SUCRA value of vildagliptin plus metformin was comparatively higher in efficacy, and that the SUCRA value of saxagliptin plus metformin was relatively lower in safety. The efficacy of vildagliptin plus metformin in patients with T2D is relatively better, while the safety of saxagliptin plus metformin in patients with T2D is relatively poorer. PMID- 28586743 TI - Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals. AB - Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits. The animals were made epileptic employing pentylenetetrazole (35mg/kg i.p. every 48+/-2h) kindling model of epilepsy and subsequently were treated with vehicle, valproic acid (300mg/kg/day i.p.) and agmatine (2.5, 5, and 10mg/kg)/day/i.p. for 15days. Except naive, all the groups were challenged with same pentylenetetrazole dose as employed during kindling on days 5, 10, and 15 to evaluate seizure severity. Two hours after seizure severity test, tail suspension test and passive shock avoidance paradigm was employed to evaluate depression and cognitive behavior respectively. Results suggested that epileptic animals were significantly associated with depression and cognitive impairment. Chronic valproate treatment significantly reduced seizure severity, but was found unable to mitigate depression and cognitive deficits. However, agmatine treatment dose dependently ameliorated seizure severity as well as associated depression and cognitive deficits. On 15th day, animals were euthanized and pertinent neurochemical estimations were carried out in cortical and hippocampal areas of the mice brain. Thus, study concluded that agmatine ameliorated seizure severity, depression and cognitive impairment in epileptic animals, possibly via restoring glutamate-GABA neurotransmission and serotonin synthesis with decreased nitrosative stress. PMID- 28586744 TI - Protective effects of green tea on olanzapine-induced-metabolic syndrome in rats. AB - Atypical antipsychotics particularly olanzapine are associated with obesity and serious metabolic disturbances. As green tea (Camellia sinensis) is generally associated with beneficial effects on obesity and other metabolic disturbances, this study was undertaken to evaluate the effect of green tea aqueous extract (GTAE) on olanzapine induced weight gain and metabolic abnormalities in rats. Male Wistar rats were divided into eight groups: control, olanzapine (5mg/kg/day, IP.), GTAE (25, 50 and 100mg/kg/day, IP.) plus olanzapine and GTAE (25, 50 and 100mg/kg/day, IP.). Treatments were continued for 11 days. Body weight gain, average food and water intake were measured during the experiment. Plasma lipid, glucose and leptin levels, mean systolic blood pressure and total locomotion were evaluated at the end of experiment. Olanzapine induced significant weight gain at the end of treatment (10.38% of body weight) when compared to control (3.13% of body weight) in male Wistar rats. Average food and water intake were increased by olanzapine treatment. 11days olanzapine administration led to hyperleptinemia, hyperglycemia and dyslipidemia. Olanzapine also increased mean systolic blood pressure and decreased total locomotion. GTAE decreased significantly body weight gain and average food and water intake, improved the changes in lipid profile as well as fasting blood glucose, and finally decreased hyperleptinemia and hypertension induced by olanzapine. Results of this study demonstrated that GTAE could exert protective effects against olanzapine induced obesity partially due to its lowering effect on leptin. GTAE improved other metabolic abnormalities including dyslipidemia, hyperglycemia and hypertension induced by olanzapine in rats. PMID- 28586745 TI - (-)-Kusunokinin and piperloguminine from Piper nigrum: An alternative option to treat breast cancer. AB - Several studies have reported that active compounds isolated from Piper nigrum possess anticancer properties. However, there are no data on anticancer activity of (-)-kusunokinin and piperlonguminine. The purposes of this study were to isolate active compounds from P. nigrum and identify the molecular mechanisms underlying growth and apoptosis pathway in breast cancer cells. Two bioactive compounds, (-)-kusunokinin and piperlonguminine, were isolated from P. nigrum. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Western blot analysis. We found that the active compounds, which effect cancer cell lines were (-)-kusunokinin and piperlonguminine. These compounds have potent cytotoxic effects on breast cancer cells (MCF-7 and MDA-MB-468) and colorectal cells (SW-620). (-)-Kusunokinin demonstrated a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.18 and 1.62MUg/mL, respectively. Piperlonguminine had a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.63 and 2.19MUg/mL, respectively. Both compounds demonstrated lower cytotoxicity against normal breast cell lines with IC50 values higher than 11MUg/mL. Cell cycle and apoptotic analysis using flow cytometry, showed that the (-)-kusunokinin and piperlonguminine induced cell undergoing apoptosis and drove cells towards the G2/M phase. Moreover, both compounds decreased topoisomerase II and bcl-2. The increasing of p53 levels further increased p21, bax, cytochrome c, caspase-8, -7 and -3 activities, except caspase-9. These results suggest that the (-)-kusunokinin and piperlonguminine have been shown to have potent anticancer activities through extrinsic pathway and G2/M phase arrest. PMID- 28586746 TI - Biochar reduces the bioaccumulation of PAHs from soil to carrot (Daucus carota L.) in the rhizosphere: A mechanism study. AB - The aim of this study was to reveal the mechanisms on how biochar reduces bioaccumulation of polycyclic aromatic hydrocarbons (PAHs) in tuberous vegetables. Corn straw-derived biochar pyrolyzed at 300 degrees C (CB300) or bamboo-derived biochar pyrolyzed at 700 degrees C (BB700) was amended into PAH contaminated soil planted with carrot (Daucus carota L.). After 150days, 2% CB300 or 2% BB700 amendments significantly reduced the bioaccumulation of PAHs in carrot root (p<0.05), especially for high-molecular-weight PAHs. In the non rhizosphere, either CB300 or BB700 suppressed PAH dissipation and decreased the bioavailability via adsorption processes. Compared to the control, the total concentration of PAHs in the rhizosphere was higher in the 2% BB700 treatment but the bioavailable concentration was lower. This indicates that BB700 decreased the bioavailability of PAHs primarily via immobilization (adsorption processes). By contrast, the total and bioavailable PAH concentrations were both lower in the 2% CB300 treatment than those in the control. The abundance of bacteria such as Arthrobacter and Flavobacterium and the total number of genes playing important roles in microbial PAH degradation processes increased significantly (p<0.05), which were likely responsible for the rapid dissipation of PAHs in the 2% CB300 treatment in the rhizosphere. These results indicate that CB300 decreased the PAH bioavailability primarily via increasing degradation of PAHs by indigenous microorganisms. The two biochars both showed better effectiveness at reducing the bioavailability of high-molecular-weight PAHs than the low-molecular-weight PAHs in the rhizosphere. Therefore, the mechanisms on how biochar reduces the PAH uptake into carrot are dependent on the type of biochar (e.g., pyrolysis temperature and feedstock) and root presence. PMID- 28586747 TI - Estimating the biomass of unevenly distributed aquatic vegetation in a lake using the normalized water-adjusted vegetation index and scale transformation method. AB - Satellite remote sensing is advantageous for the mapping and monitoring of aquatic vegetation biomass at large spatial scales. We proposed a scale transformation (CT) method of converting the field sampling-site biomass from the quadrat to pixel scale and a new normalized water-adjusted vegetation index (NWAVI) based on remotely sensed imagery for the biomass estimation of aquatic vegetation (excluding emergent vegetation). We used a modeling approach based on the proposed CT method and NWAVI as well as statistical analyses including linear, quadratic, logarithmic, cubic, exponential, inverse and power regression to estimate the aquatic vegetation biomass, and we evaluated the performance of the biomass estimation. We mapped the spatial distribution and temporal change of the aquatic vegetation biomass using a geographic information system in a test lake in different months. The exponential regression models based on CT and the NWAVI had optimal adjusted R2, F and Sig. values in both May and August 2013. The scatter plots of the observed versus the predicted biomass showed that most of the validated field sites were near the 1:1 line. The RMSE, ARE and RE values were small. The spatial distribution and change of the aquatic vegetation biomass in the study area showed clear variability. Among the NWAVI-based and other vegetation index-based models, the CT and NWAVI-based models had the largest adjusted R2, F and the smallest ARE values in both tests. The proposed modeling scheme is effective for the biomass estimation of aquatic vegetation in lakes. It indicated that the proposed method can provide a most accurate spatial distribution map of aquatic vegetation biomass for lake ecological management. More accurate biomass maps of aquatic vegetation are essential for implementing conservation policy and for reducing uncertainties in our understanding of the lake carbon cycle. PMID- 28586748 TI - Haematological malignancies following temozolomide treatment for paediatric high grade glioma. AB - BACKGROUND: Temozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG. METHODS: We analysed 487 patients from the HIT HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year. RESULTS: The incidence of SHM was 7.7 +/- 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs. CONCLUSION: Data of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing. PMID- 28586750 TI - Microbial decolorization and detoxification of emerging environmental pollutant: Cosmetic hair dyes. AB - Since the usage of hair dyes has increased in recent time, the removal of residual dye from environment is also an emerging issue. Hair dye contains mixture of chemicals including genotoxic chemical, p-phenylenediamine (p-PD or PPD). The present study reports bioremediation of hair dye using bacteria isolated from saloon effluent. Sugarcane bagasse powder (SBP) was used as a source of nutrient and surface for bacterial growth. The 16S rDNA sequencing confirmed the isolate as Enterobacter cloacae which was designated as DDB I. The decolourization of dye was studied using UV-vis spectrophotometer. The detoxification study was conducted on microbes isolated from fresh ponds using well diffusion assay. The 1mg/ml of dye was effectively decolourised within 18h of DDB I treatment in the minimal medium containing 30mg/ml of SBP. PMID- 28586749 TI - Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma. AB - BACKGROUND: Mammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. PATIENTS AND METHODS: Eighty five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan-Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. RESULTS: In cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P < 0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12-0.44; P < 0.001), PFS (HR 0.37; 95% CI 0.21-0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42-11.95; P = 0.01). In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P < 0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36-0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39-0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10 15.18; P = 0.001). In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46-0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). CONCLUSIONS: Everolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy. PMID- 28586751 TI - Direct separation of arsenic and antimony oxides by high-temperature filtration with porous FeAl intermetallic. AB - A temperature-controlled selective filtration technology for synchronous removal of arsenic and recovery of antimony from the fume produced from reduction smelting process of lead anode slimes was proposed. The chromium (Cr) alloyed FeAl intermetallic with an asymmetric pore structure was developed as the high temperature filter material after evaluating its corrosive resistance, structural stability and mechanical properties. The results showed that porous FeAl alloyed with 20wt.% Cr had a long term stability in a high-temperature sulfide-bearing environment. The separation of arsenic and antimony trioxides was realized principally based on their disparate saturated vapor pressures at specific temperature ranges and the asymmetric membrane of FeAl filter elements with a mean pore size of 1.8MUm. Pilot-scale filtration tests showed that the direct separation of arsenic and antimony can be achieved by a one-step or two-step filtration process. A higher removal percentage of arsenic can reach 92.24% at the expense of 6~7% loss of antimony in the two-step filtration process at 500~550 degrees C and 300~400 degrees C. The FeAl filters had still good permeable and mechanical properties with 1041h of uninterrupted service, which indicates the feasibility of this high-temperature filtration technology. PMID- 28586752 TI - Heterogeneously catalyzed persulfate with a CuMgFe layered double hydroxide for the degradation of ethylbenzene. AB - CuMgFe layered double hydroxide (CuMgFe-LDH) was successfully synthesized and characterized as an efficient catalyst of persulfate (PS) for the degradation of ethylbenzene. Under the conditions of 0.2gL-1 CuMgFe-LDH and 4.0mmolL-1 persulfate at pH 7.6, the degradation efficiency of 0.08mmolL-1 ethylbenzene was 93.7% with TOC removal efficiency of 65.2% in 24h, and the concentration of Cu leached into the solution was as low as 0.095mgL-1 after the reaction. The reuse of CuMgFe-LDH showed that the catalyst was highly stable after 5 recycles. Electron Spin Resonance (ESR) test and free radical quenching experiment indicated that SO4- and OH radicals were the dominant species accounted for the degradation of ethylbenzene in the CuMgFe-LDH/persulfate system. Catalytic mechanism of the formation of a complex of Cu(II)O3SOOSO32- and the subsequent redox cycle of Cu(II)/Cu(III) accounted for the generation of radicals was proposed. PMID- 28586763 TI - Aminochrome as preclinical model for Parkinson's disease. PMID- 28586753 TI - Ozonation as a pretreatment process for nanofiltration brines: Monitoring of transformation products and toxicity evaluation. AB - Considerable interest has been given to using nanofiltration (NF) in lieu of reverse osmosis for water reclamation schemes due to lower energy consumption, higher flux rates while ensuring good micropollutants rejection. The application NF results in the generation of a large concentrated waste stream. Treatment of the concentrate is a major hurdle for the implementation of membrane technologies since the concentrate is usually unusable due to a large pollutants content. This work focuses on the application of ozonation as pretreatment of urban NF concentrates, the generation of transformation products and their relative toxicity. Three pharmaceutical micropollutants largely encountered in water cycle were selected as target molecules: acetaminophen, carbamazepine and atenolol. Through accurate-mass Q-TOF LC-MS/MS analyses, more than twenty ozonation products were detected, structure proposals and formation pathways were elaborated. Attempts were made to understand the correlation between the transformation products and acute toxicity on Vibrio fischeri strain. It is the first time that an integrated study reported on the ozonation of pharmaceuticals in urban membrane concentrates, in terms of transformation products, kinetics, degradation mechanisms, as well as toxicity assessment. PMID- 28586764 TI - Ca2+ activated Cl- channels as targets for analgesics. PMID- 28586765 TI - Lipid Laden Macrophages in Respiratory Disease. PMID- 28586766 TI - SEM-induced shrinkage and site-selective modification of single-crystal silicon nanopores. AB - Solid-state nanopores with feature sizes around 5 nm play a critical role in bio sensing fields, especially in single molecule detection and sequencing of DNA, RNA and proteins. In this paper we present a systematic study on shrinkage and site-selective modification of single-crystal silicon nanopores with a conventional scanning electron microscope (SEM). Square nanopores with measurable sizes as small as 8 nm * 8 nm and rectangle nanopores with feature sizes (the smaller one between length and width) down to 5 nm have been obtained, using the SEM-induced shrinkage technique. The analysis of energy dispersive x-ray spectroscopy and the recovery of the pore size and morphology reveal that the grown material along with the edge of the nanopore is the result of deposition of hydrocarbon compounds, without structural damage during the shrinking process. A simplified model for pore shrinkage has been developed based on observation of the cross-sectional morphology of the shrunk nanopore. The main factors impacting on the task of controllably shrinking the nanopores, such as the accelerating voltage, spot size, scanned area of e-beam, and the initial pore size have been discussed. It is found that single-crystal silicon nanopores shrink linearly with time under localized irradiation by SEM e-beam in all cases, and the pore shrinkage rate is inversely proportional to the initial equivalent diameter of the pore under the same e-beam conditions. PMID- 28586767 TI - Quantification and Dosing of Renal Replacement Therapy in Acute Kidney Injury: A Reappraisal. AB - BACKGROUND/AIMS: Delivered dialysis therapy is routinely measured in the management of patients with end-stage renal disease; yet, the quantification of renal replacement prescription and delivery in acute kidney injury (AKI) is less established. While continuous renal replacement therapy (CRRT) is widely understood to have greater solute clearance capabilities relative to intermittent therapies, neither urea nor any other solute is specifically employed for CRRT dose assessments in clinical practice at present. Instead, the normalized effluent rate is the gold standard for CRRT dosing, although this parameter does not provide an accurate estimation of actual solute clearance for different modalities. METHODS: Because this situation has created confusion among clinicians, we reappraise dose prescription and delivery for CRRT. RESULTS: A critical review of RRT quantification in AKI is provided. CONCLUSION: We propose an adaptation of a maintenance dialysis parameter (standard Kt/V) as a benchmark to supplement effluent-based dosing of CRRT. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=475457. PMID- 28586768 TI - A Role of Remote Organs Effect in Acute Kidney Injury Outcome. AB - Acute kidney injury (AKI) has been associated with both short- and long-term outcomes. To date, there is still a debate whether the increase risk of morbidity and mortality is directly due to AKI occurrence. There is, however, a potential causal impact of AKI on outcome, but evidence of this association is yet lacking. The hypothesis of remote organ damage and dysfunction (heart, lung, liver, brain, etc.) has emerged over the last decade and may explain the reason for the potential negative impact of AKI on outcome. The aim of this review was to describe findings concerning the remote effect of AKI in animal models and human studies. PMID- 28586770 TI - Ureteroscopic Lithotripsy versus Laparoscopic Ureterolithotomy or Percutaneous Nephrolithotomy in the Management of Large Proximal Ureteral Stones: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To provide a systematic review and meta-analysis of studies comparing ureterolithotripsy (URS) with percutaneous nephrolithotripsy (PCNL) or laparoscopic ureterolithotomy (LU) techniques for the management of large proximal ureteral stones (diameter greater than 10 mm). METHODS: A literature search was performed using PubMed, EMBASE, EBSCO, Web of Science, and Cochrane Library to identify suitable studies until November 2016. We used weighted mean difference to measure operative time and hospital stay, OR to measure stone free rate (SFR), and complication rate. Subgroup analyses were assessed for heterogeneity. RESULTS: Fourteen publications strictly met our eligibility criteria of which 7 were randomized control studies (RCTs) and 7 non-RCTs. Meta analysis of extractable data showed that LU and PCNL had higher SFR than URS. URS led to a similar hospital stay like that of LU. However, it had a shorter operative time and lower complication rate than LU. When we compared URS with PCNL, we found a shorter hospital stay in the URS group. However, there was no significant difference in terms of the operative time and complication rate between URS and PCNL. CONCLUSION: URS should be considered standard therapy for treating large proximal ureteral stones. PMID- 28586769 TI - Validation of Surrogates of Urine Osmolality in Population Studies. AB - BACKGROUND: The importance of vasopressin and/or urine concentration in various kidney, cardiovascular, and metabolic diseases has been emphasized recently. Due to technical constraints, urine osmolality (Uosm), a direct reflect of urinary concentrating activity, is rarely measured in epidemiologic studies. METHODS: We analyzed 2 possible surrogates of Uosm in 4 large population-based cohorts (total n = 4,247) and in patients with chronic kidney disease (CKD, n = 146). An estimated Uosm (eUosm) based on the concentrations of sodium, potassium, and urea, and a urine concentrating index (UCI) based on the ratio of creatinine concentrations in urine and plasma were compared to the measured Uosm (mUosm). RESULTS: eUosm is an excellent surrogate of mUosm, with a highly significant linear relationship and values within 5% of mUosm (r = 0.99 or 0.98 in each population cohort). Bland-Altman plots show a good agreement between eUosm and mUosm with mean differences between the 2 variables within +/-24 mmol/L. This was verified in men and women, in day and night urine samples, and in CKD patients. The relationship of UCI with mUosm is also significant but is not linear and exhibits more dispersed values. Moreover, the latter index is no longer representative of mUosm in patients with CKD as it declines much more quickly with declining glomerular filtration rate than mUosm. CONCLUSION: The eUosm is a valid marker of urine concentration in population-based and CKD cohorts. The UCI can provide an estimate of urine concentration when no other measurement is available, but should be used only in subjects with normal renal function. PMID- 28586771 TI - Can In-Bag Manual Morcellation Represent an Alternative to Uncontained Power Morcellation in Laparoscopic Myomectomy? A Randomized Controlled Trial. AB - AIMS: The study aimed to evaluate feasibility and safety of in-bag manual morcellation compared to uncontained power morcellation during laparoscopic myomectomy. METHODS: A total of 72 women undergoing laparoscopic myomectomy were randomized into 2 treatment groups: 34 patients underwent in-bag manual morcellation (experimental group) and 38 were submitted to uncontained power morcellation (control group). The primary end point was the comparison of morcellation operative time (MOT). Total operative time (TOT), rate of intraoperative complication, and postoperative outcomes in the 2 groups were regarded as secondary outcomes. RESULTS: Mean MOT and TOT were longer in the experimental group than in the control one (MOT: 9.47 +/- 5.05 vs. 6.16 +/- 7.73 min; p = 0.01; TOT: 113.24 +/- 28.12 vs. 96.74 +/- 33.51 min; p = 0.01). No intraoperative complications occurred in either group and no cases of bag disruption or laparotomic conversion were recorded. No significant difference in hemoglobin drop, hospital stay, and postoperative outcomes was reported between groups. CONCLUSION: In-bag manual morcellation appears a safe and feasible procedure and, despite slightly longer operative time, could represent an alternative to uncontained power morcellation. PMID- 28586772 TI - Clinical Features and Recurrence Pattern of Perianal Abscess in Patients with Acute Myeloid Leukemia. AB - INTRODUCTION: Perianal abscess may develop during neutropenia periods in patients with acute myeloid leukemia (AML). The standard of care for perianal abscess in AML is unclear. METHODS: We retrospectively collected patient data in our institute from 2009 to 2012. RESULTS: Two hundred ninety-two patients with AML were analyzed. In total, 1,051 chemotherapy sessions were administered. Twenty three patients experienced perianal abscess. Patients with perianal abscess were younger than those without (44 vs. 60 years, p < 0.0001). Perianal abscess developed in various phases of treatment and in the stem cell transplantation period. Twelve recurrences developed in 6 patients. Patients with a prior perianal abscess have a 10-fold risk of developing a subsequent abscess following further chemotherapy. The microbiology profile revealed that most pathogens were derived from the intestinal tracts, which was similar to the findings of previous studies. The 28-day mortality was 14.3% and the direct cause of death was not perianal abscess in any case. Surgical interventions had no impact on recurrence or survival. CONCLUSION: In patients with AML, perianal abscess results from gastrointestinal tract pathogens. Many patients do not require surgical interventions. The mortality is low but recurrence is common following subsequent chemotherapies. Therefore, awareness of recurrence is important for the timely management of perianal abscess in AML. PMID- 28586773 TI - Comparison of the Clinical Effectiveness of Ultrasound-Guided Corticosteroid Injection with and without Needle Release of the Transverse Carpal Ligament in Carpal Tunnel Syndrome. AB - BACKGROUND: To compare the clinical effectiveness of ultrasound-guided corticosteroid injection with and without needle release of the transverse carpal ligament (TCL) in carpal tunnel syndrome (CTS). METHODS: Between May 2014 and June 2016, 52 patients (56 wrists) with CTS were included in this study. Among these patients, 28 wrists were treated with ultrasound-guided corticosteroid injection plus needle release of the TCL (group A) and 28 wrists were treated with a single ultrasound-guided corticosteroids injection (group B). The following parameters were assessed and compared including postoperative results of procedure based on relief of symptoms, electrophysiological parameters (distal motor latency, sensory conduction velocity, and sensory nerve action potential of median nerve), and ultrasound parameters (anteroposterior diameter and cross sectional area of the median nerve at the levels of pisiform and hamate bone, and the thicknesses of TCL on the cross-section at the level of hamate bone). RESULTS: The overall excellent and good rate regarding the postoperative results of procedure based on the relief of symptoms at 1 month postoperatively was 82.1% in group A and 46.4% in group B (p = 0.004). There was significant difference in the above electrophysiological and ultrasound parameters between the preoperative and postoperative values in both groups (all p < 0.05). Furthermore, a significant difference was also observed in the postoperative values of the above mentioned electrophysiological and ultrasound parameters in the 2 groups (all p < 0.05). CONCLUSIONS: Both approaches had treatment benefit in CTS. Ultrasound guided corticosteroid injection in combination with needle release of the TCL is superior to the single ultrasound-guided corticosteroids injection. PMID- 28586774 TI - The Use of Mouse Asthma Models to Successfully Discover and Develop Novel Drugs. AB - The past 20 years have seen a proliferation of scientific data on the pathophysiology of asthma. Most of these data were generated in mice using tool reagents, gene-deficient or transgenic animals. In contrast, studies on disease pathogenesis in patients are scarce. Previously, a good novel antiasthma target for drug development was one that abrogated asthma in mice when it was knocked out, neutralized or induced asthma when it was overexpressed. This type of approach led to many drug candidates that worked in mice but unfortunately failed in patients, thereby demonstrating that the results of experiments in mice are not always predictive of clinical efficacy. Currently, there is active debate about the use of mouse models in drug discovery. In this review, we summarize the obstacles and challenges faced when using experimental mouse models of asthma in drug discovery. We propose that the initial selection of a novel drug target begins with defining the unmet medical need and specific patient population, followed by a thorough evaluation of available human data, and, only then, well planned and executed mouse asthma experiments. Using this approach, we argue that mouse models lend support for the target when the models are tailored for the specific asthma patient population, and that targeted, reliable, and predictive mouse models can indeed improve and accelerate the drug discovery process. PMID- 28586775 TI - [Auswirkungen von Flohsamen (Psyllium) auf Parameter des Glukosestoffwechsels: Eine Ubersicht]. AB - Ziel dieser Literaturubersicht war es, den klinischen Stellenwert von Flohsamen (Psyllium) und deren Auswirkungen auf Parameter des Glukosestoffwechsels zu bewerten. Hierzu wurde in den Datenbanken CAMbase, CAM-QUEST, Cochrane Library, EMBASE und PubMed die Literatur zur glukosesenkenden Wirkung von Flohsamen herangezogen und letztmalig am 16. September 2015 systematisch erfasst. Von ursprunglich 107 als potenziell relevant identifizierten Veroffentlichungen erwiesen sich 11 als randomisierte, kontrollierte klinische Studien, in denen 417 Testpersonen Psyllium eingenommen hatten. Das Phytotherapeutikum zeigte in 2 Studien signifikante Senkungen der Nuchternglukose. In 1 Studie konnte durch die Einnahme von Flohsamen der Hamoglobin-A1c (HbA1c)-Wert signifikant um 1,6% gesenkt werden. Signifikant Auswirkungen von Psyllium auf den postprandialen Glukosewert konnten in 4 Studien gemessen werden. Ebenfalls reduzierte Psyllium in 4 Studien den Insulinspiegel nach Nahrungsaufnahme signifikant. Der Jadad Score fur die ausgewerteten Publikationen lag im Durchschnitt bei 3 Punkten, das Minimum bei 1 Punkt, das Maximum bei 5 Punkten. Gegenwartig ist die Evidenz aus publizierten, randomisierten Studien fur eine glukosesenkende Wirkung von Flohsamen fur eine behordliche Empfehlung oder eine Aufnahme in therapeutische Richtlinien ungenugend. Da aber in einigen, teilweise kleineren Studien positive Auswirkungen des pflanzlichen Arzneimittels auf Parameter des Glukosestoffwechsels beobachtet wurden, erscheint die Prufung der glukosesenkenden Wirkung von Flohsamen in grobetaeren, methodisch einwandfreien Studien sinnvoll. PMID- 28586776 TI - Mortality of Stroke and Its Subtypes in China: Results from a Nationwide Population-Based Survey. AB - BACKGROUND: In China, stroke is the leading cause of death and contributes to a heavy disease burden. However, a nationwide population-based survey of the mortality of stroke and its subtypes is lacking for this country. METHODS: Data derived from the National Epidemiological Survey of Stroke in China, which was a multistage, stratified clustering sampling-designed, cross-sectional survey, were analyzed. Mortality rate analyses were performed for 476,156 participants >=20 years old from September 1, 2012 to August 31, 2013. RESULTS: Of the 476,156 participants in the investigated population, 364 died of ischemic stroke, 373 of hemorrhagic stroke, and 21 of stroke of undetermined pathological type. The age standardized mortality rates per 100,000 person-years among those aged >=20 years were 114.8 for total stroke, 56.5 for ischemic stroke, and 55.8 for hemorrhagic stroke. The age-standardized mortality rates of total stroke, ischemic stroke, and hemorrhagic stroke were all higher in rural areas than those in urban areas. The stroke mortality rate was higher in the northern regions than in the south. An estimated 1.12 million people aged >=20 years in China died of stroke during the period from September 1, 2012 to August 31, 2013. CONCLUSIONS: The burden of stroke in China is still heavy. Greater attention should be paid to improve strategies for preventing stroke. PMID- 28586777 TI - Patients with Fever of Unknown Origin and Splenomegaly: Diagnostic Value of Splenectomy and Preoperative Risk Factors Suggestive of Underlying Lymphomas. AB - BACKGROUND: We reviewed patients with fever of unknown origin (FUO) and splenomegaly and assessed the diagnostic value of splenectomy and measured risk factors suggestive of an underlying lymphoma. METHODS: FUO patients (n = 83) who had splenomegaly and underwent splenectomy were enrolled into this retrospective single-center study. Clinical presentations were documented and risk factors suggestive of an underlying lymphoma were tested. RESULTS: Seventy-four patients (89.2%) had a diagnosis of lymphoma or not after splenectomy and follow-up. Of those (55.4%) diagnosed with lymphoma, 29 had B-cell non-Hodgkin lymphoma and 12 had T-cell non-Hodgkin lymphoma. The remaining 33 (44.6%) had diseases other than lymphoma. Using multivariate logistic analysis, the following 3 independent risk factors were found to be related to a final diagnosis of lymphoma: age (continuous) (HR 1.086; 95% CI 1.033-1.141; p = 0.001), massively enlarged spleen (HR 7.797; 95% CI 1.267-47.959; p = 0.027), and enlarged intra-abdominal lymph nodes (HR 63.925; 95% CI 7.962-513.219; p < 0.001). The calibration of the model was satisfactory (p = 0.248 using the Hosmer-Lemeshow test), and the discrimination power was good (area under the receiver operating characteristic curve 0.925; 95% CI 0.863-0.987). CONCLUSIONS: Splenectomy is an effective diagnostic procedure for patients with FUO and splenomegaly and lymphoma is a common cause. Older age, a massively enlarged spleen, and enlarged intra abdominal lymph nodes are risk factors suggesting an underlying lymphoma, and surgery for high-risk patients should be considered. PMID- 28586778 TI - Autobiographical Memory in Bipolar Disorder and Its Link to Neuropsychological Functioning. AB - OBJECTIVE: The aim of this study was to examine the specificity of autobiographical memory (AM) in bipolar disorder (BD) and to investigate the association between AM and neuropsychological functions. METHOD: Twenty bipolar patients and 22 matched healthy controls (HCs) were included in this study. AM was assessed with an extended version of the Autobiographical Memory Test (AMT) including rejection cue words. A neuropsychological test battery was used to examine verbal memory, executive functions, and attention. RESULTS: Across both groups, the number of specific memories in the AMT was significantly smaller in response to rejection cue words and positive cue words than in response to negative cue words. Participants with BD and HCs did not differ significantly in neuropsychological measures. Across both groups, scores of verbal memory, executive functions, and attention were significantly correlated with specificity of retrieved memories. LIMITATIONS: Although our clinical sample consisted of clinically stable outpatients, 6 out of 20 patients were not rated as euthymic but as mildly depressed. All BD patients were medicated. CONCLUSION: Contrary to previous results, patients with BD did not differ in the number of specific memories compared to an HC group. Our findings suggest that neuropsychological functioning is associated with AMT specificity. Further research is required to gain a better understanding of the underlying mechanisms which may influence the ease of memory retrieval. PMID- 28586779 TI - Effect of Anesthesia on the Developing Brain: Infant and Fetus. AB - The potential for commonly used anesthetics and sedatives to cause neuroapoptosis and other neurodegenerative changes in the developing mammalian brain has become evident in animal studies over the past 15 years. This concern has led to a number of retrospective studies in human infants and young children, and some of these studies observed an association between exposure to general anesthesia as an infant, and later neurobehavioral problems in childhood. This association is particularly evident for prolonged or repeated exposures. Because of the significant growth of fetal interventions requiring sedation and analgesia for the fetus, or because of maternal anesthetic effects, this concern about anesthetic neurotoxicity is relevant for the fetus. The potential for anesthetic neurotoxicity is the most important clinical and research problem in the field of pediatric anesthesiology. This review will first briefly summarize the rapid brain growth and development in the fetus and neonate. Next, animal model data of anesthetic neurotoxicity in the fetus and neonate will be presented, followed by a review of recent human clinical anesthetic neurotoxicity trials. Finally, the rationale for studying dexmedetomidine as a potential neuroprotectant agent in anesthetic neurotoxicity will be reviewed along with study design for two human clinical trials involving dexmedetomidine. PMID- 28586781 TI - House Dust Mites Induce Production of Endothelin-1 and Matrix Metalloproteinase-9 in Keratinocytes via Proteinase-Activated Receptor-2 Activation. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by skin barrier dysfunction and abnormal immune response. House dust mites (HDM) are a major source of allergens, some of which have cysteine and serine protease activities. Keratinocytes stimulated by HDM-derived proteases have been suggested to contribute to the pathogenesis of AD by producing various cytokines. However, whether keratinocytes contribute to the induction of pruritus in AD, especially by producing pruritus-related mediators upon stimulation with HDM-derived proteases, has not been fully elucidated. METHODS: We examined whether the production of endothelin-1 (ET-1), matrix metalloproteinase (MMP)-2, and MMP-9 in keratinocytes can be induced by stimulation with Dermatophagoides farinae extracts, and if so, whether pretreatment with a protease inhibitor or proteinase-activated receptor-2 (PAR-2) antagonist affects the production of these mediators in keratinocytes. RESULTS: Although MMP-2 levels were undetectable in the culture supernatants, the production of ET-1 and MMP-9 was increased upon stimulation with HDM extracts in a concentration- and time dependent manner and suppressed by pretreatment of HDM extracts with serine protease inhibitor, but not with cysteine protease inhibitor. Mite-derived serine proteases also induced ET-1 and MMP-9 production in a concentration- and time dependent manner. Moreover, pretreatment with a PAR-2 antagonist inhibited the production of ET-1 and MMP-9 in keratinocytes. CONCLUSION: These results suggest that the activation of PAR-2 on keratinocytes by HDM-derived serine proteases induces the production of ET-1 and MMP-9, and may contribute to the induction of pruritus in AD. PMID- 28586782 TI - Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity Results from a Single-Center Surgical Series. AB - INTRODUCTION: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. METHODS: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. RESULTS: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10 year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). CONCLUSION: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence. PMID- 28586780 TI - Serum Levels of MicroRNA371a-3p: A Highly Sensitive Tool for Diagnosing and Staging Testicular Germ Cell Tumours: A Clinical Case Series. AB - INTRODUCTION: MicroRNA (miR)371a-3p was suggested to be a sensitive and specific new serum biomarker of germ cell tumours (GCTs); however, its clinical usefulness remains unproven. PATIENTS, METHODS: In 312 consecutive cases with various testicular diseases, serum levels of miR371a-3p were measured. Measurement results became available only after completion of treatment. Five patients with testicular seminoma were selected for review because of unanticipated clinical courses. RESULTS: In each two patients, elevated miR levels heralded undetected primary testicular GCT and metastases despite inconclusive radiological findings. In one case, a normal miR371a-3p level correctly pointed to the absence of metastases contrary to clinical assessment. In all cases, knowledge about the miR371a-3p levels would have altered the clinical management. CONCLUSIONS: These cases highlight the exceptional usefulness of the new GCT biomarker. In contrast to classical markers, miR371a-3p can identify primary testicular GCT. The marker can aid in clinical decision making in cases with ambiguous clinical findings. PMID- 28586788 TI - Trends in Reoperation After Initial Lumpectomy for Breast Cancer: Addressing Overtreatment in Surgical Management. AB - Importance: Surgery after initial lumpectomy to obtain more widely clear margins is common and may lead to mastectomy. Objective: To describe surgeons' approach to surgical margins for invasive breast cancer, and changes in postlumpectomy surgery rates, and final surgical treatment following a 2014 consensus statement endorsing a margin of "no ink on tumor." Design, Setting, and Participants: This was a population-based cohort survey study of 7303 eligible women ages 20 to 79 years with stage I and II breast cancer diagnosed in 2013 to 2015 and identified from the Georgia and Los Angeles County, California, Surveillance, Epidemiology, and End Results registries. A total of 5080 (70%) returned a survey. Those with bilateral disease, missing stage or treatment data, and with ductal carcinoma in situ were excluded, leaving 3729 patients in the analytic sample; 98% of these identified their attending surgeon. Between April 2015 and May 2016, 488 surgeons were surveyed regarding lumpectomy margins; 342 (70%) responded completely. Pathology reports of all patients having a second surgery and a 30% sample of those with 1 surgery were reviewed. Time trends were analyzed with multinomial regression models. Main Outcomes and Measures: Rates of final surgical procedure (lumpectomy, unilateral mastectomy, bilateral mastectomy) and rates of additional surgery after initial lumpectomy over time, and surgeon attitudes toward an adequate lumpectomy margin. Results: The 67% rate of initial lumpectomy in the 3729 patient analytic sample was unchanged during the study. The rate of final lumpectomy increased by 13% from 2013 to 2015, accompanied by a decrease in unilateral and bilateral mastectomy (P = .002). Surgery after initial lumpectomy declined by 16% (P < .001). Pathology review documented no significant association between date of treatment and positive margins. Of 342 responding surgeons, 69% endorsed a margin of no ink on tumor to avoid reexcision in estrogen receptor-positive progesterone receptor-positive cancer and 63% for estrogen receptor-negative progesterone- receptor-negative cancer. Surgeons treating more than 50 breast cancers annually were significantly more likely to report this margin as adequate (85%; n = 105) compared with those treating 20 cases or fewer (55%; n = 131) (P < .001). Conclusions and Relevance: Additional surgery after initial lumpectomy decreased markedly from 2013 to 2015 concomitant with dissemination of clinical guidelines endorsing a minimal negative margin. These findings suggest that surgeon-led initiatives to address potential overtreatment can reduce the burden of surgical management in patients with cancer. PMID- 28586791 TI - Incorrect Conflicts of Interest Disclosures. PMID- 28586789 TI - The Effect of Positive SWOG Treatment Trials on Survival of Patients With Cancer in the US Population. AB - Importance: Recently, tremendous prominence has been given to the investigation of the effect of different research processes as part of the Cancer Moonshot. More than half a century ago, the National Cancer Institute (NCI) established a network of publicly funded cancer cooperative research groups to systematically evaluate new treatments for efficacy and safety. Objective: To examine the extent to which positive NCI-sponsored cancer treatment trials have benefited patients with cancer in the US population. Design, Setting, and Participants: This investigation used study data from SWOG, an NCI-sponsored network cooperative research group. All treatment trials during SWOG's 60-year history (1956-2016) were identified for which the new, experimental therapy provided a statistically significant improvement in overall survival. It was assumed that the new, proven treatments from these trials established new standards for cancer care in the treatment community. Twenty-three positive SWOG treatment trials were identified from a variety of different disease settings. Main Outcomes and Measures: This study estimated population life-years gained from the 23 treatment trials through 2015 by mapping the effect of the new treatments onto the US cancer population using an area under the Kaplan-Meier survival curve approach that combined trial specific hazard function and hazard ratio results, along with Surveillance, Epidemiology, and End Results program and life table data. Calculations were age adjusted. The US dollar return on investment was estimated as the ratio of the total investment by the NCI in the treatment trial program divided by the estimate of life-years gained. Results: In total, 12 361 patients were enrolled to the 23 positive trials from 1965 to 2012. The study estimated that 3.34 million (95% confidence limit, 2.39-4.15 million) life-years were gained from these 23 trials through 2015. Estimates were greater than 2 million life-years gained under most model simulations. The US dollar return on investment was $125 per life-year gained. Conclusions and Relevance: SWOG treatment trials have had a substantial impact on population survival for patients with cancer over 60 years. The NCI's investment in its cancer cooperative group research program has provided exceptional value and benefit to the American public through its research programs generating positive cancer treatment trials. Trial Registration: clinicaltrials.gov Identifiers: NCT00004001, NCT00075764, and NCT00644228. PMID- 28586792 TI - Your Child's First Cell Phone. PMID- 28586790 TI - Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors. PMID- 28586793 TI - Errors in Author Names and Affiliations. PMID- 28586797 TI - In Vivo Confocal Imaging of the Conjunctiva as a Predictive Tool for the Glaucoma Filtration Surgery Outcome. AB - Purpose: To examine the preoperative conjunctival dendritic cell density (DCD), goblet cell density (GCD), and stromal meshwork reflectivity (SMR) in glaucomatous patients undergoing filtration surgery, using in vivo confocal microscopy (IVCM). Methods: Sixty-six patients were enrolled. At baseline, IVCM was performed at the site planned for surgery, and was repeated after 12 months at bleb site. Surgery was successful when a one-third reduction of baseline IOP was obtained at the last follow-up. The main outcomes were baseline DCD, GCD, and SMR, and 12 months IOP. The relations between baseline confocal parameters and 12 months IOP were analyzed. Results: Filtration surgery was successful in 43 patients (group 1: complete success, 25; group 2: qualified success, 18), and unsuccessful in 23 patients (group 3). Baseline IOP (mm Hg) was 27.6 +/- 2.8, 28.8 +/- 4.1, and 27.7 +/- 3.2 in groups 1 to 3, respectively. Preoperative DCD and SMR were lower in group 1 compared with groups 2 (P < 0.001, P < 0.05), and 3 (P < 0.001); preoperative GCD was higher in group 1 compared with groups 2 and 3 (P < 0.001). DCD and GCD were also different between groups 2 and 3 (P < 0.05, P < 0.001). At 12 months, IOP reduced by 43.3%, 38.4%, and 15.8% in groups 1 to 3. Twelve-month IOP reduction negatively correlated with baseline DCD and SMR (P < 0.001, r = -0.786; P < 0.05, r = -0.618), and positively with GCD (P < 0.001, r = 0.752). Conclusions: Preoperative DCD, GCD, and SMR are parameters correlated with the filtration surgery outcome, with DCD presenting the strongest correlation. IVCM of the conjunctiva may represent an imaging tool to predict the surgical success in glaucoma. PMID- 28586796 TI - Functional Activity of Matrix Metalloproteinases 2 and 9 in Tears of Patients With Glaucoma. AB - Purpose: To evaluate the differential expression of tear matrix metalloproteinases (MMP) 2 and 9 in of patients with various forms of glaucoma. Methods: Tear samples were collected with a Schirmer's strip from 148 eyes of 113 patients (medically naive patients with primary open-angle [POAG] or angle closure glaucoma [PACG] and those with pseudoexfoliation syndrome [PXF] or glaucoma [PXG]). These were compared to patients undergoing cataract surgery (controls) for this cross-sectional study. Functional activities of tear MMP-9 and MMP-2 were analyzed by gelatin zymography. Tenon's capsules (n = 15) were harvested from the inferior quadrant in those undergoing cataract surgery and protein expression of MMP-9 was analyzed by immunohistochemistry (IHC). Hydrogen peroxide (H2O2) stress-induced effects on in vitro activities of MMP-9 in human trabecular meshwork (HTM) cells were analyzed. Results: The MMP-9 activity in tears was increased significantly in POAG, (n = 27), PACG (n = 24), and PXF (n = 40) eyes compared to controls (n = 35), and was increased significantly in eyes with glaucoma compared to moderate/severe glaucoma (P < 0.001). The MMP-9 expression was significantly lower in PXG (n = 22) eyes. Immunohistochemistry of Tenon's capsule revealed increased expression of MMP-9 in primary glaucoma eyes. Increased MMP-9 activity was seen in in vitro by gelatin zymography and was confirmed by Western and immunofluorescent assay on HTM upon 800 and 1000 MUM H2O2-induced stress for 2 to 3 hours with approximately 80% cell death. Conclusions: Increased tear MMP-9 activity in early glaucoma and pseudoexfoliation syndrome suggesting activation of extracellular matrix (ECM) degradation can be used as a tear-based predictive biomarker. Decreased expression in advanced stages suggests exhaustion of the degradation response. PMID- 28586799 TI - Error in Data Presentation in Figure and Text. PMID- 28586798 TI - Parkinson Disease and Autoimmune Disorders-What Can We Learn From Genome-wide Pleiotropy? PMID- 28586801 TI - More Rigorous Study Needed Before Claiming No Harm of Blood Glucose Test Strip Limits for Patients Using Insulin. PMID- 28586802 TI - When to Adjust for Potentially Confounding Variables. PMID- 28586803 TI - Could the Adoption of Unleaded Gasoline in the 1970s Play a Role in the Precipitous Decline in Dementia Prevalence? PMID- 28586804 TI - Glycemic Control and Functionality in Nursing Homes-More Than HbA1c. PMID- 28586805 TI - Promoting Compliance to Practice Guidelines May Improve Primary Care for Thyroid Diseases. PMID- 28586806 TI - Patient and Public Safety Maximized by Rapid Opioid Taper. PMID- 28586807 TI - Could the Adoption of Unleaded Gasoline in the 1970s Play a Role in the Precipitous Decline in Dementia Prevalence?-Reply. PMID- 28586808 TI - When to Adjust for Potentially Confounding Variables-Reply. PMID- 28586809 TI - More Rigorous Study Needed Before Claiming No Harm of Blood Glucose Test Strip Limits for Patients Using Insulin-Reply. PMID- 28586810 TI - Glycemic Control and Functionality in Nursing Homes-More Than HbA1c-Reply. PMID- 28586811 TI - Promoting Compliance to Practice Guidelines May Improve Primary Care for Thyroid Diseases-Reply. PMID- 28586812 TI - Patient and Public Safety Maximized by Rapid Opioid Taper-Reply. PMID- 28586814 TI - Alternating Ventricular Complexes After Overdose From an Herbal Medication. PMID- 28586815 TI - Speech Motor Sequence Learning: Acquisition and Retention in Parkinson Disease and Normal Aging. AB - Purpose: The aim of the current investigation was to examine speech motor sequence learning in neurologically healthy younger adults, neurologically healthy older adults, and individuals with Parkinson disease (PD) over a 2-day period. Method: A sequential nonword repetition task was used to examine learning over 2 days. Participants practiced a sequence of 6 monosyllabic nonwords that was retested following nighttime sleep. The speed and accuracy of the nonword sequence were measured, and learning was inferred by examining performance within and between sessions. Results: Though all groups exhibited comparable improvements of the nonword sequence performance during the initial session, between-session retention of the nonword sequence differed between groups. Younger adult controls exhibited offline gains, characterized by an increase in the speed and accuracy of nonword sequence performance across sessions, whereas older adults exhibited stable between-session performance. Individuals with PD exhibited offline losses, marked by an increase in sequence duration between sessions. Conclusions: The current results demonstrate that both PD and normal aging affect retention of speech motor learning. Furthermore, these data suggest that basal ganglia dysfunction associated with PD may affect the later stages of speech motor learning. Findings from the current investigation are discussed in relation to studies examining consolidation of nonspeech motor learning. PMID- 28586816 TI - Thrombophilia Testing in Provoked Venous Thromboembolism: A Teachable Moment. PMID- 28586817 TI - Trends in Visits to Specialist Physicians Involving Nurse Practitioners and Physician Assistants, 2001 to 2013. PMID- 28586819 TI - Physician Speech and Firearm Safety: Wollschlaeger v Governor, Florida. AB - To provide the highest-quality medical care, physicians must be able to communicate openly with their patients and provide advice in conformance with professional standards of care. Although states have the power to regulate many aspects of medical practice, laws that interfere with speech by preventing physicians from discussing specific subjects with patients are constitutionally suspect. In 2017, the US Court of Appeals for the Eleventh Circuit struck down key provisions of a Florida law that prohibited physicians from speaking with their patients about firearm safety as a violation of the First Amendment. We discuss this case, Wollschlaeger v Governor, Florida, and the implications of the ruling. Although courts may rule that physician "gag laws," such as the one in Florida, are unconstitutional, this area of the law remains unsettled. Legislative mandates that interfere with medical practice may decrease the quality of care by substituting politics and legislative judgment for medical expertise. PMID- 28586818 TI - Association Between Persistent Pain and Memory Decline and Dementia in a Longitudinal Cohort of Elders. AB - Importance: Chronic pain is common among the elderly and is associated with cognitive deficits in cross-sectional studies; the population-level association between chronic pain and longitudinal cognition is unknown. Objective: To determine the population-level association between persistent pain, which may reflect chronic pain, and subsequent cognitive decline. Design, Setting, and Participants: Cohort study with biennial interviews of 10 065 community-dwelling older adults in the nationally representative Health and Retirement Study who were 62 years or older in 2000 and answered pain and cognition questions in both 1998 and 2000. Data analysis was conducted between June 24 and October 31, 2016. Exposures: "Persistent pain," defined as a participant reporting that he or she was often troubled with moderate or severe pain in both the 1998 and 2000 interviews. Main Outcomes and Measures: Coprimary outcomes were composite memory score and dementia probability, estimated by combining neuropsychological test results and informant and proxy interviews, which were tracked from 2000 through 2012. Linear mixed-effects models, with random slope and intercept for each participant, were used to estimate the association of persistent pain with slope of the subsequent cognitive trajectory, adjusting for demographic characteristics and comorbidities measures in 2000 and applying sampling weights to represent the 2000 US population. We hypothesized that persistent pain would predict accelerated memory decline and increased probability of dementia. To quantify the impact of persistent pain on functional independence, we combined our primary results with information on the association between memory and ability to manage medications and finances independently. Results: Of the 10 065 eligible HRS sample members, 60% were female, and median baseline age was 73 years (interquartile range, 67-78 years). At baseline, persistent pain affected 10.9% of participants and was associated with worse depressive symptoms and more limitations in activities of daily living. After covariate adjustment, persistent pain was associated with 9.2% (95% CI, 2.8%-15.0%) more rapid memory decline compared with those without persistent pain. After 10 years, this accelerated memory decline implied a 15.9% higher relative risk of inability to manage medications and an 11.8% higher relative risk of inability to manage finances independently. Adjusted dementia probability increased 7.7% faster (95% CI, 0.55% 14.2%); after 10 years, this translates to an absolute 2.2% increase in dementia probability for those with persistent pain. Conclusions and Relevance: Persistent pain was associated with accelerated memory decline and increased probability of dementia. PMID- 28586820 TI - Sodium Reduction in US Households' Packaged Food and Beverage Purchases, 2000 to 2014. AB - Importance: Initiatives to reduce sodium in packaged foods have been launched in the United States, yet corresponding changes in the amount of sodium that US households obtain from packaged foods have not been evaluated, to our knowledge. Objective: To assess 15-year changes in the amount of sodium that US households acquire from packaged food purchases, the sodium content of purchases, and the proportion of households that have purchases with optimal sodium density. Design, Setting, and Participants: Longitudinal study of US households in the 2000 to 2014 Nielsen Homescan Consumer Panel, a population-based sample of households that used barcode scanners to record all packaged foods purchased throughout the year. Time-varying brand- and product-specific nutrition information was used for 1 490 141 products. Main Outcomes and Measures: Sociodemographic-adjusted changes in mean sodium per capita (mg/d) and sodium content (mg/100 g), overall and for top food group sources of sodium, and the proportion of households that have total purchases with sodium density of 1.1 mg/kcal or less. Results: In a nationwide sample of 172 042 US households (754 608 year-level observations), the amount of sodium that households acquired from packaged food and beverage purchases decreased significantly between 2000 and 2014 by 396 mg/d (95% CI, -407 to -385 mg/d) per capita. The sodium content of households' packaged food purchases decreased significantly during this 15-year period by 49 mg/100 g (95% CI, -50 to -48 mg/100 g), a 12.0% decline; decreases began in 2005 and continued through 2014. Moreover, the sodium content of households' purchases decreased significantly for all top food sources of sodium between 2000 and 2014, including declines of more than 100 mg/100 g for condiments, sauces, and dips (-114 mg/100 g; 95% CI, -117 to -111 mg/100 g) and salty snacks (-142 mg/100 g; 95% CI, -144 to -141 mg/100 g). However, in all years, less than 2% of US households had packaged food and beverage purchases with sodium density of 1.1 mg/kcal or less. Conclusions and Relevance: In this nationwide study, significant reductions in sodium from packaged food purchases were achieved in the past 15 years. Nonetheless, most US households had food and beverage purchases with excessive sodium density. Findings suggest that more concerted sodium reduction efforts are needed in the United States. PMID- 28586821 TI - Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment. PMID- 28586823 TI - Cross-Linguistic Differences in Bilinguals' Fundamental Frequency Ranges. AB - Purpose: We investigated cross-linguistic differences in fundamental frequency range (FFR) in Welsh-English bilingual speech. This is the first study that reports gender-specific behavior in switching FFRs across languages in bilingual speech. Method: FFR was conceptualized as a behavioral pattern using measures of span (range of fundamental frequency-in semitones-covered by the speaker's voice) and level (overall height of fundamental frequency maxima, minima, and means of speaker's voice) in each language. Results: FFR measures were taken from recordings of 30 Welsh-English bilinguals (14 women and 16 men), who read 70 semantically matched sentences, 35 in each language. Comparisons were made within speakers across languages, separately in male and female speech. Language background and language use information was elicited for qualitative analysis of extralinguistic factors that might affect the FFR. Conclusions: Cross-linguistic differences in FFR were found to be consistent across female bilinguals but random across male bilinguals. Most female bilinguals showed distinct FFRs for each language. Most male bilinguals, however, were found not to change their FFR when switching languages. Those who did change used different strategies than women when differentiating FFRs between languages. Detected cross-linguistic differences in FFR can be explained by sociocultural factors. Therefore, sociolinguistic factors are to be taken into account in any further study of language-specific pitch setting and cross-linguistic differences in FFR. PMID- 28586822 TI - Sign Language Echolalia in Deaf Children With Autism Spectrum Disorder. AB - Purpose: We present the first study of echolalia in deaf, signing children with autism spectrum disorder (ASD). We investigate the nature and prevalence of sign echolalia in native-signing children with ASD, the relationship between sign echolalia and receptive language, and potential modality differences between sign and speech. Method: Seventeen deaf children with ASD and 18 typically developing (TD) deaf children were video-recorded in a series of tasks. Data were coded for type of signs produced (spontaneous, elicited, echo, or nonecho repetition). Echoes were coded as pure or partial, and timing and reduplication of echoes were coded. Results: Seven of the 17 deaf children with ASD produced signed echoes, but none of the TD deaf children did. The echoic children had significantly lower receptive language scores than did both the nonechoic children with ASD and the TD children. Modality differences also were found in terms of the directionality, timing, and reduplication of echoes. Conclusions: Deaf children with ASD sometimes echo signs, just as hearing children with ASD sometimes echo words, and TD deaf children and those with ASD do so at similar stages of linguistic development, when comprehension is relatively low. The sign language modality might provide a powerful new framework for analyzing the purpose and function of echolalia in deaf children with ASD. PMID- 28586824 TI - The Downside of Greater Lexical Influences: Selectively Poorer Speech Perception in Noise. AB - Purpose: Although lexical information influences phoneme perception, the extent to which reliance on lexical information enhances speech processing in challenging listening environments is unclear. We examined the extent to which individual differences in lexical influences on phonemic processing impact speech processing in maskers containing varying degrees of linguistic information (2 talker babble or pink noise). Method: Twenty-nine monolingual English speakers were instructed to ignore the lexical status of spoken syllables (e.g., gift vs. kift) and to only categorize the initial phonemes (/g/ vs. /k/). The same participants then performed speech recognition tasks in the presence of 2-talker babble or pink noise in audio-only and audiovisual conditions. Results: Individuals who demonstrated greater lexical influences on phonemic processing experienced greater speech processing difficulties in 2-talker babble than in pink noise. These selective difficulties were present across audio-only and audiovisual conditions. Conclusion: Individuals with greater reliance on lexical processes during speech perception exhibit impaired speech recognition in listening conditions in which competing talkers introduce audible linguistic interferences. Future studies should examine the locus of lexical influences/interferences on phonemic processing and speech-in-speech processing. PMID- 28586826 TI - Goal-Directed Drinking Behaviors Can Be Modified Through Behavioral Mimicry. AB - Purpose: This study tested whether behavioral mimicry can alter drinking behavior. It was hypothesized that participants would increase drinking behaviors given increased confederate drinking but not cup touching. Methods: Nineteen healthy adults (Mage = 20.32 years) completed 2 picture description tasks; during 1 task, a confederate frequently sipped water (complete drinking gesture), and during the other, the confederate touched her cup but did not drink (partial gesture). Outcome measures included number of drinks per minute, number of cup touches per minute, percentage of time spent drinking, and percentage of time spent touching the cup. Results: Participants spent more time drinking and had an increased drinking rate during the drinking condition versus the cup-touching condition. For a majority of participants, drinking rate increased during the drinking condition versus baseline. Drinking, but not cup touching, rate also increased given increased confederate cup touching for many. Conclusions: Mimicry likely contributes to social modeling of drinking behaviors. This effect appears more robust given a complete target gesture (full drink); however, a partial goal directed drinking gesture may also yield a mimicked response. Beyond the theoretical implications, these results provide directions for research investigating more naturalistic mechanisms for increasing dietary intake in various patient populations (e.g., individuals with dysphagia). PMID- 28586825 TI - Typical Toddlers' Participation in "Just-in-Time" Programming of Vocabulary for Visual Scene Display Augmentative and Alternative Communication Apps on Mobile Technology: A Descriptive Study. AB - Purpose: Augmentative and alternative communication (AAC) promotes communicative participation and language development for young children with complex communication needs. However, the motor, linguistic, and cognitive demands of many AAC technologies restrict young children's operational use of and influence over these technologies. The purpose of the current study is to better understand young children's participation in programming vocabulary "just in time" on an AAC application with minimized demands. Method: A descriptive study was implemented to highlight the participation of 10 typically developing toddlers (M age: 16 months, range: 10-22 months) in just-in-time vocabulary programming in an AAC app with visual scene displays. Results: All 10 toddlers participated in some capacity in adding new visual scene displays and vocabulary to the app just in time. Differences in participation across steps were observed, suggesting variation in the developmental demands of controls involved in vocabulary programming. Conclusions: Results from the current study provide clinical insights toward involving young children in AAC programming just in time and steps that may allow for more independent participation or require more scaffolding. Technology designed to minimize motor, cognitive, and linguistic demands may allow children to participate in programming devices at a younger age. PMID- 28586828 TI - The Effects of Enhanced Milieu Teaching With Phonological Emphasis on the Speech and Language Skills of Young Children With Cleft Palate: A Pilot Study. AB - Purpose: The purpose of this pilot study was to investigate the extent to which a naturalistic communication intervention, enhanced milieu teaching with phonological emphasis (EMT+ PE), improved the language and speech outcomes of toddlers with cleft lip and/or palate (CL/P). Method: Nineteen children between 15 and 36 months (M = 25 months) with nonsyndromic CL/P and typical cognitive development were randomly assigned to a treatment (EMT+PE) or nontreatment, business-as-usual (BAU), experimental condition. Participants in the treatment group received forty-eight 30-min sessions, biweekly during a 6-month period. Treatment was delivered in a university clinic by trained speech language pathologists; fidelity of treatment was high across participants. Results: Children in the treatment group had significantly better receptive language scores and a larger percentage of consonants correct than children in the BAU group at the end of intervention. Children in the treatment group made greater gains than children in the BAU group on most language measures; however, only receptive language, expressive vocabulary (per parent report), and consonants correct were significant. Conclusions: The results of this preliminary study indicate that EMT+PE is a promising early intervention for young children with CL/P. Replication with a larger sample and long-term follow-up measures are needed. PMID- 28586827 TI - Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases. AB - Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes. Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach. Design, Setting, and Participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017. Main Outcomes and Measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases. Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes. Conclusions and Relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti inflammatory agents. PMID- 28586831 TI - Pediatricians, Firearms, and the First Amendment. PMID- 28586829 TI - The Changing View of Input in the Treatment of Children With Grammatical Deficits. AB - Purpose: The purpose of this article is to present 3 approaches that emphasize the role that input plays in the treatment of grammatical deficits in children with language impairments. Method: These approaches-input informativeness, competing sources of input, and high variability-were selected because they go beyond issues of token frequency and emphasize instead type frequency, relative frequency, and frequency at an abstract as well as a concrete level of grammar. Each of these approaches can be applied to the grammatical deficits seen in children with specific language impairment and can be readily used with well established procedures, such as focused stimulation and recasting. Results: Each approach is supported by a body of laboratory research with children with typical language skills, and the feasibility of each has been tested in studies with a treatment design. Furthermore, the assumptions of the 3 approaches are largely compatible, permitting application of combinations of these approaches without violating any of their principles. Conclusion: The positive findings from each of these approaches should serve as a basis for further clinical research. PMID- 28586830 TI - Social Confidence in Early Adulthood Among Young People With and Without a History of Language Impairment. AB - Purpose: The purposes of this study were to test the predictions that lower self esteem and higher shyness in individuals with a history of language impairment (LI) would continue from adolescence into early adulthood and that those with LI would have lower social self-efficacy in early adulthood. Method: Participants were young people with a history of LI and a comparison group of age-matched peers. Both groups were tested at ages 17 and 24 years. Participants completed measures of language ability, nonverbal IQ, shyness, global self-esteem, and (at age 24 years only) social self-efficacy. Results: Young adults with LI scored lower than age-matched peers on self-esteem, higher on shyness, and lower on social self-efficacy (medium to large effect sizes). In line with expectations, in the group with LI, language ability in adolescence predicted shyness in young adulthood, which, in turn, was negatively associated with self-esteem. There was also a direct association between language ability in adolescence and self-esteem in young adulthood. Conclusions: Young people with a history of LI are likely to be entering adulthood less socially confident than their peers. Interventions may be desirable for young adults with LI, and the present findings indicate social self-efficacy as a key area of social confidence that calls for practitioners' attention. PMID- 28586832 TI - Sound Health: An NIH-Kennedy Center Initiative to Explore Music and the Mind. PMID- 28586843 TI - Making Conscious the Unconscious. PMID- 28586845 TI - New Opportunities for Evidence in Fetal Alcohol Spectrum Disorder. PMID- 28586842 TI - Association Between Prenatal Alcohol Exposure and Craniofacial Shape of Children at 12 Months of Age. AB - Importance: Children who receive a diagnosis of fetal alcohol spectrum disorder may have a characteristic facial appearance in addition to neurodevelopmental impairment. It is not well understood whether there is a gradient of facial characteristics of children who did not receive a diagnosis of fetal alcohol spectrum disorder but who were exposed to a range of common drinking patterns during pregnancy. Objective: To examine the association between dose, frequency, and timing of prenatal alcohol exposure and craniofacial phenotype in 12-month old children. Design, Setting, and Participants: A prospective cohort study was performed from January 1, 2011, to December 30, 2014, among mothers recruited in the first trimester of pregnancy from low-risk, public maternity clinics in metropolitan Melbourne, Australia. A total of 415 white children were included in this analysis of 3-dimensional craniofacial images taken at 12 months of age. Analysis was performed with objective, holistic craniofacial phenotyping using dense surface models of the face and head. Partial least square regression models included covariates known to affect craniofacial shape. Exposures: Low, moderate to high, or binge-level alcohol exposure in the first trimester or throughout pregnancy. Main Outcomes and Measures: Anatomical differences in global and regional craniofacial shape between children of women who abstained from alcohol during pregnancy and children with varying levels of prenatal alcohol exposure. Results: Of the 415 children in the study (195 girls and 220 boys; mean [SD] age, 363.0 [8.3] days), a consistent association between craniofacial shape and prenatal alcohol exposure was observed at almost any level regardless of whether exposure occurred only in the first trimester or throughout pregnancy. Regions of difference were concentrated around the midface, nose, lips, and eyes. Directional visualization showed that these differences corresponded to general recession of the midface and superior displacement of the nose, especially the tip of the nose, indicating shortening of the nose and upturning of the nose tip. Differences were most pronounced between groups with no exposure and groups with low exposure in the first trimester (forehead), moderate to high exposure in the first trimester (eyes, midface, chin, and parietal region), and binge-level exposure in the first trimester (chin). Conclusions and Relevance: Prenatal alcohol exposure, even at low levels, can influence craniofacial development. Although the clinical significance of these findings is yet to be determined, they support the conclusion that for women who are or may become pregnant, avoiding alcohol is the safest option. PMID- 28586844 TI - Skeletal Muscle Involvement in Antisynthetase Syndrome. AB - Importance: Antisynthetase syndrome, characterized by myositis, interstitial lung disease, skin rash, arthropathy, and Raynaud phenomenon, is a clinical entity based on the presence of aminoacyl transfer RNA synthetase (ARS) antibodies in patients' serum. However, antisynthetase syndrome is not included in the histological subsets of idiopathic inflammatory myopathies. Objective: To elucidate the clinical features of myositis in patients with antisynthetase syndrome. Design, Setting, and Participants: In this cohort study, muscle biopsy and blood samples were collected from 460 patients with idiopathic inflammatory myositis from various regional referral centers throughout Japan between October 2010 and December 2014. Data were analyzed in March 2016. Exposures: Six different anti-ARS antibodies were detected in serum by RNA immunoprecipitation. Line blot assay and protein immunoprecipitation were also performed. HLA-DRB1 alleles were genotyped. Main Outcomes and Measures: The main outcomes were muscle manifestations and histological findings. Predisposing factors, extramuscular symptoms, and follow-up information were also studied. Results: Of 460 patients with idiopathic inflammatory myopathies, 51 (11.1%) had anti-ARS antibodies. Of this subset, 31 (61%) were women, with a mean (SD) age at disease onset of 60.2 (16.1) years. Among 6 different anti-ARS antibodies, only 1-the anti-OJ antibody was not detected by line blot assay but by RNA immunoprecipitation. There were no significant HLA-DRB1 alleles associated with anti-ARS antibodies. All 51 patients presented with muscle limb weakness; 14 (27%) had severe limb weakness, 17 (33%) had neck muscle weakness, 15 (29%) had dysphagia, and 15 (29%) had muscle atrophy. Although patients with anti-OJ antibodies showed severe muscle weakness, the clinical presentations of antisynthetase syndrome were relatively homogeneous. In histology, perifascicular necrosis, the characteristic finding of antisynthetase syndrome, was found in 24 patients (47%). Myositis with anti-ARS antibodies responded to the combination of immunosuppressive therapy with favorable outcomes. Interstitial lung disease, found in 41 patients (80%), was more closely associated with mortality than myositis. Conclusions and Relevance: Although clinical presentations of antisynthetase syndrome were relatively homogeneous, anti-OJ antibodies were associated with severe muscle involvement. Antisynthetase syndrome is a clinical and histological subset among idiopathic inflammatory myopathies. PMID- 28586853 TI - Development and application of the near-infrared and white-light thoracoscope system for minimally invasive lung cancer surgery. AB - In minimally invasive surgery, the white-light thoracoscope as a standard imaging tool is facing challenges of the low contrast between important anatomical or pathological regions and surrounding tissues. Recently, the near-infrared (NIR) fluorescence imaging shows superior advantages over the conventional white-light observation, which inspires researchers to develop imaging systems to improve overall outcomes of endoscopic imaging. We developed an NIR and white-light dual channel thoracoscope system, which achieved high-fluorescent signal acquisition efficiency and the simultaneously optimal visualization of the NIR and color dual channel signals. The system was designed to have fast and accurate image registration and high signal-to-background ratio by optimizing both software algorithms and optical hardware components for better performance in the NIR spectrum band. The system evaluation demonstrated that the minimally detectable concentration of indocyanine green (ICG) was 0.01 ?? ? M , and the spatial resolution was 35 ?? ? m . The in vivo feasibility of our system was verified by the preclinical experiments using six porcine models with the intravenous injection of ICG. Furthermore, the system was successfully applied for guiding the minimally invasive segmentectomy in three lung cancer patients, which revealed that our system held great promise for the clinical translation in lung cancer surgeries. PMID- 28586852 TI - Dental optical tomography with upconversion nanoparticles-a feasibility study. AB - Upconversion nanoparticles (UCNPs) have the unique ability to emit multiple colors upon excitation by near-infrared (NIR) light. Herein, we investigate the potential use of UCNPs as contrast agents for dental optical tomography, with a focus on monitoring the status of fillings after dental restoration. The potential of performing tomographic imaging using UCNP emission of visible or NIR light is established. This in silico and ex vivo study paves the way toward employing UCNPs as theranostic agents for dental applications. PMID- 28586854 TI - Noninvasive assessment of articular cartilage surface damage using reflected polarized light microscopy. AB - Articular surface damage occurs to cartilage during normal aging, osteoarthritis, and in trauma. A noninvasive assessment of cartilage microstructural alterations is useful for studies involving cartilage explants. This study evaluates polarized reflectance microscopy as a tool to assess surface damage to cartilage explants caused by mechanical scraping and enzymatic degradation. Adult bovine articular cartilage explants were scraped, incubated in collagenase, or underwent scrape and collagenase treatments. In an additional experiment, cartilage explants were subject to scrapes at graduated levels of severity. Polarized reflectance parameters were compared with India ink surface staining, features of histological sections, changes in explant wet weight and thickness, and chondrocyte viability. The polarized reflectance signal was sensitive to surface scrape damage and revealed individual scrape features consistent with India ink marks. Following surface treatments, the reflectance contrast parameter was elevated and correlated with image area fraction of India ink. After extensive scraping, polarized reflectance contrast and chondrocyte viability were lower than that from untreated explants. As part of this work, a mathematical model was developed and confirmed the trend in the reflectance signal due to changes in surface scattering and subsurface birefringence. These results demonstrate the effectiveness of polarized reflectance microscopy to sensitively assess surface microstructural alterations in articular cartilage explants. PMID- 28586855 TI - Using Pupillometry to Investigate Sentence Comprehension in Children With and Without Specific Language Impairment. AB - Purpose: In this study pupillometry was used to investigate the allocation of attentional resources associated with sentence comprehension in children with and without specific language impairment (SLI). Method: Eighteen children with SLI (age: M = 6.4 years) and 18 typically developing (TD) children (age: M = 6.3 years) participated in the study. A sentence comprehension task was presented that comprised items designated as easy or hard. Easy sentences contained 4 or 5 words, and hard sentences contained 6 or 7 words. Results: For the TD group, pupil size was significantly larger when comprehending hard sentences compared with easy sentences. There was no effect of sentence difficulty on pupil size in the SLI group. Comparisons between groups revealed pupil sizes for the SLI group were significantly larger than those for the TD group for easy sentences. There were no group differences for the hard sentences. Conclusion: In TD children, pupillometry was sensitive to the attentional demands associated with sentence comprehension. Between-subjects comparisons indicated that the TD group allocated less attention than did the children with SLI for the easy sentences but not for the hard sentences. This study provides evidence of attentional differences between children with SLI and TD children under conditions of low processing demands. PMID- 28586867 TI - Prenatal Alcohol Exposure: No Safe Amount. PMID- 28586868 TI - Fogarty International Center, a Linchpin of Global Health Research. PMID- 28586869 TI - Unfolding the Clinical Potential of DNA and Protein Origami. PMID- 28586856 TI - Comparative Effectiveness of Clinical-Community Childhood Obesity Interventions: A Randomized Clinical Trial. AB - Importance: Novel approaches to care delivery that leverage clinical and community resources could improve body mass index (BMI) and family-centered outcomes. Objective: To examine the extent to which 2 clinical-community interventions improved child BMI z score and health-related quality of life, as well as parental resource empowerment in the Connect for Health Trial. Design, Setting, and Participants: This 2-arm, blinded, randomized clinical trial was conducted from June 2014 through March 2016, with measures at baseline and 1 year after randomization. This intent-to-treat analysis included 721 children ages 2 to 12 years with BMI in the 85th or greater percentile from 6 primary care practices in Massachusetts. Interventions: Children were randomized to 1 of 2 arms: (1) enhanced primary care (eg, flagging of children with BMI >= 85th percentile, clinical decision support tools for pediatric weight management, parent educational materials, a Neighborhood Resource Guide, and monthly text messages) or (2) enhanced primary care plus contextually tailored, individual health coaching (twice-weekly text messages and telephone or video contacts every other month) to support behavior change and linkage of families to neighborhood resources. Main Outcomes and Measures: One-year changes in age- and sex-specific BMI z score, child health-related quality of life measured by the Pediatric Quality of Life 4.0, and parental resource empowerment. Results: At 1 year, we obtained BMI z scores from 664 children (92%) and family-centered outcomes from 657 parents (91%). The baseline mean (SD) age was 8.0 (3.0) years; 35% were white (n = 252), 33.3% were black (n = 240), 21.8% were Hispanic (n = 157), and 9.9% were of another race/ethnicity (n = 71). In the enhanced primary care group, adjusted mean (SD) BMI z score was 1.91 (0.56) at baseline and 1.85 (0.58) at 1 year, an improvement of -0.06 BMI z score units (95% CI, -0.10 to -0.02) from baseline to 1 year. In the enhanced primary care plus coaching group, the adjusted mean (SD) BMI z score was 1.87 (0.56) at baseline and 1.79 (0.58) at 1 year, an improvement of -0.09 BMI z score units (95% CI, -0.13 to -0.05). However, there was no significant difference between the 2 intervention arms (difference, -0.02; 95% CI, -0.08 to 0.03; P = .39). Both intervention arms led to improved parental resource empowerment: 0.29 units (95% CI, 0.22 to 0.35) higher in the enhanced primary care group and 0.22 units (95% CI, 0.15 to 0.28) higher in the enhanced primary care plus coaching group. Parents in the enhanced primary care plus coaching group, but not in the enhanced care alone group, reported improvements in their child's health-related quality of life (1.53 units; 95% CI, 0.51 to 2.56). However, there were no significant differences between the intervention arms in either parental resource empowerment (0.07 units; 95% CI, -0.02 to 0.16) or child health-related quality of life (0.89 units; 95% CI, -0.56 to 2.33). Conclusions and Relevance: Two interventions that included a package of high-quality clinical care for obesity and linkages to community resources resulted in improved family-centered outcomes for childhood obesity and improvements in child BMI. Trial Registration: clinicaltrials.gov Identifier: NCT02124460. PMID- 28586871 TI - Incorrect Data in Abstract, Text, and Figure. PMID- 28586870 TI - Error in 2 Figures. PMID- 28586872 TI - JAK2 V617F Mutation Testing in Patients Presenting With Hepatic and Portal Vein Thrombosis. PMID- 28586873 TI - Progress Toward Achieving UNAIDS 90-90-90 in Rural Communities in East Africa. PMID- 28586875 TI - New AML Therapy and Diagnostic. PMID- 28586874 TI - Gestational Weight Gain and Outcomes for Mothers and Infants. PMID- 28586876 TI - Therapy for Rare Nerve Cell Disease. PMID- 28586877 TI - Liver Cancer Treatment Approved. PMID- 28586878 TI - Dietary Intake of Omega-3 Fatty Acids From Fish and Risk of Diabetic Retinopathy. PMID- 28586880 TI - The Fogarty International Center, a National Treasure for Global Health. PMID- 28586881 TI - The Duty of the Medical Profession in This War. PMID- 28586882 TI - Measurement of Hemoglobin A1c in Patients With Sickle Cell Trait. PMID- 28586883 TI - Adjustment Strategies in Studies of Therapy. PMID- 28586884 TI - Measurement of Hemoglobin A1c in Patients With Sickle Cell Trait-Reply. PMID- 28586885 TI - Adjustment Strategies in Studies of Therapy-Reply. PMID- 28586886 TI - Prevention of Migraine. PMID- 28586889 TI - Umbilical Hernia. PMID- 28586887 TI - Association of Gestational Weight Gain With Maternal and Infant Outcomes: A Systematic Review and Meta-analysis. AB - Importance: Body mass index (BMI) and gestational weight gain are increasing globally. In 2009, the Institute of Medicine (IOM) provided specific recommendations regarding the ideal gestational weight gain. However, the association between gestational weight gain consistent with theIOM guidelines and pregnancy outcomes is unclear. Objective: To perform a systematic review, meta analysis, and metaregression to evaluate associations between gestational weight gain above or below the IOM guidelines (gain of 12.5-18 kg for underweight women [BMI <18.5]; 11.5-16 kg for normal-weight women [BMI 18.5-24.9]; 7-11 kg for overweight women [BMI 25-29.9]; and 5-9 kg for obese women [BMI >=30]) and maternal and infant outcomes. Data Sources and Study Selection: Search of EMBASE, Evidence-Based Medicine Reviews, MEDLINE, and MEDLINE In-Process between January 1, 1999, and February 7, 2017, for observational studies stratified by prepregnancy BMI category and total gestational weight gain. Data Extraction and Synthesis: Data were extracted by 2 independent reviewers. Odds ratios (ORs) and absolute risk differences (ARDs) per live birth were calculated using a random effects model based on a subset of studies with available data. Main Outcomes and Measures: Primary outcomes were small for gestational age (SGA), preterm birth, and large for gestational age (LGA). Secondary outcomes were macrosomia, cesarean delivery, and gestational diabetes mellitus. Results: Of 5354 identified studies, 23 (n = 1 309 136 women) met inclusion criteria. Gestational weight gain was below or above guidelines in 23% and 47% of pregnancies, respectively. Gestational weight gain below the recommendations was associated with higher risk of SGA (OR, 1.53 [95% CI, 1.44-1.64]; ARD, 5% [95% CI, 4%-6%]) and preterm birth (OR, 1.70 [1.32-2.20]; ARD, 5% [3%-8%]) and lower risk of LGA (OR, 0.59 [0.55 0.64]; ARD, -2% [-10% to -6%]) and macrosomia (OR, 0.60 [0.52-0.68]; ARD, -2% [ 3% to -1%]); cesarean delivery showed no significant difference (OR, 0.98 [0.96 1.02]; ARD, 0% [-2% to 1%]). Gestational weight gain above the recommendations was associated with lower risk of SGA (OR, 0.66 [0.63-0.69]; ARD, -3%; [-4% to 2%]) and preterm birth (OR, 0.77 [0.69-0.86]; ARD, -2% [-2% to -1%]) and higher risk of LGA (OR, 1.85 [1.76-1.95]; ARD, 4% [2%-5%]), macrosomia (OR, 1.95 [1.79 2.11]; ARD, 6% [4%-9%]), and cesarean delivery (OR, 1.30 [1.25-1.35]; ARD, 4% [3% 6%]). Gestational diabetes mellitus could not be evaluated because of the nature of available data. Conclusions and Relevance: In this systematic review and meta analysis of more than 1 million pregnant women, 47% had gestational weight gain greater than IOM recommendations and 23% had gestational weight gain less than IOM recommendations. Gestational weight gain greater than or less than guideline recommendations, compared with weight gain within recommended levels, was associated with higher risk of adverse maternal and infant outcomes. PMID- 28586891 TI - It's a Beautiful Thing. PMID- 28586888 TI - Association of Implementation of a Universal Testing and Treatment Intervention With HIV Diagnosis, Receipt of Antiretroviral Therapy, and Viral Suppression in East Africa. AB - Importance: Antiretroviral treatment (ART) is now recommended for all HIV positive persons. UNAIDS has set global targets to diagnose 90% of HIV-positive individuals, treat 90% of diagnosed individuals with ART, and suppress viral replication among 90% of treated individuals, for a population-level target of 73% of all HIV-positive persons with HIV viral suppression. Objective: To describe changes in the proportions of HIV-positive individuals with HIV viral suppression, HIV-positive individuals who had received a diagnosis, diagnosed individuals treated with ART, and treated individuals with HIV viral suppression, following implementation of a community-based testing and treatment program in rural East Africa. Design, Setting, and Participants: Observational analysis based on interim data from 16 rural Kenyan (n = 6) and Ugandan (n = 10) intervention communities in the SEARCH Study, an ongoing cluster randomized trial. Community residents who were 15 years or older (N = 77 774) were followed up for 2 years (2013-2014 to 2015-2016). HIV serostatus and plasma HIV RNA level were measured annually at multidisease health campaigns followed by home-based testing for nonattendees. All HIV-positive individuals were offered ART using a streamlined delivery model designed to reduce structural barriers, improve patient-clinician relationships, and enhance patient knowledge and attitudes about HIV. Main Outcomes and Measures: Primary outcome was viral suppression (plasma HIV RNA<500 copies/mL) among all HIV-positive individuals, assessed at baseline and after 1 and 2 years. Secondary outcomes included HIV diagnosis, ART among previously diagnosed individuals, and viral suppression among those who had initiated ART. Results: Among 77 774 residents (male, 45.3%; age 15-24 years, 35.1%), baseline HIV prevalence was 10.3% (7108 of 69 283 residents). The proportion of HIV-positive individuals with HIV viral suppression at baseline was 44.7% (95% CI, 43.5%-45.9%; 3464 of 7745 residents) and after 2 years of intervention was 80.2% (95% CI, 79.1%-81.2%; 5666 of 7068 residents), an increase of 35.5 percentage points (95% CI, 34.4-36.6). After 2 years, 95.9% of HIV positive individuals had been previously diagnosed (95% CI, 95.3%-96.5%; 6780 of 7068 residents); 93.4% of those previously diagnosed had received ART (95% CI, 92.8%-94.0%; 6334 of 6780 residents); and 89.5% of those treated had achieved HIV viral suppression (95% CI, 88.6%-90.3%; 5666 of 6334 residents). Conclusions and Relevance: Among individuals with HIV in rural Kenya and Uganda, implementation of community-based testing and treatment was associated with an increased proportion of HIV-positive adults who achieved viral suppression, along with increased HIV diagnosis and initiation of antiretroviral therapy. In these communities, the UNAIDS population-level viral suppression target was exceeded within 2 years after program implementation. Trial Registration: clinicaltrials.gov Identifier: NCT01864683. PMID- 28586893 TI - Growth and Rupture Risk of Small Unruptured Intracranial Aneurysms: A Systematic Review. AB - Background: Small unruptured intracranial aneurysms (UIAs) are increasingly diagnosed. Management depends on growth and rupture risks, which may vary by aneurysm size. Purpose: To summarize evidence about the growth and rupture risk of UIAs 7 mm and smaller and to explore differences in growth and rupture risks of very small (<=3 mm) and small (<=5 mm) aneurysms. Data Sources: MEDLINE, EMBASE, Scopus, and the Cochrane Library from inception to 2017 (with no language restrictions). Study Selection: Published case series and observational studies that reported natural history data on UIAs 7 mm and smaller. Data Extraction: 2 reviewers abstracted study information, evaluated study quality, and graded strength of evidence. Data Synthesis: Of 26 studies, 5, 10, and 8 described the growth rate of aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively, whereas rupture rates were reported in 7, 11, and 13 studies for aneurysms 3 mm and smaller, 5 mm and smaller, and 7 mm and smaller, respectively. The annualized growth rate was less than 3% in all but 1 study for all 3 size categories. The annualized rupture rate was 0%, less than 0.5%, and less than 1% for the 3 size categories, respectively. Strength of evidence was very low quality for growth rates and low quality for rupture rates. Limitation: Heterogeneous definitions of growth; heterogeneous and selective treatment and follow-up methods, particularly in high-risk patients. Conclusion: Poor-quality evidence suggests that small UIAs have low growth and rupture rates and very small UIAs have little or no risk for rupture. Primary Funding Source: None. PMID- 28586894 TI - Association Between Cirrhosis and Stroke in a Nationally Representative Cohort. AB - Importance: Cirrhosis is associated with hemorrhagic and thrombotic extrahepatic complications. The risk of cerebrovascular complications is less well understood. Objective: To investigate the association between cirrhosis and various stroke types. Design, Setting, and Participants: We performed a retrospective cohort study using inpatient and outpatient Medicare claims data from January 1, 2008, through December 31, 2014, for a random 5% sample of 1 618 059 Medicare beneficiaries older than 66 years. Exposures: Cirrhosis, as defined by a validated diagnosis code algorithm. Main Outcomes and Measures: The primary outcome was stroke, and secondary outcomes were ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage as defined by validated diagnosis code algorithms. Results: Among 1 618 059 beneficiaries, 15 586 patients (1.0%) had cirrhosis (mean [SD] age, 74.1 [6.9] years; 7263 [46.6%] female). During a mean (SD) of 4.3 (1.9) years of follow-up, 77 268 patients were hospitalized with a stroke. The incidence of stroke was 2.17% (95% CI, 1.99%-2.36%) per year in patients with cirrhosis and 1.11% (95% CI, 1.10%-1.11%) per year in patients without cirrhosis. After adjustment for demographic characteristics and stroke risk factors, patients with cirrhosis had a higher risk of stroke (hazard ratio [HR], 1.4; 95% CI, 1.3-1.5). The magnitude of association appeared to be higher for intracerebral hemorrhage (HR, 1.9; 95% CI, 1.5-2.4) and subarachnoid hemorrhage (HR, 2.4; 95% CI, 1.7-3.5) than for ischemic stroke (HR, 1.3; 95% CI, 1.2-1.5). Conclusions and Relevance: In a nationally representative sample of Medicare beneficiaries, cirrhosis was associated with an increased risk of stroke, particularly hemorrhagic stroke. A potential explanation of these findings implicates the mixed coagulopathy observed in cirrhosis. PMID- 28586895 TI - Data Sharing Statements for Clinical Trials: A Requirement of the International Committee of Medical Journal Editors. PMID- 28586896 TI - Cortical sources of Vernier acuity in the human visual system: An EEG-source imaging study. AB - Vernier acuity determines the relative position of visual features with a precision better than the sampling resolution of cone receptors in the retina. Because Vernier displacement is thought to be mediated by orientation-tuned mechanisms, Vernier acuity is presumed to be processed in striate visual cortex (V1). However, there is considerable evidence suggesting that Vernier acuity is dependent not only on structures in V1 but also on processing in extrastriate cortical regions. Here we used functional magnetic resonance imaging-informed electroencephalogram source imaging to localize the cortical sources of Vernier acuity in observers with normal vision. We measured suprathreshold and near threshold responses to Vernier onset/offset stimuli at different stages of the visual cortical hierarchy, including V1, hV4, lateral occipital cortex (LOC), and middle temporal cortex (hMT+). These responses were compared with responses to grating on/off stimuli, as well as to stimuli that control for lateral motion in the Vernier task. Our results show that all visual cortical regions of interest (ROIs) responded to both suprathreshold Vernier and grating stimuli. However, thresholds for Vernier displacement (Vernier acuity) were lowest in V1 and LOC compared with hV4 and hMT+, whereas all visual ROIs had identical thresholds for spatial frequency (grating acuity) and for relative motion. The cortical selectivity of sensitivity to Vernier displacement provides strong evidence that LOC, in addition to V1, is involved in Vernier acuity processing. The robust activation of LOC might be related to the sensitivity to the relative position of features, which is common to Vernier displacement and to some kinds of texture segmentation. PMID- 28586897 TI - Specular motion and 3D shape estimation. AB - Dynamic visual information facilitates three-dimensional shape recognition. It is still unclear, however, whether the motion information generated by moving specularities across a surface is congruent to that available from optic flow produced by a matte-textured shape. Whereas the latter is directly linked to the first-order properties of the shape and its motion relative to the observer, the specular flow, the image flow generated by a specular object, is less sensitive to the object's motion and is tightly related to second-order properties of the shape. We therefore hypothesize that the perceived bumpiness (a perceptual attribute related to curvature magnitude) is more stable to changes in the type of motion in specular objects compared with their matte-textured counterparts. Results from two two-interval forced-choice experiments in which observers judged the perceived bumpiness of perturbed spherelike objects support this idea and provide an additional layer of evidence for the capacity of the visual system to exploit image information for shape inference. PMID- 28586898 TI - Web Exclusives. Annals Graphic Medicine - Draw the Line. PMID- 28586899 TI - Scientific Misconduct Hurts. PMID- 28586900 TI - Scientific Misconduct Hurts. PMID- 28586901 TI - Management of Gout. PMID- 28586902 TI - Management of Gout. PMID- 28586903 TI - More Than a Rape Kit. PMID- 28586905 TI - Correction: Update in General Internal Medicine. PMID- 28586904 TI - Should This Patient Have Weight Loss Surgery?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. AB - Obesity is an important public health priority in the United States. One third of U.S. adults are obese and therefore can expect higher rates of diabetes mellitus, other obesity-related comorbidities, and mortality. In 2013, the American Association of Clinical Endocrinologists, the Obesity Society, and the American Society for Metabolic and Bariatric Surgery issued a guideline that recommended weight loss (bariatric) surgery for all patients with a body mass index (BMI) of 40 kg/m2 or higher and for those with a BMI of 35 kg/m2 or greater in the presence of at least 1 obesity-related comorbidity. Among the 3 most commonly performed surgeries, the amount of excess weight reduction ranges from 49% for laparoscopic adjustable gastric banding to 76% for Roux-en-Y gastric bypass. In accredited centers, perioperative mortality averages 0.3%. In this Beyond the Guidelines, 2 experts in obesity management, a bariatric surgeon and a general internist, discuss the role of weight loss surgery versus dietary and lifestyle modification, both in general and for a specific patient who is eligible for surgery. Ethnic and age-related variability in the effects of obesity on mortality, as well as potential long-term benefits and risks of weight loss surgery for patient subgroups, are discussed. PMID- 28586906 TI - Irritable Bowel Syndrome. AB - This issue provides a clinical overview of irritable bowel syndrome, focusing on diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers. PMID- 28586908 TI - Could This Be the Last Word on Hypertonic Saline? PMID- 28586909 TI - Sensitivity of the Speech Intelligibility Index to the Assumed Dynamic Range. AB - Purpose: This study aims to evaluate the sensitivity of the speech intelligibility index (SII) to the assumed speech dynamic range (DR) in different languages and with different types of stimuli. Method: Intelligibility prediction uses the absolute transfer function (ATF) to map the SII value to the predicted intelligibility for a given stimuli. To evaluate the sensitivity of the predicted intelligibility to the assumed DR, ATF-transformed SII scores for English (words), Korean (sentences), and Mandarin (sentences) were derived for DRs ranging from 10 dB to 60 dB. Results: Increasing the assumed DR caused steeper ATFs for all languages. However, high correlation coefficients between predicted and measured intelligibility scores were observed for DRs from 20 dB to 60 dB for ATFs in English, Korean, and Mandarin. Conclusions: Results of the present study indicate that the intelligibility computed from the SII is not sensitive to the assumed DR. The 30-dB DR commonly used in computing the SII is thus a reasonable assumption that produces accurate predictions for different languages and different types of stimuli. PMID- 28586910 TI - Corneal Potential Maps Measured With Multi-Electrode Electroretinography in Rat Eyes With Experimental Lesions. AB - Purpose: Conventional full-field flash electroretinography (ERG) yields a single response waveform that can be useful in the early detection and diagnosis of many diseases affecting the retina. It is an objective measurement that probes the entire retina. However, localized areas of dysfunction have relatively small influence on ERG amplitudes compared to normal ranges. Here we evaluate the use of corneal potential maps obtained in response to full-field flash stimuli for sensitivity to local areas of retinal damage. Methods: A contact lens electrode array was used to record 25 ERG waveforms simultaneously following saturating full-field flash stimuli (multi-electrode electroretinography, meERG) in rats. Waveforms were evaluated for a-wave and b-wave amplitudes; these values were normalized and further evaluated for spatial differences across the corneal surface. Cluster analysis and a support vector machine approach were used to classify meERG responses from healthy eyes and eyes with central (photocoagulation) or peripheral (cryocoagulation) experimental lesions. Results: A normative normalized corneal potential map was obtained from healthy eyes (n = 26). Corneal potential maps from eyes with experimental lesions (n = 13) could be classified with sensitivity and specificity of approximately 80% based solely on the normalized spatial distribution of corneal potentials, that is, with no knowledge of absolute amplitudes. Conclusions: Corneal potential maps obtained in response to full-field flash stimuli are altered in eyes with scotomas in the central and far-peripheral retina. The meERG approach yields useful spatial information following a single brief flash, analogous to body-surface potential maps used to evaluate heart and brain. PMID- 28586911 TI - SERPINA3K Ameliorates the Corneal Oxidative Injury Induced by 4-Hydroxynonenal. AB - Purpose: We previously demonstrated that SERPINA3K has anti-inflammatory, antiangiogenic, and antioxidant effects in corneas. Here we further investigated the effects of SERPINA3K on the corneal oxidant injury setting recently developed and induced by 4-hydroxynonenal (4-HNE). Methods: We applied the 4-HNE-induced corneal oxidant stress in cultured human corneal epithelial (HCE) cells in vitro and to the cornea of rats in vivo. The following experiments were conducted: cell counting kit 8 assay to detect cell viability; quantitative real-time PCR assay; Western blotting and immunofluorescent staining to measure gene expressions or protein levels of key reactive oxygen species (ROS)-associated factors (3 nitrotyrosine [3-NT]; nicotinamide adenine dinucleotide phosphate [NADPH]-oxidase 4 [NOX4]; superoxide dismutase [SOD]); catalase and nuclear factor [erythroid derived 2]-like 2 [NRF2]); as well as main factors of the Wnt/beta-catenin signaling pathway (p-LRP6, beta-catenin and transcription factor 4 [TCF4]); histologic staining; and TUNEL staining to examine sections of rat corneas. Results: We found that SERPINA3K concentration dependently protected cell viability, decreased levels of ROS marker 3-NT, suppressed NOX4, and upregulated SOD and catalase. Furthermore, SERPINA3K inhibited the activation of the ROS pathway NRF2 and its downstream factors, NAD(P)H dehydrogenase (quinone) 1 (NQO1) and heme oxygenase 1 (HO1), and also suppressed the activation of the Wnt signaling pathway p-LRP6, beta-catenin, and TCF4 in HCE cells treated with 4-HNE. Meanwhile, SERPINA3K ameliorated the oxidant injury of rat corneas induced by 4 HNE and downregulated ROS systems and the Wnt/beta-catenin pathway. Conclusions: Our findings show that SERPINA3K protected the oxidant damage induced by 4-HNE in the cornea and its underlying mechanism was through suppression of the ROS system and inhibition of the activated Wnt/beta-catenin signaling pathway. PMID- 28586913 TI - Repeatability and Reproducibility of Retinal Blood Flow Measurement Using a Doppler Optical Coherence Tomography Flowmeter in Healthy Subjects. AB - Purpose: To evaluate the repeatability and reproducibility of retinal blood flow (RBF) measurements in humans by using new auto-alignment and measurement software in a commercially available Doppler optical coherence tomography (DOCT) system. Methods: The DOCT flowmeter assessed the intrasession repeatability and the intersession and interobserver reproducibility of the RBF measurements. For intrasession repeatability, the coefficients of variation (CVs) of five repeated RBF measurements were calculated at the retinal arteries and veins in 20 normal eyes of 20 healthy volunteers. For intersession reproducibility, two sets of three measurements obtained by one observer on 2 different days were compared. For interobserver reproducibility, two sets of three measurements obtained by two observers on the same day were compared. Intraclass correlation coefficients (ICCs) also were used to evaluate the repeatability and reproducibility. The relevance of the DOCT flowmeter and laser Doppler velocimetry (LDV) also was assessed. Results: Regarding intrasession repeatability, the ICC of the RBF exceeded 0.90 in arterioles and venules (ICC: 0.994 and 0.970, respectively). The CVs of the RBF in the arterioles and venules were 6.0% +/- 3.4% and 8.8% +/- 5.1%, respectively. The intersession and interobserver RBF values had high reproducibility in the arterioles (ICC: 0.980 and 0.993, respectively) and venules (ICC: 0.982 and 0.986, respectively). The RBF measured with the DOCT flowmeter was correlated strongly with LDV in the arterioles (r = 0.76; P < 0.001). Conclusions: The DOCT flowmeter had good reproducibility in the arterioles and venules and precisely measured the RBF as compared to the LDV in the arterioles. PMID- 28586912 TI - Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open Angle Glaucoma Patients Using PCR Arrays: A Pilot Study. AB - Purpose: MicroRNAs (miRNAs) are small, endogenous noncoding RNAs that have been detected in human aqueous humor (AH). Prior studies have pooled samples to obtain sufficient quantities for analysis or used next-generation sequencing. Here, we used PCR arrays with preamplification to identify and compare miRNAs from individual AH samples between patients with primary open-angle glaucoma (POAG) and normal controls. Methods: AH was collected before cataract surgery from six stable, medically treated POAG patients and eight age-matched controls. Following reverse transcription and preamplification, individual patient samples were profiled on Taqman Low Density MicroRNA Array Cards. Differentially expressed miRNAs were stratified for fold changes larger than +/-2 and for significance of P < 0.05. Significant Kyoto Encyclopedia of Genes and Genomes pathways influenced by the differentially expressed miRNAs were identified using the predicted target module of the miRWalk 2.0 database. Results: This approach detected 181 discrete miRNAs, which were consistently expressed across all samples of both experimental groups. Significant up-regulation of miR-518d and miR-143, and significant down regulation of miR-660, was observed in the AH of POAG patients compared with controls. These miRNAs were predicted to reduce cell proliferation and extracellular matrix remodeling, endocytosis, Wnt signaling, ubiquitin-mediated proteolysis, and adherens junction function. Conclusions: This pilot study demonstrates that miRNA expression within the AH of POAG patients differs from age-matched controls. AH miRNAs exhibit potential as biomarkers of POAG, which merits further investigation in a larger case-controlled study. This technique provides a cost-effective and sensitive approach to assay miRNAs in individual patient samples without the need for pooling. PMID- 28586914 TI - Visual Performance and Optical Quality of Standardized Asymmetric Soft Contact Lenses in Patients With Keratoconus. AB - Purpose: To evaluate the visual performance and optical quality of a standardized asymmetric soft contact lens (SCL) used for correction of higher-order aberrations (HOAs) in eyes with keratoconus. Methods: We included 30 eyes (26 patients) with keratoconus (average K: 45.7 +/- 2.3 diopters [D]). The patients were subjected to corneal tomography, aberrometry, measurements of manifest refraction and visual acuity (VA), and visual analog scale (VAS) assessments. The study lenses were made using a molding method and consisted of six standardized types, in which an asymmetric power distribution of approximately 2 to 12 D (2-D step) was used to correct HOAs. The lens type suitable for each eye was selected based on the corneal tomography and aberrometry data. The on-eye performance of the lens was evaluated using aberrometry (4-mm pupil), over refraction, VA, and VAS. Results: The standardized asymmetric SCL improved the best spectacle corrected VA from -0.07 +/- 0.09 to -0.11 +/- 0.08 logMAR (P < 0.05) and the mean VAS score from 66.2 +/- 21.8 to 75.4 +/- 20.5 (P < 0.05). Vertical coma decreased significantly (-0.50 +/- 0.36 MUm without SCL; -0.36 +/- 0.34 MUm with SCL; P < 0.01). In subgroup analysis, subjects in the high VAS group (score >= 75) accounted for 70% of all subjects, and this was the group in which the vertical coma decreased significantly from the level without the lens. Conclusions: A standardized asymmetric SCL can reduce HOAs and improve vision quality when compared with spectacles in patients with keratoconus who wear rigid gas permeable lenses. PMID- 28586915 TI - Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy. AB - Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. Results: Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. Conclusions: This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease. PMID- 28586916 TI - High Glucose Induces Mitochondrial Dysfunction in Retinal Muller Cells: Implications for Diabetic Retinopathy. AB - Purpose: To investigate whether high glucose (HG) induces mitochondrial dysfunction and promotes apoptosis in retinal Muller cells. Methods: Rat retinal Muller cells (rMC-1) grown in normal (N) or HG (30 mM glucose) medium for 7 days were subjected to MitoTracker Red staining to identify the mitochondrial network. Digital images of mitochondria were captured in live cells under confocal microscopy and analyzed for mitochondrial morphology changes based on form factor (FF) and aspect ratio (AR) values. Mitochondrial metabolic function was assessed by measuring oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) using a bioenergetic analyzer. Cells undergoing apoptosis were identified by differential dye staining and TUNEL assay, and cytochrome c levels were assessed by Western blot analysis. Results: Cells grown in HG exhibited significantly increased mitochondrial fragmentation compared to those grown in N medium (FF = 1.7 +/- 0.1 vs. 2.3 +/- 0.1; AR = 2.1 +/- 0.1 vs. 2.5 +/- 0.2; P < 0.01). OCR and ECAR were significantly reduced in cells grown in HG medium compared to those grown in N medium (steady state: 75% +/- 20% of control, P < 0.02; 64% +/- 22% of control, P < 0.02, respectively). These cells also exhibited a significant increase (~2-fold) in the number of apoptotic cells compared to those grown in N medium (P < 0.01), with a concomitant increase in cytochrome c levels (247% +/- 94% of control, P < 0.05). Conclusions: Findings indicate that HG-induced mitochondrial morphology changes and subsequent mitochondrial dysfunction may contribute to retinal Muller cell loss associated with diabetic retinopathy. PMID- 28586917 TI - Toward the Virtual Benchmarking of Pneumatic Ventricular Assist Devices: Application of a Novel Fluid-Structure Interaction-Based Strategy to the Penn State 12 cc Device. AB - The pediatric use of pneumatic ventricular assist devices (VADs) as a bridge to heart transplant still suffers for short-term major complications such as bleeding and thromboembolism. Although numerical techniques are increasingly exploited to support the process of device optimization, an effective virtual benchmark is still lacking. Focusing on the 12 cc Penn State pneumatic VAD, we developed a novel fluid-structure interaction (FSI) model able to capture the device functioning, reproducing the mechanical interplay between the diaphragm, the blood chamber, and the pneumatic actuation. The FSI model included the diaphragm mechanical response from uniaxial tensile tests, realistic VAD pressure operative conditions from a dedicated mock loop system, and the behavior of VAD valves. Our FSI-based benchmark effectively captured the complexity of the diaphragm dynamics. During diastole, the initial slow diaphragm retraction in the air chamber was followed by a more rapid phase; asymmetries were noticed in the diaphragm configuration during its systolic inflation in the blood chamber. The FSI model also captured the major features of the device fluid dynamics. In particular, during diastole, a rotational wall washing pattern is promoted by the penetrating inlet jet with a low-velocity region located in the center of the device. Our numerical analysis of the 12 cc Penn State VAD points out the potential of the proposed FSI approach well resembling previous experimental evidences; if further tested and validated, it could be exploited as a virtual benchmark to deepen VAD-related complications and to support the ongoing optimization of pediatric devices. PMID- 28586921 TI - Progress on Decreasing Salt Consumption. PMID- 28586918 TI - Effect of Nebulized Hypertonic Saline Treatment in Emergency Departments on the Hospitalization Rate for Acute Bronchiolitis: A Randomized Clinical Trial. AB - Importance: Acute bronchiolitis is the leading cause of hospitalization among infants. Previous studies, underpowered to examine hospital admission, have found a limited benefit of nebulized hypertonic saline (HS) treatment in the pediatric emergency department (ED). Objective: To examine whether HS nebulization treatment would decrease the hospital admission rate among infants with a first episode of acute bronchiolitis. Design, Setting, and Participants: The Efficacy of 3% Hypertonic Saline in Acute Viral Bronchiolitis (GUERANDE) study was a multicenter, double-blind randomized clinical trial on 2 parallel groups conducted during 2 bronchiolitis seasons (October through March) from October 15, 2012, through April 15, 2014, at 24 French pediatric EDs. Among the 2445 infants (6 weeks to 12 months of age) assessed for inclusion, 777 with a first episode of acute bronchiolitis with respiratory distress and no chronic medical condition were included. Interventions: Two 20-minute nebulization treatments of 4 mL of HS, 3%, or 4 mL of normal saline (NS), 0.9%, given 20 minutes apart. Main Outcomes and Measures: Hospital admission rate in the 24 hours after enrollment. Results: Of the 777 infants included in the study (median age, 3 months; interquartile range, 2-5 months; 468 [60.2%] male), 385 (49.5%) were randomized to the HS group and 387 (49.8%) to the NS group (5 patients did not receive treatment). By 24 hours, 185 of 385 infants (48.1%) in the HS group were admitted compared with 202 of 387 infants (52.2%) in the NS group. The risk difference for hospitalizations was not significant according to the mixed-effects regression model (adjusted risk difference, -3.2%; 95% CI, -8.7% to 2.2%; P = .25). The mean (SD) Respiratory Distress Assessment Instrument score improvement was greater in the HS group (-3.1 [3.2]) than in the NS group (-2.4 [3.3]) (adjusted difference, -0.7; 95% CI, -1.2 to -0.2; P = .006) and similarly for the Respiratory Assessment Change Score. Mild adverse events, such as worsening of cough, occurred more frequently among children in the HS group (35 of 392 [8.9%]) than among those in the NS group (15 of 384 [3.9%]) (risk difference, 5.0%; 95% CI, 1.6%-8.4%; P = .005), with no serious adverse events. Conclusions and Relevance: Nebulized HS treatment did not significantly reduce the rate of hospital admissions among infants with a first episode of acute moderate to severe bronchiolitis who were admitted to the pediatric ED relative to NS, but mild adverse events were more frequent in the HS group. Trial Registration: clinicaltrials.gov Identifier: NCT01777347. PMID- 28586919 TI - Small Cerebral Aneurysms: Can We Identify Patients at Risk for Rupture? PMID- 28586924 TI - Scoring Systems for Estimating the Risk of Recurrent Venous Thromboembolism. AB - The risk of recurrence after suspension of anticoagulant treatment in patients with a first episode of unprovoked venous thromboembolism (VTE) is highly variable from patient to patient. Not all patients are candidates for life-long anticoagulant therapy, essentially because there remain concerns for such an option regarding hemorrhagic complications and clinical monitoring. Thus, the "treat all" approach may be inadequate for some patients at low risk of relapse. Proper assessment of the recurrence risk may be helpful to decide the optimal therapeutic strategy in such patients. In recent years, attempts have been made to develop and validate clinical prediction rules to estimate the absolute risk of VTE recurrence in individual patients. This article highlights the advantages and disadvantages of such options, presenting three different prediction rules that have been published so far. PMID- 28586923 TI - Presence of Human Hepegivirus-1 in a Cohort of People Who Inject Drugs. AB - Background: Next-generation metagenomic sequencing (NGMS) has opened new frontiers in microbial discovery but has been clinically characterized in only a few settings. Objective: To explore the plasma virome of persons who inject drugs and to characterize the sensitivity and accuracy of NGMS compared with quantitative clinical standards. Design: Longitudinal and cross-sectional studies. Setting: A clinical trial (ClinicalTrials.gov: NCT01285050) and a well characterized cohort study of persons who have injected drugs. Participants: Persons co-infected with hepatitis C virus (HCV) and HIV. Measurements: Viral nucleic acid in plasma by NGMS and quantitative polymerase chain reaction (PCR). Results: Next-generation metagenomic sequencing generated a total of 600 million reads, which included the expected HIV and HCV RNA sequences. HIV and HCV reads were consistently identified only when samples contained more than 10 000 copies/mL or IU/mL, respectively, as determined by quantitative PCR. A novel RNA virus, human hepegivirus-1 (HHpgV-1), was also detected by NGMS in 4 samples from 2 persons in the clinical trial. Through use of a quantitative PCR assay for HHpgV-1, infection was also detected in 17 (10.9%) of 156 members of a cohort of persons who injected drugs. In these persons, HHpgV-1 viremia persisted for a median of at least 4538 days and was associated with detection of other bloodborne viruses, such as HCV RNA and SEN virus D. Limitation: The medical importance of HHpgV-1 infection is unknown. Conclusion: Although NGMS is insensitive for detection of viruses with relatively low plasma nucleic acid concentrations, it may have broad potential for discovery of new viral infections of possible medical importance, such as HHpgV-1. Primary Funding Source: National Institutes of Health. PMID- 28586925 TI - Inhibitory Effect of Abitylguanide on Adenovirus Replication. AB - N'N'-anhydro-bis(beta-hydroxy-ethyl)biguanide.HCl (abitylguanide) demonstrated a marked inhibitory effect on replication in cell cultures of a broad spectrum of human adenoviruses both standard laboratory strains and strains isolated from epidemic keratoconjunctivitis patients. The strongest inhibitory activity was found in viruses belonging to subgroup C (Rosen's subgroup III). The compound susceptible period of human adenovirus 5 replication in primary cell cultures of human embryo kidney cells included the total replication cycle and was especially pronounced during the exponential phase of the virus growth curve. Electron microscopy established that the compound decreased the percentage of cells in which mature or empty virions with the characteristic nuclear localization were observed; a complete absence of paracrystals was registered and the number of cells with virus particles arranged in crystals in the nucleoplasm was strongly decreased. Abitylguanide can be considered as a ligand of adenovirus capsid protein(s). PMID- 28586922 TI - Noncomprehension Signaling in Males and Females With Fragile X Syndrome. AB - Purpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon study entry, participants ranged from 10 to 16 years. The average number of annual assessments per participant was 3.65 (range = 1-4), providing 198 data points for analysis. Results: Participants with FXS were less likely to signal noncomprehension than younger, typically developing, cognitively matched children. The average rate of change in noncomprehension signaling was not significantly different from 0 for either boys or girls, suggesting a plateau. Both FMRP and nonverbal IQ were significant independent predictors of noncomprehension signaling for boys. Variability in noncomprehension signaling among girls was not explained by any of the predictors, but trends similar to those observed for boys were observed. Conclusions: Noncomprehension signaling appears to be an area of weakness for individuals with FXS. Because the failure to signal noncomprehension can have negative, cumulative effects on comprehension, the results suggest a need for interventions targeting the requisite cognitive skills. PMID- 28586927 TI - [Editorial: Rare Diseases and Rare Therapies - Management in Specialised Centres Does Make Sense!] PMID- 28586926 TI - Cytoprotective Effects of Pumpkin (Cucurbita Moschata) Fruit Extract against Oxidative Stress and Carbonyl Stress. AB - Background Diabetes mellitus is a chronic endocrine disorder that is associated with significant mortality and morbidity due to microvascular and macrovascular complications. Diabetes complications accompanied with oxidative stress and carbonyl stress in different organs of human body because of the increased generation of free radicals and impaired antioxidant defense systems. In the meantime, reactive oxygen species (ROS) and reactive carbonyl species (RCS) have key mediatory roles in the development and progression of diabetes complications. Therapeutic strategies have recently focused on preventing such diabetes-related abnormalities using different natural and chemical compounds. Pumpkin (Cucurbita moschata) is one of the most important vegetables in the world with a broad-range of pharmacological activities such as antihyperglycemic effect. Methods In the present study, the cytoprotective effects of aqueous extract of C. moschata fruit on hepatocyte cytotoxicity induced by cumene hydroperoxide (oxidative stress model) or glyoxal (carbonylation model) were investigated using freshly isolated rat hepatocytes. Results The extract of C. moschata (50 MUg/ml) excellently prevented oxidative and carbonyl stress markers, including hepatocyte lysis, ROS production, lipid peroxidation, glutathione depletion, mitochondrial membrane potential collapse, lysosomal damage, and cellular proteolysis. In addition, protein carbonylation was prevented by C. moschata in glyoxal-induced carbonyl stress. Conclusion It can be concluded that C. moschata has cytoprotective effects in oxidative stress and carbonyl stress models and this valuable vegetable can be considered as a suitable herbal product for the prevention of toxic subsequent of oxidative stress and carbonyl stress seen in chronic hyperglycemia. PMID- 28586928 TI - [Biomaterials or Donor Tissue - What is the Future of Tissue Engenieering for Cornea Reconstruction?] AB - For the replacement of corneal tissue, corneal grafts or amniotic membrane are still used as a standard material. Since this is biological tissue, there is only a limited standardization regarding preparation, tissue properties and behaviour after transplantation. In addition, there is a risk of disease transmission, and the availability of both human corneas and amniotic membrane is insufficient in many regions of the world, which is why alternative biomaterials have been explored for many years now. Among the natural biomaterials, materials based on collagen or keratin provide characteristics that make them good candidates for corneal tissue replacement. However, there are still many unsolved problems, particularly regarding the degradation after implantation and the seam strength of the materials. Initial clinical studies with different biomaterials based on collagen prove their good biocompatibility to integrate and their low immunogenicity. Currently, there is no biomaterial that meets the requirements in every situation. It can be assumed that different biomaterials will be available in the future, which, depending on the underlying corneal disease, will fulfill different functions and thus make a patient- and disease-specific care possible. PMID- 28586929 TI - [Keratoprosthesis with Biological Haptic - The Dusseldorf-Offenburg-Experience with Osteo-Odonto- and Tibia-Keratoprosthesis]. AB - In severe ocular surface disease with limbal stem cell deficiency associated with severe dry eye, penetrating keratoplasty is likely to fail. In these cases, and provided the posterior segment is normal, keratoprosthesis surgery (KPro) can achieve visual rehabilitation. In KPros with an autologous biological haptic, a bone-tooth-complex (osteo-odonto-keratoprothesis, OOKPro) or a piece of tibial cortex (tibia-keratoprosthesis, TKPro) is used to carry a PMMA cylinder. This construct can successfully be implanted even in severely dry eyes and in those with autoimmune disease, in which other KPro designs frequently fail. Herein we review the published anatomic long-term results of OOKPro and TKPro on our own patients. With a mean follow-up of 7.5 years (max. 20.6) for OOKPro and 4.5 years (max. 13.3) for TKPro patients, the retention rate was 91 and 86%, respectively. We are unaware of any other technique for artificial replacement of the cornea with equally positive long-term results as KPros with a biological haptic. PMID- 28586930 TI - [Mid- and Longterm Experiences with the Boston-Keratoprosthesis. The Cologne and Salzburg Perspective]. AB - Background Eyes with severe corneal opacifications and insufficient prognosis for high-risk corneal transplantation can be considered for the implantation of a Boston-keratoprosthesis. Since 2013, this technique of "artificial" corneal replacement is provided to high-risk eyes at the Department of Ophthalmology, University of Cologne and for 9 years at the University of Salzburg. In the meantime, a type I Boston keratoprosthesis (BI-KPro) has been implanted in 24 eyes in Cologne and in 28 eyes in Salzburg. Methods In this article, results and complications according to BI-KPro are discussed, both from the literature in PubMed, as well as from our own experiences. Results Twenty-four eyes of 22 patients had been provided with a BI-KPro since September 2013, of which only one keratoprosthesis could not be obtained thus far, and an increase in visual acuity could be achieved in 23 eyes (96%). On average, 1.5 revisions per eye were required during the postoperative course. Since 2007, a BI-KPro has been implanted in 28 eyes in Salzburg. In 62% (16 of 26 eyes), visual acuity increased postoperatively, with a complication rate of 81% in a longer follow-up period. In both cohorts, the spectrum of complications ranged from retroprosthetic membrane formation, to secondary glaucoma, to infectious keratitis with or without graft melting, to vitritis, to endophthalmitis. Conclusion The range of possible complications according to BI-KPro is broad, but the BI-KPro represents currently the most widely used form of artificial corneal replacement in high-risk eyes and leads to visual improvement in most patients. PMID- 28586931 TI - [Bowman Layer Transplantation in Progressive Keratoconus - What Is It Good For?] PMID- 28586932 TI - ? PMID- 28586933 TI - A Case of Pituitary Carcinoma Initially Diagnosed as an Ectopic Growth Hormone Producing Pituitary Adenoma with a High Ki-67 Labeling Index. AB - We report a case of a 66-year-old woman with a malignant transformation of a growth hormone (GH)-producing pituitary adenoma that was mainly located in the clivus. The patient originally presented with left oculomotor and abducens nerve palsies. Magnetic resonance imaging revealed a clival tumor separated from the normal pituitary gland, and the patient subsequently underwent transsphenoidal surgery. Analysis of the resected clival tissue revealed proliferation of tumor cells with slightly irregular nuclei but no mitosis. Although the Ki-67 labeling index was as high as 8.7%, p53 was negative. Histologic analysis confirmed the diagnosis of a GH-producing pituitary adenoma. Two months after the first operation, the tumor acutely enlarged and caused a subarachnoid hemorrhage. Pathologic findings of the second surgical specimen showed significant nuclear atypia. The Ki-67 labeling index increased to 27.7% and the p53 was positive; there was no GH immunoreactivity. Following the second surgical intervention, the patient was diagnosed with an atypical pituitary adenoma and underwent postoperative local radiotherapy (50 Gy in 25 fractions). Twenty months after the first surgery, multiple bone metastases were detected that led to the diagnosis of pituitary carcinoma. This is the first report of a clival pituitary adenoma undergoing malignant transformation. Because neuroimaging may underestimate local invasiveness in ectopic pituitary tumors, it is essential to conduct a histologic examination to evaluate it. Further analysis of similar cases is necessary to improve clinical management for this confused diagnostic criterion. PMID- 28586934 TI - Brain Metastases of Non-Small Cell Lung Cancer: Prognostic Factors in Patients with Surgical Resection. AB - BACKGROUND AND STUDY AIMS: Bronchogenic carcinoma is the cancer that most commonly metastasizes to the brain. The standard treatment schedule for these patients is still unclear, although recommendation level 1 class I advocates for surgical resection together with postoperative whole-brain radiotherapy for patients with good Karnofsky performance status (KPS). We performed a study to identify prognostic factors for the long-term survival of patients with brain metastases from non-small cell lung cancer (NSCLC). PATIENTS: This retrospective single-center study included 71 patients with brain metastases from NSCLC having undergone surgical metastasectomy between January 2002 and January 2015. RESULTS: The average age was 58.8 years. A total of 85.9% of the lesions were located in the supratentorial region, 61.9% of the lesions were < 3 cm, and 80.3% of cases were solitary brain metastases. Complete resection was achieved in 90.1% of patients. Clinical debut with motor involvement was associated with higher rates of incomplete surgical resection. Patients with motor deficits had a worse preoperative KPS. The preoperative KPS was > 70 in 74.6% of patients, and the postoperative KPS was > 70 in 85.9% of patients. Overall, 84.5% of the brain surgeries had no complications. Brain metastases were diagnosed as a synchronous presentation in 64.7% of patients.The average survival after brain surgery was 20.38 months. The survival rate was 66.2% at 6 months, 45.1% at 12 months, 22.5% at 24 months, 14.1% at 36 months, and 8.5% at 48 months. Patients < 55 years of age showed a higher survival rate at 12 months and 48 months. Patients > 70 years of age showed a higher mortality rate at 6 months. Complete surgical brain metastasis resection was associated with an increased survival at 6 months, and patients undergoing primary lung surgery had better survival rates at 48 months. A preoperative KPS > 70% improved the prognosis of patients at 6 and 24 months. Surgical complications reduced survival at 6 and 12 months. CONCLUSION: Surgical resection may be beneficial for a given group of patients: a preoperative KPS > 70; age < 55 years, complete surgical brain metastasis resection, no surgical complications, patients with primary lung surgery, and complete radiotherapy treatment. We did not find any significant difference regarding further factors that probably affect survival rates such as size or number of metastases. PMID- 28586936 TI - Completely Thrombosed Aneurysms of the Posterior Cerebral Artery: A Comprehensive Review. PMID- 28586935 TI - Endoscopic Management of Arnold-Chiari Malformation Type I with or without Syringomyelia. AB - INTRODUCTION: Several different surgical techniques have been used in the treatment of patients with symptomatic Arnold-Chiari malformation type 1 (ACM-1) with or without syrinx. Endoscope-assisted decompression of the posterior fossa has been found to be safe and effective. We report our initial experience of endoscopic management of ACM-I. MATERIAL AND METHODS: This was a prospective study of 15 symptomatic patients. Pre- and postoperative clinical status and computed tomography and magnetic resonance imaging findings were recorded. Suboccipital bone of ~ 3 cm distance from the foramen of magnum and posterior arch of atlas was removed. Partial splitting of the dura mater with preservation of the inner portion and the arachnoid membrane was performed. Any change in axial and sagittal length of the syrinx, tonsillar ascension, shape of the tonsil tip, appearance of cerebrospinal fluid posterior to the tonsil, and formation of the cisterna magna were recorded. Patients with atlantoaxial instability, tethered cord, associated myelomeningocele, hydrocephalus, or elevated intracranial pressure were excluded. RESULTS: Age of patients ranged from 26 to 48 years. There were nine female patients. There were six patients with ACM-I without and nine with ACM-I with syrinx. Average pre- and postoperative Karnofsky performance score was 78 and 93, respectively. Average operative time was 130 minutes (110-190 minutes), and blood loss was 30 mL (20-180 mL). Follow-up ranged from 9 to 21 months. CONCLUSION: Although the study is limited by the small number of patients with a short follow-up, endoscopic decompression in selected patients of ACM-I with or without syrinx with dural splitting was a safe and effective alternative to microsurgical treatment. PMID- 28586937 TI - Telemetric Intracranial Pressure Recording via a Shunt System Integrated Sensor: A Safety and Feasibility Study. PMID- 28586938 TI - Superficial Temporal Artery-Middle Cerebral Artery Bypass Using a Thick STA after Endarterectomy: A Rescue Technique. AB - Background and Objective Superficial temporal artery (STA)-middle cerebral artery (MCA) bypass is a procedure to reconstruct cerebral blood flow in the MCA territory. In some cases, the STA wall is thickened and the size discrepancy between STA and MCA is apparent. In such a situation, STA-MCA bypass is challenging. We present two patients who underwent STA-MCA bypass using STA in which a thickened intima was removed. We discuss the usefulness of this rescue technique. Patients and Results A patient with an atherosclerotic MCA occlusion and another with an occluded internal carotid artery are included. Endarterectomy of STA was performed before or during anastomosis, and the intima-resected STA was anastomosed to MCA. In both cases, the STA was thick and hard, and it was difficult to anastomose the STA as it was to the MCA. Patency of the bypass was confirmed by postoperative angiography. Conclusion Endarterectomy of a thickened STA might be an effective rescue technique in cases with severely atherosclerotic STA in STA-MCA bypass. PMID- 28586939 TI - [Urgent Visits to Nursing Homes: A General Practitioner's Perspective]. AB - Aim of the study Due to demographic changes, home visits to nursing care facilities are increasing. Urgent home visits represent a challenge for general practitioners. There are no recommendations for the implementation of urgent home visits. Therefore, in this study, we investigated how GP practices deal with urgent home visits and what improvements can be made to the medical emergency care. Methods A total of 15 teaching doctors of the Department of Family Medicine at the University of Bonn were interviewed using semi-structured interviews on the subject. We evaluated the interviews with the qualitative content analysis according to Mayring. Results Urgent house visits were requested by telephone or fax. The home visits were carried out usually after the consultation hours during the lunch break of the doctors. General practitioners consider forwarding the request for a house visit to the rescue service as an absolute exception. At the nursing home, there were waiting times until the responsible nursing staff could do a joint emergency visit. In addition, there were clear differences in the qualifications of nurses and in dealing with emergencies. The physicians therefore saw improvements in their ability to provide further training to the nursing staff, to preventive house visits, and to assess the urgency of home visits. Conclusion To improve emergency care in elderly homes, the suggestions for improvement proposed by the family doctors should be tested in controlled studies. In addition, the cooperation between general practitioners and nursing homes could be strengthened by joint training in geriatric emergency care. PMID- 28586940 TI - [Morbidity Compression in Stroke: Longitudinal Analyses on Changes in the Incidence of Stroke]. AB - Summary According to Fries, morbidity compression occurs if age at onset of disease/disability and age at death increase. Morbidity compression is also present if disease/disability rates decrease to the same or to a larger extent than standardized death rates. In all cases, healthy lifetime is gained. Not many studies on morbidity compression are available, and only a small number of them refer to specific diseases. Stroke is used as an example for examining whether morbidity compression has occurred over an observation period of 9 years. Methods The study was based on pseudonymized data of a statutory health insurance covering 2006-2014 with 2 million insured per year. Analyses were performed for all types of stroke, separately for cerebral infarction, and for hemorrhages (ICD 10: I60-I62). Calculations were performed by means of survival analyses and with multiple regression. Results In women and in men, rates decreased only for hemorrhagic strokes, while changes of onset age were difficult to interpret. Standardized death rates dropped only in males. Conclusions Evidence in favor of morbidity compression was found only for decreasing rates of hemorrhagic strokes. It has, however, to be kept in mind that the findings refer to a single disease occurring relatively late in the life course. Comprehensive assessments of morbidity compression are only possible taking into consideration a broader spectrum of diseases. PMID- 28586941 TI - [Patients are Satisfied with the Physician-Patient Communication: A Pilot Study Applying the "Individual Clinician Feedback" Questionnaire]. AB - AIM OF THE STUDY: Patient-centeredness as an essential aspect of quality of patient care is becoming increasingly important. The aim of the pilot study is to gain insight into the physician-patient communication from the patient's perspective. A German questionnaire in a maximum care hospital was tested. METHODS: The German "Individual Clinician Feedback" questionnaire (ICF) was tested in a pilot study in the special consultation in a voluntary cohort of surgeons. In the survey period from June to August 2015, the questionnaire was given to the patient. The physicians received their assessment results as a compressed score. They were rated on a scale of 1-10 on which 10 is "very good". RESULTS: 12 physicians were recruited from five departments. There was a high response rate of 46% (n=219). The patients evaluated the communication as very good (on average over all items and physicians 8.5 to 9.5 points). 89% of the patients had the feeling that the doctor took adequate time for them, while 50% of the patients had a consultation time of 11-20 min. 12% of the patients had still open questions after treatment that they did not ask. 19% and 21% of patients reported that the physician has not asked them if they had any questions, or that they just forgot about it at the end of treatment. CONCLUSION: The results of the pilot study are associated with a good response rate and patients were mostly very satisfied with the physician-patient communication. However, a selection bias among participating physicians is likely. PMID- 28586942 TI - [Drawing up a Guideline for Handling Information and Communication Technology, Flexibility and Availability in Small and Medium Enterprises]. AB - Background Within the last decades the world of work has changed enormously. Due to new Information and Communication Technologies (ICT), working at any time from any place has become possible. Flexibility, availability and the dissolution of boundaries between work and private life are the possible results of this development. The spread of this development and possible consequences on the affected employee's health and wellbeing have been examined so far especially in big companies. Small and medium-sized enterprises (SME) are rarely subjects of scientific studies in this context. Objective of this paper The aim of this work was to develop a guideline based on experiences and results of a study regarding flexibility in the business world (FlexA), as well as a systematic literature research. The target populations of this guideline are SMEs, focusing on integrating a health promoting way in dealing with ICT, flexibility and availability within the corporate culture. Methods In order to delineate the current state in of research in ICT-related work interventions, a systematic review in data bases e. g. PsycINFO, EconLit and Medline was carried out. The search strategy used the key words "work", "intervention", "ICT", "mental strain", "flexibility" and "availability". In addition, grey literature and findings from the FlexA study were used to formulate the current guideline. Results Based on the exclusion criteria, all studies from the systematic literature search were excluded after title and abstract screening. Within grey literature research, 4 relevant publications could be identified. The measures, developed during the corporate workshops of the FlexA study, e. g. the implementation of collective regulations in the company, were included in the guideline. Conclusion Due to the ongoing development of ICT and flexibility in daily business life, it is getting more and more important to follow this progress. Executives and corporate management are responsible to actively shape this trend in a health-promoting way in their enterprises. The current guideline was made to support the corporate management in this task and it is an important instrument for a health-promoting use of ICT in daily business life taking in to consideration flexibility and availability. PMID- 28586944 TI - Defining Prognostic Biomarkers and Optimal Adjuvant Treatment for Gynecologic Cancer. PMID- 28586943 TI - Oxytocin and Its Relationship to Body Composition, Bone Mineral Density, and Hip Geometry Across the Weight Spectrum. AB - Context: Oxytocin (OXT), an anorexigenic hypothalamic hormone anabolic to bone, may reflect energy availability. Basal serum OXT levels are lower in anorexia nervosa (AN, state of energy deficit) than healthy controls (HC) and negatively associated with spine bone mineral density (BMD). Reports are conflicting regarding OXT levels in overweight/obesity (OB, state of energy excess). Relationships between OXT and BMD in OB and hip geometry across the weight spectrum are unknown. Objective: To determine whether overnight serum OXT levels are (1) elevated in OB and (2) associated with body composition, BMD, and hip geometry across the weight spectrum. Design: Cross-sectional. Setting: Clinical research center. Participants: Fifty-nine women, ages 18 to 45 years: amenorrheic AN (N = 16), eumenorrheic HC (N = 24), eumenorrheic OB (N = 19). Main Outcome Measures: Serum sampled every 20 minutes from 8 pm to 8 am and pooled for integrated overnight OXT levels. Body composition, BMD, and hip structural analysis measured by dual x-ray absorptiometry. Results: OXT levels were lowest in AN, higher in HC, and highest in OB (P <= 0.02). There were positive associations between OXT and (1) body mass index (P = 0.0004); (2) total, visceral, and subcutaneous fat (P <= 0.0002); (3) spine and hip BMD Z-scores (P <= 0.01); and (4) favorable hip geometry, namely buckling ratio (P <= 0.05). In a subset analysis of HC and OB, relationships between OXT and body composition, but not bone parameters, remained significant. Conclusions: These data suggest OXT is a marker of energy availability and may be a mediator of bone density, structure, and strength. OXT pathways may provide targets for obesity and osteoporosis treatment. PMID- 28586945 TI - Low-Dose-Rate Brachytherapy Versus Cryotherapy in Low- and Intermediate-Risk Prostate Cancer. AB - PURPOSE: Cryotherapy and brachytherapy are definitive local treatment options for low- to intermediate-risk prostate cancer. There are both prospective and retrospective data for brachytherapy, but the use of cryotherapy has been limited primarily to single-institution retrospective studies. Currently, no published evidence has compared low-dose-rate brachytherapy versus cryotherapy. METHODS AND MATERIALS: Institutional review board approval was obtained to conduct a retrospective chart review of consecutive patients treated at our institution from 1990 to 2012. For inclusion, patients must have received a prostate cancer diagnosis and have been considered to have low- to intermediate-risk disease according to the National Comprehensive Cancer Network criteria. All patients received brachytherapy or cryotherapy treatment. Disease specifics and failure details were collected for all patients. Failure was defined as prostate-specific antigen nadir +2 ng/mL. RESULTS: A total of 359 patients were analyzed. The groups comprised 50 low-risk cryotherapy (LRC), 92 intermediate-risk cryotherapy (IRC), 133 low-risk brachytherapy (LRB), and 84 intermediate-risk brachytherapy (IRB) patients. The median prostate-specific antigen follow-up periods were 85.6 months (LRC), 59.2 months (IRC), 74.9 months (LRB), and 59.8 months (IRB). The 5 year biochemical progression-free survival (bPFS) rate was 57.9% in the cryotherapy group versus 89.6% in the brachytherapy group (P<.0001). The 5-year bPFS rate was 70.0% (LRC), 51.4% (IRC), 89.4% (LRB), and 89.7% (IRB). The bPFS rate was significantly different between brachytherapy and cryotherapy for low- and intermediate-risk groups (P<.05). The mean nadir temperature reached for cryotherapy patients was -35 degrees C (range, -96 degrees C to -6 degrees C). Cryotherapy used a median of 2 freeze-thaw cycles (range, 2-4 freeze-thaw cycles). CONCLUSIONS: Results from this study suggest that cryotherapy is inferior to brachytherapy for patients with low- to intermediate-risk prostate cancer. Patient selection criteria for consideration of cryotherapy and brachytherapy are similar in terms of anesthesia candidacy. Therefore, cryotherapy would not be recommended as a first-line local therapy for this particular patient subset. PMID- 28586946 TI - Increasing Fractional Doses Increases the Probability of Benign PSA Bounce in Patients Undergoing Definitive HDR Brachytherapy for Prostate Cancer. AB - PURPOSE: Prostate-specific antigen (PSA) bounce is a temporary elevation of the PSA level above a prior nadir. The purpose of this study was to determine whether the frequency of a PSA bounce following high-dose-rate (HDR) interstitial brachytherapy for the treatment of prostate cancer is associated with individual treatment fraction size. METHODS AND MATERIALS: Between 1999 and 2014, 554 patients underwent treatment of low- or intermediate-risk prostate cancer with definitive HDR brachytherapy as monotherapy and had >=3 subsequent PSA measurements. Four different fraction sizes were used: 950 cGy * 4 fractions, 1200 cGy * 2 fractions, 1350 cGy * 2 fractions, 1900 cGy * 1 fraction. Four definitions of PSA bounce were applied: >=0.2, >=0.5, >=1.0, and >=2.0 ng/mL above the prior nadir with a subsequent return to the nadir. RESULTS: The median follow-up period was 3.7 years. The actuarial 3-year rate of PSA bounce for the entire cohort was 41.3%, 28.4%, 17.4%, and 6.8% for nadir +0.2, +0.5, +1.0, and +2.0 ng/mL, respectively. The 3-year rate of PSA bounce >0.2 ng/mL was 42.2%, 32.1%, 41.0%, and 59.1% for the 950-, 1200-, 1350-, and 1900-cGy/fraction levels, respectively (P=.002). The hazard ratio for bounce >0.2 ng/mL for patients receiving a single fraction of 1900 cGy compared with those receiving treatment in multiple fractions was 1.786 (P=.024). For patients treated with a single 1900 cGy fraction, the 1-, 2-, and 3-year rates of PSA bounce exceeding the Phoenix biochemical failure definition (nadir +2 ng/mL) were 4.5%, 18.7%, and 18.7%, respectively, higher than the rates for all other administered dose levels (P=.025). CONCLUSIONS: The incidence of PSA bounce increases with single-fraction HDR treatment. Knowledge of posttreatment PSA kinetics may aid in decision making regarding management of potential biochemical failures. PMID- 28586947 TI - Adjuvant Therapy in High-Risk Stage III Cutaneous Melanoma. PMID- 28586948 TI - Clinical Outcomes of Image Guided Adaptive Hypofractionated Weekly Radiation Therapy for Bladder Cancer in Patients Unsuitable for Radical Treatment. AB - PURPOSE AND OBJECTIVES: We report on the clinical outcomes of a phase 2 study assessing image guided hypofractionated weekly radiation therapy in bladder cancer patients unsuitable for radical treatment. METHODS AND MATERIALS: Fifty five patients with T2-T4aNx-2M0-1 bladder cancer not suitable for cystectomy or daily radiation therapy treatment were recruited. A "plan of the day" radiation therapy approach was used, treating the whole (empty) bladder to 36 Gy in 6 weekly fractions. Acute toxicity was assessed weekly during radiation therapy, at 6 and 12 weeks using the Common Terminology Criteria for Adverse Events version 3.0. Late toxicity was assessed at 6 months and 12 months using Radiation Therapy Oncology Group grading. Cystoscopy was used to assess local control at 3 months. Cumulative incidence function was used to determine local progression at 1 at 2 years. Death without local progression was treated as a competing risk. Overall survival was estimated using the Kaplan-Meier method. RESULTS: Median age was 86 years (range, 68-97 years). Eighty-seven percent of patients completed their prescribed course of radiation therapy. Genitourinary and gastrointestinal grade 3 acute toxicity was seen in 18% (10/55) and 4% (2/55) of patients, respectively. No grade 4 genitourinary or gastrointestinal toxicity was seen. Grade >=3 late toxicity (any) at 6 and 12 months was seen in 6.5% (2/31) and 4.3% (1/23) of patients, respectively. Local control after radiation therapy was 92% of assessed patients (60% total population). Cumulative incidence of local progression at 1 year and 2 years for all patients was 7% (95% confidence interval [CI] 2%-17%) and 17% (95% CI 8%-29%), respectively. Overall survival at 1 year was 63% (95% CI 48%-74%). CONCLUSION: Hypofractionated radiation therapy delivered weekly with a plan of the day approach offers good local control with acceptable toxicity in a patient population not suitable for radical bladder treatment. PMID- 28586950 TI - Encourage Enrollment in Clinical Trials of Neoadjuvant or Adjuvant Systemic Therapy, and Consider Adjuvant Radiation Therapy to Prevent Morbid Recurrence. PMID- 28586951 TI - Radiation Therapy Followed by Ipilimumab Is Appropriate. PMID- 28586949 TI - Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results. AB - PURPOSE: We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. METHODS: HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. RESULTS: With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01). CONCLUSION: On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL. PMID- 28586953 TI - Dry Eye Syndrome After Proton Therapy of Ocular Melanomas. AB - PURPOSE: To investigate whether proton therapy (PT) performs safely in superotemporal melanomas, in terms of risk of dry-eye syndrome (DES). METHODS AND MATERIALS: Tumor location, DES grade, and dose to ocular structures were analyzed in patients undergoing PT (2005-2015) with 52 Gy (prescribed dose, not accounting for biologic effectiveness correction of 1.1). Prognostic factors of DES and severe DES (sDES, grades 2-3) were determined with Cox proportional hazard models. Visual acuity deterioration and enucleation rates were compared by sDES and tumor locations. RESULTS: Median follow-up was 44 months (interquartile range, 18-60 months). Of 853 patients (mean age, 64 years), 30.5% had temporal and 11.4% superotemporal tumors. Five-year incidence of DES and sDES was 23.0% (95% confidence interval [CI] 19.0%-27.7%) and 10.9% (95% CI 8.2%-14.4%), respectively. Multivariable analysis showed a higher risk for sDES in superotemporal (hazard ratio [HR] 5.82, 95% CI 2.72-12.45) and temporal tumors (HR 2.63, 95% CI 1.28-5.42), age >=70 years (HR 1.90, 95% CI 1.09-3.32), distance to optic disk >=5 mm (HR 2.71, 95% CI 1.52-4.84), >=35% of retina receiving 12 Gy (HR 2.98, 95% CI 1.54-5.77), and eyelid rim irradiation (HR 2.68, 95% CI 1.49 4.80). The same risk factors were found for DES. Visual acuity deteriorated more in patients with sDES (0.86 +/- 1.10 vs 0.64 +/- 0.98 logMAR, P=.034) but not between superotemporal/temporal and other locations (P=.890). Enucleation rates were independent of sDES (P=.707) and tumor locations (P=.729). CONCLUSIONS: Severe DES was more frequent in superotemporal/temporal melanomas. Incidence of vision deterioration and enucleation was no higher in patients with superotemporal melanoma than in patients with tumors in other locations. Tumor location should not contraindicate PT. PMID- 28586952 TI - Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone. AB - PURPOSE: Prior statistical models attempted to identify risk factors for time to distant brain failure (DBF) or time to salvage whole-brain radiation therapy (WBRT) to predict the benefit of early WBRT versus stereotactic radiosurgery (SRS) alone. We introduce a novel clinical metric, brain metastasis velocity (BMV), for predicting clinical outcomes after initial DBF following upfront SRS alone. METHODS AND MATERIALS: BMV was defined as the cumulative number of new brain metastases that developed over time since first SRS in years. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new metastases per year, respectively. Histology, number of metastases at the time of first SRS, and systemic disease status were assessed for effect on BMV. RESULTS: Of 737 patients treated at our institution with upfront SRS without WBRT, 286 had >=1 DBF event. A lower BMV predicted for improved overall survival (OS) following initial DBF (log-rank P<.0001). Median OS for the low, intermediate, and high BMV groups was 12.4 months (95% confidence interval [CI], 10.4-16.9 months), 8.2 months (95% CI, 5.0-9.7 months), and 4.3 months (95% CI, 2.6-6.7 months), respectively. Multivariate analysis showed that BMV remained the dominant predictor of OS, with a hazard ratio of 2.75 for the high BMV group (95% CI, 1.94-3.89; P<.0001) and a hazard ratio of 1.65 for the intermediate BMV group (95% CI, 1.18-2.30; P<.004). A lower BMV was associated with decreased rates of salvage WBRT (P=.02) and neurologic death (P=.008). Factors predictive for a higher BMV included >=2 initial brain metastases (P=.004) and melanoma histology (P=.008). CONCLUSIONS: BMV is a novel metric associated with OS, neurologic death, and need for salvage WBRT after initial DBF following upfront SRS alone. PMID- 28586954 TI - Consider Adjuvant Intensity Modulated Radiation Therapy to the Lymph Node Basin, Especially If the Melanoma Is BRAF Wild Type. PMID- 28586955 TI - Adjuvant Therapy in High-Risk Stage III Cutaneous Melanoma. PMID- 28586956 TI - Stereotactic Radiosurgery and Fractionated Stereotactic Radiation Therapy for the Treatment of Uveal Melanoma. AB - PURPOSE: To evaluate treatment results of stereotactic radiosurgery or fractionated stereotactic radiation therapy (SRS/FSRT) for uveal melanoma. METHODS AND MATERIALS: We retrospectively evaluated 181 patients with 182 uveal melanomas receiving SRS/FSRT between 2007 and 2013. Treatment was administered with CyberKnife. RESULTS: According to Collaborative Ocular Melanoma Study criteria, tumor size was small in 1%, medium in 49.5%, and large in 49.5% of the patients. Seventy-one tumors received <45 Gy, and 111 received >=45 Gy. Median follow-up time was 24 months. Complete and partial response was observed in 8 and 104 eyes, respectively. The rate of 5-year overall survival was 98%, disease-free survival 57%, local recurrence-free survival 73%, distant metastasis-free survival 69%, and enucleation-free survival 73%. There was a significant correlation between tumor size and disease-free survival, SRS/FSRT dose and enucleation-free survival; and both were prognostic for local recurrence-free survival. Enucleation was performed in 41 eyes owing to progression in 26 and complications in 11. CONCLUSIONS: The radiation therapy dose is of great importance for local control and eye retention; the best treatment outcome was achieved using >=45 Gy in 3 fractions. PMID- 28586957 TI - Adjuvant and Neoadjuvant Therapy in High-Risk Stage III Cutaneous Melanoma. PMID- 28586958 TI - Reporting Quality of Randomized, Controlled Trials Evaluating Combined Chemoradiotherapy in Nasopharyngeal Carcinoma. AB - PURPOSE: To comprehensively assess the reporting quality of randomized, controlled trials (RCTs) in nasopharyngeal carcinoma (NPC), and to identify significant predictors of quality. METHODS AND MATERIALS: Two investigators searched MEDLINE and EMBASE for RCTs published between January 1988 and December 2015 that assessed the effect of combined chemoradiotherapy for NPC. The overall quality of each report was assessed using a 28-point overall quality score (OQS) based on the 2010 Consolidated Standards of Reporting Trials (CONSORT) statement. To provide baseline data for further evaluation, we also investigated the reporting quality of certain important issues in detail, including key methodologic items (allocation concealment, blinding, intention-to-treat principle), endpoints, follow-up, subgroup analyses, and adverse events. RESULTS: We retrieved 24 relevant RCTs including 6591 patients. Median 2010 OQS was 15.5 (range, 10-24). Half of the items in the 2010 OQS were poorly reported in at least 40% of trials. Multivariable regression models revealed that publication after 2010 and high impact factor were significant predictors of improved 2010 OQS. Additionally, many issues that we consider significant were not reported adequately. CONCLUSIONS: Despite publication of the CONSORT statement more than a decade ago, overall reporting quality for RCTs in NPC was unsatisfactory. Additionally, substantial selectivity and heterogeneity exists in reporting of certain crucial issues. This survey provides the first prompt for NPC trial investigators to improve reporting quality according to the CONSORT statement; increased scrutiny and diligence by editors and peer reviewers is also required. PMID- 28586959 TI - The Ever-Evolving Role of the Academic Clinical Physicist. PMID- 28586960 TI - Preliminary Results of a Phase 1 Dose-Escalation Trial for Early-Stage Breast Cancer Using 5-Fraction Stereotactic Body Radiation Therapy for Partial-Breast Irradiation. AB - PURPOSE: To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. METHODS AND MATERIALS: Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size <3 cm. Patients and physicians completed baseline and subsequent cosmesis outcome questionnaires. Starting dose was 30 Gy in 5 fractions and was escalated by 2.5 Gy total for each cohort to 40 Gy. RESULTS: In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. CONCLUSION: Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting. PMID- 28586961 TI - Long-Term Results of a Highly Performing Conformal Electron Therapy Technique for Chest Wall Irradiation After Mastectomy. AB - PURPOSE: To evaluate locoregional control and survival after mastectomy, as well as toxicity, in patients irradiated by a previously described postmastectomy highly conformal electron beam radiation therapy technique (PMERT). METHODS AND MATERIALS: We included all women irradiated by postmastectomy electron beam radiation therapy for nonmetastatic breast cancer between 2007 and 2011 in our department. Acute and late toxicities were retrospectively assessed using Common Terminology Criteria for Adverse Events version 3.0 criteria. RESULTS: Among the 796 women included, 10.1% were triple-negative, 18.8% HER2-positive, and 24.6% received neoadjuvant chemotherapy (CT). Multifocal lesions were observed in 51.3% of women, and 64.6% had at least 1 involved lymph node (LN). Internal mammary chain, supraclavicular, infraclavicular, and axillary LNs were treated in 85.6%, 88.3%, 77.9%, and 14.9% of cases, respectively. With a median follow-up of 64 months (range, 6-102 months), 5-year locoregional recurrence-free survival and overall survival were 90% (95% confidence interval 88.1%-92.4%) and 90.9% (95% confidence interval 88.9%-93%), respectively. Early skin toxicity was scored as grade 1 in 58.5% of patients, grade 2 in 35.9%, and grade 3 in 4.5%. Concomitant CT was associated with increased grade 3 toxicity (P<.001). At long-term follow up, 29.8% of patients presented temporary or permanent hyperpigmentation or telangiectasia or fibrosis (grade 1: 23.6%; grade 2: 5.2%; grade 3: 1%), with higher rates among smokers (P=.06); 274 patients (34.4%) underwent breast reconstruction. Only 24 patients (3%) had early esophagitis of grade 1. Only 3 patients developed ischemic heart disease: all had been treated by anthracycline based CT with or without trastuzumab, all had been irradiated to the left chest wall and LN, and all presented numerous cardiovascular risk factors (2-4 factors). CONCLUSIONS: This study demonstrated the good efficacy of this technique in terms of locoregional control and survival, and good short-term and long-term safety. Longer follow-up is required to analyze chronic cardiac events. PMID- 28586963 TI - In Reply to Jenelle and Chang. PMID- 28586962 TI - Nature of Medical Malpractice Claims Against Radiation Oncologists. AB - PURPOSE: To examine characteristics of medical malpractice claims involving radiation oncologists closed during a 10-year period. METHODS AND MATERIALS: Malpractice claims filed against radiation oncologists from 2003 to 2012 collected by a nationwide liability insurance trade association were analyzed. Outcomes included the nature of claims and indemnity payments, including associated presenting diagnoses, procedures, alleged medical errors, and injury severity. We compared the likelihood of a claim resulting in payment in relation to injury severity categories (death as referent) using binomial logistic regression. RESULTS: There were 362 closed claims involving radiation oncology, 102 (28%) of which were paid, resulting in $38 million in indemnity payments. The most common alleged errors included "improper performance" (38% of closed claims, 18% were paid; 29% [$11 million] of total indemnity), "errors in diagnosis" (25% of closed claims, 46% were paid; 44% [$17 million] of total indemnity), and "no medical misadventure" (14% of closed claims, 8% were paid; less than 1% [$148,000] of total indemnity). Another physician was named in 32% of claims, and consent issues/breach of contract were cited in 18%. Claims for injury resulting in death represented 39% of closed claims and 25% of total indemnity. "Improper performance" was the primary alleged error associated with injury resulting in death. Compared with claims involving death, major temporary injury (odds ratio [OR] 2.8, 95% confidence interval [CI] 1.29-5.85, P=.009), significant permanent injury (OR 3.1, 95% CI 1.48-6.46, P=.003), and major permanent injury (OR 5.5, 95% CI 1.89-16.15, P=.002) had a higher likelihood of a claim resulting in indemnity payment. CONCLUSIONS: Improper performance was the most common alleged malpractice error. Claims involving significant or major injury were more likely to be paid than those involving death. Insights into the nature of liability claims against radiation oncologists may help direct efforts to improve quality of care and minimize the risk of being sued. PMID- 28586964 TI - In Regard to Dr Vapiwala. PMID- 28586965 TI - In Regard to Shaverdian et al. PMID- 28586966 TI - In Reply to Scott. PMID- 28587049 TI - Female Representation in the Academic Oncology Physician Workforce: Radiation Oncology Losing Ground to Hematology Oncology. AB - PURPOSE: Our purpose was to assess comparative female representation trends for trainees and full-time faculty in the academic radiation oncology and hematology oncology workforce of the United States over 3 decades. METHODS AND MATERIALS: Simple linear regression models with year as the independent variable were used to determine changes in female percentage representation per year and associated 95% confidence intervals for trainees and full-time faculty in each specialty. RESULTS: Peak representation was 48.4% (801/1654) in 2013 for hematology oncology trainees, 39.0% (585/1499) in 2014 for hematology oncology full-time faculty, 34.8% (202/581) in 2007 for radiation oncology trainees, and 27.7% (439/1584) in 2015 for radiation oncology full-time faculty. Representation significantly increased for trainees and full-time faculty in both specialties at approximately 1% per year for hematology oncology trainees and full-time faculty and 0.3% per year for radiation oncology trainees and full-time faculty. Compared with radiation oncology, the rates were 3.84 and 2.94 times greater for hematology oncology trainees and full-time faculty, respectively. CONCLUSION: Despite increased female trainee and full-time faculty representation over time in the academic oncology physician workforce, radiation oncology is lagging behind hematology oncology, with trainees declining in recent years in radiation oncology; this suggests a de facto ceiling in female representation. Whether such issues as delayed or insufficient exposure, inadequate mentorship, or specialty competitiveness disparately affect female representation in radiation oncology compared to hematology oncology are underexplored and require continued investigation to ensure that the future oncologic physician workforce reflects the diversity of the population it serves. PMID- 28587050 TI - Application of Critical Volume-Dose Constraints for Stereotactic Body Radiation Therapy in NRG Radiation Therapy Trials. PMID- 28587052 TI - Clinical Development of Cancer Drugs in Combination With External Beam Radiation Therapy: US Food and Drug Administration Perspective. PMID- 28587051 TI - Evaluating Intensity Modulated Proton Therapy Relative to Passive Scattering Proton Therapy for Increased Vertebral Column Sparing in Craniospinal Irradiation in Growing Pediatric Patients. AB - PURPOSE: At present, proton craniospinal irradiation (CSI) for growing children is delivered to the whole vertebral body (WVB) to avoid asymmetric growth. We aimed to demonstrate the feasibility and potential clinical benefit of delivering vertebral body sparing (VBS) versus WVB CSI with passively scattered (PS) and intensity modulated proton therapy (IMPT) in growing children treated for medulloblastoma. METHODS AND MATERIALS: Five plans were generated for medulloblastoma patients, who had been previously treated with CSI PS proton radiation therapy: (1) single posteroanterior (PA) PS field covering the WVB (PS PA-WVB); (2) single PA PS field that included only the thecal sac in the target volume (PS-PA-VBS); (3) single PA IMPT field covering the WVB (IMPT-PA-WVB); (4) single PA IMPT field, target volume including thecal sac only (IMPT-PA-VBS); and (5) 2 posterior-oblique (-35 degrees , +35 degrees ) IMPT fields, with the target volume including the thecal sac only (IMPT2F-VBS). For all cases, 23.4 Gy (relative biologic effectiveness [RBE]) was prescribed to 95% of the spinal canal. The dose, linear energy transfer, and variable-RBE-weighted dose distributions were calculated for all plans using the tool for particle simulation, version 2, Monte Carlo system. RESULTS: IMPT VBS techniques efficiently spared the anterior vertebral bodies (AVBs), even when accounting for potential higher variable RBE predicted by linear energy transfer distributions. Assuming an RBE of 1.1, the V10 Gy(RBE) decreased from 100% for the WVB techniques to 59.5% to 76.8% for the cervical, 29.9% to 34.6% for the thoracic, and 20.6% to 25.1% for the lumbar AVBs, and the V20 Gy(RBE) decreased from 99.0% to 17.8% to 20.0% for the cervical, 7.2% to 7.6% for the thoracic, and 4.0% to 4.6% for the lumbar AVBs when IMPT VBS techniques were applied. The corresponding percentages for the PS VBS technique were higher. CONCLUSIONS: Advanced proton techniques can sufficiently reduce the dose to the vertebral body and allow for vertebral column growth for children with central nervous system tumors requiring CSI. This was true even when considering variable RBE values. A clinical trial is planned for VBS to the thoracic and lumbosacral spine in growing children. PMID- 28587053 TI - Quantitative Approach to Failure Mode and Effect Analysis for Linear Accelerator Quality Assurance. AB - PURPOSE: To determine clinic-specific linear accelerator quality assurance (QA) TG-142 test frequencies, to maximize physicist time efficiency and patient treatment quality. METHODS AND MATERIALS: A novel quantitative approach to failure mode and effect analysis is proposed. Nine linear accelerator-years of QA records provided data on failure occurrence rates. The severity of test failure was modeled by introducing corresponding errors into head and neck intensity modulated radiation therapy treatment plans. The relative risk of daily linear accelerator QA was calculated as a function of frequency of test performance. RESULTS: Although the failure severity was greatest for daily imaging QA (imaging vs treatment isocenter and imaging positioning/repositioning), the failure occurrence rate was greatest for output and laser testing. The composite ranking results suggest that performing output and lasers tests daily, imaging versus treatment isocenter and imaging positioning/repositioning tests weekly, and optical distance indicator and jaws versus light field tests biweekly would be acceptable for non-stereotactic radiosurgery/stereotactic body radiation therapy linear accelerators. CONCLUSIONS: Failure mode and effect analysis is a useful tool to determine the relative importance of QA tests from TG-142. Because there are practical time limitations on how many QA tests can be performed, this analysis highlights which tests are the most important and suggests the frequency of testing based on each test's risk priority number. PMID- 28587054 TI - Later Life Changes in Hippocampal Neurogenesis and Behavioral Functions After Low Dose Prenatal Irradiation at Early Organogenesis Stage. AB - PURPOSE: To investigate long-term changes in behavioral functions of mice after exposure to low-dose prenatal radiation at an early organogenesis stage. METHODS AND MATERIALS: Pregnant C57BL/6J mice were irradiated (20 cGy) at postcoitus day 5.5. The male and female offspring were subjected to different behavioral assays for affective, motor, and cognitive functions at 3, 6, and 12 months of age. Behavioral functions were further correlated with the population of CA1 and CA3 pyramidal neurons and immature neurons in hippocampal dentate gyrus. RESULTS: Prenatally exposed mice of different age groups showed a sex-specific pattern of sustained changes in behavioral functions. Male mice showed significant changes in anxiety-like phenotypes, learning, and long-term memory at age 3 months. At 6 months of age such behavioral functions were recovered to a normal level but could not be sustained at age 12 months. Female mice showed an appreciable recovery in almost all behavioral functions at 12 months. Patterns of change in learning and long-term memory were comparable to the population of CA1 and CA3 pyramidal neurons and doublecortin-positive neurons in hippocampus. CONCLUSION: Our finding suggests that prenatal (early organogenesis stage) irradiation even at a lower dose level (20 cGy) is sufficient to cause potential changes in neurobehavioral function at later stages of life. Male mice showed relatively higher vulnerability to radiation-induced neurobehavioral changes as compared with female. PMID- 28587055 TI - Radiation-Specific Clinical Data Should Be Included in Existing Large-Scale Genomic Datasets. PMID- 28587056 TI - Tolerance of the Brachial Plexus to High-Dose Reirradiation. AB - PURPOSE: To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. METHODS AND MATERIALS: Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24 months (range, 3-144 months). RESULTS: The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5 Gy to 150.1 Gy (median, 95.0 Gy). The cumulative mean (Dmean) dose ranged from 20.2 Gy to 111.5 Gy (median, 63.8 Gy). The 1-year freedom from brachial plexus-related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0 Gy, respectively (P=.05). The 1 year complication-free rate was 66% and 87%, for those reirradiated within and after 2 years from the initial course, respectively (P=.06). CONCLUSION: The development of brachial plexus-related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications. PMID- 28587059 TI - Selected Risk Nutritional Factors for Chemotherapy-Induced Polyneuropathy. AB - The present study seeks to identify the nutritional risk factors involved in the development of neuropathies induced by chemotherapeutic treatments. Unlike the gastrointestinal or hematological adverse effects of chemotherapy there is no protective treatment strategy for polyneuropathy. The aim of this study was to find possible deficiencies in nutritional factors, which can be used for supplementation in the future for prevention of chemotherapy-induced neuropathy development. We analyzed 70 patients undergoing paclitaxel chemotherapy and evaluated the risk factors involved in chemotherapy-induced peripheral neuropathy (CIPN). Several risk factors were considered in the development of CIPN, including deficiency of vitamin B1, B6, and D and fatty acids. The occurrence of CIPN complication in 60% cases was observed. We found significant differences in vitamin D and saturated fatty acid concentration. Vitamin D levels in the group without CIPN were estimated to be 38.2 (24.95, 47.63) nmol/L, whereas in the group with CIPN it was determined to be 25.6 (19.7, 32.55) nmol/L, p = 0.008. The level of total saturated fatty acids in the group without CIPN was of 32.613 Area % (31.322; 36.262), whereas in the group with CIPN it was of 34.209 Area % (32.86; 39.386), p = 0.01. The obtained results suggest a diet lower in saturated fatty acid content during chemotherapy. The most significant finding was that supplementation of vitamin D before chemotherapy could be an efficient neuroprotective in CIPN prophylaxis, as significantly lower levels 25OH derivative of vitamin D were observed in the CIPN group throughout the study period. PMID- 28587060 TI - Is Root Catalase a Bifunctional Catalase-Peroxidase? AB - Plant catalases exhibit spatial and temporal distribution of their activity. Moreover, except from the typical monofunctional catalase, a bifunctional catalase-peroxidase has been reported. The aim of this study was to investigate whether the leaf and root catalases from six different plant species (Lactuca sativa, Cichorium endivia, Apium graveolens, Petroselinum crispum, Lycopersicon esculentum, and Solanum melongena) correspond to the monofunctional or the bifunctional type based on their sensitivity to the inhibitor 3-amino-1,2,4 triazole (3-AT). The leaf catalases from all species seem to be monofunctional since they are very sensitive to 3-AT. On the other hand, the root enzymes from Lactuca sativa, Cichorium endivia, Lycopersicon esculentum, and Solanum melongena seem to be bifunctional catalase-peroxidases, considering that they are relatively insensitive to 3-AT, whereas the catalases from Apium graveolens and Petroselinum crispum display the same monofunctional characteristics as the leaves' enzymes. The leaf catalase activity is usually higher (Lactuca sativa, Petroselinum crispum, and Solanum melongena) or similar (Cichorium endivia and Apium graveolens) to the root one, except for the enzyme from Lycopersicon esculentum, while in all plant species the leaf protein concentration is significantly higher than the root protein concentration. These results suggest that there are differences between leaf and root catalases-differences that may correspond to their physiological role. PMID- 28587057 TI - Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases. AB - PURPOSE: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. METHODS AND MATERIALS: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with chi2, Kaplan-Meier, and log-rank tests. RESULTS: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9% 95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. CONCLUSIONS: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies. PMID- 28587061 TI - Enhanced Osseointegration of a Modified Titanium Implant with Bound Phospho Threonine: A Preliminary In Vivo Study. AB - Implant surface topography is a key factor in achieving osseointegration. l Threonine can be chemically and stably bonded to titanium surfaces by phosphorylation. This study investigated the degree of in vivo osseointegration of an implant with a novel o-phospho-l-threonine (p-Thr)-binding surface. MC3T3 E1 cells were seeded on the p-Thr binding surface and machined surface disks, and initial cell attachment was evaluated. p-Thr-binding and machined surface implants were tested in vivo by implantation into the femurs of three male New Zealand white rabbits, and the osseointegration was assessed by measurement of removal torque (RT) and bone-implant contact (BIC) ratio. Initial cell attachment was greater for the p-Thr-binding than for the machined surface implant group (P < 0.05). In addition, RT and BIC values were higher for the p-Thr-binding surface than for the machined surface (P < 0.05). These results indicate that our implant with a p-Thr-binding surface can achieve enhanced osseointegration. PMID- 28587063 TI - A Relative Deficiency of Lysosomal Acid Lypase Activity Characterizes Non Alcoholic Fatty Liver Disease. AB - Lysosomal acid lipase (LAL) is a key enzyme in lipid metabolism. Initial reports have suggested a role for a relative acquired LAL deficiency in non-alcoholic fatty liver disease (NAFLD)-however, it is still unclear whether this mechanism is specific for NAFLD. We aimed to determine LAL activity in a cohort of NAFLD subjects and in a control group of hepatitis C virus (HCV)-infected patients, investigating the role of liver cirrhosis. A total of 81 patients with a diagnosis of NAFLD, and 78 matched controls with HCV-related liver disease were enrolled. For each patient, LAL activity was determined on peripheral dried blood spots (DBS) and correlated with clinical and laboratory data. A subgroup analysis among cirrhotic patients was also performed. LAL activity is significantly reduced in NAFLD, compared to that in HCV patients. This finding is particularly evident in the pre-cirrhotic stage of disease. LAL activity is also correlated with platelet and white blood cell count, suggesting an analytic interference of portal-hypertension-induced pancytopenia on DBS-determined LAL activity. NAFLD is characterized by a specific deficit in LAL activity, suggesting a pathogenetic role of LAL. We propose that future studies on this topic should rely on tissue specific analyses, as peripheral blood tests are also influenced by confounding factors. PMID- 28587065 TI - Amorphous SiC/c-ZnO-Based Quasi-Lamb Mode Sensor for Liquid Environments. AB - The propagation of the quasi-Lamb modes along a-SiC/ZnO thin composite plates was modeled and analysed with the aim to design a sensor able to detect the changes in parameters of a liquid environment, such as added mass and viscosity changes. The modes propagation was modeled by numerically solving the system of coupled electro-mechanical field equations in three media. The mode shape, the power flow, the phase velocity, and the electroacoustic coupling efficiency (K2) of the modes were calculated, specifically addressing the design of enhanced-coupling, microwave frequency sensors for applications in probing the solid/liquid interface. Three modes were identified that have predominant longitudinal polarization, high phase velocity, and quite good K2: the fundamental quasi symmetric mode (qS0) and two higher order quasi-longitudinal modes (qL1 and qL2) with a dominantly longitudinal displacement component in one plate side. The velocity and attenuation of these modes were calculated for different liquid viscosities and added mass, and the gravimetric and viscosity sensitivities of both the phase velocity and attenuation were theoretically calculated. The present study highlights the feasibility of the a-SiC/ZnO acoustic waveguides for the development of high-frequency, integrated-circuit compatible electroacoustic devices suitable for working in a liquid environment. PMID- 28587066 TI - Mapping Winter Wheat with Multi-Temporal SAR and Optical Images in an Urban Agricultural Region. AB - Winter wheat is the second largest food crop in China. It is important to obtain reliable winter wheat acreage to guarantee the food security for the most populous country in the world. This paper focuses on assessing the feasibility of in-season winter wheat mapping and investigating potential classification improvement by using SAR (Synthetic Aperture Radar) images, optical images, and the integration of both types of data in urban agricultural regions with complex planting structures in Southern China. Both SAR (Sentinel-1A) and optical (Landsat-8) data were acquired, and classification using different combinations of Sentinel-1A-derived information and optical images was performed using a support vector machine (SVM) and a random forest (RF) method. The interference coherence and texture images were obtained and used to assess the effect of adding them to the backscatter intensity images on the classification accuracy. The results showed that the use of four Sentinel-1A images acquired before the jointing period of winter wheat can provide satisfactory winter wheat classification accuracy, with an F1 measure of 87.89%. The combination of SAR and optical images for winter wheat mapping achieved the best F1 measure-up to 98.06%. The SVM was superior to RF in terms of the overall accuracy and the kappa coefficient, and was faster than RF, while the RF classifier was slightly better than SVM in terms of the F1 measure. In addition, the classification accuracy can be effectively improved by adding the texture and coherence images to the backscatter intensity data. PMID- 28587064 TI - Prostaglandin E2-Induced COX-2 Expressions via EP2 and EP4 Signaling Pathways in Human LoVo Colon Cancer Cells. AB - Metastasis is the most dangerous risk faced by patients with hereditary non polyposis colon cancer (HNPCC). The expression of matrix metalloproteinases (MMPs) has been observed in several types of human cancers and regulates the efficacy of many therapies. Here, we show that treatment with various concentrations of prostaglandin E2 (PGE2; 0, 1, 5 or 10 MUM) promotes the migration ability of the human LoVo colon cancer cell line. As demonstrated by mRNA and protein expression analyses, EP2 and EP4 are the major PGE2 receptors expressed on the LoVo cell membrane. The Phosphatidylinositol-4,5-bisphosphate 3 kinase (PI3K)/Akt cell survival pathway was upregulated by EP2 and EP4 activation. Following the activation of the PI3K/Akt pathway, beta-catenin translocated into the nucleus and triggered COX2 transcription via LEF-1 and TCF 4 and its subsequent translation. COX2 expression correlated with the elevation in the migration ability of LoVo cells. The experimental evidence shows a possible mechanism by which PGE2 induces cancer cell migration and further suggests PGE2 to be a potential therapeutic target in colon cancer metastasis. On inhibition of PGE2, in order to determine the downstream pathway, the levels of PI3K/Akt pathway were suppressed and the beta-catenin expression was also modulated. Inhibition of EP2 and EP4 shows that PGE2 induces protein expression of COX-2 through EP2 and EP4 receptors in LoVo colon cancer cells. PMID- 28587062 TI - MYC Deregulation in Primary Human Cancers. AB - MYC regulates a complex biological program by transcriptionally activating and repressing its numerous target genes. As such, MYC is a master regulator of many processes, including cell cycle entry, ribosome biogenesis, and metabolism. In cancer, the activity of the MYC transcriptional network is frequently deregulated, contributing to the initiation and maintenance of disease. Deregulation often leads to constitutive overexpression of MYC, which can be achieved through gross genetic abnormalities, including copy number alterations, chromosomal translocations, increased enhancer activity, or through aberrant signal transduction leading to increased MYC transcription or increased MYC mRNA and protein stability. Herein, we summarize the frequency and modes of MYC deregulation and describe both well-established and more recent findings in a variety of cancer types. Notably, these studies have highlighted that with an increased appreciation for the basic mechanisms deregulating MYC in cancer, new therapeutic vulnerabilities can be discovered and potentially exploited for the inhibition of this potent oncogene in cancer. PMID- 28587067 TI - Diet-Induced Low-Grade Metabolic Acidosis and Clinical Outcomes: A Review. AB - Low-grade metabolic acidosis is a condition characterized by a slight decrease in blood pH, within the range considered normal, and feeding is one of the main factors that may influence the occurrence of such a condition. The excessive consumption of acid precursor foods (sources of phosphorus and proteins), to the detriment of those precursors of bases (sources of potassium, calcium, and magnesium), leads to acid-base balance volubility. If this condition occurs in a prolonged, chronic way, low-grade metabolic acidosis can become significant and predispose to metabolic imbalances such as kidney stone formation, increased bone resorption, reduced bone mineral density, and the loss of muscle mass, as well as the increased risk of chronic diseases such as type 2 diabetes mellitus, hypertension, and non-alcoholic hepatic steatosis. Considering the increase in the number of studies investigating the influence of diet-induced metabolic acidosis on clinical outcomes, this review gathers the available evidence evaluating the association of this disturbance and metabolic imbalances, as well as related mechanisms. It is necessary to look at the western dietary pattern of most countries and the increasing incidence of non-comunicable diseases for the balance between fruit and vegetable intake and the appropriate supply of protein, mainly from animal sources, so that it does not exceed the daily recommendations. PMID- 28587070 TI - Development and Initial Assessment of a Patient Education Video about Pharmacogenetics. AB - As few patient-friendly resources about pharmacogenetics are currently available, we aimed to create and assess a patient educational video on pharmacogenetic testing. A primary literature and resources review was conducted to inform the content and the format of the video. The educational video was then created using a commercially available animation program and pilot tested in focus groups of the general public and by an online survey of pharmacists. Emerging themes from the focus groups and survey indicate a desire for appropriate risk contextualization and specific examples when pharmacogenetic testing may be beneficial. Focus group participants also expressed a preference for a video with live action, and more text to reinforce concepts. Pharmacists generally felt that the video was understandable for patients and relevant for decision-making regarding testing. Using this initial feedback and the identification of important concepts to include in pharmacogenetics educational tools, we plan to revise the video, perform additional evaluations, and publish the video for public use in the future. PMID- 28587069 TI - Taste Perception of Sweet, Sour, Salty, Bitter, and Umami and Changes Due to l Arginine Supplementation, as a Function of Genetic Ability to Taste 6-n Propylthiouracil. AB - Behavioral reaction to different taste qualities affects nutritional status and health. 6-n-Propylthiouracil (PROP) tasting has been reported to be a marker of variation in taste perception, food preferences, and eating behavior, but results have been inconsistent. We showed that l-Arg can enhance the bitterness intensity of PROP, whilst others have demonstrated a suppression of the bitterness of quinine. Here, we analyze the taste perception of sweet, sour, salty, bitter, and umami and the modifications caused by l-Arg supplementation, as a function of PROP-taster status. Taste perception was assessed by testing the ability to recognize, and the responsiveness to, representative solutions of the five primary taste qualities, also when supplemented with l-Arg, in subjects classified as PROP-tasting. Super-tasters, who showed high papilla density, gave higher ratings to sucrose, citric acid, caffeine, and monosodium l-glutamate than non-tasters. l-Arg supplementation mainly modified sucrose perception, enhanced the umami taste, increased NaCl saltiness and caffeine bitterness only in tasters, and decreased citric acid sourness. Our findings confirm the role of PROP phenotype in the taste perception of sweet, sour, and bitter and show its role in umami. The results suggest that l-Arg could be used as a strategic tool to specifically modify taste responses related to eating behaviors. PMID- 28587068 TI - Genetic Variants Involved in One-Carbon Metabolism: Polymorphism Frequencies and Differences in Homocysteine Concentrations in the Folic Acid Fortification Era. AB - Folate and other B vitamins are essential co-factors of one-carbon metabolism, and genetic variants, such as polymorphisms, can alter the metabolism. Furthermore, the adoption of food fortification with folic acid showed a decrease of homocysteine concentration. The aim of this study was to investigate the frequencies of the polymorphisms of enzymes and carrier proteins involved in one carbon metabolism, and to evaluate homocysteine concentrations in the presence of these genetic variants in a population exposed to mandatory food fortification with folic acid. Using data from a population-based cross-sectional study in Sao Paulo, Brazil, the study population comprised 750 participants above 12 years of age of both genders. A linear regression model was used to evaluate the homocysteine concentrations according to genetic variants and folate level. The results showed that the minor allelic frequencies were 0.33 for MTHFR (rs1801133), 0.24 for MTHFR (rs1801131), 0.19 for MTR (rs1805087), 0.42 for MTRR (rs1801394), 0.46 for RFC1 (rs1051266), and 0.47 for DHFR (19-bp deletion). The genetic variants of MTHFR 677C>T, MTRR 66A>G and RFC-1 80G>A were different according to race. The homocysteine concentrations increased in the CT and TT compared to CC genotypes of polymorphism MTHFR 677C>T in all populations, and differences between the homocysteine concentrations according to the genotypes of MTHFR 677C>T were observed regardless of folate level. PMID- 28587071 TI - Traffic Sign Detection System for Locating Road Intersections and Roundabouts: The Chilean Case. AB - This paper presents a traffic sign detection method for signs close to road intersections and roundabouts, such as stop and yield (give way) signs. The proposed method relies on statistical templates built using color information for both segmentation and classification. The segmentation method uses the RGB normalized (ErEgEb) color space for ROIs (Regions of Interest) generation based on a chromaticity filter, where templates at 10 scales are applied to the entire image. Templates consider the mean and standard deviation of normalized color of the traffic signs to build thresholding intervals where the expected color should lie for a given sign. The classification stage employs the information of the statistical templates over YCbCr and ErEgEb color spaces, for which the background has been previously removed by using a probability function that models the probability that the pixel corresponds to a sign given its chromaticity values. This work includes an analysis of the detection rate as a function of the distance between the vehicle and the sign. Such information is useful to validate the robustness of the approach and is often not included in the existing literature. The detection rates, as a function of distance, are compared to those of the well-known Viola-Jones method. The results show that for distances less than 48 m, the proposed method achieves a detection rate of 87.5 % and 95.4 % for yield and stop signs, respectively. For distances less than 30 m, the detection rate is 100 % for both signs. The Viola-Jones approach has detection rates below 20 % for distances between 30 and 48 m, and barely improves in the 20-30 m range with detection rates of up to 60 % . Thus, the proposed method provides a robust alternative for intersection detection that relies on statistical color-based templates instead of shape information. The experiments employed videos of traffic signs taken in several streets of Santiago, Chile, using a research platform implemented at the Robotics and Automation Laboratory of PUC to develop driver assistance systems. PMID- 28587072 TI - Automatic Detection of Driver Fatigue Using Driving Operation Information for Transportation Safety. AB - Fatigued driving is a major cause of road accidents. For this reason, the method in this paper is based on the steering wheel angles (SWA) and yaw angles (YA) information under real driving conditions to detect drivers' fatigue levels. It analyzes the operation features of SWA and YA under different fatigue statuses, then calculates the approximate entropy (ApEn) features of a short sliding window on time series. Using the nonlinear feature construction theory of dynamic time series, with the fatigue features as input, designs a "2-6-6-3" multi-level back propagation (BP) Neural Networks classifier to realize the fatigue detection. An approximately 15-h experiment is carried out on a real road, and the data retrieved are segmented and labeled with three fatigue levels after expert evaluation, namely "awake", "drowsy" and "very drowsy". The average accuracy of 88.02% in fatigue identification was achieved in the experiment, endorsing the value of the proposed method for engineering applications. PMID- 28587073 TI - Epidemiological Features and Forecast Model Analysis for the Morbidity of Influenza in Ningbo, China, 2006-2014. AB - This study aimed to identify circulating influenza virus strains and vulnerable population groups and investigate the distribution and seasonality of influenza viruses in Ningbo, China. Then, an autoregressive integrated moving average (ARIMA) model for prediction was established. Influenza surveillance data for 2006-2014 were obtained for cases of influenza-like illness (ILI) (n = 129,528) from the municipal Centers for Disease Control and virus surveillance systems of Ningbo, China. The ARIMA model was proposed to predict the expected morbidity cases from January 2015 to December 2015. Of the 13,294 specimens, influenza virus was detected in 1148 (8.64%) samples, including 951 (82.84%) influenza type A and 197 (17.16%) influenza type B viruses; the influenza virus isolation rate was strongly correlated with the rate of ILI during the overall study period (r = 0.20, p < 0.05). The ARIMA (1, 1, 1) (1, 1, 0)12 model could be used to predict the ILI incidence in Ningbo. The seasonal pattern of influenza activity in Ningbo tended to peak during the rainy season and winter. Given those results, the model we established could effectively predict the trend of influenza-related morbidity, providing a methodological basis for future influenza monitoring and control strategies in the study area. PMID- 28587074 TI - Erratum: Jiang, J.; et al. Expeditious Synthesis of Dianionic-Headed 4 Sulfoalkanoic Acid Surfactants. Molecules 2017, 22, 640. AB - The authors wish to make the following change to their paper [1]. [...]. PMID- 28587076 TI - Structure Modification of an Active Azo-Compound as a Route to New Antimicrobial Compounds. AB - Some novel (phenyl-diazenyl)phenols 3a-g were designed and synthesized to be evaluated for their antimicrobial activity. A previously synthesized molecule, active against bacteria and fungi, was used as lead for modifications and optimization of the structure, by introduction/removal or displacement of hydroxyl groups on the azobenzene rings. The aim of this work was to evaluate the consequent changes of the antimicrobial activity and to validate the hypothesis that, for these compounds, a plausible mechanism could involve an interaction with protein receptors, rather than an interaction with membrane. All newly synthesized compounds were analyzed by 1H-NMR, DSC thermal analysis and UV-Vis spectroscopy. The in vitro minimal inhibitory concentrations (MIC) of each compound was determined against Gram-positive and Gram-negative bacteria and Candida albicans. Compounds 3b and 3g showed the highest activity against S. aureus and C. albicans, with remarkable MIC values of 10 ug/mL and 3 ug/mL, respectively. Structure-activity relationship studies were capable to rationalize the effect of different substitutions on the phenyl ring of the azobenzene on antimicrobial activity. PMID- 28587075 TI - Identification of Anthocyanin Composition and Functional Analysis of an Anthocyanin Activator in Solanum nigrum Fruits. AB - Solanum nigrum fruits have been conventionally used in beverages due to their nutritional substances such as minerals, vitamins, amino acids, proteins, sugars, polyphenols, and anthocyanins. The characterization of components and regulatory mechanism of anthocyanins in S. nigrum fruits have rarely been reported. In this study, we determined that the peel and flesh of S. nigrum fruits shared similar HPLC profiles but different contents and total antioxidant activities for anthocyanins. After an efficient purification method, mainly including extraction with pH 1.0 distilled water and then desorption with pH 1.0 95% ethanol after a DM-130 resin adsorption step to obtain more pure anthocyanin extracts, the purity of anthocyanins extracted from S. nigrum fruits reached 56.1%. Moreover, eight anthocyanins from S. nigrum fruit were identified with HPLC-MS/MS for the first time. A typical R2R3-MYB transcription factor gene, SnMYB, was also cloned for the first time by rapid amplification of cDNA ends (RACE)-PCR from S. nigrum. Moreover, the contents of anthocyanins were shown to correlate well (r = 0.93) with the expression levels of SnMYB gene during the fruit's developmental stages. Most significantly, SnMYB gene successfully produced high anthocyanin content (1.03 mg/g) when SnMYB gene was transiently expressed in tobacco leaves. Taken together, S. nigrum fruits are a promising resource for anthocyanin extraction, and SnMYB gene is an activator that positively regulates anthocyanin biosynthesis in S. nigrum. PMID- 28587077 TI - Floral Scent Chemistry of Luculia yunnanensis (Rubiaceae), a Species Endemic to China with Sweetly Fragrant Flowers. AB - Luculia plants are famed ornamentals with sweetly fragrant flowers. Luculia yunnanensis Hu is an endemic plant from Yunnan Province, China. Headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) was used to identify the volatile organic compounds (VOCs) of the different flower development stages of L. yunnanensis for the evaluation of floral volatile polymorphism. The results showed that a total of 40 compounds were identified at four different stages. The main aroma-active compounds were 3-carene, alpha cubebene, alpha-copaene, delta-cadinene, and isoledene. Floral scent emission had the tendency to ascend first and descend in succession, reaching its peak level at the initial-flowering stage. The richest diversity of floral volatiles was detected at the full-flowering stage. Principal component analysis (PCA) indicated that the composition and its relative content of floral scent differed at the whole flower development stage. In comparison with the other two species of Luculia (L. pinceana and L. gratissima), the composition and its relative content of floral scent were also different among the tree species. PMID- 28587079 TI - Immunomodulatory Effect of Agave tequilana Evaluated on an Autoimmunity Like-SLE Model Induced in Balb/c Mice with Pristane. AB - In this work, the immunomodulatory activity of the acetone extract and the fructans obtained from Agave tequilana were evaluated, on the systemic autoimmunity type-SLE model generated by the administration of 2,6,10,14 tetramethylpentadecane (TMPD, also known as pristane) on Balb/c female mice. The systemic autoimmunity type-SLE was observed seven months after the application of TMPD, in which the animals from the negative control group (animals with damage and without any other treatment) developed articular inflammation, proteinuria, an increment of the antinuclear antibody titters and tissue pro-inflammatory cytokines levels (IL-1beta, IL-6, TNF-alpha e IFN-gamma) as well as the anti inflammatory cytokine IL-10. The administration of the different treatments and the extracts of A. tequilana, provoked the decrease of: articular inflammation, the development of proteinuria, ssDNA/dsDNA antinuclear antibody titters and cytokines IL-1beta, IL-6, TNF-alpha, IFN-gamma and IL-10. The phytochemical analysis of the acetone extract identified the presence of the following compounds: beta-sitosterol glycoside; 3,7,11,15-tetramethyl-2-hexadecen-1-ol (phytol); octadecadienoic acid-2,3-dihydroxypropyl ester; stigmasta-3,5-dien-7 one; cycloartenone and cycloartenol. Therefore, A. tequilana contains active compounds with the capacity to modify the evolution of the systemic autoimmunity type-SLE on a murine model. PMID- 28587078 TI - Morinda citrifolia Linn. (Noni) and Its Potential in Obesity-Related Metabolic Dysfunction. AB - Cultural and economic shifts in the early 19th century led to the rapid development of companies that made good profits from technologically-produced commodities. In this way, some habits changed in society, such as the overconsumption of processed and micronutrient-poor foods and devices that gave rise to a sedentary lifestyle. These factors influenced host-microbiome interactions which, in turn, mediated the etiopathogenesis of "new-era" disorders and diseases, which are closely related, such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, hypertension, and inflammatory bowel disease, which are characterized by chronic dysregulation of metabolic and immune processes. These pathological conditions require novel and effective therapeutic approaches. Morindacitrifolia (noni) is well known as a traditional healing plant due to its medicinal properties. Thus, many studies have been conducted to understand its bioactive compounds and their mechanisms of action. However, in obesity and obesity-related metabolic (dysfunction) syndrome, other studies are necessary to better elucidate noni's mechanisms of action, mainly due to the complexity of the pathophysiology of obesity and its metabolic dysfunction. In this review, we summarize not only the clinical effects, but also important cell signaling pathways in in vivo and in vitro assays of potent bioactive compounds present in the noni plant which have been reported in studies of obesity and obesity-associated metabolic dysfunction. PMID- 28587080 TI - Predicting Zoonotic Risk of Influenza A Viruses from Host Tropism Protein Signature Using Random Forest. AB - Influenza A viruses remain a significant health problem, especially when a novel subtype emerges from the avian population to cause severe outbreaks in humans. Zoonotic viruses arise from the animal population as a result of mutations and reassortments, giving rise to novel strains with the capability to evade the host species barrier and cause human infections. Despite progress in understanding interspecies transmission of influenza viruses, we are no closer to predicting zoonotic strains that can lead to an outbreak. We have previously discovered distinct host tropism protein signatures of avian, human and zoonotic influenza strains obtained from host tropism predictions on individual protein sequences. Here, we apply machine learning approaches on the signatures to build a computational model capable of predicting zoonotic strains. The zoonotic strain prediction model can classify avian, human or zoonotic strains with high accuracy, as well as providing an estimated zoonotic risk. This would therefore allow us to quickly determine if an influenza virus strain has the potential to be zoonotic using only protein sequences. The swift identification of potential zoonotic strains in the animal population using the zoonotic strain prediction model could provide us with an early indication of an imminent influenza outbreak. PMID- 28587081 TI - Tea Drinking and Its Association with Active Tuberculosis Incidence among Middle Aged and Elderly Adults: The Singapore Chinese Health Study. AB - Experimental studies showed that tea polyphenols may inhibit growth of Mycobacterium tuberculosis. However, no prospective epidemiologic study has investigated tea drinking and the risk of active tuberculosis. We investigated this association in the Singapore Chinese Health Study, a prospective population based cohort of 63,257 Chinese aged 45-74 years recruited between 1993 and 1998 in Singapore. Information on habitual drinking of tea (including black and green tea) and coffee was collected via structured questionnaires. Incident cases of active tuberculosis were identified via linkage with the nationwide tuberculosis registry up to 31 December 2014. Cox proportional hazard models were used to estimate the relation of tea and coffee consumption with tuberculosis risk. Over a mean 16.8 years of follow-up, we identified 1249 incident cases of active tuberculosis. Drinking either black or green tea was associated with a dose dependent reduction in tuberculosis risk. Compared to non-drinkers, the hazard ratio (HR) (95% confidence interval (CI)) was 1.01 (0.85-1.21) in monthly tea drinkers, 0.84 (0.73-0.98) in weekly drinkers, and 0.82 (0.71-0.96) in daily drinkers (p for trend = 0.003). Coffee or caffeine intake was not significantly associated with tuberculosis risk. In conclusion, regular tea drinking was associated with a reduced risk of active tuberculosis. PMID- 28587084 TI - A Max-Flow Based Algorithm for Connected Target Coverage with Probabilistic Sensors. AB - Coverage is a fundamental issue in the research field of wireless sensor networks (WSNs). Connected target coverage discusses the sensor placement to guarantee the needs of both coverage and connectivity. Existing works largely leverage on the Boolean disk model, which is only a coarse approximation to the practical sensing model. In this paper, we focus on the connected target coverage issue based on the probabilistic sensing model, which can characterize the quality of coverage more accurately. In the probabilistic sensing model, sensors are only be able to detect a target with certain probability. We study the collaborative detection probability of target under multiple sensors. Armed with the analysis of collaborative detection probability, we further formulate the minimum epsilon connected target coverage problem, aiming to minimize the number of sensors satisfying the requirements of both coverage and connectivity. We map it into a flow graph and present an approximation algorithm called the minimum vertices maximum flow algorithm (MVMFA) with provable time complex and approximation ratios. To evaluate our design, we analyze the performance of MVMFA theoretically and also conduct extensive simulation studies to demonstrate the effectiveness of our proposed algorithm. PMID- 28587083 TI - Design, Synthesis, and Biological Activities of Novel Pyrazole Oxime Compounds Containing a Substituted Pyridyl Moiety. AB - In this paper, in order to find novel biologically active pyrazole oximes, a series of pyrazole oxime compounds bearing a substituted pyridyl unit were prepared. Bioassays showed that some target compounds were found to have good acaricidal activity against Tetranychus cinnabarinus at a concentration of 500 MUg/mL, compound 9q especially displayed potent acaricidal activity against T. cinnabarinus when the concentration was reduced to 100 MUg/mL. Interestingly, most target compounds possessed excellent insecticidal activities against Oriental armyworm at 500 MUg/mL. Moreover, some compounds were active against Aphis medicaginis and Nilaparvata lugens at 500 MUg/mL. Additionally, compounds 9b, 9g, 9l, 9p, 9q, 9r, 9s, 9t, 9u, and 9v displayed significant antiproliferative activities against HepG2 cells with IC50 values of 1.53-17.27 MUM, better than that of the control 5-fluorouracil (IC50 = 35.67 MUM). PMID- 28587085 TI - A Novel Complex-Coefficient In-Band Interference Suppression Algorithm for Cognitive Ultra-Wide Band Wireless Sensors Networks. AB - With the rapid development of wireless communication systems and electronic techniques, the limited frequency spectrum resources are shared with various wireless devices, leading to a crowded and challenging coexistence circumstance. Cognitive radio (CR) and ultra-wide band (UWB), as sophisticated wireless techniques, have been considered as significant solutions to solve the harmonious coexistence issues. UWB wireless sensors can share the spectrum with primary user (PU) systems without harmful interference. The in-band interference of UWB systems should be considered because such interference can severely affect the transmissions of UWB wireless systems. In order to solve the in-band interference issues for UWB wireless sensor networks (WSN), a novel in-band narrow band interferences (NBIs) elimination scheme is proposed in this paper. The proposed narrow band interferences suppression scheme is based on a novel complex coefficient adaptive notch filter unit with a single constrained zero-pole pair. Moreover, in order to reduce the computation complexity of the proposed scheme, an adaptive complex-coefficient iterative method based on two-order Taylor series is designed. To cope with multiple narrow band interferences, a linear cascaded high order adaptive filter and a cyclic cascaded high order matrix adaptive filter (CCHOMAF) interference suppression algorithm based on the basic adaptive notch filter unit are also presented. The theoretical analysis and numerical simulation results indicate that the proposed CCHOMAF algorithm can achieve better performance in terms of average bit error rate for UWB WSNs. The proposed in-band NBIs elimination scheme can significantly improve the reception performance of low-cost and low-power UWB wireless systems. PMID- 28587086 TI - Evaluation and Comparison of the Processing Methods of Airborne Gravimetry Concerning the Errors Effects on Downward Continuation Results: Case Studies in Louisiana (USA) and the Tibetan Plateau (China). AB - Gravity data gaps in mountainous areas are nowadays often filled in with the data from airborne gravity surveys. Because of the errors caused by the airborne gravimeter sensors, and because of rough flight conditions, such errors cannot be completely eliminated. The precision of the gravity disturbances generated by the airborne gravimetry is around 3-5 mgal. A major obstacle in using airborne gravimetry are the errors caused by the downward continuation. In order to improve the results the external high-accuracy gravity information e.g., from the surface data can be used for high frequency correction, while satellite information can be applying for low frequency correction. Surface data may be used to reduce the systematic errors, while regularization methods can reduce the random errors in downward continuation. Airborne gravity surveys are sometimes conducted in mountainous areas and the most extreme area of the world for this type of survey is the Tibetan Plateau. Since there are no high-accuracy surface gravity data available for this area, the above error minimization method involving the external gravity data cannot be used. We propose a semi-parametric downward continuation method in combination with regularization to suppress the systematic error effect and the random error effect in the Tibetan Plateau; i.e., without the use of the external high-accuracy gravity data. We use a Louisiana airborne gravity dataset from the USA National Oceanic and Atmospheric Administration (NOAA) to demonstrate that the new method works effectively. Furthermore, and for the Tibetan Plateau we show that the numerical experiment is also successfully conducted using the synthetic Earth Gravitational Model 2008 (EGM08)-derived gravity data contaminated with the synthetic errors. The estimated systematic errors generated by the method are close to the simulated values. In addition, we study the relationship between the downward continuation altitudes and the error effect. The analysis results show that the proposed semi parametric method combined with regularization is efficient to address such modelling problems. PMID- 28587088 TI - LOCALI: Calibration-Free Systematic Localization Approach for Indoor Positioning. AB - Recent advancements in indoor positioning systems are based on infrastructure free solutions, aimed at improving the location accuracy in complex indoor environments without the use of specialized resources. A popular infrastructure free solution for indoor positioning is a calibration-based positioning, commonly known as fingerprinting. Fingerprinting solutions require extensive and error free surveys of environments to build radio-map databases, which play a key role in position estimation. Fingerprinting also requires random updates of the database, when there are significant changes in the environment or a decrease in the accuracy. The calibration of the fingerprinting database is a time-consuming and laborious effort that prevents the extensive adoption of this technique. In this paper, we present a systematic LOCALIzation approach, "LOCALI", for indoor positioning, which does not require a calibration database and extensive updates. The LOCALI exploits the floor plan/wall map of the environment to estimate the target position by generating radio maps by integrating path-losses over certain trajectories in complex indoor environments, where triangulation using time information or the received signal strength level is highly erroneous due to the fading effects caused by multi-path propagation or absorption by environmental elements or varying antenna alignment. Experimental results demonstrate that by using the map information and environmental parameters, a significant level of accuracy in indoor positioning can be achieved. Moreover, this process requires considerably lesser effort compared to the calibration-based techniques. PMID- 28587082 TI - Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition. AB - Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies. PMID- 28587087 TI - Taurine Biosynthesis in a Fish Liver Cell Line (ZFL) Adapted to a Serum-Free Medium. AB - Although taurine has been shown to play multiple important physiological roles in teleosts, little is known about the molecular mechanisms underlying dietary requirements. Cell lines can provide useful tools for deciphering biosynthetic pathways and their regulation. However, culture media and sera contain variable taurine levels. To provide a useful cell line for the investigation of taurine homeostasis, an adult zebrafish liver cell line (ZFL) has been adapted to a taurine-free medium by gradual accommodation to a commercially available synthetic medium, UltraMEMTM-ITES. Here we show that ZFL cells are able to synthesize taurine and be maintained in medium without taurine. This has allowed for the investigation of the effects of taurine supplementation on cell growth, cellular amino acid pools, as well as the expression of the taurine biosynthetic pathway and taurine transporter genes in a defined fish cell type. After taurine supplementation, cellular taurine levels increase but hypotaurine levels stay constant, suggesting little suppression of taurine biosynthesis. Cellular methionine levels do not change after taurine addition, consistent with maintenance of taurine biosynthesis. The addition of taurine to cells grown in taurine-free medium has little effect on transcript levels of the biosynthetic pathway genes for cysteine dioxygenase (CDO), cysteine sulfinate decarboxylase (CSAD), or cysteamine dioxygenase (ADO). In contrast, supplementation with taurine causes a 30% reduction in transcript levels of the taurine transporter, TauT. This experimental approach can be tailored for the development of cell lines from aquaculture species for the elucidation of their taurine biosynthetic capacity. PMID- 28587089 TI - Prevent Effects of Lactobacillus Fermentum HY01 on Dextran Sulfate Sodium-Induced Colitis in Mice. AB - The aim of this study is to assess the preventive effects of Lactobacillus fermentum HY01 (LF-HY01) to dextran sulfate sodium induced-colitis. We observed the ratio of colon weight to its length, colon pathological changes, and the concentrations of pro-inflammatory factors (IFN-gamma, IL-12, TNFalpha, and IL-6) in serum. We also took account of the protein levels of IkappaBalpha, NF-kappaB p65, iNOS, and COX-2, and we measured the best effects of different doses of Lactobacillus fermentum HY01 (low dose group was 108 CFU/kg.bw, high dose group was 1010 CFU/kg.bw) on dextran sulfate sodium-induced colitis mice. The results were remarkable, suggesting that Lactobacillus fermentum HY01 had significant preventive effects in dextran sulfate sodium induced-colitis; simultaneously, the high dose group showed the best results among other groups. It can effectively alleviate the shortened colon length, reduce the ratio of colon weight to its length, reduce edema, inflammatory cells infiltration, and colon mucosa injury, and play an important role in the down-regulation of concentrations of pro inflammatory factors (IFN-gamma, IL-12, TNFalpha, and IL-6). Above all, Lactobacillus fermentum HY01 shows promising prevention for IkappaBalpha degradation, inhibition of NF-kappaB p65 phosphorylation cascades, and decreases the protein levels of iNOS and COX-2 as well. PMID- 28587090 TI - Bioactive Diphenyl Ethers and Isocoumarin Derivatives from a Gorgonian-Derived Fungus Phoma sp. (TA07-1). AB - Three new diphenyl ether derivatives-phomaethers A-C (1-3) and five known compounds-including a diphenyl ether analog, 2,3'-dihydroxy-4-methoxy-5',6 dimethyl diphenyl ether (4); and four isocoumarin derivatives, diaportinol (5), desmethyldiaportinol (6), citreoisocoumarinol (7), and citreoisocoumarin (8)-were isolated from a gorgonian-derived fungus Phoma sp. (TA07-1). Their structures were elucidated by extensive spectroscopic investigation. The absolute configurations of 1 and 2 were determined by acid hydrolysis reactions. It was the first report to discover the diphenyl glycoside derivatives from coral derived fungi. Compounds 1, 3, and 4 showed selective strong antibacterial activity against five pathogenic bacteria with the minimum inhibiting concentration (MIC) values and minimum bactericidal concentration (MBC) values between 0.156 and 10.0 MUM. PMID- 28587091 TI - Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs) alpha/gamma. AB - The peroxisome proliferator-activated receptors (PPARs) function as ligand activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank). Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARalpha and PPARgamma. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity. PMID- 28587092 TI - NF-kappaB Members Left Home: NF-kappaB-Independent Roles in Cancer. AB - Nuclear factor-kappaB (NF-kappaB) has been long considered a master regulator of inflammation and immune responses. Additionally, aberrant NF-kappaB signaling has been linked with carcinogenesis in many types of cancer. In recent years, the study of NF-kappaB members in NF-kappaB unrelated pathways provided novel attractive targets for cancer therapy, specifically linked to particular pathologic responses. Here we review specific functions of IkappaB kinase complexes (IKKs) and IkappaBs, which have distinctly tumor promoting or suppressing activities in cancer. Understanding how these proteins are regulated in a tumor-related context will provide new opportunities for drug development. PMID- 28587093 TI - Protective Effect of Chokeberry (Aronia melanocarpa L.) Extract against Cadmium Impact on the Biomechanical Properties of the Femur: A Study in a Rat Model of Low and Moderate Lifetime Women Exposure to This Heavy Metal. AB - The hypothesis that the consumption of Aronia melanocarpa berries (chokeberries) extract, recently reported by us to improve bone metabolism in female rats at low level and moderate chronic exposure to cadmium (1 and 5 mg Cd/kg diet for up to 24 months), may increase the bone resistance to fracture was investigated. Biomechanical properties of the neck (bending test with vertical head loading) and diaphysis (three-point bending test) of the femur of rats administered 0.1% aqueous chokeberry extract (65.74% of polyphenols) or/and Cd in the diet (1 and 5 mg Cd/kg) for 3, 10, 17, and 24 months were evaluated. Moreover, procollagen I was assayed in the bone tissue. The low-level and moderate exposure to Cd decreased the procollagen I concentration in the bone tissue and weakened the biomechanical properties of the femoral neck and diaphysis. Chokeberry extract administration under the exposure to Cd improved the bone collagen biosynthesis and femur biomechanical properties. The results allow for the conclusion that the consumption of chokeberry products under exposure to Cd may improve the bone biomechanical properties and protect from fracture. This study provides support for Aronia melanocarpa berries being a promising natural agent for skeletal protection under low-level and moderate chronic exposure to Cd. PMID- 28587094 TI - Burnout and Its Relationships with Alexithymia, Stress, and Social Support among Romanian Medical Students: A Cross-Sectional Study. AB - Medical school students often experience emotional difficulties when handling the challenges of their formation, occasionally leading to burnout. In this study, we measured the prevalence of burnout and its relationships with perceived stress, perceived social support, and alexithymia in medical students from the largest academic medical community in Romania. A cross-sectional survey was administered to a randomized sample of 299 preclinical medical students at the University of Medicine in Bucharest. Participants completed four standardized questionnaires. In addition to the assessment of burnout prevalence, stepwise backward regression was used to establish which variables had the highest correlation to burnout components. Further, t-tests were run to assess gender-related differences. Overall, burnout prevalence was 15.05%. Perceived stress was found to be the strongest predictor of emotional exhaustion and lack of accomplishment, while the strongest predictors of depersonalization were low perceived social support (in women) and alexithymia (in men). Women appear to be more vulnerable to two of the components of burnout (emotional exhaustion and low personal accomplishment) and associate higher perceived stress and alexithymia. These results suggest that interventions addressing academic burnout could benefit from being gender specific, with focus on key elements, such as perceived stress and alexithymia. PMID- 28587096 TI - The Effect of Platelet-Rich Fibrin, Calcium Sulfate Hemihydrate, Platelet-Rich Plasma and Resorbable Collagen on Soft Tissue Closure of Extraction Sites. AB - Rapid and complete soft tissue healing after tooth extraction minimizes surgical complications and facilitates subsequent implant placement. We used four treatment methods and assessed changes in soft tissue socket closure following tooth extraction in humans. The effects of platelet-rich fibrin-calcium sulfate hemihydrate (PRF-CSH), platelet-rich plasma-calcium sulfate hemihydrate (PRP CSH), a resorbable collagen dressing (RCD), and no grafting material were compared in a randomized, controlled pilot study with a blinded parallel design (N = 23). Patients with a hopeless tooth scheduled for extraction were randomly assigned to one of the four treatment groups. Socket measurements were obtained immediately after extraction and treatment, as well as after 21 days. There was a significant decrease in the total epithelialized external surface area of the extraction sockets in each group at all time points. However, there were no significant differences in soft tissue closure (p > 0.05) at any time point and PRF-CSH or PRP-CSH did not provide any additional benefit to enhance the soft tissue closure of extraction sockets compared with either RCD or sites without graft. PMID- 28587097 TI - Metabolomic Profiling of Soybeans (Glycine max L.) Reveals the Importance of Sugar and Nitrogen Metabolism under Drought and Heat Stress. AB - Soybean is an important crop that is continually threatened by abiotic stresses, especially drought and heat stress. At molecular levels, reduced yields due to drought and heat stress can be seen as a result of alterations in metabolic homeostasis of vegetative tissues. At present an incomplete understanding of abiotic stress-associated metabolism and identification of associated metabolites remains a major gap in soybean stress research. A study with a goal to profile leaf metabolites under control conditions (28/24 degrees C), drought [28/24 degrees C, 10% volumetric water content (VWC)], and heat stress (43/35 degrees C) was conducted in a controlled environment. Analyses of non-targeted metabolomic data showed that in response to drought and heat stress, key metabolites (carbohydrates, amino acids, lipids, cofactors, nucleotides, peptides and secondary metabolites) were differentially accumulated in soybean leaves. The metabolites for various cellular processes, such as glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, and starch biosynthesis, that regulate carbohydrate metabolism, amino acid metabolism, peptide metabolism, and purine and pyrimidine biosynthesis, were found to be affected by drought as well as heat stress. Computationally based regulatory networks predicted additional compounds that address the possibility of other metabolites and metabolic pathways that could also be important for soybean under drought and heat stress conditions. Metabolomic profiling demonstrated that in soybeans, keeping up with sugar and nitrogen metabolism is of prime significance, along with phytochemical metabolism under drought and heat stress conditions. PMID- 28587095 TI - Comparative Study of Lectin Domains in Model Species: New Insights into Evolutionary Dynamics. AB - Lectins are present throughout the plant kingdom and are reported to be involved in diverse biological processes. In this study, we provide a comparative analysis of the lectin families from model species in a phylogenetic framework. The analysis focuses on the different plant lectin domains identified in five representative core angiosperm genomes (Arabidopsisthaliana, Glycine max, Cucumis sativus, Oryza sativa ssp. japonica and Oryza sativa ssp. indica). The genomes were screened for genes encoding lectin domains using a combination of Basic Local Alignment Search Tool (BLAST), hidden Markov models, and InterProScan analysis. Additionally, phylogenetic relationships were investigated by constructing maximum likelihood phylogenetic trees. The results demonstrate that the majority of the lectin families are present in each of the species under study. Domain organization analysis showed that most identified proteins are multi-domain proteins, owing to the modular rearrangement of protein domains during evolution. Most of these multi-domain proteins are widespread, while others display a lineage-specific distribution. Furthermore, the phylogenetic analyses reveal that some lectin families evolved to be similar to the phylogeny of the plant species, while others share a closer evolutionary history based on the corresponding protein domain architecture. Our results yield insights into the evolutionary relationships and functional divergence of plant lectins. PMID- 28587099 TI - A Transcriptome Survey Spanning Life Stages and Sexes of the Harlequin Bug, Murgantia histrionica. AB - The harlequin bug, Murgantia histrionica (Hahn), is an agricultural pest in the continental United States, particularly in southern states. Reliable gene sequence data are especially useful to the development of species-specific, environmentally friendly molecular biopesticides and effective biolures for this insect. Here, mRNAs were sampled from whole insects at the 2nd and 4th nymphal instars, as well as sexed adults, and sequenced using Illumina RNA-Seq technology. A global assembly of these data identified 72,540 putative unique transcripts bearing high levels of similarity to transcripts identified in other taxa, with over 99% of conserved single-copy orthologs among insects being detected. Gene ontology and protein family analyses were conducted to explore the functional potential of the harlequin bug's gene repertoire, and phylogenetic analyses were conducted on gene families germane to xenobiotic detoxification, including glutathione S-transferases, carboxylesterases and cytochrome P450s. Genic content in harlequin bug was compared with that of the closely related invasive pest, the brown marmorated stink bug, Halyomorpha halys (Stal). Quantitative analyses of harlequin bug gene expression levels, experimentally validated using quantitative real-time PCR, identified genes differentially expressed between life stages and/or sexes. PMID- 28587100 TI - Excimer Laser Surgery: Biometrical Iris Eye Recognition with Cyclorotational Control Eye Tracker System. AB - A prospective comparative study assessing the importance of the intra-operative dynamic rotational tracking-especially in the treatment of astigmatisms in corneal refractive Excimer laser correction-concerning clinical outcomes is presented. The cyclotorsion from upright to supine position was measured using iris image comparison. The Group 1 of patients was additionally treated with cyclorotational control and Group 2 only with X-Y control. Significant differences were observed between the groups regarding the mean postoperative cylinder refraction (p < 0.05). The mean cyclotorsion can be calculated to 3.75 degrees with a standard deviation of 3.1 degrees . The total range of torsion was from -14.9 degrees to +12.6 degrees . Re-treatment rate was 2.2% in Group 1 and 8.2% in Group 2, which is highly significant (p < 0.01). The investigation confirms that the dynamic rotational tracking system used for LASIK results in highly predictable refraction quality with significantly less postoperative re treatments. PMID- 28587098 TI - Function of Metallothionein-3 in Neuronal Cells: Do Metal Ions Alter Expression Levels of MT3? AB - A study of factors proposed to affect metallothionein-3 (MT3) function was carried out to elucidate the opaque role MT3 plays in human metalloneurochemistry. Gene expression of Mt2 and Mt3 was examined in tissues extracted from the dentate gyrus of mouse brains and in human neuronal cell cultures. The whole-genome gene expression analysis identified significant variations in the mRNA levels of genes associated with zinc homeostasis, including Mt2 and Mt3. Mt3 was found to be the most differentially expressed gene in the identified groups, pointing to the existence of a factor, not yet identified, that differentially controls Mt3 expression. To examine the expression of the human metallothioneins in neurons, mRNA levels of MT3 and MT2 were compared in BE(2)C and SH-SY5Y cell cultures treated with lead, zinc, cobalt, and lithium. MT2 was highly upregulated by Zn2+ in both cell cultures, while MT3 was not affected, and no other metal had an effect on either MT2 or MT3. PMID- 28587103 TI - StandFood: Standardization of Foods Using a Semi-Automatic System for Classifying and Describing Foods According to FoodEx2. AB - The European Food Safety Authority has developed a standardized food classification and description system called FoodEx2. It uses facets to describe food properties and aspects from various perspectives, making it easier to compare food consumption data from different sources and perform more detailed data analyses. However, both food composition data and food consumption data, which need to be linked, are lacking in FoodEx2 because the process of classification and description has to be manually performed-a process that is laborious and requires good knowledge of the system and also good knowledge of food (composition, processing, marketing, etc.). In this paper, we introduce a semi-automatic system for classifying and describing foods according to FoodEx2, which consists of three parts. The first involves a machine learning approach and classifies foods into four FoodEx2 categories, with two for single foods: raw (r) and derivatives (d), and two for composite foods: simple (s) and aggregated (c). The second uses a natural language processing approach and probability theory to describe foods. The third combines the result from the first and the second part by defining post-processing rules in order to improve the result for the classification part. We tested the system using a set of food items (from Slovenia) manually-coded according to FoodEx2. The new semi-automatic system obtained an accuracy of 89% for the classification part and 79% for the description part, or an overall result of 79% for the whole system. PMID- 28587105 TI - Internal Model-Based Robust Tracking Control Design for the MEMS Electromagnetic Micromirror. AB - The micromirror based on micro-electro-mechanical systems (MEMS) technology is widely employed in different areas, such as scanning, imaging and optical switching. This paper studies the MEMS electromagnetic micromirror for scanning or imaging application. In these application scenarios, the micromirror is required to track the command sinusoidal signal, which can be converted to an output regulation problem theoretically. In this paper, based on the internal model principle, the output regulation problem is solved by designing a robust controller that is able to force the micromirror to track the command signal accurately. The proposed controller relies little on the accuracy of the model. Further, the proposed controller is implemented, and its effectiveness is examined by experiments. The experimental results demonstrate that the performance of the proposed controller is satisfying. PMID- 28587104 TI - C1q/TNF-Related Protein-9 Ameliorates Ox-LDL-Induced Endothelial Dysfunction via PGC-1alpha/AMPK-Mediated Antioxidant Enzyme Induction. AB - Oxidized low-density lipoprotein (ox-LDL) accumulation is one of the critical determinants in endothelial dysfunction in many cardiovascular diseases such as atherosclerosis. C1q/TNF-related protein 9 (CTRP9) is identified to be an adipocytokine with cardioprotective properties. However, the potential roles of CTRP9 in endothelial function remain largely elusive. In the present study, the effects of CTRP9 on the proliferation, apoptosis, migration, angiogenesis, nitric oxide (NO) production and oxidative stress in human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL were investigated. We observed that treatment with ox-LDL inhibited the proliferation, migration, angiogenesis and the generation of NO, while stimulated the apoptosis and reactive oxygen species (ROS) production in HUVECs. Incubation of HUVECs with CTRP9 rescued ox-LDL induced endothelial injury. CTRP9 treatment reversed ox-LDL-evoked decreases in antioxidant enzymes including heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1, and glutamate-cysteine ligase (GCL), as well as endothelial nitric oxide synthase (eNOS). Furthermore, CTRP9 induced activation of peroxisome proliferator-activated receptor gamma co activator 1alpha (PGC1-alpha) and phosphorylation of adenosine monophosphate activated protein kinase (AMPK). Of interest, AMPK inhibition or PGC1-alpha silencing abolished CTRP9-mediated antioxidant enzymes levels, eNOS expressions, and endothelial protective effects. Collectively, we provided the first evidence that CTRP9 attenuated ox-LDL-induced endothelial injury by antioxidant enzyme inductions dependent on PGC-1alpha/AMPK activation. PMID- 28587106 TI - Transfection of Antisense Oligonucleotides Mediated by Cationic Vesicles Based on Non-Ionic Surfactant and Polycations Bearing Quaternary Ammonium Moieties. AB - Three different ionene polymers with varying quaternary ammonium moieties were used as a proof of concept for the formulation of antisense oligonucleotides, which are capable of inhibiting Renilla luciferase messenger ribonucleic acid (mRNA). Cationic vesicles, consisting of cationic polymer, antisense oligonucleotide (Luc) and non-ionic surfactant polysorbate 80, were investigated regarding their zeta potential, cytotoxicity and transfection efficiency. Deoxyribonucleic acid- (DNA) forming complexes in the presence of cationic vesicles were also investigated in terms of small-angle X-ray scattering (SAXS). The studied cationic vesicles showed very little, if any, toxicity against HeLa cells. Transfection abilities proved to vary strongly depending on the present quaternary ammonium moiety. PMID- 28587102 TI - Perturbations in the Replication Program Contribute to Genomic Instability in Cancer. AB - Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program. PMID- 28587101 TI - Therapeutic Applications of Rose Hips from Different Rosa Species. AB - Rosa species, rose hips, are widespread wild plants that have been traditionally used as medicinal compounds for the treatment of a wide variety of diseases. The therapeutic potential of these plants is based on its antioxidant effects caused by or associated with its phytochemical composition, which includes ascorbic acid, phenolic compounds and healthy fatty acids among others. Over the last few years, medicinal interest in rose hips has increased as a consequence of recent research that has studied its potential application as a treatment for several diseases including skin disorders, hepatotoxicity, renal disturbances, diarrhoea, inflammatory disorders, arthritis, diabetes, hyperlipidaemia, obesity and cancer. In this review, the role of different species of Rosa in the prevention of treatment of various disorders related to oxidative stress, is examined, focusing on new therapeutic approaches from a molecular point of view. PMID- 28587107 TI - Sleep Duration, Sleep Quality, Body Mass Index, and Waist Circumference among Young Adults from 24 Low- and Middle-Income and Two High-Income Countries. AB - Obesity and its comorbidities have emerged as a leading public health concern. The aim of this study was to explore the relationship between body mass index (BMI), waist circumference (WC) and sleep patterns, including duration and disturbances. A cross-sectional questionnaire survey and anthropometric measurements were conducted with undergraduate university students that were randomly recruited in 26 universities in 24 low- and middle-income and two high income countries. The sample included 18,211 (42.1% male and 57.9% female, mean age 21.0 in male and 20.7 years in female students) undergraduate university students. The overall BMI was a mean of 22.5 kg/m2 for men and 22.0 kg/m2 for women, and the mean WC was 78.4 cm for men and 73.8 cm for women. More than 39% of the students reported short sleep duration (<=6 h/day) and over 30% reported moderate to extreme sleep problems. In a linear multivariable regression, adjusted for sociodemographic and lifestyle factors, short sleep duration was positively associated with BMI in both men and women, and was positively associated with WC among women but not among men. Sleep quality or problems among men were not associated with BMI, while among women mild sleep problems were inversely associated with BMI, and poor sleep quality or problems were positively associated with WC both among men and women. The study confirmed an association between short sleep duration and increased BMI and, among women, increased WC, and an association between poor sleep quality and increased WC but not BMI. Further, differences in the association between sleep characteristics and BMI and WC were found by region and country income. PMID- 28587108 TI - Compliance with Nutritional and Lifestyle Recommendations in 13,000 Patients with a Cardiometabolic Disease from the Nutrinet-Sante Study. AB - BACKGROUND: A healthy diet has been shown to prevent cardiovascular diseases complications. The objective of this study was to assess dietary intakes and compliance with nutritional and lifestyle recommendations in French adults diagnosed with hypertension, diabetes, dyslipidaemia or cardiovascular disease compared with healthy individuals. METHODS: Data was collected from 26,570 subjects aged 35 to 70 years (13,285 patients and 13,285 controls matched by sex and age) of the French cohort NutriNet-Sante. Dietary intakes were assessed using three 24-h records. Mean food and nutrient intakes of patients were compared to those of healthy subjects using multivariable mixed logistic and linear regressions. RESULTS: Compared to healthy controls, adults reporting cardiometabolic diseases had lower intakes of sweetened products, higher intakes of fish and seafood and a better compliance with dairy products. However, overall, they reported unhealthier lifestyles and dietary habits. Indeed, they were less often physically active and had similar habits regarding alcohol and tobacco consumption. They also had lower intakes of fruit, higher intakes of meat, processed meat and added fats. It is noteworthy that diabetic subjects tended to show the highest compliance with certain dietary recommendations (vegetables, pulses and whole grain products). CONCLUSION: Our study brings into focus the fact that some nutritional aspects still need to be improved among individuals with a cardiometabolic disease. We should encourage higher intakes of fruits and vegetables, whole grain products, and lower intakes of meat and sodium, as well as healthy lifestyle (physical activity, no-smoking and limited intake of alcohol) in order to encourage a healthier management after being diagnosed. PMID- 28587109 TI - Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs. AB - Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of 'off-target' effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic. By determining the expression changes of antioxidant genes in MCF7 cells that were treated with the potential Nrf2 activators using quantitative real-time polymerase chain reaction RT-PCR (real time polymerase chain reaction) (qRT-PCR), astemizole was found to have a greater scale of upregulating antioxidant genes NQO1, HO-1, and GCLM than the positive control d,l-sulforaphane, although the testing concentration was lower than that of the control. Astemizole is a good potential redox regulator and deserves more pharmacodynamic experimentation to test and verify its feasibility for use as an Nrf2 activator. PMID- 28587111 TI - Development of a Flexible Artificial Lateral Line Canal System for Hydrodynamic Pressure Detection. AB - Surface mounted 'smart skin' can enhance the situational and environmental awareness of marine vehicles, which requires flexible, reliable, and light-weight hydrodynamic pressure sensors. Inspired by the lateral line canal system in fish, we developed an artificial lateral line (ALL) canal system by integrating cantilevered flow-sensing elements in a polydimethylsiloxane (PDMS) canal. Polypropylene and polyvinylidene fluoride (PVDF) layers were laminated together to form the cantilevered flow-sensing elements. Both the ALL canal system and its superficial counterpart were characterized using a dipole vibration source. Experimental results showed that the peak frequencies of both the canal and superficial sensors were approximately 110 Hz, which was estimated to be the resonance frequency of the cantilevered flow-sensing element. The proposed ALL canal system demonstrated high-pass filtering capabilities to attenuate low frequency stimulus and a pressure gradient detection limit of approximately 11 Pa/m at a frequency of 115 +/- 1 Hz. Because of its structural flexibility and noise immunity, the proposed ALL canal system shows significant potential for underwater robotics applications. PMID- 28587110 TI - Current Perspective on In Vivo Molecular Imaging of Immune Cells. AB - Contemporaneous development of improved immune cell-based therapies, and powerful imaging tools, has prompted growth in technologies for immune cell tracking in vivo. Over the past couple of decades, imaging tools such as magnetic resonance imaging (MRI) and optical imaging have successfully monitored the trafficking patterns of therapeutic immune cells and assisted the evaluation of the success or failure of immunotherapy. Recent advancements in imaging technology have made imaging an indispensable module of immune cell-based therapies. In this review, emerging applications of non-radiation imaging modalities for the tracking of a range of immune cells are discussed. Applications of MRI, NIR, and other imaging tools have demonstrated the potential of non-invasively surveying the fate of both phagocytic and non-phagocytic immune cells in vivo. PMID- 28587114 TI - A Multiple Sensors Platform Method for Power Line Inspection Based on a Large Unmanned Helicopter. AB - Many theoretical and experimental studies have been carried out in order to improve the efficiency and reduce labor for power line inspection, but problems related to stability, efficiency, and comprehensiveness still exist. This paper presents a multiple sensors platform method for overhead power line inspection based on the use of a large unmanned helicopter. Compared with the existing methods, multiple sensors can realize synchronized inspection on all power line components and surrounding objects within one sortie. Flight safety of unmanned helicopter, scheduling of sensors and exact tracking on power line components are very important aspects when using the proposed multiple sensors platform, therefore this paper introduces in detail the planning method for the flight path of the unmanned helicopter and tasks of the sensors before inspecting power lines, and the method used for tracking power lines and insulators automatically during the inspection process. To validate the method, experiments on a transmission line at Qingyuan in Guangdong Province were carried out, the results show that the proposed method is effective for power line inspection. PMID- 28587113 TI - The Therapeutic Targeting of HGF/c-Met Signaling in Hepatocellular Carcinoma: Alternative Approaches. AB - The poor prognosis of hepatocellular carcinoma (HCC), one of the most devastating cancers worldwide, is due to frequent recurrence and metastasis. Among the metastatic factors in the tumor microenvironment, hepatocyte growth factor (HGF) has been well known to play critical roles in tumor progression, including HCC. Therefore, c-Met is now regarded as the most promising therapeutic target for the treatment of HCC. However, there are still concerns about resistance and the side effects of using conventional inhibitors of c-Met, such as tyrosine kinase inhibitors. Recently, many alternative strategies of c-Met targeting have been emerging. These include targeting the downstream effectors of c-Met, such as hydrogen peroxide-inducible clone 5 (Hic-5), to block the reactive oxygen species (ROS)-mediated signaling for HCC progression. Also, inhibition of endosomal regulators, such as PKCepsilon and GGA3, may perturb the c-Met endosomal signaling for HCC cell migration. On the other hand, many herbal antagonists of c Met-dependent signaling, such as saponin, resveratrol, and LZ-8, were identified. Taken together, it can be anticipated that more effective and safer c-Met targeting strategies for preventing HCC progression can be established in the future. PMID- 28587112 TI - Is There a Role for Genomics in the Management of Hypertension? AB - Hypertension (HTN) affects about 1 billion people worldwide and the lack of a single identifiable cause complicates its treatment. Blood pressure (BP) levels are influenced by environmental factors, but there is a strong genetic component. Linkage analysis has identified several genes involved in Mendelian forms of HTN and the associated pathophysiological mechanisms have been unravelled, leading to targeted therapies. The majority of these syndromes are due to gain-of-function or loss-of-functions mutations, resulting in an alteration of mineralocorticoid, glucocorticoid, or sympathetic pathways. The diagnosis of monogenic forms of HTN has limited practical implications on the population and a systematic genetic screening is not justifiable. Genome-wide linkage and association studies (GWAS) have identified single nucleotide polymorphisms (SNPs), which influence BP. Forty three variants have been described with each SNP affecting systolic and diastolic BP by 1.0 and 0.5 mmHg, respectively. Taken together Mendelian inheritance and all GWAS-identified HTN-associated variants explain 2-3% of BP variance. Epigenetic modifications, such as DNA methylation, histone modification and non coding RNAs, have become increasingly recognized as important players in BP regulation and may justify a further part of missing heritability. In this review, we will discuss how genetics and genomics may assist clinicians in managing patients with HTN. PMID- 28587115 TI - Complete Tri-Axis Magnetometer Calibration with a Gyro Auxiliary. AB - Magnetometers combined with inertial sensors are widely used for orientation estimation, and calibrations are necessary to achieve high accuracy. This paper presents a complete tri-axis magnetometer calibration algorithm with a gyro auxiliary. The magnetic distortions and sensor errors, including the misalignment error between the magnetometer and assembled platform, are compensated after calibration. With the gyro auxiliary, the magnetometer linear interpolation outputs are calculated, and the error parameters are evaluated under linear operations of magnetometer interpolation outputs. The simulation and experiment are performed to illustrate the efficiency of the algorithm. After calibration, the heading errors calculated by magnetometers are reduced to 0.5 degrees (1sigma). This calibration algorithm can also be applied to tri-axis accelerometers whose error model is similar to tri-axis magnetometers. PMID- 28587116 TI - Corrugated-Diaphragm Based Fiber Laser Hydrophone with Sub-100 MUPa/Hz1/2 Resolution. AB - In this work, a beat-frequency encoded fiber laser hydrophone is developed for high-resolution acoustic detection by using an elastic corrugated diaphragm. The diaphragm is center-supported by the fiber. Incident acoustic waves deform the diaphragm and induce a concentrated lateral load on the laser cavity. The acoustically induced perturbation changes local optical phases and frequency modulates the radio-frequency beat signal between two orthogonal lasing modes of the cavity. Theoretical analysis reveals that a higher corrugation depth/thickness ratio or larger diaphragm area can provide higher transduction efficiency. The experimentally achieved average sensitivity in beat-frequency variation is 185.7 kHz/Pa over a bandwidth of 1 kHz. The detection capability can be enhanced by shortening the cavity length to enhance the signal-to-noise ratio. The minimum detectable acoustic pressure reaches 74 uPa/Hz1/2 at 1 kHz, which is comparable to the zeroth order sea noise. PMID- 28587117 TI - DeepMap+: Recognizing High-Level Indoor Semantics Using Virtual Features and Samples Based on a Multi-Length Window Framework. AB - Existing indoor semantic recognition schemes are mostly capable of discovering patterns through smartphone sensing, but it is hard to recognize rich enough high level indoor semantics for map enhancement. In this work we present DeepMap+, an automatical inference system for recognizing high-level indoor semantics using complex human activities with wrist-worn sensing. DeepMap+ is the first deep computation system using deep learning (DL) based on a multi-length window framework to enrich the data source. Furthermore, we propose novel methods of increasing virtual features and virtual samples for DeepMap+ to better discover hidden patterns of complex hand gestures. We have performed 23 high-level indoor semantics (including public facilities and functional zones) and collected wrist worn data at a Wal-Mart supermarket. The experimental results show that our proposed methods can effectively improve the classification accuracy. PMID- 28587118 TI - Nerve Growth Factor and Related Substances: A Brief History and an Introduction to the International NGF Meeting Series. AB - Nerve growth factor (NGF) is a protein whose importance to research and its elucidation of fundamental mechanisms in cell and neurobiology far outstrips its basic physiological roles. It was the first of a broad class of cell regulators, largely acting through autocrine and paracrine interactions which will be described herein. It was of similar significance in establishing the identity and unique roles of neurotrophic factors in the development and maintenance of the peripheral and central nervous systems. Finally, it contributed to many advances in the elaboration of cell surface receptor mechanisms and intracellular cell signaling. As such, it can be considered to be a "molecular Rosetta Stone". In this brief review, the highlights of these various studies are summarized, particularly as illustrated by their coverage in the 13 NGF international meetings that have been held since 1986. PMID- 28587120 TI - Fast Preparation of Porous MnO/C Microspheres as Anode Materials for Lithium-Ion Batteries. AB - Porous MnO/C microspheres have been successfully fabricated by a fast co precipitation method in a T-shaped microchannel reactor. The structures, compositions, and electrochemical performances of the obtained MnO/C microspheres are characterized by X-ray diffraction, field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (HRTEM), Brunauer-Emmett Teller analysis, charge-discharge testing, cyclic voltammograms, and electrochemical impedance spectra. Experimental results reveal that the as prepared MnO/C, with a specific surface area of 96.66 m2.g-1 and average pore size of 24.37 nm, exhibits excellent electrochemical performance, with a discharge capacity of 655.4 mAh.g-1 after cycling 50 times at 1 C and capacities of 808.3, 743.7, 642.6, 450.1, and 803.1 mAh.g-1 at 0.2, 0.5, 1, 2, and 0.2 C, respectively. Moreover, the controlled method of using a microchannel reactor, which can produce larger specific surface area porous MnO/C with improved cycling performance by shortening lithium-ion diffusion distances, can be easily applied in real production on a large scale. PMID- 28587122 TI - Anti-Inflammatory Properties of Brazilian Green Propolis Encapsulated in a gamma Cyclodextrin Complex in Mice Fed a Western-Type Diet. AB - Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in gamma-cyclodextrin (gammaCD) or a WTD plus gammaCD for 10 weeks. GPSE-gammaCD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor alpha were significantly downregulated (p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly (p < 0.001) decreased following GPSE-gammaCD treatment. GPSE gammaCD significantly induced hepatic ferritin gene expression (p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-gammaCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-gammaCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-gammaCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation. PMID- 28587119 TI - Trigger-Responsive Gene Transporters for Anticancer Therapy. AB - In the current era of gene delivery, trigger-responsive nanoparticles for the delivery of exogenous nucleic acids, such as plasmid DNA (pDNA), mRNA, siRNAs, and miRNAs, to cancer cells have attracted considerable interest. The cationic gene transporters commonly used are typically in the form of polyplexes, lipoplexes or mixtures of both, and their gene transfer efficiency in cancer cells depends on several factors, such as cell binding, intracellular trafficking, buffering capacity for endosomal escape, DNA unpacking, nuclear transportation, cell viability, and DNA protection against nucleases. Some of these factors influence other factors adversely, and therefore, it is of critical importance that these factors are balanced. Recently, with the advancements in contemporary tools and techniques, trigger-responsive nanoparticles with the potential to overcome their intrinsic drawbacks have been developed. This review summarizes the mechanisms and limitations of cationic gene transporters. In addition, it covers various triggers, such as light, enzymes, magnetic fields, and ultrasound (US), used to enhance the gene transfer efficiency of trigger responsive gene transporters in cancer cells. Furthermore, the challenges associated with and future directions in developing trigger-responsive gene transporters for anticancer therapy are discussed briefly. PMID- 28587124 TI - Comparison Study between RMS and Edge Detection Image Processing Algorithms for a Pulsed Laser UWPI (Ultrasonic Wave Propagation Imaging)-Based NDT Technique. AB - In this study, a non-contact laser ultrasonic propagation imaging technique was applied to detect the damage of plate-like structures. Lamb waves were generated by an Nd:YAG pulse laser system, while a galvanometer-based laser scanner was used to scan the preliminarily designated area. The signals of the structural responses were measured using a piezoelectric sensor attached on the front or back side of the plates. The obtained responses were analyzed by calculating the root mean square (RMS) values to achieve the visualization of structural defects such as crack, corrosion, and so on. If the propagating waves encounter the damage, the waves are scattered at the damage and the energy of the scattered waves can be expressed by the RMS values. In this study, notch and corrosion were artificially formed on aluminum plates and were considered as structural defects. The notches were created with different depths and angles on the aluminum plates, and the corrosion damage was formed with different depths and areas. To visualize the damage more clearly, edge detection methodologies were applied to the RMS images and the feasibility of the methods was investigated. The results showed that most of the edge detection methods were good at detecting the shape and/or the size of the damage while they had poor performance of detecting the depth of the damage. PMID- 28587123 TI - Work-Related Musculoskeletal Disorders and Risk Factors among Chinese Medical Staff of Obstetrics and Gynecology. AB - Medical staff in the department of obstetrics and gynecology are a group of professionals reportedly at high risk of work-related musculoskeletal disorders (WMSD), however, little is known about the current status of this problem in China. The aim of this study was to investigate prevalence and risk factors of work-related musculoskeletal disorders among this population in China. A self developed questionnaire was distributed to 1017 obstetrics and gynecology practitioners to collect information on musculoskeletal symptoms and relevant factors. Prevalence and severity of work-related musculoskeletal disorders in different parts of the body were calculated and the relationship between personal and ergonomic factors and work-related musculoskeletal disorders was analyzed using Chi-square test and unconditional logistic regression models. The results indicated a high prevalence of 85.5% among the subjects, with the shoulder (n = 575, 62.0%), neck (n = 560, 60.3%) and lower back (n = 504, 54.3%) being the three most affected regions. Individual, postural, work-environmental as well as psychosocial factors were recognized to be associated with WMSDs in different body parts. Therefore, attention must be given to the problem of musculoskeletal disorders among Chinese obstetrics and gynecology staff. It is recommended to develop good life habits, improve work environment, adjust work organization as well as train on proper postures in their daily operation. PMID- 28587121 TI - Chemotherapeutic Drugs: DNA Damage and Repair in Glioblastoma. AB - Despite improvements in therapeutic strategies, glioblastoma (GB) remains one of the most lethal cancers. The presence of the blood-brain barrier, the infiltrative nature of the tumor and several resistance mechanisms account for the failure of current treatments. Distinct DNA repair pathways can neutralize the cytotoxicity of chemo- and radio-therapeutic agents, driving resistance and tumor relapse. It seems that a subpopulation of stem-like cells, indicated as glioma stem cells (GSCs), is responsible for tumor initiation, maintenance and recurrence and they appear to be more resistant owing to their enhanced DNA repair capacity. Recently, attention has been focused on the pivotal role of the DNA damage response (DDR) in tumorigenesis and in the modulation of therapeutic treatment effects. In this review, we try to summarize the knowledge concerning the main molecular mechanisms involved in the removal of genotoxic lesions caused by alkylating agents, emphasizing the role of GSCs. Beside their increased DNA repair capacity in comparison with non-stem tumor cells, GSCs show a constitutive checkpoint expression that enables them to survive to treatments in a quiescent, non-proliferative state. The targeted inhibition of checkpoint/repair factors of DDR can contribute to eradicate the GSC population and can have a great potential therapeutic impact aiming at sensitizing malignant gliomas to treatments, improving the overall survival of patients. PMID- 28587125 TI - Equine Welfare during Exercise: An Evaluation of Breathing, Breathlessness and Bridles. AB - Horses engaged in strenuous exercise display physiological responses that approach the upper functional limits of key organ systems, in particular their cardiorespiratory systems. Maximum athletic performance is therefore vulnerable to factors that diminish these functional capacities, and such impairment might also lead to horses experiencing unpleasant respiratory sensations, i.e., breathlessness. The aim of this review is to use existing literature on equine cardiorespiratory physiology and athletic performance to evaluate the potential for various types of breathlessness to occur in exercising horses. In addition, we investigate the influence of management factors such as rein and bit use and of respiratory pathology on the likelihood and intensity of equine breathlessness occurring during exercise. In ridden horses, rein use that reduces the jowl angle, sometimes markedly, and conditions that partially obstruct the nasopharynx and/or larynx, impair airflow in the upper respiratory tract and lead to increased flow resistance. The associated upper airway pressure changes, transmitted to the lower airways, may have pathophysiological sequelae in the alveolae, which, in their turn, may increase airflow resistance in the lower airways and impede respiratory gas exchange. Other sequelae include decreases in respiratory minute volume and worsening of the hypoxaemia, hypercapnia and acidaemia commonly observed in healthy horses during strenuous exercise. These and other factors are implicated in the potential for ridden horses to experience three forms of breathlessness-"unpleasant respiratory effort", "air hunger" and "chest tightness"-which arise when there is a mismatch between a heightened ventilatory drive and the adequacy of the respiratory response. It is not known to what extent, if at all, such mismatches would occur in strenuously exercising horses unhampered by low jowl angles or by pathophysiological changes at any level of the respiratory tract. However, different combinations of the three types of breathlessness seem much more likely to occur when pathophysiological conditions significantly reduce maximal athletic performance. Finally, most horses exhibit clear behavioural evidence of aversion to a bit in their mouths, varying from the bit being a mild irritant to very painful. This in itself is a significant animal welfare issue that should be addressed. A further major point is the potential for bits to disrupt the maintenance of negative pressure in the oropharynx, which apparently acts to prevent the soft palate from rising and obstructing the nasopharynx. The untoward respiratory outcomes and poor athletic performance due to this and other obstructions are well established, and suggest the potential for affected animals to experience significant intensities of breathlessness. Bitless bridle use may reduce or eliminate such effects. However, direct comparisons of the cardiorespiratory dynamics and the extent of any respiratory pathophysiology in horses wearing bitted and bitless bridles have not been conducted. Such studies would be helpful in confirming, or otherwise, the claimed potential benefits of bitless bridle use. PMID- 28587126 TI - Lithium in the Natural Waters of the South East of Ireland. AB - The South East of Ireland (County Carlow) contains a deposit of the valuable lithium-bearing mineral spodumene (LiAl(SiO3)2). This resource has recently attracted interest and abstractive mining in the area is a possibility for the future. The open cast mining of this resource could represent a potential hazard in the form of metalliferous pollution to local water. The population of County Carlow is just under 60,000. The local authority reports that approximately 75.7% of the population's publicly supplied drinking water is abstracted from surface water and 11.6% from groundwater. In total, 12.7% of the population abstract their water from private groundwater wells. Any potential entry of extraneous metals into the area's natural waters will have implications for people in county Carlow. It is the goal of this paper to establish background concentrations of lithium and other metals in the natural waters prior to any mining activity. Our sampling protocol totaled 115 sites along five sampling transects, sampled through 2015. From this dataset, we report a background concentration of dissolved lithium in the natural waters of County Carlow, surface water at x - = 0.02, SD = 0.02 ranging from 0 to 0.091 mg/L and groundwater at x - = 0.023, SD = 0.02 mg/L ranging from 0 to 0.097 mg/L. PMID- 28587127 TI - Gender Differences of Arterial Stiffness and Arterial Age in Smokers. AB - The present study aimed to find gender differences for arterial stiffness and arterial aging in smokers. A total of 147 smokers (71 male and 76 female, matched for age) were explored using an Arteriograph in a cross-sectional survey. Pulse wave velocity (PWV), arterial age (AA), brachial and aortic augmentation index (AixBrach, AixAo), and blood pressure variables were assessed. Data about smoking intensity, such as the number of cigarettes smoked daily, smoking period, and smoking pack years (SPY) were used. No significant differences were found for PWV, AA, AixBrach and AixAo. Significant correlations were found between SPY and PWV, augmentation indices, and AA, respectively. The cut-off values for SPY were higher for an increased arterial stiffness in male compared to female smokers (18.5 and 7.5 pack year, respectively). SPY is significantly associated with an increased arterial stiffness in smokers regardless of gender, and with an increased SBPAo only in female smokers. The results of our study indicate gender differences for arterial stiffness and arterial age in smokers. PMID- 28587128 TI - Yeast Extract Stimulates Ginsenoside Production in Hairy Root Cultures of American Ginseng Cultivated in Shake Flasks and Nutrient Sprinkle Bioreactors. AB - One of the most effective strategies to enhance metabolite biosynthesis and accumulation in biotechnological systems is the use of elicitation processes. This study assesses the influence of different concentrations of yeast extract (YE) on ginsenoside biosynthesis in Panax quinquefolium (American ginseng) hairy roots cultivated in shake flasks and in a nutrient sprinkle bioreactor after 3 and 7 days of elicitation. The saponin content was determined using HPLC. The maximum yield (20 mg g-1 d.w.) of the sum of six examined ginsenosides (Rb1, Rb2, Rc, Rd, Re and Rg1) in hairy roots cultivated in shake flasks was achieved after application of YE at 50 mg L-1 concentration and 3 day exposure time. The ginsenoside level was 1.57 times higher than that attained in control medium. The same conditions of elicitation (3 day time of exposure and 50 mg L-1 of YE) also favourably influenced the biosynthesis of studied saponins in bioreactor cultures. The total ginsenoside content was 32.25 mg g-1 d.w. and was higher than that achieved in control medium and in shake flasks cultures. Obtained results indicated that yeast extract can be used to increase ginsenoside production in hairy root cultures of P. quinquefolium. PMID- 28587130 TI - New Knowledge in Analytical, Technological, and Biological Aspects of the Maillard Reaction. AB - n/a. PMID- 28587129 TI - Characterization of Acetyl-CoA Carboxylases in the Basal Dinoflagellate Amphidinium carterae. AB - Dinoflagellates make up a diverse array of fatty acids and polyketides. A necessary precursor for their synthesis is malonyl-CoA formed by carboxylating acetyl CoA using the enzyme acetyl-CoA carboxylase (ACC). To date, information on dinoflagellate ACC is limited. Through transcriptome analysis in Amphidinium carterae, we found three full-length homomeric type ACC sequences; no heteromeric type ACC sequences were found. We assigned the putative cellular location for these ACCs based on transit peptide predictions. Using streptavidin Western blotting along with mass spectrometry proteomics, we validated the presence of ACC proteins. Additional bands showing other biotinylated proteins were also observed. Transcript abundance for these ACCs follow the global pattern of expression for dinoflagellate mRNA messages over a diel cycle. This is one of the few descriptions at the transcriptomic and protein level of ACCs in dinoflagellates. This work provides insight into the enzymes which make the CoA precursors needed for fatty acid and toxin synthesis in dinoflagellates. PMID- 28587131 TI - A Smart Power Electronic Multiconverter for the Residential Sector. AB - The future of the grid includes distributed generation and smart grid technologies. Demand Side Management (DSM) systems will also be essential to achieve a high level of reliability and robustness in power systems. To do that, expanding the Advanced Metering Infrastructure (AMI) and Energy Management Systems (EMS) are necessary. The trend direction is towards the creation of energy resource hubs, such as the smart community concept. This paper presents a smart multiconverter system for residential/housing sector with a Hybrid Energy Storage System (HESS) consisting of supercapacitor and battery, and with local photovoltaic (PV) energy source integration. The device works as a distributed energy unit located in each house of the community, receiving active power set points provided by a smart community EMS. This central EMS is responsible for managing the active energy flows between the electricity grid, renewable energy sources, storage equipment and loads existing in the community. The proposed multiconverter is responsible for complying with the reference active power set points with proper power quality; guaranteeing that the local PV modules operate with a Maximum Power Point Tracking (MPPT) algorithm; and extending the lifetime of the battery thanks to a cooperative operation of the HESS. A simulation model has been developed in order to show the detailed operation of the system. Finally, a prototype of the multiconverter platform has been implemented and some experimental tests have been carried out to validate it. PMID- 28587133 TI - Time Series Data Analysis of Wireless Sensor Network Measurements of Temperature. AB - Wireless sensor networks have gained significant traction in environmental signal monitoring and analysis. The cost or lifetime of the system typically depends on the frequency at which environmental phenomena are monitored. If sampling rates are reduced, energy is saved. Using empirical datasets collected from environmental monitoring sensor networks, this work performs time series analyses of measured temperature time series. Unlike previous works which have concentrated on suppressing the transmission of some data samples by time-series analysis but still maintaining high sampling rates, this work investigates reducing the sampling rate (and sensor wake up rate) and looks at the effects on accuracy. Results show that the sampling period of the sensor can be increased up to one hour while still allowing intermediate and future states to be estimated with interpolation RMSE less than 0.2 degrees C and forecasting RMSE less than 1 degrees C. PMID- 28587132 TI - Anti-Inflammatory Activity of a Polymeric Proanthocyanidin from Serjania schiedeana. AB - The ethyl acetate extract (SsAcOEt) from Serjania schiedeana, select fractions (F 6, F-12, F-13, F-14), and one isolated compound, were evaluated in 12-O tetradecanoylphorbol 13-acetate (TPA) ear edema and kaolin/carrageenan (KC) induced monoarthritis assays. SsEtOAc induced edema inhibition of 90% (2.0 mg/ear), fractions showed activity within a range of 67-89%. Due to the fact F-14 showed the highest effect, it was separated, yielding a proanthocyanidin-type called epicatechin-(4beta -> 8)-epicatechin-(4beta -> 8, 2beta -> O -> 7) epicatechin (ETP). This compound (2.0 mg/ear) provoked 72% of edema inhibition (ED50 = 0.25 mg/ear, Emax = 52.9%). After 9 days of treatment, joint inflammation was decreasing, and on the last day, SsEtOAc (400 mg/kg), F-14 and ETP (10 mg/kg), SsEtOAc (200 mg/kg), methotrexate (MTX) 1.0 mg/kg and meloxicam (MEL) 1.5 mg/kg, produced an inhibition articulate edema of 94, 62, 36, 21, 80, and 54%, respectively. In the joint, pro-inflammatory molecules were elevated in animals without treatment (vehicle group, VEH). Treatments from S. schiedeana induced a decrease in the concentration of interleukin (IL)-1beta, IL-17, and IL-6, and SsEtOAc at a higher dose diminished tumor necrosis factor (TNF-alpha). IL-10 and IL-4 were fewer in the VEH group in comparison with healthy mice; the animals with treatments from S. schiedeana induced an increment in the levels of these cytokines in joint and spleen. PMID- 28587134 TI - Measuring Blue Space Visibility and 'Blue Recreation' in the Everyday Lives of Children in a Capital City. AB - Blue spaces (water bodies) may promote positive mental and physical health through opportunities for relaxation, recreation, and social connections. However, we know little about the nature and extent of everyday exposure to blue spaces, particularly in settings outside the home or among children, nor whether exposure varies by individual or household characteristics. Wearable cameras offer a novel, reliable method for blue space exposure measurement. In this study, we used images from cameras worn over two days by 166 children in Wellington, New Zealand, and conducted content and blue space quantification analysis on each image (n = 749,389). Blue space was identified in 24,721 images (3.6%), with a total of 23 blue recreation events. Visual exposure and participation in blue recreation did not differ by ethnicity, weight status, household deprivation, or residential proximity to the coastline. Significant differences in both visual exposure to blue space and participation in blue recreation were observed, whereby children from the most deprived schools had significantly higher rates of blue space exposure than children from low deprivation schools. Schools may be important settings to promote equitable blue space exposures. Childhood exposures to blue space may not follow the expected income inequality trends observed among adults. PMID- 28587136 TI - Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders. AB - Mitochondrial disorders are a clinically heterogeneous group of disorders that are caused by defects in the respiratory chain, the metabolic pathway of the adenosine tri-phosphate (ATP) production system. Epilepsy is a common and important feature of these disorders and its management can be challenging. Epileptic seizures in the context of mitochondrial disease are usually treated with conventional anti-epileptic medication, apart from valproic acid. However, in accordance with the treatment of intractable epilepsy where there are limited treatment options, the ketogenic diet (KD) has been considered as an alternative therapy. The use of the KD and its more palatable formulations has shown promising results. It is especially indicated and effective in the treatment of mitochondrial disorders due to complex I deficiency. Further research into the mechanism of action and the neuroprotective properties of the KD will allow more targeted therapeutic strategies and thus optimize the treatment of both epilepsy in the context of mitochondrial disorders but also in other neurodegenerative disorders. PMID- 28587137 TI - Modelling and Optimization of Four-Segment Shielding Coils of Current Transformers. AB - Applying shielding coils is a practical way to protect current transformers (CTs) for large-capacity generators from the intensive magnetic interference produced by adjacent bus-bars. The aim of this study is to build a simple analytical model for the shielding coils, from which the optimization of the shielding coils can be calculated effectively. Based on an existing stray flux model, a new analytical model for the leakage flux of partial coils is presented, and finite element method-based simulations are carried out to develop empirical equations for the core-pickup factors of the models. Using the flux models, a model of the common four-segment shielding coils is derived. Furthermore, a theoretical analysis is carried out on the optimal performance of the four-segment shielding coils in a typical six-bus-bars scenario. It turns out that the "all parallel" shielding coils with a 45 degrees starting position have the best shielding performance, whereas the "separated loop" shielding coils with a 0 degrees starting position feature the lowest heating value. Physical experiments were performed, which verified all the models and the conclusions proposed in the paper. In addition, for shielding coils with other than the four-segment configuration, the analysis process will generally be the same. PMID- 28587135 TI - RGD-Binding Integrins in Head and Neck Cancers. AB - Alterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the alphav and beta1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors alphavbeta3 and alphavbeta5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as alphavbeta6, alphavbeta8, and beta1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the arginine glycine-aspartate (RGD)-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour-specific identification and therapy. PMID- 28587138 TI - Toxin Variability Estimations of 68 Alexandrium ostenfeldii (Dinophyceae) Strains from The Netherlands Reveal a Novel Abundant Gymnodimine. AB - Alexandrium ostenfeldii is a toxic dinoflagellate that has recently bloomed in Ouwerkerkse Kreek, The Netherlands, and which is able to cause a serious threat to shellfish consumers and aquacultures. We used a large set of 68 strains to the aim of fully characterizing the toxin profiles of the Dutch A. ostenfeldii in consideration of recent reports of novel toxins. Alexandrium ostenfeldii is known as a causative species of paralytic shellfish poisoning, and consistently in the Dutch population we determined the presence of several paralytic shellfish toxins (PST) including saxitoxin (STX), GTX2/3 (gonyautoxins), B1 and C1/C2. We also examined the production of spiroimine toxins by the Dutch A. ostenfeldii strains. An extensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a high intraspecific variability of spirolides (SPX) and gymnodimines (GYM). Spirolides included 13-desMethyl-spirolide C generally as the major compound and several other mostly unknown SPX-like compounds that were detected and characterized. Besides spirolides, the presence of gymnodimine A and 12 Methyl-gymnodimine A was confirmed, together with two new gymnodimines. One of these was tentatively identified as an analogue of gymnodimine D and was the most abundant gymnodimine (calculated cell quota up to 274 pg cell-1, expressed as GYM A equivalents). Our multi-clonal approach adds new analogues to the increasing number of compounds in these toxin classes and revealed a high strain variability in cell quota and in toxin profile of toxic compounds within a single population. PMID- 28587139 TI - Is Housing a Health Insult? AB - In seeking to understand the relationship between housing and health, research attention is often focussed on separate components of people's whole housing 'bundles'. We propose in this paper that such conceptual and methodological abstraction of elements of the housing and health relationship limits our ability to understand the scale of the accumulated effect of housing on health and thereby contributes to the under-recognition of adequate housing as a social policy tool and powerful health intervention. In this paper, we propose and describe an index to capture the means by which housing bundles influence health. We conceptualise the index as reflecting accumulated housing 'insults to health' an Index of Housing Insults (IHI). We apply the index to a sample of 1000 low income households in Australia. The analysis shows a graded association between housing insults and health on all outcome measures. Further, after controlling for possible confounders, the IHI is shown to provide additional predictive power to the explanation of levels of mental health, general health and clinical depression beyond more traditional proxy measures. Overall, this paper reinforces the need to look not just at separate housing components but to embrace a broader understanding of the relationship between housing and health. PMID- 28587140 TI - Synthesis and Structural Modification of Marine Natural Products. AB - In the last decades, marine natural products (MNPs), have attracted extensive interest from both chemists and pharmacologists due to their chemical and bioactive diversities. This special issue, collecting total synthesis and structural modification of six different type of bioactive MNPs, is expected to inspire and attract more research effects invested into MNP research. PMID- 28587141 TI - LEM Characterization of Synthetic Jet Actuators Driven by Piezoelectric Element: A Review. AB - In the last decades, Synthetic jet actuators have gained much interest among the flow control techniques due to their short response time, high jet velocity and absence of traditional piping, which matches the requirements of reduced size and low weight. A synthetic jet is generated by the diaphragm oscillation (generally driven by a piezoelectric element) in a relatively small cavity, producing periodic cavity pressure variations associated with cavity volume changes. The pressured air exhausts through an orifice, converting diaphragm electrodynamic energy into jet kinetic energy. This review paper considers the development of various Lumped-Element Models (LEMs) as practical tools to design and manufacture the actuators. LEMs can quickly predict device performances such as the frequency response in terms of diaphragm displacement, cavity pressure and jet velocity, as well as the efficiency of energy conversion of input Joule power into useful kinetic power of air jet. The actuator performance is also analyzed by varying typical geometric parameters such as cavity height and orifice diameter and length, through a suited dimensionless form of the governing equations. A comprehensive and detailed physical modeling aimed to evaluate the device efficiency is introduced, shedding light on the different stages involved in the process. Overall, the influence of the coupling degree of the two oscillators, the diaphragm and the Helmholtz frequency, on the device performance is discussed throughout the paper. PMID- 28587142 TI - Spatial Distribution of Heavy Metals and the Environmental Quality of Soil in the Northern Plateau of Spain by Geostatistical Methods. AB - The environmental quality of soil in the central part of the Northern Plateau of Spain has been analyzed by studying the heavy metal content of 166 samples belonging to the horizons A, B and C of 89 soil profiles. The analysis to assess the environmental risk of heavy metals in the soil was carried out by means of the spatial distribution of nine heavy metals and the use of several pollution indices. The results showed that the concentration values of heavy metals (x +/- S) in the superficial soil horizons were the following: With a total of 6.71 +/- 3.51 mg kg -1, the contents of Cd is 0.08 +/- 0.06 mg kg-1, Co is 6.49 +/- 3.21 mg kg-1, Cu is 17.19 +/- 10.69 mg kg-1, Cr is 18.68 +/- 12.28 mg kg-1, Hg is 0.083 +/- 0.063 mg kg-1, Ni is 12.05 +/- 6.76 mg kg-1, Pb is 14.10 +/- 11.32 mg kg-1 and Zn is 35.31 +/- 14.63 mg kg-1. These nine metals exceed the values of the natural geological background level of Tertiary period sediments and rocks that form part of the Northern Plateau in Spain. Nemerow and Potential Ecological Risk indices were calculated, with the "improved" Nemerow index allowing pollution within the soil superficial horizons to be determined. The data obtained indicated that the majority of the soil (54.61%) showed low to moderate contamination, 22.31% showed moderate contamination and 21.54% of the samples were not contaminated. If we consider the Potential of Ecological Risk Index (RI), the largest percentage of soil samples showed low (70.79%) to moderate (25.38%) ecological risk of potential contamination, where the rest of the soil presented a considerable risk of contamination. The nine trace elements were divided into three principal components: PC1 (Cu, Cr, Ni, Co and Zn), PC2 (As and Hg) and PC3 (Cd). All metals accumulated in the soil came from parent rock, agricultural practices and the run-off of residual waters towards rivers and streams caused by industrial development and an increase in population density. Finally, cartography of the spatial distribution of the heavy metal contents in the soil of the Northern Plateau of Spain was generated using Kriging interpolation methods. Furthermore, the total heavy metal contents in three soil orders present in the area, namely Entisols, Inceptisols, and Alfisols, were analyzed. Other soil parameters, such as the organic matter content, pH, clay content and cation exchange capacity, was measured to determine their influence on and correlation with the heavy metal contents. PMID- 28587143 TI - Improving Outcomes in Patients with CRC: The Role of Patient Reported Outcomes-An ESDO Report. AB - Colorectal cancer is one of the most commonly diagnosed cancers worldwide and nearly half of patients will develop metastatic disease at some point during the course of their disease. The goal of anticancer therapy in this context is to extend survival, while trying to maximise the patient's health-related quality of life. To this end, we need to understand how to incorporate patient-reported outcomes into clinical trials and routine practice to accurately assess if treatment strategies are providing clinical benefit for the patient. This review reflects the proceedings of a 2016 European Society of Digestive Oncology workshop, where the authors discussed the use of patient-reported outcomes to measure health-related quality of life when evaluating treatment during the management of colorectal cancer. A summary of the challenges associated with implementing patient-reported outcomes in clinical trials is provided, as well as a review of the current clinical evidence surrounding patient-reported outcomes in metastatic colorectal cancer. PMID- 28587144 TI - Inhibitory Activities of Blasticidin S Derivatives on Aflatoxin Production by Aspergillus Flavus. AB - Blasticidin S (BcS) is a protein synthesis inhibitor which shows strong growth inhibitory activity against a number of microorganisms. However, BcS inhibited aflatoxin production by Aspergillus flavus without affecting its growth. In order to obtain information about the structure-activity relationship of BcS as an aflatoxin production inhibitor, BcS derivatives were prepared and their aflatoxin production inhibitory activities were evaluated. Among five derivatives, blasticidin S carboxymethyl ester, deaminohydroxyblasticidin S, and pyrimidinoblasticidin S showed inhibitory activity, while the others did not. The IC50 value for aflatoxin production of the carboxymethyl ester derivative was one fifth of that of BcS although their antimicrobial activities were almost the same. These results indicate that the inhibitory activity of BcS against aflatoxin production was enhanced by esterification of its carboxyl group and that the carboxymethyl ester derivative might be more suitable for practical use than BcS because of the specificity of the carboxymethyl ester derivative, which inhibited aflatoxin production more than BcS. PMID- 28587145 TI - Influence of Cooking (Microwaving and Broiling) on Cylindrospermopsin Concentration in Muscle of Nile Tilapia (Oreochromis niloticus) and Characterization of Decomposition Products. AB - Cylindrospermopsin (CYN) has become increasingly important as a freshwater algal toxin, showing cytotoxic effects. This toxin is able to bioaccumulate in freshwater food webs, representing a serious human health problem. Normally, fish is cooked before consumption, and CYN concentration can be altered. For the first time, the effects of microwaving and broiling for 1 and 2 min on CYN concentration and its decomposition products in fish muscle (Oreochromis niloticus) contaminated in the laboratory were investigated, using UPLC-MS/MS and Orbitrap. The results show that cooking the fish reduced unconjugated CYN levels by 11, 10 and 15% after microwaving for 1 and 2 min, and broiling for 2 min, respectively, compared to control fish. Different CYN decomposition products with m/z 416.1234 (7-epi-CYN) and m/z 336.16663 (diasteroisomers C-3A, C-3C, C-3D, C 3E, C-3F) are generated in fish samples submitted to cooking. Based on the relative abundance of the decomposition products, the possible degradation pathways taking place by microwaving may be through the formation of 7-epi-CYN and m/z 336.16663 compounds, whereas in the case of broiling the last route is the only one observed in this study. The influence of cooking and the toxicity characterization of the degradation products generated in CYN-contaminated fish are of importance for more realistic risk evaluation related to their consumption. PMID- 28587147 TI - Toxoplasma gondii in the Food Supply. AB - Toxoplasmosis is caused by infection with the protozoan parasite Toxoplasma gondii. Infections are usually either asymptomatic or develop mild symptoms that are self-limited, but infections in immunosuppressed persons can be severe. Infections in pregnant women can cause serious health problems in the child such as mental retardation and blindness. Infection with T. gondii in immunocompetent adults can lead to impaired eyesight. Toxoplasmosis has ranked very highly in two studies of death and disability attributable to foodborne pathogens. The consumption of raw or undercooked meat containing T. gondii tissue cysts and the consumption of raw vegetables or water contaminated with T. gondii oocysts from cat feces is most frequently associated with human illness. The risk of acquiring a Toxoplasma infection via food varies with cultural and eating habits in different human populations. PMID- 28587146 TI - Evaluation of the Dietary Intake of Cadmium, Lead and Mercury and Its Relationship with Bone Health among Postmenopausal Women in Spain. AB - BACKGROUND: Heavy metals, such as lead, cadmium, and mercury, are absorbed through contaminated food sources and water. Few studies have investigated the extent to which dietary heavy metals are associated with low bone mineral density. AIMS: We aimed to characterize the dietary intake of the heavy metals lead, cadmium and mercury among healthy, non-smoking postmenopausal women in Spain. Furthermore, we sought to establish a putative relationship between bone health and the intake of these heavy metals in this population. STUDY DESIGN: The daily intake of the heavy metals considered for the different food groups was calculated by accounting for food content and consumption in 281 postmenopausal women. Bone measurements were performed using a Quantitative Bone Ultrasound (QUS), a Dual-Energy X-ray Absorptiometry (DXA) and a Peripheral Quantitative Computed Tomography (pQCT). RESULTS: The average estimated dietary cadmium exposure among the 281 women studied was 29.87 MUg/day (20.41-41.04) and 3.03 MUg/kg body weight (b.w.; 2.17-4.40). Dietary lead exposure was 46.24 MUg/day (38.11-54.77) and 4.87 MUg/kg b.w. (4.00-6.14). The estimated dietary mercury exposure was 11.64 MUg/day and 1.19 MUg/kg b.w. (0.82-1.76). Participants were classified according to their heavy metal intake (above or below the respective medians). After further adjustment for potential confounding factors, no significant differences were found in all the measured parameters (p > 0.05). CONCLUSIONS: We did not find associations between bone health and the dietary intake of three heavy metals in postmenopausal women. Dietary intake of the measured heavy metals were within the recommended values. PMID- 28587149 TI - Suppression of Osteoclastogenesis by Melatonin: A Melatonin Receptor-Independent Action. AB - In vertebrates, melatonin is primarily secreted from the pineal gland but it affects various biological processes including the sleep-wake cycle, vasomotor control, immune system and bone homeostasis. Melatonin has been known to promote osteoblast differentiation and bone maturation, but a direct role of melatonin on osteoclast differentiation is still elusive. The present study investigated the effect of melatonin on the differentiation of macrophages to osteoclasts. The presence of melatonin significantly reduced receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis and the siRNA-mediated knockdown of the melatonin receptor failed to overcome the anti-osteoclastogenic effect of melatonin. Although melatonin treatment did not affect the phosphorylation of extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK), it markedly inhibited the activation of NF-kappaB and subsequent induction of nuclear factor of activated T cell cytoplasmic 1(NFATc1). Thus, our results suggest that melatonin could suppress osteoclast differentiation through downregulation of NF-kappaB pathway with concomitant decrease in the NFATc1 transcription factor induction. Furthermore, melatonin seems to have an anti osteoclastogenic effect independent of plasma membrane melatonin receptors. In addition to previously reported properties of melatonin, our study proposes another aspect of melatonin and bone homeostasis. PMID- 28587151 TI - Geographical Environment Factors and Risk Assessment of Tick-Borne Encephalitis in Hulunbuir, Northeastern China. AB - Tick-borne encephalitis (TBE) is one of natural foci diseases transmitted by ticks. Its distribution and transmission are closely related to geographic and environmental factors. Identification of environmental determinates of TBE is of great importance to understanding the general distribution of existing and potential TBE natural foci. Hulunbuir, one of the most severe endemic areas of the disease, is selected as the study area. Statistical analysis, global and local spatial autocorrelation analysis, and regression methods were applied to detect the spatiotemporal characteristics, compare the impact degree of associated factors, and model the risk distribution using the heterogeneity. The statistical analysis of gridded geographic and environmental factors and TBE incidence show that the TBE patients mainly occurred during spring and summer and that there is a significant positive spatial autocorrelation between the distribution of TBE cases and environmental characteristics. The impact degree of these factors on TBE risks has the following descending order: temperature, relative humidity, vegetation coverage, precipitation and topography. A high-risk area with a triangle shape was determined in the central part of Hulunbuir; the low-risk area is located in the two belts next to the outside edge of the central triangle. The TBE risk distribution revealed that the impact of the geographic factors changed depending on the heterogeneity. PMID- 28587153 TI - Nanoporous Gold Films Prepared by a Combination of Sputtering and Dealloying for Trace Detection of Benzo[a]pyrene Based on Surface Plasmon Resonance Spectroscopy. AB - A wavelength-interrogated surface plasmon resonance (SPR) sensor based on a nanoporous gold (NPG) film has been fabricated for the sensitive detection of trace quantities of benzo[a]pyrene (BaP) in water. The large-area uniform NPG film was prepared by a two-step process that includes sputtering deposition of a 60-nm-thick AuAg alloy film on a glass substrate and chemical dealloying of the alloy film in nitric acid. For SPR sensor applications, the NPG film plays the dual roles of analyte enrichment and supporting surface plasmon waves, which leads to sensitivity enhancement. In this work, the as-prepared NPG film was first modified with 1-dodecanethiol molecules to make the film hydrophobic so as to improve BaP enrichment from water via hydrophobic interactions. The SPR sensor with the hydrophobic NPG film enables one to detect BaP at concentrations as low as 1 nmol.L-1. In response to this concentration of BaP the sensor produced a resonance-wavelength shift of DeltalambdaR = 2.22 nm. After the NPG film was functionalized with mouse monoclonal IgG1 that is the antibody against BaP, the sensor's sensitivity was further improved and the BaP detection limit decreased further down to 5 pmol.L-1 (the corresponding DeltalambdaR = 1.77 nm). In contrast, the conventional SPR sensor with an antibody-functionalized dense gold film can give a response of merely DeltalambdaR = 0.9 nm for 100 pmol.L-1 BaP. PMID- 28587152 TI - Long Term Physiologic and Behavioural Effects of Housing Density and Environmental Resource Provision for Adult Male and Female Sprague Dawley Rats. AB - There is considerable interest in refining laboratory rodent environments to promote animal well-being, as well as research reproducibility. Few studies have evaluated the long term impact of enhancing rodent environments with resources and additional cagemates. To that end, male and female Sprague Dawley (SD) rats were housed singly (n = 8/sex), in pairs (n = 16/sex), or in groups of four (n = 16/sex) for five months. Single and paired rats were housed in standard cages with a nylon chew toy, while group-housed rats were kept in double-wide cages with two PVC shelters and a nylon chew toy and were provided with food enrichment three times weekly. Animal behaviour, tests of anxiety (open field, elevated plus maze, and thermal nociception), and aspects of animal physiology (fecal corticoid levels, body weight, weekly food consumption, organ weights, and cerebral stress signaling peptide and receptor mRNA levels) were measured. Significant differences were noted, primarily in behavioural data, with sustained positive social interactions and engagement with environmental resources noted throughout the study. These results suggest that modest enhancements in the environment of both male and female SD rats may be beneficial to their well-being, while introducing minimal variation in other aspects of behavioural or physiologic responses. PMID- 28587150 TI - Variability and Global Distribution of Subgenotypes of Bovine Viral Diarrhea Virus. AB - Bovine viral diarrhea virus (BVDV) is a globally-distributed agent responsible for numerous clinical syndromes that lead to major economic losses. Two species, BVDV-1 and BVDV-2, discriminated on the basis of genetic and antigenic differences, are classified in the genus Pestivirus within the Flaviviridae family and distributed on all of the continents. BVDV-1 can be segregated into at least twenty-one subgenotypes (1a-1u), while four subgenotypes have been described for BVDV-2 (2a-2d). With respect to published sequences, the number of virus isolates described for BVDV-1 (88.2%) is considerably higher than for BVDV 2 (11.8%). The most frequently-reported BVDV-1 subgenotype are 1b, followed by 1a and 1c. The highest number of various BVDV subgenotypes has been documented in European countries, indicating greater genetic diversity of the virus on this continent. Current segregation of BVDV field isolates and the designation of subgenotypes are not harmonized. While the species BVDV-1 and BVDV-2 can be clearly differentiated independently from the portion of the genome being compared, analysis of different genomic regions can result in inconsistent assignment of some BVDV isolates to defined subgenotypes. To avoid non conformities the authors recommend the development of a harmonized system for subdivision of BVDV isolates into defined subgenotypes. PMID- 28587154 TI - Redistribution of Endosomal Membranes to the African Swine Fever Virus Replication Site. AB - African swine fever virus (ASFV) infection causes endosomal reorganization. Here, we show that the virus causes endosomal congregation close to the nucleus as the infection progresses, which is necessary to build a compact viral replication organelle. ASFV enters the cell by the endosomal pathway and reaches multivesicular late endosomes. Upon uncoating and fusion, the virus should exit to the cytosol to start replication. ASFV remodels endosomal traffic and redistributes endosomal membranes to the viral replication site. Virus replication also depends on endosomal membrane phosphoinositides (PtdIns) synthesized by PIKfyve. Endosomes could act as platforms providing membranes and PtdIns, necessary for ASFV replication. Our study has revealed that ASFV reorganizes endosome dynamics, in order to ensure a productive infection. PMID- 28587157 TI - Adaptive Estimation of Multiple Fading Factors for GPS/INS Integrated Navigation Systems. AB - The Kalman filter has been widely applied in the field of dynamic navigation and positioning. However, its performance will be degraded in the presence of significant model errors and uncertain interferences. In the literature, the fading filter was proposed to control the influences of the model errors, and the H-infinity filter can be adopted to address the uncertainties by minimizing the estimation error in the worst case. In this paper, a new multiple fading factor, suitable for the Global Positioning System (GPS) and the Inertial Navigation System (INS) integrated navigation system, is proposed based on the optimization of the filter, and a comprehensive filtering algorithm is constructed by integrating the advantages of the H-infinity filter and the proposed multiple fading filter. Measurement data of the GPS/INS integrated navigation system are collected under actual conditions. Stability and robustness of the proposed filtering algorithm are tested with various experiments and contrastive analysis are performed with the measurement data. Results demonstrate that both the filter divergence and the influences of outliers are restrained effectively with the proposed filtering algorithm, and precision of the filtering results are improved simultaneously. PMID- 28587148 TI - The Role of Caveolin 1 in HIV Infection and Pathogenesis. AB - Caveolin 1 (Cav-1) is a major component of the caveolae structure and is expressed in a variety of cell types including macrophages, which are susceptible to human immunodeficiency virus (HIV) infection. Caveolae structures are present in abundance in mechanically stressed cells such as endothelial cells and adipocytes. HIV infection induces dysfunction of these cells and promotes pathogenesis. Cav-1 and the caveolae structure are believed to be involved in multiple cellular processes that include signal transduction, lipid regulation, endocytosis, transcytosis, and mechanoprotection. Such a broad biological role of Cav-1/caveolae is bound to have functional cross relationships with several molecular pathways including HIV replication and viral-induced pathogenesis. The current review covers the relationship of Cav-1 and HIV in respect to viral replication, persistence, and the potential role in pathogenesis. PMID- 28587156 TI - Differential Sarcomere and Electrophysiological Maturation of Human iPSC-Derived Cardiac Myocytes in Monolayer vs. Aggregation-Based Differentiation Protocols. AB - Human induced pluripotent stem cells (iPSCs) represent a powerful human model to study cardiac disease in vitro, notably channelopathies and sarcomeric cardiomyopathies. Different protocols for cardiac differentiation of iPSCs have been proposed either based on embroid body formation (3D) or, more recently, on monolayer culture (2D). We performed a direct comparison of the characteristics of the derived cardiomyocytes (iPSC-CMs) on day 27 +/- 2 of differentiation between 3D and 2D differentiation protocols with two different Wnt-inhibitors were compared: IWR1 (inhibitor of Wnt response) or IWP2 (inhibitor of Wnt production). We firstly found that the level of Troponin T (TNNT2) expression measured by FACS was significantly higher for both 2D protocols as compared to the 3D protocol. In the three methods, iPSC-CM show sarcomeric structures. However, iPSC-CM generated in 2D protocols constantly displayed larger sarcomere lengths as compared to the 3D protocol. In addition, mRNA and protein analyses reveal higher cTNi to ssTNi ratios in the 2D protocol using IWP2 as compared to both other protocols, indicating a higher sarcomeric maturation. Differentiation of cardiac myocytes with 2D monolayer-based protocols and the use of IWP2 allows the production of higher yield of cardiac myocytes that have more suitable characteristics to study sarcomeric cardiomyopathies. PMID- 28587158 TI - Low-Symmetry Mixed Fluorinated Subphthalocyanines as Fluorescence Imaging Probes in MDA-MB-231 Breast Tumor Cells. AB - Boron subphthalocyanines (SPcs) are aromatic macrocycles that possess a combination of physical and optical properties that make them excellent candidates for application as fluorescent imaging probes. These molecules have intense electronic absorption and emission, and structural versatility that allows for specific tuning of physical properties. Herein, we report the synthesis of a series of low-symmetry fluorinated SPcs and compare them to analogous compounds with varying numbers of peripheral fluorine atoms and varied aromaticity. Across the series, with increasing addition of fluorine atoms to the periphery of the ring, a downfield chemical shift in 19F NMR and a bathochromic shift of electronic absorption were observed. Expanding the size of the aromatic ring by replacing peripheral benzo- groups with naphtho- groups prompted a far more drastic bathochromic shift to absorption and emission. Fluorescence quantum yields (Phif) proved to be sufficiently high to observe intracellular fluorescence from MDA-MB-231 breast tumor cells in vitro by epifluorescence microscopy; fluorination proved vital for this purpose to improve solubility. This report lays the groundwork for the future development of these promising SPcs for their ultimate application as near-infrared (NIR) fluorescent imaging probes in biological systems. PMID- 28587161 TI - Structural Health Monitoring for a Z-Type Special Vehicle. AB - Nowadays there exist various kinds of special vehicles designed for some purposes, which are different from regular vehicles in overall dimension and design. In that case, accidents such as overturning will lead to large economical loss and casualties. There are still no technical specifications to follow to ensure the safe operation and driving of these special vehicles. Owing to the poor efficiency of regular maintenance, it is more feasible and effective to apply real-time monitoring during the operation and driving process. In this paper, the fiber Bragg grating (FBG) sensors are used to monitor the safety of a z-type special vehicle. Based on the structural features and force distribution, a reasonable structural health monitoring (SHM) scheme is presented. Comparing the monitoring results with the finite element simulation results guarantees the accuracy and reliability of the monitoring results. Large amounts of data are collected during the operation and driving progress to evaluate the structural safety condition and provide reference for SHM systems developed for other special vehicles. PMID- 28587155 TI - Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer. AB - Phytochemicals are natural compounds synthesized as secondary metabolites in plants, representing an important source of molecules with a wide range of therapeutic applications. These natural agents are important regulators of key pathological processes/conditions, including cancer, as they are able to modulate the expression of coding and non-coding transcripts with an oncogenic or tumour suppressor role. These natural agents are currently exploited for the development of therapeutic strategies alone or in tandem with conventional treatments for cancer. The aim of this paper is to review the recent studies regarding the role of these natural phytochemicals in different processes related to cancer inhibition, including apoptosis activation, angiogenesis and metastasis suppression. From the large palette of phytochemicals we selected epigallocatechin gallate (EGCG), caffeic acid phenethyl ester (CAPE), genistein, morin and kaempferol, due to their increased activity in modulating multiple coding and non-coding genes, targeting the main hallmarks of cancer. PMID- 28587159 TI - Effects of Low-Dose Non-Caloric Sweetener Consumption on Gut Microbiota in Mice. AB - Abstract: Non-caloric artificial sweeteners (NASs) provide sweet tastes to food without adding calories or glucose. NASs can be used as alternative sweeteners for controlling blood glucose levels and weight gain. Although the consumption of NASs has increased over the past decade in Japan and other countries, whether these sweeteners affect the composition of the gut microbiome is unclear. In the present study, we examined the effects of sucralose or acesulfame-K ingestion (at most the maximum acceptable daily intake (ADI) levels, 15 mg/kg body weight) on the gut microbiome in mice. Consumption of sucralose, but not acesulfame-K, for 8 weeks reduced the relative amount of Clostridiumcluster XIVa in feces. Meanwhile, sucralose and acesulfame-K did not increase food intake, body weight gain or liver weight, or fat in the epididymis or cecum. Only sucralose intake increased the concentration of hepatic cholesterol and cholic acid. Moreover, the relative concentration of butyrate and the ratio of secondary/primary bile acids in luminal metabolites increased with sucralose consumption in a dose-dependent manner. These results suggest that daily intake of maximum ADI levels of sucralose, but not acesulfame-K, affected the relative amount of the Clostridium cluster XIVa in fecal microbiome and cholesterol bile acid metabolism in mice. PMID- 28587160 TI - Advances in Drug Discovery of New Antitubercular Multidrug-Resistant Compounds. AB - Tuberculosis (TB), a disease caused mainly by the Mycobacterium tuberculosis (Mtb), is according to the World Health Organization (WHO) the infectious disease responsible for the highest number of deaths worldwide. The increased number of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains, and the ineffectiveness of the current treatment against latent tuberculosis are challenges to be overcome in the coming years. The scenario of drug discovery becomes alarming when it is considered that the number of new drugs does not increase proportionally to the emergence of drug resistance. In this review, we will demonstrate the current advances in antitubercular drug discovery, focusing on the research of compounds with potent antituberculosis activity against MDR-TB strains. Herein, active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 uM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed. PMID- 28587162 TI - Glutathione-Mediated Cu(I)/Cu(II) Complexes: Valence-Dependent Effects on Clearance and In Vivo Imaging Application. AB - Contrast imaging agents need to be cleared in a reasonable time (less than 72 h), so it is quite urgent to understand the structure, biocompatibility, and metabolism features of imaging agents. In this work, luminescent Cu(I)-GSH complex and their derivative oxidized Cu(II)-GSSG complex have been easily synthesized. Through systematically probing the renal clearance and biodistribution of the as-prepared copper complexes, we found that Cu(I)-GSH complex revealed much more efficient renal clearance and remarkably lower liver accumulation than that of their oxidation states, which could be due to strong protein binding of partial forms of Cu(II)-GSSG complex. Besides, we also attempted to incorporate radioactive copper-64 into Cu(I)-GSH complex for the synthesis of radioactive contrast agent. Indeed, the as-prepared radioactive Cu(I)-GSH complex also showed consistent high efficiency renal excretion, allowing them to be potential PET imaging agents in clinical translation. PMID- 28587164 TI - Chemical Methods to Knock Down the Amyloid Proteins. AB - Amyloid proteins are closely related with amyloid diseases and do tremendous harm to human health. However, there is still a lack of effective strategies to treat these amyloid diseases, so it is important to develop novel methods. Accelerating the clearance of amyloid proteins is a favorable method for amyloid disease treatment. Recently, chemical methods for protein reduction have been developed and have attracted much attention. In this review, we focus on the latest progress of chemical methods that knock down amyloid proteins, including the proteolysis-targeting chimera (PROTAC) strategy, the "recognition-cleavage" strategy, the chaperone-mediated autophagy (CMA) strategy, the selectively light activatable organic and inorganic molecules strategy and other chemical strategies. PMID- 28587165 TI - Dynamic In Vivo Profiling of DNA Damage and Repair after Radiotherapy Using Canine Patients as a Model. AB - Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (gammaH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15-60 min after irradiation, with a rapid decrease. Time courses of gammaH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer from the heterogeneous nature of the in vivo data. It was possible to follow dynamics of comet tail intensity and gammaH2AX-foci during a course of radiation using a minimally invasive approach. DNA repair can be quantitatively investigated as time-courses of individual patients by integrating this resulting data into a dynamic mathematical model. PMID- 28587166 TI - Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases. AB - Cardiovascular diseases remain the number one diseases affecting patients' morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity. PMID- 28587167 TI - New Mild and Simple Approach to Isothiocyanates: A Class of Potent Anticancer Agents. AB - In our current work, acetyl chloride-mediated synthesis of phenethyl isothiocyanate (PEITC) derivatives proves to be convenient and provides the expected products at good to excellent yields. Biological evaluation and structure-activity relationship analysis found that the novel compound 7 showed the best anticancer activity against human cancer cell line Panc1 and HGC27 compared with PEITC. Compounds 6 and 7 induced more apoptosis in pancreatic cancer cells but less toxicity in non-cancer cells. Further biological study demonstrated that 7 substantially increased intracellular reactive oxygen species (ROS) and depleted glutathione (GSH), leading to an oxidative stress to kill cancer cell. PMID- 28587169 TI - Meta-Analyses of QTLs Associated with Protein and Oil Contents and Compositions in Soybean [Glycine max (L.) Merr.] Seed. AB - Soybean [Glycine max (L.) Merr.] is a valuable and nutritious crop in part due to the high protein meal and vegetable oil produced from its seed. Soybean producers desire cultivars with both elevated seed protein and oil concentrations as well as specific amino acid and fatty acid profiles. Numerous studies have identified quantitative trait loci (QTLs) associated with seed composition traits, but validation of these QTLs has rarely been carried out. In this study, we have collected information, including genetic location and additive effects, on each QTL for seed contents of protein and oil, as well as amino acid and fatty acid compositions from over 80 studies. Using BioMercator V. 4.2, a meta-QTL analysis was performed with genetic information comprised of 175 QTLs for protein, 205 QTLs for oil, 156 QTLs for amino acids, and 113 QTLs for fatty acids. A total of 55 meta-QTL for seed composition were detected on 6 out of 20 chromosomes. Meta QTL possessed narrower confidence intervals than the original QTL and candidate genes were identified within each meta-QTL. These candidate genes elucidate potential natural genetic variation in genes contributing to protein and oil biosynthesis and accumulation, providing meaningful information to further soybean breeding programs. PMID- 28587168 TI - Physicochemical Properties, Biological Activity, Health Benefits, and General Limitations of Aged Black Garlic: A Review. AB - Garlic (Allium sativum) has been used as a medicinal food since ancient times. However, some people are reluctant to ingest raw garlic due to its unpleasant odor and taste. Therefore, many types of garlic preparations have been developed to reduce these attributes without losing biological functions. Aged black garlic (ABG) is a garlic preparation with a sweet and sour taste and no strong odor. It has recently been introduced to Asian markets as a functional food. Extensive in vitro and in vivo studies have demonstrated that ABG has a variety of biological functions such as antioxidant, anti-inflammatory, anti-cancer, anti-obesity, anti diabetic, anti-allergic, cardioprotective, and hepatoprotective effects. Recent studies have compared the biological activity and function of ABG to those of raw garlic. ABG shows lower anti-inflammatory, anti-coagulation, immunomodulatory, and anti-allergic effects compared to raw garlic. This paper reviews the physicochemical properties, biological activity, health benefits, adverse effects, and general limitations of ABG. PMID- 28587171 TI - Optimal Time Allocation in Backscatter Assisted Wireless Powered Communication Networks. AB - This paper proposes a wireless powered communication network (WPCN) assisted by backscatter communication (BackCom). This model consists of a power station, an information receiver and multiple users that can work in either BackCom mode or harvest-then-transmit (HTT) mode. The time block is mainly divided into two parts corresponding to the data backscattering and transmission periods, respectively. The users first backscatter data to the information receiver in time division multiple access (TDMA) during the data backscattering period. When one user works in the BackCom mode, the other users harvest energy from the power station. During the data transmission period, two schemes, i.e., non-orthogonal multiple access (NOMA) and TDMA, are considered. To maximize the system throughput, the optimal time allocation policies are obtained. Simulation results demonstrate the superiority of the proposed model. PMID- 28587170 TI - The Combination of Arginine Deprivation and 5-Fluorouracil Improves Therapeutic Efficacy in Argininosuccinate Synthetase Negative Hepatocellular Carcinoma. AB - Argininosuccinate synthetase (ASS), a key enzyme to synthesize arginine is down regulated in many tumors including hepatocellular carcinoma (HCC). Similar to previous reports, we have found the decrease in ASS expression in poorly differentiated HCC. These ASS(-) tumors are auxotrophic for arginine. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine, has shown activity in these tumors, but the antitumor effect is not robust and hence combination treatment is needed. Herein, we have elucidated the effectiveness of ADI-PEG20 combined with 5-Fluorouracil (5-FU) in ASS(-)HCC by targeting urea cycle and pyrimidine metabolism using four HCC cell lines as model. SNU398 and SNU387 express very low levels of ASS or ASS(-) while Huh-1, and HepG2 express high ASS similar to normal cells. Our results showed that the augmented cytotoxic effect of combination treatment only occurs in SNU398 and SNU387, and not in HepG2 and Huh-1 (ASS(+)) cells, and is partly due to reduced anti-apoptotic proteins X linked inhibitor of apoptosis protein (XIAP), myeloid leukemia cell differentiation protein (Mcl-1) and B-cell lymphoma-2 (Bcl-2). Importantly, lack of ASS also influences essential enzymes in pyrimidine synthesis (carbamoyl phosphate synthetase2, aspartate transcarbamylase and dihydrooratase (CAD) and thymidylate synthase (TS)) and malate dehydrogenase-1 (MDH-1) in TCA cycle. ADI PEG20 treatment decreased these enzymes and made them more vulnerable to 5-FU. Transfection of ASS restored these enzymes and abolished the sensitivity to ADI PEG20 and combination treatment. Overall, our data suggest that ASS influences multiple enzymes involved in 5-FU sensitivity. Combining ADI-PEG20 and 5-FU may be effective to treat ASS(-)hepatoma and warrants further clinical investigation. PMID- 28587163 TI - A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro. AB - An emerging vision for toxicity testing in the 21st century foresees in vitro assays assuming the leading role in testing for chemical hazards, including testing for carcinogenicity. Toxicity will be determined by monitoring key steps in functionally validated molecular pathways, using tests designed to reveal chemically-induced perturbations that lead to adverse phenotypic endpoints in cultured human cells. Risk assessments would subsequently be derived from the causal in vitro endpoints and concentration vs. effect data extrapolated to human in vivo concentrations. Much direct experimental evidence now shows that disruption of epigenetic processes by chemicals is a carcinogenic mode of action that leads to altered gene functions playing causal roles in cancer initiation and progression. In assessing chemical safety, it would therefore be advantageous to consider an emerging class of carcinogens, the epigenotoxicants, with the ability to change chromatin and/or DNA marks by direct or indirect effects on the activities of enzymes (writers, erasers/editors, remodelers and readers) that convey the epigenetic information. Evidence is reviewed supporting a strategy for in vitro hazard identification of carcinogens that induce toxicity through disturbance of functional epigenetic pathways in human somatic cells, leading to inactivated tumour suppressor genes and carcinogenesis. In the context of human cell transformation models, these in vitro pathway measurements ensure high biological relevance to the apical endpoint of cancer. Four causal mechanisms participating in pathways to persistent epigenetic gene silencing were considered: covalent histone modification, nucleosome remodeling, non-coding RNA interaction and DNA methylation. Within these four interacting mechanisms, 25 epigenetic toxicity pathway components (SET1, MLL1, KDM5, G9A, SUV39H1, SETDB1, EZH2, JMJD3, CBX7, CBX8, BMI, SUZ12, HP1, MPP8, DNMT1, DNMT3A, DNMT3B, TET1, MeCP2, SETDB2, BAZ2A, UHRF1, CTCF, HOTAIR and ANRIL) were found to have experimental evidence showing that functional perturbations played "driver" roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints. PMID- 28587173 TI - Design and Implementation of a Hypothermic Machine Perfusion Device for Clinical Preservation of Isolated Organs. AB - The imbalance between limited organ supply and huge potential need has hindered the development of organ-graft techniques. In this paper a low-cost hypothermic machine perfusion (HMP) device is designed and implemented to maintain suitable preservation surroundings and extend the survival life of isolated organs. Four necessary elements (the machine perfusion, the physiological parameter monitoring, the thermostatic control and the oxygenation apparatus) involved in this HMP device are introduced. Especially during the thermostatic control process, a modified Bayes estimation, which introduces the concept of improvement factor, is realized to recognize and reduce the possible measurement errors resulting from sensor faults and noise interference. Also, a fuzzy-PID controller contributes to improve the accuracy and reduces the computational load using the DSP. Our experiments indicate that the reliability of the instrument meets the design requirements, thus being appealing for potential clinical preservation applications. PMID- 28587174 TI - Chang'E-5T Orbit Determination Using Onboard GPS Observations. AB - In recent years, Global Navigation Satellite System (GNSS) has played an important role in Space Service Volume, the region enclosing the altitudes above 3000 km up to 36,000 km. As an in-flight test for the feasibility as well as for the performance of GNSS-based satellite orbit determination (OD), the Chinese experimental lunar mission Chang'E-5T had been equipped with an onboard high sensitivity GNSS receiver with GPS and GLONASS tracking capability. In this contribution, the 2-h onboard GPS data are evaluated in terms of tracking performance as well as observation quality. It is indicated that the onboard receiver can track 7-8 GPS satellites per epoch on average and the ratio of carrier to noise spectral density (C/N0) values are higher than 28 dB-Hz for 90% of all the observables. The C1 code errors are generally about 4.15 m but can be better than 2 m with C/N0 values over 36 dB-Hz. GPS-based Chang'E-5T OD is performed and the Helmert variance component estimation method is investigated to determine the weights of code and carrier phase observations. The results reveal that the orbit consistency is about 20 m. OD is furthermore analyzed with GPS data screened out according to different C/N0 thresholds. It is indicated that for the Chang'E-5T, the precision of OD is dominated by the number of observed satellite. Although increased C/N0 thresholds can improve the overall data quality, the available number of GPS observations is greatly reduced and the resulting orbit solution is poor. PMID- 28587172 TI - The Rising Tide of Antimicrobial Resistance in Aquaculture: Sources, Sinks and Solutions. AB - As the human population increases there is an increasing reliance on aquaculture to supply a safe, reliable, and economic supply of food. Although food production is essential for a healthy population, an increasing threat to global human health is antimicrobial resistance. Extensive antibiotic resistant strains are now being detected; the spread of these strains could greatly reduce medical treatment options available and increase deaths from previously curable infections. Antibiotic resistance is widespread due in part to clinical overuse and misuse; however, the natural processes of horizontal gene transfer and mutation events that allow genetic exchange within microbial populations have been ongoing since ancient times. By their nature, aquaculture systems contain high numbers of diverse bacteria, which exist in combination with the current and past use of antibiotics, probiotics, prebiotics, and other treatment regimens singularly or in combination. These systems have been designated as "genetic hotspots" for gene transfer. As our reliance on aquaculture grows, it is essential that we identify the sources and sinks of antimicrobial resistance, and monitor and analyse the transfer of antimicrobial resistance between the microbial community, the environment, and the farmed product, in order to better understand the implications to human and environmental health. PMID- 28587175 TI - UHPLC-TQ-MS Coupled with Multivariate Statistical Analysis to Characterize Nucleosides, Nucleobases and Amino Acids in Angelicae Sinensis Radix Obtained by Different Drying Methods. AB - To explore the nutrients in roots of Angelica sinensis (Angelicae Sinensis Radix, ASR), a medicinal and edible plant, and evaluate its nutritional value, a rapid and reliable UHPLC-TQ-MS method was established and used to determine the potential nutritional compounds, including nucleosides, nucleobases and amino acids, in 50 batches of ASR samples obtained using two drying methods. The results showed that ASR is a healthy food rich in nucleosides, nucleobases and amino acids, especially arginine. The total average content of nucleosides and nucleobases in all ASR samples was 3.94 mg/g, while that of amino acids reached as high as 61.79 mg/g. Principle component analysis showed that chemical profile differences exist between the two groups of ASR samples prepared using different drying methods, and the contents of nutritional compounds in samples dried with the tempering-intermittent drying processing method (TIDM) were generally higher than those dried using the traditional solar processing method. The above results suggest that ASR should be considered an ideal healthy food and TIDM could be a suitable drying method for ASR when taking nucleosides, nucleobases and amino acids as the major consideration for their known human health benefits. PMID- 28587177 TI - Classification of K-Pop Dance Movements Based on Skeleton Information Obtained by a Kinect Sensor. AB - This paper suggests a method of classifying Korean pop (K-pop) dances based on human skeletal motion data obtained from a Kinect sensor in a motion-capture studio environment. In order to accomplish this, we construct a K-pop dance database with a total of 800 dance-movement data points including 200 dance types produced by four professional dancers, from skeletal joint data obtained by a Kinect sensor. Our classification of movements consists of three main steps. First, we obtain six core angles representing important motion features from 25 markers in each frame. These angles are concatenated with feature vectors for all of the frames of each point dance. Then, a dimensionality reduction is performed with a combination of principal component analysis and Fisher's linear discriminant analysis, which is called fisherdance. Finally, we design an efficient Rectified Linear Unit (ReLU)-based Extreme Learning Machine Classifier (ELMC) with an input layer composed of these feature vectors transformed by fisherdance. In contrast to conventional neural networks, the presented classifier achieves a rapid processing time without implementing weight learning. The results of experiments conducted on the constructed K-pop dance database reveal that the proposed method demonstrates a better classification performance than those of conventional methods such as KNN (K-Nearest Neighbor), SVM (Support Vector Machine), and ELM alone. PMID- 28587176 TI - Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story. AB - Jumonji domain-containing protein 6 (JMJD6) is a non-heme Fe(II) 2-oxoglutarate (2OG)-dependent oxygenase with arginine demethylase and lysyl hydroxylase activities. Its initial discovery as a dispensable phosphatidylserine receptor (PSR) in the cell membrane of macrophages for phagocytosis was squashed by newer studies which revealed its nuclear localization and bifunctional enzymatic activity. Though its interaction with several nuclear and cytoplasmic target proteins has been demonstrated, the exact mechanisms and clinical significance of these various biologic interplays are not yet well established. Recent investigations have shed the light on the multiple pathways by which JMJD6 can regulate cell proliferation and cause tumorigenesis. Clinically, JMJD6 has been associated with more aggressive and metastatic disease, poorer prognosis, and lower overall survival rates-particularly in lung colon and oral cancers. JMJD6 is a novel biomarker for predicting future disease outcomes and is a target for new therapeutic treatments in future studies. Aberrant expression and dysregulation of JMJD6 are implicated in various other processes such as impaired T-cell proliferation and maturation, inoculation, and virulence of foot-and-mouth disease virus (FMDV), and impaired methylation of innate immunity factor. This article reviews the association of JMJD6 with various pathological processes particularly, its role in tumorigenesis and virological interactions. PMID- 28587178 TI - Survey of Motion Tracking Methods Based on Inertial Sensors: A Focus on Upper Limb Human Motion. AB - Motion tracking based on commercial inertial measurements units (IMUs) has been widely studied in the latter years as it is a cost-effective enabling technology for those applications in which motion tracking based on optical technologies is unsuitable. This measurement method has a high impact in human performance assessment and human-robot interaction. IMU motion tracking systems are indeed self-contained and wearable, allowing for long-lasting tracking of the user motion in situated environments. After a survey on IMU-based human tracking, five techniques for motion reconstruction were selected and compared to reconstruct a human arm motion. IMU based estimation was matched against motion tracking based on the Vicon marker-based motion tracking system considered as ground truth. Results show that all but one of the selected models perform similarly (about 35 mm average position estimation error). PMID- 28587179 TI - Screening of Deoxynivalenol Producing Strains and Elucidation of Possible Toxigenic Molecular Mechanism. AB - In this study, seven strains of Fusarium graminearum were isolated from wheat, of which six were identified to produce deoxynivalenol and the production of deoxynivalenol was assessed. F. graminearum strain Fg1 was noted to produce 1.0 MUg/g deoxynivalenol during the incubation period in the Czapek yeast broth, while none was detected in F. graminearum strain Fg2. Hence, the differences in proteomes and transcriptomes of Fg1 and Fg2 were compared to analyze the mechanism underlying deoxynivalenol production. Among the 66 significantly differentially expressed proteins in Fg1, 39 and 27 were more or less abundant expressed. Functional analysis suggested that the enzymes involved in the methylerythritol 4-phosphate and mevalonate pathways, which provide a substrate for biosynthesis of farnesyl pyrophosphate, a precursor of DON, were activated in Fg1. The transcriptomics data demonstrated that the expression level of a majority of genes, including trichothecene biosynthetic genes, protein kinases, and transcription factors, involved in trichothecene biosynthesis was higher in Fg1 than in Fg2. The results also revealed differential expression profiles of deoxynivalenol biosynthesis genes in strains Fg1 and Fg2, which emphasized their deoxynivalenol producing ability and the underlying mechanism. PMID- 28587180 TI - Effect of Obstructive Sleep Apnea Treatment on Lipids in Obese Children. AB - Obesity in children is associated with several co-morbidities including dyslipidemia. Obstructive sleep apnea (OSA) is commonly seen in obese children. In adults, diagnosis of OSA independent of obesity is associated with cardiometabolic risk factors including dyslipidemia. There is limited data on the impact of treatment of OSA on lipids in children. The objective of the study was to examine the impact of treatment of OSA on lipids in 24 obese children. Methods: Seventeen children were treated with continuous positive airway pressure (CPAP) and five underwent adenotonsillectomy. Mean apnea hypopnea index prior to treatment was 13.0 + 12.1 and mean body mass index (BMI) was 38.0 + 10.6 kg/m2. Results: Treatment of OSA was associated with improvement in total cholesterol (mean change = -11 mg/dL, p < 0.001), and low-density lipoprotein cholesterol (mean change = -8.8 mg/dL, p = 0.021). Conclusion: Obese children should be routinely screened for OSA, as treatment of OSA favorably influences lipids and therefore decreases their cardiovascular risk. PMID- 28587181 TI - Chronic Inflammatory Diseases and Green Tea Polyphenols. AB - Chronic inflammatory diseases affect millions of people globally and the incidence rate is on the rise. While inflammation contributes to the tissue healing process, chronic inflammation can lead to life-long debilitation and loss of tissue function and organ failure. Chronic inflammatory diseases include hepatic, gastrointestinal and neurodegenerative complications which can lead to malignancy. Despite the millennial advancements in diagnostic and therapeutic modalities, there remains no effective cure for patients who suffer from inflammatory diseases. Therefore, patients seek alternatives and complementary agents as adjunct therapies to relieve symptoms and possibly to prevent consequences of inflammation. It is well known that green tea polyphenols (GrTPs) are potent antioxidants with important roles in regulating vital signaling pathways. These comprise transcription nuclear factor-kappa B mediated I kappa B kinase complex pathways, programmed cell death pathways like caspases and B-cell lymphoma-2 and intervention with the surge of inflammatory markers like cytokines and production ofcyclooxygenase-2. This paper concisely reviews relevant investigations regarding protective effects of GrTPs and some reported adverse effects, as well as possible applications for GrTPs in the treatment of chronic and inflammatory complications. PMID- 28587183 TI - Socioeconomic Disparity in Later-Year Group Trajectories of Depressive Symptoms: Role of Health and Social Engagement Change. AB - This study explored heterogeneous change patterns of South Korean older adults' depressive symptoms by poverty status, focusing on health status and social engagement changes. We used data from four waves (2006-2012) of the Korean Longitudinal Study of Aging (KLoSA). Our sample contained 2461 poor and 1668 non poor individuals. All were 65 years old or older at baseline. We used latent class growth analysis to identify trajectory groups' depressive symptoms. Multinomial logistic regression was used to examine how a range of changes in health conditions and social engagement was associated with trajectories among poor and non-poor participants. Among the poor, five heterogeneous trajectories with clear patterns were identified: high-to-moderate, stable-high, slightly increasing, steeply-increasing, and stable-low. Among non-poor, high-to-moderate, steeply-increasing, and stable-low groups were found. A decrease in health conditions was the most vulnerable subgroup's (steeply-increasing) primary risk factor. Poor older adults who reduced participation in, or decreased contact with, social networks were likely to belong to the steeply-increasing group. Our study provides impetus for organizational and/or environmental support systems to facilitate social engagement among poor older adults. Future research should examine whether the significance of social engagement among poor elders applies in less-developed and developed countries. PMID- 28587185 TI - Air Flow Detection in Crude Oil by Infrared Light. AB - In this paper, we used infrared light in the range of 8-12 MUm to develop and test an optical imaging system to detect air bubbles flowing in oil. The system basically comprises a broadband light source and a 31 * 32 thermopile array to generate images. To analyze the effects related to light absorption, reflection, and refraction on air-oil boundaries, a numerical model was developed and the predominance of the refraction instead of the absorption in bubbles with diameters below a certain critical value was observed. The IR region of the electromagnetic spectrum has both optical and thermic behavior. To understand the limits of each effect on the oil flow imaging, a study of the influence of temperature variation on the petroleum optical detection was performed. The developed optical imaging system allowed the detection of air flow in static oil and in oil-air two-phase flow. With the presented system, it was possible to achieve images through up to 12 mm of oil volumes, but this may be enhanced by the use of optimized IR sources and detectors. PMID- 28587182 TI - Preoperative Nutritional Conditioning of Crohn's Patients-Systematic Review of Current Evidence and Practice. AB - Crohn's disease is an incurable and frequently progressive entity with major impact on affected patients. Up to half of patients require surgery in the first 10 years after diagnosis and over 75% of operated patients require at least one further surgery within lifetime. In order to minimize surgical risk, modifiable risk factors such as nutritional status need to be optimized. This systematic review on preoperative nutritional support in adult Crohn's patients between 1997 and 2017 aimed to provide an overview on target populations, screening modalities, routes of administration, and expected benefits. Pertinent study characteristics (prospective vs. retrospective, sample size, control group, limitations) were defined a priori. Twenty-nine studies were retained, of which 14 original studies (9 retrospective, 4 prospective, and 1 randomized controlled trial) and 15 reviews. Study heterogeneity was high regarding nutritional regimens and outcome, and meta-analysis could not be performed. Most studies were conducted without matched control group and thus provide modest level of evidence. Consistently, malnutrition was found to be a major risk factor for postoperative complications, and both enteral and parenteral routes were efficient in decreasing postoperative morbidity. Current guidelines for nutrition in general surgery apply also to Crohn's patients. The route of administration should be chosen according to disease presentation and patients' condition. Further studies are needed to strengthen the evidence. PMID- 28587184 TI - Real-Time Expression Analysis of Selected Anticarsia gemmatalis multiple nucleopolyhedrovirus Gene Promoters during Infection of Permissive, Semipermissive and Nonpermissive Cell Lines. AB - Baculovirus infection follows a transcriptionally controlled sequence of gene expression that occurs by activation of different viral gene promoter sequences during infection. This sequence of promoter activation may be disrupted by cellular defenses against viral infection, which might interfere with viral progeny formation. In this work, the activity of the ie1, gp64, lef-1, vp39, p6.9 and polh promoters of the Anticarsia gemmatalis multiple nucleopolyhedrovirus was assessed during infection of permissive, semipermissive and nonpermissive cell lines by a novel methodology that detects reporter protein luminescence in real time. This technique allowed us to characterize in rich detail the AgMNPV promoters in permissive cell lines and revealed differential profiles of expression in cells with limited permissivity that correlate well with limitations in viral DNA replication. Semipermissive and nonpermissive cell lines presented delays and restrictions in late and very late promoter expression. Cells undergoing apoptosis did not inhibit late gene expression; however, viral progeny formation is severely affected. This work demonstrates the application of the real-time luminescence detection methodology and how the promoter expression profile may be used to diagnose cellular permissivity to baculovirus infection. PMID- 28587186 TI - Measuring Neighborhood Walkable Environments: A Comparison of Three Approaches. AB - Multiple studies have revealed the impact of walkable environments on physical activity. Scholars attach considerable importance to leisure and health-related walking. Recent studies have used Google Street View as an instrument to assess city streets and walkable environments; however, no study has compared the validity of Google Street View assessments of walkable environment attributes to assessments made by local residents and compiled from field visits. In this study, we involved nearby residents and compared the extent to which Google Street View assessments of the walkable environment correlated with assessments from local residents and with field visits. We determined the assessment approaches (local resident or field visit assessments) that exhibited the highest agreement with Google Street View. One city with relatively high-quality walkable environments and one city with relatively low-quality walkable environments were examined, and three neighborhoods from each city were surveyed. Participants in each neighborhood used one of three approaches to assess the walkability of the environment: 15 local residents assessed the environment using a map, 15 participants made a field visit to assess the environment, and 15 participants used Google Street View to assess the environment, yielding a total of 90 valid samples for the two cities. Findings revealed that the three approaches to assessing neighborhood walkability were highly correlated for traffic safety, aesthetics, sidewalk quality, and physical barriers. Compared with assessments from participants making field visits, assessments by local residents were more highly correlated with Google Street View assessments. Google Street View provides a more convenient, low-cost, efficient, and safe approach to assess neighborhood walkability. The results of this study may facilitate future large scale walkable environment surveys, effectively reduce expenses, and improve survey efficiency. PMID- 28587187 TI - A Spawn Mobile Agent Itinerary Planning Approach for Energy-Efficient Data Gathering in Wireless Sensor Networks. AB - Mobile agent (MA), a part of the mobile computing paradigm, was recently proposed for data gathering in Wireless Sensor Networks (WSNs). The MA-based approach employs two algorithms: Single-agent Itinerary Planning (SIP) and Multi-mobile agent Itinerary Planning (MIP) for energy-efficient data gathering. The MIP was proposed to outperform the weakness of SIP by introducing distributed multi MAs to perform the data gathering task. Despite the advantages of MIP, finding the optimal number of distributed MAs and their itineraries are still regarded as critical issues. The existing MIP algorithms assume that the itinerary of the MA has to start and return back to the sink node. Moreover, each distributed MA has to carry the processing code (data aggregation code) to collect the sensory data and return back to the sink with the accumulated data. However, these assumptions have resulted in an increase in the number of MA's migration hops, which subsequently leads to an increase in energy and time consumption. In this paper, a spawn multi-mobile agent itinerary planning (SMIP) approach is proposed to mitigate the substantial increase in cost of energy and time used in the data gathering processes. The proposed approach is based on the agent spawning such that the main MA is able to spawn other MAs with different tasks assigned from the main MA. Extensive simulation experiments have been conducted to test the performance of the proposed approach against some selected MIP algorithms. The results show that the proposed SMIP outperforms the counterpart algorithms in terms of energy consumption and task delay (time), and improves the integrated energy-delay performance. PMID- 28587189 TI - Roles of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase in Angiogenesis: Isoform-Specific Effects. AB - Angiogenesis is the formation of new blood vessels from preexisting ones and is implicated in physiologic vascular development, pathologic blood vessel growth, and vascular restoration. This is in contrast to vasculogenesis, which is de novo growth of vessels from vascular precursors, or from vascular repair that occurs when circulating endothelial progenitor cells home into an area and develop into blood vessels. The objective of this review is to discuss the isoform-specific role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) in physiologic and pathologic angiogenesis and vascular repair, but will not specifically address vasculogenesis. As the major source of reactive oxygen species (ROS) in vascular endothelial cells (ECs), NOX has gained increasing attention in angiogenesis. Activation of NOX leads to events necessary for physiologic and pathologic angiogenesis, including EC migration, proliferation and tube formation. However, activation of different NOX isoforms has different effects in angiogenesis. Activation of NOX2 promotes pathologic angiogenesis and vascular inflammation, but may be beneficial in revascularization in the hindlimb ischemic model. In contrast, activation of NOX4 appears to promote physiologic angiogenesis mainly by protecting the vasculature during ischemia, hypoxia and inflammation and by restoring vascularization, except in models of oxygen-induced retinopathy and diabetes where NOX4 activation leads to pathologic angiogenesis. PMID- 28587188 TI - A Review of Activity Trackers for Senior Citizens: Research Perspectives, Commercial Landscape and the Role of the Insurance Industry. AB - The objective assessment of physical activity levels through wearable inertial based motion detectors for the automatic, continuous and long-term monitoring of people in free-living environments is a well-known research area in the literature. However, their application to older adults can present particular constraints. This paper reviews the adoption of wearable devices in senior citizens by describing various researches for monitoring physical activity indicators, such as energy expenditure, posture transitions, activity classification, fall detection and prediction, gait and balance analysis, also by adopting consumer-grade fitness trackers with the associated limitations regarding acceptability. This review also describes and compares existing commercial products encompassing activity trackers tailored for older adults, thus providing a comprehensive outlook of the status of commercially available motion tracking systems. Finally, the impact of wearable devices on life and health insurance companies, with a description of the potential benefits for the industry and the wearables market, was analyzed as an example of the potential emerging market drivers for such technology in the future. PMID- 28587192 TI - High Dynamic Range Spectral Imaging Pipeline For Multispectral Filter Array Cameras. AB - Spectral filter arrays imaging exhibits a strong similarity with color filter arrays. This permits us to embed this technology in practical vision systems with little adaptation of the existing solutions. In this communication, we define an imaging pipeline that permits high dynamic range (HDR)-spectral imaging, which is extended from color filter arrays. We propose an implementation of this pipeline on a prototype sensor and evaluate the quality of our implementation results on real data with objective metrics and visual examples. We demonstrate that we reduce noise, and, in particular we solve the problem of noise generated by the lack of energy balance. Data are provided to the community in an image database for further research. PMID- 28587190 TI - Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress? AB - Minimal residual disease evaluation refers to a series of molecular and immunophenotypical techniques aimed at detecting submicroscopic disease after therapy. As such, its application in acute myeloid leukemia has greatly increased our ability to quantify treatment response, and to determine the chemosensitivity of the disease, as the final product of the drug schedule, dose intensity, biodistribution, and the pharmakogenetic profile of the patient. There is now consistent evidence for the prognostic power of minimal residual disease evaluation in acute myeloid leukemia, which is complementary to the baseline prognostic assessment of the disease. The focus for its use is therefore shifting to individualize treatment based on a deeper evaluation of chemosensitivity and residual tumor burden. In this review, we will summarize the results of the major clinical studies evaluating minimal residual disease in acute myeloid leukemia in adults in recent years and address the technical and practical issues still hampering the spread of these techniques outside controlled clinical trials. We will also briefly speculate on future developments and offer our point of view, and a word of caution, on the present use of minimal residual disease measurements in "real-life" practice. Still, as final standardization and diffusion of the methods are sorted out, we believe that minimal residual disease will soon become the new standard for evaluating response in the treatment of acute myeloid leukemia. PMID- 28587191 TI - New Insights in the Cytogenetic Practice: Karyotypic Chaos, Non-Clonal Chromosomal Alterations and Chromosomal Instability in Human Cancer and Therapy Response. AB - Recently, non-clonal chromosomal alterations previously unappreciated are being proposed to be included in cytogenetic practice. The aim of this inclusion is to obtain a greater understanding of chromosomal instability (CIN) and tumor heterogeneity and their role in cancer evolution and therapy response. Although several genetic assays have allowed the evaluation of the variation in a population of cancer cells, these assays do not provide information at the level of individual cells, therefore limiting the information of the genomic diversity within tumors (heterogeneity). The karyotype is one of the few available cytogenetic techniques that allow us not only to identify the chromosomal alterations present within a single cell, but also allows us to profile both clonal (CCA) and non-clonal chromosomal alterations (NCCAs). A greater understanding of CIN and tumor heterogeneity in cancer could not only improve existing therapeutic regimens but could also be used as targets for the design of new therapeutic approaches. In this review we indicate the importance and significance of karyotypic chaos, NCCAs and CIN in the prognosis of human cancers. PMID- 28587193 TI - Stability of BDNF in Human Samples Stored Up to 6 Months and Correlations of Serum and EDTA-Plasma Concentrations. AB - Brain-derived neurotrophic factor (BDNF), an important neural growth factor, has gained growing interest in neuroscience, but many influencing physiological and analytical aspects still remain unclear. In this study we assessed the impact of storage time at room temperature, repeated freeze/thaw cycles, and storage at -80 degrees C up to 6 months on serum and ethylenediaminetetraacetic acid (EDTA) plasma BDNF. Furthermore, we assessed correlations of serum and plasma BDNF concentrations in two independent sets of samples. Coefficients of variations (CVs) for serum BDNF concentrations were significantly lower than CVs of plasma concentrations (n = 245, p = 0.006). Mean serum and plasma concentrations at all analyzed time points remained within the acceptable change limit of the inter assay precision as declared by the manufacturer. Serum and plasma BDNF concentrations correlated positively in both sets of samples and at all analyzed time points of the stability assessment (r = 0.455 to rs = 0.596; p < 0.004). In summary, when considering the acceptable change limit, BDNF was stable in serum and in EDTA-plasma up to 6 months. Due to a higher reliability, we suggest favoring serum over EDTA-plasma for future experiments assessing peripheral BDNF concentrations. PMID- 28587195 TI - The Use of Chemoprophylaxis after Floods to Reduce the Occurrence and Impact of Leptospirosis Outbreaks. AB - Record-breaking and devastating rainfall events have occurred in the past decade. Rain and floods are considered the main risk factors for leptospirosis and several outbreaks have been reported following extreme weather events. In such situations, one possible intervention to prevent leptospirosis cases in high-risk groups is the use of chemoprophylaxis. However, not enough evidence of its effect is available. The objectives of this study were to review the literature on the current practices of chemoprophylaxis for leptospirosis and to explore, using a mathematical model, how various chemoprophylaxis scenarios may affect the progression of a leptospirosis outbreak. Twenty-six peer-reviewed publications were selected (10 quantitative studies, two systematic reviews and 14 articles of other types). Oral doxycycline was the most used antibiotic for chemoprophylaxis of leptospirosis. Post-exposure prophylaxis was assessed in four studies following a natural disaster. Although evidence of the effectiveness of post exposure prophylaxis is inconsistent, the direction of association supported a protective effect for morbidity and mortality. The theoretical model showed how the assumed benefit of chemoprophylaxis was influenced by the time and rate of administration. Future models should consider the heterogeneity of affected communities, improved estimates of the effect of chemoprophylaxis on leptospirosis infection and disease, as well as potential detrimental impacts. Additional research is critical to provide clear evidence-based recommendations for leptospirosis control during an outbreak. The results of this study suggest that chemoprophylaxis may provide some protection in reducing the number of leptospirosis cases after a high-risk exposure; however, the effective benefit may depend on a variety of factors such as the timing and coverage of prophylaxis. The information summarized can be used to support decision-making during a high-risk event. PMID- 28587196 TI - Optimizing the Removal of Rhodamine B in Aqueous Solutions by Reduced Graphene Oxide-Supported Nanoscale Zerovalent Iron (nZVI/rGO) Using an Artificial Neural Network-Genetic Algorithm (ANN-GA). AB - Rhodamine B (Rh B) is a toxic dye that is harmful to the environment, humans, and animals, and thus the discharge of Rh B wastewater has become a critical concern. In the present study, reduced graphene oxide-supported nanoscale zero-valent iron (nZVI/rGO) was used to treat Rh B aqueous solutions. The nZVI/rGO composites were synthesized with the chemical deposition method and were characterized using scanning electron microscopy (SEM), X-ray diffraction (XRD), Raman spectroscopy, N2-sorption, and X-ray photoelectron spectroscopy (XPS) analysis. The effects of several important parameters (initial pH, initial concentration, temperature, and contact time) on the removal of Rh B by nZVI/rGO were optimized by response surface methodology (RSM) and artificial neural network hybridized with genetic algorithm (ANN-GA). The results suggest that the ANN-GA model was more accurate than the RSM model. The predicted optimum value of Rh B removal efficiency (90.0%) was determined using the ANN-GA model, which was compatible with the experimental value (86.4%). Moreover, the Langmuir, Freundlich, and Temkin isotherm equations were applied to fit the adsorption equilibrium data, and the Freundlich isotherm was the most suitable model for describing the process for sorption of Rh B onto the nZVI/rGO composites. The maximum adsorption capacity based on the Langmuir isotherm was 87.72 mg/g. The removal process of Rh B could be completed within 20 min, which was well described by the pseudo-second order kinetic model. PMID- 28587194 TI - Cross-Kingdom Regulation of Putative miRNAs Derived from Happy Tree in Cancer Pathway: A Systems Biology Approach. AB - MicroRNAs (miRNAs) are well-known key regulators of gene expression primarily at the post-transcriptional level. Plant-derived miRNAs may pass through the gastrointestinal tract, entering into the body fluid and regulate the expression of endogenous mRNAs. Camptotheca acuminata, a highly important medicinal plant known for its anti-cancer potential was selected to investigate cross-kingdom regulatory mechanism and involvement of miRNAs derived from this plant in cancer associated pathways through in silico systems biology approach. In this study, total 33 highly stable putative novel miRNAs were predicted from the publically available 53,294 ESTs of C. acuminata, out of which 14 miRNAs were found to be regulating 152 target genes in human. Functional enrichment, gene-disease associations and network analysis of these target genes were carried out and the results revealed their association with prominent types of cancers like breast cancer, leukemia and lung cancer. Pathways like focal adhesion, regulation of lipolysis in adipocytes and mTOR signaling pathways were found significantly associated with the target genes. The regulatory network analysis showed the association of some important hub proteins like GSK3B, NUMB, PEG3, ITGA2 and DLG2 with cancer-associated pathways. Based on the analysis results, it can be suggested that the ingestion of the C. acuminata miRNAs may have a functional impact on tumorigenesis in a cross-kingdom way and may affect the physiological condition at genetic level. Thus, the predicted miRNAs seem to hold potentially significant role in cancer pathway regulation and therefore, may be further validated using in vivo experiments for a better insight into their mechanism of epigenetic action of miRNA. PMID- 28587198 TI - Resonance-Based Sparse Signal Decomposition and its Application in Mechanical Fault Diagnosis: A Review. AB - Mechanical equipment is the heart of industry. For this reason, mechanical fault diagnosis has drawn considerable attention. In terms of the rich information hidden in fault vibration signals, the processing and analysis techniques of vibration signals have become a crucial research issue in the field of mechanical fault diagnosis. Based on the theory of sparse decomposition, Selesnick proposed a novel nonlinear signal processing method: resonance-based sparse signal decomposition (RSSD). Since being put forward, RSSD has become widely recognized, and many RSSD-based methods have been developed to guide mechanical fault diagnosis. This paper attempts to summarize and review the theoretical developments and application advances of RSSD in mechanical fault diagnosis, and to provide a more comprehensive reference for those interested in RSSD and mechanical fault diagnosis. Followed by a brief introduction of RSSD's theoretical foundation, based on different optimization directions, applications of RSSD in mechanical fault diagnosis are categorized into five aspects: original RSSD, parameter optimized RSSD, subband optimized RSSD, integrated optimized RSSD, and RSSD combined with other methods. On this basis, outstanding issues in current RSSD study are also pointed out, as well as corresponding instructional solutions. We hope this review will provide an insightful reference for researchers and readers who are interested in RSSD and mechanical fault diagnosis. PMID- 28587199 TI - Impact of Sweet Potato Starch-Based Nanocomposite Films Activated With Thyme Essential Oil on the Shelf-Life of Baby Spinach Leaves. AB - Salmonella Typhimurium (S. Typhi) and Escherichia coli (E. coli) have been responsible for an increasing number of outbreaks linked to fresh produce, such as baby spinach leaves, in the last two decades. More recently, antimicrobial biodegradable packaging systems have been attracting much attention in the food packaging industry as eco-friendly alternatives to conventional plastic packaging. The objective of this study was to evaluate the effect of antibacterial nanocomposite films on inoculated spinach leaves and on the sensory properties of these leaves during eight days of refrigerated storage. In this study, an antibacterial film comprised of sweet potato starch (SPS), montmorillonite (MMT) nanoclays and thyme essential oil (TEO) as a natural antimicrobial agent was developed. Our results showed that the incorporation of TEO in the film significantly (p < 0.05) reduced the population of E. coli and S. Typhi on fresh baby spinach leaves to below detectable levels within five days, whereas the control samples without essential oil maintained approximately 4.5 Log colony forming unit (CFU)/g. The sensory scores for spinach samples wrapped in films containing TEO were higher than those of the control. This study thus suggests that TEO has the potential to be directly incorporated into a SPS film to prepare antimicrobial nanocomposite films for food packaging applications. PMID- 28587197 TI - Resveratrol, 4' Acetoxy Resveratrol, R-equol, Racemic Equol or S-equol as Cosmeceuticals to Improve Dermal Health. AB - Phytochemicals are botanical compounds used in dermatology applications as cosmeceuticals to improve skin health. Resveratrol and equol are two of the best known polyphenolic or phytoestrogens having similar chemical structures and some overlapping biological functions to 17beta-estradiol. Human skin gene expression was reviewed for 28 different biomarkers when resveratrol, 4' acetoxy resveratrol (4AR), R-equol, racemic equol or S-equol were tested. Sirtuin 1 activator (SIRT 1) was stimulated by resveratrol and 4AR only. Resveratrol, R-equol and racemic equol were effective on the aging biomarkers proliferating cell nuclear factor (PCNA), nerve growth factor (NGF), 5alpha-reductase and the calcium binding proteins S100 A8 and A9. Racemic equol and 4AR displayed among the highest levels for the collagens, elastin and tissue inhibitor of the matrix metalloproteinase 1 (TIMP 1). S-equol displayed the lowest level of effectiveness compared to the other compounds. The 4AR analog was more effective compared to resveratrol by 1.6 fold. R-equol and racemic equol were almost equal in potency displaying greater inhibition vs. resveratrol or its 4' analog for the matrix metalloproteinases (MMPs), but among the inflammatory biomarkers, resveratrol, 4AR, R-equol and racemic equol displayed high inhibition. Thus, these cosmeceuticals display promise to improve dermal health; however, further study is warranted to understand how phytochemicals protect/enhance the skin. PMID- 28587200 TI - Antioxidant and Antihypertensive Effects of a Chemically Defined Fraction of Syrah Red Wine on Spontaneously Hypertensive Rats. AB - A particularly phenolic-rich fraction extracted from red wine from the Sao Francisco valley (Northeastern Brazil) was chemically characterized and its hypotensive and antioxidant effects on spontaneously hypertensive rats were studied both in vitro and in vivo. The liquid-liquid pH dependent fractionation scheme afforded a fraction with high content of bioactive phenolics such as flavonols, flavonol glycosides, phenolic acids and anthocyanins, whose identities were confirmed by liquid chromatography coupled to mass spectrometry analysis. Pretreatment of spontaneously hypertensive rats with this wine fraction at doses of 50 and 100 mg/kg by gavage. for 15 days was able to decrease mean arterial pressure and heart rate as well as decrease serum lipid peroxidation. The fraction at concentrations of 0.01-1000 ug/mL induced concentration-dependent relaxation of isolated rat superior mesenteric artery rings pre-contracted with phenylephrine and this effect was not attenuated by endothelium removal. Our results demonstrate it is possible for phenolic constituents of red wine that are orally bioavailable to exert in vivo hypotensive and antioxidant effects on intact endothelial function. PMID- 28587201 TI - Laurus nobilis: Composition of Essential Oil and Its Biological Activities. AB - Laurus nobilis is native to the southern Mediterranean region and cultivated mainly in Europe and the USA as an ornamental and medicinal plant. The chemical composition of the essential oil (EO) from leaves of L. nobilis, collected in Southern Italy, was studied by GC and GC-MS. In all, 55 compounds were identified, accounting for 91.6% of the total oil. 1,8-Cineole (31.9%), sabinene (12.2%), and linalool (10.2%) were the main components. Antimicrobial and antifungal activities of EO and 1,8-cineole were determined in vitro. The cytotoxicity of the EO was evaluated against SH-SY5Y cell line, as well as the influence of the EO on the expression of adenylate cyclase 1 (ADCY1), suggesting possible oil effects on the Central Nervous System. PMID- 28587202 TI - Running the Stop Sign: Readthrough of a Premature UAG Termination Signal in the Translation of a Zebrafish (Danio rerio) Taurine Biosynthetic Enzyme. AB - The UAG termination codon is generally recognized as the least efficient and least frequently used of the three universal stop codons. This is substantiated by numerous studies in an array of organisms. We present here evidence of a translational readthrough of a mutant nonsense UAG codon in the transcript from the cysteine sulfinic acid decarboxylase (csad) gene (ENSDARG00000026348) in zebrafish. The csad gene encodes the terminal enzyme in the taurine biosynthetic pathway. Taurine is a critical amino acid for all animals, playing several essential roles throughout the body, including modulation of the immune system. The sa9430 zebrafish strain (ZDB-ALT-130411-5055) has a point mutation leading to a premature stop codon (UAG) 20 amino acids 5' of the normal stop codon, UGA. Data from immunoblotting, enzyme activity assays, and mass spectrometry provide evidence that the mutant is making a CSAD protein identical to that of the wild type (XP_009295318.1) in terms of size, activity, and amino acid sequence. UAG readthrough has been described in several species, but this is the first presentation of a case in fish. Also presented are the first data substantiating the ability of a fish CSAD to utilize cysteic acid, an alternative to the standard substrate cysteine sulfinic acid, to produce taurine. PMID- 28587204 TI - Comparative Analysis of gamma-Oryzanol, beta-Glucan, Total Phenolic Content and Antioxidant Activity in Fermented Rice Bran of Different Varieties. AB - Rice bran, a by-product derived from processing rice, is a rich source of bioactive compounds. Recent studies have suggested that the fermentation can improve their biological activities. This study aimed to determined the level of gamma-oryzanol, beta-glucan and total phenol contents of fermented rice bran from 21 Korean varieties, as well as to evaluate their antioxidant activities. We also assessed the validation of the analytical method for determining gamma-oryzanol content in fermented rice brans. Among the fermented rice brans, the Haedam rice bran contained the highest level of total phenol content (156.08 mg gallic acid equivalents/g), DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging activity (71.30%) and ORAC (Oxygen radical absorbance capacity) value (1101.31 MUM trolox equivalents/g). Furthermore, the fermented Migwang rice bran showed the highest level of gamma-oryzanol content (294.77 +/- 6.74 mg/100 g). PMID- 28587203 TI - Effect of n-3 Polyunsaturated Fatty Acid Supplementation on Metabolic and Inflammatory Biomarkers in Type 2 Diabetes Mellitus Patients. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is accompanied by chronic low-grade inflammation, with an imbalance in the secretion of adipokines and, worsening insulin resistance. Supplementation with n-3 PUFA in T2DM decreases inflammatory markers, the purpose of the study was to investigate the effect of n-3 PUFA supplementation on adipokines, metabolic control, and lipid profile in T2DM Mexican adults. METHODS: In a randomized, single-blind, placebo-controlled pilot study, 54 patients with T2DM received 520 mg of DHA + EPA-enriched fish-oil (FOG) or a placebo (PG) daily. Baseline and 24-week anthropometric and biochemical measurements included glucose, insulin, glycosylated hemoglobin (Hb1Ac), leptin, adiponectin, resistin, and lipid profile; n-3 PUFA intake was calculated in g/day. RESULTS: Waist circumference and blood glucose showed significant reductions in the FOG group (p = 0.001 and p = 0.011, respectively). Hb1Ac (p = 0.009 and p = 0.004), leptin (p < 0.000 and p < 0.000), and leptin/adiponectin ratio (p < 0.000 and p < 0.000) decreased significantly in both groups after 24 weeks (FOG and PG respectively). Serum resistin (FOG p < 0.000 and PG p = 0.001), insulin (FOG p < 0.000 and PG p < 0.000), and HOMA-IR (FOG p = 0.000 and PG p < 0.000) increased significantly in both groups. FOG had an overall improvement in the lipid profile with a significant decrease in triacylgycerols (p = 0.002) and atherogenic index (p = 0.031); in contrast, the PG group had increased total cholesterol (p < 0.000), non-HDL cholesterol (p < 0.000), and atherogenic index (p = 0.017). CONCLUSIONS: We found a beneficial effect of n-3 PUFA supplementation on waist circumference, glucose, Hb1Ac, leptin, leptin/adiponectin ratio, and lipid profile, without significant changes in adiponectin, and increases in resistin, insulin, and HOMA-IR in both groups. PMID- 28587205 TI - Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms. AB - The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform's higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization. PMID- 28587206 TI - Glyphosate Residues in Groundwater, Drinking Water and Urine of Subsistence Farmers from Intensive Agriculture Localities: A Survey in Hopelchen, Campeche, Mexico. AB - The use of pesticides in Mexican agriculture creates an interest in learning about the presence of these substances in different environmental matrices. Glyphosate (GLY) is an herbicide widely used in the state of Campeche, located in the Mayan zone in the western Yucatan peninsula. Despite the fact that GLY is considered a non-toxic pesticide to humans, its presence in water bodies through spillage, runoff, and leaching are a risk to human health or biota that inhabit these ecosystems. In the present study, glyphosate residues were determined in groundwater, bottled drinking water, and the urine of subsistence farmers from various localities of the Hopelchen municipality in Campeche. Determination of GLY was carried out using Enzyme-Linked Immunosorbent Assay (ELISA). The highest concentrations of GLY were observed in the groundwater (1.42 MUg/L) of Ich-Ek and urine (0.47 MUg/L) samples of subsistence farmers from the Francisco J. Mujica communities. The glyphosate concentrations in groundwater and bottled drinking water indicate an exposure and excessive use of glyphosate in these agricultural communities. This is one of the first studies that reports glyphosate concentration levels in human urine and bottled drinking water in Mexico and in the groundwater in the Yucatan Peninsula as part of a prospective pilot study, to which a follow-up will be performed to monitor this trend over time. PMID- 28587207 TI - (-)-Epigallocatechin-3-Gallate Inhibits Colorectal Cancer Stem Cells by Suppressing Wnt/beta-Catenin Pathway. AB - The beneficial effects of tea consumption on cancer prevention have been generally reported, while (-)-Epigallocatechin-3-gallate (EGCG) is the major active component from green tea. Cancer stem cells (CSCs) play a crucial role in the process of cancer development. Targeting CSCs may be an effective way for cancer intervention. However, the effects of EGCG on colorectal CSCs and the underlying mechanisms remain unclear. Spheroid formation assay was used to enrich colorectal CSCs from colorectal cancer cell lines. Immunoblotting analysis and quantitative real-time polymerase chain reaction were used to measure the alterations of critical molecules expression. Immunofluorescence staining analysis was also used to determine the expression of CD133. We revealed that EGCG inhibited the spheroid formation capability of colorectal cancer cells as well as the expression of colorectal CSC markers, along with suppression of cell proliferation and induction of apoptosis. Moreover, we illustrated that EGCG downregulated the activation of Wnt/beta-catenin pathway, while upregulation of Wnt/beta-catenin diminished the inhibitory effects of EGCG on colorectal CSCs. Taken together, this study suggested that EGCG could be an effective natural compound targeting colorectal CSCs through suppression of Wnt/beta-catenin pathway, and thus may be a promising agent for colorectal cancer intervention. PMID- 28587208 TI - Xyloketal B Attenuates Fatty Acid-Induced Lipid Accumulation via the SREBP-1c Pathway in NAFLD Models. AB - The goal of this study was to examine the effects of xyloketal B on nonalcoholic fatty liver disease (NAFLD) and to explore the molecular mechanisms underlying its effects in both in vivo and in vitro models. We discovered an association between xyloketal B and the sterol regulatory element-binding protein-1c (SREBP 1c) signaling pathway, which is related to lipid metabolism. Mice were dosed with xyloketal B (5, 10 and 20 mg/kg/d) and atorvastatin (15 mg/kg/d) via intraperitoneal injection once daily for 40 days after being fed a high fat diet plus 10% high fructose liquid (HFD+HFL) for 8 weeks. Xyloketal B significantly improved HFD+HFL-induced hepatic histological lesions and attenuated lipid and glucose accumulation in the blood as well as lipid accumulation in the liver. Xyloketal B increased the expression of CPT1A, and decreased the expression of SREBP-1c and its downstream targeting enzymes such as ACC1, ACL, and FAS. Xyloketal B also significantly reduced lipid accumulation in HepG2 cells treated with free fatty acids (FFAs). These data suggested that xyloketal B has lipid lowering effects via the SREBP-1c pathway that regulate lipid metabolism. Thus, targeting SREBP-1c activation with xyloketal B may be a promising novel approach for NAFLD treatment. PMID- 28587209 TI - Variability in the Content of Trans-Resveratrol, Trans-epsilon-Viniferin and R2 Viniferin in Grape Cane of Seven Vitis vinifera L. Varieties during a Three-Year Study. AB - Grape canes are a waste product from viticulture that show potential as an industrially extractable source of stilbenes, which are valuable for medical and other purposes. In this work, grape canes collected in three consecutive years (2014-2016) at six different places in South Moravia, Czech Republic were extracted, and the contents of trans-resveratrol, trans-epsilon-viniferin, and r2 viniferin were determined by high-performance liquid chromatography. The study included three blue grape varieties of Vitis vinifera L. (Cabernet Moravia, Blaufrankisch, and Piwi variety Laurot) and four white grape varieties (Chardonnay, Green Veltliner, Piwi variety Hibernal, and Piwi variety Malverina). From the viewpoint of producing extracts with high stilbenes content, the Hibernal variety is clearly the best. The mean amounts of the stilbenes for this variety at all localities and for all three years were 4.99 g/kg for trans resveratrol, 3.24 g/kg for trans-epsilon-viniferin, and 1.73 g/kg for r2 viniferin. The influence of vintage, locality, and variety on the amounts of stilbenes was studied using PCA analysis. In contrast to expectations, there was no strong impact of locality on stilbenes content. The differences were varietal for most varieties, regardless of the area of cultivation. Laurot and Hibernal varieties did differ significantly in that respect, however, as they exhibited clear dependence on location. PMID- 28587211 TI - Changes in Microbial (Bacteria and Archaea) Plankton Community Structure after Artificial Dispersal in Grazer-Free Microcosms. AB - Microbes are considered to have a global distribution due to their high dispersal capabilities. However, our knowledge of the way geographically distant microbial communities assemble after dispersal in a new environment is limited. In this study, we examined whether communities would converge because similar taxa would be selected under the same environmental conditions, or would diverge because of initial community composition, after artificial dispersal. To this aim, a microcosm experiment was performed, in which the temporal changes in the composition and diversity of different prokaryoplankton assemblages from three distant geographic coastal areas (Banyuls-sur-Mer in northwest Mediterranean Sea, Pagasitikos Gulf in northeast Mediterranean and Woods Hole, MA, USA in the northwest Atlantic), were studied. Diversity was investigated using amplicon pyrosequencing of the V1-V3 hypervariable regions of the 16S rRNA. The three assemblages were grown separately in particle free and autoclaved Banyuls-sur-mer seawater at 18 degrees C in the dark. We found that the variability of prokaryoplankton community diversity (expressed as richness, evenness and dominance) as well as the composition were driven by patterns observed in Bacteria. Regarding community composition, similarities were found between treatments at family level. However, at the OTU level microbial communities from the three different original locations diverge rather than converge during incubation. It is suggested that slight differences in the composition of the initial prokaryoplankton communities, resulted in separate clusters the following days even when growth took place under identical abiotic conditions. PMID- 28587213 TI - Functionalizing Graphene Oxide with Alkylamine by Gamma-ray Irradiation Method. AB - A gamma-ray irradiation technique was used to functionalize graphene oxide (GO) with alkylamines of various alkyl chain lengths. Functionalization of the alkyl chains onto the GO was confirmed by nuclear magnetic resonance (1H NMR), Fourier transform infrared (FTIR), and X-ray diffraction (XRD). FTIR of the functionalized GO showed the appearance of significant peaks around 2960-2850 cm 1 (-CH2) which came from long alkyl chains, together with a peak around 1560-1450 cm-1, indicating the formation of C-NH-C. XRD showed an additional diffraction peak at a lower 2theta angle, indicating that the intercalation of the alkylamine was successful. The effects on the morphological and thermal properties of GO functionalized with alkyl chains of various lengths were investigated. Scanning electron microscopy (SEM) analysis showed an increase in surface roughness when the alkyl chain length was increased. The addition of alkyl chains on GO surfaces significantly improved the thermal stability of the GO, suggesting that these surfaces have great potential for use as a hydrophobic material in industry. PMID- 28587210 TI - Curcumin Inhibits LIN-28A through the Activation of miRNA-98 in the Lung Cancer Cell Line A549. AB - Metastasis is common in lung cancer and is associated with poor clinical outcomes and increased mortality. Curcumin is a natural anti-cancer agent that inhibits the metastasis of various cancers by modulating the expression of micro (mi) RNAs such as miR-98, which acts as a tumor suppressor. This study investigated the effect of curcumin on miR-98 expression and in vitro cell line growth and invasiveness in lung cancer. Curcumin treatment enhanced the expression of miR-98 and reduced that of the miR-98 target gene LIN28A as well as matrix metalloproteinase (MMP) 2 and MMP9 in vitro and in vivo. MiR-98 overexpression suppressed lung cancer cell migration and invasion by inhibiting LIN28A-induced MMP2 and MMP9 expression. Meanwhile, LIN28A level was downregulated by overexpression of miR-98 mimic. Induction of miR-98 by curcumin treatment suppressed MMP2 and MMP9 by targeting LIN28A. These findings provide insight into the mechanisms by which curcumin suppresses lung cancer cell line growth in vitro and in vivo and invasiveness in vitro. PMID- 28587212 TI - Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use. AB - Extracellular vesicles (EVs) derived from stem and progenitor cells may have therapeutic effects comparable to their parental cells and are considered promising agents for the treatment of a variety of diseases. To this end, strategies must be designed to successfully translate EV research and to develop safe and efficacious therapies, whilst taking into account the applicable regulations. Here, we discuss the requirements for manufacturing, safety, and efficacy testing of EVs along their path from the laboratory to the patient. Development of EV-therapeutics is influenced by the source cell types and the target diseases. In this article, we express our view based on our experience in manufacturing biological therapeutics for routine use or clinical testing, and focus on strategies for advancing mesenchymal stromal cell (MSC)-derived EV-based therapies. We also discuss the rationale for testing MSC-EVs in selected diseases with an unmet clinical need such as critical size bone defects, epidermolysis bullosa and spinal cord injury. While the scientific community, pharmaceutical companies and clinicians are at the point of entering into clinical trials for testing the therapeutic potential of various EV-based products, the identification of the mode of action underlying the suggested potency in each therapeutic approach remains a major challenge to the translational path. PMID- 28587214 TI - Optimization of Ultrasonic-assisted Extraction of Fatty Acids in Seeds of Brucea Javanica (L.) Merr. from Different Sources and Simultaneous Analysis Using High Performance Liquid Chromatography with Charged Aerosol Detection. AB - Our research aimed to optimize the oil extraction process and determine the fatty acids in Brucea javanica (L.) Merr. seeds. The extraction technology was optimized using response surface methodology. A Box-Behnken design was employed to investigate the effects of three independent variables on an ultrasonic assisted extraction technique, namely, sonication time (X1: 20-40 min), liquid solid ratio (X2: 16:1 mL/g-24:1 mL/g), and ethanol concentration (X3: 90%-100%). The optimum conditions of sonication time, liquid-solid ratio, and ethanol concentration were 40 min, 24:1 mL/g, and 100%, respectively. The content of fatty acids and the oil yield were 14.64 mg/g and 16.87%, respectively, which match well with the predicted models. The optimum number of extraction times was eventually identified as two. A new rapid method for the qualitative and quantitative analysis of the fatty acids of B. javanica (L.) Merr. seed oil using HPLC with a charged aerosol detector was described. The fatty acid contents of 14 batches of B. javanica (L.) Merr. seed oil were determined, and the relevance and difference were analyzed by fingerprint analysis. The fingerprint has five common peaks, and the similarity was greater than 0.991. HPLC analysis represents a specialized and rational approach for the quality identification and comprehensive evaluation of B. javanica (L.) Merr. seed oils. PMID- 28587215 TI - The Use of Flexible Ultrasound Transducers for the Detection of Laser-Induced Guided Waves on Curved Surfaces at Elevated Temperatures. AB - In this study, a flexible ultrasonic transducer (FUT) was applied in a laser ultrasonic technique (LUT) for non-destructive characterization of metallic pipes at high temperatures of up to 176 degrees C. Compared with normal ultrasound transducers, a FUT is a piezoelectric film made of a PZT/PZT sol-gel composite which has advantages due to its high sensitivity, curved surface adaptability and high temperature durability. By operating a pulsed laser in B-scan mode along with the integration of FUT and LUT, a multi-mode dispersion spectrum of a stainless steel pipe at high temperature can be measured. In addition, dynamic wave propagation behaviors are experimentally visualized with two dimensional scanning. The images directly interpret the reflections from the interior defects and also can locate their positions. This hybrid technique shows great potential for non-destructive evaluation of structures with complex geometry, especially in high temperature environments. PMID- 28587217 TI - Multi-Shaped Ag Nanoparticles in the Plasmonic Layer of Dye-Sensitized Solar Cells for Increased Power Conversion Efficiency. AB - The use of dye-sensitized solar cells (DSSCs) is widespread owing to their high power conversion efficiency (PCE) and low cost of manufacturing. We prepared multi-shaped Ag nanoparticles (NPs) and introduced them into DSSCs to further enhance their PCE. The maximum absorption wavelength of the multi-shaped Ag NPs is 420 nm, including the shoulder with a full width at half maximum (FWHM) of 121 nm. This is a broad absorption wavelength compared to spherical Ag NPs, which have a maximum absorption wavelength of 400 nm without the shoulder of 61 nm FWHM. Therefore, when multi-shaped Ag NPs with a broader plasmon-enhanced absorption were coated on a mesoporous TiO2 layer on a layer-by-layer structure in DSSCs, the PCE increased from 8.44% to 10.22%, equivalent to an improvement of 21.09% compared to DSSCs without a plasmonic layer. To confirm the plasmon enhanced effect on the composite film structure in DSSCs, the PCE of DSSCs based on the composite film structure with multi-shaped Ag NPs increased from 8.58% to 10.34%, equivalent to an improvement of 20.51% compared to DSSCs without a plasmonic layer. This concept can be applied to perovskite solar cells, hybrid solar cells, and other solar cells devices. PMID- 28587216 TI - Selenium Enrichment of Horticultural Crops. AB - The ability of some crops to accumulate selenium (Se) is crucial for human nutrition and health. Selenium has been identified as a cofactor of the enzyme glutathione peroxidase, which is a catalyzer in the reduction of peroxides that can damage cells and tissues, and can act as an antioxidant. Plants are the first link in the food chain, which ends with humans. Increasing the Se quantity in plant products, including leafy and fruity vegetables, and fruit crops, without exceeding the toxic threshold, is thus a good way to increase animal and human Se intake, with positive effects on long-term health. In many Se-enriched plants, most Se is in its major organic form. Given that this form is more available to humans and more efficient in increasing the selenium content than inorganic forms, the consumption of Se-enriched plants appears to be beneficial. An antioxidant effect of Se has been detected in Se-enriched vegetables and fruit crops due to an improved antioxidative status and to a reduced biosynthesis of ethylene, which is the hormone with a primary role in plant senescence and fruit ripening. This thus highlights the possible positive effect of Se in preserving a longer shelf-life and longer-lasting quality. PMID- 28587218 TI - Determination and Pharmacokinetic Study of Three Diterpenes in Rat Plasma by UHPLC-ESI-MS/MS after Oral Administration of Rosmarinus officinalis L. Extract. AB - Rosmarinus officinalis L. is commonly used as a spice and flavoring agent. Diterpenes are the main active compounds of R. officinalis. An Ultra High Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-ESI-MS/MS) method was developed for the determination of carnosol, rosmanol, and carnosic acid isolated from R. officinalis in rat plasma, and applied to a pharmacokinetic study after oral administration of R. officinalis extract. Sample preparation involved a liquid-liquid extraction of the analytes with ethyl acetate. Butylparaben was employed as an internal standard (I.S.). Chromatographic separation was carried out on a C18 column (ACQUITY UPLC(r) HSS T3, 1.8 MUm, 2.1 mm * 100 mm) with a gradient system consisting of the mobile phase solution A (0.1% formic acid in water) and solution B (acetonitrile) at the flow rate of 0.3 mL/min. The quantification was obtained using multiple reaction monitoring (MRM) mode with electrospray ionization (ESI). The UHPLC-MS/MS assay was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. This study described a simple, sensitive and validated UHPLC-MS/MS method for the simultaneous determination of three diterpene compounds in rat plasma after oral administration of R. officinalis extract, and investigated on their pharmacokinetic studies as well. PMID- 28587219 TI - In Vitro Study of the Metabolic Characteristics of Eight Isoquinoline Alkaloids from Natural Plants in Rat Gut Microbiota. AB - Gut microbiota is populated with an immense number of microorganisms, which can be regulated by dietary components and drugs to markedly affect the nutritional and health status of the host. Eight medicinal isoquinoline alkaloids from natural plants were cultured anaerobically with rat gut microbiota and an LC/MSn IT-TOF technique was used to identify the resulting metabolites. Palmatine, tetrahydropalmatine, dauricine, and tetrandrine containing nitro-hexatomic isoquinoline rings could be easily transformed by the intestinal flora in vitro and a total of nine demethylated metabolites were detected. However, sinomenine, homoharringtonine, harringtonine, and galanthamine, which all contained benzazepine, could not undergo demethylation. Computer-assisted docking was used to analyze the binding between these compounds and sterol 14alpha-demethylase. The computational results demonstrated that hydrophobic interactions were the main driving force for binding, but the steric hindrance produced by the benzazepine structure resulted in a weak interaction between the hit compounds and the enzyme. This work illustrated that gut microbiota were important in the metabolism of isoquinoline alkaloids. PMID- 28587220 TI - A Novel Real-Time Path Servo Control of a Hardware-in-the-Loop for a Large-Stroke Asymmetric Rod-Less Pneumatic System under Variable Loads. AB - This project aims to develop a novel large stroke asymmetric pneumatic servo system of a hardware-in-the-loop for path tracking control under variable loads based on the MATLAB Simulink real-time system. High pressure compressed air provided by the air compressor is utilized for the pneumatic proportional servo valve to drive the large stroke asymmetric rod-less pneumatic actuator. Due to the pressure differences between two chambers, the pneumatic actuator will operate. The highly nonlinear mathematical models of the large stroke asymmetric pneumatic system were analyzed and developed. The functional approximation technique based on the sliding mode controller (FASC) is developed as a controller to solve the uncertain time-varying nonlinear system. The MATLAB Simulink real-time system was a main control unit of a hardware-in-the-loop system proposed to establish driver blocks for analog and digital I/O, a linear encoder, a CPU and a large stroke asymmetric pneumatic rod-less system. By the position sensor, the position signals of the cylinder will be measured immediately. The measured signals will be viewed as the feedback signals of the pneumatic servo system for the study of real-time positioning control and path tracking control. Finally, real-time control of a large stroke asymmetric pneumatic servo system with measuring system, a large stroke asymmetric pneumatic servo system, data acquisition system and the control strategy software will be implemented. Thus, upgrading the high position precision and the trajectory tracking performance of the large stroke asymmetric pneumatic servo system will be realized to promote the high position precision and path tracking capability. Experimental results show that fifth order paths in various strokes and the sine wave path are successfully implemented in the test rig. Also, results of variable loads under the different angle were implemented experimentally. PMID- 28587223 TI - Density and Habitat Relationships of the Endemic White Mountain Fritillary (Boloria chariclea montinus) (Lepidoptera: Nymphalidae). AB - We conducted point counts in the alpine zone of the Presidential Range of the White Mountains, New Hampshire, USA, to estimate the distribution and density of the rare endemic White Mountain Fritillary (Boloria chariclea montinus). Incidence of occurrence and density of the endemic White Mountain Fritillary during surveys in 2012 and 2013 were greatest in the herbaceous-snowbank plant community. Densities at points in the heath-shrub-rush plant community were lower, but because this plant community is more widespread in the alpine zone, it likely supports the bulk of adult fritillaries. White Mountain Fritillary used cushion-tussock, the other alpine plant community suspected of providing habitat, only sparingly. Detectability of White Mountain Fritillaries varied as a consequence of weather conditions during the survey and among observers, suggesting that raw counts yield biased estimates of density and abundance. Point counts, commonly used to study and monitor populations of birds, were an effective means of sampling White Mountain Fritillary in the alpine environment where patches of habitat are small, irregularly shaped, and widely spaced, rendering line-transect methods inefficient and difficult to implement. PMID- 28587221 TI - Optimal Design of an Hourglass in-Fiber Air Fabry-Perot Microcavity-Towards Spectral Characteristics and Strain Sensing Technology. AB - An hourglass in-fiber air microcavity Fabry-Perot interferometer is proposed in this paper, and its second reflecting surface of in-fiber microcavity is designed to be a concave reflector with the best curvature radius in order to improve the spectral characteristics. Experimental results proved that the extinction ratio of Fabry-Perot interferometer with cavity length of 60 MUm and concave reflector radius of 60 MUm is higher than for a rectangular Fabry-Perot interferometer with cavity length of 60 MUm (14 dB: 11 dB). Theory and numerical simulation results show that the strain sensitivity of sensor can be improved by reducing the microcavity wall thickness and microcavity diameter, and when the in-fiber microcavity length is 40 MUm, the microcavity wall thickness is 10 MUm, the microcavity diameter is 20 MUm, and the curvature radius of reflective surface II is 50 MUm, the interference fringe contrast of is greater than 0.97, an Axial pull sensitivity of 20.46 nm/N and resolution of 1 mN can be achieved in the range of 0-1 N axial tension. The results show that the performance of hourglass in-fiber microcavity interferometer is far superior to that of the traditional Fabry-Perot interferometer. PMID- 28587224 TI - Design and Performance of a Metal-Shielded Piezoelectric Sensor. AB - In certain circumstances when acoustic measurements are required in the presence of explosive atmospheres the sensor must be placed inside a Faraday Cage. Piezoelectric active materials are suitable for this purpose as they do not need an electrical power supply, although the metal shielding can considerably reduce sensor sensitivity, which is already low at the acoustic frequency range (<20 kHz). This paper describes a metal-shielded piezoelectric sensor designed to work in the range of frequencies between 1 and 2 kHz and in these environmental conditions. The main idea was to add a thin material layer to the front face of the piezoelectric ceramic in order to force the system to vibrate in flexure mode at low frequencies. The resonant frequency and sensitivity of the system was studied as a function of the radius, thickness, and material of the thin layer. The study includes a comparison of theoretical model, FEM simulation, and real data measured using three aluminum and three steel prototypes of different sizes. PMID- 28587222 TI - Anti-Inflammatory Phenolic Acid Esters from the Roots and Rhizomes of Notopterygium incisium and Their Permeability in the Human Caco-2 Monolayer Cell Model. AB - A new ferulic acid ester named 4-methyl-3-trans-hexenylferulate (1), together with eight known phenolic acid esters (2-9), was isolated from the methanolic extract of the roots and rhizomes of Notopterygium incisium. Their structures were elucidated by extensive spectroscopic techniques, including 2D NMR spectroscopy and mass spectrometry. 4-Methoxyphenethyl ferulate (8) NMR data is reported here for the first time. The uptake and transepithelial transport of the isolated compounds 1-9 were investigated in the human intestinal Caco-2 cell monolayer model. Compounds 2 and 6 were assigned for the well-absorbed compounds, compound 8 was assigned for the moderately absorbed compound, and compounds 1, 3, 4, 5, 7, and 9 were assigned for the poorly absorbed compounds. Moreover, all of the isolated compounds were assayed for the inhibitory effects against nitric oxide (NO) production in the lipopolysaccharide-activated RAW264.7 macrophages model and L-N6-(1-iminoethyl)-lysine (L-NIL) was used as a positive control. Compounds 1, 5, 8, and 9 exhibited potent inhibitory activity on NO production with the half maximal inhibitory concentration (IC50) values of 1.01, 4.63, 2.47, and 2.73 MUM, respectively, which were more effective than L-NIL with IC50 values of 9.37 MUM. These findings not only enriched the types of anti-inflammatory compounds in N. incisum but also provided some useful information for predicting their oral bioavailability and their suitability as drug leads or promising anti inflammatory agents. PMID- 28587226 TI - Identifying Factors Associated with Risk Assessment Competencies of Public Health Emergency Responders. AB - This study aimed to better understand the current situation of risk assessment and identify the factors associated with competence of emergency responders in public health risk assessment. The participants were selected by a multi-stage, stratified cluster sampling method in Heilongjiang Centers for Disease Control and Prevention (CDC). The questionnaires that measured their perceptions on risk assessment competences were administered through the face-to-face survey. A final sample of 1889 staff was obtained. Of this sample, 78.6% of respondents rated their own risk assessment competences as "relatively low", contrasting with 21.4% rated as "relatively high". Most of the respondents (62.7%) did not participate in any risk assessment work. Only 13.7% and 42.7% of respondents reported participating in risk assessment training and were familiar with risk assessment tools. There existed statistical significance between risk assessment-related characteristics of respondents and their self-rated competences scores. Financial support from the government and administrative attention were regarded as the important factors contributing to risk assessment competences of CDC responders. Higher attention should be given to risk assessment training and enhancing the availability of surveillance data. Continuous efforts should be made to remove the financial and technical obstacles to improve the competences of risk assessment for public health emergency responders. PMID- 28587225 TI - Associations among Screen Time and Unhealthy Behaviors, Academic Performance, and Well-Being in Chinese Adolescents. AB - Screen time is negatively associated with markers of health in western youth, but very little is known about these relationships in Chinese youth. Middle-school and high-school students (n = 2625) in Wuhan, China, completed questionnaires assessing demographics, health behaviors, and self-perceptions in spring/summer 2016. Linear and logistic regression analyses were conducted to determine whether, after adjustment for covariates, screen time was associated with body mass index (BMI), eating behaviors, average nightly hours of sleep, physical activity (PA), academic performance, and psychological states. Watching television on school days was negatively associated with academic performance, PA, anxiety, and life satisfaction. Television viewing on non-school days was positively associated with sleep duration. Playing electronic games was positively associated with snacking at night and less frequently eating breakfast, and negatively associated with sleep duration and self-esteem. Receiving electronic news and study materials on non-school days was negatively associated with PA, but on school days, was positively associated with anxiety. Using social networking sites was negatively associated with academic performance, but positively associated with BMI z-score, PA and anxiety. Screen time in adolescents is associated with unhealthy behaviors and undesirable psychological states that can contribute to poor quality of life. PMID- 28587227 TI - Photoreceptor PhyB Involved in Arabidopsis Temperature Perception and Heat Tolerance Formation. AB - The influence of temperature on plants is essential. However, our knowledge on the intricate regulation process underlying heat stress (HS) response in plants is limited. Recently, information about thermal sensors in vivo has begun to emerge. In this study, another primary environmental stimulus, light, was verified once again to work with temperature synergistically on plants, through the modulation of numerous biological processes. With the application of transcriptomic analysis, a substantial number of heat-responsive genes were detected involved in both light- and phytohormone-mediated pathways in Arabidopsis. During this process, phytoreceptor phyB acts as a molecular switch to turn on or turn off several other genes HS response, under different light conditions. Furthermore, a morphological study showed the afunction of phyB enhanced plants thermal tolerance, confirming the important role of this phytochrome in temperature perception and response in plants. This study adds data to the picture of light and temperature signaling cross-talk in plants, which is important for the exploration of complicated HS responses or light mediated mechanisms. Furthermore, based on its influence on Arabidopsis thermal response in both morphological and physiological levels, phyB is a photoreceptor, as revealed before, as well as an essential thermal sensor in plants. PMID- 28587228 TI - Fine Mapping and Transcriptome Analysis Reveal Candidate Genes Associated with Hybrid Lethality in Cabbage (Brassica Oleracea). AB - Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage (Brassica oleracea) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2, respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1, seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380) were found, whereas in the region of BoHL2, two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage. PMID- 28587232 TI - Fabrication of Defect-Free Cellulose Acetate Hollow Fibers by Optimization of Spinning Parameters. AB - Spinning of cellulose acetate (CA) with the additive polyvinylpyrrolidone (PVP) in N-methyl-2-pyrrolidone (NMP) solvent under different conditions was investigated. The spinning parameters of air gap, bore fluid composition, flow rate of bore fluid, and quench bath temperature were optimized based on the orthogonal experiment design (OED) method and multivariate analysis. FTIR and scanning electron microscopy were used to characterize the membrane structure and morphology. Based on the conjoint analysis in Statistical Product and Service Solutions (SPSS) software, the importance of these parameters was identified as: air gap > bore fluid composition > flow rate of bore fluid > quench bath temperature. The optimal spinning condition with the bore fluid (water + NMP (85%)), air gap (25 mm), flow rate of bore fluid (40% of dope rate), and temperature of quench bath (50 degrees C) was identified to make high PVP content, symmetric cross-section and highly cross-linked CA hollow fibers. The results can be used to guide the spinning of defect-free CA hollow fiber membranes with desired structures and properties as carbon membrane precursors. PMID- 28587229 TI - Ataxin-2: From RNA Control to Human Health and Disease. AB - RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases. PMID- 28587231 TI - A Novel Lid-Covering Peptide Inhibitor of Nicotinic Acetylcholine Receptors Derived from alphaD-Conotoxin GeXXA. AB - Nicotinic acetylcholine receptors (nAChRs) play a fundamental role in nervous signal transmission, therefore various antagonists and agonists are highly desired to explore the structure and function of nAChRs. Recently, a novel dimeric alphaD-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of alphaD GeXXA retains some inhibitory activity. In this study, the internal dimeric N terminal domain (NTD) of this conopeptide was further investigated. We first developed a regio-selective protection strategy to chemically prepare the anti parallel dimeric NTD, and found that the isolated NTD part of GeXXA possesses the nAChR-inhibitory activity, the subtype-dependence of which implies a preferred binding of NTD to the beta subunits of nAChR. Deletion of the NTD N-terminal residues did not affect the activity of NTD, indicating that the N-terminus is not involved in the interaction with nAChRs. By optimizing the sequence of NTD, we obtained a fully active single-chain cyclic NTD, based on which 4 Arg residues were found to interact with nAChRs. These results demonstrate that the NTD part of alphaD-GeXXA is a "lid-covering" nAChR inhibitor, displaying a novel inhibitory mechanism distinct from other allosteric ligands of nAChRs. PMID- 28587230 TI - Aronia melanocarpa (Black Chokeberry) Reduces Ethanol-Induced Gastric Damage via Regulation of HSP-70, NF-kappaB, and MCP-1 Signaling. AB - Aronia melanocarpa (Michx.) Ell. belongs to the Rosaceae family. The purpose of this study is to explore the gastroprotective effect of the Aronia melanocarpa hydro-alcoholic extract (AMHAE) against ethanol-induced gastric ulcer in a rat model. Different concentrations (50, 100, and 200 mg/kg) of AMHAE, or 30 mg/kg of omeprazole, significantly inhibited the gastric injury formation. The ethanol induced ulcer group showed significant increases of malondialdehyde (MDA), myeloperoxidase (MPO), tumor necrosis factor (TNF)-alpha, nuclear factor-kappaB p65 (NF-kappaB p65), and monocyte chemoattractant protein (MCP)-1, and decreased activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-px), and interleukin (IL)-4. However, AMHAE (200 mg/kg) pretreatment significantly reversed the altered pathophysiological levels of these biomolecules to near normal stages. The gastroprotective activity of AMHAE was abolished by pretreatment with l-NAME, naloxone, capsazepine, and indomethacin, demonstrating the participation of nitric oxide (NO), opioids, TRPV (vanilloid receptor-related transient receptor potential), and prostaglandins in AMHAE assisted gastroprotection against ethanol-induced gastric injuries. This gastroprotective effect of AMHAE might be due to the downregulation of TNF-alpha based NF-kappaB, MCP-1 signaling and strong antioxidant properties. PMID- 28587233 TI - Sex Differences in the Association of Urinary Concentrations of Phthalates Metabolites with Self-Reported Diabetes and Cardiovascular Diseases in Shanghai Adults. AB - Phthalate exposure was reported to be associated with diabetes mellitus (DM) and cardiovascular disease (CVD). Yet, reported associations and the potential sex differences are inconsistent. We conducted a cross-sectional study involving 2330 participants in the Fall of 2012. Urinary metabolites of 10 phthalates were measured. The status of having DM and CVD-related outcomes were self-reported. In the overall study population, the logistic regression analyses showed that the urinary levels of mono-2-ethyl-5-oxohexyphthalate (MEOHP), mono-2-ethyl-5 hydroxyhexylphthalate(MEHHP) and mono-2-ethyl-5-carboxypentylphthalate (MECPP) were positively associated with DM. Higher urinary levels of monomethyl phthalate (MMP) and mono-2-carboxymethyl-hexyl phthalate (MCMHP) were associated with increased odds of hyperlipidemia, while mono-2-ethylhexylphthalate (MEHP) was significantly inverse-associated with hyperlipidemia. We did not observe significant associations for other CVD-related outcomes with phthalate metabolites. When stratifying by sex, MEHHP, MEOHP, MECPP, MCMHP and the micromolar sums of the oxidative metabolites of DEHP (SigmaDEHPox) were all significantly related to DM in males, but not in females. No significant sex differences were found in CVD-related outcomes, except the sporadic associations between phthalates and hyperlipidemia. These findings highlight the importance of investigating the sex-specific relationship between phthalates exposure and DM. PMID- 28587236 TI - Parents' Qualitative Perspectives on Child Asking for Fruit and Vegetables. AB - Children can influence the foods available at home, but some ways of approaching a parent may be better than others; and the best way may vary by type of parent. This study explored how parents with different parenting styles would best receive their 10 to 14 years old child asking for fruits and vegetables (FV). An online parenting style questionnaire was completed and follow-up qualitative telephone interviews assessed home food rules, child influence on home food availability, parents' preferences for being asked for food, and common barriers and reactions to their child's FV requests. Parents (n = 73) with a 10 to 14 years old child were grouped into authoritative, authoritarian, permissive, or uninvolved parenting style categories based on responses to questionnaires, and interviewed. Almost no differences in responses were detected by parenting style or ethnicity. Parents reported their children had a voice in what foods were purchased and available at home and were receptive to their child's asking for FV. The most important child asking characteristic was politeness, especially among authoritarian parents. Other important factors were asking in person, helping in the grocery store, writing requests on the grocery shopping list, and showing information they saw in the media. The barrier raising the most concern was FV cost, but FV quality and safety outside the home environment were also considerations. PMID- 28587237 TI - Risk Perceptions on Hurricanes: Evidence from the U.S. Stock Market. AB - This article examines the market reaction of the main Property and Casualty (P & C) insurance companies listed in the New York Stock Exchange (NYSE) to seven most recent hurricanes that hit the East Coast of the United States from 2005 to 2012. For this purpose, we run a standard short horizon event study in order to test the existence of abnormal returns around the landfalls. P & C companies are one of the most affected sectors by such events because of the huge losses to rebuild, help and compensate the inhabitants of the affected areas. From the financial investors' perception, this kind of events implies severe losses, which could influence the expected returns. Our research highlights the existence of significant cumulative abnormal returns around the landfall event window in most of the hurricanes analyzed, except for the Katrina and Sandy Hurricanes. PMID- 28587238 TI - Machine Learning-Based Calibration of Low-Cost Air Temperature Sensors Using Environmental Data. AB - The measurement of air temperature is strongly influenced by environmental factors such as solar radiation, humidity, wind speed and rainfall. This is problematic in low-cost air temperature sensors, which lack a radiation shield or a forced aspiration system, exposing them to direct sunlight and condensation. In this study, we developed a machine learning-based calibration method for air temperature measurement by a low-cost sensor. An artificial neural network (ANN) was used to balance the effect of multiple environmental factors on the measurements. Data were collected over 305 days, at three different locations in Japan, and used to evaluate the performance of the approach. Data collected at the same location and at different locations were used for training and testing, and the former was also used for k-fold cross-validation, demonstrating an average improvement in mean absolute error (MAE) from 1.62 to 0.67 by applying our method. Some calibration failures were noted, due to abrupt changes in environmental conditions such as solar radiation or rainfall. The MAE was shown to decrease even when the data collected in different nearby locations were used for training and testing. However, the results also showed that negative effects arose when data obtained from widely-separated locations were used, because of the significant environmental differences between them. PMID- 28587235 TI - Flexible Proteins at the Origin of Life. AB - Almost all modern proteins possess well-defined, relatively rigid scaffolds that provide structural preorganization for desired functions. Such scaffolds require the sufficient length of a polypeptide chain and extensive evolutionary optimization. How ancestral proteins attained functionality, even though they were most likely markedly smaller than their contemporary descendants, remains a major, unresolved question in the origin of life. On the basis of evidence from experiments and computer simulations, we argue that at least some of the earliest water-soluble and membrane proteins were markedly more flexible than their modern counterparts. As an example, we consider a small, evolved in vitro ligase, based on a novel architecture that may be the archetype of primordial enzymes. The protein does not contain a hydrophobic core or conventional elements of the secondary structure characteristic of modern water-soluble proteins, but instead is built of a flexible, catalytic loop supported by a small hydrophilic core containing zinc atoms. It appears that disorder in the polypeptide chain imparts robustness to mutations in the protein core. Simple ion channels, likely the earliest membrane protein assemblies, could also be quite flexible, but still retain their functionality, again in contrast to their modern descendants. This is demonstrated in the example of antiamoebin, which can serve as a useful model of small peptides forming ancestral ion channels. Common features of the earliest, functional protein architectures discussed here include not only their flexibility, but also a low level of evolutionary optimization and heterogeneity in amino acid composition and, possibly, the type of peptide bonds in the protein backbone. PMID- 28587234 TI - Peptidylarginine Deiminases-Roles in Cancer and Neurodegeneration and Possible Avenues for Therapeutic Intervention via Modulation of Exosome and Microvesicle (EMV) Release? AB - Exosomes and microvesicles (EMVs) are lipid bilayer-enclosed structures released from cells and participate in cell-to-cell communication via transport of biological molecules. EMVs play important roles in various pathologies, including cancer and neurodegeneration. The regulation of EMV biogenesis is thus of great importance and novel ways for manipulating their release from cells have recently been highlighted. One of the pathways involved in EMV shedding is driven by peptidylarginine deiminase (PAD) mediated post-translational protein deimination, which is calcium-dependent and affects cytoskeletal rearrangement amongst other things. Increased PAD expression is observed in various cancers and neurodegeneration and may contribute to increased EMV shedding and disease progression. Here, we review the roles of PADs and EMVs in cancer and neurodegeneration. PMID- 28587240 TI - Adaptive Temporal Matched Filtering for Noise Suppression in Fiber Optic Distributed Acoustic Sensing. AB - Distributed vibration sensing based on phase-sensitive optical time domain reflectometry ( phi -OTDR) is being widely used in several applications. However, one of the main challenges in coherent detection-based phi -OTDR systems is the fading noise, which impacts the detection performance. In addition, typical signal averaging and differentiating techniques are not suitable for detecting high frequency events. This paper presents a new approach for reducing the effect of fading noise in fiber optic distributed acoustic vibration sensing systems without any impact on the frequency response of the detection system. The method is based on temporal adaptive processing of phi -OTDR signals. The fundamental theory underlying the algorithm, which is based on signal-to-noise ratio (SNR) maximization, is presented, and the efficacy of our algorithm is demonstrated with laboratory experiments and field tests. With the proposed digital processing technique, the results show that more than 10 dB of SNR values can be achieved without any reduction in the system bandwidth and without using additional optical amplifier stages in the hardware. We believe that our proposed adaptive processing approach can be effectively used to develop fiber optic-based distributed acoustic vibration sensing systems. PMID- 28587239 TI - Magnetic Lateral Flow Strip for the Detection of Cocaine in Urine by Naked Eyes and Smart Phone Camera. AB - Magnetic lateral flow strip (MLFS) based on magnetic bead (MB) and smart phone camera has been developed for quantitative detection of cocaine (CC) in urine samples. CC and CC-bovine serum albumin (CC-BSA) could competitively react with MB-antibody (MB-Ab) of CC on the surface of test line of MLFS. The color of MB-Ab conjugate on the test line relates to the concentration of target in the competition immunoassay format, which can be used as a visual signal. Furthermore, the color density of the MB-Ab conjugate can be transferred into digital signal (gray value) by a smart phone, which can be used as a quantitative signal. The linear detection range for CC is 5-500 ng/mL and the relative standard deviations are under 10%. The visual limit of detection was 5 ng/mL and the whole analysis time was within 10 min. The MLFS has been successfully employed for the detection of CC in urine samples without sample pre-treatment and the result is also agreed to that of enzyme-linked immunosorbent assay (ELISA). With the popularization of smart phone cameras, the MLFS has large potential in the detection of drug residues in virtue of its stability, speediness, and low-cost. PMID- 28587241 TI - Termite Species Distribution and Flight Periods on Oahu, Hawaii. AB - Termites are economically-important structural pests, costing residents of Hawaii over $100 million annually. On Oahu, the last published termite swarming survey occurred from 1969 to 1971, and the last termite hand-collection survey occurred from 1998 to 2000. To contribute data on termite occurrences on Oahu, a light trap survey took place from February 2011 to September 2012, and a hand collection survey occurred from September to November 2012. Formosan subterranean termite, Coptotermes formosanus Shiraki, swarming was compared over the duration of the study, finding peak swarming in May 2011. C. formosanus alate activity density was regressed with environmental factors, finding a negative correlation with average wind speed and a positive correlation with average rainfall. Coptotermes gestroi (Wasmann) alates were observed in April, June, and July 2011 and in June 2012. Four species of termites were found in the hand-collection survey of 44 sites: Incisitermes immigrans (Snyder) (n = 8/44), C. formosanus (n = 2/44), Cryptotermes cynocephalus Light (n = 1/44), and Neotermes sp. (n = 1/44). This study contributes to distribution data for termite species on Oahu and records alate activity for two important termite pests. PMID- 28587242 TI - Cell Microarray Technologies for High-Throughput Cell-Based Biosensors. AB - Due to the recent demand for high-throughput cellular assays, a lot of efforts have been made on miniaturization of cell-based biosensors by preparing cell microarrays. Various microfabrication technologies have been used to generate cell microarrays, where cells of different phenotypes are immobilized either on a flat substrate (positional array) or on particles (solution or suspension array) to achieve multiplexed and high-throughput cell-based biosensing. After introducing the fabrication methods for preparation of the positional and suspension cell microarrays, this review discusses the applications of the cell microarray including toxicology, drug discovery and detection of toxic agents. PMID- 28587244 TI - Quality of Life of Post-Mastectomy Women Living in a Semi-Arid Region of Brazil. AB - Health is the major reference regarding quality of life; when it comes to breast cancer in particular, the loss of a breast traumatically affects a woman's life, reflecting on her quality of life. Recognizing this problem, our aim was to investigate the quality of life of women who live in a semi-arid region of Brazil after breast cancer mastectomy. In this exploratory, transversal and observational study, a Brazilian variantof the shorter version of the original instrument from the World Health Organization Quality of Life (WHOQOL-BREF), applied in the study population, was analyzed and their socio-demographic profile was obtained. The sample was composed of 50 mastectomized women. The 50 included patients comprised women at a mean age of 54 years. Most of them had finished elementary school, and their average income was one Brazilian minimum monthly wage. Regarding the data related to quality of life, the highest score was found in the social relationships domain (4.29) followed by the psychological (4.09) and environmental (3.88) domains. The lowest score observed was for the physical domain (3.48). With these findings we can say that social and psychological parameters are driving factors of the quality of life in post-mastectomy women. Therefore, these results are useful to establish strategies to improve the quality of life of breast cancer mastectomy patients. PMID- 28587246 TI - Proof of Concept of Home IoT Connected Vehicles. AB - The way in which we interact with our cars is changing, driven by the increased use of mobile devices, cloud-based services, and advanced automotive technology. In particular, the requirements and market demand for the Internet of Things (IoT) device-connected vehicles will continuously increase. In addition, the advances in cloud computing and IoT have provided a promising opportunity for developing vehicular software and services in the automotive domain. In this paper, we introduce the concept of a home IoT connected vehicle with a voice based virtual personal assistant comprised of a vehicle agent and a home agent. The proposed concept is evaluated by implementing a smartphone linked with home IoT devices that are connected to an infotainment system for the vehicle, a smartphone-based natural language interface input device, and cloud-based home IoT devices for the home. The home-to-vehicle connected service scenarios that aim to reduce the inconvenience due to simple and repetitive tasks by improving the urban mobility efficiency in IoT environments are substantiated by analyzing real vehicle testing and lifestyle research. Remarkable benefits are derived by making repetitive routine tasks one task that is executed by a command and by executing essential tasks automatically, without any request. However, it should be used with authorized permission, applied without any error at the right time, and applied under limited conditions to sense the habitants' intention correctly and to gain the required trust regarding the remote execution of tasks. PMID- 28587243 TI - Genomic Variations in Pancreatic Cancer and Potential Opportunities for Development of New Approaches for Diagnosis and Treatment. AB - Human pancreatic cancer has a very poor prognosis with an overall five-year survival rate of less than 5% and an average median survival time of six months. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Although our understanding of the molecular events underlying multi-step carcinogenesis in pancreatic cancer has steadily increased, translation into more effective therapeutic approaches has been inefficient in recent decades. Therefore, it is imperative that novel and targeted approaches are designed to facilitate the early detection and treatment of pancreatic cancer. Presently, there are numerous ongoing studies investigating the types of genomic variations in pancreatic cancer and their impact on tumor initiation and growth, as well as prognosis. This has led to the development of therapeutics to target these genetic variations for clinical benefit. Thus far, there have been minimal clinical successes directly targeting these genomic alterations; however research is ongoing to ultimately discover an innovative approach to tackle this devastating disease. This review will discuss the genomic variations in pancreatic cancer, and the resulting potential diagnostic and therapeutic implications. PMID- 28587247 TI - Membranes of Polymers of Intrinsic Microporosity (PIM-1) Modified by Poly(ethylene glycol). AB - Until now, the leading polymer of intrinsic microporosity PIM-1 has become quite famous for its high membrane permeability for many gases in gas separation, linked, however, to a rather moderate selectivity. The combination with the hydrophilic and low permeable poly(ethylene glycol) (PEG) and poly(ethylene oxides) (PEO) should on the one hand reduce permeability, while on the other hand enhance selectivity, especially for the polar gas CO2 by improving the hydrophilicity of the membranes. Four different paths to combine PIM-1 with PEG or poly(ethylene oxide) and poly(propylene oxide) (PPO) were studied: physically blending, quenching of polycondensation, synthesis of multiblock copolymers and synthesis of copolymers with PEO/PPO side chain. Blends and new, chemically linked polymers were successfully formed into free standing dense membranes and measured in single gas permeation of N2, O2, CO2 and CH4 by time lag method. As expected, permeability was lowered by any substantial addition of PEG/PEO/PPO regardless the manufacturing process and proportionally to the added amount. About 6 to 7 wt % of PEG/PEO/PPO added to PIM-1 halved permeability compared to PIM-1 membrane prepared under similar conditions. Consequently, selectivity from single gas measurements increased up to values of about 30 for CO2/N2 gas pair, a maximum of 18 for CO2/CH4 and 3.5 for O2/N2. PMID- 28587245 TI - Has Inositol Played Any Role in the Origin of Life? AB - Phosphorus, as phosphate, plays a paramount role in biology. Since phosphate transfer reactions are an integral part of contemporary life, phosphate may have been incorporated into the initial molecules at the very beginning. To facilitate the studies into early phosphate utilization, we should look retrospectively to phosphate-rich molecules present in today's cells. Overlooked by origin of life studies until now, inositol and the inositol phosphates, of which some species possess more phosphate groups that carbon atoms, represent ideal molecules to consider in this context. The current sophisticated association of inositol with phosphate, and the roles that some inositol phosphates play in regulating cellular phosphate homeostasis, intriguingly suggest that inositol might have played some role in the prebiotic process of phosphate exploitation. Inositol can be synthesized abiotically and, unlike glucose or ribose, is chemically stable. This stability makes inositol the ideal candidate for the earliest organophosphate molecules, as primitive inositol phosphates. I also present arguments suggesting roles for some inositol phosphates in early chemical evolution events. Finally, the possible prebiotic synthesis of inositol pyrophosphates could have generated high-energy molecules to be utilized in primitive trans-phosphorylating processes. PMID- 28587248 TI - Understanding the Challenges of Improving Sanitation and Hygiene Outcomes in a Community Based Intervention: A Cross-Sectional Study in Rural Tanzania. AB - Good sanitation and clean water are basic human rights yet they remain elusive to many rural communities in Sub-Saharan Africa (SSA). We carried out a cross sectional study to examine the impact of a four-year intervention aimed at improving access to water and sanitation and reducing waterborne disease, especially diarrhea in children under five years old. The study was carried out in April and May 2015 in Busangi, Chela and Ntobo wards of Kahama District of Tanzania. The interventions included education campaigns and improved water supply, and sanitation. The percentage of households (HHs) with access to water within 30 min increased from 19.2 to 48.9 and 17.6 to 27.3 in the wet and dry seasons, respectively. The percentage of HHs with hand washing facilities at the latrine increased from 0% to 13.2%. However, the incidence of diarrhea among children under five years increased over the intervention period, RR 2.91 95% CI 2.71-3.11, p < 0.0001. Availability of water alone may not influence the incidence of waterborne diseases. Factors such as water storage and usage, safe excreta disposal and other hygiene practices are critical for interventions negating the spread of water borne diseases. A model that articulates the extent to which these factors are helpful for such interventions should be explored. PMID- 28587250 TI - Removal of Carmine from Aqueous Solution by Carbonated Hydroxyapatite Nanorods. AB - In this study, carbonated hydroxyapatite (CHA) nanorods were prepared by a novel hydrothermal method. The crystallinity and chemical structure of synthesized CHA nanorods was characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS), respectively. Carmine was selected as representative organic dyes to study the adsorption capacities of CHA nanorods. Mechanistic studies of carmine adsorption by CHA nanorods show that the adsorption processes both follow the pseudo-second order kinetic model and fit the Langmuir isotherm model well. The CHA nanorods exhibited a high adsorption capacity of 85.51 mg/g for carmine at room temperature. The experimental results prove that CHA nanorods can be promising absorbents for removing organic dye pollutants in wastewater from paper and textile plants. PMID- 28587249 TI - Investigation of the Maillard Reaction between Polysaccharides and Proteins from Longan Pulp and the Improvement in Activities. AB - The purpose of this study was to investigate the Maillard reaction between polysaccharides and proteins from longan pulp and the effects of reaction on their in vitro activities. The polysaccharide-protein mixtures of fresh longan pulp (LPPMs) were co-prepared by an alkali extraction-acid precipitation method. They were then dry-heated under controlled conditions for monitoring the characterization of the Maillard reaction by the measurement of the free amino group content, ultraviolet-visible spectrum, Fourier transform infrared spectrum and molecular weight distribution. All the physicochemical analyses indicated the development of the Maillard reaction between polysaccharides and proteins. The in vitro activity evaluation indicated that the Maillard reaction could effectively enhance the antioxidant, antitumor and immunostimulating activities of LPPMs. The enhancement of 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity and ferric reducing antioxidant power displayed both a positive correlation with the reaction time (p < 0.05). LPPMs dry-heated for three days obtained relatively strong inhibitory activity against HepG2 cells and SGC7901 cells, as well as strong immunostimulating effects on the nitric oxide production and tumor necrosis factor alpha secretion of macrophages. Maillard-type intermacromolecular interaction is suggested to be an effective and controllable method for improving the functional activities of polysaccharides and proteins from longan pulp. PMID- 28587251 TI - Pharmacokinetics and Tissue Distribution Kinetics of Puerarin in Rats Using Indirect Competitive ELISA. AB - Puerarin (PUE) is a compound isolated from the roots of Pueraria lobata. We studied the pharmacokinetics and tissue distribution kinetics of PUE in Sprague Dawley rats following intraperitoneal administration of three concentrations. Indirect competitive ELISA based on an anti-PUE monoclonal antibody was used to determine the concentration of PUE in the blood, heart, liver, spleen, lung, kidney, hippocampus, cerebral cortex, and striatum. The plasma and tissue distribution kinetic characteristics following a single injection of PUE (20, 40 and 80 mg/kg) were calculated using a non-compartment model. In the high-dose (80 mg/kg) and medium-dose (40 mg/kg) groups, the kinetic profile of PUE in blood and kidney samples showed two absorption peaks, while that of the other tissues showed only one peak. In the low-dose (20 mg/kg) group, there was only one peak, irrespective of the sample type. Pharmacokinetic parameters, such as the area under the curve, Cmax, and Tmax varied according to the administered dose. AUC and Cmax values increased dose-dependently. PUE was widely distributed in areas of the brain such as the hippocampus, cerebral cortex, and striatum, providing a foundation for guiding the use of PUE in the treatment of cerebral ischaemic stroke and neurodegenerative diseases. PMID- 28587252 TI - Multi-Axis Force Sensor for Human-Robot Interaction Sensing in a Rehabilitation Robotic Device. AB - Human-robot interaction sensing is a compulsory feature in modern robotic systems where direct contact or close collaboration is desired. Rehabilitation and assistive robotics are fields where interaction forces are required for both safety and increased control performance of the device with a more comfortable experience for the user. In order to provide an efficient interaction feedback between the user and rehabilitation device, high performance sensing units are demanded. This work introduces a novel design of a multi-axis force sensor dedicated for measuring pelvis interaction forces in a rehabilitation exoskeleton device. The sensor is conceived such that it has different sensitivity characteristics for the three axes of interest having also movable parts in order to allow free rotations and limit crosstalk errors. Integrated sensor electronics make it easy to acquire and process data for a real-time distributed system architecture. Two of the developed sensors are integrated and tested in a complex gait rehabilitation device for safe and compliant control. PMID- 28587253 TI - Identification of Proteases and Protease Inhibitors in Allergenic and Non Allergenic Pollen. AB - Pollen is one of the most common causes of allergy worldwide, making the study of their molecular composition crucial for the advancement of allergy research. Despite substantial efforts in this field, it is not yet clear why some plant pollens strongly provoke allergies while others do not. However, proteases and protease inhibitors from allergen sources are known to play an important role in the development of pollen allergies. In this study, we aim to uncover differences in the transcriptional pattern of proteases and protease inhibitors in Betula verrucosa and Pinus sylvestris pollen as models for high and low allergenic potential, respectively. We applied RNA sequencing to Betula verrucosa and Pinus sylvestris pollen. After de-novo assembly we derived general functional profiles of the protein coding transcripts. By utilization of domain based functional annotation we identified potential proteases and protease inhibitors and compared their expression in the two types of pollen. Functional profiles are highly similar between Betula verrucosa and Pinus sylvestris pollen. Both pollen contain proteases and inhibitors from 53 and 7 Pfam families, respectively. Some of the members comprised within those families are implicated in facilitating allergen entry, while others are known allergens themselves. Our work revealed several candidate proteins which, with further investigation, represent exciting new leads in elucidating the process behind allergic sensitization. PMID- 28587255 TI - A Forward GPS Multipath Simulator Based on the Vegetation Radiative Transfer Equation Model. AB - Global Navigation Satellite Systems (GNSS) have been widely used in navigation, positioning and timing. Nowadays, the multipath errors may be re-utilized for the remote sensing of geophysical parameters (soil moisture, vegetation and snow depth), i.e., GPS-Multipath Reflectometry (GPS-MR). However, bistatic scattering properties and the relation between GPS observables and geophysical parameters are not clear, e.g., vegetation. In this paper, a new element on bistatic scattering properties of vegetation is incorporated into the traditional GPS-MR model. This new element is the first-order radiative transfer equation model. The new forward GPS multipath simulator is able to explicitly link the vegetation parameters with GPS multipath observables (signal-to-noise-ratio (SNR), code pseudorange and carrier phase observables). The trunk layer and its corresponding scattering mechanisms are ignored since GPS-MR is not suitable for high forest monitoring due to the coherence of direct and reflected signals. Based on this new model, the developed simulator can present how the GPS signals (L1 and L2 carrier frequencies, C/A, P(Y) and L2C modulations) are transmitted (scattered and absorbed) through vegetation medium and received by GPS receivers. Simulation results show that the wheat will decrease the amplitudes of GPS multipath observables (SNR, phase and code), if we increase the vegetation moisture contents or the scatters sizes (stem or leaf). Although the Specular-Ground component dominates the total specular scattering, vegetation covered ground soil moisture has almost no effects on the final multipath signatures. Our simulated results are consistent with previous results for environmental parameter detections by GPS-MR. PMID- 28587254 TI - Molecular, Genetic and Agronomic Approaches to Utilizing Pulses as Cover Crops and Green Manure into Cropping Systems. AB - Cover crops constitute one of the most promising agronomic practices towards a more sustainable agriculture. Their beneficial effects on main crops, soil and environment are many and various, while risks and disadvantages may also appear. Several legumes show a high potential but further research is required in order to suggest the optimal legume cover crops for each case in terms of their productivity and ability to suppress weeds. The additional cost associated with cover crops should also be addressed and in this context the use of grain legumes such as cowpea, faba bean and pea could be of high interest. Some of the aspects of these grain legumes as far as their use as cover crops, their genetic diversity and their breeding using conventional and molecular approaches are discussed in the present review. The specific species seem to have a high potential for use as cover crops, especially if their noticeable genetic diversity is exploited and their breeding focuses on several desirable traits. PMID- 28587256 TI - Biochemical and Computational Insights on a Novel Acid-Resistant and Thermal Stable Glucose 1-Dehydrogenase. AB - Due to the dual cofactor specificity, glucose 1-dehydrogenase (GDH) has been considered as a promising alternative for coenzyme regeneration in biocatalysis. To mine for potential GDHs for practical applications, several genes encoding for GDH had been heterogeneously expressed in Escherichia coli BL21 (DE3) for primary screening. Of all the candidates, GDH from Bacillus sp. ZJ (BzGDH) was one of the most robust enzymes. BzGDH was then purified to homogeneity by immobilized metal affinity chromatography and characterized biochemically. It displayed maximum activity at 45 degrees C and pH 9.0, and was stable at temperatures below 50 degrees C. BzGDH also exhibited a broad pH stability, especially in the acidic region, which could maintain around 80% of its initial activity at the pH range of 4.0-8.5 after incubating for 1 hour. Molecular dynamics simulation was conducted for better understanding the stability feature of BzGDH against the structural context. The in-silico simulation shows that BzGDH is stable and can maintain its overall structure against heat during the simulation at 323 K, which is consistent with the biochemical studies. In brief, the robust stability of BzGDH made it an attractive participant for cofactor regeneration on practical applications, especially for the catalysis implemented in acidic pH and high temperature. PMID- 28587257 TI - Graphene-Supported Spinel CuFe2O4 Composites: Novel Adsorbents for Arsenic Removal in Aqueous Media. AB - A graphene nanoplate-supported spinel CuFe2O4 composite (GNPs/CuFe2O4) was successfully synthesized by using a facile thermal decomposition route. Scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), Electron Dispersive Spectroscopy (EDS), X-ray diffraction (XRD) and X ray Photoelectron Spectroscopy (XPS) were employed to characterize the prepared composite. The arsenic adsorption behavior of the GNPs/CuFe2O4 composite was investigated by carrying out batch experiments. Both the Langmuir and Freundlich models were employed to describe the adsorption isotherm, where the sorption kinetics of arsenic adsorption by the composite were found to be pseudo-second order. The selectivity of the adsorbent toward arsenic over common metal ions in water was also demonstrated. Furthermore, the reusability and regeneration of the adsorbent were investigated by an assembled column filter test. The GNPs/CuFe2O4 composite exhibited significant, fast adsorption of arsenic over a wide range of solution pHs with exceptional durability, selectivity, and recyclability, which could make this composite a very promising candidate for effective removal of arsenic from aqueous solution. The highly sensitive adsorption of the material toward arsenic could be potentially employed for arsenic sensing. PMID- 28587258 TI - Combination of Near Infrared Light-Activated Photodynamic Therapy Mediated by Indocyanine Green with Etoposide to Treat Non-Small-Cell Lung Cancer. AB - Indocyanine green (ICG) has been reported as a potential near-infrared (NIR) photosensitizer for photodynamic therapy (PDT) of cancer. However the application of ICG-mediated PDT is both intrinsically and physiologically limited. Here we report a combination of ICG-PDT with a chemotherapy drug etoposide (VP-16), aiming to enhance the anticancer efficacy, to circumvent limitations of PDT using ICG, and to reduce side effects of VP-16. We found in controlled in vitro cell based assays that this combination is effective in killing non-small-cell lung cancer cells (NSCLC, A549 cell line). We also found that the combination of ICG PDT and VP-16 exhibits strong synergy in killing non-small-cell lung cancer cells partially through inducing more DNA double-strand breaks (DSBs), while it has a much weaker synergy in killing human normal cells (GM05757). Furthermore, by studying the treatment sequence dependence and the cytotoxicity of laser irradiated mixtures of ICG and VP-16, we found that the observed synergy involves direct/indirect reactions between ICG and VP-16. We further propose that there exists an electron transfer reaction between ICG and VP-16 under irradiation. This study therefore shows the anticancer efficacy of ICG-PDT combined with VP 16. These findings suggest that ICG-mediated PDT may be applied in combination with the chemotherapy drug VP-16 to treat some cancers, especially the non-small cell lung cancer. PMID- 28587259 TI - New Benzenoid Derivatives and Other Constituents from Lawsonia inermis with Inhibitory Activity against NO Production. AB - Three new benzenoid derivatives, lawsoinermone (1), inermidioic acid (2), and inermic acid (3) have been isolated from the aerial part of Lawsonia inermis, together with 11 known compounds (4-14). The structures of three new compounds were determined through spectroscopic and MS analyses. Compounds 1, 4-6, 13 and 14 were evaluated for inhibition of nitric oxide production in LPS-stimulated product of nitrite in RAW 264.7 cells with IC50 values of 6.12, 16.43, 18.98, 9.30, 9.30 and 14.90 MUg/mL, respectively. PMID- 28587260 TI - An Enzyme-Induced Novel Biosensor for the Sensitive Electrochemical Determination of Isoniazid. AB - In this present work, a glassy carbon electrode (GCE) was modified primarily with multiwalled carbon nanotubes (MWCNTs) and a composite of MWCNTs and titanium oxide nanoparticles (TiO2NPs). The enzyme horseradish peroxidase (HRP) was immobilized to enhance the sensing ability of GCE. The proposed biosensor was used for the sensitive determination of isoniazid (INZ) in various pharmaceutical samples. The electrochemical behaviour of the developed MWCNT-TiO2NPs-HRP-GCE biosensor was studied by using cyclic voltammetry (CV) and differential pulse voltammetric (DPV) techniques. Fourier transform infrared spectroscopy (FT-IR), X ray diffraction (XRD), thermogravimetry (TGA) and transmission electron microscopy (TEM) techniques were used to characterize the developed sensor. Phosphate buffer solution (PBS) with pH 7 was used as supporting electrolyte in the present investigation. The cyclic voltammetric results revealed that the increment of anodic peak currents for the enzyme-induced sensor was almost 8-fold greater than that of a bare GCE. The DPV technique exhibited good limit of detection and limit of quantification values, viz., 0.0335 MUM and 0.1118 MUM, respectively. Moreover, the developed sensor showed long-lasting stability and repeatability without any interferents. This strongly indicates that the fabricated sensor shows outstanding electrochemical performance towards INZ, with excellent selectivity and sensitivity. The developed sensor was successfully applied to pharmaceutical samples and gave good percentages of recoveries. PMID- 28587261 TI - Ulmus macrocarpa Hance Extracts Attenuated H2O2 and UVB-Induced Skin Photo-Aging by Activating Antioxidant Enzymes and Inhibiting MAPK Pathways. AB - To protect from reactive oxygen species (ROS) damages, skin cells have evolved to have antioxidant enzymes, such as copper and zinc-dependent superoxide dismutase (SOD1), mitochondrial manganese-dependent superoxide dismutase (SOD2), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR), and suppressed the expression of matrix metalloproteinases (MMPs) through the mitogen activated protein kinase (MAPK) signaling pathways, such as c-Jun N-terminal kinase (JNK) and p38. Bioactive compounds analyses were performed using a high performance liquid chromatography-photodiode array detector (HPLC-PDA) system. The antioxidant activity of Ulmus macrocarpa Hance (UMH) extracts was estimated in vitro. The anti-aging activity of UMH extracts was estimated in vivo using the SKH-1 hairless mice. The UMH extracts reduced the H2O2-induced intracellular ROS production and the cell damages in human dermal fibroblasts (HDFs). Moreover, the H2O2-induced phosphorylation of JNK and p38 was detected in HDF and UMH extracts blocked the phosphorylation. These results suggest that UMH extracts can reduce the expression of MMPs and the reduced MMPs lead to the inhibition of collagen degradation. In addition, oral administration of the UMH extracts decreased the depth, thickness, and length of wrinkles on UVB exposed hairless mice. Therefore, UMH extracts play an advantage of the functional materials in antioxidant and anti-aging of skin. PMID- 28587262 TI - Trends in Pediatric and Adolescent Anterior Cruciate Ligament Injuries in Victoria, Australia 2005-2015. AB - Anterior cruciate ligament (ACL) injuries in children and adolescents have been the focus of recent media attention and parental concern, given their potential for adverse long-term health outcomes and healthcare costs. However, there is limited formal evidence on trends in the incidence of ACL injuries in children. This study utilizes the Victorian Admitted Episodes Dataset (VAED) to characterize epidemiologic trends of hospital-admitted ACL injuries in those aged 5 to 14 years over a period of 10 years from 2005 to 2015. There was a total of 320 cases and the overall annual rate of ACL injuries increased by 147.8% from 2.74 per 100,000 population in 2005/2006 to 6.79 per 100,000 in 2014/2015. The majority (96.9%) of these injuries were in 10- to 14-year-olds. The main in hospital procedure provided to over 80% of the hospitalized cases involved ACL reconstruction. Sporting activities accounted for 56.6% of ACL injuries. For females, over half (52.4%) of ACL injuries occurred whilst playing ball sports, compared to 35.4% of males. The large increase in ACL injuries in 5- to 14-year olds in the state of Victoria, Australia over a 10-year period indicates they are a significant and emerging health burden. Population-wide ACL prevention policies are required to halt these trends. Cost effective prevention programs that involve neuromuscular training must be implemented in schools and junior sports teams. PMID- 28587263 TI - Iron for Africa-Report of an Expert Workshop. AB - Scientific experts from nine countries gathered to share their views and experience around iron interventions in Africa. Inappropriate eating habits, infections and parasitism are responsible for significant prevalence of iron deficiency, but reliable and country-comparable prevalence estimates are lacking: improvements in biomarkers and cut-offs values adapted to context of use are needed. Benefits of iron interventions on growth and development are indisputable and outweigh risks, which exist in populations with a high infectious burden. Indeed, pathogen growth may increase with enhanced available iron, calling for caution and preventive measures where malaria or other infections are prevalent. Most African countries programmatically fortify flour and supplement pregnant women, while iron deficiency in young children is rather addressed at individual level. Coverage and efficacy could improve through increased access for target populations, raised awareness and lower cost. More bioavailable iron forms, helping to decrease iron dose, or prebiotics, which both may lower risk of infections are attractive opportunities for Africa. Fortifying specific food products could be a relevant route, adapted to local context and needs of population groups while providing education and training. More globally, partnerships involving various stakeholders are encouraged, that could tackle all aspects of the issue. PMID- 28587264 TI - Being-in-the-Chemotherapy-Suite versus Being-in-the-Oncology-Ward: An Analytical View of Two Hospital Sites Occupied by People Experiencing Cancer. AB - How do people with cancer occupy places within the health system during their journey through palliative care? The answer to this question was explored by the authors as part of a wider ethnographic study of eight people's journeys from referral to palliative care services to the end of life. This article reports on findings that have emerged from ongoing analysis that has been completed in the years proceeding data collection. An ethnographic research design was used to collect data about the participants and their family members over a three-year period. Data was collected using participant observation and semi-structured interviews. Over 380 transcripts based on field note entries and taped interviews were produced during the 1121 h of contact with participants and family members that made up the research period. Analysis of these texts identified two focal sites within Christchurch Hospital that were occupied by the participants. These were the Chemotherapy Suite and the Oncology Ward. Drawing on literature concerning previous anthropological analysis, research was conducted to understand how places affect people and how people affect places. The researchers have used a model outlined by the American ethnographer Miles Richardson to analyse two distinct sites within one hospital. As explained in Richardson's article, whose title is used to model the title of this article, a sense of place becomes apparent when comparing and contrasting two sites within the same location. Richardson's article is highly interpretative and relies not only on pre-existing theoretical frameworks but also on personal interpretation. The same approach has been used in the current article. Here, ethnographic methods require the researcher's interpretation of how participants occupied these sites. Following this approach, the Chemotherapy Suite is presented as a place where medicine dominates illness, and appears as distinct from the Oncology Ward, where disease predominates and death is secreted away. PMID- 28587266 TI - Comparison and Evaluation of Annual NDVI Time Series in China Derived from the NOAA AVHRR LTDR and Terra MODIS MOD13C1 Products. AB - Time series of Normalized Difference Vegetation Index (NDVI) derived from multiple satellite sensors are crucial data to study vegetation dynamics. The Land Long Term Data Record Version 4 (LTDR V4) NDVI dataset was recently released at a 0.05 * 0.05 degrees spatial resolution and daily temporal resolution. In this study, annual NDVI time series that are composited by the LTDR V4 and Moderate Resolution Imaging Spectroradiometer (MODIS) NDVI datasets (MOD13C1) are compared and evaluated for the period from 2001 to 2014 in China. The spatial patterns of the NDVI generally match between the LTDR V4 and MOD13C1 datasets. The transitional zone between high and low NDVI values generally matches the boundary of semi-arid and sub-humid regions. A significant and high coefficient of determination is found between the two datasets according to a pixel-based correlation analysis. The spatially averaged NDVI of LTDR V4 is characterized by a much weaker positive regression slope relative to that of the spatially averaged NDVI of the MOD13C1 dataset because of changes in NOAA AVHRR sensors between 2005 and 2006. The measured NDVI values of LTDR V4 were always higher than that of MOD13C1 in western China due to the relatively lower atmospheric water vapor content in western China, and opposite observation appeared in eastern China. In total, 18.54% of the LTDR V4 NDVI pixels exhibit significant trends, whereas 35.79% of the MOD13C1 NDVI pixels show significant trends. Good agreement is observed between the significant trends of the two datasets in the Northeast Plain, Bohai Economic Rim, Loess Plateau, and Yangtze River Delta. By contrast, the datasets contrasted in northwestern desert regions and southern China. A trend analysis of the regression slope values according to the vegetation type shows good agreement between the LTDR V4 and MOD13C1 datasets. This study demonstrates the spatial and temporal consistencies and discrepancies between the AVHRR LTDR and MODIS MOD13C1 NDVI products in China, which could provide useful information for the choice of NDVI products in subsequent studies of vegetation dynamics. PMID- 28587265 TI - Ultrasensitive Magnetic Nanoparticle Detector for Biosensor Applications. AB - Ta/Ru/Co/Ru/Co/Cu/Co/Ni80Fe20/Ta spin-valve giant magnetoresistive (GMR) multilayers were deposited using UHV magnetron sputtering and optimized to achieve a 13% GMR ratio before patterning. The GMR multilayer was patterned into 12 sensor arrays using a combination of e-beam and optical lithographies. Arrays were constructed with 400 nm * 400 nm and 400 nm * 200 nm sensors for the detection of reporter nanoparticles. Nanoparticle detection was based on measuring the shift in high-to-low resistance switching field of the GMR sensors in the presence of magnetic particle(s). Due to shape anisotropy and the corresponding demag field, the resistance state switching fields were significantly larger and the switching field distribution significantly broader in the 400 nm * 200 nm sensors as compared to the 400 nm * 400 nm sensors. Thus, sensor arrays with 400 nm * 400 nm dimensions were used for the demonstration of particle detection. Detection of a single 225 nm Fe3O4 magnetic nanoparticle and a small number (~10) of 100 nm nanoparticles was demonstrated. With appropriate functionalization for biomolecular recognition, submicron GMR sensor arrays can serve as the basis of ultrasensitive chemical and biological sensors. PMID- 28587268 TI - Influence of Membrane Equivalent Weight and Reinforcement on Ionic Species Crossover in All-Vanadium Redox Flow Batteries. AB - One of the major sources of lost capacity in all-vanadium redox flow batteries (VRFBs) is the undesired transport (usually called crossover) of water and vanadium ions through the ion-exchange membrane. In this work, an experimental assessment of the impact of ion-exchange membrane properties on vanadium ion crossover and capacity decay of VRFBs has been performed. Two types of cationic membranes (non-reinforced and reinforced) with three equivalent weights of 800, 950 and 1100 g.mol-1 were investigated via a series of in situ performance and capacity decay tests along with ex situ vanadium crossover measurement and membrane characterization. For non-reinforced membranes, increasing the equivalent weight (EW) from 950 to 1100 g.mol-1 decreases the V(IV) permeability by ~30%, but increases the area-specific resistance (ASR) by ~16%. This increase in ASR and decrease in V(IV) permeability was accompanied by increased through plane membrane swelling. Comparing the non-reinforced with reinforced membranes, membrane reinforcement increases ASR, but V(IV) permeability decreases. It was also shown that there exists a monotonic correlation between the discharge capacity decay over long-term cycling and V(IV) permeability values. Thus, V(IV) permeability is considered a representative diagnostic for assessing the overall performance of a particular ion-exchange membrane with respect to capacity fade in a VRFB. PMID- 28587267 TI - Insulin Treatment May Alter Fatty Acid Carriers in Placentas from Gestational Diabetes Subjects. AB - There is little information available on the effect of Gestational diabetes mellitus (GDM) treatment (diet or insulin) on placental lipid carriers, which may influence fetal fat accretion. Insulin may activate placental insulin receptors protein kinase (AKT) and extracellular signal regulated kinase ERK mediators, which might affect lipid metabolism. Placenta was collected from 25 control women, 23 GDM-Diet and 20 GDM-Insulin. Western blotting of insulin signaling mediators and lipid carriers was performed. The human choricarcinoma-derived cell line BeWo was preincubated with insulin inhibitors protein kinase (AKT) and extracellular signal regulated kinase (ERK) and ERK inhibitors to evaluate insulin regulation of lipid carriers. Maternal serum insulin at recruitment correlated to ultrasound fetal abdominal circumference in offspring of GDM and placental endothelial lipase (EL). Lipoprotein lipase in placenta was significantly reduced in both GDM, while most of the other lipid carriers tended to higher values, although not significantly. There was a significant increase in both phosphorylated-Akt and ERK in placentas from GDM-Insulin patients; both were associated to placental fatty acid translocase (FAT), fatty acid binding protein (A-FABP), and EL. BeWo cells treated with insulin pathway inhibitors significantly reduced A-FABP, fatty acid transport protein (FATP-1), and EL levels, confirming the role of insulin on these carriers. We conclude that insulin promotes the phosphorylation of placental insulin mediators contributing to higher levels of some specific fatty acid carriers in the placenta and fetal adiposity in GDM. PMID- 28587269 TI - Convolutional Neural Network-Based Finger-Vein Recognition Using NIR Image Sensors. AB - Conventional finger-vein recognition systems perform recognition based on the finger-vein lines extracted from the input images or image enhancement, and texture feature extraction from the finger-vein images. In these cases, however, the inaccurate detection of finger-vein lines lowers the recognition accuracy. In the case of texture feature extraction, the developer must experimentally decide on a form of the optimal filter for extraction considering the characteristics of the image database. To address this problem, this research proposes a finger-vein recognition method that is robust to various database types and environmental changes based on the convolutional neural network (CNN). In the experiments using the two finger-vein databases constructed in this research and the SDUMLA-HMT finger-vein database, which is an open database, the method proposed in this research showed a better performance compared to the conventional methods. PMID- 28587270 TI - Borrelidins C-E: New Antibacterial Macrolides from a Saltern-Derived Halophilic Nocardiopsis sp. AB - Chemical investigation of a halophilic actinomycete strain belonging to the genus Nocardiopsis inhabiting a hypersaline saltern led to the discovery of new 18 membered macrolides with nitrile functionality, borrelidins C-E (1-3), along with a previously reported borrelidin (4). The planar structures of borrelidins C-E, which are new members of the rare borrelidin class of antibiotics, were elucidated by NMR, mass, IR, and UV spectroscopic analyses. The configurations of borrelidines C-E were determined by the interpretation of ROESY NMR spectra, J based configuration analysis, a modified Mosher's method, and CD spectroscopic analysis. Borrelidins C and D displayed inhibitory activity, particularly against the Gram-negative pathogen Salmonella enterica, and moderate cytotoxicity against the SNU638 and K562 carcinoma cell lines. PMID- 28587271 TI - Development of Activity and Participation Norms among General Adult Populations in Taiwan. AB - : Based on the International Classification of Functioning, Disability, and Health (ICF) and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), The Functioning Disability Evaluation Scale-Adult version (FUNDES Adult) began development in 2011. The FUNDES-Adult was designed to assess the difficulty level of an individual's activities and participation in daily life. There is a lack of research regarding the profile of activity and participation for the general adult population. The purposes of this study were to establish activity and participation norms for the general adult population in Taiwan and to describe, discuss, and compare the activity and participation profile with other population. METHOD: A population-based survey was administered in 2013 using a computer-assisted telephone interviewing system (CATI system). Using probability proportional to size (PPS) sampling and systematic sampling with random digit dialing (RDD), 1500 adults from Taiwan's general population were selected to participate in the survey. The FUNDES-Adult with six domains and two dimensions (performance and capability) was used to obtain data on activities and participation levels. A higher domain score indicated higher participation restriction. RESULTS: Approximately 50% of the respondents were male, and the average age of the respondents was 45.23 years. There were no significant differences in the demographic features between the sample and the population. Among the six domains, the self-care domain score was the lowest (least restriction) and the participation domain score was the highest (most restriction). Approximately 90% of the sample scored were less than 15, and only 0.1% scored more than 80. This is the first cross-national population-based survey to assess norms of activity and participation relevant to the general population of Taiwan. As such, the results of this survey can be used as a reference for comparing the activity and participation (AP) functioning of other countries and subgroups. PMID- 28587274 TI - Parent Perspective on Care Coordination Services for Their Child with Medical Complexity. AB - The overarching goal of care coordination is communication and co-management across settings. Children with medical complexity require care from multiple services and providers, and the many benefits of care coordination on health and patient experience outcomes have been documented. Despite these findings, parents still report their greatest challenge is communication gaps. When this occurs, parents assume responsibility for aggregating and sharing health information across providers and settings. A new primary-specialty care coordination partnership model for children with medical complexity works to address these challenges and bridge communication gaps. During the first year of the new partnership, parents participated in focus groups to better understand how they perceive communication and collaboration between the providers and services delivering care for their medically complex child. Our findings from these sessions reflect the current literature and highlight additional challenges of rural families, as seen from the perspective of the parents. We found that parents appreciate when professional care coordination is provided, but this is often the exception and not the norm. Additionally, parents feel that the local health system's inability to care for their medically complex child results in unnecessary trips to urban-based specialty care. These gaps require a system level approach to care coordination and, consequently, new paradigms for delivery are urgently needed. PMID- 28587273 TI - Proteases of Dermatophagoides pteronyssinus. AB - Since the discovery that Der p 1 is a cysteine protease, the role of proteolytic activity in allergic sensitization has been explored. There are many allergens with proteolytic activity; however, exposure from dust mites is not limited to allergens. In this paper, genomic, transcriptomic and proteomic data on Dermatophagoides pteronyssinus (DP) was mined for information regarding the complete degradome of this house dust mite. D. pteronyssinus has more proteases than the closely related Acari, Dermatophagoides farinae (DF) and Sarcoptes scabiei (SS). The group of proteases in D. pteronyssinus is found to be more highly transcribed than the norm for this species. The distribution of protease types is dominated by the cysteine proteases like Der p 1 that account for about half of protease transcription by abundance, and Der p 1 in particular accounts for 22% of the total protease transcripts. In an analysis of protease stability, the group of allergens (Der p 1, Der p 3, Der p 6, and Der p 9) is found to be more stable than the mean. It is also statistically demonstrated that the protease allergens are simultaneously more highly expressed and more stable than the group of D. pteronyssinus proteases being examined, consistent with common assumptions about allergens in general. There are several significant non allergen outliers from the normal group of proteases with high expression and high stability that should be examined for IgE binding. This paper compiles the first holistic picture of the D. pteronyssinus degradome to which humans may be exposed. PMID- 28587272 TI - Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers. AB - Numerous environmental factors such as diet, alcohol use, stress, and environmental chemicals are known to elicit epigenetic changes, leading to increased rates of cancers and other diseases. The incidence of head and neck cancer, one of the most common cancers in Taiwanese males, is increasing: oral cancer and nasopharyngeal carcinoma are ranked fourth and tenth respectively, among the top ten cancers in this group, and a major cause of cancer-related deaths in Taiwanese males. Previous studies have identified smoking, alcohol use, and betel quid chewing as the three major causes of head and neck cancers; these three social habits are commonly observed in Taiwanese males, resulting in an increasing morbidity rate of head and neck cancers in this population. In this literature review, we discuss the association between specific components of betel quid, alcohol, and tobacco, and the occurrence of head and neck cancers, lung cancer, gastrointestinal cancers, and urethral cancer. We focus on regulatory mechanisms at the epigenetic level and their oncogenic effects. The review further discusses the application of FDA-approved epigenetic drugs as therapeutic strategies against cancer. PMID- 28587275 TI - A High-Speed Target-Free Vision-Based Sensor for Bus Rapid Transit Viaduct Vibration Measurements Using CMT and ORB Algorithms. AB - Bus Rapid Transit (BRT) has become an increasing source of concern for public transportation of modern cities. Traditional contact sensing techniques during the process of health monitoring of BRT viaducts cannot overcome the deficiency that the normal free-flow of traffic would be blocked. Advances in computer vision technology provide a new line of thought for solving this problem. In this study, a high-speed target-free vision-based sensor is proposed to measure the vibration of structures without interrupting traffic. An improved keypoints matching algorithm based on consensus-based matching and tracking (CMT) object tracking algorithm is adopted and further developed together with oriented brief (ORB) keypoints detection algorithm for practicable and effective tracking of objects. Moreover, by synthesizing the existing scaling factor calculation methods, more rational approaches to reducing errors are implemented. The performance of the vision-based sensor is evaluated through a series of laboratory tests. Experimental tests with different target types, frequencies, amplitudes and motion patterns are conducted. The performance of the method is satisfactory, which indicates that the vision sensor can extract accurate structure vibration signals by tracking either artificial or natural targets. Field tests further demonstrate that the vision sensor is both practicable and reliable. PMID- 28587276 TI - Changes in Typical Portion Sizes of Commonly Consumed Discretionary Foods among Australian Adults from 1995 to 2011-2012. AB - This study aimed to examine the changes in typical portion sizes of commonly consumed discretionary foods among Australian adults from 1995 to 2011-2012. Data of adults (age >=19 years) from the 1995 Australian National Nutrition Survey and 2011-2012 National Nutrition and Physical Activity Survey were used. Typical portion sizes (median portion) of fourteen discretionary foods that contributed the most to energy intake were determined. Ten out of fourteen food categories demonstrated a significant change in kJ per typical portion from 1995 to 2011 2012 (p <= 0.001). kJ per typical portion increased for pizza, cake, sausage, cereal bar, processed meat, ice cream and wine, with pizza and cake demonstrating the largest increases (+570 kJ and +950 kJ in 2011-2012, respectively; both +66% above 1995). In contrast, kJ per typical portion of pastry, snack food and potato fries decreased by 10-40% over time, and did not change for biscuit, chocolate, sugar-sweetened beverage and beer. Similar changes were observed for grams per typical portion consumed. Temporal trends in typical portion sizes were similar according to age group, gender and socioeconomic status. The findings suggest that population-wide strategies that enable consumers to choose smaller portions of discretionary foods are needed to reduce the excess consumption of these products. PMID- 28587278 TI - Tryptophan Levels during Grape Ripening: Effects of Cultural Practices. AB - Some cultural practices that are carried out during the grape ripening period are associated with vine stress, including leaf removal, grape bunch removal, and vegetable cover crops. Additionally, several nitrogen and sulfur supplements have also been used directly on leaves during the last stage of the ripening period. In the work described here, five different cultural practices and the reference were applied in three replicates in the same vineyard. The evolution of tryptophan levels was evaluated from just after grape veraison until the harvest date. In some cases, certain specific treatments were also evaluated after the regular harvest date. The cultural techniques that involved the application of nitrogen led to higher levels of tryptophan at the harvest day when compared to other cultural techniques. It was also found that the application of nitrogen without sulfur had a faster effect on the level of tryptophan. It was established that a period of around 20 days is needed for the grapes to show clear differences in tryptophan levels after the application of nitrogen. PMID- 28587277 TI - Weight Status Is Related with Gender and Sleep Duration but Not with Dietary Habits and Physical Activity in Primary School Italian Children. AB - The prevalence of overweight and obesity in children has risen greatly worldwide. Diet and poor physical activity are the two risk factors usually examined, but epidemiological evidence exists suggesting a link between sleep duration and overweight/obesity in children. The aim of this study was to describe the relationship among body mass index (BMI), diet quality, physical activity level, and sleep duration in 690 children attending the 5th grade in primary schools (9 11 years old) in the city of Parma (Italy) involved in the Giocampus educational program. This was achieved through (i) measuring anthropometric data to compute body mass index; (ii) administering a food questionnaire to evaluate adherence to the Mediterranean Diet (KIDMED score); and (iii) administering a lifestyle questionnaire to classify children physical activity level (PAL), sleep duration, and school achievement. A highly significant negative association was found between BMI and sleep hours. Moreover, there was a significant positive association between PAL and KIDMED scores. No evidence was found of association between BMI and PAL, nor between BMI and KIDMED score. Data from this study established that BMI is correlated to gender and sleep duration, defining sleep habits as one of the factors linked to overweight and obesity. PMID- 28587279 TI - Seroprevalence of Measles Antibodies and Predictors for Seropositivity among Chinese Children. AB - Background: Supplementary measles immunization has been implemented since 2010 throughout China, yet few studies have reported its effect in the northwest regions. Methods: A cross-sectional study was conducted among children aged 2 to 4 years old (n = 755) from February to September 2014 in 25 towns of Qian County, Shaanxi Province. Blood samples were analyzed for measles antibodies using enzyme linked immunosorbent immunoglobulin G (IgG) assays. Socio-demographic factors were assessed by questionnaire. Data on vaccine dose were collected from town medical records. Univariate and logistic regression analyses were used to determine factors associated with measles antibody seropositivity. Results: Measles antibody seroprevalence was 91.13% (95% CI: 89.52-92.83) in our sample. Compared with children whose mother's highest education was primary school, seroprevalence was higher in children whose maternal education was middle school (adjusted OR: 1.4, 95% CI: 0.7-2.8), high school (adjusted OR: 2.4, 95% CI: 1.3 7.7), and college/university (adjusted OR: 2.9, 95% CI: 1.2-9.3). Vaccine dose was positively associated with seropositivity. Conclusions: Measles seroprevalence is high in China and is associated with the mother's education and vaccine dose. PMID- 28587281 TI - Genome-Wide Identification and Characterization of Salinity Stress-Responsive miRNAs in Wild Emmer Wheat (Triticum turgidum ssp. dicoccoides). AB - MicroRNAs (miRNAs) are a class of endogenous small noncoding RNAs which regulate diverse molecular and biochemical processes at a post-transcriptional level in plants. As the ancestor of domesticated wheat, wild emmer wheat (Triticum turgidum ssp. dicoccoides) has great genetic potential for wheat improvement. However, little is known about miRNAs and their functions on salinity stress in wild emmer. To obtain more information on miRNAs in wild emmer, we systematically investigated and characterized the salinity-responsive miRNAs using deep sequencing technology. A total of 88 conserved and 124 novel miRNAs were identified, of which 50 were proven to be salinity-responsive miRNAs, with 32 significantly up-regulated and 18 down-regulated. miR172b and miR1120a, as well as mi393a, were the most significantly differently expressed. Targets of these miRNAs were computationally predicted, then Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that the targets of salinity-responsive miRNAs were enriched in transcription factors and stress related proteins. Finally, we investigated the expression profiles of seven miRNAs ranging between salt-tolerant and sensitive genotypes, and found that they played critical roles in salinity tolerance in wild emmer. Our results systematically identified the salinity-responsive miRNAs in wild emmer, not only enriching the miRNA resource but also laying the foundation for further study on the biological functions and evolution of miRNAs in wild wheat and beyond. PMID- 28587280 TI - Levo-Corydalmine Alleviates Neuropathic Cancer Pain Induced by Tumor Compression via the CCL2/CCR2 Pathway. AB - Background: Tumor compression-induced pain (TCIP) is a complex pathological cancer pain. Spinal glial cells play a critical role in maintenance of cancer pain by releasing proinflammatory cytokines and chemokines. In this study, we verified the role of levo-corydalmine (l-CDL) on TCIP. Methods: Spontaneous pain, paw withdrawal threshold and latency were assessed using TCIP mouse model. Immunofluorescence was used to identify the reactions of glia. RT-PCR and western blot or ELISA were used to determine mRNA or protein expression of tumor necrosis factor-alpha (TNF-alpha), interlukin-1beta (IL-1beta), CC chemokine ligand 2 (CCL2) and chemotactic cytokine receptor 2 (CCR2) in vivo and in vitro. Results: l-CDL significantly attenuated TCIP hypersensitivity, accompanying with downregulation of TNF-alpha and IL-1beta expression levels and declined astrocytes and microglial activation. It also significantly decreased the expression of the mRNA and protein level for CCL2 and CCR2. Further, l-CDL could suppress TNF-alpha-induced astrocytes activation and IL-1beta expression through downregulating the CCL2/CCR2. Besides, CCL2-induced BV-microglia activation and inflammatory factors secretion were suppressed by l-CDL via CCR2. Conclusions: Suppression of CCL2/CCR2 by l-CDL may contribute to alleviate TCIP, offering an alternative medication for TCIP. PMID- 28587282 TI - Curcumin Anti-Apoptotic Action in a Model of Intestinal Epithelial Inflammatory Damage. AB - The purpose of this study is to determine if a preventive treatment with curcumin can protect intestinal epithelial cells from inflammatory damage induced by IFNgamma. To achieve this goal we have used a human intestinal epithelial cell line (HT29) treated with IFNgamma to undergo apoptotic changes that can reproduce the damage of intestinal epithelia exposed to inflammatory cytokines. In this model, we measured the effect of curcumin (curcuminoid from Curcuma Longa) added as a pre-treatment at different time intervals before stimulation with IFNgamma. Curcumin administration to HT29 culture before the inflammatory stimulus IFNgamma reduced the cell apoptosis rate. This effect gradually declined with the reduction of the curcumin pre-incubation time. This anti-apoptotic action by curcumin pre-treatment was paralleled by a reduction of secreted IL7 in the HT29 culture media, while there was no relevant change in the other cytokine levels. Even though curcumin pre-administration did not impact the activation of the NF kappaB pathway, a slight effect on the phosphorylation of proteins in this inflammatory signaling pathway was observed. In conclusion, curcumin pre treatment can protect intestinal cells from inflammatory damage. These results can be the basis for studying the preventive role of curcumin in inflammatory bowel diseases. PMID- 28587283 TI - Influence of Hesperidin on the Systemic and Intestinal Rat Immune Response. AB - Polyphenols, widely found in edible plants, influence the immune system. Nevertheless, the immunomodulatory properties of hesperidin, the predominant flavanone in oranges, have not been deeply studied. To establish the effect of hesperidin on in vivo immune response, two different conditions of immune system stimulations in Lewis rats were applied. In the first experimental design, rats were intraperitoneally immunized with ovalbumin (OVA) plus Bordetella pertussis toxin and alum as the adjuvants, and orally given 100 or 200 mg/kg hesperidin. In the second experimental design, rats were orally sensitized with OVA together with cholera toxin and fed a diet containing 0.5% hesperidin. In the first approach, hesperidin administration changed mesenteric lymph node lymphocyte (MLNL) composition, increasing the TCRalphabeta+ cell percentage and decreasing that of B lymphocytes. Furthermore, hesperidin enhanced the interferon (IFN) gamma production in stimulated MLNL. In the second approach, hesperidin intake modified the lymphocyte composition in the intestinal epithelium (TCRgammadelta+ cells) and the lamina propria (TCRgammadelta+, CD45RA+, natural killer, natural killer T, TCRalphabeta+CD4+, and TCRalphabeta+CD8+ cells). Nevertheless, hesperidin did not modify the level of serum anti-OVA antibodies in either study. In conclusion, hesperidin does possess immunoregulatory properties in the intestinal immune response, but this effect is not able to influence the synthesis of specific antibodies. PMID- 28587285 TI - Study on an Indoor Positioning System for Harsh Environments Based on Wi-Fi and Bluetooth Low Energy. AB - This paper presents a study of positioning system that provides advanced information services based on Wi-Fi and Bluetooth Low Energy (BLE) technologies. It uses Wi-Fi for rough positioning and BLE for fine positioning. It is designed for use in public transportation system stations and terminals where the conditions are "hostile" or unfavourable due to signal noise produced by the continuous movement of passengers and buses, data collection conducted in the constant presence thereof, multipath fading, non-line of sight (NLOS) conditions, the fact that part of the wireless communication infrastructure has already been deployed and positioned in a way that may not be optimal for positioning purposes, variable humidity conditions, etc. The ultimate goal is to provide a service that may be used to assist people with special needs. We present experimental results based on scene analysis; the main distance metric used was the Euclidean distance but the Mahalanobis distance was also used in one case. The algorithm employed to compare fingerprints was the weighted k-nearest neighbor one. For Wi-Fi, with only three visible access points, accuracy ranged from 3.94 to 4.82 m, and precision from 5.21 to 7.0 m 90% of the time. With respect to BLE, with a low beacon density (1 beacon per 45.7 m2), accuracy ranged from 1.47 to 2.15 m, and precision from 1.81 to 3.58 m 90% of the time. Taking into account the fact that this system is designed to work in real situations in a scenario with high environmental fluctuations, and comparing the results with others obtained in laboratory scenarios, our results are promising and demonstrate that the system would be able to position users with these reasonable values of accuracy and precision. PMID- 28587284 TI - Bioluminescence Assays for Monitoring Chondrogenic Differentiation and Cartilage Regeneration. AB - Since articular cartilage has a limited regeneration potential, for developing biological therapies for cartilage regeneration it is important to study the mechanisms underlying chondrogenesis of stem cells. Bioluminescence assays can visualize a wide range of biological phenomena such as gene expression, signaling, metabolism, development, cellular movements, and molecular interactions by using visible light and thus contribute substantially to elucidation of their biological functions. This article gives a concise review to introduce basic principles of bioluminescence assays and applications of the technology to visualize the processes of chondrogenesis and cartilage regeneration. Applications of bioluminescence assays have been highlighted in the methods of real-time monitoring of gene expression and intracellular levels of biomolecules and noninvasive cell tracking within animal models. This review suggests that bioluminescence assays can be applied towards a visual understanding of chondrogenesis and cartilage regeneration. PMID- 28587286 TI - Novel Structurally Related Flavones Augment Cell Death Induced by rhsTRAIL. AB - TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) was identified as a powerful activator of apoptosis in tumor cells and one of the most promising candidates for cancer therapy with no toxicity against normal tissues. However, many tumor cells are resistant to TRAIL-induced apoptosis. The aim of this work was to analyze the improvement of the anticancer effect of rhsTRAIL (recombinant human soluble TRAIL) by nine flavones: 5-Hydroxyflavone, 6-Hydroxyflavone, 7 Hydroxyflavone and their new synthetic derivatives 5-acetoxyflavone, 5 butyryloxyflavone, 6-acetoxyflavone, 6-butyryloxyflavone, 7-acetoxyflavone and 7 butyryloxyflavone. We examined the cytotoxic and apoptotic effects of rhsTRAIL enhanced by novel structurally-related flavones on SW480 and SW620 colon cancer cells using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test, the lactate dehydrogenase assay and annexin V-FITC fluorescence staining. We observed a slight difference in the activities of the flavones that was dependent on their chemical structure. Our study indicates that all nine flavones significantly augment cell death by rhsTRAIL (cytotoxicity range 36.8 +/- 1.7% 91.4 +/- 1.7%; apoptosis increase of 33.0 +/- 0.7%-78.5 +/- 0.9%). Our study demonstrates the potential use of tested flavones in TRAIL-based anticancer therapy and prevention. PMID- 28587287 TI - A Routine 'Top-Down' Approach to Analysis of the Human Serum Proteome. AB - Serum provides a rich source of potential biomarker proteoforms. One of the major obstacles in analysing serum proteomes is detecting lower abundance proteins owing to the presence of hyper-abundant species (e.g., serum albumin and immunoglobulins). Although depletion methods have been used to address this, these can lead to the concomitant removal of non-targeted protein species, and thus raise issues of specificity, reproducibility, and the capacity for meaningful quantitative analyses. Altering the native stoichiometry of the proteome components may thus yield a more complex series of issues than dealing directly with the inherent complexity of the sample. Hence, here we targeted method refinements so as to ensure optimum resolution of serum proteomes via a top down two-dimensional gel electrophoresis (2DE) approach that enables the routine assessment of proteoforms and is fully compatible with subsequent mass spectrometric analyses. Testing included various fractionation and non fractionation approaches. The data show that resolving 500 ug protein on 17 cm 3 10 non-linear immobilised pH gradient strips in the first dimension followed by second dimension resolution on 7-20% gradient gels with a combination of lithium dodecyl sulfate (LDS) and sodium dodecyl sulfate (SDS) detergents markedly improves the resolution and detection of proteoforms in serum. In addition, well established third dimension electrophoretic separations in combination with deep imaging further contributed to the best available resolution, detection, and thus quantitative top-down analysis of serum proteomes. PMID- 28587288 TI - Work-Related Eye Injuries: A Relevant Health Problem. Main Epidemiological Data from a Highly-Industrialized Area of Northern Italy. AB - The province of Modena is one of the most industrialized areas of Northern Italy. The medical records of the Ophthalmological Emergency Department (OED) of Modena University Hospital were studied: there were 13,470 OED accesses in 2014 and in 754 cases that an occupational eye injury occurred. The frequency of work-related eye injuries (30/00) was lower compared to other published studies, but the absolute number is still relevant, showing the need for more adequate prevention, especially in metal work, construction work, and agriculture, where the worst prognoses were observed. Intervention programs must be implemented as early as possible in the working life, considering that the frequency in younger workers is about double that of the oldest age class (3.50/00 vs. 1.80/00), and special attention should also be given to foreigners, who have a 50% higher injury risk. Furthermore, the planning of specific interventions for eye-injured workers may be useful, considering that a previous injury does not appear to encourage the adoption of preventive interventions, and a subgroup of eye-injured workers have a potential risk for new injuries. Finally, the data presented here indicates how OED records, integrated with specific occupational information, can be applied for studies on work-related eye injuries. PMID- 28587289 TI - Dendritic Cell-Airway Epithelial Cell Cross-Talk Changes with Age and Contributes to Chronic Lung Inflammatory Diseases in the Elderly. AB - Age-associated dysregulated immune and inflammatory responses are one of the major factors responsible for the prevalence of chronic respiratory diseases in the older population. Pulmonary dendritic cells (DCs) are present below the airway epithelial cells (AECs) and are critical in initiating effective immune responses to harmful pathogens while maintaining tolerance against harmless antigens. The interaction between DCs and AECs plays a crucial role in lung immunity at homeostasis and during infections. The functions of both DCs and AECs are impacted with age. The present report reviews how the potential crosstalk between pulmonary DCs and AECs is dysregulated in the elderly impairing the capacity to maintain tolerance at the respiratory surfaces, which results in severe and chronic respiratory inflammatory diseases. We also discuss how such DC AECs crosstalk will provide insight into the mechanisms underlying the increased susceptibility of the elderly to pulmonary inflammatory diseases. PMID- 28587291 TI - In Vitro Evaluation of the Antioxidant, Cytoprotective, and Antimicrobial Properties of Essential Oil from Pistacia vera L. Variety Bronte Hull. AB - Although the chemical composition and biological properties of some species of the genus Pistacia has been investigated, studies on hull essential oil of Pistacia vera L. variety Bronte (HEO) are currently lacking. In this work, we have carried out an in-depth phytochemical profile elucidation by Gas Chromatography-Mass Spectrometry (GC-MS) analysis, and an evaluation of antioxidant scavenging properties of HEO, using several different in vitro methods, checking also its cytoprotective potential on lymphocytes treated with tert-butyl hydroperoxide. Moreover, the antimicrobial activity against Gram positive and Gram-negative strains, both American Type Culture Collection (ATCC) and clinical isolates, was also investigated. GC-MS analysis highlighted the richness of this complex matrix, with the identification of 40 derivatives. The major components identified were 4-Carene (31.743%), alpha-Pinene (23.584%), d Limonene (8.002%), and 3-Carene (7.731%). The HEO showed a strong iron chelating activity and was found to be markedly active against hydroxyl radical, while scarce effects were found against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Moreover, pre-treatment with HEO was observed to significantly increase the cell viability, decreasing the lactate dehydrogenase (LDH) release. HEO was bactericidal against all the tested strains at the concentration of 7.11 mg/mL, with the exception of Pseudomonas aeruginosa ATCC 9027. The obtained results demonstrate the strong free-radical scavenging activity of HEO along with remarkable cytoprotective and antimicrobial properties. PMID- 28587290 TI - Interpreting Microbial Biosynthesis in the Genomic Age: Biological and Practical Considerations. AB - Genome mining has become an increasingly powerful, scalable, and economically accessible tool for the study of natural product biosynthesis and drug discovery. However, there remain important biological and practical problems that can complicate or obscure biosynthetic analysis in genomic and metagenomic sequencing projects. Here, we focus on limitations of available technology as well as computational and experimental strategies to overcome them. We review the unique challenges and approaches in the study of symbiotic and uncultured systems, as well as those associated with biosynthetic gene cluster (BGC) assembly and product prediction. Finally, to explore sequencing parameters that affect the recovery and contiguity of large and repetitive BGCs assembled de novo, we simulate Illumina and PacBio sequencing of the Salinispora tropica genome focusing on assembly of the salinilactam (slm) BGC. PMID- 28587292 TI - Detection of HBV Covalently Closed Circular DNA. AB - Chronic hepatitis B virus (HBV) infection affects approximately 240 million people worldwide and remains a serious public health concern because its complete cure is impossible with current treatments. Covalently closed circular DNA (cccDNA) in the nucleus of infected cells cannot be eliminated by present therapeutics and may result in persistence and relapse. Drug development targeting cccDNA formation and maintenance is hindered by the lack of efficient cccDNA models and reliable cccDNA detection methods. Southern blotting is regarded as the gold standard for quantitative cccDNA detection, but it is complicated and not suitable for high-throughput drug screening, so more sensitive and simple methods, including polymerase chain reaction (PCR)-based methods, Invader assays, in situ hybridization and surrogates, have been developed for cccDNA detection. However, most methods are not reliable enough, and there are no unified standards for these approaches. This review will summarize available methods for cccDNA detection. It is hoped that more robust methods for cccDNA monitoring will be developed and that standard operation procedures for routine cccDNA detection in scientific research and clinical monitoring will be established. PMID- 28587293 TI - Pathological Analysis of Ocular Lesions in a Murine Model of Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is a systemic autoimmune disease characterized by severe inflammation of exocrine glands such as the salivary and lacrimal glands. When it affects the lacrimal glands, many patients experience keratoconjunctivitis due to severely dry eyes. This study investigated the pathological and immunological characteristics of ocular lesions in a mouse model of SS. Corneal epithelial injury and hyperplasia were confirmed pathologically. The number of conjunctival mucin-producing goblet cells was significantly decreased in the SS model mice compared with control mice. Expression levels of transforming growth factor (TGF) beta, interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and C-X-C motif chemokine (CXCL) 12 were significantly higher in the corneal epithelium of the SS model mice than in control mice. Inflammatory lesions were observed in the Harderian, intraorbital, and extraorbital lacrimal glands in the SS model mice, suggesting that the ocular glands were targeted by an autoimmune response. The lacrimal glands of the SS model mice were infiltrated by cluster of differentiation (CD)4+ T cells. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed significantly increased mRNA expression of TNF-alpha, TGF-beta, CXCL9, and lysozyme in the extraorbital lacrimal glands of the SS model mice compared with control mice. These results add to the understanding of the complex pathogenesis of SS and may facilitate development of new therapeutic strategies. PMID- 28587294 TI - Sesquiterpene Variation in West Australian Sandalwood (Santalum spicatum). AB - West Australian sandalwood (Santalum spicatum) has long been exploited for its fragrant, sesquiterpene-rich heartwood; however sandalwood fragrance qualities vary substantially, which is of interest to the sandalwood industry. We investigated metabolite profiles of trees from the arid northern and southeastern and semi-arid southwestern regions of West Australia for patterns in composition and co-occurrence of sesquiterpenes. Total sesquiterpene content was similar across the entire sample collection; however sesquiterpene composition was highly variable. Northern populations contained the highest levels of desirable fragrance compounds, alpha- and beta-santalol, as did individuals from the southwest. Southeastern populations were higher in E,E-farnesol, an undesired allergenic constituent, and low in santalols. These trees generally also contained higher levels of alpha-bisabolol. E,E-farnesol co-occurred with dendrolasin. Contrasting alpha-santalol and E,E-farnesol chemotypes revealed potential for future genetic tree improvement. Although chemical variation was evident both within and among regions, variation was generally lower within regions. Our results showed distinct patterns in chemical diversity of S. spicatum across its natural distribution, consistent with earlier investigations into sandalwood population genetics. These results are relevant for plantation tree improvement and conservation efforts. PMID- 28587296 TI - Diagnosis of Compound Fault Using Sparsity Promoted-Based Sparse Component Analysis. AB - Compound faults often occur in rotating machinery, which increases the difficulty of fault diagnosis. In this case, blind source separation, which usually includes independent component analysis (ICA) and sparse component analysis (SCA), was proposed to separate mixed signals. SCA, which is based on the sparsity of target signals, was developed to sever the compound faults and effectively diagnose the fault due to its advantage over ICA in underdetermined conditions. However, there is an issue regarding the vibration signals, which are inadequately sparse, and it is difficult to represent them in a sparse way. Accordingly, to overcome the above-mentioned problem, a sparsity-promoted approach named wavelet modulus maxima is applied to obtain the sparse observation signal. Then, the potential function is utilized to estimate the number of source signals and the mixed matrix based on the sparse signal. Finally, the separation of the source signals can be achieved according to the shortest path method. To validate the effectiveness of the proposed method, the simulated signals and vibration signals measured from faulty roller bearings are used. The faults that occur in a roller bearing are the outer-race flaw, the inner-race flaw and the rolling element flaw. The results show that the fault features acquired using the proposed approach are evidently close to the theoretical values. For instance, the inner race feature frequency 101.3 Hz is very similar to the theoretical calculation 101 Hz. Therefore, it is effective to achieve the separation of compound faults utilizing the suggest method, even in underdetermined cases. In addition, a comparison is applied to prove that the proposed method outperforms the traditional SCA method when the vibration signals are inadequate. PMID- 28587295 TI - Postnatal Migration of Cerebellar Interneurons. AB - Due to its continuing development after birth, the cerebellum represents a unique model for studying the postnatal orchestration of interneuron migration. The combination of fluorescent labeling and ex/in vivo imaging revealed a cellular highway network within cerebellar cortical layers (the external granular layer, the molecular layer, the Purkinje cell layer, and the internal granular layer). During the first two postnatal weeks, saltatory movements, transient stop phases, cell-cell interaction/contact, and degradation of the extracellular matrix mark out the route of cerebellar interneurons, notably granule cells and basket/stellate cells, to their final location. In addition, cortical-layer specific regulatory factors such as neuropeptides (pituitary adenylate cyclase activating polypeptide (PACAP), somatostatin) or proteins (tissue-type plasminogen activator (tPA), insulin growth factor-1 (IGF-1)) have been shown to inhibit or stimulate the migratory process of interneurons. These factors show further complexity because somatostatin, PACAP, or tPA have opposite or no effect on interneuron migration depending on which layer or cell type they act upon. External factors originating from environmental conditions (light stimuli, pollutants), nutrients or drug of abuse (alcohol) also alter normal cell migration, leading to cerebellar disorders. PMID- 28587297 TI - Biogenic Synthesis of Metal Nanoparticles Using a Biosurfactant Extracted from Corn and Their Antimicrobial Properties. AB - A new and promising biosurfactant extracted from corn steep liquor has been used for the green synthesis of gold and silver nanoparticles (NPs) in a one-step procedure induced by temperature. Most of the biosurfactants proposed in the literature are produced by pathogenic microorganisms; whereas the biosurfactant used in the current work was extracted from a liquid stream, fermented spontaneously by lactic acid bacteria, which are "generally recognized as safe" (GRAS) microorganisms. The reduction of a gold precursor in the presence of a biosurfactant gives rise to a mixture of nanospheres and nanoplates with distinct optical features. Moreover, the growth of nanoplates can be promoted by increasing the reaction temperature to 60 degrees C. In the case of silver, the biosurfactant just induces the formation of pseudo-spherical NPs. The biosurfactant plays a key role in the reduction of the metal precursor, as well as in the stabilization of the resulting NPs. Furthermore, the antimicrobial activity of the resulting silver colloids has been analyzed against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. The biosurfactant stabilized NPs slightly increased the inhibition of E. coli in comparison with citrate stabilized Ag NPs. The use of this biosurfactant extracted from corn steep liquor for the synthesis of metal NPs contributes to enhancing the application of green technologies and increasing the utilization of clean, non toxic and environmentally safe production processes. Therefore, it can help to reduce environmental impact, minimize waste and increase energy efficiency in the field of nanomaterials. PMID- 28587299 TI - Remote Sensing Image Change Detection Based on NSCT-HMT Model and Its Application. AB - Traditional image change detection based on a non-subsampled contourlet transform always ignores the neighborhood information's relationship to the non-subsampled contourlet coefficients, and the detection results are susceptible to noise interference. To address these disadvantages, we propose a denoising method based on the non-subsampled contourlet transform domain that uses the Hidden Markov Tree model (NSCT-HMT) for change detection of remote sensing images. First, the ENVI software is used to calibrate the original remote sensing images. After that, the mean-ratio operation is adopted to obtain the difference image that will be denoised by the NSCT-HMT model. Then, using the Fuzzy Local Information C means (FLICM) algorithm, the difference image is divided into the change area and unchanged area. The proposed algorithm is applied to a real remote sensing data set. The application results show that the proposed algorithm can effectively suppress clutter noise, and retain more detailed information from the original images. The proposed algorithm has higher detection accuracy than the Markov Random Field-Fuzzy C-means (MRF-FCM), the non-subsampled contourlet transform Fuzzy C-means clustering (NSCT-FCM), the pointwise approach and graph theory (PA GT), and the Principal Component Analysis-Nonlocal Means (PCA-NLM) denosing algorithm. Finally, the five algorithms are used to detect the southern boundary of the Gurbantunggut Desert in Xinjiang Uygur Autonomous Region of China, and the results show that the proposed algorithm has the best effect on real remote sensing image change detection. PMID- 28587298 TI - Serotype-Specific Killing of Large Cell Carcinoma Cells by Reovirus. AB - Reovirus is under development as a therapeutic for numerous types of cancer. In contrast to other oncolytic viruses, the safety and efficacy of reovirus have not been improved through genetic manipulation. Here, we tested the oncolytic capacity of recombinant strains (rs) of prototype reovirus laboratory strains T1L and T3D (rsT1L and rsT3D, respectively) in a panel of non-small cell lung cancer (NSCLC) cell lines. We found that rsT1L was markedly more cytolytic than rsT3D in the large cell carcinoma cell lines tested, whereas killing of adenocarcinoma cell lines was comparable between rsT1L and rsT3D. Importantly, non-recombinant T1L and T3D phenocopied the kinetics and magnitude of cell death induced by recombinant strains. We identified gene segments L2, L3, and M1 as viral determinants of strain-specific differences cell killing of the large cell carcinoma cell lines. Together, these results indicate that recombinant reoviruses recapitulate the cell killing properties of non-recombinant, tissue culture-passaged strains. These studies provide a baseline for the use of reverse genetics with the specific objective of engineering more effective reovirus oncolytics. This work raises the possibility that type 1 reoviruses may have the capacity to serve as more effective oncolytics than type 3 reoviruses in some tumor types. PMID- 28587301 TI - Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach. AB - The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a 'plant radiation biodosimeter', that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions. PMID- 28587300 TI - The 5' and 3' Untranslated Regions of the Flaviviral Genome. AB - Flaviviruses are enveloped arthropod-borne viruses with a single-stranded, positive-sense RNA genome that can cause serious illness in humans and animals. The 11 kb 5' capped RNA genome consists of a single open reading frame (ORF), and is flanked by 5' and 3' untranslated regions (UTR). The ORF is a polyprotein that is processed into three structural and seven non-structural proteins. The UTRs have been shown to be important for viral replication and immune modulation. Both of these regions consist of elements that are essential for genome cyclization, resulting in initiation of RNA synthesis. Genome mutation studies have been employed to investigate each component of the essential elements to show the necessity of each component and its role in viral RNA replication and growth. Furthermore, the highly structured 3'UTR is responsible for the generation of subgenomic flavivirus RNA (sfRNA) that helps the virus evade host immune response, thereby affecting viral pathogenesis. In addition, changes within the 3'UTR have been shown to affect transmissibility between vector and host, which can influence the development of vaccines. PMID- 28587304 TI - Node Scheduling Strategies for Achieving Full-View Area Coverage in Camera Sensor Networks. AB - Unlike conventional scalar sensors, camera sensors at different positions can capture a variety of views of an object. Based on this intrinsic property, a novel model called full-view coverage was proposed. We study the problem that how to select the minimum number of sensors to guarantee the full-view coverage for the given region of interest (ROI). To tackle this issue, we derive the constraint condition of the sensor positions for full-view neighborhood coverage with the minimum number of nodes around the point. Next, we prove that the full view area coverage can be approximately guaranteed, as long as the regular hexagons decided by the virtual grid are seamlessly stitched. Then we present two solutions for camera sensor networks in two different deployment strategies. By computing the theoretically optimal length of the virtual grids, we put forward the deployment pattern algorithm (DPA) in the deterministic implementation. To reduce the redundancy in random deployment, we come up with a local neighboring optimal selection algorithm (LNSA) for achieving the full-view coverage. Finally, extensive simulation results show the feasibility of our proposed solutions. PMID- 28587305 TI - An Approach to Speed up Single-Frequency PPP Convergence with Quad-Constellation GNSS and GIM. AB - The single-frequency precise point positioning (PPP) technique has attracted increasing attention due to its high accuracy and low cost. However, a very long convergence time, normally a few hours, is required in order to achieve a positioning accuracy level of a few centimeters. In this study, an approach is proposed to accelerate the single-frequency PPP convergence by combining quad constellation global navigation satellite system (GNSS) and global ionospheric map (GIM) data. In this proposed approach, the GPS, GLONASS, BeiDou, and Galileo observations are directly used in an uncombined observation model and as a result the ionospheric and hardware delay (IHD) can be estimated together as a single unknown parameter. The IHD values acquired from the GIM product and the multi GNSS differential code bias (DCB) product are then utilized as pseudo-observables of the IHD parameter in the observation model. A time varying weight scheme has also been proposed for the pseudo-observables to gradually decrease its contribution to the position solutions during the convergence period. To evaluate the proposed approach, datasets from twelve Multi-GNSS Experiment (MGEX) stations on seven consecutive days are processed and analyzed. The numerical results indicate that the single-frequency PPP with quad-constellation GNSS and GIM data are able to reduce the convergence time by 56%, 47%, 41% in the east, north, and up directions compared to the GPS-only single-frequency PPP. PMID- 28587303 TI - The Role of Lipid and Lipoprotein Metabolism in Non-Alcoholic Fatty Liver Disease. AB - Due to the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD) has become one of the most prevalent chronic liver disorders in children and adolescents. NAFLD comprises a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. The mechanism of the liver injury in NAFLD is currently thought to be a "multiple-hit process" where the first "hit" is an increase in liver fat, followed by multiple additional factors that trigger the inflammatory activity. At the onset of disease, NAFLD is characterized by hepatic triglyceride accumulation and insulin resistance. Liver fat accumulation is associated with increased lipotoxicity from high levels of free fatty acids, free cholesterol and other lipid metabolites. As a consequence, mitochondrial dysfunction with oxidative stress and production of reactive oxygen species and endoplasmic reticulum stress-associated mechanisms, are activated. The present review focuses on the relationship between intra-cellular lipid accumulation and insulin resistance, as well as on lipid and lipoprotein metabolism in NAFLD. PMID- 28587302 TI - The Functions of MicroRNA-200 Family in Ovarian Cancer: Beyond Epithelial Mesenchymal Transition. AB - The majority of studies on microRNA-200 family members (miR-200s) in human cancers are based on the premise that miR-200s maintain epithelial cell integrity by suppressing epithelial-mesenchymal transition (EMT) through direct inhibition of mesenchymal transcription factors zinc finger E-box-binding homeobox 1/2 (ZEB1/ZEB2) and transforming growth factor-beta (TGF-beta), a potent inducer of EMT. Hence, downregulation of miR-200 in cancer cells promotes EMT and cancer metastasis. Yet, miR-200s are highly expressed in ovarian cancer, and ovarian cancer metastasizes primarily by dissemination within the pelvic cavity. In this review, we will refocus the epithelial property of ovarian cancer cells and the role of miR-200s in safeguarding this property, as well as the diverse roles of miR-200s in inclusion cyst formation, cancer cell growth, collective movement, angiogenesis, exosome-mediated cell communication, and chemoresponse. Taken together, miR-200s play a significant role in the initiation, progression and metastasis of ovarian cancer and may serve as diagnostic biomarkers and a target in therapeutic development. PMID- 28587306 TI - Correction: Moreno, A., et al. Design of a Cooperative ITS Architecture Based on Distributed RSUs. AB - n/a. PMID- 28587307 TI - Improved Short-Term Clock Prediction Method for Real-Time Positioning. AB - The application of real-time precise point positioning (PPP) requires real-time precise orbit and clock products that should be predicted within a short time to compensate for the communication delay or data gap. Unlike orbit correction, clock correction is difficult to model and predict. The widely used linear model hardly fits long periodic trends with a small data set and exhibits significant accuracy degradation in real-time prediction when a large data set is used. This study proposes a new prediction model for maintaining short-term satellite clocks to meet the high-precision requirements of real-time clocks and provide clock extrapolation without interrupting the real-time data stream. Fast Fourier transform (FFT) is used to analyze the linear prediction residuals of real-time clocks. The periodic terms obtained through FFT are adopted in the sliding window prediction to achieve a significant improvement in short-term prediction accuracy. This study also analyzes and compares the accuracy of short-term forecasts (less than 3 h) by using different length observations. Experimental results obtained from International GNSS Service (IGS) final products and our own real-time clocks show that the 3-h prediction accuracy is better than 0.85 ns. The new model can replace IGS ultra-rapid products in the application of real time PPP. It is also found that there is a positive correlation between the prediction accuracy and the short-term stability of on-board clocks. Compared with the accuracy of the traditional linear model, the accuracy of the static PPP using the new model of the 2-h prediction clock in N, E, and U directions is improved by about 50%. Furthermore, the static PPP accuracy of 2-h clock products is better than 0.1 m. When an interruption occurs in the real-time model, the accuracy of the kinematic PPP solution using 1-h clock prediction product is better than 0.2 m, without significant accuracy degradation. This model is of practical significance because it solves the problems of interruption and delay in data broadcast in real-time clock estimation and can meet the requirements of real-time PPP. PMID- 28587308 TI - Two-Dimensional DOA Estimation for Coherently Distributed Sources with Symmetric Properties in Crossed Arrays. AB - In this paper, a novel algorithm is proposed for the two-dimensional (2D) central direction-of-arrival (DOA) estimation of coherently distributed (CD) sources. Specifically, we focus on a centro-symmetric crossed array consisting of two uniform linear arrays (ULAs). Unlike the conventional low-complexity methods using the one-order Taylor series approximation to obtain the approximate rotational invariance relation, we first prove the symmetric property of angular signal distributed weight vectors of the CD source for an arbitrary centrosymmetric array, and then use this property to establish two generalized rotational invariance relations inside the array manifolds in the two ULAs. Making use of such relations, the central elevation and azimuth DOAs are obtained by employing a polynomial-root-based search-free approach, respectively. Finally, simple parameter matching is accomplished by searching for the minimums of the cost function of the estimated 2D angular parameters. When compared with the existing low-complexity methods, the proposed algorithm can greatly improve estimation accuracy without significant increment in computation complexity. Moreover, it performs independently of the deterministic angular distributed function. Simulation results are presented to illustrate the performance of the proposed algorithm. PMID- 28587309 TI - Dynamics of Hierarchical Urban Green Space Patches and Implications for Management Policy. AB - Accurately quantifying the variation of urban green space is the prerequisite for fully understanding its ecosystem services. However, knowledge about the spatiotemporal dynamics of urban green space is still insufficient due to multiple challenges that remain in mapping green spaces within heterogeneous urban environments. This paper uses the city of Hangzhou to demonstrate an analysis methodology that integrates sub-pixel mapping technology and landscape analysis to fully investigate the spatiotemporal pattern and variation of hierarchical urban green space patches. Firstly, multiple endmember spectral mixture analysis was applied to time series Landsat data to derive green space coverage at the sub-pixel level. Landscape metric analysis was then employed to characterize the variation pattern of urban green space patches. Results indicate that Hangzhou has experienced a significant loss of urban greenness, producing a more fragmented and isolated vegetation landscape. Additionally, a remarkable amelioration of urban greenness occurred in the city core from 2002 to 2013, characterized by the significant increase of small-sized green space patches. The green space network has been formed as a consequence of new urban greening strategies in Hangzhou. These strategies have greatly fragmented the built-up areas and enriched the diversity of the urban landscape. Gradient analysis further revealed a distinct pattern of urban green space landscape variation in the process of urbanization. By integrating both sub-pixel mapping technology and landscape analysis, our approach revealed the subtle variation of urban green space patches which are otherwise easy to overlook. Findings from this study will help us to refine our understanding of the evolution of heterogeneous urban environments. PMID- 28587310 TI - Viral Encephalitis of Unknown Cause: Current Perspective and Recent Advances. AB - Viral encephalitis causes acute inflammation of the brain parenchyma and is a significant cause of human morbidity and mortality. Although Herpes Simplex encephalitis is the most frequent known cause of fatal sporadic encephalitis in humans, an increasingly wide range of viruses and other microbial pathogens are implicated. Up to 60% of cases of presumed viral encephalitis remain unexplained due to the failure of conventional laboratory techniques to detect an infectious agent. High-throughput DNA sequencing technologies have the potential to detect any microbial nucleic acid present in a biological specimen without any prior knowledge of the target sequence. While there remain challenges intrinsic to these technologies, they have great promise in virus discovery in unexplained encephalitis. PMID- 28587311 TI - Genetic Variation Controlling Wrinkled Seed Phenotypes in Pisum: How Lucky Was Mendel? AB - One of the traits studied by Mendel in pea (Pisum sativum L.) was the wrinkled seeded phenotype, and the molecular basis for a mutation underlying this phenotype was discovered in the 1990s. Although the starch-branching enzyme gene mutation identified at the genetic locus r is most likely to be that in seeds available to Mendel in the mid-1800s, it has remained an open question as to whether or not additional natural mutations in this gene exist within Pisum germplasm collections. Here, we explore this question and show that all but two wrinkled-seeded variants in one such collection correspond to either the mutant allele described previously for the r locus or a mutation at a second genetic locus, rb, affecting the gene encoding the large subunit of Adenosine diphosphoglucose (ADP-glucose) pyrophosphorylase; the molecular basis for the rb mutation is described here. The genetic basis for the phenotype of one (JI 2110) of the two lines which are neither r nor rb has been studied in crosses with a round-seeded variant (JI 281); for which extensive genetic marker data were expected. In marked contrast to the trait studied by Mendel and the rb phenotype; the data suggest that the wrinkled-seeded phenotype in JI 2110 is maternally determined, controlled by two genetic loci, and the extent to which it is manifested is very sensitive to the environment. Metabolite analysis of the cotyledons of JI 2110 revealed a profile for sucrose and sucrose-derived compounds that was more similar to that of wild-type round-seeded, than that of wrinkled-seeded r, pea lines. However, the metabolite profile of the seed coat (testa) of JI 2110 was distinct from that of other round-seeded genotypes tested which, together with analysis of recombinant inbred progeny lines, suggests an explanation for the seed phenotype. PMID- 28587312 TI - Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome. AB - Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors. PMID- 28587313 TI - MicroRNA-223-3p Regulates Ovarian Cancer Cell Proliferation and Invasion by Targeting SOX11 Expression. AB - MicroRNAs (miRNAs) often display different expression in many cancers and other diseases in current research studies. miR-223 expression is upregulated in rheumatoid arthritis. Also, miR-223 expression has been demonstrated to be highly expressed in pancreatic cancer and gastric cancer in comparison with normal tissue. However, whether miR-223 displays different expression in ovarian cancer and what its underlying functions are in ovarian cancer have remained unclear. In this study, we demonstrated that miR-223-3p was upregulated in ovarian cancer tissue. Next, we explored the functional role of miR-223-3p in ovarian cancer using SKOV3 and OVCAR3 cell lines. Our results suggested that miR-223-3p mimic promoted ovarian cancer cell proliferation, migration, and invasion in vitro. However, miR-223-3p inhibitor displayed the opposite effects. In addition, we demonstrated that miR-223-3p mimic promoted tumor growth in vivo. Furthermore, we found SOX11 (sex determining region Y-box 11) was inversely expressed with miR 223-3p in ovarian cancer (OC) cell lines and tissue specimens. miR-223-3p mimic decreased SOX11 expression. Overexpressing SOX11 inhibited ovarian cancer cell proliferation and invasion, which indicated that miR-223-3p regulated OC cell proliferation and invasion through targeting SOX11 expression. In conclusion, the findings of the present study demonstrated that miR-223-3p could be a potential therapeutic for ovarian cancer. PMID- 28587314 TI - Cellular Morphology-Mediated Proliferation and Drug Sensitivity of Breast Cancer Cells. AB - The interpretation of the local microenvironment of the extracellular matrix for malignant tumor cells is in intimate relation with metastatic spread of cancer cells involving the associated issues of cellular proliferation and drug responsiveness. This study was aimed to assess the combination of both surface topographies (fiber alignments) and different stiffness of the polymeric substrates (poly(l-lactic acid) and poly(epsilon-caprolactone), PLLA and PCL, respectively) as well as collagen substrates (coat and gel) to elucidate the effect of the cellular morphology on cellular proliferation and drug sensitivities of two different types of breast cancer cells (MDA-MB-231 and MCF 7). The morphological spreading parameter (nucleus/cytoplasm area ratio) induced by the anthropogenic substrates has correlated intimately with the cellular proliferation and the drug sensitivity the half maximal inhibitory concentration (IC50) of cancer cells. This study demonstrated the promising results of the parameter for the evaluation of cancer cell malignancy. PMID- 28587315 TI - Getting to Know a Place: Built Environment Walkability and Children's Spatial Representation of Their Home-School (h-s) Route. AB - The literature on environmental walkability to date has mainly focused on walking and related health outcomes. While previous studies suggest associations between walking and spatial knowledge, the associations between environmental walkability and spatial knowledge is yet to be explored. The current study addresses this lacuna in research by exploring children's mental representations of their home school (h-s) route, vis. PMID- 28587317 TI - Designed Synthesis of Nanostructured Magnetic Hydroxyapatite Based Drug Nanocarrier for Anti-Cancer Drug Delivery toward the Treatment of Human Epidermoid Carcinoma. AB - Superparamagnetic Fe3O4 nanoparticles on hydroxyapatite nanorod based nanostructures (Fe3O4/HAp) were synthesized using hydrothermal techniques at 180 degrees C for 12 h and were used as drug delivery nanocarriers for cancer cell therapeutic applications. The synthesized Fe3O4/HAp nanocomposites were characterized by X-ray diffraction analysis (XRD), Field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET)-analysis, and vibrating sample magnetometry (VSM). The morphologies of the Fe3O4/HAp nanocomposites show 15 nm Fe3O4 nanoparticles dispersed in the form of rods. The BET result shows that the synthesized samples have a high specific surface area of 80 m2 g-1 with mesoporous structures. Magnetic measurements revealed that the sample has high saturation magnetization of 18 emu/g with low coercivity. The Fe3O4/HAp nanocomposites had a large specific surface area (SSA), high mesoporous volume, and good magnetic property, which made it a suitable nanocarrier for targeted drug delivery systems. The chemotherapeutic agent, andrographolide, was used to investigate the drug delivery behavior of the Fe3O4/HAp nanocomposites. The human epidermoid skin cancer cells (A431) were used as the model targeting cell lines by treating with andrographolide loaded Fe3O4/HAp nanosystems and were further evaluated for their antiproliferative activities and the induction of apoptosis. Also, the present nanocomposite shows better biocompatibility, therefore it can be used as suitable drug vehicle for cancer therapy applications. PMID- 28587318 TI - Risk Assessment of Face Skin Exposure to UV Irradiance from Different Rotation Angle Ranges. AB - Ultraviolet (UV) is one of the environmental pathogenic factors causing skin damage. Aiming to assess the risk of face skin exposure to UV irradiance from different rotation angles, a rotating model was used to monitor the exposure of the skin on the face to UV irradiance, with skin damage action spectra used to determine the biologically effective UV irradiance (UVBEskin) and UVBEskin radiant exposure (HBEskin) causing skin damage. The results indicate that the UVBEskin is directly influenced by variations in rotation angles. A significant decrease of approximately 52.70% and 52.10% in UVBEskin was found when the cheek and nose measurement sites was rotated from 0 degrees to 90 degrees , while a decrease of approximately 62.70% was shown when the forehead measurement sites was rotated from an angle of 0 degrees to 108 degrees . When HBEskin was compared to the exposure limits (ELs; 30 J.m-2), the maximum relative risk ratios (RR) for cheek, nose, and forehead were found to be approximately 2.01, 2.40, and 2.90, respectively, which were all measured at a rotation angle of 0 degrees . The maximal increase in the percentage of the average HBEskin for rotation angles of 60 degrees , 120 degrees , 180 degrees , and 360 degrees facing the sun to ELs were found to be approximately 62.10%, 52.72%, 43.43%, and 26.27% for the cheek; approximately 130.61%, 109.68%, 86.43%, and 50.06% for the nose; and approximately 178.61%, 159.19%, 134.38%, and 83.41% for the forehead, respectively. PMID- 28587319 TI - Seawater-drowning-induced acute lung injury: From molecular mechanisms to potential treatments. AB - Drowning is a crucial public safety problem and is the third leading cause of accidental fatality, claiming ~372,000 lives annually, worldwide. In near drowning patients, acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is one of the most common complications. Approximately 1/3 of near drowning patients fulfill the criteria for ALI or ARDS. In the present article, the current literature of near-drowning, pathophysiologic changes and the molecular mechanisms of seawater-drowning-induced ALI and ARDS was reviewed. Seawater is three times more hyperosmolar than plasma, and following inhalation of seawater the hyperosmotic seawater may cause serious injury in the lung and alveoli. The perturbing effects of seawater may be primarily categorized into insufficiency of pulmonary surfactant, blood-air barrier disruption, formation of pulmonary edema, inflammation, oxidative stress, autophagy, apoptosis and various other hypertonic stimulation. Potential treatments for seawater-induced ALI/ARDS were also presented, in addition to suggestions for further studies. A total of nine therapeutic strategies had been tested and all had focused on modulating the over-activated immunoreactions. In conclusion, seawater drowning is a complex injury process and the exact mechanisms and potential treatments require further exploration. PMID- 28587316 TI - Bacteria from Animals as a Pool of Antimicrobial Resistance Genes. AB - Antimicrobial agents are used in both veterinary and human medicine. The intensive use of antimicrobials in animals may promote the fixation of antimicrobial resistance genes in bacteria, which may be zoonotic or capable to transfer these genes to human-adapted pathogens or to human gut microbiota via direct contact, food or the environment. This review summarizes the current knowledge of the use of antimicrobial agents in animal health and explores the role of bacteria from animals as a pool of antimicrobial resistance genes for human bacteria. This review focused in relevant examples within the ESC(K)APE (Enterococcus faecium, Staphylococcus aureus, Clostridium difficile (Klebsiella pneumoniae), Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae) group of bacterial pathogens that are the leading cause of nosocomial infections throughout the world. PMID- 28587320 TI - Distribution characteristics of Staphylococcus spp. in different phases of periprosthetic joint infection: A review. AB - Periprosthetic joint infection (PJI) is a devastating condition and Staphylococcus spp. are the predominant pathogens responsible, particularly coagulase-negative staphylococci (CoNS) and Staphylococcus aureus. The aim of the present systematic review was to evaluate the distribution characteristics of specific Staphylococcus spp. in different PJI phases, reveal the effect of pathogens' feature on their distribution and suggest recommendations for antibiotic treatment of Staphylococcal PJI. The present systematic review was performed using PubMed and EMBASE databases with the aim to identify existing literature that presented the spectrum of Staphylococcus spp. that occur in PJI. Once inclusion and exclusion criteria were applied, 20 cohort studies involving 3,344 cases in 3,199 patients were included. The predominant pathogen involved in PJI was indicated to be CoNS (31.2%), followed by S. aureus (28.8%). This trend was more apparent in hip replacement procedures. In addition, almost equal proportions of CoNS and S. aureus (28.6 and 30.0%, respectively) were indicated in the delayed phase. CoNS (36.6%) were the predominant identified organism in the early phase, whereas S. aureus (38.3%) occurred primarily in the late phase. In PJI caused by S. aureus, the number of cases of methicillin-sensitive Staphylococcus aureus (MSSA) was ~2.5-fold greater than that of methicillin resistant Staphylococcus aureus (MRSA). MRSA occurred predominantly in the early phase, whereas MSSA was largely observed in the delayed and late phases. With regards to antibiotic treatment, the feature of various pathogens and the phases of PJI were the primary considerations. The present review provides useful information for clinical practice and scientific research of PJI. PMID- 28587321 TI - Clinical evaluation of CENP-B and Scl-70 autoantibodies in silicosis patients. AB - Silicosis patients (SIL) suffer from respiratory disorders and dysregulation of autoimmunity. Frequent complications such as rheumatoid arthritis, systemic sclerosis (SSc) and vasculitis are known in SIL. Furthermore, we reported previously that some SIL exhibited better respiratory conditions in association with a worse immunological status. In this study, the clinical roles of anti-CENP B and Scl-70 autoantibodies in SIL were analyzed. The titer index (Log10) of anti CENP-B autoantibody in SIL was higher than that of healthy volunteers (HV), and that of SSc was higher than those of HV and SIL. This titer index was positively correlated with an assumed immune status of 1 for HV, 2 for SIL, and 3 for SSc. Moreover, although factor analysis revealed that the titer index of the anti-CENP B autoantibody formed the same factor with the anti-Scl-70 autoantibody, IgG value and age in SIL cases, another extracted factor indicated that the IgA value and anti-Scl-70 antibody were positively related, but anti-CENP-B showed an opposite pattern in the results of the factor analysis. These findings indicated that the titer index of anti-CENP-B autoantibody may be a biomarker for dysregulation in SIL cases. Future clinical follow-up of SIL may therefore require both respiratory and immunological assessment. PMID- 28587322 TI - Novel variant in the FGD1 gene causing Aarskog-Scott syndrome. AB - Aarskog-Scott syndrome (ASS) is a rare, X-linked recessive inherited disorder. Affected individuals may develop short stature and exhibit distinctive skeletal and genital development. Mutations in the FYVE, rhogef and pleckstrin homology domain-containing protein 1 (FGD1) gene, located within the Xp11.21 region, are responsible for the occurrence of ASS. Since it is rare and complex, it can take a long time to obtain a definitive clinical diagnosis unless clinicians are familiar with the disease. In the present study, whole-exome sequencing (WES) was performed to screen for causal variants in a Chinese pediatric patient who exhibited a number of clinical symptoms of ASS, including short stature, facial abnormalities, stubby metacarpals and swollen testis. DNA sequencing revealed a novel c.1270 A>G mutation in exon 6 of the FGD1 gene, which led to an amino acid conversion of asparagine to aspartic acid on codon 424 and in silico analysis indicated that this novel missense mutation was pathogenic. The present study identified a novel variant of the FGD1 gene and to the best of our knowledge, is the first report of ASS in a Chinese individual. The results indicated that WES is an effective tool for the diagnosis of rare and complex syndromes such as ASS. PMID- 28587323 TI - Clinical relevance of gemstone spectral CT in the diagnosis of carotid atherosclerosis. AB - A variety of imaging methods can be used in the diagnosis of atherosclerotic plaques. In the present study, we investigated the morphology and composition of atherosclerotic plaque associated with ischemic cerebral infarction by comparing gemstone spectral computed tomography (GSCT) and traditional multi-slice CT (MSCT). In total, 200 patients were enrolled and divided into the experimental group (n=100), which underwent GSCT, and the control group (n=100), which underwent MSCT. All the cases were followed up to observe disease outcomes in patients with different atherosclerotic plaque types, and adverse events in carotid artery stenosis or cerebral infarction were recorded. Compared with traditional MSCT, sensitivity (93.2%), specificity (84.5%), and accuracy (91.0%) of GSCT were significantly higher. We found a correlation between vulnerable plaque of carotid atherosclerotic plaque and the occurrence of cerebral infarction. These results suggest the advantages of GSCT in analyzing atherosclerotic plaque and predicting the risk of ischemic cerebral infarction. PMID- 28587324 TI - In vitro activity of chlorogenic acid against Aspergillus fumigatus biofilm and gliotoxin production. AB - Aspergillus (A.) fumigatus, one of the most common causes of life-threatening fungal infections in immunocompromised patients, shows resistance to antifungal agents as has a high propensity to forming a biofilm. The present study aimed to investigate the effects of chlorogenic acid (CRA) on A. fumigatus biofilm formation and integrity. Confocal laser scanning microscopy was performed to determine the inhibitory effects of CRA against A. fumigatus biofilm formation. Transmission electron microscopy was performed to investigate the ultrastructural changes of A. fumigatus biofilm after CRA exposure. High-performance liquid chromatography and reverse-transcription quantitative PCR were performed to determine the expression of gliotoxin production in biofilm culture. The results showed that CRA at sub-minimum inhibitory concentrations inhibited A. fumigatus biofilm formation. In addition, CRA could decreased the gliotoxin production in the biofilm culture supernatant through inhibiting the expression of master genes involved in gliotoxin biosynthesis. The present study provided useful information for the development of novel strategies to reduce the incidence of A. fumigatus biofilm-associated diseases. PMID- 28587325 TI - Sildenafil suppresses the proliferation and enhances the apoptosis of hemangioma endothelial cells. AB - Treatment of infantile hemangiomas (IH) with propranolol was first reported in 2008. Regressions of lymphatic malformations combined with pulmonary hypertension was first reported in 2012 after three children received treatment with oral sildenafil, which serves as an antagonist of phosphodiesterase isoform-5 (PDE-5). A marked expression of endothelial cells in the cytoplasm of IH tissues was obtained in our previous study. Therefore, the present study hypothesized that the antagonist of PDE-5, sildenafil, may lead to the regression of hemangiomas. To assess this hypothesis, the proliferation and apoptosis of specimen-derived hemangioma endothelial cells (HemECs) was determined in vitro by an MTT assay and flow cytometry, respectively, following treatment with sildenafil. The potential mechanisms underlying the mRNA and protein expression levels of inhibitor of differentiation 1 (Id-1) were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that 5 uM sildenafil suppressed the proliferation of HemECs and significantly enhanced the rate of apoptosis after 24 h. Additionally, the mRNA and protein expression levels of Id-1 were downregulated following treatment with sildenafil. Therefore, the present study concluded that PDE-5 may be a potential therapeutic target for hemangiomas and Id-1 may serve a vital role in the associated signaling transduction pathways. PMID- 28587326 TI - Degradation of Mg-6Zn alloy stents does not influence the healing of the common bile duct in vivo. AB - To investigate the effects of Mg-6Zn alloy on the healing of the common bile duct (CBD), Mg-6Zn alloy stents were implanted into the CBDs of rabbits. Stainless steel stents were transplanted into a second group of rabbits to serve as a control. Computed tomography (CT) scanning was performed and weight loss was recorded to evaluate the in vivo degradation process. Hematoxylin and eosin staining and immunohistochemical analyses were performed to determine the expressions of transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) and evaluate CBD healing. The Mg-6Zn stents maintained ~82 and ~50% of the original length, and ~90 and ~43% of the original CT value at 1 and 2 weeks post-operatively, respectively. The residual weights of the Mg-6Zn stents were ~89, ~42 and ~9% of the original weights at 1, 2 and 3 weeks post-operatively, respectively. At 3 weeks post surgery, the CBD was completely healed, with no wounds observed in the 3 groups. VEGF expression in the Mg-6Zn stent group was lower than that in the stainless steel stent group at 3 weeks post-surgery (P=0.002). No significant differences were observed between the mean expressions of the TGF-beta1 and bFGF genes at 1 and 2 weeks post-surgery. The results of the present study suggest that degradation of the Mg-6Zn alloy may not affect healing of the CBD. PMID- 28587327 TI - Microarray profiling of long non-coding RNAs associated with idiopathic pulmonary arterial hypertension. AB - Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with a poor prognosis and the molecular pathways underlying the pathogenesis of IPAH are not fully understood. In the present study, the long non-coding RNA (lncRNA) and mRNA expression profiles of lymphocytes obtained from 12 IPAH patients and 12 healthy controls were analyzed using Arraystar Human lncRNA Microarray v2.0, and their roles in the pathogenesis of IPAH were characterized using comprehensive bioinformatic tools. A total of 2,511 lncRNAs (2,004 upregulated and 507 downregulated) and 1,169 mRNAs (609 upregulated and 560 downregulated) were aberrantly expressed in IPAH patients with a fold-change of >2.0. Gene ontology analysis indicated that the coexpressed lncRNAs and mRNAs were involved in the process of translation, while pathway analysis indicated that the coexpressed RNAs were enriched during the process of oxidative phosphorylation and in the ribosome. It was concluded that dysregulated lncRNAs are potentially associated with IPAH, and aberrant lncRNA expression in blood cells may serve as a diagnostic marker of IPAH. PMID- 28587328 TI - MicroRNA-143 inhibits tumorigenesis in hepatocellular carcinoma by downregulating GATA6. AB - MicroRNAs serve a critical role in human hepatocellular carcinoma (HCC) progression. However, the exact role of microRNA-143 (miR-143) in HCC remains unclear. The current study investigates the molecular mechanism of miR-143 in HCC. In cultured HepG2 and Bel7402 cell lines, miR-143 levels were raised by lentivirus transduction. This significantly inhibited HCC progression in terms of cell invasion and proliferation in both HepG2 and Bel7402 cell lines (P<0.05). MiR-143 also significantly decreased tumor implantation in vivo (P<0.05). Regulation of miR-143 on its direct target, GATA-binding factor 6 (GATA6), was investigated by multiple strategies, including dual-luciferase assay, quantitative polymerase chain reaction and western blot analysis. The results indicated that miR-143 was downregulated in both HCC cell lines and human tumors. GATA6 was identified as the downstream target of miR-143 in HCC, and overexpressing GATA6 was able to counter the tumor-suppressive effect of miR-143 on HCC in HepG2 and Bel7402 cells by significantly increasing proliferation and invasion rates (P<0.05). Therefore, a novel epigenetic pathway was identified in which miR-143 may suppress the malignancy of HCC by targeting GATA6. PMID- 28587329 TI - Mosapride combined with probiotics on gastrointestinal function and growth in premature infants. AB - The aim of this study was to investigate the effects of mosapride combined with probiotics on gastrointestinal function and growth and development in premature infants. A total of 240 premature infants treated at Weifang People's Hospital between June 2012 and May 2015 who matched our criteria were randomly divided into three groups of 80 cases each. Group A received routine treatment, group B received routine treatment combined with live B. subtilis and E. faecium granules with multivitamins (Medilac-Vita), and group C received routine treatment and Saccharomyces boulardii sachets (Bioflor). Mosapride was administered to patients in groups B and C to promote intestinal peristalsis. Gastrin and bilirubin levels, as well as jaundice fade time, were recorded. Growth and development condition (i.e., head circumference and weight), duration and incidence of feeding intolerance (FI), as well as other symptoms were also analyzed. By day 14, gastrin concentrations in groups B and C were significantly higher than those in group A (P<0.05). Serum bilirubin levels in groups B and C showed a progressive decline from day 7 to day 14, and jaundice duration in group A was significantly longer (P<0.05). Furthermore, at 2 weeks, the average weight growth rate and head circumference were significantly greater in groups B and C, weight loss recovery time was shorter, and EUGR incidence was lower (P<0.05). The incidence rate of gastric retention and FI were lower in groups B and C than group A (P<0.05), and neonatal hyperbilirubinemia, parenteral nutrition associated cholestasis, necrotizing enterocolitis, and neonatal sepsis incidence was significantly lower in groups B and C (P<0.05). Mosapride combined with probiotics can effectively reduce FI incidence in premature infants, shorten enteral feeding time, promote the absorption of required nutrients, and promote the development and recovery of early physiological weight loss in preterm infants. PMID- 28587330 TI - Principles of antibiotic application in children with lobar pneumonia: Step-up or step-down. AB - In order to provide a scientific basis for rational use of antibiotics, we studied and compared the therapeutic effects of step-down and step-up antibiotic treatment schemes in children with lobar pneumonia. Eighty cases of children with lobar pneumonia were enrolled in this study and were randomly divided into two groups: The observation group and the control group, with 40 cases in each group. In the observation group, there were 23 cases with mild and 17 cases with severe lobar pneumonia, and in the control group, 25 were mild and 15 were severe cases. Patients in the control group were treated with antibiotics using step-up therapy method, while patients in the observation group were treated using step-down antibiotic therapy. Our results showed no significant differences in white blood cell (WBC) reduction rate, the course of antibiotic treatment, disappearance time of pulmonary rales and total efficiency in children with mild lobar pneumonia in the observation group after 72 h of treatment. The level of high-sensitivity C reactive protein (hs-CRP) and procalcitonin (PCT) in the observation group were significantly lower. After 72 h of treatment of children with severe lobar pneumonia in the observation group, the rate of WBC reduction accelerated significantly. Compared to the patients in the control group, the course of antibiotic treatment and disappearance time of pulmonary rales were shortened significantly, while the total efficiency of treatment was improved considerably in the observation group. Also in the observation group, hs-CRP and PCT levels were significantly lower than that in the control group. In severe cases, step down therapy showed a better result in relieving the inflammatory reactions. The disappearance time of pulmonary rales and the effective rate of treatment was significantly higher than those of step-up therapy. It was obvious that for children with severe lobar pneumonia, step-down therapy produced better results in relieving the inflammatory reaction. PMID- 28587331 TI - Directly reprogramming fibroblasts into adipogenic, neurogenic and hepatogenic differentiation lineages by defined factors. AB - The reprogramming of adult cells into pluripotent cells or directly into alternative adult cell types represents a great potential technology for regenerative medicine. In the present study, the potential of key developmental adipogenic, neurogenic and hepatogenic regulators to reprogram human fibroblasts into adipocytes, neurocytes and hepatocytes was investigated. The results demonstrated that direct reprogramming of octamer-binding transcription factor 4 (Oct4) and CCAAT-enhancer-binding protein (C/EBP)beta activated C/EBPalpha and peroxisome proliferator-activated receptor-gamma expression, inducing the conversion of fibroblasts into adipocytes. Similarly, direct reprogramming of the transcription factors sex determining region-box 2, trans-acting T-cell specific transcription factor (GATA-3) and neurogenic differentiation 1 in fibroblasts may induce neurogenic differentiation through hemagglutinating virus of Japan envelope (HVJ-E) transfection. Moreover, hepatogenic differentiation was induced by combining the direct reprogramming of Oct4, GATA-3, hepatocyte nuclear factor 1 homeobox alpha and forkhead box protein A2 in fibroblasts. These results demonstrate that specific transcription factors and reprogramming factors are able to directly reprogram fibroblasts into adipogenic, neurogenic and hepatogenic differentiation lineages by HVJ-E transfection. PMID- 28587332 TI - Three-dimensional arterial spin labeling imaging and dynamic susceptibility contrast perfusion-weighted imaging value in diagnosing glioma grade prior to surgery. AB - The current study aimed to investigate whole-brain three-dimensional arterial spin labeling imaging (3D ASL) and dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI), in regards to their diagnostic value of preoperative glioma grade. The parameter values obtained after correction will be correlated with the diagnostic value of 3D ASL and DSC-PWI perfusion. In the current study, 50 patients with gliomas confirmed by pathology were used, including 27 low-grade gliomas (LGGs) and 23 high-grade gliomas (HGGs). Prior to surgery all patients underwent 3 Tesla magnetic resonance imaging (MRI), 3D ASL, DSC-PWI and conventional enhanced MRI scans to obtain original 3D ASL and DSC-PWI images, and the tumor regions with the most obvious parenchyma perfusion and contralateral normal white matter were selected. In these areas, the ASL-relative cerebral blood flow (ASL-rCBF), DSC-relative cerebral blood flow (DSC-rCBF) and DSC relative cerebral blood volume (DSC-rCBV) parameter values were then obtained after correction for individual differences. The results of the present study show that ASL-CBF, DSC-CBF, DSC-CBV values and ASL-rCBF, DSC-rCBF, DSC-rCBV values increased as the grade of the glioma being imaged increased, and there was a marked difference between the HGGs and the LGGs. ASL-rCBF was significantly positively correlated with DSC-rCBF (r=0.580, P<0.01). In addition, ASL-rCBF was significantly positively correlated with DSC-rCBV (r=0.431, P<0.01). Receiver operating characteristic (ROC) curves were applied to compare the two perfusion parameters of DSC-PWI and 3D ASL in the diagnosis of glioma grade. ASL-rCBF had the highest area value under the ROC curve (0.836). The areas under the ROC curve of DSC-rCBF and DSC-rCBV were analyzed using the Z test, but the difference was not statistically significant. When ASL-rCBF, DSC-rCBF and DSC-rCBV were cutoff at 2.24, 1.85 and 1.68, the sensitivity of HGG diagnosis was 83.2, 91.3 and 91.3%, and the specificity was 77.7, 63.9 and 66.7%, respectively. PMID- 28587333 TI - Evaluation of the effect of oral administration of collagen peptides on an experimental rat osteoarthritis model. AB - Collagen is an extracellular matrix protein present in the skin, tendon, cartilage and bone. Collagen peptides (CP) are produced by the hydrolysis of gelatin (heat-denatured collagen) by proteases and are utilized as a component of nutraceuticals. The current study investigated the effect of CP on the articular cartilage of OA by evaluating the serum levels of biomarkers (CTX-II for type II collagen degradation and CPII for type II collagen synthesis), histopathological changes (Mankin score, based on the toluidine blue staining of proteoglycans), and immunohistochemical staining of matrix metalloproteinase (MMP)-13 and type II collagen, using a rat experimental osteoarthritis (OA) model. Anterior cruciate ligament transection (ACLT) was performed on the right knee joint to surgically induce OA. Animals were divided into four groups: Control group (Control), sham operated group (Sham), ACLT group without collagen peptide (ACLT group) and ACLT group with oral administration of CP (CP group). ACLT induced histological damages and significantly increased the Mankin score (P<0.05). However, CP administration markedly suppressed the Mankin score, although this difference was not significant. In addition, serum CTX-II levels were significantly decreased in CP group compared with those in the ACLT group (P<0.05). By contrast, serum CPII levels did not differ significantly among the four groups. Moreover, immunohistochemical staining of type II collagen and MMP-13 (an important type II collagen-degrading enzyme) indicated that the amount of type II collagen increased, whereas the number of MMP-13 positive chondrocytes decreased in the CP group compared with ACLT group. These observations suggest that CP has the potential to exert chondroprotective action on OA by inhibiting MMP-13 expression and type II collagen degeneration. PMID- 28587334 TI - Effect of acute peritonitis on rocuronium-induced intraperitoneal pressure reduction and the uptake function of the sarcoplasmic reticulum. AB - Previous studies have reported the incomplete relaxation effect of neuromuscular blockers on skeletal muscles in acute peritonitis (AP) and other inflammatory processes; however, the underlying mechanisms responsible for this effect have not yet been satisfactorily identified. The impaired removal of cytosolic Ca2+ through sarcoendoplasmic Ca2+-ATPase (SERCA) and defects in sarcoplasmic reticulum (SR) Ca2+ uptake are the major contributing factors to diastolic dysfunction. Previous studies on the effects of neuromuscular blockers have primarily focused on neuromuscular transmission. Because of the reduced calcium uptake in the SR itself, even when neuromuscular transmission is fully blocked, the muscle is not able to relax effectively. In the present study, the impact of AP on rocuronium-induced intraperitoneal pressure reduction and rectus abdominal muscle relaxation, and SERCA uptake function was investigated. AP was induced via gastric perforation and changes in the intraperitoneal pressure before and after the administration of rocuronium were recorded. Muscle contractile properties, uptake and release functions and SERCA activity in the rectus abdominal muscles of AP model rats were measured. The half-relaxation time in the AP group was significantly prolonged compared with that in the control group (P<0.01). The peak rate of SR Ca2+ uptake for whole muscle homogenates was significantly reduced (P<0.05) in AP model rats without reduction of the rate of Ca2+ release evoked through AgNO3. In conclusion, gastric perforation-induced AP attenuates the intraperitoneal pressure-reducing effect of rocuronium, and AP induces diastolic dysfunction of the rectus abdominal muscle. The SR Ca2+-ATPase uptake rate was also reduced by AP. PMID- 28587336 TI - Effects of polyvinylpyrrolidone-iodine on tendon-bone healing in a rabbit extra articular model. AB - Polyvinylpyrrolidone-iodine (PVP-I) is a broad-spectrum antimicrobial agent, but its effects on tendon-bone healing are unclear. The purpose of this study was to investigate the effects of PVP-I on bone marrow mesenchymal stem cells (BMSCs) in vitro and on tendon-bone healing in vivo. In this study, following investigation of the concentration-dependent effects of PVP-I on the viability and osteogenic differentiation of BMSCs, the appropriate concentration of PVP-I was selected for animal experiments. New Zealand white rabbits received autologous tendon transplantation with and without PVP-I treatment of the graft tendon. Subsequently, histological examination, biomechanical testing and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analyses were conducted. At 6 weeks post-surgery, connective tissue and osteogenesis was observed at the tendon-bone interface in the PVP-I group. At 12 weeks post surgery, the interface width in the PVP-I group was much narrower compared with that of the control group. Furthermore, the biomechanical properties of the PVP-I group were significantly stronger than those in the control group (P<0.05). RT qPCR examination revealed that the mRNA levels of bone morphogenetic protein-2 and osteopontin in the PVP-I group were higher than those in the control group at 6 weeks (P<0.05). In conclusion, these results indicated that PVP-I promoted tendon-bone healing via osteogenesis. PMID- 28587335 TI - Sex-related differences of urethane and sodium valproate effects on Ki-67 expression in urethane-induced lung tumors of mice. AB - The aim of the present study was to evaluate sex differences in tumorigenesis by assessing the number of Ki-67-positive cells [Ki-67(+)] in urethane-induced mice lung tumors and the effect of sodium valproate (NaVP) in BALB/c mice. Gonad intact and gonadectomized female and male mice were divided into the following groups: i) Treated with urethane, ii) treated with urethane and NaVP and iii) gonad-intact or gonadectomized control. Urethane (total 50 mg/mouse) was injected intraperitoneally. The NaVP 0.4% solution was administered orally for 6 months. Histologically, lung tumors were divided into adenomas and adenocarcinomas and assessed immunohistochemically using antibodies against Ki-67. The Ki-67(+) was calculated per one mm2 of a tumor. In adenomas, Ki-67(+) in the urethane-treated gonad-intact males was significantly higher than in females (P=0.001) and in castrated males (P<0.01); Ki-67(+) in adenomas of the urethane-treated gonad intact males was significantly higher than in urethane-NaVP-treated ones (P<0.04). No significant differences were found in analogous female groups. In adenocarcinomas, Ki-67(+) in urethane-treated gonad-intact males was significantly higher than in females and gonadectomized mice of both sexes (P<0.001), and in ovariectomized females was significantly higher than in ovary intact group (P=0.01). A significantly higher number of Ki-67(+) cells were observed in gonad-intact adenocarcinomas of the urethane-NaVP-treated females compared with the urethane-treated ones (P<0.001). Comparing between urethane NaVP-treated gonadectomized males and females in adenocarcinomas, determined that Ki-67(+) was significantly lower in females (P=0.005). In adenocarcinomas, Ki 67(+) in urethane-NaVP-treated gonadectomized males and females was significantly lower than in gonad-intact mice of the same sex (P<0.001). In summary, gonadectomy with NaVP treatment decreased Ki-67(+) in adenocarcinomas for mice of both sexes. The results of the present study indicate sex-related differences in mice lung tumorigenesis, and a sex-related effect of NaVP on progression in urethane-induced BALB/c mice lung tumors. PMID- 28587337 TI - Effect of adiponectin on macrophage reverse cholesterol transport in adiponectin /- mice and its mechanism. AB - The objective of the present study was to investigate the effect of adiponectin (APN) on macrophage reverse cholesterol transport (RCT) in adiponectin-/- knockout mice (APN-/-mice) and its possible anti-atherosclerotic mechanism. A total of 30 male APN-/-mice were randomly divided into the control group and four intervention groups. The intervention groups were treated with intraperitoneal injections of APN, at doses of 50, 150, 200 and 250 ug/(kg/day), respectively, for 4 weeks. The control group received normal saline. After 4 weeks, serum lipid levels were measured, the degree of severity of atherosclerotic lesions was observed by light microscopy, the 3H-TC (APN-/-mice treated with intraperitoneal injections of 3H-TC-labeled macrophages) radioactivity in serum, liver, and feces, and the expression of ABCA1 mRNA and protein in liver were determined. Compared with the control group, serum triglycerides, total cholesterol, and low density lipoproteins levels in the intervention groups were significantly decreased, while high-density lipoprotein was increased. The severity of aortic atherosclerotic lesions in the intervention groups was milder than in the control group, which had obvious aortic atherosclerotic lesions, large lipid deposition on vessel walls, and the formation of atheromatous plaques. In the intervention groups, serum 3H-TC content was significantly decreased (P<0.05), but the 3H-TC content in liver and feces was significantly increased (P<0.05). The levels of ABCA1 mRNA in liver of the intervention groups were significantly increased in a dose-dependent manner. In conclusion, APN can promote RCT and intracellular cholesterol efflux by upregulating the expression of ABCA1, to delay the occurrence and development of atherosclerosis. PMID- 28587338 TI - Mediation of insulin growth factor-1 in Alzheimer's disease and the mechanism of PRNP genetic expression and the PI3K/Akt signaling pathway. AB - The aim of the study was to examine the mediation of insulin growth factor-1 (IGF 1) in Alzheimer's disease (AD), as well as the underlying mechanism of the PRNP genetic expression and PI3K/Akt signaling pathway. The Abeta25-35-incubated rat adrenal pheochromocytoma cell (PC12) in vitro was established, constituting the AD model. Different doses (0, 20, 40 and 80 ng/ml) of IGF-1 were used in PC12 cells and the level of PRNP mRNA was tested after 24 h using the quantitative PCR method and the level of APP protein was assessed using western blot analysis. PC12 cells were divided into the control group (PC12 cells without Abeta25-35 treatment), model group (PC12 cells with Abeta25-35 treatment), IGF-1 80 ng/ml group, IGF-1 80 ng/ml+PI3K inhibitor LY294002 25 umol/l group, and IGF-1 80 ng/ml+LY294002 50 umol/l group, whose PRNP mRNA level and Akt, pAkt and APP protein level were tested 24 h later. As the dose of IGF-1 increases, the expression levels of PRNP mRNA and APP protein were more highly expressed. The difference between them was significant (P<0.05). In addition, regarding Akt protein, the expression levels of PRNP mRNA, APP protein and pAkt protein in the IGF-1 groups were significantly higher than those in the control and model groups. With the LY concentration increasing, the levels of expression of the three substances gradually decreased significantly (P<0.05). In conclusion, IGF-I can mediate the expression of the PRNP gene and APP protein through the PI3K/Akt signaling pathway, in a rat model. PMID- 28587339 TI - ORF3 as a sensitive and specific diagnostic index for hepatitis E. AB - We explored the significance of the expression of hepatitis E virus (HEV) open reading frame 3 (ORF3) in hepatitis E rat models. We also investigated its diagnostic value. Forty Sprague-Dawley (SD) rats were infected with HEV and 10 uninfected rats were selected for the control group. Rats were sacrificed at 14, 21, 35 and 70 days after infection. They were divided into 4 groups: Model group 1, model group 2, model group 3 and model group 4. ORF3 protein expression level in liver tissue, level of adipokines [fatty acid synthase (FAS), tissue inhibitor of metalloproteinase-2 (TIMP-2) and angiotensin-converting enzyme inhibitor 2 (ACE-2)], Th1/Th2 cells balance [interferon (IFN), interleukin-4 (IL-4) and Th1/Th2] and the level of immune outcome (levels of CD4+, CD8+ T lymphocytes and CD4+/CD8+) were measured and compared among groups. Our results showed that HEV IgG and HEV RNA levels in the model group 3 were higher than those in the other 3 groups. Compared with the control group, expression level of ORF3 protein in the liver tissue as well as Fas and TIMP levels were significantly higher in the model group 3. ACE-2 level was significantly lower than that of the control group (P<0.05). In the model group 3, IFN-gamma, IL-4 and Th1/Th2 levels were meaningfully higher than those of the control group. CD4+ T lymphocytes and CD4+/CD8+ ratio were obviously lower than those in the control group (P<0.05). The expression level of ORF3 was positively correlated with levels of Fas, TIMP-2 and Th1/Th2. It was negatively correlated with ACE-2 and CD4+/CD8+ levels (P<0.05). We concluded that ORF3 expression level was directly related to severity and prognosis, and that ORF3 protein can be considered as a sensitive and specific diagnostic index. PMID- 28587340 TI - Brain cell apoptosis inhibition by butylphthalide in Alzheimer's disease model in rats. AB - The present study was designed to test the hypothesis that butylphthalide protects the brain of Alzheimer's disease (AD) model rats by inhibiting apoptosis. Ninety Sprague-Dawley rats were randomly divided into drug, control and blank groups of 30 rats in each. The rats in the drug and control groups were treated to induce AD. Then, the rats in the drug group were administered with butylphthalide daily, the rats in the AD control group were given normal saline, and the rats in the healthy group were fed routinely. All rats were sacrificed after 30 days; the brain tissues were used for testing for apoptosis by the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling (TUNEL) staining method, for determining mitogen-activated protein kinase (MAPK), ERK and P21 protein by western blot analysis, and their cognate mRNA levels by RT-PCR. The results of the TUNEL staining indicated that apoptosis of the brain tissues of rats in the drug group was significantly less than that in the control group and blank group. The protein expression levels of MAPK in the drug group were significantly lower than that in the control group, but higher than that in the normal healthy group (P<0.05). The mRNA expression levels of MAPK in the drug group were significantly lower than those in the control group, but higher than those in the normal healthy group (P<0.05). Based on these results, butylphthalide showed a protective apoptosis-inhibition effect on the brain tissues of the AD rats and this seems to be a consequence of its inhibition of the expressions of MAPK mRNA and MAPK protein in the brain of the rat. PMID- 28587341 TI - Histological and functional assessment of the efficacy of constraint-induced movement therapy in rats following neonatal hypoxic-ischemic brain injury. AB - Constraint-induced movement therapy (CIMT) is used in stroke rehabilitation to promote recovery of upper limb motor function. However, its efficacy in improving functional outcomes in children with hemiplegic cerebral palsy has not been clearly determined in clinical or experimental research. The aim of our study was to assess the efficacy of a new experimental model of CIMT, evaluated in terms of mortality, stress, motor and cognitive function in rats having undergone a neonatal hypoxic-ischemic (HI) brain injury. Neonatal HI injury was induced at post-natal day 7 through unilateral ligation of the common carotid artery followed by exposure to hypoxia for 2 h. CIMT was implemented at 3 weeks, post-HI injury, using a pouch to constrain the unimpaired forelimb and forcing use of the affected forelimb using a motorized treadmill. After HI injury, animals demonstrated motor and cognitive deficits, as well as volumetric decreases in the ipsilateral hemisphere to arterial occlusion. CIMT yielded a modest recovery of motor and cognitive function, with no effect in reducing the size of the HI lesion or post-HI volumetric decreases in brain tissue. Therefore, although animal models of stroke have identified benefits of CIMT, CIMT was not sufficient to enhance brain tissue development and functional outcomes in an animal model of hemiplegic cerebral palsy. Based on our outcomes, we suggest that CIMT can be used as an adjunct treatment to further enhance the efficacy of a program of rehabilitation in children with hemiplegic cerebral palsy. PMID- 28587342 TI - Experimental study of the anti-atherosclerotic effect of demethylzeylasteral. AB - This study aimed to confirm that atherosclerosis (AS) is a systemic immune mediated chronic inflammatory disease and to investigate the anti-atherosclerotic effect of demethylzeylasteral by testing the immunocompetent cells and inflammatory mediators in the blood and atherosclerotic plaques of the rabbit model of AS. For this purpose, 60 male New Zealand white rabbits were given 150 g high-fat diet (1% cholesterol, 5% lard, and 15% egg yolk powder) daily for a total of 90 days. On day 61, the rabbits were randomly divided into the saline group (n=15), the rosuvastatin group (n=15), the low-dose demethylzeylasteral group (n=15), and the high-dose demethylzeylasteral group (n=15). The CD3+ T lymphocytes and the subsets CD4+, CD8+, and CD4+/CD8+, as well as the soluble interleukin-2 receptor (sIL-2R) were measured before and after the treatment. The contents of immunoglobulins IgG, IgA and IgM and the levels of complements C3 and C4 were also monitored. In addition, the level of anti-oxidized low-density lipoprotein (ox-LDL) antibody, the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), IL-6 and metalloproteinase-9 (MMP-9), the blood lipids triglyceride (TG), total cholesterol (TC), LDL cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) were measured, and the severity of plaque lesions was also evaluated. Our results showed that the saline group, the rosuvastatin group and the low-dose demethylzeylasteral group had significantly lower activated T lymphocyte parameters CD3+, CD4+, CD8+ and CD4+/CD8+ (P<0.05), and significantly higher levels of sIL-2R, immunoglobulins IgG, IgA and IgM, complements C3 and C4, anti-ox-LDL antibody, TNF-alpha, IL-6 and MMP-9 (P<0.01) when compared with the high-dose demethylzeylasteral group. Moreover, TG, TC, LDL C contents were found significantly lower and their HDL-C contents were significantly higher in high-dose demethylzeylasteral group (P<0.01) as compared to the other three groups. Furthermore, Sudan staining and haematoxylin and eosin staining of the thoracic aorta showed that, after 30-day treatment, the high-dose demethylzeylasteral group had the smoothest intima and the lightest plaque lesions among the four groups. Based on these results, we concluded that AS is a systemic immune-mediated chronic inflammatory disease and the relatively high dose of demethylzeylasteral used in the treatment of atherosclerotic rabbits could significantly alleviate AS. This implies that demethylzeylasteral may be considered as a suitable drug for anti-immunization therapy. PMID- 28587344 TI - Acquired uterine arteriovenous fistula due to a previous cornual pregnancy with placenta accreta: A case report. AB - The present report describes a case of an acquired uterine arteriovenous fistula, which, following surgery and postoperative pathological analysis, was confirmed as a previous cornual pregnancy with placenta accreta. The patient was a 37-year old woman (gravida 3; para 2) who had previously delivered two children via cesarean section (in 2004 and 2010, respectively) and also had a spontaneous abortion (2008). She had experienced continuous menstrual bleeding for ~20 days and had a history of prolonged (~30 days) vaginal bleeding 13 months earlier. Other pregnancy-related diseases were excluded following a negative serum human chorionic gonadotropin test, and the diagnosis was confirmed by Doppler ultrasonography. An emergency hysterectomy was subsequently performed due to the large amount of vaginal bleeding. Postoperative pathology confirmed the uterine arteriovenous malformation and demonstrated that the cause was a previous cornual pregnancy with placental implantation. The patient successfully recovered following the surgery. PMID- 28587343 TI - Alteration of stomach microbiota compositions in the progression of gastritis induces nitric oxide in gastric cell. AB - Atrophic gastritis is considered to be an antecedent to intestinal metaplasia and gastric cancer. A previous study identified that Helicobacter pylori was absent at the severe atrophic gastritis stage, and alterations in the gastric microbial composition resembled those in gastric cancer. To explore the role of the bacteria absence of H. pylori in gastric carcinogenesis, in the current study, we compared the microbiota of clinically collected H. pylori-free gastric fluids from 30 patients with non-atrophic gastritis (N) and 22 patients with severe atrophic gastritis (S). We estimated the bacterial loads in the N and S groups by colony counting in culture agar as well as by measuring the concentration of the extracted DNA. The results showed a significant increase in bacterial load in patients with atrophic gastritis in comparison to non-atrophic gastritis. Then, we analyzed the microbial communities of the gastric fluids from all 52 patients using high-throughput sequencing of 16S rRNA amplicons. The Chao 1, Shannon and Simpson diversity indexes demonstrated that the bacterial richness and diversity were not significantly different between the N and S groups. Moreover, principal component analysis illustrated that the microbiomes from the S group were more scattered. Microbiota composition analysis showed that the entire dataset was clustered into 27 phyla, 61 classes, 106 orders, 177 families, 292 genera and 121 species. At the genus level, only the abundance of Prevotella was significantly different between the N and S groups. Further analysis showed that all the higher taxonomic categories were significantly different between the N and S groups. To assess the effects of the metabolic products of Prevotella spp. on gastric cell physiology, we treated the human gastric epithelial cell line AGS with acetic acid and monitored nitric oxide (NO) production. The results showed that acetic acid at low concentrations (0.5 and 5 uM) significantly inhibited AGS cells to secrete NO compared to phosphate buffer saline-treated control cells. These results suggest that the microbiota in non-atrophic gastritis may influence gastric epithelial cell physiology. PMID- 28587345 TI - Palmitoleate inhibits insulin transcription by activating the ERK1/2 pathway in rat pancreatic beta-cells. AB - The aim of the present study was to evaluate the effects of palmitoleate on insulin secretion and insulin mRNA levels, and to investigate the transcriptional regulation of insulin. INS-1 rat insulinoma cells were treated with palmitoleate in the presence of high glucose, and the amount of secreted insulin was measured via radioimmunoassay. Reverse transcription-quantitative polymerase chain reaction was performed to evaluate the mRNA levels of insulin and pancreatic and duodenal homeobox 1 (PDX1) under palmitoleate treatment. The levels of PDX1, peroxisome proliferator-activated receptor gamma (PPARG), extracellular signal regulated kinase (ERK)1/2 and phosphorylated ERK1/2 were measured using western blot analysis. Low concentrations of palmitoleate significantly induced insulin secretion (P=0.024), whereas the mRNA levels of insulin and PDX1 were markedly reduced. However, the inhibitory effects were reversed with the addition of U0126, suggesting that the ERK1/2-mediated pathway may be the underlying mechanism responsible for palmitoleate-induced downregulation of insulin mRNA. Exposure of INS-1 cells to high glucose significantly increased the phosphorylation of ERK1/2 (P=0.039), which was further enhanced by palmitoleate (P=0.025). Exposure of INS-1 cells to high glucose significantly decreased PPARG (P=0.001), which was further decreased by the addition of palmitoleate. U0126 was able to reverse the palmitoleate-induced effects. In conclusion, the present study suggested that palmitoleate may induce insulin secretion and inhibit insulin mRNA expression in pancreatic beta-cells. PMID- 28587346 TI - LFG-500, a newly synthesized flavonoid, induces apoptosis in human ovarian carcinoma SKOV3 cells with involvement of the reactive oxygen species mitochondria pathway. AB - Ovarian cancer is the main cause of gynecologic malignancy-related mortality in women. Therefore, the disease requires improvements in treatment options and in the potency of chemotherapeutic drugs. The study of apoptosis in tumor cells is an important field for cancer therapy and cancer molecular biology. It has recently been established that LFG-500, a new synthesized flavonoid with a piperazine and benzyl group substitution, has strong anticancer activity. However, its exact molecular mechanism is not fully understood. The present study aimed to examine the effects of LFG-500 on human ovarian cancer SKOV3 cells, as well as to identify its underlying mechanisms. The data showed that LFG-500 inhibited the growth of SKOV3 cells in a concentration-dependent manner. It was found that LFG-500 induced apoptosis in SKOV3 cells, detected by DAPI staining and an Annexin V/PI double-staining assay. Moreover, LFG-500 reduced caspase-3 protein expression and increased the Bcl-2-associated X protein/B-cell lymphoma 2 protein ratio. Further findings revealed that LFG-500 treatment resulted in reactive oxygen species (ROS) accumulation and loss of mitochondrial transmembrane potential. Collectively, these results demonstrated that LFG-500 efficiently induced apoptosis in SKOV3 cells, an event possibly associated with the trigging of the mitochondrial apoptotic pathway through ROS accumulation. Therefore, LFG-500 shows potential as a potent anticancer agent for the treatment of ovarian cancer. PMID- 28587347 TI - Effect of mesenchymal stem cells on Sjogren-like mice and the microRNA expression profiles of splenic CD4+ T cells. AB - Mesenchymal stem cells (MSCs) serve immuno-regulatory functions and offer a promising novel treatment for certain autoimmune diseases. The present study investigated the therapeutic effect of mice bone marrow (BM)-MSCs on mice with relatively late stage of Sjogren-like disease and the impact of BM-MSCs on the microRNA (miRNA) expression profiles of splenic CD4+ T cells. Female NOD/Ltj mice were randomized into two groups: The disease group (n=8) and the MSC-treated group (n=8). Female ICR mice served as the healthy control group (n=8). The MSC treated group received an injection of MSCs when they were 26 weeks old. Water intake, blood glucose and salivary flow rate were measured and submandibular glands were resected and stained with hematoxylin and eosin to calculate the focus score. The concentrations of interleukin (IL)-2, IL-6, hepatocyte growth factor, interferon gamma, IL-10, prostaglandin E2, transforming growth factor beta1 and tumor necrosis factor-alpha in serum were measured using ELISA. The expression of miRNAs in splenic CD4+ T cells were measured using deep sequencing. The results demonstrated that treatment with BM-MSCs prevented a decline in the salivary flow rate and lymphocyte infiltration in the salivary glands of NOD mice, indicating that MSC-treatment had a therapeutic effect on NOD mice with relatively late stage of Sjogren-like disease. ELISA and deep sequencing results showed that the three groups of mice had different serum concentrations of cytokines/growth factors and different miRNA expression profiles of splenic CD4+ T cells. This implies that the alteration in serum levels of cytokines/growth factors and miRNA expression profiles of splenic CD4+ T cells may explain the therapeutic effect MSCs have on Sjogren's syndrome. PMID- 28587348 TI - Hepatoprotective effects of litchi (Litchi chinensis) procyanidin A2 on carbon tetrachloride-induced liver injury in ICR mice. AB - Drug tolerance, lacking liver regenerative activity and inconclusive inhibition of steatosis and cirrhosis by silymarin treatment during chronic liver injury have increased the demand for novel alternative or synergistic treatments for liver damage. Litchi fruit is abundant in polyphenolic compounds and is used in traditional Chinese medicine for treatments that include the strengthening of hepatic and pancreatic functions. Unique polyphenolic compounds obtained from litchi pericarp extract (LPE) were studied in vitro and in vivo for hepatoprotection. Epicatechin (EC) and procyanidin A2 (PA2) of LPE were obtained by fractionated-extraction from pulverized litchi pericarps. All fractions, including LPE, were screened against silymarin in carbon tetrachloride (CCl4) treated murine embryonic liver cell line (BNL). The effects of daily gavage feeding of LPE, silymarin (200 mg/kg body weight) or H2O in CCl4-intoxicated male ICR mice were evaluated by studying serum chemicals, liver pathology and glutathione antioxidative enzymes. The effects of EC and PA2 on liver cell regenerative activity were investigated using a scratch wound healing assay and flow cytometric cell cycle analysis; the results of which demonstrated that LPE protected BNL from CCl4-intoxication. Gavage-feeding of LPE decreased serum glutamic oxaloacetate transaminase and glutamic pyruvic transaminase levels, and exhibited superior retention of the hexagonal structure of hepatocytes and reduced necrotic cells following liver histopathological examinations in CCl4 intoxicated ICR mice. Glutathione peroxidise and glutathione reductase activities were preserved as the normal control level in LPE groups. EC and PA2 were principle components of LPE. PA2 demonstrated liver cell regenerative activity in scratch wound healing assays and alcohol-induced liver cell injury in vitro. The present findings suggest that litchi pericarp polyphenolic extracts, including EC and PA2, may be a synergistic alternative to silymarin in hepatoprotection and liver cell regeneration. PMID- 28587349 TI - Gut flora profiling and fecal metabolite composition of colorectal cancer patients and healthy individuals. AB - Colorectal cancer is one of the most common types of cancer in the world and its morbidity and mortality rates are increasing due to alterations to human lifestyle and dietary habits. The relationship between human gut flora and colorectal cancer has attracted increasing attention. In the present study, a metabolic fingerprinting technique that combined pyrosequencing with gas chromatography-mass spectrometry was utilized to compare the differences in gut flora profiling and fecal metabolites between healthy individuals and patients with colorectal cancer. The results demonstrated that there were no significant differences in the abundance and diversity of gut flora between healthy individuals and patients with colorectal cancer (P>0.05) and the dominant bacterial phyla present in the gut of both groups included Firmicutes, Bacteroidetes and Verrucomicrobia. At the bacterial strain/genus level, significant differences were observed in the relative abundance of 18 species of bacteria (P<0.05). Analysis of fecal metabolites demonstrated that the metabolic profiles of healthy individuals and patients with colorectal cancer were distinct. The levels of short-chain fatty acid metabolites, including acetic acid, valeric acid, isobutyric acid and isovaleric acid, and of nine amino acids in patients with colorectal cancer were significantly higher than those in healthy individuals (P<0.05). However, the levels of butyrate, oleic acid, trans oleic acid, linoleic acid, glycerol, monoacyl glycerol, myristic acid, ursodesoxycholic acid and pantothenic acid in patients with colorectal cancer were significantly lower than those in healthy individuals (P<0.05). Pearson rank correlation analysis demonstrated that there was a correlation between gut flora profiling and metabolite composition. These findings suggest that gut flora disorder results in the alteration of bacterial metabolism, which may be associated with the pathogenesis of colorectal cancer. The results of the present study are useful as a foundation for further studies to elucidate a potential colorectal cancer diagnostic index and therapeutic targets. PMID- 28587350 TI - Effects of hyperbaric factors on lidocaine-induced apoptosis in spinal neurons and the role of p38 mitogen-activated protein kinase in rats with diabetic neuropathic pain. AB - The application of lidocaine can lead to nerve damage. Evidence suggests that patients with diabetic neuropathy are at a higher risk for neurotoxicity. In the present study, the successful induction of diabetic neuropathic pain (DNP) in rats via a high-sugar, high-fat diet and intraperitoneal injection of 1% streptozotocin was verified and pronounced tactile allodynia was observed. It was found that intrathecal injections of hyperbaric lidocaine produced motor blocks of longer durations in the DNP model rats than in nondiabetic rats, or in DNP model rats injected with isobaric lidocaine. Histology of the lumbar 4-5 spinal cord revealed a significant difference in neuropathology between the DNP and nondiabetic rats. Moreover, edematous neurons and TUNEL-positive cells were observed in the hyperbaric lidocaine group. It was also found that the inhibition of p38 mitogen-activated protein kinase (p38MAPK) played a neuroprotective role in response to hyperbaric lidocaine-induced apoptosis in DNP rats, which indicates that p38MAPK plays a key role in the regulation of hyperbaric lidocaine induced apoptosis in DNP rats. These findings suggest that hyperbaric lidocaine can promote spinal cord neuronal apoptosis in rats with DNP. Furthermore, p38MAPK might play a key role in the regulation of hyperbaric lidocaine-induced apoptosis in rats with DNP. PMID- 28587351 TI - Role of RANK and Akt1 activation in human osteosarcoma progression: A clinicopathological study. AB - The receptor activator of nuclear factor kappaB (RANK) axis is the fundamental signaling pathway in bone formation as well as bone tumor pathophysiology. The aim of the present study was to evaluate the impact of the expression of RANK and its downstream signaling molecule Akt1 on tumor progression in patients with osteosarcoma. Expression of RANK and Akt1 was examined in 78 human osteosarcoma samples by immunohistochemistry using formalin-fixed samples. Following this, each graded immunohistochemistry result was correlated with clinicopathological parameters and patient survival. In total, 60 osteosarcomas (76.9%) expressed RANK and 58 cases (74.4%) showed expression of Akt1. In addition, expression of RANK was negatively correlated with disease-free survival by Kaplan-Meier analysis. A resistance was observed to chemotherapy in RANK-expressing cases, which was statistically significant (P<0.05). In addition, chemotherapy and staging of the tumor were found to independent factors that have an effect on patient survival (P<0.05). Thus, RANK was identified as a negative prognostic factor of osteosarcoma survival. PMID- 28587352 TI - Interleukin-1 receptor antagonist expression is inversely associated with outcomes of hepatitis B-related acute-on-chronic liver failure. AB - Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring anti inflammatory antagonist of the proinflammatory cytokine IL-1, a critical factor in many inflammatory diseases. The aim of the present study was to investigate the role of IL-1ra in hepatitis B-related acute-on-chronic liver failure (HB ACLF). Serum cytokine concentrations were measured using a Q-Plex array in 31 patients with HB-ACLF, 28 patients with acute hepatitis B (AHB), 31 patients with chronic hepatitis B (CHB) and 15 healthy control patients (HCs). Additionally, peripheral blood mononuclear cells (PBMCs) from patients with HB-ACLF were incubated with PBS or lipopolysaccharide and/or different concentrations of recombinant human IL-1ra (rhIL-1ra) in vitro. Cytokines in the supernatant were measured using a Q-Plex array. The median serum IL-1ra level in patients with HB ACLF was 186.46 (350.22) pg/ml, which was significantly higher than all other groups (AHB, P=0.012; CHB, P<0.001; HCs, P<0.001). However, the ratio of IL 1ra/IL-1beta was significantly lower in the HB-ACLF group compared with the AHB group (P=0.048). Median serum IL-1ra levels in patients with AHB were also significantly increased compared with those in the CHB (P<0.001) and HC (P<0.001) groups. Patients who succumbed to mortality within 3 months of the study were found to have significantly lower IL-1ra concentrations (P=0.02) and IL-1ra/IL 1beta ratios (P=0.007) compared with surviving patients with HB-ACLF. Furthermore, serum IL-1ra concentrations were negatively associated with the Model for End-stage Liver Disease score (r=-0.870; P<0.001). Cytokine secretion by PBMCs in vitro was significantly inhibited in a dose-dependent manner by rhIL 1ra (125-500 ng/ml; all P<0.05). These results suggest that IL-1ra is associated with the development of liver inflammation, which is reduced in patients with HB ACLF and inversely associated with disease severity. PMID- 28587353 TI - Clinical analysis of the effect of anti-allergy treatment on pocket-related complications following pacemaker implantation. AB - A total number of 339 patients who received a pacemaker implantation between June 2012 and June 2014 at Tongji Hospital of Tongji Medical College (Wuhan, China) were investigated in the present study. The aims of the present study were to explore the risk factors of pocket hematoma following pacemaker implantation, and to analyze the effect of anti-allergy treatment on pocket-related complications following pacemaker implantation. Predictors of hematoma occurrence were determined and analyzed via a Chi-square test. Patients suffering from pocket hematoma, which were indicated to be partially caused by an allergic reaction to the pacemaker component, were distinguished by routine blood parameters. Furthermore, the pacemaker component was distinguished by histopathological examinations in one patient. Promethazine (25 mg/day) was used to treat allergic patients. The results demonstrated that in patients with a history of allergies, the rate of pocket hematoma was significantly higher when compared with patients without a history of allergies (22.00 vs. 7.61%; P=0.027). A significantly increased incidence of hematoma was indicated in patients with a lower body mass index when compared with patients of normal weight (15.79 vs. 7.38%; P=0.042). Furthermore, implantation of larger-sized devices, such as an implantable cardioverter-defibrillator and cardiac resynchronization therapy, were significantly predictive of hematoma development (29.63 vs. 8.01%; P=0.015). Patients with diabetes were also identified to exhibit a significantly high incidence of hematoma (22.22 vs. 8.25%; P=0.023). Promethazine administration significantly decreased the incidence of re-operating (P=0.017) and the duration of hospital stay (P=0.038) in patients whose pocket hematoma was caused by an allergy. In conclusion, promethazine may be a beneficial agent to treat pocket hematoma caused by allergic reactions following pacemaker surgery. PMID- 28587354 TI - Th1/Th2 PB balance and CD200 expression of patients with active severe alopecia areata. AB - Th1/Th2 peripheral blood balance and CD200 expression in patients with severe alopecia areata (SAA) in the active stage were investigated. Fifty patients with active SAA, 50 patients with stable SAA and 50 healthy controls were continuously selected and expression of Th1/Th2 of peripheral T lymphocytes, and peripheral B lymphocytes was detected by flow cytometry; RT-PCR was used to detect the expression of the PBMC CD200 mRNA and the expression of CD200 in hair follicles of alopecia area was detected by immunohistochemically staining; ELISA was used to detect expression levels of serum LFN-gamma and serum interleukin (IL)-10. The expression of CD200 in patients with alopecia areata in active phase on CD3+ T lymphocytes and CD19+ B lymphocytes was significantly lower (P<0.05) than those in stable phase and of the control group. CD200 expression in patients with alopecia areata in stable phase on T lymphocytes was greatly lower than that of the control group (P<0.05). However, the comparison of expression of CD200 in patients with alopecia areata in stable phase on B lymphocytes with the control group were statistically non-significant. The level of the expression of CD200 mRNA in active phase was obviously lower than those of the other two groups and the difference was statistically significant (P<0.05); the moderate positive and strong positive percentage of CD200 in the active phase was significantly lower than those of the other two groups. Positive expression rate of CK15 among the three groups were compared with each other; the differences had no statistical significance. The level of LFN-gamma in the active phase had obviously increased while the IL-10 level decreased significantly (P<0.05). In conclusion, the level of expression of CD200 on peripheral blood and hair follicle outer root sheath of patients with SAA was decreased. This may be associated with the imbalance of the Th1/Th2 equilibrium. PMID- 28587355 TI - Morphological and functional changes in bone marrow mesenchymal stem cells in rats with heart failure. AB - The changes in bone marrow-derived mesenchymal stem cells (BMSCs), in terms of cell morphology and protein expression in rats with heart failure, were studied. Pressure overload chronic heart failure rat model was induced with partial constriction of the abdominal aorta. BMSCs from the model and the sham operation groups were isolated and cultured (cell density, 108 cells/l), and supernatant was collected after 72 h. Enzyme-linked immunosorbent assay was used to measure HGF, IGF-1, PDGF, SCF, FGF and VEGF levels in the supernatant. Results showed that in the model group, the minimum cell diameter, the average cell area and the protein expression in single BMSCs were significantly less than those in the sham operation group. In the model group, SCF and PDGF levels were significantly lower than those in the sham operation group. VEGF concentration in the model group was significantly higher than that in the sham operation group. Compared with normal rats, the morphology of BMSCs in rats with heart failure changed considerably, the protein expression of a single cell and the ability to secrete cytokines decreased in a meaningful way. PMID- 28587356 TI - Areca nut extract protects against ovariectomy-induced osteoporosis in mice. AB - Estrogen deficiency increases the generation of reactive oxygen species (ROS), which is a crucial pathogenic factor for osteoporosis. Areca nuts are rich in phenolics, which have high antioxidant activity. In the present study, an ovariectomy (OVX)-induced osteoporosis mouse model was used to investigate the protective effects of areca nut extract (ANE) on bone loss and related processes. A total of 24 8-week-old female mice were randomly divided into three groups (n=8 per group): I Sham-operated control; II, bilateral OVX; and III, bilateral OVX + ANE. Group III were treated orally with ANE at a single dose of 300 mg/kg body weight daily for 6 months. ANE supplementation for 6 months improved trabecular bone microarchitecture and significantly increased bone mineral density in the distal femur (P<0.05) compared with Group II. Furthermore, serum levels of the osteoclast differentiation-inducing factors, receptor activator of nuclear factor kappaB ligand and osteoprotegerin were significantly increased and decreased, respectively (both P<0.05), in OVX mice and these effects were significantly inhibited by ANE treatment (both P<0.05). ANE supplementation also resulted in significantly decreased serum hydrogen peroxide and malondialdehyde levels compared with Group II, while the levels of glutathione and catalase activity were significantly increased (P<0.05 and P<0.01, respectively). The current study indicated that the protective effects of ANE against bone loss were mediated, at least in part, via inhibition of the release of ROS and bone resorption. These results suggested that ANE could have therapeutic value in the treatment of osteoporosis. PMID- 28587357 TI - Differential proteomic screening and identification for non-traumatic necrotic femoral osseous tissue. AB - Currently, there is a lack of effective early screening and detection methods for femoral head necrosis. Current research on most orthopedic diseases focuses on proteomics in the preliminary stage. The recent fluorescence differential in gel electrophoresis (DIGE) has advantages such as a high reproducibility, high sensitivity, high throughput, and high dynamic range. It is currently one of the most widely used quantitative proteomic research means. We conducted this study to investigate the pathogenesis of non-traumatic femoral head necrosis using the fluorescence DIGE to screen non-traumatic femoral head necrosis based on proteomics and provide a theoretical basis for screening possible biomarkers and molecular targeted treatment. The DIGE technique was used to separate the protein. An electrophoretogram was established on the basis of scanning and analysis. Identification and a bioinformatics analysis were conducted for the differential protein. The protein with differential expression of over 2-fold was excavated and ionized by means of substrate assisted laser desorption. The flight time was identified with a mass spectrometer (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, MALDI-TOF/TOF). The formation on sequences, structures and functions of these proteins were obtained through database retrieval. Western blot analysis was used to verify the differential protein expression and the reliability of the DIGE result was verified. DIGE was used to successfully separate 1,500+/-40 protein spots. There were 252 significant differential protein spots. The EttanTM Spot Picker automatic work station was used to excavate 49 significant differential protein spots with expression difference over 2-fold. The MALDI-TOF/TOF mass spectrometer was used to identify these differential protein spots. Six proteins were identified in total, which include apolipoprotein A1 (APOA1), fibrous protein original chain, fibrous protein original chain, serum albumin, sulfur-oxygen protein peroxiredoxin 2 (PRDX2) and actin. APOA1 and PRDX2 were subject to western blot analysis detection; results were consistent with the DIGE result. Based on an analysis of the biological information, these proteins may be associated with the incidence and progression of femoral head necrosis. PMID- 28587358 TI - A meta-analysis of PDE-gene polymorphism and cerebral infarction risk. AB - Previous studies identified that phosphodiesterase 4D (PDE4D) gene polymorphism might be associated with cerebral infarction or ischemic stroke, and hemorrhagic stroke in human populations. However, as yet, no meta-analysis has revealed any detailed association. We retrospectively reviewed studies regarding the relationship of PDE4D gene polymorphism with ischemic stroke (IS) published during the period January 2003 to September 2012. According to the inclusion criteria, 9 of 105 initial studies were included in the subsequent analysis. The PubMed, Embase and CNKI of China were searched to identify the relevant studies. A total of 186 young patients with IS were included for the meta-analysis and 232 matched control subjects were enrolled and results were presented. The association of PDE4D gene polymorphism with IS in various populations was examined. The results suggested that single nucleotide polymorphism (SNP), SNP 83 in PDE4D gene was significantly related with susceptibility to IS. The meta analysis also showed that PDE4D gene was associated with an enhanced risk of IS. The meta-analysis suggested that PDE4D SNP 87 constitutes an independent risk factor for IS development. To the best of our knowledge, the present meta analysis reveals a number of possible associations between PDE4D gene polymorphism and IS. PMID- 28587359 TI - Effect of three-dimensional reconstruction-assisted 23G micro-invasive vitrectomy in patients with proliferative diabetic retinopathy. AB - In the present study, we investigated the effect of optical coherence tomography (OCT) three-dimensional reconstruction-assisted 23G micro-invasive vitrectomy (abbreviated to'23G') in patients with proliferative diabetic retinopathy (PDR). A total of 66 PDR patients (66 eyes) were continuously selected and randomly divided into the control and observation groups with 33 patients in each group. Patients in the control group were treated with routine OCT examination while the patients in the observation group were treated with OCT three-dimensional retinal reconstruction. The 23G surgical method was applied to the two groups, and a comparison was made on the clinical effects in the two groups. The follow-up visits lasted for approximately 6 months, and it was found that the operative time, occurrence rate of intraoperative complications and postoperative complications as shown in the observation group were significantly less than those in the control group (P<0.05). The best corrected visual acuity (BCVA) was improved, the intraocular pressure was increased and retinal thickness was decreased after the treatment. The BCVA of patients in the observation group was significantly greater than that of patients in the control group while the intraocular pressure and retinal thickness of patients in the observation group were significantly less than those of patients in the control group (P<0.05). In conclusion, the effect of 23G surgical method in PDR patients can be improved and corresponding complications can be reduced under the assistance of OCT three dimensional reconstruction. PMID- 28587360 TI - The value of Sonoclot detection technology to guide the clinical medication of the perioperative anticoagulation and antiplatelet therapy in patients with acute myocardial infarction undergoing emergent PCI. AB - The value of Sonoclot detection technology to guide the clinical medication of the perioperative anticoagulation and antiplatelet therapy in patients with acute myocardial infarction (AMI) undergoing emergent percutaneous coronary intervention (PCI) was estimated. One hundred and twenty-eight patients were randomly divided into control group and observation group with 64 cases in each group. Control group adopted routine blood coagulation indexes, including prothrombin time, activated partial thromboplastin time, fibrinogen and plasma thrombin time, platelet count and platelet aggregation turbidity analysis; observation group adopted Sonoclot detection technology, including activated clotting time, coagulation rate and platelet function. Anticoagulant therapy selected was of low molecular weight heparin calcium perioperatively, intraoperative unfractionated heparin, and clopidogrel (75 mg) combined with aspirin enteric-coated tablets (100 mg) as antiplatelet drugs. The therapy was administered in accordance with blood coagulation results. The blood coagulation time, postoperative creatine kinase isoenzyme MB, cardiac troponin I and B-type natriuretic peptide levels in the observation group are significantly lower than those in the control group (P<0.05) though the operating time and specifications of the stenting did not show any significant difference (P>0.05). The incidence of recurrent myocardial infarction, microembolism, acute and subacute thrombosis and bleeding events in the observation group are significantly lower than those in the control group (P<0.05). In the control group, there is no difference in the coagulation indexes of the patients with thrombosis events or bleeding events or no event (P>0.05). Whereas, in the observation group, there is significant difference in coagulation indexes of the patients with thrombosis events or bleeding events or no event (P<0.05). In conclusion, Sonoclot detection technology instructs emergent PCI treatment in AMI patients to shorten the detection time of blood coagulation, reduce the degree of myocardial injury, reduce the incidence of perioperative thrombosis and bleeding events. Furthermore, it has great value in guiding the clinical medication of anticoagulation and antiplatelet therapy. PMID- 28587361 TI - Biocompatibility of polypropylene mesh scaffold with adipose-derived stem cells. AB - In this study, we investigated the rejection of the synthetic patch and human tissues in the host. We observed the growth of adipose-derived stem cells (ADSCs) cultured with polypropylene mesh in vitro. The results of flow cytometry showed that the expression of CD44, CD73, CD90, CD45, CD14 and CD34 was 98.54, 95.32, 98.49, 1.21, 3.01 and 2.14%, respectively. ADSCs were isolated from rabbit subcutaneous adipose tissue after collagenase digestion, filtration and centrifugation. The ADSCs of passage 3 were seeded onto the polypropylene mesh scaffolds. New Zealand White female breeder rabbits were implanted with polypropylene mesh, ADSC-fixed polypropylene mesh in the abdomen. After 4 weeks, adhesion was performed and the erosion of the mesh was evaluated. It was found that polypropylene mesh, ADSC-fixed polypropylene mesh all had different degrees of corrosion, and adhesion, but polypropylene mesh was more corroded. ADSC-fixed polypropylene mesh induced a milder chronic inflammation response compared with polypropylene, had significantly lower scores for inflammation (t=11.083), and had significantly higher scores for neovascularization (t=14.362) and fibroblastic proliferation (t=15.979). The relative amount of VEGF mRNA was significantly lower for ADSC-fixed polypropylene compared with the other polypropylene meshes (t=94.6). In conclusion, polypropylene mesh scaffold with ADSCs exhibit excellent cellular compatibility and are promising in clinical practice. PMID- 28587362 TI - Effects of release and decompression techniques on nerve roots through percutaneous transforaminal endoscopic discectomy on patients with central lumbar disc herniation. AB - The clinical effects and safety of release and decompression techniques on nerve roots through percutaneous transforaminal endoscopic discectomy (PTED) while treating patients with central lumbar disc herniation (CLDH) were explored. Patient cases of lumbar and leg pain treated in Bethune International Peace Hospital from July 2013 to October 2015 were collected retrospectively. The patients in these cases received imaging examinations such as computed tomography and magnetic resonance imaging. Among these cases, 37 CLDH patients with no other complications were selected for this study. A total of 22 males and 15 females aged 28-54 years, with an average age of 36.8+/-1.5 years, were the subjects of the study. Their disease course was from 1 month to 3 years, with a median course time of 1.5 years. Visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) scoring and the MacNab method were used to evaluate treatment effects. After permission from patients or their family members, release and decompression techniques of nerve roots were performed through PTED. All patients had successful surgery. Their average surgery time was 41.3 (25.5-57.1) min. A physician followed-up each patient from 0 to 18 months after surgery, with the average follow-up period of 12.1 months. VAS scoring of lower limbs was 7.95+/ 0.82 before surgery and 2.28+/-0.35, 3 months after surgery. VAS scoring of lower limbs was 2.06+/-0.58, 1 year after surgery and 2.12+/-0.23 at the last follow-up appointment. JOA scoring was 12.6+/-0.72 before surgery and 20.4+/-1.08, 3 months after surgery. JOA scoring was 21.1+/-0.82 1 year after surgery and 21.2+/-0.36 at the last follow-up. Differences are of statistical significance (P<0.05). There were no complications for any of the cases. One patient did not improve after surgery, so a laminectomy and bone grafting internal fixation were performed. Two patients relapsed after surgery and received laminectomy and bone grafting internal fixation. The total percentage of excellent and good rates was 83.5%. In conclusion, release and decompression techniques on nerve roots using PTED while treating CLDH resulted in a safe, effective and less traumatic outcome with fewer complications and quicker pain relief than alternative treatments. Due to the results of this study, the use of these techniques in treating CLDH should be more widely considered. PMID- 28587364 TI - Cytotoxic effects of 15-deoxy-Delta12,14-prostaglandin J2 alone and in combination with dasatinib against uterine sarcoma in vitro. AB - Effective chemotherapeutic strategies for uterine sarcoma are lacking; existing therapies achieve poor response rates. Previous studies have identified the prostaglandin 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) as a potential anticancer treatment; however, its effectiveness in uterine sarcoma has not been examined. Furthermore, the molecular mechanisms underlying the cytotoxic mechanism of 15d-PGJ2 remain unclear. Here, we evaluated the effects of 15d-PGJ2 alone and in combination with the tyrosine kinas inhibitor (TKI) dasatinib in uterine sarcoma cell lines (MES-SA, MES-SA/DX5 and SKN). 15d-PGJ2 inhibited cell growth and increased apoptosis. Western blotting demonstrated that 15d-PGJ2 treatment increased MEK and ERK phosphorylation, and decreased levels of phosphorylated AKT. Dasatinib in combination with 15d-PGJ2 significantly reduced cell proliferation compared with 15d-PGJ2 alone, and repressed both the AKT and MAPK pathways. The cell growth inhibition rate in the PGJ2 was 21.5+/-12.0, 35.3+/-5.4 and 28.3+/-4.2%, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the cell growth inhibition rate in the combination therapy was significantly higher compared with 15d-PGJ2 alone (MES-SA; 64.2+/-0.8, MES-SA/DX5;23.9+/-8.2 and SKN; 41.4+/-17.6%). The PGJ2 IC50 determined by MTT assay was 27.41,10.46 and 17.38 umol/l, respectively (MES-SA, MES-SA/DX5 and SKN cell lines) and the dasatinib IC50 was 6.68,17.30 and 6.25 umol/l, respectively. Our findings demonstrate that 15d-PGJ2 suppresses proliferation by inactivating the AKT pathway in uterine sarcoma. Furthermore, combining 15d-PGJ2 with dasatinib produced a synergistic effect on cancer cell inhibition by repressing 15d-PGJ2 mediated activation of MAPK signaling, and further repressing AKT signaling. These results suggest that 15d-PGJ2 could be used in combination with dasatinib as a potential therapeutic approach for uterine sarcoma. PMID- 28587363 TI - Local influence of high molecular polyethylene particles on heterotopic ossification. AB - We studied the effect of molecular polyethylene particles on local heterotopic ossification. A total of 36 healthy Sprague-Dawley rats were randomly divided into the control group (n=18) and the observation group (n=18). High molecular polyethylene particles were injected to rupture Achilles tendon position in the observation group, and normal saline was injected in the control group. X-ray examinations were conducted on Achilles tendon in the 4th, 8th and 12th week after operation. The incidence rate of heterotopic ossification was evaluated, and bone trabecula morphological structure was studied under optical microscope after hematoxylin and eosin staining. Bone morphogenetic protein 2 (BMP-2), transforming growth factor-beta (TGF-beta), interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), runt-related transcription factor 2 (Runx2) and matrix metalloproteinase-9 (MMP-9) expression levels were also measured. Our results showed that heterotopic ossification incidence in the observation group was significantly lower than that in the control group. Achilles tendon structure in the control group increased in volume, and its texture was harder and cartilage like. In the observation group, trabecular bone volume, thickness and quantity were more than those observed in the control group. BMP-2, TGF-beta, IL-1, TNF alpha, Runx2 and MMP-9 levels in the observation group were significantly lower than those in the control group. We concluded that, high molecular polyethylene particles had a significant inhibiting effect on local heterotopic ossification. PMID- 28587365 TI - Assessment of different loading doses of dexmedetomidine hydrochloride in preventing adverse reaction after combined spinal-epidural anesthesia. AB - We conducted the present study to investigate the effects of the different loading doses of dexmedetomidine hydrochloride in the prevention of adverse reactions after combined spinal-epidural anesthesia. A total of 200 patients that were admitted to the Department of Obstetrics at the Second Affiliated Hospital of Xi'an Jiaotong University hospital and treated with cesarean section through the use of combined spinal-epidural anesthesia from December, 2014 to June, 2016, were randomly divided into 4 groups. The therapeutic regimens of patients were shown as follows: group A was administered an intravenous pump of 10 ml/l physiological saline in surgery until the end of the delivery. group B was administered 0.2 ug/kg dexmedetomidine. group C was administered 0.4 ug/kg dexmedetomidine. group D was administered 0.6 ug/kg dexmedetomidine. The anesthesia plane was adjusted to the level below the T10 plane. After the onset of anesthesia, participants of each group were treated with an intravenous pump of dexmedetomidine at loading dose. After intravenous pumping for 10 min in each group during the surgery, patients were administered with an intraoperative maintenance dose of 0.2 ug/kg/h until the end of the delivery. The heart rate (HR), mean arterial pressure (MAP), Narcotrend index (NI), Ramsay sedation score and the incidence of adverse reactions at each time-point of the start of drug administration (T0), 10 min (T2), 30 min (T3), 60 min (T4), 90 min (T5) and the end of surgery (T6) were recorded. Within 24 h post-delivery, the degree of amnesia from using dexmedetomidine until the end of the delivery were followed up. Compared to group A and T0, the HRs of participants at T3-6 in groups B and C were decreased. The MAP at T1 in group D was increased. In groups B and C, the NIs were significantly decreased at T2-6, the Ramsay scores were increased at T3 6, and the differences were statistically significant (P<0.05). The follow-up within 24 h after delivery showed that the degree of anterograde amnesia from groups B to D was significantly higher than group A, with statistically significant difference (P<0.05). A combined spinal-epidural anesthesia with 0.6 ug/kg loading dose of dexmedetomidine, by intravenous pumping within 10 min before cesarean section, can achieve a satisfied sedative effect at 30 min after administration. It maintains the characteristics of intraoperative hemodynamic stability and less adverse reactions. Therefore, it is of great significance to improve the quality of cesarean section delivery. PMID- 28587366 TI - Investigation of the predictive value of speckle tracking imaging for the assessment of cardiac function and clinical prognosis in patients with hypercholesterolemia. AB - The predictive value of speckle tracking imaging (STI) for the assessment of cardiac function and clinical prognosis in patients with hypercholesterolemia was explored. One hundred forty-seven patients with hypercholesterolemia diagnosed in our hospital and 137 healthy adults from our health examination center over the same period were included in this study. Using STI and color Doppler ultrasound, we carried out follow-up of cardiac function in patients with hypercholesterolemia and statistical analysis based on collected data. Global longitudinal strain, global circumferential strain, and the strains of apical long-axis, four-chamber and two-chamber planes, and short-axis mitral valve, short-axis papillary muscle, and short-axis apical levels in the hypercholesterolemia group were significantly lower than those in the control group. Global systolic and early diastolic strain rates were significantly lower than those in the control group. In the coronaries, the percentage of segments with significant differences was 80% (24/30) in the left anterior descending coronary artery (LAD), 66.7% (9/12) in the left circumflex coronary artery (LCX), and 75% (8/12) in the right coronary artery (RCA). The average strains in the long axis, radial, and circumferential directions (StrainSL, SC, SR - Avg) in the three main coronaries were significantly different between the hypercholesterolemia group and control group (P<0.0001). In the three coronaries and their basal and mid segments, there were significant differences between LCX and LAD, and between LCX and RCA (P<0.0001). In conclusion, the application of STI for monitoring cardiac function in patients with hypercholesterolemia provides physicians with useful information related to hypercholesterolemia to achieve early diagnosis and effective treatment. PMID- 28587367 TI - Seasonal trends in the prevalence of hypospadias: Aetiological implications. AB - The aim of the present study was to examine the seasonality of hypospadias in Greece in an attempt to elucidate the aetiology. All boys born between 1991-1998, who underwent hypospadias repair at 'Aghia Sophia' Children's Hospital, Athens (n=542) were analysed. All Greek live-born males during the same period (population at risk; m=421,175) served as the controls. Seasonality by month of birth was evaluated with specific statistical tools. Meteorological parameters were also analysed. All tests yielded significant results, suggesting a simple harmonic prevalence pattern (highest/lowest: autumn, peak in October/spring, trough in April). Therefore, the first trimester of hypospadiac gestations coincides more frequently with winter. Meteorological parameters varied seasonally (maximal sunlight; air temperature in summer/minimal in winter, maximal rainfall in winter/minimal in summer) and were strongly associated pairwise. Hypospadiac birth prevalence follows a simple harmonic seasonal pattern and is associated with that of cryptorchidism in Greece. The coincidence of the first or third trimester of a potentially genetically influenced gestation with winter could lead to the phenotypic expression of hypospadias or cryptorchidism, respectively. The potential role of a cyclic-varied androgen-production stimulator, such as human chorionic gonadotrophin may be speculated. The seasonality of a common environmental factor acting directly/indirectly may contribute to these patterns, and possibly to the common pathogenesis of these congenital malformations. PMID- 28587368 TI - Evaluation of the effect of recombinant thrombomodulin on a lipopolysaccharide induced murine sepsis model. AB - To evaluate the effect of recombinant human thrombomodulin (rTM) on sepsis, the levels of nucleosome as well as high-mobility group box 1 (HMGB1) and cytokines in sera and peritoneal fluids were measured in a mouse model of lipopolysaccharide (LPS)-induced sepsis after administration of rTM. C57BL/6 mice were intraperitoneally injected with LPS (15 mg/kg; Escherichia coli O111:B4) with or without the intravenous administration of rTM (3 mg/kg; 30 min prior to or 2 h after LPS injection). The survival rates were evaluated and levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, HMGB1 and nucleosome in sera and peritoneal fluids were analyzed by ELISA. Administration of rTM prior to or after LPS improved the survival rate of septic mice. In addition, rTM administered prior to or after LPS suppressed the level of pro-inflammatory cytokine TNF-alpha in sera at 1-3 h after LPS injection, whereas only the administration of rTM after LPS suppressed the levels of HMGB1 and nucleosome (late-phase mediators of sepsis) (9-12 h) in sera after the LPS injection. Furthermore, administration of rTM prior to or after LPS suppressed the level of TNF-alpha in the peritoneal fluids at 1-3 h after LPS injection, whereas only the administration of rTM after LPS suppressed the levels of IL-6 and MCP-1 in the peritoneal fluids at 6-9 h after LPS injection. These observations indicated that administration of rTM significantly improves the survival rate and suppresses the increased levels of TNF-alpha, IL-6, MCP-1, HMGB1 and nucleosome in the LPS-induced septic shock model. Thus, rTM may exert a protective action on sepsis and reduce mortality, possibly by reducing not only the levels of cytokines and chemokine but also the levels of late-phase mediators of sepsis. PMID- 28587369 TI - Efficacy and indications of transradial and transfemoral approaches for peripheral artery stent implantation. AB - The transradial approach (TRA) has become an attractive alternative to the transfemoral approach (TFA) in percutaneous coronary intervention. To date, however, these two approaches have not been systematically compared in various percutaneous peripheral artery interventions (PPAIs). In the present study 258 patients with peripheral artery disease that underwent PPAI via the TRA (n=75) or the TFA (n=183) were analyzed. Clinical factors and outcomes in these two groups were compared. The puncture time was significantly longer (P<0.05) and the prevalence of artery vasospasm significantly higher (P<0.05) in patients who underwent PPAI via the TRA rather than via the TFA. However, the complication rate was significantly lower (P<0.05) and the artery compression time (P<0.05) and time bedridden (P<0.05) were significantly shorter via the TRA than via the TFA. These results suggest that PPAI via the TRA was associated with a lower complication rate, and shorter artery compression time and bedridden time than PPAI via the TFA. The TRA may be preferable for bilateral vertebral artery stenosis, whereas the TFA may be preferable for interventional treatment of carotid and subclavian artery stenosis. Therefore, the catheter length, artery support and push force should be comprehensively considered before choosing the TRA or TFA in the interventional treatment of renal artery stenosis. PMID- 28587370 TI - A novel noninvasive ocular surface analyzer for the assessment of dry eye with Meibomian gland dysfunction. AB - Meibomian gland dysfunction (MGD) is a major cause of dry eye, and the purpose of the present study was to evaluate the differences between dry eye patients with MGD and controls using a novel noninvasive ocular surface analyzer. A total of 33 dry eye patients with MGD and 31 controls were enrolled in the present study. Testing included administration of the Ocular Surface Disease Index (OSDI), followed by Keratogragh 5M (Oculus, Wetzlar, Germany), measurements of the noninvasive tear film break-up times (NITBUTs), the first tear film break-up point and the morphology of meibomian gland. Meibomian gland loss (MGL) on the upper lid was evaluated using noncontact meibography. The first NITBUT (NITBUTf) was significantly shorter than the average NITBUT (NITBUTav; Mann-Whitney U-test, P<0.01). There was a weak negative Spearman correlation between NITBUTf and OSDI (rs=-0.251, P=0.046) as well as between NITBUTav and OSDI (rs=-0.250, P=0.046). Furthermore, MGL showed a statistically significant Spearman correlation with OSDI (rs=0.562; P<0.01). In the MGD group, NITBUTf was significantly shorter (P<0.01), and MGL and OSDI score were significantly greater (P<0.01 and <0.01, respectively) than in the control group. In the MGD group, the first tear film break-up point was most frequently located in the inferonasal quadrant, while it was most frequently located in the supertemporal quadrant in the control group, and there was a significant difference with this regard (chi2=3.937, P=0.047). In the MGD group, there were significantly more breakups in the lower quadrant than in the upper quadrant (P=0.011), whereas no differences in the number of breakups in each quadrant were observed in the control group (P=0.429). Furthermore, there was no significant difference in the breakups in the lower quadrants of the two groups (chi2=0.525, P=0.469). In the MGD group, there were significantly more breakups in the lower quadrant than in the upper quadrant (P=0.011), whereas no differences in the number of breakups in each quadrant were observed in the control group (P=0.429). Furthermore, there was no significant difference in the breakups in the lower quadrants of the two groups (chi2=0.525, P=0.469). As the NITBUTs showed only a weak correlation with OSDI, they may not be a strong indicator of the OSDI. However, MGL indicated changes of meibomian gland morphology in the MGD group and the first tear film break-up point was likely located in the inferonasal quadrant in the MGD group. PMID- 28587371 TI - Outcome of antegrade intramedullary fixation for juvenile fifth metacarpal neck fracture with titanium elastic nail. AB - The purpose of the current study was to assess the outcome of antegrade intramedullary fixation with titanium elastic nail (TEN) in displaced fifth metacarpal neck fractures. The present study included 69 consecutive juvenile patients with displaced fifth metacarpal fractures. The head-shaft angle of the fifth metacarpal and range of motion (ROM) of the metacarpophalangeal (MCP) joint were evaluated. A disabilities of the arm, shoulder and hand (DASH) questionnaire was used to assess upper arm function. The head-shaft angle of the affected side was significantly improved postoperatively (P<0.05). No marked difference was observed between the affected and unaffected side in head-shaft angle and ROM. The average DASH score was 1.7 (range, 0-6.0). All patients obtained anatomical reduction postoperatively and the average healing time was 5.7+/-1.09 weeks (range, 5-10 weeks) with no non-union cases. Therefore antegrade intramedullary fixation with TEN is recommended as an easy, reliable and minimally invasive surgical technique for treating displaced fifth metacarpal neck fractures. PMID- 28587372 TI - Di-Huang-Yi-Zhi herbal formula attenuates amyloid-beta-induced neurotoxicity in PC12 cells. AB - Traditional Chinese medicine can be used for Alzheimer's disease management, such as the modern herbal formula Di-Huang-Yi-Zhi (DHYZ). In the present study, neuronal differentiated PC12 cells were used as a model to evaluate the effects of DHYZ against amyloid-beta peptide 25-35 (Abeta25-35) induced neurotoxicity, particularly regarding cell proliferation, apoptosis and related events. Following treatment with DHYZ, cell viability, cell membrane damage, apoptosis, mitochondrial membrane potential, cytochrome c release, caspase-3 activity and levels of reactive oxygen species in PC12 cells were detected. The results demonstrated that pretreatment with DHYZ significantly protected PC12 cells from Abeta25-35-induced proliferation inhibition, lactate dehydrogenase release and apoptosis, as well as upregulating mitochondrial membrane potential and downregulating cytochrome c release and caspase-3 activation. DHYZ also inhibited the Abeta25-35-induced reactive oxygen species generation in PC12 cells. These observations suggest that DHYZ protected PC12 cells from the Abeta-induced neurotoxicity. PMID- 28587373 TI - Thrombophilia with an onset symptom of intracranial venous thrombosis: A case report and review of the literature. AB - Thrombophilia may be hereditary or acquired and is associated with a high risk of thrombosis. The diagnosis rate for thrombophilia is low, particularly for patients with non-specific symptoms. The present study describes a patient with thrombophilia, presenting with onset symptoms for intracranial venous thrombosis. The patient had increased serum homocysteine and anticardiolipin immunoglobulin G antibodies and decreased protein S activities. In addition, the patient was obese and had a one-week history of fatigue, immobilization and insufficient water intake. Radiological findings identified multiple venous thrombosis. Since the patient had multiple risk factors for thrombosis, the diagnosis of thrombophilia was made. No mutations with definite clinical significance were identified in the assessments for mutations of the protein S-alpha (PROS1) gene. The current case highlights the importance of correct diagnosis for thrombophilia in patients who present with the onset symptoms of intracranial venous thrombosis. PMID- 28587374 TI - Protective effect of Shenmai injection on knee articular cartilage of osteoarthritic rabbits and IL-1beta-stimulated human chondrocytes. AB - Shenmai injection (SMI) has been widely used as a therapy to treat a number of diseases. However, its anti-osteoarthritic properties have not yet been fully investigated. In the present study, the protective effect of SMI on knee articular cartilage of anterior cruciate ligament transected rabbits and interleukin-1beta (IL-1beta)-stimulated human chondrocytes was investigated. For the in vivo study, knee osteoarthritis (KOA) was induced in female New Zealand white rabbits by anterior cruciate ligament transection (ACLT) in the knee of right hind limb. Rabbits either underwent sham surgery or ACLT surgery. Out of the rabbits receiving ACLT surgery, half of the rabbits received one 0.3 ml Shenmai intra-articular injection in the knee per week for four weeks, following ACLT surgery. The other rabbits received the same volume of normal saline solution. The cartilage was subsequently collected for histological evaluation. For the in vitro study, cultured human chondrocytes were treated with 10 ng/ml IL 1beta in the presence or absence of 5 and 2% (v/v) SMI for 24 h. Nitric oxide (NO) and prostaglandin E2 (PGE2) levels in cell culture supernatant were assessed using a Griess reaction and ELISA respectively. The mRNA expression of cyclooxgenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP)-1, MMP-13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in chondrocytes were detected by reverse transcription-quantitative polymerase chain reaction. The results of the current study revealed that treatment with SMI ameliorated cartilage degradation in the ACLT rabbit model, and decreased levels of NO and PGE2. Furthermore, treatment with SMI decreased levels of COX-2, iNOS, MMP-1 and MMP-13 mRNA expression and increased TIMP-1 mRNA expression in IL-1beta-stimulated human chondrocytes. These results indicate that SMI suppresses inflammation and ameliorated cartilage degradation, making it a potential and promising therapeutic option to treat KOA. PMID- 28587376 TI - Clinical progress of human papillomavirus genotypes and their persistent infection in subjects with atypical squamous cells of undetermined significance cytology: Statistical and latent Dirichlet allocation analysis. AB - The present study aimed to investigate differences in prognosis based on human papillomavirus (HPV) infection, persistent infection and genotype variations for patients exhibiting atypical squamous cells of undetermined significance (ASCUS) in their initial Papanicolaou (PAP) test results. A latent Dirichlet allocation (LDA)-based tool was developed that may offer a facilitated means of communication to be employed during patient-doctor consultations. The present study assessed 491 patients (139 HPV-positive and 352 HPV-negative cases) with a PAP test result of ASCUS with a follow-up period >=2 years. Patients underwent PAP and HPV DNA chip tests between January 2006 and January 2009. The HPV positive subjects were followed up with at least 2 instances of PAP and HPV DNA chip tests. The most common genotypes observed were HPV-16 (25.9%, 36/139), HPV 52 (14.4%, 20/139), HPV-58 (13.7%, 19/139), HPV-56 (11.5%, 16/139), HPV-51 (9.4%, 13/139) and HPV-18 (8.6%, 12/139). A total of 33.3% (12/36) patients positive for HPV-16 had cervical intraepithelial neoplasia (CIN)2 or a worse result, which was significantly higher than the prevalence of CIN2 of 1.8% (8/455) in patients negative for HPV-16 (P<0.001), while no significant association was identified for other genotypes in terms of genotype and clinical progress. There was a significant association between clearance and good prognosis (P<0.001). Persistent infection was higher in patients aged >=51 years (38.7%) than in those aged <=50 years (20.4%; P=0.036). Progression from persistent infection to CIN2 or worse (19/34, 55.9%) was higher than clearance (0/105, 0.0%; P<0.001). In the LDA analysis, using symmetric Dirichlet priors alpha=0.1 and beta=0.01, and clusters (k)=5 or 10 provided the most meaningful groupings. Statistical and LDA analyses produced consistent results regarding the association between persistent infection of HPV-16, old age and long infection period with a clinical progression of CIN2 or worse. Therefore, LDA results may be presented as explanatory evidence during time-constrained patient-doctor consultations in order to deliver information regarding the patient's status. PMID- 28587375 TI - C-X-C motif chemokine ligand 8 promotes endothelial cell homing via the Akt signal transducer and activator of transcription pathway to accelerate healing of ischemic and hypoxic skin ulcers. AB - C-X-C motif chemokine ligand 8 (CXCL-8) promotes cell homing and angiogenesis. However, under hypoxic conditions, the role of CXCL-8 in the homing of human umbilical vein endothelial cells (HUVECs), and its effect on the healing of skin ulcers caused by ischemia and hypoxia remain unknown. In the current study, assays measuring cell proliferation, in vitro angiogenesis and cell migration were performed to evaluate alterations in the proliferation, angiogenic capacity and chemotaxis of HUVECs treated with CXCL-8 protein and/or an Akt inhibitor (AZD5363 group) under hypoxic conditions. Changes in the levels of Akt, signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF), malondialdehyde (MDA) and total-superoxide dismutase (total-SOD) were also detected by western blotting and ELISA. In addition, in vivo experiments were performed using a skin ulcer model in mice. Ischemic and hypoxic skin ulcers were created on the thighs of C57BL/6J mice, and the effects of CXCL 8 and HUVEC transplantation on the healing capacity of skin ulcers was determined by injecting mice with HUVECs and/or CXCL-8 recombinant protein (CXCL-8, HUVEC and HUVEC + CXCL-8 groups). Vascular endothelial cell homing, changes in vascular density and the expression of VEGF, SOD, EGF and MDA within the ulcer tissue were subsequently measured. In vitro experiments demonstrated that HUVEC proliferation, migration and tube forming capacity were significantly increased by CXCL-8 under hypoxic conditions. Additionally, levels of VEGF, MDA and SOD were significantly higher in the CXCL-8 group, though were significantly decreased by the Akt and STAT3 inhibitors. In vivo experiments demonstrated that the expression of VEGF, total-SOD and EGF proteins were higher in the skin ulcer tissue of mice treated with CXCL-8 + HUVEC, relative to mice treated with HUVECs alone. Furthermore, vascular endothelial cell homing and vascular density were significantly increased in the CXCL-8 + HUVEC group, indicating that combined use of HUVECs and CXCL-8 may promote the healing of ischemic skin ulcers. The present results demonstrate that CXCL-8 may stimulate vascular endothelial cells to secrete VEGF, SOD and other cytokines via the Akt-STAT3 pathway, which in turn serves a key regulatory role in the recruitment of vascular endothelial cells, reduction of hypoxia-related injury and promotion of tissue repair following hypoxic/ischemic injury. PMID- 28587377 TI - Network of microRNA, transcription factors, target genes and host genes in human mesothelioma. AB - Significant progress has been made into the elucidation of the etiology of mesothelioma at the level of the genes and miRNA. Nevertheless, researchers in this field remain unable to systematically construct a network that demonstrates the specific relationships between genes, miRNA and transcription factors (TFs). TFs are key regulatory elements that control gene expression. In the present study, according to the transcriptional regulatory rule, three regulatory networks were constructed using experimentally validated elements to explore the pathogenesis of mesothelioma. We focused on the regulatory relationship between the miRNA and its host gene, the miRNA and its target gene, and the miRNA and TFs. Expressed, related and global networks were constructed, and the similarities and differences between them were analyzed. Notably, the differentially expressed network used in the present study, which was based on experimentally validated data, contained numerous incorrect expression signal pathways for the pathogenesis of mesothelioma. In theory, if these errors are corrected, this cancer may be prevented or cured. Subsequent analysis of the differentially expressed nodes and pathways may help to explain the pathogenesis of mesothelioma. Notably, some of these exhibited a self-adaption relationship, which was detected by listing the upstream and downstream elements in a table with differentially expressed genes and miRNA. The findings of the present study demonstrated detailed transcriptional regulation, which may serve as a reference to aid further elucidation of the pathogenesis of mesothelioma. PMID- 28587378 TI - Protective role of alpha-lipoic acid in hyperuricemia-induced endothelial dysfunction. AB - The aim of the current study was to determine the effects of alpha-lipoic acid (LA) on hyperuricemia and endothelial dysfunction, and to uncover the underlying mechanism of its action. A hyperuricemic rat model was established by administration of uric acid (UA) and the rats were orally fed with 2 g/kg/day LA or phosphate-buffered saline. Primary rat aortic endothelial cells were subsequently isolated, and a cell viability assay, apoptosis assay, enzyme nitric oxide synthase (eNOS) activity assay and mitochondrial function assay were all performed. For the in vitro study, human umbilical vein endothelial cells were used and western blotting was performed to assess Akt signaling activity. The results of the current study indicated that LA inhibited apoptosis, enhanced eNOS activity and production of nitric oxide (NO), and rescued mitochondrial mass and function in uric acid (UA)-treated endothelial cells. LA activated Akt signaling and inhibition of Akt signaling abolished the effects of LA on cell viability, NO production, ROS production and ATP levels in UA-treated endothelial cells. Therefore, the current study demonstrated that LA attenuated oxidant stress and inhibited apoptosis in UA-treated endothelial cells by activating Akt signaling. The results indicate that LA may serve as a therapeutic approach to treat hyperuricemia-induced endothelial dysfunction. PMID- 28587379 TI - Long non-coding RNA MALAT1 is upregulated and involved in cell proliferation, migration and apoptosis in ovarian cancer. AB - Ovarian cancer (OC) is the leading cause of mortality among gynecological malignancies. Although microRNAs are known to have a key regulatory role in OC, the involvement of long non-coding RNAs in the disease is less established. Previous studies have demonstrated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a tumor oncogene in many cancers, though its role in OC remains unclear. The present study reported that MALAT1 expression was markedly upregulated in OC, by knockdown of MALAT1 expression in vivo, using RNA interference (RNAi) with small-interfering RNA (siRNA). It was found that MALAT1 expression was positively correlated with the International Federation of Gynecology and Obstetrics stages of OC, tumor histological grade and lymph node metastasis. In addition, the differential MALAT1 levels between a human ovarian epithelial cell line (HOSE) and OC cell lines (ES-2, OVCAR3, SKOV3 and HO8910) were compared in vitro. Notably, MALAT1 was expressed to a high level in OC cells. Furthermore, exogenous knockdown of MALAT1 significantly repressed growth and migration of OC cells, and promoted their apoptosis. Collectively, the current findings suggest that upregulation of MALAT1 in OC may facilitate tumorigenesis and metastasis. Knockdown of MALAT1 expression has potential as a novel target for the diagnosis and therapy of OC. PMID- 28587380 TI - A meta-analysis to determine the efficacy and tolerability of anti-B-cell monoclonal antibodies in multiple sclerosis. AB - The present study performed a meta-analysis of randomized controlled trials in multiple sclerosis (MS) patients to evaluate the efficacy and safety of anti-B cell monoclonal antibodies (mAbs). To the best of our knowledge, no previous meta analysis has evaluated this. Relevant studies published until March 2015 were retrieved from the PubMed, EMBASE and Cochrane Library using the following keywords: 'Clinical trial', 'randomized', 'multiple sclerosis' or 'MS' and 'monoclonal antibodies' or 'mAbs'. Two authors independently selected the articles and extracted the data. The meta-analysis was performed using Review Manager version 5.3 software. Four randomized clinical trials comprising a total of 745 patients were selected. Anti-B-cell mAb treatment reduced the formation of gadolinium-enhancing lesions [mean difference (MD)=-5.62; 95% confidence interval (CI)=-8.00 to -3.24; P<0.001) and was associated with smaller volume changes of lesions on T2-weighted magnetic resonance imaging (MD=-604.40; 95% CI=-941.23 to 267.57; P<0.001). It also significantly reduced the proportion of MS patients having at least one relapse [odds ratio (OR)=0.25; 95% CI=0.14-0.44; P<0.001). Compared to placebo, anti-B-cell mAb treatment did not increase the frequency of adverse events (OR=0.90; 95% CI=0.54-1.49; P=0.68) and serious adverse events (OR=1.13; 95% CI=0.70-1.80; P=0.62). In conclusion, the present meta-analysis suggested that anti-B-cell mAbs are a relatively effective and safe treatment for MS. PMID- 28587382 TI - Effect of VBC-1814/7J, a poly-phytocompound, on a non-infectious model of pharyngitis. AB - Pharyngitis presents as an inflammation of the oropharynx, and clinical examination often shows evidence of nasopharyngitis. In numerous cases the condition occurs as a self-limiting illness of non-infectious aetiology, whose clinical management remains a matter for debate given the inappropriateness of antibiotics, the reported worsening following steroid use and the recent discouragement of the use of Chinese herbal medicine. The aim of the present study was thus to test VBC-1814/7J, a poly-phytocompound with known anti inflammatory and immune-response enhancing properties, in an experimental model of non-infectious pharyngitis. Experimental non-infectious pharyngitis was induced by applying a pyridine solution to the surface of the pharyngeal mucosa in rats that were either normally fed (group A) or fed VBC-1814/7J three days prior to and three days subsequent to the induction of pharyngitis (group B). Healthy rats treated with topical saline were used as a control (group C). At time-points of 0, one hour, one day and three days sacrifices were carried out and microscopic examination, Evans blue (EB) dye extravasation and tissue concentrations of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and mRNA of alpha- and beta-defensins were studied. As compared with group C, group A showed significant microscopic damage, EB extravasation, and increases in the levels of TNF-alpha and IL-6, as well as in the mRNA of three defensins (P<0.001) on the third day of observation. VBC-1814/7J significantly mitigated these microscopic and inflammatory markers while allowing a prompter and wider defensin reaction (P<0.05 vs. group A). These data suggest that VBC-1814/7J, as demonstrated in earlier studies, has the potential to address non-infectious pharyngitis in clinical practice. PMID- 28587381 TI - Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated efficacy in the treatment of advanced non-small cell lung cancer (NSCLC). However, their clinical efficacy is limited by acquired resistance. Drug resistance may be mediated by EGFR transduction, and a number of clinical trials have demonstrated that high-dose pulsatile TKIs may be effective at treating patients with acquired resistance, though their underlying mechanisms of action remain unknown. The aim of the present study was to investigate the antitumor activity of high-dose pulsatile gefitinib in NSCLC model cell lines, namely the EGFR-TKI-sensitive cell line PC9, as a control group, and the EGFR-TKI-resistant cell lines H1975 and H1650. The cell lines were administered with different doses of gefitinib and cell viability was measured using an MTT assay. Cell apoptosis and cycling were also determined by flow cytometry and the expression of phospho (p)-EGFR, EGFR, p-AKT and AKT were measured by western blot analysis. It was observed that the apoptotic rate of H1975 cells treated with high-dose pulsatile gefitinib significantly increased, while levels of p-EGFR and p-AKT were decreased. However, there was no significant difference in the apoptotic rate or level of p-AKT in gefitinib-treated H1650 cells, while p-EGFR levels decreased. By contrast, the EGFR-TKI-sensitive cell line PC9 exhibited sensitivity to gefitinib. It was demonstrated that the apoptosis rates were markedly increased when treated with high dose pulsatile gefitinib in PC9 cell line, while a decrease was noted in p-EGFR and p-AKT. These data suggest that high-dose pulsatile gefitinib treatment may overcome acquired resistance in NSCLC, though its efficacy is dependent on the type of drug resistance mutation(s) present. Furthermore, high-dose pulsatile gefitinib may inhibit tumor growth and induce cell apoptosis by blocking the EGFR signaling pathway. Therefore, if the signaling pathways involved in drug resistance are not activated by the EGFR gene, high-dose pulsatile gefitinib may have little efficacy in the treatment of NSCLC. PMID- 28587383 TI - Mechanism of the protective effects of the combined treatment with rhynchophylla total alkaloids and sinapine thiocyanate against a prothrombotic state caused by vascular endothelial cell inflammatory damage. AB - The aim of the present study was to investigate the effect and the underlying mechanism of the combined treatment of rhynchophylla total alkaloids (RTA) and sinapine thiocyanate for protection against a prothrombotic state (PTS) associated with the tumor necrosis factor-alpha (TNF-alpha)-induced inflammatory injury of vascular endothelial cells (VECs). A TNF-alpha-induced VEC inflammatory injury model was established, and cell morphology of VECs was evaluated using scanning electron microscopy. In addition, reverse transcription-quantitative polymerase chain reaction and western blot analysis were performed to examine the mRNA and protein expression of coagulation-related factors, including nuclear factor-kappaB (NF-kappaB), transforming growth factor-beta1 (TGF-beta1), tissue factor (TF), plasminogen activator inhibitor (PAI-1), protease-activation receptors (PAR-1) and protein kinase C (PKC-alpha) in VECs. Combined treatment with RTA and sinapine thiocyanate was demonstrated to reduce, to a varying extent, the mRNA and protein expression of NF-kappaB, TGF-beta1, TF, PAR-1, PKC alpha and PAI-1. Furthermore, combined treatment with RTA and sinapine thiocyanate was able to downregulate the expression of coagulation-related factors in injured VECs, thereby inhibiting the PTS induced by vascular endothelial injury. The underlying mechanism is partially associated with the TF mediated activation of the thrombin-receptor signaling pathway that suppresses coagulation during inflammation and balances fibrinolysis in order to inhibit fibrin generation and deposition. PMID- 28587384 TI - Upregulation of glutamate metabolism by BYHWD in cultured astrocytes following oxygen-glucose deprivation/reoxygenation in part depends on the activation of p38 MAPK. AB - Recent studies have demonstrated that Buyang Huanwu Decoction (BYHWD) decreased glutamate levels subsequent to cerebral ischemia. Glutamate transporter-1 (GLT-1) and glutamine synthetase (GS), which are located in astrocytes, mainly contribute to glutamate transportation, thus reducing glutamate concentration. BYHWD has previously been demonstrated to upregulate GLT-1 and GS following ischemia in vivo. However, whether BYHWD can directly influence astrocytic GLT-1/GS levels remains unknown. In the present study, the effect of BYHWD containing serum (BYHWD-CS) on GLT-1/GS levels in astrocytes following oxygen-glucose deprivation/reoxygenation (OGD/R) was investigated. The results revealed that BYHWD-CS enhanced the expression levels of GLT-1 and GS in cultured astrocytes, which reduced glutamate concentration in the culture medium. Meanwhile, increased p38 mitogen-activated protein kinase (p38 MAPK) was phosphorylated (activation form) by BYHWD-CS in cultured astrocytes, and the specific p38 inhibitor SB203580 blocked the increase of GLT-1/GS accompanied by decreased cell viability. Furthermore, SB203580 suppressed the effect of BYHWD-CS on the level of glial fibrillary acidic protein (an astrocytic marker), thus confirming that astrocytes are directly involved in the protective role of BYHWD after OGD/R. These findings suggest that BYHWD upregulates GLT-1 and GS via p38 MAPK activation, and protects cultured astrocytes from death caused by OGD/R (typical in vitro model), which complemented the role of astrocytes in the protective effect of BYHWD. PMID- 28587385 TI - GnRH antagonist for patients with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation for in vitro fertilization and embryo transfer in fresh cycles. AB - The aim of the present study was to evaluate the influence of a gonadotropin releasing hormone (GnRH) antagonist compared with a GnRH agonist on the in vitro fertilization cycle outcome in patients with polycystic ovary syndrome. The outcomes of pregnancy were evaluated. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was also used to evaluate whether the endometrial thickness (cm) and estradiol (E2) level (pg/ml) on the day of human chorionic gonadotropin (hCG) administration (the hCG day) had the best sensitivity and specificity for predicting a clinical pregnancy. The results demonstrated that there were significant differences in the E2 and progesterone levels between the two treatment groups on the hCG day. Furthermore, the mean number of total oocytes retrieved, mean number of 2 pronuclei oocytes, mean number of oocytes cleaved (P<0.05), mean number of embryos available (P=0.022) and mean number of embryos transferred (P=0.014) were significantly different. Additionally, the rates of ectopic pregnancy (P=0.984) and ovarian hyperstimulation syndrome (P=0.976) did not differ significantly between the treatment groups. Although the biochemical pregnancy (P=0.592), clinical pregnancy (P=0.617) and live birth (P=0.365) rates were lower with the GnRH antagonist than with the GnRH agonist, there were no significant differences in the outcomes between the two groups. Analysis of the influence of endometrial thickness with respect to the clinical pregnancy using the ROC (AUC) method revealed that when the best cutoff of 9.75 cm was used, the sensitivity was 62.5%, the specificity was 43.1% and the AUC was 0.53. Additionally, the Youden index was 0.056. Analysis of the influence of the E2 level on the hCG day on clinical pregnancy, using the ROC (AUC) method showed that the best cutoff was 2,984.5 pg/ml, which had a sensitivity of 68.8% and specificity of 52.9%, while the AUC was 0.573 (with a Youden index of 0.217). Furthermore, the results demonstrated that neither the endometrial thickness nor the E2 level on the hCG day had the best sensitivity and specificity for predicting a clinical pregnancy. PMID- 28587386 TI - SOCS3 overexpression inhibits advanced glycation end product-induced EMT in proximal tubule epithelial cells. AB - Diabetic nephropathy (DN) is among the most severe complications of diabetes mellitus, and may lead to end-stage renal disease. Sustained exposure to advanced glycation end products (AGEs) typically causes renal tubular epithelial cells (TECs) to suffer from an epithelial-to-mesenchymal transition (EMT). However, there remains no consensus regarding the mechanism underlying the cause of EMT in TECs as induced by AGEs. In the present study, we investigated the promotion of EMT in TECs by AGEs, and the activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. In addition, we constructed a recombinant adenovirus (Ad) that overexpressed suppressor of cytokine signaling 3 (SOCS3), and examined the regulatory role of SOCS3 in the activation of JAK/STAT signaling and the promotion of EMT in TECs. The results demonstrated that AGE bovine serum albumin (BSA) treatment significantly promoted the expression of EMT associated proteins, while reducing the expression of the epithelial cell marker, E-cadherin. Furthermore, the Ad-mediated SOCS3 overexpression markedly inhibited the AGE-BSA-induced JAK2/STAT3 activation; phosphorylated JAK2 and phosphorylated STAT3 expression levels were reduced by the Ad-SOCS3 infection, compared with the control Ad (Ad-con) infection, in HK-2 cells subject to AGE-BSA. Moreover, the overexpression of SOCS3 markedly inhibited the AGE-BSA-promoted EMT in HK-2 cells. AGE-BSA-promoted EMT-associated proteins, such as alpha-smooth muscle actin and collagen I, were reduced by the Ad-SOCS3 virus infection, in contrast to the Ad-con virus infection. Furthermore, reduced E-cadherin expression was reversed by the Ad-SOCS3 virus infection, in contrast to the Ad-con virus infection, in epithelial HK-2 cells. In conclusion, the present study confirmed the inhibitory role of SOCS3 in the AGE-induced EMT in renal TECs, implying the protective role of SOCS3 in DN. PMID- 28587387 TI - Functions of endothelin-1 in apoptosis and migration in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality in China and the third leading cause of cancer mortality worldwide. The mechanisms involved in the development and progression of HCC are not well understood. In the present study, the functions of endothelin-1 (ET-1) in HCC were studied and its underlying mechanisms were investigated. ET-1, B-cell lymphoma 2 (Bcl-2), Bcl 2 related protein 4 (Bax), matrix metalloproteinase (MMP)-2 and MMP-9 expression was measured by reverse transcription-quantitative polymerase chain reaction and western blotting. Cell proliferation was measured via Cell Counting kit-8 assay. Flow cytometry was performed for cell cycle and apoptosis analysis. Migration was measured via Transwell assay. The results demonstrated that ET-1 expression significantly increased in HCC tissues compared with the normal tissues of patients in The Cancer Genome Atlas dataset (P<0.01). Furthermore, downregulation of ET-1 was able to significantly inhibit cell proliferation and growth in vitro (P<0.01) and in vivo (P<0.01), and induce cell cycle arrest (P<0.05) and apoptosis (P<0.01) in the HCC SMMC-7721 cell line. Bioinformatics analysis demonstrated that the cell apoptosis signaling pathway was activated by ET-1. The ratio of B-cell lymphoma (Bcl-2) -related protein 4 (Bax)/Bcl-2 was significantly increased by downregulation of ET-1 (P<0.01). ET-1 downregulation also inhibited migration of SMMC-7721 cells (P<0.05) via decreasing levels of matrix metalloproteinase (MMP) -2 (P<0.05) and MMP-9 (P>0.05). These results suggest that ET-1 may be able to affect the apoptosis and migration of HCC cells via modulation of the Bax/Bcl-2 ratio and expression levels of MMP-2 and MMP-9, which indicates that ET-1 maybe a potential novel target for HCC treatment. PMID- 28587388 TI - Roles of the u-opioid receptor and its related signaling pathways in the pathogenesis of premenstrual syndrome liver-qi stagnation. AB - The present study aimed to investigate the roles of the u-opioid receptor (MOR) and its related signaling pathways in the pathogenesis of premenstrual syndrome (PMS) liver-qi stagnation, along with the therapeutic effects of the Shu-Yu capsule in treating the condition. A PMS liver-qi stagnation rat model was established using a chronic restraint stress method. The protein expression level of MOR within rat hippocampal tissue was detected via western blot analysis and cyclic adenosine monophosphate (cAMP) levels within the supernatant of a rat hippocampal cell culture were determined by ELISA. The western blot analysis indicated that the hippocampal expression level of MOR was significantly elevated in the PMS liver-qi stagnation model group. However, subsequent treatment with a Shu-Yu capsule was found to significantly decrease the level of MOR expression. In addition, in vitro experiments were performed, whereby primary hippocampal neurons were treated with model rat serum. It was observed that the level of MOR expression was significantly elevated, while brain-derived neurotrophic factor (BDNF) and cAMP levels in the culture supernatant were significantly decreased. These effects were reversed by treatment with serum from the Shu-Yu capsule treated rats. Furthermore, when treated with the MOR activator DAMGO, the following were significantly decreased in the primary neurons: Phosphorylation levels of cAMP response element binding protein and extracellular signal regulated protein kinases (ERK); BDNF expression; and cAMP content in the culture supernatant. These effects were reversed in primary neurons treated with DAMGO and Shu-Yu-containing rat serum. Collectively, the data suggest that increased MOR expression and activation of the cAMP/ERK signaling pathway in the hippocampus may be involved in the pathogenesis of PMS liver-qi stagnation. Furthermore, the efficacy of the Shu-Yu capsule in treating the condition may be via its regulation of MOR receptor signaling. PMID- 28587389 TI - Comparison of the hemodynamics and dynamics of fluid shift of Ringer's solution before surgery in children and adults. AB - The present study investigated the hemodynamics, vascular and extravascular volume expansion induced by infusion of lactated Ringer's solution in children and adults before surgery. This was a prospective randomized double-blind study. A total of 28 patients (14 children and 14 adult patients; American Society of Anesthesiology status I) scheduled for similar minor pelvic, anal rectal or lower limb surgery were recruited for the present study. All patients were administered with 10 ml/kg of lactated Ringer's solution at a constant rate over 20 min. After fluid infusion, plasma dilutions were calculated based on the concentration of hemoglobin. Heart rate (HR), mean arterial pressure (MAP) and urine output were measured before anesthesia was administered for surgery. Results demonstrated that the plasma dilution within 90 min of infusion initiation of lactated Ringer's solution was less pronounced in children compared with adult patients (0.07 vs. 0.16; P<0.001). Children also excreted more of the infused fluid through the kidney within 90 min of infusion initiation than the adults (55% vs. 24%; P=0.01). Following completion of fluid infusion, the volume expansion efficiency was higher in adults [0.82 (0.52-1.00)] than in children [0.46 (0.26 0.68)]. The relative changes in HR were significantly greater in children than in adults 15-60 min after infusion initiation (P<0.01). After 60 min, HRs were comparable between the groups; however, MAP declined significantly from 25-90 min after infusion initiation in children (P<0.05), yet remained nearly constant in adults (P>0.05). Simple regression analysis revealed a positive relationship between the relative changes in MAP and the plasma dilution, and the reduction in MAP in children was able to explain 47% of the variation in plasma dilution (R2=0.47; P=0.007). In conclusion, different hemodynamics and dynamics of fluid shift of Ringer's solution prior to surgery in children and adults may provide anesthesiologists with new information of how to administer fluid treatment for each patient. PMID- 28587390 TI - MicroRNA-137 acts as a tumor suppressor in osteosarcoma by targeting enhancer of zeste homolog 2. AB - MicroRNA (miR) are short non-coding RNA that bind to the 3'-untranslational region of their target genes, inhibiting translation and causing mRNA degradation. miR deregulation has been implicated in human cancer; however, the detailed regulatory mechanism of miR-137 in osteosarcoma (OS) remains largely unknown. In the present study, miR-137 and enhancer of zeste homologue 2 (EZH2) mRNA and protein expression levels were analyzed using reverse transcription quantitative polymerase chain reaction and western blotting, respectively. MTT and transwell assays were performed to evaluate cell viability and invasion capacities and a luciferase reporter gene assay was used to determine the targeting relationship. The results of the current study indicated that miR-137 expression was significantly downregulated in OS tissues and cell lines (P<0.01). Moreover, it was observed that low miR-137 expression levels were significantly associated with lung metastasis and advanced TMN stage (P<0.05), but not associated with age, gender, tumor size, location, serum lactate dehydrogenase or serum alkaline phosphatase. Increasing levels of miR-137 significantly inhibited U2OS cell viability and invasion (P<0.01). By contrast, knockdown of miR-137 markedly increased U2OS cell viability and invasion. EZH2 was identified as a direct target gene of miR-137 in U2OS cells by luciferase reporter assay and EZH2 expression was found to be significantly increased in OS tissues and cell lines (P<0.01). EZH2 was significantly downregulated following miR-137 overexpression (P<0.01), and was upregulated following miR-137 knockdown in U2OS cells. Furthermore, EZH2 overexpression significantly attenuated the suppressive effects of miR-137 on U2OS cell viability and invasion (P<0.01), suggesting that miR-137 inhibits the viability and invasion of OS cells by targeting EZH2. Therefore, the results of the current study suggest that the miR-137/EZH2 axis may be a potential target for novel potential therapeutic strategies to treat OS. PMID- 28587391 TI - Immunoregulatory effects of the traditional Dai prescription Yajieshaba on food allergic mice. AB - The Dai prescription Yajieshaba is widely used in Traditional Dai Medicine to treat food allergies and intolerance. However, information on the active chemical ingredients, effects and mechanisms of action of Yajieshaba is limited. The present study aimed to elucidate the effects and underlying mechanisms of Yajieshaba in the treatment of food allergies. Liquid chromatography with a diode array detector was used to measure the levels of palmatine and berberine, the active ingredients of Yajieshaba. A food allergy model was established in female BALB/c mice by three injections of ovalbumin (OVA) at 0, 48, and 96 h. OVA sensitized mice recieved no treatments (control), Yajieshaba, loratadine, palmatine or berberine. The scratching frequency, serum immunoglobulin (Ig)G, IgE, interleukin (IL)-4, IL-10, IL-17, IL-21, interferon-gamma and tumor necrosis factor-alpha levels were assessed at 50 and 98 h. The percentage of regulatory T cells (Tregs) was evaluated by flow cytometry at 98 h. The scratching frequency induced by OVA was significantly suppressed in mice treated with loratadine, palmatine, berberine or 3.50 and 4.70 g/kg Yajieshaba. The frequency of CD4+CD25+Treg in the spleen increased from 6.80% in mice in the control group to 12.50% in mice treated with 4.70 g/kg body weight Yajieshaba. Mice treated with palmatine or 4.70 g/kg body weight Yajieshaba had increased forkhead box p3 expression compared with those in the control group. Treatment with Yajieshaba decreased the scratching frequency and increased CD4+CD25+Foxp3+ Treg frequency in the spleen. This indicated that symptoms of allergic reaction were alleviated following Yajieshaba treatment. Palmatine was identified as one of the major active components of Yajieshaba. The present study identified the possible mechanism through which Yajieshaba treatment may alleviate food allergy symptoms. PMID- 28587392 TI - The effects of 7-nitroindazole on serum neuron-specific enolase and astroglia derived protein (S100beta) levels after traumatic brain injury. AB - We investigated the possible role of 7-nitroindazole (7-NI) in regulating serum neuron-specific enolase (NSE) and S100beta levels in a rat model of traumatic brain injury (TBI). We also explored the possible mechanism by which 7-NI may affect the level of NSE and S100beta. A total of 160 healthy adult male Sprague Dawley rats were randomly divided into 2 groups: i) The saline-treated group and ii) the 7-NI-treated group. Using the random number table, the groups were further divided into four subgroups: i) The sham-injured group; ii) the TBI 6 h group; iii) the TBI 12 h group; and iv) the TBI 24 h group (n=20). Controlled cortical impact in rats was established. Serum NSE and S100beta levels, nitric oxide (NO) level, water content, Evans blue (EB) content, malondialdehyde (MDA) level and total superoxide dismutase (T-SOD) level in the brain tissue were measured. NO synthase (NOS) activity was measured at 6, 12 and 24 h after TBI. Pathological changes in brain tissue were studied by hematoxylin and eosin (H&E) staining at each time-point. NSE and S100beta levels, NO content, water content, EB content and MDA level in the brain tissue increased significantly after TBI. NOS activity was also increased significantly after TBI while T-SOD content in brain tissue was significantly reduced after TBI. H&E staining showed that brain damage was aggravated gradually after TBI. We concluded that the early application of 7-NI significantly reduced serum NSE and S100beta levels after TBI. The neuroprotective effects of 7-NI may be associated with reduced NOS activity, reduced NO content, alleviated brain edema, lower blood-brain barrier permeability and oxidative stress. Serum NSE and S100beta levels can reflect the therapeutic effect of 7-NI, which suggest a good diagnostic value. PMID- 28587393 TI - Effects of hypoxia on differentiation of menstrual blood stromal stem cells towards tenogenic cells in a co-culture system with Achilles tendon cells. AB - Achilles tendons have a very poor capacity for intrinsic regeneration. The cell based treatment strategy for Achilles tendinitis includes the application of mesenchymal stem cells (MSCs), which have high proliferative and multipotent differentiation ability, and is a promising approach. The aim of the present study was to explore the tenogenic potential of human menstrual blood stromal stem cells (MenSCs) in a co-culture system and to compare the tenogenic capability under normoxic and hypoxic conditions. MenSCs were co-cultured indirectly with Achilles tendon cells in a Transwell co-culture system for 1, 2, or 3 weeks in two different concentrations of oxygen (20 and 2% O2), whereas the control contained only MenSCs. The extracellular matrix of MenSCs in each system was evaluated by Alcian blue staining assay, histological staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot analysis. Alcian blue staining assay revealed a significant increase (P<0.05) in proteoglycan secretion by the differentiated MenSCs. Identical results were obtained by RT-qPCR for collagen I, which was validated by western blot analysis. Considerably increased collagen I and collagen III gene expression levels were exhibited by cells in the co-culture treatment group when compared with the control (P<0.05); however, no significant difference was detected between the normoxic (20% O2) and hypoxic treatment (2% O2) groups. RT-qPCR was utilized to determine the expression levels of thrombospondin 4, scleraxis and tenascin C in the differentiated MenSCs; a significant increase in the expression of these specific genes was indicated in the co-culture treatment group compared with the control (P<0.05). Although the expression levels were markedly higher in hypoxia than in normoxia conditions, this difference was not significant. To conclude, the present study indicated that MenSCs manifested a strong proliferative and multipotent capacity for differentiation and differentiated into Achilles tenogenic cells. Therefore, the use of MenSCs may be considered in Achilles tendinitis therapy. PMID- 28587394 TI - miR-206 inhibits FN1 expression and proliferation and promotes apoptosis of rat type II alveolar epithelial cells. AB - Bronchopulmonary dysplasia (BPD) is a syndrome of respiratory distress caused by chronic lung injury, primarily in preterm infants. miR-206 and fibronectin 1 (FN1) are associated with the development of BPD. The present study used rat type II alveolar epithelial cells (AECII) to investigate the underlying mechanisms of BPD. AECII were isolated using a primary cell culture prior to alkaline phosphatase staining and immunofluorescence of surfactant protein C (SP-C). These were used to verify the presence of AECII. AECII were then divided into four groups, which were transfected with four different plasmids. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the relative expression of miR-206 in the each group. The gene and protein expression level of FN1 was detected by RT-qPCR and immunofluorescence. The proliferation of AECII in each of the four groups was evaluated using an MTT assay 48 h following transfection. The percentage of apoptotic cells was determined by flow cytometric analysis. The present study demonstrated that upregulation of miR-206 decreased the expression of FN1 (P<0.05) and low levels of miR-206 led to increased expression of FN1 (P<0.05) in AECII. Furthermore, the forced expression of miR-206 suppressed proliferation and promoted apoptosis of AECII while downregulation of miR-206 had the opposite effect (P<0.05). The results of the current study provide valuable insights into the prevention of BPD and suggest that miR-206 may be used as a potential molecular target for BPD therapy in the future. PMID- 28587395 TI - Effectiveness of imatinib mesylate over etoposide in the treatment of sensitive and resistant chronic myeloid leukaemia cells in vitro. AB - Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492+/-0.024 and 0.378+/-0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6+/-16.5 and 194+/-8.46 uM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3+/-0.2 and 31.9+/-16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3+/-8.35%) relative to K562/ADM cells (5.17+/-3.3%). In addition, the MDR genes in K562/ADM cells were knocked down by short interfering RNAs. The percentage knockdowns were 15.4% for MRP1, 17.8% for MDR and 30.7% for BCL-2, which resulted in a non-significant difference in the half maximal inhibitory concentration value of K562/ADM cells relative to K562 cells upon treatment with etoposide. PMID- 28587396 TI - Identification of the miRNA-target gene regulatory network in intracranial aneurysm based on microarray expression data. AB - Intracranial aneurysm (IA) remains one of the most devastating neurological conditions. However, the pathophysiology of IA formation and rupture still remains unclear. The purpose of the present study was to identify the crucial microRNA (miRNA/miR) and genes involved in IAs and elucidate the mechanisms underlying the development of IAs. In the present study, novel miRNA regulation activities in IAs were investigated through the integration of public gene expression data of miRNA and mRNA using the Gene Expression Omnibus database, combined with bioinformatics prediction. A total of 15 differentially expressed miRNA and 1,447 differentially expressed mRNA between IAs and controls were identified. A number of miRNA-target gene pairs (770), whose expression levels were inversely correlated, were used to construct a regulatory network of miRNA target genes in IAs. The biological functions and pathways of these target genes were revealed to be associated with IAs. Specific miRNA and genes, such as hsa let-7f, hsa-let-7d, hsa-miR-7, RPS6KA3, TSC1 and IGF1 may possess key roles in the development of IAs. The integrated analysis in the present study may provide insights into the understanding of underlying molecular mechanisms of IAs and novel therapeutic targets. PMID- 28587397 TI - Herbal acupuncture for type 2 diabetes: A meta-analysis. AB - Herbal acupuncture (HA) is a modern adjunctive technique in which natural herbs or biologic substances are injected into acupuncture points. The objective of this systematic review was to evaluate evidence of the effectiveness of HA for type 2 diabetes mellitus (T2DM). Three databases were searched. The included randomized controlled trials (RCTs) evaluated HA in controls and patients with T2DM and reported at least one of the following: Fasting blood glucose (FBG), postprandial (PP2hr) glucose and glycated hemoglobin (HbA1c). In a meta-analysis of seven RCTs (n=598 patients), HA significantly reduced levels of FBG, PP2hr glucose and HbA1c (P<0.0001, P=0.0005 and P=0.004, respectively). There was no significant effect of HA on total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride level. High degrees of heterogeneity were present for all analyses except HDL cholesterol and LDL-cholesterol. HA might have a beneficial effect on FBG, PP2hr glucose and HbA1c levels in patients with T2DM; however, because of several limitations, the results are inconclusive. Therefore, additional rigorous RCTs are warranted to overcome the limitations of previous studies. PMID- 28587398 TI - Diazoxide protects rat vascular endothelial cells against hypoxia and cold induced damage. AB - The present study aimed to examine the effects of hypoxia and cold on vascular endothelial cells (VECs), as well as the protective ability of novel VECs protective drugs against these injuries. A rat model simulating exposure to hypoxia and cold at high altitude environments was established. Based on these animal experiments, rat aortic VECs were established as injury models and exposed to hypoxia and/or adrenaline (ADR) in vitro. The results revealed that hypoxia significantly altered the levels of nitric oxide and vascular endothelial growth factor, while the cold temperature significantly increased the release of ADR and noradrenaline. Exposure to hypoxia combined with cold temperature significantly affected all these indices. In vitro experiments demonstrated that hypoxia, ADR (which was used to simulate cold in the animal experiments) and the combination of the two factors resulted in damage to the VECs and endothelial dysfunction. In addition, the results also showed that diazoxide, a highly selective mitoKATP opener, protected VECs against these injuries. In conclusion, hypoxia and cold temperature induced endothelial cell dysfunction and endocrine disorders, respectively. Improving endothelial function using diazoxide may be an effective therapeutic strategy in patients with altitude-associated disorders. However, the potential for clinical application requires further study. PMID- 28587399 TI - Cytotoxic and apoptotic activities of black widow spiderling extract against HeLa cells. AB - Black widow spiders contain toxic components not only in the venom glands but also in other parts of the spider body, including the legs and abdomen. Additionally, both the eggs and newborn spiderlings of the black widow spider contain venom. It is important to investigate their potential effects on cancer cells. In the present study, the effects of newborn black widow spiderling extract on human HeLa cells were evaluated in vitro. When applied at different concentrations, the total extract decreased HeLa cell viability in a dose dependent manner, with an IC50 value of 158 ug/ml. Flow cytometry indicated that treatment of HeLa cells with the total extract of the spiderlings induced apoptosis in HeLa cells in a dose-dependent manner and led to cell cycle arrest in the S-phase. Additionally, application of the total extract at different concentrations increased apoptosis-related caspase 3 activity in a dose-dependent manner. HeLa cells treated with the total extract appeared to be morphologically changed, exhibiting membrane blebbing, nuclear fragmentation and condensation of chromatin. Further separation and activity screening demonstrated that the cytotoxic and apoptotic activities of the total extract were attributable mainly to its high molecular mass proteins, one of which was purified and characterized to determine its anti-tumor activities on HeLa cells. The results of the present study therefore have expanded understanding regarding the effect of spider toxins on cancer cells and suggested that components of black widow spiderlings may be developed as a promising novel agent to treat cancer. PMID- 28587400 TI - Improvement of cytomegalovirus pp65 DNA vaccine efficacy by co-administration of siRNAs targeting BAK and BAX. AB - The efficacy of DNA vaccines may be improved by small interfering (si)RNA adjuvants targeting pro-apoptotic genes. The aim of the present study was to investigate the capacity of siRNAs targeting B-cell lymphoma 2 homologous antagonist killer (BAK) and B-cell lymphoma 2-associated X protein (BAX) to improve the efficacy of a cytomegalovirus (CMV) vaccine. BALB/c mice were divided into four groups (n=18 in each): unimmunized and immunized with pcDNA 3.1-pp65 expressing CMV 65 kDa matrix phosphoprotein and BAK + BAX siRNAs, pcDNA 3.1-pp65 and control siRNA, or control pcDNA 3.1 and BAK + BAX siRNAs. Immunizations were performed twice with an interval of 3 weeks. CMV-specific mouse splenocyte interferon (IFN)-gamma secretion was assessed by ELISPOT; furthermore, an in vivo cytotoxic T lymphocyte assay was performed 2 weeks after the last immunization. After lethal CMV challenge of the mice, body weight, virus titers in the spleens and salivary glands as well as survival were recorded. The amount of splenocytes secreting IFN-gamma in response to CMV pp65 peptides and specific lysis of peptide-pulsed target cells were significantly higher in mice administered pcDNA3.1-pp65 and BAK + BAX siRNAs than those in mice administered pcDNA3.1-pp65 and control siRNA (P<0.05 for each). After the virus challenge, the virus titers in the spleens and salivary glands of mice given pcDNA3.1-pp65 and BAK + BAX siRNAs were significantly lower than those in mice immunized with pcDNA3.1-pp65 and control siRNA (P<0.05 for each). Furthermore, mice immunized with pcDNA 3.1 pp65 and control siRNA or BAK + BAX siRNAs survived for longer, and at 21 days after lethal CMV challenge, 66 and 100% of these mice survived, respectively. These mice also experienced less weight loss compared with mice immunized with pcDNA3.1-pp65 and control siRNA (P<0.05). In conclusion, intradermal administration of siRNAs targeting BAK and BAX improved the efficacy of CMV pp65 DNA vaccine. PMID- 28587401 TI - Antioxidant properties of the red alga Asparagopsis taxiformis collected on the North West Algerian coast. AB - The aim of the present study was to evaluate the total phenolic and lipid content, fatty acids profiles and in vitro antioxidant activities of aqueous and solvent extracts of the red seaweed Asparagopsis taxiformis, through six different investigations. The present study demonstrated that phenol contents (mg gallic acid/g dry weight) were highest in the aqueous and methanolic extracts, followed by the ethanolic, hydroethanolic and hydromethanolic extracts. The lowest phenol contents were identified in the three remaining extracts: Butanolic, petroleum ether and acetone extracts. Furthermore, the total lipid content of the algae powder amounted to 2.85% of dry weight. The fatty acid methyl ester profiles analysed by gas-liquid chromatography represented indicated that fatty acids comprised 91.0+/-0.3% of total algae lipids. The saturated to unsaturated fatty acid contents amounted to 23.2+/-0.1 and 67.9+/-0.4% respectively. C13:0 (tridecanoate), C15:0 (pentadecanoate) and C17:0 (heptadecanoate) represented 47.4% of the total saturated fatty acids. Notably, the two most abundant unsaturated fatty acids, C15:1 (pentadecenoate) and C18:2 (octadecadienoate) represented 13.4 and 11.4% respectively, of the total unsaturated fatty acid content. Furthermore, the results of the antioxidant screening performed at 1.0 mg/ml, revealed that aqueous and methanolic extracts exhibited higher inhibition against superoxide and nitric oxide radicals and excellent radical scavenging activity [with half maximal inhibitory concentration (IC50) values 5.1 and 15.0 ug/ml, respectively], demonstrating improved antioxidant behavior when compared with standard ascorbic acid (which has an IC50 value of 3.7 ug/ml). Scavenging activity of the aqueous and methanolic extracts exhibited a strong peroxidation inhibition against linoleic acid emulsion system at a concentration of 300 ug/ml in comparison to the butylated hydroxyltoluene. Although all the studied extracts exhibited ferric reducing power, the aqueous and methanolic extracts had greater hydrogen donating ability. By contrast, hydromethanolic, ethanolic, hydroethanolic, butanolic, acetone and petroleum ether extracts exhibited weak antioxidant behavior. The antioxidant activity of potent seaweed species identified in the current study means that as well as being used as a functional food, they may be developed as novel pharmaceutical compounds and may be used as anti-ageing agents. PMID- 28587402 TI - Establishment and evaluation of a reversible two-kidney, one-clip renovascular hypertensive rat model. AB - The aim of the present study was to establish and evaluate a novel and reversible two-kidney, one-clip renovascular hypertensive rat model with a titanium vascular clip. A total of 40 male Sprague-Dawley rats were evenly and randomly divided into a sham-operated group, and 3, 7, 12 and 28D groups (namely removing the vascular clip in the renovascular hypertensive model after 3, 7, 12 and 28 days, respectively). The systolic blood pressure (SBP) and plasma renin activity (PRA) were measured, and color duplex imaging was conducted before placing the clips, as well as before and after removing them. After placing the vascular clips, SBP and PRA in the 3, 7, 12 and 28D groups were significantly increased (SBP: Sham operated vs. 3D groups, P=0.020; 3 vs. 7D groups, P=0.008; 7 vs. 28D groups, P=0.019; 12 vs. 28D groups, P=0.039, and between other groups P<0.001. PRA: 3 vs. 7D groups, P=0.001; 7 vs. 12D groups, P=0.004; 12 vs. 28D groups, P=0.040, and between other groups, P<0.001). After removing the clips, SBP were significantly reduced in the 3 and 7D groups (P=0.023, 0.040, 0.066 and 0.314 in the 3, 7, 12 and 28D groups, respectively), but were still significantly higher than that before placing clips in the 7, 12 and 28D groups (P=0.067, P=0.005, P<0.001 and P<0.001 in the 3, 7, 12 and 28D groups, respectively). After removing the clips, PRA was significantly reduced in each group (P<0.001, P<0.001, P=0.012 and P=0.049 in 3, 7, 12 and 28D groups, respectively), but still higher than that before placing the clips (P<0.001, P=0.001, P=0.001 and P=0.003 in 3, 7, 12 and 28D groups, respectively). Vascular imaging also indicates this model has a reversible property. In conclusion, a reversible renovascular hypertension rat model is feasible, and provides a basis for research on clinical ischemic nephropathy and renal artery revascularization. PMID- 28587403 TI - Effects of 1,25-dihydroxyvitamin D3 on the local bone renin-angiotensin system in a murine model of glucocorticoid-induced osteoporosis. AB - Active vitamin D is closely related to the circulating renin-angiotensin system (RAS) in experimental animal models and humans; however, corresponding local bone data remain limited. The present study examined whether 1,25-dihydroxyvitamin D3 supplementation altered local bone RAS elements in a murine model of glucocorticoid-induced osteoporosis (GIOP). A total of 36 8-week-old mice were randomized into three equal-sized groups: The sham, GIOP and 1,25 dihydroxyvitamin D3 treatment groups. After 12 weeks, the cancellous bone microstructure of the third lumbar vertebra and left femur from the mice from each group were examined using micro-computed tomography. To access the impact of glucocorticoid use, the effect of 1,25-dihydroxyvitamin D3 on cancellous bone microstructure, the expression of bone turnover markers, circulation and expression of the main RAS components was assessed. Results demonstrated that bone volume fraction, trabecular number and trabecular thickness of the treatment and sham groups were significantly higher than the GIOP group (P<0.05). Furthermore, the structure model index, trabecular separation and bone surface to bone volume ratio of the sham and treatment groups were significantly reduced compared with the GIOP group (P<0.05). All assessed parameters exhibited no significant differences between the treatment and sham groups. mRNA expression levels of local bone angiotensin type 1 and 2 receptors and receptor activator of nuclear factor-kappaB ligand were significantly lower in the treatment group than in the GIOP group (P<0.05); however, there were no significant differences in circulating protein levels between the groups (P>0.05). In conclusion, 1,25 dihydroxyvitamin D3 may modulate bone metabolism by downregulating the local bone RAS in mice with GIOP. PMID- 28587404 TI - Glucose-regulated protein 78 is an antiviral against hepatitis A virus replication. AB - Infection with hepatitis A virus (HAV) is a major cause of acute hepatitis globally and it is important to identify the mechanisms of HAV replication. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum (ER) chaperone and serves a role in unfolded protein response pathways. Previous studies have demonstrated that GRP78 functions as an endogenous antiviral factor. In the present study, two loss-of-function studies using GRP78 were completed to elucidate the role of GRP78 in HAV infection. HAV replication was observed to be enhanced by deficient GRP78 although GRP78-deficiency also led to lower expression of ER stress molecules downstream of GRP78. Therefore, GRP78 appears to be a potential novel defensive molecule against HAV in hepatocytes. PMID- 28587405 TI - miRNA-186 inhibits prostate cancer cell proliferation and tumor growth by targeting YY1 and CDK6. AB - microRNAs (miRNAs) are known to be important in tumor initiation and progression. Recent studies have demonstrated that miR-186 is critical in several types of cancer, including human non-small cell lung cancer, bladder cancer and pancreatic ductal adenocarcinoma. However, the functions of miR-186 in prostate cancer (PCa) are still unclear. In the present study, downregulation of miR-186 in PCa cells was detected when compared with the normal prostate cell line. When miR-186 overexpressed in PCa cells, cell proliferation in vitro was evidently inhibited as shown using cell counting kit-8 assays and cell-cycle analysis, and tumor growth in vivo was decreased as shown by tumor growth assays in nude mice. Furthermore, through bioinformatics prediction and biochemical analyses, Yin Yang 1 (YY1) and cyclin-dependent kinase 6 (CDK6) have been proven to act as direct targets of miR-186. These results indicate that miR-186 is a negative regulator in PCa by inhibiting PCa cell proliferation via targeting YY1 and CDK6. PMID- 28587406 TI - Neuroprotective mechanisms of miR-124 activating PI3K/Akt signaling pathway in ischemic stroke. AB - The neuroprotective mechanisms of miR-124 activating phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ischemic stroke were investigated. The oxygen glucose deprivation model of nerve cells induced by PC12 cells was established in vitro, then miR-124 mimics or inhibitor was transfected and synthesized by liposome. Cells were divided into the blank control, model, mimics and inhibitor groups, and the apoptotic rate was determined using flow cytometry. Additionally, the expression levels of PI3K, Akt, Bax, Bcl-2, caspase-3 mRNA and protein were tested by quantitative PCR and western blot analysis at 0, 3, 6, 12 and 24 h, respectively. The apoptotic rate at each time-point in the blank control group was not significantly different. The apoptotic rate of the model and inhibitor groups increased over time, whereas the mimics group decreased (P<0.05). The apoptotic rate at each time-point in the mimics group was significantly lower than that of the model and inhibitor groups, and the rate of the inhibitor group was higher than that of the model group (P<0.05). PI3K, Akt and Bcl-2 mRNA and protein expression levels at the different time-points in the mimics group were significantly higher than those of the remaining groups (P<0.05). The expression levels of Bax and caspase-3 mRNA and protein in the inhibitor group were the highest, followed by the model and mimics groups, while that of the blank control group was the lowest (P<0.05). The results suggest that miR-124 participates in the neural protection of ischemic stroke by activating the PI3K/Akt signaling pathway. PMID- 28587407 TI - Clinical study of botulinum toxin A injection combined with spasmodic muscle therapeutic instrument on lower limb spasticity in patients with stroke. AB - The clinical effect of botulinum toxin A (BTX-A) injection combined with spasmodic muscle therapeutic instrument with simple BTX-A injection was compared. Eighty patients with stroke were randomly divided into the treatment and control groups of 41 and 39 cases, respectively. The two groups of patients were given routine rehabilitation therapy. Ultrasound-guide positioning technology was used; treatment group was administered BTX-A injection combined spasmodic muscle therapeutic instrument while the control group received only BTX-A injection. Muscle tension and motor function were evaluated at 1, 4, 8 and 12 weeks after treatments by rehabilitation physician who was not aware of the grouping of the patients. Muscle tension was significantly reduced after BTX-A injection in the treatment and control groups. Modified Ashworth scale scores of the treatment and control groups 1 and 4 weeks after treatment were significantly lower than those before treatment. Motor function of lower limbs of patients, 1 and 4 weeks after treatment improved significantly. The comparison of step size and walking speed of the groups showed obvious differences with statistical significance (P<0.01). In conclusion, ultrasonic guidance BTX-A injection is easy to operate with good safety. It can effectively improve extensor myospasm of lower limb of patients with rapid onset and the spasm relief can last for three months. Spasmodic muscle therapeutic instrument can improve the spasm condition of lower limb muscle after stroke as well as motor function of lower limbs and activity of daily living, which can make spasmolysis of BTX-A last for a longer period of time. PMID- 28587408 TI - Normalization of regulatory T cells, serum TGF-beta1, and LTN after 5 aminolevulinic acid-photodynamic therapy in patients with condyloma acuminate. AB - The purpose of this study was to investigate the changes in peripheral blood regulatory T (Treg) cells, serum transforming growth factor-beta1 (TGF-beta1), and lymphotactin (LTN) following treatment of patients with condyloma acuminata (CA) with 5-aminolevulinic acid-photodynamic. A total of 46 patients with CA were selected as the experimental group and 43 healthy individuals were included in the control group. Before the treatment, the CA patients had a higher number of CD4+CD25+Foxp3+ Treg cells and CD4+CD25+ Treg cells than the healthy group. CA patients also had lower levels of serum TGF-beta1 and LTN than the healthy controls. After the treatment, the number of CD4+CD25+Foxp3+ Treg cells and CD4+CD25+ Treg cells decreased significantly in the CA patients and normalized to the levels in the control group after 3 weeks. The treatment also elevated the levels of serum TGF-beta1 and LTN in the CA patients, which were close to the values in the control group after 3 weeks. The results showed that low levels of serum TGF-beta1 and LTN played important roles in the occurrence and development of CA and cellular immune functions were closely related to the occurrence and development of CA. PMID- 28587409 TI - Correlation between NF-kappaB signal pathway-mediated caspase-4 activation and Kawasaki disease. AB - The aim of the study was to investigate the role and mechanisms of action of nuclear factor-kappaB (NF-kappaB)-mediated caspase-4 activation in the induction of inflammatory cytokines during Kawasaki disease (KD) and coronary artery endothelial cell injury. Peripheral blood mononuclear cells (PBMCs) were isolated from KD patients and healthy controls and cultured. Double antibody sandwich enzyme-linked immunosorbent assay (ELISA) was applied to detect tumor necrosis factor (TNF)-alpha levels in activated PBMC-conditioned culture media. To establish a culture model for human coronary artery endothelial cells (HCAECs), we employed KD patient-origin PBMC culture-conditioned media to induce HCAEC transformation and detected the nuclear activation of NF-kappaB p65 and intracellular caspase-4 protein concentrations using western blot analysis. We also investigated the nuclear transfer of NF-kappaB p65 using immunofluorescence, as well as HCAEC interleukin (IL)-6 and IL-1beta secretion using ELISA. Finally, we investigated HCAEC apoptosis using using Annexin V/PI double staining. After PBMCs were stimulated in vitro, TNF-alpha secretion was significantly higher in the KD group versus controls (P<0.01). HCAEC cells treated with supernatant conditioned by cells from KD patients showed a significant elevation of NF-kappaB p65 and caspase-4 protein expression versus HCAEC cells treated with supernatant conditioned by control cells (P<0.01). Similarly, IL-6 and IL-1beta secretion, as well as apoptotic rate, were significantly elevated (P<0.01). SN50, an NF-kappaB inhibitor, significantly attenuated caspase-4 expression, secretion of IL-6, IL 1beta, and TNF-alpha, as well as HCAEC apoptosis in cells treated with KD patient PBMC-conditioned media. NF-kappaB can induce the generation of various inflammatory factors including IL-6 and IL-1beta, mediate the expression of caspase-4 in HCAEC cells, and affect apoptosis and injury of HCAEC cells. Therefore, the expression of caspase-4, mediated by NF-kappaB signal pathway, plays a critical role in KD. PMID- 28587410 TI - A case report of the orbit, ocular association and the lung in granulomatosis with polyangiitis: A diagnostic challenge. AB - Granulomatosis with polyangiitis (GPA) is a systemic form of vasculitis that involves small to medium sized vessels and is associated with high morbidity and mortality. GPA presents a continuous and difficult clinical diagnostic concern, due to the rarity of the disease and the diversity of the manifestations. This case report discusses the unusual symptoms presented by a particular patient, discusses these manifestations and explains how the final diagnosis was identified as GPA. A 40-year old Chinese woman was initially referred to the present institution for a progressive worsening pain, redness and gradual decrease in visual acuity in the eyes over the past 7-year period. Previous therapeutic interventions included noncompliant topical and intravenous dexamethasone for 6 years. A pre-operative examination conducted in a differing hospital to search for the presence of an orbital mass, resulted in the identification of an asymptomatic space-occupying lesion in the right middle lung, which was surgically removed in March 2015. A total of four weeks later, surgery was then applied to remove a left orbital mass, in the same hospital. A total of three months later, the patient was diagnosed with peripheral ulcerative keratitis associated with GPA, at the present institution. The corneal lesions were then treated bilaterally with cryotherapy and oral prednisone and cyclophosphamide were administered. Following surgery, the condition of the eyes appeared to be stable. A total of seven months later, the redness and pain of the right eye recurred, followed by a deep lamellar keratoplasty for the treatment of necrotizing scleritis. The condition of the two eyes was subsequently observed to be stable during the nine month follow-up. The present case study reviews various points to consider in a rare, complicated and potentially blinding case of GPA. GPA must therefore be considered in the differential diagnosis of further inflammatory conditions and tumors. Early diagnosis and an appropriate interdisciplinary approach to management, are required to decrease recurrence and morbidity in patients with GPA-mediated inflammatory ocular disease. PMID- 28587411 TI - Erythropoietin and sildenafil protect against ischemia/reperfusion injury following testicular torsion in adult rats. AB - Testicular torsion/detorsion causes severe tissue damage due to ischemia/reperfusion injury. The present study investigated the protective effect of erythropoietin and sildenafil against ischemia/reperfusion injury following unilateral testicular torsion/detorsion in adult rats. A total of 28 adult male rats were included, and were divided into the following groups: Group A (n=5), sham operated; groups B (n=5), C (n=5), D (n=5) and E (n=8), undergoing right testis torsion and detorsion after 90 min. Group B received no drug treatment. Rats in the groups C and D received low-dose (1,000 IU/kg) or high-dose (3,000 IU/kg) erythropoietin, while those in group E received sildenafil (0.7 mg/kg), through intraperitoneal injection after 60 min of torsion. The right testis was extracted 24 h after detorsion, and the tissue was subjected to histopathological examination and immunohistochemical assessment of cleaved caspase-3 expression. Histological alterations and the quality of spermatogenesis were scored according to the Cosentino and the Johnsen scoring systems, respectively. The results demonstrated normal testicular architecture in group A, while the other groups showed ischemic cellular damages, with the worst scores observed in group B. Groups D and E presented better scores compared with group C. Regarding the quality of spermatogenesis, the best scores were observed in group A, and the worst in group B. Groups C, D and E presented similar results, which were improved in comparison to group B, however, not compared to group A. Furthermore, cleaved caspase-3 levels were lower in groups A, D and E, with equal results observed. Group C had higher levels of cleaved caspase-3 compared with these groups, but lower than group B, which presented the highest cleaved caspase-3 levels. In conclusion, erythropoietin and sildenafil protect testis from ischemia/reperfusion injury by decreasing cellular damage and attenuating apoptosis. PMID- 28587412 TI - ERK1/2 pathway regulates coxsackie and adenovirus receptor expression in mouse cardiac stem cells. AB - Cardiac stem cells (CSCs) are the most promising and effective candidates for the therapy of cardiac regenerative diseases; however, they have marked limitations. For instance, the implantation of CSCs is hampered by factors such as their sustainability and long-term durability. Gene modification appears to be the most effective method of optimizing CSCs and gene therapy trials have demonstrated that efficient gene transfer is key to achieving therapeutic efficacy. However, the transduction ability of adenovirus (Ad) is limited. Previous studies have reported that low expression of coxsackie and adenovirus receptor (CAR) in target cells decreases the transduction efficiency. A promising method for improving Ad mediated gene transfer is to increase CAR expression in target cells. The present study investigated the effect of the Raf-mitogen-associated protein kinase (MAPK) kinase (MEK)-extracellular signal-associated protein kinase (ERK) signaling pathway on the expression of CAR on CSCs, as this pathway decreases cell-cell adhesion via cell surface molecules. The results demonstrated that interference with the Raf-MEK-ERK signaling pathway by knockdown of ERK1/2 upregulated the expression of CAR. The entry of the Ad into the cells was increased following inhibition of ERK1/2. Moreover, following knockdown of CAR, the entry of Ad into cells was decreased. However, knockdown of c-Jun N-terminal kinase and p38 as other components of the MAPK pathway did not affect CAR expression. Therefore, CAR expression in CSCs may be mediated via the Raf-MEK-ERK signaling pathway. Upregulation of CAR by knockdown of ERK1/2 may significantly improve Ad-mediated genetic modification of CSCs in the treatment of cardiovascular diseases. PMID- 28587413 TI - Decreased trabecular bone deterioration of proximal tibiae and lumbar vertebrae in postmenopausal women with osteoarthritis. AB - Osteoporosis and osteoarthritis (OA) are two common age-related skeletal disorders, which are associated with substantial morbidity and disability, particularly among elderly women. The present study was performed to investigate the trabecular bone deterioration of proximal tibiae and lumbar vertebrae in postmenopausal women with OA. The results demonstrated that the histomorphometric section of trabecular bone below the growth plate was markedly different between the healthy control and OA group. However, the loss of trabecular bone underneath the growth plate in the healthy control group was significantly worse than that of the OA group. Hematoxylin and eosin staining demonstrated the increased disconnection and separation of the trabecular bone network as well as the reduction of trabecular bone mass of primary and secondary spongiosa throughout the proximal metaphysis of tibia in the healthy control compared to the OA group; similar results were found when the same experiment was repeated on the lumbar vertebrae of healthy control subjects and OA patients from postmenopausal women. The biological properties of trabecular bone in the proximal tibia and lumbar vertebrae were measured in postmenopausal women with OA. Spearman's rank correlation analysis revealed that the bone volume fraction was both positively correlated with radiographic severity and Western Ontario McMaster University Osteoarthritis Index scores in in the proximal tibia and lumbar vertebrae from postmenopausal women with OA. In conclusion, the structural properties of the proximal tibia and lumbar vertebrae supported that an inverse correlation existed between postmenopausal women with OA and healthy controls. Moreover, there is an important protective mechanism of OA on trabecular microstructure in proximal tibiae and lumbar vertebrae from postmenopausal women. PMID- 28587414 TI - Effect of intravitreal injection of ranibizumab on retinal ganglion cells and microvessels in the early stage of diabetic retinopathy in rats with streptozotocin-induced diabetes. AB - The aim of the present study was to investigate the effect of intravitreal injection of ranibizumab on retinal ganglion cells and microvessels at the early stage of diabetic retinopathy (DR) in rats with streptozotocin-induced diabetes mellitus (DM). DM was induced by a single intraperitoneal injection of 60 mg/kg body weight streptozotocin. A total of 80 diabetic rats were randomly assigned to four treatment groups (n=20 in each group) and were treated with an oculus dexter intravitreal injection of ranibizumab. Groups A and B were injected with ranibizumab two and four weeks after DM-induction, respectively, while groups a and b (controls) were injected with phosphate-buffered saline at the same time points. In addition, 20 normal rats were assigned to group N (blank control; without intraocular injection). Vitreous humors were isolated for vascular endothelial growth factor (VEGF)-A ELISA and retinas were obtained for hematoxylin and eosin staining, periodic acid-Schiff staining and fluorescence imaging techniques at six and eight weeks after the onset of DM. At six and eight weeks, a significantly increased in retinal ganglion cells (RGCs) was observed in group A compared with group a (P<0.01), and in group B compared with group b (P<0.01). In addition, there was a significant difference in the RGC level between groups A and B at six weeks after DM induction (P<0.01), but not at eight weeks (P>0.05). VEGF-A concentrations in rat vitreous humors were significantly lower in groups A and B compared with groups a and b at six and eight weeks after DM induction (P<0.01). Furthermore, the ratio of endotheliocytes to pericytes in groups A and B was significantly lower compared with groups a and b at six and eight weeks (P<0.05). Furthermore, it was also demonstrated that type IV collagen positive strands were not present in group A during the eight-week observation period, which was significantly different from groups a, b and B (P<0.01). In conclusion, intravitreal injection of ranibizumab at a very early stage of DR in streptozotocin-induced DM rats slowed the progression of DR by reducing vascular regression or damage and maintaining RGC numbers, as well as reducing VEGF-A concentrations. PMID- 28587415 TI - Lymph node tuberculosis mimicking malignancy on 18F-FDG PET/CT in two patients: A case report. AB - 18F-fluorodeoxyglucose positron emission/computed tomography (18F-FDG PET/CT) imaging, an established procedure for evaluation of malignancy, reports an increased 18F-FDG uptake in acute or chronic inflammatory condition. Lymph node tuberculosis (LNTB) is the most common form of extrapulmonary tuberculosis. However, the absence of clinical symptoms and bacteriological basis makes it difficult to diagnose. In the current case report, two patients with LNTB mimicking malignant lymphoma are presented by 18F-FDG PET/CT. The objective of the present report is to emphasize that LNTB should be considered as a noteworthy differential diagnosis in patients with enlarged lymph nodes, particularly in tuberculosis-endemic countries, and that lymph node biopsy serves a vital role in diagnosing LNTB. PMID- 28587416 TI - Berberine alleviates dextran sodium sulfate-induced colitis by improving intestinal barrier function and reducing inflammation and oxidative stress. AB - Berberine has demonstrated efficacy in alleviating experimental colitis in vivo and in vitro. However, the anti-colitis mechanisms of berberine that enable it to promote intestinal barrier function in vivo remain unclear. The present study aimed to evaluate the effect of berberine on intestinal epithelial barrier function, expression of tight junction proteins and the levels of inflammatory and oxidative stress factors in the intestinal mucosa of dextran sulfate sodium (DSS)-induced colitis mice. Berberine (100 mg/kg) was administered for five days to mice with established colitis, induced by administration of DSS (3% w/v) for six days. Intestinal barrier function and the presence of proinflammatory factors, oxidative stress and active signaling pathways in the colon were determined principally by western blotting and reverse transcription-quantitative polymerase chain reaction. It was observed that berberine reduced weight loss, shortening of the colon and colon damage in DSS-colitis mice. In addition, berberine significantly inhibited the increase of fluorescein isothiocyanate dextran in serum and the decrease of zonula occluden-1 (also known as tight junction protein-1), occludin and epithelial cadherin expression in colonic tissue, relative to a DSS-treated control group. Berberine also significantly inhibited the expression of interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha mRNA and phosphorylation of signal transducer and activator of transcription 3. Furthermore, berberine reduced the levels of myeloperoxidase and increased the levels of superoxide dismutase and catalase in colon and serum samples relative to the control group. The expression of cluster of differentiation 68 in the colon of colitis mice was also reduced by berberine. Collectively, these data suggest that berberine alleviates colitis principally by improving intestinal barrier function and promoting anti-inflammatory and antioxidative stress responses. In turn these effects inhibit macrophage infiltration into the colon and thus may be central to the anti-colitis activity of berberine. PMID- 28587417 TI - A comparative study for the short-term effects of targeted high-intensity UVB and narrow-band UVB in the treatment of vitiligo. AB - Vitiligo is a common acquired depigmentation disorder for which many treatments have previously been used with varying effects. The aim of the present study was to evaluate the efficacy and safety of targeted high-intensity (TH) and narrow band (NB) ultraviolet B light (UVB) for vitiligo treatment. A total of 33 patients with vitiligo were enrolled in the present study. Patients with a symmetrical or near-symmetrical distribution of lesions on their bodies were selected for the present study. For each patient, half of the body was treated with TH-UVB and the other with NB-UVB twice weekly over a period of 12 weeks (24 times total). The patients were assessed each week for repigmentation of lesions. All data were analyzed using SPSS software, and a total of 30 patients were evaluated. The effective rate was significantly higher in the TH-UVB group (56.7%) compared with the NB-UVB group (20.0%; P<0.05). Additionally, the mean number of radiations necessary for initial repigmentation was significantly lower in the TH-UVB group (7.95+/-3.43) compared with the NB-UVB group (15.36+/-3.43; P<0.05). No correlation was found between the clinical features of patients and the efficacy of treatment. In summary, the results of the present study suggest that TH-UVB is a more effective treatment for vitiligo than NB-UVB. PMID- 28587419 TI - Regulation of the angiotensin II-p22phox-reactive oxygen species signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 retrieval in hyperoxia induced lung injury and fibrosis in rats. AB - The present study was designed to explore the impact of hyperoxia on lung injury and fibrosis via the angiotensin II (AngII)-p22phox-reactive oxygen species (ROS) signaling pathway, apoptosis and 8-oxoguanine-DNA glycosylase 1 (OGG1) repair enzyme. Newborn Sprague-Dawley rats were randomly divided in the newborn air group, newborn hyperoxia group and newborn intervention group, the latter of which was administered the chymotrypsin inhibitor, 2-(5-formylamino-6-oxo-2 phenyl-1, 6-dihydropyrimidine-1-yl)-N-[4-dioxo-1-phenyl-7-(2-pyridyloxy)] 2 heptyl-acetamide (NK3201). A group of adult rats also received hyperoxic treatment. Histomorphological changes in lung tissues were dynamically observed. AngII, ROS, angiotensin type 1 receptor (AT1R) and p22phox messenger RNA (mRNA) levels, and OGG1 and peroxisome proliferator-activated receptor-gamma (PPARgamma) protein levels in the lung tissues were detected at various times after hyperoxia. Hyperoxia led to traumatic changes in the lungs of newborn rats that resulted in decreased viability, increased mortality, morphological changes and the apoptosis of alveolar type II epithelial cells (AT-II), as well as increased expression levels of AngII, AT1R and p22phox, which would ultimately lead to secondary diseases. NK3201 significantly inhibited the hyperoxia-induced increased expression of AngII, AT1R and p22phox and further promoted OGG1 and PPARgamma protein expression, thus reducing the intrapulmonary ROS level, the apoptotic index and caspase-3 levels. However, the adult hyperoxia group only exhibited tachypnea and reduced viability. This study suggested that the AngII p22phox-ROS signaling pathway, PPARgamma and OGG1 together contributed to the hyperoxia-induced lung injury and that NK3201 was able to reverse the effects of hyperoxia. PMID- 28587418 TI - Synergistic inhibition of leukemia WEHI-3 cell growth by arsenic trioxide and Hedyotis diffusa Willd extract in vitro and in vivo. AB - Arsenic trioxide (ATO) is clinically used to treat acute promyelocytic leukemia (APL); however, the therapeutic dose of ATO may prompt critical cardiac side effects. Combination therapy may be used to improve the therapeutic efficiency. To evaluate this possibility, the present study determined the combined effects of Hedyotis diffusa Willd (HDW) extract and ATO in leukemic WEHI-3 cells. The results demonstrated that co-treatment of HDW with ATO resulted in a synergistic augmentation of cytotoxicity in cells at the concentration tested. In order to investigate the potential therapeutic application for leukemia, the combined effects of HDW and ATO were analyzed on the WEHI-3 cell-induced orthotopic leukemia animal model in vivo. The WEHI-3 cells in mice with leukemia were established by injecting murine WEHI-3 cells into BALB/c mice, and treating them with HDW and/or combined with ATO. The results indicated that HDW alone or HDW combined with ATO promoted the total survival rate of mice with leukemia, and these effects are dose-dependent. HDW alone or HDW combined with ATO did not affect the body weight, decreased the spleen weight and did not affect the liver weight. Furthermore, the results demonstrated that HDW alone or HDW combined with ATO resulted in a synergistic augmentation of apoptosis in WEHI-3 cells at the concentration tested. In order to further reveal the detailed mechanism of this synergistic effect on apoptosis, apoptosis-related proteins were also evaluated. The data revealed that HDW alone or HDW combined with ATO induced the expression of death receptor 4 (DR4) and DR5 and the activation of poly adenosine diphosphate ribose polymerase, caspase-3, -8 and -9. Furthermore, HDW alone or HDW combined with ATO decreased the expression levels of B-cell lymphoma 2, B cell lymphoma-extra large and survivin, and increased the expression levels of Bak and t-Bid. Altogether, the results indicate that the combination of HDW with ATO may be a promising strategy used to increase the clinical efficacy of ATO in the treatment of APL. PMID- 28587420 TI - Suppressive effect of microRNA-138 on the proliferation and invasion of osteosarcoma cells via targeting SIRT1. AB - MicroRNAs (miRs), a class of small non-coding RNAs, function as key regulators in gene expression through binding to the 3'-untranslated region (UTR) of their target mRNA, which further leads to translational repression or mRNA degradation. Recently, miR-138 has been found to have a tumor suppressive role in a variety of human malignancies. However, the exact role of miR-138 in regulating the malignant phenotypes of osteosarcoma (OS) has remained to be elucidated. In the present study, reverse-transcription PCR analysis showed that the expression of miR-138 was markedly reduced in OS tissues compared to that in matched adjacent non-tumorous tissues. Furthermore, it was also downregulated in several common OS cell lines, when compared with that in a normal human osteoblast cell line. Overexpression of miR-138 suppressed cell proliferation and invasion and led to a significant decrease in the protein expression of sirtuin 1 (SIRT1), which was further identified as a direct target gene of miR-138 in MG63 cells. Moreover, restoration of SIRT1 expression reversed the suppressive effects of miR-138 on MG63 cell proliferation and invasion. Finally, the expression of SIRT1 was found to be significantly upregulated in OS tissues compared to that in matched adjacent tissues, and SIRT1 levels were inversely correlated with the miR-138 levels in OS tissues. Therefore, the present study demonstrated that miR-138 has a role in inhibiting OS cell proliferation and invasion via directly targeting SIRT1, and suggested that the miR-138/SIRT1 axis may become a promising therapeutic target for OS. PMID- 28587421 TI - Effect of Suo Quan Wan on the bladder function of aging rats based on the beta adrenoceptor. AB - Suo Quan Wan (SQW) has been used to treat lower urinary tract symptoms (LUTS) in elderly patients for hundreds of years in China. beta-adrenoceptors (beta-ARs), particularly beta3-adrenoceptor (beta3-AR), was reported to be important in the bladder dysfunction of the elderly. The present study was conducted to explore the effect of beta-AR, and particularly the beta3-adrenoceptor, in aging rat bladder function in vitro and to test the therapeutic effect of SQW on LUTS in an aging rat model based on the beta3-adrenoceptor. Briefly, the bladder detrusor muscles of young (age, 3 months) and aging (age, 15 months) female rats were separated. A beta-AR non-selective agonist, isoprenaline (ISO), subtype beta3-AR agonist (BRL37344A) and beta3-AR antagonist (SR59230A) were used to define the tension change of detrusor muscles between young and aging rats in vitro. For blank controls, 12 young rats were marked, and 48 aging female rats were randomly divided into four groups as follows: Model, SQW high, SQW middle and SQW low. Following oral administration of SQW for 6 weeks in aging rats, urodynamic and bladder detrusor tests were used to evaluate the therapeutic effect of SQW. The expression of beta3-AR mRNA was investigated using reverse transcription quantitative polymerase chain reaction. Using ISO and BRL37344A in vitro, maximum relaxation (Emax), intrinsic activity (IA), and log (50% effective concentration) (PD2) were significantly decreased in aging rats compared with that in young rats (P<0.05). Significant changes were also observed in the beta3-AR antagonist experiment, which blocked ISO-induced relaxation, with significant decreases observed in Emax, IA and PD2, and a significant increase observed in PA2 for the aging rats compared with the young controls (P<0.05). SQW was demonstrated to enhance bladder control, storage and contraction ability. Furthermore, SQW was able to increase the sensitivity and expression of beta3-AR in an aging rat. In conclusion, the decrease in beta3-AR sensitivity in aging rats and the expression resulted in bladder detrusor dysfunction. In addition, the therapeutic effect of SQW against LUTS relies on the former's effect on the urethral sphincter, bladder detrusor and beta3-AR. PMID- 28587422 TI - Application of vibration response imaging technology in patients with community acquired pneumonia before and after the treatment. AB - The value of vibration response imaging (VRI) technology in patients with community-acquired pneumonia (CAP) was assessed. The VRI images of 62 cases of CAP patients with normal lung functions before and after treatment were observed and the changes in images before and after treatment were compared. The maximum vibration energy value of CAP patients was 1.64+/-0.32, patients with unsmoothed vibration energy curve accounted for 88.71%, 41 cases (66.12%) had unordered dynamic images, 56 cases (90.32%) jumping images, 54 cases (87.10%) desynchrony, 58 cases (93.55%) delay and 52 cases (83.87%) showed contrary events. The maximum vibration energy value after treatment was 1.59+/-0.29 and the difference was not statistically significant (P=0.93). Patients with unsmoothed vibration energy curve accounted for 20.97%, 11 cases (17.74%) appeared as unordered dynamic images, 28 cases (45.16%) of jumping images, 21 cases (33.87%) desynchrony, 18 cases (29.03%) delay and 10 cases (16.13%) with contrary events. The differences of these symptoms before and after treatment were statistically significant. The image scores of CAP patients before treatment were 10.33+/-1.95, higher (P<0.001) than after treatment (3.49+/-2.29). In conclusion, the changes of VRI images of CAP patients are relatively obvious and this technology can be used for the evaluation of CAP curative effects. PMID- 28587423 TI - Notch4 signaling pathway in a Kawasaki disease mouse model induced by Lactobacillus casei cell wall extract. AB - The present study aimed to explore the role of the Notch4 signaling pathway in a mouse model of Kawasaki disease (KD) induced by Lactobacillus casei cell wall extract (LCWE). BALB/c male mice (4-6 weeks old) were intraperitoneally injected with 500 ug LCWE in phosphate-buffered saline (PBS) or PBS alone (control group). At days 3, 7, 14 and 28, the numbers of circulating endothelial progenitor cells (EPCs) in the peripheral blood and the expression of Notch4 on the surface of EPCs were detected. In addition, the levels of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin in the roots of coronary arteries were evaluated. The results demonstrated that the level of circulating EPCs increased significantly at day 3, decreased progressively from day 3 onwards, and recovered to the normal level at day 28. Furthermore, the expression of Notch4 on the surface of EPCs was evidently higher in the KD model compared with that in the control group at day 7. In the endothelial cells of the coronary artery root, the protein levels of VCAM-1 and P-selectin protein increased in the KD model. In conclusion, the Notch4 signaling pathway participated in the coronary artery lesions in the KD animal model induced by LCWE. PMID- 28587424 TI - Dynamic relationship between infantile hepatitis syndrome and cytomegalovirus infection. AB - We investigated the correlation between cytomegalovirus (CMV) infection and infantile hepatitis syndrome and the correlation between blood ammonia levels in children with CMV-induced hepatitis syndrome and liver function indicators. To analyze the relationship between the positive-negative attributes of CMV infection and the recurrence rate of infantile hepatitis syndrome, a total of 86 cases of children with hepatitis syndrome admitted to Xuzhou Children's Hospital from January 2014 to March 2015 were selected for the study group. Furthermore, 86 cases of healthy children who visited our hospital for a physical examination during the same period were selected as the control group. From the two groups, serum CMV-immunoglobulin M (IgM) levels were determined via enzyme-linked immunosorbent assay, and urinary CMV-deoxyribonucleic acid (DNA) was ascertained by fluorescent ratio polymerase chain reaction. These levels were then compared between the two groups and analyzed. A fully automatic biochemical analyzer was utilized to evaluate the blood ammonia and liver function indicators of the children with infantile hepatitis syndrome induced by CMV infection and to analyze the correlation of these factors. A mean follow-up of 12 months after the children's discharge was adopted to observe the relationship between the negative positive attributes of CMV infection and the recurrence rate in the children upon cure. The positive detection rate for the serum CMV-IgM was 24.4%, and that for the urinary CMV-DNA was 34.9%; both values were significantly higher than that for the control group (P<0.05). The blood ammonia levels of the children with infantile hepatitis syndrome induced by CMV infection were not correlated with the liver function indicators, such as total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, total bile acid, and cholinesterase (P>0.05), but they were negatively correlated with blood albumin (ALB) (P<0.05). The recurrence rate of hepatitis syndrome among the children with negative CMV infection was 3.8%, which was significantly lower than that among the children with positive CMV infection (62.5%, P<0.05). A significant correlation was found between CMV infection and infantile hepatitis syndrome, with the former being a risk factor for the latter. Changes in the conditions of infantile hepatitis syndrome may be reflected by blood ammonia and ALB indicators. Through improved monitoring, these indicators facilitate the early diagnosis and treatment of children with hepatitis syndrome induced by CMV infection. Sufficient attention should be paid to preventive measures to reduce the incidence rate of infantile hepatitis syndrome. PMID- 28587426 TI - Evaluation of the shape, viability, stemness and osteogenic differentiation of cell spheroids formed from human gingiva-derived stem cells and osteoprecursor cells. AB - The present study was performed to create stem cell spheroids from human gingiva derived stem cells and osteoprecursor cells and to evaluate the maintenance of the stemness, the viability and osteogenic differentiation of the cell spheroids. Gingiva-derived stem cells were isolated, and a total of 6*105 stem cells and osteoprecursor cells were seeded into concave micromolds at various ratios. Gingiva-derived stem cells and/or osteoprecursor cells formed spheroids in concave microwells. The spheroids demonstrated a smaller diameter when the number of osteoprecursor cells seeded was lower. The majority of cells in the spheroids were identified to be live cells and the cell spheroids preserved viability throughout the experimental period. The cell spheroids, which contained stem cells, were positive for stem-cell markers. Cell spheroids in concave microwells demonstrated a statistically significant increase in alkaline phosphatase activity as time progressed (P<0.05). A statistically significant difference in phosphatase activity was observed in the stem cell alone group when compared with the osteoprecursor cell group at day 5 (P<0.05). Mineralized extracellular deposits were observed in each group after Alizarin Red S staining. Within the limits of the present study, cell spheroids from gingival cells and osteoprecursor cells maintained shape, viability, stemness and osteogenic differentiation potential. PMID- 28587427 TI - MRI features of growth hormone deficiency in children with short stature caused by pituitary lesions. AB - We verified the advantages of using magnetic resonance imaging (MRI) for improving the diagnostic quality of growth hormone deficiency (GHD) in children with short stature caused by pituitary lesions. Clinical data obtained from 577 GHD patients with short stature caused by pituitary lesions were retrospectively analyzed. There were 354 cases (61.3%) with anterior pituitary dysplasia; 45 cases (7.8%) of pituitary stalk interruption syndrome (PSIS); 15 cases (2.6%) of pituitary hyperplasia due to primary hypothyroidism; 38 cases (6.6%) of Rathke cleft cyst; 68 cases (11.8%) of empty sella syndrome; 16 cases (2.8%) of pituitary invasion from Langerhans cell histiocytosis; 2 cases (0.3%) of sellar regional arachnoid cyst and 39 cases (6.8%) of craniopharyngioma. MRI results showed that the height of anterior pituitary in patients was less than normal. Location, size and signals of posterior pituitary and pituitary stalk were normal in anterior pituitary dysplasia. In all cases pituitary hyperplasia was caused by hypothyroidism. MRI results showed that anterior pituitary was enlarged, and we detected upward apophysis and obvious homogeneous enhancement. There were no pituitary stalk interruption and abnormal signal. We also observed that after hormone replacement therapy the size of pituitary gland was reduced. Anterior pituitary atrophy was observed in Rathke cleft cyst, empty sella syndrome, sellar regional arachnoid cyst and craniopharyngioma. The microstructure of hypophysis and sellar region was studied with MRI. We detected pituitary lesions, and the characteristics of various pituitary diseases of GHD in children with short stature. It was concluded that in children with GHD caused by pituitary lesions, MRI was an excellent method for early diagnosis. This method offers clinical practicability and we believe it can be used for differential diagnosis and to monitor the therapeutic effects. PMID- 28587425 TI - Bathing effects of east saline groundwater concentrates on allergic (atopic) dermatitis-like skin lesions induced by 2,4-dinitrochlorobenzene in hairless mice. AB - In the present study, it was evaluated whether east saline groundwater concentration solution (ESGWc) exerted a favorable inhibitory effect on 2,4 dinitrochlorobenzene (DNCB)-induced allergic/atopic-like dermatitis (AD). AD was induced and boosted by sensitization with DNCB via topical application on the dorsal back skins. Mice with DNCB-induced AD were bathed in 100-, 200- and 400 fold diluted ESGWc. After 6 weeks bathing, changes to body weight, clinical skin severity scores, scratching behavior, serum total immunoglobulin (Ig)E levels, submandibular lymph node and spleen weights, splenic cytokine levels, skin cytokine mRNA expressions, antioxidant defense systems and superoxide anion productions were recorded to determine the effects of bathing on the histopathology of dorsal back skin tissues. All DNCB-induced mice demonstrated that the induction of AD through IgE-mediated hypersensitivities, oxidative stresses, activation of MMP and apoptosis of keratinocytes resulted in no significant differences in body weight between the different groups at each time point following initial sensitization. However, markers of DNCB-induced AD were significantly inhibited (P<0.05) in a concentration-dependent manner following bathing in all concentrations of ESGWc. The results obtained in the present study suggest that bathing in ESGWc may have favorable protective effects against DNCB induced AD due to favorable systemic and local immunomodulatory effects, active cytoprotective anti-apoptotic effects, inhibitory effects of matrix metalloproteinase activity, and anti-inflammatory and antioxidative effects. PMID- 28587428 TI - Early diagnosis of bacterial infection in patients with septicopyemia by laboratory analysis of PCT, CRP and IL-6. AB - The aim of the present study was to investigate the early diagnostic values of measuring procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (lL-6) levels in patients with bacterial infections and septicopyemia. Ninety-two patients with septicopyemia who were diagnosed and treated in the First Affiliated Hospital of Fujian Medical University between December 2012 and October 2013 were randomly selected. Based on results of hemoculture, the patients were divided into the Gram-negative bacterial infection group (n=47) and the Gram-positive bacterial infection group (n=45). Immune nephelometry was used for measuring serum CRP levels, electrochemiluminescence assay was used to measure serum PCT and IL-6. The levels of serum CRP, PCT, and IL-6 in the Gram negative bacterial infection group were significantly higher than in the Gram positive group. Analysis with Spearman's correlation coefficient showed that there were positive correlations between the levels of PCT and CRP, and between PCT and IL-6 (P<0.05). The diagnosis of Gram-negative bacterial infections was as follows: The area under the PCT curve was 0.974 (P<0.05) with sensitivity and specificity of 96.8 and 93.5%, respectively. The area under the CRP curve was 0.953 (P<0.05) with sensitivity and specificity of 94.2 and 91.7%, respectively. The area under the IL-6 curve was 0.925 (P<0.05) with sensitivity and specificity of 93.6 and 90.5%, respectively. The diagnosis of Gram-negative bacterial infections was as follows: The area under the PCT curve was 0.854 (P<0.05) with sensitivity and specificity of 92.7 and 91.8%, respectively. The area under the CRP curve was 0.832 (P<0.05) with sensitivity and specificity of 90.2 and 89.3%, respectively. The area under the IL-6 curve was 0.817 (P<0.05) with sensitivity and specificity of 89.4 and 81.5%, respectively. In conclusion, PCT, CRP, and lL 6 can act as early diagnostic markers for bacterial infections in patients with septicopyemia. PMID- 28587429 TI - Variation in the levels of IL-6 in pediatric patients with severe bacterial infectious diseases and correlation analysis between the levels of IL-6 and procalcitonin. AB - The objective of the present study was to investigate variations in the levels of interleukin (IL)-6, procalcitonin (PCT), and C-reactive protein (CRP) in children with severe bacterial infectious diseases and to analyze the correlation between the levels of IL-6 and PCT to determine the value of combined diagnosis with IL-6 and PCT. We analyzed 126 patients admitted to Xuzhou Children's Hospital for treatment, who were divided into severe bacterial infection (observation group, n=65) and non-bacterial infection groups (control group, n=61). The levels of IL 6, PCT, and CRP were measured and compared between the two groups. Data from both groups were statistically analyzed. The levels of IL-6, PCT, and CRT in the observation group were significantly higher than those in the control group (P<0.01); in the observation group, the levels of IL-6 and PCT on the 5th and 10th day after treatment were significantly lower than those before treatment (P<0.01); PCT showed better value for diagnosing severe bacterial infections compared with IL-6 and CRP; there was a positive correlation between the levels of IL-6 and PCT in the observation group; and the sensitivity and specificity of combined diagnosis with IL-6 and PCT for severe bacterial infection was 93.84% and 96.72%, respectively, which were significantly higher than those for diagnosis with only IL-6 (P<0.01). In conclusion, IL-6 combined with PCT can serve as an indicator with high sensitivity for detection of severe bacterial infections in children, which is of great significance for the differential diagnosis of severe bacterial infections in the early stage. PMID- 28587430 TI - The role and mechanism of NF-kappaB in viral encephalitis of children. AB - The aim of this study was to analyze the concentration changes of nuclear factor kappaB (NF-kappaB) and the related inflammatory factors of pre-treatment and post treatment in children with viral encephalitis, to examine the mechanism of NF kappaB in the pathogenesis of child viral encephalitis. Twenty-two children with severe viral encephalitis, 13 children with mild viral encephalitis and 12 normal children, who were treated in our hospital, were randomly selected. Before and after treatment, the concentrations of inflammation-related factors in serum including interleukin (IL)-1, IL-6 and tumor necrosis factor-alpha (TNF-alpha) were detected by ELISA and comparative analysis were performed. The expression of NF-kappaB in peripheral blood and cerebrospinal fluid (CSF) before and after treatment was detected by RT-PCR and western blotting, while the difference of NF kappaB expressions between viral encephalitis children and normal children was analyzed. The concentrations of inflammation-related factors in serum of children with viral encephalitis, including IL-1, IL-6 and TNF-alpha were significantly higher than those of normal children (P<0.01), and after treatment, the concentrations of IL-1, IL-6 and TNF-alpha were distinctly lower than those of pre-treatment (P<0.01). The concentrations of NF-kappaB in peripheral blood and CSF of children with viral encephalitis in the mild group and severe group were evidently increased compared to those of pre-treatment, while the degree of increase in the severe group was higher than that in mild group, which was higher than that in the control group (P<0.01). After treatment, the concentrations of serum NF-kappaB of children in the severe and mild groups were distinctly lower than those of pre-treatment (P<0.01), with statistically significant difference. In conclusion, the NF-kappaB level in serum and CSF of children with viral encephalitis was positively related to the severity of the disease. The higher the concentration of pre-treatment was, the more serious the disease would be. Our results indicate that NF-kappaB plays an important role in the occurrence and development of viral encephalitis in children. PMID- 28587431 TI - Rare de novo inversion-duplication case with pure 3qter duplication syndrome including an overlap of the dup(3q) critical region: A case report. AB - We report here a very rare case of de novo inversion-duplication chromosomal abnormality with a pure 3qter duplication syndrome. Interestingly, the 3q duplication includes an overlap of the syndromes critical region. Although there have only been 9 cases of this syndrome reported in the past, our patient had more severe neurological abnormalities than anticipated. In this regard, we have gathered the 3q chromosomal duplication abnormalities known to cause pure 3q duplication syndrome to date as a reference for comparisons and we discuss the particulars of our case. PMID- 28587432 TI - Comparison of acute cholangitis with or without common bile duct dilatation. AB - To improve the management of patients with acute cholangitis, the present study compared laboratory test variables between acute cholangitis patients with or without common bile duct (CBD) dilatation [CBDdil(+) and CBDdil(-), respectively]. The medical records of patients diagnosed with acute cholangitis and subjected to endoscopic retrograde cholangiopancreatography between February 2008 and May 2015 were retrospectively analyzed. The present study consisted of 40 men (aged 69.4+/-8.8 years) and 37 women (aged 68.8+/-11.6 years). It was observed that CBDdil(-) patients were slightly younger than CBDdil(+) patients (P=0.0976), and levels of C-reactive protein (CRP) were significantly higher in CBDdil(-) patients than in CBDdil(+) patients (P=0.0392). In addition, logistic regression analysis indicated that CRP levels were associated with the presence of CBD dilatation (P=0.0392). These data indicate that patients with acute cholangitis without CBD dilatation tend to be younger and have higher levels of CRP. Thus, in acute cholangitis patients without CBD dilatation, diagnosis should be determined using clinical symptoms and laboratory data. PMID- 28587433 TI - StatSensor-i point-of-care creatinine analyzer may identify patients at high-risk of contrast-induced nephropathy. AB - The current study assessed the accuracy of the StatSensor-i (STA) point-of-care creatinine analyzer prior to and following adjustment (offset correction) by linear regression scatter plots produced by the reference samples from patients and volunteers for detecting high risk of contrast-induced nephropathy in patients with an estimated glomerular filtration rate <45 ml/min/1.73 m2. Blood samples were obtained from 233 consecutive outpatients scheduled for contrast enhanced CT studies. Of the 233 patients, 123 patient samples were evaluated prior to adjustment and the other 110 following adjustment. Serum creatinine levels and estimated glomerular filtration rate were measured using the analyzer and compared with the values returned by laboratory tests. Analysis was with the paired t-test, the Pearson correlation coefficient and Bland-Altman plotting. The sensitivity, specificity, positive and negative predictive values (PPV, NPV), and accuracy for detecting patients with an estimated glomerular filtration rate <45 ml/min/1.73 m2 were subsequently calculated. Mean serum creatinine levels measured with the analyzer were significantly higher than those returned by laboratory tests before (P<0.0001) and after adjustment (P<0.01). Following adjustment, the difference in serum creatinine values obtained with the STA analyzer and by laboratory methods did not exceed 0.3 mg/dl. Prior to adjustment, 9.7% of the samples were overdiagnosed as having an estimated glomerular filtration rate of <45 ml/min/1.73 m2; following adjustment, the overdiagnosis rate was 2.7%. The sensitivity, specificity, PPV, NPV and accuracy were 100, 89, 50, 100 and 90.2% before and 100, 96.3, 33.3, 100 and 96.4% after adjustment, respectively. With the adjusted point-of-care creatinine analyzer, estimated glomerular filtration rate may be reliably evaluated in the radiology suite. PMID- 28587434 TI - Diagnostic accuracy of diffusion-weighted whole-body imaging with background body signal suppression/T2-weighted image fusion for the detection of abdominal solid cancer. AB - Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) images show significant contrast for cancer tissues against non-cancerous tissues. Fusion of a DWIBS and a T2-weighted image (DWIBS/T2) can be used to obtain functional, as well as anatomic, information. In the present study, the performance of DWIBS/T2 in the diagnosis of abdominal solid cancer was evaluated. The records of 14 patients were retrospectively analyzed [5 patients with hepatocellular carcinoma (HCC), 4 with metastatic liver cancer, 3 with pancreatic cancer, 1 with renal cellular carcinoma and 1 with malignant lymphoma of the para aortic lymph node]. T1WI and T2WI scans did not detect pancreatic cancer in certain cases, whereas DWIs and DWIBS/T2 clearly demonstrated pancreatic cancer in all cases. In addition, metastatic liver cancer and HCC were successfully detected with abdominal US and CECT; however, US did not detect pancreatic cancer in 1 case, while CECT and DWIBS/T2 detected pancreatic cancer in all cases. In conclusion, the diagnostic performance of DWIBS/T2 was the same as that of abdominal US and CECT in detecting primary and metastatic liver cancer. DWIBS/T2 enabled the diagnosis of pancreatic cancer in cases where it was not detected with US, T1WI or T2WI. PMID- 28587435 TI - Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva. AB - It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy. PMID- 28587436 TI - Pathology comparative study on the characteristic CT signs in solid pseudopapillary neoplasm of the pancreas. AB - In order to analyze characteristic CT signs in the solid pseudopapillary tumor of the pancreas, a retrospective analysis was conducted on 49 patients with pseudopapillary tumor of the pancreas who where treated in Liaoning Cancer Hospital. All of the patients were confirmed by pathology, CT signs were analyzed and a pathology contrast was conducted. Furthermore, all cases had single lesions; 7 cases in the pancreatic head, 23 cases in the pancreatic body, 15 cases in the pancreatic body-tail and 4 cases in the pancreatic tail. The boundaries of the lesions were clear and the tumors, which may outline the pancreas, were composed of solid and polycystic parts. In addition, calcifications could be observed in the lesions and CT results revealed varying degrees of contrast enhancement of the solid components in the arterial phase, as well as a gradual contrast enhancement in the venous and delayed phase. Enhancement of capsule could be observed, and the enhancement region was observed in the solid part, no enhancement in cystic part.. In conclusion, CT manifestations of solid pseudopapillary tumors of the pancreas are specific, which is helpful to the diagnosis. PMID- 28587437 TI - Overexpression and correlation of HIF-2alpha, VEGFA and EphA2 in residual hepatocellular carcinoma following high-intensity focused ultrasound treatment: Implications for tumor recurrence and progression. AB - Rapid growth of residual tumors can occur as a result of their recurrence and progression. The present study aimed to investigate the expression of hypoxia inducible factor-2 subunit alpha (HIF-2alpha), vascular endothelial growth factor A (VEGFA), erythropoietin-producing hepatocellular A2 (EphA2) and angiogenesis in residual hepatocellular carcinoma (HCC), following treatment with high-intensity focused ultrasound (HIFU) ablation, in order to investigate the association between protein expression and tumor recurrence and growth. Athymic BALB/c (nu/nu) mice were subcutaneously inoculated with the HCC cell line HepG2, in order to create xenograft tumors. Approximately 30 days post-inoculation, eight mice were treated with HIFU, whereas eight mice received no treatment and acted as the control group. Residual tumor tissues were obtained from the experimental groups after one month. Levels of HIF-2alpha, VEGFA, EphA2 and cluster of differentiation 31 (CD31) expression was measured by immunohistochemical staining. CD31-positive vascular endothelial cells were counted to calculate microvascular density (MVD), and western blot analysis was performed to determine levels of HIF-2alpha, VEGFA, and EphA2 protein. It was found that the expression levels of HIF-2alpha, VEGFA, EphA2, and MVD proteins in residual HCC tissues were significantly higher than in the control group tissues (P<0.05). Tumor MVD was strongly correlated with VEGFA (R=0.957, P<0.01) and EphA2 (R=0.993, P<0.01) protein expression levels. Furthermore, there was a significant positive correlation between HIF-2alpha and EphA2 expression (R=0.991, P<0.01). The correlation between VEGFA and EphA2 expression was also positive (R=0.985, P<0.01). These data suggest that overexpression of HIF-2alpha, VEGFA and EphA2 is related to angiogenesis in residual HCC following HIFU ablation, potentially via their association with key mediators of recurrence. PMID- 28587438 TI - Clinical application of the Innovance D-dimer assay in the diagnosis of acute pulmonary thromboembolism. AB - Patients with acute pulmonary thromboembolism (APTE) have a high short-term mortality rate. The current study aimed to investigate the use of D-dimer in the diagnosis of APTE in suspected APTE patients. All suspected APTE patients were classified into diagnosis or control groups according to the results of a computed tomography pulmonary angiogram. Mann-Whitney U and Kruskal-Wallis H tests were used to evaluate the association between D-dimer values and APTE. Area under the curve (AUC) values and the Youden Index were used to determine D-dimer cut-off levels for the prediction of APTE. The data of 112 suspected APTE patients (54.8% women; mean age, 70.5 years) were analyzed prospectively. There were no significant differences in age (74.5 vs. 73.5 years, P=0.538) or gender distribution (female ratio 56.5 vs. 53.0%, P=0.847) between the diagnosis and control groups. The incidence of symptoms including dyspnea (67.4 vs. 33.3%; P<0.01), chest distress (47.8 vs. 25.8%; P<0.05) and elevated D-dimer (8.49 vs. 0.97 mg/l; P<0.001) were significantly higher in patients with APTE compared with the control group. D-dimer values >3.32 mg/l fibrinogen equivalent units (FEU) were indicative of APTE and the Youden Index was 0.69. The maximum AUC was 0.87 (95% CI: 0.79-0.92), the sensitivity and specificity were 89.13 and 80.30%, respectively, the positive and negative likelihood ratios were 4.53 and 0.14, respectively, and the positive and negative predictive values were 75.90 and 91.40%, respectively. A D-dimer value <0.60 mg/l FEU was the optimal threshold for excluding APTE diagnosis, with a sensitivity of 100.0% and a specificity of 28.79%. The positive and negative likelihood ratios were 1.40 and 0.00, respectively, and the positive and negative predictive values were 49.50 and 100.00%, respectively. Thus, D-dimer levels, combined with clinical assessment, yield high sensitivity and specificity in diagnosing APTE. PMID- 28587439 TI - Small-Angle Scattering from Nanoscale Fat Fractals. AB - Small-angle scattering (of neutrons, x-ray, or light; SAS) is considered to describe the structural characteristics of deterministic nanoscale fat fractals. We show that in the case of a polydisperse fractal system, with equal probability for any orientation, one obtains the fractal dimensions and scaling factors at each structural level. This is in agreement with general results deduced in the context of small-angle scattering analysis of a system of randomly oriented, non interacting, nano-/micro-fractals. We apply our results to a two-dimensional fat Cantor-like fractal, calculating analytic expressions for the scattering intensities and structure factors. We explain how the structural properties can be computed from experimental data and show their correlation to the variation of the scaling factor with the iteration number. The model can be used to interpret recorded experimental SAS data in the framework of fat fractals and can reveal structural properties of materials characterized by a regular law of changing of the fractal dimensions. It can describe successions of power-law decays, with arbitrary decreasing values of the scattering exponents, and interleaved by regions of constant intensity. PMID- 28587440 TI - Comparative metabolomics in vanilla pod and vanilla bean revealing the biosynthesis of vanillin during the curing process of vanilla. AB - High-performance liquid chromatography-mass spectrometry (LC-MS) was used for comprehensive metabolomic fingerprinting of vanilla fruits prepared from the curing process. In this study, the metabolic changes of vanilla pods and vanilla beans were characterized using MS-based metabolomics to elucidate the biosynthesis of vanillin. The vanilla pods were significantly different from vanilla beans. Seven pathways of vanillin biosynthesis were constructed, namely, glucovanillin, glucose, cresol, capsaicin, vanillyl alcohol, tyrosine, and phenylalanine pathways. Investigations demonstrated that glucose, cresol, capsaicin, and vanillyl alcohol pathway were detected in a wide range of distribution in microbial metabolism. Thus, microorganisms might have participated in vanillin biosynthesis during vanilla curing. Furthermore, the ion strength of glucovanillin was stable, which indicated that glucovanillin only participated in the vanillin biosynthesis during the curing of vanilla. PMID- 28587441 TI - Evaluation of brewers' spent grain as a novel media for yeast growth. AB - Brewers' spent grain (BSG) is a by-product generated from the beer manufacturing industry, which is extremely rich in protein and fiber. Here we use low cost BSG as the raw material for the production of a novel growth media, through a bioconversion process utilizing a food grade fungi to hydrolyze BSG. The novel fermentation media was tested on the yeast Rhodosporidium toruloides, a natural yeast producing carotenoid. The yeast growth was analysed using the growth curve and the production of intracellular fatty acids and carotenoids. Untargeted GCMS based metabolomics was used to analyse the constituents of the different growth media, followed by multivariate data analysis. Growth media prepared using fermented BSG was found to be able to support the growth in R. toruloides (21.4 mg/ml) in comparable levels to YPD media (24.7 mg/ml). Therefore, the fermented BSG media was able to fulfill the requirement as a nitrogen source for R. toruloides growth. This media was able to sustain normal metabolomics activity in yeast, as indicated by the level of fatty acid and carotenoid production. This can be explained by the fact that, in the fermented BSG media metabolites and amino acids were found to be higher than in the unfermented media, and close to the levels in YPD media. Taken together, our study provided evidence of a growth media for yeast using BSG. This should have potential in replacing components in the current yeast culture media in a sustainable and cost effective manner. PMID- 28587442 TI - Expanding the range of polyhydroxyalkanoates synthesized by methanotrophic bacteria through the utilization of omega-hydroxyalkanoate co-substrates. AB - The first methanotrophic syntheses of polyhydroxyalkanoates (PHAs) that contain repeating units beyond 3-hydroxybutyrate and 3-hydroxyvalerate are reported. New PHAs synthesized by methanotrophs include poly(3-hydroxybutyrate-co-4 hydroxybutyrate) (P(3HB-co-4HB)), poly(3-hydroxybutyrate-co-5-hydroxyvalerate-co 3-hydroxyvalerate) (P(3HB-co-5HV-co-3HV)), and poly(3-hydroxybutyrate-co-6 hydroxyhexanoate-co-4-hydroxybutyrate) (P(3HB-co-6HHx-co-4HB)). This was achieved from a pure culture of Methylocystis parvus OBBP where the primary substrate is methane and the corresponding omega-hydroxyalkanoate monomers are added as a co substrate after the cells are subjected to nitrogen-limited conditions. PMID- 28587443 TI - In vitro antimicrobial potential of extracts and phytoconstituents from Gymnema sylvestre R.Br. leaves and their biosafety evaluation. AB - The in vitro antimicrobial screening of Gymnema sylvestre leaves against 13 test pathogens established its broad spectrum activity with average inhibition zone ranging from 14 to 23 mm. The antimicrobial activity of the classically- optimized aqueous extract was enhanced up to 1.45 folds, when subjected to statistical optimization using Response Surface Methodology (RSM) and was thermostable. Ethyl acetate was found to be the best organic extractant with Klebsiella pneumoniae 1 (31.5 mm) and Staphylococcus epidermidis (25.5 mm) being the most sensitive among Gram negative and Gram positive bacteria, respectively. Among the major group of phytoconstituents detected, tannins were the most abundant followed by flavonoids and phytosterols, while triterpenes were absent. Flavonoids and cardiac glycosides exhibited a broad range of antimicrobial potential, with inhibition zone ranging from 13 to 35 mm, where Candida albicans was the most sensitive organism. Ethyl acetate extract showed better potency with lowest Minimum inhibitory concentration (0.1-1 mg ml-1) than the aqueous extract (1-3 mg ml-1) and all partially purified phytoconstituents (0.1-10 mg ml-1). The ethyl acetate extract and flavonoids were highly potent, as they exhibited a total activity potency ranging from 41.4 to 1045 ml g-1. Time kill studies revealed their microbicidal action, where ethyl acetate extract had a kill time from 0 to 12 h. However, among phytoconstituents, flavonoids were the most effective (0-8 h). The MIC and time kill study was also compared to that of standard antibiotics. These findings indicate that Gymnema sylvestre can be a potential source for development of leading metabolites against pathogens of clinical importance like Pseudomonas aeruginosa, Candida albicans, Escherichia coli, Staphylococcus aureus etc. They were neither mutagenic nor cytotoxic, as revealed by Ames and MTT assay. PMID- 28587444 TI - Assessment of changes in the content of anthocyanins, phenolic acids, and antioxidant property of Saccharomyces cerevisiae mediated fermented black rice bran. AB - Studies on phytochemical properties and bioactivities of rice bran revealed the wealth of natural complex antioxidant compounds. The composition and the properties of the rice bran get altered after fermentation by several microbes. This study was designed to optimize the black rice bran fermentation conditions for the total anthocyanin (ACN) content, total antioxidant properties, and relative activity of beta-glucosidase (BGS) by Saccharomyces cerevisiae. The Box Behnken design and response surface methodology was employed to achieve the maximum response in fermentation. The kinetic analysis of HPLC based phytochemical determination and bioconversion of ACN, and in vitro antioxidant assays were performed during fermentation. The optimum pH, temperature and NaCl concentration to achieve maximum ACN content, antioxidant capacity, and BGS activity were pH 4.0, 40 degrees C, and 0.5%, respectively. Bioconversion of cyanidin-3-glucoside and peonidin-3-glucoside to cyanidin and peonidin was recorded at a significant level, respectively. The maximum activity of BGS on rice bran was noticed at 24 h of fermentation. The results suggested that phytochemical content was not changed significantly, whereas the antioxidant properties of rice bran were slightly enhanced after 24 h of fermentation. Additional detailed in vivo evaluation is required to explain the impact of submerged fermentation on the bioactivity of rice bran. PMID- 28587445 TI - Directing Stem Cell Differentiation via Electrochemical Reversible Switching between Nanotubes and Nanotips of Polypyrrole Array. AB - Control of stem cell behaviors at solid biointerfaces is critical for stem-cell based regeneration and generally achieved by engineering chemical composition, topography, and stiffness. However, the influence of dynamic stimuli at the nanoscale from solid biointerfaces on stem cell fate remains unclear. Herein, we show that electrochemical switching of a polypyrrole (Ppy) array between nanotubes and nanotips can alter surface adhesion, which can strongly influence mechanotransduction activation and guide differentiation of mesenchymal stem cells (MSCs). The Ppy array, prepared via template-free electrochemical polymerization, can be reversibly switched between highly adhesive hydrophobic nanotubes and poorly adhesive hydrophilic nanotips through an electrochemical oxidation/reduction process, resulting in dynamic attachment and detachment to MSCs at the nanoscale. Multicyclic attachment/detachment of the Ppy array to MSCs can activate intracellular mechanotransduction and osteogenic differentiation independent of surface stiffness and chemical induction. This smart surface, permitting transduction of nanoscaled dynamic physical inputs into biological outputs, provides an alternative to classical cell culture substrates for regulating stem cell fate commitment. This study represents a general strategy to explore nanoscaled interactions between stem cells and stimuli-responsive surfaces. PMID- 28587446 TI - Stiff, Thermally Stable and Highly Anisotropic Wood-Derived Carbon Composite Monoliths for Electromagnetic Interference Shielding. AB - Electromagnetic interference (EMI) shielding materials for electronic devices in aviation and aerospace not only need lightweight and high shielding effectiveness, but also should withstand harsh environments. Traditional EMI shielding materials often show heavy weight, poor thermal stability, short lifetime, poor tolerance to chemicals, and are hard-to-manufacture. Searching for high-efficiency EMI shielding materials overcoming the above weaknesses is still a great challenge. Herein, inspired by the unique structure of natural wood, lightweight and highly anisotropic wood-derived carbon composite EMI shielding materials have been prepared which possess not only high EMI shielding performance and mechanical stable characteristics, but also possess thermally stable properties, outperforming those metals, conductive polymers, and their composites. The newly developed low-cost materials are promising for specific applications in aerospace electronic devices, especially regarding extreme temperatures. PMID- 28587447 TI - Identification of N-Glycosites in Chicken Egg White Proteins Using an Omics Strategy. AB - Chicken egg white (CEW) is a perfect source of natural proteins that possesses outstanding functional properties and various bioactivities. The glycosylation structure of CEW proteins plays important roles in their functions, bioactivities, and allergies. The present work attempted to identify N-glycosites of CEW proteins using an omics strategy. CEW proteins were digested with trypsin and chymotrypsin; glycopeptides were enriched and deglycosylated using PNGase F in H218O water, followed by analysis using high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). A total of 71 N-glycosites in 26 CEW glycoproteins were identified. Web-Logo analysis showed that most of the N-glycosites were at N-X-T (55%) and N-X-S (32%). Furthermore, two dimensional electrophoresis of CEW clusterin demonstrated a series of spots horizontally distributed at 35-37 kDa with an extremely wide isoelectric point range of 4.54-6.68, indicating the heterogeneity of glycosylation of CEW clusterin. These results provided important information for the understanding of the structures, functions, and bioactivities of CEW glycoproteins. PMID- 28587448 TI - From Si(II) to Si(IV) and Back: Reversible Intramolecular Carbon-Carbon Bond Activation by an Acyclic Iminosilylene. AB - Reversibility is fundamental for transition metal catalysis, but equally for main group chemistry and especially low-valent silicon compounds, the interplay between oxidative addition and reductive elimination is key for a potential catalytic cycle. Herein, we report a highly reactive acyclic iminosilylsilylene 1, which readily performs an intramolecular insertion into a C?C bond of its aromatic ligand framework to give silacycloheptatriene (silepin) 2. UV-vis studies of this Si(IV) compound indicated a facile transformation back to Si(II) at elevated temperatures, further supported by density functional theory calculations and experimentally demonstrated by isolation of a silylene-borane adduct 3 following addition of B(C6F5)3. This tendency to undergo reductive elimination was exploited in the investigation of silepin 2 as a synthetic equivalent of silylene in the activation of small molecules. In fact, the first monomeric, four-coordinate silicon carbonate complex 4 was isolated and fully characterized in the reaction with carbon dioxide under mild conditions. Additionally, the exposure of 2 to ethylene or molecular hydrogen gave silirane 5 and Si(IV) dihydride 6, respectively. PMID- 28587449 TI - Synthesis of Lipophilic Guanine N-9 Derivatives: Membrane Anchoring of Nucleobases Tailored to Fatty Acid Vesicles. AB - Covalent or noncovalent surface functionalization of soft-matter structures is an important tool for tailoring their function and stability. Functionalized surfaces and nanoparticles have found numerous applications in drug delivery and diagnostics, and new functionalization chemistry is continuously being developed in the discipline of bottom-up systems chemistry. The association of polar functional molecules, e.g., molecular recognition agents, with soft-matter structures can be achieved by derivatization with alkyl chains, allowing noncovalent anchoring into amphiphilic membranes. We report the synthesis of five new guanine-N9 derivatives bearing alkyl chains with different attachment chemistries, exploiting a synthesis pathway that allows a flexible choice of hydrophobic anchor moiety. In this study, these guanine derivatives were functionalized with C10 chains for insertion into decanoic acid bilayer structures, in which both alkyl chain length and attachment chemistry determined their interaction with the membrane. Incubation of these guanine conjugates, as solids, with a decanoic acid vesicle suspension, showed that ether- and triazole linked C10 anchors yielded an increased partitioning of the guanine derivative into the membranous phase compared to directly N-9-linked saturated alkyl anchors. Decanoic acid vesicle membranes could be loaded with up to 5.5 mol % guanine derivative, a 6-fold increase over previous limits. Thus, anchor chemistries exhibiting favorable interactions with a bilayer's hydrophilic surface can significantly increase the degree of structure functionalization. PMID- 28587450 TI - Dynamic Kinetic Resolution in Rhodium-Catalyzed Asymmetric Arylation of Phospholene Oxides. AB - The reaction of 2,5-dihydro-1H-phosphole 1-oxide 1 with ArB(pin) 3 in the presence of a chiral (R)-segphos-rhodium catalyst under highly basic conditions (10 equiv of KOH) gave high yields of (1S,3S)-3-arylphospholane 1-oxide 4 with high diastereoselectivity as well as high enantioselectivity. Equilibration of 1 with its 2,3-dihydro isomer 2, which is chiral and racemic, by base-catalyzed olefin isomerization followed by kinetic resolution of 2 with the chiral rhodium catalyst realized the present dynamic kinetic resolution. PMID- 28587451 TI - Halogen Bonding in the Complexes of CH3I and CCl4 with Oxygen-Containing Halogen Bond Acceptors. AB - Methyl iodine (CH3I) and carbon tetrachloride (CCl4) are both important volatile precursors for atmospheric ozone destruction. CH3I and CCl4 can act as halogen bond donors to form molecular complexes with atmospheric organic species, such as 2,5-dihydrofuran, tetrahydrofuran, and acetone. This study characterized the halogen bonds in the CH3I and CCl4 complexes using matrix isolation infrared spectroscopy and density functional theory calculations. With the combination of vibrational frequencies in spectra and the calculated interaction energies, frequencies and atoms-in-molecules analyses, we confirmed the formation of halogen-bonded complexes. CH3I as a halogen-bond donor is comparable or slightly weaker than CCl4, and furans involving ether oxygens are better halogen acceptors than acetone. The results help to understand the possibilities of formation of atmospheric molecular complexes that may influence the atmospheric chemical activities and enhance the aerosol formation. PMID- 28587452 TI - Genetic Toxicity of Complex Mixtures of Polycyclic Aromatic Hydrocarbons: Evaluating Dose-Additivity in a Transgenic Mouse Model. AB - This study evaluates the risk assessment approach currently employed for polycyclic aromatic hydrocarbon (PAH)-contaminated media, wherein carcinogenic hazards are evaluated using a dose-addition model that employs potency equivalency factors (PEFs) for targeted carcinogenic PAHs. Here, MutaMouse mice were subchronically exposed to PAH mixtures (p.o.), and mutagenic potency (MP) values were determined for five tissues. Predicted dose-additive mixture MPs were generated by summing the products of the concentrations and MPs of the individual targeted PAHs; values were compared to the experimental MPs of the mixtures to evaluate dose-additivity. Additionally, the PEF-determined BaP-equivalent concentrations were compared to those determined using a bioassay-derived method (BDM) (i.e., an additivity-independent approach). In bone marrow, mixture mutagenicity was less than dose-additive and the PEF-method provided higher estimates of BaP-equivalents than the BDM. Conversely, mixture mutagenicity in site-of-contact tissues (e.g., small intestine) was generally more than dose additive and the PEF-method provided lower estimates of BaP-equivalents than the BDM. Overall, this study demonstrates that dose-additive predictions of mixture mutagenic potency based on the concentrations and potencies of a small number of targeted PAHs results in values that are surprisingly close to those determined experimentally, providing support for the dose-additive assumption employed for human health risk assessment of PAH mixtures. PMID- 28587453 TI - Tetranuclear Manganese Models of the OEC Displaying Hydrogen Bonding Interactions: Application to Electrocatalytic Water Oxidation to Hydrogen Peroxide. AB - Toward the development of structural and functional models of the oxygen evolving complex (OEC) of photosystem II, we report the synthesis of site-differentiated tetranuclear manganese complexes featuring three six-coordinate and one five coordinate Mn centers. To incorporate biologically relevant second coordination sphere interactions, substituents capable of hydrogen bonding are included as pyrazolates with arylamine substituents. Complexes with terminal anionic ligands, OH- or Cl-, bound to the lower coordinate metal center are supported through the hydrogen-bonding network in a fashion reminiscent of the enzymatic active site. The hydroxide complex was found to be a competent electrocatalyst for O-O bond formation, a key transformation pertinent to the OEC. In an acetonitrile-water mixture, at neutral pH, electrochemical water oxidation to hydrogen peroxide was observed, albeit with low (15%) Faradaic yield, likely due to competing reactions with organics. In agreement, 9,10-dihydroanthracene is electrochemically oxidized in the presence of this cluster both via H-atom abstraction and oxygenation with ~50% combined Faradaic yield. PMID- 28587454 TI - Solution Growth of Ultralong Gold Nanohelices. AB - Metallic nanohelices are extremely rare and, to date, have never been synthesized by a direct solution method. In this work, we report ultralong Au nanohelices grown in solution under ambient conditions. They are ultralong with several tens of micrometers in length, with extraordinary aspect ratio (length/diameter greater than 22 300) and the number of pitches (more than 22 000 pitches). The pitch and width are uniform within each helix but vary widely among the helices. Crystal analyses showed that the facets, twin boundaries, grain sizes, and orientations are aperiodic along the helices. The apparent smooth curving is only possible with a large number of surface steps, suggesting that these structural features are the mere consequence of the helix formation rather than the cause. We propose that the nanowires are formed by the active surface growth mechanism and that the helicity originates from the random and asymmetrical blocking of nuclei embedded within the floccules of ligand complexes, in the form of either asymmetric binding of ligands or asymmetric diffusion of growth materials through the floccules. The separate growth environment of these nuclei causes constant helicity within each helix but differing helicity among the individuals. The embedding also provides a robust environment for the sustained growth of the nanohelices, leading to their record length and consistency. PMID- 28587456 TI - Effective Fragment Potential Method for H-Bonding: How To Obtain Parameters for Nonrigid Fragments. AB - Accuracy of the effective fragment potential (EFP) method was explored for describing intermolecular interaction energies in three dimers with strong H bonded interactions, formic acid, formamide, and formamidine dimers, which are a part of HBC6 database of noncovalent interactions. Monomer geometries in these dimers change significantly as a function of intermonomer separation. Several EFP schemes were considered, in which fragment parameters were prepared for a fragment in its gas-phase geometry or recomputed for each unique fragment geometry. Additionally, a scheme in which gas-phase fragment parameters are shifted according to relaxed fragment geometries is introduced and tested. EFP data are compared against the coupled cluster with single, double, and perturbative triple excitations (CCSD(T)) method in a complete basis set (CBS) and the symmetry adapted perturbation theory (SAPT). All considered EFP schemes provide a good agreement with CCSD(T)/CBS for binding energies at equilibrium separations, with discrepancies not exceeding 2 kcal/mol. However, only the schemes that utilize relaxed fragment geometries remain qualitatively correct at shorter than equilibrium intermolecular distances. The EFP scheme with shifted parameters behaves quantitatively similar to the scheme in which parameters are recomputed for each monomer geometry and thus is recommended as a computationally efficient approach for large-scale EFP simulations of flexible systems. PMID- 28587455 TI - Insights on the Interaction between Transthyretin and Abeta in Solution. A Saturation Transfer Difference (STD) NMR Analysis of the Role of Iododiflunisal. AB - Several strategies against Alzheimer disease (AD) are directed to target Abeta peptides. The ability of transthyretin (TTR) to bind Abeta-peptides and the positive effect exerted by some TTR stabilizers for modulating the TTR-Abeta interaction have been previously studied. Herein, key structural features of the interaction between TTR and the Abeta(12-28) peptide (3), the essential recognition element of Abeta, have been unravelled by STD-NMR spectroscopy methods in solution. Molecular aspects related to the role of the TTR stabilizer iododiflunisal (IDIF, 5) on the TTR-Abeta complex have been also examined. The NMR results, assisted by molecular modeling protocols, have provided a structural model for the TTR-Abeta interaction, as well as for the ternary complex formed in the presence of IDIF. This basic structural information could be relevant for providing light on the mechanisms involved in the ameliorating effects of AD symptoms observed in AD/TTR+/- animal models after IDIF treatment and eventually for designing new molecules toward AD therapeutic drugs. PMID- 28587457 TI - Unsymmetrical and Symmetrical Push-Pull Phenothiazines. AB - A series of unsymmetrical and symmetrical push-pull phenothiazines (3-7) were designed and synthesized by the Pd-catalyzed Sonogashira cross-coupling reaction and subsequent [2 + 2] cycloaddition-retroelectrocyclization reaction with tetracyanoethylene (TCNE) and 7,7,8,8-tetracyanoquinodimethane (TCNQ). The effect of systematic variation of the number and nature of cyano-based acceptor TCNE and TCNQ units on the photophysical, electrochemical, and computational studies was investigated. The single-photon absorption on phenothiazines 3-7 reveals that substitution of 1,1,4,4-tetracyanobutadiene (TCBD) and a cyclohexa-2,5-diene-1,4 diylidene-expanded TCBD unit results in strong intramolecular charge transfer and lowering of the LUMO energy level. The TCBD-linked and cyclohexa-2,5-diene-1,4 diylidene-expanded TCBD-linked phenothiazines 3-7 exhibit multiredox waves. The computational studies on phenothiazines 3-7 exhibit substantial stabilization of the LUMO with the increase in acceptor strength, which results in lowering of the HOMO-LUMO gap. PMID- 28587458 TI - The U.S. Dairy Forage Research Center (USDFRC) Condensed Tannin NMR Database. AB - This Perspective describes a solution-state NMR database for flavan-3-ol monomers and condensed tannin dimers through tetramers obtained from the literature to 2015, containing data searchable by structure, molecular formula, degrees of polymerization, and 1H and 13C chemical shifts of the condensed tannins. Citations for all literature references are provided and should serve as valuable resource for scientists working in the field of condensed tannin research. The database will be periodically updated as additional information becomes available, typically on a yearly basis and is available for use, free of charge, from the U.S. Dairy Forage Research Center (USDFRC) Website. PMID- 28587459 TI - Singlet vs Triplet Reactivity of Photogenerated alpha,n-Didehydrotoluenes. AB - The reactivity of alpha,n-didehydrotoluenes (DHTs) in protic media (organic/aqueous mixtures) was explored by means of a combined computational and experimental approach. These intermediates were generated via a photoinduced double elimination process occurring in (chlorobenzyl)trimethylsilanes and led to the formation of a varied products distribution, depending on the isomer tested. Irradiation of ortho- and para-derivatives resulted, respectively, in the formation of triplet alpha,2- and alpha,4-DHTs, whose diradical reactivity led to both radical and polar products. On the other hand, irradiation of the meta precursor led to the singlet alpha,3-DHT isomer. The latter showed a marked preference for the formation of polar products and this was rationalized, as supported by computational evidence, via the involvement of a zwitterionic species arising through interaction of the nucleophilic solvent with the benzylic position of the DHT. PMID- 28587460 TI - Molecular Mechanisms Underlying gamma-Aminobutyric Acid (GABA) Accumulation in Giant Embryo Rice Seeds. AB - To uncover the molecular mechanisms underlying GABA accumulation in giant embryo rice seeds, we analyzed the expression levels of GABA metabolism genes and contents of GABA and GABA metabolic intermediates in developing grains and germinated brown rice of giant embryo rice 'Shangshida No. 5' and normal embryo rice 'Chao2-10' respectively. In developing grains, the higher GABA contents in 'Shangshida No. 5' were accompanied with upregulation of gene transcripts and intermediate contents in the polyamine pathway and downregulation of GABA catabolic gene transcripts, as compared with those in 'Chao2-10'. In germinated brown rice, the higher GABA contents in 'Shangshida No. 5' were parallel with upregulation of OsGAD and polyamine pathway gene transcripts and Glu and polyamine pathway intermediate contents and downregulation of GABA catabolic gene transcripts. These results are the first to indicate that polyamine pathway and GABA catabolic genes play a crucial role in GABA accumulation in giant embryo rice seeds. PMID- 28587461 TI - Compounds Interfering with Embryonic Lethal Abnormal Vision (ELAV) Protein-RNA Complexes: An Avenue for Discovering New Drugs. AB - RNA-binding proteins play a key role in post-transcriptional processes. Among these proteins, embryonic lethal abnormal vision (ELAV) proteins are among the best described. ELAV proteins predominantly act as positive regulators of gene expression, and their dysregulation is involved in several pathologies, such as cancer, inflammation, and neurodegenerative diseases. Only a few structurally unrelated compounds interfering with ELAV protein-mRNA complexes have been identified by applying high-throughput screening approaches. Considering the structural diversity of the compounds discovered so far and the different techniques employed for screening their ability to interfere with ELAV protein mRNA complexes, drawing conclusions from structure-activity relationships remains a challenge. We performed docking studies to understand the interactions of compounds reported over the past decade to be inhibitors of ELAV proteins and to evaluate the potential of computer-aided drug design to target this family of proteins for further drug discovery. PMID- 28587462 TI - Crystal Structural Effect of AuCu Alloy Nanoparticles on Catalytic CO Oxidation. AB - Controlling the physical and chemical properties of alloy nanoparticles (NPs) is an important approach to optimize NP catalysis. Unlike other tuning knobs, such as size, shape, and composition, crystal structure has received limited attention and not been well understood for its role in catalysis. This deficiency is mainly due to the difficulty in synthesis and fine-tuning of the NPs' crystal structure. Here, Exemplifying by AuCu alloy NPs with face centered cubic (fcc) and face centered tetragonal (fct) structure, we demonstrate a remarkable difference in phase segregation and catalytic performance depending on the crystal structure. During the thermal treatment in air, the Cu component in fcc-AuCu alloy NPs segregates more easily onto the alloy surface as compared to that in fct-AuCu alloy NPs. As a result, after annealing at 250 degrees C in air for 1 h, the fcc and fct-AuCu alloy NPs are phase transferred into Au/CuO and AuCu/CuO core/shell structures, respectively. More importantly, this variation in heterostructures introduces a significant difference in CO adsorption on two catalysts, leading to a largely enhanced catalytic activity of AuCu/CuO NP catalyst for CO oxidation. The same concept can be extended to other alloy NPs, making it possible to fine tune NP catalysis for many different chemical reactions. PMID- 28587463 TI - Lipidomics Profiling of Human Adipose Tissue Identifies a Pattern of Lipids Associated with Fish Oil Supplementation. AB - To understand the interaction between diet and health, biomarkers that accurately reflect consumption of foods of perceived health relevance are needed. The aim of this investigation was to use direct infusion-mass spectrometry (DI-MS) lipidomics to determine the effects of fish oil supplementation on lipid profiles of human adipose tissue. Adipose tissue samples from an n-3 polyunsaturated fatty acid (PUFA) supplementation study (n = 66) were analyzed to compare the pattern following supplementation equivalent to zero or four portions of oily fish per week. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were incorporated into highly unsaturated (>=5 double bonds) triglycerides (TGs), phosphocholines, and phosphoethanolamines as well as being detected directly as the nonesterified fatty acid forms. Multivariate statistics demonstrated that phospholipids were the most accurate and sensitive lipids for the assessing EPA and DHA incorporation into adipose tissue. Potential confounding factors (adiposity, age, and sex of the subject) were also considered in the analysis, and adiposity was also associated with an increase in highly unsaturated TGs as a result of incorporation of the n-6 PUFA arachidonic acid. DI-MS provides a high throughput analysis of fatty acid status that can monitor oily fish consumption, suitable for use in cohort studies. PMID- 28587464 TI - Copper Binding Sites in the Manganese-Oxidizing Mnx Protein Complex Investigated by Electron Paramagnetic Resonance Spectroscopy. AB - Manganese-oxide minerals (MnOx) are widely distributed over the Earth's surface, and their geochemical cycling is globally important. A multicopper oxidase (MCO) MnxG protein from marine Bacillus bacteria plays an essential role in producing MnOx minerals by oxidizing Mn2+(aq) at rates that are 3 to 5 orders of magnitude faster than abiotic rates. The MnxG protein is isolated as part of a multiprotein complex denoted as "Mnx" that includes accessory protein subunits MnxE and MnxF, with an estimated stoichiometry of MnxE3F3G and corresponding molecular weight of ~211 kDa. Herein, we report successful expression and isolation of the MCO MnxG protein without the E3F3 hexamer. This isolated MnxG shows activity for Mn2+(aq) oxidation to form manganese oxides. The complement of paramagnetic Cu(II) ions in the Mnx protein complex was examined by electron paramagnetic resonance (EPR) spectroscopy. Two distinct classes of type 2 Cu sites were detected. One class of Cu(II) site (denoted as T2Cu-A), located in the MnxG subunit, is identified by the magnetic parameters g? = 2.320 and A? = 510 MHz. The other class of Cu(II) sites (denoted as T2Cu-B) is characterized by g? = 2.210 and A? = 615 MHz and resides in the putative hexameric MnxE3F3 subunit. These different magnetic properties correlate with the differences in the reduction potentials of the respective Cu(II) centers. These studies provide new insights into the molecular mechanism of manganese biomineralization. PMID- 28587465 TI - Clarifying the Catalytic Mechanism of Human Glutamine Synthetase: A QM/MM Study. AB - Glutamine synthetase (GS) is a crucial enzyme responsible for the elimination of both neurotoxic glutamate and toxic ammonium, by combining them into glutamine. Alterations on the GS activity are associated with severe liver and neurodegenerative diseases and its absence or malformation results in death. In this work, the catalytic mechanism of human GS has been investigated with high level QM/MM calculations, showing a two-phase reaction cycle. During phase 1, GS activates the reactants (NH4+ and glutamate) with extreme efficiency, through NH4+ deprotonation by E305 and glutamate phosphorylation by ATP, in two spontaneous and barrierless reactions. At phase 2, NH3 attacks the gamma-glutamyl phosphate being concomitantly deprotonated by the leaving PO43-, forming the glutamine and HPO42- products. The second phase contains the rate limiting step, with a DeltaG? of 19.2 kcal.mol-1 associated with the nucleophilic substitution of the phosphate by NH3. The final reaction free energy is -34.5 kcal.mol-1. Both phases are exergonic, the first by -22.9 kcal.mol-1 and the second by -11.6 kcal.mol-1. Direct NH4+ attack is shown to be inefficient; the possible bases that perform the NH4+ deprotonation were systematically investigated. Negative E305 was shown to be the only one possibly responsible for NH4+ deprotonation. Altogether, these results provide a clear atomic level picture of the reaction cycle of GS, consistent with experimental and theoretical studies on GS of this and other organisms, and provide the necessary insights for the development of more specific therapeutic GS inhibitors. PMID- 28587466 TI - Tailor-Made Dispersion and Distribution of Stereocomplex Crystallites in Poly(l lactide)/Elastomer Blends toward Largely Enhanced Crystallization Rate and Impact Toughness. AB - Stereocomplex (SC) crystallites, formed between poly(l-lactide) (PLLA) and poly(d lactide), exhibit great potential to substantially enhance crystallization rate of PLLA-based materials as an eco-friendly nucleating agent. However, the nucleation efficiency of the SC crystallites is still far below an expected level, mostly on account of their strong aggregation tendency in PLLA/PDLA melts. Herein, taking PLLA/poly(ethylene-methyl acrylate-glycidyl methacrylate) (E-MA GMA) blends as an example, we report a unique and facile strategy to control the dispersion and distribution of SC crystallites within the PLLA matrix by using elastomeric E-MA-GMA as carrier for the incorporation of PDLA. To do this, PDLA was first blended with E-MA-GMA or chemically grafted onto the E-MA-GMA. During subsequent melt-blending of PLLA and the E-MA-GMA/PDLA master batch, the PDLA chain clusters predispersed in the E-MA-GMA phase can gradually migrate into PLLA matrix and then collaborate with the matrix chains to form large amounts of tiny and well-dispersed SC crystallites. Compared with the SC-crystallite agglomerates formed by the direct melt-blending of PLLA and PDLA components, such tiny SC crystallites are much more effective in accelerating PLLA matrix crystallization. More interestingly, when PDLA chains are grafted onto the EMA-GMA, the formed SC crystallites tend to preferentially distribute at the blend interface and thus induce not only optimal nucleation efficiency but also superior impact toughness because these interface-localized SC crystallites can also serve as bridges to enhance interface adhesion. This work could open a new avenue in designing heat resistant and supertough PLLA blends via controllable construction of SC crystallites. PMID- 28587467 TI - Highly Efficient Light-Emitting Diodes of Colloidal Metal-Halide Perovskite Nanocrystals beyond Quantum Size. AB - Colloidal metal-halide perovskite quantum dots (QDs) with a dimension less than the exciton Bohr diameter DB (quantum size regime) emerged as promising light emitters due to their spectrally narrow light, facile color tuning, and high photoluminescence quantum efficiency (PLQE). However, their size-sensitive emission wavelength and color purity and low electroluminescence efficiency are still challenging aspects. Here, we demonstrate highly efficient light-emitting diodes (LEDs) based on the colloidal perovskite nanocrystals (NCs) in a dimension > DB (regime beyond quantum size) by using a multifunctional buffer hole injection layer (Buf-HIL). The perovskite NCs with a dimension greater than DB show a size-irrespective high color purity and PLQE by managing the recombination of excitons occurring at surface traps and inside the NCs. The Buf-HIL composed of poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) (PEDOT:PSS) and perfluorinated ionomer induces uniform perovskite particle films with complete film coverage and prevents exciton quenching at the PEDOT:PSS/perovskite particle film interface. With these strategies, we achieved a very high PLQE (~60.5%) in compact perovskite particle films without any complex post-treatments and multilayers and a high current efficiency of 15.5 cd/A in the LEDs of colloidal perovskite NCs, even in a simplified structure, which is the highest efficiency to date in green LEDs that use colloidal organic-inorganic metal-halide perovskite nanoparticles including perovskite QDs and NCs. These results can help to guide development of various light-emitting optoelectronic applications based on perovskite NCs. PMID- 28587468 TI - Human Platelet Vesicles Exhibit Distinct Size and Proteome. AB - In the past 50 years, isolated blood platelets have had restricted use in wound healing, cancer therapy, and organ and tissue transplant, to name a few. The major obstacle for its unrestricted use has been, among others, the presence of ultrahigh concentrations of growth factors and the presence of both pro angiogenic and anti-angiogenic proteins. To overcome this problem requires the isolation and separation of the membrane bound secretory vesicles containing the different factors. In the current study, high-resolution imaging of isolated secretory vesicles from human platelets using atomic force microscopy (AFM) and mass spectrometry enabled characterization of the remaining vesicles size and composition following their immunoseparation. The remaining vesicles obtained following osmotic lysis, when subjected to immunoseparation employing antibody to different vesicle-associated membrane proteins (VAMPs), demonstrate for the first time that VAMP-3-, VAMP-7-, and VAMP-8-specific vesicles each possesses distinct size range and composition. These results provide a window into our understanding of the heterogeneous population of vesicles in human platelets and their stability following both physical manipulation using AFM and osmotic lysis of the platelet. This study further provides a platform for isolation and the detailed characterization of platelet granules, with promise for their future use in therapy. Additionally, results from the study demonstrate that secretory vesicles of different size found in cells reflect their unique and specialized composition and function. PMID- 28587470 TI - Surface engineering of poly(methylmethacrylate): Effects on fluorescence immunoassay. AB - The authors present surface engineering modifications through chemistry of poly(methylmethacrylate) (PMMA) that have dramatic effects on the result of surface-bound fluorescence immunoassays, both for specific and nonspecific signals. The authors deduce the most important effect to be clustering of antibodies on the surface leading to significant self-quenching. Secondary effects are attributable to the formation of sparse multilayers of antibody. The authors compare PMMA as an antibody support surface with ultraviolet-ozone oxidized PMMA and also to substrates that were, after the oxidation, surface modified by a four-unit poly(ethyleneglycol) carboxylic acid (PEG4), a branched tricarboxylic acid, and a series of carboxylic acid-terminated dendrimers, from generation 1.5 to 5.5. Fluorescence immunoassay and neutron reflectometry were used to compare the apparent antibody surface loading, antigen binding and nonspecific binding on these various surfaces using anti-human IgG as a model antibody, chemically coupled to the surface by amide formation. Simple physical adsorption of the antibody on PMMA resulted in a thick antibody multilayer with small antigen binding capacity. On the carboxylated surfaces, with chemical coupling, a simple monolayer was formed. The authors deduce that antibody clustering was driven by conformational inflexibility and high carboxylate density. The PEG4-modified surface was the most conformationally flexible. The dendrimer-modified interfaces showed a collapse and densification. In fluorescence immunoassay, the optimal combination of high specific and low nonspecific fluorescence signal was found for the G3.5 dendrimer. PMID- 28587472 TI - Key Strategies for Physical Activity Interventions Among Older Women: Process Evaluation of a Clinical Trial. AB - PURPOSE: To describe strategies salient to physical activity (PA) initiation and maintenance among older women who participated in a clinical trial that tested a PA intervention. DESIGN: A descriptive phenomenological, qualitative design for a process evaluation of a successful clinical trial. SETTING: Senior primary care clinics associated with a large medical center in a southern state. PARTICIPANTS: A total of 20 older women at least 60 years without advanced frailty. METHOD: Purposive sampling using maximum variation technique was used to select participants. A semi-structured interview guide facilitated individual, in-depth interviews lasting 45 to 90 minutes. Narratives were analyzed using content analysis with constant comparison technique to summarize the data. RESULTS: Eight African American and 12 white older women with a mean age of 68 from control and intervention arms participated. Five central themes described salient strategies to promote and maintain PA: sensed benefits, motivation, and self-efficacy were central to success, while a reduction in barriers was essential before maintaining PA. The last theme, a life-changing awareness indicated that PA had become a shared value. An explanatory model describing interrelationships is presented. CONCLUSIONS: This study suggests key strategies to include in PA interventions with older women. An unexpected finding was that PA became a shared value, an action promoted by the Culture of Health initiative to improve population health and well-being. PMID- 28587473 TI - Eliminating Female Genital Mutilation/Cutting in Iraqi Kurdistan: a challenge. PMID- 28587471 TI - Factors That Impact the Success of Interorganizational Health Promotion Collaborations: A Scoping Review. AB - OBJECTIVE: To explore published empirical literature in order to identify factors that facilitate or inhibit collaborative approaches for health promotion using a scoping review methodology. DATA SOURCE: A comprehensive search of MEDLINE, CINAHL, ScienceDirect, PsycINFO, and Academic Search Complete for articles published between January 2001 and October 2015 was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. STUDY INCLUSION AND EXCLUSION CRITERIA: To be included studies had to: be an original research article, published in English, involve at least 2 organizations in a health promotion partnership, and identify factors contributing to or constraining the success of an established (or prior) partnership. Studies were excluded if they focused on primary care collaboration or organizations jointly lobbying for a cause. DATA EXTRACTION: Data extraction was completed by 2 members of the author team using a summary chart to extract information relevant to the factors that facilitated or constrained collaboration success. DATA SYNTHESIS: NVivo 10 was used to code article content into the thematic categories identified in the data extraction. RESULTS: Twenty-five studies across 8 countries were identified. Several key factors contributed to collaborative effectiveness, including a shared vision, leadership, member characteristics, organizational commitment, available resources, clear roles/responsibilities, trust/clear communication, and engagement of the target population. CONCLUSION: In general, the findings were consistent with previous reviews; however, additional novel themes did emerge. PMID- 28587474 TI - Pollution by Nonylphenol in river, tap water, and aquatic in an acid rain-plagued city in southwest China. AB - OBJECTIVE: Nonylphenol (NP) has provoked much environmental concern because of their weak estrogenic activities; however, few data are available on the environmental levels of the chemical in China. METHOD: Environmental or river samples were assayed for NP by high-performance liquid chromatography (HPLC) technique. RESULTS: The concentration for NP measured in Xiangjiang River, ranging from 0.174 to 3.411 MUg/L with a mean value of 1.73 MUg/L, was lower than the Water Quality Criteria for NP of the US (6.6 MUg/L); however, the NP concentration was maintained at a higher level compare to the developed countries and other civil cities. NP concentration in downstream water was markedly higher than that both in midstream and upstream water. Tissue accumulation of NP was observed in aquatics. A ratio of mean concentration of NP in aquatic (chlamys farreri and hemiculter leucisculus) to that in river water was 241 and 1087, respectively. The presence of NP in tap water in two urban districts of Zunyi was common with a detectable rate reached 100.0%. Mean NP concentration in terminal tap water in Huichuan district was six times as high as Honghuagang district, which was above Standards for the Drinking Water Quality for Phenols of China (2 MUg/L). CONCLUSION: The pollution of NP in Xiangjiang River, tap water, and aquatic in Zunyi belongs to moderate or severe level in the world. PMID- 28587475 TI - Management of Severe Equinovalgus in Patients With Cerebral Palsy by Naviculectomy in Combination With Midfoot Arthrodesis. AB - BACKGROUND: Equinovalgus deformity is the second most common deformity in cerebral palsy and may be flexible or rigid. Several operative methods from joint sparing to arthrodesis have been described with varying success rates. The aim of this study was to investigate the effectiveness of naviculectomy in combination with midfoot arthrodesis (talo-cuneiform and calcaneocuboid arthrodesis) in the correction of a rigid equinovalgus foot deformity in cerebral palsy. METHODS: Forty-eight rigid equinovalgus feet were operated upon in 30 patients from 2008 to 2013. Of these, 44 feet in 26 patients with cerebral palsy (Gross Motor Function Classification System III, IV, or V) with follow-up of more than 2 years were included in the study. The mean age at surgery was 18.1 years. The outcomes were measured objectively using radiographic angles and subjectively using 5 questions to be answered by the caregiver. The feet were then graded into excellent, good, fair, and poor. The mean follow-up was 5.0 +/- 1.7 years. RESULTS: Excellent to good results were obtained in 81% of the feet. Both objective and subjective outcomes improved significantly postoperatively ( P < .001). Three feet in 2 patients were graded as poor and underwent a revision operation for pain and recurrence. CONCLUSIONS: Naviculectomy in combination with midfoot arthrodesis enabled a good 3-dimensional correction of the forefoot. However, the procedure did not necessarily correct the fixed subtalar joint deformity. Several additional bony and soft-tissue procedures were necessary to achieve a complete correction in these difficult feet. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 28587476 TI - Do the New FDA Guidance Documents Help Improving Performance of Blood Glucose Monitoring Systems Compared With ISO 15197? AB - Recently, the Food and Drug Administration (FDA) published guidance documents for point-of-care testing (POCT) and over-the-counter (OTC) blood glucose monitoring systems (BGMS). These are expected to improve weaknesses of the already established ISO 15197:2013 standard accuracy evaluation for OTC BGMS; however, the proposed criteria and procedures rather raise new questions. As an example, the OTC guidance stipulates tighter accuracy criteria in the low glycemic range than the POCT guidance for no obvious reason. Furthermore, a clear definition of requirements for the reference method is missing under consideration of the strict accuracy criteria. External surveillance of BGMS after introduction to the market is an issue that is addressed neither in the FDA documents, nor in ISO 15197, but in the Clinical and Laboratory Standards Institute (CLSI) guideline POCT12-A3. PMID- 28587477 TI - A review of binimetinib for the treatment of mutant cutaneous melanoma. AB - Although significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. In particular, patients with NRAS mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy. PMID- 28587478 TI - Operative Treatment of the Ingrown Toenail With a Less-Invasive Technique: Flashback to the Original Winograd Technique. AB - OBJECTIVE: The aim of this study was to evaluate the results of the partial nail plate excision and curettage of nail bed and matrix (the original Winograd technique) in patients with ingrown toenail. MATERIALS AND METHODS: Patients with ingrown toenail who were treated surgically from May 2014 to June 2015, with a minimum follow-up of 1 year were included in this study. Those who had previous ingrown toenail surgery were excluded. Partial nail plate excision with curettage of nail bed and nail matrix was performed for all patients. Rifampicin soaked sterile gauze was placed onto the wounds after the procedure. RESULTS: The study population included 100 males and 89 females with a mean age of 30 years. Eight patients (4.2%) had stage 1, 71 patients (37.6%) had stage 2, and 110 patients (58.2%) had stage 3 ingrown toenails. The mean operation time was 4.8 minutes. No complication occurred during the procedure. It was found that 15 patients (7.9%) had recurrence during the follow-up. CONCLUSION: The original Winograd technique is an efficient and less-invasive technique for the treatment of ingrown toenail, with lower rates of recurrence and complications. LEVELS OF EVIDENCE: Therapeutic Case Series Study, Level IV. PMID- 28587479 TI - Using 'WeChat' online social networking in a real-world needs analysis of family members of youths at clinical high risk of psychosis. AB - OBJECTIVE: The argument surrounding the safety and effectiveness of interventions for the population of individuals at a clinical high risk of developing psychosis has been ongoing for the past 30 years. However, few studies have assessed the needs of this special young population, who are struggling with the recent onset of psychotic symptoms. METHOD: The sample consisted of 171 family members of 108 clinical high-risk individuals included from the ShangHai at Risk for Psychosis research programme. A 'WeChat' group was established to provide mutual support. There were 22,007 valid messages sent within the group between 1 April 2015 and 27 June 2016. Chat records were subsequently analysed to determine the needs of families during intervention at the early stages of psychosis. RESULTS: Families of clinical high-risk individuals were highly involved in the entire medical process, and the major concerns of the families of clinical high-risk individuals focused on both functional recovery and medication. The themes of 'take medication', 'go to school' and 'study in school' were often discussed within the group. CONCLUSION: A family-focused intervention targeting functional recovery and real-time professional explanations of medication would meet the major needs of families of Chinese clinical high-risk individuals. PMID- 28587480 TI - Nutritional composition, antioxidant activity and isolation of scopoletin from Senecio nutans: support of ancestral and new uses. AB - Continuing with our study characterising Senecio nutans Sch. Bip., we have isolated and identified a simple coumarin, scopoletin, that could be relevant for the biological properties of the species related with the ancestral medical uses. This is the first report of scopoletin from S. nutans. In addition, the extract was analysed for its antioxidant activity using the ABTS and FRAP method as well as providing the first nutritional analyses of this plant from northern Chile highlands. PMID- 28587481 TI - Increased Incidence of Critical Illness in Psoriasis. AB - BACKGROUND: Psoriasis is associated with an increased risk of comorbid disease. Despite the recognition of increased morbidity in psoriasis, the effects on health care utilisation remain incompletely understood. Little is known about the risk of intensive care unit (ICU) admission in persons with psoriasis. OBJECTIVE: To compare the incidence of ICU admission and post-ICU mortality rates in a psoriasis population compared with a matched population without psoriasis. METHODS: Using population-based administrative data from Manitoba, Canada, we identified 40 930 prevalent cases of psoriasis and an age-, sex-, and geographically matched cohort from the general population (n = 150 210). We compared the incidence of ICU admission between populations using incidence rates and Cox regression models adjusted for age, sex, socioeconomic status, and comorbidity and compared mortality after ICU admission. RESULTS: Among incident psoriasis cases (n = 30 150), the cumulative 10-year incidence of ICU admission was 5.6% (95% confidence interval [CI], 5.3%-5.8%), 21% higher than in the matched cohort (incidence rate ratio, 1.21; 95% CI, 1.15-1.27). In the prevalent psoriasis cohort, crude mortality in the ICU was 11.5% (95% CI, 9.9%-13.0%), 32% higher than observed in the matched population admitted to the ICU (8.7%; 95% CI, 8.3%-9.1%). Mortality rates after ICU admission remained elevated at all time points in the psoriasis cohort compared with the matched cohort. CONCLUSION: Psoriasis is associated with an increased risk for ICU admission and with an increased risk of mortality post-ICU admission. PMID- 28587482 TI - What is the impact of volunteers providing care and support for people with dementia in acute hospitals? A systematic review. AB - A quarter of acute hospital beds are occupied by people with dementia, and a hospital stay may impact negatively on their health and wellbeing. The development and implementation of volunteers to provide social, activity-based, one-to-one support for people with dementia in acute hospitals has become routine practice. However, the evidence to support this practice has not been identified or evaluated. This systematic review considers the effect of volunteers on the care and experience of people with co-morbid cognitive impairment/dementia in acute hospitals. The systematic search identified 444 papers, although only three papers included specific analysis relating to the impact of volunteers. The evidence suggests volunteers may have potential to enhance the experiences of people with dementia in acute hospitals; however, there is currently a marked lack of evidence to support the widespread implementation of volunteers. There is therefore an urgent need for multi-site robust research to provide evidence of the impact of volunteers supporting people with cognitive impairment/dementia during an acute hospital stay. PMID- 28587483 TI - Day care for people with dementia: A qualitative study comparing experiences from Norway and Scotland. AB - Potential benefits from day care attendance are reported in the literature for both people with dementia and caregivers, although the evidence-base is limited. The study aimed to explore and compare experiences of day care services for people with dementia as described by day care attendees and their caregivers in Norway and Scotland. Whereas day care receives prominence in Norway's national dementia plan, Scotland does not highlight day care in its national dementia strategy. A qualitative cross-national comparative study was undertaken. Semi structured interviews were conducted with 17 people with dementia and 17 caregivers in Norway, and 19 people with dementia and 15 caregivers in Scotland. Data were analyzed thematically and comparatively to explore the experiences and outcomes of the participants. Findings indicate positive outcomes from day care for both people with dementia and caregivers. Satisfaction with services related to meaningful activities, getting out of the home, strengthening social connections and careful staff facilitation to create a positive and welcoming atmosphere. There were strong similarities in the content of services and experiences reported in the two countries. Some minor differences were noted, with caregiver support being an area of notable divergence in experiences. Specialist day care for people with dementia seems to provide important support and positive outcomes for people with dementia, and respite and reassurance for their caregivers. More research is needed to further explore the effect of day care designed for people with dementia both on the attendees and their caregivers. PMID- 28587484 TI - Seven-Year Follow-up of Matrix-Induced Autologous Implantation in Talus Articular Defects. AB - BACKGROUND: Osteochondral lesions of the talus (OLT) are difficult to treat because of the poor intrinsic healing capability of articular cartilage. Matrix induced autologous chondrocyte implantation (MACI) has been shown to be a reliable method for treating cartilage lesions that fail to respond to traditional microfracture and debridement. The purpose of this study was to assess 7-year clinical follow-up data of this technique and demonstrate midterm success of this implant. METHODS: A prospective investigation of MACI was performed on 10 patients with OLTs who had failed previous arthroscopic treatment. In all, 5 male and 5 female patients were included in the study. Of the 10 patients, 9 were available for 7-year follow-up. Functional and clinical evaluations were done at 7 years postoperatively using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot evaluation and the Short Form Health Survey (SF-36) and compared with preoperative values. RESULTS: SF-36 data at 7 years showed significant improvements in Physical Functioning (P < .01), Lack of Bodily Pain (P < .1), and Social Functioning (P < .001) compared with preoperative data. The mean AOFAS hindfoot scores of the 9 patients at 7 years was 78.3 +/- 18.1 (P = .05) compared with their preoperative mean of 61.8 +/- 14.3. CONCLUSIONS: MACI provides a stable midterm chondral replacement strategy for osteochondral lesions that fail initial microfracture. LEVELS OF EVIDENCE: Level IV: Prospective case series. PMID- 28587485 TI - Management of Nonunited Talar Fractures With Avascular Necrosis by Resection of Necrotic Bone, Bone Grafting, and Fusion With an Intramedullary Nail. AB - BACKGROUND: The presence of nonunion of a talar fracture with displacement, together with complete avascular necrosis, is a challenging entity to treat. METHODS: Twelve patients, 8 men (66.7%) and 4 women (33.3%), with nonunited talar fractures and extensive avascular necrosis of the talus were included. The average age was 27.7 years (range, 19-38 years). After exclusion of infection, the patients underwent resection of necrotic bone, bulk autograft, and fusion using an intramedullary nail. The posterior approach was used in 11 patients and the anterior approach in 1 patient. The primary outcome was solid osseous union at the ankle and subtalar level and between the talar head anteriorly and the posterior construct, as evidenced by computed tomographic examination. Functional assessment was performed with the American Orthopaedic Foot & Ankle Society score and subjective patient satisfaction Results: After a mean follow-up duration of 23 months (range, 12-60 months), solid osseous union was achieved in 8 patients (66.7%). Stable fibrous union was seen in 1 patient (8.3%). Three patients (25%) required reoperation, and osseous fusion was finally achieved. American Orthopaedic Foot & Ankle Society score improved from a mean of 39.3 (range, 12 56) preoperatively to 76.6 (range, 62-86) at last follow-up. Subjective patient satisfaction was graded good or excellent in all cases. CONCLUSION: Resection of necrotic talar body and bulk autograft with tibiotalocalcaneal fusion by an intramedullary nail through a posterior approach was a reasonable option for the management of type IV posttraumatic talar deformity. LEVEL OF EVIDENCE: Level IV, case series. PMID- 28587486 TI - Morphological and physicochemical evaluation of the propranolol HCl-Eudragit(r) RS100 electrosprayed nanoformulations. AB - The aim of this study was to fabricate propranolol hydrochloride (Prop. HCl) (as a water-soluble drug):Eudragit(r) RS100 (Eud) nanobeads and nanofibres applying the electrospraying method as an economical and one-step technique. Different ratios of Prop. HCl:Eud (i.e. 1:5 and 1:10) at total solution concentrations of 10-20% W/V were investigated. The FE-SEM studies revealed that morphology and size of the samples were highly affected by the solution concentration; so that, the nanobeads (a mean diameter of 82.9 nm) were formed in low concentration and at the highest concentration of the solution, nanofibres (a mean diameter of 232.3 nm) were resulted. Besides the morphological changes, the size of processed nanoformulations was increased with an increment of the solution concentrations. X-ray diffraction results as well as DSC thermograms clearly indicated that the drug crystallinity decreased in the electrosprayed samples. Furthermore, in vitro dissolution test showed that the electrosprayed samples had relatively slower release patterns toward the pure drug and physical mixtures, where the samples with the drug:polymer ratio of 1:10 indicated a faster release rate toward 1:5 ratio; nevertheless, the concentration of the injected formulations did not remarkably impressed the release behaviours. The current study established the suitability of electrospraying method in the fabrication of the water-soluble drugs nanobeads/nanofibres; however, in vivo effectiveness of the prepared nanoformulations should be meticulously considered. PMID- 28587487 TI - Chemical constituents and biological activities of Dianthus elegans var. elegans. AB - Chemical investigation of the aerial parts of Dianthus elegans var. elegans afforded two previously undescribed saponins, named dianosides M-N (1-2), together with four oleanane-type triterpenoid glycosides (3-6). Their structures were elucidated as 3-O-alpha-L-arabinofuranosyl-16alpha-hydroxyolean-12-ene 23alpha, 28beta-dioic acid (1) and 3-O-alpha-L-arabinofuranosyl-(1 -> 3)-beta-D glucopyranosyl 16alpha-hydroxyolean-12-ene-23alpha-oic acid, 28-O-beta-D glucopyranosyl-(1 -> 6)-beta-D-glycosyl ester (2) by chemical and extensive spectroscopic methods including IR, 1D, 2D NMR and HRESIMS. Both of the saponins were evaluated for their cytotoxicities against HEK-293, A-549 and HeLa human cancer cells using the MTT method. All compounds showed no substantial cytotoxic activity against tested cell lines. However, dianosides M-N and the n-butanol fraction exhibited considerable haemolysis in human erythrocyte cells. The immunomodulatory properties of dianosides M-N were also evaluated in activated whole blood cells by PMA plus ionomycin. Dianosides M-N increased IL-1beta concentration significantly whereas the n-butanol fraction slightly augmented IL 1beta secretion. All compounds did not change IL-2 and IFN-gamma levels considerably. PMID- 28587488 TI - Running multiple marathons is not a risk factor for premature subclinical vascular impairment. AB - Background In contrast to the well-accepted benefits of moderate exercise, recent research has suggested potential deleterious effects of repeated marathon running on the cardiovascular system. We thus performed a comprehensive analysis of markers of subclinical vascular damage in a cohort of runners having finished multiple marathon races successfully. Design This was a prospective, observational study. Methods A total of 97 healthy male Munich marathon participants (mean age 44 +/- 10 years) underwent detailed training history, cardiopulmonary exercise testing for assessment of peak oxygen uptake, ultrasound for assessment of intima-media-thickness as well as non-invasive assessments of ankle-brachial index, augmentation index, pulse wave velocity and reactive hyperaemia index. Results Runners had previously completed a median of eight (range 1-500) half marathons, six (1-100) full marathons and three (1-40) ultramarathons; mean weekly and annual training volumes were 59 +/- 23 and 1639 +/- 979 km. Mean peak oxygen uptake was 50 +/- 8 ml/min/kg, and the Munich marathon was finished in 3:45 +/- 0:32 h. Runners showed normal mean values for intima-media-thickness (0.60 +/- 0.14 mm), ankle-brachial index (1.2 +/- 0.1), augmentation index (17 +/- 13%), pulse wave velocity (8.7 +/- 1.4 cm/s) and reactive hyperaemia index (1.96 +/- 0.50). Age was significantly and independently associated with intima-media-thickness ( r = 0.531; p < 0.001), augmentation index ( r = 0.593; p < 0.001) and pulse wave velocity ( r = 0.357; p < 0.001). However, no independent associations of peak oxygen uptake, marathon finishing time, number of completed races or weekly and annual training km with any of the vascular parameters were observed. Conclusions In this cohort of healthy male runners, running multiple marathon races did not pose an additional risk factor for premature subclinical vascular impairment beyond age. PMID- 28587490 TI - Ethical challenges in pregnant women with brain injury. PMID- 28587489 TI - Laboratory evaluation of an optimised internet-based speech-in-noise test for occupational high-frequency hearing loss screening: Occupational Earcheck. AB - OBJECTIVE: The "Occupational Earcheck" (OEC) is a Dutch online self-screening speech-in-noise test developed for the detection of occupational high-frequency hearing loss (HFHL). This study evaluates an optimised version of the test and determines the most appropriate masking noise. DESIGN: The original OEC was improved by homogenisation of the speech material, and shortening the test. A laboratory-based cross-sectional study was performed in which the optimised OEC in five alternative masking noise conditions was evaluated. STUDY SAMPLE: The study was conducted on 18 normal-hearing (NH) adults, and 15 middle-aged listeners with HFHL. RESULTS: The OEC in a low-pass (LP) filtered stationary background noise (test version LP 3: with a cut-off frequency of 1.6 kHz, and a noise floor of -12 dB) was the most accurate version tested. The test showed a reasonable sensitivity (93%), and specificity (94%) and test reliability (intra class correlation coefficient: 0.84, mean within-subject standard deviation: 1.5 dB SNR, slope of psychometric function: 13.1%/dB SNR). CONCLUSIONS: The improved OEC, with homogenous word material in a LP filtered noise, appears to be suitable for the discrimination between younger NH listeners and older listeners with HFHL. The appropriateness of the OEC for screening purposes in an occupational setting will be studied further. PMID- 28587491 TI - Local uterine resection for placenta percreta: technical details are important. PMID- 28587492 TI - Digits and narratives of the experience of Italian families facing premature births. AB - The objective of the research was to understand the experience of families living a premature birth and to outline the current care plan in Italy. The survey was addressed to 150 parents of children born under the 34th week of pregnancy. Topics of the investigation were the implications on their family, social and working contexts, determined through a questionnaire enriched by a collection of narratives. Written testimonies were clustered through a Narrative Medicine method and matched with quantitative information. The main respondents were mothers of severe and moderate preterm children. Except for the Kangaroo Care, services were not uniformed amongst the centers and few home care supports resulted available for families. Sixty-seven percent of the mothers could not obtain a prolonged maternity leave and described the impacts on their working activities. Narratives revealed a low level of prevention, information and awareness on the risks of prematurity amongst families, few local networks among Neonatal Intensive Care Unit (NICU) teams, gynecologists and pediatricians, and the shortage of support for parents at work; these actions were collected in a Position Paper. Findings showed the integration between families' coping strategies and the offered care services for preterm births. Narrative tools could represent the bridge between families and health care teams. PMID- 28587493 TI - A randomized controlled trial of a new treatment for labor dystocia. AB - OBJECTIVE: Labor dystocia is an intransigent, high-profile issue in obstetric care. Amniotic fluid lactate (AFL) reflects the uterine metabolic status. High levels associate with subsequent need for operative intervention due to dystocia. In sports medicine, it is known that lactic acid can affect muscular performance and can be decreased by bicarbonate given orally before physical activity. MATERIAL AND METHODS: Two hundred dystocic deliveries were included. At the confirmation of dystocia, the AFL-level was analyzed. Deliveries were randomized to an intake of bicarbonate or not. In the "non-bicarbonate-group", stimulation with oxytocin was started immediately. In the "bicarbonate-group", bicarbonate was given; and oxytocin was started 1 hour after the intake. New sampling of AF was performed after 1 hour in both groups. OUTCOME MEASURED: if an oral intake of bicarbonate changes the AFL levels and enhances delivery outcome in dystocic deliveries. RESULTS: Bicarbonate decreases the AFL levels (p < .001). The spontaneous vaginal delivery rate after treatment with bicarbonate was increased (p = .007), without affecting the fetal outcome. CONCLUSIONS: An increase of spontaneous vaginal deliveries resulted from bicarbonate ingestion by dystocic women. A decreased level of AFL-level was shown. This simple, low cost treatment has the potential to improve maternal morbidity and satisfaction worldwide. PMID- 28587494 TI - Impact of information and communication technology on interprofessional collaboration for chronic disease management: a systematic review. AB - Objectives Information and communication technology is often lauded as the key to enhancing communication among health care providers. However, its impact on interprofessional collaboration is unclear. The objective of this study was to determine the extent to which it improves communication and, subsequently, enhances interprofessional collaboration in chronic disease management. Methods A systematic review of academic literature using two electronic platforms: HealthSTAR and Web of Science (core collection and MEDLINE). To be eligible for inclusion in the review, articles needed to be peer-reviewed; accessible in English and focused on how technology supports, or might support, collaboration (through enhanced communication) in chronic disease management. Studies were assessed for quality and a narrative synthesis conducted. Results The searches identified 289 articles of which six were included in the final analysis (three used qualitative methods, two were descriptive and one used mixed methods). Various forms of information and communication technology were described including electronic health records, online communities/learning resources and telehealth/telecare. Three themes emerged from the studies that may provide insights into how communication that facilitates collaboration in chronic disease management might be enhanced: professional conflict, collective engagement and continuous learning. Conclusions The success of technology in enhancing collaboration for chronic disease management depends upon supporting the social relationships and organization in which the technology will be placed. Decision makers should take into account and work toward balancing the impact of technology together with the professional and cultural characteristics of health care teams. PMID- 28587496 TI - Review article: a practical approach to the clinical management of NSAID enteropathy. AB - Co-prescription of acid suppressive therapy, together with advances in small bowel imaging techniques, have shifted the burden of NSAID-related toxicity from gastro-duodenal to more distal small bowel injury. Due to predominantly subclinical disease, NSAID enteropathy remains under-recognised, with an incidence of 53-80% amongst healthy short-term users, and a prevalence of 50-71% following long-term (>3 months) use. Despite their distinct pathogenesis, those at risk of NSAID-related gastro-duodenal and small bowel complications share several risk factors. Clinical complications of NSAID enteropathy such as protein losing enteropathy, small bowel strictures and diaphragm disease, confer significant morbidity, and are often irreversible. Small bowel prophylaxis has proven of modest efficacy after short-term, high-dose NSAID use in asymptomatic patients. While selective COX-2 inhibitors are associated with fewer gastro duodenal complications relative to non-selective NSAIDs, their comparative benefit in protecting against small bowel enteropathy remains unclear. Prophylaxis should be considered in those at high risk of small bowel complications, as treatment options for established disease remain limited; however, the optimal agent remains unclear. We propose a clinical algorithm that may help prevent, monitor, investigate, and manage the sequelae of NSAID-induced small bowel toxicity. PMID- 28587497 TI - Accelerated leukemic transformation after haplo-identical transplantation for hydroxyurea-treated sickle cell disease. PMID- 28587495 TI - Allele-specific interaction between glutathione peroxidase 1 and manganese superoxide dismutase affects the levels of Bcl-2, Sirt3 and E-cadherin. AB - Manganese superoxide dismutase (MnSOD) is a mitochondrial-resident enzyme that reduces superoxide to hydrogen peroxide (H2O2), which can be further reduced to water by glutathione peroxidase (GPX1). Data from human studies have indicated that common polymorphisms in both of these proteins are associated with the risk of several cancers, including breast cancer. Moreover, polymorphisms in MnSOD and GPX1 were shown to interact to increase the risk of breast cancer. To gain an understanding of the molecular mechanisms behind these observations, we engineered human MCF-7 breast cancer cells to exclusively express GPX1 and/or MnSOD alleles and investigated the consequences on the expression of several proteins associated with cancer aetiology. Little or no effect was observed on the ectopic expression of these genes on the phosphorylation of Akt, although allele-specific effects and interactions were observed for the impact on the levels of Bcl-2, E-cadherin and Sirt3. The patterns observed were not consistent with the steady-state levels of H2O2 determined in the transfected cells. These results indicate plausible contributing factors to the effects of allelic variations on cancer risk observed in human epidemiological studies. PMID- 28587499 TI - Loss in translation. PMID- 28587500 TI - Evaluation of Health Equity Impact of Structural Policies: Overview of Research Methods Used in the SOPHIE Project. AB - This article briefly assesses the research methods that were applied in the SOPHIE project to evaluate the impact of structural policies on population health and health inequalities. The evaluation of structural policies is one of the key methodological challenges in today's public health. The experience in the SOPHIE project was that mixed methods are essential to identify, understand, and predict the health impact of structural policies. On the one hand, quantitative studies that included spatial comparisons or time trend analyses, preferably in a quasi experimental design, showed that some structural policies were associated with improved population health and smaller health inequalities. On the other hand, qualitative studies, often inspired by realist approaches, were important to understand how these policies could have achieved the observed impact and why they would succeed in some settings but fail in others. This review ends with five recommendations for future studies that aim to evaluate, understand, and predict how health inequalities can be reduced through structural policies. PMID- 28587498 TI - Surface EEG-Transcranial Direct Current Stimulation (tDCS) Closed-Loop System. AB - Conventional transcranial direct current stimulation (tDCS) protocols rely on applying electrical current at a fixed intensity and duration without using surrogate markers to direct the interventions. This has led to some mixed results; especially because tDCS induced effects may vary depending on the ongoing level of brain activity. Therefore, the objective of this preliminary study was to assess the feasibility of an EEG-triggered tDCS system based on EEG online analysis of its frequency bands. Six healthy volunteers were randomized to participate in a double-blind sham-controlled crossover design to receive a single session of 10[Formula: see text]min 2[Formula: see text]mA cathodal and sham tDCS. tDCS trigger controller was based upon an algorithm designed to detect an increase in the relative beta power of more than 200%, accompanied by a decrease of 50% or more in the relative alpha power, based on baseline EEG recordings. EEG-tDCS closed-loop-system was able to detect the predefined EEG magnitude deviation and successfully triggered the stimulation in all participants. This preliminary study represents a proof-of-concept for the development of an EEG-tDCS closed-loop system in humans. We discuss and review here different methods of closed loop system that can be considered and potential clinical applications of such system. PMID- 28587502 TI - Ethical values in nurse education perceived by students and educators. AB - BACKGROUND: Education is considered the first function and mission of the university, and observing educational ethics guarantees the health of the teaching-learning process in the university. AIM: The aim of this study was to explore ethical values in nursing education from the perspective of Iranian nursing students and educators. RESEARCH DESIGN: This qualitative study was conducted using the Thematic Content Analyses method. The data were collected from seven semi-structured individual interviews and three focus group discussions from July to November 2015. Participants and research context: The participants were faculty educators of nursing and nursing students in Tehran, capital of Iran, who were selected through purposive sampling. They were recruited gradually. Sampling was continued until data saturation when no new codes were extracted. Ethical committee: This study was conducted after obtaining the approval of Shahid Beheshti University of Medical Sciences Ethics Committee, and informed consent were ensured before conducting the research. The principles of voluntariness, confidentiality, and anonymity were respected during the research process. FINDINGS: Seven major themes emerged: human dignity, constructive human relations, educational justice, competency enhancement, excellence view, wisdom, and commitment and accountability. CONCLUSION: The results of this study indicated that although many of the values, as universal values, were similar to those of other countries-which can be a reflection of the globalization process in the nursing profession and the presence of humanistic and spiritual approaches at the roots of the discipline, some differences could be found in the content of values due to factors such as the people's beliefs, culture, and religion. Iranian nursing students and educators revealed a unique and culture-based set of ethical values. PMID- 28587503 TI - Sense of responsibility in ICU end-of-life decision-making: Relatives' experiences. AB - BACKGROUND: Relatives of intensive care unit patients who lack or have reduced capacity to consent are entitled to information and participation in decision making together with the patient. Practice varies with legislation in different countries. In Norway, crucial decisions such as withdrawing treatment are made by clinicians, usually morally justified to relatives with reference to the principle of non-maleficence. The relatives should, however, be consulted about whether they know what the patient would have wished in the situation. RESEARCH OBJECTIVES: To examine and describe relatives' experiences of responsibility in the intensive care unit decision-making process. RESEARCH DESIGN: A secondary analysis of interviews with bereaved relatives of intensive care unit patients was performed, using a narrative analytical approach. Participants and research context: In all, 27 relatives of 21 deceased intensive care unit patients were interviewed about their experiences from the end-of-life decision-making process. Most interviews took place in the participants' homes, 3-12 months after the patient's death. Ethical considerations: Based on informed consent, the study was approved by the Data Protection Official of the Norwegian Social Science Data Services and by the Regional Committee for Medical and Health Research Ethics. FINDINGS: The results show that intensive care unit relatives experienced a sense of responsibility in the decision-making process, independently of clinicians' intention of sparing them. Some found this troublesome. Three different variants of participation were revealed, ranging from paternalism to a more active role for relatives. DISCUSSION: For the study participants, the sense of responsibility reflects the fact that ethics and responsibility are grounded in the individual's relationship to other people. Relatives need to be included in a continuous dialogue over time to understand decisions and responsibility. CONCLUSION: Nurses and physicians should acknowledge and address relatives' sense of responsibility, include them in regular dialogue and help them separate their responsibility from that of the clinicians. PMID- 28587501 TI - Crude Exploration: Portraying Industrial Disaster in Deepwater Horizon, a Film Directed By Peter Berg, 2016 Crude Exploration: Portraying Industrial Disaster in Deepwater Horizon, a Film Directed By Peter Berg, 2016 . AB - The 2016 film Deepwater Horizon offers a rare portrayal of industrial disaster. It is novel as there are few film-based treatments of this issue. The film enables the public to learn about the disaster, the lives lost, and the stories of survival, but it also provides the opportunity to examine how industrial disaster and, by extension, occupational health and safety may be publicly framed and understood. This article presents an analysis of Deepwater Horizon. Four primary industrial disaster frames are identified in the film: profit maximization, technology and technology failure, managerial conflict, and worker portrayals. Each frame offers advantages and limitations for enhancing public understandings of industrial disaster. Missing from the film is the regulatory environment of the oil drilling industry, whose omission serves to potentially reproduce messages that privilege individualistic, isolated, views of industrial disasters and prioritize immediate over distal causes. PMID- 28587504 TI - Attention to Perceive, to Learn, and to Respond. AB - Mackintosh and his collaborators (e.g., McLaren, Kaye, & Mackintosh, 1989) put forward an account of perceptual learning effects based, in part, on learned changes in stimulus salience. In the workshop held to mark Mackintosh's retirement, and published as a special issue of this journal, Hall (2003) discussed Mackintosh's theory, and proposed his own alternative account. We now want to take the story forward in the light of findings and theoretical perspectives that have emerged since then. Specifically, we will argue that neither Mackintosh nor Hall was correct in his account of the principles that govern how changes in salience occur. Both supposed (in different ways) that such changes depend on the way in which the stimulus (or stimulus element) is predicted by another event. In contrast, theories of attentional learning (Mackintosh, 1975, Pearce & Hall, 1980) have stressed the notion that changes in the properties of a stimulus might depend on the way in which it predicts its consequences. These theories have been concerned with attention-for-learning (associability). We now consider how the general principle they both employ might be relevant to the other forms of attention (for perception and for performance) that are, we will argue, critical for the perceptual learning effect. PMID- 28587507 TI - ADHD Is Comorbid to Migraine in Childhood: A Population-Based Study. AB - OBJECTIVE: Recurrent headaches and ADHD are prevalent in the pediatric population. Herein, we assess if ADHD is comorbid to headaches overall, to headache subtypes (e.g., migraine), and to headache frequency. METHOD: Informed consent and analyzable data were obtained for 5,671 children aged 5 to 12 years (65.9% of the target sample). Parents and teachers were interviewed using validated questionnaires based on the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5). Relative risks were modeled using univariate and multivariate analyses. RESULTS: As contrasted to nonheadache controls, the prevalence of ADHD was significantly higher in children with migraine ( p < .001) but not in those with tension-type headaches. In children with migraine, risk of ADHD increased as a function of headache frequency ( p < .05). CONCLUSION: Migraine and frequent migraine are comorbid to ADHD. Future studies should focus on the impact of the association on the burden to the children and their families. PMID- 28587505 TI - Chronic cervical radiculopathic pain is associated with increased excitability and hyperpolarization-activated current ( Ih) in large-diameter dorsal root ganglion neurons. AB - Cervical radiculopathic pain is a very common symptom that may occur with cervical spondylosis. Mechanical allodynia is often associated with cervical radiculopathic pain and is inadequately treated with current therapies. However, the precise mechanisms underlying cervical radiculopathic pain-associated mechanical allodynia have remained elusive. Compelling evidence from animal models suggests a role of large-diameter dorsal root ganglion neurons and plasticity of spinal circuitry attached with Abeta fibers in mediating neuropathic pain. Whether cervical radiculopathic pain condition induces plastic changes of large-diameter dorsal root ganglion neurons and what mechanisms underlie these changes are yet to be known. With combination of patch-clamp recording, immunohistochemical staining, as well as behavioral surveys, we demonstrated that upon chronic compression of C7/8 dorsal root ganglions, large diameter cervical dorsal root ganglion neurons exhibited frequent spontaneous firing together with hyperexcitability. Quantitative analysis of hyperpolarization-activated cation current ( Ih) revealed that Ih was greatly upregulated in large dorsal root ganglion neurons from cervical radiculopathic pain rats. This increased Ih was supported by the enhanced expression of hyperpolarization-activated, cyclic nucleotide-modulated channels subunit 3 in large dorsal root ganglion neurons. Blockade of Ih with selective antagonist, ZD7288 was able to eliminate the mechanical allodynia associated with cervical radiculopathic pain. This study sheds new light on the functional plasticity of a specific subset of large-diameter dorsal root ganglion neurons and reveals a novel mechanism that could underlie the mechanical allodynia associated with cervical radiculopathy. PMID- 28587506 TI - Extracorporeal photopheresis for GVHD prophylaxis after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation: a prospective multicenter phase 2 study. AB - We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP. Seven patients developed acute graft-versus-host disease (GVHD), with 15% grade >= II cumulative incidence at day 100. The cumulative incidence of chronic GVHD at 2 years was 22%. The 2 years probability of overall survival (OS) and progression free survival (PFS) were 84 and 74%, respectively. This study shows encouraging results with low acute and chronic GVHD incidence and no interference with graft versus-leukemia (GVL) effect. PMID- 28587508 TI - Threats or violence from patients was associated with turnover intention among foreign-born GPs - a comparison of four workplace factors associated with attitudes of wanting to quit one's job as a GP. AB - OBJECTIVE: General practitioners (GPs) are crucial in medical healthcare, but there is currently a shortage of GPs in Sweden and elsewhere. Recruitment of GPs from abroad is essential, but foreign-born physicians face difficulties at work that may be related to turnover intention, i.e. wanting to quit one's job. The study aims to explore the reasons to why foreign-born GPs may intend to quit their job. DESIGN: Survey data were used to compare four work-related factors that can be associated with turnover intentions; patient-related stress, threats or violence from patients, control of work pace, and empowering leadership, among native-born and foreign-born GPs. These work-related factors were subsequently examined in relation to turnover intention among the foreign-born GPs by means of linear hierarchical regression analyses. The questionnaire consisted of items from the QPS Nordic and items constructed by the authors. SETTING: A primary care setting in a central area of Sweden. SUBJECTS: Native-born (n = 208) and foreign born GPs (n = 73). RESULTS: Turnover intention was more common among foreign-born GPs (19.2% compared with 14.9%), as was the experience of threats or violence from patients (22% compared with 3% of the native-born GPs). Threats or violence was also associated with increased turnover intention. Control of work pace and an empowering leadership was associated with reduced turnover intention. PRACTICE IMPLICATIONS: The organisations need to recognise that foreign-born GPs may face increased rates of threats and/or violence from patients, which may ultimately cause job turnover and be harmful to the exposed individual. PMID- 28587509 TI - Differential involvement of reactive oxygen species in a mouse model of capsaicin induced secondary mechanical hyperalgesia and allodynia. AB - Abstract: Intradermally injected capsaicin induces secondary mechanical hyperalgesia and allodynia outside the primary (i.e., capsaicininjected)site. This secondary mechanical hypersensitivity is attributed to central sensitization in which reactive oxygenspecies (ROS) play a key role. We examined whether ROS would be differentially involved in secondary mechanical hyperalgesiaand allodynia using a mouse intraplantar capsaicin injection model. In mice, capsaicin-induced secondary mechanicalhyperalgesia outlasted its allodynia counterpart. Unlike the hyperalgesia, the allodynia was temporarily abolished by ananesthetic given at the capsaicin-injected site. The ROS scavenger phenyl-N tert-butylnitrone slowed the development ofboth secondary mechanical hyperalgesia and allodynia when administered before intraplantar capsaicin injection, whereas itinhibited only the allodynia when administered after capsaicin had already induced secondary mechanical hyperalgesia andallodynia. Intrathecal injection of the ROS donor KO2 induced both mechanical hyperalgesia and allodynia with the formeroutlasting the latter. Metformin, an activator of redox-sensitive adenosine monophosphate-activated protein kinase, selectivelyinhibited capsaicin-induced secondary mechanical allodynia and intrathecal KO2-induced mechanical allodynia. Theseresults suggest that ROS is required for rapid activation of central sensitization mechanisms for both secondary mechanicalhyperalgesia and allodynia after intraplantar capsaicin injection. Once activated, the mechanism for the hyperalgesia is longlastingwithout being critically dependent on ongoing afferent activities arising from the capsaicin-injected site and thecontinuous presence of ROS. On the contrary, the ongoing afferent activities, ROS presence and adenosine monophosphate-activatedprotein kinase inhibition are indispensable for the maintenance mechanism for capsaicin-induced secondarymechanical allodynia. PMID- 28587511 TI - Diagnosis and management of clinical reasoning difficulties: Part II. Clinical reasoning difficulties: Management and remediation strategies. AB - Part II of this AMEE Guide provides a detailed overview of the main difficulties in clinical reasoning, including the cues to look out for in clinical supervision, the root causes of each difficulty and targeted remediation strategies. Specific challenges and issues related to the management of clinical reasoning difficulties will also be discussed. PMID- 28587512 TI - Accuracy of predicted haemoglobin concentration on cardiopulmonary bypass in paediatric cardiac surgery: effect of different formulae for estimating patient blood volume. AB - INTRODUCTION: When applying a blood-conserving approach in paediatric cardiac surgery with the aim of reducing the transfusion of homologous blood products, the decision to use blood or blood-free priming of the cardiopulmonary bypass (CPB) circuit is often based on the predicted haemoglobin concentration (Hb) as derived from the pre-CPB Hb, the prime volume and the estimated blood volume. We assessed the accuracy of this approach and whether it may be improved by using more sophisticated methods of estimating the blood volume. PATIENTS AND METHODS: Data from 522 paediatric cardiac surgery patients treated with CPB with blood free priming in a 2-year period from May 2013 to May 2015 were collected. Inclusion criteria were body weight <15 kg and available Hb data immediately prior to and after the onset of CPB. The Hb on CPB was predicted according to Fick's principle from the pre-CPB Hb, the prime volume and the patient blood volume. Linear regression analyses and Bland-Altman plots were used to assess the accuracy of the Hb prediction. Different methods to estimate the blood volume were assessed and compared. RESULTS: The initial Hb on CPB correlated well with the predicted Hb (R2=0.87, p<0.001). A Bland-Altman plot revealed little bias at 0.07 g/dL and an area of agreement from -1.35 to 1.48 g/dL. More sophisticated methods of estimating blood volume from lean body mass did not improve the Hb prediction, but rather increased bias. CONCLUSION: Hb prediction is reasonably accurate, with the best result obtained with the simplest method of estimating the blood volume at 80 mL/kg body weight. When deciding for or against blood-free priming, caution is necessary when the predicted Hb lies in a range of +/- 2 g/dL around the transfusion trigger. PMID- 28587510 TI - Effects of Fluticasone Furoate Nasal Spray on Parameters of Eosinophilic Inflammation in Patients With Nasal Polyposis and Perennial Allergic Rhinitis. AB - OBJECTIVES: Regulated on activation normal T cell expressed and secreted (RANTES) and eotaxin-2 have been postulated to be responsible for eosinophilia in chronically inflamed nasal mucosa. This study evaluated mucosal production of RANTES and eotaxin-2 in patients with perennial allergic rhinitis (PAR) and nonallergic and allergic form of chronic rhinosinusitis with nasal polyps (CRSwNP) before and after nasal corticosteroid treatment. METHODS: Twenty patients with PAR, 20 nonallergic and 20 allergic CRSwNP patients, and 20 healthy controls were included. The RANTES and eotaxin-2 levels were measured in nasal secretion samples. The patients with chronic inflammation were treated with fluticasone furoate nasal spray for 2 weeks. Cytological examination and measurement of RANTES and eotaxin-2 in nasal fluid were performed before and after the treatment. RESULTS: The levels of RANTES were higher in patients with PAR ( P < .05) and nonallergic ( P < .01) and allergic CRSwNP patients ( P < .001) compared to controls. Eotaxin-2 levels were higher in all 3 inflammation groups compared to healthy subjects ( P < .001). After the treatment, we found a significant decrease of RANTES and eotaxin-2 concentrations ( P < .001) in all 3 groups of patients. CONCLUSION: The levels of RANTES and eotaxin-2 in nasal fluid could be reliable markers for assessing corticosteroid administration outcomes. PMID- 28587513 TI - Delayed care-seeking and outcome of dengue-infected patients. AB - A retrospective cohort study was conducted to assess the effect of early (1-4 days after fever onset) and delayed (>=5 days) care-seeking on outcomes of dengue infected patients. We used data of adult dengue-infected patients treated in Bangkok, Thailand between June 2012 and September 2013. There were 110 patients in the early care-seeking group and 100 in the delayed care-seeking group. There were no deaths. Bleeding complications were not significantly different between the two groups while the latter group had a significantly higher rate of admission compared with the former (98% versus 91.8%, respectively; P = 0.04). Being female was the only factor significantly associated with delayed care seeking (63.0% versus 45.5%; P = 0.01). PMID- 28587515 TI - Reply to Moreno-Garcia et al.: Using Parents and Teachers Integral to Delivering Behavior Therapy as Raters Likely Biased the Report of Outcomes. PMID- 28587514 TI - Pre-hospital oily chloramphenicol treatment in meningitis outbreaks in low resources environments. AB - Bacterial meningitis is an important cause of death and disability in sub-Saharan Africa and, with pre-treatment in peripheral health centres, the poorest populations could avoid early death, especially if they live far from hospital. During the 2001 meningitis epidemic in south Chad, Moyen Chari sanitary district peripheral health centres were equipped with oily chloramphenicol (CAP) to administer before hospital referral in suspected cases of meningitis. Eighty-six patients treated with CAP in whom the diagnosis was definitively confirmed subsequently in hospital were compared with patients receiving CAP at hospital admission during the same period. A statistically significant reduction in lethality rate, need of second line treatment or adjunctive antibiotics, and mean hospital stay were confirmed in pre-treated patients. PMID- 28587516 TI - Noise Reduction in the Neonatal Intensive Care Unit: A Quality Improvement Initiative. AB - Exogenous noise has deleterious effects on the developing fetus and infant. The aim of this quality improvement project was to lower the mean ambient noise level within a level IV neonatal intensive care unit (NICU) by 10% from the baseline in one year. Multiple noise reduction strategies were tested through Plan-Do-Study Act cycles based on the Institute for Healthcare Improvement model for improvement. Strategies targeted environmental and behavioral modifications. Noise levels were recorded continuously; means and peaks were calculated. The mean noise level decreased from 62.4 dB to 56.1 dB, and peak noise level decreased from 115 dB to 76 dB within 12 months. Day shift noise level decreased by 7.7 dB; night shift noise level decreased by 4.9 dB from baseline. Targeted education, behavioral, and environmental modifications decreased the noise level in the NICU as per the study aim. To create a change in culture, constant dialogue between the project champions and the NICU staff is necessary. PMID- 28587517 TI - Effects of low-temperature pretreatment on enhancing properties of refuse-derived fuel via microwave irradiation. AB - The present study focuses on pretreatment of enhancing the properties of refuse derived fuel (RDF) via low-temperature microwave irradiation. These improved properties include lower chlorine content, a more porous surface structure and better combustion characteristics. In this study, low-temperature microwave irradiation was carried out in a modified microwave apparatus and the range of temperature was set to be 220-300C. We found that the microwave absorbability of RDF was enhanced after being partly carbonized. Moreover, with the increasing of the final temperature, the organochlorine removal ratio was greatly increased to 80% and the content of chlorine was dramatically decreased to an extremely low level. It was also interesting to find that the chlorine of RDF was mainly released as HCl rather than organic chloride volatiles. The finding is just the same as the polyvinyl chloride pyrolysis process. In addition, pores and channels emerged during the modifying operation and the modified RDF has better combustibility and combustion stability than traditional RDF. This work revealed that low-temperature modification of RDF via microwave irradiation is significant for enhancing the quality of RDF and avoiding HCl erosion of equipment substantially. PMID- 28587518 TI - An investigation into UK medical students' knowledge of lifestyle factors on cancer. AB - Background and aim Lifestyle factor modification (alcohol, smoking, obesity, diet, physical activity) has the potential to reduce cancer incidence and cancer survival. This study assessed the knowledge of lifestyle factors and cancer in undergraduate medical students. Methods and results A total of 218 students (7 UK universities) completed an online survey of nine questions in three areas: knowledge (lifestyle factors and cancer); information sources; clinical practice (witnessed clinical counselling). Diet, alcohol, smoking and physical activity were recognised as lifestyle factors by 98% of responders, while only 69% reported weight. The links of lung cancer/smoking and alcohol/liver cancer were recognised by >90%, while only 10% reported weight or physical activity being linked to any cancer. University teaching on lifestyle factors and cancer was reported by 78%: 34% rating it good/very good. GPs were witnessed giving lifestyle advice by 85% of responders. Conclusions Most respondents were aware of a relationship between lifestyle factors and cancer, mainly as a result of undergraduate teaching. Further work may widen the breadth of knowledge, and potentially improve primary and secondary cancer prevention. PMID- 28587519 TI - Inactivation of a putative efflux pump (LmrB) in Streptococcus mutans results in altered biofilm structure and increased exopolysaccharide synthesis: implications for biofilm resistance. AB - Efflux pumps are a mechanism associated with biofilm formation and resistance. There is limited information regarding efflux pumps in Streptococcus mutans, a major pathogen in dental caries. The aim of this study was to investigate potential roles of a putative efflux pump (LmrB) in S. mutans biofilm formation and susceptibility. Upon lmrB inactivation and antimicrobial exposure, the biofilm structure and expression of other efflux pumps were examined using confocal laser scanning microscopy (CLSM) and qRT-PCR. lmrB inactivation resulted in biofilm structural changes, increased EPS formation and EPS-related gene transcription (p < 0.05), but no improvement in susceptibility was observed. The expression of most efflux pump genes increased upon lmrB inactivation when exposed to antimicrobials (p < 0.05), suggesting a feedback mechanism that activated the transcription of other efflux pumps to compensate for the loss of lmrB. These observations imply that sole inactivation of lmrB is not an effective solution to control biofilms. PMID- 28587520 TI - A Randomized Controlled Trial Examination of a Remote Parenting Intervention: Engagement and Effects on Parenting Behavior and Child Abuse Potential. AB - Technology advances increasingly allow for access to remotely delivered interventions designed to promote early parenting practices that protect against child maltreatment. Among low-income families, at somewhat elevated risk for child maltreatment, there is some evidence that parents do engage in and benefit from remote-coaching interventions. However, little is known about the effectiveness of such programs to engage and benefit families at high risk for child maltreatment due to multiple stressors associated with poverty. To address this limitation, we examined engagement and outcomes among mothers at heightened risk for child abuse, who were enrolled in a randomized controlled, intent-to treat trial of an Internet adaptation of an evidence-based infant parenting intervention. We found that engagement patterns were similar between higher and lower risk groups. Moreover, an intervention dose by condition effect was found for increased positive parent behavior and reduced child abuse potential. PMID- 28587522 TI - Protective effect of Alstonia scholaris Linn. R. Br. against Bleomycin induced chromosomal damage in cultured human lymphocytes, in vitro. AB - It is both interesting and necessary to identify and develop nontoxic radioprotective compounds. Bleomycin (BLM), a known radiomimetic drug was used as a clastogen in the present study. The possible protective effects against BLM (15 MUg/ml) induced clastogenicity by aqueous and methanolic extracts from Alstonia scholaris bark, stem and leaves were compared. The treatment of bark extracts significantly (p < 0.01) reduced total chromosomal aberrations. Such a reduction was not seen in case of stem and leaf treatments. The dose of 50 MUg/ml was fixed for all extracts throughout the study. To understand the mechanism involved with the protective property of bark extracts, sensitive G2 assay was performed. Lymphocyte cultures from 12 healthy volunteers were exposed to aqueous (50 MUg/ml) and methanolic (50 MUg/ml) extracts of A. scholaris bark alone as well as in combination with Bleomycin under two different growth phases, G0 and G2. There was a statistically significant reduction (p < 0.05) in the total chromatid breaks in all cultures which were exposed at G2 phase as compared to respective cultures exposed at G0 phase. The highest level (p < 0.0001) of reduction in total chromatid breaks was observed in cultures treated with aqueous bark extracts at G2 phase than those at G0 phase. This indicated that there could be certain compound(s) present in aqueous bark extracts which enhance DNA repair capacity. Therefore, the bark of A. scholaris could be further utilized to identify and bring out front line radio protective agents in the market with effective formulations. PMID- 28587521 TI - Can Medicaid Claims Validly Ascertain Foster Care Status? AB - Medicaid claims have been used to identify populations of children in foster care in the current literature; however, the ability of such an approach to validly ascertain a foster care population is unknown. This study linked children in the National Survey of Child and Adolescent Well-Being-I to their Medicaid claims from 36 states using their Social Security numbers. Using this match, we examined discordance between caregiver report of foster care placement and the foster care eligibility code contained in the child's Medicaid claims. Only 73% of youth placed in foster care for at least a year displayed a Medicaid code for foster care eligibility. Half of all youth coming into contact with child welfare displayed discordance between caregiver report and Medicaid claims. Children with emergency department utilization, and those in primary care case management health insurance arrangements, had the highest odds of accurate ascertainment. The use of Medicaid claims to identify a cohort of children in foster care results in high rates of underascertainment. Supplementing administrative data with survey data is one way to enhance validity of ascertainment. PMID- 28587523 TI - Defatted wheat germ application: Influence on cookies' properties with regard to its particle size and dough moisture content. AB - The introduction of agro-food industry by-products rich in bioactive compounds represents major challenge in food industry sector. The influence of wheat germ particle size (<150 um, 150-1000 um, and 800-2000 um), wheat germ content (5, 10, and 15%), and dough moisture content (20, 22, and 24%) on chemical, textural, and sensory characteristics of cookies was investigated using the Box-Behnken experimental design. The substitution of wheat flour with wheat germ increased the protein, fat, mineral, and fiber content of the cookies. The particle size of wheat germ affected the textural properties of cookies. As the particle size of wheat germ increased, the hardness of cookies decreased. The color of the cookie was most influenced by the interaction of dough moisture content and wheat germ particle size. Wheat germ level up to 15% had no significant effect on the sensory characteristics of cookies. A suitable combination of defatted wheat germ level, its particle size, and dough moisture content can improve the nutritional value of cookies, without causing a negative effect on the cookies' sensory characteristics. PMID- 28587524 TI - The Role of Peroxiredoxins in the Transduction of H2O2 Signals. AB - SIGNIFICANCE: Hydrogen peroxide (H2O2) is produced on stimulation of many cell surface receptors and serves as an intracellular messenger in the regulation of diverse physiological events, mostly by oxidizing cysteine residues of effector proteins. Mammalian cells express multiple H2O2-eliminating enzymes, including catalase, glutathione peroxidase (GPx), and peroxiredoxin (Prx). A conserved cysteine in Prx family members is the site of oxidation by H2O2. Peroxiredoxins possess a high-affinity binding site for H2O2 that is lacking in catalase and GPx and which renders the catalytic cysteine highly susceptible to oxidation, with a rate constant several orders of magnitude greater than that for oxidation of cysteine in most H2O2 effector proteins. Moreover, Prxs are abundant and present in all subcellular compartments. The cysteines of most H2O2 effectors are therefore at a competitive disadvantage for reaction with H2O2. Recent Advances: Here we review intracellular sources of H2O2 as well as H2O2 target proteins classified according to biochemical and cellular function. We then highlight two strategies implemented by cells to overcome the kinetic disadvantage of most target proteins with regard to H2O2-mediated oxidation: transient inactivation of local Prx molecules via phosphorylation, and indirect oxidation of target cysteines via oxidized Prx. Critical Issues and Future Directions: Recent studies suggest that only a small fraction of the total pools of Prxs and H2O2 effector proteins localized in specific subcellular compartments participates in H2O2 signaling. Development of sensitive tools to selectively detect phosphorylated Prxs and oxidized effector proteins is needed to provide further insight into H2O2 signaling. Antioxid. Redox Signal. 28, 537-557. PMID- 28587525 TI - The Conundrum of Hydrogen Peroxide Signaling and the Emerging Role of Peroxiredoxins as Redox Relay Hubs. AB - SIGNIFICANCE: Hydrogen peroxide (H2O2) is known to act as a messenger in signal transduction. How H2O2 leads to selective and efficient oxidation of specific thiols on specific signaling proteins remains one of the most important open questions in redox biology. Recent Advances: Increasing evidence implicates thiol peroxidases as mediators of protein thiol oxidation. Recently, this evidence has been extended to include the peroxiredoxins (Prxs). Prxs are exceptionally sensitive to H2O2, abundantly expressed and capture most of the H2O2 that is generated inside cells. CRITICAL ISSUES: The overall prevalence and importance of Prx-based redox signaling relays are still unknown. The same is true for alternative mechanisms of redox signaling. FUTURE DIRECTIONS: It will be important to clarify the relative contributions of Prx-mediated and direct thiol oxidation to H2O2 signaling. Many questions relating to Prx-based redox relays remain to be answered, including their mechanism, structural organization, and the potential role of adaptor proteins. Antioxid. Redox Signal. 28, 558-573. PMID- 28587526 TI - Optimal teicoplanin dosage regimens for methicillin-resistant Staphylococcus aureus infections in endocarditis patients and renal failure patients. AB - This study aimed to assess whether traditional initial loading and maintenance doses of teicoplanin were appropriate in endocarditis and renal failure patients with methicillin-resistant Staphylococcus aureus (MRSA) infections and to recommend optimal dosage regimens. Pharmacokinetic parameters and physicochemical properties of teicoplanin were performed to develop pharmacokinetic models using GastroPlusTM. Concentration-time curves of teicoplanin in endocarditis and renal failure patients with MRSA infections were simulated by changing clearance (CL) and volume of distribution of the central compartment (Vc). Different teicoplanin dosage regimens were assessed according to the target trough concentration, and optimal teicoplanin dosage regimens were recommended. Dosage regimen of four teicoplanin doses of 6 mg/kg q12 h followed by 6 mg/kg qd is recommended for renal failure patients infected by MRSA. And optimal dosage regimen is five teicoplanin doses of 15 mg/kg q12 h followed by doses of 12 mg/kg qd for endocarditis patients infected by MRSA. PMID- 28587527 TI - Comparison of INTERGROWTH-21 and Fenton growth standards to assess size at birth and extrauterine growth in very preterm infants. AB - AIM: This study aimed to compare the recently published prescriptive INTERGROWTH 21st standards with commonly used intrauterine based Fenton growth standards in terms of birth size classification and extrauterine growth restriction (EUGR) incidence in a sample of very preterm infants. METHODS: The anthropometric measures of preterm infants born before 32 weeks of gestation at the Dokuz Eylul University Hospital during the period from January 2012 to February 2016 were obtained at birth, at the 36th gestational weeks or at the time of discharge. Birth and growth data were presented as percentiles according to the two reference standards. RESULTS: A total of 248 infants with mean gestational age of 29.1 +/- 2.1 weeks were included. The small for gestational age (SGA) rate was significantly higher (12 versus 15%, p = .004) and the EUGR rate was significantly lower (40.2 versus 31.5%, p < .001) with the INTERGROWTH-21st charts compared with the Fentons'. Twenty-four per cent of the infants who were accepted as SGA according to the INTERGROWTH-21st standards were appropriate for gestational age (AGA) according to the Fenton preterm growth charts. However, these newly identified SGA infants according to the Intergrowth-21st standards did not have increased risks of early morbidities. Furthermore, 77% of the cases who had EUGR due to the Fenton standards were categorized as EUGR when evaluated using the INTERGROWTH-21st standards. CONCLUSIONS: Results indicated that almost one out of every five cases assessed as EUGR according to Fenton standards was within the normal interval according to Intergrowth standards. On the contrary, one out of every four cases assessed as SGA according to the INTERGROWTH-21st standards was within the normal interval according to Fentons'. These differences observed with INTERGROWTH-21st standards may affect in-hospital and postdischarge nutrition plan of these vulnerable infants. However, new standards are needed to be evaluated against currently used ones before they are implemented and further studies should be conducted to evaluate the functional impact of these differences on long-term outcomes including neurologic and cardio-metabolic morbidities. PMID- 28587529 TI - Colonoscopic surveillance - a cost-effective method to prevent hereditary and familial colorectal cancer. AB - OBJECTIVE: Approximately 20-30% of all colorectal cancer (CRC) cases may have a familial contribution. The family history of CRC can be prominent (e.g., hereditary colorectal cancer (HCRC)) or more moderate (e.g., familial colorectal cancer (FCRC)). For family members at risk, colonoscopic surveillance is a well established method to prevent both HCRC and FCRC, although the evidence for the exact procedures of the surveillance is limited. Surveillance can come at a high price if individuals are frequently examined, as this may result in unnecessary colonoscopies in relation to actual risk for CRC. This study analyses the cost effectiveness of a surveillance programme implemented in the Northern Sweden Health Care Region. METHODS: The study includes 259 individuals prospectively recorded in the colonoscopic surveillance programme registry at the Cancer Prevention Clinic, Umea University Hospital. We performed a cost-utility analysis with a contrafactual design: we compared observed costs and loss of quality adjusted life years (QALYs) due to CRC with the surveillance programme to an expected outcome without surveillance. The main measure was the incremental cost effectiveness ratio (ICER) between surveillance and non-surveillance. Scenario analysis was used to explore uncertainty. RESULTS: The ICER between surveillance and non-surveillance in the base model was 3596?/QALY. The ICER varied from 4620? in the best-case scenario to 33,779? in the worst-case scenario. CONCLUSION: Colonoscopic surveillance is a very cost-effective method to prevent HCRC and FCRC compared to current thresholds for cost-effectiveness and other cancer preventive interventions. PMID- 28587528 TI - A prospective observational cohort study of exposure to womb-like sounds to stabilize breathing and cardiovascular patterns in preterm neonates. AB - PURPOSE: We exposed premature infants to womb-like sounds to evaluate such exposure on breathing and cardiovascular patterns. We hypothesized that these sounds would reduce apnea and intermittent hypoxemia, enhance parasympathetic outflow, and improve cardiovascular patterns. METHODS: A total of 20 cases and 5 control infants at <=32-36 weeks corrected gestational age participated in a prospective observational cohort study. Twenty-four hours of continuous ECG, respiratory and oxygen saturation data were collected in all infants. Womb-like sounds were played intermittently in 6-hour blocks. Salivary samples were collected at study beginning and end for cortisol. Apnea, intermittent hypoxemia, and bradycardia were evaluated, and heart rate variability was assessed by time domain and spectral techniques. RESULTS: Intermittent hypoxemia and bradycardia significantly declined after sound exposure. No significant differences in apnea, cortisol levels, or heart rate variability were evident among the study infants. CONCLUSIONS: Exposing premature infants to womb-like sounds has the potential to reduce hypoxemic and bradycardic events, and be used as an intervention to stabilize breathing and cardiac control in preterm infants. PMID- 28587531 TI - Dapagliflozin for the treatment of type 1 diabetes mellitus. AB - INTRODUCTION: In 2017, the management of type 1 diabetes mellitus (T1DM) remains intriguing for the clinician, who has to balance between adequate glycemic control and untoward events related to insulin up-titration. Thus, agents that will complement insulin actions and reduce adverse effects are highly welcome. Areas covered: In this review, the authors summarize results from studies on the sodium glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin in T1DM. Expert opinion: In T1DM, dapagliflozin is associated with significant antihyperglycemic and metabolic properties, which are achieved with reduction or stabilization of insulin dose and with a very low trend for hypoglycemia. However, there is a lot to learn with respect to diabetic ketoacidosis (DKA), bone fractures and lower limb ischemia. PMID- 28587530 TI - Endovascular treatment of wide-neck intracranial bifurcation aneurysms with 'Y' configuration, double Neuroform(r) stents-assisted coiling technique: Experience in a single center. AB - Background Intracranial wide-neck aneurysms at the arterial bifurcations, especially in the aneurysms where the bifurcating branches emanate directly from the base of the aneurysm, have been particularly difficult on which to perform endovascular treatment. The 'Y'-configuration, double stent-assisted coil embolization is an option for the treatment of these difficult aneurysms, allowing the closure of the aneurysm, preserving the parent arteries. Material and methods In a nine-year period, 546 intracranial aneurysms in 493 patients were treated at our center by endovascular approach. We have reviewed the medical records and arteriographies from November 2007 to January 2017 of 45 patients who were treated using 'Y'-configuration double Neuroform(r) stent-assisted coil embolization. Results All patients were successfully treated. The location of the aneurysms were: middle cerebral artery (MCA) 20 (44.4%), anterior communicating artery (AComA) 17 (37.7%), basilar four (8.9%), internal carotid artery (ICA) bifurcation three (6.6%) and posterior communicating artery (PComA) one (2.2%). The mRS at hospital discharge was: mRS 0: 42 (93.3%), mRS 1: 1 (2.2%), mRS 2: 1 (2.2%) and mRS 5: 1 (2.2%). The Modified Raymond-Roy Occlusion Classification, in the control at six months, was: Class I: 41 (91.1%), Class II: 2 (4.4%), Class IIIa: 1 (2.2%) and Class IIIb: 1 (2.2%). Forty-four (97.8%) patients had a good outcome (mRS < 2) at six months. One (2.2%) patient had a poor outcome (mRS > 2) at six months that was due to sequelae of SAH. There was no mortality at six months. Conclusions This technique is safe and effective for the endovascular treatment of difficult wide-neck bifurcation aneurysms, allowing the stable closure of the aneurysm, preserving the parent arteries. PMID- 28587532 TI - Novel tetrazole and cyanamide derivatives as inhibitors of cyclooxygenase-2 enzyme: design, synthesis, anti-inflammatory evaluation, ulcerogenic liability and docking study. AB - Nineteen new compounds containing tetrazole and/or cyanamide moiety have been designed and synthesised. Their structures were confirmed using spectroscopic methods and elemental analyses. Anti-inflammatory activity for all the synthesised compounds was evaluated in vivo. The most active compounds 4c, 5a, 5d f, 8a and b and 9a and b were further investigated for their ulcerogenic liability and analgesic activity. Pyrazoline derivatives 9b and 8b bearing trimethoxyphenyl part and SO2NH2 or SO2Me pharmacophore showed equal or nearly the same ulcerogenic liability (UI: 0.5, 0.75, respectively), to celecoxib (UI: 0.50). Most of tested compounds showed potent central and/or peripheral analgesic activities. Histopathological investigations were done to evaluate test compounds effect on rat's gastric tissue. The obtained results were in consistent with the in vitro data on COX evaluation. Docking study was also done for all the target compounds inside COX-2-active site. PMID- 28587533 TI - Public Attitudes and Support for a Sugar-Sweetened Beverage Tax in America's Heartland. AB - BACKGROUND: Policy and environmental strategies are part of a comprehensive approach to obesity prevention. We investigated the association between public attitudes about how the environment influences health and support for a sugar sweetened beverage (SSB) tax in Kansas. METHOD: We collected data via a 2014 representative dual-frame (cellular and landline) telephone survey of 2,203 adult Kansans regarding healthy eating policy support and beliefs about obesity causes and solutions. RESULTS: A significant proportion of Kansas adults (40%) support an SSB tax. Support was significantly stronger among females, young people, and liberals. Causal and responsibility attributions of obesity were significantly associated with policy support. Individuals who attribute more responsibility for the solution to the obesity epidemic to environmental factors were more likely to support a tax, regardless of their political affiliation. CONCLUSIONS: Messaging that focuses on the role of the environment in creating opportunities for health may be useful in framing discussions around SSB taxes. PMID- 28587534 TI - Diagnosis and management of clinical reasoning difficulties: Part I. Clinical reasoning supervision and educational diagnosis. AB - There are many obstacles to the timely identification of clinical reasoning difficulties in health professions education. This guide aims to provide readers with a framework for supervising clinical reasoning and identifying the potential difficulties as they may occur at each step of the reasoning process. PMID- 28587535 TI - A fatal case of hypothermia caused by dog bites. AB - Death from hypothermia usually *We presented a fatal case of hypothermia after being bitten by dog in this article. occurs among people exposed to cold and humid environmental conditions when they are homeless, aged, suffering from natural or psychiatric diseases and drug or alcohol intoxication. A normal healthy person dying from hypothermia due to dog bites is unusual and rare. Here, we present a fatal case of hypothermia following dog bites causing blood loss and multiple wounds on the body. A 56-year-old man was found dead in a remote roadside puddle of a small village, early in the morning. He was naked, and his body trunk and limbs had multiple irregular wounds. Gray animal hairs could be seen in parts of the wound cavities and surrounding areas. In addition, there was a kennel near the scene. Family members argued that the deceased was bitten to death by a dog. However, autopsy revealed several findings which were strongly supportive of fatal hypothermia. Moreover, we saw no obvious changes caused by blood loss, either on the body surface or internal organs. Accordingly, we concluded the true cause of his death was fatal hypothermia; bites from a dog was a necessary causative factor. PMID- 28587536 TI - Commotio cordis: A review. AB - Commotio cordis is an increasingly reported fatal mechano-electric syndrome and is the second most common cause of sudden cardiac death in young athletes. It is most commonly associated with a sports-related injury, wherein, there is a high velocity impact between a projectile and the precordium. By virtue of this impact, malignant arrhythmias consequently develop leading to the individual's immediate demise, accompanied by a relatively normal post-mortem analysis. The importance of an autopsy remains paramount to exclude other causes of sudden death. With increasing awareness and reporting, survival rates are beginning to improve; however, prevention of the development of this condition remains the best approach for survival. PMID- 28587537 TI - Implementation of ultra-low-dose lung protocols in CT-guided lung biopsies: feasibility and safety in the clinical setting. AB - Objective To evaluate the use of ultra-low-dose computed tomography (ULDCT) for CT-guided lung biopsy versus standard-dose CT (SDCT). Methods CT-guided lung biopsies from 115 patients (50 ULDCT, 65 SDCT) were analyzed retrospectively. SDCT settings were 120 kVp with automatic mAs modulation. ULDCT settings were 80 kVp with fixed exposure (20 mAs). Two radiologists evaluated image quality (i.e., needle artifacts, lesion contouring, vessel recognition, visibility of interlobar fissures). Complications and histological results were also evaluated. Results ULDCT was considered feasible for all lung interventions, showing the same diagnostic accuracy as SDCT. Its mean total radiation dose (dose-length product) was significantly reduced to 34 mGy-cm (SDCT 426 mGy-cm). Image quality and complication rates ( P = 0.469) were consistent. Conclusions ULDCT for CT-guided lung biopsies appears safe and accurate, with a significantly reduced radiation dose. We therefore recommend routine clinical use of ULDCT for the benefit of patients and interventionalists. PMID- 28587538 TI - Plasma microRNA-9 as a diagnostic and prognostic biomarker in patients with esophageal squamous cell carcinoma. AB - Purpose Emerging evidence indicates that circulating microRNAs (miRs) might act as noninvasive biomarkers for cancer diagnosis and prognosis. We examined the expression pattern and clinical significance of plasma miR-9 in patients with esophageal squamous cell carcinoma (ESCC). Methods Venous blood samples (6 mL) were collected from 131 patients with ESCC and 131 healthy controls, and the plasma miR-9 concentration was detected by reverse transcription polymerase chain reaction. The association of plasma miR-9 expression with clinicopathologic factors and survival of patients with ESCC was evaluated. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the clinical value of plasma miR-9 for ESCC diagnosis. Results The plasma miR-9 expression levels in patients with ESCC were significantly upregulated compared with normal controls. High plasma miR-9 concentrations were significantly correlated with poor tumor differentiation, large tumor size, deep local invasion, lymph node metastasis, advanced clinical stage, and poor survival. ROC curve analysis showed that the plasma miR-9 concentration could efficiently distinguish patients with ESCC from healthy controls. Multivariate survival analysis confirmed plasma miR-9 as an independent prognostic factor for ESCC. Conclusions Plasma miR-9 expression was upregulated in ESCC and might act as a novel diagnostic and prognostic biomarker. PMID- 28587539 TI - Treatment of patients with aortic disease during pregnancy and after delivery. AB - Objective This study aimed to review treatment of patients with aortic disease during pregnancy and after delivery in Beijing Anzhen Hospital. Methods A retrospective study was conducted using data from 12 patients with aortic disease during pregnancy and after delivery in our institution from May 2005 to December 2014. Patients were provided different treatments based on the type of aortic disease and clinical characteristics. Results The mean age was 29.83 +/- 4.17 years, mean height was 171.7 +/- 8.22 cm, mean weight was 68.55 +/- 10.62 kg, and mean body mass index was 23.18 +/- 2.93 kg/m2. Two patients with Stanford type A aortic dissection died of renal failure after surgery. All of the other patients were discharged. Six foetuses survived. One patient continued her pregnancy after an aortic operation. The gestational age of the remaining five patients was less than 28 weeks at the time of the operation and all foetuses of these five patients died. Conclusions A suitable treatment strategy for aortic disease during pregnancy and after delivery should be chosen based on an individual's comprehensive clinical condition. Foetal management should be chosen based on gestational age and severity of aortic disease. PMID- 28587540 TI - INTERTAN nail versus proximal femoral nail antirotation-Asia for intertrochanteric femur fractures in elderly patients with primary osteoporosis. AB - Objectives To compare the long-term functional and radiographic outcomes of the proximal femoral nail antirotation-Asia (PFNA-II) and INTERTAN nail (IT) in the management of intertrochanteric femoral fractures (IFFs) (AO/OTA Type 31A1.1 A2.3) in elderly patients with primary osteoporosis. Methods A retrospective comparative study was performed in our institution. From January 2009 to March 2012, 243 patients with osteoporosis (243 hips) with IFFs (AO/OTA Type 3.1A1.1 A2.3) underwent repair with either a PFNA-II or IT. Follow-up assessments were performed 1, 3, 6, 9, and 12 months postoperatively and every year thereafter. All implant position changes were noted. Patient-related functional outcomes were evaluated based on the Harris hip score. Results In total, 174 patients with osteoporosis (IT, n = 86; PFNA-II, n = 88) were evaluated during a mean follow-up period of 40 months (range, 38-60 months). An increased risk of femoral shaft fracture after implant removal was observed at month 9 of follow-up in 0.0% and 4.4% of the IT and PFNA-II groups, respectively. This difference remained over time with rates of 1.1% and 6.8%, respectively, at the last follow-up. Conclusion The IT nail appears to be a reliable implant in the management of IFFs (AO/OTA Type 3.1A1.1-A2.3) in elderly patients with primary osteoporosis. PMID- 28587541 TI - Evaluation of left ventricular strain in patients with dilated cardiomyopathy. AB - Objective Dilated cardiomyopathy (DCM) can cause structural and functional changes in the left ventricle (LV). In this study, we evaluated whether cardiac magnetic resonance tissue-tracking (MR-TT) can be applied to the detection of LV abnormalities in patients with DCM. Methods We used MR-TT to analyze the global peak radial strain (GPRS), global peak circumferential strain (GPCS), and global peak longitudinal strain (GPLS) in every segment of the LV in 23 patients with DCM and 25 controls. The LV ejection fraction was also measured as a function indicator. Results Compared with the controls, the GPRS, GPCS, and GPLS were significantly reduced in patients with DCM, indicating global LV function impairment in all directions. We also identified a significant linear correlation between the GPRS, GPCS, and GPLS and the LV ejection fraction, indicating that LV function relies on coordinated wall motion from all directions. Moreover, we found that patients with DCM had a significantly reduced magnitude of the PRS, PCS, and PLS in most segments at different levels, indicating impaired myocardial function in most LV regions. Conclusions Our results demonstrate that LV myocardial strain in patients with DCM can be sensitively detected by MR-TT (not only the global LV function changes but also the segmental strain), which can help to identify the injured segment at an early stage and guide clinical treatment. PMID- 28587542 TI - Evaluation of cerebral glioma using 3T diffusion kurtosis tensor imaging and the relationship between diffusion kurtosis metrics and tumor cellularity. AB - Purpose To evaluate the clinical utility of diffusion kurtosis tensor imaging in the characterization of cerebral glioma and investigate correlations between diffusion and kurtosis metrics with tumor cellularity. Materials and Methods A group of 163 patients (age: 40.5 +/- 11.5 years) diagnosed with cerebral glioma underwent diffusion kurtosis tensor imaging with a 3 T scanner. Diffusion and kurtosis metrics were measured in the solid part of tumors, and their abilities to distinguish between tumor grades was evaluated. In addition, we analyzed correlations between the metrics and tumor cellularity. Results Mean kurtosis (MK) revealed a significant difference between each pair of tumor grades ( P < 0.05) and produced the best performance in a receiver operating characteristics analysis (area under the curve [AUC] = 0.89, sensitivity/specificity = 83.3/90). In contrast, mean diffusivity (MD) revealed a significant difference only for tumor grade II versus IV ( P < 0.05). No significant differences between grades were detected with fractional anisotropy (FA; P > 0.05). Thus, kurtosis metrics exhibited a positive and strong correlation with tumor cellularity, while MD exhibited a negative or weak correlation with tumor cellularity. Conclusion Diffusion kurtosis metrics, particularly MK, demonstrated superior performance in distinguishing cerebral glioma of different grades compared with conventional diffusion metrics, and were closely associated with tumor cellularity. PMID- 28587543 TI - Clinical and prognostic factors in 98 patients with malignant melanoma in China. AB - Objective To investigate clinical and prognostic factors in patients with malignant melanoma (MM) in China. Methods A total of 98 MM patients were enrolled in the study. Enumeration data were analyzed using Fisher's exact probability tests or chi2 tests. Survival rates were calculated using log-rank tests. A Cox multivariate regression analysis was performed to determine independent prognostic factors. Results The male: female incidence ratio was 1.88:1. The highest incidence rate was seen in the 45-65 year age group. Primary lesion ulceration was seen in 60.2% of patients. The 1-year, 3-year and 5-year survival rates were 85.7%, 34.7% and 13.3%, respectively. In univariate analyses, the 5 year survival rate in patients was significantly associated with ulceration (P < 0.01), clinical stage (P < 0.01) and surgical excision of the tumor (P < 0.01). Cox multivariate regression analysis confirmed that ulceration and clinical stage were independent prognostic factors. Conclusions Some clinical characteristics of MM patients in China are significantly different from those of patients in Western countries. Ulceration and clinical stage are independent risk factors for poor survival in MM patients. PMID- 28587545 TI - Skilled Reach Performance Correlates With Corpus Callosum Structural Integrity in Individuals With Mild Motor Impairment After Stroke: A Preliminary Investigation. AB - BACKGROUND: Recovery of arm function after stroke is often incomplete. An improved understanding of brain structure-motor behavior relationships is needed for the development of novel and targeted rehabilitation interventions. OBJECTIVE: To examine the relationship between skilled reach performance and the integrity of two putative white matter motor pathways, corticospinal tract and corpus callosum, after stroke. METHODS: Eleven individuals with chronic stroke (poststroke duration, mean 62.5 +/- 42.4 months) and mild motor impairment (upper extremity Fugl-Meyer score, mean 54.2 +/- 7.6) reached to six targets presented at three distances and two directions. Fractional anisotropy (FA) obtained from diffusion tensor imaging was used to determine the structural integrity of the corticospinal tract and the corpus callosum. RESULTS: Overall reach performance was decreased in the paretic arm compared with the nonparetic arm. While FA was decreased in the ipsilesional corticospinal tract, FA in the corticospinal tract did not correlate with variability in reach performance between individuals. Instead, FA in the premotor section of the corpus callosum correlated with reach performance; individuals with higher FA in premotor corpus callosum tended to reach faster with both the paretic and nonparetic arms. CONCLUSIONS: The structural connections between the two premotor and supplemental cortices that traverse the premotor corpus callosum may play an important role in supporting motor control and could become a target for interventions aimed at improved arm function in this population. PMID- 28587544 TI - Postoperative recurrence of adult renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion. AB - Objective To analyze the postoperative recurrence of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusion (Xp11.2 tRCC). Methods This retrospective study was approved by the institutional review board and performed in accordance with the ethical standards established by the institution. Demographic, clinical, pathological, and follow-up data were compiled for the study cohort. Results During a mean follow-up of 41.3 months (range, 3-104 months), 8 of 34 patients with Xp11.2 tRCC were confirmed to have recurrence. Three of these patients died with poor outcomes due to a vena cava tumor embolus, and one died of distant metastasis 48 months after the initial nephrectomy during which lymph node metastasis was found. Three patients survived after cytoreduction surgery. One patient was diagnosed with lung metastasis 11 months postoperatively. Conclusions The TNM classification provides significant prognostic information for Xp11.2 tRCC. A relatively active surveillance algorithm is recommended, and cytoreduction surgery is an effective approach for recurrent Xp11.2 tRCC. Larger studies are required to more extensively investigate the recurrence of these potentially aggressive tumors. PMID- 28587547 TI - A mutation in PTPN11 may drive leukemic transformation in a case of essential thrombocythemia. PMID- 28587546 TI - Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se. AB - OBJECTIVE: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. METHOD: One group of children with NF1 + ADHD ( N = 32), one group of children with ADHD ( N = 31), and one group of healthy controls ( N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. RESULTS: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. CONCLUSION: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1. PMID- 28587548 TI - A brief panorama of Brazil's contributions to psychiatry. PMID- 28587549 TI - The social action of the psychiatrist (1943). PMID- 28587550 TI - Mental illnesses in tropical climates (1906). PMID- 28587551 TI - Conceptualizations of illness among relatives of patients diagnosed with schizophrenia. AB - Family concepts of a relative's illness are an important part of the coping process and reveal the cultural construction of the experience of illness. As part of a qualitative study conducted in the Schizophrenia Outpatient Clinic of the Department of Psychiatry, Escola Paulista de Medicina - UNIFESP, 14 relatives of eight outpatients diagnosed with schizophrenia were interviewed and invited to talk freely about their ideas and feelings concerning their relative's problem. Qualitative analysis was used to identify categories of illness representations. Three main categories were discussed, including Problema de Nervoso, Problema na Cabeca and Problema Espiritual (Problem of the Nerves, Problem in the Head and Spiritual Problem). The authors present evidence of these categories as cultural constructions, and discuss the relevance of popular notions of illness to the understanding of the course and outcome of schizophrenia, and the planning of culturally meaningful interventions. PMID- 28587552 TI - Anorexia nervosa and bulimia nervosa - a psychotherapeutic cognitive constructivist approach. AB - Of the eating disorders, anorexia nervosa and bulimia nervosa are the ones that have made adolescent patients-often females and aged younger and younger-seek for help. This help is provided through a multidisciplinary treatment involving psychiatrists, psychologists and dietists. Psychotherapy has shown to be an efficient component for these patients' improvement. The present article aims at presenting a proposal of psychotherapeutic treatment based on a cognitive constructivist approach. PMID- 28587553 TI - Guidelines of the Brazilian Association of Studies on Alcohol and Other Drugs (ABEAD) for diagnosis and treatment of psychiatric comorbidity with alcohol and other substance and dependence. AB - In recent years, several studies have been focused on the comorbidity of psychiatric disorders with alcohol and other substance dependence. In this context, the Brazilian Association of Studies on Alcohol and Other Drugs initiated a project to establish Brazilian Guidelines. The aim of this study was to review diagnostic and therapeutic criteria for the most prevalent psychiatric comorbidities. Randomized clinical trials, epidemiological studies, animal testing and other forms of research are reviewed herein. The main psychiatric comorbidities are investigated and data published in the literature are reviewed, based on guidelines adopted by other countries. Epidemiological aspects, diagnostic criteria, integrated treatment and the organization of specialized service, as well as details regarding psychotherapy and pharmacological treatment are discussed. The guidelines of the Brazilian Association of Studies on Alcohol and Other Drugs reinforce the importance of adequate diagnosis and treatment regarding alcoholic and drug dependent patients suffering of comorbid psychiatric disorders. PMID- 28587554 TI - Quality-of-life and spirituality. AB - Spirituality has been identified as an important dimension of quality-of-life. The objective of this study was to review the literature on quality-of-life and spirituality, their association, and assessment tools. A search was conducted of the keyterms 'quality-of-life' and 'spirituality' in abstract or title in the databases PsycINFO and PubMed/Medline between 1979-2005, complemented by a new search at PUBMED from 2006-2016. Quality-of-life is a new concept, which encompasses and transcends the concept of health, being composed of multiple domains: physical, psychological, environmental, among others. The missing measure in health has been defined as the individual's perception of their position in life in the context of culture and value system in which they live and in relation to their goals, expectations, standards, and concerns. There is consistent evidence of an association between quality-of-life and religiosity/spirituality (R/S), through studies with reasonable methodological rigour, using several variables to assess R/S (e.g. religious affiliation, religious coping, and prayer/spirituality). There are also several valid and reliable instruments to evaluate quality-of-life and spirituality. Further studies are needed, however, especially in Brazil. Such studies will provide empirical data to be used in planning health interventions based on spirituality, seeking a better quality-of-life. In the last 10 years, research is consistently growing about quality-of-life and spirituality in many countries, and also in many areas of health research. PMID- 28587555 TI - Editorial. PMID- 28587556 TI - Methodological guidelines to investigate altered states of consciousness and anomalous experiences. AB - Anomalous experiences (AE) (uncommon experiences or one that is believed to deviate from the usually accepted explanations of reality: hallucinations, synesthesia, experiences interpreted as telepathic...) and altered states of consciousness (ASC) have been described in all societies of all ages. Even so, scientists have long neglected the studies on this theme. To study AE and ASC is not necessary to share the beliefs we explore, they can be investigated as subjective experiences and correlated with other data, like any other human experience. This article presents some methodological guidelines to investigate these experiences, among them: to avoid dogmatic prejudice and to 'pathologize' the unusual; the value of a theory and a comprehensive literature review; to utilize a variety of criteria for pathology and normality; the investigation of clinical and non-clinical populations; development of new appropriate research instruments; to be careful to choose the wording to describe the AE; to distinguished the lived experience from its interpretations; to take into account the role of culture; to evaluate the validity and reliability of reports and, last but not least, creativity and diversity in choosing methods. PMID- 28587557 TI - The madness epidemic of Canudos: Antonio Conselheiro and the Jaguncos (1897). PMID- 28587558 TI - Patient trajectories in a Norwegian unit of municipal emergency beds. AB - OBJECTIVE: The Coordination reform was implemented in Norway from 2012, aiming at seamless patient trajectories. All municipalities are required to establish emergency care beds (MEBs) to avoid unnecessary hospital admissions. We aimed to examine occupancy rate, patient characteristics, diagnoses and discharge level of municipal care in a small MEB unit. DESIGN: Cross-sectional, observational study. SETTING: A two-bed emergency care unit. SUBJECTS: All patients admitted to the unit during one year. MAIN OUTCOME MEASURES: Patients' age and gender, comorbidity, main diagnoses and municipal care level on admission and discharge, diagnostic and therapeutic initiatives, occupancy rate. RESULTS: Sixty admissions were registered, with total bed occupancy 194 days, and an occupancy rate of 0.27. The patients (median age 83 years, 57% women) had mostly infections, musculoskeletal symptoms or undefined conditions. Some 48% of the stays exceeded three days and 43% of the patients were subsequently transferred to nursing homes or hospitals. CONCLUSION: Occupancy rate was low. Patient selection was not according to national standards, and stays were longer. Many patients were transferred to nursing homes, indicating that the unit was an intermediate pathway or a short cut to institutional care. It is unclear whether the unit avoided hospital admissions. PMID- 28587559 TI - Species differences in ciprofloxacin resistance among Gram-negative bacteria: can "anti-mutant" ratios of the area under the concentration-time curve to the MIC be achieved clinically? AB - To explore if the 'anti-mutant' ratios of 24-h area under the concentration-time curve (AUC24) to the MIC overlap the clinically attainable AUC24/MICs, the selection of ciprofloxacin-resistant Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae mutants was studied in dynamic model that simulates human pharmacokinetics of ciprofloxacin. Four strains each of E. coli and P. aeruginosa and three strains of K. pneumoniae were exposed to ciprofloxacin over a 50-400 fold range of the AUC24/MIC ratio. Based on population analysis data, areas under the bacterial mutant concentration-time curves (AUBCMs) were determined for subpopulations resistant to 4*, 8* and 16* MIC of the antibiotic. The emergence of resistance among three Gram-negative organisms was concentration dependent. Based on the AUBCM vs. AUC24/MIC curves, the predicted 'anti-mutant' AUC24/MIC ratios were clinically attainable with E. coli but not with P. aeruginosa and K. pneumoniae. The emergence of fluoroquinolone resistance in a clinical setting can be predicted using dynamic models. PMID- 28587560 TI - Effectiveness of originator (Neupogen) and biosimilar (Zarzio) filgrastim in autologous peripheral blood stem cell mobilization in adults with acute myeloid leukemia: a single-center retrospective study. PMID- 28587561 TI - Short-Term Motor Learning and Retention During Visually Guided Walking in Persons With Multiple Sclerosis. AB - BACKGROUND: The ability to adapt, a form of short-term motor learning, and retain this adaptation, is essential for rehabilitation and for day-to-day living. Yet little research is available on this topic in persons with multiple sclerosis (PwMS), particularly in relation to complex walking tasks. OBJECTIVE: To determine the ability of PwMS to learn and retain a novel relationship between visual input and motor output-or visuomotor map-during visually guided walking. METHODS: Nineteen PwMS and 17 healthy controls performed a precision walking task while adapting to prism lenses that altered the normal visuomotor map on 1 day, and again after a 1-week delay. The task required individuals to walk and step onto 2 targets without stopping. To quantify motor performance, we determined foot placement error relative to the targets. RESULTS: PwMS with mild disability and healthy controls attenuated foot placement error over repeated trials when exposed to the novel mapping and demonstrated a similar rate and magnitude of adaptation in the first learning session. Both groups equally retained the adaptation 1 week later, reflected by reduced foot placement error and a faster rate of error reduction in that session. CONCLUSION: PwMS can learn and retain a novel visuomotor mapping during a precision-based walking task. This suggests that PwMS with mild disability have the capacity for short-term motor learning and retention, indicating that neural plasticity is preserved. PMID- 28587562 TI - A method to induce human cortical long-term potentiation by acoustic stimulation. AB - OBJECT: Acoustic stimulation induced LTP in the human auditory cortex was successfully recorded for the first time by electroencephalography (EEG) using a stimulus of 1 kHz pure-tone in 2005. However, it was barely reproduced, given considerable challenges to reliably elicit and accurately record the enhanced potentials in vivo. The purpose of this paper was to explore whether acoustic stimuli other than 1 kHz pure-tone could generate LTP or not. MEASURES: To answer this question, we proposed a tetanic-stimulation paradigm of pure-tones, narrow band noises (NBNs) and white noise (WN) to elicit LTP in human subjects. RESULTS: The results showed that pure-tones with different frequency could elicit LTP in human auditory cortex, and proved for the first time that NBNs and WN could also achieve the same goal. Interestingly, it was also shown that the noises with certain bandwidth induced the greatest LTP and the WN induced LTP had the least variation over time and across subjects in comparison with pure-tones and NBNs. CONCLUSIONS: In light of the results, we suggested to use the paradigm for broader studies of human in vivo cortical plasticity. PMID- 28587563 TI - How Precise Are Preinterventional Measurements Using Centerline Analysis Applications? Objective Ground Truth Evaluation Reveals Software-Specific Centerline Characteristics. AB - PURPOSE: To evaluate different centerline analysis applications using objective ground truth from realistic aortic aneurysm phantoms with precisely defined geometry and centerlines to overcome the lack of unknown true dimensions in previously published in vivo validation studies. METHODS: Three aortic phantoms were created using computer-aided design (CAD) software and a 3-dimensional (3D) printer. Computed tomography angiograms (CTAs) of phantoms and 3 patients were analyzed with 3 clinically approved and 1 research software application. The 3D centerline coordinates, intraluminal diameters, and lengths were validated against CAD ground truth using a dedicated evaluation software platform. RESULTS: The 3D centerline position mean error ranged from 0.7+/-0.8 to 2.9+/-2.5 mm between tested applications. All applications calculated centerlines significantly different from ground truth. Diameter mean errors varied from 0.5+/ 1.2 to 1.1+/-1.0 mm among 3 applications, but exceeded 8.0+/-11.0 mm with one application due to an unsteady distortion of luminal dimensions along the centerline. All tested commercially available software tools systematically underestimated centerline total lengths by -4.6+/-0.9 mm to -10.4+/-4.3 mm (maximum error -14.6 mm). Applications with the highest 3D centerline accuracy yielded the most precise diameter and length measurements. CONCLUSION: One clinically approved application did not provide reproducible centerline-based analysis results, while another approved application showed length errors that might influence stent-graft choice and procedure success. The variety and specific characteristics of endovascular aneurysm repair planning software tools require scientific evaluation and user awareness. PMID- 28587565 TI - Anterolateral Popliteal Puncture Technique: A Novel Retrograde Approach for Chronic Femoropopliteal Occlusions. AB - PURPOSE: To describe the feasibility and safety of an anterolateral popliteal puncture technique as a retrograde access to chronic total occlusions (CTOs) in the femoropopliteal segment. METHODS: Twenty consecutive patients (mean age 75.1+/-10.9 years; 13 women) with symptomatic femoropopliteal occlusive disease underwent endovascular therapy via a retrograde access using the anterolateral popliteal puncture technique. With the patient supine, the P3 segment of the popliteal artery was accessed with a sheathless technique intended to provide minimally invasive access. Subsequent to a wire rendezvous technique in the CTO, the antegrade guidewire was advanced to the below-the-knee artery. Hemostasis across the P3 segment was secured with balloon inflation alone or combined with thrombin-blood patch (TBP) injection. RESULTS: Both the anterolateral popliteal puncture technique and subsequent revascularization were successful in all patients. Mean hemostasis time for balloon inflation only was 7.73+/-4.03 vs 4.78+/-0.78 minutes for balloon inflation with TBP injection. There were no in hospital deaths or complications, including pseudoaneurysms, arteriovenous fistulas, hematomas, embolic complications, or nerve damage. CONCLUSION: The anterolateral popliteal puncture technique is useful as an alternative retrograde access vs a conventional transpopliteal approach for CTOs in the femoropopliteal segment if antegrade recanalization has failed. This technique may become one option for retrograde access in patients with severe below-the-knee lesions or with CTOs that extend to the P2 segment of the popliteal artery. Furthermore, this technique has the added benefit of allowing patients to remain in the supine position throughout treatment. PMID- 28587564 TI - How to Confirm Catheterization of Inner Branches in Aortic Endografting: The Universal Flush Test. AB - PURPOSE: To describe a quick, simple, and reliable technique to confirm successful catheterization of a branched thoracic endograft's inner branch. TECHNIQUE: Accurate cannulation of inner branches can be verified through insertion and mild retraction of a Universal Flush angiographic catheter, whose tip hooks the branch and slightly opens. CONCLUSION: The use of an angiographic catheter with a curved tip is a safe and easy procedure that can be adopted to check the correct position inside the branch of an endograft designed for treatment of the aortic arch. PMID- 28587566 TI - Buddy Needle Technique to Facilitate Retrograde Puncture of Heavily Calcified Tibial Vessels. AB - PURPOSE: To describe a technical trick to overcome a prior failed retrograde puncture of the tibial vessels secondary to arterial calcification. TECHNIQUE: Following a prior failed retrograde puncture attempt, the needle is left in place next to the artery. The tip of the needle is then moved toward the artery as a lever so that the artery is fixed between the needle, the skin, and the surrounding tissues. With the artery fixed, a standard puncture procedure is performed. Alternatively, if additional support is needed, 2 micropuncture needles are inserted one on either side of the artery, crossing under the target vessel and hence trapping it between them, providing additional support and therefore enhancing the chance of successful arterial access. CONCLUSION: The buddy needle technique may be considered as an alternative procedure in a retrograde pedal/tibial approach after prior failed standard attempts in patients with heavily calcified vessels. PMID- 28587567 TI - Quality of care in oncology: quality indicators in testicular cancer: a hospital based approach. AB - INTRODUCTION: The Belgian Health Care Knowledge Centre (KCE) conducted a literature search leading to twelve quality indicators for testicular cancer. Data obtained from three nationwide databases, showed only five fully measurable quality indicators, one was partially measurable, and two could be determined using a proxy indicator. The four remaining indicators could not be assessed. In this study, we aimed to investigate if these quality indicators were registered and measurable in a medium-volume center. METHODS: In our medium-volume cancer center new testicular cancer diagnoses were registered since 2003. 48 patients were diagnosed with testicular cancer between 2004 and 2014. Through medical file review we measured and evaluated the predefined set of indicators. The results were pooled in a database and compared to the KCE report (KCE Reports 149A. D2010/10.273/96). RESULTS: All 12 indicators could be measured in the entire patient cohort of 48 patients. Mean age was 34.9 years (range 16-85). In comparison with the KCE report, we documented higher rates of tumor marker assessment (98% vs. 73%), staging imaging (100% vs. 95%), multidisciplinary board discussion (100% vs. 58%), orchidectomy (98% vs. 84%), follow-up imaging (100% vs. 54%), and active surveillance (77% vs. 21%). In contrast, we found a lower rate of radiotherapy (6% vs. 20.3%) and chemotherapy (41.6% vs. 53%). Two patients were lost to follow-up, the remaining 46 patients are still alive. Four patients relapsed, all were seminomas. CONCLUSION: Implementation of quality indicators for testicular cancer is feasible for a medium-volume peripheral cancer center. PMID- 28587568 TI - Ultrasonographic examination of the ruptured cord after collagenase treatment or needle fasciotomy for Dupuytren's contracture. AB - : Local treatment of Dupuytren's contracture, either by collagenase or needle fasciotomy, allows disruption of the pathological cord during forced extension. The purpose of this study was to investigate the cord before and after both treatments by ultrasound. A total of 39 patients with a minimum of 20 degrees contracture in the metacarpophalangeal joint were included and randomized to treatment with either collagenase (20 patients) or needle fasciotomy (19 patients). The distance between the distal and the proximal parts of the ruptured cord was measured by ultrasound and the difference in passive joint movement before and after treatment was measured with a goniomenter. There were no significant differences between the collagenase and needle fasciotomy groups in the size of the rupture or gain of mobility. Most cords treated with collagenase and subsequent forced extension had the same ultrasonographic appearance as cords disrupted mechanically by needle fasciotomy. LEVEL OF EVIDENCE: III. PMID- 28587569 TI - Will CURE trials introduce an uncomfortable revolution in the field of HIV research? PMID- 28587570 TI - Effect of Lactobacillus rhamnosus GR-1 Supernatant on Cytokine and Chemokine Output From Human Amnion Cells Treated With Lipoteichoic Acid and Lipopolysaccharide. AB - Preterm birth occurs in 9% to 13% of all human pregnancies and accounts for 80% of all neonatal morbidities and mortalities. Approximately 40% of all preterm births are idiopathic and about half are associated with infection and/or an activated inflammatory process. Further to studies showing anti-inflammatory effects of supernatant from the probiotic Lactobacillus rhamnosus GR-1 (GR-1), we tested its ability to modulate cytokine and chemokine production from amnion cells in response to stimulation by bacterial wall components, lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Placentae were collected from women undergoing elective cesarean section at term. Amnion cells were cultured for 48 hours to confluence, serum starved for 12 hours, and then treated with GR-1 supernatant (1:20 dilution), followed after 12 hours by LPS (100 ng/mL) or LTA (10 ng/mL) for an additional 12 hours. Both LTA and LPS caused significant increases in the concentration of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-alpha; 103.9 +/- 67.5 pg/mL and 368.3 +/- 65.7 pg/mL, respectively) in medium from cultured amnion cells compared to control (<4 pg/mL). There was no significant effect of GR-1 supernatant alone on TNF-alpha output, but there was significant reduction after LPS treatment. The basal output of the immunomodulatory cytokine, interleukin 6, was 613 +/- 170 pg/mL and increased significantly after addition of GR-1 supernatant, LTA, LPS, and combinations of LTA/LPS with GR-1 supernatant. In conclusion, probiotic L rhamnosus GR-1 attenuates the effect of both LPS and LTA in stimulating the output of the pro-inflammatory cytokine TNF-alpha from mixed cultures of human amnion cells in keeping with previous findings in human trophoblast cells. PMID- 28587571 TI - Expression Profiling of lncRNAs, miRNAs, and mRNAs and Their Differential Expression in Leiomyoma Using Next-Generation RNA Sequencing. AB - The objective of this study was to identify the expression profile of long noncoding RNAs (lncRNAs) with concurrent assessment of microRNA (miRNA) and messenger RNA (mRNA) profiles in leiomyomas and paired myometrium using next generation RNA sequencing and assembly of RNA transcripts. Total RNA was isolated from leiomyoma and paired myometrium (N = 8) and samples from 3 pairs were subjected to RNA sequencing. Normalized assembly of over 48 000 lncRNAs resulted in identification of 45 936 lncRNAs. Of these lncRNAs, 22 148 representing overlapping, intergenic, intronic, and antisense subtypes were expressed in all paired tissues, with 5941 (2813 up- and 3128 downregulated at >=1.5 fold) differentially expressed in leiomyomas. Concurrent RNA sequencing revealed the expression of 2588 miRNAs and 21 814 mRNAs, of which 392 miRNAs and 16 559 mRNAs were expressed in all paired tissues. Of these transcripts, 56 and 92 miRNAs and 2030 and 1825 mRNAs were up- or downregulated at >=1.5 fold, respectively, in leiomyoma as compared to myometrium. Using quantitative reverse transcription polymerase chain reaction (QRT-PCR), we confirmed the expression of hepatocellular carcinoma upregulated (HULC), lnc-maternally expressed 3 (MEG3), long intergenic ncRNA 890 (LINC00890), TSIX, long intergenic ncRNA 473 (LINC00473), lnc-KLF9-1, and lnc-POTEM-3 (lncRNA-ATB) in leiomyoma and matched myometrium (N = 8). Collectively, the results presented here provide a comprehensive expression profile of lncRNAs in leiomyomas with concurrent integrated expression of miRNAs and mRNAs and implicate potential regulatory functions of lncRNAs through interactions with specific miRNAs and mRNAs which are known to be critical in the pathogenesis of leiomyoma. PMID- 28587572 TI - Neomacrodione: a new degraded diterpenoid from the roots of Neoboutonia macrocalyx Beng (Euphorbiaceae). AB - One new degraded diterpenoid 3,6-dihydroxy-1,7-dimethyl-9,10-phenantroquinone (neomacrodione) (1) together seven known compounds were isolated from the roots of Neoboutonia macrocalyx (Euphorbiaceae). The structures of the compounds were established based on their NMR and mass spectrometric data in conjunction with those previously reported in the literature. Compound (1) displayed moderate antibacterial activities. PMID- 28587573 TI - "They take care of their own": healthcare professionals' constructions of Sami persons with dementia and their families' reluctance to seek and accept help through attributions to multiple contexts. AB - BACKGROUND: Norwegian government white papers have stated that the Sami population is reluctant to seek help from healthcare services and has traditions of self-help and the use of local networks. OBJECTIVE: In this article we explore healthcare professionals' discursive constructions of Sami persons with dementia and their families' reluctance to seek and accept help from healthcare services. DESIGN: The article is based on an analysis of focus group interviews with healthcare professionals (n = 18) in four municipalities in Northern Norway with multiethnic populations. A narrative context analysis, which involved an examination of sequences of discourse, was employed. RESULTS: Reluctance to seek and accept help among Sami service users and assumptions about self-support were recurring themes in the focus groups. The reluctance was attributed to macro contexts, such as socio-historical processes and cultural norms, and to micro contexts, such as individual and interpersonal factors including the healthcare professionals' cultural backgrounds and language competence. The healthcare professionals' positioning as insiders or outsiders (Sami or non-Sami) affected their attributions. CONCLUSIONS: Local healthcare professionals are at the front line for providing and assessing service users' needs for healthcare services. Consequently, their perceptions of service users' needs are pivotal for achieving equity in healthcare. The established opinion that Sami "take care of their own" and are reluctant to seek and accept help may lead to omissions or neglect. Healthcare professionals' awareness about how present encounters in healthcare settings are framed and shaped by the service users' previous and prevailing experiences of marginalisation and subordination is crucial to avoid omissions or neglect resulting from assumptions about cultural preferences. Discursively shaped boundaries and differences between groups may create the impression that the distance between the groups is too wide to traverse, which in turn may lead to further marginalisation of service users in healthcare encounters. PMID- 28587574 TI - Adverse Childhood Experiences of Violent Female Offenders: A Comparison of Homicide and Sexual Perpetrators. AB - Adverse childhood experiences are associated with a multitude of health and social problems. In addition to an increased risk of poor health, mental disorders, and substance abuse, childhood maltreatment is also significantly related to adult violent offending. Although gender-specific analyses suggest that early childhood maltreatment precedes later violence for males across offense categories, it is unknown whether this association also applies to different types of female offenders. This study explores the types and quantity of adverse childhood experiences for two groups of violent female offenders: perpetrators of intentional homicide ( N = 28) and perpetrators of sexual offenses ( N = 47). A nonparametric analysis using odds ratios (OR) indicated that female homicide perpetrators experienced significantly more adverse childhood experiences (as measured by the Adverse Childhood Experiences Questionnaire) than female sex offenders. Implications for future research are discussed. PMID- 28587576 TI - Risk factors for wound complications and 30-day mortality after major lower limb amputations in patients with peripheral arterial disease. AB - Purpose Risk factors for wound complications or 30-day mortality after major amputation in patients with peripheral arterial disease remain unclear. We investigated the outcomes of major amputation in patients with peripheral arterial disease. Methods Patients who underwent major amputation from 2008 to 2015 were retrospectively analyzed. The main outcome measures were risk factors for wound complications and 30-day mortality after major lower limb amputations. Major amputation was defined as above-knee amputation or below-knee amputation. Wound complications were defined as surgical site infection or wound dehiscence. Results In total, 106 consecutive patients underwent major amputation. The average age was 77.3 +/- 11.2 years, 67.9% of patients had diabetes mellitus and 35.8% were undergoing hemodialysis. Patients who underwent primary amputation constituted 61.9% of the cohort, and the proportions of above-knee amputation and below-knee amputation were 66.9% and 33.1%, respectively. The wound complication rate was 13.3% overall, 10.3% in above-knee amputation, and 19.5% in below-knee amputation. Multivariate analysis showed that the risk factors for wound complications were female sex (hazard ratio, 4.66; 95% confidence interval, 1.40 17.3; P = 0.01) and below-knee amputation (hazard ratio, 4.36; 95% confidence interval, 1.20-17.6; P = 0.03). The 30-day mortality rate was 7.6%, pneumonia comprised the most frequent cause of 30-day mortality, followed by sepsis and cardiac death. Multivariate analysis showed that a low serum albumin concentration (hazard ratio, 3.87; 95% confidence interval, 1.12-16.3; P = 0.03) was a risk factor for 30-day mortality. Conclusions Female sex and below-knee amputation were risk factors for wound complications. A low serum albumin concentration was a risk factor for 30-day mortality after major amputation in Japanese patients with peripheral arterial disease. PMID- 28587575 TI - Comparison of Multisegmental Foot and Ankle Motion Between Total Ankle Replacement and Ankle Arthrodesis in Adults. AB - BACKGROUND: Total ankle replacement (TAR) and ankle arthrodesis (AA) are usually performed for severe ankle arthritis. We compared postoperative foot segmental motion during gait in patients treated with TAR and AA. METHODS: Gait analysis was performed in 17 and 7 patients undergoing TAR and AA, respectively. Subjects were evaluated using a 3-dimensional multisegmental foot model with 15 markers. Temporal gait parameters were calculated. The maximum and minimum values and the differences in hallux, forefoot, hindfoot, and arch in 3 planes (sagittal, coronal, transverse) were compared between the 2 groups. One hundred healthy adults were evaluated as a control. RESULTS: Gait speed was faster in the TAR ( P = .028). On analysis of foot and ankle segmental motion, the range of hindfoot sagittal motion was significantly greater in the TAR (15.1 vs 10.2 degrees in AA; P = .004). The main component of motion increase was hindfoot dorsiflexion (12.3 and 8.6 degrees). The range of forefoot sagittal motion was greater in the TAR (9.3 vs 5.8 degrees in AA; P = .004). Maximum ankle power in the TAR (1.16) was significantly higher than 0.32 in AA; P = .008). However, the range of hindfoot and forefoot sagittal motion was decreased in both TAR and AA compared with the control group ( P = .000). CONCLUSION: Although biomechanical results of TAR and AA were not similar to those in the normal controls, joint motions in the TAR more closely matched normal values. Treatment decision making should involve considerations of the effect of surgery on the adjacent joints. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 28587577 TI - Vitamin K2 can suppress the expression of Toll-like receptor 2 (TLR2) and TLR4, and inhibit calcification of aortic intima in ApoE-/- mice as well as smooth muscle cells. AB - Background and objectives Vascular calcification is a common complication in atherosclerosis. Accumulating evidence showed that Toll-like receptors (TLRs) mediate pro-inflammatory and atherosclerosis. Recent studies demonstrated that vascular calcification is one of the detrimental effects of vitamin K (Vit K) antagonists. However, the effects of Vit K on the expression of TLR2 and 4 and intimal calcification in artery remained unidentified. Methods and results Eighteen ApoE-/- mice were randomly divided into model group, Vit K-treated group, and control group. The mice of model and Vit K-treated group were fed with high-fat diet, while control group mice were fed with normal diet. Mice of Vit K treated group were administered orally with vitamin K2 (40 mg.kg-1.day-1) for 12 weeks. Twelve weeks later the aortic sections of mice were acquired and stained with hematoxylin and eosin and von Kossa, respectively. Calcium content and activity of alkaline phosphatase (ALP) at aortic tissues were measured. The expression levels of TLR2 and TLR4 in aorta sections were detected by immunohistochemisty and RT-PCR, respectively. The effects of Vit K on cellular calcification were further studied in A7r5 SMCs. Results demonstrated that high fat diet induced typical atherosclerosis with intimal calcification in ApoE-/- mice, while in Vit K-treated group atherosclerosis and calcium deposits were not serious; Vit K2 also inhibited cellular calcification in A7r5 SMCs. Quantitative analysis showed that calcium and ALP activity at aortic tissues in the Vit K treated mice were significantly lower than that of the model group ( P < 0.01); Compared to the control group, the expression levels of TLR2 and TLR4 in the model group were significantly higher ( P < 0.05), while in Vit K-treated group the levels of TLR2 and 4 were significantly lower than that in the model group. Furthermore, the content of calcium was positively related to the expression levels of TLR2 and TLR4 mRNA at aortic tissues ( r = 0.77 and r = 0.79, respectively, both P < 0.001). Conclusion VitK2 can inhibit intimal calcification of aortic artery induced by high-fat diet in ApoE-/- mice and A7r5 SMCs calcification induced by beta-sodium glycerophosphate, and meanwhile can reduce the expression of TLR2 and TLR4. These results suggested that the effects of VitK2 on vascular calcification may be associated with the expression of TLR2 and TLR4. PMID- 28587578 TI - Extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities: A retrospective study of 352 patients. AB - Background The aim of this study was to assess the prevalence and clinical significance of extra-vascular findings in patients undergoing magnetic resonance angiography of the abdomen, pelvis and lower extremities. Materials and methods Three hundred fifty-two patients underwent abdominal, pelvic and lower extremity 1.5 T magnetic resonance angiography. Clinically relevant vascular and extra vascular findings were identified. Relevant vascular findings were classified as stenosis, occlusion, aneurysm, sclerosis, dissection or vasculitis. Relevant extra-vascular findings were categorized as 'safe' (Group A), intermediate - requiring additional investigation - (Group B) and malignant/endangering - requiring change of therapy (Group C). Results A total of 2152 clinically relevant vascular findings was identified (6.1/patient). The most frequent vascular finding was femoral artery stenosis (10.6%). Four hundred fifty-one extra-vascular findings were observed (1.3/patient) and classified into Group A (78%), Group B (19.5%) and Group C findings (2.4%). The most frequent malignant findings were lung cancer, lymphoma, osteosarcoma, hepatocellular carcinoma and renal cell carcinoma (7/352 patients). Conclusions Extravascular findings are frequently encountered in magnetic resonance angiography performed for vascular indications. Clinically relevant findings are seen in a substantial part of patients and should prompt further diagnostic work-up. PMID- 28587580 TI - Remote Ischemic Conditioning in Cardiovascular Surgery. AB - The existing clinical studies on remote ischemic preconditioning in patients undergoing cardiovascular surgery are critically reviewed, with a focus on infarct size reduction and clinical outcome as end points. Confounders, notably the use of propofol anesthesia are identified. The need for better designed trials with a more targeted approach is emphasized. PMID- 28587579 TI - Metabolic Syndrome. AB - The United States is experiencing its greatest life expectancy ever. Nonetheless, the general health of the US population is far from at an all-time high. An important contributor to the pandemic of cardiovascular disease is that overweight and obesity are also the major determinants of metabolic syndrome, an all too common and all too serious clinical and public health challenge. Clinicians have traditionally evaluated each of the major risk factors contributing to metabolic syndrome on an individual basis. There is evidence, however, that the risk factors are more than additive. The overlap of these factors in each disease state, resulting in increased atherogenic risks, is worth examining as a broader entity rather than separately. While therapeutic lifestyle changes (TLCs) should be strongly recommended, clinicians should not let the perfect be the enemy of the possible. Evidence-based doses of statins, aspirin and angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers should be prescribed as adjuncts, not alternatives, to TLCs. In fact, there is cogent evidence that the benefits of these pharmacologic therapies may also be at least additive. PMID- 28587582 TI - The Effect of Clopidogrel on the Response to Ischemia Reperfusion. AB - Reperfusion in the setting of acute ischemia is essential in limiting tissue necrosis. However, reperfusion itself is associated with significant adverse effects. There is animal evidence that platelets play a role in the adverse effects of ischemia and reperfusion (IR) injury. We examined whether clopidogrel would have favorable effects on endothelial dysfunction induced by an episode of IR. Using a parallel design, we administered clopidogrel 600 mg or matching placebo to normal volunteers (n = 20) 24 hours before an episode of IR. Flow mediated dilatation (FMD, radial artery) was assessed before and after 20 minutes of upper arm ischemia. Following IR, there was a highly significant decrease in FMD in the placebo group (7.6% +/- 1.3% vs 3.4% +/- 0.1%; P < .001). In the clopidogrel group, there was no change in FMD post-IR (8.3% +/- 0.8% vs 7.1% +/- 1.2%; P = not significant). Following IR, FMD in the placebo group was significantly smaller than that observed in the clopidogrel group ( P < .01). Ischemia and reperfusion caused no change in plasma levels of biomarkers of inflammation (intercellular adhesion molecule 1, chemokine ligand 5, and interleukin 6) in either group. Therefore, a single dose of clopidogrel given 24 hours prior to an episode of IR had protective effects, limiting the adverse effects of ischemia on endothelial function. PMID- 28587581 TI - ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. OBJECTIVES: To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. METHODS: The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. RESULTS: Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. CONCLUSION: Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders. PMID- 28587584 TI - Strategies to Optimize Dual Antiplatelet Therapy After Coronary Artery Stenting in Acute Coronary Syndrome. AB - The use of aspirin and a P2Y12 receptor antagonist as dual antiplatelet therapy (DAPT) has become the treatment of choice in patients with acute coronary syndrome (ACS) and percutaneous coronary intervention to prevent recurrent thrombotic events. Although DAPT is beneficial for most patients, few patients still experience recurrent thrombotic events and increased bleeding episodes. This article reviews current literature to identify various approaches that may enhance the DAPT benefit-risk ratio in patients with ACS. Three strategies addressed in this article include the following-(1) use of more potent antiplatelet agents other than clopidogrel; (2) addition of direct oral anticoagulants (DOACs) to DAPT; and (3) optimizing DAPT duration. Although the use of prasugrel or ticagrelor improves treatment efficacy, their use has been associated with increased risk of bleeding compared to clopidogrel. The combination of DOACs and DAPT may not be the most viable strategy because of its limited cardiovascular benefits and increased bleeding risks. The optimal duration of DAPT duration remains controversial. Most guidelines recommend 6 to 12 months of DAPT, whereas emerging studies have shown benefit for both shorter and longer duration of treatment. Risk stratification tools such as the DAPT score may play a role in individualizing DAPT duration according to patient's ischemic and bleeding risks. PMID- 28587583 TI - Angiotensin Receptor-Neprilysin Inhibition. AB - The novel combination sacubitril/valsartan represents a new therapeutic approach in the management of heart failure. With the simultaneous blockage of the enzyme neprilysin (by sacubitril) and angiotensin II receptors (by valsartan), this combination reduces the degradation of natriuretic peptides and other counterregulatory peptide systems while avoiding the deleterious effect of angiotensin II receptors activation and thereby encompasses a beneficial impact of 2 important neurohormonal pathways activated in heart failure. As opposed to previously tested neprilysin inhibitors, sacubitril/valsartan represents a more effective method in reducing morbidity and mortality in heart failure, while preserving a safety profile comparable to well-established, standard, angiotensin converting enzyme inhibitor's therapy. PMID- 28587585 TI - The impact of biological treatments on the anti-dsDNA and anti-nucleosome tests. AB - Background Anti-double stranded DNA antibodies are a very heterogeneous group of antibodies, quite specific for systemic lupus erythematosus. Newer technologies, such as addressable laser bead immunoassays (ALBIA), show great potential as a diagnostic application. The production of anti-double stranded DNA antibodies is often encountered in inflammatory arthritis; however, literature reports that the actual onset of drug induced lupus in patients treated with biological drugs is a rare event. False positive results for anti-double stranded DNA and anti nucleosome antibodies detected in patients with inflammatory arthritis treated with different biologics prompted the investigation of full autoantibody profiles to evaluate each biomarker's diagnostic performance in systemic lupus erythematosus. The aim of the study was to compare the diagnostic performance of anti-double stranded DNA antibody and anti-nucleosome antibody methods and to evaluate the value of simultaneously measuring anti-double stranded DNA and anti nucleosome antibodies, along with other anti-nuclear antibody analytes, as biomarkers for systemic lupus erythematosus, using a more appropriate control cohort including inflammatory arthritis patients with a non-clinical drug induced lupus. Methods Anti-double stranded DNA and anti-nucleosome antibody levels were evaluated in 247 patient samples: 70 systemic lupus erythematosus, 177 disease controls (including 97 inflammatory arthritis during treatment with different biologics) using the Bio-Rad BioPlex(r) 2200. Results Anti-nucleosome antibodies demonstrated greater clinical sensitivity and specificity than anti-double stranded DNA antibodies. At the manufacturers' cut-off range, considering the two markers as a single or combined test, the "anti-double stranded DNA test or anti nucleosome antibodies" was the most sensitive combination (0.400) with the best negative likelihood ratio (0.62) and negative predictive value (0.803). Conclusion Anti-nucleosome antibodies are a more sensitive and specific biomarker of systemic lupus erythematosus than anti-double stranded DNA antibodies. Anti nucleosome antibodies and anti-double stranded DNA antibodies are independent and complementary markers of systemic lupus erythematosus diagnosis and, therefore, are strongly suggested as combined tests (positive predictive value = 0.938). Moreover, the combined use of the two tests may help to overcome the decreased specificity percentage of the anti-double stranded DNA test, when considering an inflammatory arthritis cohort under biological therapies. The ALBIA method for anti-nuclear specificity detection allows a full autoantibody assessment, resulting in a much higher clinical specificity for systemic lupus erythematosus in the presence of >=3 positive markers and significantly more positive likelihood ratio when >=2 positive markers are present. PMID- 28587586 TI - Depression in systemic lupus erythematosus: gender differences in the performance of the Beck Depression Inventory (BDI), Center for Epidemiologic Studies Depression Scale (CES-D), and Hospital Anxiety and Depression Scale (HADS). AB - The prevalence of depressive symptoms in patients with systemic lupus erythematosus (SLE) varies widely between different cohorts (17-75%), primarily due to factors such as the heterogeneity of the samples and the instruments used to detect depressive symptoms. Most of these instruments are self-administered questionnaires that have different characteristics and approaches to depressive symptoms. This study aimed to evaluate gender differences in the performance of three questionnaires used to assess depressive symptoms in patients with SLE: the Beck Depression Inventory (BDI), Center for Epidemiologic Studies Depression Scale (CES-D), and Hospital Anxiety and Depression Scale (HADS). This study included 54 male and 54 female SLE patients. Depressive symptoms were assessed using BDI (cutoffs 13 and 15), CES-D and HADS. The gold standard method used was the diagnostic criteria of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Regarding the performance of the BDI questionnaire, no significant differences in sensitivity or specificity were found between the genders. The specificity of the CES-D questionnaire was significantly greater for the male group (83% vs. 62.5%, p = 0.0309), and its sensitivity was non significantly higher for the female group (92.9% for women and 71.4% for men; p = 0.2474). Regarding the performance of the HADS, we found similar sensitivities between the genders (71.4%) but a higher specificity among the men (95.7% in men and 82.5% in women, p = 0.0741). In conclusion, our results suggest the presence of gender differences in the performance of the questionnaires in SLE patients. The BDI had the most similar performances between the male and female groups. In contrast, the CES-D and HADS-D showed considerable variation in performances between men and women with SLE. PMID- 28587588 TI - Contemporary Management of Renal Transplant Recipients With De Novo Urolithiasis: A Single Institution Experience and Review of the Literature. AB - OBJECTIVES: We report on the long-term follow-up of managing allograft stones at a single tertiary referral institution and review the relevant literature. MATERIALS AND METHODS: A retrospective analysis of renal allograft recipient charts was performed to identify patients who developed allograft lithiasis between 1974 and 2009. Patient and stone characteristics, diagnoses, treatments, and outcomes were described. RESULTS: Sixteen patients developed 22 stones after a median follow-up of 170 months (range, 51-351 mo). The mean (standard deviation) and median diameter of the stones were 13.8 (8.5) mm and 11 mm. Among these, 3 stones were treated conservatively, 3 by shock-wave lithotripsy, and 7 by cystolitholapaxy. Seven patients underwent percutaneous treatment in the form of percutaneous nephrostomy tube fixation and spontaneous passage of stone (1 stone), shock-wave lithotripsy (1 stone), antegrade stenting (1 stone), and percutaneous nephrolithotomy (6 stones). All patients were stone free after treatment, except for 2 patients whose stones were stable and peripheral on long term follow-up. CONCLUSIONS: Allograft lithiasis requires a multimodal treatment tailored according to stone and graft characteristics. Protocols regarding spontaneous passage can be adopted if there is no harm to the graft and the patient is compliant. Careful attention to the anatomy during percutaneous nephrostomy tube placement is mandatory to avoid intestinal loop injury. A more attentive follow-up is required for early stone management. PMID- 28587590 TI - RNA sequencing and transcriptome arrays analyses show opposing results for alternative splicing in patient derived samples. AB - BACKGROUND: RNA sequencing (RNA-seq) and microarrays are two transcriptomics techniques aimed at the quantification of transcribed genes and their isoforms. Here we compare the latest Affymetrix HTA 2.0 microarray with Illumina 2000 RNA seq for the analysis of patient samples - normal lung epithelium tissue and squamous cell carcinoma lung tumours. Protein coding mRNAs and long non-coding RNAs (lncRNAs) were included in the study. RESULTS: Both platforms performed equally well for protein-coding RNAs, however the stochastic variability was higher for the sequencing data than for microarrays. This reduced the number of differentially expressed genes and genes with predictive potential for RNA-seq compared to microarray data. Analysis of this variability revealed a lack of reads for short and low abundant genes; lncRNAs, being shorter and less abundant RNAs, were found especially susceptible to this issue. A major difference between the two platforms was uncovered by analysis of alternatively spliced genes. Investigation of differential exon abundance showed insufficient reads for many exons and exon junctions in RNA-seq while the detection on the array platform was more stable. Nevertheless, we identified 207 genes which undergo alternative splicing and were consistently detected by both techniques. CONCLUSIONS: Despite the fact that the results of gene expression analysis were highly consistent between Human Transcriptome Arrays and RNA-seq platforms, the analysis of alternative splicing produced discordant results. We concluded that modern microarrays can still outperform sequencing for standard analysis of gene expression in terms of reproducibility and cost. PMID- 28587589 TI - Sexual selection and the evolution of male pheromone glands in philanthine wasps (Hymenoptera, Crabronidae). AB - BACKGROUND: Sexual selection is thought to promote evolutionary changes and diversification. However, the impact of sexual selection in relation to other selective forces is difficult to evaluate. Male digger wasps of the tribe Philanthini (Hymenoptera, Philanthinae) scent mark territories to attract receptive females. Consequently, the organs for production and storage of the marking secretion, the mandibular gland (MG) and the postpharyngeal gland (PPG), are subject to sexual selection. In female Philanthini, these glands are most likely solely subject to natural selection and show very little morphological diversity. According to the hypothesis that sexual selection drives interspecific diversity, we predicted that the MG and PPG show higher interspecific variation in males than in females. Using histological methods, 3D-reconstructions, and multivariate statistical analysis of morphological characters, we conducted a comparative analysis of the MG and the PPG in males of 30 species of Philanthini and three species of the Cercerini and Aphilanthopsini, two related tribes within the Philanthinae. RESULTS: We found substantial interspecific diversity in gland morphology with regard to gland incidence, size, shape and the type of associated secretory cells. Overall there was a phylogenetic trend: Ensuing from the large MGs and small PPGs of male Cercerini and Aphilanthopsini, the size and complexity of the MG was reduced in male Philanthini, while their PPG became considerably enlarged, substantially more complex, and associated with an apparently novel type of secretory cells. In some clades of the Philanthini the MG was even lost and entirely replaced by the PPG. However, several species showed reversals of and exceptions from this trend. Head gland morphology was significantly more diverse among male than among female Philanthinae. CONCLUSION: Our results show considerable variation in male head glands including the loss of an entire gland system and the evolution of a novel kind of secretory cells, confirming the prediction that interspecific diversity in head gland morphology is higher in male than in female Philanthini. We discuss possible causes for the remarkable evolutionary changes in males and we conclude that this high diversity has been caused by sexual selection. PMID- 28587591 TI - Microarray expression profiling in the denervated hippocampus identifies long noncoding RNAs functionally involved in neurogenesis. AB - BACKGROUND: The denervated hippocampus provides a proper microenvironment for the survival and neuronal differentiation of neural progenitors. While thousands of lncRNAs were identified, only a few lncRNAs that regulate neurogenesis in the hippocampus are reported. The present study aimed to perform microarray expression profiling to identify long noncoding RNAs (lncRNAs) that might participate in the hippocampal neurogenesis, and investigate the potential roles of identified lncRNAs in the hippocampal neurogenesis. RESULTS: In this study, the profiling suggested that 74 activated and 29 repressed (|log fold change|>1.5) lncRNAs were differentially expressed between the denervated and the normal hippocampi. Furthermore, differentially expressed lncRNAs associated with neurogenesis were found. According to the tissue-specific expression profiles, and a novel lncRNA (lncRNA2393) was identified as a neural regulator in the hippocampus in this study. The expression of lncRNA2393 was activated in the denervated hippocampus. FISH showed lncRNA2393 specially existed in the subgranular zone of the dentate gyrus in the hippocampus and in the cytoplasm of neural stem cells (NSCs). The knockdown of lncRNA2393 depletes the EdU-positive NSCs. Besides, the increased expression of lncRNA2393 was found to be triggered by the change in the microenvironment. CONCLUSION: We concluded that expression changes of lncRNAs exists in the microenvironment of denervated hippocampus, of which promotes hippocampal neurogenesis. The identified lncRNA lncRNA2393 expressed in neural stem cells, located in the subgranular zone of the dentate gyrus, which can promote NSCs proliferation in vitro. Therefore, the question is exactly which part of the denervated hippocampus induced the expression of lncRNA2393. Further studies should aim to explore the exact molecular mechanism behind the expression of lncRNA2393 in the hippocampus, to lay the foundation for the clinical application of NSCs in treating diseases of the central nervous system. PMID- 28587592 TI - Bayesian hierarchical piecewise regression models: a tool to detect trajectory divergence between groups in long-term observational studies. AB - BACKGROUND: Bayesian hierarchical piecewise regression (BHPR) modeling has not been previously formulated to detect and characterise the mechanism of trajectory divergence between groups of participants that have longitudinal responses with distinct developmental phases. These models are useful when participants in a prospective cohort study are grouped according to a distal dichotomous health outcome. Indeed, a refined understanding of how deleterious risk factor profiles develop across the life-course may help inform early-life interventions. Previous techniques to determine between-group differences in risk factors at each age may result in biased estimate of the age at divergence. METHODS: We demonstrate the use of Bayesian hierarchical piecewise regression (BHPR) to generate a point estimate and credible interval for the age at which trajectories diverge between groups for continuous outcome measures that exhibit non-linear within-person response profiles over time. We illustrate our approach by modeling the divergence in childhood-to-adulthood body mass index (BMI) trajectories between two groups of adults with/without type 2 diabetes mellitus (T2DM) in the Cardiovascular Risk in Young Finns Study (YFS). RESULTS: Using the proposed BHPR approach, we estimated the BMI profiles of participants with T2DM diverged from healthy participants at age 16 years for males (95% credible interval (CI):13.5 18 years) and 21 years for females (95% CI: 19.5-23 years). These data suggest that a critical window for weight management intervention in preventing T2DM might exist before the age when BMI growth rate is naturally expected to decrease. Simulation showed that when using pairwise comparison of least-square means from categorical mixed models, smaller sample sizes tended to conclude a later age of divergence. In contrast, the point estimate of the divergence time is not biased by sample size when using the proposed BHPR method. CONCLUSIONS: BHPR is a powerful analytic tool to model long-term non-linear longitudinal outcomes, enabling the identification of the age at which risk factor trajectories diverge between groups of participants. The method is suitable for the analysis of unbalanced longitudinal data, with only a limited number of repeated measures per participants and where the time-related outcome is typically marked by transitional changes or by distinct phases of change over time. PMID- 28587593 TI - Low genetic and phenotypic divergence in a contact zone between freshwater and marine sticklebacks: gene flow constrains adaptation. AB - BACKGROUND: Distinct hybrid zones and phenotypic and genomic divergence is often observed between marine and freshwater threespine sticklebacks (Gasterosteus aculeatus). Nevertheless, cases also exist where marine-freshwater divergence is diffuse despite seemingly similar environmental settings. In order to assess what characterizes these highly different outcomes, we focused on the latter kind of system in the Odder River, Denmark. Here, a previous study based on RAD (Restriction site Associated DNA) sequencing found non-significant genome-wide differentiation between marine and freshwater sticklebacks. In the present study, we analyzed samples on a finer geographical scale. We assessed if the system should be regarded as panmictic, or if fine-scale genetic structure and local selection was present but dominated by strong migration. We also asked if specific population components, that is the two sexes and different lateral plate morphs, contributed disproportionally more to dispersal. RESULTS: We assessed variation at 96 SNPs and the Eda gene that affects lateral plate number, conducted molecular sex identification, and analyzed morphological traits. Genetic differentiation estimated by FST was non-significant throughout the system. Nevertheless, spatial autocorrelation analysis suggested fine scale genetic structure with a genetic patch size of 770 m. There was no evidence for sex-biased dispersal, but full-plated individuals showed higher dispersal than low- and partial-plated individuals. The system was dominated by full-plated morphs characteristic of marine sticklebacks, but in the upstream part of the river body shape and frequency of low-plated morphs changed in the direction expected for freshwater sticklebacks. Five markers including Eda were under possible diversifying selection. However, only subtle clinal patterns were observed for traits and markers. CONCLUSIONS: We suggest that gene flow from marine sticklebacks overwhelms adaptation to freshwater conditions, but the short genetic patch size means that the effect of gene flow on the most upstream region must be indirect and occurs over generations. The occurrence of both weak unimodal and strong bimodal hybrid zones within the same species is striking. We suggest environmental and demographic factors that could determine these outcomes, but also highlight the possibility that long-term population history and the presence or absence of genomic incompatibilities could be a contributing factor. PMID- 28587594 TI - Construction of a high-density linkage map and mapping of sex determination and growth-related loci in the mandarin fish (Siniperca chuatsi). AB - BACKGROUND: The mandarin fish (Siniperca chuatsi) is an important and widely cultured fish in China. However, the lack of selective breeding of mandarin fish in previous decades has resulted in a decline in the growth rate of pond-cultured fish, a shortened period of sexual maturity, and reduced disease resistance; these issues seriously affect the quality and safety of the fish products. Therefore, it is necessary to establish a selective breeding program for the mandarin fish to improve the economical traits of the fish and to sustain the development of the mandarin fish industry. RESULTS: We constructed a high-density linkage map for it based on double digest restriction site associated DNA sequencing (ddRAD-Sequencing). This map contained 3283 dimorphic single nucleotide polymorphism markers and 24 linkage groups (LGs). The total map-length was 1972.01 cM, with an average interlocus distance of 0.61 cM. One significant quantitative trait locus (QTL) for sex determination trait was detected on LG23, which was supported by five markers, clustered between 60.27 and 68.71 cM. The highest logarithm of odds value (17.73) was located at 60.27 cM, near the marker r1_73194, accounting for 53.3% of the phenotypic variance. Genotypes of all the male fish on r1_33008 were homozygous, whereas those of all females were heterozygous. Thus, LG23 was considered a sex-related linkage group. Eleven significant QTLs, for three growth traits, at two growth stages and the increased values were distributed on four LGs; their contributions to the phenotypic variation were quite low (12.4-17.2%), suggesting that multiple genes affected the growth traits. CONCLUSION: This high-resolution genetic map provides a valuable resource for fine-mapping of important traits and for identification of sex-related markers that should facilitate breeding of all-female mandarin fish for aquaculture and mechanistic studies on sex determination. PMID- 28587597 TI - "On the same page"? The effect of GP examiner feedback on differences in rating severity in clinical assessments: a pre/post intervention study. AB - BACKGROUND: Robust and defensible clinical assessments attempt to minimise differences in student grades which are due to differences in examiner severity (stringency and leniency). Unfortunately there is little evidence to date that examiner training and feedback interventions are effective; "physician raters" have indeed been deemed "impervious to feedback". Our aim was to investigate the effectiveness of a general practitioner examiner feedback intervention, and explore examiner attitudes to this. METHODS: Sixteen examiners were provided with a written summary of all examiner ratings in medical student clinical case examinations over the preceding 18 months, enabling them to identify their own rating data and compare it with other examiners. Examiner ratings and examiner severity self-estimates were analysed pre and post intervention, using non parametric bootstrapping, multivariable linear regression, intra-class correlation and Spearman's correlation analyses. Examiners completed a survey exploring their perceptions of the usefulness and acceptability of the intervention, including what (if anything) examiners planned to do differently as a result of the feedback. RESULTS: Examiner severity self-estimates were relatively poorly correlated with measured severity on the two clinical case examination types pre-intervention (0.29 and 0.67) and were less accurate post intervention. No significant effect of the intervention was identified, when differences in case difficulty were controlled for, although there were fewer outlier examiners post-intervention. Drift in examiner severity over time prior to the intervention was observed. Participants rated the intervention as interesting and useful, and survey comments indicated that fairness, reassurance, and understanding examiner colleagues are important to examiners. CONCLUSIONS: Despite our participants being receptive to our feedback and wanting to be "on the same page", we did not demonstrate effective use of the feedback to change their rating behaviours. Calibration of severity appears to be difficult for examiners, and further research into better ways of providing more effective feedback is indicated. PMID- 28587595 TI - Proteomic analysis by iTRAQ-MRM of soybean resistance to Lamprosema Indicate. AB - BACKGROUND: Lamprosema indicate is a major leaf feeding insect pest to soybean, which has caused serious yield losses in central and southern China. To explore the defense mechanisms of soybean resistance to Lamprosema indicate, a highly resistant line (Gantai-2-2) and a highly susceptible line (Wan 82-178) were exposed to Lamprosema indicate larval feedings for 0 h and 48 h, and the differential proteomic analyses of these two lines were carried out. RESULTS: The results showed that 31 differentially expressed proteins (DEPs) were identified in the Gantai-2-2 when comparing 48 h feeding with 0 h feeding, and 53 DEPs were identified in the Wan 82-178. 28 DEPs were identified when comparing Gantai-2-2 with Wan 82-178 at 0 h feeding. The bioinformatic analysis results showed that most of the DEPs were associated with ribosome, linoleic acid metabolism, flavonoid biosynthesis, phenylpropanoid biosynthesis, peroxisome, stilbenoid, diarylheptanoid and gingerol biosynthesis, glutathione metabolism, pant hormone signal transduction, and flavone and flavonol biosynthesis, as well as other resistance related metabolic pathways. The MRM analysis showed that the iTRAQ results were reliable. CONCLUSIONS: According to the analysis of the DEPs results, the soybean defended or resisted the Lamprosema indicate damage by the induction of a synthesis of anti-digestive proteins which inhibit the growth and development of insects, reactive oxygen species scavenging, signaling pathways, secondary metabolites synthesis, and so on. PMID- 28587596 TI - A systematic evaluation of nucleotide properties for CRISPR sgRNA design. AB - BACKGROUND: CRISPR is a versatile gene editing tool which has revolutionized genetic research in the past few years. Optimizing sgRNA design to improve the efficiency of target/DNA cleavage is critical to ensure the success of CRISPR screens. RESULTS: By borrowing knowledge from oligonucleotide design and nucleosome occupancy models, we systematically evaluated candidate features computed from a number of nucleic acid, thermodynamic and secondary structure models on real CRISPR datasets. Our results showed that taking into account position-dependent dinucleotide features improved the design of effective sgRNAs with area under the receiver operating characteristic curve (AUC) >0.8, and the inclusion of additional features offered marginal improvement (~2% increase in AUC). CONCLUSION: Using a machine-learning approach, we proposed an accurate prediction model for sgRNA design efficiency. An R package predictSGRNA implementing the predictive model is available at http://www.ams.sunysb.edu/~pfkuan/softwares.html#predictsgrna . PMID- 28587598 TI - Methodologic considerations in the design and analysis of nested case-control studies: association between cytokines and postoperative delirium. AB - BACKGROUND: The nested case-control study (NCC) design within a prospective cohort study is used when outcome data are available for all subjects, but the exposure of interest has not been collected, and is difficult or prohibitively expensive to obtain for all subjects. A NCC analysis with good matching procedures yields estimates that are as efficient and unbiased as estimates from the full cohort study. We present methodological considerations in a matched NCC design and analysis, which include the choice of match algorithms, analysis methods to evaluate the association of exposures of interest with outcomes, and consideration of overmatching. METHODS: Matched, NCC design within a longitudinal observational prospective cohort study in the setting of two academic hospitals. Study participants are patients aged over 70 years who underwent scheduled major non-cardiac surgery. The primary outcome was postoperative delirium from in hospital interviews and medical record review. The main exposure was IL-6 concentration (pg/ml) from blood sampled at three time points before delirium occurred. We used nonparametric signed ranked test to test for the median of the paired differences. We used conditional logistic regression to model the risk of IL-6 on delirium incidence. Simulation was used to generate a sample of cohort data on which unconditional multivariable logistic regression was used, and the results were compared to those of the conditional logistic regression. Partial R square was used to assess the level of overmatching. RESULTS: We found that the optimal match algorithm yielded more matched pairs than the greedy algorithm. The choice of analytic strategy-whether to consider measured cytokine levels as the predictor or outcome-- yielded inferences that have different clinical interpretations but similar levels of statistical significance. Estimation results from NCC design using conditional logistic regression, and from simulated cohort design using unconditional logistic regression, were similar. We found minimal evidence for overmatching. CONCLUSIONS: Using a matched NCC approach introduces methodological challenges into the study design and data analysis. Nonetheless, with careful selection of the match algorithm, match factors, and analysis methods, this design is cost effective and, for our study, yields estimates that are similar to those from a prospective cohort study design. PMID- 28587599 TI - Participation trends in holistic movement practices: a 10-year comparison of yoga/Pilates and t'ai chi/qigong use among a national sample of 195,926 Australians. AB - BACKGROUND: In recent decades, the evidence supporting the physical and mental health benefits of holistic movement practices such as yoga and t'ai chi have become increasingly established. Consequently, investigating the participation prevalence and patterns of these practices is a relevant pursuit in the public health field. Few studies have provided population-level assessment of participation rates, however, and even fewer have focused on patterns over time. The purpose of this study was to examine participation prevalence and trends in yoga/Pilates and t'ai chi/qigong over a ten-year period in a nationally representative sample of Australians aged 15 years and over, with particular attention to sex and age. A secondary purpose was to juxtapose these findings with participation trends in traditional fitness activities over the same period. METHODS: Data comprised modes and types of physical activity, age, and sex variables collected through the Exercise, Recreation and Sport Survey (ERASS), a series of independent cross-sectional Australia-wide surveys conducted yearly between 2001 and 2010. For each year, weighted population estimates were calculated for those participating in yoga/Pilates, t'ai chi/qigong, and fitness activities (e.g. aerobics, calisthenics). Linear regression and multiple logistic regression analyses were used to examine trends in prevalence rates over time and differences among sex and age (15-34; 35-54; 55+ years) groups, respectively. RESULTS: Average prevalence rates between 2001 and 2010 were 3.0% (95% CI 2.9 3.1) for yoga/Pilates, 0.6% (95% CI 0.5-0.6) for t'ai chi/qigong, and 19.2% (95% CI 18.9-19.4) for fitness activities. Across the decade, overall participation rates remained relatively stable for yoga/Pilates and t'ai chi/qigong, while increasing linearly for fitness activities. For both genders and in all three age groups, participation in fitness activities increased, whereas only in the 55+ age group was there a significant increase in yoga/Pilates participation; participation in t'ai chi/qigong declined significantly in the two younger age groups. CONCLUSIONS: Participation rates in yoga/Pilates and t'ai chi/qigong in Australia were low and relatively stable. As fitness activities increased in popularity across the decade, holistic movement practices did not. These findings point to the need to investigate activity-specific barriers and facilitators to participation, including intrapersonal, interpersonal, organisational, and environmental factors. PMID- 28587600 TI - Performance comparison of CareStartTM HRP2/pLDH combo rapid malaria test with light microscopy in north-western Tigray, Ethiopia: a cross-sectional study. AB - BACKGROUND: Rapid diagnostic tests (RDTs) are alternative methods for microscopy in the diagnosis of malaria in resource limited settings. Among commercially available RDTs, CareStartTM Malaria test was found to show reliable results. This study evaluated the performance of CareStartTM Malaria Combo test kit in Northwestern Tigray in Ethiopia. METHODS: Blood samples were collected from 320 malaria-suspected patients at Mayani Hospital in Northwestern Tigray from December 2015 to March 2016. All blood samples were examined using both light microscopy and CareStartTM Malaria HRP2/pLDH Combo Test kit. Statistical analyses were performed using SPSS version 20. RESULTS: The overall parasite positivity using light microscopy and CareStartTM RDT was 41 (12.8%) and 43 (13.4%), respectively. The sensitivity and specificity of CareStartTM RDT, regardless of species, were found to be 95.4 and 99.3%, respectively. Furthermore, the sensitivity of CareStartTM RDT for Plasmodium falciparum or mixed infection and non-falciparum malaria parasites was 94.4 and 85.0%, respectively while the specificity was found to be 98.9 and 99.7%, respectively. The agreement between the two test methods was "excellent" with a kappa value of 0.92. CONCLUSION: CareStartTM RDT has very good sensitivity and specificity for malaria diagnosis. The test kit also has an excellent agreement with light microscopy. It is therefore useful in resource-limited areas where microscopy is not available. PMID- 28587601 TI - Cavalier King Charles Spaniels with Chiari-like malformation and Syringomyelia have increased variability of spatio-temporal gait characteristics. AB - BACKGROUND: Chiari-like malformation in the Cavalier King Charles Spaniel is a herniation of the cerebellum and brainstem into or through the foramen magnum. This condition predisposes to Syringomyelia; fluid filled syrinxes within the spinal cord. The resulting pathology in spinal cord and cerebellum create neuropathic pain and changes in gait. This study aims to quantify the changes in gait for Cavalier King Charles Spaniel with Chiari-like malformation and Syringomyelia. METHODS: We compared Cavalier King Charles Spaniel with Chiari like malformation with (n = 9) and without (n = 8) Syringomyelia to Border Terriers (n = 8). Two video cameras and manual tracking was used to quantify gait parameters. RESULTS AND CONCLUSIONS: We found a significant increase in coefficient of variation for the spatio-temporal characteristics and ipsilateral distance between paws and a wider base of support in the thoracic limbs but not in the pelvic limbs for Cavalier King Charles Spaniels compared with the border terrier. PMID- 28587602 TI - Health care workers indicate ill preparedness for Ebola Virus Disease outbreak in Ashanti Region of Ghana. AB - BACKGROUND: The recent Ebola Virus Disease (EVD) epidemic that hit some countries in West Africa underscores the need to train front line high-risk health workers on disease prevention skills. Although Ghana did not record (and is yet to) any case, and several health workers have received numerous training schemes, there is no record of any study that assessed preparedness of healthcare workers (HCWS) regarding EVD and any emergency prone disease in Ghana. We therefore conducted a hospital based cross sectional study involving 101 HCWs from two facilities in Kumasi, Ghana to assess the level of preparedness of HCWs to respond to any possible EVD. METHODS: We administered a face-to-face questionnaire using an adapted WHO (2015) and CDC (2014) Checklist for Ebola Preparedness and assessed overall knowledge gaps, and preparedness of the Ghanaian HCWs in selected health facilities of the Ashanti Region of Ghana from October to December 2015. RESULTS: A total 92 (91.09%) HCWs indicated they were not adequately trained to handle an EVD suspected case. Only 25.74% (n = 26) considered their facilities sufficiently equipped to handle and manage EVD patients. When asked which disinfectant to use after attending to and caring for a suspected patient with EVD, only 8.91% (n = 9) could correctly identify the right disinfectant (chi2 = 28.52, p = 0.001). CONCLUSION: Our study demonstrates poor knowledge and ill preparedness and unwillingness of many HCWs to attend to EVD. Beyond knowledge acquisition, there is the need for more training from time to time to fully prepare HCWs to handle any possible EVD case. PMID- 28587603 TI - Vienna Summer School on Oncology: how to teach clinical decision making in a multidisciplinary environment. AB - BACKGROUND: Clinical decision making in oncology is based on both inter- and multidisciplinary approach. Hence teaching future doctors involved in oncology or general health practice is crucial. The aim of the Vienna Summer School on Oncology (VSSO) as an international, integrated, undergraduate oncology course is to teach medical students interdisciplinary team communication and application of treatment concepts/algorithms in a multidisciplinary setting. METHOD: The teaching is based on an inter- and multidisciplinary faculty and a multimodal education approach to address different learning styles. The participants rated their satisfaction of the program voluntarily after finishing the course according to a grading scale from one (not good) to five (very good). The learning success was assessed by a compulsory pre-VSSO and post-VSSO single choice questionnaire. RESULTS: Program organisation was rated with a mean score of 4.47 out of 5.0 (SD 0.51), composition of the program and range of topics with a mean score of 4.68 (SD 0.58) and all teachers with a mean score of 4.36 (SD 0.40) points. Student evaluation at the beginning and end of the program indicated significant knowledge acquisition -i.e., general aspects of cancer: median 8.75 points (IQR 7.5-9.4) vs.10.0 points (IQR 9.4-10.0) p = 0.005; specific aspects of cancer: median 4.87 points (IQR 3.33-5.71) vs. 8.72 points (IQR 6.78-9.49) p <= 0.001, respectively. CONCLUSION: Even though the participants represent a selection of students with special interest in cancer, the results of the VSSO indicate the benefit of an inter- and multidisciplinary teaching approach within an oncology module. PMID- 28587605 TI - Evaluation of arterial digital blood flow using Doppler ultrasonography in healthy dairy cows. AB - BACKGROUND: Local circulatory disturbances have been implicated in the development of foot disorders in cattle. The goals of this study were to evaluate the suitability of the interdigital artery in the pastern region in both hind limbs using pulsed-wave (PW) Doppler ultrasonography and to investigate quantitative arterial blood flow variables at that site in dairy cows. An Esaote MyLabOne ultrasound machine with a 10-MHz linear transducer was used to assess blood flow in the interdigital artery in the pastern region in both hind limbs of 22 healthy German Holstein cows. The cows originated from three commercial farms and were restrained in a standing hoof trimming chute without sedation. RESULTS: A PW Doppler signal suitable for analysis was obtained in 17 of 22 cows. The blood flow profiles were categorised into four curve types, and the following quantitative variables were measured in three uniform cardiac cycles: vessel diameter, pulse rate, maximum systolic velocity, maximum diastolic velocity, end diastolic velocity, reverse velocity, maximum time-averaged mean velocity, blood flow rate, resistance index and persistence index. The measurements did not differ among cows from the three farms. Maximum systolic velocity, vessel diameter and pulse rate did not differ but other variables differed significantly among blood flow profiles. CONCLUSIONS: Differences in weight-bearing are thought to be responsible for the normal variability of blood flow profiles in healthy cows. The scanning technique used in this report for evaluation of blood flow in the interdigital artery appears suitable for further investigations in healthy and in lame cows. PMID- 28587604 TI - KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment. AB - BACKGROUND: Type 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic beta cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic beta cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects. METHODS: Based on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl's VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively. RESULTS: Based on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl's VEP. CONCLUSIONS: Our study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy. PMID- 28587606 TI - Quality of anticoagulation management with warfarin among outpatients in a tertiary hospital in Addis Ababa, Ethiopia: a retrospective cross-sectional study. AB - BACKGROUND: Warfarin is the most widely used anticoagulant in the world. The difficulty of managing warfarin contributes to great potential for patient harm, both from excessive anticoagulation and insufficient anticoagulation. This study assessed the International Normalized Ratio (INR) control outcome measures and warfarin dose adjustment practices at cardiology and hematology outpatient clinics at a teaching hospital in Addis Ababa, Ethiopia. METHODS: The study was based on a cross - sectional study design involving 360 retrospective patients' chart review among outpatients who received warfarin for its various indications. RESULTS: The mean frequency of INR monitoring per patient was 62.9 days (17.2 143.7 days). Patients spent 52.2%, 29.0% and 18.8% of the time in sub therapeutic, therapeutic and supra-therapeutic ranges, respectively. The daily warfarin dose was increased 50.9% and 36.9% and decreased in 52.8% and 60.9% of the time for occurrences of sub-therapeutic and supra-therapeutic INRs to achieve target ranges of 2.0-3.0 and 2.5-3.5, respectively. CONCLUSION: The quality of anticoagulation management with warfarin among outpatients in Tikur Anbessa Specialized Hospital was sub-optimal. This was reflected by low Time in Therapeutic Range (TTR), longer than recommended INR monitoring frequency, and minimal actions taken to adjust warfarin dose after occurrences of non therapeutic INRs. PMID- 28587607 TI - Design of a syndemic based intervention to facilitate care for men who have sex with men with high risk behaviour: the syn.bas.in randomized controlled trial. AB - BACKGROUND: Men who have sex with men (MSM) constitute a risk group for sexual transmitted infections (STIs), including HIV. Despite counselling interventions, risk behaviour remains high. Syndemic theory holds that psychosocial problems often co-occur, interact and mutually reinforce each other, thereby increasing high risk behaviours and co-occurring diseases. Therefore, if co-occurring psychosocial problems were assessed and treated simultaneously, this might decrease high risk behaviour and disease. METHOD: An open label randomized controlled trial will be conducted among 150 MSM with high risk behaviour recruited from the STI clinic of Amsterdam. Inclusion criteria are: HIV negative MSM with two STI and/or PEP treatment in the last 24 months, or HIV positive MSM with one STI in the last 24 months. All participants get questionnaires on the following syndemic domains: ADHD, depression, anxiety disorder, alexithymia and sex- and drug addiction. Participants in the control group receive standard care: STI screenings every three months and motivational interviewing based counselling. Participants in the experimental group receive standard care plus feedback based on the results of the questionnaires. All participants can be referred to co-located mental health or addiction services. The primary outcome is help seeking behaviour for mental health problems and/or drug use problems. The secondary outcomes are STI incidence and changes in sexual risk behaviour (i.e. condom use, number of anal sex partners, drug use during sex). DISCUSSION: This study will provide information on syndemic domains among MSM who show high risk behaviour and on the effect of screening and referral on help seeking behaviour and health (behaviour) outcomes. TRIAL REGISTRATION: Trial Registration at clinicaltrail.gov, identifier NCT02859935 . PMID- 28587608 TI - Integrating clinical decision support systems for pharmacogenomic testing into clinical routine - a scoping review of designs of user-system interactions in recent system development. AB - BACKGROUND: Pharmacogenomic clinical decision support systems (CDSS) have the potential to help overcome some of the barriers for translating pharmacogenomic knowledge into clinical routine. Before developing a prototype it is crucial for developers to know which pharmacogenomic CDSS features and user-system interactions have yet been developed, implemented and tested in previous pharmacogenomic CDSS efforts and if they have been successfully applied. We address this issue by providing an overview of the designs of user-system interactions of recently developed pharmacogenomic CDSS. METHODS: We searched PubMed for pharmacogenomic CDSS published between January 1, 2012 and November 15, 2016. Thirty-two out of 118 identified articles were summarized and included in the final analysis. We then compared the designs of user-system interactions of the 20 pharmacogenomic CDSS we had identified. RESULTS: Alerts are the most widespread tools for physician-system interactions, but need to be implemented carefully to prevent alert fatigue and avoid liabilities. Pharmacogenomic test results and override reasons stored in the local EHR might help communicate pharmacogenomic information to other internal care providers. Integrating patients into user-system interactions through patient letters and online portals might be crucial for transferring pharmacogenomic data to external health care providers. Inbox messages inform physicians about new pharmacogenomic test results and enable them to request pharmacogenomic consultations. Search engines enable physicians to compare medical treatment options based on a patient's genotype. CONCLUSIONS: Within the last 5 years, several pharmacogenomic CDSS have been developed. However, most of the included articles are solely describing prototypes of pharmacogenomic CDSS rather than evaluating them. To support the development of prototypes further evaluation efforts will be necessary. In the future, pharmacogenomic CDSS will likely include prediction models to identify patients who are suitable for preemptive genotyping. PMID- 28587610 TI - Trends in GP prescribing of psychotropic medications among young patients aged 16 24 years: a case study analysis. AB - BACKGROUND: Current clinical guidelines recommend non-pharmacological interventions as first-line treatments for young patients aged 16-24 years with a mental health condition (MHC). However, several studies have noted increasing trends in psychotropic prescribing for this age group, especially in antidepressant prescribing. In Australia, the vast majority of psychotropic medications prescribed to young people come from the general practice setting. To assess whether Australian General Practitioners (GPs) are prescribing in accordance with clinical guideline recommendations, this study examined trends in GP prescribing of psychotropic medications to young patients aged 16-24 years. METHODS: We performed a retrospective analysis of routine general practice data from 9112 patients aged 16-24 years with a MHC. Data were extracted from the Melbourne East Monash General Practice Database from 1/01/2009 to 31/12/2014. The main outcome measures included the number of consultations for patients with MHCs, psychotropic prescribing by GPs, and patient characteristics associated with the likelihood of being prescribed a psychotropic. RESULTS: In total, 9112 out of a total of 77,466 young patients were identified as having a MHC in this study, and 11,934 psychotropic prescriptions were provided to 3967 (43.5%) of them over the study period. Antidepressants accounted for 81.4% of total psychotropic prescriptions, followed by anxiolytics (9.6%) and antipsychotics (9.0%). The number of prescriptions issued to individuals with MHCs increased over time. Women and patients aged 21-24 years had higher incidence rates for prescription than men and those aged 16-17 (IRR: 1.15, 95% CI 1.08-1.22, IRR: 1.93, 95% CI 1.750-2.11). CONCLUSIONS: Our findings demonstrate an increasing trend in GP prescribing of psychotropics to young people over the study period with higher levels of prescribing to women and those 21-24 years of age. Although GP prescribing corresponded with guideline recommendations on the whole, there were discrepancies between GP's antidepressant prescribing and guideline recommendations, reasons for which were unclear. Research is needed to investigate GPs decision-making processes underlying their prescribing, to target interventions to improve existing data in GP records to improve management, and to identify areas of further training if needed to facilitate greater concordance between clinical practice and guideline recommendations. PMID- 28587609 TI - Hypertension with unsatisfactory sleep health (HUSH): study protocol for a randomized controlled trial. AB - BACKGROUND: Insomnia is common in primary care medical practices. Although behavioral treatments for insomnia are safe, efficacious, and recommended in practice guidelines, they are not widely-available, and their effects on comorbid medical conditions remain uncertain. We are conducting a pragmatic clinical trial to test the efficacy of two cognitive behavioral treatments for insomnia (Brief Behavioral Treatment for Insomnia (BBTI) and Sleep Healthy Using the Internet (SHUTi)) versus an enhanced usual care condition (EUC). METHODS/DESIGN: The study is a three-arm, parallel group, randomized controlled trial. Participants include 625 adults with hypertension and insomnia, recruited via electronic health records from primary care practices affiliated with a large academic medical center. After screening and baseline assessments, participants are randomized to treatment. BBTI is delivered individually with a live therapist via web interface/telehealth sessions, while SHUTi is a self-guided, automated, interactive, web-based form of cognitive behavioral therapy for insomnia. Participants in EUC receive an individualized sleep report, educational resources, and an online educational video. Treatment outcomes are measured at 9 weeks, 6 months, and 12 months. The primary outcome is patient-reported sleep disturbances. Secondary outcomes include other self-reported sleep measures, home blood pressure, body mass index, quality of life, health functioning, healthcare utilization, and side effects. DISCUSSION: This randomized clinical trial compares two efficacious insomnia interventions to EUC, and provides a cost effective and efficient examination of their similarities and differences. The pragmatic orientation of this trial may impact sleep treatment delivery in real world clinical settings and advance the dissemination and implementation of behavioral sleep interventions. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02508129 ; Date Registered: July 21, 2015). PMID- 28587611 TI - Chronic recurrent multifocal osteomyelitis beginning with a solitary lesion of the ilium. AB - BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is an idiopathic inflammatory disease. The initial lesions are typically found in the metaphyses, generally without periosteal reaction. CASE PRESENTATION: We present a case of a 14-year-old female teenager with relapsing and remitting right iliac pain. There was no evidence of infectious organisms, neoplastic processes, or hematologic malignancy based on laboratory tests. Initial computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated atypical periosteal proliferation in the right ilium. Histopathology demonstrated only non-specific chronic inflammation compatible with CRMO. Two years later, this patient developed left humeral pain. MRI and CT images revealed thickening and marrow edema involving the humeral cortex. CONCLUSIONS: This case highlights that CRMO can begin as a unifocal lesion and also possibly within the ilium, despite usually being multifocal and involving the long bone metaphysis. PMID- 28587612 TI - Lipodox(r) (generic doxorubicin hydrochloride liposome injection): in vivo efficacy and bioequivalence versus Caelyx(r) (doxorubicin hydrochloride liposome injection) in human mammary carcinoma (MX-1) xenograft and syngeneic fibrosarcoma (WEHI 164) mouse models. AB - BACKGROUND: Doxorubicin (DXR) hydrochloride (HCl) liposome injection is an important part of the treatment armamentarium for a number of cancers. With growing needs for affordable and effective anticancer treatments, the development of generics is becoming increasingly important to facilitate patient access to vital medications. We conducted studies in relevant mouse models of cancer to compare the preclinical antitumour efficacy and plasma pharmacokinetic profile of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceutical Industries Ltd. (SPIL DXR HCl liposome injection) with Caelyx(r) (reference DXR HCl liposome injection). METHODS: Syngeneic fibrosarcoma (WEHI 164)-bearing BALB/c mice and athymic nude mice transplanted with MX-1 human mammary carcinoma xenografts were treated with SPIL DXR HCl liposome injection, reference DXR HCl liposome injection or placebo, to compare tumour volume, antitumour activity (percentage test/control [%T/C] ratio, tumour regression, and specific tumour growth delay) and toxicity (survival and weight changes) in response to treatment. The pharmacokinetic profile of the SPIL and reference product was also studied in syngeneic fibrosarcoma-bearing mice. RESULTS: Treatment with either SPIL or reference DXR HCl liposome injection resulted in significant reduction in tumour volume from baseline in both models at all doses tested. High antitumour activity (%T/C <= 10) was seen from Day 21 and Day 14 onwards in SPIL and reference DXR HCl liposome injection-treated syngeneic fibrosarcoma-bearing mice, respectively, at 9 mg/kg. Moderate antitumour activity (%T/C <= 20) was seen from Day 17 and Day 24 onwards in SPIL and reference DXR HCl liposome injection treated MX-1-bearing mice, respectively, at 6 mg/kg. No significant differences in tumour volume and %T/C were observed between SPIL and reference DXR HCl liposome injection-treated groups at any dose (p >= 0.05). Toxicity profiles were considered to be generally comparable. Evaluation of test/reference (A/B) ratios and 90% confidence intervals (CIs) for peak serum concentration (Cmax) and area under the curve (AUC0-t, and AUC0-infinity) demonstrated bioequivalence of SPIL and reference DXR HCl liposome injections. CONCLUSIONS: Establishing similarity is of critical importance during the development of generic treatments. SPIL and reference DXR HCl liposome injections were shown to be comparable with regards to antitumour activity, toxicity and pharmacokinetics. PMID- 28587614 TI - Host specificity, molecular phylogeny and morphological differences of Phyllodistomum pseudofolium Nybelin, 1926 and Phyllodistomum angulatum Linstow, 1907 (Trematoda: Gorgoderidae) with notes on Eurasian ruffe as final host for Phyllodistomum spp. AB - BACKGROUND: Host-specificity patterns are not well-defined for trematodes of the genus Phyllodistomum Braun, 1899. The Eurasian ruffe, Gymnocephalus cernuus L., has been recorded as a definitive host for Phyllodistomum folium (Olfers, 1816), P. angulatum Linstow, 1907 and P. megalorchis Nybelin, 1926 and as the type-host for P. pseudofolium Nybelin (1926). A wide range of other host fishes have been recorded for these species as well. All present host records have been based on light microscopy and the life-cycles of P. pseudofolium, P. angulatum and P. megalorchis are unknown. The validity of P. pseudofolium and P. megalorchis require verification. In this study, rDNA sequences generated from adult Phyllodistomum spp., as well as from larval stages developing in Pisidium amnicum Muller, were analysed to establish the real number of Phyllodistomum species utilizing G. cernuus, and to associate larvae with the corresponding adult forms. RESULTS: Phylogenetic analyses of adult and larval stages of Phyllodistomum spp. based on ITS2 and partial 28S rDNA data allowed the confirmation of the validity of P. pseudofolium. A macrocercous cercaria, known as Phyllodistomum sp. from P. amnicum is genetically identical to adult P. pseudofolium. Phyllodistomum megalorchis obtained from its type-host, Lota lota L., showed no genetic differences from P. angulatum parasitizing Sander lucioperca L. In our analysis, P. pseudofolium, P. angulatum and P. macrocotyle formed a highly supported clade despite the fact that these species appear to be associated with distinct patterns of first intermediate host identity and cercarial morphology. Some morphological differences between gravid specimens of P. pseudofolium and P. angulatum were observed and their SEM tegumental surface topography is described. CONCLUSIONS: The results lead us to the perception that macroevolutionary host switching in the genus Phyllodistomum is independent of host phylogeny. This study suggests strict host-specificity (oioxeny) for P. pseudofolium using one first intermediate host species (P. amnicum) and one definitive host species (G. cernuus). Phyllodistomum megalorchis is to be regarded as a synonym of P. angulatum. The close phylogenetic relatives, P. pseudofolium and P. angulatum, can be differentiated by morphological traits, the micromorphology and tegumental surface topography of these two species is intended to provide useful data for their identification and support the use of such features as a valuable taxonomic criterion. Molecular data showed that G. cernuus is a definitive host for two species: the oioxenous P. pseudofolium and the euryxenous P. folium. PMID- 28587615 TI - Genome-wide scans for the identification of Plasmodium vivax genes under positive selection. AB - BACKGROUND: The current trend of Plasmodium vivax cases imported from Southeast Asia into China has sharply increased recently, especially from the China-Myanmar border (CMB) area. High recombination rates of P. vivax populations associated with varied transmission intensity might cause distinct local selective pressures. The information on the genetic variability of P. vivax in this area is scant. Hence, this study assessed the genetic diversity of P. vivax genome sequence in CMB area and aimed to provide information on the positive selection of new gene loci. RESULTS: This study reports a genome-wide survey of P. vivax in CMB area, using blood samples from local patients to identify population-specific selective processes. The result showed that considerable genetic diversity and mean pair-wise divergence among the sequenced P. vivax isolates were higher in some important gene families. Using the standardized integrated haplotype score (|iHS|) for all SNPs in chromosomal regions with SNPs above the top 1% distribution, it was observed that the top score locus involved 356 genes and most of them are associated with red blood cell invasion and immune evasion. The XP-EHH test was also applied and some important genes associated with anti malarial drug resistance were observed in high positive scores list. This result suggests that P. vivax in CMB area is facing more pressure to survive than any other region and this has led to the strong positive selection of genes that are associated with host-parasite interactions. CONCLUSIONS: This study suggests that greater genetic diversity in P. vivax from CMB area and positive selection signals in invasion and drug resistance genes are consistent with the history of drug use during malaria elimination programme in CMB area. Furthermore, this result also demonstrates that haplotype-based detecting selection can assist the genome-wide methods to identify the determinants of P. vivax diversity. PMID- 28587613 TI - Prognostic value of plasma DPP4 activity in ST-elevation myocardial infarction. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP4) regulates blood glucose levels and inflammation, and it is also implicated in the pathophysiological process of myocardial infarction (MI). Plasma DPP4 activity (DPP4a) may provide prognostic information regarding outcomes for ST-segment elevation MI (STEMI) patients. METHODS: Blood samples were obtained from 625 consecutively admitted, percutaneous coronary intervention-treated STEMI patients with a mean age of 57 years old. DPP4a was quantified using enzymatic assays. RESULTS: The median follow-up period was 30 months. Multivariate Cox-regression analyses (adjusted for confounding variables) showed that a 1 U/L increase of DPP4a did not associate with risks of major adverse cardiac or cerebrovascular events (MACCE), cardiovascular mortality, MI, heart failure readmission, stroke, non cardiovascular mortality and repeated revascularization. However, in a subset of 149 diabetic STEMI patients, DPP4a associated with an increased risk of MACCE (HR 1.16; 95% CI 1.04-1.30; p = 0.01). CONCLUSIONS: DPP4a did not associate with cardiovascular events and non-cardiovascular mortality in non-diabetic STEMI patients. However, DPP4a may be associated with future MACCE in diabetic STEMI patients. Trial registration NCT03046576, registered on 5 February, 2017, retrospectively registered. PMID- 28587616 TI - A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): study protocol for a randomised controlled trial. AB - BACKGROUND: Delayed graft function (DGF) is traditionally defined as the requirement for dialysis during the first week after transplantation. DGF is a common complication of renal transplantation, and it negatively affects short- and long-term graft outcomes. Ischaemia reperfusion injury (IRI) is a prime contributor to the development of DGF. It is well established that complement system activation plays a pivotal role in the pathogenesis of IRI. Mirococept is a highly effective complement inhibitor that can be administered ex vivo to the donor kidney just before transplantation. Preclinical and clinical evidence suggests that Mirococept inhibits inflammatory responses that follow IRI. The EMPIRIKAL trial (REC 12/LO/1334) aims to evaluate the efficacy of Mirococept in reducing the incidence of DGF in cadaveric renal transplantation. METHODS/DESIGN: EMPIRIKAL is a multicentre double-blind randomised case-control trial designed to test the superiority of Mirococept in the prevention of DGF in cadaveric renal allografts, as compared to standard cold perfusion fluid (Soltran(r)). Patients will be randomised to Mirococept or placebo (Pbo) and will be enrolled in cohorts of N = 80 with a maximum number of 7 cohorts. The first cohort will be randomised to 10 mg of Mirococept or Pbo. After the completion of each cohort, an interim analysis will be carried out in order to evaluate the dose allocation for the next cohort (possible doses: 5-25 mg). Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. The enrolment will take approximately 24 months, and patients will be followed for 12 months. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Secondary endpoints include duration of DGF, functional DGF, renal function at 12 months, acute rejection episodes at 6 and 12 months, primary non-function and time of hospital stay on first admission and in the first year following transplant. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. DISCUSSION: The EMPIRIKAL trial is the first study to evaluate the efficacy of an ex vivo administered complement inhibitor (Mirococept) in preventing DGF in cadaveric human renal transplantation. Mirococept has a unique 'cytotopic' property that permits its retention in the organ microvasculature. TRIAL REGISTRATION: ISRCTN registry, ISRCTN49958194 . Registered on 3 August 2012. PMID- 28587617 TI - Construction of energy-conserving sucrose utilization pathways for improving poly gamma-glutamic acid production in Bacillus amyloliquefaciens. AB - BACKGROUND: Sucrose is an naturally abundant and easily fermentable feedstock for various biochemical production processes. By now, several sucrose utilization pathways have been identified and characterized. Among them, the pathway consists of sucrose permease and sucrose phosphorylase is an energy-conserving sucrose utilization pathway because it consumes less ATP when comparing to other known pathways. Bacillus amyloliquefaciens NK-1 strain can use sucrose as the feedstock to produce poly-gamma-glutamic acid (gamma-PGA), a highly valuable biopolymer. The native sucrose utilization pathway in NK-1 strain consists of phosphoenolpyruvate-dependent phosphotransferase system and sucrose-6-P hydrolase and consumes more ATP than the energy-conserving sucrose utilization pathway. RESULTS: In this study, the native sucrose utilization pathway in NK-1 was firstly deleted and generated the B. amyloliquefaciens 3Delta strain. Then four combination of heterologous energy-conserving sucrose utilization pathways were constructed and introduced into the 3Delta strain. Results demonstrated that the combination of cscB (encodes sucrose permease) from Escherichia coli and sucP (encodes sucrose phosphorylase) from Bifidobacterium adolescentis showed the highest sucrose metabolic efficiency. The corresponding mutant consumed 49.4% more sucrose and produced 38.5% more gamma-PGA than the NK-1 strain under the same fermentation conditions. CONCLUSIONS: To our best knowledge, this is the first report concerning the enhancement of the target product production by introducing the heterologous energy-conserving sucrose utilization pathways. Such a strategy can be easily extended to other microorganism hosts for reinforced biochemical production using sucrose as substrate. PMID- 28587618 TI - Effect of tryptase inhibition on joint inflammation: a pharmacological and lentivirus-mediated gene transfer study. AB - BACKGROUND: Increasing evidences indicate that an unbalance between tryptases and their endogenous inhibitors, leading to an increased proteolytic activity, is implicated in the pathophysiology of rheumatoid arthritis. The aim of the present study was to evaluate the impact of tryptase inhibition on experimental arthritis. METHODS: Analysis of gene expression and regulation in the mouse knee joint was performed by RT-qPCR and in situ hybridization. Arthritis was induced in male C57BL/6 mice with mBSA/IL-1beta. Tryptase was inhibited by two approaches: a lentivirus-mediated heterologous expression of the human endogenous tryptase inhibitor, sperm-associated antigen 11B isoform C (hSPAG11B/C), or a chronic treatment with the synthetic tryptase inhibitor APC366. Several inflammatory parameters were evaluated, such as oedema formation, histopathology, production of IL-1beta, -6, -17A and CXCL1/KC, myeloperoxidase and tryptase-like activities. RESULTS: Spag11c was constitutively expressed in chondrocytes and cells from the synovial membrane in mice, but its expression did not change 7 days after the induction of arthritis, while tryptase expression and activity were upregulated. The intra-articular transduction of animals with the lentivirus phSPAG11B/C or the treatment with APC366 inhibited the increase of tryptase-like activity, the late phase of oedema formation, the production of IL-6 and CXCL1/KC. In contrast, neutrophil infiltration, degeneration of hyaline cartilage and erosion of subchondral bone were not affected. CONCLUSIONS: Tryptase inhibition was effective in inhibiting some inflammatory parameters associated to mBSA/IL-1beta-induced arthritis, notably late phase oedema formation and IL-6 production, but not neutrophil infiltration and joint degeneration. These results suggest that the therapeutic application of tryptase inhibitors to rheumatoid arthritis would be restrained to palliative care, but not as disease-modifying drugs. Finally, this study highlighted lentivirus-based gene delivery as an instrumental tool to study the relevance of target genes in synovial joint physiology and disease. PMID- 28587619 TI - Contraceptive practices among married women of reproductive age in Bangladesh: a review of the evidence. AB - BACKGROUND: Bangladesh has experienced a sevenfold increase in its contraceptive prevalence rate (CPR) in less than forty years from 8% in 1975 to 62% in 2014. However, despite this progress, almost one-third of pregnancies are still unintended which may be attributed to unmet need for family planning and discontinuation and switching of methods after initiation of their use. METHODS: We conducted an extensive literature review on contraceptive use among married women of reproductive age (MWRA) in Bangladesh. A total of 263 articles were identified through database search and after final screening ten articles were included in this synthesis. RESULTS: Findings showed that method discontinuation and switching, method failure, and method mix may offset achievements in the CPR. Most of the women know of at least one contraceptive method. Oral pill is the most widely used (27%) method, followed by injectables (12.4%), condoms (6.4%), female sterilization (4.6%), male sterilization (1.2%), implants (1.7%), and IUDs (0.6%). There has been a decline in the use of long acting and permanent methods over the last two decades. Within 12 months of initiation, the rate of method discontinuation particularly the short-acting methods remain high at 36%. It is important to recognize the trends as married Bangladeshi women, on average, wanted 1.6 children, but the rate of actual children was 2.3. CONCLUSIONS: A renewed commitment from government bodies and independent organizations is needed to implement and monitor family planning strategies in order to ensure the adherence to and provision of the most appropriate contraceptive method for couples. PMID- 28587620 TI - Comparing the effect of buprenorphine and methadone in the reduction of methamphetamine craving: a randomized clinical trial. AB - BACKGROUND: We sought to test the effectiveness of methadone and buprenorphine in the treatment of methamphetamine withdrawal craving over a 17-day treatment period. METHODS: Patients were randomized into one of two groups. The study sample comprised 40 male subjects dependent on methamphetamine who met criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, for methamphetamine dependence and withdrawal and were seeking treatment. Furthermore, they should have a history of daily methamphetamine use for at least 6 months and should have discontinued their use just before starting the protocol. Patients received 40 mg of methadone or 8 mg of buprenorphine per day and were treated in an inpatient psychiatric hospital. We used methamphetamine craving score, negative urine drug screening test (thin-layer chromatography) during the study, and retention in treatment. RESULTS: All 40 patients completed the study. Both drugs were effective in decreasing methamphetamine craving during methamphetamine withdrawal. Reduction of craving in the buprenorphine group was significantly more than in the methadone group (P < 0.05). CONCLUSIONS: The results favor the efficacy and safety of buprenorphine as a short-term treatment for methamphetamine withdrawal craving. We should mention that it is to be expected that craving declines over time without any medication. Therefore, the conclusion may not be that methadone and buprenorphine both reduce the craving. Because buprenorphine is superior to methadone, only buprenorphine surely reduces craving. TRIAL REGISTRATION: Iranian Registry of Clinical Trials identifier: IRCT2015112125160N1 . Registered on 4 June 2016. PMID- 28587621 TI - Comparing counselling models for the hazardous use of alcohol at the Swedish National Alcohol Helpline: study protocol for a randomised controlled trial. AB - BACKGROUND: Hazardous and harmful consumption of alcohol is a leading cause of preventable disease and premature deaths. Modifying the amount and pattern of risky alcohol consumption conveys substantial benefits to individuals and to society at large. Telephone helplines provide a feasible alternative to face-to face counselling in order to increase the reach of brief interventions aiming at modifying the hazardous and harmful use of alcohol. However, there is a lack of studies on the implementation and evaluation of population-based telephone services for the prevention and treatment of alcohol misuse. METHODS/DESIGN: A randomised controlled trial was designed to compare a brief, structured intervention to usual care within the Swedish National Alcohol Helpline (SAH), concerning their effectiveness on decreasing the hazardous use of alcohol. Between May 2015 and December 2017, about 300 callers are to be individually randomised with a 1:1 ratio to a brief, structured intervention (n = 150) or to usual care (n = 150). The brief, structured intervention consists of the delivery of a self-help booklet followed by one proactive call from SAH counsellors to monitor and give feedback about the client's progression. Callers assigned to usual care receive telephone counselling according to existing practice, i.e., motivational interviewing in a tailored and client-driven combination of proactive and reactive calls. The primary outcome is defined as a change from a higher to a lower AUDIT risk-level category between baseline and follow-up. General linear modeling will be used to calculate risk ratios of the outcome events. The primary analysis will follow an intention-to-treat (ITT) approach. DISCUSSION: The trial is designed to evaluate the effectiveness in decreasing the hazardous and harmful consumption of alcohol of a brief, structured intervention compared to usual care when delivered at the SAH. The results of the study will be used locally to improve the effectiveness of the service provided at the SAH. Additionally, they will expand the evidence base about optimal counselling models in population-based telephone services for alcohol misuse prevention and treatment. TRIAL REGISTRATION: ISRCNT.com, ID: ISRCTN13160878 . Retrospectively registered on 18 January 2016. PMID- 28587622 TI - The validity and reliability of the Mandarin Chinese version of the drug abuse screening test among adolescents in Taiwan. AB - BACKGROUND: This study aimed to investigate the validity and reliability of the Mandarin Chinese version of the Drug Abuse Screening Test (DAST-20) among adolescents, as well as examining the test's predictability with regard to the actual level of drug abuse. METHOD: A total of 100 adolescent participants were recruited with their consent, in which 49 were current drug users and 51 were non users. Based on the frequency of their drug use, participants who had used drugs at least once every week during the past year were classified as regular users (34 participants); participants who had not reached the regular use frequency of once every week during the past year were classified as occasional users (15 participants). All of the participants were required to answer a sociodemographic questionnaire, and undergo a DAST-20 (Mandarin Chinese version). RESULTS: The DAST-20, which has a high reliability with a Cronbach's alpha of 0.88, and a construct validity accounting for 61.87% of the variance. The area under the receiver operating characteristics (ROC) curve was 0.96 between the users and nonusers, and 0.93 between the occasional users and non-occasional users. A cut off of three points could identify 93.5% of the drug users and 88.9% of nonusers, whereas a cut-off of six points could identify 85.3% of the regular users and 92.4% of non-regular users. CONCLUSIONS: The DAST-20 was the strongest predictor of adolescents who were regular users, occasional users, and non-users after controlling for other potential covariates. The Mandarin Chinese version of the DAST is simple to use and has a satisfactory validity and reliability. It is an effective screening tool for drug users among adolescents. PMID- 28587623 TI - Intersection of neighborhood dynamics and socioeconomic status in small-area walkability: the Heart Healthy Hoods project. AB - BACKGROUND: Previous studies found a complex relationship between area-level socioeconomic status (SES) and walkability. These studies did not include neighborhood dynamics. Our aim was to study the association between area-level SES and walkability in the city of Madrid (Spain) evaluating the potential effect modification of neighborhood dynamics. METHODS: All census sections of the city of Madrid (n = 2415) were included. Area-level SES was measured using a composite index of 7 indicators in 4 domains (education, wealth, occupation and living conditions). Two neighborhood dynamics factors were computed: gentrification, proxied by change in education levels in the previous 10 years, and neighborhood age, proxied by median year of construction of housing units in the area. Walkability was measured using a composite index of 4 indicators (Residential Density, Population Density, Retail Destinations and Street Connectivity). We modeled the association using linear mixed models with random intercepts. RESULTS: Area-level SES and walkability were inversely and significantly associated. Areas with lower SES showed the highest walkability. This pattern did not hold for areas with an increase in education level, where the association was flat (no decrease in walkability with higher SES). Moreover, the association was attenuated in newly built areas: the association was stronger in areas built before 1975, weaker in areas built between 1975 and 1990 and flat in areas built from 1990 on. CONCLUSION: Areas with higher neighborhood socioeconomic status had lower walkability in Madrid. This disadvantage in walkability was not present in recently built or gentrified areas. PMID- 28587624 TI - Genome analysis of the thermoacidophilic archaeon Acidianus copahuensis focusing on the metabolisms associated to biomining activities. AB - BACKGROUND: Several archaeal species from the order Sulfolobales are interesting from the biotechnological point of view due to their biomining capacities. Within this group, the genus Acidianus contains four biomining species (from ten known Acidianus species), but none of these have their genome sequenced. To get insights into the genetic potential and metabolic pathways involved in the biomining activity of this group, we sequenced the genome of Acidianus copahuensis ALE1 strain, a novel thermoacidophilic crenarchaeon (optimum growth: 75 degrees C, pH 3) isolated from the volcanic geothermal area of Copahue at Neuquen province in Argentina. Previous experimental characterization of A. copahuensis revealed a high biomining potential, exhibited as high oxidation activity of sulfur and sulfur compounds, ferrous iron and sulfide minerals (e.g.: pyrite). This strain is also autotrophic and tolerant to heavy metals, thus, it can grow under adverse conditions for most forms of life with a low nutrient demand, conditions that are commonly found in mining environments. RESULTS: In this work we analyzed the genome of Acidianus copahuensis and describe the genetic pathways involved in biomining processes. We identified the enzymes that are most likely involved in growth on sulfur and ferrous iron oxidation as well as those involved in autotrophic carbon fixation. We also found that A. copahuensis genome gathers different features that are only present in particular lineages or species from the order Sulfolobales, some of which are involved in biomining. We found that although most of its genes (81%) were found in at least one other Sulfolobales species, it is not specifically closer to any particular species (60-70% of proteins shared with each of them). Although almost one fifth of A. copahuensis proteins are not found in any other Sulfolobales species, most of them corresponded to hypothetical proteins from uncharacterized metabolisms. CONCLUSION: In this work we identified the genes responsible for the biomining metabolisms that we have previously observed experimentally. We provide a landscape of the metabolic potentials of this strain in the context of Sulfolobales and propose various pathways and cellular processes not yet fully understood that can use A. copahuensis as an experimental model to further understand the fascinating biology of thermoacidophilic biomining archaea. PMID- 28587625 TI - Anti-nuclear autoantibodies in the general German population: prevalence and lack of association with selected cardiovascular and metabolic disorders-findings of a multicenter population-based study. AB - BACKGROUND: We determined the prevalence of anti-nuclear autoantibodies (ANAs) in the German adult population and examined the association between ANAs and cardiovascular and metabolic disorders. METHODS: We used data and blood samples from the pretest phases of the German National Cohort, obtained from six of the 18 study centers (n = 1199). All centers applied standardized instruments including face-to-face interviews, anthropometric measurements and collection of blood samples. Self-reported histories of diabetes mellitus, heart attack and elevated blood cholesterol and/or lipids were recorded. Height, weight and blood pressure were measured. ANAs were detected using a semi-automated system (AKLIDES(r); Medipan GmbH, Dahlewitz, Germany). A positive ANA was defined as a titer >= 1:80. ANA were classified as weakly (1:80 or 1:160), moderately (1:320 or 1:640) or strongly (>=1:1280) positive. Specific autoantibodies against nuclear antigens were detected with second-step assays according to the ANA staining pattern. Associations between the assessed disorders and ANA positivity and pattern were examined using sex and age-adjusted mixed-effects logistic regression models. RESULTS: Thirty-three percent (95% confidence interval; 31 36%) of the 1196 participants (measurements could not be obtained from three samples) were ANA positive (titer >= 1:80). The proportions of weakly, moderately and strongly positive ANA were 29%, 3.3% and 1.3%, respectively. ANA positivity was more common among women than men across all titers (chi2, p = 0.03). ANA positivity, even when stratified according to height of titer or immunofluorescent pattern, was not associated with diabetes, elevated blood cholesterol and/or lipids, obesity or hypertension. Second-step autoantibody assays were positive in 41 of the 83 samples (49%) tested, with anti-DFS70 (n = 13) and anti-dsDNA (n = 7) being most frequent. These subgroups were too small to test for associations with the disorders assessed. CONCLUSIONS: The prevalence of ANA positivity in the German general population was similar to values reported from other countries. Contrary to other studies, there was no association with selected self-reported and objectively measured cardiovascular and metabolic variables. PMID- 28587626 TI - Evaluation of a novel antibody to define histone 3.3 G34R mutant brain tumours. AB - Missense somatic mutations affecting histone H3.1 and H3.3 proteins are now accepted as the hallmark of paediatric diffuse intrinsic pontine gliomas (DIPG), non-brain stem paediatric high grade gliomas (pHGG) as well as a subset of adult glioblastoma multiforme (GBM). Different mutations give rise to one of three amino acid substitutions at two critical positions within the histone tails, K27M, G34R/V. Several studies have highlighted gene expression and epigenetic changes associated with histone H3 mutations; however their precise roles in tumourigenesis remain incompletely understood. Determining how such amino acid substitutions in a protein affect its properties can be challenging because of difficulties in detecting and tracking mutant proteins within cells and tissues. Here we describe a strategy for the generation of antibodies to discriminate G34R and G34V mutant histone H3 proteins from their wild-type counterparts. Antibodies were validated by western blotting and immunocytochemistry, using recombinant H3.3 proteins and paediatric GBM cell lines. The H3-G34R antibody demonstrated a high degree of selectivity towards its target sequence. Accordingly, immunostaining on a cohort of 22 formalin-fixed paraffin embedded tumours with a previously known H3.3 G34R mutation status, detected successfully the corresponding mutant protein in 11/11 G34R cases. Since there was a high concordance between genotype and immunohistochemical analysis of G34R mutant tumour samples, we analysed a series of tissue microarrays (TMAs) to assess the specificity of the antibody in a range of paediatric brain tumours, and noted immunoreactivity in 2/634 cases. Importantly, we describe the generation and validation of highly specific antibodies for G34 mutations. Overall our work adds to an extremely valuable portfolio of antibodies, not only for histopathologic detection of tumour-associated mutant histone sequences, but also facilitating the study of spatial/anatomical aspects of tumour formation and the identification of downstream targets and pathways in malignant glioma progression. PMID- 28587627 TI - Analysis of the lipid body proteome of the oleaginous alga Lobosphaera incisa. AB - BACKGROUND: Lobosphaera incisa (L. incisa) is an oleaginous microalga that stores triacylglycerol (TAG) rich in arachidonic acid in lipid bodies (LBs). This organelle is gaining attention in algal research, since evidence is accumulating that proteins attached to its surface fulfill important functions in TAG storage and metabolism. RESULTS: Here, the composition of the LB proteome in L incisa was investigated by comparing different cell fractions in a semiquantitative proteomics approach. After applying stringent filters to the proteomics data in order to remove contaminating proteins from the list of possible LB proteins (LBPs), heterologous expression of candidate proteins in tobacco pollen tubes, allowed us to confirm 3 true LBPs: A member of the algal Major Lipid Droplet Protein family, a small protein of unknown function and a putative lipase. In addition, a TAG lipase that belongs to the SUGAR DEPENDENT 1 family of TAG lipases known from oilseed plants was identified. Its activity was verified by functional complementation of an Arabidopsis thaliana mutant lacking the major seed TAG lipases. CONCLUSIONS: Here we describe 3 LBPs as well as a TAG lipase from the oleaginous microalga L. incisa and discuss their possible involvement in LB metabolism. This study highlights the importance of filtering LB proteome datasets and verifying the subcellular localization one by one, so that contaminating proteins can be recognized as such. Our dataset can serve as a valuable resource in the identification of additional LBPs, shedding more light on the intriguing roles of LBs in microalgae. PMID- 28587628 TI - Osteoclast profile of medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy: a comparison with osteoradionecrosis and osteomyelitis. AB - BACKGROUND: The medication-related osteonecrosis of the jaw secondary to bisphosphonate therapy [MRONJ (BP)] is characterized by non-healing exposed bone in the maxillofacial region. The pathogenesis of MRONJ (BP) is not fully understood. Giant, hypernucleated, inactive osteoclasts were found in MRONJ (BP) tissues, which indicated that accelerated cell-cell fusion might play a role. Dendritic cell-specific transmembrane protein (DC-STAMP) is associated with the cell-cell fusion of osteoclasts and precursor cells. Tartrate-resistant acid phosphatase (TRAP) is essential for osteoclastic bone resorption. The cell-cell fusion, as part of the osteoclastogenesis, and the resorptive activity can determine the morphology of osteoclasts. This study analyzed jaw bone from patients with MRONJ (BP), osteomyelitis (OM) and osteoradionecrosis (ORN) because a comparison with the osteoclast profiles of OM and ORN is essential for characterizing the osteoclast profile of MRONJ (BP). METHODS: Formalin-fixed routine jaw bone specimens from 70 patients [MRONJ (BP) n = 30; OM: n = 15, ORN: n = 15, control: n = 10] were analyzed retrospectively for osteoclast quantity, morphology and the expression of TRAP and DC-STAMP. The specimens were processed for hematoxylin and eosin staining (H&E), histochemistry (TRAP) and immunohistochemistry (anti-DC-STAMP) and were analyzed via virtual microscopy. RESULTS: The quantity, diameter and nuclearity of osteoclasts were significantly higher in MRONJ (BP) specimens than in OM, ORN and control specimens. Giant, hypernucleated osteoclasts were detected in MRONJ (BP) specimens only. Osteoclastic TRAP expression was lower in MRONJ (BP) and ORN specimens than in OM and control specimens. The DC-STAMP expression of osteoclasts and mononuclear cells was significantly higher in MRONJ (BP) and ORN specimens than in OM and control specimens. CONCLUSIONS: This study indicates that the osteoclast profile of MRONJ (BP) is characterized by osteoclast inactivation and a high cell-cell fusion rate; however, the presence of giant, hypernucleated osteoclasts cannot be attributed to increased DC-STAMP-triggered cell-cell fusion alone. The incidental characterization of the osteoclast profiles of OM and ORN revealed differences that might facilitate the histopathological differentiation of these diseases from MRONJ (BP), which is essential because their therapies are somewhat different. PMID- 28587630 TI - Pulmonary arterial hypertension in scleroderma: care gaps in screening. AB - One in six patients with systemic sclerosis will develop pulmonary arterial hypertension (PAH). Screening with echocardiography and possibly pulmonary function testing (to determine the diffusing capacity of carbon monoxide) is recommended to detect PAH at a less severe stage. However, real-world screening programs have problems. Registries where echocardiograms are to be performed annually should have the best-case scenario of nearly perfect screening and referral for right heart catheterization of those highly suspect for PAH. However, registries demonstrate care gaps where patients are not referred for appropriate confirmatory testing when PAH is suspected. PMID- 28587629 TI - Efficacy of the Ubiquitous Spaced Retrieval-based Memory Advancement and Rehabilitation Training (USMART) program among patients with mild cognitive impairment: a randomized controlled crossover trial. AB - BACKGROUND: Spaced retrieval training (SRT) is a nonpharmacological intervention for mild cognitive impairment (MCI) and dementia that trains the learning and retention of target information by recalling it over increasingly long intervals. We recently developed the Ubiquitous Spaced Retrieval-based Memory Advancement and Rehabilitation Training (USMART) program as a convenient, self-administered tablet-based SRT program. We also demonstrated the utility of USMART for improving memory in individuals with MCI through an open-label uncontrolled trial. METHODS: This study had an open-label, single-blind, randomized, controlled, two-period crossover design. Fifty patients with MCI were randomized into USMART-usual care and usual care-USMART treatment sequences. USMART was completed or usual care was provided biweekly over a 4-week treatment period with a 2-week washout period between treatment periods. Primary outcome measures included the Word List Memory Test, Word List Recall Test (WLRT), and Word List Recognition Test. Outcomes were measured at baseline, week 5, and week 11 by raters who were blinded to intervention type. An intention-to-treat analysis and linear mixed modeling were used. RESULTS: Of 50 randomized participants, 41 completed the study (18% dropout rate). The USMART group had larger improvements in WLRT score (effect size = 0.49, p = 0.031) than the usual care group. There were no significant differences in other primary or secondary measures between the USMART and usual care groups. Moreover, no USMART-related adverse events were reported. CONCLUSIONS: The 4-week USMART modestly improved information retrieval in older people with MCI, and was well accepted with minimal technical support. TRIAL REGISTRATION: ClinicalTrials.gov NCT01688128 . Registered 12 September 2012. PMID- 28587631 TI - Bacterial etiologic agents causing neonatal sepsis and associated risk factors in Gondar, Northwest Ethiopia. AB - BACKGROUND: Neonatal sepsis is a blood stream infection which is seen in the first month of life of the neonate. Bacterial profile of neonatal septicemia is constantly changing thus, current knowledge on the patterns of bacterial isolates, its antibiotic resistance profile, and associated factors, are essential to design and implement appropriate interventions. Therefore, the aim of this study was to identify bacterial etiologic agents, their antimicrobial susceptibility pattern and associated risk factors of neonatal sepsis among neonates. METHODS: A cross- sectional study was conducted among neonates suspected to sepsis attending University of Gondar Hospital from September/2015 to May/2016. A total of 251 consecutive neonates with clinical sign and symptoms of sepsis were included in the study. Blood sample was collected and directly inoculated into Trypton soya broth bottle and incubated at 37 degrees C. After 24 h of incubation it was sub- cultured in to blood agar plate, chocolate agar plate, manitol salt agar and Macconkey. The bacterial pathogens and antimicrobial susceptibility tests were identified using standard microbiological methods. Bivariate and multivariate logistic regressions were used to identify possible associated risk factors. Prior to the study ethical clearance was obtained from the School of Biomedical and Laboratory Sciences, University of Gondar. RESULTS: Of the 251 study participants suspected of neonatal sepsis, 117 (46.6%) showed bacterial growths, of them 120 bacteria were isolated. Gram positive bacteria were commonly isolated 81 (67.5%).The commonly isolated bacterial species were S. aureus 49 (40.8%) followed by coagulase negative Staphylococci 26 (21.6%) and K. pneumoniae19 (15.8%). The overall rate of multidrug resistance isolates was 78 (65%: CI 95%: 56.7-72.5%). Multidrug resistant (MDR) among Gram positive and negative bacteria were 56 (69.1%) and 22 (56.4%), respectively. Independent risk factors for the occurrence of neonatal sepsis were; Apgar score < 7/5 min (Adjusted odds ratio [AOR] =0.5), birth weight < 1.5 kg (AOR = 12.37), birth weight, 1.5-2.5 kg (AOR = 2.6), gestational week <37 weeks (AOR = 9) and caesarian section delivery (AOR = 5.2). CONCLUSION: The isolation rate of bacterial pathogens in neonatal sepsis was considerably high. In addition, nearly 70% of isolates were MDR strains. Low birth weight, low Apgar score, preterm delivery and caesarian section modes of delivery were associated risk factors. Therefore, appropriate antenatal care follow up, and health education should be encouraged, especially on the importance of natural way of delivery. PMID- 28587632 TI - Meta-analysis of cell- specific transcriptomic data using fuzzy c-means clustering discovers versatile viral responsive genes. AB - BACKGROUND: Despite advances in the gene-set enrichment analysis methods; inadequate definitions of gene-sets cause a major limitation in the discovery of novel biological processes from the transcriptomic datasets. Typically, gene-sets are obtained from publicly available pathway databases, which contain generalized definitions frequently derived by manual curation. Recently unsupervised clustering algorithms have been proposed to identify gene-sets from transcriptomics datasets deposited in public domain. These data-driven definitions of the gene-sets can be context-specific revealing novel biological mechanisms. However, the previously proposed algorithms for identification of data-driven gene-sets are based on hard clustering which do not allow overlap across clusters, a characteristic that is predominantly observed across biological pathways. RESULTS: We developed a pipeline using fuzzy-C-means (FCM) soft clustering approach to identify gene-sets which recapitulates topological characteristics of biological pathways. Specifically, we apply our pipeline to derive gene-sets from transcriptomic data measuring response of monocyte derived dendritic cells and A549 epithelial cells to influenza infections. Our approach apply Ward's method for the selection of initial conditions, optimize parameters of FCM algorithm for human cell-specific transcriptomic data and identify robust gene-sets along with versatile viral responsive genes. CONCLUSION: We validate our gene-sets and demonstrate that by identifying genes associated with multiple gene-sets, FCM clustering algorithm significantly improves interpretation of transcriptomic data facilitating investigation of novel biological processes by leveraging on transcriptomic data available in the public domain. We develop an interactive 'Fuzzy Inference of Gene-sets (FIGS)' package (GitHub: https://github.com/Thakar-Lab/FIGS ) to facilitate use of of pipeline. Future extension of FIGS across different immune cell-types will improve mechanistic investigation followed by high-throughput omics studies. PMID- 28587633 TI - Insidious intraoperative ureteral injury as a complication in oblique lumbar interbody fusion surgery: a case report. AB - BACKGROUND: Oblique lumbar interbody fusion surgery is a recently introduced minimally invasive lateral interbody fusion surgery for degenerative lumbar disease. There have been no reports of associated ureteral injury. CASE PRESENTATION: A 77-year-old Japanese woman underwent oblique lumbar interbody fusion surgery for lumbar spondylolisthesis with refractory low back pain and pain in both legs. The patient experienced abdominal pain 2 days after surgery. Delayed contrast-enhanced computed tomography and retrograde urography revealed leakage of contrasted urine from the ureter into the retroperitoneal space, indicating a ureteral injury. Immediate percutaneous nephrostomy was performed to recover her condition, followed by additional ureteral stenting. She is now free from preoperative symptoms but requires periodic changing of the ureteral stent, with no urinary symptoms. CONCLUSION: The current report described a rare but possible case of ureteral injury following oblique lumbar interbody fusion surgery. Iatrogenic ureteral injury, as reported in the current case, is uncommon following oblique lumbar interbody fusion surgery, and the injury may have been caused by a procedural error. Considering the findings from urological examinations, we speculate that the thread pin that fixates the retractor injured the ureter during its installation. This case highlights the importance of careful attention while exposing the retroperitoneal space to avoid minor organs, including the ureters, as well as major organs. Ureteral injuries should ideally be detected and diagnosed as soon as possible by careful physical and radiological examinations, such as with delayed contrast-enhanced computed tomography and retrograde urography, to salvage the injured nephroureteral system. The current report also highlights that careful use of surgical instruments is key for preventing intraoperative complications, including ureteral injury. PMID- 28587634 TI - Sinapic acid or its derivatives interfere with abscisic acid homeostasis during Arabidopsis thaliana seed germination. AB - BACKGROUND: Sinapic acid and its esters have broad functions in different stages of seed germination and plant development and are thought to play a role in protecting against ultraviolet irradiation. To better understand the interactions between sinapic acid esters and seed germination processes in response to various stresses, we analyzed the role of the plant hormone abscisic acid (ABA) in the regulation of sinapic acid esters involved in seed germination and early seedling growth. RESULTS: We found that exogenous sinapic acid promotes seed germination in a dose-dependent manner in Arabidopsis thaliana. High-performance liquid chromatography mass spectrometry analysis showed that exogenous sinapic acid increased the sinapoylcholine content of imbibed seeds. Furthermore, sinapic acid affected ABA catabolism, resulting in reduced ABA levels and increased levels of the ABA-glucose ester. Using mutants deficient in the synthesis of sinapate esters, we showed that the germination of mutant sinapoylglucose accumulator 2 (sng2) and bright trichomes 1 (brt1) seeds was more sensitive to ABA than the wild-type. Moreover, Arabidopsis mutants deficient in either abscisic acid deficient 2 (ABA2) or abscisic acid insensitive 3 (ABI3) displayed increased expression of the sinapoylglucose:choline sinapoyltransferase (SCT) and sinapoylcholine esterase (SCE) genes with sinapic acid treatment. This treatment also affected the accumulation of sinapoylcholine and free choline during seed germination. CONCLUSIONS: We demonstrated that sinapoylcholine, which constitutes the major phenolic component in seeds among various minor sinapate esters, affected ABA homeostasis during seed germination and early seedling growth in Arabidopsis. Our findings provide insights into the role of sinapic acid and its esters in regulating ABA-mediated inhibition of Arabidopsis seed germination in response to drought stress. PMID- 28587636 TI - Recognizing RNA structural motifs in HT-SELEX data for ribosomal protein S15. AB - BACKGROUND: Proteins recognize many different aspects of RNA ranging from single stranded regions to discrete secondary or tertiary structures. High-throughput sequencing (HTS) of in vitro selected populations offers a large scale method to study RNA-proteins interactions. However, most existing analysis methods require that the binding motifs are enriched in the population relative to earlier rounds, and that motifs are found in a loop or single stranded region of the potential RNA secondary structure. Such methods do not generalize to all RNA protein interaction as some RNA binding proteins specifically recognize more complex structures such as double stranded RNA. RESULTS: In this study, we use HT SELEX derived populations to study the landscape of RNAs that interact with Geobacillus kaustophilus ribosomal protein S15. Our data show high sequence and structure diversity and proved intractable to existing methods. Conventional programs identified some sequence motifs, but these are found in less than 5-10% of the total sequence pool. Therefore, we developed a novel framework to analyze HT-SELEX data. Our process accounts for both sequence and structure components by abstracting the overall secondary structure into smaller substructures composed of a single base-pair stack, which allows us to leverage existing approaches already used in k-mer analysis to identify enriched motifs. By focusing on secondary structure motifs composed of specific two base-pair stacks, we identified significantly enriched or depleted structure motifs relative to earlier rounds. CONCLUSIONS: Discrete substructures are likely to be important to RNA-protein interactions, but they are difficult to elucidate. Substructures can help make highly diverse sequence data more tractable. The structure motifs provide limited accuracy in predicting enrichment suggesting that G. kaustophilus S15 can either recognize many different secondary structure motifs or some aspects of the interaction are not captured by the analysis. This highlights the importance of considering secondary and tertiary structure elements and their role in RNA-protein interactions. PMID- 28587637 TI - Literature evidence in open targets - a target validation platform. AB - BACKGROUND: We present the Europe PMC literature component of Open Targets - a target validation platform that integrates various evidence to aid drug target identification and validation. The component identifies target-disease associations in documents and ranks the documents based on their confidence from the Europe PMC literature database, by using rules utilising expert-provided heuristic information. The confidence score of a given document represents how valuable the document is in the scope of target validation for a given target disease association by taking into account the credibility of the association based on the properties of the text. The component serves the platform regularly with the up-to-date data since December, 2015. RESULTS: Currently, there are a total number of 1168365 distinct target-disease associations text mined from >26 million PubMed abstracts and >1.2 million Open Access full text articles. Our comparative analyses on the current available evidence data in the platform revealed that 850179 of these associations are exclusively identified by literature mining. CONCLUSIONS: This component helps the platform's users by providing the most relevant literature hits for a given target and disease. The text mining evidence along with the other types of evidence can be explored visually through https://www.targetvalidation.org and all the evidence data is available for download in json format from https://www.targetvalidation.org/downloads/data . PMID- 28587635 TI - Improved detection of gene-microbe interactions in the mouse skin microbiota using high-resolution QTL mapping of 16S rRNA transcripts. AB - BACKGROUND: Recent studies highlight the utility of quantitative trait locus (QTL) mapping for determining the contribution of host genetics to interindividual variation in the microbiota. We previously demonstrated that similar to the gut microbiota, abundances of bacterial taxa in the skin are significantly influenced by host genetic variation. In this study, we analyzed the skin microbiota of mice from the 15th generation of an advanced intercross line using a novel approach of extending bacterial trait mapping to both the 16S rRNA gene copy (DNA) and transcript (RNA) levels, which reflect relative bacterial cell number and activity, respectively. RESULTS: Remarkably, the combination of highly recombined individuals and 53,203 informative SNPs allowed the identification of genomic intervals as small as <0.1 megabases containing single genes. Furthermore, the inclusion of 16S rRNA transcript-level mapping dramatically increased the number of significant associations detected, with five versus 21 significant SNP-bacterial trait associations based on DNA- compared to RNA-level profiling, respectively. Importantly, the genomic intervals identified contain many genes involved in skin inflammation and cancer and are further supported by the bacterial traits they influence, which in some cases have known genotoxic or probiotic capabilities. CONCLUSIONS: These results indicate that profiling based on the relative activity levels of bacterial community members greatly enhances the capability of detecting interactions between the host and its associated microbes. Finally, the identification of several genes involved in skin cancer suggests that similar to colon carcinogenesis, the resident microbiota may play a role in skin cancer susceptibility and its potential prevention and/or treatment. PMID- 28587638 TI - Erratum to: Maternal near miss and mortality due to postpartum infection: a cross sectional analysis from Rwanda. PMID- 28587639 TI - Unravelling mummies: cryptic diversity, host specificity, trophic and coevolutionary interactions in psyllid - parasitoid food webs. AB - BACKGROUND: Parasitoids are hyperdiverse and can contain morphologically and functionally cryptic species, making them challenging to study. Parasitoid speciation can arise from specialisation on niches or diverging hosts. However, which process dominates is unclear because cospeciation across multiple parasitoid and host species has rarely been tested. Host specificity and trophic interactions of the parasitoids of psyllids (Hemiptera) remain mostly unknown, but these factors are fundamentally important for understanding of species diversity, and have important applied implications for biological control. RESULTS: We sampled diverse parasitoid communities from eight Eucalyptus-feeding psyllid species in the genera Cardiaspina and Spondyliaspis, and characterised their phylogenetic and trophic relationships using a novel approach that forensically linked emerging parasitoids with the presence of their DNA in post emergence insect mummies. We also tested whether parasitoids have cospeciated with their psyllid hosts. The parasitoid communities included three Psyllaephagus morphospecies (two primary and, unexpectedly, one heteronomous hyperparasitoid that uses different host species for male and female development), and the hyperparasitoid, Coccidoctonus psyllae. However, the number of genetically delimited Psyllaephagus species was three times higher than the number of recognisable morphospecies, while the hyperparasitoid formed a single generalist species. In spite of this, cophylogenetic analysis revealed unprecedented codivergence of this hyperparasitoid with its primary parasitoid host, suggesting that this single hyperparasitoid species is possibly diverging into host-specific species. Overall, parasitoid and hyperparasitoid diversification was characterised by functional conservation of morphospecies, high host specificity and some host switching between sympatric psyllid hosts. CONCLUSIONS: We conclude that host specialisation, host codivergence and host switching are important factors driving the species diversity of endoparasitoid communities of specialist host herbivores. Specialisation in parasitoids can also result in heteronomous life histories that may be more common than appreciated. A host generalist strategy may be rare in endoparasitoids of specialist herbivores despite the high conservation of morphology and trophic roles, and endoparasitoid species richness is likely to be much higher than previously estimated. This also implies that the success of biological control requires detailed investigation to enable accurate identification of parasitoid-host interactions before candidate parasitoid species are selected as biological control agents for target pests. PMID- 28587640 TI - Using technology to engage hospitalised patients in their care: a realist review. AB - BACKGROUND: Patient participation in health care is associated with improved outcomes for patients and hospitals. New technologies are creating vast potential for patients to participate in care at the bedside. Several studies have explored patient use, satisfaction and perceptions of health information technology (HIT) interventions in hospital. Understanding what works for whom, under what conditions, is important when considering interventions successfully engaging patients in care. This realist review aimed to determine key features of interventions using bedside technology to engage hospital patients in their care and analyse these in terms of context, mechanisms and outcomes. METHODS: A realist review was chosen to explain how and why complex HIT interventions work or fail within certain contexts. The review was guided by Pawson's realist review methodology, involving: clarifying review scope; searching for evidence; data extraction and evidence appraisal; synthesising evidence and drawing conclusions. Author experience and an initial literature scope provided insight and review questions and theories (propositions) around why interventions worked were developed and iteratively refined. A purposive search was conducted to find evidence to support, refute or identify further propositions, which formed an explanatory model. Each study was 'mined' for evidence to further develop the propositions and model. RESULTS: Interactive learning was the overarching theme of studies using technology to engage patients in their care. Several propositions underpinned this, which were labelled: information sharing; self assessment and feedback; tailored education; user-centred design; and support in use of HIT. As studies were mostly feasibility or usability studies, they reported patient-centred outcomes including patient acceptability, satisfaction and actual use of HIT interventions. For each proposition, outcomes were proposed to come about by mechanisms including improved communication, shared decision making, empowerment and self-efficacy; which acted as facilitators to patient participation in care. Overall, there was a stronger representation of health than IT disciplines in studies reviewed, with a lack of IT input in terms of theoretical underpinning, methodological design and reporting of outcomes. CONCLUSION: HIT interventions have great potential for engaging hospitalised patients in their care. However, stronger interdisciplinary collaboration between health and IT researchers is needed for effective design and evaluation of HIT interventions. PMID- 28587641 TI - Changing educational inequalities in sporting inactivity among adults in Germany: a trend study from 2003 to 2012. AB - BACKGROUND: Social inequalities in health can be explained in part by the social patterning of leisure-time physical activity, such as non-participation in sports. This study is the first to explore whether absolute and relative educational inequalities in sporting inactivity among adults have changed in Germany since the early 2000s. METHODS: Data from four cross-sectional national health surveys conducted in 2003 (n = 6890), 2009 (n = 16,418), 2010 (n = 17,145) and 2012 (n = 13,744) were analysed. The study population was aged 25-69 years in each survey. Sporting inactivity was defined as no sports participation during the preceding 3 months. The regression-based Slope Index of Inequality (SII) and Relative Index of Inequality (RII) were calculated to estimate the extent of absolute and relative educational inequalities in sporting inactivity, respectively. RESULTS: Sporting inactivity was consistently more prevalent in less-educated groups. The overall prevalence of sporting inactivity declined significantly over time. However, the decline was observed only in the high and medium education groups, while no change was observed in the low education group. Both absolute and relative educational inequalities in sporting inactivity were found to have widened significantly between 2003 (SII = 0.30, 95% CI = 0.25-0.35; RII = 2.08, 95% CI = 1.83-2.38) and 2012 (SII = 0.41, 95% CI = 0.37-0.45; RII = 3.44, 95% CI = 3.03-3.91). Interaction analysis showed that these increases in inequalities were larger in the younger population under the age of 50 than among the elderly. CONCLUSIONS: The findings suggest that the gap in sports participation between adults with high and low educational attainment has widened in both absolute and relative terms because of an increase in sports participation among the better educated. Health-enhancing physical activity interventions specifically targeted to less-educated younger adults are needed to prevent future increases in social inequalities in health. PMID- 28587642 TI - Differential expression analysis at the individual level reveals a lncRNA prognostic signature for lung adenocarcinoma. AB - BACKGROUND: Deregulations of long non-coding RNAs (lncRNAs) have been implicated in cancer initiation and progression. Current methods can only capture differential expression of lncRNAs at the population level and ignore the heterogeneous expression of lncRNAs in individual patients. METHODS: We propose a method (LncRIndiv) to identify differentially expressed (DE) lncRNAs in individual cancer patients by exploiting the disrupted ordering of expression levels of lncRNAs in each disease sample in comparison with stable normal ordering. LncRIndiv was applied to lncRNA expression profiles of lung adenocarcinoma (LUAD). Based on the expression profile of LUAD individual-level DE lncRNAs, we used a forward selection procedure to identify prognostic signature for stage I-II LUAD patients without adjuvant therapy. RESULTS: In both simulated data and real pair-wise cancer and normal sample data, LncRIndiv method showed good performance. Based on the individual-level DE lncRNAs, we developed a robust prognostic signature consisting of two lncRNA (C1orf132 and TMPO-AS1) for stage I-II LUAD patients without adjuvant therapy (P = 3.06 * 10-6, log-rank test), which was confirmed in two independent datasets of GSE50081 (P = 1.82 * 10 2, log-rank test) and GSE31210 (P = 7.43 * 10-4, log-rank test) after adjusting other clinical factors such as smoking status and stages. Pathway analysis showed that TMPO-AS1 and C1orf132 could affect the prognosis of LUAD patients through regulating cell cycle and cell adhesion. CONCLUSIONS: LncRIndiv can successfully detect DE lncRNAs in individuals and be applied to identify prognostic signature for LUAD patients. PMID- 28587644 TI - Current and future perspectives on the management of polypharmacy. AB - BACKGROUND: Because of ageing populations, the growth in the number of people with multi-morbidity and greater compliance with disease-specific guidelines, polypharmacy is becoming increasingly common. Although the correct drug treatment in patients with complex medical problems can improve clinical outcomes, quality of life and life expectancy, polypharmacy is also associated with an increased risk of adverse drug events, some severe enough to result in hospital admission and even death. Hence, having systems in place to ensure that medications are started only when there is a suitable indication, ensuring patients are fully aware of the benefits and complications that may arise from their treatment, and reviewing patients regularly to ensure their medication regime remains appropriate, are essential. DISCUSSION: The development and rapid uptake of electronic patient records - particularly in primary care settings where the majority of prescribing takes place - makes monitoring of patients more straightforward than in the past; and allows identification of sub-groups of patients at particularly high risk of adverse drug events and complications. It also facilitates 'deprescribing' the process by which medications are reviewed and stopped if not clinically beneficial. In recent years, we have also seen the development of smartphone 'apps' to improve communication between patients and healthcare professionals, improve people's understanding of their conditions and their treatment, and maintain a record of changes made to patient's medication. In the longer term, developments such as the introduction of artificial intelligence and clinical decision support systems also have the potential to improve prescribing and minimise the risks from polypharmacy. Finally, there is considerable scope to improve the quality of prescribing and reduce risks from poly-pharmacy using non-medical groups such as pharmacists, specialist nurses and physician assistants. Polypharmacy has increased in recent decades and will continue to increase as populations age and the number of people with multiple long-term conditions increases. As with all areas of medicine, the evidence-base in this area continues to evolve. Further trials on the impact on patients with polypharmacy of new interventions such as technology-based solutions and the use of different professional groups are needed to improve the evidence-base in this area. PMID- 28587643 TI - Effects of topical insulin on second-intention wound healing in the red-eared slider turtle (Trachemys scripta elegans) - a controlled study. AB - BACKGROUND: Compared with mammals, wound healing in reptiles is characterized by reduced wound contraction and longer healing times. The aim of this study is to describe the clinical and histopathological effects of topical insulin on second intention healing of experimentally induced wounds in skin without dermal bony plates of Trachemys scripta elegans exposed to daily variations in ambient temperature and in an aquatic environment. Forty-four healthy adult females were assigned to two groups: Group 1 (n = 24) was used to assess clinical features such as wound contraction; Group 2 (n = 20) was used for histological evaluation and morphometric analysis. Topical porcine insulin (5 IU/ml diluted in glycerol) was applied daily 1 week. For each control time (2, 7, 14, 21 and 28 days post wounding), re-epithelisation and wound remodelling were evaluated histologically and the number of main inflammatory cells (heterophils, macrophages, lymphocytes and fibroblasts) was scored. RESULTS: Mean wound contraction was higher in the insulin-treated group at each time point and differences were significant at day 28 (P < 0.0001). Histologically, these clinical findings were associated with better re-epithelisation, inflammatory response, collagen synthesis and remodelling of the wounds. Morphometrically, insulin-treated wounds had significantly higher mean counts of heterophils (day 7), macrophages (days 2, 7 and 14) and fibroblasts (days 14 and 21), whereas lymphocyte counts were significantly lower at day 21. These results demonstrate that topical insulin modifies the inflammatory response of turtle skin up-regulating inflammatory cells at early stages and promoting wound healing. CONCLUSIONS: Topical insulin is a potentially useful therapy in skin wounds of Trachemys scripta and should be evaluated in non-experimental wounds of turtles and other reptiles. PMID- 28587645 TI - Transcriptome profiling of Staphylococci-infected cow mammary gland parenchyma. AB - BACKGROUND: Genome-wide gene expression profiling allows for identification of genes involved in the defense response of the host against pathogens. As presented here, transcriptomic analysis and bioinformatics tools were applied in order to identify genes expressed in the mammary gland parenchyma of cows naturally infected with coagulase-positive and coagulase-negative Staphylococci. RESULTS: In cows infected with coagulase-positive Staphylococci, being in 1st or 2nd lactation, 1700 differentially expressed genes (DEGs) were identified. However, examination of the 3rd or 4th lactations revealed 2200 DEGs. Gene ontology functional classification showed the molecular functions of the DEGs overrepresented the activity of cytokines, chemokines, and their receptors. In cows infected with coagulase-negative Staphylococci, in the 1st or 2nd lactations 418 DEGs, while in the 3rd or 4th lactations, 1200 DEGs were identified that involved in molecular functions such as protein, calcium ion and lipid binding, chemokine activity, and protein homodimerization. Gene network analysis showed DEGs associated with inflammation, cell migration, and immune response to infection, development of cells and tissues, and humoral responses to infections caused by both types of Staphylococci. CONCLUSION: A coagulase-positive Staphylococci infection caused a markedly stronger host response than that of coagulase-negative, resulting in vastly increased DEGs. A significant increase in the expression of the FOS, TNF, and genes encoding the major histocompatibility complex proteins (MHC) was observed. It suggests these genes play a key role in the synchronization of the immune response of the cow's parenchyma against mastitis-causing bacteria. Moreover, the following genes that belong to several physiological pathways (KEGG pathways) were selected for further studies as candidate genes of mammary gland immune response for use in Marker Assisted Selection (MAS): chemokine signaling pathway (CCL2, CXCL5, HCK, CCR1), cell adhesion molecules (CAMs) pathway (BOLA-DQA2, BOLA-DQA1, F11R, ITGAL, CD86), antigen processing and presentation pathway (CD8A, PDIA3, LGMN, IFI30, HSPA1A), and NOD-like receptor signaling pathway (TNF, IL8, IL18, NFKBIA). PMID- 28587646 TI - Trends in sex differences in the receipt of quality of care indicators among adults with diabetes: United States 2002-2011. AB - BACKGROUND: Evidence suggests disparities in quality of care (QoC) indicators based on sex exist in adults diagnosed with diabetes; however, this research is limited. Therefore, the objective of this research study was to assess differences in QOC indicators in a nationally representative sample of men and women with diabetes. METHODS: Cross-sectional study of 17,702 men and women (>=18 years of age) with diabetes from the 2002-2011 Medical Expenditure Panel Survey Household Component. Sex was the main predictor variable, and the dependent variables were five binary indicators to measure QOC, which included testing of hemoglobin A1c, examining feet annually, getting eyes dilated, checking blood pressure, and visiting the doctor annually. Sample demographics by sex were assessed. Unadjusted analyses were computed for descriptive statistics by sex and proportions of QOC indicators over time. Logistic regression evaluated associations between QOC indicators and sex, while controlling for sociodemographic characteristics, time, and comorbid conditions. RESULTS: Approximately 44% and 56% of the sample was comprised of men and women, respectively. Unadjusted analyses showed significant differences in A1c testing (p < 0.001) and foot examinations (p = 0.002) for the entire sample, and significant differences in A1c testing (p = 0.027), foot examinations (p = 0.01), and dilated eye exams (p = 0.026) among men and A1c testing (p < 0.001) among women overtime. Adjusted analyses found women to be significantly more likely to have dilated eye examinations during a given year (OR = 1.14; 95% CI 1.04, 1.24), to get their blood pressure checked by a doctor in a given year (OR = 1.44; 95% CI 1.13, 1.84), and to visit a doctor annually (OR = 1.39; 95% CI 1.22, 1.58) compared to men. CONCLUSIONS: In this sample of adults with diabetes, women had significantly higher odds of receiving quality of care compared to men. These findings suggest the importance of educating patients about appropriate metrics of diabetes management, especially men, and the need for continuous empowerment of women to receive proper and optimal care. Additional research is needed to identify causes and reduce sex and gender disparities associated with diabetes quality of care. PMID- 28587647 TI - Risk factors and implications of progressive coronary dilatation in children with Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis that occurs in children and may lead to cardiovascular morbidity and mortality. Progressive coronary dilatation for at least 2 months is associated with worse late coronary outcomes in patients with KD having medium or giant aneurysms. However, the risk factors and occurrence of progressive coronary dilatation in patients with KD but without medium or giant aneurysms have been insufficiently explored. METHODS: We retrospectively enrolled 169 patients with KD from a tertiary medical center in Taiwan during 2009-2013. Medical records of all patients were reviewed. Echocardiography was performed during the acute KD phase and at 3-4 weeks, 6-8 weeks, 6 months, and 12 months after KD onset. Progressive coronary dilatation was defined as the progressive enlargement of coronary arteries on three consecutive echocardiograms. Logistic regression analysis was conducted to evaluate the potential risk factors for coronary aneurysms and progressive coronary dilatation. RESULTS: Of a total of 169 patients with KD, 31 (18.3%) had maximal coronary Z-scores of >= + 2.5 during the acute KD phase, 16 (9.5%; male/female: 9/7) had coronary aneurysms at 1 month after KD onset, and 5 (3.0%) satisfied the definition of progressive coronary dilatation. Multivariate logistic regression analysis revealed that an initial maximal coronary Z-score of >= + 2.5 [odds ratio (OR): 5.24, 95% confidence interval (CI): 1.31-21.3, P = 0.020] and hypoalbuminemia (OR: 4.83, 95% CI: 1.11-20.9, P = 0.035) were independent risk factors for coronary aneurysms and were significantly associated with progressive coronary dilatation. However, the association between intravenous immunoglobulin unresponsiveness and the development of coronary aneurysms at 1 month after KD onset didn't reach the level of significance (P = 0.058). CONCLUSIONS: In the present study, 3% (5/169) of patients with KD had progressive coronary dilatation, which was associated with persistent coronary aneurysms at 1 year after KD onset. Initial coronary dilatation and hypoalbuminemia were independently associated with the occurrence of progressive coronary dilatation. Therefore, such patients may require intensive cardiac monitoring and adjuvant therapies apart from immunoglobulin therapies. PMID- 28587648 TI - Timing of menarche in Norwegian girls: associations with body mass index, waist circumference and skinfold thickness. AB - BACKGROUND: Research studies show conflicting results regarding the association between menarche and body weight. The purpose of the present study was to investigate if anthropometric indicators of body composition, body mass index (BMI), waist circumference (WC), triceps (TSF) and subscapular skinfold (SSF) thicknesses, were differentially associated with age at menarche in Norwegian girls. METHODS: The association between menarche and BMI, WC, TSF and SSF was investigated in 1481 girls aged 8-15.5 years, and in a subgroup of 181 girls with menarche during the 12 months prior to examination. Anthropometric measures were categorized as low (< -1SDS), average (-1 <= SDS <= +1) or high (> 1SDS), and menarche according to this classification was analysed with Kaplan-Meier curves and unadjusted and adjusted Cox regression. RESULTS: The median age at menarche in the total sample was 13.1 years. In the unadjusted models, low categories of all traits were associated with later menarche, and high categories with earlier menarche. When adjusted for other covariates, earlier menarche was only related with a high BMI (Hazard Ratio 1.41, 95% confidence interval (CI) 1.07, 1.85), and later menarche with a low BMI (HR 0.53, 95%CI 0.38, 0.75) and low SSF (HR 0.54, 95%CI 0.39, 0.75). In girls with recent menarche, early menarche was significantly associated with a high BMI in the final model (HR 1.79, 95%CI 1.23, 2.62). CONCLUSIONS: The timing of menarche was associated with the BMI, WC, TSF and SSF, but more strongly so with the BMI. These associations may be related to a common tempo of growth, as the mean age at menarche has remained stable during the last decades during a time period while the prevalence of overweight and obesity has increased significantly. PMID- 28587649 TI - COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): statistical and economic analysis plan for a randomised controlled trial. AB - BACKGROUND: Dissociative seizures (DSs), also called psychogenic non-epileptic seizures, are a distressing and disabling problem for many patients in neurological settings with high and often unnecessary economic costs. The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) trial is an evaluation of a specifically tailored psychological intervention with the aims of reducing seizure frequency and severity and improving psychological well-being in adults with DS. The aim of this paper is to report in detail the quantitative and economic analysis plan for the CODES trial, as agreed by the trial steering committee. METHODS: The CODES trial is a multicentre, pragmatic, parallel group, randomised controlled trial performed to evaluate the clinical effectiveness and cost-effectiveness of 13 sessions of cognitive behavioural therapy (CBT) plus standardised medical care (SMC) compared with SMC alone for adult outpatients with DS. DISCUSSION: The objectives and design of the trial are summarised, and the aims and procedures of the planned analyses are illustrated. The proposed analysis plan addresses statistical considerations such as maintaining blinding, monitoring adherence with the protocol, describing aspects of treatment and dealing with missing data. The formal analysis approach for the primary and secondary outcomes is described, as are the descriptive statistics that will be reported. This paper provides transparency to the planned inferential analyses for the CODES trial prior to the extraction of outcome data. It also provides an update to the previously published trial protocol and guidance to those conducting similar trials. TRIAL REGISTRATION: ISRCTN registry ISRCTN05681227 (registered on 5 March 2014); ClinicalTrials.gov NCT02325544 (registered on 15 December 2014). PMID- 28587651 TI - Erratum to: Pancreatic beta-cell regeneration: advances in understanding the genes and signaling pathways involved. PMID- 28587650 TI - Impact of diabetes duration and degree of carotid artery stenosis on major adverse cardiovascular events: a single-center, retrospective, observational cohort study. AB - BACKGROUND: We aimed to investigate the impact of diabetes duration and carotid artery stenosis (CAS) on the occurrence of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) without clinical cardiovascular disease. METHODS: A total of 2006 patients with T2DM, without clinical cardiovascular disease, aged >50 years, and who underwent baseline carotid Doppler ultrasound screening with regular follow-ups at the outpatient clinic of our diabetes center, were stratified into four subgroups according to diabetes duration and CAS degree. The primary outcomes included the occurrence of MACE, defined as fatal or nonfatal stroke and myocardial infarction, and all cause mortality. RESULTS: The difference in the MACE incidence was significantly greater in patients with a longer diabetes duration (>=10 years) and significant CAS (50-69% luminal narrowing) (p < 0.001). Analysis of individual MACE components indicated a trend towards an increased incidence of stroke (p < 0.001), parallel to a longer diabetes duration and significant CAS. In contrast, the risk of myocardial infarction was significantly higher in patients with a diabetes duration <10 years and significant CAS (p = 0.039). Multivariate regression analysis showed that patients with both a longer diabetes duration and significant CAS demonstrated additive and very high risks of MACE (hazard ratio [HR], 2.07; 95% confidence interval [CI] 1.17-3.66; p = 0.012) and stroke (HR, 3.38; 95% CI 1.54-7.44; p = 0.002). CONCLUSIONS: The risk of MACE is significantly greater in patients with T2DM, without clinical cardiovascular disease, who have both a longer diabetes duration and significant CAS, compared with those who have a shorter duration and/or nonsignificant CAS. PMID- 28587653 TI - The short term burden of ambient fine particulate matter on chronic obstructive pulmonary disease in Ningbo, China. AB - BACKGROUND: Numerous studies have found associations between ambient fine particulate matter (PM2.5) and increased mortality risk. However, little evidence is available on associations between PM2.5 and years of life lost (YLL). We aimed to estimate the YLL due to chronic obstructive pulmonary disease (COPD) mortality related to ambient PM2.5 exposure. METHODS: A time-series study was conducted based on the data on air pollutants, meteorological conditions and 18,472 registered COPD deaths in Ningbo, China, 2011-2015. The effects of PM2.5 on YLL and daily death of COPD were estimated, after controlling long term trend, meteorological index and other confounders. RESULTS: The impact of PM2.5 on YLL due to COPD lasted for 5 days (lag 0-4). Per 10 MUg/m3 increase in PM2.5 was associated with 0.91 (95%CI: 0.16, 1.66) years increase in YLL. The excess YLL of COPD mortality were 8206 years, and 0.38 day per person in Ningbo from 2011 to 2015. The exposure-response curve of PM2.5 and YLL due to COPD showed a non linear pattern, with relatively steep at low levels and flattened out at higher exposures.. Furthermore, the effects were significantly higher in the elderly than those in the younger. CONCLUSIONS: Our findings explored burden of PM2.5 on YLL due to COPD and highlight the importance and urgency of ambient PM2.5 pollution control and protection of the vulnerable populations. PMID- 28587652 TI - Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F. AB - BACKGROUND: Sarcospan (SSPN) is a transmembrane protein that interacts with the sarcoglycans (SGs) to form a tight subcomplex within the dystrophin-glycoprotein complex that spans the sarcolemma and interacts with laminin in the extracellular matrix. Overexpression of SSPN ameliorates Duchenne muscular dystrophy in murine models. METHODS: Standard cloning approaches were used to identify nanospan, and nanospan-specific polyclonal antibodies were generated and validated. Biochemical isolation of skeletal muscle membranes and two-photon laser scanning microscopy were used to analyze nanospan localization in muscle from multiple murine models. Duchenne muscular dystrophy biopsies were analyzed by immunoblot analysis of protein lysates as well as indirect immunofluorescence analysis of muscle cryosections. RESULTS: Nanospan is an alternatively spliced isoform of sarcospan. While SSPN has four transmembrane domains and is a core component of the sarcolemmal dystrophin-glycoprotein complex, nanospan is a type II transmembrane protein that does not associate with the dystrophin-glycoprotein complex. We demonstrate that nanospan is enriched in the sarcoplasmic reticulum (SR) fractions and is not present in the T-tubules. SR fractions contain membranes from three distinct structural regions: a region flanking the T-tubules (triadic SR), a SR region across the Z-line (ZSR), and a longitudinal SR region across the M-line (LSR). Analysis of isolated murine muscles reveals that nanospan is mostly associated with the ZSR and triadic SR, and only minimally with the LSR. Furthermore, nanospan is absent from the SR of delta-SG-null (Sgcd-/-) skeletal muscle, a murine model for limb girdle muscular dystrophy 2F. Analysis of skeletal muscle biopsies from Duchenne muscular dystrophy patients reveals that nanospan is preferentially expressed in type I (slow) fibers in both control and Duchenne samples. Furthermore, nanospan is significantly reduced in Duchenne biopsies. CONCLUSIONS: Alternative splicing of proteins from the SG-SSPN complex produces delta-SG3, microspan, and nanospan that localize to the ZSR and the triadic SR, where they may play a role in regulating resting calcium levels as supported by previous studies (Estrada et al., Biochem Biophys Res Commun 340:865 71, 2006). Thus, alternative splicing of SSPN mRNA generates three protein isoforms (SSPN, microspan, and nanospan) that differ in the number of transmembrane domains affecting subcellular membrane association into distinct protein complexes. PMID- 28587654 TI - Determinants of self-perceived health for Canadians aged 40 and older and policy implications. AB - BACKGROUND: Perceived health status indicates people's overall perception of their health, including both physical and psychological dimensions. The aim of this study was to examine the determinants of self-perceived health for Canadians aged 40 and older using data from the Canadian Community Health Survey (2010). METHODS: Multiple logistic regression models were employed to identify factors associated with self-perceived health in two age groups: Adults aged 65+ and Adults aged 40-64. RESULTS: We found that higher income was significantly associated with better health status while chronic conditions and stress were associated with worse health status. In the 40-64 and 65+ age groups, individuals in the highest income bracket were 4.65 and 1.94 times, respectively, more likely to report better health than individuals in the lowest income bracket. The difference in the level of income associated health inequities between the two age groups point to the need for understanding the reasons behind lower inequities among seniors and how much the social protections provided by the Canadian government to seniors contribute to lowering inequities. CONCLUSIONS: Though Canada has a national public health insurance system providing coverage to all Canadians, health inequities associated with income persist providing further evidence of the importance of the social determinants of health. Examining the extent of these inequities and what factors influence them helps direct policy attention. In addition to documenting inequities, this paper discusses policy options for reducing the identified inequities. PMID- 28587655 TI - Gout and subsequent erectile dysfunction: a population-based cohort study from England. AB - BACKGROUND: An association has been suggested between gout and erectile dysfunction (ED), however studies quantifying the risk of ED amongst gout patients are lacking. We aimed to precisely determine the population-level absolute and relative rate of ED reporting among men with gout over a decade in England. METHODS: We utilised the UK-based Clinical Practice Research Datalink to identify 9653 men with incident gout age- and practice-matched to 38,218 controls. Absolute and relative rates of incident ED were calculated using Cox regression models. Absolute rates within specific time periods before and after gout diagnosis were compared to control using a Poisson regression model. RESULTS: Overall, the absolute rate of ED post-gout diagnosis was 193 (95% confidence interval (CI): 184-202) per 10,000 person-years. This corresponded to a 31% (hazard ratio (HR): 1.31 95%CI: 1.24-1.40) increased relative risk and 0.6% excess absolute risk compared to those without gout. We did not observe statistically significant differences in the risk of ED among those prescribed ULT within 1 and 3 years after gout diagnosis. Compared to those unexposed, the risk of ED was also high in the year before gout diagnosis (relative rate = 1.63 95%CI 1.27-2.08). Similar findings were also observed for severe ED warranting pharmacological intervention. CONCLUSIONS: We have shown a statistically significant increased risk of ED among men with gout. Our findings will have important implications in planning a multidisciplinary approach to managing patients with gout. PMID- 28587656 TI - The correlations between DNA methylation and polymorphisms in the promoter region of the human telomerase reverse transcriptase (hTERT) gene with postoperative recurrence in patients with thyroid carcinoma (TC). AB - BACKGROUND: This study aims at exploring the correlations between DNA methylation and polymorphisms in the promoter region of the human telomerase reverse transcriptase (hTERT) gene and postoperative recurrence in patients with thyroid carcinoma (TC). METHODS: A total of 312 patients diagnosed with TC were chosen for the study and categorized into recurrence (n = 75) and non-recurrence (n = 237) groups. The hTERT rs2736100 and rs2736098 polymorphisms were detected by performing polymerase chain reaction-restriction fragment length polymorphism. DNA methylation in the promoter region of hTERT gene was evaluated by pyrosequencing. A telephonic and/or outpatient follow-up was conducted for all patients. The correlations of DNA methylation and polymorphisms in the promoter region of hTERT with postoperative recurrence of TC patients underwent analysis. RESULTS: The patient in the recurrence group showed evidently different pathological types and tumor stages in comparison to the non-recurrence group. The GG genotype of hTERT rs2736100 might increase the recurrence risk of TC patients. No correlations between hTERT rs2736098 polymorphisms and recurrence risk were observed. Compared to the TT + TG genotype frequency, the rs2736100 GG genotype frequency increased in patients without multicentricity, patients with extrathyroidal invasion, patients with lymph node metastasis, patients with undifferentiated carcinoma, and patients in the III + IV stage. The recurrence group showed significantly higher DNA methylation level compared to the non recurrence group. The DNA methylation level was closely associated to tumor stage and lymph node metastasis of TC patients in the recurrence group. CONCLUSIONS: The DNA methylation and rs2736100 polymorphisms in the promoter region of hTERT gene might be in correlation to postoperative recurrence of TC patients. PMID- 28587657 TI - Modified pedicle screw-rod fixation as a minimally invasive treatment for anterior pelvic ring injuries: an initial case series. AB - BACKGROUND: Unstable pelvic ring injuries often involve high mortality and morbidity. This study was aimed to evaluate the modified minimally invasive pedicle screw-rod fixation for anterior pelvic ring injuries, in the respects of its feasibility, merits, and limitations. METHODS: Twenty-three patients with unstable pelvic ring injuries underwent the modified anterior pedicle screw-rod fixation, with or without posterior fixation. The clinical outcomes were assessed using Majeed scores, and the quality of reduction was evaluated according to the criteria of Matta. RESULTS: Majeed scores showed that the clinical outcomes at postoperatively 1 year were excellent in 14 patients, good in 7, and fair in 2. One woman complained of persistent pain at the pubic tubercle during sexual intercourse. Iatrogenic neuropraxia of the unilateral lateral femoral cutaneous nerve occurred in 3 patients. Unilateral femoral nerve palsy occurred in 1 patient. The reduction was found to be excellent in 12 patients, good in 8, and fair in 3. Heterotopic ossification occurred in 8 patients, all being asymptomatic. CONCLUSIONS: The modified pedicle screw-rod fixation with the minimally invasive technique offered an effective alternative for unstable anterior pelvic ring injuries. PMID- 28587658 TI - MRI evidence of structural changes in the sacroiliac joints of patients with non radiographic axial spondyloarthritis even in the absence of MRI inflammation. AB - BACKGROUND: Studies have shown that structural lesions may be present in patients with non-radiographic axial spondyloarthritis (nr-axSpA). However, the relevance of structural lesions in these patients is unclear, particularly without signs of inflammation on magnetic resonance imaging (MRI). We assessed the presence of structural lesions at baseline on MRI in the sacroiliac joints (SIJ) of patients with nr-axSpA with and without SIJ inflammation on MRI. METHODS: Bone marrow edema (BME) was assessed on short tau inversion recovery (STIR) scans from 185 patients with nr-axSpA, by two independent readers at baseline using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Structural lesions were evaluated on T1 weighted spin echo scans, with readers blinded to STIR scans, using the SPARCC MRI SIJ structural score. Disease characteristics and structural lesions were compared in patients with SIJ BME (score >=2) and without SIJ BME (score <2). RESULTS: Both SIJ BME and structural lesions scores were available for 183 patients; 128/183 (69.9%) patients had SIJ BME scores >=2 and 55/183 (30.1%) had scores <2. Frequencies of MRI structural lesions in patients with vs without SIJ BME were: erosions (45.3% vs 10.9%, P < 0.001), backfill (20.3% vs 0%, P < 0.001), fat metaplasia (10.9% vs 1.8%, P = 0.04), and ankylosis (2.3% vs 1.8%, P = ns). Significantly more patients with both SIJ BME and structural lesions were male and/or HLA-B27 positive than patients with only SIJ BME. Mean (SD) spinal scores (23 discovertebral units) were significantly higher in patients with SIJ structural lesions than without: 6.5 (11.5) vs 3.3 (5.1), respectively, P = 0.01. CONCLUSIONS: In patients with nr-axSpA, SIJ structural lesions, particularly erosions, may be present on MRI when radiographs are normal or inconclusive, even in patients negative for MRI SIJ inflammation. They may reflect more severe disease with greater spinal inflammation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01258738 . Registered on 9 December 2010. PMID- 28587660 TI - Recommendations for cerebrospinal fluid collection for the analysis by ELISA of neurogranin trunc P75, alpha-synuclein, and total tau in combination with Abeta(1 42)/Abeta(1-40). AB - BACKGROUND: The pathophysiology of neurodegeneration is complex. Its diagnosis requires an early identification of sequential changes in several hallmarks in the brains of affected subjects. The presence of brain pathology can be visualized in the cerebrospinal fluid (CSF) by protein profiling. It is clear that the field of Alzheimer's disease (AD) will benefit from an integration of algorithms including CSF concentrations of individual proteins, especially as an aid in clinical decision-making or to improve patient enrolment in clinical trials. The protein profiling approach requires standard operating procedures for collection and storage of CSF which must be easy to integrate into a routine clinical lab environment. Our study provides recommendations for analysis of neurogranin trunc P75, alpha-synuclein, and tau, in combination with the ratio of beta-amyloid Abeta(1-42)/Abeta(1-40). METHODS: Protocols for CSF collection were compared with CSF derived from subjects with normal pressure hydrocephalus (n = 19). Variables included recipient type (collection, storage), tube volume, and addition of detergents at the time of collection. CSF biomarker analysis was performed with enzyme-linked immunosorbent assays (ELISAs). Data were analyzed with linear repeated measures and mixed effects models. RESULTS: Adsorption to recipients is lower for neurogranin trunc P75, alpha-synuclein, and tau (<10%), as compared to Abeta(1-42). For neurogranin trunc P75 and total tau, there is still an effect on analyte concentrations as a function of the tube volume. Protocol-related differences for Abeta(1-42) can be normalized at the (pre )analytical level using the ratio Abeta(1-42)/Abeta(1-40), but not by using the ratio Abeta(1-42)/tau. The addition of detergent at the time of collection eliminates differences due to adsorption. CONCLUSIONS: Our study recommends the use of low protein binding tubes for quantification in CSF (without additives) of all relevant CSF biomarkers. Pre-analytical factors have less effect on alpha synuclein, neurogranin trunc P75, and total tau, as compared to Abeta(1-42). The ratio of Abeta(1-42)/Abeta(1-40), but not Abeta(1-42)/tau, can be used to adjust for pre-analytical differences in analyte concentrations. Our study does not recommend the inclusion of detergents at the time of collection of CSF. The present results provide an experimental basis for new recommendations for parallel analysis of several proteins using one protocol for collection and storage of CSF. PMID- 28587659 TI - Glutaminyl cyclase activity correlates with levels of Abeta peptides and mediators of angiogenesis in cerebrospinal fluid of Alzheimer's disease patients. AB - BACKGROUND: Pyroglutamylation of truncated Abeta peptides, which is catalysed by enzyme glutaminyl cyclase (QC), generates pE-Abeta species with enhanced aggregation propensities and resistance to most amino-peptidases and endo peptidases. pE-Abeta species have been identified as major constituents of Abeta plaques and reduction of pE-Abeta species is associated with improvement of cognitive tasks in animal models of Alzheimer's disease (AD). Pharmacological inhibition of QC has thus emerged as a promising therapeutic approach for AD. Here, we question whether cerebrospinal fluid (CSF) QC enzymatic activity differs between AD patients and controls and whether inflammatory or angiogenesis mediators, some of which are potential QC substrates, and/or Abeta peptides may serve as pharmacodynamic read-outs for QC inhibition. METHODS: QC activity, Abeta peptides and inflammatory or angiogenesis mediators were measured in CSF of a clinically well-characterized cohort of 20 mild AD patients, 20 moderate AD patients and 20 subjective memory complaints (SMC) controls. Correlation of these parameters with core diagnostic CSF AD biomarkers (Abeta42, tau and p-tau) and clinical features was evaluated. RESULTS: QC activity shows a tendency to decrease with AD progression (p = 0.129). The addition of QC activity to biomarkers tau and p-tau significantly increases diagnostic power (ROC-AUCTAU = 0.878, ROC-AUCTAU&QC = 0.939 and ROC-AUCpTAU = 0.820, ROC-AUCpTAU&QC = 0.948). In AD and controls, QC activity correlates with Abeta38 (r = 0.83, p < 0.0001) and Abeta40 (r = 0.84, p < 0.0001), angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM-1, r > 0.5, p < 0.0001) and core diagnostic biomarkers (r > 0.35, p = <0.0057). QC activity does not correlate with MMSE or ApoE genotype. CONCLUSIONS: Abeta38, Abeta40 and angiogenesis mediators (Flt1, Tie2, VEGFD, VCAM-1 and ICAM 1) are potential pharmacodynamic markers of QC inhibition, because their levels closely correlate with QC activity in AD patients. The addition of QC activity to core diagnostic CSF biomarkers may be of specific interest in clinical cases with discordant imaging and biochemical biomarker results. PMID- 28587662 TI - A nonparametric multiple imputation approach for missing categorical data. AB - BACKGROUND: Incomplete categorical variables with more than two categories are common in public health data. However, most of the existing missing-data methods do not use the information from nonresponse (missingness) probabilities. METHODS: We propose a nearest-neighbour multiple imputation approach to impute a missing at random categorical outcome and to estimate the proportion of each category. The donor set for imputation is formed by measuring distances between each missing value with other non-missing values. The distance function is calculated based on a predictive score, which is derived from two working models: one fits a multinomial logistic regression for predicting the missing categorical outcome (the outcome model) and the other fits a logistic regression for predicting missingness probabilities (the missingness model). A weighting scheme is used to accommodate contributions from two working models when generating the predictive score. A missing value is imputed by randomly selecting one of the non-missing values with the smallest distances. We conduct a simulation to evaluate the performance of the proposed method and compare it with several alternative methods. A real-data application is also presented. RESULTS: The simulation study suggests that the proposed method performs well when missingness probabilities are not extreme under some misspecifications of the working models. However, the calibration estimator, which is also based on two working models, can be highly unstable when missingness probabilities for some observations are extremely high. In this scenario, the proposed method produces more stable and better estimates. In addition, proper weights need to be chosen to balance the contributions from the two working models and achieve optimal results for the proposed method. CONCLUSIONS: We conclude that the proposed multiple imputation method is a reasonable approach to dealing with missing categorical outcome data with more than two levels for assessing the distribution of the outcome. In terms of the choices for the working models, we suggest a multinomial logistic regression for predicting the missing outcome and a binary logistic regression for predicting the missingness probability. PMID- 28587663 TI - Parent experiences and information needs relating to procedural pain in children: a systematic review protocol. AB - BACKGROUND: There exist many evidence-based interventions available to manage procedural pain in children and neonates, yet they are severely underutilized. Parents play an important role in the management of their child's pain; however, many do not possess adequate knowledge of how to effectively do so. The purpose of the planned study is to systematically review and synthesize current knowledge of the experiences and information needs of parents with regard to the management of their child's pain and distress related to medical procedures in the emergency department. METHODS: We will conduct a systematic review using rigorous methods and reporting based on the PRISMA statement. We will conduct a comprehensive search of literature published between 2000 and 2016 reporting on parents' experiences and information needs with regard to helping their child manage procedural pain and distress. Ovid MEDLINE, Ovid PsycINFO, CINAHL, and PubMed will be searched. We will also search reference lists of key studies and gray literature sources. Two reviewers will screen the articles following inclusion criteria defined a priori. One reviewer will then extract the data from each article following a data extraction form developed by the study team. The second reviewer will check the data extraction for accuracy and completeness. Any disagreements with regard to study inclusion or data extraction will be resolved via discussion. Data from qualitative studies will be summarized thematically, while those from quantitative studies will be summarized narratively. The second reviewer will confirm the overarching themes resulting from the qualitative and quantitative data syntheses. The Critical Appraisal Skills Programme Qualitative Research Checklist and the Quality Assessment Tool for Quantitative Studies will be used to assess the quality of the evidence from each included study. DISCUSSION: To our knowledge, no published review exists that comprehensively reports on the experiences and information needs of parents related to the management of their child's procedural pain and distress. A systematic review of parents' experiences and information needs will help to inform strategies to empower them with the knowledge necessary to ensure their child's comfort during a painful procedure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016043698. PMID- 28587661 TI - Symbionts in waiting: the dynamics of incipient endosymbiont complementation and replacement in minimal bacterial communities of psyllids. AB - BACKGROUND: Obligate bacterial primary (P-) endosymbionts that are maternally inherited and codiverge with hosts are widespread across insect lineages with nutritionally restricted diets. Secondary (S-) endosymbionts are mostly facultative, but in some hosts, they complement P-endosymbiont function and therefore become obligate. Phylogenetic evidence exists for host switching and replacement of S-endosymbionts. The community dynamics that precede endosymbiont replacement and complementation have been little studied across host species, yet they are fundamental to the evolution of endosymbiosis. RESULTS: We performed bacterial 16S rRNA gene amplicon sequencing of 25 psyllid species (Hemiptera, Psylloidea) across different developmental stages and ecological niches by focusing on the characterisation of the bacteria other than the universally present P-endosymbiont Carsonella (Gammaproteobacteria). Most species harboured only one dominant representative of diverse gammaproteobacterial S-endosymbionts that was consistently detected across all host individuals and populations (Arsenophonus in eight species, Sodalis or Sodalis-like bacteria in four species, unclassified Enterobacteriaceae in eight species). The identity of this dominant obligate S-endosymbiont varied across closely related host species. Unexpectedly, five psyllid species had two or three co-occurring endosymbiont species other than Carsonella within all host individuals, including a Rickettsiella-like bacterium (Gammaproteobacteria) in one psyllid species. Based on standard and quantitative PCR, all psyllids carried Carsonella, at higher titres than their dominant S-endosymbionts. Some psyllids also had Alphaproteobacteria (Lariskella, Rickettsia, Wolbachia) at varying prevalence. Incidence of other bacteria, including known plant pathogens, was low. Ecological niche of gall-forming, lerp forming and free-living psyllid species did not impact endosymbiont communities. Two flush-feeding psyllid species had population-specific differences, and this was attributable to the higher endosymbiont diversity in native ranges and the absence of some endosymbionts in invasive ranges. CONCLUSIONS: Our data support the hypothesis of strict vertical transmission of minimal core communities of bacteria in psyllids. We also found evidence for S-endosymbiont replacement across closely related psyllid species. Multiple dominant S-endosymbionts present in some host species, including at low titre, constitute potential examples of incipient endosymbiont complementation or replacement. Our multiple comparisons of deep-sequenced minimal insect bacterial communities exposed the dynamics involved in shaping insect endosymbiosis. PMID- 28587664 TI - Characterization of tau prion seeding activity and strains from formaldehyde fixed tissue. AB - Tauopathies such as Alzheimer's disease (AD) feature progressive intraneuronal deposition of aggregated tau protein. The cause is unknown, but in experimental systems trans-cellular propagation of tau pathology resembles prion pathogenesis. Tau aggregate inoculation into mice produces transmissible pathology, and tau forms distinct strains, i.e. conformers that faithfully replicate and create predictable patterns of pathology in vivo. The prion model predicts that tau seed formation will anticipate neurofibrillary tau pathology. To test this idea requires simultaneous assessment of seed titer and immunohistochemistry (IHC) of brain tissue, but it is unknown whether tau seed titer can be determined in formaldehyde-fixed tissue. We have previously created a cellular biosensor system that uses flow cytometry to quantify induced tau aggregation and thus determine seed titer. In unfixed tissue from PS19 tauopathy mice that express 1 N,4R tau (P301S), we have measured tau seeding activity that precedes the first observable histopathology by many months. Additionally, in fresh frozen tissue from human AD subjects at early to mid-neurofibrillary tangle stages (NFT I-IV), we have observed tau seeding activity in cortical regions predicted to lack neurofibrillary pathology. However, we could not directly compare the same regions by IHC and seeding activity in either case. We now describe a protocol to extract and measure tau seeding activity from small volumes (.04 mm3) of formaldehyde-fixed tissue immediately adjacent to that used for IHC. We validated this method with the PS19 transgenic mouse model, and easily observed seeding well before the development of phospho-tau pathology. We also accurately isolated two tau strains, DS9 and DS10, from fixed brain tissues in mice. Finally, we have observed robust seeding activity in fixed AD brain, but not controls. The successful coupling of classical IHC with seeding and strain detection should enable detailed study of banked brain tissue in AD and other tauopathies. PMID- 28587665 TI - Hospitalization for community-acquired febrile urinary tract infection: validation and impact assessment of a clinical prediction rule. AB - BACKGROUND: There is a lack of severity assessment tools to identify adults presenting with febrile urinary tract infection (FUTI) at risk for complicated outcome and guide admission policy. We aimed to validate the Prediction Rule for Admission policy in Complicated urinary Tract InfeCtion LEiden (PRACTICE), a modified form of the pneumonia severity index, and to subsequentially assess its use in clinical practice. METHODS: A prospective observational multicenter study for model validation (2004-2009), followed by a multicenter controlled clinical trial with stepped wedge cluster-randomization for impact assessment (2010-2014), with a follow up of 3 months. Paricipants were 1157 consecutive patients with a presumptive diagnosis of acute febrile UTI (787 in validation cohort and 370 in the randomized trial), enrolled at emergency departments of 7 hospitals and 35 primary care centers in the Netherlands. The clinical prediction rule contained 12 predictors of complicated course. In the randomized trial the PRACTICE included guidance on hospitalization for high risk (>100 points) and home discharge for low risk patients (<75 points), in the control period the standard policy regarding hospital admission was applied. Main outcomes were effectiveness of the clinical prediction rule, as measured by primary hospital admission rate, and its safety, as measured by the rate of low-risk patients who needed to be hospitalized for FUTI after initial home-based treatment, and 30-day mortality. RESULTS: A total of 370 patients were included in the randomized trial, 237 in the control period and 133 in the intervention period. Use of PRACTICE significantly reduced the primary hospitalization rate (from 219/237, 92%, in the control group to 96/133, 72%, in the intervention group, p < 0.01). The secondary hospital admission rate after initial outpatient treatment was 6% in control patients and 27% in intervention patients (1/17 and 10/37; p < 0.001). CONCLUSIONS: Although the proposed PRACTICE prediction rule is associated with a lower number of hospital admissions of patients presenting to the ED with presumptive febrile urinary tract infection, futher improvement is necessary to reduce the occurrence of secondary hospital admissions. TRIAL REGISTRATION: NTR4480 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4480 , registered retrospectively 25 mrt 2014 (during enrollment of subjects). PMID- 28587666 TI - Protocol for a systematic review of the efficacy of fat grafting and platelet rich plasma for wound healing. AB - BACKGROUND: The use of fat grafting as a reconstructive surgical option is becoming much more common. Adipose-derived stem cells found in fat grafts are believed to facilitate wound healing via differentiation into fibroblasts and keratinocytes and the release of pro-healing growth factors. Several small studies have shown a positive effect of fat grafting in healing of wounds of a variety of aetiologies. When fat is combined with autologous platelet-rich plasma (PRP), there may be enhanced healing effects. This may be due to the pro angiogenic and anti-inflammatory effects of PRP. We aim to synthesise the current evidence on combination fat grafting and PRP for wound healing to establish the efficacy of this technique. METHODS/DESIGN: We will conduct a comprehensive literature search in the MEDLINE, EMBASE, CENTRAL, Science Citation Index, and Google Scholar databases (up to July 2017) to identify studies on fat grafting and PRP for wound healing. All primary studies and systematic reviews of these studies will be included, except case reports and case series with fewer than three patients, to evaluate the outcome of fat grafting and PRP on wound healing either on its own or when compared to other studies. Primary outcome measures are expected to be the proportion of total wounds healed at 12 weeks and the average wound healing time (time for 100% re-epithelialisation). Expected secondary outcome measures are the proportion of wounds achieving 50% wound healing, the type of wound benefitting most from fat grafting, economic evaluation, health related quality of life, and adverse events. Subgroup analysis will be performed for the proportions of wounds healed based on wound aetiology. DISCUSSION: This review will provide robust evidence of the efficacy of fat grafting and PRP for wound healing. This is an emerging technique, and this review is expected to guide clinical practice and ongoing research aimed at improving wound care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049881. PMID- 28587668 TI - Alterations of hair cortisol and dehydroepiandrosterone in mother-infant-dyads with maternal childhood maltreatment. AB - BACKGROUND: Child maltreatment (CM) has severe effects on psychological and physical health. The hypothalamic-pituitary-adrenal (HPA) axis, the major stress system of the body, is dysregulated after CM. The analysis of cortisol and dehydroepiandrosterone (DHEA) in scalp hair presents a new and promising methodological approach to assess chronic HPA axis activity. This study investigated the effects of CM on HPA axis activity in the last trimester of pregnancy by measuring the two important signaling molecules, cortisol and DHEA in hair, shortly after parturition. In addition, we explored potential effects of maternal CM on her offspring's endocrine milieu during pregnancy by measuring cortisol and DHEA in newborns' hair. METHODS: CM was assessed with the Childhood Trauma Questionnaire (CTQ). Cortisol and DHEA were measured in hair samples of 94 mothers and 30 newborns, collected within six days after delivery. Associations of maternal CM on her own and her newborn's cortisol as well as DHEA concentrations in hair were analyzed with heteroscedastic regression models. RESULTS: Higher CM was associated with significantly higher DHEA levels, but not cortisol concentrations in maternal hair. Moreover, maternal CM was positively, but only as a non-significant trend, associated with higher DHEA levels in the newborns' hair. CONCLUSIONS: Results suggest that the steroid milieu of the mother, at least on the level of DHEA, is altered after CM, possibly leading to non-genomic transgenerational effects on the developing fetus in utero. Indeed, we observed on an explorative level first hints that the endocrine milieu for the developing child might be altered in CM mothers. These results need extension and replication in future studies. The measurement of hair steroids in mothers and their newborns is promising, but more research is needed to better understand the effects of a maternal history of CM on the developing fetus. PMID- 28587667 TI - The effects of basal insulin peglispro vs. insulin glargine on lipoprotein particles by NMR and liver fat content by MRI in patients with diabetes. AB - BACKGROUND: In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine. METHODS: In three cohorts of patients with diabetes (type 1, type 2 insulin naive, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures. RESULTS: In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naive patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine. CONCLUSIONS: The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012). PMID- 28587669 TI - Ivermectin-treated cattle reduces blood digestion, egg production and survival of a free-living population of Anopheles arabiensis under semi-field condition in south-eastern Tanzania. AB - BACKGROUND: Anopheles arabiensis feed on cattle and contributes to residual transmission of malaria in areas with high coverage of long-lasting insecticide treated nets and indoor residual spraying in East Africa. This study aimed to evaluate the effects of ivermectin-treated cattle as a complementary vector control tool against population of An. arabiensis under the semi-field conditions in south-eastern Tanzania. METHODS: The free-living population of An. arabiensis was allowed to forage on untreated or ivermectin-treated cattle in alternating nights within the semi-field system in south-eastern Tanzania. Fresh blood fed mosquitoes were collected in the morning using mouth aspirators and assessed for their blood meal digestion, egg production, and survivorship. The residual activity of ivermectin-treated cattle was also determined by exposing mosquitoes to the same treatments after every 2 days until day 21 post-treatments. These experiments were replicated 3 times using different individual cattle. RESULTS: Overall, the ivermectin-treated cattle reduced blood meal digestion in the stomach of An. arabiensis, and their subsequent egg production and survival over time. The ivermectin-treated cattle halved blood meal digestion in mosquitoes, but reduced their egg production for up to 15 days. The ivermectin-treated cattle reduced the survival, and median survival times (1-3 days) of An. arabiensis than control cattle. The daily mortality rates of mosquitoes fed on ivermectin-treated cattle increased by five-fold relative to controls in the first week, and it gradually declined up to 21 days after treatment. CONCLUSION: This study demonstrates that long-lasting effects of ivermectin-treated cattle on egg production and survival of An. arabiensis may sustainably suppress their vector density, and reduce residual transmission of malaria. This study suggests that ivermectin-treated non-lactating cattle (i.e. calves, heifers and bulls) could be suitable option for large-scale malaria vector control without limiting consumption of milk and meat by communities in rural settings. Furthermore, simulation models are underway to predict the impact of ivermectin-treated cattle alone, or in combination with LLIN/IRS, the frequency of treatment, and their coverage required to significantly suppress population of An. arabiensis and reduce residual transmission of malaria. PMID- 28587670 TI - High mobility group box-1 contributes to anti-myeloperoxidase antibody-induced glomerular endothelial cell injury through a moesin-dependent route. AB - BACKGROUND: Our previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation. Cross reactivity between moesin and anti-myeloperoxidase (MPO) antibody has been reported in both human and mouse. The current study investigated whether HMGB1 participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV. METHODS: The effects of HMGB1 on expression of moesin on GEnCs and anti-MPO antibody binding to GEnCs were measured. MPO expression on GEnCs was explored. The effects of HMGB1 in MPO-ANCA induced GEnC injury were measured, during which the role of moesin was explored. Antagonists for various relevant receptors were employed. RESULTS: Sera from AAV patients at the active stage could mediate GEnC injury, while this effect could be attenuated by preblocking HMGB1. HMGB1 could increase the expression of moesin on GEnCs and the binding of anti-MPO antibody to moesin. The colocalization of moesin expression and anti-MPO antibody binding can be detected. Little, if any, MPO was expressed in GEnCs. HMGB1 increased GEnC activation and injury in the presence of patient-derived MPO-ANCA-positive IgGs through moesin. The effects of HMGB1 on expression of moesin on GEnCs, anti-MPO antibody binding to GEnCs, GEnC activation and injury were mainly toll like receptor 4 (TLR4) dependent. CONCLUSIONS: HMGB1 can increase the expression of moesin but not MPO on GEnCs, and can further participate in MPO-ANCA-induced GEnC activation and injury by cross-reactivity between moesin and anti-MPO antibody. PMID- 28587672 TI - Exploring parent-reported barriers to supporting their child's health behaviors: a cross-sectional study. AB - BACKGROUND: Parents can influence the health behaviors of their children by engaging in supportive behaviors (e.g., playing outside with their child, limiting recreational screen time). How, and the extent to which parents engage in supportive behaviors may be influenced by perceived barriers. The purpose of this study is to explore whether the frequency, and types, of barriers to providing parental support are dependent on the type of child health behavior being supported (i.e., physical activity, recreational screen time reduction, healthy eating, and sleep). METHODS: Study participants were 1140 Ontario parents with at least one child under the age of 18 who completed a Computer Assisted Telephone Interview (CATI) survey about parental support behaviors. Open-ended responses about perceived barriers to parental support were coded, and aggregated to meta-categories adopted from the social-ecological model (i.e., individual child, individual parent, interpersonal, environmental). Freidman rank sum tests were used to assess differences across child behaviors. Wilcoxon rank sum tests with Bonferroni adjustments were used as a post hoc test for significant Freidman results. RESULTS: There were more barriers reported for supporting physical activity than for any other child behavior (ps < .01, As >= .53). Parents reported more parent level and environmental level barriers to supporting child physical activity versus other behaviors (ps < .001, As >= .55), child level barriers were more frequently reported for supporting healthy eating and sleep (ps < .001, As >= .57), and interpersonal barriers were more frequently reported for supporting recreational screen time reduction (ps < .001, As >= .52). Overall, parents reported more child and parent level barriers versus interpersonal and environmental barriers to supporting child health. CONCLUSIONS: Parents experience a variety of barriers to supporting their children's health behaviors. Differences in types of barriers across child health behaviors emerged; however, some frequently reported barriers (e.g., child preferences) were common across behaviors. Interventions promoting parental support should consider strategies that can accommodate parents' busy schedules, and relate to activities that children find enjoyable. Creating supportive environments that help facilitate support behaviors, while minimizing parent level barriers, may be of particular benefit. Future research should explore the impact of barriers on parental support behaviors, and effective strategies for overcoming common barriers. PMID- 28587671 TI - Integrative taxonomy by molecular species delimitation: multi-locus data corroborate a new species of Balkan Drusinae micro-endemics. AB - BACKGROUND: Taxonomy offers precise species identification and delimitation and thus provides basic information for biological research, e.g. through assessment of species richness. The importance of molecular taxonomy, i.e., the identification and delimitation of taxa based on molecular markers, has increased in the past decade. Recently developed exploratory tools now allow estimating species-level diversity in multi-locus molecular datasets. RESULTS: Here we use molecular species delimitation tools that either quantify differences in intra- and interspecific variability of loci, or divergence times within and between species, or perform coalescent species tree inference to estimate species-level entities in molecular genetic datasets. We benchmark results from these methods against 14 morphologically readily differentiable species of a well-defined subgroup of the diverse Drusinae subfamily (Trichoptera, Limnephilidae). Using a 3798 bp (6 loci) molecular data set we aim to corroborate a geographically isolated new species by integrating comparative morphological studies and molecular taxonomy. CONCLUSIONS: Our results indicate that only multi-locus species delimitation provides taxonomically relevant information. The data further corroborate the new species Drusus zivici sp. nov. We provide differential diagnostic characters and describe the male, female and larva of this new species and discuss diversity patterns of Drusinae in the Balkans. We further discuss potential and significance of molecular species delimitation. Finally we argue that enhancing collaborative integrative taxonomy will accelerate assessment of global diversity and completion of reference libraries for applied fields, e.g., conservation and biomonitoring. PMID- 28587673 TI - Pathohistological investigation of osteochondral tissue obtained during total knee arthroplasty after osteochondral autologous transfer: a case report. AB - BACKGROUND: Osteochondral autologous transfer is one of the repair techniques for cartilage defects of knee with promising knee function recovery. There are no reports including histopathological images concerning human osteochondral tissue after osteochondral autologous transfer. This is the first report to present pathohistological findings of transplanted plugs and host tissues extracted from the human body 3 years after osteochondral autologous transfer. This study aimed to explore the cause factor of chronic pain using histological techniques. CASE PRESENTATION: A 67-year-old Japanese man presented with adjusted total knee arthroplasty 3 years after osteochondral autologous transfer. Although in pain, arthroscopic assessment was not severe. The specimens which was gained during total knee arthroplasty were investigated in gross and microscopically using immunohistochemical staining technic. Histological examination revealed that the gap between grafted plugs and host osteochondral tissues was filled with fibrous tissue that stained positive for type I collagen. A degenerative change and some neovascularity were observed in the regenerated tissue and host trabecular bone. Furthermore, cysts and bone marrow edema were observed. CONCLUSION: Our data suggests that the host osteochondral morbidity around grafted plugs might be related to chronical pain and revision surgery. PMID- 28587674 TI - NaviSE: superenhancer navigator integrating epigenomics signal algebra. AB - BACKGROUND: Superenhancers are crucial structural genomic elements determining cell fate, and they are also involved in the determination of several diseases, such as cancer or neurodegeneration. Although there are pipelines which use independent pieces of software to predict the presence of superenhancers from genome-wide chromatin marks or DNA-interaction protein binding sites, there is not yet an integrated software tool that processes automatically algebra combinations of raw data sequencing into a comprehensive final annotated report of predicted superenhancers. RESULTS: We have developed NaviSE, a user-friendly streamlined tool which performs a fully-automated parallel processing of genome wide epigenomics data from sequencing files into a final report, built with a comprehensive set of annotated files that are navigated through a graphic user interface dynamically generated by NaviSE. NaviSE also implements an 'epigenomics signal algebra' that allows the combination of multiple activation and repression epigenomics signals. NaviSE provides an interactive chromosomal landscaping of the locations of superenhancers, which can be navigated to obtain annotated information about superenhancer signal profile, associated genes, gene ontology enrichment analysis, motifs of transcription factor binding sites enriched in superenhancers, graphs of the metrics evaluating the superenhancers quality, protein-protein interaction networks and enriched metabolic pathways among other features. We have parallelised the most time-consuming tasks achieving a reduction up to 30% for a 15 CPUs machine. We have optimized the default parameters of NaviSE to facilitate its use. NaviSE allows different entry levels of data processing, from sra-fastq files to bed files; and unifies the processing of multiple replicates. NaviSE outperforms the more time-consuming processes required in a non-integrated pipeline. Alongside its high performance, NaviSE is able to provide biological insights, predicting cell type specific markers, such as SOX2 and ZIC3 in embryonic stem cells, CDK5R1 and REST in neurons and CD86 and TLR2 in monocytes. CONCLUSIONS: NaviSE is a user-friendly streamlined solution for superenhancer analysis, annotation and navigation, requiring only basic computer and next generation sequencing knowledge. NaviSE binaries and documentation are available at: https://sourceforge.net/projects/navise superenhancer/ . PMID- 28587675 TI - Bactericidal effects of 310 nm ultraviolet light-emitting diode irradiation on oral bacteria. AB - BACKGROUND: Ultraviolet (UV) light is used for phototherapy in dermatology, and UVB light (around 310 nm) is effective for treatment of psoriasis and atopic dermatitis. In addition, it is known that UVC light (around 265 nm) has a bactericidal effect, but little is known about the bactericidal effect of UVB light. In this study, we examined the bactericidal effects of UVB-light emitting diode (LED) irradiation on oral bacteria to explore the possibility of using a 310 nm UVB-LED irradiation device for treatment of oral infectious diseases. METHODS: We prepared a UVB (310 nm) LED device for intraoral use to examine bactericidal effects on Streptococcus mutans, Streptococcus sauguinis, Porphyromonas gingivalis, and Fusobacterium nucleatum and also to examine the cytotoxicity to a human oral epithelial cell line (Ca9-22). We also examined the production of nitric oxide and hydrogen peroxide from Ca9-22 cells after irradiation with UVB-LED light. RESULTS: Irradiation with the 310 nm UVB-LED at 105 mJ/cm2 showed 30-50% bactericidal activity to oral bacteria, though 17.1 mJ/cm2 irradiation with the 265 nm UVC-LED completely killed the bacteria. Ca9-22 cells were strongly injured by irradiation with the 265 nm UVC-LED but were not harmed by irradiation with the 310 nm UVB-LED. Nitric oxide and hydrogen peroxide were produced by Ca9-22 cells with irradiation using the 310 nm UVB-LED. P. gingivalis was killed by applying small amounts of those reactive oxygen species (ROS) in culture, but other bacteria showed low sensitivity to the ROS. CONCLUSIONS: Narrowband UVB-LED irradiation exhibited a weak bactericidal effect on oral bacteria but showed low toxicity to gingival epithelial cells. Its irradiation also induces the production of ROS from oral epithelial cells and may enhance bactericidal activity to specific periodontopathic bacteria. It may be useful as a new adjunctive therapy for periodontitis. PMID- 28587677 TI - Anti-obesity activity, acute toxicity, and chemical constituents of aqueous and ethanol Viola mandshurica extracts. AB - BACKGROUND: Viola mandshurica has traditionally been used as an expectorant, diuretic, and anti-inflammatory drug. The present study was designed to test the hypothesis that low doses of two different V. mandshurica extracts have anti obesity effects. METHODS: We evaluated the effects of ethanol extract (VME) and aqueous extract (VMA) from V. mandshurica on high-fat diet (HFD)-induced obese mice as well as the acute oral toxicities and chemical compositions of both extracts. RESULTS: Oral administration of VME or VMA (50, 100, or 200 mg/kg) decreased body weight gain, liver and adipose tissue mass, adipocyte size, and serum lipid levels. Both extracts increased adiponectin serum concentrations and mRNA expression in epididymal adipose tissue. VME and VMA also reversed the HFD induced mRNA expression of lipogenic genes such as CCAAT/enhancer binding protein (C/EBP)alpha, C/EBPbeta, sterol regulatory element-binding protein 1c, and leptin in adipose tissue, whereas they increased mRNA expression of uncoupling protein 2 and adenosine monophosphate-activated protein kinase (AMPK). VME and VMA increased the phosphorylation of AMPK and acetyl-coA carboxylase with a concomitant decrease in fat accumulation in the liver. High performance liquid chromatography analysis revealed that both VME and VMA contained esculetin (0.566% for VME, 0.231% for VMA) and schaftoside (0.147% for VME, 0.126% for VMA). In a 2-week acute toxicity study, administration of a single oral dose of VME or VMA (5000 mg/kg) caused no signs of toxicity or mortality. CONCLUSIONS: These results suggest that both VM extracts exert anti-obesity effects in HFD induced obese mice by suppressing lipogenesis and activating AMPK in the liver and adipose tissue. Our findings suggest that VM extracts could be a safe and effective treatment for obesity. PMID- 28587679 TI - Somatic cell selection for chlorsulfuron-resistant mutants in potato: identification of point mutations in the acetohydroxyacid synthase gene. AB - BACKGROUND: Somatic cell selection in plants allows the recovery of spontaneous mutants from cell cultures. When coupled with the regeneration of plants it allows an effective approach for the recovery of novel traits in plants. This study undertook somatic cell selection in the potato (Solanum tuberosum L.) cultivar 'Iwa' using the sulfonylurea herbicide, chlorsulfuron, as a positive selection agent. RESULTS: Following 5 days' exposure of potato cell suspension cultures to 20 MUg/l chlorsulfuron, rescue selection recovered rare potato cell colonies at a frequency of approximately one event in 2.7 * 105 of plated cells. Plants that were regenerated from these cell colonies retained resistance to chlorsulfuron and two variants were confirmed to have different independent point mutations in the acetohydroxyacid synthase (AHAS) gene. One point mutation involved a transition of cytosine for thymine, which substituted the equivalent of Pro-197 to Ser-197 in the AHAS enzyme. The second point mutation involved a transversion of thymine to adenine, changing the equivalent of Trp-574 to Arg 574. The two independent point mutations recovered were assembled into a chimeric gene and binary vector for Agrobacterium-mediated transformation of wild-type 'Iwa' potato. This confirmed that the mutations in the AHAS gene conferred chlorsulfuron resistance in the resulting transgenic plants. CONCLUSIONS: Somatic cell selection in potato using the sulfonylurea herbicide, chlorsulfuron, recovered resistant variants attributed to mutational events in the AHAS gene. The mutant AHAS genes recovered are therefore good candidates as selectable marker genes for intragenic transformation of potato. PMID- 28587676 TI - Access barriers to obstetric care at health facilities in sub-Saharan Africa-a systematic review. AB - BACKGROUND: Since 2000, the United Nations' Millennium Development Goals, which included a goal to improve maternal health by the end of 2015, has facilitated significant reductions in maternal morbidity and mortality worldwide. However, despite more focused efforts made especially by low- and middle-income countries, targets were largely unmet in sub-Saharan Africa, where women are plagued by many challenges in seeking obstetric care. The aim of this review was to synthesise literature on barriers to obstetric care at health institutions in sub-Saharan Africa. METHODS: This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus databases were electronically searched to identify studies on barriers to health facility-based obstetric care in sub-Saharan Africa, in English, and dated between 2000 and 2015. Combinations of search terms 'obstetric care', 'access', 'barriers', 'developing countries' and 'sub-Saharan Africa' were used to locate articles. Quantitative, qualitative and mixed-methods studies were considered. A narrative synthesis approach was employed to synthesise the evidence and explore relationships between included studies. RESULTS: One hundred and sixty articles met the inclusion criteria. Currently, obstetric care access is hindered by several demand- and supply-side barriers. The principal demand-side barriers identified were limited household resources/income, non-availability of means of transportation, indirect transport costs, a lack of information on health care services/providers, issues related to stigma and women's self esteem/assertiveness, a lack of birth preparation, cultural beliefs/practices and ignorance about required obstetric health services. On the supply-side, the most significant barriers were cost of services, physical distance between health facilities and service users' residence, long waiting times at health facilities, poor staff knowledge and skills, poor referral practices and poor staff interpersonal relationships. CONCLUSION: Despite similarities in obstetric care barriers across sub-Saharan Africa, country-specific strategies are required to tackle the challenges mentioned. Governments need to develop strategies to improve healthcare systems and overall socioeconomic status of women, in order to tackle supply- and demand-side access barriers to obstetric care. It is also important that strategies adopted are supported by research evidence appropriate for local conditions. Finally, more research is needed, particularly, with regard to supply-side interventions that may improve the obstetric care experience of pregnant women. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2014 CRD42014015549. PMID- 28587678 TI - SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is in most cases caused by a contraction of the D4Z4 macrosatellite repeat on chromosome 4 (FSHD1) or by mutations in the SMCHD1 or DNMT3B gene (FSHD2). Both situations result in the incomplete epigenetic repression of the D4Z4-encoded retrogene DUX4 in somatic cells, leading to the aberrant expression of DUX4 in the skeletal muscle. In mice, Smchd1 regulates chromatin repression at different loci, having a role in CpG methylation establishment and/or maintenance. METHODS: To investigate the global effects of harboring heterozygous SMCHD1 mutations on DNA methylation in humans, we combined 450k methylation analysis on mononuclear monocytes from female heterozygous SMCHD1 mutation carriers and unaffected controls with reduced representation bisulfite sequencing (RRBS) on FSHD2 and control myoblast cell lines. Candidate loci were then evaluated for SMCHD1 binding using ChIP-qPCR and expression was evaluated using RT-qPCR. RESULTS: We identified a limited number of clustered autosomal loci with CpG hypomethylation in SMCHD1 mutation carriers: the protocadherin (PCDH) cluster on chromosome 5, the transfer RNA (tRNA) and 5S rRNA clusters on chromosome 1, the HOXB and HOXD clusters on chromosomes 17 and 2, respectively, and the D4Z4 repeats on chromosomes 4 and 10. Furthermore, minor increases in RNA expression were seen in FSHD2 myoblasts for some of the PCDHbeta cluster isoforms, tRNA isoforms, and a HOXB isoform in comparison to controls, in addition to the previously reported effects on DUX4 expression. SMCHD1 was bound at DNAseI hypersensitivity sites known to regulate the PCDHbeta cluster and at the chromosome 1 tRNA cluster, with decreased binding in SMCHD1 mutation carriers at the PCDHbeta cluster sites. CONCLUSIONS: Our study is the first to investigate the global methylation effects in humans resulting from heterozygous mutations in SMCHD1. Our results suggest that SMCHD1 acts as a repressor on a limited set of autosomal gene clusters, as an observed reduction in methylation associates with a loss of SMCHD1 binding and increased expression for some of the loci. PMID- 28587680 TI - In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells. AB - BACKGROUND: Epilepsy is a frequent symptom in patients with glioma. Although treatment with antiepileptic drugs is generally effective in controlling seizures, drug-resistant patients are not uncommon. Multidrug resistance proteins (MRPs) and P-gp are over-represented in brain tissue of patients with drug resistant epilepsy, suggesting their involvement in the clearance of antiepileptic medications. In addition to their anticonvulsant action, some drugs have been documented for cytotoxic effects. Aim of this study was to evaluate possible in vitro cytotoxic effects of two new-generation antiepileptic drugs on a human glioma cell line U87MG. METHODS: Cytotoxicity of brivaracetam and lacosamide was tested on U87MG, SW1783 and T98G by MTS assay. Expression of chemoresistance molecules was evaluated using flow cytometry in U87MG and human umbilical vein endothelial cells (HUVECs). To investigate the putative anti proliferative effect, apoptosis assay, microRNA expression profile and study of cell cycle were performed. RESULTS: Brivaracetam and lacosamide showed a dose dependent cytotoxic and anti-migratory effects. Cytotoxicity was not related to apoptosis. The exposure of glioma cells to brivaracetam and lacosamide resulted in the modulation of several microRNAs; particularly, the effect of miR-195-5p modulation seemed to affect cell cycle, while miR-107 seemed to be implicated in the inhibition of cells migration. Moreover, brivaracetam and lacosamide treatment did not modulate the expression of chemoresistance-related molecules MRPs1-3-5, GSTpi, P-gp on U87MG and HUVECs. CONCLUSION: Based on antineoplastic effect of brivaracetam and lacosamide on glioma cells, we assume that patients with glioma could benefit by the treatment with these two molecules, in addition to standard therapeutic options. PMID- 28587681 TI - PET/CT-guided dose-painting versus CT-based intensity modulated radiation therapy in locoregional advanced nasopharyngeal carcinoma. AB - BACKGROUND: The effect of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)-guided dose-painting intensity modulated radiation therapy (IMRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the efficacy and toxicity of such combination. METHODS: From 2012 to 2014, 213 patients with stage III-IVB NPC received chemoradiotherapy by PET/CT-guided DP-IMRT (group A, n = 101) or CT based IMRT (group B, n = 112). In group A, subvolume GTVnx-PET (gross tumor volume of nasopharynx in PET images) was defined within GTVnx (gross tumor volume of nasopharynx) as the SUV50%max isocontour; the dose to GTVnx-PET was escalated to DT 75.2 Gy/32 and 77.55 Gy/33 Fx, respectively, for patients with T1-2 and T3 4 disease, respectively. In group B, PGTVnx was irradiated at DT 70.4-72.6 Gy/32 33 Fx in 2.2 Gy per fraction. RESULTS: Complete response rates were 99.0% (100/101) and 92.9% (104/112) in groups A and B, respectively (P = 0.037). Compared with CT-based IMRT, FDG-PET/CT guided DP-IMRT significantly improved 3 year local failure-free survival (LFFS, 98.8% vs. 91.3%; P = 0.032), locoregional failure-free survival (LRFFS, 97.2 vs. 91.2%; P = 0.049), distant metastasis-free survival (DMFS, 92.9% vs. 87.4%; P = 0.041), disease free survival (DFS, 87.9% vs. 82.4%; P = 0.02), and overall survival (OS, 91.8% vs. 82.6%; P = 0.049). No statistically significant differences in acute and late toxic effects were observed. Multivariate analysis showed that dose painting (PET/CT-guided DP-IMRT vs CT-based IMRT without DP) was a significant independent prognostic factor for LFFS and DFS. CONCLUSION: FDG-PET/CT guided DP-IMRT plus chemotherapy is associated with a considerable survival benefit, without increasing toxicity in patients with locoregional advanced NPC. Further randomized trials are needed to fully assess the role of PET/CT-guided DP-IMRT. PMID- 28587684 TI - CASTE DIFFERENTIALS IN DEATH CLUSTERING IN CENTRAL AND EASTERN INDIAN STATES. AB - This study assessed caste differentials in family-level death clustering, linked survival prospects of siblings (scarring) and mother-level unobserved heterogeneity affecting infant mortality risk in the central and eastern Indian states of Jharkhand, Madhya Pradesh, Odisha and Chhattisgarh. Family-level infant death clustering was examined using bivariate analysis, and the linkages between the survival prospects of siblings and mother-specific unobserved heterogeneity were captured by applying a random effects logit model in the selected Indian states using micro-data from the National Family Health Survey-III (2005-06). The raw data clustering analysis showed the existence of clustering in all four states and among all caste groups with the highest clustering found in the Scheduled Castes of Jharkhand. The important factor from the model that increased the risk of infant deaths in all four states was the causal effect of a previous infant death on the risk of infant death of the subsequent sibling, after controlling for mother-level heterogeneity and unobserved factors. The results show that among the Scheduled Castes and Scheduled Tribes, infant death clustering is mainly affected by the scarring factor in Jharkhand and Madhya Pradesh, while mother-level unobserved factors were important in Odisha and both (scarring and mother-level unobserved factors) were key factors in Chhattisgarh. Similarly, the Other Caste Group was mainly influenced by the scarring factor only in Odisha, mother-level unobserved factors in Jharkhand and Chhattisgarh and both (scarring and mother-level unobserved factors) in Madhya Pradesh. From a government policy perspective, these results would help in identifying high-risk clusters of women among all caste groups in the four central and eastern Indian states that should be targeted to address maternal and child health related indicators. PMID- 28587682 TI - PLGF, a placental marker of fetal brain defects after in utero alcohol exposure. AB - Most children with in utero alcohol exposure do not exhibit all features of fetal alcohol syndrome (FAS), and a challenge for clinicians is to make an early diagnosis of fetal alcohol spectrum disorders (FASD) to avoid lost opportunities for care. In brain, correct neurodevelopment requires proper angiogenesis. Since alcohol alters brain angiogenesis and the placenta is a major source of angiogenic factors, we hypothesized that it is involved in alcohol-induced brain vascular defects. In mouse, using in vivo repression and overexpression of PLGF, we investigated the contribution of placenta on fetal brain angiogenesis. In human, we performed a comparative molecular and morphological analysis of brain/placenta angiogenesis in alcohol-exposed fetuses. Results showed that prenatal alcohol exposure impairs placental angiogenesis, reduces PLGF levels and consequently alters fetal brain vasculature. Placental repression of PLGF altered brain VEGF-R1 expression and mimicked alcohol-induced vascular defects in the cortex. Over-expression of placental PGF rescued alcohol effects on fetal brain vessels. In human, alcohol exposure disrupted both placental and brain angiogenesis. PLGF expression was strongly decreased and angiogenesis defects observed in the fetal brain markedly correlated with placental vascular impairments. Placental PGF disruption impairs brain angiogenesis and likely predicts brain disabilities after in utero alcohol exposure. PLGF assay at birth could contribute to the early diagnosis of FASD. PMID- 28587683 TI - Spatial and temporal distribution of American cutaneous leishmaniasis in Acre state, Brazil. AB - BACKGROUND: Acre has reported the highest incidence of American cutaneous leishmaniasis (ACL) in Brazil in recent years. The present study seeks to identify high and low risk agglomerations of ACL in space and space-time during the period from 2007 to 2013 in Acre, and also to characterize the occurrence of the disease in time and according to sociodemographic variables. METHODS: This is an ecological study, the study population of which consisted of autochthonous ACL cases notified in the municipalities of Acre by an epidemiological surveillance system. Scan statistics of SaTScanTM software were used to identify spatial and space-time clusters. In addition, the cases were characterized by sex, age, home situation (in a rural or urban area), and temporal tendency. RESULTS: Acre reported an incidence rate of 12.4 cases per 10 000 inhabitant-years in the study period, with the rates varied greatly (standard deviation of 21.8) among their 22 municipalities. One agglomeration of high risk and three of low risk were detected in space and space-time. Four of the five micro-regions of Acre presented a stationary temporal tendency. The profile of transmission varied according to the micro-region. Generally speaking, the disease occurred more often among young people, those of male gender, and those living in rural areas. CONCLUSIONS: Acre has stood out within the Brazilian national context due to its high rates of ACL incidence in the central region of the Acre Valley. The high rates in the micro-region of Brasileia are related to the disease's intra/peridomiciliary occurrence, and it would seem that the municipality of Sena Madureira is approaching a transmission pattern similar to that of Brasileia. In other micro-regions, the profile of the disease's transmission is mainly related to the forest/sylvatic cycle of ACL. PMID- 28587685 TI - Carotenoid dietary intakes and plasma concentrations are associated with heel bone ultrasound attenuation and osteoporotic fracture risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort. AB - Carotenoids are found in abundance in fruit and vegetables, and may be involved in the positive association of these foods with bone health. This study aimed to explore the associations of dietary carotenoid intakes and plasma concentrations with bone density status and osteoporotic fracture risk in a European population. Cross-sectional analyses (n 14 803) of bone density status, using calcaneal broadband ultrasound attenuation (BUA) and longitudinal analyses (n 25 439) of fracture cases were conducted on data from the prospective European Prospective Investigation into Cancer and Nutrition-Norfolk cohort of middle-aged and older men and women. Health and lifestyle questionnaires were completed, and dietary nutrient intakes were derived from 7-d food diaries. Multiple regression demonstrated significant positive trends in BUA for women across quintiles of dietary alpha-carotene intake (P=0.029), beta-carotene intake (P=0.003), beta cryptoxanthin intake (P=0.031), combined lutein and zeaxanthin intake (P=0.010) and lycopene intake (P=0.005). No significant trends across plasma carotenoid concentration quintiles were apparent (n 4570). The Prentice-weighted Cox regression showed no trends in fracture risk across dietary carotenoid intake quintiles (mean follow-up time 12.5 years), except for a lower risk for wrist fracture in women with higher lutein and zeaxanthin intake (P=0.022); nevertheless, inter-quintile differences in fracture risk were found for both sexes. Analysis of plasma carotenoid data (mean follow-up time 11.9 years) showed lower hip fracture risk in men across higher plasma alpha-carotene (P=0.026) and beta-carotene (P=0.027) quintiles. This study provides novel evidence that dietary carotenoid intake is relevant to bone health in men and women, demonstrating that associations with bone density status and fracture risk exist for dietary intake of specific carotenoids and their plasma concentrations. PMID- 28587687 TI - Physiological importance of polyamines. AB - Polyamines are polycationic molecules that contain two or more amino groups (-NH3 +) and are present in all eukaryotic and prokaryotic cells. Polyamines are synthesized from arginine, ornithine, and proline, and from methionine as the methyl-group donor. In the traditional pathway for polyamine synthesis, arginase converts arginine into ornithine, which is decarboxylated by ornithine decarboxylase (ODC1) to generate putrescine. The latter is converted to spermidine and spermine. Recent studies have indicated the existence of 'non classical pathways' for the generation of putrescine from arginine and proline in animal cells. Specifically, arginine decarboxylase (ADC) catalyzes the conversion of arginine into agmatine, which is hydrolyzed by agmatinase (AGMAT) to form putrescine. Additionally, proline is oxidized by proline oxidase to yield pyrroline-5-carboxylate, which undergoes transamination with glutamate to produce ornithine for decarboxylation by ODC1. Intracellular production of polyamines is controlled by antizymes binding to and inactivating ODC1. Polyamines exert effects that include stimulation of cell division and proliferation, gene expression for the survival of cells, DNA and protein synthesis, regulation of apoptosis, oxidative stress, angiogenesis, and cell-cell communication activity. Accordingly, polyamines are essential for early embryonic development and successful pregnancy outcome in mammals. In this paper the main concepts on the history, structure and molecular pathways of polyamines as well as their physiological role on angiogenesis, and reproductive physiology are reviewed. PMID- 28587686 TI - SOCIETAL PERSPECTIVE ON COST DRIVERS FOR HEALTH TECHNOLOGY ASSESSMENT IN SINDH, PAKISTAN. AB - BACKGROUND: Understanding cost-drivers and estimating societal costs are important challenges for economic evaluation of health technologies in low- and middle-income countries (LMICs). This study assessed community experiences of health resource usage and perceived cost-drivers from a societal perspective to inform the design of an economic model for the Community Level Interventions for Pre-eclampsia (CLIP) trials. METHODS: Qualitative research was undertaken alongside the CLIP trial in two districts of Sindh province, Pakistan. Nine focus groups were conducted with a wide range of stakeholders, including pregnant women, mothers-in-law, husbands, fathers-in-law, healthcare providers at community and health facility-levels, and health decision/policy makers at district-level. The societal perspective included out-of-pocket (OOP), health system, and program implementation costs related to CLIP. Thematic analysis was performed using NVivo software. RESULTS: Most pregnant women and male decision makers reported a large burden of OOP costs for in- and out-patient care, informal care from traditional healers, self-medication, childbirth, newborn care, transport to health facility, and missed wages by caretakers. Many healthcare providers identified health system costs associated with human resources for hypertension risk assessment, transport, and communication about patient referrals. Health decision/policy makers recognized program implementation costs (such as the mobile health infrastructure, staff training, and monitoring/supervision) as major investments for the health system. CONCLUSIONS: Our investigation of care-seeking practices revealed financial implications for families of pregnant women, and program implementation costs for the health system. The societal perspective provided comprehensive knowledge of cost drivers to guide an economic appraisal of the CLIP trial in Sindh, Pakistan. PMID- 28587688 TI - Hot and cold executive functions in youth with psychotic symptoms. AB - BACKGROUND: Psychotic symptoms are common in children and adolescents and may be early manifestations of liability to severe mental illness (SMI), including schizophrenia. SMI and psychotic symptoms are associated with impairment in executive functions. However, previous studies have not differentiated between 'cold' and 'hot' executive functions. We hypothesized that the propensity for psychotic symptoms is specifically associated with impairment in 'hot' executive functions, such as decision-making in the context of uncertain rewards and losses. METHODS: In a cohort of 156 youth (mean age 12.5, range 7-24 years) enriched for familial risk of SMI, we measured cold and hot executive functions with the spatial working memory (SWM) task (total errors) and the Cambridge Gambling Task (decision-making), respectively. We assessed psychotic symptoms using the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia interview, Structured Interview for Prodromal Syndromes, Funny Feelings, and Schizophrenia Proneness Instrument - Child and Youth version. RESULTS: In total 69 (44.23%) youth reported psychotic symptoms on one or more assessments. Cold executive functioning, indexed with SWM errors, was not significantly related to psychotic symptoms [odds ratio (OR) 1.36, 95% confidence interval (CI) 0.85-2.17, p = 0.204). Poor hot executive functioning, indexed as decision-making score, was associated with psychotic symptoms after adjustment for age, sex and familial clustering (OR 2.37, 95% CI 1.25-4.50, p = 0.008). The association between worse hot executive functions and psychotic symptoms remained significant in sensitivity analyses controlling for general cognitive ability and cold executive functions. CONCLUSIONS: Impaired hot executive functions may be an indicator of risk and a target for pre-emptive early interventions in youth. PMID- 28587690 TI - Family members' experience of the pre-diagnostic phase of dementia: a synthesis of qualitative evidence. AB - BACKGROUND: Most research on family members' experience of dementia has focused on the time after diagnosis. Yet, once people reach clinical attention, families have already been living with the changes for some time. These pre-diagnosis experiences can influence later caregiving. We aimed to synthesize qualitative research exploring family members' experiences of the pre-diagnostic phase of dementia to inform clinical practice. METHODS: We conducted a thematic synthesis of 11 studies that met our inclusion criteria following a comprehensive literature search. RESULTS: An overarching theme, sense-making, captured the primary process that family members engage in throughout the pre-diagnostic period. Within this, four major analytic themes were extracted as central concepts in understanding family members' experiences of the pre-diagnostic phase of dementia: the nature of change; appraisals of change; reactions to change; and the influence of others. CONCLUSIONS: Relevant features of the family experience of dementia onset can be characterized within several major themes. These findings highlight the complex process of recognizing early symptoms of dementia for people living with this condition and their families. Our findings also provide the foundation for developing theoretical frameworks that will ultimately assist with improving recognition of dementia onset, clinical communication with family members, and interventions to reduce family burden. PMID- 28587689 TI - Neurocognitive subtypes in patients with bipolar disorder and their unaffected siblings. AB - BACKGROUND: Our previous work revealed substantial heterogeneity in the cognitive profile of bipolar disorder (BD) due to the presence of three underlying cognitive subgroups characterized as: globally impaired, selectively impaired, or cognitively intact. In an effort to determine whether these subgroups are differentially related to genetic risk for the illness, we investigated whether cognitive deficits were more pronounced in unaffected siblings (UAS) of BD probands within identified clusters. METHODS: Cluster analysis was used to identify cognitive clusters in BD (N = 60). UAS (N = 49) were classified into groups according to their proband sibling's cluster assignment; comparisons were made across all clusters and healthy controls (HCs; N = 71). RESULTS: Three cognitive clusters in BD emerged: a globally impaired (36.7%), a selectively impaired (30%), and a cognitively intact cluster (33.3%). UAS showed a qualitatively similar pattern to their BD siblings; UAS of the globally impaired BD cluster showed verbal memory and general cognitive impairments relative to HCs. In contrast, UAS of the other two clusters did not differ from HCs. CONCLUSIONS: This study corroborates findings from prior work regarding the presence of cognitive heterogeneity in BD. UAS of subjects in the globally impaired BD cluster presented with a qualitatively similar cognitive profile to their siblings and performed worse than all other BD clusters and UAS groups. This suggests that inherited risk factors may be contributing to cognitive deficits more notably in one subgroup of patients with BD, pointing toward differential causes of cognitive deficits in discrete subgroups of patients with the disorder. PMID- 28587691 TI - Exploring the influence of local food environments on food behaviours: a systematic review of qualitative literature. AB - OBJECTIVE: Systematic reviews investigating associations between objective measures of the food environment and dietary behaviours or health outcomes have not established a consistent evidence base. The present paper aims to synthesise qualitative evidence regarding the influence of local food environments on food and purchasing behaviours. DESIGN: A systematic review in the form of a qualitative thematic synthesis. SETTING: Urban localities. SUBJECTS: Adults. RESULTS: Four analytic themes were identified from the review including community and consumer nutrition environments, other environmental factors and individual coping strategies for shopping and purchasing decisions. Availability, accessibility and affordability were consistently identified as key determinants of store choice and purchasing behaviours that often result in less healthy food choices within community nutrition environments. Food availability, quality and food store characteristics within consumer nutrition environments also greatly influenced in-store purchases. Individuals used a range of coping strategies in both the community and consumer nutrition environments to make optimal purchasing decisions, often within the context of financial constraints. CONCLUSIONS: Findings from the current review add depth and scope to quantitative literature and can guide ongoing theory, interventions and policy development in food environment research. There is a need to investigate contextual influences within food environments as well as individual and household socio-economic characteristics that contribute to the differing use of and views towards local food environments. Greater emphasis on how individual and environmental factors interact in the food environment field will be key to developing stronger understanding of how environments can support and promote healthier food choices. PMID- 28587692 TI - Atomic Scale Structural Characterization of Epitaxial (Cd,Cr)Te Magnetic Semiconductor. AB - A detailed knowledge of the atomic structure of magnetic semiconductors is crucial to understanding their electronic and magnetic properties, which could enable spintronic applications. Energy-dispersive X-ray spectrometry (EDX) in the scanning transmission electron microscope and atom probe tomography (APT) experiments reveal the formation of Cr-rich regions in Cd1-x Cr x Te layers grown by molecular beam epitaxy. These Cr-rich regions occur on a length scale of 6-10 nm at a nominal Cr composition of x=0.034 and evolve toward an ellipsoidal shape oriented along directions at a composition of x=0.083. Statistical analysis of the APT reconstructed volume reveals that the Cr aggregation increases with the average Cr composition. The correlation with the magnetic properties of such (Cd,Cr)Te layers is discussed within the framework of strongly inhomogeneous materials. Finally, difficulties in accurately quantifying the Cr distribution in the CdTe matrix on an atomic scale by EDX and APT are discussed. PMID- 28587694 TI - A survey of front-line paramedics examining the professional relationship between paramedics and physician medical oversight. AB - OBJECTIVE: Paramedicine is often dependent on physician medical directors and their associated programs for direction and oversight. A positive relationship between paramedics and their oversight physicians promotes safety and quality care while a strained or ineffective one may threaten these goals. The objective of this study was to explore and understand the professional relationship between paramedics and physician medical oversight as viewed by front-line paramedics. METHODS: All active front-line paramedics from four municipal paramedic services involving three medical oversight groups in Ontario were invited to complete an online survey. RESULTS: Five hundred and four paramedics were invited to participate in the study, with 242 completing the survey (48% response rate); 66% male, 76% primary care paramedics with an average of 13 (SD=9) years of experience. Paramedics had neutral or positive perceptions regarding their autonomy, opportunities to interact with their medical director, and medical director understanding of the prehospital setting. Paramedics perceived medical directives as rigid and ambiguous. A significant amount of respondents reported a perception of having provided suboptimal patient care due to fear of legal or disciplinary consequences. Issues of a lack of support for critical thinking and a lack of trust between paramedics and medical oversight groups were often raised. CONCLUSIONS: Paramedic perceptions of physician medical oversight were mixed. Concerning areas identified were perceptions of ambiguous written directives and concerns related to the level of trust and support for critical thinking. These perceptions may have implications for the system of care and should be explored further. PMID- 28587693 TI - Content analysis of targeted food and beverage advertisements in a Chinese American neighbourhood. AB - OBJECTIVES: The current descriptive study aimed to: (i) quantify the number and type of advertisements (ads) located in a Chinese-American neighbourhood in a large, urban city; and (ii) catalogue the targeted marketing themes used in the food/beverage ads. DESIGN: Ten pairs of trained research assistants photographed all outdoor ads in a 0.6 mile2 (1.6 km2) area where more than 60.0 % of residents identify as Chinese American. We used content analysis to assess the marketing themes of ads, including references to: Asian cultures; health; various languages; children; food or beverage type (e.g. sugar-sweetened soda). SETTING: Lower East Side, a neighbourhood located in the borough of Manhattan in New York City, USA. SUBJECTS: Ads (n 1366) in the designated neighbourhood. RESULTS: Food/beverage ads were the largest ad category (29.7 %, n 407), followed by services (e.g. mobile phone services; 21.0 %, n 288). Sixty-seven per cent (66.9 %) of beverages featured were sugar-sweetened, and 50.8 % of food ads promoted fast food. Fifty-five per cent (54.9 %) of food/beverage ads targeted Asian Americans through language, ethnicity of person(s) in the ad or inclusion of culturally relevant images. Fifty per cent (50.2 %) of ads were associated with local/small brands. CONCLUSIONS: Food/beverage marketing practices are known to promote unhealthy food and beverage products. Research shows that increased exposure leads to excessive short-term consumption among consumers and influences children's food preferences and purchase requests. Given the frequency of racially targeted ads for unhealthy products in the current study and increasing rates of obesity-related diseases among Asian Americans, research and policies should address the implications of food and beverage ads on health. PMID- 28587695 TI - Hyper-responsivity to losses in the anterior insula during economic choice scales with depression severity. AB - BACKGROUND: Commonly observed distortions in decision-making among patients with major depressive disorder (MDD) may emerge from impaired reward processing and cognitive biases toward negative events. There is substantial theoretical support for the hypothesis that MDD patients overweight potential losses compared with gains, though the neurobiological underpinnings of this bias are uncertain. METHODS: Twenty-one unmedicated patients with MDD were compared with 25 healthy controls (HC) using functional magnetic resonance imaging (fMRI) together with an economic decision-making task over mixed lotteries involving probabilistic gains and losses. Region-of-interest analyses evaluated neural signatures of gain and loss coding within a core network of brain areas known to be involved in valuation (anterior insula, caudate nucleus, ventromedial prefrontal cortex). RESULTS: Usable fMRI data were available for 19 MDD and 23 HC subjects. Anterior insula signal showed negative coding of losses (gain > loss) in HC subjects consistent with previous findings, whereas MDD subjects demonstrated significant reversals in these associations (loss > gain). Moreover, depression severity further enhanced the positive coding of losses in anterior insula, ventromedial prefrontal cortex, and caudate nucleus. The hyper-responsivity to losses displayed by the anterior insula of MDD patients was paralleled by a reduced influence of gain, but not loss, stake size on choice latencies. CONCLUSIONS: Patients with MDD demonstrate a significant shift from negative to positive coding of losses in the anterior insula, revealing the importance of this structure in value-based decision-making in the context of emotional disturbances. PMID- 28587696 TI - Uncomplicated urinary tract infections in the emergency department: a review of local practice patterns. AB - OBJECTIVES: To determine the number of urine cultures ordered for women who presented to the emergency department (ED) with symptoms of uncomplicated UTI, and whether a culture result impacted subsequent management. METHODS: This was a retrospective chart review of non-pregnant women aged 18-39 presenting to one of two academic EDs with a discharge diagnosis of uncomplicated UTI over a one-year study period. Patients were excluded if there was documentation of fever, immunocompromised state, diabetes mellitus, absence of lower urinary tract symptoms, ED administration of intravenous antibiotics, a previous UTI treated with antibiotics in the last 90 days, two weeks post-partum or post instrumentation. RESULTS: Of the 512 charts included in the analysis, 494 (96.5%) patients had a urinalysis, of which 463 (93.7%) had positive leukocyte esterase and 90 (18.2%) had positive nitrites. 370 patients (72.3%) had urine cultures performed, of which 236 (63.8%) were positive. 505 (98.6%) patients received antibiotics (53.9% Macrobid; 22.6% Ciprofloxacin; 15.0% Septra; 6.7% other; 1.8% not documented). 7 (1.9%) cultures grew organisms resistant to the prescribed antibiotic; 2 (0.5%) patients received new prescriptions. CONCLUSIONS: For the majority of young female patients with an uncomplicated UTI, urine cultures did not change management in the ED setting. However, when the diagnosis is uncertain based on symptomology and urinalyses alone, a urine culture may be warranted. Greater efforts should be directed towards educating emergency physicians on accurately diagnosing uncomplicated cystitis and the limited impact of urine cultures on treatment once a diagnosis has been made. PMID- 28587697 TI - ppGpp and cytotoxicity diversity in Shiga toxin-producing Escherichia coli (STEC) isolates. AB - Shiga toxin-producing Escherichia coli (STEC) is a known food pathogen, which main reservoir is the intestine of ruminants. The abundance of different STEC lineages in nature reflect a heterogeneity that is characterised by the differential expression of certain genotypic characteristics, which in turn are influenced by the environmental conditions to which the microorganism is exposed. Bacterial homeostasis and stress response are under the control of the alarmone guanosine tetraphosphate (ppGpp), which intrinsic levels varies across the E. coli species. In the present study, 50 STEC isolates from healthy sheep were evaluated regarding their ppGpp content, cytotoxicity and other relevant genetic and phenotypic characteristics. We found that the level of ppGpp and cytotoxicity varied considerably among the examined strains. Isolates that harboured the stx2 gene were the least cytotoxic and presented the highest levels of ppGpp. All stx2 isolates belonged to phylogroup A, while strains that carried stx1 or both stx1 and stx2 genes pertained to phylogroup B1. All but two stx2 isolates belonged to the stx2b subtype. Strains that belonged to phylogroup B1 displayed on average low levels of ppGpp and high cytotoxicity. Overall, there was a negative correlation between cytotoxicity and ppGpp. PMID- 28587699 TI - Accurate diagnosis of CHD by Paediatricians with Expertise in Cardiology. AB - : Introduction Paediatricians with Expertise in Cardiology assess children with a full history, examination, and often perform an echocardiogram. A minority are then referred to an outreach clinic run jointly with a visiting paediatric cardiologist. The accuracy of the echocardiography diagnosis made by the Paediatrician with Expertise in Cardiology is unknown. Materials and methods We conducted a retrospective review of clinic letters for children seen in the outreach clinic for the first time between March, 2004 and March, 2011. Children with CHD diagnosed antenatally or elsewhere were excluded. We recorded the echocardiography diagnosis made by the paediatric cardiologist and previously by the Paediatrician with Expertise in Cardiology. RESULTS: The Paediatrician with Expertise in Cardiology referred 317/3145 (10%) children seen in the local cardiac clinics to the outreach clinic over this period, and among them 296 were eligible for inclusion. Their median age was 1.5 years (range 1 month-15.1 years). For 244 (82%) children, there was complete diagnostic agreement between the Paediatrician with Expertise in Cardiology and the paediatric cardiologist. For 29 (10%) children, the main diagnosis was identical with additional findings made by the paediatric cardiologist. The abnormality had resolved in 17 (6%) cases by the time of clinic attendance. In six (2%) patients, the paediatric cardiologist made a different diagnosis. In total, 138 (47%) patients underwent a surgical or catheter intervention. Discussion Paediatricians with Expertise in Cardiology can make accurate diagnoses of CHD in children referred to their clinics. This can allow effective triage of children attending the outreach clinic, making best use of limited specialist resources. PMID- 28587698 TI - Folate status in women of childbearing age with obesity: a review. AB - Several studies have described a positive association between elevated BMI and birth defects risk. Data on plasma concentration of folate in pregnant women with obesity have shown values far below those recommended, regardless of diet, while folate levels should increase before pregnancy to reduce neural tube defects. We report a descriptive review of the most recent studies (from 2005 to 2015) to evaluate folate status through a population of women of childbearing age affected by obesity. The literature contains few studies, which present conflicting results regarding folate status in non-pregnant women of childbearing age affected by obesity, and it appears that there is a modification in folate metabolism, with a reduction in plasma folate levels and an increase in erythrocyte folate uptake. In conclusion, the folate status in women of childbearing age should be assessed by both plasma and erythrocyte levels to start a personalised and more adequate supplementation before conception. Further studies need to be conducted in a larger population, which take into account variables that can affect folate metabolism, such as dietary intake, lifestyle and genetic factors, oral contraceptives or other drug use, previous weight-loss programmes, or a history of bariatric surgery. PMID- 28587700 TI - The Composition of Poly(Ethylene Terephthalate) (PET) Surface Precipitates Determined at High Resolving Power by Tandem Mass Spectrometry Imaging. AB - We present the first demonstration of a general method for the chemical characterization of small surface features at high magnification via simultaneous collection of mass spectrometry (MS) imaging and tandem MS imaging data. High lateral resolution tandem secondary ion MS imaging is employed to determine the composition of surface features on poly(ethylene terephthalate) (PET) that precipitate during heat treatment. The surface features, probed at a lateral resolving power of<200 nm using a surface-sensitive ion beam, are found to be comprised of ethylene terephthalate trimer at a greater abundance than is observed in the surrounding polymer matrix. This is the first chemical identification of PET surface precipitates made without either an extraction step or the use of a reference material. The new capability employed for this study achieves the highest practical lateral resolution ever reported for tandem MS imaging. PMID- 28587701 TI - Brain atrophy is a frequent finding in elderly patients with first episode psychosis. AB - BACKGROUND: To characterize the yearly incidence, diagnostic distribution, and neuro-radiologic findings in patients aged over 60 years, referred to psychiatric treatment with first episode psychosis (FEP). METHODS: A computerized search, including all patients referred to psychiatric treatment during 12 consecutive months with a de novo diagnosis of psychosis was performed in the Helsinki region catchment area with 1.2 million inhabitants. Diagnoses based on hospital records were made by a group of one neurologist and three psychiatrists. MRI- or CT scans performed as a part of routine clinical management were used when available. RESULTS: 107 patients (27 males and 80 females) with FEP were identified and categorized into four diagnostic groups: schizophrenia, delusional disorder, psychotic depression, and psychosis due to another medical condition. No patients with de novo onset mania were found. Psychosis due to another medical condition was the most common diagnosis. A high frequency of signs of cortical brain atrophy was seen in all diagnostic groups, while central atrophy was more frequent in patients with psychosis due to another medical condition than in the other groups. CONCLUSION: Organic brain changes related to ageing or degenerative illnesses may be an etiologic factor in elderly patients with FEP. PMID- 28587703 TI - Make it two: A case report of dual sequential external defibrillation. AB - ABSTRACTDual sequential external defibrillation (DSED) is the process of near simultaneous discharge of two defibrillators with differing pad placement to terminate refractory arrhythmias. Previously used in the electrophysiology suite, this technique has recently been used in the emergency department and prehospital setting for out-of-hospital cardiac arrest (OHCA). We present a case of successful DSED in the emergency department with neurologically intact survival to hospital discharge after refractory ventricular fibrillation (RVF) and review the putative mechanisms of action of this technique. PMID- 28587702 TI - Protective Effects of Coenzyme Q10 on Developmental Competence of Porcine Early Embryos. AB - Coenzyme Q10 (Q10) plays an important role in the cellular antioxidant system by protecting the cells from free-radical oxidative damage and apoptosis. In the present study, we have investigated the effect of Q10 on the preimplantation development of porcine parthenogenetic embryos, as well as the underlying mechanism. The results showed that 100 MUM was the optimal concentration of Q10, which resulted in significantly increased cleavage and blastocyst formation rates and improvement of blastocyst quality. Q10 improved the blastocyst hatching rate and cellular proliferation rate in hatching blastocysts and increased the expression of hatching-related genes. Furthermore, Q10 not only decreased reactive oxygen species production, DNA damage levels, and apoptosis in the blastocysts from H2O2-induced oxidative injury, but also maintained mitochondrial function. Taken together, these results indicate that Q10 has beneficial effects on the development of porcine parthenogenetic embryos by preventing oxidative damage and apoptosis. PMID- 28587704 TI - Between- and within-site variation in medication choices and adverse events during procedural sedation for electrical cardioversion of atrial fibrillation and flutter. AB - OBJECTIVES: Although procedural sedation for cardioversion is a common event in emergency departments (EDs), there is limited evidence surrounding medication choices. We sought to evaluate geographic and temporal variation in sedative choice at multiple Canadian sites, and to estimate the risk of adverse events due to sedative choice. METHODS: This is a secondary analysis of one health records review, the Recent Onset Atrial Fibrillation or Flutter-0 (RAFF-0 [n=420, 2008]) and one prospective cohort study, the Recent Onset Atrial Fibrillation or Flutter 1 (RAFF-1 [n=565, 2010 - 2012]) at eight and six Canadian EDs, respectively. Sedative choices within and among EDs were quantified, and the risk of adverse events was examined with adjusted and unadjusted comparisons of sedative regimes. RESULTS: In RAFF-0 and RAFF-1, the combination of propofol and fentanyl was most popular (63.8% and 52.7%) followed by propofol alone (27.9% and 37.3%). There were substantially more adverse events in the RAFF-0 data set (13.5%) versus RAFF 1 (3.3%). In both data sets, the combination of propofol/fentanyl was not associated with increased adverse event risk compared to propofol alone. CONCLUSION: There is marked variability in procedural sedation medication choice for a direct current cardioversion in Canadian EDs, with increased use of propofol alone as a sedation agent over time. The risk of adverse events from procedural sedation during cardioversion is low but not insignificant. We did not identify an increased risk of adverse events with the addition of fentanyl as an adjunctive analgesic to propofol. PMID- 28587705 TI - Cultural effects on neurodevelopmental testing in children from six European countries: an analysis of NUTRIMENTHE Global Database. AB - Cultural background is an important variable influencing neuropsychological performance. Multinational projects usually involve gathering data from participants from different countries and/or different cultures. Little is known about the influence of culture on neuropsychological testing results in children and especially in European children. The objectives of this study were to compare neuropsychological performance of children from six European countries (Belgium, Germany, Italy, The Netherlands, Poland and Spain) using a comprehensive neuropsychological battery and to apply a statistical procedure to reduce the influence of country/cultural differences in neuropsychological performance. As expected, the results demonstrated differences in neuropsychological performance among children of the six countries involved. Cultural differences remained after adjusting for other confounders related to neuropsychological execution, such as sex, type of delivery, maternal age, gestational age and maternal educational level. Differences between countries disappeared and influence of culture was considerably reduced when standardised scores by country and sex were used. These results highlight the need for developing specific procedures to compare neuropsychological performance among children from different cultures to be used in multicentre studies. PMID- 28587707 TI - Periungual Fibroma. PMID- 28587706 TI - Coma After Acute Head Injury. AB - BACKGROUND: Coma after acute head injury is always alarming. Depending on the type of injury, immediate treatment may be life-saving. About a quarter of a million patients are treated for traumatic brain injury in Germany each year. Treatment recommendations must be updated continually in the light of advancing knowledge. METHODS: This review of treatment recommendations, prognostic factors, and the pathophysiology of coma after acute head injury is based on a 2015 German guideline for the treatment of head injury in adults and on pertinent publications retrieved by a selective search in PubMed for literature on post traumatic coma. RESULTS: As soon as the vital functions have been secured, patients with acute head injury should undergo cranial computed tomography, which is the method of choice for identifying intracranial injuries needing immediate treatment. Patients who have an intracranial hematoma with mass effect should be taken to surgery at once. The prognosis is significantly correlated with the patient's age, the duration of coma, accompanying neurological manifestations, and the site of brain injury. The case fatality rate of patients who have been comatose for 24 hours and who have accompanying lateralizing signs, a unilaterally absent pupillary light reflex, or hemiparesis lies between 30% and 50%. This figure rises to 50-60% in patients with abnormal extensor reflexes and to over 90% in those with bilaterally absent pupillary light reflexes. Current neuropathological and neuroradiological studies indicate that coma after acute head injury is due to reversible or irreversible dysfunction of the brainstem. CONCLUSION: Brain tissue can tolerate ischemia and elevated pressure only for a very limited time. Comatose head-injured patients must therefore be evaluated urgently to determine whether they can be helped by the surgical removal of a hematoma or by a decompressive hemicraniectomy. PMID- 28587708 TI - Complication Rates in Colonoscopy Screening for Cancer. AB - BACKGROUND: Screening colonoscopy has been offered in Germany since 2002. Complications during colonoscopy were reported to be rare, but data on potential complications after colonoscopy are sparse. We aimed to comprehensively assess the frequency of complications arising during or within four weeks of screening colonoscopy. METHODS: Residents of the German federal state of Saarland without a history of colorectal cancer and without previous polypectomy who underwent a screening colonoscopy between 2010 and 2013 were included. A follow-up was conducted three months after the screening colonoscopy, including participant questionnaires and subsequent validation of self-reported complications arising during or within four weeks of screening colonoscopy, by reviewing colonoscopy records and contacting the treating physicians. A comprehensive mortality follow up was conducted for non-responders. RESULTS: We recruited a total of 5527 participants from 26 practices (median age 61 years, 52% women). 5252 (95%) fully completed the questionnaire on complications and met the inclusion criteria for analysis. Among these participants, 16 cases of physician-confirmed bleeding (0.30%) and four cases of physician-confirmed perforation (0.08%) occurred during or within four weeks of colonoscopy. According to consistent reports from patients and physicians, bleeding and perforation led to hospitalization in 5 (0.095%) and 2 (0.04%) cases, respectively. Three participants died within three months of colo - noscopy. In none of these cases was the cause of death related to colonoscopy. CONCLUSION: We found the risk of complications of screening colonoscopy to be low, even when taking into account a potential delay of up to four weeks. PMID- 28587709 TI - An Ongoing Task. PMID- 28587710 TI - Video-based Approaches. PMID- 28587711 TI - In Reply. PMID- 28587712 TI - Questionnaire Should not Be Used any Longer. PMID- 28587713 TI - In Reply. PMID- 28587714 TI - Real-world effectiveness of sucroferric oxyhydroxide in patients on chronic hemodialysis: A retrospective analysis of pharmacy data?. AB - AIMS: Hyperphosphatemia has been associated with an increased risk of mortality in patients with end-stage renal disease. We sought to assess the real-world effectiveness of sucroferric oxyhydroxide (SO), an iron-based phosphate binder (PB), in control of serum phosphorus levels, and to determine the associated pill burden in hemodialysis patients. MATERIALS AND METHODS: Adult, in-center hemodialysis patients first prescribed SO through a renal pharmacy service as part of routine clinical care between April 1, 2014 and March 31, 2015 were included in the analysis. The proportion of patients with phosphorus levels <= 5.5 mg/dL and the mean prescribed PB pills/day were compared between baseline (3 months prior to SO) and SO follow-up at 3 (SO 1 - 3) and 6 months (SO 4 - 6). Mineral bone disease markers, hemoglobin, iron indices, and erythropoiesis stimulating agents and intravenous iron use were assessed. RESULTS: At baseline, all patients (n = 1,029) were prescribed PB, and 13.9% had mean serum phosphorus <= 5.5 mg/dL. Comparing baseline to SO 1 - 3, the mean prescribed PB pills/day declined from 9.6 to 3.8 pills/day (p < 0.001), and the proportion of patients with serum phosphorus <= 5.5 mg/dL increased from 13.9 to 26.1% (+88%). Comparing baseline to SO 4 - 6 (n = 424), the mean prescribed PB pills/day declined from 9.7 to 4.0 pills/day (p < 0.001), and the proportion of patients with serum phosphorus <= 5.5 mg/dL increased from 15.6 to 30.4% (+95%). CONCLUSIONS: Prescription of SO was associated with an increase in the proportion of patients achieving serum phosphorus levels <= 5.5 mg/dL along with fewer prescribed PB pills/day.?. PMID- 28587715 TI - Diffusion-weighted whole-body MRI for evaluation of early response in multiple myeloma. AB - AIM: To evaluate the modifications of the apparent diffusion coefficient (ADC) in myelomatous lesions before and after induction treatment and the correlation with patient response to therapy according to International Myeloma Working Group (IMWG) criteria. MATERIALS AND METHODS: A homogeneous group of 18 patients with a diagnosis of symptomatic multiple myeloma who underwent whole-body MRI with diffusion-weighted imaging (DWI-MRI) before and after bortezomib-based induction chemotherapy were evaluated prospectively. Quantitative analysis of ADC maps of myelomatous lesions was performed with the following pattern types: focal pattern, diffuse pattern (moderate and severe), and "salt and pepper" pattern. Lesions were evaluated by quantitative image analysis including measurement of the mean ADC in three measurements. Imaging results were compared to laboratory results as the clinical reference standard. RESULTS: A statistically significant increase in ADC values were found in the lesions of patients that responded to treatment. Interestingly, focal lesions showed a strongly significant increase in ADC values in responders, whereas no significant variation in ADC value in non focal lesions (diffuse pattern and "salt and peppers" pattern) between responders and non-responders group was demonstrated. CONCLUSIONS: DWI-MRI could provide additional quantitative information useful in monitoring early therapy response according to ADC changes of focal lesions. PMID- 28587717 TI - Hyperkeratotic lesions on legs. PMID- 28587716 TI - [Predictive factors of functional decline at hospital discharge in elderly patients hospitalised due to acute illness]. AB - OBJECTIVE: To compare baseline characteristics and those found during hospitalisation as predictors of functional decline at discharge (FDd) in elderly patients hospitalised due to acute illness. MATERIAL AND METHOD: A review was made of the computerized records of patients admitted to a Geriatric Acute Unit of a tertiary hospital over a 10 year period. A record was made of demographic, clinical, functional and health-care variables. Functional decline at discharge (FDd) was defined by the difference between the previous Barthel Index (pBI) and the discharge Barthel Index (dBI). The percentage of FDd (%FDd=(pBI-dBI/pBI)*100) was calculated. The variables associated with greater %FDd in the bivariate analysis were included in multivariate logistic regression models. The predictive capacity of each model was assessed using the area under the ROC curve. RESULTS: The factors associated with greater %FDd were advanced age, female gender, to live in a nursing home, cognitive impairment, better baseline functional status and worse functional status at admission, number of diagnoses, and prolonged stay. The area under the ROC curve for the predictive models of %FDd was 0.638 (95% CI: 0.615-0.662) based on the previous situation, 0.756 (95% CI: 0.736 0.776) based on the situation during admission, and 0.952 (95% CI: 0.944-0.959) based on a combination of these factors. CONCLUSIONS: The overall assessment of patient characteristics, both during admission and baseline, may have greater value in prediction of FDd than analysis of factors separately in elderly patients hospitalised due to acute illness. PMID- 28587718 TI - beta-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog-Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models. AB - BACKGROUND: Mitophagy and mitochondrial dynamics alterations are two major hallmarks of neurodegenerative diseases. Dysfunctional mitochondria accumulate in Alzheimer's disease-affected brains by yet unexplained mechanisms. METHODS: We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which presenilins control phosphatase and tensin homolog-induced kinase 1 (Pink-1) expression and transcription. In vivo approaches were carried out on various transgenic and knockout animals as well as in adeno-associated virus-infected mice. Functional readout and mitochondrial physiology (mitochondrial potential) were assessed by combined procedures including flow cytometry, live imaging analysis, and immunohistochemistry. RESULTS: We show that presenilins 1 and 2 trigger opposite effects on promoter transactivation, messenger RNA, and protein expression of Pink-1. This control is linked to gamma-secretase activity and beta-amyloid precursor protein but is independent of phosphatase and tensin homolog. We show that amyloid precursor protein intracellular domain (AICD) accounts for presenilin-dependent phenotype and upregulates Pink-1 transactivation in cells as well as in vivo in a Forkhead box O3a-dependent manner. Interestingly, the modulation of gamma-secretase activity or AICD expression affects Pink-1-related control of mitophagy and mitochondrial dynamics. Finally, we show that parkin acts upstream of presenilins to control Pink-1 promoter transactivation and protein expression. CONCLUSIONS: Overall, we delineate a molecular cascade presenilins-AICD-Forkhead box O3a linking parkin to Pink-1. Our study demonstrates AICD-mediated Pink-1-dependent control of mitochondrial physiology by presenilins. Furthermore, it unravels a parkin-Pink-1 feedback loop controlling mitochondrial physiology that could be disrupted in neurodegenerative conditions. PMID- 28587719 TI - Clinical audits to improve critical care: Part 2: Analyse, benchmark and feedback. AB - Clinical audits are an essential part of the cycle designed to ensure that patients receive the best quality of care. By measuring the care delivered against established best practice standards, it becomes possible to identify shortcomings and to plan targeted strategies and processes for continuous improvement. The success of a clinical audit depends upon defined goals, motivation of stakeholders, appropriate tools and resources, and clear communication. In part 1 of this series, an overview of the structures and processes needed to prepare and collect data for clinical audits in the critical care setting was provided [A.J. Ullman, G. Ray-Barruel, C.M. Rickard, M. Cooke, Clinical audits to improve critical care: Part 1 Prepare and collect data, Aust Crit Care, 2017, in press]. In part 2, we discuss how to analyse the collected audit data, benchmark findings with internal and external data sets, and feedback audit results to critical care clinicians to promote evidence-based practice and improve patient outcomes. PMID- 28587720 TI - Stabilization of systems with interval time-varying delay based on delay decomposing approach. AB - The paper considers the stabilization for systems with interval time-varying delay. By decomposing the delay interval into multiple equidistant subintervals and considering the triple integral terms, a novel Lyapunov-krasovskii functional(LKF) is defined. Then extended integral inequality and convex combination approach are used to estimate the derivative of the constructed functional, and as a result, the new stability criterion with less conservatism and decision variables is obtained. On this basis, the state feedback controller is designed, by using linearization method, the existence condition of controller is obtained in terms of linear matrix inequalities(LMIs), and the specific form of controller is also given, moreover, by selecting the appropriate parameter value, the stabilization time of the system can be reduced. Numerical examples are given to illustrate the effectiveness of the proposed method. PMID- 28587721 TI - Editorial. PMID- 28587722 TI - Comparative evaluation of topographical data of dental implant surfaces applying optical interferometry and scanning electron microscopy. AB - OBJECTIVE: Comparability of topographical data of implant surfaces in literature is low and their clinical relevance often equivocal. The aim of this study was to investigate the ability of scanning electron microscopy and optical interferometry to assess statistically similar 3-dimensional roughness parameter results and to evaluate these data based on predefined criteria regarded relevant for a favorable biological response. METHODS: Four different commercial dental screw-type implants (NanoTite Certain Prevail, TiUnite Branemark Mk III, XiVE S Plus and SLA Standard Plus) were analyzed by stereo scanning electron microscopy and white light interferometry. Surface height, spatial and hybrid roughness parameters (Sa, Sz, Ssk, Sku, Sal, Str, Sdr) were assessed from raw and filtered data (Gaussian 50MUm and 5MUm cut-off-filters), respectively. Data were statistically compared by one-way ANOVA and Tukey-Kramer post-hoc test. For a clinically relevant interpretation, a categorizing evaluation approach was used based on predefined threshold criteria for each roughness parameter. RESULTS: The two methods exhibited predominantly statistical differences. Dependent on roughness parameters and filter settings, both methods showed variations in rankings of the implant surfaces and differed in their ability to discriminate the different topographies. Overall, the analyses revealed scale-dependent roughness data. Compared to the pure statistical approach, the categorizing evaluation resulted in much more similarities between the two methods. SIGNIFICANCE: This study suggests to reconsider current approaches for the topographical evaluation of implant surfaces and to further seek after proper experimental settings. Furthermore, the specific role of different roughness parameters for the bioresponse has to be studied in detail in order to better define clinically relevant, scale-dependent and parameter-specific thresholds and ranges. PMID- 28587723 TI - 'Organising objects': Adult safeguarding practice and article 16 of the United Nations Convention on the Rights of Persons with Disabilities. PMID- 28587724 TI - Corrigendum to "Effects of co-administration of ketamine and ethanol on the dopamine system via the cortex-striatum circuitry" [Life Sci. (Apr 25 2017) pii: S0024-3205(17)30198-4]. PMID- 28587725 TI - A hermeneutic phenomenological explorations of living in old age. AB - Although there have been some studies that explore the meaning of aging and give voice to older people, the impact that the aging experience can have on them justifies continued research in this area. In this study, with a hermeneutic phenomenological design and an interpretation method inspired by the philosophy of Ricoeur, we conducted in-depth interviews with 14 elderly people at a social day center in Rome (Italy). The analysis revealed three central themes associated with the experience of being old: changes and limitations related with being aged, the experience that comes from having lived a long life, and an awareness of death. The findings could help health professionals, families and caregivers to achieve a deeper understanding of what old age entails, and may also serve as a platform for interventions that seek to enable older people to experience aging as a meaningful and positive process. PMID- 28587726 TI - Occult cancer detection in patients with hemostatic disorder and venous thromboembolism. AB - There are physiologic ties between Von Willebrand Factor (VWF) and circulating tumor cells. VWF appears to play a role in tumor biology, but it is unclear whether cancer behavior differs in Von Willebrand Disease. In patients presenting with venous thromboembolism (VTE), occult cancer is frequently considered as an underlying cause. The prevalence of occult cancer after provoked VTE is low (3%); therefore, cancer screening in these patients is not routinely recommended. In those with unprovoked VTE, occult cancer is more prevalent, estimated between 4 and 10%. Due to this elevated risk, occult cancer screening is recommended in this population. Multiple studies have investigated whether a "limited" approach (including history and physical exam, basic labs, and chest X-ray) versus "extensive" approach (addition of advanced imaging, such as computer tomography) is more effective. Current data fails to demonstrate extensive screening strategies diagnose more occult cancer, miss fewer cancers during follow up, or improve cancer-related mortality. Furthermore, many patients may be needlessly exposed to unnecessary diagnostic procedures with their associated complications and costs, as well as significant anxiety. Therefore, the decision to perform additional testing should be made on a case-by-case basis. Additional studies are needed to identify subgroups of patients with unprovoked VTE at highest risk for occult cancer. PMID- 28587727 TI - [Sleep bruxism in children]. AB - Bruxism is defined as repetitive activity of the masticatory muscles, characterized by clenching the teeth or teeth grinding and/or by tapping and swaying. This study investigated sleep bruxism. The etiology is multifactorial: mainly central (neuropathic disorder, anxiety) but also genetic and local (posture, mouth breathing). The diagnosis is based primarily on the anamnesis and examination of dental wear and progression over time (photos and dental castings). A diagnostic guide is proposed in this article. Frequently found in children, bruxism is not always considered pathological. The severity criteria relate intensity (number of dental attrition facets) as well as the context found in children: anxiety, ventilation disorders, and fragile dental structures. Management is multidisciplinary and depends on the etiologic diagnosis. PMID- 28587728 TI - Incidence of children at risk for obstructive sleep apnea undergoing common day surgery procedures. AB - OBJECTIVE: The purpose of this study was to evaluate the prevalence of sleep related breathing disorders (SRBD) in children undergoing elective day surgery procedures. METHODS: A validated Pediatric Sleep Questionnaire (PSQ) was distributed to the parents of children aged 2months to 18 years who met inclusion criteria and were undergoing urologic, otolaryngologic, and general surgical day surgery procedures a 3-month period of time. The prevalence of children at risk for pediatric SRBD was determined from PSQ results. RESULTS: From a total of 288 PSQ Questionnaires, 9.1% of urology, 11.1% of general surgery, and 51.9% of otolaryngology patients admitted to day surgery were found to be at risk for sleep disordered breathing. The median PSQ score for the children at risk was 9.2 for urological surgeries, 10.9 for general surgery, and 11.3 for otolaryngological procedures. CONCLUSIONS: There is an increased prevalence of children at risk of SRBD awaiting common day surgery procedures than previously expected based on existing literature. Patients undergoing otolaryngological procedures were at greater risk of sleep-related breathing disorders when compared with patients undergoing urological or general surgical procedures. There may be a role for screening of pediatric patients with a PSQ prior to day surgery. LEVEL OF EVIDENCE: Type of study: prognosis study, level IV. PMID- 28587729 TI - Glycolysis-related proteins are broad spectrum vaccine candidates against aquacultural pathogens. AB - Reverse vaccinology (RV) has become a popular method for developing vaccines. Although Edwardsiella tarda is deemed to be an important fish pathogen, so far, no reports have used a genome-based approach to screen vaccine candidates against E. tarda. In the current study, protective antigens of E. tarda were screened using RV. Large-scale cloning, expression and purification of potential candidates were carried out, and their immunoprotective potential was evaluated. A candidate fructose-bisphosphate aldolase (FBA) exhibited broad spectrum protection, as did another glycolysis-related protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which we reported previously, indicating the potential of other glycolysis-related proteins of E. tarda as broad spectrum protective antigens. In total, half (5 out 10) of these proteins showed prominent immunoprotective potential. Therefore, we suggest that glycolysis-related proteins are a class of potential broad spectrum protective antigens and that these proteins should be preferentially selected. PMID- 28587730 TI - Deep brain stimulation failure due to external cardioversion in a patient with Parkinson's disease. AB - We report a case of deep brain stimulation (DBS) hardware failure due to emergently performed subcutaneous coronary angioplasties complicated by cardioversion for rapid worsening of angina pectoris and some trouble shooting problems emerged after invasive cardiovascular procedures. The patient with prior implantation of permanent pacemaker due to vasovagal syndrome underwent successful left-sided unilateral electrode implantation into the subthalamic nucleus. During 21 months follow-up period the patient experienced 2 times episodes of aggravation of unstable angina pectoris 15 and 21 months respectively, which necessities emergent coronary angioplasties. After the first emergently performed coronary angioplasty with cardioversion the interrogation of DBS system revealed the depletion of an internal pulse generator (IPG). The secondly performed coronary angioplasty complicated by ventricular tachyarrhythmia with DBS system switched on during emergent cardioversion resulted in partial dysfunction of DBS electrode. Patients harboring cardiovascular implantable electronic devices (CIEDs) and DBS systems require special attention and good cooperation of neurosurgeons, interventional cardiologist, and neurologist. Some emergently performed invasive cardiovascular procedures which necessities cardioversion may cause DBS hardware failure with subsequent worsening of movement disorder symptoms. PMID- 28587731 TI - Prediction of clinical outcome using blood flow volume in the superior mesenteric artery in patients with pseudomyxoma peritonei treated by cytoreductive surgery. AB - BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare carcinomatosis limited to the peritoneal cavity, mainly supplied by the superior mesenteric artery (SMA). The only curative treatment is cytoreductive surgery (CRS) associated with hyperthermic intraperitoneal chemotherapy. This study aimed to evaluate the ability of blood flow volume (BFV) recorded in the SMA using Doppler ultrasonography pre-operatively to predict the extent and resectability of the disease and post-operatively to assess clinical outcome. METHODS: BFV was measured in the SMA of forty-nine patients before and the year following CRS. Patients were categorized in 3 groups according to clinical and surgical outcomes: group-1 (n = 22): patient with completed CRS, group-2 (n = 16): incomplete resection with slowly progressive disease (alive at 2 years without severe clinical symptoms), group-3 (n = 11): incomplete resection and with severe clinical symptoms or dead within two years. RESULTS: Pre-operative mean SMA BFV was higher in group-2 (510 mL/min, p = 0.027) and in group-3 (572 mL/min, p = 0.004) than in group-1 (378 mL/min). After surgery, BFV dropped to normal values (203 mL/min, p = 0.001) in group-1, and to 423 mL/min (p = 0.047) in group-2. It remained elevated in group-3 (626 mL/min, p = 0.566). BFV allowed stratification of 1) resectability before CRS (group-2 and -3 vs group-1, area under the ROC curve: 0.794 [0.650-0.939]), and 2) non progression after incomplete CRS (group-3 vs group-2, area under the ROC curve: 0.827 [0.565-1.00]. CONCLUSIONS: Pre operative BFV in the SMA correlates with extent and resectability of PMP. After incomplete surgery, post-operative BFV might aid in identifying patients who may benefit of post-operative therapy. PMID- 28587732 TI - For Certain, SIRT4 Activities! AB - Despite the fact that SIRT4 regulates important biological processes, its primary enzymatic activity has remained ambiguous. A recent study by Anderson, Huynh et al. has uncovered deacylase activities of SIRT4 towards newly described lysine modifications derived from reactive acyl-CoAs generated in leucine catabolism. PMID- 28587733 TI - Corrigendum to "Novel high-throughput and widely-targeted liquid chromatography time of flight mass spectrometry method for d-amino acids in foods" [J. Biosci. Bioeng. 123 (2017) 126-133]. PMID- 28587734 TI - Editorial-Sequences and topology. PMID- 28587736 TI - A combination of low-dose systemic etretinate and topical calcipotriol/betamethasone dipropionate treatment for hyperkeratosis and itching in Olmsted syndrome associated with a TRPV3 mutation. PMID- 28587735 TI - The invasive MenC cc103 lineage with penicillin reduced susceptibility persisting in Brazil. AB - Penicillin is the antibiotic of choice for the treatment of meningococcal infections, and mutations in penA gene are involved with reduced susceptibility (penI) emergence to this antibiotic. This study aimed to characterize the penA allelic diversity, their association with penI phenotype and distribution among prevalent meningococci serogroups in Brazil. The entire penA from 49 invasive strains of distinct serogroups circulating in Brazil for more than two decades were obtained by PCR and sequencing. Additionally, the penA from 22 publicly available complete Neisseria meningitidis genomes from Brazil were included in the study. The allelic diversity was determined and a genetic tree was built using the penA sequence alignment. The penicillin MIC was obtained by the E-Test method. In general, the identified penA alleles correlated with the observed penI phenotype. The canonical penA1 was the most prevalent allele, however, several altered penA were also identified in strains presenting increased penicillin MICs. It was identified a new penA amino acid position (residue 480) that possibly influence the penicillin MIC in some strains. Interestingly, the altered penA14 was found in penI invasive MenC cc103 strains spread in Brazil and persisting since 2011, indicating that the biological cost imposed by penI phenotype can be ameliorated by particular features present in this lineage, which represents an additional public health threat. PMID- 28587737 TI - Overexpression of Human Leukocyte Antigen-G and Interleukin 10 in acral lentiginous melanoma. PMID- 28587738 TI - Important Non-Technical Skills in Video-Assisted Thoracoscopic Surgery Lobectomy: Team Perspectives. AB - BACKGROUND: Safety in the operating room is dependent on the team's non-technical skills. The importance of non-technical skills appears to be different for minimally invasive surgery as compared with open surgery. The aim of this study was to identify which non-technical skills are perceived by team members to be most important for patient safety, in the setting of video-assisted thoracoscopic surgery (VATS) lobectomy. METHODS: This was an explorative, semistructured interview-based study with 21 participants from all four thoracic surgery centers in Denmark that perform VATS lobectomy. Data analysis was deductive, and directed content analysis was used to code the text into the Oxford Non-Technical Skills system for evaluating operating teams' non-technical skills. RESULTS: The most important non-technical skills described by the VATS teams were planning and preparation, situation awareness, problem solving, leadership, risk assessment, and teamwork. These non-technical skills enabled the team to achieve shared mental models, which in turn facilitated their efforts to anticipate next steps. This was viewed as important by the participants as they saw VATS lobectomy as a high-risk procedure with complementary and overlapping scopes of practice between surgical and anesthesia subteams. CONCLUSIONS: This study identified six non technical skills that serve as the foundation for shared mental models of the patient, the current situation, and team resources. These findings contribute three important additions to the shared mental model construct: planning and preparation, risk assessment, and leadership. Shared mental models are crucial for patient safety because they enable VATS teams to anticipate problems through adaptive patterns of both implicit and explicit coordination. PMID- 28587740 TI - Evaluation of traditional and novel echocardiographic methods of cardiac diastolic dysfunction post radiotherapy in breast cancer. AB - BACKGROUND: To investigate alterations in left ventricular (LV) diastolic function using traditional and novel echocardiographic parameters, following radiation therapy (RT) in breast cancer patients in the acute setting. METHODS: 40 chemotherapy-naive women with left-sided breast cancer undergoing RT were prospectively recruited. A comprehensive transthoracic echocardiogram (TTE) was performed at baseline, during RT and 6weeks post-RT. Traditional echocardiographic diastolic parameters and diastolic strain rate were measured and analysed. The relationship between alterations in diastolic parameters, changes in global longitudinal systolic strain (GLS) and radiation dose were investigated. RESULTS: Traditional diastolic parameters remained largely unchanged; however diastolic strain parameters, E-Sr and A-Sr were significantly reduced 6weeks post-RT [Longitudinal E-Sr (s-1) 1.47+/-0.32 vs 1.29+/-0.27*; Longitudinal A-Sr (s-1) 1.19+/-0.31 vs 1.03+/-0.24*; *p<0.05 vs baseline]. When patients were divided by a reduction >=10% versus <10% in GLS post-RT, a greater reduction in both traditional diastolic and diastolic strain parameters was observed in the group with >10% reduction in systolic function as evaluated by GLS. When patients were divided by mean v30 dose, a greater % change in E-Sr was noted in those receiving more than mean V30 dose. CONCLUSION: Diastolic dysfunction was only evident acutely, post-RT with the use of newer methods like strain analysis. A significant reduction in diastolic function was seen in the patient subgroup with >=10% reduction in systolic function, enhancing the notion of diastolic function as a potential indicator for systolic dysfunction. Future longitudinal studies are required to determine the specific prognostic value of these observations. PMID- 28587739 TI - Aortic Valve Pathology as a Predictive Factor for Acute Aortic Dissection. AB - BACKGROUND: In this study, the effect of aortic valve (AV) pathology on local hemodynamic conditions was evaluated as a potential trigger for the onset of acute type A and B aortic dissection. METHODS: A time- and pressure-related four dimensional (4-D) computed fluid dynamic model of the aorta was established. In an experimental setup, AV stenosis and AV insufficiency were created. 4-D pressure-related geometry of the aortic root (AR) with valve insufficiency and valve stenosis were determined by high-fidelity (200 Hz) microsonometric crystals. Flow and pressure were obtained at the left ventricle, ascending aorta, and aortic arch. RESULTS: Expansion of the AR in AV insufficiency was higher with expansion in AV stenosis, at peak ejection, and at the end of systole. In AV insufficiency, there was low shear stress (0 to 0.6 Pa), turbulent flow, and high pressure (80 to 95 mm Hg) at the anterior wall of the ascending aorta, at the proximal aortic arch, and at the aortic isthmus. In stenosis, high shear stress (>2 Pa) and high pressure (>95 mm Hg) were found at the ascending aorta and at the bifurcation of the brachiocephalic trunk. CONCLUSIONS: In AV insufficiency, low shear stresses and turbulent flow regions were documented at the traditional levels of entry tears for acute type A and B dissection. In AV stenosis, high shear stress with elevated pressure at the ascending aorta may be a trigger element for vessel dilatation, aneurysm formation, and intimal tear, which is typical for type A aortic dissection. PMID- 28587741 TI - Plasma level of big endothelin-1 predicts the prognosis in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Cardiac remodeling is one of major pathological process in hypertrophic cardiomyopathy (HCM). Endothelin-1 has been linked to cardiac remodeling. Big endothelin-1 is the precursor of endothelin-1. METHODS: A total of 245 patients with HCM were enrolled from 1999 to 2011 and partitioned to low, middle and high level groups according to their plasma big endothelin-1 levels. RESULTS: At baseline, significant associations were found between high level of big endothelin-1 and left atrium size, heart function and atrial fibrillation. Big endothelin-1 was positively correlated with N-terminal B-type natriuretic peptide (r=0.291, p<0.001) and late gadolinium enhancement (LGE) on magnetic resonance imaging (r=0.222, p=0.016). During a follow-up of 3 (range, 2-5) years, big endothelin-1 level was positively associated with the risks of all-cause mortality, cardiovascular death and progression to NYHA class 3 or 4 (p=0.020, 0.044 and 0.032, respectively). The rate of above events in the highest tertile were 18.1%, 15.7%, 24.2%, respectively. After adjusting for multiple factors related to survival and cardiac function, the significance remained in the association of big endothelin-1 with the risk of all-cause mortality (hazard ratio (HR)=4.94, 95% confidence interval (CI) 1.07-22.88; p=0.041) and progression to NYHA class 3 or 4 (HR=4.10, 95%CI 1.32-12.75, p=0.015). CONCLUSION: Our study showed that high level of plasma big endothelin-1 predicted prognosis for patients with HCM and it can be added to the marker panel in stratifying HCM patients for giving treatment priority to those at high risk. PMID- 28587742 TI - Systemic Th17/IL-17A response appears prior to hippocampal neurodegeneration in rats exposed to low doses of ozone. AB - INTRODUCTION: Exposure to low doses of O3 leads to a state of oxidative stress. Some studies show that oxidative stress can modulate both the CNS and systemic inflammation, which are important factors in the development of Alzheimer disease (AD). OBJECTIVE: This study aims to evaluate changes in the frequency of Th17 like cells (CD3+CD4+IL-17A+), the concentration of IL-17A in peripheral blood, and hippocampal immunoreactivity to IL-17A in rats exposed to low doses of O3. METHODS: One hundred eight male Wistar rats were randomly assigned to 6 groups (n=18) receiving the following treatments: control (O3 free) or O3 exposure (0.25ppm, 4hours daily) over 7, 15, 30, 60, and 90 days. Twelve animals from each group were decapitated and a peripheral blood sample was taken to isolate plasma and mononuclear cells. Plasma IL-17A was quantified using LUMINEX, while Th17 like cells were counted using flow cytometry. The remaining 6 rats were deeply anaesthetised and underwent transcardial perfusion for immunohistological study of the hippocampus. RESULTS: Results show that exposure to O3 over 7 days resulted in a significant increase in the frequency of Th17-like cells and levels of IL-17A in peripheral blood. However, levels of Th17/IL-17A in peripheral blood were lower at day 15 of exposure. We also observed increased IL-17A in the hippocampus beginning at 30 days of exposure. CONCLUSION: These results indicate that O3 induces a short-term, systemic Th17-like/IL-17A effect and an increase of IL-17A in the hippocampal tissue during the chronic neurodegenerative process. PMID- 28587743 TI - A novel alignment-free vector method to cluster protein sequences. AB - Classification of protein are crucial topics in biology. The number of protein sequences stored in databases increases sharply in the past decade. Traditionally, comparison of protein sequences is usually carried out through multiple sequence alignment methods. However, these methods may be unsuitable for clustering of protein sequences when gene rearrangements occur such as in viral genomes. The computation is also very time-consuming for large datasets with long genomes. In this paper, based on three important biochemical properties of amino acids: the hydropathy index, polar requirement and chemical composition of the side chain, we propose a 24 dimensional feature vector describing the composition of amino acids in protein sequences. Our method not only utilizes the chemical properties of amino acids but also counts on their numbers and positions. The results on beta-globin, mammals, and three virus datasets show that this new tool is fast and accurate for classifying proteins and inferring the phylogeny of organisms. PMID- 28587744 TI - Mathematical comparison of memory functions between mutual activation and repression networks in a stochastic environment. AB - Biological memory is a ubiquitous function that can generate a sustained response to a transient inductive stimulus. To better understand this function, we must consider the mechanisms by which different structures of genetic networks achieve memory. Here, we investigated two competitive gene regulatory network models: the regulated mutual activation network (MAN) and the regulated mutual repression network (MRN). Stochasticity deteriorated the persistence of memory of both the MAN and the MRN. Mathematical comparison by simulation and theoretical analysis identified functional differences in the stochastic memory between the competitive models: specifically, the MAN provided much more robust, persistent memory than the MRN. The stochastic persistent memory pattern of the MAN can be adjusted by changing the binding strength of the activators, whereas the MRN required highly cooperative and strong binding repressors for robust memory. PMID- 28587745 TI - An ex vivo spinal cord injury model to study ependymal cells in adult mouse tissue. AB - Traumatic spinal cord injury is characterized by an initial cell loss that is followed by a concerted cellular response in an attempt to restore the damaged tissue. Nevertheless, little is known about the signaling mechanisms governing the cellular response to injury. Here, we have established an adult ex vivo system that exhibits multiple hallmarks of spinal cord injury and allows the study of complex processes that are difficult to address using animal models. We have characterized the ependymal cell response to injury in this model system and found that ependymal cells can become activated, proliferate, migrate out of the central canal lining and differentiate in a manner resembling the in vivo situation. Moreover, we show that these cells respond to external adenosine triphosphate and exhibit spontaneous Ca2+ activity, processes that may play a significant role in the regulation of their response to spinal cord injury. This model provides an attractive tool to deepen our understanding of the ependymal cell response after spinal cord injury, which may contribute to the development of new treatment options for spinal cord injury. PMID- 28587746 TI - Corrigendum to "Quantitative prediction of histamine H1 receptor occupancy by the sedative and non-sedative antagonists in the human central nervous system based on systemic exposure and preclinical data" [Drug Metab Pharmacokinet 32 (2017) 135-144]. PMID- 28587747 TI - Flexible endoscopic diagnosis and treatment of esophageal stenosis in children with noninvasive ventilation support. AB - BACKGROUND: Esophageal stenosis (ES) is characterized by dysphagia, failure to thrive, and long-term disability. It requires repeated management because it is refractory. Traditionally, these procedures are performed under general anesthesia with airway intubation. PURPOSE: This study investigated the safety and efficacy of the management of interventional flexible endoscopy (IFE) performed with a novel noninvasive ventilation (NIV) support. METHODS: Use of a short-length flexible endoscope with NIV of pharyngeal oxygen, nose closure, and abdominal compression during IFE was investigated. Medical charts of patients aged <=10 years with a diagnosis of ES in our hospital between 1990 and 2014 were reviewed and analyzed. The outcome measurement included the number of IFE with balloon dilatation (BD), laser therapy (LT), stent placement, procedural complications, and the success rate. RESULTS: Ten patients were enrolled. The most common etiologies were esophageal atresia with/without tracheoesophageal fistula (n = 6), followed by caustic injury (n = 2), and unknown etiology (n = 2). Nine patients who were considered successfully managed received an average of 2.8 BD sessions and 1.6 LT sessions. The complication rate of IFE in this study was 1.08% (1/93). One esophageal perforation developed after BD (1/63) and none after LT (0/30). CONCLUSION: In this study, IFE with this NIV support is a safe, feasible and valuable modality which could rapidly examine and manage ES. PMID- 28587749 TI - Pluripotent stem cell models of Blau syndrome reveal an IFN-gamma-dependent inflammatory response in macrophages. AB - BACKGROUND: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. OBJECTIVES: To elucidate the mechanisms of autoinflammation in patients with Blau syndrome, we sought to clarify the relation between disease-associated mutant NOD2 and the inflammatory response in human samples. METHODS: Blau syndrome-specific induced pluripotent stem cell (iPSC) lines were established. The disease-associated NOD2 mutation of iPSCs was corrected by using a CRISPR-Cas9 system to precisely evaluate the in vitro phenotype of iPSC-derived cells. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the statuses of nuclear factor kappaB pathway and proinflammatory cytokine secretion were investigated. RESULTS: IFN-gamma acted as a priming signal through upregulation of NOD2. In iPSC-derived macrophages with mutant NOD2, IFN-gamma treatment induced ligand-independent nuclear factor kappaB activation and proinflammatory cytokine production. RNA sequencing analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN-gamma treatment. Patient-derived macrophages demonstrated a similar IFN gamma-dependent inflammatory response. CONCLUSIONS: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of patients with Blau syndrome. PMID- 28587748 TI - Liquid biopsy of PIK3CA mutations in cervical cancer in Hong Kong Chinese women. AB - INTRODUCTION: Cervical cancer is the fourth most common female cancer worldwide. The prognosis for women with advanced-stage or recurrent cervical cancer remains poor and response to treatment is variable. Standardized management protocols leave little room for individualization. We report on a novel blood-based liquid biopsy for specific PIK3CA mutations as a clinically useful biomarker in patients with invasive cervical cancer. METHODS: One hundred seventeen Hong Kong Chinese women with primary invasive cervical cancer and their pre-treatment plasma samples were investigated. Two PIK3CA mutations, p.E542K and p.E545K were measured in cell free DNA (cfDNA) extracted from plasma using droplet digital PCR. This liquid biopsy of PIK3CA in cervical cancer was correlated to clinico pathological features to verify the potential of PIK3CA as a clinically useful molecular biomarker for predicting disease prognosis and monitoring for progression. RESULTS: PIK3CA mutations, either p.E542K or p.E545K, were detected in plasma cfDNA from 22.2% of the patients. PIK3CA mutation status was significantly correlated to median tumor size (p<0.01). PIK3CA mutations detected in the plasma were significantly associated with decreased disease-free survival and overall survival (p<0.05). CONCLUSIONS: As a liquid molecular biopsy, analysis of circulating PIK3CA mutations shows promise as a way to refine risk stratification of individual patients with cervical cancer, and provides a platform for further research to offer individualized therapy with the purpose of improving outcomes. PMID- 28587750 TI - Dieulafoy of cecum: A rare cause of a refractory gastrointestinal bleeding in an uncommon location. PMID- 28587753 TI - Comment on relative brain size in early primates and the use of encephalization quotients in primate evolution. PMID- 28587752 TI - Dickkopf-1 inhibits Wnt3a-induced migration and epithelial-mesenchymal transition of human lens epithelial cells. AB - Posterior capsular opacification (PCO) is a major post-operative complication of cataract surgery. Epithelial-mesenchymal transition (EMT) contributes to PCO. We previously indicated that Wnt3a induces the EMT of human lens epithelial cells (LECs) and plays an important role in the development of PCO. The present study aimed to test the potential effect of Dickkopf-1 (Dkk1) on Wnt3a-induced cell migration and the EMT of LECs and to explore possible cellular mechanisms. The secretion of Dkk1 was reduced in the rabbit PCO model, and Dkk1 injected into the eyes post-surgical manipulation prevented PCO formation. Cultured HLE-B3 cells were then transfected with Wnt3a in the presence or absence of Dkk1. Dkk1 treatment restored the epithelial phenotype and reversed the expression of EMT associated proteins induced by Wnt3a. Dkk1 suppressed LEC migration and the expression of matrix metalloproteinase-1 (MMP-1), and the activity of MMP-2 and MMP-9. Dkk1 inhibited the nuclear accumulation of beta-catenin, which is the key regulator of the canonical Wnt signaling. Our results indicate that Dkk1 inhibits Wnt3a-induced migration and the EMT of human LECs.The results contribute to the prevention of PCO formation and development. PMID- 28587751 TI - Usability of a home-based test for the measurement of fecal calprotectin in asymptomatic IBD patients. AB - : The aim of our work was to test the usability of fecal calprotectin (FC) home based test in inflammatory bowel disease (IBD) patients. METHODS: IBD patients were prospectively recruited. They had to measure FC with a dedicated tool and smartphone application, 5 times at two weeks intervals over an 8 weeks period. They had to fill in a usability questionnaire at the first and the last FC measurement. A System Usability Scale (SUS: 0-100) and the Global Score of Usability (GSU: 0-85) were calculated. FC was also centrally measured by ELISA. RESULTS: Fifty-eight patients were recruited. Forty-two performed at least one FC measurement and 27 performed all the FC requested measurements. The median (IQR) SUS (0-100) at the first and last use were 85 (78-90) and 81 (70-88), respectively; the median (IQR) GSU (0-85) at the first and last use were 74 (69 80) and 77 (68-83), respectively. Adherence to the planned measurements and usability of the tool were higher in females and in less severe disease. The intra-class correlation coefficient between home-based and centrally measured FC was 0.88. CONCLUSION: The adherence to home-based measurement of FC was fair. Usability scores for the home-based test were high. There was a good correlation with the centrally measured FC by ELISA. PMID- 28587754 TI - Delirium screening in intensive care: A life saving opportunity. AB - BACKGROUND: Delirium is described as 'acute brain failure' and constitutes a medical emergency which presents a hazard for people cared for in intensive care units. The Scottish intensive care society audit group recommend that all people cared for in intensive care units be screened for signs of delirium so that treatment and management of complications can be implemented at an early stage. CLINICAL IMPLICATION: There is inconsistent evidence about when and how the assessment of delirium is carried out by nursing staff in the intensive care setting. AIM: This narrative review explores the pathophysiology and current practices of delirium screening in intensive care. Consideration is given to the role of the nurse in detecting and managing delirium and some barriers to routine daily delirium screening are critically debated. CONCLUSION: It is argued that routine delirium screening is an essential element of safe, effective and person centred nursing care which has potential to reduce morbidity and mortality. PMID- 28587755 TI - Empathy, loneliness, burnout, and life satisfaction in Chilean nurses of palliative care and homecare services. AB - INTRODUCTION: Empathy has been described as an essential competence of healthcare professionals who are working in palliative care and homecare services. In these services, usually accompanied by a high risk of physical and emotional burnout, empathy can play an important role in the improvement of occupational wellbeing. The aim of this study was to confirm the role of empathy in the prevention of loneliness and burn out, and in the promotion of life satisfaction. METHODS: In 2016, an observational study was carried out in Chile with professional nurses who were working in palliative care and homecare services. Empathy with the patients, loneliness, life satisfaction, and burnout were measured using psychometric scales. Correlation analyses were applied to confirm relationships among the elements measured. RESULTS: In a sample of 64 participants, positive correlations were confirmed between empathy and life satisfaction (P = 0.40; p = 0.003), and between empathy and professional experience (P = 0.29; p = 0.04). On the other hand, inverse correlations were confirmed between empathy and burnout (P = -0.38; p = 0. 01), and between empathy and loneliness (P = -0.41; p = 0.004). CONCLUSIONS: These findings confirm the important role that empathy plays in the prevention of loneliness and burnout, and in the promotion of life satisfaction. Evidence found suggests that empathetic abilities can be improved by the professional experience. PMID- 28587756 TI - Perceived self-efficacy, personality and bioethics before a heart rehabilitation programme in primary health care. AB - OBJECTIVES: There is a clear evidence of the benefit of cardiac rehabilitation after a cardiovascular event on patients' mood and perceived self-efficacy in terms of their own health care. Our aim is to define the correlation between mood related variables, biotype and self-efficacy in this population. DESIGN: Descriptive study. BACKGROUND, PARTICIPANTS: The entire population of patients discharged from thecardiac rehabilitation unit over 12 months. MAIN MEASUREMENTS: Universal anthropometric and psychometric (general self-efficacy scale, Salamanca personality traits questionnaire, Hamilton anxiety scale and Beck depression inventory) variables are determined. Descriptive statistics and association between variables (correlation) is determined. RESULTS: This study involved 88 patients, response rate 92%. The average age was 53 years old, 80.23% were males. Descriptive statistics and Pearson correlations for the main dependent variable and associated variables is performed. Significant evidence is shown, self efficacy is negatively correlated with anxiety (r=-0.4009) and depression (r= 0.4152), as well as dependent(r=-03 175) and impulsive (r=-0.4243) personality traits. Higher levels of anxiety positively correlate with endomorph biotype (r=0.3304), and depression-associated symptoms (r=0.2563). Age and gender do not correlate with self-perceived efficacy. CONCLUSIONS: Self-efficacy in the study population is correlated with personality traits, mood and body biotype. PMID- 28587757 TI - CEVL interactive - Best surgical practices for Open Mitrofanoff Procedure. PMID- 28587758 TI - Epigenetics for Plant Improvement: Current Knowledge and Modeling Avenues. AB - Epigenetic variations are involved in the control of plant developmental processes and participate in shaping phenotypic plasticity to the environment. Intense breeding has eroded genetic diversity, and epigenetic diversity now emerge as a new source of phenotypic variations to improve adaptation to changing environments and ensure the yield and quality of crops. Here, we review how the characterization of the stability and heritability of epigenetic variations is required to drive breeding strategies, which can be assisted by process-based models. We propose future directions to hasten the elucidation of complex epigenetic regulatory networks that should help crop modelers to take epigenetic modifications into account and assist breeding strategies for specific agronomical traits. PMID- 28587759 TI - Con: Extracorporeal Membrane Oxygenation Should Not Routinely Replace Cardiopulmonary Bypass As the Preferred Method of Support During Lung Transplantation. PMID- 28587760 TI - Protective Lung Strategy During Bronchoscopic Laser Resection of Tracheobronchial Tumors: A Case Series. PMID- 28587761 TI - ITV, mid-ventilation, gating or couch tracking - A comparison of respiratory motion-management techniques based on 4D dose calculations. AB - PURPOSE: Respiratory motion-management techniques (MMT) aim to ensure tumor dose coverage while sparing lung tissue. Dynamic treatment-couch tracking of the moving tumor is a promising new MMT and was compared to the internal-target volume (ITV) concept, the mid-ventilation (MidV) principle and the gating approach in a planning study based on 4D dose calculations. METHODS: For twenty patients with lung lesions, planning target volumes (PTV) were adapted to the MMT and stereotactic body radiotherapy treatments were prepared with the 65%-isodose enclosing the PTV. For tracking, three concepts for target volume definition were considered: Including the gross tumor volume of one phase (single-phase tracking), including deformations between phases (multi-phase tracking) and additionally including tracking latencies of a couch tracking system (reliable couch tracking). The accumulated tumor and lung doses were estimated with 4D dose calculations based on 4D-CT datasets and deformable image registration. RESULTS: Single-phase tracking showed the lowest ipsilateral lung Dmean (median: 3.3Gy), followed by multi-phase tracking, gating, reliable couch tracking, MidV and ITV concepts (3.6, 3.8, 4.1, 4.3 and 4.8Gy). The 4D dose calculations showed the MidV and single-phase tracking overestimated the target mean dose (-2.3% and -1.3%), while it was slightly underestimated by the other MMT (<+1%). CONCLUSION: The ITV concept ensures tumor coverage, but exposes the lung tissue to a higher dose. The MidV, gating and tracking concepts were shown to reduce the lung dose. Neglecting non-translational changes of the tumor in the target volume definition for tracking results in a slightly reduced target coverage. The slightly inferior dose coverage for MidV should be considered when applying this technique clinically. PMID- 28587762 TI - Two novel roles of buffalo milk lactoperoxidase, antibiofilm agent and immunomodulator against multidrug resistant Salmonella enterica serovar Typhi and Listeria monocytogenes. AB - The increasing occurrence of multidrug resistant bacteria causing bacteremia infection, constitutes a major health problem, difficult-to-treat bacteremia due to its ability to form biofilm. Buffalo milk lactoperoxidase (BMLpo) is effective and safe to use as bacteriostatic agent. The MIC of BMLpo and amikacin were used to evaluate the antibiofilm activity against resistant L. monocytogenes and S. typhi. Prophylactic effects of BMLpo against L. monocytogenes and S. typhi bacteremia in vivo have been tested and ELISA test used to evaluate serum cytokines. Significant antibiofilm activity of BMLpo observed against the highest biofilm producer isolates. Our results showed that the prophylactic effect of BMLpo in BALB/c mice bacteremic model. A significant clearance of L. monocytogenes and S. typhi, investigated in blood and different organs tissues in BMLpo-treated infected groups when compared to the non-treated groups. Further, analysis of serum cytokines levels revealed that BMLpo prophylaxis modulates their release in different way when it compared to the control. This study showed, BMLpo effects as an alternative antibiofilm agent to compact gram negative pathogens, and protects the host against bacteremia infection. Moreover, the BMLpo role as an immunomodulatory. These investigations indicated the BMLpo crucial role in the practical clinical applications. PMID- 28587763 TI - Mechano-electrical feedback in the clinical setting: Current perspectives. AB - Mechano-electric feedback (MEF) is an established mechanism whereby myocardial deformation causes changes in cardiac electrophysiological parameters. Extensive animal, laboratory and theoretical investigation has demonstrated that abnormal patterns of cardiac strain can induce alteration of electrical excitation and recovery through MEF, which can potentially contribute to the establishment of dangerous arrhythmias. However, the clinical relevance of MEF in patients with heart disease remains to be established. This paper reviews up-to date experimental evidence describing the response to different types of mechanical stimuli in the intact human heart with the support of new data collected during cardiac surgery. It discusses modulatory effects of MEF that may contribute to increase the vulnerability to arrhythmia and describes MEF interaction with clinical conditions where mechanically induced changes in cardiac electrophysiology are likely to be more relevant. Finally, directions for future studies, including the need for in-vivo human data providing simultaneous assessment of the distribution of structural, functional and electrophysiological parameters at the regional level, are identified. PMID- 28587765 TI - Comparative aspects of GnRH-Stimulated signal transduction in the vertebrate pituitary - Contributions from teleost model systems. AB - Gonadotropin-releasing hormone (GnRH) is a major regulator of reproduction through actions on pituitary gonadotropin release and synthesis. Although it is often thought that pituitary cells are exposed to only one GnRH, multiple GnRH forms are delivered to the pituitary of teleost fishes; interestingly this can include the cGnRH-II form usually thought to be non-hypophysiotropic. GnRHs can regulate other pituitary cell-types, both directly as well as indirectly, and multiple GnRH receptors (GnRHRs) may also be expressed in the pituitary, and even within a single pituitary cell-type. Literature on the differential actions of native GnRH isoforms in primary pituitary cells is largely derived from teleost fishes. This review will outline the diversity and complexity of GnRH-GnRHR signal transduction found within vertebrate gonadotropes as well as extra gonadotropic sites with special emphasis on comparative studies from fish models. The implications that GnRHR transduction mechanisms are GnRH isoform-, function-, and cell-specific are also discussed. PMID- 28587764 TI - Toxicity of phenolipids: Protocatechuic acid alkyl esters trigger disruption of mitochondrial membrane potential and caspase activation in macrophages. AB - Phenolipids are a class of phenolic compounds with a lipidic moiety that have been receiving increasing attention due to their promising biological activities; however data regarding their toxicity and mechanism of action are scarce. A series of 11 phenolipids consisting of alkyl esters derivatives of the natural molecule protocatechuic acid was synthesized and evaluated against a panel of cancer and non-cancer cell lines. The macrophage cell line RAW 264.7, widely used as a tool for screening anti-inflammatory drugs, was more susceptible to the toxicity of these molecules than human cancer cells, reason for which mechanist studies were conducted. The parent molecule was not toxic up to 100MUM, however structural modifications by inclusion of carbon side chains resulted in increased toxicity, compounds bearing 8-14 carbons being the most toxic and displaying IC50 in the nanomolar range. Mechanistic studies showed that phenolipids elicit chromatin condensation, loss of cell viability and disruption of mitochondrial membrane potential (DeltaPsim), increased reactive oxygen species (ROS) and activation of caspase-9/3, thus pointing to the involvement of mitochondria in the programmed cell death process taking place. This is the first study addressing the toxicity and mechanism of action of protocatechuic acid derivatives, which is relevant in light of the recent interest in these molecules. PMID- 28587766 TI - Circulating 25-hydroxyvitamin D level and prognosis of lung cancer patients: A systematic review and meta-analysis. AB - BACKGROUND: Previous studies suggested a possible influence of circulating 25 hydroxyvitamin D [25(OH)D] level on the prognosis of lung cancer patients, but conflicting findings were reported. A systematic review and meta-analysis was thus conducted to comprehensively assess the influence of circulating 25(OH)D level on the prognosis of lung cancer patients. METHODS: Prospective or retrospective cohort studies assessing the influence of circulating 25(OH)D level on the prognosis of lung cancer patients were considered eligible. Hazard Ratios (HR) were pooled using meta-analysis. RESULTS: Eight studies with 2166 lung cancer patients were included. Meta-analysis of unadjusted HRs from four studies showed low circulating 25(OH)D level was significantly correlated with poor overall survival in lung cancer (HR=1.30, 95%CI 1.08-1.55, P=0.004). Meta analysis of adjusted HRs from eight studies suggested that low circulating 25(OH)D level was not significantly correlated with poor overall survival (HR=1.25; P=0.13). However, sensitivity analysis suggested an obvious change in the pooled HRs when excluding single study by turns. When the study by Liu et al. was omitted, low circulating 25(OH)D level was significantly correlated with poor overall survival (HR=1.34; P=0.04). CONCLUSION: The present systematic review and meta-analysis suggested a correlation between low circulating 25(OH)D level and poor overall survival in lung cancer. More studies are needed to further validate the finding above. PMID- 28587768 TI - Small things matter: Implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease with tens of millions of people affected worldwide. The pathogenesis is still poorly understood and various therapeutical approaches targeting the amyloid beta (Abeta) peptide, a product of the amyloidogenic cleavage of the amyloid precursor protein (APP), failed. Moreover, a couple of studies critically questioned the relevance of Abeta in the pathogenesis of AD. Thus, new ideas need to be studied and one highly interesting hypothesis is the APP mediated signal transduction to the nucleus. As a consequence nuclear -potentially toxic- structures emerge, which were recently found to a high extent in human AD tissue and thus, may contribute to neurodegeneration. Relevant for the signaling machinery are modifications at the very C-terminal end of the precursor protein, the APP intracellular domain (AICD). In this review we update the knowledge on mechanisms on AICD referring to our 2008 article: The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics-Relevance for Alzheimer's disease (T. Muller, et al., 2008). We summarize how AICD is generated and degraded, we describe its intramolecular motifs, translational modifications, and how those as well as APP dimerization influence AICD generation and function. Moreover, we resume the AICD interactome and elucidate AICDs involvement in nuclear signaling, transcriptional regulation, cell death, DNA repair and cell cycle re-entry and we give insights in its physiological function. Results are summarized in the comprehensive poster "The world of AICD". PMID- 28587767 TI - Frontal alpha asymmetry predicts inhibitory processing in youth with attention deficit/hyperactivity disorder. AB - INTRODUCTION: Atypical asymmetry in brain activity has been implicated in the behavioral and attentional dysregulation observed in ADHD. Specifically, asymmetry in neural activity in the right versus left frontal regions has been linked to ADHD, as well as to symptoms often associated with ADHD such as heightened approach behaviors, impulsivity and difficulties with inhibition. Clarifying the role of frontal asymmetry in ADHD-like traits, such as disinhibition, may provide information on the neurophysiological processes underlying these behaviors. METHOD: ADHD youth (ADHD: n = 25) and healthy, typically developing controls (TD: n = 25) underwent an electroencephalography (EEG) recording while completing a go/no-go task-a commonly used test measuring behavioral inhibition. In addition, advanced signal processing for source localization estimated the location of signal generators underlying frontal alpha asymmetry (FA) during correct and incorrect trials. RESULTS: This is the first study in ADHD to demonstrate that the dorsal-lateral prefrontal cortex (DLPFC) may be responsible for generating frontal alpha. During failed inhibition trials, ADHD youth displayed greater FA than TD youth. In addition, within the ADHD group, frontal asymmetry during later processing stages (i.e., 400-800ms after stimulus) predicted a higher number of commission errors throughout the task. CONCLUSIONS: These results suggest that frontal alpha asymmetry may be a specific biomarker of cognitive disinhibition among youth with ADHD. PMID- 28587769 TI - Device to stablise nasoendotracheal tube during intraoral or orthognathic surgery. PMID- 28587771 TI - Hypercholesterolemia: The role of PCSK9. AB - Heart disease ends the life of more people than any other disease in the United States. High levels of low density lipoprotein (LDL)-cholesterol cause heart diseases by increasing the formation of atherosclerotic plaques. Proprotein convertase subtilisin/kexin-9 (PCSK9) indirectly regulates plasma LDL levels by controlling the LDL receptor expression at the plasma membrane. PCSK9 also appears to modulate glucose intolerance, insulin resistance, abdominal obesity, inflammation, and hypertension. The magnitude of PCSK9's involvement in the onset of these metabolic abnormalities appears to be associated with age, sex, and ethnic background. Another regulator, the inducible degrader of the LDL receptor (IDOL), works by enhancing the ubiquitination of the LDL receptor. Herein, we will review the functions and regulatory mechanisms of PCSK9. The effects of PCSK9 on the LDL receptor, the relationship of this convertase with IDOL, and treatments currently available against hypercholesterolemia are also discussed. PMID- 28587770 TI - Functional communication between PKC-targeted cardiac troponin I phosphorylation sites. AB - Increased protein kinase C (PKC) activity is associated with heart failure, and can target multiple cardiac troponin I (cTnI) residues in myocytes, including S23/24, S43/45 and T144. In earlier studies, cTnI-S43D and/or -S45D augmented S23/24 and T144 phosphorylation, which suggested there is communication between clusters. This communication is now explored by evaluating the impact of phospho mimetic cTnI S43/45D combined with S23/24D (cTnIS4D) or T144D (cTnISDTD). Gene transfer of epitope-tagged cTnIS4D and cTnISDTD into adult cardiac myocytes progressively replaced endogenous cTnI. Partial replacement with cTnISDTD or cTnIS4D accelerated the time to peak (TTP) shortening and time to 50% re lengthening (TTR50%) on day 2, but peak shortening was only diminished by cTnIS4D. Extensive cTnIS4D replacement continued to accelerate TTP, and decrease shortening amplitude, while TTR50% returned to baseline levels on day 4. In contrast, cTnISDTD modestly reduced shortening amplitude and continued to accelerate myocyte TTP and TTR50%. These results indicate cTnIS43/45 communicates with S23/24 and T144, with S23/24 exacerbating and T144 attenuating the S43/45D dependent functional deficit. In addition, more severe functional alterations in cTnIS4D myocytes were accompanied by higher levels of secondary phosphorylation compared to cTnISDTD. These results suggest that secondary phosphorylation helps to maintain steady-state contractile function during chronic cTnI phosphorylation at PKC sites. PMID- 28587772 TI - Gastric inflammatory myofibroblastic tumor identified as ectopic pancreas and treated by endoscopic submucosal dissection. PMID- 28587773 TI - Colovesical fistula: visualization of the bladder during colonoscopy. PMID- 28587774 TI - Is a low FODMAP diet beneficial for patients with inflammatory bowel disease? A meta-analysis and systematic review. AB - BACKGROUND & AIMS: To assess the current evidence regarding the benefit of a low fermentable oligosaccharides, disaccharides, monosaccharides, and polyol (FODMAP) diet in the treatment of patients with inflammatory bowel disease (IBD). METHODS: Databases such as PubMed, Web of Science, Medline were comprehensively searched for relevant studies through January 2017. The pooled odds ratio (OR) and weighted mean difference (WMD) with 95% confidence intervals (CIs) were used to analyze the dichotomous variables (diarrhea response, abdominal pain and bloating, etc.) and the continuous variables. Random- and fixed-effects models were chosen according to heterogeneity. RESULTS: Two RCTs and four before-after studies with a total of 319 patients (96% in remission) were identified. Except for the constipation response, there was a significant improvement in other symptoms: diarrhea response (OR: 0.24, 95% CI: 0.11-0.52, p = 0.0003), satisfaction with gut symptoms (OR: 26.84, 95% CI: 4.6-156.54, p < 0.00001), abdominal bloating (OR: 0.10, 95% CI: 0.06-0.16, p < 0.00001), abdominal pain (OR: 0.24, 95% CI: 0.16-0.35, p < 0.00001), fatigue (OR: 0.40, 95% CI: 0.24-0.66, p = 0.0003) and nausea (OR: 0.51, 95% CI: 0.31-0.85, p = 0.009). CONCLUSIONS: The present meta-analysis offers proof to support that a low FODMAP diet is beneficial for reducing gastrointestinal symptoms in patients with quiescent IBD. With the inherent limitations, the findings of this analysis remain to be confirmed and updated by further high-volume, well-designed and long-term follow up studies. PMID- 28587775 TI - Diagnosis of exclusion in works of art. PMID- 28587776 TI - Pharmacological characterization of a novel potent, selective, and orally active phosphodiesterase 2A inhibitor, PDM-631. AB - Recently, we identified a novel phosphodiesterase 2A (PDE2A) inhibitor, PDM-631 ((S)-3-cyclopropyl-6-methyl-1-(1-(4-(trifluoromethoxy)phenyl)propan-2-yl)-1,5 dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one). PDM-631 showed potent inhibitory activities for human and rat PDE2A with IC50 values of 1.5 and 4.2nM, respectively and more than 2000-fold selectivity against other phosphodiesterases. In rat studies, PDM-631 showed oral bioavailability and good brain penetration, and increased the cGMP levels in the cortex. These data indicate that PDM-631 is a potent, selective, orally active, and brain-penetrable PDE2A inhibitor. In behavioral studies using rat models, PDM-631 (3-30mg/kg) resulted in better discrimination between a novel object and a familiar one 48h after the acquisition phase in the novel object recognition test, thus indicating that PDM-631 increased object recognition memory. In contrast, PDM-631 did not attenuate the conditioned avoidance response at the same dose range (3-30mg/kg) in rats, indicating that PDM-631 did not show an antipsychotic-like effect. In test for extrapyramidal side effect, PDM-631 had no effect on catalepsy at the effective doses (10 and 30mg/kg) in the novel object recognition test, while haloperidol caused catalepsy at a dose of 3mg/kg. Our results suggest that PDM 631 is a good pharmacological tool that can be used to investigate the role of PDE2A and may have therapeutic potential for the treatment of cognitive impairments associated with schizophrenia and neurodegenerative disorders, without any extrapyramidal side effects. PMID- 28587777 TI - Effect of ionic strength on the aggregation kinetics of the amidated amyloid beta peptide Abeta (1-40) in aqueous solutions. AB - In this work we study the effect of solution ionic strength on the structural evolution of amidated amyloid beta peptide Abeta (1-40) oligomers at the early stages of fibril formation. By light scattering, we follow the time evolution of the structure and short-time dynamics of peptide structures at low ionic strengths. Our results allow identifying initial oligomer structures as the effective building blocks in the amyloid fibrils formation and indicate that the oligomers growth pathway, from compact structures to flexible chain-like structures, becomes faster as the solution ionic strength is increased. Furthermore, we find no evidence of structural branching what suggests that elongation of amyloid fibrils is dominated by linear association. To describe our results we adapt a phenomenological model based on population balance equations and linear polymer growth, where the parameters required are obtained from the experiments. Model calculations are in good agreement with experimentally obtained estimates for the radius of gyration of Abeta (1-40) oligomers, thus further supporting our findings. Additionally, we introduce a model for the effective interaction among initial Abeta structures that captures the dependence of the effective association rates on solution ionic strength. PMID- 28587778 TI - Advanced method optimization for volatile aroma profiling of beer using two dimensional gas chromatography time-of-flight mass spectrometry. AB - The complex mixture of volatile organic compounds (VOCs) present in the headspace of Trappist and craft beers was studied to illustrate the efficiency of thermal desorption (TD) comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS) for highlighting subtle differences between highly complex mixtures of VOCs. Headspace solid-phase microextraction (HS-SPME), multiple (and classical) stir bar sorptive extraction (mSBSE), static headspace (SHS), and dynamic headspace (DHS) were compared for the extraction of a set of 21 representative flavor compounds of beer aroma. A Box-Behnken surface response methodology experimental design optimization (DOE) was used for convex hull calculation (Delaunay's triangulation algorithms) of peak dispersion in the chromatographic space. The predicted value of 0.5 for the ratio between the convex hull and the available space was 10% higher than the experimental value, demonstrating the usefulness of the approach to improve optimization of the GC*GC separation. Chemical variations amongst aligned chromatograms were studied by means of Fisher Ratio (FR) determination and F-distribution threshold filtration at different significance levels (alpha=0.05 and 0.01) and based on z-score normalized area for data reduction. Statistically significant compounds were highlighted following principal component analysis (PCA) and hierarchical cluster analysis (HCA). The dendrogram structure not only provided clear visual information about similarities between products but also permitted direct identification of the chemicals and their relative weight in clustering. The effective coupling of DHS-TD-GC*GC-TOFMS with PCA and HCA was able to highlight the differences and common typical VOC patterns among 24 samples of different Trappist and selected Canadian craft beers. PMID- 28587779 TI - Use of dual-filtering to create training sets leading to improved accuracy in quantitative structure-retention relationships modelling for hydrophilic interaction liquid chromatographic systems. AB - The development of quantitative structure retention relationships (QSRR) having sufficient accuracy to support high performance liquid chromatography (HPLC) method development is still a major issue. To tackle this challenge, this study presents a novel QSRR methodology to select a training set of compounds for QSRR modelling (i.e. to filter the database to identify the most appropriate compounds for the training set). This selection is based on a dual filtering strategy which combines Tanimoto similarity (TS) searching as the primary filter and retention time (tR) similarity clustering as the secondary filter, using a database of pharmaceutical compound retention times collected over a wide range of hydrophilic interaction liquid chromatography (HILIC) systems. To employ tR similarity filtering, correlation to a molecular descriptor is used as a measure of retention time. For the retention time of a compound to be modelled a relationship between experimental chromatographic data and various molecular descriptors is calculated using a genetic algorithm-partial least squares (GA PLS) regression. The proposed dual-filtering-based QSRR model significantly improves the retention time predictability compared to the diverse, global, and TS-based QSRR models, with an average root mean square error in prediction (RMSEP) of 11.01% over five different HILIC stationary phases. The average CPU time for implementing the proposed approach is less than 10min, which makes it quite favorable for rapid method development in HILIC. In addition, interpretation of the molecular descriptors selected by this novel approach provided some insight into the HILIC mechanism. PMID- 28587780 TI - A pressure-affected headspace-gas chromatography method for determining calcium carbonate content in paper sample. AB - The present work reports on the development of a pressure-affected based headspace (HS) analytical technique for the determination of calcium carbonate content in paper samples. By the acidification, the carbonate in the sample was converted to CO2 and released into the headspace of a closed vial and then measured by gas chromatography (GC). When the amount of carbonate in the sample is significant, the pressure created by the CO2 affects the accuracy of the method. However, the pressure also causes a change in the O2 signal in the HS-GC measurement, which is a change that can be used as an indirect measure of the carbonate in the sample. The results show that the present method has a good precision (the relative standard deviation<2.32%), and good accuracy (the relative differences compared to a reference method was<5.76%). Coupled with the fact that the method is simple, rapid, and accurate, it is suitable for a variety of applications that call for the analysis of high carbonate content in paper samples. PMID- 28587782 TI - Fragility Fracture Special Issue: Optimum care and avoiding a second fracture. PMID- 28587783 TI - The use of diacetyl (2,3-butanedione) and related flavoring substances as flavorings added to foods-Workplace safety issues. AB - In 2001, staff of the National Institute of Occupational Safety and Health (NIOSH) identified diacetyl (2,3-butanedione) as a "marker" of exposure in a microwave popcorn manufacturing facility in which workers developed severe respiratory illness. Subsequent investigations identified additional workers in food and flavor manufacturing facilities also with severe respiratory illness. The flavor industry, NIOSH, and federal and state regulators conducted significant programs to address workplace safety concerns related to the manufacture of flavors and foods containing added flavors. These programs, initiated in 2001, continue today. Key to the success of these programs is understanding what flavors added to foods are and how they are manufactured, how they are incorporated into foods, the specific characteristics of diacetyl and related flavoring substances, and what actions may be taken to assure the safest workplaces possible. PMID- 28587781 TI - Wnt5a induces catabolic signaling and matrix metalloproteinase production in human articular chondrocytes. AB - OBJECTIVE: Aberrant Wnt signaling may contribute to osteoarthritis (OA) but the Wnt family members involved have not been fully identified. The purpose of this study was to investigate the role of Wnt5a as a potential mediator of cartilage destruction in OA. DESIGN: Immunohistochemistry to detect Wnt5a was performed using normal and OA human articular cartilage. Cultured normal human chondrocytes were treated with fibronectin fragments (FN-f) as a catabolic stimulus or recombinant Wnt5a protein with or without pretreatment using a panel of signaling inhibitors. Expression of Wnt5a, anabolic genes and catabolic genes were determined by quantitative real-time PCR. Production of Wnt5a protein and matrix metalloproteinases (MMPs) as well as activation of signaling proteins were analyzed by immunoblotting. RESULTS: Wnt5a was present in human articular cartilage with OA changes and its expression and secretion were increased in FN-f stimulated chondrocytes. FN-f stimulated Wnt5a production through the c-Jun N terminal kinase (JNK) and extracellular signal-related kinase (ERK) pathways. Wnt5a reduced aggrecan gene expression after 48 h of treatment. Wnt5a seemed to promote MMP1, -3, and -13 expression as well as MMP1 and MMP13 protein production in normal human chondrocytes. Wnt5a inhibitor peptides did not affect FN-f induced MMP production. Wnt5a activated beta-catenin independent signaling including calmodulin-dependent protein kinase II (CaMKII), JNK, p38, ERK1/2, p65 and Akt. Inhibition of JNK, p38, ERK, PI-3 kinase and CaMKII by specific signaling inhibitors suppressed Wnt5a mediated MMP1 and MMP13 production. CONCLUSIONS: Wnt5a is present in human OA cartilage and can promote chondrocyte catabolic activity through non-canonical Wnt signaling, which suggests a potential role in OA. PMID- 28587785 TI - Dihydrotestosterone as mediator for cisplatin induced nephrotoxicity: New insight down the road. PMID- 28587784 TI - Gender-specific expression of ATP-binding cassette (Abc) transporters and cytoprotective genes in mouse choroid plexus. AB - The choroid plexus (CP) and blood-brain barrier (BBB) control the movement of several drugs and endogenous compounds between the brain and systemic circulation. The multidrug resistance associated protein (Mrp) efflux transporters form part of these barriers. Several Mrp transporters are positively regulated by the transcription factor nuclear factor erythroid-2-related factor (Nrf2) in liver. The Mrps, Nrf2 and Nrf2-dependent genes are cytoprotective and our aim was to examine basal gender differences in expression of Mrp transporters, Nrf2 and Nrf2-dependent genes (Nqo1 and Ho-1) in the brain barriers. Previous studies have shown higher expression of Mrp1, Mrp2 and Mrp4 in female mouse liver and kidney. We hypothesized that similar renal/hepatic gender specific patterns are present in the brain-barrier epithelia interfaces. qPCR and immunoblot analyses showed that Mrp4, Ho-1 and Nqo1 expression was higher in female CP. Mrp1, Mrp2 and Nrf2 expression in the CP had no gender pattern. Female Mrp1, Mrp2 and Mrp4 mouse brain expressions in remaining brain areas, excluding CP, were higher than male. Functional analysis of Mrp4 in CP revealed active accumulation of the Mrp4 model substrate fluo-cAMP. WT female CP had 10-fold higher accumulation in the vascular spaces than males and 60% higher than Mrp4-/- females. Probenecid blocked all transport. Methotrexate did as well except in Mrp4-/- females where it had no effect, suggesting compensatory induction of transport occurred in Mrp4-/-. Collectively, our findings indicate significant gender differences in expression of Mrp transporters and cytoprotective genes in the CP and BBB. PMID- 28587786 TI - The history of bone densitometry. AB - Bone densitometry (dual energy x-ray absorptiometry-DXA) is a vital medical tool needed for the diagnosis of osteoporosis in non-fractured patients; predicting future fracture risk; and monitoring bone mineral density (BMD) in untreated or treated patients. The history of the pivotal international society involved in the science and clinical interpretation of DXA, the International Society for Clinical Densitometry (ISCD) is defined in this manuscript. Since DXA and Osteoporosis management are intimately linked, the ISCD has over the years developed strong bonds with both the National Osteoporosis Foundation (NOF) and the International Osteoporosis Foundation (IOF). The positive impact that ISCD has led in the proper performance and clinical interpretation of bone mass measurements has been enormous worldwide. PMID- 28587787 TI - Importance of N- and C-terminal residues of substance P 1-7 for alleviating allodynia in mice after peripheral administration. AB - The heptapeptide SP1-7 (1, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7) is the major bioactive metabolite formed after proteolytic processing of the neuropeptide substance P (SP, Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2). The heptapeptide 1 frequently exhibits opposite effects to those induced by SP, such as exerting antinociception, or attenuating thermal hyperalgesia and mechanical allodynia. The heptapeptide SP1-7 amide (2, Arg1-Pro2-Lys3-Pro4-Gln5 Gln6-Phe7-NH2) is often more efficacious than 1 in experimental pain models. We have now assessed the anti-allodynic outcome after systemic administration of 2 and a series of Ala-substituted and truncated analogues of 2, in the spared nerve injury (SNI) mice model and the results obtained were correlated with in vitro plasma stability and permeability measurements. It is herein demonstrated that an intact Arg1 in SP1-7 amide analogues is fundamental for retaining a potent in vivo effect, while Lys3 of 2 is less important. A displacement with Ala1 or truncation rendered the peptide analogues either inactive or with a significantly attenuated in vivo activity. Thus, the pentapeptide SP3-7 amide (7, t1/2=11.1 min) proven to be the major metabolite of 2, demonstrated an in vivo effect itself although considerably less significant than 2 in the SNI model. Intraperitoneal administration of 2 in a low dose furnished the most powerful anti-allodynic effect in the SNI model of all the analogous evaluated, despite a fast proteolysis of 2 in plasma (t1/2=6.4 min). It is concluded that not only the C-terminal residue, that we previously demonstrated, but also the N-terminal with its basic side chain, are important for achieving effective pain relief. This information is of value for the further design process aimed at identifying more drug-like SP1-7 amide related peptidomimetics with pronounced anti-allodynic effects. PMID- 28587788 TI - Two novel cocrystals of lamotrigine with isomeric bipyridines and in situ monitoring of the cocrystallization. AB - Crystal engineering strategy was applied to develop new solid forms of lamotrigine. Two novel cocrystals of lamotrigine forming with 4,4'-bipyridine (2:1) and 2,2'-bipyridine cocrystal (1:1.5) were successfully obtained by neat grinding and liquid assisted grinding. The novel cocrystals were fully characterized and confirmed by X-ray diffraction, thermal and spectroscopic analysis. DXRxi Raman microscope was also used to identify the cocrystals. The factors such as solvent and the structure of coformers which influenced the cocrystal formation were discussed. Furthermore, the novel cocrystals were both obtained by slurry crystallization. Process analytical technologies including focused beam reflectance measurement and attenuated total reflectance Fourier Transform Infrared were applied to investigate the cocrystallization process and the mechanism. HPLC analysis showed that the dissolution rate and the solubility of the two novel cocrystals were both improved. PMID- 28587790 TI - Better information sharing and reinforcement of facts needed during transition of young people with epilepsy. PMID- 28587789 TI - Once weekly glucagon-like peptide-1 receptor agonist albiglutide vs. prandial insulin added to basal insulin in patients with type 2 diabetes mellitus: Results over 52 weeks. AB - We have previously reported that once-weekly albiglutide was noninferior to thrice-daily lispro for glycemic lowering, with decreased weight and risk of hypoglycemia, in patients inadequately controlled on basal insulin over 26 weeks. Findings after 52 weeks reveal similar responses to albiglutide as an add-on to insulin glargine. PMID- 28587791 TI - Evaluation of anti-botulinum neurotoxin single domain antibodies with additional optimization for improved production and stability. AB - Botulinum neurotoxin (BoNT) is a highly potent and lethal toxin, which even in minute quantities can lead to death. BoNT occurs in seven well described serotypes, A-G, and it is critical to not only detect the presence of BoNT, but also to determine the serotype to which a person has been exposed, as the degree of toxicity and persistence of symptoms varies greatly between the various types. Recently, Conway et al. 2010 developed single domain antibodies (sdAb), the recombinant variable domains of heavy-chain-only antibodies derived from camelids, for the detection of all seven serotypes of BoNT; identifying pairs of sdAb for each serotype they demonstrated the sensitive detection of each toxin. Using the sequence information provided in that work, fourteen of their sdAb were recreated with one goal being confirmation of their binding ability and specificity for the seven serotypes of BoNT. This was accomplished using a direct binding assay with the toxins immobilized on microtiter plates. In addition, the melting temperatures and production yields from E. coli shake flask fermentation were determined for each of the sdAb produced. In several instances, alternatives or variants of the previously described sdAb were prepared, either to improve the stability or production yields of the anti-BoNT sdAb. Insertion of four framework 1 point mutations (1E or D, 3Q, 5V, and 6E) gave repeated improvement in thermal stability by 5-9 degrees C, offering a method for increasing sdAb melting temperatures. This work provides for the independent verification of the ability of these sdAb to recognize all seven serotypes of BoNT, furnishing melting temperature, relative affinity, and production yield information that will allow for their future utilization with increased confidence. PMID- 28587792 TI - Breaking fat! How mycobacteria and other intracellular pathogens manipulate host lipid droplets. AB - Tuberculosis (Tb) is a lung infection caused by Mycobacterium tuberculosis (Mtb). With one third of the world population latently infected, it represents the most prevalent bacterial infectious diseases worldwide. Typically, persistence is linked to so-called "dormant" slow-growing bacteria, which have a low metabolic rate and a reduced response to antibiotic treatments. However, dormant bacteria regain growth and virulence when the immune system is weakened, leading again to the active form of the disease. Fatty acids (FAs) released from host triacylglycerols (TAGs) and sterols are proposed to serve as sole carbon sources during infection. The metabolism of FAs requires beta-oxidation as well as gluconeogenesis and the glyoxylate shunt. Interestingly, the Mtb genome encodes more than hundred proteins involved in the five reactions of beta-oxidation, clearly demonstrating the importance of lipids as energy source. FAs have also been proposed to play a role during resuscitation, the resumption of replicative activities from dormancy. Lipid droplets (LDs) are energy and carbon reservoirs and have been described in all domains. TAGs and sterol esters (SEs) are stored in their hydrophobic core, surrounded by a phospholipid monolayer. Importantly, host LDs have been described as crucial for several intracellular bacterial pathogens and viruses and specifically translocate to the pathogen-containing vacuole (PVC) during mycobacteria infection. FAs released from host LDs are used by the pathogen as energy source and as building blocks for membrane synthesis. Despite their essential role, the mechanisms by which pathogenic mycobacteria induce the cellular redistribution of LDs and gain access to the stored lipids are still poorly understood. This review describes recent evidence about the dual interaction of mycobacteria with host LDs and membrane phospholipids and integrates them in a broader view of the underlying cellular processes manipulated by various intracellular pathogens to gain access to host lipids. PMID- 28587793 TI - Miglustat therapy in a case of early-infantile Niemann-Pick type C. AB - Niemann-Pick disease type C (NPC) is a rare, progressive autosomal recessive disease. It is caused by mutations in either the NPC1 or NPC2 genes, resulting in defective regulation of intracellular lipid trafficking. Miglustat, which reversibly inhibits glucosylceramide synthase, reportedly has beneficial effects on the progressive neurological symptoms of NPC and was approved in Japan in 2012. Some reports suggested that miglustat therapy delayed the onset or progression of NPC when treatment was initiated before the onset of neurological manifestation or at an early stage. We report here a patient with the early infantile form of NPC who started on miglustat at 4months of ages. To our knowledge, this patient is the youngest reported patient with NPC in which miglustat therapy was initiated. Our patient, who had hypotonia and developmental delay before treatment, remained stable and showed no new neurological symptoms. In addition, pulmonary involvement was improved during miglustat therapy. Our case and previous reports underscore the importance of early initiation of miglustat therapy for NPC. PMID- 28587794 TI - Biomechanical analysis of ankle ligamentous sprain injury cases from televised basketball games: Understanding when, how and why ligament failure occurs. AB - OBJECTIVES: Ankle sprains due to landing on an opponent's foot are common in basketball. There is no analysis to date that provides a quantification of this injury mechanism. The aim of this study was to quantify the kinematics of this specific injury mechanism and relate this to lateral ankle ligament biomechanics. DESIGN: Case series. METHODS: The model-based image-matching technique was used to quantify calcaneo-fibular-talar kinematics during four ankle inversion sprain injury incidents in televised NBA basketball games. The four incidents follow the same injury pattern in which the players of interest step onto an opponent's foot with significant inversion and a diagnosed ankle injury. A geometric analysis was performed to calculate the in vivo ligament strains and strain rates for the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL). RESULTS: Despite the controlled selection of cases, the results show that there are two distinct injury mechanisms: sudden inversion and internal rotation with low levels of plantarflexion; and a similar mechanism without internal rotation. The first of these mechanisms results in high ATFL and CFL strains, whereas the second of these strains the CFL in isolation. CONCLUSIONS: The injury mechanism combined with measures of the ligament injury in terms of percentage of strain to failure correlate directly with the severity of the injury quantified by return to-sport. The opportunity to control excessive internal rotation through proprioceptive training and/or prophylactic footwear or bracing could be utilised to reduce the severity of common ankle injuries in basketball. PMID- 28587795 TI - Bullying, Social Support, and Psychological Distress: Findings From RELACHS Cohorts of East London's White British and Bangladeshi Adolescents. AB - PURPOSE: The purpose of the study is to test whether bullying in adolescents relates to poor mental health and whether social support mitigated this effect. METHODS: In 2001, 28 schools in East London were randomly selected for surveys of two representative mixed ability classes: year 7 (11-12 years) and year 9 (13-14 years). Repeated measures were obtained from the same pupils 2 years later, using the Strengths and Difficulties Questionnaire (total difficulties score [TDS]) as a measure of psychological distress. A simple one-level random intercepts model with measurements nested within pupils was used to investigate the effects of bullying and social support from friends and family on TDS. We also assessed whether culturally congruent friendships offered a mental health advantage. RESULTS: Bullying was associated with a higher mean TDS (coefficient, 95% confidence interval: White British: 2.15, 1.41-2.88; Bangladeshi: 1.65, .91-2.4); a high level of family social support was associated with a lower TDS (White British: -2.36, -3.33 to -1.39; Bangladeshi: -2.34, -3.15 to -.149). Social support from friends was helpful for White British adolescents (-1.06, -2.07 to .04). Culturally congruent friendships offered no general advantage. CONCLUSION: Bullying is associated with psychological distress; family social support is independently associated with less psychological distress. PMID- 28587796 TI - Effect of Hospitalization on Percent Median Body Mass Index at One Year, in Underweight Youth With Restrictive Eating Disorders. AB - PURPOSE: Data from low-weight patients with restrictive eating disorders (EDs) treated in outpatient adolescent medicine-based ED treatment programs were analyzed to determine whether there was an association between hospitalization and gain to at least 90% median body mass index (mBMI) at 1-year follow-up. METHODS: Data were retrospectively collected for 322 low-weight (<85% mBMI at intake) patients aged 9-21 years, who presented with restrictive EDs to 14 adolescent medicine-based ED programs in 2010. Positive outcome was defined as being at least 90% mBMI (%mBMI = patient's body mass index/mBMI for age * 100) at 1-year follow-up. Association between treatment at a higher level of care and gain to at least 90% mBMI was analyzed for 140 patients who were <85% mBMI at the time of presentation, had not been previously hospitalized, and had 1-year follow up data available. RESULTS: For patients presenting at <85% mBMI, those who were hospitalized in the year following intake had 4.0 (95% confidence interval: 1.6 10.1) times the odds of gain to at least 90% mBMI, compared with patients who were not hospitalized, when controlling for baseline %mBMI. CONCLUSION: In this national cohort of patients with restrictive EDs presenting to adolescent medicine-based ED programs at <85% mBMI, those who were hospitalized had greater odds of being at least 90% mBMI at 1-year follow-up. PMID- 28587798 TI - Is Vein Bypass Truly Superior to Endovascular Intervention for Tibial Disease With "Severe" Limb Ischaemia? PMID- 28587797 TI - Comparison of Long-term Outcomes of Heparin Bonded Polytetrafluoroethylene and Autologous Vein Below Knee Femoropopliteal Bypasses in Patients with Critical Limb Ischaemia. AB - OBJECTIVE/BACKGROUND: Endovascular first is the preferred therapy approach to critical limb ischaemia (CLI). However, in spite of new endovascular techniques, bypass surgery still plays an important role, especially in patients with complex anatomy in whom endovascular therapy is not considered feasible, or has failed. The goal of this study was to analyse the outcomes of prosthetic or autologous vein for femoropopliteal (P3) bypasses performed under the abovementioned conditions. METHODS: A retrospective analysis of patients who underwent a femoropopliteal (P3) bypass for CLI (March 2007-December 2015) was conducted. Endovascular therapy was not possible. Patency rates, limb salvage, major adverse limb event (MALE) free survival, and survival after 5 years were analysed. RESULTS: In total, 151 cases were included in the analysis (rest pain 35.8%, ulcer/gangrene 64.3%). The graft material was autologous vein in 76 cases (vein group) and heparin bonded expanded polytetrafluoroethylene (HePTFE) in 75 cases (HePTFE group). Indications, risk factors, previous revascularisation procedures, and runoff vessels were similar in both groups. Thirty day mortality was 6.6% in the vein group and 5.3% in the HePTFE group (p = .508), early graft occlusion (6.6% vs. 5.3%; p = .508) and 30 day major amputation rate (0% vs. 2.7%; p = .245) were similar between the two groups. Overall primary patency was 51.7% (55.5% [vein group] vs. 51.7% [HePTFE group]; p = .897) and overall secondary patency was 64.2% (74.6% [vein group] vs. 55.6% [HePTFE group]; p = .119), all without significance after 5 years. However, limb salvage (79.1%) was significantly different (90.0% [vein group] vs. 62.9% [HePTFE group]; p = .021). Survival was similar between the groups (47.3% vs. 42.9%; p = .582) as well as MALE free survival (69.4% vs. 55.0%; p = .348). CONCLUSION: Bypasses to the below knee popliteal artery show good results in patients with CLI unsuitable for endovascular therapy. Vein is still the first line graft material. PMID- 28587799 TI - Factors Associated With Lower Extremity Dysmorphia Caused by Lower Extremity Lymphoedema: Comment on Data Sparsity. PMID- 28587800 TI - Commentary on "Factors Associated with Lower Extremity Dysmorphia Caused by Lower Extremity Lymphedema". PMID- 28587802 TI - Cytokine filtration modulates pulmonary metabolism and edema formation during ex vivo lung perfusion. AB - BACKGROUND: Ex vivo lung perfusion (EVLP) has improved the process of donor lung management. Cytokine accumulation during EVLP has been shown to correlate with worse outcome after lung transplantation. Our objective in this study was to test the safety and efficacy of cytokine filtration during EVLP in a large animal model. METHODS: Pig donor lungs were preserved for 24 hours at 4 degrees C, followed by 12 hours of EVLP, according to the Toronto protocol. The perfusate was continuously run through an absorbent device (CytoSorb) via a veno-venous shunt from the reservoir in the filter group. EVLP was performed according to the standard protocol in the control group (n = 5 each). EVLP physiology, lung X-ray, perfusate biochemistry, inflammatory response and microscopic injury were assessed. RESULTS: Cytokine filtration significantly improved airway pressure and dynamic compliance during the 12-hour perfusion period. Lung X-rays acquired at the end of perfusion showed increased consolidation in the control group. Electrolyte imbalance, determined by increased hydrogen, potassium and calcium ion concentrations in the perfusate, was markedly worsened in the control group. Glucose consumption and lactate production were markedly reduced, along with the lactate/pyruvate ratio in the filter group. Cytokine expression profile, tissue myeloperoxidase activity and microscopic lung injury were significantly reduced in the filter group. CONCLUSIONS: Continuous perfusate filtration through sorbent beads is effective and safe during prolonged EVLP. Cytokine removal decreased the development of pulmonary edema and electrolyte imbalance through the suppression of anaerobic glycolysis and neutrophil activation in this setting. Further studies are needed to test the beneficial effect of cytokine filtration on post transplant lung function. PMID- 28587801 TI - Response to Commentary on "Is There an Accurate Pre-operative Criterion for Dialysis Access Artery or Vein Diameter?" PMID- 28587803 TI - Effects of moisture content of food waste on residue separation, larval growth and larval survival in black soldier fly bioconversion. AB - In order to foster sustainable management of food waste, innovations in food waste valorization technologies are crucial. Black soldier fly (BSF) bioconversion is an emerging technology that can turn food waste into high protein fish feed through the use of BSF larvae. The conventional method of BSF bioconversion is to feed BSF larvae with food waste directly without any moisture adjustment. However, it was reported that difficulty has been experienced in the separation of the residue (larval excreta and undigested material) from the insect biomass due to excessive moisture. In addition to the residue separation problem, the moisture content of the food waste may also affect the growth and survival aspects of BSF larvae. This study aims to determine the most suitable moisture content of food waste that can improve residue separation as well as evaluate the effects of the moisture content of food waste on larval growth and survival. In this study, pre-consumer and post-consumer food waste with different moisture content (70%, 75% and 80%) was fed to BSF larvae in a temperature controlled rotary drum reactor. The results show that the residue can be effectively separated from the insect biomass by sieving using a 2.36mm sieve, for both types of food waste at 70% and 75% moisture content. However, sieving of the residue was not feasible for food waste at 80% moisture content. On the other hand, reduced moisture content of food waste was found to slow down larval growth. Hence, there is a trade-off between the sieving efficiency of the residue and the larval growth rate. Furthermore, the larval survival rate was not affected by the moisture content of food waste. A high larval survival rate of at least 95% was achieved using a temperature-controlled rotary drum reactor for all treatment groups. The study provides valuable insights for the waste management industry on understanding the effects of moisture content when employing BSF bioconversion for food waste recycling. PMID- 28587804 TI - Extraction of lead from waste CRT funnel glass by generating lead sulfide - An approach for electronic waste management. AB - Waste cathode ray tube (CRT) funnel glass is the key and difficult points in waste electrical and electronic equipment (WEEE) disposal. In this paper, a novel and effective process for the detoxification and reutilization of waste CRT funnel glass was developed by generating lead sulfide precipitate via a high temperature melting process. The central function in this process was the generation of lead sulfide, which gathered at the bottom of the crucible and was then separated from the slag. Sodium carbonate was used as a flux and reaction agent, and sodium sulfide was used as a precipitating agent. The experimental results revealed that the lead sulfide recovery rate initially increased with an increase in the amount of added sodium carbonate, the amount of sodium sulfide, the temperature, and the holding time and then reached an equilibrium value. The maximum lead sulfide recovery rate was approximately 93%, at the optimum sodium carbonate level, sodium sulfide level, temperature, and holding time of 25%, 8%, 1200 degrees C, and 2h, respectively. The glass slag can be made into sodium and potassium silicate by hydrolysis in an environmental and economical process. PMID- 28587805 TI - The effect of temperature, storage time and collection method on biomethane potential of source separated household food waste. AB - The aim of this study was to mimic real conditions for storage and transport and to evaluate how much of the biomethane potential is lost before the organic fraction of municipal solid waste (OFMSW) from households in Sweden reaches the biogas plant. The laboratory biomethane potential (BMP) experiments was carried out with respect to the storage time, collection method (paper or plastic bag) and storage temperature (22 degrees C and 6 degrees C) in order to evaluate the effect of these factors on the biomethane potential. A recipe representative for OFMSW from households in Sweden was designed with the help of literature and modification of recipes from technical reports and scientific literature. Laboratory experiments showed that the difference in the BMP of OFMSW stored in plastic- compared to paper bags were obvious at 22 degrees C with a lower biomethane potential for paper bags, but there was no difference at 6 degrees C. Provided that the loss of organic matter during pre-treatment is equivalent for both paper and plastic bags it is possible to get more biomethane from OFMSW collected in plastic bags during the warmest part of the year, since they have a more preservative effect on OFMSW than paper bags. This could be explained by the plastic bags being denser than paper and therefore maintain the volatile organic compounds inside the bag and promote a pre-hydrolysis of the material rather than aerobic degradation. PMID- 28587806 TI - Thermodynamic performance of SNG and power coproduction from MSW with recovery of chemical unreacted gas. AB - A cogeneration system for simultaneously producing synthetic natural gas (SNG) and electric power from municipal solid waste (MSW) is developed. This process provides a disposal method for MSW that is environmentally sustainable and uses as an alternative energy sources. Rather than converting all of the synthesis gas into end products, in the proposed system the unconverted gas is recovered for power generation in a combined-cycle unit. The overall efficiency of the proposed system is 36.33%. The energy efficiency of this system is approximately 8.7% higher than that of a standalone SNG production system, and 15.02% higher than that of an MSW incineration system. A sensitivity analysis shows that by increasing the H2/CO ratio (alpha), SNG production and SNG conversion efficiency can be increased, but the overall efficiency does not increase. Increasing the recycling ratio of the unconverted gas (Ru) benefits for the SNG yield up to a value before Ru/(Ru+1)=0.7, and the overall system efficiency reaches its maximum value at Ru/(Ru+1)=0.9. Therefore, partial recycling of the unreacted gas is more efficient up to a point, and higher recycling ratios are less efficient. PMID- 28587808 TI - Retinoic acid prevents synaptic deficiencies induced by alcohol exposure during gastrulation in zebrafish embryos. AB - In this study, we examined the effects of alcohol exposure during gastrulation on zebrafish embryos, specifically focusing on excitatory synaptic activity associated with neurons (Mauthner cells) that are born during gastrulation. Furthermore, we determined whether co-treatment of alcohol and retinoic acid (RA) could prevent the effects of alcohol exposure during gastrulation. We exposed zebrafish embryos to ethanol (150mM), RA (1nM), or a combination of RA (1nM) plus ethanol (150mM) for 5.5h from 5.25h post fertilization (hpf) to 10.75 hpf (gastrulation). Ethanol treatment resulted in altered hatching rates, survivability and body lengths. Immunohistochemical analysis of Mauthner cells (M cells) suggested that ethanol treatment resulted in smaller M-cell bodies and thinner axons, while electrophysiological recordings of AMPA miniature excitatory postsynaptic currents (mEPSCs) associated with M-cells showed that ethanol treated animals had a significantly reduced mEPSC frequency. Other mEPSC parameters such as amplitude, rise times and decay kinetics were not altered by exposure to alcohol. Locomotor studies showed that ethanol treatment resulted in altered C-bend escape responses. For instance, the C-bends of alcohol-treated fish were larger than control embryos. Thus, ethanol treatment during gastrulation altered a range of features in embryonic zebrafish. Importantly, co treatment with RA prevented all of the effects of ethanol including survivability, body length, M-cell morphology, AMPA mEPSC frequency and escape response movements. Together these findings show that ethanol exposure during the brief period of gastrulation has a significant effect on neuronal morphology and activity, and that this can be prevented with RA co-treatment. PMID- 28587807 TI - Association of MRI T1 relaxation time with neuropsychological test performance in manganese- exposed welders. AB - This study examines the results of neuropsychological testing of 26 active welders and 17 similar controls and their relationship to welders' shortened MRI T1 relaxation time, indicative of increased brain manganese (Mn) accumulation. Welders were exposed to Mn for an average duration of 12.25 years to average levels of Mn in air of 0.11+/-0.05mg/m3. Welders scored significantly worse than controls on Fruit Naming and the Parallel Lines test of graphomotor tremor. Welders had shorter MRI T1 relaxation times than controls in the globus pallidus, substantia nigra, caudate nucleus, and the anterior prefrontal lobe. 63% of the variation in MRI T1 relaxation times was accounted for by exposure group. In welders, lower relaxation times in the caudate nucleus and substantia nigra were associated with lower neuropsychological test performance on tests of verbal fluency (Fruit Naming), verbal learning, memory, and perseveration (WHO-UCLA AVLT). Results indicate that verbal function may be one of the first cognitive domains affected by brain Mn deposition in welders as reflected by MRI T1 relaxation times. PMID- 28587809 TI - Inpatient interventions are infrequent during pediatric hospitalizations for food induced anaphylaxis. PMID- 28587810 TI - Subcellular localization of Na/K-ATPase isoforms in ventricular myocytes. AB - The sodium/potassium ATPase (NKA) is essential for establishing the normal intracellular [Na+] and [K+] and transmembrane gradients that are essential for many cellular functions, including cardiac electrophysiology and contractility. Different NKA isoforms exhibit differential expression levels, cellular localization, and function in different tissues and species. Prior work has indicated that the NKA-alpha1 isoform is quantitatively predominant in cardiac myocytes, but that the alpha2 isoform is preferentially concentrated in the transverse tubules (TT), possibly at junctions with the sarcoplasmic reticulum (SR) where alpha2 may preferentially modulate cardiac contractility. Here we measured subcellular localization of NKA-alpha1 and alpha2 using super-resolution microscopy (STED and STORM) and isoform-selective antibodies in mouse ventricular myocytes. We confirm the preferential localization of NKA-alpha2 in TT vs. surface sarcolemma, but also show that alpha2 is relatively excluded from longitudinal TT elements. In contrast NKA-alpha1 is relatively uniformly expressed in all three sarcolemmal regions. We also tested the hypothesis that NKA-alpha2 (vs. alpha1) is preferentially concentrated at SR junctional sites near ryanodine receptors (RyR2). The results refute this hypothesis, in that NKA alpha1 and alpha2 were equally close to RyR2 at the TT, with no preferential NKA isoform localization near RyR2. We conclude that in contrast to relatively uniform NKA-alpha1 distribution, NKA-alpha2 is preferentially concentrated in the truly transverse (and not longitudinal) TT elements. However, NKA-alpha2 does not preferentially cluster at RyR2 junctions, so the TT NKA-alpha2 concentration may suffice for preferential effects of NKA-alpha2 inhibition on cardiac contractility. PMID- 28587811 TI - Dansylglycine, a fluorescent probe for specific determination of halogenating activity of myeloperoxidase and eosinophil peroxidase. AB - Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are enzymes present in neutrophil and eosinophil leukocytes, respectively. Here, we present the development of a sensitive and specific assay for determination of the halogenating enzymatic activity of MPO and EPO based on the electrophilic attack of HOCl and HOBr on aromatic ring of dansylglycine (DG). We found that the intrinsic fluorescence of DG was promptly depleted by the action of these acids. In the presence of the enzymes, the fluorescence bleaching was dependent of chloride (Cl-) and bromide (Br-), which makes the assay able to distinguish the halogenating from the peroxidase activity. A linear correlation was obtained between the hydrogen peroxide (H2O2) concentration and the fluorescent decay. Similarly, the enzyme activity was measured by keeping constant H2O2. The method was applied for studding MPO/EPO specific inhibitors as 5-fluortryptamine (reversible inhibitor) and 4-hydroxybenzhydrazide (irreversible inhibitor). Differently of the taurine chloramine/3,3',5,5'-tetramethylbenzidine assay, which is among the most used technique, the dansylglycine assay was able to differentiate these inhibitors based on their kinetic behavior. In conclusion, this assay can differentiate the peroxidase and halogenating activity of MPO and EPO. Moreover, the method is adequate for real-time measurement of the production of HOCl and HOBr. PMID- 28587812 TI - Why is systolic blood pressure drop >=10mmHg post RSD in patients with resistant hypertension considered responsiveness to the treatment? Should we interpret as science or arbitrariness? PMID- 28587813 TI - Abnormal regional homogeneity as a potential imaging biomarker for adolescent onset schizophrenia: A resting-state fMRI study and support vector machine analysis. AB - OBJECTIVE: Structural and functional abnormalities have been reported in the brain of patients with adolescent-onset schizophrenia (AOS). The brain regional functional synchronization in patients with AOS remains unclear. METHODS: We analyzed resting-state functional magnetic resonance scans in 48 drug-naive patients with AOS and 31 healthy controls by using regional homogeneity (ReHo), a measurement that reflects brain local functional connectivity or synchronization and indicates regional integration of information processing. Then, receiver operating characteristic curves and support vector machines were used to evaluate the effect of abnormal regional homogeneity in differentiating patients from controls. RESULTS: Patients with AOS showed significantly increased ReHo values in the bilateral superior medial prefrontal cortex (MPFC) and significantly decreased ReHo values in the left superior temporal gyrus (STG), right precentral lobule, right inferior parietal lobule (IPL), and left paracentral lobule when compared with controls. A combination of the ReHo values in bilateral superior MPFC, left STG, and right IPL was able to discriminate patients from controls with the sensitivity of 88.24%, specificity of 91.89%, and accuracy of 90.14%. CONCLUSION: The brain regional functional synchronization abnormalities exist in drug-naive patients with AOS. A combination of ReHo values in these abnormal regions might serve as potential imaging biomarker to identify patients with AOS. PMID- 28587814 TI - Motion energy analysis reveals altered body movement in youth at risk for psychosis. AB - BACKGROUND: Growing evidence suggests that movement abnormalities occur prior to the onset of psychosis. Innovations in technology and software provide the opportunity for a fine-tuned and sensitive measurement of observable behavior that may be particularly useful to detecting the subtle movement aberrations present during the prodromal period. METHODS: In the present study, 54 youth at ultrahigh risk (UHR) for psychosis and 62 healthy controls participated in structured clinical interviews to assess for an UHR syndrome. The initial 15min of the baseline clinical interview was assessed using Motion Energy Analysis (MEA) providing frame-by-frame measures of total movement, amplitude, speed, and variability of both head and body movement separately. RESULTS: Result showed region-specific group differences such that there were no differences in head movement but significant differences in body movement. Specifically, the UHR group showed greater total body movement and speed of body movements, and lower variation in body movement compared to healthy controls. However, there were no significant associations with positive, negative or disorganized symptom domains. CONCLUSION: This study represents an innovative perspective on gross motor function in the UHR group. Importantly, the automated approach used in this study provides a sensitive and objective measure of body movement abnormalities, potentially guiding novel assessment and prevention of symptom development in those at risk for psychosis. PMID- 28587815 TI - The role of estradiol in schizophrenia diagnosis and symptoms in postmenopausal women. AB - Schizophrenia is one of the most common mental illnesses in our society, affecting up to 1% of the population. There has been an increase in the number of people who are living longer with schizophrenia and people are being diagnosed later in life, with the majority of those later diagnoses being in women. In addition, there is a spike in diagnoses after women go through menopause, suggesting an important role for gonadal steroids in the disease. This paper examined aspects of aging and schizophrenia in the context of hormonal changes in women. With the rising prevalence rate of schizophrenia and the unique challenges that women face while aging with this disease, the idea of estrogen as a therapeutic agent to reduce symptom severity in postmenopausal women should be considered. In addition, we reviewed literature that suggests that estrogen interacts with the dopaminergic system to affect cognition and this should be studied further in older women with schizophrenia. Positive results in these studies have the potential to drastically improve the aging process for postmenopausal women with schizophrenia. PMID- 28587816 TI - Prognostic Value of the Preoperative Platelet-to-leukocyte Ratio for Oncologic Outcomes in Patients Undergoing Radical Cystectomy for Bladder Cancer. AB - BACKGROUND: Currently, stratification of patients with bladder cancer (BC) mainly relies on histopathologic and clinical staging. Furthermore, inflammation plays an important role in the pathogenesis of BC. With the preoperative platelet-to leukocyte ratio (PLR), we introduce a novel prognostic marker based on routine hematologic values in patients undergoing radical cystectomy (RC). PATIENTS AND METHODS: In our cohort of 665 patients undergoing RC (2004-2015) for urothelial carcinoma of the bladder (UCB), we analyzed a variety of preoperative hematologic parameters. We investigated the effect of thrombocytosis, leukocytosis, and the PLR on the oncologic outcomes, including cancer-specific survival (CSS), progression-free survival (PFS), and overall survival (OS). Both univariate (log rank test) and multivariate (Cox regression) analysis were performed. The prevalence of thrombocytosis and leukocytosis and differences in the PLR was assessed using the Mann-Whitney U test. The cutoff levels for leukocytosis, thrombocytosis, and the PLR were defined using receiver operating characteristic curve analysis, with the 5-year CSS as the binary classifier. RESULTS: A PLR of <= 28 (CSS, P = .033; OS, P = .029) and leukocytosis (CSS, P = .01; OS, P = .001; PFS, P = .003) were significantly associated with adverse oncologic outcomes using the log-rank test. On multivariate regression analysis, the PLR (CSS, P = .022; OS, P = .025) remained a significant prognostic marker among the standard staging variables and hemoglobin level. Advanced BC disease was significantly more prevalent in the patient subgroup with a low PLR (pT2-pT4, 35%; vs. pT <= 1, 24%; P = .006) and leukocytosis (pT2-pT4, 46%; vs. pT <= 1, 30%; P < .001; pN+, 49%; vs. pN0, 39%; P < .047). CONCLUSION: To the best of our knowledge, the present study is the first report of the preoperative PLR as a prognostic factor in patients undergoing RC for UCB. Compared with other inflammatory markers in BC, the PLR can be assessed without additional effort. External validation and its combination with other parameters might improve current prognostication systems for UCB. PMID- 28587817 TI - Human renal tubular cells contain CD24/CD133 progenitor cell populations: Implications for tubular regeneration after toxicant induced damage using cadmium as a model. AB - The proximal tubules of the kidney are target sites of injury by various toxicants. Cadmium (Cd+2), an environmental nephrotoxicant can cause adverse effects and overt renal damage. To decipher the mechanisms involved in nephrotoxicity, an in vitro model system is required. Mortal cultures of human proximal tubule (HPT) cells have served, as models but are difficult to acquire and do not lend themselves to stable transfection. The immortalized human proximal tubule cell line HK-2, has served as a model but it lacks vectorial active transport and shows signs of lost epithelial features. Recently a new proximal tubule cell line was developed, the RPTEC/TERT1, and the goal of this study was to determine if this cell line could serve as a model to study nephrotoxicity. Global gene expression analysis of this cell line in comparison to the HK-2 and HPT cells showed that the RPTEC/TERT1 cells had gene expression patterns similar to HPT cells when compared to the HK-2 cells. The HPT and the RPTEC/TERT1 cell line had an increased population of stem/progenitor cells co expressing CD24 and CD133 when compared to the HK-2 cells. The level of expression of cadherins, claudins and occludin molecules was also similar between the RPTEC/TERT1 and the HPT cells. Acute exposure to Cd+2 resulted in necrosis of the RPTEC/TERT1 cells when compared to the HK-2 cells which died by apoptosis. Thus, the RPTEC/TERT1 cells are similar to HPT cells and can serve as a good model system to study mechanisms involved in toxicant induced renal damage. PMID- 28587818 TI - Astrocyte-derived CCL2 participates in surgery-induced cognitive dysfunction and neuroinflammation via evoking microglia activation. AB - Neuroinflammation induced by peripheral trauma plays a key role in the development of postoperative cognitive dysfunction (POCD). Substantial evidence points to reactive glia as a pivotal factor during the inflammation process. However, little is known about the functional interactions between astrocytes and microglia. Recent evidence suggests the involvement of the CCL2-CCR2 pathway in CNS inflammation-related diseases. Our previous studies have suggested that astrocyte-derived CCL2 can induce microglial activation in vitro. Within this context, we sought to determine if the CCL2/CCR2 axis is involved in the crosstalk between astrocytes and microglia, contributing to increased neuroinflammation. Here, we show that tibial fracture surgery promoted CCL2 upregulation in activated astrocytes, increased CCR2 expression in activated microglia, and induced deficits in learning and memory. Site-directed pre injection of RS504393, a CCR2 antagonist, inhibited this effect by reducing microglial activation, M1 polarization, inflammatory cytokines, and neuronal injury and death and improving cognitive function. Taken together, these data implicate CCL2-CCR2 signaling in astrocyte-mediated microglial activation in central nervous system (CNS) inflammation and suggest that interference with CCL2 signaling could constitute another potential therapeutic target for POCD. PMID- 28587821 TI - Structural development of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs) to improve metabolic stability, and investigation of metabolic fate. AB - We synthesized a series of 1,2,3,4-tetrahydroisoquinoline-type positive allosteric modulators of prostacyclin receptor (IPPAMs), aiming to improve the metabolic stability of the previously identified hit compound IPPAM-3 (2). Our results indicated that the 3-position of the 2-substituted phenyl ring in this series of IPPAM-3 derivatives is a hot spot for metabolism catalyzed by human hepatic microsomes. This conclusion was confirmed by the finding that 8, in which the 3-position is blocked by a fluorine substituent, exhibited superior metabolic stability (t1/2 21min versus 7min for parent compound 2). The primary route of metabolism of 8 was found to be oxidative defluorination, i.e., ipso-substitution of the fluorine atom to a hydroxyl group, affording catechol derivative 12. The primary metabolite 12 underwent further hydroxylation mainly on the 1,2,3,4 tetrahydroisoquinoline moiety. These findings should be helpful for design of IPPAMs with longer duration of action. PMID- 28587820 TI - Fluorescence detection of serum albumin with a turnover-based sensor utilizing Kemp elimination reaction. AB - The Kemp elimination reaction is a well-known chemical reaction that is facilitated on a protein surface microenvironment, and in particular is highly accelerated in a unique binding pocket of serum albumin. We have designed and synthesized a fluorescently activatable coumarin derivative with a benzisoxazole scaffold to enable monitoring of the Kemp elimination reaction in terms of fluorescence change for the first time. We show that this fluorescent sensor can sensitively and selectively quantitate serum albumin in blood samples. It also works in a dry-chemistry format. PMID- 28587819 TI - Prodepressant- and anxiogenic-like effects of serotonin-selective, but not noradrenaline-selective, antidepressant agents in mice lacking alpha2-containing GABAA receptors. AB - Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/ and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2 containing GABAA-Rs in the response to serotonin-selective antidepressants. PMID- 28587822 TI - Initial evaluation of Cu-64 labeled PARPi-DOTA PET imaging in mice with mesothelioma. AB - Poly(ADP-ribose) polymerase (PARP) has emerged as an important molecular target for the treatment of several oncological diseases. A couple of molecular probes based on Olaparib scaffold have been developed by incorporation of F-18 or fluorophore for positron emission tomography (PET) or optical imaging in several types of tumor. PARP has been reported overexpressed in mesothelioma. We hereby synthesized an analogue of Olaparib containing DOTA moiety and radiolabeled it with Cu-64 to evaluate its utility of PET tracer for mesothelioma. The Cu-64 labeling was conveniently achieved at 90% yield with final compound at >99% radiochemistry purity. The biodistribution and PET imaging were performed at 0.5, 1, 2 and 18h to confirm the in vivo tumor targeting. The tumor uptake in study group was significant higher than that in control group (3.45+/-0.47% ID/g vs 2.26+/-0.30% ID/g) and tumor were clearly detected by PET imaging. These results suggest the feasibility to develop an Olaparib-based theranostic agent for mesothelioma. PMID- 28587824 TI - Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9 tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones. AB - Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2 e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8 tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6-8.85MUM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8-2.6MUM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively. PMID- 28587823 TI - Identification and synthesis of novel inhibitors of mycobacterium ATP synthase. AB - A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv. PMID- 28587825 TI - Synthesis of 3- and 29-substituted celastrol derivatives and structure-activity relationship studies of their cytotoxic activities. AB - A series of 3-carbamate and 29-ester celastrol derivatives (compounds 1-26) were designed and synthesized. These analogues were evaluated for their cytotoxic activities against several cancer cell lines. Cytotoxicity data revealed that the properties of substituents and substitution position had important influence on cytotoxic activity. Modification of C-3 hydroxyl with size-limited groups did not reduce the activity obviously. The introduction of polarity group like piperazine could improve the solubility. Compound 23 was chosen to further evaluate anti tumor efficacy in vivo. It showed higher inhibition rate and better safety than celastrol during in vivo experiment by intragastric administration. The preliminary antitumor studies of compound 23in vivo showed that it might be promising for the development of new antitumor agents. PMID- 28587826 TI - Safety assessment of cultivated fruiting body of Ophiocordyceps sinensis evaluated through subacute toxicity in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ophiocordyceps sinensis (Berk.) G.H. Sung, J.M. Sung, Hywel-Jones & Spatafora is one of the most renowned traditional Chinese medicine used as tonic, renal, respiratory and reproductive health, promote longevity and overall improvement in quality of life. Natural production of O. sinensis is limited due to its extreme specificity in host range and confined geographic distribution. Therefore, cultivation of the fungus was developed to meet high demand for commercialization as nutraceutical. O. sinensis fruiting body has recently been successfully cultivated in large scale using rice based solid medium, providing wider source options for consumers and scientific researchers. AIMS OF THE STUDY: The present study aims to establish safety profile for the consumption of cultivated fruiting body of O. sinensis (FBOS) by 28-days sub-acute toxicity study in Sprague Dawley rats. MATERIALS AND METHODS: Rats were orally administered with cultivated FBOS at three graded doses (250, 500 and 1000mg/kg), once daily for 28 consecutive days. Control group received distilled water. General observations (gross behavioral changes and toxic symptoms) and body weight of each animal were monitored daily. Haematological, serum biochemical and histopathological analysis were carried out at the end of the experiment (Day 29). RESULTS: No behavioral changes, toxic symptoms or death was observed in rats throughout the dosing period. Cultivated FBOS treatment up to 1000mg/kg did not cause any adverse effect on the growth of the animals. Results from haematology and serum biochemistry revealed no toxic effect following cultivated FBOS treatment at three graded doses for 28 days. In addition, no treatment related histopathological changes were noted in heart, spleen, kidney, lung and liver of the animals. CONCLUSION: The present study revealed that oral administration of cultivated FBOS for 28 days, at dosage up to 1000mg/kg did not pose toxicological concern in rats. Therefore, the no-observed adverse-effect level (NOAEL) dose of cultivated FBOS in 28-days subacute toxicity study is higher than 1000mg/kg. PMID- 28587827 TI - Combined effects of deoxynivalenol and zearalenone on oxidative injury and apoptosis in porcine splenic lymphocytes in vitro. AB - Deoxynivalenol (DON) and zearalenone (ZEA) are the two most common mycotoxins in animal feed. In this study, we examined oxidative injury and apoptosis of porcine splenic lymphocytes induced by DON or ZEA and their combination in vitro. Based on IC50 values, porcine splenic lymphocytes were treated with 0.06, 0.3, 1.5, and 7.5MUg/mL DON, 0.08, 0.4, 2, and 10MUg/mL ZEA, or both DON and ZEA at 0.06 and 0.08MUg/mL, 0.3 and 0.4MUg/mL, and 1.5 and 2MUg/mL, respectively. After 48h of DON and/or ZEA exposure, the cells were analyzed for antioxidant functions, apoptosis, and mRNA and protein expression of apoptosis-related genes p53, Bcl-2, Bax, caspase-3, and caspase-8 to determine their apoptosis and oxidative damage effects and mechanisms. The results showed that, compared with the control group, SOD, CAT, GPx, GSH, and Bcl-2 mRNA and protein expression levels were significantly reduced in exposed groups (P<0.05 or P<0.01). Furthermore, MDA contents, apoptosis rates, and p53, Bax, caspase-3 and caspase-8 protein and mRNA expression levels were increased significantly (P<0.01). The effects of DON and ZEA were dose dependent and synergistic in combination. These data suggest that DON and ZEA induce oxidative damage and apoptosis of porcine splenic lymphocytes. PMID- 28587828 TI - Diphytanoyl lipids as model systems for studying membrane-active peptides. AB - The branched chains in diphytanoyl lipids provide membranes with unique properties, such as high chemical/physical stability, low water permeability, and no gel-to-fluid phase transition at ambient temperature. Synthetic diphytanoyl phospholipids are often used as model membranes for electrophysiological experiments. To evaluate whether these sturdy lipids are also suitable for solid state NMR, we have examined their interactions with a typical amphiphilic peptide in comparison with straight-chain lipids. First, their phase properties were monitored using 31P NMR, and the structural behaviour of the antimicrobial peptide PGLa was studied by 19F NMR and circular dichroism in oriented membrane samples. Only lipids with choline headgroups (DPhPC) were found to form stable lipid bilayers in oriented samples, while DPhPG, DPhPE and DPhPS display non lamellar structures. Hence, the experimental temperature and hydration are crucial factors when using supported diphytanoyl lipids, as both parameters must be maintained in an appropriate range to avoid the formation of non-bilayer structures. For the same reason, a high content of other diphytanoyl lipids besides DPhPC in mixed lipid systems is not favourable. Unlike the situation in straight-chain membranes, we found that the alpha-helical PGLa was not able to insert into the tightly packed fluid bilayer of DPhPC but remained in a surface bound state even at very high peptide concentration. This behaviour can be explained by the high cohesivity and the negative spontaneous curvature of the diphytanoyl lipids. These characteristic features must therefore be taken into consideration, both, in electrophysiological studies, and when interpreting the structural behaviour of membrane-active peptides in such lipid environment. PMID- 28587829 TI - PEGylation with the thiosuccinimido butylamine linker significantly increases the stability of haloalkane dehalogenase DhaA. AB - Haloalkane dehalogenase (HLD) can catalyze the hydrolytic dehalogenation of halogenated compounds. However, HLD suffers from the poor stability to resist the environmental stress. PEGylation is an effective approach to enhance the stability of enzymes. The linker is an important stabilization factor of PEGylation. Thus, the linkers of the PEGylated HLD were optimized to improve the stability of HLD in the present study. The PEGylated haloalkane dehalogenase DhaAs with methylamine (Ml), carbamate (Cm) and thiosuccinimido butylamine (Tb) linkers were prepared, respectively. The effects of the Ml, Cm and Tb linkers on the stability of the PEGylated DhaAs were investigated under different environmental stresses. Among the three linkers, the Tb linker showed the highest efficacy to improve the stability of the PEGylated DhaA. The Tb linker significantly increased the thermal stability of the PEGylated DhaA by slowing its structural unfolding, and the pH stability of the PEGylated DhaA by slowing the protonation process. In addition, the PEGylated DhaA with the Tb linker showed the maximum resistance to high ionic strength (1M NaCl) and organic solvent (40% DMSO). PEGylation with the Tb linker is of general interest to effectively improve the stability of proteins, particularly the protein with poor stability. PMID- 28587831 TI - Clinical characteristics and risk factors for mortality in adult patients with persistent candidemia. AB - BACKGROUND: We investigated the clinical characteristics and risk factors for mortality in adults with persistent candidemia. METHODS: All patients >=18 years old with candidemia in two Korean tertiary hospitals from 2007 to 2014 were investigated. Persistent candidemia was defined as isolation of the same Candida species >=5 days after initiation of antifungal therapy. Non-persistent candidemia was defined as candidemia persisting for <=3 days after initiation of antifungal therapy. RESULTS: Candida tropicalis (29.2%) was the most common pathogen in persistent candidemia, and Candida albicans (35.9%) was the most common in non-persistent candidemia. Central venous catheter (CVC) (OR, 1.99; 95% CI, 1.05-3.78; P = 0.034), longer hospital stay (OR 1.01; 95% CI, 1.01-1.02; P = 0.025), and severe sepsis (OR 2.25; 95% CI, 1.11-4.56; P = 0.024) were independent risk factors for persistent candidemia. C. tropicalis was independently related to 30-day mortality (OR, 4.12; 95% CI, 1.27-13.36; P = 0.018), together with septic shock (OR, 5.81; 95% CI, 1.32-24.70; P = 0.017) and use of a corticosteroids (OR, 5.31; 95% CI, 1.07-26.29; P = 0.041) in persistent candidemia. CONCLUSION: C. tropicalis is the predominant pathogen and cause of death in patients with persistent candidemia. PMID- 28587832 TI - Identification and expression analysis of three XCR1-like receptors from Epinephelus coioides after Cryptocaryon irritans infection. AB - The unique receptor XCR1 of the XC subfamily of chemokines is specially expressed in CD8alpha-like dendritic cells. This receptor has one ligand in mice (XCL1) and two ligands in humans (XCL1 and XCL2). In mammals, the XCR1-XCL1 complex performs a vital role in regulating the localization and function of T cells, dendritic cells, and other cell types. In this study, three XCR1-like receptors (EcXCR1, EcXCR1L, and EcCCR12) were identified from a transcriptome database of orange spotted grouper. The open reading frames (ORFs) of EcXCR1, EcXCR1L, and EcCCR12 predictably encode 337, 348, and 358 amino acids, respectively. All receptors are seven trans-membrane proteins, and contain conserved functional regions, and conserved sites, that are crucial for the role of chemokine receptors in mammals. Conserved features include four cysteine residues in the extracellular regions, a "DRY" motif in the second intracellular loop, and common characteristics at the N terminus that are important for ligand interaction. In healthy grouper, EcXCR1, EcXCR1L, and EcCCR12 were broadly expressed in all the tissues tested. EcXCR1 was expressed at high levels in the liver, and EcXCR1L, and EcCCR12 in the thymus. After grouper infection with Cryptocaryon irritans, EcXCR1 and EcCCR12 were up regulated in the skin and the spleen, and EcCCR12 in the skin, gill, and spleen. EcXCR1L expression changed only slightly. These results imply that EcXCR1 and EcCCR12 may be involved in host defense against parasite infection. A polyclonal antibody was produced against EcCCR12, and used to detect EcCCR12-positive cells in peripheral blood. These results will contribute considerably to elucidate the biological role of piscine XCR1-like receptors and their ligands system in the future. PMID- 28587830 TI - Early Detection of Cancer in Blood Using Single-Cell Analysis: A Proposal. AB - Here, we explore the potential of single-cell genomic analysis in blood for early detection of cancer; we consider a method that screens the presence of recurrent patterns of copy number (CN) alterations using sparse single-cell sequencing. We argue for feasibility, based on in silico analysis of existing single-cell data and cancer CN profiles. Sampling procedures from existing diploid single cells can render data for a cell with any given profile. Sampling from multiple published tumor profiles can interrogate cancer clonality via an algorithm that tests the multiplicity of close pairwise similarities among single-cell cancer genomes. The majority of common solid cancers would be detectable in this manner. As any early detection method must be verifiable and actionable, we describe how further analysis of suspect cells can aid in determining risk and anatomic origin. Future affordability rests on currently available procedures for tumor cell enrichment and inexpensive methods for single-cell analysis. PMID- 28587833 TI - An update on mechanism of entry of white spot syndrome virus into shrimps. AB - Host-parasite relationships can be best understood at the level of protein protein interaction between host and pathogen. Such interactions are instrumental in understanding the important stages of life cycle of pathogen such as adsorption of the pathogen on host surface followed by effective entry of pathogen into the host body, movement of the pathogen across the host cytoplasm to reach the host nucleus and replication of the pathogen within the host. White Spot Disease (WSD) is a havoc for shrimps and till date no effective treatment is available against the disease. Moreover information regarding the mechanism of entry of White Spot Syndrome Virus (WSSV) into shrimps, as well as knowledge about the protein interactions occurring between WSSV and shrimp during viral entry are still at very meagre stage. A cumulative and critically assessed information on various viral-shrimp interactions occurring during viral entry can help to understand the exact pathway of entry of WSSV into the shrimp which in turn can be used to device drugs that can stop the entry of virus into the host. In this context, we highlight various WSSV and shrimp proteins that play role in the entry mechanism along with the description of the interaction between host and pathogen proteins. PMID- 28587835 TI - Effect of physicochemical properties of peptides from soy protein on their antimicrobial activity. AB - Antimicrobial peptides (AMPs) kill microbial cells through insertion and damage/permeabilization of the cytoplasmic cell membranes and has applications in food safety and antibiotic replacement. Soy protein is an attractive, abundant natural source for commercial production of AMPs. In this research, explicit solvent molecular dynamics (MD) simulation was employed to investigate the effects of (i) number of total and net charges, (ii) hydrophobicity (iii) hydrophobic moment and (iv) helicity of peptides from soy protein on their ability to bind to lipid bilayer and their transmembrane aggregates to form pores. Interaction of possible AMP segments from soy protein with 1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine/1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoglycerol (POPC/POPG) bilayers, a mimic of bacterial cell membrane, was investigated. Pore formation was insensitive to helicity and occurred for hydrophobicity threshold in the range of -0.3-0kcal/mol, hydrophobic moment threshold of 0.3kcal/mol, net charge threshold of 2. Though low hydrophobicity and high number of charges help in the formation of water channel for transmembrane aggregates, insertion of peptides with these properties requires overcome of energy barrier, as shown by potential of mean force calculations, thereby resulting in low antimicrobial activity. Experimental evaluation of antimicrobial activity of these peptides against Gram positive L. monocytogenes and Gram negative E. coli as obtained by spot-on-lawn assay was consistent with simulation results. These results should help in the development of guidelines for selection of peptides with antimicrobial activity based on their physicochemical properties. PMID- 28587834 TI - Spasmogenic Effects of the Proteasome Inhibitor Carfilzomib on Coronary Resistance, Vascular Tone and Reactivity. AB - BACKGROUND: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials. AIM OF STUDY: To test the effects of CFZ (10-9 to 10-7mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta. METHODS AND RESULTS: CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreated with CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium-dependent vasodilating agent, on the plateau of NA contraction (p<0.05). CONCLUSIONS: CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm. PMID- 28587837 TI - A Response. PMID- 28587836 TI - Functional characterization of Aedes aegypti alkaline phosphatase ALP1 involved in the toxicity of Cry toxins from Bacillus thuringiensis subsp. israelensis and jegathesan. AB - Presently three major groups of proteins from Aedes aegypti, cadherin, alkaline phosphatases (ALP) and aminopeptidases N (APN), have been identified as Cry11Aa toxin receptors. To further characterize their role on toxicity, transgenic mosquitoes with silenced Aedes cadherin expression were previously generated and the role of cadherin in mediating the toxicity of four different mosquitocidal toxins (Cry11Aa, Cry11Ba, Cry4Aa and Cry4Ba) was demonstrated. Here, we investigated the role of another reported Cry11Aa receptor, ALP1. As with Aedes cadherin, this protein is localized in the apical cell membrane of distal and proximal gastric caecae and the posterior midgut. We also successfully generated transgenic mosquitoes that knockdowned ALP1 transcript levels using an inducible Aedes heat shock promoter, Hsp70A driving dsALP1RNA. Four different mosquitocidal toxins were used for larval bioassays against this transgenic mosquito. Bioassay results show thatCry11Aa toxicity to these transgenic larvae following a heat shock decreased (4.4 fold) and Cry11Ba toxicity is slightly attenuated. But Cry4Aa and Cry4Ba toxicity to ALP1 silenced larvae is unchanged. Without heat shock, toxicity of all four toxins does not change, suggesting this heat shock promoter is heat-inducible. Notably, transgenic mosquitoes with ALP1 knockdown are about 3.7 times less resistant to Cry11Aa toxin than those with Aedes cadherin knockdown. These results demonstrate that the ALP1 is an important secondary receptor for Cry11Aa and Cry11Ba, but it might not be involved in Cry4Aa and Cry4Ba toxicity. PMID- 28587838 TI - Effects of water pH on the uptake and elimination of the piscicide, 3 trifluoromethyl-4-nitrophenol (TFM), by larval sea lamprey. AB - Invasive sea lamprey (Petromyzon marinus) populations in the Great Lakes are controlled by applying the piscicide, 3-trifluoromethyl-4-nitrophenol (TFM), to infested streams with larval sea lamprey (ammocoetes). While treatment mortality is >90%, surviving lamprey, called residuals, can undermine control efforts. A key determinant of TFM effectiveness is water pH, which can fluctuate daily and seasonally in surface waters. The objectives of this research were to evaluate the influence of pH on the uptake, elimination, and accumulation of TFM by larval sea lamprey using radio-labeled TFM (14C-TFM), when exposed to a nominal concentration of 4.6mgTFML-1 or 7.6mgTFML-1, 3h or 1h, respectively. TFM uptake rates were approximately 5.5-fold greater at low pH (6.86) compared to the high pH (8.78), most likely due to the unionized, lipophilic form of TFM existing in greater amounts at a lower pH. In contrast, elimination rates following the injection of 85nmolTFMg-1 body mass were 1.7-1.8 fold greater at pH8.96 than at pH6.43 during 2-4h of depuration in TFM-free water. Greater initial excretion rates at pH8.96 were presumably due to predicted increases in outward concentration gradients of un-ionized TFM. The present findings suggest that TFM is mainly taken-up in its un-ionized form, more lipophilic form, but there is also significant uptake of the ionized form of TFM via an unknown mechanism. Moreover, we provide an explanation to how small increases in pH can undermine lampricide treatment success increasing residual lamprey populations. PMID- 28587839 TI - Leishmaniasis in Turkey: Visceral and cutaneous leishmaniasis caused by Leishmania donovani in Turkey. AB - In Turkey, the main causative agents are Leishmania tropica (L. tropica) and Leishmania infantum (L. infantum) for cutaneous leishmaniasis (CL) and L. infantum for visceral leishmaniasis (VL). In this study, we investigated leishmaniasis cases caused by L. donovani and established animal models for understanding its tropism in in vivo conditions. Clinical samples (lesion aspirations and bone marrow) obtained from CL/VL patients were investigated using parasitological (smear/NNN) and DNA-based techniques. For species identification, a real time ITS1-PCR was performed using isolates and results were confirmed by hsp70 PCR-N/sequencing and cpb gene PCR/sequencing in order to reveal Leishmania donovani and Leishmania infantum discrimination. Clinical materials from CL and VL patients were also inoculated into two experimental groups (Group CL and Group VL) of Balb/C mice intraperitoneally for creating clinical picture of Turkish L. donovani strains. After 45days, the samples from visible sores of the skin were taken, and spleens and livers were removed. Measurements of the internal organs were done and touch preparations were prepared for checking the presence of amastigotes. The strains were isolated from all patients and amastigotes were seen in all smears of the patients, and then isolates were immediately stored in liquid nitrogen. In real time ITS1-PCR, the melting temperatures of all samples were out of range of L. infantum, L. tropica and L. major. Sequencing of hsp70 PCR-N showed that all isolates highly identical to previously submitted L. donovani sequences in GenBank, and cpb gene sequencing showed five isolates had longer cpbF allele, whereas one isolate contained a mixed sequence of both cpbF and cpbE. All mice in both experimental groups became infected. Compared to controls, the length and width of both liver and spleen were significantly elevated (p<0.001) in both groups of mice. However, the weight of the liver increased significantly in all mice whereas the weight of spleen increased only in VL group. Amastigotes were also seen in all touch preparations prepared from skin sores, spleen and liver. L. donovani strain was isolated from autocutaneous a VL patient first time in Turkey. Animal models using clinical samples were successfully established and important clinical differences of the isolated strains were observed. PMID- 28587840 TI - Control of biting lice, Mallophaga - a review. AB - The chewing lice (Mallophaga) are common parasites of different animals. Most of them infest terrestrial and marine birds, including pigeons, doves, swans, cormorants and penguins. Mallophaga have not been found on marine mammals but only on terrestrial ones, including livestock and pets. Their bites damage cattle, sheep, goats, horses and poultry, causing itch and scratch and arousing phthiriasis and dermatitis. Notably, Mallophaga can vector important parasites, such as the filarial heartworm Sarconema eurycerca. Livestock losses due to chewing lice are often underestimated, maybe because farmers notice the presence of the biting lice only when the infestation is too high. In this review, we examined current knowledge on the various strategies available for Mallophaga control. The effective management of their populations has been obtained through the employ of several synthetic insecticides. However, pesticide overuse led to serious concerns for human health and the environment. Natural enemies of Mallophaga are scarcely studied. Their biological control with predators and parasites has not been explored yet. However, the entomopathogenic fungus Metarhizium anisopliae has been reported as effective in vitro and in vivo experiments against Damalinia bovis infestation on cattle. Furthermore, different Bacillus thuringiensis preparations have been tested against Mallophaga, the most effective were B. thuringiensis var. kurstaki, kenyae and morrisoni. Lastly, plant-borne insecticides have been evaluated against Mallophaga. Tested products mainly contained bioactive principles from two Meliaceae, Azadirachta indica, and Carapa guianensis. High efficacy of neem-borne preparations was reported, leading to the development of several products currently marketed. Overall, our review highlighted that our knowledge about Mallophaga vector activity and control is extremely patchy. Their control still relied on the employ of chemical pesticides widely used to fight other primary pests and vectors of livestock, such as ticks, while the development of eco-friendly control tool is scarce. Behavior-based control of Mallophaga, using pheromone-based lures or even the Sterile Insect Technique (SIT) may also represent a potential route for their control, but our limited knowledge on their behavioral ecology and chemical communication strongly limit any possible approach. PMID- 28587841 TI - 3'nucleotidase/nuclease in protozoan parasites: Molecular and biochemical properties and physiological roles. AB - 3'-nucleotidase/nuclease (3'NT/NU) is a bi-functional enzyme that is able to hydrolyze 3'-monophosphorylated nucleotides and nucleic acids. This review summarizes the major molecular and biochemical properties of this enzyme in different trypanosomatid species. Sequence analysis of the gene encoding 3'NT/NU in Leishmania and Crithidia species showed that the protein possesses five highly conserved regions that are characteristic of members of the class I nuclease family. 3'NT/NU presents a molecular weight of approximately 40 kDa, which is conserved among the studied species. Throughout the review, we discuss inhibitors and substrate specificity, relating them to the putative structure of the enzyme. Finally, we present the major biological roles performed by 3'NT/NU. The involvement of 3'NT/NU in the purine salvage pathway was confirmed by the increase of activity and expression of the enzyme when the parasites were submitted to purine starvation. The generation of extracellular adenosine is also important to the modulation of the host immune response. Interaction assays involving Leishmania parasites and macrophages indicated that 3'-nucleotidase activity increases the association index between them. Recently, it was shown that 3'NT/NU plays a role in parasite escape from neutrophil extracellular traps, one of the first mechanisms of the host immune system for preventing infection. PMID- 28587843 TI - Prevalence of urinary incontinence and its relation with sedentarism in Spain. AB - OBJECTIVES: To determine the prevalence of urinary incontinence in the elderly Spanish population of both sexes and identify a possible relationship between physical activity habits and the presence of urinary incontinence in the elderly. MATERIAL AND METHODS: We used data from 8146 individuals older than 60 years (age range, 60-94 years), from which data from a 15-year cohort were obtained. Of these, 4745 (58.2%) were women and 3401 (41.8%) were men. We analysed the presence of urinary incontinence, physical activity habits and the influence of other variables such as sex, age, weight and body mass index. RESULTS: We detected a prevalence of urinary incontinence of 15% for the women and 11.6% for the men. Those with urinary incontinence had a greater average age, weight and body mass index than the healthy participants. At the same time, the patient group with incontinence showed more sedentary habits compared with the healthy participants. CONCLUSIONS: A strong relationship was observed between the body mass index and prevalence of urinary incontinence. Urinary incontinence was also related to attitudinal aspects such as physical inactivity, a behaviour that predisposes the elderly to developing incontinence. For the first time, we observed a reduction in the prevalence of incontinence compared with previous studies. PMID- 28587844 TI - Postoperative management of radical cystectomy. Review of the evidence on the prevention and treatment of urological complications. AB - INTRODUCTION AND OBJECTIVES: This review article focuses on the prevention and management of the most common postoperative urological complications of radical cystectomy. We reviewed the current literature and conducted an analysis of frequency, prevention and treatment of complications. ACQUISITION OF EVIDENCE: We conducted a search on Medline to identify original articles, literature reviews and editorials focusing on the urological complications of radical cystectomy during the first 90 days after surgery. We identified those series that included more than 100 patients. SYNTHESIS OF THE EVIDENCE: The literature regarding the prevention and treatment of complications after cystectomy is in general retrospective and nonstandardised. The level of evidence is generally low, and it is difficult to make evidence-based recommendations. CONCLUSIONS: Progress has been made in recent years in reducing mortality and preventing the complications of cystectomy. The most common complications are gastrointestinal, for which significant efforts have been made to implement ERAS and Fast Track protocols. The complications that can most significantly change patients' quality of life are urinary stoma. PMID- 28587842 TI - Sustained sensitizing effects of tumor necrosis factor alpha on sensory nerves in lung and airways. AB - Tumor necrosis factor alpha (TNFalpha) plays a significant role in the pathogenesis of airway inflammatory diseases. Inhalation of aerosolized TNFalpha induced airway hyperresponsiveness accompanied by airway inflammation in healthy human subjects, but the underlying mechanism is not fully understood. We recently reported a series of studies aimed to investigate if TNFalpha elevates the sensitivity of vagal bronchopulmonary sensory nerves in a mouse model; these studies are summarized in this mini-review. Our results showed that intratracheal instillation of TNFalpha induced pronounced airway inflammation 24 h later, as illustrated by infiltration of eosinophils and neutrophils and the release of inflammatory mediators and cytokines in the lung and airways. Accompanying these inflammatory reactions, the sensitivity of vagal pulmonary C-fibers and silent rapidly adapting receptors to capsaicin, a selective agonist of transient receptor potential vanilloid type 1 receptor, was markedly elevated after the TNFalpha treatment. A distinct increase in the sensitivity to capsaicin induced by TNFalpha was also observed in isolated pulmonary sensory neurons, suggesting that the sensitizing effect is mediated primarily through a direct action of TNFalpha on these neurons. Furthermore, the same TNFalpha treatment also induced a lingering (>7days) cough hyperresponsiveness to inhalation challenge of NH3 in awake mice. Both the airway inflammation and the sensitizing effect on pulmonary sensory neurons caused by the TNFalpha treatment were abolished in the TNF receptor double homozygous mutant mice, indicating the involvement of TNF receptor activation. These findings suggest that the TNFalpha-induced hypersensitivity of vagal bronchopulmonary afferents may be responsible for, at least in part, the airway hyperresponsiveness caused by inhaled TNFalpha in healthy individuals. PMID- 28587845 TI - Trends in the management of urolithiasis in Latin America, Spain and Portugal: results of a survey in the Confederacion Americana de Urologia (CAU). AB - OBJECTIVE: To describe the trends in the current management of urolithiasis in the Confederacion Americana de Urologia (CAU) setting to recognise patterns of clinical practice and identify educational needs. MATERIAL AND METHOD: An online survey was created with 31 multiple-choice questions (Spanish and Portuguese) through www.caunet.org, which revealed demographic data, patterns of clinical practice and approaches for specific clinical conditions. RESULTS: A total of 463 practitioners from Brazil, Mexico, Argentina, Spain, Colombia, Chile and other countries (3.96% of the members of CAU) completed the survey. All participants performed some type of urolithiasis treatment: 98.5% performed semirigid ureteroscopy (URS), 83.8% performed percutaneous nephrolithotomy (PCNL), 78.2% performed flexible URS, and 67.2% performed extracorporeal lithotripsy. The youngest physicians tended to perform PCNL (P<.001), and the proportion of users of flexible URS was greater in the Portuguese countries (P=.037). The main energy source was laser (60.7%). Small-calibre PCNL was performed by 15.3% of the respondents, more often in university hospitals (P<.01) and by older practitioners (P<.01). Only 3.2% of the respondents used percutaneous access to the kidney guided exclusively by ultrasound, especially the older practitioners (P<.001). The supine position was used by 40.4% of the respondents, more often in Spain (P<.001) and in the university setting (P=.017). PCNL without nephrostomy was practiced by 3.9% of the respondents. For flexible URS, 19.2% of the respondents did not use ureteral access sheaths, and the older practitioners preferred thinner calibre sheaths (P<.001). CONCLUSIONS: The management of lithiasis in the CAU setting follows a profile similar to that recognised in the European and American clinical guidelines, although there are interesting variations based on the practitioner's age and preferences. We identified potential areas for improvement in small-calibre PCNL and ultrasound-guided puncture. PMID- 28587846 TI - Approach of the patient with renal cancer: Is there a collaboration between urology and oncology? PMID- 28587847 TI - Molecular cloning and tissue distribution of Crh and Pomc mRNA in the fat-tailed dunnart (Sminthopsis crassicaudata), an Australian marsupial. AB - Like all vertebrates, marsupials respond to stressors with the activation of the hypothalamo-pituitary-adrenal axis. However, peptides operating at the higher regulatory levels of this hormonal system, i.e. corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH), have not been investigated in marsupials. Here we report the molecular cloning of the precursor cDNAs of CRH (prepro-CRH) and of ACTH (proopiomelanocortin; POMC) in an Australian marsupial, the fat-tailed dunnart (Sminthopsis crassicaudata). Dunnart POMC and prepro-CRH are predicted to be peptides of 399 and 200 amino acids, respectively. While the ACTH and beta-endorphin sequences within the POMC sequence are highly conserved, the POMC sequence shows some unique features in this species, and perhaps all Australian marsupials, including the loss of a gamma-melanotropin sequence and duplications of the ACTH sequence. Mature dunnart CRH is identical to CRH in human, mouse, rat and chicken. Pomc and Crh mRNA is mainly expressed in dunnart pituitary gland and brain, respectively, but both are also present in a range of peripheral tissues. PMID- 28587848 TI - miR-148a-3p regulates adipocyte and osteoblast differentiation by targeting lysine-specific demethylase 6b. AB - Recent emerging studies of miRNAs in mesenchymal stem cell commitment toward adipocyte and osteoblast provide new insights for the understanding of the molecular basis of adipogenesis and osteogenesis. The current study revealed that miR-148a-3p was altered in primary cultured marrow stromal cells and established stromal ST2 line after adipogenic and/or osteogenic treatment. Supplementing miR 148a-3p activity inhibited cell growth and induced ST2 to differentiate into mature adipocytes. Conversely, inactivation of the endogenous miR-148a-3p suppressed ST2 to fully differentiate. By contrast, supplementation of the miR 148a-3p blunted osteoblast differentiation. Lysine-specific demethylase 6b (Kdm6b), a recently identified regulator of osteoblast differentiation was shown to be a direct target of miR-148a-3p by using the luciferase assay. Overexpression of Kdm6b attenuated miR-148a-3p stimulation of adipogenic differentiation. Taken together, our study provides evidences that miR-148a-3p reciprocally regulates adipocyte and osteoblast differentiation through directly targeting Kdm6b. PMID- 28587850 TI - Frailty and Risk of Adverse Outcomes in Hospitalized Older Adults: A Comparison of Different Frailty Measures. AB - OBJECTIVES: There is a paucity of data for the assessment of frailty in acutely ill hospitalized older adults. We aim to (1) compare the performance of frailty measures [5-item scale of fatigue, resistance, ambulation, illnesses, and loss of weight) (FRAIL), Tilburg Frailty Indicator (TFI), and Clinical Frailty Scale (CFS)] in identifying frailty, using the widely adopted Frailty Index (FI) as "gold standard," and (2) compare their ability to predict negative outcomes among hospitalized older adults. DESIGN: Prospective cohort study. SETTING: Acute inpatient care. PARTICIPANTS: A total of 210 patients (mean age 89.4 +/- 4.6 years, 69.5% female) admitted to the Department of Geriatric Medicine. MEASUREMENTS: Premorbid frailty status was assessed by FI, FRAIL, TFI, and CFS. We collected data on comorbidities, severity of illness, functional status, and cognitive status. We compared area under receiver operator characteristic curves for FRAIL, TFI, and CFS against the reference FI. Multiple logistic regression was performed to examine the association between frailty and the primary outcome of in-hospital mortality. RESULTS: Frailty prevalence estimates were 87.1% (FI), 50% (FRAIL), 80% (TFI), and 81% (CFS). Area under receiver operator characteristics against FI ranged from 0.81 [95% confidence interval (CI) 0.72 0.90: FRAIL] to 0.91 (95% CI 0.87-0.95: CFS), with no significant difference on receiver operating characteristic curve contrast. Frailty, as defined by FRAIL score >=3, was associated with higher in-hospital mortality (6.7% vs 1.0%, P = .031) and length of hospitalization [10 days (6.0-17.5) vs 8 days (5.0-14.0), P = .043]. FI [odds ratio (OR) = 1.15, 95% CI 1.00-1.33, P = .05], FRAIL (OR = 3.31, 95% CI 1.43-7.67, P = .005), and CFS (OR = 2.57, 95% CI 1.14-5.83, P = .023) independently predicted in-hospital mortality adjusted for age, sex, and severity of illness. CONCLUSIONS: FRAIL and CFS are simple frailty measures that may identify older adults at highest risk of adverse outcomes of hospitalization. FRAIL performed better in predicting in-hospital mortality. PMID- 28587849 TI - MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes. AB - Liquid biopsies have advanced rapidly in recent years for use in diagnostic and prognostic applications. One important aspect of this advancement is the growth in our understanding of microRNA (miRNA) biology. The measurement of miRNAs packaged within exosomes, which are constantly released into the blood stream, may reflect pathological changes within the body. The current study performed miRNA profiling using plasma and plasma-derived exosome samples from two animal models of kidney disease, the 5/6th partial nephrectomy (PNx) and two-kidney-one clip (2K1C) models. The RT-qPCR-based profiling results revealed that the overall miRNA expression level was much higher in plasma than in plasma-derived exosomes. With 200MUl of either plasma or exosomes derived from the same volume of plasma, 629 out of 665 total miRNAs analyzed were detectable in plasma samples from sham operated rats, while only 403 were detectable in exosomes with a cutoff value set at 35cycles. Moreover, the average miRNA expression level in plasma was about 16 fold higher than that in exosomes. We also found a select subset of miRNAs that were enriched within exosomes. The number of detectable miRNAs from plasma derived exosomes was increased in rats subjected to PNx or 2K1C surgery compared to sham-operated animals. Importantly, we found that the changes of individual miRNAs measured in plasma had very poor concordance with that measured in plasma derived exosomes in both animal models, suggesting that miRNAs in plasma and plasma-derived exosomes are differentially regulated in these disease conditions. Interestingly, PNx and 2K1C surgeries induced similar changes in miRNA expression, implying that common pathways were activated in these two disease models. Pathway analyses using DIANA-miRPath v3.0 showed that significantly changed exosomal miRNAs were associated with extracellular matrix (ECM) receptor interaction and mucin type-O-glycan synthesis pathways, which are related with tissue fibrosis and kidney injury, respectively. In conclusion, our results demonstrated that due to the differential changes in miRNAs, the measurement of exosomal miRNAs cannot be replaced by the measurement of miRNAs in plasma, or vice versa. We also showed that a set of miRNAs related with kidney injury and organ fibrosis were dysregulated in plasma-derived exosomes from animal models of kidney disease. PMID- 28587851 TI - Incidence of Pressure Ulcers During Home and Institutional Care Among Long-Term Care Insurance Beneficiaries With Dementia Using the Korean Elderly Cohort. AB - OBJECTIVE: To assess whether type of long-term care service is a risk factor of the incidence of pressure ulcers among older adults with dementia who are receiving long-term care insurance (LTCI). METHODS: Data from LTCI beneficiaries (benefit level 1 or 2) with dementia, aged 60 and older (n = 7841), in the Korean Elderly Cohort data set from 2008 to 2013 were used. Type of long-term care service was categorized into home or institutional care using the LTCI Claims Database. The National Health Insurance Claims Database was used to identify the incidence of pressure ulcers as the outcome variable in a survival analysis using the time-dependent Cox proportional hazard model. RESULTS: Of the 7841 participants, 98 (1.2%) exhibited pressure ulcers. Compared with beneficiaries receiving home care, those receiving institutional care had a higher adjusted hazard ratio for pressure ulcers (hazard ratio 6.48, 95% confidence interval 3.48 10.86). These associations were particularly strong among beneficiaries without pressure ulcers during the mandatory assessment for benefit eligibility and who were partially ambulatory. DISCUSSION: Beneficiaries receiving institutional care were more likely to have pressure ulcers than were those receiving home care. The government must monitor the quality of institutional long-term care services and encourage service providers to improve such care. PMID- 28587852 TI - Extracorporeal membrane oxygenation (ECMO). Current indications and infectious complications. PMID- 28587853 TI - Fulminant reversible cerebral vasoconstriction syndrome. PMID- 28587854 TI - Farmer's lung disease: Analysis of 75 cases. AB - INTRODUCTION: Farmer's lung disease (FLD) is a common form of hypersensitivity pneumonitis possibly underdiagnosed in our midst. The aim of this study was to describe clinical characteristics, evolution and factors that influence the prognosis of patients with FLD. PATIENTS AND METHODS: A retrospective study that included all patients diagnosed with FLD presenting an environmental exposure risk, a clinic, lung function and a compatible radiology, in which antigen sensitisation was demonstrated and/or a concordant pathology. RESULTS: We selected 75 patients with FLD, 50 with acute or subacute form (ASF) and 25 with chronic form (CF). Forty-four percent of patients (n=33) were diagnosed during the months of March and April, especially those with ASF compared to CF (52 vs. 28%; P=.0018). In the ASF group, DLco showed an improvement during follow-up (P=.047). The determination of specific IgG antibodies was positive in 39 patients (78%) with ASF (44% of them against Aspergillus) and CF 12 (48%). The realisation of antigenic avoidance (OR 9.26, 95% CI 1.3-66.7, P=.026) and the administration of immunosuppressive therapy (OR 16.13, 95% CI 1.26-200, P=.033) were predictors of better disease progression. CONCLUSIONS: FLD is predominantly seasonal in our environment. CF usually has a negative specific IgG antibodies unlike ASF, where antibodies against Aspergillus are the most common. The realisation of antigenic avoidance and immunosuppressive treatment are possible predictors of better disease progression. PMID- 28587855 TI - Pheophorbide a, a compound isolated from the leaves of Arrabidaea chica, induces photodynamic inactivation of Trypanosoma cruzi. AB - BACKGROUND: Approximately 6-7 million people are infected with Trypanosoma cruzi, the etiological agent of Chagas' disease. Only two therapeutic compounds have been found to be useful against this disease: nifurtimox and benznidazole. These drugs have been effective in the acute phase of the disease but less effective in the chronic phase; they also have many side effects. Thus, the search for new compounds with trypanocidal action is necessary. Natural products can be the source of many important substances for the development of drugs to treat this infection. The present study evaluated the biological activity of an extract and fractions of Arrabidaea chica against T. cruzi and observed morphological and ultrastructural characteristics of parasites exposed to the isolated compound pheophorbide a. METHODS: The crude hydroethanolic extract of A. chica was prepared. Fractions were obtained by partition and separated by liquid chromatography. RESULTS: We observed a progressive increase in activity against epimastigote, trypomastigote, and amastigote forms of the parasite over the course of the fractionation process. Interestingly, we isolated a compound known as a photosensitizer that is used in photodynamic therapy. This method of treatment involving a photosensitizer, activation light and molecular oxygen is of great importance due to its selectivity. Pheophorbide a had activity against the protozoan in the presence of light and caused morphological and ultrastructural changes, demonstrating its potential in photodynamic therapy. CONCLUSIONS: Based on the ability of pheophorbide a to eliminate bloodstream forms of T. cruzi, we suggest its use in blood banks for hemoprophylaxis. PMID- 28587856 TI - Optimization and characterization of a murine lung infection model for the evaluation of novel therapeutics against Burkholderia cenocepacia. AB - Several B. cenocepacia mouse models are available to study the pulmonary infection by this Burkholderia cepacia complex (BCC) species. However, a characterized B. cenocepacia mouse model to evaluate the efficacy of potential new antibacterial therapies is not yet described. Therefore, we optimized and validated the course of infection (i.e. bacterial proliferation in lung, liver and spleen) and the efficacy of a reference antibiotic, tobramycin (TOB), in a mouse lung infection model. Furthermore, the local immune response and histological changes in lung tissue were studied during infection and treatment. A reproducible lung infection was observed when immunosuppressed BALB/c mice were infected with B. cenocepacia LMG 16656. Approximately 50 to 60% of mice infected with this BCC species demonstrated a dissemination to liver and spleen. TOB treatment resulted in a two log reduction in lung burden, prevented dissemination of B. cenocepacia to liver and spleen and significantly reduced levels of proinflammatory cytokines. As this mouse model is characterized by a reproducible course of infection and efficacy of TOB, it can be used as a tool for the in vivo evaluation of new antibacterial therapies. PMID- 28587857 TI - Comparison of the XTT and resazurin assays for quantification of the metabolic activity of Staphylococcus aureus biofilm. AB - We assessed whether resazurin was as efficient as XTT in the measurement of the metabolic activity of 209 clinical Staphylococcus aureus biofilm using an vitro model comparing the percentage of formazan and resorufin. The overall categorical agreement was 61.2% (r=0.024), which means that resazurin can not substitute XTT. PMID- 28587858 TI - Rebamipide reduces amyloid-beta 1-42 (Abeta42) production and ameliorates Abeta43 lowered cell viability in cultured SH-SY5Y human neuroblastoma cells. AB - Amyloid-beta (Abeta) peptides, Abeta 1-42 (Abeta42) and Abeta43, in particular, have been implicated in the pathophysiology of neurodegenerative disease such as Alzheimer's disease (AD). Rebamipide (REB), a gastrointestinal protective drug, can cross the blood-brain barrier after oral administration; however, the effects of REB on neuronal cells have not yet been reported. In this study, we investigated the effects of REB on Abeta43-induced cytotoxicity (monomers, 10MUM) in cultured SH-SY5Y human neuroblastoma cells. Addition of REB (10-1000nM) into the media partially ameliorated the reduced cell viability observed after Abeta43 treatment, which was determined by the MTT assay. REB reduced the levels of intracellular Abeta oligomers (100-150kDa) that were formed from the exogenous addition of Abeta43 monomers. In addition, REB (30nM) reduced endogenous Abeta42 secretion, which was analyzed by the enzyme-linked immunosorbent assay. Furthermore, REB enhanced the expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase-17, neprilysin, matrix metalloproteinase-14 (MMP-14)/membrane type-1 MMP, cyclooxygenase-2, and sirtuin 1, even in cells challenged with Abeta43. These results suggest that REB improves the cell viability by inducing genes that regulate Abeta levels and also genes that are cytoprotective. The secondary use of REB may have potential in the prevention of Abeta-mediated diseases, particularly AD. PMID- 28587859 TI - Characterization and function of a tachylectin 5-like immune molecule in Penaeus monodon. AB - Tachylectin5A and its homolog, tachylectin5B both contain a fibrinogen-related domain (FReD) and have been studied in horseshoe crabs, Tachypleus tridentatus and Carcinoscorpius rotundicauda and shown to be involved in host defense. Here, we demonstrate the presence of tachylectin5-like genes in shrimp, Penaeus monodon, designated as Penlectin5-1 (PL5-1) and Penlectin5-2 (PL5-2), which both contain a signal peptide and a single FReD with an acetyl group and a calcium binding sites and they are both structurally similar to horseshoe crab tachylectin/carcinolectin5. The PL5-1and PL5-2 transcript were expressed in various shrimp tissues in normal shrimp, and their expression was upregulated in tissues such as hemocytes and hindgut following challenge with pathogenic Vibrio harveyi. The PL5-2 protein was detected in various tissues as well as in cell free hemolymph. The biological function of the PL5-2 protein is to recognize some Gram-positive and Gram-negative bacteria regardless whether they are non pathogenic or pathogenic. They have hemagglutination activity on human erythrocyte and bacterial agglutination activity to both Gram negative and Gram positive bacteria. Possible binding sites of PL5-2 to bacteria could be at the N acetyl moiety of the GlcNAc-MurNAc cell wall of the peptidoglycan since the binding could be inhibited by GlcNAc or GalNAC. The presence of PL5-2 protein in both circulating hemolymph and intestine, where host and microbes are usually interacting, may suggest that the physiological function of shrimp tachylectin like proteins is to recognize and bind to invading bacteria to immobilize and entrap these microbes and subsequently clear them from circulation and the host body, and probably to control and maintain the normal flora in the intestine. PMID- 28587860 TI - The oyster immunity. AB - Oysters, the common name for a number of different bivalve molluscs, are the worldwide aquaculture species and also play vital roles in the function of ecosystem. As invertebrate, oysters have evolved an integrated, highly complex innate immune system to recognize and eliminate various invaders via an array of orchestrated immune reactions, such as immune recognition, signal transduction, synthesis of antimicrobial peptides, as well as encapsulation and phagocytosis of the circulating haemocytes. The hematopoietic tissue, hematopoiesis, and the circulating haemocytes have been preliminary characterized, and the detailed annotation of the Pacific oyster Crassostrea gigas genome has revealed massive expansion and functional divergence of innate immune genes in this animal. Moreover, immune priming and maternal immune transfer are reported in oysters, suggesting the adaptability of invertebrate immunity. Apoptosis and autophagy are proved to be important immune mechanisms in oysters. This review will summarize the research progresses of immune system and the immunomodulation mechanisms of the primitive catecholaminergic, cholinergic, neuropeptides, GABAergic and nitric oxidase system, which possibly make oysters ideal model for studying the origin and evolution of immune system and the neuroendocrine-immune regulatory network in lower invertebrates. PMID- 28587861 TI - Evolutionary dynamics of an expressed MHC class IIbeta locus in the Ranidae (Anura) uncovered by genome walking and high-throughput amplicon sequencing. AB - The Major Histocompatibility Complex (MHC) is a genomic region encoding immune loci that are important and frequently used markers in studies of adaptive genetic variation and disease resistance. Given the primary role of infectious diseases in contributing to global amphibian declines, we characterized the hypervariable exon 2 and flanking introns of the MHC Class IIbeta chain for 17 species of frogs in the Ranidae, a speciose and cosmopolitan family facing widespread pathogen infections and declines. We find high levels of genetic variation concentrated in the Peptide Binding Region (PBR) of the exon. Ten codons are under positive selection, nine of which are located in the mammal defined PBR. We hypothesize that the tenth codon (residue 21) is an amphibian specific PBR site that may be important in disease resistance. Trans-species and trans-generic polymorphisms are evident from exon-based genealogies, and co phylogenetic analyses between intron, exon and mitochondrial based reconstructions reveal incongruent topologies, likely due to different locus histories. We developed two sets of barcoded adapters that reliably amplify a single and likely functional locus in all screened species using both 454 and Illumina based sequencing methods. These primers provide a resource for multiplexing and directly sequencing hundreds of samples in a single sequencing run, avoiding the labour and chimeric sequences associated with cloning, and enabling MHC population genetic analyses. Although the primers are currently limited to the 17 species we tested, these sequences and protocols provide a useful genetic resource and can serve as a starting point for future disease, adaptation and conservation studies across a range of anuran taxa. PMID- 28587862 TI - Brain networks activated to form object recognition memory. AB - Object recognition memory allows discrimination of familiar and novel objects. Previous studies have shown the importance of several brain regions for object recognition memories; however, the mechanisms underlying the consolidation of object recognition (OR) memory at the anatomic level remain unknown. Here, we analyzed the brain network for the generation of OR memory in mice by measuring the expression of the immediate-early gene c-fos. We found that c-fos expression was induced in the hippocampus (CA1 and CA3 regions), insular cortex (IC), perirhinal cortex (PRh), and medial prefrontal cortex (mPFC) when OR memory was generated, suggesting that gene expression in these brain regions contributes to the formation of OR memory. Consistently, inhibition of protein synthesis in the mPFC blocked the formation of long-term OR memory. Importantly, network analyses suggested that the hippocampus, IC, PRh and mPFC show increased connectivity with other brain regions when OR memory is formed. Thus, we suggest that a brain network composed of the hippocampus, IC, PRh, and mPFC is required for the generation of OR memory by connecting with other brain regions. PMID- 28587863 TI - The mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury among adolescents: Findings from community and inpatient mental health settings in Ontario, Canada. AB - Although bullying victimization has been linked to a number of behavioral and emotional problems among adolescents, few studies have investigate the mechanism through which bullying victimization affect non-suicidal self-injury. The objectives of this study were to examine the effect of bullying victimization on non-suicidal self-injury and the mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury among adolescents. Data for this study came from the interRAI Child and Youth Mental Health dataset. A total of 1650 adolescents aged 12-18 years (M =14.56; SD =1.79; 54.2% males) were analyzed. Binary logistic and Poisson regression models were conducted to identify the mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury. Of the 1650 adolescents studied, 611 representing 37% engaged in non-suicidal self injury and 26.7% were victims of bullying. The effect of bullying victimization on non-suicidal self-injury was partially mediated by depressive symptoms after adjusting for the effect of demographic characteristics, history of childhood abuse, social support, and mental health diagnoses. The contribution of bullying victimization and depression to non-suicidal self-injury adds to the case for the development of trauma-focused interventions in reducing the risk of non-suicidal self-injury among adolescents. PMID- 28587864 TI - Up-regulation of circulating miRNA146a correlates with viral load via IRAK1 and TRAF6 in hepatitis C virus-infected patients. AB - BACKGROUND: Hepatitis C virus (HCV) is a life threatening human pathogen. It has been found that miRNA146a regulates innate immunity, inflammatory response and antiviral pathway. We evaluated miRNA146a expression by real-time PCR and IL-1 receptor associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) levels by ELISA in serum of 36 HCV viremia patients and 42 age and gender matched healthy controls. RESULTS: miRNA146a expression was significantly higher in HCV patients with a best cut off value 1.63 to discriminate between HCV patients and healthy controls. Meanwhile, it was negatively correlated to IRAK1 and TRAF6 levels and positively correlated to viral load in HCV patients. CONCLUSIONS: miRNA146a has a potential role in HCV infection and viral replication through IRAK1 and TRAF6. It can also serve as a new screening method for HCV. PMID- 28587865 TI - Impact of Vat resistance in melon on viral epidemics and genetic structure of virus populations. AB - Cultivar choice is at the heart of cropping systems and resistant cultivars should be at the heart of disease management strategies whenever available. They are the easiest, most efficient and environmentally friendly way of combating viral diseases at the farm level. Among the melon genetic resources, Vat is a unique gene conferring resistance to both the melon aphid Aphis gossypii and the viruses it carries. The 'virus side' of this pleiotropic phenotype is seldom regarded as an asset for virus control. Indeed, the effect of Vat on virus epidemics in the field is expected to vary according to the composition of aphid populations in the environment and long-term studies are needed to draw a correct trend. Therefore, the first objective of the study was to re-evaluate the potential of Vat to reduce viral diseases in melon crops. The second objective was to investigate the potential of Vat to exert a selection pressure on virus populations. We monitored the epidemics of Cucurbit aphid-borne yellows virus (CABYV), Cucumber mosaic virus (CMV), Watermelon mosaic virus (WMV) and Zucchini yellow mosaic virus (ZYMV) in two melon lines having a common genetic background, a resistant line (R) and a susceptible line (S), in eight field trials conducted in southeastern France between 2011 and 2015. Vat had limited impact if any on WMV epidemics probably because A. gossypii is not the main vector of WMV in the field, but a favorable impact on CMV, yet of variable intensity probably related to the importance of A. gossypii in the total aphid population. Vat had a significant impact on CABYV epidemics with mean incidence reduction exceeding 50% in some trials. There was no effect of Vat on the structure of virus populations, both for the non-persistent WMV transmitted by numerous aphid species and for the persistent CABYV transmitted predominantly by A. gossypii. PMID- 28587866 TI - Digging more in the genetic risk prediction of hepatitis C virus epidemic in Egypt: Apoptosis genes polymorphisms in the susceptibility of hepatitis C virus and association with viral load. AB - Egypt is confronted with the highest hepatitis C virus (HCV) epidemic. Apoptosis and cellular immune responses are crucial to the clearance or persistence of viral infections. This case-control study was carried out to detect whether apoptosis genes single nucleotide polymorphisms (SNPs) confer risk to HCV in a cohort of Egyptian patients and to explore their association with viral load. One hundred and ninety six blood samples were withdrawn from 96 HCV patients and 100 controls. The Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) 1525G>A and FasL-844T>C SNPs were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Hepatitis C viral load was measured using Real time PCR. Results Genotypes distributions of TRAIL -1525G>A and FasL-844 T>C polymorphisms in controls were in accordance with Hardy-Weinberg equilibrium (p>0.05). The study showed a statistically significant difference in the distribution of the TRAIL -1525G>A polymorphism genotypes and the FasL-844 T>C polymorphism genotypes between the HCV patients and the controls (p=0.001 and 0.02 respectively), with association of the -1525GA genotype and -844 TT genotype with increased risk of HCV infection (OR=2.68, 1.942 respectively, 95% CI=1.482 4.846, 1.1-3.43, respectively). No significant association was detected between TRAIL, FasL and the viral load. Our results suggest that the FasL -844T>C SNP is implicated in the susceptibility to HCV in Egyptian patients and firstly report the involvement of TRAIL gene polymorphism in the risk of the disease. Therefore we recommend national programs to delineate genetic factors that may put individuals at risk for contracting HCV. PMID- 28587867 TI - Spatiotemporal dynamics of influenza A(H1N1)pdm09 in Brazil during the pandemic and post-pandemic periods. AB - Influenza A(H1N1)pdm09 was responsible for the first global flu pandemic in 21st century affecting all the world. In Brazil, A(H1N1)pdm09 is still circulating as a seasonal virus, causing deaths every year. Nevertheless, the viral diffusion process that yearly seeds new influenza strains in the country was not investigated yet. The aim of the current study was to describe the phylodynamics and phylogeography of influenza A(H1N1)pdm09 in Brazil between 2009 and 2014. Neuraminidase sequences from Brazil and other regions of the World were retrieved and analyzed. Bayesian phylogeographic and phylodynamic model approaches were used to reconstruct the spatiotemporal and demographic history of influenza A(H1N1)pdm09 in Brazil (divided in subtropical and tropical regions) and related countries. Our analyses reveal that new influenza A(H1N1)pdm09 lineages are seeded in Brazil in almost each year and the main sources of viral diversity are North America, Europe and East Asia. The phylogeographic asymmetric model also revealed that Brazil, mainly the subtropical region, seeds viral lineages into other countries. Coalescent analysis of the compiled dataset reconstructed the peak of viral transmissions in the winter months of Southern hemisphere. The results presented in this study can be informative to public health, guide intervention strategies and in the understanding of flu virus migration, which helps to predict antigenic drift and consequently the developing of new vaccines. PMID- 28587868 TI - 'You do not cross them': Hierarchy and emotion in doctors' narratives of power relations in specialist training. AB - Studies of medical education often focus on experiences and socialisation processes among undergraduate students, with fewer examining emotionality among postgraduate trainees. This article explores the relationship between power and emotion, questioning how affective relations between senior and junior doctors are patterned on the hierarchical structure of medicine. The study employs qualitative methods of in-depth, face-to-face and telephone interviews with fifty doctors at initial and advanced stages of specialist postgraduate training in teaching hospitals across Ireland, conducted between May and July, 2015. The study found that respect for hierarchy, anger and fear, intimidation, and disillusion were key themes in participants' narratives of relationships with senior staff who oversaw their postgraduate training. The implications of these emotional subjectivities for quality of training, patient care and willingness of junior doctors to pursue careers in Ireland, are discussed and recommendations and areas for further research proposed. PMID- 28587869 TI - Genetic and biochemical characterisation of CTX-M-37 extended-spectrum beta lactamase from an Enterobacter cloacae clinical isolate from Mongolia. AB - OBJECTIVES: The aims of this study were to determine the resistance level of a blaCTX-M-37-carrying Enterobacter cloacae isolate from Mongolia, to analyse kinetic parameters of the purified enzyme and to compare the genetic environment of the gene. METHODS: Minimum inhibitory concentrations (MICs) were determined using the Clinical and Laboratory Standards Institute (CLSI) agar dilution method. Purified CTX-M-37 enzyme was used to determined kinetic parameters. The genetic environment of the blaCTX-M-37 gene in E. cloacae was compared with a Kluyvera cryocrescens isolate. RESULTS: The E. cloacae isolate showed relatively low-level resistance to cefotaxime (MIC=16mg/L) compared with a CTX-M-3-producing strain (MIC=256mg/L), and CTX-M-37 had a lower kcat/Km value for cefotaxime (2.0MUM-1s-1) compared with CTX-M-3 (3.5MUM-1s-1), possibly due to Asn114Asp substitution. The blaCTX-M-37 gene in the E. cloacae isolate was carried on a conjugative plasmid and was associated with an ISEcp1 element containing the -35 and -10 putative promoter sequences TTGAAA and TACAAT, respectively, unlike in the K. cryocrescens isolate. CONCLUSIONS: The CTX-M-37-producing E. cloacae isolate showed relatively low-level resistance to cefotaxime and the purified enzyme had lower kinetic parameters as the result of Asn114Asp substitution. Presence of an ISEcp1 element and putative promoters upstream of the blaCTX-M-37 gene in E. cloacae, but not in the K. cryocrescens isolate, indicated their roles in mobilisation and expression of the gene. PMID- 28587870 TI - Evaluation of the in vitro antimicrobial activity of selected Saudi scorpion venoms tested against multidrug-resistant micro-organisms. AB - OBJECTIVES: Scorpion venoms are a rich source of bioactive peptides with promising clinical value that may lead to the discovery and development of new drugs. The present study was designed to evaluate the in vitro antimicrobial activities of the venoms extracted from three medically important Saudi scorpions (Androctonus crassicauda, Androctonus bicolor and Leiurus quinquestriatus). METHODS: Antimicrobial assays were performed using a microplate growth inhibition assay against 10 multidrug-resistant (MDR) micro-organisms (4 Gram-negative bacteria, 2 Gram-positive bacteria and 4 fungi and yeasts) at concentrations ranging from 0 to 20mg/mL of each venom. Following qualitative analysis, dose response assays were performed for bacterial and fungal killing curves using the MTT colorimetric assay. RESULTS: Among the three tested scorpion venoms, only L. quinquestriatus venom showed significant broad-spectrum antimicrobial activity in a dose-dependent manner from 5 to 20mg/mL. Leiurus quinquestriatus venom inhibited the growth and survival of MDR Escherichia coli (55.2%), Acinetobacter baumannii (50.6%), Klebsiella pneumoniae (35.1%), Pseudomonas aeruginosa (31.3%), Staphylococcus aureus (36.4%), Enterococcus faecalis (47.6%), Candida albicans (31.2%) and Candida glabrata (39.0%), whereas no significant activity against Fusarium oxysporum and Aspergillus flavus was observed. In contrast, the venoms of A. crassicauda and A. bicolor did not show noticeable antimicrobial activity against any of the tested organisms. CONCLUSIONS: The findings of the current study demonstrate that L. quinquestriatus venom possesses antimicrobial activity and thus can be used as a template for designing and development of novel antimicrobial drugs. PMID- 28587871 TI - Synthesis, docking study and neuroprotective effects of some novel pyrano[3,2 c]chromene derivatives bearing morpholine/phenylpiperazine moiety. AB - Novel pyrano[3,2-c]chromene derivatives bearing morpholine/phenylpiperazine moiety were synthesized and evaluated against acetylcholinestrase (AChE) and butylcholinestrase (BuChE). Among the synthesized compounds, N-(3-cyano-4-(4 methoxyphenyl)-5-oxo-4,5-dihydropyrano[3,2-c]chromen-2-yl)-2-(4-phenylpiperazin-1 yl)acetamide (6c) exhibited the highest acetylcholinestrase inhibitory (AChEI) activity (IC50=1.12uM) and most of them showed moderate butylcholinestrase inhibitory activity (BChEI). Kinetic study of compound 6c confirmed mixed type of inhibition towards AChE which was in covenant with the results obtained from docking study. Also, it was evaluated against beta-secretase which demonstrated low activity (inhibition percentage: 18%). It should be noted that compounds 6c, 7b, 6g, and 7d showed significant neuroprotective effects against H2O2-induced PC12 oxidative stress. PMID- 28587872 TI - Validation of an automated tractography method for the optic radiations as a biomarker of visual acuity in neurofibromatosis-associated optic pathway glioma. AB - INTRODUCTION: Fractional anisotropy (FA) of the optic radiations has been associated with vision deficit in multiple intrinsic brain pathologies including NF1 associated optic pathway glioma, but hand-drawn regions of interest used in previous tractography methods limit consistency of this potential biomarker. We created an automated method to identify white matter tracts in the optic radiations and compared this method to previously reported hand-drawn tractography. METHOD: Automated tractography of the optic radiation using probabilistic streamline fiber tracking between the lateral geniculate nucleus of the thalamus and the occipital cortex was compared to the hand-drawn method between regions of interest posterior to Meyer's loop and anterior to tract branching near the calcarine cortex. Reliability was assessed by two independent raters in a sample of 20 healthy child controls. Among 50 children with NF1 associated optic pathway glioma, the association of FA and visual acuity deficit was compared for both tractography methods. RESULTS: Hand-drawn tractography methods required 2.6+/-0.9min/participant; automated methods were performed in <1min of operator time for all participants. Cronbach's alpha was 0.83 between two independent raters for FA in hand-drawn tractography, but repeated automated tractography resulted in identical FA values (Cronbach's alpha=1). On univariate and multivariate analyses, FA was similarly associated with visual acuity loss using both methods. Receiver operator characteristic curves of both multivariate models demonstrated that both automated and hand-drawn tractography methods were equally able to distinguish normal from abnormal visual acuity. CONCLUSION: Automated tractography of the optic radiations offers a fast, reliable and consistent method of tract identification that is not reliant on operator time or expertise. This method of tract identification may be useful as DTI is developed as a potential biomarker for visual acuity. PMID- 28587875 TI - The effectiveness of the anti-CD11d treatment is reduced in rat models of spinal cord injury that produce significant levels of intraspinal hemorrhage. AB - We have previously reported that administration of a CD11d monoclonal antibody (mAb) improves recovery in a clip-compression model of SCI. In this model the CD11d mAb reduces the infiltration of activated leukocytes into the injured spinal cord (as indicated by reduced intraspinal MPO). However not all anti inflammatory strategies have reported beneficial results, suggesting that success of the CD11d mAb treatment may depend on the type or severity of the injury. We therefore tested the CD11d mAb treatment in a rat hemi-contusion model of cervical SCI. In contrast to its effects in the clip-compression model, the CD11d mAb treatment did not improve forelimb function nor did it significantly reduce MPO levels in the hemi-contused cord. To determine if the disparate results using the CD11d mAb were due to the biomechanical nature of the cord injury (compression SCI versus contusion SCI) or to the spinal level of the injury (12th thoracic level versus cervical) we further evaluated the CD11d mAb treatment after a T12 contusion SCI. In contrast to the T12 clip compression SCI, the CD11d mAb treatment did not improve locomotor recovery or significantly reduce MPO levels after T12 contusion SCI. Lesion analyses revealed increased levels of hemorrhage after contusion SCI compared to clip-compression SCI. SCI that is accompanied by increased intraspinal hemorrhage would be predicted to be refractory to the CD11d mAb therapy as this approach targets leukocyte diapedesis through the intact vasculature. These results suggest that the disparate results of the anti-CD11d treatment in contusion and clip-compression models of SCI are due to the different pathophysiological mechanisms that dominate these two types of spinal cord injuries. PMID- 28587874 TI - Neuropathies in the setting of Neurofibromatosis tumor syndromes: Complexities and opportunities. AB - The term 'Neurofibromatosis' (NF) comprises a group of rare diseases with related clinical presentations but distinct genetic conditions. All currently known types - NF1, NF2 and Schwannomatosis - predispose afflicted individuals to the development of glial cell-derived (gliogenic) tumors. Furthermore, the occurrence of neuropathic symptoms, which add to the overall neurologic disability of patients, has been described in all disease entities. We show that neuropathic symptoms are a common and clinically important, yet infrequently studied feature in the NF spectrum. However, the clinical relevance and respective underlying pathogenesis, varies greatly among the different NF types. In this review, we summarize and interpret the latest basic research findings, as well as clinical observations, in respect of Neurofibromatosis-associated neuropathies. PMID- 28587873 TI - Regulation of transient receptor potential cation channel subfamily V1 protein synthesis by the phosphoinositide 3-kinase/Akt pathway in colonic hypersensitivity. AB - The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor or vanilloid receptor 1 (VR1), is expressed in nociceptive neurons in the dorsal root ganglia (DRG) and participates in the transmission of pain. The present study investigated the underlying molecular mechanisms by which TRPV1 was regulated by nerve growth factor (NGF) signaling pathways in colonic hypersensitivity in response to colitis. We found that during colitis TRPV1 protein levels were significantly increased in specifically labeled colonic afferent neurons in both L1 and S1 DRGs. TRPV1 protein up-regulation in DRG was also enhanced by NGF treatment. We then found that TRPV1 protein up regulation in DRG was regulated by activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway both in vivo and in vitro. Suppression of endogenous PI3K/Akt activity during colitis or NGF treatment with a specific PI3K inhibitor LY294002 reduced TRPV1 protein production in DRG neurons, and also reduced colitis-evoked TRPV1-mediated visceral hypersensitivity tested by hyper-responsiveness to colorectal distention (CRD) and von Frey filament stimulation of abdomen. Further studies showed that TRPV1 mRNA levels in the DRG were not regulated by either colitis or NGF. We then found that an up-regulation of the protein synthesis pathway was involved by which both colitis and NGF caused a PI3K-dependent increase in the phosphorylation level of eukaryotic translation initiation factor 4E-binding protein (4E-BP)1. These results suggest a novel mechanism in colonic hypersensitivity which involves PI3K/Akt-mediated TRPV1 protein, not mRNA, up regulation in primary afferent neurons, likely through activation of the protein synthesis pathways. PMID- 28587878 TI - It is better to be readmitted than dead. PMID- 28587877 TI - Cardiothoracic surgical training in Canada and the United States: Divergent paths, converging goals. PMID- 28587879 TI - Toward a more rational approach in treating type B aortic dissection. PMID- 28587876 TI - Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia. AB - Balance between cholinergic and dopaminergic signaling is central to striatal control of movement and cognition. In dystonia, a common disorder of movement, anticholinergic therapy is often beneficial. This observation suggests there is a pathological increase in cholinergic tone, yet direct confirmation is lacking. In DYT1, an early-onset genetic form of dystonia caused by a mutation in the protein torsinA (TorA), the suspected heightened cholinergic tone is commonly attributed to faulty dopamine D2 receptor (D2R) signaling where D2R agonists cause excitation of striatal cholinergic interneurons (ChIs), rather than the normal inhibition of firing observed in wild-type animals, an effect known as "paradoxical excitation". Here, we provide for the first time direct measurement of elevated striatal extracellular acetylcholine (ACh) in a knock-in mouse model of human DYT1 dystonia (TorA?E/+ mice), confirming a striatal hypercholinergic state. We hypothesized that this elevated extracellular ACh might cause chronic over-activation of muscarinic acetylcholine receptors (mAChRs) and disrupt normal D2R function due to their shared coupling to Gi/o-proteins. We tested this concept in vitro first using a broad-spectrum mAChR antagonist, and then using a M2/M4 mAChR selective antagonist to specifically target mAChRs expressed by ChIs. Remarkably, we found that mAChR inhibition reverses the D2R-mediated paradoxical excitation of ChIs recorded in slices from TorA?E/+ mice to a typical inhibitory response. Furthermore, we recapitulated the paradoxical D2R excitation of ChIs in striatal slices from wild-type mice within minutes by simply increasing cholinergic tone through pharmacological inhibition of acetylcholinesterase (AChE) or by prolonged agonist activation of mAChRs. Collectively, these results show that enhanced mAChR tone itself is sufficient to rapidly reverse the polarity of D2R regulation of ChI excitability, correcting the previous notion that the D2R mediated paradoxical ChI excitation causes the hypercholinergic state in dystonia. Further, using a combination of genetic and pharmacological approaches, we found evidence that this switch in D2R polarity results from a change in coupling from the preferred Gi/o pathway to non-canonical beta-arrestin signaling. These results highlight the need to fully understand how the mutation in TorA leads to pathologically heightened extracellular ACh. Furthermore the discovery of this novel ACh-dopamine interaction and the participation of beta arrestin in regulation of cholinergic interneurons is likely important for other basal ganglia disorders characterized by perturbation of ACh-dopamine balance, including Parkinson and Huntington diseases, l-DOPA-induced dyskinesia and schizophrenia. PMID- 28587880 TI - ACCIDENTAL DUPLICATION: Colorado-Retinopathy of Prematurity (CO-ROP) Screening Algorithm: a validation study at a tertiary care center. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.009. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28587881 TI - ACCIDENTAL DUPLICATION: MR Imaging Findings in Children with Spasmus Nutans. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28587882 TI - ACCIDENTAL DUPLICATION: Combined Vitrectomy and Glaucoma Drainage Device Implantation Surgical Approach for Complex Pediatric Glaucomas. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.02.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28587883 TI - ACCIDENTAL DUPLICATION: Investigation of the effect of hemoglobin F and A levels on development of retinopathy of prematurity. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.jaapos.2017.03.006. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 28587884 TI - Carbon source effects on the mono/dirhamnolipid ratio produced by Pseudomonas aeruginosa L05, a new human respiratory isolate. AB - Pseudomonas strains produce rhamnolipid mixtures (RLs) that generally consist of one or two molecules of rhamnose linked to one or two molecules of 3 hydroxyalkanoic acid. This study evaluates carbon source effects (glycerol, glucose, myristic acid, and Brassica carinata oil) on the synthesis of monorhamnolipids (mono-RLs) versus dirhamnolipids (di-RLs) in a human isolate of Pseudomonas aeruginosa PAL05. Spectrophotometry, an emulsifying index (E24) test, and an orcinol assay confirmed the production of RLs by PAL05. Purified RLs were characterized by 1H NMR analysis. PAL05 primarily produces mono-RLs when provided carbon sources containing long chain fatty acids (FAs) (myristic acid and B. carinata oil) and di-RLs when provided glycerol or glucose. qRT-PCR analysis showed that delayed expression of rhlC occurred when B. carinata oil was used, but not glycerol, glucose, or myristic acid. Our data show that the carbon source influenced the transcriptional expression of the rhlC gene and, consequently, the predominance of mono-RLs or di-RLs in PAL05 cultures. PMID- 28587885 TI - Destination bioeconomy - The path towards a smarter, more sustainable future. AB - Five years following the publication of the EU Bioeconomy Strategy, this article discusses the state of play of the bioeconomy in Europe. Placing specific focus on Industrial Biotech, it outlines ten pragmatic recommendations from BIO-TIC [BIO-TIC, A roadmap to a thriving industrial biotechnology sector in Europe, 2015], an EU FP7 funded project completed in 2015 and coordinated by EuropaBio, comprehensively examining the hurdles to the development of a bioeconomy in Europe, enabled by industrial biotech. These include improving opportunities for feedstock producers within the bioeconomy; investigating the scope for using novel biomass; developing a workforce which can maintain Europe's competitiveness in industrial biotechnology; introducing a long-term, stable and transparent policy and incentive framework to promote the bioeconomy; improving public perception and awareness of industrial biotechnology and bio-based products; identifying, leveraging and building upon EU capabilities for pilot and demonstration facilities; promoting the use of co-products from processing; improving the bioconversion and downstream processing steps; improving access to financing for large-scale biorefinery projects; developing stronger relationships between conventional and non-conventional players. PMID- 28587886 TI - Microbial selection strategies for polyhydroxyalkanoates production from crude glycerol: Effect of OLR and cycle length. AB - Crude glycerol from biodiesel manufacture can be used as carbon source for microbial fermentations. The production of polyhydroxyalkanoates by manipulating the Sequencing Batch Reactor (SBR) selection stage of microbial mixed cultures (MMC) using high organic loading rates (OLR, 50CmM/day) and different cycles lengths (6, 12 and 24h) were optimized. Batch-production of polyhydroxybutyrate (PHB) presented an accumulation capacity in the high range (0.44g/g) after 3 pulses of 50CmM, with a final content of 59% PHB/wt., for the culture selected with 50CmM/day and a 24h cycle length. These values were in the range to those obtained with pure cultures and higher than the ones for MMC. With this strategy three main advantages in terms of the PHA production can be considered: utilization of a real waste without the resort to pure microbial cultures and a pre-fermentation step, consolidating the role of MMC in the valorisation of complex wastes/by-products. PMID- 28587887 TI - Effect of diet and gut environment on the gastrointestinal formation of N-nitroso compounds: A review. AB - Diet is associated with the development of cancer in the gastrointestinal (GI) tract, because dietary nitrate and nitrite are the main nitrosating agents that are responsible for the formation of carcinogenic N-nitroso compounds (NOCs) when nitrosatable substrates, such as amine and amide, are present in the GI tract. However, whether the nitroso compounds become beneficial S-nitroso compounds or carcinogenic NOCs might depend on dietary and environmental factors including food stuffs, gastric acidity, microbial flora, and the mean transit time of digesta. This review focused on GI NOC formation and environmental risk factors affecting its formation to provide appropriate nutritional strategies to prevent the development of GI cancer. PMID- 28587889 TI - Corrigendum to 'An Anatomic Investigation Into the Relationship Between Posterior Condylar Offset and Posterior Tibial Slope of One Thousand One Hundred Thirty Eight Cadaveric Knees' [The Journal of Arthroplasty 32 (2017) 1659-1664]. PMID- 28587888 TI - Outcome of 4 Surgical Treatments for Wear and Osteolysis of Cementless Acetabular Components. AB - BACKGROUND: Loosening and periprosthetic osteolysis are some of the most common long-term complications after hip arthroplasty. The decision-making process and surgical treatment options are controversial. METHODS: We retrospectively reviewed 96 acetabular revisions (91 patients) performed between 2002 and 2012, with a minimum of 2 years of follow-up and a mean of 5.7 years of follow-up. Clinical outcome was assessed using the Harris Hip Score. The size and location of osteolytic lesions were evaluated using the preoperative radiographs; healing of the defects was categorized using a standardized protocol. RESULTS: Thirty three (34.4%) hips had isolated liner exchanges (ILEs), 10 (10.4%) hips had cemented liners into well-fixed shells (CLS), 45 (46.9%) hips had full acetabular revisions (FARs), and 8 (8.3%) hips had revision with a roof ring/antiprotrusio cage (RWC). All procedures showed significant improvement in Harris Hip Score after revision (P <= .001). Fifteen patients had moderate residual pain (pain score <=20): 8 (24%) ILE, 3 (30%) CLS, and 4 (9%) FAR. Complete bone defect healing after grafting was lower with acetabular component retention procedures (ILE and CLS; 27%) compared with full acetabular component revision procedures (FAR and RWC; 57%). Fifteen patients underwent reoperation: 3 ILE, 1 CLS, 8 FAR, and 3 RWC. CONCLUSION: Acetabular component retention demonstrates a low risk of reoperation; however, residual pain and limited potential for bone graft incorporation are a concern. FAR is technically challenging and may have an elevated risk of reoperation; however, higher degrees of bone graft incorporation and satisfactory clinical outcome can be expected. PMID- 28587890 TI - Spectral-dynamic representation of DNA sequences. AB - A graphical representation of DNA sequences in which the distribution of a particular base B=A,C,G,T is represented by a set of discrete lines has been formulated. The methodology of this approach has been borrowed from two areas of physics: spectroscopy and dynamics. Consequently, the set of discrete lines is referred to as the B-spectrum. Next, the B-spectrum is transformed to a rigid body composed of material points. In this way a dynamic representation of the DNA sequence has been obtained. The centers of mass of these rigid bodies, divided by their moments of inertia, have been taken as the descriptors of the spectra and, thus, of the DNA sequences. The performance of this method on a standard set of data commonly applied by authors introducing new approaches to bioinformatics (the first exons of beta-globin genes of different species) proved to be very good. PMID- 28587891 TI - The accessibility, readability, and quality of online resources for gender affirming surgery. AB - BACKGROUND: The transgender population is disproportionally affected by health disparities related to access to care. In many communities, transgender specialists are geographically distant and locally available medical professionals may be unfamiliar with unique needs of transgender patients. As a result, use of Internet resources for information about gender affirming surgery is particularly important. This study simulates a patient search for online educational material about gender affirming surgery and evaluates the accessibility, readability, and quality of the information. METHODS: An Internet search for the term "transgender surgery" was performed, and the first 10 relevant hits were identified. Readability was assessed using 10 established tests: Coleman-Liau, Flesch-Kincaid, FORCAST, Fry, Gunning Fog, New Dale-Chall, New Fog Count, Raygor Estimate, Simple Measure of Gobbledygook, and Flesch Reading Ease. Quality was assessed using Journal of the American Medical Association criteria and the DISCERN instrument. RESULTS: Review of 69 results was required to identify 10 sites with relevant patient information. There were 97 articles collected; overall mean reading level was 14.7. Individual Web site reading levels ranged from 12.0 to 17.5. All articles and Web sites exceeded the recommended sixth grade level. Quality ranged from 0 to 4 (Journal of the American Medical Association) and 35 to 79 (DISCERN) across Web sites. CONCLUSIONS: Web sites with relevant patient information about gender affirming surgery were difficult to identify from search results. The content of these sites universally exceeded the recommended reading level. A wide range of Web site quality was noted, and this may further complicate successful navigation. Barriers in access to appropriately written patient information on the Internet may contribute to disparities in referral, involvement, satisfaction, and outcomes. PMID- 28587893 TI - Comparison of estimates of neuronal number obtained using the isotropic fractionator method and unbiased stereology in day old chicks (Gallus domesticus). AB - BACKGROUND: The relative size and neuronal density of brain regions are important metrics in both comparative and experimental studies in neuroscience. Consequently, it is imperative to have accurate, reliable and reproducible methods of quantifying cell number. NEW METHOD: The isotropic fractionator (IF) method estimates the number of neurons and non-neurons in the central nervous system by homogenizing tissue into discrete nuclei and determining the proportion of neurons from non-neurons using immunohistochemistry (Herculano- Herculano Houzel and Lent, 2005). COMPARISON WITH EXISTING METHOD: One of the advantages of IF is that it is considerably faster than stereology. However, as the method is relatively new, concerns about its accuracy remain, particularly whether homogenization results in underestimation of cell number. In this study, we compared estimates of neuronal number in the telencephalon and 'rest of brain' (i.e. the diencephalon and brainstem excluding the optic lobes) of day old chicks using the IF method and stereology. RESULTS: In the telencephalon, there was a significant difference in estimates of neuronal number between the 2 methods, but not estimates of neuronal density (neurons/mg of tissue). Whereas in the 'rest of brain', there was a significant difference in estimates of neuronal density, but not neuronal number. In all cases, stereological estimates were lower than those obtained using the IF method. CONCLUSION: Despite the statistically significant differences, there was considerable overlap (all estimates were within 16% of one another) between estimates obtained using the two methods suggesting that the two methods provide comparable estimates of neuronal number in birds. PMID- 28587892 TI - The modified frailty index to predict morbidity and mortality for retroperitoneal sarcoma resections. AB - BACKGROUND: The modified frailty index (mFI) is an important method to risk stratify surgical patients and has been validated for general surgery and selected surgical subspecialties. However, there are currently no data assessing the efficacy of the mFI to predict acute morbidity and mortality in patients undergoing surgery for retroperitoneal sarcoma. METHODS: Using the American College of Surgeons' National Surgical Quality Improvement Program from 2007 to 2012, we performed a retrospective analysis of patients with a diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The mFI was calculated according to standard published methods. Univariate and multivariate statistical analyses including chi2 and logistic regression were used to identify predictors of 30-d overall morbidity, 30-d severe morbidity (Clavien III/IV), and 30-d mortality. RESULTS: We identified 846 patients with the diagnosis of primary malignant retroperitoneal neoplasm who underwent surgical resection. The distribution mFI scores was 0 (48.5%) or 1 (36.3%), with only 4.5% of patients presenting with a score >=3. Rates of 30-d overall morbidity, serious morbidity, and mortality were 22.6%, 12.9%, and 1.2%, respectively. Only selected mFI scores were associated with serious morbidity and overall morbidity on multivariate analysis (P < 0.05), and mFI did not predict 30 d mortality (P > 0.05). CONCLUSIONS: Our data demonstrate that the majority of patients undergoing retroperitoneal sarcoma resections have few, if any, comorbidities. The mFI was a limited predictor of overall and serious complications and was not a significant predictor of mortality. Better discriminators of preoperative risk stratification may be needed for this patient population. PMID- 28587894 TI - Burrowing as a novel voluntary strength training method for mice: A comparison of various voluntary strength or resistance exercise methods. AB - BACKGROUND: Voluntary strength training methods for rodents are necessary to investigate the effects of strength training on cognition and the brain. However, few voluntary methods are available. NEW METHOD: The current study tested functional and muscular effects of two novel voluntary strength training methods, burrowing (digging a substrate out of a tube) and unloaded tower climbing, in male C57Bl6 mice. To compare these two novel methods with existing exercise methods, resistance running and (non-resistance) running were included. Motor coordination, grip strength and muscle fatigue were measured at baseline, halfway through and near the end of a fourteen week exercise intervention. Endurance was measured by an incremental treadmill test after twelve weeks. RESULTS: Both burrowing and resistance running improved forelimb grip strength as compared to controls. Running and resistance running increased endurance in the treadmill test and improved motor skills as measured by the balance beam test. Post-mortem tissue analyses revealed that running and resistance running induced Soleus muscle hypertrophy and reduced epididymal fat mass. Tower climbing elicited no functional or muscular changes. COMPARISON WITH EXISTING METHODS: As a voluntary strength exercise method, burrowing avoids the confounding effects of stress and positive reinforcers elicited in forced strength exercise methods. Compared to voluntary resistance running, burrowing likely reduces the contribution of aerobic exercise components. CONCLUSIONS: Burrowing qualifies as a suitable voluntary strength training method in mice. Furthermore, resistance running shares features of strength training and endurance (aerobic) exercise and should be considered a multi-modal aerobic-strength exercise method in mice. PMID- 28587895 TI - A novel operant task to assess social reward and motivation in rodents. AB - BACKGROUND: Social reward plays a critical role in the development of beneficial social relationships, and disorders of the mechanisms controlling social reward are involved in the etiology of many psychiatric diseases. NEW METHOD: We present a novel operant social preference task to quantify social reward in rodents using an apparatus with three chambers separated by one-way vertical-swing doors. The experimental animal is placed in the larger chamber while the two smaller chambers either remain empty or contain a stimulus animal or other potential reward stimulus. Adding weights to the door can alter effort required for rewards. RESULTS: Hamsters (Mesocricetus auratus) entered the chamber containing a stimulus hamster significantly more frequently than an empty chamber. When the reinforcing effects of social interactions were compared to food reward under progressive cost requirements, the reinforcing effects of social interaction and sunflower seeds were similar. Progressively increasing the door weight decreased number of entries, but increased time spent attempting to open the doors. COMPARISON WITH EXISTING METHODS: The quantification of the rewarding properties of social interactions has almost exclusively used the conditioned place preference (CPP) paradigm. Although robust and reliable, CPP includes a memory component, because it relies on the association of place with the social interaction while the operant task presented here does not. CONCLUSIONS: This task allows for detailed and direct assessment of social and non-social rewards that may serve as effective behavioral reinforcers in this operant conditioning model, and it can be used to investigate the neural mechanisms regulating motivation. PMID- 28587896 TI - Development of a histologically validated segmentation protocol for the hippocampal body. AB - BACKGROUND: Recent findings have demonstrated that hippocampal subfields can be selectively affected in different disease states, which has led to efforts to segment the human hippocampus with in vivo magnetic resonance imaging (MRI). However, no studies have examined the histological accuracy of subfield segmentation protocols. The presence of MRI-visible anatomical landmarks with known correspondence to histology represents a fundamental prerequisite for in vivo hippocampal subfield segmentation. In the present study, we aimed to: 1) develop a novel method for hippocampal body segmentation, based on two MRI visible anatomical landmarks (stratum lacunosum moleculare [SLM] & dentate gyrus [DG]), and assess its accuracy in comparison to the gold standard direct histological measurements; 2) quantify the accuracy of two published segmentation strategies in comparison to the histological gold standard; and 3) apply the novel method to ex vivo MRI and correlate the results with histology. METHODS: Ultra-high resolution ex vivo MRI was performed on six whole cadaveric hippocampal specimens, which were then divided into 22 blocks and histologically processed. The hippocampal bodies were segmented into subfields based on histological criteria and subfield boundaries and areas were directly measured. A novel method was developed using mean percentage of the total SLM distance to define subfield boundaries. Boundary distances and subfield areas on histology were then determined using the novel method and compared to the gold standard histological measurements. The novel method was then used to determine ex vivo MRI measures of subfield boundaries and areas, which were compared to histological measurements. RESULTS: For direct histological measurements, the mean percentages of total SLM distance were: Subiculum/CA1 = 9.7%, CA1/CA2 = 78.4%, CA2/CA3 = 97.5%. When applied to histology, the novel method provided accurate measures for CA1/CA2 (ICC = 0.93) and CA2/CA3 (ICC = 0.97) boundaries, but not for the Subiculum/CA1 (ICC = -0.04) boundary. Accuracy was poorer using previous techniques for CA1/CA2 (maximum ICC = 0.85) and CA2/CA3 (maximum ICC = 0.88), with the previously reported techniques also performing poorly in defining the Subiculum/CA1 boundary (maximum ICC = 0.00). Ex vivo MRI measurements using the novel method were linearly related to direct measurements of SLM length (r2 = 0.58), CA1/CA2 boundary (r2 = 0.39) and CA2/CA3 boundary (r2 = 0.47), but not for Subiculum/CA1 boundary (r2 = 0.01). Subfield areas measured with the novel method on histology and ex vivo MRI were linearly related to gold standard histological measures for CA1, CA2, and CA3/CA4/DG. CONCLUSIONS: In this initial proof of concept study, we used ex vivo MRI and histology of cadaveric hippocampi to develop a novel segmentation protocol for the hippocampal body. The novel method utilized two anatomical landmarks, SLM & DG, and provided accurate measurements of CA1, CA2, and CA3/CA4/DG subfields in comparison to the gold standard histological measurements. The relationships demonstrated between histology and ex vivo MRI supports the potential feasibility of applying this method to in vivo MRI studies. PMID- 28587898 TI - A decade of decoding reward-related fMRI signals and where we go from here. AB - Information about potential rewards in the environment is essential for guiding adaptive behavior, and understanding neural reward processes may provide insights into neuropsychiatric dysfunctions. Over the past 10 years, multivoxel pattern analysis (MVPA) techniques have been used to study brain areas encoding information about expected and experienced outcomes. These studies have identified reward signals throughout the brain, including the striatum, medial prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, and parietal cortex. This review article discusses some of the assumptions and models that are used to interpret results from these studies, and how they relate to findings from animal electrophysiology. The article reviews and summarizes some of the key findings from MVPA studies on reward. In particular, it first focuses on studies that, in addition to mapping out the brain areas that process rewards, have provided novel insights into the coding mechanisms of value and reward. Then, it discusses examples of how multivariate imaging approaches are being used more recently to decode features of expected rewards that go beyond value, such as the identity of an expected outcome or the action required to obtain it. The study of such complex and multifaceted reward representations highlights the key advantage of using representational methods, which are uniquely able to reveal these signals and may narrow the gap between animal and human research. Applied in a clinical context, MVPA may advance our understanding of neuropsychiatric disorders and the development of novel treatment strategies. PMID- 28587897 TI - Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease. AB - The recent development of tau-specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimer's disease (AD). Tau PET imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current study was to evaluate multiple whole-brain and region-specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid-positive (Abeta+) patients with mild cognitive impairment (MCI) or AD-dementia underwent [18F]AV-1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole-brain measures of tracer uptake, (iv) regional uptake in AD-vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing Abeta controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel-wise contrasts. Braak staging, global and region-specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Our data indicate that whole-brain tau PET measures might be adequate biomarkers to detect AD-related tau pathology. However, regional measures covering AD-vulnerable regions may increase sensitivity to early tau PET signal, atrophy and memory decline. PMID- 28587899 TI - Anticonvulsant effect of flupirtine in an animal model of neonatal hypoxic ischemic encephalopathy. AB - Research studies suggest that neonatal seizures, which are most commonly associated with hypoxic-ischemic injury, may contribute to brain injury and adverse neurologic outcome. Unfortunately, neonatal seizures are often resistant to treatment with current anticonvulsants. In the present study, we evaluated the efficacy of flupirtine, administered at clinically relevant time-points, for the treatment of neonatal seizures in an animal model of hypoxic-ischemic injury that closely replicates features of the human syndrome. We also compared the efficacy of flupirtine to that of phenobarbital, the current first-line drug for neonatal seizures. Flupirtine is a KCNQ potassium channel opener. KCNQ channels play an important role in controlling brain excitability during early development. In this study, hypoxic-ischemic injury was induced in neonatal rats, and synchronized video-EEG records were acquired at various time-points during the experiment to identify seizures. The results revealed that flupirtine, administered either 5 min after the first electroclinical seizure, or following completion of 2 h of hypoxia, i.e., during the immediate reperfusion period, reduced the number of rats with electroclinical seizures, and also the frequency and total duration of electroclinical seizures. Further, daily dosing of flupirtine decreased the seizure burden over 3 days following HI-induction, and modified the natural evolution of acute seizures. Moreover, compared to a therapeutic dose of phenobarbital, which was modestly effective against electroclinical seizures, flupirtine showed greater efficacy. Our results indicate that flupirtine is an extremely effective treatment for neonatal seizures in rats and provide evidence for a trial of this medication in newborn humans. PMID- 28587900 TI - Altered reactivity of central amygdala to GABAAR antagonist in the BACHD rat model of Huntington disease. AB - In Huntington's disease (HD), dysfunctional affective processes emerge as key symptoms of disturbances. In human HD and transgenic rat models of the disease, the amygdala was previously shown to have a reduced volume and to carry a high load of mutant huntingtin (mHTT) aggregates. In search of the pathophysiology of affective dysregulation in HD, we hypothesized a specific role of the central amygdala (CeA), known to be particularly involved in emotional regulation. Using transgenic BACHD rats carrying full-length human mHTT, we compared behavioral consequences of pharmacological modulation of CeA function by infusing GABAA receptor (GABAAR) antagonist picrotoxin into ~4.5 month old BACHD and WT rats before confronting them to potentially threatening situations. Our results show that disinhibition of the CeA induced differential behaviors in WT and BACHD rats in our tasks: it increased social contacts and responses to the threatening warning signal in an avoidance task in BACHD rats but not in WT animals. At the cellular level, analyzes of amygdala alteration/dysfunction showed (1) an age dependent increase in number and size of mHTT aggregates specifically in the CeA of BACHD rats; (2) no alteration of GABA and GABAAR expression level, but (3) an increased neuronal reactivity (Arc labelling) to a threatening stimulus in the medial part of this nucleus in 4.5 months old BACHD rats. These results suggest a basal pathological hyper-reactivity in the CeA (in particular its medial part) in the transgenic animals. Such amygdala dysfunction could account, at least in part, for affective symptoms in HD patients. PMID- 28587903 TI - Cardiac arrest among patients with infections. PMID- 28587901 TI - Flexible weighting of diverse inputs makes hippocampal function malleable. AB - Classic theories of hippocampal function have emphasized its role as a dedicated memory system, but recent research has shown that it contributes broadly to many aspects of cognition, including attention and perception. We propose that the reason the hippocampus plays such a broad role in cognition is that its function is particularly malleable. We argue that this malleability arises because the hippocampus receives diverse anatomical inputs and these inputs are flexibly weighted based on behavioral goals. We discuss examples of how hippocampal representations can be flexibly weighted, focusing on hippocampal modulation by attention. Finally, we suggest some general neural mechanisms and core hippocampal computations that may enable the hippocampus to support diverse cognitive functions, including attention, perception, and memory. Together, this work suggests that great progress can and has been made in understanding the hippocampus by considering how the domain-general computations it performs allow it to dynamically contribute to many different behaviors. PMID- 28587902 TI - Involvement of Charcot-Marie-Tooth disease gene mitofusin 2 expression in paclitaxel-induced mechanical allodynia in rats. AB - Paclitaxel induces peripheral neuropathy, which is dose-limiting and results in loss of quality of life. Therefore, the prevention and treatment of paclitaxel induced peripheral neuropathy are major concerns in clinical cancer therapy. However, the detailed mechanisms have not been fully elucidated. It has recently been reported that allelic variability in the Charcot-Marie-Tooth disease (CMT) genes, mitofusin 2 (MFN2), Rho guanine nucleotide exchange factor 10 (ARHGEF10), and periaxin (PRX), affected paclitaxel-induced peripheral neuropathy in clinical cases. Therefore, we hypothesized that paclitaxel may induce peripheral neuropathy due to changes in Mfn2, Arhgef10, and Prx mRNA expression. Paclitaxel (6mg/kg) was administered intraperitoneally, on two consecutive days per week for 4 weeks in rats. Paclitaxel-induced peripheral neuropathy was measured by the von Frey test and acetone test, mechanical allodynia, and cold hyperalgesia, respectively, on days 0, 3, 10, 17, and 24. Mfn2, Arhgef10, and Prx mRNA expression in the spinal cord were analyzed by qRT-PCR on days 3 and 24. Paclitaxel induced mechanical allodynia from days 17-24, but did not induce cold hyperalgesia. In addition, paclitaxel reduced Mfn2 mRNA expression, but not Arhgef10 or Prx mRNA expression, on days 3 and 24. In addition, Mfn2 mRNA level was decreased before the appearance of mechanical allodynia. The results of the present study suggest that a reduction in Mfn2 mRNA expression contributes to paclitaxel-induced mechanical allodynia. PMID- 28587904 TI - Evaluation of a novel line probe assay to detect resistance to pyrazinamide, a key drug used for tuberculosis treatment. AB - OBJECTIVES: The development of rapid molecular diagnostic assays for pyrazinamide (PZA) resistance is considered technically challenging as mutations are highly diverse, scattered along the full length of the pncA gene and not all are associated with PZA resistance. We evaluated the performance of the novel Genoscholar PZA-TB II line probe assay (PZA-LPA2; NIPRO Corporation, Japan). METHODS: To evaluate the applicability of the PZA-LPA2 in clinical settings, we compared the performance of the PZA-LPA2 to a composite reference standard pncA Sanger and Illumina sequencing plus phenotypic susceptibility testing on a panel of 87 Mycobacterium tuberculosis isolates from World Health Organization (WHO) drug resistance surveys, harbouring mutations previously classified as associated or not associated with resistance according to data from peer-reviewed literature. In addition, the PZA-LPA2 was challenged against a selection of isolates with lineage-specific and non-resistance-associated mutations, for which the frequency among clinical isolates is unknown, and tested directly on 59 sputum extracts. RESULTS: For the survey isolates, the PZA-LPA2 reached an overall agreement with the composite reference of 97.6% (80/82) or 94.3% (82/87) excluding or including heteroresistance, respectively. The PZA-LPA2 failed on 8.5% (5/59) of clinical samples; among valid results, 100% (14/14) sensitivity and 100% (7/7) specificity was reached relative to pncA Sanger sequencing. CONCLUSIONS: The PZA-LPA2 represents a valid and rapid alternative for indirect PZA susceptibility testing. Preliminary findings on clinical samples show promise for direct testing. Further studies are needed to assess the clinical risk of missing heteroresistance and falsely detecting lineage-specific, silent and nonassociated mutations. PMID- 28587905 TI - Rapid identification of imported influenza viruses at Xiamen International Airport via an active surveillance program. AB - OBJECTIVES: The cross-border transmission of infectious diseases is a worldwide public health issue. Current border screening measures are insufficiently sensitive. The study objectives were to describe the epidemiologic pattern of influenza infection among incoming travellers at Xiamen International Airport during nonpandemic periods and to assess the performance of a rapid influenza diagnostic test in border screening. METHODS: Between May 2015 and May 2016, travellers with influenza-like illnesses entering China at Xiamen International Airport were screened with a rapid test, Flu Dot-ELISA, and the collected specimens were further subjected to virus isolation and phylogenetic analysis. RESULTS: Of the 1 540 076 incoming travellers, 1224 cases of influenza-like illness were identified; 261 tested positive in the rapid test, and 176 were confirmed to be influenza through virus culture. The sensitivity and specificity of the rapid test were demonstrated to be 96.6% (170/176) and 91.3% (957/1048), respectively, and the positive predictive and negative predictive values were 65.1% (170/261) and 99.4% (957/963), respectively. The epidemiologic study indicated that H3N2 and (H1N1)pdm09 were dominant in 2015 and 2016, respectively. In 2016, an increased number of influenza B isolates and cocirculation of both Victoria and Yamagata lineage influenza B viruses were observed, and mismatches between circulating influenza A(H1N1)pdm09 and influenza B Victoria lineage strains and vaccine strains also occurred. CONCLUSIONS: We demonstrated the suitability and value of a high-sensitivity rapid influenza test in border screening and highlighted the importance of incoming travellers as a source of imported infectious diseases. PMID- 28587906 TI - [Early hypophosphataemia in at risk newborns. Frequency and magnitude]. AB - OBJECTIVE: To determine the frequency and magnitude of neonatal hypophosphataemia (<4mg/dL) in a neonatal Intensive Care Unit and to describe risk groups. PATIENTS AND METHODS: Retrospective study of hospitalised newborns over a 44 month period (phase 1). Retrospective study of <1,500g/<32 weeks of gestation newborns over a 6 month period (phase 2). Prospective study of <1,500g or 1,550-2,000g, and intrauterine growth restriction (IUGR) newborns. Measurements were made on the 1st, 3rd, 7th, and 14th days of life (phase 3). RESULTS: Phase 1: 34 (2.4%) of 1,394 patients had a diagnosis of hypophosphataemia, 76% of them <=32 weeks of gestation and <1500 grams, and 24% >32 weeks with weight10% reduction in maximal isometric ankle plantarflexor torque production and a downward shift in the median power frequency of both heads of the gastrocnemius muscle of the fatigued limb) was achieved in 18 individuals, and only their data were used for analysis purposes. Compared to pre fatigue walking trials, medial gastrocnemius activity was significantly reduced in the study (fatigued) limb. Other main changes following fatigue included significantly more knee flexion during loading, and an associated larger external knee flexion moment in the study limb. At the ankle joint, participants exhibited significantly less peak plantarflexion (occurring at toe-off) with fatigue. No significant differences were observed in the contralateral (non-fatigued) limb. Findings from this study indicate that fatigue of the ankle plantarflexor muscle does not produce widespread changes in gait biomechanics, suggesting that small to moderate changes in maximal ankle plantarflexor force production capacity (either an increase or decrease) will not have a substantial impact on normal lower limb functioning during gait. PMID- 28587935 TI - Human antimicrobial peptides in ocular surface defense. AB - Sight depends on the passage of light through the transparent cornea and being focused on the fovea. Its exposed position renders it vulnerable to microbial infection. The cornea has developed a wide array of defense mechanisms against infection, of which endogenous antimicrobial peptides (AMPs) are key. AMPs are essentially small molecular weight cationic peptides with a wide range of activity against virus, bacteria, fungi and parasites. Some proteins such as RNases and S100As are also included in this group. Several AMPs act synergistically allowing low expression of multiple AMPs to act efficiently. AMPs also have a range of non-microbicidal functions and serve as signaling molecules, immunomodulators; show anti-tumour activity, and influence vascularization and wound healing. Different toll-like receptors (TLR) have been implicated in the preferential induction of specific AMPs. A range of bacteria, including mycobacteria tuberculosis, viruses including herpes virus, fungi and parasites including acanthamoeba, that cause ocular infections have been shown to induce specific AMPs via TLR activation. Non-TLR mediated induction of AMP expression can occur and several molecules such as L-isoleucine, sodium butyrate, vitamin D3, phenylbutyrate, vasoactive intestinal peptide, and etinostat have been identified in this regard. Given the rising microbe resistance to antibiotics, the slow rate of development of new antibiotics and the limited access to effective antibiotics by patients living in the developing world, an ideal solution would be to find AMPs that are effective singly or in combination with each other or other antimicrobial proteins to reduce, if possible eliminate reliance on antibiotics alone. PMID- 28587936 TI - Intra-hippocampal microinjection of oxytocin produced antiepileptic effect on the pentylenetetrazol-induced epilepsy in rats. AB - BACKGROUND: In addition to its role as a circulating hormone, oxytocin can also act as a neurotransmitter and a neuromodulator within the brain. In this study, we investigated the intra-hippocampal effect of oxytocin on an experimental seizure model induced by pentylenetetrazole (PTZ) in rats. We also used atosiban (oxytocin antagonist), diazepam and flumazenil (gamma-aminobutyric acid or GABA benzodiazepine receptor agonist and antagonist, respectively) to clarify the involved mechanism. METHOD: In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Epileptic behaviors were induced by intraperitoneal (ip) injection of PTZ (60mg/kg), and the latency time to onset of first myoclonic jerk, and the duration of epileptic seizures were determined for 30min. RESULTS: Intra hippocampal microinjections of oxytocin at doses of 10 and 20ng/site, diazepam (100 and 200ng/site) and co-administration of their ineffective doses significantly (p<0.01) increased the onset of first myoclonic jerk and decreased duration of epileptic seizure. Antiepileptic effects of oxytocin (20ng/site) were inhibited by atosiban (20 and 40ng/site) and flumazenil (100 and 200ng/site) pretreatments. On the other hand, prior administration of flumazenil (100 and 200ng/site) and atosiban (20 and 40ng/site) prevented the antiepileptic effects induced by diazepam (100 and 200ng/site). CONCLUSIONS: The results of the present study showed that at the level of the hippocampus oxytocin suppressed the severity of epileptic behaviors. A hippocampal GABA-benzodiazepine receptor mechanism may be involved in antiepileptic effect of oxytocin. PMID- 28587937 TI - Anti-inflammatory and anti-nociceptive effects of strontium ranelate on the zymosan-induced temporomandibular joint inflammatory hypernociception in rats depend on TNF-alpha inhibition. AB - BACKGROUND: Temporomandibular joint (TMJ) disorders show inflammatory components, heavily impacting on quality of life. Strontium ranelate has previously shown anti-inflammatory and antinociceptive effects on other experimental inflammatory pain models. Thus, we aim to investigate the strontium ranelate efficacy in reducing the zymosan-induced inflammatory hypernociception in the TMJ of rats by evaluating the TNF-alpha, IL-1beta, and hemeoxygenase-1 (HO-1) involvement. METHODS: Wistar rats were treated with strontium ranelate (0.5, 5 or 50 mg/kg, per os) 1 h before zymosan injection (iart). Mechanical threshold was assessed by Von Frey test and synovial lavage was collected for leukocyte counting and myeloperoxidase measurement, joint tissue and trigeminal ganglion were excised for histopathological analysis (H&E) and TNF-alpha/IL-1beta levels dosage (ELISA). Moreover, rats were pre-treated with ZnPP-IX (3 mg/kg, sc), a specific HO-1 inhibitor, before strontium ranelate administration (0.5 mg/kg, per os), and Evans Blue (5 mg/kg, iv) was administered to assess plasma extravasation. Pre treatment with indomethacin (5 mg/kg, sc) was used as positive control while the sham group received 0.9% sterile saline (per os and iart). RESULTS: Strontium ranelate did not reduce leukocyte counting, myeloperoxidase activity, Evans Blue extravasation, IL-1beta levels, and TNF-alpha/IL-1beta immunolabeling; but it increased the nociceptive threshold and reduced TNF-alpha levels. Additionally, HO-1 inhibition did not change the strontium ranelate effects. CONCLUSION: Strontium ranelate may achieve its antinociceptive effects through the reduction of TNF-alpha levels in the trigeminal ganglion, but not suppressing IL-1beta expression nor inducing the HO-1 pathway. PMID- 28587939 TI - Temozolomide and sorafenib as programmed cell death inducers of human glioma cells. AB - BACKGROUND: Gliomas are aggressive brain tumors with very high resistance to chemotherapy. Therefore, the aim of the present study was to investigate the effectiveness of sorafenib and Temozolomide in elimination of human glioma cells through apoptosis and autophagy. METHODS: MOGGCCM (anaplastic astrocytoma) and T98G (glioblastoma multiforme) cell lines incubated with sorafenib and/or Temozolomide were used in the experiments. Cell morphology (ER stress, apoptosis, autophagy, and necrosis) was analyzed microscopically while apoptosis and mitochondrial membrane potential were assessed with flow cytometry. Beclin1, LC3, p62, Hsp27, and Hsp72 levels were analyzed by immunoblotting. The activity of caspase 3, 8, and 9 was evaluated fluorometrically. Expression of Hsps was blocked by transfection with specific siRNA. RESULTS: In MOGGCCM cells, Temozolomide most frequently induced autophagy, which was accompanied by decreased p62 and increased beclin1 and LC3II levels. Sorafenib initiated mainly apoptosis. Additional incubation with Temozolomide, synergistically potentiated the pro-apoptotic properties of sorafenib, but it was mediated in a caspase independent way. In T98G cells, the effect of the analyzed drugs on programmed cell death induction was different from that in MOGGCCM cells. Sorafenib induced autophagy, while Temozolomide initiated mainly apoptosis. After simultaneous drug application, apoptosis dominated, suggesting synergistic action of both drugs. Inhibition of Hsp27 and Hsp72 expression increased the sensitivity of both cell lines to ER stress and, to a lesser extent, to induction of apoptosis, but not autophagy. CONCLUSIONS: Sorafenib and Temozolomide applied in combination are potent apoptosis inducers in T98G and MOGGCCM cells. ER stress precedes the elimination. Blocking of Hsp expression has a greater impact on ER stress rather than apoptosis induction. PMID- 28587938 TI - Etidronate down-regulates Toll-like receptor (TLR) 2 ligand-induced proinflammatory cytokine production by inhibiting NF-kappaB activation. AB - BACKGROUND: Etidronate is a non-nitrogen-containing bisphosphonate (non-NBP) used for anti-bone resorptive therapy as well as having inhibitory effects on atherosclerotic plaques. The present study examined the effects of etidronate on the production of proinflammatory cytokines and chemokines by the macrophage-like cell line, J774.1, incubated with Pam3Cys-Ser-(Lys)4 (Pam3CSK4, a Toll-like receptor (TLR) 2 agonist) and lipid A (a TLR4 agonist). METHODS: J774.1 cells and human monocytic THP-1 cells were pretreated with or without etidronate for 5min, and then incubated with or without Pam3CSK4 or lipid A for 24h. Levels of secreted interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha) in culture supernatants were measured by enzyme-linked immunosorbent assay (ELISA). Cytotoxicity was determined by LDH activity in the supernatants. We also examined the effects of etidronate on the activation of nuclear factor kappaB (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) in J774.1 cells by ELISA and Western blotting. RESULTS: Treatment of J774.1 cells with etidronate down-regulated TLR2 ligand-induced production of IL-6, TNF-alpha, MCP 1, and MIP-1alpha. Etidronate also inhibited Pam3CSK4-induced MCP-1 and TNF-alpha production by THP-1 cells. However, etidronate did not induce cytotoxicity and reduced lipid A-induced cytotoxicity in J774.1 cells. In addition, this agent did not down-regulate TLR4 ligand-induced proinflammatory cytokine production. Furthermore, etidronate inhibited the translocation of NF-kappaB but not p38 MAPK in J774.1 cells stimulated with Pam3CSK4 or lipid A. CONCLUSION: Etidronate likely inhibits proinflammatory cytokine production in J774.1 cells by suppressing NF-kappaB activation in the TLR2 and not the TLR4 pathway. PMID- 28587940 TI - Learning to make things happen: Infants' observational learning of social and physical causal events. AB - Infants learn about cause and effect through hands-on experience; however, they also can learn about causality simply from observation. Such observational causal learning is a central mechanism by which infants learn from and about other people. Across three experiments, we tested infants' observational causal learning of both social and physical causal events. Experiment 1 assessed infants' learning of a physical event in the absence of visible spatial contact between the causes and effects. Experiment 2 developed a novel paradigm to assess whether infants could learn about a social causal event from third-party observation of a social interaction between two people. Experiment 3 compared learning of physical and social events when the outcomes occurred probabilistically (happening some, but not all, of the time). Infants demonstrated significant learning in all three experiments, although learning about probabilistic cause-effect relations was most difficult. These findings about infant observational causal learning have implications for children's rapid nonverbal learning about people, things, and their causal relations. PMID- 28587942 TI - The association of addictive-like eating with food intake in children. AB - OBJECTIVES: The potential role of an addictive process in problematic eating is a growing area of interest and debate. Children are more vulnerable to the negative effects of addictive substances than adults and may be at increased risk for addictive-like eating behavior. No prior study has evaluated the association of addictive-like eating with objectively measured eating behavior in adults or children. We examined the association between "food addiction" and observed food consumption among children and whether age moderated this association. METHOD: Seventy children participated in an observed dinner meal, completed a dietary recall interview, and answered the Yale Food Addiction Scale for Children (YFAS C), a questionnaire assessing symptoms of "food addiction". Children's total calories ordered, calories consumed at dinner, calories consumed post-dinner, and a total of calories consumed at dinner and post-dinner were calculated along with their BMI percentile. We used generalized estimated equation models to investigate the relationship between the YFAS-C and food consumption. RESULTS: Elevated "food addiction" symptoms, but not BMI percentile, were positively associated with an increased amount of calories consumed at dinner and post dinner. Age significantly moderated the relationship between YFAS-C and caloric intake, with only younger children exhibiting this association. CONCLUSIONS: As the first study of objectively measured eating behavior, we found addictive-like eating scores in children were positively associated with the total amount of calories consumed. Among younger children, "food addiction" was more strongly associated with the total calories consumed than BMI percentile, highlighting the importance of assessing behavioral phenotypes when evaluating caloric intake. This association between addictive-like eating and caloric intake among younger, but not older children may be due to differences in inhibitory control and dietary restraint. PMID- 28587943 TI - Delivering direct acting antiviral therapy for hepatitis C to highly marginalised and current drug injecting populations in a targeted primary health care setting. AB - BACKGROUND: The Kirketon Road Centre (KRC) is a community-based public health facility in Sydney, Australia, that provides healthcare to people who inject drugs (PWID), including hepatitis C virus (HCV) treatment. From March 2016, the Australian Government has provided access to direct-acting antivirals (DAA) for adults with chronic HCV, without liver disease stage or drug and alcohol use restrictions. The aim of this study was to report DAA treatment outcomes among highly marginalised PWID treated at KRC. METHODS: All individuals initiating DAA treatment at KRC and due for sustained virological response (SVR12) testing by end 2016 were included. Demographic, drug use behaviour, clinical parameters, adherence support and HCV treatment outcomes, including SVR12 were recorded. Factors associated with SVR12, loss-to-follow-up (LTFU) and delayed SVR12 testing (>SVR16) were assessed by multivariate analysis. SVR12 was assessed by intention to-treat (ITT) and modified ITT, the latter excluding individuals with an end-of treatment response (ETR) but no SVR12 assessment, or who postponed their SVR12 date due to treatment interruption. RESULTS: A total of 72 individuals commencing DAAs were included, of whom 67% were male, 30% homeless, and 32% Aboriginal. All had a lifetime history of injecting drug use, with 75% having injected within the last six months, and 44% injecting at least weekly; 25% were also enrolled in opioid substitution therapy. Twenty-five (35%) individuals elected to receive an enhanced adherence-support package. Fifty-nine of 72 (82%) individuals due for SVR12 attended for testing, of whom 59/59 (100%) achieved SVR, providing an ITT SVR of 82%. A further six individuals had undetectable HCV RNA at ETR, but no SVR12 assessment, and one interrupted treatment, providing a mITT SVR of 91%. Homelessness was associated with delayed SVR12 testing (OR 24.9 95%CI 2.9-212.8, p=0.003). There was no association between LTFU and frequency of drug injection, last drug injected, or planned treatment duration. CONCLUSION: This study confirms that PWID can be successfully treated for HCV in a real-world setting using an integrated primary health care model. It also demonstrates feasibility to upscale DAA therapy in high-risk PWID populations, with potential individual and population-level public health benefits. Enhanced efforts are required to optimise post-treatment follow-up. PMID- 28587941 TI - Family food talk, child eating behavior, and maternal feeding practices. AB - Families discuss food and eating in many ways that may shape child eating habits. Researchers studying how families talk about food have examined this process during meals. Little work has examined parent-child food-related interactions outside of mealtime. We assessed family food talk at home outside of mealtime and tested whether food talk was associated with obesogenic child eating behaviors, maternal feeding practices, or child weight. Preschool and school-aged mother child dyads (n = 61) participated in naturalistic voice recording using a LENA (Language ENvironment Analysis) recorder. A coding scheme was developed to reliably characterize different types of food talk from LENA transcripts. Mothers completed the Children's Eating Behavior Questionnaire (CEBQ) and Child Feeding Questionnaire (CFQ) to assess child eating behaviors and maternal feeding practices. Child weight and height were measured and body mass index z-score (BMIz) calculated. Bivariate associations among food talk types, as a proportion of total speech, were examined and multivariate regression models used to test associations between food talk and child eating behaviors, maternal feeding practices, and child BMIz. Proportion of child Overall Food Talk and Food Explanations were positively associated with CEBQ Food Responsiveness and Enjoyment of Food (p's < 0.05). Child food Desire/Need and child Prep/Planning talk were positively associated with CEBQ Enjoyment of Food (p < 0.05). Child Food Enjoyment talk and mother Overt Restriction talk were positively associated with CEBQ Emotional Over-Eating (p < 0.05). Mother Monitoring talk was positively associated with CFQ Restriction (p < 0.05). Mother Prep/Planning talk was negatively associated with child BMIz. Food talk outside of mealtimes related to child obesogenic eating behaviors and feeding practices in expected ways; examining food talk outside of meals is a novel way to consider feeding practices and child eating behavior. PMID- 28587945 TI - A new "on-off-on" fluorescent probe containing triarylimidazole chromophore to sequentially detect copper and sulfide ions. AB - A novel compound TPI-H containing triphenylimidazole chromophore is synthesized and employed as fluorescent probe for sequential detection of Cu2+ and S2-. With three binding sites in its molecular structure, TPI-H exhibits highly selective binding towards Cu2+ and results in an apparent fluorescence "on-off" behavior. Fluorescence intensity is linear with the Cu2+ concentration, and the detection limit can be down to 8.7nM. Furthermore, the in-situ generated ensemble between TPI-H and Cu2+ (TPI-H-Cu(II)) can be used to detect S2- with a low detection limit of 15.6nM through Cu2+ displacement method. In addition, the potential utility of the probe for the detection of Cu2+ and further S2- in biological system is investigated by cell imaging. PMID- 28587944 TI - Short-term injection drug use changes following hepatitis C virus (HCV) assessment and treatment among persons who inject drugs with acute HCV infection. AB - BACKGROUND: It is unclear whether treatment and care for hepatitis C virus (HCV) infection can help people who inject drugs (PWID) modify their injection drug use behaviours. This study examined changes in injection drug use among PWID with acute HCV systematically referred for HCV clinical assessment and treatment and offered targeted health care services, over the course of one year. METHODS: The study sample included PWID with documented acute HCV infection recruited and followed-up semi-annually at least twice in IMPACT (2007-2015), a longitudinal community-based prospective study in Montreal, Canada. Following enrolment, participants with contra-indications to treatment due to severe co-morbidity were offered targeted health care services. Pegylated interferon-alpha (12-24 weeks) was offered to all other participants who did not spontaneously resolve their infection. At each study visit, data were collected on socio-demographic factors and drug use patterns. Logistic regression was used to assess changes in injection drug use at one-year follow-up. RESULTS: Of the 87 eligible participants (mean age: 35.6; 78.2% male), 21.8% received treatment [(RT), Sustained virological response: 84.2%], 25.3% spontaneously resolved their infection (SR), 14.9% had contra-indication(s) (CI) and 37.9% chose not to engage in HCV care post-diagnosis (NE). In multivariate analyses adjusting for age, gender and injection drug use at baseline, the RT [Adjusted odds ratio (AOR): 0.18; 95% Confidence interval (CI): 0.04-0.76], SR (AOR: 0.34; 95% CI: 0.08 1.40), and CI (AOR: 0.24; 95% CI: 0.05-1.22) groups were less likely to report injection drug use at follow-up relative to the NE group. CONCLUSION: PWID who received treatment, spontaneously resolved their infection or presented with treatment contra-indication(s) reported reduced injection drug use at one-year follow-up relative to those who did not engage in therapy. Findings suggest that the benefits of HCV assessment and treatment may extent to helping PWID modify their injection drug use patterns. PMID- 28587946 TI - New approach for the quantification of metallic species in healthcare products based on optical switching of a Schiff base possessing ONO donor set. AB - A new method is reported for the quantification of some metallic components of healthcare products utilizing a Schiff base chelator derived from 2 hydroxyacetophenone and ethanolamine. The Schiff base chelator recognizes some metallic species such as iron, copper and zinc (important components of some healthcare products), and cadmium (common contaminant in healthcare products) giving colorimetric/fluorimetric response. It coordinates with Fe2+/Fe3+ and Cu2+ ions via ONO donor set and switches the colour to bright red, green and orange, respectively. Similarly, it switches 'ON' a fluorometric response when coordinates with Zn2+ and Cd2+ ions. In the present approach, detailed studies on the colorimetric and fluorimetric response of ONO Schiff base is investigated in detail. The Job plot for the complexation of ONO switch with various metal ions suggested formation of 1:1 (metal-chelator) complex with Fe2+, Fe3+, and Cu2+ while 1:2 (metal-chelator) for Zn2+ and Cd2+ ions. The limit of detection, limit of quantification are 6.73, 18.0, 25.0, 0.65, 1.10MUM and 27.0, 72.0, 100.0, 2.60 and 4.40MUM for Fe2+, Fe3+, Cu2+, Zn2+ and Cd2+ ions, respectively. Under the optimized conditions, chelator was used for the quantification of important metals present in healthcare products via direct dissolution and furnace treatment during sample preparation. The results were found precise and accurate for both sample preparation techniques using the developed method. PMID- 28587947 TI - Colorimetric assay of copper ions based on the inhibition of peroxidase-like activity of MoS2 nanosheets. AB - The peroxidase-like catalytic activity of MoS2 nanomaterials has been utilized for colorimetric bioassays and medical diagnostics. However, the application of peroxidase-like catalytic activity of MoS2 nanomaterials in environmental analysis was seldom explored. Herein, copper ions were found to inhibit the peroxidase-like catalytic activity of MoS2 nanosheets, which can catalyze the oxidation of 3, 3', 5, 5'-tetramethylbenzidine by H2O2 to produce a colorimetric product. Based on this finding, a simple sensitive colorimetric method for the detection of copper ions was developed. In the presence of copper ions, the absorbance and color of the solution decreased with the increasing concentration of copper ions. The color of the solution can be used to semi-quantitative on site assay of copper ions by naked eyes. A linear relationship between the absorbance and the concentration of copper ions was observed in the range of 0.4 4.0MUmolL-1 with a detection limit of 92nmolL-1, which was much lower than the maximum contaminant level of copper in drinking water legislated by the Environmental Protection Agency of USA and the World Health Organization. The method was applied to detect copper ions in environmental water samples with satisfactory results. PMID- 28587948 TI - Digoxin use in atrial fibrillation. PMID- 28587950 TI - Anemia considerations when assessing natriuretic peptide levels in ED patients. AB - INTRODUCTION: The incidence of heart failure (HF) has reached epidemic levels in western populations, and the majority of these patients are admitted to hospitals through the emergency department (ED). We aimed to aid clinicians assessing natriuretic peptide (NP) levels in cases with suspected HF. In this study, we investigated the effect of anemia on amino-terminal pro-BNP (NT-proBNP) and on B type natriuretic peptide (BNP) levels. METHODS: This retrospective study examined patients who were admitted to the ED with suspected HF. After admission, the treating physician requested complete blood count and creatinine tests with NT proBNP (n=2.637) or BNP (n=11.159). The exclusion criteria were used to minimize the factors that could affect the NT-proBNP and BNP results. We examined the data using the Mann-Whitney U test, Chi-square test, Spearman correlation test, and multivariate linear regression analyses. RESULTS: The NT-proBNP and BNP levels were statistically higher in the groups with anemia (p=0.016 and p=0.009, respectively). There was a statistically significant negative correlation between hemoglobin and NP levels (r=-0.272, p<0.001 for NT-proBNP and r=-0.179, p<0.001 for BNP). The results indicated that advanced age and low hemoglobin levels were significantly associated with the increase in NT-proBNP (p=0.024 and p=0.004, respectively). Advanced age, low hemoglobin and low GFR-MDRD levels were significantly associated with the increase in BNP (p<0.001, p=0.002 and p=0.013, respectively). DISCUSSION: The data suggest that clinicians examining patients admitted to the ED with suspected HF should consider that anemia could lead to increases in NT-proBNP and BNP levels. PMID- 28587949 TI - Usefulness of direct W-plasty application to wound debridement for minimizing scar formation in the ED. AB - PURPOSE: A suture line placed with the same direction as the relaxed skin tension line leads to good healing, but a suture line with over 30 degrees of angle from the relaxed skin tension line leads to longer healing time and more prominent scarring. W-plasty is widely used to change the direction of the scar or to divide it into several split scars. In this study, we applied W-plasty to patients with facial lacerations in the emergency department. METHODS: From June 2012 to December 2014, 35 patients underwent simple repair or W-plasty for facial lacerations. Patients in the simple repair group underwent resection following a thermal margin, and the W-plasty group was resected within a pre-designed margin of W-shaped laceration. We assessed prognosis using the Stony Brook Scar Evaluation Scale (SBSES) after 10 days (short-term) and six months (long-term), respectively, following suture removal. RESULTS: Among 35 patients, 15 (42.9%) underwent simple debridement and 20 (57.1%) underwent W-plasty. In the W-plasty group, there was no difference between short-term and long-term follow-up showing high SBSES, but in the simple debridement group, long-term follow-up SBSES significantly decreased. W-plasty SBSES was higher than simple debridement at short-term as well as long-term follow-up. CONCLUSION: We experienced good results of direct W-plasty application at six-month long-term follow-up. Therefore, W-plasty application is more effective in reducing scar appearance than a simple debridement method for facial laceration patients with an angle of 30 degrees or more to the relaxed skin tension line. PMID- 28587951 TI - Treatment-naive spontaneous tumor lysis syndrome in metastatic prostate adenocarcinoma: An unusual suspect. AB - Tumor lysis syndrome (TLS) is a potentially fatal condition defined both by laboratory and clinical criteria. It is caused by the catabolism of tumor cells which leads to considerable release and elevated levels of phosphate, potassium and uric acid in the bloodstream. These electrolyte derangements predispose patients to renal tubule uric acid precipitation, acute kidney injury, arrhythmias, neuromuscular irritability and even seizures. Although this phenomenon is well described with hematological malignancies, it is also known to occur among solid tumors. We present a rare case of treatment-naive spontaneous TLS that occurred in a 69-year-old male with metastatic prostate adenocarcinoma with hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, elevated liver enzymes, AKI and hemodynamic instability. Despite our best resuscitative efforts with intravenous hydration, electrolyte monitoring, Rasburicase and renal replacement therapy, the patient continued to decline, was made comfort care and expired shortly thereafter. Physicians encountering patients with the above presentation must entertain a diagnosis of TLS despite its rarity in solid tumors, as early diagnosis leads to timely treatment, thereby maximizing patients' chances at survival. PMID- 28587953 TI - Can we imagine a survival chain also for ischemic stroke? PMID- 28587952 TI - The effect of trimetazidine treatment in patients with type 2 diabetes undergoing percutaneous coronary intervention for AMI. AB - PURPOSE: Trimetazidine (TMZ) improves clinical outcomes in patients with chronic heart failure and stable coronary artery disease. No study has yet evaluated the efficacy of TMZ in type 2 diabetes patients with acute myocardial infarction (AMI) undergoing Percutaneous Coronary Intervention (PCI). We performed this study to evaluate the efficacy TMZ in DM patients with AMI undergoing PCI, such as the effect on reductions in myocardial enzyme, improvements in liver function, modulation of glucose levels, and improvement in cardiac function. METHODS: For this randomized study, we enrolled 173 AMI patients with type 2 diabetes undergoing PCI between January 1, 2014, and January 1, 2016. All patients received aspirin and ticagrelor upon admission and throughout their hospitalization. Patients in the experimental group were treated with a loading dose of 60mg TMZ at admission, and 20 mg TMZ three times a day thereafter. 89 patients were included in experimental group, and 84 patients were included in control group. All patients received PCI treatments. The endpoints evaluated were serum creatine kinase and its isoenzyme (CK and CK-MB), cardiac troponin I (cTNI), serum creatinine (Cr), serum urea, blood glucose, serum glutamic pyruvic transaminase (ALT), serum glutamic oxaloacetictransaminase (AST), left atrial dimension (LA), left ventricular ejection fraction (LVEF), left ventricular end diastolic dimension (LVEDD), and cardiac output (CO). FINDINGS: Compared with the control group, TMZ treatment significantly reduced CK and CK-MB on the second day in hospital ([797+/-582] vs. [1092+/-1114]; [80+/-60] vs. [105+/-100]; p=0.029, p=0.041, respectively), and cTNI after one and six days in hospital ([13.5+/ 12.7] vs. [19.8+/-19.2]; [3.3+/-3.2] vs. [4.8+/-4.7]; two-tailed p=0.012). In addition, TMZ significantly lowered liver enzymes (ALT, AST) at 6days ([29.0+/ 11.6] vs. [42.4+/-24.5]; [39.8+/-17.3] vs. [69.2+/-70.0]; two-tailed p=0.000), lowered glucose after 6days ([6.80+/-2.12] vs. [7.59+/-2.24]; p=0.019), and increased LVEF after ten to fourteen days ([58.4+/-8.6] vs. [54.9+/-8.4]; p=0.008). There were no significant effect on Cr and serum urea (p=0.988, p=0.569, respectively), nor on LA, LVEDD, and CO ([36.3+/-4.5] vs. [37.0+/-4.1], p=0.264; [52.0+/-4.9] vs. [53.1+/-4.6], p=0.128; [5.4+/-0.9] vs. [5.4+/-0.9], p=0.929, respectively). IMPLICATIONS: Among type 2 diabetic patients with AMI undergoing PCI, TMZ significantly reduces serum myocardial enzyme, improves liver function, adjusts blood glucose and improves cardiac function. PMID- 28587954 TI - Increased admission serum cold-inducible RNA-binding protein concentration is associated with prognosis of severe acute pancreatitis. AB - BACKGROUND: Cold-inducible RNA-binding protein (CIRP) is a pro-inflammatory cytokine. This study assessed its relation to disease severity and major adverse events (namely local complications, organ failure and in-hospital mortality) of severe acute pancreatitis (SAP) and its discriminatory ability for SAP. METHODS: This prospective and observational study recruited a total of 102 SAP patients, 48 patients with mild acute pancreatitis and 102 healthy individuals. Serum CIRP concentrations were determined using enzyme-linked immunosorbent assay. RESULTS: Serum CIRP concentrations were significantly higher in patients compared to controls. Serum CIRP concentrations were highly correlated with the circulating concentrations of common inflammatory mediators (i.e., procalcitonin, C-reactive protein and white blood cell) and the traditional predictors of disease severity (namely Acute Physiology and Chronic Health Care Evaluation II score, Ranson score, multiple organ dysfunction score and sequential organ failure assessment score). CIRP in serum was an independent predictor for major adverse events. Serum CIRP concentrations showed high predictive value for major adverse events, and possessed high discriminatory performance for SAP. Moreover, its effects significantly exceeded those of the preceding inflammatory mediators. CONCLUSIONS: Increased serum CIRP concentrations clearly reflect SAP severity and prognosis and significantly distinguish SAP, substantializing CIRP as a potential SAP biomarker. PMID- 28587955 TI - "Daisy-like" crystals: A rare and unknown type of urinary crystal. AB - BACKGROUND: Crystals are well known structures of urinary sediment, most of which are identified by the combined knowledge of crystal morphology, birefringence features at polarized light, and urine pH. In this paper, we report on a cohort of subjects whose urine contained a very rare type of crystal, which we first described in 2004 and which, based on its peculiar morphology, we define as "daisy-like crystal" (DLcr). METHODS: Reports on DLcr were spontaneously sent to our laboratory over a 10.5-year period by different laboratory professionals and by one veterinary clinician who, in their everyday work, had come across DLcr. After the examination of DLcr images submitted, a number of other information were requested and partly obtained. RESULTS: DLcr were found in 9 human beings in 7 different laboratories, located in 4 countries (Italy, Belgium, Croatia, France). DLcr were found mostly in female (8/9), at all ages (3.5 to 93years), mostly in alkaline urine (pH6.0 to 7.5), at variable specific gravity values (1.010 to 1.030), either as isolated particles (2/8) or in association with other crystals (5/8) and/or leucocytes or bacteria (3/8). In addition, DLcr were found in the urine of a 1-year-old dog, examined in a veterinary clinic of Czech Republic. In 3 cases, DLcr were identified by manual microscopy, while in 7 cases by automated urine sediment analyzers. CONCLUSIONS: This paper confirms the possible presence in the urine of DLcr. However, further cases are needed to clarify their frequency, clinical meaning, and composition. PMID- 28587957 TI - Role of physical exercise on cognitive function in healthy older adults: A systematic review of randomized clinical trials. AB - Cognitive impairment has a harmful effect on quality of life, is associated with functional limitations and disability in older adults. Physical activity (PA) has shown to have beneficial effects on cognition but the results and conclusions of randomized controlled trials (RCTs) are less consistent. Update of knowledge was necessary to examine the effects on cognitive function of new training modalities developed in recent years, such as multicomponent exercise training. Therefore, the purpose of this review was to examine the role of multicomponent training versus aerobic or resistance training alone on cognition in healthy older adults (>65 years) without known cognitive impairment. The mean differences (MD) of the parameters from pre-intervention to post-intervention between groups were pooled using a random-effects model. Twenty-one RCTs published between 2002 and 2016 were included. Multicomponent exercise training may have the most positive effects on cognitive function in older adults. The small number of included studies and the large variability in study populations, study design, exercise protocols, adherence rates and outcome measures complicate the interpretation of the results and contribute to discrepancies within the exercise research literature. PMID- 28587956 TI - Activated Natural Killer Cells Mediate the Suppressive Effect of Interleukin-4 on Tumor Development via STAT6 Activation in an Atopic Condition Melanoma Model. AB - A protective effect of allergy for cancer has been suggested, but the results are somewhat conflicting, and the mechanism remains elusive. Interleukin-4 (IL-4) signaling has been identified as a potentially important pathway in the development of allergies and the suppression of cancer development. To evaluate the allergy responses in IL-4-mediated tumor development, we compared the growth of B16F10 melanoma cells in 4% phthalic anhydride (PA)-treated IL-4/Luc/CNS-1 transgenic mice (IL-4 mice) and acetone-olive oil (AOO)-treated IL-4 mice as a control for 3 weeks. Much higher allergic responses and natural killer (NK) and STAT6 activation were found in PA-treated IL-4 mice compared with AOO-treated IL 4 control mice. Tumor volume and weight showed an inverse association with the higher allergic response and were significantly reduced in the PA-treated IL-4 mice when compared with those of AOO-treated IL-4 control mice. Significantly higher activation of STAT6, as well as IL-4 and NK cell activation, was found in the tumor tissues of PA-treated IL-4 mice. Infiltration of immune cells and cytokine levels were also higher in the tumor tissues of PA-treated IL-4 mice. We further found that IL-4-activated NK-92MI cells showed increased anticancer effects in human melanoma cells. Overall, these results showed that allergy responses further accelerated the IL-4-induced inhibition of tumor development through the activation of STAT6 pathways. PMID- 28587958 TI - Calcium and TNFalpha additively affect the chondroitinase ABC I activity. AB - Experimental models have repeatedly shown the therapeutic potential of cABC I in spinal cord injury (SCI) by degrading chondroitin sulfate proteoglycans that hinder neurite outgrowth. Following SCI, some molecules are released from injured cells. This study is designed to determine the effects of some of these molecules at the SCI loci on activity, stability and structure of wild type and Q140A variant of cABC I. The effect of Ca2+, ATP, adenosine, Asp, Glu, Gln, TNFalpha, and a combination of them in physiologic and pathologic concentrations was assessed. The results showed that Ca2+ and TNFalpha have increasing and additive effects on the enzymes activity. Meanwhile, the other molecules had neither considerable effect on the activity nor on thermal stability of the enzymes, significantly. Structural analyses of wild type and mutant cABC I in the presence and absence of Ca2+ were also carried out using fluorescence and far-UV circular dichroism techniques. Although, the secondary and tertiary structure of enzymes showed no significant alterations in the presence of Ca2+, but fluorescence quenching data indicated that calcium increases flexibility of the wild type enzyme, slightly. Therefore, it can be concluded that this ion affect enzyme activity without remarkable conformational changes. PMID- 28587959 TI - Cellulose nanocrystals from Actinidia deliciosa pruning residues combined with carvacrol in PVA_CH films with antioxidant/antimicrobial properties for packaging applications. AB - Kiwi Actinidia deliciosa pruning residues were here used for the first time as precursors for the extraction of high performing cellulose nanocrystals (CNC) by applying a bleaching treatment followed by an acidic hydrolysis. The resultant cellulosic nanostructures, obtained by an optimize extraction procedure (0.7% wt/v two times of sodium chlorite NaClO2) followed by an hydrolysis step, were then used as reinforcements phases in poly(vinyl alcohol) (PVA) blended with natural chitosan (CH) based films and also combined, for the first time, with carvacrol used here as active agent. Morphological and optical characteristics, mechanical response, thermal and migration properties, moisture content and antioxidant and antimicrobial assays were conducted. The morphological, optical and colorimetric results underlined that no particular alterations were induced on the transparency and color of PVA and PVA_CH blend by the presence of CNC and carvacrol, while they were able to modulate the mechanical responses, to induce antioxidant activities maintaining the migration levels below the permitted limits and suggesting the possible application in industrial sectors. Finally, inhibitions on bacterial development were detected for multifunctional systems, suggesting their protective function against microorganisms contamination. PMID- 28587960 TI - Mathematical modeling of gallic acid release from chitosan films with grape seed extract and carvacrol. AB - Controlled release of antimicrobial and antioxidant compounds from packaging films is of utmost importance for extending the shelf-life of perishable foods. This study focused on the mathematical modeling of gallic acid release into an aqueous medium from three chitosan films, formulated with grape seed extract (GSE) and carvacrol. We quantified the release by HPLC technique during 30days at three temperatures (5, 25 and 45 degrees C). The diffusion coefficients, varying with temperature according to an Arrhenius-type relationship, and the respective activation energies for Film-1 and Film-2 were, respectively [Formula: see text] m2s-1 and [Formula: see text] m2s-1, Ea1=58kJmol-1 and Ea2=60kJmol-1 as obtained from the Fickian fit. The low concentrations of gallic acid released by Film-3 could not be detected by HPLC, therefore the respective diffusion coefficient was not estimated. This study will help with the development and optimization of active packaging (AP) films aiming at improved food preservation and shelf-life extension. PMID- 28587961 TI - Expression and comparative characterization of complete and C-terminally truncated forms of saccharifying alpha-amylase from Lactobacillus plantarum S21. AB - Lactobacillus plantarum S21 alpha-amylase possesses 475 amino acids at the C terminal region identified as the starch-binding domain (SBD) and has been previously reported to play a role in raw starch degradation. To understand the specific roles of this SBD, cloning and expression of the complete (AmyL9) and C terminally truncated (AmyL9DeltaSBD) forms of alpha-amylase were conducted for enzyme purification and comparative characterization. AmyL9 and AmyL9DeltaSBD were overproduced in Escherichia coli at approximately 10- and 20-times increased values of volumetric productivity when compared to alpha-amylase produced by the wild type, respectively. AmyL9DeltaSBD was unable to hydrolyze raw starch and exhibited substrate specificity in a similar manner to that of AmyL9, but it was weakly active toward amylopectin and glycogen. The hydrolysis products obtained from the amylaceous substrates of both enzymes were the same. In addition, AmyL9DeltaSBD showed comparatively higher Km values than AmyL9 when it reacted with starch and amylopectin, and lower values for other kinetic constants namely vmax, kcat, and kcat/Km. The results indicated that the C-terminal SBDs of L. plantarum S21 alpha-amylase contribute to not only substrate preference but also substrate affinity and the catalytic efficiency of the alpha-amylase without any changes in the degradation mechanisms of the enzyme. PMID- 28587962 TI - An overview on cellulose-based material in tailoring bio-hybrid nanostructured photocatalysts for water treatment and renewable energy applications. AB - A combination between the nanostructured photocatalyst and cellulose-based materials promotes a new functionality of cellulose towards the development of new bio-hybrid materials for various applications especially in water treatment and renewable energy. The excellent compatibility and association between nanostructured photocatalyst and cellulose-based materials was induced by bio combability and high hydrophilicity of the cellulose components. The electron rich hydroxyl group of celluloses helps to promote superior interaction with photocatalyst. The formation of bio-hybrid nanostructured are attaining huge interest nowadays due to the synergistic properties of individual cellulose-based material and photocatalyst nanoparticles. Therefore, in this review we introduce some cellulose-based material and discusses its compatibility with nanostructured photocatalyst in terms of physical and chemical properties. In addition, we gather information and evidence on the fabrication techniques of cellulose-based hybrid nanostructured photocatalyst and its recent application in the field of water treatment and renewable energy. PMID- 28587963 TI - A polysaccharide of Dendrobium officinale ameliorates H2O2-induced apoptosis in H9c2 cardiomyocytes via PI3K/AKT and MAPK pathways. AB - Dendrobium officinale is one valuable traditional Chinese medicine, which has skyscraping medicinal value. Polysaccharide is the main active ingredient in D. officinale; its antioxidant activity is a hot research topic nowadays. Oxidative stress plays an important role in the pathological progress of a variety of cardiovascular disease, as one of key factors of cardiomyocyte apoptosis. This research adopts a model of H2O2 induction-H9c2 cardiomyocytes apoptosis, aiming to study the effect of Dendrobium officinale Polysaccharide (DOP-GY) for cardiomyocyte apoptosis caused by oxidative stress and its possible mechanism. Our results showed that pretreatment of DOP-GY (low dose: 6.25MUg/mL, medium dose: 12.5MUg/mL, high dose: 25MUg/mL) followed by a 2h incubation with 200MUM H2O2 elevated the survival rate, cutted the LDH leakage, reduced lipid peroxidation damage, improved the activity of the endogenous antioxidant enzymes. In addition, the pretreatment of DOP-GY significantly inhibited the production of ROS, declined of the mitochondrial membrane potential, down-regulated pro apoptosis protein and up-regulated anti-apoptosis protein. The protective effect was correlated with the PI3K/Akt and MAPK signal pathway. Collectively, these observations suggest that DOY-GY has the potential to exert cardioprotective effects against H2O2-induced H9c2 cardiomyocyte apoptosis. PMID- 28587964 TI - Nicotinic acetylcholine receptor alpha 1(nAChRalpha1) subunit peptides as potential antiviral agents against rabies virus. AB - Rabies virus (RABV) is neurotropic and infects all warm-blooded animals. The binding of the virus with host cell receptor components is critical for infection. The present study reports the interaction of nicotinic acetylcholine receptor alpha 1 (nAChRalpha1) peptides with the rabies virus glycoprotein (RABVG) to design potential anti-rabies agents. The nAChRalpha1peptide sequences from different species (bovine, human and electric fish/torpedo) were synthesized and their secondary structures were characterized using CD spectroscopy. The molecular docking analysis of nAChRalpha1 peptides with RABVG indicated the involvement of specific domains and their particular amino acid contributions. Bovine peptide (C-32) (docking score of 14146kJ/mol) and torpedo peptide (T-32) (docking score of 13704kJ/mol) were found to interact strongly with RABVG. T-32 peptides had the highest binding and inhibiting property against RABV compared to other peptide sequences. The results of both computational and experimental methods demonstrated that nAChRalpha1 peptides and their analogs may serve as potential antiviral agents against RABV infection. PMID- 28587965 TI - Preparation and characterization of dialdehyde starch by one-step acid hydrolysis and oxidation. AB - Dialdehyde starch was prepared by one-step synthesis of acid hydrolysis and oxidation, using corn starch as the raw material, sodium periodate (NaIO4) as the oxidant, and hydrochloric acid (HCl) as the acid solution. The prepared dialdehyde starch was characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and gel permeation chromatography (GPC). The results confirmed that oxidation occurred between the starch and NaIO4. The acid hydrolysis reaction reduced the molecular weight of starch and effectively improved the aldehyde group contents (92.7%). Scanning electron microscope (SEM) analysis indicated that the average particle size decreased after acid hydrolysis and oxidation reaction. X-ray diffraction (XRD) and thermal gravimetric analyzer (TGA) analysis demonstrated that the crystallinity of the obtained dialdehyde starch showed a downward trend and a decelerated thermal decomposition rate. The starch after acid hydrolysis and oxidation exhibited lower hot paste viscosity and higher reactivity. PMID- 28587966 TI - Bio-composites based on polylactic acid and argan nut shell: Production and properties. AB - The aim of this work is to develop a new bio-composite based on polylactic acid (PLA) reinforced with argan nut shells (ANS). In this study, the effect of ANS chemical surface treatments on the morphological, mechanical, thermal, and rheological properties of PLA was investigated. In particular, a comparison between three chemical treatments (alkali, bleaching, and silane) is made for two filler concentrations (8 and 15% wt.). Scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, dynamic mechanical analysis, and tensile measurements were used to determine the morphology (particle distribution/dispersion/adhesion), thermal stability, mechanical behavior and rheological properties of the bio-composites compared with neat PLA. The results showed that the highest Young's modulus improvement (16%) was obtained with 15% of bleached ANS particles, while the highest tensile strength (1%) and strain at yield (8.5%) improvements were obtained with a silane treatment. These results were associated with good ANS-PLA interfacial adhesion and distribution in the matrix. Nevertheless, lower thermal stability (onset degradation temperature) for all the bio-composites was observed when compared to neat PLA. To complete the characterizations, water absorption and water contact angle were determined indicating better resistance of the bio-composites when ANS surface treatment was applied. PMID- 28587968 TI - Fabrication, characterization and stability of oil in water nano-emulsions produced by apricot gum-pectin complexes. AB - In this study, the effects of apricot gum-apple pectin (AG/pectin) complex as an emulsifier and stabilizer on the sunflower oil in water nano-emulsion parameters including droplet size, zeta-potential, and the creaming index was investigated. The first independent variables were AG concentration in AG/pectin complex. Applying a 21.4 (w/w) ratio of AG/pectin resulted in nano-emulsions with the highest creaming stability, and most stable droplet size and zeta-potential during 10days storage. Then, droplet size, zeta-potential, and stability of this emulsion (21.4 (w/w) ratio) were further investigated under environmental and process stresses including thermal processing, sonication, and pH changes. Emulsions with smaller droplet sizes, higher zeta-potentials, and higher creaming stability were obtained by applying sonication treatment. A 10min ultrasound treatment with the amplitude of 25% was proposed as the optimum conditions for ultra-sonication. Also, emulsions prepared by AG/pectin ratio of 21.4 (w/w) showed best stability at 60 degrees C and pH of 2. PMID- 28587967 TI - Thermal stability of red algal galactans: Effect of molecular structure and counterions. AB - Thermal degradation of kappa-, iota-, lambda-carrageenans, furcellaran, funoran and agarose samples in dry and sol states was investigated. The polysaccharides subjected to heat treatment were characterized by 1H NMR, 13C NMR and FTIR spectroscopy, size exclusion chromatography and static rheometry methods. The microstructure of galactan gels was studied using a cryofixation method in combination with freeze-drying and SEM techniques. Thermal stability at high temperatures decreases in the order of agarose>furcellaran>funoran>kappa carrageenan>lambda-carrageenan>iota-carrageenan for dry preparations. The respective sequence for sol state is iota-carrageenan>lambda-carrageenan>kappa carrageenan>furcellaran>funoran>agarose. The presence of methoxy groups stabilizes algal polysaccharides whereas divalent cations as counterions increase the susceptibility towards thermal degradation. In dry state the thermal treatment leads to significant desulfation of the galactan before the complete depolymerization occurs. Depending on the sulfation degree and the presence of 3,6-anhydrogalactose residues in the galactan, a notable amount of 5 hydroxymethylfurfural (yield 0.7-21.8%) is formed during the decomposition in sol state. PMID- 28587969 TI - Understanding physicochemical properties changes from multi-scale structures of starch/CNT nanocomposite films. AB - From the view of multi-scale structures of hydroxypropyl starch (HPS)/carbon nanotube (CNT) nanocomposite films, the film physicochemical properties were affected by comprehensive factors including molecular interaction, short range molecular conformation, crystalline structure and aggregated structure. The less original HPS hydrogen bonding that was broken, less decreased order of HPS short range molecular conformation, lower film crystallinity and larger size of micro ordered regions contributed to higher tensile strength and Young's modulus of the film with CNT content of 0.5% (g/g, CNT in HPS). The higher film overall crystallinity and larger size of micro-ordered regions of the film with CNT content of 0.05%-0.3% compared with those of control contributed to better film barrier property. The addition of CNT with the content of 0.05%-0.5% broke the original HPS hydrogen bonding and decreased the order of starch short range molecular conformation, which counteracted the positive effect of CNT on the thermal stability of the material, thus thermal degradation temperature of these nanocomposite films did not increase. But the sharp increase of film crystallinity increased film thermal degradation temperature. This study provided a better understanding of film physicochemical properties changes which guides to rational design of starch-based nanocomposite films for packaging and coating application. PMID- 28587970 TI - Bacterial cellulose in biomedical applications: A review. AB - Bacterial cellulose (BC) derived materials represents major advances to the current regenerative and diagnostic medicine. BC is a highly pure, biocompatible and versatile material that can be utilized in several applications - individually or in the combination with different components (e.g. biopolymers and nanoparticles) - to provide structural organization and flexible matrixes to distinct finalities. The wide application and importance of BC is described by its common utilization as skin repair treatments in cases of burns, wounds and ulcers. BC membranes accelerate the process of epithelialization and avoid infections. Furthermore, BC biocomposites exhibit the potential to regulate cell adhesion, an important characteristic to scaffolds and grafts; ultra-thin films of BC might be also utilized in the development of diagnostic sensors for its capability in immobilizing several antigens. Therefore, the growing interest in BC derived materials establishes it as a great promise to enhance the quality and functionalities of the current generation of biomedical materials. PMID- 28587971 TI - A case of clear cell sarcoma-A rare malignancy. AB - INTRODUCTION: Clear cell sarcoma (CCS) is a rare tumour of the soft tissue often misdiagnosed, as it shares characteristics with malignant melanoma (MM). Previously, CCS has been characterised, as malignant melanoma of the soft tissue, contemporary immunohistochemical techniques, however, have made this designation obsolete. The true incidence remains unknown, but CCS is believed to represent less than one percent of all sarcomas. PRESENTATION OF CASE: A 22-year-old patient presented with a mass sized 2.6*2.7*2.7cm of the left gluteal region, pain, and malaise. Initially, the symptoms were interpreted as an infection. Subsequent, pathological diagnosis after surgical removal was tentatively MM albeit definitive pathological diagnosis was CCS. DISCUSSION: The patient of this case underwent definitive surgical treatment with 2cm margin. In spite of time delay, because of prolonged time for definitive diagnosis, PET-CT and sentinel lymph node biopsy did not show any metastasis. One-year postoperatively, multidisciplinary follow-up is without suspicion of relapse. CONCLUSION: Accurate and timely diagnosis of CCS are imperative, as initial misdiagnosis, may cause delay and further tumour growth, which is correlated to the prognosis. PMID- 28587972 TI - Salvage photodynamic therapy accompanied by extended lymphadenectomy for advanced esophageal carcinoma: A case report. AB - INTRODUCTION: Salvage surgery for locoregional failures after definitive chemoradiotherapy (dCRT) for esophageal cancer is widely practiced, but treatment options complementing it are also needed due to the high morbidity and mortality and low rate of curative resection. PRESENTATION OF CASE: A 58-year-old man with a surgical history of right upper lobectomy for lung cancer was diagnosed as having esophageal squamous cell carcinoma. Computed tomography revealed swelling of the lesser curvature lymph node, and it had invaded the stomach, the body and tail of the pancreas and the left gastric artery, splenic artery and celiac artery. The patient underwent definitive-dose radiation with chemotherapy. Complete response was attained for the primary tumor, but the metastatic lymph node infiltrating the stomach, pancreas and major vessels remained. Therefore, the Appleby operation was proposed to the patient and subsequently performed aiming at curability. However, the primary tumor recurred 38 months after surgery, so the novel modality of photodynamic therapy using talaporfin sodium and a diode laser was performed, and a complete response was attained for this lesion. The patient is alive at 50 months after the salvage Appleby operation. DISCUSSION AND CONCLUSION: Salvage lymphadenectomy for esophageal cancer may be insufficient as a curative treatment because of regrowth of the primary lesion. However, photodynamic therapy may be applicable as a curative treatment option for recurrence of the primary lesion after salvage lymphadenectomy. PMID- 28587973 TI - Role of centrally active cardiovascular agents in cognitive disorders. AB - Cardiovascular drugs are used to treat patients with cardiac function and hemodynamic problems. Because of the relationship between the cardiovascular (CVS), and central nervous (CNS) systems, alteration of CVS activity can potentially alter CNS function. Of particular concern is regulation of lipids, because of the link between neural functionality, lipids, and cognitive disorders, and perfusion, because of the link between hypo-perfusion and vascular dementia. Positive and negative evidence of the effect of CVS drugs in cognitive disorders is available. Awareness of the need to tailor treatments with CVS drugs to patients with consideration of gender, race, lifestyle, and co-morbidities is increasing. Evidence for the importance of cerebral perfusion in vascular dementia development is strong, supporting the importance of physician vigilance in the treatment of hypertension, particularly in vulnerable populations. Evidence for the role of plasma lipid control in development of Alzheimer disease is not as strong. However, physician vigilance in treating hyperlipidemias is strongly encouraged, particularly in vulnerable populations. PMID- 28587974 TI - A randomized controlled trial of sitafloxacin vs. ertapenem as a switch therapy after treatment for acute pyelonephritis caused by extended-spectrum beta lactamase-producing Escherichia coli: A pilot study. AB - BACKGROUND: The overuse and misuse of carbapenems have contributed to the antibiotic resistance crisis. The role of oral fluoroquinolones as a switch therapy for the treatment of urinary tract infection from Escherichia coli (ESBL EC) is limited. OBJECTIVE: To compare the clinical and bacteriological efficacy of sitafloxacin and ertapenem for non-bacteremic acute pyelonephritis caused by ESBL-EC. METHODS: A prospective randomized controlled trial of patients with acute pyelonephritis caused by ESBL-EC was performed as a pilot study. One of the carbapenems was initially given to the patients. After day 3, patients were randomized to receive either sitafloxacin or ertapenem. RESULTS: Thirty-six patients were enrolled: 19 (52.8%) in the sitafloxacin group and 17 (47.2%) in the ertapenem group. There was no statistically significant difference in baseline characteristics between the two groups except a lower proportion of previous urinary catheter insertion in the sitafloxacin group (15.8% vs. 52.9%, p = 0.018). Signs and symptoms at presentation were similar between the two groups except a higher proportion of patients with chills in the sitafloxacin group (68.4% vs. 29.4%, p = 0.019). At day 10, all but one patient in the ertapenem group had clinical cure. Microbiological eradication was comparable between the sitafloxacin and ertapenem groups (84.2% vs. 75%, p = 0.677). There were no significant adverse effects. CONCLUSIONS: Treatment of non-bacteremic acute pyelonephritis caused by ESBL-EC with carbapenem followed by oral sitafloxacin is effective and well-tolerated. Sitafloxacin may be considered as an alternative choice of switch therapy in this clinical setting. PMID- 28587975 TI - ROS signalling in the biology of cancer. AB - Increased reactive oxygen species (ROS) production has been detected in various cancers and has been shown to have several roles, for example, they can activate pro-tumourigenic signalling, enhance cell survival and proliferation, and drive DNA damage and genetic instability. Counterintuitively ROS can also promote anti tumourigenic signalling, initiating oxidative stress-induced tumour cell death. Tumour cells express elevated levels of antioxidant proteins to detoxify elevated ROS levels, establish a redox balance, while maintaining pro-tumourigenic signalling and resistance to apoptosis. Tumour cells have an altered redox balance to that of their normal counterparts and this identifies ROS manipulation as a potential target for cancer therapies. This review discusses the generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer. It also provides an insight into how pro- and anti tumourigenic ROS signalling pathways could be manipulated in the treatment of cancer. PMID- 28587977 TI - Combination of straight and tilted implants for supporting screw-retained dental prostheses in atrophic posterior maxillae: A 2-year prospective study. AB - OBJECTIVES: To evaluate the two-year survival rate (SR) and marginal bone loss (MBL) of fixed dental prostheses (FDPs) supported by straight (S) and tilted (T) implants under the influence of diverse study variables. METHODS: A prospective investigation comprising 21 patients provided with a total of 27 maxillary screw retained restorations fixed to 70 dental implants was developed. Two groups of implants were considered depending on their inclination with respect to the occlusal plane: Group 1 (S, n=37): straight/axial implants and Group 2 (T, n=33): tilted/angled fixations. Each FDP was supported by a combination of S and T implants. SR and MBL were assessed at the time of loading and two years after surgery. Patient-, surgical- and/or rehabilitation-related information was gathered. Data were statistically analysed at the alpha=0.05 significance level. RESULTS: After 24 months, a 100% SR was achieved and the MBL of S and T implants were statistically similar. T implants located in the molar region showed lower MBL than did those replacing premolars (p=0.031). CONCLUSIONS: Upright and angled fixations inserted at posterior maxillary areas resulted in comparable survival rates and peri-implant MBL after two years. The marginal bone resorption around tilted implants depended on their location. CLINICAL SIGNIFICANCE: Screw-retained restorations fixed to straight and tilted implants seem to be a safe treatment option in posterior atrophic maxillae. PMID- 28587976 TI - Mechanosensing of matrix by stem cells: From matrix heterogeneity, contractility, and the nucleus in pore-migration to cardiogenesis and muscle stem cells in vivo. AB - Stem cells are particularly 'plastic' cell types that are induced by various cues to become specialized, tissue-functional lineages by switching on the expression of specific gene programs. Matrix stiffness is among the cues that multiple stem cell types can sense and respond to. This seminar-style review focuses on mechanosensing of matrix elasticity in the differentiation or early maturation of a few illustrative stem cell types, with an intended audience of biologists and physical scientists. Contractile forces applied by a cell's acto-myosin cytoskeleton are often resisted by the extracellular matrix and transduced through adhesions and the cytoskeleton ultimately into the nucleus to modulate gene expression. Complexity is added by matrix heterogeneity, and careful scrutiny of the evident stiffness heterogeneity in some model systems resolves some controversies concerning matrix mechanosensing. Importantly, local stiffness tends to dominate, and 'durotaxis' of stem cells toward stiff matrix reveals a dependence of persistent migration on myosin-II force generation and also rigid microtubules that confer directionality. Stem and progenitor cell migration in 3D can be further affected by matrix porosity as well as stiffness, with nuclear size and rigidity influencing niche retention and fate choices. Cell squeezing through rigid pores can even cause DNA damage and genomic changes that contribute to de-differentiation toward stem cell-like states. Contraction of acto-myosin is the essential function of striated muscle, which also exhibit mechanosensitive differentiation and maturation as illustrated in vivo by beating heart cells and by the regenerative mobilization of skeletal muscle stem cells. PMID- 28587979 TI - Diet and metabolic state are the main factors determining concentrations of perfluoroalkyl substances in female polar bears from Svalbard. AB - Perfluoroalkyl substances (PFASs) have been detected in organisms worldwide, including Polar Regions. The polar bear (Ursus maritimus), the top predator of Arctic marine ecosystems, accumulates high concentrations of PFASs, which may be harmful to their health. The aim of this study was to investigate which factors (habitat quality, season, year, diet, metabolic state [i.e. feeding/fasting], breeding status and age) predict PFAS concentrations in female polar bears captured on Svalbard (Norway). We analysed two perfluoroalkyl sulfonates (PFSAs: PFHxS and PFOS) and C8-C13 perfluoroalkyl carboxylates (PFCAs) in 112 plasma samples obtained in April and September 2012-2013. Nitrogen and carbon stable isotope ratios (delta15N, delta13C) in red blood cells and plasma, and fatty acid profiles in adipose tissue were used as proxies for diet. We determined habitat quality based on movement patterns, capture position and resource selection functions, which are models that predict the probability of use of a resource unit. Plasma urea to creatinine ratios were used as proxies for metabolic state (i.e. feeding or fasting state). Results were obtained from a conditional model averaging of 42 general linear mixed models. Diet was the most important predictor of PFAS concentrations. PFAS concentrations were positively related to trophic level and marine diet input. High PFAS concentrations in females feeding on the eastern part of Svalbard, where the habitat quality was higher than on the western coast, were likely related to diet and possibly to abiotic factors. Concentrations of PFSAs and C8-C10 PFCAs were higher in fasting than in feeding polar bears and PFOS was higher in females with cubs of the year than in solitary females. Our findings suggest that female polar bears that are exposed to the highest levels of PFAS are those 1) feeding on high trophic level sea ice associated prey, 2) fasting and 3) with small cubs. PMID- 28587978 TI - A new arginine-based dental adhesive system: formulation, mechanical and anti caries properties. AB - : Secondary caries at the margins of composite restorations has been attributed to adhesive failure and consequent accumulation of cariogenic biofilms. OBJECTIVES: To develop and evaluate an etch-and-rinse adhesive system containing arginine for sustainable release and recharge without affecting its mechanical properties. Arginine metabolism by oral bacteria generates ammonia, which neutralizes glycolytic acids and creates a neutral environmental pH that is less favorable to the growth of caries pathogens, thus reducing the caries risk at the tooth-composite interface. METHODS: Experimental adhesives were formulated with methacrylate monomers and arginine at 5%, 7%, and 10% or no arginine (control). Adhesives were tested for: (i) mechanical properties of true stress (FS and UTS), modulus of elasticity (E), degree of conversion (DC), Knoop hardness number (KHN) and dentin microtensile bond strength (MU-TBS), (ii) arginine release and recharge, and (iii) antibacterial activities. Data was analyzed by t-test, one way ANOVA and Tukey's tests. RESULTS: FS and UTS results showed no statistically significant differences between the 7% arginine-adhesive and control, while the results for E, DC, KHN and MU-TBS showed no difference among all groups. The 7% arginine-adhesive showed a high release rate of arginine (75.0MUmol/cm2) at 2h, and a more sustainable, controlled release rate (up to 0.2MUmol/cm2) at 30days. CONCLUSIONS: Incorporation of 7% arginine did not affect the physical and mechanical properties of the adhesive. Arginine was released from the adhesive at a rate and concentration that exhibited antibacterial effects, regardless of shifts in biofilm conditions such as sugar availability and pH. CLINICAL SIGNIFICANCE: Secondary caries is recognized as the main reason for failure of dental restorations. The development of an arginine-based adhesive system has the potential to dramatically reduce the incidence and severity of secondary caries in adhesive restorations in a very economical fashion. PMID- 28587980 TI - Classification of Meningiomas Based on Their Surgical Removal, World Health Organization Grade, and Cytogenetic Profile: A Treatment Algorithm. AB - BACKGROUND: Meningiomas are the most common primary intracranial tumor, but the lack of prospective randomized trials has led to different guidelines for their treatment. We proposed a classification of meningiomas that considers surgical removal, histology, and cytogenetic profile, based on a literature review of these 3 criteria. The classification can be used to guide adjuvant treatment and follow-up. METHODS: A retrospective literature review was performed of PubMed from 2007 to 2016. Search terms were "meningioma," "surgery," "WHO classification," "cytogenetic," and "algorithm." RESULTS: Meningiomas were classified into 5 groups (A-E) according to the Simpson resection grade, World Health Organization grade, and cytogenetic profile. Adjuvant therapy, follow-up magnetic resonance imaging, and management of recurrence and/or regrowth were proposed according to the classification. CONCLUSIONS: The proposed meningioma classification was based on our experience and retrospective evidence collated from the literature and supported by recommendations. The application of the classification criteria yielded an algorithm for treatment and follow-up of patients with meningioma. PMID- 28587981 TI - Predatory Publishing and Academic Integrity. PMID- 28587982 TI - The Histological Effects of Ozone Therapy on Sciatic Nerve Crush Injury in Rats. AB - OBJECTIVE: Peripheral nerve injury is a common, important problem that lacks a definitive, effective treatment. It can cause neurologic deficits ranging from paresthesia to paralysis. This study evaluated the effect of ozone therapy on sciatic nerve crush injury in rats. MATERIALS AND METHODS: Twenty-four male rats were divided into control sham surgery, sciatic nerve injury, and sciatic nerve injury with ozone groups (each n = 8). The sciatic nerve injury was inflicted via De Koning's crush-force method. The sciatic nerve injury group received medical air and the sciatic nerve injury ozone group received 0.7 mg/kg ozone. Sciatic nerve samples were obtained 4 weeks after injury. Vascular congestion, vacuolization, edema formation, S100 expression, and the thicknesses of the perineurium and endoneurium and diameter of the injured sciatic nerves were evaluated. RESULTS: The diameter of the sciatic nerve and thicknesses of the perineurium and epineurium were significantly greater in the sciatic nerve injury group (P < 0.05) and significantly less in the sciatic nerve injury with ozone group (P < 0.001). High S100 immunoreactivity was seen in the sciatic nerve injury group compared with the other 2 groups (P < 0.05). The distributions of vascular congestion and vacuolization were significantly less in the sciatic nerve injury with ozone group (P < 0.05). CONCLUSIONS: Ozone therapy improved sciatic nerve injury recovery without causing an increase in fibrotic tissue. Ozone reduced fibrosis, vascular congestion, vacuolization, and edema in rodents. Ozone treatment might be used to assist in sciatic nerve injury. PMID- 28587983 TI - Ophiopogonin D and EETs ameliorate Ang II-induced inflammatory responses via activating PPARalpha in HUVECs. AB - CYP2J2 is highly expressed in cardiovascular tissue including the heart and vascular endothelial cells. CYP2J2 and the EETs have been shown owning diverse biological effects. Our previous study found that ophiopogonin D (OP-D) suppressed drug-induced endoplasmic reticulum (ER) stress by upregulating the levels of CYP2J3/EETs in cardiomyocytes. The aim of this research was to investigate whether CYP2J2/EETs-PPARalpha pathway involved in endothelium protective effects of OP-D in human umbilical vein endothelial cells (HUVECs). The results showed that OP-D significantly inhibited Ang II induced NF-kappaB nuclear translocation, IkappaBalpha down-regulation and activation of pro inflammatory cytokines (TNF-alpha, IL-6 and VCAM-1) by increasing the expression of CYP2J2/EETs and PPARalpha in HUVECs. Furthermore, treatment with exogenous 11,12-EET attenuated endothelial inflammation induced by Ang II as evidenced by inhibited NF-kappaB nuclear translocation, increased IkappaBalpha expression and decreased inflammation factor level. Finally, the activation of NF-kappaB nuclear translocation induced by Ang II was also markedly suppressed by fenofibrate. Co incubation with 6-(2-proparglyloxyphenyl) hexanoic acid (PPOH) and PPARalpha inhibitor GW6471 before drug treatment abolished the endothelium protective effects of OP-D. Taken together, these data suggest that OP-D has the endothelial protective effect through activation of CYP2J and increasing EETs, and PPARalpha involves in this process. PMID- 28587984 TI - Abcb1a but not Abcg2 played a predominant role in limiting the brain distribution of Huperzine A in mice. AB - Huperzine A has been used for improving symptoms of Alzheimer's disease. Its cholinergic side effect is thought to be an exaggerated pharmacological outcome linked to its high brain or CNS concentrations. Although Huperzine A is brain penetrable, its interaction with efflux transporters (ABCB1 and ABCG2) has not been fully investigated. The aim of the present study was to characterize roles of ABCB1 and ABCG2 in the transmembrane transport of Huperzine A and identify a rate limiting step in its brain distribution. Data obtained from stably transfected MDCK II cells showed that Huperzine A is a substrate of ABCB1 but not ABCG2. ABCB1 inhibitors significantly inhibited ABCB1 mediated efflux of Huperzine A. In Abcb1a-/- mice, the brain to plasma concentration ratio of Huperzine A was significantly increased as compared to the wild type mice, while there were no obvious differences between the wild type and Abcg2-/- mice. Taken together, the present study demonstrated that ABCB1 but not ABCG2 played a predominant role in the efflux of Huperzine A across BBB. The current finding is clinically relevant as changes in ABCB1 activity in the presence of ABCB1 inhibitors or genetic polymorphism may affect efficacy and safety of Huperzine A. PMID- 28587985 TI - Naturally occurring xanthone and benzophenone derivatives exert significant anti proliferative and proapoptotic effects in vitro on synovial fibroblasts and macrophages from rheumatoid arthritis patients. AB - There is a need for novel, safer and cheaper drugs for the therapy of rheumatoid arthritis (RA), better targeted against the cellular processes involved in the disease pathogenesis. Using advanced analysis of microscopic images and flow cytometry, we demonstrate that naturally occurring xanthone and benzophenone derivatives exert strong, dose- and O2 concentration-dependent anti-proliferative and pro-apoptotic effects on RA patients' fibroblast-like synoviocytes (FLS) and macrophages. Suspensions containing fibroblasts, macrophages and other infiltrating cells were obtained from inflamed synovial tissue collected from female RA patients. Cells were grown in the presence of xanthone (mangiferin, isomangiferin, neomangiferin, norathyriol) or benzophenone (iriflophenone 3-C glucoside, maclurin) derivatives for 48h or 7days, at 5% or 21% O2. Proportions of macrophages, FLS and infiltrating T cells undergoing apoptosis (annexin- or annexin and 7-AAD-positive) were determined by flow cytometry. The extent of late apoptosis (DNA degradation) was assessed by fluorescent microscopy and image analysis in cultures where DNA was stained with Hoechst 33342. Majority of tested compounds exert anti-proliferative and pro-apoptotic, O2-dependent effects on T cells, FLS and macrophages. The results indicate that xanthone- and benzophenone rich plant products provide a basis for the development of dietary strategy for rheumatoid arthritis management. PMID- 28587987 TI - Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site. AB - The sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) signaling pathway is a crucial target for numerous human diseases from cancer to cardiovascular diseases. However, available SK1 inhibitors that target the active site suffer from poor potency, selectivity and pharmacokinetic properties. The selectivity issue of the kinases, which share a highly-conserved ATP-pocket, can be overcome by targeting the less-conserved allosteric sites. SK1 is known to function minimally as a dimer; however, the crystal structure of the SK1 dimer has not been determined. In this study, a template-based algorithm implemented in PRISM was used to predict the SK1 dimer structure and then the possible allosteric sites at the dimer interface were determined via SiteMap. These sites were used in a virtual screening campaign that includes an integrated workflow of structure based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential allosteric SK1 inhibitors. Finally, the stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand 7 having a 4,9-dihydro-1H-purine scaffold and ligand 12 having a 2,3,4,9 tetrahydro-1H-beta-carboline scaffold were found to be potential selective inhibitors for SK1. PMID- 28587988 TI - Codon usage bias and its influencing factors for Y-linked genes in human. AB - The non-uniform usage of synonymous codons during translation of a protein is the codon usage bias and is mainly influenced by natural selection and mutation pressure. We have used bioinformatic approaches to analyze codon usage bias of human Y-linked genes. Effective number of codon (ENC) suggested that the overall extent of codon usage bias of genes was low. The relative synonymous codon usage (RSCU) analysis revealed that AGA and CTG codons were over-represented in Y linked genes. Compositional constraint under mutation pressure influenced the codon usage pattern as revealed by the correspondence analysis (COA). Parity plot suggests that both natural selection and mutation pressure might have influenced the codon usage bias of Y-linked genes. PMID- 28587986 TI - Angle-ply biomaterial scaffold for annulus fibrosus repair replicates native tissue mechanical properties, restores spinal kinematics, and supports cell viability. AB - : Annulus fibrosus (AF) damage commonly occurs due to intervertebral disc (IVD) degeneration/herniation. The dynamic mechanical role of the AF is essential for proper IVD function and thus it is imperative that biomaterials developed to repair the AF withstand the mechanical rigors of the native tissue. Furthermore, these biomaterials must resist accelerated degradation within the proteolytic environment of degenerate IVDs while supporting integration with host tissue. We have previously reported a novel approach for developing collagen-based, multi laminate AF repair patches (AFRPs) that mimic the angle-ply architecture and basic tensile properties of the human AF. Herein, we further evaluate AFRPs for their: tensile fatigue and impact burst strength, IVD attachment strength, and contribution to functional spinal unit (FSU) kinematics following IVD repair. Additionally, AFRP resistance to collagenase degradation and cytocompatibility were assessed following chemical crosslinking. In summary, AFRPs demonstrated enhanced durability at high applied stress amplitudes compared to human AF and withstood radially-directed biaxial stresses commonly borne by the native tissue prior to failure/detachment from IVDs. Moreover, FSUs repaired with AFRPs and nucleus pulposus (NP) surrogates had their axial kinematic parameters restored to intact levels. Finally, carbodiimide crosslinked AFRPs resisted accelerated collagenase digestion without detrimentally effecting AFRP tensile properties or cytocompatibility. Taken together, AFRPs demonstrate the mechanical robustness and enzymatic stability required for implantation into the damaged/degenerate IVD while supporting AF cell infiltration and viability. STATEMENT OF SIGNIFICANCE: The quality of life for millions of individuals globally is detrimentally impacted by IVD degeneration and herniation. These pathologies often result in the structural demise of IVD tissue, particularly the annulus fibrosus (AF). Biomaterials developed for AF repair have yet to demonstrate the mechanical strength and durability required for utilization in the spine. Herein, we demonstrate the development of an angle-ply AF repair patch (AFRP) that can resist the application of physiologically relevant stresses without failure and which contributes to the restoration of functional spinal unit axial kinematics following repair. Furthermore, we show that this biomaterial can resist accelerated degradation in a simulated degenerate environment and supports AF cell viability. PMID- 28587989 TI - Hypertension alters the endothelial-dependent biphasic response of bradykinin in isolated Microminipig basilar artery. AB - Angiotensin (Ang) II is known to promote vascular disease and hypertension, partly through its effect on vascular endothelium. Bradykinin (BK) is an endothelium-dependent agonist that induces relaxation followed by contraction of the porcine basilar artery through release of NO and PGF2alpha, respectively. In this study, we evaluated the effect of Ang II-induced hypertension on basilar artery responsiveness to BK in the Microminipig (MMPig). Ang II (200ng/kg/min) or vehicle was infused into MMPigs for 14days using an osmotic mini-pump and blood pressure was monitored regularly. The responsiveness of subsequently isolated basilar arteries was then measured using a micro organ bath system. MMPig basilar artery endothelial cells were cultured and stimulated with Ang II or vehicle for 48h. Mean blood pressure was significantly (P<0.05; n=5) higher in Ang II-infused MMPigs than in vehicle-infused MMPigs. In vitro, BK-induced endothelium-dependent dilation of isolated basilar artery specimens was abolished and BK-induced contraction was significantly increased (Emax: 15.85+/-2.42% and 56.54+/-2.71% of 60mM KCl in control and Ang II group respectively at 10-7M concentration of BK; P<0.01; n=5) in Ang II-infused MMPigs. Ang II stimulation of the endothelial cells significantly decreased (54.15% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited NO and increased (44.27% at 24h; P<0.05; n=three independent experiment performed in triplicate) the amount of BK-elicited PGF2alpha. These results suggest that the decrease of NO and increase of PGF2alpha production from endothelial cells are responsible for cerebrovascular dysfunction in hypertension, possibly causing cerebrovascular contraction and thus increasing the risk of brain infarction. PMID- 28587990 TI - Suppression of the beta-carotene hydroxylase gene increases beta-carotene content and tolerance to abiotic stress in transgenic sweetpotato plants. AB - beta-carotene, a carotenoid that plays a key photo-protective role in plants is converted into zeaxanthin by beta-carotene hydroxylase (CHY-beta). Previous work showed that down-regulation of IbCHY-beta by RNA interference (RNAi) results in higher levels of beta-carotene and total carotenoids, as well as salt stress tolerance, in cultured transgenic sweetpotato cells. In this study, we introduced the RNAi-IbCHY-beta construct into a white-fleshed sweetpotato cultivar (cv. Yulmi) by Agrobacterium-mediated transformation. Among the 13 resultant transgenic sweetpotato plants (referred to as RC plants), three lines were selected for further characterization on the basis of IbCHY-beta transcript levels. The RC plants had orange flesh, total carotenoid and beta-carotene contents in storage roots were 2-fold and 16-fold higher, respectively, than those of non-transgenic (NT) plants. Unlike storage roots, total carotenoid and beta-carotene levels in the leaves of RC plants were slightly increased compared to NT plants. The leaves of RC plants also exhibited tolerance to methyl viologen (MV)-mediated oxidative stress, which was associated with higher 2,2-diphenyl-1- picrylhydrazyl (DPPH) radical-scavenging activity. In addition, RC plants maintained higher levels of chlorophyll and higher photosystem II efficiency than NT plants after 250 mM NaCl stress. Yield of storage roots did not differ significantly between RC and NT plants. These observations suggest that RC plants might be useful as a nutritious and environmental stress-tolerant crop on marginal lands around the world. PMID- 28587991 TI - Controlled water deficit during ripening affects proanthocyanidin synthesis, concentration and composition in Cabernet Sauvignon grape skins. AB - The influence of controlled water deficit on the phenolic composition and gene expression of VvLAR2, VvMYBPA1, VvMYBPA2 and VvMYB4a in Cabernet Sauvignon grape skins throughout ripening was investigated. The assay was carried out on own rooted Vitis vinifera plants cv. Cabernet Sauvignon in a commercial vineyard from veraison until commercial harvest. Three irrigation regimes were used from veraison until harvest with the following treatments: T1: 3.6 mm day-1; T2: 1.8 mm day-1 and T3: 0.3 mm day-1. The content of total phenols and total anthocyanins in grape skins increased during ripening, but water deficit did not produce differences among treatments in the total anthocyanin concentration. Proanthocyanidins (PAs) decreased throughout ripening, although approximately 25 days after veraison (DAV), their content slightly increased. This effect was more pronounced in the most restrictive treatment (T3). A similar pattern was observed in the transcript abundance of VvLAR2, VvMYBPA1 and VvMYB4a. PAs separation revealed differences in concentration but not in the proportion among fractions among the irrigation treatments. Additionally, controlled water deficit increased the mean degree of polymerization and the flavan-3-ol polymeric concentration in grape skins throughout ripening but with no effects on the extent of PAs galloylation. Our results suggest that the water status of Cabernet Sauvignon grapevines affects the gene expression for proteins involved in the synthesis of PAs, increasing their concentration and also their composition, with further evidence for the efficacy of a convenient, controlled water deficit strategy for grapevine cultivation. PMID- 28587992 TI - The isolation and functional characterization of three liverwort genes encoding cinnamate 4-hydroxylase. AB - The plant phenylpropanoid pathway is responsible for the synthesis of a wide variety of secondary metabolites. The second step in phenylpropanoid synthesis is carried out by the cytochrome P450 monooxygenase enzyme cinnamate 4-hydroxylase (C4H), which catalyzes the p-hydroxylation of trans-cinnamic acid to p-coumarate. Genes encoding C4H have been characterized in many vascular plant species, but as yet not in any bryophyte species. Here, a survey of the transcriptome sequences of four liverwort species was able to identify eight putative C4Hs. The three liverwort C4H genes taken forward for isolation and functional characterization were harbored by Plagiochasma appendiculatum (PaC4H) and Marchantia paleacea (MpC4H1 and MpC4H2). When the genes were heterologously expressed in yeast culture, an assay of enzyme activity indicated that PaC4H and MpC4H1 had a higher level of activity than MpC4H2. The favored substrate (trans-cinnamic acid) of all three liverwort C4Hs was the same as that of higher plant C4Hs. The co-expression of PaC4H in yeast cells harboring PaPAL (a P. appendiculatum ene encoding phenylalanine ammonia lyase) allowed the conversion of L-phenylalanine to p coumaric acid. Furthermore, the expression level of PaC4H was enhanced after treatment with abiotic stress inducers UV irradiation or salicylic acid in the thallus of P. appendiculatum. The likelihood is that high activity C4Hs evolved in the liverworts and have remained highly conserved across the plant kingdom. PMID- 28587994 TI - Functional analyses of NDPK2 in Populus trichocarpa and overexpression of PtNDPK2 enhances growth and tolerance to abiotic stresses in transgenic poplar. AB - Nucleoside diphosphate kinases (NDPKs) are multifunctional proteins that regulate a variety of eukaryotic cellular activities, including cell proliferation, development, and differentiation. NDPK2 regulates the expression of antioxidant genes in plants. In a previous study, the Arabidopsis thaliana NDPK2 gene (AtNDPK2) was found to be associated with H2O2-mediated mitogen-activated protein kinase signaling in Arabidopsis thaliana. Proteins from transgenic plants overexpressing AtNDPK2 showed higher levels of autophosphorylation and NDPK activity and lower levels of reactive oxygen species (ROS) than those of wild type (WT) plants. Therefore, constitutive overexpression of AtNDPK2 in Arabidopsis plants conferred enhanced tolerance to multiple environmental stresses that elicit ROS accumulation in situ. In this study, we cloned the Populus trichocarpa NDPK2 gene and analyzed its molecular structure and function. We generated and evaluated transgenic poplar plants expressing the PtNDPK2 gene under the control of the 35S promoter to achieve enhanced tolerance to various abiotic stresses. Transgenic poplar plants showed enhanced tolerance to salt and drought stress at the whole-plant level. The transgenic poplar plants showed significantly greater tolerance to 200 mM NaCl and drought stresses than WT poplar plants. In addition, the transgenic plants exhibited better growth due to increased expression of auxin-related indole acetic acid genes under normal growth conditions compared with WT plants. Our results suggest that induction of PtNDPK2 overexpression in poplars will be useful for increasing biomass production in the presence of various abiotic stresses. PMID- 28587995 TI - Duffy blood group system: New genotyping method and distribution in a Brazilian extra-Amazonian population. AB - Duffy blood group system is of interest in several fields of science including transfusion medicine, immunology and malariology. Although some methods have been developed for Duffy polymorphism genotyping, not all of them have been sufficiently described and validated, and all present limitations. At the same time, the frequency of Duffy alleles and antigens in some densely populated regions of the world are still missing. In this study we present new tests for genotyping the major alleles of the Duffy blood system and describe Duffy alleles and antigens in blood donors and transfusion-dependent patients in Minas Gerais, Brazil. A simple and reproducible strategy was devised for Duffy genotyping based on real-time PCR that included SNPs rs12075 and rs2814778. No significant differences between the allele frequencies were observed comparing blood donors and patients. Among the blood donors, the phenotype Fy(a-b+) was the most common and the Fy(a-b-) phenotype, associated with populations of African descent, was remarkably less common among subjects who self-identified as black in comparison to other ethnoracial categories. However, the African ancestry estimated by molecular markers was significantly higher in individuals with the allele associated to the Duffy null phenotype. The genotyping method presented may be useful to study Duffy genotypes accurately in different contexts and populations. The results suggest a reduced risk of alloimmunization for Duffy antigens and increased susceptibility for malaria in Minas Gerais, considering the high frequency of Duffy-positive individuals. PMID- 28587996 TI - Women's health in Africa: a major issue in the new sustainable development goals. PMID- 28587993 TI - Superoxide-responsive gene expression in Arabidopsis thaliana and Zea mays. AB - Superoxide (O2-) and other reactive oxygen species (ROS) are generated in response to numerous biotic and abiotic stresses. Different ROS have been reported to elicit different transcriptional responses in plants, and so ROS responsive marker genes and promoter::reporter gene fusions have been proposed as indirect means of detecting ROS and discriminating among different species. However, further information about the specificity of transcriptional responses to O2- is needed in order to assess potential markers for this critical stress responsive signaling molecule. Using qRT-PCR, the expression of 12 genes previously reported to be upregulated by O2- was measured in Arabidopsis thaliana plants exposed to elicitors of common stress-responsive ROS: methyl viologen (an inducer of O2-), rose bengal (an inducer of singlet oxygen, 1DeltaO2), and exogenous hydrogen peroxide (H2O2). Surprisingly, Zinc-Finger Protein 12 (AtZAT12), which had previously been used as a reporter for H2O2, responded more strongly to O2- than to H2O2; moreover, the expression of an AtZAT12 promoter reporter fusion (AtZAT12::Luc) was enhanced by diethyldithiocarbamate, which inhibits dismutation of O2- to H2O2. These results suggest that AtZAT12 is transcriptionally upregulated in response to O2-, and that AtZAT12::Luc may be a useful biosensor for detecting O2- generation in vivo. In addition, transcripts encoding uncoupling proteins (AtUCPs) showed selectivity for O2- in Arabidopsis, and an AtUCP homolog upregulated by methyl viologen was also identified in maize (Zea mays L.), indicating that there are O2--responsive members of this family in monocots. These results expand our limited knowledge of ROS-responsive gene expression in monocots, as well as O2--selective responses in dicots. PMID- 28587998 TI - WITHDRAWN: Clinical and genetic analysis of two Chinese families with vitamin D dependent rickets type IA and follow-up. AB - Ahead of Print article withdrawn by publisher. PMID- 28587997 TI - Long-term follow-up of two siblings with adult-onset neuronal ceroid lipofuscinosis, Kufs type A. AB - Reports on the clinical presentation of adult-onset neuronal ceroid lipofuscinoses (NCL) are scarce compared to infantile- and childhood-onset forms. Here, we aimed to present detailed temporal evolution of clinical and electrophysiological features of two siblings with adult-onset NCL and homozygous mutation in the CLN6 gene. We retrospectively analysed medical records and electrophysiological data in order to delineate evolution of clinical and electrophysiological findings. Electrophysiological studies included routine EEG and video-EEG, as well as polymyographic analysis of myoclonus and brainstem reflex studies. Both patients had seizures and cerebellar signs. Despite the slow progression of ataxia, they developed no mental deterioration, but had severe obsessive compulsive disorder and depression. EEG revealed frequent generalized spikes, polyspikes, and waves, prominent on awakening and during photic stimulation without significant change throughout the clinical course. Abnormalities concerning the blink reflex, auditory startle response, and startle response to somatosensory inputs manifested within four years. The patients underwent transient and mild improvement with valproate, whereas ataxia and seizures were dramatically ameliorated following high-dose piracetam. Patients with adult-onset NCL may present with slowly progressive ataxia, persistent photosensitivity, and seizures without dementia or extrapyramidal findings. Brainstem abnormalities become more evident with time, in line with ataxia. Piracetam is effective for both seizures and ataxia. PMID- 28587999 TI - Liver Transplantation in a Patient with Acquired Dysfibrinogenemia Who Presented with Subdural Hematoma: A Case Report. PMID- 28588000 TI - Effect of Maternal Obesity on Fetal Growth and Expression of Placental Fatty Acid Transporters. AB - OBJECTIVE: To explore the effects of maternal high-fat (HF) diet-induced obesity on fetal growth and the expression of placental nutrient transporters. METHODS: Maternal obesity was established in rats by 8 weeks of pre-pregnancy fed HF diet, while rats in the control group were fed normal (CON) diet. Diet-induced obesity (DIO) rats and diet-induced obesity-resistant (DIR) rats were selected according to body weight gain over this period. After copulation, the CON rats were divided into two groups: switched to HF diet (CON-HF group) or maintained on the CON diet (CON-CON group). The DIO rats and DIR rats were maintained on the HF diet throughout pregnancy. Pregnant rats were euthanized at day 21 gestation, fetal and placental weights were recorded, and placental tissue was collected. Reverse transcription-polymerase chain reaction was used to determine mRNA expression of placental nutrient transporters. Protein expression was determined by Western blot. RESULTS: Average fetal weight of DIO dams was reduced by 6.9%, and the placentas of CON-HF and DIO dams were significantly heavier than the placentas of CON-CON and DIR dams at day 21 of gestation (p<0.05). The fetal/placental weight ratio of DIO dams was significantly reduced compared with the fetal/placental weight ratio of CON-CON dams (p<0.05). The mRNA expression of GLUT-1 and SNAT-2 were not significantly different between groups. The mRNA and protein expression levels of CD36, FATP-1, and FATP-4 in DIO dams were decreased significantly (p<0.05). CONCLUSION: Maternal obesity induced by a HF diet led to intrauterine growth retardation and down-regulated the expression of placental fatty acid transporters. PMID- 28588001 TI - Successful Growth Hormone Therapy in Cornelia de Lange Syndrome. AB - Cornelia de Lange syndrome (CdLS) is a both clinically and genetically heterogeneous syndrome. In its classical form, it is characterised by distinctive facial features, intra-uterine growth retardation, short stature, developmental delay, and anomalies in multiple organ systems. NIPBL, SMC1A, SMC3, RAD21 and HDAC8, all involved in the cohesin pathway, have been identified to cause CdLS. Growth hormone (GH) secretion has been reported as normal, and to our knowledge, there are no reports on the effect of recombinant human GH treatment in CdLS patients. We present a patient born small for gestational age with persistent severe growth retardation [height -3.4 standard deviation score (SDS)] and mild dysmorphic features, who was treated with GH from 4.3 years of age onward and was diagnosed 6 years later with CdLS using whole-exome sequencing. Treatment led to a height gain of 1.6 SDS over 8 years. Treatment was interrupted shortly due to high serum insulin-like growth factor-1 serum values. In conclusion, GH therapy may be effective and safe for short children with CdLS. PMID- 28588002 TI - Myelodysplastic Syndrome in Pakistan: Clinicohematological Characteristics, Cytogenetic Profile, and Risk Stratification. AB - OBJECTIVE: Myelodysplastic syndrome (MDS) is a group of bone marrow diseases that not only have variable morphological presentation and heterogeneous clinical courses but also have a wide range of cytogenetic abnormalities. Clinicohematological parameters have a significant role in diagnosis and along with identification of cytogenetic abnormalities are important for prognostic scoring and risk stratification of patients to plan management and make treatment decisions. This study aimed to determine the clinicohematological characteristics, cytogenetic abnormalities, and risk stratification of newly diagnosed de novo MDS patients. MATERIALS AND METHODS: This cross-sectional study was conducted in the Department of Hematology, Armed Forces Institute of Pathology, Rawalpindi, from January 2013 to January 2017. Patients were diagnosed on the basis of World Health Organization criteria for MDS, clinicohematological parameters were noted, and cytogenetic analysis was performed. Risk stratification was done using the Revised International Prognostic Scoring System. RESULTS: A total of 178 cases of MDS were analyzed, including 119 males (66.9%) and 59 females (33.1%). The median age was 58 years. The most common presenting feature was anemia in 162 (91%) of the patients. MDS with multilineage dysplasia was the most common diagnosis, seen in 103 (57.9%) patients. A normal karyotype was seen in 95 (53.4%), while 83 (46.6%) showed clonal karyotypic abnormalities at diagnosis. Of these, the common abnormalities found were trisomy 8, complex karyotype, and del 5q. Risk stratification revealed low-risk disease in 73 (41%) patients. CONCLUSION: Cytogenetic analysis showed the normal karyotype to be the most common while risk stratification revealed a predominance of low-risk disease at the time of presentation. PMID- 28588003 TI - Pituitary Adenoma Apoplexy in an Adolescent: A Case Report and Review of the Literature. AB - We present a 13-year-old boy who was admitted with complaints of a state of progressive sleepiness and a sudden headache with vomiting and fever. Laboratory testing showed hypoglycemia, multiple pituitary hormonal deficiencies, and an elevated C-reactive protein level. A cranial magnetic resonance imaging (MRI) showed an opaque sphenoid sinus and an intrasellar mass suggesting hemorrhage, so that we suspected pituitary apoplexy (PA) originating from a non-functioning adenoma, although a pituitary abscess could not completely be excluded. The boy was treated with antibiotics, hydrocortisone, and levothyroxine. Due to his rapid clinical improvement, no surgery was performed and we considered the diagnosis of PA as confirmed. At follow-up, the MRI scan showed a small residual lesion. Pituitary deficiencies of growth hormone, adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone, and vasopressin persisted. A literature search of all well-documented cases of PA in children or adolescents (n=30, 13 boys and 17 girls) indicated that this condition is rare below 20 years of age but must be considered when a patient experiences headache with or without visual disturbances, even in the presence of clinical and laboratory signals suggestive of pituitary abscess. MRI neuroimaging is helpful in the differential diagnosis. In both conditions, the possibility of ACTH deficiency should always be considered, investigated, and treated. In cases without severe neuro ophthalmological deficits and/or with a rapid and positive response to acute medical management, one can abstain from surgical treatment. PMID- 28588004 TI - Long-Term Follow-up of a Case with Proprotein Convertase 1/3 Deficiency: Transient Diabetes Mellitus with Intervening Diabetic Ketoacidosis During Growth Hormone Therapy. AB - Proprotein convertase 1/3 (PC1/3) deficiency is a very rare disease characterized by severe intractable diarrhea in the first years of life, followed by obesity and several hormonal deficiencies later. Diabetes mellitus requiring insulin treatment and diabetic ketoacidosis have not been reported in this disorder. We herein present a girl with PC1/3 deficiency who has been followed from birth to 17 years of age. She developed deficiencies of all pituitary hormones over time as well as diabetes mellitus while receiving growth hormone (GH) therapy. She was complicated with diabetic ketoacidosis during dietary management of diabetes mellitus, thus insulin treatment was initiated. Insulin requirement to regulate hyperglycemia was short-lived. Repeat oral glucose tolerance test five years later was normal. The findings of this patient show that diabetes mellitus can develop at any time during follow-up of cases with proportein convertase 1/3 deficiency especially under GH therapy. PMID- 28588005 TI - Delivering Cognitive Behavior Therapy to Young Adults With Symptoms of Depression and Anxiety Using a Fully Automated Conversational Agent (Woebot): A Randomized Controlled Trial. AB - BACKGROUND: Web-based cognitive-behavioral therapeutic (CBT) apps have demonstrated efficacy but are characterized by poor adherence. Conversational agents may offer a convenient, engaging way of getting support at any time. OBJECTIVE: The objective of the study was to determine the feasibility, acceptability, and preliminary efficacy of a fully automated conversational agent to deliver a self-help program for college students who self-identify as having symptoms of anxiety and depression. METHODS: In an unblinded trial, 70 individuals age 18-28 years were recruited online from a university community social media site and were randomized to receive either 2 weeks (up to 20 sessions) of self-help content derived from CBT principles in a conversational format with a text-based conversational agent (Woebot) (n=34) or were directed to the National Institute of Mental Health ebook, "Depression in College Students," as an information-only control group (n=36). All participants completed Web-based versions of the 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder scale (GAD-7), and the Positive and Negative Affect Scale at baseline and 2-3 weeks later (T2). RESULTS: Participants were on average 22.2 years old (SD 2.33), 67% female (47/70), mostly non-Hispanic (93%, 54/58), and Caucasian (79%, 46/58). Participants in the Woebot group engaged with the conversational agent an average of 12.14 (SD 2.23) times over the study period. No significant differences existed between the groups at baseline, and 83% (58/70) of participants provided data at T2 (17% attrition). Intent-to-treat univariate analysis of covariance revealed a significant group difference on depression such that those in the Woebot group significantly reduced their symptoms of depression over the study period as measured by the PHQ-9 (F=6.47; P=.01) while those in the information control group did not. In an analysis of completers, participants in both groups significantly reduced anxiety as measured by the GAD-7 (F1,54= 9.24; P=.004). Participants' comments suggest that process factors were more influential on their acceptability of the program than content factors mirroring traditional therapy. CONCLUSIONS: Conversational agents appear to be a feasible, engaging, and effective way to deliver CBT. PMID- 28588008 TI - David Oliver: Unproductive activity and NHS consultants. PMID- 28588006 TI - Attitudes Toward the Ethics of Research Using Social Media: A Systematic Review. AB - BACKGROUND: Although primarily used for social networking and often used for social support and dissemination, data on social media platforms are increasingly being used to facilitate research. However, the ethical challenges in conducting social media research remain of great concern. Although much debated in the literature, it is the views of the public that are most pertinent to inform future practice. OBJECTIVE: The aim of our study was to ascertain attitudes on the ethical considerations of using social media as a data source for research as expressed by social media users and researchers. METHODS: A systematic review was conducted, wherein 16 databases and 2 Internet search engines were searched in addition to handsearching, reference checking, citation searching, and contacting authors and experts. Studies that conducted any qualitative methods to collect data on attitudes on the ethical implications of research using social media were included. Quality assessment was conducted using the quality of reporting tool (QuaRT) and findings analyzed using inductive thematic synthesis. RESULTS: In total, 17 studies met the inclusion criteria. Attitudes varied from overly positive with people expressing the views about the essential nature of such research for the public good, to very concerned with views that social media research should not happen. Underlying reasons for this variation related to issues such as the purpose and quality of the research, the researcher affiliation, and the potential harms. The methods used to conduct the research were also important. Many respondents were positive about social media research while adding caveats such as the need for informed consent or use restricted to public platforms only. CONCLUSIONS: Many conflicting issues contribute to the complexity of good ethical practice in social media research. However, this should not deter researchers from conducting social media research. Each Internet research project requires an individual assessment of its own ethical issues. Guidelines on ethical conduct should be based on current evidence and standardized to avoid discrepancies between, and duplication across, different institutions, taking into consideration different jurisdictions. PMID- 28588007 TI - A Medical Student-Delivered Smoking Prevention Program, Education Against Tobacco, for Secondary Schools in Germany: Randomized Controlled Trial. AB - BACKGROUND: More than 8.5 million Germans suffer from chronic diseases attributable to smoking. Education Against Tobacco (EAT) is a multinational network of medical students who volunteer for school-based prevention in the classroom setting, amongst other activities. EAT has been implemented in 28 medical schools in Germany and is present in 13 additional countries around the globe. A recent quasi-experimental study showed significant short-term smoking cessation effects on 11-to-15-year-old adolescents. OBJECTIVE: The aim of this study was to provide the first randomized long-term evaluation of the optimized 2014 EAT curriculum involving a photoaging software for its effectiveness in reducing the smoking prevalence among 11-to-15-year-old pupils in German secondary schools. METHODS: A randomized controlled trial was undertaken with 1504 adolescents from 9 German secondary schools, aged 11-15 years in grades 6-8, of which 718 (47.74%) were identifiable for the prospective sample at the 12 month follow-up. The experimental study design included measurements at baseline (t1), 6 months (t2), and 12 months postintervention (t3), via questionnaire. The study groups consisted of 40 randomized classes that received the standardized EAT intervention (two medical student-led interactive modules taking 120 minutes total) and 34 control classes within the same schools (no intervention). The primary endpoint was the difference in smoking prevalence from t1 to t3 in the control group versus the difference from t1 to t3 in the intervention group. The differences in smoking behavior (smoking onset, quitting) between the two groups, as well as gender-specific effects, were studied as secondary outcomes. RESULTS: None of the effects were significant due to a high loss-to-follow-up effect (52.26%, 786/1504). From baseline to the two follow-up time points, the prevalence of smoking increased from 3.1% to 5.2% to 7.2% in the control group and from 3.0% to 5.4% to 5.8% in the intervention group (number needed to treat [NNT]=68). Notable differences were observed between the groups for the female gender (4.2% to 9.5% for control vs 4.0% to 5.2% for intervention; NNT=24 for females vs NNT=207 for males), low educational background (7.3% to 12% for control vs 6.1% to 8.7% for intervention; NNT=30), and migrational background (students who claimed that at least one parent was not born in Germany) at the 12 month follow-up. The intervention appears to prevent smoking onset (NNT=63) but does not appear to initiate quitting. CONCLUSIONS: The intervention appears to prevent smoking, especially in females and students with a low educational background. PMID- 28588010 TI - Micronuclei Frequency in Tumors Is a Predictive Biomarker for Genetic Instability and Sensitivity to the DNA Repair Inhibitor AsiDNA. AB - Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. Cancer Res; 77(16); 4207-16. (c)2017 AACR. PMID- 28588011 TI - Relationship between rate of fentanyl infusion and time to achieve sedation in nonobese and obese critically ill children. AB - PURPOSE: The relationship between initial fentanyl infusion dosage and time to goal sedation in nonobese and obese critically ill children was examined. METHODS: A retrospective cohort study of 75 fentanyl infusions initiated in mechanically ventilated children age 2-17 years with an inpatient admission between January 1, 2012, and May 31, 2014, who subsequently received a fentanyl infusion was conducted. The primary outcomes of the study included the time to goal sedation and fentanyl dosage characteristics (i.e., underdosage, optimal dosage, or overdosage). Sedation scores were assessed by the State Behavioral Scale, a validated instrument to assess sedation in children. Key independent (predictor) variables were collected, including baseline demographics and admission diagnoses. Multivariable regression models were used to examine the association between initial fentanyl infusion dosage and time to goal sedation or dosing characteristics while controlling for obesity status and other modifying or confounding factors. RESULTS: A total of 75 infusions met the study's inclusion criteria, representing 74 patients. The majority of patients (52%) were boys, and the median age was 8.1 years. Eighteen children (24%) were obese. The median time to goal sedation was 10.9 hours. Among nonobese children, every 10 MUg/hr increase in initial fentanyl dosage was associated with a 19% lower probability of achieving goal sedation at any point in time. Initial fentanyl dosage was not associated with time to goal sedation in obese children. CONCLUSION: Fentanyl infusion rates in obese and nonobese children varied widely in the time needed to achieve goal sedation. At any given time, initial fentanyl infusion rates were less likely to result in goal sedation in nonobese than in obese children. PMID- 28588009 TI - Exosome-Derived miR-25-3p and miR-92a-3p Stimulate Liposarcoma Progression. AB - Despite the development of combined modality treatments against liposarcoma in recent years, a significant proportion of patients respond only modestly to such approaches, possibly contributing to local or distant recurrence. Early detection of recurrent or metastatic disease could improve patient prognosis by triggering earlier clinical intervention. However, useful biomarkers for such purposes are lacking. Using both patient plasma samples and cell lines, we demonstrate here that miR-25-3p and miR-92a-3p are secreted by liposarcoma cells through extracellular vesicles and may be useful as potential biomarkers of disease. Both miR-25-3p and miR-92a-3p stimulated secretion of proinflammatory cytokine IL6 from tumor-associated macrophages in a TLR7/8-dependent manner, which in turn promoted liposarcoma cell proliferation, invasion, and metastasis via this interaction with the surrounding microenvironment. Our findings provide novel and previously unreported insight into liposarcoma progression, identifying communication between liposarcoma cells and their microenvironment as a process critically involved in liposarcoma progression. This study establishes the possibility that the pattern of circulating miRNAs may identify recurrence prior to radiological detectability while providing insight into disease outcome and as a possible approach to monitor treatment efficacy. Cancer Res; 77(14); 3846-56. (c)2017 AACR. PMID- 28588012 TI - GP vows to keep up pressure over Brexiteers' use of NHS logo. PMID- 28588013 TI - Building a visual aid for a triage tool in a developing health service. AB - Resources in the modern day emergency department are often stretched, and this holds true more so in developing services. With limited manpower, it is essential that efficient tools are created so that processes can be run safely. Here we pilot the use of a vital signs matrix in a medical camp in Dhaka to screen patients at triage. We further modified this matrix to include the National Early Warning Score as our recording of the NEWS have remained poor in triage. A trial and validation study for the use of this matrix in an NHS setting is currently underway. PMID- 28588014 TI - Different Approaches for Catheter Ablation of Para-Hisian Accessory Pathways: Implications for Mapping and Ablation. AB - BACKGROUND: Catheter ablation of para-Hisian accessory pathways (APs) can be challenging because of adjacent conduction tissue. Some different approaches for ablation, including the inferior vena cava approach (IVC-A), the noncoronary cusp approach (NCC-A), or the superior vena cava approach (SVC-A), have been reported. However, when should para-Hisian APs be mapped and ablated by the IVC-A, NCC-A, or SVC-A is not well established. METHODS AND RESULTS: This study included 55 consecutive patients (mean age, 53+/-11 years, 36 males) with para-Hisian APs. On the basis of the approach resulting in successful ablation, patients were divided into IVC-A, NCC-A, and SVC-A groups. The clinical characteristics, surface ECG, intracardiac electrogram findings, and response to ablation were analyzed. Para Hisian APs were eliminated by IVC-A in 48 of the 55 (87%) patients. The rates of para-Hisian APs requiring NCC-A (4/55 patients, 7%) and SVC-A (3/55 patients, 6%) were relatively low. During mapping at the para-Hisian region, the local ventricular and atrial potentials were well fused during retrograde AP conduction in 45 of the 48 patients in IVC-A group, 0 of the 4 patients in NCC-A group, and 1 of the 3 patients in SVC-A group, respectively. There was no significant difference in the preexcitation characteristics among the 3 groups. CONCLUSION: Most para-Hisian APs can be safely and effectively ablated by IVC-A, and ablation in the NCC is not an initial or a preferred approach. The degree of local ventriculoatrial fusion in the para-Hisian region during retrograde AP conduction can differentiate or predict the successful ablation site. PMID- 28588015 TI - Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer. AB - Intravesical bacillus Calmette-Guerin (BCG) immunotherapy is the standard of care in treating non-muscle-invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. Although prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T-cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the N-methyl-N-nitrosourea (MNU) rat model of bladder cancer was characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. In contrast, treatment with intravesical BCG led to a large, transient rise in the CD4+ T-cell population in the urothelium and was both more effective and immunogenic compared with intravesical chemotherapy. Whole-transcriptome expression profiling of posttreatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that although BCG induces T-cell recruitment to the bladder, the T-cell phenotype does not markedly change, implying that combining T cell-activating agents with BCG might improve clinical activity. Cancer Immunol Res; 5(7); 594-603. (c)2017 AACR. PMID- 28588017 TI - CD27 marks murine embryonic hematopoietic stem cells and type II prehematopoietic stem cells. PMID- 28588016 TI - Commensal microbes provide first line defense against Listeria monocytogenes infection. AB - Listeria monocytogenes is a foodborne pathogen that causes septicemia, meningitis and chorioamnionitis and is associated with high mortality. Immunocompetent humans and animals, however, can tolerate high doses of L. monocytogenes without developing systemic disease. The intestinal microbiota provides colonization resistance against many orally acquired pathogens, and antibiotic-mediated depletion of the microbiota reduces host resistance to infection. Here we show that a diverse microbiota markedly reduces Listeria monocytogenes colonization of the gut lumen and prevents systemic dissemination. Antibiotic administration to mice before low dose oral inoculation increases L. monocytogenes growth in the intestine. In immunodeficient or chemotherapy-treated mice, the intestinal microbiota provides nonredundant defense against lethal, disseminated infection. We have assembled a consortium of commensal bacteria belonging to the Clostridiales order, which exerts in vitro antilisterial activity and confers in vivo resistance upon transfer into germ free mice. Thus, we demonstrate a defensive role of the gut microbiota against Listeria monocytogenes infection and identify intestinal commensal species that, by enhancing resistance against this pathogen, represent potential probiotics. PMID- 28588018 TI - Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of alphabeta T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after alphabeta T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120. PMID- 28588023 TI - What is oncolytic virotherapy? PMID- 28588019 TI - Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. AB - Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including ~12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2 hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies. PMID- 28588021 TI - Accelerometer-Measured Daily Activity in Heart Failure With Preserved Ejection Fraction: Clinical Correlates and Association With Standard Heart Failure Severity Indices. AB - BACKGROUND: Daily physical activity assessed by accelerometers represents a novel method to assess the impact of interventions on heart failure (HF) patients' functional status. We hypothesized that daily activity varies by patient characteristics and correlates with established measures of HF severity in HF with preserved ejection fraction. METHODS AND RESULTS: In this ancillary study of the NEAT-HFpEF trial (Nitrate's Effects on Activity Tolerance in HF With Preserved Ejection Fraction), average daily accelerometer units (ADAU) and hours active per day were assessed during a 14-day period before starting isosorbide mononitrate or placebo (n=110). Baseline ADAU was negatively associated with age, female sex, height, and body mass index, and these variables accounted for 28% of the variability in ADAU (P<0.007 for all). Adjusting for these factors, patients with lower ADAU were more likely to have had an HF hospitalization, orthopnea, diabetes mellitus and anemia, be treated with beta-blockers, have higher ejection fraction, relative wall thickness and left atrial volume, and worse New York Heart Association class, HF-specific quality of life scores, 6-minute walk distance, and NT-proBNP (N-terminal pro-B-type natriuretic peptide; P<0.05 for all). Associations between hours active per day and clinical characteristics were similar. Relative to baseline, there were no significant associations between changes in ADAU or hours active per day and changes in standard functional assessments (New York Heart Association, quality of life, 6-minute walk distance, and NT-proBNP) with isosorbide mononitrate. CONCLUSIONS: Daily activity is a measure of HF-related and global functional status in HF with preserved ejection fraction. As compared with intermittently assessed standard HF assessments, change in daily activity may provide unique information about the impact of HF interventions on functional status. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02053493. PMID- 28588020 TI - Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. AB - Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib related adverse events included indirect hyperbilirubinemia (12%) and IDH inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498. PMID- 28588024 TI - Bromodomain and extraterminal inhibitors block the Epstein-Barr virus lytic cycle at two distinct steps. AB - Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. Proteins in the bromodomain and extraterminal (BET) family regulate multiple stages of viral life cycles and provide promising intervention targets. Synthetic small molecules can bind to the bromodomains and disrupt function by preventing recognition of acetylated lysine substrates. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV lytic cycle. BET inhibitors prevent expression of the viral immediate-early protein BZLF1. JQ1 alters transcription of genes controlled by the host protein BACH1, and BACH1 knockdown reduces BZLF1 expression. BET proteins also localize to the lytic origin of replication (OriLyt) genetic elements, and BET inhibitors prevent viral late gene expression. There JQ1 reduces BRD4 recruitment during reactivation to preclude replication initiation. This represents a rarely observed dual mode of action for drugs. PMID- 28588025 TI - Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity. AB - Na+/K+-ATPase transports Na+ and K+ ions across the cell membrane via an ion binding site becoming alternatively accessible to the intra- and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free-energy perturbation approaches to identify probable protonation states of Na+- and K+-coordinating residues in E1P and E2P conformations of Na+/K+-ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na+ coordinating residue Asp926 This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion-binding stoichiometry and selectivity. PMID- 28588026 TI - Discovery and characterization of family 39 glycoside hydrolases from rumen anaerobic fungi with polyspecific activity on rare arabinosyl substrates. AB - Enzyme activities that improve digestion of recalcitrant plant cell wall polysaccharides may offer solutions for sustainable industries. To this end, anaerobic fungi in the rumen have been identified as a promising source of novel carbohydrate active enzymes (CAZymes) that modify plant cell wall polysaccharides and other complex glycans. Many CAZymes share insufficient sequence identity to characterized proteins from other microbial ecosystems to infer their function; thus presenting challenges to their identification. In this study, four rumen fungal genes (nf2152, nf2215, nf2523, and pr2455) were identified that encode family 39 glycoside hydrolases (GH39s), and have conserved structural features with GH51s. Two recombinant proteins, NF2152 and NF2523, were characterized using a variety of biochemical and structural techniques, and were determined to have distinct catalytic activities. NF2152 releases a single product, beta1,2 arabinobiose (Ara2) from sugar beet arabinan (SBA), and beta1,2-Ara2 and alpha 1,2-galactoarabinose (Gal-Ara) from rye arabinoxylan (RAX). NF2523 exclusively releases alpha-1,2-Gal-Ara from RAX, which represents the first description of a galacto-(alpha-1,2)-arabinosidase. Both beta-1,2-Ara2 and alpha-1,2-Gal-Ara are disaccharides not previously described within SBA and RAX. In this regard, the enzymes studied here may represent valuable new biocatalytic tools for investigating the structures of rare arabinosyl-containing glycans, and potentially for facilitating their modification in industrial applications. PMID- 28588030 TI - Sixty seconds on . . . #crazysocks4docs. PMID- 28588028 TI - The lysine methyltransferase SMYD2 methylates the kinase domain of type II receptor BMPR2 and stimulates bone morphogenetic protein signaling. AB - Lysine methylation of chromosomal and nuclear proteins is a well-known mechanism of epigenetic regulation, but relatively little is known about the role of this protein modification in signal transduction. Using an RNAi-based functional screening of the SMYD family of lysine methyltransferases (KMTs), we identified SMYD2 as a KMT essential for robust bone morphogenic protein (BMP)- but not TGFbeta-induced target gene expression in HaCaT keratinocyte cells. A role for SMYD2 in BMP-induced gene expression was confirmed by shRNA knockdown and CRISPR/Cas9-mediated knock-out of SMYD2 We further demonstrate that SMYD2 knockdown or knock-out impairs BMP-induced phosphorylation of the signal transducing protein SMAD1/5 and SMAD1/5 nuclear localization and interaction with SMAD4. The SMYD2 KMT activity was required to facilitate BMP-mediated signal transduction, as treatment with the SMYD2 inhibitor AZ505 suppressed BMP2-induced SMAD1/5 phosphorylation. Furthermore, we present evidence that SMYD2 likely modulates the BMP response through its function in the cytosol. We show that, although SMYD2 interacted with multiple components in the BMP pathway, it specifically methylated the kinase domain of BMP type II receptor BMPR2. Taken together, our findings suggest that SMYD2 may promote BMP signaling by directly methylating BMPR2, which, in turn, stimulates BMPR2 kinase activity and activation of the BMP pathway. PMID- 28588027 TI - Exogenous neutrophil elastase enters bronchial epithelial cells and suppresses cigarette smoke extract-induced heme oxygenase-1 by cleaving sirtuin 1. AB - An imbalance between oxidative stress and antioxidant activity plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke, a major risk factor of COPD, induces cellular oxidative stress, but levels of antioxidants such as heme oxygenase-1 (HO-1) are reduced in individuals with severe COPD. In this study, we evaluated the molecular mechanism of reduced HO-1 expression in human bronchial epithelial cells. We found that cigarette smoke extract (CSE) increases HO-1 levels via activation of NFE2 related factor 2 (Nrf2). However, pretreating cells with the protease neutrophil elastase (NE) suppressed the CSE-induced expression of HO-1 mRNA and protein. NE also decreased the sirtuin 1 (SIRT1) level, but did not inhibit CSE-induced nuclear translocation and DNA-binding activity of Nrf2. Transfection of cells with a Myc/His-tagged SIRT1 expression vector completely blocked the NE-mediated suppression of HO-1 expression. We further noted that the NE-induced down regulation of SIRT1 was not due to decreased transcription or proteasomal/lysosomal degradation or loss of solubility. Immunofluorescence staining revealed that NE enters the cell cytoplasm, and we observed that NE directly cleaved SIRT1 in vitro, indicating that SIRT1 levels are decreased via direct degradation by internalized NE. Of note, we observed decreased SIRT1 levels in NE-treated primary human bronchial epithelial cells and in lung homogenates from both smokers and patients with COPD. In conclusion, NE suppresses CSE-induced HO-1 expression by cleaving SIRT1. This finding indicates the importance of cross-talk between oxidative stress and protease responses in the pathogenesis of COPD. PMID- 28588029 TI - TGF-beta inhibits IL-7-induced proliferation in memory but not naive human CD4+ T cells. AB - TGF-beta is a potent suppressor of T cell activation and expansion. Although the antiproliferative effects of TGF-beta are well characterized in TCR-activated cells, the effects of TGF-beta on T cell proliferation driven by homeostatic cytokines, such as IL-7, are poorly defined. In the current study, we found that TGF-beta inhibits IL-7-induced proliferation in memory, but not in naive human CD4+ T cells. TGF-beta impaired c-myc induction in all CD4+ T cell maturation subsets, although the impairment was less sustained in naive CD4+ T cells. TGF beta had no discernible effect on IL-7R signaling (p-STAT-5, p-Akt, or p-S6) in memory T cells but selectively enhanced p-S6 signaling in naive T cells. The inhibitory effects of TGF-beta on memory T cell proliferation were partially overcome by chemical inhibition of GSK-3, which also led to enhanced c-myc expression. These data suggest that TGF-beta could play an important role in limiting homeostatic proliferation of memory T cells. Our observations also point toward a novel strategy to subvert TGF-beta-mediated inhibition of memory T cells by targeting GSK-3 for inhibition. PMID- 28588031 TI - Digital innovation is needed to deal with complexity of current medicine. PMID- 28588034 TI - A helping hand. PMID- 28588033 TI - What is the best treatment to reduce the need for caesarean section in nulliparous women at term with delayed first stage of labour? PMID- 28588032 TI - Inactivation of gamma-secretases leads to accumulation of substrates and non Alzheimer neurodegeneration. AB - gamma-Secretases are a family of intramembrane cleaving aspartyl proteases and important drug targets in Alzheimer's disease. Here, we generated mice deficient for all gamma-secretases in the pyramidal neurons of the postnatal forebrain by deleting the three anterior pharynx defective 1 (Aph1) subunits (Aph1abc cKO Cre+). The mice show progressive cortical atrophy, neuronal loss, and gliosis. Interestingly, this is associated with more than 10-fold accumulation of membrane bound fragments of App, Aplp1, Nrg1, and Dcc, while other known substrates of gamma-secretase such as Aplp2, Lrp1, and Sdc3 accumulate to lesser extents. Despite numerous reports linking neurodegeneration to accumulation of membrane bound App fragments, deletion of App expression in the combined Aph1 knockout does not rescue this phenotype. Importantly, knockout of only Aph1a- or Aph1bc secretases causes limited and differential accumulation of substrates. This was not associated with neurodegeneration. Further development of selective Aph1 gamma-secretase inhibitors should be considered for treatment of Alzheimer's disease. PMID- 28588035 TI - Control of a Novel Spermatocyte-Promoting Factor by the Male Germline Sex Determination Factor PHF7 of Drosophila melanogaster. AB - A key aspect of germ cell development is to establish germline sexual identity and initiate a sex-specific developmental program to promote spermatogenesis or oogenesis. Previously, we have identified the histone reader Plant Homeodomain Finger 7 (PHF7) as an important regulator of male germline identity. To understand how PHF7 directs sexual differentiation of the male germline, we investigated the downstream targets of PHF7 by combining transcriptome analyses, which reveal genes regulated by Phf7, with genomic profiling of histone H3K4me2, the chromatin mark that is bound by PHF7. Through these genomic experiments, we identify a novel spermatocyte factor Receptor Accessory Protein Like 1 (REEPL1) that can promote spermatogenesis and whose expression is kept off by PHF7 in the spermatogonial stage. Loss of Reepl1 significantly rescues the spermatogenesis defects in Phf7 mutants, indicating that regulation of Reepl1 is an essential aspect of PHF7 function. Further, increasing REEPL1 expression facilitates spermatogenic differentiation. These results indicate that PHF7 controls spermatogenesis by regulating the expression patterns of important male germline genes. PMID- 28588037 TI - Dennis Newton. PMID- 28588036 TI - Brown fat depots in adult humans remain static in their locations on PET/CT despite changes in seasonality. AB - Active brown adipose tissue (BAT) in humans has been demonstrated through use of positron emission tomography with 2-deoxy-2-(fluorine-18) fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) scans. The aim of our study was to determine whether active human BAT depots shown on 18F-FDG PET/CT scans remain static in their location over time. This was a retrospective study. Adult human subjects (n = 15) who had had 18F-FDG PET/CT imaging (n = 38 scans in total) for clinical reasons were included on the basis of 18F-FDG uptake patterns consistent with BAT activity. For each subject, 18F-FDG BAT uptake pattern on serial 18F-FDG PET/CT images was compared to an index 18F-FDG PET/CT image with the largest demonstrable BAT volume. Object-based colocalization was expressed as Mander's correlation coefficient (where 1 = 100% overlap, 0 = no overlap). Distribution of 18F-FDG BAT activity over time and across multiple 18F-FDG BAT scans was equivalent in 60% (n = 9) of the subjects. The degree of consistency in the pattern of 18F-FDG BAT uptake in each subject over time was greater than expected by chance in 87% (n = 13) of the subjects (pair-wise agreement 75-100%, Fleiss' kappa 0.4-1). The degree of BAT colocalization on serial scans was greater than that expected by chance in 93% (n = 14) of the subjects (mean Mander's coefficient 0.81 +/- 0.21 [95% CI]). To our knowledge, our study provides the most conclusive evidence to date to support the notion that active BAT depots in humans (volumes and activities of which were measured through use of 18F-FDG PET/CT scans) remain static in location over sustained periods. PMID- 28588038 TI - The AMP-Related Kinase (AMPK) Induces Ca2+-Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation. AB - RATIONALE: Decreasing Ca2+ sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca2+. This may be particularly important in states requiring maintained dilation, such as hypoxia. AMP-related kinase (AMPK) is an important cellular energy sensor in VSM. Regulation of Ca2+ sensitivity usually is attributed to myosin light chain phosphatase activity, but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown. OBJECTIVE: To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca2+ desensitization of VSM contractile apparatus. METHODS AND RESULTS: AMPK induced a slowly developing dilation at unchanged cytosolic Ca2+ levels in potassium chloride-constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of myosin light chain phosphatase regulatory subunit. Using ultracentrifugation and confocal microscopy, we found that AMPK induced depolymerization of F-actin (filamentous actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the midcellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Coimmunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein. CONCLUSIONS: AMPK induces actin depolymerization, which reduces vascular tone and the response to vasoconstrictors. Our findings demonstrate a new role of AMPK in the control of actin cytoskeletal dynamics, potentially allowing for long-term dilation of microvessels without substantial changes in cytosolic Ca2+. PMID- 28588040 TI - Five sentence letter from 1980 helped create US opioid addiction crisis, study concludes. PMID- 28588039 TI - Alcohol consumption and brain health. PMID- 28588041 TI - Trauma staff change routines in wake of terrorist attack. PMID- 28588042 TI - The need for incorporating emotional intelligence and mindfulness training in modern medical education. PMID- 28588044 TI - Treatment of obesity in adolescents: where should interventions focus? PMID- 28588043 TI - Heme A synthesis and CcO activity are essential for Trypanosoma cruzi infectivity and replication. AB - Trypanosoma cruzi, the causative agent of Chagas disease, presents a complex life cycle and adapts its metabolism to nutrients' availability. Although T. cruzi is an aerobic organism, it does not produce heme. This cofactor is acquired from the host and is distributed and inserted into different heme-proteins such as respiratory complexes in the parasite's mitochondrion. It has been proposed that T. cruzi's energy metabolism relies on a branched respiratory chain with a cytochrome c oxidase-type aa3 (CcO) as the main terminal oxidase. Heme A, the cofactor for all eukaryotic CcO, is synthesized via two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). Previously, TcCox10 and TcCox15 (Trypanosoma cruzi Cox10 and Cox15 proteins) were identified in T. cruzi They presented HOS and HAS activity, respectively, when they were expressed in yeast. Here, we present the first characterization of TcCox15 in T. cruzi, confirming its role as HAS. It was differentially detected in the different T. cruzi stages, being more abundant in the replicative forms. This regulation could reflect the necessity of more heme A synthesis, and therefore more CcO activity at the replicative stages. Overexpression of a non functional mutant caused a reduction in heme A content. Moreover, our results clearly showed that this hindrance in the heme A synthesis provoked a reduction on CcO activity and, in consequence, an impairment on T. cruzi survival, proliferation and infectivity. This evidence supports that T. cruzi depends on the respiratory chain activity along its life cycle, being CcO an essential terminal oxidase. PMID- 28588046 TI - Breastfeeding and obesity. PMID- 28588045 TI - Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development. AB - Human male reproductive disorders (cryptorchidism, hypospadias, testicular cancer and low sperm counts) are common and some may be increasing in incidence worldwide. These associated disorders can arise from subnormal testosterone production during fetal life. This has resulted in a focus on in-utero environmental influences that may result in reproductive effects on the offspring in later life. Over recent years, there has been a dramatic increase in the scientific literature describing associations between in-utero environmental exposures (eg, industrial chemicals and pharmaceuticals) and subsequent reproductive outcomes in male offspring. This includes studies investigating a potential role for in-utero analgesic exposure(s) on the fetal testis; however, providing definitive evidence of such effects presents numerous challenges. In this review, we describe an approach to assessing the potential clinical relevance of in-utero (and postnatal) environmental exposures on subsequent male reproductive function using exposure to the analgesic paracetamol as an example. PMID- 28588047 TI - Availability and Quality of Family Planning Services in the Democratic Republic of the Congo: High Potential for Improvement. AB - OBJECTIVE: To determine the availability and quality of family planning services within health facilities throughout the Democratic Republic of the Congo (DRC). METHODS: Data were collected for the cross-sectional study from April 2014 to June 2014 by the Ministry of Public Health. A total of 1,568 health facilities that reported data to the National Health Information System were selected by multistage random sampling in the 11 provinces of the DRC existing at that time. Data were collected through interviews, document review, and direct observation. Two dependent variables were measured: availability of family planning services (consisting of a room for services, staff assigned to family planning, and evidence of client use of family planning) and quality of family planning services (assessed as "high" if the facility had at least 1 trained staff member, family planning service delivery guidelines, at least 3 types of methods, and a sphygmomanometer, or "low" if the facility did not meet any of these 4 criteria). Pearson's chi-square test and odds ratios (ORs) were used to test for significant associations, using the alpha significance level of .05. RESULTS: We successfully surveyed 1,555 facilities (99.2%) of those included in the sample. One in every 3 facilities (33%) offered family planning services as assessed by the index of availability, of which 20% met all 4 criteria for providing high-quality services. Availability was greatest at the highest level of the health system (hospitals) and decreased incrementally with each health system level, with disparities between provinces and urban and rural areas. Facilities in urban areas were more likely than in rural areas to meet the standard for high-quality services (P<.001). Public facilities were less likely than private facilities to have high-quality services (P=.02). Among all 1,555 facilities surveyed, 14% had at least 3 types of methods available at the time of the survey; the most widely available methods were male condoms, combined oral contraceptive pills, and progestin-only injectable contraceptives. CONCLUSION: Availability and quality of family planning services in health facilities in the DRC remain low, with inequitable distribution of services throughout the country. To improve access to and use of family planning, efforts should focus on improving availability and quality at lower health system levels and in rural areas where the majority of the population lives. PMID- 28588049 TI - Junior doctors hesitate to speak up over unprofessional behaviour, study finds. PMID- 28588048 TI - The sphingosine 1-phosphate breakdown product, (2E)-hexadecenal, forms protein adducts and glutathione conjugates in vitro. AB - Sphingosine 1-phosphate (S1P), a bioactive lipid involved in various physiological processes such as cell proliferation and apoptosis, can be irreversibly cleaved by S1P lyase, yielding phosphoethanolamine and (2E) hexadecenal (2EHD). The latter metabolite, an alpha,beta-unsaturated fatty aldehyde, may be susceptible to nucleophilic attack by cellular biomolecules. Hence, we studied whether 2EHD forms reaction products with GSH and proteins in vitro. Using LC-MS/MS and stable isotopically labeled reference material, we identified a total of nine novel reaction products of 2EHD in a cell-free approach: two GSH conjugates and seven l-amino acid adducts. Both GSH conjugates were also found in HepG2 cell lysates incubated with 2EHD. Likewise, we detected four out of seven amino acid adducts released from the model protein, BSA, and proteins extracted from HepG2 cells. On this occasion, the 2EHD Michael adduct with l-histidine proved to be the most prominent adduct. Most interestingly, inhibition of the enzymatically driven oxidative degradation of 2EHD resulted in increased levels of both GSH conjugates and protein adducts in HepG2 cell lysates. Hence, our data provide new insights into sphingolipid metabolism and will be useful to investigate certain disorders linked to an impaired fatty aldehyde metabolism in more detail. PMID- 28588051 TI - WITHDRAWN: Correlations of CTLA-4 exon-1 rs231775A>G and promoter region rs5742909C>T polymorphisms with the therapeutic efficacy of 131I radionuclide in Graves' disease. AB - The Accepted Manuscript version of this article (published on 6 June 2017) was withdrawn on 16 November 2017 at the request of the authors. PMID- 28588052 TI - Effects of monovalent cations on folding kinetics of G-quadruplexes. AB - G-quadruplexes are special structures existing at the ends of human telomeres, the folding kinetics of which are essential for their functions, such as in the maintenance of genome stability and the protection of chromosome ends. In the present study, we investigated the folding kinetics of G-quadruplex in different monovalent cation environments and determined the detailed kinetic parameters for Na+- and K+-induced G-quadruplex folding, and for its structural transition from the basket-type Na+ form to the hybrid-type K+ form. More interestingly, although Li+ was often used in previous studies of G-quadruplex folding as a control ion supposed to have no effect, we have found that Li+ can actually influence the folding kinetics of both Na+- and K+-induced G-quadruplexes significantly and in different ways, by changing the folding fraction of Na+-induced G-quadruplexes and greatly increasing the folding rates of K+-induced G-quadruplexes. The present study may shed new light on the roles of monovalent cations in G quadruplex folding and should be useful for further studies of the underlying folding mechanism. PMID- 28588056 TI - Inner Workings: Listening in on the deep sea. PMID- 28588050 TI - Development of a Novel Maternal-Fetal Physiologically Based Pharmacokinetic Model I: Insights into Factors that Determine Fetal Drug Exposure through Simulations and Sensitivity Analyses. AB - Determining fetal drug exposure (except at the time of birth) is not possible for both logistical and ethical reasons. Therefore, we developed a novel maternal fetal physiologically based pharmacokinetic (m-f-PBPK) model to predict fetal exposure to drugs and populated this model with gestational age-dependent changes in maternal-fetal physiology. Then, we used this m-f-PBPK to: 1) perform a series of sensitivity analyses to quantitatively demonstrate the impact of fetoplacental metabolism and placental transport on fetal drug exposure for various drug-dosing regimens administered to the mother; 2) predict the impact of gestational age on fetal drug exposure; and 3) demonstrate that a single umbilical venous (UV)/maternal plasma (MP) ratio (even after multiple-dose oral administration to steady state) does not necessarily reflect fetal drug exposure. In addition, we verified the implementation of this m-f-PBPK model by comparing the predicted UV/MP and fetal/MP AUC ratios with those predicted at steady state after an intravenous infusion. Our simulations yielded novel insights into the quantitative contribution of fetoplacental metabolism and/or placental transport on gestational age-dependent fetal drug exposure. Through sensitivity analyses, we demonstrated that the UV/MP ratio does not measure the extent of fetal drug exposure unless obtained at steady state after an intravenous infusion or when there is little or no fluctuation in MP drug concentrations after multiple-dose oral administration. The proposed m-f-PBPK model can be used to predict fetal exposure to drugs across gestational ages and therefore provide the necessary information to assess the risk of drug toxicity to the fetus. PMID- 28588057 TI - Core Concept: How Bose-Einstein condensates keep revealing weird physics. PMID- 28588054 TI - Sustained Neurological Recovery After Stroke in Aged Rats Treated With a Novel Prostacyclin Analog. AB - BACKGROUND AND PURPOSE: Targeting the prostaglandin I2 prostanoid (IP) receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension. We hypothesized that postischemic treatment with MRE-269 provides long-lasting neuroprotection with improved neurological outcomes in a clinically relevant rat stroke model. METHODS: Aged male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly selected to receive either vehicle or MRE-269 (0.25 mg/kg) intravenously starting at 4.5 hours post ischemia. Accelerating rotarod and adhesive removal tests were conducted before and at 3, 7, 14, and 21 days after stroke. Infarct volume was quantified by magnetic resonance imaging at 48 hours and 21 days post middle cerebral artery occlusion. In parallel experiments, cerebral cortex samples from stroke and nonstroke sides from vehicle- and MRE-269-treated groups were collected at 18 hours post middle cerebral artery occlusion for molecular biology analyses. RESULTS: Quantitative magnetic resonance imaging data showed that postischemic MRE-269 treatment significantly reduced infarct volume compared with vehicle treated rats at both 48 hours and 3 weeks after stroke. MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions after middle cerebral artery occlusion, which was associated with a reduced weight loss in animals receiving the IP receptor agonist. Postischemic MRE-269 treatment reduced proinflammatory cytokines/chemokines and oxidative stress. Damage to the blood-brain barrier, as assessed by extravasation of immunoglobulin G to the ischemic brain, was significantly reduced by MRE-269, which was associated with a reduction in matrix metalloproteinase-9 activity in the brain of stroked aged rats given the IP agonist at 4.5 hours after ischemia onset. CONCLUSIONS: Our data suggest that targeting the IP receptor with MRE-269 is a novel strategy to reduce cerebral ischemia injury and promote long-term neurological recovery in ischemic stroke. PMID- 28588060 TI - Sending CAR T Cells After Multiple Myeloma. AB - Preliminary results from an ongoing phase I clinical trial in China suggest that chimeric antigen receptor T cells engineered to home in on a protein called BCMA may be a potent therapeutic option for multiple myeloma. The therapy was well tolerated and induced complete, durable responses in patients with relapsed/refractory disease. PMID- 28588061 TI - Dual HER2 Blockade Helps Prevent Breast Cancer Return. AB - Adding pertuzumab to an adjuvant regimen of trastuzumab for women with early stage HER2+ breast cancer reduces the risk of disease recurrence, especially among those with node-positive and hormone receptor-negative disease. Results from the phase III APHINITY trial, which could help pertuzumab earn full approval for this indication, were presented at the 2017 American Society of Clinical Oncology Annual Meeting. PMID- 28588059 TI - Near-Infrared Photoimmunotherapy Targeting Prostate Cancer with Prostate-Specific Membrane Antigen (PSMA) Antibody. AB - Prostate-specific membrane antigen (PSMA) is a membrane protein that is overexpressed manifold in prostate cancer and provides an attractive target for molecular therapy. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photoabsorber conjugate (APC). Here, we describe the efficacy of NIR-PIT, using a fully human IgG1 anti-PSMA monoclonal antibody (mAb), conjugated to the photoabsorber, IR700DX, in a PSMA expressing PC3 prostate cancer cell line. Anti-PSMA-IR700 showed specific binding and cell-specific killing was observed after exposure of the cells to NIR light in vitro In the in vivo study, anti-PSMA-IR700 showed high tumor accumulation and high tumor-background ratio. Tumor-bearing mice were separated into 4 groups: (i) no treatment; (ii) 100 MUg of anti-PSMA-IR700 i.v.; (iii) NIR light exposure; (iv) 100 MUg of anti-PSMA-IR700 i.v., NIR light exposure was administered. These were performed every week for up to 3 weeks. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other control groups (P < 0.001), and significantly prolonged survival was achieved (P < 0.0001 vs. other control groups). More than two thirds of tumors were cured with NIR-PIT. In conclusion, the anti-PSMA antibody is suitable as an APC for NIR-PIT. Furthermore, NIR-PIT with the anti-PSMA-IR700 antibody is a promising candidate of the treatment of PSMA-expressing tumors and could be readily translated to humans.Implications: NIR-infrared photoimmunotherapy (NIR-PIT) using a fully human anti-PSMA-IR700 conjugate showed potential therapeutic effects against a PSMA-expressing prostate cancer that is readily translated to humans. Mol Cancer Res; 15(9); 1153-62. (c)2017 AACR. PMID- 28588062 TI - Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. AB - High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51CIn vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.Significance: Analyses of primary and secondary mutations in RAD51C and RAD51D provide evidence for these primary mutations in conferring PARPi sensitivity and secondary mutations as a mechanism of acquired PARPi resistance. PARPi resistance due to secondary mutations underpins the need for early delivery of PARPi therapy and for combination strategies. Cancer Discov; 7(9); 984-98. (c)2017 AACR.See related commentary by Domchek, p. 937See related article by Quigley et al., p. 999See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920. PMID- 28588063 TI - Moderate alcohol consumption as risk factor for adverse brain outcomes and cognitive decline: longitudinal cohort study. AB - Objectives To investigate whether moderate alcohol consumption has a favourable or adverse association or no association with brain structure and function.Design Observational cohort study with weekly alcohol intake and cognitive performance measured repeatedly over 30 years (1985-2015). Multimodal magnetic resonance imaging (MRI) was performed at study endpoint (2012-15).Setting Community dwelling adults enrolled in the Whitehall II cohort based in the UK (the Whitehall II imaging substudy).Participants 550 men and women with mean age 43.0 (SD 5.4) at study baseline, none were "alcohol dependent" according to the CAGE screening questionnaire, and all safe to undergo MRI of the brain at follow-up. Twenty three were excluded because of incomplete or poor quality imaging data or gross structural abnormality (such as a brain cyst) or incomplete alcohol use, sociodemographic, health, or cognitive data.Main outcome measures Structural brain measures included hippocampal atrophy, grey matter density, and white matter microstructure. Functional measures included cognitive decline over the study and cross sectional cognitive performance at the time of scanning.Results Higher alcohol consumption over the 30 year follow-up was associated with increased odds of hippocampal atrophy in a dose dependent fashion. While those consuming over 30 units a week were at the highest risk compared with abstainers (odds ratio 5.8, 95% confidence interval 1.8 to 18.6; P<=0.001), even those drinking moderately (14-21 units/week) had three times the odds of right sided hippocampal atrophy (3.4, 1.4 to 8.1; P=0.007). There was no protective effect of light drinking (1-<7 units/week) over abstinence. Higher alcohol use was also associated with differences in corpus callosum microstructure and faster decline in lexical fluency. No association was found with cross sectional cognitive performance or longitudinal changes in semantic fluency or word recall.Conclusions Alcohol consumption, even at moderate levels, is associated with adverse brain outcomes including hippocampal atrophy. These results support the recent reduction in alcohol guidance in the UK and question the current limits recommended in the US. PMID- 28588067 TI - Consultant is struck off for dishonesty over sildenafil prescription. PMID- 28588064 TI - Autotaxin-lysophosphatidic acid-LPA3 signaling at the embryo-epithelial boundary controls decidualization pathways. AB - During pregnancy, up-regulation of heparin-binding (HB-) EGF and cyclooxygenase-2 (COX-2) in the uterine epithelium contributes to decidualization, a series of uterine morphological changes required for placental formation and fetal development. Here, we report a key role for the lipid mediator lysophosphatidic acid (LPA) in decidualization, acting through its G-protein-coupled receptor LPA3 in the uterine epithelium. Knockout of Lpar3 or inhibition of the LPA-producing enzyme autotaxin (ATX) in pregnant mice leads to HB-EGF and COX-2 down-regulation near embryos and attenuates decidual reactions. Conversely, selective pharmacological activation of LPA3 induces decidualization via up-regulation of HB-EGF and COX-2. ATX and its substrate lysophosphatidylcholine can be detected in the uterine epithelium and in pre-implantation-stage embryos, respectively. Our results indicate that ATX-LPA-LPA3 signaling at the embryo-epithelial boundary induces decidualization via the canonical HB-EGF and COX-2 pathways. PMID- 28588065 TI - The Hierarchical Cortical Organization of Human Speech Processing. AB - Speech comprehension requires that the brain extract semantic meaning from the spectral features represented at the cochlea. To investigate this process, we performed an fMRI experiment in which five men and two women passively listened to several hours of natural narrative speech. We then used voxelwise modeling to predict BOLD responses based on three different feature spaces that represent the spectral, articulatory, and semantic properties of speech. The amount of variance explained by each feature space was then assessed using a separate validation dataset. Because some responses might be explained equally well by more than one feature space, we used a variance partitioning analysis to determine the fraction of the variance that was uniquely explained by each feature space. Consistent with previous studies, we found that speech comprehension involves hierarchical representations starting in primary auditory areas and moving laterally on the temporal lobe: spectral features are found in the core of A1, mixtures of spectral and articulatory in STG, mixtures of articulatory and semantic in STS, and semantic in STS and beyond. Our data also show that both hemispheres are equally and actively involved in speech perception and interpretation. Further, responses as early in the auditory hierarchy as in STS are more correlated with semantic than spectral representations. These results illustrate the importance of using natural speech in neurolinguistic research. Our methodology also provides an efficient way to simultaneously test multiple specific hypotheses about the representations of speech without using block designs and segmented or synthetic speech.SIGNIFICANCE STATEMENT To investigate the processing steps performed by the human brain to transform natural speech sound into meaningful language, we used models based on a hierarchical set of speech features to predict BOLD responses of individual voxels recorded in an fMRI experiment while subjects listened to natural speech. Both cerebral hemispheres were actively involved in speech processing in large and equal amounts. Also, the transformation from spectral features to semantic elements occurs early in the cortical speech-processing stream. Our experimental and analytical approaches are important alternatives and complements to standard approaches that use segmented speech and block designs, which report more laterality in speech processing and associated semantic processing to higher levels of cortex than reported here. PMID- 28588069 TI - Special Meeting Sections. PMID- 28588066 TI - Identification of AICP as a GluN2C-Selective N-Methyl-d-Aspartate Receptor Superagonist at the GluN1 Glycine Site. AB - N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of d-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2 amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent differences in agonist efficacy at recombinant NMDA receptor subtypes. AICP is a full agonist at GluN1/2A (100% response compared with glycine), a partial agonist at GluN1/2B and GluN1/2D (10% and 27%, respectively), and a highly efficacious superagonist at GluN1/2C receptors (353%). Furthermore, AICP potencies are enhanced compared with DCS with EC50 values in the low nanomolar range (1.7 nM at GluN1/2C). We show that GluN1/2C superagonism of AICP and DCS is mediated by overlapping but distinct mechanisms and that AICP selectively enhances responses from recombinant GluN1/2C receptors in the presence of physiological glycine concentrations. This functional selectivity of AICP for GluN2C-containing NMDA receptors is more pronounced compared with DCS, suggesting that AICP can be a useful tool compound for uncovering the roles of GluN2C subunits in neuronal circuit function and in the development of new therapeutic strategies. PMID- 28588070 TI - Risk Factors for Fractures in Children Hospitalized in Intensive and Intermediate Care Units. AB - BACKGROUND AND OBJECTIVES: Fragility fractures are increasingly recognized in hospitalized children. Our study aim was to identify risk factors for fracture in children hospitalized in intensive and intermediate care units. METHODS: We conducted a retrospective, case-control study comparing the clinical characteristics of children with fractures (cases) to children without fractures (controls) matched for age, sex, hospital unit, admission quarter and year, ICU length of stay, severity of illness, and resource utilization. Bivariate comparisons and matched multivariable logistic regression modeling were used to determine associations between potential risk factors and fracture. RESULTS: Median age at fracture for the 35 patients was 5.0 months (interquartile range 2.0 to 10.0 months) and at a comparable interval for the 70 matched controls was 3.5 months (interquartile range 2.0 to 7.0 months). In bivariate analyses, factors associated with fracture included: primary diagnosis of tracheoesophageal fistula, esophageal atresia and stenosis; diagnosis of kidney disease; and per 5 day increase in median cumulative ICU days at risk. In the final model, a respiratory disease diagnosis (odds ratio 3.9, 95% confidence interval 1.1-13.7) and per 5-day increase in median cumulative ICU days at risk (odds ratio 1.3, 95% confidence interval 1.0-1.6) were significant independent risk factors for fracture. CONCLUSIONS: Children prone to fracture in the hospital are young, medically complex patients who require extended periods of intensive level medical care and potentially life-sustaining treatment modalities. The children who would benefit most from fracture reduction efforts are those with respiratory disease and prolonged ICU stays. PMID- 28588071 TI - The RNA helicase DHX9 establishes nucleolar heterochromatin, and this activity is required for embryonic stem cell differentiation. AB - Long non-coding RNAs (lncRNAs) have been implicated in the regulation of chromatin conformation and epigenetic patterns. lncRNA expression levels are widely taken as an indicator for functional properties. However, the role of RNA processing in modulating distinct features of the same lncRNA is less understood. The establishment of heterochromatin at rRNA genes depends on the processing of IGS-rRNA into pRNA, a reaction that is impaired in embryonic stem cells (ESCs) and activated only upon differentiation. The production of mature pRNA is essential since it guides the repressor TIP5 to rRNA genes, and IGS-rRNA abolishes this process. Through screening for IGS-rRNA-binding proteins, we here identify the RNA helicase DHX9 as a regulator of pRNA processing. DHX9 binds to rRNA genes only upon ESC differentiation and its activity guides TIP5 to rRNA genes and establishes heterochromatin. Remarkably, ESCs depleted of DHX9 are unable to differentiate and this phenotype is reverted by the addition of pRNA, whereas providing IGS-rRNA and pRNA mutants deficient for TIP5 binding are not sufficient. Our results reveal insights into lncRNA biogenesis during development and support a model in which the state of rRNA gene chromatin is part of the regulatory network that controls exit from pluripotency and initiation of differentiation pathways. PMID- 28588068 TI - Comprehensive global genome dynamics of Chlamydia trachomatis show ancient diversification followed by contemporary mixing and recent lineage expansion. AB - Chlamydia trachomatis is the world's most prevalent bacterial sexually transmitted infection and leading infectious cause of blindness, yet it is one of the least understood human pathogens, in part due to the difficulties of in vitro culturing and the lack of available tools for genetic manipulation. Genome sequencing has reinvigorated this field, shedding light on the contemporary history of this pathogen. Here, we analyze 563 full genomes, 455 of which are novel, to show that the history of the species comprises two phases, and conclude that the currently circulating lineages are the result of evolution in different genomic ecotypes. Temporal analysis indicates these lineages have recently expanded in the space of thousands of years, rather than the millions of years as previously thought, a finding that dramatically changes our understanding of this pathogen's history. Finally, at a time when almost every pathogen is becoming increasingly resistant to antimicrobials, we show that there is no evidence of circulating genomic resistance in C. trachomatis. PMID- 28588074 TI - The long-term health risks of ART: Epidemiological data and research on animals indicate that in vitro fertilization might create health problems later in life. PMID- 28588073 TI - Brd4-Brd2 isoform switching coordinates pluripotent exit and Smad2-dependent lineage specification. AB - Pluripotent stem cells (PSCs) hold great clinical potential, as they possess the capacity to differentiate into fully specialised tissues such as pancreas, liver, neurons and cardiac muscle. However, the molecular mechanisms that coordinate pluripotent exit with lineage specification remain poorly understood. To address this question, we perform a small molecule screen to systematically identify novel regulators of the Smad2 signalling network, a key determinant of PSC fate. We reveal an essential function for BET family bromodomain proteins in Smad2 activation, distinct from the role of Brd4 in pluripotency maintenance. Mechanistically, BET proteins specifically engage Nodal gene regulatory elements (NREs) to promote Nodal signalling and Smad2 developmental responses. In pluripotent cells, Brd2-Brd4 occupy NREs, but only Brd4 is required for pluripotency gene expression. Brd4 downregulation facilitates pluripotent exit and drives enhanced Brd2 NRE occupancy, thereby unveiling a specific function for Brd2 in differentiative Nodal-Smad2 signalling. Therefore, distinct BET functionalities and Brd4-Brd2 isoform switching at NREs coordinate pluripotent exit with lineage specification. PMID- 28588072 TI - Salt-inducible kinase induces cytoplasmic histone deacetylase 4 to promote vascular calcification. AB - A pathologic osteochondrogenic differentiation of vascular smooth muscle cells (VSMCs) promotes arterial calcifications, a process associated with significant morbidity and mortality. The molecular pathways promoting this pathology are not completely understood. We studied VSMCs, mouse aortic rings, and human aortic valves and showed here that histone deacetylase 4 (HDAC4) is upregulated early in the calcification process. Gain- and loss-of-function assays demonstrate that HDAC4 is a positive regulator driving this pathology. HDAC4 can shuttle between the nucleus and cytoplasm, but in VSMCs, the cytoplasmic rather than the nuclear activity of HDAC4 promotes calcification, and a nuclear-localized mutant of HDAC4 fails to promote calcification. The cytoplasmic location and function of HDAC4 is controlled by the activity of salt-inducible kinase (SIK). Pharmacologic inhibition of SIK sends HDAC4 to the nucleus and inhibits the calcification process in VSMCs, aortic rings, and in vivo In the cytoplasm, HDAC4 binds and its activity depends on the adaptor protein ENIGMA (Pdlim7) to promote vascular calcification. These results establish a cytoplasmic role for HDAC4 and identify HDAC4, SIK, and ENIGMA as mediators of vascular calcification. PMID- 28588075 TI - Cerebral Perfusion and the Risk of Dementia: A Population-Based Study. AB - BACKGROUND: Cerebral hypoperfusion has previously been associated with mild cognitive impairment and dementia in various cross-sectional studies, but whether hypoperfusion precedes neurodegeneration is unknown. We prospectively determined the association of cerebral perfusion with subsequent cognitive decline and development of dementia. METHODS: Between 2005 and 2012, we measured cerebral blood flow by 2-dimensional phase-contrast magnetic resonance imaging in participants of the population-based Rotterdam Study without dementia. We determined the association of cerebral perfusion (mL/100mL/min) with risk of dementia (until 2015) using a Cox model, adjusting for age, sex, demographics, cardiovascular risk factors, and apolipoprotein E genotype. We repeated analyses for Alzheimer disease and accounting for stroke. We used linear regression to determine change in cognitive performance during 2 consecutive examination rounds in relation to perfusion. Finally, we investigated whether associations were modified by baseline severity of white matter hyperintensities. RESULTS: Of 4759 participants (median age 61.3 years, 55.2% women) with a median follow-up of 6.9 years, 123 participants developed dementia (97 Alzheimer disease). Lower cerebral perfusion was associated with higher risk of dementia (adjusted hazard ratio, 1.31; 95% confidence interval per standard deviation decrease, 1.07-1.61), similar for Alzheimer disease only, and unaltered by accounting for stroke. Risk of dementia with hypoperfusion was higher with increasing severity of white matter hyperintensities (with severe white matter hyperintensities; hazard ratio, 1.54; 95% confidence interval, 1.11-2.14). At cognitive reexamination after on average 5.7 years, lower baseline perfusion was associated with accelerated decline in cognition (global cognition: beta=-0.029, P=0.003), which was similar after excluding those with incident dementia, and again most profound in individuals with higher volume of white matter hyperintensities (P value for interaction=0.019). CONCLUSIONS: Cerebral hypoperfusion is associated with accelerated cognitive decline and an increased risk of dementia in the general population. PMID- 28588078 TI - Walking as a Window to Risk and Resiliency. PMID- 28588077 TI - Predictors and Association With Clinical Outcomes of the Changes in Exercise Capacity After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: At present, there are no objective data specifically examining the clinical impact of variations in exercise capacity post-transcatheter aortic valve replacement (TAVR). We describe the changes in exercise capacity between baseline and 6 months post-TAVR, and ascertain factors associated with and clinical implications of a lack of improvement in exercise capacity post-TAVR. METHODS: A total of 305 patients (mean age, 79+/-9 years; 44% men; Society of Thoracic Surgeons predicted risk mortality score, 6.7+/-4.2%) undergoing TAVR completed both baseline and follow-up exercise capacity assessments at 6 months post-TAVR. Exercise capacity was evaluated by the 6-minute walk test (6MWT). Clinical outcomes were compared between patients displaying greater than (n=152; improving group) versus less than (n=153; nonimproving group) the median percentage change in distance walked between baseline and 6-month follow-up examinations. The primary outcome measure was clinical event rates, measured from the 6-month post-TAVR period onward. Further dichotomization according to baseline 6MWT distance (less than versus more than median walking distance, or slow walker versus fast walker) was also assessed. RESULTS: The mean overall distances walked pre- and post-TAVR (6 months post-TAVR) were 204+/-119 and 263+/ 116 m, respectively (Delta6MWT=60+/-106 m), with 219 (72%) patients demonstrating an increase in their walking distance (median percentage increase of the entire population was 20% [interquartile range, 0%-80%]). Factors independently correlated with reduced exercise capacity improvement included a range of baseline clinical characteristics (older age, female sex, chronic obstructive pulmonary disease; P<0.05 for all), periprocedural major or life-threatening bleeding (P=0.009) and new-onset anemia at 6 months post-TAVR (P=0.009). Failure to improve the 6MWT distance by at least 20% was independently associated with all-cause mortality (P=0.002) and cardiovascular death or rehospitalization for cardiovascular causes (P=0.001). Baseline slow walkers who were able to improve the 6MWT distance presented with significantly better outcomes than nonimprovers (P=0.01 for all-cause mortality; P=0.001 for cardiovascular end point). CONCLUSIONS: Approximately one-third of patients undergoing TAVR did not improve their exercise capacity postprocedure. The lack of functional improvement post TAVR was predicted by a mix of baseline and periprocedural factors translating into poorer clinical outcomes. These results suggest that systematically implementing exercise capacity assessment pre- and post-TAVR may help to improve patient risk stratification. PMID- 28588076 TI - Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-beta and Cardiac Fibrosis. AB - BACKGROUND: Fibrosis is the pathological consequence of stress-induced tissue remodeling and matrix accumulation. Increased levels of plasminogen activator inhibitor type I (PAI-1) have been shown to promote fibrosis in multiple organ systems. Paradoxically, homozygous genetic deficiency of PAI-1 is associated with spontaneous age-dependent, cardiac-selective fibrosis in mice. We have identified a novel PAI-1-dependent mechanism that regulates cardiomyocyte-derived fibrogenic signals and cardiac transcriptional pathways during injury. METHODS: Cardiac fibrosis in subjects with homozygous mutation in SERPINE-1 was evaluated with late gadolinium-enhanced cardiac magnetic resonance imaging. A murine cardiac injury model was performed by subcutaneous infusion of either saline or Angiotensin II by osmotic minipumps. We evaluated blood pressure, cardiac function (by echocardiography), fibrosis (with Masson Trichrome staining), and apoptosis (with TUNEL staining), and we performed transcriptome analysis (with RNA sequencing). We further evaluated fibrotic signaling in isolated murine primary ventricular myocytes. RESULTS: Cardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in SERPINE-1. In addition to its suppressive role during spontaneous cardiac fibrosis in multiple species, we hypothesized that PAI-1 also regulates fibrosis during cardiac injury. Treatment of young PAI-1-/- mice with Angiotensin II induced extensive hypertrophy and fibrotic cardiomyopathy, with increased cardiac apoptosis and both reactive and replacement fibrosis. Although Angiotensin II-induced hypertension was blunted in PAI-1-/- mice, cardiac hypertrophy was accelerated. Furthermore, ventricular myocytes were found to be an important source of cardiac transforming growth factor-beta (TGF-beta) and PAI 1 regulated TGF-beta synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. Transcriptome analysis of ventricular RNA after Angiotensin II treatment confirmed that PAI-1 deficiency significantly enhanced multiple TGF-beta signaling elements and transcriptional targets, including genes for extracellular matrix components, mediators of extracellular matrix remodeling, matricellular proteins, and cardiac integrins compared with wild-type mice. CONCLUSIONS: PAI-1 is an essential repressor of cardiac fibrosis in mammals. We define a novel cardiomyocyte-specific regulatory mechanism for TGF beta production by PAI-1, which explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-beta axis and its early transcriptional effects that lead to myocardial fibrosis. PMID- 28588079 TI - Focal accumulation of preribosomes outside the nucleolus during metaphase anaphase in budding yeast. AB - Saccharomyces cerevisiae contains one nucleolus that remains intact in the mother cell side of the nucleus throughout most of mitosis. Based on this, it is assumed that the bulk of ribosome production during cell division occurs in the mother cell. Here, we show that the ribosome synthesis machinery localizes not only in the nucleolus but also at a center that is present in the bud side of the nucleus after the initiation of mitosis. This center can be visualized by live microscopy as a punctate body located in close proximity to the nuclear envelope and opposite to the nucleolus. It contains ribosomal DNA (rDNA) and precursors of both 40S and 60S ribosomal subunits. Proteins that actively participate in ribosome synthesis, but not functionally defective variants, accumulate in that site. The formation of this body occurs in the metaphase-to-anaphase transition when discrete regions of rDNA occasionally exit the nucleolus and move into the bud. Collectively, our data unveil the existence of a previously unknown mechanism for preribosome accumulation at the nuclear periphery in budding yeast. We propose that this might be a strategy to expedite the delivery of ribosomes to the growing bud. PMID- 28588080 TI - Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase 3 and loss of SOCE through a TRPM2-dependent pathway. AB - Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3 mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. After irradiation, acinar cells from the submandibular glands of TRPM2+/+ , but not those from TRPM2-/- mice, displayed an increase in the concentrations of mitochondrial Ca2+ and reactive oxygen species, a decrease in mitochondrial membrane potential, and activation of caspase-3, which was associated with a sustained decrease in STIM1 abundance and attenuation of SOCE. In a salivary gland cell line, silencing the mitochondrial Ca2+ uniporter or caspase-3 or treatment with inhibitors of TRPM2 or caspase-3 prevented irradiation-induced loss of STIM1 and SOCE. Expression of exogenous STIM1 in the salivary glands of irradiated mice increased SOCE and fluid secretion. We suggest that targeting the mechanisms underlying the loss of STIM1 would be a potentially useful approach for preserving salivary gland function after radiation therapy. PMID- 28588083 TI - Science Signaling Podcast for 6 June 2017: Calcium signaling and dry mouth. AB - This Podcast features a conversation with Indu Ambudkar, senior author of a Research Resource that appears in the 6 June 2017 issue of Science Signaling, about how activation of the cation channel TRPM2 is involved in radiation-induced dry mouth. Patients who receive radiation therapy for head and neck cancers often develop dry mouth as a side effect, and this condition is frequently permanent. Radiation does not kill cells in the salivary gland, yet it causes the acinar cells of the gland to reduce the amount of saliva they secrete. Liu et al found that radiation-induced activation of the cation channel TRPM2 triggered cleavage of the endoplasmic reticulum Ca2+ sensor STIM1, thus inhibiting store-operated Ca2+ entry and interfering with saliva production. These findings identify proteins that could potentially be targeted to prevent dry mouth in patients undergoing radiation therapy.Listen to Podcast. PMID- 28588084 TI - Highlight: Understanding radiation sialadenitis. AB - A nonapoptotic function of caspase-3 underlies the salivary gland complications of radiation therapy of head and neck cancers. PMID- 28588081 TI - Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. AB - Increased protein translation in cells and various factors in the tumor microenvironment can induce endoplasmic reticulum (ER) stress, which initiates the unfolded protein response (UPR). We have previously reported that factors released from cancer cells mounting a UPR induce a de novo UPR in bone marrow derived myeloid cells, macrophages, and dendritic cells that facilitates protumorigenic characteristics in culture and tumor growth in vivo. We investigated whether this intercellular signaling, which we have termed transmissible ER stress (TERS), also operates between cancer cells and what its functional consequences were within the tumor. We found that TERS signaling induced a UPR in recipient human prostate cancer cells that included the cell surface expression of the chaperone GRP78. TERS also activated Wnt signaling in recipient cancer cells and enhanced resistance to nutrient starvation and common chemotherapies such as the proteasome inhibitor bortezomib and the microtubule inhibitor paclitaxel. TERS-induced activation of Wnt signaling required the UPR kinase and endonuclease IRE1. However, TERS-induced enhancement of cell survival was predominantly mediated by the UPR kinase PERK and a reduction in the abundance of the transcription factor ATF4, which prevented the activation of the transcription factor CHOP and, consequently, the induction of apoptosis. When implanted in mice, TERS-primed cancer cells gave rise to faster growing tumors than did vehicle-primed cancer cells. Collectively, our data demonstrate that TERS is a mechanism of intercellular communication through which tumor cells can adapt to stressful environments. PMID- 28588085 TI - An adenosine receptor for olfaction. AB - Extracellular processing of ATP in the fish olfactory epithelium produces adenosine that is perceived by olfactory neurons. PMID- 28588082 TI - IRE1alpha promotes viral infection by conferring resistance to apoptosis. AB - The unfolded protein response (UPR) is an ancient cellular pathway that detects and alleviates protein-folding stresses. The UPR components X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1alpha (IRE1alpha) promote type I interferon (IFN) responses. We found that Xbp1-deficient mouse embryonic fibroblasts and macrophages had impaired antiviral resistance. However, this was not because of a defect in type I IFN responses but rather an inability of Xbp1 deficient cells to undergo viral-induced apoptosis. The ability to undergo apoptosis limited infection in wild-type cells. Xbp1-deficient cells were generally resistant to the intrinsic pathway of apoptosis through an indirect mechanism involving activation of the nuclease IRE1alpha. We observed an IRE1alpha-dependent reduction in the abundance of the proapoptotic microRNA miR 125a and a corresponding increase in the amounts of the members of the antiapoptotic Bcl-2 family. The activation of IRE1alpha by the hepatitis C virus (HCV) protein NS4B in XBP1-proficient cells also conferred apoptosis resistance and promoted viral replication. Furthermore, we found evidence of IRE1alpha activation and decreased miR-125a abundance in liver biopsies from patients infected with HCV compared to those in the livers of healthy controls. Our results reveal a prosurvival role for IRE1alpha in virally infected cells and suggest a possible target for IFN-independent antiviral therapy. PMID- 28588090 TI - Associations Between Cardiac Troponin, Mechanism of Myocardial Injury, and Long Term Mortality After Noncardiac Vascular Surgery. AB - BACKGROUND: The time-sensitive hazard of perioperative cardiac troponin T (cTnT) elevation and whether long-term mortality differs by mechanism of myocardial injury are poorly understood. METHODS AND RESULTS: In this observational study of 12 882 patients who underwent noncardiac vascular surgery, patients were assessed for cTnT sampling within 96 hours postoperatively. Mortality out to 5-years was stratified by cTnT level and mechanism of myocardial injury. During a median follow-up of 26.9 months, there were 2149 (16.7%) deaths. By multivariable Cox proportional hazards analysis, there was a graded increase in mortality with any detectable cTnT compared to <0.01 ng/mL; cTnT 0.01 to 0.029 ng/mL hazard ratio (HR) 1.54 (95% CI 1.18-2.00, P=0.002), 0.03 to 0.099 ng/mL HR 1.86 (95% CI 1.49 2.31, P<0.001), 0.10 to 0.399 ng/mL HR 1.83 (95% CI 1.46-2.31, P<0.001), >=0.40 ng/mL HR 2.62 (95% CI 2.06-3.32, P<0.001). Mortality for each mechanism of injury was greater than for patients with normal cTnT; baseline cTnT elevation HR 1.71 (95% CI 1.31-2.24; P<0.001), Type 2 myocardial infarction HR 1.88 (95% CI 1.57 2.24; P<0.001), Type 1 MI HR 2.56 (95% CI 2.56, 1.82-3.60; P<0.001). On Kaplan Meier analysis, long-term survival did not differ between mechanisms. The hazard of mortality was greatest within the first 10 months postsurgery. Consistent results were obtained in confirmatory propensity-score matched analyses. CONCLUSIONS: Any detectable cTnT >=0.01 ng/mL is associated with increased long term mortality after vascular surgery. This risk is greatest within the first 10 months postoperatively. While short-term mortality is greatest with Type 1 myocardial infarction, long-term mortality appears independent of the mechanism of injury. PMID- 28588089 TI - Role of Circulating Fibroblast Growth Factor 21 Measurement in Primary Prevention of Coronary Heart Disease Among Chinese Patients With Type 2 Diabetes Mellitus. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated beneficial effects on lipid and carbohydrate metabolism. In cross-sectional studies, an association of raised circulating FGF21 levels with coronary heart disease (CHD) was found in some but not all studies. Here we investigated prospectively whether baseline serum FGF21 levels could predict incident CHD in subjects with type 2 diabetes mellitus and no known cardiovascular diseases. METHODS AND RESULTS: Baseline serum FGF21 levels were measured in 3528 Chinese subjects with type 2 diabetes mellitus recruited from the Hong Kong West Diabetes Registry. The role of baseline serum FGF21 levels in predicting incident CHD over a median follow-up of 3.8 years was analyzed using Cox regression analysis. Among 3528 recruited subjects without known cardiovascular diseases, 147 (4.2%) developed CHD over a mean follow-up of 4 years. Baseline serum log-transformed FGF21 levels were significantly higher in those who had incident CHD than those who did not (222.7 pg/mL [92.8-438.4] versus 151.1 pg/mL [75.6-274.6]; P<0.001). On multivariable Cox regression analysis, baseline serum FGF21 levels, using an optimal cutoff of 206.22 pg/mL derived from our study, independently predicted incident CHD (hazard ratio, 1.55; 95% CI, 1.10-2.19; P=0.013) and significantly improved net reclassification index and integrated discrimination improvement after adjustment for conventional cardiovascular risk factors. CONCLUSIONS: We have demonstrated, for the first time, that serum FGF21 level is an independent predictor of incident CHD and might be usefully utilized as a biomarker for identifying type 2 diabetes mellitus subjects with raised CHD risk, for primary prevention. PMID- 28588091 TI - Associations of Abdominal Obesity and New-Onset Atrial Fibrillation in the General Population. AB - BACKGROUND: Higher height and weight are known to be associated with higher risk of atrial fibrillation (AF); however, whether the risk of AF is related to abdominal obesity is unclear. METHODS AND RESULTS: We studied 501 690 adults (mean age: 47.6+/-14.3 years; 250 664 women [50.0%]) without baseline AF in the National Sample Cohort released by the National Health Insurance Service in Korea. Body mass index (underweight defined as <18.5; normal, 18.5 to <25.0; overweight, 25.0 to <30.0; and obese, >=30.0) and waist circumference (abdominal obesity defined as >=90 cm for men and >=80 cm for women) were evaluated. During a mean follow-up of 3.9+/-1.3 years, 3443 participants (1432 women [41.6%]) developed AF. In multivariable models adjusted for clinical variables, the AF risk of underweight, overweight, and obese individuals increased by 21% (95% confidence interval, 1.01-1.45, P=0.043), 14% (95% confidence interval, 1.06 1.23, P<0.001), and 52% (95% confidence interval, 1.30-1.78, P<0.001), respectively, compared with those with normal body mass index. AF risk with confounder-adjusted hazards for abdominal obesity was 18% (95% confidence interval, 1.10-1.27, P<0.001). The increased AF risk was present in abdominally obese individuals regardless of body mass index except for the obese group. In subgroup analysis, abdominal obesity by waist circumference conferred increased risk of new-onset AF, particularly in participants without comorbidities. CONCLUSIONS: Abdominal obesity is an important, potentially modifiable risk factor for AF in nonobese Asian persons. These data suggest that interventions to decrease abdominal obesity may reduce the population burden of AF. PMID- 28588092 TI - Stunning and Right Ventricular Dysfunction Is Induced by Coronary Balloon Occlusion and Rapid Pacing in Humans: Insights From Right Ventricular Conductance Catheter Studies. AB - BACKGROUND: We sought to determine whether right ventricular stunning could be detected after supply (during coronary balloon occlusion [BO]) and supply/demand ischemia (induced by rapid pacing [RP] during transcatheter aortic valve replacement) in humans. METHODS AND RESULTS: Ten subjects with single-vessel right coronary artery disease undergoing percutaneous coronary intervention with normal ventricular function were studied in the BO group. Ten subjects undergoing transfemoral transcatheter aortic valve replacement were studied in the RP group. In both, a conductance catheter was placed into the right ventricle, and pressure volume loops were recorded at baseline and for intervals over 15 minutes after a low-pressure BO for 1 minute or a cumulative duration of RP for up to 1 minute. Ischemia-induced diastolic dysfunction was seen 1 minute after RP (end-diastolic pressure [mm Hg]: 8.1+/-4.2 versus 12.1+/-4.1, P<0.001) and BO (end-diastolic pressure [mm Hg]: 8.1+/-4.0 versus 8.7+/-4.0, P=0.03). Impairment of systolic and diastolic function after BO remained at 15-minutes recovery (ejection fraction [%]: 55.7+/-9.0 versus 47.8+/-6.3, P<0.01; end-diastolic pressure [mm Hg]: 8.1+/ 4.0 versus 9.2+/-3.9, P<0.01). Persistent diastolic dysfunction was also evident in the RP group at 15-minutes recovery (end-diastolic pressure [mm Hg]: 8.1+/-4.1 versus 9.9+/-4.4, P=0.03) and there was also sustained impairment of load independent indices of systolic function at 15 minutes after RP (end-systolic elastance and ventriculo-arterial coupling [mm Hg/mL]: 1.25+/-0.31 versus 0.85+/ 0.43, P<0.01). CONCLUSIONS: RP and right coronary artery balloon occlusion both cause ischemic right ventricular dysfunction with stunning observed later during the procedure. This may have intraoperative implications in patients without right ventricular functional reserve. PMID- 28588093 TI - Implantable Cardioverter-Defibrillator Therapy in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Predictors of Appropriate Therapy, Outcomes, and Complications. AB - BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy is characterized by ventricular arrhythmias and sudden cardiac death. Once the diagnosis is established, risk stratification to determine whether implantable cardioverter-defibrillator (ICD) placement is warranted is critical. METHODS AND RESULTS: The cohort included 312 patients (163 men, age at presentation 33.6+/ 13.9 years) with definite arrhythmogenic right ventricular dysplasia/cardiomyopathy who received an ICD. Over 8.8+/-7.33 years, 186 participants (60%) had appropriate ICD therapy and 58 (19%) had an intervention for ventricular fibrillation/flutter. Ventricular tachycardia at presentation (hazard ratio [HR]: 1.86; 95% confidence interval [CI], 1.38-2.49; P<0.001), inducibility on electrophysiology study (HR: 3.14; 95% CI, 1.95-5.05; P<0.001), male sex (HR: 1.62; 95% CI, 1.20-2.19; P=0.001), inverted T waves in >=3 precordial leads (HR: 1.66; 95% CI, 1.09-2.52; P=0.018), and premature ventricular contraction count >=1000/24 hours (HR: 2.30; 95% CI, 1.32-4.00; P=0.003) were predictors of any appropriate ICD therapy. Inducibility at electrophysiology study (HR: 2.28; 95% CI, 1.10-4.70; P=0.025) remained as the only predictor after multivariable analysis. The predictors for ventricular fibrillation/flutter were premature ventricular contraction >=1000/24 hours (HR: 4.39; 95% CI, 1.32-14.61; P=0.016), syncope (HR: 1.85; 95% CI, 1.10-3.11; P=0.021), aged <=30 years at presentation (HR: 1.76; 95% CI, 1.04-3.00; P<0.036), and male sex (HR: 1.73; 95% CI, 1.01-2.97; P=0.046). Younger age at presentation (HR: 3.14; 95% CI, 1.32-7.48; P=0.010) and high premature ventricular contraction burden (HR: 4.43; 95% CI, 1.35-14.57; P<0.014) remained as independent predictors of ventricular fibrillation/flutter. Complications occurred in 66 participants (21%), and 64 (21%) had inappropriate ICD interventions. Overall mortality was low at 2%, and 4% underwent heart transplantation. CONCLUSION: These findings represent an important step in identifying predictors of ICD therapy for potentially fatal ventricular fibrillation/flutter and should be considered when developing a risk stratification model for arrhythmogenic right ventricular dysplasia/cardiomyopathy. PMID- 28588096 TI - CNS beta3-adrenergic receptor activation regulates feeding behavior, white fat browning, and body weight. AB - Pharmacological beta3-adrenergic receptor (beta3AR) activation leads to increased mitochondrial biogenesis and activity in white adipose tissue (WAT), a process commonly referred to as "browning", and transiently increased insulin release. These effects are associated with improved metabolic function and weight loss. It is assumed that this impact of beta3AR agonists is mediated solely through activation of beta3ARs in adipose tissue. However, beta3ARs are also found in the brain, in areas such as the brain stem and the hypothalamus, which provide multisynaptic innervation to brown and white adipose depots. Thus, contrary to the current adipocentric view, the central nervous system (CNS) may also have the ability to regulate energy balance and metabolism through actions on central beta3ARs. Therefore, this study aimed to elucidate whether CNS beta3ARs can regulate browning of WAT and other aspects of metabolic regulation, such as food intake control and insulin release. We found that acute central injection of beta3AR agonist potently reduced food intake, body weight, and increased hypothalamic neuronal activity in rats. Acute central beta3AR stimulation was also accompanied by a transient increase in circulating insulin levels. Moreover, subchronic central beta3AR agonist treatment led to a browning response in both inguinal (IWAT) and gonadal WAT (GWAT), along with reduced GWAT and increased BAT mass. In high-fat, high-sugar-fed rats, subchronic central beta3AR stimulation reduced body weight, chow, lard, and sucrose water intake, in addition to increasing browning of IWAT and GWAT. Collectively, our results identify the brain as a new site of action for the anorexic and browning impact of beta3AR activation. PMID- 28588098 TI - Information technology in the NHS: aspirations and reality. PMID- 28588097 TI - High-intensity interval training and calorie restriction promote remodeling of glucose and lipid metabolism in diet-induced obesity. AB - Calorie restriction (CR) decreases adiposity, but the magnitude and defense of weight loss is less than predicted due to reductions in total daily energy expenditure (TEE). The purpose of the current investigation was to determine whether high-intensity interval training (HIIT) would increase markers of sympathetic activation in white adipose tissue (WAT) and rescue CR-mediated reductions in EE to a greater extent than moderate-intensity aerobic exercise training (MIT). Thirty-two 5-wk-old male C57BL/6J mice were placed on ad libitum HFD for 11 wk, followed by randomization to one of four groups (n = 8/group) for an additional 15 wk: 1) CON (remain on HFD), 2) CR (25% lower energy intake), 3) CR + HIIT (25% energy deficit created by 12.5% CR and 12.5% EE through HIIT), and 4) CR + MIT (25% energy deficit created by 12.5% CR and 12.5% EE through MIT). Markers of adipose thermogenesis (Ucp1, Prdm16, Dio2, and Fgf21) were unchanged in either exercise group in inguinal or epididymal WAT, whereas CR + HIIT decreased Ucp1 expression in retroperitoneal WAT and brown adipose tissue. HIIT rescued CR-mediated reductions in lean body mass (LBM) and resting energy expenditure (REE), and both were associated with improvements in glucose/insulin tolerance. Improvements in glucose metabolism in the CR + HIIT group appear to be linked to a molecular signature that enhances glucose and lipid storage in skeletal muscle. Exercise performed at either moderate or high intensity does not increase markers of adipose thermogenesis when performed in the presence of CR but remodels skeletal muscle metabolic and thermogenic capacity. PMID- 28588100 TI - Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease in Individuals With Type 1 Diabetes: A 12-Year Follow-up Study. AB - Methylglyoxal (MGO), a major precursor for advanced glycation end products, is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline and recorded fatal and nonfatal CVD over a median follow-up of 12.3 years (interquartile range 7.6-12.5 years). Data were analyzed by Cox regression, with adjustment for sex, age, HbA1c, DN, diabetes duration, smoking, systolic blood pressure, antihypertensive medication, and BMI. During follow-up, 73 individuals suffered at least one CVD event (36 fatal and 53 nonfatal). Higher MGO levels were associated with total, fatal, and nonfatal incident CVD (hazard ratios [HRs] 1.47 [95% CI 1.13-1.91], 1.42 [1.01-1.99], and 1.46 [1.08-1.98], respectively). We observed a similar trend for total mortality (HR 1.24 [0.99 1.56]). This study shows for the first time in our knowledge that plasma MGO levels are associated with cardiovascular events in individuals with type 1 diabetes. MGO may explain, at least in part, the increased risk for CVD in type 1 diabetes. PMID- 28588099 TI - Age-Dependent Decline in the Coordinated [Ca2+] and Insulin Secretory Dynamics in Human Pancreatic Islets. AB - Aging is associated with increased risk for type 2 diabetes, resulting from reduced insulin sensitivity and secretion. Reduced insulin secretion can result from reduced proliferative capacity and reduced islet function. Mechanisms underlying altered beta-cell function in aging are poorly understood in mouse and human islets, and the impact of aging on intraislet communication has not been characterized. Here, we examine how beta-cell [Ca2+] and electrical communication are impacted during aging in mouse and human islets. Islets from human donors and from mice were studied using [Ca2+] imaging, static and perifusion insulin secretion assays, and gap junction permeability measurements. In human islets, [Ca2+] dynamics were coordinated within distinct subregions of the islet, invariant with islet size. There was a marked decline in the coordination of [Ca2+] dynamics, gap junction coupling, and insulin secretion dynamics with age. These age-dependent declines were reversed by pharmacological gap junction activation. These results show that human islet function declines with aging, which can reduce insulin action and may contribute to increased risk of type 2 diabetes. PMID- 28588101 TI - Eggs in Early Complementary Feeding and Child Growth: A Randomized Controlled Trial. AB - BACKGROUND: Eggs are a good source of nutrients for growth and development. We hypothesized that introducing eggs early during complementary feeding would improve child nutrition. METHODS: A randomized controlled trial was conducted in Cotopaxi Province, Ecuador, from March to December 2015. Children ages 6 to 9 months were randomly assigned to treatment (1 egg per day for 6 months [n = 83]) and control (no intervention [n = 80]) groups. Both arms received social marketing messages to encourage participation in the Lulun Project (lulun meaning "egg" in Kichwa). All households were visited once per week to monitor morbidity symptoms, distribute eggs, and monitor egg intakes (for egg group only). Baseline and end point outcome measures included anthropometry, dietary intake frequencies, and morbidity symptoms. RESULTS: Mothers or other caregivers reported no allergic reactions to the eggs. Generalized linear regression modeling showed the egg intervention increased length-for-age z score by 0.63 (95% confidence interval [CI], 0.38-0.88) and weight-for-age z score by 0.61 (95% CI, 0.45-0.77). Log-binomial models with robust Poisson indicated a reduced prevalence of stunting by 47% (prevalence ratio [PR], 0.53; 95% CI, 0.37-0.77) and underweight by 74% (PR, 0.26; 95% CI, 0.10-0.70). Children in the treatment group had higher dietary intakes of eggs (PR, 1.57; 95% CI, 1.28-1.92) and reduced intake of sugar-sweetened foods (PR, 0.71; 95% CI, 0.51-0.97) compared with control. CONCLUSIONS: The findings supported our hypothesis that early introduction of eggs significantly improved growth in young children. Generally accessible to vulnerable groups, eggs have the potential to contribute to global targets to reduce stunting. PMID- 28588102 TI - Best Fed Beginnings: A Nationwide Quality Improvement Initiative to Increase Breastfeeding. AB - BACKGROUND AND OBJECTIVE: In response to a low number of Baby-Friendly-designated hospitals in the United States, the Centers for Disease Control and Prevention funded the National Institute for Children's Health Quality to conduct a national quality improvement initiative between 2011 and 2015. The initiative was entitled Best Fed Beginnings and enrolled 90 hospitals in a nationwide initiative to increase breastfeeding and achieve Baby-Friendly designation. METHODS: The intervention period lasted from July 2012 to August 2014. During that period, data on process indicators aligned with the Ten Steps to Successful Breastfeeding and outcome measures (overall and exclusively related to breastfeeding) were collected. In addition, data on the Baby-Friendly designation were collected after the end of the intervention through April 2016. Hospitals assembled multidisciplinary teams that included parent partners and community representatives. Three in-person learning sessions were interspersed with remote learning and tests of change, and a Web-based platform housed resources and data for widespread sharing. RESULTS: By April 2016, a total of 72 (80%) of the 90 hospitals received the Baby-Friendly designation, nearly doubling the number of designated hospitals in the United States. Participation in the Best Fed Beginnings initiative had significantly high correlation with designation compared with hospital applicants not in the program (Pearson's r [235]: 0.80; P < .01). Overall breastfeeding increased from 79% to 83% (t = 1.93; P = .057), and exclusive breastfeeding increased from 39% to 61% (t = 9.72; P < .001). CONCLUSIONS: A nationwide initiative of maternity care hospitals accomplished rapid transformative changes to achieve Baby-Friendly designation. These changes were accompanied by a significant increase in exclusive breastfeeding. PMID- 28588103 TI - Mycobacterium tuberculosis Rv3615c is a highly immunodominant antigen and specifically induces potent Th1-type immune responses in tuberculosis pleurisy. AB - T-cell responses have been demonstrated to be essential for preventing Mycobacterium tuberculosis infection. The Th1-cytokines produced by T cells, such as INF-gamma, IL-2, and TNF-alpha, not only limit the invasion of M. tuberculosis but also eliminate the pathogen at the site of infection. Bacillus Calmette Guerin (BCG) is known to induce Th1-type responses but the protection is inadequate. Identification of immunogenic components, in addition to those expressed in BCG, and induction of a broad spectrum of Th1-type responses provide options for generating sufficient adaptive immunity. Here, we studied human pulmonary T-cell responses induced by the M. tuberculosis-specific antigen Rv3615c, a protein with a similar size and sequence homology to ESAT-6 and CFP 10, which induced dominant CD4+ T-cell responses in human tuberculosis (TB) models. We characterized T-cell responses including cytokine profiling, kinetics of activation, expansion, differentiation, TCR usage, and signaling of activation induced by Rv3615c compared with other M. tuberculosis-specific antigens. The expanded CD4+ T cells induced by Rv3615c predominately produced Th1, but less Th2 and Th17, cytokines and displayed effector/memory phenotypes (CD45RO+CD27-CD127 CCR7-). The magnitude of expansion and cytokine production was comparable to those induced by well-characterized the 6 kDa early secreted antigenic target (ESAT-6), the 10 kDa culture filtrate protein (CFP-10) and BCG. Rv3615c contained multiple epitopes Rv3615c1-15, Rv3615c6-20, Rv3615c66-80, Rv3615c71-85 and Rv3615c76-90 that activated CD4+ T cells. The Rv3615c-specific CD4+ T cells shared biased of T-cell receptor variable region of beta chain (TCR Vbeta) 1, 2, 4, 5.1, 7.1, 7.2 and/or 22 chains to promote their differentiation and proliferation respectively, by triggering a signaling cascade. Our data suggest that Rv3615c is a major target of Th1-type responses and can be a highly immunodominant antigen specific for M. tuberculosis infection. PMID- 28588104 TI - A content analysis of outdoor non-alcoholic beverage advertisements in Ghana. AB - OBJECTIVES: This was a two-part descriptive study designed to (1) assess the marketing themes and sugar content of beverages promoted in outdoor advertisements (ads) within a portion of Accra, Ghana and (2) quantify the types of ads that appeared along the Accra-Cape Coast Highway. SETTING: A 4.7 km2 area of Accra, Ghana and a 151 km region along the highway represented the target areas for collecting photos of outdoor beverage ads. PRIMARY AND SECONDARY OUTCOME MEASURES: Number and types of beverage ads, sugar content of beverage products featured in ads and marketing themes used in ads. DESIGN: Two researchers photographed outdoor beverage ads in a 4.7 km2 area of Accra and used content analysis to assess marketing themes of ads, including the portrayal of children, local culture, music, sports and health. Researchers also recorded the number and type of ads along a 151 km stretch of the Accra-Cape Coast Highway. Researchers assessed the added sugar content to determine which beverages were sugar-sweetened beverages (SSBs). RESULTS: Seventy-seven photographed ads were analysed. Seventy-three per cent (72.7%) of ads featured SSBs, and Coca-Cola accounted for 59.7% of ads. Sixty-five per cent (64.9%) of all ads featured sodas, while 35.1% advertised energy drinks, bottled or canned juice drinks and coffee-based, milk-based and water-based beverages. Thirteen per cent (13%) of ads featured children and 5.2% were located near schools or playgrounds. Nine per cent (9.1%) of ads contained a reference to health and 7.8% contained a reference to fitness/strength/sport. Along the Accra-Cape Coast Highway, Coca-Cola accounted for 60% of branded ads. CONCLUSION: This study demonstrates the frequency of outdoor SSB ads within a 4.7 km2 area of Accra, Ghana. Coca-Cola was featured in the majority of ads, and the child-targeted nature of some ads indicates a need to expand the Children's Food and Beverage Advertising Initiative pledge to reduce child-targeted marketing on a global scale. PMID- 28588105 TI - A register-based 13-year to 43-year follow-up of 70 patients with obsessive compulsive disorder treated with capsulotomy. AB - OBJECTIVES: Little is known about the long-term medical status of patients with severe obsessive-compulsive disorder (OCD) undergoing capsulotomy, a neurosurgical last-resort treatment. The present study used national registers to identify all operated patients with OCD in Sweden and evaluated their long-term medical status, including mortality, hospital admissions and psychotropic medication after capsulotomy for OCD. DESIGN: Register-based long-term follow-up cohort study. PARTICIPANTS: We used the procedural and diagnostic codes in the Swedish National Patient Register to define the study population between 1970 and March 2013. Verification by manual review of medical records of the indication for surgery in those identified by the register yielded the final study cohort of 70 patients, followed 13-43 years after surgery. The sensitivity of the case selection method was 86%. OUTCOME MEASURES: We studied hospitalisation 5 years before and after surgery. Mortality data were derived from the Causes of Death Register. The Prescribed Drug Register was used to study psychotropic drug utilisation. RESULTS: By March 2013, 29 of the 70 patients were deceased. Their mean age at the time of death was 68 years (SD=14). Two patients had committed suicide and one had died of suspected suicide. Seventy per cent had been admitted to a psychiatric ward in the 5 years preceding surgery, and 84% in the first five postoperative years. Seventy-five per cent of those alive in 2012 were prescribed at least two psychotropic medications, often at high doses, the most common being antidepressants. CONCLUSIONS: Malignant OCD has a poor long-term prognosis. Patients who are candidates for surgery should be informed that, while OCD symptoms may be ameliorated with surgery, they should not expect long-term freedom from medication and psychiatric care. PMID- 28588106 TI - Evidence for the effectiveness of minimum pricing of alcohol: a systematic review and assessment using the Bradford Hill criteria for causality. AB - OBJECTIVES: To assess the evidence for price-based alcohol policy interventions to determine whether minimum unit pricing (MUP) is likely to be effective. DESIGN: Systematic review and assessment of studies according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, against the Bradford Hill criteria for causality. Three electronic databases were searched from inception to February 2017. Additional articles were found through hand searching and grey literature searches. CRITERIA FOR SELECTING STUDIES: We included any study design that reported on the effect of price-based interventions on alcohol consumption or alcohol-related morbidity, mortality and wider harms. Studies reporting on the effects of taxation or affordability and studies that only investigated price elasticity of demand were beyond the scope of this review. Studies with any conflict of interest were excluded. All studies were appraised for methodological quality. RESULTS: Of 517 studies assessed, 33 studies were included: 26 peer-reviewed research studies and seven from the grey literature. All nine of the Bradford Hill criteria were met, although different types of study satisfied different criteria. For example, modelling studies complied with the consistency and specificity criteria, time series analyses demonstrated the temporality and experiment criteria, and the analogy criterion was fulfilled by comparing the findings with the wider literature on taxation and affordability. CONCLUSIONS: Overall, the Bradford Hill criteria for causality were satisfied. There was very little evidence that minimum alcohol prices are not associated with consumption or subsequent harms. However the overall quality of the evidence was variable, a large proportion of the evidence base has been produced by a small number of research teams, and the quantitative uncertainty in many estimates or forecasts is often poorly communicated outside the academic literature. Nonetheless, price-based alcohol policy interventions such as MUP are likely to reduce alcohol consumption, alcohol-related morbidity and mortality. PMID- 28588107 TI - Staffs' and managers' perceptions of how and when discrete event simulation modelling can be used as a decision support in quality improvement: a focus group discussion study at two hospital settings in Sweden. AB - OBJECTIVE: To explore healthcare staffs' and managers' perceptions of how and when discrete event simulation modelling can be used as a decision support in improvement efforts. DESIGN: Two focus group discussions were performed. SETTING: Two settings were included: a rheumatology department and an orthopaedic section both situated in Sweden. PARTICIPANTS: Healthcare staff and managers (n=13) from the two settings. INTERVENTIONS: Two workshops were performed, one at each setting. Workshops were initiated by a short introduction to simulation modelling. Results from the respective simulation model were then presented and discussed in the following focus group discussion. RESULTS: Categories from the content analysis are presented according to the following research questions: how and when simulation modelling can assist healthcare improvement? Regarding how, the participants mentioned that simulation modelling could act as a tool for support and a way to visualise problems, potential solutions and their effects. Regarding when, simulation modelling could be used both locally and by management, as well as a pedagogical tool to develop and test innovative ideas and to involve everyone in the improvement work. CONCLUSIONS: Its potential as an information and communication tool and as an instrument for pedagogic work within healthcare improvement render a broader application and value of simulation modelling than previously reported. PMID- 28588108 TI - Cross-sectional analysis of two social determinants of health in California cities: racial/ethnic and geographic disparities. AB - OBJECTIVE: To study the magnitude and direction of city-level racial and ethnic differences in poverty and education to characterise health equity and social determinants of health in California cities. DESIGN: We used data from the American Community Survey, United States Census Bureau, 2006-2010, and calculated differences in the prevalence of poverty and low educational attainment in adults by race/ethnicity and by census tracts within California cities. For race/ethnicity comparisons, when the referent group (p2) to calculate the difference (p1-p2) was the non-Hispanic White population (considered a historically advantaged group), a positive difference was considered a health inequity. Differences with a non-White reference group were considered health disparities. SETTING: Cities of the State of California, USA. RESULTS: Within city differences in the prevalence of poverty and low educational attainment disfavoured Black and Latinos compared with Whites in over 78% of the cities. Compared with Whites, the median within-city poverty difference was 7.0% for Latinos and 6.2% for Blacks. For education, median within-city difference was 26.6% for Latinos compared with Whites. In a small, but not negligible proportion of cities, historically disadvantaged race/ethnicity groups had better social determinants of health outcomes than Whites. The median difference between the highest and lowest census tracts within cities was 14.3% for poverty and 15.7% for low educational attainment. Overall city poverty rate was weakly, but positively correlated with within-city racial/ethnic differences. CONCLUSIONS: Disparities and inequities are widespread in California. Local health departments can use these findings to partner with cities in their jurisdiction and design strategies to reduce racial, ethnic and geographic differences in economic and educational outcomes. These analytic methods could be used in an ongoing surveillance system to monitor these determinants of health. PMID- 28588109 TI - Finnish Subacromial Impingement Arthroscopy Controlled Trial (FIMPACT): a protocol for a randomised trial comparing arthroscopic subacromial decompression and diagnostic arthroscopy (placebo control), with an exercise therapy control, in the treatment of shoulder impingement syndrome. AB - INTRODUCTION: Arthroscopic subacromial decompression (ASD) is the most commonly performed surgical intervention for shoulder pain, yet evidence on its efficacy is limited. The rationale for the surgery rests on the tenet that symptom relief is achieved through decompression of the rotator cuff tendon passage. The primary objective of this superiority trial is to compare the efficacy of ASD versus diagnostic arthroscopy (DA) in patients with shoulder impingement syndrome (SIS), where DA differs only by the lack of subacromial decompression. A third group of supervised progressive exercise therapy (ET) will allow for pragmatic assessment of the relative benefits of surgical versus non-operative treatment strategies. METHODS AND ANALYSIS: Finnish Subacromial Impingement Arthroscopy Controlled Trial is an ongoing multicentre, three-group randomised controlled study. We performed two-fold concealed allocation, first by randomising patients to surgical (ASD or DA) or conservative (ET) treatment in 2:1 ratio and then those allocated to surgery further to ASD or DA in 1:1 ratio. Our two primary outcomes are pain at rest and at arm activity, assessed using visual analogue scale (VAS). We will quantify the treatment effect as the difference between the groups in the change in the VAS scales with the associated 95% CI at 24 months. Our secondary outcomes are functional assessment (Constant score and Simple shoulder test), quality of life (15D and SF-36), patient satisfaction, proportions of responders and non-responders, reoperations/treatment conversions, all at 2 years post randomisation, as well as adverse effects and complications. We recruited a total of 210 patients from three tertiary referral centres. We will conduct the primary analysis on the intention-to-treat basis. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of the Pirkanmaa Hospital District and duly registered at ClinicalTrials.gov. The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT00428870; Pre-results. PMID- 28588110 TI - Clinicians' perspectives of parental decision-making following diagnosis of a severe congenital anomaly: a qualitative study. AB - OBJECTIVE: To explore clinicians' perspectives on supporting parents' decision making following diagnosis of a severe congenital anomaly, and how this is shaped by current policy. METHODS: This paper reports data collated as part of a larger project examining parents' decision-making following antenatal diagnosis. The focus of this paper is the data arising from semistructured interviews conducted with 18 clinicians, with findings further supported by data generated from consultations between clinicians and parents. All interviews and consultations were audio-recorded and transcribed verbatim, with analysis based on the constant comparative approach. RESULTS: Three key themes emerged which together shape the practice of clinicians working in this area: first, the law governing termination of pregnancy (TOP) and how clinicians believe this influences the context in which decisions about whether to terminate or continue an affected pregnancy are made; second, approaches to the management of cases seen as particularly challenging; and third, how clinicians understand their role when working with parents. These themes combine to create a strong desire on the part of clinicians for parents to engage in a particular 'rational' form of decision-making and to be able to demonstrate the enactment of this. This is seen as important in order to ensure the 'right' decision has been reached and, particularly when the decision is to terminate, will withstand possible scrutiny. CONCLUSIONS: The policy context in which these decisions are made strongly shapes how clinicians practise and what they want to see from the parents with whom they work. The ways in which they seek to overcome the difficulties in interpreting the law may result in variations in the offer of late TOP, both between and within units. This may inadvertently affect the options available to women least able to engage in this idealised form of decision-making. PMID- 28588111 TI - Dietary determinants of serum total cholesterol among middle-aged and older adults: a population-based cross-sectional study in Dar es Salaam, Tanzania. AB - OBJECTIVE: To assess the dietary determinants of serum total cholesterol. DESIGN: Cross-sectional population-based study. SETTING: Peri-urban region of Dar es Salaam, Tanzania. PARTICIPANTS: 347 adults aged 40 years and older from the Dar es Salaam Urban Cohort Hypertension Study. MAIN OUTCOME MEASURE: Serum total cholesterol measured using a point-of-care device. RESULTS: Mean serum total cholesterol level was 204 mg/dL (IQR 169-236 mg/dL) in women and 185 mg/dL (IQR 152-216 mg/dL) in men. After adjusting for demographic, socioeconomic, lifestyle and dietary factors, participants who reported using palm oil as the major cooking oil had serum total cholesterol higher by 15 mg/dL (95% CI 1 to 29 mg/dL) compared with those who reported using sunflower oil. Consumption of one or more servings of meat per day (p for trend=0.017) and less than five servings of fruits and vegetables per day (p for trend=0.024) were also associated with higher serum total cholesterol. A combination of using palm oil for cooking, eating more than one serving of meat per day and fewer than five servings of fruits and vegetables per day, was associated with 46 mg/dL (95% CI 16 to 76 mg/dL) higher serum total cholesterol. CONCLUSIONS: Using palm oil for cooking was associated with higher serum total cholesterol levels in this peri-urban population in Dar es Salaam. Reduction of saturated fat content of edible oil may be considered as a population-based strategy for primary prevention of cardiovascular diseases. PMID- 28588112 TI - The Hoorn Diabetes Care System (DCS) cohort. A prospective cohort of persons with type 2 diabetes treated in primary care in the Netherlands. AB - PURPOSE: People with type 2 diabetes (T2D) have a doubled morbidity and mortality risk compared with persons with normal glucose tolerance. Despite treatment, clinical targets for cardiovascular risk factors are not achieved. The Hoorn Diabetes Care System cohort (DCS) is a prospective cohort representing a comprehensive dataset on the natural course of T2D, with repeated clinical measures and outcomes. In this paper, we describe the design of the DCS cohort. PARTICIPANTS: The DCS consists of persons with T2D in primary care from the West Friesland region of the Netherlands. Enrolment in the cohort started in 1998 and this prospective dynamic cohort currently holds 12 673 persons with T2D. FINDINGS TO DATE: Clinical measures are collected annually, with a high internal validity due to the centrally organised standardised examinations. Microvascular complications are assessed by measuring kidney function, and screening feet and eyes. Information on cardiovascular disease is obtained by 1) self-report, 2) electrocardiography and 3) electronic patient records. In subgroups of the cohort, biobanking and additional measurements were performed to obtain information on, for example, lifestyle, depression and genomics. Finally, the DCS cohort is linked to national cancer and all-cause mortality registers. A selection of published findings from the DCS includes identification of subgroups with distinct development of haemoglobin A1c, blood pressure and retinopathy, and their predictors; validation of a prediction model for personalised retinopathy screening; the assessment of the role of genetics in development and treatment of T2D, providing options for personalised medicine. FUTURE PLANS: We will continue with the inclusion of persons with newly diagnosed T2D, follow-up of persons in the cohort and linkage to morbidity and mortality registries. Currently, we are involved in (inter)national projects on, among others, biomarkers and prediction models for T2D and complications and we are interested in collaborations with external researchers. TRIAL REGISTRATION: ISRCTN26257579. PMID- 28588113 TI - Interpregnancy weight changes and impact on pregnancy outcome in a cohort of women with a macrosomic first delivery: a prospective longitudinal study. AB - OBJECTIVE: To determine the median interpregnancy maternal weight change between first and second pregnancies, and second and third pregnancies and to assess the impact of this weight change on pregnancy outcome in a cohort of women with a macrosomic first delivery. STUDY DESIGN: Prospective longitudinal study conducted over three pregnancies from 2007 to 2015. SETTING: Tertiary referral maternity hospital, Dublin, Ireland. PARTICIPANTS: Women were recruited if their first baby weighed >4.0 kg. METHODS: The pregnancy outcomes in the second and third pregnancies were analysed separately. Data were also analysed for both interpregnancy intervals comparing outcomes for those who gained any weight, or more weight than the median, with those who did not. MAIN OUTCOME MEASURES: Recurrent fetal macrosomia >=4.0 kg and gestational diabetes mellitus. RESULTS: There were 280 women who delivered a third baby between 2011 and 2015. There were no differences in pregnancy outcomes for the second pregnancy in women who gained interpregnancy weight compared with those who did not and those who gained more interpregnancy weight than the median compared with those who did not. There was a statistically significant increase in birth weight >=4.0 kg (54.0% vs 39.6% p=0.03) in those women who gained any weight between the second and third pregnancies. In those women who gained more interpregnancy weight than the median (1.70 kg) between a second and third pregnancy, there was a significant increase in the rate of gestational diabetes (6.5% vs 1.4%, p=0.03). CONCLUSIONS: This longitudinal study demonstrates that within this cohort maternal interpregnancy weight change between a second and third pregnancy is associated with an increase in birth weight >=4.0 kg. Additionally, a gain of more weight than the median (1.70 kg) is associated with a higher rate of gestational diabetes. PMID- 28588114 TI - Two Glycerol-3-Phosphate Dehydrogenases from Chlamydomonas Have Distinct Roles in Lipid Metabolism. AB - The metabolism of glycerol-3-phosphate (G3P) is important for environmental stress responses by eukaryotic microalgae. G3P is an essential precursor for glycerolipid synthesis and the accumulation of triacylglycerol (TAG) in response to nutrient starvation. G3P dehydrogenase (GPDH) mediates G3P synthesis, but the roles of specific GPDH isoforms are currently poorly understood. Of the five GPDH enzymes in the model alga Chlamydomonas reinhardtii, GPD2 and GPD3 were shown to be induced by nutrient starvation and/or salt stress. Heterologous expression of GPD2, a putative chloroplastic GPDH, and GPD3, a putative cytosolic GPDH, in a yeast gpd1Delta mutant demonstrated the functionality of both enzymes. C. reinhardtii knockdown mutants for GPD2 and GPD3 showed no difference in growth but displayed significant reduction in TAG concentration compared with the wild type in response to phosphorus or nitrogen starvation. Overexpression of GPD2 and GPD3 in C. reinhardtii gave distinct phenotypes. GPD2 overexpression lines showed only subtle metabolic phenotypes and no significant alteration in growth. In contrast, GPD3 overexpression lines displayed significantly inhibited growth and chlorophyll concentration, reduced glycerol concentration, and changes to lipid composition compared with the wild type, including increased abundance of phosphatidic acids but reduced abundance of diglycerides, triglycerides, and phosphatidylglycerol lipids. This may indicate a block in the downstream glycerolipid metabolism pathway in GPD3 overexpression lines. Thus, lipid engineering by GPDH modification may depend on the activities of other downstream enzyme steps. These results also suggest that GPD2 and GPD3 GPDH isoforms are important for nutrient starvation-induced TAG accumulation but have distinct metabolic functions. PMID- 28588115 TI - Hydroxystilbenes Are Monomers in Palm Fruit Endocarp Lignins. AB - Lignin, the plant cell wall polymer that binds fibers together but makes processing difficult, is traditionally formed from three monomers, the so-called monolignols (p-coumaryl, coniferyl, and sinapyl alcohols). Recently, we discovered, in grass lignins, a phenolic monomer that falls outside the canonical lignin biosynthetic pathway, the flavone tricin. As we show here, palm fruit (macauba [Acrocomia aculeata], carnauba [Copernicia prunifera], and coconut [Cocos nucifera]) endocarps contain lignin polymers derived in part from a previously unconsidered class of lignin monomers, the hydroxystilbenes, including the valuable compounds piceatannol and resveratrol. Piceatannol could be released from these lignins upon derivatization followed by reductive cleavage, a degradative method that cleaves beta-ether bonds, indicating that at least a fraction is incorporated through labile ether bonds. Nuclear magnetic resonance spectroscopy of products from the copolymerization of piceatannol and monolignols confirms the structures in the natural polymer and demonstrates that piceatannol acts as an authentic monomer participating in coupling and cross-coupling reactions during lignification. Therefore, palm fruit endocarps contain a new class of stilbenolignin polymers, further expanding the definition of lignin and implying that compounds such as piceatannol and resveratrol are potentially available in what is now essentially a waste product. PMID- 28588116 TI - High Oxygen Concentrations Adversely Affect the Performance of Pulmonary Surfactant. AB - BACKGROUND: Although effective in the neonatal population, exogenous pulmonary surfactant has not demonstrated a benefit in pediatric and adult subjects with hypoxic lung injury despite a sound physiologic rationale. Importantly, neonatal surfactant replacement therapy is administered in conjunction with low fractional FIO2 while pediatric/adult therapy is administered with high FIO2 . We suspected a connection between FIO2 and surfactant performance. Therefore, we sought to assess a possible mechanism by which the activity of pulmonary surfactant is adversely affected by direct oxygen exposure in in vitro experiments. METHODS: The mechanical performance of pulmonary surfactant was evaluated using 2 methods. First, Langmuir-Wilhelmy balance was utilized to study the reduction in surface area (deltaA) of surfactant to achieve a low bound value of surface tension after repeated compression and expansion cycles. Second, dynamic light scattering was utilized to measure the size of pulmonary surfactant particles in aqueous suspension. For both experiments, comparisons were made between surfactant exposed to 21% and 100% oxygen. RESULTS: The deltaA of surfactant was 21.1 +/- 2.0% and 35.8 +/- 2.0% during exposure to 21% and 100% oxygen, respectively (P = .02). Furthermore, dynamic light-scattering experiments revealed a micelle diameter of 336.0 +/- 12.5 MUm and 280.2 +/- 11.0 MUm in 21% and 100% oxygen, respectively (P < .001), corresponding to a ~16% decrease in micelle diameter following exposure to 100% oxygen. CONCLUSIONS: The characteristics of pulmonary surfactant were adversely affected by short-term exposure to oxygen. Specifically, surface tension studies revealed that short-term exposure of surfactant film to high concentrations of oxygen expedited the frangibility of pulmonary surfactant, as shown with the deltaA. This suggests that reductions in pulmonary compliance and associated adverse effects could begin to take effect in a very short period of time. If these findings can be demonstrated in vivo, a role for reduced FIO2 during exogenous surfactant delivery may have a clinical benefit. PMID- 28588117 TI - Aerosol Delivery Through Adult High Flow Nasal Cannula With Heliox and Oxygen. AB - BACKGROUND: Heliox (helium-oxygen mixture) has been shown to reduce turbulence and improve aerosol delivery in a range of clinical settings. We questioned whether heliox as compared with oxygen via high-flow nasal cannula (HFNC) would affect aerosol delivery. We hypothesized that heliox would have a significant effect on aerosol delivery as compared with oxygen with both quiet and distressed breathing patterns. METHODS: A vibrating mesh nebulizer was placed at the inlet of a humidifier via HFNC with small adult cannula distal to the heated-wire circuit with prongs placed into simulated nares with a T-shaped trap and absolute filter connected to a breath simulator set to adult quiet and distressed breathing parameters. Albuterol sulfate (0.083% 2.5 mg/3 mL) was aerosolized with heliox (80:20) and oxygen (100%) at 10, 30, and 50 L/min. Drug eluted from the filter was assayed with UV spectrophotometry (276 nm). Descriptive statistics, Kruskal-Wallis test, and Mann-Whitney U test were used for data analysis. P < .05 was considered statistically significant. RESULTS: Increasing flows with heliox and oxygen significantly decreased percentage inhaled dose (inhaled dose) of aerosol with a quiet breathing pattern (P = .02 and P = .030, respectively). In contrast, with a distressed breathing pattern, inhaled dose at 10 L/min was lower than at 30 and 50 L/min (P = .009 and P = .01, respectively) with both oxygen and heliox (P = .009 and P = .009, respectively). Despite a trend to higher aerosol deposition with heliox versus oxygen, the differences were not significant. CONCLUSIONS: With a distressed breathing pattern, aerosol delivery was greater at 30 and 50 L/min than with a quiet breathing pattern. Trends toward higher inhaled dose with heliox during HFNC were not significant. PMID- 28588118 TI - Clinical Management Strategies for Airway Pressure Release Ventilation: A Survey of Clinical Practice. AB - BACKGROUND: Airway pressure release ventilation (APRV) is a commonly used mode of ventilation designed to increase mean airway pressure and thus oxygenation. Different strategies for clinical management have been described in the literature but are largely based on physiologic concepts, animal data, and small clinical trials. The purpose of this study was to determine how APRV is currently managed by surveying practicing respiratory therapists with experience using APRV. METHODS: A 15-item survey was developed by the authors and posted on the AARConnect online media platform in January 2016 after being declared exempt by our institution's institutional review board. Survey questions were derived from a literature review of recommended APRV settings. Responses were limited to one per institution. RESULTS: The survey was completed by 60 respondents who used APRV. Of the 4 key initial APRV settings (P high, P low, T high, and T low), there was good agreement among survey responders and published guidelines for setting initial T high (4-6 s) and initial P low (0 cm H2O). There was some disagreement regarding initial P high, with 48% of responders matching P high to conventional ventilation plateau pressures but another 31% using conventional ventilation mean airway pressure plus 2-5 cm H2O. The most disagreement was with the T low setting, with only 47% of survey responders agreeing with published guidelines about using the expiratory flow signal to set T low. There was good agreement among survey responders and published guidelines for what changes to make when gas exchange was outside of the targeted range. A substantial number of respondents accepted P high and APRV release volumes that may exceed lung protective limits. CONCLUSIONS: There is only limited consensus among practitioners for initial APRV settings, probably reflecting the paucity of good clinical outcome data and confusion surrounding the physiology of this mode. PMID- 28588120 TI - Nanoplatforms for Circulating Tumor Cell Detection in Lung Cancer. PMID- 28588119 TI - High-Flow Nasal Cannula Utilization in Pediatric Critical Care. AB - BACKGROUND: High-flow nasal cannula (HFNC) is increasingly utilized in pediatrics, delivering humidified air and oxygen for respiratory conditions causing hypoxia and distress. In the neonatal ICU, it has been associated with better tolerance, lower complications, and lower cost. Few data exist regarding indications for use and the epidemiology of disease/pathology that warrants HFNC in the pediatric ICU. METHODS: This study is a retrospective cohort study of patients admitted to a tertiary children's hospital pediatric ICU and placed on HFNC from October 1, 2011 to October 31, 2013. Descriptive statistics were used to describe demographics and utilization data. t test comparisons were used for comparison data. RESULTS: Over the enrollment study period, 620 subjects with HFNC were managed, which represented 27% of total ICU admissions. The average age was 3.74 y (range 0-18.1 y), and subjects were 44% female and 65% African American. Reported primary indications for the utilization of HFNC were status asthmaticus (24%), status asthmaticus with pneumonia (17%), and bronchiolitis (16%). Of the subjects admitted with a primary diagnosis of status asthmaticus, 41% required management with terbutaline. Respiratory viral infections were detected by polymerase chain reaction in 334 subjects managed with HFNC (53.8%) and included 260 subjects testing positive for rhinovirus/enterovirus. When compared with all other respiratory viral illness, subjects with rhinovirus/enterovirus required a higher peak flow (14.9 L vs 13.1 L, P = .01); however, this was an older population, and peak oxygen concentration did not differ between the 2 groups (49.8% vs 47.1%, P = .25). HFNC was used as postextubation support in 16% of the subjects. Of the 63 subjects with congenital heart disease, 92% of the utilization was postextubation. CONCLUSIONS: HFNC was utilized in 27% of all pediatric ICU admissions for a wide range of indications. Development of protocols for the initiation, escalation, and weaning of HFNC would optimize the utilization. PMID- 28588121 TI - Assessing Agreement between Methods of Measurement. PMID- 28588122 TI - Patient Privacy and Clinical Laboratory Data. PMID- 28588123 TI - A Genoproteomic Approach to Detect Peptide Markers of Bacterial Respiratory Pathogens. AB - BACKGROUND: Rapid identification of respiratory pathogens may facilitate targeted antimicrobial therapy. Direct identification of bacteria in bronchoalveolar lavage (BAL) by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is confounded by interfering substances. We describe a method to identify unique peptide markers of 5 gram-negative bacteria by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for direct pathogen identification in BAL. METHODS: In silico translation and digestion were performed on 14-25 whole genomes representing strains of Acinetobacter baumannii, Moraxella catarrhalis, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Klebsiella pneumoniae. Peptides constituting theoretical core peptidomes in each were identified. Rapid tryptic digestion was performed; peptides were analyzed by LC-MS/MS and compared with the theoretical core peptidomes. High-confidence core peptides (false discovery rate <1%) were identified and analyzed with the lowest common ancestor search to yield potential species-specific peptide markers. The species specificity of each peptide was verified with protein BLAST. Further, 1 or 2 pathogens were serially diluted into pooled inflamed BAL, and a targeted LC MS/MS assay was used to detect 25 peptides simultaneously. RESULTS: Five unique peptides with the highest abundance for each pathogen distinguished these pathogens with varied detection sensitivities. Peptide markers for A. baumannii and P. aeruginosa, when spiked simultaneously into inflamed BAL, were detected with as few as 3.6 (0.2) * 103 and 2.2 (0.6) * 103 colony-forming units, respectively, by targeted LC-MS/MS. CONCLUSIONS: This proof-of-concept study shows the feasibility of identifying unique peptides in BAL for 5 gram-negative bacterial pathogens, and it may provide a novel approach for rapid direct identification of bacterial pathogens in BAL. PMID- 28588124 TI - Antenatal consultations for preterm labour: how are future mothers reassured? AB - OBJECTIVE: To evaluate whether the antenatal consultation for preterm labour worries or reassures women, and to identify factors contributing to these feelings. DESIGN: This is a prospective survey study from April 2012 to September 2013. This mixed-methodology tool was co-constructed with patients and first tested in a single-centre pilot study. SETTING: Three university-affiliated, tertiary care, high-risk obstetrics inpatient units in Quebec, Canada. PARTICIPANTS: Women hospitalised with threatened preterm labour between 26 and 32 weeks' gestational age completed the survey within 72 hours of an antenatal consultation by neonatology. 341 women were invited to participate and 226 mothers completed the survey (72% response rate), at a median gestational age of 30 weeks. MAIN OUTCOME MEASURES: Participant worry, reassurance and change in perception after the antenatal consultation were the main outcome measures. Multivariable logistic regression was used to identify factors associated with these outcomes. RESULTS: 23% of participants were worried by the consultation, and 87% were reassured by it. Lower gestational age and higher maternal education were associated with feeling worried (adjusted OR=0.83, 95% CI 0.70 to 0.99; and adjusted OR=2.15, 95% CI 1.04 to 4.44, respectively). Longer consultations were associated with reassurance (adjusted OR=8.21, 95% CI 2.67 to 25.26). Women were reassured by (1) feeling well informed about prematurity with optimistic outlooks, and (2) a trusting and reassuring expert neonatology team. High-quality interactions with neonatologists were associated with reassurance, while poorer communications were associated with feelings of worry. CONCLUSIONS: To be reassuring, neonatologists should strive to establish a trusting relationship with mothers, in which realistic and clear, but optimistic, information is offered. PMID- 28588125 TI - Neonatal ethanol exposure from ethanol-based hand sanitisers in isolettes. AB - OBJECTIVE: The aims of this study is to measure the ethanol vapours in the isolette after use of hands cleaned with ethanol-based hand sanitiser (EBHS). METHODS: Two squirts (1.5 mL) of hand sanitiser were rubbed on hands for 10 or 20 s before inserting the hands in the isolette for 5 min. Ethanol vapours were measured in the isolette with photoionisation detector and alcohol breathalyser for 30 min. RESULTS: Peak ethanol concentration in the isolette was considerably higher with a 10 s hand rub (381+/-192 ppm) compared with a 20 s hand rub (99+/ 50 ppm), and dissipated to <=5 ppm within 30 min. Under routine care, EBHS use by care providers exposes neonates in isolettes to 3.7-7.3 or 1.4-2.8 mg/kg ethanol per day with 10 or 20 s hand rubs, respectively. The expected blood level from average single exposure is 0.036 mg/dL with 10 s hand rub and may increase further with multiple exposures in a short period. CONCLUSION: Preterm neonates in the isolette are at risk of inadvertent exposure to ethanol. The expected blood alcohol level from this exposure is small and below 1 mg/dL level recommended by European Medicines Agency to limit the ethanol exposure in children. The unintended ethanol exposure can be avoided by rubbing hands for at least 20 s after applying EBHS. PMID- 28588126 TI - Differences in subependymal vein anatomy may predispose preterm infants to GMH IVH. AB - BACKGROUND AND PURPOSE: The anatomy of the deep venous system plays an important role in the pathogenesis of brain lesions in the preterm brain as shown by different histological studies. The aims of this study were to compare the subependymal vein anatomy of preterm neonates with germinal matrix haemorrhage intraventricular haemorrhage (GMH-IVH), as evaluated by susceptibility-weighted imaging (SWI) venography, with a group of age-matched controls with normal brain MRI, and to explore the relationship between the anatomical features of subependymal veins and clinical risk factors for GMH-IVH. METHODS: SWI venographies of 48 neonates with GMH-IVH and 130 neonates with normal brain MRI were retrospectively evaluated. Subependymal vein anatomy was classified into six different patterns: type 1 represented the classic pattern and types 2-6 were considered anatomic variants. A quantitative analysis of the venous curvature index was performed. Variables were analysed by using Mann-Whitney U and chi2 tests, and a multiple logistic regression analysis was performed to evaluate the association between anatomical features, clinical factors and GMH-IVH. RESULTS: A significant difference was noticed among the six anatomical patterns according to the presence of GMH-IVH (chi2=14.242, p=0.014). Anatomic variants were observed with higher frequency in neonates with GMH-IVH than in controls (62.2% and 49.6%, respectively). Neonates with GMH-IVH presented a narrower curvature of the terminal portion of subependymal veins (p<0.05). These anatomical features were significantly associated with GMH-IVH (p<0.05). CONCLUSION: Preterm neonates with GMH-IVH show higher variability of subependymal veins anatomy confirming a potential role as predisposing factor for GMH-IVH. PMID- 28588127 TI - A 6-Nucleotide Regulatory Motif within the AbcR Small RNAs of Brucella abortus Mediates Host-Pathogen Interactions. AB - In Brucella abortus, two small RNAs (sRNAs), AbcR1 and AbcR2, are responsible for regulating transcripts encoding ABC-type transport systems. AbcR1 and AbcR2 are required for Brucella virulence, as a double chromosomal deletion of both sRNAs results in attenuation in mice. Although these sRNAs are responsible for targeting transcripts for degradation, the mechanism utilized by the AbcR sRNAs to regulate mRNA in Brucella has not been described. Here, two motifs (M1 and M2) were identified in AbcR1 and AbcR2, and complementary motif sequences were defined in AbcR-regulated transcripts. Site-directed mutagenesis of M1 or M2 or of both M1 and M2 in the sRNAs revealed transcripts to be targeted by one or both motifs. Electrophoretic mobility shift assays revealed direct, concentration dependent binding of both AbcR sRNAs to a target mRNA sequence. These experiments genetically and biochemically characterized two indispensable motifs within the AbcR sRNAs that bind to and regulate transcripts. Additionally, cellular and animal models of infection demonstrated that only M2 in the AbcR sRNAs is required for Brucella virulence. Furthermore, one of the M2-regulated targets, BAB2_0612, was found to be critical for the virulence of B. abortus in a mouse model of infection. Although these sRNAs are highly conserved among Alphaproteobacteria, the present report displays how gene regulation mediated by the AbcR sRNAs has diverged to meet the intricate regulatory requirements of each particular organism and its unique biological niche.IMPORTANCE Small RNAs (sRNAs) are important components of bacterial regulation, allowing organisms to quickly adapt to changes in their environments. The AbcR sRNAs are highly conserved throughout the Alphaproteobacteria and negatively regulate myriad transcripts, many encoding ABC-type transport systems. In Brucella abortus, AbcR1 and AbcR2 are functionally redundant, as only a double abcR1 abcR2 (abcR1/2) deletion results in attenuation in vitro and in vivo In the present study, we confirmed that the AbcR sRNAs have redundant regulatory functions and defined two six nucleotide motifs, M1 and M2, that the AbcR sRNAs utilize to control gene expression. Importantly, only M2 was linked to B. abortus virulence. Further investigation of M2-regulated targets identified BAB2_0612 as critical for colonization of B. abortus in mice, highlighting the significance of AbcR M2 regulated transcripts for Brucella infection. Overall, our findings define the molecular mechanism of the virulence-associated AbcR system in the pathogenic bacterium B. abortus. PMID- 28588128 TI - Novel Chromosome Organization Pattern in Actinomycetales-Overlapping Replication Cycles Combined with Diploidy. AB - Bacteria regulate chromosome replication and segregation tightly with cell division to ensure faithful segregation of DNA to daughter generations. The underlying mechanisms have been addressed in several model species. It became apparent that bacteria have evolved quite different strategies to regulate DNA segregation and chromosomal organization. We have investigated here how the actinobacterium Corynebacterium glutamicum organizes chromosome segregation and DNA replication. Unexpectedly, we found that C. glutamicum cells are at least diploid under all of the conditions tested and that these organisms have overlapping C periods during replication, with both origins initiating replication simultaneously. On the basis of experimental data, we propose growth rate-dependent cell cycle models for C. glutamicumIMPORTANCE Bacterial cell cycles are known for few model organisms and can vary significantly between species. Here, we studied the cell cycle of Corynebacterium glutamicum, an emerging cell biological model organism for mycolic acid-containing bacteria, including mycobacteria. Our data suggest that C. glutamicum carries two pole attached chromosomes that replicate with overlapping C periods, thus initiating a new round of DNA replication before the previous one is terminated. The newly replicated origins segregate to midcell positions, where cell division occurs between the two new origins. Even after long starvation or under extremely slow growth conditions, C. glutamicum cells are at least diploid, likely as an adaptation to environmental stress that may cause DNA damage. The cell cycle of C. glutamicum combines features of slow-growing organisms, such as polar origin localization, and fast-growing organisms, such as overlapping C periods. PMID- 28588129 TI - Complete Biosynthesis of Anthocyanins Using E. coli Polycultures. AB - Fermentation-based chemical production strategies provide a feasible route for the rapid, safe, and sustainable production of a wide variety of important chemical products, ranging from fuels to pharmaceuticals. These strategies have yet to find wide industrial utilization due to their inability to economically compete with traditional extraction and chemical production methods. Here, we engineer for the first time the complex microbial biosynthesis of an anthocyanin plant natural product, starting from sugar. This was accomplished through the development of a synthetic, 4-strain Escherichia coli polyculture collectively expressing 15 exogenous or modified pathway enzymes from diverse plants and other microbes. This synthetic consortium-based approach enables the functional expression and connection of lengthy pathways while effectively managing the accompanying metabolic burden. The de novo production of specific anthocyanin molecules, such as calistephin, has been an elusive metabolic engineering target for over a decade. The utilization of our polyculture strategy affords milligram per-liter production titers. This study also lays the groundwork for significant advances in strain and process design toward the development of cost-competitive biochemical production hosts through nontraditional methodologies.IMPORTANCE To efficiently express active extensive recombinant pathways with high flux in microbial hosts requires careful balance and allocation of metabolic resources such as ATP, reducing equivalents, and malonyl coenzyme A (malonyl-CoA), as well as various other pathway-dependent cofactors and precursors. To address this issue, we report the design, characterization, and implementation of the first synthetic 4-strain polyculture. Division of the overexpression of 15 enzymes and transcription factors over 4 independent strain modules allowed for the division of metabolic burden and for independent strain optimization for module-specific metabolite needs. This study represents the most complex synthetic consortia constructed to date for metabolic engineering applications and provides a new paradigm in metabolic engineering for the reconstitution of extensive metabolic pathways in nonnative hosts. PMID- 28588130 TI - Lateral Gene Transfer Dynamics in the Ancient Bacterial Genus Streptomyces. AB - Lateral gene transfer (LGT) profoundly shapes the evolution of bacterial lineages. LGT across disparate phylogenetic groups and genome content diversity between related organisms suggest a model of bacterial evolution that views LGT as rampant and promiscuous. It has even driven the argument that species concepts and tree-based phylogenetics cannot be applied to bacteria. Here, we show that acquisition and retention of genes through LGT are surprisingly rare in the ubiquitous and biomedically important bacterial genus Streptomyces Using a molecular clock, we estimate that the Streptomyces bacteria are ~380 million years old, indicating that this bacterial genus is as ancient as land vertebrates. Calibrating LGT rate to this geologic time span, we find that on average only 10 genes per million years were acquired and subsequently maintained. Over that same time span, Streptomyces accumulated thousands of point mutations. By explicitly incorporating evolutionary timescale into our analyses, we provide a dramatically different view on the dynamics of LGT and its impact on bacterial evolution.IMPORTANCE Tree-based phylogenetics and the use of species as units of diversity lie at the foundation of modern biology. In bacteria, these pillars of evolutionary theory have been called into question due to the observation of thousands of lateral gene transfer (LGT) events within and between lineages. Here, we show that acquisition and retention of genes through LGT are exceedingly rare in the bacterial genus Streptomyces, with merely one gene acquired in Streptomyces lineages every 100,000 years. These findings stand in contrast to the current assumption of rampant genetic exchange, which has become the dominant hypothesis used to explain bacterial diversity. Our results support a more nuanced understanding of genetic exchange, with LGT impacting evolution over short timescales but playing a significant role over long timescales. Deeper understanding of LGT provides new insight into the evolutionary history of life on Earth, as the vast majority of this history is microbial. PMID- 28588131 TI - Rationally Designed Influenza Virus Vaccines That Are Antigenically Stable during Growth in Eggs. AB - Influenza virus vaccine production is currently limited by the ability to grow circulating human strains in chicken eggs or in cell culture. To facilitate cost effective growth, vaccine strains are serially passaged under production conditions, which frequently results in mutations of the major antigenic protein, the viral hemagglutinin (HA). Human vaccination with an antigenically drifted strain is known to contribute to poor vaccine efficacy. To address this problem, we developed a replication-competent influenza A virus (IAV) with an artificial genomic organization that allowed the incorporation of two independent and functional HA proteins with different growth requirements onto the same virion. Vaccination with these viruses induced protective immunity against both strains from which the HA proteins were derived, and the magnitude of the response was as high as or higher than vaccination with either of the monovalent parental strains alone. Dual-HA viruses also displayed remarkable antigenic stability; even when using an HA protein known to be highly unstable during growth in eggs, we observed high-titer virus amplification without a single adaptive mutation. Thus, the viral genomic design described in this work can be used to grow influenza virus vaccines to high titers without introducing antigenic mutations.IMPORTANCE Influenza A virus (IAV) is a major public health threat, and vaccination is currently the best available strategy to prevent infection. While there have been many advances in influenza vaccine production, the fact that we cannot predict the growth characteristics of a given strain under vaccine production conditions a priori introduces fundamental uncertainty into the process. Clinically relevant IAV strains frequently grow poorly under vaccine conditions, and this poor growth can result in the delay of vaccine production or the exchange of the recommended strain for one with favorable growth properties. Even in strains that grow to high titers, adaptive mutations in the antigenic protein hemagglutinin (HA) that make it antigenically dissimilar to the circulating strain are common. The genomic restructuring of the influenza virus described in this work offers a solution to the problem of uncertain or unstable growth of IAV during vaccine production. PMID- 28588132 TI - Enteroaggregative Escherichia coli Adherence Fimbriae Drive Inflammatory Cell Recruitment via Interactions with Epithelial MUC1. AB - Enteroaggregative Escherichia coli (EAEC) causes diarrhea and intestinal inflammation worldwide. EAEC strains are characterized by the presence of aggregative adherence fimbriae (AAF), which play a key role in pathogenesis by mediating attachment to the intestinal mucosa and by triggering host inflammatory responses. Here, we identify the epithelial transmembrane mucin MUC1 as an intestinal host cell receptor for EAEC, demonstrating that AAF-mediated interactions between EAEC and MUC1 facilitate enhanced bacterial adhesion. We further demonstrate that EAEC infection also causes elevated expression of MUC1 in inflamed human intestinal tissues. Moreover, we find that MUC1 facilitates AAF dependent migration of neutrophils across the epithelium in response to EAEC infection. Thus, we show for the first time a proinflammatory role for MUC1 in the host response to an intestinal pathogen.IMPORTANCE EAEC is a clinically important intestinal pathogen that triggers intestinal inflammation and diarrheal illness via mechanisms that are not yet fully understood. Our findings provide new insight into how EAEC triggers host inflammation and underscores the pivotal role of AAFs-the principal adhesins of EAEC-in driving EAEC-associated disease. Most importantly, our findings add a new dimension to the signaling properties of the transmembrane mucin MUC1. Mostly studied for its role in various forms of cancer, MUC1 is widely regarded as playing an anti-inflammatory role in response to infection with bacterial pathogens in various tissues. However, the role of MUC1 during intestinal infections has not been previously explored, and our results describe the first report of MUC1 as a proinflammatory factor following intestinal infection. PMID- 28588133 TI - Novel Nonreplicating Vaccinia Virus Vector Enhances Expression of Heterologous Genes and Suppresses Synthesis of Endogenous Viral Proteins. AB - Viruses are used as expression vectors for protein synthesis, immunology research, vaccines, and therapeutics. Advantages of poxvirus vectors include the accommodation of large amounts of heterologous DNA, the presence of a cytoplasmic site of transcription, and high expression levels. On the other hand, competition of approximately 200 viral genes with the target gene for expression and immune recognition may be disadvantageous. We describe a vaccinia virus (VACV) vector that uses an early promoter to express the bacteriophage T7 RNA polymerase; has the A23R intermediate transcription factor gene deleted, thereby restricting virus replication to complementing cells; and has a heterologous gene regulated by a T7 promoter. In noncomplementing cells, viral early gene expression and DNA replication occurred normally but synthesis of intermediate and late proteins was prevented. Nevertheless, the progeny viral DNA provided templates for abundant expression of heterologous genes regulated by a T7 promoter. Selective expression of the Escherichia coli lac repressor gene from an intermediate promoter reduced transcription of the heterologous gene specifically in complementing cells, where large amounts might adversely impact VACV replication. Expression of heterologous proteins mediated by the A23R deletion vector equaled that of a replicating VACV, was higher than that of a nonreplicating modified vaccinia virus Ankara (MVA) vector used for candidate vaccines in vitro and in vivo, and was similarly immunogenic in mice. Unlike the MVA vector, the A23R deletion vector still expresses numerous early genes that can restrict immunogenicity as demonstrated here by the failure of the prototype vector to induce interferon alpha. By deleting immunomodulatory genes, we anticipate further improvements in the system.IMPORTANCE Vaccines provide an efficient and effective way of preventing infectious diseases. Nevertheless, new and better vaccines are needed. Vaccinia virus, which was used successfully as a live vaccine to eradicate smallpox, has been further attenuated and adapted as a recombinant vector for immunization against other pathogens. However, since the initial description of this vector system, only incremental improvements largely related to safety have been implemented. Here we described novel modifications of the platform that increased expression of the heterologous target gene and decreased expression of endogenous vaccinia virus genes while providing safety by preventing replication of the candidate vaccine except in complementing cells used for vector propagation. PMID- 28588136 TI - A Cautionary Tale: Tn903 aph, Kanamycin Resistance Redux in the Environment. PMID- 28588135 TI - Spatial Distribution and Ribosome-Binding Dynamics of EF-P in Live Escherichia coli. AB - In vitro assays find that ribosomes form peptide bonds to proline (Pro) residues more slowly than to other residues. Ribosome profiling shows that stalling at Pro Pro-X triplets is especially severe but is largely alleviated in Escherichia coli by the action of elongation factor EF-P. EF-P and its eukaryotic/archaeal homolog IF5A enhance the peptidyl transfer step of elongation. Here, a superresolution fluorescence localization and tracking study of EF-P-mEos2 in live E. coli provides the first in vivo information about the spatial distribution and on-off binding kinetics of EF-P. Fast imaging at 2 ms/frame helps to distinguish ribosome-bound (slowly diffusing) EF-P from free (rapidly diffusing) EF-P. Wild type EF-P exhibits a three-peaked axial spatial distribution similar to that of ribosomes, indicating substantial binding. The mutant EF-PK34A exhibits a homogeneous distribution, indicating little or no binding. Some 30% of EF-P copies are bound to ribosomes at a given time. Two-state modeling and copy number estimates indicate that EF-P binds to 70S ribosomes during 25 to 100% of translation cycles. The timescale of the typical diffusive search by free EF-P for a ribosome-binding site is taufree ~ 16 ms. The typical residence time of an EF-P on the ribosome is very short, taubound ~ 7 ms. Evidently, EF-P binds to ribosomes during many or most elongation cycles, much more often than the frequency of Pro-Pro motifs. Emptying of the E site during part of the cycle is consistent with recent in vitro experiments indicating dissociation of the deacylated tRNA upon translocation.IMPORTANCE Ribosomes translate the codon sequence within mRNA into the corresponding sequence of amino acids within the nascent polypeptide chain, which in turn ultimately folds into functional protein. At each codon, bacterial ribosomes are assisted by two well-known elongation factors: EF-Tu, which aids binding of the correct aminoacyl-tRNA to the ribosome, and EF-G, which promotes tRNA translocation after formation of the new peptide bond. A third factor, EF-P, has been shown to alleviate ribosomal pausing at rare Pro-Pro motifs, which are translated very slowly without EF-P. Here, we use superresolution fluorescence imaging to study the spatial distribution and ribosome-binding dynamics of EF-P in live E. coli cells. We were surprised to learn that EF-P binds to and unbinds from translating ribosomes during at least 25% of all elongation events; it may bind during every elongation cycle. PMID- 28588134 TI - The Rcs-Regulated Colanic Acid Capsule Maintains Membrane Potential in Salmonella enterica serovar Typhimurium. AB - The Rcs phosphorelay and Psp (phage shock protein) systems are envelope stress responses that are highly conserved in gammaproteobacteria. The Rcs regulon was found to be strongly induced during metal deprivation of Salmonella enterica serovar Typhimurium lacking the Psp response. Nineteen genes activated by the RcsA-RcsB response regulator make up an operon responsible for the production of colanic acid capsular polysaccharide, which promotes biofilm development. Despite more than half a century of research, the physiological function of colanic acid has remained elusive. Here we show that Rcs-dependent colanic acid production maintains the transmembrane electrical potential and proton motive force in cooperation with the Psp response. Production of negatively charged exopolysaccharide covalently bound to the outer membrane may enhance the surface potential by increasing the local proton concentration. This provides a unifying mechanism to account for diverse Rcs/colanic acid-related phenotypes, including susceptibility to membrane-damaging agents and biofilm formation.IMPORTANCE Colanic acid is a negatively charged polysaccharide capsule produced by Escherichia coli, Salmonella, and other gammaproteobacteria. Research conducted over the 50 years since the discovery of colanic acid suggests that this exopolysaccharide plays an important role for bacteria living in biofilms. However, a precise physiological role for colanic acid has not been defined. In this study, we provide evidence that colanic acid maintains the transmembrane potential and proton motive force during envelope stress. This work provides a new and fundamental insight into bacterial physiology. PMID- 28588138 TI - When are species invasions useful for addressing fundamental questions in plant biology? PMID- 28588137 TI - The real significance of ancient DNA. PMID- 28588139 TI - Manipulating the ABCs of self-assembly via low-chi block polymer design. AB - Block polymer self-assembly typically translates molecular chain connectivity into mesoscale structure by exploiting incompatible blocks with large interaction parameters (chiij). In this article, we demonstrate that the converse approach, encoding low-chi interactions in ABC bottlebrush triblock terpolymers (chiAC [Formula: see text] 0), promotes organization into a unique mixed-domain lamellar morphology, which we designate LAMP Transmission electron microscopy indicates that LAMP exhibits ACBC domain connectivity, in contrast to conventional three domain lamellae (LAM3) with ABCB periods. Complementary small-angle X-ray scattering experiments reveal a strongly decreasing domain spacing with increasing total molar mass. Self-consistent field theory reinforces these observations and predicts that LAMP is thermodynamically stable below a critical chiAC, above which LAM3 emerges. Both experiments and theory expose close analogies to ABA' triblock copolymer phase behavior, collectively suggesting that low-chi interactions between chemically similar or distinct blocks intimately influence self-assembly. These conclusions provide fresh opportunities for block polymer design with potential consequences spanning all self-assembling soft materials. PMID- 28588140 TI - Reconstitution of a minimal machinery capable of assembling periplasmic type IV pili. AB - Type IV pili (Tfp), which are key virulence factors in many bacterial pathogens, define a large group of multipurpose filamentous nanomachines widespread in Bacteria and Archaea. Tfp biogenesis is a complex multistep process, which relies on macromolecular assemblies composed of 15 conserved proteins in model gram negative species. To improve our limited understanding of the molecular mechanisms of filament assembly, we have used a synthetic biology approach to reconstitute, in a nonnative heterologous host, a minimal machinery capable of building Tfp. Here we show that eight synthetic genes are sufficient to promote filament assembly and that the corresponding proteins form a macromolecular complex at the cytoplasmic membrane, which we have purified and characterized biochemically. Our results contribute to a better mechanistic understanding of the assembly of remarkable dynamic filaments nearly ubiquitous in prokaryotes. PMID- 28588141 TI - Tetragonal CH3NH3PbI3 is ferroelectric. AB - Halide perovskite (HaP) semiconductors are revolutionizing photovoltaic (PV) solar energy conversion by showing remarkable performance of solar cells made with HaPs, especially tetragonal methylammonium lead triiodide (MAPbI3). In particular, the low voltage loss of these cells implies a remarkably low recombination rate of photogenerated carriers. It was suggested that low recombination can be due to the spatial separation of electrons and holes, a possibility if MAPbI3 is a semiconducting ferroelectric, which, however, requires clear experimental evidence. As a first step, we show that, in operando, MAPbI3 (unlike MAPbBr3) is pyroelectric, which implies it can be ferroelectric. The next step, proving it is (not) ferroelectric, is challenging, because of the material's relatively high electrical conductance (a consequence of an optical band gap suitable for PV conversion) and low stability under high applied bias voltage. This excludes normal measurements of a ferroelectric hysteresis loop, to prove ferroelectricity's hallmark switchable polarization. By adopting an approach suitable for electrically leaky materials as MAPbI3, we show here ferroelectric hysteresis from well-characterized single crystals at low temperature (still within the tetragonal phase, which is stable at room temperature). By chemical etching, we also can image the structural fingerprint for ferroelectricity, polar domains, periodically stacked along the polar axis of the crystal, which, as predicted by theory, scale with the overall crystal size. We also succeeded in detecting clear second harmonic generation, direct evidence for the material's noncentrosymmetry. We note that the material's ferroelectric nature, can, but need not be important in a PV cell at room temperature. PMID- 28588142 TI - Recent evolution of extreme cestode growth suppression by a vertebrate host. AB - Parasites can be a major cause of natural selection on hosts, which consequently evolve a variety of strategies to avoid, eliminate, or tolerate infection. When ecologically similar host populations present disparate infection loads, this natural variation can reveal immunological strategies underlying adaptation to infection and population divergence. For instance, the tapeworm Schistocephalus solidus persistently infects 0-80% of threespine stickleback (Gasterosteus aculeatus) in lakes on Vancouver Island. To test whether these heterogeneous infection rates result from evolved differences in immunity, we experimentally exposed laboratory-reared fish from ecologically similar high-infection and no infection populations to controlled doses of Schistocephalus We observed heritable between-population differences in several immune traits: Fish from the naturally uninfected population initiated a stronger granulocyte response to Schistocephalus infection, and their granulocytes constitutively generate threefold more reactive oxygen species in cell culture. Despite these immunological differences, Schistocephalus was equally successful at establishing initial infections in both host populations. However, the no-infection fish dramatically suppressed tapeworm growth relative to high-infection fish, and parasite size was intermediate in F1 hybrid hosts. Our results show that stickleback recently evolved heritable variation in their capacity to suppress helminth growth by two orders of magnitude. Data from many natural populations indicate that growth suppression is widespread but not universal and, when present, is associated with reduced infection prevalence. Host suppression of helminth somatic growth may be an important immune strategy that aids in parasite clearance or in mitigating the fitness costs of persistent infection. PMID- 28588144 TI - Effect of water flow and chemical environment on microbiota growth and composition in the human colon. AB - The human gut harbors a dynamic microbial community whose composition bears great importance for the health of the host. Here, we investigate how colonic physiology impacts bacterial growth, which ultimately dictates microbiota composition. Combining measurements of bacterial physiology with analysis of published data on human physiology into a quantitative, comprehensive modeling framework, we show how water flow in the colon, in concert with other physiological factors, determine the abundances of the major bacterial phyla. Mechanistically, our model shows that local pH values in the lumen, which differentially affect the growth of different bacteria, drive changes in microbiota composition. It identifies key factors influencing the delicate regulation of colonic pH, including epithelial water absorption, nutrient inflow, and luminal buffering capacity, and generates testable predictions on their effects. Our findings show that a predictive and mechanistic understanding of microbial ecology in the gut is possible. Such predictive understanding is needed for the rational design of intervention strategies to actively control the microbiota. PMID- 28588145 TI - Ecosystem-based management and the wealth of ecosystems. AB - We merge inclusive wealth theory with ecosystem-based management (EBM) to address two challenges in the science of sustainable management of ecosystems. First, we generalize natural capital theory to approximate realized shadow prices for multiple interacting natural capital stocks (species) making up an ecosystem. These prices enable ecosystem components to be better included in wealth-based sustainability measures. We show that ecosystems are best envisioned as portfolios of assets, where the portfolio's performance depends on the performance of the underlying assets influenced by their interactions. Second, changes in ecosystem wealth provide an attractive headline index for EBM, regardless of whether ecosystem wealth is ultimately included in a broader wealth index. We apply our approach to the Baltic Sea ecosystem, focusing on the interacting community of three commercially important fish species: cod, herring, and sprat. Our results incorporate supporting services embodied in the shadow price of a species through its trophic interactions. Prey fish have greater shadow prices than expected based on market value, and predatory fish have lower shadow prices than expected based on market value. These results are because correctly measured shadow prices reflect interdependence and limits to substitution. We project that ecosystem wealth in the Baltic Sea fishery ecosystem generally increases conditional on the EBM-inspired multispecies maximum sustainable yield management beginning in 2017, whereas continuing the current single-species management generally results in declining wealth. PMID- 28588143 TI - Ambient nitrogen reduction cycle using a hybrid inorganic-biological system. AB - We demonstrate the synthesis of NH3 from N2 and H2O at ambient conditions in a single reactor by coupling hydrogen generation from catalytic water splitting to a H2-oxidizing bacterium Xanthobacter autotrophicus, which performs N2 and CO2 reduction to solid biomass. Living cells of X. autotrophicus may be directly applied as a biofertilizer to improve growth of radishes, a model crop plant, by up to ~1,440% in terms of storage root mass. The NH3 generated from nitrogenase (N2ase) in X. autotrophicus can be diverted from biomass formation to an extracellular ammonia production with the addition of a glutamate synthetase inhibitor. The N2 reduction reaction proceeds at a low driving force with a turnover number of 9 * 109 cell-1 and turnover frequency of 1.9 * 104 s-1?cell-1 without the use of sacrificial chemical reagents or carbon feedstocks other than CO2 This approach can be powered by renewable electricity, enabling the sustainable and selective production of ammonia and biofertilizers in a distributed manner. PMID- 28588146 TI - PCSK9 Is Increased in Youth With Type 1 Diabetes. PMID- 28588147 TI - A Plutocratic Proposal: an ethical way for rich patients to pay for a place on a clinical trial. AB - Many potential therapeutic agents are discarded before they are tested in humans. These are not quack medications. They are drugs and other interventions that have been developed by responsible scientists in respectable companies or universities and are often backed up by publications in peer-reviewed journals. These possible treatments might ease suffering and prolong the lives of innumerable patients, yet they have been put aside. In this paper, we outline a novel mechanism-the Plutocratic Proposal-to revive such neglected research and fund early phase clinical trials. The central idea of the Proposal is that any patient who rescues a potential therapeutic agent from neglect by funding early phase clinical trials (either entirely or in large part) should be offered a place on the trial. PMID- 28588148 TI - Functional Optical Imaging of Primary Human Tumor Organoids: Development of a Personalized Drug Screen. AB - Primary tumor organoids are a robust model of individual human cancers and present a unique platform for patient-specific drug testing. Optical imaging is uniquely suited to assess organoid function and behavior because of its subcellular resolution, penetration depth through the entire organoid, and functional endpoints. Specifically, optical metabolic imaging (OMI) is highly sensitive to drug response in organoids, and OMI in tumor organoids correlates with primary tumor drug response. Therefore, an OMI organoid drug screen could enable accurate testing of drug response for individualized cancer treatment. The objective of this perspective is to introduce OMI and tumor organoids to a general audience in order to foster the adoption of these techniques in diverse clinical and laboratory settings. PMID- 28588149 TI - Tumor Metabolic Features Identified by 18F-FDG PET Correlate with Gene Networks of Immune Cell Microenvironment in Head and Neck Cancer. AB - The importance of 18F-FDG PET in imaging head and neck squamous cell carcinoma (HNSCC) has grown in recent decades. Because PET has prognostic values, and provides functional and molecular information in HNSCC, the genetic and biologic backgrounds associated with PET parameters are of great interest. Here, as a systems biology approach, we aimed to investigate gene networks associated with tumor metabolism and their biologic function using RNA sequence and 18F-FDG PET data. Methods: Using RNA sequence data of HNSCC downloaded from The Cancer Genome Atlas data portal, we constructed a gene coexpression network. PET parameters including lesion-to-blood-pool ratio, metabolic tumor volume, and tumor lesion glycolysis were calculated. The Pearson correlation test was performed between module eigengene-the first principal component of modules' expression profile-and the PET parameters. The significantly correlated module was functionally annotated with gene ontology terms, and its hub genes were identified. Survival analysis of the significantly correlated module was performed. Results: We identified 9 coexpression network modules from the preprocessed RNA sequence data. A network module was significantly correlated with total lesion glycolysis as well as maximum and mean 18F-FDG uptake. The expression profiles of hub genes of the network were inversely correlated with 18F-FDG uptake. The significantly annotated gene ontology terms of the module were associated with immune cell activation and aggregation. The module demonstrated significant association with overall survival, and the group with higher module eigengene showed better survival than the other groups with statistical significance (P = 0.022). Conclusion: We showed that a gene network that accounts for immune cell microenvironment was associated with 18F-FDG uptake as well as prognosis in HNSCC. Our result supports the idea that competition for glucose between cancer cell and immune cell plays an important role in cancer progression associated with hypermetabolic features. In the future, PET parameters could be used as a surrogate marker of HNSCC for estimating molecular status of immune cell microenvironment. PMID- 28588150 TI - Dose Mapping After Endoradiotherapy with 177Lu-DOTATATE/DOTATOC by a Single Measurement After 4 Days. AB - Dosimetry of organs and tumors helps to assess risks and benefit of treatment with 177Lu-DOTATATE/DOTATOC. However, it is often not performed in clinical routine because of additional efforts, the complexity of data collection and analysis, and the additional burden for the patients. Aiming at a simplification of dosimetry, we analyzed the accuracy of a theoretically substantiated approximation, which allows the calculation of absorbed doses from a single measurement of the abdominal activity distribution. Methods: Activity kinetics were retrospectively assessed from planar images in 29 patients with neuroendocrine tumors (NETs; n = 21) or meningioma (n = 8) after the administration of 177Lu-DOTATATE (n = 22) or 177Lu-DOTATOC (n = 7). Mono- or biexponential functions were fitted to measured data in 54 kidneys, 25 livers, 27 spleens, and 30 NET lesions. It was evaluated for each fit function how well the integral over time was represented by an approximation calculated as the product of the time tl of a single measurement, the expected reading at time tl, and the factor 2/ln(2). Tissue-specific deviations of the approximation from the time integral were calculated for time points tl of 24, 48, 72, 96, 120, and 144 h. Results: The correlation between time integral and approximation improved with increasing time tl Pearson r exceeded 0.95 for a tl of 96 h or more in all tissues. The lowest maximum errors were observed at a tl of 96 h, with deviations of the approximation from the time integral of median +5% (range, -9% to +17%) for kidneys, +6% (range, -7% to +12%) for livers, +8% (range, +2% to +20%) for spleens, and +6% (range, -11% to +16%) for NET lesions. Accuracy was reduced for measurements after 72 or 120 h. For measurements after 24, 48, and 144 h, the approximation led to large deviations for some of the patients, in particular unacceptable underestimates of the absorbed dose to the kidneys. Conclusion: A single quantitative measurement of the abdominal activity concentration by SPECT/CT 4 d after the administration of 177Lu-DOTATATE/DOTATOC provides a 3 dimensional dose map and can be used to estimate the doses actually absorbed in the treatment cycle with minor additional resources and effort. PMID- 28588151 TI - In Vivo Imaging of the Programmed Death Ligand 1 by 18F PET. AB - Programmed death ligand 1 (PD-L1) is an immune regulatory ligand that binds to the T-cell immune check point programmed death 1. Tumor expression of PD-L1 is correlated with immune suppression and poor prognosis. It is also correlated with therapeutic efficacy of programmed death 1 and PD-L1 inhibitors. In vivo imaging may enable real-time follow-up of changing PD-L1 expression and heterogeneity evaluation of PD-L1 expression across tumors in the same subject. We have radiolabeled the PD-L1-binding Affibody molecule NOTA-ZPD-L1_1 with 18F and evaluated its in vitro and in vivo binding affinity, targeting, and specificity. Methods: The affinity of the PD-L1-binding Affibody ligand ZPD-L1_1 was evaluated by surface plasmon resonance. Labeling was accomplished by maleimide coupling of NOTA to a unique cysteine residue and chelation of 18F-AlF. In vivo studies were performed in PD-L1-positive, PD-L1-negative, and mixed tumor-bearing severe combined immunodeficiency mice. Tracer was injected via the tail vein, and dynamic PET scans were acquired for 90 min, followed by gamma-counting biodistribution. Immunohistochemical staining with an antibody specific for anti PD-L1 (22C3) was used to evaluate the tumor distribution of PD-L1. Immunohistochemistry results were then compared with ex vivo autoradiographic images obtained from adjacent tissue sections. Results: NOTA-ZPD-L1_1 was labeled, with a radiochemical yield of 15.1% +/- 5.6%, radiochemical purity of 96.7% +/- 2.0%, and specific activity of 14.6 +/- 6.5 GBq/MUmol. Surface plasmon resonance showed a NOTA-conjugated ligand binding affinity of 1 nM. PET imaging demonstrated rapid uptake of tracer in the PD-L1-positive tumor, whereas the PD L1-negative control tumor showed little tracer retention. Tracer clearance from most organs and blood was quick, with biodistribution showing prominent kidney retention, low liver uptake, and a significant difference between PD-L1-positive (percentage injected dose per gram [%ID/g] = 2.56 +/- 0.33) and -negative (%ID/g = 0.32 +/- 0.05) tumors (P = 0.0006). Ex vivo autoradiography showed excellent spatial correlation with immunohistochemistry in mixed tumors. Conclusion: Our results show that Affibody ligands can be effective at targeting tumor PD-L1 in vivo, with good specificity and rapid clearance. Future studies will explore methods to reduce kidney activity retention and further increase tumor uptake. PMID- 28588152 TI - Treatment of Transverse with or without Posterior Wall Fractures of Acetabulum Using a Modified Smith-Petersen Combined with Kocher-Langenbeck Approach. AB - BACKGROUND The aim of this study was to explore the surgical treatment of transverse with or without posterior wall fractures of the acetabulum. MATERIAL AND METHODS We surgically treated 21 consecutive cases of pure transverse (7 cases) and with posterior wall (14 cases) fractures of the acetabulum. The anterior column fractures were firstly reduced, temporarily fixed through a modified Smith-Petersen small incision, and finally fixed after the fixation of the posterior column and wall fractures, which were reduced and fixed through a Kocher-Langenbeck approach. The operative time, intra-operative blood loss, quality of reduction (Matta criteria), perioperative complications, osseous union, subsequent complications, and hip function evaluation were recorded. RESULTS The mean operative time was 198.1 min and the mean intra-operative blood loss was 938.1 ml. Anatomic reduction of the anterior column was obtained in 20 cases and was imperfect in 1 case. All posterior column and wall fractures were anatomically reduced. We followed up 18 cases for a mean duration of 16.3 (8-30) months. All the fractures achieved osseous union. The mean Harris score was 85.1 points, with an excellent result in 7 cases, good in 8, fair in 2, and poor in 1. According to modified Merle d' Aubigne and Postel score system, the results were excellent in 2 cases, good in 15, and poor in 1. Avascular necrosis of the femoral head occurred in 1 case, heterotopic ossification in 3 cases, and numbness of the anterolateral thigh in 6 cases. CONCLUSIONS For transverse with or without posterior wall fractures of the acetabulum, reduction and fixation of anterior and posterior column should be done in sequence, and a modified Smith Petersen small incision might be a good choice in reduction and fixation of the anterior column because it possesses advantages of direct visualization and minimal invasion. PMID- 28588153 TI - Gastric Dilatation and Abdominal Compartment Syndrome in a Child with Prader Willi Syndrome. AB - BACKGROUND Prader-Willi syndrome (PWS) is a genetic disorder characterized by initial muscular hypotonia and feeding difficulties, and later an insatiable appetite, hyperphagia and obesity along with mild to moderate intellectual impairment. Affected individuals' food-seeking behavior and suspected delayed gastric emptying can lead to gastric dilatation with subsequent necrosis and perforation. CASE REPORT We present the case of a 5-year-old boy diagnosed with Prader-Willi syndrome at neonatal age due to muscular hypotonia, who started growth hormone therapy at 20 months. He presented with two episodes of a rapidly progressing gastric dilatation that led to abdominal hypertension and secondary shock at the age of 2 and 5. No large amount of food was eaten before any of the episodes, and he had abdominal pain and vomiting on both occasions. On arrival at the emergency room, a nasogastric tube was placed and aspiration of food material was performed. Abdominal X-ray and CT scan revealed massive gastric dilatation. He was admitted at the Pediatric Intensive Care Unit and after a variable period of fasting, tolerated oral intake and could be discharged. CONCLUSIONS Gastric dilatation due to gastroparesis in PWS is a rare complication. However, it is a life-threatening situation and physicians should therefore maintain a high level of suspicion for gastric dilatation when patients present with warning symptoms such as abdominal pain or discomfort and vomiting. PMID- 28588154 TI - Ultrasonographic Evaluation of Palpable Breast Mass and Correlation with Histopathology. AB - Breast cancer is the most common malignancy in women and the second most common cause of cancer-related mortality. The distinction by physical examination of physiologic nodularity from abnormal masses can be difficult, while the clinical differentiation of a malignant mass from a benign one is difficult; the medical as well as potential legal consequences of missing a palpable carcinoma are high. There are significant number of reported cases of false-negative findings on mammography and the great desire not to miss a malignant lesion in the early stage of disease lead to aggressive biopsy, but the biopsy rate for cancer is only 10.0% to 30.0%. This means that 70.0% to 90.0% of breast biopsies are performed for benign diseases, which induce unnecessary patients discomfort and anxiety in addition to increasing costs to the patient. Clearly, there is a great need for development of additional reliable methods to complement the existing diagnostic procedures to avoid unnecessary biopsy. This cross sectional study was carried out on 43 patients having palpable breast mass, attended in the Department of Radiology and Imaging Mymensingh Medical College Hospital, Mymensingh from 1st January 2012 to 31st December 2013 for the period of two year. These patients were evaluated by USG at the Department of Radiology and Imaging and histopathological examination at the Department of Pathology of the same College to confirm the diagnosis. In diagnosis of malignant mass by USG, 9(20.9%) cases were diagnosed as malignant and 34(79.1%) cases as other than malignant. Eight out of 9 were sonographically diagnosed as malignant lesions also proved as malignant lesion by histopathology and 1 other than malignant. Out of 34 sonographically diagnosed cases of other than malignant lesions 32 were proved histopathologically and 2 did not match with sonographic findings. USG, in diagnosis of malignant lesion, sensitivity was 80.0%, specificity 96.97%, positive predictive value (PPV) (88.89%), negative predictive value 94.12% and accuracy was 93.02% and comparable to other study. In diagnosis of benign lesion by USG, sensitivity was 96.97%, specificity 80.0%, positive predictive value (PPV) (94.12%), negative predictive value 88.89% and accuracy was 93.02%. So, USG is an appropriate imaging method for diagnosis & differential diagnosis of palpable breast mass. PMID- 28588155 TI - Effect of Obesity on Hemoglobin Concentration. AB - Obesity is a disorder of body weight regulatory systems characterized by an accumulation of excess body fat. World Health Organization recommended that 66% of deaths now occur in developing countries and recognizes obesity as a leading risk factor. Obesity is associated with chronic, low grade, systemic inflammation. The inflammatory state play a causal role in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. This descriptive type of cross sectional study will design to evaluate the relation between obesity with hemoglobin concentration. One hundred obese and 100 normal weight persons from both sexes, aged between 25 to 60 years will be selected from Mymensingh Medical College, Mymensingh and locality from July 2014 to January 2016. Data are collected through a simple questionnaire after informed consent taken. The result was calculated and analyzed by using SPSS (statistical package for social science, version 11.5). Statistical significance of difference between two groups were evaluated by unpaired Student's 't' test. Data were expressed as Mean+/-SE. P value less than 0.05 was taken as the level of significance. Anthropometric measurements such as height and weight were taken in meter and kilogram respectively. Pulse, systolic and diastolic blood pressure was measured by aneroid sphygmomanometer (ALPK2, Japan), laboratory analysis of hemoglobin was done by Cyanmethemoglobin Method. In this study we found that hemoglobin concentration is significantly increased in both male and female obese persons. PMID- 28588156 TI - Clinical Presentation of Adult Pulmonary Tuberculosis (PTB): A Study of 103 Cases from a Tertiary Care Hospital. AB - Tuberculosis, one of the oldest diseases known to affect humans, is a major cause of death worldwide. The disease, which is caused by the bacteria Mycobacterium tuberculosis complex, usually affects the lungs, although other organs are involved in up to one-third of causes. If properly treated, tuberculosis caused by drug-susceptible strains is curable in virtually all cases. If untreated, the disease may be fatal within five years in 50-65% of cases. Transmission usually takes place through the airborne spread of droplet nuclei produced by patients with infectious pulmonary tuberculosis. This cross sectional observational study was conducted to detect various clinical presentations of pulmonary tuberculosis patients in the Department of Medicine, Sir Salimullah Medical College and Hospital from January 2009 to December 2009. Sample was selected through inclusion methods from patients who was admitted in to hospital and confirmed as pulmonary tuberculosis after appropriate investigations and who gave informed written consent was finally enrolled in this study. A total 103 patients were selected for the study. Out of 103 cases 34.9% were above 50 years old, followed by 26.2% between 30-40 years old, 22.3% between 40-50 years old and remaining 16.5% bellow 30 years old. The male to female ratio was roughly 1.2:1. The most of the patients were housewife and farmer which were 31% and 28.1% respectively. The most of the patients came from low socio-economic group. About 55.3% cases were smoker and 43.7 were non smoker. Among the frequency of symptoms 73.7% were chronic cough for above one month followed by 70.8% were low grade fever, 41.8% were night sweats and the 2% were admitted in hospital for other complaints and after evaluation diagnosed as PTB. The most of the patients about 67% were suffering from less than six weeks duration. Among the physical findings the 67% cases were lost significant weight, 56.3% had fever and 56.3% had apical crepitation over chest. There was sputum positive for acid fast bacilli about 64.7%. The traditional TB diagnosis methods are time consuming and the most of the patients are poor in our country, they are unable to afford the modern costly investigations. Therefore we should more emphasis on clinical examinations, so that we can diagnosis pulmonary TB rapidly and can start treatment as early as possible. PMID- 28588158 TI - Helicobacter Pylori Stool Antigen Assay in Hyperemesis Gravidarum. AB - Hyperemesis gravidarum is the most severe form of nausea and vomiting in pregnancy that seriously affects the pregnancy outcome. It is a disease with unknown etiology and varieties of contributing factors like hormonal changes, psychological and immunological factors. A significantly high prevalence of Helicobacter pylori among pregnant women with Hyperemesis gravidarum has been revealed recently. A descriptive, cross-sectional study was carried out at antenatal ward, Department of Obstetrics and Gynaecology, Mymensingh Medical College Hospital, Mymensingh for a period of twenty-one months among purposively selected thirty-six patients with Hyperemesis gravidarum with a view to assess the involvement of H. pylori in Hyperemesis gravidarum. Data were collected through interview, physical examinations and laboratory investigations by using case record form. Statistical analysis was performed using SPSS version 20.0 for Windows. Highest number 16(44.44%) of respondents were in age group 20 to 24 years with a mean of 23.81 years and a standard deviation (SD) of 4.55 years. Majority 29(80.56%) of the women had education less than 12 years, as many as 28(77.78%) women were housewives, and at least 14(38.89%) women had unplanned pregnancies. An overwhelming majority 29(80.56%) of women had their pregnancy duration between 8 to 12 weeks with a mean duration of 10.64 weeks and a standard deviation of 2.35 weeks. Majority 20(55.56%) of women were pregnant for first time, as many as 19(52.78%) women had duration of illness for 5 to 9 weeks. Of 16 multi-gravid women, 7(43.75%) had history of similar condition in their previous pregnancies. As many as 9 (25.00%) women had family history of similar condition in their mothers and sisters. First trimester was time of manifestation of the condition.At least 11 (30.56%) stool samples were positive for H. pylori stool antigen. Family history of Hyperemesis gravidarum and presence of H. pylori stool antigen are statistically associated (p<0.05). Pregnancy at young age, low educational status of women, nulliparity, unplanned pregnancy, past history, family history and H. pylori infection are the identified risk factors of Hyperemesis gravidarum. PMID- 28588157 TI - An Evaluation of Faculty Wise Teaching Performance in a Public Medical College of Bangladesh. AB - Teaching is a complex and demanding activity that involves Mastery of content, classroom control and techniques of organization and command of teaching skills. Teachers' continuous engagement in learning, skill acquisition and refinement to practice is essential for meeting student learning needs. Medical education is principally centered on the transmission of medical knowledge and assisting medical students to acquire the necessary skills and attitudes associated with medical practice. Evaluation of teaching is important in the teaching-learning process. The medical profession demands to be increasingly concerned with evaluation of teachers' performance as a part of its accountability. This study was designed to evaluate teaching performance in the department of Pharmacology, Forensic Medicine, Microbiology, Community Medicine and Pathology in Mymensingh Medical College and this descriptive cross sectional study was conducted among 94 students of 5th year MBBS students (session 2011-2012) of Mymensingh Medical College, Bangladesh from January 2016 to June 2016. A semi-structured self administered questionnaire was used for collection of data. All the respondents provided opinion regarding scholarship of teachers, methods of presentation, communication and interaction, learning, coverage of contents and approachability by a 5 points rating scale. Attained score was variable in the context of different statements and different faculties. Students were also asked to provide suggestions for improvement of teachers' performance in each subject. Remarkable number of the students demanded for deployment of subject-specific teachers in adequate number. A significant number of students called for more practical classes in Pathology, Microbiology and Pharmacology. They also desired for the improvement of teaching quality and student friendly attitude from the teachers. A significant number of students opined that teaching materials and other logistics in the class rooms and even the class rooms were inadequate and need improvement in this regards. Regular conduction of classes by adequate number of teachers having post-graduate degree in the relevant faculty with adequate skill in teaching, student-friendly attitude of the teachers, adequate physical facilities and teaching materials help in improvement of teaching quality. PMID- 28588159 TI - Ramadan Perspective Epidemiology and Education in Diabetes (RAPEED) Study. AB - Ramadan fasting is one of the five pillars of Islam and is obligatory for all healthy adult and adolescent Muslims. A significant number of patients with diabetes observe fasting during Ramadan. The objectives of this Ramadan Perspective Epidemiology and Education in Diabetes (RAPEED) study were to find out the current knowledge, attitude, and practices about Ramadan fasting among people with diabetes in Bangladesh. This retrospective cross-sectional study recruited 648 subjects with diabetes mellitus attending the Endocrinology outpatient department of a tertiary level hospital of Bangladesh within two months of the end of Ramadan in 2016. Socio-demographic data, data related to diabetes treatment, complications and co-morbidities; changes in lifestyle and diabetes treatment during Ramadan and frequency of hypoglycemia were collected from all. The mean age of the study population was 50.32+/-12.1 years and the majority (98.6%) had type 2 diabetes and 63.9% were overweight or obese. The majority (89.35%) of the patients fasted in Ramadan and among them, more than half of the fasters received physicians' advice for Ramadan fasting (60.6%) and changed diabetes medication (69.90%) during Ramadan. Although the amount of total food consumption was unchanged in more than one half (60.6%) of the fasters, majority of them reduced sugar-sweet intake (75.5%), increased fluid drinking (75.8%) and decreased physical activity (75.8%) during the month. A large portion (37.48%) of them did not check blood glucose and more than half (54.06%) of fasters failed to visit their physicians during Ramadan. Among them 14.85% experienced mild to moderate episodes of hypoglycemia and none had severe hypoglycemia and the most (61.6%) episodes of hypoglycemia occurred in the late evening. Hypoglycemic episodes were more frequent among insulin users, patients who had received fasting advice from physicians and in those who had adjusted diabetes drugs before Ramadan fasting. Safe Ramadan fasting is a great challenge not only for the patients but also the consulting physicians. Current study reflects the necessity of both physicians' expertise and patients' awareness for safe fasting. PMID- 28588160 TI - Adherence Pattern of Lipid Lowering Drugs in a Tertiary Care Hospital. AB - Dyslipidemia is one of the major risk factors of cardiovascular diseases. Worldwide, dyslipidemia is estimated to cause about 2.6 million deaths annually. Low drug adherence has been found to be a significant problem leading to poor health outcome. Medication non-adherence in chronic conditions is a recognized, but understudied public health problem. The present study was conducted to observe pattern of adherence to lipid lowering drugs, to find out the causes of non-adherence to medication and see the medication adherence in relation to various factor. The study was performed among 125 cardiovascular disease patients (both indoor and outdoor) of Cardiology department in Mymensingh Medical College Hospital (MMCH) who received lipid lowering drugs at least 6 months.Among them 21.6% patients were highly adherent, 34.4% patient showed medium adherent and 44% patients were low adherence to their treatment plan. Most important cause of non adherence was financial problem (52.04%). Among them 46-55 years age group were highly adherent, male were more adherent to medication than female. Rich patient were highly adherent. Patient with above higher secondary level of education were highly adherent than others. Patients lived in urban area were more adherent than rural patients. Immediate efforts are required to tackle this situation. Multiple kinds of processes are required to improve the drug adherence such as to provide proper health education focusing on preventive aspect as well as financial support for the care. Such acts might prevent future complication thereby reducing costs of health care and eventually turns out to be reducing morbidity and mortality in the long run. PMID- 28588161 TI - Multimodality Treatment Outcome of Hepatoblastoma in a Resource Limited Country. AB - Our objective is to review the records of management of hepatoblastoma (HB) at the Paediatric Haematology and Oncology (PHO) department in the Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from January 2004 to December 2012. This is a retrospective study of clinical, radiological and pathological data of hepatoblastoma patients treated at our institution. Thirteen patients were treated for HB between 2004 and 2012. The records of clinical presentations, chemotherapy tolerance and response, surgical procedure undertaken, and complications were analyzed. Median age of the study population was 12 months (3-60 months) and male: female was 3.3:1. Nine patients were treated with neoadjuvant chemotherapy consists of cisplatin and adriamycin. Primary surgery was done in four patients. Extent of hepatic resection in the operated patients varied. Mixed type was the predominant histopathological diagnosis. Adjuvant chemotherapy was well tolerated with no morbidity or mortality. Five-year event-free survival (EFS) and overall survival (OS) of all the 13 patients is 76.9%. All the nine patients who could complete multimodality treatment are alive with no evidence of disease or complications with median follow-up of 63 months (46-122 months). Treatment of HB with multidisciplinary approach was well tolerated. OS and EFS of patients were comparable with published studies. PMID- 28588162 TI - Role of pRIFLE Criteria in Early Diagnosis of Severity Staging of Neonatal AKI and its Impact on Management. AB - Mortality is high among sick neonates who have concomitant acute kidney injury (AKI). This observational study was done at Special Care Baby Unit (SCABU) of Dhaka Medical College Hospital (DMCH), Bangladesh from October 2013 to March 2014 to find out the role of pRIFLE criteria in prediction of severity stages of AKI in neonate and early intervention to see the immediate outcome. A total of 44 neonates with AKI were included, all were treated conservatively and with intermittent peritoneal dialysis (IPD) as needed. The neonate of <=7 days old comprised the main bulk (n=28) and M: F = 21: 23. The diagnosis was based on eCCL criteria of pRIFLE showed that 40.9% neonates were at risk of AKI, 20.5% have had already injured. Higher proportions of neonates were classified as failure (38.6%). The distribution of biochemical parameters among three stages of AKI showed serum potassium was significantly higher in failure group (p<0.001). The serum creatinine both at baseline and at next evaluations were significantly raised in the failure group (p<0.001). However, failure group had a significantly longer hospital stay compared to risk and injury group (p<0.001). Multiorgan failure was found to be lower in the risk group compared to other two groups (p=0.026). Majority of the failure group needed dialysis as compared to the risk and injury group (p<0.001). The mortality was progressively higher from risk to failure groups (p=0.106). Overall 27% of the neonates diagnosed AKI by pRIFLE were died of the disease. The study concluded that pRIFLE staging in AKI is useful and sensitive in the diagnosis and management of AKI in neonates. PMID- 28588163 TI - Evaluation of Pelvic Lymphadenectomy during Radical Hysterectomy for Cervical Cancer. AB - Cervical cancer is the most common cancer in women in developing countries comprising 20-30% of female cancer. More than 70% of cervical cancer patients of Bangladesh attend in hospital in inoperable stages (IIB, III & IV). Only 30% cases can be treated by primary surgery. This prospective cross-sectional study was conducted by Gynaecologic Oncology Division of the Department of Obstetrics & Gynaecology of Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from November 2011 to May 2012. The objectives of this study were to evaluate the number of pelvic lymph nodes removed, to determine the rate of pelvic lymph node involvement & also to evaluate the relationship between parametrial invasion and pelvic lymph node metastasis. During this period 105 cases underwent type III radical hysterectomy with bilateral pelvic lymph nodes dissection. Majority of the patients (60%) were in the age group of 31-50 years. Regarding histological type, most of the cases were invasive squamous cell carcinoma (85%), followed by adenocarcinoma (9%) and adenosquamous type (2%). According to grading of the tumours, grade I, II, III were 45%, 43%, 8% respectively and in 3% cases grading could not be identified. PMID- 28588164 TI - Diagnosis of Dermatophytosis by Conventional Methods and Comparatative analysis of Sabouraud Dextrose Agar and Dermatophyte Test Medium for Isolation of Dermatophytes. AB - Dermatophytosis is a fungal disease which ranked as one of the most common cutaneous condition in all over the world. The aim of this cross sectional observational study is to identify the etiological agent of dermatophytosis and comparison of Sabouraud dextrose agar (SDA) and Dermatophyte test medium (DTM) for the primary isolation of dermatophytes among the clinically suspected cases of dermatophytosis from the outpatient Department of Dermatology and Venereology, Mymensingh Medical College Hospital from July 2013 to December 2015. Two hundred thirty clinically suspected cases of dermatophytosis were subjected in this study. Sixty three cases (27.4%) were positive for fungus in direct microscopy while 53(23%) were culture positive. Trichophyton rubrum (83%) was found common etiological dermatophyte species followed by Trichophyton mentagrophytes 5(9.4%) and Epidermophyton floccosum 4(7.5%). There was no statistically significant difference between the SDA and DTM (p<0.01) in primary isolation of dermatophytes. PMID- 28588165 TI - Immediate & Short Term Outcome of Using Single Bolus Eptifibatide in Percutaneous Coronary Intervention: A Randomized Control Study. AB - The purpose of this study was to assess the immediate and short term outcome of single bolus dose of eptifibatide in elective percutaneous coronary intervention (PCI). We enrolled 146 patients who underwent elective PCI from May 2013 to May 2014 in University Cardiac Centre, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Among 146 patients, seventy four patients received single bolus dose of eptifibatide (10 mg intra coronary single bolus dose) just after crossing the lesion were selected as case. The other 72 patients, who did not receive eptifibatide, were selected as control. All patients of both the groups were treated with aspirin, clopidogrel before and after the procedure and all received a single bolus dose of Clopidogrel (300mg) before the procedure. All patient received weight adjusted doses of heparin during and after the procedure. The outcome measures were 24-hours and 30-day morbidity (complications or adverse events) and mortality. The patients of eptifibatide group experienced significantly lower incidence of QMI lesions and complete absence of NQMI lesion in 24 hours of PCI as compared to 5.6% and 6.9% of the lesions respectively in their control counterparts (p=0.027 and p=0.025 respectively). However, the incidence of bleeding and target vessel revascularization (TVR) were no different between the groups (p=0.255 and p=0.117). There was no incidence of TVR at all in the eptifibatide group as opposed to 5.6% in the control group in 30 days following stenting (p=0.017). Single bolus dose of eptifibatite reduces the Major adverse cardiac events as immediate and short term outcome in elective percutaneous coronary intervention. PMID- 28588166 TI - Comparative Efficacy of Local Steroid and Therapeutic Ultrasound for Quicker Functional Improvement in Tennis Elbow. AB - Lateral epicondylitis or Tennis elbow is very common repetitive stress injury or cumulative trauma disorder among active professionals and tennis players. Local steroid injection can provide quick functional improvement as sought by most of the patients. Therapeutic ultrasound and eccentric exercises can also improve the function. This study was carried out to see the comparative efficacy of these two modalities of treatments in terms of quicker functional improvement and this randomized interventional clinical trial was carried out in a private rehabilitation hospital in Dhaka. Patients attended the authors private chamber from January 2013 to December 2013 with clinical diagnosis of tennis elbow were included. Eighty adult patients diagnosed as lateral epicondylitis or tennis elbow were randomly divided into two groups. Group A received local steroid injection (triamcinolone acetate) and group B received therapeutic ultrasound for two weeks. Both the groups received eccentric exercises and advised to avoid provocative activities like twisting and lifting activities. Pain, tenderness and functional improvements were measured in traditional methods like visual analogue scale (VAS) and tenderness grade 0 to 4. Data were analyzed by SPSS. Most of the patients were female. None of them were tennis player. Younger housewives were common sufferer. Almost all patients in group A had very little or no pain or tenderness and no difficulty in lifting object at one week and two weeks. VAS was 13.62+/-6.503 and 4.15+/-5.517 respectively. Group B patients had mild improvement of pain and function at one week and moderate improvement at two weeks. VAS was 52.57+/-7.80 and 25.57+/-5.392 respectively. Similarly tenderness' were markedly improved in Group A at one and two weeks. They were 0.68+/-0.616 and 0.02+/-0.405 respectively for Group A and 1.60+/-0.553 and 1.14+/-0.335 respectively for Group B. Results were statistically significant in both groups at the end of two weeks. Local corticosteroid injections at extensor origin in tennis elbow patients are found to have better relief of pain and tenderness and quicker functional improvement than therapeutic ultrasound treatment. None of the patients were followed up for long term efficacy in either group. PMID- 28588167 TI - Primary and Revision Lumbar Discectomy: A Four-Year Review from Our Private Practice. AB - The surgical treatment of symptomatic lumbar disc herniation is now focused on nerve root decompression with preservation of the bony and ligamentous stabilizers of the spine. Various techniques of discectomy have been devised in accordance with this principle and irrespective of the technique used; primary disc surgeries have generally known to give good results. This retrospective study was done in different private clinics & hospitals of Dhaka city, Bangladesh from January 2012 to December 2015. Of the 105 lumbar discectomies performed during the study period, 95(90.4%) patients fulfilled the inclusion criteria and were included in the analysis. Of these, 90 patients had primary discectomy, while the remaining 5 were revision surgeries. The follow-up varied from 1-4 years, but the clinical outcomes were evaluated at the end of one year from surgery in all the patients. In the primary surgery group there were 50(55.56%) men and 40(44.44%) women, while the revision group had 01(20%) men and 04(80%) women. The age distribution was similar in both the groups, with the maximum numbers (44% and 42.9%) in the fourth decade of life. Of the 05 patients who underwent revision surgery, 03 belonged to the primary surgery group of this study, while the remaining 02 had undergone their primary surgery elsewhere. Excluding the two residual discs, the remaining 03 patients with recurrences gave a history of complete resolution of symptoms after the primary surgery. Amongst these, 3(60%) had a history of a precipitating event prior to onset of pain, 2 had a definitive history of significant lack of physical activity. The time interval between the primary and revision surgery ranged from three months to 10 years (average 2.6 years). PMID- 28588168 TI - Randomized Controlled Trial of Slow Versus Rapid Enteral Feeding Advancements on the Clinical Outcomes in Very Low Birth Weight Neonates. AB - Starting and advancement of feeding in very low birth weight (VLBW) infants are big challenges for the neonatal practitioners. Wide variations in volume of feed advancement have observed in earlier trials both in slow and rapid advancement groups. Volume advancement in slow advancement groups have ranged from 10ml/kg/day to 23ml/kg/day and in rapid advancement groups have ranged from 15ml/kg/day to 45ml/kg/day in earlier different studies. This randomized controlled trial was conducted in neonatal intensive care unit (NICU) of Bangabandhu Sheikh Mujib Medical University (BSMMU) from April 2013 to July 2014 to evaluate the effects of slow versus rapid rates of feeding advancements on the clinical outcomes in very low birth weight infants. A total 95 infants were enrolled into two strata according to their birth weight. Infants of each stratum were randomly allocated to either slow or rapid advancement group during initiation of feeding. After gut priming over five days, feeding was advanced daily 10ml/kg in slow and 15ml/kg in rapid advancement group for 1000 - <1250gm weighing infants. For 1250 - <1500gm weighing infants, feeding was advanced daily 15ml/kg in slow and 20ml/kg in rapid advancement group. The primary outcome variable was time taken to achieve full enteral feed. Total 82 infants completed the trial. Demographically both groups were same. Infants in the rapid feeding advancement group achieved full enteral feedings before the slow advancement group, had significantly fewer days of parenteral nutrition and regained birth weight earlier. There were no statistical differences in episodes of feed interruption, number of infants with apnea, feed intolerance or diagnosis of sepsis. Rapid enteral feeding advancements were well tolerated by very low birth weight infants. PMID- 28588169 TI - Outcome of Surgical Drainage of the Pancreatic Duct in Chronic Pancreatitis. AB - Abdominal pain, one of the major symptoms of chronic pancreatitis, is believed to be caused by obstruction of the pancreatic duct system by stones or strictures. This results in increased intraductal pressure and parenchymal ischemia. Surgical decompression of the duct and ductal drainage can achieve best pain relieve and slow the progression of the disease. We want to share our experience of surgical drainage of pancreatic duct in chronic pancreatitis in our hospital. We studied 20 cases operated in our hospital between January 2010 and October 2015. Patients were selected with pre-operative ultrasonography. Dilatation of the main pancreatic duct by at least 7 mm proximal to the obstruction were recruited for operation. We did Roux-Y lateral pancreato-jejunostomy (LPJ) for patients with obstruction of the pancreatic duct due to stricture or intraductal stones or both. We did additional distal pancreatectomy in case of stone in the tail area.We did one Frey's operation for stone and fibro-calcification of the head. We evaluated their symptoms, their duration, post-operative hospital stay and complications following surgery. We studied their pain control, recurrence and mortality during this period. We followed these patients for more than 5 years. We found 16 out of 20 patients got complete remission of the abdominal pain with no progression of their disease. Ultrasonic evidence of chronic pancreatitis have improved or resolved. Ductal diameter has decreased. They did not develop diabetes or malabsorbtion. One had a recurrence of stone in the head within a year. Three died during this follow-up period. One died three months after LPJ due to massive gangrene of the small intestine distal to LPJ and jejuno jejunostomy and subsequent short bowel syndrome. Other two developed carcinoma of the pancreas within one year and six months after LPJ respectively. Rate of pain free survival is about 75% and recurrence is 5%. Mortality during this follow up period is 15%. In this small series, we found that surgery if done early, can have good remission of abdominal pain and can slow the progression of chronic pancreatitis in majority of patient. Patient with chronic calcific pancreatitis and diabetes are likely to have unfavorable outcome even after decompressive surgery. PMID- 28588170 TI - Early Postoperative Parathyroid Hormone Level as a Predictor of Hypocalcaemia after Total Thyroidectomy. AB - Postoperative transient hypocalcaemia is a common squeal after total thyroidectomy usually due to parathyroid insufficiency. Objective of this study is to find out the optimum cut-off value of parathyroid hormone (PTH) level in early postoperative period as a best predictor for hypocalcaemia. This prospective observational study was carried out from July 2013 to July 2014 in the Department of Surgery Sir Salimullah Medical College & Mitford Hospital (SSMC&MH), in collaboration with department of Otolaryngology SSMC&MH, department of Otolaryngology Bangabandhu Sheikh Mujib Medical University (BSMMU) and department of Otolaryngology Dhaka Medical College & Hospital (DMC&H), Dhaka. Total 92 patients were selected those came for total thyroidectomy. PTH was measured at different percentile 6 hours after surgery to find out optimum cut off point. In 47.5th percentile at 8.02 cut-off point of PTH found with good combination of sensitivity, specificity, positive and negative predictive value, accuracy and it was 83.33%, 91.66%, 90.90%, 84.62% and 91.30% respectively. We found PTH level as a predictor of hypocalcaemia and PTH 8.02pg/ml was the optimum cut-off point to predict hypocalcaemia within 6 hours after total thyroidectomy. PMID- 28588171 TI - Clinical and Laboratory Predictors of Esophageal Varices in Children with Chronic Liver Disease. AB - Esophageal varices are a serious consequence of portal hypertension in patients with chronic liver diseases. Several studies have evaluated possible noninvasive markers of esophageal varices to reduce the number of unnecessary endoscopies in patients with chronic liver disease. Aim of this study was to identify clinical and laboratory predictors of esophageal varices in children with chronic liver disease. This cross sectional observational study was done at Pediatric Gastroenterology and Nutrition Department of Bangabandhu Sheikh Mujib Medical University, Dhaka, over a period of 6 months. Fifty (50) consecutive cases of chronic liver disease patient under 15 years of age were evaluated clinically, biochemically and endoscopically. Esophageal varices were classified into 4 grades according to Conn's grading system. Based on endoscopic findings (presence/absence of esophageal varices) all the patients were categorized into two groups; Group I: Chronic liver disease with esophageal varices and Group II: Chronic liver disease without esophageal varices. Most (51.5%) of the patients in Group I belong to age 10-12 years and majority 35.3% of Group II patients belong to <=2 years. More than half of the (51.5%) patients had grade III varices followed by 24.2% grade II, 21.2% grade I and only 3.0% had grade IV. All patients had splenomegaly in Group I and 70.6% of Group II, which was significantly (p<0.05) higher in Group I. Jaundice, spider angioma, hepatomegaly and ascites werealmost alike between two groups. Platelet count <1,50,000/mm3 in 72.73% patients of Group I and 41.18% in Group II, which was significantly (p<0.05) higher in Group I. Similarly, Serum albumin <3.5mg/dl in 78.79% patients of Group I and 47.6% of Group II, was also significantly (p<0.05) higher in Group I. Serum bilirubin, serum alanine aminotransferase and International normalized ratio (INR) were almost similar between two groups. Wilson's disease was found in 42.4% of chronic liver disease with esophageal varices and 35.3% of Chronic liver disease without esophageal varices. Hepatitis B virus infections were 6.1% and 5.9% in Group I and Group II respectively. Unknown cause was found 42.4% and 17.6% in Group I and Group II respectively. Splenomegaly, Platelet count <1,50,000/mm3 and serum albumin <3.5mg/dl are important predictors of esophageal varices. These three parameters can be used independently to predict esophageal varices in children with chronic liver disease. PMID- 28588172 TI - Primary Angioplasty for the Treatment of Acute ST Elevated Myocardial Infarction: Single Centre Experience. AB - Worldwide primary angioplasty is a recommended strategy of reperfusion in patient with acute myocardial infarction as because it ensures reperfusion of the infarct related vessels more than 90% whereas, with thrombolytics it is only 60-70%. This retrospective observational study includes all patients treated with primary angioplasty at United Hospital from Between March 2007 to January 2011. Total 114 consecutive patients with acute myocardial infarction were treated with primary angioplasty included. Those presented beyond 12 hours of onset of chest pain, in cardiogenic shock, resuscitate and intubated before the procedure were excluded from the study. Majority (89%) of the patient were male, age was minimum 30 years and maximum 90 years, 41.5% were diabetics, 58.4% were hypertensive, 43.5% were dyslipidaemic, 17% were smoker, 29.3% with positive family history. Fifty seven percent patients presented with anterior MI , 42 % with inferior MI and 1% with lateral MI. Left anterior descending (LAD) is the most common vessel involved (57%), followed by Right coronary artery (RCA) 31%, Left circumflex artery (LCX) 8 %, Ramus 1.3% and Graft vessel 2.7%. Our door to balloon time was minimum 23 min, maximum 184 min. We used drug eluting stents for most of the patients, GP IIb- IIIa receptor blockers used in 50% cases and thrombus suction device were used when indicated. We faced complications like arrhythmias in 24%, hypotension in18%, no flow or slow flow in 45%, cardiac arrest in 3% and coronary perforation in 1%. Our overall survival was 97.9%. Primary angioplasty is an emerging area in context of our country. Many of the new centers start this novel strategy which helps to save many lives Primary angioplasty is feasible and safe method of reperfusion in patient with acute myocardial infarction in our center. With the help of our initial experience we can perform PAMI with confidence to those who can afford and who need most. PMID- 28588173 TI - Macrophage Activation Syndrome in Paediatric Rheumatic Diseases. AB - Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic disorders, which commonly occurs in systemic juvenile idiopathic arthritis (sJIA).This study was carried out with the aims of describing the clinical features, laboratory findings and outcomes of MAS associated with paediatric rheumatic diseases in the Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU) and compare these results with previous studies on MAS. This retrospective study was conducted in the paediatric rheumatology wing of the Department of Paediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. Clinical and laboratory profile of all the diagnosed cases of MAS were analyzed from the medical records from January 2010 to July 2015. Among 10 MAS patients, 6 were female and 4 were male. Seven patients of systemic JIA, two patients of SLE and one patient with Kawasaki Disease developed MAS in their course of primary disease. Mean duration of primary disease prior to development of MAS was 2.9 years and mean age of onset was 9.1 years. High continued fever and new onset hepatosplenomegaly were the hallmark of the clinical presentation. White blood cell count and platelet count came down from the mean of 16.2 to 10.2*109/L and 254 to 90*109/L. Mean erythrocyte sedimentation rate was dropped from 56 to 29 mm/hr. Six patients had abnormal liver enzyme level (ALT) and 5 had evidence of coagulopathy (prolonged prothrombin time and APTT) at the onset of disease. Hyperferritinnemia were found in all the patients. Bone marrow study was done in 5 patients but features of hamophagocytosis were found only in 2 patients. All patients received intravenous steroid and 3 patients who did not respond to steroid received additional cyclosporine. Mortality rate was 30% in this series. Macrophage activation syndrome is a fatal complication of paediatric rheumatic diseases among which s JIA was predominant. Early diagnosis and aggressive therapy is essential to reduce the morbidity and mortality of this illness. PMID- 28588174 TI - C-reactive Protein (CRP) as a Single Biomarker for Diagnosis of Neonatal Sepsis: A Comprehensive Meta-analysis. AB - Neonatal sepsis (NS) is a life-threatening disorder and an important cause of morbidity and mortality in neonates. Blood culture, the gold standard for diagnosis of neonatal sepsis is costly, not available at all centres and test result not readily available. CRP is low cost diagnostic test for neonatal sepsis which is possible to perform at all centres and test result is easily available. We aimed to evaluate the usefulness of C-reactive protein (CRP) measurement to identify neonatal sepsis. We conducted this meta-analysis to investigate the diagnostic accuracy of the CRP in neonatal sepsis. The literature was searched in PUBMED, Cochrane Library, Google scholar and other Medical Databases using set search criteria. Each included study was evaluated by quality assessment of diagnostic accuracy studies (QUADAS) tool. Four investigators independently extracted the data and study characteristics, and disagreements, if any, were resolved by consensus. Meta-disc software was used to calculate the pooled sensitivity, specificity and summary diagnostic odds ratio (SDOR), I2 or Cochrane Q to test heterogeneity. False positive report probability (FPRP) was calculated to confirm the significance of the results. Eleven studies (1557 neonates) were included in this meta-analysis. The pooled sensitivity and specificity of CRP were 71% and 86% respectively, which had moderate accuracy in the diagnosis of NS. The pooled diagnostic odds ratio (DOR) and area under curve (AUC) was 19.10 and 0.8535 (Q*=0.7845), respectively. The diagnostic threshold analysis showed that there was no threshold effect. Meta-analysis showed that CRP had a moderate accuracy (AUC=0.8535) for the diagnosis of NS. CRP is a helpful biomarker for diagnosis of NS. However, we should combine the results with clinical symptoms and signs, laboratory and microbial results. PMID- 28588176 TI - Evaluation of Bcr-Abl Gene Rearrangement among Bangladeshi Chronic Myeloid Leukaemia Patients. AB - Chronic Myeloid Leukaemia (CML) is a clonal myeloproloferative disorder. Presence of molecular translocation t (9; 22) in CML patients can be confirmed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). Among haematological malignancies CML is the commonest leukaemia of adults in Asia. Despite this, there are very few studies published from Bangladesh, documenting the frequency of bcr-abl fusion transcripts. So, we would like to perform this observational study to evaluate bcr-abl fusion transcripts and demographic status among RT-PCR positive chronic phase CML patients at BIRDEM & other two centers of Dhaka city, Bangladesh where patients admitted from different districts of Bangladesh in the period of January 2010 to June 2012. Twenty patients from three centers willing to perform RT-PCR test and showed positive PCR result, were enrolled under written consent before starting treatment with targeted molecular therapy. The age range of the sample was 18 to 52 years, with mean age of 34.80 and male - female ratio of 4:1. This study showed among chronic phase CML patients bcr-abl transcript rearrangement frequency was b3a2 (e14a 2) 45% while b2a2 (e13a2) was 55% by RT-PCR testing method. Cytogenetic and molecular analysis has become mandatory in order to make a correct diagnosis and monitoring response to newer molecular targeted treatment modalities. So our health sector should be enriched with laboratories with modern technology to diagnose haemato-oncological diseases as per WHO guideline. PMID- 28588175 TI - HER2 status in Gastric and Gastroesophageal Junction Adenocarcinoma. AB - Gastric carcinoma is a biologically heterogenous disease and survival varies among the patients with same stage. Recent studies have shown that a subset of gastric and gastroesophageal junction adenocarcinoma over express the HER2/neu protein and these patients can be treated by monoclonal antibody against HER2/neu protein. The purpose of this study was to detect the frequency of HER2 expression in gastric and gastroesophageal junction adenocarcinoma and to evaluate the relationship between HER2 expression and clinicopathological features in these patients. This descriptive cross sectional study was carried out at the Department of Pathology, Dhaka Medical College, from January 2013 to December 2014. A total of 130 patients with primary gastric and gastroesophageal junction adenocarcinomas were included in this study. All the cases were evaluated for routine histological examination and immunohistochemical examination was done for HER2/neu protein. Among the 130 cases, HER2 over expression was found in 12.3% cases and was more frequent in gastroesophageal junction (28%) than in gastric carcinoma (8.6%) (P=0.026). HER2 positivity was found significantly more in intestinal type carcinoma (19%), papillary carcinoma (63%) and in fungating growth pattern (P=0.003, 0.001 and 0.001 respectively). HER2 expression was also positive in grade-I or grade-II tumor but negative in grade-III tumor (P=0.001). No significant association of HER2 expression was found with age, sex, lymph node metastasis and extent of tumor. In conclusion it can be stated that gastric and gastroesophageal junction adenocarcinoma of intestinal type or papillary and tubular type with well to moderate differentiation can be targeted for therapy using Herceptin. PMID- 28588177 TI - Antibiotic Susceptibility Pattern of Bacteria Isolated From Various Specimens of Patients with Hematological Malignancy. AB - Infection is a life threatening complication in patients with hematological malignancy. So, proper treatment of infection with suitable antibiotic is very important in these patients. The aim of this study was to determine the antibiotic susceptibility of bacteria isolated from various specimens of patients with hematological malignancy, so that, an appropriate regimen of empiric antibiotic treatment can be established for these patients. This observational study was done in the Department of Microbiology and Immunology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from March 2012 to August 2012. Forty (40) diagnosed patients of hematological malignancies who were admitted in the Department of Hematology and Paediatric Hemato-oncology, BSMMU with symptoms of sepsis &/ or urinary tract infection (UTI) or respiratory tract infection (RTI) were enrolled in this study. Blood, throat swab and urine were collected from each patient and sputum was collected from four patients. Susceptibility pattern of Gram positive bacteria to antibiotics was satisfactory. But Gram negative bacteria were resistant to commonly used antibiotics. Enterobacteriaceae group of organisms were found completely resistant to Ceftriaxone & Aztreonam. The best drugs for them were Imipenem, Amikacin & Netilmicin. P. aeruginosa & Acinetobacter spp. were completely resistant to several antibiotics including Cephalosporines & Ciprofloxacin. The best drug for them was Imipenem, Netilmicin & combination of Tazobactam & Piperacilin. PMID- 28588178 TI - Assessment of Difficulties Associated with Endotracheal Intubation using Modified Mallampati and Upper Lip Bite Test. AB - This study was aimed at finding the parameters for prediction of difficulty in endotracheal intubation, that are easy to examine and that could better predict difficulty. The current observational prospective, cross sectional study was conducted in the department of Anaesthesia, Analgesia and Intensive Care Medicine, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from March 2015 to September 2015 comprising 180 patient of both sexes requiring endotracheal intubation were arranged into two groups, Group A: Modified Mallampati test Group and Group B: Modified Mallampati & upper lip bite test group (combined) Assessment of difficulty in intubation was done by Cormack & Lehane direct Laryngoscopic grading. Outcome was measured as no difficulty or difficulty in intubation. In Group A 33 cases were true positive, 15 false negative, 26 false positive, 16 true negative. In Group B 53 cases were true positive, 1 false positive, 8 false negative, 28 true negative. The validity tests for Group A for evaluation of difficult intubation were indicated by sensitivity 55.9%, Specificity 51.6%, Accuracy 54.41%, Positive predictive value 68.8% and Negative predictive value 38.1%. The values for Group-B were 86.9%, 96.6%, 90.0%, 98.1% and 77.8% respectively. Combined modified Mallampati & Upper Lip Bite Test has definite value in the diagnosis of difficulty in intubation and can be regarded as sensitive & specific test for operative discrimination of the patient. PMID- 28588179 TI - Childhood Wilson Disease: Bangladesh Perspective. AB - Wilson's disease (WD) is an autosomal recessive disorder affecting copper metabolism causing copper induced damage to various organs. In children liver is commonly involved. Central nervous system, eyes, RBC, kidneys, brain and bones may also be affected. Aim of the study is to evaluate clinical & laboratory profile of Wilson's disease in children. This cross sectional descriptive study was conducted at the department of Paediatric Gastroenterology and Nutrition, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from January 2011 to December, 2013. One hundred consecutive children of WD between 3 to 18 years of age were evaluated for clinical & biochemical profile. Mean age of studied children was 8.5+/-1.5 years. Male female ratio was 2:1. Ninety one percent patients were Muslim and nine percent Hindu. Consanguinity of marriage was found in 30% cases. Seven parents were first degree cousin. Family history of chronic liver disease was present in 15% of patients. Most (53%) cases of the hepatic WD presented between 5 to 10 years of age and most of the neurologic WD manifested in 10-15 years age group. Among 100 patients of WD, 69 children presented only with hepatic manifestations, 6 only with neurological manifestations, 14 with both hepatic & neurological manifestation, 10 children was asymptomatic and 1 patient presented with psychiatric features. WD presented as chronic liver disease (CLD) in 42%, CLD with portal hypertension in 34%, acute hepatitis in 20% and fulminant hepatic failure in 4% cases. Stigmata of chronic liver disease were found in 18% patients. Commonest stigmata was thenar and hypothenar wasting (n=8). Keiser- Fleischser ring (K-F ring) was found in 76% of the total patients. K-F ring was present in 84% ( 58 out of 69) of the hepatic only Wilsonian patients and in 90% (18 out of 20) of all neurologic Wilsonian patients. Asymptomatic and psychiatric patient had no K-F ring. About 26% of the WD patients had Coombs negative hemolytic anemia in PBF. Most of the WD patients had altered liver function. Elevated serum transaminase was found in 85% of all cases, prolonged prothrombin time in 59% cases & low serum albumin in 53% cases. Seventy three percent patients had low serum ceruloplasmin, basal urinary copper of >100MUgm/day was found in 81% cases and urinary copper following penicillamine challenge of >1200MUgm/day was found in 92% cases. In 28 cases with hepatic presentation esophageal varices were identified by upper gastrointestinal endoscopy. WD patient with hepatic presentations were given zinc sulphate along with penicillamine. All patients with neurological manifestation as well as asymptomatic cases were maintained on zinc therapy. WD is a treatable metabolic cause of liver disease. Majority of studied WD children presented with hepatic manifestation of which 76% presented with CLD. Any child presented with jaundice after the age of 3 years should be investigated for WD. PMID- 28588180 TI - Impact of Adrenocortical Insufficiency on Biochemical Parameters in Haemodynamically Stable Cirrhotic Patients with Ascites. AB - Cirrhosis has many complications regardless of the aetiology. Among them, adrenal insufficiency is recently identified entity. A prospective cohort study was done to evaluate the biochemical impact of adrenocortical insufficiency in haemodynamically stable, non-septic, cirrhotic patients with ascites and had been performed at the inpatient of GHPD department, BIRDEM, Dhaka from April 2011 to March 2012. A total of fifty three (53) patients fulfilling inclusion criteria were included in the study. Patients were divided into two groups: Group A (patients of normal adrenal function) and Group B (patients of insufficient adrenal function) and those were followed up for the next 6 months. In Group A, the total number of patients was 25(47%) and in Group B it was 28(53%). Between two groups, mean age difference and gender difference were not statistically significant. (p value was 0.278 and 0.933, respectively). At enrollment, there was significant lower mean Hb concentration in Group B (p=0.008). There was no significant difference of means of WBC count and platelet count between two groups (p value was 0.829 and 0.333, respectively). There were significant abnormalities in serum bilirubin, serum albumin, INR, SBP, HRS, Serum Na concentration, TCO2 concentration in Group B patients at follow up after 6 months. Adrenal insufficient decompensated cirrhotic patients have higher biochemical abnormalities, thus higher morbidities. PMID- 28588181 TI - Magnetic Resonance Cholangiopancreatography (MRCP) Evaluation of Obstructive Jaundice in Comparison with Endoscopic Retrograde Cholangiopancreatography (ERCP). AB - This cross sectional study was carried out in the department of Radiology and Imaging in collaboration with Department of Gastroenterology of Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from July 2013 to June 2014 to evaluate the efficacy of Magnetic resonance cholangiopancreatography (MRCP) and ERCP in the management of obstructive jaundice and also to determine diagnostic validity accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of MRCP in evaluation of obstructive jaundice. For this purpose, a total of 60 patients with obstructive jaundice who underwent MRCP and Endoscopic retrograde cholangiopancreatography (ERCP) in the above mentioned hospital were enrolled. More than one third (35.0%) patients were in 5th decade and the mean age was 46.2+/-12.9 years. Male female ratio was 1.1:1. Most (45.0%) of the patients had filling defect, 28.3% had concentric stenosis and 26.7% eccentric stenosis. In MRCP findings more than one third (35.0%) patients had choledocholithiasis followed by 26.7% had cholangiocarcinoma, 10.0% benign CBD stricture and 8.3% had ascariasis. In ERCP findings 31.7% patients had choledocholithiasis followed by 16.7% had cholangiocarcinoma, 13.3% benign CBD stricture and 10.0% ascariasis. All patients had increased serum bilirubin. PMID- 28588182 TI - Role of Computed Tomography in the Evaluation of Nasopharyngeal Mass. AB - In Indian subcontinent, all types of nasopharyngeal masses are rare. However, Nasopharyngeal carcinoma is not uncommon in Bangladesh. It is very important to differentiate malignant from benign lesions early in the disease process. In recent years, CT is the primary diagnostic screening modality for the detection of nasopharyngeal pathology. This cross sectional study was carried out in the Department of Radiology & Imaging, BSMMU in collaboration with Department of otolaryngology of the same hospital from July 2012 to June 2014. Sensitivity of CT scan in diagnosis of nasopharyngeal carcinoma was 100%, specificity was 93.10%, positive predictive value (PPV) was 93.94%, negative predictive value (NPV) was 100% and accuracy was 96.67%. Sensitivity of CT scan in diagnosis of benign angiofibroma was 78.26 %, specificity was 89.19%, positive predictive value (PPV) was 81.82%, negative predictive value (NPV) was 86.84% and accuracy was 85% of CT scan. CT scan findings of the present study correlated well in most of the cases with the histopathological evaluations. Considering the high validity parameter it can come to a conclusion that CT scan is as highly effective as histopathology in diagnosis of nasopharyngeal mass. PMID- 28588183 TI - Orlistat (The Lipase Inhibitor) Therapy in Overweight and Obese Subfertile Women. AB - This experimental study was carried out to evaluate the efficacy of orlistat (a pancreatic lipase inhibitor) therapy over lifestyle change on weight reduction and ovulation in overweight and obese subfertile women. It was carried out in Department of Gynecology and Obstetrics, Bangabandhu Sheikh Mujib Medical University (BSMMU) Dhaka, Bangladesh from August 2015 to January 2016. Subfertile obese and overweight female patients attending the study centre during study period was considered as study population. Subfertile women with normozoospermic husband with BMI (25-40) Kg/M2, age (18-35) years with no history of taking medication or dietary modification for weight loss currently or for the preceding 3 months were included in this study but subfertile patients having laparoscopic ovarian drilling and metformin and those with structural abnormalities in reproductive tract and known hormonal and medical disorder were excluded from this study. Detailed history taking, physical examination including weight, Body Mass Index (BMI) and baseline relevant investigations were done. Transvaginal sonography (TVS) on day 12 and day 14 of menstrual cycle was done for evaluation of ovulatory status of the patients. Counseling was done about life style change by diet of low glycemic index and moderate exercise. Following written informed consent, 120 patients were enrolled into either of the two groups. Group I received capsule Orlistat 120 mg twice daily for 3 months period. Group II was counseled for life style modification only. Post treatment weight measurement and TVS on day 12 and 14 were done after completion of intervention. Then pre and post-treatment parameters were assessed between two groups. Mean age was (27.31+/ 4.58) years in Group I and (26.20+/-4.71) years in Group II. Majority patients, (78.3%) in Group I and (76.7%) in Group II had oligomenorrhoea. Hirsuitism was observed in (25%) in Group I and (43.3%) in Group II. Mean weight (kg) at booking was (72.26+/-7.81) in Group I and (67.10+/-5.93) in Group II; after 3 months (67.77+/-7.82) and (63.55+/-6.07). Reduction of weight (%): (6.52+/-2.28) in Group I and (5.33+/-2.14) in Group II which was significantly higher in Group I than that of Group II in (25.0-29.9) BMI. Ovulation assessed by TVS at booking and after 3 months in Group I: 13(21.7%) and 37 (61.7%) and in Group II: 14 (23.3%) and 27 (45.0%). Ovulation was higher in Group I than that of Group II, but the difference was not statistically significant. Majority of the overweight and obese subfertile patients suffered from oligomenorrhoea and anovulation. Weight significantly reduced in both groups along with ovulation improvement, more in Group I, but insignificant in between groups. Therefore this study suggested that orlistat can improve ovulation as it acts indirectly by weight reduction more than life style modification alone. PMID- 28588184 TI - Association of Relationship between Periodontal Disease and Cardiovascular Disease. AB - The present study was undertaken to determine the relationship between periodontal and cardiovascular disease. Previous studies have shown some co relation between the two conditions. We included 186 patients divided into four groups. First two Groups (A1 & A2) were the patients with cardiac disease (100 in numbers) whilst Groups (B1 & B2) (86 in numbers) were treated as controls (without cardiac disease). Following markers of periodontal disease were assessed - plaque index, calculus index, gingival and periodontal index. Markers of cardiovascular disease included were LDL, HDL, total cholesterol and CRP. Ramfjords periodontal index was used to assess the extent of periodontal disease. In the present study there was a significant increase in CRP levels in Group A1 (CVD + PD) compared to controls and overall the two cardiac groups showed a significant increase in CRP compared to controls. There was a non-significant change in lipid profile markers (LDL, HDL and total cholesterol). Periodontal Disease Index (PDI) was also increased in Group A1 compared to other groups except Group B1 and overall in cardiac groups compared to non-cardiac (PD) groups. In this study no correlation between periodontal and cardiovascular disease was found. This may be due intake of statins by few patients in Group A with a confirmed diagnosis of cardiovascular disease. PMID- 28588186 TI - Post-operative Supplementary Motor Area Syndrome: A Case Report. AB - The supplementary motor area (SMA-proper) is important for the programming and execution of motor, speech, and other elaborative functions. SMA is frequently involved by brain tumors (particularly WHO grade II gliomas). Surgery in this area can be followed by the 'SMA syndrome', characterised by contralateral akinesia and mutism. We present a case of Falcine meningioma in the region of the right SMA which developed SMA syndrome. Our patient showed complete recovery of neurological function but the process was slow with a specific pattern. PMID- 28588185 TI - Mucinous Adenocarcinoma of the Appendix: A Case Report. AB - Primary tumors of the appendix are unusual and most of them are carcinoids. Their main presentation is that of an acute appendicitis or as a palpable mass, mainly in the right lower quadrant. A 40 years old male patient presented in Dhaka Community Medical College Hospital, Dhaka, Bangladesh on 31st October 2013 with mucous adenocarcinoma of the appendix, which primarily presented as heaviness in right lower abdomen and atypical abdominal pain. Diagnosis of the disease was made after right hemicolectomy and histopathological analysis of the specimen. Mucin producing adenocarcinomas of the appendix are a category of rare cancers of the gastrointestinal tract. Although at present they are a well studied pathological entity, the crucial issue of their preoperative diagnosis remains unsolved. PMID- 28588187 TI - Primary Sclerosing Cholangitis in a Young Female. AB - Primary sclerosing cholangitis (PSC) is a liver disease characterized by inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts resulting in cholestasis. Due to nonspecific symptoms it is difficult to diagnose until complication arises. It is common in male and usually associated with other autoimmune diseases. Here, we report a case of PSC in a young female which was initially thought to be drug induced cholestasis without presence of any other autoimmunity. PMID- 28588188 TI - A Young Boy with L-asparaginase-Induced Seizure. AB - L-Asparaginase is a critical component in the treatment of acute lymphoblastic leukemia in children. It is known to cause coagulation abnormalities, thrombosis and hemorrhage in the central nervous system in addition to vasculitis and hypersensitivity reactions. This syndrome generally occurs after a few weeks of therapy and may occur after L-asparaginase therapy is completed. Seizures are uncommon symptoms. We report a case of seizure associated with L-asparaginase therapy but no evidence of hemorrhagic or thrombotic cerebrovascular events, completed in the department of Hematology of Bangabandhu Sheikh Mujib Medical University during March & April 2016. PMID- 28588189 TI - Metabolic injury-induced NLRP3 inflammasome activation dampens phospholipid degradation. AB - The collateral effects of obesity/metabolic syndrome include inflammation and renal function decline. As renal disease in obesity can occur independently of hypertension and diabetes, other yet undefined causal pathological pathways must be present. Our study elucidate novel pathological pathways of metabolic renal injury through LDL-induced lipotoxicity and metainflammation. Our in vitro and in vivo analysis revealed a direct lipotoxic effect of metabolic overloading on tubular renal cells through a multifaceted mechanism that includes intralysosomal lipid amassing, lysosomal dysfunction, oxidative stress, and tubular dysfunction. The combination of these endogenous metabolic injuries culminated in the activation of the innate immune NLRP3 inflammasome complex. By inhibiting the sirtuin-1/LKB1/AMPK pathway, NLRP3 inflammasome dampened lipid breakdown, thereby worsening the LDL-induced intratubular phospholipid accumulation. Consequently, the presence of NLRP3 exacerbated tubular oxidative stress, mitochondrial damage and malabsorption during overnutrition. Altogether, our data demonstrate a causal link between LDL and tubular damage and the creation of a vicious cycle of excessive nutrients-NLRP3 activation-catabolism inhibition during metabolic kidney injury. Hence, this study strongly highlights the importance of renal epithelium in lipid handling and recognizes the role of NLRP3 as a central hub in metainflammation and immunometabolism in parenchymal non-immune cells. PMID- 28588191 TI - Safety and Efficacy of a New Smartphone-controlled Vibrating Capsule on Defecation in Beagles. AB - Constipation, mainly manifesting as abdominal discomfort and painful defecation, is considered as a chronic disorder. Due to a lack of effective therapy, it imposes a significant economic burden and greatly impacts patients' quality of life which prompt searches for new, original approaches. Based on the research of vibrating capsule (VC) carried out by Ron et al., we investigated the safety and efficacy of an innovative, multi-mode VC in terms of its effect on defecation in animal studies. The parameters associated with different operation modes of VCs can be detected and adjusted by smartphone controlled external configuration device (ECD). The results of blood tests, physiological parameters, CT scan and pathological examination showed no significant abnormality, which undoubtedly confirmed the safety of VCs. For efficacy studies, defecation frequency of beagles increased after administration of these capsules without influence on stool characters. Meanwhile, the mean time of capsule evacuation tended to be reduced while showing no significant difference between different modes. In summary, this study elucidates the safety and effectiveness of VC in prompting the passage of gastrointestinal walls thus greatly increasing the defecation frequency. This study innovatively displays the promising application of VC in the treatment of constipation. PMID- 28588192 TI - Disentangling Auger decays in O2 by photoelectron-ion coincidences. AB - In non-resonant Auger electron spectroscopies, multi core-ionized states lead to numerous energetically close-lying electronic transitions in Auger spectra, this hampering the assignment and interpretation of the experimental results. Here we reveal a new method to overcome this intrinsic limitation of non-resonant inner shell spectroscopies. In a proof-of-principle experiment performed for the O2 molecule, most of the Auger final states are dissociative, and we measure in coincidence the kinetic energy of the photoelectron and the kinetic energy release of the (O+, O+) ion pairs produced after the Auger decay of the O 1s-1 core-ionized states. The Auger final states are assigned using energy conservation. We fully separate the contributions from the 4Sigma- and 2Sigma- intermediate ionic states and conclusively demonstrate that the Auger decay probability can dramatically depend on the different O2 1s -1 intermediate multiplet states. In addition, a metastable Auger final state also exists, with lifetime longer than 3.8 MUs, and clear changes are observed in both branching ratio and spectral profile of the O 1s photoelectron spectrum when they are recorded in coincidence with either [Formula: see text] or with other ionic species. These changes are attributed to the population of the metastable [Formula: see text] Auger final state via different intermediate states. PMID- 28588190 TI - An optimal distance cutoff for contact-based Protein Structure Networks using side-chain centers of mass. AB - Proteins are highly dynamic entities attaining a myriad of different conformations. Protein side chains change their states during dynamics, causing clashes that are propagated at distal sites. A convenient formalism to analyze protein dynamics is based on network theory using Protein Structure Networks (PSNs). Despite their broad applicability, few efforts have been devoted to benchmarking PSN methods and to provide the community with best practices. In many applications, it is convenient to use the centers of mass of the side chains as nodes. It becomes thus critical to evaluate the minimal distance cutoff between the centers of mass which will provide stable network properties. Moreover, when the PSN is derived from a structural ensemble collected by molecular dynamics (MD), the impact of the MD force field has to be evaluated. We selected a dataset of proteins with different fold and size and assessed the two fundamental properties of the PSN, i.e. hubs and connected components. We identified an optimal cutoff of 5 A that is robust to changes in the force field and the proteins. Our study builds solid foundations for the harmonization and standardization of the PSN approach. PMID- 28588193 TI - The anti-cholesterolaemic effect of a consortium of probiotics: An acute study in C57BL/6J mice. AB - Hypercholesterolaemia is a major risk factor for cardiovascular disease and it has been found that some probiotic bacteria possess cholesterol-lowering capabilities. In this study, the ability of the Lab4 probiotic consortium to hydrolyse bile salts, assimilate cholesterol and regulate cholesterol transport by polarised Caco-2 enterocytes was demonstrated. Furthermore, in wild-type C57BL/6J mice fed a high fat diet, 2-weeks supplementation with Lab4 probiotic consortium plus Lactobacillus plantarum CUL66 resulted in significant reductions in plasma total cholesterol levels and suppression of diet-induced weight gain. No changes in plasma levels of very low-density lipoprotein/low-density lipoprotein, high-density lipoprotein, triglycerides, cytokines or bile acids were observed. Increased amounts of total and unconjugated bile acids in the faeces of the probiotic-fed mice, together with modulation of hepatic small heterodimer partner and cholesterol-7alpha-hydroxylase mRNA expression, implicates bile salt hydrolase activity as a potential mechanism of action. In summary, this study demonstrates the cholesterol-lowering efficacy of short-term feeding of the Lab4 probiotic consortium plus L. plantarum CUL66 in wild-type mice and supports further assessment in human trials. PMID- 28588194 TI - Electro-optic comb based real time ultra-high sensitivity phase noise measurement system for high frequency microwaves. AB - Recent progress in ultra low phase noise microwave generation indispensably depends on ultra low phase noise characterization systems. However, achieving high sensitivity currently relies on time consuming averaging via cross correlation, which sometimes even underestimates phase noise because of residual correlations. Moreover, extending high sensitivity phase noise measurements to microwaves beyond 10 GHz is very difficult because of the lack of suitable high frequency microwave components. In this work, we introduce a delayed self heterodyne method in conjunction with sensitivity enhancement via the use of higher order comb modes from an electro-optic comb for ultra-high sensitivity phase noise measurements. The method obviates the need for any high frequency RF components and has a frequency measurement range limited only by the bandwidth (100 GHz) of current electro-optic modulators. The estimated noise floor is as low as -133 dBc/Hz, -155 dBc/Hz, -170 dBc/Hz and -171 dBc/Hz without cross correlation at 1 kHz, 10 kHz, 100 kHz and 1 MHz Fourier offset frequency for a 10 GHz carrier, respectively. Moreover, since no cross correlation is necessary, RF oscillator phase noise can be directly suppressed via feedback up to 100 kHz frequency offset. PMID- 28588196 TI - Direct measurement of optical trapping force gradient on polystyrene microspheres using a carbon nanotube mechanical resonator. AB - Optical tweezers based on optical radiation pressure are widely used to manipulate nanoscale to microscale particles. This study demonstrates direct measurement of the optical force gradient distribution acting on a polystyrene (PS) microsphere using a carbon nanotube (CNT) mechanical resonator, where a PS microsphere with 3 MUm diameter is welded at the CNT tip using laser heating. With the CNT mechanical resonator with PS microsphere, we measured the distribution of optical force gradient with resolution near the thermal noise limit of 0.02 pN/MUm in vacuum, in which condition enables us to high accuracy measurement using the CNT mechanical resonator because of reduced mechanical damping from surrounding fluid. The obtained force gradient and the force gradient distribution agree well with theoretical values calculated using Lorenz Mie theory. PMID- 28588197 TI - Piezoelectric Microstructured Fibers via Drawing of Multimaterial Preforms. AB - We demonstrate planar laminated piezoelectric generators and piezoelectric microstructured fibers based on BaTiO3-polyvinylidene and carbon-loaded polyethylene materials combinations. The laminated piezoelectric generators were assembled by sandwiching the electrospun BaTiO3-polyvinylidene mat between two carbon-loaded-polyethylene films. The piezoelectric microstructured fiber was fabricated via drawing of the multilayer fiber preform, and features a swissroll geometry that have ~10 alternating piezoelectric and conductive layers. Both piezoelectric generators have excellent mechanical durability, and could retain their piezoelectric performance after 3 day's cyclic bend-release tests. Compared to the laminated generators, the piezoelectric fibers are advantageous as they could be directly woven into large-area commercial fabrics. Potential applications of the proposed piezoelectric fibers include micro-power-generation and remote sensing in wearable, automotive and aerospace industries. PMID- 28588195 TI - Population genetics analysis of the Nujiang catfish Creteuchiloglanis macropterus through a genome-wide single nucleotide polymorphisms resource generated by RAD seq. AB - Advances in genome scanning using high-throughput sequencing technologies has led to a revolution in studies of non-model organisms. The glyptosternoid fish Creteuchiloglanis macropterus, is widely distributed in the main stem and tributaries of the Nujiang River basin. Here, we analyzed IIB restriction-site associated DNA (2b-RAD) sequences and mitochondrial DNA sequences, to assess the genomic signature of adaptation by detecting and estimating the degree of genetic differentiation among ten Creteuchiloglanis macropterus populations from the Nujiang River. The analyses revealed significant population differentiation among the up-tributaries, main stem, mid-tributary and low-tributary. Annotation of contigs containing outlier SNPs revealed that the candidate genes showed significant enrichment in several important biological process terms between up tributaries and low-tributary, and exhibited prominent enrichment in the term macromolecular metabolic process between all tributaries and the main stem. Population dynamics analyses indicated that the Late Pleistocene glaciations strongly influenced the demographic history of C. macropterus. Our results provide strong evidence for the utility of RAD-seq in population genetics studies, and our generated SNP resource should provide a valuable tool for population genomics studies of C. macropterus in the future. PMID- 28588198 TI - In vitro assembly of the Rous Sarcoma Virus capsid protein into hexamer tubes at physiological temperature. AB - During a proteolytically-driven maturation process, the orthoretroviral capsid protein (CA) assembles to form the convex shell that surrounds the viral genome. In some orthoretroviruses, including Rous Sarcoma Virus (RSV), CA carries a short and hydrophobic spacer peptide (SP) at its C-terminus early in the maturation process, which is progressively removed as maturation proceeds. In this work, we show that RSV CA assembles in vitro at near-physiological temperatures, forming hexamer tubes that effectively model the mature capsid surface. Tube assembly is strongly influenced by electrostatic effects, and is a nucleated process that remains thermodynamically favored at lower temperatures, but is effectively arrested by the large Gibbs energy barrier associated with nucleation. RSV CA tubes are multi-layered, being formed by nested and concentric tubes of capsid hexamers. However the spacer peptide acts as a layering determinant during tube assembly. If only a minor fraction of CA-SP is present, multi-layered tube formation is blocked, and single-layered tubes predominate. This likely prevents formation of biologically aberrant multi-layered capsids in the virion. The generation of single-layered hexamer tubes facilitated 3D helical image reconstruction from cryo-electron microscopy data, revealing the basic tube architecture. PMID- 28588199 TI - Contributions of the maternal oral and gut microbiome to placental microbial colonization in overweight and obese pregnant women. AB - A distinct bacterial signature of the placenta was reported, providing evidence that the fetus does not develop in a sterile environment. The oral microbiome was suggested as a possible source of the bacterial DNA present in the placenta based on similarities to the oral non-pregnant microbiome. Here, the possible origin of the placental microbiome was assessed, examining the gut, oral and placental microbiomes from the same pregnant women. Microbiome profiles from 37 overweight and obese pregnant women were examined by 16SrRNA sequencing. Fecal and oral contributions to the establishment of the placental microbiome were evaluated. Core phylotypes between body sites and metagenome predictive functionality were determined. The placental microbiome showed a higher resemblance and phylogenetic proximity with the pregnant oral microbiome. However, similarity decreased at lower taxonomic levels and microbiomes clustered based on tissue origin. Core genera: Prevotella, Streptococcus and Veillonella were shared between all body compartments. Pathways encoding tryptophan, fatty-acid metabolism and benzoate degradation were highly enriched specifically in the placenta. Findings demonstrate that the placental microbiome exhibits a higher resemblance with the pregnant oral microbiome. Both oral and gut microbiomes contribute to the microbial seeding of the placenta, suggesting that placental colonization may have multiple niche sources. PMID- 28588200 TI - Fluorometric evaluation of CYP3A4 expression using improved transgenic HepaRG cells carrying a dual-colour reporter for CYP3A4 and CYP3A7. AB - Primary human hepatocytes are necessary to evaluate cytotoxicity, drug metabolism, and drug-drug interactions for candidate compounds in early-phase drug discovery and development. However, these analyses are often hampered by limited resources and functional or genetic variation among lots. HepaRG human hepatocellular carcinoma cells can differentiate into mature hepatocyte-like cells (HepLCs) that possess similar metabolic activity to human hepatocytes. We previously established transgenic HepaRG cells carrying a dual reporter that express red fluorescent protein (RFP) under the transcriptional regulation of CYP3A7 in the hepatoblast-like cell state and enhanced green fluorescent protein (EGFP) under the transcriptional regulation of CYP3A4 following HepLC differentiation. In this study, we successfully isolated a subclone of transgenic CYP3A4G/7R HepaRG cells with an improved HepLC differentiation potency. Midazolam metabolism by CYP3A4 in these HepLCs was comparable to that in wild-type HepLCs. The EGFP fluorescence intensity was greatly induced by rifampicin (RIF) treatment. There was a strong correlation between fluorometric and metabolic analyses. The fold change in EGFP-positive cells was comparable to those in the CYP3A4 mRNA level and luminescence of proluciferin metabolites. RIF treatment and cell proliferation increased the RFP-positive cell number. Thus, CYP3A4G/7R HepLCs provide a real-time, multiwell-based system to co-evaluate CYP3A4 induction and hepatic regeneration. PMID- 28588201 TI - Aureobasidium pullulans produced beta-glucan is effective to enhance Kurosengoku soybean extract induced Thrombospondin-1 expression. AB - Black yeast, Aureobasidium pullulans is extracellularly produced beta-(1,3), (1,6)-D-glucan (beta-glucan) under certain conditions. In this study, using Glycine max cv. Kurosengoku (Kurosengoku soybeans), the production of beta-glucan through fermentation of A. pullulans was evaluated, and the effects of A. pullulans cultured fluid (AP-CF) containing beta-glucan made with Kurosengoku soybeans (kAP-CF) on a human monocyte derived cell line, Mono Mac 6 cells were investigated. Concentration of beta-glucan in kAP-CF reached the same level as normal AP-CF. An anti-angiogenic protein, Thrombospondin-1 (THBS1) was effectively induced after the stimulation with kAP-CF for comparison with AP-CF. The THBS1 is also induced after stimulation with hot water extract of Kurosengoku soybeans (KS-E), while the combined stimulation of beta-glucan with KS-E more effectively induced THBS1 than that with KS-E alone. These results suggest effects of A. pullulans-produced beta-glucan on the enhancement of Kurosengoku soybean-induced THBS1 expression. PMID- 28588202 TI - Terahertz electromagnetic fences on a graphene surface plasmon polariton platform. AB - Controlling the loss of graphene can be used in the field of transformation optics. We propose a new concept of electromagnetic fence on a monolayer graphene surface plasmon polariton platform. Using a Dot-Density-Renderer quasicrystal metasurface, we can simulate the absorption of gradient index optics structures. Numerical simulations show that the incident waves to our designed electromagnetic fence are trapped toward the central lines and quickly absorbed by the high-loss region. Two basic types of electromagnetic fence and its composite structures have been designed and analyzed, which exhibit excellent broadband absorbing performances at 8 THz-12 THz. Because of its advantages in controlling the soft-boundary effects and easy manufacturing characteristics, the proposed electromagnetic fence seems very promising for THz-frequency transformation plasmonics applications. PMID- 28588203 TI - Quantum - coherent dynamics in photosynthetic charge separation revealed by wavelet analysis. AB - Experimental/theoretical evidence for sustained vibration-assisted electronic (vibronic) coherence in the Photosystem II Reaction Center (PSII RC) indicates that photosynthetic solar-energy conversion might be optimized through the interplay of electronic and vibrational quantum dynamics. This evidence has been obtained by investigating the primary charge separation process in the PSII RC by two-dimensional electronic spectroscopy (2DES) and Redfield modeling of the experimental data. However, while conventional Fourier transform analysis of the 2DES data allows oscillatory signatures of vibronic coherence to be identified in the frequency domain in the form of static 2D frequency maps, the real-time evolution of the coherences is lost. Here we apply for the first time wavelet analysis to the PSII RC 2DES data to obtain time-resolved 2D frequency maps. These maps allow us to demonstrate that (i) coherence between the excitons initiating the two different charge separation pathways is active for more than 500 fs, and (ii) coherence between exciton and charge-transfer states, the reactant and product of the charge separation reaction, respectively; is active for at least 1 ps. These findings imply that the PSII RC employs coherence (i) to sample competing electron transfer pathways, and ii) to perform directed, ultrafast and efficient electron transfer. PMID- 28588205 TI - Human uterine lymphocytes acquire a more experienced and tolerogenic phenotype during pregnancy. AB - Pregnancy requires a delicate immune balance that nurtures the allogeneic fetus, while maintaining reactivity against pathogens. Despite increasing knowledge, data is lacking on the transition of pre-pregnancy endometrial lymphocytes to a pregnancy state. Here, we immunophenotyped lymphocytes from endometrium (MMC), term decidua parietalis (DPMC), and PBMC for direct comparison. We found that the immune cell composition of MMC and DPMC clearly differ from each other, with less NK-cells, and more NKT-cells and T-cells in DPMC. An increased percentage of central memory and effector memory T-cells, and less naive T-cells in DPMC indicates that decidual T-cells are more experienced than endometrial T-cells. The increased percentage of CD4+CD25highCD127- Treg in DPMC, including differentiated Treg, is indicative of a more experienced and tolerogenic environment during pregnancy. The Th cell composition of both MMC and DPMC was different from PBMC, with a preference for Th1 over Th2 in the uterine environment. Between MMC and DPMC, percentages of Th cell subsets did not differ significantly. Our results suggest that already before pregnancy a tightly controlled Th1/Th2/Th17 balance is present. These findings create opportunities to further investigate the underlying immune mechanism of pregnancy complications using menstrual blood as a source for endometrial lymphocytes. PMID- 28588206 TI - In-situ freeze-drying - forming amorphous solids directly within capsules: An investigation of dissolution enhancement for a poorly soluble drug. AB - Conversion into the amorphous form enhances the dissolution of poorly soluble drugs, however the barrier to market for medicines containing an amorphous drug is poor stability. The aim was to produce the amorphous form of a drug within a capsule, without thermal or mechanical stress during manufacture. To facilitate this aim, the mechanism for drug-polymer interaction was explored. Nifedipine and polyvinylpyrrolidone were dissolved in tert-butanol at different drug/polymer ratios. These solutions were dispensed into gelatin capsules and freeze-dried. Differential scanning calorimetry (DSC) & novel FT-IR analysis based on peak symmetry measurements confirmed the absence of crystallinity when polyvinylpyrrolidone exceeded 50%w/w. Capsules containing 10 mg of nifedipine were amorphous and stable for over 3 months at ~40 degrees C. Evidence of hydrogen bonding between the N-H group of nifedipine and the C=O group of PVP was observed and this interaction inhibited nifedipine crystallisation. PVP's high affinity for water and the nifedipine-polymer interaction lead to a significant dissolution rate enhancement. The freeze-dried capsule, 10%w/w nifedipine/PVP, had the highest dissolution rate constant of 0.37 +/- 0.05 min-1, and the lowest time to achieve 50% dissolution or t1/2 of 1.88 +/- 0.05 min. This formulation reached 80% dissolved in less than 6 min whereas the equivalent marketed liquid filled nifedipine capsule took 3 times longer to reach 80% dissolution. PMID- 28588204 TI - Gut Dysbiosis and Neurobehavioral Alterations in Rats Exposed to Silver Nanoparticles. AB - Due to their antimicrobial properties, silver nanoparticles (AgNPs) are being used in non-edible and edible consumer products. It is not clear though if exposure to these chemicals can exert toxic effects on the host and gut microbiome. Conflicting studies have been reported on whether AgNPs result in gut dysbiosis and other changes within the host. We sought to examine whether exposure of Sprague-Dawley male rats for two weeks to different shapes of AgNPs, cube (AgNC) and sphere (AgNS) affects gut microbiota, select behaviors, and induces histopathological changes in the gastrointestinal system and brain. In the elevated plus maze (EPM), AgNS-exposed rats showed greater number of entries into closed arms and center compared to controls and those exposed to AgNC. AgNS and AgNC treated groups had select reductions in gut microbiota relative to controls. Clostridium spp., Bacteroides uniformis, Christensenellaceae, and Coprococcus eutactus were decreased in AgNC exposed group, whereas, Oscillospira spp., Dehalobacterium spp., Peptococcaeceae, Corynebacterium spp., Aggregatibacter pneumotropica were reduced in AgNS exposed group. Bacterial reductions correlated with select behavioral changes measured in the EPM. No significant histopathological changes were evident in the gastrointestinal system or brain. Findings suggest short-term exposure to AgNS or AgNC can lead to behavioral and gut microbiome changes. PMID- 28588208 TI - Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance. AB - Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1 mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1-10 MUmol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI -0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use. PMID- 28588207 TI - Capping Enzyme mRNA-cap/RNGTT Regulates Hedgehog Pathway Activity by Antagonizing Protein Kinase A. AB - Hedgehog (Hh) signaling plays a pivotal role in animal development and its deregulation in humans causes birth defects and several types of cancer. Protein Kinase A (PKA) modulates Hh signaling activity through phosphorylating the transcription factor Cubitus interruptus (Ci) and G protein coupled receptor (GPCR) family protein Smoothened (Smo) in Drosophila, but how PKA activity is regulated remains elusive. Here, we identify a novel regulator of the Hh pathway, the capping-enzyme mRNA-cap, which positively regulates Hh signaling activity through modulating PKA activity. We provide genetic and biochemical evidence that mRNA-cap inhibits PKA kinase activity to promote Hh signaling. Interestingly, regulation of Hh signaling by mRNA-cap depends on its cytoplasmic capping-enzyme activity. In addition, we show that the mammalian homolog of mRNA-cap, RNGTT, can replace mRNA-cap to play the same function in the Drosophila Hh pathway and that knockdown of Rngtt in cultured mammalian cells compromised Shh pathway activity, suggesting that RNGTT is functionally conserved. Our study makes an unexpected link between the mRNA capping machinery and the Hh signaling pathway, unveils a new facet of Hh signaling regulation, and reveals a potential drug target for modulating Hh signaling activity. PMID- 28588209 TI - Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis. AB - Numerous genome-wide association studies (GWAS) have been performed to identify susceptibility genes to various human complex diseases. However, in many cases, neither a functional variant nor a disease susceptibility gene have been clarified. Here, we show an efficient approach for identification of a functional variant in a primary biliary cholangitis (PBC)-susceptible region, chromosome 17q12-21 (ORMDL3-GSDMB-ZPBP2-IKZF3). High-density association mapping was carried out based on SNP imputation analysis by using the whole-genome sequence data from a reference panel of 1,070 Japanese individuals (1KJPN), together with genotype data from our previous GWAS (PBC patients: n = 1,389; healthy controls: n = 1,508). Among 23 single nucleotide polymorphisms (SNPs) with P < 1.0 * 10-8, rs12946510 was identified as the functional variant that influences gene expression via alteration of Forkhead box protein O1 (FOXO1) binding affinity in vitro. Moreover, expression-quantitative trait locus (e-QTL) analyses showed that the PBC susceptibility allele of rs12946510 was significantly associated with lower endogenous expression of ORMDL3 and GSDMB in whole blood and spleen. This study not only identified the functional variant in chr.17q12-21 and its molecular mechanism through which it conferred susceptibility to PBC, but it also illustrated an efficient systematic approach for post-GWAS analysis that is applicable to other complex diseases. PMID- 28588210 TI - Curing the Toxicity of Multi-Walled Carbon Nanotubes through Native Small molecule Drugs. AB - With the development and application of nanotechnology, large amounts of nanoparticles will be potentially released to the environment and possibly cause many severe health problems. Although the toxicity of nanoparticles has been investigated, prevention and treatment of damages caused by nanoparticles have been rarely studied. Therefore, isotope tracing and improved CT imaging techniques were used to investigate the biodistribution influence between oMWCNTs(oxidized multi-walled carbon nanotubes) and 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC)/or simvastatin (TD) in vivo. What's more, biochemical indices in plasma and tissue histology were measured to further study therapeutic effects on the damages of oMWCNTs in mice. Isotope tracing and improved CT imaging results showed that low dosages of DOPC and TD didn't affect the distribution of oMWCNTs in mice; conversely, the distribution and metabolism of DOPC and TD were influenced by oMWCNTs. Moreover, DOPC and/or TD improved the biocompatibility of oMWCNTs in erythrocyte suspension in vitro. Biochemical index and histopathological results indicated that DOPC and TD didn't prevent injuries caused by oMWCNTs effectively. But TD showed a good therapeutic effect for damages. This study is the first to investigate prevention and treatment effects of drugs on damages caused by oMWCNTs and provides new insights and breakthroughs for management of nanoparticles on health hazards. PMID- 28588212 TI - Changes in soil microbial community composition and organic carbon fractions in an integrated rice-crayfish farming system in subtropical China. AB - Integrated rice-crayfish farming system is a highly efficient artificial ecosystem in which the rice (Oryza sativa) variety 'Jianzhen 2' is cultivated in waterlogged paddy fields along with crayfish (Procambarus clarkii). We investigated soil carbon fractions and microbial community structure by phospholipid fatty acids (PLFA) analysis in a 10-year field experiment using an integrated rice-crayfish (CR) model and a rice monoculture (MR) model at soil depths of 0-10 cm, 10-20 cm, 20-30 cm, and 30-40 cm. Compared with the MR model, the CR model had significantly more total organic carbon, particulate organic carbon, and dissolved organic carbon contents in all of the layers examined and microbial biomass carbon content in the 20-40 cm layer. Principal components analysis revealed that microbial community composition in the CR model differed from that in the MR model in the 20-30 cm layer. Higher proportions of gram negative bacteria, aerobic bacteria and fungi in the 20-30 cm soil layer were observed for the CR model than the MR model. These results indicate that the CR model increases soil carbon levels, and strongly affects microbial community composition and structure in the deeper layers of soil, thereby accelerating subsurface soil nutrient cycling. PMID- 28588211 TI - Transcription Factor Networks derived from Breast Cancer Stem Cells control the immune response in the Basal subtype. AB - Breast cancer is the most common cancer in women worldwide and metastatic dissemination is the principal factor related to death by this disease. Breast cancer stem cells (bCSC) are thought to be responsible for metastasis and chemoresistance. In this study, based on whole transcriptome analysis from putative bCSC and reverse engineering of transcription control networks, we identified two networks associated with this phenotype. One controlled by SNAI2, TWIST1, BNC2, PRRX1 and TBX5 drives a mesenchymal or CSC-like phenotype. The second network is controlled by the SCML4, ZNF831, SP140 and IKZF3 transcription factors which correspond to immune response modulators. Immune response network expression is correlated with pathological response to chemotherapy, and in the Basal subtype is related to better recurrence-free survival. In patient-derived xenografts, the expression of these networks in patient tumours is predictive of engraftment success. Our findings point out a potential molecular mechanism underlying the balance between immune surveillance and EMT activation in breast cancer. This molecular mechanism may be useful to the development of new target therapies. PMID- 28588213 TI - Bacterial protease uses distinct thermodynamic signatures for substrate recognition. AB - Porphyromonas gingivalis and Porphyromonas endodontalis are important bacteria related to periodontitis, the most common chronic inflammatory disease in humans worldwide. Its comorbidity with systemic diseases, such as type 2 diabetes, oral cancers and cardiovascular diseases, continues to generate considerable interest. Surprisingly, these two microorganisms do not ferment carbohydrates; rather they use proteinaceous substrates as carbon and energy sources. However, the underlying biochemical mechanisms of their energy metabolism remain unknown. Here, we show that dipeptidyl peptidase 11 (DPP11), a central metabolic enzyme in these bacteria, undergoes a conformational change upon peptide binding to distinguish substrates from end products. It binds substrates through an entropy driven process and end products in an enthalpy-driven fashion. We show that increase in protein conformational entropy is the main-driving force for substrate binding via the unfolding of specific regions of the enzyme ("entropy reservoirs"). The relationship between our structural and thermodynamics data yields a distinct model for protein-protein interactions where protein conformational entropy modulates the binding free-energy. Further, our findings provide a framework for the structure-based design of specific DPP11 inhibitors. PMID- 28588214 TI - Evidence for exocellular Arsenic in Fronds of Pteris vittata. AB - The arsenic (As) hyperaccumulating fern species Pteris vittata (PV) is capable of accumulating large quantities of As in its aboveground tissues. Transformation to AsIII and vacuolar sequestration is believed to be the As detoxification mechanism in PV. Here we present evidence for a preponderance of exocellular As in fronds of Pteris vittata despite numerous reports of a tolerance mechanism involving intracellular compartmentalization. Results of an extraction experiment show that 43-71% of the As extruded out of the fronds of PV grown in 0.67, 3.3 and 6.7 mM AsV. SEM-EDX analysis showed that As was localized largely on the lower pinna surface, with smaller amounts on the upper surface, as crystalline deposits. X-ray fluorescence imaging of pinna cross-sections revealed preferential localization of As on the pinna surface in the proximity of veins, with the majority localized near the midrib. Majority of the As in the pinnae is contained in the apoplast rather than vacuoles. Our results provide evidence that exocellular sequestration is potentially a mechanism of As detoxification in PV, particularly at higher As concentrations, raising concern about its use for phytoremediation. PMID- 28588215 TI - Singlet Exciton Fraction in Electroluminescence from Conjugated Polymer. AB - The efficiency of electrofluorescent polymer light-emitting diodes is determined by singlet exciton fraction (chiS) formation and its value still remains controversial. In this work, chiS in spiropolyfluorene (SPF) is determined by analyzing transient emission of phosphor-dopant probe. The chiS is found to range from 50% to 76%, depending on applied voltage. Higher applied voltage gives larger chiS. Besides, more rapid increment in chiS with applied voltage is observed in the higher-molecular-weight polymer. The voltage or molecular weight dependence of chiS suggests the probability of singlet exciton (SE) generation through triplet-triplet annihilation (TTA) is enhanced due to higher triplet exciton (TE) concentration at higher applied voltage or accommodation of more TEs in a polymer chain with high molecular weight, thereby increasing probability of TTA. At lower applied voltage, chiS is contributed by charge recombination. Its value (chiS ~50%) higher than the statistical limit 25% is in agreement with efficient interconversion between triplet and singlet polaron pairs (PP) and with larger formation rate of SE relative to that of TE. PMID- 28588216 TI - Size and specimen-dependent strategy for x-ray micro-ct and tem correlative analysis of nervous system samples. AB - Correlative approaches are a powerful tool in the investigation of biological samples, but require specific preparation procedures to maintain the strength of the employed methods. Here we report the optimization of the embedding protocol of nervous system samples for a correlative synchrotron X-ray computed microtomography (micro-CT) and transmission electron microscopy (TEM) approach. We demonstrate that it is possible to locate, with the micrometric resolution of micro-CT, specific volumes of interest for a further ultrastructural characterization to be performed with TEM. This approach can be applied to samples of different size and morphology up to several cm. Our optimized method represents an invaluable tool for investigating those pathologies in which microscopic alterations are localized in few confined regions, rather than diffused in entire tissues, organs or systems. We present a proof of concept of our method in a mouse model of Globoid Cells Leukodistrophy. PMID- 28588217 TI - A Haptotaxis Assay for Neutrophils using Optical Patterning and a High-content Approach. AB - Neutrophil recruitment guided by chemotactic cues is a central event in host defense against infection and tissue injury. While the mechanisms underlying neutrophil chemotaxis have been extensively studied, these are just recently being addressed by using high-content approaches or surface-bound chemotactic gradients (haptotaxis) in vitro. Here, we report a haptotaxis assay, based on the classic under-agarose assay, which combines an optical patterning technique to generate surface-bound formyl peptide gradients as well as an automated imaging and analysis of a large number of migration trajectories. We show that human neutrophils migrate on covalently-bound formyl-peptide gradients, which influence the speed and frequency of neutrophil penetration under the agarose. Analysis revealed that neutrophils migrating on surface-bound patterns accumulate in the region of the highest peptide concentration, thereby mimicking in vivo events. We propose the use of a chemotactic precision index, gyration tensors and neutrophil penetration rate for characterizing haptotaxis. This high-content assay provides a simple approach that can be applied for studying molecular mechanisms underlying haptotaxis on user-defined gradient shape. PMID- 28588219 TI - Electron Ptychographic Diffractive Imaging of Boron Atoms in LaB6 Crystals. AB - Ptychographic diffractive imaging has the potential for structural determination of materials without the constraints of relatively small, isolated samples required for conventional coherent diffractive imaging. The increased illumination diversity introduced using multiple measurements (overlapped probe positions) also provides higher sensitivity to phase changes in weakly scattering samples. The resolution of a ptychographic reconstruction is ultimately determined by the diffraction limit for the wavelength of the radiation used. However, in practical experiments using electrons either the maximum collection angle of the detector used to record the data or the partial coherence of the source impose lower resolution limits. Nonetheless for medium energy electrons this suggests a potential sub 0.1 nm spatial resolution limit, comparable to that obtained using aberration corrected instruments. However, simultaneous visualization of light and heavier atoms in specimens using ptychography at sub 0.1 nm resolution presents a significant challenge. Here, we demonstrate a ptychographic reconstruction of a LaB6 crystal in which light B atoms were clearly resolved together with the heavy La atoms in the reconstructed phase. The technique used is general and can also be applied to non-crystalline and extended crystalline samples. As such it offers an alternative future basis for imaging the atomic structure of materials, particularly those containing low atomic number elements. PMID- 28588218 TI - A semi high-throughput method for screening small bispecific antibodies with high cytotoxicity. AB - Small bispecific antibodies that induce T-cell-mediated cytotoxicity have the potential to damage late-stage tumor masses to a clinically relevant degree, but their cytotoxicity is critically dependent on their structural and functional properties. Here, we constructed an optimized procedure for identifying highly cytotoxic antibodies from a variety of the T-cell-recruiting antibodies engineered from a series of antibodies against cancer antigens of epidermal growth factor receptor family and T-cell receptors. By developing and applying a set of rapid operations for expression vector construction and protein preparation, we screened the cytotoxicity of 104 small antibodies with diabody format and identified some with 103-times higher cytotoxicity than that of previously reported active diabody. The results demonstrate that cytotoxicity is enhanced by synergistic effects between the target, epitope, binding affinity, and the order of heavy-chain and light-chain variable domains. We demonstrate the importance of screening to determine the critical rules for highly cytotoxic antibodies. PMID- 28588220 TI - Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. AB - Previous trial evidence suggested potential risk of serious urinary tract infections (UTIs) and genital infections in type 2 diabetes patients using sodium glucose co-transporter-2 inhibitors (SGLT2) inhibitors. We conducted a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on UTIs and genital infections in patients with type 2 diabetes. In total, 77 RCTs involving 50,820 participants were eligible. The meta-analyses of randomized controlled trials (RCTs) showed no significant difference in UTIs between SGLT2 inhibitors versus control (2,526/29,086 vs. 1,278/14,940; risk ratio (RR) 1.05, 95% confidence interval (CI) 0.98 to 1.12; moderate quality evidence), but suggested increased risk of genital infections with SGLT2 inhibitors (1,521/24,017 vs. 216/12,552; RR 3.30, 95% CI 2.74 to 3.99; moderate quality evidence). Subgroup analyses by length of follow up (interaction p = 0.005), type of control (interaction p = 0.04) and individual SGLT2 inhibitors (interaction p = 0.03) also showed statistically significant differences in genital infections. The upcoming major trials may provide important additional insights on UTIs, and more efforts are needed to address comparative effects of each individual SGLT2 inhibitors on the infections. PMID- 28588222 TI - Collective navigation of complex networks: Participatory greedy routing. AB - Many networks are used to transfer information or goods, in other words, they are navigated. The larger the network, the more difficult it is to navigate efficiently. Indeed, information routing in the Internet faces serious scalability problems due to its rapid growth, recently accelerated by the rise of the Internet of Things. Large networks like the Internet can be navigated efficiently if nodes, or agents, actively forward information based on hidden maps underlying these systems. However, in reality most agents will deny to forward messages, which has a cost, and navigation is impossible. Can we design appropriate incentives that lead to participation and global navigability? Here, we present an evolutionary game where agents share the value generated by successful delivery of information or goods. We show that global navigability can emerge, but its complete breakdown is possible as well. Furthermore, we show that the system tends to self-organize into local clusters of agents who participate in the navigation. This organizational principle can be exploited to favor the emergence of global navigability in the system. PMID- 28588221 TI - Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that might be involved in muscle thermogenesis. AB - We recently found that the mRNA expression of Slc25a25, a Ca2+-sensitive ATP carrier in the inner mitochondrial membrane, fluctuates in a circadian manner in mouse skeletal muscle. We showed here that the circadian expression of muscle Slc25a25 was damped in Clock mutant, muscle-specific Bmal1-deficient, and global Bmal1-deficient mice. Furthermore, a ketogenic diet (KD) that induces time-of-day dependent hypothermia (torpor), induced Slc25a25 mRNA expression in skeletal muscle. Hypothermia induced by KD did not affect thermogenic genes such as Sarcolipin and Pgc1a in muscles and Ucp1 in adipose tissues. Sciatic denervation abolished circadian and KD-induced Slc25a25 expression, suggesting that the circadian clock regulates muscle Slc25a25 expression via neural pathways. We measured body temperature (Tb) in sciatic denervated mice fed with KD to determine the functional role of KD-induced Slc25a25 expression. Sciatic denervation abolished Slc25a25 expression and augmented KD-induced hypothermia compared with sham-operated mice, but did not affect Tb in mice given a normal diet. These findings suggest that KD feeding induces expression of the muscle circadian gene Slc25a25 via neural pathways, and that SLC25A25 might be involved in muscle thermogenesis under KD-induced hypothermia in mammals. PMID- 28588223 TI - D-cycloserine increases the effectiveness of vancomycin against vancomycin-highly resistant Staphylococcus aureus. AB - Vancomycin is a widely used clinical drug to treat for infection by methicillin resistant Staphylococcus aureus. Some patients show a weak response to vancomycin treatment. We previously reported that beta-lactams increase the susceptibility to vancomycin by vancomycin-highly resistant S. aureus (VRSA) strains obtained following repeated in vitro mutagenesis and vancomycin selection. Here we found that the susceptibility of the VRSA strains to vancomycin was remarkably increased by combined treatment with D-cycloserine. On the other hand, VRSA did not show increased susceptibility to vancomycin in combination with bacitracin, fosfomycin, erythromycin, lincomycin, gentamicin, levofloxacin or nisin. Furthermore, in an in vivo infection model with silkworms, combined treatment with vancomycin and D-cycloserine exhibited therapeutic effects, whereas treatment with each compound alone did not. These findings suggest that combined treatment with vancomycin and D-cycloserine could be therapeutically effective against infectious diseases caused by VRSA. PMID- 28588225 TI - Albiducins A and B, salicylaldehyde antibiotics from the ash tree-associated saprotrophic fungus Hymenoscyphus albidus. PMID- 28588226 TI - The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. The purpose of this study was to clarify effects of brazilian green propolis and the active ingredient against ALS-associated mutant copper-zinc superoxide dismutase (SOD1) mediated toxicity. Ethanol extract of brazilian green propolis (EBGP) protected N2a cells against mutant SOD1-induced neurotoxicity and reduced aggregated mutant SOD1 by induction of autophagy. Kaempferide and kaempferol, the active ingredients of EBGP, also inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Both kaempferide and kaempferol significantly suppressed mutant SOD1-induced superoxide in mitochondria. Western blot analysis showed that kaempferol potentially induced autophagy via the AMP activated protein kinase (AMPK) - the mammalian target of rapamycin (mTOR) pathway. These results suggest that EBGP containing the active ingredient against mutant SOD1-mediated toxicity is a promising medicine or health food for prevention and treatment of ALS. PMID- 28588227 TI - Melon13-lipoxygenase CmLOX18 may be involved in C6 volatiles biosynthesis in fruit. AB - To better understand the function role of the melon CmLOX18 gene in the biosynthesis of C6 volatiles during fruit ripening, we biochemically characterized CmLOX18 and identified its subcellular localization in transgenic tomato plants. Heterologous expression in yeast cells showed that the molecular weight of the CmLOX18 protein was identical to that predicted, and that this enzyme possesseed lipoxygenase activity. Linoleic acid was demonstrated to be the preferred substrate for the purified recombinant CmLOX18 protein, which exhibited optimal catalytic activity at pH 4.5 and 30 degrees C. Chromatogram analysis of the reaction product indicated that the CmLOX18 protein exhibited positional specificity, as evidenced by its release of only a C-13 oxidized product. Subcellular localization analysis by transient expression in Arabidopsis protoplasts showed that CmLOX18 was localized to non-chloroplast organelles. When the CmLOX18 gene was transgenically expressed in tomato via Agrobacterium tumefaciens-mediated transformation, it was shown to enhance expression levels of the tomato hydroperoxide lyase gene LeHPL, whereas the expression levels of six TomLox genes were little changed. Furthermore, transgenic tomato fruits exhibited increases in the content of the C6 volatiles, namely hexanal, (Z)-3-hexanal, and (Z)-3-hexen-1-ol, indicating that CmLOX18 probably plays an important role in the synthesis of C6 compounds in fruits. PMID- 28588224 TI - The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo. AB - Pseudomonas aeruginosa is an opportunistic pathogen that can be very hard to treat because of high resistance to different antibiotics and alternative treatment regimens are greatly needed. An alternative or a complement to traditional antibiotic is to inhibit virulence of the bacteria. The salicylidene acylhydrazide, INP0341, belongs to a class of compounds that has previously been shown to inhibit virulence in a number of Gram-negative bacteria. In this study, the virulence blocking effect of INP0341 on P. aeruginosa was studied in vitro and in vivo. Two important and closely related virulence system were examined, the type III secretion system (T3SS) that translocates virulence effectors into the cytosol of the host cell to evade immune defense and facilitate colonization and the flagella system, needed for motility and biofilm formation. INP0341 was shown to inhibit expression and secretion of the T3SS toxin exoenzyme S (ExoS) and to prevent bacterial motility on agar plates and biofilm formation. In addition, INP0341 showed an increased survival of P. aeruginosa-infected mice. In conclusion, INP0341 attenuates P. aeruginosa virulence. PMID- 28588228 TI - Photo-acoustic spectroscopy revealing resonant absorption of self-assembled GaAs based nanowires. AB - III-V semiconductors nanowires (NW) have recently attracted a significant interest for their potential application in the development of high efficiency, highly-integrated photonic devices and in particular for the possibility to integrate direct bandgap materials with silicon-based devices. Here we report the absorbance properties of GaAs-AlGaAs-GaAs core-shell-supershell NWs using photo acoustic spectroscopy (PAS) measurements in the spectral range from 300 nm to 1100 nm wavelengths. The NWs were fabricated by self-catalyzed growth on Si substrates and their dimensions (length ~5 MUm, diameter ~140-150 nm) allow for the coupling of the incident light to the guided modes in near-infrared (IR) part of the spectrum. This coupling results in resonant absorption peaks in the visible and near IR clearly evidenced by PAS. The analysis reveal broadening of the resonant absorption peaks arising from the NW size distribution and the interaction with other NWs. The results show that the PAS technique, directly providing scattering independent absorption spectra, is a very useful tool for the characterization and investigation of vertical NWs as well as for the design of NW ensembles for photonic applications, such as Si-integrated light sources, solar cells, and wavelength dependent photodetectors. PMID- 28588229 TI - Diagnostic Performance of 18F-FDG PET/CT in Papillary Thyroid Carcinoma with Negative 131I-WBS at first Postablation, Negative Tg and Progressively Increased TgAb Level. AB - Differentiated thyroid cancer (DTC) patients with negative serum thyroglobulin (Tg), negative 131I whole-body scintigraphy (131I-WBS) at first post-ablation and progressively increased TgAb level are a relatively rare entity in the follow-up after total thyroidectomy and radioactive iodine therapy. The value of 18F-FDG PET/CT in detecting the recurrence of disease in these patients has only been reported in a small case series. The goal of this study was to investigate the diagnostic accuracy of 18F-FDG PET/CT in detecting recurrent disease in these specific PTC patients and to identify risk factors for patients with positive 18F FDG PET/CT results. Eighty-two PTC patients who had 18F-FDG PET/CT scans with negative Tg, negative 131I-WBS at first post-ablation and progressively increased TgAb levels were included. We found that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 18F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively. 18F-FDG PET/CT scan had a good diagnostic performance and should be performed routinely in PTC patients with negative Tg, negative 131I-WBS at first postablation and progressively increased TgAb level, especially when span for progressively increased TgAb level >= 3 years and/or progressively increased TgAb value up to 150 IU/mL. PMID- 28588230 TI - Characterization of developmental defects in the forebrain resulting from hyperactivated mTOR signaling by integrative analysis of transcriptomic and proteomic data. AB - Hyperactivated mTOR signaling in the developing brain has been implicated in multiple forms of pathology including tuberous sclerosis complex (TSC). To date, various phenotypic defects such as cortical lamination irregularity, subependymal nodule formation, dysmorphic astrocyte differentiation and dendritic malformation have been described for patients and animal models. However, downstream networks affected in the developing brain by hyperactivated mTOR signaling have yet to be characterized. Here, we present an integrated analysis of transcriptomes and proteomes generated from wild-type and Tsc1/Emx1-Cre forebrains. This led to comprehensive lists of genes and proteins whose expression levels were altered by hyperactivated mTOR signaling. Further incorporation of TSC patient data followed by functional enrichment and network analyses pointed to changes in molecular components and cellular processes associated with neuronal differentiation and morphogenesis as the key downstream events underlying developmental and morphological defects in TSC. Our results provide novel and fundamental molecular bases for understanding hyperactivated mTOR signaling-induced brain defects which can in turn facilitate identification of potential diagnostic markers and therapeutic targets for mTOR signaling-related neurological disorders. PMID- 28588231 TI - Genome-wide association study of 1,5-anhydroglucitol identifies novel genetic loci linked to glucose metabolism. AB - 1,5-anhydroglucitol (1,5-AG) is a biomarker of hyperglycemic excursions associated with diabetic complications. Because of its structural similarity to glucose, genetic studies of 1,5-AG can deliver complementary insights into glucose metabolism. We conducted genome-wide association studies of serum 1,5-AG concentrations in 7,550 European ancestry (EA) and 2,030 African American participants (AA) free of diagnosed diabetes from the ARIC Study. Seven loci in/near EFNA1/SLC50A1, MCM6/LCT, SI, MGAM, MGAM2, SLC5A10, and SLC5A1 showed genome-wide significant associations (P < 5 * 10-8) among EA participants, five of which were novel. Six of the seven loci were successfully replicated in 8,790 independent EA individuals, and MCM6/LCT and SLC5A10 were also associated among AA. Most of 1,5-AG-associated index SNPs were not associated with the clinical glycemic markers fasting glucose or the HbA1c, and vice versa. Only the index variant in SLC5A1 showed a significant association with fasting glucose in the expected opposing direction. Products of genes in all 1,5-AG-associated loci have known roles in carbohydrate digestion and enteral or renal glucose transport, suggesting that genetic variants associated with 1,5-AG influence its concentration via effects on glucose metabolism and handling. PMID- 28588233 TI - Genomic Selection in Commercial Perennial Crops: Applicability and Improvement in Oil Palm (Elaeis guineensis Jacq.). AB - Genomic selection (GS) uses genome-wide markers to select individuals with the desired overall combination of breeding traits. A total of 1,218 individuals from a commercial population of Ulu Remis x AVROS (UR x AVROS) were genotyped using the OP200K array. The traits of interest included: shell-to-fruit ratio (S/F, %), mesocarp-to-fruit ratio (M/F, %), kernel-to-fruit ratio (K/F, %), fruit per bunch (F/B, %), oil per bunch (O/B, %) and oil per palm (O/P, kg/palm/year). Genomic heritabilities of these traits were estimated to be in the range of 0.40 to 0.80. GS methods assessed were RR-BLUP, Bayes A (BA), Cpi (BC), Lasso (BL) and Ridge Regression (BRR). All methods resulted in almost equal prediction accuracy. The accuracy achieved ranged from 0.40 to 0.70, correlating with the heritability of traits. By selecting the most important markers, RR-BLUP B has the potential to outperform other methods. The marker density for certain traits can be further reduced based on the linkage disequilibrium (LD). Together with in silico breeding, GS is now being used in oil palm breeding programs to hasten parental palm selection. PMID- 28588232 TI - Identification of MyoD-Responsive Transcripts Reveals a Novel Long Non-coding RNA (lncRNA-AK143003) that Negatively Regulates Myoblast Differentiation. AB - Myogenic differentiation factor (MyoD) is a master transcription factor in muscle development and differentiation. Although several long non-coding RNAs (lncRNAs) linked to MyoD have been found to influence muscle development, the functions of many lncRNAs have not been explored. Here we utilized lncRNA and mRNA microarray analysis to identify potential lncRNAs regulated by MyoD in muscle cells. A total of 997 differentially expressed lncRNAs (335 up-regulated and 662 down-regulated) and 1,817 differentially expressed mRNAs (148 up-regulated and 1,669 down regulated) were identified after MyoD knockdown in C2C12 cells. Functional predictions suggested that most lncRNAs are involved in the biological pathways related to muscle differentiation and cell cycle with co-expressed genes. To gain further insight into the MyoD-mediated lncRNA expression in muscle differentiation, tissue expression profiles and MyoD overexpression were performed, and we found one of the candidate lncRNAs-AK143003 was significantly regulated by MyoD. Further analyses showed its noncoding ability and cytoplasmic localisation. Silencing of AK143003 stimulated the accumulation of myogenic marker genes, whereas AK143003 overexpression led to their decreased synthesis. This study identified a multitude of MyoD-mediated lncRNAs for further investigation and identified a novel lncRNA, lnc-AK143003, which plays a role in controlling muscle differentiation. PMID- 28588235 TI - Parasitic nematode Meloidogyne incognita interactions with different Capsicum annum cultivars reveal the chemical constituents modulating root herbivory. AB - Plant volatile signatures are often used as cues by herbivores to locate their preferred hosts. Here, we report on the volatile organic compounds used by the subterranean root-knot nematode (RKN) Meloidogyne incognita for host location. We compared responses of infective second stage juveniles (J2s) to root volatiles of three cultivars and one accession of the solanaceous plant, Capsicum annum against moist sand in dual choice assays. J2s were more attracted to the three cultivars than to the accession, relative to controls. GC/MS analysis of the volatiles identified common constituents in each plant, five of which were identified as alpha-pinene, limonene, 2-methoxy-3-(1-methylpropyl)-pyrazine, methyl salicylate and tridecane. We additionally identified thymol as being specific to the accession. In dose-response assays, a blend of the five components elicited positive chemotaxis (71-88%), whereas individual components elicited varying responses; Methyl salicylate (MeSA) elicited the highest positive chemotaxis (70-80%), alpha-pinene, limonene and tridecane were intermediate (54-60%), and 2-methoxy-3-(1-methylpropyl)-pyrazine the lowest (49 55%). In contrast, thymol alone or thymol combined with either the preferred natural plant root volatiles or the five-component synthetic blend induced negative chemotaxis. Our results provide insights into RKN-host plant interactions, creating new opportunities for plant breeding programmes towards management of RKNs. PMID- 28588234 TI - Plasmon-induced nanoscale quantised conductance filaments. AB - Plasmon-induced phenomena have recently attracted considerable attention. At the same time, relatively little research has been conducted on electrochemistry mediated by plasmon excitations. Here we report plasmon-induced formation of nanoscale quantized conductance filaments within metal-insulator-metal heterostructures. Plasmon-enhanced electromagnetic fields in an array of gold nanodots provide a straightforward means of forming conductive CrOx bridges across a thin native chromium oxide barrier between the nanodots and an underlying metallic Cr layer. The existence of these nanoscale conducting filaments is verified by transmission electron microscopy and contact resistance measurements. Their conductance was interrogated optically, revealing quantised relative transmission of light through the heterostructures across a wavelength range of 1-12 MUm. Such plasmon-induced electrochemical processes open up new possibilities for the development of scalable devices governed by light. PMID- 28588236 TI - Foliar nitrogen and phosphorus stoichiometry of three wetland plants distributed along an elevation gradient in Dongting Lake, China. AB - We examined foliar nitrogen (N) and phosphorus (P) stoichiometry of 3 wetland plants (Phalaris arundinacea, Miscanthus sacchariflorus, and Carex brevicuspis) distributed along an elevation gradient in the Dongting Lake, China, and how this stoichiometry is related to soil physico-chemical characteristics, elevation, and flooding days. Plant and soil samples were collected from 3 lakeshore sites. Total N and P concentrations of plants and six physico-chemical characteristics of the soil were measured, in addition to the elevation and flooding days. P. arundinacea and M. sacchariflorus had higher total N and P concentrations than C. brevicuspis. The foliar N:P ratio decreased with increasing elevation, and only increased with increasing foliar total N concentration. Canonical correspondence analysis indicated that the foliar stoichiometry was primarily regulated by soil water content, followed by soil nutrient concentration. The foliar N and P stoichiometry of the 3 wetland plants was insignificantly correlated with soil total P concentration. However, foliar stoichiometric characteristics and soil total N concentration significantly differed among the 3 species. These results demonstrate that spatial variation of foliar stoichiometry in wetland plants exists along an elevation gradient, with this information being useful for the conservation and management of wetland plants in this lake. PMID- 28588238 TI - Disruption of Small GTPase Rab7 Exacerbates the Severity of Acute Pancreatitis in Experimental Mouse Models. AB - Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7Deltapan) mice. In Rab7Deltapan pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7Deltapan mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7Deltapan pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7Deltapan pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes. PMID- 28588237 TI - TCM-Mesh: The database and analytical system for network pharmacology analysis for TCM preparations. AB - With the advancement of systems biology research, we have already seen great progress in pharmacology studies, especially in network pharmacology. Network pharmacology has been proven to be effective for establishing the "compounds proteins/genes-diseases" network, and revealing the regulation principles of small molecules in a high-throughput manner, thus would be very effective for the analysis of drug combinations, especially for TCM preparations. In this work, we have proposed the TCM-Mesh system, which records TCM-related information collected from various resources and could serve for network pharmacology analysis for TCM preparations in a high-throughput manner (http://mesh.tcm.microbioinformatics.org/). Currently, the database contains 6,235 herbs, 383,840 compounds, 14,298 genes, 6,204 diseases, 144,723 gene disease associations, 3,440,231 pairs of gene interactions, 163,221 side effect records and 71 toxic records, and web-based software construct a network between herbs and treated diseases, which will help to understand the underlying mechanisms for TCM preparations at molecular levels. We have used 1,293 FDA approved drugs, as well as compounds from an herbal material Panax ginseng and a patented drug Liuwei Dihuang Wan (LDW) for evaluating our database. By comparison of different databases, as well as checking against literature, we have demonstrated the completeness, effectiveness, and accuracy of our database. PMID- 28588239 TI - Down-dip variations in a subducting low-velocity zone linked to episodic tremor and slip: a new constraint from ScSp waves. AB - Fluids are thought to play an important role in controlling episodic tremor and slow slip (ETS) in subduction zones. Therefore, constraining the along-dip distribution of fluids is necessary to better understand source mechanism of ETS, and particularly the role played by fluids in ETS generation. Here, we report clear observations of coherent ScSp phases with a dense seismic array in western Shikoku, Japan, where ETS has been most active over the past decade. Using numerical simulations of elastic-wave propagation to reproduce the observed ScSp phases, we demonstrate that, relative to shallower depths, either the Vp/Vs ratio or the thickness of a low-velocity zone (LVZ) within the subducting oceanic crust increases with depth beneath the mantle wedge corner where ETS has been observed. Based on these depth dependences of the structural elements, a wide semi-ductile shear zone appears to be lubricated by high-pressurized fluid in the subducting oceanic crust at ETS source depths, and to be a key factor regulating ETS activity. PMID- 28588240 TI - Structural Modeling of Chromatin Integrates Genome Features and Reveals Chromosome Folding Principle. AB - How chromosomes fold into 3D structures and how genome functions are affected or even controlled by their spatial organization remain challenging questions. Hi-C experiment has provided important structural insights for chromosome, and Hi-C data are used here to construct the 3D chromatin structure which are characterized by two spatially segregated chromatin compartments A and B. By mapping a plethora of genome features onto the constructed 3D chromatin model, we show vividly the close connection between genome properties and the spatial organization of chromatin. We are able to dissect the whole chromatin into two types of chromatin domains which have clearly different Hi-C contact patterns as well as different sizes of chromatin loops. The two chromatin types can be respectively regarded as the basic units of chromatin compartments A and B, and also spatially segregate from each other as the two chromatin compartments. Therefore, the chromatin loops segregate in the space according to their sizes, suggesting the excluded volume or entropic effect in chromatin compartmentalization as well as chromosome positioning. Taken together, these results provide clues to the folding principles of chromosomes, their spatial organization, and the resulted clustering of many genome features in the 3D space. PMID- 28588241 TI - Tunable Magneto-Optical Kerr Effects of Nanoporous Thin Films. AB - Magnetoplasmonics, combining magnetic and plasmonic functions, has attracted increasing attention owing to its unique magnetic and optical properties in various nano-architectures. In this work, Ag, CoFeB and ITO layers are fabricated on anodic aluminum oxide (AAO) porous films to form hybrid multi-layered nanoporous thin films by magnetron sputtering deposition process. The designed nanostructure supports localized surface plasmon resonance (LSPR) and tunable magneto-optical (MO) activity, namely, the sign inversion, which can be controlled by AAO porous film geometry (pore diameter and inter-pore spacing) flexibly. The physical mechanism of this special MO phenomena is further analyzed and discussed by the correlation of Kerr rotation and electronic oscillations controlled by the surface plasmon resonance that is related to the nanoporous structure. PMID- 28588242 TI - Photoswitchable phospholipid FRET acceptor: Detergent free intermembrane transfer assay of fluorescent lipid analogs. AB - We have developed and characterized a novel photoswitchable phospholipid analog termed N-nitroBIPS-DPPG. The fluorescence can be switched on and off repeatedly with minimal photobleaching by UV or visible light exposure, respectively. The rather large photochromic head group is inserted deeply into the interfacial membrane region conferring a conical overall lipid shape, preference for a positive curvature and only minimal intermembrane transfer. Utilizing the switchable NBD fluorescence quenching ability of N-nitroBIPS-DPPG, a detergent free intermembrane transfer assay system for NBD modified lipids was demonstrated and validated. As NBD quenching can be turned off, total NBD associated sample fluorescence can be determined without the need of detergents. This not only reduces detergent associated systematic errors, but also simplifies assay handling and allows assay extension to detergent insoluble lipid species. PMID- 28588243 TI - A novel network regularized matrix decomposition method to detect mutated cancer genes in tumour samples with inter-patient heterogeneity. AB - Inter-patient heterogeneity is a major challenge for mutated cancer genes detection which is crucial to advance cancer diagnostics and therapeutics. To detect mutated cancer genes in heterogeneous tumour samples, a prominent strategy is to determine whether the genes are recurrently mutated in their interaction network context. However, recent studies show that some cancer genes in different perturbed pathways are mutated in different subsets of samples. Subsequently, these genes may not display significant mutational recurrence and thus remain undiscovered even in consideration of network information. We develop a novel method called mCGfinder to efficiently detect mutated cancer genes in tumour samples with inter-patient heterogeneity. Based on matrix decomposition framework incorporated with gene interaction network information, mCGfinder can successfully measure the significance of mutational recurrence of genes in a subset of samples. When applying mCGfinder on TCGA somatic mutation datasets of five types of cancers, we find that the genes detected by mCGfinder are significantly enriched for known cancer genes, and yield substantially smaller p values than other existing methods. All the results demonstrate that mCGfinder is an efficient method in detecting mutated cancer genes. PMID- 28588244 TI - Wandering behaviour prevents inter and intra oceanic speciation in a coastal pelagic fish. AB - Small pelagic fishes have the ability to disperse over long distances and may present complex evolutionary histories. Here, Old World Anchovies (OWA) were used as a model system to understand genetic patterns and connectivity of fish between the Atlantic and Pacific basins. We surveyed 16 locations worldwide using mtDNA and 8 microsatellite loci for genetic parameters, and mtDNA (cyt b; 16S) and nuclear (RAG1; RAG2) regions for dating major lineage-splitting events within Engraulidae family. The OWA genetic divergences (0-0.4%) are compatible with intra-specific divergence, showing evidence of both ancient and contemporary admixture between the Pacific and Atlantic populations, enhanced by high asymmetrical migration from the Pacific to the Atlantic. The estimated divergence between Atlantic and Pacific anchovies (0.67 [0.53-0.80] Ma) matches a severe drop of sea temperature during the Gunz glacial stage of the Pleistocene. Our results support an alternative evolutionary scenario for the OWA, suggesting a coastal migration along south Asia, Middle East and eastern Africa continental platforms, followed by the colonization of the Atlantic via the Cape of the Good Hope. PMID- 28588245 TI - Retinol-binding protein-4 expression marks the short-term mortality of critically ill patients with underlying liver disease: Lipid, but not glucose, matters. AB - The implications of retinol-binding protein-4 (RBP4) expression in critically ill patients with underlying liver diseases remain unclear. A prospective cohort study involving 200 liver intensive care unit (ICU) patients was conducted, with 274 blood donors as controls. Patient outcomes were assessed using Cox and Kaplan Meier analyses. Of the 200 ICU patients (mean age: 56.0 yrs), 79.5% were male, 72.5% were cirrhotic, 62% were septic, 29.5% were diabetic, and 29% expired in the ICU (median admission: 7.5 days). ICU patients had lower baseline RBP4 (25.6+/-18.4 vs. 43.8+/-35.0 mg/L, p < 0.001) and total cholesterol (TC) levels than controls. The surviving ICU patients had lower baseline international normalized ratios (INRs) of prothrombin time, model for end-stage liver disease (MELD) scores and sepsis rates, but higher estimated glomerular filtration rates (eGFRs) and RBP4 levels than non-surviving patients. eGFRs, INRs and TC levels were independently associated with RBP4 levels. Only surviving patients exhibited significantly increased RBP4 levels after ICU discharge. Baseline RBP4 levels and MELD scores predicted 21-day (<=10 mg/L) and 1-year (>=25) mortality, respectively. In critically ill patients with underlying liver disease, with a link to eGFRs, INRs and TC levels, the baseline RBP4 may serve as a marker for short-term mortality. PMID- 28588246 TI - Phylogenetic evidence that both ancient vicariance and dispersal have contributed to the biogeographic patterns of anchialine cave shrimps. AB - Cave shrimps from the genera Typhlatya, Stygiocaris and Typhlopatsa (Atyidae) are restricted to specialised coastal subterranean habitats or nearby freshwaters and have a highly disconnected distribution (Eastern Pacific, Caribbean, Atlantic, Mediterranean, Madagascar, Australia). The combination of a wide distribution and a limited dispersal potential suggests a large-scale process has generated this geographic pattern. Tectonic plates that fragment ancestral ranges (vicariance) has often been assumed to cause this process, with the biota as passive passengers on continental blocks. The ancestors of these cave shrimps are believed to have inhabited the ancient Tethys Sea, with three particular geological events hypothesised to have led to their isolation and divergence; (1) the opening of the Atlantic Ocean, (2) the breakup of Gondwana, and (3) the closure of the Tethys Seaway. We test the relative contribution of vicariance and dispersal in the evolutionary history of this group using mitochondrial genomes to reconstruct phylogenetic and biogeographic scenarios with fossil-based calibrations. Given that the Australia/Madagascar shrimp divergence postdates the Gondwanan breakup, our results suggest both vicariance (the Atlantic opening) and dispersal. The Tethys closure appears not to have been influential, however we hypothesise that changing marine currents had an important early influence on their biogeography. PMID- 28588249 TI - Estimating age-related incidence of HBsAg seroclearance in chronic hepatitis B virus infections of China by using a dynamic compartmental model. AB - The age-specific seroclearance pattern of hepatitis B surface antigen (HBsAg) in chronic hepatitis B virus (HBV) infections of China remains unclear. In this study, based on three national serosurvey data of hepatitis B in China, we propose an age- and time-dependent discrete model and use the method of non linear least squares to estimate the age-specific annual rate of HBsAg seroclearance. We found that the HBsAg seroclearance in chronic HBV infections of China aged 1-59 years occurred at an average annual rate of 1.80% (95% CI, 1.54 2.06%) from 1993 to 2006. The HBsAg seroclearance occurred predominantly in the early childhood, 20-24 and 35-39 year age groups. Moreover, our model estimated that HBsAg seroclearance resulted in 23.38% of the decrease of total HBsAg prevalence for population aged 1-59 years in 2006. It also prevented 9.30% of new HBV infections (about 7.43 million people) and 9.95% of HBV-related deaths (about 0.25 million people) from 1993 to 2006. This study develops a new and efficient method to estimate the age-specific incidence of HBsAg seroclearance at a population-level and evaluate its effect. PMID- 28588247 TI - High-resolution promoter map of human limbal epithelial cells cultured with keratinocyte growth factor and rho kinase inhibitor. AB - An in vitro model of corneal epithelial cells (CECs) has been developed to study and treat corneal disorders. Nevertheless, conventional CEC culture supplemented with epidermal growth factor (EGF) results in a loss of CEC characteristics. It has recently been reported that limbal epithelial cells (LECs) cultured with keratinocyte growth factor (KGF) and the rho kinase inhibitor Y-27632 could maintain the expression of several CEC-specific markers. However, the molecular mechanism underlying the effect of culture media on LECs remains to be elucidated. To elucidate this mechanism, we performed comprehensive gene expression analysis of human LECs cultured with EGF or KGF/Y-27632, by cap analysis of gene expression (CAGE). Here, we found that LECs cultured with KGF and Y-27632 presented a gene expression profile highly similar to that of CECs in vivo. In contrast, LECs cultured with EGF lost the characteristic CEC gene expression profile. We further discovered that CEC-specific PAX6 promoters are highly activated in LECs cultured with KGF and Y-27632. Our results provide strong evidence that LECs cultured with KGF and Y-27632 would be an improved in vitro model in the context of gene expression. These findings will accelerate basic studies of CECs and clinical applications in regenerative medicine. PMID- 28588248 TI - Expanded CCUG repeat RNA expression in Drosophila heart and muscle trigger Myotonic Dystrophy type 1-like phenotypes and activate autophagocytosis genes. AB - Myotonic dystrophies (DM1-2) are neuromuscular genetic disorders caused by the pathological expansion of untranslated microsatellites. DM1 and DM2, are caused by expanded CTG repeats in the 3'UTR of the DMPK gene and CCTG repeats in the first intron of the CNBP gene, respectively. Mutant RNAs containing expanded repeats are retained in the cell nucleus, where they sequester nuclear factors and cause alterations in RNA metabolism. However, for unknown reasons, DM1 is more severe than DM2. To study the differences and similarities in the pathogenesis of DM1 and DM2, we generated model flies by expressing pure expanded CUG ([250]*) or CCUG ([1100]*) repeats, respectively, and compared them with control flies expressing either 20 repeat units or GFP. We observed surprisingly severe muscle reduction and cardiac dysfunction in CCUG-expressing model flies. The muscle and cardiac tissue of both DM1 and DM2 model flies showed DM1-like phenotypes including overexpression of autophagy-related genes, RNA mis-splicing and repeat RNA aggregation in ribonuclear foci along with the Muscleblind protein. These data reveal, for the first time, that expanded non-coding CCUG repeat-RNA has similar in vivo toxicity potential as expanded CUG RNA in muscle and heart tissues and suggests that specific, as yet unknown factors, quench CCUG repeat toxicity in DM2 patients. PMID- 28588250 TI - An atypical phosphodiesterase capable of degrading haloalkyl phosphate diesters from Sphingobium sp. strain TCM1. AB - Sphingobium sp. strain TCM1 can degrade tris(2-chloroethyl) phosphate (TCEP) to inorganic phosphate and 2-chloroethanol. A phosphotriesterase (PTE), phosphodiesterase (PDE) and phosphomonoesterase (PME) are believed to be involved in the degradation of TCEP. The PTE and PME that respectively catalyze the first and third steps of TCEP degradation in TCM1 have been identified. However, no information has been reported on a PDE catalyzing the second step. In this study, we identified, purified, and characterized a PDE capable of hydrolyzing haloalkyl phosphate diesters. The final preparation of the enzyme had a specific activity of 29 umol min-1 mg-1 with bis(p-nitrophenyl) phosphate (BpNPP) as the substrate. It also possessed low PME activity with p-nitrophenyl phosphate (pNPP) as substrate. The catalytic efficiency (k cat/K m) with BpNPP was significantly higher than that with pNPP, indicating that the enzyme prefers the organophosphorus diester to the monoester. The enzyme degraded bis(2,3 dibromopropyl) phosphate, bis(1,3-dichloro-2-propyl) phosphate and bis(2 chloroethyl) phosphate, suggesting that it is involved in the metabolism of haloalkyl organophosphorus triesters. The primary structure of the PDE from TCM1 is distinct from those of typical PDE family members and the enzyme belongs to the polymerase and histidinol phosphatase superfamily. PMID- 28588251 TI - Fused Deposition Modeling (FDM) 3D Printed Tablets for Intragastric Floating Delivery of Domperidone. AB - The aim of this study was to explore the feasibility of fused deposition modeling (FDM) 3D printing to prepare intragastric floating sustained release (FSR) tablets. Domperidone (DOM), an insoluble weak base, was chosen as a model drug to investigate the potential of FSR in increasing its oral bioavailability and reducing its administration frequency. DOM was successfully loaded into hydroxypropyl cellulose (HPC) filaments using hot melt extrusion (HME). The filaments were then printed into hollow structured tablets through changing the shell numbers and the infill percentages. Physical characterization results indicated that the majority of DOM gradually turned into the amorphous form during the fabrication process. The optimized formulation (contain 10% DOM, with 2 shells and 0% infill) exhibited the sustained release characteristic and was able to float for about 10 h in vitro. Radiographic images showed that the BaSO4 labeled tablets were retained in the stomach of rabbits for more than 8 h. Furthermore, pharmacokinetic studies showed the relative bioavailability of the FSR tablets compared with reference commercial tablets was 222.49 +/- 62.85%. All the results showed that FDM based 3D printing might be a promising way to fabricate hollow tablets for the purpose of intragastric floating drug delivery. PMID- 28588252 TI - Candida albicans Sap6 amyloid regions function in cellular aggregation and zinc binding, and contribute to zinc acquisition. AB - Candida albicans is an opportunistic fungal pathogen colonizing the oral cavity. C. albicans secreted aspartic protease Sap6 is important for virulence during oral candidiasis since it degrades host tissues to release nutrients and essential transition metals. We found that zinc specifically increased C. albicans autoaggregation induced by Sap6; and that Sap6 itself bound zinc ions. In silico analysis of Sap6 predicted four amyloidogenic regions that were synthesized as peptides (P1-P4). All peptides, as well as full length Sap6, demonstrated amyloid properties, and addition of zinc further increased amyloid formation. Disruption of amyloid regions by Congo red significantly reduced auotoaggregation. Deletion of C. albicans genes that control zinc acquisition in the ZAP1 regulon, including zinc transporters (Pra1 and Zrt1) and other zinc regulated surface proteins, resulted in lower autoaggregation and reduction of surface binding of Sap6. Cells with high expression of PRA1 and ZRT1 also showed increased Sap6-mediated autoaggregation. C. albicans ?sap6 deletion mutants failed to accumulate intracellular zinc comparable to ?zap1, ?zrt1, and ?pra1 cells. Thus Sap6 is a multi-functional molecule containing amyloid regions that promotes autoaggregation and zinc uptake, and may serve as an additional system for the community acquisition of zinc. PMID- 28588254 TI - Magnetic anisotropy and high-frequency property of flexible FeCoTa films obliquely deposited on a wrinkled topography. AB - We investigated the magnetic anisotropy and the high-frequency property of flexible Fe60Co26Ta14 (FeCoTa) thin films obtained by oblique sputtering onto a wrinkled surface. The sinuously wrinkled topography is produced by growing Ta layer on a pre-strained polydimethylsiloxane (PDMS) membrane. Due to the enhanced effect of shadowing, the oblique deposition of FeCoTa layer gives rise to a shift of wrinkle peak towards the incident atomic flux. With increasing the PDMS pre strain or increasing the oblique sputtering angle, both the uniaxial magnetic anisotropy and the ferromagnetic resonance frequency of FeCoTa films are enhanced, but the initial permeability decreases. The magnetization reversal mechanism of wrinkled FeCoTa films can be interpreted by a two-phase model composed of both coherent rotation and domain wall nucleation. With the enhancement of uniaxial magnetic anisotropy, the domain wall nucleation becomes pronounced in FeCoTa films. PMID- 28588253 TI - Nucleotide excision repair is a potential therapeutic target in multiple myeloma. AB - Despite the development of novel drugs, alkylating agents remain an important component of therapy in multiple myeloma (MM). DNA repair processes contribute towards sensitivity to alkylating agents and therefore we here evaluate the role of nucleotide excision repair (NER), which is involved in the removal of bulky adducts and DNA crosslinks in MM. We first evaluated NER activity using a novel functional assay and observed a heterogeneous NER efficiency in MM cell lines and patient samples. Using next-generation sequencing data, we identified that expression of the canonical NER gene, excision repair cross-complementation group 3 (ERCC3), significantly impacted the outcome in newly diagnosed MM patients treated with alkylating agents. Next, using small RNA interference, stable knockdown and overexpression, and small-molecule inhibitors targeting xeroderma pigmentosum complementation group B (XPB), the DNA helicase encoded by ERCC3, we demonstrate that NER inhibition significantly increases sensitivity and overcomes resistance to alkylating agents in MM. Moreover, inhibiting XPB leads to the dual inhibition of NER and transcription and is particularly efficient in myeloma cells. Altogether, we show that NER impacts alkylating agents sensitivity in myeloma cells and identify ERCC3 as a potential therapeutic target in MM. PMID- 28588255 TI - PKM2 promotes cell migration and inhibits autophagy by mediating PI3K/AKT activation and contributes to the malignant development of gastric cancer. AB - Pyruvate kinase M2 (PKM2) is a key kinase of glycolysis and is characteristic of all proliferating cells. The role of PKM2 in gastric cancer (GC) is still ambiguous and yet to be determined. To better understand the role of PKM2 in both the migration and invasion of GC, we measured the expression of PKM2 in GC cell lines using qRT-PCR and western blot. The prognostic value of PKM2 was analyzed by Immunohistochemistry in a cohort containing 88 GC patients. PKM2 was knocked down by the short hairpin RNA plasmid vector in NCI-N87 and BGC-823 cells, and the biological behavior and downstream signaling pathways were also investigated in vitro. Subcutaneous xenografts and pulmonary metastases models were constructed in nude mice to compare the differences in tumorgenesis and metastasis after Knockdown of PKM2. Our results obtained from in vitro cell biological behavior, in vivo tumorigenicity studies, and primary GC samples revealed an oncogenic role for PKM2 in GC. Furthermore, for those GC patients who received radical resection, PKM2 might serve as a novel prognostic biomarker and target which would allow for a brand new treatment strategy for GC in the clinical settings. PMID- 28588256 TI - Rapamycin Attenuates Acute Seizure-induced Astrocyte Injury in Mice in Vivo. AB - Astrocytes have been implicated in epileptogenesis and seizure-induced brain injury. Pathological studies reveal a variety of structural abnormalities in astrocytes, such as vacuolization and astrogliosis. While in vivo imaging methods have demonstrated rapid changes in astrocytes under a variety of physiological and pathological conditions, the acute effects of seizures on astrocyte morphology in vivo and corresponding mechanisms of seizure-induced astrocytic injury have not been documented. In this study, we utilized in vivo two-photon imaging to directly monitor the acute structural effects of kainate-induced seizures on cortical astrocytes. Kainate seizures cause an immediate, but transient, vacuolization of astrocytes, followed over several days by astrogliosis. These effects are prevented by pre- or post-treatment with rapamycin, indicating the mTOR pathway is involved in mediating seizure-induced astrocyte injury. These finding have clinical implications for mechanisms of seizure-induced astrocyte injury and potential therapeutic applications with mTOR inhibitors. PMID- 28588257 TI - Gene expression: ACSS2 boosts local histone acetylation. PMID- 28588258 TI - Non-uniform salinity in the root zone alleviates salt damage by increasing sodium, water and nutrient transport genes expression in cotton. AB - Non-uniform salinity alleviates salt damage through sets of physiological adjustments in Na+ transport in leaf and water and nutrient uptake in the non saline root side. However, little is known of how non-uniform salinity induces these adjustments. In this study, RNA sequencing (RNA-Seq) analysis shown that the expression of sodium transport and photosynthesis related genes in the non uniform treatment were higher than that in the uniform treatment, which may be the reason for the increased photosynthetic (Pn) rate and decreased Na+ content in leaves of the non-uniform salinity treatment. Most of the water and nutrient transport related genes were up-regulated in the non-saline root side but down regulated in roots of the high-saline side, which might be the key reason for the increased water and nutrient uptake in the non-saline root side. Furthermore, the expression pattern of most differentially expressed transcription factor and hormone related genes in the non-saline root side was similar to that in the high saline side. The alleviated salt damage by non-uniform salinity was probably attributed to the increased expression of salt tolerance related genes in the leaf and that of water and nutrient uptake genes in the non-saline root side. PMID- 28588259 TI - Peritumoral Artery Scoring System: a Novel Scoring System to Predict Renal Function Outcome after Laparoscopic Partial Nephrectomy. AB - The present study aimed to assess the impact of peritumoral artery characteristics on renal function outcome prediction using a novel Peritumoral Artery Scoring System based on computed tomography arteriography. Peritumoral artery characteristics and renal function were evaluated in 220 patients who underwent laparoscopic partial nephrectomy and then validate in 51 patients with split and total glomerular filtration rate (GFR). In particular, peritumoral artery classification and diameter were measured to assign arteries into low, moderate, and high Peritumoral Artery Scoring System risk categories. Univariable and multivariable logistic regression analyses were then used to determine risk factors for major renal functional decline. The Peritumoral Artery Scoring System and four other nephrometry systems were compared using receiver operating characteristic curve analysis. The Peritumoral Artery Scoring System was significantly superior to the other systems for predicting postoperative renal function decline (p < 0.001). In receiver operating characteristic analysis, our category system was a superior independent predictor of estimated glomerular filtration rate (eGFR) decline (area-under-the-curve = 0.865, p < 0.001) and total GFR decline (area-under-the-curve = 0.796, p < 0.001), and split GFR decline (area-under-the-curve = 0.841, p < 0.001). Peritumoral artery characteristics were independent predictors of renal function outcome after laparoscopic partial nephrectomy. PMID- 28588261 TI - Persistent effects of the Yellow River on the Chinese marginal seas began at least ~880 ka ago. AB - The Yellow River (or Huanghe and also known as China's Sorrow in ancient times), with the highest sediment load in the world, provides a key link between continental erosion and sediment accumulation in the western Pacific Ocean. However, the exact age of its influence on the marginal sea is highly controversial and uncertain. Here we present high-resolution records of clay minerals and lanthanum to samarium (La/Sm) ratio spanning the past ~1 million years (Myr) from the Bohai and Yellow Seas, the potential sedimentary sinks of the Yellow River. Our results show a climate-driven provenance shift from small, proximal mountain rivers-dominance to the Yellow River-dominance at ~880 ka, a time period consistent with the Mid-Pleistocene orbital shift from 41-kyr to 100 kyr cyclicity. We compare the age of this provenance shift with the available age data for Yellow River headwater integration into the marginal seas and suggest that the persistent influence of the Yellow River on the Chinese marginal seas must have occurred at least ~880 ka ago. To our knowledge, this study provides the first offshore evidence on the drainage history of the Yellow River within an accurate chronology framework. PMID- 28588260 TI - Remodeling pathway control of mitochondrial respiratory capacity by temperature in mouse heart: electron flow through the Q-junction in permeabilized fibers. AB - Fuel substrate supply and oxidative phosphorylation are key determinants of muscle performance. Numerous studies of mammalian mitochondria are carried out (i) with substrate supply that limits electron flow, and (ii) far below physiological temperature. To analyze potentially implicated biases, we studied mitochondrial respiratory control in permeabilized mouse myocardial fibers using high-resolution respirometry. The capacity of oxidative phosphorylation at 37 degrees C was nearly two-fold higher when fueled by physiological substrate combinations reconstituting tricarboxylic acid cycle function, compared with electron flow measured separately through NADH to Complex I or succinate to Complex II. The relative contribution of the NADH pathway to physiological respiratory capacity increased with a decrease in temperature from 37 to 25 degrees C. The apparent excess capacity of cytochrome c oxidase above physiological pathway capacity increased sharply under hypothermia due to limitation by NADH-linked dehydrogenases. This mechanism of mitochondrial respiratory control in the hypothermic mammalian heart is comparable to the pattern in ectotherm species, pointing towards NADH-linked mt-matrix dehydrogenases and the phosphorylation system rather than electron transfer complexes as the primary drivers of thermal sensitivity at low temperature. Delineating the link between stress and remodeling of oxidative phosphorylation is important for understanding metabolic perturbations in disease evolution and cardiac protection. PMID- 28588263 TI - Gut microbiota: Intestinal fungi fuel the inflammatory fire in alcoholic liver disease. PMID- 28588264 TI - Neurogastroenterology: Cell lineage relationships dictate ENS organization. PMID- 28588262 TI - Identification of New Shikonin Derivatives as Antitumor Agents Targeting STAT3 SH2 Domain. AB - Signal transducer and activator of transcription 3 (STAT3) is hyper-activated in diversiform human tumors and has been validated as an attractive therapeutic target. Current research showed that a natural product, shikonin, along with its synthetic analogues, is able to inhibit the activity of STAT3 potently. The potential space of shikonin in developing novel anti-cancer agents encouraged us to carry out the investigation of the probable binding mode with STAT3. From this foundation, we have designed new types of STAT3 SH2 inhibitors. Combined simulations were performed to filter for the lead compound, which was then substituted, synthesized and evaluated by a variety of bioassays. Among the entities, PMM-172 exhibited the best anti-proliferative activity against MDA-MB 231 cells with IC50 value 1.98 +/- 0.49 MUM. Besides, it was identified to decrease luciferase activity, induce cell apoptosis and reduce mitochondrial transmembrane potential in MDA-MB-231 cells. Also, PMM-172 inhibited constitutive/inducible STAT3 activation without affecting STAT1 and STAT5 in MDA MB-231 cells, and had no effect in non-tumorigenic MCF-10A cells. Moreover, PMM 172 suppressed STAT3 nuclear localization and STAT3 downstream target genes expression. Overall, these results indicate that the antitumor activity of PMM 172 is at least partially due to inhibition of STAT3 in breast cancer cells. PMID- 28588266 TI - Rumen Fluid Metabolomics Analysis Associated with Feed Efficiency on Crossbred Steers. AB - The rumen has a central role in the efficiency of digestion in ruminants. To identify potential differences in rumen function that lead to differences in average daily gain (ADG), rumen fluid metabolomic analysis by LC-MS and multivariate/univariate statistical analysis were used to identify differences in rumen metabolites. Individual feed intake and body-weight was measured on 144 steers during 105 d on a high concentrate ration. Eight steers with the greatest ADG and 8 steers with the least-ADG with dry matter intake near the population average were selected. Blood and rumen fluid was collected from the 16 steers 26 d before slaughter and at slaughter, respectively. As a result of the metabolomics analysis of rumen fluid, 33 metabolites differed between the ADG groups based on t-test, fold changes and partial least square discriminant analysis. These metabolites were primarily involved in linoleic and alpha linolenic metabolism (impact-value 1.0 and 0.75, respectively; P < 0.05); both pathways were down-regulated in the greatest-ADG compared with least-ADG group. Ruminal biohydrogenation might be associated with the overall animal production. The fatty acids were quantified in rumen and plasma using targeted MS to validate and evaluate the simple combination of metabolites that effectively predict ADG. PMID- 28588265 TI - Network Analysis Reveals the Recognition Mechanism for Dimer Formation of Bulb type Lectins. AB - The bulb-type lectins are proteins consist of three sequential beta-sheet subdomains that bind to specific carbohydrates to perform certain biological functions. The active states of most bulb-type lectins are dimeric and it is thus important to elucidate the short- and long-range recognition mechanism for this dimer formation. To do so, we perform comparative sequence analysis for the single- and double-domain bulb-type lectins abundant in plant genomes. In contrast to the dimer complex of two single-domain lectins formed via protein protein interactions, the double-domain lectin fuses two single-domain proteins into one protein with a short linker and requires only short-range interactions because its two single domains are always in close proximity. Sequence analysis demonstrates that the highly variable but coevolving polar residues at the interface of dimeric bulb-type lectins are largely absent in the double-domain bulb-type lectins. Moreover, network analysis on bulb-type lectin proteins show that these same polar residues have high closeness scores and thus serve as hubs with strong connections to all other residues. Taken together, we propose a potential mechanism for this lectin complex formation where coevolving polar residues of high closeness are responsible for long-range recognition. PMID- 28588267 TI - PHLDA3 impedes somatic cell reprogramming by activating Akt-GSK3beta pathway. AB - Reprogramming of adult somatic cells into induced pluripotent stem cells holds great promise in clinical therapy. Increasing evidences have shown that p53 and its target genes play important roles in somatic cell reprogramming. In this study, we report that PHLDA3, a p53 target gene, functions as a blockage of iPSCs generation by activating the Akt-GSK3beta pathway. Furthermore, PHLDA3 is found to be transcriptionally regulated by Oct4. These findings reveal that PHLDA3 acts as a new member of the regulatory network of somatic cell reprogramming. PMID- 28588269 TI - Temporal evolution of a seismic sequence induced by a gas injection in the Eastern coast of Spain. AB - Induced seismicity associated with energy production is becoming an increasingly important issue worldwide for the hazard it poses to the exposed population and structures. We analyze one of the rare cases of induced seismicity associated with the underwater gas storage operations observed in the Castor platform, located in the Valencia gulf, east Spain, near a complex and important geological structure. In September 2013, some gas injection operations started at Castor, producing a series of seismic events around the reservoir area. The larger magnitude events (up to 4.2) took place some days after the end of the injection, with EMS intensities in coastal towns up to degree III. In this work, the seismic sequence is analyzed with the aim of detecting changes in statistical parameters describing the earthquake occurrence before and after the injection and identifying possible proxies to be used for monitoring the sequence evolution. Moreover, we explore the potential predictability of these statistical parameters which can be used to control the field operations in injection/storage fluid reservoirs. We firstly perform a retrospective approach and next a perspective analysis. We use different techniques for estimating the value of the expected maximum magnitude that can occur due to antropogenic activities in Castor. PMID- 28588268 TI - Optimisation of a murine splenocyte mycobacterial growth inhibition assay using virulent Mycobacterium tuberculosis. AB - In the absence of a validated correlate of protection or robust animal models for human tuberculosis, Mycobacterial growth inhibition assays (MGIAs) aim to assess vaccines ability to inhibit mycobacterial growth in-vitro. We optimised a reproducible murine splenocyte MGIA based on in-vitro infection with virulent Mycobacterium tuberculosis (M.tb) Erdman. We identified splenocyte viability as a problem in state-of-art MGIA protocols, which can be improved by simple changes in culture conditions (viability increase from 21% to 46% at last day of culture). The growth inhibitory potential in mice immunised with either BCG, H56:CAF01 or H56:CAF01 administered side-by-side with BCG was significantly better compared to placebo in all groups (0.3 log10 CFU [+/-0.2, p = 0.049], 0.5 [+/-0.2, p = 0.016] and 0.6 [+/-0.1, p = 0.0007], respectively) corresponding to the levels of in-vivo protection. Unexpectedly the CAF01 adjuvant control group also induced significant growth inhibition of 0.3 log10 CFU (+/-0.2, p = 0.047). Finally, we explored vaccine-associated T cell effector functions. Despite presence of high levels of vaccine-specific T cells, we found no increase in CD4+ T cell number or cytokine expression profile, nor a difference in cytokine levels in the supernatant after four days culture with or without M.tb. Spontaneous IFN gamma release correlated with growth inhibition levels (p = 0.02), however the cellular source was not found. PMID- 28588270 TI - Maternal-placental-fetal biodistribution of multimodal polymeric nanoparticles in a pregnant rat model in mid and late gestation. AB - Multimodal polymeric nanoparticles have many exciting diagnostic and therapeutic applications, yet their uptake and passage by the placenta, and applications in the treatment of pregnancy complications have not been thoroughly investigated. In this work, the maternal-fetal-placental biodistribution of anionic and cationic multimodal poly(glycidyl methacrylate) (PGMA) nanoparticles in pregnant rats at mid (ED10) and late (ED20) gestation was examined. Fluorescently-labelled and superparamagnetic PGMA nanoparticles functionalized with/without poly(ethyleneimine) (PEI) were administered to pregnant rats at a clinically relevant dose and biodistribution and tissue uptake assessed. Quantitative measurement of fluorescence intensity or magnetic resonance relaxometry in tissue homogenates lacked the sensitivity to quantify tissue uptake. Confocal microscopy, however, identified uptake by maternal organs and the decidua (ectoplacental cone) and trophoblast giant cells of conceptuses at ED10. At ED20, preferential accumulation of cationic vs. anionic nanoparticles was observed in the placenta, with PGMA-PEI nanoparticles localised mainly within the chorionic plate. These findings highlight the significant impact of surface charge and gestational age in the biodistribution of nanoparticles in pregnancy, and demonstrate the importance of using highly sensitive measurement techniques to evaluate nanomaterial biodistribution and maternal-fetal exposure. PMID- 28588272 TI - Mechanism of superior luminescent and high-efficiency photocatalytic properties of Eu-doped calcium aluminate by low-cost self-propagating combustion synthesis technique. AB - Eu-doped calcium aluminate was synthesized via the low-cost self-propagating combustion synthesis (SPCS) technique, whose phase constitutions were identified as Ca9Al6O18 and Ca3Al2O6. The Ca2+ ions in Ca9Al6O18 rather than Ca3Al2O6 phase were replaced by Eu3+ ions. The product exhibits the superior luminescent property and photocatalytic activity, which may find potential applications in the display devices and environment treatments. PMID- 28588273 TI - Myricetin protects Galleria mellonella against Staphylococcus aureus infection and inhibits multiple virulence factors. AB - Staphylococcus aureus is an opportunistic pathogen related to a variety of life threatening infections but for which antimicrobial resistance is liming the treatment options. We report here that myricetin, but not its glycosylated form, can remarkably decrease the production of several S. aureus virulence factors, including adhesion, biofilm formation, hemolysis and staphyloxanthin production, without interfering with growth. Myricetin affects both surface proteins and secreted proteins which indicate that its action is unrelated to inhibition of the agr quorum sensing system. Analysis of virulence related gene expression and computational simulations of pivotal proteins involved in pathogenesis demonstrate that myricetin downregulates the saeR global regulator and interacts with sortase A and alpha-hemolysin. Furthermore, Myr confers a significant degree of protection against staphylococcal infection in the Galleria mellonella model. The present findings reveal the potential of Myr as an alternative multi-target antivirulence candidate to control S. aureus pathogenicity. PMID- 28588274 TI - Pre- and post-diagnostic beta-blocker use and lung cancer survival: A population based cohort study. AB - Beta-blockers have been associated with decreased cancer mortality. However, evidence for lung cancer is sparse and reported beneficial effects might be based on biased analyses. In this so far largest study we investigated the association between beta-blocker use and lung cancer survival. Therefore, patients with a lung cancer diagnosis between April 1998 and December 2011 were selected from a database linkage of the Netherlands Cancer Registry and the PHARMO Database Network. After matching eligible patients on the propensity score, adjusted hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were calculated using Cox proportional hazards regression to investigate the association between pre-diagnostic and time-dependent beta-blocker use and overall survival. Duration and dose-response analyses and stratified analyses by beta-blocker type, histological subgroups and stage were conducted. Of 3,340 eligible lung cancer patients, 1437 (43%) took beta-blockers four months prior to diagnosis. Pre-diagnostic beta-blocker use was not associated with overall survival (HR 1.00 (0.92-1.08)) in the adjusted model. Time-dependent post diagnostic analysis showed similar results with a HR of 1.03 (0.94-1.11). Trend analyses showed no association for cumulative dose (HR 0.99 (0.97-1.02)) and cumulative duration (HR 1.00 (0.96-1.05)). In conclusion, beta-blocker use is not associated with reduced mortality among lung cancer patients. PMID- 28588271 TI - PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation. AB - Patients with secondary acute myeloid leukemia (sAML) arising from myelodysplastic syndromes have a poor prognosis marked by an increased resistance to chemotherapy. An urgent need exists for adjuvant treatments that can enhance or replace current therapeutic options. Here we show the potential of LB100, a small-molecule protein phosphatase 2 A (PP2A) inhibitor, as a monotherapy and chemosensitizing agent for sAML using an in-vitro and in-vivo approach. We demonstrate that LB100 decreases cell viability through caspase activation and G2/M cell-cycle arrest. LB100 enhances daunorubicin (DNR) cytotoxicity resulting in decreased xenograft volumes and improved overall survival. LB100 profoundly upregulates miR-181b-1, which we show directly binds to the 3' untranslated region of Bcl-2 mRNA leading to its translational inhibition. MiR-181b-1 ectopic overexpression further diminishes Bcl-2 expression leading to suppression of sAML cell growth, and enhancement of DNR cytotoxicity. Our research highlights the therapeutic potential of LB100, and provides new insights into the mechanism of LB100 chemosensitization. PMID- 28588275 TI - De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. AB - Here we report de novo non-synonymous single-nucleotide variants (SNVs) by conducting whole exome sequencing of 18 trios consisting of Japanese patients with sporadic schizophrenia and their parents. Among nine SNVs, we explored the functional impact of the de novo mutation in TBL1XR1 [c.30 C > G (p.Phe10Leu)], a gene previously found to be associated with autism spectrum disorder and epilepsy. Protein structural analysis revealed that Phe10Leu mutation may decrease the structural stability of the TBL1XR1 protein. We demonstrate that Phe10Leu mutation alters the interaction of TBL1XR1 with N-CoR and beta-catenin, which play critical roles in regulation of Wnt-mediated transcriptional activity. Consistently, TBL1XR1-mediated activation of Wnt signaling was up-regulated by Phe10Leu mutation. These results suggest that a de novo TBL1XR1 point mutation could alter Wnt/beta-catenin signaling activity. Further studies are required to clarify the involvement of TBL1XR1 mutations in neuropsychiatric conditions. PMID- 28588277 TI - Effects of hydraulic retention time on adsorption behaviours of EPS in an A/O MBR: biofouling study with QCM-D. AB - Extra-cellular polymeric substances (EPS) are a major cause of membrane fouling in membrane bioreactors (MBRs). In this study, an anoxic-oxic membrane bioreactor (A/O-MBR) was run continuously for 98 days. The runs were divided into three stages according to hydraulic retention time (HRT) (11.8, 12.5 and 14.3 h, respectively). EPS were extracted from the reactor under the different HRTs. A quartz crystal microbalance with dissipation monitoring (QCM-D) and Fourier transform infrared (FT-IR) were used to study the adherence layer structures and the adsorption behaviours of EPS on the membrane surface. The results indicated that the removal rate of TN was more susceptible to HRT than NH3-N. The observations in the QCM-D suggested that at the lowest HRT (11.8 h), the structure of the adsorption layer is loose and soft and the fluidity was better than for HRTs of 12.5 or 14.3 h. It is likely one of the major reasons for the rapidly blocking of the membrane pores. Furthermore, the higher EPS adherence as analyzed in the QCM-D and EPS concentration could induce a higher osmotic pressure effect, leading to a rapid membrane-fouling rate. PMID- 28588276 TI - Single-axon level morphological analysis of corticofugal projection neurons in mouse barrel field. AB - Corticofugal projection neurons are key components in connecting the neocortex and the subcortical regions. In the barrel field, these neurons have various projection targets and play crucial roles in the rodent whisker sensorimotor system. However, the projection features of corticofugal projection neurons at the single-axon level are far from comprehensive elucidation. Based on a brain wide positioning system with high-resolution imaging for Thy1-GFP M-line mice brains, we reconstructed and analyzed more than one hundred corticofugal projection neurons in both layer V and VI of barrel cortex. The dual-color imaging made it possible to locate the neurons' somata, trace their corresponding dendrites and axons and then distinguish the neurons as L5 type I/II or L6 type. The corticofugal projection pattern showed significant diversity across individual neurons. Usually, the L5 type I neurons have greater multi-region projection potential. The thalamus and the midbrain are the most frequent projection targets among the investigated multidirectional projection neurons, and the hypothalamus is particularly unique in that it only appears in multidirectional projection situations. Statistically, the average branch length of apical dendrites in multi-region projection groups is larger than that of single-region projection groups. This study demonstrated a single-axon-level analysis for barrel corticofugal projection neurons, which could provide a micro anatomical basis for interpreting whisker sensorimotor circuit function. PMID- 28588279 TI - Atomistic Corrective Scheme for Supercell Density Functional Theory Calculations of Charged Defects. AB - A new method to correct formation energies of charged defects obtained by supercell density-functional calculations is presented and applied to bulk, surface, and low-dimensional systems. The method relies on atomistic models and a polarizable force field to describe a material system and its dielectric properties. The polarizable force field is based on a minimal set of fitting parameters, it accounts for the dielectric screening arising from ions and electrons separately, and it can be easily implemented in any software for atomistic molecular dynamics simulations. This work illustrates both technical aspects and applications of the new corrective scheme. The method is tested on systems in vacuo to validate the energy scheme. It is applied to charged defects in the bulk and at the surface of realistic materials to achieve comparison with published results obtained by using available corrective schemes based on continuum electrostatics treatments. Moreover, to demonstrate its generality, the method is used to correct the formation energy obtained by DFT of a singly negatively charged S vacancy in monolayer, bilayer, trilayer and bulk MoS2. PMID- 28588278 TI - Associations among ADHD, Abnormal Eating and Overweight in a non-clinical sample of Asian children. AB - Attention-deficit/hyperactivity disorder (ADHD) has been found to be comorbid with obesity in adults, but the association in children is uncertain. Because the underlying mechanism of comorbidity in children has not been researched sufficiently, this study aims to explore the associations among ADHD, abnormal eating, and body mass index (BMI), as well as the mediating effect of depression in children. We conducted a cross-sectional study of 785 primary students in China. The parent-report version of ADHD Rating Scale-IV (ADHDRS-IV), the Child Eating Behaviour Questionnaire (CEBQ) and the Children's Eating Attitude Test (ChEAT) were used to identify ADHD symptoms and abnormal eating. The Child Behavior Checklist (CBCL) was applied to assess depression. Structural Equation Modeling was carried out to clarify the associations between ADHD symptoms, depression, abnormal eating, and overweight of students. We found that ADHD positively contributed to emotional eating and Bulimia Nervosa symptoms. However, neither emotional eating nor Bulimia Nervosa symptoms was related to BMI in children. We also found that ADHD significantly contributed to depression, and depression directly predicted emotional eating. In conclusion, ADHD increased the risk of abnormal eating in children, while no significant relationship existed between ADHD and BMI. Comorbid depression raised the risk of emotional eating, rather than Bulimia Nervosa symptoms. PMID- 28588280 TI - Heterogeneity of Diffusion-Weighted Imaging in Tumours and the Surrounding Stroma for Prediction of Ki-67 Proliferation Status in Breast Cancer. AB - Breast tissue heterogeneity is related to risk factors that lead to more aggressive tumour growth and worse prognosis, yet such heterogeneity has not been well characterized. The aim of this study is to reveal the heterogeneous signal patterns of the apparent diffusion coefficient (ADC) of a tumour and its surrounding stromal tissue and to predict the Ki-67 proliferation status in oestrogen receptor (ER)-positive breast cancer patients. A dataset of 82 patients who underwent diffusion-weighted imaging (DWI) examination was collected. The ADC map was segmented into regions comprising the tumour and the surrounding stromal shells. To reflect correlations between each region in terms of its mean ADC value, a functional graph was constructed consisting of nodes as regions and edges as interactions between two nodes. Analysis of the graph revealed a higher average degree in samples over-expressing Ki-67 than in samples with low Ki-67 expression. In the low-Ki-67 group, most of the identified edges represented correlations between adjacent regions, whereas additional edges representing correlations between non-adjacent regions were found in the high-Ki-67 group. The ADC signal in various breast stromal regions surrounding the tumour showed a discriminative pattern and would be valuable for estimating the Ki-67 proliferation status by DWI. PMID- 28588281 TI - A Central Small Amino Acid in the VAMP2 Transmembrane Domain Regulates the Fusion Pore in Exocytosis. AB - Exocytosis depends on cytosolic domains of SNARE proteins but the function of the transmembrane domains (TMDs) in membrane fusion remains controversial. The TMD of the SNARE protein synaptobrevin2/VAMP2 contains two highly conserved small amino acids, G100 and C103, in its central portion. Substituting G100 and/or C103 with the beta-branched amino acid valine impairs the structural flexibility of the TMD in terms of alpha-helix/beta-sheet transitions in model membranes (measured by infrared reflection-absorption or evanescent wave spectroscopy) during increase in protein/lipid ratios, a parameter expected to be altered by recruitment of SNAREs at fusion sites. This structural change is accompanied by reduced membrane fluidity (measured by infrared ellipsometry). The G100V/C103V mutation nearly abolishes depolarization-evoked exocytosis (measured by membrane capacitance) and hormone secretion (measured biochemically). Single-vesicle optical (by TIRF microscopy) and biophysical measurements of ATP release indicate that G100V/C103V retards initial fusion-pore opening, hinders its expansion and leads to premature closure in most instances. We conclude that the TMD of VAMP2 plays a critical role in membrane fusion and that the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re arrangements of the lipid membrane that are necessary for fusion pore opening and expansion. PMID- 28588282 TI - Comparison and immunobiological characterization of retinoic acid inducible gene I-like receptor expression in mesenchymal stromal cells. AB - Due to their immunomodulatory and regenerative properties, Mesenchymal stromal cells (MSC) have generated major interests in several clinical settings including transplantation and inflammatory diseases. MSC functions can be influenced by their tissue origin. Their microenvironment strongly affects their biology notably through TLR sensing. In this study, we show that MSC isolated from four different sources express another type of cytosolic pathogen recognition receptors known as retinoic acid inducible gene-I (RIG-I)-like receptors (RLR). RLR activation in MSC induces the production of Type I IFN (IFN-beta) and Type III IFN (IFN-lambda1). The highest producers are adipose tissue(AT)-MSC. We further show that Interferon production is induced through TBK1/IKK-epsilon signaling and IRF7 phosphorylation. Depending on MSC source, the knockdown of TLR3 and/or RIG-I decreases the MSC response to RLR ligand poly(I:C)/Lyovec. Among the different MSC types, AT-MSCs display the highest sensitivity to viral stimuli as shown by the alteration of their viability after prolonged stimulation. Our work indicates that this could be linked to an increase of pro apoptotic Noxa expression. Finally, the expression of IDO1 and LIF upon RLR activation indicate the increase of MSC immunomodulatory potential, especially in AT-MSCs. Altogether, these data should be considered when designing MSC-based therapy in clinical settings where inflammation or infection are present. PMID- 28588283 TI - Additional molecular testing of saliva specimens improves the detection of respiratory viruses. AB - Emerging infectious diseases in humans are often caused by respiratory viruses such as pandemic or avian influenza viruses and novel coronaviruses. Microbiological testing for respiratory viruses is important for patient management, infection control and epidemiological studies. Nasopharyngeal specimens are frequently tested, but their sensitivity is suboptimal. This study evaluated the incremental benefit of testing respiratory viruses in expectorated saliva using molecular assays. A total of 258 hospitalized adult patients with suspected respiratory infections were included. Their expectorated saliva was collected without the use of any special devices. In the first cohort of 159 patients whose nasopharyngeal aspirates (NPAs) tested positive for respiratory viruses during routine testing, the viral load was measured using quantitative reverse transcription PCR. Seventeen percent of the patients (27/159) had higher viral loads in the saliva than in the NPA. The second cohort consisted of 99 patients whose NPAs tested negative for respiratory viruses using a direct immunofluorescence assay. Their NPA and saliva specimens were additionally tested using multiplex PCR. In these patients, the concordance rate by multiplex PCR between NPA and saliva was 83.8%. Multiplex PCR detected viruses in saliva samples from 16 patients, of which nine (56.3%) had at least one virus that was not detected in the NPA. Decisions on antiviral or isolation precautions would be affected by salivary testing in six patients. Although NPAs have high viral loads and remain the specimen of choice for most patients with respiratory virus infections, supplementary molecular testing of saliva can improve the clinical management of these patients. PMID- 28588284 TI - A novel preventive strategy against HIV-1 infection: combinatorial use of inhibitors targeting the nucleocapsid and fusion proteins. AB - The strategy of simultaneously attacking multiple targets is worthy of exploration in the field of microbicide development to combat HIV-1 sequence diversity and minimize the transmission of resistant variants. A combination of S acyl-2-mercaptobenzamide thioester-10 (SAMT10), an inhibitor of the HIV-1 nucleocapsid protein (NCp7), and the fusion inhibitor sifuvirtide (SFT) may exert synergistic effects, since SFT can block viral fusion at an early stage of the viral cycle and SAMT10 can disrupt viral particles at a later stage. In this study, we investigated the effect of the combination of SAMT10 and SFT on HIV-1 infection using in vitro cell culture and ex vivo mucosal explant models. A range of doses for each compound was tested at 10-fold serial dilutions based on their 50% effective concentrations (EC50). We observed a synergistic effect of SAMT10 and SFT in vitro against both the laboratory-adapted HIV-1 strain HIV-1IIIB (subtype B, X4) and three pseudotyped viruses prevalent in Chinese sexually transmitted populations (SVPB16 (subtype B, R5), SVPC12 (subtype C, R5) and SH1.81 (CRF01_AE, R5)). In the ex vivo study, the EC50 values of the inhibitor combinations were reduced 1.5- to 2-fold in colorectal mucosal explants compared to treatment with SAMT10 or SFT alone by using with HIV-1IIIB. These results may provide a novel strategy for microbicide development against HIV-1 sexual transmission. PMID- 28588286 TI - Mycobacterium tuberculosis Beijing genotype family strain isolated from naturally infected plateau zokor (Myospalax baileyi) in China. PMID- 28588285 TI - Isolation and characterization of Listeria species from rodents in natural environments in China. AB - Listeria is ubiquitous in a variety of environments and can be isolated from a wide range of animal hosts. Rodents are capable of carrying pathogenic bacteria in their intestines, such as Listeria, and can disseminate those pathogens into the natural environment and to where human activity occurs. In this study, we investigated the occurrence and antimicrobial susceptibility of Listeria spp. isolated from wild rodents found in natural environments in China. We collected 341 intestinal fecal samples of rodents from five different regions of China, all representing different rodent habitats. The antimicrobial susceptibility of the Listeria spp. isolates obtained were firstly assessed using the Kirby-Bauer disk diffusion method. Thirty-one samples were positive for Listeria spp., of which 11 were positive for Listeria monocytogenes and seven were positive for Listeria ivanovii. Other species identified include Listeria innocua, Listeria fleischmannii and Listeria floridensis. All Listeria spp. isolates were sensitive to the majority of the antimicrobials tested, but largely resistant to oxacillin (94.1%) and cefuroxime (70.6%). All L. monocytogenes isolates were further characterized by serotyping, multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). L. monocytogenes strains were grouped into three serotypes, five sequence types and five pulsotypes (PTs) by serotyping, MLST and PFGE, respectively. Almost half of the isolates (five of 11) belonged to serotype 1/2b, ST87 and PT1. This study determined that Listeria is carried in the intestinal tracts of wild rodents from multiple regions at a low rate, filling an epidemiological data gap on Listeria in natural environments in China. PMID- 28588287 TI - Identification and evaluation of the novel immunodominant antigen Rv2351c from Mycobacterium tuberculosis. AB - There is an urgent need for new immunodominant antigens to improve the diagnosis of tuberculosis (TB) and the efficacy of the TB vaccine to control the disease worldwide. In this study, we evaluated the diagnostic potential of a novel Mycobacterium tuberculosis (MTB)-specific antigen, Rv2351c, from region of difference (RD) 7 of the MTB genome, and investigated the potency of the vaccine by identifying its immunological function in human and animal immunological experiments. Twenty T-cell epitopes were identified using TEpredict and prediction tools from the Immune Epitope Database and Analysis Resource. A total of 159 subjects, including 61 patients with pulmonary TB, 38 patients with no TB and 55 healthy donors, were recruited and analyzed with an enzyme-linked immunospot (ELISpot) assay. The ELISpot assay using Rv2351c to detect TB infection, as compared with bacteriological tests as the gold standard, had a sensitivity and specificity of 61.4% (35/57) and 91.4% (85/93), respectively. The ELISpot assay using Rv2351c had a good conformance (kappa=0.554) as compared with the bacteriological test. Rv2351c also elicited a potent cellular immune response with a high expression of cytokines (IFN-gamma (4978+/-596.7 MUg/mL) and IL-4 (68.3+/-15.5 MUg/mL)) and a potent humoral immune response with a high concentration of IgG (1:2.2 * 106), IgG1 (1:4.5 * 105) and IgG2a (1:1.6 * 106) in immunized BALB/c mice. In addition, the ratio of IgG2a/IgG1 indicated that Rv2351c induced cellular immunity in the mice. The results of this study indicated that Rv2351c is an antigen with good immunogenicity that may potentially be used to develop diagnostic techniques and new TB vaccines. PMID- 28588288 TI - T-cell-dependent mechanisms promote Ebola VLP-induced antibody responses, but are dispensable for vaccine-mediated protection. AB - Humoral responses are essential for the protective efficacy of most Ebola virus (EBOV) candidate vaccines; however, the in vivo development of protective anti EBOV B-cell responses is poorly defined. Here, by using the virus-like particle (VLP) as a model antigen, we demonstrate that humoral responses are generated through follicular B-cell and T-cell-dependent mechanisms in a mouse model of EBOV infection. In addition, we show that the inclusion of the clinical-grade dsRNA adjuvant known as poly-ICLC in VLP vaccinations both augments and sustains germinal center B-cell reactions, antigen-specific B-cell frequencies and anti EBOV serum titers. Finally, we used mice that were deficient in either B-cells or T-cell-dependent antibody production to distinguish the contributing roles of EBOV humoral responses. We demonstrate that while anti-EBOV antibody responses promote protection, VLP-vaccinated mice can survive EBOV infection in the absence of detectable anti-EBOV antibodies. Moreover, we found that adjuvant signaling could circumvent the complete requirement for B-cell immunity in protection against EBOV. Collectively, these studies may prove valuable for the characterization and future development of additional EBOV vaccine candidates. PMID- 28588289 TI - West Nile virus infection in suspected febrile typhoid cases in Xinjiang, China. PMID- 28588290 TI - Comparative epidemiology of Middle East respiratory syndrome coronavirus (MERS CoV) in Saudi Arabia and South Korea. AB - MERS-CoV infection emerged in the Kingdom of Saudi Arabia (KSA) in 2012 and has spread to 26 countries. However, 80% of all cases have occurred in KSA. The largest outbreak outside KSA occurred in South Korea (SK) in 2015. In this report, we describe an epidemiological comparison of the two outbreaks. Data from 1299 cases in KSA (2012-2015) and 186 cases in SK (2015) were collected from publicly available resources, including FluTrackers, the World Health Organization (WHO) outbreak news and the Saudi MOH (MOH). Descriptive analysis, t tests, Chi-square tests and binary logistic regression were conducted to compare demographic and other characteristics (comorbidity, contact history) of cases by nationality. Epidemic curves of the outbreaks were generated. The mean age of cases was 51 years in KSA and 54 years in SK. Older males (?70 years) were more likely to be infected or to die from MERS-CoV infection, and males exhibited increased rates of comorbidity in both countries. The epidemic pattern in KSA was more complex, with animal-to-human, human-to-human, nosocomial and unknown exposure, whereas the outbreak in SK was more clearly nosocomial. Of the 1186 MERS cases in KSA with reported risk factors, 158 (13.3%) cases were hospital associated compared with 175 (94.1%) in SK, and an increased proportion of cases with unknown exposure risk was found in KSA (710, 59.9%). In a globally connected world, travel is a risk factor for emerging infections, and health systems in all countries should implement better triage systems for potential imported cases of MERS-CoV to prevent large epidemics. PMID- 28588292 TI - Recombinant feline parvovirus infection of immunized tigers in central China. PMID- 28588291 TI - Seroprevalence of neutralizing antibodies against adenovirus type 14 and 55 in healthy adults in Southern China. AB - Re-emerging human adenovirus types 14 (Ad14) and 55 (Ad55) have caused severe respiratory diseases and even deaths during recent outbreaks. However, the seroprevalence of neutralizing antibodies (nAbs) in healthy adults, which may reflect previous circulation and help to predict potential outbreaks, remains unclear. In this study, we established micro-neutralizing (MN) assays on the basis of recombinant Ad14 and Ad55 reporter viruses, and we investigated serum nAbs in healthy blood donors from Southern China. We found that the overall seropositive rates were 24.8% and 22.4% for Ad14 and Ad55 nAbs, respectively. The seropositive rates were low in individuals younger than 20, and they gradually increased with age. Ad55-seropositive individuals tended to have high nAb titers (>1000), while low (72-200) and moderate (201-1000) nAb levels were frequently observed in Ad14-seropositive ones. Surprisingly, the seropositive rates and nAb levels were associated with the blood type but not the gender of the blood donors, with type AB individuals displaying higher seropositive rates and nAb levels. Interestingly, a significant positive correlation was observed between Ad14 and Ad55 seroprevalence, and higher titers of nAbs were detected in double positive individuals compared to single-positive ones. These results clarified the human humoral immune responses against Ad14 and Ad55 and revealed a low level of herd immunity in some subpopulations, which emphasized the importance of monitoring these two highly virulent adenoviruses and reinforced the development of prophylactic vaccines. PMID- 28588293 TI - Human infections with novel reassortant H5N6 avian influenza viruses in China. PMID- 28588294 TI - Predictors of seropositivity for human herpesvirus type 8 in patients with mild cirrhosis. AB - The high seroprevalence of human herpesvirus type 8 (HHV-8) in moderate or severe cirrhotics appears to be associated with male sex, hepatitis B virus (HBV) infection, alcoholism, and disease severity. The status of HHV-8 infection in mild cirrhotics remains unclear. Plasma samples collected from 93 mild cirrhotics and 93 age- and sex-matched healthy controls were analyzed for HHV-8 antibody and HHV-8 DNA. Mild cirrhotics had higher seropositivity for HHV-8 antibodies than healthy controls (P=0.0001). Univariate logistic regression analysis revealed that an age >=55 years (odds ratio (OR) 2.88, P=0.02), hepatitis C virus (HCV) infection (OR 3.42, P=0.01), and hepatitis activity (OR 4.10, P=0.004) were associated with HHV-8 seropositivity in cirrhotics. Stepwise multivariate logistic regression analysis confirmed that age >=55 years (adjusted OR (aOR) 1.92, P=0.04) and hepatitis activity (aOR 3.55, P=0.005) were independent factors. The rate of hepatitis activity was higher in HCV-infected than in HBV infected patients (P<0.0001) and in women than in men (P=0.0001). Cirrhotics who were seropositive for HHV-8 or HCV or had hepatitis activity were significantly older (P=0.02, <0.0001 and <0.0001, respectively). Plasma samples from all participants were negative for HHV-8 DNA. HHV-8 antibody titers in mild cirrhotics also markedly exceeded those in controls (P<0.0001), as did those in patients >=55 years old vs. younger patients (P=0.01), those in patients with vs. without HCV infection (P=0.0008), and those in patients with vs. without hepatitis activity (P=0.0005). Mild cirrhotics had high HHV-8 seroprevalence and HCV infection, and, in particular, old age and hepatitis activity were predictors. PMID- 28588295 TI - Cell fiber-based three-dimensional culture system for highly efficient expansion of human induced pluripotent stem cells. AB - Human pluripotent stem cells are a potentially powerful cellular resource for application in regenerative medicine. Because such applications require large numbers of human pluripotent stem cell-derived cells, a scalable culture system of human pluripotent stem cell needs to be developed. Several suspension culture systems for human pluripotent stem cell expansion exist; however, it is difficult to control the thickness of cell aggregations in these systems, leading to increased cell death likely caused by limited diffusion of gases and nutrients into the aggregations. Here, we describe a scalable culture system using the cell fiber technology for the expansion of human induced pluripotent stem (iPS) cells. The cells were encapsulated and cultured within the core region of core-shell hydrogel microfibers, resulting in the formation of rod-shaped or fiber-shaped cell aggregations with sustained thickness and high viability. By encapsulating the cells with type I collagen, we demonstrated a long-term culture of the cells by serial passaging at a high expansion rate (14-fold in four days) while retaining its pluripotency. Therefore, our culture system could be used for large scale expansion of human pluripotent stem cells for use in regenerative medicine. PMID- 28588296 TI - PCDH18 is frequently inactivated by promoter methylation in colorectal cancer. AB - Protocadherin18 (PCDH18) was found to be preferentially methylated and inactivated in colorectal cancer (CRC) using bioinformatics tools. However, its biologic role in tumorgenesis remains unclear. Herein, we aimed to elucidate its epigenetic regulation and biological functions in CRC. The methylation status of PCDH18 was significant higher in CRC tissues than in adjacent non-tumor tissues (median, 15.17% vs. median, 0.4438%). Expression level of PCDH18 was significantly lower in primary CRCs than in nonmalignant tissues. Importantly, methylation status of PCDH18 in cell-free DNA of CRC patients was also significantly higher than in healthy subjects. PCDH18 was readily expressed in NCM460 cells, but downregulated in 100% (4/4) of CRC cell lines by promoter methylation, despite its expression could be restored through demethylation treatment. Overexpression of PCDH18 suppressed CRC cell viability, colony formation and migration. Meanwhile, the depletion of PCDH18 by siRNA in NCM460 cells enhanced the colonogenicity and migration ability and promoted beta-catenin nuclear accumulation, whereas it inhibited cell cycle arrest. These effects were associated with upregulation of phospho-GSK-3beta and cyclin D1, and downregulation of caspase3 and p21. Our results suggested that PCDH18 was a putative tumor suppressor with epigenetic silencing in CRC and a potential biomarker for CRC diagnosis. PMID- 28588298 TI - Statistical study of ductility-dip cracking induced plastic deformation in polycrystalline laser 3D printed Ni-based superalloy. AB - Ductility-dip cracking in Ni-based superalloy, resulting from heat treatment, is known to cause disastrous failure, but its mechanism is still not completely clear. A statistical study of the cracking behavior as a function of crystal orientation in a laser 3D-printed DL125L Ni-based superalloy polycrystal is investigated here using the synchrotron X-ray microdiffraction. The dislocation slip system in each of the forty crystal grains adjacent to the 300 MUm long crack has been analyzed through Laue diffraction peak shapes. In all these grains, edge-type geometrically necessary dislocations (GNDs) dominate, and their dislocation line directions are almost parallel to the crack plane. Based on Schmid's law, the equivalent uniaxial tensile force direction is revealed normal to the trace of the crack. A qualitative mechanism is thus proposed. Thermal tensile stress perpendicular to the laser scanning direction is elevated due to a significant temperature gradient, and thus locations in the materials where the thermal stress exceeds the yield stress undergo plastic deformation mediated by GND activations. As the dislocations slip inside the crystal grains and pile up at the grain boundaries, local strain/stress keeps increasing, until the materials in these regions fail to sustain further deformation, leading to voids formation and cracks propagation. PMID- 28588297 TI - Targeted Patching and Dendritic Ca2+ Imaging in Nonhuman Primate Brain in vivo. AB - Nonhuman primates provide an important model not only for understanding human brain but also for translational research in neurological and psychiatric disorders. However, many high-resolution techniques for recording neural activity in vivo that were initially established for rodents have not been yet applied to the nonhuman primate brain. Here, we introduce a combination of two-photon targeted patching and dendritic Ca2+ imaging to the neocortex of adult common marmoset, an invaluable primate model for neuroscience research. Using targeted patching, we show both spontaneous and sensory-evoked intracellular dynamics of visually identified neurons in the marmoset cortex. Using two-photon Ca2+ imaging and intracellular pharmacological manipulation, we report both action-potential associated global and synaptically-evoked NMDA (N-methyl-D-aspartate) receptor mediated local Ca2+ signals in dendrites and spines of the superficial-layer cortical neurons. Therefore, we demonstrate the presence of synaptic Ca2+ signals in neuronal dendrites in living nonhuman primates. This work represents a proof of-principle for exploring the primate brain functions in vivo by monitoring neural activity and morphology at a subcellular resolution. PMID- 28588299 TI - Protective effect of rosiglitazone on kidney function in high-fat challenged human-CRP transgenic mice: a possible role for adiponectin and miR-21? AB - Obesity-related albuminuria is associated with decline of kidney function and is considered a first sign of diabetic nephropathy. Suggested factors linking obesity to kidney dysfunction include low-grade inflammation, insulin resistance and adipokine dysregulation. Here, we investigated the effects of two pharmacological compounds with established anti-inflammatory properties, rosiglitazone and rosuvastatin, on kidney dysfunction during high-fat diet (HFD) induced obesity. For this, human CRP transgenic mice were fed standard chow, a lard-based HFD, HFD+rosuvastatin or HFD+rosiglitazone for 42 weeks to study effects on insulin resistance; plasma inflammatory markers and adipokines; and renal pathology. Rosiglitazone but not rosuvastatin prevented HFD-induced albuminuria and renal fibrosis and inflammation. Also, rosiglitazone prevented HFD-induced KIM-1 expression, while levels were doubled with rosuvastatin. This was mirrored by miR-21 expression, which plays a role in fibrosis and is associated with renal dysfunction. Plasma insulin did not correlate with albuminuria. Only rosiglitazone increased circulating adiponectin concentrations. In all, HFD-induced albuminuria, and renal inflammation, injury and fibrosis is prevented by rosiglitazone but not by rosuvastatin. These beneficial effects of rosiglitazone are linked to lowered miR-21 expression but not connected with the selectively enhanced plasma adiponectin levels observed in rosiglitazone-treated animals. PMID- 28588300 TI - Pre-RC Protein MCM7 depletion promotes mitotic exit by Inhibiting CDK1 activity. AB - MCM7, a subunit of mini-chromosome maintenance proteins (MCM) complex, plays an important role in initiating DNA replication during the G1 phase and extending DNA strands during the S phase. Here, we demonstrated that MCM7 is not only sustained but maintains association with chromatin during M phase. Remarkably, MCM7 siRNA can accelerate mitotic exit. MCM7 depletion leads to CDK1 inactivation and promotes subsequent cohesin/RAD21 cleavage, which eventually leads to sister chromatin segregation. Moreover, MCM7 is co-localized with tubulin in the mitotic cells and MCM7 depletion results in aberrant mitosis. Our results indicate that MCM7 may exert certain functions on spindle formation to prevent cytokinesis during early mitosis by regulating CDK1 activity. PMID- 28588301 TI - Protective effects of gingerol on streptozotocin-induced sporadic Alzheimer's disease: emphasis on inhibition of beta-amyloid, COX-2, alpha-, beta - secretases and APH1a. AB - Gingerol is a major dietary compound that occurs in several plants belonging to the Zingiberaceae family. In the current study, the protective effect of gingerol on STZ-induced sporadic Alzheimer's disease (SAD) was determined. Gingerol was isolated from the seeds of Aframomum melegueta K. Schum and tested at doses of 10 and 20 mg/kgbwt for its possible effect on the SAD model in mice, using celecoxib (30 mg/kg bwt) as a reference standard. The curative effects of gingerol were assessed through measurement of beta-amyloid (Abeta-42), alpha-, beta- secretases, APH1a and COX-2 levels. In addition, improvement in the cognitive deficit in mice after treatment was confirmed using the water maze and Y-maze with intra-maze cues. Gingerol improved the cognitive and behavioral impairment and AD-like pathology in streptozotocin model mice. These beneficial effects occurred with an increase in alpha-secretase activity and a decrease in cerebral Abeta-42, beta- secretase, APH1a activity and COX-2-linked neuro-inflammation. PMID- 28588302 TI - Spectral comb of highly chirped pulses generated via cascaded FWM of two frequency-shifted dissipative solitons. AB - Dissipative solitons generated in normal-dispersion mode-locked lasers are stable localized coherent structures with a mostly linear frequency modulation (chirp). The soliton energy in fiber lasers is limited by the Raman effect, but implementation of the intracavity feedback at the Stokes-shifted wavelength enables synchronous generation of a coherent Raman dissipative soliton. Here we demonstrate a new approach for generating chirped pulses at new wavelengths by mixing in a highly-nonlinear fiber of these two frequency-shifted dissipative solitons, as well as cascaded generation of their clones forming in the spectral domain a comb of highly chirped pulses. We observed up to eight equidistant components in the interval of more than 300 nm, which demonstrate compressibility from ~10 ps to ~300 fs. This approach, being different from traditional frequency combs, can inspire new developments in fundamental science and applications such as few-cycle/arbitrary-waveform pulse synthesis, comb spectroscopy, coherent communications and bio-imaging. PMID- 28588303 TI - Critical dynamics of endogenous fluctuations predict cognitive flexibility in the Go/NoGo task. AB - Fluctuations with power-law scaling and long-range temporal correlations (LRTCs) are characteristic to human psychophysical performance. Systems operating in a critical state exhibit such LRTCs, but phenomenologically similar fluctuations and LRTCs may also be caused by slow decay of the system's memory without the system being critical. Theoretically, criticality endows the system with the greatest representational capacity and flexibility in state transitions. Without criticality, however, slowly decaying system memory would predict inflexibility. We addressed these contrasting predictions of the 'criticality' and 'long-memory' candidate mechanisms of human behavioral LRTCs by using a Go/NoGo task wherein the commission errors constitute a measure of cognitive flexibility. Response time (RT) fluctuations in this task exhibited power-law frequency scaling, autocorrelations, and LRTCs. We show here that the LRTC scaling exponents, quantifying the strength of long-range correlations, were negatively correlated with the commission error rates. Strong LRTCs hence parallel optimal cognitive flexibility and, in line with the criticality hypothesis, indicate a functionally advantageous state. This conclusion was corroborated by a positive correlation between the LRTC scaling exponents and executive functions measured with the Rey Osterrieth Complex Figure test. Our results hence support the notion that LRTCs arise from critical dynamics that is functionally significant for human cognitive performance. PMID- 28588304 TI - Plasma FGF21 levels in obese patients undergoing energy-restricted diets or bariatric surgery: a marker of metabolic stress? AB - BACKGROUND: Fibroblast growth factor 21 (FGF21) has been suggested to be an endocrine signal of nutritional status and an active regulator of metabolism. However, there is no agreement on the effect of weight-loss therapies on circulating levels of FGF21 in humans. OBJECTIVE: To assess FGF21 circulating levels in adiposity excess and after different weight-loss strategies prescribed in five different groups from four independent centers. SUBJECTS AND METHODS: Body composition, ketosis, insulin sensitivity and FGF21 were evaluated in 181 excess body weight and 14 normal-weight subjects. From the excess body weight patients, two independent groups (discovery cohort; n=20 and validation cohort; n=28) undertook a very low-calorie ketogenic (VLCK) diet, a third group followed a low-calorie (LC) diet (n=84) and other two groups underwent bariatric surgery (discovery cohort; n=24 and validation cohort; n=25). The follow-up was 4 to 6 or 12 months, respectively. RESULTS: FGF21 levels were higher in excess body weight patients than in normal-weight subjects. The energy-restriction therapy to lose weight induced a significant decrease, with respect to baseline, in circulating levels of FGF21 (VLCK: -62.5 pg ml-1 or -14.8 pg ml-1 and LC diet: -67.9 pg ml 1). There were no differences in FGF21 levels between both energy-restriction treatments. On the contrary, after bariatric surgery morbidly obese patients showed a significant increase in FGF21, especially 1 month after surgery (148.8 pg ml-1 higher than baseline). The FGF21 differential changes occur concomitantly with a non-induced ketosis situation (0.66+/-0.56 mm) in bariatric surgery, and an improvement in adiposity and insulin sensitivity induced by the three therapies. CONCLUSIONS: FGF21 levels were reduced after energy-restricted treatments and severely increased after bariatric surgery, independently of the weight reduction magnitude, insulin sensitivity or ketosis. Therefore, FGF21 appears to be a marker of severe nutritional stress. PMID- 28588305 TI - Chronic maternal inflammation or high-fat-feeding programs offspring obesity in a sex-dependent manner. AB - BACKGROUND/OBJECTIVES: The current world-wide obesity epidemic partially results from a vicious circle whereby maternal obesity during pregnancy predisposes the offspring for accelerated weight gain and development of metabolic syndrome. Here we investigate whether low-grade inflammation, characteristic of the obese state, provides a causal role for this disastrous fetal programming in mice. METHODS: We exposed pregnant and lactating C57BL/6JBom female mice to either high-fat diet (HFD), or continuous infusion of lipopolysaccharide (LPS), a potent trigger of innate immunity, and studied offspring phenotypes. RESULTS: Both maternal LPS or HFD treatments rendered the offspring hyperphagic and inept of coping with a HFD challenge during adulthood, increasing their adiposity and weight gain. The metabolic effects were more pronounced in female offspring, while exposed male offspring mounted a larger inflammatory response to HFD at adulthood. CONCLUSIONS: This supports our hypothesis and highlights the programming potential of inflammation in obese pregnancies. PMID- 28588307 TI - Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. AB - We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses. PMID- 28588306 TI - Metabolomics allows the discrimination of the pathophysiological relevance of hyperinsulinism in obese prepubertal children. AB - BACKGROUND/OBJECTIVES: Insulin resistance (IR) is the cornerstone of the obesity associated metabolic derangements observed in obese children. Targeted metabolomics was employed to explore the pathophysiological relevance of hyperinsulinemia in childhood obesity in order to identify biomarkers of IR with potential clinical application. SUBJECTS/METHODS: One hundred prepubertal obese children (50 girls/50 boys, 50% IR and 50% non-IR in each group), underwent an oral glucose tolerance test for usual carbohydrate and lipid metabolism determinations. Fasting serum leptin, total and high molecular weight-adiponectin and high-sensitivity C-reactive protein (CRP) levels were measured and the metabolites showing significant differences between IR and non-IR groups in a previous metabolomics study were quantified. Enrichment of metabolic pathways (quantitative enrichment analysis) and the correlations between lipid and carbohydrate metabolism parameters, adipokines and serum metabolites were investigated, with their discriminatory capacity being evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Twenty-three metabolite sets were enriched in the serum metabolome of IR obese children (P<0.05, false discovery rate (FDR)<5%). The urea cycle, alanine metabolism and glucose-alanine cycle were the most significantly enriched pathways (PFDR<0.00005). The high correlation between metabolites related to fatty acid oxidation and amino acids (mainly branched chain and aromatic amino acids) pointed to the possible contribution of mitochondrial dysfunction in IR. The degree of body mass index standard deviation score (BMI-SDS) excess did not correlate with any of the metabolomic components studied. In the ROC analysis, the combination of leptin and alanine showed a high IR discrimination value in the whole cohort (area under curve, AUCALL=0.87), as well as in boys (AUCM=0.84) and girls (AUCF=0.91) when considered separately. However, the specific metabolite/adipokine combinations with highest sensitivity were different between the sexes. CONCLUSIONS: Combined sets of metabolic, adipokine and metabolomic parameters can identify pathophysiological relevant IR in a single fasting sample, suggesting a potential application of metabolomic analysis in clinical practice to better identify children at risk without using invasive protocols. PMID- 28588308 TI - A Four-Biomarker Blood Signature Discriminates Systemic Inflammation Due to Viral Infection Versus Other Etiologies. AB - The innate immune system of humans and other mammals responds to pathogen associated molecular patterns (PAMPs) that are conserved across broad classes of infectious agents such as bacteria and viruses. We hypothesized that a blood based transcriptional signature could be discovered indicating a host systemic response to viral infection. Previous work identified host transcriptional signatures to individual viruses including influenza, respiratory syncytial virus and dengue, but the generality of these signatures across all viral infection types has not been established. Based on 44 publicly available datasets and two clinical studies of our own design, we discovered and validated a four-gene expression signature in whole blood, indicative of a general host systemic response to many types of viral infection. The signature's genes are: Interferon Stimulated Gene 15 (ISG15), Interleukin 16 (IL16), 2',5'-Oligoadenylate Synthetase Like (OASL), and Adhesion G Protein Coupled Receptor E5 (ADGRE5). In each of 13 validation datasets encompassing human, macaque, chimpanzee, pig, mouse, rat and all seven Baltimore virus classification groups, the signature provides statistically significant (p < 0.05) discrimination between viral and non-viral conditions. The signature may have clinical utility for differentiating host systemic inflammation (SI) due to viral versus bacterial or non-infectious causes. PMID- 28588309 TI - Alteration of the gut microbiota in Chinese population with chronic kidney disease. AB - We evaluated differences in the compositions of faecal microbiota between 52 end stage renal disease (ESRD) patients and 60 healthy controls in southern China using quantitative real-time polymerase chain reaction (qPCR) and high-throughput sequencing (16S ribosomal RNA V4-6 region) methods. The absolute quantification of total bacteria was significantly reduced in ESRD patients (p < 0.01). In three enterotypes, Prevotella was enriched in the healthy group whereas Bacteroides were prevalent in the ESRD group (LDA score > 4.5). 11 bacterial taxa were significantly overrepresented in samples from ESRD and 22 bacterial taxa were overrepresented in samples from healthy controls. The butyrate producing bacteria, Roseburia, Faecalibacterium, Clostridium, Coprococcus and Prevotella were reduced in the ESRD group (LDA values > 2.0). Canonical correspondence analysis (CCA) indicated that Cystatin C (CysC), creatinine and eGFR appeared to be the most important environmental parameters to influence the overall microbial communities. In qPCR analysis, The butyrate producing species Roseburia spp., Faecalibacterium prausnitzii, Prevotella and Universal bacteria, were negatively related to CRP and CysC. Total bacteria in faeces were reduced in patients with ESRD compared to that in healthy individuals. The enterotypes change from Prevotella to Bacteroides in ESRD patients. The gut microbiota was associated with the inflammatory state and renal function of chronic kidney disease. PMID- 28588311 TI - Low frequency of NS5A relevant resistance-associated substitutions to Elbasvir among hepatitis C virus genotype 1a in Spain: a cross-sectional study. AB - Relevant resistance-associated substitutions (RASs) to elbasvir, the new HCV NS5A inhibitor, may limit its efficacy and lead to virological failure in HCV-GT1a infected patients. There are few data outside clinical trials evaluating their prevalence and impact of elbasvir/grazoprevir. A multicenter cross-sectional study of 617 HCV-GT1a-infected individuals attended in 84 Spanish hospitals from the 17 Autonomous Communities and two Autonomous cities was performed. HCV population sequencing was used to identify RASs to elbasvir and the mutational pattern and drug sensitivity were confirmed by geno2pheno[HCV]. Viruses bearing RASs to elbasvir were present in 6.2% of HCV-GT1a infected patients. The most common RASs were the Y93C/H/N and Q30E/H/R (2.4% and 2.3%; respectively). Only 3.4% of patients had viruses with RASs that confer reduced susceptibility to elbasvir by geno2pheno[HCV] that identified exclusively the positions Q30H/R (n = 7) and Y93C/H/N (n = 8) as single mutations and Q30H + Y93H (n = 4) and Q30R + Y93H (n = 2) as double mutations considered as RASs to elbasvir. Lower prevalence of RASs to elbasvir in our HCV-GT1a-Spanish cohort was observed than reported previously in clinical trials. This information may be essential to guiding the implementation of elbasvir/grazoprevir in Spain, expected at the beginning of 2017 and the management of GT1a-infected patients. PMID- 28588310 TI - The development of fluorescent protein tracing vectors for multicolor imaging of clinically isolated Staphylococcus aureus. AB - Recent advances in fluorescent protein technology provide a wide variety of biological imaging applications; however current tools for bio-imaging in the Gram-positive bacterium Staphylococcus aureus has necessitated further developments for fluorescence intensity and for a multicolor palette of fluorescent proteins. To enhance the expression of multicolor fluorescent proteins in clinical S. aureus strains, we developed new fluorescent protein expression vectors, containing the blaZ/sodp promoter consisting of the beta lactamase gene (blaZ) promoter and the ribosome binding site (RBS) of superoxide dismutase gene (sod). We found S. aureus-adapted GFP (GFPsa) driven by the blaZ/sodp promoter was highly expressed in the S. aureus laboratory strain RN4220, but not in the clinical strains, MW2 and N315, harboring the endogenous blaI gene, a repressor of the blaZ gene promoter. We therefore constructed a constitutively induced blaZ/sodp promoter (blaZ/sodp(Con)) by introducing substitution mutations into the BlaI binding motif, and this modification allowed enhanced expression of the multicolor GFP variants (GFPsa, EGFP, mEmerald, Citrine, Cerulean, and BFP) as well as codon-optimized reef coral fluorescent proteins (mCherry and AmCyan) in the S. aureus clinical strains. These new fluorescent probes provide new tools to enhance expression of multicolor fluorescent proteins and facilitate clear visualization of clinical S. aureus strains. PMID- 28588312 TI - Light generated bubble for microparticle propulsion. AB - Light activated motion of micron-sized particles with effective forces in the range of micro-Newtons is hereby proposed and demonstrated. Our investigation shows that this exceptional amount of force results from accumulation of light generated heat by a micron-sized particle that translates into motion due to a phase transition in the nearby water. High-speed imagery indicates the role of bubble expansion and later collapse in this event. Comparing observations with known models reveals a dynamic behavior controlled by polytropic trapped vapor and the inertia of the surrounding liquid. The potential of the proposed approach is demonstrated by realization of disordered optical media with binary light activated switching from opacity to high transparency. PMID- 28588315 TI - Psychosocial correlates of apparent treatment-resistant hypertension in the Jackson Heart Study. AB - This corrects the article DOI: 10.1038/jhh.2016.100. PMID- 28588314 TI - Frequency of GNAS R201H substitution mutation in polyostotic fibrous dysplasia: Pyrosequencing analysis in tissue samples with or without decalcification. AB - Guanine nucleotide-binding protein/alpha-subunit (GNAS) mutations are involved in fibrous dysplasia (FD) pathogenesis. Here, we analyzed GNAS mutations in FD which were performed by pyrosequencing DNA isolated from formalin-fixed paraffin embedded (FFPE) tissue. The mutation detection rate was determined in FD specimens with and without decalcification. GNAS mutation was identified in 28 cases out of 87 FDs (32.18%) [p.R201C (N = 14) and p.R201H (N = 14)]. GNAS mutation was more likely to occur in polyostotic FD (7/28, 25.0%); FD without GNAS mutation was mostly monostotic form (56/59, 94.9%, P = 0.011). The G > A (R201H) mutation was more frequent in polyostotic FD (6/14 patients, 42.9%) than the C > T (R201C) mutation (1/14, 7.1%) (P = 0.077). We divided the FD cases into two subgroups: tissue specimens that were not decalcified (N = 35, 40.2%), and tissue specimens that were decalcified (N = 52, 59.8%). GNAS mutation was more frequently identified in FD specimens that were not subjected to decalcification (23/35, 65.7%) than in FD specimens that were decalcified (5/52, 9.6%) (P = 0.001). In conclusion, mutation analysis of GNAS by pyrosequencing has diagnostic value in FFPE tissue of patients with FD, especially in specimens that were not decalcified. The R201H substitution mutation of GNAS may be involved in the pathogenesis of polyostotic FD. PMID- 28588313 TI - Insoluble (1 -> 3), (1 -> 4)-beta-D-glucan is a component of cell walls in brown algae (Phaeophyceae) and is masked by alginates in tissues. AB - Brown algae are photosynthetic multicellular marine organisms. They belong to the phylum of Stramenopiles, which are not closely related to land plants and green algae. Brown algae share common evolutionary features with other photosynthetic and multicellular organisms, including a carbohydrate-rich cell-wall. Brown algal cell walls are composed predominantly of the polyanionic polysaccharides alginates and fucose-containing sulfated polysaccharides. These polymers are prevalent over neutral and crystalline components, which are believed to be mostly, if not exclusively, cellulose. In an attempt to better understand brown algal cell walls, we performed an extensive glycan array analysis of a wide range of brown algal species. Here we provide the first demonstration that mixed linkage (1 -> 3), (1 -> 4)-beta-D-glucan (MLG) is common in brown algal cell walls. Ultra-Performance Liquid Chromatography analyses indicate that MLG in brown algae solely consists of trisaccharide units of contiguous (1 -> 4)-beta linked glucose residues joined by (1 -> 3)-beta-linkages. This regular conformation may allow long stretches of the molecule to align and to form well structured microfibrils. At the tissue level, immunofluorescence studies indicate that MLG epitopes in brown algae are unmasked by a pre-treatment with alginate lyases to remove alginates. These findings are further discussed in terms of the origin and evolution of MLG in the Stramenopile lineage. PMID- 28588316 TI - Renin-angiotensin blockade in atrial fibrillation: where are we now? PMID- 28588317 TI - A Pilot Study of 18F-Alfatide PET/CT Imaging for Detecting Lymph Node Metastases in Patients with Non-Small Cell Lung Cancer. AB - Angiogenesis plays a key role in tumor development and alphavbeta3 integrin are overexpressed on the endothelial cell surface of newly forming vessels. 18F Alfatide has favorable properties for alphavbeta3 integrin targeting and showed potential for imaging angiogenesis with Positron Emission Tomography (PET)/computed tomography (CT). In this study, 13 patients with non-small cell lung cancer (NSCLC) who underwent 18F-Alfatide PET/CT before surgery were enrolled. The uptake of all dissected lymph nodes (LNs) of 18F-Alfatide were assessed visually and analyzed with a maximum and mean standard uptake value (SUVmax, SUVmean) and SUV ratios. LN metastases were pathologically confirmed and 20 of 196 LNs were malignant. All malignant LNs were successfully visualized on 18F-Alfatide PET/CT in patients and the sensitivity, specificity and accuracy was 100.0%, 94.9% and 95.4%, respectively. SUVmax, SUVmean and SUV ratios in malignant LNs were significantly higher than in benign LNs for NSCLC patients (P < 0.001). The same result was observed in patients with adenocarcinoma and squamous cell carcinoma (P < 0.001). The 18F-Alfatide parameter shows high sensitivity (83.9-100%), specificity (78.6-96.7%) and accuracy (81.7-96.9%) according to thresholds calculated from receiver operating characteristic curve. Our results suggest that 18F-Alfatide PET/CT is valuable in the diagnosis of metastatic LNs for NSCLC patients. PMID- 28588318 TI - Inhibition of autophagy prevents cadmium-induced prostate carcinogenesis. AB - BACKGROUND: Cadmium, an established carcinogen, is a risk factor for prostate cancer. Induction of autophagy is a prerequisite for cadmium-induced transformation and metastasis. The ability of Psoralidin (Pso), a non-toxic, orally bioavailable compound to inhibit cadmium-induced autophagy to prevent prostate cancer was investigated. METHODS: Psoralidin was studied using cadmium transformed prostate epithelial cells (CTPE), which exhibit high proliferative, invasive and colony forming abilities. Gene and protein expression were evaluated by qPCR, western blot, immunohistochemistry and immunofluorescence. Xenograft models were used to study the chemopreventive effects in vivo. RESULTS: Cadmium transformed prostate epithelial cells were treated with Pso resulting in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE 1). Psoralidin-treatment of CTPE cells inhibited the expression of Placenta Specific 8, a lysosomal protein essential for autophagosome and autolysosome fusion, which resulted in growth inhibition. Additionally, Pso treatment caused decreased expression of pro-survival signalling proteins, NFkappaB and Bcl2, and increased expression of apoptotic genes. In vivo, Pso effectively suppressed CTPE xenografts growth, without any observable toxicity. Tumours from Pso-treated animals showed decreased autophagic morphology, mesenchymal markers expression and increased epithelial protein expression. CONCLUSIONS: These results confirm that inhibition of autophagy by Pso plays an important role in the chemoprevention of cadmium-induced prostate carcinogenesis. PMID- 28588319 TI - Subcutaneous adiposity is an independent predictor of mortality in cancer patients. AB - BACKGROUND: Prognostic significance of adiposity, at the time of cancer diagnosis, on survival is not clear. Body mass index (kg m-2) does not provide an appropriate assessment of body composition; therefore, the concept of the 'obesity paradox' needs to be investigated based on the prognostic significance of fat and muscle. Independent prognostic significance of adipose tissue in predicting mortality, importance of visceral and subcutaneous adiposity in the presence and absence of sarcopenia on survival, was investigated. METHODS: Adiposity markers including total adipose index (TATI), visceral adipose tissue index (VATI) and subcutaneous adipose tissue index (SATI) were estimated for 1473 gastrointestinal and respiratory cancer patients and 273 metastatic renal cell carcinoma patients using computed tomography. Univariate and multivariate analysis to determine mortality hazard ratios (HR) were conducted using cox proportional hazard models. RESULTS: Low SATI (SATI <50.0 cm2 m-2 in males and <42.0 cm2 m-2 in females) independently associated with increased mortality (HR: 1.26; 95% CI: 1.11-1.43; P<0.001) and shorter survival (13.1 months; 95% CI, 11.4 14.7) compared to patients with high SATI (19.3 months; 95% CI, 17.6-21.0; P<0.001). In the presence of sarcopenia, the longest survival was observed in patients with high subcutaneous adiposity. CONCLUSIONS: Subcutaneous adipose tissues appear to associate with reduction in mortality risk demonstrating the prognostic importance of fat distribution. The effect of sarcopenia on survival was more pronounced in patients with low subcutaneous adiposity. PMID- 28588320 TI - The influence of timing of radiation therapy following breast-conserving surgery on 10-year disease-free survival. AB - BACKGROUND: The Dutch guidelines advise to start radiation therapy (RT) within 5 weeks following breast-conserving surgery (BCS). However, much controversy exists regarding timing of RT. This study investigated its effect on 10-year disease free survival (DFS) in a Dutch population-based cohort. METHODS: All women diagnosed with primary invasive stage I-IIIA breast cancer in 2003 treated with BCS+RT were included. Two populations were studied. Population 1 excluded patients receiving chemotherapy before RT. Analyses were stratified for use of adjuvant systemic therapy (AST). Population 2 included patients treated with chemotherapy, and compared chemotherapy before (BCS-chemotherapy-RT) and after RT (BCS-RT-chemotherapy). DFS was estimated using multivariable Cox regression. Locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were secondary outcomes. RESULTS: Population 1 (n=2759) showed better DFS and DMFS for a time interval of >55 than a time interval of <42 days. Patients treated with AST showed higher DFS for >55 days (hazards ratio (HR) 0.60 (95% confidence interval (CI): 0.38-0.94)) and 42-55 days (HR 0.64 (95% CI: 0.45-0.91)) than <42 days. Results were similar for DMFS, while timing did not affect LRRFS and OS. For patients without AST, timing was not associated with DFS, DMFS and LLRFS, but 10-year OS was significantly lower for 42-55 and >55 days compared to <42 days. In population 2 (n=1120), timing did not affect survival in BCS-chemotherapy-RT. In BCS-RT-chemotherapy, DMFS was higher for >55 than <42 days. CONCLUSIONS: Starting RT shortly after BCS seems not to be associated with a better long-term outcome. The common position that RT should start as soon as possible following surgery in order to increase treatment efficacy can be questioned. PMID- 28588321 TI - MicroRNA-199b-5p attenuates TGF-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. AB - BACKGROUND: Accumulating evidence indicates that N-cadherin is a cell adhesion molecule that has critical roles in tumour progression. However, the role of N cadherin in hepatocellular carcinoma (HCC) remains controversial. METHODS: This study aims to investigate the expression status of N-cadherin and its molecular mechanisms in HCC. RESULTS: The expression of N-cadherin was markedly overexpressed in HCC tissues and cell lines. We identified that miR-199b-5p binds to the 3'-UTR of N-cadherin mRNA, thus decreasing N-cadherin expression in HCC cells. We also found the downregulation of miR-199b-5p in HCC specimens, which was inversely correlated with N-cadherin upregulation, predicted poor clinical outcomes in HCC patients. Next, we determined that miR-199b-5p overexpression promoted cell aggregation, suppressed cell migration and invasion in HCC cells, and inhibited xenografts tumour metastasis in nude mice. Moreover, we demonstrated that miR-199b-5p attenuated TGF-beta1 induced epithelial-mesenchymal transition (EMT) -associated traits, while its effects could be partially reversed by N-cadherin restoration. Finally, we examined that N-cadherin downregulation or miR-199b-5p overexpression suppressed TGF-beta1-induced Akt phosphorylation, and inhibition of PI3K/Akt pathway blocked TGF-beta1-induced N cadherin overexpression in HCC cells. CONCLUSIONS: Our data demonstrate that N Cadherin was markedly overexpressed and miR-199b-5p was significantly downregulated in HCC. MiR-199b-5p exerts inhibitory effects on EMT, and directly targets N-cadherin in HCC, supporting the potential utility of miR-199b-5p as a promising strategy to treat HCC. Also, a positive regulatory loop exists between N-cadherin and Akt signalling represents a novel mechanism of TGF-beta1-mediated EMT in HCC cells. PMID- 28588324 TI - Raw food diets for pets. PMID- 28588323 TI - Impact of body mass index on ovarian cancer survival varies by stage. AB - BACKGROUND: Research on the effect of body mass index (BMI) on ovarian cancer survival is inconsistent, but previous studies did not consider the possible impact of ascites, bowel obstruction, or cachexia, which commonly occur in late stage disease. METHODS: We evaluated the association of BMI, before and around the time of diagnosis, with overall and disease-specific survival in a cohort study of primary invasive epithelial ovarian cancers diagnosed from 2000 to 2013 in Kaiser Permanente Northern California (KPNC) (n=1184). Deaths were identified through December 2014, with a median follow-up of 37 months. Proportional hazards regression was used to estimate overall and ovarian cancer-specific mortality, accounting for prognostic variables including age at diagnosis, race, stage, grade, histology, comorbidities, treatment, post-treatment CA125 levels, ascites, and bowel obstruction. RESULTS: There was no evidence of an association between BMI and overall or ovarian cancer-specific survival. However, we found strong effect modification by stage (Pinteraction<0.01). Compared with normal prediagnosis BMI (18.5-24.9 kg m-2), for women who were obese before diagnosis (BMI?35 kg m-2) ovarian cancer-specific survival was lower among those diagnosed at stages I/II (hazard ratio (HR): 3.40; 95% confidence interval (CI): 1.16 9.99), but increased among those diagnosed with stage IV disease (HR: 0.58; 95% CI: 0.35-0.96). Associations were attenuated after excluding those diagnosed with cachexia (n=82) and further adjustment for ascites and bowel obstruction, with no evidence of effect modification by these factors. CONCLUSIONS: Associations of obesity with ovarian cancer survival may differ by stage, with decreased survival among those with localised disease and increased survival among those with late stage disease. Stage-specific effects of obesity on survival suggest a tailored approach to improve prognosis may be appropriate. PMID- 28588325 TI - Ethical question of the month - June 2017. PMID- 28588322 TI - A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). AB - BACKGROUND: Pembrolizumab (P) is an anti-PD-1 antibody that blocks the interaction between programmed cell death protein 1 (PD-1) on T-cells and PD-L1 and PD-L2 on tumour cells. A phase Ib trial of P plus chemotherapy was undertaken to evaluate the safety and efficacy. METHODS: Patients with advanced, metastatic solid tumours were enrolled onto one of six treatment arms. Pembrolizumab was given: with gemcitabine (G), G+docetaxel (D), G+nab-paclitaxel (NP), G+vinorelbine (V) or irinotecan (I) until progression or toxicity, or with liposomal doxorubicin (LD) for up to 15 cycles, progression or toxicity. Safety monitoring and response assessments were conducted. RESULTS: Forty-nine patients were enrolled and treated. The most common adverse events were transaminitis, cytopenias, rash, diarrhoea, fatigue, nausea and vomiting. Arm 2 was closed due to poor accrual. The recommended phase II dose (RP2D) was determined for Arms 1, 3a, 4, 5 and 6. There were eight partial responses across multiple tumour types. CONCLUSIONS: Standard dose P can be safely combined with G, G+NP, G+V, I and LD. Efficacy was observed in multiple tumour types and evaluation to determine if response and duration of response are more robust than what would be expected for chemotherapy or immunotherapy alone requires further validation. PMID- 28588326 TI - Canine laparoscopic ovariectomy using two 3- and 5-mm portal sites: A prospective randomized clinical trial. AB - Laparoscopic ovariectomy (LapOve) was performed in 3 groups (2.7-mm/5-mm, 5-mm/3 mm, and 5-mm telescope/5-mm bipolar forceps) of small dogs (n = 60). Surgical times, bleeding rates, complications, and laparoscopic visualization were recorded and compared among groups. Use of the 3-mm bipolar forceps significantly increased the surgical time and showed higher bleeding rates compared with the 5 mm bipolar forceps. The 2.7-mm telescope significantly decreased the laparoscopic view. No complications were seen in any group. In conclusion, the 2.7-mm 30 degrees telescope or the 3-mm bipolar forceps combined with the 5-mm instruments could be used as an alternative technique for LapOve in dogs up to 10 kg. The 2.7 mm telescope with the 5-mm bipolar forceps was the most efficient combination based on surgical time. PMID- 28588327 TI - Biosecurity practices and causes of enteritis on Ontario meat rabbit farms. AB - Infectious enterocolitis is a significant cause of mortality in meat rabbits. Disease risk is enhanced by intensive rearing practices and poor on-farm biosecurity. This investigation was undertaken in farmed meat rabbits during an Ontario-wide outbreak of enteritis with high mortality to determine the prevalence of causative agents. A survey evaluating on-farm biosecurity practices was also conducted to identify potential means of pathogen contamination and zoonotic risks. Gross and microscopic pathology evaluations combined with microbiologic testing were conducted on 95 rabbits over spring and winter months. Escherichia coli and Clostridium spiroforme were most commonly associated with enteritis in rabbits regardless of age or season and lesions were significantly more severe in mature does (P < 0.0001). The survey results demonstrated a lack of consistent on-farm biosecurity practices. The infectious nature of enteric disease of rabbits combined with poor biosecurity practices may contribute to disease transmission within and between farms. PMID- 28588328 TI - Internal fixation of fractured ribs in neonatal foals with nylon cable tie using a modified technique. AB - Nylon cable tie has been shown to be an effective and economical method for fixing fractured ribs in the neonatal foal. This article describes a modification of the previously described technique. Under general anesthesia, the fractured ribs were exposed and a hole was drilled in the dorsal and ventral fragments. The fracture was not reduced, leaving the fragments overriding each other. The nylon cable tie was passed through the hole in the dorsal fragment from the external surface of the rib. The free end of the cable tie was then passed through the hole in the ventral fragment from the external surface of the rib and the tie was tightened. This technique was used in 4 neonatal foals with no complications. The modification of the original technique represents a method to minimize soft tissue trauma, implant failure, and complications. PMID- 28588329 TI - Buccal feed impaction and surgical correction in captive reindeer. AB - An 8-year-old female captive reindeer (Rangifer tarandus) (1) was presented for evaluation of bilateral protrusion of the cheeks of 1-month duration. Several members of the herd displayed similar clinical signs. Examination revealed stretching and laxity of the cheek muscles and buccal food impaction. The defect of each cheek was surgically repaired in the field under heavy sedation and local anesthesia in staged procedures; no surgical complications were encountered. The patient recovered uneventfully and long-term prognosis is good. This report describes a surgical treatment for individual animals with cheek laxity and buccal food impaction. PMID- 28588330 TI - Supracutaneous plating using a locking plate for the treatment of a tibial fracture in a cat. AB - Radiographs revealed a slightly displaced long oblique diaphyseal tibial fracture with bone fissures running distally in a 2-year-old, 4.5 kg cat that had been hit by a car. An angle stable implant was applied in a supracutaneous fashion. The patient tolerated the external implant and had a satisfactory functional recovery. Radiographic follow-up after 60 days revealed sign of osseous union; therefore, the plate was removed. PMID- 28588331 TI - Presumptive primary pulmonary mast cell tumor in 2 dogs. AB - Two dogs were presented, each with a large solitary pulmonary mass, and cytology confirmed mast cell tumor (MCT) in each dog. One dog was euthanized following diagnosis. Thoracic computed tomography scan and exploratory thoracotomy of the second dog revealed a right pulmonary mass that would require a radical lung resection. The patient was euthanized and histopathology confirmed a poorly granulated MCT with characteristics suggestive of epitheliotropism, an uncommon finding with MCT. These represent the first reported cases of presumptive primary pulmonary MCT in dogs. PMID- 28588332 TI - Diaphragmatic hernia in a pet chinchilla (Chinchilla lanigera). AB - A 10-year-old pet chinchilla (Chinchilla lanigera) was referred for ultrasound investigation of a thoracic mass. The mass was initially believed to be a pulmonary abscess or tumor based on radiographs and ultrasound. Cytological examination suggested the presence of a gastrointestinal structure in the thorax, and necropsy revealed a true diaphragmatic hernia subdividing the stomach into thoracic and abdominal portions. PMID- 28588333 TI - Bovine astrovirus infection in feedlot cattle with neurological disease in western Canada. AB - A novel bovine astrovirus (BoAstV CH13/NeuroS1) has been associated with encephalitis in cattle in Europe and the USA. We retrospectively analyzed feedlot cattle with encephalitis of unknown etiology for this virus by in-situ hybridization. Results suggest that BoAstV CH13/NeuroS1 is a major cause of encephalitis in western Canadian feedlot cattle. PMID- 28588334 TI - Use of a non-invasive surgical skin closure device in dogs following dorsolateral hemilaminectomy. AB - The ZipLine 16 surgical skin closure device (ZipLine 16; Zipline Medical, Campbell, California, USA) provides noninvasive surgical wound closure. This prospective study investigated its use in dogs undergoing a dorsolateral hemilaminectomy. Although the device produced normal appositional healing compared with controls, unacceptable traumatic dermatitis that is likely related to the device adhesive was noted after removal. PMID- 28588335 TI - Identification of bovine astrovirus in cases of bovine non-suppurative encephalitis in eastern Canada. AB - Bovine astrovirus (BoAstV) was identified by reverse transcriptase polymerase chain reaction on brain tissue of 2 feedlot cattle that died of non-suppurative encephalitis. Sequencing demonstrated a high degree of identity with neurotropic US and Swiss BoAstV strains. To our knowledge, this is the first confirmed report of BoAstV-associated encephalitis in cattle residing in eastern Canada. PMID- 28588336 TI - Outcomes in dogs with uncomplicated, presumptive bacterial pneumonia treated with short or long course antibiotics. AB - This is a prospective, observational investigation without a placebo arm to evaluate the resolution rate of pneumonia when using 14 days or less of antibiotic therapy compared to longer therapy in dogs. There was no significant difference in radiographic resolution or relapse rates between the 2 treatment groups. PMID- 28588337 TI - Intra-operative hyperthermia in a young Angus bull with a fatal outcome. AB - A healthy, 9-month-old black Angus bull was presented for elective penile preputial translocation and caudal epididymectomy. After premedication and induction, general anesthesia was maintained with inhalant anesthetic. Over an hour into the anesthetic period the bull developed severe hyperthermia and hypercapnia that resulted in fatality despite treatment efforts. PMID- 28588338 TI - Successful treatment of blastomycosis in a 7-year-old, female golden retriever dog on Manitoulin Island, Ontario. AB - A 7-year-old female golden retriever dog was presented with a 2-week history of coughing and inappetence. Examination, radiographs, and blood analysis showed classic evidence of blastomycosis, confirmed with the MVista EIA urine antigen test. A 2-month course of itraconazole and a course of mirtazapine, meloxicam, furosemide, and tetracycline resulted in a successful outcome. PMID- 28588340 TI - Comments on the Ethical Question of the Month: January 2017 (CVJ 2017;58:15). PMID- 28588339 TI - Becoming a vet; What may be in your first year. PMID- 28588341 TI - No-win communication. PMID- 28588342 TI - Cutaneous cytology and the dermatology patient. PMID- 28588343 TI - Mammary gland neoplasia in a Canadian mare: Challenges of diagnosis and treatment in a rural setting. PMID- 28588346 TI - A Rational Adoption of the High Sensitive Assay for Cardiac Troponin I in Diagnostic Routine. AB - We describe the adoption of high sensitive troponin I (hsTnI) in clinical practice in two hospital settings in Italy. Samples from 426 consecutive patients (mean age 68.8 +/- 17.0) admitted to the Emergency Department with a suspected acute coronary syndrome (ACS) have been tested at admittance and after 3 and 6 hours by contemporary TnI and hsTnI. Results have been compared to the final clinical diagnosis. Troponin was detectable in 68.6% by TnI and 89.9% by hsTnI. Since hsTnI has a lower threshold for females, 38/41 patients with positive values only by hsTnI were women. The correlation between the assays was very high (r = 0.92). A diagnosis of acute myocardial infarction (AMI) was made in 45 cases (10.5%). The negative and positive predictive values for a 50% troponin variation at 3 hours were 95.8% and 66.7% for hsTnI and 95.0% and 52.6% for TnI and at 6 hours 90.3% and 100% for hsTnI and 88.9% and 78.9% for TnI, respectively. Receiver operating characteristic (ROC) curve analysis demonstrated a greater efficiency by hsTnI at 3 hours versus 6 hours (AUC = 0.91 versus 0.72). The main benefits of hsTnI are the adoption of gender-specific 99th percentile and the shortening of time to decision. PMID- 28588345 TI - Neuroanatomic Variations in Graves' Dysthyroid Ophthalmopathy as Studied With MRI. AB - PURPOSE: To evaluate whether patients with Graves' dysthyroid ophthalmopathy (GDO) have changes in brain anatomy that can be assessed by neuroimaging as compared to age-matched controls. METHODS: We examined 10 female, euthyroid patients with GDO and 14 age and gender matched controls using high-resolution structural MRI scanning. An automatic cortical segmentation algorithm was used to estimate the thickness of each subject's gray matter across the brain. The resulting cortical thickness measurements were transferred to a standard reference space via a template-based warping procedure. A statistical analysis of between-group cortical thickness differences using a general linear model with a combination of cluster-based and bootstrapped corrections for multiple comparisons was performed. RESULTS: Patients with GDO have statistically significant thinning of the gray matter sheet in a minimum of eight locations: six in the right hemisphere (insula, paracentral, precuneus, superior frontal cingulate, superioparietal and postcentral) and two in the left hemisphere (lateral occipital sulcus, fusiform gyrus). Left hemisphere thinning occurred in portions of the occipital lobe while right hemisphere thinning occurred in a set of frontal and parietal areas known to be involved in self-evaluation and emotional and cognitive regulation. CONCLUSION: Patients with GDO exhibit localized changes in gray matter thickness. These changes may be associated with cognitive changes reported by GDO patients. Further research before and after treatment with larger patient cohorts and experimental protocols including psychiatric evaluation and functional MRI are recommended. PMID- 28588347 TI - Glycoprotein YKL-40 Levels in Plasma Are Associated with Fibrotic Changes on HRCT in Asbestos-Exposed Subjects. AB - YKL-40 is a chitinase-like glycoprotein produced by alternatively activated macrophages that are associated with wound healing and fibrosis. Asbestosis is a chronic asbestos-induced lung disease, in which injury of epithelial cells and activation of alveolar macrophages lead to enhanced collagen production and fibrosis. We studied if YKL-40 is related to inflammation, fibrosis, and/or lung function in subjects exposed to asbestosis. Venous blood samples were collected from 85 men with moderate or heavy occupational asbestos exposure and from 28 healthy, age-matched controls. Levels of plasma YKL-40, CRP, IL-6, adipsin, and MMP-9 were measured with enzyme-linked immunosorbent assay (ELISA). Plasma YKL-40 levels were significantly higher in subjects with asbestosis (n = 19) than in those with no fibrotic findings in HRCT following asbestos exposure (n = 66) or in unexposed healthy controls. In asbestos-exposed subjects, plasma YKL-40 correlated negatively with lung function capacity parameters FVC (Pearson's r 0.259, p = 0.018) and FEV1 (Pearson's r -0.240, p = 0.028) and positively with CRP (Spearman's rho 0.371, p < 0.001), IL-6 (Spearman's rho 0.314, p = 0.003), adipsin (Spearman's rho 0.459, p < 0.001), and MMP-9 (Spearman's rho 0.243, p = 0.025). The present finding suggests YKL-40 as a biomarker associated with fibrosis and inflammation in asbestos-exposed subjects. PMID- 28588348 TI - Analysis of Microarray-Identified Genes and MicroRNAs Associated with Idiopathic Pulmonary Fibrosis. AB - The aim of this study was to identify potential microRNAs and genes associated with idiopathic pulmonary fibrosis (IPF) through web-available microarrays. The microRNA microarray dataset GSE32538 and the mRNA datasets GSE32537, GSE53845, and GSE10667 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed miRNAs (DE-miRNAs)/genes (DEGs) were screened with GEO2R, and their associations with IPF were analyzed by comprehensive bioinformatic analyses. A total of 45 DE-microRNAs were identified between IPF and control tissues, whereas 67 common DEGs were determined to exhibit the same expression trends in all three microarrays. Furthermore, functional analysis indicated that microRNAs in cancer and ECM-receptor interaction were the most significant pathways and were enriched by the 45 DE-miRNAs and 67 common DEGs. Finally, we predicted potential microRNA-target interactions between 17 DE-miRNAs and 17 DEGs by using at least three online programs. A microRNA-mediated regulatory network among the DE-miRNAs and DEGs was constructed that might shed new light on potential biomarkers for the prediction of IPF progression. PMID- 28588351 TI - Demonetized Cost of Neuroscience: Time for "Modi" Brain Fund. PMID- 28588352 TI - Building Genetic Database at Medical Institutes: Implement Patient Cost Audit and Improve Biomedical Research. PMID- 28588349 TI - Distinct Roles of Wnt/beta-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. AB - Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/beta-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/beta-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/beta-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/beta catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/beta-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases. PMID- 28588350 TI - Elevated Glucose and Interleukin-1beta Differentially Affect Retinal Microglial Cell Proliferation. AB - Diabetic retinopathy is considered a neurovascular disorder, hyperglycemia being considered the main risk factor for this pathology. Diabetic retinopathy also presents features of a low-grade chronic inflammatory disease, including increased levels of cytokines in the retina, such as interleukin-1 beta (IL 1beta). However, how high glucose and IL-1beta affect the different retinal cell types remains to be clarified. In retinal neural cell cultures, we found that IL 1beta and IL-1RI are present in microglia, macroglia, and neurons. Exposure of retinal neural cell cultures to high glucose upregulated both mRNA and protein levels of IL-1beta. High glucose decreased microglial and macroglial cell proliferation, whereas IL-1beta increased their proliferation. Interestingly, under high glucose condition, although the number of microglial cells decreased, they showed a less ramified morphology, suggesting a more activated state, as supported by the upregulation of the levels of ED-1, a marker of microglia activation. In conclusion, IL-1beta might play a key role in diabetic retinopathy, affecting microglial and macroglial cells and ultimately contributing to neural changes observed in diabetic patients. Particularly, since IL-1beta has an important role in retinal microglia activation and proliferation under diabetes, limiting IL-1beta-triggered inflammatory processes may provide a new therapeutic strategy to prevent the progression of diabetic retinopathy. PMID- 28588353 TI - Age-Wise Association of Carotid Intima Media Thickness in Ischemic Stroke. AB - BACKGROUND: Ischemic stroke is often a sequel of atherosclerotic risk factors. Carotid intima-media thickness (CIMT) is a surrogate marker of early atherosclerotic changes. PURPOSE: It was hypothesized that CIMT is associated with ischemic stroke in adults across all ages. METHODS: A case control study was performed on 163 diagnosed cases of first-time ischemic stroke and age-(+/-1 SD) and gender-matched healthy control attendants reporting at a tertiary care hospital. Data were collected on atherosclerotic risk factors for ischemic stroke. CIMT from both the carotids was measured using carotid vascular Doppler. The demographic profile and CIMT with atherosclerotic risk factors of cases and controls across different age groups were compared using unpaired t test if they passed the test of normality, else the Mann-Whitney test was used. OR for vascular risk factors for the development of stroke was calculated. The relationship of CIMT to atherosclerotic risk factors was analyzed by using Spearman correlation and regression analysis. The level of significance was set at 0.05. RESULTS: Age-specific value of CIMT was significantly higher in stroke cases than in age-matched controls across all age groups. Right CIMT, along with the history of hypertension (HTN; OR 2.3), are important risk factors for ischemic stroke in the younger age group (20-40 years). With increasing age along with the history of HTN and right CIMT (OR >7), presence of plaque (OR 6.3) and daily smoking (OR 5.1) are also significant risk factors. CIMT is significantly related to the daily alcohol and smoking intake and the presence of plaques. Right CIMT is positively related to increasing age in normal population (R2 = 0.041; p < 0.001). CONCLUSIONS: Right CIMT and comorbid HTN are significant risk factors associated with the development of ischemic stroke across all adult age groups. PMID- 28588354 TI - Pax6 Binds to Promoter Sequence Elements Associated with Immunological Surveillance and Energy Homeostasis in Brain of Aging Mice. AB - BACKGROUND: Patients having mutations of Pax6 bear phenotypes that match age associated neurological disorders. Mutations affect most cellular functions such as cell division, growth, differentiation, and cell death in brain, eyes, pituitary, pineal, and pancreas. The progressive reduction in the level of Pax6 during aging has also been observed. However, information about downstream targets of Pax6 in brain is unclear. Therefore, it is presumed that age-dependent alterations of Pax6 may also affect cascades of promoter sequence recognition in brain during aging. PURPOSE: This study is aimed at studying the interaction of Pax6 with DNA sequence elements to explore alteration in gene targets and transcription networks of Pax6 in brain during aging. METHODS: Chromatin immunoprecipitation with anti-Pax6 using tissue extracts of brain from newborn, young, adult, and old mice was done. Pulled DNA from brain was analysed by gene specific polymerase chain reaction (PCR). Amplified PCR products were sequenced and analyzed. RESULTS: Age-associated alterations in binding to genetic sequence elements by Pax6 were observed. Promoter analysis predicts genes involved in neuronal survival (Bdnf, Sparc), specificity of astrocyte (S100beta, Gfap), cell proliferation (Pcna), inflammation and immune response (interferon-gamma, tumour necrosis factor-alpha), management of oxidative stress (Sod, Cat), and hypoxia (Ldh). CONCLUSION: The Pax6 either directly or indirectly binds to promoter sequences of genes essential for immunological surveillance and energy metabolism in brain that alters during aging. PMID- 28588355 TI - Gene Expression Analysis in Rat Pancreas Observed with Whole-Transcript Exon Array after Ventromedial Hypothalamic Lesions. AB - BACKGROUND: It was reported previously that using Affymetrix Rat Genome 230 2.0, one of a class of standard 3' based arrays, ventromedial hypothalamic (VMH) lesions affected the expressions of cell proliferation-related genes, neuron related genes, and metabolism-related genes. The released Affymetrix Rat Gene 1.0 ST array has 2 major differences compared with standard 3' based arrays, including Rat Genome 230 2.0: it interrogates the entire mRNA transcript and uses DNA targets. PURPOSE: This study is aimed at assessing the impact of these differences on the array performance. METHODS: The study used Rat Gene 1.0 ST array, one of a class of whole-transcript rat exon arrays to examine the cellular mechanisms of gene regulation in the rat pancreas after VMH lesions. RESULTS: Although the results showed that VMH lesions regulated genes involved in enzymes, metabolism, transport, binding differentiation, migration, morphology, apoptosis, neuron and immunity, the probes identified by these 2 arrays were remarkably different. CONCLUSION: This study also confirmed that VMH lesions may affect the expression of many functional genes in rat pancreas. PMID- 28588357 TI - Manesar Declaration for Integrative Medicine. PMID- 28588359 TI - Homecoming. PMID- 28588358 TI - Marchiafava-Bignami's Disease, as Etiologic Diagnosis of Athetosis. AB - The Marchiafava-Bignami disease, characterized by demyelination and necrosis of the corpus callosum, has typically been associated with chronic alcohol intake, and clinically has various symptoms and signs. However, several cases have been reported without alcohol association, and these - according to several publications - have some common points, such as preference for female, related to malnutrition, and radiological involvement of the splenium of the corpus callosum. We report a case of a patient with the characteristics described above and whose clinical manifestation was Athetosis. The authors associate this manifestation with the somatotopic distribution of the corpus callosum, and contribute to the etiologic diagnosis of Athetosis as a manifestation of the Marchiafava-Bignami disease, which has not been reported in the medical literature according to our review of the database. PMID- 28588360 TI - Arrow of Time or Providence Divine? An Amusing But Thought Provoking Poem on Relative Positioning of Primary Motor and Sensory Cortices of Human Brain. PMID- 28588356 TI - Molecular Pathogenesis of Alzheimer's Disease: An Update. AB - Dementia is a chronic or progressive syndrome, characterized by impaired cognitive capacity beyond what could be considered a consequence of normal aging. It affects the memory, thinking process, orientation, comprehension, calculation, learning ability, language, and judgment; although awareness is usually unaffected. Alzheimer's disease (AD) is the most common form of dementia; symptoms include memory loss, difficulty solving problems, disorientation in time and space, among others. The disease was first described in 1906 at a conference in Tubingen, Germany by Alois Alzheimer. One hundred and ten years since its first documentation, many aspects of the pathophysiology of AD have been discovered and understood, however gaps of knowledge continue to exist. This literature review summarizes the main underlying neurobiological mechanisms in AD, including the theory with emphasis on amyloid peptide, cholinergic hypothesis, glutamatergic neurotransmission, the role of tau protein, and the involvement of oxidative stress and calcium. PMID- 28588361 TI - Caffeine and Cannabis Effects on Vital Neurotransmitters and Enzymes in the Brain Tissue of Juvenile Experimental Rats. AB - BACKGROUND: Caffeine and cannabis are globally consumed and abused psychoactive substances. While caffeine is legally used in various forms, including in tea and coffee as beverages, it is also consumed in soda and energy drinks as additives. Cannabis, on the other hand, is considered illegal in most countries; albeit, it is being consumed globally particularly by adolescents. PURPOSE: The adolescent stage marks a critical stage of brain development and maturation. Influences of agents on the brain at this stage may affect neuronal structural and functional attributes. To this end, the current experiment considered the effects of cannabis and caffeine on selected key neurotransmitters and enzymes in the brain tissues after regimented caffeine and cannabis treatment for 21 days. METHODS: A total of 72 juvenile Wistar rats that were approximately 40 days old were divided into 6 groups A-F. The group A served as the control. Other groups were administered various dosages of caffeine or cannabis in distilled water, using oral gavages as follows: group B animals received 100 mg/kg body weight of caffeine, group C animals received 50 mg/kg body weight of caffeine, group D animals received 500 mg/kg body weight of cannabis, group E animals received 200 mg/kg body weight of cannabis, and group F received a low dose of cannabis (200 mg/kg body weight) plus a low dose of caffeine (50 mg/kg body weight). The animals were killed by cervical dislocation 24 h after the last administration. The brain tissues were excised and homogenized. The enzymes cytochrome C oxidase and glucose-6-phosphate dehydrogenase were assayed to observe tissue energy metabolism while the neurotransmitters gamma-amino butyric acid (GABA), glutamate, and dopamine were assayed to observe the effects of the psychoactive substances on their activities relative to mental activities. RESULTS: GABA, glutamate, and dopamine were generally higher in the treated groups of animals. The levels of G-6-PDH were higher in all treated animals' brains. Caffeine produced quite more significant effects relative to cannabis and the combination of both increased the level of G-6-PDH significantly. CONCLUSION: Results showed that caffeine and cannabis influenced the activities of the enzymes and neurotransmitters in the brain. Both stimulants altered brain chemistry relative to the tested enzymes and neurotransmitters. PMID- 28588363 TI - Blood Oxygenation Level-Dependent Functional MRI of Early Evidences of Brain Plasticity after Hemodialysis Session by Helixone Membrane of Patients with Indices of Adrenal Deficiency. AB - BACKGROUND: Various alterations of hypothalamic-pituitary-adrenal axis function have been described in patients with chronic renal failure. Nevertheless, controversial evidences were stated about the association between adrenal function deficiency (AD) and hemodialysis (HD). PURPOSE: The goal of this paper was to estimate indirect indices of the adrenal gland dysfunction which is potentially influenced by oxidative stress (OS) that still generates brain plasticity and reorganization of the functional control. METHODS: Two male patients undergoing HD by the synthetic Helixone membrane for more than 6 months at the HD Center of the University Hospital of Fez, Fez, Morocco, were recruited. They underwent identical assessment immediately before and after the full HD session; this consisted of a blood ionogram revealing rates of sodium and calcium, and brain blood oxygenation level-dependent functional MRI (BOLD-fMRI) using a motor paradigm in block design. RESULTS: The blood ionogram revealed hypercalcemia and hyponatremia in both patients. Both biological assessment and BOLD-fMRI study results revealed a high level of OS that induced activation of a significantly large brain volume area suggesting the occurrence of possible brain plasticity and functional control reorganization induced by free radicals and enhanced by AD. CONCLUSION: The occurrence of brain plasticity and functional control reorganization was demonstrated in both patients studied who were undergoing HD by BOLD-fMRI with a notable sensitivity; this plasticity is induced by elevated OS occasioned by HD technique itself and probably amplified by AD. Similar results were found in a previous study performed on the same patients undergoing HD by a polysulfone membrane. PMID- 28588362 TI - Folic Acid Modulates Matrix Metalloproteinase-2 Expression, Alleviates Neuropathic Pain, and Improves Functional Recovery in Spinal Cord-Injured Rats. AB - BACKGROUND: The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases (MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. PURPOSE: Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI induced NP. METHODS: Sprague-Dawley male rats weighing 250-270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 ug/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP 2 expression analysis. RESULT: The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35, indicative of a decrease in NP. However, when tested 25 days after stopping FA administration on day 42 of cSCI, no significant difference in TH was observed between FA-treated and control animals. Western blot analysis of the injured spinal cord from FA-treated animals showed significant decline in MMP2 expression compared to spinal cord samples from water treated controls. CONCLUSION: Together, these data suggest that FA could alleviate NP and improve functional recovery post-SCI, possibly by reducing the expression of MMP2. Further studies will open up a novel and easy natural therapy, ideal for clinical translation with minimal side effects, for managing SCI-induced NP. Such studies might also throw light on a possible epigenetic mechanism in FA-induced recovery after SCI. PMID- 28588364 TI - Extinction of Contextual Fear with Timed Exposure to Enriched Environment: A Differential Effect. AB - BACKGROUND: Extinction of fear memory depends on the environmental and emotional cues. Furthermore, consolidation of extinction is also dependent on the environmental exposure. But, the relationship of the time of the exposure to a variety of environmental cues is not well known. The important region involved in facilitation of extinction of fear memory is through diversion of the flow of information leaving the lateral nucleus of amygdala. PURPOSE: The study aimed to address a question to explain how these brain regions react to environmental stimulation during the retention and extinction of fear memory. METHODS: An enriched environment (EE) is assumed to mediate extinction of fear memory, we examined the apparent discrepancy between the effects of defensive response, the freezing behavior induced by Pavlovian classical fear conditioning by subjecting them to variance in the timing to EE. The different timing of EE exposure was 10 days of EE either before fear conditioning and/or after extinction training to the rats. The local field potentials was recorded from CA1 hippocampus, lateral nucleus of amygdala and infralimbic region of medial prefrontal cortex (mPFC) during the fear learning and extinction from the control rats and rats exposed to EE before and after fear conditioning. RESULTS: Exposure to EE before the fear conditioning and after extinction training was more effective in the extinction fear memory. In addition, we also found switching from exploratory locomotion to freezing during retention of contextual fear memory which was associated with decreased theta power and reduced synchronized theta oscillations in CA1 hippocampus, lateral nucleus of amygdala, and infralimbic region of mPFC. CONCLUSION: Thus, we propose that the timing of exposure to EE play a key role in the extinction of fear memory. PMID- 28588365 TI - Prevalence and Trends in the Neuropsychological Burden of Patients having Intracranial Tumors with Respect to Neurosurgical Intervention. AB - BACKGROUND: The burden of neuropsychological symptoms evidenced by behavioral changes among patients with intracranial tumors has not been studied in detail. PURPOSE: This study was conducted to prospectively assess the neuropsychological symptoms in patients with intracranial tumors undergoing treatment. METHODS: A longitudinal study was conducted using purposive sampling to assess the neuropsychological symptoms in conscious and consenting patients with intracranial tumors who were availing treatment from a tertiary care center. Neuropsychiatric Inventory Questionnaire (NPI-Q), which identifies 12 behavioral disturbances, was assessed at baseline, and later at 1 month and 6 months after treatment, and scored as symptom severity as well as symptom scores. RESULTS: Among the 34 patients studied, all had experienced at least one neuropsychological symptom. The commonest neuropsychological symptoms at baseline were anxiety (82%), agitation (75%), irritability (74%), depression (74%), and sleep disturbances (70%). The neuropsychiatric symptom and severity scores were 5.84 (SD +/-2.7) and 11.8 (+/-7.1) at baseline, which reduced significantly to 4.3 (+/-3.1) and 5.6 (+/-3.2) at 1 month, and further to 2.3 (+/-2.9) and 3.6 (+/ 3.2) at 6 months, respectively. The neuropsychological symptoms persistent at 6 months were anxiety (33%), depression (33%), sleep disturbances (33%), agitation (25%), irritability (25%), and disinhibition (25%). CONCLUSION: There is substantial neuropsychological burden among patients with intracranial tumors. The severity score improved immediately after surgery, while the symptom score improved gradually. The variable spectrum of improvement in neuropsychological symptoms at 6 months after surgical treatment needs further consideration. Addressing these symptoms should be one of the long-term goals of the neuro oncology teams. PMID- 28588367 TI - Neuroscience Symposium and Workshop on SAAPCON-2016, Nepal. AB - Physiological Society of Nepal, with support from the South Asian Association of Physiologists (SAAP), organized the 5th Biennial Conference of the South Asian Association of Physiologists in conjunction with the 2nd Annual Conference of Physiological Society of Nepal. The purpose of this conference is to bring the scientists, researchers, and students from the South Asian countries in one platform to share and discuss the recent advances and achievements in the field of physiology. Since physiology is the backbone of medical science which deals with the functions of the human body, the theme of the conference was given as "Redefining health in nature." Giving the emphasis on this theme, the conference was organized on November 10-14, 2016, in Kathmandu University, Dhulikhel, Nepal. A total of 300 participants from 15 countries including the South Asian Association of Regional Cooperation (SAARC) and Non-SAARC countries participated in the conference. The scientific program of main conference, which ran for 2 days, was divided into 7 symposia - neuroscience, cardiopulmonary physiology, cellular and integrative physiology, health and lifestyle, role of physiology and medical education, endocrine and reproductive physiology, and high altitude and respiratory physiology - to highlight the latest progresses made in the field of physiology around the globe. Neuroscience symposium held on the second day consisted of 7 advance lectures and 3 young scientist presentations and poster session. Post-conference workshop on system neuroscience was held in BP Koirala Institute of Health Sciences, Dharan, Nepal. PMID- 28588368 TI - Two Cases of Esophageal Injury Following Anterior Cervical Discectomy and Fusion: One Overt and One Covert. AB - Esophageal perforation is a dreaded complication of anterior cervical spinal surgery. A 52-year-old diabetic man had undergone a surgery for a C6-C7 disc prolapse and developed spiking fever with chills and rigor on the 7th postoperative day. No cause could be found out but a CT scan of thorax done in the course of investigations revealed pneumomediastimum. The patient succumbed on the 10th day after surgery. Autopsy revealed the cause of death to be mediastinitis following iatrogenic esophageal perforation. A second patient, 53 years of age, following surgery for C5-C6 disc prolapse and developed intractable dysphagia. Later, fever and purulent discharge from the wound prompted an MRI showing prevertebral collection extending to the superior mediastinum. Presuming only wound infection, debridement and implant removal was done. However persistent serous discharge from the wound revealed an esophageal injury. Late diagnosis precluded primary repair. With conservative treatment, the fistula finally closed after 42 days. Postoperative dysphagia, a common complaint following surgery, may not always be present in cases of esophageal injury. A high index of suspicion is required for diagnosing and initiating treatment for esophageal perforation before complications set in. PMID- 28588370 TI - About Melinda D. Maryniuk, MEd, RD, CDE, FADA: Guest Editor, Perspectives on Meal Planning. PMID- 28588369 TI - From Pyramids to Plates to Patterns: Perspectives on Meal Planning. PMID- 28588366 TI - Neurocognitive Effect of Nootropic Drug Brahmi (Bacopa monnieri) in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease of the elderly. The rapid increase in its incidence has necessitated development of newer drugs. Ayurvedic herbal medications are increasingly researched due to their biosafety profile and usefulness in cognitive impairment. In this article, we critically reviewed one such Medhya Rasayana (nootropic drug) Brahmi-derived from extract of Bacopa monnieri (EBm). Studies have shown that EBm promotes free radical scavenger mechanisms and protects cells in prefrontal cortex, hippocampus, and striatum against cytotoxicity and DNA damage implicated in AD. It also reduces lipoxygenase activity reducing lipid peroxidation, increases glutathione peroxidase and chelates iron. Administration of EBm was seen to protect the cholinergic neurons and reduce anticholinesterase activity comparable to donepezil, rivastigmine, and galantamine. It also reduces hippocampal beta amyloid deposition and stress-induced hippocampal damage. The neuroprotective effect of EBm is also due to nitric oxide-mediated cerebral vasodilation. EBm improved the total memory score and maximum improvement was seen in logical memory and paired associate learning in humans and reversed phenytoin-induced memory impairment in experimental model. EBm has not shown any serious clinical, neurological, hematological complications, or vital organs damage in experimental studies. Rats showed marked reduction in fertility; however, libido was unaffected. There is no experimental evidence of genotoxicity or teratogenesis by use of EBm. Mild nausea and gastrointestinal upset are seen in humans. Brahmi promises to be a novel agent in AD; however, further human trials are recommended to verify the efficacy and rule out any side effects as evidenced by the experimental models. PMID- 28588371 TI - Mediterranean Eating Pattern. AB - IN BRIEF The Mediterranean-style eating pattern (MEP) has long been touted as a healthful way of eating. However, the health benefits of the eating pattern and key elements contributing to those benefits are still being researched. In people with type 2 diabetes, the majority of studies report that the MEP improves glycemic control and cardiovascular risk factors. In people at risk for diabetes, the majority of studies report a protective effect of the MEP against the development of type 2 diabetes. Although more research is needed to determine whether study results can be achieved outside the Mediterranean geographical region, and especially in the United States, the high-quality individual foods and combinations of foods included in the MEP can be recommended as a healthful eating approach. PMID- 28588372 TI - DASH Eating Plan: An Eating Pattern for Diabetes Management. AB - IN BRIEF The DASH (Dietary Approaches to Stop Hypertension) eating plan is an acceptable eating pattern for people who have diabetes. In addition to promoting blood pressure control, this eating pattern has been shown to improve insulin resistance, hyperlipidemia, and even overweight/obesity. This balanced approach promotes consumption of a variety of foods (whole grains, fat-free or low-fat dairy products, fruits, vegetables, poultry, fish, and nuts) and is appropriate for the entire family. PMID- 28588374 TI - Mindful Eating With Diabetes. AB - IN BRIEF This article provides a description of mindfulness and mindful eating and addresses the application of mindful eating as a component of diabetes self management education. Mindful eating helps individuals cultivate awareness of both internal and external triggers to eating, interrupt automatic eating, and eat in response to the natural physiological cues of hunger and satiety. Mindful eating interventions have been effective in facilitating improvement in dysregulated eating and dietary patterns. Through practice over time, eating mindfully can interrupt habitual eating behaviors and provide greater regulation of food choice. More research is needed to determine the long-term impact of mindful eating programs. PMID- 28588373 TI - Vegetarian Diets in the Prevention and Management of Diabetes and Its Complications. AB - IN BRIEF Epidemiological studies have found a lower prevalence of type 2 diabetes among vegetarians compared to nonvegetarians. This reduced risk is likely a function of improved weight status, higher intake of dietary fiber, and the absence of animal protein and heme iron in the diet. Interventional studies have shown that vegetarian diets, especially a vegan diet, are effective tools in glycemic control and that these diets control plasma glucose to a greater level than do control diets, including diets traditionally recommended for patients with diabetes (e.g., diets based on carbohydrate counting). Vegetarian diets are associated with improvement in secondary outcomes such as weight reduction, serum lipid profile, and blood pressure. Studies indicate that vegetarian diets can be universally used in type 2 diabetes prevention and as tools to improve blood glucose management. PMID- 28588375 TI - Insights From the National Diabetes Education Program National Diabetes Survey: Opportunities for Diabetes Self-Management Education and Support. AB - IN BRIEF Diabetes self-management education and support (DSMES) provides the foundation to help people with diabetes (PWD) navigate the numerous self management decisions and complex care activities they face daily and has been shown to improve outcomes. Without DSMES, PWD often lack the skills and knowledge necessary to handle the demands of managing this chronic disease. Understanding self-management behaviors and responses to DSMES is essential for improving DSMES processes and diabetes outcomes. This article provides the most recent findings from questions regarding self-management behaviors and DSMES practices obtained through the National Diabetes Education Program National Diabetes Survey. Insights and gaps in self-management behaviors and DSMES delivery are examined to identify challenges and offer opportunities for improvement. PMID- 28588376 TI - Phosphate Additive Avoidance in Chronic Kidney Disease. AB - IN BRIEF Dietary guidelines for patients with diabetes extend beyond glycemic management to include recommendations for mitigating chronic disease risk. This review summarizes the literature suggesting that excess dietary phosphorus intake may increase the risk of skeletal and cardiovascular disease in patients who are in the early stages of chronic kidney disease (CKD) despite having normal serum phosphorus concentrations. It explores strategies for limiting dietary phosphorus, emphasizing that food additives, as a major source of highly bioavailable dietary phosphorus, may be a suitable target. Although the evidence for restricting phosphorus-based food additives in early CKD is limited, diabetes clinicians should monitor ongoing research aimed at assessing its efficacy. PMID- 28588377 TI - Young Adults With Type 1 Diabetes: Romantic Relationships and Implications for Well-Being. AB - OBJECTIVE: The study goal was to examine whether young adults with type 1 diabetes involve romantic partners in their illness, and, if so, how their involvement is related to relationship quality and psychological well-being. METHODS: A total of 68 people (mean age 25.5 years, [SD 3.7 years]) with type 1 diabetes (mean diabetes duration 6 years, [SD 6.7]) involved in a romantic relationship (mean relationship duration 25 months, [SD 27 months]) completed phone interviews. Communal coping (shared illness appraisal and collaborative problem-solving), partner supportive and unsupportive behavior, relationship quality, and psychological well-being were assessed with standardized measures. The study was partly descriptive in identifying the extent of communal coping and specific supportive and unsupportive behaviors and partly correlational in connecting communal coping and supportive or unsupportive behaviors to relationship quality and psychological well-being. RESULTS: Descriptive findings showed that partners were somewhat involved in diabetes, but communal coping was less common compared to other chronically ill populations. The most common partner supportive behaviors were emotional and instrumental support. The most common partner unsupportive behavior was worry about diabetes. Correlational results showed that communal coping was related to greater partner emotional and instrumental support, but also to greater partner overprotective and controlling behaviors (P <0.01 for all). Communal coping was unrelated to relationship quality or psychological distress. Partner overinvolvement in diabetes management had a mixed relation to outcomes, whereas partner underinvolvement was uniformly related to poor outcomes. CONCLUSION: People with type 1 diabetes may benefit from increased partner involvement in illness. This could be facilitated by health care professionals. PMID- 28588378 TI - The Gluten-Free Diet: Fad or Necessity? PMID- 28588379 TI - Interactive Video Telehealth Models to Improve Access to Diabetes Specialty Care and Education in the Rural Setting: A Systematic Review. PMID- 28588381 TI - Oxygen Therapy and Ventilatory Support. PMID- 28588380 TI - A Review of the Efficacy and Safety of Sodium-Glucose Cotransporter 2 Inhibitors: A Focus on Diabetic Ketoacidosis. PMID- 28588382 TI - County Smoke-Free Laws and Asthma Discharges: Evidence from 17 US States. AB - BACKGROUND: Although approximately 82 percent of the US population was covered by some form of law that restricted smoking in public establishments as of 2014, most research examining the relationship between smoke-free laws and health has been focused at the state level. PURPOSE: To examine the effect of county workplace smoke-free laws over and above the effect of other (restaurant or bar) smoke-free laws on adult asthma. METHODS: The study estimated the effect of rates of adult asthma discharges before and after the implementation of county nonhospitality workplace smoke-free laws and county restaurant and bar smoke-free laws. Data were from 2002 to 2009, and all analyses were performed in 2011 through 2013. RESULTS: A statistically significant relationship (-5.43, p < .05) was found between county restaurant or bar smoke-free laws and reductions in working age adult asthma discharges. There was no statistically significant effect of nonhospitality workplace smoke-free laws over and above the effect of county restaurant or bar laws. CONCLUSIONS: This study suggests that further gains in preventable asthma-related hospitalizations in the US are more likely to be made by focusing on smoke-free laws in bars or restaurants rather than in nonhospitality workplaces. PMID- 28588383 TI - Comparison of Different Disease-Specific Health-Related Quality of Life Measurements in Patients with Long-Term Noninvasive Ventilation. AB - BACKGROUND: Two disease-specific questionnaires have been developed to assess health-related quality of life (HRQL) in patients with chronic respiratory failure: the Severe Respiratory Insufficiency (SRI) Questionnaire and the Maugeri Respiratory Failure (MRF) Questionnaire. We aimed to compare the characteristics of the SRI, MRF-26, and St. George's Respiratory Questionnaire (SGRQ) for use in patients with home noninvasive ventilation (NIV). METHODS: Fifty-six outpatients receiving long-term NIV were recruited and underwent assessments of pulmonary function, arterial blood gas, HRQL, dyspnea, and psychological status. RESULTS: Correlations of the SRI and MRF-26 with the SGRQ were modest. While pulmonary function was weakly related to only some domains of the SRI and MRF-26, the modified Medical Research Council (mMRC) dyspnea scale and Hospital Anxiety and Depression Scale (HADS) were significantly related to all domains of the SRI and MRF-26. Multiple regression analyses showed that HADS depression and mMRC accounted for 34% and 27% of the variance in the SRI, 24% and 37% in the MRF-26, and 17% and 46% in the SGRQ, respectively. CONCLUSIONS: The SRI and MRF-26 were reliable questionnaires for patients receiving long-term NIV. Dyspnea and psychological status were their main common determinants. The SRI covers more psychological health impairments than the MRF. This trial is registered with ClinicalTrials.gov Identifier: NCT00905476. PMID- 28588384 TI - SNP-based association analysis for seedling traits in durum wheat (Triticum turgidum L. durum (Desf.)). AB - In the present study, 150 accessions of worldwide originated durum wheat germplasm (Triticum turgidum spp. durum) were observed for major seedling traits and their growth. The accessions were evaluated for major seedling traits under controlled conditions of hydroponics at the 13th, 20th, 27th and 34th day-after germination. Biomass traits were measured at the 34th day-after germination. Correlation analysis was conducted among the seedling traits and three field traits at maturity, plant height, grain weight and 1000-grain weight observed in four consecutive years. Associations of the measured seedling traits and SNP markers were analyzed based on the mixed linear model (MLM). The results indicated that highly significant genetic variation and robust heritability were found for the seedling and field mature traits. In total, 259 significant associations were detected for all the traits and four growth stages. The phenotypic variation explained (R2) by a single SNP marker is higher than 10% for most (84%) of the significant SNP markers. Forty-six SNP markers associated with multiple traits, indicating non-neglectable pleiotropy in seedling stage. The associated SNP markers could be helpful for genetic analysis of seedling traits, and marker-assisted breeding of new wheat varieties with strong seedling vigor. PMID- 28588385 TI - Linkage mapping of Mungbean yellow mosaic India virus (MYMIV) resistance gene in soybean. AB - Mungbean Yellow Mosaic India Virus (MYMIV) is one of the most prevalent pathogen that limits soybean production in India. In this study RILs derived from JS335, dominant but MYMIV susceptible variety and PI171443, donor of MYMIV resistance gene in most of the MYMIV resistant varieties released in India and F2 population derived from SL525, a resistant variety released for northern India and NRC101, a susceptible genotype were used to study the inheritance of MYMIV resistance and map the gene responsible for MYMIV resistance. F1s were found to be completely susceptible. F2:3 and RILs population segregated to fit a ratio of 1:2:1 and 1:1 indicating that a single recessive gene controlled resistance to MYMIV. BSA was performed using 144 polymorphic SSR markers. MYMIV resistance gene was mapped on chr 6 (LG C2) within a 3.5-cM genome region between two SSR markers GMAC7L and Satt322 whose size was estimated to be 77.115 kb (position of 12,259,594 12,336,709 bp). This is the first report on linkage mapping of MYMIV resistance gene in soybean. This will be helpful in breeding soybean varieties for resistance against MYMIV responsible for wide spread damage to soybean crop in India using Marker Assisted Selection. PMID- 28588386 TI - Detection of novel QTLs qDTH4.5 and qDTH6.3, which confer late heading under short-day conditions, by SSR marker-based and QTL-seq analysis. AB - Heading date is one of the most important traits in rice breeding. It is governed by multiple genes, including known quantitative trait loci (QTLs). In general, almost all japonica cultivars, including Nipponbare, head early under short-day (SD) conditions, but some indica cultivars, including Kasalath, head late. To explain this difference, we identified QTLs controlling heading date under SD conditions. We used NILs, CSSLs, and BILs from a cross between Nipponbare and Kasalath, and evaluated days to heading (DTH) under SD conditions. No NILs or CSSLs showed late heading, but two BILs (BIL-55 and BIL-78) had almost the same DTH as Kasalath. We developed an F2 population from a cross between BIL-55 and Nipponbare and performed QTL analysis using SSR markers. The late-heading phenotype was controlled by two known genes and at least two novel QTLs on chromosomes 4 and 6, named qDTH4.5 and qDTH6.3. These QTLs were confirmed by QTL seq. The QTLs and polymorphisms detected here will provide useful information for further genetic studies and breeding under SD conditions at lower latitudes. PMID- 28588387 TI - Application of a Bayesian ordinal animal model for the estimation of breeding values for the resistance to Monilinia fruticola (G.Winter) Honey in progenies of peach [Prunus persica (L.) Batsch]. AB - Fruit brown rot caused by Monilinia spp. is the most important fungal disease of stone fruits worldwide. Several phenotyping protocols to accurately characterize and evaluate brown rot infection have been proposed; however, the outcomes from those studies have not led to consistent advances in resistance breeding programs. Breeding for disease resistance is one of the most challenging objectives for crop improvement because disease expression is tetrahedral: it is simultaneously influenced by agent, host, environment, and human management. The present study presents a strategy based on Bayesian inference to analyze a peach breeding progeny for resistance to brown rot, evaluated using a polytomous ordinal scale. A pedigree containing two sources of resistance, one from peach and the other from almond, several commercial cultivars, and two segregating populations were analyzed to estimate the narrow-sense heritability (h2 ) and breeding values (EBVs) for brown rot resistance in progenies. Results show promise for genetic improvement of disease resistance and other traits characterized by strong environmental interactions. PMID- 28588388 TI - Identification of environmentally stable QTLs controlling Saponin content in Glycine max. AB - Saponins are secondary metabolites that are widely distributed in plants. There are two major saponin precursors in soybean: soyasapogenol A, contributing to the undesirable taste, and soyasapogenol B, some of which have health benefits. It is important to control the ratio and content of the two major saponin groups to enhance the appeal of soybean as a health food. The structural diversity of saponin in the sugar chain composition makes it hard to quantify the saponin content. We measured the saponin content in soybean by removing the sugar chain from the saponin using acidic hydrolysis and detected novel quantitative trait loci (QTLs) for saponin content. Major QTLs in the hypocotyl were identified on chromosome 5 near the SSR marker, Satt 384, while those in the cotyledon were on chromosome 6 near Sat_312, which is linked to the T and E1 loci. Our results suggest that saponin contents in the hypocotyl and cotyledon are controlled by different genes and that it is difficult to increase the beneficial group B saponin and to decrease the undesirable group A saponin at the same time. PMID- 28588389 TI - Microsatellite markers for the Triticum timopheevi-derived leaf rust resistance gene Lr18 on wheat 5BL chromosome. AB - Leaf rust, caused by Puccinia triticina, is a common wheat disease worldwide. Developing resistant cultivars through deploying new or pyramiding resistance genes in a suitable line, is the most effective approach to control this disease. However, to stack genes in a genotype, efficient and reliable markers are required. In the present study, F2 plants and their corresponding F3 families from a cross between the resistant line; Thatcher (Tc) Lr18, and the susceptible cultivar 'Boolani' were used to map rust resistance gene, Lr18 using SSR markers on chromosome 5BL of hexaploid wheat. The P. triticina pathotype no 15 was used to inoculate plants. Out of 20 primers tested, eight showed polymorphism between the two parents and were subsequently genotyped in the entire F2 population. The markers Xgpw7425 and Xwmc75 flanked the locus at a distance of 0.3 and 1.2 cM, respectively. Analysis of 81 genotypes from different backgrounds with these two markers confirmed their usefulness in screening absence or presence of Lr18. Therefore, these markers can be used for gene postulation and marker-assisted selection (MAS) of this gene in wheat breeding programs in future. PMID- 28588390 TI - Establishment of uracil auxotrophic dikaryotic strains of Lentinula edodes by crossbreeding. AB - The uracil auxotrophic monokaryotic strain 423-9 of Lentinula edodes was crossed with nine monokaryons (cro2-2-9, W66-1, xd2-3-2, QingKe 20A, 241-1-1, 9015-1, L66 2, 241-1-2, and Qing 23A) derived from wild type strains of L. edodes. Nine dikaryotic hybrids were established from these crosses. These hybrids were fruited and 496 single spore isolates were obtained. Among these single spore isolates, 166 were identified as monokaryons under a microscope. We screened these monokaryons on selective medium and obtained 19 uracil auxotrophic monokaryons. By using the Monkaryon-monkaryon crossing method among the uracil auxotrophic monokaryons, 56 uracil auxotrophic dikaryotic strains were established on selective medium. These dikaryotic strains were unable to grow on minimal medium without uracil and exhibited slow growth rates on PDA plates compared to the wild type strain. The uracil auxotrophic dikaryotic strains also showed more vigorous growth on sawdust cultivation medium containing uracil than that without uracil. The fruiting tests showed that they formed normal fruiting bodies on the sawdust medium containing uracil. The results show that the uracil auxotrophic dikaryotic strain of L. edodes could be produced by mating, and will provide a valuable resource for future genetic studies and for spawn protection and identification. PMID- 28588391 TI - Genetic analysis and association of simple sequence repeat markers with storage root yield, dry matter, starch and beta-carotene content in sweetpotato. AB - Molecular markers are needed for enhancing the development of elite sweetpotato (Ipomoea batatas (L.) Lam) cultivars with a wide range of commercially important traits in sub-Saharan Africa. This study was conducted to estimate the heritability and determine trait correlations of storage root yield, dry matter, starch and beta-carotene content in a cross between 'New Kawogo' * 'Beauregard'. The study was also conducted to identify simple sequence repeat (SSR) markers associated with these traits. A total of 287 progeny and the parents were evaluated for two seasons at three sites in Uganda and genotyped with 250 SSR markers. Broad sense heritability (H2) for storage root yield, dry matter, starch and beta-carotene content were 0.24, 0.68, 0.70 and 0.90, respectively. Storage root beta-carotene content was negatively correlated with dry matter (r = -0.59, P < 0.001) and starch (r = -0.93, P < 0.001) content, while storage root yield was positively correlated with dry matter (r = 0.57, P = 0.029) and starch (r = 0.41, P = 0.008) content. Through logistic regression, a total of 12, 4, 6 and 8 SSR markers were associated with storage root yield, dry matter, starch and beta carotene content, respectively. The SSR markers used in this study may be useful for quantitative trait loci analysis and selection for these traits in future. PMID- 28588392 TI - Multiple organ gigantism caused by mutation in VmPPD gene in blackgram (Vigna mungo). AB - Seed size is one of the most important traits in leguminous crops. We obtained a recessive mutant of blackgram that had greatly enlarged leaves, stems and seeds. The mutant produced 100% bigger leaves, 50% more biomass and 70% larger seeds though it produced 40% less number of seeds. We designated the mutant as multiple organ-gigantism (mog) and found the mog phenotype was due to increase in cell numbers but not in cell size. We also found the mog mutant showed a rippled leaf (rl) phenotype, which was probably caused by a pleiotropic effect of the mutation. We performed a map-based cloning and successfully identified an 8 bp deletion in the coding sequence of VmPPD gene, an orthologue of Arabidopsis PEAPOD (PPD) that regulates arrest of cell divisions in meristematic cells. We found no other mutations in the neighboring genes between the mutant and the wild type. We also knocked down GmPPD genes and reproduced both the mog and rl phenotypes in soybean. Controlling PPD genes to produce the mog phenotype is highly valuable for breeding since larger seed size could directly increase the commercial values of grain legumes. PMID- 28588394 TI - The two-row malting barley cultivar 'New Sachiho Golden' with null lipoxygenase-1 improves flavor stability in beer and was developed by marker-assisted selection. AB - Lipoxygenase-1 (LOX-1) null 'New Sachiho Golden' is a two-row malting barley (Hordeum vulgare L.) cultivar released in 2015 that was developed at the Tochigi Prefectural Agricultural Experimental Station by backcross breeding using the high-yield leading cultivar 'Sachiho Golden' as a recurrent parent and the LOX-1 null mutant 'Daikei LM1' as a non-recurrent parent. To develop 'New Sachiho Golden' we used a simple LOX activity assay and marker-assisted selection. This is the first LOX-1 null malting barley cultivar in Japan that is resistant to barley yellow mosaic virus (types I-III). Agronomic characteristics and malting qualities of 'New Sachiho Golden' were similar to those of 'Sachiho Golden', except that 'New Sachiho Golden' had no LOX activity in ungerminated grains and had clearly lower LOX activity during malting than 'Sachiho Golden'. The concentrations of a trans-2-nonenal (T2N) precursor in wort and beer made from 'New Sachiho Golden' were significantly lower than in those made from 'Sachiho Golden', both before and after storage. PMID- 28588393 TI - Quantitative trait loci analysis of blast resistance in Oryza sativa L. 'Hokuriku 193'. AB - To investigate the genetic background responsible for blast resistance in Oryza sativa L. 'Hokuriku 193', QTL analysis was conducted using the F3 lines from the cross [ms-bo] Nekken 2 * Hokuriku 193 that were artificially infected with rice blast fungus (Magnaporthe grisea). QTLs were detected on chromosomes 1, 4, 6 and 12 that correlated with greater blast resistance in the Hokuriku 193-type lines. Notably, the QTL on chromosome 12 had a major effect and localized to the same region where Pi20(t), a broad-spectrum blast resistance gene, is positioned, suggesting strongly that the blast resistance of Hokuriku 193 was controlled by Pi20(t). Also, QTL analysis of the lines found to have no Pi20(t) detected two QTLs on chromosome 4 (qBR4-1 and qBR4-2) and one QTL on chromosome 6 (qBR6), of which qBR4-2 and qBR6 correlated with higher percentages of resistant plants in the Hokuriku 193-type lines. The blast susceptibility of BR_NIL (a NIL of Hokuriku 193 from which Pi20(t) was eliminated) was greater than that of Hokuriku 193, suggesting that elimination of Pi20(t) may markedly increase blast susceptibility. The disease severity of BR_NIL was mild, which might be the effect of qBR4-2 and/or qBR6. PMID- 28588395 TI - Erratum: Evaluation of the yield of abiotic-stress-tolerant AtDREB1A transgenic potato under saline conditions in advance of field trials. AB - [This corrects the article on p. 703 in vol. 66, PMID: 28163586.]. PMID- 28588396 TI - Results of a Qualitative Study to Develop a Patient Reported Outcome Measure for Patients with 4 Subtypes of Soft Tissue Sarcoma. AB - OBJECTIVE: The objective of this research was to develop a disease-specific symptom inventory for soft tissue sarcoma. METHODS: Literature review and clinical expert and patient interviews were conducted to determine disease specific symptoms important to patients with one of the four STS subtypes. Clinical experts identified the most relevant STS symptom items from the item pool developed from literature review. Concept elicitation interviews were conducted with patients to elicit their STS symptom experiences followed by a completion of the draft symptom list via web survey. A cognitive interview was conducted on the comprehension and importance of the symptom items. RESULTS: Eighty-three symptom items were compiled and discussed with three clinical experts who identified 26 symptoms specific to the four STS subtypes. A total sample of 27 STS participants with self-reported leiomyosarcoma (74%), undifferentiated sarcoma (15%), synovial sarcoma (7%), or liposarcoma (4%) diagnosis completed the web survey and 10 were interviewed. The draft 12-item STS specific symptom inventory includes abdominal pain, pressure in abdomen, early satiety, bloating, gastrointestinal pain, muscle pain, bone pain, heavy menstrual flow, shortness of breath, chest pain, cough, and painful menstruation. CONCLUSION: A number of symptoms are common across STS subtypes and may form a single STS symptom inventory. PMID- 28588397 TI - Causal dissipation for the relativistic dynamics of ideal gases. AB - We derive a general class of relativistic dissipation tensors by requiring that, combined with the relativistic Euler equations, they form a second-order system of partial differential equations which is symmetric hyperbolic in a second-order sense when written in the natural Godunov variables that make the Euler equations symmetric hyperbolic in the first-order sense. We show that this class contains a unique element representing a causal formulation of relativistic dissipative fluid dynamics which (i) is equivalent to the classical descriptions by Eckart and Landau to first order in the coefficients of viscosity and heat conduction and (ii) has its signal speeds bounded sharply by the speed of light. Based on these properties, we propose this system as a natural candidate for the relativistic counterpart of the classical Navier-Stokes equations. PMID- 28588398 TI - A note on the self-similar solutions to the spontaneous fragmentation equation. AB - We provide a method to compute self-similar solutions for various fragmentation equations and use it to compute their asymptotic behaviours. Our procedure is applied to specific cases: (i) the case of mitosis, where fragmentation results into two identical fragments, (ii) fragmentation limited to the formation of sufficiently large fragments, and (iii) processes with fragmentation kernel presenting a power-like behaviour. PMID- 28588399 TI - From arteries to boreholes: steady-state response of a poroelastic cylinder to fluid injection. AB - The radially outward flow of fluid into a porous medium occurs in many practical problems, from transport across vascular walls to the pressurization of boreholes. As the driving pressure becomes non-negligible relative to the stiffness of the solid structure, the poromechanical coupling between the fluid and the solid has an increasingly strong impact on the flow. For very large pressures or very soft materials, as is the case for hydraulic fracturing and arterial flows, this coupling can lead to large deformations and, hence, to strong deviations from a classical, linear-poroelastic response. Here, we study this problem by analysing the steady-state response of a poroelastic cylinder to fluid injection. We consider the qualitative and quantitative impacts of kinematic and constitutive nonlinearity, highlighting the strong impact of deformation-dependent permeability. We show that the wall thickness (thick versus thin) and the outer boundary condition (free versus constrained) play a central role in controlling the mechanics. PMID- 28588401 TI - Elementary exact calculations of degree growth and entropy for discrete equations. AB - Second-order discrete equations are studied over the field of rational functions [Formula: see text], where z is a variable not appearing in the equation. The exact degree of each iterate as a function of z can be calculated easily using the standard calculations that arise in singularity confinement analysis, even when the singularities are not confined. This produces elementary yet rigorous entropy calculations. PMID- 28588402 TI - Well-posed continuum equations for granular flow with compressibility and MU(I) rheology. AB - Continuum modelling of granular flow has been plagued with the issue of ill-posed dynamic equations for a long time. Equations for incompressible, two-dimensional flow based on the Coulomb friction law are ill-posed regardless of the deformation, whereas the rate-dependent MU(I)-rheology is ill-posed when the non dimensional inertial number I is too high or too low. Here, incorporating ideas from critical-state soil mechanics, we derive conditions for well-posedness of partial differential equations that combine compressibility with I-dependent rheology. When the I-dependence comes from a specific friction coefficient MU(I), our results show that, with compressibility, the equations are well-posed for all deformation rates provided that MU(I) satisfies certain minimal, physically natural, inequalities. PMID- 28588400 TI - Quantum effects in biology: golden rule in enzymes, olfaction, photosynthesis and magnetodetection. AB - Despite certain quantum concepts, such as superposition states, entanglement, 'spooky action at a distance' and tunnelling through insulating walls, being somewhat counterintuitive, they are no doubt extremely useful constructs in theoretical and experimental physics. More uncertain, however, is whether or not these concepts are fundamental to biology and living processes. Of course, at the fundamental level all things are quantum, because all things are built from the quantized states and rules that govern atoms. But when does the quantum mechanical toolkit become the best tool for the job? This review looks at four areas of 'quantum effects in biology'. These are biosystems that are very diverse in detail but possess some commonality. They are all (i) effects in biology: rates of a signal (or information) that can be calculated from a form of the 'golden rule' and (ii) they are all protein-pigment (or ligand) complex systems. It is shown, beginning with the rate equation, that all these systems may contain some degree of quantumeffect, and where experimental evidence is available, it is explored to determine how the quantum analysis aids in understanding of the process. PMID- 28588403 TI - Dispersionless (3+1)-dimensional integrable hierarchies. AB - In this paper, we introduce a multi-dimensional version of the R-matrix approach to the construction of integrable hierarchies. Applying this method to the case of the Lie algebra of functions with respect to the contact bracket, we construct integrable hierarchies of (3+1)-dimensional dispersionless systems of the type recently introduced in Sergyeyev (2014 (http://arxiv.org/abs/1401.2122)). PMID- 28588404 TI - Probing quantum state space: does one have to learn everything to learn something? AB - Determining the state of a quantum system is a consuming procedure. For this reason, whenever one is interested only in some particular property of a state, it would be desirable to design a measurement set-up that reveals this property with as little effort as possible. Here, we investigate whether, in order to successfully complete a given task of this kind, one needs an informationally complete measurement, or if something less demanding would suffice. The first alternative means that in order to complete the task, one needs a measurement which fully determines the state. We formulate the task as a membership problem related to a partitioning of the quantum state space and, in doing so, connect it to the geometry of the state space. For a general membership problem, we prove various sufficient criteria that force informational completeness, and we explicitly treat several physically relevant examples. For the specific cases that do not require informational completeness, we also determine bounds on the minimal number of measurement outcomes needed to ensure success in the task. PMID- 28588405 TI - Aeroacoustic catastrophes: upstream cusp beaming in Lilley's equation. AB - The downstream propagation of high-frequency acoustic waves from a point source in a subsonic jet obeying Lilley's equation is well known to be organized around the so-called 'cone of silence', a fold catastrophe across which the amplitude may be modelled uniformly using Airy functions. Here we show that acoustic waves not only unexpectedly propagate upstream, but also are organized at constant distance from the point source around a cusp catastrophe with amplitude modelled locally by the Pearcey function. Furthermore, the cone of silence is revealed to be a cross-section of a swallowtail catastrophe. One consequence of these discoveries is that the peak acoustic field upstream is not only structurally stable but also at a similar level to the known downstream field. The fine structure of the upstream cusp is blurred out by distributions of symmetric acoustic sources, but peak upstream acoustic beaming persists when asymmetries are introduced, from either arrays of discrete point sources or perturbed continuum ring source distributions. These results may pose interesting questions for future novel jet-aircraft engine designs where asymmetric source distributions arise. PMID- 28588406 TI - [Formula: see text] graded discrete Lax pairs and Yang-Baxter maps. AB - We recently introduced a class of [Formula: see text] graded discrete Lax pairs and studied the associated discrete integrable systems (lattice equations). In this paper, we introduce the corresponding Yang-Baxter maps. Many well-known examples belong to this scheme for N=2, so, for N>=3, our systems may be regarded as generalizations of these. In particular, for each N we introduce a class of multi-component Yang-Baxter maps, which include HBIII (of Papageorgiou et al. 2010 SIGMA 6, 003 (9 p). (doi:10.3842/SIGMA.2010.033)), when N=2, and that associated with the discrete modified Boussinesq equation, for N=3. For N>=5 we introduce a new family of Yang-Baxter maps, which have no lower dimensional analogue. We also present new multi-component versions of the Yang-Baxter maps FIV and FV (given in the classification of Adler et al. 2004 Commun. Anal. Geom. 12, 967-1007. (doi:10.4310/CAG.2004.v12.n5.a1)). PMID- 28588407 TI - Passive vibration control: a structure-immittance approach. AB - Linear passive vibration absorbers, such as tuned mass dampers, often contain springs, dampers and masses, although recently there has been a growing trend to employ or supplement the mass elements with inerters. When considering possible configurations with these elements broadly, two approaches are normally used: one structure-based and one immittance-based. Both approaches have their advantages and disadvantages. In this paper, a new approach is proposed: the structure immittance approach. Using this approach, a full set of possible series-parallel networks with predetermined numbers of each element type can be represented by structural immittances, obtained via a proposed general formulation process. Using the structural immittances, both the ability to investigate a class of absorber possibilities together (advantage of the immittance-based approach), and the ability to control the complexity, topology and element values in resulting absorber configurations (advantages of the structure-based approach) are provided at the same time. The advantages of the proposed approach are demonstrated through two case studies on building vibration suppression and automotive suspension design, respectively. PMID- 28588408 TI - Nonlinear waves in solids with slow dynamics: an internal-variable model. AB - In heterogeneous solids such as rocks and concrete, the speed of sound diminishes with the strain amplitude of a dynamic loading (softening). This decrease, known as 'slow dynamics', occurs at time scales larger than the period of the forcing. Also, hysteresis is observed in the steady-state response. The phenomenological model by Vakhnenko et al. (2004 Phys. Rev. E 70, 015602. (doi:10.1103/PhysRevE.70.015602)) is based on a variable that describes the softening of the material. However, this model is one dimensional and it is not thermodynamically admissible. In the present article, a three-dimensional model is derived in the framework of the finite-strain theory. An internal variable that describes the softening of the material is introduced, as well as an expression of the specific internal energy. A mechanical constitutive law is deduced from the Clausius-Duhem inequality. Moreover, a family of evolution equations for the internal variable is proposed. Here, an evolution equation with one relaxation time is chosen. By construction, this new model of the continuum is thermodynamically admissible and dissipative (inelastic). In the case of small uniaxial deformations, it is shown analytically that the model reproduces qualitatively the main features of real experiments. PMID- 28588410 TI - The effect of surface tension on steadily translating bubbles in an unbounded Hele-Shaw cell. AB - New numerical solutions to the so-called selection problem for one and two steadily translating bubbles in an unbounded Hele-Shaw cell are presented. Our approach relies on conformal mapping which, for the two-bubble problem, involves the Schottky-Klein prime function associated with an annulus. We show that a countably infinite number of solutions exist for each fixed value of dimensionless surface tension, with the bubble shapes becoming more exotic as the solution branch number increases. Our numerical results suggest that a single solution is selected in the limit that surface tension vanishes, with the scaling between the bubble velocity and surface tension being different to the well studied problems for a bubble or a finger propagating in a channel geometry. PMID- 28588409 TI - Simulating tubulin-associated unit transport in an axon: using bootstrapping for estimating confidence intervals of best-fit parameter values obtained from indirect experimental data. AB - In this paper, we first develop a model of axonal transport of tubulin-associated unit (tau) protein. We determine the minimum number of parameters necessary to reproduce published experimental results, reducing the number of parameters from 18 in the full model to eight in the simplified model. We then address the following questions: Is it possible to estimate parameter values for this model using the very limited amount of published experimental data? Furthermore, is it possible to estimate confidence intervals for the determined parameters? The idea that is explored in this paper is based on using bootstrapping. Model parameters were estimated by minimizing the objective function that simulates the discrepancy between the model predictions and experimental data. Residuals were then identified by calculating the differences between the experimental data and model predictions. New, surrogate 'experimental' data were generated by randomly resampling residuals. By finding sets of best-fit parameters for a large number of surrogate data the histograms for the model parameters were produced. These histograms were then used to estimate confidence intervals for the model parameters, by using the percentile bootstrap. Once the model was calibrated, we applied it to analysing some features of tau transport that are not accessible to current experimental techniques. PMID- 28588411 TI - Crossing the quasi-threshold manifold of a noise-driven excitable system. AB - We consider the noise-induced escapes in an excitable system possessing a quasi threshold manifold, along which there exists a certain point of minimal quasi potential. In the weak noise limit, the optimal escaping path turns out to approach this particular point asymptotically, making it analogous to an ordinary saddle. Numerical simulations are performed and an elaboration on the effect of small but finite noise is given, which shows that the ridges where the prehistory probability distribution peaks are located mainly within the region where the quasi-potential increases gently. The cases allowing anisotropic noise are discussed and we found that varying the noise term in the slow variable would dramatically raise the whole level of quasi-potentials, leading to significant changes in both patterns of optimal paths and exit locations. PMID- 28588412 TI - An integral equation method for the homogenization of unidirectional fibre reinforced media; antiplane elasticity and other potential problems. AB - In Parnell & Abrahams (2008 Proc. R. Soc. A464, 1461-1482. (doi:10.1098/rspa.2007.0254)), a homogenization scheme was developed that gave rise to explicit forms for the effective antiplane shear moduli of a periodic unidirectional fibre-reinforced medium where fibres have non-circular cross section. The explicit expressions are rational functions in the volume fraction. In that scheme, a (non-dilute) approximation was invoked to determine leading order expressions. Agreement with existing methods was shown to be good except at very high volume fractions. Here, the theory is extended in order to determine higher-order terms in the expansion. Explicit expressions for effective properties can be derived for fibres with non-circular cross section, without recourse to numerical methods. Terms appearing in the expressions are identified as being associated with the lattice geometry of the periodic fibre distribution, fibre cross-sectional shape and host/fibre material properties. Results are derived in the context of antiplane elasticity but the analogy with the potential problem illustrates the broad applicability of the method to, e.g. thermal, electrostatic and magnetostatic problems. The efficacy of the scheme is illustrated by comparison with the well-established method of asymptotic homogenization where for fibres of general cross section, the associated cell problem must be solved by some computational scheme. PMID- 28588413 TI - Uncertainty relations on nilpotent Lie groups. AB - We give relations between main operators of quantum mechanics on one of most general classes of nilpotent Lie groups. Namely, we show relations between momentum and position operators as well as Euler and Coulomb potential operators on homogeneous groups. Homogeneous group analogues of some well-known inequalities such as Hardy's inequality, Heisenberg-Kennard type and Heisenberg Pauli-Weyl type uncertainty inequalities, as well as Caffarelli-Kohn-Nirenberg inequality are derived, with best constants. The obtained relations yield new results already in the setting of both isotropic and anisotropic [Formula: see text], and of the Heisenberg group. The proof demonstrates that the method of establishing equalities in sharper versions of such inequalities works well in both isotropic and anisotropic settings. PMID- 28588414 TI - Innovative and collaborative industrial mathematics in Europe. AB - This paper presents a brief review of how industrial mathematics, inspired by the Oxford Study Group activity, organized itself in Europe, gave rise to the European Consortium for Mathematics in Industry, the series of European Study Groups with Industry, and to new modes of productive contacts between industry and applied mathematicians in academia. PMID- 28588415 TI - Curvature-driven morphing of non-Euclidean shells. AB - We investigate how thin structures change their shape in response to non mechanical stimuli that can be interpreted as variations in the structure's natural curvature. Starting from the theory of non-Euclidean plates and shells, we derive an effective model that reduces a three-dimensional stimulus to the natural fundamental forms of the mid-surface of the structure, incorporating expansion, or growth, in the thickness. Then, we apply the model to a variety of thin bodies, from flat plates to spherical shells, obtaining excellent agreement between theory and numerics. We show how cylinders and cones can either bend more or unroll, and eventually snap and rotate. We also study the nearly isometric deformations of a spherical shell and describe how this shape change is ruled by the geometry of a spindle. As the derived results stem from a purely geometrical model, they are general and scalable. PMID- 28588416 TI - Mathematics delivering the advantage: the role of mathematicians in manufacturing and beyond. AB - Much has been written about the benefits that mathematics can bring to the UK economy and the manufacturing sector in particular, but less on the value of mathematicians and a mathematical training. This article, written from an industry perspective, considers the value of mathematicians to the UK's industrial base and the importance to the UK economy of encouraging young people in the UK to choose to study mathematics at school as a gateway to a wide range of careers. The points are illustrated using examples from the author's 20 years' experience in the security and intelligence and manufacturing sectors. PMID- 28588417 TI - Photosynthetic pigment-protein complexes as highly connected networks: implications for robust energy transport. AB - Photosynthetic pigment-protein complexes (PPCs) are a vital component of the light-harvesting machinery of all plants and photosynthesizing bacteria, enabling efficient transport of the energy of absorbed light towards the reaction centre, where chemical energy storage is initiated. PPCs comprise a set of chromophore molecules, typically bacteriochlorophyll species, held in a well-defined arrangement by a protein scaffold; this relatively rigid distribution leads to a viewpoint in which the chromophore subsystem is treated as a network, where chromophores represent vertices and inter-chromophore electronic couplings represent edges. This graph-based view can then be used as a framework within which to interrogate the role of structural and electronic organization in PPCs. Here, we use this network-based viewpoint to compare excitation energy transfer (EET) dynamics in the light-harvesting complex II (LHC-II) system commonly found in higher plants and the Fenna-Matthews-Olson (FMO) complex found in green sulfur bacteria. The results of our simple network-based investigations clearly demonstrate the role of network connectivity and multiple EET pathways on the efficient and robust EET dynamics in these PPCs, and highlight a role for such considerations in the development of new artificial light-harvesting systems. PMID- 28588419 TI - Reviewers in 2016. PMID- 28588420 TI - Correction to 'Microprocessors: the engines of the digital age'. AB - [This corrects the article DOI: 10.1098/rspa.2016.0893.]. PMID- 28588418 TI - Biological imaging using light-addressable potentiometric sensors and scanning photo-induced impedance microscopy. AB - Light-addressable potentiometric sensors (LAPS) and scanning photo-induced impedance microscopy (SPIM) use photocurrent measurements at electrolyte insulator-semiconductor substrates for spatio-temporal imaging of electrical potentials and impedance. The techniques have been used for the interrogation of sensor arrays and the imaging of biological systems. Sensor applications range from the detection of different types of ions and the label-free detection of charged molecules such as DNA and proteins to enzyme-based biosensors. Imaging applications include the temporal imaging of extracellular potentials and dynamic concentration changes in microfluidic channels and the lateral imaging of cell surface charges and cell metabolism. This paper will investigate the current state of the art of the measurement technology with a focus on spatial and temporal resolution and review the biological applications, these techniques have been used for. An outlook on future developments in the field will be given. PMID- 28588422 TI - A rare case of poorly differentiated thyroid carcinoma probably arising from a nodular goiter. AB - BACKGROUND: Some poorly differentiated thyroid carcinomas (PDTC) arise from pre existing, well-differentiated carcinomas of follicular cell origin; however, others most likely arise de novo. The case of a PDTC adjacent to a pre-existing nodular goiter is very rare. CASE PRESENTATION: A patient had a PDTC, a widely invasive, cellular tumor with cells that lacked the nuclear features of a papillary thyroid carcinoma. Carcinoma cells were arranged in trabecular, solid, and microfollicular histological patterns and displayed high mitotic activity. A nodule partially encapsulated in a thick fibrous capsule was found adjacent to the PDTC. The nodule was composed of small or dilated follicles, without papillary carcinoma-like nuclear features, that were consistent with a nodular goiter. The PDTC showed a high Ki-67 labeling index and an NRAS gene mutation (codon 61, Q61K). CONCLUSION: These results support our diagnosis of a PDTC, probably arising from a nodular goiter. PMID- 28588421 TI - Evaluation of the safety and efficacy of a novel product for the removal of impacted human cerumen. AB - BACKGROUND: This open-label study evaluated the safety and efficacy of a novel product for the removal of impacted cerumen in adult patients. METHODS: This was a prospective, single-center, single-arm, self-controlled clinical trial conducted in a community general practice setting. The novel product contains glycolic acid in an otologically-acceptable buffer containing sodium bicarbonate and glycerin and other buffering agents. The product was instilled into the ear canal prior to irrigation with warm water. Severity of cerumen impaction was graded using a 5-point scale. Improvement in tympanic membrane visualization was assessed after instillation and irrigation. RESULTS: A majority (83%, 25/30) of ears showed improvement with one application: with 53% (16/30) totally dissolved and gained 100% TM visualization. Total dissolution was observed in 80% (24/30) of the study ears per the intent-to-treat analysis and 86% (24/28) if irrigation instructions were followed. Most of the ears/participants that had cerumen blockage symptoms experienced significant improvement with the application. Feelings of fullness disappeared in 92% (11/12) of the affected ears; ears itching, 91% (10/11); water trapping or cracking, 78%, and decreased hearing disappeared in 71% (10/14). All (100%, 18) of the participants who completed the application satisfaction assessment were satisfied with the application process in terms of time needed and the overall rinse procedure. Only one mild adverse event (ear pruritis) occurred that was related to application. CONCLUSIONS: The tested cerumen removal product was effective and safe for removing moderate to severe blockage in patients with impacted cerumen. Procedure satisfaction for the product was high. TRIAL REGISTRATION: This trial is registered on http://www.clinicaltrials.gov/. The registration number is NCT02829294. The trial was retrospectively registered on July 8, 2016. PMID- 28588423 TI - Dysphagia screening after acute stroke: a quality improvement project using criteria-based clinical audit. AB - BACKGROUND: Dysphagia is common after stroke and represents a major risk factor for developing aspiration pneumonia. Early detection can reduce the risk of pulmonary complications and death. Despite the fact that evidence-based guidelines recommend screening for swallowing deficit using a standardized screening tool, national audits has identified a gap between practice and this recommendation. The aim was to determine the level of adherence to an evidence based recommendation on swallow assessment and to take actions to improve practice if necessary. METHODS: We carried out a criteria-based clinical audit (CBCA) in a small stroke unit at a Norwegian hospital. Patients with hemorrhagic stroke, ischemic stroke and transient ischemic attack were included. A power calculation informed the number of included patients at baseline (n = 80) and at re-audit (n = 35). We compared the baseline result with the evidence-based criteria and gave feedback to management and staff. A brainstorming session, a root-cause analysis and implementation science were used to inform the quality improvement actions which consisted of workshops, use of local opinion leaders, manual paper reminders and feedback. We completed a re-audit after implementation. Percentages and median are reported with 95% confidence intervals (CI). RESULTS: Among 88 cases at baseline, documentation of swallow screening was complete for 6% (95% CI 2-11). In the re-audit (n = 51) 61% (95% CI 45-74) had a complete screening. CONCLUSION: A CBCA involving management and staff, and using multiple tailored intervention targeting barriers, led to greater adherence with the recommendation for screening stroke patients for dysphagia. PMID- 28588425 TI - Retraction Note: Long noncoding RNA ANRIL is activated by hypoxia-inducible factor-1alpha and promotes osteosarcoma cell invasion and suppresses cell apoptosis upon hypoxia. AB - [This retracts the article DOI: 10.1186/s12935-016-0349-7.]. PMID- 28588424 TI - The use of life stories and its influence on persons with dementia, their relatives and staff - a systematic mixed studies review. AB - BACKGROUND: Dementia is an important predictor of nursing home admissions. Due to progressive dementia symptoms, over time it becomes difficult for persons with dementia to communicate their wishes and participate in decisions concerning their everyday lives. Their well-being, sense of dignity, integrity and personhood are at risk. The persons' life stories have been highlighted as particularly important in dementia care and are referred to as seeing the person beyond the dementia. The aim of this study was to explore and describe the use of life stories and its influence on persons with dementia living in nursing homes, their relatives and staff. METHODS: A systematic mixed studies review was conducted. The literature searches were performed in the following databases: CINAHL, PubMed and PsycINFO and the Cochrane library, as well as by hand searching references in the studies included. An updated search was performed eight months after the first search. Data was synthesised inspired by integrative analysis. RESULTS: Three studies using quantitative design and two studies (presented in three papers) using qualitative design representing research from 2006 to 2015 were included in the review. Life stories generally had a positive influence on the persons with dementia, their relatives, and staff. The use of life stories might contribute to 'Maintenance of the person with dementia as a whole person rather than a demented patient'. On the other hand, enabling persons with dementia to tell their own story could be a challenge. For the staff it could be challenging when sensitive information emerged uninvited. Involving relatives could also be difficult as to whose story were uncovered. CONCLUSIONS: The use of person's life story might be of significance, but there is not enough evidence to make any statement about its importance as the research is scarce. Studies, including randomised controlled trials, are needed to measure the impact of life story work on the physiological and psychological aspects of persons with dementia, and also how it influences their relatives and staff. PMID- 28588428 TI - Umbelliprenin Mediates Its Apoptotic Effect by Hormesis: A Commentary. PMID- 28588426 TI - Effects of Ramadan fasting on platelet reactivity in diabetic patients treated with clopidogrel. AB - BACKGROUND: The effects of Ramadan fasting (RF) on clopidogrel antiplatelet inhibition were not previously investigated. The present study evaluated the influence of RF on platelet reactivity in patients with high cardiovascular risk (CVR) in particular those with type 2 diabetes mellitus (DM). METHODS: A total of 98 stable patients with >=2 CVR factors were recruited. All patients observed RF and were taking clopidogrel at a maintenance dose of 75 mg. Clinical findings and serum lipids data were recorded before Ramadan (Pre-R), at the last week of Ramadan (R) and 4 weeks after the end of Ramadan (Post-R). During each patient visit, nutrients intakes were calculated and platelet reactivity assessment using Verify Now P2Y12 assay was performed. RESULTS: In DM patients, the absolute PRU changes from baseline were +27 (p = 0.01) and +16 (p = 0.02) respectively at R and Post-R. In addition, there was a significant increase of glycemia and triglycerides levels with a significant decrease of high-density lipoprotein. In non DM patients there was no significant change in absolute PRU values and metabolic parameters. Clopidogrel resistance rate using 2 cut-off PRU values (235 and 208) did not change significantly in DM and non DM patients. CONCLUSIONS: RF significantly decreased platelet sensitivity to clopidogrel in DM patients during and after Ramadan. This effect is possibly related to an increase of glycemia and serum lipids levels induced by fasting. TRIAL REGISTRATION: Clinical Trials.gov NCT02720133. Registered 24 July 2014.Retrospectively registered. PMID- 28588427 TI - Evaluation of anti-fatigue property of the extruded product of cereal grains mixed with Cordyceps militaris on mice. AB - BACKGROUND: Fatigue is a biological phenomenon that involves a feeling of extreme physical or mental tiredness that could potentially cause some severe chronic diseases. Recently, diet therapy has provided a new alternative to alleviate physical fatigue. In our previous study, addition of Cordyceps militaris (C. militaris) into an extruded product was shown to provide high nutrition and unique flavors; however, little is known whether this product has some scientific evidence regarding anti-fatigue property. The purpose of this study was to evaluate the anti-fatigue effects of extruded products of cereal grains (EC) and EC mixed with C. militaris (ECC). METHODS: The mice were divided into seven groups: one group received distilled water (Control group, n = 20), and the other groups received different dosages of EC (5, 10 and 20 g/kg body weight, n = 20 per group) or of ECC (5, 10 and 20 g/kg body weight, n = 20 per group) solution in water. All of the mice were administered with distilled water, EC or ECC continuously for 30 days by gavage and the anti-fatigue activity was evaluated using a weight-loaded swimming test, along with assessments of fatigue-related indicators. The mode of fighting fatigue was investigated by determining changes in exercise endurance and biochemical markers, including exhaustive swimming time, lactate dehydrogenase (LDH), blood lactic acid (BLA), creatine kinase (CK), blood urea nitrogen (BUN), malondialdehyde (MDA), glutathione peroxidase (GSH Px), superoxide dismutase (SOD), catalase (CAT), and hepatic and muscle glycogen levels. RESULTS: EC and ECC prolonged the swimming endurance time of mice compared to the control. The content of BLA at high dose of ECC group (20 g/kg) was significantly lower than that in the negative control group. CK, BUN and MDA levels were significantly reduced by treatment with EC and ECC compared to the negative control, while the low and middle dose of EC had no significant effect on MDA levels. Additionally, only the middle and high dose of EC (10, 20 g/kg) could significantly decrease the BUN level. EC and ECC treatments increased glycogen, LDH, SOD, CAT and GSH-Px levels. Low and middle dose of EC had no significant effects on muscle glycogen. Moreover, low dose of EC could increase the level of SOD but it was not statistically significant. Compared to the EC treatment groups, ECC demonstrated the efficacy of anti-fatigue potential, particularly at a high dose of ECC, the best performance in relieving fatigue. CONCLUSIONS: These results suggest that EC and ECC could prevent exercise-induced fatigue in mice and ECC provided a better effect. In addition, C. militaris in ECC might play a crucial role in the anti-fatigue activity of ECC. PMID- 28588429 TI - The associations between cigarette smoking and health-related behaviors among Chinese school-aged adolescents. AB - BACKGROUND: Evidence on the interrelations between cigarette smoking and a cluster of lifestyle behaviors is scarce for the Chinese youth population. This study is conducted to identify the associations between cigarette smoking and multiple health-related behaviors in a Chinese sample of adolescents. METHODS: We used data from 2012 Zhejiang Youth Risk Behavior Survey, which is a school-based survey of 19,542 adolescents that assess risk behaviors using a self-reported questionnaire. The interrelations of cigarette smoking with lifestyle behaviors were investigated using logistic regression models. RESULTS: Cigarette smoking was significantly inversely associated with breakfast (AOR = 0.58), vegetables (AOR = 0.81), fruits (AOR = 0.81), milk consumption (AOR = 0.69) and attending physical education classes (AOR = 0.69), while positively associated with soft drinks (AOR = 2.05), fast food consumption (AOR = 1.21), muscle strengthening activity (AOR = 1.67), computer use (AOR = 1.93) and alcohol drinking (AOR = 5.40). CONCLUSIONS: The results suggested that cigarette smoking was associated with a cluster of health-related behaviors in adolescents, which should be considered in health promotion interventions to target multiple health behaviors. PMID- 28588430 TI - Gut microbial diversity in health and disease: experience of healthy Indian subjects, and colon carcinoma and inflammatory bowel disease patients. AB - Background: The intestinal microbiota, through complex interactions with the gut mucosa, play a key role in the pathogenesis of colon carcinoma and inflammatory bowel disease (IBD). The disease condition and dietary habits both influence gut microbial diversity. Objective: The aim of this study was to assess the gut microbial profile of healthy subjects and patients with colon carcinoma and IBD. Healthy subjects included 'Indian vegetarians/lactovegetarians', who eat plant produce, milk and milk products, and 'Indian non-vegetarians', who eat plant produce, milk and milk products, certain meats and fish, and the eggs of certain birds and fish. 'Indian vegetarians' are different from 'vegans', who do not eat any foods derived wholly or partly from animals, including milk products. Design: Stool samples were collected from healthy Indian vegetarians/lactovegetarians and non-vegetarians, and colon cancer and IBD patients. Clonal libraries of 16S ribosomal DNA (rDNA) of bacteria were created from each sample. Clones were sequenced from one representative sample of each group. Approximately 500 white colonies were picked at random from each sample and 100 colonies were sequenced after amplified rDNA restriction analysis. Results: The dominant phylum from the healthy vegetarian was Firmicutes (34%), followed by Bacteroidetes (15%). The balance was reversed in the healthy non-vegetarian (Bacteroidetes 84%, Firmicutes 4%; ratio 21:1). The colon cancer and IBD patients had higher percentages of Bacteroidetes (55% in both) than Firmicutes (26% and 12%, respectively) but lower Bacteroidetes:Firmicutes ratios (3.8:1 and 2.4:1, respectively) than the healthy non-vegetarian. Bacterial phyla of Verrucomicrobiota and Actinobacteria were detected in 23% and 5% of IBD and colon patients, respectively. Conclusions: Ribosomal Database Project profiling of gut flora in this study population showed remarkable differences, with unique diversity attributed to different diets and disease conditions. PMID- 28588431 TI - Microbial trimethylamine-N-oxide as a disease marker: something fishy? AB - Production of trimethylamine-N-oxide (TMAO) via the gut microbiota has recently been proposed as an important pathophysiological mechanism linking ingestion of 'unhealthy foods', such as beef (containing carnitine) and eggs (containing choline), and the development of atherosclerosis. Hence, TMAO has gained attention as a novel biomarker for cardiovascular disease. However, fish and seafood contain considerable amounts of TMAO and are generally accepted as cardioprotective: a puzzling paradox that seems to have been neglected. We suspect that the TMAO story may be a red herring. PMID- 28588432 TI - Of Simple and Complex Genome Rearrangements, Chromothripsis, Chromoanasynthesis, and Chromosome Chaos. PMID- 28588435 TI - Variable Penetrance of the 15q11.2 BP1-BP2 Microduplication in a Family with Cognitive and Language Impairment. AB - The 15q11.2 BP1-BP2 region is found duplicated or deleted in people with cognitive, language, and behavioral impairment. We report on a family (a father and 3 male twin siblings) that presents with a duplication of the 15q11.2 BP1-BP2 region and a variable phenotype: the father and the fraternal twin are normal carriers, whereas the monozygotic twins exhibit severe language and cognitive delay as well as behavioral disturbances. The genes located within the duplicated region are involved in brain development and function, and some of them are related to language processing. The probands' phenotype may result from changes in the expression level of some of these genes important for cognitive development. PMID- 28588434 TI - Maternal Uniparental Disomy 14 (Temple Syndrome) as a Result of a Robertsonian Translocation. AB - Maternal uniparental disomy of chromosome 14 (upd(14)mat) or Temple syndrome is an imprinting disorder associated with a relatively mild phenotype. The absence of specific congenital malformations makes this condition underdiagnosed in clinical practice. A boy with a de novo robertsonian translocation 45,XY,rob(13;14)(q10;q10) is reported; a CGH/SNP array showed a loss of heterozygosity in 14q11.2q13.1. The final diagnosis of upd(14)mat was made by microsatellite analysis, which showed a combination of heterodisomy and isodisomy for different regions of chromosome 14. Obesity after initial failure to thrive developed, while compulsive eating habits were not present, which was helpful for the clinical differential diagnosis of Prader-Willi syndrome. In addition, the boy presented with many phenotypic features associated with upd(14)mat along with hypoesthesia to pain, previously unreported in this disorder, and bilateral cryptorchidism, also rarely described. These features, as well as other clinical manifestations (i.e., truncal obesity, altered pubertal timing), may suggest a hypothalamic-pituitary involvement. A detailed cytogenetic and molecular characterization of the genomic rearrangement is presented. Early genetic diagnosis permits a specific follow-up of children with upd(14)mat in order to optimize the long-term outcome. PMID- 28588433 TI - Intragenic CNTNAP2 Deletions: A Bridge Too Far? AB - Intragenic deletions of the contactin-associated protein-like 2 gene (CNTNAP2) have been found in patients with Gilles de la Tourette syndrome, intellectual disability (ID), obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, stuttering, and attention deficit hyperactivity disorder. A variety of molecular mechanisms, such as loss of transcription factor binding sites and perturbation of penetrance and expressivity, have been proposed to account for the phenotypic variability resulting from CNTNAP2 mutations. Deletions of both CNTNAP2 alleles produced truncated proteins lacking the transmembrane or some of the extracellular domains, or no protein at all. This observation can be extended to heterozygous intragenic deletions by assuming that such deletion-containing alleles lead to expression of a Caspr2 protein lacking one or several extracellular domains. Such altered forms of Capr2 proteins will lack the ability to bridge the intercellular space between neurons by binding to partners, such as CNTN1, CNTN2, DLG1, and DLG4. This presumed effect of intragenic deletions of CNTNAP2, and possibly other genes involved in connecting neuronal cells, represents a molecular basis for the postulated neuronal hypoconnectivity in autism and probably other neurodevelopmental disorders, including epilepsy, ID, language impairments and schizophrenia. Thus, CNTNAP2 may represent a paradigmatic case of a gene functioning as a node in a genetic and cellular network governing brain development and acquisition of higher cognitive functions. PMID- 28588436 TI - Novel Marfan Syndrome-Associated Mutation in the FBN1 Gene Caused by Parental Mosaicism and Leading to Abnormal Limb Patterning. AB - Marfan syndrome is an autosomal dominant disorder of the connective tissue caused by mutations in the fibrillin-1 (FBN1) gene. Mutations affecting cysteine residues within the epidermal growith factor-like calcium-binding domains (EGF_CA) of FBN1 are associated with Marfan syndrome features and, especially, with ectopia lentis. We report a novel substitution, affecting the first cysteine of an EGF_CA-binding module encoded by exon 63 of FBN1 (C2571Y), in a patient presenting with typical Marfan syndrome features but without ectopia lentis. The involvement of this particular carboxi-terminal domain in bone morphogenetic protein signaling is evidenced by patterning defects in the apendicular skeleton shown by the gain of a phalange at digit 1 and the fusion of some wrist bones. Although the mutation appeared as sporadic, detailed analysis revealed that the asymptomatic father was a gonosomal mosaic, and that aproximately 25% of his body cells carry the mutation. Based on this and previous evidence on the origin of sporadic mutations, we would like to stress the importance of detailed parental genetic screening, so the risk of recurrence may be evaluated. PMID- 28588437 TI - Molecular Characterization of Koolen De Vries Syndrome in Two Girls with Idiopathic Intellectual Disability from Central Brazil. AB - Koolen de Vries syndrome (KDVS; MIM 610443) is a genomic disorder caused by a recurrent microdeletion derived from nonallelic homologous recombination mediated by flanking segmental duplications. Clinical manifestations of this syndrome are characterized by intellectual disability, hypotonia, a friendly behavior, distinctive facial features, and epilepsy. Herein, we report a case of 2 girls who revealed global developmental delay, mild facial dysmorphisms, friendly behavior, and epileptic seizure with a de novo 17q21.31 microdeletion detected by chromosomal microarray analysis (CMA). Conventional cytogenetics analysis by GTG banding showed a female karyotype 46,XX for both girls. CMA revealed a microdeletion spanning approximately 500 kb in 17q21.31 in both girls, encompassing the following genes: CRHR1, MGC57346, CRHR1-IT1, MAPT-AS1, SPPL2C, MAPT, MAPT-IT1, STH, and KANSL1. Haploinsufficiency of one or more of these genes within the deleted region is the most probable cause of the probands' phenotype and is responsible for the phenotype seen in KDVS. CMA is a powerful diagnostic tool and an effective method to identify the de novo 17q21.31 microdeletion associated with KDVS in our probands. PMID- 28588438 TI - A New Case of the Rare 10q22.3q23.2 Microdeletion Flanked by Low-Copy Repeats 3/4. AB - Deletions in the 10q22.3q23.2 region are rare and mediated by 2 low-copy repeats (LCRs 3 and 4). These deletions have already been recognized as the 10q22q23 deletion syndrome. The phenotype associated with this condition is rather uncharacteristic, and most common features are craniofacial dysmorphisms and developmental delay. We describe a boy with craniofacial dysmorphic features, developmental delay, tetralogy of Fallot, hand/foot abnormalities, and recurrent respiratory tract infections. Chromosomal microarray analysis disclosed a 7.8-Mb microdeletion at 10q22.3q23.2, flanked by LCRs 3/4, and an additional 16q12.1 microdeletion of 189 kb. This article reviews the clinical signs of reported cases with similar deletions and compares them with our patient, contributing to a better understanding of genotype-phenotype correlation. PMID- 28588439 TI - DNA Methylation Changes in Intron 1 of Triggering Receptor Expressed on Myeloid Cell 2 in Japanese Schizophrenia Subjects. AB - A hypothesis for schizophrenia (SCZ) called the "microglia hypothesis" has been suggested. In SCZ, expression of triggering receptor expressed on myeloid cell 2 (TREM2) mRNA is higher in leukocytes than in healthy individuals. Here, the methylation rates of four CpG sites in TREM2 intron 1 that may bind important transcription factors and the correlation between the methylation rate and mRNA expression were determined. We compared the methylation rates in SCZ patients and age-matched controls (n = 50 each). SCZ patients had significantly lower methylation rates of CpG 2 (17.0 +/- 6.7 vs. 20.2 +/- 5.0; p = 0.02) and CpG 3 (23.8 +/- 8.2 vs. 28.1 +/- 6.2; p = 0.01). The average methylation rate (15.3 +/- 5.2 vs. 17.6 +/- 3.9; p = 0.009) was also lower. A significant negative correlation was found between TREM2 mRNA expression and the methylation rate of CpG 2 (r = -0.252, p = 0.012). SCZ susceptibility markers may include low methylation at TREM2 intron 1 and increased TREM2 mRNA levels. Our pilot study requires validation with higher numbers of participants and with other myeloid cell types. PMID- 28588440 TI - Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes. AB - Our team has been a pioneer in harvesting extracellular vesicles (EVs) enriched for neuronal origin from peripheral blood and using them as a biomarker discovery platform for neurological disorders. This methodology has demonstrated excellent diagnostic and predictive performance for Alzheimer's and other neurodegenerative diseases in multiple studies, providing a strong proof of concept for this approach. Here, we describe our methodology in detail and offer further evidence that isolated EVs are enriched for neuronal origin. In addition, we present evidence that EVs enriched for neuronal origin represent a more sensitive and accurate base for biomarkers than plasma, serum, or non-enriched total plasma EVs. Finally, we proceed to investigate the protein content of EVs enriched for neuronal origin and compare it with other relevant enriched and non-enriched populations of plasma EVs. Neuronal-origin enriched plasma EVs contain higher levels of signaling molecules of great interest for cellular metabolism, survival, and repair, which may be useful as biomarkers and to follow response to therapeutic interventions in a mechanism-specific manner. PMID- 28588441 TI - Tempering Proactive Cognitive Control by Transcranial Direct Current Stimulation of the Right (but Not the Left) Lateral Prefrontal Cortex. AB - Behavioral and neuroimaging data support the distinction of two different modes of cognitive control: proactive, which involves the active and sustained maintenance of task-relevant information to bias behavior in accordance with internal goals; and reactive, which entails the detection and resolution of interference at the time it occurs. Both control modes may be flexibly deployed depending on a variety of conditions (i.e., age, brain alterations, motivational factors, prior experience). Critically, and in line with specific predictions derived from the dual mechanisms of control account (Braver, 2012), findings from neuroimaging studies indicate that the same lateral prefrontal regions (i.e., left dorsolateral cortex and right inferior frontal junction) may implement different control modes on the basis of temporal dynamics of activity, which would be modulated in response to external or internal conditions. In the present study, we aimed to explore whether transcraneal direct current stimulation over either the left dorsolateral prefrontal cortex or the right inferior frontal junction would differentially modulate performance on the AX-CPT, a well validated task that provides sensitive and reliable behavioral indices of proactive/reactive control. The study comprised six conditions of real stimulation [3 (site: left dorsolateral, right dorsolateral and right inferior frontal junction) * 2 (polarity: anodal and cathodal)], and one sham condition. The reference electrode was always placed extracephalically. Performance on the AX-CPT was assessed through two blocks of trials. The first block took place while stimulation was being delivered, whereas the second block was administered after stimulation completion. The results indicate that both offline cathodal stimulation of the right dorsolateral prefrontal cortex and online anodal stimulation of the right inferior frontal junction led participants to be much less proactive, with such a dissociation suggesting that both prefrontal regions differentially contribute to the adjustment of cognitive control modes. tDCS of the left-DLPFC failed to modulate cognitive control. These results partially support the predictions derived from the dual mechanisms of control account. PMID- 28588443 TI - Differential GR Expression and Translocation in the Hippocampus Mediates Susceptibility vs. Resilience to Chronic Social Defeat Stress. AB - While social stress exposure is a common risk factor for affective disorders, most individuals exposed to it can maintain normal physical and psychological functioning. However, factors that determine susceptibility vs. resilience to social stress remain unclear. Here, the resident-intruder model of social defeat was used as a social stressor in male C57BL/6J mice to investigate the difference between susceptibility and resilience. As depression is often characterized by hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, we conducted the present study to further investigate the individual differences in the HPA axis response and glucocorticoid receptor (GR) protein expression and translocation between susceptible mice and resilient mice. We found that hypercortisolemia, induced by social defeat stress occurred in susceptible mice, but not in resilient mice. Moreover, susceptible mice exhibited significantly less GR protein expression and nuclear translocation in the hippocampus than resilient mice. Treatment with escitalopram could decrease the serum corticosterone (CORT), increase GR protein expression as well as nuclear translocation in the hippocampus and ultimately reverse social withdrawal behaviors in susceptible mice. These results indicate that the up-regulation of GR and the enhancement of GR nuclear translocation in the hippocampus play an important role in resilience to chronic social defeat stress. PMID- 28588442 TI - A Multifunctional Brain-Computer Interface Intended for Home Use: An Evaluation with Healthy Participants and Potential End Users with Dry and Gel-Based Electrodes. AB - Current brain-computer interface (BCIs) software is often tailored to the needs of scientists and technicians and therefore complex to allow for versatile use. To facilitate home use of BCIs a multifunctional P300 BCI with a graphical user interface intended for non-expert set-up and control was designed and implemented. The system includes applications for spelling, web access, entertainment, artistic expression and environmental control. In addition to new software, it also includes new hardware for the recording of electroencephalogram (EEG) signals. The EEG system consists of a small and wireless amplifier attached to a cap that can be equipped with gel-based or dry contact electrodes. The system was systematically evaluated with a healthy sample, and targeted end users of BCI technology, i.e., people with a varying degree of motor impairment tested the BCI in a series of individual case studies. Usability was assessed in terms of effectiveness, efficiency and satisfaction. Feedback of users was gathered with structured questionnaires. Two groups of healthy participants completed an experimental protocol with the gel-based and the dry contact electrodes (N = 10 each). The results demonstrated that all healthy participants gained control over the system and achieved satisfactory to high accuracies with both gel-based and dry electrodes (average error rates of 6 and 13%). Average satisfaction ratings were high, but certain aspects of the system such as the wearing comfort of the dry electrodes and design of the cap, and speed (in both groups) were criticized by some participants. Six potential end users tested the system during supervised sessions. The achieved accuracies varied greatly from no control to high control with accuracies comparable to that of healthy volunteers. Satisfaction ratings of the two end-users that gained control of the system were lower as compared to healthy participants. The advantages and disadvantages of the BCI and its applications are discussed and suggestions are presented for improvements to pave the way for user friendly BCIs intended to be used as assistive technology by persons with severe paralysis. PMID- 28588444 TI - A Brain Unfixed: Unlimited Neurogenesis and Regeneration of the Adult Planarian Nervous System. AB - Powerful genetic tools in classical laboratory models have been fundamental to our understanding of how stem cells give rise to complex neural tissues during embryonic development. In contrast, adult neurogenesis in our model systems, if present, is typically constrained to one or a few zones of the adult brain to produce a limited subset of neurons leading to the dogma that the brain is primarily fixed post-development. The freshwater planarian (flatworm) is an invertebrate model system that challenges this dogma. The planarian possesses a brain containing several thousand neurons with very high rates of cell turnover (homeostasis), which can also be fully regenerated de novo from injury in just 7 days. Both homeostasis and regeneration depend on the activity of a large population of adult stem cells, called neoblasts, throughout the planarian body. Thus, much effort has been put forth to understand how the flatworm can continually give rise to the diversity of cell types found in the adult brain. Here we focus on work using single-cell genomics and functional analyses to unravel the cellular hierarchies from stem cell to neuron. In addition, we will review what is known about how planarians utilize developmental signaling to maintain proper tissue patterning, homeostasis, and cell-type diversity in their brains. Together, planarians are a powerful emerging model system to study the dynamics of adult neurogenesis and regeneration. PMID- 28588445 TI - Lights from the Dark: Neural Responses from a Blind Visual Hemifield. AB - Here we present evidence that a hemianopic patient with a lesion of the left primary visual cortex (V1) showed an unconscious above-chance orientation discrimination with moving rather than static visual gratings presented to the blind hemifield. The patient did not report any perceptual experience of the stimulus features except for a feeling that something appeared in the blind hemifield. Interestingly, in the lesioned left hemisphere, following stimulus presentation to the blind hemifield, we found an event-related potential (ERP) N1 component at a post-stimulus onset latency of 180-260 ms and a source generator in the left BA 19. In contrast, we did not find evidence of the early visual components C1 and P1 and of the later component P300. A positive component (P2a) was recorded between 250 and 320 ms after stimulus onset frontally in both hemispheres. Finally, in the time range 320-440 ms there was a negative peak in right posterior electrodes that was present only for the moving condition. In sum, there were two noteworthy results: Behaviorally, we found evidence of above chance unconscious (blindsight) orientation discrimination with moving but not static stimuli. Physiologically, in contrast to previous studies, we found reliable ERP components elicited by stimuli presented to the blind hemifield at various electrode locations and latencies that are likely to index either the perceptual report of the patient (N1 and P2a) or, the above-chance unconscious performance with moving stimuli as is the case of the posterior ERP negative component. This late component can be considered as the neural correlate of a kind of blindsight enabling feature discrimination only when stimuli are moving and that is subserved by the intact right hemisphere through interhemispheric transfer. PMID- 28588446 TI - Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain containing 1 (ANKFY1), beta-arrestin 2 (ARRB2) and kinesin family member 1C (KIF1C), was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+) mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs) in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease. PMID- 28588447 TI - The Effects of Epidermal Neural Crest Stem Cells on Local Inflammation Microenvironment in the Defected Sciatic Nerve of Rats. AB - Cell-based therapy is a promising strategy for the repair of peripheral nerve injuries (PNIs). epidermal neural crest stems cells (EPI-NCSCs) are thought to be important donor cells for repairing PNI in different animal models. Following PNI, inflammatory response is important to regulate the repair process. However, the effects of EPI-NCSCs on regulation of local inflammation microenviroment have not been investigated extensively. In the present study, these effects were studied by using 10 mm defected sciatic nerve, which was bridged with 15 mm artificial nerve composed of EPI-NCSCs, extracellular matrix (ECM) and poly (lactide-co-glycolide) (PLGA). Then the expression of pro- and anti-inflammatory cytokines, polarization of macrophages, regulation of fibroblasts and shwann cells (SCs) were assessed by western blot, immunohistochemistry, immunofluorescence staining at 1, 3, 7 and 21 days after bridging. The structure and the function of the bridged nerve were determined by observation under light microscope and by examination of right lateral foot retraction time (LFRT), sciatic function index (SFI), gastrocnemius wet weight and electrophysiology at 9 weeks. After bridging with EPI-NCSCs, the expression of anti-inflammatory cytokines (IL-4 and IL-13) was increased, but decreased for pro-inflammatory cytokines (IL-6 and TNF-alpha) compared to the control bridging, which was consistent with increase of M2 macrophages and decrease of M1 macrophages at 7 days after transplantation. Likewise, myelin-formed SCs were significantly increased, but decreased for the activated fibroblasts in their number at 21 days. The recovery of structure and function of nerve bridged with EPI-NCSCs was significantly superior to that of DMEM. These results indicated that EPI-NCSCs could be able to regulate and provide more suitable inflammation microenvironment for the repair of defected sciatic nerve. PMID- 28588448 TI - Structural Changes of Amyloid Beta in Hippocampus of Rats Exposed to Ozone: A Raman Spectroscopy Study. AB - The aim of this work was to study the effect of oxidative stress on the structural changes of the secondary peptide structure of amyloid beta 1-42 (Abeta 1-42), in the dentate gyrus of hippocampus of rats exposed to low doses of ozone. The animals were exposed to ozone-free air (control group) and 0.25 ppm ozone during 7, 15, 30, 60, and 90 days, respectively. The samples were studied by: (1) Raman spectroscopy to detect the global conformational changes in peptides with alpha-helix and beta-sheet secondary structure, following the deconvolution profile of the amide I band; and (2) immunohistochemistry against Abeta 1-42. The results of the deconvolutions of the amide I band indicate that, ozone exposure causes a progressively decrease in the abundance percentage of alpha-helix secondary structure. Furthermore, the beta-sheet secondary structure increases its abundance percentage. After 60 days of ozone exposure, the beta-sheet band is identified in a similar wavenumber of the Abeta 1-42 peptide standard. Immunohistochemistry assays show an increase of Abeta 1-42 immunoreactivity, coinciding with the conformational changes observed in the Raman spectroscopy of Abeta 1-42 at 60 and 90 days. In conclusion, oxidative stress produces changes in the folding process of amyloid beta peptide structure in the dentate gyrus, leading to its conformational change in a final beta-sheet structure. This is associated to an increase in Abeta 1-42 expression, similar to the one that happens in the brain of Alzheimer's Disease (AD) patients. PMID- 28588449 TI - Long-Term Assessment of AAV-Mediated Zinc Finger Nuclease Expression in the Mouse Brain. AB - Gene editing tools like TALENs, ZFNs and Crispr/Cas now offer unprecedented opportunities for targeted genetic manipulations in virtually all species. Most of the recent research in this area has concentrated on manipulation of the genome in isolated cells, which then give rise to transgenic animals or modified stem cell lines. Much less is known about applicability of genetic scissors in terminally differentiated, non-dividing cells like neurons of the adult brain. We addressed this question by expression of a pair of ZFNs targeting the murine cathepsin D gene in CNS neurons by means of an optimized AAV viral vector. We show that ZFN expression resulted in substantial depletion of cathepsin D from neuronal lysosomes, demonstrating a robust gene deletion. Importantly, long-term ZFN expression in CNS neurons did not impair essential neuronal functionality and did not cause inflammation or neurodegeneration, suggesting that potent genetic scissors can be expressed safely in the mouse brain. This finding opens up new venues to create novel research models for neurodegenerative disorders. PMID- 28588451 TI - Neurogenic to Gliogenic Fate Transition Perturbed by Loss of HMGB2. AB - Mouse cortical development relies heavily on a delicate balance between neurogenesis and gliogenesis. The lateral ventricular zone produces different classes of excitatory pyramidal cells until just before birth, when the production of astroglia begins to prevail. Epigenetic control of this fate shift is of critical importance and chromatin regulatory elements driving neuronal or astroglial development play an vital role. Different classes of chromatin binding proteins orchestrate the transcriptional repression of neuronal-specific genes, while allowing for the activation of astrocyte-specific genes. Through proteomic analysis of embryonic neural progenitor cells (NPCs) our group had previously identified high mobility group B2 (HMGB2), a chromatin protein dynamically expressed throughout embryonic development. In the current study using cultures of perinatal NPCs from HMGB2+/+ and HMGB2-/- mice we discovered that vital elements of the polycomb group (PcG) epigenetic complexes polycomb repressive complexes 1 and 2 (PRC1/2) were downregulated during the differentiation process of HMGB2-null NPCs. These epigenetic changes led to downstream changes in specific histone modification levels, specifically the trimethylation of H3K27, and a subsequent shift in the perinatal neurogenesis to gliogenesis fate transition. Collectively these results demonstrate that chromatin binding proteins, such as HMGB2, can have significant effects on the epigenetic landscape of perinatal neural stem/progenitor cells. PMID- 28588450 TI - Puzzling Out Synaptic Vesicle 2 Family Members Functions. AB - Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or neurotransmitters transport or priming of SVs. Moreover, several recent studies highlighted the link between SV2 and different neuronal disorders such as epilepsy, Schizophrenia (SCZ), Alzheimer's or Parkinson's disease. In this review article, we will summarize our present knowledge on SV2A function(s) and its potential role(s) in the pathophysiology of various brain disorders. PMID- 28588452 TI - Structure-Function Analysis of the GlyR alpha2 Subunit Autism Mutation p.R323L Reveals a Gain-of-Function. AB - Glycine receptors (GlyRs) containing the alpha2 subunit regulate cortical interneuron migration. Disruption of the GlyR alpha2 subunit gene (Glra2) in mice leads to disrupted dorsal cortical progenitor homeostasis, leading to a depletion of projection neurons and moderate microcephaly in newborn mice. In humans, rare variants in GLRA2, which is located on the X chromosome, are associated with autism spectrum disorder (ASD) in the hemizygous state in males. These include a microdeletion (GLRA2?ex8-9) and missense mutations in GLRA2 (p.N109S and p.R126Q) that impair cell-surface expression of GlyR alpha2, and either abolish or markedly reduce sensitivity to glycine. We report the functional characterization of a third missense variant in GLRA2 (p.R323L), associated with autism, macrocephaly, epilepsy and hypothyroidism in a female proband. Using heterosynapse and macroscopic current recording techniques, we reveal that GlyR alpha2R323L exhibits reduced glycine sensitivity, but significantly increased inhibitory postsynaptic current (IPSC) rise and decay times. Site-directed mutagenesis revealed that the nature of the amino acid switch at position 323 is critical for impairment of GlyR function. Single-channel recordings revealed that the conductance of alpha2R323Lbeta channels was higher than alpha2beta channels. Longer mean opening durations induced by p.R323L may be due to a change in the gating pathway that enhances the stability of the GlyR open state. The slower synaptic decay times, longer duration active periods and increase in conductance demonstrates that the GlyR alpha2 p.R323L mutation results in an overall gain of function, and that GlyR alpha2 mutations can be pathogenic in the heterozygous state in females. PMID- 28588453 TI - Refining the Role of 5-HT in Postnatal Development of Brain Circuits. AB - Changing serotonin (5-hydroxytryptamine, 5-HT) brain levels during critical periods in development has long-lasting effects on brain function, particularly on later anxiety/depression-related behaviors in adulthood. A large part of the known developmental effects of 5-HT occur during critical periods of postnatal life, when activity-dependent mechanisms remodel neural circuits. This was first demonstrated for the maturation of sensory brain maps in the barrel cortex and the visual system. More recently this has been extended to the 5-HT raphe circuits themselves and to limbic circuits. Recent studies overviewed here used new genetic models in mice and rats and combined physiological and structural approaches to provide new insights on the cellular and molecular mechanisms controlled by 5-HT during late stages of neural circuit maturation in the raphe projections, the somatosensory cortex and the visual system. Similar mechanisms appear to be also involved in the maturation of limbic circuits such as prefrontal circuits. The latter are of particular relevance to understand the impact of transient 5-HT dysfunction during postnatal life on psychiatric illnesses and emotional disorders in adult life. PMID- 28588454 TI - Reelin Signaling Inactivates Cofilin to Stabilize the Cytoskeleton of Migrating Cortical Neurons. AB - Neurons are highly polarized cells. They give rise to several dendrites but only one axon. In addition, many neurons show a preferred orientation. For example, pyramidal neurons of the cerebral cortex extend their apical dendrites toward the cortical surface while their axons run in opposite direction toward the white matter. This characteristic orientation reflects the migratory trajectory of a pyramidal cell during cortical development: the leading process (the future apical dendrite) extends toward the marginal zone (MZ) and the trailing process (the future axon) toward the intermediate zone (IZ) while the cells migrate radially to reach their destination in the cortical plate (CP). In this review article, we summarize the function of Reelin, an extracellular matrix protein synthesized by Cajal-Retzius cells in the MZ, in the development of the characteristic orientation of the leading processes running perpendicular to the cortical surface. Reelin promotes migration toward the cortical surface since late-generated cortical neurons in the reeler mutant are unable to reach upper cortical layers. Likewise, Reelin is important for the orientation and maintenance of the leading processes of migrating neurons since they are misoriented in the developing reeler cortex, as are the apical dendrites of pyramidal cells in the mature mutant. Reelin-induced phosphorylation of cofilin, an actin-associated protein, is crucial since pyramidal neurons transfected by in utero electroporation (IUE) with a non-phosphorylatable form of cofilin (cofilinS3A) show severe migration defects reminiscent of those in the reeler mutant. Remarkably, migration of neurons in the cortex of reeler mice was partially rescued by transfecting them with LIM kinase 1 (LIMK1), the kinase that induces phosphorylation of cofilin at serine3, or with a pseudo-phosphorylated cofilin mutant (cofilinS3E). Together these results indicate that Reelin-induced phosphorylation of cofilin is an important component in the orientation and directed migration of cortical neurons and in their correct lamination. PMID- 28588455 TI - Circuits Regulating Pleasure and Happiness in Bipolar Disorder. AB - According to our model, the motivation for appetitive-searching vs. distress avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side to the centromedial amygdala on the other side, control the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). From an evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities. PMID- 28588457 TI - Sensitivity to an Illusion of Sound Location in Human Auditory Cortex. AB - Human listeners place greater weight on the beginning of a sound compared to the middle or end when determining sound location, creating an auditory illusion known as the Franssen effect. Here, we exploited that effect to test whether human auditory cortex (AC) represents the physical vs. perceived spatial features of a sound. We used functional magnetic resonance imaging (fMRI) to measure AC responses to sounds that varied in perceived location due to interaural level differences (ILD) applied to sound onsets or to the full sound duration. Analysis of hemodynamic responses in AC revealed sensitivity to ILD in both full-cue (veridical) and onset-only (illusory) lateralized stimuli. Classification analysis revealed regional differences in the sensitivity to onset-only ILDs, where better classification was observed in posterior compared to primary AC. That is, restricting the ILD to sound onset-which alters the physical but not the perceptual nature of the spatial cue-did not eliminate cortical sensitivity to that cue. These results suggest that perceptual representations of auditory space emerge or are refined in higher-order AC regions, supporting the stable perception of auditory space in noisy or reverberant environments and forming the basis of illusions such as the Franssen effect. PMID- 28588456 TI - Activity Dependent Modulation of Granule Cell Survival in the Accessory Olfactory Bulb at Puberty. AB - The vomeronasal system (VNS) is specialized in the detection of salient chemical cues triggering social and neuroendocrine responses. Such responses are not always stereotyped, instead, they vary depending on age, sex, and reproductive state, yet the mechanisms underlying this variability are unclear. Here, by analyzing neuronal survival in the first processing nucleus of the VNS, namely the accessory olfactory bulb (AOB), through multiple bromodeoxyuridine birthdating protocols, we show that exposure of female mice to male soiled bedding material affects the integration of newborn granule interneurons mainly after puberty. This effect is induced by urine compounds produced by mature males, as bedding soiled by younger males was ineffective. The granule cell increase induced by mature male odor exposure is not prevented by pre-pubertal ovariectomy, indicating a lesser role of circulating estrogens in this plasticity. Interestingly, the intake of adult male urine-derived cues by the female vomeronasal organ increases during puberty, suggesting a direct correlation between sensory activity and AOB neuronal plasticity. Thus, as odor exposure increases the responses of newly born cells to the experienced stimuli, the addition of new GABAergic inhibitory cells to the AOB might contribute to the shaping of vomeronasal processing of male cues after puberty. Consistently, only after puberty, female mice are capable to discriminate individual male odors through the VNS. PMID- 28588458 TI - Modes of Effective Connectivity within Cortical Pathways Are Distinguished for Different Categories of Visual Context: An fMRI Study. AB - Context contributes to accurate and efficient information processing. To reveal the dynamics of the neural mechanisms that underlie the processing of visual contexts during the recognition of color, shape, and 3D structure of objects, we carried out functional magnetic resonance imaging (fMRI) of subjects while judging the contextual validity of the three visual contexts. Our results demonstrated that the modes of effective connectivity in the cortical pathways, as well as the patterns of activation in these pathways, were dynamical depending on the nature of the visual contexts. While the fusiform gyrus, superior parietal lobe, and inferior prefrontal gyrus were activated by the three visual contexts, the temporal and parahippocampal gyrus/Amygdala (PHG/Amg) cortices were activated only by the color context. We further carried out dynamic causal modeling (DCM) analysis and revealed the nature of the effective connectivity involved in the three contextual information processing. DCM showed that there were dynamic connections and collaborations among the brain regions belonging to the previously identified ventral and dorsal visual pathways. PMID- 28588459 TI - The Different Inhibition of Return (IOR) Effects of Emergency Managerial Experts and Novices: An Event-Related Potentials Study. AB - Inhibition of return (IOR) is an important effect of attention. However, the IOR of emergency managerial experts is unknown. By employing emergency and natural scene pictures in expert-novice paradigm, the present study explored the neural activity underlying the IOR effects for emergency managerial experts and novices. In behavioral results, there were no differences of IOR effects between novices and emergency managerial experts, while the event-related potentials (ERPs) results were different between novices and experts. In Experiment 1 (novice group), ERPs results showed no any IOR was robust at both stimulus-onset asynchrony (SOA) of 200 ms and 400 ms. In Experiment 2 (expert group), ERPs results showed an enhanced N2 at SOA of 200 ms and attenuated P3 at cued location in the right parietal lobe and adjacent brain regions than uncued location at SOA of 200 ms. The findings of the two experiments showed that, relative to the novices, IOR for the emergency managerial experts was robust, and dominated in the right parietal lobe and adjacent brain regions, suggesting more flexible attentional processing and higher visual search efficiency of the emergency managerial experts. The findings indicate that the P3, possible N2, over the right parietal lobe and adjacent brain regions are the biological indicators for IOR elicited by post-cued emergency pictures for emergency managerial experts. PMID- 28588460 TI - Aversive Learning of Colored Lights in Walking Honeybees. AB - The honeybee has been established as an important model organism in studies on visual learning. So far the emphasis has been on appetitive conditioning, simulating floral discrimination, and homing behavior, where bees perform exceptionally well in visual discrimination tasks. However, bees in the wild also face dangers, and recent findings suggest that what is learned about visual percepts is highly context dependent. A stimulus that follows an unpleasant period, is associated with the feeling of relief- or safety in humans and animals, thus acquiring a positive meaning. Whether this is also the case in honeybees is still an open question. Here, we conditioned bees aversively in a walking arena where each half was illuminated by light of a specific wavelength and intensity, one of which was combined with electric shocks. In this paradigm, the bees' preferences to the different lights were modified through nine conditioning trials, forming robust escape, and avoidance behaviors. Strikingly, we found that while 465 nm (human blue) and 590 nm (human yellow) lights both could acquire negative valences (inducing avoidance response), 525 nm (human green) light could not. This indicates that green light holds an innate meaning of safety which is difficult to overrule even through intensive aversive conditioning. The bees had slight initial preferences to green over the blue and the yellow lights, which could be compensated by adjusting light intensity. However, this initial bias played a minor role while the chromatic properties were the most salient characteristics of the light stimuli during aversive conditioning. Moreover, bees could learn the light signaling safety, revealing the existence of a relief component in aversive operant conditioning, similar to what has been observed in other animals. PMID- 28588461 TI - Modulation of Ethanol-Metabolizing Enzymes by Developmental Lead Exposure: Effects in Voluntary Ethanol Consumption. AB - This review article provides evidence of the impact of the environmental contaminant lead (Pb) on the pattern of the motivational effects of ethanol (EtOH). To find a mechanism that explains this interaction, the focus of this review article is on central EtOH metabolism and the participating enzymes, as key factors in the modulation of brain acetaldehyde (ACD) accumulation and resulting effect on EtOH intake. Catalase (CAT) seems a good candidate for the shared mechanism between Pb and EtOH due to both its antioxidant and its brain EtOH-metabolizing properties. CAT overactivation was reported to increase EtOH consumption, while CAT blockade reduced it, and both scenarios were modified by Pb exposure, probably as the result of elevated brain and blood CAT activity. Likewise, the motivational effects of EtOH were enhanced when brain ACD metabolism was prevented by ALDH2 inhibition, even in the Pb animals that evidenced reduced brain ALDH2 activity after chronic EtOH intake. Overall, these results suggest that brain EtOH metabolizing enzymes are modulated by Pb exposure with resultant central ACD accumulation and a prevalence of the reinforcing effects of the metabolite in brain against the aversive peripheral ACD accumulation. They also support the idea that early exposure to an environmental contaminant, even at low doses, predisposes at a later age to differential reactivity to challenging events, increasing, in this case, vulnerability to acquiring addictive behaviors, including excessive EtOH intake. PMID- 28588462 TI - Atypical Modulations of N170 Component during Emotional Processing and Their Links to Social Behaviors in Ex-combatants. AB - Emotional processing (EP) is crucial for the elaboration and implementation of adaptive social strategies. EP is also necessary for the expression of social cognition and behavior (SCB) patterns. It is well-known that war contexts induce socio-emotional atypical functioning, in particular for those who participate in combats. Thus, ex-combatants represent an ideal non-clinical population to explore EP modulation and to evaluate its relation with SCB. The aim of this study was to explore EP and its relation with SCB dimensions such as empathy, theory of mind and social skills in a sample of 50 subjects, of which 30 were ex combatants from illegally armed groups in Colombia, and 20 controls without combat experience. We adapted an Emotional Recognition Task for faces and words and synchronized it with electroencephalographic recording. Ex-combatants presented with higher assertion skills and showed more pronounced brain responses to faces than Controls. They did not show the bias toward anger observed in control participants whereby the latter group was more likely to misclassify neutral faces as angry. However, ex-combatants showed an atypical word valence processing. That is, words with different emotions yielded no differences in N170 modulations. SCB variables were successfully predicted by neurocognitive variables. Our results suggest that in ex-combatants the links between EP and SCB functions are reorganized. This may reflect neurocognitive modulations associated to chronic exposure to war experiences. PMID- 28588463 TI - Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution. AB - There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as "drug-induced ego dissolution (DIED)", for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the "minimal" or "embodied" self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On the other hand, it suggests that ordinary conscious experience might involve a minimal kind of self-awareness rooted in multisensory processing, which is what appears to fade away during DIED. PMID- 28588465 TI - Electrophysiological Correlates of Subliminal Perception of Facial Expressions in Individuals with Autistic Traits: A Backward Masking Study. AB - People with Autism spectrum disorder (ASD) show difficulty in social communication, especially in the rapid assessment of emotion in faces. This study examined the processing of emotional faces in typically developing adults with high and low levels of autistic traits (measured using the Autism Spectrum Quotient-AQ). Event-related potentials (ERPs) were recorded during viewing of backward-masked neutral, fearful and happy faces presented under two conditions: subliminal (16 ms, below the level of visual conscious awareness) and supraliminal (166 ms, above the time required for visual conscious awareness). Individuals with low and high AQ differed in the processing of subliminal faces, with the low AQ group showing an enhanced N2 amplitude for subliminal happy faces. Some group differences were found in the condition effects, with the Low AQ showing shorter frontal P3b and N4 latencies for subliminal vs. supraliminal condition. Although results did not show any group differences on the face specific N170 component, there were shorter N170 latencies for supraliminal vs. subliminal conditions across groups. The results observed on the N2, showing group differences in subliminal emotion processing, suggest that decreased sensitivity to the reward value of social stimuli is a common feature both of people with ASD as well as people with high autistic traits from the normal population. PMID- 28588464 TI - Neural Basis of Video Gaming: A Systematic Review. AB - Background: Video gaming is an increasingly popular activity in contemporary society, especially among young people, and video games are increasing in popularity not only as a research tool but also as a field of study. Many studies have focused on the neural and behavioral effects of video games, providing a great deal of video game derived brain correlates in recent decades. There is a great amount of information, obtained through a myriad of methods, providing neural correlates of video games. Objectives: We aim to understand the relationship between the use of video games and their neural correlates, taking into account the whole variety of cognitive factors that they encompass. Methods: A systematic review was conducted using standardized search operators that included the presence of video games and neuro-imaging techniques or references to structural or functional brain changes. Separate categories were made for studies featuring Internet Gaming Disorder and studies focused on the violent content of video games. Results: A total of 116 articles were considered for the final selection. One hundred provided functional data and 22 measured structural brain changes. One-third of the studies covered video game addiction, and 14% focused on video game related violence. Conclusions: Despite the innate heterogeneity of the field of study, it has been possible to establish a series of links between the neural and cognitive aspects, particularly regarding attention, cognitive control, visuospatial skills, cognitive workload, and reward processing. However, many aspects could be improved. The lack of standardization in the different aspects of video game related research, such as the participants' characteristics, the features of each video game genre and the diverse study goals could contribute to discrepancies in many related studies. PMID- 28588466 TI - Attentional Bias for Uncertain Cues of Shock in Human Fear Conditioning: Evidence for Attentional Learning Theory. AB - We conducted a human fear conditioning experiment in which three different color cues were followed by an aversive electric shock on 0, 50, and 100% of the trials, and thus induced low (L), partial (P), and high (H) shock expectancy, respectively. The cues differed with respect to the strength of their shock association (L < P < H) and the uncertainty of their prediction (L < P > H). During conditioning we measured pupil dilation and ocular fixations to index differences in the attentional processing of the cues. After conditioning, the shock-associated colors were introduced as irrelevant distracters during visual search for a shape target while shocks were no longer administered and we analyzed the cues' potential to capture and hold overt attention automatically. Our findings suggest that fear conditioning creates an automatic attention bias for the conditioned cues that depends on their correlation with the aversive outcome. This bias was exclusively linked to the strength of the cues' shock association for the early attentional processing of cues in the visual periphery, but additionally was influenced by the uncertainty of the shock prediction after participants fixated on the cues. These findings are in accord with attentional learning theories that formalize how associative learning shapes automatic attention. PMID- 28588468 TI - Editorial: The Role of Primary Motor Cortex as a Marker and Modulator of Pain Control and Emotional-Affective Processing. PMID- 28588467 TI - Literature Review on the Effects of tDCS Coupled with Robotic Therapy in Post Stroke Upper Limb Rehabilitation. AB - Today neurological diseases such as stroke represent one of the leading cause of long-term disability. Many research efforts have been focused on designing new and effective rehabilitation strategies. In particular, robotic treatment for upper limb stroke rehabilitation has received significant attention due to its ability to provide high-intensity and repetitive movement therapy with less effort than traditional methods. In addition, the development of non-invasive brain stimulation techniques such as transcranial Direct Current Stimulation (tDCS) has also demonstrated the capability of modulating brain excitability thus increasing motor performance. The combination of these two methods is expected to enhance functional and motor recovery after stroke; to this purpose, the current trends in this research field are presented and discussed through an in-depth analysis of the state-of-the-art. The heterogeneity and the restricted number of collected studies make difficult to perform a systematic review. However, the literature analysis of the published data seems to demonstrate that the association of tDCS with robotic training has the same clinical gain derived from robotic therapy alone. Future studies should investigate combined approach tailored to the individual patient's characteristics, critically evaluating the brain areas to be targeted and the induced functional changes. PMID- 28588470 TI - Examining Brain Morphometry Associated with Self-Esteem in Young Adults Using Multilevel-ROI-Features-Based Classification Method. AB - Purpose: This study is to exam self-esteem related brain morphometry on brain magnetic resonance (MR) images using multilevel-features-based classification method. Method: The multilevel region of interest (ROI) features consist of two types of features: (i) ROI features, which include gray matter volume, white matter volume, cerebrospinal fluid volume, cortical thickness, and cortical surface area, and (ii) similarity features, which are based on similarity calculation of cortical thickness between ROIs. For each feature type, a hybrid feature selection method, comprising of filter-based and wrapper-based algorithms, is used to select the most discriminating features. ROI features and similarity features are integrated by using multi-kernel support vector machines (SVMs) with appropriate weighting factor. Results: The classification performance is improved by using multilevel ROI features with an accuracy of 96.66%, a specificity of 96.62%, and a sensitivity of 95.67%. The most discriminating ROI features that are related to self-esteem spread over occipital lobe, frontal lobe, parietal lobe, limbic lobe, temporal lobe, and central region, mainly involving white matter and cortical thickness. The most discriminating similarity features are distributed in both the right and left hemisphere, including frontal lobe, occipital lobe, limbic lobe, parietal lobe, and central region, which conveys information of structural connections between different brain regions. Conclusion: By using ROI features and similarity features to exam self-esteem related brain morphometry, this paper provides a pilot evidence that self-esteem is linked to specific ROIs and structural connections between different brain regions. PMID- 28588469 TI - Oxytocin Increases the Perceived Value of Both Self- and Other-Owned Items and Alters Medial Prefrontal Cortex Activity in an Endowment Task. AB - The neuropeptide oxytocin (OXT) can influence self-processing and may help motivate us to value the attributes of others in a more self-like manner by reducing medial prefrontal cortex (mPFC) responses. We do not know however whether this OXT effect extends to possessions. We tend to place a higher monetary value on specific objects that belong to us compared to others, known as the "endowment effect". In two double-blind, between-subject placebo (PLC) controlled experiments in subjects from a collectivist culture, we investigated the influence of intranasal OXT on the endowment effect, with the second study incorporating functional magnetic resonance imaging (fMRI). In the task, subjects decided whether to buy or sell their own or others' (mother/father/classmate/stranger) possessions at various prices. Both experiments demonstrated an endowment effect in the self-owned condition which extended to close others (mother/father) and OXT increased this for self and all other-owned items. This OXT effect was associated with reduced activity in the ventral mPFC (vmPFC) in the self-owned condition but increased in the mother condition. For the classmate- and stranger-owned conditions OXT increased activity in the dorsal mPFC (dmPFC). Changes in vmPFC activation were associated with the size of the endowment effect for self- and mother-owned items. Functional connectivity between the dmPFC and ventral striatum (VStr) was reduced by OXT in self- and mother-owned conditions and between vmPFC and precuneus in the self-condition. Overall our results show that OXT enhances the endowment effect for both self- and other-owned items in Chinese subjects. This effect is associated with reduced mPFC activation in the self-condition but enhanced activation in all other-conditions and involves differential actions on both dorsal and ventral regions as well as functional connectivity with brain reward and other self-processing regions. Overall our findings suggest that OXT increases the perceived value of both self- and other-owned items by acting on neural circuitry involved in self-processing and reward. PMID- 28588472 TI - Key Insights into Hand Biomechanics: Human Grip Stiffness Can Be Decoupled from Force by Cocontraction and Predicted from Electromyography. AB - We investigate the relation between grip force and grip stiffness for the human hand with and without voluntary cocontraction. Apart from gaining biomechanical insight, this issue is particularly relevant for variable-stiffness robotic systems, which can independently control the two parameters, but for which no clear methods exist to design or efficiently exploit them. Subjects were asked in one task to produce different levels of force, and stiffness was measured. As expected, this task reveals a linear coupling between force and stiffness. In a second task, subjects were then asked to additionally decouple stiffness from force at these force levels by using cocontraction. We measured the electromyogram from relevant groups of muscles and analyzed the possibility to predict stiffness and force. Optical tracking was used for avoiding wrist movements. We found that subjects were able to decouple grip stiffness from force when using cocontraction on average by about 20% of the maximum measured stiffness over all force levels, while this ability increased with the applied force. This result contradicts the force-stiffness behavior of most variable stiffness actuators. Moreover, we found the thumb to be on average twice as stiff as the index finger and discovered that intrinsic hand muscles predominate our prediction of stiffness, but not of force. EMG activity and grip force allowed to explain 72 +/- 12% of the measured variance in stiffness by simple linear regression, while only 33 +/- 18% variance in force. Conclusively the high signal to-noise ratio and the high correlation to stiffness of these muscles allow for a robust and reliable regression of stiffness, which can be used to continuously teleoperate compliance of modern robotic hands. PMID- 28588471 TI - Functional Network Connectivity Patterns between Idiopathic Generalized Epilepsy with Myoclonic and Absence Seizures. AB - The extensive cerebral cortex and subcortical structures are considered as the major regions related to the generalized epileptiform discharges in idiopathic generalized epilepsy. However, various clinical syndromes and electroencephalogram (EEG) signs exist across generalized seizures, such as the loss of consciousness during absence seizures (AS) and the jerk of limbs during myoclonic seizures (MS). It is presumed that various functional systems affected by discharges lead to the difference in syndromes of these seizures. Twenty epileptic patients with MS, 21 patients with AS, and 21 healthy controls were recruited in this study. The functional network connectivity was analyzed based on the resting-state functional magnetic resonance imaging scans. The statistical analysis was performed in three groups to assess the difference in the functional brain networks in two types of generalized seizures. Twelve resting-state networks were identified in three groups. Both patient groups showed common abnormalities, including decreased functional connectivity in salience network (SN), cerebellum network, and primary perceptional networks and decreased connection between SN and visual network, compared with healthy controls. Interestingly, the frontal part of high-level cognitive resting-state networks showed increased functional connectivity (FC) in patients with MS, but decreased FC in patients with AS. Moreover, patients with MS showed decreased negative connections between high-level cognitive networks and primary system. The common alteration in both patient groups, including SN, might reflect a similar mechanism associated with the loss of consciousness during generalized seizures. This study provided the evidence of brain network in generalized epilepsy to understand the difference between MS and AS. PMID- 28588473 TI - A Human-Robot Interaction Perspective on Assistive and Rehabilitation Robotics. AB - Assistive and rehabilitation devices are a promising and challenging field of recent robotics research. Motivated by societal needs such as aging populations, such devices can support motor functionality and subject training. The design, control, sensing, and assessment of the devices become more sophisticated due to a human in the loop. This paper gives a human-robot interaction perspective on current issues and opportunities in the field. On the topic of control and machine learning, approaches that support but do not distract subjects are reviewed. Options to provide sensory user feedback that are currently missing from robotic devices are outlined. Parallels between device acceptance and affective computing are made. Furthermore, requirements for functional assessment protocols that relate to real-world tasks are discussed. In all topic areas, the design of human-oriented frameworks and methods is dominated by challenges related to the close interaction between the human and robotic device. This paper discusses the aforementioned aspects in order to open up new perspectives for future robotic solutions. PMID- 28588475 TI - Distinct Role of Striatal Functional Connectivity and Dopaminergic Loss in Parkinson's Symptoms. AB - Degeneration of dopaminergic neurons is a hallmark of Parkinson's disease. However, its link to Parkinson's disease symptoms remains unclear. Striatal resting state functional connectivity differentiates between Parkinson's disease patients and healthy controls and might be a potential mediator of the effects of striatal dopaminergic degeneration onto Parkinson's disease symptoms. Here, we evaluated the relationship between dopaminergic deficits, striatal functional connectivity (SFC) at rest and different Parkinson's disease clinical symptoms in the largest currently established cohort of de novo Parkinson's disease patients. We show that SFC is an independent predictor of symptom severity in Parkinson's disease in addition to striatal dopaminergic deficits. Furthermore, we find that distinct SFC networks are associated with symptoms reflecting the ability to perform daily routine automatized motor tasks and clinician-rated Parkinson's disease motor symptoms. We find that reduced SFC is a major and independent predictor of Parkinson's disease symptoms going beyond the mere reflection of striatal dopaminergic input loss. These findings indicate the high value of SFC as a clinically relevant biomarker in Parkinson's disease. PMID- 28588474 TI - A Life-Long Approach to Physical Activity for Brain Health. AB - It is well established that engaging in lifelong Physical activity (PA) can help delay the onset of many chronic lifestyle related and non-communicable diseases such as cardiovascular disease, type two diabetes, cancer and chronic respiratory diseases. Additionally, growing evidence also documents the importance of PA for brain health, with numerous studies indicating regular engagement in physical activities may be protective against cognitive decline and dementia in late life. Indeed, the link between PA and brain health may be different at each stage of life from childhood, mid-life and late life. Building on this emerging body of multidisciplinary research, this review aims to summarize the current body of evidence linking regular PA and brain health across the lifespan. Specifically, we will focus on the relationship between PA and brain health at three distinct stages of life: childhood and adolescence, mid-life, late life in cognitively healthy adults and later life in adults living with age-related neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). PMID- 28588476 TI - Age-Related Differences in Dynamic Interactions Among Default Mode, Frontoparietal Control, and Dorsal Attention Networks during Resting-State and Interference Resolution. AB - Resting-state fMRI (rs-fMRI) can identify large-scale brain networks, including the default mode (DMN), frontoparietal control (FPN) and dorsal attention (DAN) networks. Interactions among these networks are critical for supporting complex cognitive functions, yet the way in which they are modulated across states is not well understood. Moreover, it remains unclear whether these interactions are similarly affected in aging regardless of cognitive state. In this study, we investigated age-related differences in functional interactions among the DMN, FPN and DAN during rest and the Multi-Source Interference task (MSIT). Networks were identified using independent component analysis (ICA), and functional connectivity was measured during rest and task. We found that the FPN was more coupled with the DMN during rest and with the DAN during the MSIT. The degree of FPN-DMN connectivity was lower in older compared to younger adults, whereas no age-related differences were observed in FPN-DAN connectivity in either state. This suggests that dynamic interactions of the FPN are stable across cognitive states. The DMN and DAN were anti correlated and age-sensitive during the MSIT only, indicating variation in a task-dependent manner. Increased levels of anticorrelation from rest to task also predicted successful interference resolution. Additional analyses revealed that the degree of DMN-DAN anticorrelation during the MSIT was associated to resting cerebral blood flow (CBF) within the DMN. This suggests that reduced DMN neural activity during rest underlies an impaired ability to achieve higher levels of anticorrelation during a task. Taken together, our results suggest that only parts of age-related differences in connectivity are uncovered at rest and thus, should be studied in the functional connectome across multiple states for a more comprehensive picture. PMID- 28588477 TI - Associations between Mobility, Cognition, and Brain Structure in Healthy Older Adults. AB - Mobility limitations lead to a cascade of adverse events in old age, yet the neural and cognitive correlates of mobility performance in older adults remain poorly understood. In a sample of 387 adults (mean age 69.0 +/- 5.1 years), we tested the relationship between mobility measures, cognitive assessments, and MRI markers of brain structure. Mobility was assessed in 2007-2009, using gait, balance and chair-stands tests. In 2012-2015, cognitive testing assessed executive function, memory and processing-speed; gray matter volumes (GMV) were examined using voxel-based morphometry, and white matter microstructure was assessed using tract-based spatial statistics of fractional anisotropy, axial diffusivity (AD), and radial diffusivity (RD). All mobility measures were positively associated with processing-speed. Faster walking speed was also correlated with higher executive function, while memory was not associated with any mobility measure. Increased GMV within the cerebellum, basal ganglia, post central gyrus, and superior parietal lobe was associated with better mobility. In addition, better performance on the chair-stands test was correlated with decreased RD and AD. Overall, our results indicate that, even in non-clinical populations, mobility measures can be sensitive to sub-clinical variance in cognition and brain structures. PMID- 28588478 TI - Lower Activation in Frontal Cortex and Posterior Cingulate Cortex Observed during Sex Determination Test in Early-Stage Dementia of the Alzheimer Type. AB - Face-labeling refers to the ability to classify faces into social categories. This plays a critical role in human interaction as it serves to define concepts of socially acceptable interpersonal behavior. The purpose of the current study was to characterize, what, if any, impairments in face-labeling are detectable in participants with early-stage clinically diagnosed dementia of the Alzheimer type (CDDAT) through the use of the sex determination test (SDT). In the current study, four (1 female, 3 males) CDDAT and nine (4 females, 5 males) age-matched neurotypicals (NT) completed the SDT using chimeric faces while undergoing BOLD fMRI. It was expected that CDDAT participants would have poor verbal fluency, which would correspond to poor performance on the SDT. This could be explained by decreased activation and connectivity patterns within the fusiform face area (FFA) and anterior cingulate cortex (ACC). DTI was also performed to test the association of pathological deterioration of connectivity in the uncinate fasciculus (UF) and verbally-mediated performance. CDDAT showed lower verbal fluency test (VFT) performance, but VFT was not significantly correlated to SDT and no significant difference was seen between CDDAT and NT for SDT performance as half of the CDDAT performed substantially worse than NT while the other half performed similarly. BOLD fMRI of SDT displayed differences in the left superior frontal gyrus and posterior cingulate cortex (PCC), but not the FFA or ACC. Furthermore, although DTI showed deterioration of the right inferior and superior longitudinal fasciculi, as well as the PCC, it did not demonstrate significant deterioration of UF tracts. Taken together, early-stage CDDAT may represent a common emerging point for the loss of face labeling ability. PMID- 28588479 TI - Theta and Alpha Alterations in Amnestic Mild Cognitive Impairment in Semantic Go/NoGo Tasks. AB - Growing evidence suggests that cognitive control processes are impaired in amnestic mild cognitive impairment (aMCI); however the nature of these alterations needs further examination. The current study examined differences in electroencephalographic theta and alpha power related to cognitive control processes involving response execution and response inhibition in 22 individuals with aMCI and 22 age-, sex-, and education-matched cognitively normal controls. Two Go/NoGo tasks involving semantic categorization were used. In the basic categorization task, Go/NoGo responses were made based on exemplars of a single car (Go) and a single dog (NoGo). In the superordinate categorization task, responses were made based on multiple exemplars of objects (Go) and animals (NoGo). Behavioral data showed that the aMCI group had more false alarms during the NoGo trials compared to controls. The EEG data revealed between group differences related to response type in theta (4-7 Hz) and low-frequency alpha (8 10 Hz) power. In particular, the aMCI group differed from controls in theta power during the NoGo trials at frontal and parietal electrodes, and in low-frequency alpha power during Go trials at parietal electrodes. These results suggest that alterations in theta power converge with behavioral deterioration in response inhibition, whereas alterations in low-frequency alpha power appear to precede behavioral changes in response execution. Both behavioral and electrophysiological correlates combined provide a more comprehensive characterization of cognitive control deficits in aMCI. PMID- 28588480 TI - Reduced Gray Matter Volume in Patients with Type 2 Diabetes Mellitus. AB - Background and Purpose: Previous studies of voxel-based morphometry (VBM) have found that patients with type 2 diabetes mellitus (T2DM) exhibit gray matter alterations, but these findings are inconsistent and have not been quantitatively reviewed. Therefore, the aim of this study was to conduct a quantitative meta analysis of VBM studies of patients with T2DM. Materials and Methods: The seed based d mapping method was applied to quantitatively estimate the regional gray matter abnormalities in T2DM patients. We also used meta-regression to explore the effects of some demographics and clinical characteristics. Results: Seven studies, with 8 datasets comprising 530 participants with T2DM and 549 non-T2DM controls, were included. The pooled and subgroup meta-analyses found that T2DM patients showed robustly reduced gray matter in the bilateral superior temporal gyrus, middle temporal gyrus, medial superior frontal gyrus, insula, median cingulate cortex, precuneus cortex and the left lentiform nucleus extending into the parahippocampus. The meta-regression also found that the percentage of female patients with T2DM was negatively associated with gray matter in the right superior temporal gyrus and illness duration was negatively associated with gray matter in the right middle temporal gyrus. Conclusion: This meta-analysis indicates that T2DM patients have significantly and robustly reduced gray matter mainly in the cortical-striatal-limbic networks, which are associated with human cognition. Thereby implicating this finding in the pathophysiology of cognitive impairment in T2DM patients. PMID- 28588481 TI - Medicinally Used Asarum Species: High-Resolution LC-MS Analysis of Aristolochic Acid Analogs and In vitro Toxicity Screening in HK-2 Cells. AB - Species of Asarum are used in traditional Chinese medicine and, similar to members of the genus Aristolochia, they contain aristolochic acid analogs (AAAs). These compounds are known for their nephrotoxic and carcinogenic effects. So far, the phytochemistry and nephrotoxicity of species of Asarum is not well studied. A high-resolution LC-MS-based metabolomic approach was used to study the phytochemical variation in medicinally used Asarum species. The cytotoxicity of the samples was assessed using human kidney (HK-2) cells. The majority of samples contained potentially nephrotoxic AAAs, including 9-methoxy aristolactam (AL) IV, AL I, and AL IV. These compounds were present in methanol as well as water extracts. AAAs were detected in all parts of the plant. The majority of the extracts were not cytotoxic to HK-2 cells at the doses tested. However, other mechanisms relating to aristolochic acid nephropathy and cancer development, such as DNA adduct formation may occur. The results of this study provide a model for assessing lesser-known plant species for toxicity. PMID- 28588484 TI - AkrinorTM, a Cafedrine/ Theodrenaline Mixture (20:1), Increases Force of Contraction of Human Atrial Myocardium But Does Not Constrict Internal Mammary Artery In Vitro. AB - Background: Intraoperative hypotension is a common problem and direct or indirect sympathomimetic drugs are frequently needed to stabilize blood pressure. AkrinorTM consists of the direct and the indirect sympathomimetic noradrenaline and norephedrine. Both substances are covalently bound to the phosphodiesterase (PDE) inhibitor theophylline, yielding theodrenaline and cafedrine, respectively. We investigated pharmacodynamic effects of AkrinorTM and its constituents on contractile force and tension in human atrial trabeculae and internal A. mammaria rings. Methods: Isometric contractions were measured in human atrial trabeculae at 1 Hz and 37 degrees C. CGP 20712A and ICI 118,551 were used to elaborate beta1 and beta2-adrenoceptor (AR) subtypes involved and phenoxybenzamine to estimate indirect sympathomimetic action. PDE-inhibition was measured as a potentiation of force increase upon direct activation of adenylyl cyclase by forskolin. Human A. mammaria preparations were used to estimate intrinsic vasoconstriction and impact on the noradrenaline-induced vasoconstriction. Results: Clinically relevant concentrations of AkrinorTM (4.2-420 mg/l) robustly increased force in human atrial trabeculae (EC50 41 +/- 3 mg/l). This direct sympathomimetic action was mediated via beta1-AR and the effect size was as large as with high concentrations of calcium. Only the highest and clinically irrelevant concentration of AkrinorTM increased the potency of forskolin to a minor extent. Norephedrine has lost its indirect sympathomimetic effect when bound to theophylline. Increasing concentrations of AkrinorTM (4.2-168 mg/l) alone did not affect the tension of human A. mammaria interna rings, but shifted the noradrenaline curve rightward from -logEC50 6.18 +/- 0.08 to 5.23 +/- 0.05 M. Conclusion: AkrinorTM increased cardiac contractile force by direct sympathomimetic actions and PDE inhibition, did not constrict A. mammaria preparations, but shifted the concentration-response curve to the right, compatible with an alpha-AR antagonistic effect or PDE inhibition. The pharmacodynamic profile and potency of AkrinorTM differs from noradrenaline and norephedrine in vitro. We anticipate metabolism of theodrenaline and cafedrine resulting in a different pharmacodynamic profile of AkrinorTMin vivo. PMID- 28588482 TI - Antioxidant Effect of Fructus Ligustri Lucidi Aqueous Extract in Ovariectomized Rats Is Mediated through Nox4-ROS-NF-kappaB Pathway. AB - Purpose: This study is designed to explore whether Fructus ligustri lucidi (FLL) exhibits antioxidant effect in ovariectomized (OVX) rats, and to identify the signaling pathway involved in this process. Methods: OVX rats were treated with FLL aqueous extract (3.5 g/kg) for 12 weeks. Serum, uteri, and tibias were harvested from the rats and the levels of total antioxidant capacity (TAC), nitric oxide (NO), malondialdehyde (MDA), 8-hydroxy-desoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were determined. Changes in the levels of NF-kappaB p65, phosphorylation of NF-kappaB-p65 (NF-kappaB-pp65), NF-kappaB inhibitor alpha (IkappaBalpha), phosphorylation of IkappaBalpha (p-IkappaBalpha), and NADPH oxidase 4 (Nox4) in uteri and tibias were determined by western blot, immunofluorescent and immunohistochemical analysis, respectively. In addition, the expression of cytochrome C (Cyto-C) and B-cell lymphoma-2 (Bcl-2) were determined in the tibias of rats. Histopathological changes in the bones were evaluated by hematoxylin-eosin staining. Bone mineral density (BMD) was determined in rat femurs by dual X-ray absorptiometry. Results: Treatment of OVX rats with FLL aqueous extract improved redox homeostasis by increasing the levels of TAC and NO as well as decreasing the levels of MDA and 8-OHdG in serum, tibias, and uteri. Further, FLL extract also downregulated the expression of Nox4, NF-kappaB-p65, NF-kappaB-pp65, and p-IkappaBalpha in the uteri and tibias. Furthermore, administration of FLL-OVX rats increased Bcl-2 expression and prevented cytoplasmic release of mitochondrial Cyto-C in the tibias. In addition, FLL treatment also improved bone microstructure and increased cortical bone thickness as well as increased BMD values in the femurs of OVX rats. Conclusions: FLL treatment may suppress oxidative stress response in OVX rats via regulating the Nox4/ROS/NF-kappaB signaling pathway. These results suggest the potential of using FLL as a natural antioxidant agent in preventing the development of osteoporosis. PMID- 28588485 TI - Beneficial Effects and Toxicity Studies of Xian-ling-gu-bao on Bone Metabolism in Ovariectomized Rats. AB - Xian-ling-gu-bao (XLGB) is a well-known patented traditional Chinese prescription widely used to treat osteoporosis, osteoarthritis, aseptic bone necrosis, or climacteric syndrome. However, recent reports have suggested that XLGB may cause liver injury in humans. In the present study, we aimed to evaluate the efficacy of XLGB in the prevention of osteoporosis in the zebrafish and ovariectomized (OVX) rats, both of which have been used as osteoporosis models. The safety of XLGB after long-term administration to OVX rats was also assessed. OVX rats were administered by oral gavage 270 mg/kg (recommended daily dose), 1350 mg/kg, and 1800 mg/kg of XLGB for 26 weeks. Bone mineral density, relative bone surface to bone volume, relative bone volume to total volume, trabecular number, mean trabecular thickness, and mean trabecular spacing in OVX rats were examined at the end of the 26-week dosing period. Additionally, OPG and RANKL expression in the femur were determined by western blot and immunohistochemical staining. To evaluate the safety of XLGB, body weight, hematology, serum biochemistry markers related to toxicology, and organ histopathology were determined in each group of OVX rats. Conversely, the zebrafish was treated with prednisolone to induce osteoporosis in the embryo. Disodium etidronate was used as a treatment control. XLGB was shown to be effective in preventing osteoporosis in both the OVX rats and the prednisolone-treated zebrafish. Similarly, XLGB increased OPG protein and decreased RANKL protein in OVX rats. Interestingly, no obvious toxicity was observed in the heart, liver, kidney, small intestine, or stomach at dosages of up to 1800 mg/kg after treating the OVX rats for 26 weeks. XLGB was shown to be very effective in treating osteoporosis in OVX rats. No obvious toxicity or adverse effects developed in OVX rats at dosages up to 1800 mg/kg, which is equivalent to six times the daily-recommended dose. Therefore, XLGB should be considered a good option for the treatment of post-menopausal osteoporosis. PMID- 28588487 TI - GYF-21, an Epoxide 2-(2-Phenethyl)-Chromone Derivative, Suppresses Innate and Adaptive Immunity via Inhibiting STAT1/3 and NF-kappaB Signaling Pathways. AB - Multiple sclerosis is a chronic inflammatory autoimmune disease of the central nervous system characterized by demyelinating plaques and axonal loss. Inhibition on over activation of innate and adaptive immunity provides a rationale strategy for treatment of multiple sclerosis. In the present study, we investigated the inhibitory effects of GYF-21, an epoxide 2-(2-phenethyl)-chromone derivative isolated from Chinese agarwood, on innate and adaptive immunity for revealing its potential to treat multiple sclerosis. The results showed that GYF-21 markedly inhibited the activation of microglia, and dendritic cells as well as neutrophils, all of which play important roles in innate immunity. Furthermore, GYF-21 significantly suppressed adaptive immunity via inhibiting the differentiation of naive CD4+ T cells into T helper 1 (Th1) and T helper 17 (Th17) cells, and suppressing the activation, proliferation, and IFN-gamma secretion of CD8+ T cells. The mechanism study showed that GYF-21 evidently inhibited the activation of STAT1/3 and NF-kappaB signaling pathways in microglia. In conclusion, we demonstrated that GYF-21 can significantly inhibit innate and adaptive immunity via suppressing STAT1/3 and NF-kappaB signaling pathways, and has potential to be developed into therapeutic drug for multiple sclerosis. PMID- 28588483 TI - Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders. AB - Beneficial effects of cannabidiol (CBD) have been described for a wide range of psychiatric disorders, including anxiety, psychosis, and depression. The mechanisms responsible for these effects, however, are still poorly understood. Similar to clinical antidepressant or atypical antipsychotic drugs, recent findings clearly indicate that CBD, either acutely or repeatedly administered, induces plastic changes. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in a pharmacological model of schizophrenia. More recently, it was found that CBD modulates cell fate regulatory pathways such as autophagy and others critical pathways for neuronal survival in neurodegenerative experimental models, suggesting the potential benefit of CBD treatment for psychiatric/cognitive symptoms associated with neurodegeneration. These changes and their possible association with CBD beneficial effects in psychiatric disorders are reviewed here. PMID- 28588488 TI - Antinociceptive Activity of Borreria verticillata: In vivo and In silico Studies. AB - Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0.9% NaCl control group (CTRL), 10 mg/kg memantine (MEM), 10 mg/kg indomethacin (INDO), 500 mg/kg EHBv (EHBv 500), 25 mg/kg FAc (FAc 25) and 50 mg/kg FAc (FAc 50). EHBv, FAc 25 and 50 treatments exhibited anti edematous and peripheral antinociceptive effects. For in silico assessment, compounds identified in FAc were subjected to molecular docking with COX-2, GluN1a and GluN2B. Ursolic acid (UA) was the compound with best affinity parameters (binding energy and inhibition constant) for COX-2, GluN1a, GluN2B, and was selected for further analysis with molecular dynamics (MD) simulations. In MD simulations, UA exhibited highly frequent interactions with residues Arg120 and Glu524 in the COX-2 active site and NMDA, whereby it might prevent COX-2 and NMDA receptor activation. Treatment with UA 10 mg/Kg showed peripheral and central antinociceptive effect. The antinociceptive effect of B. verticillata might be predominantly attributed to peripheral actions, including the participation of anti-inflammatory components. Ursolic acid is the main active component and seems to be a promising source of COX-2 inhibitors and NMDA receptor antagonists. PMID- 28588489 TI - FH535 Suppresses Osteosarcoma Growth In Vitro and Inhibits Wnt Signaling through Tankyrases. AB - Osteosarcoma (OS) is an aggressive primary bone tumor which exhibits aberrantly activated Wnt signaling. The canonical Wnt signaling cascade has been shown to drive cancer progression and metastasis through the activation of beta-catenin. Hence, small molecule inhibitors of Wnt targets are being explored as primary or adjuvant chemotherapy. In this study, we have investigated the ability of FH535, an antagonist of Wnt signaling, to inhibit the growth of OS cells. We found that FH535 was cytotoxic in all OS cell lines which were tested (143b, U2OS, SaOS-2, HOS, K7M2) but well tolerated by normal human osteoblast cells. Additionally, we have developed an in vitro model of doxorubicin-resistant OS and found that these cells were highly responsive to FH535 treatment. Our analysis provided evidence that FH535 strongly inhibited markers of canonical Wnt signaling. In addition, our findings demonstrate a reduction in PAR-modification of Axin2 indicating inhibition of the tankyrase 1/2 enzymes. Moreover, we observed inhibition of auto modification of PARP1 in the presence of FH535, indicating inhibition of PARP1 enzymatic activity. These data provide evidence that FH535 acts through the tankyrase 1/2 enzymes to suppress Wnt signaling and could be explored as a potent chemotherapeutic agent for the control of OS. PMID- 28588486 TI - Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases. AB - In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1beta and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1beta-induced neutrophil recruitment to the skin. IL-1beta blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1alpha monoclonal antibody MABp1 and anti-IL-1beta Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases. PMID- 28588490 TI - An Overview of Pickering Emulsions: Solid-Particle Materials, Classification, Morphology, and Applications. AB - Pickering emulsion, a kind of emulsion stabilized only by solid particles locating at oil-water interface, has been discovered a century ago, while being extensively studied in recent decades. Substituting solid particles for traditional surfactants, Pickering emulsions are more stable against coalescence and can obtain many useful properties. Besides, they are more biocompatible when solid particles employed are relatively safe in vivo. Pickering emulsions can be applied in a wide range of fields, such as biomedicine, food, fine chemical synthesis, cosmetics, and so on, by properly tuning types and properties of solid emulsifiers. In this article, we give an overview of Pickering emulsions, focusing on some kinds of solid particles commonly serving as emulsifiers, three main types of products from Pickering emulsions, morphology of solid particles and as-prepared materials, as well as applications in different fields. PMID- 28588491 TI - Therapeutic Effects of Breviscapine in Cardiovascular Diseases: A Review. AB - Breviscapine is a crude extract of several flavonoids of Erigeron breviscapus (Vant.) Hand.-Mazz., containing more than 85% of scutellarin, which has been traditionally used in China as an activating blood circulation medicine to improve cerebral blood supply. Accumulating evidence from various in vivo and in vitro studies has shown that breviscapine exerts a broad range of cardiovascular pharmacological effects, including vasodilation, protection against ischaemia/reperfusion (I/R), anti-inflammation, anticoagulation, antithrombosis, endothelial protection, myocardial protection, reduction of smooth muscle cell migration and proliferation, anticardiac remodeling, antiarrhythmia, blood lipid reduction, and improvement of erectile dysfunction. In addition, several clinical studies have reported that breviscapine could be used in conjunction with Western medicine for cardiovascular diseases (CVDs) including coronary heart disease, myocardial infarction, hypertension, atrial fibrillation, hyperlipidaemia, viral myocarditis, chronic heart failure, and pulmonary heart disease. However, the protective effects of breviscapine on CVDs based on experimental studies along with its underlying mechanisms have not been reviewed systematically. This paper reviewed the underlying pharmacological mechanisms in the cardioprotective effects of breviscapine and elucidated its clinical applications. PMID- 28588492 TI - Cytotoxic and Enzyme Inhibitory Potential of Two Potentilla species (P. speciosa L. and P. reptans Willd.) and Their Chemical Composition. AB - In this work, the biological and chemical fingerprints of three extracts (ethyl acetate, methanol, and water) from two Potentilla species (Potentilla reptans and P. speciosa) were investigated. Antioxidant, enzyme inhibitory, and cytotoxic activities were performed for the biological fingerprint. For the chemical characterization, total bioactive components, and individual phenolic components were determined using photometric and HPLC methods, respectively. The main identified phenolic compounds in these extracts were rutin and catechin. Methanol and water extracts contained the highest total phenolic and flavonoid content. The results of antioxidant assays showed that methanol and water extracts displayed higher antioxidant activity compared to the ethyl acetate extract. Generally, methanol and water extracts exhibited higher biological activities correlated with higher levels the bioactive components. For P. speciosa, the methanol extract exhibited the highest enzyme inhibitory activity (except BChE inhibitory activity). P. reptans exhibited also high antiproliferative activity against MCF-7 cells whilst P. speciosa had weak to moderate activity against both of A549 and MCF-7 cell lines. The results suggest that Potentilla species could be potential candidates for developing new phyto-pharmaceuticals and functional ingredients. PMID- 28588494 TI - Myosin Light Chain Kinase: A Potential Target for Treatment of Inflammatory Diseases. AB - Myosin light chain kinase (MLCK) induces contraction of the perijunctional apical actomyosin ring in response to phosphorylation of the myosin light chain. Abnormal expression of MLCK has been observed in respiratory diseases, pancreatitis, cardiovascular diseases, cancer, and inflammatory bowel disease. The signaling pathways involved in MLCK activation and triggering of endothelial barrier dysfunction are discussed in this review. The pharmacological effects of regulating MLCK expression by inhibitors such as ML-9, ML-7, microbial products, naturally occurring products, and microRNAs are also discussed. The influence of MLCK in inflammatory diseases starts with endothelial barrier dysfunction. The effectiveness of anti-MLCK treatment may depend on alleviation of that primary pathological mechanism. This review summarizes evidence for the potential benefits of anti-MLCK agents in the treatment of inflammatory disease and the importance of avoiding treatment-related side effects, as MLCK is widely expressed in many different tissues. PMID- 28588493 TI - P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology. AB - Adenosine 5'-triphosphate is a well-known extracellular signaling molecule and neurotransmitter known to activate purinergic P2X receptors. Information has been elucidated about the structure and gating of P2X channels following the determination of the crystal structure of P2X4 (zebrafish), however, there is still much to discover regarding the role of this receptor in the central nervous system (CNS). In this review we provide an overview of what is known about P2X4 expression in the CNS and discuss evidence for pathophysiological roles in neuroinflammation and neuropathic pain. Recent advances in the development of pharmacological tools including selective antagonists (5-BDBD, PSB-12062, BX430) and positive modulators (ivermectin, avermectins, divalent cations) of P2X4 will be discussed. PMID- 28588496 TI - Clinical Efficacy and Residue Depletion of 10% Enrofloxacin Enteric-Coated Granules in Pigs. AB - A new, more palatable formulation of 10% enrofloxacin enteric-coated granules was investigated to evaluate the pharmacokinetic effect in plasma, the residue elimination in tissues and the clinical efficacy against Actinobacillus pleuropneumonia (APP) and Mycoplasam suis (MS) in pigs. In this study, the enrofloxacin concentrations in plasma and tissues were detected using high performance liquid chromatography with phosphate buffer (pH = 3) and acetonitrile. The pharmacokinetics and elimination of enrofloxacin enteric-coated granules were performed after oral administration at a single dose of 10 mg/kg body weight (bw) and 5 mg/kg twice per day for 5 consecutive days, respectively. The in vivo antibacterial efficacy and clinical effectiveness of enrofloxacin enteric-coated granules against APP and MS were assayed at 2.5, 5, 10 mg/kg, compared with tiamulin (8 mg/kg) based on establishment of APP and MS infection models. 56 APP strains were selected and tested for in vitro antibacterial activity of enrofloxacin enteric-coated granules. The main parameters of elimination half-life (t1/2beta), Tmax, and area under the curve (AUC) were 14.99 +/- 4.19, 3.99 +/- 0.10, and 38.93 +/- 1.52 MUg h/ml, respectively, revealing that the enrofloxacin concentration remained high and with a sustainable distribution in plasma. Moreover, the analysis on the evaluation of enrofloxacin and ciprofloxacin in muscle, fat, liver and kidney showed that the recovery were more than 84% recovery in accordance with the veterinary drug residue guidelines of United States pharmacopeia, and the withdrawal periods were 4.28, 3.81, 4.84, and 3.51 days, respectively, suggesting that the withdrawal period was 5 d after oral administration of 5 mg/kg twice per day. The optimal dosage of enrofloxacin enteric-coated granules against APP and MS was 5 mg/kg, with over 90% efficacy, which was significantly different (p < 0.05) to the 2.5 mg/kg group, but not to the 10 mg/kg group or the positive control group (tiamulin). In conclusion, 10% enrofloxacin enteric-coated granules had significant potential for treating APP and MS, and it provided an alternative enrofloxacin palatability formulation. PMID- 28588495 TI - A Brief History of IL-1 and IL-1 Ra in Rheumatology. AB - The history of what, in 1979, was called interleukin-1 (IL-1), orchestrator of leukocyte inter-communication, began many years before then, initially by the observation of fever induction via the endogenous pyrogen (EP) (1974) and then in rheumatology on the role in tissue destruction in rheumatoid diseases via the induction of collagenase and PGE2 in human synovial cells by a mononuclear cell factor (MCF) (1977). Since then, the family has exploded to presently 11 members as well as many membrane-bound and soluble receptor forms. The discovery of a natural Interleukin-1 receptor antagonist (IL-1Ra) in human biological fluids has highlighted the importance of IL-1 and IL-1Ra in human diseases. Evidence delineating its role in autoinflammatory syndromes and the elucidation of the macromolecular complex referred to as "inflammasome" have been instrumental to our understanding of the link with IL-1. At present, the IL-1blockade as therapeutic approach is crucial for many hereditary autoinflammatory diseases, as well as for adult-onset Still's disease, crystal-induced arthropathies, certain skin diseases including neutrophil-triggered skin diseases, Behcet's disease and deficiency of IL-1Ra and other rare fever syndromes. Its role is only marginally important in rheumatoid arthritis and is still under debate with regard to osteoarthritis, type 2 diabetes mellitus, cardiovascular diseases and cancer. This brief historical review focuses on some aspects of IL-1, mainly IL-1beta and IL-Ra, in rheumatology. There are many excellent reviews focusing on the IL-1 family in general or with regard to specific diseases or biological discoveries. PMID- 28588497 TI - On the Integration of In Silico Drug Design Methods for Drug Repurposing. AB - Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug-target, target-disease, and ultimately drug-disease associations. PMID- 28588498 TI - A Comparison of Fully-Coupled 3D In-Stent Restenosis Simulations to In-vivo Data. AB - We describe our fully-coupled 3D multiscale model of in-stent restenosis, with blood flow simulations coupled to smooth muscle cell proliferation, and report results of numerical simulations performed with this model. This novel model is based on several previously reported 2D models. We study the effects of various parameters on the process of restenosis and compare with in vivo porcine data where we observe good qualitative agreement. We study the effects of stent deployment depth (and related injury score), reendothelization speed, and simulate the effect of stent width. Also we demonstrate that we are now capable to simulate restenosis in real-sized (18 mm long, 2.8 mm wide) vessel geometries. PMID- 28588499 TI - Intake of a Ketone Ester Drink during Recovery from Exercise Promotes mTORC1 Signaling but Not Glycogen Resynthesis in Human Muscle. AB - Purpose: Ketone bodies are energy substrates produced by the liver during prolonged fasting or low-carbohydrate diet. The ingestion of a ketone ester (KE) rapidly increases blood ketone levels independent of nutritional status. KE has recently been shown to improve exercise performance, but whether it can also promote post-exercise muscle protein or glycogen synthesis is unknown. Methods: Eight healthy trained males participated in a randomized double-blind placebo controlled crossover study. In each session, subjects undertook a bout of intense one-leg glycogen-depleting exercise followed by a 5-h recovery period during which they ingested a protein/carbohydrate mixture. Additionally, subjects ingested a ketone ester (KE) or an isocaloric placebo (PL). Results: KE intake did not affect muscle glycogen resynthesis, but more rapidly lowered post exercise AMPK phosphorylation and resulted in higher mTORC1 activation, as evidenced by the higher phosphorylation of its main downstream targets S6K1 and 4E-BP1. As enhanced mTORC1 activation following KE suggests higher protein synthesis rates, we used myogenic C2C12 cells to further confirm that ketone bodies increase both leucine-mediated mTORC1 activation and protein synthesis in muscle cells. Conclusion: Our results indicate that adding KE to a standard post exercise recovery beverage enhances the post-exercise activation of mTORC1 but does not affect muscle glycogen resynthesis in young healthy volunteers. In vitro, we confirmed that ketone bodies potentiate the increase in mTORC1 activation and protein synthesis in leucine-stimulated myotubes. Whether, chronic oral KE intake during recovery from exercise can facilitate training-induced muscular adaptation and remodeling need to be further investigated. PMID- 28588500 TI - Temporal Expression Patterns of Clock Genes and Aquaporin 5/Anoctamin 1 in Rat Submandibular Gland Cells. AB - Circadian rhythms are essential for health and regulate various physiological functions. These rhythms are regulated by a negative-feedback loop involving clock genes in the suprachiasmatic nucleus (SCN) and peripheral tissues. The rate of secretion of salivary substances, ions, and water follows a circadian rhythm, however, the relationship between the molecular mechanism of salivary secretion and peripheral circadian rhythm is not yet clear. Anoctamin 1 (ANO1, also known as TMEM16A) and Aquaporin 5 (AQP5) play an important role in the transport of ions and water in the submandibular glands (SGs). We examined the interaction between the rhythmic expression pattern of the clock genes, Ano1 and Aqp5, in rat whole SGs as well as isolated acinar and ductal cells. Circadian rhythmic expression for Bmal1, Per1, Per2, Clock, Cry1, Cry2, Roralpha, and Rev-erbalpha mRNAs, also called the clock genes, was observed in rat SGs by semi-quantitative RT-PCR analysis. We also observed rhythmic patterns in Ano1 and Aqp5 mRNA expression. The expression of ANO1 protein also showed circadian rhythm, as confirmed by western blot analysis. We could not observe any time delay between the peak expression of ANO1 protein and its mRNA. Expression levels of the clock gene mRNAs in the ductal cells was higher than that in acinar cells, however, rhythmic oscillations were observed in both. Our results suggest that SGs have peripheral clocks, and rhythmic expressions of Ano1 and Aqp5 along with the clock genes, may play an important role in the circadian regulation of salivary secretion. PMID- 28588502 TI - Transient Hypothyroidism: Dual Effect on Adult-Type Leydig Cell and Sertoli Cell Development. AB - Transient neonatal 6-propyl-2-thiouracil (PTU) induced hypothyroidism affects Leydig and Sertoli cell numbers in the developing testis, resulting in increased adult testis size. The hypothyroid condition was thought to be responsible, an assumption questioned by studies showing that uninterrupted fetal/postnatal hypothyroidism did not affect adult testis size. Here, we investigated effects of transient hypothyroidism on Leydig and Sertoli cell development, employing a perinatal iodide-deficient diet in combination with sodium perchlorate. This hypothyroidism inducing diet was continued until days 1, 7, 14, or 28 postpartum (pp) respectively, when the rats were switched to a euthyroid diet and followed up to adulthood. Continuous euthyroid and hypothyroid, and neonatal PTU-treated rats switched to the euthyroid diet at 28 days pp, were included for comparison. No effects on formation of the adult-type Leydig cell population or on Sertoli cell proliferation and differentiation were observed when the diet switched at/or before day 14 pp. However, when the diet was discontinued at day 28 pp, Leydig cell development was delayed similarly to what was observed in chronic hypothyroid rats. Surprisingly, Sertoli cell proliferation was 6- to 8-fold increased 2 days after the diet switch and remained elevated the next days. In adulthood, Sertoli cell number per seminiferous tubule cross-section and consequently testis weight was increased in this group. These observations implicate that increased adult testis size in transiently hypothyroid rats is not caused by the hypothyroid condition per se, but originates from augmented Sertoli cell proliferation as a consequence of rapid normalization of thyroid hormone concentrations. PMID- 28588501 TI - Genome-Wide Characterization and Expression Profiling of Sugar Transporter Family in the Whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae). AB - Sugar transporters (STs) play pivotal roles in the growth, development, and stress responses of phloem-sucking insects, such as the whitefly, Bemisia tabaci. In this study, 137 sugar transporters (STs) were identified based on analysis of the genome and transcriptome of B. tabaci MEAM1. B. tabaci MEAM1 encodes a larger number of STs than other selected insects. Phylogenetic and molecular evolution analysis showed that the 137 STs formed three expanded clades and that the genes in Sternorrhyncha expanded clades had accelerated rates of evolution. B. tabaci sugar transporters (BTSTs) were divided into three groups based on their expression profiles across developmental stages; however, no host-specific BTST was found in B. tabaci fed on different host plants. Feeding of B. tabaci adults with feeding diet containing dsRNA significantly reduced the transcript level of the target genes in B. tabaci and mortality was significantly improved in B. tabaci fed on dsRNA compared to the control, which indicates the sugar transporters may be used as potential RNAi targets for B. tabaci bio-control. These results provide a foundation for further studies of STs in B. tabaci. PMID- 28588503 TI - Hepcidin Protects Neuron from Hemin-Mediated Injury by Reducing Iron. AB - Hemin plays a key role in mediating secondary neuronal injury after intracerebral hemorrhage (ICH) and the cell toxicity of hemin is thought to be due to iron that is liberated when hemin is degraded. In a recent study, we demonstrated the iron regulatory hormone hepcidin reduces brain iron in iron-overloaded rats. Therefore, we hypothesized that hepcidin might be able to reduce iron and then protect neurons from hemin or iron-mediated neurotoxicity in hemin-treated neuronal cells. Here, we tested the hypothesis and demonstrated that ad-hepcidin and hepcidin peptide both have the ability to suppress the hemin-induced increase in LDH release and apoptotic cell numbers, to reduce cell iron and ferritin contents, and to inhibit expression of transferrin receptor 1, divalent metal transporter 1, and ferroportin 1 in hemin-treated neurons. We conclude that hepcidin protects neuron from hemin-mediated injury by reducing iron via inhibition of expression of iron transport proteins. PMID- 28588504 TI - TNFalpha Modulates Cardiac Conduction by Altering Electrical Coupling between Myocytes. AB - Background: Tumor Necrosis Factor alpha (TNFalpha) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNFalpha levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic. Methods and Results: Hearts were optically mapped to determine CV from control, TNFalpha and TNFalpha + high calcium (2.5 vs. 1.25 mM) treated guinea pig hearts over 90 mins. Transmission electron microscopy was performed to measure changes in intercellular separation in the gap junction adjacent extracellular nanodomain-perinexus (WP). Cx43 expression and phosphorylation were determined by Western blotting and Cx43 distribution by confocal immunofluorescence. At 90 mins, longitudinal and transverse CV (CVL and CVT, respectively) increased with control Tyrode perfusion but TNFalpha slowed CVT alone relative to control and anisotropy of conduction increased, but not significantly. TNFalpha increased WP relative to control at 90 mins, without significantly changing GJ coupling. Increasing extracellular calcium after 30 mins of just TNFalpha exposure increased CVT within 15 mins. TNFalpha + high calcium also restored CVT at 90 mins and reduced WP to control values. Interestingly, TNFalpha + high calcium also improved GJ coupling at 90 mins, which along with reduced WP may have contributed to increasing CV. Conclusions: Elevating extracellular calcium during acute TNFalpha exposure reduces perinexal expansion, increases ephaptic, and GJ coupling, improves CV and may be a novel method for preventing inflammation induced CV slowing. PMID- 28588506 TI - The Role of Infection and Immune Responsiveness in a Case of Treatment-Resistant Pediatric Bipolar Disorder. AB - A case of psychotropic-resistant pediatric bipolar disorder is presented. Both awareness and proper treatment of previously unrecognized infections and their effects on the immune system were very important in stabilizing the patient's psychiatric symptoms. PMID- 28588505 TI - Multiple Calcium Export Exchangers and Pumps Are a Prominent Feature of Enamel Organ Cells. AB - Calcium export is a key function for the enamel organ during all stages of amelogenesis. Expression of a number of ATPase calcium transporting, plasma membrane genes (ATP2B1-4/PMCA1-4), solute carrier SLC8A genes (sodium/calcium exchanger or NCX1-3), and SLC24A gene family members (sodium/potassium/calcium exchanger or NCKX1-6) have been investigated in the developing enamel organ in earlier studies. This paper reviews the calcium export pathways that have been described and adds novel insights to the spatiotemporal expression patterns of PMCA1, PMCA4, and NCKX3 during amelogenesis. New data are presented to show the mRNA expression profiles for the four Atp2b1-4 gene family members (PMCA1-4) in secretory-stage and maturation-stage rat enamel organs. These data are compared to expression profiles for all Slc8a and Slc24a gene family members. PMCA1, PMCA4, and NCKX3 immunolocalization data is also presented. Gene expression profiles quantitated by real time PCR show that: (1) PMCA1, 3, and 4, and NCKX3 are most highly expressed during secretory-stage amelogenesis; (2) NCX1 and 3, and NCKX6 are expressed during secretory and maturation stages; (3) NCKX4 is most highly expressed during maturation-stage amelogenesis; and (4) expression levels of PMCA2, NCX2, NCKX1, NCKX2, and NCKX5 are negligible throughout amelogenesis. In the enamel organ PMCA1 localizes to the basolateral membrane of both secretory and maturation ameloblasts; PMCA4 expression is seen in the basolateral membrane of secretory and maturation ameloblasts, and also cells of the stratum intermedium and papillary layer; while NCKX3 expression is limited to Tomes' processes, and the apical membrane of maturation-stage ameloblasts. These new findings are discussed in the perspective of data already present in the literature, and highlight the multiplicity of calcium export systems in the enamel organ needed to regulate biomineralization. PMID- 28588508 TI - Individual Differences in Subjective Utility and Risk Preferences: The Influence of Hedonic Capacity and Trait Anxiety. AB - Individual differences in decision-making are important in both normal populations and psychiatric conditions. Variability in decision-making could be mediated by different subjective utilities or by other processes. For example, while traditional economic accounts attribute risk aversion to a concave subjective utility curve, in practice other factors could affect risk behavior. This distinction may have important implications for understanding the biological basis of variability in decision-making and for developing interventions to improve decision-making. Another aspect of decision-making that may vary between individuals is the sensitivity of subjective utility to counterfactual outcomes (outcomes that could have occurred, but did not). We investigated decision-making in relation to hedonic capacity and trait anxiety, two traits that relate to psychiatric conditions but also vary in the general population. Subjects performed a decision-making task, in which they chose between low- and high-risk gambles to win 0, 20, or 40 points on each trial. Subjects then rated satisfaction after each outcome on a visual analog scale, indicating subjective utility. Hedonic capacity was positively associated with the subjective utility of winning 20 points but was not associated with the concavity of the subjective utility curve (constructed using the mean subjective utility of winning 0, 20, or 40 points). Consistent with economic theory, concavity of the subjective utility curve was associated with risk aversion. Hedonic capacity was independently associated with risk seeking (i.e., not mediated by the shape of the subjective utility curve), while trait anxiety was unrelated to risk preferences. Contrary to our expectations, counterfactual sensitivity was unrelated to hedonic capacity and trait anxiety. Nevertheless, trait anxiety was associated with a self-report measure of regret-proneness, suggesting that counterfactual influences may occur via a pathway that is separate from immediate counterfactual processing biases. Taken together, our results show that hedonic capacity but not trait anxiety affects risk-taking through a mechanism that appears independent of the shape of the subjective utility curve, while hedonic capacity and trait anxiety do not affect the influence of counterfactual outcomes on subjective utility. The results have implications for understanding the underlying mechanisms of variable decision-making and for developing interventions to improve decision-making. PMID- 28588509 TI - Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive Compulsive Disorder. AB - Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive-compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5 HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl] piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD. PMID- 28588507 TI - Neurovascular Unit Dysfunction and Blood-Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. AB - Schizophrenia is a psychotic disorder characterized by delusions, hallucinations, negative symptoms, as well as behavioral and cognitive dysfunction. It is a pathoetiologically heterogeneous disorder involving complex interrelated mechanisms that include oxidative stress and neuroinflammation. Neurovascular endothelial dysfunction and blood-brain barrier (BBB) hyperpermeability are established mechanisms in neurological disorders with comorbid psychiatric symptoms such as epilepsy, traumatic brain injury, and Alzheimer's disease. Schizophrenia is frequently comorbid with medical conditions associated with peripheral vascular endothelial dysfunction, such as metabolic syndrome, cardiovascular disease, and diabetes mellitus. However, the existence and etiological relevance of neurovascular endothelial dysfunction and BBB hyperpermeability in schizophrenia are still not well recognized. Here, we review the growing clinical and experimental evidence, indicating that neurovascular endotheliopathy and BBB hyperpermeability occur in schizophrenia patients. We present a theoretical integration of human and animal data linking oxidative stress and neuroinflammation to neurovascular endotheliopathy and BBB breakdown in schizophrenia. These abnormalities may contribute to the cognitive and behavioral symptoms of schizophrenia via several mechanisms involving reduced cerebral perfusion and impaired homeostatic processes of cerebral microenvironment. Furthermore, BBB disruption can facilitate interactions between brain innate and peripheral adaptive immunity, thereby perpetuating harmful neuroimmune signals and toxic neuroinflammatory responses, which can also contribute to the symptoms of schizophrenia. Taken together, these findings support the "mild encephalitis" hypothesis of schizophrenia. If neurovascular abnormalities prove to be etiologically relevant to the neurobiology of schizophrenia, then targeting these abnormalities may represent a promising therapeutic strategy. PMID- 28588510 TI - The Representation of Motor (Inter)action, States of Action, and Learning: Three Perspectives on Motor Learning by Way of Imagery and Execution. AB - Learning in intelligent systems is a result of direct and indirect interaction with the environment. While humans can learn by way of different states of (inter)action such as the execution or the imagery of an action, their unique potential to induce brain- and mind-related changes in the motor action system is still being debated. The systematic repetition of different states of action (e.g., physical and/or mental practice) and their contribution to the learning of complex motor actions has traditionally been approached by way of performance improvements. More recently, approaches highlighting the role of action representation in the learning of complex motor actions have evolved and may provide additional insight into the learning process. In the present perspective paper, we build on brain-related findings and sketch recent research on learning by way of imagery and execution from a hierarchical, perceptual-cognitive approach to motor control and learning. These findings provide insights into the learning of intelligent systems from a perceptual-cognitive, representation-based perspective and as such add to our current understanding of action representation in memory and its changes with practice. Future research should build bridges between approaches in order to more thoroughly understand functional changes throughout the learning process and to facilitate motor learning, which may have particular importance for cognitive systems research in robotics, rehabilitation, and sports. PMID- 28588511 TI - Female vs. Male Ampelmannchen-Gender-Specific Reaction Times to Male and Female Traffic Light Figures. AB - Traffic signs are important visual guiding signals for the safe navigation through complex road traffic. Interestingly, there is little variation in the traffic signs for cars around the world. However, remarkable variation exists for pedestrian traffic signs. Following up from an earlier study, we investigated the visual efficacy of female vs. male German Ampelmannchen pedestrian traffic signs. In a Stroop-like test, 30 subjects were presented with female and male go and no go traffic light figures that were shown either in the corresponding or opposing color. Subjects had to indicate, based either solely on the form or the color of the figure, whether they were allowed to go. Accuracy and response times across all subjects did not differ for the female vs. male signs, indicating that Ampelfrau and Ampelmann signs have equal visual efficacy. However, subjects responded faster to signs of their own vs. the opposite gender. This preference for signs of one's own gender is in accordance with effects in social psychology described by social learning theory. An introduction of such novel traffic lights may, thus, contribute to higher compliance with the traffic sign signals. PMID- 28588512 TI - Temporal Changes in Individualism and Their Ramification in Japan: Rising Individualism and Conflicts with Persisting Collectivism. AB - Many studies have shown that American culture has become more individualistic over time. However, it was unclear whether other cultures, especially East Asian cultures, have also shifted toward greater individualism. Therefore, this article reviewed studies investigating temporal changes in individualism in Japan and their ramifications on psychology and behavior. Japan has experienced rapid and dramatic economic growth and urbanization and has adopted more social systems based on individualistic concepts in various contexts (e.g., workplace, school). Recent studies have suggested that, along with these socioeconomic changes, Japanese culture has become more individualistic over time. Specifically, the divorce rate increased and household size decreased. Moreover, people give more unique names to their children and dogs, and individualistic words such as "individual" and "uniqueness" appear more frequently in newspapers. Furthermore, social values became more individualistic. Yet, it has also been shown that some collectivistic values still remain. As a result, people have difficulty in adapting to this coexistence, which injures interpersonal relationships and well being. This paper discussed how Japanese culture changed over time and how such changes affected Japanese psychology and behavior. PMID- 28588513 TI - Testing Separability and Independence of Perceptual Dimensions with General Recognition Theory: A Tutorial and New R Package (grtools). AB - Determining whether perceptual properties are processed independently is an important goal in perceptual science, and tools to test independence should be widely available to experimental researchers. The best analytical tools to test for perceptual independence are provided by General Recognition Theory (GRT), a multidimensional extension of signal detection theory. Unfortunately, there is currently a lack of software implementing GRT analyses that is ready-to-use by experimental psychologists and neuroscientists with little training in computational modeling. This paper presents grtools, an R package developed with the explicit aim of providing experimentalists with the ability to perform full GRT analyses using only a couple of command lines. We describe the software and provide a practical tutorial on how to perform each of the analyses available in grtools. We also provide advice to researchers on best practices for experimental design and interpretation of results when applying GRT and grtools. PMID- 28588515 TI - Does Gender of Administrator Matter? National Study Explores U.S. University Administrators' Attitudes About Retaining Women Professors in STEM. AB - Omnipresent calls for more women in university administration presume women will prioritize using resources and power to increase female representation, especially in STEM fields where women are most underrepresented. However, empirical evidence is lacking for systematic differences in female vs. male administratorsAS attitudes. Do female administrators agree on which strategies are best, and do men see things differently? We explored United States college and university administratorsAS opinions regarding strategies, policies, and structural changes in their organizations designed to increase women professorsAS representation and retention in STEM fields. A comprehensive review of past research yielded a database of potentially-effective, recommended policies. A survey based on these policies was sent to provosts, deans, associate deans, and department chairs of STEM fields at 96 public and private research universities across the U.S. These administrators were asked to rate the quality and feasibility of each strategy; 474 provided data, of which 334 contained complete numerical data used in the analyses. Our data revealed that female (vs. male) administrators believed the 44 strategies were higher in quality overall-but not higher in feasibility-with 9 strategies perceived differently by women and men, after imposing conservative statistical controls. There was broad general agreement on the relative-quality rankings of the 44 strategies. Women (vs. men) gave higher quality ratings to increasing the value of teaching, service, and administrative experience in tenure/promotion decisions, increasing flexibility of federal-grant funding to accommodate mothers, conducting gender-equity research, and supporting shared tenure lines enabling work-life balance. Women (vs. men) believed it was more feasible for men to stop the tenure clock for 1 year for childrearing and for universities to support requests for shared tenure lines, but less feasible for women to chair search committees. Our national survey thus supported the belief that placing women into administration creates greater endorsement of strategies to attract and retain women in STEM, although the effectiveness of these strategies was outside the scope of this research. Topics of disagreement between women and men are potentially important focuses of future policy, because female administrators may have insights into how to retain women that male administrators do not share. PMID- 28588514 TI - Pathways from Trauma to Psychotic Experiences: A Theoretically Informed Model of Posttraumatic Stress in Psychosis. AB - In recent years, empirical data and theoretical accounts relating to the relationship between childhood victimization and psychotic experiences have accumulated. Much of this work has focused on co-occurring Posttraumatic Stress Disorder or putative causal mechanisms in isolation from each other. The complexity of posttraumatic stress reactions experienced in psychosis remains poorly understood. This paper therefore attempts to synthesize the current evidence base into a theoretically informed, multifactorial model of posttraumatic stress in psychosis. Three trauma-related vulnerability factors are proposed to give rise to intrusions and to affect how people appraise and cope with them. First, understandable attempts to survive trauma become habitual ways of regulating emotion, manifesting in cognitive-affective, behavioral and interpersonal responses. Second, event memories, consisting of perceptual and episodic representations, are impacted by emotion experienced during trauma. Third, personal semantic memory, specifically appraisals of the self and others, are shaped by event memories. It is proposed these vulnerability factors have the potential to lead to two types of intrusions. The first type is anomalous experiences arising from emotion regulation and/or the generation of novel images derived from trauma memory. The second type is trauma memory intrusions reflecting, to varying degrees, the retrieval of perceptual, episodic and personal semantic representations. It is speculated trauma memory intrusions may be experienced on a continuum from contextualized to fragmented, depending on memory encoding and retrieval. Personal semantic memory will then impact on how intrusions are appraised, with habitual emotion regulation strategies influencing people's coping responses to these. Three vignettes are outlined to illustrate how the model accounts for different pathways between victimization and psychosis, and implications for therapy are considered. The model is the first to propose how emotion regulation and autobiographical memory may lead to a range of intrusive experiences in psychosis, and therefore attempts to explain the different phenomenological associations observed between trauma and intrusions. However, it includes a number of novel hypotheses that require empirical testing, which may lead to further refinement. It is anticipated the model will assist research and practice, in the hope of supporting people to manage the impact of victimization on their lives. PMID- 28588516 TI - Children's Failure in Analogical Reasoning Tasks: A Problem of Focus of Attention and Information Integration? AB - Children's improved performance with age in analogy tasks has been explained by an increase in semantic knowledge of the items and the relations between them or by the development of an increased ability to inhibit irrelevant information. We tested the so-called "unbalanced attentional focus hypothesis" that claims that a failure to choose the "analogical" match can be the result of a difficulty to focus on all the relevant information available. Previous eye-tracking research has suggested, in analogies of the A:B::C:D format, that 5-6 year-olds organize their search around the C item. They focused significantly less than adults on the A:B pair, thereby hindering their discovering the relation(s) between A and B. We hypothesized that inducing them to focus their attention on the A:B pair at the beginning of the trial would affect their performance. In Experiment 1, increasing children's focus on the A:B pair did, indeed, lead to better performance. In contrast, in Experiment 2, focusing their attention on the A:B pair impaired performance when the most salient relation holding between A and B was, in fact, irrelevant for the analogy. By contrast, the obvious-but-irrelevant relation in the A:B pair had no negative effect on performance when no explicit A:B focusing was induced. These results are discussed in terms of the temporal organization of the task and availability of information, and of children's difficulties to disengage from the main goal of the task, when necessary. PMID- 28588519 TI - Editorial: From Organizational Welfare to Business Success: Higher Performance in Healthy Organizational Environments. PMID- 28588517 TI - Sleep, Affect, and Social Competence from Preschool to Preadolescence: Distinct Pathways to Emotional and Social Adjustment for Boys and for Girls. AB - Using a normative sample of 1,057 children studied across 4 waves over 6 years with multiple informants, we investigated transactional relations for sleep problems, anxious-depressed symptoms, and social functioning from preschool to preadolescence, assessing cumulative effects on children's emotional and social adjustment. To examine sex differences in the developmental processes, we conducted separate analyses for boys and girls. For both boys and girls, longitudinal cross-lagged panel analyses showed that preschool sleep problems directly predicted anxious-depressed symptoms 2 years later; indirect effects continued into preadolescence. For girls, early and later sleep problems directly or indirectly predicted a wide variety of preadolescent emotional and social adjustment domains (e.g., depressive symptoms, school competence, emotion regulation, risk-taking behaviors). For boys, social competence played a more important role than sleep problems in predicting preadolescent adjustment. Among the first set of findings that demonstrate longitudinal relations between sleep problems and social functioning in middle childhood and preadolescence, these results support Dahl's and Walker's neurological models of sleep and emotional functioning. We discuss these findings in light of relations between sleep and affect during pre-pubertal development and discuss differential findings for boys and girls. PMID- 28588518 TI - "I Want It All, and I Want It Now": Lifetime Prevalence and Reasons for Using and Abstaining from Controlled Performance and Appearance Enhancing Substances (PAES) among Young Exercisers and Amateur Athletes in Five European Countries. AB - Doping use in recreational sports is an emerging issue that has received limited attention so far in the psychological literature. The present study assessed the lifetime prevalence of controlled performance and appearance enhancing substances (PAES), and used behavioral reasoning theory to identify the reasons for using and for avoiding using controlled PAES in young exercisers across five European countries, in the context of the "SAFE YOU" Project. Participants were 915 young amateur athletes and exercisers (M = 21.62; SD = 2.62) from Cyprus, Germany, Greece, Italy, and UK who completed an anonymous questionnaire that included measures of self-reported use of controlled PAES, as well as reasons for using and not using controlled PAES. The results of the descriptive analyses demonstrated that almost one out five exercisers in the sample had a previous experience with controlled PAES. Higher prevalence rates were found in Greece and Cyprus and lower in Italy. The most frequently reported reasons for using controlled PAES included achieving the desired results faster; pushing the self to the (physical) limits; and recovering faster after exercise/training. Furthermore, the most frequently reported reasons for not using controlled PAES involved worry about any possible adverse health effects; not feeling the need for using them; and wanting to see what can be achieved naturally without using any controlled PAES. The findings of the present study indicate that the use of controlled PAES is fast becoming a crisis in amateur sports and exercise settings and highlight the need for preventive action and concerted anti-doping education efforts. PMID- 28588520 TI - Emotional Expression in Simple Line Drawings of a Robot's Face Leads to Higher Offers in the Ultimatum Game. AB - In the present study, we investigated whether expressing emotional states using a simple line drawing to represent a robot's face can serve to elicit altruistic behavior from humans. An experimental investigation was conducted in which human participants interacted with a humanoid robot whose facial expression was shown on an LCD monitor that was mounted as its head (Study 1). Participants were asked to play the ultimatum game, which is usually used to measure human altruistic behavior. All participants were assigned to be the proposer and were instructed to decide their offer within 1 min by controlling a slider bar. The corners of the robot's mouth, as indicated by the line drawing, simply moved upward, or downward depending on the position of the slider bar. The results suggest that the change in the facial expression depicted by a simple line drawing of a face significantly affected the participant's final offer in the ultimatum game. The offers were increased by 13% when subjects were shown contingent changes of facial expression. The results were compared with an experiment in a teleoperation setting in which participants interacted with another person through a computer display showing the same line drawings used in Study 1 (Study 2). The results showed that offers were 15% higher if participants were shown a contingent facial expression change. Together, Studies 1 and 2 indicate that emotional expression in simple line drawings of a robot's face elicits the same higher offer from humans as a human telepresence does. PMID- 28588521 TI - The Effect of Extreme Response and Non-extreme Response Styles on Testing Measurement Invariance. AB - Extreme and non-extreme response styles (RSs) are prevalent in survey research using Likert-type scales. Their effects on measurement invariance (MI) in the context of confirmatory factor analysis are systematically investigated here via a Monte Carlo simulation study. Using the parameter estimates obtained from analyzing a 2007 Trends in International Mathematics and Science Study data set, a population model was constructed. Original and contaminated data with one of two RSs were generated and analyzed via multi-group confirmatory factor analysis with different constraints of MI. The results indicated that the detrimental effects of response style on MI have been underestimated. More specifically, these two RSs had a substantially negative impact on both model fit and parameter recovery, suggesting that the lack of MI between groups may have been caused by the RSs, not the measured factors of focal interest. Practical implications are provided to help practitioners to detect RSs and determine whether RSs are a serious threat to MI. PMID- 28588523 TI - Normal Theory GLS Estimator for Missing Data: An Application to Item-Level Missing Data and a Comparison to Two-Stage ML. AB - Structural equation models (SEMs) can be estimated using a variety of methods. For complete normally distributed data, two asymptotically efficient estimation methods exist: maximum likelihood (ML) and generalized least squares (GLS). With incomplete normally distributed data, an extension of ML called "full information" ML (FIML), is often the estimation method of choice. An extension of GLS to incomplete normally distributed data has never been developed or studied. In this article we define the "full information" GLS estimator for incomplete normally distributed data (FIGLS). We also identify and study an important application of the new GLS approach. In many modeling contexts, the variables in the SEM are linear composites (e.g., sums or averages) of the raw items. For instance, SEMs often use parcels (sums of raw items) as indicators of latent factors. If data are missing at the item level, but the model is at the composite level, FIML is not possible. In this situation, FIGLS may be the only asymptotically efficient estimator available. Results of a simulation study comparing the new FIGLS estimator to the best available analytic alternative, two stage ML, with item-level missing data are presented. PMID- 28588522 TI - The Positive and Negative Experiences of Caregiving for Siblings of Young People with First Episode Psychosis. AB - Background: The impact of first episode psychosis (FEP) upon parents' experience of caregiving has been well-documented. However, the determinants and nature of this remain poorly understood in siblings. It is hypothesized that siblings of young people with FEP are also impacted by caregiving and burden. This study aimed to characterize the experience of caregiving for siblings of young people with FEP. Method: Survey methodology was used to explore the experience of 157 siblings in the first 18 months of their brother or sister's treatment for FEP. Participants reported on their appraisal of the negative and positive aspects of caregiving as measured by the Experience of Caregiving Inventory (ECI). Descriptive statistics were used to establish the results for the total sample as well as for gender and birth order differences. A series of multivariate regression analyses were conducted to determine the relationships between illness characteristics and siblings' experience of caregiving. Results: Older brothers reported the lowest scores for negative experiences in caregiving and younger sisters reported the highest. Negative experiences in caregiving resulted in less warmth within the sibling relationship and impacted negatively upon quality of life. When the young person with FEP had attempted suicide and/or been physically violent, siblings experienced more caregiver burden. Multivariate analysis showed that female gender was a significant factor in explaining the impact of illness related variables on the experience of caregiving. Conclusion: Suicide attempts and a history of violence resulted in higher caregiving burden for siblings regardless of whether they lived with the young person experiencing FEP or not. Female siblings are at higher risk of negative experiences from caregiving resulting in a reduced quality of life and a changed sibling relationship. Suicide attempts and violence are indicators for intensive case management to improve outcomes for the individual with FEP which may in turn reduce the burden experienced by the sibling. Clinicians can use these findings to identify siblings, assertively intervene and provide increased psychological support, psychoeducation and practical problem solving to reduce the burden. The caregiving role that they already play for their ill brother or sister should be recognized. PMID- 28588525 TI - Interventions for Subjects with Depressive Symptoms with or without Unhealthy Alcohol Use: Are There Different Patterns of Change? AB - Background: It has been suggested that alcohol problems negatively affect therapeutic interventions for depression. This study examines the patterns of change in depressive symptoms following an intervention for depression, in participants with or without comorbid unhealthy alcohol use. Methods: Depressive symptoms (BDI-II), perceived control of depressive symptoms (UNCONTROL) and unhealthy alcohol use (AUDIT) were assessed in 116 patients before and after attending a cognitive behavioral psychoeducational intervention for depression. At pretest the mean score of AUDIT was 8.1, indicating a, on average, risk of harmful level of alcohol abuse. At pretest the majority of the total sample had a moderate degree of depressive symptoms, with a mean BDI-II score of 25.1 and 36.2% had a risky use of alcohol as measured with AUDIT score at 8 points or above. To assess the relationship between depressive symptoms, perceived uncontrollability of depression and alcohol use across time, a cross-lagged panel model was estimated. Results: A clinical significant reduction of depressive symptoms, and a parallel and statistically significant increase in the perceived control of depressive symptoms, was identified after attending a cognitive behavioral psychoeducational intervention for depression. At posttest, the mean BDI-II score was 17.8, demonstrating a statistically significant decrease of 7.3 points in depressive symptoms from before starting the course to 6 months later. The effect size (d-value) of 0.83 can be interpreted as a large decrease in depressive symptoms. In this sample alcohol use and depressive symptoms seemed to be unrelated. The cross-lagged correlation panel analysis indicated that a high degree of perceived control of depressive symptoms leads to a reduction in depressive symptoms, and not vice versa. Conclusion: We found that this intervention for depression were effective in reducing depressive symptoms. The patterns of change seemed to be independent of risky use of alcohol, although leaving the study was systematically associated with higher AUDIT-scores. As participants with or without unhealthy alcohol use show the same patterns of change regarding reduction of depressive symptoms and perceived control of depression, both groups could be offered the same cognitive behavioral psychoeducational interventions for depression. PMID- 28588526 TI - Reading Words or Pictures: Eye Movement Patterns in Adults and Children Differ by Age Group and Receptive Language Ability. AB - This study was conducted to explore the differences in the degree of attention given to Chinese print and pictures by children and adults when they read picture books with and without Chinese words. We used an eye tracker from SensoMotoric Instruments to record the visual fixations of the subjects. The results showed that the adults paid more attention to Chinese print and looked at the print sooner than the children did. The stronger the children's receptive language abilities were, the less time it took them to view the pictures. All participants spent the same amount of time looking at the pictures whether Chinese words were present or absent. PMID- 28588524 TI - Perceptual Plasticity for Auditory Object Recognition. AB - In our auditory environment, we rarely experience the exact acoustic waveform twice. This is especially true for communicative signals that have meaning for listeners. In speech and music, the acoustic signal changes as a function of the talker (or instrument), speaking (or playing) rate, and room acoustics, to name a few factors. Yet, despite this acoustic variability, we are able to recognize a sentence or melody as the same across various kinds of acoustic inputs and determine meaning based on listening goals, expectations, context, and experience. The recognition process relates acoustic signals to prior experience despite variability in signal-relevant and signal-irrelevant acoustic properties, some of which could be considered as "noise" in service of a recognition goal. However, some acoustic variability, if systematic, is lawful and can be exploited by listeners to aid in recognition. Perceivable changes in systematic variability can herald a need for listeners to reorganize perception and reorient their attention to more immediately signal-relevant cues. This view is not incorporated currently in many extant theories of auditory perception, which traditionally reduce psychological or neural representations of perceptual objects and the processes that act on them to static entities. While this reduction is likely done for the sake of empirical tractability, such a reduction may seriously distort the perceptual process to be modeled. We argue that perceptual representations, as well as the processes underlying perception, are dynamically determined by an interaction between the uncertainty of the auditory signal and constraints of context. This suggests that the process of auditory recognition is highly context-dependent in that the identity of a given auditory object may be intrinsically tied to its preceding context. To argue for the flexible neural and psychological updating of sound-to-meaning mappings across speech and music, we draw upon examples of perceptual categories that are thought to be highly stable. This framework suggests that the process of auditory recognition cannot be divorced from the short-term context in which an auditory object is presented. Implications for auditory category acquisition and extant models of auditory perception, both cognitive and neural, are discussed. PMID- 28588528 TI - Music Audiences 3.0: Concert-Goers' Psychological Motivations at the Dawn of Virtual Reality. AB - Reviewing consumers' motivations to attend performances in a continuously evolving social and technological context is essential because live concerts generate an important and growing share of revenues for the music industry. Evolving fans' preferences and technological innovations constantly alter the way music is distributed and consumed. In a marketing 3.0 era, what consumers do with music is becoming more significant than simply owning or listening to a song. These changes are not only blurring the lines between production and consumption (i.e., co-creation), but also distorting the concept of live attendance altogether. Although mediated performances typically lack presence and authenticity, recent advances in immersive technologies, such as spherical videos and virtual reality goggles, could represent a new form of experiencing live music. PMID- 28588529 TI - Program to Promote Personal and Social Responsibility in the Secondary Classroom. AB - The performance of school children has been studied by considering partial relationships between several personal variables such as the link between cognition and motivation. However, contextual variables, such as a child's willingness to accept social responsibility, also influence students' social and academic performance. Thus, students with greater responsibility have a better attitude toward their studies, resulting in higher academic achievement. This 2 year study aims to reveal to what extent an intervention program affects student performance and is based on the Theory of Positive Action among young people proposed by Don Hellison and the Theory of Reasoned Action by Fishbein and Ajzen. The program focuses on positive influences on social and personal responsibility, taking into consideration parental styles, gender, and academic performance. The program was a part of the educational curricula in participating schools and it targeted four main areas: (a) teaching units using academic texts about social responsibility, (b) student training in mediation processes, (c) teacher training, and (d) family training and involvement. A total of 271 students took part from first and second year of Secondary Education (12-14 years old). The experimental group was made up of 132 students while the remaining 139 formed the control group. All participants completed the Assessment Scale of Social Responsibility Attitudes in Secondary Education and the Parent-Adolescent Communication Scale. Results show that students in the experimental group performed significantly better than those in the control group. Additionally, the issue of social responsibility seems to be related to commitment, self-discipline and perseverance. Regarding gender, males appear to score higher in the factor for well-mannered, friendly and tidy. Finally, a positive relationship has been identified between social responsibility attitudes and parenting with an open communicational style. This paper discusses the results so that schools can include programs aimed at improving social and personal responsibility. PMID- 28588527 TI - Unconscious Imagination and the Mental Imagery Debate. AB - Traditionally, philosophers have appealed to the phenomenological similarity between visual experience and visual imagery to support the hypothesis that there is significant overlap between the perceptual and imaginative domains. The current evidence, however, is inconclusive: while evidence from transcranial brain stimulation seems to support this conclusion, neurophysiological evidence from brain lesion studies (e.g., from patients with brain lesions resulting in a loss of mental imagery but not a corresponding loss of perception and vice versa) indicates that there are functional and anatomical dissociations between mental imagery and perception. Assuming that the mental imagery and perception do not overlap, at least, to the extent traditionally assumed, then the question arises as to what exactly mental imagery is and whether it parallels perception by proceeding via several functionally distinct mechanisms. In this review, we argue that even though there may not be a shared mechanism underlying vision for perception and conscious imagery, there is an overlap between the mechanisms underlying vision for action and unconscious visual imagery. On the basis of these findings, we propose a modification of Kosslyn's model of imagery that accommodates unconscious imagination and explore possible explanations of the quasi-pictorial phenomenology of conscious visual imagery in light of the fact that its underlying neural substrates and mechanisms typically are distinct from those of visual experience. PMID- 28588530 TI - Do Online Privacy Concerns Predict Selfie Behavior among Adolescents, Young Adults and Adults? AB - Selfies, or self-portraits, are often taken and shared on social media for online self-presentation reasons, which are considered essential for the psychosocial development and well-being of people in today's culture. Despite the growing popularity and widespread sharing of selfies in the online space, little is known about how privacy concerns moderate selfie behavior. In addition to this, it is also not known whether privacy concerns across age and gender groups influence selfie behavior. To address this timely issue, a survey assessing common selfie behaviors, that is, frequency of taking (individual and group selfies), editing (cropping and filtering), and posting selfies online, and social media privacy concerns (over personal data being accessed and misused by third parties) was conducted. The web-survey was administered to 3,763 Norwegian social media users, ranging from 13 to 50 years, with a preponderance of women (n = 2,509, 66.7%). The present study investigated the impact of privacy concerns on selfie behaviors across gender and age groups (adolescent, young adult, and adult) by use of the structural equation modeling approach. The results suggest that young adults have greater privacy concerns compared to adolescents and adults. Females have greater privacy concerns than males. Greater privacy concerns among female social media users were linked to lower engagement in selfie behavior, but privacy concerns did not influence selfie behavior in the case of male adolescents and young adults. Overall, privacy concerns were more consistently and inversely related to selfie behavior (taking and posting) among females than males. The study results have theoretical as well as practical implications for both researchers and policy makers. PMID- 28588531 TI - The Effects of Objective and Subjective Socioeconomic Status on Subjective Well Being among Rural-to-Urban Migrants in China: The Moderating Role of Subjective Social Mobility. AB - Although previous investigations have agreed that Chinese rural-to-urban migrants' socioeconomic status (SES) increases with their migration, the association between SES and subjective well-being is uncertain. To address this research gap, the present study proposed that the association between objective SES and subjective well-being is mediated by subjective SES. This model was tested with a sample of 432 Chinese rural-to-urban migrants. The results indicate a significant association between objective SES and subjective well-being and a partial mediating effect of subjective SES. Furthermore, subjective social mobility, which is one's expectation about the possibility to move upward in the social hierarchy, was found to moderate both the direct path from objective SES to subjective well-being and the indirect path from subjective SES to subjective well-being. These findings suggest that Chinese rural-to-urban migrants gained in subjective well-being not only because of direct financial achievement but also because of their perceptions and beliefs about their relative social status. PMID- 28588532 TI - Immune to Situation: The Self-Serving Bias in Unambiguous Contexts. AB - Traditionally, the self-serving bias has been investigated in ambiguous contexts in which participants work on tasks that measure novel abilities before making attributions without clear criteria for success or failure feedback. Prior studies have confirmed that the self-serving bias is pervasive in the general population, yet it varies significantly across situations involving ambiguous contexts. The present study features an unambiguous context encompassing interpersonal events that involved implicit causality (with the "self" as an actor or recipient), the inherent logic of which indicated attribution criteria. The aim of this study was to explore whether there is a self-serving bias in unambiguous contexts and to examine whether it is as sensitive to situation as it has been shown to be in ambiguous contexts. The results showed that, in an unambiguous context, participants exhibited self-serving bias in relation to attribution associated with negative interpersonal events. Additionally, the self serving bias was greater in the actor condition relative to the recipient condition (Study 1), and this effect was not affected by the level of self awareness, which was manipulated by the use or otherwise of a camera during the experiment (Study 2). Our findings provide evidence for the existence of the self serving bias in unambiguous contexts. Moreover, the self-serving bias was shown to be immune to situation in unambiguous contexts, but it did depend on factors associated with the events per se, such as the actor versus recipient role that the self played in interpersonal events. PMID- 28588533 TI - A Probabilistic Model of Meter Perception: Simulating Enculturation. AB - Enculturation is known to shape the perception of meter in music but this is not explicitly accounted for by current cognitive models of meter perception. We hypothesize that the induction of meter is a result of predictive coding: interpreting onsets in a rhythm relative to a periodic meter facilitates prediction of future onsets. Such prediction, we hypothesize, is based on previous exposure to rhythms. As such, predictive coding provides a possible explanation for the way meter perception is shaped by the cultural environment. Based on this hypothesis, we present a probabilistic model of meter perception that uses statistical properties of the relation between rhythm and meter to infer meter from quantized rhythms. We show that our model can successfully predict annotated time signatures from quantized rhythmic patterns derived from folk melodies. Furthermore, we show that by inferring meter, our model improves prediction of the onsets of future events compared to a similar probabilistic model that does not infer meter. Finally, as a proof of concept, we demonstrate how our model can be used in a simulation of enculturation. From the results of this simulation, we derive a class of rhythms that are likely to be interpreted differently by enculturated listeners with different histories of exposure to rhythms. PMID- 28588535 TI - Understanding Why Children Commit Scale Errors: Scale Error and Its Relation to Action Planning and Inhibitory Control, and the Concept of Size. AB - Scale error is a phenomenon where young children attempt to perform inappropriate actions on miniature object without considering the actual size of the object. The present study examined two hypotheses on what factors contribute to the occurrence of scale errors, focusing on the following possible factors: action planning and inhibitory control, and concept of size. Thus, we hypothesize that scale errors derived from either immaturity of their action planning and inhibitory control abilities or understanding of size concepts. The results revealed that the concept of size was significantly negatively associated with the occurrence of scale errors. However, action planning and inhibitory control were not significantly associated with the occurrence of scale errors. These results suggest that scale errors may arise from a misunderstanding of size concepts. PMID- 28588534 TI - Cognitive Effects of ThinkRx Cognitive Rehabilitation Training for Eleven Soldiers with Brain Injury: A Retrospective Chart Review. AB - Cognitive rehabilitation training is a promising technique for remediating the cognitive deficits associated with brain injury. Extant research is dominated by computer-based interventions with varied results. Results from clinician delivered cognitive rehabilitation are notably lacking in the literature. The current study examined the cognitive outcomes following ThinkRx, a clinician delivered cognitive rehabilitation training program for soldiers recovering from traumatic brain injury and acquired brain injury. In a retrospective chart review, we examined cognitive outcomes of 11 cases who had completed an average of 80 h of ThinkRx cognitive rehabilitation training delivered by clinicians and supplemented with digital training exercises. Outcome measures included scores from six cognitive skill batteries on the Woodcock Johnson - III Tests of Cognitive Abilities. Participants achieved gains in all cognitive skills tested and achieved statistically significant changes in long-term memory, processing speed, auditory processing, and fluid reasoning with very large effect sizes. Clinically significant changes in multiple cognitive skills were also noted across cases. Results of the study suggest that ThinkRx clinician-delivered cognitive training supplemented with digital exercises may be a viable method for targeting the cognitive deficits associated with brain injury. PMID- 28588536 TI - Differential Signatures of Second Language Syntactic Performance and Age on the Structural Properties of the Left Dorsal Pathway. AB - In adult second language (L2) acquisition, individual differences are considerably large even among people with similar experiences. The neural mechanisms underlying this variability would include structural plasticity of language-related pathways. To elucidate such neuroplasticity, we focused on the transitional period of adolescence, which is associated with certain plasticity toward maturation following the sensitive period of language acquisition (<=12 years old). The adolescent brain would thus be influenced by age-dependent factors, as well as performances in L2. Here, we examined individual differences in L2 performances controlling the duration of experience to reveal the differential signatures of performances and age on the plasticity of structural properties in major language-related pathways. We recruited Japanese students at two ages, i.e., junior (age: 13-14) and senior (age: 16-17) high-school students, all of whom started to expose to English at age 12 or 13. We divided them into subgroups, so that either L2 performance [Junior (High)/Senior (Low)] or age [Senior (Low)/Senior (High)] was matched in group comparisons; the duration of L2 experience was also controlled between the Senior (Low) and Senior (High) groups. We then examined the thickness and fractional anisotropy (FA) of the dorsal and ventral pathways, i.e., the arcuate fasciculus (Arcuate) and inferior fronto occipital fasciculus (IFOF), respectively, using semi-automatic methods for selecting regions without branches. Regarding FA in the left Arcuate, the Senior (High) group showed significantly higher FA than the other two groups, indicating performance-related group differences. Further, FA in the left Arcuate was selectively correlated with the accuracy of a syntactic task. Regarding the thickness of the left Arcuate, the Senior (High) and Senior (Low) groups showed significantly larger thickness than the Junior (High) group, indicating age related group differences. These differential performance-related and age-related signatures were evident on the left Arcuate alone, in contrast to the right Arcuate that showed only mild differences in thickness, and to the bilateral IFOF that lacked either signature. Our results suggest that the left dorsal pathway continued to develop to adolescence, and that performance differences in a syntactic task can be predicted by its FA, independent of age and the duration of experience. PMID- 28588537 TI - Using CNN Features to Better Understand What Makes Visual Artworks Special. AB - One of the goal of computational aesthetics is to understand what is special about visual artworks. By analyzing image statistics, contemporary methods in computer vision enable researchers to identify properties that distinguish artworks from other (non-art) types of images. Such knowledge will eventually allow inferences with regard to the possible neural mechanisms that underlie aesthetic perception in the human visual system. In the present study, we define measures that capture variances of features of a well-established Convolutional Neural Network (CNN), which was trained on millions of images to recognize objects. Using an image dataset that represents traditional Western, Islamic and Chinese art, as well as various types of non-art images, we show that we need only two variance measures to distinguish between the artworks and non-art images with a high classification accuracy of 93.0%. Results for the first variance measure imply that, in the artworks, the subregions of an image tend to be filled with pictorial elements, to which many diverse CNN features respond (richness of feature responses). Results for the second measure imply that this diversity is tied to a relatively large variability of the responses of individual CNN feature across the subregions of an image. We hypothesize that this combination of richness and variability of CNN feature responses is one of properties that makes traditional visual artworks special. We discuss the possible neural underpinnings of this perceptual quality of artworks and propose to study the same quality also in other types of aesthetic stimuli, such as music and literature. PMID- 28588538 TI - Object Recognition in Mental Representations: Directions for Exploring Diagnostic Features through Visual Mental Imagery. AB - One of the fundamental goals of object recognition research is to understand how a cognitive representation produced from the output of filtered and transformed sensory information facilitates efficient viewer behavior. Given that mental imagery strongly resembles perceptual processes in both cortical regions and subjective visual qualities, it is reasonable to question whether mental imagery facilitates cognition in a manner similar to that of perceptual viewing: via the detection and recognition of distinguishing features. Categorizing the feature content of mental imagery holds potential as a reverse pathway by which to identify the components of a visual stimulus which are most critical for the creation and retrieval of a visual representation. This review will examine the likelihood that the information represented in visual mental imagery reflects distinctive object features thought to facilitate efficient object categorization and recognition during perceptual viewing. If it is the case that these representational features resemble their sensory counterparts in both spatial and semantic qualities, they may well be accessible through mental imagery as evaluated through current investigative techniques. In this review, methods applied to mental imagery research and their findings are reviewed and evaluated for their efficiency in accessing internal representations, and implications for identifying diagnostic features are discussed. An argument is made for the benefits of combining mental imagery assessment methods with diagnostic feature research to advance the understanding of visual perceptive processes, with suggestions for avenues of future investigation. PMID- 28588539 TI - What We Talk about When We Talk about Unconscious Processing - A Plea for Best Practices. AB - In this perspective article, we first outline the large diversity of methods, measures, statistical analyses, and concepts in the field of the experimental study of unconscious processing. We then suggest that this diversity implies that comparisons between different studies on unconscious processing are fairly limited, especially when stimulus awareness has been assessed in different ways. Furthermore, we argue that flexible choices of methods and measures will inevitably lead to an overestimation of unconscious processes. In the concluding paragraph, we briefly present solutions and strategies for future research. We make a plea for the introduction of "best practices," similar to previous attempts to constitute practicing standards for functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). PMID- 28588540 TI - Evaluation-Dependent Representation in Risk Defusing. PMID- 28588541 TI - Parenting Stress, Mental Health, Dyadic Adjustment: A Structural Equation Model. AB - Objective: In the 1st year of the post-partum period, parenting stress, mental health, and dyadic adjustment are important for the wellbeing of both parents and the child. However, there are few studies that analyze the relationship among these three dimensions. The aim of this study is to investigate the relationships between parenting stress, mental health (depressive and anxiety symptoms), and dyadic adjustment among first-time parents. Method: We studied 268 parents (134 couples) of healthy babies. At 12 months post-partum, both parents filled out, in a counterbalanced order, the Parenting Stress Index-Short Form, the Edinburgh Post-natal Depression Scale, the State-Trait Anxiety Inventory, and the Dyadic Adjustment Scale. Structural equation modeling was used to analyze the potential mediating effects of mental health on the relationship between parenting stress and dyadic adjustment. Results: Results showed the full mediation effect of mental health between parenting stress and dyadic adjustment. A multi-group analysis further found that the paths did not differ across mothers and fathers. Discussion: The results suggest that mental health is an important dimension that mediates the relationship between parenting stress and dyadic adjustment in the transition to parenthood. PMID- 28588543 TI - Commentary: The poverty of embodied cognition. PMID- 28588542 TI - Prior Knowledge of Object Associations Shapes Attentional Templates and Information Acquisition. AB - Studies on attentional selection typically use unpredictable and meaningless stimuli, such as simple shapes and oriented lines. The assumption is that using these stimuli minimizes effects due to learning or prior knowledge, such that the task performance indexes a "pure" measure of the underlying cognitive ability. However, prior knowledge of the test stimuli and related stimuli acquired before or during the task impacts performance in meaningful ways. This mini review focuses on prior knowledge of object associations, because it is an important, yet often ignored, aspect of attentional selection. We first briefly review recent studies demonstrating that how objects are selected during visual search depends on the participant's prior experience with other objects associated with the target. These effects appear with both task-relevant and task-irrelevant knowledge. We then review how existing object associations may influence subsequent learning of new information, which is both a driver and a consequence of selection processes. These insights highlight the importance of one aspect of prior knowledge for attentional selection and information acquisition. We briefly discuss how this work with young adults may inform other age groups throughout the lifespan, as learners gradually increase their prior knowledge. Importantly, these insights have implications for developing more accurate measurements of cognitive abilities. PMID- 28588544 TI - Editorial: Personality and Cognition in Economic Decision Making. PMID- 28588545 TI - The Role of Motivation in Complex Problem Solving. PMID- 28588546 TI - Neuroprotective Effects of Physical Activity: Evidence from Human and Animal Studies. AB - In the present article, we provide a review of current knowledge regarding the role played by physical activity (PA) in preventing age-related cognitive decline and reducing risk of dementia. The cognitive benefits of PA are highlighted by epidemiological, neuroimaging and behavioral studies. Epidemiological studies identified PA as an influential lifestyle factor in predicting rates of cognitive decline. Individuals physically active from midlife show a reduced later risk of cognitive impairment. Neuroimaging studies documented attenuation of age-related brain atrophy, and also increase of gray matter and white matter of brain areas, including frontal and temporal lobes. These structural changes are often associated with improved cognitive performance. Importantly, the brain regions that benefit from PA are also those regions that are often reported to be severely affected in dementia. Animal model studies provided significant information about biomechanisms that support exercise-enhanced neuroplasticity, such as angiogenesis and upregulation of growth factors. Among the growth factors, the brain-derived neurotrophic factor seems to play a significant role. Another putative factor that might contribute to beneficial effects of exercise is the neuropeptide orexin-A. The beneficial effects of PA may represent an important resource to hinder the cognitive decline associated with aging. PMID- 28588547 TI - Improving Dual-Task Walking Paradigms to Detect Prodromal Parkinson's and Alzheimer's Diseases. AB - Gait control is a complex movement, relying on spinal, subcortical, and cortical structures. The presence of deficits in one or more of these structures will result in changes in gait automaticity and control, as is the case in several neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). By reviewing recent findings in this field of research, current studies have shown that gait performance assessment under dual-task conditions could contribute to predict both of these diseases. Such suggestions are relevant mainly for people at putatively high risk of developing AD (i.e., older adults with mild cognitive impairment subtypes) or PD (i.e., older adults with either Mild Parkinsonian signs or LRRK2 G2019S mutation). Despite the major importance of these results, the type of cognitive task that should be used as a concurrent secondary task has to be selected among the plurality of tasks proposed in the literature. Furthermore, the key aspects of gait control that represent sensitive and specific "gait signatures" for prodromal AD or PD need to be determined. In the present perspective article, we suggest the use of a Stroop interference task requiring inhibitory attentional control and a set-shifting task requiring reactive flexibility as being particularly relevant secondary tasks for challenging gait in prodromal AD and PD, respectively. Investigating how inhibition and cognitive flexibility interfere with gait control is a promising avenue for future research aimed at enhancing early detection of AD and PD, respectively. PMID- 28588548 TI - Thyroxine (T4) Transfer from Blood to Cerebrospinal Fluid in Sheep Isolated Perfused Choroid Plexus: Role of Multidrug Resistance-Associated Proteins and Organic Anion Transporting Polypeptides. AB - Thyroxine (T4) enters the brain either directly across the blood-brain barrier (BBB) or indirectly via the choroid plexus (CP), which forms the blood cerebrospinal fluid barrier (B-CSF-B). In this study, using isolated perfused CP of the sheep by single-circulation paired tracer and steady-state techniques, T4 transport mechanisms from blood into lateral ventricle CP has been characterized as the first step in the transfer across the B-CSF-B. After removal of sheep brain, the CPs were perfused with 125I-T4 and 14C-mannitol. Unlabeled T4 was applied during single tracer technique to assess the mode of maximum uptake (Umax) and the net uptake (Unet) on the blood side of the CP. On the other hand, in order to characterize T4 protein transporters, steady-state extraction of 125I T4 was measured in presence of different inhibitors such as probenecid, verapamil, BCH, or indomethacin. Increasing the concentration of unlabeled-T4 resulted in a significant reduction in Umax%, which was reflected by a complete inhibition of T4 uptake into CP. In fact, the obtained Unet% decreased as the concentration of unlabeled-T4 increased. The addition of probenecid caused a significant inhibition of T4 transport, in comparison to control, reflecting the presence of a carrier mediated process at the basolateral side of the CP and the involvement of multidrug resistance-associated proteins (MRPs: MRP1 and MRP4) and organic anion transporting polypeptides (Oatp1, Oatp2, and Oatp14). Moreover, verapamil, the P-glycoprotein (P-gp) substrate, resulted in ~34% decrease in the net extraction of T4, indicating that MDR1 contributes to T4 entry into CSF. Finally, inhibition in the net extraction of T4 caused by BCH or indomethacin suggests, respectively, a role for amino acid "L" system and MRP1/Oatp1 in mediating T4 transfer. The presence of a carrier-mediated transport mechanism for cellular uptake on the basolateral membrane of the CP, mainly P-gp and Oatp2, would account for the efficient T4 transport from blood to CSF. The current study highlights a carrier-mediated transport mechanism for T4 movement from blood to brain at the basolateral side of B-CSF-B/CP, as an alternative route to BBB. PMID- 28588549 TI - Amyotrophic Lateral Sclerosis and Myasthenia Gravis Overlap Syndrome: A Review of Two Cases and the Associated Literature. AB - OBJECTIVE: To describe the characteristics of patients with amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG) overlap syndrome and explore the relationship between the two diseases. METHODS: We conducted a search of medical records at Peking Union Medical University Hospital from 1983 to 2015 for coexistence of ALS and MG and searched the PubMed database for all literature describing ALS and MG overlap syndrome published through December 2016. We analyzed the clinical and neurophysiological characteristics of patients by groups according to strict diagnostic criteria. RESULTS: We presented 2 patients in our database with combined ALS and MG, and together with 25 cases reported in the literature, the patients were divided into 4 groups: 12 patients with MG followed by ALS, 8 patients with ALS followed by MG, 5 ALS patients with false positive anti-acetylcholine receptor, and the other 2 ALS patients with only myasthenia symptoms. Most patients had limb onset ALS, and myasthenia symptoms mainly affected ocular and bulbar muscles. Clinical and neurophysiological characteristics were summarized. CONCLUSION: These findings support the conclusion that immunological mechanisms and alterations in the neuromuscular junction are related to ALS pathogenesis. PMID- 28588550 TI - The Role of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) in Adipogenesis: Applying Knowledge from the Fish Aquaculture Industry to Biomedical Research. AB - The tropical freshwater zebrafish has recently emerged as a valuable model organism for the study of adipose tissue biology and obesity-related disease. The strengths of the zebrafish model system are its wealth of genetic mutants, transgenic tools, and amenability to high-resolution imaging of cell dynamics within live animals. However, zebrafish adipose research is at a nascent stage and many gaps exist in our understanding of zebrafish adipose physiology and metabolism. By contrast, adipose research within other, closely related, teleost species has a rich and extensive history, owing to the economic importance of these fish as a food source. Here, we compare and contrast knowledge on peroxisome proliferator-activated receptor gamma (PPARG)-mediated adipogenesis derived from both biomedical and aquaculture literatures. We first concentrate on the biomedical literature to (i) briefly review PPARG-mediated adipogenesis in mammals, before (ii) reviewing Pparg-mediated adipogenesis in zebrafish. Finally, we (iii) mine the aquaculture literature to compare and contrast Pparg-mediated adipogenesis in aquaculturally relevant teleosts. Our goal is to highlight evolutionary similarities and differences in adipose biology that will inform our understanding of the role of adipose tissue in obesity and related disease. PMID- 28588552 TI - Commentary: Prolactin Alters Blood Pressure by Modulating the Activity of Endothelial Nitric Oxide Synthase. PMID- 28588551 TI - Functional Thyroid Follicular Cells Differentiation from Human-Induced Pluripotent Stem Cells in Suspension Culture. AB - The replacement of regenerated thyroid follicular cells (TFCs) is a promising therapeutic strategy for patients with hypothyroidism. Here, we have succeeded in inducing functional TFCs from human-induced pluripotent stem cells (iPSCs) in scalable suspension culture. Differentiation of iPSCs with Activin A treatment produced Sox17- and FoxA2-expressing definitive endodermal cells that also expressed thyroid transcription factors Pax8 and Nkx2-1. Further treatment with thyroid-stimulating hormone (TSH) induced TFCs expressing various types of thyroid proteins including TSH receptor, sodium-iodide symporter, thyroglobulin, and thyroid peroxidase. Interestingly, differentiated cells secreted free thyroxine in vitro. These results indicate successful differentiation of human iPSCs to functional TFCs that may enable us to fabricate thyroid tissues for regenerative medicine and disease models. PMID- 28588553 TI - Running from Disease: Molecular Mechanisms Associating Dopamine and Leptin Signaling in the Brain with Physical Inactivity, Obesity, and Type 2 Diabetes. AB - Physical inactivity is a primary contributor to diseases such as obesity, cardiovascular disease, and type 2 diabetes. Accelerometry data suggest that a majority of US adults fail to perform substantial levels of physical activity needed to improve health. Thus, understanding the molecular factors that stimulate physical activity, and physical inactivity, is imperative for the development of strategies to reduce sedentary behavior and in turn prevent chronic disease. Despite many of the well-known health benefits of physical activity being described, little is known about genetic and biological factors that may influence this complex behavior. The mesolimbic dopamine system regulates motivating and rewarding behavior as well as motor movement. Here, we present data supporting the hypothesis that obesity may mechanistically lower voluntary physical activity levels via dopamine dysregulation. In doing so, we review data that suggest mesolimbic dopamine activity is a strong contributor to voluntary physical activity behavior. We also summarize findings suggesting that obesity leads to central dopaminergic dysfunction, which in turn contributes to reductions in physical activity that often accompany obesity. Additionally, we highlight examples in which central leptin activity influences physical activity levels in a dopamine-dependent manner. Future elucidation of these mechanisms will help support strategies to increase physical activity levels in obese patients and prevent diseases caused by physical inactivity. PMID- 28588556 TI - Bioremediation of Wastewater by Iron Oxide-Biochar Nanocomposites Loaded with Photosynthetic Bacteria. AB - It has been reported that bacteria-mediated degradation of contaminants is a practical and innocuous wastewater treatment. In addition, iron oxide nanoparticles (NP) are wastewater remediation agents with great potentials due to their strong adsorption capacity, chemical inertness and superparamagnetism. Therefore, a combination of NPs and microbes could produce a very desirable alternative to conventional wastewater treatment. For this purpose, we first prepared Fe3O4/biochar nano-composites, followed by loading photosynthetic bacteria (PSB) onto them. It was found that Fe3O4/biochar nano-composites exhibited a high adsorption capacity for PSB (5.45 * 109 cells/g). The efficiency of wastewater pollutants removal by this PSB/Fe3O4/biochar agent was then analyzed. Our results indicated that when loaded onto Fe3O4/biochar nano composites, PSB's nutrient removal capability was significantly enhanced (P < 0.05). This agent removed 83.1% of chemical oxygen demand, 87.5% of NH4+, and 92.1% of PO43- from the wastewater in our study. Our experiments also demonstrated that such composites are outstanding recyclable agents. Their nutrient removal capability remained effective even after five cycles. In conclusion, we found the PSB/Fe3O4/biochar composites as a very promising material for bioremediation in the wastewater treatment. PMID- 28588554 TI - Female Reproductive Factors and Differentiated Thyroid Cancer. AB - Differentiated thyroid cancer (DTC) is markedly more common in women than men, the highest female-to-male ratio being recorded during the reproductive period. This evidence has led to the suggestion that female hormonal and reproductive factors may account for the observed DTC gender disparity. This review focuses on current evidence on the risk of DTC in conjunction with major female reproductive factors, including the impact of pregnancy on DTC occurrence and progression/recurrence. Overall, studies exploring the link between the risk of DTC and menstrual and menopausal factors, oral contraceptives and/or hormone replacement therapy, showed these associations, if any, to be generally weak. Nonetheless, there is some evidence that higher levels of exposure to estrogens during reproductive years may confer an increased risk of DTC. As far as pregnancy is concerned, it is unclear whether a potential association between parity and risk of DTC actually exists, and whether it is enhanced in the short term following delivery. A possible role for pregnancy-related factors in DTC progression has been recently suggested by some reports, the results of which are consistent with a worse outcome in the short-term of women diagnosed with DTC during gestation compared to non-pregnant control patients. Also, some progression of disease has been described in women with structural evidence of disease prior to pregnancy. However, there seems to be no impact from pregnancy in DTC-related death or overall survival. Several in vitro and animal studies have evaluated the influence of estrogens (E) and estrogen receptors (ERs) on thyroid cell proliferation. Presently available data are indicative of a role of E and ERs in thyroid cancer growth, although considerable discrepancies in respect to ER expression patterns in thyroid cancer tissues actually exist. Further studies providing more direct evidence on the possible role of E and of placental hormones and growth factors on thyroid growth may expand our knowledge on the mechanisms beyond the gender disparity of proliferative thyroid diseases. PMID- 28588555 TI - Bacterial Community Associated with the Reef Coral Mussismilia braziliensis's Momentum Boundary Layer over a Diel Cycle. AB - Corals display circadian physiological cycles, changing from autotrophy during the day to heterotrophy during the night. Such physiological transition offers distinct environments to the microbial community associated with corals: an oxygen-rich environment during daylight hours and an oxygen-depleted environment during the night. Most studies of coral reef microbes have been performed on samples taken during the day, representing a bias in the understanding of the composition and function of these communities. We hypothesized that coral circadian physiology alters the composition and function of microbial communities in reef boundary layers. Here, we analyzed microbial communities associated with the momentum boundary layer (MBL) of the Brazilian endemic reef coral Mussismilia braziliensis during a diurnal cycle, and compared them to the water column. We determined microbial abundance and nutrient concentration in samples taken within a few centimeters of the coral's surface every 6 h for 48 h, and sequenced microbial metagenomes from a subset of the samples. We found that dominant taxa and functions in the coral MBL community were stable over the time scale of our sampling, with no significant shifts between night and day samples. Interestingly, the two water column metagenomes sampled 1 m above the corals were also very similar to the MBL metagenomes. When all samples were analyzed together, nutrient concentration significantly explained 40% of the taxonomic dissimilarity among dominant genera in the community. Functional profiles were highly homogenous and not significantly predicted by any environmental variables measured. Our data indicated that water flow may overrule the effects of coral physiology in the MBL bacterial community, at the scale of centimeters, and suggested that sampling resolution at the scale of millimeters may be necessary to address diurnal variation in community composition. PMID- 28588557 TI - The Mechanism of Starch Over-Accumulation in Chlamydomonas reinhardtii High Starch Mutants Identified by Comparative Transcriptome Analysis. AB - The focus of this study was the mechanism of starch accumulation in Chlamydomonas reinhardtii high-starch mutants. Three C. reinhardtii mutants showing high-starch content were generated using gamma irradiation. When grown under nitrogen deficient conditions, these mutants had more than twice as much starch than a wild-type control. The mechanism of starch over-accumulation in these mutants was studied with comparative transcriptome analysis. In all mutants, induction of phosphoglucomutase 1 (PGM1) expression was detected; PGM1 catalyzes the inter conversion of glucose 1-phosphate and glucose 6-phosphate in both starch biosynthetic and glycolytic pathway. Interestingly, transcript levels of phosphoglucose isomerase 1 (PGI1), fructose 1,6-bisphosphate aldolase 1 and 2 (FBA1 and FBA2) were down-regulated in all mutants; PGI1, FBA1, and FBA2 act on downstream of glucose 6-phosphate conversion in glycolytic pathway. Therefore, down-regulations of PGI1, FBA1, and FBA2 may lead to accumulation of upstream metabolites, notably glucose 6-phosphate, resulting in induction of PGM1 expression through feed-forward regulation and that PGM1 overexpression caused starch over-accumulation in mutants. These results suggest that PGI1, FBA1, FBA2, and PGM1 correlate with each other in terms of coordinated transcriptional regulation and play central roles for starch over-accumulation in C. reinhardtii. PMID- 28588558 TI - Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination? AB - Following the 2009 H1N1 influenza virus pandemic, numerous studies identified the striking link between diabetes mellitus and influenza disease severity. Typically, influenza virus is a self-limiting infection but in individuals who have a pre-existing chronic illness, such as diabetes mellitus, severe influenza can develop. Here, we discuss the latest clinical and experimental evidence for the role of diabetes in predisposing the host to severe influenza. We explore the possible mechanisms that underlie this synergy and highlight the, as yet, unexplored role that blood glucose oscillations may play in disease development. Diabetes is one of the world's fastest growing chronic diseases and influenza virus represents a constant and pervasive threat to human health. It is therefore imperative that we understand how diabetes increases influenza severity in order to mitigate the burden of future influenza epidemics and pandemics. PMID- 28588559 TI - A Perspective on the Application of Pro-/Synbiotics in Clinical Practice. PMID- 28588560 TI - Molecular Epidemiology and Antifungal Susceptibility of Candida glabrata in China (August 2009 to July 2014): A Multi-Center Study. AB - Candida glabrata is an increasingly important cause of invasive candidiasis. In China, relatively little is known of the molecular epidemiology of C. glabrata and of its antifungal susceptibility patterns. Here we studied 411 non-duplicate C. glabrata isolates from 411 patients at 11 hospitals participating in the National China Hospital Invasive Fungal Surveillance Net program (CHIF-NET; 2010 2014). Genotyping was performed using multilocus sequence typing (MLST) employing six genetic loci and by microsatellite analysis. Antifungal susceptibility testing was performed using Sensititre YeastOneTM YO10 methodology. Of 411 isolates, 35 sequence types (ST) were identified by MLST and 79 different genotypes by microsatellite typing; the latter had higher discriminatory power than MLST in the molecular typing of C. glabrata. Using MLST, ST7 and ST3 were the most common STs (66.4 and 9.5% of all isolates, respectively) with 24 novel STs identified; the most common microsatellite types were T25 (30.4% of all isolates) and T31 (12.4%). Resistance to fluconazole (MIC > 32 MUg/mL) was seen in 16.5% (68/411) of isolates whilst MICs of >0.5 MUg/mL for voriconazole, >2 MUg/mL for itraconazole and >2 MUg/mL for posaconazole were seen for 28.7, 6.8, and 7.3% of isolates, respectively; 14.8% of all isolates cross-resistant/non wide-type to fluconazole and voriconazole. Fluconazole resistant rates increased 3-fold over the 5-year period whilst that of isolates with non-WT MICs to voriconazole, 7-fold. All echinocandins exhibited >99% susceptibility rates against all isolates but notably one isolate exhibited multi-drug resistance to the azoles and echinocandins. The study has provided a global picture of the molecular epidemiology and drug resistance rates of C. glabrata in China during the period of the study. PMID- 28588561 TI - Bacterial Biogeography across the Amazon River-Ocean Continuum. AB - Spatial and temporal patterns in microbial biodiversity across the Amazon river ocean continuum were investigated along ~675 km of the lower Amazon River mainstem, in the Tapajos River tributary, and in the plume and coastal ocean during low and high river discharge using amplicon sequencing of 16S rRNA genes in whole water and size-fractionated samples (0.2-2.0 MUm and >2.0 MUm). River communities varied among tributaries, but mainstem communities were spatially homogeneous and tracked seasonal changes in river discharge and co-varying factors. Co-occurrence network analysis identified strongly interconnected river assemblages during high (May) and low (December) discharge periods, and weakly interconnected transitional assemblages in September, suggesting that this system supports two seasonal microbial communities linked to river discharge. In contrast, plume communities showed little seasonal differences and instead varied spatially tracking salinity. However, salinity explained only a small fraction of community variability, and plume communities in blooms of diatom-diazotroph assemblages were strikingly different than those in other high salinity plume samples. This suggests that while salinity physically structures plumes through buoyancy and mixing, the composition of plume-specific communities is controlled by other factors including nutrients, phytoplankton community composition, and dissolved organic matter chemistry. Co-occurrence networks identified interconnected assemblages associated with the highly productive low salinity near-shore region, diatom-diazotroph blooms, and the plume edge region, and weakly interconnected assemblages in high salinity regions. This suggests that the plume supports a transitional community influenced by immigration of ocean bacteria from the plume edge, and by species sorting as these communities adapt to local environmental conditions. Few studies have explored patterns of microbial diversity in tropical rivers and coastal oceans. Comparison of Amazon continuum microbial communities to those from temperate and arctic systems suggest that river discharge and salinity are master variables structuring a range of environmental conditions that control bacterial communities across the river-ocean continuum. PMID- 28588562 TI - Phylogeography and Coevolution of Bamboo Mosaic Virus and Its Associated Satellite RNA. AB - Bamboo mosaic virus (BaMV), a plant potexvirus, has been found only in infected bamboo species. It is frequently associated with a large, linear single-stranded satellite RNA (satBaMV) that encodes a non-structural protein. Decades of collecting across a wide geographic area in Asia have accumulated a sizable number of BaMV and satBaMV isolates. In this study, we reconstructed the BaMV phylogeny and satBaMV phylogeny with partial coat protein gene sequences and partial genomic sequences, respectively. The evolutionary relationships allowed us to infer the phylogeography of BaMV and satBaMV on the Asian continent and its outlying islands. The BaMV phylogeny suggests that the BaMV isolates from Taiwan, unsurprisingly, are most likely derived from China. Interestingly, the newly available satBaMV isolates from China were found to be most closely related to the previously established Clade III, which is found in India. The general pattern of clustering along the China/India and Taiwan divide led us to hypothesize that the Taiwan Strait has been a physical barrier to gene flow in the past evolutionary history of both BaMV and satBaMV. Lastly, cophylogeny analyses revealed a complex association pattern between BaMV and satBaMV isolates from China. In general, closely related BaMV sequences tend to carry closely related satBaMV sequences as well; but instances of mismatching with distantly related satBaMV isolates were also found. We hypothesize plausible scenarios of infection and superinfection of bamboo hosts that may be responsible for the observed association pattern. However, a more systematic sampling throughout the geographic distribution of various bamboo species is needed to unambiguously establish the origin, movement, and evolution of BaMV and satBaMV. PMID- 28588563 TI - Insight into Potential Probiotic Markers Predicted in Lactobacillus pentosus MP 10 Genome Sequence. AB - Lactobacillus pentosus MP-10 is a potential probiotic lactic acid bacterium originally isolated from naturally fermented Alorena green table olives. The entire genome sequence was annotated to in silico analyze the molecular mechanisms involved in the adaptation of L. pentosus MP-10 to the human gastrointestinal tract (GIT), such as carbohydrate metabolism (related with prebiotic utilization) and the proteins involved in bacteria-host interactions. We predicted an arsenal of genes coding for carbohydrate-modifying enzymes to modify oligo- and polysaccharides, such as glycoside hydrolases, glycoside transferases, and isomerases, and other enzymes involved in complex carbohydrate metabolism especially starch, raffinose, and levan. These enzymes represent key indicators of the bacteria's adaptation to the GIT environment, since they involve the metabolism and assimilation of complex carbohydrates not digested by human enzymes. We also detected key probiotic ligands (surface proteins, excreted or secreted proteins) involved in the adhesion to host cells such as adhesion to mucus, epithelial cells or extracellular matrix, and plasma components; also, moonlighting proteins or multifunctional proteins were found that could be involved in adhesion to epithelial cells and/or extracellular matrix proteins and also affect host immunomodulation. In silico analysis of the genome sequence of L. pentosus MP-10 is an important initial step to screen for genes encoding for proteins that may provide probiotic features, and thus provides one new routes for screening and studying this potentially probiotic bacterium. PMID- 28588564 TI - Viral-Induced Mortality of Prokaryotes in a Tropical Monsoonal Estuary. AB - Viruses are recognized as the most abundant and dynamic biological entities in the marine and estuarine environment. However, studies on the dynamics and activity of viruses in transient estuarine systems are limited. This study examines temporal and spatial variations in viral abundance (VA) and viral activity across the salinity gradient in a monsoon-driven tropical estuarine system (Cochin estuary, CE) along the southwest coast of India. Water samples were collected from five stations (with different hydrological settings) every 3 h for 24 h period during two distinct seasons, namely pre-monsoon (PRM, dry season) and monsoon (MON, wet season). Time series measurements were made for a spring and neap tidal cycle for each season at all the stations. The results showed marked spatial and seasonal variability with relatively low diel and tidal variations in VA and lytic activity. Viral activity was found to be distinct in five stations studied with the maximum activity in the mesohaline regions (salinity <20) of the estuary. This region was characterized by high VA, lytic infection and viral production, accompanied by low (BGE) and high bacterial respiration. Based on viral lytic production, lytic viruses were found to be responsible for the release of ca. 72.9 +/- 58.5 MUg C L-1d-1 of bacterial carbon. The contribution of the viral shunt to the dissolved organic carbon (DOC) pool was higher during the dry season (PRM) than MON. Statistical analysis confirmed a significant association of viruses with the host availability and salinity. This work demonstrates the spatiotemporal distribution of viruses in a tropical estuarine ecosystem and highlights their role in microbial mortality across different salinity gradients. This study forms the first report on viral processes from a monsoon-driven tropical estuarine ecosystem. PMID- 28588565 TI - Diversity of Ligninolytic Enzymes and Their Genes in Strains of the Genus Ganoderma: Applicable for Biodegradation of Xenobiotic Compounds? AB - White-rot fungi (WRF) and their ligninolytic enzymes (laccases and peroxidases) are considered promising biotechnological tools to remove lignin related Persistent Organic Pollutants from industrial wastewaters and contaminated ecosystems. A high diversity of the genus Ganoderma has been reported in Cuba; in spite of this, the diversity of ligninolytic enzymes and their genes remained unexplored. In this study, 13 native WRF strains were isolated from decayed wood in urban ecosystems in Havana (Cuba). All strains were identified as Ganoderma sp. using a multiplex polymerase chain reaction (PCR)-method based on ITS sequences. All Ganoderma sp. strains produced laccase enzymes at higher levels than non-specific peroxidases. Native-PAGE of extracellular enzymatic extracts revealed a high diversity of laccase isozymes patterns between the strains, suggesting the presence of different amino acid sequences in the laccase enzymes produced by these Ganoderma strains. We determined the diversity of genes encoding laccases and peroxidases using a PCR and cloning approach with basidiomycete-specific primers. Between two and five laccase genes were detected in each strain. In contrast, only one gene encoding manganese peroxidase or versatile peroxidase was detected in each strain. The translated laccases and peroxidases amino acid sequences have not been described before. Extracellular crude enzymatic extracts produced by the Ganoderma UH strains, were able to degrade model chromophoric compounds such as anthraquinone and azo dyes. These findings hold promises for the development of a practical application for the treatment of textile industry wastewaters and also for bioremediation of polluted ecosystems by well-adapted native WRF strains. PMID- 28588567 TI - Biofilm vs. Planktonic Lifestyle: Consequences for Pesticide 2,4-D Metabolism by Cupriavidus necator JMP134. AB - The development of bacterial biofilms in natural environments may alter important functions, such as pollutant bioremediation by modifying both the degraders' physiology and/or interactions within the matrix. The present study focuses on the influence of biofilm formation on the metabolism of a pesticide, 2,4 dichlorophenoxyacetic acid (2,4-D), by Cupriavidus necator JMP134. Pure cultures were established in a liquid medium with 2,4-D as a sole carbon source with or without sand grains for 10 days. Bacterial numbers and 2,4-D concentrations in solution were followed by spectrophotometry, the respiration rate by gas chromatography and the surface colonization by electron microscopy. In addition, isotopic techniques coupled with Fatty Acid Methyl Ester (FAME) profiling were used to determine possible metabolic changes. After only 3 days, approximately 80% of the cells were attached to the sand grains and microscopy images showed that the porous medium was totally clogged by the development of a biofilm. After 10 days, there was 25% less 2,4-D in the solution in samples with sand than in control samples. This difference was due to (1) a higher (+8%) mineralization of 2,4-D by sessile bacteria and (2) a retention (15%) of 2,4-D in the biofilm matrix. Besides, the amount of carbohydrates, presumably constituting the biofilm polysaccharides, increased by 63%. Compound-specific isotope analysis revealed that the FAME isotopic signature was less affected by the biofilm lifestyle than was the FAME composition. These results suggest that sessile bacteria differ more in their anabolism than in their catabolism compared to their planktonic counterparts. This study stresses the importance of considering interactions between microorganisms and their habitat when studying pollutant dynamics in porous media. PMID- 28588566 TI - Gut Bacteria Missing in Severe Acute Malnutrition, Can We Identify Potential Probiotics by Culturomics? AB - Severe acute malnutrition is the world-leading cause of children under-five's death. Recent metagenomics studies have established a link between gut microbiota and severe acute malnutrition, describing an immaturity with a striking depletion in oxygen-sensitive prokaryotes. Amoxicillin and therapeutic diet cure most of the children with severe acute malnutrition but an irreversible disruption of the gut microbiota is suspected in the refractory and most severe cases. In these cases, therapeutic diet may be unable to reverse the microbiota alteration leading to persistent impaired development or death. In addition, as enteric sepsis is a major cause of death in this context, identification of missing gut microbes to be tested as probiotics (live bacteria that confer a benefit to the host) to restore rapidly the healthy gut microbiota and prevent the gut pathogenic invasion is of foremost importance. In this study, stool samples of malnourished patients with kwashiorkor and healthy children were collected from Niger and Senegal and analyzed by culturomics and metagenomics. We found a globally decreased diversity, a decrease in the hitherto unknown diversity (new species isolation), a depletion in oxygen-sensitive prokaryotes including Methanobrevibacter smithii and an enrichment in potentially pathogenic Proteobacteria, Fusobacteria and Streptococcus gallolyticus. A complex of 12 species identified only in healthy children using culturomics and metagenomics were identified as probiotics candidates, providing a possible, defined, reproducible, safe, and convenient alternative to fecal transplantation to restore a healthy gut microbiota in malnourished children. Microbiotherapy based on selected strains has the potential to improve the current treatment of severe acute malnutrition and prevent relapse and death by reestablishing a healthy gut microbiota. PMID- 28588569 TI - Methane Dynamics in a Tropical Serpentinizing Environment: The Santa Elena Ophiolite, Costa Rica. AB - Uplifted ultramafic rocks represent an important vector for the transfer of carbon and reducing power from the deep subsurface into the biosphere and potentially support microbial life through serpentinization. This process has a strong influence upon the production of hydrogen and methane, which can be subsequently consumed by microbial communities. The Santa Elena Ophiolite (SEO) on the northwestern Pacific coast of Costa Rica comprises ~250 km2 of ultramafic rocks and mafic associations. The climatic conditions, consisting of strongly contrasting wet and dry seasons, make the SEO a unique hydrogeological setting, where water-rock reactions are enhanced by large storm events (up to 200 mm in a single storm). Previous work on hyperalkaline spring fluids collected within the SEO has identified the presence of microorganisms potentially involved in hydrogen, methane, and methanol oxidation (such as Hydrogenophaga, Methylobacterium, and Methylibium spp., respectively), as well as the presence of methanogenic Archaea (such as Methanobacterium). Similar organisms have also been documented at other serpentinizing sites, however their functions have not been confirmed. SEO's hyperalkaline springs have elevated methane concentrations, ranging from 145 to 900 MUM, in comparison to the background concentrations (<0.3 MUM). The presence and potential activity of microorganisms involved in methane cycling in serpentinization-influenced fluids from different sites within the SEO were investigated using molecular, geochemical, and modeling approaches. These results were combined to elucidate the bioenergetically favorable methane production and/or oxidation reactions in this tropical serpentinizing environment. The hyperalkaline springs at SEO contain a greater proportion of Archaea and methanogens than has been detected in any terrestrial serpentinizing system. Archaea involved in methanogenesis and anaerobic methane oxidation accounted from 40 to 90% of total archaeal sequences. Genes involved in methanogenic metabolisms were detected from the metagenome of one of the alkaline springs. Methanogenic activities are likely to be facilitated by the movement of nutrients, including dissolved inorganic carbon (DIC), from surface water and their infiltration into serpentinizing groundwater. These data provide new insight into methane cycle in tropical serpentinizing environments. PMID- 28588568 TI - Food Safety in the Age of Next Generation Sequencing, Bioinformatics, and Open Data Access. AB - Public health labs and food regulatory agencies globally are embracing whole genome sequencing (WGS) as a revolutionary new method that is positioned to replace numerous existing diagnostic and microbial typing technologies with a single new target: the microbial draft genome. The ability to cheaply generate large amounts of microbial genome sequence data, combined with emerging policies of food regulatory and public health institutions making their microbial sequences increasingly available and public, has served to open up the field to the general scientific community. This open data access policy shift has resulted in a proliferation of data being deposited into sequence repositories and of novel bioinformatics software designed to analyze these vast datasets. There also has been a more recent drive for improved data sharing to achieve more effective global surveillance, public health and food safety. Such developments have heightened the need for enhanced analytical systems in order to process and interpret this new type of data in a timely fashion. In this review we outline the emergence of genomics, bioinformatics and open data in the context of food safety. We also survey major efforts to translate genomics and bioinformatics technologies out of the research lab and into routine use in modern food safety labs. We conclude by discussing the challenges and opportunities that remain, including those expected to play a major role in the future of food safety science. PMID- 28588570 TI - The Profile and Antimicrobial Activity of Bacillus Lipopeptide Extracts of Five Potential Biocontrol Strains. AB - In this study the efficacy of two different methods for extracting lipopeptides produced by five Bacillus strains-ethyl acetate extraction, and acid precipitation followed by methanol extraction-was investigated using mass spectrometry. High performance thin layer chromatography (HPTLC) was also used for the simultaneous separation of complex mixtures of lipopeptide extracts and for the determination of antimicrobial activity of their components. The mass spectra clearly showed well-resolved groups of peaks corresponding to different lipopeptide families (kurstakins, iturins, surfactins, and fengycins). The ethyl acetate extracts produced the most favorable results. The extracts of SS-12.6, SS 13.1, and SS-38.4 showed the highest inhibition zones. An iturin analog is responsible for the inhibition of Xanthomonas arboricola and Pseudomonas syringae phytopathogenic strains. HPTLC bioautography effectively identified the active compounds from a mixture of lipopeptide extracts, proving in situ its potential for use in direct detection and determination of antimicrobials. In the test of potential synergism among individual extracts used in different mixtures, stronger antimicrobial effects were not observed. Biochemical and phylogenetic analysis clustered isolates SS-12.6, SS-13.1, SS-27.2, and SS-38.4 together with Bacillus amyloliquefaciens, while SS-10.7 was more closely related to Bacillus pumilus. PMID- 28588571 TI - Genome-Wide Transcriptome Analysis Reveals Extensive Alternative Splicing Events in the Protoscoleces of Echinococcus granulosus and Echinococcus multilocularis. AB - Alternative splicing (AS), as one of the most important topics in the post genomic era, has been extensively studied in numerous organisms. However, little is known about the prevalence and characteristics of AS in Echinococcus species, which can cause significant health problems to humans and domestic animals. Based on high-throughput RNA-sequencing data, we performed a genome-wide survey of AS in two major pathogens of echinococcosis-Echinococcus granulosus and Echinococcus multilocularis. Our study revealed that the prevalence and characteristics of AS in protoscoleces of the two parasites were generally consistent with each other. A total of 6,826 AS events from 3,774 E. granulosus genes and 6,644 AS events from 3,611 E. multilocularis genes were identified in protoscolex transcriptomes, indicating that 33-36% of genes were subject to AS in the two parasites. Strikingly, intron retention instead of exon skipping was the predominant type of AS in Echinococcus species. Moreover, analysis of the Kyoto Encyclopedia of Genes and Genomes pathway indicated that genes that underwent AS events were significantly enriched in multiple pathways mainly related to metabolism (e.g., purine, fatty acid, galactose, and glycerolipid metabolism), signal transduction (e.g., Jak-STAT, VEGF, Notch, and GnRH signaling pathways), and genetic information processing (e.g., RNA transport and mRNA surveillance pathways). The landscape of AS obtained in this study will not only facilitate future investigations on transcriptome complexity and AS regulation during the life cycle of Echinococcus species, but also provide an invaluable resource for future functional and evolutionary studies of AS in platyhelminth parasites. PMID- 28588572 TI - Positively Selected Sites at HCMV gB Furin Processing Region and Their Effects in Cleavage Efficiency. AB - Human cytomegalovirus is a ubiquitous infectious agent that affects mainly immunosuppressed, fetuses, and newborns. The virus has several polymorphic regions, in particular in the envelope glycoproteins. The UL55 gene encodes the glycoprotein B that has a variable region, containing a furin cleavage site and according to the variability different genotypes are characterized. Here we investigated variability and existence of selective pressure on the UL55 variable region containing the furin cleavage site in 213 clinical sequences from patients worldwide. We showed the occurrence of positive selective pressure on gB codons 461 and 462, near the furin cleavage site. Cleavage analysis of synthesized peptides demonstrated that most mutations confer better cleavage by furin, suggesting that evolution is acting in order to increase the efficiency cleavage and supporting the hypothesis that gB processing is important in the host. We also demonstrated that peptides containing sequences, that characterize genotypes gB2 and 3, are differentially cleaved by furin. Our data demonstrate for the first time that variability in the cleavage site is related to degree of gB processing by furin. PMID- 28588573 TI - Bovine WC1+ and WC1neg gammadelta T Lymphocytes Influence Monocyte Differentiation and Monocyte-Derived Dendritic Cell Maturation during In Vitro Mycobacterium avium Subspecies paratuberculosis Infection. AB - During early Mycobacterium avium subspecies paratuberculosis (Map) infection, complex interactions occur between the bacteria, cells from the mononuclear phagocyte system (MPS) including both resident (macrophages and dendritic cells) and recruited (monocytes) cells, and other mucosal sentinel cells such as gammadelta T lymphocytes. Though the details of early host-pathogen interactions in cattle remain largely underexplored, our hypothesis is that these significantly influence development of host immunity and ultimate success or failure of the host to respond to Map infection. The aims of the present study were to first characterize monocyte-derived MPS cells from young calves with respect to their immunophenotype and function. Then, we set out to investigate the effects of WC1+ and WC1neg gammadelta T lymphocytes on (1) the differentiation of autologous monocytes and (2) the maturation of autologous monocyte-derived dendritic cells (MDDCs). To achieve this, peripheral blood WC1+ or WC1neg gammadelta T lymphocytes were cocultured with either autologous freshly isolated peripheral blood-derived monocytes or autologous immature MDDCs (iMDDCs). We began by measuring several markers of interest on MPS cells. Useful markers to distinguish monocyte-derived macrophages (MDMs) from MDDCs include CD11b, CD163, and CD172a, which are expressed significantly higher on MDMs compared with MDDCs. Function, but not phenotype, was influenced by WC1neg gammadelta T lymphocytes: viability of Map harvested from monocytes differentiated in the presence of WC1neg gammadelta T lymphocytes (dMonWC1neg) was significantly lower compared to MDMs and MDDCs. With respect to DC maturation, we first showed that mature MDDCs (mMDDCs) have significantly higher expression of CD11c, CD80, and CD86 compared with iMDDCs, and the phagocytic capacity of mMDDCs is significantly reduced compared to iMDDCs. We then showed that gammadelta T lymphocyte subsets induce functional (reduced phagocytosis) but not phenotypic (surface marker expression) iMDDC maturation. These data collectively show that gammadelta T lymphocytes influence differentiation, maturation, and ultimately the function of monocytes during Map infection, which has significant implications on survival of Map and success of host defense during early Map infection. PMID- 28588574 TI - Predicting RTS,S Vaccine-Mediated Protection from Transcriptomes in a Malaria Challenge Clinical Trial. AB - The RTS,S candidate malaria vaccine can protect against controlled human malaria infection (CHMI), but how protection is achieved remains unclear. Here, we have analyzed longitudinal peripheral blood transcriptome and immunogenicity data from a clinical efficacy trial in which healthy adults received three RTS,S doses 4 weeks apart followed by CHMI 2 weeks later. Multiway partial least squares discriminant analysis (N-PLS-DA) of transcriptome data identified 110 genes that could be used in predictive models of protection. Among the 110 genes, 42 had known immune-related functions, including 29 that were related to the NF-kappaB signaling pathway and 14 to the IFN-gamma-signaling pathway. Post-dose 3 serum IFN-gamma concentrations were also correlated with protection; and N-PLS-DA of IFN-gamma-signaling pathway transcriptome data selected almost all (44/45) of the representative genes for predictive models of protection. Hence, the identification of the NF-kappaB and IFN-gamma pathways provides further insight into how vaccine-mediated protection may be achieved. PMID- 28588575 TI - Gut-Associated Lymphoid Tissue: A Key Tissue Inside the Mucosal Immune System of Hens Immunized with Escherichia coli F4. AB - Immunoglobulin Y (IgY) is the predominant antibody found in hen's (Gallus domesticus) egg yolk. This antibody, developed against several microorganisms in hen egg yolk, has been successfully used as an alternative to immunoglobulins from mammals for use in immunodiagnostics and immunotherapy. Enteropathogenic Escherichia coli (E.coli) F4 is the main etiological agent associated with swine neonatal diarrhea, and it causes notable economic losses in swine production. The aim of the present study was to evaluate the relationship between humoral immune response and the activation of gut-associated lymphoid tissue (GALT) in laying hens intramuscularly immunized with E. coli F4. Adult laying Shaver hens were immunized with a bacterin based on an inactivated lysate E. coli F4 strain that was originally isolated from neonatal piglet diarrhea, following a recommended schedule. The percentage of B lymphocytes in blood and spleen homogenates was determined by flow cytometry. Villi histomorphometry and the size of germinal centers (GC) activated in GALT and the spleen were measured in histological samples either stained with hematoxylin/eosin or through immunofluorescence. Antibody and isotype-specific antibodies in serum and egg yolk were measured using indirect enzyme-linked immunosorbent assay (ELISA). Secretory and serum immunoglobulin A (IgA) were measured by ELISA tests. Laying hen with intramuscular immunization with E. coli F4 lysate, activated both mucosal and systemic protection. Mucosal protection was provided through B lymphocytes, and most of them were activated on Peyer's patches and esophageal tonsils, in GALT. Furthermore, increased B lymphocyte number in the lamina propria of the gut, and increased intraepithelial plasmatic cell number, produced high levels of mucosal IgA. Activated B lymphocytes interacted with absorptive cells, immune cells, and microbiota in the gut, producing signals that were translated into a powerful physical defense by producing a greater volume of mucin from an increased number of goblet cells. Systemic protection was provided through B lymphocyte activation of spleen GC, which produced hugely specific IgY serum levels. One week later, this specific IgY was deposited in the yolk. This suggests that GALT is a key immunologic tissue inside the mucosal immune system, acting as the "command center" for humoral reaction. PMID- 28588577 TI - Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review. AB - Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/MUl (0-301) and 101/MUl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML IRIS should be considered in HIV-infected patients with worsening neurological symptoms after initiation or resumption of effective cART, independently of CD4 cell count prior to cART. If PCR for JCV is negative in CSF, brain biopsy should be discussed. Only large multicentric randomized trials could potentially demonstrate the possible efficacy of corticosteroids and/or CCR5 antagonists in the management of PML-IRIS. PMID- 28588576 TI - PD-1 Blockade Promotes Emerging Checkpoint Inhibitors in Enhancing T Cell Responses to Allogeneic Dendritic Cells. AB - Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Other checkpoint inhibitors failed to significantly augment T cell responses when used alone. However, antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in presence of a PD 1 antibody. Upregulation of coinhibitory T cell receptors upon PD-1 blockade was identified as a potential mechanism for synergistic effects between checkpoint inhibitors. Donor-specific variation in response to immune checkpoint inhibitors was attributed to the T cells rather than DCs. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients. PMID- 28588578 TI - GRP78 Impairs Production of Lipopolysaccharide-Induced Cytokines by Interaction with CD14. AB - The 78-kDa glucose-regulated protein (GRP78) is a stress-inducible chaperone that resides primarily in the endoplasmic reticulum. GRP78 has been described to be released at times of cellular stress and as having extracellular properties that are anti-inflammatory or favor the resolution of inflammation. In the current study, we confirmed that GRP78 impaired the production of lipopolysaccharide induced pro-inflammatory cytokines in GRP78-treated bone-marrow-derived dendritic cells (DCs). To explore the underlying mechanism, first of all, GRP78 was checked to be bound to the plasma membrane. Interestingly, such binding promoted endocytosis of toll-like receptor (TLR) 4 and reduction in TLR4 on the plasma surface had a key role in desensitization of GRP78-treated DCs to lipopolysaccharide. Given that cluster of differentiation (CD)14 is a crucial regulator of TLR4 endocytosis, interaction of GRP78 with CD14 was investigated next. Data showed that GRP78 co-localized with CD14 on the plasma membrane and glutathione-S-transferase-GRP78 precipitated CD14. In CD14 knockout mice, down regulation of tumor necrosis factor-alpha and reduction in TLR4 on the plasma surface were abrogated in GRP78-treated DCs. Overall, these data suggested that GRP78 mediates endocytosis of TLR4 by targeting CD14 to favor the resolution of inflammation. PMID- 28588579 TI - Pathophysiology of CD4+ T-Cell Depletion in HIV-1 and HIV-2 Infections. AB - The hall mark of human immunodeficiency virus (HIV) infection is a gradual loss of CD4+ T-cells and imbalance in CD4+ T-cell homeostasis, with progressive impairment of immunity that leads ultimately to death. HIV infection in humans is caused by two related yet distinct viruses: HIV-1 and HIV-2. HIV-2 is typically less virulent than HIV-1 and permits the host to mount a more effective and sustained T-cell immunity. Although both infections manifest the same clinical spectrum, the much lower rate of CD4+ T-cell decline and slower progression of disease in HIV-2 infected individuals have grabbed the attention of several researchers. Here, we review the most recent findings on the differential rate of decline of CD4+ T-cell in HIV-1 and HIV-2 infections and provide plausible reasons for the observed differences between the two groups. PMID- 28588580 TI - Specific Antibody Deficiency: Controversies in Diagnosis and Management. AB - Specific antibody deficiency (SAD) is a primary immunodeficiency disease characterized by normal immunoglobulins (Igs), IgA, IgM, total IgG, and IgG subclass levels, but with recurrent infection and diminished antibody responses to polysaccharide antigens following vaccination. There is a lack of consensus regarding the diagnosis and treatment of SAD, and its clinical significance is not well understood. Here, we discuss current evidence and challenges regarding the diagnosis and treatment of SAD. SAD is normally diagnosed by determining protective titers in response to the 23-valent pneumococcal polysaccharide vaccine. However, the definition of an adequate response to immunization remains controversial, including the magnitude of response and number of pneumococcal serotypes needed to determine a normal response. Confounding these issues, anti polysaccharide antibody responses are age- and probably serotype dependent. Therapeutic strategies and options for patients with SAD are often based on clinical experience due to the lack of focused studies and absence of a robust case definition. The mainstay of therapy for patients with SAD is antibiotic prophylaxis. However, there is no consensus regarding the frequency and severity of infections warranting antibiotic prophylaxis and no standardized regimens and no studies of efficacy. Published expert guidelines and opinions have recommended IgG therapy, which are supported by observations from retrospective studies, although definitive data are lacking. In summary, there is currently a lack of evidence regarding the efficacy of therapeutic strategies for patients with SAD. We believe that it is best to approach each patient as an individual and progress through diagnostic and therapeutic interventions together with existing practice guidelines. PMID- 28588582 TI - Nanoparticle-Based Magnetic Resonance Imaging on Tumor-Associated Macrophages and Inflammation. AB - The inflammatory response, mediated by tissue-resident or newly recruited macrophages, is an underlying pathophysiological condition for many diseases, including diabetes, obesity, neurodegeneration, atherosclerosis, and cancer. Paradoxically, inflammation is a double-edged sword in oncology. Macrophages are, generally speaking, the major drivers of inflammatory insult. For many solid tumors, high density of cells expressing macrophage-associated markers have generally been found in association with a poor clinical outcome, characterized by inflamed microenvironment, a high level of dissemination and resistance to conventional chemotherapies. On another hand, radiation treatment also triggers an inflammatory response in tumors (often referred to as pseudoprogression), which can be associated with a positive treatment response. As such, non-invasive imaging of cancer inflammation and tumor-associated macrophages (TAMs) provides a revolutionary diagnostic tool and monitoring strategy for anti-inflammatory, immuno- and radiotherapies. Recently, quantitative T2-weighted magnetic resonance imaging (qT2wMRI), using injection of superparamagnetic iron oxide nanoparticles (SPIONs), has been reported for the assessment of TAMs non-invasively in animal models and in human trials. The SPIONs are magnetic resonance imaging (MRI) contrast agents that significantly decrease T2 MR relaxation times in inflamed tissues due to the macrophage-specific uptake and retention. It has been shown that macrophage-populated tumors and metastases will accumulate iron oxide nanoparticles and decrease T2-relaxation time that will result in a negative (dark) contrast in qT2wMRI. Non-invasive imaging of TAMs using SPION holds a great promise for staging the inflammatory microenvironment of primary and metastatic tumors as well monitoring the treatment response of cancer patients treated with radiation and immunotherapy. PMID- 28588581 TI - Role of Sphingosine-1-Phosphate in Mast Cell Functions and Asthma and Its Regulation by Non-Coding RNA. AB - Sphingolipid metabolites are emerging as important signaling molecules in allergic diseases specifically asthma. One of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), is involved in cell differentiation, proliferation, survival, migration, and angiogenesis. In the allergic diseases, alteration of S1P levels influences the differentiation and responsiveness of mast cells (MCs). S1P is synthesized by two sphingosine kinases (SphKs), sphingosine kinase 1, and sphingosine kinase 2. Engagement of IgE to the FcepsilonRI receptor induces the activation of both the SphKs and generates S1P. Furthermore, SphKs are also essential to FcepsilonRI-mediated MC activation. Activated MCs export S1P into the extracellular space and causes inflammatory response and tissue remodeling. S1P signaling has dual role in allergic responses. Activation of SphKs and secretion of S1P are required for MC activation; however, S1P signaling plays a vital role in the recovery from anaphylaxis. Several non-coding RNAs have been shown to play a crucial role in controlling the MC-associated inflammatory and allergic responses. Thus, S1P signaling pathway and its regulation by non-coding RNA could be explored as an exciting potential therapeutic target for asthma and other MC-associated diseases. PMID- 28588584 TI - Protein Arginine Methyltransferase 5 Inhibition Upregulates Foxp3+ Regulatory T Cells Frequency and Function during the Ulcerative Colitis. AB - Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFbeta and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1) expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFalpha, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC. PMID- 28588583 TI - Hypercapnia Impairs ENaC Cell Surface Stability by Promoting Phosphorylation, Polyubiquitination and Endocytosis of beta-ENaC in a Human Alveolar Epithelial Cell Line. AB - Acute lung injury is associated with formation of pulmonary edema leading to impaired gas exchange. Patients with acute respiratory distress syndrome (ARDS) require mechanical ventilation to improve oxygenation; however, the use of relatively low tidal volumes (to minimize further injury of the lung) often leads to further accumulation of carbon dioxide (hypercapnia). Hypercapnia has been shown to impair alveolar fluid clearance (AFC), thereby causing retention of pulmonary edema, and may lead to worse outcomes; however, the underlying molecular mechanisms remain incompletely understood. AFC is critically dependent on the epithelial sodium channel (ENaC), which drives the vectorial transport of Na+ across the alveolar epithelium. Thus, in the current study, we investigated the mechanisms by which hypercapnia effects ENaC cell surface stability in alveolar epithelial cells (AECs). Elevated CO2 levels led to polyubiquitination of beta-ENaC and subsequent endocytosis of the alpha/beta-ENaC complex in AECs, which were prevented by silencing the E3 ubiquitin ligase, Nedd4-2. Hypercapnia induced ubiquitination and cell surface retrieval of ENaC were critically dependent on phosphorylation of the Thr615 residue of beta-ENaC, which was mediated by the extracellular signal-regulated kinase (ERK)1/2. Furthermore, activation of ERK1/2 led to subsequent activation of AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK)1/2 that in turn phosphorylated Nedd4-2 at the Thr899 residue. Importantly, mutation of Thr899 to Ala markedly inhibited the CO2-induced polyubiquitination of beta-ENaC and restored cell surface stability of the ENaC complex, highlighting the critical role of Nedd4-2 phosphorylation status in targeting ENaC. Collectively, our data suggest that elevated CO2 levels promote activation of the ERK/AMPK/JNK axis in a human AEC line, in which ERK1/2 phosphorylates beta-ENaC whereas JNK mediates phosphorylation of Nedd4-2, thereby facilitating the channel-ligase interaction. The hypercapnia-induced ENaC dysfunction may contribute to impaired alveolar edema clearance and thus, interfering with these molecular mechanisms may improve alveolar fluid balance and lead to better outcomes in patients with ARDS. PMID- 28588585 TI - Leaky Gut As a Danger Signal for Autoimmune Diseases. AB - The intestinal epithelial lining, together with factors secreted from it, forms a barrier that separates the host from the environment. In pathologic conditions, the permeability of the epithelial lining may be compromised allowing the passage of toxins, antigens, and bacteria in the lumen to enter the blood stream creating a "leaky gut." In individuals with a genetic predisposition, a leaky gut may allow environmental factors to enter the body and trigger the initiation and development of autoimmune disease. Growing evidence shows that the gut microbiota is important in supporting the epithelial barrier and therefore plays a key role in the regulation of environmental factors that enter the body. Several recent reports have shown that probiotics can reverse the leaky gut by enhancing the production of tight junction proteins; however, additional and longer term studies are still required. Conversely, pathogenic bacteria that can facilitate a leaky gut and induce autoimmune symptoms can be ameliorated with the use of antibiotic treatment. Therefore, it is hypothesized that modulating the gut microbiota can serve as a potential method for regulating intestinal permeability and may help to alter the course of autoimmune diseases in susceptible individuals. PMID- 28588586 TI - The Research Progress on Intestinal Stem Cells and Its Relationship with Intestinal Microbiota. AB - The intestine is home to trillions of microorganisms, and the vast diversity within this gut microbiota exists in a balanced state to protect the intestinal mucosal barrier. Research into the association of the intestinal microbiota with health and disease (including diet, nutrition, obesity, inflammatory bowel disease, and cancer) continues to expand, with the field advancing at a rapid rate. Intestinal stem cells (ISCs) are the fundamental component of the mucosal barrier; they undergo continuous proliferation to replace the epithelium, which is also intimately involved in intestinal diseases. The intestinal microbiota, such as Lactobacillus, communicates with ISCs both directly and indirectly to regulate the proliferation and differentiation of ISCs. Moreover, Salmonella infection significantly decreased the expression of intestinal stem cell markers Lgr5 and Bmi1. However, the detailed interaction of intestinal microbiota and ISCs are still unclear. This review considers the progress of research on the model and niches of ISCs, as well as the complex interplay between the gut microbiota and ISCs, which will be crucial for explaining the mechanisms of intestinal diseases related to imbalances in the intestinal microbiota and ISCs. PMID- 28588587 TI - A Dynamic Tandem Repeat in Monocotyledons Inferred from a Comparative Analysis of Chloroplast Genomes in Melanthiaceae. AB - Chloroplast genomes (cpDNA) are highly valuable resources for evolutionary studies of angiosperms, since they are highly conserved, are small in size, and play critical roles in plants. Slipped-strand mispairing (SSM) was assumed to be a mechanism for generating repeat units in cpDNA. However, research on the employment of different small repeated sequences through SSM events, which may induce the accumulation of distinct types of repeats within the same region in cpDNA, has not been documented. Here, we sequenced two chloroplast genomes from the endemic species Heloniopsis tubiflora (Korea) and Xerophyllum tenax (USA) to cover the gap between molecular data and explore "hot spots" for genomic events in Melanthiaceae. Comparative analysis of 23 complete cpDNA sequences revealed that there were different stages of deletion in the rps16 region across the Melanthiaceae. Based on the partial or complete loss of rps16 gene in cpDNA, we have firstly reported potential molecular markers for recognizing two sections (Veratrum and Fuscoveratrum) of Veratrum. Melathiaceae exhibits a significant change in the junction between large single copy and inverted repeat regions, ranging from trnH_GUG to a part of rps3. Our results show an accumulation of tandem repeats in the rpl23-ycf2 regions of cpDNAs. Small conserved sequences exist and flank tandem repeats in further observation of this region across most of the examined taxa of Liliales. Therefore, we propose three scenarios in which different small repeated sequences were used during SSM events to generate newly distinct types of repeats. Occasionally, prior to the SSM process, point mutation event and double strand break repair occurred and induced the formation of initial repeat units which are indispensable in the SSM process. SSM may have likely occurred more frequently for short repeats than for long repeat sequences in tribe Parideae (Melanthiaceae, Liliales). Collectively, these findings add new evidence of dynamic results from SSM in chloroplast genomes which can be useful for further evolutionary studies in angiosperms. Additionally, genomics events in cpDNA are potential resources for mining molecular markers in Liliales. PMID- 28588589 TI - Tolerance and Reduction of Chromium(VI) by Bacillus sp. MNU16 Isolated from Contaminated Coal Mining Soil. AB - The bacterium MNU16 was isolated from contaminated soils of coal mine and subsequently screened for different plant growth promoting (PGP) activities. The isolate was further identified by 16S rRNA sequencing as Bacillus subtilis MNU16 with IAA concentration (56.95 +/- 0.43 6MUg/ml), siderophore unit (9.73 +/- 2.05%), phosphate solubilization (285.13 +/- 1.05 MUg/ml) and ACC deaminase activity (116.79 +/- 0.019 MUmoles alpha-ketobutyrate/mg/24 h). Further, to evaluate the metal resistance profile of bacterium, the isolate was screened for multi-metal resistance (viz. 900 mg/L for Cr, 600 mg/L for As, 700 mg/L for Ni and 300 mg/L for Hg). Additionally, the resistance pattern of B. subtilis MNU16 against Cr(VI) (from 50 to 300 mg/L) treatments were evaluated. An enriched population was observed at 0-200 mg/L Cr(VI) concentration while slight reductions were observed at 250 and 300 mg/L Cr(VI). Further, the chromium reduction ability at 50 mg/L of Cr(VI) highlighted that the bacterium B. subtilis MNU16 reduced 75% of Cr(VI) to 13.23 mg/L within 72 h. The localization of electron dense precipitates was observed in the TEM images of B. subtilis MNU16 which is might be due to the reduction of Cr(VI) to Cr(III). The data of fluorescence microscopy and flow cytometry with respect to Cr(VI) treatments (50 300 mg/L) showed a similar pattern and clearly revealed the less toxic effect of hexavalent chromium upto 200 mg/L Cr(VI) concentration. However, toxicity effects were more pronounced at 300 mg/L Cr(VI). Therefore, the present study suggests that the plant growth promoting potential and resistance efficacy of B. subtilis MNU16 will go a long way in developing an effective bioremediation approach for Cr(VI) contaminated soils. PMID- 28588588 TI - Genome-Wide Association Studies In Plant Pathosystems: Toward an Ecological Genomics Approach. AB - The emergence and re-emergence of plant pathogenic microorganisms are processes that imply perturbations in both host and pathogen ecological niches. Global change is largely assumed to drive the emergence of new etiological agents by altering the equilibrium of the ecological habitats which in turn places hosts more in contact with pathogen reservoirs. In this context, the number of epidemics is expected to increase dramatically in the next coming decades both in wild and crop plants. Under these considerations, the identification of the genetic variants underlying natural variation of resistance is a pre-requisite to estimate the adaptive potential of wild plant populations and to develop new breeding resistant cultivars. On the other hand, the prediction of pathogen's genetic determinants underlying disease emergence can help to identify plant resistance alleles. In the genomic era, whole genome sequencing combined with the development of statistical methods led to the emergence of Genome Wide Association (GWA) mapping, a powerful tool for detecting genomic regions associated with natural variation of disease resistance in both wild and cultivated plants. However, GWA mapping has been less employed for the detection of genetic variants associated with pathogenicity in microbes. Here, we reviewed GWA studies performed either in plants or in pathogenic microorganisms (bacteria, fungi and oomycetes). In addition, we highlighted the benefits and caveats of the emerging joint GWA mapping approach that allows for the simultaneous identification of genes interacting between genomes of both partners. Finally, based on co-evolutionary processes in wild populations, we highlighted a phenotyping-free joint GWA mapping approach as a promising tool for describing the molecular landscape underlying plant - microbe interactions. PMID- 28588591 TI - Molecular Mapping of Oil Content and Fatty Acids Using Dense Genetic Maps in Groundnut (Arachis hypogaea L.). AB - Enhancing seed oil content with desirable fatty acid composition is one of the most important objectives of groundnut breeding programs globally. Genomics assisted breeding facilitates combining multiple traits faster, however, requires linked markers. In this context, we have developed two different F2 mapping populations, one for oil content (OC-population, ICGV 07368 * ICGV 06420) and another for fatty acid composition (FA-population, ICGV 06420 * SunOleic 95R). These two populations were phenotyped for respective traits and genotyped using Diversity Array Technology (DArT) and DArTseq genotyping platforms. Two genetic maps were developed with 854 (OC-population) and 1,435 (FA-population) marker loci with total map distance of 3,526 and 1,869 cM, respectively. Quantitative trait locus (QTL) analysis using genotyping and phenotyping data identified eight QTLs for oil content including two major QTLs, qOc-A10 and qOc-A02, with 22.11 and 10.37% phenotypic variance explained (PVE), respectively. For seven different fatty acids, a total of 21 QTLs with 7.6-78.6% PVE were identified and 20 of these QTLs were of major effect. Two mutant alleles, ahFAD2B and ahFAD2A, also had 18.44 and 10.78% PVE for palmitic acid, in addition to oleic (33.8 and 17.4% PVE) and linoleic (41.0 and 19.5% PVE) acids. Furthermore, four QTL clusters harboring more than three QTLs for fatty acids were identified on the three LGs. The QTLs identified in this study could be further dissected for candidate gene discovery and development of diagnostic markers for breeding improved groundnut varieties with high oil content and desirable oil quality. PMID- 28588590 TI - A Conserved Carbon Starvation Response Underlies Bud Dormancy in Woody and Herbaceous Species. AB - Plant shoot systems give rise to characteristic above-ground plant architectures. Shoots are formed from axillary meristems and buds, whose growth and development is modulated by systemic and local signals. These cues convey information about nutrient and water availability, light quality, sink/source organ activity and other variables that determine the timeliness and competence to maintain development of new shoots. This information is translated into a local response, in meristems and buds, of growth or quiescence. Although some key genes involved in the onset of bud latency have been identified, the gene regulatory networks (GRNs) controlled by these genes are not well defined. Moreover, it has not been determined whether bud dormancy induced by environmental cues, such as a low red to-far-red light ratio, shares genetic mechanisms with bud latency induced by other causes, such as apical dominance or a short-day photoperiod. Furthermore, the evolution and conservation of these GRNs throughout angiosperms is not well established. We have reanalyzed public transcriptomic datasets that compare quiescent and active axillary buds of Arabidopsis, with datasets of axillary buds of the woody species Vitis vinifera (grapevine) and apical buds of Populus tremula x Populus alba (poplar) during the bud growth-to-dormancy transition. Our aim was to identify potentially common GRNs induced during the process that leads to bud para-, eco- and endodormancy. In Arabidopsis buds that are entering eco- or paradormancy, we have identified four induced interrelated GRNs that correspond to a carbon (C) starvation syndrome, typical of tissues undergoing low C supply. This response is also detectable in poplar and grapevine buds before and during the transition to dormancy. In all eukaryotes, C-limiting conditions are coupled to growth arrest and latency like that observed in dormant axillary buds. Bud dormancy might thus be partly a consequence of the underlying C starvation syndrome triggered by environmental and endogenous cues that anticipate or signal conditions unfavorable for sustained shoot growth. PMID- 28588592 TI - In-Depth Genomic and Transcriptomic Analysis of Five K+ Transporter Gene Families in Soybean Confirm Their Differential Expression for Nodulation. AB - Plants have evolved a sophisticated network of K+ transport systems to regulate growth and development. Limited K+ resources are now forcing us to investigate how plant demand can be satisfied. To answer this complex question, we must understand the genomic and transcriptomic portfolio of K+ transporters in plants. Here, we have identified 70 putative K+ transporter genes from soybean, including 29 HAK/KT/KUP genes, 16 genes encoding voltage-gated K+ channels, 9 TPK/KCO genes, 4 HKT genes, and 12 KEA genes. To clarify the molecular evolution of each family in soybean, we analyzed their phylogeny, mode of duplication, exon structures and splice sites, and paralogs. Additionally, ortholog clustering and syntenic analysis across five other dicots further explored the evolution of these gene families and indicated that the soybean data is suitable as a model for all other legumes. Available microarray data sets from Genevestigator about nodulation was evaluated and further confirmed with the RNA sequencing data available by a web server. For each family, expression models were designed based on Transcripts Per Kilobase Million (TPM) values; the outcomes indicated differential expression linked to nodulation and confirmed the genes' putative roles. In-depth studies such as ours provides the basis for understanding K+ inventories in all other plants. PMID- 28588594 TI - Quantitative Trait Locus Analysis for Deep-Sowing Germination Ability in the Maize IBM Syn10 DH Population. AB - Deep-sowing is an effective measure to ensure seeds absorbing water from deep soil layer and emerging normally in arid and semiarid regions. However, existing varieties demonstrate poor germination ability in deep soil layer and some key quantitative trait loci (QTL) or genes related to deep-sowing germination ability remain to be identified and analyzed. In this study, a high-resolution genetic map based on 280 lines of the intermated B73 * Mo17 (IBM) Syn10 doubled haploid (DH) population which comprised 6618 bin markers was used for the QTL analysis of deep-sowing germination related traits. The results showed significant differences in germination related traits under deep-sowing condition (12.5 cm) and standard-germination condition (2 cm) between two parental lines. In total, 8, 11, 13, 15, and 18 QTL for germination rate, seedling length, mesocotyl length, plumule length, and coleoptile length were detected for the two sowing conditions, respectively. These QTL explained 2.51-7.8% of the phenotypic variance with LOD scores ranging from 2.52 to 7.13. Additionally, 32 overlapping QTL formed 11 QTL clusters on all chromosomes except for chromosome 8, indicating the minor effect genes have a pleiotropic role in regulating various traits. Furthermore, we identified six candidate genes related to deep-sowing germination ability, which were co-located in the cluster regions. The results provide a basis for molecular marker assisted breeding and functional study in deep-sowing germination ability of maize. PMID- 28588593 TI - Salinity-Induced Palmella Formation Mechanism in Halotolerant Algae Dunaliella salina Revealed by Quantitative Proteomics and Phosphoproteomics. AB - Palmella stage is critical for some unicellular algae to survive in extreme environments. The halotolerant algae Dunaliella salina is a good single-cell model for studying plant adaptation to high salinity. To investigate the molecular adaptation mechanism in salinity shock-induced palmella formation, we performed a comprehensive physiological, proteomics and phosphoproteomics study upon palmella formation of D. salina using dimethyl labeling and Ti4+-immobilized metal ion affinity chromatography (IMAC) proteomic approaches. We found that 151 salinity-responsive proteins and 35 salinity-responsive phosphoproteins were involved in multiple signaling and metabolic pathways upon palmella formation. Taken together with photosynthetic parameters and enzyme activity analyses, the patterns of protein accumulation and phosphorylation level exhibited the mechanisms upon palmella formation, including dynamics of cytoskeleton and cell membrane curvature, accumulation and transport of exopolysaccharides, photosynthesis and energy supplying (i.e., photosystem II stability and activity, cyclic electron transport, and C4 pathway), nuclear/chloroplastic gene expression regulation and protein processing, reactive oxygen species homeostasis, and salt signaling transduction. The salinity-responsive protein-protein interaction (PPI) networks implied that signaling and protein synthesis and fate are crucial for modulation of these processes. Importantly, the 3D structure of phosphoprotein clearly indicated that the phosphorylation sites of eight proteins were localized in the region of function domain. PMID- 28588595 TI - The Role of SHI/STY/SRS Genes in Organ Growth and Carpel Development Is Conserved in the Distant Eudicot Species Arabidopsis thaliana and Nicotiana benthamiana. AB - Carpels are a distinctive feature of angiosperms, the ovule-bearing female reproductive organs that endow them with multiple selective advantages likely linked to the evolutionary success of flowering plants. Gene regulatory networks directing the development of carpel specialized tissues and patterning have been proposed based on genetic and molecular studies carried out in Arabidopsis thaliana. However, studies on the conservation/diversification of the elements and the topology of this network are still scarce. In this work, we have studied the functional conservation of transcription factors belonging to the SHI/STY/SRS family in two distant species within the eudicots, Eschscholzia californica and Nicotiana benthamiana. We have found that the expression patterns of EcSRS-L and NbSRS-L genes during flower development are similar to each other and to those reported for Arabidopsis SHI/STY/SRS genes. We have also characterized the phenotypic effects of NbSRS-L gene inactivation and overexpression in Nicotiana. Our results support the widely conserved role of SHI/STY/SRS genes at the top of the regulatory network directing style and stigma development, specialized tissues specific to the angiosperm carpels, at least within core eudicots, providing new insights on the possible evolutionary origin of the carpels. PMID- 28588596 TI - Evaluating Hyperspectral Vegetation Indices for Leaf Area Index Estimation of Oryza sativa L. at Diverse Phenological Stages. AB - Hyperspectral reflectance derived vegetation indices (VIs) are used for non destructive leaf area index (LAI) monitoring for precise and efficient N nutrition management. This study tested the hypothesis that there is potential for using various hyperspectral VIs for estimating LAI at different growth stages of rice under varying N rates. Hyperspectral reflectance and crop canopy LAI measurements were carried out over 2 years (2015 and 2016) in Meichuan, Hubei, China. Different N fertilization, 0, 45, 82, 127, 165, 210, 247, and 292 kg ha-1, were applied to generate various scales of VIs and LAI values. Regression models were used to perform quantitative analyses between spectral VIs and LAI measured under different phenological stages. In addition, the coefficient of determination and RMSE were employed to evaluate these models. Among the nine VIs, the ratio vegetation index, normalized difference vegetation index (NDVI), modified soil-adjusted vegetation index (MSAVI), modified triangular vegetation index (MTVI2) and exhibited strong and significant relationships with the LAI estimation at different phenological stages. The enhanced vegetation index performed moderately. However, the green normalized vegetation index and blue normalized vegetation index confirmed that there is potential for crop LAI estimation at early phenological stages; the soil-adjusted vegetation index and optimized soil-adjusted vegetation index were more related to the soil optical properties, which were predicted to be the least accurate for LAI estimation. The noise equivalent accounted for the sensitivity of the VIs and MSAVI, MTVI2, and NDVI for the LAI estimation at phenological stages. The results note that LAI at different crop phenological stages has a significant influence on the potential of hyperspectral derived VIs under different N management practices. PMID- 28588597 TI - Protein Biochemistry and Expression Regulation of Cadmium/Zinc Pumping ATPases in the Hyperaccumulator Plants Arabidopsis halleri and Noccaea caerulescens. AB - P1B-ATPases are decisive for metal accumulation phenotypes, but mechanisms of their regulation are only partially understood. Here, we studied the Cd/Zn transporting ATPases NcHMA3 and NcHMA4 from Noccaea caerulescens as well as AhHMA3 and AhHMA4 from Arabidopsis halleri. Protein biochemistry was analyzed on HMA4 purified from roots of N. caerulescens in active state. Metal titration of NcHMA4 protein with an electrochromic dye as charge indicator suggested that HMA4 reaches maximal ATPase activity when all internal high-affinity Cd2+ binding sites are occupied. Although HMA4 was reported to be mainly responsible for xylem loading of heavy metals for root to shoot transport, the current study revealed high expression of NcHMA4 in shoots as well. Further, there were additional 20 and 40 kD fragments at replete Zn2+ and toxic Cd2+, but not at deficient Zn2+ concentrations. Altogether, the protein level expression analysis suggested a more multifunctional role of NcHMA4 than previously assumed. Organ-level transcription analysis through quantitative PCR of mRNA in N. caerulescens and A. halleri confirmed the strong shoot expression of both NcHMA4 and AhHMA4. Further, in shoots NcHMA4 was more abundant in 10 MUM Zn2+ and AhHMA4 in Zn2+ deficiency. In roots, NcHMA4 was up-regulated in response to deficient Zn2+ when compared to replete Zn2+ and toxic Cd2+ treatment. In both species, HMA3 was much more expressed in shoots than in roots, and HMA3 transcript levels remained rather constant regardless of Zn2+ supply, but were up-regulated by 10 MUM Cd2+. Analysis of cellular expression by quantitative mRNA in situ hybridisation showed that in A. halleri, both HMA3 and HMA4 mRNA levels were highest in the mesophyll, while in N. caerulescens they were highest in the bundle sheath of the vein. This is likely related to the different final storage sites for hyperaccumulated metals in both species: epidermis in N. caerulescens, mesophyll in A. halleri. PMID- 28588598 TI - Genetic Gains in Grain Yield of a Maize Population Improved through Marker Assisted Recurrent Selection under Stress and Non-stress Conditions in West Africa. AB - Marker-assisted recurrent selection (MARS) is a breeding method used to accumulate favorable alleles that for example confer tolerance to drought in inbred lines from several genomic regions within a single population. A bi parental cross formed from two parents that combine resistance to Striga hermonthica with drought tolerance, which was improved through MARS, was used to assess changes in the frequency of favorable alleles and its impact on inbred line improvement. A total of 200 testcrosses of randomly selected S1 lines derived from the original (C0) and advanced selection cycles of this bi-parental population, were evaluated under drought stress (DS) and well-watered (WW) conditions at Ikenne and under artificial Striga infestation at Abuja and Mokwa in Nigeria in 2014 and 2015. Also, 60 randomly selected S1 lines each derived from the four cycles (C0, C1, C2, C3) were genotyped with 233 SNP markers using KASP assay. The results showed that the frequency of favorable alleles increased with MARS in the bi-parental population with none of the markers showing fixation. The gain in grain yield was not significant under DS condition due to the combined effect of DS and armyworm infestation in 2015. Because the parents used for developing the bi-parental cross combined tolerance to drought with resistance to Striga, improvement in grain yield under DS did not result in undesirable changes in resistance to the parasite in the bi-parental maize population improved through MARS. MARS increased the mean number of combinations of favorable alleles in S1 lines from 114 in C0 to 124 in C3. The level of heterozygosity decreased by 15%, while homozygosity increased by 13% due to the loss of some genotypes in the population. This study demonstrated the effectiveness of MARS in increasing the frequency of favorable alleles for tolerance to drought without disrupting the level of resistance to Striga in a bi parental population targeted as a source of improved maize inbred lines. PMID- 28588599 TI - Investigation of Amino Acids As Herbicides for Control of Orobanche minor Parasitism in Red Clover. AB - Certain amino acids induce inhibitory effects in plant growth due to feedback inhibition of metabolic pathways. The inhibition patterns depend on plant species and the plant developmental stage. Those amino acids with inhibitory action on specific weeds could be utilized as herbicides, however, their use for weed control has not been put into practice. Orobanche minor is a weed that parasitizes red clover. O. minor germination is stimulated by clover root exudates. The subsequent seedling is an obligated parasite that must attach quickly to the clover root to withdraw its nutrients. Early development of O. minor is vulnerable to amino acid inhibition and therefore, a series of in vitro, rhizotron, and field experiments were conducted to investigate the potential of amino acids to inhibit O. minor parasitism. In in vitro experiments it was found that among a collection of 20 protein amino acids, lysine, methionine and tryptophan strongly interfere with O. minor early development. Field research confirmed their inhibitory effect but revealed that methionine was more effective than lysine and tryptophan, and that two successive methionine applications at 308 and 543 growing degree days inhibited O. minor emergence in red clover up to 67%. We investigated additional effects with potential to influence the practical use of amino acids against broomrape weeds, whether the herbicidal effect may be reversible by other amino acids exuded by host plants or may be amplified by inducing host resistance barriers against O. minor penetration. This paper suggests that amino acids may have the potential to be integrated into biorational programs of broomrape management. PMID- 28588600 TI - Date Palm Tree (Phoenix dactylifera L.): Natural Products and Therapeutic Options. AB - Many plants, including some of the commonly consumed herbs and spices in our daily food, can be safely and effectively used to prevent and/or treat some health concerns. For example, caffeine the active ingredient found in coffee beans (Coffea), shows biological activity in the treatment of the central nervous system (CNS) disorders, indole-3-carbinol, and 3,3'-diindolylmethane are both broccoli (Brassica oleracea) derived phytochemicals with potential anti-cancer activity, and resveratrol, isolated from grape (Vitis vinifera), is reported to extend lifespan and provide cardio-neuro-protective, anti-diabetic, and anti cancer effects. Date palm fruits possess high nutritional and therapeutic value with significant antioxidant, antibacterial, antifungal, and anti-proliferative properties. This review focuses on the date fruit extracts and their benefits in individual health promoting conditions and highlights their applications as useful to the pharmaceutical and nutraceutical industries in the development of natural compound-based industrial products. PMID- 28588602 TI - The Sulfate Supply Maximizing Arabidopsis Shoot Growth Is Higher under Long- than Short-Term Exposure to Cadmium. AB - The processes involved in cadmium detoxification in plants deeply affect sulfate uptake and thiol homeostasis and generate increases in the plant nutritional request for sulfur. Here, we present an analysis of the dependence of Arabidopsis growth on the concentration of sulfate in the growing medium with the aim of providing evidence on how plants optimize growth at a given sulfate availability. Results revealed that short-term (72 h) exposure to a broad range of Cd concentrations (0.1, 1, and 10 MUM) inhibited plant growth but did not produce any significant effects on the growth pattern of both shoots and roots in relation to the external sulfate. Conversely, long-term (22 days) exposure to 0.1 MUM Cd significantly changed the pattern of fresh weight accumulation of the shoots in relation to the external sulfate, without affecting that of the roots, although their growth was severely inhibited by Cd. Moreover, under long-term exposure to Cd, increasing the sulfate external concentration up to the critical value progressively reduced the inhibitory effects exerted by Cd on shoot growth, indicating the existence of sulfate-dependent adaptive responses protecting the shoot tissues against Cd injury. Transcriptional induction of the high-affinity sulfate transporter genes (SULTR1; 1 and SULTR1; 2) involved in sulfate uptake by roots was a common adaptive response to both short- and long-term exposure to Cd. Such a response was closely related to the total amount of non-protein thiols accumulated by a single plant under short-term exposure to Cd, but did not showed any clear relation with thiols under long-term exposure to Cd. In this last condition, Cd exposure did not change the level of non-protein thiols per plant and thus did not alter the nutritional need for sulfur. In conclusion, our results indicate that long term-exposure to Cd, although it induces sulfate uptake, decreases the capacity of the Arabidopsis roots to efficiently absorb the sulfate ions available in the growing medium making the adaptive response of SULTR1; 1 and SULTR1; 2 "per se" not enough to optimize the growth at sulfate external concentrations lower than the critical value. PMID- 28588604 TI - Effects of Light Quality on Morphology, Enzyme Activities, and Bioactive Compound Contents in Anoectochilus roxburghii. AB - The aim of this study was to investigate the effects of light quality on the morphological traits, leaf anatomical characteristics, antioxidant enzyme (superoxide dismutase, catalase, and peroxidase) activities, photosynthetic pigments content, and bioactive compounds (phenols, flavonoids, and polysaccharides) content in Anoectochilus roxburghii. Plants of A. roxburghii were grown under light filtered through four differently colored films for 8 months. The four treatments were red film (RF), blue film (BF), yellow film (YF), and colorless plastic film (control, CK). Compared with the A. roxburghii plants in CK, those in the BF treatment showed significantly greater stem diameter, fresh weight, leaf area, stomatal frequency, chlorophyll content (Chl a, Chl b, Chl a+b), antioxidant enzyme activities, and active compound (polysaccharides, flavones) content. The plants in the RF treatment showed the greatest plant height and phenolics contents. These results show that growing A. roxburghii plants under blue film is a useful technique to improve quality. This technique is conducive to achieving large-scale sustainable production of high-quality plant materials. PMID- 28588601 TI - In Favor of Establishment: Regulation of Chromatid Cohesion in Plants. AB - In eukaryotic organisms, the correct regulation of sister chromatid cohesion, whereby sister chromatids are paired and held together, is essential for accurate segregation of the sister chromatids and homologous chromosomes into daughter cells during mitosis and meiosis, respectively. Sister chromatid cohesion requires a cohesin complex comprised of structural maintenance of chromosome adenosine triphosphatases and accessory proteins that regulate the association of the complex with chromosomes or that are involved in the establishment or release of cohesion. The cohesin complex also plays important roles in the repair of DNA double-strand breaks, regulation of gene expression and chromosome condensation. In this review, we summarize progress in understanding cohesion dynamics in plants, with the aim of uncovering differences at specific stages. We also highlight dissimilarities between plants and other eukaryotes with respect to the key players involved in the achievement of cohesion, pointing out areas that require further study. PMID- 28588603 TI - Short Term Effect of Salt Shock on Ethylene and Polyamines Depends on Plant Salt Sensitivity. AB - In the present manuscript the short term effect (3-24 h) of a saline shock (NaCl 100 mM) on fresh weight, water content, respiration rate, ethylene production and Na+, Cl-, ACC and polyamine concentration was studied in four plant species with different salt sensitivity, pepper, lettuce, spinach, and beetroot. Higher reduction in fresh weight and water content as a consequence of saline shock was found in pepper and lettuce plants than in spinach and beetroot, the latter behaving as more salinity tolerant. In general, salinity led to rapid increases in respiration rate, ethylene production and ACC and polyamine (putrescine, spermidine, and spermine) concentrations in shoot and root. These increases were related to plant salinity sensitivity, since they were higher in the most sensitive species and vice versa. However, ethylene and respiration rates in salt stressed plants recovered similar values to controls after 24 h of treatment in salt tolerant plants, while still remaining high in the most sensitive. On the other hand, sudden increases in putrescine, spermidine, and spermine concentration were higher and occurred earlier in pepper and lettuce, the most sensitive species, than in spinach and beetroot, the less sensitive ones. These increases tended to disappear after 24 h, except in lettuce. These changes would support the conclusion that ethylene and polyamine increases could be considered as a plant response to saline shock and related to the plant species sensitivity to this stress. In addition, no competition between polyamines and ethylene biosynthesis for their common precursor was observed. PMID- 28588605 TI - miR397/Laccase Gene Mediated Network Improves Tolerance to Fenoxaprop-P-ethyl in Beckmannia syzigachne and Oryza sativa. AB - Herbicide resistance can be either target-site or non-target-site based. The molecular mechanisms underlying non-target-site resistance (NTSR) are poorly understood, especially at the level of gene expression regulation. MicroRNAs (miRNAs) represent key post-transcriptional regulators of eukaryotic gene expression and play important roles in stress responses. In this study, the miR397 gene from Beckmannia syzigachne (referred to as bsy-miR397) was functionally characterized to determine its role in regulating fenoxaprop-P-ethyl resistance. We showed that (1) bsy-miR397 transcript level is constitutively higher in resistant than in sensitive B. syzigachne plants, whereas bsy-Laccase expression and activity show the opposite trend, and (2) bsy-miR397 suppresses the expression of bsy-Laccase in tobacco, indicating that it negatively regulates bsy-Laccase at the transcriptional level. We found evidences that miR397/laccase regulation might be involved in fenoxaprop-P-ethyl NTSR. First, the rice transgenic line overexpressing OXmiR397 showed improved fenoxaprop-P-ethyl tolerance. Second, following activation of bsy-Laccase gene expression by CuSO4 treatment, fenoxaprop resistance in B. syzigachne tended to decrease. Therefore, we suggest that bsy-miR397 might play a role in fenoxaprop-P-ethyl NTSR in B. syzigachne by down-regulating laccase expression, potentially leading to the enhanced expression of three oxidases/peroxidases genes to introduce an active moiety into herbicide molecules in Phase-2 metabolism. Bsy-miR397, bsy-Laccase, and other regulatory components might form a regulatory network to detoxify fenoxaprop-P-ethyl in B. syzigachne, supported by the differential expression of transcription factors and oxidases/peroxidases in the rice transgenic line overexpressing OXmiR397. This implies how down-regulation of a gene (laccase) can enhance NTSR. Our findings shed light on the daunting task of understanding and managing complex NTSR in weedy plant species. PMID- 28588607 TI - Single-Cell RNA-Sequencing: Assessment of Differential Expression Analysis Methods. AB - The sequencing of the transcriptomes of single-cells, or single-cell RNA sequencing, has now become the dominant technology for the identification of novel cell types and for the study of stochastic gene expression. In recent years, various tools for analyzing single-cell RNA-sequencing data have been proposed, many of them with the purpose of performing differentially expression analysis. In this work, we compare four different tools for single-cell RNA sequencing differential expression, together with two popular methods originally developed for the analysis of bulk RNA-sequencing data, but largely applied to single-cell data. We discuss results obtained on two real and one synthetic dataset, along with considerations about the perspectives of single-cell differential expression analysis. In particular, we explore the methods performance in four different scenarios, mimicking different unimodal or bimodal distributions of the data, as characteristic of single-cell transcriptomics. We observed marked differences between the selected methods in terms of precision and recall, the number of detected differentially expressed genes and the overall performance. Globally, the results obtained in our study suggest that is difficult to identify a best performing tool and that efforts are needed to improve the methodologies for single-cell RNA-sequencing data analysis and gain better accuracy of results. PMID- 28588606 TI - Mutations in the NOT Genes or in the Translation Machinery Similarly Display Increased Resistance to Histidine Starvation. AB - The NOT genes encode subunits of the conserved Ccr4-Not complex, a global regulator of gene expression, and in particular of mRNA metabolism. They were originally identified in a selection for increased resistance to histidine starvation in the yeast S. cerevisiae. Recent work indicated that the Not5 subunit, ortholog of mammalian CNOT3, determines global translation levels by defining binding of the Ccr4-Not scaffold protein Not1 to ribosomal mRNAs during transcription. This is needed for optimal translation of ribosomal proteins. In this work we searched for mutations in budding yeast that were resistant to histidine starvation using the same selection that originally led to the isolation of the NOT genes. We thereby isolated mutations in ribosome-related genes. This common phenotype of ribosome mutants and not mutants is in good agreement with the positive role of the Not proteins for translation. In this regard, it is interesting that frequent mutations in RPL5 and RPL10 or in CNOT3 have been observed to accumulate in adult T-cell acute lymphoblastic leukemia (T ALL). This suggests that in metazoans a common function implicating ribosome subunits and CNOT3 plays a role in the development of cancer. In this perspective we suggest that the Ccr4-Not complex, according to translation levels and fidelity, could itself be involved in the regulation of amino acid biosynthesis levels. We discuss how this could explain why mutations have been identified in many cancers. PMID- 28588608 TI - An Enhancer's Length and Composition Are Shaped by Its Regulatory Task. AB - Enhancers drive the gene expression patterns required for virtually every process in metazoans. We propose that enhancer length and transcription factor (TF) binding site composition-the number and identity of TF binding sites-reflect the complexity of the enhancer's regulatory task. In development, we define regulatory task complexity as the number of fates specified in a set of cells at once. We hypothesize that enhancers with more complex regulatory tasks will be longer, with more, but less specific, TF binding sites. Larger numbers of binding sites can be arranged in more ways, allowing enhancers to drive many distinct expression patterns, and therefore cell fates, using a finite number of TF inputs. We compare ~100 enhancers patterning the more complex anterior-posterior (AP) axis and the simpler dorsal-ventral (DV) axis in Drosophila and find that the AP enhancers are longer with more, but less specific binding sites than the (DV) enhancers. Using a set of ~3,500 enhancers, we find enhancer length and TF binding site number again increase with increasing regulatory task complexity. Therefore, to be broadly applicable, computational tools to study enhancers must account for differences in regulatory task. PMID- 28588609 TI - Metabolic and Genetic Markers of Biological Age. AB - Biological age is a concept that takes into account the heterogeneity of the aging process in different individuals that results in differences in survival and variations in relative health. Any measure of biological age must be better than chronological age at predicting mortality. Several quantitative measures of biological age have been developed. Among them are frailty indices, one of which called FI34 is discussed here in greater detail. FI34 increases exponentially with age reflecting decline in health and function ability. It readily depicts different patterns and trajectories of aging, and it is moderately heritable. Thus, it has been used to identify a genomic region on chromosome 12 associated with healthy aging. FI34 has also been useful in describing the metabolic characteristics of this phenotype, revealing both sex and genetic differences. These differences give rise to specific, testable models regarding healthy aging, which involve cell and tissue damage and mitochondrial metabolism. FI34 has been directly compared to various metrics based on DNA methylation as a predictor of mortality, demonstrating that it outperforms them uniformly. This and other frailty indices take a top-down, systems based view of aging that is cognizant of the integrated function of the complex aging system. PMID- 28588611 TI - Refining Automatically Extracted Knowledge Bases Using Crowdsourcing. AB - Machine-constructed knowledge bases often contain noisy and inaccurate facts. There exists significant work in developing automated algorithms for knowledge base refinement. Automated approaches improve the quality of knowledge bases but are far from perfect. In this paper, we leverage crowdsourcing to improve the quality of automatically extracted knowledge bases. As human labelling is costly, an important research challenge is how we can use limited human resources to maximize the quality improvement for a knowledge base. To address this problem, we first introduce a concept of semantic constraints that can be used to detect potential errors and do inference among candidate facts. Then, based on semantic constraints, we propose rank-based and graph-based algorithms for crowdsourced knowledge refining, which judiciously select the most beneficial candidate facts to conduct crowdsourcing and prune unnecessary questions. Our experiments show that our method improves the quality of knowledge bases significantly and outperforms state-of-the-art automatic methods under a reasonable crowdsourcing cost. PMID- 28588610 TI - Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction. AB - Telomeres are essential nucleoprotein structures at linear chromosomes that maintain genome integrity by protecting chromosome ends from being recognized and processed as damaged DNA. In addition, they limit the cell's proliferative capacity, as progressive loss of telomeric DNA during successive rounds of cell division eventually causes a state of telomere dysfunction that prevents further cell division. When telomeres become critically short, the cell elicits a DNA damage response resulting in senescence, apoptosis or genomic instability, thereby impacting on aging and tumorigenesis. Over the past years substantial progress has been made in understanding the role of post-translational modifications in telomere-related processes, including telomere maintenance, replication and dysfunction. This review will focus on recent findings that establish an essential role for ubiquitination and SUMOylation at telomeres. PMID- 28588613 TI - Preoperative Serum IL-12p40 Is a Potential Predictor of Kasai Portoenterostomy Outcome in Infants with Biliary Atresia. AB - The standard-of-care treatment for biliary atresia (BA) is surgical restoration of bile flow by Kasai portoenterostomy. We aimed to study serum interleukin- (IL ) 12p40, a natural antagonist for the proinflammatory IL-12p70, and its relation to surgical outcomes of BA. The study included 75 infants with neonatal cholestasis: BA group (n = 25), non-BA cholestasis group (n = 30), and neglected BA group (n = 20), in addition to thirty healthy neonates serving as controls. IL 12p40 was measured by ELISA in all individuals and a second assessment was performed 3 months postoperatively in the BA group. The surgical outcomes were classified as successful (bilirubin <= 2 mg/dl) or failed (bilirubin > 2 mg/dl). IL-12p40 was higher in BA compared to that in the non-BA and control groups (P values were 0.036 and <0.0001, resp.) but comparable to that in the neglected BA group. Preoperative IL-12p40 levels in BA patients were significantly higher in successful Kasai compared with failed Kasai and a cutoff level of 547.47 pg/ml could predict the successful outcome with 87.5% sensitivity and 82.4% specificity. Three-month postoperative IL-12p40 tended to decrease in both the successful and failed groups. In conclusion, preoperative serum IL-12p40 is a potential predictor of Kasai outcome. Serial postoperative measurements may anticipate the failure of an initially successful operation, hence the need for liver transplantation. PMID- 28588614 TI - Optimization of Aflatoxin B1 Aptasensing. AB - Combination of aptamers with DNAzymes attracted intense attention for development of DNA-based biosensors for detection of mycotoxins. In the present study a combination of aflatoxin B1 specific aptamer and HRP- (horseradish peroxidase-) mimicking DNAzyme was optimized for detecting aflatoxin B1. Detecting approach is based on the binding affinity of aflatoxin B1 to its specific aptamer and conversion of substrate to a detectable colorimetric signal by a linked DNAzyme. Compared to conventional methods for aflatoxin B1 detection, DNA-based assay has the advantages of low cost, long-term stability, and rapid, simple, and user friendly steps. PMID- 28588612 TI - The Roles of Carcinoembryonic Antigen in Liver Metastasis and Therapeutic Approaches. AB - Metastasis is a highly complicated and sequential process in which primary cancer spreads to secondary organic sites. Liver is a well-known metastatic organ from colorectal cancer. Carcinoembryonic antigen (CEA) is expressed in most gastrointestinal, breast, and lung cancer cells. Overexpression of CEA is closely associated with liver metastasis, which is the main cause of death from colorectal cancer. CEA is widely used as a diagnostic and prognostic tumor marker in cancer patients. It affects many steps of liver metastasis from colorectal cancer cells. CEA inhibits circulating cancer cell death. CEA also binds to heterogeneous nuclear RNA binding protein M4 (hnRNP M4), a Kupffer cell receptor protein, and activates Kupffer cells to secrete various cytokines that change the microenvironments for the survival of colorectal cancer cells in the liver. CEA also activates cell adhesion-related molecules. The close correlation between CEA and cancer has spurred the exploration of many CEA-targeted approaches as anticancer therapeutics. Understanding the detailed functions and mechanisms of CEA in liver metastasis will provide great opportunities for the improvement of anticancer approaches against colorectal cancers. In this report, the roles of CEA in liver metastasis and CEA-targeting anticancer modalities are reviewed. PMID- 28588615 TI - Relationship between Central Arterial Stiffness and Insulin Resistance in Chinese Community-Dwelling Population without Diabetes Mellitus. AB - OBJECTIVE: Insulin resistance (IR) is a pathological condition present not only in patients with type 2 diabetes mellitus (DM), but also in community-dwelling population without DM. Both central arterial stiffness and IR are closely correlated with cardiovascular morbidity and mortality. The relationship between central arterial stiffness and IR has not been described in Chinese community dwelling population without DM. The current analysis was designed to investigate the relationship between central arterial stiffness and IR in Chinese community dwelling population without DM. METHODS: There were 1150 participants fully assessed for not only homeostasis model assessment of insulin resistance (HOMA IR) but also carotid-femoral pulse wave velocity (cfPWV). RESULTS: Median age was 39 (18-80) years, and 69.7% were men. Bivariate correlation analysis showed that cfPWV was significantly related to HOMA-IR (P < 0.05). Logistic regression analysis indicated that cfPWV was independently associated with HOMA-IR (P < 0.05). CONCLUSIONS: This community-based analysis testified that the relationship between central arterial stiffness and IR was evident as early as during nondiabetic stage. Early interventions in Chinese community-dwelling population without DM to improve the IR are also important in the prevention of cardiovascular diseases. PMID- 28588616 TI - A Comparison of Impact of Chronic Periodontal Diseases and Nonsurgical Periodontal Therapy on Oral Health-Related Quality of Life. AB - OBJECTIVES: To evaluate the impact of chronic periodontal diseases (PDs) and compare phases of nonsurgical periodontal therapy (NSPT) on oral health-related quality of life (OHRQoL) in patients attending a tertiary care center of eastern Nepal. MATERIALS AND METHODS: Matched for socioeconomic status, participants were recruited in two groups: moderate-to-severe chronic periodontitis (n = 24, 43 +/- 46 years) and chronic gingivitis (n = 25, 30 +/- 96 years). The treatment modalities were scaling and root surface debridement (RSD) and supragingival scaling, respectively. The impact of periodontal disease treatment status was assessed by a self-reported questionnaire of Nepali Oral Health Impact Profile (OHIP-14) at baseline and 9-12 weeks after NSPT. RESULTS: The median (IQR) OHIP 14 total scores for PDs reduced from 7 (3-11) to 3 (1-7.5) after NSPT. Both groups showed a significant improvement on OHRQoL (p value < 0.001). The periodontitis group showed an increased median (IQR) reduction of 52% (35.22 86.15) compared with the gingivitis group with 27% (0.00-50.00). The impact on orofacial pain, orofacial appearance, and psychosocial dimensions was observed, which improved after NSPT in both groups. CONCLUSION: PDs are directly associated with OHRQoL and treatment of the disease may enhance quality of life from a patient's perspective. Scaling and RSD provided better influence on OHRQoL than supragingival scaling. PMID- 28588618 TI - Ventilator Management of Bronchopleural Fistula Secondary to Methicillin Resistant Staphylococcus aureus Necrotizing Pneumonia in a Pregnant Patient with Systemic Lupus Erythematosus. AB - Managing mechanical ventilation in patient with bronchopleural fistula with coexisting acute respiratory distress syndrome is a challenging situation for the intensivist. We are reporting a case of a pregnant patient with systemic lupus erythematosus on immunosuppressive medications who developed methicillin resistant Staphylococcus aureus necrotizing pneumonia complicated by bronchopleural fistula and acute respiratory distress syndrome. PMID- 28588617 TI - Outcomes of Six-Dose High-Dose Cytarabine as a Salvage Regimen for Patients with Relapsed/Refractory Acute Myeloid Leukemia. AB - Relapsed/refractory acute myeloid leukemia (RR-AML) is associated with poor prognosis and long-term disease-free survival requires allogeneic hematopoietic cell transplantation (allo-HCT). Limited data exists, regarding the optimal regimen to obtain remission prior to allo-HCT. Single agent high-dose cytarabine (10-12 doses administered every 12 hours) has been previously used as induction therapy. Six-dose high-dose cytarabine (HiDAC-6), commonly used as a consolidation regimen, has never been evaluated as induction therapy. We present a retrospective review of 26 consecutive patients with RR-AML receiving single agent cytarabine 3 g/m2 intravenously every 12 hours on days 1, 3, and 5 for a total of six doses (HiDAC-6). Median follow-up for surviving patients was 10.4 months (range 1.6-112.2 months). Complete remission was obtained in 62% (54% CR and 8% CRi) of the patients. The median relapse-free survival (RFS) was 22.3 months (range 0.7-112 months), event-free survival (EFS) was 4.7 months (range 0.5-112 months), and the overall survival (OS) was 9.6 months (range 1-112 months). Thirty-five percent of patients were able to subsequently proceed to allo-HCT. Treatment-related toxicities included neutropenic fever (38%), infection (35%), neurotoxicity (8%), and skin toxicity (8%). This is the first study to demonstrate HiDAC-6 as an active treatment option for younger patients with RR-AML which can effectively serve as a bridge to allo-HCT without significant toxicity. PMID- 28588619 TI - Portal Hypertensive Biliopathy Presents with Massive Bleeding during ERCP after Balloon Sphincteroplasty in a Noncirrhotic Saudi Sickler Patient. AB - Portal hypertensive biliopathy (PHB) is described as abnormalities of the walls of the biliary tree secondary to portal hypertension. Gastrointestinal bleeding caused by PHB is rare. PHB as a cause of serious bleeding after sphincteroplasty during ERCP is extremely rare. Here, we report a case of PHB in a young Saudi male with cell sickle anemia who developed massive hemorrhage during ERCP after balloon dilation of the ampulla of Vater. We further discussed the diagnosis and management. To the best of our knowledge, no such case has been reported. PMID- 28588620 TI - Human Bone Marrow Mesenchymal Stem/Stromal Cells Preserve Their Immunomodulatory and Chemotactic Properties When Expanded in a Human Plasma Derived Xeno-Free Medium. AB - Due to their immunomodulatory and chemotactic properties, hMSC are being explored to treat immune-related diseases. For their use in human therapies, it is necessary to culture hMSC in xeno-free conditions. In this study, the impact that a xeno-free medium based on a human plasma derivate has on these properties was analysed. Bone marrow-derived hMSC preserved their immunosuppressive and immunostimulatory properties, as observed with in vitro assays with hMSC cocultured with mixed leukocyte reactions or with mitogen-stimulated leukocytes. Moreover, hMSC expanded in xeno-free medium were recruited by macrophages in both migration and invasion assays, which indicates that the cells maintained their chemotactic properties. These data suggest that xeno-free expanded hMSC preserved their immunomodulatory and chemotactic properties, indicating that the described xeno-free medium composition is a potential candidate to culture and expand hMSC for human cell therapies. PMID- 28588621 TI - Environmental Factors That Influence Stem Cell Migration: An "Electric Field". AB - Environmental Stimulus of Electric Fields on Stem Cell Migration. The movement of cells in response to electric potential gradients is called galvanotaxis. In vivo galvanotaxis, powered by endogenous electric fields (EFs), plays a critical role during development and wound healing. This review aims to provide a perspective on how stem cells transduce EFs into directed migration and an understanding of the current literature relating to the mechanisms by which cells sense and transduce EFs. We will comment on potential EF-based regenerative medicine therapeutics. PMID- 28588622 TI - Delayed Mesoderm and Erythroid Differentiation of Murine Embryonic Stem Cells in the Absence of the Transcriptional Regulator FUBP1. AB - The transcriptional regulator far upstream binding protein 1 (FUBP1) is essential for fetal and adult hematopoietic stem cell (HSC) self-renewal, and the constitutive absence of FUBP1 activity during early development leads to embryonic lethality in homozygous mutant mice. To investigate the role of FUBP1 in murine embryonic stem cells (ESCs) and in particular during differentiation into hematopoietic lineages, we generated Fubp1 knockout (KO) ESC clones using CRISPR/Cas9 technology. Although FUBP1 is expressed in undifferentiated ESCs and during spontaneous differentiation following aggregation into embryoid bodies (EBs), absence of FUBP1 did not affect ESC maintenance. Interestingly, we observed a delayed differentiation of FUBP1-deficient ESCs into the mesoderm germ layer, as indicated by impaired expression of several mesoderm markers including Brachyury at an early time point of ESC differentiation upon aggregation to EBs. Coculture experiments with OP9 cells in the presence of erythropoietin revealed a diminished differentiation capacity of Fubp1 KO ESCs into the erythroid lineage. Our data showed that FUBP1 is important for the onset of mesoderm differentiation and maturation of hematopoietic progenitor cells into the erythroid lineage, a finding that is supported by the phenotype of FUBP1-deficient mice. PMID- 28588623 TI - Angiogenic Capacity of Dental Pulp Stem Cell Regulated by SDF-1alpha-CXCR4 Axis. AB - Previously, the perivascular characteristics of dental pulp stem cells (DPSCs) were reported, which suggested the potential application of DPSCs as perivascular cell source. In this study, we investigated whether DPSCs had angiogenic capacity by coinjection with human umbilical vein endothelial cells (HUVECs) in vivo; in addition, we determined the role of stromal cell-derived factor 1-alpha (SDF 1alpha) and C-X-C chemokine receptor type 4 (CXCR4) axis in the mutual interaction between DPSCs and HUVECs. Primarily isolated DPSCs showed mesenchymal stem cell- (MSC-) like characteristics. Moreover, DPSCs expressed perivascular markers such as NG2, alpha-smooth muscle actin (alpha-SMA), platelet-derived growth factor receptor beta (PDGFRbeta), and CD146. In vivo angiogenic capacity of DPSCs was demonstrated by in vivo Matrigel plug assay. We could observe microvessel-like structures in the coinjection of DPSCs and HUVECs at 7 days postinjection. To block SDF-1alpha and CXCR4 axis between DPSCs and HUVECs, AMD3100, a CXCR4 antagonist, was added into Matrigel plug. No significant microvessel-like structures were observed at 7 days postinjection. In conclusion, DPSCs have perivascular characteristics that contribute to in vivo angiogenesis. The findings of this study have potential applications in neovascularization of engineered tissues and vascular diseases. PMID- 28588624 TI - Distribution of Parasites Detected in Stool Samples of Patients in Le Dantec University Hospital of Dakar, Senegal, from 2011 to 2015. AB - To identify the parasites responsible for intestinal parasitic infections diagnosed at Le Dantec University Hospital of Dakar, distribution of parasites detected in stool samples of patients was studied. From 2011 to 2015, 2578 patients were included in the study. A direct examination and Ritchie technique were performed as parasite search techniques. In total, 408 samples were positive showing 440 intestinal parasites; this corresponds to prevalence of 15.8%. Parasites were detected in monoparasitism (85.7%) and multiparasitism (14.3%). The most common species found in monoparasitism were Entamoeba coli (38.9%), E. histolytica/dispar (12.7%), Giardia intestinalis (8%), and Ascaris lumbricoides (7.3%). The most common associations were A. lumbricoides-Trichuris trichiura (3.6%) and E. coli-G. intestinalis (2.7%). Nonhospitalized patients were significantly more affected with 65.4% compared to hospitalized counterparts; and also there were more men (50.7%) than women. With 67.4%, adults were the most affected age group, while the elderly were less affected with only 7% (p = 0.5). This study shows increasing prevalence of intestinal parasitic infections over the years. So health education should be promoted in addition to the already begun mass treatment program. This would help to limit or even halt the spread of these diseases. PMID- 28588625 TI - Change in BMI after radioactive iodine ablation for graves disease. AB - BACKGROUND: We aimed to determine the extent of post-treatment weight gain that occurs in pediatric patients in the first year following radioactive iodine (RAI) therapy for Graves disease (GD) and its relationship to clinical characteristics. METHODS: A retrospective chart review of patients receiving RAI therapy for GD between 1998-2015 was performed. Change in BMI SDS (?BMI SDS) from baseline to one year after treatment was determined. We also investigated whether individual clinical and/or biochemical factors were associated with the weight trajectory in these patients. RESULTS: One hundred fifty seven patients aged 12.7 +/- 3 years (80% girls) were included in the analysis. Average ?BMI SDS was 0.70 +/- 0.71 (p < 0.001) at 1 year. Patients with weight loss at presentation had a greater ?BMI SDS than those without (0.92 vs 0.56, p = 0.005), whereas no association was seen with gender, pubertal status, use of antithyroid drugs, history of ADHD, or Down syndrome. Baseline BMI SDS was negatively correlated with ?BMI SDS, with a stronger correlation in males. From baseline to 1 year, the proportion of overweight and obese patients increased from 9.6% to 18.5% and from 6.4% to 21%, respectively. In a subset of 81 patients, a positive correlation was noted between time to euthyroidism and ?BMI SDS, particularly in boys. CONCLUSIONS: The number of our patients in the overweight category doubled and the number in the obese category more than tripled in the first year following RAI treatment for GD. Anticipatory guidance regarding this important issue is badly needed. PMID- 28588626 TI - Clinical and paraclinical evaluation of partial nephrectomy using laparoscopy and open surgery in dogs: new suturing technique. AB - Partial nephrectomy, using open surgery or laparoscopy, is a standard surgical approach to treat renal disorders. The objective of this study was to compare and evaluate the feasibility and safety of laparoscopic partial nephrectomy using figure eight ligation technique. Mixed-breed dogs were randomly dedicated for partial nephrectomy using laparoscopy (n=6) and open surgery (n=6). During 30 days after operation, clinical, hematological and ultrasonographic findings, intra- and post-operative complications, operation and ischemia times, urine analysis and incision length were recorded. Operations were performed successfully and dogs recovered without serious complications. All clinical and hematological findings were within normal range. Comparing two experimental groups, operation time and length of incisional scar were longer in open surgery and ischemia time was longer in laparoscopy (P<0.05). In conclusion, using figure eight ligation, laparoscopy seems to be safer, more feasible, less time consuming in association with less bleeding for partial nephrectomy compared with conventional open surgery in dog. PMID- 28588627 TI - Comparative investigations of infectious runting and stunting syndrome in vaccinated breeder chicks by inactivated reovirus and chicks from non-vaccinated breeders. AB - Reoviruses are important pathogens responsible for poor growth performance and silent losses in the poultry industry. They are associated with many disease and syndromes such as malabsorption (runting and stunting syndrome), respiratory diseases and immunosuppression. Broiler birds are most susceptible to viral infections during the early post hatching period. Therefore, the transfer of maternal immunity to embryonated eggs is proved to be a primary means of protection from viral infections. In the present investigation, growth performance and pathology in breeder vaccinated and non-vaccinated chicks were studied after a challenge with the homologous malabsorption strain of the reovirus. Improvements in growth performance (mean live body weight, feed conversion ratio, broiler performance efficiency index, and protein efficiency index) in breeder vaccinated chicks were compared with non-vaccinated breeder chicks. The non vaccinated chicks showed various signs and lesions indicative of the reoviral malabsorption syndrome (MAS), whereas the vaccinated chicks showed very minimal alterations, demonstrating that the vaccination of breeders with homologous strains of the reovirus is profitable, and can help to increase the performance of broiler birds. PMID- 28588628 TI - The effect of bovine viral diarrhea virus on bovine monocyte phenotype. AB - Bovine viral diarrhea virus (BVDV) is an economically important pathogen of the livestock industry worldwide. BVDV is classified into cytopathic (cp) and noncytopathic (ncp), depending on its effects on cultured cells. BVDV is known to alter the host's immune response. Of this, major histocompatibility complex (MHC) class II molecules play a central role in the development and function of the immune system, and are comprised of two types, DR and DQ, in cattle. In this study, we investigated the expression of MHC class II on monocytes infected with ncp BVDV1 or ncp BVDV2. Using flow cytometry (P<0.01), mRNA level quantification (quantitative real time RT-PCR, P<0.01), and western blot (P<0.001), we found that the expressions of MHC class IIDQ was significantly decreased in ncp BVDV2 infected monocytes compared with that in ncp BVDV1-infected cells. Furthermore, interferon gamma (IFN) production was markedly decreased in ncp BVDV2-infected monocytes (P<0.001) compared to those with ncp BVDV1 infection. These findings suggest that ncp BVDV2 causes reduced expressions of MHC class II DQ and a decreased production of IFN, resulting in evasion of immune recognition and suppression of the antiviral defense mechanism of the innate immune response. Consequently, the results demonstrate that ncp BVDV1 and ncp BVDV2 interact differently with the host innate immune response. Thus, our data provide insight into the mechanism by which, unlike ncp BVDV1, ncp BVDV2 impairs antigen presentation, fails to control the viral infection, and causes more severe disease. PMID- 28588629 TI - In vitro and in vivo activity of Artemisia sieberi against Trichomonas gallinae. AB - In Iranian folk medicine Artemisia sieberi has been used for treatment of parasite infections in human and animals. The present study was designed to evaluate the in vitro and in vivo effects of A. sieberi essential oil (EO) against Trichomonas gallinae. Trichomonas gallinae were recovered by wet mount method from infected native pigeons. The in vitro assays were accomplished in multi-well plates containing metronidazole (MTZ) as a standard antitrichomonal and EO in final concentrations of 2.5, 5, 10, 20, 50, and 100 MUg/ml of culture medium containing 104 parasites. The invivo assay was performed on 40 experimentally infected pigeons receiving 25 and 50 mg/kg of MTZ and EO for 7 successive days. Gas chromatographic (GC) analysis was performed to reveal chemical constituents of the EO. At 20 ug/ml, MTZ resulted in no viable trophozoite in culture medium after 24 h incubation period. While the 24 h MIC of EO was 10 ug/ml. Treatment with EO at dose of 50 mg/kg after 4 days led to full recovery of infected pigeons but for MTZ at the same dose 5 days were spent. Major constituents of EO were alpha-thujone (31.5%) and beta-thujone (11.92%). Data of the present study introduced A. sieberi as a natural potent antitrichomonal agent effective against T. gallinae. PMID- 28588630 TI - Echocardiographic assessment of myocardial infarction: comparison of a rat model in two strains. AB - The purpose of this study was to induce myocardial infarction (MI) and compare the echocardiographic parameters and mortality ratio of Lewis inbred and Wistar outbred strain before and after the procedure to help choose the best one for MI studies. In this study MI was induced in 46 Lewis and 34 Wistar by occlusion of left anterior descending artery (LAD). Doppler, two-dimensional (2-D) and 2-D guided M-mode images were recorded from parasternal long-axis and parasternal short-axis and apical four-chamber views. The following parameters were acquired. Interventricular septum diastolic and systolic dimension (IVSd, s), diastolic and systolic left ventricular internal diameter (LVIDd, s), diastolic and systolic left ventricular posterior wall dimension (LVPWd, s), ejection fraction (EF), and fractional shortening (FS). The significant changes were observed in systolic IVS, LVID and EF and FS before and after MI and no significant difference was detected between Lewis and Wistar. The high mortality rate of 51% was seen in the procedure, including anesthesia in Lewis compared to 34% in Wistar. As a conclusion the echocardiographic parameters of these two strains were similar, but according to mortality rate and more cardiac anatomic variation in Lewis rats, Wistar is better for MI studies. PMID- 28588631 TI - Cloning and expression of fragment of the rabies virus nucleoprotein gene in Escherichia coli and evaluation of antigenicity of the expression product. AB - Rabies virus nucleoprotein (N protein) encapsidates genomic RNA of the virus and forms the viral ribonucleoprotein complex. These N proteins represent highly organized structures which activate proliferation of B cells and production antibodies against the N protein. In addition to the B cell, the rabies virus N protein has been shown to induce potent T helper cell responses resulting in a long-lasting and strong humoral immune response. Rabies virus N protein is a molecular target of choice for development of tools to diagnose acute rabies infection. We produced a recombinant immune reactive C-terminal fragment of the rabies virus N protein which contains an antigenic determinant located between positions 360-389. Synthetic gene encoding the N protein was cloned into an expression plasmid to produce the recombinant antigen in Escherichiacoli cells BL21 (DE3). SDS-PAGE showed presence of the product with expected molecular weight (44 kDa). The recombinant fragment of the N protein efficiently recognized antibodies in sera from mice immunized with an inactivated rabies virus. Thus produced recombinant antigen of the rabies virus N protein can be used in an enzyme-linked immunosorbent assay (ELISA) for diagnosis of the rabies infection. PMID- 28588632 TI - Age-dependent electrocardiographic and echocardiographic changes in German Shepherd dogs. AB - By causing numerous changes in the cardiovascular system, ageing leads to a decreased threshold for clinical manifestation of heart disease. The aim of this study was to define the existence of cardiac structural and functional changes in healthy dogs of different age. Radiographic, electrocardiographic (ECG) and echocardiographic examinations of 20 clinically healthy German Shepherd dogs were performed in order to define the values of relevant parameters. Afterwards, the values of cardio examinations were compared between young and old dogs and statistically analyzed. The ECG recordings did not show the appearance of clinically significant arrhythmias, nor was their appearance significantly different between dogs of different age. Statistically significant differences in QRS duration (P<0.05) and R wave amplitude (P<0.05) existed between groups, but all values were within the range of ECG reference values for healthy dogs. Concerning structural changes, the left ventricle wall thickness at end-diastole (LVWd) and end-systole (LVWs), and the relative wall thickness (RWT) between young and old dogs differed significantly (P<0.001, P<0.05, P<0.05, respectively). These differences in heart structure were not accompanied by systolic dysfunction, estimated by a left ventricle shortening fraction. The diastolic wall stress index (WSID) was significantly decreased in old dogs (P<0.05). Young and old dogs showed similar electrical and systolic function. Old dogs had different cardiac structure compared to the young dogs, which could result in diastolic function change. PMID- 28588633 TI - Determination of renal handling of marbofloxacin in Lohi sheep (Ovis aries) following a single intravenous administration. AB - The objective of present study was to investigate renal clearance, urinary excretion and underlying excretory mechanism of marbofloxacin in Lohi sheep. For this purpose, marbofloxacin was administered intravenously (IV) as single bolus dose (2.5 mg/kg body weight) to eight healthy sheep of Lohi breed. After start of experiment, blood and urine samples were drawn at predetermined time intervals and marbofloxacin concentrations in the samples were measured by reverse phase high performance liquid chromatography (RP-HPLC) using UV/Vis detector. The mean +/- SD values of creatinine in plasma and urine were 15.37 +/- 0.65 ug/ml and 246.7 +/- 48.05 ug/ml, respectively. Glomerular filtration rate was 1.29 +/- 0.22 ml/min/kg whereas urinary flow rate was observed to be 0.084 +/- 0.016 ml/min/kg. The renal clearance of marbofloxacin in Lohi sheep was 9.45 +/- 2.12 ml/min/kg. Cumulative percentage dose excreted was seen to be maximum at 24 h post drug administration. It was concluded that renal handling of marbofloxacin in Lohi sheep involved both glomerular filtration and active tubular secretion. PMID- 28588634 TI - In silico identification of epitopes from house cat and dog proteins as peptide immunotherapy candidates based on human leukocyte antigen binding affinity. AB - The objective of this descriptive study was to determine Felis domesticus (cat) and Canis familiaris (dog) protein epitopes that bind strongly to selected HLA class II alleles to identify synthetic vaccine candidate epitopes and to identify individuals/populations who are likely to respond to vaccines. FASTA amino acid sequences of experimentally validated allergenic proteins of house cat and dog were identified using International Union of Immunological Societies (IUIS) allergen nomenclature database. NetMHCII 2.2 server was used to determine binding affinities in the form of 1-log 50 k and in nM with commonly found HLA II alleles. Screening of house cat and dog allergenic proteins identified 4 (with 2 isoforms for chain 1 and 3 isoforms for chain 2 for fel d 1) and 6 proteins, respectively. Number of strong binders from each protein against each HLA type was determined as potential candidate for allergen immunotherapy. HLA-DRB1*0101 bound maximum number of epitopes (207 and 275 from house cat and dog, respectively) while HLA-DRB1*0802 bound none. We conclude that HLA specific epitope prediction can help identify synthetic peptide vaccine candidates and predict response as well. PMID- 28588635 TI - Effects of using eucalyptus (Eucalyptusglobulus L.) leaf powder and its essential oil on growth performance and immune response of broiler chickens. AB - The aim of this study was to evaluate the effects of eucalyptus leaf powder (ELP) and eucalyptus essential oil (EEO) on growth performance and immune response of broiler chickens. A total of 160 broiler chicks were assigned randomly into five dietary treatments from 7-42 days of age. Dietary treatments included: a control diet, control diets plus 1,000 or 3,000 mg/kg of ELP, and control diets plus 250 or 500 mg/kg of EEO. Dietary inclusion of ELP decreased body weight gain (BWG) during 7-28 days of age. Broilers fed diet containing 3,000 mg/kg of ELP had lower feed intake (FI) during 7-28 days compared to the other treatments. Broilers fed ELP or EEO had greater primary antibody response to sheep red blood cells (SRBC) compared to the control, but differences in secondary antibody response were not significant. In conclusion, dietary EEO has the potential to enhance immune response of broiler chickens. PMID- 28588636 TI - A case of spontaneous abortion related to ovarian endometriosis in a Golden Retriever dog. AB - This report describes a case of spontaneous abortion in a 4-year-old Golden Retriever dog with ovarian endometriosis. Clinical findings indicated that there was not any senstivity in the abdomen and the viability parameters were within the reference values. On vaginal examination, serosanguineous discharge was determined. Ultrasonographic examination revealed that no fetus was observed in cornu uteri and an hypoechoic cystic structure, measuring 3.2 * 3.4 cm was found behind the left kidney. Ovarian cyst was suspected, and then ovariohysterectomy was performed. On laparotomy, the presence of a cystic structure was confirmed in the left ovary similar to ultrasonographic findings. Cyst was smooth, flat, hemorrhagic and thick-walled structure. Histopathologic examination of the ovarian stroma revealed covered luteinizing cells and midline hemorrhagic cyst. However, the internal surface of the cyst wall was covered by an endometrial lining. Interestingly, the endometriotic tissue had a maximal penetration into the cyst wall. It was thought that the ovarian endometriosis caused a failure in the luteinizing hormone action which is responsible for luteal function and spontaneous abortion was observed in this case. Although ovarian endometriosis is quite usual in human, this case could be the first report to describe ovarian endometriosis in a dog, and thus it has been reported to cause spontaneous abortion. PMID- 28588637 TI - Effect of Acupuncture on Endometrial Angiogenesis and Uterus Dendritic Cells in COH Rats during Peri-Implantation Period. AB - This study was to explore the mechanism of acupuncture on regulating the endometrial angiogenesis and uterus dendritic cells (uDCs) during the peri implantation period. Rats, in early pregnancy, were randomized into five groups: normal (N), model (M), acupuncture (A), progesterone (P), and A + P groups. The COH model was established using pregnant mare serum, combined with human chorionic gonadotrophin. Endometrium was collected on days 4, 6, and 8 (D4, D6, and D8) of gestation. Compared with group M, both VEGF and FGF-2 protein and mRNA levels were significantly lower on D4 and higher on D6 and D8 (P < 0.05), except for VEGF of group P on D8; the proportion of uterus dendritic cells (uDCs) in the endometrium was significantly lower on D4 and D6 and higher on D8 (P < 0.05). In vitro, except for the proliferation of group P on D8, proliferation, tube formation, and migration of uDCs were significantly decreased on D4 and increased on D8 (P < 0.05). In addition, acupuncture or progesterone regulated the secretion levels of VEGF, IL-15, and IL-18 secreted by uDCs instead of soluble sFLT-1. In conclusion, acupuncture may regulate angiogenesis of the endometrium and the number and roles of uDCs after COH, and the specific mechanism may be different with progesterone. PMID- 28588638 TI - Simultaneous Determination of 8 Compounds in Gancao-Ganjiang-Tang by HPLC-DAD and Analysis of the Relations between Compatibility, Dosage, and Contents of Medicines. AB - Gancao-Ganjiang-Tang (GGT) is a traditional Chinese medicine (TCM) prescription and is a representative prescription for recuperating depleted Yang in Treatise on Febrile Diseases. The TCM theory believes that the efficacy of medicinal herbs is decided by the multicompounds which consist of different kinds of chemical constituents with bioactivities, but not by a monomeric constituent. From ancient times until today, GGT have 5 different kinds of compatibilities that can be verified. In this study, a HPLC-DAD method was established for the simultaneous determination of 8 compounds including 6-gingerol, 8-gingerol, 6-shogaol, liquiritin, liquiritigenin, isoliquiritin, isoliquiritigenin, and glycyrrhizic acid in the five GGT. The total contents of the 8 compounds in GGT varied from 555.56 to 956.33 MUg/mL. The effects showed that the dosage and compatibility of medicinal herbs have influenced the content of chemical compounds of TCM prescription while the content of chemical compounds has acted on clinical efficacy. Quality evaluation and active essence screening of TCM (including single herb and prescription) should be based on the TCM theory and clinical effectiveness. The method was proven to be suitable for quality control of GGT. PMID- 28588639 TI - Elephantorrhiza elephantina: Traditional Uses, Phytochemistry, and Pharmacology of an Important Medicinal Plant Species in Southern Africa. AB - Elephantorrhiza elephantina is used in southern Africa as traditional remedy for a wide range of human diseases and ailments including dermatological diseases, gastrointestinal system disorders, sexual dysfunction, sexually transmitted infections, and wounds. The rhizome decoction of E. elephantina is widely used by small-scale farmers in Botswana and South Africa as ethnoveterinary medicine for cattle, goats, horses, pigs, poultry, and sheep. Several classes of phytochemical compounds including anthocyanidins, anthraquinones, esters, fatty acids, phenolic compounds, flavonoids, glycosides, polysterols, saponins, sugars, tannins, and triterpenoids have been isolated from E. elephantina. Scientific studies on E. elephantina indicate that it has a wide range of biological activities including anthelmintic, antibacterial, antifungal, anti-inflammatory and antinociceptive, antiplasmodial, antioxidant, antibabesial, and antirickettsial activities. Elephantorrhiza elephantina is a valuable source of traditional medicine in southern Africa that it is worth additional research attention because of its wide ethnomedicinal applications and promising biological activities. However, the current health-related information on E. elephantina is not sufficiently explored as diverse studies on its chemical and pharmacological activities are required to understand its mechanism of action and to characterize the metabolites responsible for these activities. PMID- 28588641 TI - The Significant Pathways and Genes Underlying the Colon Cancer Treatment by the Traditional Chinese Medicine PHY906. AB - BACKGROUND: We attempted to explore the molecular mechanism underlying PHY906 intervention of colon cancer. METHODS: The microarray data of tumors treated by PHY906 and PBS alone were downloaded from the public Gene Expression Omnibus database. The dataset was further analyzed for the differentially expressed genes (DEGs) and their related biological functions were analyzed, followed by function and pathways. Protein-protein interaction (PPI) network was constructed and the significant nodes were screened by network centralities and then the significant modules analysis. Besides, they were clustered and transcriptional factors (TFs) were predicted. RESULTS: The gene expression patterns changed induced by PHY906 treatment, including 414 upregulated and 337 downregulated DEGs. The biological process of response to steroid hormone stimulus and regulation of interferon gamma production were significantly enriched by DEGs. Ezh2 (enhancer of zeste 2) was found to be the key node in PPI network. There are 12 significant TFs predicted for module 1 genes and 3 TFs for module 2 genes. CONCLUSIONS: PHY906 treatment may function in protecting the epithelial barrier against tumor cell invasion by modulating IFN-gamma level and mediating cancer cell death by activating the response to steroid hormone stimulus and activating the response to steroid hormone stimulus. E2f1, Hsfy2, and Nfyb may be therapeutic targets for colon cancer. PHY906 showed treatment efficacy in modulating cell apoptosis by intervening interferon-gamma production and response to steroid hormone stimulus. Ezh2 and its TFs such as E2f1, Hsfy2, and Nfyb may be the potential therapeutic targets for anticancer agents development. PMID- 28588640 TI - Compounds from Cynomorium songaricum with Estrogenic and Androgenic Activities Suppress the Oestrogen/Androgen-Induced BPH Process. AB - OBJECTIVE: To investigate the phytoestrogenic and phytoandrogenic activities of compounds isolated from CS and uncover the role of CS in prevention of oestrogen/androgen-induced BPH. METHODS: Cells were treated with CS compounds, and immunofluorescence assay was performed to detect the nuclear translocation of ERalpha or AR in MCF-7 or LNCaP cells; luciferase reporter assay was performed to detect ERs or AR transcriptional activity in HeLa or AD293 cells; MTT assay was performed to detect the cell proliferation of MCF-7 or LNCaP cells. Oestrogen/androgen-induced BPH model was established in rat and the anti-BPH, anti-estrogenic, and anti-androgenic activities of CS in vivo were further investigated. RESULTS: The nuclear translocation of ERalpha was stimulated by nine CS compounds, three of which also stimulated AR translocation. The transcriptional activities of ERalpha and ERbeta were induced by five compounds, within which only ECG induced AR transcriptional activity as well. Besides, ECG stimulated the proliferation of both MCF-7 cells and LNCaP cells. CS extract suppressed oestrogen/androgen-induced BPH progress in vivo by downregulation of E2 and T level in serum and alteration of the expressions of ERalpha, ERbeta, and AR in the prostate. CONCLUSION: Our data demonstrates that compounds from CS exhibit phytoestrogenic and phytoandrogenic activities, which may contribute to inhibiting the oestrogen/androgen-induced BPH development. PMID- 28588642 TI - The Preventive Control of Zoonotic Visceral Leishmaniasis: Efficacy and Economic Evaluation. AB - Zoonotic Visceral Leishmaniasis (ZVL) is one of the world's deadliest and neglected infectious diseases, according to World Health Organization. This disease is one of major human and veterinary medical significance. The sandfly and the reservoir in urban areas remain among the major challenges for the control activities. In this paper, we evaluated five control strategies (positive dog elimination, insecticide impregnated dog collar, dog vaccination, dog treatment, and sandfly population control), considering disease control results and cost-effectiveness. We elaborated a mathematical model based on a set of differential equations in which three populations were represented (human, dog, and sandfly). Humans and dogs were divided into susceptible, latent, clinically ill, and recovery categories. Sandflies were divided into noninfected, infected, and infective. As the main conclusions, the insecticide impregnated dog collar was the strategy that presented the best combination between disease control and cost-effectiveness. But, depending on the population target, the control results and cost-effectiveness of each strategy may differ. More and detailed studies are needed, specially one which optimizes the control considering more than one strategy in activity. PMID- 28588643 TI - Molecular cloning, expression, and characterization of four novel thermo alkaliphilic enzymes retrieved from a metagenomic library. AB - BACKGROUND: Enzyme discovery is a promising approach to aid in the deconstruction of recalcitrant plant biomass in an industrial process. Novel enzymes can be readily discovered by applying metagenomics on whole microbiomes. Our goal was to select, examine, and characterize eight novel glycoside hydrolases that were previously detected in metagenomic libraries, to serve biotechnological applications with high performance. RESULTS: Here, eight glycosyl hydrolase family candidate genes were selected from metagenomes of wheat straw-degrading microbial consortia using molecular cloning and subsequent gene expression studies in Escherichia coli. Four of the eight enzymes had significant activities on either pNP-beta-d-galactopyranoside, pNP-beta-d-xylopyranoside, pNP-alpha-l arabinopyranoside or pNP-alpha-d-glucopyranoside. These proteins, denoted as proteins 1, 2, 5 and 6, were his-tag purified and their nature and activities further characterized using molecular and activity screens with the pNP-labeled substrates. Proteins 1 and 2 showed high homologies with (1) a beta-galactosidase (74%) and (2) a beta-xylosidase (84%), whereas the remaining two (5 and 6) were homologous with proteins reported as a diguanylate cyclase and an aquaporin, respectively. The beta-galactosidase- and beta-xylosidase-like proteins 1 and 2 were confirmed as being responsible for previously found thermo-alkaliphilic glycosidase activities of extracts of E. coli carrying the respective source fosmids. Remarkably, the beta-xylosidase-like protein 2 showed activities with both pNP-Xyl and pNP-Ara in the temperature range 40-50 degrees C and pH range 8.0-10.0. Moreover, proteins 5 and 6 showed thermotolerant alpha-glucosidase activity at pH 10.0. In silico structure prediction of protein 5 revealed the presence of a potential "GGDEF" catalytic site, encoding alpha-glucosidase activity, whereas that of protein 6 showed a "GDSL" site, encoding a 'new family' alpha-glucosidase activity. CONCLUSION: Using a rational screening approach, we identified and characterized four thermo-alkaliphilic glycosyl hydrolases that have the potential to serve as constituents of enzyme cocktails that produce sugars from lignocellulosic plant remains. PMID- 28588644 TI - Directed evolution of a beta-mannanase from Rhizomucor miehei to improve catalytic activity in acidic and thermophilic conditions. AB - BACKGROUND: beta-Mannanase randomly cleaves the beta-1,4-linked mannan backbone of hemicellulose, which plays the most important role in the enzymatic degradation of mannan. Although the industrial applications of beta-mannanase have tremendously expanded in recent years, the wild-type beta-mannanases are still defective for some industries. The glycoside hydrolase (GH) family 5 beta mannanase (RmMan5A) from Rhizomucor miehei shows many outstanding properties, such as high specific activity and hydrolysis property. However, owing to the low catalytic activity in acidic and thermophilic conditions, the application of RmMan5A to the biorefinery of mannan biomasses is severely limited. RESULTS: To overcome the limitation, RmMan5A was successfully engineered by directed evolution. Through two rounds of screening, a mutated beta-mannanase (mRmMan5A) with high catalytic activity in acidic and thermophilic conditions was obtained, and then characterized. The mutant displayed maximal activity at pH 4.5 and 65 degrees C, corresponding to acidic shift of 2.5 units in optimal pH and increase by 10 degrees C in optimal temperature. The catalytic efficiencies (kcat/Km) of mRmMan5A towards many mannan substrates were enhanced more than threefold in acidic and thermophilic conditions. Meanwhile, the high specific activity and excellent hydrolysis property of RmMan5A were inherited by the mutant mRmMan5A after directed evolution. According to the result of sequence analysis, three amino acid residues were substituted in mRmMan5A, namely Tyr233His, Lys264Met, and Asn343Ser. To identify the function of each substitution, four site-directed mutations (Tyr233His, Lys264Met, Asn343Ser, and Tyr233His/Lys264Met) were subsequently generated, and the substitutions at Tyr233 and Lys264 were found to be the main reason for the changes of mRmMan5A. CONCLUSIONS: Through directed evolution of RmMan5A, two key amino acid residues that controlled its catalytic efficiency under acidic and thermophilic conditions were identified. Information about the structure-function relationship of GH family 5 beta-mannanase was acquired, which could be used for modifying beta-mannanases to enhance the feasibility in industrial application, especially in biorefinery process. This is the first report on a beta-mannanase from zygomycete engineered by directed evolution. PMID- 28588646 TI - The effects of tolterodine on anterior segment and choroidal thickness in patients with overactive bladder syndrome. AB - BACKGROUND: To evaluate the effects of tolterodine on anterior segment and choroidal thickness by using the Pentacam system and optical coherence tomography (OCT) (Pentacam). METHODS: A total of 122 eyes of 61 patients (34 female; 27 male) were included in the study. All patients underwent a regular ocular examination and intraocular pressure measurements before and after 3 months of antimuscarinic drug tolterodine treatment, in addition, pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle, and lens thickness were measured through Pentacam (Oculus Inc., Wetzlar, Germany) system. Measurements of choroidal thickness were performed by OCT (Spectralis(r), Heidelberg Engineering, Heidelberg, Germany). RESULTS: The mean age was 58.4 +/- 7.3 years and 56.5 +/- 11.1 years for female and male patients. The mean intraocular pressure was 15.10 +/- 2.75 mmHg before treatment and 15.18 +/- 2.65 mmHg after treatment. Pupil diameters were 3.09 +/- 0.48 mm before treatment and 3.12 +/- 0.43 mm after treatment. Anterior chamber depth, before and after treatment were 2.68 +/- 0.65 mm and 2.70 +/- 0.61 mm. The mean value for subfoveal choroidal thickness was 267.92 +/- 81.35 MUm before the administration of tolterodine, whereas the mean choroidal thickness was 271.83 +/- 75.42 MUm after the administration of tolterodine. The alterations in the subfoveal choroidal thickness were not statistically significant (p = 0.862). CONCLUSIONS: After 3 months of therapy with tolterodine, there were no significant changes in anterior segment parameters and choroidal thickness. PMID- 28588645 TI - Predisposing factors for recurrence of chronic posttraumatic osteomyelitis: a retrospective observational cohort study from a tertiary referral center in Brazil. AB - BACKGROUND: The incidence of posttraumatic osteomyelitis (PTO) is increasing despite new treatment strategies. Assessment of patients' outcomes following PTO is challenging due to multiple variables. The study goals are to determine the frequency of recurrence following PTO treatment and identify factors predisposing patients to treatment failure. METHODS: Between August 01, 2007 to August 30, 2012, a single-center retrospective cohort study was performed among 193 patients diagnosed with PTO following orthopedic surgery for fracture care. Bone and soft tissues were collected for cultures and PTO was defined according to CDC/NHSN criteria. Patient, injury, surgery-associated variables, and microbiological records were reviewed for risk factors associated to recurrence of PTO. Univariate and multivariable analyses using logistic regression were performed, with p <0.05 considered significant. RESULTS: Thirty-eight patients (20%) of 192 diagnosed and treated for PTO failed their treatment. Factors associated with recurrence were age between 61 and 80 years [hazard ratio (HR) = 6.086, 95% confidence interval (CI) = 2.459;15.061, p = <0.001], age above 80 years [HR = 9.975 (95% CI = 3.591;27.714), p = <0.001], intraoperative blood transfusion [HR = 2.239 (95% CI = 1.138;4.406), p = 0.020], and positive culture for Pseudomonas aeruginosa [HR = 2.700 (95% CI = 1.370;5.319), p = 0.004]. CONCLUSIONS: Risk factors associated with recurrence of PTO are difficult to measure. The present study revealed that elderly patients, intraoperative blood transfusions, and infection due to P. aeruginosa were independently associated with recurrence of PTO. These factors should warn clinicians of a higher failure rate following treatment of PTO. Trial registration: ISRCTN71648577. Registered 18 May 2017. Retrospectively registered. PMID- 28588647 TI - An update on best practice in the diagnosis and management of post-prostatectomy anastomotic strictures. AB - Postprostatectomy vesicourethral anastomotic stenosis (VUAS) remains a challenging problem for both patient and urologist. Improved surgical techniques and perioperative identification and treatment of risk factors has led to a decline over the last several decades. High-level evidence to guide management is lacking, primarily relying on small retrospective studies and expert opinion. Endourologic therapies, including dilation and transurethral incision or resection with or without adjunct injection of scar modulators is considered first-line management. Recalcitrant VUAS requires surgical reconstruction of the vesicourethral anastomosis, and in poor surgical candidates, a chronic indwelling catheter or urinary diversion may be the only option. This review provides an update in the diagnosis and management of postprostatectomy VUAS. PMID- 28588649 TI - Late recurrence of colorectal adenocarcinoma as a renal tumour by direct spread via the ureter. PMID- 28588648 TI - Strategies to minimize readmission rates following major urologic surgery. AB - Readmissions after major surgical procedures are prevalent across multiple disciplines. Specifically, in urology, with incorporation of early discharge and recovery pathways, readmissions are emerging as an important problem and effecting an epidemic proportion of urology patients. As expected, readmissions have garnered the attention of major healthcare payers in the United States who see readmissions as easy targets because of the association with astronomical costs. More importantly, readmissions have a significant negative impact on patient sense of wellbeing, and places economic and other hardships on the doors of our patients and their families. Here, we explore the reasons patients are readmitted, using radical cystectomy as a case study, and means to decrease the incidence of readmissions. Since time to readmission for most major urologic oncology surgeries is within the first 2 weeks after discharge, this time frame is critical for efforts to improve symptom identification and reduce the total number and severity of readmissions. Readmission reduction to zero is unlikely for any major surgery, but with effective coordinated strategies, we must strive to reduce the rates as much as possible, as a means to improve the care continuum for our patients. PMID- 28588651 TI - Testosterone suppression with a unique form of leuprorelin acetate as a solid biodegradable implant in patients with advanced prostate cancer: results from four trials and comparison with the traditional leuprorelin acetate microspheres formulation. AB - BACKGROUND: There are two slow-release ready-to-use forms of leuprorelin acetate (1-month and 3-month) that are available as solid, biodegradable implants for the treatment of advanced, hormone-sensitive prostate cancer. These implants have been shown to be as effective as traditional leuprorelin acetate microspheres for achieving successful testosterone suppression (?0.5 ng/ml) and lowering prostate specific antigen (PSA) levels. Here we further evaluate testosterone suppression levels from four clinical trials evaluating the 3-month leuprorelin implant, including analysis below the European Association of Urology (EAU) castration level (<0.2 ng/ml). METHODS: Studies were conducted in patients with locally advanced/metastatic prostate cancer: (1) a randomised, controlled single-dose study comparing the leuprorelin implant with leuprorelin microspheres; (2) a single-arm, single-dose study of the leuprorelin implant; (3 and 4) two long-term studies with the leuprorelin implant administered twice, 12 or 16 weeks apart. Patients received 3-month leuprorelin (5 mg) implant or 3-month leuprorelin (10.72 mg) microspheres. Testosterone levels were analysed using radioimmunoassay or ultrasensitive liquid chromatography tandem mass spectrometry. RESULTS: Both the leuprorelin implant and the leuprorelin microspheres achieved mean testosterone suppression (?0.5 ng/ml) within 4 weeks for >3 months. In both long term, single-arm studies with the leuprorelin implant, median values of testosterone ?0.2 ng/ml were achieved at Week 4 and maintained until study completion (6 and 8 months); PSA decrease was also observed versus baseline. CONCLUSIONS: Long-lasting steady serum levels of testosterone, comparable with orchiectomy and consistent with the EAU-recommended castration level (<0.2 ng/ml), were achieved at Week 4 and maintained up to 8 months in men with advanced prostate cancer who received the leuprorelin implant. PMID- 28588652 TI - Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies. AB - BACKGROUND: Oral pharmacotherapies to treat overactive bladder (OAB) are used less in men despite a similar prevalence of storage symptoms as women. The efficacy and safety of once-daily mirabegron 50 mg was evaluated in male OAB patients from five phase III studies that included placebo or antimuscarinic (tolterodine ER 4 mg or solifenacin 5 mg) as a comparator. METHODS: Three pooled 12-week placebo-controlled studies (mirabegron 50 mg versus placebo) and one 12 week non-inferiority phase IIIb study (BEYOND; mirabegron 50 mg versus solifenacin 5 mg) were used for efficacy (daily micturition frequency, urgency and incontinence episodes) and safety analyses. An additional 52-week active controlled phase III safety study (mirabegron 50 mg versus tolterodine ER 4 mg) was included in the safety analysis. Male patients aged ?18 years with OAB for ?3 months were included in the analyses. Patients may also have a history of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)/benign prostatic enlargement (BPE) or concomitant use of alpha1-blockers. RESULTS: In the pooled studies, mirabegron 50 mg demonstrated superiority versus placebo (treatment difference: -0.37 [95% confidence interval (CI): -0.74, 0.01]) for reducing micturition frequency; improvements in urgency and incontinence were not significantly different between mirabegron 50 mg and placebo. In BEYOND, mirabegron 50 mg was comparable with solifenacin 5 mg for reducing micturition frequency, urgency, and incontinence episodes. Mirabegron was well tolerated at 12 and 52 weeks and overall treatment-emergent adverse events (AEs) were similar to those with placebo. CONCLUSIONS: In a male OAB population with or without LUTS associated with BPH/BPE, mirabegron 50 mg provided similar improvements in urgency, frequency, and incontinence as solifenacin 5 mg, and is a well-tolerated alternative to antimuscarinics. In the three pooled 12-week studies, significant differences were not seen for urgency and incontinence versus placebo, although mirabegron 50 mg did demonstrate significant improvements versus placebo for frequency. PMID- 28588653 TI - Renal cell carcinoma with inferior vena cava thrombus extending to the right atrium diagnosed during pregnancy. AB - Only one case of renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus diagnosed and treated during pregnancy has been reported in the literature. In that report, the tumor thrombus extended to the infrahepatic IVC (level II tumor thrombus). In the present case, a 37-year-old woman with lupus anticoagulant antibodies was diagnosed with RCC and IVC tumor thrombus extending to the right atrium (level IV tumor thrombus) at 24 weeks of pregnancy. The fetus was safely delivered by cesarean section at 30 weeks of gestation. At 4 days later, an open right radical nephrectomy and IVC and right atrial thrombectomy were performed on cardiopulmonary bypass (CPB) once the patient's hemodynamic status had been optimized. Fetal and maternal concerns included the risk of a thromboembolic event (due to increased hypercoagulability from pregnancy, active malignancy, and lupus anticoagulant), intraoperative hemorrhage risk (due to extensive venous collaterals and anticoagulation), and fetal morbidity and mortality (due to fetal lung immaturity). Standardized guidelines for treatment of RCC with or without IVC tumor thrombus during pregnancy are unavailable due to the infrequency of such cases. Treatment decisions are therefore individualized and this case report may inform the management of future patients diagnosed with RCC with level IV tumor thrombus during pregnancy. PMID- 28588654 TI - Complete genome sequence of Clostridium perfringens CBA7123 isolated from a faecal sample from Korea. AB - BACKGROUND: Clostridium perfringens is an opportunistic human pathogen that causes necrotic enteritis, mild diarrhea, clostridial myonecrosis or gas gangrene, sepsis, etc. In this study, we aim to determine the pathogenesis of this bacterium at the genomic level. The genome of strain CBA7123 was sequenced, and a comparative genomic analysis between strain CBA7123 and four other related C. perfringens strains was performed. RESULTS: The genome of strain CBA7123 consisted of one circular chromosome and one plasmid that were 3,088,370 and 46,640 bp long with 28.5 and 27.1 mol% G+C content, respectively. The genomic DNA was predicted to contain 2798 open reading frames (ORFs), 10 rRNA genes, and 94 tRNA genes. The genomic comparison analysis between the five strains revealed the distinctive virulence properties of strain CBA7123 by highlighting certain strain specific genes. CONCLUSIONS: In this study, the C. perfringens CBA7123 genome was sequenced and compared with other C. perfringens genomes. Among the various genes sequenced, the detection of antimicrobial resistance genes and those encoding various virulence factors may extend the understanding of the pathogenesis of C. perfringens strains. PMID- 28588656 TI - Measurement of combined glenoid and Hill-Sachs lesions in anterior shoulder instability. AB - BACKGROUND: Recurrent glenohumeral anterior instability (RGAI) frequently induces combined glenoid and Hill-Sachs bone lesions and is a risk factor for soft tissue repair failure. This cohort study describes a simple preoperative quantification method for bone loss, the Clock method, the first that combines glenoid and humeral lesions. METHODS: Computed tomography scans of 34 shoulders with RGAI were twice reviewed by three independent observers, who measured bone lesions using the new Clock method and existing validated methods. Intra- and inter observer reliability of the Clock method was evaluated (intraclass correlation coefficient). Pearson correlation was used to correlate Clock method with existing methods, and with function (Western Ontario Shoulder Instability, Quick Disabilities of the Arm, Shoulder and Hand). RESULTS: Thirty-two patients met the inclusion criteria: three females and 29 males, mean age 28 years. The intra- and inter-observer reliability was excellent, with intraclass correlation coefficient ranging from 0.817 to 0.938 for the novel Clock method. Humeral Clock and Glenoid Clock strongly correlated with Humeral Ratio (r = 0.882, p < 0.001) and Glenoid Surface Area and Glenoid Ratio (r = 0.793 and 0.717, p < 0.001), respectively. The classic threshold of 25% of the glenoid diameter with the Glenoid Ratio method corresponds to 4 hours with the Glenoid Clock method. CONCLUSIONS: The Clock method is quick and reliable, with more studies being needed to investigate whether it is correlated with surgical outcomes. PMID- 28588655 TI - How should I fixate the subscapularis in total shoulder arthroplasty? A systematic review of pertinent subscapularis repair biomechanics. AB - BACKGROUND: The present study aimed to review the biomechanical outcomes of subscapularis repair techniques during total shoulder arthroplasty (TSA) to assist in clinical decision making. METHODS: A systematic review of multiple databases was performed by searching PubMed, Scopus, Cochrane Library, Google Scholar, and all databases within EBSCOhost to find biomechanical studies of subscapularis repair techniques in cadaveric models of TSA. RESULTS: Nine studies met the inclusion criteria. In the majority of studies, lesser tuberosity osteotomy (LTO) techniques had greater load to failure and less cyclic displacement compared to subscapularis tenotomy or peel methods. LTO repairs with sutures wrapped around the humeral stem demonstrated superior biomechanical outcomes compared to techniques using only a tension band. In terms of load to failure, the strongest repair of any study was a dual-row fleck LTO using four sutures wrapped around the stem. CONCLUSIONS: Several cadaveric studies have shown superior biomechanical outcomes with LTO techniques compared to tenotomy. In the majority of studies, the strongest subscapularis repair technique in terms of biomechanical outcomes is a compression LTO. Using three or more sutures wrapped around the implant and the addition of a tension suture may increase the biomechanical strength of the LTO repair. PMID- 28588657 TI - Analysis of hydrodilatation as part of a combined service for stiff shoulder. AB - BACKGROUND: Adhesive capsulitis is a common cause of stiff shoulder and may result in pain and restriction of movement. The study aimed to investigate the role of hydrodilatation of the glenohumeral joint in the management of adhesive capsulitis. METHODS: Patients referred from the shoulder clinic underwent hydrodilatation under ultrasound guidance. Of 209 referred for hydrodilatation, 163 underwent the procedure and attended follow-up physiotherapy. Outcome measures were available for 118 patients (58 men and 60 women). Mean age of the study group was 52.6 years. RESULTS: There was a statistically significant improvement in both Oxford Shoulder Score (OSS) and Disability Arm Shoulder Hand Scores (Quick DASH) in the first 4 weeks after the procedure, which was maintained but not improved to the end of the study period. Patients presenting with pain, those who had a history of steroid injections and older patients all had worse functional scores at presentation. Diabetes (both Type I and II), previous physiotherapy, length of history and whether pain or stiffness, or both, were the predominant symptom did not have any statistical significance at presentation. These factors were not predictors of any statistically significant improvement in functional scores. CONCLUSIONS: Hydrodilatation results in a significant improvement of symptoms in patients with adhesive capsulitis. PMID- 28588658 TI - Supraspinatus detachment causes musculotendinous degeneration and a reduction in bone mineral density at the enthesis in a rat model of chronic rotator cuff degeneration. AB - BACKGROUND: To evaluate biological strategies that enhance tendon-bone healing in humans, it is imperative that suitable animal models accurately reproduce the pathological changes observed in the clinical setting following a tear. The purpose of the present study was to investigate rotator cuff degeneration in a rat, as well as assess the development of osteopenia at the enthesis following tendon detachment. METHODS: Eighteen female Wistar rats underwent unilateral detachment of the supraspinatus tendon. Specimens were retrieved at 4 weeks (n = 6), 6 weeks (n = 6) and 9 weeks (n = 6) postoperatively for histological analysis and peripheral quantitative computer tomography. RESULTS: Three weeks following tendon detachment, there was a significant increase in the modified Movin score, characterized by a loss of muscle mass, fatty infiltration, an increase in musculotendinous cellularity, loss of normal collagen fibre structure/arrangement, rounded tenocyte nuclei and an increase in the number of vascular bundles. This was accompanied by a reduction in bone mineral density at the tendon insertion site. After 3 weeks however, these changes were less prominent. CONCLUSIONS: The rotator cuff tendon-muscle-bone unit in a rat model 3 weeks after detachment of supraspinatus represents a valid model for investigating rotator cuff degeneration. PMID- 28588659 TI - The incidence of flare reaction and short-term outcome following steroid injection in the shoulder. AB - BACKGROUND: To determine the short-term effects following corticosteroid injection into the shoulder. METHODS: Type-specific shoulder injection was administered, followed by physiotherapy 7 days to 10 days later. One hundred and sixteen adult patients were prospectively followed-up. The primary outcome was a visual analogue score (VAS) for pain. Scores were recorded immediately before injection, 30 minutes after, daily until day 7 and then at 6 weeks. Post injection pain was defined as an increase of 2 or more points in the VAS score after the injection. The secondary outcome was determined at 6 months as successful discharge or progression onto surgery. RESULTS: The VAS showed a significant reduction from the pre-injection score for all patients at day 1 and was maintained until week 6. Forty-one (35.3%) patients experienced post injection pain. The mean duration of symptoms was 3.9 days. At 6 months, 81 (69.8%) patients were discharged successfully and, at a mean of 23.2 months, did not require re-referral; 29 (25%) had surgery; and six (5.2%) were referred for a spinal opinion. CONCLUSIONS: One in three patients developed delayed post injection pain. Flare phenomenon had no determinate effect on outcome. Patients' pain response by 6 weeks is predictive of final outcome at 6 months and may help clinicians plan further treatment without delay. PMID- 28588660 TI - Simple elbow dislocation. AB - The elbow is the second most commonly dislocated major joint in adults. Good long term outcomes have been reported after non-operative management; however, a small proportion (<10%) of patients have a poor outcome and some do require surgical intervention. A review of the anatomy, pathoanatomy, management and outcomes of simple elbow dislocations is presented. Emphasis is placed on emerging concepts regarding the soft tissue injury, the stabilising structures that are injured, the sequence and mechanism of injury and the relationship to elbow stability. The benefits of nonsurgical and surgical management are discussed and a treatment algorithm based on the pathoanatomy is proposed. PMID- 28588661 TI - Quantification of the articular view of the elbow afforded by standard portals using 30 degrees arthroscopy. AB - BACKGROUND: The present study quantifies the field of view (FOV) from standard arthroscopy portals and aims to identify anatomical regions where the FOV is limited. METHODS: Eleven cadaveric elbows were examined through standard anteromedial, anterolateral and posterior portals. The FOV was marked with dye using a spinal needle. The articular surfaces were then exposed and the percentage FOV seen was calculated. FOV percentage areas were compared using a Student's t-test (JMP, version 10, SAS Institute Inc., Cary, NC, USA). P < 0.05 was considered statistically significant. RESULTS: The mean (SD) FOV percentage area seen from the anteromedial portal and anterolateral portal was 91.69% (3.63%) and 92.03% (3.93%), respectively, for the anterior humerus articular surface. There was no significant difference in the mean FOV percentage area seen from the anteromedial and anterolateral portals (p = 0.99). The mean (SD) FOV percentage area of the posterior humerus articular surface was 84.69% (2.28%). The mean (SD) FOV percentage area seen of the radial head and trochlear was 16.05% (2.66%) and 4.14% (1.76%), respectively. CONCLUSIONS: The present study is the first to quantify the FOV of elbow arthroscopy. The majority of the anterior and posterior humerus articular surface can be seen through standard portals. The limitations in FOV are primarily confined to the radial head and trochlear notch. PMID- 28588662 TI - Management of painful reverse shoulder arthroplasty. AB - Even though reverse shoulder arthroplasty is a very successful procedure, painful complications occur. During the initial postoperative years, the most common reasons for pain are instability, postoperative fracture of the acromion or spine, and periprosthetic infection. Later, aseptic loosening, with humeral loosening being more frequent that glenoid loosening, can be a source of pain and reduction in function. A careful patient history, clinical examination, plain radiographs, computed tomography and blood tests give an explanation for the pain in most cases. The majority of these complications can be successfully treated, maintaining a functional reverse shoulder arthroplasty. However, if all examinations are normal, it is important to remember that nonshoulder conditions such as tumour of the lung or degenerative changes of the cervical spine can give shoulder pain. PMID- 28588663 TI - MicroRNA-17-5p inhibits proliferation and triggers apoptosis in non-small cell lung cancer by targeting transforming growth factor beta receptor 2. AB - MicroRNAs (miRs) are small non-coding RNAs that suppress gene expression by directly binding to the 3'-untranslated region of their target mRNAs. Specific miRs serve key roles in the development and progression of non-small cell lung cancer (NSCLC). The aim of the present study was to determine the mechanism of miR-17-5p in the regulation of NSCLC cell survival and proliferation. Reverse transcription-quantitative polymerase chain reaction data indicated that miR-17 5p was significantly downregulated in 28 NSCLC tissues compared with 7 non tumorous lung tissues. Furthermore, lower miR-17-5p expression was associated with a higher pathological stage in NSCLC patients. Lower miR-17-5p expression was also observed in several common NSCLC cell lines, including SK-MES-1, A549, SPCA-1, H460, H1229 and HCC827, compared with the bronchial epithelium cell line, BEAS-2B. Additionally, overexpression of miR-17-5p significantly inhibited proliferation while inducing the apoptosis of NSCLC H460 cells. Subsequently, transforming growth factor beta receptor 2 (TGFbetaR2) was identified as a direct target of miR-17-5p using a luciferase reporter assay. Western blot analysis confirmed that miR-17-5p negatively mediated the expression of TGFbetaR2 in NSCLC cells. Furthermore, small interfering RNA-induced downregulation of TGFbetaR2 also suppressed the proliferation of H460 cells while triggering apoptosis. Therefore, the results of the current study suggest that miR-17-5p may inhibit proliferation and trigger apoptosis in NSCLC H460 cells at least partially by targeting TGFbetaR2. PMID- 28588664 TI - Impact of Botox-A SNAP-25 protein expression and the mechanism of inhibitory neurotransmitter imbalance in chronic sciatic nerve pain rat model. AB - The Botox-A impact on the expression of SNAP-25 protein in rat chronic sciatic nerve pain model was assessed and the mechanism of inhibitory neurotransmitter imbalance was studied. A chronic constriction injury (CCI) model consisted of 30 healthy male rats. The rats were randomly divided into the sham-operated group, CCI group and BoNT/A intervention group, and during 1, 7 and 14 days we conducted mechanical withdrawal threshold (MWT) test and thermal withdrawal latency (TWL) test before and after operation. After 14 days, the animals were sacrificed. SNAP 25 protein expression level, mRNA subunit NR2B within excitatory neurotransmitter glutamate GLT and protein expression level, as well as GAT mRNA, the inhibitory GABA neurotransmitter transporter and protein expression level were studied by RT polymerase chain reaction and western blot analysis. The difference between MWT and TWL at each point in time before and after operation showed no statistical significance (P>0.05) in the sham-operated group. For the CCI group at each time point, MWT and TWL were obviously lower than the sham-operated group and the difference was statistically significant (P<0.05) while the internal difference at each time point showed no statistical significance (P>0.05). The expression level of protein of SNAP-25 and NR2B mRNA in the CCI group was clearly higher than sham-operated group. Additionally, the expression level of GAT-1 mRNA and protein in CCI group was apparently lower than the sham-operated group. In conclusion, Botox-A helped reduce SNAP-25 within rat chronic sciatic nerve pain model thereby relieving pain. PMID- 28588665 TI - Role of S100A3 in human hepatocellular carcinoma and the anticancer effect of sodium cantharidinate. AB - The fifth most common cancer worldwide is hepatocellular carcinoma (HCC), which has an annual mortality rate of ~800,000. Although surgical procedures for HCC, such as hepatic resection and liver transplantation, have progressed and the outcomes of patients have improved, HCC is still characterized by frequent recurrence, even after liver transplantation. In the present study the expression of the protein coding gene, S100 calcium binding protein A3 (S100A3), was observed in 62 HCC tissues and tumor-surrounding tissues. The present study indicated that S100A3 activation was involved in tumorigenesis and tumor aggressiveness. The protein and mRNA expression levels of S100A3 in the human HCC cell line (HepG2) were investigated using western blotting and reverse transcription-quantitative polymerase chain reaction analysis, respectively. The function of sodium cantharidinate in inducing HCC cell apoptosis was also investigated. Sodium cantharidinate inhibited the protein and gene expression of S100A3 in HepG2 cells in vitro. These data suggested that S100A3 has an important role in human HCC. The present study indicates that the functional properties of sodium cantharidinate are promising for the development of a novel drug that may control the expression of S100A3 and improve the treatment of human HCC in the near future. PMID- 28588666 TI - Molecular analysis of the novel IDS allele in a Thai family with mucopolysaccharidosis type II: The c.928C>T (p.Gln310*) transcript is sensitive to nonsense-mediated mRNA decay. AB - Hunter syndrome (or mucopolysaccharidosis type II, MPS II) is an X-linked recessive disorder induced by a deficiency of the iduronate 2-sulfatase (IDS) enzyme, resulting in the accumulation of glycosaminoglycan substrates, heparan sulfate and dermatan sulfate, in the lysosomes. The progressive accumulation of undegraded metabolites induces cell and tissue dysfunction, leading to multi systemic pathology. The heterogeneity of clinical phenotypes, ranging from mild to severe forms, results from different mutations in the IDS gene. To date, >550 MPS II causal mutations have been reported in the IDS gene, of which ~10% are nonsense mutations that lead to premature protein termination. In the present study, the IDS mutation causing MPS II in an extended Thai family was identified using IDS enzyme assay and IDS gene exon sequencing. Three family members were enzymatically confirmed to have MPS II and to carry the novel IDS nonsense allele c.928C>T (p.Gln310*). The IDS mRNA levels were evaluated by reverse transcription quantitative polymerase chain reaction, which demonstrated that all patients exhibited a reduction of IDS mRNA, suggesting its degradation by nonsense mediated mRNA decay. Expression of wild type and mutant IDS in COS-7 cells revealed that the IDS p.Gln310* mutant lacked IDS activity, consistent with production of a nonfunctional, prematurely truncated protein. Taken together, these results indicate that the IDS c.928C>T (p.Gln310*) mutation is a severe disease-causing mutation for MPS II. PMID- 28588667 TI - Physical inactivity associated with the risk of non-communicable diseases in Japanese working mothers with young children: A cross-sectional study in Nagano city, Japan. AB - Physical activity helps to prevent the development of chronic non-communicable diseases. However, childbearing generally reduces parents' level of physical activity, particularly in mothers. Therefore, mothers with young children generally have lower levels of physical activity and have a higher risk of developing non-communicable diseases. The aim of the present study was to examine this risk in Japanese working mothers with young children. A cross-sectional study was conducted in four nursery schools in Nagano city, Japan. All mothers were asked to complete a questionnaire regarding abnormal findings at their proximate annual medical examination, and were asked to record their normal physical activity. A total of 182 mothers completed the questionnaires, and 36 reported having abnormal findings (ABN group). Mothers in the ABN group were significantly older than those without abnormal findings (NOR; P=0.043). No significant differences in physical activity were observed between the two groups; however, mothers in the ABN group spent a significantly longer time sitting than those in the NOR group (P=0.028). Regarding socioeconomic characteristics, mothers in the ABN group had a significantly higher educational background (P=0.040) and a higher annual family income (P<0.001) compared with those in the NOR group, and significantly more mothers held full-time jobs (55.9 vs. 36.0%; P=0.005). Full-time working mothers typically had a significantly higher family income (P<0.001) and spent a significantly longer time sitting (P<0.001) compared with mothers in part-time and other work. Therefore, the results of the present study suggest that sedentary lifestyles, namely the amount of time spent sitting, may increase the risk of Japanese working mothers with young children developing non-communicable diseases. PMID- 28588668 TI - Fluid-fluid level on magnetic resonance images may predict the occurrence of pituitary adenomas in cystic sellar-suprasellar masses. AB - The aim of the present study was to evaluate the value of identifying fluid-fluid level via preoperative magnetic resonance (MR) images in differentiating pituitary adenomas from craniopharyngioma, Rathke's cleft cyst (RCC), and other cystic sellar-suprasellar lesions. The data of 293 consecutive patients who underwent surgery for sellar-suprasellar lesions between July 2010 and December 2012 was retrospectively reviewed, and a total of 133 cystic cases were included in the present study. MR images and pathological features of all subjects were examined. Among the 133 cystic sellar-suprasellar masses, there were 78 cases of pituitary adenomas, 31 cases of craniopharyngioma, 21 cases of RCC, one case of epidermoid cyst and two cases of abscess. Fluid-fluid levels were identified n 43 cases (55.13%) of cystic pituitary adenomas, with a single fluid level in 23 cases, two fluid levels in 8 cases, and three levels or more in 12 cases. Two cases (6.45%) of craniopharyngioma, and one case (4.76%) of RCC presented single fluid level. No instances of fluid-fluid levels were observed in epidermoid cyst or abscess. Fluid-fluid levels were typically exhibited on axial T2-weighted images. The identification of fluid-fluid level in cysts provides useful diagnostic value in distinguishing pituitary adenoma from other sellar suprasellar lesions. The findings of the present study suggest that a sellar suprasellar mass with a fluid-fluid level inside the tumor is most likely a pituitary adenoma, particularly if multiple fluid levels are observed in the same tumor. The fluid-fluid level is typically clearly depicted on axial or sagittal MR images, suggesting subacute or chronic hemorrhage in pituitary adenomas. PMID- 28588669 TI - Metformin combined with acarbose vs. single medicine in the treatment of type 2 diabetes: A meta-analysis. AB - The present meta-analysis aimed to evaluate metformin combined with acarbose compared with monotherapy with either of the two drugs for type 2 diabetes (T2DM). Relevant trials were retrieved through searching PubMed, Embase, Cochrane library, China National Knowledge Infrastructure, Wanfang and Chongqing VIP information network databases. Heterogeneous and homogeneous data were statistically combined using a random- and fixed-effects model, respectively. For dichotomous and continuous data, the merged effect size was presented as the risk ratio (RR) and weighted mean differences (WMD), respectively, with 95% confidence interval (CI). All included studies were divided into subgroups. A Funnel plot was used to detect publication bias. Review Manager 5.2 software was applied to perform the statistical analyses. Meta-analysis revealed that compared with metformin monotherapy, combined therapy was significantly more efficacious regarding indexes including the total effective rate, fasting blood glucose (FBG), blood glucose levels at two post-prandial hours (2HPG) and hemoglobin A1C (HbA1c). Similarly, combined therapy showed advantages on indexes including FBG, 2HPG and HbA1c over acarbose therapy after 4 months of treatment. In conclusion, the findings of the present meta-analysis suggested that combined therapy of metformin and acarbose appears to be more efficacious than metformin or acarbose monotherapy. PMID- 28588670 TI - Anticancer effects of beta-elemene with hyperthermia in lung cancer cells. AB - beta-elemene is a novel, plant-derived anticancer drug, which has been used to target multiple solid tumor types. Hyperthermia is an adjuvant therapeutic modality to treat cancer. However, the underlying mechanisms associated with the efficacy of these two treatments are largely unknown. The aim of the present study was to evaluate the effects of beta-elemene combined with hyperthermia in lung cancer cell lines. An MTT assay was used to determine cell viability. The cell cycle and apoptosis were analyzed using flow cytometry. The morphology of cells during apoptosis was determined using a transmission electron microscope. The expression levels of P21, survivin, caspase-9, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4 (Bax) mRNA were detected using quantitative polymerase chain reaction. beta-elemene with hyperthermia treatment significantly inhibited the viability and increased the apoptosis rate of A549 cells compared with beta elemene treatment alone (P<0.01), and significantly decreased the proportion of cells in S phase compared with the control (P<0.01). Morphological observation using transmission electron microscopy indicated cross-sectional features of apoptosis: Chromatin condensation, reduced integrity of the plasma membrane, increased cellular granularity, nuclear collapse and the formation of apoptotic bodies. beta-elemene with hyperthermia treatment significantly promoted P21 and Bax mRNA expression (P<0.01) and significantly decreased caspase-9, Bcl-2 and survivin mRNA expression (P<0.01) in A549 cells. In conclusion, beta-elemene with hyperthermia has a significant inhibitory effect on A549 cells. This occurs through reducing S phase and inducing apoptosis, via an increase in P21 and Bax expression and a decrease in caspase-9, Bcl-2 and survivin expression. PMID- 28588671 TI - Multiple sclerosis: Pathology, diagnosis and treatments. AB - Multiple sclerosis (MS) is a complex neurodegenerative disease affecting the central nervous system (CNS). The onset of MS has been typically observed in individuals aged from 20 to 40-years, with the female to male ratio of 1:2. MS appears as abrupt onset of focal sensory disturbances that is accompanied by unilateral painless damage of vision, double vision, limb weakness, unsteadiness of gait, and bowel or bladder symptoms. Whereas the exact etiology of the disease is unknown, observational research has suggested genetic and environment influences through an underlined pathophysiology widely believed to be autoimmune in nature. Indeed, plaque of demyelination inside of the CNS with relative conservation of axons remains the clinical symptoms of MS. However, considerable advances in understanding the pathology have contributed to an early diagnosis, particularly the exact neuroanatomical setting of plaques. Accordingly, magnetic resonance imaging has been considered as the primarily adjunctive modality for the constant detection of abnormal white matter. In addition, the analysis of cerebrospinal fluid contents has also been of interest for the diagnosis to discriminate other affections such infection or vasculitis. These resulted in a broad variety of therapies that considerably control the activity and change the course and prognosis of the disease. In the present review, we evaluate the current state of knowledge on MS with emphasis on the pathology itself, the diagnosis and common therapeutical approaches accurately used. PMID- 28588672 TI - ABCG1 as a potential oncogene in lung cancer. AB - ATP-binding cassette transporter G1 (ABCG1) is a member of the ABC transporter family and regulates cellular cholesterol homeostasis. It has important roles in cholesterol homeostasis and tumor immunity, which has, however, not been reported in lung cancer. The present study showed that ABCG1 protein is upregulated in lung cancer compared with adjacent normal tissues and furthermore, aberrant ABCG1 expression was detected in lung cancer cell lines. ABCG1 was shown to promote the proliferation of HKULC4 lung cancer cells. Moreover, ABCG1 was found to regulate proliferation-, apoptosis- and cancer stem cell-associated markers in HKULC4 cells, implying that ABCG1 has important roles not only in the regulation of proliferation but also of apoptosis and cancer stem cells. A microRNA microarray analysis showed that ABCG1 significantly downregulated miR-29a, -b and -c expression in HKULC4 cells. Finally, it was demonstrated that ABCG1 promoted the migration and invasion in HKULC4 cells. Thus, ABCG1 may be a novel therapeutic target to improve the treatment of non-small cell lung cancer. PMID- 28588673 TI - Modulatory effects of hydrochlorothiazide and triamterene on resistant hypertension patients. AB - The present study explored the modulatory potential of hydrochlorothiazide and triamterene on resistant hypertension patients. The mechanistic information for resistant hypertension was explored by studying the pressure-natriuresis curves between the salt sensitive population and non-salt sensitive population. A cohort of 23 patients with non-hypertension (NH) (13 males and 10 females; aged from 23 to 62 years), 26 patients with controlled hypertension (CH) (14 males and 12 females; aged from 19 to 72 years) and 23 patients with resistant hypertension (RH) (13 males and 10 females; aged from 19 to 76 years) were selected. The patients were divided into two main groups on the basis of salt sensitivity viz. salt sensitive (SS) and non-SS (NSS) groups. These two groups were further classified into four subgroups based on the diuretic drug used. Hydrochlorothiazide-treated subgroups were named as salt sensitive hydrochlorothiazide (SSHy) and non-SSHy (NSSHy) groups. Similarly, triamterene treated subgroups were named as salt sensitive triamterene (SSTr) and non-SSTr (NSSTr) groups. Treatment continued for 2 weeks and the pressure-natriuresis curves were recorded. Additionally, the plasma aldosterone and renin activity was monitored by radioimmunoassay. The pressure-natriuresis curves of the SS group were shifted towards the right relative to NSS group. On the other hand, hydrochlorothiazide and triamterene treatments reversed the changes of pressure natriuresis curves. Moreover, significant differences were observed among various important indices including plasma aldosterone, renin activity, office blood pressure as evaluated by the chronic salt load test and diuretic intervention tests. The study concludes that hydrochlorothiazide and triamterene hold good potential as an efficient modulator of resistive hypertension. PMID- 28588674 TI - Resveratrol ameliorates diabetic nephropathy in rats through negative regulation of the p38 MAPK/TGF-beta1 pathway. AB - Resveratrol (RSV) has been shown to have a renoprotective effect against diabetic nephropathy, but the underlying mechanisms of this have not been fully elucidated. The aim of the current study was to explore the mechanisms responsible for the therapeutic effects of RSV in rat mesangial cells in vitro and in a rat model of diabetic nephropathy. The viability of CRL-2573 rat mesangial cells and their expression levels of p38, phosphorylated (p)-p38, transforming growth factor beta 1 (TGF-beta1) and fibronectin were assessed in response to treatment with high glucose, with or without RSV. Diabetic nephropathy was also induced in Sprague-Dawley rats by streptozotocin treatment. At 8 weeks, basic biochemical parameters and histopathological abnormalities as well as the expression of p38, p-p38, TGF-beta1 and fibronectin in rat kidneys were compared between control diabetic rats and those treated with 20 mg/kg RSV daily for 4 weeks. In the mesangial cell line, RSV inhibited high glucose-induced increases in cell viability and fibronectin expression by significantly reducing p38 mitogen-activated protein kinase (MAPK) activation and TGF-beta1 expression (P<0.05). In diabetic rats, RSV significantly decreased blood glucose, serum creatinine and urinary albumin levels, as well as the kidney weight and ratio of kidney weight/body weight compared with the control group (P<0.05). Moreover, RSV ameliorated renal histological changes and downregulated the expression of p-p38, TGF-beta1 and fibronectin in the kidneys of diabetic rats. These data suggested that RSV protected renal tissue from diabetes-induced injury and that this activity may be via inhibition of the p38 MAPK/TGF-beta1 signaling pathway. PMID- 28588675 TI - Fragmented QRS complex is a prognostic marker of microvascular reperfusion and changes in LV function occur in patients with ST elevation myocardial infarction who underwent primary percutaneous coronary intervention. AB - The present study aimed to investigate the in-hospital and long-term prognostic value of fragmented QRS complex (fQRS) for microvascular reperfusion and changes in left ventricular (LV) function in patients with ST elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI). A total of 216 patients with STEMI undergoing primary PCI were included in the current study. Patients were divided into two groups based on the presence (n=126) or absence (n=90) of fQRS following electrocardiograms (ECGs) on admission. Following primary PCI and follow up, patients were divided into four groups based on new onset, resolution, persistence and absence of fQRS. Major adverse cardiac events were defined to include cardiovascular death, arrhythmia, heart failure, reinfarction and target vessel revascularization. The percentage of patients with heart failure and microvascular reperfusion differed significantly between the fQRS(+) and fQRS(-) groups. Levels of N-terminal pro brain natriuretic peptide (NT-proBNP), Peak creatine kinase-MB (CK-MB) and Troponin I levels were observed to be significantly higher in the fQRS(+) group compared with the fQRS(-) group. In univariate logistic regression analysis, left ventricular ejection fraction (LVEF), NT-proBNP, Troponin I, Peak CK-MB and microvascular reperfusion were found to be associated with fQRS. Multivariate analysis identified that LVEF, NT-proBNP, Troponin I and microvascular reperfusion may be independent predictors of fQRS. The presence of fQRS was demonstrated to be associated with left ventricular dysfunction at follow up assessments. The presence of fQRS was not only significantly associated with myocardial microvascular reperfusion and left ventricular function, but was also a prognostic marker in STEMI. PMID- 28588676 TI - Xuebijing injection attenuates pulmonary injury by reducing oxidative stress and proinflammatory damage in rats with heat stroke. AB - The present study aimed to investigate the protective effect of Xuebijing injection (XBJ) on lung injury in heat-stroke rats and the underlying mechanisms. In total, 54 rats were randomly assigned to non-thermal, saline vehicle and XBJ groups. The rectal temperature (Tc), mean arterial pressure (MAP) and respiratory rate (RR) of the rats were recorded. The time-point of heat stroke and the time of survival were assessed, and indicators of arterial blood gas were regularly measured from 0 to 60 min. The concentration of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and IL-10 was also determined. At the end of the experiment, lung tissue was harvested for histopathological analysis. Inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD) expression was measured by immunohistochemistry. Terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling was used to measure apoptosis. XBJ pretreatment prolonged the decline of clinical characteristics, as demonstrated by increases in Tc, MAP, RR and indicators in arterial blood gas in rats under heat stress. The time until heat stroke and the survival time in the Saline group were shorter than in rats treated with XBJ. The expression of iNOS in lung tissue and the concentration of TNF-alpha, IL-1beta and IL-10 in the bronchoalveolar lavage fluid of rats treated with saline was higher than in rats with XBJ pre-treatment. Contrarily, SOD expression in rats treated with saline was decreased compared with that in rats treated with XBJ. Moreover, the apoptotic rate in the lung tissues of rats with saline treatment was higher than that in rats treated with XBJ. In conclusion, XBJ delayed the development of heat stroke and increased the survival time in rats under heat-stress by ameliorating pulmonary failure and acute lung injury. The underlying mechanisms of this effect may be the reduction of inflammatory cytokines as well as attenuation of oxidative stress and apoptosis by XBJ. PMID- 28588677 TI - Comparative study of conventional US, contrast enhanced US and enhanced MR for the follow-up of prostatic radiofrequency ablation. AB - The aim of the present study was to evaluate and compare the effectiveness of different imaging methods during follow-up of prostatic radiofrequency ablation. Prostatic radiofrequency ablation (RFA) was performed in 20 healthy beagle dogs. Various imaging examinations were used to monitor the results of RFA, including conventional ultrasound (US), contrast enhanced ultrasound (CEUS) and enhanced magnetic resonance (MR). Imaging exams were performed at five phases: Immediately following RFA, one week later, one month later, three months later and six months later. The morphology for each imaging test and histological results were recorded and compared in each phase. Based on the actual results from autopsy, the accuracy of those imaging exams was evaluated. The canine prostate gland demonstrated typical coagulative necrosis immediately following RFA. The lesion would develop into stable cyst if no other complications occurred within the six month follow-up. Regarding the RFA lesion volume measurement and the reflection of pathological changes, conventional US was not able to accurately measure the volume of RFA lesion and missed many more details concerning the RFA-treated area than CEUS and MR during the three months. The results from CEUS exhibited comparable accuracy to those from enhanced MR at each phase. However, there were no significant differences in the results from US, CEUS and MR at six months, which may contribute to the complete formation of lesion cyst. In the early phase, conventional US was not sufficient for evaluating the efficacy of RFA. Enhanced US and MR provided clear images and accurate information. However, CEUS has the advantage of being more economical, using more convenient equipment and faster scanning, thus identifying it as the more feasible choice. Furthermore, no notable advantages were observed among any image examinations in the long-term follow-up. PMID- 28588678 TI - Mechanism of N-acetyl-cysteine inhibition on the cytotoxicity induced by titanium dioxide nanoparticles in JB6 cells transfected with activator protein-1. AB - The present study investigated the mechanism of N-acetyl-cysteine (NAC) inhibition on the cytotoxicity induced by titanium dioxide (TiO2) nanoparticles (NPs) using murine epidermal JB6 cells transfected with activator protein-1 (AP 1), JB6-AP-1 cells. Confocal microscopy was performed to localize TiO2 NPs in cultured cells. The level of reactive oxygen species (ROS) present in cells was evaluated by staining with 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium. AP-1 gene expression levels in the cells were detected using the luciferase assay. Confocal microscopy indicated that TiO2 NPs passed through the cell membrane into the cytoplasm; however, they did not penetrate the nuclear membrane. The present findings indicated that NAC markedly inhibited ROS generation and significantly inhibited cytotoxicity (P<0.05) induced by TiO2 NPs. Furthermore, alternative studies have demonstrated that AP-1 luciferase activity induced by TiO2 NPs may be significantly inhibited by NAC. In conclusion, the ability for NAC to inhibit the cytotoxicity induced by TiO2 NPs may primarily occur by blocking ROS generation in the cultured cells. PMID- 28588679 TI - microRNA-664 enhances proliferation, migration and invasion of lung cancer cells. AB - Altered microRNA (miR) expression serves an important role in the development and progression of lung cancer. In the present study, the effect of miR-664 on proliferation, migration and invasion of lung cancer cells was assessed. The proliferation of lung cancer cells with an overexpression of miR-664 was examined via MTT assay. The Caspase-Glo3/7 assay was used to examine the effect of miR-664 on cisplatin-induced apoptosis in lung cancer cells. The migration and invasion of lung cancer cells were assessed by Transwell migration and matrigel invasion assays. Western blot analysis was used to examine the protein expression levels. miR-664 improved the proliferation of lung cancer cells and inhibited cisplatin induced apoptosis of A549 and A427 cells. Furthermore, altered expression of miR 664 affected migration and invasion of lung cancer cells. In addition, a miR-664 mimic decreased E-cadherin expression and increased vementin and Snail expression in lung cancer cells. Notably, the expression level of protein kinase B in A549 cells was changed following altered expression of miR-664. The results of the present study suggest that miR-664 serves an essential role in tumor development and progression in lung cancer. PMID- 28588680 TI - Early clinical characteristics of bacterial endophthalmitis in retinopathy of prematurity after intravitreal bevacizumab injection: A case report. AB - Intravitreal bevacizumab injection (IVB) is emerging as a safe and effective therapy for retinopathy of prematurity (ROP); however, follow-up investigations after IVB have indicated that endophthalmitis, a rare and devastating complication, may develop. The present study reports a case of an infant with ROP who developed endophthalmitis after IVB infection. The infant was administered with an intravitreal injection of broad-spectrum antibiotics to treat the endophthalmitis. A favorable anatomic outcome was achieved after follow-up. From this case, it was discovered that the early clinical characteristics of endophthalmitis infection secondary to IVB in premature infants include: i) The clinical symptoms of endophthalmitis infection appearing as early as 3-5 days after IVB; ii) a white membranous plaque on the retina surface with an obscure circular boundary; iii) a plaque that enlarges to a gray flocculent mass and intrudes the vitreous body, where the hazing surrounds the lesion; and iv) conjunctival hyperemia and cornea edema in the anterior segment of the affected eye. This case also indicated that timely retinal screening with RetCam or a binocular ophthalmoscope 3-5 days after IVB may be effective for detecting early stage endophthalmitis in infants who are unable to complain of a loss of visual acuity. From the present case report, it is advisable that the same type of screening be performed 3-5 days after other types of eye surgery, such as cataract extraction surgery, to detect early stage endophthalmitis. Furthermore, the present case also revealed that an early intravitreal injection of broad spectrum antibiotics may be an effective treatment for premature infants with bacterial endophthalmitis. PMID- 28588681 TI - Effects of Gui Zhu Yi Kun formula on the P53/AMPK pathway of autophagy in granulosa cells of rats with polycystic ovary syndrome. AB - The aim of the present study was to investigate the molecular mechanism associated with the traditional Chinese medicine formula Gui Zhu Yi Kun formula (GZYKF), in the treatment of polycystic ovary syndrome (PCOS). In this study, granulosa cells (GCs) of rats with PCOS were cultured and treated with testosterone propionate (TP) alone or with serum from rats treated with different doses of GZYKF. The effect of TP on cell growth was assayed using the MTT method. Expression levels of Beclin-1, light chain (LC)3, mechanistic target of rapamycin (mTOR), tumor suppressor p53 (p53), adenosine monophosphate-activated protein kinase (AMPK), sestrin2 and tuberous sclerosis protein 1/2 were evaluated using quantitative polymerase chain reaction and western blotting. It was demonstrated that TP increased the expression of Beclin-1 and LC3, whereas GZYKF significantly decreased the TP-induced expression of Beclin-1 (P<0.01). Additionally, GCs treated with GZYKF exhibited significant increases in mTOR, phosphorylated mTOR and AMPKalpha expression levels, and significant reductions in p53 and sestrin2 expression levels were observed. In conclusion, the findings of the present study suggest that a reduction in ovarian GCs in rats with PCOS may be associated with GC autophagy. Furthermore, the effects of GZYKF in mediating the p53/AMPK pathway may inhibit GC autophagy, which suggests a possible novel mechanism underlying the treatment of PCOS with GZYKF. PMID- 28588683 TI - Expression and immunogenicity of NY-ESO-1 in colorectal cancer. AB - Serum assays of NY-ESO-1 antibodies provide a guide to discriminate between patients who suffer from different types of cancer. In the present study, the expression of NY-ESO-1 was detected with the aim to identify a novel tumor antigen in colorectal cancer (CRC). Sera were obtained from 89 healthy individuals and 236 patients with CRC with stage I, II, III and IV tumors. The NY ESO-1 autoantibody levels were determined using an enzyme-linked immunosorbent assay. The mRNA and protein expression levels of NY-ESO-1 were detected using reverse transcription-polymerase chain reaction and immunohistochemistry, respectively, in 60 CRC and paired adjacent non-tumor tissues. NY-ESO-1 antibody was detected in 40 of the 236 (16.9%) patients with CRC. The NY-ESO-1 antibody combined with carcinoembryonic antigen enhanced the sensitivity, from 52.1 to 62.7%, of the diagnosis of CRC. The frequency of antibody positivity increased with the TNM cancer stage (8.8 vs. 28.3% in stages I+II and III+IV, respectively). The mRNA and protein expression levels of NY-ESO-1 were significantly higher in CRC tissue than in adjacent non-tumor tissue. In conclusion, NY-ESO-1 is frequently expressed in CRC with the capacity of inducing a humoral immune response in CRC patients, exhibiting the potential to be a promising biomarker for CRC. PMID- 28588684 TI - Successful treatment of granulomatosis with polyangiitis with hydropneumothorax using corticosteroids and immunosuppressant. AB - Pneumothorax and pleural effusion is a rare and serious complication of granulomatosis with polyangiitis (GPA). The present study reported a case with a history of sinusitis for 20 years, dry cough for three years and exacerbated purulent nasal discharge and recurrent skin ulcers for two years. The patient experienced sudden difficulty in breathing two months prior to presentation. Lung computed tomography (CT) showed multiple bilateral lung nodules and cavitary nodules as well as right hydropneumothorax. Paranasal sinus CT showed soft tissue infiltration. The cytoplasmic pattern of anti-neutrophil cytoplasmic antibody (c ANCA) was positive and anti-proteinase 3 (PR3) antibodies, erythrocyte sedimentation rate and C-reactive protein were elevated. After pleural drainage and methylprednisolone pulse treatment, followed by cyclophosphamide and cyclosporine, the patient's symptoms were ameliorated, lungs were re-expanded, and c-ANCA, PR3 and inflammatory markers returned to normal levels. PMID- 28588682 TI - Comparison of biological characteristics of nucleus pulposus mesenchymal stem cells derived from non-degenerative and degenerative human nucleus pulposus. AB - Cell therapy using mesenchymal stem cells provides a promising approach for the treatment of intervertebral disc degeneration (IDD). In recent years, human nucleus pulposus mesenchymal stem cells (NPMSCs) have been identified in nucleus pulposus tissue and displayed great potential for the regeneration of IDD. However, biological differences between non-degenerative and degenerative nucleus pulposus-derived NPMSCs have remained to be defined. The aim of the present study was to compare the biological characteristics of human NPMSCs derived from non degenerative and degenerative nucleus pulposus. NPMSCs were isolated from non degenerative and degenerative nucleus pulposus, which were assessed using the Pfirrmann grading system. The biological characteristics of the NPMSCs, including the expression of surface markers, multipotent differentiation, colony formation, chemotactic cell migration, cell activity and stemness gene expression were compared. It was found that NPMSCs could be obtained from non-degenerative and degenerative human nucleus pulposus. However, degenerative nucleus pulposus derived NPMSCs displayed decreased ability of colony formation, chemotactic migration, cell activity and expression of stemness genes compared with non degenerative nucleus pulposus-derived NPMSCs. Therefore, NPMSCs derived from non degenerative and degenerative nucleus pulposus show different biological behaviors. The degenerative status of nucleus pulposus tissue should be considered when selecting NPMSCs as a source for clinical application. PMID- 28588685 TI - Lumbar spinal intradural neurocysticercosis: A case report. AB - Neurocysticercosis is a parasitic disease that results from the larvae of Taenia solium. While neurocysticercosis is considered as the most common parasitic infection of the nervous system, spinal neurocysticercosis is rare. The present case study investigated a 59-year-old woman, who was admitted to our hospital with pain in the bilateral lower limbs and urinary complaints in the form of straining of micturition with increasing frequency. Magnetic resonance imaging revealed an intradural extramedullary lesion extending from L1/2 to S1 of the spine. Subsequently, a laminectomy from L1 to S1 was performed 3 days post presentation. Intraoperatively, a thin-walled cyst with clear fluid was identified, extending from L2 to S1. The exposed, white and mucoid cysticerci was removed completely. Which on pathological examination was identified to be cysticercosis. PMID- 28588687 TI - Retroperitoneal fibrosis and constrictive pericarditis-IgG4 related diseases: A case report. AB - Retroperitoneal fibrosis (RPF) is a rare disease characterized by infiltration of inflammatory cells and deposition of thickened fibrous tissues. The present study presents the case of a 53-year-old patient treated for generalized weakness and fatigue for 1 year prior to hospitalization. A cardiac ultrasound revealed pericardial effusion that required pericardiocentesis, during which 1,400 ml serous fluid with the characteristics of an exudate was aspirated. A pericardiectomy was performed due to persistent effusion and histological examination indicated pericardial fibrosis. A thoracic-abdominal computed tomography scan revealed the presence of retroperitoneal fibrosis. The patient was treated with corticosteroids and azathioprine. Follow-up examinations showed a significant reduction in the amount of abdominal fibrous tissue and no increase in pericardial effusion 1 year following the end of treatment. The patient continues to have regular follow-up control examinations with a cardiologist and nephrologist. PMID- 28588686 TI - Effect of continuous renal replacement therapy on kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in patients with septic acute kidney injury. AB - Kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) have been investigated as biomarkers for acute kidney injury (AKI). However, they are seldom investigated in patients with septic AKI treated with continuous renal replacement therapy (CRRT). The aim of the present study was to investigate the therapeutic effectiveness and possible mechanisms of CRRT in septic AKI by observing the changes in Kim-1 and NGAL levels. A group of 38 patients with septic AKI was randomly divided into the conventional drug treatment group (group A) and the CRRT group (group B). All patients were treated with standard antisepsis agents, and group B was additionally submitted to CRRT for 24 h. The levels of Kim-1 and NGAL in serum, urine and the ultrafiltrate of CRRT were measured prior to and at 12, 24, and 48 h after treatment. In group A, urinary Kim-1 (uKim-1) levels at 12, 24 and 48 h were lower than prior to treatment (P<0.05), whereas urinary NGAL (uNGAL) showed no difference among the various time points (P>0.05). In group B, uKim-1 was decreased at 24 and 48 h compared with before treatment (all P<0.05), whereas uNGAL was decreased at 48 h (P<0.05). Serum Kim-1 did not change with time in groups A and B (P>0.05), whereas serum NGAL was increased after treatment in group A (P<0.05) but did not change in group B (P>0.05). Kim-1 and NGAL were not detected in the ultrafiltrate of CRRT. uKim-1 and uNGAL decreased significantly after CRRT, and therefore may be used to reflect the change of renal function during CRRT and to evaluate the therapeutic effectiveness of the method. PMID- 28588690 TI - Insight into the binding interaction of kaempferol-7-O-alpha-L-rhamnopyranoside with human serum albumin by multiple fluorescence spectroscopy and molecular modeling. AB - Human serum albumin (HSA) is a transporting protein that has multiple functions. The binding interaction between HSA and small molecules affects its function and efficacy of small molecules. The present study reports that kaempferol-7-O-alpha L-rhamnopyranoside (KR) interacts with HSA as indicated by multiple fluorescence spectroscopy and molecular modeling. KR can quench the intrinsic fluorescence of HSA through the formation of a KR-HSA complex in a static manner. In addition, the binding site is located in subdomain IIA as confirmed by competitive experiments using site-specific warfarin and ibuprofen, and the driving forces include hydrogen bonds, van der Waals forces and electrostatic interaction derived from a thermodynamic analysis. The formation of KR-HSA is exothermic and spontaneous. Although there is no hydrophobic interaction around Tyr and Trp residues, the secondary structure of HSA changes through the formation of the KR HSA complex. In addition, docking results visualized and further supported these results. Finally, these results can provide more information to further investigate the use of KR on the prevention of diabetic complications. PMID- 28588688 TI - Combined effects of long-pulsed neodymium-yttrium-aluminum-garnet laser, diprospan and 5-fluorouracil in the treatment of keloid scars. AB - Keloids are benign tumors that originate from scar tissues, but they usually overgrow beyond the original wounds. In a three-month single-center clinical trial, 69 patients were randomly divided into three groups. Patients in group 1 were treated with intralesional injection of diprospan (2 mg betamethasone disodium phosphate and 5 mg betamethasone dipropionate in 1 ml) with one-month intervals for three months. Patients in groups 2 and 3 were injected with a combination of 0.5 ml 5-fluorouracil (5-FU; 25 mg/ml) and diprospan as above for three months also. Prior to each injection, the keloids of patients in group 3 were additionally irradiated by a 1,064-nm neodymium-yttrium-aluminum-garnet (Nd:YAG) laser with a single pulse at an energy density of 90-100 J/cm2 and a pulse width of 12 msec. Clinical responses were evaluated by patient self assessment and overall assessment by an observer according to the clinical signs of erythema, pruritus and pliability. A total of sixty-two patients completed the tests of the present study. At 2 and 3 months, the patients in all treatment groups showed an acceptable improvement in nearly all measurements. At the end of the study, the erythema and toughness score was significantly reduced and itch reduction was significantly greater in the diprospan + 5-FU + Nd:YAG group when compared to those in the other groups (P<0.05 for all indexes). The acceptable responses (good to excellent improvements) reported by blinded observers were as follows: 12% in the diprospan group, 48% in the diprospan + 5-FU group and 69% in the diprospan + 5-FU + Nd:YAG group. All of the results indicated that the combination of diprospan + 5-FU + Nd:YAG was the most efficacious therapy for keloid scars. PMID- 28588689 TI - Safety of neural stem cell transplantation in patients with severe traumatic brain injury. AB - Neural stem cell (NSC) therapy is a promising treatment for traumatic brain injury (TBI). In addition, mesenchymal stem cells (MSCs) have been investigated for the treatment of TBI due to their functions in neural regeneration and their neurotrophic effect. In the present study, the safety, feasibility and biological effects of autologous MSC-derived NSC-like cell transplantation were investigated in 10 patients with severe TBI. All patients received intravenous or intrathecal injections of human NSC-like cells and were evaluated with physical and neurological examinations, routine laboratory tests and neuroradiological findings. The results indicated that the majority of patients experienced improved neurological function in different degrees during the follow-up period. No mortality or serious adverse events were observed in any patient subsequent to transplantation. Higher serum levels of nerve growth factor and brain-derived neurotrophic factor were detected following the transplantation, as compared with the levels prior to treatment. Overall, the present results suggest that transplantation of autologous NSC-like cells is feasible and appears to be safe for the treatment of non-acute severe TBI. PMID- 28588691 TI - Chronic hepatitis B patients with high liver fibrosis levels should receive antiviral treatment. AB - The present study aimed to evaluate improvements in liver stiffness (LS) measured by transient elastography (TE) and associated factors in Chinese patients with chronic hepatitis B (CHB) treated with entecavir (ETV). A total of 190 consecutive CHB patients who received entecavir therapy and two LS measurements (LSMs) were enrolled in this retrospective study (average age, 47 years; 137 males [72.1%]), including 111 patients without liver cirrhosis (group 0) and 79 patients with liver cirrhosis (group 1). Each patient received LSM twice with an interval of six months. Normalized aspartate aminotransferase (AST) levels were accompanied by a significant reduction in LSM values (P<0.001) in each group. Multivariate analysis revealed that a higher initial LS value in groups 0 and 1, and a higher prothrombin time activity in group 1 was associated with a greater decline of the LS value. Higher initial quantitative hepatitis B surface antigen (qHBsAg) levels were correlated with a greater decline of the qHBsAg value in the two groups. In conclusion, LS values in CHB patients significantly improved after 24 weeks of entecavir therapy. The results suggested that higher LSM values at baseline contributed to a greater regression of LSM, and higher initial qHBsAg values could lead to greater qHBsAg reduction during ETV therapy. Extrapolating our results, we might be able to consider CHB patients who have higher initial LSM values or have higher levels of qHBsAg values when enrolled would have more benefit during ETV treatment. PMID- 28588692 TI - Strategies for the evaluation of DNA damage and repair mechanisms in cancer. AB - DNA lesions and the repair mechanisms that maintain the integrity of genomic DNA are important in preventing carcinogenesis and its progression. Notably, mutations in DNA repair mechanisms are associated with cancer predisposition syndromes. Additionally, these mechanisms maintain the genomic integrity of cancer cells. The majority of therapies established to treat cancer are genotoxic agents that induce DNA damage, promoting cancer cells to undergo apoptotic death. Effective methods currently exist to evaluate the diverse effects of genotoxic agents and the underlying molecular mechanisms that repair DNA lesions. The current study provides an overview of a number of methods that are available for the detection, analysis and quantification of underlying DNA repair mechanisms. PMID- 28588693 TI - Effect of traditional Chinese medicine components on multidrug resistance in tumors mediated by P-glycoprotein. AB - Multidrug resistance (MDR) is a major cause of chemotherapy failure. It occurs when an organism is resistant to one type of drug, but also develops resistance to other drugs with different structures and targets. There is a high incidence of MDR in cancer chemotherapy, therefore, finding an effective and non-toxic MDR reversal agent is an important goal, particularly for P-glycoprotein-mediated MDR in cancer. Improvements continue to be made to the status and understanding of traditional Chinese medicine (TCM), due to the advantages of low toxicity and relatively minor side effects. Therefore TCM is currently being used in the treatment of various types of diseases. In recent years, numerous components of TCM have been identified to be effective in reversing MDR by downregulating expression of the drug transporter membrane protein, recovering changes in enzymes involved in detoxification and metabolism and repairing the cell apoptosis pathway. The present study summarizes the anticancerous properties and MDR reversing components of traditional medicinal plants commonly used in the treatment of cancer. PMID- 28588694 TI - High level of calpain1 promotes cancer cell invasion and migration in oral squamous cell carcinoma. AB - Calpain1, termed conventional calpain and a member of the Ca2+-dependent neutral cysteine proteases, is considered to be involved in cancer formation and development. However, the effect of calpain1 on oral squamous cell carcinoma (OSCC) remains poorly understood. The aim of the present study was to evaluate the possibility of calpain1 as a potential molecular target for OSCC diagnosis and therapy. The present study demonstrates that calpain1 was overexpressed in OSCC cell lines and 4/7 of the tumor tissues in paired samples of tumor and noncancerous matched tissues (NCMT). In a cohort of 125 patients with primary OSCC, the high expression of calpain1 was an independent predictor for overall survival in a multivariate analysis (P=0.022). Furthermore, RNA interference mediated suppression of calpain1 expression reduced the proliferation, migration and invasion potential of the HSC3 and CAL27 OSCC cell lines, but did not increase their apoptosis. These findings indicate that calpain1 may be a useful biomarker for novel prognostic and therapeutic strategies in oral squamous cell carcinoma. PMID- 28588696 TI - MAPK/P53-mediated FASN expression in bone tumors. AB - The correlation between mitogen-activated protein kinase (MAPK)/P53 signaling dependent fatty acid synthase (FASN) expression and bone tumors was examined in the present study. We established the SH081 bone tumor cell line, which was used to determine the expression of FASN and MAPK/P53 at the mRNA and protein levels in bone tumor cells and normal cells. Compared with the normal cells, the expression of MAPK/P53 and FASN mRNA was significantly elevated, whereas inhibition of MAPK/P53 decreased FASN expression. Similarly, the expression of FASN and MAPK/P53 proteins were significantly elevated in the bone tumor cells and treatment with the MAPK/P53 inhibitor decreased the expression of FASN. To determine the role of MAPK/P53 in cell proliferation, bone cancer cells were treated with MAPK/P53 inhibitor and the results showed a reduced proliferation rate. Thus, FASN promotes the development of bone tumors and MAPK/P53 signaling contributes to bone tumors by upregulating the expression of FASN. PMID- 28588695 TI - Canonical and alternative transcript expression of PAX6 and CXCR4 in pancreatic cancer. AB - Pancreatic cancer is a lethal disease with a propensity for invading and metastasizing into the surrounding tissues, including the liver and intestines. A number of factors are aberrantly overexpressed in this tumor type and actively promote cancer progression and metastasis. The present study demonstrates that paired box transcription factor 6 (PAX6) and C-X-C chemokine receptor 4 (CXCR4) are frequently co-expressed in primary pancreatic adenocarcinoma tumors and established cell lines. Expression analysis methods used in the present study included evaluation of protein expression by western blot analysis and immunofluorescence, transcript expression levels by reverse transcription quantitative polymerase chain reaction (RT-qPCR), and luciferase assays utilizing regulatory elements from the CXCR4 gene locus. Canonical PAX6 and alternative splice variant PAX6(5a) proteins are expressed in pancreatic cancer and can drive gene expression through a conserved enhancer element within the first intron of the CXCR4 gene. As demonstrated by the introduction of an exogenous reporter construct with or without the intronic enhancer, loss of this element inhibited gene expression within numerous pancreatic cancer cell lines including Panc1, MIA PaCa2 and BxPC3. All of the pancreatic cancer cell lines expressed the canonical CXCR4B transcript in addition to the alternatively spliced variant CXCR4A as determined by RT-qPCR experiments. The discovery of variant transcripts in pancreatic cancer cells may provide new candidates for future targeted therapies. PMID- 28588697 TI - MicroRNA-18a inhibits ovarian cancer growth via directly targeting TRIAP1 and IPMK. AB - The role of microRNA-18a (miRNA/miR-18a) as a tumor suppressor or promoter in a number of different types of cancer has been reported. However, to date, the expression and the effects of miR-18a in epithelial ovarian cancer (EOC) remain elusive. In the present study, the expression of miR-18a in patient EOC tissues and ovarian cancer cell lines was investigated using the reverse transcription quantitative polymerase chain reaction. Luciferase assays and western blotting were performed to detect the potential direct targets of miR-18a. An A2780cp intraperitoneal mouse model, and Cell Counting Kit 8, flow cytometry and terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling assays, were used to investigate the effect of miR-18a on tumor growth in vivo and in vitro. The results indicated that the expression of miR-18a was reduced in EOC tissue and in the investigated ovarian cancer cell lines compared with non-malignant (normal) ovarian tissues and the human ovarian epithelium cell line, respectively. Overexpression of miR-18a in the A2780s and A2780cp cell lines significantly induced cell cycle arrest and apoptosis. It was demonstrated that miR-18a directly targets tumor protein p53-regulating inhibitor of apoptosis gene 1 and inositol phosphate multikinase, hence regulating the expression of downstream targets. The A2780cp intraperitoneal mouse model was employed and the results indicated that miR-18a may inhibit A2780cp intraperitoneal tumor growth in vivo by inhibiting proliferation and inducing apoptosis. Together, the results of the present study demonstrated that miR-18a has a role as a tumor suppressor by inhibiting proliferation and inducing apoptosis. Assessment of miR-18a expression may provide a novel method for diagnosis and be a therapeutic target for EOC. PMID- 28588699 TI - Irradiation of peripheral blood mononuclear cells with 7.5 Gy X-rays prior to donor lymphocyte infusion inhibits proliferation while preserving cytotoxicity, and improves the effectiveness of HSCT in patients with hematological malignancies. AB - The aim of the present study was to explore the effect of different X-ray doses on the proliferation and cytotoxic activity of peripheral blood mononuclear cells (PBMCs), particularly lymphocytes, in order to assess whether this reduces the incidence of graft vs. host disease (GVHD) while preserving the graft vs. tumor (GVT) effect in patients with hematological malignancies following hematopoietic stem cell transplantation (HSCT). PBMCs from healthy donors were irradiated with X-rays at doses of 0, 2.5, 5, 7.5, 10, 15, 25 or 50 Gy, and their proliferative activity was determined using a WST-8 assay kit. The cytotoxic activity of non irradiated PBMCs and PBMCs irradiated with 7.5 Gy X-rays was tested in the leukemic cell line K562 and its Adriamycin-resistant strain K562A using a lactate dehydrogenase assay. The clinical data of 7 patients who received 7.5 Gy X-ray irradiated PBMC infusions following autologous HSCT were analyzed. PBMCs irradiated with >=7.5 Gy X-rays exhibited a complete inhibition of proliferation. PBMCs irradiated with 7.5 Gy X-rays exhibited significantly increased cytotoxic activity towards K562 cells compared with K562A cells (P<0.05). There was no significant difference in cytotoxicity between irradiated and non-irradiated PBMCs, irrespective of the target cell, K562 or K562A (P>0.05). Based on the in vitro data, clinical data from patients who received 7.5 Gy X-ray-irradiated PBMC infusions following HSCT between January 2005 and January 2013 were assessed retrospectively. A total of 7 patients were included in the current study. The majority achieved various degrees of remission following donor lymphocyte infusion (DLI) and none suffered from GVHD. This indicates that 7.5 Gy-irradiated PMBCs have a potential application in DLI for the treatment of patients following HSCT. However, further studies on larger patient cohorts are required to assess the clinical potential of 7.5 Gy-irradiated PBMCs for preserving the GVT effect while avoiding GVHD following HSCT. PMID- 28588698 TI - Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer. AB - 17beta-estradiol (E2) can contribute to the progression of epithelial ovarian cancer (EOC). Although the majority of patients with EOC are postmenopausal woman, when de novo estrogen production in the ovary has ceased, ovarian cancer cells remain exposed to estrogens synthesized locally in the cancer cells from inactive sulfonated steroid hormone precursors-such as estrone sulfate taken up from the circulation via the sulfatase pathway. An abundance of the estrogen modifying enzymes, including estrogen-activating steroid sulfatase (STS) and estrogen-inactivating estrogen-sulfotransferase (SULT1E1), is important for providing active estrogen to EOC cells. Therefore, the present study determined the levels of SULT1E1, STS and estrogen receptor alpha (ERalpha) protein in paraffin-embedded specimens from 206 patients with Federation of Gynecology and Obstetrics stage II-IV EOC treated with debulking surgery and standard platinum based adjuvant chemotherapy. The levels of STS, SULT1E1 and ERalpha were assessed by automated quantitative microscopy-based image analysis subsequent to immunohistochemical staining. Significantly higher SULT1E1 levels were observed in better differentiated EOC tumors compared to grade 3 EOC tumors (P=0.001). STS and SULT1E1 levels were positively associated with ERalpha abundance (P<0.001 and P=0.001, respectively). In advanced stage high-grade serous EOC (HGSOC; n=132), the most frequent and lethal type of ovarian cancer, SULT1E1 expression was significantly associated with a better overall survival rate (hazard ratio 0.66, 95% confidence interval, 0.45-0.94; P=0.005). These results highlight the importance of SULT1E1-mediated estrogen inactivation in EOC, particularly HGSOC. Therefore, targeting the sulfatase pathway is a potential endocrine therapeutic intervention for certain patients with estrogen-responsive EOC. PMID- 28588700 TI - Relationship between DLK1 gene promoter region DNA methylation and non-small cell lung cancer biological behavior. AB - We investigated the possible association between DLKI gene promoter region methylation and the increased invasion capacity of non-small cell lung cancer (NSCLC). Lung cancer cell line H1299, as well as the gene transfection and RNA interference technology were used to build DLK gene overexpression and knockdown cells. An in vitro invasion assay was performed to observe the changes in the invasion ability of lung cancer cells. Western blot analysis was used to verify Notchl and matrix metalloproteinase-9 (MMP-9) expression levels and a sulfurous acid sequencing technique was used to test the DNA methylation level in the promoter region. Our results showed that the invasion ability of cells in the overexpression group was significantly enhanced. This ability was considerably reduced in the knockdown group. The Notchl and MMP-9 expression level increased significantly in the overexpression group, while it was reduced considerably in the knockdown group. We detected significantly lower levels of DNA methylation in the promoter region in the overexpression group. It was concluded that methylation of the DLK1 gene promoter region increased the invasion ability of NSCLC. Furthermore, it is possible that this process is related to the Notch signaling pathway. PMID- 28588701 TI - Aberrant expression of AID and AID activators of NF-kappaB and PAX5 is irrelevant to EBV-associated gastric cancers, but is associated with carcinogenesis in certain EBV-non-associated gastric cancers. AB - Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric cancer characterized by clinicopathological features including lymphoepithelioma-like histology. Aberrant expression of activation-induced cytidine deaminase (AID) as a genomic modulator was demonstrated through pathogen related nuclear factor kappaB (NF-kappaB) signaling in Helicobacter pylori associated gastric cancer. To elucidate whether or not AID expression is relevant to carcinogenesis in EBVaGC, immunohistochemical expression of AID and AID regulatory factors between EBVaGC and EBV-non-associated gastric carcinoma (GC) were evaluated, each using 15 cases of GC with lymphoid stroma (GCLS) and other types of GC. Aberrant expression of AID, NF-kappaB and paired box 5 (PAX5) were significantly decreased in EBVaGC (0/11, 1/11 and 1/11) compared with in EBV-non associated GC (7/19, 12/19 and 11/19) (P=0.025, 0.005 and 0.01, respectively); however, no significant difference in c-Myb proto-oncogene expression was identified. AID expression was also decreased in EBV-associated GCLS (0/10) compared with in EBV-non-associated GCLS (3/5). Unexpectedly, decreased expression of NF-kappaB and PAX5 was observed in GCLS (1/15 and 2/15) compared with in GC without LS (12/15 and 10/15) (P<0.001 and P=0.003, respectively). Decreased AID expression observed in EBVaGC is consistent with the reported molecular characterization of hypermethylation and rare somatic gene mutation in EBVaGC. Only PAX5 was identified to be significantly associated with venous invasion (P=0.022). The results of the present study suggest that pathogen induced AID expression may be irrelevant to carcinogenesis of EBVaGC, whereas it contributes to carcinogenesis in certain types of EBV-non-associated GC. PMID- 28588702 TI - miR-564 is downregulated in gastric carcinoma and targets E2F3. AB - Numerous aberrantly expressed microRNAs (miRNAs/miRs) have been identified in gastric cancer (GC); however, only a fraction of these have been functionally investigated and novel deregulated miRNAs in GC remain to be explored. Through examining two public miRNA expression profile datasets, the present study identified aberrantly expressed miRNAs in GC. One of these miRNA, miR-564, was identified to be downregulated in GC, which was validated in tissue samples from patients with GC by reverse transcription-quantitative polymerase chain reaction analysis. Targets of miR-564 were then predicted bioinformatically, including transcription factor E2F3 (E2F3), which was identified to be functionally enriched in several cancer signaling pathways. Furthermore, overexpression of miR 564 decreased the activity of a luciferase reporter carrying the 3'-untranslated region of E2F3, in addition to the mRNA and protein level of E2F3, indicating that miR-564 directly targets E2F3. These data suggest that by targeting E2F3, miR-564 may act as a tumor suppressor gene in gastric carcinogenesis. PMID- 28588703 TI - Decreased expression of insulin-like growth factor binding protein 6 is associated with gastric adenocarcinoma prognosis. AB - The present study aimed to investigate the expression and prognostic significance of insulin-like growth factor binding protein 6 (IGFBP-6) in gastric adenocarcinoma. The expression of IGFBP-6 was examined in 263 specimens from gastric adenocarcinoma patients using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and immunohistochemical (IHC) staining. The association between IGFBP-6 expression, clinicopathological factors and clinical outcomes was investigated. Akaike information criterion (AIC) and Harrell's concordance index (c-index) were used to evaluate the accuracy of the predictive prognosis. RT-qPCR and western blotting results showed that IGFBP-6 mRNA expression was lower in the tumors compared with that in adjacent non-tumor tissues. IGFBP-6 showed significantly decreased expression in 170 out of 263 patients based on IHC data and this was associated with a larger tumor size (P<0.001) and poorly-differentiated adenocarcinoma (P=0.001), as well as with palliative gastrectomy (P=0.015). Additionally, decreased expression of IGFBP-6 was associated with stage T3/4a/4b disease and lymph node-positive metastasis (P<0.001). The association between decreased expression and a poor prognosis was revealed by Kaplan-Meier curves. Cox regression model identified IGFBP-6 as an independent prognostic factor. The prognostic value of the model with IGFBP-6 expression (AIC, 924.881; c-index, 0.878) was superior to that without IGFBP-6 expression (AIC, 947.164; c-index, 0.825). In conclusion, IGFBP-6 involves the development and progression of gastric adenocarcinoma, and its decreased expression predicts poor clinical outcomes. PMID- 28588704 TI - Ell3 stimulates 5-FU resistance in a breast cancer cell line. AB - Ell3 is an RNA polymerase II transcription elongation factor that acts as a negative regulator of p53 expression, and regulates cell proliferation and survival. Recent studies by our group have demonstrated that ectopic expression of Ell3 in breast cancer cell lines enhances cell proliferation, potentiates cancer stem cell properties, and promotes 5-Fluorouracil (5-FU) resistance. In the present study, the underlying mechanism for the induction of 5-FU resistance was investigated in Ell3 over-expressing MCF-7 cells (Ell3 OE cells). By comparing the gene expression profiles of Ell3 OE cells with control cells, the present data revealed that Lipocalin2 (LCN2) and Wnt signaling activity are associated with 5-FU resistance of Ell3 OE. siRNA-mediated suppression of LCN2 reversed 5-FU resistance in Ell3 OE cells. Chemical inhibition of Wnt signaling also reversed 5-FU resistance in Ell3 OE cells. Furthermore, the expression levels of survivin, which is a direct transcriptional target of Wnt/beta-catenin and an inhibitor of apoptosis, were markedly elevated when Ell3 OE cells were treated with 5-FU, as detected by western blot analysis. These findings suggest that enhanced expression of LCN2 and activation of the Wnt signaling pathway may induce 5-FU resistance in Ell3 OE cells as a means of evading apoptosis. PMID- 28588705 TI - GALNT14 genotype is associated with perineural invasion, lymph node metastasis and overall survival in resected cholangiocarcinoma. AB - Cholangiocarcinoma is a rare, sporadic and aggressive type of cancer. The genetic basis of cholangiocarcinoma remains poorly understood. The present study investigated the prognostic role of the N-acetylgalactosaminyltransferase 14 (GALNT14)-rs9679162 genotype, an effective therapeutic response predictor for hepatocellular carcinoma in patients with cholangiocarcinoma receiving surgical resection. A cohort of patients with intrahepatic or perihilar cholangiocarcinoma (n=112) were retrospectively recruited. Of these patients, 31.3, 49.1 and 19.6% had GALNT14 'TT', 'TG' and 'GG' genotypes, respectively. The patient's genotype distributions did not deviate significantly from those of the ethnic reference cohorts, HapMap-Chinese Han Beijing and Chinese Han Metropolitan Denver. The genotype 'TT' was associated with unfavorable overall survival in univariate analysis (P=0.023). Furthermore, two tumor characteristics, perineural and vascular invasion, were independently associated with unfavorable overall survival (P=0.001 and P=0.002, respectively). The 'TT' genotypes were independently associated with two known predictors of unfavorable prognosis, perineural invasion (P=0.035) and lymph node metastasis (P=0.005) in a multivariate linear regression analysis. When compared with the two reference genotype cohorts, the 'TT' genotype was significantly higher in patients with perineural invasion (P=0.049, Beijing cohort; P=0.034, Denver cohort). Similar enrichment of the 'TT' genotype was also revealed in patients with lymph node metastasis (P=0.046, Beijing cohort; P=0.032 Denver cohort). In conclusion, the GALNT14-rs9679162 'TT' genotype was associated with perineural invasion and lymph node metastasis, as well as unfavorable overall survival in patients with resected cholangiocarcinoma. PMID- 28588706 TI - IL-17A promotes the proliferation of human nasopharyngeal carcinoma cells through p300-mediated Akt1 acetylation. AB - Interleukin (IL)-17A is a T helper (Th)17 cell-secreted cytokine that is able to induce various inflammatory responses. There is emerging evidence that IL-17A is generated in the cancer microenvironment of human nasopharyngeal carcinoma (NPC). However, the role of IL-17A in NPC remains unclear. Thus, the present study aimed to examine the direct influence of IL-17A stimulation on the proliferation of human NPC cells and identify the underlying molecular mechanisms. Furthermore, E1A binding protein p300 (p300)-mediated AKT serine/threonine kinase 1 (Akt1) acetylation and its role in regulating the proliferation of NPC cells was investigated. The results of the current study demonstrated that IL-17A stimulation in vitro increased the proliferation of human NPC cells. Furthermore, Akt1 acetylation was identified to be enhanced in human NPC cells induced by IL 17A. Additionally, p300 induction was demonstrated to be required for Akt1 acetylation in human NPC cells following exposure to IL-17A. Functionally, p300 mediated Akt1 acetylation contributed to the proliferation of human NPC cells stimulated by IL-17A. In conclusion, the results of the present demonstrate a novel activity of IL-17A that promotes human NPC cell proliferation via p300 mediated Akt1 acetylation. This may provide a potential strategy for the treatment of patients with NPC through the inhibition of IL-17A or its receptors. PMID- 28588707 TI - Identification of potential target genes associated with the effect of propranolol on angiosarcoma via microarray analysis. AB - The purpose of the present study was to explore the effect of propranolol on angiosarcoma, and the potential target genes involved in the processes of proliferation and differentiation of angiosarcoma tumor cells. The mRNA expression profile (GSE42534) was downloaded from the Gene Expressed Omnibus database, including three samples without propranolol treatment (control), three samples with propranolol treatment for 4 h and three samples with propranolol treatment for 24 h. The differentially expressed genes (DEGs) in angiosarcoma tumor cells with or without propranolol treatment were obtained via the limma package of R and designated DEGs-4 h and DEGs-24 h. The DEGs-24 h group was divided into two sets. Set 1 contained the DEGs also contained in the DEGs-4 h group. Set 2 contained the remainder of the DEGs. Functional and pathway enrichment analysis of sets 1 and 2 was performed. The protein-protein interaction (PPI) networks of sets 1 and 2 were constructed, termed PPI 1 and PPI 2, and visualized using Cytoscape software. Modules of the two PPI networks were analyzed, and their topological structures were simulated using the tYNA platform. A total of 543 and 2,025 DEGs were identified in angiosarcoma tumor cells treated with propranolol for 4 and 24 h, respectively, compared with the control group. A total of 401 DEGs were involved in DEGs-4 h and DEGs-24 h, including metallothionein 1, heme oxygenase 1, WW domain-binding protein 2 and sequestosome 1. Certain significantly enriched gene ontology (GO) terms and pathways of sets 1 and 2 were identified, containing 28 overlapping GO terms. Furthermore, 121 nodes and 700 associated pairs were involved in PPI 1, whereas 1,324 nodes and 11,839 associated pairs were involved in PPI 2. A total of 45 and 593 potential target genes were obtained according to the node degrees of PPI 1 and PPI 2. The results of the present study indicated that a number of potential target genes, including AXL receptor tyrosine kinase, coatomer subunit alpha, DR1 associated protein 1 and ERBB receptor feedback inhibitor 1 may be involved in the effect of propranolol on angiosarcoma. PMID- 28588709 TI - Growth inhibition of human breast carcinoma cells by overexpression of regulator of G-protein signaling 4. AB - Breast cancer remains the second largest cause of mortality in women with cancer and does not respond well to conventional therapies. Regulator of G-protein signaling 4 (RGS4) is a GTPase-activating protein of the heterotrimeric Gq and Gi proteins. Altered levels of RGS4 are reportedly linked with several human diseases, including cancer. The present study investigated whether overexpression of RGS4 inhibited the growth of human breast cancer cells. Protein expression was investigated by western blot analysis. Cell viability and apoptosis were analyzed by MTT assay and flow cytometric analysis, respectively. Cell cycle analysis was performed using propidium iodide staining in order to examine the anti proliferative function of increased RGS4 levels. Next, changes in the expression levels of G2/M cell cycle-related proteins were examined. Overexpression of RGS4 led to the upregulation of phosphorylayed (p)-Ser216 cell division cycle (Cdc)25C and p-Tyr15 Cdc2. Importantly, MG132-induced proteasome blockade prevented degradation of RGS4. Suppression of proliferation was associated with G2/M-phase cell cycle arrest. Furthermore, enhanced endogenous RGS4 protein levels significantly inhibited breast cancer cell growth, which was reversed by a pharmacological inhibitor of RGS4. Taken together, these results suggest that overexpression of RGS4 in human breast cancer cells by molecular means may offer a potential therapeutic approach. PMID- 28588710 TI - The clinical analysis of small supernumerary marker chromosomes in 17 children with mos 45,X/46,X,+mar karyotype. AB - Small supernumerary maker chromosome (sSMC) is a type of structurally abnormal chromosome. In order to identify the origin, morphology and other characteristics of sSMCs in children with mos 45,X/46,X,+mar karyotype, 17 patients (16 females and 1 male) were analyzed. All patients underwent general physical examination, gonadal imaging and molecular cytogenetic analyses, including Giemsa banding, dual-color fluorescence in situ hybridization and detection of the sex determining region Y gene by polymerase chain reaction. Cytogenetic analyses indicated sSMCs in 14/17 cases were derived from the X chromosome, of which 8 individuals presented with ring-shaped sSMCs and 6 with centric minute-shaped sSMCs. The remaining 3 cases were derived from the Y chromosome, and all presented with minute-shaped sSMCs. All female patients exhibited short stature, gonadal dysgenesis and other typical features of Turner syndrome. The male patient exhibited short stature, hypospadias and bilateral cryptorchidism. In conclusion, the majority of the sSMCs in patients with a mos 45,X/46,X,+mar karyotype were derived from the sex chromosomes. The molecular cytogenetic features of sSMCs may provide useful information for genetic counseling, prenatal diagnosis and individualized treatment. PMID- 28588708 TI - Indolent growth of low-grade myofibroblastic sarcoma of the cheek mimics benign lesions: A case report and literature review. AB - Low-grade myofibroblastic sarcoma (LGMS) is a neoplasm of the soft tissue characterized by myofibroblastic differentiation. This type of tumor has been observed in various sites in the whole body, but frequently occurs in the head and neck region. It typically presents as a slow-growing painless mass, which is often mistaken for a benign lesion due to its indolent growth; however, LGMS is a malignant neoplasm. In the present study, a 43-year-old female presented with a 14-mm LGMS lesion in the buccal subcutaneous tissues of the buccinator muscle. The patient had initially noticed the lesion 2-months prior to presenting at the hospital. Following biopsy, the tumor was surgically resected and no recurrence or metastasis was observed during a follow-up time of 2 years. To the best of our knowledge, this case is the first report of LGMS located in the buccal subcutaneous tissue of the buccinator muscle. The present study a literature review of 55 cases of this tumor type in the head and neck region was conducted, revealing that the indolent growth of these lesions may contribute to a delay in diagnosis. The average time between the onset of clinical symptoms and hospital admission is 3.9 months, and this form of tumor is frequently misdiagnosed as a benign lesion. Therefore, the present study suggests that an incisional biopsy may be performed to rule out LGMS when clinicians encounter patients with the aforementioned indolent lesions anywhere in the body. In addition, the avoidance of radiotherapy is recommended following resection of the LGMS tumor, as it may induce LGMS recurrence. PMID- 28588711 TI - Overexpression of microRNA-96-5p inhibits autophagy and apoptosis and enhances the proliferation, migration and invasiveness of human breast cancer cells. AB - MicroRNAs (miRNA/miR) are short non-coding RNAs that function in the endogenous regulation of genes. miRNAs serve important roles in cellular events such as apoptosis, cell proliferation, migration, invasion, autophagy and the cell cycle. They also control the genesis and progression of tumors. Autophagy is a self digestive process that occurs as a response to stress, and serves two opposite roles in tumor promotion or inhibition that may result in resistance to therapy. A number of studies have revealed that miRNAs control autophagic activity by targeting autophagy-associated genes, particularly in cancer. These previous studies demonstrated that miR-96-5p is upregulated in several types of malignant tumors. However, other functions of miR-96-5p in breast cancer, particularly those that are associated with autophagy, remain unknown. miR-96-5p expression was demonstrated to be upregulated in breast cancer cells compared with in normal breast epithelial cells. The overexpression of miR-96-5p inhibited autophagy, particularly starvation-induced autophagy, in MCF-7 and MDA-MB-231 cells. In addition, this inhibitory effect may have resulted in the suppression of Forkhead box O1. Additionally, the overexpression of miR-96-5p may promote cell proliferation, migration and invasion and inhibit apoptosis in MCF-7 and MDA-MB 231 cells. These data indicate that miR-96-5p is involved in the progression of breast cancer cells and may represent a potential therapeutic target for the treatment of breast cancer. PMID- 28588712 TI - Maximum standardized uptake value on FDG-PET predicts survival in stage I non small cell lung cancer following carbon ion radiotherapy. AB - The present study (University Hospital Medical Information Network study no. UMIN000003797) aimed to evaluate whether the maximum standardized uptake value (SUVmax) of pretreatment 18F-fluorodeoxyglucose-positron emission tomography (FDG PET) is prognostic factor for stage I non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy (C-ion RT). Patients treated between June 2010 and June 2013 at Gunma University Heavy Ion Medical Center (Maebashi, Japan) on a prospective protocol were included in the present study. Patients with T1a-b and T2a NSCLC were treated with C-ion RT at a dose of 52.8 Gy [relative biological effectiveness (RBE)] and 60.0 Gy (RBE), respectively, in four fractions. Prior to treatment, all patients underwent FDG-PET, in which the SUVmax of primary tumors was evaluated. Local control, progression-free survival (PFS), and overall survival (OS) were calculated. A total of 45 patients were analyzed and the median follow-up period was 28.9 months. The 2-year local control, PFS and OS rates for all patients were 93, 78 and 89%, respectively. The mean SUVmax of primary tumors was 5.5, and patients were divided into higher (>=5.5) and lower (<5.5) SUVmax groups. The 2-year PFS rates were 61 and 89% for the higher and lower SUVmax groups, respectively (P=0.01), and the 2-year OS rates for the higher and lower SUVmax groups were 76 and 96%, respectively (P=0.01). The higher SUVmax group exhibited a significantly worse PFS and OS compared with the lower SUVmax group; however, the SUVmax was not associated with the local control rate. In total, 2 patients (4%) experienced grade 2 or 3 radiation pneumonitis, with their symptoms improved through conservative treatment. No patients experienced any grade 4 or 5 toxicities. The results of the present study indicate that pretreatment SUVmax is a prognostic indicator for outcomes in patients with stage I NSCLC treated with C-ion RT. PMID- 28588714 TI - Oxymatrine inhibits proliferation of human bladder cancer T24 cells by inducing apoptosis and cell cycle arrest. AB - Oxymatrine has been shown to exert an antitumor effect on several types of cancer cells. However, the role of oxymatrine in bladder cancer has not yet been evaluated. The present study was designed to investigate the potential anti proliferative effect of oxymatrine on bladder cancer T24 cells and the possible mechanisms involved. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell growth, and the cell morphology was examined using hematoxylin and eosin staining, wrights' staining and electron microscopy. The caspase-3 and survivin mRNA and protein levels were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The expression of tumor protein p53 (p53), Bcl-2 associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) were analyzed using immunohistochemistry. Oxymatrine inhibited the proliferation of the T24 cells in a dose- and time-dependent manner. Oxymatrine also induced apoptosis and cell cycle arrest in the cells, in association with the upregulation of caspase-3 and Bax, and the downregulation of survivin, Bcl-2 and p53 expression. Overall, oxymatrine inhibits the proliferation of human bladder cancer cells by inducing apoptosis and cell cycle arrest via mechanisms that involve p53-Bax signaling and the downregulation of survivin expression. PMID- 28588713 TI - Neoadjuvant chemotherapy in borderline resectable pancreatic cancer: A case report. AB - Pancreatic cancer is the fourth leading cause of cancer mortality and is associated with a poor overall survival even when diagnosed early and considered resectable. Complete surgical removal with negative histological margins is an independent predictor of survival and remains the only potential curative treatment. In borderline resectable pancreatic adenocarcinoma (BRPAC), preoperative systemic therapy may increase resectability and margin-negative resection rate. There is no current consensus on the optimal chemotherapy regimen for BRPAC. The present case describes a patient with BRPAC who achieved a pathological complete response to neoadjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin), but early relapse following a pancreaticoduodenectomy without vascular resection, with an uneventful postoperative course, except for a pulmonary embolism. PMID- 28588715 TI - AURKA mRNA expression is an independent predictor of poor prognosis in patients with non-small cell lung cancer. AB - Deregulation of mitotic spindle genes has been reported to contribute to the development and progression of malignant tumours. The aim of the present study was to explore the association between the expression profiles of Aurora kinases (AURKA, AURKB and AURKC), cytoskeleton-associated protein 5 (CKAP5), discs large associated protein 5 (DLGAP5), kinesin-like protein 11 (KIF11), microtubule nucleation factor (TPX2), monopolar spindle 1 kinase (TTK), and beta-tubulins (TUBB) and (TUBB3) genes and clinicopathological characteristics in human non small cell lung carcinoma (NSCLC). Reverse transcription-quantitative polymerase chain reaction-based RNA gene expression profiles of 132 NSCLC and 44 adjacent wild-type tissues were generated, and Cox's proportional hazard regression was used to examine associations. With the exception of AURKC, all genes exhibited increased expression in NSCLC tissues. Of the 10 genes examined, only AURKA was significantly associated with prognosis in NSCLC. Multivariate Cox's regression analysis demonstrated that AURKA mRNA expression [hazard ratio (HR), 1.81; 95% confidence interval (CI), 1.16-2.84; P=0.009], age (HR, 1.03; 95% CI, 1.00-1.06; P=0.020), pathological tumour stage 2 (HR, 2.43; 95% CI, 1.16-5.10; P=0.019) and involvement of distal nodes (pathological node stage 2) (HR, 3.14; 95% CI, 1.24 7.99; P=0.016) were independent predictors of poor prognosis in patients with NSCLC. Poor prognosis of patients with increased AURKA expression suggests that those patients may benefit from surrogate therapy with AURKA inhibitors. PMID- 28588716 TI - Low expression of miR-1469 predicts disease progression and unfavorable post surgical clinical outcomes in patients with esophageal squamous cell cancer. AB - Recent studies have demonstrated that deregulated microRNA (miRNA/miR) expression has a profound impact on biological and pathological processes; abnormal miR-1469 expression was detected in several human malignancies. In the present study, the clinicopathological and prognostic significance of miR-1469 was assessed in 129 patients with esophageal squamous cell cancer (ESCC) who successfully underwent esophagectomy and esophagogastrostomy. Low miR-1469 expression was identified to be significantly associated with tumor invasion depth (P=0.026), lymph node metastasis status (P<0.001) and pathological tumor stage (P<0.001). Survival analysis demonstrated that patients with low miR-1469 expression had significantly poorer disease-free survival (DFS) (18.2 vs. 43.2%; P=0.004) and overall survival (29.1 vs. 47.3%; P=0.029) 5 years following surgery compared with patients with high miR-1469 expression. Univariate survival analysis demonstrated that low miR-1469 expression significantly predicted unfavorable 5 year DFS among patients with N1-3 disease (7.1 vs. 31.8%; P=0.043). The results from the present study indicate that miR-1469 expression could be used in the clinic to predict ESCC progression and prognosis. This will aid in the identification of high-risk patients with ESCC that require more aggressive therapeutic interventions. PMID- 28588718 TI - Renal cell carcinoma with synchronous ipsilateral urothelial carcinoma of the renal pelvis. AB - The simultaneous occurrence of renal cell carcinoma (RCC) and urothelial carcinoma (UC) in the same kidney is extraordinarily rare, and is also known as multiple primary malignant tumors. The present study reports the case of a 76 year-old female with synchronous ipsilateral RCC and UC of the renal pelvis, who underwent operation, chemotherapy and reoperation when recurrence of RCC or UC was identified. Cluster of differentiation 44 (CD44) is one of the promising markers for identifying cancer stem cells in various solid tumors, along with aldehyde dehydrogenase 1 A1 (ALDH1A1). Detection of CD44 and ALDH1A1 prior to and subsequent to chemotherapy could provide useful prognostic information. New treatments against the cancer stem cells fraction should be used in combination with chemotherapy to improve the outcome for patients with overexpression of CSC markers. PMID- 28588717 TI - lncRNA C22orf32-1 contributes to the tumorigenesis of nasopharyngeal carcinoma. AB - The mechanism of nasopharyngeal carcinoma (NPC) remains unclear. The present study investigated the abnormal expression of long non-coding (lnc)RNAs in NPC tissues and one NPC cell line to identify the involvement of lncRNAs in the tumorigenesis of NPC. Using a quantitative reverse transcription polymerase chain reaction (RT-qPCR), the expression of lncRNA C22orf32-1 in NPC tissues and an NPC cell line was verified. The effects of lncRNA C22orf32-1 on NPC cells were investigated with a cell proliferation assay, cell scratch assay, Transwell assay and a cell apoptosis assay. The expression levels of lncRNA C22orf32-1 in NPC tissues and an NPC cell line were upregulated. lncRNA C22orf32-1 promoted the proliferation, migration and invasion of NPC cells, and reduced the apoptosis of NPC cells. The data demonstrated that lncRNA C22orf32-1 may facilitate the tumorigenesis of NPC, and may be used for the early diagnosis and treatment of NPC. PMID- 28588719 TI - E-cadherin: A potential biomarker of colorectal cancer prognosis. AB - Colorectal cancer (CRC) is a common and lethal disease. It is the third most common type of cancer in the world, behind lung and breast cancer, with almost 1.4 million new cases diagnosed in 2012. The risk of developing CRC is influenced by environmental and genetic factors. Adenocarcinomas comprise the vast majority (98%) of CRCs. A patient's likelihood of survival is associated with the tumor stage at the time of diagnosis. With regular screening, CRC can be identified early, when treatment is the most effective. However, CRC is typically asymptomatic until the advanced stages. The combination of the absence of symptoms and current screening methodology results in a significant number of patients being diagnosed in advanced stages. The purpose of the present review is to discuss and summarize the biomarkers linked to CRC progression, particularly the controversial E-cadherin, which is a calcium-dependent cell-cell adhesion molecule involved in the mesenchymal-epithelial transition. PMID- 28588720 TI - Synergistic activity of the histone deacetylase inhibitor trichostatin A and the proteasome inhibitor PS-341 against taxane-resistant ovarian cancer cell lines. AB - Although a combination of platinum- and taxane-based chemotherapy is recommended for at least 70% patients with ovarian cancer as treatment subsequent to surgery, the initial response to the chemotherapy is not durable and tumors become resistant. Histone deacetylase and proteasome inhibitors are novel therapeutic agents. However, the moderate antitumoral effect of the inhibitors has restricted their clinical use when used as single agents. The aim of the present study was to investigate the synergistic activity of trichostatin A (TSA) and PS-341 in ovarian cancer cells, along with the investigation of the molecular mechanisms of taxane resistance. The taxane-sensitive ovarian cancer A2780 cell line and its resistant variant, A2780T, were treated with taxane, TSA and PS-341 at various concentrations. An Annexin V assay was performed to determine the levels of cell viability and apoptosis, while flow cytometry and immunofluorescence staining for the mitotic phase-specific protein phosphorylated-histone H3 (Ser10) were used for cell cycle detection. The effects of combined TSA and PS-341 on cell cycle associated proteins were tested by western blot analysis. Furthermore, the present study examined the apoptosis and cell cycle arrest induced by the 3 agents subsequent to overexpression or downregulation of cyclin B1 in A2780 and A2780T cells, respectively. It was found that TSA interacted synergistically with PS-341, resulting in a marked increase in apoptosis and the rate of G2/M arrest in A2780T cells. A lower basal level of cyclin B1 expression and the incompetence of the upregulation of the cyclin may explain the taxane resistance found in A2780T cells. Collectively, the combination of TSA and PS-341 increased cyclin B1 expression level regardless of the basal expression level, resulting in the proliferation inhibition and apoptosis in A2780 and A2780T cells, which raised the possibility that a combination of the two drugs may represent a novel strategy for the treatment of ovarian cancer, particularly in taxane-resistant ovarian cancer. PMID- 28588721 TI - Palliative treatment of patients with inoperable locally advanced, recurrent or metastatic head and neck squamous cell cancer, using a low-dose and personalized chemotherapeutic regimen. AB - Inoperable or metastatic head and neck squamous cell cancer (HNSCC) is known to be associated with a poor patient prognosis. First line therapies include a Taxol, platinum-based antineoplastic and fluorouracil (FU) treatment regimen (TPF) or a platinum-based antineoplastic, FU and EGFR inhibitor treatment regimen (PFE). The toxicity of these regimens is one of the major limiting factors, particularly for palliative treatment. The present study is a retrospective study of 15 patients with HNSCC, where the treatment goal was palliative. Of the 15 patients, 8 received a TPF, while 7 received a PFE. A total of 129 treatment cycles were administered with a median of 9 cycles (range, 3-14). Chemotherapy began with low doses and was subsequently titrated up based on tolerance and response. Positive responses were noted with the lower doses compared with the conventional doses, and maximal doses were not required. The median dose of cisplatin, paclitaxel and 5-FU administered was 40 mg/m2, 80 mg/m2 and 360 mg/m2/day for 5 days, respectively. Cetuximab was used at a standard dose. At the initial follow-up (mean, 64 days; 3 cycles), a 100% disease control rate (DCR) and 80% overall response rate (ORR) was achieved. A positive response, 60% DCR and 60% ORR, was maintained until the late stages of the study (mean, 217 days; 9 cycles). Following termination of chemotherapy after >9 cycles, 4 patients remained disease free for ~1 year. A total of 3 patients exhibited a pathologic complete response despite radiologically exhibiting residual disease. The median progression-free survival time was 10.03 months and the overall survival time was 15.77 months. The only grade 3 hematologic toxicity noted was neutropenia in 3 (20%) patients. Grade 3 vomiting was noted in 1 (6.67%) patient and grade 3 stomatitis was noted in 1 (6.67%) patient. Due to low toxicity patients exhibited improved tolerance to this approach, particularly in terms of palliative care. Furthermore, these results are in contrast to the axiom that increased doses are more effective. PMID- 28588722 TI - MED23 in endocrinotherapy for breast cancer. AB - We investigated the role of the transcriptional mediator subunit 23 (MED23) in everolimus drug resistance, invasion and metastasis during breast cancer treatment and its molecular mechanism. We also evaluated the endocrinotherapy and prevention method for breast cancer. Breast cancer cell strains were established that can continuously express MED23, as well as inducible MED23-shRNA expression plasmids. The inductive agent, doxycycline (Dox), was added to the water for long term silencing of MED23 in intratumoral cells. We conducted experiments on the role of MED23 in the regulation of invasion and metastasis of breast cancer using cell culture, western blotting, MTT proliferation experiment, fluorescent quantitative PCR and chromatin immunoprecipitation (ChIP). The silencing of MED23 significantly inhibited cellular growth and proliferation as well as soft agar cloning. Silencing of MED23 strengthened the sensitivity of the everolimus resistant breast cancer cell strains BT474 and MCF-7/ADM cells to everolimus medication. The silencing of MED23, in combination with everolimus, inhibits the cell cycle progress of breast cancer cells. ChIP indicated that the mutual regulation of HER2 and MED23 also participates in the formation of the everolimus drug resistance mechanism. Therefore, MED23 plays an important role in everolimus drug resistance, invasion, and metastasis of breast cancer. As a potential molecular therapeutic target of breast cancer, MED23 overcomes drug resistance in clinical endocrinotherapy and controls the distal relapse and metastasis in breast cancer by the targeted silencing of MED23. PMID- 28588724 TI - Upregulation of microRNA-143 reverses drug resistance in human breast cancer cells via inhibition of cytokine-induced apoptosis inhibitor 1. AB - Cytokine-induced apoptosis inhibitor 1 (CIAPIN1), originally termed anamorsin, is an anti-apoptotic molecule that acts as a downstream effector of the receptor tyrosine kinase-Ras signaling pathway. Overexpression of CIAPIN1 contributes to multidrug resistance (MDR) and microRNA (miR)-143 is typically considered a tumor suppressor in breast cancer. The present study aimed to evaluate the therapeutic potential of miR-143 as a treatment for drug-resistant breast cancer via the downregulation of CIAPIN1 in vitro. The expression levels of miR-143 were measured using quantitative polymerase chain reaction and the expression levels of CIAPIN1 were detected via western blot analysis. Bioinformatic analyses was additionally conducted to search for miR-143, which may potentially target CIAPIN1. Luciferase reporter plasmids were created and used to verify direct targeting. In addition, Taxol-induced drug-resistant (TDR) breast cancer cell proliferation was evaluated using the Cell Counting Kit-8 assay in vitro. The present study identified an inverse association between miR-143 and CIAPIN1 protein expression levels in breast cancer MCF-7, MDA-MB-231 and MDA-MB-453 TDR cells. Specific targeting sites for miR-143 in the 3'-untranslated region of the CIAPIN1 gene were identified, which exhibit the ability to regulate CIAPIN1 expression. It was revealed that the repression of CIAPIN1 via miR-143 suppressed the proliferation of breast cancer TDR cells. The findings of the present study verified the role of miR-143 as a tumor suppressor in breast cancer MDR via inhibition of CIAPIN1 translation. PMID- 28588723 TI - Analysis of the correlation between the expression of miR-655 and esophageal cancer prognosis. AB - The correlation between the expression level of microRNA (miR)-655 in esophageal cancer with proliferation, invasion and prognosis was investigated. Reverse transcription-quantitative polymerase chain reaction technique was used to detect the expression level of miR-655 in esophageal cancer cell lines KYSE410 and EC9706, tumor tissues and normal cancer-adjacent tissues of 63 cases of patients with esophageal squamous cell carcinoma (ESCC). The expression of miR-655 was upregulated in ESCC cells through the transfection of miR-655 mimics, and the influence of miR-655 on proliferation and invasion ability of ESCC cells was observed. Combined with the clinical data, the correlation between the expression of miR-655 and the prognosis of esophageal cancer was analyzed. The expression of miR-655 was downregulated in 2 ESCC cell lines and 73.02% of ESCC tissues. The results showed that the increased expression of miR-655 via transfection of mimics inhibited the proliferation and invasion ability of ESCC cells. Combined with clinical data analysis, it was found that the low-expression of miR-655 was related to poorer progression-free survival. In conclusion, the high-expression of miR-655 can inhibit the proliferation and invasion of ESCC, and plays a negative regulation role in the prognosis process of tumor patients. The targeted regulation of miR-655 can be used as a new treatment method of ESCC. PMID- 28588725 TI - Molecular characterization of breast cancer cell lines by clinical immunohistochemical markers. AB - Breast cancer is the leading cause of cancer mortality in females worldwide. Studies based on gene expression profiles have identified different breast cancer molecular subtypes, such as luminal A and B cells, cancer cells that are estrogen receptor (ER) and/or progesterone receptor (PR) positive, human epidermal growth factor 2 (HER2)-enriched cells, cancer cells that exhibit an overexpression of the oncogene HER2, and triple-negative cells, cancer cells that are negative for ER, PR and HER2 expression. Immunohistochemistry is the most common type of method used for the identification of these molecular subtypes, through the identification of specific cell receptors. The present study aimed to evaluate the ER, PR and HER2 receptor expression in human breast cancer cell lines, and to classify the corresponding molecular subtype comparing two alternative methods. In the present study, a panel of human mammary carcinoma cell lines: BT-20; Hs578T; MCF-7; MCF-7/AZ; MDA-MB-231; MDA-MB-468; SKBR3; and T47D were used. Immunohistochemical and immunocytochemistry assays were used to characterize the breast cancer subtypes of these cell lines according to the expression of ER, PR and HER2 receptors. The results revealed the molecular characterization of this panel of breast cancer cell lines, using the differential expression of classical and clinically used markers in concordance with previous studies. In addition, these data are important for additional in vitro studies of these specific receptors. PMID- 28588726 TI - Pathogenic mechanism of miR-21 in autoimmune lymphoid hyperplasia syndrome. AB - miR-21 plays an important role in immune responses and inflammatory diseases, but the mechanism of action of miR-21 in autoimmune lymphoid hyperplasia syndrome still remains unclear. The aim of the present study was to assess the mechanism of miR-21 in autoimmune disease, particularly, the autoimmune lymphoid hyperplasia syndrome. The pathology and immunity-related phenotypes of miR-21 transgenic mice, and the lymphocyte subsets were analyzed. The related T cell subsets and germinal center B (GCB) cells generated at the germinal center were detected with flow cytometry. The target genes of miR-21 were evaluated with the luciferase reporter gene method. The homeostatic proliferation of the lymphocytes was detected with the EdU incorporation assay. Inflammatory infiltration occurred to the lung and liver of the transgenic mice at 8 weeks. The frequency of the regulatory helper T cells decreased slightly. Significantly increased double negative T cells were observed in the spleen of the transgenic mice (P<0.05). The immunoglobulins IgG1, IgG2a, IgG2b, and IgG3 in the serum of the transgenic mice aged 8 weeks were significantly higher than those in the wild-type mice aged 8 weeks (P<0.05). The percentages of the GCB cells in the peripheral lymphoid organs such as lymph nodes, mesenteric lymph nodes, PP and spleen in the transgenic mice aged 8-52 weeks increased significantly (P<0.05). The percentage (26.32%) of the newly-formed GCB cells derived from transgenic mice was significantly higher than that (3.87%) of the GCB cells derived from the wild type mice. miR-21 played a role of negative feedback regulation by inhibiting the NF-kappaB signal pathway. The highly-expressed miR-21 B cells promoted homeostatic proliferation of the T cells. miR-21 can promote homeostatic proliferation of lymphocytes by inhibiting the NF-kappaB signal pathway. PMID- 28588727 TI - Synergistic cytotoxic effects of a combined treatment of a Pinellia pedatisecta lipid-soluble extract and cisplatin on human cervical carcinoma in vivo. AB - Herbal medicines are known to have numerous benefits, including lower toxicity and fewer side effects than traditional chemotherapeutic drugs. In traditional Chinese medicine, the rhizome of Pinellia pedatisecta (PE) Schott has long been used to treat cancer, undiagnosed swelling and erythema toxicum. However, its medical benefits lack support from scientific evidence. A novel lipid-soluble extract from PE has been previously verified to enhance the cytotoxicity of cis dichlorodiammineplatinum-II (CDDP) against human cervical cancer cells in vitro. The present study evaluated the synergistic cytotoxic effects of PE and CDDP against human cervical cancer. Combination therapy of PE with CDDP exhibited synergistic cytotoxicity towards CaSki cell growth in mouse xenograft tumors. PE exhibited a cytotoxic effect on tumor size and weight, although the inhibitory ratio of tumor weight was only 26.3% in the PE-treated group. However, when mice were co-treated with PE and CDDP, the inhibitory ratio was higher than that of mice treated with CDDP alone (50.8 vs. 68.4%, respectively). The potential synergistic mechanism was likely via inhibiting the signaling E6/p53 pathway, restoring p53 function and inducing downstream tumor suppressor chain effects on apoptosis. Western blot analysis and immunohistochemistry indicated thatE6protein expression was significantly decreased upon treatment with combined PE and CDDP. The expression of p53 was increased in the combined PE and CDDP treatment group. Upregulation of p53-dependent apoptosis-associated proteins, including Bcl-2 associated X protein and cleaved caspases-9 and -3, was observed in the combined PE and CDDP treatment group. Our results present a molecular basis for the future application of the combination of PE and CDDP in the treatment of cervical cancer as a novel and pharmacologically safe chemotherapeutic strategy. PMID- 28588729 TI - Grifolin induces apoptosis and promotes cell cycle arrest in the A2780 human ovarian cancer cell line via inactivation of the ERK1/2 and Akt pathways. AB - Grifolin, a secondary metabolic product isolated from the mushroom Albatrellus confluence, has been demonstrated to possess antitumor activities in a variety of malignant cells. However, the signaling pathways and the molecular mechanisms underlying the anticancer effects of the agent in human ovarian cancer remain to be elucidated. The aim of the present study was to examine the effect of grifolin treatment on the human ovarian cancer cell line, A2780. MTT and flow cytometry analysis were used to analyze the viability of A2780 cells following treatment with grifolin. Western blotting was used analyze the expression of apoptosis associated and cell cycle arrest-associated proteins. The results of MTT assays and flow cytometry analysis revealed that grifolin suppressed cell viability, induced apoptosis and triggered cell cycle arrest. Western blotting revealed that grifolin treatment resulted in inactivation of protein kinase B (Akt) and extracellular signal-related kinase 1/2 (ERK1/2), accompanied by upregulation of Bcl-2 associated X, apoptosis regulator, cleaved-caspase-3 and cleaved-poly (ADP ribose) polymerase, and downregulation of B cell lymphoma-2, cyclin dependent kinase 4 and cyclinD1. The results of the present study indicated that grifolin had significant anti-cancer effects on the human ovarian cancer A2780 cells, which occurred via the Akt and ERK1/2 signaling pathways to at least a certain extent. These results demonstrate the therapeutic potential of grifolin as a treatment for ovarian cancer. PMID- 28588728 TI - Maternal embryonic leucine zipper kinase inhibits epithelial-mesenchymal transition by regulating transforming growth factor-beta signaling. AB - Maternal embryonic leucine zipper kinase (MELK) performs an important role in self-renewal and proliferation of progenitor cells or tumor stem cells, and is expressed in aggressive cancers, contributing to tumorigenesis. However, the function of MELK in metastasis is unknown. In the present study, the lung cancer A549 cell line was utilized in order to study the role of MELK in epithelial mesenchymal transitions (EMTs), the initial step of tumor metastasis. It was identified that transforming growth factor-beta (TGF-beta) could downregulate the expression of MELK, and that MELK could inhibit EMT by regulating TGF-beta signaling. MELK can interact with Smad proteins, which represses TGF-beta/Smad mediated signaling activity. The findings of the present study identified the effect of MELK in TGF-beta signaling and the EMT process. PMID- 28588730 TI - Conversion to monotherapy with luteinizing-hormone releasing hormone agonist or orchiectomy after reaching PSA nadir following maximal androgen blockade is able to prolong progression-free survival in patients with metastatic prostate cancer: A propensity score matching analysis. AB - The present study evaluated androgen deprivation methods to determine the approach that most improves the progression-free survival (PFS) of patients with metastatic prostate cancer. Patients had received continuous maximal androgen blockade (MAB) or monotherapy [luteinizing-hormone releasing hormone (LHRH) agonist or orchiectomy] following the reaching of the prostate specific antigen (PSA) nadir. The medical records of 293 patients who received MAB following a diagnosis of metastatic prostate cancer were retrospectively reviewed. Following attainment of the PSA nadir and treatment with MAB, patients were maintained on continuous MAB (group CMAB) or converted to monotherapy (group MONO). Disease progression, defined as progression to castration-resistant prostate cancer, was evaluated and compared between the treatment modalities. PFS was compared between patients who received CMAB vs. MONO using 2:1 (102:53) propensity score matching; the basic clinicopathological characteristics (age, Gleason score, PSA and extent of bone metastasis) were similar between the groups. Disease progression was observed in 70.9% of all patients, with a median treatment period of 22.7 months. The median PFS time was 19.5 months in the CMAB group and 28.8 months in the MONO group (P=0.008). Kaplan-Meier analysis demonstrated that PFS was significantly associated with the type of maintenance androgen deprivation therapy (ADT; log rank <0.005). Multivariate analysis revealed that the type of maintenance ADT and the pretreatment extent of bone metastasis were independent predictors of prolonged PFS. In this propensity score matched-analysis, conversion to monotherapy with a LHRH agonist or orchiectomy following attainment of the PSA nadir with initial MAB, prolonged the PFS, suggesting that monotherapy maintenance following initial MAB may benefit patients by reducing side effects without decreasing treatment efficacy. PMID- 28588732 TI - TRUS-guided transperineal prostate 12+X core biopsy with template for the diagnosis of prostate cancer. AB - The objective of the present study was to explore the clinical value and safety of trans-rectal ultrasound (TRUS)-guided transperineal prostate 12+X core biopsy in the diagnosis of prostate cancer. Patients who received a TRUS-guided transperineal prostate biopsy for suspected prostate cancer at the General Hospital of The People's Liberation Army between September 2009 and May 2014 were retrospectively analyzed, this consisted of 1,300 patients. These patients were randomly divided into the 12+X core group or the standard 12-core group. The mean age of all the patients was 70.5 years old. Levels of prostate-specific antigen, digital rectal examination, transrectal ultrasound and magnetic resonance imaging (MRI) were checked and used as reference prior and subsequent to the biopsy procedure. The 12+X core group consisted of 937 patients and the 12-core group consisted of 363 patients. The mean number of core samples taken from both groups was 14.5 (ranging from 12 to 24) and the mean operative time of the whole group was 20.4 min (ranging from 15 to 40 min). The puncture positive detection rate of abnormal rectal examination, trans-rectal ultrasound, and MRI was 24.0, 30.1, and 59.2%, respectively, whereas the puncture positive rate was 47.2% in 12+X core group and 34.5% in 12-core group. Improved prostate needle biopsy with 12+X cores was found to have significantly higher detection rate than that with 12 cores as well as fewer post-operative complications, therefore making the method ideal for diagnosing prostate cancer. PMID- 28588731 TI - Anti-rheumatic drug iguratimod protects against cancer-induced bone pain and bone destruction in a rat model. AB - The bone is one of the most common sites of metastasis in patients with cancer. Current treatments for bone metastases include bisphosphonates, denosumab, non steroidal anti-inflammatory drugs and analgesics, but each of them has certain limitations. Cytokines and mediators released from various cells in the bone microenvironment may drive a vicious cycle of osteolytic bone metastases. Iguratimod (T-614), a novel disease-modifying anti-rheumatic drug, has demonstrated therapeutic effects by suppressing the production of inflammatory cytokines in rats and patients with rheumatoid arthritis. Therefore, the current study evaluated the hypothesis that iguratimod may protect against cancer-induced bone pain and bone metastasis in a rat model. For this purpose, rats inoculated with Walker 256 cells were treated with iguratimod from days 11-17 post-surgery. Mechanical paw withdrawal thresholds and expression levels of phosphorylated extracellular signal-related kinase (pERK) and c-Fos in the spinal cord were investigated to detect changes in bone pain. Bone destruction levels were detected using X-rays, hematoxylin and eosin and tartrate-resistant acid phosphatase staining. The results revealed that mechanical paw withdrawal thresholds and the expression levels of pERK and c-Fos declined in a dose dependent manner in rats treated with iguratimod, and bone destruction severity was also reduced. These findings may provide important new insights into the treatment of bone metastasis symptoms. PMID- 28588733 TI - Differences in the sensitivity of ovarian cancer to photodynamic therapy and the mechanisms for those differences. AB - Protoporphyrin IX (PpIX) levels are crucial to the antitumor action of photodynamic therapy (PDT). In the present study, the underling molecular mechanisms for the variation in PpIX levels in ovarian cancer cells were investigated. Five ovarian cancer cell lines were subcutaneously grafted onto the backs of nude mice. Once tumors had developed, 5-aminolevulinic acid methyl ester hydrochloride (methyl-ALA) was administered intraperitoneally and the tumor was irradiated twice/week. PpIX levels in the tumor were assayed using high performance liquid chromatography. Enzymes involved in heme synthesis and degradation were screened using a microarray technique. Expression of the glutathione transferase Omega-1 (GSTO1) gene involved in the conversion of PpIX into heme in cells was quantified using the reverse transcription-quantitative polymerase chain reaction. In HTOA, HRA and DISS cells, PDT resulted in significant tumor shrinkage in comparison with the controls. In MCAS and TOV21G cells, no significant alterations in tumor growth were identified compared with the untreated cells. PpIX levels increased significantly in HTOA, DISS and HRA cells compared with in MCAS and TOV21G cells. A comparison of genetic profiles using PDT-sensitive DISS cells and PDT-resistant MCAS cells indicated that MCAS cells exhibited significantly increased levels of delta-aminolevulinate synthase (a rate-limiting enzyme in heme synthesis), heme oxygenase 2 (an enzyme that degrades heme into biliverdin), and biliverdin reductase B (an enzyme that reduces biliverdin into bilirubin) in comparison with DISS cells. The level of GSTO1 expression in HTOA, HRA and DISS cells was ~2.5-fold that in MCAS and TOV21G cells. Sensitivity to PDT is related to PpIX levels in cells. The results of the present study suggested that PpIX tends not to accumulate in PDT-resistant cells despite active heme synthesis and degradation, and that high levels of GSTO1 expression are associated with increased sensitivity to PDT. PMID- 28588734 TI - Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge. AB - Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system. HGF levels in the plasma were measured by enzyme-linked immunosorbent assay, and the ratio of HGF levels prior to re-challenge to those prior to the previous EGFR-TKI treatment was calculated. Two re-challenges demonstrated partial response, six remained as stable disease and eight had progressive disease (PD). A total of 4 of the 5 patients with a history of T790M positivity based on plasma DNA levels had PD. A total of 7 of the 8 patients who had >=1.5-fold elevation of HGF prior to re-challenge with EGFR-TKI suffered PD. Elevation of the HGF ratio to >=1.5 was significantly associated with poor response to EGFR-TKI re-challenge. Having no history of T790M and an HGF ratio <1.5 was significantly associated with a positive response to EGFR-TKI re challenge. A combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re challenge. Future prospective studies are required to confirm the predictive validity of these markers. PMID- 28588735 TI - Comparison of hand-assisted laparoscopic surgery (HALS) and conventional laparotomy in patients with colorectal cancer: Final results from a single center. AB - In recent years, the use of laparoscopic surgery has been expanded to include radical curative resection. In a previous study, 212 patients with primary colorectal cancer (stages I-III) underwent radical curative resection by hand assisted laparoscopic surgery (HALS) (n=98) or conventional laparotomy (CL) (n=114) and were compared with respect to 3-year relapse-free survival (3Y-RFS) and 3-year overall survival (3Y-OS). The study included 210/212 patients who were followed up to 5 years, including 96 patients who underwent HALS and 114 treated with CL. The two groups were matched for stage, clinical background, and postoperative management. Patient characteristics were compared and the 5Y-RFS and 5Y-OS were determined. The 5-year follow-up rate was 97.6%. In stage I-III patients, 5Y-RFS and 5Y-OS showed no significant differences between HALS and CL. The patients with stage I disease accounted for 41.7% (40/96) of the patients undergoing HALS, while stage I patients only accounted for 23.7% (27/114) of the patients undergoing CL, and the difference was significant (P=0.005). Stage II patients undergoing CL were older than those treated with HALS (P=0.017). However, there were no differences in the characteristics of stage III patients undergoing HALS or CL. In conclusion, HALS achieved a similar survival to CL in patients with stage I to III colorectal cancer. Compared with CL, HALS was performed more safely and achieved superior cosmetic results. PMID- 28588736 TI - Treatment outcomes of concurrent hyperthermia and chemoradiotherapy for pancreatic cancer: Insights into the significance of hyperthermia treatment. AB - Patients with locally advanced unresectable pancreatic cancer (LAUPC) have a poor prognosis. In addition their quality of life impaired by cancer pain and biliary tract infections. Therefore, multimodality therapy and selection of optimal treatment methods are essential for achieving prolonged survival. The present study investigated the significance of using hyperthermia concurrently with multimodality therapy to improve treatment outcomes in patients with LAUPC. In total, 13 patients receiving concurrent hyperthermia and chemoradiotherapy (HCR) or chemoradiotherapy (CR) alone for LAUPC between 2002 and 2013 were analyzed retrospectively. Of the 13 patients, 5 received concurrent HCR and 8 received CR. The chemotherapy regimens were 5-fluorouracil (5-FU) in 5 patients and gemcitabine hydrochloride (GEM) in the other 8. Patients who gave consent for hyperthermia treatment received GEM plus CR. The median overall survival period for all patients was 12 months and the 1-year survival rate was 55%; the corresponding values were 12 months and 57% in the GEM CR group, and 15 months and 80% in the HCR group. Univariate analyses was perfomed to identify factors predicting recurrence after treatment. The potential prognostic factors analyzed were: Age, sex, performance status, location, tumor size, the tumor marker CA 19 9, total radiation dose, chemotherapy and hyperthermia. Univariate analysis for factors associated with outcomes revealed a significant difference favoring the HCR group [relative risk=15.97 (95% confidence interval: 12.87-19.83) P=0.021]. In conclusion, hyperthermia merits active recommendation to pancreatic cancer patients who have a positive attitude toward this treatment and whose performance status is satisfactory. PMID- 28588737 TI - Myricetin induces apoptosis and enhances chemosensitivity in ovarian cancer cells. AB - Ovarian cancer is the most lethal type of gynecological cancer and is the fifth leading cause of cancer-associated mortality in females globally. The majority of patients with ovarian cancer suffer from recurrent, progressive disease, due to the acquisition of a resistance phenotype towards various conventional chemotherapy drugs. Although paclitaxel has been demonstrated to be effective against ovarian tumors, there have been reports of the development of a resistant phenotype against Taxol(r) treatment. The multidrug resistance (MDR)-1/P glycoprotein has previously been demonstrated to be associated with the acquisition of paclitaxel resistance in certain ovarian tumors. Therefore, the screening of novel drug candidates able to target MDR-1 in ovarian cancer cells and increase the sensitivity to Taxol(r) is required in order to improve the treatment of this disease. In the present study, the underlying mechanisms by which the dietary flavonoid myricetin enhances the cytotoxic potential of paclitaxel in ovarian cancer cells, was investigated. It was observed that myricetin induced significant cytotoxicity in A2780 and OVCAR3 ovarian cancer cells, with the IC50 value obtained at 25 uM. Myricetin treatment also resulted in the induction of apoptosis in the two cell lines, accompanied by the modulation of certain pro- and anti-apoptotic markers. It was also determined that the pre-incubation of ovarian cancer cells with a lower dose of myricetin was able to increase the cytotoxicity of paclitaxel, due to the significant downregulation of MDR-1 in these cells. PMID- 28588738 TI - Prostate cancer downregulated SIRP-alpha modulates apoptosis and proliferation through p38-MAPK/NF-kappaB/COX-2 signaling. AB - The present study investigated the regulatory mechanism of signal-regulatory protein (SIRP)-alpha in the apoptosis and proliferation of prostate cancer (CaP) cells. The expression profile of SIRP-alpha in prostate cancer cells was analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting. Then SIRP-alpha function in CaP cells was further analyzed with the overexpression and RNA interference of SIRP-alpha. The results revealed that SIRP alpha expression levels were decreased in CaP tissues and cell lines, with androgen-independent CaP exhibiting a lower SIRP-alpha expression compared with androgen-dependent CaP. Overexpression of SIRP-alpha resulted in a significantly reduced number of live CaP cells by enhancing apoptosis, whereas SIRP-alpha silencing increased CaP cell proliferation. Mechanistically, SIRP-alpha decreases cyclooxygenase-2 (COX-2) expression and cytokine production by negatively regulating p38 mitogen-activated protein kinase and nuclear factor-kappaB pathway. Therefore, SIRP-alpha knockdown decreases cell apoptosis by enhancing COX-2 expression. The present results indicate that SIRP-alpha may function as a novel negative regulator to modulate cellular proliferation, survival and migration in CaP cells. The heightened sensitivity of cells restoring SIRP-alpha function could be exploited in the development of therapeutics that may potentiate the antineoplastic effects of conventional cytokines or chemotherapeutic agents. PMID- 28588739 TI - The clinicopathological and prognostic role of thrombocytosis in patients with cancer: A meta-analysis. AB - Previous studies have linked the presence of thrombocytosis with the progression and development of cancer; however, this trend requires further investigation. The present study aimed to derive an estimation of the degree of association between thrombocytosis and the 5-year overall survival rate of patients with cancer, as well as common clinicopathological features, by performing a meta analysis of 20 (n=12,778) published studies. The PubMed and Embase databases were searched systematically for all relevant articles published in English. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using a fixed effects or random effects model to evaluate the degree of the observed associations. The results suggested that thrombocytosis (platelet count, >400*109/l) correlated with a decreased 5-year overall survival rate (OR=2.70, 95% CI=2.03-3.61) and an advanced tumor-node-metastasis stage (III + IV; OR=2.14, 95% CI=1.58-2.90). Furthermore, these associations remained robust following stratification of the data by cancer type and ethnicity. In addition, thrombocytosis (platelet count, >300*109/l) correlated with a decreased 5-year overall survival rate in patients with colorectal cancer (OR=3.49, 95% CI=1.44 8.46). Although certain biases were not able to be eliminated, the present meta analysis suggested that thrombocytosis is a valuable indicator for the evaluation of pathological diagnosis and prognosis for patients with cancer. Further studies are required to investigate the effect of thrombocytosis on the prognosis of patients with cancer. PMID- 28588740 TI - microRNA-497 overexpression decreases proliferation, migration and invasion of human retinoblastoma cells via targeting vascular endothelial growth factor A. AB - The expression level and roles of microRNA-497 (miR-497) have been frequently reported in previous studies on cancer. However, its expression, function and associated molecular mechanisms in retinoblastoma remain unknown. In the present study, miR-497 expression levels in human retinoblastoma tissues, normal retinal tissues and retinoblastoma cell lines were determined using reverse transcription quantitative polymerase chain reaction. In addition, a Cell Counting Kit-8 assay, cell migration assay, cell invasion assay, western blot analysis and Dual Luciferase reporter assay were used to explore the expression, functions and molecular mechanisms of miR-497 in human retinoblastoma. It was demonstrated that miR-497 was significantly downregulated in retinoblastoma tissues and cell lines compared with normal retinal tissues. Ectopic expression of miR-497 decreased the proliferation, migration and invasion of retinoblastoma cells. Furthermore, VEGFA was verified as a potential direct target of miR-497 in vitro. Taken together, the results indicate that miR-497 functions as a tumor suppressor in the carcinogenesis and progression of retinoblastoma via targeting VEGFA. miR-497 should be investigated as a potential therapeutic target for the treatment of retinoblastoma. PMID- 28588741 TI - Erratum: Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis. AB - [This corrects the article DOI: 10.3892/ol.2016.4775.]. PMID- 28588743 TI - ZAR1 is a novel epigenetically inactivated tumour suppressor in lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related deaths with 1.8 million new cases each year and poor 5-year prognosis. Promoter hypermethylation of tumour suppressors leads to their inactivation and thereby can promote cancer development and progression. RESULTS: In this study, we analysed ZAR1 (zygote arrest 1), which has been said to be a maternal-effect gene and its expression mostly limited to certain reproductive tissues. Our study shows that ZAR1 is expressed in normal lung but inactivated by promoter methylation in lung cancer. ZAR1 is hypermethylated in primary lung cancer samples (22% small cell lung carcinoma (SCLC) and 76% non-small cell lung carcinoma (NSCLC), p < 0.001) vs. normal control lung tissue (11%). In lung cancer cell lines, ZAR1 was significantly methylated in 75% of SCLC and 83% of NSCLC vs. normal tissue (p < 0.005/0.05). In matching tumours and control tissues, we observed that NSCLC primary tumour samples exhibited a tumour-specific promoter methylation of ZAR1 in comparison to the normal control lung tissue. Demethylation treatment of various lung cancer cell lines reversed ZAR1 promoter hypermethylation and subsequently re-established ZAR1 expression. In addition, we could show the growth inhibitory potential of ZAR1 in lung cancer cell lines and cancer cell lines. Exogenous expression of ZAR1 not only inhibited colony formation but also blocked cell cycle progression of cancer cell lines. CONCLUSIONS: Our study shows for the first time the lung tumour-specific epigenetic inactivation of ZAR1 due to DNA methylation of its CpG island promoter. Furthermore, ZAR1 was characterised by the ability to block tumour growth through the inhibition of cell cycle progression in cancer cell lines. We propose that ZAR1 could serve as an epigenetically inactivated biomarker in lung cancer. PMID- 28588745 TI - Maternal characteristics and immunization status of children in North Central of Nigeria. AB - INTRODUCTION: Routine immunization coverage in Nigeria is one of the lowest national coverage rates in the world. The objective of this study was to compare the mother' characteristics and the child's Immunization status in some selected rural and urban communities in the North central part of Nigeria. METHODS: A descriptive cross sectional study, using a multistage sampling technique to select 600 respondent women with an index child between 0-12 months. RESULTS: Mean age of rural respondents was 31.40+/-7.21 years and 32.72+6.77 years among urban respondents, though there was no statistically significant difference in age between the 2 locations (p-0.762). One hundred and ninetyseven (65.7%) and 241(80.3%) of rural and urban respondents respectively were aware of immunization, the difference was statistically significant (p-0.016). knowledge in urban areas was better than among rural respondents. There was statistically significant association between respondents age, employment status, mothers' educational status and the child's immunization status (P<0.05), while variables like parity, age at marriage, marital status, No of children, household income and place of index were not statistically associated with immunization status as P>0.05. More than half 179(59.7%) of rural and 207(69.0%) of urban had good practice of immunization though the difference was not statistically significant (p-0.165). CONCLUSION: The immunization coverage in urban community was better than that of the rural community. The result of this study has clearly indicated that mothers in Nigeria have improved on taking their children for immunization in both rural and urban area compared to previous reports. PMID- 28588742 TI - Folate deficiency as predisposing factor for childhood leukaemia: a review of the literature. AB - BACKGROUND: Folic acid and its derivates, known as folates, are chemoprotective micronutrients of great interest because of their essential role in the maintenance of health and genomic integrity. The supplementation of folic acid during pregnancy has long been known to reduce the risk of neural tube defects (NTDs) in the foetus. Folate metabolism can be altered by many factors, including adequate intake through diet. Folate deficiency can compromise the synthesis, repair and methylation of DNA, with deleterious consequences on genomic stability and gene expression. These processes are known to be altered in chronic diseases, including cancer and cardiovascular diseases. MAIN BODY: This review focuses on the association between folate intake and the risk of childhood leukaemia. Having compiled and analysed studies from the literature, we show the documented effects of folates on the genome and their role in cancer prevention and progression with particular emphasis on DNA methylation modifications. These changes are of crucial importance during pregnancy, as maternal diet has a profound impact on the metabolic and physiological functions of the foetus and the susceptibility to disease in later life. Folate deficiency is capable of modifying the methylation status of certain genes at birth in both animals and humans, with potential pathogenic and tumorigenic effects on the progeny. Pre-existing genetic polymorphisms can modify the metabolic network of folates and influence the risk of cancer, including childhood leukaemias. The protective effects of folic acid might be dose dependent, as excessive folic acid could have the adverse effect of nourishing certain types of tumours. CONCLUSION: Overall, maternal folic acid supplementation before and during pregnancy seems to confer protection against the risk of childhood leukaemia in the offspring. The optimal folic acid requirements and supplementation doses need to be established, especially in conjunction with other vitamins in order to determine the most successful combinations of nutrients to maintain genomic health and wellbeing. Further research is therefore needed to uncover the role of maternal diet as a whole, as it represents a main factor capable of inducing permanent changes in the foetus. PMID- 28588744 TI - Effect of personal exposure to black carbon on changes in allergic asthma gene methylation measured 5 days later in urban children: importance of allergic sensitization. AB - BACKGROUND: Asthma gene DNA methylation may underlie the effects of air pollution on airway inflammation. However, the temporality and individual susceptibility to environmental epigenetic regulation of asthma has not been fully elucidated. Our objective was to determine the timeline of black carbon (BC) exposure, measured by personal sampling, on DNA methylation of allergic asthma genes 5 days later to capture usual weather variations and differences related to changes in behavior and activities. We also sought to determine how methylation may vary by seroatopy and cockroach sensitization and by elevated fractional exhaled nitric oxide (FeNO). METHODS: Personal BC levels were measured during two 24-h periods over a 6-day sampling period in 163 New York City children (age 9-14 years), repeated 6 months later. During home visits, buccal cells were collected as noninvasive surrogates for lower airway epithelial cells and FeNO measured as an indicator of airway inflammation. CpG promoter loci of allergic asthma genes (e.g., interleukin 4 (IL4), interferon gamma (IFNgamma), inducible nitric oxide synthase (NOS2A)), arginase 2 (ARG2)) were pyrosequenced at the start and end of each sampling period. RESULTS: Higher levels of BC were associated with lower methylation of IL4 promoter CpG-48 5 days later. The magnitude of association between BC exposure and demethylation of IL4 CpG-48 and NOS2A CpG+5099 measured 5 days later appeared to be greater among seroatopic children, especially those sensitized to cockroach allergens (RR [95% CI] 0.55 [0.37-0.82] and 0.67 [0.45 0.98] for IL4 CpG-48 and NOS2A CpG+5099, respectively), compared to non sensitized children (RR [95% CI] 0.87 [0.65-1.17] and 0.95 [0.69-1.33] for IL4 CpG-48 and NOS2A CpG+5099, respectively); however, the difference was not statistically different. In multivariable linear regression models, lower DNA methylation of IL4 CpG-48 and NOS2A CpG+5099 were associated with increased FeNO. CONCLUSIONS: Our results suggest that exposure to BC may exert asthma proinflammatory gene demethylation 5 days later that in turn may link to airway inflammation. Our results further suggest that seroatopic children, especially those sensitized to cockroach allergens, may be more susceptible to the effect of acute BC exposure on epigenetic changes. PMID- 28588746 TI - The Stimulated Glycolytic Pathway Is Able to Maintain ATP Levels and Kinetic Patterns of Bovine Epididymal Sperm Subjected to Mitochondrial Uncoupling. AB - Studies have reported the importance of mitochondria in sperm functionality. However, for some species, the glycolytic pathway appears to be as important as oxidative phosphorylation in ATP synthesis and sperm kinetics. These mechanisms have not been fully elucidated for bovine spermatozoa. Therefore, the aim of this study was to evaluate the role of mitochondria and the glycolytic pathway in ATP synthesis, sperm movement patterns, and oxidative homeostasis of epididymal spermatozoa in bovine specimens. We observed that mitochondrial uncoupling with protonophores significantly reduced ATP levels. However, these levels were reestablished after stimulation of the glycolytic pathway. We verified the same pattern of results for sperm kinetic variables and the production of reactive oxygen species (ROS). Thus, we suggest that, after its appropriate stimulation, the glycolytic pathway is capable of maintaining ATP levels, sperm kinetic patterns, and oxidative balance of bovine epididymal spermatozoa submitted to mitochondrial uncoupling. PMID- 28588747 TI - Antifatigue Effect of Luteolin-6-C-Neohesperidoside on Oxidative Stress Injury Induced by Forced Swimming of Rats through Modulation of Nrf2/ARE Signaling Pathways. AB - Luteolin-6-C-neohesperidoside (LN) is a flavonoid isolated from moso bamboo leaf. This study was performed to evaluate the antifatigue effect of LN on a rat model undergoing the weight-loaded forced swimming test (FST). Briefly, male Sprague Dawley rats (20-22 weeks old) were forced to undertake exhaustive swimming every other day for 3 weeks. Each swimming session was followed by the administration of distilled water, LN (25-75 mg/kg), or ascorbic acid (100 mg/kg) 1 h later. Oral administration of LN significantly improved exercise endurance; normalized alterations in energy metabolic markers; and decreased serum lactic acid, lactate dehydrogenase, and blood urea nitrogen levels of rats that underwent FST. Moreover, LN enhanced the activities of antioxidant enzymes and antioxidant capacity, as measured by enzyme activity assays, RT-PCR, and Western blotting, as well as decreasing the levels of proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), and IL-6 and increasing the level of anti-inflammatory (IL-10) in the liver and skeletal muscle. These results suggested that LN reduces both physical and mental effects of chronic fatigue, probably by attenuating oxidative stress injury and inflammatory responses in the liver and skeletal muscle. This study thus supports the use of LN in functional foods for antifatigue and antioxidant effects. PMID- 28588748 TI - Camellia sinensis Prevents Perinatal Nicotine-Induced Neurobehavioral Alterations, Tissue Injury, and Oxidative Stress in Male and Female Mice Newborns. AB - Nicotine exposure during pregnancy induces oxidative stress and leads to behavioral alterations in early childhood and young adulthood. The current study aimed to investigate the possible protective effects of green tea (Camellia sinensis) against perinatal nicotine-induced behavioral alterations and oxidative stress in mice newborns. Pregnant mice received 50 mg/kg C. sinensis on gestational day 1 (PD1) to postnatal day 15 (D15) and were subcutaneously injected with 0.25 mg/kg nicotine from PD12 to D15. Nicotine-exposed newborns showed significant delay in eye opening and hair appearance and declined body weight at birth and at D21. Nicotine induced neuromotor alterations in both male and female newborns evidenced by the suppressed righting, rotating, and cliff avoidance reflexes. Nicotine-exposed newborns exhibited declined memory, learning, and equilibrium capabilities, as well as marked anxiety behavior. C. sinensis significantly improved the physical development, neuromotor maturation, and behavioral performance in nicotine-exposed male and female newborns. In addition, C. sinensis prevented nicotine-induced tissue injury and lipid peroxidation and enhanced antioxidant defenses in the cerebellum and medulla oblongata of male and female newborns. In conclusion, this study shows that C. sinensis confers protective effects against perinatal nicotine-induced neurobehavioral alterations, tissue injury, and oxidative stress in mice newborns. PMID- 28588750 TI - Image quality and diagnostic performance of free-breathing diffusion-weighted imaging for hepatocellular carcinoma. AB - AIM: To retrospectively evaluate the diagnostic performance of free-breathing diffusion-weighted imaging (FB-DWI) with modified imaging parameter settings for detecting hepatocellular carcinomas (HCCs). METHODS: Fifty-one patients at risk for HCC were scanned with both FB-DWI and respiratory-triggered DWI with the navigator echo respiratory-triggering technique (RT-DWI). Qualitatively, the sharpness of the liver contour, the image noise and the chemical shift artifacts on each DWI with b-values of 1000 s/mm2 were independently evaluated by three radiologists using 4-point scoring. We compared the image quality scores of each observer between the two DWI methods, using the Wilcoxon signed-rank test. Quantitatively, we compared the signal-to-noise ratios (SNRs) of the liver parenchyma and lesion-to-nonlesion contrast-to-noise ratios (CNRs) after measuring the signal intensity on each DWI with a b-factor of 1000 s/mm2. The average SNRs and CNRs between the two DWI methods were compared by the paired t test. The detectability of HCC on each DWI was also analyzed by three radiologists. The detectability provided by the two DWI methods was compared using McNemar's test. RESULTS: For all observers, the averaged image quality scores of FB-DWI were: Sharpness of the liver contour [observer (Obs)-1, 3.08 +/- 0.81; Obs-2, 2.98 +/- 0.73; Obs-3, 3.54 +/- 0.75], those of the distortion (Obs 1, 2.94 +/- 0.50; Obs-2, 2.71 +/- 0.70; Obs-3, 3.27 +/- 0.53), and the chemical shift artifacts (Obs-1, 3.38 +/- 0.60; Obs-2, 3.15 +/- 1.07; Obs-3, 3.21 +/- 0.85). The averaged image quality scores of RT-DWI were: Sharpness of the liver contour (Obs-1, 2.33 +/- 0.65; Obs-2, 2.37 +/- 0.74; Obs-3, 2.75 +/- 0.81), distortion (Obs-1, 2.81 +/- 0.56; Obs-2, 2.25 +/- 0.74; Obs-3, 2.96 +/- 0.71), and the chemical shift artifacts (Obs-1, 2.92 +/- 0.59; Obs-2, 2.21 +/- 0.85; Obs 3, 2.77 +/- 1.08). All image quality scores of FB-DWI were significantly higher than those of RT-DWI (P < 0.05). The average SNR of the normal liver parenchyma by FB-DWI (11.0 +/- 4.8) was not significantly different from that shown by RT DWI (11.0 +/- 5.0); nor were the lesion-to-nonlesion CNRs significantly different (FB-DWI, 21.4 +/- 17.7; RT-DWI, 20.1 +/- 15.1). For all three observers, the detectability of FB-DWI (Obs-1, 43.6%; Obs-2, 53.6%; and Obs-3, 45.0%) was significantly higher than that of RT-DWI (Obs-1, 29.1%; Obs-2, 43.6%; and Obs-3, 34.5%) (P < 0.05). CONCLUSION: FB-DWI showed better image quality and higher detectability of HCC compared to RT-DWI, without significantly reducing the SNRs of the liver parenchyma and lesion-to-nonlesion CNRs. PMID- 28588749 TI - Strategies to tackle the challenges of external beam radiotherapy for liver tumors. AB - Primary and metastatic liver cancer is an increasingly common and difficult to control disease entity. Radiation offers a non-invasive treatment alternative for these patients who often have few options and a poor prognosis. However, the anatomy and aggressiveness of liver cancer poses significant challenges such as accurate localization at simulation and treatment, management of motion and appropriate selection of dose regimen. This article aims to review the options available and provide information for the practical implementation and/or improvement of liver cancer radiation programs within the context of stereotactic body radiotherapy and image-guided radiotherapy guidelines. Specific patient inclusion and exclusion criteria are presented given the significant toxicity found in certain sub-populations treated with radiation. Indeed, certain sub populations, such as those with tumor thrombosis or those with larger lesions treated with transarterial chemoembolization, have been shown to have significant improvements in outcome with the addition of radiation and merit special consideration. Implementing a liver radiation program requires three primary challenges to be addressed: (1) immobilization and motion management; (2) localization; and (3) dose regimen and constraint selection. Strategies to deal with motion include simple internal target volume (ITV) expansions, non-gated ITV reduction strategies, breath hold methods, and surrogate marker methods to enable gating or tracking. Localization of the tumor and organs-at-risk are addressed using contrast infusion techniques to take advantage of different normal liver and cancer vascular anatomy, imaging modalities, and margin management. Finally, a dose response has been demonstrated and dose regimens appear to be converging. A more uniform approach to treatment in terms of technique, dose selection and patient selection will allow us to study liver radiation in larger and, hopefully, multicenter randomized studies. PMID- 28588751 TI - Protein tolerance to standard and high protein meals in patients with liver cirrhosis. AB - AIM: To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis. METHODS: The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the "number connection test" (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage. RESULTS: The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients. CONCLUSION: Patients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis. PMID- 28588752 TI - Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review. AB - AIM: To investigate interferon-gamma-inducible protein-10's (IP-10) potential to anticipate rapid (RVR)- and sustained virological responses (SVR) to chronic hepatitis C (CHC) treatment. METHODS: We included case series examining RVR or SVR in relation to 24 or 48 wk treatment for CHC, in patients treatment free for at least six months, with genotype 1 or 4, and in relation to 24 wk treatment for genotype 2 and 3, with pegylated interferon in combination with ribavirin. Patients had to have both a baseline IP-10 level as well as a hepatitis C virus (HCV)-RNA determination 4 wk after treatment initiation or 24 wk after end of treatment. Studies including patients with liver diseases other than CHC, human immunodeficiency virus-infection, treatment with immunosuppresents or cytostatica, alcohol dependency or active intravenous drug-use were excluded. We found 81 articles by searching the MEDLINE and EMBASE databases. Eight studies were eligible for inclusion. Their quality were assesed using an 18 point checklist for case series, developed using a modified Delphi technique. Information was extracted from the articles, and no raw data was requisitioned. The review protocol was registered at the International Prospective Register of Systematic Reviews (reg. number: CRD42014008736). RESULTS: Three studies reported on baseline IP-10 level in association with RVR. A signigficant association was found for HCV genotype 1 infection by two studies. Only two studies reported on HCV genotype 4 infected and genotype 2 and 3 infected patients, respectively. A trend was seen for an association between RVR and baseline IP-10 for genotype 4, while no association was found for genotype 2 and 3. Seven studies provided information regarding baseline IP-10 and SVR. Following the pattern regarding rapid virological response all five studies examining SVR in relation to baseline IP-10 levels for HCV, genotype 1 infected patients showed a significant association. Likewise a significant association was seen for HCV, genotype 4 infected, while no association was found for HCV, genotype 2 and 3 infected. Though only two studies examined the assosiation for HCV genotype 4 infected and HCV genotype 2 and 3 infected respectively. CONCLUSION: We found indications of a possible association between baseline IP-10 level and virological responses in patients with CHC genotype 1 and 4. PMID- 28588753 TI - Common therapeutic target for both cancer and obesity. AB - Obesity and cancer are two interrelated conditions of high epidemiological need, with studies showing that obesity is responsible for nearly 25% of the relative contribution to cancer incidence. Given the connection between these conditions, a drug that can operate on both obesity and cancer is highly desirable. Such a drug is accomplishable through the development of potent anti-angiogenesis agents due to the shared underlying role of angiogenesis in the development of both diseases. Prior research has demonstrated a key role of type-2 methionine aminopeptidase (MetAP2) for angiogenesis, which has led to the development of numerous of novel inhibitors. Several irreversible MetAP2 inhibitors have entered clinical trials without great success. Though this lack of success could be attributed to off-target adverse effects, the underlying causes remain unclear. More promising reversible inhibitors have been recently developed with excellent pre-clinical results. However, due to insufficient knowledge of the biological functions of N-terminal protein processing, it is hard to predict whether these novel inhibitors would successfully pass clinical trials and thereby benefit cancer and obesity patients. Significantly more efforts are needed to advance our understanding of the regulation of methionine aminopeptidases and the processes by which they govern the function of proteins. PMID- 28588755 TI - Role of pro- and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity. AB - In obesity, persistent low-grade inflammation is considered as a major contributor towards the progression to insulin resistance and type 2 diabetes while in lean subjects the immune environment is non-inflammatory. Massive adipose tissue (AT) infiltration by pro-inflammatory M1 macrophages and several T cell subsets as obesity develops leads to the accumulation - both in the AT and systemically - of numerous pro-inflammatory cytokines, including interleukin 1beta (IL-1beta), tumor necrosis factor alpha, IL-17 and IL-6 which are strongly associated with the progression of the obese phenotype towards the metabolic syndrome. At the same time, anti-inflammatory M2 macrophages and Th subsets producing the anti-inflammatory cytokines IL-10, IL-5 and interferon-gamma, including Th2 and T-reg cells are correlated to the maintenance of AT homeostasis in lean individuals. Here, we discuss the basic principles in the control of the interaction between the AT and infiltrating immune cells both in the lean and the obese condition with a special emphasis on the contribution of pro- and anti inflammatory cytokines to the establishment of the insulin-resistant state. In this context, we will discuss the current knowledge about alterations in the levels on pro- and anti-inflammatory cytokines in obesity, insulin resistance and type 2 diabetes mellitus, in humans and animal models. Finally, we also briefly survey the recent novel therapeutic strategies that attempt to alleviate or reverse insulin resistance and type 2 diabetes via the administration of recombinant inhibitory antibodies directed towards some pro-inflammatory cytokines. PMID- 28588754 TI - Endocrine disrupting chemicals in mixture and obesity, diabetes and related metabolic disorders. AB - Obesity and associated metabolic disorders represent a major societal challenge in health and quality of life with large psychological consequences in addition to physical disabilities. They are also one of the leading causes of morbidity and mortality. Although, different etiologic factors including excessive food intake and reduced physical activity have been well identified, they cannot explain the kinetics of epidemic evolution of obesity and diabetes with prevalence rates reaching pandemic proportions. Interestingly, convincing data have shown that environmental pollutants, specifically those endowed with endocrine disrupting activities, could contribute to the etiology of these multifactorial metabolic disorders. Within this review, we will recapitulate characteristics of endocrine disruption. We will demonstrate that metabolic disorders could originate from endocrine disruption with a particular focus on convincing data from the literature. Eventually, we will present how handling an original mouse model of chronic exposition to a mixture of pollutants allowed demonstrating that a mixture of pollutants each at doses beyond their active dose could induce substantial deleterious effects on several metabolic end-points. This proof-of-concept study, as well as other studies on mixtures of pollutants, stresses the needs for revisiting the current threshold model used in risk assessment which does not take into account potential effects of mixtures containing pollutants at environmental doses, e.g., the real life exposure. Certainly, more studies are necessary to better determine the nature of the chemicals to which humans are exposed and at which level, and their health impact. As well, research studies on substitute products are essential to identify harmless molecules. PMID- 28588756 TI - Immunological aspects of age-related diseases. AB - The proportion of elderly people rises in the developed countries. The increased susceptibility of the elderly to infectious diseases is caused by immune dysfunction, especially T cell functional decline. Age-related hematopoietic stem cells deviate from lymphoid lineage to myeloid lineage. Thymus shrinks early in life, which is followed by the decline of naive T cells. T-cell receptor repertoire diversity declines by aging, which is caused by cytomegalovirus-driven T cell clonal expansion. Functional decline of B cell induces antibody affinity declines by aging. Many effector functions including phagocytosis of myeloid cells are down regulated by aging. The studies of aging of myeloid cells have some controversial results. Although M1 macrophages have been shown to be replaced by anti-inflammatory (M2) macrophages by advanced age, many human studies showed that pro-inflammatory cytokines are elevated in older human. To solve this discrepancy here we divide age-related pathological changes into two categories. One is an aging of immune cell itself. Second is involvement of immune cells to age-related pathological changes. Cellular senescence and damaged cells in aged tissue recruit pro-inflammatory M1 macrophages, which produce pro inflammatory cytokines and proceed to age-related diseases. Underlying biochemical and metabolic studies will open nutritional treatment. PMID- 28588757 TI - Identification of neuron selective androgen receptor inhibitors. AB - AIM: To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness. METHODS: Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuron-selective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-qPCR of AR regulated genes and immunohistochemistry. RESULTS: We identified the thiazole class of antibiotics as compounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that shRNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles. CONCLUSION: Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms. PMID- 28588758 TI - B-1 cells modulate the murine macrophage response to Leishmania major infection. AB - AIM: To investigate the modulatory effect of B-1 cells on murine peritoneal macrophages infected with Leishmania major (L. major) in vitro. METHODS: Peritoneal macrophages obtained from BALB/c and BALB/c XID mice were infected with L. major and cultured in the presence or absence of B-1 cells obtained from wild-type BALB/c mice. Intracellular amastigotes were counted, and interleukin-10 (IL-10) production was quantified in the cellular supernatants using an enzyme linked immunosorbent assay. The levels of the lipid mediator prostaglandin E2 (PGE2) were determined using a PGE2 enzyme immunoassay kit (Cayman Chemical, Ann Arbor, MI), and the number of lipid bodies was quantified in the cytoplasm of infected macrophages in the presence and absence of B-1 cells. Culturing the cells with selective PGE2-neutralizing drugs inhibited PGE2 production and confirmed the role of this lipid mediator in IL-10 production. In contrast, we demonstrated that B-1 cells derived from IL-10 KO mice did not favor the intracellular growth of L. major. RESULTS: We report that B-1 cells promote the growth of L. major amastigotes inside peritoneal murine macrophages. We demonstrated that the modulatory effect was independent of physical contact between the cells, suggesting that soluble factor(s) were released into the cultures. We demonstrated in our co-culture system that B-1 cells trigger IL-10 production by L. major-infected macrophages. Furthermore, the increased secretion of IL-10 was attributed to the presence of the lipid mediator PGE2 in supernatants of L. major-infected macrophages. The presence of B-1 cells also favors the production of lipid bodies by infected macrophages. In contrast, we failed to obtain the same effect on parasite replication inside L. major-infected macrophages when the B-1 cells were isolated from IL-10 knockout mice. CONCLUSION: Our results show that elevated levels of PGE2 and IL-10 produced by B 1 cells increase L. major growth, as indicated by the number of parasites in cell cultures. PMID- 28588759 TI - CRISPR-based gene replacement reveals evolutionarily conserved axon guidance functions of Drosophila Robo3 and Tribolium Robo2/3. AB - BACKGROUND: Axon guidance receptors of the Roundabout (Robo) family regulate a number of axon guidance outcomes in bilaterian animals in addition to their canonical role in Slit-dependent midline repulsion. In the fruit fly Drosophila melanogaster, three Robo paralogs (Robo1, Robo2, and Robo3) each have specialized roles in regulating midline crossing and the formation of longitudinal axon pathways in the embryonic ventral nerve cord. The number of robo genes differs in other insects, and it is unknown whether the roles and/or signaling mechanisms of Drosophila Robos are shared in other insect species. To directly compare the axon guidance activities of Robo receptors in Drosophila and the flour beetle Tribolium castaneum, I have used a CRISPR/Cas9-based approach to replace Drosophila robo3 with Tribolium robo2/3. RESULTS: I show that when expressed from the robo3 locus in Drosophila embryos, Tribolium Robo2/3 (TcRobo2/3) protein is properly translated and localized to axons, where it reproduces the normal expression pattern of Drosophila Robo3. In embryos expressing TcRobo2/3 in place of robo3, two distinct subsets of longitudinal axons are guided properly to their normal positions in the intermediate neuropile, indicating that TcRobo2/3 can promote Robo3-dependent axon guidance decisions in developing Drosophila neurons. CONCLUSIONS: These observations suggest that the mechanism by which Drosophila Robo3 promotes longitudinal pathway formation is evolutionarily conserved in Tribolium, where it is performed by TcRobo2/3. The CRISPR/Cas9-based gene replacement approach described here can be applied to comparative evolutionary developmental studies of other Drosophila genes and their orthologs in other species. PMID- 28588760 TI - The impact of database restriction on pharmacovigilance signal detection of selected cancer therapies. AB - BACKGROUND: The aim of this study was to investigate whether database restriction can improve oncology drug pharmacovigilance signal detection performance. METHODS: We used spontaneous adverse event (AE) reports in the United States (US) Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Positive control (PC) drug medical concept (DMC) pairs were selected from safety information not included in the product's first label but subsequently added as label changes. These medical concepts (MCs) were mapped to the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms (PTs) used in FAERS to code AEs. Negative controls (NC) were MCs with circumscribed PTs not included in the corresponding US package insert (USPI). We calculated shrinkage-adjusted observed-to-expected (O/E) reporting frequencies for the aforementioned drug-PT pairs. We also formulated an adjudication framework to calculate performance at the MC level. Performance metrics [sensitivity, specificity, positive and negative predictive value (PPV, NPV), signal/noise (S/N), F and Matthews correlation coefficient (MCC)] were calculated for each analysis and compared. RESULTS: The PC reference set consisted of 11 drugs, 487 PTs, 27 MCs, 37 drug-MC combinations and 638 drug-event combinations (DECs). The NC reference set consisted of 11 drugs, 9 PTs, 5 MCs, 40 drug-MC combinations and 67 DECs. Most drug-event pairs were not highlighted by either analysis. A small percentage of signals of disproportionate reporting were lost, more noise than signal, with no gains. Specificity and PPV improved whereas sensitivity, NPV, F and MCC decreased, but all changes were small relative to the decrease in sensitivity. The overall S/N improved. CONCLUSION: This oncology drug restricted analysis improved the S/N ratio, removing proportionately more noise than signal, but with significant credible signal loss. Without broader experience and a calculus of costs and utilities of correct versus incorrect classifications in oncology pharmacovigilance such restricted analyses should be optional rather than a default analysis. PMID- 28588761 TI - Apixaban, concomitant medicines and spontaneous reports of haemorrhagic events. AB - INTRODUCTION: Little is known about the potential safety issues associated with apixaban in clinical practice and their reporting in spontaneous adverse event (SAE) databases. OBJECTIVE: To describe SAE reports associated with the oral anticoagulant apixaban from Australia, Canada and USA and to examine associated concomitant medicine use. METHODS: SAE report databases from Australia, Canada and the USA were examined for all reports of adverse events associated with apixaban and concomitant medicines from 1 January 2012 to 30 September 2014. Disproportionality analysis (proportional reporting ratio (PRR) and reporting odds ratio (ROR)) was conducted for the quantitative detection of signals using the USA database. RESULTS: There were 97 SAE reports associated with apixaban from Australia, 77 from Canada and 2877 from the USA. Reporting of haemorrhage (any type) was common, ranging from 18% for USA to 31% for Australia. Gastrointestinal (GI) haemorrhage was the most commonly reported haemorrhage, accounting for approximately 10% of adverse event reports across all countries. Positive signals were confirmed in the USA data (haemorrhage (any type) PRR, 12.1; chi2, 5582.2 and ROR, 13.4; 95% CI: 12.13-14.6; GI haemorrhage PRR, 11.8; chi2, 2325.4 and ROR, 12.3; 95% CI, 10.8-14.0). Reporting of concomitant use of medicines with the potential to increase bleeding risk ranged from 47.6% in Canada to 65.5% in Australia. CONCLUSION: A large proportion of adverse event reports for apixaban were associated with use of concomitant medicines which may have increased the risk of haemorrhage. PMID- 28588762 TI - Baclofen overdose mimicking anoxic encephalopathy: a case report and review of the literature. AB - A patient who has overdosed on baclofen can present with significant neurological symptoms suggestive of a serious brain insult, but with appropriate diagnosis and treatment they often fully recover within 72 h. If the patient had been maintained on chronic baclofen therapy prior to the overdose, one must be watchful for signs of baclofen withdrawal as recovery from the overdose occurs. PMID- 28588763 TI - Proof of concept of faecal egg nematode counting as a practical means of veterinary engagement with planned livestock health management in a lower income country. AB - BACKGROUND: The wellbeing and livelihood of farmers in impoverished regions of the world is intrinsically linked to the health and welfare of their livestock; hence improved animal health is a pragmatic component of poverty alleviation. Prerequisite knowledge and understanding of the animal health challenges facing cattle keepers in Malawi is constrained by the lack of veterinary infrastructure, which inevitably accompanies under-resourced rural development in a poor country. METHODS: We collaborated with public and private paraveterinary services to locate 62 village Zebu calves and 60 dairy co-operative calves dispersed over a wide geographical area. All calves were visited twice about 2 to 3 weeks apart, when they were clinically examined and faecal samples were collected. The calves were treated with 7.5 mg/kg of a locally-available albendazole drench on the first visit, and pre- and post- treatment trichostrongyle and Toxocara faecal egg counts were performed using a modified McMaster method. RESULTS: Our clinical findings point towards a generally poor level of animal health, implying a role of ticks and tick-transmitted diseases in village calves and need for improvement in neonatal calf husbandry in the dairy co-operative holdings. High faecal trichostrongyle egg counts were not intuitive, based on our interpretation of the animal management information that was provided. This shows the need for better understanding of nematode parasite epidemiology within the context of local husbandry and environmental conditions. The albendazole anthelmintic was effective against Toxocara, while efficacy against trichostrongyle nematodes was poor in both village and dairy co-operative calves, demonstrating the need for further research to inform sustainable drug use. CONCLUSIONS: Here we describe the potential value of faecal nematode egg counting as a platform for communicating with and gaining access to cattle keepers and their animals, respectively, in southern Malawi, with the aim of providing informative background knowledge and understanding that may aid in the establishment of effective veterinary services in an under-resourced community. PMID- 28580128 TI - Imagining tomorrow's university in an era of open science. AB - As part of a recent workshop entitled "Imagining Tomorrow's University", we were asked to visualize the future of universities as research becomes increasingly data- and computation-driven, and identify a set of principles characterizing pertinent opportunities and obstacles presented by this shift. In order to establish a holistic view, we take a multilevel approach and examine the impact of open science on individual scholars and how this impacts as well as on the university as a whole. At the university level, open science presents a double edged sword: when well executed, open science can accelerate the rate of scientific inquiry across the institution and beyond; however, haphazard or half hearted efforts are likely to squander valuable resources, diminish university productivity and prestige, and potentially do more harm than good. We present our perspective on the role of open science at the university. PMID- 28588765 TI - Evidence of disease control: a realistic concept beyond NEDA in the treatment of multiple sclerosis. AB - Although no evidence of disease activity (NEDA) permits evaluation of response to treatment in the systematic follow-up of patients with multiple sclerosis (MS), its ability to accomplish detection of surreptitious activity of disease is limited, thus being unable to prevent patients from falling into a non-reversible progressive phase of disease. A protocol of evaluation based on the use of validated biomarkers that is conducted at an early stage of disease would permit the capture of abnormal neuroimmunological phenomena and lead towards intervention with modifying therapy before tissue damage has been reached. PMID- 28588766 TI - How externalities impact an evaluation of strategies to prevent antimicrobial resistance in health care organizations. AB - BACKGROUND: The rates of antimicrobial-resistant organisms (ARO) continue to increase for both hospitalized and community patients. Few resources have been allocated to reduce the spread of resistance on global, national and local levels, in part because the broader economic impact of antimicrobial resistance (i.e. the externality) is not fully considered when determining how much to invest to prevent AROs, including strategies to contain antimicrobial resistance, such as antimicrobial stewardship programs. To determine how best to measure and incorporate the impact of externalities associated with the antimicrobial resistance when making resource allocation decisions aimed to reduce antimicrobial resistance within healthcare facilities, we reviewed the literature to identify publications which 1) described the externalities of antimicrobial resistance, 2) described approaches to quantifying the externalities associated with antimicrobial resistance or 3) described macro-level policy options to consider the impact of externalities. Medline was reviewed to identify published studies up to September 2016. MAIN BODY: An externality is a cost or a benefit associated with one person's activity that impacts others who did not choose to incur that cost or benefit. We did not identify a well-accepted method of accurately quantifying the externality associated with antimicrobial resistance. We did identify three main methods that have gained popularity to try to take into account the externalities of antimicrobial resistance, including regulation, charges or taxes on the use of antimicrobials, and the right to trade permits or licenses for antimicrobial use. To our knowledge, regulating use of antimicrobials is the only strategy currently being used by health care systems to reduce antimicrobial use, and thereby reduce AROs. To justify expenditures on programs that reduce AROs (i.e. to formally incorporate the impact of the negative externality of antimicrobial resistance associated with antimicrobial use), we propose an alternative approach that quantifies the externalities of antimicrobial use, combining the attributable cost of AROs with time-series analyses showing the relationship between antimicrobial utilization and incidence of AROs. CONCLUSION: Based on the findings of this review, we propose a methodology that healthcare organizations can use to incorporate the impact of negative externalities when making resource allocation decisions on strategies to reduce AROs. PMID- 28588767 TI - Effectiveness of various cleaning and disinfectant products on Clostridium difficile spores of PCR ribotypes 010, 014 and 027. AB - BACKGROUND: In healthcare facilities, Clostridium difficile infections spread by transmission of bacterial spores. Appropriate sporicidal disinfectants are needed to prevent development of clusters and outbreaks. In this study different cleaning/disinfecting wipes and sprays were tested for their efficacy against spores of distinctive C. difficile PCR ribotypes. METHODS: Four different products were tested; 1) hydrogen peroxide 1.5%; 2) glucoprotamin 1.5%; 3) a mixture of ethanol, propane and N-alkyl amino propyl glycine; and 4) a mixture of didecyldimonium chloride, benzalkonium chloride, polyaminopropyl, biguanide and dimenthicone as active ingredients. Tiles were contaminated with a test solution containing a concentration of 5x106CFU/ml spores of C. difficile strains belonging to PCR ribotypes 010, 014 or 027. The tiles were left to dry for an hour and then wiped or sprayed with one of the sprays or wipes as intended by the manufacturers. When products neutralized after 5 min, microbiological cultures and ATP measures were performed. RESULTS: Irrespective of the disinfection method, the microbial count log10 reduction of C. difficile PCR ribotype 010 was highest, followed by the reduction of C. difficile 014 and C. difficile 027. Overall, the wipes performed better than the sprays with the same active ingredient. On average, although not significantly, a difference in relative light units (RLU) reduction between the wipes and sprays was found. The wipes had a higher RLU log10 reduction, but no significant difference for RLU reduction was observed between the different C. difficile strains (p = 0.16). CONCLUSION: C. difficile spores of PCR ribotypes 014 and 027 strains are more difficult to eradicate than non-toxigenic PCR ribotype 010. In general, impregnated cleaning/disinfection wipes performed better than ready-to-use sprays. Wipes with hydrogen peroxide (1.5%) showed the highest bactericidal activity. PMID- 28588768 TI - Ovarian function following targeted anti-angiogenic therapy with bevacizumab. AB - Improvements in cancer therapy have enabled further insight into the long-term effects of treatment, including the highly prevalent gonadal failure. The focus of treatment has been shifted to the preservation of fertility, which may be achieved by preventing ovarian toxicity. To this end, new molecular-targeted agents, including monoclonal antibodies, have been developed and used in a standard procedure for managing different cancers. However, the prolonged antitumor activity of these drugs may cause the emergence of new toxic effects. The aim of the present review was to discuss the leading toxic effect of the anti angiogenic agent bevacizumab on ovarian function in female patients of reproductive age, which may be observed and expected during in clinical practice. The majority of bevacizumab-induced side effects are expected to be transient and eliminated within the anticipated drug clearance time frame; however, fundamental investigations on these effects are required for generating more evidence-based practice guidelines. PMID- 28588769 TI - The Glasgow prognostic score: Useful information when prescribing palliative radiotherapy. AB - The purpose of the present retrospective study was to investigate whether a score reflecting systemic inflammatory processes [the Glasgow Prognostic Score (GPS)] provides relevant information for radiation oncologists. GPS is a three-tiered score [0: normal C-reactive protein (CRP) and albumin; 1: one abnormal result; 2: increased CRP and low albumin]. Correlations between disease type and extent, resource utilization, survival and GPS were analyzed in 703 patients. In the subgroup with GPS 2, significantly higher rates of lung, adrenal gland and liver metastases were observed. An increasing GPS score was associated with a higher likelihood of anemia, leukocytosis and thrombocytosis. Comparable findings were made regarding utilization of palliative care resources, need for blood transfusion and intravenous administration of antibiotics. Compared with GPS 0 or 1, more patients with GPS 2 did not complete their prescribed course of radiotherapy. One-third of patients with GPS 2 received treatment during the final month of life. Multivariate analysis demonstrated that GPS was a significant prognostic factor for overall survival (median, 479, 136, and 61 days, for GPS 0, 1 and 2, respectively). In patients with GPS 2 and additional leukocytosis, the median survival was 38 days. In conclusion, GPS provides important prognostic information. This biomarker-based score may be considered for deciding fractionation, and should be validated further. PMID- 28588771 TI - Renal metastases as the initial presentation of papillary thyroid carcinoma: A case report and literature review. AB - Distant metastasis of thyroid carcinoma is rare, and it occurs particularly rarely in renal regions, which represent ~3% of all thyroid distant metastases, with fewer than 30 single case study reports existing in the literature. The present study (and subsequent literature review) of papillary thyroid carcinoma (PTC) reports the case of a 53-year-old male patient who presented with a left renal mass and who had no previous history of thyroid disease. Following renal and thyroid surgery, postoperative pathology confirmed the case to be a follicular variant of PTC, accompanied by renal metastasis. The patient exhibited brain metastasis during a later follow-up. In conclusion, thyroid metastases to the renal site are extremely rare events, particularly for men who present initially with renal neoplasms, which may easily be misdiagnosed as renal cell carcinoma. PTC tends to have a good prognosis; however, when it is accompanied by distant metastasis, the prognosis becomes less favorable. PMID- 28588770 TI - Radiation-associated colon cancer: A case report. AB - Radiation-associated colon cancer is a rare clinical entity. We herein describe the case of a patient with radiation-associated colon cancer who had undergone low anterior resection for rectal cancer following preoperative radiotherapy. Certain characteristics of radiation-associated colon cancer are highlighted. The patient was a 48-year-old man who had undergone low anterior resection for rectal cancer following preoperative radiotherapy at a total dose of 50 Gy, at the age of 29 years. When the patient presented at the University of Tokyo Hospital, 19 years after the surgery, he complained of severe anal pain and frequent defecation. Colonoscopy revealed two flat tumors in the sigmoid colon, located 10 cm to the oral side of the anastomosis site, which were diagnosed as well differentiated adenocarcinomas. In addition, colonoscopy identified five flat polyps near the tumors, which were resected endoscopically. Computed tomography and magnetic resonance imaging revealed a mass in the sigmoid colon and no evidence of distant metastasis. Laparoscopic-assisted intersphincteric resection of the rectum and sigmoid colon with diverting ileostomy was performed. There were no specific postoperative complications and the patient was discharged from the hospital on the 20th postoperative day. On pathological examination, the resected rectum and sigmoid colon contained two separate tumors and six flat polyps. The two tumors were diagnosed as well-differentiated adenocarcinomas with invasion of the subserosa and submucosa, respectively. A total of 17 regional lymph nodes without metastasis were resected. The six flat polyps were diagnosed as tubular adenomas. We herein present a case of a radiation-associated colon cancer in a patient who had undergone low anterior resection for rectal cancer following preoperative radiotherapy 19 years prior. Colonoscopic surveillance of radiation-associated colon cancer may be indicated for rectal cancer patients treated with preoperative radiotherapy, particularly for those with long-standing radiation-induced colitis. PMID- 28588772 TI - Ultrasound-guided core needle biopsy for differential diagnosis of thyroid nodules: A systematic review and meta-analysis. AB - Ultrasound-guided core needle biopsy (US-CNB) of thyroid nodules is a relatively new technique used in surgical workup. However, no systematic review of this method has yet been performed. In the present meta-analysis, literature databases consisting of Cochrane Library, Medline, Embase, Scopus and Google Scholar were searched. Following eligibility assessments of the studies, quality appraisals were performed on the included studies using the Quality Assessment Tool for Diagnostic Accuracy Studies-2 method. The data were systematically analyzed by using Review Manager (version 5.3) and Meta-Disc (version 1.4). Eight investigations were included, and the study qualities were good. There were 1,621 nodules included in the final meta-analysis. The summary estimated that US-CNB had a sensitivity of 0.96 [95% confidence interval (CI)=0.94-0.97] and a specificity of 0.96 (95% CI=0.94-0.97). Positive and negative likelihood ratios, and the diagnostic odds ratio of US-CNB were 18.20 (95% CI=2.21-156.41), 0.08 (95% CI=0.02-0.27) and 250.60 (95% CI=19.11-3286.76), respectively. The area under the summary receiver operating characteristic curve was 0.979. Therefore, US-CNB may be considered as a reliable method in the assessment of thyroid nodules, and has an acceptable risk of complications. PMID- 28588773 TI - Target volume dose and clinical outcome in radiotherapy for primary marginal zone lymphoma of the ocular adnexa. AB - The aim of the present study was to determine the optimal dose and optimal target volume for marginal zone lymphoma of the ocular adnexa. Between January, 2008 and December, 2013, 40 patients with histologically proven primary marginal zone lymphoma of the ocular adnexa who underwent radiotherapy at the Tokyo Medical University were evaluated. The prescribed dose was 30 Gy in 15 fractions to the iso-center. Doses to the gross tumor volume (GTV), conjunctiva, bulbus oculi, retina and retrobulbar space were investigated, and the association between dose volume factors and clinical outcome was analyzed. The overall and local progression-free survival rates at 3 and 5 years were 100% during a median observation period of 32 months. Two patients relapsed in the contralateral ocular adnexa. The progression-free survival rates at 3 and 5 years were 100 and 93.3%, respectively. The mean dose was 2.0 and 1.9 Gy for targets receiving 95% of the GTV dose (D95). The minimum dose was 0.9-2.0 Gy (median, 1.8 Gy). Thus, primary marginal zone lymphoma of the ocular adnexa favorably responded to lower doses of radiation, compared with prescribed doses to the iso-center. A radiation dose of 27 Gy in 15 fractions at D95 of GTV appeared to be optimal. PMID- 28588774 TI - Solitary pulmonary caseating granulomas: A 5-year retrospective single-center analysis. AB - Solitary pulmonary caseating granulomas (SPCGs) are a characteristic type of tuberculomas associated with infection with non-tuberculous mycobacteria (NTM) and other microbes; however, their significance remains unclear. The aim of the present study was to describe the clinical characteristics of patients with SPCGs in terms of diagnosis, presence of lung cancer and treatment status. A retrospective analysis of 17 immunocompetent patients with histopathologically confirmed caseating granulomas after undergoing video-assisted thoracoscopic surgery (VATS) was conducted at our center between 2011 and 2015. The patients comprised 10 men and 7 women with a mean age of 59.1+/-14.4 years. Of the 17 patients, 14 (82.4%) were asymptomatic and the lesions were discovered incidentally. In 2 patients the SPCGs were accompanied by a small satellite nodule (SPCG mean diameter, 16.2+/-5.1 mm). Mycobacteria, including Mycobacterium tuberculosis (11.8%), Mycobacterium avium (11.8%) Mycobacterium kansasii (23.5%) and other Mycobacterium spp. (5.9%), were isolated from 9 of the patients (52.9%). Concurrent lung cancer was present in 3 patients (17.6%). When microbial agents could not be isolated, the interferon-gamma release assay was useful for diagnosis. Positron emission tomography was not found to be useful for differentiating SPCGs from lung cancer, or for differentiating tuberculomas from NTM pulmonary nodules (NTMPNs). NTMPNs in cases of SPCGs were diagnosed more frequently in men. The findings indicate that a course of observation may be sufficient for patients in whom an SPCG from NTM (NTMPN) is identified by VATS. However, the presence of concurrent lung cancer in certain cases indicates that malignancy should not necessarily be excluded, particularly in NTMPNs, and highlights the necessity of aggressive diagnosis by VATS. PMID- 28588775 TI - A meta-analysis: The diagnostic values of long non-coding RNA as a biomarker for gastric cancer. AB - Long non-coding RNAs (lncRNAs) have been identified as novel biomarkers for the diagnosis, staging and prognosis for gastric cancer. However, various studies have reported a series of significances based on different diagnostic values. Therefore, the current study performed a systematic review and meta-analysis to evaluate the diagnostic accuracy of lncRNAs for gastric cancer, and to discuss lncRNA types and sources of heterogeneity. The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, EMBASE, the Chinese Biomedical Literature Database, the China Academic Journals Full-text Database and the Chinese Scientific Journals Database were systematically searched for potential studies. Studies were included if they were associated with lncRNAs, gastric cancer and reported diagnostic outcomes. Analysis of diagnostic values was used to summarize the overall test performance of lncRNAs. Ten studies were included in this meta analysis. The ranges of the diagnostic value of lncRNAs for gastric cancer were as follows: Sensitivity was 0.45-0.83, and pooled sensitivity was 0.63; specificity was 0.60-0.93, and pooled specificity was 0.75; positive likelihood ratio was 1.80-6.92, and pooled positive likelihood ratio was 2.51; negative likelihood ratio was 0.23-0.67, and pooled negative likelihood ratio was 0.50; diagnostic odds ratio was 3.33-13.75, and pooled diagnostic odds ratio was 5.47. An overall area under the curve value of the summary receiver operating characteristic curve was 0.7550. LncRNAs did not have a high accuracy for identifying gastric cancer at present, but may be a useful screening tool for diagnosing gastric cancer due to their correlation with gastric cancer biological features. LncRNAs are potential biomarkers for gastric cancer if the screening strategy is altered, or they are combined with other biomarkers to diagnose gastric cancer. PMID- 28588776 TI - Management of infusion reactions associated with cetuximab treatment: A case report. AB - Cetuximab is a drug targeting the epidermal growth factor receptor, which is indicated for the treatment of unresectable advanced or recurrent head and neck or colorectal cancer. Cetuximab also enhances the cytotoxic effects of radiation in squamous cell carcinoma. The severity of infusion reactions (IR) is categorized from grade 1 to 5; grades 3 and 4 are associated with life threatening reactions (anaphylaxis), whereas grade 5 indicates death. The incidence of grade 3-4 IR with premedication is reported to be 1.1%. We herein describe a case of a 77-year-old man who developed IR during intravenous administration of cetuximab. The patient developed grade 3-4 anaphylaxis with pruritus, rash and urticaria, followed by hypotension and bradycardia. The timely diagnosis and treatment with intravenous infusion of a vasopressor drug and Ringer's acetate solution proved to be effective. The case presented herein demonstrated an unfeatured aspect of cetuximab-related IR as dermatological reactions over the entire body followed by circulatory collapse. PMID- 28588777 TI - The combination of systemic chemotherapy and local treatment may improve the survival of patients with unresectable metastatic colorectal cancer. AB - With the development of systemic chemotherapy, the survival time of patients with advanced colorectal cancer (CRC) has increased. In addition, local treatments, such as microwave ablation and radioactive seed implantation, have been shown to be effective. However, the number of studies reporting on the effect of systemic chemotherapy combined with local treatments is limited. The present study was conducted to determine the effect of local treatment combined with systemic chemotherapy in patients with initial unresectable metastatic CRC (mCRC). Clinicopathological and follow-up data from 273 patients with initial unresectable mCRC between April, 2007 and October, 2013 were retrospectively analyzed. A total of 51 patients received minimally invasive treatments combined with systemic chemotherapy and 39 patients achieved tumor-free survival (TFS). The median TFS time was 9 months (range, 2-45 months); the median overall survival (OS) time was 40 months (range, 12-108 months). In patients who did not achieve TFS, the OS was 37 months. Thus, patients who achieved TFS exhibited a significantly longer OS compared with those who did not achieve TFS (P=0.049). The results of the univariate analysis demonstrated that certain characteristics, such as the number of lesions and maximum tumor diameter, were associated with the achievement of TFS. The patients assessed herein achieved TFS in response to local treatments combined with systemic chemotherapy. Furthermore, the achieved TFS provided an OS benefit. PMID- 28588778 TI - Rexin-G(r), a tumor-targeted retrovector for malignant peripheral nerve sheath tumor: A case report. AB - Soft tissue sarcoma is a rare neoplasm of mesenchymal origin, accounting for only ~1% of all adult cancers and consisting of 75 histological subtypes. In the present report, the unique case of a 14 year-old female with metastatic malignant peripheral nerve sheath tumor (formerly, malignant melanotic schwannoma) of the parotid gland, who experienced a durable response and sustained tumor control with Rexin-G(r), a tumor-targeted retroviral expression vector encoding an anti cyclin G1 construct, is described. Post-parotidectomy, and prior to the administration of Rexin-G(r), the patient received various chemotherapy regimens, including doxorubicin, ifosfamide, temozolomide, sorafenib, and an immunological therapy with interleukin-2, which only resulted in the further progression of lung metastases. The patient subsequently participated in a Phase 1/2 gene therapy study, during which she received intravenous Rexin-G(r) as monotherapy for two years with minimal drug-associated adverse events. Currently, the patient has no evidence of active disease 9 years after commencing the Rexin-G(r) treatment, and with no additional anti-cancer therapy. In conclusion, Rexin-G(r) may be a viable therapeutic option for malignant peripheral nerve sheath tumors, and should be further investigated in prospective histology-specific clinical trials for this type, and possibly other types, of chemotherapy-resistant sarcoma. PMID- 28588779 TI - Pancreatic acinar cell carcinoma presenting with panniculitis, successfully treated with FOLFIRINOX: A case report. AB - Pancreatic acinar cell carcinoma (PACC) is a rare tumor of the exocrine pancreas, representing only 1% of all pancreatic malignancies. A 50-year-old man presented with edema of the thumb joints bilaterally, followed by an appearance of masses in the bilateral lower extremities and fever (38 degrees C). The masses were diagnosed as panniculitis by skin biopsy, and multiple intraperitoneal masses were incidentally detected on pelvic magnetic resonance imaging performed to investigate the leg abnormalities. The patient was referred to the Kyushu University Hospital for further investigation, and fluorodeoxyglucose-positron emission tomography/computed tomography (CT) revealed high-uptake tumors in the pancreatic tail, in the periphery of the liver, and in the pelvis. Laboratory examinations revealed high serum concentrations of pancreatic exocrine enzymes, such as lipase, trypsin, elastase 1 and pancreatic phospholipase A2. Histological examination of a bioptic specimen obtained from a hepatic lesion revealed proliferation of atypical cells arranged in a tubular or glandular pattern. Immunohistochemical staining revealed that the atypical cells were positive for cytokeratin (CK)7, CK19 and lipase, but negative for CK20 and thyroid transcription factor-1, leading to a final diagnosis of acinar cell carcinoma of the pancreatic tail (T4bN0M1, stage IV according to the 7th edition of the TNM Classification of Malignant Tumors). Combined chemotherapy with oxaliplatin, irinotecan and fluorouracil (FOLFIRINOX) was administered and fever was soon alleviated. The serum levels of lipase also declined and panniculitis completely resolved. As of the start of the 8th course of chemotherapy, the levels of the pancreatic exocrine enzymes were within normal ranges and CT revealed partial response. Therefore, the severe lipase hypersecretion syndrome was well controlled by the FOLFIRINOX regimen and shrinkage of the mass was also achieved. Thus, the FOLFIRINOX regimen may represent an effective treatment option for advanced PACC. PMID- 28588780 TI - Clinical outcome of patients treated with re-irradiation for spine or pelvic bone metastasis: A multi-institutional analysis of 98 patients. AB - The present study aimed to describe the clinical results of re-irradiation (Re RT) for spine or pelvic bone metastasis at the same initial irradiated area. Between April 2010 and March 2014, cases involving 98 patients with spine or pelvic bone metastasis who had undergone Re-RT at five institutions were reviewed. The clinical outcomes following Re-RT were evaluated, including overall survival (OS) and severe adverse events. The median time interval from initial radiation therapy (RT) to Re-RT was 439 days (range, 23-4,993 days), and the median duration of patient follow-up was 256 days (range, 11-2,284 days). The median biological effective dose for the Re-RT was 150 Gy2 (range, 17-240 Gy2; alpha/beta = 2). Severe late adverse events occurred in two patients who underwent three-dimensional conformal radiotherapy for lumbar spine or pelvic bone metastases, which may be associated with tumor progression. The median survival time following Re-RT was 255 days, and the actuarial OS rate at 1 year was 36%. The interval between initial RT and Re-RT, and their performance statuses (PS) were significant independent prognostic factors for OS rates in multivariate analysis. Re-RT for spine or pelvic bone metastases is a relatively acceptable option with low risk of anticipated severe adverse events, particularly for patients with good PS following a long disease-free interval. PMID- 28588782 TI - Rapidly progressing large-cell neuroendocrine carcinoma arising from the uterine corpus: A case report and review of the literature. AB - Large-cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine tumor. LCNECs arising from the genital organs are highly malignant and rare, with <20 cases of LCNEC developing from the uterine endometrium reported to date. We herein present the case of a patient with LCNEC of the endometrium. The patient was a 52-year-old woman, who exhibited lower abdominal pain and rapid uterine enlargement during outpatient treatment for uterine myoma. The endometrial biopsy suggested a diagnosis of poorly differentiated carcinoma or carcinosarcoma. Based on magnetic resonance imaging and positron emission tomography/computed tomography, endometrial stromal sarcoma was suspected. The serum lactate dehydrogenase level was abnormally high. Due to the suspicion of stage IIIC malignant tumor of the uterine corpus, surgery was performed. The pathological diagnosis was stage IIIC2 LCNEC of the endometrium. Recurrence occurred in the vaginal stump, and concurrent chemoradiotherapy (CCRT) was initiated 1 month after the surgery. The residual lesions markedly shrank, but metastasis to the upper abdominal region and cervix subsequently developed. CCRT was attempted, but the associated adverse effects were severe and was switched to palliative treatment. The patient eventually succumbed to the disease 309 days after surgery. PMID- 28588781 TI - p53 protein expression in patients with myelodysplasia treated with allogeneic bone marrow transplantation. AB - Tumor protein 53 mutations adversely affect the prognosis of myelodysplastic syndromes (MDS); however, few studies have reported on the prognostic significance of the expression of p53 protein in MDS. The current study investigated p53 immunoreactivity (p53-IR) in bone marrow biopsies (BMBs) obtained at diagnosis from 18 patients (6 females and 12 males; mean age, 50.5 years) with MDS that underwent bone marrow transplantation (BMT) to determine the associations between clinical and histopathological data and outcome. There were 5 refractory cytopenia with multilineage dysplasia (RCMD) and 13 refractory anemia with excess blasts, type 2 (RAEB-2) cases. p53-IR was assessed as the percentage of hematopoietic cells exhibiting intense nuclear staining. The cut off for positivity was 5% of stained cells. A positive p53-IR was detected in 7 patients (38.9%) and was associated with age (P=0.005) and pattern of BM fibrosis (P=0.03). A positive p53-IR was more frequent in females, in highly cellular BMBs and in RAEB-2 cases. Overall survival (OS) was associated with patients' age (P=0.01), hemoglobin level (P=0.04), type of MDS (P=0.05), degree of BM fibrosis (P=0.006) and number of BM blasts (P=0.05). The OS of patients with negative p53 IR tended to be longer compared with that of patients with positive p53-IR, although this difference was not statistically significant (P=0.1). Despite the limitation of the low number of cases, the present results indicate that a positive p53-IR at diagnosis is associated with clinically more aggressive MDS subtypes and adverse histological prognostic factors, such as BM fibrosis. Therefore, the evaluation of p53 expression of BMBs of patients with MDS may be introduced in the histopathological work-up of the disease. PMID- 28588783 TI - Salivary duct carcinoma treated with cetuximab-based targeted therapy: A case report. AB - Salivary duct carcinoma is a highly aggressive disease with a poor prognosis. Surgical resection is currently the only curative treatment, as there is no effective systemic therapy for this malignancy. Recently, trastuzumab has been shown to exhibit therapeutic efficacy in the treatment of salivary duct carcinoma; similarly, molecularly targeted agents, such as cetuximab, are expected to be useful for salivary duct carcinoma treatment. We herein describe the case of a 56-year-old man diagnosed with salivary duct carcinoma in the left submandibular region, with ipsilateral multiple metastases to the neck lymph nodes. Radical resection of the tumor and submandibular gland with neck dissection were performed. One month after radical surgery, computed tomography (CT) scans indicated metastasis in the lower lobe of the left lung. CT-guided transthoracic fine-needle aspiration biopsy revealed a single metastasis and lung metastasectomy was immediately performed. The tumor cells of the primary lesion and those of the lung metastasis were immunohistochemically positive for epidermal growth factor receptor. One month later, multiple right lung metastases appeared, and the patient was treated with cisplatin/5-fluorouracil (5-FU) chemotherapy plus cetuximab, achieving a complete radiographic response. However, multiple lung metastases developed during adjuvant weekly cetuximab monotherapy. Subsequently, treatment with S-1 and weekly cetuximab was initiated, and the multiple lung metastases have been maintained as stable disease for 5 months. To the best of our knowledge, this is the first report of cetuximab use for the treatment of salivary duct carcinoma. Although cisplatin/5-FU chemotherapy plus cetuximab was efficacious in treating the lung metastasis, cetuximab monotherapy was insufficient for controlling tumor growth. PMID- 28588784 TI - Thyrolipomatosis: A case report with review of the literature. AB - Fatty tissue is not usually present within the thyroid gland. Only a few fat containing thyroid lesions have been reported to date, and thyrolipoma is the most common fat-containing lesion of the thyroid gland. Thyrolipomatosis is a condition characterized by diffuse mature adipose cell infiltration of the normal thyroid gland. In this report, we describe what is, to the best of our knowledge, the 12th documented case of thyrolipomatosis, and review the fat-containing lesions of the thyroid gland. A 68-year-old Japanese woman presented with a neck mass that had first been noticed ~7 years earlier. A computed tomography scan revealed diffuse thyroid gland enlargement and total thyroidectomy was performed. The histopathological examination revealed that mature fatty tissue was diffusely distributed throughout the thyroid gland, as well as among the hyperplastic follicles. Capsular formation or amyloid deposition were not observed. Nuclear grooves or intranuclear cytoplasmic inclusions were not observed. Accordingly, thyrolipomatosis was diagnosed. Albeit rare, various neoplastic and non neoplastic thyroid lesions may contain mature fatty tissue. Therefore, thyrolipomatosis must be included in the differential diagnostic consideration of fat-containing lesions of the thyroid gland. PMID- 28588785 TI - Sporadic giant intra-abdominal desmoid tumor: A radiological case report. AB - Desmoid tumor (DT) is a locally invasive form of fibromatosis, comprising only 0.03% of all tumors. DTs occur more frequently in patients with familial adenomatous polyposis and Gardner's syndrome, as intra-abdominal or anterior abdominal wall tumors, whereas sporadic DTs are more likely to be extra-abdominal (only 5% of sporadic DTs are intra-abdominal). There is also an association of DTs with prior trauma, surgery, estrogen exposure and childbirth. Imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI) are used for preoperative diagnosis and for the planning of the surgery. Following surgery, CT and MRI are used to detect recurrence and to monitor the tumor's response to radiotherapy or medical therapy for unresectable or recurrent tumors. We herein report a rare case of a sporadic giant intra-abdominal DT in a 28-year-old female patient without any predisposing factors, and highlight the importance of including DT in the differential diagnosis of huge intra-abdominal masses. PMID- 28588786 TI - Isolated brain metastases prior to locoregional recurrence in hilar cholangiocarcinoma. AB - Isolated brain metastases prior to locoregional recurrence from hilar cholangiocarcinoma (HCCA) following curative resection are an extremely rare event. Very few reports regarding brain metastasis prior to locoregional recurrence following curative resection have been published due to the fact that to differentiate brain metastases from HCCA recurrence is challenging, particular in the early stages, since the neurological findings of brain metastasis are occult and subtle. Any patient with HCCA who has undergone radical resection and subsequently presented with a further onset of neurological symptoms should be evaluated for brain involvement. The present case study describes a patient with HCCA who underwent curative resection, and experienced isolated brain metastases prior to locoregional recurrence. PMID- 28588788 TI - Survival of patients with lung cancer and diabetes mellitus. AB - Diabetes mellitus (DM) and lung cancer are two highly globally prevalent diseases. The current study aimed to determine the prognostic significance of DM comorbidity in patients with lung cancer. All patients diagnosed at Tsukuba Medical Center Hospital and Mito Medical Center, (University of Tsukuba, Ibaraki, Japan) between April 1999 and March 2012 were followed up to 2015 and were retrospectively analyzed. DM was defined as a fasting plasma glucose (FPG) level >=126 mg/dl, a non-FPG level >=200 mg/dl, or a hemoglobin (Hb) A1c level >=6.5%. Additionally, patients taking medication for diabetes and those with a history of using such medications were also classified as having DM. During the study period, 1,798 patients with lung cancer were diagnosed. Within this cohort, 338 (18.8%) were classed as having lung cancer and DM. In univariate and multivariate analyses, smoking status, poorer performance status, small cell lung cancer pathology, metastatic disease and supportive care were the only unfavorable prognostic factors (all P=0.001). Additionally, multivariate analysis revealed that existing DM was an unfavorable disease-modifying factor (P=0.03612). Therefore, DM comorbidity adversely affects lung cancer outcomes. To provide prolonged quality of survival, appropriate pre-evaluation of lung cancer, as well as the patient's medical condition, including DM, is required. PMID- 28588787 TI - Allogenic natural killer cell immunotherapy of sizeable ovarian cancer: A case report. AB - Masses are often detected in the abdomen of patients with sizeable ovarian cancer. There are currently no effective treatments available for late-stage ovarian cancer. Immunotherapy is gaining increasing attention worldwide in the clinical setting due to its ability to eliminate tumor cells and its favorable toxicity profile. We herein report the case of a 60-year-old woman who received allogenic natural killer (NK) cell immunotherapy for a sizeable ovarian carcinoma and achieved a noteworthy response. NK cells were isolated from the patient's own peripheral blood mononuclear cells, and the cell numbers were increased to 8-10 billion. The activated cells were expanded ex vivo for 14 days prior to intravenous infusion. After six infusions of NK cell therapy >3 months, the level of carbohydrate antigen 125 decreased significantly (from 11,270 to 580 U/ml). Furthermore, the size of the masses in the abdomen was markedly reduced. Overall, the treatment had few adverse effects and it prolonged patient survival. The present data and the patient response suggest that allogenic NK cell immunotherapy is a promising approach for ovarian cancer, with few treatment related adverse effects. The patient received six intravenous infusions of allogenic HANK cells between March, 2015 and June, 2015, but discontinued in October, 2015 and succumbed to the disease in March, 2016 following relapse. PMID- 28588789 TI - Curative effect of stereotactic body radiotherapy for unresectable massive primary liver cancer. AB - The aim of this study was to evaluate the curative effect of gamma knife stereotactic body radiotherapy (SBRT) for unresectable massive primary liver cancer. A total of 69 patients with unresectable massive (>10 cm) primary liver cancer who were treated by SBRT at the Department of Radiation Oncology of the 323 Hospital of People's Liberation Army (Xi'an, China) between October, 2006 and October, 2010, were analyzed. According to the Union for International Cancer Control TNM staging guidelines, the patients were graded as stage T1 (n=8), T2 (n=12), T3 (n=21) and T4 (n=28). None of the patients had lymph node metastasis, whereas 45 patients had portal vein tumor thrombosis. The Child-Pugh class was A (n=49), B (n=15) and C (n=5). The visible tumor volume +/- standard deviation was 810+/-213 cm3. The patients received a total radiation dose of 50-60 Gy, with a dose fractionation of 4-6 Gy/fx, administered for a total of 9-12 times, 2-5 times/week. A total of 8 patients succumbed to the disease within 3 months after gamma knife treatment and were not included in the evaluation of the curative effect. The total effectiveness rate was 59.0% (36/61) and the median survival was 17.4 months for all the patients included in the study. The 1-, 2-, and 3 year overall survival rates were 71, 30 and 22%, respectively. In conclusion, SBRT appears to be effective for unresectable massive primary liver cancer. PMID- 28588790 TI - Ibuprofen and fatal lung cancer: A brief report of the prospective results from the Third National Health and Nutrition Examination Survey (NHANES III). AB - Chronic inflammation appears to increase the risk of lung cancer and, reciprocally, agents that reduce inflammation have been found to reduce this risk. However, few prospective studies have assessed whether there exists an association between lung cancer and the use of non-steroidal anti-inflammatory drugs (NSAIDs). In the present study, the association between fatal lung cancer and NSAIDs was investigated using cohort data from the Third National Health and Nutrition Examination Study (NHANES III). Baseline data were collected on smoking, NSAID use and other lifestyle factors for 10,735 participants during 1988-1994, with cause-specific mortality status ascertained through probabilistic record matching based on the National Death Index until 2006. Cox proportional hazards regression models were conducted to estimate hazard ratios (HRs) and confidence intervals (CIs) for NSAID use and death from lung cancer, controlling for current smoking and other covariates. During the 18 years of follow-up, 269 participants succumbed to lung cancer, of whom 252 (93.6%) reported a history of cigarette smoking. Since all but 17 of the 269 fatal lung cancer cases occurred among current or former smokers, estimates of NSAID effects were ascertained from a sub-cohort of 5,882 individuals who reported a history of past or current cigarette smoking. Multivariate regression models revealed that regular use of ibuprofen resulted in a 48% reduced risk of lung cancer mortality (HR=0.52, 95% CI: 0.33-0.82, P<0.01). The main effects of other compounds tested, such as aspirin or acetaminophen, were not statistically significant. Our results suggest that high-risk subgroups of smokers may benefit from the regular use of specific NSAIDs, which may prove to be a useful strategy for lung cancer prevention. PMID- 28588791 TI - Synchronous Adie's syndrome and type 1 antineuronal nuclear antibody (anti-Hu) related paraneoplastic neurological syndromes as predictors of complete response in limited-stage small-cell lung cancer: A case report. AB - Adie's syndrome (AS) and paraneoplastic sensorimotor neuropathy with cerebellar ataxia (PSN CA) are extremely rare, rapidly progressive, autoimmune diseases associated with the development of antibodies against neuronal-specific Hu proteins that are abnormally expressed in small-cell lung cancer (SCLC). We herein present the unique case of a 55-year-old obese woman, previous heavy smoker, who, during treatment with standard cisplatin-etoposide chemotherapy for limited-stage SCLC, developed simultaneous AS and worsening symptoms consistent with PSN CA that led to significant neurological disability and severe axonal electrophysiological pattern on nerve conduction studies. Serology confirmed the presence of low-titre type 1 antineuronal nuclear antibodies (ANNA-1), previously referred to as anti-Hu antibodies. Following plasmapheresis, immunosuppressive therapy and physical rehabilitation, the neurological symptoms progressively improved. The tumour completely regressed, with no recurrence detected on subsequent radiological examinations. The aim of this case was to highlight the importance of a multidisciplinary team approach for early recognition and rapid treatment of paraneoplastic neurological syndromes (PNS) as key to achieving significant recovery and marked improvement of the neurological deficit. This report extends the literature by confirming earlier studies showing that the presence of serum ANNA-1 in SCLC, an aggressive type of pulmonary carcinoma that is challenging to treat, may portend a more favourable prognosis and response to chemotherapy. Thus, patients with SCLC and new-onset neurological symptoms should be tested for ANNA-1. The role of a multimodality approach to treating PNS is also emphasized. PMID- 28588792 TI - Erythropoietin for cancer-associated malignant anemia: A meta-analysis. AB - The present study aimed to evaluate the effectiveness of erythropoietin (EPO) for improving cancer-associated malignant anemia. A search was performed for randomized clinical trials, conducted according to the Cochrane manual, using electronic databases including PubMed, EMBASE, the Cochrane Library and ClinicalTrails.gov up to 15 August 2015. A total of 6 eligible studies from 5 articles enrolling a total of 453 patients were entered into the current meta analysis. Upon EPO treatment, there were significant differences in the change in hemoglobin (HB) levels compared with the placebo at short-term follow-up [mean difference (MD)=0.66; 95% confidence interval (CI), 0.14-1.18; I2=Not applicable; P=0.01) and long-term follow-up (MD=0.10; 95% CI, 0.02-0.18; I2=Not applicable; P=0.01) under the random effects model. For changes in hematocrit (HCT) compared with the placebo, the results revealed there were significant differences at short-term follow-up (MD=2.47; 95% CI, 0.75-4.19; I2=Not applicable; P=0.005) and long-term follow-up (MD=7.60; 95% CI, 6.15-9.05; I2=Not applicable; P<0.00001) under the random effects model. Compared with the placebo in short-term follow-up under the fixed effects model with homogeneity, the result was a significant difference for the transfusion ratio [relative risk (RR)=0.81; 95% CI, 0.67- 0.97; I2=34%; P=0.02) and the transfusion requirements (MD=-0.45; 95% CI, -0.92, 0.03; I2=6%; P=0.07). Funnel plots did not detect any publication bias. These results suggest that EPO was beneficial to alleviate cancer-associated anemia and improve survival outcomes for patients with cancer. PMID- 28588793 TI - Double-blind randomized study of oral glutamine on the management of radio/chemotherapy-induced mucositis and dermatitis in head and neck cancer. AB - This randomized clinical trial was designed to determine whether glutamine administration was effective in reducing the incidence and severity of mucositis and dermatitis induced by radiotherapy (RT) or chemoradiotherapy (CHRT) in patients with head and neck cancer (HNC). Fifty patients were randomized to receive orally either L-Glutamine or placebo (25 patients in each arm). In the glutamine-treated group, 10 g of oral glutamine was administered three times daily. The primary endpoint was to compare the appearance of clinical mucositis between groups at the 6th week, according to the Common Terminology Criteria for Adverse Events. Secondary endpoints were: Functional mucositis, mucositis onset, cervicofacial dermatitis, pain, weight loss and assessment of quality of life (according to the M.D. Anderson Symptom Inventory-Head and Neck). In total, 76 and 87.5% developed clinical mucositis in the glutamine and placebo group, respectively. The incidence and severity grade of mucositis at the 6th week did not exhibit statistically significantly differences between the two groups, although it had a higher value in the placebo group. Significant reduction of dermatitis incidence (P=0.038) and severity (P=0.032) was found in the glutamine group. There were no differences in other outcomes such as pain, weight loss and mucositis onset, in treatment parameters including concomitant chemotherapy, radiation dose and previous surgery, or in quality of life. The present study revealed that glutamine provided slight clinical effects compared with placebo in terms of reducing oral mucositis induced by RT or CHRT in patients with HNC at the 6th week; however, the results were not statistically significant. Although the findings suggested a significant benefit in reducing the incidence and severity of dermatitis, further confirmatory studies are required. PMID- 28588794 TI - Intrahepatic biloma following transcatheter arterial chemoembolization for hepatocellular carcinoma: Incidence, imaging features and management. AB - Repeat transcatheter arterial chemoembolization (TACE) becomes more challenging for patients with intrahepatic biloma following TACE for hepatocellular carcinoma (HCC). The purpose of this study was to investigate the clinical course, incidence, imaging features and outcome and to explore the reasonable therapy scheme for intrahepatic biloma following TACE for HCC.A total of 4,695 TACE procedures were performed for 1,923 patients with HCC. Twenty patients with intrahepatic biloma following TACE were studied retrospectively. The incidence of intrahepatic biloma was 1.04% in this study. The 20 patients underwent 55 TACE procedures (mean, 2.75). Portal vein invasion was found in half of the patients. Eleven patients developed round solitary or multiple cystic biloma, 6 patients had branched biloma and 3 patients developed both cystic and branched biloma. Percutaneous drainage was applied for 4 patients. One patient underwent partial hepatectomy and one mortality occurred due to progressive biloma and multiple organ failure. Although severe intrahepatic biloma following TACE is rare, the procedure should be performed with caution. Timely and appropriate management, including percutaneous drainage, partial hepatectomy and antibiotic administration should be performed in the case of any signs of infection. PMID- 28588796 TI - Analysis of the incidence of tumor lysis syndrome in patients with hematological malignancies treated with rasburicase. AB - The purpose of this study was to assess the incidence of tumor lysis syndrome (TLS) in patients with hematological malignancies treated with rasburicase, and to evaluate the dose and duration of rasburicase administration. A total of 52 patients were enrolled. The background of the patients, incidence of TLS and laboratory data were retrospectively examined; in addition, the dose and duration of rasburicase administration and the factors affecting the onset of TLS were evaluated and compared among TLS risk categories. During the study period, 2 (3.8%) of the patients developed clinical TLS and 24 (46.2%) developed laboratory TLS (LTLS). Although the LTLS rate was very high, there were no life-threatening cases of TLS. The median daily dose of rasburicase administered to all patients was 7.5 mg/day (interquartile range, 7.5-9.0 mg/day), and the daily weight-based dose was 0.147 mg/kg/day (range, 0.126-0.178 mg/kg/day). The administration duration was 3 days (interquartile range, 3-4 days). Additionally, there was no significant association between TLS risk classification and daily rasburicase administration dose, duration, or post-administration laboratory data. The factors affecting the onset of TLS included serum uric acid level, as well as serum creatinine and phosphate levels. Rasburicase was highly effective in the prevention and management of hyperuricemia, even at a low-dose (7.5 mg/day) and a duration that was 3 days shorter compared with that recommended by the manufacturer. Therefore, clinicians should administer rasburicase based on their clinical judgment, taking into consideration the cost-effectiveness of this therapy. PMID- 28588795 TI - Cancer survival in Qidong between 1972 and 2011: A population-based analysis. AB - Population-based cancer survival is an improved index for evaluating the overall efficiency of cancer health services in a given region. The current study analysed the observed survival and relative survival of leading cancer sites from a population-based cancer registry between 1972 and 2011 in Qidong, China. A total of 92,780 incident cases with cancer were registered and followed-up for survival status. The main sites of the cancer types, based on the rank order of incidence, were the liver, stomach, lung, colon and rectum, oesophagus, breast, pancreas, leukaemia, brain and central nervous system (B and CNS), bladder, blood [non-Hodgkin's lymphoma (NHL)] and cervix. For all malignancies combined, the 5 year observed survival was 13.18% and the relative survival was 15.80%. Females had higher observed survival and relative survival (19.32 and 22.71%, respectively) compared with males (9.63 and 11.68%, respectively). The cancer sites with the highest five-year relative survival rates were the female breast, bladder, cervix and colon and rectum; followed by NHL, stomach, B and CNS cancer and leukaemia. The poorest survival rates were cancers of oesophagus, lung, pancreas and liver. Higher survival rates were observed in younger patients compared with older patients. Cancers of the oesophagus, female breast and bladder were associated with higher survival in middle-aged groups. Improved survival rates in the most recent two 5-year calendar periods were identified for stomach, lung, colon and rectum, oesophagus, female breast and bladder cancer, as well as leukaemia and NHL. The observations of the current study provide the opportunity for evaluation of the survival outcomes of frequent cancer sites that reflects the changes and improvement in a rural area in China. PMID- 28588797 TI - Widespread subdural metastasis from breast cancer progressing rapidly with cerebral herniation: A case report. AB - We herein present the case of a 49-year-old female patient presenting with nausea and headache. The patient's medical history included breast cancer with bone and lymph node metastasis. Computed tomography (CT) examination revealed a high density lesion in the right subdural space, suggesting hematoma. During surgery planned for subdural hematoma drainage, an en plaque subdural yellowish-white tumor was identified, without hematoma. Histopathological examination revealed metastatic breast cancer. The patient was administered predonisolone and her neurological symptoms gradually recovered. However, 12 days after the first operation, the clinical course was complicated by vomiting and rapid loss of consciousness. Emergency CT revealed that the subdural tumor had enlarged and decompression was performed as life-saving surgery. However, the patient's condition progressively deteriorated and she finally succumbed to the disease 2 months after the second operation. The aim of this study was to present the case of a patient with a large en plaque subdural tumor mimicking subdural hematoma and causing rapid loss of consciousness and cerebral herniation. PMID- 28588798 TI - Combination therapy with gemcitabine and nab-paclitaxel for locally advanced unresectable pancreatic cancer. AB - The aim of the present study was to investigate the early treatment outcomes of combined gemcitabine and nab-paclitaxel treatment for locally advanced unresectable pancreatic cancer (LURPC). The subjects comprised 7 patients with LURPC receiving the abovementioned combination therapy at the Hirosaki University Hospital (Hirosaki, Japan) between January and September, 2015. The clinicopathological factors, adverse events and response to treatment were investigated. To determine whether the cases were unresectable, the National Comprehensive Cancer Network guidelines, version 2. 201,) were applied. The patients underwent a median of 4 (range, 2-7) courses of treatment. The response to treatment was evaluated using the Response Evaluation Criteria In Solid Tumors. The subjects included 1 male and 6 female LURPC patients, with a median age of 71 years (range, 59-78 years). The tumor was located in the head and body of the pancreas in 6 and 1 patients, respectively. No patients achieved a complete response, 5 achieved a partial response, 2 had stable disease, and none exhibited progressive disease. The response rate was 71%. The mean tumor diameter decreased significantly from 35 mm (range, 24-60 mm) prior to treatment to 22 mm (range, 20-35 mm) following treatment. Two patients were downstaged. The mean carbohydrate antigen (CA) 19-9 values decreased significantly from 767 U/ml (range, 14-1,977 U/ml) prior to treatment to 35 U/ml (range, 14-123 U/ml) following treatment. Adverse events classified as grade >=3 occurred in 4 patients (57%): 3 patients (43%) suffered from neutropenia and 1 patient (14%) developed bilateral cellulitis of the lower extremities. No patients experienced an increase in disease severity, and all were able to continue treatment following temporary withdrawal or dosage reduction. Therefore, combined treatment with gemcitabine and nab-paclitaxel had favorable tumor-reducing effects and was not associated with severe adverse events, suggesting that this is a useful therapeutic strategy for patients with LURPC. PMID- 28588799 TI - Determining the optimum way to maintain quality of life for very elderly patients with advanced bladder cancer and poor performance status: A case report. AB - Locally advanced bladder cancer causes unpleasant symptoms such as irritative voiding symptoms, lower abdominal pain, gross hematuria and urinary retention, and lowers the quality of life. Treatment decisions in elderly patients may be difficult, as elderly patients are physically and psychologically different from younger patients. An 89-year-old male was referred to hospital for the treatment of an invasive bladder tumor with right hydronephrosis from tumor obstruction. The patient was elderly and did not have a good performance status; therefore curative radical cystectomy or chemotherapy was not indicated. Left retroperitoneoscopic ureterocutaneostomy was performed to alleviate gross hematuria and voiding difficulty. Intensity-modulated radiotherapy was administered 9 days after the surgery to control bleeding in the bladder tumor. After completing 8 days of radiotherapy, the patient was discharged from hospital. The patient exhibited no signs of either postrenal failure or gross hematuria for 7 months prior to mortality. Retroperitoneoscopic ureterocutaneostomy for very elderly patients with advanced bladder cancer with a poor performance status may be an important procedure for alleviating symptoms and improving quality of life. PMID- 28588800 TI - Ibrutinib-induced severe liver injury. AB - Ibrutinib, an inhibitor of the Bruton's tyrosine kinase of the B-cell receptor pathway, is an effective therapeutic agent for B-cell lymphomas. As these drugs are novel, long-term or rare adverse events are not yet known. We report the first case of ibrutinib-induced severe liver injury in a patient with relapsed/refractory CLL. PMID- 28588801 TI - Interstitial lung disease of infancy caused by a new NKX2-1 mutation. AB - Patients with personal or family history of congenital hypothyroidism, and/or neurological findings that also have chronic respiratory symptoms may have a mutation in the NKX2.1 gene as the unifying cause of their disease. Brain-lung thyroid disease is the ensuing condition, which although rare, needs to be part of the differential diagnosis. PMID- 28588802 TI - Complications caused by adenosine during catheter ablation of atrial fibrillation. AB - Adenosine is increasingly used to assess for dormant conduction following pulmonary vein isolation during atrial fibrillation ablation. While the half-life of adenosine is typically short and side effects transient, operators should be aware of more serious, lasting adverse reactions including anaphylaxis and bronchospasm. PMID- 28588803 TI - Syndrome of progressive bone marrow failure and pancreatic insufficiency remains cryptic despite whole exome sequencing: variant of Shwachman-Diamond syndrome or new condition? AB - This case underscores the difficulty in diagnosis of bone marrow failure disorders, as the presentation of disease can be inconsistent, complicated by complex and ever-expanding genetic etiologies. A patient who presents with bone marrow failure and pancreatic insufficiency raises the question of Shwachman Diamond syndrome (SDS) or a new condition which resembles SDS. PMID- 28588804 TI - Peripartum cardiomyopathy, what if your patient plans to reconceive? AB - Patients with peripartum cardiomyopathy (PPCM) often express a desire to conceive again, and the risk of relapse in future pregnancies should be disclosed. No consensus is available that can determine that risk. Adequate contractile reserve, evidenced by a stress echocardiogram (exercise or dobutamine), can identify those with lower relapse risk. PMID- 28588805 TI - "Chronic myelogenous leukemia in primary blast crisis" rather than "de novo BCR ABL1-positive acute myeloid leukemia". AB - Differentiating chronic myelogenous leukemia in primary blast crisis (CML-BC) from de novo BCR-ABL1-positive acute myeloid leukemia (AML) is a diagnostic challenge with therapeutic consequences. In our case, a basophilia, the presence of the Philadelphia chromosome in all metaphases and the strict exclusion of molecular hallmarks of AML lead us to retain the diagnosis of CML-BC rather than BCR-ABL1+ AML. PMID- 28588806 TI - Hypoglycemia and decreased insulin requirement caused by malignant insulinoma in a type 1 diabetic patient: when the hoof beats are from a zebra, not a horse. AB - Insulinomas are uncommon tumors, and in patients with diabetes mellitus they are extremely rare. We describe a patient with type 1 diabetes who developed malignant insulinoma. When hypoglycemic episodes persist in a patient with diabetes and treatment-induced and other causes of hypoglycemia have been ruled out, an insulin-producing tumor should be considered. PMID- 28588808 TI - Pallister-Killian syndrome in a two-year-old boy. AB - Pallister-Killian syndrome (PKS) is a rare, sporadic, multisystem developmental disorder characterized by craniofacial dysmorphic features. We report a case of a two-year-old boy with PKS to highlight the cutaneous findings and emphasize the importance of diagnostic skin biopsies in patients with cutaneous pigmentation changes and distinctive facial features. PMID- 28588807 TI - Eosinophilic angiitis presenting with a true, fusiform, temporal artery aneurysm. AB - Temporal artery aneurysm is a rare cause of temporal artery swelling in the absence of preceding trauma. Vasculitis other than giant cell arteritis, such as eosinophilic granulomatosis with polyangiitis, should be considered in such cases and a careful assessment of other medium-sized arteries undertaken. PMID- 28588809 TI - Cytopenia first - hepatitis second: an unusual sequence in aplastic anemia. AB - To the best of our knowledge, this is the first report of aplastic anemia (AA) preceding autoantibody-negative autoimmune hepatitis (AIH) with successful treatment of both conditions with the same immunosuppressive regimen, resulting in hematopoietic reconstitution and remission of AIH. PMID- 28588810 TI - Shortened dental arch as a solution for maxillary sinus proximity in dental implant restoration. AB - This case report demonstrates the benefit of using the shortened dental arch (SDA) design for a comprehensive implant-supported restoration and the avoidance of the complexities of implant placement near the maxillary sinus. The SDA concept as a treatment option is encouraging in terms of function, patient satisfaction, and cost-effectiveness. PMID- 28588811 TI - Minimization of door-to-balloon time for ST-elevation acute myocardial infarction: a case report. AB - It is of utmost importance to minimize the door-to-balloon time for the initial treatment of ST-elevation acute myocardial infarction. In this case report, we made all kinds of efforts to minimize procedures in the emergency department (ED minimization) as well as in the catheter laboratory without sacrificing safety. PMID- 28588812 TI - Chronic sinusitis in a patient with selective IgG4 subclass deficiency controlled with enriched immunoglobulins. AB - A 71-year-old female patient with no major history of infection had presented with recurrent chronic purulent sinusitis over the past 3 years. These recurrent infections started in 2000 with otolaryngologists' support before diagnosis of IgG4 deficiency be asked. The patient was treated with increasingly extensive courses of antibiotics and underwent several maxillary and sphenoidal sinus washouts. She continued to present with purulent nasal discharge containing Staphylococcus epidermidis. The blood and immune work-ups were normal. Her antinuclear antibody count was 1/320, with no unusual types. The total immunoglobulin (Ig)E, serology, CD4 count, and lymphocyte B phenotype results were all normal. No humoral immune deficiency was detected. The analyses confirmed an underlying specific IgG4 deficiency with values of 3-4 mg/L over 4 months. The patient was treated in March 2011 with prophylactic antibiotic therapy, sinus drainage, and IV infusions of enriched immunoglobulins (IVIg 10%) administered at the outpatient clinic every 4 weeks for 3 months. The IgIV treatment was not interrupted. Her general condition improved within a few months, with her IgG4 levels rising to 44 mg/L. The IVIg infusions were well tolerated. The purulent nasal discharge was controlled, and the antibiotics were stopped. The follow-up visits at 2 and 9 months after introduction of IVIg showed that her IgG4 level had improved, rising to 15 and 11 mg/L, respectively, although it had not yet returned to normal. The infusions were then given every 3 weeks. At her last visit, the patient's clinical condition had substantially improved. She was able to start using the subcutaneous Ig concentrate form (20% SCIg), 15 g every 2 weeks, leading to a clear improvement in her clinical condition, with stabilization of her otolaryngologists' symptoms and signs. The complete blood count was normal, IgG4 were stable at 40 mg/L, and the other immunoglobulins and IgG subclasses were normal. It was then possible to reduce the SCIg dose to 10 g every 3 weeks, while continuing to monitor her clinical condition and laboratory test results. This is one of the rare cases of selective IgG4 subclass deficiency treated with immunoglobulins. Treatment resulted in a significant improvement in IgG4 levels versus pretreatment levels. The first improvement noted was the stabilization otolaryngologists' infections particularly purulent nasal discharge. PMID- 28588813 TI - Severe dermatitis might be caused by a cross-reaction between nickel and palladium and dental amalgam resolved following removal of dental restorations. AB - This report demonstrates a case of atopic dermatitis that was unresponsive to topical steroid therapy. This clinical report highlights the fact that metals used in dental treatment, such as mercury, as well as cross-reactions between nickel and palladium, may cause systemic hypersensitivity or toxicity. PMID- 28588814 TI - Coincidence of follicular lymphoma and hurtle cell thyroid carcinoma in a patient at presentation: which one is the source of bone metastasis? Case report and review of the literature. AB - Thyroid incidentaloma is defined as a new identified thyroid lesion occasionally detected during imaging studies. Incidence of thyroid incidentalomas is relatively rare in patients with lymphoma. Because of high rate of malignancy, these lesions with high intensity focal 18 FDG uptake detected on positron emission tomography with computed tomography (PET/CT) should undergo to biopsy regardless of size. PMID- 28588815 TI - Familial cerebral abscesses caused by hereditary hemorrhagic telangiectasia. AB - In case of a cerebral abscess without known cause, Pulmonary arteriovenous malformations (PAVM) screening should be performed. If PAVM(s) is identified, Hereditary hemorrhagic telangiectasia (HHT) is very likely and should always be considered. This case shows the benefit of familial screening for HHT and PAVM. PMID- 28588816 TI - Diabetic ketoacidosis inducing myocardial infarction secondary to treatment with dapagliflozin: a case report. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are able to provoke diabetic ketoacidosis (DKA) with absence or low levels of ketone bodies in urine and slightly elevated blood glucose levels, which could delay the diagnosis; however, the presence of high urine output, due to the excretion of glucose, can help to identify the true cause. PMID- 28588817 TI - Nasopharyngeal amyloidoma with osteolytic lesions leading to diagnosis of systemic light-chain amyloidosis. AB - Amyloidomas of the head and neck region are uncommon and generally considered a benign localized form of amyloidosis. Here, we describe "the unusual case of a young man" with a nasopharyngeal mass and osteolytic lesions caused by systemic light-chain amyloidosis treated successfully with a combined surgical and chemotherapy approach. PMID- 28588818 TI - Conglomeration of Trabecular and Psammomatoid variants of juvenile ossifying fibroma - a rare case report. AB - Juvenile ossifying fibroma is an uncommon benign fibro-osseous lesion occurring in the craniofacial skeleton with a high recurrence rate. It has two distinct histopathologic variants: one trabecular and the other which are exclusive to each other. This case reveals a rare and unique combination of both the patterns in the same lesion. PMID- 28588819 TI - Three cases of acute distal demyelinating neuropathy with recovery. AB - Guillain-Barre syndrome (GBS) may present as distal acute inflammatory demyelinating polyradiculoneuropathy (AIDP), with severe distal demyelination of the peripheral nerves in the absence of radiculitis. Clinical course is benign, and prognosis seems favorable, but nerve conduction studies (NCS) findings at nadir may resemble some chronic forms of polyneuropathy, so close follow-up during recovery is needed. PMID- 28588820 TI - Endocardial and epicardial focal activation pattern due to microreentry ventricular tachycardia in a patient with cardiac sarcoidosis. AB - Majority of ventricular tachycardias (VTs) are caused by scar-related macroreentry in patients with cardiac sarcoidosis. These VTs usually exhibit the reentry circuit on electroanatomic maps. We here describe a rare case of VT that exhibits a focal activation pattern on the electroanatomic map despite reentrant VT. PMID- 28588821 TI - Coupling clinical exome sequencing with functional characterization studies to diagnose a patient with familial Mediterranean fever and MED13L haploinsufficiency syndromes. AB - Clinicians should consider that clinical exome sequencing provides the unique potential to disentangle complex phenotypes into multiple genetic etiologies. Further, functional studies on variants of uncertain significance are necessary to arrive at an accurate diagnosis for the patient. PMID- 28588822 TI - De novo balanced reciprocal translocation t(2;3)(q31;q27) in a fetus conceived using PGD in a t(2;14)(q35;q32.1) balanced reciprocal translocation carrier mother. AB - We reported a case of a t(2;14) balanced reciprocal translocation carrier mother that conceived by IVF accompanied by PGD/PGS using array-CGH; however, de novo t(2;3) was detected in the prenatal diagnosis. A healthy baby was delivered, and careful observation is needed for PGD/PGS cases. PMID- 28588823 TI - Achieving a satisfactory clinical and biochemical response in antiphospholipid syndrome and severe thrombocytopenia with rituximab: two case reports. AB - In AP syndrome (APS) with severe thrombocytopenia, rituximab represents a unique drug which can balance the effect of bleeding and thrombosis. By reducing the production of autoantibodies, rituximab can simultaneously raise the platelets and reduce the chance of thrombosis by suppressing APL antibodies. Rituximab can supersede splenectomy as second-line therapy in similar patients. PMID- 28588824 TI - Stress fractures in older athletes: a case report and literature review. AB - The incidence of stress injuries in older athletes is increasing, associated with a more active older population. The same principles apply for its prevention and treatment, but older athletes usually present a more adverse outcome. It is mandatory to raise awareness to this common, but frequently neglected pathology. PMID- 28588825 TI - A presentation of postcardiac injury syndrome after successful chronic total occlusion percutaneous coronary intervention using dissection re-entry techniques. AB - Retrograde dissection re-entry can cause pericardial trauma of sufficient degree to lead to the development of an auto-immune postpericardial injury syndrome. Clinical suspicion for this condition should be high in the event of fever, symptoms, pericardial/pleural effusion, and pleuritic chest pain following chronic total occlusion (CTO) Post cardiac injury syndromes (PCI). PMID- 28588826 TI - Novel case of resolution of hypsarrhythmia following tuber resection in a patient with infantile spasms and tuberous sclerosis. AB - This article describes a case involving the resolution of hypsarrhythmia, a generalized abnormal EEG pattern, following focal resection of a cortical tuber in a patient with tuberous sclerosis. PMID- 28588827 TI - A case of a pulmonary artery sling misdiagnosed as refractory asthma for 20 years. AB - We report the case of a 25-year-old woman with a pulmonary artery sling who was misdiagnosed as having childhood-onset refractory asthma for approximately 20 years. The use of computed tomography may be useful for diagnosing this rare condition. PMID- 28588828 TI - Measles hepatitis in a vaccinated liver transplant recipient: case report and review of literature. AB - Measles infection, postliver transplant, may lead to a fatal graft loss. Individuals who have been previously exposed to the measles antigen may have a modified disease presentation. Although vaccination may not provide solid immunity, it ameliorates the severity of the disease. PMID- 28588829 TI - Recurrent myxoinflammatory fibroblastic sarcoma: a case report. AB - Myxoinflammatory fibroblastic sarcoma is a rare sarcoma which typically presents in the extremities and is treated by definitive surgery. In recurrent disease, the reported utilization of radiotherapy is increasing, and more modern techniques such as intensity-modulated radiotherapy may be improving long-term outcomes. PMID- 28588830 TI - Classification of the spliceogenic BRCA1 c.4096+3A>G variant as likely benign based on cosegregation data and identification of a healthy homozygous carrier. AB - BRCA1, c.4096+3A>G was identified in a consanguineous Danish family with several cases of breast/ovarian cancer. In silico analysis and splicing assays indicated that the variant caused aberrant splicing. However, based on segregation data and the finding of a healthy homozygous carrier, we classify the BRCA1 c.4096+3A>G variant as likely benign. PMID- 28588831 TI - Surgical and medical treatment of ocular disease in a dog with Ehlers-Danlos syndrome. AB - Correctional surgery was performed on a 3-year-old intact male shih tzu presenting with Ehlers-Danlos syndrome, ocular disease, and skin fold dermatitis. A one-year follow-up showed that no further clinical corrections were needed. Therefore, surgery could be considered in some canine patients with Ehlers-Danlos syndrome. PMID- 28588832 TI - Diffuse hepatic hemangioma with single cutaneous hemangioma: an alerting occurrence. AB - Screening of infants with five or more cutaneous infantile hemangiomas with abdominal ultrasound is often recommended. However, diffuse hepatic hemangioma can develop even in patients with single cutaneous hemangioma. This highlights the importance of physical examination and screening ultrasound in these patients. PMID- 28588833 TI - Obinutuzumab-induced serum sickness following salvage therapy for chronic lymphocytic leukemia. AB - The incidence of serum sickness following treatment of CLL with obinutuzumab has not been fully characterized, but is likely rare. Consideration should be given to this diagnosis in appropriate circumstances so that effective corticosteroid therapy can be initiated to alleviate inflammatory symptoms and organ dysfunction in a timely manner. PMID- 28588834 TI - Successful bailout stenting strategy against lethal coronary dissection involving left main bifurcation. AB - Catheter-induced coronary dissection involving left main bifurcation is a rare complication during cardiac catheterization but can become lethal unless it is treated appropriately. Interventional cardiologists always have to pay attention to the risk of complications related to cardiac catheterization and prepare for determining the best bailout strategy for the situation. PMID- 28588835 TI - Concomitant imatinib and ibrutinib in a patient with chronic myelogenous leukemia and chronic lymphocytic leukemia. AB - The availability of kinase and other small-molecule inhibitors to treat hematologic malignancies is increasing. Accordingly, novel regimens that employ these therapeutics are rapidly evolving. Herein we report the safe and effective administration of two targeted kinase inhibitors in a patient with concomitant chronic myelogenous leukemia and chronic lymphocytic leukemia. PMID- 28588836 TI - A case of HIV-negative plasmablastic lymphoma of the bone marrow with a unique immunophenotype. AB - We present an interesting case of plasmablastic lymphoma, which is a rare type of non-Hodgkin lymphoma that is typically diagnosed in HIV-positive patients and has an immunophenotype that overlaps with multiple myeloma. Our patient is unique because he is HIV-negative, has primary bone marrow disease, and has an atypical immunophenotype. PMID- 28588837 TI - Rare presentation of 6q16.3 microdeletion syndrome with severe upper limb reduction defects and duodenal atresia. AB - We present a patient with a 17.31 MB interstitial deletion of 6q16.3-6q22.31, who demonstrates a unique constellation of 6q- features. Among 6q- patients, he has limb reduction among the most severe reported, he is the second patient with duodenal atresia, and is the first documented case of diaphragmatic eventration. PMID- 28588838 TI - Lyme carditis with complete heart block: management with an external pacemaker. AB - Timely diagnosis and prompt initiation of treatment is essential in Lyme carditis to achieve favorable prognosis. Externalized permanent pacemaker with an active fixation lead as supportive pacing modality is a feasible option till complete resolution of conduction block with continued antibiotic therapy. PMID- 28588839 TI - Human embryonic stem cell therapy for aplastic anemia. AB - Human embryonic stem cell (hESC) therapy is the potential therapeutic option for the treatment of patients with aplastic anemia (AA). The study showed a remarkable improvement in the AA patient subsequent to hESC administration. No adverse events occurred in the patient. hESC therapy is safe and effective for AA patients. PMID- 28588840 TI - Additional coronary sinus shocking lead as rescue therapy after multiple internal and external defibrillation failures. AB - High defibrillation threshold (DFT) and defibrillation failure can lead to intractable ventricular arrhythmias. Additional coronary sinus coil is an effective strategy to achieve marked reduction in DFT. However, physicians should retain this might prevent future coronary sinus lead placement in case the patient would develop complete left bundle branch block. PMID- 28588841 TI - Nasogastric tube-administered alectinib achieved long-term survival in a crizotinib-refractory nonsmall cell lung cancer patient with a poor performance status. AB - Alectinib shows remarkable efficacy against anaplastic lymphoma kinase (ALK) positive nonsmall cell lung cancer (NSCLC), with minimal adverse effects. Therefore, alectinib may provide a survival benefit to ALK-positive NSCLC patients with a poor performance status. If the medication cannot be taken by mouth, the patient may be given alectinib through a nasogastric tube. PMID- 28588842 TI - Neurological and immunological dysfunction in two patients with Bartonella henselae bacteremia. AB - Recently, BAPGM enrichment culture has documented Bartonella bacteremia in previously healthy, "nonimmunocompromised" patients following arthropod exposures. Neurobartonellosis should be among the differential diagnoses for patients with persistent or recurrent neurological symptoms of undetermined etiology. Microbiological and immunological testing should be concurrently pursued to determine whether defective immune function accompanies Bartonella bacteremia. PMID- 28588843 TI - Bilateral hydronephrosis due to obstructive ureteral stone associated with norovirus gastroenteritis. AB - Recently, cases of urinary tract calculi causing hydronephrosis and postrenal renal failure associated with viral gastroenteritis were documented, yet few were related to norovirus. During norovirus gastroenteritis, observation of oliguria, aciduria, low FENa value, and elevation of blood or urinary uric acid level may necessitate clinical workout for nephrolithiasis. PMID- 28588844 TI - Major salivary gland aplasia and hypoplasia in Down syndrome: review of the literature and report of a case. AB - Salivary gland aplasia and hypoplasia are rarely described in the medical literature. This article presents a case of aplasia and hypoplasia of the major salivary glands in a patient with Down syndrome. A literature review, as well as an overview of the diagnosis and management of this condition, is presented. PMID- 28588845 TI - Inflammatory myofibroblastic tumor mimicking a relapse in a patient with Hodgkin's lymphoma: report of an unusual case and review of the literature. AB - New PET-positive lesions in previously treated patients with lymphomatous malignancies need further investigations. Relapse, sarcoidosis and secondary malignancies are the most important differential diagnosis. Inflammatory myofibroblastic tumors (IMT) is a rare complication after treatment of Hodgkin's disease and every PET-positive lesion should be biopsied to prevent unnecessary intervention. PMID- 28588846 TI - Early detection of twiddler syndrome due a congestion alert by remote monitoring. AB - There are often false-positive alerts of thoracic impedance monitoring; however, the "false-positive alerts" might indicate any clinical problem of patient. In the present case, an alert for a drop in intrathoracic impedance, which generally indicates exacerbation of heart failure, enabled early detection of twiddler syndrome. PMID- 28588847 TI - A case of long QT syndrome: challenges on a bumpy road. AB - Beta-agonist treatment during pregnancy may unmask the diagnosis of long QT syndrome. The QT prolongation can result in functional AV block. A history of seizure and/or sudden death in a family member should raise suspicion of ventricular tachycardia. More than one mutation may coexist. Refusal of beta blocker therapy complicates risk stratification. PMID- 28588848 TI - A case of megalencephalic leukoencephalopathy with subcortical cysts type 1 was identified with a novel compound heterozygous alteration (c.135delC; c.423+2dupT) in China. AB - We report a compound heterozygous mutation (c.135delC; c.423+2dupT) of MLC1 gene in a Chinese patient underlying infantile macrocephaly and neurological deterioration in early childhood. Brain MRI revealed diffusion abnormality in swollen white matter and a subcortical cyst. The cDNA sequencing analysis for the c.423+2dupT variant revealed skipping of exon 5. PMID- 28588849 TI - Acromelia-oligodontia syndrome. AB - This case report describes a patient with ankyloglossia, oligodontia, unilateral hypoplasia of the zygoma and mandible, along with bilateral distal reduction anomalies of his limbs without long bone abnormalities. This may represent a mild variant of oromandibular limb hypogenesis syndrome, expanding the phenotypic spectrum, or a previously unrecognized malformation syndrome. PMID- 28588850 TI - Case report of myometrial window following fetoscopic treatment of twin-twin transfusion syndrome: indications of underlying collagen vascular disease? AB - Intraperitoneal amniotic fluid leak is a known complication of fetoscopic procedures that usually resolves spontaneously with expectant management. Intraperitoneal amniotic fluid leak may persist after fetoscopic procedures due to a myometrial window as well as to persistent chorioamniotic membrane disruption, which may be amenable to surgical repair. PMID- 28588851 TI - Identification of EPCAM mutation: clinical use of microarray. AB - We report a case of an infant with congenital tufting enteropathy (CTE) who presented with severe failure to thrive despite multiple interventions. This study illustrates that CTE may be missed by endoscopy, and the use of chromosomal microarray and immunohistological analysis may be integral to diagnosis. PMID- 28588852 TI - Partial trisomy 9: prenatal diagnosis and recurrence within same family. AB - Trisomy 9 can be suspected and confirmed in the prenatal period since the 11-13.6 weeks of screening. In cases of partial trisomy 9, the diagnosis is important especially to counseling the couple due to the increased likelihood of recurrence in subsequent pregnancies. PMID- 28588853 TI - Prenatal identification of two discontinuous maternally inherited chromosome 7q36.3 microduplications totaling 507 kb including the sonic hedgehog gene in a fetus with multiple congenital anomalies. AB - Duplications of the SHH gene, an important developmental gene, are rare. Disruption of this gene produces a variable phenotype in humans from major anomalies to isolated facial defects. This is the first reported case of a maternally inherited 507 kb discontinuous chromosome 7q36.3 microduplication resulting in duplication of SHH and nearby enhancer sequences. PMID- 28588854 TI - A "tetra-axial" system in transfemoral lead extraction. AB - Pacemaker lead extractors must become familiar with transfemoral approaches for lead extraction as a bail-out procedure for a failed superior approach. We presented a "tetra-axial" system for transfemoral lead extraction. This system would be more widely applicable in cases with difficulties in extraction, resulting in more procedural success. PMID- 28588855 TI - Colchicine reduced pericardial effusion due to postcardiac injury syndrome following cardiac resynchronization therapy implantation. AB - We present a case of postcardiac injury syndrome with pericardial effusion following cardiac resynchronization therapy implantation which was treated by only colchicine. Although treatment using colchicine is not as common as NSAIDs or steroids, colchicine seems to be an effective and safe treatment option for the syndrome. PMID- 28588856 TI - Metastatic pulmonary artery sarcoma presented with tamponade: a case report. AB - Pulmonary artery sarcoma is a rare tumor with varying presentations including pericardial effusion and pulmonary metastasis. Single-nucleotide polymorphism array is a novel method that can be used to define tumor genome and be used as a guidance to choose the proper treatment regimen. PMID- 28588857 TI - Hemoglobin Titusville: a rare low oxygen affinity hemoglobinopathy. AB - The relevance of this case lies in the extensive diagnostic workup that can be avoided with proper laboratory evaluation of relatively unsophisticated tests. PMID- 28588859 TI - The successful use of autologous skin in management of guidewire-induced distal coronary perforation. AB - The successful use of autologous skin to management may provide a useful and widely applicable method for dealing with the troublesome complication of guidewire-induced coronary perforation. PMID- 28588858 TI - A chromosomal microdeletion of 15q in a female patient with epilepsy, ID, and autism spectrum disorder: a case report. AB - 15q deletions have been described in association with intellectual disability and autism spectrum disorder (ASD). Previous reports have supported the role of 15q24 low copy repeats (LCRs) in mediating alternatively sized genomic rearrangements. Based on our reported finding of a 15q24 deletion coinciding with two LCR regions in a patient with epilepsy and ASD, we recommend that patients with 15q24 deletions be evaluated for ASD for early institution of therapy. PMID- 28588861 TI - A rare cause of mechanical bowel obstruction: ingested vinyl glove. Unexpected diagnosis at laparoscopy. AB - The report suggests that, when the patient's history, clinical examination, and findings do not lead to a clear diagnosis in case of an acute abdomen, a laparoscopic approach, that has both, diagnostic and therapeutic value, is advised. PMID- 28588860 TI - Myocardial ischemia induced by major aortopulmonary collateral arteries treated with transcatheter coil embolization. AB - Major aortopulmonary collateral arteries branching from coronary arteries may cause coronary steal. The careful follow-up is needed irrespective of symptoms because increasing physical activities and oxygen demand along with the age may induce myocardial ischemia. Transcatheter intervention by well-trained physician would be a treatment option in patients with myocardial ischemia. PMID- 28588862 TI - Surfer's ear. AB - Exostosis in external auditory canal is common among surfers. Common symptoms are decreased hearing or loss of hearing, ear infection, and/or plugging sensation. Repeated exposure to cold water is a key clinical history to suspect this condition. Based on symptoms and existence of infection, surgical removal of the exostosis is recommended. PMID- 28588863 TI - Hemodynamic collapse due to the stenosis of four pulmonary veins in a patient with mediastinal tumor. AB - Cardiogenic shock can occur due to compression of the four pulmonary veins and the left atrium by a mediastinal tumor. Steroid infusion can be a temporary alternative therapy before obtaining a definite diagnosis and performing an intervention with stents to dilate the pulmonary veins. PMID- 28588864 TI - Coexistence of chronic lymphocytic leukemia and multiple myeloma, do the roots of these entities originate from the same place? AB - Multiple myeloma is a plasma cell disease, whereas CLL (Chronic Lymphocytic Leukemia) affects mature B-cell lymphocytes. Even though the coexistence of those two conditions is extremely rare, as both cell types differentiate from the same multipotent stem cells, the clinician should evaluate patients carefully not to misdiagnose such a concomitancy. PMID- 28588865 TI - Diffuse large B-cell lymphoma mimicking cardiac amyloidosis. AB - Our case highlights that cardiac lymphoma may mimic amyloid infiltration of the myocardium on cardiac magnetic resonance (CMR), and is a particularly challenging diagnosis in the setting of transformed Waldenstrom's macroglobulinemia. Heightened suspicion and early diagnosis of cardiac lymphoma is paramount as chemotherapy has been demonstrated to portent an increased survival rate. PMID- 28588866 TI - Gastric foreign body: a comb. AB - The ingestion of a foreign body is a common occurrence. Psychiatric patients and prisoners may swallow objects on purpose. Occasionally emergent exploratory laparotomy may be indicated if the diagnosis is uncertain, and emergent removal of the foreign body may be needed to prevent substantial risk of serious complications including perforation, fistula, or gastrointestinal bleeding. PMID- 28588867 TI - Cardiac arrest reveals a mobile large left atrial myxoma. AB - Left atrial myxoma could be a rare cause of cardiac arrest as this mass could impinge on the mitral orifice causing left ventricular inflow tract obstruction. PMID- 28588868 TI - Fracture guide wire during an elective percutaneous coronary intervention. AB - Dose the fractured guide wire should be removed during or after percutaneous coronary interventions? In case when the patients have unstable hemodynamic status the fractured guide wire should be removed with percutaneous or surgical method. Antiplatelet drug administration should be considered after procedure to prevention of the coronary artery thrombosis. PMID- 28588869 TI - Mycobacterium genavense invading the bone marrow in a HIV-positive patient. AB - Nontuberculous mycobacteria infrequently cause disseminated infections in immunocompetent hosts. However, they are increasingly being recognized in immunocompromised patients. We present the case of a 40-year-old HIV-positive male presenting with lymphadenopathies and pancytopenia in whom disseminated infection, with bone marrow involvement by Mycobacterium genavense (M. genavense) was diagnosed. PMID- 28588870 TI - Virchow's node together with an Irish node. AB - Classical lymphadenopathies, such as Virchow's node (left supraclavicular lymph node metastasis) and Irish node (left axillary lymph node metastasis), are important findings that may indicate the presence of gastric cancer and other gastrointestinal malignancies. PMID- 28588871 TI - Post-radiosynovectomy imaging of Er-169 using scintigraphy and autoradiography. AB - Currently, there is no protocol for the detection of intra-articular distribution of Er-169 citrate after radiosynovectomy. We propose post-therapeutic imaging using scintigraphy and cobalt-57 pen-marker autoradiography. This technique evaluates the efficacy of the radiosynovectomy and patient safety and could be utilized for dosimetric protocol. PMID- 28588872 TI - Cefazolin as a cause of leukocytoclastic vasculitis. AB - Leukocytoclastic vasculitis (LCV) is a cutaneous small vessel vasculitis characterized by cutaneous manifestations in the form of palpable purpura, and rarely bullae, vesicles, and ulcerations. Although rare, cephalosporins such as cefazolin, should be recognized to have a potential to trigger LCV. PMID- 28588873 TI - A 72-year-old with eyelid opening apraxia in Steele-Richardson-Olszewski syndrome. AB - In our patient with Steele-Richardson-Olszewski syndrome presenting with apraxia of eyelid opening, there is a possibility to be readily confused with conditions presenting in similar pattern such as blepharospasm and eyelid ptosis. Therefore, it is essential to correlate the clinical findings with electromyographic recordings and dopamine transporter scan (DaT). PMID- 28588874 TI - Radiation-induced tongue myokymia with hypoglossal nerve damage, mimicker of motor neuron disease. AB - This teaching case of tongue myokymia offers clear electromyographic findings of myokymic discharges on two different sweeps. Radiation-induced tongue myokymia should be considered in the differential diagnosis for motor neuron disease (MND). PMID- 28588876 TI - Increased risk for metachronous gastric adenocarcinoma following gastric MALT lymphoma-A US population-based study. AB - BACKGROUND: Gastric mucosa-associated lymphoid tissue lymphoma (gMALT) and gastric adenocarcinoma (GC) are long-term complications of chronic Helicobacter pylori (HP) gastritis. Treatment of HP infection induces remission in most patients with gMALT. Endoscopic follow-up is not currently endorsed after complete remission. However, the risk of GC in these patients is unclear. OBJECTIVE: The objective of this study is to estimate GC risk in gMALT patients. METHODS: The National Cancer Institute Surveillance, Epidemiology and End Results 13 (SEER) database-Nov 2014 Sub (1992-2012) was used to identify adult patients diagnosed with gMALT between 1992 and 2012. The standardized incidence ratio of second primary GC after a latency period of 12 months was calculated and compared to a reference SEER cohort of identical age, sex and time period. The risk of GC in these patients was also stratified by latency period (five years) and age. RESULTS: We identified 2195 cases of gMALT lymphoma, and 20 (0.91%) of them subsequently developed GC with a relative risk (RR) of 4.32 (95% CI 2.64-6.67) compared to the American population. The median latency time was five years and the risk was maintained afterward (RR 4.92, 95% CI 2.45-8.79). When stratified by age group the risk was highest for the 45-64 group (RR 14.04, 95% CI 5.64-28.93). CONCLUSION: gMALT lymphoma is associated with an increased risk of metachronous gastric adenocarcinoma. The risk is still present after more than five years of follow-up. Further studies may clarify the most adequate follow-up strategy. PMID- 28588875 TI - Management of chronic constipation in adults. AB - Chronic constipation (CC) is an extremely common condition with an estimated prevalence of up to 24%. Most patients with CC should be treated in primary care. Changes in lifestyle, including increased intake of dietary fibre, fluid, and exercise, should be attempted in most patients. Osmotic or stimulant laxatives are indicated if there are insufficient effects of lifestyle changes. Prokinetics and secretagogues should be restricted to those not responding to basic treatment. Anorectal physiology tests and assessment of colorectal transit time are indicated if medical treatment fails or if symptoms indicate severely obstructed defecation. If symptoms indicate an underlying structural disorder, barium or magnetic resonance evacuation proctography is indicated. Biofeedback therapy is effective in patients with dyssynergic defecation. In patients with other evacuation disorders, rectally administered laxatives or transanal irrigation should be attempted. Surgery is restricted to the minority of CC patients with very severe symptoms not responding to conservative treatment. PMID- 28588877 TI - Endoscopic removal of over-the-scope clips: Clinical experience with a bipolar cutting device. AB - BACKGROUND: Over-the-scope clips (OTSCs) are increasingly used for the closure of perforations/fistulae, hemostasis and endoscopic full-thickness resection (FTRD system). When OTSC-associated complications occur or re-therapy at the OTSC site is needed, OTSC removal may be indicated. An experimental study in an animal model and a case series have shown good results for OTSC removal with a bipolar cutting device. We present a larger clinical study using this device. METHODS: Data of all consecutive patients with indication for OTSC removal were collected and analyzed retrospectively. OTSCs were cut at two opposing sites using a bipolar grasping device to apply short direct current impulses. OTSC fragments were extracted with a standard forceps and a cap at the tip of the endoscope to avoid tissue damage. RESULTS: Between December 2012 and February 2016 a total of 42 OTSC removals in the upper (n = 25) and lower (n = 17) gastrointestinal tract have been performed at our department. Overall technical success, defined as cutting the OTSC at two opposing sites and extraction of both fragments, was achieved in 92.9% (39/42) of all cases. Successful fragmentation of the OTSC was achieved in 97.6% (41/42). Minor bleedings were rare and could be managed endoscopically in all cases. There were no perforations and no major or delayed bleedings. CONCLUSION: Endoscopic OTSC removal with a bipolar cutting device is feasible, effective and safe. This technique can be applied in the upper and lower gastrointestinal tract. PMID- 28588878 TI - A novel purgative protocol for capsule endoscopy of the small bowel produces better quality of visibility than 2 l of PEG: Timing is of the essence. AB - INTRODUCTION: The ideal way of preparing patients for small-bowel capsule endoscopy has been controversial. Previous studies have shown that ingestion of 2 l of polyethylenglycol (PEG) 12 hours prior to capsule ingestion leads to improved visibility in comparison to no preparation at all. We speculated that using a post-ingestion (PI), booster-based cleansing protocol might provide an alternative to the PEG cleansing protocol. METHODS: This randomized, blinded, prospective study enrolled 45 individuals. Patients were allocated to either of two groups. The PEG group ingested 2 l PEG 12 hours prior to the exam (n = 22) and the PI group ingested one sachet of Picolax(r) dissolved in 250 ml of water one hour after swallowing the capsule with 500 ml of water (n = 18). Primary endpoints were overall small bowel and distal third of small bowel cleansing levels. Secondary endpoints were average gastric and small-bowel transit time. RESULTS: Forty-five patients participated in this study. Five individuals were excluded because of incomplete study. Percentage of patients with adequate visibility in the distal third of the small bowel in the PEG group was 9% vs 72% in the PI group (p < 0.0001). Average gastric time and total transit time were shorter in the PI group vs the PEG group (p = 0.0065). CONCLUSION: Timing of ingestion of the Picolax(r) purgative 60 minutes after swallowing the capsule endoscopy delivers better visibility in the distal third of the small bowel than the accepted cleansing protocol of ingesting 2 l PEG 12 hours prior to the capsule endoscopy procedure. PMID- 28588880 TI - Estimation of the prevalence of intraductal papillary mucinous neoplasm of the pancreas in the French population through patients waiting for liver transplantation. AB - BACKGROUND AND AIMS: Some studies have explored the prevalence of pancreatic cystic lesions (PCLs). Only one study based on magnetic resonance imaging (MRI) report examination focused specifically on intraductal papillary mucinous neoplasm (IPMN) in a European general population. The aim of this study was to evaluate the prevalence of IPMN in a population of patients who had MRI for a non pancreatic disease. METHODS: We conducted a retrospective, single-center study. All consecutive patients placed on the French liver transplant waiting list who had MRI for a non-pancreatic disease before liver transplantation between 2009 and 2013 were included. Only diagnoses consistent with IPMN were retained (cyst(s) clearly communicating with the main pancreatic duct). RESULTS: Among 315 patients on the national waiting list, 212 patients had an MRI. PCLs with ductal communication were diagnosed in 14 patients (6.6%; six women, eight men, median age 62 years (45-70)). Liver disease was caused by a virus in seven cases, alcohol in three cases, other in four cases (multiple causes possible). Four patients had hepatocellular carcinoma. No patient had clinical or radiological sign of chronic pancreatitis. The median diameter of the largest cystic lesion was 14 mm (7-22). The number of PCLs was one (n = 4), two (n = 2), four (n = 3), five (n = 2), > 5 (n = 3), respectively. There was no worrisome or main pancreatic duct involvement. CONCLUSIONS: Prevalence of pancreatic cystic lesions consistent with the diagnosis of IPMN was 6.6% in French patients waiting for liver transplantation. These results underscore that IPMN can be considered as a public health problem and justify a screening. PMID- 28588879 TI - An international multicenter study of early intravenous fluid administration and outcome in acute pancreatitis. AB - AIMS: Early aggressive fluid resuscitation in acute pancreatitis is frequently recommended but its benefits remain unproven. The aim of this study was to determine the outcomes associated with early fluid volume administration in the emergency room (FVER) in patients with acute pancreatitis. METHODS: A four-center retrospective cohort study of 1010 patients with acute pancreatitis was conducted. FVER was defined as any fluid administered from the time of arrival to the emergency room to 4 h after diagnosis of acute pancreatitis, and was divided into tertiles: nonaggressive (<500 ml), moderate (500 to 1000 ml), and aggressive (>1000 ml). RESULTS: Two hundred sixty-nine (26.6%), 427 (42.3%), and 314 (31.1%) patients received nonaggressive, moderate, and aggressive FVER respectively. Compared with the nonaggressive fluid group, the moderate group was associated with lower rates of local complications in univariable analysis, and interventions, both in univariable and multivariable analysis (adjusted odds ratio (95% confidence interval): 0.37 (0.14-0.98)). The aggressive resuscitation group was associated with a significantly lower need for interventions, both in univariable and multivariable analysis (adjusted odds ratio 0.21 (0.05-0.84)). Increasing fluid administration categories were associated with decreasing hospital stay in univariable analysis. CONCLUSIONS: Early moderate to aggressive FVER was associated with lower need for invasive interventions. PMID- 28588882 TI - Transarterial chemoembolization vs bland embolization in hepatocellular carcinoma: A meta-analysis of randomized trials. AB - BACKGROUND: Although transarterial chemoembolization is considered the standard of care for intermediate hepatocellular carcinoma patients, robust data in favor of a clear superiority of chemoembolization (with chemotherapy injection) over bland embolization are lacking. OBJECTIVE: The objective of this article is to systematically analyze the results provided by randomized controlled trials comparing these two treatments in hepatocarcinoma patients. METHODS: A computerized bibliographic search on the main databases was performed. Survival rates assessed at one, two, and three years, objective response, one-year progression-free survival, and severe adverse event rate were analyzed. Comparisons were performed by using the Mantel-Haenszel test in cases of low heterogeneity or DerSimonian and Laird test in cases of high heterogeneity. RESULTS: Six trials with 676 patients were included. No difference in one-year (risk ratio: 0.93, 0.85-1.03, p = 0.16), two-year (risk ratio: 0.88, 0.74-1.06, p = 0.18) and three-year survival (risk ratio: 0.97, 0.74-1.27, p = 0.81) was observed. Objective response and one-year progression-free survival showed no significant difference between the two treatments (p = 0.36 and p = 0.40, respectively). A statistically significant increase in severe toxicity after chemoembolization was found (risk ratio: 1.44, 1.08-1.92, p = 0.01), although this result could be affected by the heterogeneity of techniques adopted. CONCLUSIONS: Our meta-analysis demonstrates a non-superiority of transarterial chemoembolization with respect to bland embolization in hepatocarcinoma patients. PMID- 28588881 TI - Endoscopic classification of the papilla of Vater. Results of an inter- and intraobserver agreement study. AB - BACKGROUND: Many endoscopists acknowledge that the appearance of the papilla of Vater seems to affect biliary cannulation. To assess the association between the macroscopic appearance of the papilla and biliary cannulation and other related clinical issues, a system is needed to define the appearance of the papilla. OBJECTIVE: The purpose of this study was to validate an endoscopic classification of the papilla of Vater by assessing the interobserver and intraobserver agreements among endoscopist with varying experience. METHODS: An endoscopic classification, based on pictures captured from 140 different papillae, containing four types of papillae was proposed. The four types are (a) Type 1: regular papilla, no distinctive features, 'classic appearance'; (b) Type 2: small papilla, often flat, with a diameter <= 3 mm (approximately 9 Fr); (c) Type 3: protruding or pendulous papilla, a papilla that is standing out, protruding or bulging into the duodenal lumen or sometimes hanging down, pendulous with the orifice oriented caudally; and (d) Type 4: creased or ridged papilla, where the ductal mucosa seems to extend distally, rather out of the papillary orifice, either on a ridge or in a crease. To assess the level of interobserver agreement, a web-based survey was sent out to 18 endoscopists, containing 50 sets of still images of the papilla, distributed between the four different types. Three months later a follow-up survey, with images from the first survey was sent to the same endoscopists. RESULTS: Interobserver agreement was substantial (kappa = 0.62, 95% confidence interval (CI) 0.58-0.65) and were similar for both experts and non experts. The intraobserver agreement assessed with the second survey was also substantial (kappa = 0.66, 95% CI 0.59-0.72). CONCLUSION: The proposed endoscopic classification of the papilla of Vater seems to be easy to use, irrespective of the level of experience of the endoscopist. It carries a substantial inter- and intraobserver agreement and now the clinical relevance of the four different papilla types awaits to be determined. PMID- 28588883 TI - Compliance with evidence-based multidisciplinary guidelines on perihilar cholangiocarcinoma. AB - BACKGROUND: Discrepancies are often noted between management of perihilar cholangiocarcinoma (PHC) in regional hospitals and the eventual treatment plan in specialized centers. OBJECTIVE: The objective of this article is to evaluate whether regional centers adhere to guideline recommendations following implementation in 2013. METHODS: Data were analyzed from all consecutive patients with suspected PHC referred to our academic center between June 2013 and December 2015. Frequency and quality of biliary drainage and imaging at referring centers were assessed as well as the impact of inadequate initial drainage. RESULTS: Biliary drainage was attempted at regional centers in 83 of 158 patients (52.5%), with a technical and therapeutic success rate of 79.5% and 50%, respectively, and a complication rate of 45.8%. The computed tomography protocol was not in accordance with guidelines in 52.8% of referrals. In 45 patients (54.2%) who underwent drainage in regional centers, additional drainage procedures were required after referral. Initial inadequate biliary drainage at a regional center was significantly associated with more procedures and a prolonged waiting time until surgery. A trend toward more drainage-related complications was observed among patients with inadequate initial drainage (54.7% vs. 39.0%, p = 0.061). CONCLUSION: Despite available guidelines, suboptimal management of PHC persists in many regional centers and affects eventual treatment strategies. PMID- 28588884 TI - Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia. AB - BACKGROUND: The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. OBJECTIVE: The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. METHODS: Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. RESULTS: The PBC associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301-DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5-6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94-5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2 25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). CONCLUSIONS: Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301 DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study. PMID- 28588885 TI - Elevated trimethylamine-N-oxide (TMAO) is associated with poor prognosis in primary sclerosing cholangitis patients with normal liver function. AB - BACKGROUND: Trimethylamine-N-oxide (TMAO) is produced in the liver from trimethylamine, which is exclusively generated by gut bacteria. OBJECTIVE: The objective of this article is to investigate the relationship between TMAO and primary sclerosing cholangitis (PSC) and its clinical characteristics. METHODS: Serum TMAO was measured in 305 PSC patients, 90 ulcerative colitis patients and 99 healthy controls. RESULTS: In PSC patients with normal liver function (n = 197), TMAO was higher in patients reaching liver transplantation or death during follow-up than those who did not, with an optimal TMAO cut-off of 4.1 uM (AUC = 0.64, p < 0.001). PSC patients with high TMAO (>4.1 uM, n = 77) exhibited shorter transplantation-free survival than patients with low TMAO (n = 120, log-rank test: p < 0.0001). High TMAO (>4.1 uM) was associated with reduced transplantation-free survival (HR 1.87, p = 0.011), independently of the Mayo risk score (HR 1.74, p < 0.001). Overall, PSC patients demonstrated reduced TMAO values compared with ulcerative colitis and healthy controls, mainly caused by PSC patients with reduced liver function (INR > 1.2), suggesting impaired oxidation of trimethylamine to TMAO. PSC patients with and without inflammatory bowel disease had similar TMAO levels. CONCLUSION: In PSC patients with normal liver function, elevated TMAO was associated with shorter transplantation-free survival, potentially reflecting clinically relevant metabolic changes resulting from dietary interactions with the gut microbiota. PMID- 28588887 TI - Risk factors for proximal disease extension and colectomy in left-sided ulcerative colitis. AB - OBJECTIVE: The primary objective of this study was to assess proximal disease extension of ulcerative colitis (UC) over time, with disease behaviour pattern and risk factors for proximal disease extension and colectomy as secondary aims. METHODS: All cumulative incident cases diagnosed with UC at the Academic Medical Center between January 1990 and December 2009 were studied. The cumulative risk of colectomy was calculated by Kaplan-Meier analysis. The Cox proportional hazards regression was used to identify risk factors associated with proximal disease extension and colectomy. RESULTS: In total, 506 UC patients were included with a median age of 33 years (IQR 23-41) at diagnosis. Ninety-five (18.8%) patients underwent colectomy during follow-up. Median follow-up was 10 years (IQR 5-15). Initial disease extent was evaluable in 416 patients, of whom 142 (34.1%) had proctitis, 155 (37.3%) left-sided colitis and 119 (28.6%) pancolitis. Proximal disease extension was observed in 120 (28.8%) patients during follow-up (51 proctitis to left-sided colitis, 39 proctitis to extensive colitis and 30 left-sided to extensive colitis). Disease behaviour was evaluable in 378 patients, of whom 244 (64.6%) had less than one relapse per year. Younger age at diagnosis (HR 0.98, 95% CI 0.96-0.99) and continuous active disease (HR 2.18, 95% CI 1.27-3.73) were independent risk factors for proximal disease extension. The cumulative risk of colectomy did not change over time between patients diagnosed before and after the year 2000 (p = 0.341). Continuous active disease (HR 7.05, 95% CI 4.23-11.77), systemic steroids (HR 3.25, 95% CI 1.37-7.71) and cyclosporine treatment (HR 2.80, 95% CI 1.66-4.72) were independent risk factors for colectomy, whereas proctitis at diagnosis (HR 0.43, 95% CI 0.22-0.86) carried a lower risk. CONCLUSION: In one-third of UC patients, left-sided disease at diagnosis will extend proximally during 10 years of follow-up. Proximal disease extension was not a risk factor for colectomy, but the risk of colectomy is rather determined by continuous disease activity, and use of systemic steroids and cyclosporine. PMID- 28588886 TI - Laparoscopic versus open appendectomy in adults and children: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this study was to evaluate the differences of laparoscopic appendectomy (LA) versus open appendectomy (OA) in adults and children. METHODS: Randomized controlled trials (RCTs) comparing LA and OA in adults and children between January 1992-March 2016 were included in this study. A meta-analysis was performed to evaluate wound infection, intra-abdominal abscess, postoperative complications, reoperation rate, operation time, postoperative stay, and return to normal activity. RESULT: Thirty-three studies including 3642 patients (1810 LA, 1832 OA) were included. Compared with OA, LA in adults was associated with lower incidence of wound infection, fewer postoperative complications, shorter postoperative stay, and earlier return to normal activity, but a longer operation time. There was no difference in levels of intra-abdominal abscess and reoperation between the groups. Subgroup analysis in children did not reveal significant differences between the two techniques in wound infection, postoperative complications, postoperative stay, and return to normal activity. CONCLUSION: LA in adults is worth recommending as an effective and safe procedure for acute appendicitis, and further high-quality randomized trials comparing the two techniques in children are needed. PMID- 28588888 TI - Thioguanine in inflammatory bowel disease: Long-term efficacy and safety. AB - BACKGROUND: Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators. METHODS: This is a retrospective, single-centre study of IBD patients treated with TG from 2001-2013. Response was defined as clinical remission (Harvey-Bradshaw Index < 5 for Crohn's disease (CD), Simple Clinical Colitis Activity Index < 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI). RESULTS: 54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20-40 mg/d)) as monotherapy (n = 36) or concomitantly with anti-TNF (n = 18) for a median inter-quartile range of 16 (5-37) months (126 patient-years of follow-up). 32 (59%) patients responded to TG at 6 months and 23 (43%) at 12 months. Pancreatitis did not recur amongst the 19 patients with prior thiopurine induced pancreatitis. 16 (30%) patients ceased TG due to intolerance or toxicity (four serious); NRH was not observed. 6-thioguanine nucleotide concentrations did not correlate with efficacy nor with toxicity. CONCLUSIONS: TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur. PMID- 28588889 TI - Validation of the Crohn's and Ulcerative Colitis questionnaire in patients with acute severe ulcerative colitis. AB - BACKGROUND: The Crohn's and Ulcerative Colitis questionnaire (CUCQ) has previously been validated in patients with mild to moderate Crohn's and ulcerative colitis (UC). The aim of this study was to validate the tool in patients with acute severe UC. METHODS: We undertook a validation of the CUCQ in patients recruited to the COmparison of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis Trial (CONSTRUCT). We carried out psychometric analysis to examine the underlying dimensions of the scale, internal consistency and construct validity. We carried out stepwise regression to examine which items accounted for the greatest variance in the scale. RESULTS: We obtained complete data for 270 patients. The internal consistency of the CUCQ was excellent (Cronbach's alpha > 0.8). The CUCQ scores achieved significant correlations with two generic quality of life scales (SF-12 and EQ-5D), demonstrating good construct validity. Stepwise regression identified 16 items that accounted for greater than 95% of the variance of the CUCQ. Only three of the eight items selected for a short form in mild to moderate patients were selected for patients with acute severe UC. CONCLUSIONS: The CUCQ demonstrated good validity in our sample of acute severe UC patients. Stepwise regression identified potential to shorten the tool, but that different items would be selected compared with less severe patients. If the tool is to be applied across the spectrum of disease it would be more appropriate to use the full 32 items in the scale. Further work to explore test-retest is required in acute patients. PMID- 28588890 TI - Cognitive impairment in Crohn's disease is associated with systemic inflammation, symptom burden and sleep disturbance. AB - BACKGROUND: Patients with Crohn's disease (CD) frequently complain of cognitive difficulties such as problems with concentration and clouding of thought, yet this has scarcely been objectively defined and underlying mechanisms remain unknown. OBJECTIVE: The objective of this article is to objectively measure cognitive impairments in patients with CD compared with healthy controls, and if present, to identify potentially modifiable, contributing factors associated with cognitive impairment. METHODS: CD patients and healthy age-/sex-matched controls completed surveys encompassing clinical, demographic, psychiatric, fatigue and sleep parameters. Contemporaneously, disease activity assessment with serum CRP, faecal calprotectin, Harvey-Bradshaw Index and the Subtle Cognitive Impairment test (SCIT) were performed, with the primary measure of response time (SCIT-RT) compared between groups. Multiple linear regression assessed for factors associated with slower SCIT-RT, denoting subtle cognitive impairment. RESULTS: A total of 49 CD and 31 control individuals participated, with median age 44 years (range 22-65) and 43 years (21-63), respectively. Compared to controls, SCIT-RT was slower across all timepoints in CD patients (ANOVA p < 0.001). In multivariate analysis, serum CRP (standardised beta coefficient 0.27, 95% CI (0.02, 0.51)), abdominal pain (0.43 (0.16, 0.70)), plasma haemoglobin (1.55 (1.42, 1.68)), and concurrent fatigue (0.56 (0.25, 0.88)) were each independently associated with slower SCIT-RT in CD (each p < 0.05), with a trend for poorer sleep quality 0.54 (-0.03, 1.11) (p = 0.06), yet conversely, higher faecal calprotectin titres were associated with faster SCIT-RT (-1.77 (-1.79, -1.76), p < 0.01). CONCLUSIONS: Patients with CD demonstrated subtle cognitive impairment utilising the objective SCIT, correlating with systemic inflammation and other disease burden measures, although higher faecal calprotectin titres were unexpectedly associated with less cognitive impairment. PMID- 28588891 TI - Prevalence and clinical features of opioid-induced constipation in the general population: A French study of 15,000 individuals. AB - BACKGROUND: Constipation is common during opioid therapy and can compromise analgesia. AIM: The aim of this article is to determine the prevalence and clinical characteristics of opioid-induced constipation (OIC) in France. METHODS: A questionnaire study was conducted in a representative sample of the French general population. Participants completed a 31-item questionnaire covering opioid use during the previous six months, and the occurrence of constipation (defined as <3 bowel movements per week, straining during defaecation, or both) during opioid treatment. RESULTS: Data were obtained from 15,213 participants, of whom 4753 (31.2%) reported opioid use. Most analgesics (96.5%) were classified as World Health Organization step II analgesics, and the remainder were step III. The most common indications for opioids were bone or joint pain, and soft tissue pain. Overall, 414/4753 (8.7%) opioid users reported OIC while the prevalence of OIC reached 21% in case of regular or prolonged (>1 month) opioid use. Other characteristics associated with OIC included female gender, age >=50 years and use of step III opioids. Only 177/414 (42.8%) participants with OIC had used medications (most commonly osmotic laxatives) to treat constipation, and satisfaction with constipation medication was moderate (mean (SD) score 7.2 (1.3) on a scale of 0-10). CONCLUSIONS: Approximately one-third of a representative French population had used opioids within the previous six months, and 9% of users had experienced OIC, which is more frequent in case of regular use. OIC appears to be under-treated, and participants' satisfaction with their constipation medications was only moderate, suggesting that significant unmet need remains in OIC management. PMID- 28588892 TI - Young GI angle: Effective data presentation. PMID- 28588893 TI - E-learning in gastroenterology-What have we learned so far? PMID- 28588895 TI - Evaluation of cough peak expiratory flow as a predictor of successful mechanical ventilation discontinuation: a narrative review of the literature. AB - A crucial step in the transition from mechanical ventilation to extubation is the successful performance of a spontaneous breathing trial (SBT). The American College of Chest Physicians (ACCP) Guidelines recommend removal of the endotracheal tube upon successful completion of a SBT. However, this does not guarantee successful extubation as there remains a risk of re-intubation. Guidelines have outlined ventilator liberation protocols, selected use of non invasive ventilation on extubation, early mobilization, and dynamic ventilator metrics to prevent and better predict extubation failure. However, a significant percentage of patients still fail mechanical ventilation discontinuation. A common reason for re-intubation is having a weak cough strength, which reflects the inability to protect the airway. Evaluation of cough strength via objective measures using peak expiratory flow rate is a non-invasive and easily reproducible assessment which can predict extubation failure. We conducted a narrative review of the literature regarding use of cough strength as a predictive index for extubation failure risk. Results of our review show that cough strength, quantified objectively with a cough peak expiratory flow measurement (CPEF), is strongly associated with extubation success. Furthermore, various cutoff thresholds have been identified and can provide reasonable diagnostic accuracy and predictive power for extubation failure. These results demonstrate that measurement of the CPEF can be a useful tool to predict extubation failure in patients on MV who have passed a SBT. In addition, the data suggest that this diagnostic modality may reduce ICU length of stay, ICU expenditures, and morbidity and mortality. PMID- 28588894 TI - Aetiological pathways to Borderline Personality Disorder symptoms in early adolescence: childhood dysregulated behaviour, maladaptive parenting and bully victimisation. AB - BACKGROUND: Developmental theories for the aetiology of Borderline Personality Disorder (BPD) suggest that both individual features (e.g., childhood dysregulated behaviour) and negative environmental experiences (e.g., maladaptive parenting, peer victimisation) may lead to the development of BPD symptoms during adolescence. Few prospective studies have examined potential aetiological pathways involving these two factors. METHOD: We addressed this gap in the literature using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We assessed mother-reported childhood dysregulated behaviour at 4, 7 and 8 years using the Strengths and Difficulties Questionnaire (SDQ); maladaptive parenting (maternal hitting, punishment, and hostility) at 8 to 9 years; and bully victimisation (child and mother report) at 8, 9 and 10 years. BPD symptoms were assessed at 11 years using the UK Childhood Interview for DSM-IV BPD. Control variables included adolescent depression (assessed with the Short Moods and Feelings Questionnaire-SMFQ) and psychotic symptoms (assessed with the Psychosis-Like Symptoms Interview-PLIKS) at 11 to 14 years, and mother's exposure to family adversity during pregnancy (assessed with the Family Adversity Scale FAI). RESULTS: In unadjusted logistic regression analyses, childhood dysregulated behaviour and all environmental risk factors (i.e., family adversity, maladaptive parenting, and bully victimisation) were significantly associated with BPD symptoms at 11 years. Within structural equation modelling controlling for all associations simultaneously, family adversity and male sex significantly predicted dysregulated behaviour across childhood, while bully victimisation significantly predicted BPD, depression, and psychotic symptoms. Children displaying dysregulated behaviour across childhood were significantly more likely to experience maladaptive parenting (beta = 0.075, p < 0.001) and bully victimisation (beta = 0.327, p < 0.001). Further, there was a significant indirect association between childhood dysregulated behaviour and BPD symptoms via an increased risk of bullying (beta = 0.097, p < 0.001). While significant indirect associations between dysregulated behaviour, bully victimisation and depression (beta = 0.063, p < 0.001) and psychotic (beta = 0.074, p < 0.001) outcomes were also observed, the indirect association was significantly stronger for the BPD outcome (BPD - depression = 0.034, p < 0.01; BPD - psychotic symptoms = 0.023, p < 0.01). CONCLUSIONS: Childhood dysregulated behaviour is associated with BPD in early adolescence via an increased risk of bully victimisation. This suggests that childhood dysregulation may influence the risk of bully victimisation, which in turn influences the development of BPD. Effective interventions should target dysregulated behaviour early on to reduce exposure to environmental risks and the subsequent development of BPD. PMID- 28588896 TI - Promoting transparency, accountability, and access through a multi-stakeholder initiative: lessons from the medicines transparency alliance. AB - BACKGROUND: Barriers to expanding access to medicines include weak pharmaceutical sector governance, lack of transparency and accountability, inadequate attention to social services on the political agenda, and financing challenges. Multi stakeholder initiatives such as the Medicines Transparency Alliance (MeTA) may help overcome these barriers. Between 2008 and 2015, MeTA engaged stakeholders in the pharmaceutical sectors of seven countries (Ghana, Jordan, Kyrgyzstan, Peru, Philippines, Uganda, and Zambia) to promote access goals through greater transparency. METHODS: We reviewed archival data to document MeTA activities and results related to transparency and accountability in the seven countries where it was implemented. We identified common themes and content areas, noting specific activities used to make information transparent and accessible, how data were used to inform discussions, and the purpose and timing of meetings and advocacy activities to help set priorities and influence governance decisions. The cross-case analysis looked for pathways which might link the MeTA strategies to results such as better policies or program improvements. RESULTS: Countries used evidence gathering, open meetings, and proactive information dissemination to increase transparency. MeTA fostered policy dialogue to bring together the many government, civil society and private company stakeholders concerned with access issues, and provided them with information to understand barriers to access at policy, organizational, and community levels. We found strong evidence that transparency was enhanced. Some evidence suggests that MeTA efforts contributed to new policies and civil society capacity strengthening although the impact on government accountability is not clear. CONCLUSION: MeTA appears to have achieved its goal of creating a multi-stakeholder shared policy space in which government, civil society, and private sector players can come together and have a voice in the national pharmaceutical policy making process. Assuming that transparency is in place to leverage accountability, the success of MeTA's efforts to promote accountability by the government as well as other stakeholders in the pharmaceutical sector will depend on how well efforts are sustained over time. PMID- 28588897 TI - A physical fitness profile of state highway patrol officers by gender and age. AB - BACKGROUND: Law enforcement officers perform physically demanding tasks that generally remain constant as they age. However, there is limited population specific research on age, gender and normative fitness values for law enforcement officers as opposed to those of the general population. The purpose of this study was to profile the current level of fitness for highway patrol officers based on age and gender and provide percentile ranking charts unique to this population. METHODS: Retrospective data for six-hundred and thirty-one state troopers (? = 597; mean age = 39.52 +/- 8.09 yrs; mean height = 180.72 +/- 7.06 cm; mean weight = 93.66 +/- 15.72 kg: ? = 34; mean age = 36.20 +/- 8.45 years; mean height = 169.62 +/- 6.65 cm; mean weight = 74.02 +/- 14.91 kg) collected in 2014-2015 were provided for analysis. Data included demographic (age), anthropometric (height and weight), and select fitness (VJ, push-ups, sit ups, isometric leg/back strength, isometric grip strength and 20 m shuttle run test) information. RESULTS: There were generally significant differences between genders for all anthropometric and fitness measures, most consistently in the 30-39 age groups. While there was a general decline in push-up and shuttle run performance in female officers, these results did not reach significance. For male officers, there were significant differences between the 20-29 year-old age group and the 30-39, 40-49 and 50-59 year-old groups with the younger group performing better in VJ, push-ups, sit ups and number of shuttle runs than the older groups. There were no differences in isometric grip strength and leg back dynamometer measures between age groups. CONCLUSION: Male officers tended to be heavier, taller and perform significantly better than female officers in all measures bar sit-ups. While there appeared to be a general decline in certain physical characteristics across genders with increasing age the notable differences were between the youngest male age group (20-29 years) and all other male age groups with a potential reason being the lack of fitness requirements once typically younger cadets leave the academy. Percentile rankings for the assessed measures were found to have elements very specific to this population when compared to the general population and those provided in this paper can be used to inform future profiling and research in this population. PMID- 28588898 TI - Gender, alexithymia and physical inactivity associated with abdominal obesity in type 1 diabetes mellitus: a cross sectional study at a secondary care hospital diabetes clinic. AB - BACKGROUND: Obesity is linked to cardiovascular diseases and increasingly common in type 1 diabetes mellitus (T1DM) since the introduction of intensified insulin therapy. Our main aim was to explore associations between obesity and depression, anxiety, alexithymia and self-image measures and to control for lifestyle variables in a sample of persons with T1DM. Secondary aims were to explore associations between abdominal and general obesity and cardiovascular complications in T1DM. METHODS: Cross sectional study of 284 persons with T1DM (age 18-59 years, men 56%), consecutively recruited from one secondary care hospital diabetes clinic in Sweden. Assessments were performed with self-report instruments (Hospital Anxiety and Depression Scale, Toronto Alexithymia Scale-20 items and Structural Analysis of Social Behavior). Anthropometrics and blood samples were collected for this study and supplemented with data from the patients' medical records. Abdominal obesity was defined as waist circumference men/women (meters): >=1.02/>=0.88, and general obesity as BMI >=30 kg/m2 for both genders. Abdominal obesity was chosen in the analyses due to the high association with cardiovascular complications. Different explanatory logistic regression models were elaborated for the associations and calibrated and validated for goodness of fit with the data variables. RESULTS: The prevalence of abdominal obesity was 49/284 (17%), men/women: 8%/29% (P < 0.001). Abdominal obesity was associated with women (AOR 4.9), physical inactivity (AOR 3.1), alexithymia (AOR 2.6) and age (per year) (AOR 1.04). One of the three alexithymia sub factors, "difficulty identifying feelings" (AOR 3.1), was associated with abdominal obesity. Gender analyses showed that abdominal obesity in men was associated with "difficulty identifying feelings" (AOR 7.7), and in women with use of antidepressants (AOR 4.3) and physical inactivity (AOR 3.6). Cardiovascular complications were associated with abdominal obesity (AOR 5.2). CONCLUSIONS: Alexithymia, particularly the alexithymia subfactor "difficulty identifying feelings", physical inactivity, and women, as well as cardiovascular complications were associated with abdominal obesity. As abdominal obesity is detrimental in diabetes due to its association with cardiovascular complications, our results suggest two risk factor treatment targets: increased emotional awareness and increased physical activity. PMID- 28588899 TI - Mechanistic insights into ADXS11-001 human papillomavirus-associated cancer immunotherapy. AB - Immune responses to the facultative intracellular bacterium Listeria monocytogenes (Lm) are robust and well characterized. Utilized for decades as a model of host-disease immunology, Lm is well suited for use as an immunotherapeutic bacterial vector for the delivery of foreign antigen. Genetic modification of Lm has been undertaken to create an attenuated organism that is deficient in its master transcriptional regulator, protein-related factor A, and incorporates a truncated, nonhemolytic version of the listeriolysin O (LLO) molecule to ensure its adjuvant properties while also preventing escape of the live organism from the phagolysosome. Delivery of a vaccine construct (Lm-LLO-E7; axalimogene filolisbac [AXAL] or ADXS11-001) in which the modified LLO molecule is fused with the E7 oncoprotein of human papillomavirus type 16 (HPV-16) consistently stimulates strong innate and E7 antigen-specific adaptive immune responses, resulting in reduction of tumor burden in animal cancer models. In the clinical setting, AXAL has shown early promise in phase I/II trials of women with cervical cancer, and several more trials are currently underway to assess the efficacy and safety of this antitumor vaccine in patients with HPV-positive head and neck and anal cancers. PMID- 28588902 TI - Hypertensive response to exercise and exercise training in hypertension: odd couple no more. AB - The diagnostic and prognostic implication of exaggerated blood pressure response to exercise has been controversial, with opinions ranging from a benign process to a harbinger of potential cardiovascular morbidity. Nonetheless, lowering of blood pressure and prevention of hypertension is in first instance preferable by lifestyle changes, and many studies have shown the inverse association between physical activity level and the incidence of cardiovascular diseases suggesting low aerobic fitness as a strong predictor for future cardiovascular disease and all-cause mortality in both healthy and cardiovascular disease patients, including those with hypertension. Endothelial function, large artery stiffness and neurohormonal response are surely implicated both in the development of exaggerated blood pressure response to exercise and in the positive effect of physical exercise in the prevention and management of hypertension and cardiovascular disease in general. In their interesting and well documented review published in this issue Kim and Ha broadly described the possible pathophysiologic mechanisms of exaggerated blood pressure response to exercise and its clinical implications: in this regard, a very interesting issue could be represented by the role of exercise training. In fact, there is an the ample evidence in the literature that physical activity could positively affect endothelial function, arterial stiffness, neurohormonal response and finally blood pressure levels both in healthy men and in hypertensive patients and so should be considered a very important element in the prevention and management of cardiovascular disease. PMID- 28588903 TI - Correction: Improving documentation of clinical care within a clinical information network: an essential initial step in efforts to understand and improve care in Kenyan hospitals. AB - [This corrects the article DOI: 10.1136/bmjgh-2016-000028.]. PMID- 28588901 TI - Development and evaluation of adsorption sheet (HD safe sheet-U) using active carbon for the purpose of the preventing the contamination diffusion of urinary excreted anticancer drug. AB - BACKGROUND: Certain amount of anticancer drugs is excreted in the urine of patients receiving anticancer drugs, and urinary scattering including anticancer drugs at excretion has become a route of anticancer drug contamination. Therefore, we developed an active carbon sheet (HD safe sheet-U) that prevented diffusion by adsorbing anticancer drugs including that excreted in urine. The present study conducted a performance evaluation of this sheet. METHODS: The adsorption performance of active carbon to anticancer drug in the urine was evaluated by determining concentration changes in the active carbon suspension (5 mg/mL) of 14 kinds of anticancer drugs (cyclophosphamide, ifosfamide, carboplatin, cisplatin, methotrexate, 5-fluorouracil, cytarabine, gemcitabine, doxorubicin, epirubicin, paclitaxel, docetaxel, etoposide, and irinotecan) diluted with artificial urine. Adhesion of the anticancer drug dropping on the sheet to a slipper sole was evaluated because urine including anticancer drugs is scattered on the floor, which can spread by adhering to shoe soles of patients and healthcare workers. The performance of the active carbon sheet was compared with two other types of medical adsorption sheets used as control sheets. Anticancer drugs diluted with artificial urine (1 mL) were dropped on the active carbon sheet and the two control sheets. The sheets were trod with slippers made by polyvinyl chloride. The adhered anticancer drug was wiped off and its quantity was determined. RESULTS: A remarkable decrease in anticancer drug concentrations, except for cisplatin, was detected by mixture of active carbon in the artificial urine (0-79.6%). The quantity of anticancer drug adhesion to slipper soles from the active carbon sheet was significantly lower compared with that observed for the two control sheets for eight kinds of anticancer drugs (cyclophosphamide, ifosfamide, carboplatin, methotrexate, cytarabine, gemcitabine, doxorubicin, and docetaxel). There was no adhesion in cyclophosphamide and docetaxel. Furthermore, the quantities of adhesion in cytarabine, gemcitabine, doxorubicin, paclitaxel, and irinotecan were lower than determination limit. CONCLUSION: Active carbon might be effective in adsorbing urinary anticancer drugs. The active carbon sheet adsorbed urinary excreted anticancer drugs, and use of such sheets might prevent diffusion of contamination due to urinary excreted anticancer drugs. PMID- 28588900 TI - Associations between serum 25(OH)D concentrations and prevalent asthma among children living in communities with differing levels of urbanization: a cross sectional study. AB - BACKGROUND: Prior evidence suggests that vitamin D deficiency may increase the risk of asthma and atopy and impair pulmonary function in children. METHODS: In this cross-sectional analysis nested in a case-control study, we analyzed serum 25(OH)D concentrations in 413 children with asthma and 471 children without asthma living in two geographically adjacent study communities (Pampas and Villa El Salvador). We measured total and antigen-specific IgE levels, pulmonary function, asthma control, and exhaled nitric oxide. RESULTS: Mean 25(OH)D concentrations were 25.2 ng/mL (SD 10.1) in children with asthma and 26.1 ng/mL (SD 13.7) in children without asthma (p = 0.28). Vitamin D deficiency (25(OH)D < 20 ng/ml) was more common in Pampas than in Villa El Salvador (52.7% vs. 10.5%; p < 0.001). In the overall study population, a 10 ng/ml decrease in serum 25(OH)D concentrations was not significantly associated with odds of asthma (OR 1.09, 95% CI: 0.94 to 1.25). However, vitamin D deficiency was associated with a 1.6-fold increase in odds of asthma in the overall cohort (95% CI: 1.14 to 2.25). After stratifying by site, a 10 ng/mL decrease in serum 25(OH)D concentrations was associated with 18% higher odds of having asthma in Pampas (OR = 1.18, 95% CI 1.02 to 1.38), whereas there was no significant association between 25(OH)D concentrations and asthma in Villa El Salvador (OR = 0.95, 95% CI 0.87 to 1.05). Combined data from these geographically adjacent populations suggests a possible threshold for the relationship between 25(OH)D levels and asthma at approximately 27.5 ng/ml. Serum 25(OH)D concentrations were not clearly associated with asthma control, total serum IgE, atopy, or airway inflammation. CONCLUSION: Serum 25(OH)D concentrations were inversely associated with asthma in one study community with a high prevalence of deficiency. Studies are needed to investigate a possible threshold 25(OH)D concentration after which higher vitamin D levels show no further benefit for asthma. PMID- 28588904 TI - Health impact of human rights testimony: harming the most vulnerable? AB - BACKGROUND: Current legal efforts to document human rights violations typically include interviews in which survivors are asked to provide detailed descriptions of their traumatic experiences during a single meeting. Research on similar interview techniques used as part of a mental health treatment (eg, debriefing) has raised concerns that they might worsen mental health-more than doubling the risk of post-traumatic stress disorder in some studies. While controversy over the mental health impact of debriefing continues, debriefing treatments have been discontinued in most clinics nearly 2 decades ago. The purpose of this article is to promote the development and integration of preventative measures to limit potential mental health damage associated with legal endeavours to address human rights violations and international crimes. METHODS AND FINDINGS: Given the recent growth of the field of global mental health and its current capacity to provide feasible, acceptable, effective care in low-resource settings, we propose a research agenda to identify the mental health impact of current human rights legal practices and test a model of scalable medicolegal care that minimises risk by integrating mental health monitoring and applying up-to-date models of trauma treatment, including multiple meeting sessions, as indicated. CONCLUSIONS: As the fields of global health, human rights law, international criminal law and transitional justice increasingly overlap in their efforts to assist communities affected by grave violence, we propose that synchronising efforts may offer important opportunities to improve mental health for survivors. PMID- 28588905 TI - Data for development in health: a case study and monitoring framework from Kazakhstan. AB - Healthcare reforms are often not coupled with a relevant and appropriate monitoring framework, leaving policymakers and the public without evidence about the implications of such reforms. Kazakhstan has embarked on a large-scale reform of its healthcare system in order to achieve Universal Health Coverage. The health-related 2020 Strategic Development Goals reflect this political ambition. In a case-study approach and on the basis of published and unpublished evidence as well as personal involvement and experience (A) the indicators in the 2020 Strategic Development Goals were assessed and (B) a 'data-mapping' exercise was conducted, where the WHO health system framework was used to describe the data available at present in Kazakhstan and comment on the different indicators regarding their usefulness for monitoring the current health-related 2020 Strategic Development Goals in Kazakhstan. It was concluded that the country's current monitoring framework needs further development to track the progress and outcomes of policy implementation. The application of a modified WHO/World Bank/Global Fund health system monitoring framework was suggested to examine the implications of recent health sector reforms. Lessons drawn from the Kazakhstan experience on tailoring the suggested framework, collecting the data, and using the generated intelligence in policy development and decision-making can serve as a useful example for other middle-income countries, potentially enabling them to fast-track developments in the health sector. PMID- 28588906 TI - Trends in bidi and cigarette smoking in India from 1998 to 2015, by age, gender and education. AB - OBJECTIVES: Smoking of cigarettes or bidis (small, locally manufactured smoked tobacco) in India has likely changed over the last decade. We sought to document trends in smoking prevalence among Indians aged 15-69 years between 1998 and 2015. DESIGN: Comparison of 3 nationally representative surveys representing 99% of India's population; the Special Fertility and Mortality Survey (1998), the Sample Registration System Baseline Survey (2004) and the Global Adult Tobacco Survey (2010). SETTING: India. PARTICIPANTS: About 14 million residents from 2.5 million homes, representative of India. MAIN OUTCOME MEASURES: Age-standardised smoking prevalence and projected absolute numbers of smokers in 2015. Trends were stratified by type of tobacco smoked, age, gender and education level. FINDINGS: The age-standardised prevalence of any smoking in men at ages 15-69 years fell from about 27% in 1998 to 24% in 2010, but rose at ages 15-29 years. During this period, cigarette smoking in men became about twofold more prevalent at ages 15 69 years and fourfold more prevalent at ages 15-29 years. By contrast, bidi smoking among men at ages 15-69 years fell modestly. The age-standardised prevalence of any smoking in women at these ages was 2.7% in 2010. The smoking prevalence in women born after 1960 was about half of the prevalence in women born before 1950. By contrast, the intergenerational changes in smoking prevalence in men were much smaller. The absolute numbers of men smoking any type of tobacco at ages 15-69 years rose by about 29 million or 36% in relative terms from 79 million in 1998 to 108 million in 2015. This represents an average increase of about 1.7 million male smokers every year. By 2015, there were roughly equal numbers of men smoking cigarettes or bidis. About 11 million women aged 15-69 smoked in 2015. Among illiterate men, the prevalence of smoking rose (most sharply for cigarettes) but fell modestly among men with grade 10 or more education. The ex-smoking prevalence in men at ages 45-59 years rose modestly but was low: only 5% nationally with about 4 current smokers for every former smoker. CONCLUSIONS: Despite modest decreases in smoking prevalence, the absolute numbers of male smokers aged 15-69 years has increased substantially over the last 15 years. Cigarettes are displacing bidi smoking, most notably among young adult men and illiterate men. Tobacco control policies need to adapt to these changes, most notably with higher taxation on tobacco products, so as to raise the currently low levels of adult smoking cessation. PMID- 28588907 TI - Patterns of demand for non-Ebola health services during and after the Ebola outbreak: panel survey evidence from Monrovia, Liberia. AB - INTRODUCTION: The recent Ebola virus disease (EVD) outbreak was unprecedented in magnitude, duration and geographic scope. Hitherto there have been no population based estimates of its impact on non-EVD health outcomes and health-seeking behaviour. METHODS: We use data from a population-based panel survey conducted in the late-crisis period and two postcrisis periods to track trends in (1) the prevalence of adult and child illness, (2) subsequent usage of health services and (3) the determinants thereof. RESULTS: The prevalence of child and adult illness remained relatively steady across all periods. Usage of health services for children and adults increased by 77% and 104%, respectively, between the late crisis period and the postcrisis periods. In the late-crisis period, (1) socioeconomic factors weakly predict usage, (2) distrust in government strongly predicts usage, (3) direct exposure to the EVD outbreak, as measured by witnessing dead bodies or knowing Ebola victims, negatively predicts trust and usage and (4) exposure to government-organised community outreach predicts higher trust and usage. These patterns do not obtain in the post-crisis period. INTERPRETATION: Supply-side and socioeconomic factors are insufficient to account for lower health-seeking behaviour during the crisis. Rather, it appears that distrust and negative EVD-related experiences reduced demand during the outbreak. The absence of these patterns outside the crisis period suggests that the rebound after the crisis reflects recovery of demand. Policymakers should anticipate the importance of demand-side factors, including fear and trust, on usage of health services during health crises. PMID- 28588909 TI - Out of control: profit-seeking behaviour, unnecessary medical procedures and rising costs of private medical care in South Africa. AB - The World Health Assembly passed a resolution on the importance of engaging with the private health sector. However, the reality is that universal health coverage aspirations are particularly challenging when there is a significant private health sector. This sector in South Africa suffers from rapidly increasing costs, inflation and volume of services (unnecessary medical tests or treatments). This commentary draws on the international literature, particularly the Japanese model of healthcare, to illustrate that it is necessary and possible to curtail costs and volume in the private sector in South Africa, and possibly in other low income and middle-income settings. PMID- 28588910 TI - Improving hospital death certification in Viet Nam: results of a pilot study implementing an adapted WHO hospital death report form in two national hospitals. AB - BACKGROUND: Viet Nam does not have a system for the national collection of death data that meets international requirements for mortality reporting. It is identified as a 'no-report' country by the WHO. Verbal autopsy reports are used in the community but exclude deaths in hospitals. METHODS: This project was undertaken in Bach Mai National General Hospital and Viet Duc Surgical and Trauma Hospital in Viet Nam from 1 March 2013 to 31 March 2015. In phase 1, a modified hospital death report form, consistent with the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, was developed. Small group training in use of the report form was delivered to 427 doctors. In phase two, death data were collected, collated and analysed. In phase three, a random sample (7%) of all report forms was checked for accuracy and completeness against medical records. FINDINGS: During the 23 months of the study, 3956 deaths were recorded. Across both hospitals, 222 distinct causes of deaths were recorded. Traumatic cerebral oedema was the immediate cause of death (15% of cases, 575/3956 patients), followed by septic shock (13%, 528/3956), brain compression (11%, 416/3956), intracerebral haemorrhage (8%, 336/3956) and pneumonia (5%, 186/3956); 67% (2639/3956) of patients were discharged home to die and 33% (1314/3956) of deaths were due to a road traffic accident, or injury at home or at work. CONCLUSIONS: This study confirms the viability of implementing a death report form system compliant with international standards in hospitals in Viet Nam and provides the foundation for introducing a national death report form scheme. These data are critical to comprehensive knowledge of causes of death in Viet Nam. Death data about patients discharged home to die is presented for the first time, with implications for countries where this is a cultural preference. PMID- 28588908 TI - Global Surgery 2030: a roadmap for high income country actors. AB - The Millennium Development Goals have ended and the Sustainable Development Goals have begun, marking a shift in the global health landscape. The frame of reference has changed from a focus on 8 development priorities to an expansive set of 17 interrelated goals intended to improve the well-being of all people. In this time of change, several groups, including the Lancet Commission on Global Surgery, have brought a critical problem to the fore: 5 billion people lack access to safe, affordable surgical and anaesthesia care when needed. The magnitude of this problem and the world's new focus on strengthening health systems mandate reimagined roles for and renewed commitments from high income country actors in global surgery. To discuss the way forward, on 6 May 2015, the Commission held its North American launch event in Boston, Massachusetts. Panels of experts outlined the current state of knowledge and agreed on the roles of surgical colleges and academic medical centres; trainees and training programmes; academia; global health funders; the biomedical devices industry, and news media and advocacy organisations in building sustainable, resilient surgical systems. This paper summarises these discussions and serves as a consensus statement providing practical advice to these groups. It traces a common policy agenda between major actors and provides a roadmap for maximising benefit to surgical patients worldwide. To close the access gap by 2030, individuals and organisations must work collectively, interprofessionally and globally. High income country actors must abandon colonial narratives and work alongside low and middle income country partners to build the surgical systems of the future. PMID- 28588913 TI - UN-led Universal Periodic Review highly critical of Australia's record on human rights and health for Indigenous Australians. PMID- 28588911 TI - Design of a randomised intervention study: the effect of dumbbell exercise therapy on physical activity and quality of life among breast cancer survivors in Malaysia. AB - BACKGROUND: Participation in physical activity has a positive impact on the overall health and quality of life, whereas physical inactivity is associated with a poor prognosis among breast cancer survivors. Despite the health-enhancing benefits of physical activity, the majority of Malaysian breast cancer survivors are not physically active. This paper presents the design of a randomised study to evaluate the feasibility and effect of exercise therapy intervention using light resistance dumbbell exercise to promote active lifestyle and improve the quality of life of breast cancer survivors in Malaysia. METHODS/DESIGN: This is an intervention study of a 12-week exercise therapy that will explore and compare the effects of light resistance and aerobic exercise on physical activity level and quality of life components in 102 female breast cancer survivors. Major eligibility criteria include histologically confirmed diagnosis of breast cancer stages I-III, 3-12 months post-diagnosis, and absence of any disorder contraindicating exercise. Participants will be stratified based on menopausal status (pre-menopause vs post-menopause) and then assigned randomly to one of three groups. Participants in group A will participate in a three-times weekly supervised resistance exercise using light resistance dumbbells; participants in group B will participate in a three-times weekly supervised aerobic exercise; while participants in group C (control group) will be given aerobic exercise after completion of the intervention. The primary end points include physical activity level and quality of life components. The secondary end points are body mass index, body composition, total caloric intake, and waist-to-hip ratio. DISCUSSION: Although there have been many studies of resistance exercise in breast cancer survivors, this is the first study using this specific mode of resistance. Findings will contribute data on the feasibility and effects of light resistance dumbbell exercises, and provide knowledge on the physical activity intervention programme that will maximally promote better overall health and well being of survivors. PMID- 28588912 TI - A landscape analysis of universal health coverage for mothers and children in South Asia. AB - The United Nations made universal health coverage (UHC) a key health goal in 2012 and it is one of the Sustainable Development Goals' targets. This analysis focuses on UHC for mothers and children in the 8 countries of South Asia. A high level overview of coverage of selected maternal, newborn and child health services, equity, quality of care and financial risk protection is presented. Common barriers countries face in achieving UHC are discussed and solutions explored. In countries of South Asia, except Bhutan and Maldives, between 42% and 67% of spending on health comes from out-of-pocket expenditure (OOPE) and government expenditure does not align with political aspirations. Even where reported coverage of services is good, quality of care is often low and the poorest fare worst. There are strong examples of ongoing successes in countries such as Bhutan, the Maldives and Sri Lanka. Related to this success are factors such as lower OOPE and higher spending on health. To make progress in achieving UHC, financial and non-financial barriers to accessing and receiving high-quality healthcare need to be reduced, the amount of investment in essential health services needs to be increased and allocation of resources must disproportionately benefit the poorest. PMID- 28588914 TI - Availability and provision of emergency obstetric care under a public-private partnership in three districts of Gujarat, India: lessons for Universal Health Coverage. AB - OBJECTIVE: The state of Gujarat in India (population 60 million) has implemented a public-private partnership (PPP) with private obstetricians called the Chiranjeevi Yojana (CY) since 2006. This study investigated the adequacy of basic and comprehensive emergency obstetric care (BEmOC and CEmOC) services through the public and private sectors with reference to the United Nations (UN) guidelines. DESIGN: A cross-sectional facility survey was conducted in three districts. RESULTS: A total of 300 facilities, 151 public and 149 private, had provided obstetric services to a total of 53 896 births in the past 6 months. Nearly half, 135 facilities (104 public and 31 private), individually reported <10 births per month (low load), and, as a group, reported only 4% of all births in the past 6 months. The remaining 165 high-load facilities consisted of 23 (3 public; 20 private) full CEmOC, 66 (1; 65) 'potential' CEmOC, 12 (3; 9) BEmOC and 57 (40; 17) non-EmOC facilities. All the three districts exceeded the UN recommendation for EmOC availability by 3.3 to 11.3 times. Free provision, through both public and PPP facilities, ranged from 1.42 to 3.43. The actual performance was nearly double the recommendation for CEmOC but inadequate for BEmOC. CONCLUSIONS: Public sector EmOC availability and provision is negligible. Private sector availability is well beyond the recommended UN norms. The CY programme has resulted in increased availability and provision of EmOC services. However, the overall provision of EmOC is compromised due to the poor performance of BEmOC functions and clustering of private facilities in towns. PMID- 28588915 TI - Up-skilling associate clinicians in Malawi in emergency obstetric, neonatal care and clinical leadership: the ETATMBA cluster randomised controlled trial. AB - BACKGROUND: The ETATMBA (Enhancing Training And Technology for Mothers and Babies in Africa) project-trained associate clinicians (ACs/clinical officers) as advanced clinical leaders in emergency obstetric and neonatal care. This trial aimed to evaluate the impact of training on obstetric health outcomes in Malawi. METHOD: A cluster randomised controlled trial with 14 districts of Malawi (8 intervention, 6 control) as units of randomisation. Intervention districts housed the 46 ACs who received the training programme. The primary outcome was district (health facility-based) perinatal mortality rates. Secondary outcomes included maternal mortality ratios, neonatal mortality rate, obstetric and birth variables. The study period was 2011-2013. Mortality rates/ratios were examined using an interrupted time series (ITS) to identify trends over time. RESULTS: The ITS reveals an improving trend in perinatal mortality across both groups, but better in the control group (intervention, effect -3.58, SE 2.65, CI (-9.85 to 2.69), p=0.20; control, effect -17.79, SE 6.83, CI (-33.95 to -1.64), p=0.03). Maternal mortality ratios are seen to have improved in intervention districts while worsening in the control districts (intervention, effect -38.11, SE 50.30, CI (-157.06 to 80.84), p=0.47; control, effect 11.55, SE 87.72, CI (-195.87 to 218.98), p=0.90). There was a 31% drop in neonatal mortality rate in intervention districts while in control districts, the rate rises by 2%. There are no significant differences in the other secondary outcomes. CONCLUSIONS: This is one of the first randomised studies looking at the effect of structured training on health outcomes in this setting. Notwithstanding a number of limitations, this study suggests that up-skilling this cadre is possible, and could impact positively on health outcomes. TRIAL REGISTRATION NUMBER: ISRCTN63294155; Results. PMID- 28588916 TI - Modelling the health impact and cost-effectiveness of lymphatic filariasis eradication under varying levels of mass drug administration scale-up and geographic coverage. AB - BACKGROUND: A global programme to eliminate lymphatic filariasis (GPELF) is underway, yet two key programmatic features are currently still lacking: (1) the extension of efforts to all lymphatic filariasis (LF) endemic countries, and (2) the expansion of geographic coverage of mass drug administration (MDA) within countries. For varying levels of scale-up of MDA, we assessed the health benefits and the incremental cost-effectiveness ratios (ICERs) associated with LF eradication, projected the potential savings due to decreased morbidity management needs, and estimated potential household productivity gains as a result of reduced LF-related morbidity. METHODS: We extended an LF transmission model to track hydrocele and lymphoedema incidence in order to obtain estimates of the disability adjusted life years (DALYs) averted due to scaling up MDA over a period of 50 years. We then estimated the ICERs and the cost-effectiveness acceptability curves associated with different rates of MDA scale-up. Health systems savings were estimated by considering the averted morbidity, treatment seeking behaviour and morbidity management costs. Gains in worker productivity were estimated by multiplying estimated working days lost as a result of morbidity with country-specific per-worker agricultural wages. RESULTS: Our projections indicate that a massive scaling-up of MDA could lead to 4.38 million incremental DALYs averted over a 50-year time horizon compared to a scenario which mirrors current efforts against LF. In comparison to maintaining the current rate of progress against LF, massive scaling-up of MDA-pursuing LF eradication as soon as possible-was most likely to be cost-effective above a willingness to pay threshold of US$71.5/DALY averted. Intensified MDA scale-up was also associated with lower ICERs. Furthermore, this could result in health systems savings up to US$483 million. Extending coverage to all endemic areas could generate additional economic benefits through gains in worker productivity between US$3.4 and US$14.4 billion. CONCLUSIONS: In addition to ethical and political motivations for scaling-up MDA rapidly, this analysis provides economic support for increasing the intensity of MDA programmes. PMID- 28588917 TI - Improving the Standards-Based Management-Recognition initiative to provide high quality, equitable maternal health services in Malawi: an implementation research protocol. AB - BACKGROUND: The Government of Malawi is seeking evidence to improve implementation of its flagship quality of care improvement initiative-the Standards Based Management-Recognition for Reproductive Health (SBM-R(RH)). OBJECTIVE: This implementation study will assess the quality of maternal healthcare in facilities where the SBM-R(RH) initiative has been employed, identify factors that support or undermine effectiveness of the initiative and develop strategies to further enhance its operation. METHODS: Data will be collected in 4 interlinked modules using quantitative and qualitative research methods. Module 1 will develop the programme theory underlying the SBM-R(RH) initiative, using document review and in-depth interviews with policymakers and programme managers. Module 2 will quantitatively assess the quality and equity of maternal healthcare provided in facilities where the SBM-R(RH) initiative has been implemented, using the Malawi Integrated Performance Standards for Reproductive Health. Module 3 will conduct an organisational ethnography to explore the structures and processes through which SBM-R(RH) is currently operationalised. Barriers and facilitators will be identified. Module 4 will involve coordinated co-production of knowledge by researchers, policymakers and the public, to identify and test strategies to improve implementation of the initiative. POTENTIAL IMPACT: The research outcomes will provide empirical evidence of strategies that will enhance the facilitators and address the barriers to effective implementation of the initiative. It will also contribute to the theoretical advances in the emerging science of implementation research. PMID- 28588918 TI - Cost-effectiveness of club-foot treatment in low-income and middle-income countries by the Ponseti method. AB - BACKGROUND: Club foot is a common congenital deformity affecting 150 000-200 000 children every year. Untreated patients end up walking on the side or back of the affected foot, with severe social and economic consequences. Club foot is highly treatable by the Ponseti method, a non-invasive technique that has been described as highly suitable for use in resource-limited settings. To date, there has been no evaluation of its cost-effectiveness ratio, defined as the cost of averting one disability-adjusted life year (DALY), a composite measure of the impact of premature death and disability. In this study, we aimed to calculate the average cost-effectiveness ratio of the Ponseti method for correcting club foot in sub Saharan Africa. METHODS: Using data from 12 sub-Saharan African countries provided by the international non-profit organisation CURE Clubfoot, which implements several Ponseti treatment programmes around the world, we estimated the average cost of the point-of-care treatment for club foot in these countries. We divided the cost of treatment with the average number of DALYs that can be averted by the Ponseti treatment, assuming treatment is successful in 90% of patients. RESULTS: We found the average cost of the Ponseti treatment to be US$167 per patient. The average number of DALYs averted was 7.42, yielding a cost effectiveness ratio of US$22.46 per DALY averted. To test the robustness of our calculation different variables were used and these yielded a cost range of US$5.28-29.75. This is less than a tenth of the cost of many other treatment modalities used in resource-poor settings today. CONCLUSIONS: The Ponseti method for the treatment of club foot is cost-effective and practical in a low-income country setting. These findings could be used to raise the priority for implementing Ponseti treatment in areas where patients are still lacking access to the life-changing intervention. PMID- 28588920 TI - Associations between bride price obligations and women's anger, symptoms of mental distress, poverty, spouse and family conflict and preoccupations with injustice in conflict-affected Timor-Leste. AB - OBJECTIVES: Bride price is a widespread custom in many parts of the world, including in most countries in sub-Saharan Africa and parts of Asia. We hypothesised that problems relating to the obligatory ongoing remittances made by the husband and his family to the bride's family may be a source of mental disturbance (in the form of explosive anger and severe mental distress) among women. In addition, we postulated that problems arising with bride price would be associated with conflict with the spouse and family, poverty and women's preoccupations with injustice. DESIGN: A mixed-methods study comprising a total community household survey and semistructured qualitative interviews. SETTING: Two villages, one urban, the other rural, in Timor-Leste. PARTICIPANTS: 1193 married women participated in the household survey and a structured subsample of 77 women participated in qualitative interviews. RESULTS: Problems with bride price showed a consistent dose-effect relationship with sudden episodes of explosive anger, excessive anger and severe psychological distress. Women with the most severe problems with bride price had twice the poverty scores as those with no problems with the custom. Women with the most severe problems with bride price also reported a threefold increase in conflict with their spouse and a fivefold increase in conflict with family. They also reported heightened preoccupations with injustice. CONCLUSIONS: Our study is the first to show consistent associations between problems with bride price obligations and mental distress, poverty, conflict with spouse and family and preoccupations with injustice among women in a low-income, postconflict country. PMID- 28588919 TI - IndOSS-Assam: investigating the feasibility of introducing a simple maternal morbidity surveillance and research system in Assam, India. AB - OBJECTIVE: To assess the feasibility of establishing a simple maternal morbidity surveillance system in Assam (Indian Obstetric Surveillance System-Assam (IndOSS Assam)) to investigate the incidence and trends in severe maternal complications. This study presents the surveillance platform of IndOSS-Assam. DESIGN: Four tasks were undertaken: (1) setting up of a steering committee; (2) establishing priorities for the region; (3) mapping of surveillance sites; (4) piloting case notification systems in selected centres. SETTING: Two government tertiary hospitals in the state. STUDY POPULATION: Pregnant women delivering in the hospitals between March and August 2015. MAIN OUTCOME MEASURES: Incidence and case fatality rates with 95% CIs. RESULTS: Local stakeholder ownership and a simple uncomplicated anonymous system for case notification were the key strengths of this project. Cases and deaths were reported for six conditions: eclampsia, postpartum haemorrhage, puerperal sepsis, septic abortion, uterine rupture and anaemic heart failure. Among 10 475 women delivering over 6 months, 402 had one of these conditions and 66 died (case fatality 16%). The incidence of eclampsia was 17 per 1000 deliveries (95% CI 14 to 19), postpartum haemorrhage was 11 per 1000 deliveries (95% CI 10 to 13) and anaemic heart failure was 3 per 1000 deliveries (95% CI 2 to 5). For each of the other three conditions-puerperal sepsis, septic abortion and uterine rupture-the incidence rate was 2 per 1000 deliveries. CONCLUSIONS: IndOSS-Assam was shown to be a feasible and simple system for ongoing surveillance of maternal morbidity that can be used to monitor the trends in the incidence of specific severe life-threatening conditions during pregnancy. PMID- 28588921 TI - Association between maternal anaemia and pregnancy outcomes: a cohort study in Assam, India. AB - OBJECTIVES: To examine the association between maternal anaemia and adverse maternal and infant outcomes, and to assess the feasibility of conducting epidemiological studies through the Indian Obstetric Surveillance System-Assam (IndOSS-Assam). DESIGN: Retrospective cohort study using anonymised hospital records. Exposure: maternal iron deficiency anaemia; outcomes: postpartum haemorrhage (PPH), low birthweight, small-for-gestational age babies, perinatal death. SETTING: 5 government medical colleges in Assam. STUDY POPULATION: 1007 pregnant women who delivered in the 5 medical colleges from January to June 2015. MAIN OUTCOME MEASURES: ORs with 95% CIs to estimate the association between maternal iron deficiency anaemia and the adverse maternal and infant outcomes. Potential interactive roles of infections and induction of labour on the adverse outcomes were explored. RESULTS: 35% (n=351) pregnant women had moderate-severe anaemia. Women with severe anaemia had a higher odds of PPH (adjusted OR (aOR) =9.45; 95% CI 2.62 to 34.05), giving birth to low birthweight (aOR=6.19; 95% CI 1.44 to 26.71) and small-for-gestational age babies (aOR=8.72; 95% CI 1.66 to 45.67), and perinatal death (aOR=16.42; 95% CI 4.38 to 61.55). Odds of PPH increased 17-fold among women with moderate-severe anaemia who underwent induction of labour, and 19-fold among women who had infection and moderate severe anaemia. CONCLUSIONS: Maternal iron deficiency anaemia is a major public health problem in Assam. Maternal anaemia was associated with increased risks of PPH, low birthweight, small-for-gestational age babies and perinatal death. While the best approach is prevention, a large number of women present with severe anaemia late in pregnancy and there is no clear guidance on how these women should be managed during labour and delivery. PMID- 28588922 TI - Ebola Holding Units at government hospitals in Sierra Leone: evidence for a flexible and effective model for safe isolation, early treatment initiation, hospital safety and health system functioning. AB - The 2014-2015 West African outbreak of Ebola Virus Disease (EVD) claimed the lives of more than 11,000 people and infected over 27,000 across seven countries. Traditional approaches to containing EVD proved inadequate and new approaches for controlling the outbreak were required. The Ministry of Health & Sanitation and King's Sierra Leone Partnership developed a model for Ebola Holding Units (EHUs) at Government Hospitals in the capital city Freetown. The EHUs isolated screened or referred suspect patients, provided initial clinical care, undertook laboratory testing to confirm EVD status, referred onward positive cases to an Ebola Treatment Centre or negative cases to the general wards, and safely stored corpses pending collection by burial teams. Between 29th May 2014 and 19th January 2015, our five units had isolated approximately 37% (1159) of the 3097 confirmed cases within Western Urban and Rural district. Nosocomial transmission of EVD within the units appears lower than previously documented at other facilities and staff infection rates were also low. We found that EHUs are a flexible and effective model of rapid diagnosis, safe isolation and early initial treatment. We also demonstrated that it is possible for international partners and government facilities to collaborate closely during a humanitarian crisis. PMID- 28588923 TI - Poverty-Related Diseases College: a virtual African-European network to build research capacity. AB - The Poverty-Related Diseases College was a virtual African-European college and network that connected young African and European biomedical scientists working on poverty-related diseases. The aim of the Poverty-Related Diseases College was to build sustainable scientific capacity and international networks in poverty related biomedical research in the context of the development of Africa. The Poverty-Related Diseases College consisted of three elective and mandatory training modules followed by a reality check in Africa and a science exchange in either Europe or the USA. In this analysis paper, we present our experience and evaluation, discuss the strengths and encountered weaknesses of the programme, and provide recommendations to policymakers and funders. PMID- 28588924 TI - Prioritising the care of critically ill children: a pilot study using SCREEN reduces clinic waiting times. AB - OBJECTIVE: In low-resource settings, childhood mortality secondary to delays in triage and treatment remains high. This paper seeks to evaluate the impact of the novel Sick Children Require Emergency Evaluation Now (SCREEN) tool on the waiting times of critically ill children who present for care to primary healthcare clinics in Cape Town, South Africa. METHODS: We used a pre/postevaluation study design to calculate the median waiting times of all children who presented to four randomly chosen clinics for 5 days before, and 5 days after, the implementation of SCREEN. FINDINGS: The SCREEN programme resulted in statistical and clinically significant reductions in waiting times for children with critical illness to see a professional nurse (2 hours 45 min to 1 hour 12 min; p<0.001). There was also a statistically significant reduction in the proportion of children who left without being seen by a professional nurse (25.8% to 18.48%; p<0.001). CONCLUSIONS: SCREEN is a novel programme that uses readily available laypersons, trained to make a subjective assessment of children arriving at primary healthcare centres, and provides a low cost, simple methodology to prioritise children and reduce waiting times in low-resource healthcare clinics. PMID- 28588925 TI - No right to food and nutrition in the SDGs: mistake or success? AB - Although the recently approved Sustainable Development Goals (SDGs) explicitly mention access to water, health and education as universally guaranteed human rights, access to affordable and sufficient food is not given such recognition. The SDGs road map assumes that market mechanisms will suffice to secure nutritious and safe food for all. We question how and why the right to food has disappeared from such an international agreement and we will provide insights on the likely causes of this and the options to make good on such a regrettable omission. Analysis of political stances of relevant western stakeholders, such as the United States (US) and the European Union (EU), is also included. PMID- 28588926 TI - Evidence-based medicine for all: what we can learn from a programme providing free access to an online clinical resource to health workers in resource-limited settings. AB - The rapidly changing landscape of medical knowledge and guidelines requires health professionals to have immediate access to current, reliable clinical resources. Access to evidence is instrumental in reducing diagnostic errors and generating better health outcomes. UpToDate, a leading evidence-based clinical resource is used extensively in the USA and other regions of the world and has been linked to lower mortality and length of stay in US hospitals. In 2009, the Global Health Delivery Project collaborated with UpToDate to provide free subscriptions to qualifying health workers in resource-limited settings. We evaluated the provision of UpToDate access to health workers by analysing their usage patterns. Since 2009, ~2000 individual physicians and healthcare institutions from 116 countries have received free access to UpToDate through our programme. During 2013-2014, users logged into UpToDate ~150 000 times; 61% of users logged in at least weekly; users in Africa were responsible for 54% of the total usage. Search patterns reflected local epidemiology with 'clinical manifestations of malaria' as the top search in Africa, and 'management of hepatitis B' as the top search in Asia. Our programme demonstrates that there are barriers to evidence-based clinical knowledge in resource-limited settings we can help remove. Some assumed barriers to its expansion (poor internet connectivity, lack of training and infrastructure) might pose less of a burden than subscription fees. PMID- 28588927 TI - Terrorist attack of 15 January 2016 in Ouagadougou: how resilient was Burkina Faso's health system? AB - In Africa, health systems are often not very responsive. Their resilience is often tested by health or geopolitical crises. The Ebola epidemic, for instance, exposed the fragility of health systems, and recent terrorist attacks have required countries to respond to urgent situations. Up until 2014, Burkina Faso's health system strongly resisted these pressures and reforms had always been minor. However, since late 2014, Burkina Faso has had to contend with several unprecedented crises. In October 2014, there was a popular insurrection. Then, in September 2015, the Security Regiment of the deposed president attempted a coup d'etat. Finally, on 15 January 2016, a terrorist attack occurred in the capital, Ouagadougou. These events involved significant human injury and casualties. In these crises, the Burkinabe health system was sorely tried, testing its responsiveness, resiliency and adaptability. We describe the management of the recent terrorist attack from the standpoint of health system resilience. It would appear that the multiple crises that had occurred within the previous 2 years led to appropriate management of that terrorist attack thanks to the rapid mobilisation of personnel and good communication between centres. For example, the health system had put in place a committee and an emergency response plan, adapted blood bank services and psychology services, and made healthcare free for victims. Nevertheless, the system encountered several challenges, including the development of framework documents for resources (financial, material and human) and their use and coordination in crisis situations. PMID- 28588928 TI - Boundary-spanning: reflections on the practices and principles of Global Health. AB - As Global Health evolves, not merely as a metaphor for international collaboration, but as a distinct field of practice, it warrants greater consideration of how it is practiced, by whom, and for what goals. We believe that, to become more relevant for the health systems and communities that are their intended beneficiaries, Global Health practices must actively span and disrupt boundaries of geography, geopolitics and constituency, some of which are rooted in imbalances of power and resources. In this process, fostering cross country learning networks and communities of practice, and building local and national institutions with a global outlook in low and middle-income countries, are critically important. Crucially, boundary-spanning practices in Global Health require a mindset of inclusiveness, awareness of and respect for different coexisting realities. PMID- 28588929 TI - Improving the detection of environmental enteric dysfunction: a lactulose, rhamnose assay of intestinal permeability in children aged under 5 years exposed to poor sanitation and hygiene. AB - BACKGROUND: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder affecting populations living in conditions of poor sanitation and hygiene. The study tested intestinal barrier function in infants with EED. METHODS: We prospectively studied an advanced high-performance liquid chromatography mass spectrometry assay of urine collected after oral intake of the monosaccharide, L-rhamnose and the disaccharide, lactulose, in 112 children from three continents. FINDINGS: Compared to the US cohort (n=27), the cohorts of children from Peru (n=19) and Zambia (n=85) were older with evidence of growth impairment. The median (range) of age (months) was 8.0 (2.0 to 13.0), 27.0 (15.0 to 29.0) and 21.0 (12.0 to 36.0), respectively. The median (range) of height for age Z score was -0.1 (-1.8 to 2.4), -1.8 (-3.3 to -0.2) and -2.3 (-8.5 to 1.2), respectively. Among children with valid sugar data (n=22 USA, n=19 Peru, n=73 Zambia), there were no significant differences in the median rhamnose urine concentrations between the three groups. The median (range) lactulose concentration (ug/mL) was 6.78 (0.29 to 31.90), 47.60 (4.23 to 379.00) and 75.40 (0.67 to 873.00) in the US, Peruvian and Zambian cohorts, respectively (p<0.001). The lactulose/rhamnose ratio (LRR) was higher in cohorts from Peru (0.75, 0.15, 5.02) and Zambia (2.26, 0.08, 14.48) compared to the US (0.14, 0.06, 1.00) cohort (p<0.001). In a multivariate effect modification model, higher weight-for-age z scores were associated with lower post-dose lactulose when rhamnose excretion was constant (p=0.003). CONCLUSIONS: This non-invasive two saccharide permeability protocol measures changes in intestinal permeability in children with EED and permits the identification of individuals for interventional trials. PMID- 28588930 TI - Validation of a portable, deployable system for continuous vital sign monitoring using a multiparametric wearable sensor and personalised analytics in an Ebola treatment centre. AB - BACKGROUND: The recent Ebola epidemic in West Africa strained existing healthcare systems well beyond their capacities due to the extreme volume and severity of illness of the patients. The implementation of innovative digital technologies within available care centres could potentially improve patient care as well as healthcare worker safety and effectiveness. METHODS: We developed a Modular Wireless Patient Monitoring System (MWPMS) and conducted a proof of concept study in an Ebola treatment centre (ETC) in Makeni, Sierra Leone. The system was built around a wireless, multiparametric 'band-aid' patch sensor for continuous vital sign monitoring and transmission, plus sophisticated data analytics. Results were used to develop personalised analytics to support automated alerting of early changes in patient status. RESULTS: During the 3-week study period, all eligible patients (n=26) admitted to the ETC were enrolled in the study, generating a total of 1838 hours of continuous vital sign data (mean of 67.8 hours/patient), including heart rate, heart rate variability, activity, respiratory rate, pulse transit time (inversely related to blood pressure), uncalibrated skin temperature and posture. All patients tolerated the patch sensor without problems. Manually determined and automated vital signs were well correlated. Algorithm-generated Multivariate Change Index, pulse transit time and arrhythmia burden demonstrated encouraging preliminary findings of important physiological changes, as did ECG waveform changes. CONCLUSIONS: In this proof of concept study, we were able to demonstrate that a portable, deployable system for continuous vital sign monitoring via a wireless, wearable sensor supported by a sophisticated, personalised analytics platform can provide high-acuity monitoring with a continuous, objective measure of physiological status of all patients that is achievable in virtually any healthcare setting, anywhere in the world. PMID- 28588931 TI - The information problem in global health. PMID- 28588932 TI - Fasting with diabetes: a prospective observational study. AB - OBJECTIVES: To determine the proportion of diabetic patients who develop adverse glycaemic events when fasting regularly. DESIGN: Prospective observational study conducted at a tertiary care hospital in South Asia. Five hundred and twenty three patients were assessed for eligibility, and 150 were included in the final analysis. Diabetic patients over 18 years of age who were willing to fast regularly and make a chart of their daily blood sugar levels were included in the study. The main outcome measures were hypoglycaemic and hyperglycaemic events. Frequencies and percentages were calculated for quantitative variables, while mean+/-SD were documented for qualitative variables. Relative risk was calculated as a measure of association. RESULTS: Of a total of 150 individuals, 10% experienced hypoglycaemia, while 3.3% reported hyperglycaemic episodes. Only 8.7% of the participants discontinued one or more fasts; however, none of them required hospitalisation. There is a negative association between a visit to a physician by diabetic patients before they begin to fast regularly and the risk of developing hypoglycaemia (relative risk 0.73). CONCLUSIONS: Many diabetic patients who fast regularly are at high risk of adverse glycaemic events. Most diabetics do not consult their physicians before fasting to adjust medications and lifestyle. Various strategies should be planned and implemented for the awareness and education of such patients to avoid adverse glycaemic events and subsequent complications. PMID- 28588934 TI - Need for a standardised procedure classification system in global surgery. PMID- 28588935 TI - The Internet of Things to come: digital technologies and the End TB Strategy. PMID- 28588933 TI - Can the UNAIDS 90-90-90 target be achieved? A systematic analysis of national HIV treatment cascades. AB - BACKGROUND: In 2014, the Joint United Nations Programme on HIV and AIDS (UNAIDS) and partners set the '90-90-90 targets'; aiming to diagnose 90% of all HIV positive people, provide antiretroviral therapy (ART) for 90% of those diagnosed and achieve viral suppression for 90% of those treated, by 2020. This results in 81% of all HIV positive people on treatment and 73% of all HIV positive people achieving viral suppression. We aimed to analyse how effective national HIV treatment programmes are at meeting these targets, using HIV care continuums or cascades. METHODS: We searched for HIV treatment cascades for 196 countries in published papers, conference presentations, UNAIDS databases and national reports. Cascades were constructed using reliable, generalisable, recent data from national, cross-sectional and longitudinal study cohorts. Data were collected for four stages; total HIV positive people, diagnosed, on treatment and virally suppressed. The cascades were categorised as complete (four stages) or partial (3 stages), and analysed for 'break points' defined as a drop >10% in coverage between consecutive 90-90-90 targets. RESULTS: 69 country cascades were analysed (32 complete, 37 partial). Diagnosis (target one-90%) ranged from 87% (the Netherlands) to 11% (Yemen). Treatment coverage (target two-81% on ART) ranged from 71% (Switzerland) to 3% (Afghanistan). Viral suppression (target three-73% virally suppressed) was between 68% (Switzerland) and 7% (China). CONCLUSIONS: No country analysed met the 90-90-90 targets. Diagnosis was the greatest break point globally, but the most frequent key break point for individual countries was providing ART to those diagnosed. Large disparities were identified between countries. Without commitment to standardised reporting methodologies, international comparisons are complex. PMID- 28588936 TI - Early initiation of breast feeding on the rise in India. PMID- 28588937 TI - Outsourcing: how to reform WHO for the 21st century. PMID- 28588938 TI - Primary healthcare policy implementation in South Asia. AB - Primary healthcare is considered an essential feature of health systems to secure population health and contain costs of healthcare while universal health coverage forms a key to secure access to care. This paper is based on a workshop at the 2016 World Organization of Family Doctors (WONCA) South Asia regional conference, where the health systems of Bangladesh, India, Nepal, Pakistan and Sri Lanka were presented in relation to their provision of primary healthcare. The five countries have in recent years improved the health of their populations, but currently face the challenges of non-communicable diseases and ageing populations. Primary healthcare should be a core component in restructuring health systems. However, there is a lack of understanding among policymakers of the unique contribution of primary healthcare to the health of populations. This results in insufficient investment in facilities and low priority of specialty training in the community setting. Regional collaboration could strengthen the advocacy for primary healthcare to policymakers and other stakeholders. Priorities were investment in community-based health facilities, and access to healthcare through professionals specialty-trained in the primary healthcare setting. This development fits the strategy of the WHO South East Asian Region to use community-based healthcare in achieving universal health coverage for the Asian populations. PMID- 28588939 TI - Cost-effectiveness of triage testing for facility-based systematic screening of tuberculosis among Ugandan adults. AB - BACKGROUND: Systematic screening is often proposed as a way to improve case finding for tuberculosis (TB), but the cost-effectiveness of specific strategies for systematic screening remains poorly studied. METHODS: We constructed a Markov based decision analytic model to analyse the cost-effectiveness of triage testing for TB in Uganda, compared against passive case detection with Xpert MTB/RIF. We assumed a triage algorithm whereby all adults presenting to healthcare centres would be screened for cough, and those with cough of at least 2 weeks would receive the triage test, with positive triage results confirmed by Xpert MTB/RIF. We adopted the perspective of the TB control sector, using a primary outcome of the cost per year of life gained (YLG) over a lifetime time horizon. RESULTS: Systematic screening in a population with a 5% underlying prevalence of TB was estimated to cost US$610 per YLG (95% uncertainty range US$200-US$1859) with chest X-ray (CXR) (US$5 per test, specificity 0.67), or US$588 (US$221-US$1746) with C reactive protein (CRP) (US$3 per test, specificity 0.59). In addition to the cost and specificity of the triage test, cost-effectiveness was most sensitive to the underlying prevalence of TB, monthly risk of mortality in people with untreated TB and the proportion of patients with TB who would be treated in the absence of systematic screening. CONCLUSIONS: To optimise the cost effectiveness of facility-based systematic screening of TB with a triage test, it must be carried out in a high-risk population, or use triage tests that are cheaper or more specific than CXR or CRP. PMID- 28588940 TI - Wealth, education and urban-rural inequality and maternal healthcare service usage in Malawi. AB - BACKGROUND: Malawi is among the 5 sub-Saharan African countries presenting with very high maternal mortality rates, which remain a challenge. This study aims to examine the impact of wealth inequality and area of residence (urban vs rural) and education on selected indicators of maternal healthcare services (MHS) usage in Malawi. METHODS: This study was based on data from the 5th round of Multiple Indicator Cluster Surveys (MICS) conducted in 2013-2014 in Malawi. Study participants were 7572 mothers aged between 15 and 49 years. The outcome variable was usage status of maternal health services of the following types: antenatal care, skilled delivery assistance and postpartum care. Univariate, bivariate and multivariate methods were used to describe the pattern of MHS usage in the sample population. Association between household wealth status, education as well as the type of residence, whether urban or rural, as independent variables and usage of MHS as dependent variables were analysed using the generalised estimating equations (GEE) method. RESULTS: Mean age of the sample population was 26.88 (SD 6.68). Regarding the usage of MHS, 44.7% of women had at least 4 ANC visits, 87.8% used skilled delivery attendants and 82.2% of women had used postnatal care. Regarding the wealth index, about a quarter of the women were in the poorest wealth quintile (23.6%) while about 1/6 were in the highest wealth quintile (15%). Rate of usage for all 3 types of services was lowest among women belonging to the lowest wealth quintile. In terms of education, only 1/5 completed their secondary or a higher degree (20.1%) and nearly 1/10 of the population lives in urban areas (11.4%) whereas the remaining majority live in rural areas (88.6%). The rates of usage of MHS, although reasonable on an overall basis, were consistently lower in women with lower education and those residing in rural areas. CONCLUSIONS: Maternal health service usage in Malawi appears to be reasonable, yet the high maternal mortality rate is disturbing and calls for analysing factors hindering the achievement of maternal health-related Sustainable Development Goals (SDGs). The findings of this study underscore the need to minimise the wealth inequality, urban-rural divide and the low level of education among mothers to improve the usage of MHS. An equity-based policy approach considering the sociodemographic inequity in terms of wealth index, education and urban-rural divide might prove beneficial in further improving the MHS usage, as well as addressing the possible issues of quality gaps in MHS, which might be beneficial towards reducing maternal mortality. It should be noted that the study of quality gaps in MHS is beyond the scope of this paper and calls for further research in this arena. PMID- 28588941 TI - Physicochemical equivalence of generic antihypertensive medicines (EQUIMEDS): protocol for a quality of medicines assessment. AB - BACKGROUND: Prevention and optimal management of hypertension in the general population is paramount to the achievement of the World Heart Federation (WHF) goal of reducing premature cardiovascular disease (CVD) mortality by 25% by the year 2025 and widespread access to good quality antihypertensive medicines is a critical component for achieving the goal. Despite research and evidence relating to other medicines such as antimalarials and antibiotics, there is very little known about the quality of generic antihypertensive medicines in low-income and middle-income countries. The aim of this study was to determine the physicochemical equivalence (percentage of active pharmaceutical ingredient, API) of generic antihypertensive medicines available in the retail market of a developing country. METHODS: An observational design will be adopted, which includes literature search, landscape assessment, collection and analysis of medicine samples. To determine physicochemical equivalence, a multistage sampling process will be used, including (1) identification of the 2 most commonly prescribed classes of antihypertensive medicines prescribed in Nigeria; (2) identification of a random sample of 10 generics from within each of the 2 most commonly prescribed classes; (3) a geographical representative sampling process to identify a random sample of 24 retail outlets in Nigeria; (4) representative sample purchasing, processing to assess the quality of medicines, storage and transport; and (5) assessment of the physical and chemical equivalence of the collected samples compared to the API in the relevant class. In total, 20 samples from each of 24 pharmacies will be tested (total of 480 samples). DISCUSSION: Availability of and access to quality antihypertensive medicines globally is therefore a vital strategy needed to achieve the WHF 25*25 targets. However, there is currently a scarcity of knowledge about the quality of antihypertensive medicines available in developing countries. Such information is important for enforcing and for ensuring the quality of antihypertensive medicines. PMID- 28588943 TI - Towards an equitable internship programme at WHO: is reform nigh? PMID- 28588942 TI - Epidemiology of Zika virus, 1947-2007. AB - INTRODUCTION: Since 1947, Zika virus has been identified sporadically in humans in Africa and Asia; however, clinically consequential Zika virus disease had not been documented prior to the current outbreak in the Americas. Considering 6 decades have passed since the first identification of the virus, it is perhaps unexpected that Zika virus was recognised only recently as capable of causing disease epidemics. Substantial work on understanding the epidemiology of Zika virus has been conducted since the virus' first outbreak in 2007 in Micronesia; however, there has been little study of the earlier data on Zika virus. METHODS: A systematic literature search was conducted to identify evidence of Zika virus infection in humans from 1947 to 2007. Data extracted included seroprevalence of Zika virus infection, age distributions of positive test results and serologic test modalities used. Country-level and age-specific seroprevalence was calculated. Estimates of seroprevalence by different serologic test modalities were compared. RESULTS: 12 026 citations were retrieved by the literature search, and 76 articles were included in this review. Evidence of Zika virus infection in humans was found in 29 countries in Africa, 8 countries in Asia and 1 country in Europe. Country-level seroprevalence of Zika virus infection ranged from 0.4% to 53.3%. Seroprevalence of Zika virus infection was found to increase across the lifespan; 15-40% of reproductive-age individuals may have been previously infected. No significant difference was found between estimates of seroprevalence by different serologic test modalities. DISCUSSION: Zika virus has likely been endemic for decades in certain regions of the world; however, the majority of reproductive-age individuals have likely not been infected. Historical evidence of Zika virus infection exists regardless of the serologic test modality used. PMID- 28588944 TI - Onsite midwife-led birth units (OMBUs) for care around the time of childbirth: a systematic review. AB - INTRODUCTION: To ensure timely access to comprehensive emergency obstetric care in low- and middle-income countries, a number of interventions have been employed. This systematic review assesses the effects of onsite midwife-led birth units (OMBUs) embedded within hospitals which provide comprehensive emergency obstetric and newborn care. METHODS: Both interventional and observational studies that compared OMBUs with standard medical-led obstetric care were eligible for inclusion. Cochrane Central Register of Controlled Trials, PubMed/Medline, EMBASE, CINAHL, Science Citation and Social Sciences Citation Index, Global Health Library and one Chinese database were searched. Meta analysis was conducted to synthesise data from randomised controlled trials (RCTs). Findings of observational studies were summarised by forest plots with brief narratives. RESULTS: Three RCTs, one controlled before-and-after study and six cohort studies were included. There were no or very few maternal and perinatal deaths in either OMBUs or standard obstetric units, with no significant differences between the two. Women giving birth in OMBUs were less likely to use epidural analgesia (risk ratio (RR) 0.67, 95% CI 0.55 to 0.82; three trials, n=2431). The UK national cohort study and two other cohorts in China and Nepal found less oxytocin augmentation, more spontaneous vaginal deliveries, fewer caesarean sections and fewer episiotomies performed in OMBUs than in standard obstetric units. These differences were not statistically significant in RCTs and the remaining cohorts. One study investigated satisfaction with midwife-led birth care among women and midwives, with positive findings in both groups favouring OMBUs. In addition, two studies found that the total cost of birth was lower in OMBUs than in standard obstetric units. CONCLUSIONS: OMBUs could be an alternative model for providing safe and cost-effective childbirth care, which may be particularly important in low- and middle-income countries to meet the growing demand for facility-based birth for low-risk women and improve efficiency of health systems. PMID- 28588945 TI - What the InBev merger means for health in Africa. PMID- 28588947 TI - Need for more and better implementation science in global health. PMID- 28588948 TI - Manmade earthquake: the hidden health effects of a blockade-induced fuel crisis in Nepal. PMID- 28588946 TI - Assessing the independent and combined effects of subsidies for antimalarials and rapid diagnostic testing on fever management decisions in the retail sector: results from a factorial randomised trial in western Kenya. AB - OBJECTIVES: There is an urgent need to understand how to improve targeting of artemisinin combination therapy (ACT) to patients with confirmed malaria infection, including subsidised ACTs sold over-the-counter. We hypothesised that offering an antimalarial subsidy conditional on a positive malaria rapid diagnostic test (RDT) would increase uptake of testing and improve rational use of ACTs. METHODS: We designed a 2*2 factorial randomised experiment evaluating 2 levels of subsidy for RDTs and ACTs. Between July 2014 and June 2015, 444 individuals with a malaria-like illness who had not sought treatment were recruited from their homes. We used scratch cards to allocate participants into 4 groups in a ratio of 1:1:1:1. Participants were eligible for an unsubsidised or fully subsidised RDT and 1 of 2 levels of ACT subsidy (current retail price or an additional subsidy conditional on a positive RDT). Treatment decisions were documented 1 week later. Our primary outcome was uptake of malaria testing. Secondary outcomes evaluated ACT consumption among those with a negative test, a positive test or no test. RESULTS: Offering a free RDT increased the probability of testing by 18.6 percentage points (adjusted probability difference (APD), 95% CI 5.9 to 31.3). An offer of a conditional ACT subsidy did not have an additional effect on the probability of malaria testing when the RDT was free (APD=2.7; 95% CI -8.6 to 14.1). However, receiving the conditional ACT subsidy increased the probability of taking an ACT following a positive RDT by 19.5 percentage points (APD, 95% CI 2.2 to 36.8). Overall, the proportion who took ACT following a negative test was lower than those who took ACT without being tested, indicated improved targeting among those who were tested. CONCLUSIONS: Both subsidies improved appropriate fever management, demonstrating the impact of these costs on decision making. However, the conditional ACT subsidy did not increase testing. We conclude that each of the subsidies primarily impacts the most immediate decision. TRIAL REGISTRATION NUMBER: NCT02199977. PMID- 28588949 TI - Systematic review and meta-analysis of the adolescent HIV continuum of care in South Africa: the Cresting Wave. AB - CONTEXT: South Africa has the most HIV infections of any country in the world, yet little is known about the adolescent continuum of care from HIV diagnosis through viral suppression. OBJECTIVE: To determine the adolescent HIV continuum of care in South Africa. DATA SOURCES: We searched PubMed, Google Scholar and online conference proceedings from International AIDS Society (IAS), International AIDS Conference (AIDS) and Conference on Retrovirology and Opportunistic Infections (CROI) from 1 January 2005 to 31 July 2015. DATA EXTRACTION: We selected published literature containing South African cohorts and epidemiological data reporting primary data for youth (15-24 years of age) at any stage of the HIV continuum of care (ie, diagnosis, treatment, retention, viral suppression). For the meta-analysis we used six sources for retention in care and nine for viral suppression. RESULTS: Among the estimated 867 283 HIV-infected youth from 15 to 24 years old in South Africa in 2013, 14% accessed antiretroviral therapy (ART). Of those on therapy, ~83% were retained in care and 81% were virally suppressed. Overall, we estimate that 10% of HIV-infected youth in South Africa in 2013 were virally suppressed. LIMITATIONS: This analysis relies on published data from large mostly urban South Africa cohorts limiting the generalisability to all adolescents. CONCLUSIONS: Despite a large increase in ART programmes in South Africa that have relatively high retention rates and viral suppression rates among HIV-infected youth, only a small percentage are virally suppressed, largely due to low numbers of adolescents and young adults accessing ART. PMID- 28588950 TI - Psychosocial wellbeing of patients with multidrug resistant tuberculosis voluntarily confined to long-term hospitalisation in Nigeria. AB - BACKGROUND AND OBJECTIVE: Patient isolation, which is a widely successful treatment strategy for tuberculosis (TB), has been suspected to have effects on patient psychosocial wellbeing. We assessed the psychosocial wellbeing of multidrug resistant TB (MDR-TB) patients in voluntary and isolated long-term hospitalisation in Nigeria. METHODS: 98 accessible and consenting patients in four drug-resistant treatment centres (University College Hospital and Government Chest Hospital, Ibadan; Mainland Hospital, Lagos, and Lawrence Henshaw Memorial Hospital, Calabar) were enrolled in this study. Data were collected using an 18 item psychosocial wellbeing questionnaire including sociodemographic characteristics. We used descriptive statistics to present demographic characteristics; the chi2 test was used to assess associations between psychosocial wellbeing and independent variables and the relationship was modelled using logistic regression. RESULTS: The mean age of respondents was 36.1+/-11.9 years and 63% were males. Respondents had been in hospital an average of 4.5+/-1.9 months. Females had more psychosocial concerns compared with males. The most common concerns recorded among respondents were concern that people will get to know that the respondent had a bad type of TB (70%), discontent with being separated from and longing for the company of their marital partner (72%), concerns that they may have taken too many drugs (73%), and displeasure with being unable to continue to engage in their usual social and economic activities (75%). Respondents who were employed had eight times the odds of having more psychosocial concerns than the median number among respondents. Respondents who were supported by their own families during hospitalisation experienced a lower burden of psychosocial concerns compared with those who were supported by third parties. CONCLUSIONS: Prolonged hospitalisation resulted in significant psychosocial burden for the MDR-TB patients in our study centres. There is a need to consider alternative approaches that place less psychosocial burden on patients without compromising quality of care. PMID- 28588951 TI - Cholera in the time of war: implications of weak surveillance in Syria for the WHO's preparedness-a comparison of two monitoring systems. AB - BACKGROUND: Public health breakdown from the Syrian government's targeting of healthcare systems in politically unsympathetic areas has yielded a resurgence of infectious diseases. Suspected cholera recently reappeared but conflict-related constraints impede laboratory confirmation. Given the government's previous under reporting of infectious outbreaks and the reliance of the WHO on government reporting, we sought to assess the reliability of current surveillance systems. METHODS: We compared weekly surveillance reports of waterborne diseases from the Syrian government's (WHO-associated) Early Warning and Response System (EWARS), based in Damascus, and the independent, non-governmental Early Warning and Response Network (EWARN) headquartered in Gaziantep, Turkey. We compared raw case rates by EWARS and EWARN and assessed the quality of reporting against the WHO benchmarks. RESULTS: We identified significant under-reporting and delays in the government's surveillance. On average, EWARS reports were published 24 days (range 12-61) after the reference week compared with 11 days (5-21) for EWARN. Average completeness for EWARS was 75% (55-84%), compared with 92% for EWARN (85 99%). Average timeliness for EWARS was 79% (51-100%), compared with 88% for EWARN (70-97%). EWARS made limited use of rapid diagnostic tests, and rates of collection of stool samples for laboratory cholera testing were well below reference levels. CONCLUSIONS: In the context of the current Syrian war, the government's surveillance is inadequate due to lack of access to non-government held territory, an incentive to under-report the consequence of government attacks on health infrastructure, and an impractical insistence on laboratory confirmation. These findings should guide the WHO reform for surveillance in conflict zones. PMID- 28588952 TI - Cooperative societies: a sustainable platform for promoting universal health coverage in Bangladesh. PMID- 28588954 TI - 'Women and babies are dying but not of Ebola': the effect of the Ebola virus epidemic on the availability, uptake and outcomes of maternal and newborn health services in Sierra Leone. AB - BACKGROUND: We sought to determine the impact of the Ebola virus epidemic on the availability, uptake and outcome of routine maternity services in Sierra Leone. METHODS: The number of antenatal and postnatal visits, institutional births, availability of emergency obstetric care (EmOC), maternal deaths and stillbirths were assessed by month, by districts and by level of healthcare for 10 months during, and 12 months prior to, the Ebola virus disease (EVD) epidemic. All healthcare facilities designated to provide comprehensive (n=13) or basic (n=67) EmOC across the 13 districts of Sierra Leone were included. RESULTS: Preservice students were not deployed during the EVD epidemic. The number of healthcare providers in facilities remained constant (incidence rate ratio (IRR) 1.03, 95% CI 1.00 to 1.07). Availability of antibiotics, oxytocics, anticonvulsants, manual removal of placenta, removal of retained products of conception, blood transfusion and caesarean section were not affected by the EVD epidemic. Across Sierra Leone, following the onset of the EVD epidemic, there was a 18% decrease in the number of women attending for antenatal (IRR 0.82, 95% CI 0.79 to 0.84); 22% decrease in postnatal attendance (IRR 0.78, 95% CI 0.75 to 0.80) visits and 11% decrease in the number of women attending for birth at a healthcare facility (IRR 0.89, 95% CI 0.87 to 0.91). There was a corresponding 34% increase in the facility maternal mortality ratio (IRR 1.34, 95% CI 1.07 to 1.69) and 24% increase in the stillbirth rate (IRR 1.24, 95% CI 1.14 to 1.35). CONCLUSIONS: During the EVD epidemic, fewer pregnant women accessed healthcare. For those who did, an increase in maternal mortality and stillbirth was observed. In the post Ebola phase, 'readiness' (or not) of the global partners for large-scale epidemics has been the focus of debate. The level of functioning of the health system with regard to ability to continue to provide high-quality effective routine care needs more attention. PMID- 28588953 TI - Trends and level of control of hypertension among adults attending an ambulatory HIV clinic in Kampala, Uganda: a retrospective study. AB - BACKGROUND: With an ageing HIV-positive population, sub-Saharan Africa is now facing a dual epidemic of communicable and non-communicable diseases (NCDs). This study aimed to assess trends in the prevalence of hypertension and factors associated with hypertension, among adults attending an ambulatory HIV clinic in Kampala, Uganda. METHODS: We conducted a retrospective chart review to identify patients with hypertension. We used a random number generator to select 400 patient charts from each year from 2009 to 2014. Blood pressure, age, body mass index (BMI), WHO disease stage and Karnofsky scores were extracted. Logistic regression was used to estimate the strength of the association between each of these factors and the presence of hypertension. RESULTS: In total, 1996 charts were included in this analysis. The mean age of participants was 31 years and 1311/1996 (65.7%) were female. The overall prevalence of hypertension was 418/1996 (20.9%). This rose from 16.9% in 2009 to 32.3% in 2013. Of the patients with hypertension, 96/418 (23.0%) were receiving adequate treatment. Patients >50 years of age had 3.12 times the odds of hypertension compared with patients aged 20-29 years (95% CI 2.00 to 4.85). Men had 1.65 times the odds of hypertension compared with women (95% CI 1.34 to 2.03) and patients with a BMI of 35-39 kg/m2 had 3.93 times the odds of hypertension compared with patients with a BMI <25 kg/m2. CONCLUSIONS: The prevalence of hypertension is rising in the Ugandan HIV positive population. There remains inadequate management and control of hypertension in this group highlighting the need to better integrate NCD care within the HIV clinical settings. PMID- 28588955 TI - The importance of an integrating framework for achieving the Sustainable Development Goals: the example of health and well-being. AB - The 2030 Agenda for Sustainable Development came into force in January 2016 as the central United Nations (UN) platform for achieving 'integrated and indivisible' goals and targets across the three characteristic dimensions of sustainable development: the social, environmental and economic. We argue that, despite the UN adoption of the Sustainable Development Goals (SDGs), a framework for operationalising them in an integrated fashion is lacking. This article puts forth a framework for integrating health and well-being across the SDGs as both preconditions and outcomes of sustainable development. We present a rationale for this approach, and identify the challenges and opportunities for implementing and monitoring such a framework through a series of examples. We encourage other sectors to develop similar integrating frameworks for supporting a more coordinated approach for operationalising the 2030 Agenda for Sustainable Development. PMID- 28588956 TI - Gender disparities in the experience, effects and reporting of electronic aggression among secondary school students in Nigeria. AB - BACKGROUND: Electronic aggression is the use of electronic communication technologies to harass others. It is a problem among adolescents and young people worldwide. There is a dearth of information on this problem in developing countries in spite of the increasing use of electronic media technology in these countries. OBJECTIVE: To explore gender differences in the prevalence, effects and reporting of electronic aggression among secondary school students in Oyo state, Nigeria. METHODS: A cross-sectional study was conducted using mixed methods (a quantitative survey of 653 students and 18 in-depth interviews with victims and/or perpetrators). Survey students were selected using multi-stage sampling and in-depth interviewees were selected purposively. History of electronic aggression (as a perpetrator and/or victim) in the 3 months preceding the study was obtained. Respondents also provided information on the effects of the last incident of bullying on them and whether or not they reported this incident. RESULTS: 25.8% of males and 22.1% of females had perpetrated electronic aggression, while 42.7% of females were victims compared to 36.8% of males. More females (58.1%) than males (40.3%) perpetrated electronic aggression via phone calls and more males (33.8%) than females (22.6%) perpetrated electronic aggression via chatrooms. 45.4% of male victims and 39.4% of female victims felt angry following the last cyberbully incident. Findings from the in-depth interviewees corroborated the survey findings and a male victim reported feeling very sad and even tried to stay away from school following repeated episodes of electronic aggression. More female (59.1%) than male (42.7%) victims reported the incident to someone (p=0.035). CONCLUSIONS: Incidents of electronic aggression were common and the experiences of male and female students were comparable, although more female victims reported the incidents they had experienced. Victims, especially males, should be encouraged to report incidents so that the relevant authorities can institute interventions to address the problem. PMID- 28588957 TI - Spiritual issues of people living and dying with advanced heart failure in Kenya: a qualitative serial interview study. AB - BACKGROUND: Exploring patients' spiritual issues is vital for informing holistic care. The spiritual concerns of patients living and dying with advanced heart failure in sub-Saharan Africa remains unknown. Our aim was to describe spiritual issues in the context of the lived experiences of patients with heart failure in Kenya. METHODS: We purposively recruited 18 patients admitted with advanced heart failure at a rural district hospital in Kenya. We conducted serial in-depth interviews with patients at 0, 3 and 6 months after recruitment. We conducted bereavement interviews with their carers. Interviews were recorded, transcribed into English and analysed using a thematic approach, assisted by Nvivo software package. RESULTS: Patients expressed traditional and Christian spiritual beliefs in response to their illness. At diagnosis, some patients felt their illness had occurred because they had wronged God, while others felt betrayed by God. Some expressed comfort from God and optimism believing that God was in control and would heal their illness. During acute episodes patients questioned whether witchcraft or curses caused their illness. Younger patients experienced more spiritual distress. Although church fellowship generally offered spiritual and social support, some patients felt let down by the church which they perceived to favour those who offered more tithes. CONCLUSIONS: This is the first study to explore the spiritual issues of people living with advanced heart failure in Kenya. Understanding patients' spiritual concerns is important for developing evidence-based patient-centred holistic care to promote multidimensional well being. PMID- 28588958 TI - Women's health: a new global agenda. AB - Global efforts to improve the health of women largely focus on improving sexual and reproductive health. However, the global burden of disease has changed significantly over the past decades. Currently, the greatest burden of death and disability among women is attributable to non-communicable diseases (NCDs), most notably cardiovascular diseases, cancers, respiratory diseases, diabetes, dementia, depression and musculoskeletal disorders. Hence, to improve the health of women most efficiently, adequate resources need to be allocated to the prevention, management and treatment of NCDs in women. Such an approach could reduce the burden of NCDs among women and also has the potential to improve women's sexual and reproductive health, which commonly shares similar behavioural, biological, social and cultural risk factors. Historically, most medical research was conducted in men and the findings from such studies were assumed to be equally applicable to women. Sex differences and gender disparities in health and disease have therefore long been unknown and/or ignored. Since the number of women in studies is increasing, evidence for clinically meaningful differences between men and women across all areas of health and disease has emerged. Systematic evaluation of such differences between men and women could improve the understanding of diseases, as well as inform health practitioners and policymakers in optimising preventive strategies to reduce the global burden of disease more efficiently in women and men. PMID- 28588959 TI - Assessment of the implementation fidelity of the Arctic Char Distribution Project in Nunavik, Quebec. AB - BACKGROUND: In September 2011, the Nunavik Regional Board of Health and Social Services began supporting the Arctic Char Distribution Project (AC/DP) for pregnant women. This initiative promoted consumption of the fish Arctic char-a traditional Inuit food-by pregnant women living in villages of Nunavik, an area in northern Quebec (Canada) inhabited predominantly by people of Inuit ethnicity. This intervention was intended to reduce exposure to contaminants and improve food security in Inuit communities. METHODS: We assessed the project's implementation based on data collected from background documentation, field notes and qualitative interviews with project recipients and implementers. Themes emerging from the data are critically discussed in the light of the framework for implementation fidelity developed by Carroll et al in 2007. RESULTS: Pregnant women fully embraced the initiative because of its cultural appropriateness. However, project implementation was incomplete: first because it did not cover all intended geographic areas, and second because of a recurring inconsistency in the supply and distribution of the fish. In addition, the initiative has been inconsistently funded and relies on multiple funding sources. DISCUSSION: This work highlights the extent to which project complexity can impede successful implementation, particularly in terms of communication and coordination. We provide recommendations for improving project implementation and suggest amendments to the implementation fidelity framework. PMID- 28588960 TI - Perspectives of host faculty and trainees on international visiting faculty to paediatric academic departments in East Africa. AB - BACKGROUND: Investments in faculty exchanges to build physician workforce capacity are increasing. Little attention has been paid to the expectations of host institution faculty and trainees. This prospective qualitative research study explored faculty and resident perspectives about guest faculty in paediatric departments in East Africa, asking (1) What are the benefits and challenges of hosting guest faculty, (2) What factors influence the effectiveness of faculty visits and (3) How do host institutions prepare for faculty visits? METHODS: We recruited 36 faculty members and residents from among four paediatric departments in East Africa to participate in semistructured interviews which were audio recorded and transcribed. Data were qualitatively analysed using principles of open coding and thematic analysis. We achieved saturation of themes. RESULTS: Benefits of faculty visits varied based on the size and needs of host institutions. Emergent themes included the importance of guest faculty time commitment, and mutual preparation to ensure that visit goals and scheduling met host needs. We documented conflicts that developed around guest emotional responses and ethical approaches to clinical resource limitations, which some hosts tried to prepare for and mitigate. Imbalance in resources led to power differentials; some hosts sought partnerships to re-establish control over the process of having guests. CONCLUSIONS: We identified that guest faculty can assist paediatric institutions in building capacity; however, effective visits require: (1) mutually agreed on goals with appropriate scheduling, visit length and commitment to ensure that the visits meet the host's needs, (2) careful selection and preparation of guest faculty to meet the host's goals, (3) emotional preparation by prospective guests along with host orientation to clinical work in the host's setting and (4) attention to funding sources for the visit and mitigation of resulting power differentials. PMID- 28588961 TI - Lasting impact: insights from a surgical mission-based mentoring training programme in the Republic of Congo. AB - The global shortage of surgeons, anaesthetists and obstetricians is significant, especially in low and middle income countries (LMICs). A significant amount of LMIC surgical volume is provided by surgical missions and non-governmental organisations (NGOs) who are often well resourced, making them ideal environments for training. However, there are few publications addressing how to train in this setting, or the long-term impact of such training. Mercy Ships operates the largest non-governmental hospital ship in the world, the Africa Mercy, serving LMICs at the invitation of their President by providing free surgery and training for the surgical workforce. Mercy Ships developed and offered a comprehensive training programme across surgical specialties and disciplines in the Republic of Congo, 2013-2014. In this analysis paper, we present our experiences in developing and implementing the training portion of the programme. We also present the findings of an evaluation of the programme, which show a sustained positive impact and lasting change on personal and organisational practice 12-18 months post-training. We also make recommendations to NGOs and surgical mission organisations seeking to augment the impact of surgical missions with effective surgical training programmes. PMID- 28588962 TI - Impact of a community-based package of interventions on child development in Zambia: a cluster-randomised controlled trial. AB - BACKGROUND: Community-based programmes are a critical platform for improving child health and development. We tested the impact of a community-based early childhood intervention package in rural Zambia. METHODS: We conducted a non blinded cluster randomised controlled trial in Southern Province, Zambia. 30 clusters of villages were matched based on population density and distance from the nearest health centre, and randomly assigned to intervention (15 clusters and 268 caregiver-child dyads) or control (15 clusters and 258 caregiver-child dyads). Caregivers were eligible if they had a child aged 6-12 months at baseline. In intervention clusters, health workers screened children for infections and malnutrition, and invited caregivers to attend fortnightly group meetings covering a nutrition and child development curriculum. 220 intervention and 215 control dyads were evaluated after 1 year. The primary outcomes were stunting and INTERGROWTH-21st neurodevelopmental assessment (NDA) scores. Weight for-age and height-for-age z-scores based on WHO growth standards were also analysed. Secondary outcomes were child illness symptoms, dietary intake and caregiver-child interactions based on self-report. Impact was estimated using intention-to-treat analysis. RESULTS: The intervention package was associated with a 0.12 SD increase in weight-for-age (95% CI -0.14 to 0.38), a 0.15 SD increase in height-for-age (95% CI -0.18 to 0.48) and a reduction in stunting (OR 0.68; 95% CI 0.36 to 1.28), whereas there was no measurable impact on NDA score. Children receiving the intervention package had fewer symptoms, a more diverse diet and more caregiver interactions. CONCLUSIONS: In settings like Zambia, community-based early childhood programmes appear to be feasible and appreciated by caregivers, as evidenced by high rates of uptake. The intervention package improved parenting behaviours and had a small positive, though statistically insignificant, impact on child development. Given the short time frame of the project, larger developmental impact is likely if differential parenting behaviours persist. TRIAL REGISTRATION NUMBER: NCT02234726; Results. PMID- 28588964 TI - Persisting trend in the breach of medical neutrality: a wake-up call to the international community. PMID- 28588963 TI - 'Once there is life, there is hope' Ebola survivors' experiences, behaviours and attitudes in Sierra Leone, 2015. AB - BACKGROUND: In Sierra Leone, over 4000 individuals survived Ebola since the outbreak began in 2014. Because Ebola survivorship was largely unprecedented prior to this outbreak, little is known about survivor experiences during and post illness. METHODS: To assess survivors' experiences and attitudes related to Ebola, 28 in-depth interviews and short quantitative surveys with survivors from all four geographic regions of Sierra Leone were conducted in May 2015. RESULTS: Survivor experiences, emotions and attitudes changed over time as they moved from disease onset to treatment, discharge and life post-discharge. Survivors mentioned experiencing acute fear and depression when they fell ill. Only half reported positive experiences in holding centres but nearly all were positive about their treatment centre experiences. Survivor euphoria on discharge was followed by concerns about their financial situation and future. While all reported supportive attitudes from family members, about a third described discrimination and stigma from their communities. Over a third became unemployed, especially those previously engaged in petty trade. Survivor knowledge about sexual transmission risk reflected counselling messages. Many expressed altruistic motivations for abstinence or condom use. In addition, survivors were strongly motivated to help end Ebola and to improve the healthcare system. Key recommendations from survivors included improved counselling in holding centres and long-term government support for survivors, including opportunities for participation in Ebola response efforts. CONCLUSIONS: Survivors face myriad economic, social and health challenges. Addressing survivor concerns, including the discrimination they face, could facilitate their reintegration into communities and their contributions to future Ebola responses. PMID- 28588965 TI - Long shadow of fear in an epidemic: fearonomic effects of Ebola on the private sector in Nigeria. AB - BACKGROUND: The already significant impact of the Ebola epidemic on Guinea, Liberia and Sierra Leone, was worsened by a fear of contagion that aggravated the health crisis. However, in contrast to other Ebola-affected countries, Nigeria fared significantly better due to its swift containment of the disease. The objective of our study was to describe the impact of Ebola on the Nigerian private sector. This paper introduces and defines the term fearonomic effect as the direct and indirect economic effects of both misinformation as well as fear induced aversion behaviour, exhibited by individuals, organisations or countries during an outbreak or an epidemic. METHODS: This study was designed as a cross sectional mixed-methods study that used semistructured in-depth interviews and a supporting survey to capture the impact of Ebola on the Nigerian private sector after the outbreak. Themes were generated from the interviews on the direct and indirect impact of Ebola on the private sector; the impact of misinformation and fear-based aversion behaviour in the private sector. RESULTS: Our findings reveal that the fearonomic effects of Ebola included health service outages and reduced healthcare usage as a result of misinformation and aversion behaviour by both patients and providers. Although certain sectors (eg, health sector, aviation sector, hospitality sector) in Nigeria were affected more than others, no business was immune to Ebola's fearonomic effects. We describe how sectors expected to prosper during the outbreak (eg, pharmaceuticals), actually suffered due to the changes in consumption patterns and demand shocks. CONCLUSION: In a high-stressor epidemic-like setting, altered consumption behaviour due to distorted disease perception, misinformation and fear can trigger short-term economic cascades that can disproportionately affect businesses and lead to financial insecurity of the poorest and the most vulnerable in a society. PMID- 28588966 TI - Challenges constraining access to insulin in the private-sector market of Delhi, India. AB - OBJECTIVE: India's majority of patients-including those living with diabetes-seek healthcare in the private sector through out-of-pocket (OOP) payments. We studied access to insulin in the private-sector market of Delhi state, India. METHODS: A modified World Health Organization/Health Action International (WHO/HAI) standard survey to assess insulin availability and prices, and qualitative interviews with insulin retailers (pharmacists) and wholesalers to understand insulin market dynamics. RESULTS: In 40 pharmacy outlets analysed, mean availability of the human and analogue insulins on the 2013 Delhi essential medicine list was 44.4% and 13.1%, respectively. 82% of pharmacies had domestically manufactured human insulin phials, primarily was made in India under licence to overseas pharmaceutical companies. Analogue insulin was only in cartridge and pen forms that were 4.42 and 5.81 times, respectively, the price of human insulin phials. Domestically manufactured human phial and cartridge insulin (produced for foreign and Indian companies) was less expensive than their imported counterparts. The lowest paid unskilled government worker in Delhi would work about 1.5 and 8.6 days, respectively, to be able to pay OOP for a monthly supply of human phial and analogue cartridge insulin. Interviews suggest that the Delhi insulin market is dominated by a few multinational companies that import and/or license in-country production. Several factors influence insulin uptake by patients, including doctor's prescribing preference. Wholesalers have negative perceptions about domestic insulin manufacturing. CONCLUSIONS: The Delhi insulin market is an oligopoly with limited market competition. Increasing competition from Indian companies is going to require some additional policies, not presently in place. As more Indian companies produce biosimilars, brand substitution policies are needed to be able to benefit from market competition. PMID- 28588967 TI - WHO Multi-Country Survey on Abortion-related Morbidity and Mortality in Health Facilities: study protocol. AB - INTRODUCTION: According to the WHO, abortion accounts for about 8% (4.7-13.2) of maternal mortality worldwide. In 2010, the WHO Multi-Country Survey (MCS) on Maternal and Newborn Health collected data on over 300 000 women who were admitted in health facilities to receive pregnancy-related care. Abortion data were partially captured by centring on severe maternal outcomes (ie, near-miss or maternal deaths). Building on the experiences of the prior MCS as well as current WHO reproductive health projects, we are undertaking a multi-country survey to better capture the burden and severity of abortion-related complications and management among women presenting to the health facilities. METHODS AND ANALYSIS: This is a large cross-sectional study with prospective data collection. It will be implemented in health facilities in 30 countries across the WHO regions of Africa, Americas, Eastern Mediterranean, Europe, South East Asia and Western Pacific. Countries and facilities will be identified through a multistage sampling methodology. Data collection will be at both the facility and individual levels, involving review of medical records and exit surveys with eligible women using audio computer-assisted self-interview. All women presenting to the health facilities with signs and symptoms of abortion complications will comprise the study population. Online data entry and management will be performed on a web based data management system. Analysis will include prevalence of abortion related complications and descriptive frequencies of procedural/non-procedural management and experience of care. ETHICS AND DISSEMINATION: Ethical issues of the consent process are addressed. Dissemination plans will involve the participating facilities and communities to further strengthen abortion-related research capacity within the MCS on Abortion (MCS-A) countries. Furthermore, dissemination of results will be an iterative process at both the facility and national level to potentially propagate positive changes to abortion-related policies and practices. PMID- 28588968 TI - WHO and national lists of essential medicines in Mexico, Central and South America, and the Caribbean: are they adequate to promote paediatric endocrinology and diabetes care? AB - Paediatric endocrinology and diabetes is a paediatric specialty with less common conditions and higher cost medicines. Access to medicines for our specialty in low and middle income countries remains limited. We analysed the content of the WHO (children and adults) and of all available national Model Lists of Essential Medicines (EMLs) for Mexico, the Caribbean, Central and South America from a paediatric endocrinology and diabetes standpoint. A master list of medicines deemed necessary in paediatric endocrinology and diabetes was established and compared with the WHO and national EMLs, taking into account the gross national income. The WHO EMLs, which are largely recognised as an international benchmark and drive the content of the national EMLs, included many but not all medicines present on our master list. Interestingly, several national EMLs from richer countries included medicines that were not present in the WHO EMLs. Our analysis suggests that these medicines could be considered by the WHO for inclusion in their EMLs, which may promote the adoption of more medicines by individual countries. We also propose several changes to the WHO and national EMLs that could facilitate access to medicines in our specialty: age cut-off for a child using physical maturity rather than a set age limit; greater standardisation of the formatting of the national EMLs for easier comparison and collaborations between countries; greater emphasis on age-specificity and population-specificity for some medicines; and formatting of the EMLs in a disease-focused manner rather than as individual medicines. PMID- 28588969 TI - It is time to revise the international Good Clinical Practices guidelines: recommendations from non-commercial North-South collaborative trials. AB - The Good Clinical Practices (GCP) codes of the WHO and the International Conference of Harmonization set international standards for clinical research. But critics argue that they were written without consideration for the challenges faced in low and middle income countries (LMICs). Based on our field experience in LMICs, we developed a non-exhaustive set of recommendations for the improvement of GCP. These cover 3 domains: ethical, legal and operational, and 8 specific issues: the double ethical review of 'externally sponsored' trials; the informed consent procedure in minors and in illiterate people; post-trial access to newly-developed products for the trial communities; the role of communities as key research actors; the definition of sponsor; and the guidance for contractual agreements, laboratory quality management systems, and quality assurance of investigational medicinal products. Issues not covered in our analysis include among others biobanking, standard of care, and study designs. The international GCP codes de facto guide national legislators and funding agencies, so the current shortcomings may weaken the regulatory oversight of international research. In addition, activities neglected by GCP are less likely to be implemented or funded. If GCP are meant to serve the interests of global society, a comprehensive revision is needed. The revised guidelines should be strongly rooted in ethics, sensitive to different sociocultural perspectives, and allow consideration for trial-specific and context-specific challenges. This can be only achieved if all stakeholders, including researchers, sponsors, regulators, ethical reviewers and patients' representatives from LMICs, as well as non commercial researchers and sponsors from affluent countries, are transparently involved in the revision process. We hope that our limited analysis would foster advocacy for a broad and inclusive revision of the international GCP codes, to make them at the same time 'global', 'context centred' and 'patient centred'. PMID- 28588970 TI - Modifying the Interagency Emergency Health Kit to include treatment for non communicable diseases in natural disasters and complex emergencies. AB - The Interagency Emergency Health Kit (IEHK) provides a standard package of medicines and simple medical devices for aid agencies to use in emergencies such as disasters and armed conflicts. Despite the increasing burden of non communicable diseases (NCDs) in such settings, the IEHK includes few drugs and devices for management of NCDs. Using published data to model the population burden of acute and chronic presentations of NCDs in emergency-prone regions, we estimated the quantity of medications and devices that should be included in the IEHK. NCDs considered were cardiovascular diseases, diabetes, hypertension and chronic respiratory disease. In scenario 1 (the primary scenario), we assumed that resources in the IEHK would only include those needed to manage acute life threatening conditions. In scenario 2, we included resources required to manage both acute and chronic presentations of NCDs. Drugs and devices that might be required included amlodipine, aspirin, atenolol, beclomethasone, dextrose 50%, enalapril, furosemide, glibenclamide, glyceryl trinitrate, heparin, hydralazine, hydrochlorothiazide, insulin, metformin, prednisone, salbutamol and simvastatin. For scenario 1, the number of units required ranged from 12 (phials of hydralazine) to ~15 000 (tablets of enalapril). Space and weight requirements were modest and total cost for all drugs and devices was approximately US$2078. As expected, resources required for scenario 2 were much greater. Space and cost requirements increased proportionately: estimated total cost of scenario 2 was $22 208. The resources required to treat acute NCD presentations appear modest, and their inclusion in the IEHK seems feasible. PMID- 28588972 TI - Ethics in times of conflict: some reflections on Syria, in the backdrop of Iraq. AB - Ethical challenges facing research and reporting from conflict-affected zones are well known; among them is the difficulty of finding reliable information; the tendency to take sides and define actors as either good or evil; the precarious security situation of residents and the ever-changing scenarios on the ground. We observed, however, that these challenges go unacknowledged in research and reporting on health state and on the health system from the conflict in Iraq and Syria, with the lines between science and journalistic reporting routinely blurred in the literature. What should be the restraining factor of academic research against prejudiced reporting on injury, death and the healthcare system has mostly failed in the Syrian conflict. Even social media, with its promise of 'independent' and 'citizens' voice', can be skewed, with much of the output in the Syria crisis coming from one side only, largely due to access issues. While researchers in conflict-affected zones, such as Syria, may need to take a position on one side or another when reporting, death, destruction and disease, it is important that they admit to the challenges of accessing unbiased data, the near impossibility of obtaining representative samples and the risk of the contamination of evidence, clinical or otherwise. The example of the Syrian and Iraqi conflicts (as context) indicates a need to reassess research ethics in conflict zones and their implications for policy. PMID- 28588971 TI - Rethinking the cost of healthcare in low-resource settings: the value of time driven activity-based costing. AB - Low-income and middle-income countries account for over 80% of the world's infectious disease burden, but <20% of global expenditures on health. In this context, judicious resource allocation can mean the difference between life and death, not just for individual patients, but entire patient populations. Understanding the cost of healthcare delivery is a prerequisite for allocating health resources, such as staff and medicines, in a way that is effective, efficient, just and fair. Nevertheless, health costs are often poorly understood, undermining effectiveness and efficiency of service delivery. We outline shortcomings, and consequences, of common approaches to estimating the cost of healthcare in low-resource settings, as well as advantages of a newly introduced approach in healthcare known as time-driven activity-based costing (TDABC). TDABC is a patient-centred approach to cost analysis, meaning that it begins by studying the flow of individual patients through the health system, and measuring the human, equipment and facility resources used to treat the patients. The benefits of this approach are numerous: fewer assumptions need to be made, heterogeneity in expenditures can be studied, service delivery can be modelled and streamlined and stronger linkages can be established between resource allocation and health outcomes. TDABC has demonstrated significant benefits for improving health service delivery in high-income countries but has yet to be adopted in resource-limited settings. We provide an illustrative case study of its application throughout a network of hospitals in Haiti, as well as a simplified framework for policymakers to apply this approach in low-resource settings around the world. PMID- 28588973 TI - Responding to ever-changing epidemiological dynamics of Ebola virus disease. AB - With the incidence and mortality rates of Ebola virus disease (EVD) in Guinea, Liberia and Sierra Leone now at zero and reports of the largest and most complex EVD outbreak in history no longer on the front pages of newspapers worldwide, the urgency of that crisis seems to have subsided. During this lull after the storm and before the next one, the international community needs to engage in a 'lessons-learned' exercise with respect to our collective scientific, clinical and public health preparedness. This engagement must identify pragmatic, innovative mechanisms at multinational, national and community levels that allow research and development of next generation diagnostics and therapeutics, the safe and effective practice of medicine, and the maintenance of public health to keep pace with the rapid epidemiological dynamics of EVD and other deadly infectious diseases. PMID- 28588974 TI - Practical issues in the measurement of child survival in health systems trials: experience developing a digital community-based mortality surveillance programme in rural Nepal. AB - Child mortality measurement is essential to the impact evaluation of maternal and child healthcare systems interventions. In the absence of vital statistics systems, however, assessment methodologies for locally relevant interventions are severely challenged. Methods for assessing the under-5 mortality rate for cross country comparisons, often used in determining progress towards development targets, pose challenges to implementers and researchers trying to assess the population impact of targeted interventions at more local levels. Here, we discuss the programmatic approach we have taken to mortality measurement in the context of delivering healthcare via a public-private partnership in rural Nepal. Both government officials and the delivery organisation, Possible, felt it was important to understand child mortality at a fine-grain spatial and temporal level. We discuss both the short-term and the long-term approach. In the short term, the team chose to use the under-2 mortality rate as a metric for mortality measurement for the following reasons: (1) as overall childhood mortality declines, like it has in rural Nepal, deaths concentrate among children under the age of 2; (2) 2-year cohorts are shorter and thus may show an impact more readily in the short term of intervention trials; and (3) 2-year cohorts are smaller, making prospective census cohorts more feasible in small populations. In the long term, Possible developed a digital continuous surveillance system to capture deaths as they occur, at which point under-5 mortality assessment would be desirable, largely owing to its role as a global standard. PMID- 28588975 TI - Economic valuation of the impact of a large surgical charity using the value of lost welfare approach. AB - BACKGROUND: The assessment of the economic burden of surgical disease is integral to determining allocation of resources for health globally. We estimate the economic gain realised over an 11-year period resulting from a vertical surgical programme addressing cleft lip (CL) and cleft palate (CP). METHODS: The database from a large non-governmental organisation (Smile Train) over an 11-year period was analysed. Incidence-based disability-adjusted life years (DALYs) averted through the programme were calculated, discounted 3%, using disability weights from the Global Burden of Disease (GBD) study and an effectiveness factor for each surgical intervention. The effectiveness factor allowed for the lack of 100% resolution of the disability from the operation. We used the value of lost welfare approach, based on the concept of the value of a statistical life (VSL), to assess the economic gain associated with each operation. Using income elasticities (IEs) tailored to the income level of each country, a country specific VSL was calculated and the VSL-year (VSLY) was determined. The VSLY is the economic value of a DALY, and the DALYs averted were converted to economic gain per patient and aggregated to give a total value and an average per patient. Sensitivity analyses were performed based on the variations of IE applied for each country. RESULTS: Each CL operation averted 2.2 DALYs on average and each CP operation 3.3. Total averted DALYs were 1 325 678 (CP 686 577 and CL 639 102). The economic benefit from the programme was between US$7.9 and US$20.7 billion. Per patient, the average benefit was between US$16 133 and US$42 351. Expense per DALY averted was estimated to be $149. CONCLUSIONS: Addressing basic surgical needs in developing countries provides a massive economic boost through improved health. Expansion of surgical capacity in the developing world is of significant economic and health value and should be a priority in global health efforts. PMID- 28588976 TI - The How Project: understanding contextual challenges to global surgical care provision in low-resource settings. AB - INTRODUCTION: 5 billion people around the world do not have access to safe, affordable, timely surgical care. This series of qualitative interviews was launched by The Lancet Commission on Global Surgery (LCoGS) with the aim of understanding the contextual challenges-the specific circumstances-faced by surgical care providers in low-resource settings who care for impoverished patients, and how those providers overcome these challenges. METHODS: From January 2014 to February 2015, 20 LCoGS collaborators conducted semistructured interviews with 148 surgical providers in low-resource settings in 21 countries. Stratified purposive sampling was used to include both rural and urban providers, and reputational case selection identified individuals. Interviewers were trained with an implementation manual. Following immersion into de-identified texts from completed interviews, topical coding and further analysis of coded texts was completed by an independent analyst with periodic validation from a second analyst. RESULTS: Providers described substantial financial, geographic and cultural barriers to patient access. Rural surgical teams reported a lack of a trained workforce and insufficient infrastructure, equipment, supplies and banked blood. Urban providers face overcrowding, exacerbated by minimal clinical and administrative support, and limited interhospital care coordination. Many providers across contexts identified national health policies that do not reflect the realities of resource-poor settings. Some findings were region-specific, such as weak patient-provider relationships and unreliable supply chains. In all settings, surgical teams have created workarounds to deliver care despite the challenges. DISCUSSION: While some differences exist between countries, the barriers to safe surgery and anaesthesia are overall consistent and resource dependent. Efforts to advance and expand global surgery must address these commonalities, while local policymakers can tailor responses to key contextual differences. PMID- 28588978 TI - Improving Ebola infection prevention and control in primary healthcare facilities in Sierra Leone: a single-group pretest post-test, mixed-methods study. AB - BACKGROUND: Accomplishing infection prevention and control (IPC) in health facilities in Sub-Saharan Africa is challenging. Owing to poor IPC, healthcare workers (HCWs) were frequently infected during Sierra Leone's Ebola epidemic. In late 2014, IPC was rapidly and nationally scaled up. We carried out workshops in sampled facilities to further improve adherence to IPC. We investigated HCW experiences and observed practice gaps, before and after the workshops. METHODS: We conducted an uncontrolled, before and after, mixed-methods study in eight health facilities in Bo and Kenema Districts during December 2014 and January 2015. Quantitative methods administered to HCWs at baseline and follow-up included a survey on attitudes and self-efficacy towards IPC, and structured observations of behaviours. The intervention involved a workshop for HCWs to develop improvement plans for their facility. We analysed the changes between rounds in survey responses and behaviours. We used interviews to explore attitudes and self-efficacy throughout the study period. RESULTS: HCWs described IPC as 'life-saving' and personal protective equipment (PPE) as uncomfortable for providers and frightening for patients. At baseline, self-efficacy was high (median=4/strongly agree). Responses reflecting unfavourable attitudes were low for glove use (median=1/strongly disagree, IQR, 1-2) and PPE use with ill family members (median=1, IQR, 1-2), and mixed for PPE use with ill HCWs (median=2/disagree, IQR, 1-4). Observations demonstrated consistent glove reuse and poor HCW handwashing. The maintenance of distance (RR 1.09, 95% CI 1.02 to 1.16) and patient handwashing (RR 1.19, 95% CI 1.3 to 1.25) improved to >90%. CONCLUSIONS: We found favourable attitudes towards IPC and gaps in practice. Risk perceptions of HCWs and tendencies to ration PPE where chronic supply chain issues normally lead to PPE stock-outs may affect practice. As Sierra Leone's Ebola Recovery Strategy aims to make all facilities IPC compliant, socio behavioural improvements and a secure supply chain are essential. PMID- 28588980 TI - Addressing the challenges of diagnostics demand and supply: insights from an online global health discussion platform. AB - Several barriers challenge development, adoption and scale-up of diagnostics in low and middle income countries. An innovative global health discussion platform allows capturing insights from the global health community on factors driving demand and supply for diagnostics. We conducted a qualitative content analysis of the online discussion 'Advancing Care Delivery: Driving Demand and Supply of Diagnostics' organised by the Global Health Delivery Project (GHD) (http://www.ghdonline.org/) at Harvard University. The discussion, driven by 12 expert panellists, explored what must be done to develop delivery systems, business models, new technologies, interoperability standards, and governance mechanisms to ensure that patients receive the right diagnostic at the right time. The GHD Online (GHDonline) platform reaches over 19 000 members from 185 countries. Participants (N=99) in the diagnostics discussion included academics, non-governmental organisations, manufacturers, policymakers, and physicians. Data was coded and overarching categories analysed using qualitative data analysis software. Participants considered technical characteristics of diagnostics as smaller barriers to effective use of diagnostics compared with operational and health system challenges, such as logistics, poor fit with user needs, cost, workforce, infrastructure, access, weak regulation and political commitment. Suggested solutions included: health system strengthening with patient-centred delivery; strengthened innovation processes; improved knowledge base; harmonised guidelines and evaluation; supply chain innovations; and mechanisms for ensuring quality and capacity. Engaging and connecting different actors involved with diagnostic development and use is paramount for improving diagnostics. While the discussion participants were not representative of all actors involved, the platform enabled a discussion between globally acknowledged experts and physicians working in different countries. PMID- 28588981 TI - Community health workers in Ghana: the need for greater policy attention. AB - From the 1970s to the 1990s, the WHO, United Nations and other agencies mooted the idea of formally training and recognising community health workers (CHWs) to complement efforts to improve primary healthcare delivery in low and middle income countries. Recently, CHWs have been recognised as important players in the achievement of the health-related Millennium Development Goals (MDGs). Despite this recognition, little understanding exists in Ghana about the activities of CHWs: who they are; how they are recruited; what they do; level of health policy support; contribution to healthcare delivery and the challenges they face. Based on a rapid scoping review of the existing literature, and our experience working in Ghana, this paper reflects on the role of CHWs in healthcare delivery in Ghana. We argue that CHWs have played critical roles in improving health service delivery and outcomes, including guinea worm eradication, expanded immunisation coverage, maternal and child health, and HIV/AIDS treatment and management. However, these achievements notwithstanding, CHWs face challenges which prevent them from being optimally productive, including capacity problems, neglect by the healthcare system, high attrition rates and inadequate supervision. Policymakers in Ghana therefore need to give increased attention to CHWs, provide remuneration for their activities, create career opportunities and other means of motivations to boost their productivity and sustain gains associated with their activities. PMID- 28588979 TI - Determinants of adherence to antiretroviral therapy among HIV-positive adults in sub-Saharan Africa: a systematic review. AB - OBJECTIVE: The rapid scale up of antiretroviral treatment (ART) in sub-Saharan Africa (SSA) has resulted in an increased focus on patient adherence. Non adherence can lead to drug-resistant HIV caused by failure to achieve maximal viral suppression. Optimal treatment requires the identification of patients at high risk of suboptimal adherence and targeted interventions. The aim of this review was to identify and summarise determinants of adherence to ART among HIV positive adults. DESIGN: Systematic review of adherence to ART in SSA from January 2002 to October 2014. METHODS: A systematic search was performed in 6 databases (PubMed, Cochrane Library, EMBASE, Web of Science, Popline, Global Health Library) for qualitative and quantitative articles. Risk of bias was assessed. A meta-analysis was conducted for pooled estimates of effect size on adherence determinants. RESULTS: Of the 4052 articles screened, 146 were included for final analysis, reporting on determinants of 161 922 HIV patients with an average adherence score of 72.9%. Main determinants of non-adherence were use of alcohol, male gender, use of traditional/herbal medicine, dissatisfaction with healthcare facility and healthcare workers, depression, discrimination and stigmatisation, and poor social support. Promoters of adherence included counselling and education interventions, memory aids, and active disclosure among people living with HIV. Determinants of health status had conflicting influence on adherence. CONCLUSIONS: The sociodemographic, psychosocial, health status, treatment-related and intervention-related determinants are interlinked and contribute to optimal adherence. Clinics providing ART in SSA should therefore design targeted interventions addressing these determinants to optimise health outcomes. PMID- 28588982 TI - Efficacy of three feeding regimens for home-based management of children with uncomplicated severe acute malnutrition: a randomised trial in India. AB - OBJECTIVE: To assess the efficacy of ready-to-use therapeutic food (RUTF), centrally produced RUTF (RUTF-C) or locally prepared RUTF (RUTF-L) for home-based management of uncomplicated severe acute malnutrition (SAM) compared with micronutrient-enriched (augmented) energy-dense home-prepared foods (A-HPF, the comparison group). METHODS: In an individually randomised multicentre trial, we enrolled 906 children aged 6-59 months with uncomplicated SAM. The children enrolled were randomised to receive RUTF-C, RUTF-L or A-HPF. We provided foods, counselling and feeding support until recovery or 16 weeks, whichever was earlier and measured outcomes weekly (treatment phase). We subsequently facilitated access to government nutrition services and measured outcomes once 16 weeks later (sustenance phase). The primary outcome was recovery during treatment phase (weight-for-height >=-2 SD and absence of oedema of feet). RESULTS: Recovery rates with RUTF-L, RUTF-C and A-HPF were 56.9%, 47.5% and 42.8%, respectively. The adjusted OR was 1.71 (95% CI 1.20 to 2.43; p=0.003) for RUTF-L and 1.28 (95% CI 0.90 to 1.82; p=0.164) for RUTF-C compared with A-HPF. Weight gain in the RUTF L group was higher than in the A-HPF group (adjusted difference 0.90 g/kg/day, 95% CI 0.30 to 1.50; p=0.003). Time to recovery was shorter in both RUTF groups. Morbidity was high and similar across groups. At the end of the study, the proportion of children with weight-for-height Z-score (WHZ) >-2 was similar (adjusted OR 1.12, 95% CI 0.74 to 1.95; p=0.464), higher for moderate malnutrition (WHZ<-2 and >=-3; adjusted OR 1.46, 95% CI 1.02 to 2.08; p=0.039), and lower for those with SAM (adjusted OR 0.58, 95% CI 0.40 to 0.85; p=0.005) in the RUTF-L when compared with the A-HPF group. CONCLUSIONS: This first randomised trial comparing options for home management of uncomplicated SAM confirms that RUTF-L is more efficacious than A-HPF at home. Recovery rates were lower than in African studies, despite longer treatment and greater support for feeding. TRIAL REGISTRATION NUMBER: NCT01705769; Pre-results. PMID- 28588983 TI - Breast feeding initiation rate across Western countries: does religion matter? An ecological study. AB - BACKGROUND: Breast feeding initiation rates remain below 80% in some Western countries. Many individual-level determinants are known; however, less is known regarding cultural and societal determinants, such as religion, that could explain population-level variations. We examined the correlations of the proportions of Catholics and Protestants with the breast feeding initiation rates across and within Western countries. METHODS: Using publicly available data, we carried out an ecological study comparing the proportions of Catholics and Protestants with the rates of breast feeding initiation. We correlated data at the country level, and additionally explored within-country data in five Western countries: France (Departments), Ireland (counties), the UK (countries), Canada (provinces) and the USA (states). Our analyses accounted for human development index, gross domestic product and population density. RESULTS: We observed a negative correlation (r=-0.30) between the proportion of Catholics and the rate of breast feeding initiation in Western countries. This correlation was consistent when using within-country data in France (r=-0.27), Ireland (r=-0.23), the UK (r=-0.79) and Canada (r=-0.62). In the USA, the positive correlation (r=0.26) between a state's proportion of Catholics and its breast feeding initiation rate was confounded by race, education and socioeconomic status (SES). After controlling for education and SES, the state proportion of non-Hispanic white Catholics was negatively correlated (r=-0.29) with the rate of breast feeding initiation. CONCLUSIONS: In this ecological study, we found consistent negative correlations between Catholicism and breast feeding initiation rates. Qualitative and quantitative studies at the individual level are needed to confirm and explain our findings. Our results suggest that women living in a country or region where Catholicism has historically dominated are less likely to initiate breast feeding, and that breast feeding promotion policies should be adapted to better fit populations' cultural and religious norms. PMID- 28588984 TI - Providers' knowledge of diagnosis and treatment of tuberculosis using vignettes: evidence from rural Bihar, India. AB - BACKGROUND: Almost 25% of all new cases of tuberculosis (TB) worldwide are in India, where drug resistance and low quality of care remain key challenges. METHODS: We conducted an observational, cross-sectional study of healthcare providers' knowledge of diagnosis and treatment of TB in rural Bihar, India, from June to September 2012. Using data from vignette-based interviews with 395 most commonly visited healthcare providers in study areas, we scored providers' knowledge and used multivariable regression models to examine their relationship to providers' characteristics. FINDINGS: 80% of 395 providers had no formal medical qualifications. Overall, providers demonstrated low levels of knowledge: 64.9% (95% CI 59.8% to 69.8%) diagnosed correctly, and 21.7% (CI 16.8% to 27.1%) recommended correct treatment. Providers seldom asked diagnostic questions such as fever (31.4%, CI 26.8% to 36.2%) and bloody sputum (11.1%, CI 8.2% to 14.7%), or results from sputum microscopy (20.0%, CI: 16.2% to 24.3%). After controlling for whether providers treat TB, MBBS providers were not significantly different, from unqualified providers or those with alternative medical qualifications, on knowledge score or offering correct treatment. MBBS providers were, however, more likely to recommend referrals relative to complementary medicine and unqualified providers (23.2 and 37.7 percentage points, respectively). INTERPRETATION: Healthcare providers in rural areas in Bihar, India, have low levels of knowledge regarding TB diagnosis and treatment. Our findings highlight the need for policies to improve training, incentives, task shifting and regulation to improve knowledge and performance of existing providers. Further, more research is needed on the incentives providers face and the role of information on quality to help patients select providers who offer higher quality care. PMID- 28588986 TI - EPHP 2016, Bangalore, 8-9 July 2016, Third national conference on bringing Evidence into Public Health Policy Equitable India: All for Health and Wellbeing. PMID- 28588985 TI - How did rapid scale-up of HIV services impact on workplace and interpersonal trust in Zambian primary health centres: a case-based health systems analysis. AB - BACKGROUND: In sub-Saharan Africa, large amounts of funding continue to be directed towards HIV-specific care and treatment, often with claims of 'health system strengthening' effect. Such claims rarely account for the impact on human relationships and decisions that are core to functional health systems. This research examined how establishment of externally funded HIV services influenced trusting relationships in Zambian health centres. METHODS: An in-depth, multicase study included four health centres selected for urban, peri-urban and rural characteristics. Case data included healthcare worker (HCW) interviews (60); patient interviews (180); direct observation of facility operations (2 weeks/centre) and key informant interviews (14) which were recorded and transcribed verbatim. Thematic analysis adopted inductive and deductive coding guided by a framework incorporating concepts of workplace trust, patient-provider trust, intrinsic and extrinsic motivation. RESULTS: HIV service scale-up impacted trust in positive and negative ways. Investment in HIV-specific infrastructure, supplies and quality assurance mechanisms strengthened workplace trust, HCW motivation and patient-provider trust in HIV departments in the short-term. In the health centres more broadly and over time, however, non-governmental organisation-led investment and support of HIV departments reinforced HCW's perceptions of the government as uninterested or unable to provide a quality work environment. Exacerbating existing perceptions of systemic workplace inequity and nepotism, uneven distribution of personal and professional opportunities related to HIV service establishment contributed to interdepartmental antagonism and reinforced workplace practices designed to protect individual HCW's interests. CONCLUSIONS: Findings illustrate long-term negative effects of the vertical HIV resourcing and support structures which failed to address and sometimes exacerbated HCW (dis)trust with their own government and supervisors. The short term and long-term effects of weakened workplace trust on HCWs' motivation and performance signal the importance of understanding how such relationships play a role in generating virtuous or perverse cycles of actor interactions, with implications for service outcomes. PMID- 28588987 TI - Cognitive capital for children in Asia and Pacific. PMID- 28588988 TI - How prevention of violence in childhood builds healthier economies and smarter children in the Asia and Pacific region. AB - Investments in preventing violence against children in the Asia and Pacific region will bring important social and economic returns that contribute to building the region's 'cognitive capital'. An analysis of burden of violence research in the region is presented to identify the impacts of violence and to demonstrate these returns. Violence is an everyday experience in the lives of many children in the Asia-Pacific, and the toxic stress associated with such routine forms of violence may permanently impact the architecture and chemistry of the developing brain. This can undermine learning and affect behavioural, social and emotional functioning as children grow into adulthood. Given the hundreds of millions of children affected by violence in the region each year, its cumulative impact translates into the annual loss of hundreds of billions of dollars-or about 2% of gross domestic product of the Asia and Pacific region. Violence prevention can affect positively on health and productivity, reduce expenditure on crisis response, improve children's developmental and educational outcomes, and prevent crime. The sustainable development goals and the emerging global consensus on effective prevention strategies constitute a powerful new agenda to end violence against children, and there are critical steps that governments can take to accelerate action. PMID- 28588989 TI - Accelerating progress towards universal health coverage in Asia and Pacific: improving the future for women and children. AB - Universal health coverage generates significant health and economic benefits and enables governments to reduce inequity. Where universal health coverage has been implemented well, it can contribute to nation-building. This analysis reviews evidence from Asia and Pacific drawing out determinants of successful systems and barriers to progress with a focus on women and children. Access to healthcare is important for women and children and contributes to early childhood development. Universal health coverage is a political process from the start, and public financing is critical and directly related to more equitable health systems. Closing primary healthcare gaps should be the foundation of universal health coverage reforms. Recommendations for policy for national governments to improve universal health coverage are identified, including countries spending < 3% of gross domestic product in public expenditure on health committing to increasing funding by at least 0.3%/year to reach a minimum expenditure threshold of 3%. PMID- 28588990 TI - Cognitive capital, equity and child-sensitive social protection in Asia and the Pacific. AB - Promoting child development and welfare delivers human rights and builds sustainable economies through investment in 'cognitive capital'. This analysis looks at conditions that support optimal brain development in childhood and highlights how social protection promotes these conditions and strengthens the achievement of the Sustainable Development Goals (SDGs) in Asia and the Pacific. Embracing child-sensitive social protection offers multiple benefits. The region has been a leader in global poverty reduction but the underlying pattern of economic growth exacerbates inequality and is increasingly unsustainable. The strategy of channelling low-skilled rural labour to industrial jobs left millions of children behind with limited opportunities for development. Building child sensitive social protection and investing better in children's cognitive capacity could check these trends and trigger powerful long-term human capital development enabling labour productivity to grow faster than populations age. While governments are investing more in social protection, the region's spending remains low by international comparison. Investment is particularly inadequate where it yields the highest returns: during the first 1000 days of life. Five steps are recommended for moving forward: (1) building cognitive capital by adjusting the region's development paradigms to reflect better the economic and social returns from investing in children; (2) understand and track better child poverty and vulnerability; (3) progressively build universal, child-sensitive systems that strengthen comprehensive interventions within life cycle frameworks; (4) mobilise national resources for early childhood investments and child sensitive social protection; and (5) leverage the SDGs and other channels of national and international collaboration. PMID- 28588991 TI - Healthcare use and expenditure for diabetes in Bangladesh. AB - BACKGROUND: Diabetes imposes a huge social and economic impact on nations. However, information on the costs of treating and managing diabetes in developing countries is limited. The aim of this study was to estimate healthcare use and expenditure for diabetes in Bangladesh. METHODS: We conducted a matched case control study between January and July 2014 among 591 adults with diagnosed diabetes mellitus (DMs) and 591 age-matched, sex-matched and residence-matched persons without diabetes mellitus (non-DMs). We recruited DMs from consecutive patients and non-DMs from accompanying persons in the Bangladesh Institute of Health Science (BIHS) hospital in Dhaka, Bangladesh. We estimated the impact of diabetes on healthcare use and expenditure by calculating ratios and differences between DMs and non-DMs for all expenses related to healthcare use and tested for statistical difference using Student's t-tests. RESULTS: DMs had two times more days of inpatient treatment, 1.3 times more outpatient visits, and 9.7 times more medications than non-DMs (all p<0.005). The total annual per capita expenditure on medical care was 6.1 times higher for DMs than non-DMs (US$635 vs US$104, respectively). Among DMs, 9.8% reported not taking any antidiabetic medications, 46.4% took metformin, 38.7% sulfonylurea, 40.8% insulin, 38.7% any antihypertensive medication, and 14.2% took anti-lipids over the preceding 3 months. CONCLUSIONS: Diabetes significantly increases healthcare use and expenditure and is likely to impose a huge economic burden on the healthcare systems in Bangladesh. The study highlights the importance of prevention and optimum management of diabetes in Bangladesh and other developing countries, to gain a strong economic incentive through implementing multisectoral approach and cost-effective prevention strategies. PMID- 28588992 TI - Introducing rapid tests for malaria into the retail sector: what are the unintended consequences? AB - : The observation that many people in Africa seek care for febrile illness in the retail sector has led to a number of public health initiatives to try to improve the quality of care provided in these settings. The potential to support the introduction of rapid diagnostic tests for malaria (mRDTs) into drug shops is coming under increased scrutiny. Those in favour argue that it enables the harmonisation of policy around testing and treatment for malaria and maintains a focus on market-based solutions to healthcare. Despite the enthusiasm among many global health actors for this policy option, there is a limited understanding of the consequences of the introduction of mRDTs in the retail sector. We undertook an interpretive, mixed methods study with drug shop vendors (DSVs), their clients and local health workers to explore the uses and interpretations of mRDTs as they became part of daily practice in drug shops during a trial in Mukono District, Uganda. This paper reports the unintended consequences of their introduction. It describes how the test engendered trust in the professional competence of DSVs; was misconstrued by clients and providers as enabling a more definitive diagnosis of disease in general rather than malaria alone; that blood testing made drug shops more attractive places to seek care than they had previously been; was described as shifting treatment-seeking behaviour away from formal health centres and into drug shops; and influenced an increase in sales of medications, particularly antibiotics. TRIAL REGISTRATION NUMBER: NCT01194557; Results. PMID- 28588993 TI - Analysis of out-of-pocket costs associated with hospitalised injuries in Vietnam. AB - BACKGROUND: In Vietnam, over 39 000 people die and millions are hospitalised due to injuries every year. Injuries create a significant financial burden for families. In this study, we estimated out-of-pocket payment for medical care of injuries and the role of health insurance in containing such costs. METHOD: A prospective cohort study of 892 hospitalised injury patients admitted to a provincial general hospital in 2010 in Vietnam was conducted. Data on demographic, injury characteristics and costs by specific categories paid out-of pocket by patients were included in the analyses. Generalised linear models with log link and gamma distribution were employed to examine the associations between insurance status and total costs. RESULTS: The average total medical care costs paid out-of-pocket by patients during hospitalisation were over US$ 270. Major drivers of the costs related to surgery (nearly 25%), diagnostic test/examination (24%) and drugs (23%). Burns incurred the highest total costs during hospitalisation ($321) and assault incurred the lowest ($167). Total costs were higher for more severe injuries and those that required a more complex surgery. Patients using health insurance paid less those who did not. However, there were no statistically significant associations between health insurance and total costs, costs for surgery, diagnostic tests/examinations or drugs. CONCLUSIONS: The study provides estimates and distribution of medical care costs for injuries in hospital. In addition to ongoing efforts in prevention, the study provides further evidence on the limited benefits of health insurance in protecting patients and their family from the high costs of hospitalisation in Vietnam. PMID- 28588994 TI - Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa. AB - OBJECTIVES: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions. DESIGN: A mathematical modelling and cost-effectiveness study. SETTING: Sub-Saharan Africa. PARTICIPANTS: People of all ages. INTERVENTIONS: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long-lasting insecticide-treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC). MAIN OUTCOME MEASURE: The number of Plasmodium falciparum cases averted in all age groups over a 10-year period. RESULTS: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions. CONCLUSIONS: RTS,S was consistently implemented later in the cost effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals. PMID- 28588995 TI - Decentralising and integrating HIV services in community-based health systems: a qualitative study of perceptions at macro, meso and micro levels of the health system. AB - INTRODUCTION: HIV services at the community level in Kenya are currently delivered largely through vertical programmes. The funding for these programmes is declining at the same time as the tasks of delivering HIV services are being shifted to the community. While integrating HIV into existing community health services creates a platform for increasing coverage, normalising HIV and making services more sustainable in high-prevalence settings, little is known about the feasibility of moving to a more integrated approach or about how acceptable such a move would be to the affected parties. METHODS: We used qualitative methods to explore perceptions of integrating HIV services in two counties in Kenya, interviewing national and county policymakers, county-level implementers and community-level actors. Data were recorded digitally, translated, transcribed and coded in NVivo10 prior to a framework analysis. RESULTS: We found that a range of HIV-related roles such as counselling, testing, linkage, adherence support and home-based care were already being performed in the community in an ad hoc manner. However, respondents expressed a desire for a more coordinated approach and for decentralising the integration of HIV services to the community level as parallel programming had resulted in gaps in HIV service and planning. In particular, integrating home-based testing and counselling within government community health structures was considered timely. CONCLUSIONS: Integration can normalise HIV testing in Kenyan communities, integrate lay counsellors into the health system and address community desires for a household-led approach. PMID- 28588996 TI - Implementing One Health as an integrated approach to health in Rwanda. AB - It is increasingly clear that resolution of complex global health problems requires interdisciplinary, intersectoral expertise and cooperation from governmental, non-governmental and educational agencies. 'One Health' refers to the collaboration of multiple disciplines and sectors working locally, nationally and globally to attain optimal health for people, animals and the environment. One Health offers the opportunity to acknowledge shared interests, set common goals, and drive toward team work to benefit the overall health of a nation. As in most countries, the health of Rwanda's people and economy are highly dependent on the health of the environment. Recently, Rwanda has developed a One Health strategic plan to meet its human, animal and environmental health challenges. This approach drives innovations that are important to solve both acute and chronic health problems and offers synergy across systems, resulting in improved communication, evidence-based solutions, development of a new generation of systems-thinkers, improved surveillance, decreased lag time in response, and improved health and economic savings. Several factors have enabled the One Health movement in Rwanda including an elaborate network of community health workers, existing rapid response teams, international academic partnerships willing to look more broadly than at a single disease or population, and relative equity between female and male health professionals. Barriers to implementing this strategy include competition over budget, poor communication, and the need for improved technology. Given the interconnectedness of our global community, it may be time for countries and their neighbours to follow Rwanda's lead and consider incorporating One Health principles into their national strategic health plans. PMID- 28588997 TI - Taking the health aid debate to the subnational level: the impact and allocation of foreign health aid in Malawi. AB - OBJECTIVE: Cross-national studies provide inconclusive results as to the effectiveness of foreign health aid. We highlight a novel application of using subnational data to evaluate aid impacts, using Malawi as a case study. DESIGN: We employ two rounds of nationally representative household surveys (2004/2005 and 2010/2011) and geo-referenced foreign aid data. We examine the determinants of Malawi's traditional authorities receiving aid according to health, environmental risk, socioeconomic and political factors. We use two approaches to estimate the impact of aid on reducing malaria prevalence and increasing healthcare quality: difference-in-difference models, which include traditional authority and month-of-interview fixed effects and control for individual and household level time-varying factors, and entropy balancing, where models balance on health-related and socioeconomic baseline characteristics. General health aid and four specific health aid sectors are examined. RESULTS: Traditional authorities with greater proportions of individuals living in urban areas, more health facilities and greater proportions of those in major ethnic groups were more likely to receive aid. Difference-in-difference models show health infrastructure and parasitic disease control aid reduced malaria prevalence by 1.20 (95% CI -0.36 to 2.76) and 2.20 (95% CI 0.43 to 3.96) percentage points, respectively, and increased the likelihood of individuals reporting healthcare as more than adequate by 12.1 (95% CI 1.51 to 22.68) and 14.0 (95% CI 0.11 to 28.11) percentage points. Entropy balancing shows similar results. CONCLUSIONS: Aid was targeted to areas with greater existing health infrastructure rather than areas most in need, but still effectively reduced malaria prevalence and enhanced self reported healthcare quality. PMID- 28588998 TI - Significance of informal (on-the-job) learning and leadership development in health systems: lessons from a district finance team in South Africa. AB - BACKGROUND: The district health system (DHS) has a critical role to play in the delivery of primary healthcare (PHC). Effective district management, particularly leadership is considered to be crucial element of the DHS. Internationally, the debate around developing leadership competencies such as motivation or empowerment of staff, managing relationships, being solution driven as well as fostering teamwork are argued to be possible through approaches such as formal and informal training. Despite growing multidisciplinary evidence in fields such as engineering, computer sciences and health sciences there remains little empirical evidence of these approaches, especially the informal approach. Findings are based on a broader doctoral thesis which explored district financial management; although the core focus of this paper draws attention to the significance of informal learning and its practical value in developing leadership competencies. METHODS: A qualitative case study was conducted in one district in the Gauteng province, South Africa. Purposive and snowballing techniques yielded a sample of 18 participants, primarily based at a district level. Primary data collected through in-depth interviews and observations (participant and non-participant) were analysed using thematic analysis. FINDINGS: Results indicate the sorts of complexities, particularly financial management challenges which staff face and draws attention to the use of two informal learning strategies-learning from others (how to communicate, delegate) and fostering team-based learning. Such strategies played a role in developing a cadre of leaders at a district level who displayed essential competencies such as motivating staff, and problem solving. CONCLUSIONS: It is crucial for health systems, especially those in financially constrained settings to find cost effective ways to develop leadership competencies such as being solution driven or motivating and empowering staff. This study illustrates that it is possible to develop such competencies through creating and nurturing a learning environment (on-the-job training) which could be incorporated into everyday practice. PMID- 28588999 TI - What is the value of palliative care provision in low-resource settings? PMID- 28589000 TI - System-wide analysis of health financing equity in Cambodia: a study protocol. AB - BACKGROUND: To assess progress towards universal health coverage, countries like Cambodia require evidence on equity in the financing and distribution of healthcare benefits. This evidence must be based on a system-wide perspective that recognises the complex roles played by the public and private sectors in many contemporary healthcare systems. OBJECTIVE: To undertake a system-wide assessment of who pays and who benefits from healthcare in Cambodia and to understand the factors influencing this. METHODS: Financing and benefit incidence analysis will be used to calculate the financing burden and distribution of healthcare benefits across socioeconomic groups. Data on healthcare usage, living standards and self-assessed health status will be derived from a cross-sectional household survey designed for this study involving a random sample of 5000 households. This will be supplemented by secondary data from the Cambodian National Health Accounts 2014 and the Cambodian Socioeconomic Survey (CSES) 2014. We will also collect qualitative data through focus group discussions and in depth interviews to inform the interpretation of the quantitative analyses. POTENTIAL IMPACT: This study will produce previously unavailable information on who pays for, and who benefits from, health services across the entire health system of Cambodia. This evidence comes at a critical juncture in healthcare reform in South-East Asia with so many countries seeking guidance on the equity impact of their current financing arrangements that include a complex mix of public and private providers. PMID- 28589001 TI - Multisite prospective investigation of psychological outcomes following cataract surgery in Vietnam. AB - BACKGROUND: Cataract surgery is a low-cost and effective intervention. There is increasing evidence to suggest that cataract surgery is associated with improvements in mobility, overall functioning and reductions in psychological distress. Within low-income and middle-income countries, cataract surgery has also been documented to lead to reductions in psychological distress; however, differences in economic activity and engagement in paid and domestic work in these countries may moderate such reductions. We aimed to examine the psychological outcomes following cataract surgery among a diverse Vietnamese sample. METHODS: We report findings from the VISIONARY study, a 12-month multisite prospective study of cataract surgery outcomes conducted in Vietnam (N=462). Generalised estimating equations (GEEs) were used to identify the variables which were associated with reduced psychological distress. RESULTS: A high proportion of participants (56.6%) reported psychological distress before surgery and severity of psychological distress had decreased by 12 months following surgery (95% CI (4.13 to 4.95)). There were regional differences in the extent of improvement in psychological distress and change in paid and unpaid work. The extent of improvement in visual acuity, male gender, and increase in paid and unpaid work hours were significant predictors of reductions in psychological distress. CONCLUSIONS: Cataract surgery appears to result in the greatest reductions in psychological distress in communities where work engagement is highest. FUNDING: The VISIONARY study was funded by a grant provided by the Fred Hollows Foundation, Australia. During the course of this work, BME was in receipt of an Ian Potter Foundation Fellowship and a National Health and Medical Research Council (NHMRC) fellowship (1072148), SJ received an NHMRC Senior Research Fellowship, MLH was in receipt of a National Heart Foundation Future Leader Fellowship 100034. PMID- 28589002 TI - Randomised controlled trial of a livestock productive asset transfer programme to improve economic and health outcomes and reduce intimate partner violence in a postconflict setting. AB - BACKGROUND: Diverse economic empowerment programmes (eg, microcredit, village-led savings and loan, cash and productive asset transfers) for the poor have demonstrated mixed results as vehicles for improved economic stability, health and women's empowerment. However, limited rigorous evaluations exist on the impact of financial and non-financial outcomes of these programmes, especially in conflict-affected areas. METHODS: The team evaluated the effectiveness of an innovative livestock productive asset transfer intervention-Pigs for Peace (PFP) on economic, health and women's empowerment outcomes with participants in households in 10 villages in Eastern Democratic Republic of Congo. Residual change analysis was used to examine the amount of change from baseline to 18 months between the intervention and delayed control groups, controlling for baseline scores. FINDINGS: The majority of the 833 household participants were women (84%), 25 years of age or older, married, had on average 3 children and had never attended school. At 18 months postbaseline, the number of participants in the PFP households having outstanding credit/loans was 24.7% lower than households in the control group (p=0.028), and they had an 8.2% greater improvement in subjective health (p=0.026), a 57.1% greater reduction in symptoms of anxiety (p=0.020) and a 5.7% greater improvement in symptoms of post-traumatic stress disorder (p<-0.001). At 18 months postbaseline, partnered women and men reported a reduction in experience and perpetration of all forms of intimate partner violence, although not statistically significant between groups. INTERPRETATION: The findings support scalability of a livestock productive asset transfer programme in rural and conflict-affected settings where residents have extremely limited access to financial institutions or credit programmes, health or social services and where social norms that sustain gender inequality are strong. TRIAL REGISTRATION NUMBER: NCT02008708. PMID- 28589003 TI - Household expenditures on pneumonia and diarrhoea treatment in Ethiopia: a facility-based study. AB - BACKGROUND: Out-of-pocket (OOP) medical payments can lead to catastrophic health expenditure and impoverishment. We quantified household OOP expenditure for treatment of childhood pneumonia and diarrhoea and its impact on poverty for different socioeconomic groups in Ethiopia. METHODS: This study employs a mix of retrospective and prospective primary household data collection for direct medical and non-medical costs (2013 US$). Data from 345 pneumonia and 341 diarrhoea cases (0-59 months of age) were collected retrospectively through exit interviews from 35 purposively sampled health facilities in Ethiopia. Prospective 2-week follow-up interviews were conducted at the household level using a structured questionnaire. RESULTS: The mean total medical expenditures per outpatient visit were US$8 for pneumonia and US$6 for diarrhoea, while the mean for inpatient visits was US$64 for severe pneumonia and US$79 for severe diarrhoea. The mean associated direct non-medical costs (mainly transport costs) were US$2, US$2, US$13 and US$20 respectively. 7% and 6% of the households with a case of severe pneumonia and severe diarrhoea, respectively, were pushed below the extreme poverty threshold of purchasing power parity (PPP) US$1.25 per day. Wealthier and urban households had higher OOP payments, but poorer and rural households were more likely to be impoverished due to medical payments. CONCLUSIONS: Households in Ethiopia incur considerable costs for the treatment of childhood diarrhoea and pneumonia with catastrophic consequences and impoverishment. The present circumstances call for revisiting the existing health financing strategy for high-priority services that places a substantial burden of payment on households at the point of care. PMID- 28589004 TI - Aftermath of Boko Haram violence in the Lake Chad Basin: a neglected global health threat. PMID- 28589005 TI - Synergies and tensions between universal health coverage and global health security: why we need a second 'Maximizing Positive Synergies' initiative. PMID- 28589006 TI - Modifying the Interagency Emergency Health Kit to include treatment for non communicable diseases in natural disasters and complex emergencies: the missing clinical, operational and humanitarian perspectives. PMID- 28589007 TI - Are national policies on global health in fact national policies on global health governance? A comparison of policy designs from Norway and Switzerland. AB - BACKGROUND: Since the signing of the Oslo Ministerial Declaration in 2007, the idea that foreign policy formulation should include health considerations has gained traction on the United Nations agenda as evidenced by annual General Assembly resolutions on global health and foreign policy. The adoption of national policies on global health (NPGH) is one way that some member states integrate health and foreign policymaking. This paper explores what these policies intend to do and how countries plan to do it. METHODS: Using a most similar systems design, we carried out a comparative study of two policy documents formally adopted in 2012. We conducted a directed qualitative content analysis of the Norwegian White Paper on Global health in foreign and development policy and the Swiss Health Foreign Policy using Schneider and Ingram's policy design framework. After replicating analysis methods for each document, we analysed them side by side to explore the commonalities and differences across elements of NPGH design. RESULTS: Analyses indicate that NPGH expect to influence change outside their borders. Targeting the international level, they aim to affect policy venues, multilateral partnerships and international institutions. Instruments for supporting desired changes are primarily those of health diplomacy, proposed as a tool for negotiating interests and objectives for global health between multiple sectors, used internally in Switzerland and externally in Norway. CONCLUSION: Findings suggest that NPGH designs contribute to constructing the global health governance system by identifying it as a policy target, and policy instruments may elude the health sector actors unless implementation rules explicitly include them. Research should explore how future NPGH designs may construct different kinds of targets as politicised groups of actors on which national governments seek to exercise influence for global health decision making. PMID- 28589008 TI - Disease prevalence among nursery school children after the Great East Japan earthquake. AB - OBJECTIVE: To investigate the relationship between personal experience of the Great East Japan Earthquake and various disease types among nursery school children. DESIGN: We conducted a nationwide survey of nursery school children born between 2 April 2006 and 1 April 2007. Nursery school teachers completed questionnaires if they agreed to join the study. Questionnaire items for children consisted of their birth year and month, sex, any history of moving into or out of the current nursery school, presence of diseases diagnosed by a physician at the age of 66-78 months and type of disaster experience. The survey was conducted from September 2012 to December 2012. SETTING: Japan, nationwide. PARTICIPANTS: A total of 60 270 nursery school children were included in the analysis, 840 of whom experienced the disaster on 11 March 2011. MAIN OUTCOME MEASURES: The health status of children 1.5 years after the disaster based on nursery school records. RESULTS: Experiencing the disaster significantly affected the prevalence of overall and individual diseases. Furthermore, there was a difference in disease prevalence between boys and girls. In boys, experiencing the tsunami (OR 2.53, 95% CI 1.22 to 5.24) and living in an evacuation centre (OR 2.92, 95% CI 1.46 to 5.83) were remarkably associated with a higher prevalence of atopic dermatitis, but these trends were not observed among girls. Instead, the home being destroyed (OR 3.50, 95% CI 2.02 to 6.07) and moving house (OR 4.19, 95% CI 2.01 to 8.71) were positively associated with a higher prevalence of asthma among girls. CONCLUSIONS: Our study indicates that experiencing the disaster may have affected the health status of nursery school children at least up to 1.5 years after the disaster. Continuous monitoring of the health status of children is necessary to develop strategic plans for child health. PMID- 28589009 TI - Impact of the global financial crisis on low birth weight in Portugal: a time trend analysis. AB - BACKGROUND: The 2007-2008 global financial crisis had adverse consequences on population health of affected European countries. Few contemporary studies have studied its effect on perinatal indicators with long-lasting influence on adult health. Therefore, in this study, we investigated the impact of the 2007-2008 global financial crisis on low birth weight (LBW) in Portugal. METHODS: Data on 2 045 155 singleton births of 1995-2014 were obtained from Statistics Portugal. Joinpoint regression analysis was performed to identify the years in which changes in LBW trends occurred, and to estimate the annual per cent changes (APC). LBW risk by time period expressed as prevalence ratios were computed using the Poisson regression. Contextual changes in sociodemographic and economic factors were provided by their trends. RESULTS: The joinpoint analysis identified 3 distinct periods (2 jointpoints) with different APC in LBW, corresponding to 1995-1999 (APC=4.4; 95% CI 3.2 to 5.6), 2000-2006 (APC=0.1; 95% CI -050 to 0.7) and 2007-2014 (APC=1.6; 95% CI 1.2 to 2.0). For non-Portuguese, it was, respectively, 1995-1999 (APC=1.4; 95% CI -3.9 to 7.0%), 2000-2007 (APC=-4.2; 95% CI -6.4 to -2.0) and 2008-2014 (APC=3.1; 95% CI 0.8 to 5.5). Compared with 1995 1999, all specific maternal characteristics had a 10-15% increase in LBW risk in 2000-2006 and a 20-25% increase in 2007-2014, except among migrants, for which LBW risk remained lower than in 1995-1999 but increased after the crisis. The increasing LBW risk coincides with a deceleration in gross domestic product growth rate, reduction in health expenditure, social protection allocation on family/children support and sickness. CONCLUSIONS: The 2007-2008 global financial crisis was associated with a significant increase in LBW, particularly among infants of non-Portuguese mothers. We recommend strengthening social policies aimed at maternity protection for vulnerable mothers and health system maintenance of social equity in perinatal healthcare. PMID- 28589010 TI - Effects of economic downturns on child mortality: a global economic analysis, 1981-2010. AB - OBJECTIVES: To analyse how economic downturns affect child mortality both globally and among subgroups of countries of variable income levels. DESIGN: Retrospective observational study using economic data from the World Bank's Development Indicators and Global Development Finance (2013 edition). Child mortality data were sourced from the Institute for Health Metrics and Evaluation. SETTING: Global. PARTICIPANTS: 204 countries between 1981 and 2010. MAIN OUTCOME MEASURES: Child mortality, controlling for country-specific differences in political, healthcare, cultural, structural, educational and economic factors. RESULTS: 197 countries experienced at least 1 economic downturn between 1981 and 2010, with a mean of 7.97 downturns per country (range 0-21; SD 0.45). At the global level, downturns were associated with significant (p<0.0001) deteriorations in each child mortality measure, in comparison with non-downturn years: neonatal (coefficient: 1.11, 95% CI 0.855 to 1.37), postneonatal (2.00, 95% CI 1.61 to 2.38), child (2.93, 95% CI 2.26 to 3.60) and under 5 years of age (5.44, 95% CI 4.31 to 6.58) mortality rates. Stronger (larger falls in the growth rate of gross domestic product/capita) and longer (lasting 2 years rather than 1) downturns were associated with larger significant deteriorations (p<0.001). During economic downturns, countries in the poorest quartile experienced ~11/2 times greater deterioration in neonatal mortality, compared with their own baseline; a 3-fold deterioration in postneonatal mortality; a 9-fold deterioration in child mortality and a 3-fold deterioration in under-5 mortality, than countries in the wealthiest quartile (p<0.0005). For 1-5 years after downturns ended, each mortality measure continued to display significant deteriorations (p<0.0001). CONCLUSIONS: Economic downturns occur frequently and are associated with significant deteriorations in child mortality, with worse declines in lower income countries. PMID- 28589012 TI - 'They will be afraid to touch you': LGBTI people and sex workers' experiences of accessing healthcare in Zimbabwe-an in-depth qualitative study. AB - OBJECTIVES: To examine experiences of key populations (lesbian, gay, bisexual, trans and intersex (LGBTI) people, men who have sex with men (MSM) and sex workers) in Zimbabwe regarding access to, and experiences of, healthcare. DESIGN: Qualitative study using in-depth interviews and focus groups, with thematic analysis. PARTICIPANTS: Sixty individuals from key populations in Zimbabwe. SETTING: Participants were recruited from four locations (Harare, Bulawayo, Mutare, Beitbridge/Masvingo). RESULTS: Participants described considerable unmet needs and barriers to accessing basic healthcare due to discrimination regarding key population status, exacerbated by the sociopolitical/legal environment. Three main themes emerged: (1) key populations' illnesses were caused by their behaviour; (2) equal access to healthcare is conditional on key populations conforming to 'sexual norms' and (3) perceptions that healthcare workers were ill informed about key populations, and that professionals' personal attitudes affected care delivery. Participants felt unable to discuss their key population status with healthcare workers. Their healthcare needs were expected to be met almost entirely by their own communities. CONCLUSIONS: This is one of very few studies of healthcare access beyond HIV for key populations in Africa. Discrimination towards key populations discourages early diagnosis, limits access to healthcare/treatment and increases risk of transmission of infectious diseases. Key populations experience unnecessary suffering from untreated conditions, exclusion from healthcare and extreme psychological distress. Education is needed to reduce stigma and enhance sensitive clinical interviewing skills. Clinical and public health implications of discrimination in healthcare must be addressed through evidence-based interventions for professionals, particularly in contexts with sociopolitical/legal barriers to equality. PMID- 28589011 TI - Modelling the health and economic impacts of the elimination of river blindness (onchocerciasis) in Africa. AB - BACKGROUND: Onchocerciasis (river blindness) is endemic mostly in remote and rural areas in sub-Saharan Africa. The treatment goal for onchocerciasis has shifted from control to elimination in Africa. For investment decisions, national and global policymakers need evidence on benefits, costs and risks of elimination initiatives. METHODS: We estimated the health benefits using a dynamical transmission model, and the needs for health workforce and outpatient services for elimination strategies in comparison to a control mode. We then estimated the associated costs to both health systems and households and the potential economic impacts in terms of income gains. RESULTS: The elimination of onchocerciasis in Africa would avert 4.3 million-5.6 million disability-adjusted life years over 2013-2045 when compared with staying in the control mode, and also reduce the required number of community volunteers by 45-53% and community health workers by 56-60%. The elimination of onchocerciasis in Africa when compared with the control mode is predicted to save outpatient service costs by $37.2 million-$39.9 million and out-of-pocket payments by $25.5 million-$26.9 million over 2013-2045, and generate economic benefits up to $5.9 billion-$6.4 billion in terms of income gains. DISCUSSION: The elimination of onchocerciasis in Africa would lead to substantial health and economic benefits, reducing the needs for health workforce and outpatient services. To realise these benefits, the support and collaboration of community, national and global policymakers would be needed to sustain the elimination strategies. PMID- 28589013 TI - Quality assurance of medicines supplied to low-income and middle-income countries: poor products in shiny boxes? AB - OBJECTIVE: In today's context of globalisation of pharmaceutical production and distribution, international and national procurement agencies play a de facto key role in defining the quality of medicines available in sub-Saharan Africa. We evaluated the compliance of a sample of pharmaceutical distributors active in sub Saharan Africa with the standards of the WHO guideline 'Model Quality Assurance System (WHO MQAS) for procurement agencies', and we investigated factors favouring or hindering the adequate implementation of the guideline. METHODS: We used mixed-methods methodology to analyse quantitative and qualitative data. The quantitative study consisted of a retrospective secondary analysis of data collected by QUAMED (Quality Medicines for all), a partnership that pleads for universal access to quality-assured medicines. The qualitative survey consisted of formal and informal interviews with key informants. We adopted an embedded multiple-case study design. FINDINGS: Our analysis suggests that international distributors based in Europe perform, on average, better than sub-Saharan African distributors. However, some weaknesses are ubiquitous and concern critical processes, such as the initial selection of the products and the ongoing reassessment of their quality. This is due to several different factors: weak regulatory oversight, insufficient human/financial resources, weak negotiating power, limited judicial autonomy and/or lack of institutional commitment to quality. CONCLUSIONS: Our findings suggest that pharmaceutical distributors active in sub-Saharan Africa generally do not apply stringent criteria for selecting products and suppliers. Therefore, product quality is not consistently assured but depends on the requirements of purchasers. While long-term solutions are awaited, the WHO MQAS guideline should be used as an evaluation and training tool to upgrade current standards. PMID- 28589014 TI - Unethical randomised controlled trial of cervical screening in India: US Freedom of Information Act disclosures. AB - A randomised controlled trial conducted in Mumbai, India, compared invasive cervical cancer rates among women offered cervical screening with invasive cervical cancer rates among women offered no-screening. The US Office for Human Research Protections determined the Mumbai trial was unethical because informed consent was not obtained from trial participants. Reportedly, cervical screening in the Mumbai trial reduced invasive cervical cancer mortality rates, but not invasive cervical cancer incidence rates. Documents obtained through the US Freedom of Information Act disclose that the US National Cancer Institute funded the Mumbai trial from 1997 to 2015 to study 'visual inspection/downstaging' tests. However, 'visual inspection/downstaging' tests had been judged unsatisfactory for cancer control before the Mumbai trial began. 'Visual inspection/downstaging' tests failed to reduce invasive cervical cancer incidence rates in Mumbai because 'visual inspection/downstaging' tests, by design, failed to detect preinvasive cervical lesions. None of the 151 538 Mumbai trial participants, in either the intervention or control arms, received cervical screening tests that detected preinvasive cervical lesions. Because of missing/discrepant clinical staging data, it is uncertain whether 'visual inspection/downstaging' tests actually reduced invasive cervical cancer mortality rates in Mumbai. Documents obtained through the US Freedom of Information Act disclose that US National Cancer Institute leaders avoided accountability by making false and misleading statements to Congressional oversight staff. Our findings contradict assurances given to President Barack Obama that regulations pertaining to global health research supported by the US government adequately protect human participants from unethical treatment. US National Cancer Institute leaders should develop policies to compensate victims of unethical global health research. All surviving Mumbai trial participants should finally receive cervical screening tests that detect preinvasive cervical lesions. PMID- 28589016 TI - 'We identify, discuss, act and promise to prevent similar deaths': a qualitative study of Ethiopia's Maternal Death Surveillance and Response system. AB - INTRODUCTION: Ethiopia introduced national Maternal Death Surveillance and Response (MDSR) in 2013 and is among the first sub-Saharan African countries to capture data on facility-based and community-based maternal deaths. We interviewed frontline MDSR implementers about their experiences of the first 2 years of MDSR, including perceptions of its introduction and outcomes for health services. METHODS: We conducted a qualitative case study in 4 zones in the largest regions, interviewing 69 key informants from regional, zonal, district and facility levels. RESULTS: A defining feature of Ethiopia's MDSR system is its integration within existing disease surveillance, with both benefits and challenges. Facilitators of the system's introduction were strong political support, alignment with broader health strategies and strong links across health system departments. Barriers included confusion around new responsibilities, high staff turnover and fear of legal repercussions. Stakeholders believed MDSR increased confidence in using local data to improve maternal health services and enhanced communication across the health system. CONCLUSIONS: MDSR systems take time to establish, encountering challenges in early implementation. Ensuring MDSR has a clear purpose, explicitly defined roles and responsibilities, and adequate supervisory support from the start will ensure it becomes embedded within the health system as routine practice rather than perceived as a stand-alone system. Countries planning to adopt or extend MDSR can learn from Ethiopia's experience, particularly the decision to make maternal mortality a weekly reportable condition within Public Health Emergency Management. PMID- 28589017 TI - Financing for universal health coverage in small island states: evidence from the Fiji Islands. AB - BACKGROUND: Universal health coverage (UHC) is critical to global poverty alleviation and equity of health systems. Many low-income and middle-income countries, including small island states in the Pacific, have committed to UHC and reforming their health financing systems to better align with UHC goals. This study provides the first comprehensive evidence on equity of the health financing system in Fiji, a small Pacific island state. The health systems of such states are poorly covered in the international literature. METHODS: The study employs benefit and financing incidence analyses to evaluate the distribution of health financing benefits and burden across the public and private sectors. Primary data from a cross-sectional survey of 2000 households were used to assess healthcare benefits and secondary data from the 2008-2009 Fiji Household Income and Expenditure Survey to assess health financing contributions. These were analysed by socioeconomic groups to determine the relative benefit and financing incidence across these groups. FINDINGS: The distribution of healthcare benefits in Fiji slightly favours the poor-around 61% of public spending for nursing stations and 26% of spending for government hospital inpatient care were directed to services provided to the poorest 20% of the population. The financing system is significantly progressive with wealthier groups bearing a higher share of the health financing burden. CONCLUSIONS: The healthcare system in Fiji achieves a degree of vertical equity in financing, with the poor receiving a higher share of benefits from government health spending and bearing a lower share of the financing burden than wealthier groups. PMID- 28588977 TI - Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries. AB - BACKGROUND: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally. METHODS: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression. RESULTS: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed. CONCLUSIONS: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas. TRIAL REGISTRATION NUMBER: NCT02179112; Pre-results. PMID- 28589015 TI - Going beyond personal protection against mosquito bites to eliminate malaria transmission: population suppression of malaria vectors that exploit both human and animal blood. AB - Protecting individuals and households against mosquito bites with long-lasting insecticidal nets (LLINs) or indoor residual spraying (IRS) can suppress entire populations of unusually efficient malaria vector species that predominantly feed indoors on humans. Mosquitoes which usually feed on animals are less reliant on human blood, so they are far less vulnerable to population suppression effects of such human-targeted insecticidal measures. Fortunately, the dozens of mosquito species which primarily feed on animals are also relatively inefficient vectors of malaria, so personal protection against mosquito bites may be sufficient to eliminate transmission. However, a handful of mosquito species are particularly problematic vectors of residual malaria transmission, because they feed readily on both humans and animals. These unusual vectors feed often enough on humans to be potent malaria vectors, but also often enough on animals to evade population control with LLINs, IRS or any other insecticidal personal protection measure targeted only to humans. Anopheles arabiensis and A. coluzzii in Africa, A. darlingi in South America and A. farauti in Oceania, as well as A. culicifacies species E, A. fluviatilis species S, A. lesteri and A. minimus in Asia, all feed readily on either humans or animals and collectively mediate residual malaria transmission across most of the tropics. Eliminating malaria transmission by vectors exhibiting such dual host preferences will require aggressive mosquito population abatement, rather than just personal protection of humans. Population suppression of even these particularly troublesome vectors is achievable with a variety of existing vector control technologies that remain underdeveloped or underexploited. PMID- 28589018 TI - Public health impact of the 2014-2015 Ebola outbreak in West Africa: seizing opportunities for the future. PMID- 28589019 TI - Provider-initiated delivery, late preterm birth and perinatal mortality: a secondary analysis of the WHO multicountry survey on maternal and newborn health. AB - INTRODUCTION: In high-income countries, a reduced clinical threshold for obstetric interventions such as labour induction (LI) and prelabour caesarean delivery (PLCD) has played a substantial role in increasing rates of late preterm births. However, the association between provider-initiated delivery and perinatal outcomes have not been studied in a multicountry setting including low income and middle-income countries. METHODS: 286 hospitals in 29 countries participated in the WHO Multi-Country Survey on Maternal and Newborn Health and yielded 2 52 198 singleton births of at least 34 weeks in 2010-2011. We used an ecological analysis based on generalised estimating equations under multilevel logistic regression to estimate associations between hospital rates of PLCD and LI with rates of late preterm birth (34-36 weeks), stillbirth and intrahospital early neonatal death, in relation to country development based on the Human Development Index (HDI). RESULTS: Rates of LI were higher in hospitals from very high-HDI (median 10.9%) and high-HDI (11.2%) countries compared with medium-HDI (4.0%) or low-HDI (3.8%) countries. Rates of PLCD were by far the lowest in low HDI countries compared with countries in the other three categories (5.1% vs 12.0%-17.9%). Higher rates of PLCD were associated with lower perinatal death rates (OR 0.87 (0.79, 0.95) per 5% increase in PLCD) and non-significantly with late preterm birth (1.04 (0.98, 1.10)) regardless of country development. LI rates were positively associated with late preterm birth (1.04 (1.01, 1.06)) regardless of country development and with perinatal death (1.06 (0.98, 1.15)) only in middle-HDI and low- HDI countries. CONCLUSION: PLCD was associated with reduced perinatal mortality and non-significantly with increased late preterm birth. LI was associated with increases in both late preterm birth and, in less developed countries, perinatal mortality. Efforts to provide sufficient, but avoid excessive, access to provider-initiated delivery should be tailored to the local context. PMID- 28589021 TI - Earned print media in advancing tobacco control in Himachal Pradesh, India: a descriptive study. AB - BACKGROUND: The Union-Bloomberg Initiative tobacco control projects were implemented in Himachal Pradesh (a hilly state in North India) from 2007 to 2014. The project focused on the establishment of an administrative framework; increasing the capacity of stakeholders; enforcement of legislation; coalition and networking with multiple stakeholders; awareness generation with focus on earned media and monitoring and evaluation with policy-focussed research. This study aimed to systematically analyse all earned print news items related to the projects. METHODS: In this cross-sectional descriptive study, quantitative content analysis of earned print news items was carried out using predetermined codes related to areas of tobacco control policies. We also carried out a cost description of the hypothetical value of this earned media. The area of the news item in cm2 was multiplied by the average rate of space for the paid news item in that particular newspaper. RESULTS: There were 6348 news items: the numbers steadily increased with time. Focus on Monitoring tobacco use, Protecting people from tobacco smoke, Offering help to quit, Warning about dangers of tobacco, Enforcing a ban on tobacco advertising and promotion, Raising tax on tobacco products was seen in 24, 17, 9, 23, 22 and 3% of news items, respectively. Press releases were highest at 44% and report by correspondents at 24%. Further, 55, 23 and 21% news items focused on smoking, smokeless and both forms of tobacco use, respectively. Sixty-six per cent and 34% news items, respectively, were focused on youth and women. The news items had a hypothetical value of US$1503 628.3, which was three times more than the funds spent on all project activities. CONCLUSIONS: In the absence of funding for paid media, the project strategically used earned media to promote tobacco control policies in the state. PMID- 28589020 TI - Countdown to 2015: an analysis of donor funding for prenatal and neonatal health, 2003-2013. AB - BACKGROUND: In 2015, 5.3 million babies died in the third trimester of pregnancy and first month following birth. Progress in reducing neonatal mortality and stillbirth rates has lagged behind the substantial progress in reducing postneonatal and maternal mortality rates. The benefits to prenatal and neonatal health (PNH) from maternal and child health investments cannot be assumed. METHODS: We analysed donor funding for PNH over the period 2003-2013. We used an exhaustive key term search followed by manual review and classification to identify official development assistance and private grant (ODA+) disbursement records in the Countdown to 2015 ODA+ Database. RESULTS: The value of ODA+ mentioning PNH or an activity that would directly benefit PNH increased from $105 million in 2003 to $1465 million in 2013, but this included a 3% decline between 2012 and 2013. Projects exclusively benefitting PNH reached just $6 million in 2013. Records mentioning PNH accounted for 3% of the $2708 million disbursed in 2003 for maternal, newborn and child health (MNCH) and increased to 13% of the $9287 million disbursed for MNCH in 2013. In 11 years, only nine records ($6 million) mentioned stillbirth, miscarriage, or the fetus, although the two leading infectious causes of stillbirth were mentioned in records worth $832 million. The USA disbursed the most ODA+ mentioning PNH ($2848 million, 40% of the total) and Unicef disbursed the most ODA+ exclusively benefitting PNH ($18 million, 30%). We found evidence that funding mentioning and exclusively benefitting PNH was targeted to countries with greater economic needs, but the evidence of targeting to health needs was weak and inconsistent. CONCLUSIONS: Newborn health rose substantially on the global agenda between 2003 and 2013, but prenatal health received minimal attention in donor funding decisions. Declines in 2013 and persistently low funding exclusively benefitting PNH indicate a need for caution and continued monitoring of donors' support for newborn health. PMID- 28589022 TI - Developing an expanded vector control toolbox for malaria elimination. AB - Vector control using long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) accounts for most of the malaria burden reductions achieved recently in low and middle-income countries (LMICs). LLINs and IRS are highly effective, but are insufficient to eliminate malaria transmission in many settings because of operational constraints, growing resistance to available insecticides and mosquitoes that behaviourally avoid contact with these interventions. However, a number of substantive opportunities now exist for rapidly developing and implementing more diverse, effective and sustainable malaria vector control strategies for LMICs. For example, mosquito control in high-income countries is predominantly achieved with a combination of mosquito proofed housing and environmental management, supplemented with large-scale insecticide applications to larval habitats and outdoor spaces that kill off vector populations en masse, but all these interventions remain underused in LMICs. Programmatic development and evaluation of decentralised, locally managed systems for delivering these proactive mosquito population abatement practices in LMICs could therefore enable broader scale-up. Furthermore, a diverse range of emerging or repurposed technologies are becoming available for targeting mosquitoes when they enter houses, feed outdoors, attack livestock, feed on sugar or aggregate into mating swarms. Global policy must now be realigned to mobilise the political and financial support necessary to exploit these opportunities over the decade ahead, so that national malaria control and elimination programmes can access a much broader, more effective set of vector control interventions. PMID- 28589023 TI - Measuring, manipulating and exploiting behaviours of adult mosquitoes to optimise malaria vector control impact. AB - Residual malaria transmission can persist despite high coverage with effective long-lasting insecticidal nets (LLINs) and/or indoor residual spraying (IRS), because many vector mosquitoes evade them by feeding on animals, feeding outdoors, resting outdoors or rapidly exiting from houses after entering them. However, many of these behaviours that render vectors resilient to control with IRS and LLINs also make them vulnerable to some emerging new alternative interventions. Furthermore, vector control measures targeting preferred behaviours of mosquitoes often force them to express previously rare alternative behaviours, which can then be targeted with these complementary new interventions. For example, deployment of LLINs against vectors that historically fed predominantly indoors on humans typically results in persisting transmission by residual populations that survive by feeding outdoors on humans and animals, where they may then be targeted with vapour-phase insecticides and veterinary insecticides, respectively. So while the ability of mosquitoes to express alternative behaviours limits the impact of LLINs and IRS, it also creates measurable and unprecedented opportunities for deploying complementary additional approaches that would otherwise be ineffective. Now that more diverse vector control methods are finally becoming available, well-established entomological field techniques for surveying adult mosquito behaviours should be fully exploited by national malaria control programmes, to rationally and adaptively map out new opportunities for their effective deployment. PMID- 28589024 TI - Healthcare-seeking behaviour, barriers and mental health of non-domestic migrant workers in Singapore. AB - BACKGROUND: Low-wage migrant workers are vulnerable to healthcare inequities. We sought to identify potential barriers to healthcare and risk factors for mental health issues in non-domestic migrant workers in Singapore, and identify high risk subgroups. METHODS: A cross-sectional, interviewer-administered survey of 433 non-domestic migrant workers was conducted at subsidised clinics and a foreign worker dormitory from July to August 2016. Questions assessed healthcare usage patterns, affordability issues, barriers to care and psychological distress using a validated screening scale (Kessler-6). FINDINGS: Bangladeshi workers surveyed were more likely to be single, have more financial dependents, a lower level of education and salary and pay higher agent fees (p<0.01). 61.4% of workers reported that they had insurance, but had poor understanding of whether it covered inpatient/outpatient expenses. The majority of workers had not, or were not sure if they had, received information about company-bought insurance (72.4%). Among those who had, most reported that information was not in their native language (67.7%). Non-specific psychological distress was found in 21.9%, as estimated by the Kessler-6 scale. Multivariate analysis found that psychological distress was independently associated with Bangladeshi nationals (OR 2.98, 95% CI 1.58 to 5.62; p=0.001) and previous experience of financial barriers to healthcare (OR 3.86, 95% CI 2.25 to 6.62; p<0.0001). INTERPRETATION: We identified gaps in non-domestic migrant workers' knowledge of healthcare coverage, and substantial financial barriers to healthcare. The Bangladeshi population in our study was at higher risk of such barriers and psychological distress. These represent areas for further research and intervention. PMID- 28589025 TI - Assessing the Brazilian surgical system with six surgical indicators: a descriptive and modelling study. AB - BACKGROUND: Brazil boasts a health scheme that aspires to provide universal coverage, but its surgical system has rarely been analysed. In an effort to strengthen surgical systems worldwide, the Lancet Commission on Global Surgery proposed a collection of 6 standardised indicators: 2-hour access to surgery, surgical workforce density, surgical volume, perioperative mortality rate (POMR) and protection against impoverishing and catastrophic expenditure. This study aims to characterise the Brazilian surgical health system with these newly devised indicators while gaining understanding on the complexity of the indicators themselves. METHODS: Using Brazil's national healthcare database, commonly reported healthcare variables were used to calculate or simulate the 6 surgical indicators. Access to surgery was calculated using hospital locations, surgical workforce density was calculated using locations of surgeons, anaesthesiologists and obstetricians (SAO), and surgical volume and POMR were identified with surgical procedure codes. The rates of protection against impoverishing and catastrophic expenditure were modelled using cost of surgical inpatient hospitalisations and a gamma distribution of incomes based on Gini and gross domestic product/capita. FINDINGS: In 2014, SAO density was 34.7/100 000 population, surgical volume was 4433 procedures/100 000 people and POMR was 1.71%. 79.4% of surgical patients were protected against impoverishing expenditure and 84.6% were protected against catastrophic expenditure due to surgery each year. 2-hour access to surgery was not able to be calculated from national health data, but a proxy measure suggested that 97.2% of the population has 2-hour access to a hospital that may be able to provide surgery. Geographic disparities were seen in all indicators. INTERPRETATION: Brazil's public surgical system meets several key benchmarks. Geographic disparities, however, are substantial and raise concerns of equity. Policies should focus on stimulating appropriate geographic allocation of the surgical workforce and better distribution of surgical volume. In some cases, where benchmarks for each indicator are met, supplemental analysis can further inform our understanding of health systems. This measured and systematic evaluation should be encouraged for all nations seeking to better understand their surgical systems. PMID- 28589026 TI - UNAIDS 90-90-90 targets to end the AIDS epidemic by 2020 are not realistic: comment on "Can the UNAIDS 90-90-90 target be achieved? A systematic analysis of national HIV treatment cascades". PMID- 28589027 TI - Developing a globally applicable evidence-informed competency framework to support capacity strengthening in clinical research. AB - Capacity development for clinical research is held back by a lack of recognition for the skills acquired through involvement in clinical trials and in other varied types of global health research studies. Although some competency frameworks and associated recognised career pathways exist for different clinical research roles, they mostly apply to a single role or study setting. Our experience supports the need for an integrated approach, looking at the many roles in parallel and at all types of clinical research beyond trials. Here, we propose a single, flexible framework which is applicable to the full global health research team, and can be used for recognising staff by highlighting acquired skills and possible progression between various roles. It can also illuminate where capacity needs strengthening and contribute to raising research engagement. Through systematic analysis of existing competency frameworks and current job descriptions covering 11 distinct, broad clinical research roles, we identified and defined 50 key competencies required by the team as a whole and throughout the study life cycle. The competencies are relevant and adaptable to studies that differ in design, geographical location or disease, and fall in five main areas-(1) Ethics, Quality and Risk Management; (2) Study and Site Management; (3) Research Operations; (4) Scientific Thinking; and (5) Professional Skills. A pilot framework and implementation tools are now available online and in paper format. They have the potential to be a new mechanism for enabling research skills development and career progression for all staff engaged in clinical research globally. PMID- 28589028 TI - Do changes to supply chains and procurement processes yield cost savings and improve availability of pharmaceuticals, vaccines or health products? A systematic review of evidence from low-income and middle-income countries. AB - INTRODUCTION: Improving health systems performance, especially in low-resource settings facing complex disease burdens, can improve population health. Specifically, the efficiency and effectiveness of supply chains and procurement processes for pharmaceuticals, vaccines and other health products has important implications for health system performance. Pharmaceuticals, vaccines and other health products make up a large share of total health expenditure in low-income and middle-income countries (LMICs), and they are critical for delivering health services. Therefore, programmes which achieve cost savings on these expenditures may help improve a health system's efficiency, whereas programmes that increase availability of health products may improve a health system's effectiveness. This systematic review investigates whether changes to supply chains and procurement processes can achieve cost savings and/or improve the availability of drugs in LMICs. METHODS: Using the PRISMA guidelines for systematic reviews, we searched PubMed, Embase, CINAHL and the Health Economic Evaluation Database to identify. RESULTS: We identified 1264 articles, of which 38 were included in our study. We found evidence that centralised procurement and tendering can achieve direct cost savings, while supply chain management programmes can reduce drug stock outs and increase drug availability for populations. CONCLUSIONS: This research identifies a broad set of programmes which can improve the ways that health systems purchase and delivery health products. On the basis of this evidence, policymakers and programme managers should examine the root causes of inefficiencies in pharmaceutical supply chain and procurement processes in order to determine how best to improve health systems performance in their specific contexts. PMID- 28589029 TI - Redefining universal health coverage in the age of global health security. PMID- 28589030 TI - WHO's reply to 'Cholera in the time of War: implications of weak surveillance in Syria for the WHO's preparedness-a comparison of two monitoring systems. PMID- 28589031 TI - Governing the mixed health workforce: learning from Asian experiences. AB - Examination of the composition of the health workforce in many low and middle income countries (LMICs) reveals deep-seated heterogeneity that manifests in multiple ways: varying levels of official legitimacy and informality of practice; wide gradation in type of employment and behaviour (public to private) and diverse, sometimes overlapping, systems of knowledge and variably specialised cadres of providers. Coordinating this mixed workforce necessitates an approach to governance that is responsive to the opportunities and challenges presented by this diversity. This article discusses some of these opportunities and challenges for LMICs in general, and illustrates them through three case studies from different Asian country settings. PMID- 28589032 TI - Global health governance: we need innovation not renovation. PMID- 28589033 TI - Sex differences in coronary heart disease and stroke mortality: a global assessment of the effect of ageing between 1980 and 2010. AB - BACKGROUND: Cardiovascular disease mortality rates are well known to be lower in women than men and to increase with age. Whether these sex and age effects have changed over recent decades, and how much they differ by country, is unclear. METHOD: From the WHO Mortality Database, we obtained age-specific and sex specific coronary heart disease (CHD) and stroke mortality rates for the world's most populous countries with data available between 1980 and 2010. We calculated age-specific, country-specific and period-specific men-to-women CHD and stroke mortality rate ratios for 26 countries and compared the differences between and within countries over time. RESULTS: CHD and stroke mortality decreased substantially between 1980 and 2010 in most countries, in both sexes. Mostly there was an attenuation of the effect of ageing over calendar time, more so in men than in women. CHD mortality was higher in men than in women throughout adulthood, but the magnitude of the difference varied by age. Men-to-women CHD mortality rate ratios were 4-5 in middle age (30-64 years) and 2 thereafter (65 89 years). Stroke mortality was more similar between sexes, with men-to-women stroke mortality rate ratios of around 1.5-2 until old age. CONCLUSIONS: While CHD and stroke mortality rates declined considerably between 1980 and 2010 in both sexes, there was some indication for stronger age-specific reductions in CHD in men than women. Mortality from CHD and stroke remains higher among men than women until old age across a range of economically, socially and culturally diverse countries. PMID- 28589036 TI - Abstracts of the Eighth EDCTP Forum, 6-9 November 2016. PMID- 28589035 TI - India's plan to eliminate tuberculosis by 2025: converting rhetoric into reality. PMID- 28589034 TI - Primary prevention of cardiovascular disease through population-wide motivational strategies: insights from using smartphones in stroke prevention. AB - The fast increasing stroke burden across all countries of the world suggests that currently used primary stroke and cardiovascular disease (CVD) prevention strategies are not sufficiently effective. In this article, we overview the gaps in, and pros and cons of, population-wide and high-risk prevention strategies. We suggest that motivating and empowering people to reduce their risk of having a stroke/CVD by using increasingly used smartphone technologies would bridge the gap in the population-wide and high-risk prevention strategies and reduce stroke/CVD burden worldwide. We emphasise that for primary stroke prevention to be effective, the focus should be shifted from high-risk prevention to prevention at any level of CVD risk, with the focus on behavioural risk factors. Such a motivational population-wide strategy could open a new page in primary prevention of not only stroke/CVD but also other non-communicable disorders worldwide. PMID- 28589037 TI - Review of Small Gauge Vitrectomy: Progress and Innovations. AB - Purpose. To summarise the surgical advances and evolution of small gauge vitrectomy and discuss its principles and application in modern vitreoretinal surgery. The advent of microincisional vitrectomy systems (MIVS) has created a paradigm shift away from twenty-gauge vitrectomy systems, which have been the gold standard in the surgical management of vitreoretinal diseases for over thirty years. Advances in biomedical engineering and surgical techniques have overcome the technical hurdles of shifting to smaller gauge instrumentation and sutureless surgery, improving surgical capabilities and expanding the indications for MIVS. PMID- 28589038 TI - Inhibition of alpha-Amylases by Condensed and Hydrolysable Tannins: Focus on Kinetics and Hypoglycemic Actions. AB - The aim of the present study was to compare the in vitro inhibitory effects on the salivary and pancreatic alpha-amylases and the in vivo hypoglycemic actions of the hydrolysable tannin from Chinese natural gall and the condensed tannin from Acacia mearnsii. The human salivary alpha-amylase was more strongly inhibited by the hydrolysable than by the condensed tannin, with the concentrations for 50% inhibition (IC50) being 47.0 and 285.4 MUM, respectively. The inhibitory capacities of both tannins on the pancreatic alpha-amylase were also different, with IC50 values being 141.1 MUM for the hydrolysable tannin and 248.1 MUM for the condensed tannin. The kinetics of the inhibition presented complex patterns in that for both inhibitors more than one molecule can bind simultaneously to either the free enzyme of the substrate-complexed enzyme (parabolic mixed inhibition). Both tannins were able to inhibit the intestinal starch absorption. Inhibition by the hydrolysable tannin was concentration dependent, with 53% inhibition at the dose of 58.8 MUmol/kg and 88% inhibition at the dose of 294 MUmol/kg. For the condensed tannin, inhibition was not substantially different for doses between 124.4 MUmol/kg (49%) and 620 MUmol/kg (57%). It can be concluded that both tannins, but especially the hydrolysable one, could be useful in controlling the postprandial glycemic levels in diabetes. PMID- 28589039 TI - Gum Arabic Reduces C-Reactive Protein in Chronic Kidney Disease Patients without Affecting Urea or Indoxyl Sulfate Levels. AB - INTRODUCTION: Gum Arabic (GA) is a complex polysaccharide with proven prebiotic properties and potentially beneficial systemic effects. METHODS: We randomly allocated 36 chronic kidney disease (CKD) patients to receive 10, 20, or 40 grams daily of GA for four weeks and studied the systemic effects of this intervention. RESULTS: Thirty participants completed the study with baseline glomerular filtration rate 29.1 +/- 9.9 mL/min/1.7 m2. In contrast to previous observations, we found no effect on serum urea or creatinine levels. GA supplementation was associated with a small but statistically significant drop in serum sodium level (138 +/- 2 to 136 +/- 3 mmol/L, p = 0.002) without affecting other electrolytes, urine volume, or indoxyl sulfate (IS) levels. GA supplementation was also associated with a significant drop in C-reactive protein (CRP) level (3.5 +/- 1.5 to 2.8 +/- 1.6 ng/mL, p = 0.02) even in patients who received only 10 g/day (4.4 +/- 1.2 to 3.2 +/- 1.5 ng/mL, p = 0.03). CONCLUSIONS: Supplementing the diet of CKD patients with 10-40 g/day of GA significantly reduced CRP level which could have a positive impact on these patients' morbidity and mortality. This trial is registered with Saudi Clinical Trial Registry number 15011402. PMID- 28589042 TI - Pyridostigmine Induced Prolonged Asystole in a Patient with Myasthenia Gravis Successfully Treated with Hyoscyamine. AB - Reversible acetylcholinesterase inhibitors are used as first-line treatment for myasthenia gravis. They improve symptoms by increasing concentration of acetylcholine at the neuromuscular junction and stimulating nicotinic receptors. Serious bradyarrhythmias can occur from muscarinic stimulation in heart, which in rare cases may progress to asystole. These patients can initially be managed with hyoscyamine, a muscarinic antagonist. Persistence of bradyarrhythmias even after hyoscyamine treatment may warrant pacemaker placement. We present a case of 65 year-old female patient who presented with diplopia, dysphagia, and muscle weakness who was diagnosed with myasthenia gravis. She developed significant sinoatrial node block with prolonged asystole after starting treatment with pyridostigmine which was successfully treated with hyoscyamine, thus avoiding pacemaker placement. PMID- 28589040 TI - Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short Term Exposure to Moderate Noise. AB - Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks) and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons. PMID- 28589041 TI - Attenuated Late-Phase Arc Transcription in the Dentate Gyrus of Mice Lacking Egr3. AB - The dentate gyrus (DG) engages in sustained Arc transcription for at least 8 hours following behavioral induction, and this time course may be functionally coupled to the unique role of the DG in hippocampus-dependent learning and memory. The factors that regulate long-term DG Arc expression, however, remain poorly understood. Animals lacking Egr3 show less Arc expression following convulsive stimulation, but the effect of Egr3 ablation on behaviorally induced Arc remains unknown. To address this, Egr3-/- and wild-type (WT) mice explored novel spatial environments and were sacrificed either immediately or after 5, 60, 240, or 480 minutes, and Arc expression was quantified by fluorescence in situ hybridization. Although short-term (i.e., within 60 min) Arc expression was equivalent across genotypes, DG Arc expression was selectively reduced at 240 and 480 minutes in mice lacking Egr3. These data demonstrate the involvement of Egr3 in regulating the late protein-dependent phase of Arc expression in the DG. PMID- 28589043 TI - Anomalous Papillary Muscle Insertion Causing Dynamic Left Ventricular Outflow Tract Obstruction without Hypertrophic Obstructive Cardiomyopathy. AB - Anomalous papillary muscle insertion directly into the surface of the mitral valve leaflet is rare, especially in a subject without apparent evidence of hypertrophic cardiomyopathy. We present a case of this isolated congenital malformation producing two hemodynamic sequelae of dynamic left ventricular outflow tract obstruction and severe mitral regurgitation. PMID- 28589045 TI - Recurrent Enterolithiasis Small Bowel Obstruction: A Case Seldom Described. AB - BACKGROUND: Enterolithiasis of the small bowel is a rare phenomenon in humans although it has been frequently described in equines. Primary enteroliths have been described including those occurring secondary to conditions like Crohn's disease, small bowel diverticula, tuberculous or postoperative strictures, and blind loops but those occurring in an otherwise normal gut are exceedingly rare. Of even greater rarity is a recurrent small bowel enterolith presenting with obstruction. This may be the first report of such kind. CASE PRESENTATION: A 70 year-old man undergoing treatment for stable alcoholic liver disease presented to the emergency with gradually progressive diffuse abdominal pain associated with vomiting and constipation for 7 days. He had gaseous abdominal distention but was not obstipated. He had a history of 2 laparotomies in the past for small bowel obstruction secondary to enterolith impaction. He was initially managed conservatively but since there was no significant clinical improvement, he underwent an exploratory laparotomy. A recurrent enterolith 5 * 5 cm in size was found impacted in the mid ileum with multiple dense serosal adhesions and bands. Adhesiolysis and enterotomy with removal of enterolith were performed. CONCLUSION: Recurrent enterolithiasis of the small bowel is a rare phenomenon and may present with recurrent obstruction. Definitive preoperative diagnosis is not always possible and a high index of suspicion is required to avoid table misdiagnosis. Surgery is the mainstay of treatment once conservative measures fail. Laparoscopic methods may help in diagnosis and avoid possibility of a subsequent adhesive bowel obstruction but are associated with technical challenges. PMID- 28589044 TI - Asymmetric Expansion with a Modified Quad Helix for Treatment of Isolated Crossbite. AB - Unilateral posterior crossbite often involves only one tooth, especially upper first molar; in these cases it is never easy to obtain an asymmetrical movement of a molar and a proper planning of the orthodontic device with its anchorage is necessary to avoid arch overexpansion. Thanks to its simplicity and efficacy, the modified Quad Helix here described represents a valid therapeutic tool in cases of isolated posterior crossbite. PMID- 28589046 TI - Coexistence of Antiphospholipid Syndrome and Heparin-Induced Thrombocytopenia in a Patient with Recurrent Venous Thromboembolism. AB - Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse drug reaction in which heparin forms complexes with platelet factor 4 forming neoantigens that are recognized by autoantibodies. Antiphospholipid syndrome (APS) is similar to HIT in that it is mediated by autoantibodies that are also prothrombotic. We present a case of rare coexistence of antiphospholipid antibody syndrome and heparin-induced thrombocytopenia. PMID- 28589047 TI - Native Valve Endocarditis due to Veillonella Species: A Case Report and Review of the Literature. AB - Veillonella species are fastidious bacteria that have been isolated from skin, dental, and respiratory tract infections and rarely have been implicated in serious infections like meningitis, endocarditis, and osteomyelitis. A 76-year old woman presented to our hospital with fever, vomiting, and generalized weakness for 3 days. A transthoracic echocardiogram showed a mobile structure on anterior mitral valve leaflet measuring 0.9 cm suggestive of vegetation. Empiric therapy with vancomycin and piperacillin-tazobactam was started with clinical resolution of her symptoms. On day 6, the blood culture drawn at admission grew Veillonella species. A transesophageal echocardiogram confirmed a 1.2 * 0.4 cm echo dense structure attached to the left ventricular side of the anterior mitral leaflet. The patient was discharged home after 10 days of inpatient antibiotic therapy and completed 4 weeks of IV ceftriaxone at home without any adverse events. She was reevaluated in the clinic after completion of treatment and repeat blood cultures remained negative. We report the first case of successful treatment of endocarditis due to Veillonella species with once daily ceftriaxone. PMID- 28589048 TI - The Cushing Reflex: Oliguria as a Reflection of an Elevated Intracranial Pressure. AB - Oliguria is one of the clinical hallmarks of renal failure. The broad differential diagnosis is well known, but a rare cause of oliguria is intracranial hypertension (ICH). The actual knowledge to explain this relationship is scarce. Almost all literature is about animals where authors describe the Cushing reflex in response to ICH. We hypothesize that the Cushing reflex is translated towards the sympathetic nervous system and renin-angiotensin aldosterone system with a subsequent reduction in medullary blood flow and oliguria. Recently, we were confronted with a patient who had complicated pituitary surgery and displayed multiple times an oliguria while he developed ICH. PMID- 28589049 TI - Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids, with Cranial and Caudal Extension. AB - A 23-year-old lady presented with vertigo and imbalance in walking, blurring of vision, diplopia, and headache, in addition to numbness in the lower limbs over a period of six days. On examination patient had nystagmus, ataxia, positive Romberg test, and hyperreflexia. MRI examination of the brain and spinal cord showed evidence of faint bright signal intensity foci in T2/FLAIR involving bilateral cerebral hemispheres, subcortical deep white matter, bilateral thalami, posterior pons and left brachium pontis, and basal ganglia, with small nodular enhancement that aligned along curvilinear structures; those lesions also were apparent along the spinal cord at multiple levels. The clinical and radiological features suggested CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) syndrome. Symptoms improved dramatically with high dose oral corticosteroids. Our report addresses the radiological and clinical pattern of a case of CLIPPERS rhombencephalitis, with added superior and inferior extension to involve the brain and spinal cord, which is to emphasize the importance of raising the awareness of this disease and the combined role of radiologist and physicians for the diagnosis of this potentially treatable entity, responsive to glucocorticosteroid immunosuppression. PMID- 28589050 TI - A Case of Chronic Ectopic Pregnancy Manifested by Rectal Bleeding. AB - Ectopic pregnancy resulting in perforation of the rectum and rectal bleeding is clinically rare. We report an extremely rare case of chronic ectopic pregnancy with decreasing low levels of serum beta-HCG resulting in rectal bleeding. A 31 year-old woman, gravida 3, para 3, with moderate abdominal pain and rectal bleeding was diagnosed with a tubal pregnancy. The tube was adherent to the rectum. Following salpingo-oophorectomy, the perforation of the rectum was sutured. Biopsies from the rectum as well as the tube confirmed chronic ectopic pregnancy. This case illustrates that diagnosing ectopic pregnancy is sometimes extremely challenging and it underlines the importance of follow-up consultations when the final diagnosis has not yet been reached. PMID- 28589051 TI - Review and Long-Term Outcomes of Cruciate Ligament Reconstruction versus Conservative Treatment in Siblings with Congenital Anterior Cruciate Ligament Aplasia. AB - There is no consensus on the best treatment for anterior cruciate ligament hypoplasia or aplasia. To our knowledge, no comparative study between operative and conservative treatment of this condition has ever been performed. Conservative treatment is a viable alternative to surgery for ACL aplasia. Two siblings were examined at our outpatient clinic. The male patient underwent bilateral ACL reconstruction, while his sister was treated conservatively. Our results show a worse long-term outcome for the operative patient. At her last follow-up, the female patient treated conservatively showed subjective improvement in stability and gait. A review of the literature shows inconsistent outcomes after reconstruction in contrast to reports with cruciate ligament agenesis that did not undergo reconstruction with acceptable to good outcomes. Cruciate reconstruction should be reserved for cases of impaired articular instability, objectively manifest in the frequency of giving-way episodes. Treatment depends on the patient's condition and expectations. Surgery should therefore only be suggested after proper patient counseling. PMID- 28589052 TI - Safe and Effective Reduction Technique for Intertrochanteric Fracture with Ipsilateral Below-Knee Amputated Limb. AB - The positioning of the patient on the fracture table is critical for the successful reduction and operative fixation of intertrochanteric hip fractures. However, this manipulation is challenging with patients who have undergone amputations of their legs. A 97-year-old man presented to the emergency department with symptom of right hip pain following a mechanical fall. He had a below-knee amputation on his right leg following a traffic accident as a 19-year old and had a below-knee patellar tendon bearing prosthesis fitted to his lower limb for mobility. Radiographs of his pelvis revealed a displaced intertrochanteric fracture of the right side femur. The patient was positioned on a fracture table, as in the standard procedure. The method of inverting the traction boot to accommodate the flexed knee and stump described by Al-Harthy could be used to provide traction and rotational control. Internal fixation was performed using a short femoral nail. Postoperatively, the patient could walk with full weight bearing using a prosthesis on his affected limb. The method of inverting the traction boot to accommodate the flexed knee and stump can be used safely and effectively to achieve and maintain fracture reduction during fixation of intertrochanteric fractures for patients with a below-knee amputated limb. PMID- 28589053 TI - High-Grade Transformation (Dedifferentiation) of Acinic Cell Carcinoma of the Parotid Gland: Report of an Unusual Variant. AB - Acinic cell carcinoma with high-grade transformation of the salivary gland is an unusual variant with less than fifty cases being reported in the literature. It is characterized by a low- and high-grade component juxtaposed with one another and tends to take on a more aggressive clinical course than its low-grade counterpart, suggesting a poor clinical outcome. We, hereby, report a case of acinic cell carcinoma in a 48-year-old woman with a 6-month history of a right parotid facial swelling rapidly increasing in size. The tumor was initially resected; however, residual focal tissue subsequently revealed areas typical of low-grade acinic cell carcinoma as well as high-grade transformation/dedifferentiation via histopathology. PMID- 28589054 TI - A Patient with MSUD: Acute Management with Sodium Phenylacetate/Sodium Benzoate and Sodium Phenylbutyrate. AB - In treatment of metabolic imbalances caused by maple syrup urine disease (MSUD), peritoneal dialysis, and hemofiltration, pharmacological treatments for elimination of toxic metabolites can be used in addition to basic dietary modifications. Therapy with sodium phenylacetate/benzoate or sodium phenylbutyrate (NaPB) in urea-cycle disorder cases has been associated with a reduction in branched-chain amino acid (BCAA) concentrations when the patients are on adequate dietary protein intake. Moreover, NaPB in treatment of MSUD patients is also associated with reduction of BCAA levels in a limited number of cases. However, there are not enough studies in the literature about application and efficacy of this treatment. Our case report sets an example of an alternative treatment's efficacy when extracorporeal procedures are not available due to technical difficulties during attack period of the disease. PMID- 28589055 TI - Lingual Foramina and Canals of the Mandible: Anatomic Variations in a Lebanese Population. AB - OBJECTIVE: The aim of this study was to evaluate the mandibular lingual foramina (LF) and canals and their anatomic variations using cone-beam computed tomography (CBCT) technology in a Lebanese population. MATERIALS AND METHODS: In this study, we analyzed CBCT images of 90 adult Lebanese patients (41 males and 49 females). We assessed the number and location of the LF. In additional, we measured: (a) The distance from both the alveolar crest and the inferior border of the mandible to the LF and (b) the length of the lingual canals (LCs). The data obtained was analyzed statistically using Shapiro-Wilk normality test, t-test, Chi-square, and Fisher's exact tests. Statistical significance was set at 0.05. RESULTS: In our sample, the LF and canals were present in 93.33% of the CBCT analyzed, and the majority (76.64%) was located above the genial tubercles. The distance from the foramen of the superior and the inferior LCs to the alveolar crest was 16.24 +/- 2.82 mm and 25.49 +/- 2.43 mm, respectively. The distance from the foramen of the superior canal to the inferior border of the mandible was 14 +/- 2.32 mm. The mean length of the superior canal was 5.81 +/- 1.6 mm and 4.25 +/- 1.2 mm for the inferior one. There were no gender-related differences in the anatomic characteristics of the LF and canals except for the distance measured from the superior canal foramina to the alveolar crest where the measurement was significantly greater in males compared to females. Neither the number of canals nor the positions of the foramina were different between males and females. CONCLUSION: Within the limits of this study, we concluded that in our sample of Lebanese adults, there was substantial variability in the LF and canals anatomy and location. PMID- 28589056 TI - Vaginal Ewing Sarcoma: An Uncommon Clinical Entity in Pediatric Patients. AB - Ewing sarcoma, including classical Ewing sarcoma of the bone and primitive neuroectodermal tumors arising in bone or extraosseous primary sites, is a highly aggressive childhood neoplasm. We present two cases of Ewing sarcoma arising from the vagina in young girls. Previously reported cases in literature focused on their pathologic rather than radiographic features. We describe the spectrum of multimodality imaging appearances of Ewing sarcoma at this unusual primary site. Awareness of vaginal Ewing tumors may facilitate prompt diagnosis and lead to a different surgical approach than the more commonly encountered vaginal rhabdomyosarcoma. PMID- 28589058 TI - Metoprolol-induced Severe Liver Injury and Successful Management with Therapeutic Plasma Exchange. AB - Liver injury caused by metoprolol is very rare with current reports limited to an isolated elevation in transaminases. We report the first case of severe icteric liver injury leading to hepatic encephalopathy secondary to metoprolol use in a patient diagnosed with coronary heart disease. We also describe the histopathology of metoprolol-related liver injury, discuss mechanisms of injury with new insights on the immunological phenomenon, and shed light on the successful utility of early plasmapheresis as a salvage therapy in metoprolol induced severe liver damage. PMID- 28589057 TI - Treatment of Sydenham's Chorea: A Review of the Current Evidence. AB - BACKGROUND: Sydenham's chorea (SC), the neurologic manifestation of rheumatic fever, remains the most prevalent form of chorea in children. Suggested treatments of chorea in SC include prophylactic penicillin, symptomatic (antipsychotic and anticonvulsant) medications, and immunomodulatory therapy (steroids, intravenous immunoglobulin (IVIG), and plasma exchange). In this manuscript, we undertook a systematic review of the published literature to examine the data supporting these therapeutic recommendations. METHODS: A search of PubMed, Embase, Psychinfo, and clinicaltrials.gov was conducted for publications pertaining to the treatment of SC/rheumatic chorea from 1956 to 2016. RESULTS: Penicillin prophylaxis appears to reduce the likelihood of further cardiac complications and the recurrence rate of chorea. Data on symptomatic therapy for chorea are limited to individual case reports or series and rare comparison studies. The efficacy of steroid use is supported by a single placebo controlled study and several case series. Information on other immunomodulatory therapies such as IVIG and plasmapheresis are limited to a small number of reports and a single comparison study. DISCUSSION: Treatment decisions in SC are currently based on the treating physician's clinical experience, the desire to avoid side effects, and the existence of only limited scientific evidence. Based on a review of the available literature, chorea often improves with symptomatic therapy and immunotherapy tends to be reserved for those who fail to respond. Steroids are beneficial; however, data using IVIG and plasmapheresis are very limited. Larger, well-controlled studies, using standardized assessment scales, are required if therapeutic decisions for SC are to be based on meaningful information. PMID- 28589059 TI - Undetected Small Accessory Mental Foramina Using Cone-Beam Computed Tomography. AB - INTRODUCTION: The accessory foramina could not be identified on some imaging modalities such as surface-rendered images. The purpose of this study was to investigate the ability of surface-rendered images in detecting these foramina. MATERIALS AND METHODS: We analyzed 20 accessory mental foramina (AMF) in nine mandibles removed from cadavers with cone-beam computed tomography (CBCT) and assessed in surface-rendered images. All AMF were divided into three groups depending on their visibility. RESULTS: Group 1 included AMF that were clearly visible as foramina, Group 2 were not clearly visible but could be recognized with concave parts, and Group 3 were not visible and the smooth surface of the bone was observed. Group 1 ranged from 1.3 to 5.1 mm2, Group 2 from 0.3 to 3.8 mm2, and Group 3 from 0.2 to 1.1 mm2. A statistically significant difference in the mean size between Groups 1 and 3 was observed. Even if the AMF are smaller (e.g., 1 mm in diameter), they should still be avoided to prevent injury. CONCLUSIONS: The clinician should be aware that smaller foramina might not be detected on these images. PMID- 28589060 TI - Seeding of a Pituitary Adenoma or Atypical Pituitary Carcinoma? AB - Pituitary carcinomas are defined as pituitary tumors with craniospinal and/or systemic metastasis. These are rare and highly aggressive lesions. We present an unusual case of a 52-year-old male who had a pituitary adenoma removed via craniotomy. The tumor recurred three years post-op near the surgical tract, and slowly enlarged before removal two years later. Technically, this lesion was defined as a pituitary carcinoma, even though the histology and clinical course were atypical. There is no standardized grading system for pituitary tumors and ideal criteria should correlate clinically. Treatment for pituitary carcinoma is multimodal and largely empiric. We believe this case illustrates that current definitions of pituitary carcinoma are incomplete. PMID- 28589061 TI - Importance Of Thorough Physical Examination: A Lost Art. AB - Several recent studies have described a deterioration in physical examination skills among modern physicians. Reasons hypothesized for this change are improvements in technology and time constraints. Poor physical exam skills are a noteworthy threat to patient safety as they can lead to incorrect as well as missed diagnoses, causing delays in timely implementation of life-saving treatments. Here, we present a case of extensive acute embolic strokes secondary to infective endocarditis. The patient was initially misdiagnosed as having Bell's palsy due to incorrect physical examination. Through this case, we highlight the importance of management guided by a thorough history and physical examination to minimize diagnostic errors. PMID- 28589062 TI - Impact of Caregiving on Various Aspects of the Lives of Caregivers. AB - OBJECTIVE: This study was designed to assess the impact of caregiving on the lives of the caregivers. METHODS: A cross-sectional study was conducted between July and September 2015 at a teaching hospital in Karachi, Pakistan. Participants who were more than 18 years old and were involved in caregiving (former or current) of a family member were invited to participate in the study. The participants were recruited through consecutive sampling technique. A total of 400 caregivers were interviewed. Written informed consent was obtained from all the participants. A pretest structured questionnaire was used for data collection and included sections on demographic details and impact of caregiving on various aspects of the lives of caregivers. The data was analyzed using SPSS version 19 (IBM, NY, USA). RESULTS: Information about a total of 400 caregivers (215 men and 185 women) was included in the final analysis. The majority (57.0%) of the participants were aged between 18 and 30 years. About three-fifths (60%) of the participants were single and the majority of the participants were students. Approximately 64% of the participants were currently involved in caregiving and about 48% of the participants responded that caregiving has an overall negative impact on various aspects, such as physical (40.8%), psychological (47.8%), and professional aspects (51.8%) of their lives. CONCLUSION: Negative impact of caregiving was observed among caregivers due to extensive demands of caregiving and limited resources. Therefore, it is imperative for health care providers to explore, identify and support caregivers to cope in a better way to the challenging task of caregiving. PMID- 28589063 TI - Teaching the Retropubic Midurethral Sling Using a Novel Cadaver and Model-Based Approach. AB - OBJECTIVE: To measure the impact of a model-based teaching program on resident comfort and skill with retropubic midurethral sling (MUS). STUDY DESIGN: Residents were assessed before and after a retropubic MUS teaching session, which included a brief lecture and three interactive teaching stations (cadaver pelvis, retropubic MUS pelvic model, cystoscopy model). Self-assessment measures included MUS-related visual analog scale (VAS), Likert, and open-ended questions. Objective assessment measures were used to score blinded videos of trocar passage on a pelvic model, including a modified objective structured assessment of technical skills (mOSAT) and a retropubic MUS-specific checklist of surgical steps. Emerging themes from the open-ended questions were identified using grounded theory; analysis ceased once theme saturation was achieved. RESULTS: Twenty-five of 37 total residents participated in the training session and 24 participated in this study. Following training, VAS scores, Likert scores, and qualitative analysis indicated greater resident comfort with performing retropubic MUS, with relevant anatomy, and with trocar passage. Residents demonstrated improvement in model trocar passage post-training, with a rise in mOSAT score (47% to 65%; p = .01) and a rise in checklist score (61% to 75%; p = .11). Residents expressed discomfort due to inexperience with MUS, concern regarding trocar passage, and worry over potential complications. Residents reported feeling more prepared to perform MUS after the session. They stressed the importance of repetition and a comfortable learning environment for surgical training, and praised the "hands-on" training session. CONCLUSION: We demonstrate success using a short, single-session, hands-on group training session to improve comfort and skill with retropubic MUS. PMID- 28589065 TI - Management of the Positive Axilla in 2017. AB - The role of surgery in breast cancer treatment and axillary staging is changing. It is not very far from today, when axillary dissection was the standard treatment and staging procedure for all stages of breast cancer. Today, we are on the edge of omitting axillary dissection even in patients with the axillary disease. In this review, we walked through the changes in axillary management throughout the past hundred years. PMID- 28589064 TI - Assessment and Improvement of Quality of Life in Patients Undergoing Treatment for Head and Neck Cancer. AB - INTRODUCTION: We compared the pre and post-treatment quality of life in head and neck cancer (HNC) patients and identified factors that could improve the quality of life in such patients. Methods: The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire was administered to 84 patients' pre and post-treatment. Patients who had non-metastatic, measurable, and untreated HNCs were invited, provided that their age was below 80 years. We did not discriminate based on treatment modality, stage of cancer, or co-morbidities. Patients who were mentally incapacitated, with secondary or recurrent HNC, distant metastasis, skin cancer, congenital anomaly of the head and neck, chronic illness, or any previous or current psychiatric illness were excluded from the study. A high mean score on the functional scale and a low score on symptom scale signify a better quality of life. We used the dependent t-test to compare pre and post-treatment scores. RESULTS: We found no statistically significant differences in any variables, except the four symptom scales of diarrhoea, constipation, nausea/vomiting, and financial difficulty. All of these variables had increased mean scores with p values of < 0.001. Also, we found no statistical significance (p = 0.250) when comparing the pre-treatment (59.4 +/- 18.3) and post-treatment (61.2 +/- 16.2) scores for the global health status. CONCLUSION: We found no improvement in the quality of life in HNC patients despite intervention. In fact, diarrhoea, constipation, nausea/vomiting, and financial difficulty of these patients worsened post-treatment. PMID- 28589066 TI - Differences in Parotid Dosimetry and Expected Normal Tissue Complication Probabilities in Whole Brain Radiation Plans Covering C1 Versus C2. AB - OBJECTIVES: There is no consensus standard regarding the placement of the inferior field border in whole brain radiation therapy (WBRT) plans, with most providers choosing to cover the first versus (vs.) second cervical vertebrae (C1 vs. C2). We hypothesize that extending coverage to C2 may increase predicted rates of xerostomia. METHODS: Fifteen patients underwent computed tomography (CT) simulation; two WBRT plans were then produced, one covering C2 and the other covering C1. The plans were otherwise standard, and patients were prescribed doses of 25, 30 and 37.5 gray (Gy). Dose-volume statistics were obtained and normal tissue complication probabilities (NTCPs) were estimated using the Lyman Burman-Kutcher model. Mean parotid dose and predicted xerostomia rates were compared for plans covering C2 vs. C1 using a two-sided patient-matched t-test. Plans were also evaluated to determine whether extending the lower field border to cover C2 would result in a violation of commonly accepted dosimetric planning constraints. RESULTS: The mean dose to both parotid glands was significantly higher in WBRT plans covering C2 compared to plans covering C1 for all dose prescriptions (p<0.01). Normal tissue complication probabilities were also significantly higher when covering C2 vs. C1, for all prescribed doses (p<0.01). Predicted median rates of xerostomia ranged from <0.03%-21% for plans covering C2 vs. <0.001%-12% for patients treated with plans covering C1 (p<0.01), dependent on the treatment dose and NTCP model. Plans covering C2 were unable to constrain at least one parotid to <20 Gy in 31% of plans vs. 9% of plans when C1 was covered. A total parotid dose constraint of <25 Gy was violated in 13% of plans covering C2 vs. 0% of plans covering C1. CONCLUSIONS: Coverage of C2 significantly increases the mean parotid dose and predicted NTCPs and results in more frequent violation of commonly accepted dosimetric planning constraints. PMID- 28589067 TI - Intraoperative Dexmedetomidine-Induced Polyuric Syndrome. AB - A 23-year-old male trauma patient with a cervical spine fracture underwent an anterior and posterior discectomy and spinal fusion surgery. The patient presented to the operating room with a stabilizing halo fixation device in place, and a fiberoptic intubation was performed with dexmedetomidine for sedation. During the surgical procedure, general anesthesia was maintained with a propofol and remifentanil infusion as the patient was monitored using somatosensory and motor evoked potentials. The patient's urine output increased gradually during the nine-hour surgical procedure from 150 mL/hour to over 700 mL/hour in the eighth hour of the procedure, where it remained until the end of the procedure. Postoperatively, the patient's laboratory values and urine output returned to baseline levels the following day. A search of the literature revealed few case reports of polyuria under similar conditions. Dexmedetomidine, being an alpha-2 agonist that blocks arginine-vasopressin release, may be responsible for inducing the polyuria noted in this patient case. PMID- 28589069 TI - Looks Can Be Deceiving: A Case Report on Multicentric Reticulohistiocytosis Successfully Treated with Rituximab. AB - Multicentric reticulohistiocytosis (MRH) is an idiopathic multisystemic inflammatory disease characterized by symmetric erosive polyarthritis and typical papulonodular skin lesions. MRH can be associated with autoimmune diseases, malignancy, mycobacterial infections, and hyperlipidemia, and it is important to consider appropriate screening in this population. There is no specific diagnostic laboratory test for MRH. The gold standard for diagnosis is skin or synovial biopsy, which shows characteristic multinucleated non-Langerhans giant cells and ground glass eosinophilic cytoplasm. Although the disease spontaneously remits in approximately 10 years, MRH can rapidly progress to arthritis mutilans in the majority of cases. The diagnosis and treatment are challenging due to its low prevalence and lack of robust guidelines from major rheumatological societies. Corticosteroids and methotrexate are generally first-line treatment options. However, more recently, biologic agents have been increasingly used in refractory cases with some success. Early diagnosis is crucial in preventing disease progression. We report a case of MRH in a patient whose clinical presentation mimicked rheumatoid arthritis and was subsequently treated successfully with rituximab. PMID- 28589068 TI - Endovascular Treatment of Large Unruptured Fusiform Fenestrated Vertebrobasilar Junction Aneurysm. AB - Fenestrated vertebrobasilar junction aneurysms are rare vascular lesions. Microsurgical intervention is extremely difficult due to the complex anatomy in the vicinity of these aneurysms. Endovascular neurosurgery appears to be safe and should be considered as the first modality of treatment. This case study details the treatment of an unruptured fusiform fenestrated vertebrobasilar junction aneurysm with endovascular occlusion with stent-assisted coiling. The optimal angiographic exposure and selective microcatheterization of the aneurysm were challenging due to the patient's body habitus, and the aneurysm was large with one dominant fenestrated limb. PMID- 28589070 TI - Agranulocytosis - Sequelae of Chronic Cocaine Use: Case Series and Literature Review. AB - Agranulocytosis is a rare condition with a reported incidence ranging from one to five cases per million population per year. Most commonly, agranulocytosis is secondary to chemotherapeutic agents, however, other medications have also been associated with it. An immune mediated destruction of circulating granulocytes and/or granulocyte precursors secondary to drug-dependent or drug-induced antibodies is the postulated mechanism. Agranulocytosis has also been reported secondary to recreational drug use. Cocaine is one of the most commonly used recreational drugs and is often laced with Levamisole to enhance its psychostimulatory properties. Levamisole is an immune modulator and can cause bone marrow suppression. It can be detected in urine by gas chromatography-mass spectrometry. We report two cases of recurrent agranulocytosis in non-oncology patients secondary to chronic cocaine abuse, who were treated with granulocyte colony-stimulating factor (GCSF) and broad spectrum antibiotics without sustained response. The high prevalence of cocaine use continues to be a serious public health concern. This case series discusses the association of adulterated cocaine as an etiology of unexplained neutropenia and highlights the diverse clinical complications of chronic cocaine abuse. Currently, the available literature is reviewed. PMID- 28589072 TI - Pediatric Intrafalcine Empyema from a Sinogenic Origin: A Case Report. AB - Sinusitis and otitis are common within the pediatric population. If left untreated, these can extend intracranially and lead to the development of infections in the various intracranial compartments resulting in a high rate of morbidity and mortality. We report the first case of an intrafalcine empyema, absent subdural purulence, in a patient with the likely spread from a sinogenic origin. This case illustrates the novelty of this as a pathological entity as well as the surgical considerations for intrafalcine purulence in the absence of expected subdural collections. PMID- 28589071 TI - A Case Report on Complicated Tuberculous Meningitis. AB - Tuberculous meningitis (TBM) is associated with significant complications of central nervous system. It is accompanied by nonspecific and heterogeneous clinical symptoms. We focused on the significance of early diagnosis and prompt treatment. We describe a case of TBM in a 19-year-old Asian female. She had a progressive motor weakness with no sensory findings. She was started on antituberculous therapy. Her magnetic resonance imaging (MRI) contrast of dorsolumbar spine showed syringomyelia. Her culture and sensitivity for Mycobacterium tuberculosis (MTB) came negative. She was given a therapeutic trial of quinolones and Steroids. She had an uneventful recovery and was followed up for the past one year. PMID- 28589073 TI - Curated Collections for Educators: Five Key Papers about Program Evaluation. AB - The evaluation of educational programs has become an expected part of medical education. At some point, all medical educators will need to critically evaluate the programs that they deliver. However, the evaluation of educational programs requires a very different skillset than teaching. In this article, we aim to identify and summarize key papers that would be helpful for faculty members interested in exploring program evaluation. In November of 2016, the 2015-2016 Academic life in emergency medicine (ALiEM) Faculty Incubator program highlighted key papers in a discussion of program evaluation. This list of papers was augmented with suggestions by guest experts and by an open call on Twitter. This resulted in a list of 30 papers on program evaluation. Our authorship group then engaged in a process akin to a Delphi study to build consensus on the most important papers about program evaluation for medical education faculty. We present our group's top five most highly rated papers on program evaluation. We also summarize these papers with respect to their relevance to junior medical education faculty members and faculty developers. Program evaluation is challenging. The described papers will be informative for junior faculty members as they aim to design literature-informed evaluations for their educational programs. PMID- 28589075 TI - Chylous Ascites in Systemic Lupus Erythematosus: A Diagnostic Challenge. AB - Systemic lupus erythematous (SLE) is a chronic inflammatory disease of unknown etiology. It can affect nearly any organ. Gastrointestinal (GI) involvement in SLE is frequent but is mostly related to medication side effects and concomitant infections. Chylous ascites is a rare form of ascites that is milky appearing due to the high concentration of triglycerides. Chylous ascites as a complication of SLE is atypical. Our case highlights an extremely rare presentation of chylous ascites in SLE as an initial manifestation of the disease itself, posing diagnostic and therapeutic challenges. Through this case, we aim to raise awareness of SLE as a rare but reversible cause of chylous ascites. PMID- 28589074 TI - Liddle Syndrome in Association with Aortic Dissection. AB - Liddle syndrome is a rare form of autosomal dominant monogenic hypertension manifested as an early onset of resistant hypertension with either no response or suboptimal response to conventional antihypertensive therapy. If there is a delay in diagnosis, uncontrolled hypertension can lead to end organ damage. To our knowledge, aortic dissection has not been reported in association with this disease. We report a case of a dissecting aortic aneurysm occurring in association with Liddle syndrome.. PMID- 28589076 TI - Non-Contrast Computed Tomography Scan Based Parameters of Ureteric Stones Affecting the Outcome of Extracorporeal Shock Wave Lithotripsy. AB - OBJECTIVE : To compare the non-contrast computed tomography (NCCT) scan-based parameters of ureteric stones affecting the outcome of extracorporeal shock wave lithotripsy (ESWL). MATERIALS AND METHODS: We retrospectively evaluated the pre procedure NCCT of 74 patients who had ESWL for solitary ureteric calculi of 5-20 mm in diameter. We assessed the age, sex, basal metabolic index (BMI), laterality, location, presence of double 'J' (DJ) stent, skin to stone distance (SSD), stone maximum diameter, Hounsfield unit (HU), Hounsfield density (HD), area, and volume. All those who had no stone on follow-up imaging within 30 days were declared successful while those who had residual stone were declared failures. RESULTS: The overall success rate was 78% (58/74). Sixty (81.1%) patients were male. The success of ESWL was correlated with lower SSD, Hounsfield units (HU) and Hounsfield density (HD). However, in multivariate analysis, SSD, Hounsfield unit, and stone area showed correlation with success of procedure but Hounsfield density failed to show correlation. The success rate in patients with stone HU <500, 500-1000 and >1000 were 93.9%, 69%, and 58.3%, respectively. Patients with lower BMI (<30 kg/m2) and HD (<76 HU/mm) were more prone towards success of the procedure than those with higher BMI (>30 kg/m2) and higher HD (>76 HU/mm). CONCLUSION: BMI, SSD, stone Hounsfield units and Hounsfield unit density were strong predictors of outcome of ESWL for ureteric stone. PMID- 28589078 TI - Recent clinical trials of cancer immunogene therapy in companion animals. AB - This mini-review presents the results of veterinary clinical trials on immunogene therapy published from 2014 to 2016. A variety of tumors, among them melanoma (canine and equine), mastocytoma (canine), mammary adenocarcinoma (canine) and fibrosarcoma (feline) were treated by using diverse strategies. Non-viral vectors were usually employed to transfer genes of cytokines, suicide enzymes and/or tumor associated antigens. In general terms, minor or no adverse collateral effects were related to these procedures, and treated patients frequently improved their conditions (better quality of life, delayed or suppressed recurrence or metastatic spread, increased survival). Some of these new methodologies have a promising future if applied as adjuvant treatments of standard approaches. The auspicious results, derived from immunogene therapy studies carried out in companion animals, warrant their imperative usage in veterinary clinical oncology. Besides, they provide a strong preclinical basis (safety assays and proofs of concept) for analogous human clinical trials. PMID- 28589077 TI - Application of CRISPR/Cas9 in plant biology. AB - The CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR associated proteins) system was first identified in bacteria and archaea and can degrade exogenous substrates. It was developed as a gene editing technology in 2013. Over the subsequent years, it has received extensive attention owing to its easy manipulation, high efficiency, and wide application in gene mutation and transcriptional regulation in mammals and plants. The process of CRISPR/Cas is optimized constantly and its application has also expanded dramatically. Therefore, CRISPR/Cas is considered a revolutionary technology in plant biology. Here, we introduce the mechanism of the type II CRISPR/Cas called CRISPR/Cas9, update its recent advances in various applications in plants, and discuss its future prospects to provide an argument for its use in the study of medicinal plants. PMID- 28589079 TI - Role of LIGHT in the pathogenesis of joint destruction in rheumatoid arthritis. AB - AIM: To characterise the role of substitutes for receptor-activator nuclear factor kappa-B ligand (RANKL) in rheumatoid arthritis (RA) joint destruction. METHODS: Synovial fluid (SF) macrophages isolated from the knee joint of RA patients were incubated with 25 ng/mL macrophage-colony stimulating factor (M CSF) and 50 ng/mL LIGHT (lymphotoxin-like, exhibits inducible expression and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes) in the presence and absence of 25 ng/mL RANKL and 100 ng/mL osteoprotegerin (OPG) on glass coverslips and dentine slices. Osteoclastogenesis was assessed by the formation of multinucleated cells (MNCs) expressing tartrate-resistant acid phosphatase (TRAP) on coverslips and the extent of lacunar resorption pit formation on dentine slices. The concentration of LIGHT in RA and osteoarthritis (OA) synovial fluid was measured by an enzyme-linked immunosorbent assay (ELISA) and the expression of LIGHT in RA and OA synovium was determined by immunohistochemistry using an indirect immunoperoxidase technique. RESULTS: In cultures of RA SF macrophages treated with LIGHT and M-CSF, there was significant formation of TRAP + MNCs on coverslips and extensive lacunar resorption pit formation on dentine slices. SF macrophage-osteoclast differentiation was not inhibited by the addition of OPG, a decoy receptor for RANKL. Resorption pits were smaller and less confluent than in RANKL-treated cultures but the overall percentage area of the dentine slice resorbed was comparable in LIGHT- and RANKL-treated cultures. LIGHT significantly stimulated RANKL-induced lacunar resorption compared with RA SF macrophages treated with either RANKL or LIGHT alone. LIGHT was strongly expressed by synovial lining cells, subintimal macrophages and endothelial cells in RA synovium and the concentration of LIGHT was much higher in RA compared with OA SF. CONCLUSION: LIGHT is highly expressed in RA synovium and SF, stimulates RANKL independent/dependent osteoclastogenesis from SF macrophages and may contribute to marginal erosion formation. PMID- 28589081 TI - Inhibitory Effect of 1,8-Cineol on beta-Catenin Regulation, WNT11 Expression, and Cellular Progression in HNSCC. AB - OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumors worldwide. The high mortality rates have not changed during the last three decades, and thus there is an enormous need for innovative therapy approaches. Several recent studies suggest an important role of the Wnt/beta catenin signaling pathway in the tumorigenesis of HNSCC. We analyzed the effect of the monoterpene oxide 1,8-cineol on the regulation of the Wnt/beta-catenin signaling pathway and the cellular progression of different HNSCC cell lines. METHODS: Permanent HNSCC cell lines were exposed to varying concentrations and times of 1,8-cineol. Regulation and activity profiles of the Wnt/beta-catenin signaling cascade were analyzed using Western hybridization experiments, MTT assays, real-time PCR-based epithelial to mesenchymal transition array, and immunohistochemistry. RESULTS: Exposure of different cell lines to 1,8-cineol treatment resulted in a dose-dependent inhibition of proliferation and a decreased activity of the WNT/beta-catenin pathway. We can show the inhibition of glycogen synthase kinase 3 (GSK-3)alpha/beta (Ser-9/21) as well as a corresponding decreased endolysosomal localization, leading to a decreased beta catenin activity. Furthermore, we can show that exposure to cineol functionally results in a reduced expression of WNT11. CONCLUSION: In this work, we demonstrate for the first time that 1,8-cineol acts as an inhibitor of the Wnt/beta-catenin activity in HNSCC via a decreased inhibition of GSK-3, which lead to reduced levels of WNT11 and a dose-dependent decrease of the cellular progression. Our data represent a new mechanism of 1,8-cineol activity, which may lead to novel molecular targets and treatment approaches of this natural drug. PMID- 28589082 TI - Genetically Engineered Vaccinia Viruses As Agents for Cancer Treatment, Imaging, and Transgene Delivery. AB - Despite advances in technology, the formidable challenge of treating cancer, especially if advanced, still remains with no significant improvement in survival rates, even with the most common forms of cancer. Oncolytic viral therapies have shown great promise for the treatment of various cancers, with the possible advantages of stronger treatment efficacy compared to conventional therapy due to higher tumor selectivity, and less toxicity. They are able to preferentially and selectively propagate in cancer cells, consequently destroying tumor tissue mainly via cell lysis, while leaving non-cancerous tissues unharmed. Several wild type and genetically engineered vaccinia virus (VACV) strains have been tested in both preclinical and clinical trials with promising results. Greater understanding and advancements in molecular biology have enabled the generation of genetically engineered oncolytic viruses for safer and more efficacious treatment, including arming VACVs with cytokines and immunostimulatory molecules, anti-angiogenic agents, and enzyme prodrug therapy, in addition to combining VACVs with conventional external and systemic radiotherapy, chemotherapy, immunotherapy, and other virus strains. Furthermore, novel oncolytic vaccinia virus strains have been generated that express reporter genes for the tracking and imaging of viral therapy and monitoring of therapeutic response. Further study is needed to unlock VACVs' full potential as part of the future of cancer therapy. PMID- 28589084 TI - Calreticulin in Essential Thrombocythemia: StressINg OUT the Megakaryocyte Nucleus. AB - Calreticulin (CALR) is a multifaceted protein primarily involved in intracellular protein control processes. The identification of CALR mutations in essential thrombocythemia (ET) and primary myelofibrosis that are mutually exclusive with the JAK2 V617F mutation has stirred an intensive research interest about the molecular functions of CALR and its mutants in myeloproliferative neoplasms (MPNs) and its diagnostic/prognostic value. The recently characterized protein protein interaction of CALR mutants and MPL receptor has advanced our knowledge on the functional role of CALR mutants in thrombocythemia but it has also uncovered limitations of the current established research models. Human cell lines and mouse models provide useful information but they lack the advantages provided by ex vivo primary cultures of physiologically relevant to the disease cell types [i.e., megakaryocytes (MKs), platelets]. The results from gene expression and chromatin occupancy analysis have focused on the JAK-STAT pathway activated in both JAK2 V617F- and CALR-mutated MPN patient groups, although a more complete analysis is needed to be performed in MKs. Stress related processes seem to be affected in CALR mutant ET-MKs, but the precise mechanism is not known yet. Herein, we describe a culture method for human MKs from peripheral blood progenitors, which could help further toward an unbiased characterization of the role of CALR in ET and MK differentiation. PMID- 28589083 TI - The Concerted Action of Mitochondrial Dynamics and Positioning: New Characters in Cancer Onset and Progression. AB - Mitochondria are dynamic organelles whose morphology and activity are extremely variable, depending on the metabolic state of the cell. In particular, their shape and movements within the cell are finely regulated by an increasing number of proteins, which take part in the process of mitochondrial fission/fusion and connect the organelles to the cytoskeleton. As to their activities, mitochondria are considered to be at the crossroad between cell life and death since, on the one hand, they are essential in ATP production and in multiple metabolic pathways but, on the other, they are involved in the intrinsic apoptotic cascade, triggered by different stress conditions. Importantly, the process of mitochondrial Ca2+ uptake, as well as the morphology and the dynamics of these organelles, is known to deeply impact on both pro-survival and pro-death mitochondrial activities. Recently, increasing evidence has accrued on a central role of deregulated mitochondrial functionalities in the onset and progression of different pathologies, ranging from neurodegenerative diseases to cancer. In this contribution, we will present the latest findings connecting alterations in the machineries that control mitochondrial dynamics and localization to specific cancer hallmarks, highlighting the importance of mitochondria for the viability of cancer cells and discussing their role as promising targets for the development of novel anticancer therapies. PMID- 28589080 TI - Radiation-Induced Oral Mucositis. AB - Radiation-induced oral mucositis (RIOM) is a major dose-limiting toxicity in head and neck cancer patients. It is a normal tissue injury caused by radiation/radiotherapy (RT), which has marked adverse effects on patient quality of life and cancer therapy continuity. It is a challenge for radiation oncologists since it leads to cancer therapy interruption, poor local tumor control, and changes in dose fractionation. RIOM occurs in 100% of altered fractionation radiotherapy head and neck cancer patients. In the United Sates, its economic cost was estimated to reach 17,000.00 USD per patient with head and neck cancers. This review will discuss RIOM definition, epidemiology, impact and side effects, pathogenesis, scoring scales, diagnosis, differential diagnosis, prevention, and treatment. PMID- 28589085 TI - Immune System, Friend or Foe of Oncolytic Virotherapy? AB - Oncolytic viruses (OVs) are an emerging class of targeted anticancer therapies designed to selectively infect, replicate in, and lyse malignant cells without causing harm to normal, healthy tissues. In addition to direct oncolytic activity, OVs have shown dual promise as immunotherapeutic agents. The presence of viral infection and subsequently generated immunogenic tumor cell death trigger innate and adaptive immune responses that mediate further tumor destruction. However, antiviral immune responses can intrinsically limit OV infection, spread, and overall therapeutic efficacy. Host immune system can act both as a barrier as well as a facilitator and sometimes both at the same time based on the phase of viral infection. Thus, manipulating the host immune system to minimize antiviral responses and viral clearance while still promoting immune mediated tumor destruction remains a key challenge facing oncolytic virotherapy. Recent clinical trials have established the safety, tolerability, and efficacy of virotherapies in the treatment of a variety of malignancies. Most notably, talimogene laherparepvec (T-VEC), a genetically engineered oncolytic herpesvirus expressing granulocyte macrophage colony stimulating factor, was recently approved for the treatment of melanoma, representing the first OV to be approved by the FDA as an anticancer therapy in the US. This review discusses OVs and their antitumor properties, their complex interactions with the immune system, synergy between virotherapy and existing cancer treatments, and emerging strategies to augment the efficacy of OVs as anticancer therapies. PMID- 28589086 TI - Lymph Node Metastases in Papillary and Medullary Thyroid Carcinoma Are Independent of Intratumoral Lymphatic Vessel Density. AB - BACKGROUND: Blood and lymph vessel invasion are well-recognized markers of tumor aggressiveness, as these are the routes that lead to metastases. Thyroid tumors, depending on the histological variant, tend to have distinctive biological behaviors and use different vascular routes to metastasize, yet the mechanisms underlying the metastatic process are still poorly understood. OBJECTIVES: The aim of this study was to assess how the lymph vessel density (LVD) in different histological types of thyroid tumors, and in their surrounding tissue, correlate with the presence of lymph node metastases (LNM) and tumor pathological features. METHODS: Lymph vessels of papillary thyroid carcinomas (PTC), of the classical (CVPTC, n = 50) and follicular variants (FVPTC, n = 18), and medullary thyroid carcinomas (MTC, n = 34) were immunohistochemically stained against antigen D2 40. The stained area was quantified using a computerized morphometric analysis tool and correlated with the tumor pathological characteristics. RESULTS: LVD within all analyzed thyroid tumor subtypes was significantly lower than in the surrounding thyroid tissues (p < 0.001). Despite intratumoral LVD being significantly higher in CVPTC than in FVPTC, and peritumoral LVD being significantly higher in MTC than in PTC (p < 0.05), no correlations were found between LVD (either intratumoral or peritumoral) and the presence of lymph node metastasis. CONCLUSIONS: As no LVD differences were found amongst thyroid tumors with or without LNM, dissemination is more likely to depend on the tumor ability to invade the abundant lymph vessel network of the surrounding thyroid tissue than on the ability of the tumor to promote de novo lymphangiogenesis. PMID- 28589087 TI - Nodular Thyroid Disease and Thyroid Cancer in the Era of Precision Medicine. AB - The management of thyroid nodules, one of the main clinical challenges in endocrine clinical practice, is usually straightforward. Although the most important concern is ruling out malignancy, there are grey areas where uncertainty is frequently present: the nodules labelled as indeterminate by cytology and the extent of therapy when thyroid cancer is diagnosed pathologically. There is evidence that the current available precision medicine tools (from all the "-omics" to molecular analysis, fine-tuning imaging or artificial intelligence) may help to fill present gaps in the future. We present here a commentary on some of the current challenges faced by endocrinologists in the field of thyroid nodules and cancer, and illustrate how precision medicine may improve their diagnostic and therapeutic capabilities in the future. PMID- 28589088 TI - A 2016 Italian Survey about Guidelines and Clinical Management of Thyroid Nodules. AB - BACKGROUND: While thyroid nodules are frequent in endocrine clinical practice, patients are often asymptomatic and euthyroid, and death is rare in cases of malignancy. OBJECTIVES: To evaluate the perception of current international guidelines regarding thyroid nodule management among Italian endocrinologists, and to compare daily clinical practice with suggested recommendations. METHODS: Italian Association of Clinical Endocrinologists (AME) members were invited to participate in a Web-based survey. RESULTS: A total of 566 physicians responded. About 50% had read the full text of the guidelines. Over half appreciated the suggested ultrasound (US) risk categories. Fine-needle aspiration (FNA) was obtained more frequently than recommended. Follow-up of a cytologically benign nodule was largely performed according to the guidelines. Molecular testing would be most commonly requested when cytology reports showed atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (TIR3A for Italian System). Iodine and/or levothyroxine were largely prescribed for cytologically benign asymptomatic nodules. Laser/radiofrequency ablation and percutaneous ethanol injection were commonly considered as alternatives to surgery (46.2 and 71.4%, respectively). CONCLUSIONS: Efforts are needed to make the guidelines more user-friendly and to encourage the use of codified risk categories in thyroid US reports. FNA indications remain a matter of debate as FNA is obtained in clinical practice more often than is recommended. Current US follow-up modalities for a benign nodule are correct, but probably could be performed less frequently without any harm. Molecular testing, if accessible, would be helpful in guiding clinicians' strategies in cases of AUS/FLUS-TIR3A cytologic results. Nonsurgical procedures are favorably embraced. PMID- 28589089 TI - Reference Values for TSH and Free Thyroid Hormones in Healthy Pregnant Women in Poland: A Prospective, Multicenter Study. AB - OBJECTIVES: The diagnosis and treatment of thyroid diseases in pregnant women remains a challenge. Various medical associations recommend establishing the reference intervals for thyroid hormones by a local laboratory. Considering differences within geophysical, socioeconomic conditions, and iodine prophylaxis in various populations, it is advisable to assess reference intervals for thyroid hormones specific to a region of residence. The objective was to assess trimester specific reference intervals for TSH, fT3, and fT4 for pregnant women in the Polish population. METHODS AND RESULTS: We conducted a prospective study in 4 centers representing different regions of Poland (Krakow, Warsaw, Poznan, and Bialystok). Our study included consecutive, healthy pregnant women (172 patients), with an age range of 27-47 years. All women had a negative history for thyroid diseases, normal thyroid peroxidase antibody levels, and proper iodine prophylaxis. All newborns had TSH levels in the appropriate reference range. Serum TSH, fT3, fT4, and thyroid-peroxidase antibodies were measured in each trimester. The reference intervals were calculated using the percentile method, as recommended by the International Federation of Clinical Chemistry. The reference values calculated were 0.009-3.177, 0.05-3.442, and 0.11-3.53 mIU/L for TSH; 3.63-6.55, 3.29-5.45, and 3.1-5.37 pmol/L for fT3; and 11.99-21.89, 10.46 16.67, and 8.96-17.23 pmol/L for fT4 in consecutive trimesters of pregnancy. Reference intervals for pregnant women when compared to the general population showed a lower concentration of TSH in every trimester of pregnancy and lower fT4 in the 2nd and 3rd trimesters. CONCLUSIONS: Using appropriate trimester-specific reference intervals may improve care of pregnant women by preventing misdiagnosis and inadequate treatment. PMID- 28589090 TI - Neither Baseline nor Changes in Serum Triiodothyronine during Levothyroxine/Liothyronine Combination Therapy Predict a Positive Response to This Treatment Modality in Hypothyroid Patients with Persistent Symptoms. AB - BACKGROUND: Despite biochemical euthyroidism, some levothyroxine (L-T4)-treated hypothyroid patients report persisting symptoms and some of these patients are tentatively treated with a combination of L-T4 and liothyronine (L-T3). Combination therapy and the appropriate choice of blood tests to monitor treatment are highly debated among specialists and patients. AIM: To evaluate whether measuring serum triiodothyronine (S-T3) at baseline or during combination therapy can be used as an indicator of a positive effect from L-T4/L-T3 combination therapy. MATERIALS AND METHODS: Observational retrospective study of patients (n = 42) with persisting symptoms of hypothyroidism despite L-T4 therapy who had normal TSH levels and did not have any comorbidities that could explain their symptoms. All were then treated with L-T4/L-T3 combination therapy at a dose ratio of 17/1 according to European Thyroid Association guidelines. Based on patient-reported outcome, they were divided into responders and nonresponders. RESULTS: Five patients were lost to follow-up and thus excluded. At the 3-month follow-up, 11 were classified as nonresponders and 26 as responders. At 12 months these figures had changed to 13 (35%) and 24 (65%), respectively. When comparing responders versus nonresponders, no differences were seen at baseline or during follow-up in S-T3 and in free T3 estimates. Further, logistic regression showed no correlation between S-T3 and free T3 estimates and responder/nonresponder status. CONCLUSION: Our data indicate that serum T3 measurements are not suitable to predict which patient will benefit from L-T4/L-T3 combination therapy, and treatment response cannot be followed by repeated T3 measurements either. PMID- 28589091 TI - When Is Thyroidectomy the Right Choice? Comparison between Fine-Needle Aspiration and Final Histology in a Single Institution Experience. AB - OBJECTIVES: The aim of this study was to compare SIAPEC-IAP-based cytological reports with their corresponding histological diagnoses to establish when thyroidectomy is the right choice in the management of thyroid diseases. STUDY DESIGN: This is a retrospective review of all the consecutive thyroidectomies/lobectomies performed at Maria Vittoria Hospital during the 10 year period between January 2005 and December 2015. Patients who underwent both fine-needle aspiration (FNA) and surgical procedures in our institution were included in the study. RESULTS: A total of 260 patients underwent both FNA and a thyroid surgical procedure at Maria Vittoria Hospital; 111 (42.69%) had a malignant histological report. The final cytological diagnosis was nondiagnostic (TIR-1) in 19 cases (7.31%), benign (TIR-2) in 83 cases (31.92%), indeterminate (TIR-3) in 96 cases (36.92%), suspicious for malignancy (TIR-4) in 22 cases (8.46%), and diagnostic for malignancy (TIR-5) in 40 cases (15.38%). Among the 96 cases with TIR-3 cytology, after the review, 44 (16.92%) were classified as TIR 3A and 52 (20%) as TIR-3B. The prevalence of malignancy among TIR-3A cases was 20.45% (9/44) and among TIR-3B cases 53.85% (28/52). The difference was statistically significant (p = 0.0007). CONCLUSIONS: Our data suggest that follow up alone is not sufficient in TIR-3A patients given the high prevalence of malignancy within that diagnostic category (20.45%) and the low sensitivity (75.68%) and specificity (59.32%) in the distinction between TIR-3A and TIR-3B. Regarding patients with a multinodular goiter and TIR-2 at FNA, the surgical approach should not be excluded. PMID- 28589092 TI - "Nodule in Nodule" on Thyroid Ultrasonography: Possibility of Follicular Carcinoma Transformed from Benign Thyroid Tumor. AB - BACKGROUND: It is generally considered impossible to differentiate follicular carcinomas from follicular adenomas by means of ultrasonography or cytology before surgery. Therefore, follicular carcinoma is histopathologically diagnosed by verifying capsular and/or vascular invasion after surgery. However, ultrasonography may play an important role in diagnosing follicular carcinoma preoperatively in a small number of cases. CASE DESCRIPTION: Four cases of follicular carcinoma or follicular neoplasm that transformed from a benign thyroid tumor and demonstrated a "nodule in nodule" appearance on ultrasonography are presented in this report. Characteristic ultrasound features of such patients are: (1) a "nodule in nodule" appearance, (2) a well-defined boundary line between the nodules, and (3) separate distribution of blood signals within each nodule. CONCLUSION: A small number of patients with follicular carcinomas or follicular neoplasms may present with a "nodule in nodule" appearance on ultrasonography. It was suggested a long time ago that follicular carcinomas may develop from benign thyroid tumors. The fact that follicular carcinomas appear within benign tumors may be evidence of thyroid tumorigenesis. PMID- 28589093 TI - Successful Pretreatment Using Plasma Exchange before Thyroidectomy in a Patient with Amiodarone-Induced Thyrotoxicosis. AB - INTRODUCTION: Amiodarone, used for the management of tachyarrhythmias, is associated with both hypothyroidism and thyrotoxicosis. Total thyroidectomy is an effective procedure for promptly reducing circulating thyroid hormone levels. It has been proposed in patients who have severe amiodarone-induced thyrotoxicosis (AIT) or are refractory to medical therapy, or when such therapy is contraindicated. Therapeutic plasma exchange (TPE) may be considered as a pretreatment for restoring a euthyroid state preoperatively, thereby reducing a patient's symptoms and the potential perioperative risk associated with thyrotoxicosis. CASE REPORT: We describe the case of a 62-year-old man with type 2 AIT who presented with severe unremitting thyrotoxicosis after 8 weeks of medical therapy with glucocorticosteroids, thiamazole, and potassium perchlorate. Given the severity of his presentation, a total thyroidectomy was indicated. TPE was performed preoperatively and was successful in rapidly restoring euthyroidism. This dramatically improved the patient's symptoms which had been suggestive of ischemic heart disease. Subsequently, the patient underwent total thyroidectomy under general anesthesia without any major complications. CONCLUSION: TPE is successful in rapidly restoring a clinical and biochemical euthyroid state, and may be used to decrease the perioperative risks associated with thyroidectomy in patients with life-threatening thyrotoxicosis or in cases refractory to medical treatment. PMID- 28589094 TI - Selenium in the Treatment of Thyroid Diseases. PMID- 28589096 TI - Identification of S-Nitrosylated (SNO) Proteins in Entamoeba histolytica Adapted to Nitrosative Stress: Insights into the Role of SNO Actin and In vitro Virulence. AB - We have recently reported that Entamoeba histolytica trophozoites can adapt to toxic levels of the nitric oxide (NO) donor, S-nitrosoglutathione (GSNO). Even if the consequences of this adaptation on the modulation of gene expression in NO adapted trophozoites (NAT) have been previously explored, insight on S nitrosylated (SNO) proteins in NAT is missing. Our study aims to fill this knowledge gap by performing a screening of SNO proteins in NAT. Employing SNO resin-assisted capture (RAC), we identified 242 putative SNO proteins with key functions in calcium binding, enzyme modulation, redox homeostasis, and actin cytoskeleton. Of the SNO proteins in NAT, proteins that are associated with actin family cytoskeleton protein are significantly enriched. Here we report that the formation of actin filaments (F-actin) is impaired in NAT. Consequently, the ability of NAT to ingest erythrocytes and their motility and their cytopathic activity are impaired. These phenotypes can be imitated by treating control parasite with cytochalasin D (CytD), a drug that binds to F-actin polymer and prevent polymerization of actin monomers. Removal of GSNO from the culture medium of NAT restored the sensitivity of the parasite to nitrosative stress (NS) and its ability to form F-actin formation and its virulence. These results establish the central role of NO in shaping the virulence of the parasite through its effect on F-actin formation and highlight the impressive ability of this parasite to adapt to NS. PMID- 28589095 TI - Diversity and Versatility of Phagocytosis: Roles in Innate Immunity, Tissue Remodeling, and Homeostasis. AB - Phagocytosis, a critical early event in the microbicidal response of neutrophils, is now appreciated to serve multiple functions in a variety of cell types. Professional phagocytes play a central role in innate immunity by eliminating pathogenic bacteria, fungi and malignant cells, and contribute to adaptive immunity by presenting antigens to lymphocytes. In addition, phagocytes play a part in tissue remodeling and maintain overall homeostasis by disposing of apoptotic cells, a task shared by non-professional phagocytes, often of epithelial origin. This functional versatility is supported by a vast array of receptors capable of recognizing a striking variety of foreign and endogenous ligands. Here we present an abbreviated overview of the different types of phagocytes, their varied modes of signaling and particle engulfment, and the multiple physiological roles of phagocytosis. PMID- 28589097 TI - AGO2 Negatively Regulates Type I Interferon Signaling Pathway by Competition Binding IRF3 with CBP/p300. AB - Viral infection triggers a series of signaling cascades and host innate immune responses, including interferon (IFN) production, which depends on coordinated activity of multiple transcription factors. IFN regulatory factor 3 (IRF3) and transcriptional coactivator CREB binding protein (CBP) and/or p300 are core factors that participate in transcriptional complex formation in the nucleus. In general, cells balance the production of IFNs through suppressive and stimulative mechanisms, but viral infections can disrupt such equilibrium. This study determined that H5N1 viral infection reduced the distribution of human argonaute 2 (AGO2) in A549 cell nucleus. AGO2 did not block phosphorylation, nuclear translocation, and DNA binding ability of IRF3 but inhibited its association with CBP. Therefore, this newly revealed mechanism shows that cellular response leads to transfer of AGO2 from cell nucleus and promotes IFN-beta expression to increase host survival during viral infection. PMID- 28589098 TI - Manipulation of Neutrophils by Porphyromonas gingivalis in the Development of Periodontitis. AB - The pathogenesis of the chronic periodontal disease is associated with a skewed host inflammatory response to periodontal pathogens, such as Porphyromonas gingivalis, that accounts for the majority of periodontal tissue damage. Neutrophils are the most abundant leukocytes in periodontal pockets and depending on the stage of the disease, also plentiful PMNs are present in the inflamed gingival tissue and the gingival crevice. They are the most efficient phagocytes and eliminate pathogens by a variety of means, which are either oxygen-dependent or -independent. However, these secretory lethal weapons do not strictly discriminate between pathogens and host tissue. Current studies describe conflicting findings about neutrophil involvement in periodontal disease. On one hand literature indicate that hyper-reactive neutrophils are the main immune cell type responsible for this observed tissue damage and disease progression. Deregulation of neutrophil survival and functions, such as chemotaxis, migration, secretion of antimicrobial peptides or enzymes, and production of reactive oxygen species, contribute to observed tissue injury and the clinical signs of periodontal disease. On the other hand neutrophils deficiencies in patients and mice also result in periodontal phenotype. Therefore, P. gingivalis represents a periodontal pathogen that manipulates the immune responses of PMNs, employing several virulence factors, such as gingipains, serine proteases, lipid phosphatases, or fimbriae. This review will sum up studies devoted to understanding different strategies utilized by P. gingivalis to manipulate PMNs survival and functions in order to inhibit killing by a granular content, prolong inflammation, and gain access to nutrient resources. PMID- 28589100 TI - MicroRNA-21 Limits Uptake of Listeria monocytogenes by Macrophages to Reduce the Intracellular Niche and Control Infection. AB - MiRNAs are important post-transcriptional regulators of gene expression. MiRNA expression is a crucial part of host responses to bacterial infection, however there is limited knowledge of their impact on the outcome of infections. We investigated the influence of miR-21 on macrophage responses during infection with Listeria monocytogenes, which establishes an intracellular niche within macrophages. MiR-21 is induced following infection of bone marrow-derived macrophages (BMDMs) with Listeria. MiR-21-/- macrophages display an increased bacterial burden with Listeria at 30 min and 2 h post-infection. This phenotype was reversed by the addition of synthetic miR-21 mimics to the system. To assess the immune response of wildtype (WT) and miR-21-/- macrophages, BMDMs were treated with bacterial LPS or infected with Listeria. There was no difference in IL-10 and IL-6 between WT and miR-21-/- BMDMs in response to LPS or Listeria. TNF alpha was increased in miR-21-/- BMDMs stimulated with LPS or Listeria compared to WT macrophages. We next assessed the production of nitric oxide (NO), a key bactericidal factor in Listeria infection. There was no significant difference in NO production between WT and miR-21-/- cells, indicating that the increased bacterial burden may not be due to impaired killing. As the increased bacterial load was observed early following infection (30 min), we questioned whether this is due to differences in uptake of Listeria by WT and miR-21-/- macrophages. We show that miR-21-deficiency enhances uptake of FITC-dextran and FITC-Escherichia coli bioparticles by macrophages. The previously observed Listeria burden phenotype was ablated by pre-treatment of cells with the actin polymerization inhibitor cytochalasin-D. From analysis of miR-21 targets, we selected the pro phagocytic regulators myristoylated alanine-rich C-kinase substrate (MARCKS) and Ras homolog gene family, member B (RhoB) for further investigation. MARCKS and RhoB are increased in miR-21-/- BMDMs, correlating with increased uptake of Listeria. Finally, intra-peritoneal infection of mice with Listeria led to increased bacterial burden in livers of miR-21-/- mice compared to WT mice. These findings suggest a possible role for miR-21 in regulation of phagocytosis during infection, potentially by repression of MARCKS and RhoB, thus serving to limit the availability of the intracellular niche of pathogens like L. monocytogenes. PMID- 28589101 TI - Recombineering in Streptococcus mutans Using Direct Repeat-Mediated Cloning Independent Markerless Mutagenesis (DR-CIMM). AB - Studies of the dental caries pathogen Streptococcus mutans have benefitted tremendously from its sophisticated genetic system. As part of our own efforts to further improve upon the S. mutans genetic toolbox, we previously reported the development of the first cloning-independent markerless mutagenesis (CIMM) system for S. mutans and illustrated how this approach could be adapted for use in many other organisms. The CIMM approach only requires overlap extension PCR (OE-PCR) protocols to assemble counterselectable allelic replacement mutagenesis constructs, and thus greatly increased the speed and efficiency with which markerless mutations could be introduced into S. mutans. Despite its utility, the system is still subject to a couple limitations. Firstly, CIMM requires negative selection with the conditionally toxic phenylalanine analog p-chlorophenylalanine (4-CP), which is efficient, but never perfect. Typically, 4-CP negative selection results in a small percentage of naturally resistant background colonies. Secondly, CIMM requires two transformation steps to create markerless mutants. This can be inherently problematic if the transformability of the strain is negatively impacted after the first transformation step, which is used to insert the counterselection cassette at the mutation site on the chromosome. In the current study, we develop a next-generation counterselection cassette that eliminates 4-CP background resistance and combine this with a new direct repeat mediated cloning-independent markerless mutagenesis (DR-CIMM) system to specifically address the limitations of the prior approach. DR-CIMM is even faster and more efficient than CIMM for the creation of all types of deletions, insertions, and point mutations and is similarly adaptable for use in a wide range of genetically tractable bacteria. PMID- 28589099 TI - Serine Protease Inhibitors in Ticks: An Overview of Their Role in Tick Biology and Tick-Borne Pathogen Transmission. AB - New tick and tick-borne pathogen control approaches that are both environmentally sustainable and which provide broad protection are urgently needed. Their development, however, will rely on a greater understanding of tick biology, tick pathogen, and tick-host interactions. The recent advances in new generation technologies to study genomes, transcriptomes, and proteomes has resulted in a plethora of tick biomacromolecular studies. Among these, many enzyme inhibitors have been described, notably serine protease inhibitors (SPIs), whose importance in various tick biological processes is only just beginning to be fully appreciated. Among the multiple active substances secreted during tick feeding, SPIs have been shown to be directly involved in regulation of inflammation, blood clotting, wound healing, vasoconstriction and the modulation of host defense mechanisms. In light of these activities, several SPIs were examined and were experimentally confirmed to facilitate tick pathogen transmission. In addition, to prevent coagulation of the ingested blood meal within the tick alimentary canal, SPIs are also involved in blood digestion and nutrient extraction from the meal. The presence of SPIs in tick hemocytes and their involvement in tick innate immune defenses have also been demonstrated, as well as their implication in hemolymph coagulation and egg development. Considering the involvement of SPIs in multiple crucial aspects of tick-host-pathogen interactions, as well as in various aspects of the tick parasitic lifestyle, these molecules represent highly suitable and attractive targets for the development of effective tick control strategies. Here we review the current knowledge regarding this class of inhibitors in tick biology and tick-borne pathogen transmission, and their potential as targets for future tick control trials. PMID- 28589104 TI - Intratympanic Injection of Dexamethasone and Electrocochleographic Data in Cases of Definite One Sided Refractory Meniere's Disease. AB - INTRODUCTION: Meniere's disease (MD) is a disease of the inner ear that presents itself with repeated episodes of vertigo (96.2%), tinnitus (91.1%), and sensorineural hearing loss (87.7 %). In this article we sought to assess the effects of intratympanic (IT) injections of dexamethasone on definite cases of MD using electrocochleography (ECOG). MATERIALS AND METHODS: In this hospital-based case series in 36 patients, we measured audiometric values and ECOG in all patients before, 1 month and 6 months after 4-mg/mL IT injections of dexamethasone. RESULTS: Four patients (11%) had improved hearing following the intervention. No difference in pure tone audiometry (PTA) was observed following IT injections (P=0.492), while speech discrimination score (SDS) was significantly improved (P=0.008). There was a significant improvement in vertigo 1 month after IT injections (P<0.001), although this effect did not last for 6 months. No significant change in ECOG was observed between before and after treatment (P=0.052). CONCLUSION: IT dexamethasone injections can improve vertigo in definite cases of MD, although it seems that the effect is only temporary. PMID- 28589103 TI - Effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in patients with non-obese type 2 diabetes: a randomized, double blind, clinical trial. AB - BACKGROUND: The prevalent raise of type 2 diabetes (T2D) around the globe, are creating higher risk for cardiovascular diseases (CVDs) and increasing strain on each country's health care budget in the world. Microalbuminuria has appeared as a key parameter in diabetic patients. Microalbuminuria is also related to increased cardiovascular morbidity in people who are non-obese diabetic. Some studies have suggested that consumption of symbiotic foods might help improve the metabolic profile, inflammatory factors and biomarkers of oxidative stress. The aim of trial was to determine the effect of symbiotic supplementation on glycemic control, lipid profiles and microalbuminuria in non-obese T2D. METHODS: In this randomized, double-blind, clinically controlled trial, 70 patients with T2D (28 females, 42 males) were randomly divided into two groups (n = 35 for each group). The symbiotic group (SG) consumed 500 mg/d of symbiotic supplementations containing probiotics (Lactobacillus family, Bifidobacterium family, Streptococus thermophilus), Prebiotics (Fructo oligosaccharide) and B group vitamins (1 mg), lactose (0.5 mg), malt-dextrin, magnesium saturate and the placebo group (PG) consumed capsules filled with row starch and also B group vitamins (1 mg), lactose (0.5 mg), malt-dextrin, magnesium saturate for 9 weeks. Fasting blood glucose (FBG), hemoglobin A1c (HbA1c), blood lipid profiles, 24-h dietary recalls, and anthropometric measurements were measured at the baseline and at the end of trial. SPSS software, version 16 was used to test the data and the results were expressed as mean +/- standard deviation. Paired samples T-Test were used to compare continuous variables within groups. Comparison between different groups was performed through two independent samples T-Test. In the absence of normal distribution, the comparison between the groups was made using non-parametric Wilcoxon on signed ranks and Mann-Whitney tests. P values <0.05 was considered significant. RESULTS: Symbiotic supplementation decreased significantly, FBG (P = 0.05) and HbA1c (P < 0.01). There were no significant differences in lipid profiles within and between the groups at the end of study (P > 0.05). Microalbuminuria (P < 0.05) and HbA1c (P < 0.05) are increased significantly in PG at the end of the study. Furthermore, the mean changes of microalbuminuria and HbA1c experienced significant between the two groups. There was significant reduction in urea between two groups from baseline (P = 0.051). No significant changes in baseline were shown in creatinine among the two groups or within either groups (P > 0.05). CONCLUSION: The consumption of 500 mg/d symbiotic supplementation for 9 weeks could improve the HbA1c, BMI and Microalbuminuria in T2D. Although, No effect has been indicated on FBS, lipid profiles, urea and creatinine. TRIAL REGISTRATION: The trial has been registered in the Iranian Registry of Clinical Trials IRCT2015072223284N1, identifier. Registered 21 May 2016 "retrospectively registered". PMID- 28589105 TI - The Prevalence of Hearing Loss in Patients with Hepatitis B Infection Compared with Healthy Volunteers. AB - INTRODUCTION: Hepatitis B virus is a virus that creates significant hepatic and extra-hepatic complications, with widespread prevalence across the community and body systemic involvement, and can impact on hearing performance. This study aims to evaluate hearing loss among individuals with hepatitis B compared with healthy subjects. MATERIALS AND METHODS: In this case-control study, 83 HBsAg-positive patients with a 1-year history of disease were selected for pure tone audiometry (PTA) testing, while 108 HBsAg-negative patients were selected as the control group. Subjects in both groups were aged 20-40 years. The threshold was set at 25 db for hearing loss. Final data were analyzed using SPSS software. RESULTS: Significant differences were found between the case group and control group in average PTA and hearing loss. There was also a significant difference between the two groups in average PTA at frequencies of 250, 4,000, and 8,000 Hz, but not at speech frequencies of 500, 1,000 and 2,000 Hz, despite the difference in average PTA. CONCLUSION: According to significant differences in average PTA between patients with hepatitis B virus and healthy subjects in this study, hearing loss may be attributed to the presence HBV of in the patient group. PMID- 28589106 TI - Rate of Occult Cervical Lymph Node Involvement in Supraglottic Squamous Cell Carcinoma. AB - INTRODUCTION: To assess the rate of cervical lymph node involvement in patients with supraglottic squamous cell carcinoma (SCC) with no lymph node in clinical assessments and radiological studies. MATERIALS AND METHODS: Fifty-six patients who underwent elective dissection of the cervical lymph node of the second through fourth level were enrolled, and pathologic evaluation of the dissected lymph nodes was performed. Lymph node involvement and association between tumor grade, smoking and gender with lymph node involvement were assessed. RESULTS: The rate of the occult neck metastasis in this series was 37.5%. There was no statistically significant association between lymph node involvement and tumor grade, smoking, or gender. CONCLUSION: Based on the results of our study, we recommend elective bilateral neck dissection in all stages of N0 supraglottic SCC patients. PMID- 28589102 TI - Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections. AB - Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, gamma-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host. PMID- 28589107 TI - Head and Neck Cancers in North-East Iran: A 25 year Survey. AB - INTRODUCTION: Cancers are among the worst noncommunicable diseases around the world. Head and neck cancers are ranked as the fifth most common cancers worldwide. As there are different distributions of risk factors around the world, the incidence of these cancers varies from one place to another. MATERIALS AND METHODS: We conducted a descriptive analytic cross-sectional study, based on census-based records from the private oncology clinic in Mashhad, Iran. Data from 1,075 patients with head and neck cancers were analyzed from 1986 to 2010. We categorized the duration of study into five periods: 1986-1990, 1991-1995, 1996 2000, 2001-2005, and 2006-2010. Head and neck cancers refers to cancers originating from seven sites in the head and neck including the nasal cavity, oral cavity, pharynx, larynx, salivary glands, paranasal sinuses, and thyroid. RESULTS: Data of 1,075 patients were analyzed. 66.2% were male. Mean +/- standard deviation (SD) age at the time of diagnosis was 55.37+/-15.55 years. The most frequent type of head and neck cancer was larynx cancer (36%), followed by pharynx (28.5%), oral (17.5%), thyroid (6.8%), sinus (6.4%), salivary gland (4.10%), and nasal cancer (0.70%). although larynx cancer was the most frequent cancer over the whole study duration, there was a significant (P=0.04) difference in the relative frequency of these cancers across the five time periods. There was a significant difference in mean age between cancer categories (P<0.001). The only cancer with a different mean age at different time periods was pharynx cancer (P=0.02). There was a significant difference between sex and cancer categories (P<0.001). CONCLUSION: Laryngeal cancer was the most common head and neck cancer over the whole duration of this study. The differences in the patterns of other head and neck cancers could be due to geographical differences and also different risk factors and lifestyles all over the world. Further investigations in these fields are suggested in future studies. PMID- 28589108 TI - Asthma and Allergic Rhinitis Correlation in Palm Tree Workers of Jahrom City in 2016. AB - INTRODUCTION: Allergic rhinitis and asthma can be related to occupation. The present study aimed to investigate the correlation between asthma or allergic rhinitis and employment in the palm tree gardens of Jahrom, Iran. MATERIALS AND METHODS: This was a cross-sectional study including 50 palm tree garden workers and a control group of 50 office employees. Data collection included demographics, as well as standard International Study of Asthma and Allergies in Childhood (ISAAC) and A New Symptom-Based Questionnaire for Predicting the Presence of Asthma (ASQ) questionnaires. Data were analyzed using SPSS22. Descriptive statistics, chi-square test, t-test, and logistics regression were used to analyze data. RESULTS: The correlation between asthma and occupation was significant ( P=0.046); and asthma prevalence was higher in palm tree garden workers. However, no relationship was observed between age, duration of employment, smoking cigarettes, hookah, or opium addiction with asthma. Furthermore, in this study, no significant relation was observed between the prevalence of asthma and contact with dust, contact with pets' skin and hair, family history of asthma, or the use of perfume and air freshener. The symptoms of allergic rhinitis (including sneezing, runny nose, and blocked nose) were significantly greater in palm tree garden workers (P=0.038). These symptoms in both workers and office employees were higher in spring. CONCLUSION: In our study, allergic rhinitis and asthma were more common in palm tree garden workers than in the general population. According to our study, people working in this occupation should take necessary precautions. PMID- 28589109 TI - Laryngo-Tracheo-Bronchial Foreign Bodies in Children: Clinical Presentations and Complications. AB - INTRODUCTION: Foreign-body (FB) aspiration in the airway of children is a life threatening clinical situation responsible for many deaths each year. The aim of this study was to evaluate the different clinical presentations, methods of diagnosis, types and complications of FB inhalation in the pediatric age group. MATERIALS AND METHODS: The study included patients who presented with a definitive or suspicious history of FB aspiration. Detailed data for each patient were recorded concerning the age, sex, nature and site of the FB, presenting symptoms and signs, and radiological findings. RESULTS: Fifty-six patients were enrolled in this study. The age of patients ranged from 6 months to 14 years, with a mean age of 4.5 years. Sixty percent of patients were under 3 years of age. The time interval between aspiration of foreign body and onset of diagnosis ranged from 2 hours to 5 months. Thirty-four (60.7%) patients had normal chest X ray findings, while opaque FB was seen in eight patients (14.3%). Signs of bronchitis were seen in five patients (9%), while pneumonia and atelectasis were seen in six (10.7%) and three cases (5.3%), respectively. CONCLUSION: FB aspiration is a life-threatening clinical situation, with children <3 years of age being most commonly affected. FB aspiration must be considered a matter of emergency, especially in the case of organic FBs. This study aimed to increase the awareness of laryngo-tracheo-bronchial FBs, as early diagnosis and management decrease the incidence of complications and make removal of aspirated FB easier. PMID- 28589110 TI - Citelli's Abscess Following Otitis Media: A Case Report. AB - INTRODUCTION: Citelli's abscess is an extratemporal complication of otitis media. It occurs when pus from the mastoid tip trickles down along the posterior belly of the digastric muscle to the occipital and cervical region. It is a very unusual presenting complication of chronic otitis media with no available data in the until now. CASE REPORT: A 10-year-old female was presented to our outpatient department with a 1 month history of hi-grade fever and headache and pain around the left half of the face. During physical examination a huge swelling present in the left temporal and occipital region was observed. The swelling crossed the midline, was tender to touch, and was fluctuant. During otological examination left sided chronic suppurative otitis media, of the attico-antral type with cholesteatoma, and a profuse foul smelling purulent discharge was observed. After complete investigation, drainage of the patient's abscess was performed under general anesthesia. A postaural incision was administered and around 500 ml of pus drained out. Immediately after the operation, the patient showed signs of recovery. After 3 weeks of parenteral antibiotic therapy, the primary focus was debrided by performing left modified radical mastoidectomy. CONCLUSION: Citelli's abscess is a rare complication of otitis media. Urgent radiology, followed by drainage of pus is performed to reduce pain and further progression of the infective process. The primary ear pathology is managed surgically after adequate treatment with intra venous antibiotics. PMID- 28589111 TI - Acute Otitis Media-Induced Gradenigo Syndrome, a Dramatic Response to Intravenous Antibiotic. AB - INTRODUCTION: Petrositis is a rare but severe complication of acute otitis media and mastoiditis. Despite efficient antibiotic therapy, there are still reports of both intratemporal and intracranial complications of otitis media with the potential risk of high morbidity and mortality. Petrositis has traditionally been treated with surgery, but recent advances in imaging, with improved antibiotic treatment, allow more conservative management. CASE REPORT: In this case report we describe the clinical course and treatment of a 33-year-old man with petrous apicitis who presented with severe otalgia, retro-orbital pain, and sixth cranial nerve palsy Gradenigo syndrome. Our patient showed a dramatic response to intravenous antibiotics only, without need for any surgical intervention, even myringotomy. CONCLUSION: It seems that early detection and management of this syndrome before development of other intratemporal or intracranial complications may prevent the need for surgical intervention. PMID- 28589112 TI - Congenital Vomer Agenesis: Report of Two Cases. AB - INTRODUCTION: Congenital vomer agenesis is an extremely rare condition in which the vomer bone does not fully develop, which can lead to septal perforation. CASE REPORT: We report two cases with a defect in the vomer bone in the posteroinferior portion of the septum, found accidentally while performing a pre operative CT scan for nasal obstruction evaluation. They were diagnosed with congenital vomer agenesis. CONCLUSION: There are afew reports of vomer agenesis in literatures. By increasing usage of sinonasal endoscopic examination,we expect to address more cases in the future. PMID- 28589113 TI - Chondroradionecrosis of the Larynx in a Patient with Laryngeal: A Case Report. AB - INTRODUCTION: Actinomycosis of the larynx has been rarely reported in the literature and usually occurs in patients with a history of laryngeal carcinoma and radiation therapy. However, its co-existence with chondroradionecrosis due to radiotherapy is even rarer. The most common site of infection is the cervicofacial region, especially in the submandibular area. CASE REPORT: Here we report a 63-year-old male with a history of chemoradiotherapy because of laryngeal cancer 1 year earlier who presented with laryngeal actinomycosis. After prolonged penicillin-based treatment, the patient underwent thyroid cartilage defect reconstructive surgery because of a laryngocutaneous fistula due to chondroradionecrosis. The diagnosis, work-up, and management of the case are discussed, as well as a review of the literature. CONCLUSION: Although actinomycotic infection of the larynx is rare, it should be considered in the differential diagnosis of laryngeal complaints, especially in immunocompromised patients. PMID- 28589114 TI - Unexpected Findings in a Child with Atypical Hemolytic Uremic Syndrome: An Example of How Genomics Is Changing the Clinical Diagnostic Paradigm. AB - CBL is a tumor suppressor gene on chromosome 11 encoding a multivalent adaptor protein with E3 ubiquitin ligase activity. Germline CBL mutations are dominant. Pathogenic de novo mutations result in a phenotype that overlaps Noonan syndrome (1). Some patients with CBL mutations go on to develop juvenile myelomonocytic leukemia (JMML), an aggressive malignancy that usually necessitates bone marrow transplantation. Using whole exome sequencing methods, we identified a known mutation in CBL in a 4-year-old Caucasian boy with atypical hemolytic uremic syndrome, moyamoya phenomenon, and dysmorphology consistent with a mild Noonan like phenotype. Exome data revealed loss of heterozygosity across chromosome 11q consistent with JMML but in the absence of clinical leukemia. Our finding challenges conventional clinical diagnostics since we have identified a pathogenic variant in the CBL gene previously only ascertained in children presenting with leukemia. The increasing affordability of expansive sequencing is likely to increase the scope of clinical profiles observed for previously identified pathogenic variants and calls into question the interpretability and indications for clinical management. PMID- 28589116 TI - Gene-Environment Interactions-What Can These Tell Us about the Relationship between Asthma and Allergy? AB - Asthma is a common condition, which is associated with atopy and allergic conditions including hay fever, eczema, and food allergies. Asthma and atopy are both complex conditions where genetic and environmental factors are implicated in causation. Interactions between genetic and environmental factors, likely via epigenetic mechanisms, are widely thought to be important in determining the risk for developing asthma and atopy. The nature of the relationship between asthma and atopy is unclear and the answer to the question "does atopy cause asthma?" remains unknown. This review explores the relationship between asthma and atopy from a gene-environment interaction perspective and tackles the question "are similar gene-environment interactions present for asthma and atopy?" The main finding is that gene-environment interactions are described for asthma and atopy in children but these interactions are seldom sought for both asthma and atopy in the same population. In the few instances where a gene-environment interaction is related to both asthma and atopy, there is no consistent evidence that similar interactions are common to asthma and atopy. Many plausible gene-environment interactions for asthma and atopy are yet to be explored. Overall, from the gene environment interaction perspective, there is absence of evidence to better understand the complex relationship between asthma and atopy. PMID- 28589118 TI - Innovative Programmable Bio-Nano-Chip Digitizes Biology Using Sensors That Learn Bridging Biomarker Discovery and Clinical Implementation. AB - The lack of standard tools and methodologies and the absence of a streamlined multimarker approval process have hindered the translation rate of new biomarkers into clinical practice for a variety of diseases afflicting humankind. Advanced novel technologies with superior analytical performance and reduced reagent costs, like the programmable bio-nano-chip system featured in this article, have potential to change the delivery of healthcare. This universal platform system has the capacity to digitize biology, resulting in a sensor modality with a capacity to learn. With well-planned device design, development, and distribution plans, there is an opportunity to translate benchtop discoveries in the genomics, proteomics, metabolomics, and glycomics fields by transforming the information content of key biomarkers into actionable signatures that can empower physicians and patients for a better management of healthcare. While the process is complicated and will take some time, showcased here are three application areas for this flexible platform that combines biomarker content with minimally invasive or non-invasive sampling, such as brush biopsy for oral cancer risk assessment; serum, plasma, and small volumes of blood for the assessment of cardiac risk and wellness; and oral fluid sampling for drugs of abuse testing at the point of need. PMID- 28589119 TI - A "Light Bulb Moment" in Understanding Public Health for Undergraduate Students: Evaluation of the Experiential "This Is Public Health" Photo Essay Task. AB - : A lack of understanding of the importance of public health both within the community and in the tertiary education setting is a significant impediment to improvement in population health. The international campaign "This is Public Health" (TIPH) has been promoted widely as a strategy to increase community awareness and attract and inspire the next generation of public health professionals. This paper describes and evaluates student perceptions of a TIPH photo essay and reflective task in order to explore the pedagogical and learning outcomes related to undergraduate students' public health knowledge. The aim of the analysis was to understand (1) if the task led to increased awareness of public health, and if so, the process of how an understanding of public health develops, and (2) how the interactive nature of the experiential TIPH task leads to depth of understanding. METHODS: This study was undertaken at the University of Newcastle (UON), NSW, Australia. A qualitative study design using a descriptive case study methodology was employed. One-hundred and thirty-nine undergraduate students taking part in a semester-long, introductory public health course provided informed consent and completed a TIPH photo essay and reflective task as a compulsory assessment. Analysis of the student reflections was performed using a general inductive approach to qualitative thematic analysis. RESULTS AND DISCUSSION: Analysis of the reflections indicated that completion of the photo essay and reflective task revealed two strong thematic clusters each with a number of subthemes. The most important findings were the six strong data clusters around students' new and deeper understanding of Public Health. Additionally, four separate data clusters around the pedagogy of the task were revealed. The task also impacted beyond knowledge improvement and academic performance. Students alluded to an increased appreciation of their own health, a new recognition of the importance of preventative health measures, and an improved analytical awareness of health determinants and the measures in place to protect health. CONCLUSION: The TIPH photo essay and reflective task was successful in providing undergraduate students with an experiential activity that resulted in increased knowledge and understanding of public health strategies. The task was a valuable pedagogical experience. PMID- 28589117 TI - XMRV and Public Health: The Retroviral Genome Is Not a Suitable Template for Diagnostic PCR, and Its Association with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Appears Unreliable. AB - A few years ago, a highly significant association between the xenotropic murine leukemia virus-related virus (XMRV) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex debilitating disease of poorly understood etiology and no definite treatment, was reported in Science, raising concern for public welfare. Successively, the failure to reproduce these findings, and the suspect that the diagnostic PCR was vitiated by laboratory contaminations, led to the retraction of the paper. Notwithstanding, XMRV continued to be the subject of researches and public debates. Occasional positivity in humans was also detected recently, even if the data always appeared elusive and non-reproducible. In this study, we discuss the current status of this controversial association and propose that a major role in the unreliability of the results was played by the XMRV genomic composition in itself. In this regard, we present bioinformatic analyses that show: (i) aspecific, spurious annealings of the available primers in multiple homologous sites of the human genome; (ii) strict homologies between whole XMRV genome and interspersed repetitive elements widespread in mammalian genomes. To further detail this scenario, we screen several human and mammalian samples by using both published and newly designed primers. The experimental data confirm that available primers are far from being selective and specific. In conclusion, the occurrence of highly conserved, repeated DNA sequences in the XMRV genome deeply undermines the reliability of diagnostic PCRs by leading to artifactual and spurious amplifications. Together with all the other evidences, this makes the association between the XMRV retrovirus and CFS totally unreliable. PMID- 28589115 TI - Regulatory T Cells in Allergy and Asthma. AB - The immune system's correct functioning requires a sophisticated balance between responses to continuous microbial challenges and tolerance to harmless antigens, such as self-antigens, food antigens, commensal microbes, allergens, etc. When this equilibrium is altered, it can lead to inflammatory pathologies, tumor growth, autoimmune disorders, and allergy/asthma. The objective of this review is to show the existing data on the importance of regulatory T cells (Tregs) on this balance and to underline how intrauterine and postnatal environmental exposures influence the maturation of the immune system in humans. Genetic and environmental factors during embryo development and/or early life will result in a proper or, conversely, inadequate immune maturation with either beneficial or deleterious effects on health. We have focused herein on Tregs as a reflection of the maturity of the immune system. We explain the types, origins, and the mechanisms of action of these cells, discussing their role in allergy and asthma predisposition. Understanding the importance of Tregs in counteracting dysregulated immunity would provide approaches to diminish asthma and other related diseases in infants. PMID- 28589120 TI - A CRISPR New World: Attitudes in the Public toward Innovations in Human Genetic Modification. AB - The potential to genetically modify human germlines has reached a critical tipping point with recent applications of CRISPR-Cas9. Even as researchers, clinicians, and ethicists weigh the scientific and ethical repercussions of these advances, we know virtually nothing about public attitudes on the topic. Understanding such attitudes will be critical to determining the degree of broad support there might be for any public policy or regulation developed for genetic modification research. To fill this gap, we gave an online survey to a large (2,493 subjects) and diverse sample of Americans. Respondents supported genetic modification research, although demographic variables influenced these attitudes conservatives, women, African-Americans, and older respondents, while supportive, were more cautious than liberals, men, other ethnicities, and younger respondents. Support was also was slightly muted when the risks (unanticipated mutations and possibility of eugenics) were made explicit. The information about genetic modification was also presented as contrasting vignettes, using one of five frames: genetic editing, engineering, hacking, modification, or surgery. Despite the fact that the media and academic use of frames describing the technology varies, these frames did not influence people's attitudes. These data contribute a current snapshot of public attitudes to inform policy with regard to human genetic modification. PMID- 28589121 TI - Pancreatic Beta Cell Identity in Humans and the Role of Type 2 Diabetes. AB - Pancreatic beta cells uniquely synthetize, store, and release insulin. Specific molecular, functional as well as ultrastructural traits characterize their insulin secretion properties and survival phentoype. In this review we focus on human islet/beta cells, and describe the changes that occur in type 2 diabetes and could play roles in the disease as well as represent possible targets for therapeutical interventions. These include transcription factors, molecules involved in glucose metabolism and insulin granule handling. Quantitative and qualitative insulin release patterns and their changes in type 2 diabetes are also associated with ultrastructural features involving the insulin granules, the mitochondria, and the endoplasmic reticulum. PMID- 28589123 TI - Editorial: Second Line Treatment of Non-Small Cell Lung Cancer: Clinical, Pathological and Molecular Aspects of Novel Promising Drugs. PMID- 28589124 TI - A Multidisciplinary Phenotyping and Genotyping Analysis of a Mapping Population Enables Quality to Be Combined with Yield in Rice. AB - In this study a mapping population (F8) of ca 200 progeny from a cross between the commercial rice varieties Apo and IR64 has been both genotyped and phenotyped. A genotyping-by-sequencing approach was first used to identify 2,681 polymorphic SNP markers which gave dense coverage of the genome with a good distribution across all 12 chromosomes. The coefficient of parentage was also low, at 0.13, confirming that the parents are genetically distant from each other. The progeny, together with both parents, were grown under irrigated and water restricted conditions in a randomised block design. All grain was harvested to determine variation in yield across the population. The grains were then polished following standard procedures prior to performing the phenotyping analyses. A Gas Chromatography-Mass Spectrometry approach was used to determine the volatile biochemical profiles of each line and after data curation and processing, discriminatory metabolites were putatively identified based on in house and commercial spectral libraries. These data were used to predict the potential role of these metabolites in determining differences in aroma between genotypes. A number of QTLs for yield and for individual metabolites have been identified. Following these combined multi-disciplinary analyses, it proved possible to identify a number of lines which appeared to combine the favourable aroma attributes of IR64 with the favourable (higher) yield potential of Apo. As such, these lines are excellent candidates to assess further as potential genotypes to work up into a new variety of rice which has both good yield and good quality, thus meeting the needs of both farmer and consumer alike. PMID- 28589122 TI - The Future of Bronchopulmonary Dysplasia: Emerging Pathophysiological Concepts and Potential New Avenues of Treatment. AB - Yearly more than 15 million babies are born premature (<37 weeks gestational age), accounting for more than 1 in 10 births worldwide. Lung injury caused by maternal chorioamnionitis or preeclampsia, postnatal ventilation, hyperoxia, or inflammation can lead to the development of bronchopulmonary dysplasia (BPD), one of the most common adverse outcomes in these preterm neonates. BPD patients have an arrest in alveolar and microvascular development and more frequently develop asthma and early-onset emphysema as they age. Understanding how the alveoli develop, and repair, and regenerate after injury is critical for the development of therapies, as unfortunately there is still no cure for BPD. In this review, we aim to provide an overview of emerging new concepts in the understanding of perinatal lung development and injury from a molecular and cellular point of view and how this is paving the way for new therapeutic options to prevent or treat BPD, as well as a reflection on current treatment procedures. PMID- 28589125 TI - Multifunctional Mitochondrial AAA Proteases. AB - Mitochondria perform numerous functions necessary for the survival of eukaryotic cells. These activities are coordinated by a diverse complement of proteins encoded in both the nuclear and mitochondrial genomes that must be properly organized and maintained. Misregulation of mitochondrial proteostasis impairs organellar function and can result in the development of severe human diseases. ATP-driven AAA+ proteins play crucial roles in preserving mitochondrial activity by removing and remodeling protein molecules in accordance with the needs of the cell. Two mitochondrial AAA proteases, i-AAA and m-AAA, are anchored to either face of the mitochondrial inner membrane, where they engage and process an array of substrates to impact protein biogenesis, quality control, and the regulation of key metabolic pathways. The functionality of these proteases is extended through multiple substrate-dependent modes of action, including complete degradation, partial processing, or dislocation from the membrane without proteolysis. This review discusses recent advances made toward elucidating the mechanisms of substrate recognition, handling, and degradation that allow these versatile proteases to control diverse activities in this multifunctional organelle. PMID- 28589126 TI - Myocardial Architecture, Mechanics, and Fibrosis in Congenital Heart Disease. AB - Congenital heart disease (CHD) is the most common category of birth defect, affecting 1% of the population and requiring cardiovascular surgery in the first months of life in many patients. Due to advances in congenital cardiovascular surgery and patient management, most children with CHD now survive into adulthood. However, residual and postoperative defects are common resulting in abnormal hemodynamics, which may interact further with scar formation related to surgical procedures. Cardiovascular magnetic resonance (CMR) has become an important diagnostic imaging modality in the long-term management of CHD patients. It is the gold standard technique to assess ventricular volumes and systolic function. Besides this, advanced CMR techniques allow the acquisition of more detailed information about myocardial architecture, ventricular mechanics, and fibrosis. The left ventricle (LV) and right ventricle have unique myocardial architecture that underpins their mechanics; however, this becomes disorganized under conditions of volume and pressure overload. CMR diffusion tensor imaging is able to interrogate non-invasively the principal alignments of microstructures in the left ventricular wall. Myocardial tissue tagging (displacement encoding using stimulated echoes) and feature tracking are CMR techniques that can be used to examine the deformation and strain of the myocardium in CHD, whereas 3D feature tracking can assess the twisting motion of the LV chamber. Late gadolinium enhancement imaging and more recently T1 mapping can help in detecting fibrotic myocardial changes and evolve our understanding of the pathophysiology of CHD patients. This review not only gives an overview about available or emerging CMR techniques for assessing myocardial mechanics and fibrosis but it also describes their clinical value and how they can be used to detect abnormalities in myocardial architecture and mechanics in CHD patients. PMID- 28589127 TI - Function and Therapeutic Potential of Mesenchymal Stem Cells in Atherosclerosis. AB - Atherosclerosis is a complicated disorder and largely attributable to dyslipidaemia and chronic inflammation. Despite therapeutic advances over past decades, atherosclerosis remains the leading cause of mortality worldwide. Due to their capability of immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have evolved as an attractive therapeutic agent in various diseases including atherosclerosis. Accumulating evidences support the protective role of MSCs in all stages of atherosclerosis. In this review, we highlight the current understanding of MSCs including their characteristics such as molecular markers, tissue distribution, migratory property, immune-modulatory competence, etc. We also summarize MSC functions in animal models of atherosclerosis. MSC transplantation is able to modulate cytokine and chemokine secretion, reduce endothelial dysfunction, promote regulatory T cell function, decrease dyslipidemia, and stabilize vulnerable plaques during atherosclerosis development. In addition, MSCs may migrate to lesions where they develop into functional cells during atherosclerosis formation. Finally, the perspectives of MSCs in clinical atherosclerosis therapy are discussed. PMID- 28589128 TI - Low-Density Lipoprotein Receptor-Related Protein-1 Signaling in Angiogenesis. AB - Low-density lipoprotein receptor-related protein-1 (LRP1) plays multifunctional roles in lipid homeostasis, signaling transduction, and endocytosis. It has been recognized as an endocytic receptor for many ligands and is involved in the signaling pathways of many growth factors or cytokines. Dysregulation of LRP1 dependent signaling events contributes to the development of pathophysiologic processes such as Alzheimer's disease, atherosclerosis, inflammation, and coagulation. Interestingly, recent studies have linked LRP1 with endothelial function and angiogenesis, which has been underappreciated for a long time. During zebrafish embryonic development, LRP1 is required for the formation of vascular network, especially for the venous development. LRP1 depletion in the mouse embryo proper leads to angiogenic defects and disruption of endothelial integrity. Moreover, in a mouse oxygen-induced retinopathy model, specific depletion of LRP1 in endothelial cells results in abnormal development of neovessels. These loss-of-function studies suggest that LRP1 plays a pivotal role in angiogenesis. The review addresses the recent advances in the roles of LRP1 dependent signaling during angiogenesis. PMID- 28589129 TI - Whole-Genome Sequence Analysis of Antimicrobial Resistance Genes in Streptococcus uberis and Streptococcus dysgalactiae Isolates from Canadian Dairy Herds. AB - The objectives of this study are to determine the occurrence of antimicrobial resistance (AMR) genes using whole-genome sequence (WGS) of Streptococcus uberis (S. uberis) and Streptococcus dysgalactiae (S. dysgalactiae) isolates, recovered from dairy cows in the Canadian Maritime Provinces. A secondary objective included the exploration of the association between phenotypic AMR and the genomic characteristics (genome size, guanine-cytosine content, and occurrence of unique gene sequences). Initially, 91 isolates were sequenced, and of these isolates, 89 were assembled. Furthermore, 16 isolates were excluded due to larger than expected genomic sizes (>2.3 bp * 1,000 bp). In the final analysis, 73 were used with complete WGS and minimum inhibitory concentration records, which were part of the previous phenotypic AMR study, representing 18 dairy herds from the Maritime region of Canada (1). A total of 23 unique AMR gene sequences were found in the bacterial genomes, with a mean number of 8.1 (minimum: 5; maximum: 13) per genome. Overall, there were 10 AMR genes [ANT(6), TEM-127, TEM-163, TEM-89, TEM 95, Linb, Lnub, Ermb, Ermc, and TetS] present only in S. uberis genomes and 2 genes unique (EF-TU and TEM-71) to the S. dysgalactiae genomes; 11 AMR genes [APH(3'), TEM-1, TEM-136, TEM-157, TEM-47, TetM, bl2b, gyrA, parE, phoP, and rpoB] were found in both bacterial species. Two-way tabulations showed association between the phenotypic susceptibility to lincosamides and the presence of linB (P = 0.002) and lnuB (P < 0.001) genes and the between the presence of tetM (P = 0.015) and tetS (P = 0.064) genes and phenotypic resistance to tetracyclines only for the S. uberis isolates. The logistic model showed that the odds of resistance (to any of the phenotypically tested antimicrobials) was 4.35 times higher when there were >11 AMR genes present in the genome, compared with <7 AMR genes (P < 0.001). The odds of resistance was lower for S. dysgalactiae than S. uberis (P = 0.031). When the within-herd somatic cell count was >250,000 cells/mL, a trend toward higher odds of resistance compared with the baseline category of <150,000 cells/mL was observed. When the isolate corresponded to a post-mastitis sample, there were lower odds of resistance when compared with non-clinical isolates (P = 0.01). The results of this study showed the strength of associations between phenotypic AMR resistance of both mastitis pathogens and their genotypic resistome and other epidemiological characteristics. PMID- 28589130 TI - The Effect of Botulinum Toxin A on Ischemia-Reperfusion Injury in a Rat Model. AB - INTRODUCTION: While studies using various materials to overcome ischemia reperfusion (IR) injury are becoming increasingly common, studies on the effects of botulinum toxin A (BoTA) on IR injury in musculocutaneous flaps are still limited. The purpose of this study was to examine our hypotheses that BoTA provide protection of musculocutaneous flap from ischemia-reperfusion injury. METHOD: Five days after pretreatment injection (BoTA versus normal saline), a right superior musculocutaneous flap (6 * 1.5 cm in size) was made. Ischemia was created by a tourniquet strictly wrapping the pedicle containing skin and muscle for 8 h. After ischemia, the tourniquet was cut, and the musculocutaneous flap was reperfused. RESULTS: The overall survival percentage of flap after 8 h of pedicle clamping followed by reperfusion was 87.32 +/- 3.67% in the control group versus 95.64 +/- 3.25% in the BoTA group (p < 0.001). The BoTA group had higher expression of CD34, HIF-1alpha, VEGF, and NF-kB comparing to control group in qRT PCR analysis. CONCLUSIONS: In this study, we found that local BoTA preconditioning yielded significant protection against IR injury in a rat musculocutaneous flap model. PMID- 28589132 TI - Corrigendum to "Instructors' Perceptions of Mostly Seated Exercise Classes: Exploring the Concept of Chair Based Exercise". AB - [This corrects the article DOI: 10.1155/2016/3241873.]. PMID- 28589131 TI - The Association of Chemokine Gene Polymorphisms with VKH and Behcet's Disease in a Chinese Han Population. AB - To investigate the association of chemokine gene polymorphisms and Behcet's disease (BD) and Vogt Koyanagi Harada (VKH) disease in a Chinese Han population. A case-control study was performed. Three hundred and seventy-one BD patients, 371 VKH disease patients, and 605 healthy controls were recruited to determine genetic variants of 26 SNPs in 12 chemokine genes with iPLEX Gold genotyping assay and Sequenom MassARRAY or TaqMan SNP assays. In this study, Puncorr values showed a weak association of five SNPs of five genes in BD and three SNPs of three genes in VKH disease. However, after Bonferroni correction, the 26 investigated SNPs showed no significant differences in genetic variants, including genotype and allele frequencies, between BD or VKH disease patients and healthy individuals. Haplotype analysis for the chemokine genes showed a significant association with the TC haplotype of CXCL12 in VKH. Stratified gender analysis and genotype-phenotype analysis were conducted to analyze the association of the 26 SNPs of 12 chemokine genes with BD and VKH disease. However, no significant association was observed after Bonferroni correction. This study showed no association of 26 SNPs in 12 chemokine genes with both BD and VKH disease in a Chinese Han population. PMID- 28589133 TI - Comparisons of Quality of Life and Functional and Oncological Outcomes after Orthotopic Neobladder Reconstruction: Prostate-Sparing Cystectomy versus Conventional Radical Cystoprostatectomy. AB - OBJECTIVES: To compare health-related quality of life and oncological and functional outcomes on erectile function, continence, and voiding function among bladder patients who underwent orthotopic neobladder reconstruction after prostate-sparing cystectomy (PSC) and conventional radical cystoprostatectomy (CRC). METHODS: This is a retrospective cohort study from a single surgeon. During 2007 to 2015, we identified 25 of 186 male patients receiving radical cystectomies due to bladder cancer who underwent orthotopic neobladder reconstruction, 14 patients with PSC and the other 11 patients with CRC. International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-item questionnaire (EORTC-QLQ-C30), and self-catheterizations were used to evaluate functional outcomes in the baseline and 1 year after operation. RESULTS: There were better physical and social functioning scales, less fatigue symptoms, better IIEF (16 versus 3.7, p = 0.01), and less self-catheterization rate (33% versus 89% p = 0.006) in the PSC group. The oncologic outcomes were the same between two groups. CONCLUSIONS: For selected patients with bladder cancer who underwent neobladder reconstruction, prostate-sparing cystectomy provided better sexuality preservation, less daily self-catheterization, and better physical function and social function scales without compromising overall survival. PMID- 28589134 TI - Effect of Hydraulic Retention Time on Anaerobic Digestion of Wheat Straw in the Semicontinuous Continuous Stirred-Tank Reactors. AB - Three semicontinuous continuous stirred-tank reactors (CSTR) operating at mesophilic conditions (35 degrees C) were used to investigate the effect of hydraulic retention time (HRT) on anaerobic digestion of wheat straw. The results showed that the average biogas production with HRT of 20, 40, and 60 days was 46.8, 79.9, and 89.1 mL/g total solid as well as 55.2, 94.3, and 105.2 mL/g volatile solids, respectively. The methane content with HRT of 20 days, from 14.2% to 28.5%, was the lowest among the three reactors. The pH values with HRT of 40 and 60 days were in the acceptable range compared to that with HRT of 20 days. The propionate was dominant in the reactor with HRT of 20 days, inhibiting the activities of methanogens and causing the lower methane content in biogas. The degradation of cellulose, hemicellulose, and crystalline cellulose based on XRD was also strongly influenced by HRTs. PMID- 28589135 TI - Effect of Lower and Upper Body High Intensity Training on Genes Associated with Cellular Stress Response. AB - This study aimed to compare the effect of upper and lower body high intensity exercise (HIE) on select gene expression in athletes. Fourteen elite male artistic gymnasts (age 20.9 +/- 2.6 years; weight 68.6 +/- 7.2 kg; fat free mass 63.6 +/- 6.7 kg; height 1.70 +/- 0.04 m) performed lower and upper body 30 s Wingate Tests (WAnTs) before and after eight weeks of specific HIIT. Two milliliters of blood was collected before and after (5, 30 min, resp.) lower and upper body WAnTs, and select gene expression was determined by PCR. Eight weeks of HIIT caused a significant increase in maximal power (722 to 751 Wat), relative peak power in the lower body WAnTs (10.1 to 11 W/kg), mean power (444 to 464 W), and relative mean power (6.5 to 6.8 W/kg). No significant differences in lower versus upper body gene expression were detected after HIIT, and a significant decrease in the IL6/IL10 ratio was observed after lower (-2?0.57 p = 0.0019) and upper (-2?0.5 p = 0.03) WAnTs following eight weeks of HIIT. It is hypothesized that a similar adaptive response to exercise may be obtained by lower and upper body exercise. PMID- 28589136 TI - Low Molecular Weight Heparin Nebulization Attenuates Acute Lung Injury. AB - BACKGROUND: As acute lung injury (ALI) caused high mortality rate, it is important to explore the protection and treatment of ALI. The aim of the current study is to evaluate the effect of low molecular weight heparin (LMWH) nebulization on attenuating acute lung injury and the associated mechanism. METHODS: The arterial blood gas, total protein content in bronchoalveolar lavage fluid, lung wet/dry weight ratio, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and Akt phosphorylation were evaluated after the ALI rabbits were treated with or without LMWH nebulization. RESULTS: PaO2 was increased and lung wet/dry weight ratio as well as total protein content in BALF was decreased after LMWH nebulization. After the application of LMWH nebulization therapy, the SOD and GSH-Px activity was rebounded and the increase of MDA content was significantly inhibited. The Akt protein phosphorylation level was decreased after LMWH nebulization therapy. CONCLUSIONS: LMWH nebulization treatment can relieve the traumatic ALI in rabbits and inhibit oxidative stress possibly by suppressing the Akt phosphorylation. PMID- 28589137 TI - MicroRNA-16-5p Inhibits Osteoclastogenesis in Giant Cell Tumor of Bone. AB - Giant cell tumor (GCT) of bone is an aggressive skeletal tumor characterized by localized bone resorption. MicroRNA-16-5p (miR-16-5p) has been reported to be downregulated in lesions of patients with GCT, but little is known about its role in GCT. To explore the underlying function of miR-16-5p in GCT, we first detected its expression in patients with GCT. The results showed that osteoclast formation increased, whereas miR-16-5p expression considerably decreased with the severity of bone destruction. Furthermore, we found that miR-16-5p expression considerably decreased with the progression of receptor activator of nuclear factor-kappaB ligand- (RANKL-) induced osteoclastogenesis. Functionally, miR-16-5p mimics significantly reduced RANKL-induced osteoclast formation. However, treatment with an inhibitor of miR-16-5p significantly promoted osteoclastogenesis. These findings reveal that miR-16-5p inhibits osteoclastogenesis and that it may represent a therapeutic target for giant cell tumor of bone. PMID- 28589138 TI - Appendectomy as a Risk Factor for Bacteremic Biliary Tract Infection Caused by Antibiotic-Resistant Pathogens. AB - BACKGROUND/AIMS: Recent evidence has suggested that appendix plays a pivotal role in the development and preservation of intestinal immune system. The aim of this study is to examine whether prior appendectomy is associated with an increased risk for the development of antibiotic-resistant bacteria in bacteremia from biliary tract infection (BTI). METHODS: Charts from 174 consecutive cases of bacteremia derived from BTI were retrospectively reviewed. Using multivariate analysis, independent risk factors for development of antibiotic-resistant bacteria were identified among the clinical parameters, including a history of appendectomy. RESULTS: In total, 221 bacteria strains were identified from 174 BTI events. Of those, 42 antibiotic-resistant bacteria were identified in 34 patients. Multivariate analysis revealed that prior appendectomy (Odds ratio (OR), 3.02; 95% confidence interval (CI), 1.15-7.87; p = 0.026), antibiotic use within the preceding three months (OR, 3.06; 95% CI, 1.26-7.64; p = 0.013), and bilioenteric anastomosis or sphincterotomy (OR, 3.77; 95% CI, 1.51-9.66; p = 0.0046) were independent risk factors for antibiotic-resistant bacteria. CONCLUSIONS: Prior appendectomy was an independent risk factor for the development of antibiotic-resistant bacteria in bacteremia from BTI. PMID- 28589139 TI - Red Cell Storage Duration Does Not Affect Outcome after Massive Blood Transfusion in Trauma and Nontrauma Patients: A Retrospective Analysis of 305 Patients. AB - BACKGROUND: Prolonged storage of packed red blood cells (PRBCs) may increase morbidity and mortality, and patients having massive transfusion might be especially susceptible. We therefore tested the hypothesis that prolonged storage increases mortality in patients receiving massive transfusion after trauma or nontrauma surgery. Secondarily, we considered the extent to which storage effects differ for trauma and nontrauma surgery. METHODS: We considered surgical patients given more than 10 units of PRBC within 24 hours and evaluated the relationship between mean PRBC storage duration and in-hospital mortality using multivariable logistic regression. Potential nonlinearities in the relationship were assessed via restricted cubic splines. The secondary hypothesis was evaluated by considering whether there was an interaction between the type of surgery (trauma versus nontrauma) and the effect of storage duration on outcomes. RESULTS: 305 patients were given a total of 8,046 units of PRBCs, with duration ranging from 8 to 36 days (mean +/- SD: 22 +/- 6 days). The odds ratio [95% confidence interval (CI)] for in-hospital mortality corresponding to a one-day in mean PRBC storage duration was 0.99 (0.95, 1.03, P = 0.77). The relationship did not differ for trauma and nontrauma patients (P = 0.75). Results were similar after adjusting for multiple potential confounders. CONCLUSIONS: Mortality after massive blood transfusion was no worse in patients transfused with PRBC stored for long periods. Trauma and nontrauma patients did not differ in their susceptibility to prolonged PRBC storage. PMID- 28589140 TI - Brain-Derived Neurotropic Factor Val66Met Polymorphism and Posttraumatic Stress Disorder among Survivors of the 1998 Dongting Lake Flood in China. AB - OBJECTIVE: This study mainly aimed to explore the association between brain derived neurotropic factor (BDNF) Val66Met polymorphism and posttraumatic stress disorder (PTSD) among flood survivors in China. METHODS: Individuals who experienced the 1998 Dongting Lake flood in Southeast Huarong, China, were enrolled in this study. Qualified health personnel carried out face-to-face interviews with participants. PTSD was identified using PTSD Checklist-Civilian version (PCL-C). Blood samples were collected from the participants to extract DNA for genotyping. RESULTS: A total of 175 participants were enrolled in this study. The prevalence of PTSD among flood survivors at 17-year follow-up was 16.0% (28/175). Individuals with PTSD were more likely to be female, experience at least three flood-related stressors, experience at least three postflood stressors, and carry the Met than those without PTSD. Compared with Val/Val homozygotes, Met carriers had higher scores of PCL-C (mean +/- standard error: 23.60 +/- 7.23 versus 27.19 +/- 9.48, P < 0.05). Multivariable logistic regression analysis indicated that Met carriers (aOR = 4.76, 95% CI = 1.02-22.15, P < 0.05) were more likely to develop PTSD than Val/Val homozygotes. CONCLUSIONS: Met carriers for BDNF rs6265 are at higher risk of developing PTSD and also exhibit more severe PTSD symptoms than Val/Val homozygotes among flood survivors in China. PMID- 28589141 TI - Postoperative Echocardiographic Reduction of Right Ventricular Function: Is Pericardial Opening Modality the Main Culprit? AB - Echocardiographic reduction of RV function, measured using TAPSE, is a well described phenomenon after cardiac surgery. The aim of the present study was to investigate the relation between the modality of pericardial opening (lateral versus anterior) and the postoperative right ventricular systolic function by comparing echocardiographic parameters in patients undergoing minimally invasive or traditional mitral valve repair. 34 patients with severe mitral regurgitation due to mitral valve prolapse underwent traditional (sternotomy) operation (Group A) or minimally invasive surgery with right anterolateral thoracotomy (Group B). A postoperative TAPSE fall was found in both groups. Group A experienced a significant postoperative TAPSE fall versus Group B with p < 0.0001. PMID- 28589142 TI - Specific-Locus Amplified Fragment Sequencing Reveals Spontaneous Single Nucleotide Mutations in Rice OsMsh6 Mutants. AB - Genomic stability depends in part on an efficient DNA lesion recognition and correction by the DNA mismatch repair (MMR) system. We investigated mutations arising spontaneously in rice OsMsh6 mutants by specific-locus amplified fragment sequencing. Totally 994 single-nucleotide mutations were identified in three mutants and on average the mutation density is about 1/136.72 Kb per mutant line. These mutations were relatively randomly distributed in genome and might be accumulated in generation-dependent manner. All possible base transitions and base transversions could be seen and the ratio of transitions to transversions was about 3.12. We also observed the nearest-neighbor bias around the mutated base. Our data suggests that OsMsh6 (LOC_Os09g24220) is important in ensuring genome stability by recognizing mismatches that arise spontaneously and provides useful information for investigating the function of the OsMsh6 gene in DNA repair and exploiting MMR mutants in rice induced mutation breeding. PMID- 28589144 TI - Asymmetric Dimethylarginine Induced Apoptosis and Dysfunction of Endothelial Progenitor Cells: Role of Endoplasmic Reticulum Stress Pathway. AB - Asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, is a novel risk factor of cardiovascular disease. Endothelial progenitor cells (EPCs) bear typical endothelial characteristics and are thought to contribute to neovascularization by providing new endothelial cells (ECs) after arterial injury. Many studies have shown that ADMA can induce EPC apoptosis and dysfunction, but the underlying mechanism is not well understood. EPCs from umbilical cord blood were cultured in EGM-2 medium with particular growth factors and supplemented with 10% fetal bovine serum. The cells were treated with different concentrations of ADMA (5, 10, and 50 MUmol/L). Endoplasmic reticulum (ER) stress marker levels were examined by western blot analysis. After 24-hour incubation, ADMA induced apoptosis of EPCs and significantly decreased the proliferation, migration, and vasculogenesis capacity of EPCs. We also found that ADMA treatment activated phosphorylated protein kinase RNA-activated-like ER kinase (PERK), a stress sensor protein in the endoplasmic reticulum (ER). The activated PERK induced 78 kDa glucose-regulated protein (GRP-78) and C/EBP homologous protein (CHOP) expression. Additionally, the inhibition of the ER stress pathway by Salubrinal (a specific ER stress inhibitor) can attenuate ADMA induced apoptosis of EPCs. Overall, these observations indicate that ADMA may induce the apoptosis and dysfunction of EPCs through the ER stress pathway. PMID- 28589143 TI - Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Inflammatory Bowel Disease in Mice. AB - Exosomes secreted by mesenchymal stem cells (MSCs) have shown repairing effects on several tissue injury diseases. In this study, we aimed to investigate the effects of exosomes released from human umbilical cord mesenchymal stem cells (hucMSCs) on the treatment of dextran sulfate sodium- (DSS-) induced inflammatory bowel disease (IBD) and to explore the underlying mechanism. We found that indocyanine green (ICG) labeled exosomes homed to colon tissues of IBD mice at 12 hours after injection. Exosomes significantly relieved the severity of IBD in mice as hucMSCs. The expression of IL-10 gene was increased while that of TNF alpha, IL-1beta, IL-6, iNOS, and IL-7 genes was decreased in the colon tissues and spleens of exosomes-treated mice. Furthermore, the infiltration of macrophages into the colon tissues was decreased by exosome treatment in IBD mice. In addition, we provided evidence that in vitro coculture with exosomes inhibited the expression of iNOS and IL-7 in mouse enterocoelia macrophages. Moreover, we found that the expression of IL-7 was higher in the colon tissues of colitis patients than that of healthy controls. Our findings suggest that exosomes from hucMSCs have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages. PMID- 28589145 TI - Metastasis-Associated Protein 1 Is Involved in Angiogenesis after Transarterial Chemoembolization Treatment. AB - BACKGROUND: Transarterial chemoembolization (TACE), a well-established treatment for unresectable hepatocellular carcinoma (HCC), blocks the arterial blood supply to the tumor, which can be short-lived as development of collateral neovessels, leading to the failure of treatment. Metastasis-associated protein 1 (MTA1) is involved in development of tumors and metastases. However, the role of MTA1 in angiogenesis is still obscure. METHODS: We detected the expression of MTA1 and hypoxia-inducible factor-1alpha (HIF-1alpha) and microvessel density (MVD) value in liver tumor tissues and tumor periphery before and after TACE treatment. Hepatocellular carcinoma cell line HepG2, tube formation assay, and chorioallantoic membrane (CAM) assay were applied to explore the mechanism of MTA1 in angiogenesis. RESULTS: We found that expression of MTA1 increased after TACE treatment, especially in tumor periphery, which was accompanied by markedly elevated MVD value, indicating a significant correlation between MTA1 and MVD value. Moreover, MTA1 contributed to neovascularization of residual tumors. Cellular experiments further revealed that MTA1 increased the stability and the expression of HIF-1alpha, and overexpression of MTA1 enhanced tube formation and neovessels of chick embryos. CONCLUSIONS: MTA1 is an active angiogenic regulator; our results shed light on better understanding in neovascularization, which are helpful to predict prognosis of TACE, and provide evidences for intervention to improve therapeutic effects on HCC. PMID- 28589146 TI - Gastrointestinal Bleeding Is an Independent Risk Factor for Poor Prognosis in GIST Patients. AB - A retrospective analysis of prognosis of GIST was used to assess the prognostic effects of hemorrhage of digestive tract induced by mucosal invasion of primary gastrointestinal stromal tumors and related mechanisms. The conclusion is that GISTs with gastrointestinal hemorrhage are more likely to recur, which indicates poor prognosis. Therefore, gastrointestinal hemorrhage may be used as a significant indicator to assess the prognosis of patients. PMID- 28589147 TI - Ultrasonography Is Not Inferior to Fluoroscopy to Guide Extracorporeal Shock Waves during Treatment of Renal and Upper Ureteric Calculi: A Randomized Prospective Study. AB - OBJECTIVE: To investigate whether the visualization modality (ultrasound or fluoroscopy) used during shockwave lithotripsy (SWL) affects the clinical outcome in those instances where both imaging modalities are optional. METHODS: Between November 2014 and July 2016, 114 patients with radiopaque upper urinary tract calculi were randomly assigned to an ultrasound- or fluoroscopy-guided SWL group in a prospective, open-label, single-center study. A standardized SWL protocol was used. The stone-free rate and the positive outcome rate (stone-free or asymptomatic residual fragments <= 4 mm) were compared. RESULTS: The stone-free rate was 52% in the ultrasound-guided group compared to 42% in the fluoroscopy guided group (p = 0.06) and the positive outcome rate was 79% in the ultrasound guided group compared to 70% in the fluoroscopy-guided group (p = 0.28). These results were not significantly different but proved to be noninferior based on a Wilson confidence interval of independent proportions (noninferiority limit 10%). The mean number of SWL sessions was not significantly different (p = 0.4). CONCLUSION: Our study demonstrated that the clinical results of ultrasound-guided SWL were not inferior to the results of fluoroscopy-guided SWL, while no ionizing radiation is needed. PMID- 28589149 TI - Dexamethasone Modulates Nonvisual Opsins, Glucocorticoid Receptor, and Clock Genes in Danio rerio ZEM-2S Cells. AB - Here we report, for the first time, the differential cellular distribution of two melanopsins (Opn4m1 and Opn4m2) and the effects of GR agonist, dexamethasone, on the expression of these opsins and clock genes, in the photosensitive D. rerio ZEM-2S embryonic cells. Immunopositive labeling for Opn4m1 was detected in the cell membrane whereas Opn4m2 labeling shows nuclear localization, which did not change in response to light. opn4m1, opn4m2, gr, per1b, and cry1b presented an oscillatory profile of expression in LD condition. In both DD and LD condition, dexamethasone (DEX) treatment shifted the peak expression of per1b and cry1b transcripts to ZT16, which corresponds to the highest opn4m1 expression. Interestingly, DEX promoted an increase of per1b expression when applied in LD condition but a decrease when the cells were kept under DD condition. Although DEX effects are divergent with different light conditions, the response resulted in clock synchronization in all cases. Taken together, these data demonstrate that D. rerio ZEM-2S cells possess a photosensitive system due to melanopsin expression which results in an oscillatory profile of clock genes in response to LD cycle. Moreover, we provide evidence that glucocorticoid acts as a circadian regulator of D. rerio peripheral clocks. PMID- 28589148 TI - Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis. AB - Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis. PMID- 28589153 TI - Calciphylaxis in the Setting of Alcoholic Cirrhosis: Case Report and Literature Review. AB - Calciphylaxis can be a severe life-threatening dermatologic disease that is a known complication associated with end-stage renal disease. However, multiple non uremic etiologies that are not yet well studied can cause calciphylaxis. We report a rare care of a 40-year-old female with history of alcoholic cirrhosis without any evidence of renal dysfunction who presents with calciphylaxis. PMID- 28589152 TI - Increased mortality in women: sex differences in burn outcomes. AB - BACKGROUND: There is increasing evidence that sex differences may influence responses after thermal injury and affect clinical outcomes. The objective of this study was to evaluate the relationships between sex, thermal injury, body size, and inpatient mortality in burn patients. METHODS: Medical records of adults with >20% total body surface area (TBSA) burn injury admitted to two American Burn Association (ABA)-verified burn centers between 2008 and 2014 were retrospectively reviewed. Injury details and baseline characteristics, including body size as estimated by body surface area (BSA) and body mass index (BMI) were recorded, along with details of the hospital course. The primary outcome of inpatient mortality was compared between sexes. RESULTS: Out of 334 subjects, 60 were women (18%). Median TBSA was 33% (IQR 25-49) in this cohort, with 19% full thickness burns and 30% inhalation injury. Despite no significant difference in age, presence of inhalation injury, TBSA, or depth of burn, women had significantly higher rates of inpatient mortality (45 vs. 29%, P = 0.01). BSA was significantly lower in women vs. men (P < 0.001), but this difference was not more pronounced among non-survivors. There was no difference in BMI between men and women non-survivors. Although not significant (P = 0.28), women succumbed to their injuries sooner than men (day 4 vs. 10 post-injury). CONCLUSIONS: Women are less likely to survive burn injuries and die sooner than men with similar injuries. Body size does not appear to modulate this effect. Burn centers should be aware of the higher mortality risk in women with large burns. PMID- 28589150 TI - Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice. AB - The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10-100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO2, 30 MUg). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNFalpha, IL-1beta, IL-10, COX-2, preproET-1, gp91phox, Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO2 induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO2 were successfully inhibited by tempol. KO2-induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain. PMID- 28589154 TI - Prolonged Ketosis in a Patient With Euglycemic Diabetic Ketoacidosis Secondary to Dapagliflozin. AB - Since the approval of sodium-glucose cotransporter 2 (SGLT2) inhibitors by the US Food and Drug Administration for type 2 diabetes, there have been several reports of euglycemic diabetic ketoacidosis in patients using this class of medication. We present a case of euglycemic diabetic ketoacidosis where ketonemia and glucosuria persisted well beyond the expected effect of dapagliflozin. Our patient is a 50-year-old woman with type 2 diabetes since age 35 who was taking metformin and dapagliflozin. She presented with fatigue, constipation, and 3 days of reduced oral intake. Laboratory data indicated anion gap acidosis, ketonemia, severe hypokalemia, and minimally elevated blood glucose. She was treated with sliding scale short-acting insulin and electrolyte replacement until hospital day 6, when endocrinology was consulted. An insulin drip was initiated due to persistent ketonemia and reopening of the anion gap, despite improved oral intake and normoglycemia. On stopping the insulin drip on day 9, the beta hydroxybutyrate increased again. It finally stabilized within normal range with the initiation of basal subcutaneous insulin. This case indicates that clinical effects of dapagliflozin persist much longer than the reported half-life of 12.9 hours would predict. To prevent this potentially dangerous complication, patients taking SGLT2 inhibitors who become ill should discontinue the medication, undergo ketone evaluation, and start basal insulin, if ketones are positive. In addition, patients should be educated to stop their SGLT2 inhibitor at least 1 week prior to elective procedures. PMID- 28589155 TI - A Severe Case of Cutaneous Adverse Drug Reaction Secondary to a Novice Drug: Idelalisib. AB - Phosphatidylinositol 3-kinase delta (PIK3delta) is a tyrosine kinase essential for B cell survival, making it an important target in the treatment of chronic lymphocytic leukemia. Idelalisib is an inhibitor of PIK3delta demonstrating initial success in disease response, but is now shown to have a decreased overall survival and life-threatening serious adverse events. The following is an unfortunate case of a grade III adverse skin reaction secondary to idelalisib with the likely complication of methicillin-resistant Staphylococcus aureus bacteremia. PMID- 28589156 TI - Outcome of Expedited Rotator Cuff Surgery in Injured Workers: Determinants of Successful Recovery. AB - BACKGROUND: Work-related rotator cuff injuries are a common cause of disability and employee time loss. PURPOSE: To examine the effectiveness of expedited rotator cuff surgery in injured workers who underwent rotator cuff decompression or repair and to explore the impact of demographic, clinical, and psychosocial factors in predicting the outcome of surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Injured workers who were seen at a shoulder specialty program and who underwent expedited arthroscopic rotator cuff decompression or repair were observed for a period of 6 to 12 months based on their type of surgery and recovery trajectory. The primary outcome measure was the American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment Form. The impact of surgery was assessed by whether the change in the ASES score exceeded the minimal clinically important difference (MCID) of 17 points. Secondary outcomes were range of motion (ROM), medication consumption, and work status. RESULTS: One hundred forty-six patients (43 women [29%], 103 men [71%]; mean age, 52 years; SD, 8 years) completed the study. Sixty-seven (46%) patients underwent rotator cuff repair. The mean time between the date the patient consented to have surgery and the date of surgery was 82 (SD, 44) days. There was a statistically significant improvement in ASES score and ROM and work status (52 returned to regular duties and 59 to modified duties) (P < .0001). Eighty-four percent (n = 122) of patients exceeded the MCID of 17 points. Individual factors that affected patient overall disability were preoperative ASES, work status prior to surgery, access to care, and autonomy at work. Achieving a minimal clinically meaningful change was influenced by perceived access to care, autonomy and stress at work, and overall satisfaction with the job. CONCLUSION: Expedited rotator cuff surgery improved disability, ROM, and work status in injured workers. Successful recovery after work-related shoulder injuries may further be facilitated by improving the psychosocial work environment and increasing access to care. PMID- 28589157 TI - Return to Preoperative Function After Autologous Cartilage Implantation of the Knee in Active Military Servicemembers. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) has been shown to provide adequate durability, pain relief, and improved long-term functional outcomes in the average patient, but proof of its efficacy in individuals with greater than average physical demands is scarce. Further knowledge is required to understand which patients may benefit from ACI and to identify which risk factors are associated with failure to return to the preinjury activity level. PURPOSE: To determine the occupational outcomes, rates of reoperation, and variables predictive of suboptimal outcomes after ACI. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: All active-duty military servicemembers in the United States who underwent ACI of the knee between 2004 and 2014 were identified. Demographic information, injury characteristics, surgical variables, and clinical and surgical outcomes were extracted from the medical record. Univariate and multivariate analyses were used to determine significant independent predictors of clinical and surgical failures. RESULTS: A total of 90 patients (91 knees) met the inclusion criteria. The cohort was predominantly male (86%), with a mean age of 34.5 +/- 6.3 years (range, 20-50 years). The most common location of the articular cartilage lesion was the patellofemoral compartment (54 lesions, 59%), and the mean Outerbridge grade and size were 3.8 +/- 0.4 and 4.00 +/- 2.77 cm2 (range, 1.2-15.0 cm2), respectively. A total of 72 patients (79%) had at least 1 previous knee procedure. Nearly three-quarters of patients (71%) underwent concomitant procedures. At a mean follow-up of 59.9 +/- 27.1 months (range, 24.0 140.1 months), 60% of our patients reported significant improvement in knee pain and did not require further surgical intervention. Multivariate analysis identified age <30 years as the only significant independent predictor of both clinical (P = .011) and overall failure (P = .014). Moderate-demand military occupational specialties (P = .036), exclusive involvement of the patellofemoral compartment (P = .045), and use of a periosteal patch (P = .0173) were additionally found to be independent predictors of surgical failure. CONCLUSION: Treatment of articular cartilage defects of the knee with ACI in physically active young individuals can return nearly two-thirds of individuals to daily activity with decreased pain and improved function. Risk factors for failure after ACI surgery were age younger than 30 years, lower demand occupation, exclusive involvement of the patellofemoral compartment, prior microfracture, and use of a periosteal patch. PMID- 28589151 TI - Advanced Role of Neutrophils in Common Respiratory Diseases. AB - Respiratory diseases, always being a threat towards the health of people all over the world, are most tightly associated with immune system. Neutrophils serve as an important component of immune defense barrier linking innate and adaptive immunity. They participate in the clearance of exogenous pathogens and endogenous cell debris and play an essential role in the pathogenesis of many respiratory diseases. However, the pathological mechanism of neutrophils remains complex and obscure. The traditional roles of neutrophils in severe asthma, chronic obstructive pulmonary diseases (COPD), pneumonia, lung cancer, pulmonary fibrosis, bronchitis, and bronchiolitis had already been reviewed. With the development of scientific research, the involvement of neutrophils in respiratory diseases is being brought to light with emerging data on neutrophil subsets, trafficking, and cell death mechanism (e.g., NETosis, apoptosis) in diseases. We reviewed all these recent studies here to provide you with the latest advances about the role of neutrophils in respiratory diseases. PMID- 28589158 TI - Three-Dimensional CT Evaluation of Tunnel Positioning in ACL Reconstruction Using the Single Anteromedial Bundle Biological Augmentation (SAMBBA) Technique. AB - BACKGROUND: Remnant preservation may confer important advantages in the anterior cruciate ligament (ACL)-reconstructed knee. However, the presence of a large remnant may obscure visualization and impair the ability to correctly place tunnels during surgery. PURPOSE: To determine whether tunnel placement during anatomic ACL reconstruction using the single anteromedial bundle biological augmentation (SAMBBA) technique is consistent and precise when a large native remnant is preserved. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Included in this study were 99 patients undergoing an ACL reconstruction during which at least 50% of the native ACL was preserved. The femoral tunnel was created using an outside-in specific guide. The tibial tunnel was positioned in the anteromedial region of the ACL footprint, and the remnant was carefully preserved while drilling and passing the semitendinosus graft through it. Postoperatively, 3-dimensional computed tomography (3D CT) was used to evaluate tunnel placement. The mean tunnel locations were calculated and the standard deviation was used to evaluate precision of positioning. Inter- and intrareader agreement were determined to assess reliability of evaluation of tunnel position. RESULTS: The center of the femoral tunnel was positioned at a mean 19.4% (SD, 2%) of the depth of the notch and a mean 23.1% (SD, 3.5%) of the lateral wall height. The center of the tibial tunnel was positioned at a mean 36.3% (SD, 3.8%) of the anteroposterior length of the tibial plateau and at a mean 47.0% (SD, 2.7%) of the mediolateral width. The small standard deviations demonstrate that this technique allows precise tunnel placement. The tunnel positions achieved were consistent with previous anatomic studies of femoral and tibial anteromedial bundle insertion. Intra- and interobserver reliability were high. CONCLUSION: Three-dimensional CT evaluation demonstrated that despite the presence of a large remnant, placement of femoral and tibial tunnels for anatomic ACL reconstruction using the SAMBBA technique is consistent and precise. PMID- 28589159 TI - Demographics and Injuries Associated With Knee Dislocation: A Prospective Review of 303 Patients. AB - BACKGROUND: Information on the incidence, injury mechanisms, ligament injury patterns, and associated injuries of knee dislocations is lacking in the literature. There is a need to characterize ligament injury patterns and associated injuries in knee dislocations to avoid missing common associated diagnoses and to plan surgical treatment. PURPOSE: To evaluate patient demographics, ligament injury patterns and associated injury patterns, and associated injuries in patients with knee dislocation. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: A total of 303 patients with knee dislocations treated at a single level 1 trauma center were followed prospectively. Injury mechanism; ligament injury patterns; associated neurovascular, meniscal, and cartilage injuries; and surgical complications were recorded. The Schenck knee dislocation classification was used to classify the ligament injury patterns. RESULTS: The mean age at injury was 37.8 +/- 15.3 years. Of the 303 patients included, 65% were male and 35% were female. There was an equal distribution of high-energy and low-energy injuries. Injury to 3 major ligaments was the most common, with Schenck classification type KD III-M constituting 52.4% of the injuries and KD III-L comprising 28.1%. Meniscal injuries and cartilage injuries occurred in 37.3% and 28.3% of patients, respectively. Patients with acute injuries had significantly lower odds of a cartilage injury than those with chronic injuries (odds ratio [OR], 0.28; 95% CI, 0.15-0.50; P < .001). Peroneal nerve injuries were recorded in 19.2% of patients (10.9% partial and 8.3% complete deficit), while vascular injuries were recorded in 5%. The odds of having a common peroneal nerve injury were 42 times greater (P < .001) among those with posterolateral corner injury (KD III-L) than those without. The odds for popliteal artery injury were 9 times greater (P = .001) among those with KD III-L injuries than other ligament injury types. CONCLUSION: Medial-sided bicruciate injuries were the most common injury pattern in knee dislocations. Cartilage injuries were common in chronically treated patients. There was a significant risk of peroneal nerve injury with lateral-sided injuries. PMID- 28589161 TI - Arthroscopic Mechanical Chondroplasty of the Knee Is Beneficial for Treatment of Focal Cartilage Lesions in the Absence of Concurrent Pathology. AB - BACKGROUND: Articular cartilage lacks the ability for intrinsic repair after acute injury, and focal articular cartilage lesions cause significant morbidity worldwide. Arthroscopic debridement (chondroplasty) represents the majority of cartilage procedures of the knee; however, limited data exist regarding outcomes after chondroplasty performed in isolation of concurrent procedures or not as a primary treatment for osteoarthritis (OA). HYPOTHESIS: Arthroscopic mechanical chondroplasty is beneficial for patients with a focal cartilage lesion of the knee in the absence of meniscal pathology or OA. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Potential participants were identified by querying billing data from a 3-year period in a single-surgeon practice, and eligible patients were verified to meet inclusion criteria through electronic medical record review. OA was quantified through Kellgren-Lawrence (KL) scoring. Subjective patient-reported outcome (PRO) scores, including International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Tegner, Lysholm, and Veterans RAND 12-Item Health Survey (VR-12), were collected preoperatively and at follow-up intervals. International Cartilage Repair Society (ICRS) grade and lesion size were determined at arthroscopy. Linear regression was used to determine the effect of baseline score on final follow-up score. Correlated regression equations were used to assess the relationship of covariates and change in PRO scores. RESULTS: Fifty-three of 86 (62%) eligible participants completed postoperative questionnaires at an average of 31.5 months (range, 11.5-57 months). The mean patient age was 37.3 +/- 9.7 years and mean body mass index (BMI) was 27.7 +/- 5.6 kg/m2; 33 (62%) participants were women. The mean treated lesion size was 3.3 +/- 1.9 cm2, of these, 36 (68%) were ICRS grade 2 or 3, and 42 (79%) patients had a KL score of 0 to -2. On average, the cohort demonstrated significant improvement from baseline for almost all PRO scores. Regression analysis of change in score versus baseline indicated participants with lower preoperative scores gained more benefit from chondroplasty. Correlated regression equations showed KL score >0 and male sex had a consistent positive effect on change in PRO scores, high ICRS grade had a consistent negative effect, and lesion size, age, and obesity had no effect. Eight patients (15%) required further surgical intervention within the follow-up period. CONCLUSION: The clinical efficacy of chondroplasty for repair of focal cartilage defects of the knee has not been studied in isolation from concurrent orthopaedic procedures. Our data show that arthroscopic mechanical chondroplasty is beneficial to patients, and response to surgical intervention is correlated with baseline PRO scores, sex, ICRS grade, and KL score. PMID- 28589160 TI - Flexion Posteroanterior Radiographs Affect Both Enrollment for and Outcomes After Injection Therapy for Knee Osteoarthritis. AB - BACKGROUND: Knee injection therapy is less effective for severe osteoarthritis (OA), specifically Kellgren-Lawrence (KL) grade 4. Patient selection for knee injection trials has historically been based on extension anteroposterior (AP) radiographic evaluation; however, emerging evidence suggests that KL grading using a flexion posteroanterior (PA) radiograph more accurately and reproducibly predicts disease severity. The impact of radiographic view on patient selection and outcome after knee injection therapy remains unknown. HYPOTHESIS: A 45 degrees flexion PA radiograph will reveal more advanced knee OA in certain patients. These patients will report worse pre- and postinjection outcomes. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Four raters independently graded extension AP and flexion PA radiographs from 91 patients previously enrolled in a knee injection trial. Patients determined to have KL grade 4 OA by any rater on extension AP radiographs were excluded. Among included patients, those upgraded to KL grade 4 on flexion PA radiographs by at least 2 raters constituted group 2, while all remaining patients constituted group 1. Demographic data and patient-reported outcome scores before injection and at 6 weeks, 3 months, 6 months, and 12 months postinjection were compared between groups. RESULTS: Overall, 64 patients met the inclusion criteria, of which 19 patients (30%) constituted group 2. Compared with group 1, patients in group 2 were older (58.7 vs 52.3 years, P = .02), had worse visual analog scale pain scores before (6.6 vs 5.3, P = .03) and 6 months after injection (5.3 vs 3.5, P = .01), had less improvement in both Lysholm (8.5 vs 20.5, P = .02) and Short Form 12 physical component (-2.2 vs 1.7, P = .03) scores from preinjection to 6 months postinjection, and had less improvement in both Lysholm (1.6 vs 13.1, P = .03) and Knee injury and Osteoarthritis Outcome Score sport subscale (-2.1 vs 16, P = .01) scores from preinjection to 12 months postinjection. CONCLUSION: One in 3 patients considered to have mild to moderate knee OA on extension AP radiography is upgraded to severe knee OA (KL grade 4) on flexion PA radiography. These patients report worse preinjection outcomes, worse pain scores at short-term follow-up, and decreased improvement in knee function scores between 6 months and 1 year postinjection. PMID- 28589162 TI - Age-Specific Prevalence and Clinical Characteristics of Humeral Medial Epicondyle Apophysitis and Osteochondritis Dissecans: Ultrasonographic Assessment of 4249 Players. AB - BACKGROUND: Traction apophysitis of medial epicondyle (MEC) lesions and osteochondritis dissecans (OCD) of the capitellum are common elbow injuries in adolescent baseball players. However, the age-specific prevalence of these pathologies and their influence on elbow pain remain unknown. PURPOSE: To investigate the age-specific prevalence of each MEC lesion and capitellar OCD and to identify the incidence of elbow pain in each condition. STUDY DESIGN: Descriptive epidemiology study. METHODS: Study participants consisted of 4249 baseball players aged 6 to 17 years. A questionnaire was used to assess history of elbow pain, and morphological changes of the elbow joint were assessed using ultrasonography. RESULTS: Regarding MEC lesions, fragmented (FG) and irregular (IR) lesions both reached their greatest respective prevalence at 11 to 12 years of age. After 14 years of age, IR decreased sharply, whereas FG was maintained at approximately 10%. Hypertrophic (HT) lesions increased sharply, reaching over 50% at 16 years of age, while there was a decrease in IR and FG lesions in the same age group. The prevalence of capitellar OCD remained the same (approximately 2%) throughout all ages except for in players aged 7 to 8 years (>7%). Players with MEC lesions had significantly greater prevalence of a history of elbow pain compared with those without (68.0% vs 39.1%) and were at a significantly greater risk for FG lesions (odds ratio [OR], 4.04; 95% CI, 3.16-5.22) compared with IR (OR, 3.22; 95% CI, 2.44-4.27) and HT lesions (OR, 2.03; 95% CI, 1.75-2.36). Players with capitellar OCD also had a significantly greater risk of a history of elbow pain (OR, 2.34; 95% CI, 1.40-4.11). CONCLUSION: Controlling the amount of practice and its intensity according to the condition of each player in the preadolescent and adolescent periods may be important in accelerating bony healing and decreasing preventable elbow pain in adulthood. PMID- 28589163 TI - A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY-PD III). AB - OBJECTIVE: To describe the rationale for a novel study design and baseline characteristics of a disease-modifying trial of isradipine 10 mg daily in early Parkinson disease (PD). METHODS: STEADY-PDIII is a 36-month, Phase 3, parallel group, placebo-controlled study of the efficacy of isradipine 10 mg daily in 336 participants with early PD as measured by the change in the Unified Parkinson Disease Rating Scale (UPDRS) Part I-III score in the practically defined ON state. Secondary outcome measures include clinically meaningful measures of disability progression in early PD: (1) Time to initiation and utilization of dopaminergic therapy; (2) Time to onset of motor complications; (3) Change in nonmotor disability. Exploratory measures include global measures of functional disability, quality of life, change in the ambulatory capacity, cognitive function, and pharmacokinetic analysis. Rationale for the current design and alternative design approaches are discussed. RESULTS: The entire cohort of 336 participants was enrolled at 55 Parkinson Study Group sites in North America. The percentage of male participants were 68.5% with a mean age of 61.9 years (sd 9.0), mean Hoehn and Yahr stage of 1.7 (sd 0.5), mean UPDRS total of 23.1 (sd 8.6), and MoCA of 28.1 (sd 1.4). INTERPRETATION: STEADY-PD III has a novel and innovative design allowing for the determination of longer duration benefits on clinically relevant outcomes in a relatively small cohort on top of the benefit derived from symptomatic therapy. Baseline characteristics are similar to those in previously enrolled de novo PD trials. This study represents a unique opportunity to evaluate the potential impact of a novel therapy to slow progression of PD disability and provide clinically meaningful benefits. PMID- 28589164 TI - CNS Aquaporin-4-specific B cells connect with multiple B-cell compartments in neuromyelitis optica spectrum disorder. AB - OBJECTIVES: Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disorder of the central nervous system (CNS) targeted against aquaporin-4 (AQP4). The origin and trafficking of AQP4-specific B cells in NMOSD remains unknown. METHODS: Peripheral (n = 7) and splenic B cells (n = 1) recovered from seven NMOSD patients were sorted into plasmablasts, naive, memory, and CD27-IgD- double negative (DN) B cells, and variable heavy chain (VH) transcriptome sequences were generated by deep sequencing. Peripheral blood (PB) VH repertoires were compared to the same patient's single-cell cerebrospinal fluid (CSF) plasmablast (PB) VH transcriptome, CSF immunoglobulin (Ig) proteome, and serum Ig proteome. Recombinant antibodies were generated from paired CSF heavy- and light chains and tested for AQP4 reactivity. RESULTS: Approximately 9% of the CSF VH sequences aligned with PB memory B cells, DN B cells, and plasmablast VH sequences. AQP4-specific VH sequences were observed in each peripheral B-cell compartment. Lineage analysis of clonally related VH sequences indicates that CSF AQP4-specific B cells are closely related to an expanded population of DN B cells that may undergo antigen-specific B-cell maturation within the CNS. CSF and serum Ig proteomes overlapped with the VH sequences from each B-cell compartment; the majority of matches occurring between the PB VH sequences and serum Ig proteome. INTERPRETATION: During an acute NMOSD relapse, a dynamic exchange of B cells occurs between the periphery and CNS with AQP4 specific CSF B cells emerging from postgerminal center memory B cells and plasmablasts. Expansion of the PB DN B-cell compartment may be a potential biomarker of NMOSD activity. PMID- 28589165 TI - Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation. AB - OBJECTIVE: Dimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed. METHODS: Primary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL-1beta for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers. RESULTS: In both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL-6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs -146a and -155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells. INTERPRETATION: These results suggest that DMF, and to a lesser extent MMF, mediates the anti-inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti-inflammatory effects independent from altered antioxidant gene expression. PMID- 28589166 TI - Elevated glutamate and lactate predict brain death after severe head trauma. AB - OBJECTIVE: Clinical neurological assessment is challenging for severe traumatic brain injury (TBI) patients in the acute setting. Waves of neurochemical abnormalities that follow TBI may serve as fluid biomarkers of neurological status. We assessed the cerebrospinal fluid (CSF) levels of glutamate, lactate, BDNF, and GDNF, to identify potential prognostic biomarkers of neurological outcome. METHODS: This cross-sectional study was carried out in a total of 20 consecutive patients (mean [SD] age, 29 [13] years; M/F, 9:1) with severe TBI Glasgow Coma Scale <= 8 and abnormal computed tomography scan on admission. Patients were submitted to ventricular drainage and had CSF collected between 2 and 4 h after hospital admission. Patients were then stratified according to two clinical outcomes: deterioration to brain death (nonsurvival, n = 6) or survival (survival, n = 14), within 3 days after hospital admission. CSF levels of brain derived substances were compared between nonsurvival and survival groups. Clinical and neurological parameters were also assessed. RESULTS: Glutamate and lactate are significantly increased in nonsurvival relative to survival patients. We tested the accuracy of both biomarkers to discriminate patient outcome. Setting a cutoff of >57.75, glutamate provides 80.0% of sensitivity and 84.62% of specificity (AUC: 0.8214, 95% CL: 54.55-98.08%; and a cutoff of >4.65, lactate has 100% of sensitivity and 85.71% of specificity (AUC: 0.8810, 95% CL: 54.55 98.08%). BDNF and GDNF did not discriminate poor outcome. INTERPRETATION: This early study suggests that glutamate and lactate concentrations at hospital admission accurately predict death within 3 days after severe TBI. PMID- 28589167 TI - Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy. AB - OBJECTIVE: The aim of this study was to investigate whether the extent and topography of cerebral demyelination correlates with and predicts disease progression in patients with juvenile metachromatic leukodystrophy (MLD). METHODS: A total of 137 MRIs of 46 patients with juvenile MLD were analyzed. Demyelination load and brain volume were quantified using the previously developed Software "clusterize." Clinical data were collected within the German Leukodystrophy Network and included full scale intelligence quotient (FSIQ) and gross motor function data. Voxel-based lesion-symptom mapping (VLSM) across the whole brain was performed to investigate the spatial relationship of cerebral demyelination with motor or cognitive function. The prognostic value of the demyelination load at disease onset was assessed to determine the severity of disease progression. RESULTS: The demyelination load (corrected by the individual brain volume) correlated significantly with gross motor function (r = +0.55) and FSIQ (r = -0.55). Demyelination load at disease onset was associated with the severity of disease progression later on (P < 0.01). VLSM results associated frontal lobe demyelination with loss in FSIQ and more central region demyelination with decline of motor function. Especially progression of demyelination within the motor area was associated with severe disease progression. INTERPRETATION: We were able to show for the first time in a large cohort of patients with juvenile MLD that the demyelination load correlates with motor and cognitive symptoms. Moreover, demyelination load at disease onset, especially the involvement of the central region, predicts severity of disease progression. Thus, demyelination load seems a functionally relevant MRI parameter. PMID- 28589168 TI - First-in-man allopregnanolone use in super-refractory status epilepticus. AB - Super-refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120-h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes. PMID- 28589169 TI - Partial duplication of DHH causes minifascicular neuropathy: A novel mutation detection of DHH. AB - Minifascicular neuropathy (MN) is an extremely rare developmental malformation in which peripheral nerves are composed of many small fascicles. Only one patient with MN with 46XY gonadal dysgenesis (GD) was found to carry a mutation affecting the start codon in desert hedgehog (DHH). We identified an identical novel rearrangement mutation of DHH in two consanguineous families with MN, confirming mutations in DHH cause MN with 46XY GD. The patients with the 46XY karyotype developed GD, whereas a patient with the 46XX karyotype did not. These findings further support that DHH has important roles in perineural formation and male gonadal differentiation. PMID- 28589171 TI - Microarray dataset of transient and permanent DNA methylation changes in HeLa cells undergoing inorganic arsenic-mediated epithelial-to-mesenchymal transition. AB - The novel dataset presented here represents the results of the changing pattern of DNA methylation profiles in HeLa cells exposed to chronic low dose (0.5 uM) sodium arsenite, resulting in epithelial-to-mesenchymal transition, as well as DNA methylation patterns in cells where inorganic arsenic has been removed. Inorganic arsenic is a known carcinogen, though not mutagenic. Several mechanisms have been proposed as to how inorganic arsenic drives carcinogenesis such as regulation of the cell's redox potential and/or epigenetics. In fact, there are gene specific studies and limited genome-wide studies that have implicated epigenetic factors such as DNA methylation in inorganic arsenic-mediated epithelial-to-mesenchymal transition (EMT). However, genome-wide studies about the impact of 1) chronic, low-dose inorganic arsenic exposure on DNA methylation patterns during inorganic arsenic-induced epithelial-to-mesenchymal transition, and 2) the removal inorganic arsenic (reversal) on DNA methylation patterns, is lacking. For this dataset, two replicates were performed with each of the samples - non-treated, inorganic arsenic-treated, and reverse-treated cells. We provide normalized and processed data, and log2 fold change in DNA methylation. The raw microarray data are available through NCBI GEO, accession number GSE95232 and a related research paper has been accepted for published in Toxicology and Applied Pharmacology (Eckstein et al., 2017) [1]. PMID- 28589172 TI - Genome-wide gene expression dataset used to identify potential therapeutic targets in androgenetic alopecia. AB - The microarray dataset attached to this report is related to the research article with the title: "A genomic approach to susceptibility and pathogenesis leads to identifying potential novel therapeutic targets in androgenetic alopecia" (Dey Rao and Sinha, 2017) [1]. Male-pattern hair loss that is induced by androgens (testosterone) in genetically predisposed individuals is known as androgenetic alopecia (AGA). The raw dataset is being made publicly available to enable critical and/or extended analyses. Our related research paper utilizes the attached raw dataset, for genome-wide gene-expression associated investigations. Combined with several in silico bioinformatics-based analyses we were able to delineate five strategic molecular elements as potential novel targets towards future AGA-therapy. PMID- 28589173 TI - Prevalence, Impact, and Management Practice of Dysmenorrhea among University of Gondar Students, Northwestern Ethiopia: A Cross-Sectional Study. AB - BACKGROUND: Dysmenorrhea is an important health problem of adolescents in school, as well as health practitioners, that badly affects the daily activities and quality of life. The aim of this study was to measure the prevalence of dysmenorrhea and assess its management practice among University of Gondar students. METHODS: A cross-sectional study was done from April 06 to May 08, 2016, on female students of University of Gondar. Descriptive and binary logistic regression analyses were used to describe and assess the association between different variables. RESULTS: More than two-thirds (75.3%) of the respondents were nonmedical students and the prevalence of dysmenorrhea was 77.6%. About half (50.6%) of the participants reported that they have a family history of dysmenorrhea and experienced continuous type of pain (53%) which lasts 1-2 days (47.8%). Abdominal spasm (70.4%), back pain (69.7%) fatigue, and weakness (63.5%) were the most commonly experienced dysmenorrhea symptoms. More than half (63%) of the respondents had encountered social withdrawal and decrease in academic performance (51.4%). More than two-thirds (63.8%) of the respondents use home remedies as a primary management option. Ibuprofen and diclofenac were the most commonly used medications to manage dysmenorrhea. CONCLUSIONS: The present study revealed that high proportion of University of Gondar female students had dysmenorrhea. Findings suggest the need for educating adolescent girls on appropriate and effective management of dysmenorrhea. PMID- 28589174 TI - Effectiveness of Positive Thinking Training Program on Nurses' Quality of Work Life through Smartphone Applications. AB - AIM: Job stress is a part of nurses' professional life that causes the decrease of the nurses' job satisfaction and quality of work life. This study aimed to determine the effect of positive thinking via social media applications on the nurses' quality of work life. METHODS: This was a pretest-posttest quasi experimental study design with a control group. The samples were selected among the nurses in two hospitals in Fasa University of Medical Sciences and divided randomly into two interventional (n = 50) and control (n = 50) groups. Positive thinking training through telegrams was sent to the intervention group during a period of 3 months. Data were collected by using Brooks and Anderson's questionnaire of work life quality and analyzed by SPSS 18. RESULTS: The mean total scores of pretest and posttest in the intervention group improved noticeably and there were significant differences between mean scores of quality of work life in pretest and posttest scores in interventional groups (p < 0.001) and in dimensions of work life quality, home life (p < 0.001), work design (p < 0.001), work context (p < 0.001), and work world (p = 0.003). CONCLUSION: This study concluded that positive thinking training via social media application enhanced nurses' quality of work life. This study is necessary to carry out on a larger sample size for generalizing findings better. PMID- 28589177 TI - ARHGEF9 mutations cause a specific recognizable X-linked intellectual disability syndrome. PMID- 28589175 TI - Secondary Ammonium Agonists Make Dual Cation-pi Interactions in alpha4beta2 Nicotinic Receptors. AB - A cation-pi interaction between the ammonium group of an agonist and a conserved tryptophan termed TrpB is a near universal feature of agonist binding to nicotinic acetylcholine receptors (nAChRs). TrpB is one of five residues that form the aromatic box of the agonist binding site, and for the prototype agonists ACh and nicotine, only TrpB makes a functional cation-pi interaction. We report that, in addition to TrpB, a significant cation-pi interaction is made to a second aromatic, TyrC2, by the agonists metanicotine, TC299423, varenicline, and nornicotine. A common structural feature of these agonists, and a distinction from ACh and nicotine, is a protonated secondary amine that provides the cation for the cation-pi interaction. These results indicate a distinction in binding modes between agonists with subtly different structures that may provide guidance for the development of subtype-selective agonists of nAChRs. PMID- 28589178 TI - Intramyocellular lipid excess in the mitochondrial disorder MELAS: MRS determination at 7T. AB - OBJECTIVE: There is a paucity of objective, quantifiable indicators of mitochondrial disease available for clinical and scientific investigation. METHODS: To this end, we explore intramyocellular lipid (IMCL) accumulation noninvasively by 7T magnetic resonance spectroscopy (MRS) as a reporter of metabolic dysfunction in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). We reasoned that mitochondrial dysfunction may impair muscle fat metabolism, resulting in lipid deposition (as is sometimes observed in biopsies), and that MRS is well suited to quantify these lipids. RESULTS: In 10 MELAS participants and relatives, IMCL abundance correlates with percent mitochondrial DNA mutation abundance and with disease severity. CONCLUSIONS: These results indicate that IMCL accumulation is a novel potential disease hallmark in MELAS. PMID- 28589176 TI - ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation. AB - OBJECTIVE: We aimed to generate a review and description of the phenotypic and genotypic spectra of ARHGEF9 mutations. METHODS: Patients with mutations or chromosomal disruptions affecting ARHGEF9 were identified through our clinics and review of the literature. Detailed medical history and examination findings were obtained via a standardized questionnaire, or if this was not possible by reviewing the published phenotypic features. RESULTS: A total of 18 patients (including 5 females) were identified. Six had de novo, 5 had maternally inherited mutations, and 7 had chromosomal disruptions. All females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. Symptoms presented in early childhood with delayed motor development alone or in combination with seizures. Intellectual disability was severe in most and moderate in patients with milder mutations. Males with severe intellectual disability had severe, often intractable, epilepsy and exhibited a particular facial dysmorphism. Patients with mutations in exon 9 affecting the protein's PH domain did not develop epilepsy. CONCLUSIONS: ARHGEF9 encodes a crucial neuronal synaptic protein; loss of function of which results in severe intellectual disability, epilepsy, and a particular facial dysmorphism. Loss of only the protein's PH domain function is associated with the absence of epilepsy. PMID- 28589179 TI - The role of surgeons on the development and performance of endoscopy. AB - Endoscopy is being frequently performed for both diagnostic and therapeutic applications in surgical practice. Surgery, as a scientific area, has an important role in the propagation of therapeutic endoscopic procedures. The contribution of surgeons to the evolution of endoscopic applications and its practice is a triggering factor for the improvement of endoscopic instruments and their widespread use. Training and education on basic diagnostic and therapeutic surgical endoscopy should be implemented as part of general surgery residency core program, according to accepted standardized criteria, in order for general surgeons to perform endoscopic applications in the future. In light of this information, it can be concluded that endoscopy training and skills should be standardized within accepted general principles. Standards to be used during post graduate endoscopic practice should be precisely stated. In addition to accreditation of both surgeons and endoscopic centers, theoretical and practical education programs should be composed and organized. PMID- 28589170 TI - Immune and myodegenerative pathomechanisms in inclusion body myositis. AB - Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM. PMID- 28589180 TI - Treatment of pilonidal disease by phenol application. AB - The literature indicates various approaches regarding the properties of phenol, the target patient group, and the complication and recurrence rates. Although phenol is most frequently used to treat the fistulated form of the disease, it can also be applied for other types. The overall success and complication rates of the application is reported as 62-95% and 0%-2%, respectively. Phenol treatment in pilonidal disease can be used more frequently as an alternative method with acceptable success, complication, and recurrence rates. PMID- 28589181 TI - Reliability of fine needle aspiration biopsy in large thyroid nodules. AB - OBJECTIVE: Fine needle aspiration biopsy provides one of the most important data that determines the treatment algorithm of thyroid nodules. Nevertheless, the reliability of fine needle aspiration biopsy is controversial in large nodules. The aim of this study was to evaluate the adequacy of fine needle aspiration biopsy in thyroid nodules that are four cm or greater. MATERIAL AND METHODS: We retrospectively examined 219 patients files who underwent thyroidectomy for thyroid nodules that were greater than four centimeter between May 2007 and December 2012. Seventy-four patients with hyperthyroidism, and 18 patients without preoperative fine needle aspiration cytology were excluded from the study. Histopathologic results after thyroidectomy were compared with preoperative cytology results, and sensitivity and specificity rates were calculated. RESULTS: False-negativity, sensitivity and specificity rates of fine needle aspiration biopsy of thyroid nodules were found to be 9.7%, 55.5%, and 85%, respectively. Within any nodule of the 127 patients, 28 (22.0%) had thyroid cancer. However, when only nodules of at least 4 cm were evaluated, thyroid cancer was detected in 22 (17.3%) patients. CONCLUSION: In this study, fine needle aspiration biopsy of large thyroid nodules was found to have a high false negativity rate. The limitations of fine-needle aspiration biopsy should be taken into consideration in treatment planning of thyroid nodules larger than four centimeters. PMID- 28589182 TI - Recurrent laryngeal nerve injury and hypoparathyroidism rates in reoperative thyroid surgery. AB - OBJECTIVE: Reoperative thyroid surgery is rare and has a high complication rate. This retrospective cohort study was performed to determine the recurrent laryngeal nerve injury and hypoparathyroidism rates after reoperative thyroid surgery in two university hospitals in Benghazi, Libya. MATERIAL AND METHODS: All consecutive patients who underwent reoperative thyroid surgery between January 2002 and July 2014 were included retrospectively. The cohort was divided according to whether the reoperation was in the previously operated lobe or both lobes (ipsilateral group), or only in the previously non-operated lobe (contralateral group). RESULTS: Of the 73 patients, 66 were female and seven were male. The median age was 37 (19-80) years. Nine (12.3%), five (6.8%), and one (1.4%) patient developed postoperative transient hypocalcemia, transient recurrent laryngeal nerve palsy, and permanent recurrent laryngeal nerve injury, respectively. None of the patients developed permanent hypocalcemia. The ipsilateral group had a higher rate of permanent recurrent laryngeal nerve injury after reoperation than the contralateral group (3.1% vs. 0%). It also had higher rates of transient recurrent laryngeal nerve injury (12.5% vs. 2.4%) and transient hypocalcemia (28.1% vs. 0%), but the two groups did not differ in terms of permanent hypocalcemia rates (both 0%). CONCLUSION: Reoperative thyroid surgery is technically challenging with a high incidence of complications. The ipsilateral group had more complications after reoperative thyroid surgery than the contralateral group. Hemi- or total thyroidectomy at the primary surgery is recommended to reduce the frequency of reoperative thyroid surgery. PMID- 28589183 TI - The clinicopathologic characteristics and prognostic factors of gastroesophageal junction tumors according to Siewert classification. AB - OBJECTIVE: The treatment of gastroesophageal junction tumors remains controversial due to confusion on whether they should be considered as primary esophageal or as gastric tumors. The incidence of these tumors with poor prognosis has increased, thus creating scientific interest on gastroesophageal cancers. Esophagogastric cancers are classified according to their location by Siewert, and the treatment of each type varies. We evaluated the prognostic factors and differences in clinicopathologic factors of patients with gastroesophageal junction tumor, who have been treated and followed-up in our clinics. MATERIAL AND METHODS: We retrospectively analyzed 187 patients with gastroesophageal junction tumors who have been operated and treated in the Oncology Department between 2005 and 2014. The chi-square test was used to evaluate differences in clinicopathologic factors among Siewert groups I, II and III. Prognostic factors were analyzed by univariate and multivariate analysis. RESULTS: The median age of our patients was 62 years, and approximately 70% was male. Nineteen patients (10.2%) had Siewert I tumors, 40 (21.4%) II, and the remaining 128 (64.4%) had Siewert III tumors. Siewert III tumors were at more advanced pathologic and T stages. Preoperative chemoradiotherapy was mostly applied to Siewert group I patients. There was no difference between the 3 groups in terms of recurrence. While the median overall survival and 2-year overall survival rate were 26.6 months and 39.6%, the median disease free survival and disease free survival rates were 16.5 months and 30.1%, respectively. The N stage, pathologic stage, vascular invasion, lymphatic invasion, perineural invasion, surgical margin, and grade were associated with both overall survival and disease free survival, while pathologic stage and presence of recurrence were significant factors for overall survival. The median disease free survival for Siewert III tumors was 20 months, 11.3 month for Siewert I tumors, and 14 months for Siewert II tumors, but the finding was not statistically significant (p=0.08). CONCLUSION: Although gastroesophageal junction tumors were grouped according to their location and they exerted different clinicopathologic properties, their prognosis was similar. PMID- 28589184 TI - A new approach in bowel preparation before colonoscopy in patients with constipation: A prospective, randomized, investigator-blinded trial. AB - OBJECTIVE: Enema administration in the morning of routine colonoscopy is known to be useless. However, the potential bowel cleansing effects of distal colon emptying with enema prior to purgatives are not known. The aim of this study is to investigate the effects of enema use before purgatives in preparation for colonoscopy. MATERIAL AND METHODS: Two hundred twenty-seven patients were randomly assigned into three groups; enema before purgative use, enema after purgative use, and no enema. Patients were compared in terms of age, sex, BMI, Rome III constipation criteria, history of abdominal surgery, tolerance to the preparation procedure, complications during preparation such as nausea, vomiting, headache and dizziness, cecal insertion time, total duration of colonoscopy, polyp determination rate and colonic cleansing based on the Boston Bowel Preparation Scale. RESULTS: One hundred two (44.9%) patients were male and 125 (55.1%) female. The mean age and BMI was 55.4+/-11.8 years and 28.8+/-4.7, respectively. No difference was observed between the groups in terms of sex, age, or BMI. The number of fulfilled Rome criteria and of previous abdominal surgeries were significantly higher in females than in men. Right colon Boston Bowel Preparation Scale score was higher in the group using enemas before purgatives than the scores of other groups. This improvement was statistically significant in the female patient group with higher constipation rate. CONCLUSIONS: Use of enemas before purgatives in patients with constipation significantly improves adequacy of right colon cleansing. PMID- 28589186 TI - Extremely rare presentation of an omphalomesenteric cyst in a 61-year-old patient. AB - The umbilicus is remaining scar tissue from the umbilical cord in the fetus. If the omphalomesenteric duct in the umbilicus is not properly closed, an ileal umbilical fistula, sinus formation, cysts, or, most commonly, Meckel's diverticulum can develop. The others are very rare and mostly occur in the pediatric population. We describe herein a 61-year-old female with a giant omphalomesenteric cyst presented as an asymptomatic infraumbilical mass. To our knowledge, this is the oldest patient reported and the largest cyst described in the literature. The diagnosis of a painless abdominal mass frequently suggests malignancy in older patients. But, extremely rare conditions can be detected, such as an omphalomesenteric cyst. PMID- 28589185 TI - Damage-control laparoscopic partial cholecystectomy with an endoscopic linear stapler. AB - OBJECTIVE: Several damage-control procedures have been described in the literature in case of severe Calot's triangle inflammation and fibrosis. In this report, we describe patients who underwent laparoscopic partial cholecystectomy using an endoscopic linear stapler. MATERIALS AND METHODS: Five patients with acute cholecystitis underwent laparoscopic partial cholecystectomy in our clinic between January - December 2011. All patients had severe fibrosis and inflammation of Calot's triangle. The anterior and posterior walls of the gallbladder were totally resected if possible. The gallbladder was transected at its neck or Hartmann's pouch, leaving a remnant gallbladder pouch behind. RESULTS: Five patients had laparoscopic partial cholecystectomy with an endoscopic linear stapler. The main symptom of all patients on admission to the emergency room was abdominal pain. The mean time for the surgical procedure was 140 minutes (range, 120-180 minutes). Inflammation and fibrosis of Calot's triangle was detected in all patients during surgery and a phlegmonous gallbladder was detected in one patient. Surgical drains were used in all patients and no biliary leakage was detected. Remnant common bile duct calculi were detected in one patient and this patient underwent endoscopic retrograde cholangiopancreatography one month after surgery. CONCLUSIONS: When a reliable view of Calot's triangle cannot be obtained due to severe inflammation and fibrosis during laparoscopy, laparoscopic partial cholecystectomy seems to be a safe and feasible alternative to open surgery with an acceptable morbidity rate. PMID- 28589187 TI - Editorial comment on: Laparoscopic resection for colorectal diseases: short-term outcomes of a single center. PMID- 28589188 TI - Editorial comment on: Analysis of the Istanbul Forensic Medicine Institute expert decisions on recurrent laryngeal nerve injuries due to thyroidectomy between 2008 2012. PMID- 28589189 TI - A facile approach toward 1,2-diazabenzo[ghi]perylene derivatives: structures and electronic properties. AB - A new class of pyridazine fused aromatics, 1,2-diazabenzo[ghi]perylenes, is conveniently synthesized from 2,7-dihydroxynaphthalene via intermolecular oxidative coupling followed by a condensation reaction. These new compounds are fully characterized via X-ray crystallographic analysis, optical spectroscopy and electrochemistry, in addition to DFT calculations. They show a twisted structure and unique P-/P- and M-/M-enantiomer pairs are observed in their single crystals. They exhibit intramolecular charge transfer character and emit at a longer wavelength with a larger Stokes shift compared with their all-carbon analog. PMID- 28589190 TI - Cholesteric liquid crystals in living matter. AB - Liquid crystals play an important role in biology because the combination of order and mobility is a basic requirement for self-organisation and structure formation in living systems. Cholesteric liquid crystals are omnipresent in living matter under both in vivo and in vitro conditions and address the major types of molecules essential to life. In the animal and plant kingdoms, the cholesteric structure is a recurring design, suggesting a convergent evolution to an optimised left-handed helix. Herein, we review the recent advances in the cholesteric organisation of DNA, chromatin, chitin, cellulose, collagen, viruses, silk and cholesterol ester deposition in atherosclerosis. Cholesteric structures can be found in bacteriophages, archaea, eukaryotes, bacterial nucleoids, chromosomes of unicellular algae, sperm nuclei of many vertebrates, cuticles of crustaceans and insects, bone, tendon, cornea, fish scales and scutes, cuttlebone and squid pens, plant cell walls, virus suspensions, silk produced by spiders and silkworms, and arterial wall lesions. This article specifically aims at describing the consequences of the cholesteric geometry in living matter, which are far from being fully defined and understood, and discusses various perspectives. The roles and functions of biological cholesteric liquid crystals include maximisation of packing efficiency, morphogenesis, mechanical stability, optical information, radiation protection and evolution pressure. PMID- 28589191 TI - Is there any fundamental difference between ionic, covalent, and others types of bond? A canonical perspective on the question. AB - The concept of chemical bonding is normally presented and simplified through two models: the covalent bond and the ionic bond. Expansion of the ideal covalent and ionic models leads chemists to the concepts of electronegativity and polarizability, and thus to the classification of polar and non-polar bonds. In addition, the intermolecular interactions are normally viewed as physical phenomena without direct correlation to the chemical bond in any simplistic model. Contrary to these traditional concepts of chemical bonding, recently developed canonical approaches demonstrate a unified perspective on the nature of binding in pairwise interatomic interactions. This new canonical model, which is a force-based approach with a basis in fundamental molecular quantum mechanics, confirms much earlier assertions that in fact there are no fundamental distinctions among covalent bonds, ionic bonds, and intermolecular interactions including the hydrogen bond, the halogen bond, and van der Waals interactions. PMID- 28589192 TI - Modeling the absorption spectrum of the permanganate ion in vacuum and in aqueous solution. AB - The absorption spectrum of the MnO4- ion has been a test-bed for quantum-chemical methods over the last decades. Its correct description requires highly-correlated multiconfigurational methods, which are incompatible with the inclusion of finite temperature and solvent effects due to their high computational demands. Therefore, implicit solvent models are usually employed. Here we show that implicit solvent models are not sufficiently accurate to model the solvent shift of MnO4-, and we analyze the origins of their failure. We obtain the correct solvent shift for MnO4- in aqueous solution by employing the polarizable embedding (PE) model combined with a range-separated complete active space short range density functional theory method (CAS-srDFT). Finite-temperature effects are taken into account by averaging over structures obtained from ab initio molecular dynamics simulations. The explicit treatment of finite-temperature and solvent effects facilitates the interpretation of the bands in the low-energy region of the MnO4- absorption spectrum, whose assignment has been elusive. PMID- 28589193 TI - Free-standing monolayer films of ordered colloidal particles. AB - We report a novel method for the fabrication of large area, free standing monolayer films of close-packed colloidal particles. The method involves creating a free-standing, wet film of colloidal dispersion containing mono-dispersed hard particles (such as polystyrene or silica) mixed with smaller and softer polymer particles. During drying, hard particles present in the free standing film arrange in a hexagonal close-packed structure in a monolayer while the softer particles fill the interstices, and deform and coalesce to produce a continuous matrix around the hard particles. The deformation of the soft particles dissipates the stress generated during drying thereby preventing rupture of the monolayer film. The method is facile and very general, applicable to a large variety of colloidal particles. The monolayer films exhibit strong iridescence indicating potential application in photonic devices. PMID- 28589194 TI - Surface science under reaction conditions: CO oxidation on Pt and Pd model catalysts. AB - Platinum and palladium are frequently used as catalytic materials, for example for the oxidation of CO. This is one of the most widely studied reactions in the field of surface science. Although seemingly uncomplicated, it remains an active and interesting topic, which is partially explained by the push to conduct experiments on model systems under relevant reaction conditions. Recent developments in the surface-science methodology have allowed obtaining chemical and structural information on the active phase of model catalysts. Tools of the trade include near-ambient-pressure X-ray photoelectron spectroscopy, high pressure scanning tunneling microscopy, high-pressure surface X-ray diffraction, and high-pressure vibrational spectroscopy. Interpretation is often aided by density functional theory in combination with thermodynamic and kinetic modeling. In this review, results for the catalytic oxidation of CO obtained by these techniques are compared. On several of the Pt and Pd surfaces, new structures develop in excess O2. For Pt, this requires a much larger excess of O2 than for Pd. Most of these structures also develop in pure O2 and are identified as (surface) oxides. A large body of evidence supports the conjecture that these oxides are more reactive than the corresponding O-covered metallic surfaces under similar conditions, although still debated in the literature. An outlook on this developing field, including directions that move away from CO oxidation towards more complex chemistry, concludes this review. PMID- 28589195 TI - Patterned oscillating topographical changes in photoresponsive polymer coatings. AB - The light-induced surface topography of a liquid crystal polymer coating is brought into a patterned oscillatory deformation. A dichroic photo-responsive azobenzene is co-aligned with the planar oriented nematic liquid crystal network molecules which makes the surface deformation sensitive to polarized UV light. Locally selective actuation is achieved in coatings with a complex alignment pattern. Dynamic oscillation, as controlled by the actuation and relaxation kinetics of the polymer, is obtained by a continuous change in the polarization of the UV source. The atypical deformation at the defect lines between the domains is of special interest. The amplitude and presence of the oscillation can be manipulated by changing the ratio between blue and UV light and by varying the ambient temperature of the coating. PMID- 28589196 TI - Cancer cell targeting driven by selective polyamine reactivity with glycine propargyl esters. AB - Rapidly growing cancer cells have increased levels of intracellular polyamines compared to normal, healthy tissues. Based on the selective reactivity of glycine propargyl esters, probes were synthesized that show evidence for selective polyamine reactivity, which was then applied for selective cancer cell imaging studies. PMID- 28589197 TI - Coordination strategy-induced selective C-H amination of 8-aminoquinolines. AB - In this study, we broke through the directing function of the amide group. The coordination interaction between metal and directing-group enhanced the reactivity of the substrate. Using this strategy, we realized the selective amination of 8-aminoquinolines at the C5 position via employing azoles as the source of amine. Various kinds of 8-aminoquinolines and different substituted azoles were compatible to afford the corresponding C-N coupling products. PMID- 28589198 TI - Excellent peroxidase mimicking property of CuO/Pt nanocomposites and their application as an ascorbic acid sensor. AB - Due to low cost and high stability, the applications of inorganic nanomaterials as efficient alternatives to natural enzymes are drawing much attention. In this work, novel CuO/Pt nanocomposites with high peroxidase-like activity were designed and applied for the colorimetric detection of ascorbic acid (AA). The nanocomposites were prepared by decorating Pt NPs on the surface of CuO nanosheets, which displayed good uniformity and showed improved distribution and stability. The catalytic activity of the prepared CuO/Pt nanocomposites was tested against various chromogenic substrates in the presence of H2O2, which displayed efficient peroxidase-like activity and high catalytic stability against temperature. The catalytic mechanism of the CuO/Pt nanocomposites was investigated by hydroxyl radical detection. The peroxidase-like activity decreased significantly in the presence of AA. On the basis of the inhibition property, a colorimetric biosensor was constructed by using the CuO/Pt nanocomposites for the detection of AA. It showed a high selectivity against amino acids, carbohydrates and normal ions. Thus, this work provides new insights into the application of inorganic nanocomposite-based nanozymes in the biosensing field. PMID- 28589199 TI - The strategies for identification and quantification of SUMOylation. AB - SUMOylation is a post-translational modification that plays critical roles in a multitude of cellular processes including transcription, cellular localization, DNA repair and cell cycle progression. Similar to ubiquitin, the small ubiquitin like modifiers (SUMOs) are covalently attached to the epsilon amino group of lysine residues in the substrates. To understand the regulation and the dynamics of post-translational modifications (PTMs), the identification and quantification of SUMOylation is strictly needed. Although numerous proteomic approaches have been developed to identify hundreds of SUMO target proteins, the number of SUMOylation signatures identified from endogenous modified proteins is limited, and the identification of precise acceptor sites remains a challenge due to the low abundance of in vivo SUMO-modified proteins and the high activity of SUMO specific proteases in cell lysates. In particular, very few sensitive strategies are available for accurate quantification of SUMO target proteins. Within the past decade, mass spectrometry-based strategies have been the most popular technologies for proteome-wide studies of SUMOylation. Recently, some new approaches such as single-molecule detection have been introduced. In this review, we summarize the strategies that have been exploited for enrichment, purification and identification of SUMOylation substrates and acceptor sites as well as ultrasensitive quantification of SUMOylation. We highlight the emerging trends in this field as well. PMID- 28589200 TI - Protein hydration in living cells probed by Fourier transform infrared (FT-IR) spectroscopic imaging. AB - An application of disrelation mapping to Fourier transform infrared (FT-IR) spectroscopic imaging datasets is provided to reveal different H-bonded water species within a mammalian cell. 2D correlation analysis revealed a disrelation peak at (3420 cm-1, 3220 cm-1), showing the existence of a specific water band at around 3220 cm-1 whose variation of absorbance did not follow the trend of water molecules with a well-coordinated H-bonding network. Disrelation maps constructed with disrelation intensities between (3420 cm-1, 3220 cm-1) and (3420 cm-1, 1540 cm-1) reveal that the disruption of the water network occurs around the interfacial regions between the cell and media, indicating the disintegration of the H-bonding network of bulk water due to the entrapment of water by the protein inside the cell. This hydration effect also becomes apparent around the area adjacent to the cellular nucleus, reflecting the fact that protein synthesis mainly occurs in this region. These results clearly show the presence of different molecular states of water inside living cells, which are not readily identified by conventional analysis methods. PMID- 28589201 TI - Magnesia-stabilised zirconia solid electrolyte assisted electrochemical investigation of iron ions in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K. AB - Production of metallic iron through molten oxide electrolysis using inert electrodes is an alternative route for fast ironmaking without CO2 emissions. The fact that many inorganic oxides melt at ultrahigh temperatures (>1500 K) challenges conventional electro-analytical techniques used in aqueous, organic and molten salt electrolytes. However, in order to design a feasible and effective electrolytic process, it is necessary to best understand the electrochemical properties of iron ions in molten oxide electrolytes. In this work, a magnesia-stabilised zirconia (MSZ) tube with a closed end was used to construct an integrated three-electrode cell with a "MSZ|Pt|O2 (air)" assembly functioning as the solid electrolyte, the reference electrode and also the counter electrode. Electrochemical reduction of iron ions was systematically investigated on an iridium (Ir) wire working electrode in a SiO2-CaO-MgO-Al2O3 molten slag at 1723 K by cyclic voltammetry (CV), square wave voltammetry (SWV), chronopotentiometry (CP) and potentiostatic electrolysis (PE). The results show that the electroreduction of the Fe2+ ion to Fe on the Ir electrode in the molten slag follows a single two-electron transfer step, and the rate of the process is diffusion controlled. The peak current on the obtained CVs is proportional to the concentration of the Fe2+ ion in the molten slag and the square root of scan rate. The diffusion coefficient of Fe2+ ions in the molten slag containing 5 wt% FeO at 1723 K was derived to be (3.43 +/- 0.06) * 10-6 cm2 s-1 from CP analysis. However, a couple of subsequent processes, i.e. alloy formation on the Ir electrode surface and interdiffusion, were found to affect the kinetics of iron deposition. An ECC mechanism is proposed to account for the CV observations. The findings from this work confirm that zirconia-based solid electrolytes can play an important role in electrochemical fundamental research in high temperature molten slag electrolytes. PMID- 28589202 TI - Electrochemiluminescence behavior of AgNCs and its application in immunosensors based on PANI/PPy-Ag dendrite-modified electrode. AB - In this study, hyperbranched polyethyleneimine-protected silver nanoclusters (hPEI-AgNCs) with excellent electrochemiluminescence (ECL) emission in the presence of coreactant K2S2O8 were prepared by chemical reduction of silver ions (silver nitrate) coordinated with dendrigraft polymer, and successfully used for the construction of an ECL immunosensor. Polyaniline (PANI)/polypyrrole (PPy) silver (Ag) dendrites with good electrical conductivity and biocompatibility were electropolymerized on the surface of indium tin oxide (ITO) electrode as carriers. Porous ZnO sphere-loaded hPEI-AgNCs-induced signal amplification strategies were integrated exquisitely and applied sufficiently. Taking carcinoembryonic antigen (CEA) as an example, under optimal conditions, the CEA concentration was determined to be in the range of 10-3 ng mL-1-100 ng mL-1 and with a detection limit of 0.4 pg mL-1 using this method; it exhibited excellent selectivity, high stability, and acceptable fabrication reproducibility. It was anticipated that hPEI-AgNCs would have promising applications in green, selective, and sensitive detection of target analytes in the future. PMID- 28589203 TI - Tuning the sound speed in macroporous polymers with a hard or soft matrix. AB - In this paper, we investigate the factors affecting the sound speed in air-filled macroporous polymer materials at ultrasound frequencies. Due to the presence of large proportion of gas, these porous materials present high compressibility and, as a consequence, low sound speed which may fall down to values as low as 40 m s 1. Using an emulsion-templating method, we synthesize macroporous samples with similar porous structures but with three different matrices, i.e. a hard poly(styrene-divinylbenzene (DVB)) matrix, a soft epoxy-modified polydimethylsiloxane (PDMS) matrix and a very soft polyaddition PDMS matrix. We characterize the matrix mechanical properties by measuring both the bulk modulus K0 and the shear modulus G0. Next, we compare the sound speed measured in porous samples with porosity varying from 0 to 50%. We show that, in agreement with theoretical predictions, the sound speed is mainly controlled by two parameters, the porosity value and the K0/G0 ratio of the polymer matrix. These parameters may be used to control the sound propagation in porous polymers, which opens the way to the realization of gradient-index materials. PMID- 28589204 TI - Stepwise self-assembly of a discrete molecular honeycomb using a multitopic metallo-organic ligand. AB - Self-assembly of a metallo-organic ligand, composed of an inner uncomplexed 120 degrees -bis(terpyridine) and an outer extended free 120 degrees bis(terpyridine) linked by a triple <-tpy-Ru2+-tpy-> connector, and complexed with Zn2+, gave rise to a discrete planar supramolecular honeycomb patterned fractal. The central metallo-hexagon was surrounded by six identical metallo hexagons which perfectly mimicked the natural simple honeycomb structure. PMID- 28589205 TI - Effects of Teriparatide and Sequential Minodronate on Lumbar Spine Bone Mineral Density and Microarchitecture in Osteoporosis. AB - The trabecular bone score (TBS) is a new surrogate for trabecular bone microarchitecture assessment, independent of bone mineral density (BMD), calculated from pixel gray-level variations in the lumbar spine (LS) dual-energy X-ray absorptiometry (DXA) image. Although Teriparatide (TPTD) increased LS-BMD as well as TBS in 2 years, the precise time-course of these parameters was not well known. The aim of this study was to determine the changes in LS-BMD and the TBS in osteoporotic patients treated with TPTD, followed by minodronate (MINO). Primary osteoporotic patients with a low LS-BMD (T-score < -2.5) and/or at least one vertebral fracture were treated with TPTD subcutaneously at 20 ug/day for 12 24 months, followed by MINO (orally at 50 mg/once monthly) for 12 months. LS-BMD and the TBS were measured at 0, 3, 6, 12, and 24 months after the initiation of TPTD treatment, and 12 months after the initiation of MINO. The increments of LS BMD, significant at 6 months, increased until 12 months, whereas the increments of TBS, significant at 3 months (0.035 +/- 0.011; p = 0.045 vs. the baseline), stabilized until 12 months. TPTD treatment, followed by 12 months of MINO, maintained both BMD and the TBS. Comparing the increments of the TBS to those of LS-BMD, our results indicate that TPTD treatment improved trabecular microarchitecture faster than mineralization. TPTD treatment, followed by MINO, can maintain both BMD and the TBS. PMID- 28589206 TI - MicroRNAs and Fracture Healing. AB - MicroRNAs (miRNAs) are small molecules found to have major regulatory roles in many biological processes. This review aims to provide an overview of the recent advances in knowledge of the role of miRNAs in fracture healing and bone repair. A search of the published literature was performed (using the PubMed database) to include all relevant studies published in English. These studies were then reviewed and the results condensed into this review paper. MiRNAs have now been shown to have significant alterations in expression levels in bone tissue in the presence of fractures. This is thought to be related to the process of fracture healing through effects on osteoblasts and bone growth factors. These small molecules are also detectable in the circulation where their expression appears to be altered by the presence of fractures. Although further research is required in this area, miRNAs may present an opportunity for future clinical applications in fracture management. PMID- 28589208 TI - Cues of control modulate the ascription of object ownership. AB - Knowing whether an object is owned and by whom is essential to avoid costly conflicts. We hypothesize that everyday interactions around objects are influenced by a minimal sense of object ownership grounded on respect of possession. In particular, we hypothesize that tracking object ownership can be influenced by any cue that predicts the establishment of individual physical control over objects. To test this hypothesis we used an indirect method to determine whether visual cues of physical control like spatial proximity to an object, temporal priority in seeing it, and touching it influence this minimal sense of object ownership. In Experiment 1 participants were shown a neutral object located on a table, in the reaching space of one of two characters. In Experiment 2 one character was the first to find the object then another character appeared and saw the object. In Experiments 3 and 4, spatial proximity, temporal priority, and touch are pitted against each other to assess their relative weight. After having seen the scenes, participants were required to judge the sensibility of sentences in which ownership of the object was ascribed to one of the two characters. Responses were faster when the objects were located in the reaching space of the character to whom ownership was ascribed in the sentence and when ownership was ascribed to the character who was the first to find the object. When contrasting the relevant cues, results indicate that touch is stronger than temporal priority in modulating the ascription of object ownership. However, all these effects were also influenced by contextual social cues like the gender of both characters and participants, the presence of a third party observer, and the co-presence of characters. Consistently with our hypothesis, results indicate that many different cues of physical control influence the ascription of ownership in daily social contexts. PMID- 28589207 TI - Prediction and in vitro verification of potential CTL epitopes conserved among PRRSV-2 strains. AB - Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is the causative agent of one of the most important porcine diseases with a high impact on animal health, welfare, and production economy. PRRSV exhibits a multitude of immunoevasive strategies that, in combination with a very high mutation rate, has hampered the development of safe and broadly protective vaccines. Aiming at a vaccine inducing an effective cytotoxic T cell response, a bioinformatics approach was taken to identify conserved PRRSV-derived peptides predicted to react broadly with common swine leukocyte antigen (SLA) class I alleles. Briefly, all possible 9- and 10-mer peptides were generated from 104 complete PRRSV type 2 genomes of confirmed high quality, and peptides with high binding affinity to five common SLAs were identified combining the NetMHCpan and positional scanning combinatorial peptide libraries binding predictions. Predicted binders were prioritized according to genomic conservation and SLA coverage using the PopCover algorithm. From this, 53 peptides were acquired for further analysis. Binding affinity and stability of a subset of 101 peptide-SLA combinations were validated in vitro for 4 of the 5 SLAs. Eventually, 23% of the predicted peptide-SLA combinations showed to form complexes with a dissociation half-life >=30 min. Additionally, combining the two prediction methods proved to be more robust across alleles than either method used alone in terms of predicted-to-observed correlations. In summary, our approach represents a finely tuned epitope prediction pipeline providing a rationally selected ensemble of peptides for future in vivo experiments with pigs expressing the included SLAs. PMID- 28589210 TI - Abdominal distention and continuous feeding intolerance after intraperitoneal kidney transplant: Questions. PMID- 28589209 TI - Bioengineering in renal transplantation: technological advances and novel options. AB - End-stage kidney disease (ESKD) is one of the most prevalent diseases in the world with significant morbidity and mortality. Current modes of renal replacement therapy include dialysis and renal transplantation. Although dialysis is an acceptable mode of renal replacement therapy, it does have its shortcomings, which include poorer life expectancy compared with renal transplantation, risk of infections and vascular thrombosis, lack of vascular access and absence of biosynthetic functions of the kidney. Renal transplantation, in contrast, is the preferred option of renal replacement therapy, with improved morbidity and mortality rates and quality of life, compared with dialysis. Renal transplantation, however, may not be available to all patients with ESKD. Some of the key factors limiting the availability and efficiency of renal transplantation include shortage of donor organs and the constant risk of rejection with complications associated with over immunosuppression respectively. This review focuses chiefly on the potential roles of bioengineering in overcoming limitations in renal transplantation via the development of cell-based bioartificial dialysis devices as bridging options before renal transplantation, and the development of new sources of organs utilizing cell and organ engineering. PMID- 28589212 TI - Erratum to: A New Deep-Sea Suctorian-Nematode Epibiosis (Loricophrya-Tricoma) from the Blanes Submarine Canyon (NW Mediterranean). PMID- 28589211 TI - Abdominal distention and continuous feeding intolerance after intraperitoneal kidney transplant: Answers. PMID- 28589213 TI - [Individualized infection medicine : Challenges and opportunities]. PMID- 28589214 TI - [Individualized treatment strategies for Clostridium difficile infections]. AB - Upon hospitalization, up to 15.5% of patients are already colonized with a toxigenic Clostridium difficile strain (TCD). The rate of asymptomatic colonization is 0-3% in healthy adults and up to 20-40% in hospitalized patients. The incidence and mortality of C. difficile infection (CDI) has significantly increased during recent years. Mortality lies between 3 and 14%. CDI is generally caused by intestinal dysbiosis, which can be triggered by various factors, including antibiotics or immune suppressants. If CDI occurs, ongoing antibiotic therapy should be discontinued. The choice of treatment is guided by the clinical situation: Mild courses of CDI should be treated with metronidazole. Oral vancomycin is suitable as a first-line therapy of mild CDI occurring during pregnancy and lactation, as well as in cases of intolerance or allergy to metronidazole. Severe courses should be treated with vancomycin. Recurrence should be treated with vancomycin or fidaxomicin. Multiple recurrences should be treated with vancomycin or fidaxomicin; if necessary, a vancomycin taper regimen may also be used. An alternative is fecal microbiota transplant (FMT), with healing rates of more than 80%. Bezlotoxumab is the first available monoclonal antibody which neutralizes the C. difficile toxin B, and in combination with an antibiotic significantly reduces the rate of a new C. difficile infection compared to placebo. A better definition of clinical and microbiota-associated risk factors and the ongoing implementation of molecular diagnostics are likely to lead to optimized identification of patients at risk, and an increasing individualization of prophylactic and therapeutic approaches. PMID- 28589215 TI - Utilities of scrotal flap for reconstruction of penile skin defects after severe burn injury. AB - OBJECTIVE: In the present study, we aimed to present our experience of an effective two-stage surgical approach using scrotal skin flap for patients with penile skin defects following severe burn injury. MATERIALS AND METHODS: A total of 17 patients with penile skin defects underwent scheduled two-stage reconstruction using scrotal skin flap from January 2004 to October 2016. Patients, who were selected as eligible candidates for scrotal flap, exhibited a wide range of indications, including iatrogenic injuries (e.g., diathermy treatment after circumcision), scalding, flame injuries and electrical burns. During the first stage, the denuded penis secondary to debridement was temporally embedded in scrotal skin flap through an intrascrotal tunnel created between the skin and darto's fascia. During the second stage, the skin around the penis was separated and divided from the scrotum after incising the scrotal skin at the ventral penile base. After a mean follow-up of 30 months, the reconstructed penises yielded satisfactory aesthetic outcomes and maintained erectile function. RESULTS: The mean age of patients was 35 years (19-55 years), and the median follow-up was 30 months (12-60 months). No major perioperative complication occurred except for dehiscence of scrotal skin after 2nd stage in three patients, and split-thickness skin grafts were applied for recovery of scrotum. Of 17 cases, 15 patients (88.2%) were in satisfactory cosmetic appearance. All patients regained penile sensation and normal voiding function in standing position. The International Index of Erectile Function (IIEF) was used to assess sexual function, with 13 patients (76.5%) reported normal erectile function, while the rest 4 reported mild erectile dysfunction. With regards to intercourse satisfaction domain, encouraging results indicated a total of 17 patients resumed sexual intercourse after surgery. In overall satisfaction domain, 11/17 (64.7%) reported a satisfaction from "very" to "moderately" with their overall sex life and sexual relationship with their partners, while only one patient reported "moderately dissatisfied" with his overall sex life. CONCLUSIONS: We report a series of particular cases, including rare iatrogenic injury (diathermy treatment after circumcision) and severe compound electrical injury. Meanwhile, we show our successful experience that scrotal skin flap could be used as an effective surgical alternative to cover severe burn injury wound in male genitalia. The scrotal flap, with higher anti-infection ability and flexible contexture, is available for recovering penile skin defects following severe burn injury resulting in good aesthetic and sexual outcomes. PMID- 28589216 TI - Mathematical modeling of the ethanol fermentation of cashew apple juice by a flocculent yeast: the effect of initial substrate concentration and temperature. AB - In this work, the effect of initial sugar concentration and temperature on the production of ethanol by Saccharomyces cerevisiae CCA008, a flocculent yeast, using cashew apple juice in a 1L-bioreactor was studied. The experimental results were used to develop a kinetic model relating biomass, ethanol production and total reducing sugar consumption. Monod, Andrews, Levenspiel and Ghose and Tyagi models were investigated to represent the specific growth rate without inhibition, with inhibition by substrate and with inhibition by product, respectively. Model validation was performed using a new set of experimental data obtained at 34 degrees C and using 100 g L-1 of initial substrate concentration. The model proposed by Ghose and Tyagi was able to accurately describe the dynamics of ethanol production by S. cerevisiae CCA008 growing on cashew apple juice, containing an initial reducing sugar concentration ranging from 70 to 170 g L-1 and temperature, from 26 to 42 degrees C. The model optimization was also accomplished based on the following parameters: percentage volume of ethanol per volume of solution (%V ethanol/V solution), efficiency and reaction productivity. The optimal operational conditions were determined using response surface graphs constructed with simulated data, reaching an efficiency and a productivity of 93.5% and 5.45 g L-1 h-1, respectively. PMID- 28589217 TI - A prospective randomized comparison of micropercutaneous nephrolithotomy (Microperc) and retrograde intrarenal surgery (RIRS) for the management of lower pole kidney stones. AB - OBJECTIVE: To make a comparison between the safety and efficacy of micropercutaneous nephrolithotomy (microperc) and retrograde intrarenal surgery (RIRS) for the management of lower pole kidney stones up to 15 mm. PATIENTS AND METHODS: 60 patients presenting with solitary lower pole kidney stones up to 15 mm were included in the study between March 2013 and December 2015. Patients were randomized into Microperc or RIRS groups with computer-generated numbers. RESULTS: The mean stone size was 10.6 (5-15) and 11.5 (7-15) mm for Microperc and RIRS groups, respectively (P = 0.213). In the Microperc group, the scopy time was 158.5 s, while in the RIRS group, the scopy time was 26.6 s (P = 0.001). The hospitalization period in the Microperc group was 542 h, while it was 19 h in the RIRS group (P = 0.001). No statistical differences were observed during the operating time, pre-operative-post-operative hemoglobin (Hb), serum creatinine, and estimated glomerular filtration speed (e-GFR) values and stone-free rates. No intraoperative complications were observed in either of the groups, while post operative complications were observed in six patients in Microperc Group and five patients belonging to the RIRS Group (P = 0.922). CONCLUSIONS: Both Microperc and RIRS are safe and effective alternatives, and have similar stone clearance and complication rates for the management of lower pole kidney stones up to 15 mm in diameter. However, prolonged hospital stay and scopy times are the main disadvantages of Microperc and further research is needed to evaluate the renal tubular damages caused by both of these methods. PMID- 28589218 TI - HN, N, Calpha and Cbeta assignments of the two periplasmic domains of Neisseria meningitidis DsbD. AB - DsbD is a disulfide bond reductase present in the inner membrane of many Gamma Proteobacteria. In the human pathogen Neisseria meningitidis, DsbD is required for viability and represents a potential target for the development of antibiotics. Here we report the chemical shift assignments (HN, N, Calpha and Cbeta) for the reduced and oxidized forms of the two periplasmic domains of N. meningitidis DsbD, n-NmDsbD and c-NmDsbD. The backbone amide resonances in all four forms were completely assigned, and the secondary structures for the core regions of the proteins were calculated using 13Calphabeta shifts. The reduced and oxidized forms of each domain have similar secondary shifts suggesting they retain the same fold. We anticipate that these data will provide an important basis for studying the interaction between n-NmDsbD and c-NmDsbD, which is required for electron transfer across the bacterial cytoplasmic membrane. PMID- 28589219 TI - 1H, 13C, and 15N backbone chemical shift assignments of 4E-BP144-87 and 4E-BP144 87 bound to eIF4E. AB - The eukaryotic translational initiation factor 4G (eIF4G) interacts with the cap binding protein eIF4E through a consensus binding motif, Y(X)4LPhi (where X is any amino acid and Phi is a hydrophobic residue). 4E binding proteins (4E-BPs), which also contain a Y(X)4LPhi motif, regulate the eIF4E/eIF4G interaction. The non- or minimally-phosphorylated form of 4E-BP1 binds eIF4E, preventing eIF4E from interacting with eIF4G, thus inhibiting translation initiation. 4EGI-1, a small molecule inhibitor of the eIF4E/eIF4G interaction that is under investigation as a novel anti-cancer drug, has a dual activity; it disrupts the eIF4E/eIF4G interaction and stabilizes the binding of 4E-BP1 to eIF4E. Here, we report the complete backbone NMR resonance assignment of an unliganded 4E-BP1 fragment (4E-BP144-87). We also report the near complete backbone assignment of the same fragment in complex to eIF4E/m7GTP (excluding the assignment of the last C-terminus residue, D87). The chemical shift data constitute a prerequisite to understanding the mechanism of action of translation initiation inhibitors, including 4EGI-1, that modulate the eIF4E/4E-BP1 interaction. PMID- 28589221 TI - An efficient method to generate conditional knockout cell lines for essential genes by combination of auxin-inducible degron tag and CRISPR/Cas9. AB - Generation of cells with a loss-of-function mutation in a gene (knockout cells) is a valuable technique for studying the function of a given gene product. However, if the product of the target gene is essential for cell viability, conditional knockout cell lines must be generated. Recently, as gene editing technology using CRISPR/Cas9 has developed, it has become possible to produce conditional knockout cell lines using this technique. However, to obtain final conditional knockout cell lines, it is necessary to perform several experiments with multiple complicated steps. In this paper, we introduce an easy and efficient method to generate conditional knockout cell lines based on combining auxin-inducible degron (AID) technology with CRISPR/Cas9 gene editing. Our method only requires performing a single transfection and is therefore an easy and rapid method to obtain a conditional knockout cell line. PMID- 28589220 TI - Binding Properties of Split tRNA to the C-terminal Domain of Methionyl-tRNA Synthetase of Nanoarchaeum equitans. AB - The C-terminal domain of methionyl-tRNA synthetase (MetRS-C) from Nanoarchaeum equitans is homologous to a tRNA-binding protein consisting of 111 amino acids (Trbp111) from Aquifex aeolicus. The crystal structure of MetRS-C showed that it existed as a homodimer, and that each monomer possessed an oligonucleotide/oligosaccharide-binding fold (OB-fold). Analysis using a quartz crystal microbalance indicated that MetRS-C freshly isolated from N. equitans was bound to tRNA. However, binding of the split 3'-half tRNA species was stronger than that of the 5'-half species. The T-loop and the 3'-end regions of the split 3'-half tRNA were found to be responsible for the binding. The minimum structure for binding to MetRS-C might be a minihelix-like stem-loop with single-stranded 3'-terminus. After successive duplications of such a small hairpin structure with the assistance of a Trbp-like structure, the interaction of the T-loop region of the 3'-half with a Trbp-like structure could have been evolutionarily replaced by RNA-RNA interactions, along with many combinational tertiary interactions, to form the modern tRNA structure. PMID- 28589223 TI - Erratum to: Risk of over-diagnosis of hypotension in children: a comparative analysis of over 50,000 blood pressure measurements. PMID- 28589222 TI - Prescribing of medication for attention deficit hyperactivity disorder among young people in the Clinical Practice Research Datalink 2005-2013: analysis of time to cessation. AB - The aim of this study was to examine the time to cessation of ADHD medication amongst young people with ADHD aged 16 in the period 2005-2013. Previous studies of prescribing in primary care reported high rates of medication cessation amongst 16 and 17 year olds with ADHD. The examination of trends since the introduction of new NICE guidance in 2008 will support service planning and improvement of outcomes over the vulnerable transition period from child to adult services. We used primary care records from the Clinical Practice Research Datalink and identified cases prescribed ADHD medication at the time of their 16th birthday during the study period. The outcome was time to medication cessation from the age of 16. Cessation of medication was defined as occurring at the beginning of a gap of over 6 months in prescriptions. 1620 cases were included. The median time to cessation was 1.51 years (95% CI 1.42-1.67).The estimated probability of remaining on medication was 0.63 (95% CI 0.61-0.65) at age 17 (i.e., at 1 year) and 0.41 (95% CI 0.39-0.43) at age 18. Young people with ADHD remain at high risk of cessation of medication during the transition from child to adult services. Despite the restriction that only primary care prescribing data were available, the results suggest continuing disparity between expected levels of symptom persistence and continuation of medication. PMID- 28589224 TI - Molecular engineering of L-aspartate-alpha-decarboxylase for improved activity and catalytic stability. AB - beta-Alanine is an important precursor for the production of food additives, pharmaceuticals, and nitrogen-containing chemicals. Compared with the conventional chemical routes for beta-alanine production, the biocatalytic routes using L-aspartate-alpha-decarboxylase (ADC) are more attractive when energy and environment are concerned. However, ADC's poorly understood properties and its inherent mechanism-based inactivation significantly limited the application of this enzyme. In this study, three genes encoding the ADC enzymes from Escherichia coli, Corynebacterium glutamicum, and Bacillus subtilis were overexpressed in E. coli. Their properties including specific activity, thermostability, and mechanism-based inactivation were characterized. The ADC enzyme from B. subtilis, which had higher specific activity and thermostability than the others, was selected for further study. In order to improve its activity and relieve its mechanism-based inactivation by molecular engineering so as to improve its catalytic stability, a high-throughput fluorometric assay of beta-alanine was developed. From a library of 4000 mutated enzymes, two variants with 18-22% higher specific activity and 29-64% higher catalytic stability were obtained. The best variant showed 50% higher beta-alanine production than the wild type after 8 h of conversion of L-aspartate, showing great potential for industrial biocatalytic production of beta-alanine. PMID- 28589225 TI - Characterization of the newly isolated omega-oxidizing yeast Candida sorbophila DS02 and its potential applications in long-chain dicarboxylic acid production. AB - alpha, omega-Dicarboxylic acids (DCAs) are multipurpose chemicals widely used in polymers, perfumes, plasticizers, lubricants, and adhesives. The biotransformation of DCAs from alkanes and fatty acids by microorganisms has attracted recent interest, since synthesis via chemical oxidation causes problems in terms of the environment and safety. We isolated an omega-oxidizing yeast from a wastewater disposal facility of a petrochemical factory by chemostat enrichment culture. The haploid strain identified as Candida sorbophila DS02 grew on glucose and dodecane, exhibiting greater cell shrinkage on the latter. In flask cultures with mixed alkanes (C10-16) and fatty acid methyl esters (C10-16), DS02 used mixed alkanes simultaneously unlike Candida tropicalis and Yarrowia lipolytica and showed high substrate resistance. In flask cultures with acrylic acid-a known inhibitor of beta-oxidation-DS02 produced 0.28 g/l dodecanedioic acid (DDDA) from dodecane, similar to wild-type C. tropicalis ATCC 20336. In fed-batch fermentation, DS02 produced 9.87 g/l DDDA, which was 5.7-fold higher than wild type C. tropicalis. These results suggest that C. sorbophila strain DS02 has potential applications for the large-scale production of DCA. PMID- 28589226 TI - The first acidobacterial laccase-like multicopper oxidase revealed by metagenomics shows high salt and thermo-tolerance. AB - Metagenomics is a powerful tool that allows identifying enzymes with novel properties from the unculturable component of microbiomes. However, thus far only a limited number of laccase or laccase -like enzymes identified through metagenomics has been subsequently biochemically characterized. This work describes the successful bio-mining of bacterial laccase-like enzymes in an acidic bog soil metagenome and the characterization of the first acidobacterial laccase-like multicopper oxidase (LMCO). LMCOs have hitherto been mostly studied in fungi and some have already found applications in diverse industries. However, improved LMCOs are in high demand. Using molecular screening of a small metagenomic library (13,500 clones), a gene encoding a three-domain LMCO (LacM) was detected, showing the highest similarity to putative copper oxidases of Candidatus Solibacter (Acidobacteria). The encoded protein was expressed in Escherichia coli, purified by affinity chromatography and biochemically characterized. LacM oxidized a variety of phenolic substrates, including two standard laccase substrates (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), k cat/k M = 8.45 s-1 mM-1; 2,6-dimethoxyphenol (2,6-DMP), k cat/k M = 6.42 s-1 mM-1), next to L-3,4-dihydroxyphenylalanine (L-DOPA), vanillic acid, syringaldazine, pyrogallol, and pyrocatechol. With respect to the latter two lignin building blocks, LacM showed the highest catalytic activity (k cat/k M = 173.6 s-1 mM-1) for pyrogallol, with ca. 20% activity preserved even at pH 8.0. The enzyme was thermostable and heat-activated in the interval 40-60 degrees C, with an optimal activity on ABTS at 50 degrees C. It was rather stable at high salt concentration (e.g., 34% activity preserved at 500 mM NaCl) and in the presence of organic solvents. Remarkably, LacM decolored azo and triphenylmethane dyes, also in the absence of redox mediators. PMID- 28589227 TI - Laccase-mediated synthesis of lignin-core hyperbranched copolymers. AB - Lignin, one of the major chemical constituents of woody biomass, is the second most abundant biopolymer found in nature. The pulp and paper industry has long produced lignin on the scale of millions of tons annually as a by-product of the pulping process, and the dawn of cellulosic ethanol production has further contributed to this amount. Historically, lignin has been perceived as a waste material and burned as a fuel for the pulping process. However, recent research has been geared toward developing cost-effective technologies to convert lignin into valuable commodities. Attributing to the polyphenolic structure of lignin, enzymatic modification of its surface using laccases (benzenediol:oxygen oxidoreductases, EC 1.10.3.2) has demonstrated to be highly successful. The current study aims at developing lignin-core hyperbranched copolymers via the laccase-assisted copolymerization of kraft lignin with methylhydroquinone and a trithiol. Based on the physical properties of the resulting material, it is likely that crosslinking reactions have taken place during the drying process to produce a copolymeric network rather than discrete hyperbranched copolymers, with NMR data providing evidence of covalent bonding between monomers. Preliminary thermal analysis data reveals that the copolymeric material possesses a moderate glass transition temperature and exhibits good thermostability, thus may have potential application as a lignin-based thermoplastic. Scanning electron microscopy images confirm the smooth, glossy surface of the material and that it is densely packed. The presented results are a sustainable, ecofriendly, economic method to create an exciting novel biomaterial from a renewable feedstock while further enhancing lignin valorization. PMID- 28589228 TI - Case-crossover analysis of heat-coded deaths and vulnerable subpopulations: Oklahoma, 1990-2011. AB - The extent of the association between temperature and heat-coded deaths, for which heat is the primary cause of death, remains largely unknown. We explored the association between temperature and heat-coded deaths and potential interactions with various demographic and environmental factors. A total of 335 heat-coded deaths that occurred in Oklahoma from 1990 through 2011 were identified using heat-related International Classification of Diseases codes, cause-of-death nomenclature, and narrative descriptions. Conditional logistic regression models examined the association between temperature and heat index on heat-coded deaths. Interaction by demographic factors (age, sex, marital status, living alone, outdoor/heavy labor occupations) and environmental factors (ozone, PM10, PM2.5) was also explored. Temperatures >=99 degrees F (the median value) were associated with approximately five times higher odds of a heat-coded death as compared to temperatures <99 degrees F (adjusted OR = 4.9, 95% CI 3.3, 7.2). The effect estimates were attenuated when exposure to heat was characterized by heat index. The interaction results suggest that effect of temperature on heat coded deaths may depend on sex and occupation. For example, the odds of a heat coded death among outdoor/heavy labor workers exposed to temperatures >=99 degrees F was greater than expected based on the sum of the individual effects (observed OR = 14.0, 95% CI 2.7, 72.0; expected OR = 4.1 [2.8 + 2.3-1.0]). Our results highlight the extent of the association between temperature and heat coded deaths and emphasize the need for a comprehensive, multisource definition of heat-coded deaths. Furthermore, based on the interaction results, we recommend that states implement or expand heat safety programs to protect vulnerable subpopulations, such as outdoor workers. PMID- 28589229 TI - [Stroke in children and adolescents]. AB - The occurrence of a stroke in children and adolescents constitutes a rare, critical event that is associated with substantial morbidity and mortality. In addition to the individual suffering for the young patient and the medical burden for the affected family, a stroke is also associated with high follow-up costs for the health system because of the necessary long-term rehabilitative treatment. Establishing an early and prompt diagnosis is of great therapeutic importance. Because of the rarity of the illness and the plethora of clinical manifestations, diagnosis is often delayed. The most frequent clinical presentation is an acute focal-neurological deficit, usually in the form of hemiparesis, but headache, seizures or alteration of consciousness may also be seen. Nowadays, the prompt performance of diffusion-weighted, blood-sensitive magnetic resonance imaging (MRI) constitutes the gold standard. The most relevant risk factors for the occurrence of a stroke in this age cohort are vasculopathies, infections, pathological cardiac conditions or coagulopathies. Recurrence of stroke is dependent on the underlying risk factors. In a substantial percentage of patients, residual neurological deficits are seen.Owing to a lack of randomized controlled trials in children and adolescents with stroke, the optimal treatment approach is still under debate. In addition to anti platelet medication and heparinization, systematic intravenous thrombolysis and endovascular thrombectomy are other potentially effective treatment options. The long-term prognosis in children is dependent on establishing a correct, early diagnosis. PMID- 28589230 TI - The Immune Response in Periodontal Tissues. AB - The uniqueness of periodontal diseases is caused by several factors. This group of diseases is caused by numerous bacterial species formed in the dental biofilm, and one cannot distinguish the specific pathogen that is responsible for the disease initiation or progress (though Gram-negative anaerobic rods are associated with the advanced form of the disease). The disease is both infectious and inflammatory in its nature, and in the state of health there is always a subclinical level of inflammatory response, caused by the so-called harmless bacteria. Negligence in oral hygiene may result in maturation of the biofilm and trigger host response, manifesting clinically as gingivitis or-later and in susceptible subjects-as periodontitis. The article presents the contemporary knowledge of the inflammatory reaction occurring in tissues surrounding the tooth during periodontal inflammation. The most important mechanisms are described, together with implications for clinicists. PMID- 28589231 TI - A multicenter randomized comparison of paclitaxel-coated balloon with plain balloon angioplasty in patients with small vessel disease. AB - AIM: We investigated the efficacy and safety of using paclitaxel-coated balloon (PCB) to treat small vessel disease. METHODS AND RESULTS: In this multicenter, prospective, randomized controlled trial, one-hundred and thirty-five patients with native coronary lesions in small vessels were randomized into a PCB group and plain balloon angioplasty (POBA) group at a ratio of 2:1. There were no differences in target vessel failure (TVF) that was defined as cardiac death or target vessel-related myocardial infarction or target lesion revascularization (TLR), between the two groups (3.4 vs. 10.3%; P = 0.20), and TLR was slightly lower in the PCB group (2.3%) than that in the POBA group (10.3%) during 24 weeks follow-up. The late lumen loss (LLL) was significantly lower in the PCB group (0.01 +/- 0.31 vs. 0.32 +/- 0.34 mm; P < 0.01) and late lumen enlargement (LLE) was more frequently observed in the PCB group (48 vs. 15%; P < 0.01) by angiographic follow-up after 24 weeks. There were no cases of death, myocardial infarction, thrombosis and reocclusion in either group. CONCLUSIONS: This study was not able to demonstrate superiority of PCB compared with POBA. PMID- 28589232 TI - Lingual tactile sensitivity: effect of age group, sex, and fungiform papillae density. AB - Despite its contribution to food perception, lingual tactile sensitivity has been understudied. We hypothesized that sensitivity to threshold and suprathreshold tactile stimuli varies in the population and sought to determine proximate sources of variability. Forty-eight adults were tested for lingual threshold sensitivity via a modified letter identification task and suprathreshold sensitivity via estimation of stimulus size using magnitude estimation. In addition, taste bud density on the anterior tip of each panelist's tongue was estimated by counting the number of fungiform papillae in a 0.317 cm2 circumscribed area. Lingual tactile thresholds were significantly impacted by age group as subjects 40 years or older had higher thresholds than those in their 20s. Moreover, threshold sensitivity increased with increasing fungiform papillae count. Suprathreshold estimates of size were not affected by age group, sex, or fungiform papillae count. PMID- 28589233 TI - Altered tuning in primary motor cortex does not account for behavioral adaptation during force field learning. AB - Although primary motor cortex (M1) is intimately involved in the dynamics of limb movement, its inputs may be more closely related to higher-order aspects of movement and multi-modal sensory feedback. Motor learning is thought to result from the adaption of internal models that compute transformations between these representations. While the psychophysics of motor learning has been studied in many experiments, the particular role of M1 in the process remains the subject of debate. Studies of learning-related changes in the spatial tuning of M1 neurons have yielded conflicting results. To resolve the discrepancies, we recorded from M1 during curl field adaptation in a reaching task. Our results suggest that aside from the addition of the load itself, the relation of M1 to movement dynamics remains unchanged as monkeys adapt behaviorally. Accordingly, we implemented a musculoskeletal model to generate synthetic neural activity having a fixed dynamical relation to movement and showed that these simulated neurons reproduced the observed behavior of the recorded M1 neurons. The stable representation of movement dynamics in M1 suggests that behavioral changes are mediated through progressively altered recruitment of M1 neurons, while the output effect of those neurons remained largely unchanged. PMID- 28589235 TI - Metazoan parasite communities in Alosa alosa (Linnaeus, 1758) and Alosa fallax (Lacepede, 1803) (Clupeidae) from North-East Atlantic coastal waters and connected rivers. AB - Metazoan parasites were studied in 96 Alosa alosa and 78 Alosa fallax from North East Atlantic coastal waters and connected rivers (among them three sympatric sites) in order to increase knowledge on these anadromous endangered fish and measure the parasitic impact on host condition. All shads were infected by one to six metazoan parasite taxa among the 12 identified in the whole sampling, with a mean abundance of parasites higher for A. alosa (167 +/- 10) than for A. fallax (112 +/- 11). Helminths, mostly trophically transmitted, were the best represented (eight taxa, prevalence up to 99%) in contrast with crustaceans and Petromyzontidae that rarely occurred (four taxa, prevalence <6%). Despite some quantitative differences, metazoan parasite communities of A. alosa and A. fallax remained stable in composition whatever the host developmental stage, sex, sample site, and salinity. Among the nine parasite taxa harbored by each Alosa species, six were shared with some differences in distribution patterns including in sympatric conditions, suggesting increasing dissimilarities between A. alosa and A. fallax with the age. Information on feeding ecology provided by trophically transmitted helminths confirmed euryphagous opportunistic diet of immatures and adults of both shad species, and assessed feeding of adults during spawning migrations. Our study also revealed the significant negative impact of Hemiurus appendiculatus on A. alosa and Pronoprymna ventricosa on A. fallax. Because helminth parasites are omnipresent in the shads and decrease their fitness, parasitological data must be included in further investigations and management programs on A. alosa and A. fallax. PMID- 28589234 TI - Action of nitromezuril against Eimeria tenella with clinically anticoccidial indices and histopathology. AB - Nitromezuril is a novel triazine compound for preventing coccidiosis in broiler chickens. A single treatment of chickens inoculated with Eimeria tenella during the endogenous phase were used to evaluate the developmental stages of action of nitromezuril by clinically anticoccidial indices and histopathology. Results showed that a single dose of nitromezuril at 5 mg/kg b.w. during 56 to 80 h post inoculation can most effectively prevent weight loss and reduce both oocyst shedding and caecal lesions. The anticoccidial index reached the level of middle efficacy. Histological examinations indicated that administration of nitromezuril during 44 to 104 h after infection significantly reduced the merozoite population and the pathological damage to the caecum. Nitromezuril treatment could disturb the process of schizonts division into schizoites and produce abnormal schizonts. Overall, nitromezuril may exert its effects during the entire endogenous stage of the parasites but the schizogony stages were intrinsically more vulnerable. Nitromezuril is a potential novel anticoccidial agent suitable for further development. PMID- 28589236 TI - Geographic variation in mental health care disparities among racially/ethnically diverse adults with psychiatric disorders. AB - PURPOSE: The main purpose of this paper is to examine geographic variation in unmet need for mental health care among racially/ethnically diverse adults with psychiatric disorders in the US. METHODS: Drawn from the Collaborative Psychiatric Epidemiology Surveys (CPES; 2001-2003), adults with any past year psychiatric disorder diagnosis (n = 3211) from diverse racial/ethnic backgrounds were selected for analyses. Using weighted data, descriptive analyses and logistic regression analyses were conducted. RESULTS: Two-thirds of the total sample had unmet mental health care need, which differed significantly by race/ethnicity (p < .001). Logistic regression analyses show regional variation of the effect of race/ethnicity in unmet need: after adjusting for covariates, Latinos in the South, Blacks and Latinos in the Midwest, and Latinos and Asians in the West had higher unmet need than non-Hispanic Whites, whereas no significant racial/ethnic effects were found in the Northeast. CONCLUSIONS: Findings suggest that geographic region plays an important role in the sufficient use of mental health services among racial/ethnic minorities. Further research should elucidate reasons for geographic disparities in mental health care among racial/ethnic minority adults to reduce disparities. PMID- 28589239 TI - Population health intervention research: three important advancements. PMID- 28589237 TI - Choledochal Malformation in Children: Lessons Learned from a Dutch National Study. AB - INTRODUCTION: A choledochal malformation (CM) is a rare entity, especially in the Western world. We aimed to determine the incidence of CM in the Netherlands and the outcome of surgery for CM in childhood. METHODS: All pediatric patients who underwent a surgical procedure for type I-IV CM between 1989 and 2014 were entered into the Netherlands Study group on choledochal cyst/malformation. Patients with type V CM were excluded from the present analysis. Symptoms, surgical details, short-term (<30 days) and long-term (>30 days) complications were studied retrospectively. RESULTS: Between January 1989 and December 2014, 91 pediatric patients underwent surgery for CM at a median age of 2.1 years (0.0 17.7 years). All patients underwent resection of the extrahepatic biliary tree with restoration of the continuity via Roux-en-Y hepaticojejunostomy. Twelve patients (12%) were operated laparoscopically. Short-term complications, mainly biliary leakage and cholangitis, occurred in 20 patients (22%), without significant correlations with weight or age at surgery or surgical approach. Long term postoperative complications were mainly cholangitis (13%) and anastomotic stricture (4%). Eight patients (9%) required radiological intervention or additional surgery. Surgery before 1 year of age (OR 9.3) and laparoscopic surgery (OR 4.4) were associated with more postoperative long-term complications. We did not observe biliary malignancies during treatment or follow-up. CONCLUSION: Surgery for CM carries a significant short- and long-term morbidity. Given the low incidence, we would suggest that (laparoscopic) hepatobiliary surgery for CM should be performed in specialized pediatric surgical centers with a wide experience in laparoscopy and hepatobiliary surgery. PMID- 28589238 TI - Repeat Rifaximin for Irritable Bowel Syndrome: No Clinically Significant Changes in Stool Microbial Antibiotic Sensitivity. AB - BACKGROUND: Rifaximin has demonstrated efficacy and safety for diarrhea predominant irritable bowel syndrome (IBS-D). AIM: To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. METHODS: Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. RESULTS: Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 ug/mL] and rifampin (MIC range 0.004-0.25 ug/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC50 range <=0.06-32 ug/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. CONCLUSIONS: In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS. GOV IDENTIFIER: NCT01543178. PMID- 28589241 TI - Laparoscopic ventral rectopexy with percutaneous surgical system. PMID- 28589240 TI - Dynamic cystocolpoproctography to confirm the efficacy of laparoscopic rectopexy in the treatment of hedrocele associated with full-thickness rectal prolapse. PMID- 28589243 TI - RNAi targeting STMN alleviates the resistance to taxol and collectively contributes to down regulate the malignancy of NSCLC cells in vitro and in vivo. AB - Stathmin (STMN) plays a vital role in maintaining the malignant behavior of cancer through directly regulating microtubule dynamics equilibrium. Taxol, an effective chemotherapeutics mainly acting to promote microtubule polymerization, has been commercially applied in treating solid tumors, which results in serious drug resistance. Our study demonstrated that STMN RNA interference (RNAi) enlarged taxol-induced inhibitions in cellular proliferation, colony formation, and multidimensional spaces of cell immigration and decreased half maximal inhibitory concentration (IC50) of taxol in nonsmall cell lung cancer (NSCLC) NCI H1299 cells; STMN RNAi and taxol jointly attenuated the expressions of extracellular regulated kinase (ERK), nuclear factor kappa B (NF-kappaB) and B cell lymphoma-2 (Bcl-2), but up regulated Bax expression and initiated intrinsic cell death pathway by activating caspase-3 and caspase-9, while inhibited interleukin 10 (IL-10) autocrine from cell culture supernatant and xenografted mouse serum, as well as intracellular expressions of IL-10 protein and mRNA in vitro; additionally, neutralizing IL-10 alone would incur cell apoptosis to some degree; the further study confirmed that RNAi targeting STMN promoted the sensitivity of taxol in different NSCLC cells. In vivo animal experiments proved that STMN RNAi and taxol cooperatively inhibited the tumorigenicity of NCI-H1299 cells and histological atypia and Ki-67 proliferative index of xenografted tumors and promoted cell differentiation to a higher grade with well-differentiated indicators of glandular lumen-like structure and proliferative fibroblasts. These findings suggest that silencing STMN alleviates the resistance to taxol and collectively contributes to induce the dysfunction of multiple signals and down regulate the malignancy of tumors; thus, STMN is a promising target in treating refractory tumors. PMID- 28589242 TI - Surgery beyond the visible light spectrum: theoretical and applied methods for localization of the male urethra during transanal total mesorectal excision. AB - The risk of urethral injury during transanal total mesorectal excision (taTME) is delineated, and potential risk factors for iatrogenic transection are reviewed. A variety of applied and theoretical techniques can be used by surgeons to diminish the risk of injury in males undergoing this operation. Many of the approaches utilize non-optic media and wavelengths beyond the visible light spectrum which can enhance the surgeon's frame of reference. The aim of the present study was to assess the techniques and theoretical approaches to urethral localization during taTME. Future directions in surgical imaging are also discussed, including the use of organic dyes, quantum dots, and carbon nanotubes; collectively, technology that could someday provide surgeons with an ability to identify anatomic structures prone to injury. PMID- 28589244 TI - Does spinal excitability scale to the difficulty of the dual-task? AB - PURPOSE: This study examined whether spinal excitability, as measured by the soleus Hoffmann reflex (H-reflex), is scaled to the difficulty level of the dual task being performed. METHODS: Twenty-two participants completed a combination of three balance task and three secondary cognitive (visuo-motor) task difficulty levels for a total of nine dual-task conditions. An additional eight participants were tested while performing the same three balance task difficulty levels on its own (i.e., single-tasking). The balance task required participants to maintain their balance on a fixed or rotating stabilometer while the visuo-motor task required participants to respond to moving targets presented on a monitor. Throughout each single- and dual-task trial, H-reflexes were elicited from the soleus. RESULTS: Although dual-task performance, as quantified by visuo-motor task accuracy as well as the root mean square of the stabilometer position and velocity, decreased by 10-34% with increasing dual-task difficulty (p < 0.05), no changes in the soleus H-reflex amplitude were observed between dual-task conditions (p = 0.483-0.758). This contrasts to when participants performed the balance task as a single-task, where the H-reflex amplitude decreased by ~25% from the easy to the hard balance task difficulty level (p = 0.037). CONCLUSIONS: In contrast to the commonly reported finding of a reduced soleus H-reflex amplitude when individuals perform a less posturally stable task by itself, the results indicate that spinal excitability is not modulated as a function of dual task difficulty. It is possible that when an individual's attentional resource capacity is exceeded during dual-tasking, they become ineffective in regulating spinal excitability for balance control. PMID- 28589245 TI - Quitting Mental Health Services among Racial and Ethnic Groups of Americans with Depression. AB - Research on racial/ethnic differences in quitting mental health services has yet to examine the multiple forms of services offered and reasons why racial/ethnic groups quit. Data from the Collaborative Psychiatric Epidemiology Surveys (CPES) examined whether race/ethnicity was related to quitting nine types of mental health services within a multivariate framework, and whether any racial/ethnic differences emerged among 16 assessed reasons for quitting mental health services (N = 437). Odds of quitting mental health services provided by social workers, non-medical health professionals, counselors, psychiatrists, and psychologists varied significantly by race/ethnicity. The most common reasons for quitting services included individuals wanting to handle the problem on their own, getting better, or not needing help anymore. The increased likelihood of quitting services represents an underexplored area for mental health service disparities and calls for improved efforts to retain racial and ethnic minorities in the mental health system. PMID- 28589246 TI - Insights into the genetic relationships among plants of Beta section Beta using SNP markers. AB - KEY MESSAGE: Using a much higher number of SNP markers and larger sample sizes than all the previous studies, we characterized the genetic relationships among wild and cultivated plants of section Beta. We analyzed the genetic variation of Beta section Beta, which includes wild taxa (Beta macrocarpa, B. patula, B. vulgaris subsp. adanensis and B. vulgaris subsp. maritima) and cultivars (fodder beet, sugar beet, garden beet, leaf beet, and swiss chards), using 9724 single nucleotide polymorphism markers. The analyses conducted at the individual level without a priori groups confirmed the strong differentiation of B. macrocarpa and B. vulgaris subsp. adanensis from the other taxa. B. vulgaris subsp. maritima showed a complex genetic structure partly following a geographical pattern, which confounded the differences between this taxon and the cultivated varieties. Cultivated varieties were structured into three main groups: garden beets, fodder and sugar beets, and leaf beets and swiss chards. The genetic structure described here will be helpful to correctly estimate linkage disequilibrium and to test for statistical associations between genetic markers and environmental variables. PMID- 28589247 TI - Challenges in Laboratory Detection of Fungal Pathogens in the Airways of Cystic Fibrosis Patients. AB - Study of the clinical significance of fungal colonization/infection in the airways of cystic fibrosis (CF) patients, especially by filamentous fungi, is challenged by the absence of standardized methodology for the detection and identification of an ever-broadening range of fungal pathogens. Culture-based methods remain the cornerstone diagnostic approaches, but current methods used in many clinical laboratories are insensitive and unstandardized, rendering comparative studies unfeasible. Guidelines for standardized processing of respiratory specimens and for their culture are urgently needed and should include recommendations for specific processing procedures, inoculum density, culture media, incubation temperature and duration of culture. Molecular techniques to detect fungi directly from clinical specimens include panfungal PCR assays, multiplex or pathogen-directed assays, real-time PCR, isothermal methods and probe-based assays. In general, these are used to complement culture. Fungal identification by DNA sequencing methods is often required to identify cultured isolates, but matrix-assisted laser desorption/ionization time-of-flight mass spectrometry is increasingly used as an alternative to DNA sequencing. Genotyping of isolates is undertaken to investigate relatedness between isolates, to pinpoint the infection source and to study the population structure. Methods range from PCR fingerprinting and amplified fragment length polymorphism analysis, to short tandem repeat typing, multilocus sequencing typing (MLST) and whole genome sequencing (WGS). MLST is the current preferred method, whilst WGS offers best case resolution but currently is understudied. PMID- 28589249 TI - Phenylpropanoid composition in fig (Ficus carica L.) leaves. AB - The leaves of fig (Ficus carica L.) have been used for traditional and Chinese medicine. We determined the composition of phenylpropanoids (polyphenols and furanocoumarins) as a functional agent in the leaves of 37 cultivars of fig. The most abundant polyphenol was caffeoylmalic acid (12.0-26.6 mg/g dry weight), followed by rutin (4.7-14.6 mg/g dry weight) and isoschaftoside (2.5-6.4 mg/g dry weight). Psoralen (3.8-23.0 mg/g dry weight) was dominant in the furanocoumarins. In molar amounts, psoralic acid glucoside (PAG), a precursor of psoralen, was equivalent to psoralen. Furanocoumarins and PAG were not detected in the leaves of only one cultivar, Grise de Tarascon. Fig leaves are potentially an excellent source of polyphenols such as caffeoylmalic acid and rutin. From the result of cluster analysis, some cultivars that contained large amount of polyphenols, and a small amount (e.g., Grise de Saint Jean) or no (Grise de Tarascon) furanocoumarins, were found. These cultivars are considered suitable for functional foods or medicinal products. PMID- 28589250 TI - Histopathological and Bacteriological Analysis of Thrombus Material Extracted During Mechanical Thrombectomy in Acute Stroke Patients. AB - PURPOSE: Management of stroke secondary to septic emboli (SE) remains challenging, due to both the lack of specific recommendations and the gravity of the underlying pathology.The aim of this study is to describe the presence of SE in a series of mechanical thrombectomies (MT), analyzing technical complexity and outcomes with respect to the patients by means of histological analysis and microbiological study of the clot. METHODS: All the retrieved clots were studied under an established protocol, including histopathological and bacteriological study with hematoxylin-eosin, Gram and Gomori trichrome staining.Technical complexity in SE with respect to the series was evaluated by analyzing time of the procedures, number of passes and use of intracranial definitive stents. RESULTS: Over a 24-month period, bacteria were detected in the retrieved clot of four out of 65 patients (incidence 6.2%). Two cases were eventually diagnosed with infective endocarditis, while the remaining two were diagnosed with urinary tract infection and respiratory septicemia, respectively. Three of the four patients (75%) required an intracranial definitive stent in order to achieve successful recanalization.These procedures were significantly longer (137.7 vs. 59.8 min, p < 0.001), needed a higher number of passes (5.8 vs. 2.2, p < 0.001), and delivery of an intracranial stent more frequently (75% vs. 1.6%, p = 0.008), with respect to the rest of the series. CONCLUSIONS: In our series, systematic histopathological and bacteriological study of the MT samples allowed a higher proportion of SE diagnosis in comparison with previous reports. PMID- 28589248 TI - Quercetin and tin protoporphyrin attenuate hepatic ischemia reperfusion injury: role of HO-1. AB - Ischemia reperfusion (IR) injury occurs in many clinical situations such as organ transplantation and hepatectomies resulting in oxidative stress and immune activation. Heme oxygenase-1(HO-1) is the rate-limiting step in the heme degradation pathway and has a critical cytoprotective role. Induction of HO-1 improves liver I/R injury. Quercetin, a plant pigment (flavonoid), is an antioxidant and HO-1 inducer. Tin protoporphyrin (SnPP) is a HO-1 inhibitor. This study was designed to investigate the protective effect of quercetin in hepatic I/R injury and the role of HO-1. Wister rats were randomly divided into four groups (sham, I/R, quercetin, and SnPP). Liver ischemia was induced for 45 min then reperfusion was allowed for 1 h. Quercetin and surprisingly SnPP ameliorate the deleterious effect of I/R by reducing the oxidative stress and hepatocyte degeneration. Both agents decreased the elevated inflammatory cytokines and improved the inhibition of the antiapoptotic marker, Bcl2. They induced HO-1 content and expression. Quercetin has better cytoprotective effect than SnPP. These findings suggest that quercetin has a hepatoprotective effect against I/R injury via HO-1 induction and unexpectedly, SnPP showed the similar effect. Quercetin has more prominent protective effect than SnPP because of its superior ability to induce HO-1. PMID- 28589251 TI - A systematic review and dose-response meta-analysis of sleep duration and the occurrence of cognitive disorders. AB - PURPOSE: Previous researches have shown inconsistent findings on the relationship between sleep duration and cognitive disorders (including cognitive decline, dementia, Alzheimer's disease, and cognitive impairment). Furthermore, the possible dose-response association of sleep duration and cognitive disorders is still not clear. METHODS: Two databases (PubMed and Embase) were searched for relevant studies from inception to May 4, 2016. We used the generic inverse variance method to combine the outcomes with a random-effects model for the association between sleep duration (the shortest or longest vs. middle category) and cognitive disorders. Additionally, we used the generalized least-squares trend estimation model to estimate the potential dose-response association. RESULTS: Finally, nine eligible cohort studies involving 22,187 participants were included in the present systematic review and meta-analysis. Compared with the middle category, both short and long sleep duration were accompanied by a significantly higher incident risk of cognitive disorders, and the relative risks (RRs) and 95% confidence intervals (CIs) were 1.34 (1.15, 1.56) and 1.21 (1.06, 1.39), respectively. Moreover, an approximately "U-shaped" dose-response relationship was observed. Stratified analyses showed that the association between short sleep duration and cognitive disorders was more robust in the subgroup of the measurement of sleep duration based on self-report. CONCLUSIONS: The lowest incident risk of cognitive disorders was found at the sleep duration of 7-8 h per day. The present study includes a small number of studies, and the study participants mostly consist of Caucasian population. In the future, researches are also warranted to confirm the association in different groups of people. PMID- 28589252 TI - Manifestations of HIV stigma and their impact on retention in care for people transitioning from prisons to communities. AB - BACKGROUND: While most people living with HIV who are incarcerated in United States receive appropriate HIV care while they are in prison, interruptions in antiretroviral therapy and virologic failure are extremely common after they are released. The purpose of this study was to describe whether and how HIV stigma influences continuity of care for people living with HIV while they transition from prison to community settings. METHODS: We conducted semi-structured, telephone-based interviews with 32 adults who received HIV care while residing in a Wisconsin state prison, followed by a second interview 6 months after they returned to their home community. Interview transcripts were analyzed by an interdisciplinary research team using conventional content analysis. We identified themes based on commonly-reported experiences that were characterized as internalized stigma, perceived stigma, vicarious stigma, or enacted stigma. RESULTS: All four forms of HIV stigma appeared to negatively influence participants' engagement in community-based HIV care. Mechanisms described by participants included care avoidance due to concerns about HIV status disclosure and symptoms of depression and anxiety caused by internalized stigma. Supportive social relationships with clinic staff, professional case managers and supportive peers appeared to mitigate the impact of HIV stigma by increasing motivation for treatment adherence. CONCLUSIONS: HIV stigma is manifest in several different forms by people living with HIV who were recently incarcerated, and are perceived by patients to negatively influence their desire and ability to engage in HIV care. By being cognizant of the pervasive influence of HIV stigma on the lives of criminal justice involved adults, HIV care providers and clinical support staff can ameliorate important barriers to optimal HIV care for a vulnerable group of patients. PMID- 28589253 TI - Early PET imaging with [68]Ga-PSMA-11 increases the detection rate of local recurrence in prostate cancer patients with biochemical recurrence. AB - PURPOSE: PET/CT using 68Ga-labelled prostate-specific membrane antigen PSMA-11 (HBEDD-CC) has emerged as a promising imaging method in the diagnostic evaluation of prostate cancer (PC) patients with biochemical recurrence. However, assessment of local recurrence (LR) may be limited by intense physiologic tracer accumulation in the urinary bladder on whole-body scans, normally conducted 60 min post-tracer injection (p.i.). It could be shown on early dynamic imaging studies that 68Ga-PSMA-11 uptake in PC lesions occurs earlier than tracer accumulation in the urinary bladder. This study aims to investigate whether early static PET acquisition increases detection rate of local recurrence on 68Ga-PSMA 11 PET/CT in comparison to PET imaging 60 min p.i.. METHODS: 203 consecutive PC patients with biochemical failure referred to 68Ga-PSMA-11 PET/CT were analysed retrospectively (median prostate specific antigen (PSA) value: 1.44 ng/ml). In addition to whole-body PET/CT scans 60 min p.i., early static imaging of the pelvis was performed, starting at a median time of 283 s p.i. (range: 243-491 s). Assessment was based on visual analysis and calculation of maximum standardized uptake value (SUVmax) of pathologic lesions present in the pelvic area found on early PET imaging and on 60 min-PET scans. RESULTS: 26 patients (12.8%) were judged positive for LR on PET scans 60 min p.i. (median SUVmax: 10.8; range: 4.7 40.9), whereas 50 patients (24.6%) revealed a lesion suggestive of LR on early PET imaging (median SUVmax: 5.9; range: 2.9-17.6), resulting in a significant rise in detection rate (p < 0.001). Equivocal findings on PET scans 60 min p.i. decreased significantly with the help of early imaging (15.8% vs. 4.5% of patients; p < 0.001). Tracer activity in the urinary bladder with a median SUVmax of 8.2 was present in 63 patients on early PET scans (31.0%). However, acquisition starting time of early PET scans differed significantly in the patient groups with and without urinary bladder activity (median starting time of 321 vs. 275 s p.i.; range: 281-491 vs. 243-311 s p.i.; p < 0.001). Median SUVmax value of lesions suggestive of LR on early images was significantly higher in comparison to gluteal muscle, inguinal vessels and seminal vesicle/anastomosis (median SUVmax: 5.9 vs. 1.9, 4.0 and 2.4, respectively). CONCLUSIONS: Performance of early imaging in 68Ga-PSMA-11 PET/CT in addition to whole-body scans 60 min p.i. increases the detection rate of local recurrence in PC patients with biochemical recurrence. Acquisition of early PET images should be started as early as 5 min p.i. in order to avoid disturbing tracer activity in the urinary bladder occuring at a later time point. PMID- 28589254 TI - Characterisation of malignant peripheral nerve sheath tumours in neurofibromatosis-1 using heterogeneity analysis of 18F-FDG PET. AB - PURPOSE: Measurement of heterogeneity in 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) images is reported to improve tumour phenotyping and response assessment in a number of cancers. We aimed to determine whether measurements of 18F-FDG heterogeneity could improve differentiation of benign symptomatic neurofibromas from malignant peripheral nerve sheath tumours (MPNSTs). METHODS: 18F-FDG PET data from a cohort of 54 patients (24 female, 30 male, mean age 35.1 years) with neurofibromatosis-1 (NF1), and clinically suspected malignant transformation of neurofibromas into MPNSTs, were included. Scans were performed to a standard clinical protocol at 1.5 and 4 h post injection. Six first-order [including three standardised uptake value (SUV) parameters], four second-order (derived from grey-level co-occurrence matrices) and four high-order (derived from neighbourhood grey-tone difference matrices) statistical features were calculated from tumour volumes of interest. Each patient had histological verification or at least 5 years clinical follow-up as the reference standard with regards to the characterisation of tumours as benign (n = 30) or malignant (n = 24). RESULTS: There was a significant difference between benign and malignant tumours for all six first-order parameters (at 1.5 and 4 h; p < 0.0001), for second-order entropy (only at 4 h) and for all high order features (at 1.5 h and 4 h, except contrast at 4 h; p < 0.0001-0.047). Similarly, the area under the receiver operating characteristic curves was high (0.669-0.997, p < 0.05) for the same features as well as 1.5-h second-order entropy. No first-, second- or high-order feature performed better than maximum SUV (SUVmax) at differentiating benign from malignant tumours. CONCLUSIONS: 18F FDG uptake in MPNSTs is higher than benign symptomatic neurofibromas, as defined by SUV parameters, and more heterogeneous, as defined by first- and high-order heterogeneity parameters. However, heterogeneity analysis does not improve on SUVmax discriminative performance. PMID- 28589255 TI - Potential anti-cholinesterase and beta-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits. AB - Cholinesterase (ChE) and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors are promising agents for the treatment of Alzheimer's disease (AD). In the present study, we examined the inhibitory activity of seven compounds isolated from the fruits of Cornus officinalis, cornuside, polymeric proanthocyanidins, 1,2,3-tri-O-galloyl-beta-D-glucose, 1,2,3,6-tetra-O-galloyl beta-D-glucose, tellimagrandin I, tellimagrandin II, and isoterchebin, against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and BACE1. All of the compounds displayed concentration-dependent in vitro inhibitory activity toward the ChEs and BACE1. Among them, tellimagrandin II exhibited the best inhibitory activity toward ChEs, whereas the best BACE1 inhibitor was 1,2,3,6-tetra-O galloyl-beta-D-glucose. Isoterchebin and polymeric proanthocyanidins were also significant ChE inhibitors. The kinetic and docking studies demonstrated that all compounds interacted with both the catalytic active sites and the peripheral anionic sites of the ChEs and BACE1. Tellimagrandin II, isoterchebin, and the polymeric proanthocyanidins exhibited concentration-dependent inhibition of peroxynitrite-mediated protein tyrosine nitration. In conclusion, we identified significant ChE and BACE1 inhibitors from Corni Fructus that could have value as new multi-targeted compounds for anti-AD agents. PMID- 28589256 TI - Treatment of congenital pulmonary airway malformations: a systematic review from the APSA outcomes and evidence based practice committee. AB - PURPOSE: Variation in management characterizes treatment of infants with a congenital pulmonary airway malformation (CPAM). This review addresses six clinically applicable questions using available evidence to provide recommendations for the treatment of these patients. METHODS: Questions regarding the management of a pediatric patient with a CPAM were generated. English language articles published between 1960 and 2014 were compiled after searching Medline and OvidSP. The articles were divided by subject area and by the question asked, then reviewed and included if they specifically addressed the proposed question. RESULTS: 1040 articles were identified on initial search. After screening abstracts per eligibility criteria, 130 articles were used to answer the proposed questions. Based on the available literature, resection of an asymptomatic CPAM is controversial, and when performed is usually completed within the first six months of life. Lobectomy remains the standard resection method for CPAM, and can be performed thoracoscopically or via thoracotomy. There is no consensus regarding a monitoring protocol for observing asymptomatic lesions, although at least one chest computerized tomogram (CT) should be performed postnatally for lesion characterization. An antenatally identified CPAM can be evaluated with MRI if fetal intervention is being considered, but is not required for the fetus with a lesion not at risk for hydrops. Prenatal consultation should be offered for infants with CPAM and encouraged for those infants in whom characteristics indicate risk of hydrops. CONCLUSIONS: Very few articles provided definitive recommendations for care of the patient with a CPAM and none reported Level I or II evidence. Based on available information, CPAMs are usually resected early in life if at all. A prenatally diagnosed congenital lung lesion should be evaluated postnatally with CT, and prenatal counseling should be undertaken in patients at risk for hydrops. PMID- 28589257 TI - Traumatic brain injury causes long-term behavioral changes related to region specific increases of cerebral blood flow. AB - Traumatic brain injury (TBI) is a leading cause of disability and death and survivors often suffer from long-lasting motor impairment, cognitive deficits, anxiety disorders and epilepsy. Few experimental studies have investigated long term sequelae after TBI and relations between behavioral changes and neural activity patterns remain elusive. We examined these issues in a murine model of TBI combining histology, behavioral analyses and single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (CBF) as a proxy for neural activity. Adult C57Bl/6N mice were subjected to unilateral cortical impact injury and investigated at early (15-57 days after lesion, dal) and late (184-225 dal) post-traumatic time points. TBI caused pronounced tissue loss of the parietal cortex and subcortical structures and enduring neurological deficits. Marked perilesional astro- and microgliosis was found at 57 dal and declined at 225 dal. Motor and gait pattern deficits occurred at early time points after TBI and improved over the time. In contrast, impaired performance in the Morris water maze test and decreased anxiety-like behavior persisted together with an increased susceptibility to pentylenetetrazole-induced seizures suggesting alterations in neural activity patterns. Accordingly, SPECT imaging of CBF indicated asymmetric hemispheric baseline neural activity patterns. In the ipsilateral hemisphere, increased baseline neural activity was found in the amygdala. In the contralateral hemisphere, homotopic to the structural brain damage, the hippocampus and distinct cortex regions displayed increased baseline neural activity. Thus, regionally elevated CBF along with behavioral alterations indicate that increased neural activity is critically involved in the long lasting consequences of TBI. PMID- 28589259 TI - Molecular identification of victim species and its sex from the ash: a case of burning alive leopard (Panthera pardus). AB - In a case of negative human-leopard (Panthera pardus) interaction, an animal was burnt alive in South Rajasthan, India. We identified the species and sex of the victim animal from the ash using forensic DNA analysis. We recovered three objects (half burnt clot, stone, and shrub twig) from the ash having suspected blood stains. We extracted DNA from these items and amplified a partial fragment of mitochondrial DNA cytochrome b and 12S RNA genes. The sequence generated from these amplicons suggested that the victim animal was a leopard. Furthermore, amplification of a fragment of SRY (224 bp) and ZFX/Y (442 bp) genes indicated that the blood clot was of a male leopard. Although attempts have been made to remove every possible evidence from the crime scene, the species and sex of the victim animal were determined from the challenging and invisible blood stains wrapped in the ash. PMID- 28589258 TI - A latent measure explains substantial variance in white matter microstructure across the newborn human brain. AB - A latent measure of white matter microstructure (g WM) provides a neural basis for information processing speed and intelligence in adults, but the temporal emergence of g WM during human development is unknown. We provide evidence that substantial variance in white matter microstructure is shared across a range of major tracts in the newborn brain. Based on diffusion MRI scans from 145 neonates [gestational age (GA) at birth range 23+2-41+5 weeks], the microstructural properties of eight major white matter tracts were calculated using probabilistic neighborhood tractography. Principal component analyses (PCAs) were carried out on the correlations between the eight tracts, separately for four tract-averaged water diffusion parameters: fractional anisotropy, and mean, radial and axial diffusivities. For all four parameters, PCAs revealed a single latent variable that explained around half of the variance across all eight tracts, and all tracts showed positive loadings. We considered the impact of early environment on general microstructural properties, by comparing term-born infants with preterm infants at term equivalent age. We found significant associations between GA at birth and the latent measure for each water diffusion measure; this effect was most apparent in projection and commissural fibers. These data show that a latent measure of white matter microstructure is present in very early life, well before myelination is widespread. Early exposure to extra-uterine life is associated with altered general properties of white matter microstructure, which could explain the high prevalence of cognitive impairment experienced by children born preterm. PMID- 28589260 TI - Allele frequencies of 17 autosomal STR loci in the Va ethnic minority from Yunnan Province, Southwest China. AB - Allele frequencies and forensic parameters for 17 autosomal short tandem repeat (STR) loci were investigated from 1542 individuals of Va ethnic minority in Yunnan Province in the southwest of China. Also, genetic distances between Va and 13 published populations were compared, and a neighbor-joining (NJ) phylogenetic tree was developed and visualized using averaged F ST matrix. Results demonstrate that these loci are highly polymorphic in the Va population and can be applied in forensic, population genetic, and linguistic fields. PMID- 28589261 TI - Nonmotor Symptoms in Patients with Spinocerebellar Ataxia Type 10. AB - Nonmotor symptoms (NMS) have been described in several neurodegenerative diseases but have not been systematically evaluated in spinocerebellar ataxia type 10 (SCA10). The objective of the study is to compare the frequency of NMS in patients with SCA10, Machado-Joseph disease (MJD), and healthy controls. Twenty eight SCA10, 28 MJD, and 28 healthy subjects were prospectively assessed using validated screening tools for chronic pain, autonomic symptoms, fatigue, sleep disturbances, psychiatric disorders, and cognitive function. Chronic pain was present with similar prevalence among SCA10 patients and healthy controls but was more frequent in MJD. Similarly, autonomic symptoms were found in SCA10 in the same proportion of healthy individuals, while the MJD group had higher frequencies. Restless legs syndrome and REM sleep behavior disorder were uncommon in SCA10. The mean scores of excessive daytime sleepiness were worse in the SCA10 group. Scores of fatigue were higher in the SCA10 sample compared to healthy individuals, but better than in the MJD. Psychiatric disorders were generally more prevalent in both spinocerebellar ataxias than among healthy controls. The cognitive performance of healthy controls was better compared with SCA10 patients and MJD, which showed the worst scores. Although NMS were present among SCA10 patients in a higher proportion compared to healthy controls, they were more frequent and severe in MJD. In spite of these comparisons, we were able to identify NMS with significant functional impact in patients with SCA10, indicating the need for their systematic screening aiming at optimal treatment and improvement in quality of life. PMID- 28589262 TI - The surgical outcomes of lung cancer combined with interstitial pneumonia: a single-institution report. AB - PURPOSE: Several studies have reported that an acute exacerbation (AE) of idiopathic interstitial pneumonia (IIP) can occur after lung resection in patients with non-small cell lung cancer (NSCLC); however, the perioperative management strategy is controversial. METHODS: The data of lung cancer patients at Nagasaki University Hospital from June 1994 to October 2013 were retrospectively reviewed. RESULTS: Among all 1701 NSCLC patients who underwent lung resection, 59 (3.5%) had IIP. Five patients (8.5%) had an AE of IIP following lung resection, three (60%) of whom died in hospital. Univariate and multivariate analyses were performed to identify possible risk factors for AE. The univariate analyses identified LDH and the volume of blood loss as risk factors. The multivariate analysis identified no factors. The treatment for an AE included steroid pulse therapy and neutrophil elastase inhibitor therapy. Direct hemoperfusion with polymyxin B immobilized the fiber column and immunosuppressant therapy was attempted in some of the patients who did not respond to these treatments. CONCLUSION: Patients with lung cancer and IIP have a higher risk of chest surgery and a poor prognosis. Very careful surgery and perioperative management are needed, because AEs are often difficult to AE predict. PMID- 28589264 TI - Habitual nicotine-seeking in rats following limited training. AB - RATIONALE AND OBJECTIVES: A potential reason that cigarette smoking can persist despite multiple quit attempts is that repeated voluntary nicotine intake may facilitate a transition from goal-directed to habitual behavioral control. Although accelerated habit formation for self-administered ethanol or cocaine has been previously demonstrated, this phenomenon has not been extensively studied with nicotine. We therefore examined the liability of nicotine self administration to become habitual, while also examining that of orally consumed saccharin as an experimental control. METHODS: Under fixed ratio 1 (FR-1) schedules, male Sprague-Dawley rats (n = 8-11/group) lever-pressed for intravenous (IV) nicotine (30 MUg/kg/infusion) for 10 consecutive days, while also lever-pressing for saccharin solution (0.1% w/v, 0.19 mL/delivery) in separate operant sessions. In experiment 1, either nicotine or saccharin was devalued by pairing with the aversive agent lithium chloride (LiCl; 0.15 M, 14.1 mL/kg) prior to extinction and reacquisition testing. In experiment 2, the contingency between lever pressing and delivery of either nicotine or saccharin was degraded in six sessions, followed by extinction testing. RESULTS: LiCl pairings selectively reduced responding for nicotine (-35% from control) and saccharin (-48%) in reacquisition testing, indicating that both rewards were effectively devalued. During extinction testing, saccharin-seeking responses were reduced by both manipulations (devaluation -30%, degradation -79%), suggesting that responding for saccharin was goal-directed. In contrast, nicotine-seeking responses were not significantly affected by either manipulation (devaluation 4%, degradation -21%), suggesting that responding for nicotine was habitually driven. CONCLUSIONS: Operant responding for IV nicotine may rapidly come under habitual control, potentially contributing to the tenacity of tobacco use. PMID- 28589263 TI - Assessment of tolerance to the effects of methamphetamine on daytime and nighttime activity evaluated with actigraphy in rhesus monkeys. AB - RATIONALE: Methamphetamine is one of the most largely consumed illicit drugs, and its use is associated with abuse liability and several adverse health effects, such as sleep impairment. Importantly, sleep quality can influence addiction treatment outcomes. Evidence suggests that tolerance can develop to the sleep disrupting effects of stimulant drugs. OBJECTIVE: The aim of the present study was to investigate the development of tolerance to the actigraphy-based sleep disrupting and stimulant effects of methamphetamine self-administration in rhesus monkeys. METHODS: Methamphetamine (0.03 mg/kg/inf, i.v.) self-administration was carried out following three different protocols: 14 consecutive days of self administration, 5 days/week for 3 weeks, with a 2-day interval between 5-day blocks of self-administration, and 3 days/week for 3 weeks, with a 4-day interval between 3-day blocks of self-administration. Daytime activity and activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline parameters) and throughout each protocol. RESULTS: Methamphetamine self administration markedly disrupted sleep-like measures and increased daytime activity. Tolerance developed to those effects with repeated methamphetamine intake exceeding five consecutive days. Inclusion of washout periods (2 or 4 days) between blocks of methamphetamine self-administration attenuated the development of tolerance, with longer breaks from methamphetamine intake being more effective in maintaining the sleep-disrupting and stimulant effects of methamphetamine. CONCLUSIONS: Tolerance can develop to the stimulant and sleep disrupting effects of methamphetamine self-administration. Interruption of drug intake extends the effects of methamphetamine on sleep-like measures and daytime activity. PMID- 28589266 TI - Metal Nanoparticles in Ionic Liquids. AB - During the last years ionic liquids (ILs) were increasingly used and investigated as reaction media, hydrogen sources, catalysts, templating agents and stabilizers for the synthesis of (monometallic and bimetallic) metal nanoparticles (M-NPs). Especially ILs with 1,3-dialkyl-imidazolium cations featured prominently in the formation and stabilization of M-NPs. This chapter summarizes studies which focused on the interdependencies of the IL with the metal nanoparticle and tried to elucidate, for example, influences of the IL-cation, -anion and alkyl chain length. Qualitatively, the size of M-NPs was found to increase with the size of the IL-anion. The influence of the size of imidazolium-cation is less clear. The M-NP size was both found to increase and to decrease with increasing chain lengths of the 1,3-dialkyl-imidazolium cation. It is evident from such reports on cation and anion effects of ILs that the interaction between an IL and a (growing) metal nanoparticle is far from understood. Factors like IL-viscosity, hydrogen-bonding capability and the relative ratio of polar and non-polar domains of ILs may also influence the stability of nanoparticles in ionic liquids and an improved understanding of the IL-nanoparticle interaction would be needed for a more rational design of nanomaterials in ILs. Furthermore, thiol-, ether-, carboxylic acid-, amino- and hydroxyl-functionalized ILs add to the complexity by acting also as coordinating capping ligands. In addition imidazolium cations are precursors to N-heterocyclic carbenes, NHCs which form from imidazolium-based ionic liquids by in situ deprotonation at the acidic C2-H ring position as intermediate species during the nanoparticle seeding and growth process or as surface coordinating ligand for the stabilization of the metal nanoparticle. PMID- 28589265 TI - Effects of ketamine on the unconditioned and conditioned locomotor activity of preadolescent and adolescent rats: impact of age, sex, and drug dose. AB - RATIONALE: Ketamine is used by preadolescent and adolescent humans for licit and illicit purposes. OBJECTIVE: The goal of the present study was to determine the effects of acute and repeated ketamine treatment on the unconditioned behaviors and conditioned locomotor activity of preadolescent and adolescent rats. METHODS: To assess unconditioned behaviors, female and male rats were injected with ketamine (5-40 mg/kg), and distance traveled was measured on postnatal day (PD) 21-25 or PD 41-45. To assess conditioned activity, male and female rats were injected with saline or ketamine in either a novel test chamber or the home cage on PD 21-24 or PD 41-44. One day later, rats were injected with saline and conditioned activity was assessed. RESULTS: Ketamine produced a dose-dependent increase in the locomotor activity of preadolescent and adolescent rats. Preadolescent rats did not exhibit sex differences, but ketamine-induced locomotor activity was substantially stronger in adolescent females than males. Repeated ketamine treatment neither caused a day-dependent increase in locomotor activity nor produced conditioned activity in preadolescent or adolescent rats. CONCLUSIONS: The activity-enhancing effects of ketamine are consistent with the actions of an indirect dopamine agonist, while the inability of ketamine to induce conditioned activity is unlike what is observed after repeated cocaine or amphetamine treatment. This dichotomy could be due to ketamine's ability to both enhance DA neurotransmission and antagonize N-methyl-D-aspartate (NMDA) receptors. Additional research will be necessary to parse out the relative contributions of DA and NMDA system functioning when assessing the behavioral effects of ketamine during early ontogeny. PMID- 28589267 TI - Associations Between Parental BMI and the Family Nutrition and Physical Activity Environment in a Community Sample. AB - The purpose of this study was to examine the relationship between parental BMI and the family environment and determine if differences exist in child diet and physical activity related parenting behaviors by parental BMI in a community sample of families recruited through elementary schools in a local school district. We found an association between parental BMI category and family nutrition and physical activity (FNPA) score. Families with an underweight or normal weight parent had a larger proportion (64.3%) of high (indicating a healthier family environment) FNPA scores and families with an overweight or obese parent had a smaller proportion (45.2%) of high FNPA scores (chi 2 = 5.247, P = 0.022). Families with a parent who was overweight or obese had 2.18 times the odds (95% CI 1.11-4.27) of being in the low FNPA ("less healthy" environment) group. Further, underweight/normal weight parents reported higher levels of monitoring of child diet (Z = -3.652, P < 0.0001), higher levels of parental monitoring of child physical activity (Z = -3.471, p < 0.001), and higher levels of parental limit setting related to child sedentary activities compared to overweight/obese parents (Z = -2.443, P = 0.01). Parent BMI and parenting behaviors are known to have a major impact on childhood obesity. In this study, lower parent BMI and authoritative parenting behaviors were associated with a less obesogenic home environment and a positive parenting style related to child eating and physical activity behaviors. PMID- 28589268 TI - E-Cigarette Users' Attitudes on the Banning of Sales of Nicotine E-Liquid, Its Implication on E-Cigarette Use Behaviours and Alternative Sources of Nicotine E Liquid. AB - The banning of sales of nicotine e-liquid in e-cigarette shops has been implemented in several states in Malaysia. The distribution of nicotine e-liquid can only be allowed by licensed pharmacies or registered medical practitioners. This study aimed to evaluate e-cigarette users' responses to the control policy in a cross-sectional survey of 851 e-cigarette users by utilizing a self-report questionnaire that assessed (1) attitudes on regulation policy of e-cigarette banning; (2) e-cigarette use behaviors; and (3) sources of e-liquid after the regulation policy has been implemented. Participants from the state of Selangor where the banning policy was implemented were surveyed. The majority (95.8%) opposed the banning and believed e-cigarettes should be sold to anyone aged 18 years or above as with tobacco cigarettes, only a minority believed that nicotine e-liquid should only be available for sale over the counter in pharmacy stores (14.6%) and in clinics with a doctor's prescription (11.8%). The majority (44.2%) reported that they would continue their e-cigarette use as before the banning policy, while 20% plan to completely stop e-cigarette usage without replacing it with any alternatives. The vast majority (87.9%) was still able to obtained nicotine e-liquid from e-cigarette shops in spite of the ban and the second most common source was from online purchase (63.1%). The sales of nicotine e-liquid from black-market were evidenced as many reported obtaining zero nicotine e liquid from the black market (54.4%). Self- or home-made (30.8%) nicotine e liquid was also reported. Majority of respondents that self-made e-liquid were from the average monthly income group (below MYR3000). Obtaining nicotine from the pharmacy was least preferred (21.4%). Provision of professional advice to nicotine e-liquid users along with the ban may lessen the likelihood of users switching to tobacco cigarettes or other nicotine alternatives. Banning of sales of nicotine e-liquid in e-cigarette shops resulted in a boom in the black market supplying nicotine e-liquid and, self- or home-made nicotine e-liquid. Enforcing regulations and monitoring black market sales is warranted. Efforts to educate e cigarette users of the danger of sourcing nicotine e-liquid from the black market and self- or home-made nicotine e-liquid are essential. PMID- 28589269 TI - Improving STD Screening Rates on a University Campus. AB - Gonorrhea and chlamydia infections have a high incidence among young adults. To increase screening rates among individuals aged 25 years of age and younger on a university campus, this quality improvement project was implemented to improve providers' knowledge of CDC guidelines through education. Education was provided to providers and staff members at a health clinic on a private residential university campus through informational sessions to increase knowledge of guideline-directed screening for gonorrhea and chlamydia. This education was coupled with a multifaceted approach for provider-reminder interventions: flagging patients in the EHR system that fall within the age group (25 years of age and younger) to generate an alert, patients completing a questionnaire while in the exam room, and identification of a project champion. Screening rates were evaluated during pre- and post-implementation phases to determine if a change in practice occurred among providers. Post-intervention revealed the average number of patients screened for gonorrhea and chlamydia was 65.85% (349/530). This change represented a marked increase from pre-intervention screening of 2% (11/405). The testing rate increased during the post-intervention phase to 17.86% (65/364), up from 7.90% (32/405) pre-implementation. Provider education on guideline-directed screening for gonorrhea and chlamydia increased screening among providers at a university health clinic. This intervention, combined with provider-reminder interventions, increased screening of patients, leading to an increased testing rate for gonorrhea and chlamydia. PMID- 28589270 TI - Community Health Workers Promote Civic Engagement and Organizational Capacity to Impact Policy. AB - Community health workers (CHW) have historically served to link structurally vulnerable populations to broad support systems. Emerging evidence suggests that CHWs engage in various forms of advocacy to promote policy and systems change. We assessed the impact of CHW community advocacy on community change, defined as civic engagement, organizational capacity and policy and systems change. Data are drawn from the 2014 National Community Health Worker Advocacy Survey (N = 1776) aimed to identify the state of the CHW profession, and their impact on health disparities through community advocacy and policy engagement. Our primary analysis used multiple linear regression to assess the association between CHW advocacy and community change. As predicted, there was a significant, positive association between CHW advocacy and change in community conditions. Additionally, both adjusted and sensitivity models had similar standardized beta estimates for advocacy, and adjusted R 2 statistics. CHW advocacy predicts positive change in community conditions and further advances the CHW Community Advocacy Framework designed to support and monitor CHW community advocacy to reduce health disparities through advocacy and policy change. PMID- 28589271 TI - Surveillance of pesticide residues in fruits and vegetables from Accra Metropolis markets, Ghana, 2010-2012: a case study in Sub-Saharan Africa. AB - Monitoring of pesticide residues in food commodities of plant origin is part of the regular controls on food to safeguard consumer's health. This study reports for the first time in Ghana a 3-year (2010-2012) monitoring of pesticide contamination of fruits and vegetables and their health implications. A total of 3483 samples were purchased in notable markets within Accra Metropolis and analysed for pesticide residues, employing the modified quick, easy, cheap, effective, rugged and safe analytical procedure. The results indicated that almost all the fruits and vegetables studied had residues above maximum residue limits (MRLs). The commodities with the greatest concentrations exceeding the European Union (EU) MRLs were long green beans (60.6%) and lettuce (57.1%) with watermelon (10%) and green pepper (8.6%) having the least. The relative occurrence of the pesticides was fenvalerate 11.3%, fenitrothion 5.6%, lambda cyhalothrin 3.6%, dimethoate 3.2%, permethrin 2.7% and deltamethrin 2.2%. These results will serve as a baseline on which annual or other long-term studies could be compared with, thus emphasizing the need for continuous monitoring programmes to regulate trends of pesticide residues in fruits and vegetables to safeguard the consumers' health. PMID- 28589273 TI - Synoptic sampling and principal components analysis to identify sources of water and metals to an acid mine drainage stream. AB - Combining the synoptic mass balance approach with principal components analysis (PCA) can be an effective method for discretising the chemistry of inflows and source areas in watersheds where contamination is diffuse in nature and/or complicated by groundwater interactions. This paper presents a field-scale study in which synoptic sampling and PCA are employed in a mineralized watershed (Lion Creek, Colorado, USA) under low flow conditions to (i) quantify the impacts of mining activity on stream water quality; (ii) quantify the spatial pattern of constituent loading; and (iii) identify inflow sources most responsible for observed changes in stream chemistry and constituent loading. Several of the constituents investigated (Al, Cd, Cu, Fe, Mn, Zn) fail to meet chronic aquatic life standards along most of the study reach. The spatial pattern of constituent loading suggests four primary sources of contamination under low flow conditions. Three of these sources are associated with acidic (pH <3.1) seeps that enter along the left bank of Lion Creek. Investigation of inflow water (trace metal and major ion) chemistry using PCA suggests a hydraulic connection between many of the left bank inflows and mine water in the Minnesota Mine shaft located to the north-east of the river channel. In addition, water chemistry data during a rainfall-runoff event suggests the spatial pattern of constituent loading may be modified during rainfall due to dissolution of efflorescent salts or erosion of streamside tailings. These data point to the complexity of contaminant mobilisation processes and constituent loading in mining-affected watersheds but the combined synoptic sampling and PCA approach enables a conceptual model of contaminant dynamics to be developed to inform remediation. PMID- 28589272 TI - Heavy metals distribution and risk assessment in soil from an informal E-waste recycling site in Lagos State, Nigeria. AB - Informal E-waste recycling can pose a risk to human health and the environment which this study endeavours to evaluate. The distribution of a number of heavy metals in soil from an informal recycling site in the largest market for used and new electronics and electrical equipment in West Africa was investigated. The potential bioavailability of heavy metals, extent of contamination, potential risk due to the recycling activities and impact of external factors such as rainfall were also assessed. The concentrations of all the heavy metals tested were higher in the area where burning of the waste occurred than at the control site, suggesting an impact of the recycling activities on the soil. The order of total metal concentrations was Cu > Pb > Zn > Mn > Ni > Sb > Cr > Cd for both the dry and wet seasons. The total concentrations of Cd, Cu, Mn, Ni and Zn were all significantly higher (p < 0.001) in the dry season than in the wet season. The concentrations of Cu (329-7106 mg kg-1), Pb (115-9623 mg kg-1) and Zn (508-8178 mg kg-1) were consistently higher than international soil guideline values. Using a sequential extraction method, the potential bioavailability of the heavy metals was indicated as Cd > Sb > Zn > Cu > Ni > Pb > Cr. When the risk was assessed using the Potential Ecological Risk Index (PERI), Cu was found to contribute the most to the potential ecological risk and Cd gave rise to the greatest concern due to its high toxic-response factor within the study site. Similarly, utilising the Risk Assessment Code (RAC) suggested that Cd posed the most risk in this site. This research establishes a high level of contamination in the study site and underscores the importance of applying the appropriate chemical speciation in risk assessment. PMID- 28589274 TI - Green synthesis and characterization of gold and silver nanoparticles using Mussaenda glabrata leaf extract and their environmental applications to dye degradation. AB - Plant-derived nanomaterials opened a green approach in solving the current environment issues. Present study focused on rapid microwave-assisted synthesis and applications of gold and silver nanoparticles mediated by aqueous leaf extract of Mussaenda glabrata. The synthesized nanoparticles were characterized by UV-vis, FT-IR, powder XRD, energy-dispersive X-ray spectroscopy (EDX), transmission electron (TEM), and atomic force microscopic techniques (AFM). FCC crystal structure of both nanoparticles was confirmed by peaks corresponding to (111), (200), (220), and (311) planes in XRD spectra and bright circular spots in SAED pattern. IC50 values shown by gold and silver nanoparticles (44.1 +/- 0.82 and 57.92 +/- 1.33 MUg/mL) reflected their high free radical scavenging potential. The synthesized gold and silver nanoparticles revealed their potency to inhibit pathogenic microorganisms Bacillus pumilus, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Aspergillus niger, and Penicillium chrysogenum. Anthropogenic pollutants rhodamine B and methyl orange were effectively degraded from aquatic environment and waste water sewages of dye industries using the prepared nanocatalysts. The catalytic capacities of the synthesized nanoparticles were also exploited in the reduction of 4-nitrophenol. Graphical abstract. PMID- 28589276 TI - Nitrate in drinking water and vegetables: intake and risk assessment in rural and urban areas of Nagpur and Bhandara districts of India. AB - The study focuses on the estimation of health risk from nitrate present in the drinking water and vegetables in Nagpur and Bhandara districts in the state of Maharashtra, India. Drinking water samples from 77 locations from the rural as well as urban areas and 22 varieties of vegetable were collected and analyzed for the presence of nitrate for a period of 1 year (two seasons). The daily intake of nitrate from these water and vegetable samples was then computed and compared with standard acceptable intake levels to assess the associated health risk. The mean nitrate concentration of 59 drinking water samples exceeded the Bureau of Indian Standards limit of 45 mg/L in drinking water. The rural and urban areas were found to have mean nitrate concentration in drinking water as 45.69 +/- 2.08 and 22.53 +/- 1.97 mg/L, respectively. The estimated daily intake of drinking water samples from 55 study sites had nitrate concentration far below the safety margin indicating serious health risk. The sanitation survey conducted in 12 households reported contaminated source with positive E. coli count in 20 samples as the major factor of health risk. The average nitrate concentration was maximum in beetroot (1349.38 mg/kg) followed by spinach (1288.75 mg/kg) and amaranthus (1007.64 mg/kg). Among the samples, four varieties of the vegetables exceeded the acceptable daily intake (ADI) with an assumption of 0.5 kg consumption of vegetables for an average of a 60-kg individual. Therefore, irrigation of these locally grown vegetables should be monitored periodically for nitrogen accumulation by the crop above the ADI limit. The application of nitrogenous fertilizers should also be minimized in the rural areas to help protect the nitrate contamination in groundwater sources. PMID- 28589275 TI - Visualization and quantification of transparent exopolymer particles (TEP) in freshwater using an auto-imaging approach. AB - Most water sources are full of microscopic transparent exopolymer particles (TEP), which are currently regarded as a major initiator of biofilm formation. This study developed and applied an auto-imaging FlowCAM-based method for online observation and quantification of TEP in freshwater. Samples from reservoirs in Taiwan with a wide range of water quality were directly used to develop this methodology. Factors that potentially affect the measurement were tested. The results showed that characteristics of the particles measured instantaneously after staining samples with Alcian blue differed significantly from those measured at steady states, as a result of particle aggregation. Compared to traditional microscopic methods, this proposed method provides a simple, rapid, and less labor-intensive analysis with particle morphological conservation and a large number of particle attributes. By overcoming the limitations from the former, this technique would offer routine monitoring of these transparent particles from various freshwater sources and feed water in membrane filtration, hence facilitating the use of TEP as a critical parameter for biofouling investigation in water treatment. Application of the method for Taiwan reservoirs showed a wide variety of morphological forms of TEP and its abundance, up to 25,000 ppm. PMID- 28589277 TI - An insight into salt stress tolerance mechanisms of Chenopodium album. AB - Salt stress is one of the most dramatic abiotic stresses that induce oxidative and osmotic stress simultaneously. Salt stress is known to be more effective in reducing growth and yield of glycophytes; however, halophytes are able to withstand salt stress. Nonetheless, variability exists among different halophytic plants species from different plant families. Chenopodium album belongs to Chenopodiacea family and is known as weed in many regions of world; however, it is a very interesting halophytic plant. Little research has conducted so far by considering C. album as model plant to study salt stress tolerance mechanisms. This article attempts to compile current literature in order to explain C. album salt stress tolerance mechanism and to highlight the knowledge gap relating to salt stress tolerance mechanism in C. album. Briefly, C. album has remarkable ability of seed dimorphism, sodium exclusion, and potassium retention. C. album further tolerates salt stress by increasing redox potential associated with high production of osmolytes and antioxidants. PMID- 28589278 TI - Hydrologic monitoring tools for freshwater municipal planning in the Arctic: the case of Iqaluit, Nunavut, Canada. AB - Freshwater and the services it provides are vital to both natural ecosystems and human needs; however, extreme climates and their influence on freshwater availability can be challenging for municipal planners and engineers to manage these resources effectively. In Arctic Canada, financial and human capital limitations have left a legacy of freshwater systems that underserve current communities and may be inadequate in the near future under a warming climate, growing population, and increasing demand. We address this challenge to community water resource planning by applying several novel water supply forecasting methods to evaluate the Apex River as an alternative freshwater source for Iqaluit, Nunavut (Canada). Surveys of water isotope composition of the Apex River and tributaries indicated that rainfall is the main source of water replenishment. This information was utilized to calibrate a water resource assessment that considered climate forecasting scenarios and their influence on supply, and alternative scenarios for freshwater management to better adapt to a changing climate. We found that under current climate and demand conditions, the freshwater supply of Iqaluit would be in a perpetual state of drawdown by 2024. Analysis of current infrastructure proposals revealed significant deficiencies in the supply extensions proposed whereby the Apex replenishment pipeline would only provide a 2-year extension to current municipal supply. Our heuristic supply forecast methods allowed for several alternative supply strategies to be rapidly evaluated, which will aid the community planning process by specifically quantifying the service life of the city's current and future primary water supply. PMID- 28589279 TI - Development of a real-time polymerase chain reaction assay for the detection of the invasive Mediterranean fanworm, Sabella spallanzanii, in environmental samples. AB - The Mediterranean fanworm, Sabella spallanzanii Gmelin 1791, was first detected in the Southern Hemisphere in the 1990s and is now abundant in many parts of southern Australia and in several locations around northern New Zealand. Once established, it can proliferate rapidly, reaching high densities with potential ecological and economic impacts. Early detection of new S. spallanzanii incursions is important to prevent its spread, guide eradication or control efforts and to increase knowledge on the species' dispersal pathways. In this study, we developed a TaqMan probe real-time polymerase chain reaction assay targeting a region of the mitochondrial cytochrome oxidase I gene. The assay was validated in silico and in vitro using DNA from New Zealand and Australian Sabellidae with no cross-reactivity detected. The assay has a linear range of detection over seven orders of magnitude with a limit of detection reached at 12.4 * 10-4 ng/MUL of DNA. We analysed 145 environmental (water, sediment and biofouling) samples and obtained positive detections only from spiked samples and those collected at a port where S. spallanzanii is known to be established. This assay has the potential to enhance current morphological and molecular-based methods, through its ability to rapidly and accurately identify S. spallanzanii in environmental samples. PMID- 28589281 TI - Preparation and characterization of glass hollow fiber membrane for water purification applications. AB - This work discusses the preparation and characterizations of glass hollow fiber membranes prepared using zeolite-5A as a starting material. Zeolite was formed into a hollow fiber configuration using the phase inversion technique. It was later sintered at high temperatures to burn off organic materials and change the zeolite into glass membrane. A preliminary study, that used thermogravimetric analysis (TGA), X-ray diffraction (XRD), and Fourier transform infrared (FTIR), confirmed that zeolite used in this study changed to glass at temperatures above 1000 degrees C. The glass hollow fiber membranes prepared using the phase inversion technique has three different microstructures, namely (i) sandwich-like structure that originates from inner layer, (ii) sandwich-like that originates from outer layer, and (iii) symmetric sponge like. These variations were influenced by zeolite weight loading and the flow rate of water used to form the lumen. The separation performances of the glass hollow fiber membrane were studied using the pure water permeability and the rejection test of bovine serum albumin (BSA). The glass hollow fiber membrane prepared from using 48 wt% zeolite loading and bore fluid with 9 mL min-1 flow rate has the highest BSA rejection of 85% with the water permeability of 0.7 L m-2 h-1 bar-1. The results showed that the separation performance of glass hollow fiber membranes was in the ultrafiltration range, enabled the retention of solutes with molecular sizes larger than 67 kDa such as milk proteins, endotoxin pyrogen, virus, and colloidal silica. PMID- 28589280 TI - Remediation and cytotoxicity study of polycyclic aromatic hydrocarbon contaminated marine sediments using synthesized iron oxide-carbon composite. AB - The study developed a new and cost-effective method for the remediation of marine sediments contaminated with polycyclic aromatic hydrocarbons (PAHs). Iron oxide (Fe3O4) nanoparticles were synthesized as the active component, supported on carbon black (CB), to form a composite catalyst (Fe3O4-CB) by using a wet chemical method. The oxidation of 16 PAH contaminants present in marine sediments significantly activated sodium persulfate (Na2S2O8) to form sulfate free radicals (SO4-.); this was investigated in a slurry system. In addition, in vitro cytotoxic activity and oxidative stress studies were performed. The synthesized composite catalysts (Fe3O4-CB) were characterized using X-ray diffraction, Fourier transform infrared spectroscopy, a superconducting quantum interference device magnetometry, and environmental scanning electron microscopy. The efficiency of PAH removal was 39-63% for unactivated persulfate (PS) from an initial dose of 1.7 * 10-7-1.7 * 10-2 M. The removal of PAHs was evaluated using Fe3O4/PS, CB/PS, and Fe3O4/PS and found to be 75, 64, and 86%, respectively, at a temperature of 303 K, PS concentration of 1.7 * 10-5 M, and pH of 6.0. An MTT assay was used to assess the cytotoxicity of the composite catalyst at five concentrations (25, 50, 100, 200, and 400 MUg/mL) on human hepatoma carcinoma (HepG2) cells for 24 h. This revealed a dose-dependent decrease in cell viability. A dichlorofluorescein diacetate assay was performed to evaluate the generation of reactive oxygen species, which principally originated from the ferrous ions of the composite catalyst. PMID- 28589282 TI - A comparison between two full-scale MBR and CAS municipal wastewater treatment plants: techno-economic-environmental assessment. AB - A holistic assessment procedure has been used in this study for comparing conventional activated sludge (CAS) and membrane bioreactor (MBR) processes for the treatment of municipal wastewater. Technical, social, administrative, economic and environmental impacts have been evaluated based on 1 year of operational data from three full-scale lines (one MBR and two CAS) working in parallel in a large municipal treatment plant. The comparative assessment evidences a slight advantage of the conventional process in the studied case, essentially due to lower costs, complexity and energy consumption. On the other hand, the MBR technology has a better social acceptance and similar overall environmental footprint. Although these results are influenced by site-specific parameters and cannot be generalized, the assessment procedure allowed identifying the most important factors affecting the final scores for each technology and the main differences between the compared technologies. Local conditions can affect the relative importance of the assessed impacts, and the use of weighting factors is proposed for better tailoring the comparative assessment to the local needs and circumstances. A sensitivity analysis on the weighted final scores demonstrated how local factors are very important and must be carefully evaluated in the decision making process. PMID- 28589283 TI - Evaluation of FOCUS surface water pesticide concentration predictions and risk assessment of field-measured pesticide mixtures-a crop-based approach under Mediterranean conditions. AB - FOCUS models are used in the European regulatory risk assessment (RA) to predict individual pesticide concentrations in edge-of-field surface waters. The scenarios used in higher tier FOCUS simulations were mainly based on Central/North European, and work is needed to underpin the validity of simulated exposure profiles for Mediterranean agroecosystems. In addition, the RA of chemicals are traditionally evaluated on the basis of single substances although freshwater life is generally exposed to a multitude of pesticides. In the present study, we monitored 19 pesticides in surface waters of five locations in the Portuguese 'Leziria do Tejo' agricultural area. FOCUS step 3 simulations were performed for the South European scenarios to estimate predicted environmental concentrations (PECs). We verified that 44% of the PECs underestimated the measured environmental concentrations (MEC) of the pesticides, showing a non compliance with the field data. Risk was assessed by comparing the environmental quality standards (EQS) and regulatory acceptable concentrations with their respective MECs. Risk of mixtures was demonstrated in 100% of the samples with insecticides accounting for 60% of the total risk identified. The overall link between the RA and the actual situation in the field must be considerably strengthened, and field studies on pesticide exposure and effects should be carried out to assist the improvement of predictive approaches used for regulatory purposes. PMID- 28589285 TI - Characterization of plastic beach debris finalized to its removal: a proposal for a recycling scheme. AB - Characterization of beach debris is crucial to assess the strategy to answer questions such as recycling. With the aim to assess its use in a recycling scheme, in this note, we carried out a physical and chemical characterization of plastic litter from a pilot beach in Central Italy, using the FT-IR spectroscopy and thermoanalysis. Fourteen polymers, having mainly thermoplastic origin, were identified; among them, the most represented are polyethylene (41.7%) and polypropylene (36.9%). Chemical and mechanical degradation were clearly observed by an IR spectrum. The thermogravimetric analysis curve of the plastic blend shows the melting point at 120-140 degrees C, and degradation occurs almost totally in a one-step process within 300-500 degrees C. The high heating value of the plastic debris is 43.9 MJ kg-1. Polymer blends obtained by beach debris show mechanical properties similar to the virgin high-density polyethylene polymer. Following the beach plastic debris characterization, a recycling scheme was suggested. PMID- 28589284 TI - Evaluation on subcellular partitioning and biodynamics of pulse copper toxicity in tilapia reveals impacts of a major environmental disturbance. AB - Fluctuation exposure of trace metal copper (Cu) is ubiquitous in aquatic environments. The purpose of this study was to investigate the impacts of chronically pulsed exposure on biodynamics and subcellular partitioning of Cu in freshwater tilapia (Oreochromis mossambicus). Long-term 28-day pulsed Cu exposure experiments were performed to explore subcellular partitioning and toxicokinetics/toxicodynamics of Cu in tilapia. Subcellular partitioning linking with a metal influx scheme was used to estimate detoxification and elimination rates. A biotic ligand model-based damage assessment model was used to take into account environmental effects and biological mechanisms of Cu toxicity. We demonstrated that the probability causing 50% of susceptibility risk in response to pulse Cu exposure in generic Taiwan aquaculture ponds was ~33% of Cu in adverse physiologically associated, metabolically active pool, implicating no significant susceptibility risk for tilapia. We suggest that our integrated ecotoxicological models linking chronic exposure measurements with subcellular partitioning can facilitate a risk assessment framework that provides a predictive tool for preventive susceptibility reduction strategies for freshwater fish exposed to pulse metal stressors. PMID- 28589287 TI - Transitive Versus Intransitive Complex Gesture Representation: A Comparison Between Execution, Observation and Imagination by fNIRS. AB - The aim of the present study was to examine cortical correlates of motor execution, motor observation and motor imagery of hand complex gestures, in particular by comparing meaningful gestures implying the use of an object (transitive action) or not (intransitive action). Functional near-infrared spectroscopy (fNIRS) was used to verify the presence of partial overlapping between some cortical areas involved in those different tasks. Participants were instructed to observe videos of transitive vs. intransitive gestures and then to execute or imagine them. Gesture execution was associated to greater brain activity (increased oxygenated hemoglobin levels) with respect to observation and imagination in motor areas (premotor cortex, PMC; primary sensorimotor cortex, SM1). In contrast, the posterior parietal cortex (PPC) was more relevantly involved in both execution and observation tasks compared to gesture imagination. Moreover, execution and observation of transitive gestures seemed primarily supported by similar parietal posterior areas when compared with intransitive gestures, which do not imply the presence on a object. PMID- 28589286 TI - Extracorporeal cytokine elimination as rescue therapy in refractory septic shock: a prospective single-center study. AB - Sepsis is the most common cause of death in medical intensive care units (ICU). If sepsis progresses to refractory septic shock, mortality may reach 90-100% despite optimum current therapy. Extracorporeal cytokine adsorption in addition to regular therapy was studied prospectively in refractory septic shock patients on a medical ICU. Refractory shock was defined as increasing vasopressor dose required to maintain mean arterial blood pressure above 65 mmHg or increasing lactate levels despite protocol-guided shock therapy for 6 h. We analysed noradrenaline requirements after 6 and 12 h (primary endpoint), lactate clearance after 6 and 12 h, SOFA-scores in the first days and achievement of shock reversal (i.e., normalization of lactate concentrations and sustained discontinuation of vasopressors; secondary endpoints). Twenty consecutive patients with refractory septic shock were included; CytoSorb(r) treatment was started after 7.8 +/- 3.7 h of shock therapy. Following the initiation of adsorption therapy, noradrenaline dose could be significantly reduced after 6 (-0.4 ug/kg/min; p = 0.03) and 12 h ( 0.6 ug/kg/min; p = 0.001). Lactate clearance improved significantly. SOFA-scores on day 0, 1 and 2 remained unchanged. Shock reversal was achieved in 13 (65%) patients; 28-day survival was 45%. In severe septic shock unresponsive to standard treatment, haemodynamic stabilization was achieved using cytokine adsorption therapy, resulting in shock reversal in two-thirds of these patients. The study was registered in the German Register for Clinical Trials (DRKS) No. 00005149. PMID- 28589289 TI - Human papillomavirus (HPV)-associated trilateral squamous neoplasia in immunocompetent individual. AB - PURPOSE: To describe a case of bilateral conjunctival and cervical human papillomavirus (HPV)-related squamous neoplasia. CASE DESCRIPTION: A healthy immunocompetent 55-year-old lady came to our attention for prosecution of care of a right recurrent conjunctival squamous cell carcinoma. Upon examination, she was found disease-free in the right eye but displayed a left conjunctival intraepithelial neoplasia (CIN grade I) and low-grade cervical squamous dysplasia. HPV infection with genotypes 16 (right eye), 11 and 39 (left eye) and 39 (uterine cervix) was also detected. CONCLUSION: Simultaneous uterine and conjunctival HPV-related squamous neoplasia can occur in immunocompetent individuals. Auto-inoculation and repeated exposure to HPV could explain coexistence of different genotypes. PMID- 28589288 TI - In focus in HCB. PMID- 28589290 TI - Validation of a single summary score for the Prolapse/Incontinence Sexual Questionnaire-IUGA revised (PISQ-IR). AB - INTRODUCTION AND HYPOTHESIS: The Prolapse/Incontinence Sexual Questionnaire International Urogynecology Association (IUGA) Revised (PISQ-IR) measures sexual function in women with pelvic floor disorders (PFDs) yet is unwieldy, with six individual subscale scores for sexually active women and four for women who are not. We hypothesized that a valid and responsive summary score could be created for the PISQ-IR. METHODS: Item response data from participating women who completed a revised version of the PISQ-IR at three clinical sites were used to generate item weights using a magnitude estimation (ME) and Q-sort (Q) approaches. Item weights were applied to data from the original PISQ-IR validation to generate summary scores. Correlation and factor analysis methods were used to evaluate validity and responsiveness of summary scores. RESULTS: Weighted and nonweighted summary scores for the sexually active PISQ-IR demonstrated good criterion validity with condition-specific measures: Incontinence Severity Index = 0.12, 0.11, 0.11; Pelvic Floor Distress Inventory 20 = 0.39, 0.39, 0.12; Epidemiology of Prolapse and Incontinence Questionnaire Q35 = 0.26 0,.25, 0.40); Female Sexual Functioning Index subscale total score = 0.72, 0.75, 0.72 for nonweighted, ME, and Q summary scores, respectively. Responsiveness evaluation showed weighted and nonweighted summary scores detected moderate effect sizes (Cohen's d > 0.5). Weighted items for those NSA demonstrated significant floor effects and did not meet criterion validity. CONCLUSIONS: A PISQ-IR summary score for use with sexually active women, nonweighted or calculated with ME or Q item weights, is a valid and reliable measure for clinical use. The summary scores provide value for assesing clinical treatment of pelvic floor disorders. PMID- 28589291 TI - Hydroxylation of Human Type III Collagen Alpha Chain by Recombinant Coexpression with a Viral Prolyl 4-Hydroxylase in Escherichia coli. AB - High-level expression of recombinant collagen by genetic engineering is urgently required. Recombinant collagen is different from natural collagen in its hydroxyproline (Hyp) content and thermal stability. To obtain hydroxylated collagen for applications in biomedicine and biomaterials, the human collagen alpha1(III) chain was co-expressed with the viral prolyl 4-hydroxylase A085R in Escherichia coli. Unlike previous reports using human prolyl 4-hydroxylase, this study examined the hydroxylation of full-length human collagen alpha1(III) chain (COL3A1) by viral prolyl 4-hydroxylase. The genes encoding these two proteins were controlled by different promoters, Ptac and PRPL, on a recombinant pKK223-3 plasmid. The sequencing results verified that the target genes were successfully inserted into the recombinant vector. Based on quantitative PCR, SDS-PAGE, and western blotting, successful expression by E. coli BL21(DE3) was detected at the mRNA and protein levels for both loci. Liquid chromatography-mass spectrometry (LC-MS/MS) results suggested that the highest Hyp yield was obtained when the two proteins were induced with 0.5 mM IPTG and heat-shock treatment at 50 degrees C, corresponding to high enzyme expression and low human collagen alpha1(III) chain expression levels. A biological activity analysis indicated that the recombinant collagen with the highest hydroxylation level supported the growth of baby hamster kidney cells, similar to observations for native collagen. The production of hydroxylated collagen in this study establishes a new method for collagen hydroxylation and provides a basis for the application of recombinant collagen expressed in E. coli. PMID- 28589292 TI - Detection of diverse viruses in alimentary specimens of bats in Macau. AB - Bats carry a variety of viruses, and some of them cause public health problems. Macau, which is famous for its gambling industry, has a complex population structure. The globalization in such an international metropolis has enhanced the chance of disease transmission. Therefore, surveillance of zoonotic viruses is necessary for the early warning of potential emerging infectious diseases. Here, we report the first surveillance of bat viruses in Macau. In this study, we collected 1004 samples involving 10 bat species from 7 sites from April 2015 to May 2016, and examined the presence of viruses using nucleic acid-based methods. Coronaviruses, adenoviruses and paramyxoviruses were detected in these samples, with a high prevalence of coronaviruses. While, none was positive for hepatitis A virus, hepatitis E virus or hantavirus. Co-infections are not common in those bat species, but coronavirus HKU6 and adenovirus can be found commonly occurred in Myotis ricketti. PMID- 28589293 TI - Impairment of osmotic challenge-induced neurohypophyseal hormones secretion in sepsis survivor rats. AB - BACKGROUND/PURPOSE: Recent studies have reported that sepsis survivors show impaired central nervous system functions. The osmoregulation in this post-sepsis condition has not been well investigated. In the present study, we evaluated the secretion of neurohypophyseal hormones, arginine vasopressin (AVP) and oxytocin (OT), and water intake induced by osmotic challenge in survivor rats. METHODS: Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP). Five days after CLP surgery, the survivor and naive animals were stimulated with an osmotic challenge consisting of hypertonic saline administration. Thirty minutes later, blood and brain were collected for determination of osmolality, nitrite, interleukin (IL)-1beta, IL-6, AVP and OT levels and c-fos expression analysis of hypothalamic supraoptic nuclei (SON), respectively. In another set of sepsis survivor animals, water intake was measured for 240 min after the osmotic stimulus. RESULTS: High levels of nitrite and IL-1beta, but not IL-6, were found in the plasma of sepsis survivors and this long-term systemic inflammation was not altered by the osmotic challenge. Moreover, the AVP and OT secretion (but not the osmolality) and c-fos expression in SON were significantly attenuated in CLP survivor animals. Additionally, there was no alteration in the water intake response induced by osmotic challenge in the sepsis survivor group. CONCLUSION: The results suggest that the inflammatory components mediated a persistent impairment in the component of the osmoregulatory reflex affecting the secretion of neurohypophyseal hormones in sepsis survivor animals. PMID- 28589294 TI - Acromegaly: surgical results in 548 patients. AB - PURPOSE: The goal of this study was to quantified the results of microsurgery, in all the patients with acromegaly treated by the same endocrinologist and the same surgeon between 1975 and 2015. METHODS: A series of 548 patients with acromegaly were operated and followed-up from 6 months to 40 years. Patients were selected according to five criteria: (1) Operated by the same surgeon. (2) No previous treatment. (3) Complete endocrinological preoperative studies including GH, OGTT, IGF-I, PRL test and TC/MRI. (4) Complete postoperative endocrinological evaluation for at least one determination of GH, OGTT, PRL test and IGF-I six months after surgery. (5) All the patients were supervised by the same endocrinologist. RESULTS: Microadenomas were present in 119 patients and 109 (91,5%) achieved remission. Non invasive macroadenomas were present in 200 patients and 164 achieved remission (82%). Results were worse for invasive macroadenomas but even with great invasions some patients achieved clinical remission. Follow-up range from 6 months to 40 years (mean 3.3 +/- 2.3) A long term follow-up of 15 years was achieved in 61 patients. Four of them had a recurrence 4, 7, 8, 12 years after surgery (6.5%). There was not mortality and the rate of complications was low. CONCLUSIONS: Surgery remains the first line of therapy for a majority of acromegalic patients. This series proves to be very valuable in circumscribed adenomas but also in invasive tumours. Levels of GH and IGF-I were decreased in almost all the patients without remission. PMID- 28589295 TI - [The qSOFA in the emergency department for early diagnosis of sepsis]. PMID- 28589296 TI - [Neglected, lonely and sick - the social breakdown : A special patient group in the emergency department]. AB - BACKGROUND: The emergency department (ED) is increasingly becoming the primary care unit of patients who are no longer able to meet the necessary minimum requirements for a healthy life. In the emergency medical care of these patients, fixation errors and stereotyped thinking can distract from serious illnesses, which can be tended by emergency medicine. This group of patients, with their multifactorial problems, represents a special challenge for the staff of the ED. The aim of this study is to improve the quality of the care for a special patient group. MATERIALS AND METHODS: A monocentric retrospective observation study was conducted at the University Hospital Bonn (UKB). On the basis of case studies, the emergency medical care of this special patient group was examined in the ED. RESULTS: Over the period of 7 years (2009 to 2016), 17 patients in a state of total neglect could be examined. The endpoints identified, during the emergency care, are the therapy of life-threatening diseases, laboratory pathologies, introduction of infectious protective measures, initiation of diagnostic measures, measures to be initiated within different departments (operating room, intensive care unit) and outcome. CONCLUSION: Patients in a state of total neglect require interdisciplinary primary care at a hospital with extended care structures. The apparent primary impression of these patients must not lead to a fixation error. Due to the often not obtainable history of the patient's and the complex appearance of these patients, the evaluation should be carried out according to a defined algorithm in the emergency room. PMID- 28589297 TI - Sulfate turpentine: a resource of tick repellent compounds. AB - Compounds with tick (Ixodes ricinus) repellent properties were isolated from sulfate turpentine consisting of Norway spruce (80%) and Scots pine (20%) from southern Sweden. The turpentine was divided into two fractions by distillation under reduced pressure resulting in one monoterpene hydrocarbon fraction and a residual containing higher boiling terpenoids. The monoterpene fraction was further oxidized with SeO2 to obtain oxygenated monoterpenes with potential tick repellent properties. The oxidized fraction and the high boiling distillation residual were each separated by medium pressure liquid chromatography. The fractions were tested for tick repellency and the compounds in those with highest tick repellency were identified by GC-MS. The fractions with highest repellency contained, mainly (-)-borneol, and mixtures of (+)- and (-)-1-terpineol and terpinen-4-ol. The enantiomers of borneol showed similar tick repellent properties. PMID- 28589298 TI - Changes in Esophageal Motility after Acupuncture. AB - BACKGROUND: Chinese medicine is widely used in the East with good results for the treatment of many diseases. Acupuncture has been increasingly used and recognized as a complementary medical treatment. Some studies on gastrointestinal motility are available; however, acupuncture effect on esophageal motility is still elusive due to the lack of studies with adequate methodology. This study aims to evaluate acupuncture effect on esophageal motility. METHODS: We studied 16 (50% females, mean age 26 years) volunteers. No individual underwent acupuncture sessions previously. All individuals underwent high-resolution manometry. The test was performed in three phases: basal measurements, 20 min after acupuncture stimulation of the gastrointestinal point (ST36), or 20 min after acupuncture stimulation of a sham point (5 cm medial to ST36) (crossover). ST36 or sham points were alternated in order based on randomization. Lower esophageal sphincter (LES) resting and residual pressure, distal latency (DL) ,and distal contractility integral (DCI) were recorded. All tests were reviewed by two experienced investigators blinded to the acupuncture point. RESULTS: LES resting pressure was significantly reduced after acupuncture (p = 0.015, Wilcoxon signed rank test). DL was significantly increased after acupuncture (either Sham or ST36) as compared to basal measurement. CONCLUSION: Our results showed that acupuncture on the digestive point decreases LES basal pressure. Acupuncture may be an alternative treatment to spastic disorders of the LES. PMID- 28589299 TI - Implementation and Evaluation of a Clinical Pathway for Pancreaticoduodenectomy Procedures: a Prospective Cohort Study. AB - INTRODUCTION: Medical and nursing protocols in perioperative care for pancreaticoduodenectomy are mainly mono-disciplinary, limiting their integration and transparency in a continuous health care system. The aims of this study were to evaluate adherence to a multidisciplinary clinical pathway for all pancreaticoduodenectomy patients during their entire hospital stay and to determine if the use of this clinical pathway is associated with beneficial effects on clinical end points. MATERIALS AND METHODS: A prospective cohort study was conducted in 95 pancreaticoduodenectomy patients treated according to a clinical pathway, including a variance report, compared to a historical control group (n = 52) with a traditional treatment regime. RESULTS: Process evaluation of the clinical pathway group revealed that protocol adherence throughout all units was above 80%. Major complications according to Clavien-Dindo classification grade >=3 decreased from 27 to 13%; p = 0.02. Hospital length of stay was significantly shorter in the clinical pathway group, median 10 days [IQR 8-15], compared with the control group, median 13 days [IQR 10-18]; p = 0.02. CONCLUSION: The use of a clinical pathway in pancreaticoduodenectomy patients was associated with high protocol adherence, improved outcome and shorter hospital length of stay. Variance report analysis and protocol adherence with a Prepare Act-Reflect Cycle are essential in surveillance of outcome. PMID- 28589300 TI - Extracorporeal devices for treatment of refractory pruritus in cholestatic liver disease. PMID- 28589302 TI - Implementation of an institutional protocol to improve inferior vena cava utilization and outcomes. AB - To evaluate the impact of an institutional protocol on patterns of use and outcomes of inferior vena cava filters (IVCF). Following a multidisciplinary effort, an institutional protocol involving dedicated follow-up of patients receiving IVCF and a physician education program regarding IVCF utilization, was established. We prospectively collected data of patients who received IVCF during 2015-2016, following protocol implementation (POST group). For comparison, we reviewed records of patients who received IVCF during 2009-2014, before implementation of the institutional protocol (PRE group). In the PRE and POST groups, 76 and 38 IVCF per year were inserted respectively, with an overall decrease of 50%. IVCF were more likely to be placed for therapeutic rather than prophylactic indications in the POST compared to the PRE group (P = 0.003). Follow-up rates at our coagulation clinic were significantly higher in the POST than the PRE group (100 vs. 22.9%, P < 0.0001), as were rates of attempted retrieval: 60.5% (23/38) vs. 16.7% (76/455), P < 0.0001. Failed retrieval occurred at similar rates: 15.8% (12/76) vs. 18.2% (4/22), P = 0.75. There was a trend towards a lower thrombotic complication rate in the POST than the PRE group: 2.6 vs. 11.2%, P = 0.16. Implementation of an institutional protocol significantly decreased the use of IVCF and increased the retrieval rate. Such intervention could potentially lead to lower rates of IVCF-related complications in the future. PMID- 28589301 TI - Investigating the role(s) of SufT and the domain of unknown function 59 (DUF59) in the maturation of iron-sulfur proteins. AB - Comprehending biology at the molecular and systems levels is predicated upon understanding the functions of proteins. Proteins are typically composed of one or more functional moieties termed domains. Members of Bacteria, Eukarya, and Archaea utilize proteins containing a domain of unknown function (DUF) 59. Proteins requiring iron-sulfur (FeS) clusters containing cofactors are necessary for nearly all organisms making the assembly of functional FeS proteins essential. Recently, studies in eukaryotic and bacterial organisms have shown that proteins containing a DUF59, or those composed solely of DUF59, function in FeS protein maturation and/or intracellular Fe homeostasis. Herein, we review the current literature, discuss potential roles for DUF59, and address future studies that will help advance the field. PMID- 28589303 TI - Three types of sagittal alignment regarding compensation in asymptomatic adults: the contribution of the spine and lower limbs. AB - PURPOSE: A comprehensive understanding of normative sagittal profile is necessary for adult spinal deformity. Roussouly described four sagittal alignment types based on sacral slope, lumbar lordosis, and location of lumbar apex. However, the lower limb, a newly described component of spinal malalignment compensation, is missing from this classification. This study aims to propose a full-body sagittal profile classification in an asymptomatic population based on full-body imaging. METHODS: This is a retrospective analysis of a prospective single-center study of 116 asymptomatic volunteers. Cluster analysis including all sagittal parameters was first performed, and then ANOVA was performed between sub-clusters to eliminate the non-significantly different parameters. This loop was repeated until all parameters were significantly different between each sub-cluster. RESULTS: Three types of full-body sagittal profiles were finalized according to cluster analysis with ten radiographic parameters: hyperlordosis type (77 subjects), neutral type (28 subjects), and compensated type (11 subjects). Radiographic parameters included knee angle, pelvic shift, pelvic angle, PT, PI LL, C7-S1 SVA, TPA, T1 slope, C2-C7 angle, and C2-C7 SVA. Age was significantly different across compensation types, while BMI and gender were comparable. Age matched subjects were randomly selected with 11 subjects in each type. ANOVA analysis revealed that all parameters but PT and C2-C7 angle remained significantly different. CONCLUSIONS: The current three compensation types of full-body sagittal profiles in asymptomatic adults included significant changes from cervical region to knee, indicating that subjects should be evaluated with full-length imaging. All three types exist regardless of age, but the distribution may vary. PMID- 28589305 TI - Discriminating Ability of Abbreviated Impactor Measurement Approach (AIM) to Detect Changes in Mass Median Aerodynamic Diameter (MMAD) of an Albuterol/Salbutamol pMDI Aerosol. AB - This article reports on results from a two-lab, multiple impactor experiment evaluating the abbreviated impactor measurement (AIM) concept, conducted by the Cascade Impaction Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS). The goal of this experiment was to expand understanding of the performance of an AIM-type apparatus based on the Andersen eight-stage non-viable cascade impactor (ACI) for the assessment of inhalation aerosols and sprays, compared with the full-resolution version of that impactor described in the pharmacopeial compendia. The experiment was conducted at two centers with a representative commercially available pressurized metered dose inhaler (pMDI) containing albuterol (salbutamol) as active pharmaceutical ingredient (API). Metrics of interest were total mass (TM) emitted from the inhaler, impactor-sized mass (ISM), as well as the ratio of large particle mass (LPM) to small particle mass (SPM). ISM and the LPM/SPM ratio together comprise the efficient data analysis (EDA) metrics. The results of the comparison demonstrated that in this study, the AIM approach had adequate discrimination to detect changes in the mass median aerodynamic diameter (MMAD) of the ACI-sampled aerodynamic particle size distribution (APSD), and therefore could be employed for routine product quality control (QC). As with any test method considered for inclusion in a regulatory filing, the transition from an ACI (used in development) to an appropriate AIM/EDA methodology (used in QC) should be evaluated and supported by data on a product-by-product basis. PMID- 28589304 TI - Prevalence of abnormal lactose breath hydrogen tests in children with functional abdominal pain. AB - OBJECTIVES: The study was undertaken to determine the prevalence of abnormal lactose breath hydrogen test in children with non-organic chronic abdominal pain. METHODS: Children with chronic abdominal pain were examined and investigated for organic causes. All children without a known organic cause underwent lactose and glucose breath hydrogen test. After a standard dose of 2 g/kg of lactose to a maximum of 50 g, hydrogen in breath was measured at 15 min intervals for 3 h. A rise of 20 ppm above baseline was considered suggestive of lactose malabsorption. RESULTS: Of 108 children screened, organic causes were found in 46 children. Sixty-two patients without any organic cause underwent hydrogen breath test. Lactose hydrogen breath test (HBT) was positive in 36 of 62 (58%), while 11 (17%) had positive HBT with glucose suggestive of small intestinal bacterial overgrowth (SIBO). Twenty out of 34 (59%) improved on lactose free diet while 8 out of 11 (72%) children of SIBO improved on antibiotics. CONCLUSIONS: Lactose malabsorption was seen in 58% of children with non-organic chronic abdominal pain. PMID- 28589307 TI - Cultivating Community-Responsive Future Healthcare Professionals: Using Service Learning in Pre-Health Humanities Education. AB - This essay argues that service-learning pedagogy is an important tool in pre health humanities education that provides benefits to the community and produces more compassionate, culturally competent, and community-responsive future healthcare professionals. Further, beginning this approach at the baccalaureate level instills democratic and collaborative values at an earlier, crucial time in the career socialization process. The discussion focuses on learning outcomes and reciprocity between the university and community in a Medical Humanities course for junior and senior premedical students, an elective in the premedical curriculum. The course includes an experiential learning element in which students shadow physicians and a service-learning component in which students complete medically-relevant service work, working with partners such as the veteran's hospital, a hospice home, and organizations that serve individuals with disabilities. We cover topics such as narrative medicine, ethics, cross-cultural medicine, patient/practitioner relationships, the human life cycle, and the illness experience, and the writing, discussion, and reflection we engage in is enriched by the real-world experiences from which the students are able to draw. The shadowing and service experiences and the classroom texts and topics combine to form a symbiosis that leads to especially meaningful teaching and learning outcomes. PMID- 28589306 TI - Application of a Biodegradable Polyesteramide Derived from L-Alanine as Novel Excipient for Controlled Release Matrix Tablets. AB - This pre-formulation study assays the capacity of the polyesteramide PADAS, poly (L-alanine-dodecanediol-L-alanine-sebacic), as an insoluble tablet excipient matrix for prolonged drug release. The flow properties of PADAS were suitable for tableting, and the compressibility of tablets containing exclusively PADAS was evaluated by ESEM observation of the microstructure. The tablets were resistant to crushing and non-friable and they did not undergo disintegration (typical features of an inert matrix). Tablets containing 33.33% sodium diclofenac (DF), ketoprofen (K) or dexketoprofen trometamol (DK-T) as a model drug, in addition with 66.67% of polymer, were formulated, and the absence of interactions between the components was confirmed by differential scanning calorimetry. Dissolution tests showed that PADAS retained DF and K and prolonged drug release, following a Higuchi kinetic. The tablets containing DK-T did not retain the drug sufficiently for prolonged release to be established. Tablets containing DK-T and 66.67, 83.33 or 91.67% PADAS, compressed at 44.48 or 88.96 kN, were elaborated to determine the influence of the polymer amount and of the compression force on DK-T release. Both parameters significantly delayed drug release, except when the proportion of polymer was 91.67%. PMID- 28589308 TI - The Medical Humanities Effect: a Pilot Study of Pre-Health Professions Students at the University of Rochester. AB - Qualitative and quantitative research on the impact of medical and health humanities teaching in baccalaureate education is sparse. This paper reviews recent studies of the impact of medical and health humanities coursework in pre health professions education and describes a pilot study of baccalaureate students who completed semester-long medical humanities courses in the Division of Medical Humanities & Bioethics at the University of Rochester. The study format was an email survey. All participants were current or former baccalaureate students who had taken one or more courses in literature and narrative in medicine, bioethics, history of medicine, and/or visual arts and healthcare during the past four years. The survey gathered numerical data in several areas: demographic information, career plans, self-reported influence of coursework on educational and career plans, and self-reported influence of coursework on intellectual skills and abilities. It also gathered narrative commentary that elaborated on students' responses to the numerically-based questions. Notable findings from preliminary analysis of the data include higher scores of self reported impact of the coursework on specific habits of mind and on preparedness for intended career rather than on gaining admission to future educational programs. Discussion of the results focuses on several potential future directions this type of study might take, including multi-center, longitudinal, and sequential approaches. PMID- 28589309 TI - Influential factors on treatment decision making among patients with colorectal cancer: A scoping review. AB - PURPOSE: In recent years, a greater emphasis has been placed on shared decision making (SDM) techniques between providers and patients with the goal of helping patients make informed decisions about their care and subsequently to improve patient health outcomes. Previous research has shown variability in treatment decision-making among patients with colorectal cancer (CRC), and there is little comprehensive information available to help explain this variability. Thus, the purpose of this study was to evaluate the current state of the literature on factors that are influential in treatment decision-making among patients with CRC. METHOD: A priori search terms using Boolean connectors were used to examine PubMed, PsycINFO, Web of Science, CINAHL, and MEDLINE for relevant studies. Eligibility criteria for inclusion in the study included patients with CRC and examination of influences on CRC treatment decision-making. All relevant data were extracted including, author, title and year, study methodology, and study results. RESULTS: Findings (n = 13) yielded influences in four areas: informational, patient treatment goals, patient role preferences, and relationship with provider. Quality of life and trust in physician were rated a high priority among patients when making decisions between different therapeutic options. Several studies found that patients wanted to be informed and involved but did not necessarily want to make autonomous treatment choices, with many preferring a more passive role. CONCLUSIONS: Providers who initiate a dialog to better understand their patients' treatment goals can establish rapport, increase patient understanding of treatment options, and help patients assume their desired role in their decision-making. Overall, there were a small number of studies that met all inclusion criteria with most used a cross-sectional design. PMID- 28589311 TI - Needs assessment of primary care physicians in the management of chronic pain in cancer survivors. AB - INTRODUCTION: Cancer patients live longer with effective anti-cancer therapy and supportive care. About 30% of cancer survivors (non-palliative cancer patients who completed treatment) suffer from chronic pain, which will be managed by their primary care physician (PCP). The aim of this study was to assess practice patterns and treatment barriers in the management of chronic pain in cancer survivors among PCPs. METHODS: A survey using a 16-item questionnaire was sent to PCPs across Canada. RESULTS: A total of 162 responses were collected. The majority of participants were in group (59%) or solo (33%) practice, with an average of 25 years of clinical experience. Seventy-one percent of PCPs were practicing in communities of 10,000 to 100,000 people. Respondents were treating approximately 10 cancer survivors with chronic pain per month. The majority of PCPs (59%) reported having "little knowledge" or "some understanding" of chronic pain management in cancer survivors. They did not usually refer these patients to other specialists. Patient comorbidities (79%), pain medication side effects (78%), previous pain treatment (76%), effect of pain on daily functioning (75%), and drug interactions (71%) were identified as factors that guided PCP treatment choices. Major barriers included medication cost (54%), concerns about opioid abuse (51%), and patient non-compliance (46%). PCPs indicated that treatment guidelines (74%) and knowledge of pharmacological (64%) and non-pharmacological (62%) treatment options would help their chronic pain management. CONCLUSION: Most PCPs report a lack of knowledge in the management of chronic pain in cancer survivors but are keen to receive medical education on treatment options and clinical practice guidelines. PMID- 28589310 TI - Optimal clinical assessment strategies for chemotherapy-induced peripheral neuropathy (CIPN): a systematic review and Delphi survey. AB - BACKGROUND/PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a prominent side effect of the treatment of cancer. Despite this frequent complication, there has been no comprehensive review and quality appraisal of CIPN assessments. The purpose of this study is to provide a definitive quality appraisal of CIPN assessment strategies for clinical use. METHODS: Relevant studies were identified through database searches of Medline, Embase, CINAHL, and Cochrane. CIPN assessment strategies from included articles were extracted and initially rated by an oncologist and neurophysiologist according to criteria related to assessment depth, comprehensiveness, appropriateness, and reliability. The six highest scoring assessment strategies were the focus of a two-round Delphi survey of a working party of 32 physicians, nurses, and consumers to achieve consensus on the highest rated assessments for each criterion. RESULTS: The database search yielded 117 distinct CIPN assessments that were extracted from 2373 articles. Three patient-reported outcome surveys and three clinician based assessments were included in the Delphi survey. No consensus was generated regarding the best overall CIPN assessment, although good (>=70%) consensus was achieved regarding the best assessment within each criterion. The Participant Neurotoxicity Questionnaire (PNQ) was rated the highest overall and patient reported outcome (PRO) assessment, while the Total Neuropathy Score clinical version (TNSc) was the highest rated clinician-based assessment. CONCLUSIONS: A diverse range of CIPN assessments currently exists. While several assessments assess CIPN symptoms with adequate comprehensiveness, depth, language, and feasibility, the consensus 'gold standard' clinical assessment remains to be established. PMID- 28589312 TI - Assessing the diversity of preferences of suburban smallholder sheep keepers for breeding rams in Ouagadougou, Burkina Faso. AB - Urbanisation in developing countries entails deep changes in the livestock sector and the management of animal genetic resources (AnGR). Sheep breeding around Ouagadougou (Burkina Faso) illustrates these changes and the need to coordinate genetic improvement in general and the use of crossbreeding in particular. For this, it is important to understand breeders' choices and improvement strategy, to accompany them within a national plan for AnGR management. In a context of missing market for breeding rams, a stated choice experiment was conducted with 137 farmers, together with a characterisation of herd management practices. This survey analyses farmers' preferences for breeding rams, estimating their willingness to pay (WTP) for different traits (attributes). Their practices were characterised by a high reliance on natural pastures (82% of farmers) and a minority of crossbreeding (23%). The highest WTP was observed for disease resistance. However, the subgroup of farmers practicing crossbreeding showed a tolerance to high susceptibility. A strong preference for the white colour was revealed. Although significant, the influence of sheep body size on decision making showed a lesser importance, again with a distinct behaviour in the subgroup practicing crossbreeding. These results illustrate the need to take account of the diversity of goals and preferences among smallholder sheep keepers to gain their adhesion to a coordinated genetic improvement framework. PMID- 28589313 TI - Effect of a collar on subsidence and local micromotion of cementless femoral stems: in vitro comparative study based on micro-computerised tomography. AB - PURPOSE: The aim of this study is to quantitatively compare the difference in primary stability between collarless and collared versions of the same femoral stem. Specifically, we tested differences in subsidence and micromotion. METHODS: Collarless and collared versions of the same cementless femoral stem were implanted in two groups of six fresh-frozen cadaveric femurs. Each implanted femur was then subsequently tested for axial compressive and torsional loadings. A micro-CT based technique was applied to quantify implant subsidence and compute the map of local micromotion around the femoral stems. Micromotion of collarless and collared stems was compared in each Gruen zone. RESULTS: Subsidence was higher but not significantly (p = 0.352) with collarless (41.0 +/- 29.9 MUm) than with collared stems (37.0 +/- 44.6 MUm). In compression, micromotion was lower (p = 0.257) with collarless (19.5 +/- 5 MUm) than with collared stems (43.3 +/- 33.1 MUm). In torsion, micromotion was also lower (p = 0.476) with collarless (96.9 +/ 59.8 MUm) than collared stems (118.7 +/- 45.0 MUm). Micromotion was only significantly lower (p = 0.001) in Gruen zone 1 and for compression with collarless (7.0 +/- 0.6 MUm) than with collared stems (22.6 +/- 25.5 MUm). CONCLUSIONS: Primary stability was achieved for both stem designs, with a mean micromotion below the osseointegration threshold. Under loading conditions similar to those observed in normal daily activity and with good press-fit, the collar had no influence on subsidence or micromotion. Further studies are required to test the potential advantage of collar with higher loads, undersized stems, or osteoporotic femurs. PMID- 28589314 TI - The Health-Related Quality of Life of Chinese Patients on Hemodialysis and Peritoneal Dialysis. AB - AIMS: Our aim was to compare health-related quality of life (HRQOL) between end stage renal disease (ESRD) patients and the Hong Kong general population to identify how the mode of dialysis and other factors were associated with HRQOL. METHODS: We conducted a cross-sectional study involving 253 hemodialysis (HD) patients and 103 peritoneal dialysis (PD) patients recruited in 2014-2015. Their HRQOL was evaluated using Kidney Disease and Quality of Life-36 (KDQOL-36) sub scale scores and the Short Form-6 Dimensions (SF-6D) health preference score. One way analysis of variance was used to analyze the difference in mean KDQOL-36 and SF-6D scores among PD patients, HD patients, and an exact age- and sex-matched general population. Multiple linear regressions were conducted to evaluate factors associated with the KDQOL-36 and SF-6D scores. RESULTS: The physical HRQOL of ESRD patients on dialysis was worse than that of the age- and sex matched general population (38.4 vs. 49.6), but mental HRQOL was similar (50.7 vs. 52.0). After adjusting for all baseline characteristics, male subjects was associated with higher physical component summary (PCS), SF-6D, and symptom scores. A higher level of education (secondary or tertiary) was associated with higher mental component summary (MCS), SF-6D, symptom, and effects scores. Patients who were female, younger, married, and less educated and had a history of cardiovascular disease (CVD) and did not achieve target hemoglobin and albumin levels were associated with poorer HRQOL outcomes. CONCLUSIONS: HD was associated with a greater negative impact of ESRD on daily lives than was PD, which may be a consideration when deciding on the dialysis modality for first-line renal replacement therapy. To improve HRQOL among patients on maintenance dialysis, more attention should be paid to those with demographic risk factors, preventing CVD, and meeting clinical dialysis outcome targets such as hemoglobin and albumin levels. PMID- 28589315 TI - Effect of blood glucose level on acute stress response of grass carp Ctenopharyngodon idella. AB - Stress has a considerable impact on welfare and productivity of fish, and blood glucose level of fish may be a factor modulating stress response. This study evaluated the effect of blood glucose level and handling on acute stress response of grass carp Ctenopharyngodon idella. Fish were intraperitoneally injected with glucose at 0, 0.2, 0.5, and 1.0 mg g-1 body mass (BM) and then were exposed to handling for 5 min. Glucose injection resulted in increase of plasma glucose level and liver glycogen content and decrease of plasma lactate level. Handling resulted in increase of plasma levels of cortisol, glucose, and lactate and plasma lactic dehydrogenase (LDH) activity and decrease of liver glycogen content. At 1 h post-stress, the plasma cortisol level was lower in the stressed fish injected with glucose at 0.5 mg g-1 BM than the stressed fish injected with glucose at 0, 0.2, and 1.0 mg g-1 BM. No significant differences were found in the activities of phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate kinase (PK) in the liver between the stressed and unstressed fish, regardless of the dose of glucose injection. At 1 h post-stress, the liver glucose-6-phosphatase (G6Pase) activity was higher in the fish without glucose injection than in the fish injected with glucose. This study reveals that blood glucose level can affect stress response of grass carp by modulating cortisol release and glucose homeostasis through glycogen metabolism and gluconeogenesis in the liver. PMID- 28589316 TI - Androgen-induced pseudo-hermaphroditic phenotypes in female Brevimyrus niger Gunther 1866 (Teleostei, Mormyridae). AB - This paper explores the plasticity of sexually dimorphic characters in subadult female Brevimyrus niger, an African weakly electric mormyrid species. Thirty-five fish were exposed in a staggered fashion (five fish a week) to aromatizable 17alpha-methyltestosterone over a period of 7 weeks; 18 fish served as untreated controls. 17alpha-MT induced precocious vitellogenesis that mirrored the natural maturational process during seasonal ovarian recrudescence. At the same time, 17alpha-MT exposure resulted in complete masculinization of the females' anal fin support structure normally observed during rainy season in adult males. We discuss possible hormonal mechanisms acting along the brain-pituitary-gonad axis that would explain the occurrence of precocious vitellogenesis and the male typical transformation of the female's anal fin ray bases. Our findings are relevant to commercial aquaculture as the use of 17alpha-MT in fish hatcheries can pose serious environmental issues. PMID- 28589317 TI - Bcl6 gene-silencing facilitates PMA-induced megakaryocyte differentiation in K562 cells. AB - Targeted therapy via imatinib appears to be a promising approach for chronic myeloid leukemia (CML) therapy. However, refractory and resistance to imatinib therapy has encouraged many investigators to get involved in development of new therapeutic agents such as Phorbol 12-myrestrat 13-acetate (PMA) for patients with CML. In that line, we attempted to investigate the chemosensitizing effect of PMA on the imatinib-resistant cells. Based on our western blot analyses, resistant K562 cells (K562R) showed high levels of FoxO3a and Bcl6 expressions which were not modulated by imatinib treatment. However, upon PMA treatment, the levels of both FoxO3a and Bcl6 were up-regulated among both the sensitive and the resistant cells and this treatment was associated with initiation of megakaryocytic differentiation of the cells. SiRNA-silencing of FoxO3a led to augmentation of megakaryocytic differentiation of the cells. Similarly, siRNA gene silencing of Bcl6 enhanced the differentiation and induced cell apoptosis among both types of cells. Regarding these results, it might be concluded that Bcl6 knockdown combined with PMA therapy could present a new therapeutical strategy for refractory CML patients to imatinib. PMID- 28589319 TI - The transotic approach for vestibular schwannoma: indications and results. AB - To analyze retrospectively the indications and the results obtained with the transotic approach in a series of patients with vestibular schwannoma. The study included 36 patients from 2007 to 2013 with a vestibular schwannoma that was removed with a transotic approach. All patients underwent preoperative pure tone audiometry, evaluation of facial function and CT and MR imaging. All patients having (1) a hearing loss of more than 50 dB, (2) an average tumor size of 2.7 cm (range 0.5-5.0 cm) and (3) signs of a contracted mastoid (high jugular bulb, anteriorly located sigmoid sinus, low middle cranial fossa, or reduced pneumatization) were selected. The tumor was totally removed in 34 and near totally removed in 2 patients. The facial nerve was preserved in all patients. The postoperative facial function after 6 weeks was House-Brackmann grade I in 7, grade II in 27, and grade III in 2 patients. All patients presented postoperatively with unilateral total deafness. Seven patients experienced transitory postoperative imbalance. There were two patients who required revision surgery, one with intracranial hemorrhage and another with a CSF leak. There were no deaths and no severe complications such as hemiplegia or intracranial infections. The transotic approach has proven to be of value for the removal of vestibular schwannomas up to 5.0 cm in the presence of temporal bone contraction. Hearing was not preserved; however, other clinical outcomes were very favorable, including high rates of total tumor removal and facial nerve preservation, and low rates of complications. PMID- 28589318 TI - Matricellular proteins in cancer: a focus on secreted Frizzled-related proteins. AB - Tumours are complex entities, wherein cancer cells interact with myriad soluble, insoluble and cell associated factors. These microenvironmental mediators regulate tumour growth, progression and metastasis, and are produced by cancer cells and by stromal components such as fibroblast, adipocytes and immune cells. Through their ability to bind to extracellular matrix proteins, cell surface receptors and growth factors, matricellular proteins enable a dynamic reciprocity between cancer cells and their microenvironment. Hence, matricellular proteins play a critical role in tumour progression by regulating where and when cancer cells are exposed to key growth factors and regulatory proteins. Recent studies suggest that, in addition to altering Wingless (Wnt) signalling, certain members of the Secreted Frizzled Related Protein (sFRP) family are matricellular in nature. In this review, we outline the importance of matricellular proteins in cancer, and discuss how sFRPs may function to both inhibit and promote cancer progression in a context-dependent manner. By considering the matricellular functionality of sFRPs, we may better understand their apparently paradoxical roles in cancers. PMID- 28589320 TI - Impact of the round window membrane accessibility on hearing preservation in adult cochlear implantation. AB - This study was conducted to evaluate the effect of the round window membrane accessibility on the residual hearing after cochlear implantation surgery in adults. Moreover, the effects of the other demographics and intra-operative factors on the residual hearing loss have been evaluated. The hearing preservation cochlear implantation surgery was performed on 64 adults with residual hearing thresholds <=80 dB at 250 and 500 Hz, who had referred to our tertiary academic center. All the patients underwent a standardized surgical approach with the same straight electrode inserted through the round window membrane. The hearing thresholds at 250, 500, and 1000 Hz were compared in pre operative and 1 month postoperative pure-tone audiograms. The average hearing threshold shifts at these frequencies was used to evaluate the hearing preservation. The effects of the round window accessibility and other factors (including gender, age, side of the surgery, necessity of anterior-inferior drilling of the round window margin and average insertion speed) on hearing threshold shifts were analyzed. The mean low-frequency hearing threshold shift was found to be 17.5 dB for all the patients. The hearing preservation goal (threshold shifts <=30 dB) was achieved in 58 patients. Among the evaluated parameters, only accessibility of the round window membrane could change the hearing threshold shifts significantly (p = 0.026), and was a predictor for the hearing loss (B coefficient = 7.5, p = 0.006). Incomplete accessibility of the round window membrane may be a predictor for increased hearing threshold shifts in short-term evaluations after cochlear implantation. PMID- 28589321 TI - Latent tuberculosis infection and tuberculosis in patients with rheumatic diseases treated with anti-tumor necrosis factor agents. AB - The introduction of biological agents, especially the tumor necrosis factor inhibitors (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI) is strongly recommended before starting therapy with anti-TNF agents. The objective of this study was to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF agents. This is a cross-sectional study. The electronic medical records of all adult patients (>=18 years old) undergoing anti TNF treatment were reviewed. Every patient underwent tuberculin skin test (TST) before starting anti-TNF treatment. In total, 176 patients were included; the mean age was 51.9 +/- 12.4 years, 34.7% were males, and 90.9% were white. The underlying diseases were rheumatoid arthritis (RA) in 50.6% (N = 89), ankylosing spondylitis (AS) in 27.8% (N = 49), and psoriatic arthritis (PsA) in 17.6% (N = 31). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p = 0.020). RA patients had lower TST reactions than AS patients (p = 0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR's recommendation that patients who live in high TB incidence settings should be tested annually for LTBI. PMID- 28589322 TI - Comparison of systemic lupus erythematosus (SLE) patients managed early after diagnosis in specialty versus community care clinics. AB - To compare management and outcomes of SLE patients treated in community clinics (Cc) with those treated in specialty clinic (Sc) within 10 years after SLE diagnosis. A single-center, matched cohort study design was used. We identified 54 SLE patients who were referred to a Sc from Cc within 5 years of SLE diagnosis, and 101 inception SLE patients who followed in a Sc. Patients in Cc were matched 1:2 based on gender, decade of SLE diagnosis, and age at diagnosis within 3 years with Sc patients. Disease characteristics, damage accumulation, death, cardiovascular (CVS) risk factors, and events were compared at 5 and 10 years of disease. Regression analyses taking into account the paired data were conducted. At 5 years of disease, patients referred from Cc had less cumulative ACR criteria, but more active disease. They were on higher doses of glucocorticoids (GCS) but less antimalarial treatment. At 10 years of disease and follow-up entirely in Sc, Sc patients had less disease activity. They had lower cumulative GCS doses. They had less hypertension and osteoporosis but more hypercholesterolemia than Cc patients. No statistically significant difference in damage accrual, CVS events, and death were detected. Regression analysis confirmed an association between being inception Sc patients and less active disease at 10 years. Lupus patients should be under the care of a lupus specialist early in their disease course for better control of their disease activity and to minimize use of GCS. PMID- 28589324 TI - Psychotherapy for the Medical Student. PMID- 28589325 TI - The "Virtual Preceptor": A Teaching Tool Developed to Increase Resident Access to Supervision. PMID- 28589323 TI - Elderly psoriatic arthritis patients on TNF-alpha blockers: results of an Italian multicenter study on minimal disease activity and drug discontinuation rate. AB - Psoriatic arthritis (PsA) is an inflammatory arthropathy, associated with skin and/or nail psoriasis. Real world data on efficacy and safety of TNF-alpha blockers in the elderly with PsA are lacking. The aim of this study was to evaluate the effectiveness, through the achievement of minimal disease activity (MDA), drug discontinuation rate, and safety in elderly patients with PsA on TNF alpha blockers. A multicenter, observational study was carried out in four Italian centers. The assessment of disease activity and safety were performed at the start of anti-TNF-alpha (T0), at 6 months (T6) and at 12 months (T12). A total of 145 PsA patients were included in the study. At baseline 68 (46.9%) patients were on etanercept, 60 (41.3%) on adalimumab, 11 (7.6%) on golimumab, and 6 (4.1%) on infliximab. All the variables concerning PsA activity showed a statistically significant improvement when comparing T6 and T12 with T0. After 6 and 12 months of therapy, respectively, 31 (22.6%) and 71 (51.8%) patients achieved MDA (p < 0.001). The drug discontinuation rate was 5.5% with a mean of 6.8 months (range 2-10 months), and it was due to lack of efficacy, adverse events, and lost to follow-up. Nine patients (6.2%) reported the onset of mild infections resolved with antimicrobial specific oral regimen without therapy interruption. TNF-alpha blockers are effective in the achievement of a low disease status and safe in elderly patients with PsA. Therefore, age should not be considered a limitation to their use. PMID- 28589326 TI - Therapeutic Assignments: Piloting a Way for Medical Students on the Psychiatry Clerkship to Interact with Patients Beyond the Initial Interview. PMID- 28589327 TI - Collaborative Integration of Ethics Education. PMID- 28589328 TI - Results from the Field: Development and Evaluation of a Psychiatry Residency Training Rotation in Cognitive-Behavioral Therapies. AB - OBJECTIVE: The goal of this project was to develop and evaluate a new residency training rotation focused on cognitive-behavioral therapies (CBT) and to assess outcomes across multiple domains. METHODS: Data are presented from 30 psychiatry residents. Primary learning-related outcomes included content knowledge, self efficacy, and attitudes and behavioral intentions towards evidence-based psychotherapies (e.g., CBT). RESULTS: Residents reported significant increases in CBT knowledge, CBT-specific self-efficacy, overall psychotherapy self-efficacy, belief in patient benefit from CBT, and behavioral intention to use CBT. However, there were almost no changes in attitudes towards evidence-based practice more broadly, with one significant finding showing an increase in skepticism towards such practices. CONCLUSIONS: This empirically based example of training program development, implementation, and evaluation appears largely successful and represents one approach for addressing the CBT competency goals outlined by the Accreditation Council for Graduate Medical Education (ACGME) and Milestone Project Guidelines. Despite these initial, positive findings, conclusions should be tempered by limitations of the project design (e.g., the lack of comparison group, absence of objective measures of resident behavioral change, or assessment of the effect of such changes on patient outcomes). Findings highlight the need for continued development and evaluation of training methods in CBT for residency programs. PMID- 28589329 TI - Time for a Change? How Rethinking Delivery of Undergraduate Medical Education in Psychiatry May Add Value to Healthcare Systems. PMID- 28589330 TI - Triple Combination Therapy and Drug Cycling-Tangential Strategies for Countering Artemisinin Resistance. AB - PURPOSE OF REVIEW: This review attempts to understand the reasons for the successes and failures of the two novel strategies that have slowly begun to emerge as potential counters for anti-malarial drug resistance-"Triple Combination Therapy" and "Drug Cycling." RECENT FINDINGS: Recent reports have suggested that increasing the heterogeneity within the parasite's environment, both at an individual and the population level, may help raise the probabilistic barrier of development of resistance in the parasite. The encouraging results following the implementation of a few experimental triple combination therapies like atovaquone-proguanil-artesunate along with the re-emergence of chloroquine sensitive Plasmodium falciparum parasites in the sub-Saharan African nations have re-kindled mankind's hope of curbing anti-malarial drug resistance. The addition of a third drug with traits like a medium half-life and benign safety profile is crucial to achieving SERCAP (single encounter radical cure and preventive therapy), the principle of a triple combination therapy. Simultaneously, the plausible reasons behind the re-emergence of chloroquine sensitive Plasmodium falciparum malaria in the high transmission regions could be the re-expansion of an existing chloroquine susceptible parasite reservoir and a greater predisposition towards the development of polyclonal infections. Another potential reason for this observation could be an impaired deoxyribonucleic acid (DNA) repair mechanisms in the south-east Asian Plasmodium falciparum parasites. These strategies may potentially emerge as the key players in warding off anti malarial drug resistance in the near future. However, their implementation would be dictated by a host of factors like the epidemiological knowledge, population pharmacokinetics, drug-resistance patterns, cost, availability, and ease of adherence. PMID- 28589331 TI - CORR Insights(r): Variations in Knee Kinematics After ACL Injury and After Reconstruction Are Correlated With Bone Shape Differences. PMID- 28589332 TI - CORR Insights(r): Reliability and Validity of the Musculoskeletal Tumor Society Scoring System for the Upper Extremity in Japanese Patients. PMID- 28589333 TI - CORR (r) Tumor Board: Do Orthopaedic Oncologists Agree on the Diagnosis and Treatment of Cartilage Tumors of the Appendicular Skeleton? PMID- 28589334 TI - Are There Differences in Gait Mechanics in Patients With A Fixed Versus Mobile Bearing Total Ankle Arthroplasty? A Randomized Trial. AB - BACKGROUND: Total ankle arthroplasty (TAA) is an alternative to arthrodesis, but no randomized trial has examined whether a fixed bearing or mobile bearing implant provides improved gait mechanics. QUESTIONS/PURPOSES: We wished to determine if fixed- or mobile-bearing TAA results in a larger improvement in pain scores and gait mechanics from before surgery to 1 year after surgery, and to quantify differences in outcomes using statistical analysis and report the standardized effect sizes for such comparisons. METHODS: Patients with end-stage ankle arthritis who were scheduled for TAA between November 2011 and June 2013 (n = 40; 16 men, 24 women; average age, 63 years; age range, 35-81 years) were prospectively recruited for this study from a single foot and ankle orthopaedic clinic. During this period, 185 patients underwent TAA, with 144 being eligible to participate in this study. Patients were eligible to participate if they were able to meet all study inclusion criteria, which were: no previous diagnosis of rheumatoid arthritis, a contralateral TAA, bilateral ankle arthritis, previous revision TAA, an ankle fusion revision, or able to walk without the use of an assistive device, weight less than 250 pounds (114 kg), a sagittal or coronal plane deformity less than 15 degrees , no presence of avascular necrosis of the distal tibia, no current neuropathy, age older than 35 years, no history of a talar neck fracture, or an avascular talus. Of the 144 eligible patients, 40 consented to participate in our randomized trial. These 40 patients were randomly assigned to either the fixed (n = 20) or mobile bearing implant group (n = 20). Walking speed, bilateral peak dorsiflexion angle, peak plantar flexion angle, sagittal plane ankle ROM, peak ankle inversion angle, peak plantar flexion moment, peak plantar flexion power during stance, peak weight acceptance, and propulsive vertical ground reaction force were analyzed during seven self selected speed level walking trials for 33 participants using an eight-camera motion analysis system and four force plates. Seven patients were not included in the analysis owing to cancelled surgery (one from each group) and five were lost to followup (four with fixed bearing and one with mobile bearing implants). A series of effect-size calculations and two-sample t-tests comparing postoperative and preoperative increases in outcome variables between implant types were used to determine the differences in the magnitude of improvement between the two patient cohorts from before surgery to 1 year after surgery. The sample size in this study enabled us to detect a standardized shift of 1.01 SDs between group means with 80% power and a type I error rate of 5% for all outcome variables in the study. RESULTS: This randomized trial did not reveal any differences in outcomes between the two implant types under study at the sample size collected. In addition to these results, effect size analysis suggests that changes in outcome differ between implant types by less than 1 SD. Detection of the largest change score or observed effect (propulsive vertical ground reaction force [Fixed: 0.1 +/- 0.1; 0.0-1.0; Mobile: 0.0 +/- 0.1; 0.0-0.0; p = 0.0.051]) in this study would require a future trial to enroll 66 patients. However, the smallest change score or observed effect (walking speed [Fixed: 0.2 +/- 0.3; 0.1-0.4; Mobile: 0.2 +/- 0.3; 0.0-0.3; p = 0.742]) requires a sample size of 2336 to detect a significant difference with 80% power at the observed effect sizes. CONCLUSIONS: To our knowledge, this is the first randomized study to report the observed effect size comparing improvements in outcome measures between fixed and mobile bearing implant types. This study was statistically powered to detect large effects and descriptively analyze observed effect sizes. Based on our results there were no statistically or clinically meaningful differences between the fixed and mobile bearing implants when examining gait mechanics and pain 1 year after TAA. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 28589337 TI - ? PMID- 28589336 TI - [Organ support in intensive care medicine]. PMID- 28589335 TI - A non-destructive BFCOD assay for in vivo measurement of cytochrome P450 3A (CYP3A) enzyme activity in fish embryos and larvae. AB - There is increasing interest in quantifying the exposure and effects of anthropogenic contaminants in fish. Determination of exposures in wild fish is routinely performed, but methods to investigate potential effects are less established. One of the most relevant approaches would be the use of in vivo assays, but existing assays are often limited to in vitro determination of enzyme activity. Many pharmaceuticals and some persistent pollutants activate, and are metabolized by cytochrome P4503A (CYP3A), which make it a relevant and desirable target for biomarker research. We altered the established 7-benzyloxy-4 trifluoromethylcoumarin-O-debenzylation (BFCOD) in vitro protocol for CYP3A activity determination, developing a rapid and inexpensive method to measure in vivo (and in ovo) CYP3A activity in two fish systems: Gulf killifish (Fundulus grandis) and zebrafish (Danio rerio) early life stages. Even with very low concentrations of 7-benzyloxy-4-trifluoromethyl coumarin (BFC, 0.06 uM or 20 ug/L), we were able to detect significant induction in CYP3A activity in embryos of F. grandis, as well as in larvae of D. rerio in response to benzo[a]pyrene (BaP) and fluoranthene (FL) exposures. Because of concerns regarding the possible contribution of CYP1A to BFCOD activity from previous research, we have used a CYP1A post-translational inhibitor (FL) in order to calculate the contribution of CYP1A to the BFCOD assay. We also dosed with benzo[k]fluoranthene (BkF) and showed significant induction of CYP1A activity, with no concurrent increase in CYP3A activity. In this paper, we have taken an established in vitro CYP3A activity assay, and utilized the reaction in a novel way to allow for the non destructive determination of CYP3A. In summary, we describe a sensitive, cheap, fast and easy modified BFCOD assay for in ovo and in vivo determination of CYP3A activity for use in moderate throughput early-life-stage fish experiments. PMID- 28589338 TI - The identification of celiac disease in asymptomatic children: the Generation R Study. AB - BACKGROUND: The objective of our study was to assess whether TG2A levels in the healthy childhood population can be predictive of subclinical CD. METHODS: A total of 4442 children (median age, 6.0 years) participating in a population based prospective cohort study were screened on serum TG2A. Those with positive TG2A (>=7 U/ml; n = 60, 1.4%) were invited for clinical evaluation (median age, 9.0 years). Medical history, physical examination, serum TG2A, and IgA-endomysium (EMA) were assessed, as well as HLA DQ 2.2/2.5/8 typing. Patients with positive serologies and genetic risk types underwent duodenal biopsies. TG2A levels at the time of biopsy were compared with the degree of enteropathy. RESULTS: Fifty-one TG2A-positive children were included in the follow-up: 31 (60.8%) children had CD, ten (19.6%) did not have CD, and ten (19.6%) were considered potential CD cases because of inconclusive serologies. Duodenal biopsies were performed in 26/31 children. CD with Marsh 3a/b enteropathy was observed in 75% (15/20) of children having TG2A levels >=10ULN at 6 years of age, as well as in 75% (6/8) of children having a positive TG2A <10 ULN (OR 1.00; 95% CI 0.15-6.64). CD cases had a lower BMI SDS (mean -0.49, SD 0.92) than children without CD (mean 0.47, SD 1.37; p = 0.02). No differences were observed in gastrointestinal symptoms. CONCLUSIONS: Serum TG2A screening at 6 years of age in the healthy childhood population has a positive predictive value of 61% to detect subclinical CD. We did not find a positive correlation between serum TG2A levels and the degree of enteropathy. PMID- 28589339 TI - A simple scoring system using type IV collagen 7S and aspartate aminotransferase for diagnosing nonalcoholic steatohepatitis and related fibrosis. AB - BACKGROUND: Recently we reported novel noninvasive scoring systems for diagnosing nonalcoholic steatohepatitis (NASH) and related fibrosis, namely FM-NASH index and FM-fibro index. They are highly accurate, however, they contain some items not widely used in clinical practice and require six or more items to diagnose both NASH and related fibrosis. By focusing on widely used items, we tried to identify convenient markers in common with the both diagnoses. METHODS: To explore the markers for NASH and related fibrosis in nonalcoholic fatty liver disease (NAFLD) patients, we used data of 24 clinical items in our previous report. By logistic regression analysis, we identified items suitable for the both diagnoses. We then evaluated their accuracies by area under the receiver operator characteristic curves (AUROCs) on independent validation data. RESULTS: We identified the combination of type IV collagen 7S and aspartate aminotransferase (AST) as the predictor both for NASH and related fibrosis. We developed a scoring system based on the combination and evaluated the prediction accuracy: the AUROCs for training/validation data sets are 0.857/0.769 for NASH and 0.918/0.842 for NASH-related fibrosis. The former was higher than that of NAFIC score, and the latter was higher than those of existing fibrosis markers: BARD score, FIB-4 index and NAFLD fibrosis score but lower than FM-fibro index. CONCLUSIONS: The scoring system using type IV collagen 7S and AST named CA index can predict both NASH and related fibrosis in NAFLD patients with sufficient accuracy and could be a convenient diagnostic and screening tool for NASH and related fibrosis. The scoring system needs to be validated in independent larger populations from multiple clinical centers. PMID- 28589340 TI - Cigarette Smoking among Women Who Are Homeless or Unstably Housed: Examining the Role of Food Insecurity. AB - Smoking prevalence remains high among individuals who are homeless, partly due to stressors related to homelessness. Beyond housing insecurity, homelessness involves financial stresses and unmet subsistence needs. In particular, food insecurity contributes to negative health outcomes and other health risks. This study examined associations between food insecurity severity and smoking among homeless and marginally housed women in San Francisco, California. We used data from 247 women from a longitudinal cohort study. Generalized estimating equations were used to estimate longitudinal associations between study factors and smoking based on data from five biannual assessment points between 2009 and 2012. The longitudinal adjusted odds of smoking were higher among severely food insecure individuals compared to those who were not food insecure (AOR = 1.68, 95% CI [1.02, 2.78]), while associations with other study factors, including demographics, time, HIV status, mental health, and substance use (except marijuana use), did not reach levels of significance. Similar adjusted longitudinal results were observed when food insecurity was the dependent variable and smoking an independent variable, suggesting the possibility of a bidirectional association. Considering unmet needs, such as food and hunger, may improve comprehensive smoking cessation strategies targeting individuals for whom mainstream tobacco control efforts have not been effective. Similarly, offering improved access to smoking cessation resources should be considered in efforts to address food insecurity among individuals experiencing homelessness. PMID- 28589341 TI - Highly Sensitive and Reliable Detection of EGFR Exon 19 Deletions by Droplet Digital Polymerase Chain Reaction. AB - BACKGROUND: Analysis of EGFR mutations is becoming a routine clinical practice but the optimal EGFR mutation testing method is still to be determined. METHODS: We determined the nucleotide sequence of deletions located in exon 19 of the EGFR gene in lung tumor samples of patients residing in different regions of Russia (153 tumor DNA specimens), using Sanger sequencing. We developed a droplet digital polymerase chain reaction assay capable of detecting all common EGFR deletions in exon 19. We also compared the therascreen amplification refractory mutation system assay with a droplet digital polymerase chain reaction assay for the detection of all the deletions in our study. RESULTS: The droplet digital polymerase chain reaction assay demonstrated 100% sensitivity against polymerase chain reaction fragment length analysis and detected all possible types of deletions revealed in our study (22 types). At the same time, the therascreen EGFR RGQ PCR Kit was not able to detect deletions c.2252-2276>A and c.2253-2276 and showed low performance for another long deletion. CONCLUSION: Thus, we can conclude that the extraordinary length of deletions and their atypical locations (shift at the 3'-region compared to known deletions) could be problematic for the therascreen EGFR RGQ PCR Kit and should be taken into account during targeted mutation test development. However, droplet digital polymerase chain reaction is a promising and reliable assay that can be used as a diagnostic tool to genotype formalin-fixed paraffin-embedded cancer samples for EGFR or another clinically relevant somatic mutation. PMID- 28589343 TI - Analysis of the Germinal Center Reaction in Tissue Sections. AB - Germinal centers are short-lived microanatomical compartments with essential roles in adaptive immunity. These lymphoid structures can be identified in secondary lymphoid organs using both flow cytometry and immunohistological analyses, but only the latter provides useful architectural and spatial information. Here we describe how to use immunofluorescence and immunohistochemistry with specific antibodies to precisely highlight the cellular and architectural features of germinal centers, both in human and mouse secondary lymphoid organs, and to study their normal development and disturbance in disease. PMID- 28589342 TI - Streptomyces asenjonii sp. nov., isolated from hyper-arid Atacama Desert soils and emended description of Streptomyces viridosporus Pridham et al. 1958. AB - A polyphasic study was undertaken to establish the taxonomic status of Streptomyces strains isolated from hyper-arid Atacama Desert soils. Analysis of the 16S rRNA gene sequences of the isolates showed that they formed a well defined lineage that was loosely associated with the type strains of several Streptomyces species. Multi-locus sequence analysis based on five housekeeping gene alleles showed that the strains form a homogeneous taxon that is closely related to the type strains of Streptomyces ghanaensis and Streptomyces viridosporus. Representative isolates were shown to have chemotaxonomic and morphological properties consistent with their classification in the genus Streptomyces. The isolates have many phenotypic features in common, some of which distinguish them from S. ghanaensis NRRL B-12104T, their near phylogenetic neighbour. On the basis of these genotypic and phenotypic data it is proposed that the isolates be recognised as a new species within the genus Streptomyces, named Streptomyces asenjonii sp. nov. The type strain of the species is KNN35.1bT (NCIMB 15082T = NRRL B-65050T). Some of the isolates, including the type strain, showed antibacterial activity in standard plug assays. In addition, MLSA, average nucleotide identity and phenotypic data show that the type strains of S. ghanaensis and S. viridosporus belong to the same species. Consequently, it is proposed that the former be recognised as a heterotypic synonym of the latter and an emended description is given for S. viridosporus. PMID- 28589345 TI - Tracking Plasma Cell Differentiation in Living Mice with Two-Photon Microscopy. AB - Due to the multitude of cell types involved in the differentiation of plasma cells during the germinal center reaction, and due to a lack of in vitro systems, which recapitulate germinal centers, the most suitable way to study plasma cell generation in germinal centers is in vivo. In this chapter we describe how to induce humoral immune responses to defined model antigens and how to visualize and track plasma cells and their interactions with other cells in the lymph nodes of living mice. PMID- 28589344 TI - Detecting Gene Expression in Lymphoid Microenvironments by Laser Microdissection and Quantitative RT-PCR. AB - Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) is a valuable tool for measuring gene expression in cells and tissues. Unique challenges are encountered when studies are performed on cells microdissected from small specific areas of frozen animal or human tissue. This chapter describes the analysis of gene expression of chemokines and cytokines that are important for the differentiation and migration of germinal center (GC) derived plasmablasts/plasma cells and memory B cells by using laser capture microdissection (LCM) and qRT-PCR to examine tissue sections. PMID- 28589346 TI - Microanatomical Labeling of Germinal Center Structures for Flow Cytometry Using Photoactivation. AB - Germinal centers (GCs) are inducible microanatomical structures required for the generation of high-affinity antibodies. Migration of B and T cells within and into/out of GCs plays a key role in the evolutionary process that underlies affinity maturation, and thus microanatomical location of cells is an important variable when studying GC processes. We describe a protocol in which in situ photoactivation by multiphoton microscopy can be used to add microanatomical information to flow cytometry, allowing for identification and isolation of GC cells based on their location. Cells in different microanatomical compartments can then be sorted and analyzed for surface marker and mRNA expression. PMID- 28589347 TI - Fate Mapping and Transcript Profiling of Germinal Center Cells by Two-Photon Photoconversion. AB - The germinal center (GC) reaction is the key process for the generation of high affinity antibodies to foreign antigen. Standard experimental techniques such as fluorescence-activated cell sorting and histology have provided numerous insights into the composition and function of the GC. However, these approaches are limited to a "snapshot" in time and are unable to fully capture the dynamic nature of the GC. Intravital two-photon microscopy overcomes these disadvantages and has led to several major advances in the field but is restricted by practical and technical limits that prevent long-range mapping and molecular studies. Here we describe procedures for optical marking or "tagging" of cells in precise microanatomical compartments by two-photon photoconversion that can be used for long-term fate mapping and transcript profiling of GC T and B cells. PMID- 28589348 TI - Intravital Microscopy of T-B Cell Interactions in Germinal Centers. AB - Dynamic imaging analyses of antigen-specific T-B interactions in germinal centers have advanced our understanding of the molecular mechanisms underlying affinity maturation and provided a wealth of information about how follicular helper T cells function in vivo. Here we describe a routine method to visualize fluorescence protein-expressing, antigen-specific T and B cells in germinal centers. The protocol for incorporating functional reporters or genetic perturbation of the T cells by retroviral transduction is also briefly described, using the FRET-based calcium reporter as an example. PMID- 28589349 TI - Identifying Follicular Regulatory T Cells by Confocal Microscopy. AB - Follicular regulatory T cells are a subset of Foxp3+ regulatory T cells that migrate into the B cell follicle after infection or immunization and modulate the germinal center response. The anatomical positioning of follicular regulatory T cells within the germinal center is a defining characteristic of this subset of regulatory T cells; because of this, it is critical that studies of follicular regulatory T cells are able to identify them in situ. In this chapter we describe an immunofluorescence staining method to visualize follicular regulatory T cells in frozen secondary lymphoid tissue sections by confocal imaging. PMID- 28589350 TI - Cytokine Expression by T Follicular Helper Cells. AB - T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells located within temporary structures known as germinal centers (GC) formed within B cell follicles of secondary lymphoid organs. In the GC, Tfh cells facilitate the production of high-affinity antibodies through secretion of effector cytokines, such as IL-21 and IL-4, and through cell-to-cell interactions. The flow cytometric-based method described here allows the detection of intracellular cytokines within the Tfh population of secondary lymphoid organs (e.g., spleen, lymph nodes, and lymphoid nodules such as Peyer's patches), enabling the study of Tfh responses to different stimuli in the context of immunity and autoimmunity. PMID- 28589351 TI - Follicular Dendritic Cell Isolation and Loading of Immune Complexes. AB - Follicular dendritic cells (FDCs) are stromal cells that are centrally located within B cell follicles of lymph nodes and other lymphoid organs such as the spleen. Due to their relative low abundance and difficulty to isolate, FDCs are still largely an enigma. Here we describe how to isolate FDCs for ex vivo cell culture, sorting by flow cytometry and how to load them in vivo or in vitro with immune complexes. PMID- 28589352 TI - Isolation and Characterization of Mouse and Human Follicular Dendritic Cells. AB - Follicular dendritic cells (FDCs) reside in the B cell follicles of secondary and tertiary lymphoid tissues where they play key roles in the development and maintenance of lymphoid tissue architecture and function. FDCs trap native antigens for extended periods of time in the form of immune complexes which critcally regulate germinal center reactions in health and disease. Here, we describe how to isolate and characterize FDCs from murine and human lymphoid tissues. PMID- 28589353 TI - In Vitro-Induced Germinal Center B Cell Culture System. AB - In germinal centers (GCs), B cells undergo repeated cycles of proliferation and affinity-based selection, and differentiate into memory B cells or long-lived plasma cells. It has been difficult to elucidate regulatory mechanisms for the dynamic GC B cell maturation and differentiation, partly because experimental manipulation of GC B cells has been limited. Here we describe a culture system in which we can induce massive expansion of naive B cells that exhibit GC B cell like phenotype and acquire abilities to differentiate into memory B cells or bone marrow plasma cells depending on cytokine conditions. This system will allow us to elucidate the molecular mechanisms of GC B cell differentiation. PMID- 28589355 TI - Germinal Center Formation with Retrovirally Transduced B Cells for Determining the Role of Specific Molecules In Vivo. AB - Retrovirus-mediated gene transfer has become a powerful tool to investigate roles of specific molecules in B cells, due to its efficiency and expeditiousness. This technology is applicable to activated B cells in order to determine effects of a gene of interest during germinal center (GC) reactions in combination with adoptive transfer. To achieve this, B cells derived from SWHEL mice expressing hen egg lysozyme (HEL)-specific B cell receptors (BCR) are stimulated with HEL antigen in vivo and then with anti-CD40 antibody ex vivo. These cells are then transduced with a retrovirus allowing bicistronic co-expression of a gene of interest and GFP, enabling differentiation of transgene positive cells. The retrovirally transduced cells are then adoptively transferred into immunized CD45.1+ congenic recipient mice, to enable differentiation between donor and host cells. This chapter describes methods for (1) activation of HEL-specific mature B cells, (2) retroviral transduction of the activated B cells, (3) adoptive transfer of the cells into recipients, and (4) analysis of the resultant mice by flow cytometry. PMID- 28589354 TI - CRISPR/Cas9-Mediated In Vitro Mutagenesis in GC-Like B Cells. AB - The CRISPR/Cas9 technology has developed into a powerful tool for genome editing, both in terms of gene silencing and the insertion of precise mutations. However, the application of CRISPR/Cas9-mediated mutagenesis in primary immune cells, in particular in B cells, is still in its infancy because of the difficulty to deliver the CRISPR/Cas9 system into these cells. Here, we describe a new method to use CRISPR/Cas9 for manipulating genes in germinal center (GC)-like B cells in vitro. We isolated Cas9-expressing B cells from R26-Cas9iGFP/+ mice (expressing Cas9 constitutively from the Rosa26 locus) and mixed them with control B cells. Primary B cells were cultured on CD40L- and BAFF-expressing feeder cells and transduced with retroviral particles expressing the sgRNAs of interest. Using this system, we have achieved complete gene knockouts in up to 92% of activated B cells. PMID- 28589356 TI - Characterization of the B Cell Transcriptome Bound by RNA-Binding Proteins with iCLIP. AB - Posttranscriptional regulation of gene expression shapes the B cell transcriptome and controls messenger RNA (mRNA) translation into protein. Recent reports have highlighted the importance of RNA binding proteins (RBPs) for mRNA splicing, subcellular location, stability, and translation during B lymphocyte development, activation, and differentiation. Here we describe individual-nucleotide resolution UV cross-linking and immunoprecipitation (iCLIP) in primary lymphocytes, a method that maps RNA-protein interactions in a genome-wide scale allowing mechanistic analysis of RBP function. We discuss the latest improvements in iCLIP technology and provide some examples of how integration of the RNA protein interactome with other high-throughput mRNA sequencing methodologies uncovers the important role of RBP-mediated RNA regulation in key biological cell processes. PMID- 28589357 TI - Flow-Cytometric Method Measuring B Cell Surface Immunoglobulin Avidity. AB - The affinity of antibodies for their cognate antigens is a critical aspect of humoral immunity. The immune system has gone to great lengths to evolve a mechanism that enables real time increases in antibody affinity during the course of an immune response. This occurs in germinal centers (GC), which form in spleen and lymph nodes following immunization. GC B cell competition for limiting amount of antigen drives the selection of B cells expressing higher affinity Abs. Remarkably little is known about affinity maturation of B cells in immune responses to all but a handful of small model antigens. It has proven challenging to measure the avidity of specific Abs in polyclonal sera to more complex antigens, including viruses. In this chapter we present a simple, flow cytometry based, method that determines the average avidity of GC B cells for the influenza A virus hemagglutinin glycoprotein, the target antigen of traditional influenza vaccines. Flow cytometry using fluorescent hemagglutinin and B cell marker specific Abs enables high throughput qualitative and quantitative detection of individual B cells. By using a graded amount of antigen and gating on GC B cells we define the AC50 the amount of antigen required to stain 50% of hemagglutinin specific B cells. This number is in remarkable agreement with the avidity of the B cell population. This method can be generally employed to include antibody avidity measurements basic and clinical studies of immunity to viruses and other medically relevant immunogens. PMID- 28589358 TI - Somatic Hypermutation and Affinity Maturation Analysis Using the 4-Hydroxy-3 Nitrophenyl-Acetyl (NP) System. AB - Somatic hypermutation of immunoglobulin variable region (IgV) genes and affinity maturation of the antibody response are the hallmarks of the germinal center (GC) reaction in T cell-dependent immune responses. Determining the consequences of the experimental manipulation of the GC response on somatic hypermutation and affinity maturation requires the availability of a system that allows measuring these parameters. Immunization of mice of the C57/Bl6 genetic background with the hapten 4-hydroxy-3-nitrophenyl-acetyl (NP) coupled to a carrier protein leads to the predominant usage of one particular IgV heavy chain gene segment, V186.2, among the responding B cells. Moreover, a specific somatic mutation in codon 33 of V186.2 that leads to a tryptophan to leucine amino acid exchange increases the affinity of the corresponding antibody by ~10-fold, thus representing a molecular marker for affinity maturation. In addition, due to the simplicity of the antigen and the virtual absence of NP-specific plasma cells prior to immunization, NP based immunizations represent ideal tools to quantify the plasma cell response by measuring NP-specific antisera by ELISA and the generation of NP-specific plasma cells by ELISPOT analysis. We here describe approaches to (1) measure the anti-NP plasma cell response by ELISA and ELISPOT analysis, and to (2) amplify and sequence V186.2 rearrangements from GC B cells and plasma cells to determine the level of somatic hypermutation and the extent of affinity maturation in the anti NP response. PMID- 28589359 TI - Targeting Gene Function in Germinal Center B Cells: A Practical Approach. AB - The germinal center (GC) reaction represents an essential phase of an adaptive immune response. Dysfunction of GC B cells can lead to life-threatening diseases including autoimmune disorders, lymphomas, and opportunistic infections. Defining the molecular circuitries controlling GC B cell physiology is crucial to understand the pathogenesis of GC B cell disorders, as well as to develop improved vaccines against foreign pathogens. Conditional gene targeting based on the Cre/loxP recombination system has substantially accelerated our comprehension of the genetic networks controlling GC B cell function. Several independent studies in the past 10 years have highlighted the many advantages and the few limitations and pitfalls associated to conditional gene manipulation in GC B cells using the Cre/loxP recombination system. Here, we describe the basic features of GC B cell-specific gene targeting experiments. We provide indications on the type of Cre transgene and controls to be chosen, way-out strategies to overcome leakiness of the Cre/loxP system, and approaches to minimize the number of experimental animals and to speed up analyses on conditional mutant GC B cells. PMID- 28589360 TI - Development of Mouse Model Systems of Germinal Center Lymphomas. AB - Germinal centers (GC) are the predominant origin of human B cell lymphomagenesis. Transgenic mice in which gene expression is altered specifically in GC B cells have broadened our knowledge about the mechanisms of malignant transformation. However, extensive resources are needed due to the genetic complexity of these mouse models. Thus, bone marrow (BM)-derived chimerism is an attractive approach to study GC B cell derived lymphomagenesis, as it allows for an efficient allocation of resources and reduces the number of animals used. PMID- 28589362 TI - Determining the Origin of Human Germinal Center B Cell-Derived Malignancies. AB - Most human B cell lymphomas originate from germinal center (GC) B cells. This is partly caused by the high proliferative activity of GC B cells and the remodeling processes acting at the immunoglobulin (Ig) loci of these cells, i.e., somatic hypermutation and class-switching. Mistargeting of these processes can cause chromosomal translocations, and the hypermutation machinery may also target non Ig genes. As somatic hypermutation is exclusively active in GC B cells, the presence of somatic mutations in rearranged IgV genes is a standard criterium for a GC or post-GC B cell origin of lymphomas. Beyond this, ongoing somatic hypermutation during lymphoma clone expansion indicates that the lymphoma has an active GC B cell differentiation program. The proto-oncogene BCL6 is specifically expressed in GC B cells and also acquires somatic mutations as a physiological by product of the somatic hypermutation process, albeit at a lower level than IgV genes. Thus, detection of BCL6 mutations is a further genetic trait of a GC experience of a B cell lymphoma. Typically, B cell lymphomas retain key features of their specific cells of origin, including a differentiation stage-specific gene expression pattern. This is at least partly due to genetic lesions, which "freeze" the lymphoma cells at the differentiation stage at which the transformation occurred. Therefore, identification of the normal B cell subset with the most similar gene expression pattern to a particular type of B cell lymphoma has been instrumental to deduce the precise cell of origin of lymphomas.We present here protocols to analyze human B cell lymphomas for a potential origin from GC B cells by determining the presence of mutations in rearranged IgV genes and the BCL6 gene, and by comparing the gene expression pattern of lymphoma cells with those of normal B cell subsets by genechip or RNA sequencing analysis. PMID- 28589361 TI - The AID-Cre-ERT2 Model: A Tool for Monitoring B Cell Immune Responses and Generating Selective Hybridomas. AB - Expression of activation-induced cytidine deaminase (AID) is the hallmark of B cells engaged in an immune response in germinal centers. We designed an inducible fate-mapping reporter mouse in which AID-expressing B cells could be timely and irreversibly marked, by knockin at the Aicda locus of a tamoxifen-inducible Cre recombinase. This mouse model allows notably for the long-term follow-up of memory B cells and plasma cells engaged in an immune response. We describe here a protocol to generate hybridomas from small memory subsets that can be easily traced and identified in this mouse line through Cre-activated fluorescent reporters. PMID- 28589363 TI - Tracking B-Cell Repertoires and Clonal Histories in Normal and Malignant Lymphocytes. AB - Methods for tracking B-cell repertoires and clonal history in normal and malignant B-cells based on immunoglobulin variable region (IGV) gene analysis have developed rapidly with the advent of massive parallel next-generation sequencing (mpNGS) protocols. mpNGS permits a depth of analysis of IGV genes not hitherto feasible, and presents challenges of bioinformatics analysis, which can be readily met by current pipelines. This strategy offers a potential resolution of B-cell usage at a depth that may capture fully the natural state, in a given biological setting. Conventional methods based on RT-PCR amplification and Sanger sequencing are also available where mpNGS is not accessible. Each method offers distinct advantages. Conventional methods for IGV gene sequencing are readily adaptable to most laboratories and provide an ease of analysis to capture salient features of B-cell use. This chapter describes two methods in detail for analysis of IGV genes, mpNGS and conventional RT-PCR with Sanger sequencing. PMID- 28589364 TI - How to Simulate a Germinal Center. AB - Germinal centers host a mini-evolutionary environment where B cells can mutate their receptor and be selected depending on its affinity to target antigens in a process called affinity maturation. Starting from founder cells with a weak B cell receptor affinity, germinal centers release output cells as antibody secreting cells or memory cells with a very high affinity, a property which is essential for pathogen clearance and immune memory. Therapeutic interventions on the germinal centers are tantalizing approaches to improve vaccines or to support rejection of chronic pathogens such as HIV. However, the complexity of the selection processes makes it very hard to make reliable predictions. Here, we present in detail how to build an agent-based model (hyphasma), accounting for the dynamics of the germinal center. It encompasses the core quantitative traits of affinity maturation, and allowed to make reliable predictions in previous studies. PMID- 28589365 TI - Variability of platelet response to clopidogrel is not related to adverse cardiovascular events in patients with stable coronary artery disease undergoing percutaneous coronary intervention. AB - BACKGROUND: Antiplatelet response to clopidogrel and its influence upon the risk of cardiovascular adverse events among patients with stable coronary artery disease undergoing percutaneous coronary intervention (PCI) has not been investigated fully. METHODS: Two hundred eleven patients treated with aspirin and clopidogrel were included in the study. Immediately before PCI, residual platelet reactivity testing with impedance aggregometry assay and a single-nucleotide polymorphism genotyping analysis targeting variants of CYP2C19, ABCB1, and PON1 genes was performed. After the index PCI, the patients were screened for cardiovascular events 6 months following bare-metal stent implantation or 12 months following drug-eluting stent implantation. RESULTS: High on-treatment platelet reactivity (HTPR) was observed in 19.43% individuals and low-TPR (LTPR) in 26.54%. In multivariate analysis, HTPR was significantly (p < 0.05) associated with a history of diabetes, higher systolic blood pressure, and platelet count comparing to that of other patients. LTPR was significantly associated with no history of hypertension, younger age, lower platelet count, absence of the CYP2C19*2 variant, and lower CRP plasma level. Overall, cardiac adverse events were noted in 14.23% patients. Survival analysis with the Cox proportional hazard model showed no influence of residual platelet reactivity during clopidogrel therapy upon both ischemic and hemorrhagic events. However, significant predictors for composite of major adverse cardiac events and hospitalization for cardiovascular causes were identified (the higher CCS class prior to coronary intervention and the higher creatinine serum concentration). CONCLUSIONS: The platelet response to clopidogrel has no impact upon post-procedural adverse events at mid-term follow-up in patients with stable CAD undergoing PCI. This finding suggests that routine platelet reactivity testing is not beneficial in this group of patients. PMID- 28589366 TI - Meta-analysis of pre-operative magnetic resonance imaging (MRI) and surgical treatment for breast cancer. AB - BACKGROUND: Although there is no consensus on whether pre-operative MRI in women with breast cancer (BC) benefits surgical treatment, MRI continues to be used pre operatively in practice. This meta-analysis examines the association between pre operative MRI and surgical outcomes in BC. METHODS: A systematic review was performed to identify studies reporting quantitative data on pre-operative MRI and surgical outcomes (without restriction by type of surgery received or type of BC) and using a controlled design. Random-effects logistic regression calculated the pooled odds ratio (OR) for each surgical outcome (MRI vs. no-MRI groups), and estimated ORs stratified by study-level age. Subgroup analysis was performed for invasive lobular cancer (ILC). RESULTS: Nineteen studies met eligibility criteria: 3 RCTs and 16 comparative studies that included newly diagnosed BC of any type except for three studies restricted to ILC. Primary analysis (85,975 subjects) showed that pre-operative MRI was associated with increased odds of receiving mastectomy [OR 1.39 (1.23, 1.57); p < 0.001]; similar findings were shown in analyses stratified by study-level median age. Secondary analyses did not find statistical evidence of an effect of MRI on the rates of re-excision, re operation, or positive margins; however, MRI was significantly associated with increased odds of receiving contralateral prophylactic mastectomy [OR 1.91 (1.25, 2.91); p = 0.003]. Subgroup analysis for ILC did not find any association between MRI and the odds of receiving mastectomy [OR 1.00 (0.75, 1.33); p = 0.988] or the odds of re-excision [OR 0.65 (0.35, 1.24); p = 0.192]. CONCLUSIONS: Pre-operative MRI is associated with increased odds of receiving ipsilateral mastectomy and contralateral prophylactic mastectomy as surgical treatment in newly diagnosed BC patients. PMID- 28589367 TI - Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post menopausal breast cancer risk. AB - PURPOSE: To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. METHODS: Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and >=50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. RESULTS: Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. CONCLUSIONS: Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR /HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status. PMID- 28589368 TI - Reassessing risk models for atypical hyperplasia: age may not matter. AB - PURPOSE: The aim of this study was to investigate the influence of age at diagnosis of atypical hyperplasia ("atypia", ductal [ADH], lobular [ALH], or severe ADH) on the risk of developing subsequent invasive breast cancer or ductal carcinoma in situ (DCIS). METHODS: Using standard survival analysis methods, we retrospectively analyzed 1353 women not treated with chemoprevention among a cohort of 2370 women diagnosed with atypical hyperplasia to determine the risk relationship between age at diagnosis and subsequent breast cancer. RESULTS: For all atypia diagnoses combined, our cohort showed a 5-, 10-, and 15-year risk of invasive breast cancer or DCIS of 0.56, 1.25, and 1.30, respectively, with no significant difference in the (65,75] year age group. For women aged (35,75] years, we observed no significant difference in the 15-year risk of invasive breast cancer or DCIS after atypical hyperplasia, although the baseline risk for a 40-year-old woman is approximately 1/8 the risk of a 70-year-old woman. The risks associated with invasive breast cancer or DCIS for women in our cohort diagnosed with ADH, severe ADH, or ALH, regardless of age, were 7.6% (95% CI 5.9 9.3%) at 5 years, 25.1% (20.7-29.2%) at 10 years, and 40.1% (32.8-46.6%) at 15 years. CONCLUSION: In contrast to current risk prediction models (e.g., Gail, Tyrer-Cuzick) which assume that the risk of developing breast cancer increases in relation to age at diagnosis of atypia, we found the 15-year cancer risk in our cohort was not significantly different for women between the ages of 35 (excluded) and 75. This implies that the "hits" received by the breast tissue along the "high-risk pathway" to cancer might possibly supersede other factors such as age. PMID- 28589369 TI - Extensions of the Rosner-Colditz breast cancer prediction model to include older women and type-specific predicted risk. AB - PURPOSE: A breast cancer risk prediction rule previously developed by Rosner and Colditz has reasonable predictive ability. We developed a re-fitted version of this model, based on more than twice as many cases now including women up to age 85, and further extended it to a model that distinguished risk factor prediction of tumors with different estrogen/progesterone receptor status. METHODS: We compared the calibration and discriminatory ability of the original, the re fitted, and the type-specific models. Evaluation used data from the Nurses' Health Study during the period 1980-2008, when 4384 incident invasive breast cancers occurred over 1.5 million person-years. Model development used two-thirds of study subjects and validation used one-third. RESULTS: Predicted risks in the validation sample from the original and re-fitted models were highly correlated (rho = 0.93), but several parameters, notably those related to use of menopausal hormone therapy and age, had different estimates. The re-fitted model was well calibrated and had an overall C-statistic of 0.65. The extended, type-specific model identified several risk factors with varying associations with occurrence of tumors of different receptor status. However, this extended model relative to the prediction of any breast cancer did not meaningfully reclassify women who developed breast cancer to higher risk categories, nor women remaining cancer free to lower risk categories. CONCLUSIONS: The re-fitted Rosner-Colditz model has applicability to risk prediction in women up to age 85, and its discrimination is not improved by consideration of varying associations across tumor subtypes. PMID- 28589372 TI - Erratum to: Surfactants in Acute Respiratory Distress Syndrome in Infants and Children: Past, Present and Future. PMID- 28589370 TI - Splicing factors differentially expressed in psoriasis alter mRNA maturation of disease-associated EDA+ fibronectin. AB - The EDA+ fibronectin splicing variant is overexpressed in psoriatic non-lesional epidermis and sensitizes keratinocytes to mitogenic signals. However, regulation of its abundance is only partially understood. In our recent cDNA microarray experiment, we identified three SR-rich splicing factors-splicing factor, arginine/serine-rich 18 (SFRS18), peptidyl-prolyl cis-trans isomerase G (PPIG), and luc-7 like protein 3 (LUC7L3)-which might be implicated in the preactivated states of keratinocytes in psoriatic non-involved skin and could also contribute to the regulation of fibronectin mRNA maturation. In this study, we investigated the role of LUC7L3, PPIG, and SFRS18 in psoriasis and in the mRNA maturation process of fibronectin. Regarding tissue staining experiments, we were able to demonstrate a characteristic distribution of the splicing factors in healthy, psoriatic non-involved and involved epidermis. Moreover, the expression profiles of these SR-rich proteins were found to be very similar in synchronized keratinocytes. Contribution of splicing facwwtors to the EDA+ fibronectin formation was also confirmed: their siRNA silencing leads to altered fibronectin mRNA and protein expression patterns, suggesting the participation in the EDA domain inclusion. Our results indicate that LUC7L3, PPIG, and SFRS18 are not only implicated in EDA+ fibronectin formation, but also that they could possess multiple roles in psoriasis-associated molecular abnormalities. PMID- 28589371 TI - Activator protein-1 (AP-1): a bridge between life and death in lung epithelial (A549) cells under hypoxia. AB - Activator protein-1 (AP-1) transcription factor plays a central role in hypoxia to modulate the expression of genes that decides the fate of the cell. The aim of the present study was to explore the role of AP-1 subunits in lung epithelial (A549) cells under hypoxia. Cell cycle studies by flow cytometry indicated that cell viability was unaffected by the initial hypoxia exposure (0.5% O2 at 37 degrees C) for 6 and 12 h. However, both transient cell cycle arrest and cell death was detected at 24 and 48 h. Flow cytometry and spectrofluorometry data confirmed the increase in ROS levels. Elevated ROS and calcium levels activated the stress-related MAPK signaling cascade. ERK and JNK were activated in early hypoxic exposure (within 6 h), whereas p38 were activated in 48 h of hypoxia. These subtypes further stimulated the subunits of AP-1 at different times of hypoxia exposure to orchestrate different genes responsible for cell proliferation (6 and 12 h) and apoptosis (24 and 48 h). Our results clearly depict the role of AP-1 heterodimer, i.e., p-c-jun/c-fos, p-c-jun/fosB, junD/c fos, and junD/fosB in cell proliferation/survival by regulating the expression of Bcl-2 and cyclins (D1 and B1) at 6 h and 12 h of hypoxia, whereas junB/Fra-1 heterodimer have important role in apoptosis by regulating the expression of p53, Bax, and cyclin-dependent kinase inhibitors (p16, p21, p27) at 24 h and 48 h of hypoxia. Also, the cell survival signaling pathway NO-AKT interrupted at 24 h and 48 h of hypoxia indicating cell death. In conclusion, hypoxia for different time points activated different subunits of AP-1 that combined to form different heterodimers. These dimers regulated the expression of genes responsible for cell proliferation and apoptosis. Since, AP-1 plays a role in the decisive phenomenon of the cell to choose between proliferation and apoptosis; thus, its subunits or dimers could be a good therapeutic target for many diseases. PMID- 28589374 TI - [Integration of palliative care into intensive care : Systematic review]. AB - BACKGROUND: One of the prime aims of intensive care is to cure patients or at least to extend life duration, sometimes to the extent of losing quality of life. Palliative care aims to improve the quality of life of patients with life limiting conditions; however, some patients need both intensive and palliative care. About 5-10% of all deaths in Germany and 20% of all deaths in the USA occur in an intensive care unit (ICU) and many of those as well as other patients may benefit from palliative care consultation. Palliative care consultations are increasingly available for intensive care patients but are still infrequently used. OBJECTIVES: We aimed to determine the current situation of palliative patients in ICU settings: what is the impact of palliative care interventions on the quality of care of ICU patients? To what extent is palliative care support at ICUs available and to what extent is it used? Which factors trigger palliative care consultations? METHOD: We set out with a search of PubMed, Scopus and other databases in English and on a) the impact of palliative care interventions on the quality of care of ICU patients, b) the utilization of palliative care support in ICUs and c) the factors which trigger palliative care consultations. We included both quantitative and qualitative studies to reflect the views of all parties involved. To emphasize the situation in German-speaking countries we also searched Google Scholar with search terms in German and added those results to the review. Additionally, hand-searched studies in English and in German were included. RESULTS: We screened 695 abstracts and identified 18 relevant articles of which 15 were from the USA and Great Britain, 1 each was from Austria, Germany and Switzerland. Palliative care is a meaningful addition to ICU standard treatment: it can improve quality of care and helps reduce length of stay in an ICU. It is unclear if the reduced length of stay leads to economic benefits; however, the utilization of palliative care is inconsistent and infrequent as is its acceptance among ICU physicians. Trigger factors can be used to improve the integration of palliative care support in ICUs and point out patients' unmet palliative needs. DISCUSSION: Trigger factors can reduce barriers which hold back the integration of palliative care in ICUs. Early integration of palliative care can improve quality of care by offering psychological support to patients and their families and by providing collegial consultation. An ongoing prospective study is investigating the acceptance of trigger factors in the daily routine among ICU physicians in Germany. PMID- 28589375 TI - [Benchmarking in pathology]. PMID- 28589376 TI - ? PMID- 28589373 TI - 3D structural complexity analysis of cerebellum in Chiari malformation type I. AB - Chiari malformation type I (CM-I), described by a descent of the cerebellar tonsils, is assumed to be a neurological developmental disorder. The aim of the present study was to investigate morphological variance in cerebellar sub structures, including gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF), using magnetic resonance (MR) images with three-dimensional (3D) fractal dimension (FD) analysis in patients with CM-I. MRI data of 16 patients and 15 control subjects were obtained, and structural complexity analyses were performed using a box-counting FD algorithm. Results showed that patients with CM I had significantly reduced FD values for WM and CSF in comparison with controls, and statistically significant differences in cerebellar GM and CSF volumes between patients and controls were found. Moreover, a significant difference was not found between the WM volumes. This may suggest that there are changes in structural complexity in WM even when its volume is unaffected. We conclude that the findings of this preliminary study indicate the possibility of using FD analysis to understand the pathophysiology of CM-I in patients. PMID- 28589377 TI - Erratum to: What is this image? 2016: Image 2 result. PMID- 28589378 TI - Erratum to: Automatic determination of cardiovascular risk by CT attenuation correction maps in Rb-82 PET/CT. AB - Regrettably an error was introduced in Table 3 during the article's production. The very first cell (row: Very low 0; column: Very low) should read '12' and not '21' as originally published. PMID- 28589379 TI - Mechanical dyssynchrony with phase analysis of gated SPECT: Nap time is over. PMID- 28589380 TI - Persistence with denosumab therapy in women affected by osteoporosis with fragility fractures: a multicenter observational real practice study in Italy. AB - BACKGROUND: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. AIM: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. MATERIAL/SUBJECTS AND METHODS: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia(r)) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. RESULTS: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 +/- 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was -2.76 +/- 1.14 standard deviations (SD) and the mean femoral neck T-score was -2.49 +/- 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6 month period of treatment. CONCLUSIONS: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures. PMID- 28589381 TI - The diagnostic value of glycated albumin in gestational diabetes mellitus. AB - PURPOSE: Our objective was to compare the diagnostic performance of glycated hemoglobin (HbA1c), GA, and fasting plasma glucose (FPG) for the diagnosis of GDM. METHODS: Women at their late second or early third trimesters seen from October 2011 to April 2012 were studied. GDM was diagnosed based on oral glucose tolerance test results, and GA and HbA1c were measured at the same time. Patients were divided into two groups (with and without GDM), and areas under the receiver operating characteristic curves (AUCs) were calculated to determine the diagnostic value of FPG, GA, and HbA1c. RESULTS: A total of 698 women were included, of which 232 (33.2%) had GDM. Overall, FPG had the highest AUC for the detection of GDM, and was significantly higher than that of GA (0.692 vs. 0.568, p < 0.001) and HbA1c (0.692 vs. 0.619, p = 0.014). The AUC of FPG was significantly greater than that of GA and HbA1c. At 24-28 weeks' gestation, the AUCs of FPG were significantly greater than those of GA and HbA1c. CONCLUSIONS: These results do not support the use of GA as a screening tool for GDM. PMID- 28589382 TI - Vitamin D receptor and progesterone receptor protein and gene expression in papillary thyroid carcinomas: associations with histological features. AB - PURPOSE: Vitamin D receptor (VDR) and progesterone receptor (PR) expression has been described in papillary thyroid carcinoma (PTC) but data regarding association with tumor histological characteristics and localization of the protein expression are scarce. MATERIALS AND METHODS: Formalin-fixed, paraffin embedded specimens from 45 patients with PTC (cases) were retrieved and tumor histological data were recorded. We analyzed gene and protein expression of VDR and PR and gene expression of vitamin D-inactivating 24-hyroxylase (CYP24A1) and the activating 1-alpha-hydroxylase (CYP27B1) enzymes in follicular cancer cells and the adjacent non-neoplastic thyroid tissue (NNTT). RESULTS: VDR mRNA and protein expression was higher in PTC compared with NNTT (p < 0.05). The protein was globally localized in the cytoplasm and cell membranes of the neoplastic cells in all cases, with differences in intensity. Cytoplasmic positivity was stronger in the majority of cases. Membranous positivity was also evident in cases, whereas in NNTT was generally weak and in a low percentage of the cells. Expression of CYP 24A1, but not CYP27B1, was increased in approximately all PTC specimens and was associated with lymph node metastasis and extrathyroidal extension. PR mRNA was increased in 34% and protein expression was present in 57% of cases, and none of NNTT. PR, but not VDR, mRNA expression was significantly associated with the tumor size (r = 0.645, p = 0.007). CONCLUSIONS: We provide evidence for the expression pattern of VDR, PR and CYP24A1 in the progression of PTC. Rapid anti-tumor responses of vitamin D in PTC may be blocked due to inactivation of local vitamin D metabolism. PMID- 28589383 TI - Von Hippel-Lindau disease: a single gene, several hereditary tumors. AB - The Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder characterized by the predisposition for multiple tumors caused by germline mutations in the tumor suppressor gene VHL. This disease is associated with a high morbidity and mortality and presents a variable expression, with different phenotypes from family to family, affecting different organs during the lifetime. The main manifestations of VHL are hemangioblastomas of the central nervous system and retina, renal carcinomas and cysts, bilateral pheochromocytomas, cystic and solid tumors of the pancreas, cystadenomas of the epididymis, and endolymphatic sac tumors. The discovery of any of the syndrome components should raise suspicion of this disease and other stigmas must then be investigated. Due to the complexities associated with management of the various VHL manifestation, the diagnosis and the follow-up of this syndrome is a challenge in the clinical practice and a multidisciplinary approach is needed. The particular relevance to endocrinologists is the detection of pheochromocytomas in 35% and islet cell tumors in 17% of VHL patients, which can be associated with hypertension, hypoglycemia, cardiac arrhythmias, and carcinoid syndrome. The purpose of this review is to define the Von Hippel-Lindau syndrome addressing its clinical aspects and classification, the importance of genetic counseling and to propose a protocol for clinical follow-up. PMID- 28589385 TI - Quantitative analysis of Rice stripe virus in a transovarial transmission cycle during the development and reproduction of its vector, Laodelphax striatellus. AB - The amount of Rice stripe virus (RSV) maintained through transovarial transmission was analyzed during the development and reproduction of its vector, Laodelphax striatellus. Reverse transcription quantitative PCR analysis was used to quantify RNA expressed from the RSV coat protein (CP) gene as an estimate of RSV content in nymphs and adults of L. striatellus at various developmental stages. The 18S ribosome RNA gene of L. striatellus was chosen as the reference for calculating RSV CP expression using the comparative Ct method. Based on the CP transcript levels, the amount of RSV did not differ significantly throughout the nymphal stage or between adult females of different ages; however, RSV content tended to increase slightly as males became older. The average RSV content in males was 1.30-2.49 times that in females. The amount of RSV in L. striatellus adults was compared between generations. The RSV content of female adults did not differ significantly between the parent and progeny populations three of three different females. L. striatellus grown to adults on a susceptible cultivar and five RSV-resistant cultivars were compared to analyze whether the amount of RSV varied among cultivars. Although the amount of RSV in L. striatellus adults differed significantly among the six rice cultivars evaluated, the difference seemed independent of whether resistance genes were present. In addition, the percentage of viruliferous insects was similar among cultivars. PMID- 28589384 TI - The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). PMID- 28589386 TI - Navigating the jungles of tropical infectious gastrointestinal pathology: a pattern-based approach to the endoscopic biopsy. AB - International travels and global human migration have had the unforeseen consequence of increasing the exposure of histopathologists in developed countries to the pathology of tropical infectious disease. The gastrointestinal tract (GIT) is often the primary site of infection due to the faecal-oral route of transmission and the high risk of exposure to contaminated water, food or soil when travelling to these regions. Whilst current microbiologic techniques are far more sensitive than histology in detecting infectious pathogens, the histopathologist nonetheless retains a pivotal role in diagnosing tropical GIT disease. This role entails evaluating endoscopic biopsies for any characteristic inflammatory pattern, identifying pathogens which may be present and excluding other look-alike pathologies. Recent advances in commercially available diagnostic modalities, including molecular techniques, have further broadened the scope of the histopathologist's armamentarium. This review outlines a practical pattern-based approach to diagnosing tropical GIT infections in endoscopic material, so as to assist pathologists less familiar with this spectrum of pathology. PMID- 28589387 TI - Non-invasive papillary urothelial carcinoma of the vagina: molecular analysis of a rare case identifies clonal relationship to non-invasive urothelial carcinoma of the bladder. AB - We present a rare case of non-invasive papillary urothelial carcinoma of the vagina as the initial presentation of a multicentric urothelial carcinoma also involving bladder and renal pelvis and report for the first time in the literature the molecular alterations observed in the vaginal urothelial lesion and the synchronous lesions of the urinary tract. In this case, the non-invasive papillary urothelial carcinoma in the vagina displayed the same genetic alterations in the FGFR3 and PIK3CA genes as those seen in the non-invasive papillary urothelial carcinoma of the bladder contrasting with the wild phenotype observed in the invasive urothelial carcinoma of the renal pelvis. This observation could reinforce the theory of "seeding" of carcinoma cells as a valid and most likely explanation of this multifocality. In addition, we emphasize in this report the importance of recognizing this rare lesion in the female genital tract and its differential diagnosis. PMID- 28589388 TI - [Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from a German registry (GRAID2)]. AB - OBJECTIVE: To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in a real-life setting in Germany. METHODS: The German Register of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with a biologic agent. RESULTS: Data from 26 patients with AIF and 5 with MAS were collected. Of the AIF patients 13 (50%) were diagnosed with adult onset Still's disease (AOSD), 6 (23%) with familial Mediterranean fever (FMF), 4 (15.4%) with tumor necrosis factor associated periodic syndrome (TRAPS), 1 (3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2 (8%) with undifferentiated fever syndromes. The 5 MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2 cases AOSD. In 1 patient a chronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6 cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had a moderate response. There were no non-responders. Within the group of AIF patients the physicians documented a very effective or effective treatment in 38.5%, a moderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5 of the MAS and in 92% of the AIF patients. CONCLUSION: The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice. PMID- 28589389 TI - [Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. AB - BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities. PMID- 28589390 TI - [Unloading with insoles, orthotics and braces : Pre-operative leg axis correction or independent treatment?] AB - BACKGROUND: Knee osteoarthritis (OA) is a leading joint disease. In most of the early stages it does not involve the whole knee joint. Often, symptoms only or mainly concern the medial compartment combined with a slight varus malalignment. OBJECTIVES: Do valgus braces or laterally wedged insoles influence biomechanics and thus improve pain and function in patients with medial OA? Does the OA grade, severity of malalignment or patient's body weight predict the efficacy of the above-mentioned conservative treatment options? MATERIALS AND METHODS: The current literature was reviewed in regard to biomechanical changes to joint loading and their correlation to clinical results. RESULTS: Valgus braces and laterally wedged insoles reduce knee adduction moment, varus malalignment and analgesic consumption. Some authors suggest that mainly an alteration in muscle activity (diminished muscle co-contractions) is responsible for pain relief. Body weight and severity of varus malalignment did not influence treatment results; a significant correlation with OA severity was shown only for laterally wedged insoles. For both devices, compliance problems - especially long-term - should be considered, and conclusive evidence of positive clinical effects cannot be stated. CONCLUSIONS: Despite positive evidence in the current literature, a recommendation for or against valgus (unloader) braces in medial OA is not possible due to inconclusive results. Laterally wedged insoles are not recommended. Especially the long-term results are doubtful, and are possibly related to lacking compliance. PMID- 28589391 TI - [Spondylodiscitis : Current strategies for diagnosis and treatment]. AB - Spondylodiscitis is a severe infectious disease of the intervertebral discs and of the adjacent parts of the vertebral bodies, culminating in destruction of the mobile segment. It is accompanied by a mortality rate of approximately 15%. Severe courses of the disease can also lead to abscess formation and dispersal of sepsis. Malpositioning of the axis organ and deficits in neurological function up to paraplegia are also possible complications. Timely diagnostics and targeted therapy contribute to minimizing the risk of significant health disorders. This review article gives a summary of important algorithms in the diagnostics and treatment and discusses them against the background of currently available literature. According to the current state of knowledge the surgical treatment of spondylodiscitis provides many advantages and is therefore the method choice, even if a conservative approach can be successful in selected cases. The endpoints of treatment are cleansing of the infection with normalization of laboratory parameters of inflammation and the osseous fusion of the mobile segment. PMID- 28589392 TI - Naming CRISPR alleles: endonuclease-mediated mutation nomenclature across species. AB - The widespread use of CRISPR/Cas and other targeted endonuclease technologies in many species has led to an explosion in the generation of new mutations and alleles. The ability to generate many different mutations from the same target sequence either by homology-directed repair with a donor sequence or non homologous end joining-induced insertions and deletions necessitates a means for representing these mutations in literature and databases. Standardized nomenclature can be used to generate unambiguous, concise, and specific symbols to represent mutations and alleles. The research communities of a variety of species using CRISPR/Cas and other endonuclease-mediated mutation technologies have developed different approaches to naming and identifying such alleles and mutations. While some organism-specific research communities have developed allele nomenclature that incorporates the method of generation within the official allele or mutant symbol, others use metadata tags that include method of generation or mutagen. Organism-specific research community databases together with organism-specific nomenclature committees are leading the way in providing standardized nomenclature and metadata to facilitate the integration of data from alleles and mutations generated using CRISPR/Cas and other targeted endonucleases. PMID- 28589394 TI - Single and chronic L-serine treatments exert antidepressant-like effects in rats possibly by different means. AB - In the present study, the effects of both single (6 mmol L-serine/10 ml/kg orally administrated) and chronic (2% L-serine solution freely given for 28 days) treatments on depression-like behavior were evaluated in Wistar rats, representing the control, and Wistar Kyoto rats, representing an animal model of depression. Both single and chronic L-serine treatments decreased the duration of immobility, which is an index of a depressive-like state, in the forced swimming test in both strains. However, the decreases in the duration of immobility appear to be regulated differently by the different mechanisms involved in single and chronic L-serine treatments. In the prefrontal cortex and hippocampus, single L serine treatment increased the concentrations of L-serine, but not D-serine, while chronic L-serine treatment increased those of D-serine, but not L-serine. These data suggest that the antidepressant-like effects of single and chronic L serine treatments may have been induced by the increased L-serine and D-serine concentrations, respectively, in the brain. In addition, chronic L-serine treatment increased cystathionine concentrations in the hippocampus and prefrontal cortex in Wistar rats, but not in Wistar Kyoto rats, suggesting that Wistar Kyoto rats have an abnormality in the serine-cystathionine metabolic pathway. In conclusion, single and chronic L-serine treatments may induce antidepressant-like effects via the different mechanisms related to serine metabolism in the brain. PMID- 28589395 TI - Testosterone Therapy on Active Surveillance and Following Definitive Treatment for Prostate Cancer. AB - PURPOSE OF REVIEW: Previously considered an absolute contraindication, the use of testosterone therapy in men with prostate cancer has undergone an important paradigm shift. Recent data has changed the way we approach the treatment of testosterone deficiency in men with prostate cancer. In the current review, we summarize and analyze the literature surrounding effects of testosterone therapy on patients being treated in an active surveillance protocol as well as following definitive treatment for prostate cancer. RECENT FINDINGS: The conventional notion that defined the relationship between increasing testosterone and prostate cancer growth was based on limited studies and anecdotal case reports. Contemporary evidence suggests testosterone therapy in men with testosterone deficiency does not increase prostate cancer risk or the chances of more aggressive disease at prostate cancer diagnosis. Although the studies are limited, men who received testosterone therapy for localized disease did not have higher rates of recurrences or worse clinical outcomes. Current review of the literature has not identified adverse progression events for patients receiving testosterone therapy while on active surveillance/watchful waiting or definitive therapies. The importance of negative effects of testosterone deficiency on health and health-related quality of life measures has pushed urologists to re evaluate the role testosterone plays in prostate cancer. This led to a paradigm shift that testosterone therapy might in fact be a viable option for a select group of men with testosterone deficiency and a concurrent diagnosis of prostate cancer. PMID- 28589393 TI - A history of genome editing in mammals. AB - Genome editing is now a routine procedure in many mammalian genetics laboratories. The ostensibly short but intense history of genome-editing approaches illustrates how a disruptive technology can universally colonize a field when this new methodology, conceived to alter mammalian genomes at specific locations, is found to efficiently and robustly deliver results. This review summarizes the early development of genome editing using nucleases, from the pioneering experiments using yeast meganucleases, to the latest prokaryotic nucleases used for precise genome manipulation. Gene-editing nucleases belong to one of three known categories: zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats (CRISPR) and their associated proteins (Cas) tools. All operate on the same principle; they are all capable of inducing a double-strand break (DSB) at a defined genomic sequence that is subsequently corrected by endogenous DNA repair mechanisms. DSBs can be repaired through non-homologous end joining (NHEJ), resulting in small insertions and/or deletions (INDELs) and, hence, often leading to gene disruption. Alternatively, DSBs can be repaired through homology-driven repair (HDR), in the presence of donor homologous DNA sequences, resulting in gene-editing events. PMID- 28589396 TI - The use of Hormonal Therapy to Augment Radiation Therapy in Prostate Cancer: An Update. AB - PURPOSE OF REVIEW: Androgen deprivation therapy (ADT) is an important adjunctive therapy to external beam radiation therapy (RT) for the definitive management of prostate cancer. The role of ADT is well-established for locally advanced or high risk disease in conjunction with standard doses of RT, but less defined for intermediate-risk disease or with dose-escalated RT. The goal of this review is to summarize evidence evaluating the combination of ADT/RT, focusing on recent trials and current controversies as they pertain to the practicing clinician. RECENT FINDINGS: The benefit of ADT on biochemical control is maintained with dose-escalated RT according to recently reported phase III studies. Furthermore, there is now prospective, randomized evidence to support the addition of ADT to RT in the post-prostatectomy setting. ADT continues to play an important role for prostate cancer patients receiving dose-escalated RT. Future research is needed to identify subgroups most likely to benefit from this combination. PMID- 28589397 TI - Therapeutic Value of Standard Versus Extended Pelvic Lymph Node Dissection During Radical Prostatectomy for High-Risk Prostate Cancer. AB - Extent of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) remains a subject of debate. Here, we review the literature covering the value of extended PLND (ePLND) during RP for high-risk prostate cancer (PCa) over a standard PLND, with a focus on potential therapeutic advantage. PLND may provide valuable prognostic information to high-risk PCa patients, and incorporating the common iliac and presacral nodes to ePLND templates further improves pathologic nodal staging accuracy. Although increased PLND extent is associated with increased lymphocele/lymphedema rates, it is not associated with increased venous thromboembolism rates. The therapeutic role of ePLND remains uncertain. While recent retrospective studies suggest an increased number of nodes removed within the ePLND template are associated with improved survival outcomes, such retrospective studies cannot completely adjust for the Will Rodgers phenomenon or surgeon-specific factors. Thus, the results of randomized trials are eagerly awaited in this arena. PMID- 28589398 TI - The Contemporary Role of Multiparametric Magnetic Resonance Imaging in Active Surveillance for Prostate Cancer. AB - PURPOSE OF REVIEW: Growing research supports the use of multiparametric magnetic resonance imaging (mpMRI) for the evaluation of localized prostate cancer (PCa). We highlight contemporary evidence supporting its use in active surveillance (AS). RECENT FINDINGS: The emerging approach to localized PCa favors risk-adapted screening, image-guided biopsies, and selective therapeutic interventions. mpMRI is increasingly critical to achieve each of these aims. Early evidence suggests a value of mpMRI before initial biopsy to guide fusion targeting and to rule out non-organ confined disease as well as in the initiation and serial monitoring of men on AS. There remain concerns regarding understaging cancer with mpMRI and the standardization of expertise beyond the most experienced centers. mpMRI is emerging as a critical decision point for staging localized PCa and guiding AS strategies. While there is increasing enthusiasm, the optimal clinical scenario and sequencing remains to be defined. PMID- 28589399 TI - Prostate Biopsy in Active Surveillance Protocols: Immediate Re-biopsy and Timing of Subsequent Biopsies. AB - PURPOSE OF REVIEW: This manuscript reviews contemporary literature regarding prostate cancer active surveillance (AS) protocols as well as other tools that may guide the management of biopsy frequency and assess the possibility of progression in low-risk prostate cancer. RECENT FINDINGS: There is no consensus regarding the timing of surveillance biopsies; however, an immediate repeat biopsy within 12 months of diagnosis for patients considering AS confirms patients who have favorable risk disease yet also identifies patients who were undersampled initially. Studies regarding multiparametric MRI, nomograms, and biomarkers show promise in risk stratifying and counseling patients during AS. Further studies are needed to determine if these supplemental tests can decrease the frequency of surveillance biopsies. An immediate re-biopsy can help to reduce the risk of missing clinically significant disease. Other clinical tools, including mpMRI, exist that can be used as an adjunct to counsel patients and guide a personalized discussion regarding the frequency of surveillance biopsies. PMID- 28589401 TI - Tissue Preservation Techniques at the Time of Urethroplasty for Urethral Stricture Disease. AB - Reconstructive surgery for urethral stricture disease seeks to re-establish long lasting urethral patency while minimizing associated adverse effects. In recent years, genitourinary reconstructive surgeons have developed and refined a number of techniques that seek to decrease the impact of urethroplasty on local tissues including blood supply and innervation. This review presents an outline of recent advances in urethral reconstructive techniques that seek to minimize surgical impact, including tissue preservation, tissue engineering, and minimally invasive approaches and reviews the current state of the literature related to these techniques. PMID- 28589400 TI - Radical Prostatectomy for High-risk Localized or Node-Positive Prostate Cancer: Removing the Primary. AB - PURPOSE OF REVIEW: We reviewed the literature to determine what role, if any, radical prostatectomy should play in the treatment of high-risk and/or node positive prostate cancer. RECENT FINDINGS: The AUA, NCCN, and EAU all include radical prostatectomy as a treatment option for high-risk prostate cancer based on evidence that has shown improvements in biochemical-free and disease-specific survival. Lymph node-positive patients may also derive benefit from radical prostatectomy with lymph node dissection, however, only retrospective studies with high risk of selection bias have been published to date. High-risk prostate cancer is a heterogeneous disease representing a wide range of disease characteristics. Radical surgery, historically avoided in such patients, may now be considered a valid treatment option for select cases. The adverse effects of surgery using modern techniques lead to similar quality of life outcomes as radiation therapy, and treatment of the primary tumor is likely beneficial when compared to ADT alone. PMID- 28589404 TI - Erratum to: Secukinumab is Efficacious and Safe in Hispanic Patients with Moderate-to-Severe Plaque Psoriasis: Pooled Analysis of Four Phase 3 Trials. PMID- 28589402 TI - The Preoperative Assessment and Optimization of Patients Undergoing Major Urological Surgery. AB - PURPOSE OF REVIEW: Improving patient outcomes from major urological surgery requires not only advancement in surgical technique and technology, but also the practice of patient-centered, multidisciplinary, and integrated medical care of these patients from the moment of contemplation of surgery until full recovery. This review examines the evidence for recent developments in preoperative assessment and optimization that is of relevance to major urological surgery. RECENT FINDINGS: Current perioperative medicine recommendations aim to improve the short-term safety and long-term effectiveness of surgical treatments by the delivery of multidisciplinary integrated medical care. New strategies to deliver this aim include preoperative risk stratification using a frailty index and cardiopulmonary exercise testing for patients undergoing intra-abdominal surgery (including radical cystectomy), preoperative management of iron deficiency and anemia, and preoperative exercise intervention. Proof of the utility and validity for improving surgical outcomes through advances in preoperative care is still evolving. Evidence-based developments in this field are likely to benefit patients undergoing major urological surgery, but further research targeted at high-risk patients undergoing specific urological operations is required. PMID- 28589403 TI - Adjuvant Versus Early Salvage Radiation Therapy Following Radical Prostatectomy for Men with Localized Prostate Cancer. AB - Radical prostatectomy (RP) is now the most common definitive treatment for high risk prostate cancer. Unfortunately, many men will have residual microscopic disease after surgery alone. Despite level 1 evidence supporting the use of adjuvant radiation therapy (ART), <10% of men with adverse pathology (positive margins or T3 disease) receive ART in the USA. Early salvage radiation therapy (eSRT) at the time of biochemical recurrence has been proposed as an alternative strategy despite the lack of published randomized trials to support this approach. Multiple randomized trials are ongoing or recently completed to compare ART to eSRT, but given the long natural history of prostate cancer, long-term oncologic outcomes from these trials will not be reported for several years. In this review, we discuss the shifting trends in the diagnosis of high-risk prostate cancer given a decline in PSA screening, use of RP for high-risk disease, and compare and contrast the retrospective and randomized evidence regarding ART and SRT. PMID- 28589406 TI - Erratum to: Preprocedural Risk Assessment Prior to PPVI with CMR and Cardiac CT. PMID- 28589405 TI - Drug-Coated Balloon Angioplasty: A Novel Treatment for Pulmonary Artery In-Stent Stenosis in a Patient with Williams Syndrome. AB - A 20-month-old boy with Williams syndrome had undergone multiple surgical and catheter-based interventions for resistant peripheral pulmonary arterial stenoses with eventual bilateral stent placement and conventional balloon angioplasty. He persistently developed suprasystemic right ventricular (RV) pressure. Angioplasty with a drug-coated balloon (DCB) was performed for in-stent restenosis and to remodel his distal pulmonary vessels bilaterally. This resulted in immediate improvement in the in-stent stenosis and resultant decrease in RV pressure. Follow-up catheterization two months later continued to show long-lasting improvement in the in-stent stenosis. We hypothesize that the anti-proliferative effects of DCBs may be of benefit in the arteriopathy associated with Williams syndrome. We report this as a novel use of a DCB in the pulmonary arterial circulation in a patient with Williams syndrome. PMID- 28589407 TI - Changes of Cerebral Oxygenation in Sequential Glenn and Fontan Procedures in the Same Children. AB - Recently, it is common to perform the Fontan procedure after the Glenn procedure as surgical repair for the univentricular heart. How the brain oxygen saturation (rSO2) values change with the cardiac restoration and the process of growth during these procedures in individual children remains unknown. In this study, we retrospectively studied rSO2 data as well as the perioperative clinical records of 30 children who underwent both Glenn and Fontan procedures by the same surgeon in the same institute. The rSO2 was measured at the beginning and end of each procedure with an INVOS 5100C. Cerebral perfusion pressure was calculated by subtracting central venous pressure from mean arterial pressure. Arterial oxygen saturation (SaO2) and the hemoglobin concentration were obtained as candidates affecting rSO2 changes at the start and the end of both procedures. The rSO2 increased during the Glenn procedure, but this increase was slight and insignificant. On the other hand, the rSO2 significantly increased during the Fontan procedure. Significant increases in SaO2 were observed only between the beginning and end of the Fontan procedure. Correlation coefficients determined by linear regression analysis were more than 0.5 between rSO2 and SaO2 in both procedures. Multiple linear regression analysis showed that SaO2 was the key determinant of the rSO2. The rSO2 increases step by step from the Glenn to the Fontan procedure in the same patient. Within each procedure, SaO2 is the key determinant of the rSO2. The significance of rSO2 monitoring in these procedures should be further evaluated. PMID- 28589408 TI - Critically Underdeveloped Left Heart Morphology Associated with Prematurity and Low Birth Weight: Conditional Staged Rehabilitation Towards Biventricular Repair and Time-Related Growth of Left Heart Structures. AB - This is a case report of premature low birth weight infant with hypoplasia of left heart structures and a large malaligned VSD who underwent successful staged approach of biventricular repair. We obtained qualitative and quantitative echocardiographic, MRI, and conventional catheterization data to support stepwise strategy towards LV rehabilitation to sustain adequate cardiac output. A thorough and intense follow-up has shown significant growth of left heart structures and favorable clinical status following staged biventricular repair. Our data indicate usefulness of qualitative and quantitative advanced complimentary multi imaging modalities in predicting the postnatal growth potential of critically underdeveloped left heart structures. PMID- 28589409 TI - Application of biodegradable 3D-printed cage for cervical diseases via anterior cervical discectomy and fusion (ACDF): an in vitro biomechanical study. AB - OBJECTIVES: To design and fabricate a 3D-printed cervical cage composite of polylactic acid (PLA)/nano-sized and beta-tricalcium phosphate (beta-TCP). RESULTS: CAD analysis provided a useful platform to design the preliminary cage. In vitro cell culture and in vivo animal results showed promising results in the biocompatibility of the constructs. Endplate matching evaluation showed better matching degree of 3D-printed cages than those of conventional cages. Biomechanical evaluation showed better mechanical properties of 3D-printed cages than those of conventional cages. CONCLUSION: The novel 3D printed PLA/pbeta-TCP cage showed good application potential, indicating a novel, feasible, and inexpensive method to manufacture cervical fusion cages. PMID- 28589411 TI - Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is characterized by excessive bone formation with syndesmophytes, leading to bony ankylosis. The contribution of osteoblasts to the pathogenesis of ankylosis is poorly understood. The aim of this study was to determine molecular differences between disease controls (Ct) and AS bone-derived cells (BdCs) during osteogenic differentiation with or without inflammation using AS patient serum. We confirmed osteoblastic differentiation of Ct and AS BdCs under osteogenic medium by observing morphological changes and measuring osteoblastic differentiation markers. Osteoblast differentiation was detected by alkaline phosphatase (ALP) staining and activity, and alizarin red and hydroxyapatite staining. Osteoblast-specific markers were analyzed by quantitative reverse-transcriptase-polymerase chain reaction, immunoblotting, and immunostaining. To examine the effects of inflammation, we added AS and healthy control serum to Ct and AS BdCs, and then analyzed osteoblast-specific markers. AS BdCs showed elevated basal intercellular and extracellular ALP activity compared to Ct. When osteoblast differentiation was induced, AS BdCs exhibited higher expression of osteoblast-specific marker genes and faster mineralization than Ct, indicating that these cells differentiated more rapidly into osteoblasts. ALP activity and mineralization accelerated when serum from AS patients was added to Ct and AS BdCs. Our results revealed that AS BdCs showed significantly increased osteoblastic activity and differentiation capacity by regulating osteoblast-specific transcription factors and proteins compared to Ct BdCs. Active inflammation of AS serum accelerated osteoblastic activity. Our study could provide useful basic data for understanding the molecular mechanism of ankylosis in AS. PMID- 28589410 TI - Computational segmentation of collagen fibers in bone matrix indicates bone quality in ovariectomized rat spine. AB - Bone loss varies according to disease and age and these variations affect bone cells and extracellular matrix. Osteoporosis rat models are widely investigated to assess mechanical and structural properties of bone; however, bone matrix proteins and their discrepant regulation of diseased and aged bone are often overlooked. The current study considered the spine matrix properties of ovariectomized rats (OVX) against control rats (Sham) at 16 months of age. Diseased bone showed less compact structure with inhomogeneous distribution of type 1 collagen (Col1) and changes in osteocyte morphology. Intriguingly, demineralization patches were noticed in the vicinity of blood vessels in the OVX spine. The organic matrix structure was investigated using computational segmentation of collagen fibril properties. In contrast to the aged bone, diseased bone showed longer fibrils and smaller orientation angles. The study shows the potential of quantifying transmission electron microscopy images to predict the mechanical properties of bone tissue. PMID- 28589413 TI - Single particle Brownian motion with solid friction. AB - We study the Brownian dynamics of a solid particle on a vibrating solid surface. Phenomenologically, the interaction between the two solid surfaces is modeled by solid friction, and the Gaussian white noise models the vibration of the solid surface. The solid friction force is proportional to the sign of relative velocity. We derive the Fokker-Planck (FP) equation for the time-dependent probability distribution to find the particle at a given location. We calculate analytically the steady state velocity distribution function, mean-square velocity and diffusion coefficient in d-dimensions. We present a generic method of calculating the autocorrelations in d-dimensions. This results in one dimension in an exact evaluation of the steady state velocity autocorrelation. In higher dimensions our exact general expression enables the analytic evaluation of the autocorrelation to any required approximation. We present approximate analytic expressions in two and three dimensions. Next, we numerically calculate the mean-square velocity and steady state velocity autocorrelation function up to d = 3 . Our numerical results are in good agreement with the analytically obtained results. PMID- 28589412 TI - Serum CTX levels and histomorphometric analysis in Src versus RANKL knockout mice. AB - Src knockout (KO) and RANKL KO mice both exhibit near complete osteopetrosis in terms of 3D-bone volume (BV) fraction by micro-CT, whereas the serum CTX concentration of Src KO is apparently normal and that of RANKL KO is 30% of wild type (WT) despite the fact that they lack osteoclasts. By histomorphometry we found that, whereas eroded surface (ES) and osteoid surface (OS) are zero values in RANKL KO, they are indistinguishable from WT in Src KO; because of marked increase in bone surface (BS), ES/BS and OS/BS of Src KO are 30-40% of WT. While RANKL KO lack both osteoclasts and osteoblasts, Src KO reveal increased numbers of osteoclasts and indistinguishable numbers of osteoblasts compared with WT; again, on the basis of BS, N.Oc/BS is comparable to WT and N.Ob/BS is markedly decreased in Src KO. The apparently increased number of total osteoclasts may be due to increased expression of RANKL found in Src KO bone in vivo. Src has a gene dosage-dependent effect on osteoclast function in vitro, with Src-/- osteoclasts completely lacking bone-resorbing function as determined by CTX release on dentin. Thus, Src KO osteoclasts retain some bone-resorbing function in vivo. The number of osteocytes is proportionally increased in RANKL KO, while Src KO mice have relative osteocyte deficiency, raising the possibility that RANKL and Src has an unrecognized role in osteocyte survival. PMID- 28589414 TI - [What is the situation with human rights of the elderly? : UN Open-ended Working Group on Ageing - review and prospects]. AB - In November 2010 the United Nations General Assembly set up a working group to strengthen the protection of human rights for older persons (UN Open-ended Working Group on Ageing) with the United Nations Resolution A/C.3/65/L.8/Rev.1. In December 2016 the members of the working group met for the seventh time and discussed how they can approach the fulfillment of the mandate. In addition to better implementation, the strengthening of rights can consist of closing existing gaps or further differentiation of the rights in order to give the member states better guidance on how to implement them. To improve the human rights of older persons a task of the members of the working group would be to examine the existing rights and, where possible, adjust them to the real needs of the group. One of the major challenges facing the working group is already apparent: who belongs to the group of older persons and how could the group be described? This article deals with the presentation of the international process, new developments at the regional level and the attitudes of the member states and the civil society. A further aim is to present the possibilities and effects of a comprehensive legally binding instrument. PMID- 28589416 TI - The Anticancer Activities Phenolic Amides from the Stem of Lycium barbarum. AB - Four new phenolic amides, 4-O-methylgrossamide (1), (E)-2-(4,5-dihydroxy-2-{3-[(4 hydroxyphenethyl)amino]-3-oxopropyl}-phenyl)-3-(4-hydroxy-3-methoxyphenyl)-N-(4 hydroxyphenethyl)acryl-amide (2), (Z)-lyciumamide C (3), (Z)-thoreliamide B (4), together with thirteen known phenolic amides were identified from the stem of Lycium barbarum. The structures of the new compounds were determined by spectroscopic methods. All compounds were evaluated for their anti-cancer activities against human glioma stem cell lines. PMID- 28589415 TI - Noma in an HIV infected patient in Guinea-Bissau: a case report. AB - BACKGROUND: Noma is a multifactorial and multibacterial opportunistic infection that initially causes necrotic gingivitis but rapidly spreads to the nearby orofacial tissue resulting in sloughing and severe deformation of the facial structures. The majority of cases are seen in young children under the age of 6 years. Noma is strongly associated with poverty, malnutrition and immunosuppression, and is often preceded by severe systemic infections such as measles and malaria. Only few cases of noma infection in adults have been described. CASE REPORT: We present here a case report with a 32-year-old Guinean woman who was diagnosed with noma infection and on that occasion discovered that she was HIV-1 seropositive. After treatment with amoxicillin/clavulanic acid and metronidazole for her noma infection the woman was transferred to the national hospital where antiretroviral treatment was initiated. CONCLUSION: Noma is an opportunistic infection and immunodeficiencies such as HIV should always be suspected when presenting in an adult patient. PMID- 28589418 TI - Possible protective effect of switching from denosumab to zoledronic acid on vertebral fractures. PMID- 28589417 TI - Bone loss with antiepileptic drug therapy: a twin and sibling study. AB - : Changes in areal bone mineral density (aBMD) and other predictors of bone loss were evaluated in 48 same-sex twin/age-matched sibling pairs discordant for antiepileptic drug (AED) use. AED users had reduced BMD at the hip regions. Prolonged AED users had greater aBMD loss, predicting a higher risk of bone fragility. INTRODUCTION: To investigate the longitudinal associations of bone mineral measures with antiepileptic drug (AED) use, including enzyme-inducing (EIAED) and non-enzyme-inducing (NEIAED) types, and other predictors of bone loss in a study of 48 same-sex twin/age-matched sibling pairs (40 female, 8 male) discordant for AED use. METHODS: Using dual-energy X-ray absorptiometry (DXA), areal bone mineral density (aBMD) and content (BMC) at the hip regions, forearm, lumbar spine, and whole body were measured twice, at least 2 years apart. The mean within-pair difference (MWPD), MWPD%, and mean annual rate of aBMD change were adjusted for age, weight, and height. Predictors of bone loss were evaluated. RESULTS: AED users, compared to non-users, at baseline and follow-up, respectively, had reduced aBMD at the total hip (MWPD% 3.8, 4.4%), femoral neck (4.7, 4.5%), and trochanter regions (4.1, 4.6%) (p < 0.05). For the whole cohort, the annual rate of change in all aBMD/BMC (p > 0.05) regions did not differ within pairs. Nevertheless, EIAED users had greater aBMD loss than non-users (n = 20 pairs) at the total hip (1.7 vs. 0.3%, p = 0.013) and whole body regions (0.7% loss vs. 0.1% BMD gain, p = 0.019), which was not found in NEIAED-discordant pairs (n = 16). AED use >20 years predicted higher aBMD loss at the forearm (p = 0.028), whole body (p = 0.010), and whole body BMC (p = 0.031). CONCLUSIONS: AED users had reduced aBMD at the hip regions. Prolonged users and EIAED users had greater aBMD loss, predicting a higher risk of bone fragility. Further prospective studies of AED effects on bone microarchitecture are needed. PMID- 28589420 TI - The Use of Salmonella Typhim Vaccine to Diagnose Antibody Deficiency. AB - PURPOSE: The specific antibody response to the unconjugated 23-valent pneumococcal polysaccharide vaccine is one of the most common tests used to assess for possible humoral immunodeficiency. The results can be difficult to interpret because most people have been immunized with one or more of the pneumococcal vaccines and there is controversy regarding what constitutes a normal response. To circumvent this problem, we developed an ELISA to measure IgG specific antibodies to the Salmonella Vi Typhim (S. Typhim) vaccine, a pure polysaccharide vaccine, which is a neoantigen for the vast majority of people in the USA. METHODS: We compared the pre- and post-vaccination serum titers to the Vi Typhim vaccine in healthy controls (n = 22), patients previously diagnosed with a primary immunodeficiency (n = 30), and patients referred for possible humoral immune deficiency (n = 29). We also determined if the S. Typhim vaccine could be used to assess specific antibody responses in people on antibody replacement therapy. RESULTS: Following immunization with the S. Typhim vaccine, we found that a 2-fold increase in titers is 100% sensitive and specific in detecting known humoral immune deficiencies as determined by ROC curve analysis. This cut-off value was successfully applied to possible immune deficiency patients (n = 29), resulting in the diagnosis of seven subjects with humoral immunodeficiency. The use of immunoglobulin replacement therapy did not affect the median response ratios compared to subjects not receiving gammaglobulin. CONCLUSION: This study suggests that measurement of the specific antibody response to the S. Typhim vaccine may have advantages over pneumococcal vaccination in the evaluation of the humoral immune response. PMID- 28589419 TI - Breastfeeding as the sole source of milk for 6 months and adolescent bone mineral density. AB - : Little is known regarding the relationship between early life factors and bone mineral density (BMD). We found a positive association between breastfeeding for at least 6 months, without formula supplementation, and whole body adolescent BMD z-score. INTRODUCTION: The aim of the study is to assess the role of breastfeeding BF on adolescent bone mineral density (BMD) in a cohort prospectively followed since infancy. METHODS: We studied 679 participants from an infancy iron deficiency anemia preventive trial in Santiago, Chile, followed to adolescence. Breast and bottle feeding were ascertained weekly from 4 to 12 months. At 16 years, whole body BMD was assessed by DEXA. Using linear regression, we evaluated associations between BF duration and BF as the sole source of milk and adolescent BMD z-score, adjusting for possible infancy, adolescent, and background confounders. RESULTS: Mean birth weight and length were 3.5 (0.3) kg and 50.7 (1.6) cm. For at least 6 months, BF was the sole source of milk for 26.3% and with supplementation for 36.7%. For 37%, BF was provided for less than 6 months. Mean 16-year BMD z-score was 0.25 (1.0). Covariates included male sex, birth length, and gestational age. BF as the sole source of milk >=6 months, compared to BF < 6 months, was associated with higher adolescent BMD z-score adjusting for covariates (beta = 0.29, p < 0.05). Mixed BF was not significantly related to adolescent BMD z-score (beta = 0.06, p = 0.47). For every 30 days of BF as the sole source of milk, adolescent BMD z-score increased by 0.03 (p = 0.01). CONCLUSION: BF without formula supplementation for at least 6 months was associated with higher adolescent BMD z-score and a suggestive trend in the same direction for BMD suggests that exclusivity and duration of BF may play a role in adolescent bone health. PMID- 28589421 TI - Tat-MyoD fused proteins, together with C2c12 conditioned medium, are able to induce equine adult mesenchimal stem cells towards the myogenic fate. AB - The Tat protein is able to translocate through the plasma membrane and when it is fused with other peptides may acts as a protein transduction system. This ability appears particularly interesting to induce tissue-specific differentiation when the Tat protein is associated to transcription factors. In the present work, the potential of the complex Tat-MyoD in inducing equine peripheral blood mesenchymal stem cells (PB-MSCs) towards the myogenic fate, was evaluated. Results showed that the internalization process of Tat-MyoD happens only in serum free conditions and that the nuclear localization of the fused complex is observed after 15 hours of incubation. However, the supplement of Tat-MyoD only was not sufficient to induce myogenesis and, therefore, in order to achieve the myogenic differentiation of PB-MSCs, conditioned medium from C2C12 cells was added without direct contact. Real Time PCR and immunofluorescence methods evaluated the establishment of a myogenic program. Our results suggest that TAT- transduction of Tat-MyoD, when supported by conditioned medium, represents a useful methodology to induce myogenic differentiation. PMID- 28589422 TI - Modulatory function of NMDA glutamate receptor on MC3/MC4 receptors agonist induced hypophagia in neonatal meat-type chicken. AB - Melanocortin 3 and 4 receptors (MC3R and MC4R) are known as the main receptors for melanocortin-induced hypophagia in mammalian and poultry. Also, central glutamatergic system has mediatory role on function of the melanocortin system in some brain areas. So, the aim of the current study was to determine the role of MC3/MC4 receptors agonist on food intake and its interaction with glutamatergic in 3-h food-deprived (FD3) neonatal broilers. In experiment 1, chickens were intracerebroventricular (ICV) injected with control solution, MTII (MC3/MC4 receptors agonist; 2.45, 4.8 and 9.8 pmol). In experiment 2, control solution, SHU9119 (MC3/MC4 receptors antagonist; 0.5, 1 and 2 nmol) were ICV injected. In experiment 3, birds ICV injected with control solution, SHU9119 (0.5 nmol), MTII (9.8 pmol) and co-injection of the SHU9119 + MTII. Experiments 4-8 were similar to experiment 3, except birds injected with MK-801 (NMDA glutamate receptors antagonist, 15 nmol), CNQX (AMPA glutamate receptors antagonist; 390 nmol), AIDA (mGLUR1 glutamate receptors antagonist; 2 nmol), LY341495 (mGLUR2 glutamate receptors antagonist; 150 nmol) and UBP1112 (mGLUR3 glutamate receptors antagonist; 2 nmol) instead of SHU9119. Then, cumulative food intake was recorded until 120 min after injection. According to the results, dose dependent hypophagia observed after ICV injection of the MTII (p < 0.05). ICV injection of SHU9119 significantly increased food intake in birds (p < 0.05). Co-injection of SHU9119 + MTII significantly inhibited MTII- induced hypophagia in neonatal chicks (p < 0.05). In addition, hypophagia- induced by MTII was significantly attenuated with co-injection of MTII + MK-801(p < 0.05). These results suggested MC3 and MC4 receptors have inhibitory role on food intake and this effect is probably mediated by NMDA glutamate receptors in neonatal chickens. PMID- 28589424 TI - Molecular landscape of pediatric diffuse intrinsic pontine gliomas: about 22 cases. PMID- 28589423 TI - The Perennial Penstemon: Variation in Defensive Chemistry Across Years, Populations, and Tissues. AB - Plants produce a variety of secondary metabolites that function as a defense against their natural enemies. Production of these secondary metabolites is genetically controlled, but is also phenotypically plastic and varies in response to both biotic and abiotic factors. Therefore, plant species may vary widely in their chemical defenses and such variation can be evident at temporal, spatial and tissue levels. Focusing on the chemical defenses of a native Colorado wildflower, Penstemon virgatus, we assessed the variation in iridoid glycoside (IG) content across two non-consecutive growing seasons, six natural populations and three tissue types: leaves, stems and flowers. Our results indicate that P. virgatus plants contain high concentrations of IGs (mean = 23.36% dry weight of leaves) and that IGs were differentially allocated among tissue types. Leaves contained the highest concentration of IGs, which varied quantitatively between sampling years, among plant populations, and plant parts. We also quantified leaf herbivore damage at all six populations but we found very little herbivore damage. Our study indicates that the IG concentrations of P. virgatus plants are both spatially and temporally variable. Furthermore, the high concentrations of secondary metabolites combined with the low levels of damage suggest that these plants are well defended against generalist herbivores. PMID- 28589425 TI - Comparison of the ImmuView and the BinaxNOW antigen tests in detection of Streptococcus pneumoniae and Legionella pneumophila in urine. AB - The use of urinary antigen tests (UATs) may provide early etiology in pneumonia, and facilitates rapid and directed antibiotic treatment. In this study, we evaluated the novel lateral flow ImmuView Streptococcus pneumoniae and Legionella pneumophila UAT, which detects pneumococcal and L. pneumophila serogroup 1 antigens in a combined test. We compared the ImmuView UAT with the BinaxNOW S. pneumoniae UAT and the BinaxNOW L. pneumophila UAT in 147 patients with pneumococcal bacteremia (n = 48), non-pneumococcal non-Legionella bacteremia (n = 93) and Legionella infections in the lower airways (L. pneumophila, n = 5; L. bozemanii, n = 1). In three cases, the ImmuView test was invalid before and after boiling while the BinaxNOW tests were valid in all cases. In 144 cases, the three UATs demonstrated a very good inter-assay agreement for detection of pneumococcal antigen (kappa = 0.86) and L. pneumophila antigen (kappa = 1.00). The ImmuView and BinaxNOW S. pneumoniae tests had similar sensitivities (62% vs 60%; p = ns) in 48 cases with pneumococcal bacteremia and both tests had specificities of 97% in 96 cases with non-pneumococcal infections. Furthermore, the ImmuView and BinaxNOW L. pneumophila tests were positive for Legionella antigen in five patients with confirmed L. pneumophila serogroup 1 infections, and negative in all non-L. pneumophila cases. The ImmuView and BinaxNOW tests performed similarly when evaluated on urine samples from bacteremic and non-bacteremic patients with identified etiology. PMID- 28589427 TI - Erratum to: Stimulated thyroglobulin values above 5.6 ng/ml before radioactive iodine ablation treatment following levothyroxine withdrawal is associated with a 2.38-fold risk of relapse in Tg-ab negative subjects with differentiated thyroid cancer. PMID- 28589426 TI - Clinical condition and comorbidity as determinants for blood culture positivity in patients with skin and soft-tissue infections. AB - The utility of performing blood cultures in patients with a suspected skin infection is debated. We investigated the association between blood culture positivity rates and patients' clinical condition, including acute disease severity and comorbidity. We performed a retrospective study, including patients with cellulitis and wound infection who had been enrolled in three Dutch multicenter studies between 2011 and 2015. Patients' acute clinical condition was assessed using the Modified Early Warning Score (MEWS; severe: MEWS >=2) and comorbidity with the Charlson Comorbidity Index (CCI; severe: CCI >=2). A total of 334 patients with a suspected skin infection were included. Blood cultures were performed in 175 patients (52%), 28 of whom (16%) had a positive blood culture. Data on the clinical condition were collected in 275 patients. Blood cultures were performed in 76% of the patients with a severe acute condition, compared with 48% with a non-severe acute condition (OR 3.5; 95% confidence interval: 2.0-6.2; p < 0.001). Blood cultures were positive in 18% and 12% respectively (OR 1.7 (0.7-4.1); p = 0.3). Blood cultures were performed in 53% of patients with severe comorbidity, compared with 61% without severe comorbidity (OR 0.7; 0.4-1.2; p = 0.2). Blood cultures were positive in 25% and 10% respectively (OR = 3.1; 1.2-7.5; p = 0.02). The blood culture positivity rate among hospitalized patients diagnosed with skin infections was higher than the rates reported by the Infectious Diseases Society of America guidelines, particularly in patients with severe comorbidity. Therefore, the recommendations concerning blood culture performance in patients with a skin infection should be reconsidered. PMID- 28589428 TI - Annual hazard rate of relapse of stage II and III colorectal cancer after primary therapy. AB - PURPOSE: To report the annual hazard of relapse in stages II and III colorectal cancer (CRC) Tunisian patients treated with curative intent. We also aim to evaluate impact of oxaliplatine according to anatomo-clinical features. METHODS: We collected data about clinico-pathological parameters of 331 CRCs. We analyzed annual hazard of recurrence (locoregional and/or distant) of the overall population and several subgroups: colon cancer vs rectal cancer and stage II vs stage III. We also analyzed impact of adjuvant oxaliplatine on recurrence within these subgroups. RESULTS: Relapse rate was 38.1%, with a mean time to relapse of 27.6 months. We noted 23.8% local recurrence, 69.8% distant recurrence, and 6.4% both. We observed higher local relapse rate in rectal cancer (26.8 vs 3.2%) vs colon cancer (p = 0.004). Stage III had a higher metastatic relapse rate vs stage II (31.6 vs 20.8%, p = 0.043). Annual hazard of recurrence for the overall population showed two peaks: [1-2] year-interval by 10.1% and [3-4] year-interval by 11.3%. Stage III showed significantly higher and earlier recurrence hazard peak compared to stage II (16.3 vs 8.1% in [1-2] year-interval). Oxaliplatine significantly improved annual hazard of recurrence in each year-interval from year 1-4, in colon cancer and in stage III but without impact in rectal cancer and stage II. CONCLUSION: Extended follow-up to 4 years should be considered in Tunisian population. Impact of oxaliplatine showed same features to reported occidental series. PMID- 28589429 TI - Influence of ovarian cancer type I and type II microenvironment on the phenotype and function of monocyte-derived dendritic cells. AB - PURPOSE: The aim of this study was to evaluate the influence of ovarian cancer cell lysates isolated from type I or type II ovarian cancer (OC) on the phenotype of monocyte-derived dendritic cells (Mo-DCs) and the cytokine profile. We also determined whether the Mo-DCs and tumor microenvironment, reflected by peritoneal fluid (PF) from type I or II ovarian cancer, could promote regulatory T cell (Tregs) differentiation from naive CD4+ lymphocytes in vitro. RESULTS: Our results show a significant role of the ovarian cancer microenvironment reflected by PF from type I or II OC in the inhibition of the DC differentiation process. Interestingly, the percentage of cells co-expressing CD45 and CD14 antigens in the cultures stimulated with PF from both type I and type II OC was higher than in the control. Furthermore, the percentage of cells expressing CD1a, i.e., a marker of immature DCs, was significantly reduced in the cultures stimulated with PF from type I and type II OC. The results obtained show that ovarian cancer type II lysates induce differentiation of monocytes into macrophage-like cells with a CD1a+/HLA-DR+/CD83- phenotype and significantly higher CD86/HLA-DR expression. We show that ovarian cancer type II Mo-DCs are able to prevent an immune response by release of IL-10, whereas OC type I Mo-DCs can promote the generation of Tregs. CONCLUSIONS: We demonstrate that each type of ovarian cancer can induce a unique phenotype of DCs and differentiation of Tregs, both associated with immune suppressive function, which may be an obstacle while developing effective anticancer dendritic cell vaccination. PMID- 28589430 TI - SLC14A1: a novel target for human urothelial cancer. AB - Urinary bladder cancer is the second commonly diagnosed genitourinary malignancy. Previously, bio-molecular alterations have been observed within certain locations such as chromosome 9, retinoblastoma gene and fibroblast growth factor receptor 3. Solute carrier family 14 member 1 (SLC14A1) gene encodes the type-B urea transporter (UT-B) which facilitates the passive movement of urea across cell membrane, and has recently been related with human malignancies, especially for bladder cancer. Herein, we discussed the SLC14A1 gene and UT-B protein properties, aiming to elucidate the expression behavior of SLC14A1 in human bladder cancer. Furthermore, by reviewing some well-established theories regarding the carcinogenesis of bladder cancer, including several genome wide association researches, we have bridged the mechanisms of cancer development with the aberrant expression of SLC14A1. In conclusion, the altered expression of SLC14A1 gene in human urothelial cancer may implicate its significance as a novel target for research. PMID- 28589431 TI - Bone marrow fibrosis at diagnosis predicts survival for primary acute myeloid leukemia. AB - PURPOSE: As a desmoplastic reaction, tissue fibrosis played crucial roles in solid tumor progression, chemo-resistance, and consequently heralded poor clinical outcome. Previous studies implied the effects of marrow fibrosis on prognosis for acute lymphoblastic leukemia were disputable. In this study, we aimed to investigate the potential role of bone marrow fibrosis on clinical survival in acute myeloid leukemia (AML) patients. METHODS: Bone marrow fibrosis (evaluated as reticulin fiber density, RFD) in bone marrow sections was evaluated at diagnosis via computer technology. Receiver operating characteristic curve (ROC) was used to analyze the predictive value of RFD for relapse and survival status. Kaplan-Meier method was used to estimate survival rates per subgroup between patients with different RFD. Cox proportional hazard regression was used to model the overall survival. RESULTS: High RFD at diagnosis in bone marrow sections from primary AML might predict early relapse and shorter survival (P = 0.003 and 0.001, respectively). The optimal cutoff value of RFD at diagnosis was determined to be 7.2%. Furthermore, the Kaplan-Meier analysis indicated that patients with high marrow RFD had shorter relapse-free survival (RFS) and overall survival (OS) than patients with low RFD (P = 0.007 and 0.000, respectively). Multivariate analysis suggested that similar with cytogenetics, marrow RFD at diagnosis was an independent prognostic factor for RFS [HR 0.564, 95% confidence interval (CI) 0.338-0.940, P = 0.028] and OS (HR 0.457, 95% CI 0.225-0.929, P = 0.031) in primary AML patients. CONCLUSIONS: Our data suggest that marrow RFD before treatment should be seemed as prognostic factor in primary AML, it may provide valuable clues for developing new targeted therapy. PMID- 28589432 TI - Comparative efficacy and toxicity of induction chemotherapy with concurrent stereotactic body radiotherapy and stereotactic body radiotherapy with subsequent chemotherapy in patients with clinical stage T1-3N0M0 non-small cell lung carcinoma. AB - PURPOSE: We compared the clinical efficacy and toxicity of stereotactic body radiotherapy with induction chemotherapy and concurrent radiochemotherapy vs stereotactic body radiotherapy with subsequent chemotherapy in patients with clinical stage T1-3N0M0 non-small cell lung carcinoma. METHODS: We retrospectively analyzed 38 patients with c-stage T1-3N0M0 non-small cell lung carcinoma who received stereotactic body radiotherapy. All patients received six cycles of chemotherapy. Fifteen of the patients were treated with three cycles of induction chemotherapy, one cycle of concurrent radiochemotherapy, and then two cycles of consolidation chemotherapy, while 23 patients received Sequential Radiotherapy/Chemotherapy. RESULTS: Patients in the induction chemotherapy group experienced a longer duration of esophagitis (median 2 vs 0, range 0-6 vs 0-3.6 weeks, p = 0.04). We divided the patients into two groups based on their median pre-treatment tumor volume (cm3): >32.11 and <=32.11. The tumor response rate in patients with larger tumor volume was substantially higher in the induction chemotherapy group than in the Sequential Radiotherapy/Chemotherapy group (66.67 vs 40%). Among patients with pre-treatment tumor volume (cm3) >32.11, the median local progression-free survival (LPFS) in the induction chemotherapy group and Sequential Radiotherapy/Chemotherapy group was 18 months (range 7-72 months) and 11 months (range 6-53 months), respectively. There was a statistically significant difference between the two groups (p = 0.006). CONCLUSIONS: Simultaneous SBRT and chemotherapy can result in a longer duration of esophagitis. However, for patients with large tumor volume, ICT combined with concurrent radiochemotherapy may result in better local tumor response as well as longer LPFS and progression-free survival. To better elucidate the best treatment, further clinical trials are needed. PMID- 28589433 TI - Overexpression of dishevelled 2 is involved in tumor metastasis and is associated with poor prognosis in hepatocellular carcinoma. AB - PURPOSE: Although hepatocellular carcinoma (HCC) is one of the most common malignant tumors, its molecular mechanism is still unknown. Dishevelled 2 (Dvl2) is one of the downstream targets of non-canonical Wnt signaling, which has been demonstrated to be of great importance in the progression of cancers. Nevertheless, the expression mechanisms and physiological significance of Dvl2 in HCC remain unclear. METHODS: Western blotting and immunohistochemistry were used to measure Dvl2 protein expression in HCC and adjacent normal tissues of 101 patients. Wound healing and transwell assays were used to determine cell migration and invasion. RESULTS: Dvl2 expression was upregulated in HCC tissues compared to the adjacent normal tissues. Moreover, its expression level was significantly correlated with histological grade (P = 0.042), metastasis (P = 0.005) and vein invasion (P = 0.009) in patients with HCC. Wound healing and transwell assays showed that knockdown of Dvl2 reduced cell migration and invasion in HepG2 cells. Finally, we confirmed that Dvl2 could regulate the migration and invasion of HCC cells by interacting with P62 in non-canonical Wnt signaling. CONCLUSIONS: Our data showed that Dvl2 was overexpressed in HCC tissues and was also correlated with poor prognosis, suggesting that Dvl2 is a novel therapeutic target for HCC. PMID- 28589434 TI - Outcome and toxicity of intensity modulated radiotherapy with simultaneous integrated boost in locally advanced non-small cell lung cancer patients. AB - PURPOSE: The aim of this study was to assess the feasibility and treatment outcome of intensity modulated radiation therapy with simultaneous integrated boost (SIB-IMRT) in locally advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: A total of 64 NSCLC patients with stage IIB (3%), IIIA (36%), and IIIB (61%) were treated with concomitant (N = 47; 73%) or sequential (N = 9; 14%) chemotherapy between February 2009 and January 2014. Eight patients (13%) received RT alone. All patients received the same irradiation scheme using IMRT: prophylactic dose for mediastinum was 56 Gy at 1.65 Gy/fraction and SIB to macroscopic disease up to 68 Gy at 2 Gy/fraction. RESULTS: The median follow-up was 16 months (range, 1-70 months). The overall survival rate for all patients was 79% after 1 year and 46% after 2 years. Disease-free survival (DFS) was 81 and 45% after 1 and 2 years, respectively, resulting in a median DFS of 16 months. Multivariate analysis showed a statistically significant association between stage IIIB patients and a higher risk of mortality (HR 2.11; P = 0.019). In addition, T4 stage associated with higher risk of recurrence (HR 2.23; P = 0.024) while concomitant chemoradiation was associated with lower risk of any recurrence (HR 0.34; P = 0.004) No patient experienced grade >=3 esophagitis and only 6 cases (9%) had grade 3 pneumonitis. Only having a higher lung volume was associated with higher risk of pneumonitis in the multivariate analysis (HR 16.21; P = 0.022). CONCLUSION: This study in advanced NSCLC patients shows that SIB-IMRT is an effective technique with acceptable toxicity, also when combined with chemotherapy. PMID- 28589436 TI - Angioleiomyoma (Vascular Leiomyoma) of the Oral Cavity. AB - A 70-year-old male presented with a slow growing, dome shaped and painless mass of the hard palate. The mass was excised. Histopathological examination confirmed the diagnosis of a angioleiomyoma (vascular leiomyoma). A leiomyoma is an uncommon benign tumor of smooth muscle differentiation. True leiomyomas of the oral cavity are rare and most oral tumors are derived from the smooth muscle of walls of blood vessels. Therefore, they are called vascular leiomyomas or angioleiomyomas. Clinically, they may resemble a myriad other conditions both benign and malignant. A definitive diagnosis depends upon histopathological examination of the biopsied tissue in correlation with the tumor cell immunohistochemistry. Tumors are excised and recurrence is rare. The histopathological findings and differential diagnosis of a case of a palatal angioleiomyoma are discussed. PMID- 28589435 TI - Epigenetic regulation of RTK signaling. AB - Receptor tyrosine kinase (RTK) signaling cascades coordinate intracellular signaling in response to growth factors, chemokines, and other extracellular stimuli to control fundamental biological processes such as cellular proliferation, metabolism, and survival. Hyperactivation of pathways associated with growth factor signaling (e.g., RTK and downstream effectors including Ras, PI3K/AKT, and Raf) is a frequent event in human cancers, which uncouples ligand mediated activation with signal transduction. While the contributions of direct genomic events are well understood as causative agents of hyperactive signal transduction, other non-heritable genomic modifications promote the activation of growth factor-associated signaling cascades. In this review, we highlight epigenomic mechanisms by which hyperactivation of RTK-associated signaling cascades occurs and may contribute to cancer. PMID- 28589437 TI - Low Grade Carcinoma Ex-Pleomorphic Adenoma: Diagnosis and Diagnostic Challenges Caused by Fine Needle Aspiration: Report of Three Cases and Review of Literature. AB - Low grade carcinoma ex pleomorphic adenoma (LG CXPA) is a rare low grade malignant neoplasm arising from preexisting pleomorphic adenoma (PA). LG CXPA demonstrates no overt cytological atypia, and can be difficult to distinguish from cellular PA. Invasive growth is one of the hallmarks of LG CXPA, e.g., tumor extends beyond the capsule and into adjacent non-neoplastic tissue. However, it is known that capsular and vascular invasion, as well as the presence of stroma rich PA in soft tissue without a capsule (pseudopodia) can be seen in PA. These histological findings have no prognostic significance and are not diagnostic of malignancy. In addition, recurrent PA typically presents as numerous nodules extending into soft tissue and skeletal muscle, which again are not considered malignant features. Thus, "infiltrative growth" of LG CXPA is difficult to define and diagnosis is challenging to many practicing pathologists. In this study, we report three cases of LG CXPA. We review the diagnostic criteria for LG CXPA, and discuss the diagnostic challenges caused by fine needle aspiration (FNA) changes. FNA is widely used as a cost-effective, quick and accurate method for diagnosing salivary gland lesions. Histological changes post-FNA are usually focal and mild, and are not causes of diagnostic difficulties. According to our knowledge, this is the first report of LG CXPA complicated with FNA changes. PMID- 28589438 TI - Obstetrical history of women with cerebral vein thrombosis: outcome of the pregnancies before and after the thrombotic event. AB - Cerebral vein thrombosis (CVT) is a rare disease usually affecting young people, especially women, with a high prevalence of thrombophilic defects. It is known that thrombophilia is associated with pregnancy complications; therefore, a high rate of complications could be expected in women with the previous CVT who become pregnant. This study examined the whole obstetric history of women who suffered from CVT to evaluate the incidence of pregnancy complications during their entire lifespan. We prospectively followed consecutive patients with CVT, limiting the analysis to females and their obstetrical history. We studied 123 pregnancies in 99 consecutive women who had a CVT; 71 women had 91 pregnancies before the CVT; 19 women had 23 pregnancies after the CVT; and nine women had a CVT related to pregnancy. All women with CVT before pregnancy were treated with LMWH at prophylactic dosage during pregnancy. No recurrent CVT, venous thromboembolic events, or death was recorded during the observed pregnancies. Ten miscarriages were recorded (rate 8.1%), with a rate similar to that expected in the general population. We confirm the favorable outcome of pregnancies in women who suffered from CVT during their entire lifespan, whether they have occurred before and after or in relation to CVT. PMID- 28589439 TI - Serum endocan levels in patients with cardiac syndrome X. AB - BACKGROUND: Endocan is a recently introduced marker of endothelial dysfunction and is also associated with inflammation and atherosclerosis. To date, the relationship between cardiac syndrome X (CSX) and endocan has not been studied. The objective of this study was to compare the serum endocan levels of patients with CSX with those of control subjects. PATIENTS AND METHODS: In this study, 50 patients were included in the CSX group and 28 patients in the control group. Patients with pathological conditions that could potentially influence endothelial functions were excluded. Endocan serum concentrations were measured using an enzyme-linked immunosorbent assay. RESULTS: The mean endocan level of the CSX group was significantly higher than that of the control group (3051.3 +/- 1900.5 ng/l vs. 2088.1 +/- 522.2 ng/l; p = 0.002). There was no difference between the two groups in terms of age, gender, hypertension, diabetes mellitus, dyslipidemia, and smoking status. In receiver operating characteristic (ROC) curve analysis, endocan levels greater than 2072 ng/l had a 72% sensitivity and 54% specificity (p = 0.002) for accurately predicting a diagnosis of CSX. CONCLUSION: The results of this study suggest that patients with CSX have higher endocan levels. Therefore, endocan may be valuable in helping uncover the underlying pathogenesis of CSX. PMID- 28589440 TI - Intrinsic disorder here, there, and everywhere, and nowhere to escape from it. AB - The concept of protein intrinsic disorder persistently penetrates into all areas of modern protein science. It cannot be ignored anymore, and cannot be shrugged off, as it represents a vital feature (or, more correctly, a broad spectrum of important features), which, when added to and mixed with features arising from the well established protein structure-function paradigm, complete the picture of a functioning protein. The field of protein intrinsic disorder is very dynamic and fast developing. This Multi-Author Review represents a snapshot of this field by introducing some recent advances. Articles assembled in this Multi-Author Review introduce some of the new aspects of intrinsic disorder, outline some fascinating ideas related to the intrinsically disordered proteins, their structure, and functionality, and show challenges related to the analysis of proteins carrying intrinsic disorder. PMID- 28589442 TI - Comprehensive review of methods for prediction of intrinsic disorder and its molecular functions. AB - Computational prediction of intrinsic disorder in protein sequences dates back to late 1970 and has flourished in the last two decades. We provide a brief historical overview, and we review over 30 recent predictors of disorder. We are the first to also cover predictors of molecular functions of disorder, including 13 methods that focus on disordered linkers and disordered protein-protein, protein-RNA, and protein-DNA binding regions. We overview their predictive models, usability, and predictive performance. We highlight newest methods and predictors that offer strong predictive performance measured based on recent comparative assessments. We conclude that the modern predictors are relatively accurate, enjoy widespread use, and many of them are fast. Their predictions are conveniently accessible to the end users, via web servers and databases that store pre-computed predictions for millions of proteins. However, research into methods that predict many not yet addressed functions of intrinsic disorder remains an outstanding challenge. PMID- 28589444 TI - Reflections on the Future of Pharmaceutical Public-Private Partnerships: From Input to Impact. AB - Public Private Partnerships (PPPs) are multiple stakeholder partnerships designed to improve research efficacy. We focus on PPPs in the biomedical/pharmaceutical field, which emerged as a logical result of the open innovation model. Originally, a typical PPP was based on an academic and an industrial pillar, with governmental or other third party funding as an incentive. Over time, other players joined in, often health foundations, patient organizations, and regulatory scientists. This review discusses reasons for initiating a PPP, focusing on precompetitive research. It looks at typical expectations and challenges when starting such an endeavor, the characteristics of PPPs, and approaches to assessing the success of the concept. Finally, four case studies are presented, of PPPs differing in size, geographical spread, and research focus. PMID- 28589441 TI - Ephrin ligands and Eph receptors contribution to hematopoiesis. AB - Hematopoietic stem and progenitor cells reside predominantly in the bone marrow. They supply billions of mature blood cells every day during life through maturation into multilineage progenitors and self-renewal. Newly produced mature cells serve to replenish the pool of circulating blood cells at the end of their life-span. These mature blood cells and a few hematopoietic progenitors normally exit the bone marrow through the sinusoidal vessels, a specialized venous vascular system that spreads throughout the bone marrow. Many signals regulate the coordinated mobilization of hematopoietic cells from the bone marrow to the circulation. In this review, we present recent advances on hematopoiesis and hematopoietic cell mobilization with a focus on the role of Ephrin ligands and their Eph receptors. These constitute a large family of transmembrane ligands and receptors that play critical roles in development and postnatally. New insights point to distinct roles of ephrin and Eph in different aspects of hematopoiesis. PMID- 28589443 TI - Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla. AB - Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Abeta (beta-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage. PMID- 28589445 TI - Chemoprevention of Breast Cancer by Transdermal Delivery of alpha-Santalol through Breast Skin and Mammary Papilla (Nipple). AB - PURPOSE: Almost all breast cancers originate from epithelial cells lining the milk ducts in the breast. To this end, the study investigated the feasibility of localized transdermal delivery of alpha-santalol, a natural chemopreventive agent to the breast. METHODS: Different alpha-santalol formulations (cream, solution and microemulsion) were developed and the in vitro permeability was studied using excised animal (porcine and rat) and human breast skin/mammary papilla (nipple). The in vivo biodistribution and efficacy studies were conducted in female rats. A chemical carcinogenesis model of breast cancer was used for the efficacy studies. RESULTS: Phospholipid based alpha-santalol microemulsion showed the highest penetration through the nipple and breast skin. Delivery of alpha-santalol through the entire breast (breast skin and nipple) in vivo in rats resulted in significantly higher concentration in the mammary gland compared to transdermal delivery through the breast skin or nipple. There was no measurable alpha santalol concentration in the blood. Transdermal delivery of alpha-santalol reduced the tumor incidence and tumor multiplicity. Furthermore, the tumor size was significantly reduced with alpha-santalol treatment. CONCLUSIONS: The findings from this study demonstrate the feasibility of localized transdermal delivery of alpha-santalol for chemoprevention of breast cancer. PMID- 28589448 TI - [Laser in situ keratomileusis with microkeratome or femtosecond laser]. AB - OBJECTIVE AND PRINCIPLES: In LASIK, after cutting a lamellating stromal corneal incision (flap) with a microkeratome or a femtosecond laser, the underlying tissue is treated with an excimer laser for refractive correction. The objective is to achieve independency from spectacles and contact lenses due to correction of ametropia. INDICATIONS: Surgery is indicated when the patient wishes to achieve independency from spectacles and contact lenses. For LASIK, the German Commission for Refractive Surgery defined a range of applicability for myopic correction up to -8 diopters (D), astigmatic correction up to 5 D and hyperopic correction up to +3 D. Borderline applicability is defined as myopic correction up to -10 D, astigmatic correction up to 6 D and hyperopic correction up to +4 D. OPERATIVE TECHNIQUE: The surgical technique is demonstrated in detail with the help of a video of the operation, which is available online. The flap incision is created with a microkeratome or a femtosecond laser. After lifting and folding the flap, excimer ablation is performed. An eye tracking system ensures correct location of ablation by compensating for intraoperative eye movements. After repositioning the flap, the interface is irrigated and the edge of the flap is adapted with a sponge. RESULTS: The LASIK procedure is safe, predictable and efficient with a high rate of patient satisfaction. The complication rate can be minimized by using a careful and standardized surgical approach. PMID- 28589449 TI - Surprising Twist in the Plot - Sister Mary Joseph's Nodule of Pancreatic Cancer Mimicking Wound Infection after Umbilical Hernia Repair. PMID- 28589447 TI - Cognitive, neurophysiologic and metabolic sequelae of previous hypoglycemic coma revealed by hyperinsulinemic-hypoglycemic clamp in type 1 diabetic patients. AB - To examine the relationship between electroencephalographic (EEG) activity and hypoglycemia unawareness, we investigated early parameters of vigilance and awareness of various symptom categories in response to hypoglycemia in intensively treated type 1 diabetic (T1DM) patients with different degrees of hypoglycemia unawareness. Hypoglycemia was induced with a hyperinsulinemic hypoglycemic clamp in six T1DM patients with a history of hypoglycemia unawareness previous severe hypoglycemic coma (SH) and in six T1DM patients without (C) history of hypoglycemia unawareness previous severe hypoglycemic coma. Cognitive function tests (four choice reaction time), counterregulatory responses (adrenaline), and symptomatic responses were evaluated at euglycemia (90 mg/dl) and during step-wise plasma glucose reduction (68, 58 and 49 mg/dl). EEG activity was recorded continuously throughout the study and analyzed by spectral analysis. Cognitive function deteriorated significantly at a glucose threshold of 55 +/- 1 mg/dl in both groups (p = ns) during hypoglycemia, while the glucose threshold for autonomic symptoms was significantly lower in SH patients than in C patients (49 +/- 1 vs. 54 +/- 1 mg/dl, p < 0.05, respectively). In SH patients, eye-closed resting EEG showed a correlation between the mean dominance frequency and plasma glucose (r = 0.62, p < 0.001). Theta relative power increased during controlled hypoglycemia compared to euglycemia (21.6 +/- 6 vs. 15.5 +/- 3% Hz p < 0.05) and was higher than in the C group (21.6 +/- 6 vs. 13.8 +/- 3%, p < 0.03). The cognitive task beta activity was lower in the SH group than in the C group (14.8 +/- 3 Hz, vs. 22.6 +/- 4 vs. p < 0.03). Controlled hypoglycemia elicits cognitive dysfunction in both C and SH patients; however, significant EEG alterations during hypoglycemia were detected mainly in patients with a history of hypoglycemia unawareness and previous severe hypoglycemic coma. These data suggest that prior episodes of hypoglycemic coma modulate brain electric activity. PMID- 28589446 TI - Bioprinting and Organ-on-Chip Applications Towards Personalized Medicine for Bone Diseases. AB - The skeleton supports and confers structure to the whole body but several pathological and traumatic conditions affect the bone tissue. Most of those pathological conditions are specific and different among different patients, such as bone defects due to traumatic injuries or bone remodeling alterations due to congenital diseases. In this context, the development of personalized therapies would be highly desirable. In recent years the advent of innovative techniques like bioprinting and microfluidic organ-on-chip raised hopes of achieving key tools helping the application of personalized therapies for bone diseases. In this review we will illustrate the latest progresses in the bioprinting of personalized bone grafts and generation of patient-specific bone-on-chip devices, describing current approaches and limitations and possible future improvements for more effective personalized bone grafts and disease models. PMID- 28589450 TI - Central nervous system involvement in adults with haemophagocytic lymphohistiocytosis: a single-center study. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem disorder characterized by proliferation and diffuse infiltration multiple organs with histiocytes, including the central nervous system (CNS). Neurological manifestations of HLH have been recognized in different studies with children, but they remain relatively ill-defined in adults with HLH. From March 2008 to October 2014, 289 adult patients with HLH were admitted to our center. Clinical, radiological, and cerebral spinal fluid (CSF) data of the patients with CNS involvement were reviewed, and a retrospective study in our single-center was carried out. CNS involvement was observed in 29 patients (10%) either in their diagnosis process or during disease course. CNS symptoms included disturbance of consciousness, cranial nerve palsies, seizures, headache, limb paralysis, irritability, meningism, and memory loss. CSF analysis was conducted in 17 patients (59%). Among them, 11 patients (65%) were reported as having abnormal CSF. Neuroradiological studies were performed in 25 patients (86%). Among the 13 cases that underwent CT scan, one patient hemorrhaged. Single or multiple hypodense foci were detected in the other 2 patients. Magnetic resonance imaging (MRI) abnormalities were found in 15 patients, including focal lesions in cortical and adjacent subcortical regions with or without variable nodular or ring contrast-enhancement, multiple lesions in white matter, diffuse white matter signal changes, and meningeal enhancement. Basal ganglia, cerebellum, and brainstem lesions were also observed. CNS involvement could also be found in adult patients with HLH, but not as frequent as it was in children. The clinical manifestations could be diversified. By carrying out rigorous CNS examinations, an early diagnosis could be made and it was of the utmost importance for the prevention of further lesions. PMID- 28589451 TI - Sweet syndrome secondary to myelodysplastic syndrome mimicking necrotizing fasciitis. PMID- 28589454 TI - Synthesis, physico-chemical characterization, and antioxidant effect of PEGylated cerium oxide nanoparticles. AB - Cerium oxide nanoparticles (CNPs) represent a promising class of antioxidant nanoparticles with potential therapeutic value. Due to the easily reversible oxidation states of cerium (Ce3+ and Ce4+) at the nanoscale, CNPs scavenge excessive reactive oxygen and nitrogen species in a self-regenerative manner. In this study, we have demonstrated a simple method to functionalize shape-specific CNPs (i.e., rod- and cube-shaped) with polyethylene glycol (PEG) and studied the effect of PEGylation on the physico-chemical properties, antioxidant activity, and biocompatibility of rod- and cube-shaped CNPs. The chemical conjugation of PEG onto the CNP surface was confirmed by a series of physico-chemical characterizations (1H-NMR, FTIR, and surface zeta potential). Rod-shaped CNPs demonstrated greater reactive oxygen species scavenging ability compared to cube shaped CNPs. PEGylation of CNPs did not affect shape, cerium oxidation state, and cytocompatibility. Importantly, PEGylation significantly reduced the amount of proteins adsorbed onto the CNPs. The antioxidant effects of CNPs were maintained in PEGylated CNPs. We envision that PEGylated rod-shaped CNPs synthesized in this study have the potential to be biocompatible nanoparticles that can combat oxidative stress-related diseases. PMID- 28589455 TI - Terrestrially derived glomalin-related soil protein quality as a potential ecological indicator in a peri-urban watershed. AB - Glomalin, which sequesters substantial amounts of carbon, plays a critical role in sustaining terrestrial biome functions and contributes to the fate of many pollutants from terrestrial to aquatic ecosystems. Despite having focused on the amount of glomalin produced, very few attempts have been made to understand how landscapes and environmental conditions influence glomalin composition and characteristics. This study focused on glomalin-related soil protein (GRSP) exported as storm runoff including eroded sediment and water that was collected before flowing to surface waters in a peri-urban watershed. GRSP characteristics were assessed by Bradford protein analysis, fluorescence spectroscopy combined with parallel factor analysis (PARAFAC), and the determination of aromaticity based on the specific ultraviolet absorption value (280 nm) and molecular weight. General linear models (GLMs) was established by integrating microbial activity, land cover, water temperature, precipitation, and other solution chemical properties to explain the variations in GRSP characteristics. Results showed that a higher GRSP concentration in agricultural reference sites was produced in the form of specific materials with low molecular weight and aromaticity, as well as high percentage of C1 and C5 components which indicate microbial-processed sources, relative to urbanized and forested sites. Compared with forested land, urbanized land clearly produced runoff GRSP with low molecular weight and aromaticity, as well as more degradation of humic-like materials (C3 component). The highest GLM explaining 89% of the variables, including significant variables (p < 0.05) such as microbial activity, water temperature, and water conductivity, was observed for GRSP characteristics. Therefore, changes in eroded soil GRSP quality can serve as an indicator for improving watershed management and thus protecting aquatic ecosystems. PMID- 28589452 TI - On-demand microbicide products: design matters. AB - Sexual intercourse (vaginal and anal) is the predominant mode of human immunodeficiency virus (HIV) transmission. Topical microbicides used in an on demand format (i.e., immediately before or after sex) can be part of an effective tool kit utilized to prevent sexual transmission of HIV. The effectiveness of prevention products is positively correlated with adherence, which is likely to depend on user acceptability of the product. The development of an efficacious and acceptable product is therefore paramount for the success of an on-demand product. Acceptability of on-demand products (e.g., gels, films, and tablets) and their attributes is influenced by a multitude of user-specific factors that span behavioral, lifestyle, socio-economic, and cultural aspects. In addition, physicochemical properties of the drug, anatomical and physiological aspects of anorectal and vaginal compartments, issues relating to large-scale production, and cost can impact product development. These factors together with user preferences determine the design space of an effective, acceptable, and feasible on-demand product. In this review, we summarize the interacting factors that together determine product choice and its target product profile. PMID- 28589456 TI - Zn2+ sequestration by Nostoc muscorum: study of thermodynamics, equilibrium isotherms, and biosorption parameters for the metal. AB - Microbial biosorption has evolved as an effective strategy for heavy metal removal from contaminated waters. The common cyanobacterium Nostoc muscorum isolated from the banks of a polluted river in Meghalaya, India, was tested for its potential to remove Zn2+ from aqueous solutions. Energy-dispersive X-ray (EDX) study verified Zn binding on the cyanobacterial biomass, and FTIR analysis revealed many negatively charged functional groups (hydroxyl, carbonyl, alcohol, amine, phosphoryl, sulfhydryl, and carboxyl) on the cell surface that aided in metal binding. Thermodynamic studies established the biosorption process to be energetically favorable with negative free energy change (-10.404, -10.599, and 10.796 kJ/mol at 298, 303, and 308 K, respectively). Sorption isotherm data fitted best in the Langmuir isotherm indicating monolayer nature of Zn sorption. The organism showed hyper-accumulation tendency towards Zn with a maximum sorption capacity as high as 2500 mg of Zn taken up per gram of biomass. The separation factor R L calculated from Langmuir isotherm ranged between 0 and 1 signifying favorable interaction between the cyanobacterial biomass and the Zn ions. Various experimental parameters, viz. pH, temperature, inoculum age and size, and shaking rate, influenced Zn biosorption. Optimized experimental conditions significantly enhanced the sorption percentage. Sorption was primarily a fast surface phenomenon in the beginning with internalization of zinc ions by the live cells on prolonged exposure. PMID- 28589453 TI - Bone-seeking agents for the treatment of bone disorders. AB - The targeting and delivery of therapeutic and diagnostic agents to bone tissue presents both a challenge and opportunity. Osteoporosis, Paget's disease, cancer, and bone metastases are all skeletal diseases whose treatment would benefit from new targeted therapeutic strategies. Osteoporosis, in particular, is a very prevalent disease, affecting over one in three women and one in five men in Canada alone with the cost to the healthcare system estimated at over $2.3 billion in 2010. Bone tissue is often considered a rigid structure when in reality there is a process of continuous remodeling that takes place via complex endocrine-regulated cell signaling pathways in addition to the signaling pathways unique to bone tissue. It is these specific boneremodeling processes that provide unique targeting opportunities but also present a number of challenges. PMID- 28589457 TI - Assessing the accuracy and stability of variable selection methods for random forest modeling in ecology. AB - Random forest (RF) modeling has emerged as an important statistical learning method in ecology due to its exceptional predictive performance. However, for large and complex ecological data sets, there is limited guidance on variable selection methods for RF modeling. Typically, either a preselected set of predictor variables are used or stepwise procedures are employed which iteratively remove variables according to their importance measures. This paper investigates the application of variable selection methods to RF models for predicting probable biological stream condition. Our motivating data set consists of the good/poor condition of n = 1365 stream survey sites from the 2008/2009 National Rivers and Stream Assessment, and a large set (p = 212) of landscape features from the StreamCat data set as potential predictors. We compare two types of RF models: a full variable set model with all 212 predictors and a reduced variable set model selected using a backward elimination approach. We assess model accuracy using RF's internal out-of-bag estimate, and a cross validation procedure with validation folds external to the variable selection process. We also assess the stability of the spatial predictions generated by the RF models to changes in the number of predictors and argue that model selection needs to consider both accuracy and stability. The results suggest that RF modeling is robust to the inclusion of many variables of moderate to low importance. We found no substantial improvement in cross-validated accuracy as a result of variable reduction. Moreover, the backward elimination procedure tended to select too few variables and exhibited numerous issues such as upwardly biased out-of-bag accuracy estimates and instabilities in the spatial predictions. We use simulations to further support and generalize results from the analysis of real data. A main purpose of this work is to elucidate issues of model selection bias and instability to ecologists interested in using RF to develop predictive models with large environmental data sets. PMID- 28589458 TI - The applicability of a large-volume injection (LVI) system for quantitative analysis of permanent gases O2 and N2 using a gas chromatograph/barrier discharge ionization detector. AB - To develop accurate quantitation methods for two major permanent gases, N2 and O2, a series of calibration experiments were carried out using a gas chromatograph (GC)/barrier discharge ionization detector (BID) equipped with a large-volume injection (LVI) system. To this end, gaseous working standards (WSs) diluted with helium gas were prepared at ten different concentration levels representing three different concentration ranges (in ppm) in 1-L polyester aluminum (PEA) bags ((1) low, 209~2090 (O2) and 791~7910 (N2); (2) moderate, 2090 ~ 20,900 (O2) and 7910~79,100 (N2); and (3) high, 20,900~209,000 (O2) and 79,100~791,000 (N2)). Cross-calibration experiments for each individual WS were carried out using the loop injection system with four different capacities (0.01, 0.5, 1, and 10 mL). The calibration results were then evaluated with respect to key variables including loop capacity, concentration, and mass quantity. Accordingly, we observed the optimal performance of the BID in terms of sensitivity and linearity (R 2 > 0.98) when the WS of the moderate concentration range was analyzed with the small loop (0.01 and 0.5 mL). The method detection limit (MDL) values of the four loop sizes (between 0.01 and 10 mL) were 7~500 ng for O2 (38.4~557 ppm) and 24~2230 ng for N2 (195~2105 ppm). PMID- 28589459 TI - Quality of groundwater resources in Afghanistan. AB - Water is the main source of energy production and economy in Afghanistan where agriculture accounts for more than 50% of the country's gross domestic product (GDP). Access to safe drinking water is still a problem in the country, which has caused different health issues and even child mortality especially in rural areas. Groundwater is the main source of drinking water in the country. However, little knowledge is available about the quality of groundwater throughout the entire country, and its quality has not been investigated extensively yet like in other countries in the world. While most people think that consuming groundwater is a reliable and safe source of drinking water for health, the United Nations (UN) agencies report various kinds of waterborne diseases and even child mortalities due to drinking water quality in the country. In this article, significant geogenic and anthropogenic factors that play a vital role in groundwater contamination of the country are identified and explained. Different geogenic contaminations such as arsenic, fluoride, sulfate, and boron occur in several areas of Afghanistan that have a direct effect on human health. The water quality mapping for Afghanistan is completed for half of the country, which shows that groundwater is plagued by high levels of fluoride and arsenic in some areas. The water quality mapping of the other half of the country cannot be completed due to security concerns currently. Also, there are different kinds of waterborne diseases such as diarrhea, cholera, and dysentery that can be seen in different parts of the country because of anthropogenic activities which continuously deteriorate groundwater. PMID- 28589460 TI - Is soil microbial diversity affected by soil and groundwater salinity? Evidences from a coastal system in central Italy. AB - Little is known about composition, diversity, and abundance of microbial communities in environments affected by primary soil salinization, such as coastal lagoon systems. The main objective of this study was to investigate the impact of lagoon salinity, soil type, and land-use on inland soil and groundwater quality, and soil microbial community structure, diversity, and gene abundance, as evaluated by T-RFLP (terminal-restriction fragment length polymorphism) and qPCR (quantitative polymerase-chain-reaction). For this purpose, four sites oriented along a groundwater salinity gradient (Fogliano lagoon, central Italy) were studied under different recreational, grazing, and land-use conditions. Spatial variability in groundwater attributes was observed depending on salinity and soil electrical conductivity, both influenced by salt intrusion. A comparison of community abundance and number of phylotypes of bacteria, archaea, and fungi across varying soil depths pointed out marked differences across soils characterized by different soil type, land-use, and salinity. The latter significantly affected the microbial population richness and diversity and showed a dominance in terms of bacteria species. Our study provides a comprehensive overview of the spatial relationship between soil microbial community and soil degradation processes along a relatively underexplored environmental gradient in a coastal system, coming to the conclusion that salinity acts differently as a driver of microbial community structure in comparison with other saline environments. PMID- 28589461 TI - Association study of multiple antibiotic resistance and virulence: a strategy to assess the extent of risk posed by bacterial population in aquatic environment. AB - The present study explored the association between multiple antibiotic resistance (MAR) index and virulence index to determine what percent of environmental antibiotic-resistant (eARB) bacteria could pose threat as potential pathogen. 16srRNA-based sequencing of 113 non-duplicate isolates identified majority of them to be gram negative belonging to Enterobacter, Pseudomonas, Aeromonas, Proteus, Acinetobacter, and Klebsiella. Statistical comparison of MAR indices of the abovementioned genera indicated differences in the median values among the groups (p < 0.001). Pair-wise multiple comparison by Dunn's method indicated significant difference in MAR indices (p < 0.05), based on which multiple antibiotic resistance phenotype could be ranked in the order Pseudomonas > Klebsiella = Acinetobacter > Proteus > Aeromonas > Enterobacter. Association between MAR index and virulence index revealed that 25% of isolates in the population under study posed high threat to human/animal or both; out of which 75% isolates belonged to genus Pseudomonas. Based on observations of comparative analysis of the six gram-negative genera, it could be concluded that Pseudomonas isolates from environment pose significantly high threat as potential pathogens while Enterobacter isolates posed no threat. PMID- 28589462 TI - Discharge or admit? Emergency department management of incidental pulmonary embolism in patients with cancer: a retrospective study. AB - BACKGROUND: Hospitalization and early anticoagulation therapy remain standard care for patients who present to the emergency department (ED) with pulmonary embolism (PE). For PEs discovered incidentally, however, optimal therapeutic strategies are less clear-and all the more so when the patient has cancer, which is associated with a hypercoagulable state that exacerbates the threat of PE. METHODS: We conducted a retrospective review of a historical cohort of patients with cancer and incidental PE who were referred for assessment to the ED in an institution whose standard of care is outpatient treatment of selected patients and use of low-molecular-weight heparin for anticoagulation. Eligible patients had received a diagnosis of incidental PE upon routine contrast enhanced chest CT for cancer staging. Survival data was collected at 30 days and 90 days from the date of ED presentation and at the end of the study. RESULTS: We identified 193 patients, 135 (70%) of whom were discharged and 58 (30%) of whom were admitted to the hospital. The 30-day survival rate was 92% overall, 99% for the discharged patients and 76% for admitted patients. Almost all (189 patients, 98%) commenced anticoagulation therapy in the ED; 170 (90%) of these received low-molecular weight heparin. Patients with saddle pulmonary artery incidental PEs were more likely to die within 30 days (43%) than were those with main or lobar (11%), segmental (6%), or subsegmental (5%) incidental PEs. In multivariate analysis, Charlson comorbidity index (age unadjusted), hypoxemia, and incidental PE location (P = 0.004, relative risk 33.5 (95% CI 3.1-357.4, comparing saddle versus subsegmental PE) were significantly associated with 30-day survival. Age, comorbidity, race, cancer stage, tachycardia, hypoxemia, and incidental PE location were significantly associated with hospital admission. CONCLUSIONS: Selected cancer patients presenting to the ED with incidental PE can be treated with low-molecular-weight heparin anticoagulation and safely discharged. Avoidance of unnecessary hospitalization may decrease in-hospital infections and death, reduce healthcare costs, and improve patient quality of life. Because the natural history and optimal management of this condition is not well described, information supporting the creation of straightforward evidence-based practice guidelines for ED teams treating this specialized patient population is needed. PMID- 28589463 TI - Experimental and theoretical description of the optical properties of Myrcia sylvatica essential oil. AB - We present an extensive study of the optical properties of Myrcia sylvatica essential oil with the goal of investigating the suitability of its material system for uses in organic photovoltaics. The methods of extraction, experimental analysis, and theoretical modeling are described in detail. The precise composition of the oil in our samples is determined via gas chromatography, mass spectrometry, and X-ray scattering techniques. The measurements indicate that, indeed, the material system of Myrcia sylvatica essential oil may be successfully employed for the design of organic photovoltaic devices. The optical absorption of the molecules that compose the oil are calculated using time-dependent density functional theory and used to explain the measured UV-Vis spectra of the oil. We show that it is sufficient to consider the alpha-bisabolol/cadalene pair, two of the main constituents of the oil, to obtain the main features of the UV-Vis spectra. This finding is of importance for future works that aim to use Myrcia sylvatica essential oil as a photovoltaic material. PMID- 28589464 TI - EPSP synthase flexibility is determinant to its function: computational molecular dynamics and metadynamics studies. AB - Flexibility is involved in a wide range of biological processes, such as protein assembly and binding recognition. EPSP synthase is an enzyme that must undergo a large conformational change to accommodate its ligands into its binding cavity. However, although the structure of EPSP synthase has been determined, its plasticity has not been explored in depth. Therefore, in this work, we extensively examined the influence of the flexibility of Mycobacterium tuberculosis EPSP (MtEPSP) synthase on the function of this protein using classical and replica-exchange metadynamics simulations. We were able to identify five well-populated conformational clusters for MtEPSP synthase: two corresponding to open, one to ajar, and two to closed conformations. We also pinpointed three hydrophobic regions that are responsible for guiding transitions among these states. Taken together, the new findings presented here indicate how the hydrophobic regions modulate the flexibility of MtEPSP synthase, and they highlight the importance of considering these dynamic features in drug design projects employing this enzyme as a target. Graphical abstract The flexibility of EPSP synthase as a function of the pincer angles. PMID- 28589465 TI - Timescales and Mechanisms of Sigh-Like Bursting and Spiking in Models of Rhythmic Respiratory Neurons. AB - Neural networks generate a variety of rhythmic activity patterns, often involving different timescales. One example arises in the respiratory network in the pre Botzinger complex of the mammalian brainstem, which can generate the eupneic rhythm associated with normal respiration as well as recurrent low-frequency, large-amplitude bursts associated with sighing. Two competing hypotheses have been proposed to explain sigh generation: the recruitment of a neuronal population distinct from the eupneic rhythm-generating subpopulation or the reconfiguration of activity within a single population. Here, we consider two recent computational models, one of which represents each of the hypotheses. We use methods of dynamical systems theory, such as fast-slow decomposition, averaging, and bifurcation analysis, to understand the multiple-timescale mechanisms underlying sigh generation in each model. In the course of our analysis, we discover that a third timescale is required to generate sighs in both models. Furthermore, we identify the similarities of the underlying mechanisms in the two models and the aspects in which they differ. PMID- 28589467 TI - Ossification foci act as stabilizers in continuous-type ossification of the posterior longitudinal ligament: a comparative study between laminectomy and laminoplasty. AB - BACKGROUND: In multilevel ossification of the posterior longitudinal ligament (OPLL), laminectomy is an effective surgical technique; however, there is a possibility of kyphotic alignment change after surgery. Nevertheless, in the continuous type of OPLL, the ossification foci are connected and may act as stabilizers preventing alignment change. We here compare the surgical outcome of laminectomy and laminoplasty in continuous-type OPLL of the cervical spine. METHODS: Seventy-three patients who underwent cervical laminectomy or laminoplasty for continuous-type OPLL from 2004 to 2014 were enrolled. The clinical outcomes were assessed by using the neck disability index, visual analogue scale, and Japanese Orthopedic Association scoring systems. Radiological evaluation with plain lateral radiographs was performed to observe alignment changes. RESULTS: The perioperative clinical outcome with laminectomy did not differ significantly from that of laminoplasty. Kyphotic change was observed in 3 of 35 patients with laminectomy and 3 of 38 patients with laminoplasty. Although loss of lordosis was observed in both groups, the C2-7 Cobb angle, sagittal vertical axis (SVA), and T1 slope did not demonstrate significant statistical differences between laminectomy and laminoplasty. Moreover, the C2-7 SVA in the C7-included laminectomy group (33.9 +/- 13.4) became greater than that in the C7 excluded laminectomy group (24.8 +/- 11.3) at the final follow-up (p = 0.049). CONCLUSIONS: In continuous-type OPLL, the surgical outcome did not show any significant difference between laminectomy and laminoplasty. Laminectomy alone is also a good choice in continuous-type OPLL, similar to laminoplasty. PMID- 28589466 TI - Antibacterial Prophylaxis for Surgical Site Infection in the Elderly: Practical Application. AB - Surgical site infections are among the most common healthcare-associated infections and are linked with increased length of hospitalization, re-admission, mortality and significant financial burden. Risk factors for the occurrence of surgical site infections include variables related to the surgical procedure as well as host factors. Increasing age is associated with the occurrence of surgical site infections. The aim of this review is to give an update on the antibiotic prophylaxis for surgical site infection in elderly people. We focused on specific issues and practical applications, such as the importance of targeting the antimicrobial agent to the susceptibility pattern of colonizing flora in selected cases and the need for dosage modifications. PMID- 28589468 TI - Optimal treatment of jugular foramen schwannomas: long-term outcome of a multidisciplinary approach for a series of 29 cases in a single institute. AB - BACKGROUND: The goal of treatment for jugular foramen schwannomas (JFSs) is to achieve complete tumor removal with cranial nerve preservation. However, achieving this goal remains a challenge despite the advances in microsurgical techniques. The aim of this study was to determine optimal treatment strategies for JFSs based on a review of a series of 29 surgical cases in our institute. MATERIALS AND METHODS: Between 1997 and 2013, 29 patients with JFSs underwent surgical treatment by multidisciplinary otoneurosurgical approaches. We retrospectively evaluated various clinical outcomes including the extent of tumor resection, postoperative cranial nerve deficits, and the recurrence rate. Tumor extension was classified using the Kaye and Pellet classification (KPC) system, and the extent of tumor resection was graded as gross total resection (GTR), near total resection (NTR), and subtotal resection (STR). We utilized the House Brackmann facial nerve grading system (HBFNGS), the average pure-tone audiometry and speech audiometry (PTA/SA) tests, and the American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) swallowing scale (ASHA level) for assessment of functional outcomes. RESULTS: The extent of tumor resection was not related to the degree of immediate postoperative cranial nerve deficits. However, the surgical approach was significantly related to postoperative hearing status and immediate postoperative facial function. Also, among the ten patients who were below the level of acceptable facial function immediately postoperatively, nine patients (90%) recovered to acceptable facial function by the last follow-up. Concerning postoperative swallowing status, all 21 patients recovered swallowing function by the last follow-up. Postoperative Gamma Knife stereotactic radiosurgery (GKRS) was performed for three recurrent and seven residual tumors, and recurrence was not observed in the mean 36-month follow-up period. CONCLUSIONS: A surgical strategy should be tailored to the individual case, and clinicians should consider the possibility of recurrence and further adjuvant treatment. PMID- 28589469 TI - Examining a momentary mediation model of appearance-related stress, anxiety, and eating disorder behaviors in adult anorexia nervosa. AB - PURPOSE: Appearance-related stress may result from appearance-focused events such as seeing one's reflection, seeing media images, and shopping for clothes. The purpose of this study was to examine the prospective association between momentary appearance-related stress and eating disorder (ED) behaviors (i.e., binge eating and vomiting) among women with anorexia nervosa (AN) using ecological momentary assessment (EMA). We hypothesized that appearance-related stress at Time 1 would predict binge eating and vomiting at Time 2, and that this prospective association would be mediated by momentary anxiety at Time 2 (controlling for anxiety at Time 1). METHODS: Women with AN completed a 2-week EMA protocol involving repeated daily assessments of experiences and behaviors. RESULTS: Momentary appearance-related stress preceded binge eating and vomiting, and momentary anxiety mediated the prospective association between appearance related stress and ED behaviors. CONCLUSIONS: Targeted momentary interventions delivered in the natural environment that address appearance-related stress may have utility in the treatment of ED behaviors. PMID- 28589470 TI - A narrative review of potential treatment strategies for food addiction. AB - The concept of food addiction (FA) remains controversial with research being in the nascent stages; FA like any addiction can have a devastating impact on the lives of those afflicted. There exists a clinical need for treatment strategies for those affected. This article reviews potential treatment strategies for FA. The treatment strategies target four core behaviours of the addiction phenotype specifically craving through the opioid system, impulsivity as a personality trait, compulsivity through the serotonergic system and lastly motivation through the dopaminergic system. A range of pharmacological and psychological interventions are reviewed. Future research should seek to test and validate the proposed clinical treatment strategies. PMID- 28589471 TI - Catching the moving target of adolescent personality and its disorders. A commentary on the article (doi:10.1007/s40519-017-0368-y) by Gaudio and Dakanalis: What about the assessment of personality disturbance in adolescents with eating disorders? PMID- 28589473 TI - The effect of triclosan on posttranslational modification of proteins through citrullination and carbamylation. AB - OBJECTIVES: The aim of this study was evaluate the effect of triclosan on citrullination and carbamylation, two important protein posttranslational modifications associated with inflammatory conditions such as periodontitis and rheumatoid arthritis. MATERIALS AND METHODS: A range of triclosan concentrations were incubated in the presence of appropriate substrates used for the generation of either citrullinated or carbamylated proteins. The effect of triclosan on protein citrullination and carbamylation in macrophages was also assessed. RESULTS: Citrullination and carbamylation were both significantly decreased by triclosan at concentrations six times lower than the 0.3% triclosan approved by the FDA to use in mouthwash and toothpaste. When macrophages were exposed to triclosan, carbamylation was significantly deceased (p = 0.01), and while citrullination also decreased, this reduction was not statistically significant (p = 0.06). CONCLUSION: Triclosan reduced the generation of protein citrullination and carbamylation in vitro. CLINICAL RELEVANCE: Triclosan may be useful as an adjunct therapy in the management of inflammatory periodontal diseases and help to reduce posttranslational protein modification citrullination and carbamylation) in these tissues. PMID- 28589472 TI - Clinical comparison of the effectiveness of 7- and 14-day intracanal medications in root canal disinfection and inflammatory cytokines. AB - OBJECTIVE: This clinical study compared the effectiveness of 7- and 14-day intracanal medications in the reduction of bacteria/endotoxins from primarily infected root canals and determined their antigenicity against macrophages through the levels of cytokines. METHODS: Seventy-two primarily infected teeth were randomly divided into six groups according to medication and time of application: 7-day groups = G1, Ca(OH)2 + saline solution (SSL); G2, Ca(OH)2 + 2% chlorhexidine (CHX) gel; and G3, 2% CHX gel and 14-day groups = G4, Ca(OH)2 + SSL; G5, Ca(OH)2 + 2% CHX gel; and G6, 2% CHX gel (all groups, n = 12). Bacterial and endotoxin samples were collected from root canals and inflammatory cytokines of macrophages supernatants. Culture techniques were used to determine bacterial counts and limulus amebocyte lysate (LAL) assay to quantify endotoxins. IL-1beta, TNF-alpha, and PGE2 were measured by ELISA-assay. RESULTS: With regard to the bacterial reduction, no differences were found between all protocols tested (p > 0.05). The CHX protocols (G3 and G6) exhibited the lowest effectiveness against endotoxins (p < 0.05). All protocols were effective in lowering the levels of IL 1beta, TNF-alpha, and PGE2 (p < 0.05), with no difference between the medications tested on days 7 or 14 (p > 0.05). Particularly, the 7-day CHX-protocol (G3) exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols (G6) (p < 0.05). CONCLUSIONS: All the 7- and 14 day intracanal medications were effective in reducing bacteria and endotoxins as well as in lowering the levels of inflammatory cytokines, with CHX showing limited effectiveness against endotoxins. Moreover, 7-day CHX-protocol exhibited the lowest effectiveness in lowering the levels of most cytokines compared to the 14-day protocols. CLINICAL SIGNIFICANCE: Seven-day CHX protocol is the less effective protocol and should be carefully applied by the clinician. PMID- 28589474 TI - Triglyceride to high density lipoprotein cholesterol ratio and its association with periodontal disease in Korean adults: findings based on the 2012-2014 Korean national health and nutrition examination survey. AB - OBJECTIVES: The aim of this study is to evaluate whether the triglyceride to high density lipoprotein cholesterol (TG/HDL-C) ratio is associated with periodontal disease in Korean adults. MATERIALS AND METHODS: This cross-sectional study included 12,249 individuals (4,941 men and 7,308 women) who took part in the 2012 2014 Korean National Health and Nutrition Examination Survey. We categorized the TG/HDL-C ratio into three groups. Periodontal disease was defined as a community pocket index score >=3 with at least one affected site. Multiple logistic analyses were used to analyze the association between TG/HDL-C ratio and periodontal disease. RESULTS: In the study population, prevalence of periodontal disease was 31.6% in men and 21% in women. Compared to the lowest tertile group, OR (95% CI) of the highest tertile group for periodontal disease was 1.474 (1.220 1.780) in men and 1.259 (1.041-1.522) in women after adjusting for age, waist circumference, systolic blood pressure, fasting glucose, current smoking, alcohol drinking, physical activity, household income, oral health behavior, and use of anti-dyslipidemia medication. CONCLUSION: Our study suggests that the TG/HDL-C ratio is associated with periodontal disease in Korean adults. CLINICAL RELEVANCE: TG/HDL-C ratio is a simple and useful marker to reflect insulin resistance. And periodontal disease is also known to be related with insulin resistance. This study indicates that TG/HDL-C ratio was associated with periodontal disease in Korean adults. PMID- 28589476 TI - Endometrial thickness influences neonatal birth weight in pregnancies with obstetric complications achieved after fresh IVF-ICSI cycles. AB - PURPOSE: Pregnancy-associated complications, duration of gestation and parity are well-known predictors of neonatal birth weight. Assisted reproductive technology (ART) affects neonatal birth weight as well. Endometrial thickness as measured on the day of HCG triggering may therefore impact on the neonatal birth weight. METHODS: The data of 764 singleton deliveries achieved after fresh transfer between November 1997 and 2014 were collected retrospectively with the intention to analyze the relationship of maternal and neonatal characteristics with endometrial thickness and the possible predictive value of endometrial thickness on neonatal birth weight. RESULTS: Higher maternal age (p < 0.001), diminished ovarian reserve (p < 0.001), endometriosis (p = 0.008) and hypogonadotropic hypogonadism (p < 0.001) predicted thin endometrium. Neonatal birth weight (p = 0.004), longer duration of pregnancy (p = 0.008), parity (p = 0.026) and higher maternal BMI (p = 0.003) were correlated significantly with the degree of endometrial proliferation. Endometrial thickness strongly predicted neonatal birth weight (p = 0.004). After adjusting regression analysis for maternal age and BMI, parity, neonatal gender and pregnancy duration, endometrial thickness remained predictive for neonatal birth weight in pregnancies with obstetric complications (p = 0.017). In uneventful pregnancies duration and parity are determinants of neonatal birth weight. CONCLUSIONS: Our findings suggest that endometrial thickness is an additional ART-related factor influencing neonatal birth weight. This finding should be confirmed in large cohort studies. PMID- 28589477 TI - The impact of postpartum cervical tear on the occurrence of preterm birth in subsequent pregnancy. AB - PURPOSE: To examine the occurrence of subsequent preterm birth (PTB) among women who experienced a cervical tear during prior delivery. METHODS: A retrospective study conducted at a single teaching hospital on data from January 1994 to March 2014. The study group included all women who had a cervical tear detected at uterine and cervical examination, performed due to early postpartum hemorrhage. The control group consisted of women who delivered vaginally, experienced an early postpartum hemorrhage, and had an intact cervix at uterine and cervical examination. The control group was matched for maternal age and ethnicity at a ratio of 1:2. Women who had a cervical tear but then did not have a subsequent delivery, or had multiple fetal gestations or cervical cerclage at subsequent pregnancies were excluded. Primary outcome was spontaneous PTB rate (<37 weeks) in the subsequent pregnancy. Secondary outcomes included any PTBs in other subsequent pregnancies. RESULTS: Overall, 389 women were included. Of all cases of cervical tear, 129 were identified eligible and included in the final analysis. The control group included 260 women with an intact cervix. No significant differences were found between the study and control groups in the incidence of spontaneous PTB in the immediate subsequent pregnancy [1.6% (2/129) vs. 3.8% (10/260), respectively, p = 0.35]. The incidence of any spontaneous PTBs in all subsequent pregnancies did not differ also [4.7% (6/129) vs. 7.3% (19/260), respectively, p = 0.31]. CONCLUSION: Cervical tear detected after delivery does not increase the risk of spontaneous PTB in subsequent pregnancies. PMID- 28589475 TI - Cleft palate with/without cleft lip in French children: radiographic evaluation of prevalence, location and coexistence of dental anomalies inside and outside cleft region. AB - INTRODUCTION: Prevalence of dental anomalies in cleft patients is higher than that in general population. The objectives of this study were to assess the prevalence of dental anomalies and their coexistence in French children with cleft and, then, to investigate the relation between the dental anomalies and the cleft type. MATERIAL AND METHODS: Seventy-four non-syndromic cleft patients (6-16 years old) from Lille Regional University and Mondor-Chenevier Hospitals (France) were included. Clefts were classified as right/left unilateral cleft lip and palate (UCLP), bilateral cleft lip and palate (BCLP) and cleft palate (CP). Dental anomalies were investigated on panoramic radiographs and categorized as agenesis, supernumerary teeth, incisor rotations, impacted canines and shape anomalies. Prevalence and gender distribution of dental anomalies, mean number of affected teeth per patient, agenesis occurrence and location, and coexistence of dental anomalies were analysed by cleft type. RESULTS: 96.0% of patients presented at least one dental anomaly (agenesis 83.8%, incisor rotations 25.7%, shape anomalies 21.6%, impacted canines 18.9%, supernumerary teeth 8.1%). BCLP patients had a higher number of affected teeth, and left UCLP patients had a higher one compared to right UCLP patients. Distribution of inside (45.3%) and outside (54.7%) cleft region agenesis was similar. Adjacent (31.8%) and not adjacent (33.3%) combined dental anomalies were often encountered. CONCLUSIONS: Dental anomalies were localized inside as well as outside cleft region and were often associated with each other. BCLP patients were more affected. CLINICAL RELEVANCE: Early radiographic evaluation allows a comprehensive diagnosis of inside and outside cleft region anomalies, required for the multidisciplinary dental treatment. PMID- 28589478 TI - Placental and cord blood brain derived neurotrophic factor levels are decreased in nondiabetic macrosomia. AB - PURPOSE: To measure levels of placental brain derived neurotrophic factor (BDNF) gene expression and umbilical cord blood BDNF in neonates with nondiabetic macrosomia and determine associations between these levels and macrosomia. METHODS: This case-control study included 58 nondiabetic macrosomic and 59 normal birth weight mother-infant pairs. Data were collected from interviews and our hospital's database. BDNF gene expression was quantified in placental tissues using quantitative real-time polymerase chain reaction (n = 117). Umbilical cord blood BDNF levels were measured by enzyme-linked immunosorbent assay (n = 90). Multivariate logistic regression models were used to evaluate associations between BDNF levels and macrosomia. RESULTS: Placental BDNF gene expression (P = 0.026) and cord blood BDNF (P = 0.008) were lower in neonates with nondiabetic macrosomia than in normal birth weight controls. Cord blood BDNF was significantly lower in vaginally delivered macrosomic neonates than vaginally delivered controls (P = 0.014), but cord BDNF did not differ between vaginal and cesarean section delivery modes in macrosomic neonates. Cord blood BDNF was positively associated with gestational age in control neonates (r = 0.496, P < 0.001), but not in macrosomic neonates. Cord blood BDNF was positively associated with placental BDNF relative expression (r s = 0.245, P = 0.02) in the total group. Higher cord blood BDNF levels were independently associated with protection against nondiabetic macrosomia (adjusted odds ratio 0.992; 95% confidence interval 0.986-0.998). CONCLUSIONS: Both placental BDNF gene expression and cord blood BDNF were downregulated in neonates with nondiabetic macrosomia compared with normal birth weight neonates. Cord BDNF may partly derive from BDNF secreted by the placenta. Higher cord plasma BDNF levels protected against nondiabetic macrosomia. PMID- 28589479 TI - Risk factors for incomplete healing of the uterine incision after cesarean section. AB - OBJECTIVE: To analyze related risk factors of post-cesarean scar defects (PCSDs). METHODS: A retrospective study of full-term women delivered by cesarean with singleton infants at our hospital from April 2014 to December 2015 was performed. 69 cases of diagnosed PCSDs and 107 cases with no PCSD who accepted cesarean were recruited for analysis. Individual medical case and operative report review were retrieved for maternal clinical characteristics analysis. RESULTS: There was no difference in age, gestational age, BMI and baby's weight between the two groups. PCSD group has more cases of anemia, higher neutrophil percentage and more cases of elected cesarean and emergency cesarean than controls (all p < 0.05). For woman who received emergency cesarean, there were more cases with cervix dilated larger than 3 cm in operation and more cases received cesarean at least one time before. In addition, women with cesarean interval of at least 5 years, women with ultrasonic measured echo longer than 3 cm, women with poor healing in uterine incision, women with retroposition of uterus and women who had intrauterine separation are more prone to develop PCSDs. CONCLUSIONS: The occurrence of a defective uterine scar after cesarean section is primarily a by-product of the combination of multiple factors: age >=30 years, BMI >=27.30, premature rupture of membranes, elective cesarean section, post-operative anemia, WBC count >=12.5 * 109 g/L and retroposition of uterus. These are high risk factors of PCSDs. PMID- 28589480 TI - Dark Flow, Depression and Multiline Slot Machine Play. AB - Multiline slot machines allow for a unique outcome type referred to as a loss disguised as a win (LDW). An LDW occurs when a player gains credits on a spin, but fewer credits than their original wager (e.g. 15-cent gain on a 20-cent wager). These outcomes alter the gambler's play experience by providing frequent, albeit smaller, credit gains throughout a playing session that are in fact net losses. Despite this negative overall value, research has shown that players physiologically respond to LDWs as if they are wins, not losses. These outcomes also create a "smoother" experience for the player that seems to promote a highly absorbing, flow-like state that we have called "dark flow". Past research has indicated that there may be a relationship between problem gambling status and dark flow, as well as between dark flow, depression, and gambling expectancies. In this study, we sought to further understand these relationships, while examining the influence of LDWs on game preference in the context of single versus multiline slots play. We used a realistic slot machine simulator equipped with a force transducer to measure how hard players pressed the spin button following different outcomes. This measure of arousal showed that LDWs were treated similarly to small wins. Participants overwhelmingly preferred the multiline game and experienced more positive affect while playing it, compared to the single-line game. Problem gambling severity index scores were related to dark flow in both games, but this relationship was stronger for the multiline game. Additionally, depression symptomatology and dark flow were strongly correlated in the multiline game, with significant relationships between depression and gambling expectancy, and gambling expectancy and dark flow ratings also emerging. PMID- 28589481 TI - Surgical case of isolated pulmonary valve endocarditis in a patient without predisposing factors. AB - We report a case of isolated pulmonary valve endocarditis in a 47-year-old woman without predisposing factors. She had episodes of low-grade fever and non productive cough and was initially diagnosed with bacterial pneumonia. With antibiotic treatment, her condition improved transiently, but she had repeated respiratory events. Forty days after her first visit, she complained of severe dyspnea. Echocardiography revealed a large vegetation adhering to the pulmonary valve and she was diagnosed with isolated pulmonary valve endocarditis. Surgical treatment was selected because antibiotic treatment was not effective. The main pulmonary artery was transected above the annulus and the infected valve was excised. To avoid contact of the prosthetic valve with the infected pulmonary annulus, a stentless bioprosthesis was interposed between the transected parts of the pulmonary trunk. Two years after the surgery, the patient is stable with no sign of infection. PMID- 28589482 TI - SASHA versus ShMOLLI: a comparison of T1 mapping methods in health and dilated cardiomyopathy at 3 T. AB - Cardiac Magnetic Resonance derived T1 mapping parameters are a non-invasive method of estimating diffuse myocardial fibrosis. This study aims to to determine the native T1 time, post contrast T1 time and extracellular volume (ECV) derived from T1 mapping and to evaluate the ability of T1 mapping techniques to discriminate healthy myocardium from dilated cardiomyopathy. Seventy-nine participants underwent cardiac magnetic resonance imaging at the Baker Heart and Diabetes Institute, Melbourne, Australia. Fifty-seven healthy volunteers and twenty-two patients with Dilated cardiomyopathy were included in the study. Each participant had T1 mapping sequences performed at 3 T in the mid short axis slice both SASHA and ShMOLLI T1 mapping were performed. Native T1, post contrast T1 and ECV values were compared in health and dilated cardiomyopathy. Native T1, post contrast T1 and ECV differed significantly between SASHA and ShMOLLI techniques (P < 0.001). All T1 parameters had similar ability to discriminate normal from abnormal myocardium (ROC AUC 0.691 to 0.830). Converting T1 values to Z scores significantly improved the agreement between SASHA and ShMOLLI techniques, particularly for post contrast T1 (ICC 0.19 to 0.895) and ECV (ICC 0.461 to 0.880). T1 mapping values from SASHA and ShMOLLI show strong correlation for post contrast measures, though with a consistent offset for all measures in health and dilated cardiomyopathy. All measures obtained using SASHA and ShMOLLI allow good discrimination between dilated cardiomyopathy and normal myocardium. PMID- 28589483 TI - High electrical activity at the connection site of previously undetected anomalous pulmonary venous drainage in a patient presenting with atrial fibrillation. PMID- 28589485 TI - Changing SNAP-Participation Trends Among Farmworker Households in the U.S., 2003 2012. AB - We investigated Supplemental Nutrition Assistance Program (SNAP) participation among citizen, documented and undocumented immigrant hired crop farmworkers for ten recent years. We analyzed population representative data from the National Agricultural Workers Survey for 2003-2012 (N = 18,243 households). Time-chart, simple mean differences, and logistic regressions described farmworker household participation in SNAP. The 2008 financial crisis almost doubled SNAP participation by agriculture households (6.5% in 2003-2007 vs. 11.3% in 2008 2012). The increasing SNAP-participation was found for citizen, documented and undocumented immigrant households. We found low participation among documented (OR 0.67, 95% CI 0.56-0.8) and undocumented immigrants (OR 0.63, 95% CI 0.54 0.74) compared to citizens. Low odds ratios (OR 0.70, 95% CI 0.55-0.89) were found for Hispanic-citizens as compared with non-Hispanic white-citizens. Our results may help inform the debate surrounding the effects of the financial crisis on SNAP-participation and on differences in participation among citizens, immigrants, Hispanics and non-Hispanics, the latter suggesting ethnic farmworker disparities in SNAP-participation. PMID- 28589484 TI - Longitudinal Volume Quantification of Deep Medullary Veins in Patients with Cerebral Venous Sinus Thrombosis : Venous Volume Assessment in Cerebral Venous Sinus Thrombosis Using SWI. AB - PURPOSE: Susceptibility-weighted imaging (SWI) visualizes small cerebral veins with high sensitivity and could, thus, enable quantification of hemodynamics of deep medullary veins. We aimed to evaluate volume changes of deep medullary veins in patients with acute cerebral venous sinus thrombosis (CVST) over time in comparison to healthy controls. METHODS: All magnetic resonance imaging (MRI) experiments were executed at 3 T using a 32-channel head coil. Based on SWI and semiautomatic postprocessing (statistical parametric mapping [SPM8] and ANTs), the volume of deep medullary veins was quantified in 14 patients with acute CVST at baseline and the 6-month follow-up, as well as in 13 healthy controls undergoing repeated MRI examination with an interscan interval of at least 1 month. RESULTS: Deep medullary venous volume change over time was significantly different between healthy controls and patient groups (p < 0.001). Patients with superior sagittal sinus thrombosis (SSST) showed a significant decline from baseline to follow-up measurements (9.8 +/- 4.9 ml versus 7.5 +/- 4.2 ml; p = 0.02), whereas in patients with transverse sinus thrombosis (TST) and healthy controls no significant volume changes were observable. CONCLUSIONS: Venous volume quantification was feasible and reproducible both in healthy volunteers and in patients. The decrease of venous volume in patients over time represents improvement of venous drainage, reduction of congestion, and normalization of microcirculation due to treatment. Thus, quantification of venous microcirculation could be valuable for estimation of prognosis and guidance of CVST therapy in the future. PMID- 28589486 TI - Tensions and Coping Strategies in Ethnically Mixed Teams: Findings from a Study in Two Emergency Departments. AB - Diversity of the workforce in healthcare facilities, representative of the general population's ethnic/racial composition, is an important health priority. Nevertheless, this diversity may generate tensions. The objective of the study was to assess tensions and coping strategies among ethnic minority and majority healthcare workers. A questionnaire was delivered to 60 healthcare workers employed in emergency departments in two hospitals, where Jewish majority and Arab minority workers care for a mixed Jewish and Arab population. Internal consistency reliability was assessed and the survey data were statistically analyzed. Several differences were found between Arab and Jewish healthcare workers. The questionnaire may be used to examine tensions in other healthcare systems, characterized by ethnic/racial diversity in the workforce. By exploring ethnic/racial tensions, health organizations should be able to manage them better and reduce their frequency. PMID- 28589487 TI - Factors Predicting Sodium Intake of Korean Americans with Type 2 Diabetes. AB - The increasing prevalence of type 2 diabetes mellitus (T2DM) and its complications including cardiovascular disease and chronic kidney disease threaten Korean Americans (KAs). High dietary sodium intake contributes to both conditions. The purpose of the study was to assess dietary sodium consumption and to examine the predictors of sodium intake among KA with T2DM. A total 232 KA who had uncontrolled diabetes participated in this study. The majority of the sample (69%) consumed more sodium than current national guidelines. A high level of energy intake was the strongest predictor for sodium intake with gender and marital status also related. Our findings identified predictive factors to excessive sodium intake and these data support the need for culturally-tailored education about appropriate dietary sodium and energy intake are needed for patients about T2DM. PMID- 28589488 TI - Negative Electron Transfer Dissociation Sequencing of Increasingly Sulfated Glycosaminoglycan Oligosaccharides on an Orbitrap Mass Spectrometer. AB - The structural characterization of sulfated glycosaminoglycan (GAG) carbohydrates remains an important target for analytical chemists attributable to challenges introduced by the natural complexity of these mixtures and the defined need for molecular-level details to elucidate biological structure-function relationships. Tandem mass spectrometry has proven to be the most powerful technique for this purpose. Previously, electron detachment dissociation (EDD), in comparison to other methods of ion activation, has been shown to provide the largest number of useful cleavages for de novo sequencing of GAG oligosaccharides, but such experiments are restricted to Fourier transform ion cyclotron resonance mass spectrometers (FTICR-MS). Negative electron transfer dissociation (NETD) provides similar fragmentation results, and can be achieved on any mass spectrometry platform that is designed to accommodate ion-ion reactions. Here, we examine for the first time the effectiveness of NETD-Orbitrap mass spectrometry for the structural analysis of GAG oligosaccharides. Compounds ranging in size from tetrasaccharides to decasaccharides were dissociated by NETD, producing both glycosidic and cross-ring cleavages that enabled the location of sulfate modifications. The highly-sulfated, heparin-like synthetic GAG, ArixtraTM, was also successfully sequenced by NETD. In comparison to other efforts to sequence GAG chains without fully ionized sulfate constituents, the occurrence of sulfate loss peaks is minimized by judicious precursor ion selection. The results compare quite favorably to prior results with electron detachment dissociation (EDD). Significantly, the duty cycle of the NETD experiment is sufficiently short to make it an effective tool for on-line separations, presenting a straightforward path for selective, high-throughput analysis of GAG mixtures. Graphical Abstract ?. PMID- 28589489 TI - Sexual distress and quality of life among women with bipolar disorder. AB - BACKGROUND: Information on the association between bipolar disorder (BD), sexual satisfaction, sexual function, sexual distress and quality of life (QoL) is sparse. This study aims, in women with BD, to (i) investigate sexual dysfunction, sexual distress, general sexual satisfaction and QoL; (ii) explore whether sexual distress was related to affective symptoms and (iii) investigate whether QoL was associated with sexual distress. The study is a questionnaire survey in an outpatient cohort of women with BD using: Changes in Sexual Functioning Questionnaire, Female Sexual Distress Scale, Altman Self-Rating Mania Scale (ASRM), Major Depression Inventory (MDI) and The World Health Organisation Quality of Life-Brief. RESULTS: In total, 61 women (age range 19-63, mean 33.7 years) were recruited. Overall, 54% reported sexual distress (n = 33) and 39% were not satisfied with their sexual life (n = 24). Women with BD were significantly more sexually distressed in comparison with Danish women from the background population but they did not have a higher prevalence of impaired sexual function. Better sexual function was positively associated with ASRM scores while MDI scores were associated with more distress. Finally, the group of non-sexually distressed women with BD reported higher QoL scores compared with the sexually distressed group. CONCLUSIONS: Women with BD exhibited a high prevalence of sexual distress and their sexual function seemed associated with their actual mood symptoms and perception of QoL. PMID- 28589490 TI - Bifurcation thresholds and optimal control in transmission dynamics of arboviral diseases. AB - In this paper, we derive and analyse a model for the control of arboviral diseases which takes into account an imperfect vaccine combined with some other control measures already studied in the literature. We begin by analysing the basic model without control. We prove the existence of two disease-free equilibrium points and the possible existence of up to two endemic equilibrium points (where the disease persists in the population). We show the existence of a transcritical bifurcation and a possible saddle-node bifurcation and explicitly derive threshold conditions for both, including defining the basic reproduction number, [Formula: see text], which provides whether the disease can persist in the population or not. The epidemiological consequence of saddle-node bifurcation is that the classical requirement of having the reproduction number less than unity, while necessary, is no longer sufficient for disease elimination from the population. It is further shown that in the absence of disease-induced death, the model does not exhibit this phenomenon. The model is extended by reformulating the model as an optimal control problem, with the use of five time dependent controls, to assess the impact of vaccination combined with treatment, individual protection and two vector control strategies (killing adult vectors and reduction of eggs and larvae). By using optimal control theory, we establish conditions under which the spread of disease can be stopped, and we examine the impact of combined control tools on the transmission dynamic of disease. The Pontryagin's maximum principle is used to characterize the optimal control. Numerical simulations and efficiency analysis show that, vaccination combined with other control mechanisms, would reduce the spread of the disease appreciably. PMID- 28589491 TI - Synthesis and Characterization of Novel BMI1 Inhibitors Targeting Cellular Self Renewal in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) represents one of the most lethal cancers worldwide due to therapy resistance and disease recurrence. Tumor relapse following treatment could be driven by the persistence of liver cancer stem-like cells (CSCs). The protein BMI1 is a member of the polycomb epigenetic factors governing cellular self-renewal, proliferation, and stemness maintenance. BMI1 expression also correlates with poor patient survival in various cancer types. OBJECTIVE: We aimed to elucidate the extent to which BMI1 can be used as a potential therapeutic target for CSC eradication in HCC. METHODS: We have recently participated in characterizing the first known pharmacological small molecule inhibitor of BMI1. Here, we synthesized a panel of novel BMI1 inhibitors and examined their ability to alter cellular growth and eliminate cancer progenitor/stem-like cells in HCC with different p53 backgrounds. RESULTS: Among various molecules examined, RU-A1 particularly downregulated BMI1 expression, impaired cell viability, reduced cell migration, and sensitized HCC cells to 5 fluorouracil (5-FU) in vitro. Notably, long-term analysis of HCC survival showed that, unlike chemotherapy, RU-A1 effectively reduced CSC content, even as monotherapy. BMI1 inhibition with RU-A1 diminished the number of stem-like cells in vitro more efficiently than the model compound C-209, as demonstrated by clonogenic assays and impairment of CSC marker expression. Furthermore, xenograft assays in zebrafish showed that RU-A1 abrogated tumor growth in vivo. CONCLUSIONS: This study demonstrates the ability to identify agents with the propensity for targeting CSCs in HCC that could be explored as novel treatments in the clinical setting. PMID- 28589492 TI - A Phase 1 Study of LY2874455, an Oral Selective pan-FGFR Inhibitor, in Patients with Advanced Cancer. AB - BACKGROUND: We report here a phase 1 study of LY2874455, a potent oral selective pan-fibroblast growth factor receptor (FGFR) inhibitor. OBJECTIVE: The primary objective was to determine the recommended phase 2 dosing (RP2D). Secondary objectives included determining toxicity, antitumor activity, pharmacokinetics (PK), and pharmacodynamic (PD) properties of LY2874455. PATIENTS AND METHODS: This study comprised two parts: (a) dose escalation with 3 + 3 cohorts in patients with solid tumors and (b) dose-expansion cohorts in patients with gastric cancer (GC) and non-small cell lung cancer (NSCLC). Part A: 36 patients in 11 dose cohorts ranging from 2 to 24 mg twice daily (BID). RP2D was 16 mg BID. Part B: GC cohort, 29 patients, NSCLC cohort, 27 patients, all treated at the RP2D. RESULTS: LY2874455 was slowly absorbed and generally showed linear PK. The effective half-life was ~12 h. PD properties of LY2874455 occurred at doses >=10 mg by increases in serum phosphorus. Phosphate binders were administered to control serum phosphorus. LY2874455 was generally well tolerated; most toxicities were grade 1 or 2; most frequent were hyperphosphatemia, diarrhea, and stomatitis. EFFICACY: part A: 24 patients evaluable: 1 patient in the 14-mg BID cohort with GC had a partial response (PR); 14 patients had stable disease (SD); part B: NSCLC cohort: 11 of 12 evaluable patients had SD; GC cohort: 15 patients evaluable: 1 patient with PR; 12 patients with SD. CONCLUSIONS: LY2874455 has an RP2D of 16 mg BID and demonstrated good tolerability and activity in solid-organ cancer patients. The role of FGFR inhibition on tumor growth in patients requires further study. (NCT01212107). PMID- 28589493 TI - A Randomized, Placebo-Controlled Trial Evaluating the Safety and Efficacy of Adding Omarigliptin to Antihyperglycemic Therapies in Japanese Patients with Type 2 Diabetes and Inadequate Glycemic Control. AB - INTRODUCTION: Daily dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used with other orally administered antihyperglycemic agents (AHA), as combination therapy, to treat Japanese patients with type 2 diabetes. When combination therapy is indicated, use of a once-weekly (q.w.) orally administered DPP-4 inhibitor might be an appropriate therapeutic option for some patients. METHODS: A 52-week trial was conducted to assess the safety and tolerability (primary objectives) and glycemic efficacy (secondary objectives) of the q.w. DPP-4 inhibitor omarigliptin as add-on therapy to five different classes of orally administered AHA [sulfonylurea (SU), glinide (GL), biguanide (BG), thiazolidinedione (TZD), or alpha-glucosidase inhibitor (AGI)] commonly used in Japan and having different mechanisms of drug action from DPP-4 inhibitors. The trial consisted of an initial 24-week double-blind, placebo-controlled period during which patients (stratified by background AHA) were randomized to omarigliptin 25 mg q.w. or placebo, followed by a 28-week open-label period during which patients on placebo were switched to omarigliptin. RESULTS: After 24 weeks, the percentages of patients with adverse events (AEs), serious AEs, drug related AEs, AEs of symptomatic hypoglycemia, or who discontinued from trial medication because of an AE were generally similar in the omarigliptin and placebo groups, in all background AHA strata and in the overall population. From a mean baseline HbA1c of approximately 8.0%, the placebo-adjusted least-squares mean changes from baseline ranged from -0.80% (AGI stratum) to -1.16% (TZD stratum); p < 0.001 for all background AHA strata. During the open-label period, no safety signals emerged with longer-term treatment. At week 52, the change from baseline in HbA1c in the omarigliptin/omarigliptin group was similar to that of the placebo/omarigliptin group. CONCLUSIONS: Addition of once-weekly omarigliptin to AHA therapy with an SU, GL, BG, TZD, or AGI for up to 52 weeks was generally safe and well tolerated, and provided persistent efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01697592. FUNDING: MSD K.K., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. PMID- 28589494 TI - The Accuracy of the ADOS-2 in Identifying Autism among Adults with Complex Psychiatric Conditions. AB - The Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Module 4 is considered a "gold-standard" instrument for diagnosing autism spectrum disorder (ASD) in adults. Although the ADOS-2 shows good sensitivity and specificity in lab-based settings, it is unknown whether these results hold in community clinics that serve a more psychiatrically impaired population. This study is the first to evaluate the diagnostic accuracy of the ADOS-2 among adults in community mental health centers (n = 75). The ADOS-2 accurately identified all adults with ASD; however, it also had a high rate of false positives among adults with psychosis (30%). Findings serve as a reminder that social communication difficulties measured by the ADOS-2 are not specific to ASD, particularly in clinically complex settings. PMID- 28589495 TI - Diagnostic Substitution for Intellectual Disability: A Flawed Explanation for the Rise in Autism. AB - Time trends in autism spectrum disorder (ASD) and intellectual disability (ID) prevalence from the United States Individuals with Disabilities Education Act data were computed from 2000 to 2011 for each state and each age from 6 to 17. These trends did not support the hypothesis that diagnostic substitution for ID can explain the ASD rise over recent decades, although the hypothesis appeared more plausible when the data were aggregated across all states and ages. Nationwide ID prevalence declined steeply over the last two decades, but the decline was driven mainly by ~15 states accounting for only one-fourth of the U.S. school population. More commonly, including in the most populous states, ID prevalence stayed relatively constant while ASD prevalence rose sharply. PMID- 28589496 TI - Screening of Autism Spectrum Disorders in Geriatric Psychiatry. AB - Autism spectrum disorders (ASD) are difficult to detect in old age. This study examined if ASD symptoms in older adults (age > 60) can be detected with the Dutch informant personality questionnaire, (Hetero-Anamnestische Persoonlijkheidsvragenlijst, HAP) in a mental health setting. Patients with ASD (N = 40) were compared to patients with a different psychiatric diagnosis (N = 43; personality disorders excluded). The ASD group had significant higher scores on the scales 'Socially avoidant behavior', 'Rigid behavior' and 'Unpredictable and impulsive behavior'. These scales were able to discriminate between individuals with or without ASD. The HAP can thus be used as a screening instrument for ASD symptoms in elderly patients. Further research is needed to clarify what items have the best predictive validity for ASD symptoms. PMID- 28589497 TI - Frequency of Dendritic Cells and Their Expression of Costimulatory Molecules in Children with Autism Spectrum Disorders. AB - The aim of our study was to evaluate the frequencies of myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) in children with ASD. Subjects were 32 children with ASD and 30 healthy children as controls. The numbers of mDCs and pDCs and the expression of CD86 and CD80 on the entire DCs were detected by flow cytometry. ASD children had significantly higher percentages of mDCs and pDCs when compared to controls. We found significant inverse relationships between serum 25-hydroxyvitamin D levels and the frequencies of mDCs and pDCs in autistic children. Our data suggested that DCs could play a role in the clinical course of ASD. The relationship of DCs to immune disorders in ASD remains to be determined. PMID- 28589498 TI - Higher local recurrence rates after intralesional surgery for giant cell tumor of the proximal femur compared to other sites. AB - PURPOSE: The treatment of giant cell tumor (GCT) of bone remains controversial. Intralesional surgery (curettage) results in a higher rate of local recurrence, but better functional results compared to resection. The aim of this study was to assess whether the use of curettage was successful in the treatment of GCT of long bones. We evaluated the influence of adjuvant treatment, local tumor presentation, and demographic factors on the risk of recurrence. METHODS: We retrospectively reviewed the records of patients treated for GCT of long bones between 1990 and 2013, using curettage. No patient had any treatment other than surgery. After detailed curettage, the bone cavity was filled with bone allografts and/or cement. Recurrence rates, risk factors for recurrence and the development of pulmonary metastases were determined. The minimum follow-up was 24 months. RESULTS: We enrolled 210 patients with GCT of long bones treated by curettage. The rate of local recurrence was 16.2% (34/210 patients). The median follow-up was 89.2 months. In the multivariate analysis, no significant statistical effect on the local recurrence rate could be identified for gender, patient's age, Campanacci's grading, or cement versus bone allografts. The only independent risk factor related to the local recurrence was the site, with a statistically significant higher risk for patients with GCT of the proximal femur. CONCLUSIONS: Our observation on the correlation of tumor location and risk of local recurrence is new. We suggest that patients with GCT of bone in the proximal femur should be followed closely soon after surgery to identify any possible recurrence. PMID- 28589500 TI - [MR Spectroscopy for clinical diagnostics]. PMID- 28589501 TI - ? PMID- 28589499 TI - Results from the surgical resection of severe heterotopic ossification of the hip: a case series of 26 patients. AB - INTRODUCTION: Surgical resection of heterotopic ossification (HO) around the hip joint is often challenging. The aim of this study is to evaluate the clinical and radiological outcomes following surgical resection of Brooker's type III and IV HO of the hip. METHODS: We retrospectively reviewed clinical and radiological data, between November 2006 and January 2013, of all patients who underwent surgical resection of severe HO of the hip. Brooker's grading, range of motion and the Harris Hip Score before and after surgery were recorded in all cases. The combined radiation (700 cGy preoperatively) and indomethacin regimen was used to prevent heterotopic ossification recurrence. RESULTS: Twenty-six patients (22 males and 4 females) were included in our study. Mean patient age was 47.38 years (range 24-72). The HO was graded as Brooker grade III in 3 patients (11.5%) and Brooker grade IV in 23 patients (88.5%). Mean time interval between HO development and resection was 40.8 months (range 13-156 months). All patients had CT scans prior to surgery. Mean follow-up was 31.4 months (range 24-40 months). There was no severe HO recurrence. Complications included one intraoperative injury of a femoral artery branch, one intraoperative femoral neck fracture treated with intramedullary nailing, one sciatic nerve injury and one superficial infection treated conservatively. CONCLUSIONS: Surgical resection of severe HO of the hip along with preoperative radiation and indomethacin provides excellent results; however, the complication rate is relatively high. Careful evaluation of the preoperative CT scan and wide exposure are required in order to identify all the involved neurovascular structures. PMID- 28589502 TI - Endoscopic removal of an impacted barolith at the sigmoid colon: a rare case report. AB - A 45-year-old woman visited our hospital complaining of abdominal pain 1 week after undergoing an annual medical checkup. Her vital signs and blood test results were normal, but tenderness was found in the lower abdomen. A high density round structure found at the midline of the lower abdomen on an abdominal radiograph was thought to be an accumulation of barium (a barolith) from upper gastrointestinal barium radiography. Two liters of an oral gastrointestinal cleaning agent was administered, but defecation did not occur. Lower gastrointestinal endoscopy revealed that the barolith was impacted at the sigmoid colon. We unsuccessfully attempted to move it using a pressurized water jet and forceps, but it was too large to be captured by the net. Therefore, we broke it down using a snare. After a successful endoscopic procedure, 120 mL of a glycerin enema solution was injected through the forceps opening, causing the barolith to be excreted. There is only one similar case of successful endoscopic treatment of a barolith in the literature. PMID- 28589504 TI - Age-Related Differences in Socio-demographic and Behavioral Determinants of HIV Testing and Counseling in HPTN 043/NIMH Project Accept. AB - Youth represent a large proportion of new HIV infections worldwide, yet their utilization of HIV testing and counseling (HTC) remains low. Using the post intervention, cross-sectional, population-based household survey done in 2011 as part of HPTN 043/NIMH Project Accept, a cluster-randomized trial of community mobilization and mobile HTC in South Africa (Soweto and KwaZulu Natal), Zimbabwe, Tanzania and Thailand, we evaluated age-related differences among socio demographic and behavioral determinants of HTC in study participants by study arm, site, and gender. A multivariate logistic regression model was developed using complete individual data from 13,755 participants with recent HIV testing (prior 12 months) as the outcome. Youth (18-24 years) was not predictive of recent HTC, except for high-risk youth with multiple concurrent partners, who were less likely (aOR 0.75; 95% CI 0.61-0.92) to have recently been tested than youth reporting a single partner. Importantly, the intervention was successful in reaching men with site specific success ranging from aOR 1.27 (95% CI 1.05-1.53) in South Africa to aOR 2.30 in Thailand (95% CI 1.85-2.84). Finally, across a diverse range of settings, higher education (aOR 1.67; 95% CI 1.42, 1.96), higher socio-economic status (aOR 1.21; 95% CI 1.08-1.36), and marriage (aOR 1.55; 95% CI 1.37-1.75) were all predictive of recent HTC, which did not significantly vary across study arm, site, gender or age category (18-24 vs. 25-32 years). PMID- 28589505 TI - Association between suPAR and cardiac diastolic dysfunction among patients with preserved ejection fraction. AB - Serum levels of the soluble urokinase-type plasminogen activator receptor (suPAR) reflect immune and inflammatory activation, and are shown to be associated with cardiovascular outcomes. We herein investigated the potential association between suPAR and left ventricular diastolic dysfunction among patients with preserved left ventricular ejection fraction (LVEF) and sinus rhythm. Among 291 patients who had sinus rhythm and an LVEF of >=50% enrolled in the study, 26 (8.9%) were considered to have diastolic dysfunction. Patients with diastolic dysfunction had lower estimated glomerular filtration rate (eGFR), and higher systolic blood pressure (BPs), BNP, C-reactive protein, and suPAR than those without diastolic dysfunction. As compared with the first suPAR quartile, the fourth suPAR quartile was significantly associated with both diastolic dysfunction with an odds ratio of 8.95 [95% confidence interval (CI), 1.04-77.0, P < 0.05] after adjusting for sex, age, BPs log(eGFR), CRP, and diuretic use. On the other hand, receiver operating characteristic curve (ROC) analysis showed that addition of log(suPAR) to the combination of age, sex, and log(eGFR), CRP, and diuretic use did not significantly improve the prediction of diastolic dysfunction. Among cardiac patients with preserved LVEF, serum suPAR was associated with diastolic dysfunction independent of confounding factors by logistic regression analysis. However, according to the ROC analysis, the utility of suPAR as a biomarker for diastolic dysfunction may be limited from a clinical point of view. PMID- 28589506 TI - Pre-existing medical comorbidity is not associated with neurological outcomes in patients undergoing targeted temperature management following cardiac arrest. AB - The prognostic significance of chronic medical illness in comatose survivors of cardiac arrest who undergo targeted temperature management (TTM) remains largely unknown. We sought to assess the association between overall burden of pre existing medical comorbidity and neurological outcomes in survivors of cardiac arrest undergoing TTM. We analyzed a prospectively collected cohort of 314 patients treated with TTM following cardiac arrest at a tertiary care hospital between 2007 and 2014. Overall burden of medical comorbidity was approximated with the use of the Charlson Comorbidity Index (CCI). Poor neurological outcome at hospital discharge, defined as a cerebral performance category (CPC) score >2, was the primary outcome. Secondary outcomes included death prior to hospital discharge and at 1 year following cardiac arrest. Multivariable logistic regression was used to assess the association between CCI scores and outcomes. A poor neurological outcome at hospital discharge was observed in 193 (61%) patients. One hundred and seventy-nine (57%) patients died prior to hospital discharge and a total of 195 (62%) patients had died at 1-year post-arrest. In multivariable logistic regression, elevated CCI scores were not associated with increased odds of poor neurological outcomes (OR 1.04, 95% CI 0.90-1.19, p = 0.608) or death (OR 0.99, 95% CI 0.86-1.13, p = 0.816) at hospital discharge. No association was seen between CCI scores and death at 1-year post-arrest (OR 1.09, 95% CI 0.95-1.26, p = 0.220). Increasing burden of medical comorbidity, as defined by CCI scores, is not associated with neurological outcomes or survival in patients treated with TTM. PMID- 28589507 TI - Biliary stone removal through the percutaneous transhepatic biliary drainage route, focusing on the balloon sphincteroplasty flushing technique: a single center study with 916 patients. AB - PURPOSE: To present our experience in biliary stone removal (BSR) through the percutaneous transhepatic biliary drainage (PTBD) route in 916 patients, and discuss its clinical usefulness. MATERIALS AND METHODS: From 2001 to 2015, 916 patients (479 male patients and 437 female patients; age range, 22-92 years; mean age, 67 years) with 52 recurring cases, so a total of 968 cases, were enrolled in this study and retrospectively reviewed. PTBD was performed in all patients. BSR was performed using a combination of a balloon sphincteroplasty flushing technique, a pushing technique after sphincteroplasty, and classical extraction technique, decided case by case. RESULTS: A complete removal was achieved in 893 cases (92.3%) and the overall clinical success rate was 99.3%. Failure occurred in 7 cases (0.7%), and the causes of failure were stone impaction (n = 5) and intrahepatic bile duct stricture (n = 2). Sphincteroplasty was performed in 902 cases (93.2%). Balloon sphincteroplasty flushing technique was used in 829 (85.6%) cases. There was no major complication. Transient minor complications were seen in 86 cases (8.9%). CONCLUSIONS: BSR through the PTBD route using a combination of techniques, including balloon sphincteroplasty flushing, is a safe and effective treatment modality to remove biliary stones. PMID- 28589503 TI - Promise of adeno-associated virus as a gene therapy vector for cardiovascular diseases. AB - Cardiovascular diseases pose a unique threat to global mortality because it presents as one of the most diverse conglomerations of pathophysiological conditions that can create significant casualty even without straying into its collateral damage. This puts them right beside obesity and cancer in terms of severity. Their pervasive nature and high prevalence prompted biologists to seek newer prophylactic avenues of addressing this global hazard, among which adeno associated virus (AAV) gene therapy rose to significant prominence. By virtue of its unrivaled clinical safety quotient, AAVs have been used to rectify various subtypes of cardiovascular ailments, beginning from commonly occurring heart failure to vascular diseases. The review focuses on the history of AAV-mediated gene therapy and contemporary breakthroughs in terms of novel innovations in vector engineering to reduce detargeting, immune response, untimely expression, and so on. We have also focused on the molecular world of cardiomyocytes and endothelial cells but interpreted the therapies in a broader context of cardiovascular pathology. The advances made in each mode of intervention as well as the ones that are beyond the scope of AAV gene therapy or has not been approached through AAV gene therapy as of now have been provided in detail to illustrate the bigger picture of where we stand to combat cardiovascular diseases most efficiently. PMID- 28589508 TI - Synergies in coupled hydrolysis and fermentation of cellulose using a Trichoderma reesei enzyme preparation and a recombinant Saccharomyces cerevisiae strain. AB - We describe a procedure by which filter paper is digested with a cellulolytic enzyme preparation, obtained from Trichoderma reesei cultivated under solid state fermentation conditions and then fermented by a recombinant Saccharomyces cerevisiae strain. The yeast strain produces a beta-glucosidase encoded by the BGL1 gene from Saccharomycopsis fibuligera that quantitatively and qualitatively complements the limitations that the Trichoderma enzyme complex shows for this particular activity. The supplemental beta-glucosidase activity fuels the progression of cellulose hydrolysis and fermentation by decreasing the inhibitory effects caused by the accumulation of cellobiose and glucose. Fermentation of filter paper by this procedure yields ethanol concentrations above 70 g/L. PMID- 28589510 TI - Singlicate Ligand Binding Assay Using an Automated Microfluidic System: a Clinical Case Study. AB - The bioanalytical strategy for monoclonal antibody therapeutics, intended for multiple oncology indications, includes multiple integrated measurements of pharmacologically relevant therapeutics from discovery through development. Three ligand binding assays were cohesively developed and validated, as applicable, using the Gyrolab microfluidic system for the measurement of a free monoclonal antibody BMS-986207. Accuracy and precision demonstrate %bias from -6.3 to 4.4%, percent coefficient of variation (%CV) from 2.6 to 9.8%, and total error from 4.2 to 13.4% in the nonclinical assay; %bias from -0.3 to 3.3%, %CV from 3.5 to 18.2%, and total error from 6.1 to 19.7% in the clinical assay; and >97% of the sample meeting incurred sample reanalysis criteria. The clinical assay was validated using singlicate wells after gaining significant data in the early phase studies to support this cost-effective and efficient strategy. Each assay met fit-for-purpose and/or regulated bioanalytical method validation criteria including stability, selectivity, dilutional linearity, carryover, and specificity criteria with no interference from co-administered monoclonal antibody. PMID- 28589511 TI - Complete genome sequence of a novel S-insertion variant of porcine epidemic diarrhea virus from South Korea. AB - Porcine epidemic diarrhea virus (PEDV) is an emerging and re-emerging viral pathogen of pigs that is causing significant economic concerns in the global pork industry. The virulent G2b PEDV subgroup, which was responsible for the 2013-2014 pandemics on the American and Asian continents, hit Jeju Island in 2014, which had been PEDV-free since 2004. This study presents molecular characterization of a novel PEDV variant with a 5-amino acid (aa) insertion (DTHPE) in the spike (S) gene (an S-insertion) that was identified in diarrheic piglets from Jeju Island. The genome of the PEDV strain KOR/KNU-1601/2016 was sequenced and analyzed to characterize the S-insertion variant circulating on Jeju Island. The full-length genome sequence of KNU-1601 is 28,053 nucleotides (nt) in length, which is 24 nt and 15 nt longer than the genome sequences of G1 classical and G2 epidemic field strains, respectively. KNU-1601 shares 99.5-99.6% nucleotide sequence identity at the genome level and 98.0-98.6% amino acid sequence identity at the S gene level with other global G2b PEDV strains. Genetic and phylogenetic analyses indicated that the KNU-1601 variant is most closely related to the G2b field isolates but appears to undergo continuous evolution in the field. These data advance our understanding of the genetic diversity and evolutionary characteristics of the PEDV field strains circulating in South Korea. PMID- 28589509 TI - Strategies of Drug Transporter Quantitation by LC-MS: Importance of Peptide Selection and Digestion Efficiency. AB - Huge variation of drug transporter abundance was seen in the literature, making PBPK prediction difficult when transporters play a major role. Among multiple factors such as membrane fraction, digestion, and peptide selection that contributed to such variation, peptide selection is the least discussed. Herein, a strategy was established by using a small amount of purified protein standard to select a peptide with near 100% digestion efficiency for quantitation of a transporter protein MDR1. The impact of native membrane protein's tertiary structure on the digestion efficiency of surrogate peptides of MDR1 was investigated. Peptides in more solvent accessible regions are found to be digested much more efficiently than those in large stretches of helical structures. The concentration of peptide EALDESIPPVSFWR(EAL) in the most solvent accessible linker region of MDR1 was found closest to the true protein concentration. When using EAL for MDR1 quantitation, the abundance is over 10 times higher than previously reported, indicating the importance of peptide selection for transporter quantitation. In addition, this study also proposes a screening strategy to select peptides appropriate for relative quantitation for in vitro-in vivo extrapolation in the absence of any protein standard. PMID- 28589512 TI - Molecular insights into RNA-binding properties of Escherichia coli-expressed RNA dependent RNA polymerase of Antheraea mylitta cytoplasmic polyhedrosis virus. AB - Antheraea mylitta cytoplasmic polyhedrosis virus (AmCPV) is responsible for morbidity of the Indian non-mulberry silkworm, A. mylitta. AmCPV belongs to the family Reoviridae and has 11 double-stranded (ds) RNA genome segments (S1-S11). Segment 2 (S2) encodes a 123-kDa polypeptide with RNA-dependent RNA polymerase (RdRp) activity. To examine the RNA-binding properties of the viral polymerase, the full-length RdRp and its three domains (N-terminal, polymerase and C-terminal domains) were expressed in Escherichia coli BL21 (DE3) cells with hexahistidine and trigger factor tag fused consecutively at its amino terminus, and the soluble fusion proteins were purified. The purified full-length polymerase specifically bound to the 3' untranslated region (3'-UTR) of a viral plus-sense (+) strand RNA with strong affinity regardless of the salt concentrations, but the isolated polymerase domain of the enzyme exhibited poor RNA-binding ability. Further, the RdRp recognition signals were found to be different from the cis-acting signals that promote minus-sense (-) strand RNA synthesis, because different internal regions of the 3'-UTR of the (+) strand RNA did not effectively compete out the binding of RdRp to the intact 3'-UTR of the (+) strand RNA, but all of these RNA molecules could serve as templates for (-) strand RNA synthesis by the polymerase. PMID- 28589513 TI - Prevalence of HIV-1 transmitted drug resistance in recently infected, treatment naive persons in the Southwest of Iran, 2014-2015. AB - The emergence and transmission of drug resistant HIV mutants is a major concern, especially in resource-limited countries with expanding antiretroviral therapy. Studies have recently reported the prevalence of HIV-1 transmitted drug resistance (TDR) mutations in certain Iranian cities; however, no information is currently available about the level of TDR, as well as the nature of the circulating HIV-1 subtypes, in the Southwestern bordering province of Iran, Khuzestan. Herein, we used a WHO-recommended TDR survey method to classify the prevalence of TDR in indigenous people of Khuzestan province. For this purpose, between March 2014 and February 2015, blood samples were collected from 52 newly diagnosed, antiretroviral treatment-naive, HIV-1 infected persons aged from 18 to 30 years. TDR mutations were determined by sequencing the protease (PR) and reverse transcriptase (RT) genes and interpreted using the WHO drug resistance mutations surveillance list. HIV-1 subtypes were characterized by sequencing the PR-RT, C2-V5, and p17 regions of the pol, env and gag genes, respectively. Two participants had non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations, specifically K103N in one individual and K101EK/K103KN/G190AG in the other. No nucleoside reverse transcriptase inhibitor (NRTI) or major protease inhibitor (PI) mutations were identified. HIV-1 subtyping revealed that all participants were infected with HIV-1 CRF35_AD. According to the WHO sequential sampling method, the prevalence of HIV-1 TDR in the sampling area (Khuzestan province) was classified as moderate for NNRTIs and low for NRTIs and PIs. This is the first HIV-1 drug resistance threshold survey in the Khuzestan province of Iran and shows a predominance of NNRTI TDR mutations in this area. PMID- 28589515 TI - Erratum to: Ethical Issues Related to the Promotion of a "100 mSv Threshold Assumption" in Japan after the Fukushima Nuclear Accident in 2011: Background and Consequences. PMID- 28589514 TI - The Effect of Breastfeeding on Childhood Otitis Media. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the literature regarding the association between breastfeeding and childhood otitis media (OM), with focus on the literature published within the past 5 years. The review comprises original articles and recent reviews. RECENT FINDINGS: The effect of a protective effect of breastfeeding on the risk of OM is still being discussed. Within the past 5 years, 6 reviews and 15 original articles have been published. No randomized controlled trials have been published, and the diversity of exposure and outcome measures in the studies was significant. Also, we provide a summary of the recent literature on cost-benefit of breastfeeding and believed mechanism of protection against OM. Breastfeeding for more than 6 months seems to protect against OM during the first 6 years of life. Exclusive breastfeeding may have a more protective effect than non-exclusive breastfeeding. Introduction of formula feeding before the age of 6 months increased the risk of OM. PMID- 28589516 TI - (Yet) Another chance for good reasoning? A commentary and reply on Pighin, Tentori, and Girotto (2017). PMID- 28589517 TI - Inhibition of Gap Junction Elevates Glutamate Uptake in Cultured Astrocytes. AB - Glutamate uptake is a main function of astrocytes to keep extracellular glutamate levels low and protect neurons against glutamate-induced excitotoxicity. On the other hand, astrocyte networks formed by gap junctions, which are consisted with connexins and connecting neighboring cells, are reported to play a critical role in maintaining the homeostasis in the brain. In the present study, we examined the effects of gap junction inhibitors on the glutamate uptake activity in cultured rat cortical astrocytes. At first, we confirmed the effects of gap junction inhibitors, 1-octanol and carbenoxolone, on cell-cell communication by the scrape-loading assay using a fluorescent dye Lucifer yellow. Both of 1 octanol and carbenoxolone treatments for 20 min in cultured astrocytes significantly suppressed the cell-cell communication assessed as the distance of dye-spreading. 1-octanol and carbenoxolone increased the glutamate uptake by astrocytes and glutamate aspartate transporter (GLAST) expression on the cell membrane. These results suggest that gap junction inhibitors increase the glutamate uptake activity through the increase of GLAST proteins located on the cell membrane. The regulation of gap junction in astrocytes might protect neurons against glutamate-induced excitotoxicity. PMID- 28589518 TI - Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy. AB - Voltage-gated sodium channels initiate action potentials in brain neurons. In the 1970s, much was known about the function of sodium channels from measurements of ionic currents using the voltage clamp method, but there was no information about the sodium channel molecules themselves. As a postdoctoral fellow and staff scientist at the National Institutes of Health, I developed neurotoxins as molecular probes of sodium channels in cultured neuroblastoma cells. During those years, Bruce Ransom and I crossed paths as members of the laboratories of Marshall Nirenberg and Philip Nelson and shared insights about sodium channels in neuroblastoma cells from my work and electrical excitability and synaptic transmission in cultured spinal cord neurons from Bruce's pioneering electrophysiological studies. When I established my laboratory at the University of Washington in 1977, my colleagues and I used those neurotoxins to identify the protein subunits of sodium channels, purify them, and reconstitute their ion conductance activity in pure form. Subsequent studies identified the molecular basis for the main functions of sodium channels-voltage-dependent activation, rapid and selective ion conductance, and fast inactivation. Bruce Ransom and I re connected in the 1990s, as ski buddies at the Winter Conference on Brain Research and as faculty colleagues at the University of Washington when Bruce became our founding Chair of Neurology and provided visionary leadership of that department. In the past decade my work on sodium channels has evolved into structural biology. Molecular modeling and X-ray crystallographic studies have given new views of sodium channel function at atomic resolution. Sodium channels are also the molecular targets for genetic diseases, including Dravet Syndrome, an intractable pediatric epilepsy disorder with major co-morbidities of cognitive deficit, autistic-like behaviors, and premature death that is caused by loss-of function mutations in the brain sodium channel NaV1.1. Our work on a mouse genetic model of this disease has shown that its multi-faceted pathophysiology and co-morbidities derive from selective loss of electrical excitability and action potential firing in GABAergic inhibitory neurons, which disinhibits neural circuits throughout the brain and leads directly to the epilepsy, premature death and complex co-morbidities of this disease. It has been rewarding for me to use our developing knowledge of sodium channels to help understand the pathophysiology and to suggest potential therapeutic approaches for this devastating childhood disease. PMID- 28589519 TI - Hydrogel Environment Supports Cell Culture Expansion of a Grade IV Astrocytoma. AB - Malignant astrocytomas are aggressive cancers of glial origin that can develop into invasive brain tumors. The disease has poor prognosis and high recurrence rate. Astrocytoma cell lines of human origin are an important tool in the experimental pathway from bench to bedside because they afford a convenient intermediate system for in vitro analysis of brain cancer pathogenesis and treatment options. We undertook the current study to determine whether hydrogel culture methods could be adapted to support the growth of astrocytoma cell lines, thereby facilitating a system that may be biologically more similar to in vivo tumor tissue. Our experimental protocols enabled maintenance of Grade IV astrocytoma cell lines in conventional monolayer culture and in the extracellular matrix hydrogel, GeltrexTM. Light and fluorescence microscopy showed that hydrogel environments promoted cellular reorganization from dispersed cells into multilayered aggregates. Transmission electron microscopy revealed the prevalence of autophagy and nuclear membrane distortions in both culture systems. Analysis of microarray Gene Expression Omnibus (GEO) DataSets highlighted expression of genes implicated in pathways for cancer progression and autophagy. A pilot quantitative polymerase chain reaction (qPCR) analysis of the autophagic biomarkers, Beclin 1 (BECN1) and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B), with two reference genes (beta actin, ACTB; glyceraldehyde 3 phosphate dehydrogenase, GAPDH), uncovered a relative increase of BECN1 and LC3B in hydrogel cultures of astrocytoma as compared to the monolayer. Taken together, results establish that ultrastructural and molecular characteristics of autophagy are features of this astrocytoma cell line, and that hydrogel culture systems can afford novel opportunities for in vitro studies of glioma. PMID- 28589521 TI - Strengthening the Case for Epilepsy Drug Development: Bridging Experiences from the Alzheimer's Disease Field-An Opinion. AB - Given the sheer number of drugs (over 20!) available for treatment of seizures, epilepsy can be considered one of the most successful areas in pharmaceutical development and especially for neuroscience. However, despite the large number of drug treatment options available for managing patients with epilepsy, there remains considerable unmet need. For example, the overall impact on seizure control has not been substantial with approximately 30% of patients remaining refractory or their seizures not adequately controlled. Also there is need for epilepsy prevention and for certain sub-populations with severe intractable epilepsy. High unmet need often drives new industry investment into therapeutic market opportunities, however the profound success of antiepileptic drugs has contributed to the hurdles for industry investment in new therapies for epilepsy. Furthermore, the payor environment has also changed with new challenges for evidence generation and demonstration of additive value above existing standard of care treatments. Challenges in translational science, in the clinical trial environment including cost and operational technical difficulty, and in the commercial environment have resulted in the pharmaceutical industry directing investments away from epilepsy into other therapeutic areas such as oncology and immunology as opportunities for higher probabilities of success and returns of investment. The neuroscience area in general is perceived a high risk area and a notable exception has been the active industry involvement in Alzheimer's disease (AD), especially for therapeutics that could modify the course or prevent AD. AD is a very high risk area with no successful efficacious treatments found to date despite recent failures, there remains promise that therapies are forthcoming. The promise is fueled by a number of innovative factors that reduced R&D challenges in the AD field and contributed to a high level of drug development activity and investment. This paper addresses hurdles facing epilepsy drug discovery and development and focuses on some key solutions that could be eased to facilitate industry interest. Similarities in drug development challenges provide opportunities that bridge experiences and learnings from AD to epilepsy. Overall, the epilepsy field is probably in a good position for advancing into the next generation therapeutics of antiepileptic drugs targeted for increased efficacy in refractory epilepsy and for antiepileptogenesis. PMID- 28589523 TI - Unexpected brain finding in pre-autopsy postmortem CT. AB - A case is presented in which pre-autopsy postmortem computed tomography (PMCT) revealed an unexpected brain abscess with a related frontal sinusitis and an erosion of the posterior wall of the frontal sinus. PMCT findings enabled the forensic pathologists to adapt protective measures during autopsy and protect their health from infection. Pre-autopsy PMCT has been also useful in the early differential diagnosis procedure. The complementary use of postmortem imaging and autopsy can improve the quality of forensic death investigations. PMID- 28589522 TI - Virtopsy shows a high status funerary treatment in an early 18th Dynasty non royal individual. AB - This work presents the multidisciplinary investigation of the head of Nebiri (Museo Egizio, Turin S_5109), Chief of Stables, a high status elite person from the 18th Dynasty involving MDCT, 3D brain surface and facial reconstructions accompanied by a consideration of previously presented chemical analysis of the embalming materials found in fragments of bandages used on the head and viscera (lung) found in one of the four canopic jars. Comparison of the techniques used for the cosmetic treatment of Nebiri with those used in other elite and high status non-royal persons confirms the validity of the use of the term "high status elite" in the case of Nebiri. This case highlights the importance of using modern forensic techniques both to enhance new technologies of retrospective diagnosis on altered human remains and to increase knowledge of past populations. PMID- 28589525 TI - Cerliponase Alfa: First Global Approval. AB - Cerliponase alfa (BrineuraTM) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline. This article summarizes the milestones in the development of cerliponase alfa leading to its first global approval in the USA for the treatment of motor function loss in paediatric patients >=3 years of age with CLN2, and subsequent approval in the EU for CLN2 in all ages. PMID- 28589524 TI - Common Psychosocial Factors Predicting Return to Work After Common Mental Disorders, Cardiovascular Diseases, and Cancers: A Review of Reviews Supporting a Cross-Disease Approach. AB - Purpose This systematic review aimed at identifying the common psychosocial factors that facilitate or hinder the return to work (RTW) after a sick leave due to common mental disorders (CMDs), cardiovascular diseases (CVDs), or cancers (CAs). Methods We conducted a review of reviews searching 13 databases from 1994 to 2016 for peer-reviewed, quantitative, cohort studies investigating factors influencing RTW after a CMD, CVD, or CA. Then, for each disease we identified additional cohort studies published after the date of the latest review included. Data were extracted following a three steps best-evidence synthesis method: the extraction of results about each predictor from studies within each single review and in the additional papers; the synthesis of results across the reviews and additional papers investigating the same disease; and the synthesis of results across the diseases. Results The search strategy identified 1029 unique records from which 27 reviews and 75 additional studies underwent comprehensive review. 14 reviews and 32 additional cohort studies met eligibility criteria. Specific predictors of RTW with different levels of evidence are provided for each disease. We found four common facilitators of RTW (job control, work ability, perceived good health and high socioeconomic status), and six barriers of RTW (job strain, anxiety, depression, comorbidity, older age and low education). Conclusion This is the first review to systematically analyze commonalities in RTW after CMDs, CVDs, or CAs. The common factors identified indicate that the RTW process presents many similarities across various diseases, thus supporting the validity of a cross-disease approach. PMID- 28589520 TI - Role of Mitochondria in Methamphetamine-Induced Dopaminergic Neurotoxicity: Involvement in Oxidative Stress, Neuroinflammation, and Pro-apoptosis-A Review. AB - Methamphetamine (MA), an amphetamine-type psychostimulant, is associated with dopaminergic toxicity and has a high abuse potential. Numerous in vivo and in vitro studies have suggested that impaired mitochondria are critical in dopaminergic toxicity induced by MA. Mitochondria are important energy-producing organelles with dynamic nature. Evidence indicated that exposure to MA can disturb mitochondrial energetic metabolism by inhibiting the Krebs cycle and electron transport chain. Alterations in mitochondrial dynamic processes, including mitochondrial biogenesis, mitophagy, and fusion/fission, have recently been shown to contribute to dopaminergic toxicity induced by MA. Furthermore, it was demonstrated that MA-induced mitochondrial impairment enhances susceptibility to oxidative stress, pro-apoptosis, and neuroinflammation in a positive feedback loop. Protein kinase Cdelta has emerged as a potential mediator between mitochondrial impairment and oxidative stress, pro-apoptosis, or neuroinflammation in MA neurotoxicity. Understanding the role and underlying mechanism of mitochondrial impairment could provide a molecular target to prevent or alleviate dopaminergic toxicity induced by MA. PMID- 28589526 TI - A large-inner-diameter multi-walled carbon nanotube-based dual-drug delivery system with pH-sensitive release properties. AB - A novel dual-drug delivery system (DDDS) for cancer chemotherapy has been established by employing highly purified and mildly oxidized large-inner-diameter multi-walled carbon nanotubes (LID-MWCNTs) as the vector. The LID-MWCNTs were modified with the antitumor drugs, cisplatin (CDDP) and doxorubicin (DOX). CDDP was encapsulated inside the nanotube vectors by a wet-chemical approach while DOX was attached to the external surfaces through non-covalently interaction. The loading efficiencies of CDDP and DOX were as high as 84.56 and 192.67%, respectively. Notably, after CDDP was encapsulated inside the nanotubes, a three level blocking strategy, which included polyethylene glycol, folic acid and DOX, was employed to block the CDDP exits at different levels. The pH-sensitive release profile of CDDP was demonstrated using a modified characterization method, as well as that of DOX. Finally, the anticancer activity of the DDDS on MCF-7 cells was tested and a synergistic effect was recorded. This work is part of our LID-MWCNTs based drug delivery system studies, and provides a basis for developing a novel comprehensive antitumor treatment that combines chemotherapy and photothermal therapy. PMID- 28589528 TI - Functional Evaluation in Obese Patients Before and After Sleeve Gastrectomy. AB - BACKGROUND: Although sleeve gastrectomy (SG) has become an important treatment option in severe obesity, cardiorespiratory and muscle function after SG has not adequately been investigated. METHODS: This is an observational study in 26 obese patients (BMI 45.2 +/- 5.8 kg/m2), comparing physical function before and after 6 months from SG. All available patients listed for SG were here included. Incremental cardiopulmonary exercise tests, standardized strength tests, and balance analysis were performed. RESULTS: The substantial weight loss (-33.4 +/- 11.0 kg) after SG led to increased peak work capacity (metabolic equivalents, METs) and relative peak oxygen uptake (VO2peak/kg) (both p < 0.001). However, the absolute VO2peak, oxygen pulse (VO2/heart rate (HR)), and the oxygen uptake efficiency slope (OUES) significantly declined after SG (all p < 0.001). Furthermore, HR/VO2-slope significantly worsened after SG (p < 0.001), whereas the HR reserve and HR recovery improved (all p <= 0.01). Parameters of ventilatory efficiency were not affected by SG. The time-constant (Tau tau) of the fundamental component of VO2-kinetics, reflecting oxygen metabolism in skeletal muscles, was found to be significantly worsened after SG (p < 0.05). Finally, muscle strength and balance parameters were not much affected by SG. CONCLUSIONS: The ventilatory and cardiac function do not appear negatively affected by SG; thus, we hypothesize that the decrease in aerobic capacity could be due to alterations in peripheral muscles. This might in part be due to a loss of muscle mass, although our patients' muscle strength did not decrease. Pilot results from VO2-kinetics analysis seem to support the hypothesis of a deterioration of oxidative muscle metabolism after SG. PMID- 28589527 TI - Targeting the Tumor Stroma: the Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20). AB - The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy. PMID- 28589530 TI - Erratum to: Poor Health Behaviors Prior to Laparoscopic Sleeve Gastrectomy Surgery. PMID- 28589529 TI - Dietary Intake and Weight Changes 5 Years After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming a leading primary bariatric surgery but long-term outcome remains unclear. The amount of food eaten is drastically reduced after LSG and may lead to nutritional deficiencies potentially. The aim of this study is to investigate long-term dietary intake and weight status after LSG. METHODS: Forty patients underwent LSG had more than 5 year follow-up with complete clinical data and food frequency questionnaires were analyzed. RESULTS: The mean age of subjects is 33.5 years old with mean body mass index (BMI) 37.9 kg/m2. Mean BMI loss at 5 years after LSG is 10.6 kg/m2. Weight regain appeared in 20% of patients. Dietary composition analysis at 5 years showed mean calorie intake of 1230 kcal/day, protein 70 g/day (22.5% of calorie), fat 50 g/day (36.1%), carbohydrate 126 g (41.4%), iron 7.5 mg/day, calcium 536.2 mg/day, and fiber 11.7 g/day. Calorie intake at 5 years after LSG is correlated with weight loss but weight regain is not related to a higher calorie intake. All comorbidities were significantly improved after LSG but hemoglobin and parathyroid hormone significantly changed. Incidence of iron deficiency anemia increased from 7.5% at pre-operation to 41.2% after LSG. Incidence of secondary hyperparathyroidism increased from 17.5 to 60.7%. CONCLUSION: LSG is an effective and durable bariatric procedure but with significant changes in nutritional status. Dietary instruction for LSG should include foods rich in protein, iron, calcium, and fiber. PMID- 28589531 TI - How can clinical practices pragmatically increase physical activity for patients with type 2 diabetes? A systematic review. AB - Although regular physical activity (PA) is a cornerstone of treatment for type 2 diabetes (T2D), most adults with T2D are sedentary. Randomized controlled trials (RCTs) have proven the effectiveness of PA behavioral interventions for adults with T2D but have rarely been conducted in healthcare settings. We sought to identify PA interventions that are effective and practical to implement in clinical practice settings. Our first aim was to use the valid Pragmatic Explanatory Continuum Indicator Summary 2 (PRECIS-2) tool to assess the potential for future implementation of PA interventions in clinical practice settings. Our second aim was to identify interventions that effectively increased PA and glycemic control among the interventions in the top tertile of PRECIS-2 scores. We searched PubMed MEDLINE from January 1980 through May 2015 for RCTs of behavioral PA interventions coordinated by clinical practices for patients with T2D. Dual investigators assessed pragmatism by PRECIS-2 scores, and study effectiveness was extracted from original RCT publications. The PRECIS-2 scores of the 46 behavioral interventions (n = 13,575 participants) ranged from 3.0 to 4.8, where 5 is the most pragmatic score. In the most pragmatic tertile of interventions (n = 16) by PRECIS-2 scores, 30.8 and 31.3% of interventions improved PA outcomes and hemoglobin A1c, respectively. A minority of published evidence-based PA interventions for adults with T2D were both effective and pragmatic for clinical implementation. These should be tested for dissemination using implementation trial designs. PMID- 28589532 TI - Contextual factors related to implementation of classroom physical activity breaks. AB - Brief structured physical activity in the classroom is effective for increasing student physical activity. The present study investigated the association between implementation-related contextual factors and intervention implementation after adoption of a structured classroom physical activity intervention. Six elementary school districts adopted structured classroom physical activity programs in 2013 2014. Implementation contextual factors and intervention implementation (structured physical activity provided in past week or month, yes/no) were assessed using surveys of 337 classroom teachers from 24 schools. Mixed-effects models accounted for the nested design. Availability of resources (yes/no, ORs = 1.91-2.93) and implementation climate z-scores (ORs = 1.36-1.47) were consistently associated with implementation. Teacher-perceived classroom behavior benefits (OR = 1.29) but not student enjoyment or health benefits, and time (OR = 2.32) and academic (OR = 1.63) barriers but not student cooperation barriers were associated with implementation (all z-scores). Four implementation contextual factor composites had an additive association with implementation (OR = 1.64 for each additional favorable composite). Training and technical assistance alone may not support a large proportion of teachers to implement structured classroom physical activity. In addition to lack of time and interference with academic lessons, school climate related to whether administrators and other teachers were supportive of the intervention were key factors explaining whether teachers implemented the intervention. Evidence-based implementation strategies are needed for effectively communicating the benefits of classroom physical activity on student behavior and improving teacher and administrator climate/attitudes around classroom physical activity. PMID- 28589533 TI - Effects of exendin-4 and selenium on the expression of GLP-1R, IRS-1, and preproinsulin in the pancreas of diabetic rats. AB - The mechanisms by which exendin-4 and selenium exert their antidiabetic actions are still unclear. Here, we investigated the effects of exendin-4 or selenium administration on the expression of glucagon-like peptide-1 receptor (GLP-1R), insulin receptor substrate-1 (IRS-1), and preproinsulin in the pancreas of diabetic rats. Diabetes was induced by streptozotocin administration. Diabetic rats were injected intraperitoneally with 0.03 MUg exendin-4/kg body weight/daily or treated with 5 ppm selenium in drinking water for a period of 4 weeks. GLP-1R and IRS-1 levels were decreased while the level of preproinsulin messenger RNA (mRNA) was increased in the pancreas of diabetic untreated rats, as compared to that in control rats. Treatment of diabetic rats with exendin-4 increased protein and mRNA levels of GLP-1R, and IRS-1, and the mRNA level of preproinsulin in the pancreas, as compared to their levels in diabetic untreated rats. Selenium treatment of diabetic rats increased the pancreatic mRNA levels of GLP-1R, IRS-1, and preproinsulin. Exendin-4 or selenium treatment of diabetic rats also increased the numbers of pancreatic islets and GLP-1R molecules in the pancreas. Therefore, exendin-4 and selenium may exert their antidiabetic effects by increasing GLP-1R, IRS-1, and preproinsulin expression in the pancreas and by increasing the number of pancreatic islets. PMID- 28589534 TI - Noninvasive ventilation with helium-oxygen mixture in hypercapnic COPD exacerbation: aggregate meta-analysis of randomized controlled trials. AB - When used as a driving gas during NIV in hypercapnic COPD exacerbation, a helium oxygen (He/O2) mixture reduces the work of breathing and gas trapping. The potential for He/O2 to reduce the rate of NIV failure leading to intubation and invasive mechanical ventilation has been evaluated in several RCTs. The goal of this meta-analysis is to assess the effect of NIV driven by He/O2 compared to air/O2 on patient-centered outcomes in hypercapnic COPD exacerbation. Relevant RCTs were searched using standard procedures. The main endpoint was the rate of NIV failure. The effect size was computed by a fixed-effect model, and estimated as odds ratio (OR) with 95% confidence interval (CI). Additional endpoints were ICU mortality, NIV-related side effects, and the length and costs of ICU stay. Three RCTs fulfilled the selection criteria and enrolled a total of 772 patients (386 patients received He/O2 and 386 received air/O2). Pooled analysis showed no difference in the rate of NIV failure when using He/O2 mixture compared to air/O2: 17 vs 19.7%, respectively; OR 0.84, 95% CI 0.58-1.22; p = 0.36; I 2 for heterogeneity = 0%, and no publication bias. ICU mortality was also not different: OR 0.8, 95% CI 0.45-1.4; p = 0.43; I 2 = 5%. However, He/O2 was associated with less NIV-related adverse events (OR 0.56, 95% CI 0.4-0.8, p = 0.001), and a shorter length of ICU stay (difference in means = -1.07 day, 95% CI -2.14 to -0.004, p = 0.049). Total hospital costs entailed by hospital stay and NIV gas were not different: difference in means = -279$, 95% CI -2052-1493, p = 0.76. Compared to air/O2, He/O2 does not reduce the rate of NIV failure in hypercapnic COPD exacerbation. It is, however, associated with a lower incidence of NIV-related adverse events and a shortening of ICU length of stay with no increase in hospital costs. PMID- 28589536 TI - Distinguishing pathogenic mutations from background genetic noise in cardiology: The use of large genome databases for genetic interpretation. AB - Advances in clinical genetic testing have led to increased insight into the human genome, including how challenging it is to interpret rare genetic variation. In some cases, the ability to detect genetic mutations exceeds the ability to understand their clinical impact, limiting the advantage of these technologies. Obstacles in genomic medicine are many and include: understanding the level of certainty/uncertainty behind pathogenicity determination, the numerous different variant interpretation-guidelines used by clinical laboratories, delivering the certain or uncertain result to the patient, helping patients evaluate medical decisions in light of uncertainty regarding the consequence of the findings. Through publication of large publicly available exome/genome databases, researchers and physicians are now able to highlight dubious variants previously associated with different cardiac traits. Also, continuous efforts through data sharing, international collaborative efforts to develop disease-gene-specific guidelines, and computational analyses using large data, will indubitably assist in better variant interpretation and classification. This article discusses the current, and quickly changing, state of variant interpretation resources within cardiovascular genetic research, e.g., publicly available databases and ways of how cardiovascular genetic counselors and geneticists can aid in improving variant interpretation in cardiology. PMID- 28589535 TI - Low HDL levels in sepsis versus trauma patients in intensive care unit. AB - BACKGROUND: The protective cardiovascular effect of high-density lipoproteins (HDLs) is considered to chiefly rely on reverse cholesterol transport from peripheral tissues back to the liver. However, HDL particles display pleiotropic properties, including anti-inflammatory, anti-apoptotic or antioxidant functions. Some studies suggest that HDL concentration decreases during sepsis, and an association was reported between low HDL levels and a poor outcome. Like sepsis, trauma is also associated with a systemic inflammatory response syndrome. However, no study has yet explored changes in lipid profiles during trauma. We sought to compare lipid profiles between sepsis and trauma patients in intensive care unit (ICU). In septic patients, we analyzed the association between lipid profile, severity and prognosis. METHODS: A prospective, observational, single centered study was conducted in a surgical ICU. For each patient, total cholesterol, HDL, triglyceride and low-density lipoprotein cholesterol levels were assessed at admission. Short-term prognosis outcome was prospectively assessed. RESULTS: Seventy-five consecutive patients were admitted (50 sepsis and 25 trauma). There was no difference in SOFA and SAPSII scores between the two groups. Patients with sepsis had lower total cholesterol levels than patients with trauma. Regarding the lipoprotein profile, only HDLs differed significantly between the two groups (median [IQR] = 0.33 mmol/l [0.17-0.78] in sepsis patients versus median [IQR] = 0.99 mmol/l [0.74-1.28] in trauma patients; P < 0.0001). Whereas ICU mortality was not associated with lipid levels in the sepsis group, a significant negative correlation was found between HDL concentration and the length of ICU stay (r = -0.35; P = 0.03) in the group of survivor septic patients at ICU discharge. In addition, poor outcome defined as death or a SOFA score >6 at day 3 was associated with lower HDL levels (median [IQR] = 0.20 mmol/l [0.11 0.41] vs. 0.35 mmol/l [0.19-0.86] in patients with poor outcome versus others; P = 0.03). CONCLUSIONS: Lipid profile was totally different between sepsis and trauma in ICU patients: HDL levels were low in septic patients, whereas their concentration was not altered in trauma patients. This major difference reinforces the necessity to explore the therapeutic potential of HDL in sepsis. PMID- 28589537 TI - "Political co-authorships" in medical science journals. AB - The issue of co-author relationships on medical sciences journal publications has become more pronounced as advances in technology have enabled collaboration across countries and institutions to occur much more efficiently. These relationships often have underlying political motivations and outcomes, including career advancement, attempting to increase prestige of a project, and maintaining research grants. Some authors may be listed as senior or honorary authors despite offering little or no contribution to the original research project. This may be done in an effort to enhance the gravitas of a research project, and attain publication in a highly regarded medical journal. The current review covers the topic of political co-authorship and germane literature and lists strategies to combat this phenomenon. Such co-authorship practices corrupt the integrity of the research process as they attempt to bypass the safeguard that medical journals and institutions have put in place to prevent fraud and falsification. A number of strategies have been proposed to combat the practice of co-authorship, but it may ultimately be an unavoidable feature of contemporary medical research publishing that is difficult to police. Clin. Anat. 30:831-834, 2017. (c) 2017Wiley Periodicals, Inc. PMID- 28589539 TI - Extinction and time help drive the marine-terrestrial biodiversity gradient: is the ocean a deathtrap? AB - The marine-terrestrial richness gradient is among Earth's most dramatic biodiversity patterns, but its causes remain poorly understood. Here, we analyse detailed phylogenies of amniote clades, paleontological data and simulations to reveal the mechanisms underlying low marine richness, emphasising speciation, extinction and colonisation. We show that differences in diversification rates (speciation minus extinction) between habitats are often weak and inconsistent with observed richness patterns. Instead, the richness gradient is explained by limited time for speciation in marine habitats, since all extant marine clades are relatively young. Paleontological data show that older marine invasions have consistently ended in extinction. Simulations show that marine extinctions help drive the pattern of young, depauperate marine clades. This role for extinction is not discernible from molecular phylogenies alone, and not predicted by most previously hypothesised explanations for this gradient. Our results have important implications for the marine-terrestrial biodiversity gradient, and studies of biodiversity gradients in general. PMID- 28589540 TI - Depletion Mapping and Constrained Optimization to Support Managing Groundwater Extraction. AB - Groundwater models often serve as management tools to evaluate competing water uses including ecosystems, irrigated agriculture, industry, municipal supply, and others. Depletion potential mapping-showing the model-calculated potential impacts that wells have on stream baseflow-can form the basis for multiple potential management approaches in an oversubscribed basin. Specific management approaches can include scenarios proposed by stakeholders, systematic changes in well pumping based on depletion potential, and formal constrained optimization, which can be used to quantify the tradeoff between water use and stream baseflow. Variables such as the maximum amount of reduction allowed in each well and various groupings of wells using, for example, K-means clustering considering spatial proximity and depletion potential are considered. These approaches provide a potential starting point and guidance for resource managers and stakeholders to make decisions about groundwater management in a basin, spreading responsibility in different ways. We illustrate these approaches in the Little Plover River basin in central Wisconsin, United States-home to a rich agricultural tradition, with farmland and urban areas both in close proximity to a groundwater-dependent trout stream. Groundwater withdrawals have reduced baseflow supplying the Little Plover River below a legally established minimum. The techniques in this work were developed in response to engaged stakeholders with various interests and goals for the basin. They sought to develop a collaborative management plan at a watershed scale that restores the flow rate in the river in a manner that incorporates principles of shared governance and results in effective and minimally disruptive changes in groundwater extraction practices. PMID- 28589538 TI - Lentigo maligna of the face: A quantitative simple method to identify individual patient risk probability on dermoscopy. AB - BACKGROUND/OBJECTIVES: The clinical and dermoscopic differential diagnosis of flat pigmented facial lesions represents a great challenge for the clinicians. Our aim was to report a quantitative method based on dermoscopic features to better classify pigmented facial lesions. METHODS: This is a retrospective case series study that analysed the dermoscopic features of 582 pigmented facial lesions. RESULTS: The individual patient probability of lentigo maligna (LM) was predicted by a multivariate model, with an accuracy of 0.72. According to the odds ratio at the multivariate analysis, an individual scoring index was assigned to each criterion, and a value of 4.56 was identified as optimal cut-off point. Up to a score of 2.5, the probability that a lesion is an LM is 0. The probability increases from 10 to 50% for a score ranging between 4.5 and 6. It is about 90% for a score of 7. CONCLUSION: The optimal cut-off point obtained and the curve that identifies the probability of a patient having a LM could improve the classification and the management strategies of equivocal pigmented facial lesions. PMID- 28589542 TI - Is insulin the preferred treatment for HbA1c >9%? AB - The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are "symptomatic," referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naive people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c >11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c >9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent approaches are more effective than monotherapy, with a combination regimen the HbA1c reduction will not be directly additive, because the expected reduction decreases at lower baseline HbA1c levels. As an example of this, administration of canagliflozin 300 mg daily to patients with baseline HbA1c >9% reduced levels from 9.6% by 1.8%, whereas at a baseline HbA1c of 10% either canagliflozin 300 mg or metformin 2 g/day reduced HbA1c by 2%; the addition of both agents led to an HbA1c reduction by somewhat less than 3%, which appears concordant with a reduction by the second agent from approximately 8% (10% to 2%). Similar less-than-additive effects of the addition of exenatide QW to dapagliflozin have been reported, with HbA1c reduction from a baseline of 10.0%-10.1% of 1.9% and 1.6% with the individual agents, respectively, and a reduction of 2.2% with their combination. However, one may consider these approaches inferior to the expected HbA1c reduction with insulin, suggesting that insulin should, indeed, be the preferred treatment for people with T2D and HbA1c >9%. Rather, studies comparing basal insulin directly with glucagon-like peptide-1 (GLP-1) receptor agonists (RA) suggest that the latter agents may offer superior benefit. The Diabetes Therapy Utilization: Researching Changes in HBA1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly (DURATION)-3 and Liraglutide Effect and Action in Diabetes (LEAD)-5 studies compared exenatide QW and liraglutide, respectively, with insulin glargine. Those study participants in the highest quartile of baseline HbA1c had levels >=9.0% and >=8.9%, with the GLP-1RA leading to 0.3% and 0.2% greater reductions in HbA1c, respectively, than insulin glargine. Another study comparing T2D patients receiving oral agents given liraglutide with those given insulin glargine showed that those in the highest baseline HbA1c quartile (mean 10.6%) had an HbA1c reduction of 3.1% with either agent. In the exenatide QW study, the reduction in HbA1c with this agent exceeded that with insulin glargine for those groups of study participants with HbA1c 9.0%-9.4%, 9.5%-9.9%, 10.0%-10.4%, 10.5% 10.9%, and even >=11.0%. Similar superiority of the HbA1c-lowering effect of exenatide QW compared with that of insulin glargine was reported in a study with baseline HbA1c 8.5%. An individual-patient meta-analysis of six studies of another weekly GLP-1RA, namely dulaglutide, showed that at a baseline HbA1c of 10% the expected HbA1c reduction would be nearly 2.5%, and a study directly comparing dulaglutide with insulin glargine also showed a superior HbA1c-lowering effect of the former. Another advantage of the GLP-1RAs is their association with weight loss, rather than the weight gain associated with insulin treatment. An interesting potential combination is that of a GLP-1RA with a thiazolidinedione. In a study comparing the addition of exenatide QW and pioglitazone with the addition of basal-bolus insulin in 101 people receiving sulfonylureas and metformin with baseline HbA1c >10%, HbA1c fell from >11% by >4% compared with <4%, respectively, and the GLP-1RA plus thiazolidinedione treatment was associated with less weight gain and hypoglycemia. What can we conclude? Should HbA1c 11% be the new "use insulin" point? Insulin is an important part of our armamentarium for T2D, and is certainly needed for many patients, but with current therapeutic approaches including metformin, incretin-based treatments, SGLT2 inhibitors, and, possibly, thiazolidinediones, we can reconsider its use in many instances. Although there is no doubt that insulin is necessary for truly uncontrolled diabetes, we may wish to better define its correct indications. PMID- 28589541 TI - Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls. AB - BACKGROUND: The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS: Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS: Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS: NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies. PMID- 28589545 TI - Tonic immobility during sexual assault - a common reaction predicting post traumatic stress disorder and severe depression. AB - INTRODUCTION: Active resistance is considered to be the 'normal' reaction during rape. However, studies have indicated that similar to animals, humans exposed to extreme threat may react with a state of involuntary, temporary motor inhibition known as tonic immobility. The aim of the present study was to assess the occurrence of tonic immobility during rape and subsequent post-traumatic stress disorder and severe depression. MATERIAL AND METHODS: Tonic immobility at the time of the assault was assessed using the Tonic Immobility Scale in 298 women who had visited the Emergency clinic for raped women within 1 month of a sexual assault. Information about the assault and the victim characteristics were taken from the structured clinical data files. After 6 months, 189 women were assessed regarding the development of post-traumatic stress disorder and depression. RESULTS: Of the 298 women, 70% reported significant tonic immobility and 48% reported extreme tonic immobility during the assault. Tonic immobility was associated with the development of post-traumatic stress disorder (OR 2.75; 95% CI 1.50-5.03, p = 0.001) and severe depression (OR 3.42; 95% CI 1.51-7.72, p = 0.003) at 6 months. Further, previous trauma history (OR 2.36; 95% CI 1.48-3.77, p < 0.001) and psychiatric treatment history (OR 2.00; 95% CI 1.26-3.19, p = 0.003) were associated with the tonic immobility response. CONCLUSIONS: Tonic immobility during rape is a common reaction associated with subsequent post traumatic stress disorder and severe depression. Knowledge of this reaction in sexual assault victims is important in legal matters and for healthcare follow up. PMID- 28589544 TI - Accuracy of predictive ability measures for survival models. AB - One aspect of an analysis of survival data based on the proportional hazards model that has been receiving increasing attention is that of the predictive ability or explained variation of the model. A number of contending measures have been suggested, including one measure, R2 (beta), which has been proposed given its several desirable properties, including its capacity to accommodate time dependent covariates, a major feature of the model and one that gives rise to great generality. A thorough study of the properties of available measures, including the aforementioned measure, has been carried out recently. In that work, the authors used bootstrap techniques, particularly complex in the setting of censored data, in order to obtain estimates of precision. The motivation of this work is to provide analytical expressions of precision, in particular confidence interval estimates for R2 (beta). We use Taylor series approximations with and without local linearizing transforms. We also consider a very simple expression based on the Fisher's transformation. This latter approach has two great advantages. It is very easy and quick to calculate, and secondly, it can be obtained for any of the methods given in the recent review. A large simulation study is carried out to investigate the properties of the different methods. Finally, three well-known datasets in breast cancer, lymphoma and lung cancer research are given as illustrations. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589546 TI - Ulcerated nodules in the groin of an immunosuppressed patient. PMID- 28589547 TI - Preoperative exercise training for patients with non-small cell lung cancer. AB - BACKGROUND: Surgical resection for early stage non-small cell lung cancer (NSCLC) offers the best chance of cure, but is associated with a risk of postoperative pulmonary complications (i.e. pneumonia (new infiltrate coupled with either fever (> 38o C) and purulent secretions, or fever and white cell count > 11,000), bronchopleural fistula, severe atelectasis that requires chest physiotherapy or bronchoscopy, and prolonged mechanical ventilation (> 48 hours)). It is currently unclear if preoperative exercise training, and the potential resultant improvement in exercise capacity, may also improve postoperative outcomes, such as the risk of developing postoperative pulmonary complications, the length of postoperative intercostal drainage, or the length of hospital stay. OBJECTIVES: The primary aims of this study were to determine the effect of preoperative exercise training on postoperative outcomes, such as risk of developing a postoperative pulmonary complication, and postoperative duration of intercostal catheter use in adults scheduled to undergo lung resection for NSCLC. The secondary aims of this study were to determine the effect of preoperative exercise training on length of hospital stay, fatigue, dyspnoea, exercise capacity, lung function, and postoperative mortality. SEARCH METHODS: We searched CENTRAL, MEDLINE (PubMed), Embase Ovid, PEDro, and SciELO on the 28th of November 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in which study participants who were scheduled to undergo lung resection for NSCLC were allocated to receive either preoperative exercise training or no exercise training. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the studies and selected those for inclusion. We performed meta-analyses for the outcomes: risk of developing a postoperative pulmonary complication; postoperative duration of intercostal catheter; length of hospital stay; post intervention exercise capacity (6-minute walk distance), and post-intervention forced vital capacity (FVC). Although three studies reported post-intervention forced expiratory volume in 1 second (FEV1), we did not perform meta-analysis on this outcome due to significant statistical heterogeneity (I2 = 93%) across the studies. Data were not available for fatigue or dyspnoea. One study reported no in-hospital postoperative mortality in either the exercise or the non-exercise groups. MAIN RESULTS: We identified five RCTs involving 167 participants (mean age ranged from 54 to 72.5 years; sample size ranged from 19 to 60 participants). Overall, we found that the risk of bias in the included studies was high, and the quality of evidence for all outcomes was low. Pooled data from four studies demonstrated that preoperative exercise training reduced the risk of developing a postoperative pulmonary complication by 67% (risk ratio (RR) 0.33, 95% CI 0.17 to 0.61). The number of days patients in the exercise group needed an intercostal catheter was lower than in the non-exercise group (mean difference (MD) -3.33 days, 95% CI -5.35 to -1.30 days; two studies); postoperative length of hospital stay was also lower in the exercise group (MD -4.24 days, 95% CI -5.43 to -3.06 days; four studies). Pooled data from two studies demonstrated that compared to the non-exercise group, post-intervention 6-minute walk distance (MD 18.23 m, 95% CI 8.50 to 27.96 m), and post-intervention FVC (MD 2.97% predicted, 95% CI 1.78 to 4.16% predicted) were higher in the exercise group. AUTHORS' CONCLUSIONS: Preoperative exercise training may reduce the risk of developing a postoperative pulmonary complication, the duration of intercostal catheter use, postoperative length of hospital stay, and improve both exercise capacity and FVC in people undergoing lung resection for NSCLC. The findings of this review should be interpreted with caution due to disparities between the studies, risk of bias, and small sample sizes. This review emphasises the need for larger RCTs. PMID- 28589543 TI - Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis. AB - AIMS: To investigate the association between use of beta-blockers and beta blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. METHODS: Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged >=55 years. Fall incidents were recorded prospectively. Time-varying beta-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between beta blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. RESULTS: In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any beta-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective beta-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective beta-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other beta-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. CONCLUSION: Our study suggests that use of a nonselective beta blocker, contrary to selective beta-blockers, is associated with an increased fall risk in an older population. In clinical practice, beta-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a beta-blocker in this age group, and the pros and cons for beta-blocker classes should be taken into consideration. PMID- 28589548 TI - A pilot study of community-based self-sampling for HPV testing among non attenders of cervical cancer screening programs in El Salvador. AB - OBJECTIVE: To establish the feasibility and acceptability of home-based HPV self sampling among women who did not attend screening appointments in rural El Salvador. METHODS: In a cross-sectional study, data were collected from May 2015 to January 2016 among 60 women aged 30-59 years who were not pregnant, provided informed consent, had not been screened in 2 years, had no history of pre-cancer treatment, and did not attend a scheduled HPV screening. Participants completed questionnaires and received educational information before being given an opportunity to self-sample with the Hybrid Capture 2 High Risk HPV DNA Test. RESULTS: Self-sampling was accepted by 41 (68%) participants. Almost all women chose to self-sample because the process was easy (40/41, 98%), could be performed at home (40/41, 98%), and saved time (38/41, 93%), and because they felt less embarrassed (33/41, 80%). The most common reason for declining the test was not wanting to be screened (8/19, 42%). The prevalence of high-risk HPV types among women who accepted self-sampling was 17% (7/41). CONCLUSION: For most women, community-based self-sampling was an acceptable way to participate in a cervical cancer screening program. In low-resource countries, incorporating community-based self-sampling into screening programs might improve coverage of high-risk women. PMID- 28589549 TI - Quantitative analysis Of hepatocellular adenoma and focal nodular hyperplasia in the hepatobiliary phase: External validation of LLCER method using gadobenate dimeglumine as contrast agent. PMID- 28589550 TI - Characterization of a "low-risk" cohort of grade group 2 prostate cancer patients: Results from the Shared Equal Access Regional Cancer Hospital database. AB - OBJECTIVES: To examine if there is a subset of men with grade group 2 prostate cancer who could be potential candidates for active surveillance. METHODS: We used the Shared Equal Access Regional Cancer Hospital database to identify 776 men undergoing radical prostatectomy from 2006 to 2015 with >8 biopsy cores obtained and complete information. We compared men who fulfilled low-risk disease criteria (clinical stage T1c/T2a; grade group 1; prostate-specific antigen <=10 ng/mL) with the exception of grade group 2 versus men who met all three low-risk criteria. Logistic regression was used to test the association between grade group and radical prostatectomy pathological features. Biochemical recurrence was examined using Cox models. To examine whether there was a subset of men with low volume grade group 2 with comparable outcomes to low-risk men, we repeated all analyses limiting the percentage of positive cores in the grade group 2 group to <=33%, and positive cores to <=4, <=3 or <=2. RESULTS: Grade group 2 low-risk men had increased risk of pathological grade group 3 or higher (P < 0.001), extraprostatic extension (P < 0.001), seminal vesicle invasion (P < 0.001) and higher risk of biochemical recurrence (hazard ratio = 1.76, P = 0.006). Using increasingly strict definitions of low-volume disease, at <=2 positive cores there was no difference in adverse pathology between groups (all P > 0.2), except higher pathological grade group (P = 0.006). Biochemical recurrence was similar in men in grade group 1 and grade group 2 (hazard ratio = 1.24; P = 0.529). CONCLUSIONS: Among men with prostate-specific antigen <=10 ng/mL and clinical stage T1c/T2a, those in grade group 2 with <=2 total positive cores have similar rates of adverse pathology and biochemical recurrence as men with grade group 1. PMID- 28589552 TI - Urinary incontinence and quality of life of women living in nursing homes in the Mediterranean region of Turkey. AB - BACKGROUND: This study was conducted to determine the effect of urinary incontinence (UI) on the quality of life of women living in nursing homes in the Mediterranean region of Turkey. METHODS: The study was conducted on 95 women living in nursing homes in the Mediterranean region. Data were collected from a questionnaire on sociodemographic characteristics, the Urinary Incontinence Quality of Life Scale, the Index of Activities of Daily Living, and the International Consultation on Incontinence Questionnaire Short Form. RESULTS: The quality of life of women who did not consider UI a health problem was significantly higher than that of those who considered otherwise. Mixed UI was the most common UI type among the women living in nursing homes, with a rate of 31.7%. According to the overall mean scores on the Urinary Incontinence Quality of Life Scale, quality of life was the most affected among women who had nocturnal incontinence. Quality of life was affected from most to least by the mixed type, stress type, and urge type of incontinence. CONCLUSION: Early diagnosis and treatment of UI could be improved if health professionals, who have a unique role in changing the perception of society, offered training to women experiencing incontinence. Identifying this problem and determining and preventing the risk factors are important for enhancing women's quality of life. PMID- 28589553 TI - Hypomegakaryocytic thrombocytopenia and increased number of PNH-phenotype cells - an emerging subgroup of myelodysplastic syndrome showing frequent response to immunosuppression - RESPONSE to Rafferty & Leach. PMID- 28589554 TI - Vesiculobullous melanoma: an unusual manifestation of in-transit metastasis. AB - Malignant melanoma (MM), a well-known skin cancer with a poor prognosis, has various clinical manifestations, but vesiculobullous lesions have seldom been reported. We report a case of MM forming amelanotic vesicles at the site of an in transit metastasis, and we also review the published reports on vesiculobullous MM. Our patient was an 87-year-old man with a history of a treated plantar MM 2 years previously, who had recurrence of the MM and development of an in-transit metastasis in his lower leg. Histopathological findings revealed vesicles caused by infiltration of the tumour. A review of the English literature revealed nine cases with various clinical presentations of the vesicles or blisters. For patients with MM with vesiculobullous lesions, an accurate medical history and examination of biopsies are of primary importance for management. PMID- 28589551 TI - Centre characteristics and procedure-related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: a retrospective analysis from the European Society for Blood and Marrow Transplantation (EBMT). AB - The best approach for allogeneic haematopoietic stem cell transplantations (alloHCT) in patients with chronic lymphocytic leukaemia (CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival (EFS) in a large retrospective study. Data of 684 CLL patients who received a first alloHCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [CI], 34-42%). Larger numbers of CLL alloHCTs (hazard ratio [HR] 0.96, P = 0.002), certification of quality management (HR 0.7, P = 0.045) and a higher gross national income per capita (HR 0.4, P = 0.04) improved EFS. In vivo T-cell depletion (TCD) with alemtuzumab compared to no TCD (HR 1.5, P = 0.03), and a female donor compared to a male donor for a male patient (HR 1.4, P = 0.02) had a negative impact on EFS, but not non myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL. PMID- 28589555 TI - Common and Distinctive Functions of the Hippo Effectors Taz and Yap in Skeletal Muscle Stem Cell Function. AB - Hippo pathway downstream effectors Yap and Taz play key roles in cell proliferation and regeneration, regulating gene expression especially via Tead transcription factors. To investigate their role in skeletal muscle stem cells, we analyzed Taz in vivo and ex vivo in comparison with Yap. Small interfering RNA knockdown or retroviral-mediated expression of wild-type human or constitutively active TAZ mutants in satellite cells showed that TAZ promoted proliferation, a function shared with YAP. However, at later stages of myogenesis, TAZ also enhanced myogenic differentiation of myoblasts, whereas YAP inhibits such differentiation. Functionally, while muscle growth was mildly affected in Taz (gene Wwtr1-/- ) knockout mice, there were no overt effects on regeneration. Conversely, conditional knockout of Yap in satellite cells of Pax7Cre-ERT2/+ : Yapfl degrees x/fl degrees x :Rosa26Lacz mice produced a regeneration deficit. To identify potential mechanisms, microarray analysis showed many common TAZ/YAP target genes, but TAZ also regulates some genes independently of YAP, including myogenic genes such as Pax7, Myf5, and Myod1 (ArrayExpress-E-MTAB-5395). Proteomic analysis revealed many novel binding partners of TAZ/YAP in myogenic cells, but TAZ also interacts with proteins distinct from YAP that are often involved in myogenesis and aspects of cytoskeleton organization (ProteomeXchange PXD005751). Neither TAZ nor YAP bind members of the Wnt destruction complex but both regulated expression of Wnt and Wnt-cross talking genes with known roles in myogenesis. Finally, TAZ operates through Tead4 to enhance myogenic differentiation. In summary, Taz and Yap have overlapping functions in promoting myoblast proliferation but Taz then switches to enhance myogenic differentiation. Stem Cells 2017;35:1958-1972. PMID- 28589557 TI - Does a blood pressure J curve exist for patients with chronic kidney disease? AB - Aggressive reduction of blood pressure may increase cardiovascular events (the J curve phenomenon) in certain populations. In this regard, most studies in patients with chronic kidney disease have shown a J curve for cardiovascular morbidity and mortality, and this phenomenon persists after adjusting for confounding factors. Since there is no evidence that a straighter blood pressure target (<130/70 mm Hg) could improve renal outcomes, the increased cardiovascular risk associated with extreme blood pressure reduction should be seen as undesirable. Moreover, the intensive control of blood pressure may induce an unintended reduction of renal function and this decrease, in turn, may increase cardiovascular risk. PMID- 28589558 TI - Potential applications and human biosafety of nanomaterials used in nanomedicine. AB - With the rapid development of nanotechnology, potential applications of nanomaterials in medicine have been widely researched in recent years. Nanomaterials themselves can be used as image agents or therapeutic drugs, and for drug and gene delivery, biological devices, nanoelectronic biosensors or molecular nanotechnology. As the composition, morphology, chemical properties, implant sites as well as potential applications become more and more complex, human biosafety of nanomaterials for clinical use has become a major concern. If nanoparticles accumulate in the human body or interact with the body molecules or chemical components, health risks may also occur. Accordingly, the unique chemical and physical properties, potential applications in medical fields, as well as human biosafety in clinical trials are reviewed in this study. Finally, this article tries to give some suggestions for future work in nanomedicine research. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589556 TI - Characterization of functional MU opioid receptor turnover in rat locus coeruleus: an electrophysiological and immunocytochemical study. AB - BACKGROUND AND PURPOSE: Regulation of MU receptor dynamics such as its trafficking is a possible mechanism underlying opioid tolerance that contributes to inefficient recycling of opioid responses. We aimed to characterize the functional turnover of MU receptors in the noradrenergic nucleus locus coeruleus (LC). EXPERIMENTAL APPROACH: We measured opioid effect by single-unit extracellular recordings of LC neurons from rat brain slices. Immunocytochemical techniques were used to evaluate MU receptor trafficking. KEY RESULTS: After near complete, irreversible MU receptor inactivation with beta-funaltrexamine (beta FNA), opioid effect spontaneously recovered in a rapid and efficacious manner. In contrast, alpha2 -adrenoceptor-mediated effect hardly recovered after receptor inactivation with the irreversible antagonist EEDQ. When the recovery of opioid effect was tested after various inactivating time schedules, we found that the longer the beta-FNA pre-exposure, the less efficient and slower the functional MU receptor turnover became. Interestingly, MU receptor turnover was slower when beta-FNA challenge was repeated in the same cell, indicating constitutive MU receptor recycling by trafficking from a depletable pool. Double immunocytochemistry confirmed the constitutive nature of MU receptor trafficking from a cytoplasmic compartment. The MU receptor turnover was slowed down when LC neuron calcium- or firing-dependent processes were prevented or vesicular protein trafficking was blocked by a low temperature or transport inhibitor. CONCLUSIONS AND IMPLICATIONS: Constitutive trafficking of MU receptors from a depletable intracellular pool (endosome) may account for its rapid and efficient functional turnover in the LC. A finely-tuned regulation of MU receptor trafficking and endosomes could explain neuroadaptive plasticity to opioids in the LC. PMID- 28589559 TI - Thyroid autoimmunity in patients with hidradenitis suppurativa: a case-control study. AB - The aetiopathogenesis of hidradenitis suppurativa (HS) is not fully understood; however, increasing evidence suggests that it may be an immune-mediated disorder. Autoimmune thyroid disease (AITD) has classically been considered as the 'paradigm' of autoimmunity, and it has been linked to a variety of skin disorders. To our knowledge, the prevalence of AITD has not been investigated in patients with HS. The aim of the present study was to assess and compare, for the first time, the prevalence of thyroid autoimmunity in 70 patients with HS and in 70 age- and sex-matched controls. In all participants, thyroid autoantibodies and thyroid function tests were analysed. No statistically significant difference was detected between patients with HS and controls, either for the prevalence of thyroid antibodies or for thyroid function parameters. This lack of an association between HS and thyroid autoimmunity suggests that conventional autoimmune mechanisms may not be implicated in the pathogenesis of HS. PMID- 28589560 TI - Religious Coping and Glycemic Control in Couples with Type 2 Diabetes. AB - This study examines the role of religious coping in couples' diabetes management processes. Eighty-seven couples where one spouse had type 2 diabetes were surveyed. The relationships between religious coping (positive and negative), shared glycemic control activities (e.g., planning a healthy diet), and glycemic control were examined using repeated measures ANOVA and SEM. Findings show spousal engagement in shared activities is significantly associated with glycemic control. Furthermore, the use of negative religious coping by the diabetic spouse, and positive religious coping by the nondiabetic spouse, related to lower levels and higher levels of shared glycemic control activities, respectively. Religious coping and shared glycemic control activities appear integral to couples managing type 2 diabetes and, may serve as useful points of intervention. PMID- 28589561 TI - Computer-assisted Orthopaedic Surgery. AB - Nowadays, operating rooms can be inefficient and overcrowded. Patient data and images are at times not well integrated and displayed in a timely fashion. This lack of coordination may cause further reductions in efficiency, jeopardize patient safety, and increase costs. Fortunately, technology has much to offer the surgical disciplines and the ongoing and recent operating room innovations have advanced preoperative planning and surgical procedures by providing visual, navigational, and mechanical computerized assistance. The field of computer assisted surgery (CAS) broadly refers to surgical interface between surgeons and machines. It is also part of the ongoing initiatives to move away from invasive to less invasive or even noninvasive procedures. CAS can be applied preoperatively, intraoperatively, and/or postoperatively to improve the outcome of orthopaedic surgical procedures as it has the potential for greater precision, control, and flexibility in carrying out surgical tasks, and enables much better visualization of the operating field than conventional methods have afforded. CAS is an active research discipline, which brings together orthopaedic practitioners with traditional technical disciplines such as engineering, computer science, and robotics. However, to achieve the best outcomes, teamwork, open communication, and willingness to adapt and adopt new skills and processes are critical. Because of the relatively short time period over which CAS has developed, long-term follow-up studies have not yet been possible. Consequently, this review aims to outline current CAS applications, limitations, and promising future developments that will continue to impact the operating room (OR) environment and the OR in the future, particularly within orthopedic and spine surgery. PMID- 28589562 TI - The complete genome sequence of Exiguobacterium arabatum W-01 reveals potential probiotic functions. AB - Shrimp is extensively cultured worldwide. Shrimp farming is suffering from a variety of diseases. Probiotics are considered to be one of the effective methods to prevent and cure shrimp diseases. Exiguobacterium arabatum W-01, a gram positive and orange-pigmented bacterium, was isolated from the intestine of a healthy Penaeus vannamei specimen. Whole-genome sequencing revealed a genome of 2,914,854 bp, with 48.02% GC content. In total, 3,083 open reading frames (ORFs) were identified, with an average length of 843.98 bp and a mean GC content of 48.11%, accounting for 89.27% of the genome. Among these ORFs, 2,884 (93.5%) genes were classified into Clusters of Orthologous Groups (COG) families comprising 21 functional categories, and 1,650 ORFs were classified into 83 functional Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. A total of 27 rRNA operons and 68 tRNAs were identified, with all 20 amino acids represented. In addition, 91 genomic islands, 68 potential prophages, and 33 tandem repeats, but no clustered regularly interspaced short palindromic repeats (CRISPRs), were found. No resistance genes and only one virulence gene were identified. Among the 150 secreted proteins of E. arabatum W-01, a variety of transport system substrate-binding proteins, enzymes, and biosynthetic proteins, which play important roles in the uptake and metabolism of nutrients, were found. Two adherence-related protein genes and 31 flagellum-related protein genes were also identified. Taken together, these results indicate potential probiotic functions for E. arabatum W-01. PMID- 28589563 TI - BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. AB - We propose a flexible Bayesian optimal phase II (BOP2) design that is capable of handling simple (e.g., binary) and complicated (e.g., ordinal, nested, and co primary) endpoints under a unified framework. We use a Dirichlet-multinomial model to accommodate different types of endpoints. At each interim, the go/no-go decision is made by evaluating a set of posterior probabilities of the events of interest, which is optimized to maximize power or minimize the number of patients under the null hypothesis. Unlike other existing Bayesian designs, the BOP2 design explicitly controls the type I error rate, thereby bridging the gap between Bayesian designs and frequentist designs. In addition, the stopping boundary of the BOP2 design can be enumerated prior to the onset of the trial. These features make the BOP2 design accessible to a wide range of users and regulatory agencies and particularly easy to implement in practice. Simulation studies show that the BOP2 design has favorable operating characteristics with higher power and lower risk of incorrectly terminating the trial than some existing Bayesian phase II designs. The software to implement the BOP2 design is freely available at www.trialdesign.org. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589564 TI - Editorial Comment to Robot-assisted laparoscopic versus open partial nephrectomy in patients with chronic kidney disease: A propensity score-matched comparative analysis of surgical outcomes. PMID- 28589565 TI - Detailed analysis of the Japanese version of the Rapid Dementia Screening Test, revised version. AB - AIM: The number-transcoding task on the Japanese version of the Rapid Dementia Screening Test (RDST-J) requires mutual conversion between Arabic and Chinese numerals (209 to , 4054 to , to 681, to 2027). In this task, question and answer styles of Chinese numerals are written horizontally. We investigated the impact of changing the task so that Chinese numerals are written vertically. METHODS: Subjects were 211 patients with very mild to severe Alzheimer's disease and 42 normal controls. Mini-Mental State Examination scores ranged from 26 to 12, and Clinical Dementia Rating scores ranged from 0.5 to 3. RESULTS: Scores of all four subtasks of the transcoding task significantly improved in the revised version compared with the original version. The sensitivity and specificity of total scores >=9 on the RDST-J original and revised versions for discriminating between controls and subjects with Clinical Dementia Rating scores of 0.5 were 63.8% and 76.6% on the original and 60.1% and 85.8% on revised version. CONCLUSIONS: The revised RDST-J total score had low sensitivity and high specificity compared with the original RDST-J for discriminating subjects with Clinical Dementia Rating scores of 0.5 from controls. PMID- 28589566 TI - Prevalence of optimal valve morphology for MitraClip in patients with mitral regurgitation. AB - AIMS: To evaluate how often patients with moderate-to-severe or severe mitral regurgitation (MR) meet the anatomical criteria for MitraClip implant and to examine the role of transthoracic echocardiography (TTE) for this task. METHODS AND RESULTS: From February to June 2015, all patients undergoing a TTE in nine Spanish hospitals were prospectively included. Patients with moderate-to-severe and severe mitral regurgitation were selected for analysis. Anatomical eligibility criteria for MitraClip were defined according to the EVEREST trial. A total of 39 855 consecutive TTE were reviewed, and 1403 patients with moderate-to severe and severe MR were finally included. Primary MR was found in 779 patients (56%). Only in 74 patients (16%), all anatomical criteria for MitraClip could be assessed by TTE. Of these, 56% of patients had optimal valve morphology. Secondary MR was described in 361 patients (26%), and at least 249 of these (69%) had a high surgical risk. All five criteria for MitraClip were adequately assessed by TTE in 299 patients (83%). Of them, 118 patients (39%) had optimal valve morphology. CONCLUSIONS: A considerable proportion of patients have optimal mitral valve morphology for MitraClip. Moreover, TTE was particularly useful in determining whether or not the anatomical criteria for MitraClip implant were met in the majority of patients with secondary MR but in only a minority of those with primary MR. PMID- 28589567 TI - Particulate matter air pollution and liver cancer survival. AB - Particulate matter (PM) air pollution exposure has been associated with cancer incidence and mortality especially with lung cancer. The liver is another organ possibly affected by PM due to its role in detoxifying xenobiotics absorbed from PM. Various studies have investigated the mechanistic pathways between inhaled pollutants and liver damage, cancer incidence, and tumor progression. However, little is known about the effects of PM on liver cancer survival. Twenty thousand, two hundred and twenty-one California Cancer Registry patients with hepatocellular carcinoma (HCC) diagnosed between 2000 and 2009 were used to examine the effect of exposure to ambient PM with diameter <2.5 MUm (PM2.5 ) on HCC survival. Cox proportional hazards models were used to estimate hazard ratios (HRs) relating PM2.5 to all-cause and liver cancer-specific mortality linearly and nonlinearly-overall and stratified by stage at diagnosis (local, regional and distant)-adjusting for potential individual and geospatial confounders.PM2.5 exposure after diagnosis was statistically significantly associated with HCC survival. After adjustment for potential confounders, the all-cause mortality HR associated with a 1 standard deviation (5.0 ug/m3 ) increase in PM2.5 was 1.18 (95% CI: 1.16-1.20); 1.31 (95% CI:1.26-1.35) for local stage, 1.19 (95% CI:1.14 1.23) for regional stage, and 1.05 (95% CI:1.01-1.10) for distant stage. These associations were nonlinear, with substantially larger HRs at higher exposures. The associations between liver cancer-specific mortality and PM2.5 were slightly attenuated compared to all-cause mortality, but with the same patterns.Exposure to elevated PM2.5 after the diagnosis of HCC may shorten survival, with larger effects at higher concentrations. PMID- 28589570 TI - Transapical transcatheter valve-in-ring implantation following mitral annuloplasty. AB - Despite advances in surgical techniques for mitral valve repair, more than 20% of patients require reoperation within 10 years due to recurrence of severe mitral regurgitation. However, reoperations on the mitral valve are often associated with increased morbidity and mortality. We report a transapical mitral valve-in ring implantation in a patient who had undergone mitral valve repair for ischemic mitral regurgitation using a complete semi-rigid Memo 3D mitral ring (LivaNova Group, Milan, Italy). PMID- 28589569 TI - Identification of novel BCL11A variants in patients with epileptic encephalopathy: Expanding the phenotypic spectrum. AB - BCL11A encodes a zinc finger protein that is highly expressed in hematopoietic tissues and the brain, and that is known to function as a transcriptional repressor of fetal hemoglobin (HbF). Recently, de novo variants in BCL11A have been reported in individuals with intellectual disability syndrome without epilepsy. In this study, we performed whole-exome sequencing of 302 patients with epileptic encephalopathies (EEs), and identified 2 novel BCL11A variants, c.577delC (p.His193Metfs*3) and c.2351A>C (p.Lys784Thr). Both the patients shared major physical features characteristic of BCL11A-related intellectual disability syndrome, suggesting that characteristic physical features and the persistence of HbF should lead clinicians to suspect EEs caused by BCL11A pathogenic variants. Patient 1, with a frameshift variant, presented with Lennox-Gastaut syndrome, which expands the phenotypic spectrum of BCL11A haploinsufficiency. Patient 2, with a p.Lys784Thr variant, presented with West syndrome followed by drug resistant focal seizures and more severe developmental disability. These 2 newly described patients contribute to delineating the associated, yet uncertain phenotypic characteristics of BCL11A disease-causing variants. PMID- 28589568 TI - Ionic-Liquid-Assisted Microwave Synthesis of Solid Solutions of Sr1-x Bax SnO3 Perovskite for Photocatalytic Applications. AB - Nanocrystalline Sr1-x Bax SnO3 (x=0, 0.2, 0.4, 0.8, 1) perovskite photocatalysts were prepared by microwave synthesis in an ionic liquid (IL) and subsequent heat treatment. The influence of the Sr/Ba substitution on the structure, crystallization, morphology, and photocatalytic efficiency was investigated and the samples were fully characterized. On the basis of X-ray diffraction results, as the Ba content in the SrSnO3 lattice increases, a symmetry increase was observed from the orthorhombic perovskite structure for SrSnO3 to the cubic BaSnO3 structure. The analysis of the sample morphology by SEM reveals that the Sr1-x Bax SnO3 samples favor the formation of nanorods (500 nm-5 MUm in diameter and several micrometers long). The photophysical properties were examined by UV/Vis diffuse reflectance spectroscopy. The band gap decreases from 3.85 to 3.19 eV with increasing Ba2+ content. Furthermore, the photocatalytic properties were evaluated for the hydroxylation of terephthalic acid (TA). The order of the activities for TA hydroxylation was Sr0.8 Ba0.2 SnO3 >SrSnO3 >BaSnO3 >Sr0.6 Ba0.4 SnO3 >Sr0.2 Ba0.8 SnO3 . The highest photocatalytic activity was observed for Sr0.8 Ba0.2 SnO3 , and this can be attributed to the synergistic impacts of the modification of the crystal structure and morphology, the relatively large surface area associated with the small crystallite size, and the suitable band gap and band-edge position. PMID- 28589572 TI - Harnessing White-Light Luminescence via Tunable Singlet-and Triplet-Derived Emissions Based on Gold(III) Complexes. AB - White light emitting gold(III) complexes were synthesized by tuning the percentage of metal dpi contribution in the charge transfer. This was achieved through specific tailoring of the ligand scaffold, which led to increase in the HOMO pi-energy properties, resulting in a decrease of efficiency on the intersystem crossing (ISC). As a consequence, monomolecular based singlet- and triplet-derived emission covering the entire visible spectrum with quantum yield up to 28 % and CIE-1931 chromaticity coordinates of (0.29, 0.33) to (0.32, 0.40) could be obtained. Furthermore, two complexes displayed excitation-dependent emission property due to hyper-ISC allowing the regulation of the ratio between fluorescence versus phosphorescence intensity and accomplish precise tuning of white light emission. PMID- 28589571 TI - Laparoscopic total pancreatectomy for multiple endocrine neoplasia type 1 syndrome-associated multifocal, non-functioning pancreatic neuroendocrine tumor: A case report. AB - Pancreatic neuroendocrine tumors are rare, accounting for less than 3% of all pancreatic tumors. Although laparoscopic pancreas-preserving surgery for managing sporadic pancreatic neuroendocrine tumors has been described in the literature, laparoscopic total pancreatectomy has rarely been reported. We present a 30-year old man who was incidentally diagnosed with multiple endocrine neoplasia type 1 syndrome with parathyroid hyperplasia and a non-functioning pancreatic neuroendocrine tumor. He underwent laparoscopic total pancreatectomy with splenectomy. This report highlights the technical details of laparoscopic total pancreatectomy, which appears to be a feasible and safe option in select cases. PMID- 28589574 TI - Editorial: the diminishing returns of normalisation of the oesophageal mucosa. PMID- 28589575 TI - Corrigendum. PMID- 28589573 TI - In vitro and in vivo effect of flutamide on steroid hormone secretion in canine and human inflammatory breast cancer cell lines. AB - The aim was to study the effects of flutamide on cell proliferation, in vivo tumour growth and steroid production in canine and human IBC cell lines. IPC-366 and SUM149 cell cultures were exposed to flutamide concentrations for 72 hours. Additionally, IPC-366 and SUM149 xenotransplanted mice were treated subcutaneously with flutamide 3 times a week for 2 weeks. Steroid hormones determination in culture media, serum and tumour homogenates (pregnenolone, progesterone, androstenedione, testosterone, dihydrotestosterone, 17beta oestradiol and oestrone sulphate) were assayed by EIA. in vitro cell proliferation percentages showed a decrease in all flutamide dosages in IPC-366 and SUM149. in vivo flutamide reduced tumour size by 55% to 65%, and metastasis rates decreased. In treated groups, androgen levels in culture media, serum and tumour homogenates were increased as oestrogen levels decreased. These results suggest that flutamide treatment inhibits cell proliferation and promotes tumour reduction by increasing androgen levels and also support future therapy approaches. PMID- 28589576 TI - Editorial: non-alcoholic fatty liver disease-a pandemic in need of novel treatments and endpoints. PMID- 28589577 TI - Letter: determining the dominant role of environmental factors in UC development. PMID- 28589578 TI - Editorial: functional dyspepsia-a disorder of duodenal permeability? PMID- 28589579 TI - Editorial: tacrolimus-how low can you go? PMID- 28589580 TI - Letter: sublingual dosing of tacrolimus in transplant patients-interesting concept to overcome first pass effects. Authors' reply. PMID- 28589582 TI - Letter: determining the dominant role of environmental factors in UC development Authors' reply. PMID- 28589583 TI - Editorial: the diminishing returns of normalisation of the oesophageal mucosa Authors' reply. PMID- 28589584 TI - Editorial: developing a stimulation test to identify FGF19 deficiency in bile acid diarrhoea. PMID- 28589585 TI - Editorial: the Millennium study cohort-evaluating environmental determinates of IBD in the 21st century. PMID- 28589586 TI - Editorial: the Millennium study cohort-evaluating environmental determinates of IBD in the 21st Century. Authors' reply. PMID- 28589587 TI - Letter: the efficacy of interferon-free regimens in HCV-related Child C cirrhosis needs careful interpretation-Authors' reply. PMID- 28589588 TI - Editorial: biologics in inflammatory bowel disease-time for direct comparisons. PMID- 28589589 TI - Letter: the efficacy of interferon-free regimens in HCV-related Child C cirrhosis needs careful interpretation. PMID- 28589591 TI - Editorial: should we recommend oesophageal biopsies for all patients with symptoms suggestive of GERD? PMID- 28589590 TI - Letter: should Barrett's oesophagus be considered a potential cardiovascular risk factor? PMID- 28589592 TI - Letter: sublingual dosing of tacrolimus in transplant patients-interesting concept to overcome first pass effects. PMID- 28589593 TI - Editorial: repeat duodenal biopsy for patients with coeliac disease-physician heal thyself and dietitian heal the patient! PMID- 28589594 TI - An unusual case of idiopathic localized giant cell lichenoid dermatitis. PMID- 28589595 TI - High-Speed Counter-Current Chromatography with an Online Storage Technique for the Preparative Isolation and Purification of Dihydroflavonoids from Sophora alopecuroides L. AB - INTRODUCTION: High-speed counter-current chromatography (HSCCC) is an efficient and non-absorption separation technique, but limitations still exist in simultaneous isolation of complex structures of natural products. Moreover, particular methods are various for different kinds of natural products. OBJECTIVE: A novel HSCCC strategy combined with an online storage recycling elution (OSR-CCC) technique was developed for the quick separation of naturally occurring dihydroflavonoids from the extract of the herb Sophora alopecuroides L. METHODOLOGY: In the separation procedure, a storage loop and two six-port valves were connected to a HSCCC system. Effluent A was subjected to an online storage loop and then to recycling separation three times after effluent B was collected in head-to-tail mode. After completion of the recycling separation of effluent A, the elution was switched to tail-to-head mode to collect effluent C. A biphasic solvent system of n-hexane/ethyl acetate/methanol/water (9:6:6:8, v/v/v/v) was used as the separation solvent during the whole elution. RESULTS: Six constituents were isolated simultaneously from the extract (200 mg) of S. alopecuroides by running HSCCC non-stop, and their purities were higher than 95.0%. Their structures were determined as the pterocarpan glycoside sophoratonkin (1) (10.0 mg) and five dihydroflavonoids, alopecurone F (2) (5.4 mg), lehmannin (3) (11.0 mg), alopecurone A (4) (35.0 mg), sophoraflavanone G (5) (21.0 mg), alopecurone B (6) (31.0 mg). CONCLUSION: This recycling HSCCC method combined with an online storage technique could be a rapid, effective and simple approach to isolate stilbene-dihydroflavonoids from herbs of the Sophora genus simultaneously. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589596 TI - Amorphous Nickel-Cobalt-Borate Nanosheet Arrays for Efficient and Durable Water Oxidation Electrocatalysis under Near-Neutral Conditions. AB - Electrolytic hydrogen generation needs earth-abundant oxygen evolution reaction electrocatalysts that perform efficiently at mild pH. Here, the development of amorphous nickel-cobalt-borate nanosheet arrays on macroporous nickel foam (NiCo Bi/NF) as a 3D catalyst electrode for high-performance water oxidation in near neutral media is reported. To drive a current density of 10 mA cm-2 , the resulting NiCo-Bi/NF demands an overpotential of only 430 mV in 0.1 m potassium borate (K-Bi, pH 9.2). Moreover, it also shows long-term electrochemical durability with maintenance of catalytic activity for 20 h, achieving a high turnover frequency of 0.21 s-1 at an overpotential of 550 mV. PMID- 28589597 TI - How the Trump Administration's Policies May Harm the Public's Health. PMID- 28589599 TI - A Blow for Sanity: Guns, Children, and the Courts. PMID- 28589601 TI - "America First": Prospects for Global Health. PMID- 28589600 TI - Timing and Characteristics of Cumulative Evidence Available on Novel Therapeutic Agents Receiving Food and Drug Administration Accelerated Approval. AB - : Policy Points: Randomized trials-the gold standard of evaluating effectiveness constitute a small minority of existing evidence on agents given accelerated approval. One-third of randomized trials are in therapeutic areas outside of FDA approval and less than half evaluate the therapeutic benefits of these agents but use them instead as common backbone treatments. Agents receiving accelerated approval are often tested concurrently in several therapeutic areas. For most agents, no substantial time lag is apparent between the average start dates of randomized trials evaluating their effectiveness and those using them as part of background therapies. There appears to be a tendency for therapeutic agents receiving accelerated approval to quickly become an integral component of standard treatment, despite potential shortcomings in their evidence base. CONTEXT: Therapeutic agents treating serious conditions are eligible for Food and Drug Administration (FDA) accelerated approval. The clinical evidence accrued on agents receiving accelerated approval has not been systematically evaluated. Our objective was to assess the timing and characteristics of available studies. METHODS: We first identified clinical studies of novel therapeutic agents receiving accelerated approval. We then (1) categorized those studies as randomized or nonrandomized, (2) explored whether they evaluated the FDA-approved indications, and (3) documented the available treatment comparisons. We also meta analyzed the difference in start times between randomized studies that (1) did or did not evaluate approved indications and (2) were or were not designed to evaluate the agent's effectiveness. FINDINGS: In total, 37 novel therapeutic agents received accelerated approval between 2000 and 2013. Our search of ClinicalTrials.gov identified 7,757 studies, which included 1,258,315 participants. Only one-third of identified studies were randomized controlled trials. Of 1,631 randomized trials with advanced recruitment status, 906 were conducted in therapeutic areas for which agents received initial accelerated approval, 202 were in supplemental indications, and 523 were outside approved indications. Only 411 out of 906 (45.4%) trials were designed to test the effectiveness of agents that received accelerated approval ("evaluation" trials); others used these agents as common background treatment in both arms ("background" trials). There was no detectable lag between average start times of trials conducted within and outside initially approved indications. Evaluation trials started on average 1.52 years (95% CI: 0.87 to 2.17) earlier than background trials. CONCLUSIONS: Cumulative evidence on agents with accelerated approvals has major limitations. Most clinical studies including these agents are small and nonrandomized, and about a third are conducted in unapproved areas, typically concurrently with those conducted in approved areas. Most randomized trials including these therapeutic agents are not designed to directly evaluate their clinical benefits but to incorporate them as standard treatment. PMID- 28589603 TI - Let's Not Forget About Medicare. PMID- 28589602 TI - UNAIDS 90-90-90 Campaign to End the AIDS Epidemic in Historic Perspective. PMID- 28589604 TI - Deregulating Safety: The Case of the Effort to Ban Asbestos. PMID- 28589605 TI - Requiem David Willis, 1930-2017. PMID- 28589607 TI - The Democrats' Dilemma. PMID- 28589606 TI - Financing Long-Term Services and Supports: Ideas From Singapore. PMID- 28589608 TI - Risks for Mental Illness in Indigenous Australian Children: A Descriptive Study Demonstrating High Levels of Vulnerability. PMID- 28589609 TI - Coming Problems in Behavioral Health Care. PMID- 28589611 TI - A Molecular Boroauride: A Donor-Acceptor Complex of Anionic Gold. AB - Gold is unique among the transition metals in that it is stable as an isolated anion (auride). Despite this fact, the coordination chemistry of anionic gold is virtually nonexistent, and this unique oxidation state is not readily exploited in conventional solution chemistry owing to its high reactivity. Through the use of a new molecular scaffold based on diboraanthracene (B2 P2 , 1), we have overcome these issues by avoiding the intermediacy of zerovalent gold and stabilizing the highly reduced gold anion through acceptor interactions. We have thus synthesized a molecular boroauride [(B2 P2 )Au]- ([2]- ) and showed its reversible conversion between Au-I and AuI states. Through a combination of spectroscopic and computational studies, we show the neutral state to be a AuI complex with a ligand radical anion. Bonding analyses (NBO and QTAIM) and the isolobal relationship between gold and hydrogen provide support for the description of [2]- as a boroauride complex. PMID- 28589610 TI - Consumer Perspectives on Access to Direct-to-Consumer Genetic Testing: Role of Demographic Factors and the Testing Experience. PMID- 28589612 TI - Renal Targeted Therapies of Antihypertensive and Cardiovascular Drugs for Patients With Stages 3 Through 5d Kidney Disease. AB - The prevalence of chronic kidney disease (CKD) has risen remarkably over the past decades, and the number of patients with CKD is expected to continue to grow significantly in the next 10 years. The mean global prevalence of CKD was estimated to be 14.8% in the latest United States Renal Data System (USRDS) 2016 report, making CKD an important public health problem that has encompassed diabetes mellitus in prevalence. 45% of patients with CKD have Stage 3 disease, defined as an estimated glomerular filtration rate (eGFR) of 30-59 mL/min. PMID- 28589614 TI - Optimization of Maternal Magnesium Sulfate Administration for Fetal Neuroprotection: Application of a Prospectively Constructed Pharmacokinetic Model to the BEAM Cohort. AB - The aim of the study was to identify the optimal therapeutic maternal magnesium drug exposure and maternal serum concentration to prevent cerebral palsy in the extremely preterm fetus. We applied a previously constructed pharmacokinetic model adjusted for indication to a large cohort of pregnant women receiving magnesium sulfate to prevent cerebral palsy in their preterm offspring at 20 different US academic centers between December 1997 and May 2004. We simulated the population-based individual maternal serum magnesium concentration at the time of delivery and the total magnesium dose for each woman who received magnesium sulfate to determine the relationship between maternal serum magnesium level at the time of delivery and the development of cerebral palsy. Among 1905 women who met inclusion criteria, the incidence of cerebral palsy in the cohort was 3.6% for women who had received magnesium sulfate and 6.4% for controls. The simulated maternal serum concentration at delivery associated with the lowest probability of delivering an infant with cerebral palsy was 4.1 mg/dL (95%CI 3.7 to 4.4). Our population-based estimates of magnesium disposition suggest that to optimize fetal neuroprotection and prevent cerebral palsy, magnesium sulfate administration should target a maternal serum magnesium level between 3.7 and 4.4 mg/dL at delivery. PMID- 28589613 TI - The role of the microbiome and the use of probiotics in gastrointestinal disorders in adults in the Asia-Pacific region - background and recommendations of a regional consensus meeting. AB - The Asia-Pacific region is diverse, with regard to ethnicity, culture, and economic development incorporating some of the world's least and most developed nations. Gastrointestinal diseases are common in the Asia-Pacific region, and their prevalence, presentation, and management vary considerably within the region. There is growing evidence for an important role for the human gut microbiota in gastrointestinal health. As a consequence, geographic variations in the composition of the gut microbiota may contribute to variations in both the prevalence and response to therapy of specific diseases. Probiotics have been proposed as a valuable option in the prevention and treatment of a number of gastrointestinal illnesses, but the quality of available evidence to support their efficacy is variable. A meeting of international experts in adult and pediatric gastroenterology was held at the Sorbonne University, Paris, France, on April 11 and 12, 2016, to discuss current evidence supporting the use of probiotics in gastrointestinal disorders in the Asia-Pacific region. This article provides an overview of the discussions held at this meeting and recommends the formation of an Asia-Pacific Consortium on Gut Microbiota similar to those established in Europe and North America. PMID- 28589615 TI - Safety and efficacy of recombinant activated coagulation factor VII in congenital hemophilia with inhibitors in the home treatment setting: A review of clinical studies and registries. AB - Self-administration of factor and bypassing agents by persons with hemophilia in the home setting is recommended to facilitate earlier intervention after bleeding episodes. The objective of this review was to summarize recombinant activated coagulation factor VII (rFVIIa) safety and efficacy data from clinical trials and patient registries documenting use in the home treatment setting in people with congenital hemophilia with inhibitors (CHwI). A total of 16 studies and registries were identified for inclusion; 14 evaluated on-demand treatment of acute bleeding episodes (865 patients, 9024 bleeding episodes) and 2 evaluated use for secondary prophylaxis (108 patients, 42,861 prophylaxis days). In the on demand studies, efficacy was consistently high (81%-96%), and thrombotic events were uncommon (n = 3). In the secondary prophylaxis studies, rFVIIa was associated with a 45% to 59% reduction in bleeding episodes and no thrombotic events. These data support the clinical practice of administering rFVIIa in patients in the home treatment setting after initiation under a physician's care. PMID- 28589616 TI - Cellular and molecular attributes of neural stem cell niches in adult zebrafish brain. AB - Adult neurogenesis is a complex, presumably conserved phenomenon in vertebrates with a broad range of variations regarding neural progenitor/stem cell niches, cellular composition of these niches, migratory patterns of progenitors and so forth among different species. Current understanding of the reasons underlying the inter-species differences in adult neurogenic potential, the identification and characterization of various neural progenitors, characterization of the permissive environment of neural stem cell niches and other important aspects of adult neurogenesis is insufficient. In the last decade, zebrafish has emerged as a very useful model for addressing these questions. In this review, we have discussed the present knowledge regarding the neural stem cell niches in adult zebrafish brain as well as their cellular and molecular attributes. We have also highlighted their similarities and differences with other vertebrate species. In the end, we shed light on some of the known intrinsic and extrinsic factors that are assumed to regulate the neurogenic process in adult zebrafish brain. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1188-1205, 2017. PMID- 28589617 TI - Recording patient bodyweight in hospitals: are we doing well enough? AB - Recording patient weight is a standard practice for all hospital admissions, with this measurement influencing other daily practices that rely on the delivery of safe and effective patient care. Patient weight is important in the areas of medication prescribing, fluid balance and assessment of nutrition. In particular, prescribing narrow therapeutic index medications may result in significant harm as a potential consequence of inaccurate dosing. Despite its importance, it is evident that bodyweight measurements are recorded in only 13.5-55% of hospital patients, in a variety of settings including the emergency department, intensive care unit, medical and surgical wards. Barriers to compliance of healthcare staff include additional workload, patient handling and availability of appropriate weighing equipment. Hospitals and patients would benefit from enhancing compliance with the systematic weighing of patients, staff training and removing barriers to performing this task. PMID- 28589618 TI - Comparison of different regimens of pimecrolimus 1% cream in the treatment of facial seborrheic dermatitis. AB - BACKGROUND: Pimecrolimus 1% cream has already been proved to be an effective and safe alternative to treat seborrheic dermatitis. However, the treatment periods were inconstant in previous studies. OBJECTIVE: To evaluate the comparative efficacy of pimecrolimus 1% cream with different regimens for the treatment of facial seborrheic dermatitis. METHOD: Thirty patients with facial seborrheic dermatitis were enrolled and randomly distributed to three groups. Patients of Group 1 were treated with topical pimecrolimus cream 1% twice daily for 2 weeks and then a moisturizer cream twice daily for 2 weeks. Patients of Group 2 were treated with pimecrolimus cream 1% twice daily for 2 weeks and then once daily for another 2 weeks. Patients of Group 3 had a consecutive course of pimecrolimus cream 1% twice daily for 4 weeks. Objective symptoms, subjective symptoms, and dermatology life quality index (DLQI) were measured at weeks 0, 2, 4, and 6. RESULTS: At week 4, the clinical severity scores of all three regimens significantly decreased (P<.01). The improvement of total severity score in Group 3 was more remarkable than groups 1 and 2 (both P<.05). This effect was maintained until the end of the study in Group 3. Life quality of all three groups was significantly improved at week 4 (P<.001), while there was no statistical difference on the improvement of life quality among three groups. CONCLUSION: We recommend pimecrolimus 1% cream could be applied twice a day for 4 weeks to treat seborrheic dermatitis. PMID- 28589619 TI - Topological Transformation of pi-Conjugated Molecules Reduces Resistance to Crystallization. AB - Two electronically delocalized molecules were designed as models to understand how molecular shape impacts the tradeoff between solubility and crystallization tendencies in molecular semiconductors. The more soluble compound TT contains a non-planar bithiophene central fragment, whereas CT has a planar cyclopentadithiophene unit. Calorimetry studies show that CT can crystallize more easily than TT. However, absorption spectroscopy shows that the initially amorphous TT film can eventually form crystals in which the molecular shape is significantly more planar. Two thermally reversible polymorphs for TT were observed by XRD and grazing-incidence wide-angle X-ray scattering (GIWAXS) measurements. These findings are relevant within the context of designing soft semiconductors that exhibit high solubility and a tendency to provide stable organized structures with desirable electronic properties. PMID- 28589620 TI - The role of ultrasound in modern medical curricula: A medical student perspective. PMID- 28589621 TI - Concise Review: Mesenchymal Stem Cells in Neurodegenerative Diseases. AB - Stem cell-based therapies for neurodegenerative diseases aim at halting clinical deterioration by regeneration and by providing local support for damaged tissue. Mesenchymal stem cells (MSCs) hold great potential for cell therapy as they can be efficiently derived from adult tissue, ex vivo expanded in culture and safely transplanted autologously. MSCs were also shown to be able to differentiate toward neural fates and to secrete a broad range of factors able to promote nervous tissue maintenance and repair. Moreover, upon transplantation, MSCs were shown capable of homing toward lesioned areas, implying their potential use as vehicles for therapeutic agents administration. Indeed, various advantageous effects were reported following human MSCs transplantation into rodent models of neurodegenerative diseases, such as neurotrophic factor-mediated protection, enhanced neurogenesis, modulation of inflammation, and abnormal protein aggregate clearance. Per journal style, most nonstandard abbreviations must be used at least two times in the abstract to be retained; NTF was used once and thus has been deleted. Recent studies have also used ex vivo manipulation for enhanced expression of potentially favorable factors, by so exploiting the homing capacity of MSCs for effective expression at the lesion site. Here, we will summarize current advancements in MSCs-based therapies for neurodegenerative diseases. We will examine the roles of central mechanisms suggested to mediate the beneficial effects of MSCs-based therapy and consider the augmentation of these mechanisms for superior clinical outcomes in rodent models of neurodegeneration as well as in clinical trials. Stem Cells 2017;35:1867-1880. PMID- 28589622 TI - Cutaneous malignancies simulating seborrheic keratoses: An underappreciated phenomenon? AB - BACKGROUND: Seborrheic keratosis (SK), a common and benign entity, is generally diagnosed clinically without the need for a biopsy. Given their variable appearance, SK may mimic cancer clinically and require biopsy for clinically equivocal cases. A clinician may also choose to perform biopsies on SK based on other circumstances, such as cosmetic reasons or SK being in an inconvenient and irritative location. METHODS: Dermatopathology samples from 2015 obtained from private and university locations were retrospectively assessed. Cases included in the study were those with "SK" or "ISK" (irritated seborrheic keratosis) and no other diagnosis in the clinical data. Cases with modifiers suggestive of malignancy such as "SK rule out others," changing, growing and so on were excluded. A total of 4361 eligible cases were identified and used for analysis. RESULTS: Of the 4361 cases identified as only "SK" or "ISK" in the clinical data, 3759 (86.2%) were, in fact, SK or ISK. A total of 466 (10.7%) were an assortment of non-malignancy diagnoses such as dermatofibroma. There were 136 (3.1%) cases histologically diagnosed as malignancies. The majority (9/136 cases; 67%) were in situ or invasive squamous cell carcinoma; 24.3% (33/136) were basal cell carcinoma and 8.8% (12/136) were melanoma. CONCLUSION: SK may mimic cancer even in clinically unsuspicious cases. PMID- 28589623 TI - Impact of red blood cell transfusion strategies in haemato-oncological patients: a systematic review and meta-analysis. AB - Haemato-oncological patients receive many red blood cell (RBC) transfusions, however evidence-based guidelines are lacking. Our aim is to quantify the effect of restrictive and liberal RBC transfusion strategies on clinical outcomes and blood use in haemato-oncological patients. A literature search, last updated on 11 August 2016, was performed in PubMed, EMBASE (Excerpta Medica Database), Web of Science, Cochrane, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and Academic Search Premier without restrictions on language and year of publication. Randomized controlled trials and observational studies that compared different RBC transfusion strategies in haemato-oncological patients were eligible for inclusion. Risk of bias assessment according to the Cochrane collaboration's tool and Newcastle-Ottawa scale was performed. After removing duplicates, 1142 publications were identified. Eventually, 15 studies were included, reporting on 2636 patients. The pooled relative risk for mortality was 0.68 [95% confidence interval (CI) 0.46-1.01] in favour of the restrictive strategy. The mean RBC use was reduced with 1.40 units (95% CI 0.70-2.09) per transfused patient per therapy cycle in the restrictive strategy group. There were no differences in safety outcomes. All currently available evidence suggests that restrictive strategies do not have a negative impact regarding clinical outcomes in haemato-oncological patients, while it reduces RBC use and associated costs. PMID- 28589624 TI - A systematic review of feeding practices among postoperative patients: is practice in-line with evidenced-based guidelines? AB - BACKGROUND: Early oral feeding after surgery is best practice among adult, noncritically ill patients. Evidenced-based guidelines (EBG) recommend commencing liquid and solid feeding within 24 h of surgery to improve patient (e.g. reduced morbidity) and hospital (e.g. reduced length of stay) outcomes. Whether these EBG are adhered to in usual clinical practice remains unknown. The present study aimed to identify the time to commencement of first oral feed (liquid or solid) and first solid feed among postoperative, noncritically ill, adult patients. METHODS: MEDLINE, CINAHL, SCOPUS and Web of Science databases were searched from inception to June 2016 for observational studies reporting liquid and/or solid feeding practices among postoperative patients. Studies reporting a mean/median time to first feed or first solid feed within 24 h of surgery or where >=75% of patients were feeding by postoperative day one were considered in-line with EBG. RESULTS: Of 5826 articles retrieved, 29 studies were included. Only 40% and 22% of studies reported time to first feed and time to first solid feed in-line with EBG, respectively. Clear and free liquids were the first diet types commenced in 86% of studies. When solids were commenced, 44% of studies reported using various therapeutic diet types (e.g. light) prior to the commencement of a regular diet. Patients who underwent gastrointestinal procedures appeared more likely to experience delayed postoperative feeding. CONCLUSIONS: Our findings demonstrate a gap between postoperative feeding evidence and its practical application. This information provides a strong rationale for interventions targeting improved nutritional care following surgery. PMID- 28589626 TI - Greening the Processes of Metal-Organic Framework Synthesis and their Use in Sustainable Catalysis. AB - Given the shortage of sustainable resources and the increasingly serious environmental issues in recent decades, the demand for clean technologies and sustainable feedstocks is of great interest to researchers worldwide. With regard to the fields of energy saving and environmental remediation, the key point is the development of efficient catalysts, not only in terms of facile synthesis methods, but also the benign utilization of such catalysts. This work reviews the use of metal-organic frameworks (MOFs) and MOF-based materials in these fields. The definition of MOFs and MOF-based materials will be primarily introduced followed by a brief description of the characterization and stability of MOF related materials under the applied conditions. The greening of MOF synthesis processes will then be discussed and catalogued by benign solvents and conditions and green precursors of MOFs. Furthermore, their suitable application in sustainable catalysis will be summarized, focusing on several typical atom economic reactions, such as the direct introduction of H2 or O2 and C-C bond formation. Approaches towards reducing CO2 emission by MOF-based catalysts will be described with special emphasis on CO2 fixation and CO2 reduction. In addition, driven by the explosive growth of energy consumption in the last century, much research has gone into biomass, which represents a renewable alternative to fossil fuels and a sustainable carbon feedstock for chemical production. The advanced progress of biomass-related transformations is also illustrated herein. Fundamental insights into the nature of MOF-based materials as constitutionally easily recoverable heterogeneous catalysts and as supports for various active sites is thoroughly discussed. Finally, challenges facing the development of this field and the outlook for future research are presented. PMID- 28589625 TI - Index cholecystectomy in a rural hospital: it can be done. AB - BACKGROUND: Index cholecystectomy (IC) refers to an operation during a patient's first hospital admission with symptomatic gallstone (GS) disease. There are proven reductions in cost, hospital bed days and GS-related complications while awaiting elective surgery. IC has not been universally adopted, particularly in smaller centres where logistics can present a barrier. The aim of this paper is to describe the introduction of routine IC at Hastings Hospital and the effects in terms of waiting time until surgery; GS-related re-presentations and complications while awaiting surgery; operative complications and overall hospital stay. METHODS: Data were collected for all patients who underwent cholecystectomy in the year following the introduction of IC (2015/2016). The results were compared with data from the year 2009/2010. RESULTS: A total of 259 cholecystectomies were performed over the 2015/2016 study period compared with 186 in the 2009/2010 study period. The IC rate increased from 9.89% in 2009 to 75.4% in 2015 (P < 0.001). The incidence of GS pancreatitis whilst waiting for surgery reduced from six in 2009 compared with one in 2015 (P = 0.046). The operative complications were similar in both groups. Total hospital stay was also similar. CONCLUSION: The study shows that it is possible to perform IC in a rural setting reducing complications of waiting and in particular, rates of GS-related pancreatitis were significantly reduced. It can be done safely with an accommodating acute on-call system. PMID- 28589627 TI - Benzothiazolium Single Crystals: A New Class of Nonlinear Optical Crystals with Efficient THz Wave Generation. AB - Highly efficient nonlinear optical organic crystals are very attractive for various photonic applications including terahertz (THz) wave generation. Up to now, only two classes of ionic crystals based on either pyridinium or quinolinium with extremely large macroscopic optical nonlinearity have been developed. This study reports on a new class of organic nonlinear optical crystals introducing electron-accepting benzothiazolium, which exhibit higher electron-withdrawing strength than pyridinium and quinolinium in benchmark crystals. The benzothiazolium crystals consisting of new acentric core HMB (2-(4-hydroxy-3 methoxystyryl)-3-methylbenzo[d]thiazol-3-ium) exhibit extremely large macroscopic optical nonlinearity with optimal molecular ordering for maximizing the diagonal second-order nonlinearity. HMB-based single crystals prepared by simple cleaving method satisfy all required crystal characteristics for intense THz wave generation such as large crystal size with parallel surfaces, moderate thickness and high optical quality with large optical transparency range (580-1620 nm). Optical rectification of 35 fs pulses at the technologically very important wavelength of 800 nm in 0.26 mm thick HMB crystal leads to one order of magnitude higher THz wave generation efficiency with remarkably broader bandwidth compared to standard inorganic 0.5 mm thick ZnTe crystal. Therefore, newly developed HMB crystals introducing benzothiazolium with extremely large macroscopic optical nonlinearity are very promising materials for intense broadband THz wave generation and other nonlinear optical applications. PMID- 28589628 TI - Chemical tools to modulate 2-arachidonoylglycerol biosynthesis. AB - 2-Arachidonoylglycerol (2-AG) is an important endogenous signaling lipid that activates the cannabinoid receptors (CB1 R and CB2 R), thereby regulating a diverse range of physiological processes including anxiety, appetite, inflammation, memory, pain sensation, and nociception. Diacylglycerol lipases (DAGLs) are the principle enzymes responsible for 2-AG biosynthesis. Recently, the (patho)physiological functions of DAGLs have been explored by both genetic methods and chemical tools. This review will focus on the recent efforts to develop highly selective and in vivo active DAGLs inhibitors using activity-based protein profiling. PMID- 28589629 TI - Observation of Various and Spontaneous Magnetic Skyrmionic Bubbles at Room Temperature in a Frustrated Kagome Magnet with Uniaxial Magnetic Anisotropy. AB - The quest for materials hosting topologically protected skyrmionic spin textures continues to be fueled by the promise of novel devices. Although many materials have demonstrated the existence of such spin textures, major challenges remain to be addressed before devices based on magnetic skyrmions can be realized. For example, being able to create and manipulate skyrmionic spin textures at room temperature is of great importance for further technological applications because they can adapt to various external stimuli acting as information carriers in spintronic devices. Here, the first observation of skyrmionic magnetic bubbles with variable topological spin textures formed at room temperature in a frustrated kagome Fe3 Sn2 magnet with uniaxial magnetic anisotropy is reported. The magnetization dynamics are investigated using in situ Lorentz transmission electron microscopy, revealing that the transformation between different magnetic bubbles and domains is via the motion of Bloch lines driven by an applied external magnetic field. These results demonstrate that Fe3 Sn2 facilitates a unique magnetic control of topological spin textures at room temperature, making it a promising candidate for further skyrmion-based spintronic devices. PMID- 28589630 TI - Synthesis of a Bioreversibly Masked Lipophilic Adenosine Diphosphate Ribose Derivative. AB - The design of a bioreversibly protected lipophilic sugar nucleotide as a potential membrane-permeable precursor of adenosine diphosphate ribose (ADPR) is described. ADPR is the most potent activator of the transient receptor potential melastatin 2 (TRPM2) ion channel. Membrane-permeable, lipophilic derivatives of ADPR are of great interest as tools for study of the mechanism of TRPM2. The approach described here was based on our recently disclosed "DiPPro" and "TriPPPro" prodrug approaches developed for the intracellular delivery of nucleotides. A lipophilic, bioreversibly masked ADPR analogue containing an enzymatically cleavable 4-pentanoyloxybenzyl (PB) mask at the phosphate moiety next to the 5'-position of adenosine, together with O-acetyl groups, was prepared in high yields. Chemical and enzymatic hydrolysis studies in phosphate buffer (pH 7.3) were performed to assess chemical stability and possible (selective) enzymatic demasking of the ADPR analogue. HPLC-MS revealed that the PB group was readily cleaved enzymatically. In addition, the formation of partially deacetylated ADPR compounds and also of fully unprotected ADPR was observed. PMID- 28589631 TI - Systematic review: exercise-induced gastrointestinal syndrome-implications for health and intestinal disease. AB - BACKGROUND: "Exercise-induced gastrointestinal syndrome" refers to disturbances of gastrointestinal integrity and function that are common features of strenuous exercise. AIM: To systematically review the literature to establish the impact of acute exercise on markers of gastrointestinal integrity and function in healthy populations and those with chronic gastrointestinal conditions. METHODS: Search literature using five databases (PubMed, EBSCO, Web of Science, SPORTSdiscus, and Ovid Medline) to review publications that focused on the impact of acute exercise on markers of gastrointestinal injury, permeability, endotoxaemia, motility and malabsorption in healthy populations and populations with gastrointestinal diseases/disorders. RESULTS: As exercise intensity and duration increases, there is considerable evidence for increases in indices of intestinal injury, permeability and endotoxaemia, together with impairment of gastric emptying, slowing of small intestinal transit and malabsorption. The addition of heat stress and running mode appears to exacerbate these markers of gastrointestinal disturbance. Exercise stress of >=2 hours at 60% VO2max appears to be the threshold whereby significant gastrointestinal perturbations manifest, irrespective of fitness status. Gastrointestinal symptoms, referable to upper- and lower-gastrointestinal tract, are common and a limiting factor in prolonged strenuous exercise. While there is evidence for health benefits of moderate exercise in patients with inflammatory bowel disease or functional gastrointestinal disorders, the safety of more strenuous exercise has not been established. CONCLUSIONS: Strenuous exercise has a major reversible impact on gastrointestinal integrity and function of healthy populations. The safety and health implications of prolonged strenuous exercise in patients with chronic gastrointestinal diseases/disorders, while hypothetically worrying, has not been elucidated and requires further investigation. PMID- 28589632 TI - Effect of a brief cognitive behavioural intervention on criminal thinking and prison misconduct in male inmates: Variable-oriented and person-oriented analyses. AB - BACKGROUND: There is some consensus on the value of cognitive-behaviourally informed interventions in the criminal justice system, but uncertainty about which components are of critical value. AIMS: To test the hypothesis that change in prisoners - criminal thinking and institutional misconduct - will both follow completion of a brief cognitive behavioural intervention. METHODS: A one-group pre-test-post-test quasi-experimental design was used to assess change on the General Criminal Thinking (GCT) scale of the Psychological Inventory of Criminal Thinking Styles among 219 male prisoners completing a 10-week cognitive behavioural intervention, referred to as 'Lifestyle Issues'. Institutional misconduct was measured for 1 year prior to completion of the course and 2 years subsequently. Using variable-oriented analysis, post-test GCT scores were compared with change in prison conduct, controlling for the pre-test thinking scores. Calculations were repeated by using person-oriented analysis. RESULTS: Prisoners who displayed a drop in GCT scores between pre-test and post-test levels were significantly more likely to show a reduction in prison misconduct, whereas prison misconduct was likely to escalate among those who displayed a rise in criminal thinking scores from pre-test to post-test. CONCLUSIONS: These findings must still be regarded as preliminary, but taken together with other work and with cognitive behavioural theory, they suggest that development of more prosocial thinking and abilities may have an early beneficial effect on institutional behaviour. Their measurement may offer a practical way in which men could be assessed for readiness to return to the community. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589633 TI - Does climate variability influence the demography of wild primates? Evidence from long-term life-history data in seven species. AB - Earth's rapidly changing climate creates a growing need to understand how demographic processes in natural populations are affected by climate variability, particularly among organisms threatened by extinction. Long-term, large-scale, and cross-taxon studies of vital rate variation in relation to climate variability can be particularly valuable because they can reveal environmental drivers that affect multiple species over extensive regions. Few such data exist for animals with slow life histories, particularly in the tropics, where climate variation over large-scale space is asynchronous. As our closest relatives, nonhuman primates are especially valuable as a resource to understand the roles of climate variability and climate change in human evolutionary history. Here, we provide the first comprehensive investigation of vital rate variation in relation to climate variability among wild primates. We ask whether primates are sensitive to global changes that are universal (e.g., higher temperature, large-scale climate oscillations) or whether they are more sensitive to global change effects that are local (e.g., more rain in some places), which would complicate predictions of how primates in general will respond to climate change. To address these questions, we use a database of long-term life-history data for natural populations of seven primate species that have been studied for 29-52 years to investigate associations between vital rate variation, local climate variability, and global climate oscillations. Associations between vital rates and climate variability varied among species and depended on the time windows considered, highlighting the importance of temporal scale in detection of such effects. We found strong climate signals in the fertility rates of three species. However, survival, which has a greater impact on population growth, was little affected by climate variability. Thus, we found evidence for demographic buffering of life histories, but also evidence of mechanisms by which climate change could affect the fates of wild primates. PMID- 28589634 TI - Systematic review and meta-analysis of the role of metronidazole in post haemorrhoidectomy pain relief. AB - AIM: Conventional haemorrhoidectomy is still considered the reference standard for the management of severe or recurrent haemorrhoids. Pain is reported by patients to be the most common postoperative complication. Although the literature lacks a consensus on its effectiveness, metronidazole is often used to reduce postoperative pain. We have performed a meta-analysis of all randomized controlled trials (RCTs) that investigated the use of metronidazole for pain relief after haemorrhoidectomy. METHOD: A systematic review was undertaken in accordance with the PRISMA protocol using the MESH headings 'haemorrhoidectomy', 'hemorhoidectomy', 'hemorrhoidectomy', 'haemorrhoid', 'metronidazole', 'Flagyl(r) ' 'antibiotic' and 'pain'. The search returned 421 articles of which eight were RCTs suitable for inclusion in the review with a total population of 437 patients. The outcomes of interest were postoperative pain intensity on days 1, 2 and 7 and on first defaecation as measured using a visual analogue scale. RESULTS: The meta-analysis demonstrated a significant reduction in postoperative pain for patients treated with metronidazole with a reduced mean difference for the metronidazole group on day 1 of -1.42 (95% CI: -2.14 to -0.69, P = 0.0001), on day 2 of -1.43 (95% CI: -2.45 to -0.40, P = 0.006) and on day 7 of -2.40 (95% CI: -3.10 to -1.71, P < 0.00001). Pain on first defaecation was likewise reduced with a mean difference of -1.38 (95% CI: -2.15 to -0.60, P = 0.0005). Limitations of this study include variation in the grade of haemorrhoids treated and variability in the quality of included studies. CONCLUSION: Metronidazole is a cheap, safe and effective intervention for reducing postoperative pain following conventional haemorrhoidectomy. PMID- 28589635 TI - Comparison of Intramedullary Nail Versus Conventional Ilizarov Method for Lower Limb Lengthening: A Systematic Review and Meta-Analysis. AB - The objective of this systematic review and meta-analysis was to compare the lengthening and then nailing (LATN) technique to the conventional Ilizarov method for limb lengthening. A systemic search of potential relevant literature was performed in databases, including the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, and the ISI Web of Knowledge, from their inception to 22 May 2015 using medical subject heading (MeSH) terms "Ilizarov," "bone lengthening," or "intramedullary nail." A total of 89 titles and abstracts were preliminarily reviewed, of which 4 studies eventually satisfied the eligibility criteria, consisting of one randomized controlled trial (RCT), two clinical controlled trials and one retrospective cohort study. A total of 354 limbs were included in the study, among which 183 were lengthened over an intramedullary nail, and 171 limbs were lengthened conventionally. The mean difference (MD) was -50.21 for the external fixation index between the two groups (95% CI, -51.83 to -48.59; P < 0.00001) with high heterogeneity (I2 = 99%); no significant difference in length was gained (MD = -0.30, 95% CI = -0.72 to 0.12; P = 0.16) with high heterogeneity (I2 = 80%); and there was high significant difference for the consolidation index (MD = -19.97; 95% CI, -21.59 to -18.35; P < 0.00001) with high heterogeneity (I2 = 100%). The overall rate of complications was relatively low, and differed significantly between the two groups. Through this meta-analysis, we find that LATN is superior to the conventional method in regards to the external fixation index and the consolidation index, which means that LATN is an effective technique that can decrease the time needed in external fixation. PMID- 28589638 TI - Inter-observer reliability in reading amplitude-integrated electroencephalogram in the newborn intensive care unit. AB - AIM: Amplitude-integrated electroencephalogram (aEEG) is widely used in neonates to detect electrical seizure and predict outcome following hypoxic ischaemic encephalopathy and other encephalopathy. Because accurate interpretation is important for clinical decision-making and family counselling, inter-observer reliability is a major concern. We aimed to evaluate inter-observer reliability in the interpretation of aEEG tracings in a neonatal intensive care unit. METHODS: Three neonatal intensive care unit clinicians with different levels of experience in reading aEEG independently reviewed and scored aEEG traces using standardised criteria, categories and interpretation rules. Inter-observer reliability was evaluated using weighted Cohen's kappa and intra-class correlation coefficients. RESULTS: All 131 tracings from 120 neonates were reviewed by the neontalogist, 128 (97.7%) by the clinical nurse specialist, 73 (55.7%) by the nurse educator and 70 (53.4%) by all three clinicians. The majority (88 of 120, 73.3%) were term infants (mean gestational age 38 weeks, standard deviation 3.2). Average duration of recording was 27 h (standard deviation 19.1, range 1-105 h). Inter-observer reliability varied across categories and observers - from very good to excellent for the main background activity (intra-class correlation coefficients 0.93-0.98); good to very good for seizures; and moderate to very good for sleep-wake cycle and quality of recording (weighted kappas' 0.71-0.85, 0.50-0.75, 0.46-0.81, respectively). CONCLUSION: While certain aEEG features appear challenging to inter-observer reliability, our findings suggest that with training and consensus guidelines, levels of reliability needed to enhance clinical and prognostic usefulness of aEEG are achievable across clinicians with different levels of experience in reading aEEG. PMID- 28589639 TI - Significance of presence of microvascular invasion in specimens obtained after surgical treatment of hepatocellular carcinoma. AB - Partial hepatectomy and liver transplantation are potentially curative treatments in selected patients with hepatocellular carcinoma (HCC). Unfortunately, a high postoperative tumor recurrence rate significantly decreases long-term survival outcomes. Among multiple prognostic factors, the presence of microvascular invasion (MVI) has increasingly been recognized to reflect enhanced abilities of local invasion and distant metastasis of HCC. Unfortunately, MVI can only currently be identified through histopathological studies on resected surgical specimens. Accurate preoperative tests to predict the presence of MVI are urgently needed. This paper reviews the current studies on incidence, pathological diagnosis, and classification of MVI; possible mechanisms of MVI formation; and preoperative prediction of the presence of MVI. Furthermore, focusing on how the postoperative management can be improved on histopathologically confirmed patients with HCC with MVI, and the potential roles of using predictive tests to estimate the risk of presence of MVI, helps in preoperative therapeutic decision-making in patients with HCC. PMID- 28589636 TI - 25-Hydroxyvitamin D3 and its C-3 epimer are elevated in the skin and serum of Skh 1 mice supplemented with dietary vitamin D3. AB - SCOPE: UV exposure is a risk factor for keratinocyte carcinoma (KC) while critical for endogenous vitamin D production. We investigated dietary modulation of skin and serum 25-hydroxyvitamin D3 (25OHD3 ) and its C-3 epimer (C3epi) in a mouse model of KC. C3epi is an under-investigated metabolite of vitamin D with respect to its biological implications. METHODS AND RESULTS: Male and female Skh 1 mice were supplemented with 25, 150 or 1000 IU/kg diet vitamin D3 for 25 weeks, with some exposed to UV light. Skin and serum vitamin D metabolites were quantitated using HPLC-MS/MS (n = 3 per dose/sex/UV treatment). Serum and skin 25OHD3 and C3epi significantly increased with dose (P<0.0001), but with different response patterns. UV exposure significantly attenuated serum, but not skin, levels of both metabolites (P<0.001, P = 0.0287), while up-regulating expression of renal Cyp24a1 (P < 0.01). A dose by sex interaction trended toward significance with serum and skin levels of C3epi, wherein male mice attained higher levels of C3epi with higher dietary vitamin D3 . This reflected a similar, but non-significant pattern in average tumor size. CONCLUSION: The complex relationship between vitamin D and KC requires further investigation. This study provides insight into modulation of local and systemic vitamin D status with dietary supplementation. PMID- 28589637 TI - Performance of BRCA1/2 mutation prediction models in male breast cancer patients. AB - : To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources. PMID- 28589640 TI - Self-assembly of t-butyloxycarbonyl protected dipeptide methyl esters composed of leucine, isoleucine, and valine into highly organized structures from alcohol and aqueous alcohol mixtures. AB - Short peptides composed of phenylalanine and sequences derived from amyloidogenic peptides have the ability to self-assemble to form nanostructures including hydrogels. The self-assembly of peptides composed of only hydrophobic amino acids and aliphatic protecting groups have not been investigated in detail. We have examined various aspects of nanostructures formed by N-terminal t butyloxycarbonyl-protected aliphatic dipeptide methyl esters dissolved in various solvents. Scanning electron microscopic images indicate that depending on the sequence, position of the amino acid and solvent of dissolution, the peptides self-assemble into superstructures such as nanotubes and needles particularly from aqueous mixtures of organic solvents. Crystallization was not required for self-assembly into nanostructures. Circular dichroism and attenuated total internal reflection fourier transform infrared spectroscopy studies indicate that the peptides adopt beta-conformation in the superstructures both in solution and solid state. The nanostructures composed of entirely aliphatic moieties have the ability to bind to aromatic dyes such as Rhodamine 6G, Nile red and Congo red. They also bind to Thioflavin T although the structures do not resemble amyloid fibrils. The powder X-ray diffraction patterns suggest distinctive packing of the monomers. These structures are stabilized by intermolecular hydrogen bonds and hydrophobic interactions resulting in superstructures containing long distance order and were devoid of hemolytic activity. PMID- 28589641 TI - Yield of head computed tomography in patients with new onset of transient headaches. AB - BACKGROUND: Headache is a common patient complaint. The threshold for brain imaging in headache is debated, especially when the headache is transient, although even if the headache has resolved at presentation, a sentinel bleed heralding a subarachnoid haemorrhage (SAH) often remains a concern. AIM: To assess the yield of computed tomography (CT) head scan referrals for patients with transient headache symptoms. METHODS: This study looked at 6 months of CT results in order to assess for brain pathology, with a particular focus on subarachnoid haemorrhage. Where any pathology was identified, detailed chart review looked for potential high-risk indicators. RESULTS: Between January and July 2015, 531 undifferentiated headache patients were referred for head CT. Of these, 177 (33.3%) presented with a transient or episodic pattern. None of these cases had SAH on imaging nor re-presented with SAH within 3 months of initial CT. However, 7.3% (13/177) had other significant intracranial pathologies. The only significant risk factor for CT abnormality in this setting was focal neurology on presentation (odds ratio 3.1 (95% confidence interval (CI) 1.2-11.0); P = 0.044). All identified cases of SAH over the 6-month study period occurred in patients with persistent headache, and their clinical presentations showed a similar cluster of symptoms to previous literature (including thunderclap headache, vomiting and loss of consciousness). CONCLUSION: This study suggests that patients with transient headache are at a low risk of SAH; however, further study is needed to quantify this, and other serious pathologies remains a concern, especially in the setting of focal neurology at presentation. PMID- 28589642 TI - A new VLAD-based control chart for detecting surgical outcomes. AB - The timely detection of surgical quality changes is becoming increasingly important. Variable life-adjusted display (VLAD) has a wide range of applications in the medical field. However, the control limits of VLAD are not defined; thus, the charts alone cannot reveal whether surgical quality underwent a significant change. This paper proposes a new risk-adjusted exponentially weighted moving average VLAD (RAEV) chart and provides a control limit that can be used with the VLAD. The RAEV chart is designed to detect shifts in the odds ratios of patients' surgical risk. Simulation is used to demonstrate that the proposed RAEV chart efficiently detects shifts of various magnitudes, and an example is provided to illustrate the implementation of the RAEV control limits in a VLAD chart. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28589643 TI - Residual risk of transmission of human immunodeficiency virus and hepatitis C virus infections by blood transfusion in northern Brazil. AB - BACKGROUND: Nucleic acid test (NAT) blood screening for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) was introduced in northern Brazil in July 2012. There are several Brazilian articles that have evaluated transfusion transmission risks for HIV and HCV. However, to our knowledge, this article is the first to evaluate the impact of HIV and HCV NAT implementation for blood screening in northern Brazil. The aim of this study was to determine the prevalence and incidence rates of HIV and HCV among blood donors and to compare the residual risk of transfusion transmission of these infections, before (2009 2011) and after (2012-2014) NAT implementation. STUDY DESIGN AND METHODS: HIV and HCV prevalence and incidence were calculated based on rates of confirmed positive samples. Residual risk estimates were based on the incidence and window model described previously. Logistic and Poisson regressions were used in the statistical analysis. A p value of not more than 0.05 was considered significant. RESULTS: HIV and HCV prevalence were 209.9 and 66.3 per 100,000 donations, respectively. Residual risk for HIV and HCV decreased significantly throughout the two study periods, mainly for HCV in which the reduction was one in 169,492 to one in 769,231 donations. For HIV, the decrease was one in 107,527 to one in 769,231 donations. HIV and HCV incidence rates were 21.13 and 3.06 per 100,000 persons/year before NAT and 14.03 and 2.65 per 100,000 persons/year after NAT. CONCLUSION: The HIV and HCV NAT implementation significantly increased the transfusion safety in northern Brazil, bringing benefits to recipients due to better quality of blood products produced. PMID- 28589645 TI - What the neighbors say. PMID- 28589644 TI - Endothelial to mesenchymal transformation is induced by altered extracellular matrix in aortic valve endothelial cells. AB - Alterations in shear stress, mechanical deformation, extracellular matrix (ECM) composition and exposure to inflammatory conditions are known to cause endothelial to mesenchymal transformation (EndMT). This change in endothelial phenotype has only recently been linked to adult pathologies such as cancer progression, organ fibrosis, and calcific aortic valve disease; and its function in adult physiology, especially in response to tissue mechanics, has not been rigorously investigated. EndMT is a response to mechanical and biochemical signals that results in the remodeling of underlying tissues. In diseased aortic valves, glycosaminoglycans (GAGs) are present in the collagen-rich valve fibrosa, and are deposited near calcified nodules. In this study, in vitro models of early and late-stage valve disease were developed by incorporating the GAGs chondroitin sulfate (CS), hyaluronic acid, and dermatan sulfate into 3D collagen hydrogels with or without exposure to TGF-beta1 to simulate EndMT in response to microenvironmental changes. High levels of CS induced the highest rate of EndMT and led to the most collagen I and GAG production by mesenchymally transformed cells, which indicates a cell phenotype most likely to promote fibrotic disease. Mesenchymal transformation due to altered ECM was found to depend on cell-ECM bond strength and extracellular signal-regulated protein kinases 1/2 signaling. Determining the environmental conditions that induce and promote EndMT, and the subsequent behavior of mesenchymally transformed cells, will advance understanding on the role of endothelial cells in tissue regeneration or disease progression. (c) 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2729-2741, 2017. PMID- 28589646 TI - Focal laser treatment in addition to chemotherapy for retinoblastoma. AB - BACKGROUND: Retinoblastoma is the most common primary intraocular malignancy of childhood. Systemic chemotherapy is a common treatment for intraocular retinoblastoma, and laser treatment is used as adjuvant therapy during or immediately after chemotherapy courses in selected cases. OBJECTIVES: To compare the effectiveness and safety of adding focal laser therapy to systemically delivered chemotherapy in treating intraocular retinoblastoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 9), MEDLINE Ovid (1946 to 20 October 2016), Embase Ovid (1980 to 20 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 20 October 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 20 October 2016, ClinicalTrials.gov (www.clinicaltrials.gov); searched 20 October 2016, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 20 October 2016. We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of systemic chemotherapy with versus without adjuvant laser therapy for postequatorial retinoblastoma. DATA COLLECTION AND ANALYSIS: We planned to use standard methodological procedures expected by Cochrane. We planned to meta analyse the primary outcome, that is the proportion of eyes with recurrence of tumours within three years from treatment MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: No evidence from randomised controlled trials was found to support or refute laser therapy in addition to systemic chemotherapy for postequatorial retinoblastoma. PMID- 28589648 TI - Effects of exercise-based interventions on postpartum depression: A meta-analysis of randomized controlled trials. AB - BACKGROUND: There is inconsistent evidence about the effect of physical activity on the prevention and treatment of depression during the postnatal period. The aim of this meta-analysis was to determine the effect of physical activity interventions during pregnancy and the postpartum period for controlling postpartum depressive symptoms. METHODS: We systematically searched Cochrane Library Plus, Science Direct, EMBASE, CINAHL, PubMed, Web of Science, and Scopus, from January 1990 to May 2016, for randomized or nonrandomized controlled trials addressing the effect of physical activity on postpartum depression. The inverse variance-weighted method was used to compute pooled estimates of effect size and respective 95% confidence intervals (95% CI) for physical activity intervention on postpartum depression. Subgroup analyses were performed comparing women with and without postpartum depressive symptoms according to specific scales measuring this construct. Meta-regression and sensitivity analysis were computed to evaluate heterogeneity. RESULTS: Twelve studies were included in the meta analysis. Effect size for the relationship between physical activity interventions during pregnancy and the postpartum period on postpartum depressive symptoms was 0.41 (95% CI 0.28-0.54). Heterogeneity was I2 = 33.1% (P = .117). When subgroup analyses were done, pooled effect sizes were 0.67 (95% CI 0.44 0.90) for mothers who met postpartum depressive symptoms criteria at baseline based on specific scales, and 0.29 (95% CI 0.14-0.45) for mothers who did not meet those depressive symptoms criteria at baseline. CONCLUSION: Physical exercise during pregnancy and the postpartum period is a safe strategy to achieve better psychological well-being and to reduce postpartum depressive symptoms. PMID- 28589647 TI - Using primary tumor volumetry to predict treatment outcome for patients with oropharyngeal cancer who were treated with definitive chemoradiotherapy. AB - AIM: This study aimed to determine predictive values for volumetric measures in patients with oropharyngeal cancer who received definitive chemoradiotherapy (CCRT). METHODS: Contrast-enhanced computed tomography (CT) scans were obtained before radiotherapy (RT) (I), after delivering a median RT of 50.6 Gy (R) and three months after RT (F). Primary site gross tumor volumes (GTV) were assessed using these scans (GTVI , GTVR and GTVF ). The percentage volume change between GTVI and GTVR (GTV change) was calculated. Volumetric analyses of primary site local control (LC) and progression-free survival (PFS) were performed. RESULTS: In total, 35 patients were evaluated, with a median 31 months of follow-up. The 2 year LC rates (LCRs) were 95.0% for patients with GTVI <23 cc, and 42.9% for those with GTVI >=23 cc (P = 0.001); the 2-year PFS rates were 85.9% and 21.9% (P = 0.002), respectively. Using GTVR classifications <11 cc or >=11 cc, log-rank tests demonstrated differences in 2-year LCR (95.2% vs 33.3%, P < 0.001) and 2 year PFS (86.5% vs 0%, P < 0.001). There was no local progression in patients with GTV change >=75%, and GTV change predicted poor PFS (P = 0.026). On multivariate analysis, GTVR >=11 cc was a significant predictor of poor LCR (hazard ratio [HR] = 26, P = 0.009) and PFS (HR = 8.33, P = 0.046). CONCLUSION: For patients with oropharyngeal cancer treated with definitive CCRT, GTVI , GTVR and GTV changes predicted LC and PFS; GTVR was the most significant predictor of LC and PFS. RT intensification should be considered for patients with larger remaining tumors after CCRT. PMID- 28589649 TI - Cervical cancer screening in the era of HPV vaccination: A review of shifting paradigms in cytopathology. AB - Significant changes in cervical cancer screening practice, guidelines, and prevention of cervical cancer have taken place in recent years including the raising of initial cervical cancer screening age, changes in frequency of cytology screening, and the adoption of high risk HPV and cytology co-testing for some patients; the introduction of the bivalent, quadrivalent, and 9-valent HPV vaccines; and the recent approval of high risk HPV testing as primary screening with the use of cytology as triage in positive cases. This review discusses the significance of primary HPV screening, the impact of HPV vaccination in the prevalence of cervical cancer and its precursors, the interplay between high risk HPV testing and vaccination, and the implications for clinical and cytological management. Future strategies for cervical screening in the post-vaccination era are also discussed. PMID- 28589650 TI - Validity and reliability of a structured-light 3D scanner and an ultrasound imaging system for measurements of facial skin thickness. AB - Three-dimensional (3 D)-scanning-based morphological studies of the face are commonly included in various clinical procedures. This study evaluated validity and reliability of a 3 D scanning system by comparing the ultrasound (US) imaging system versus the direct measurement of facial skin. The facial skin thickness at 19 landmarks was measured using the three different methods in 10 embalmed adult Korean cadavers. Skin thickness was first measured using the ultrasound device, then 3 D scanning of the facial skin surface was performed. After the skin on the left half of face was gently dissected, deviating slightly right of the midline, to separate it from the subcutaneous layer, and the harvested facial skin's thickness was measured directly using neck calipers. The dissected specimen was then scanned again, then the scanned images of undissected and dissected faces were superimposed using Morpheus Plastic Solution (version 3.0) software. Finally, the facial skin thickness was calculated from the superimposed images. The ICC value for the correlations between the 3 D scanning system and direct measurement showed excellent reliability (0.849, 95% confidence interval = 0.799 0.887). Bland-Altman analysis showed a good level of agreement between the 3 D scanning system and direct measurement (bias = 0.49 +/- 0.49 mm, mean+/-SD). These results demonstrate that the 3 D scanning system precisely reflects structural changes before and after skin dissection. Therefore, an in-depth morphological study using this 3 D scanning system could provide depth data about the main anatomical structures of face, thereby providing crucial anatomical knowledge for utilization in various clinical applications. Clin. Anat. 30:878 886, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28589651 TI - Measuring and Modeling Highly Accurate 15 N Chemical Shift Tensors in a Peptide. AB - NMR studies measuring chemical shift tensors are increasingly being employed to assign structure in difficult-to-crystallize solids. For small organic molecules, such studies usually focus on 13 C sites, but proteins and peptides are more commonly described using 15 N amide sites. An important and often neglected consideration when measuring shift tensors is the evaluation of their accuracy against benchmark standards, where available. Here we measure 15 N tensors in the dipeptide glycylglycine at natural abundance using the slow-spinning FIREMAT method with SPINAL-64 decoupling. The accuracy of these 15 N tensors is evaluated by comparing to benchmark single crystal NMR 15 N measurements and found to be statistically indistinguishable. These FIREMAT experimental results are further used to evaluate the accuracy of theoretical predictions of tensors from four different density functional theory (DFT) methods that include lattice effects. The best theoretical approach provides a root mean square (rms) difference of +/ 3.9 ppm and is obtained from a fragment-based method and the PBE0 density functional. PMID- 28589653 TI - Assessment of HNA alloimmunisation risk in Northeastern Thais, Burmese and Karen. AB - OBJECTIVES: This study aimed to determine human neutrophil antigen (HNA) frequency, estimate possible HNA incompatibilities and predict the risk of HNA alloimmunisation in the Northeastern Thai, Burmese and Karen populations. BACKGROUND: Alloantibodies against HNA are implicated in a number of clinical conditions, including immune-mediated neutropenia and transfusion reactions. METHODS: A total of 400 unrelated healthy Thais, 261 Burmese and 249 Karen was included in this study. DNA samples were typed for HNA-1, -3, -4 and -5 systems using polymerase chain reactions with sequence-specific primers (PCR-SSP). RESULTS: In this cohort, HNA-1a was more prevalent than HNA-1b. Accordingly, the possible risk of HNA-1a alloimmunisation against HNA-1a is lower than HNA-1b (0.0802-0.1351 vs 0.2293-0.2497). This is in contrast to the situation reported in Caucasian and African populations. The predicted risk of HNA-3 incompatibility in Thais, Burmese and Karen were 28.09%, 30.66% and 22.77%, respectively. The possible risks of HNA-3a alloimmunisation were 0.0493 in Thais, 0.0608 in Burmese and 0.0196 in Karen, respectively. No individuals were found to be homozygous for HNA-4bb. The probability of developing alloantibodies against HNA-4a was low in these populations and every population in Asia. In contrast, the overall frequency of HNA-5bb homozygous individuals was high in this study, peaking at 0.192. CONCLUSIONS: This is the first study that reported the allele frequencies of HNA-1, -3, -4, and -5 in a large sample of healthy unrelated individuals from ethnic Thais, Burmese and Karen. Our results indicated the high possible risk of HNA-1, -3 and -5 alloimmunisation in these populations. PMID- 28589654 TI - The importance of full skin examination in diagnosing cutaneous melanoma. PMID- 28589652 TI - Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial. AB - Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin-II receptor-1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase-2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a >=25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold-change in UACR was -0.74 for MacroA and -0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142?104 mL/minute/1.73 m2 ), N = 1; rise in serum creatinine >50% (0.2?0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase 3, randomized, placebo-controlled trial of losartan for the nephropathy of SCA. PMID- 28589655 TI - Cannulation-Related Complications on Veno-Arterial Extracorporeal Membrane Oxygenation: Prevalence and Effect on Mortality. AB - Cannulation-related complications are a known source of morbidity in patients supported on veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Despite its prevalence, little is known regarding the outcomes of patients who suffer such complications. This is a single institution review of cannulation-related complications and its effect on mortality in patients supported on VA-ECMO from January 2010-2015 using three cannulation strategies: axillary, femoral, and central. Complications were defined as advanced if they required major interventions (fasciotomy, amputation, site conversion). Patients were divided into two groups (complication present vs. not present) and Kaplan-Meier analysis was performed to determine any differences in their survival distributions. There were 103 patients supported on VA-ECMO: 41 (40%), 36 (35%), and 26 (25%) were cannulated via axillary, femoral, and central access, respectively. Cannulation related complications occurred in 33 (32%) patients and this did not differ significantly between either axillary (34%), femoral (36%), or central (23%) strategies (P = 0.52). The most common complications encountered were hemorrhage and limb ischemia in 19 (18%) and 11 (11%) patients. Hemorrhagic complications did not differ between groups (P = 0.37), while limb ischemia and hyperperfusion were significantly associated with femoral and axillary cannulation, at a rate of 25% (P < 0.01) and 15% (P = 0.01), respectively. There was no difference in the incidence of advanced complications between cannulation groups: axillary (12%) vs. femoral (14%) vs. central (8%; P = 0.75). In addition, no increase in mortality was noted in patients who developed a cannulation-related complication by Kaplan-Meier estimates (P = 0.37). Cannulation-related complications affect a significant proportion of patients supported on VA-ECMO but do not differ in incidence between different cannulation strategies and do not affect patient mortality. Improved efforts at preventing these complications need to be developed to avoid the additional morbidity in an already critical patient population. PMID- 28589656 TI - Small-Molecule Solar Cells with Simultaneously Enhanced Short-Circuit Current and Fill Factor to Achieve 11% Efficiency. AB - High-efficiency small-molecule-based organic photovoltaics (SM-OPVs) using two electron donors (p-DTS(FBTTh2 )2 and ZnP) with distinctively different absorption and structural features are reported. Such a combination works well and synergically improves device short-circuit current density (Jsc ) to 17.99 mA cm 2 and fill factor (FF) to 77.19%, yielding a milestone efficiency of 11%. To the best of our knowledge, this is the highest power conversion efficiency reported for SM-OPVs to date and the first time to combine high Jsc over 17 mA cm-2 and high FF over 77% into one SM-OPV. The strategy of using multicomponent materials, with a selecting role of balancing varied electronic and structural necessities can be an important route to further developing higher performance devices. This development is important, which broadens the dimension and versatility of existing materials without much chemistry input. PMID- 28589657 TI - Water-Plasma-Enabled Exfoliation of Ultrathin Layered Double Hydroxide Nanosheets with Multivacancies for Water Oxidation. AB - An earth-abundant and highly efficient electrocatalyst is essential for oxygen evolution reaction (OER) due to its poor kinetics. Layered double hydroxide (LDH) based nanomaterials are considered as promising electrocatalysts for OER. However, the stacking structure of LDHs limits the exposure of the active sites. Therefore, the exfoliation is necessary to expose more active sites. In addition, the defect engineering is proved to be an efficient strategy to enhance the performance of OER electrocatalysts. For the first time, this study prepares ultrathin CoFe LDHs nanosheets with multivacancies as OER electrocatalysts by water-plasma-enabled exfoliation. The water plasma can destroy the electrostatic interactions between the host metal layers and the interlayer cations, resulting in the fast exfoliation. On the other hand, the etching effect of plasma can simultaneously and effectively produce multivacancies in the as-exfoliated ultrathin LDHs nanosheets. The increased active sites and the multivacancies significantly contribute to the enhanced electrocatalytic activity for OER. Compared to pristine CoFe LDHs, the as-exfoliated ultrathin CoFe LDHs nanosheets exhibit excellent catalytic activity for OER with a ultralow overpotential of only 232 mV at 10 mA cm-2 and possesses outstanding kinetics (the Tafel slope of 36 mV dec-1 ). This work provides a novel strategy to exfoliate LDHs and to produce multivacancies simultaneously as highly efficient electrocatalysts for OER. PMID- 28589658 TI - Introduction of a drug-detection dog programme in mental health inpatient units: A mixed-methods study of consumer, staff, and carers' perceptions. AB - Many consumers admitted to mental health inpatient units also use illicit drugs, and some continue to do so while receiving treatment. In an attempt to curb the impact of illicit drug use, one of Australia's largest mental health services introduced a programme of drug-detection dog (DDD) searches. Our aim was to evaluate perceptions of the DDD programme among mental health consumers, staff, and carers. A mixed-methods research design using a concurrent triangulation approach was adopted, involving three focus group discussions with consumer, staff, and carer groups, and a structured survey among 94 consumers who were receiving treatment and 102 staff working in the units at the time of a DDD visit. Data were analysed using thematic analysis, and descriptive and inferential statistics. Major themes were that: (i) drug use in these units is perceived as 'prevalent' and 'destructive'; (ii) the DDD programme is 'beneficial' but 'incongruous' in a health-care setting; (iii) consumers are 'uninformed'; and (iv) consequences should be 'customized' to circumstances. Survey results corroborated qualitative themes, with the exception that although concerns about incongruity do exist, they were not prevalent and were outweighed by positive perceptions of the programme. Most perceptions were consistent between consumers and staff. However, consumers tended to think that, if found, drugs should be confiscated, whereas staff were more strongly in favour of the consumer being discharged. In conclusion, the DDD programme was seen as a positive step towards addressing drug use in mental health units. However, improved dissemination of information to consumers through verbal and written communication is required. PMID- 28589659 TI - Validity and reliability of Abbreviated Mental Test Score (AMTS) among older Iranian. AB - BACKGROUND: Cognitive impairment is common among older people and is associated with increased morbidity and mortality. The main aim of this study was to evaluate the validity of the Persian version of the Abbreviated Mental Test Score (AMTS) as a screening tool for dementia. METHODS: Data were obtained from a cross sectional study. One hundred and one older adults who were members of Iranian Alzheimer Association and 101 of their siblings were entered into this study by convenient sampling. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, criteria for diagnosing dementia and the Mini-Mental State Examination were used as the study tools. The gathered data were analyzed by the Mann-Whitney U-test, the Kruskal-Wallis test, Spearman's rank correlation coefficient, and the receiver-operating characteristic. RESULTS: The AMTS could successfully differentiate the dementia group from the non-dementia group. Scores were significantly correlated with Diagnostic and Statistical Manual of Mental Disorders diagnosis for dementia and Mini-Mental State Examination scores (P < 0.001). Educational level (P < 0.001) and male sex (P = 0.015) were positively associated with AMTS, whereas (P < 0.001) was negatively associated with AMTS. Total Cronbach's alpha coefficient was 0.90. The scores 6 and 7 showed the optimum balance between sensitivity (99% and 94%, respectively) and specificity (85% and 86%, respectively). CONCLUSIONS: The Persian version of the AMTS is a valid cognitive assessment tool for older Iranian adults and can be used for dementia screening in Iran. PMID- 28589662 TI - State of the Art 2017. PMID- 28589661 TI - Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects. AB - BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular "Nottingham test meal" (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. METHODS: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. KEY RESULTS: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45+/-20). The NTM produced normal postprandial fullness (VAS >=30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS >=30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. CONCLUSIONS AND INFERENCES: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity. PMID- 28589660 TI - Simultaneous Quantification of Bone Edema/Adiposity and Structure in Inflamed Bone Using Chemical Shift-Encoded MRI in Spondyloarthritis. AB - PURPOSE: To evaluate proton density fat fraction (PDFF) and R2* as markers of bone marrow composition and structure in inflamed bone in patients with spondyloarthritis. METHODS: Phantoms containing fat, water, and trabecular bone were constructed with proton density fat fraction (PDFF) and bone mineral density (BMD) values matching those expected in healthy bone marrow and disease states, and scanned using chemical shift-encoded MRI (CSE-MRI) at 3T. Measured PDFF and R2* values in phantoms were compared with reference FF and BMD values. Eight spondyloarthritis patients and 10 controls underwent CSE-MRI of the sacroiliac joints. PDFF and R2* in areas of inflamed bone and fat metaplasia in patients were compared with normal bone marrow in controls. RESULTS: In phantoms, PDFF measurements were accurate over the full range of PDFF and BMD values. R2* measurements were positively associated with BMD but also were influenced by variations in PDFF. In patients, PDFF was reduced in areas of inflammation and increased in fat metaplasia compared to normal marrow. R2* measurements were significantly reduced in areas of fat metaplasia. CONCLUSION: PDFF measurements reflect changes in marrow composition in areas of active inflammation and structural damage and could be used for disease monitoring in spondyloarthritis. R2* measurements may provide additional information bone mineral density but also are influenced by fat content. Magn Reson Med 79:1031-1042, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 28589663 TI - Co-morbid OSA and insomnia increases depression prevalence and severity in men. AB - BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) and insomnia coexist in clinical populations but prevalence in the community and risk factors remain largely unknown. We examined the prevalence and profile of previously undiagnosed co-morbid OSA and insomnia symptoms (COMISA) in community-dwelling men. METHODS: Men (n = 700, aged 58.5 +/- 11.0 (mean +/- SD) years) without a prior diagnosis of OSA completed full at-home unattended polysomnography, the Pittsburgh Sleep Quality Index and 36-item short form (SF-36) survey (2007-2012). Insomnia symptoms included difficulty initiating/maintaining sleep in the presence of daytime fatigue (DIMS-F). Depressive symptoms were assessed using the Beck Depression Inventory-1A, Centre for Epidemiological Studies Depression Scale and Patient Health Questionnaire-9 (PHQ-9) (2007-2010). Univariate (chi2 and analysis of variance (ANOVA)) and multiple linear regressions were used to compare data from four groups of individuals: neither disorder; previously undiagnosed OSA (apnoea-hypopnoea index >= 10) or DIMS-F alone; and COMISA. RESULTS: COMISA prevalence was 6.7%. Depression prevalence (COMISA, 42.6%; DIMS-F, 21.6%; OSA, 8.4%, chi2 = 71.6, P < 0.00) and symptom scale scores (e.g. PHQ-9 mean +/- SD: 16.1 +/- 5.5 c.f. DIMS-F: 14.0 +/- 4.9, P < 0.01 and OSA: 11.4 +/- 3.0, P = 0.01) were highest in men with COMISA. In COMISA, respiratory and arousal indices were similar to those observed in OSA whilst reductions in subjective sleep and day dysfunction scores were similar to DIMS-F. After adjustment, predicted mean depression scores were all higher in DIMS-F and COMISA using linear regression (e.g. PHQ-9 beta (95% CI): DIMS-F: 2.3 (1.2, 3.5); COMISA: 4.1 (3.0, 5.1)). CONCLUSION: Men with COMISA have a greater prevalence, and severity, of depression than men with only one disorder. PMID- 28589665 TI - Tony Woo (1970-2017). PMID- 28589666 TI - Continuing Professional Development. PMID- 28589664 TI - Fluidic Manufacture of Star-Shaped Gold Nanoparticles. AB - Star-shaped gold nanoparticles (StarAuNPs) are extremely attractive nanomaterials, characterized by localized surface plasmon resonance which could be potentially employed in a large number of applications. However, the lack of a reliable and reproducible synthetic protocols for the production of StarAuNPs is the major limitation to their spreading. For the first time, here we present a robust protocol to manufacture reproducible StarAuNPs by exploiting a fluidic approach. Star-shaped AuNPs have been synthesized by means of a seed-less protocol, employing ascorbic acid as reducing agent at room temperature. Moreover, the versatility of the bench-top microfluidic protocol has been exploited to afford hydrophilic, hydrophobic and solid-supported engineered StarAuNPs, by avoiding intermediate NP purifications. PMID- 28589667 TI - In vitro and in vivo assessment of lactic acid-modified chitosan scaffolds for potential treatment of full-thickness burns. AB - Autologous skin transplantation is today's "gold standard" treatment for full thickness burns. However, when > 30% of total body surface area is damaged, there is an important shortage of autologous donor sites for skin grafting; then, treatment alternatives become crucial. Such alternatives can be based on polymeric scaffolds capable of functioning as protective covers and cells/factors carriers. Chitosan (CTS) is a natural-derived polymer with relevant biological related properties but poor mechanical performance. Improved mechanical properties can be achieved through lactic acid grafting (LA-g); nevertheless, LA g affects the biological response towards the CTS-based materials. In this work, CTS-LA scaffolds with different LA-g percentages were synthesized and evaluated to determine appropriate LA-g degrees for full-thickness burns treatment. In vitro results indicated that the higher the LA-g percentage, the lower the capability of the scaffolds to sustain fibroblasts culture. Scaffolds with LA-g around 28% (CTS-LA28) sustained cell culture and allowed normal cell functionality. Further evaluation of CTS-LA28 as acellular and cellular grafts in a full-thickness burn mouse model showed that at 28 days post-burn, macroscopic characteristic of the reparation tissue were closer to healthy skin when cellular grafts were used for treatment; histological evaluation also showed that dermis cellularity and collagenous fibers structure were similar to those in healthy skin when cellular grafts were used for burns treatment. (c) 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2875-2891, 2017. PMID- 28589668 TI - Strongly positive anti-CCP antibodies in patients with sacroiliitis or reactive arthritis post-E. coli infection: A mini case-series based review. AB - We report here on four cases of patients with strongly positive anti citrullinated cyclic peptides (anti-CCP) antibodies and clinical features of seronegative spondyloarthritis (SpA) and reactive arthritis. The four patients had various clinical presentations: one had an initial diagnosis of seropositive rheumatoid arthritis (RA) with involvement of the sacroiliac joints (similar to previous reports of the association of two diseases); one had a clinical picture of reactive arthritis following an episode of an Escherichia coli positive urinary tract infection; and two had asymmetrical sacroiliitis (SII), but no evidence of peripheral joint involvement (never reported before). In all cases, high titers of anti-CCP antibodies were found. We present a comparison of the clinical manifestations, radiographic features and treatment regimens of these cases. Our report supports previous literature data of possible overlap existing between RA and SpA, but also presents for the first time the association of high titers of anti-CCP antibodies with SII and reactive arthritis in patients with no peripheral small joint involvement. PMID- 28589669 TI - An economic evaluation of a multicomponent self-management intervention for adults with epilepsy (ZMILE study). AB - OBJECTIVE: The objective of this (trial-based) economic evaluation was, from a societal perspective, to compare the cost-effectiveness of a multicomponent self management intervention (MCI) with care as usual (CAU) in adult patients with epilepsy over a 12-month period. METHODS: In a randomized-controlled trial, participants were randomized into intervention or CAU group. Adherence, self efficacy (Epilepsy Self-Efficacy Scale [ESES]), quality-adjusted life years (QALYs), healthcare costs, production losses, and patient and family costs were assessed at baseline and during the 12-month study period. Incremental cost effectiveness ratios (ICERs) (i.e., cost per increased adherence, self-efficacy, or QALY), and cost-effectiveness acceptability curves were calculated. RESULTS: In total, 102 patients were included in the study, of whom 52 were in the intervention group. Adherence rates over 6 months were 63.7% for the CAU group and 75.9% for the intervention group. Adherence, ESES, and quality of life did not differ significantly between groups. An ICER of ?54 per point increase in ESES score at 6 months and ?1,105 per point increase at 12-month follow-up was found. The intervention resulted in an ICER of ?88 per percentage of adherence increase at 6 months. ICERs of ?8,272 and ?15,144 per QALY gained were found at 6 and 12-month follow-up, respectively. SIGNIFICANCE: Although no statistically significant difference was found after baseline adjustments, cost-effectiveness estimates for MCI appear promising. As rules of inference are arbitrary, it has been argued that decisions should be based only on the net benefits, irrespective of whether differences are statistically significant. Hence, the MCI may be a cost-effective addition to the current standard care for adults with epilepsy. PMID- 28589670 TI - Texture analysis of ultrasound images is a sensitive method to follow-up muscle damage induced by eccentric exercise. AB - The grey level of co-occurrence matrix (GLCM) is a texture analysis approach accounting for spatial distribution of the pixels from an image and can be a promising method for exercise-induced muscle damage (EIMD) studies. We followed up the time changes of two GLCM texture parameters and echo intensity (EI) on ultrasound images after eccentric contractions. Thirteen untrained women performed two sets of ten elbow flexions eccentric contractions. Ultrasound images were acquired at baseline and 24 h, 48 h, 72 h and 96 h after exercise. Two GLCM texture parameters were calculated for the brachialis muscle: contrast (CON) and correlation (COR). Peak torque, EI, muscle thickness (MT) and soreness were measured. The peak torque and soreness decreased immediately after the intervention in comparison with all the measures. MT increased immediately after the intervention remaining for 72 h (P<0.05). Significant increases (P<0.05) were observed for COR (48, 72 and 96 h) and EI only at 72 and 96 h. The increasing COR represents high similarity between grey levels, which could be observed on US images after few days on eccentric training for elbow flexors. PMID- 28589671 TI - Pain and Mortality in Older Adults: The Influence of Pain Phenotype. AB - OBJECTIVE: Moderate to severe chronic pain affects 1 in 5 adults. Pain may increase the risk of mortality, but the relationship is unclear. This study investigated whether mortality risk was influenced by pain phenotype, characterized by pain extent or pain impact on daily life. METHODS: The study population was drawn from 2 large population cohorts of adults ages >=50 years, the English Longitudinal Study of Ageing (n = 6,324) and the North Staffordshire Osteoarthritis Project (n = 10,985). Survival analyses (Cox's proportional hazard models) estimated the risk of mortality in participants reporting any pain and then separately according to the extent of pain (total number of pain sites, widespread pain according to the American College of Rheumatology [ACR] criteria, and widespread pain according to Manchester criteria) and pain impact on daily life (pain interference and often troubled with pain). Models were cumulatively adjusted for age, sex, education, and wealth/adequacy of income. RESULTS: After adjustments, the report of any pain (mortality rate ratio [MRR] 1.06 [95% confidence interval (95% CI) 0.95-1.19]) or having widespread pain (ACR 1.07 [95% CI 0.92-1.23] or Manchester 1.16 [95% CI 0.99-1.36]) was not associated with an increased risk of mortality. Participants who were often troubled with pain (MRR 1.29 [95% CI 1.12-1.49]) and those who reported quite a bit of pain interference (MRR 1.38 [95% CI 1.20-1.59]) and extreme pain interference (MRR 1.88 [1.54 2.29]) had an increased risk of all-cause mortality. CONCLUSION: Pain that interferes with daily life, rather than pain per se, was associated with an increased risk of mortality. Future studies should investigate the mechanisms through which pain increases mortality risk. PMID- 28589672 TI - An international survey about nail histology processing techniques. AB - BACKGROUND: There are limited data on nail histopathology techniques. The objective of this study was to examine nail histopathology techniques currently in use internationally. METHODS: An online survey was sent to the European Nail Society and Council for Nail Disorders during 2015-2016. RESULTS: There were 57 respondents, from twenty countries comprising dermatologists, podiatrists and pathologists. Specimens were unmarked or marked using ink or a suture and fixed in 10% formalin, from 6 to 48 hours before embedding in paraffin wax (90% [17/19]), liquid nitrogen (frozen section, 1/19) and 2-hydroxyethylmethacrylate (plastic, 1/19). Nail softening was undertaken by 71% (17/24) of respondents for 6 to 48 hours using Mollifex Gurr (12.5%, 3/24), 10% potassium hydroxide solution (12.5%, 3/24) or 10% potassium thioglycolate cream (12.5%, 3/24). Section thickness was 4 to 9 um (62.5%), using a steel microtome (92%,12/13) on glass slides (91.6%, 11/12). Hematoxylin and eosin (H&E) was routine for all biopsies and Periodic acid Schiff (PAS) for fungus. The favored stain for differentiating melanin and hemoglobin was Fontana-Masson (60%, 6/10). For pigmented lesions, Melan-A was always employed by all respondents (9/9). CONCLUSION: Nail histopathology processing has some small variations from normal skin processing. PMID- 28589673 TI - Lung cancer samples preserved in liquid medium: One step beyond cytology. AB - Lung cancer is one of the most common cancer types in men and women worldwide with a high mortality rate. World Health Organization (WHO) classification has accepted biopsy as the primary sample for lung cancer diagnosis, pathological classification and molecular testing for management of patients, yet, the use of alternative sampling procedures is highly encouraged. Bronchial cytological samples require a less invasive collection technique and may be suitable for pathological and molecular analysis and storage in liquid medium. Furthermore, the molecular analysis of bronchial cytological samples allows the detection of molecular biomarkers, which may be useful for the selection of molecular targeted therapies. Thus, the purpose of this review is to describe the usefulness of bronchial cytological samples preserved in liquid medium from lung cancer patients for pathological diagnosis and molecular investigation. PMID- 28589674 TI - Differences in the early stages of social information processing for adolescents involved in bullying. AB - Bullying victimization has commonly been associated with deficiencies in social information processing (SIP). In contrast, findings regarding bullying perpetration are mixed, with some researchers claiming that bullies may have superior SIP abilities than victimized or uninvolved youth. This study investigated the effects of bullying and victimization on early SIP; specifically the recognition and interpretation of social information. In stage 1, 2,782 adolescents (11-16 years) were screened for bullying involvement, and in stage 2, 723 of these participants (mean age = 13.95) were assessed on measures of emotion recognition, hostile attribution bias, and characterological self-blame (CSB). No associations between bullying and early SIP were found. In contrast, victimization was associated with more hostile attribution bias and CSB attributions. Girls performed better than boys on the emotion recognition task while boys showed greater hostile attribution biases. No interaction effects of bullying or victimization with gender were found. Follow-up categorical analyses that considered pure victims versus victims who also bullied (bully-victims) on SIP, found a similar pattern of findings. These findings suggest that those who purely bully others are neither superior nor deficient in the early stages of SIP. Victimized adolescents, however, show biases in their interpretations of social situations and the intentions of others. These biases may lead to maladaptive responses and may increase risk for further victimization by peers. PMID- 28589675 TI - Cdk5 activity is required for Purkinje cell dendritic growth in cell-autonomous and non-cell-autonomous manners. AB - Cyclin-dependent kinase 5 (Cdk5) is recognized as a unique member among other Cdks due to its versatile roles in many biochemical processes in the nervous system. The proper development of neuronal dendrites is required for the formation of complex neural networks providing the physiological basis of various neuronal functions. We previously reported that sparse dendrites were observed on cultured Cdk5-null Purkinje cells and Purkinje cells in Wnt1cre -mediated Cdk5 conditional knockout (KO) mice. In the present study, we generated L7cre mediated p35; p39 double KO (L7cre -p35f/f ; p39-/- ) mice whose Cdk5 activity was eliminated specifically in Purkinje cells of the developing cerebellum. Consequently, these mice exhibited defective Purkinje cell migration, motor coordination deficiency and a Purkinje dendritic abnormality similar to what we have observed before, suggesting that dendritic growth of Purkinje cells was cell autonomous in vivo. We found that mixed and overlay cultures of WT cerebellar cells rescued the dendritic deficits in Cdk5-null Purkinje cells, however, indicating that Purkinje cell dendritic development was also supported by non cell-autonomous factors. We then again rescued these abnormalities in vitro by applying exogenous brain-derived neurotrophic factor (BDNF). Based on the results from culture experiments, we attempted to rescue the developmental defects of Purkinje cells in L7cre -p35f/f ; p39-/- mice by using a TrkB agonist. We observed partial rescue of morphological defects of dendritic structures of Purkinje cells. These results suggest that Cdk5 activity is required for Purkinje cell dendritic growth in cell-autonomous and non-cell-autonomous manners. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1175-1187, 2017. PMID- 28589676 TI - Effect of carrageenans alone and in combination with casein or lipopolysaccharide on human epithelial intestinal HT-29 cells. AB - The research described here was focused on the effect on human intestinal epithelial cell monolayers of sulfated red algal polysaccharides (kappa-, lambda , and kappa/beta-carrageenans) alone and in combination with casein or lipopolysaccharide (LPS). HT-29 cells were investigated under normal and stress conditions; stress was induced by exposure to ethanol. Cell viability was monitored with a real-time system. The change in binding properties of negatively sulfated red algal polysaccharides assessed by the measurement of free carrageenans in mixtures with casein or McCoy's 5 A culture medium by means of toluidine blue O. Low sulfate content and the presence of 3,6-anhydogalactose are prerequisites for the recovery of ethanol-exposed HT-29 cells by carrageenans. Analysis of carrageenan binding ability confirmed that casein and LPS should affect carrageenan activity. Whether the combined action of the mucin-containing layer and carrageenans or the action of carrageenans alone was responsible for enhanced cell viability under stress conditions induced by ethanol is a subject for further research. (c) 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2843-2850, 2017. PMID- 28589677 TI - Telehealth in paediatric surgery: Accuracy of clinical decisions made by videoconference. AB - AIM: Telehealth is a useful method of providing specialist consultation to a geographically diverse population. Canadian studies of telehealth for paediatric surgery demonstrate good accuracy, but have low numbers of cryptorchid patients in their cohorts. Our aim was to confirm Canadian studies for our cohort and to assess accuracy regarding cryptorchidism. METHODS: We conducted a cohort study of patients seen via paediatric surgical telehealth over a 12-month period, to determine accuracy of telediagnosis with respect to face-to-face diagnosis and plan. RESULTS: A total of 183 children had 224 videoconferences, resulting in 74 surgical bookings. There was high diagnostic concordance, except for undescended testes. One discharged patient, and two patients booked for review, have subsequently required an orchidopexy (false negatives). Of 15 patients booked for surgery, three did not require an operation (false positives). Other patients had their procedures upgraded (from open to laparoscopic) or downgraded (from laparoscopic to open) due to inaccuracies in far-end assessment. CONCLUSION: Telehealth for paediatric surgery is accurate for most conditions seen, but for cryptorchidism there are significant concerns. PMID- 28589679 TI - Self-Regulating Iris Based on Light-Actuated Liquid Crystal Elastomer. AB - The iris, found in many animal species, is a biological tissue that can change the aperture (pupil) size to regulate light transmission into the eye in response to varying illumination conditions. The self-regulation of the eye lies behind its autofocusing ability and large dynamic range, rendering it the ultimate "imaging device" and a continuous source of inspiration in science. In optical imaging devices, adjustable apertures play a vital role as they control the light exposure, the depth of field, and optical aberrations of the systems. Tunable irises demonstrated to date require external control through mechanical actuation, and are not capable of autonomous action in response to changing light intensity without control circuitry. A self-regulating artificial iris would offer new opportunities for device automation and stabilization. Here, this paper reports the first iris-like, liquid crystal elastomer device that can perform automatic shape-adjustment by reacting to the incident light power density. Similar to natural iris, the device closes under increasing light intensity, and upon reaching the minimum pupil size, reduces the light transmission by a factor of seven. The light-responsive materials design, together with photoalignment based control over the molecular orientation, provides a new approach to automatic, self-regulating optical systems based on soft smart materials. PMID- 28589681 TI - Corrigendum: Strain uses gap junctions to reverse stimulation of osteoblast proliferation by osteocytes. PMID- 28589678 TI - Barriers and facilitators to young children's physical activity and sedentary behaviour: a systematic review and synthesis of qualitative literature. AB - Positive activity behaviours (i.e. higher physical activity [PA]/lower sedentary behaviour [SB]) are beneficial from infancy, yet evidence suggests that young children (0- to 6-year-olds) are relatively inactive. To better understand the perceived influences on these behaviours and to aid intervention development, this paper systematically synthesizes the extensive qualitative literature regarding perceived barriers and facilitators to PA and SB in young children (0-6 years old). A search of eight electronic databases (July 2016) identified 43 papers for inclusion. Data extraction and evidence synthesis were conducted using thematic content analysis, underpinned by the socio-ecological model (i.e. individual, interpersonal, community, organizational and policy levels). Parents, childcare providers and children perceived seven broad themes to be important for PA and SB, including the child; the home; out-of-home childcare; parent-childcare provider interactions; environmental factors; safety; and weather. Each theme mapped onto between one and five levels of the socio-ecological model; barriers and facilitators at the interpersonal level (e.g. parents, care providers and family) were most frequently cited, reflecting the important (perceived) role adults/peers play in shaping young children's behaviours. We provide an overarching framework to explain PA and SB in early childhood. We also highlight where gaps in the current literature exist (e.g. from male carers; in developing countries; and barriers and facilitators in the environmental and policy domains) and where future quantitative work may focus to provide novel insights about children's activity behaviours (e.g. safety and weather). PMID- 28589680 TI - All-trans retinoic acid upregulates the expression of ciliary neurotrophic factor in retinal pigment epithelial cells. AB - Retinopathy of prematurity, a leading cause of visual impairment in low birth weight infants, remains a crucial therapeutic challenge. Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that promotes rod and cone photoreceptor survival and cone outer segment regeneration in the degenerating retina. Ciliary neurotrophic factor expression is regulated by many factors such as all-trans retinoic acid (ATRA). In this study, we found that ATRA increased CNTF expression in mouse retinal pigment epithelial (RPE) cells in a dose- and time-dependent manner, and PKA signaling pathway is necessary for ATRA-induced CNTF upregulation. Furthermore, we showed that ATRA promoted CNTF expression through CREB binding to its promoter region. In addition, CNTF levels were decreased in serum of retinopathy of prematurity children and in retinal tissue of oxygen-induced retinopathy mice. In mouse RPE cells cultured with high oxygen, CNTF expression and secretion were decreased, but could be recovered after treatment with ATRA. In conclusion, our data suggest that ATRA administration upregulates CNTF expression in RPE cells. PMID- 28589682 TI - Expansion of adipose tissue-derived stromal cells at "physiologic" hypoxia attenuates replicative senescence. AB - Multipotent mesenchymal stromal cells are considered as a perspective tool in cell therapy and regenerative medicine. Unfortunately, autologous cell therapy does not always provide positive outcomes in elder donors, perhaps as a result of the alterations of stem cell compartments. The mechanisms of stem and progenitor cell senescence and the factors engaged are investigated intensively. In present paper, we elucidated the effects of tissue-related O2 on morphology, functions, and transcriptomic profile of adipose tissue-derived stromal cells (ASCs) in replicative senescence in vitro model. Replicatively senescent ASCs at ambient (20%) O2 (12-21 passages) demonstrated an increased average cell size, granularity, reactive oxygen species level, including anion superoxide, lysosomal compartment activity, and IL-6 production. Decreased ASC viability and proliferation, as well as the change of more than 10 senescence-associated gene expression were detected (IGF1, CDKN1C, ID1, CCND1, etc). Long-term ASC expansion at low O2 (5%) revoked in part the replicative senescence-associated alterations. PMID- 28589684 TI - Chimeric RNAs in cancer and normal physiology. AB - Traditionally, chimeric RNAs were considered to be exclusive to cancer cells. When occasionally observed in normal samples, they were usually considered to be transcriptional 'noises,' or artifacts due to template switching during the reverse transcription and/or Polymerase chain reaction (PCR) steps of experimentation. However, with the advances being made in next generation sequencing technologies and software tools, as well as the accumulation of new experimental evidences, increasing numbers of chimeric transcripts are being identified in noncancerous tissues and cells. Recent studies have also demonstrated functional relevance, for at least a subset of chimeric RNAs in normal physiology. The advances have resulted in an influx of knowledge; this knowledge indicates that chimeric RNAs are a component of basic biology, and thus challenging traditional dogma. In addition to chromosomal rearrangement, chimeric RNAs can also be formed via different molecular mechanisms including cis-splicing of adjacent genes (cis-SAGe) and trans-splicing, as well as others. Little is known about the details of these noncanonical splicing processes. However, research in this new field promises to not only advance our basic understanding of the human genome and gene regulation, but also lead to improvements in clinical practice, especially in the areas of cancer diagnostics and treatment. WIREs RNA 2017, 8:e1427. doi: 10.1002/wrna.1427 For further resources related to this article, please visit the WIREs website. PMID- 28589683 TI - Early detection and integrated care for adolescents and young adults with psychotic disorders: the ACCESS III study. AB - OBJECTIVE: The objective of the study was to investigate whether a combined intervention composed of early detection plus integrated care (EDIC) enhances outcomes in patients with early psychosis compared to standard care (SC). METHODS: ACCESS III is a prospective non-randomized historical control design 1 year study examining the efficacy of EDIC (n = 120) vs. SC (n = 105) in patients aged 12-29 years. Primary outcome was the rate of >=6 months combined symptomatic and functional remission. Additional outcomes comprised the reduction of DUP and course of psychopathology, functioning, quality of life, and satisfaction with care. RESULTS: In observed cases, 48.9% in the EDIC and 15.2% in the SC group reached the primary endpoint. Remission was predicted by EDIC (OR = 6.8, CI: 3.15 14.53, P < 0.001); younger age predicted non-remission (OR = 1.1, CI: 1.01-1.19, P = 0.038). Linear regressions indicated a reduction of DUP in EDIC (P < 0.001), but not in SC (P = 0.41). MMRMs showed significantly larger improvements in PANSS positive (P < 0.001) and GAF (P < 0.01) scores in EDIC vs. SC, and in EDIC over time in CGI-Severity (P < 0.001) and numerically in Q-LES-Q-18 (P = 0.052). CONCLUSIONS: EDIC lead to significantly higher proportions of patients achieving combined remission. Moderating variables included a reduction of DUP and EDIC, offering psychotherapeutic interventions. PMID- 28589685 TI - Efficiency performance of China's health care delivery system. AB - Improving efficiency performance of the health care delivery system has been on the agenda for the health system reform that China initiated in 2009. This study examines the changes in efficiency performance and determinants of efficiency after the reform to provide evidence to assess the progress of the reform from the perspective of efficiency. Descriptive analysis, Data Envelopment Analysis, the Malmquist Index, and multilevel regressions are used with data from multiple sources, including the World Bank, the China Health Statistical Yearbook, and routine reports. The results indicate that over the last decade, health outcomes compared with health investment were relatively higher in China than in most other countries worldwide, and the trend was stable. The overall efficiency and total factor productivity increased after the reform, indicating that the reform was likely to have had a positive impact on the efficiency performance of the health care delivery system. However, the health care delivery structure showed low system efficiency, mainly attributed to the weakened primary health care system. Strengthening the primary health care system is central to enhancing the future performance of China's health care delivery system. PMID- 28589686 TI - G-CSF loaded nanofiber/nanoparticle composite coated with collagen promotes wound healing in vivo. AB - Sustained release of functional growth factors can be considered as a beneficial methodology for wound healing. In this study, recombinant human granulocyte colony-stimulating factor (G-CSF)-loaded chitosan nanoparticles were incorporated in Poly(epsilon-caprolactone) (PCL) nanofibers, followed by surface coating with collagen type I. Physical and mechanical properties of the PCL nanofibers containing G-CSF loaded chitosan nanoparticles PCL/NP(G-CSF) and in vivo performance for wound healing were investigated. G-CSF structural stability was evaluated through SDS_PAGE, reversed phase (RP) HPLC and size-exclusion chromatography, as well as circular dichroism. Nanofiber/nanoparticle composite scaffold was demonstrated to have appropriate mechanical properties as a wound dresser and a sustained release of functional G-CSF. The PCL/NP(G-CSF) scaffold showed a suitable proliferation and well-adherent morphology of stem cells. In vivo study and histopathological evaluation outcome revealed that skin regeneration was dramatically accelerated under PCL/NP(G-CSF) as compared with control groups. Superior fibroblast maturation, enhanced collagen deposition and minimum inflammatory cells were also the beneficial properties of PCL/NP(G-CSF) over the commercial dressing. The synergistic effect of extracellular matrix mimicking nanofibrous membrane and G-CSF could develop a suitable supportive substrate in order to extensive utilization for the healing of skin wounds. (c) 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2830-2842, 2017. PMID- 28589687 TI - Adaptive DBS in a Parkinson's patient with chronically implanted DBS: A proof of principle. PMID- 28589688 TI - Polymerization of 1-Phosphaisoprene: Synthesis and Characterization of a Chemically Functional Phosphorus Version of Natural Rubber. AB - Macromolecules derived from 1,3-dienes, such as polyisoprene (or natural rubber), are of considerable importance in polymer science. Given the parallels between P=C and C=C bonds, the prospect of polymerizing P-containing 1,3-dienes, such as 1-phosphaisoprene, is intriguing due to the unique chemical functionality imparted by the heavier element combined with their structural relationship to natural rubber. Herein, we report the synthesis, characterization and coordination chemistry of the first polymers derived from Mes*P=CR-CH=CH2 (Mes*=2,4,6-t-Bu3 C6 H2 ; R=H, Me). In the case of 1-phosphaisoprene (R=Me), the monomer is isolable and its anionic polymerization affords a polymer that retains P=C bonds in its microstructure. The chemical functionality of these novel materials is demonstrated by forming the macromolecular gold(I) complex where the P=C bond is retained for further chemical elaboration. PMID- 28589689 TI - Genetic variation in the developmental regulation of cortical avpr1a among prairie voles. AB - Early experiences can have enduring impacts on brain and behavior, but the strength of these effects can be influenced by genetic variation. In principle, polymorphic CpGs (polyCpGs) may contribute to gene-by-environment interactions (G * E) by altering DNA methylation. In this study, we investigate the influence of polyCpGs on the development of vasopressin receptor 1a abundance in the retrosplenial cortex (RSC-V1aR) of prairie voles (Microtus ochrogaster). Two alternative alleles ('HI'/'LO') predict RSC avpr1a expression, V1aR abundance and sexual fidelity in adulthood; these alleles differ in the frequency of CpG sites and in methylation at a putative intron enhancer. We hypothesized that the elevated CpG abundance in the LO allele would make homozygous LO/LO voles more sensitive to developmental perturbations. We found that genotype differences in RSC-V1aR abundance emerged early in ontogeny and were accompanied by differences in methylation of the putative enhancer. As predicted, postnatal treatment with an oxytocin receptor antagonist (OTA) reduced RSC-V1aR abundance in LO/LO adults but not their HI/HI siblings. Similarly, methylation inhibition by zebularine increased RSC-V1aR in LO/LO adults, but not in HI/HI siblings. These data show a gene-by-environment interaction in RSC-V1aR. Surprisingly, however, neither OTA nor zebularine altered adult methylation of the intronic enhancer, suggesting that differences in sensitivity could not be explained by CpG density at the enhancer alone. Methylated DNA immunoprecipiation-sequencing showed additional differentially methylated regions between HI/HI and LO/LO voles. Future research should examine the role of these regions and other regulatory elements in the ontogeny of RSC-V1aR and its developmentally induced changes. PMID- 28589690 TI - Perioperative management of new oral anticoagulants in patients undergoing elective surgery at a tertiary hospital. AB - BACKGROUND: Increasing numbers of patients receiving new oral anticoagulants (NOAC) are undergoing elective surgery. The extent to which perioperative interruption of NOAC therapy and use of bridging heparin are concordant with best evidence is uncertain. AIMS: To determine: (i) concordance of NOAC and bridging heparin use with guidelines; and (ii) associations between guideline concordance and patient characteristics, surgical factors and perioperative adverse events. METHODS: Retrospective study of consecutive adult patients undergoing elective surgery at a tertiary hospital between 1 January 2014 and 30 June 2015 and were receiving NOAC for at least 3 months prior to surgery. Concordance of perioperative anticoagulation management with hospital guidelines was rated by two independent researchers according to explicit thrombosis and bleeding risk tables. RESULTS: One hundred and fifty patients of mean (+/-SD) age 72.0 (+/ 11.6) years were studied; 75% had atrial fibrillation as NOAC indication. Decision to interrupt anticoagulation in 142 patients was rated guideline concordant in 59 (41.5%) based on low bleeding risk in all cases and high thrombotic risk in one-third. Concordant decisions were associated with past myocardial infarction (P = 0.009), chronic kidney disease (P = 0.05), use of dabigatran (P = 0.06) and major surgery (P < 0.001). Bridging heparin was prescribed in 51 (35.9%) patients and not prescribed in 91 (64.1%), with 64 (45.1%) decisions rated guideline-discordant comprising 27 decisions to prescribe and 37 not to prescribe. Guideline concordant bridging was associated with chronic kidney disease (P = 0.02); discordant bridging with use of dabigatran (P = 0.04), high thrombotic risk (P = 0.004), past ischaemic stroke (P = 0.07). At 30 days, only one adverse event (major bleed) was noted. CONCLUSION: Considerable discordance exists between guideline recommendations and perioperative NOAC management. Assistive tools are required that better align decision-making with current best practice. PMID- 28589691 TI - Medical scribes have no impact on the patient experience of an emergency department. AB - OBJECTIVE: We aimed to evaluate patient perceptions of medical scribes in the ED and to test for scribe impacts on ED Net Promoter Scores, Press Ganey Surveys and other patient-centred topics. METHODS: Exploratory semi-structured interviews were conducted in the ED during wait times after scribed consultations. Interview results were used to derive topics relating to scribes. Items addressing these topics from validated surveys were combined with items from widely used patient satisfaction questionnaires. Questionnaires were administered in the ED by face to-face approach while patients were waiting for admission/discharge or test results. Patients and doctors were blinded to the purpose of the questionnaire. The survey evaluated for non-inferiority of scribed consultations, using Net Promoter Scores, Press Ganey questions and questions specific to the presence of the scribe. RESULTS: Patient interviews did not identify any negative views regarding the presence of scribes during consultations. Thematic saturation was achieved after seven interviews. Two hundred and fifty-eight patients were approached to complete the questionnaire, and 215 participated (83%); 95 and 118 participants in the scribed and non-scribed groups, respectively. There was no difference between scribed and non-scribed consultations on the following measures of satisfaction: the Net Promoter Score, Press Ganey questions, quality of information received from doctors, communication, privacy concerns or inhibition about revealing private information and room crowding. CONCLUSION: We found no evidence that scribes reduce patient satisfaction during emergency consultations, nor prompt discomfort that might cause a patient to withhold information. PMID- 28589692 TI - A gatekeeping procedure to test a primary and a secondary endpoint in a group sequential design with multiple interim looks. AB - Glimm et al. (2010) and Tamhane et al. (2010) studied the problem of testing a primary and a secondary endpoint, subject to a gatekeeping constraint, using a group sequential design (GSD) with K=2 looks. In this article, we greatly extend the previous results to multiple (K>2) looks. If the familywise error rate (FWER) is to be controlled at a preassigned alpha level then it is clear that the primary boundary must be of level alpha. We show under what conditions one alpha level primary boundary is uniformly more powerful than another. Based on this result, we recommend the choice of the O'Brien and Fleming (1979) boundary over the Pocock (1977) boundary for the primary endpoint. For the secondary endpoint the choice of the boundary is more complicated since under certain conditions the secondary boundary can be refined to have a nominal level alpha'>alpha, while still controlling the FWER at level alpha, thus boosting the secondary power. We carry out secondary power comparisons via simulation between different choices of primary-secondary boundary combinations. The methodology is applied to the data from the RALES study (Pitt et al., 1999; Wittes et al., 2001). An R library package gsrsb to implement the proposed methodology is made available on CRAN. PMID- 28589693 TI - Antipsychotic prescription and mortality in hospitalized older persons. AB - BACKGROUND: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3 month follow-up in elderly inpatients. METHODS: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Societa Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. RESULTS: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score >=10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score <5 (indicative of normal cognition). In-hospital mortality was slightly higher in patients prescribed antipsychotic drugs (14.3% vs 9.4%; P = 0.109), but in multivariate analysis only male sex, older age, and higher SBT scores were significantly related to mortality during hospitalization. At 3-month follow-up, only male sex, older age, and higher SBT scores were associated with mortality. CONCLUSION: We found that the prescription of antipsychotic drugs during hospitalization was not associated with in-hospital or follow-up mortality. Short-term antipsychotic prescriptions (for acutely ill patients) may have a different effect than long-term, repeated prescriptions. PMID- 28589694 TI - Can members of the south-western Gila robusta species complex be distinguished by morphological features? AB - The goal for this project was to re-examine key morphological characters hypothesized to differentiate Gila intermedia, Gila robusta and Gila nigra and outline methods better suited for making species designations based on morphology. Using a combination of meristic counts, morphological measurements and geometric morphometrics, morphological dissimilarities were quantified among these three putative species. Traditional meristic counts and morphological measurements (i.e. distances between landmarks) were not useful for species identification. Geometric morphometrics, however, identified differences among species, while also suggesting an effect of geographic location on morphological variation. Using canonical variate analysis for the 441 fish sampled in this study, geometric morphometrics accurately predicted true group membership 100% of the time for G. nigra, 97% of the time for G. intermedia and 91% of the time for G. robusta. These results suggest that geometric morphometric analysis is necessary to identify morphological differences among the three species. Geometric morphometric analysis used in this study can be adopted by management officials as a tool to classify unidentified individuals. PMID- 28589695 TI - Effect of orally administered zinc oxide nanoparticles on albino rat thymus and spleen. AB - This study aimed to evaluate the toxicological effects of oral intake of Zinc oxide nanoparticles (ZnO NPs) on the structure of thymus and spleen. Twenty-four young male Wistar albino rats were assigned into two groups: group I (control) and group II (ZnO NPs treated group).The thymus and spleen were analyzed biochemically, histopathologically and immunohistochemically. After ZnO NPs intake, hematologically, the total leucocytic count was significantly increased while the RBCs and platelets counts and Hb % were significantly decreased. Biochemically, a significant decrease in serum total antioxidant capacity and anti-inflammatory cytokines including interleukin 4 and 10 (IL-4 and IL-10) levels was noted. While a significant increase in splenic and thymic malondialdehyde (MDA) and DNA shearing, as well as the studied proinflammatory cytokines; IL-1beta, tumor necrotic factor (TNF-alpha) and interferon (INF-gamma) levels was detected. Notably, we noted upregulation of the immunomodulatory [CD3, CD11b, heme oxygenase (HO-1)] and the inflammatory [toll-like receptor 4 and 6 (TLR4 and TLR6)] genes. Histopathologically, degenerative changes were detected in thymus and spleen of ZnO NPs treated group. While the immunohistochemical analysis of the ZnO NPs treated group revealed a decrease in the number of cells expressed positive reactions of anti-PCNA and an increase in the number of cells expressed positive reaction of anti-p53 in the thymus and spleen. In conclusion, ZnO NPs induced obvious immunotoxicity in the thymus and spleen, where oxidative/inflammatory pathway may be the potential mechanism underlying this immunotoxicity. (c) 2017 IUBMB Life, 69(7):528-539, 2017. PMID- 28589697 TI - Immediate hypersensitivity to chlorhexidine. AB - Chlorhexidine is a widely used and effective antiseptic agent. Although skin contact is usually well tolerated, it may cause both immediate and delayed hypersensitivity reactions. We report a case of immediate hypersensitivity to chlorhexidine causing both skin and respiratory symptoms following occupational exposure to chlorhexidine in a health-care worker. PMID- 28589696 TI - Cross-altitude analysis suggests a turning point at the elevation of 4,500 m for polycythemia prevalence in Tibetans. PMID- 28589699 TI - Genetic relationships of Plagioscion squamosissimus (Perciformes, Sciaenidae) from five Neotropical river basins evaluated using mitochondrial atpase6/8 gene sequences. AB - The genetic relationships of native or introduced Plagioscion squamosissimus in five Brazilian Neotropical basins were evaluated using the mitochondrial atpase6/8 genes. Results revealed that the population of the Tocantins River basin is more basal than the native populations of the Amazon and Parnaiba River basins. Moreover, the populations of P. squamosissimus that were introduced in the Sao Francisco and upper Parana River basins originated from the population of the Parnaiba River. PMID- 28589698 TI - Wnt and Shh signals regulate neural stem cell proliferation and differentiation in the optic tectum of adult zebrafish. AB - Adult neurogenesis occurs more commonly in teleosts, represented by zebrafish, than in mammals. Zebrafish is therefore considered a suitable model to study adult neurogenesis, for which the regulatory molecular mechanisms remain little known. Our previous study revealed that neuroepithelial-like neural stem cells (NSCs) are located at the edge of the dorsomedial region. We also showed that Notch signaling inhibits NSC proliferation in this region. In the present study, we reported the expression of Wnt and Shh signaling components in this region of the optic tectum. Moreover, inhibitors of Wnt and Shh signaling suppressed NSC proliferation, suggesting that these pathways promote NSC proliferation. Shh is particularly required for maintaining Sox2-positive NSCs. Our experimental data also indicate the involvement of these signaling pathways in neural differentiation from NSCs. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1206-1220, 2017. PMID- 28589700 TI - Highly Anisotropic Sb2 Se3 Nanosheets: Gentle Exfoliation from the Bulk Precursors Possessing 1D Crystal Structure. AB - 2D materials, particularly those bearing in-plane anisotropic optical and electrical properties such as black phosphorus and ReS2 , have spurred great research interest very recently as promising building blocks for future electronics. However, current progress is limited to layered compounds that feature atomic arrangement asymmetry within the covalently bonded planes. Herein, a series of highly anisotropic nanosheets (Sb2 Se3 , Sb2 S3 , Bi2 S3 , and Sb2 (S, Se)3 ), which are composed of 1D covalently linked ribbons stacked together via van der Waals force, is introduced as a new member to the anisotropic 2D material family. These unique anisotropic nanosheets are successfully fabricated from their polymer-like bulk counterparts through a gentle water freezing-thawing approach. Angle-resolved polarized Raman spectroscopy characterization confirms the strong in-plane asymmetry of Sb2 Se3 nanosheets, and photodetection study reveals their high responsivity and anisotropic in-plane transport. This work can enlighten the synthesis and application of new anisotropic 2D nanosheets that can be potentially applied for future electronic and optoelectronic devices. PMID- 28589701 TI - IGHV mutational status testing in chronic lymphocytic leukemia. AB - As the therapeutic landscape for chronic lymphocytic leukemia (CLL) continues to expand, biological predictors of response to therapy are becoming increasingly important. One such predictive biomarker is the mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene, which is a powerful predictor of duration of response and overall survival with chemoimmunotherapy (CIT). As this test may influence choice of therapy between CIT and novel agents, it is critical that providers understand how mutational status is determined and the limitations of testing. Here, we describe the details of IGHV mutational status testing, highlighting the appropriate way to interpret this information and best apply it to the care of patients with CLL. PMID- 28589702 TI - Choto-san versus placebo for patients with dementia: systematic review and meta analysis. AB - BACKGROUND: Choto-san is a traditional medicine used for hypertension and headaches in Japan and China. Some studies have shown its effectiveness in the treatment of dementia. The present review aimed to assess the effectiveness and acceptability of Choto-san in the treatment of adults with cognitive impairment. METHODS: We included randomized controlled trials comparing Choto-san with placebo for patients with dementia or mild cognitive impairment. RESULTS: Three randomized controlled trials evaluating 219 participants were included. Two were studies on vascular dementia, and the other was on Alzheimer's dementia. There was no difference between Choto-san and placebo in terms of short-term dichotomous judgement of improvement, but Choto-san was more effective than placebo in terms of short-term improvement of cognitive function as measured by continuous outcomes. Also, dropouts judged it to be acceptable. However, the results were imprecise and/or heterogeneous. The number of participants included in the analysis was small (n = 199 in the primary analysis) and sometimes inconsistent, as indicated by the large I 2 (72% in the primary analysis). CONCLUSION: Low-quality evidence was suggestive of Choto-san's efficacy for vascular dementia, but the present results may be overestimated. Studies with a larger sample size and conducted over longer periods should be performed. Regardless, Choto-san can be one of the choices for the treatment of vascular dementia as it is well tolerated. PMID- 28589703 TI - Who is afraid of ISIS? ISIS anxiety and its correlates. AB - Islamic State of Iraq and the Levant (ISIS) is a relatively small organization, yet it wields its terror and media campaigns efficiently. Its presence has altered security measures in many western counties. In the current study, I assess anxiety of the ISIS threat and its correlates in a convenience sample of 1,007 adult Israelis (mean age = 29.61, SD = 7.16). Findings show that being female, a lower socioeconomic status, and having elevated post-traumatic stress disorder (PTSD) symptom levels were all associated with ISIS anxiety. Likewise, exposure to ISIS media, as well as having low resilience, was also correlated with ISIS anxiety. The correlations between ISIS anxiety on the one hand and ISIS media exposure, PTSD symptoms, and resilience on the other hand remained significant even after controlling for general anxiety symptoms. Finally, the PTSD- ISIS anxiety relationship was especially pronounced when resources (resilience/optimism) were low. This critical interaction also remained significant after controlling for general anxiety. Theoretical and practical ramifications of ISIS anxiety are discussed. Both resources for addressing current tasks (resilience), as well as those aimed at future outcomes (optimism), may be required for addressing ISIS anxiety, especially when PTSD symptoms are high. PMID- 28589705 TI - Functional capacity and obesity reflect the cognitive performance of older adults living in long-term care facilities. AB - BACKGROUND: With the increase in life expectancy, the elderly Brazilian population has grown considerably. However, longevity is usually accompanied by problems such as the loss of functional capacity, cognitive decline, and deterioration in anthropometric parameters, particularly among those living in long-term care facilities. We analyzed the relationship among cognitive performance, anthropometry, and functional capacity in institutionalized elderly individuals. METHODS: In a sample of 38 older adults (20 men, 18 women) aged 73.4 +/- 8.1 years, data regarding anthropometric and functional measurements as well as the Mini-Mental State Examination were collected. Functional tests were based on a battery adapted from the Functional Fitness Test. The independent t-test and chi2 test were applied. P < 0.05 was set as the significance threshold. RESULTS: The rate of cognitive impairment among obese individuals (78.6%) differed from that among eutrophic subjects (45.8%), but there was no difference between sexes. There was a significant positive correlation between handgrip strength and Mini Mental State Examination score, and the scores of the timed up-and-go test and the sitting-rising test were negatively correlated with Mini-Mental State Examination score. CONCLUSION: Cognitive impairment in the elderly living in long term care facilities was more pronounced and frequent in obese individuals. This study also demonstrated that better functional capacity reflects better cognitive performance. PMID- 28589704 TI - Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients. AB - This multicentre study evaluated 5-year progression-free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles (PET-2). Between September 2006 and August 2013, 359 patients aged 18-60 years, were recruited in nine Israeli centres. Early-HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) *2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy (ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD *2; those with unfavourable disease received ABVD *2 with ISRT or, alternatively, ABVD *4. Advanced-HL patients initially received ABVD *2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) *2 based on their international prognostic score (<=2 or >=3). PET-2-negative patients further received ABVD *4; PET-2-positive patients received EB *4 and ISRT to residual masses. With a median follow-up of 55 (13-119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early-HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced-HL, the PFS was 81% and 68%, respectively (P = 0.08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early-HL, even with additional ABVD and ISRT. Advanced-HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients. PMID- 28589706 TI - Technical Performance and Clinical Effectiveness of Drop Type With Adjustable Concentrator-Cell Free and Concentrated Ascites Reinfusion Therapy. AB - Cell-free and concentrated ascites reinfusion therapy (CART) is a very useful treatment method for refractory ascites but is difficult for many hospitals to employ due to its need for specialized equipment. We have therefore developed drop-type with adjustable concentrator CART (DC-CART) that uses a drop-type filtration mechanism and requires only a simple pump and pressure monitor for its concentration process. Easy adjustment of ascites concentration is possible through a recirculation loop, and filter membrane washing is aided by DC-CART's external pressure-type filtration to enable the processing of any quality or quantity of ascites. Moreover, the absence of a roller pump before filtration avoids inflammatory substance release from compressed cells. A total of 268 sessions of DC-CART using ascites from 98 patients were performed with good clinical results at our hospitals between January 2012 and June 2016. This report presents the detailed methods of DC-CART and summarizes its clinical effectiveness using patient ascites and blood data obtained from 59 sessions between March 2015 and February 2016. This novel technique successfully processed refractory ascites in numerous diseases with no serious adverse events. DC-CART could concentrate large amounts of ascites (from median weight: 4900 g [max: 20 200 g] to median weight: 695 g; median concentration ratio: 7.4), and a high amount of protein (median weight: 73 g [max: 294 g]) could be reinfused. Serum albumin levels were significantly increased (P = 0.010) and kidney function and systemic hemodynamics were well maintained in treated subjects. Additional concentration of ascites and adjustment of ascites volume were easily performed by recirculation (from median weight: 615 g to median weight: 360 g; median concentration ratio: 1.5). Time was needed during DC-CART for filter membrane cleaning, especially for viscous ascites. Overall, DC-CART represents a safe and useful treatment method for various forms of refractory ascites that can be performed at a wide range of health care institutions. PMID- 28589707 TI - Sequence-based typing identification of a novel HLA-C allele, C*12:214, in a Han Chinese individual. AB - One nucleotide substitution at position 497 of HLA-C*12:02:01 results in a novel allele, HLA-C*12:214. PMID- 28589708 TI - Modified continuity equation using left ventricular outflow tract three dimensional imaging for aortic valve area estimation. AB - PURPOSE: Aortic valve area (AVA) is usually estimated by the continuity equation (CE) in which the left ventricular outflow tract (LVOT) area is calculated assuming a circular shape. This study aimed to compare measurements of LVOT area using standard 2D transthoracic echocardiography (2DTTE), 3D transesophageal echocardiography (3DTEE), and multidetector computed tomography (MDCT) and assess their relative impact on AVA estimated by the CE. METHODS AND RESULTS: We prospectively enrolled 60 patients with severe aortic stenosis (AS) referred for transcatheter aortic valve replacement (TAVR) who systematically underwent 2DTTE, 3DTEE, and MDCT. Mean LVOT areas obtained by 2DTTE (3.28+/-0.66 cm2 ) and 3DTEE (3.95+/-0.90 cm2 ) were significantly underestimated when compared to the mean MDCT LVOT area (4.31+/-0.99 cm2 ). LVOT was rather elliptical than round, with a mean eccentricity index of 1.47 (ratio of maximum to minimum LVOT diameters) assessed by MDCT. Mean TTE AVA estimated by the CE was 0.62+/-0.20 cm2 . Substitution of 2DTTE LVOT area by 3DTEE LVOT area in the CE resulted in AVA of 0.74+/-0.24 cm2 , while using MDCT LVOT area held an AVA of 0.80+/-0.24 cm2 . MDCT-derived AVA was similar to MDCT planimetric AVA and allowed 24% of patients to be reclassified from severe to moderate AS. CONCLUSIONS: 2DTTE and 3DTEE underestimate LVOT area when compared to MDCT with significant impact on AVA estimation. Assessment through MDCT fusion AVA may be of incremental value in patients with discrepant severity criteria for AS. PMID- 28589710 TI - HLA-DRB3*02:61Q , a novel HLA-DRB3 allele identified in a volunteer bone marrow donor. AB - HLA-DRB3*02:61Q , a novel HLA-DRB3 allele identified in a volunteer bone marrow donor. PMID- 28589709 TI - Generation of Nkx2-5/CreER transgenic mice for inducible Cre expression in developing hearts. AB - Nkx2-5 is a homeobox-containing transcriptional regulator that serves as one of the earliest markers of cardiac lineage commitment. To study the role of Nkx2-5 expressing progenitors at specific time points in cardiac development, we have generated a novel and inducible NKX2-5 mouse line by knocking in a CreER cassette into the Nkx2-5 genomic locus, while preserving the endogenous Nkx2-5 gene to avoid haploinsufficiency. We evaluated the specificity and efficiency of CreER activity after 4-OHT injection by crossing Nkx2-5CreER/+ mice with a Rosa26tdT/+ reporter strain. Our immunohistochemistry results confirmed Cre-induced tdTomato expression specifically in cells expressing Nkx2-5. These cells were mainly cardiomyocytes and were observed in the embryonic heart as early as day 9.5. Additionally, quantitative polymerase chain reaction on postnatal hearts showed enriched expression of Nkx2-5 in isolated tdTomato-expressing cells. No tdTomato expression was observed in Nkx2-5CreER/+ ;Rosa26tdT/+ mice in the absence of 4 OHT, confirming the inducible nature of CreER activity. The Nkx2-5/CreER mouse model described in this article will serve as an invaluable tool to trace myocardial lineage and to temporally induce genetic manipulation in a selective population of cardiac progenitors during embryonic development and in the adult heart. PMID- 28589711 TI - Nonheme Iron-Oxo-Catalyzed Methane Formation from Methyl Thioethers: Scope, Mechanism, and Relevance for Natural Systems. AB - A range of nonheme oxo-iron(IV) model systems with tetra- or pentadentate ligands is shown to produce methane from methionine and other thioethers. This model reaction for the natural aerobic production of methane is shown to proceed via two sulfoxidation steps involving the oxo-iron(IV) complexes, with a bifurcation in the second step that either produces the sulfone or leads to demethylation with similar probabilities. In the presence of O2 , the resulting methyl radicals produce methanol and formate or, in an O2 -depleted environment, lead to formation of methane. PMID- 28589713 TI - Gas Suppression via Copper Interlayers in Magnetron Sputtered Al-Cu2O Multilayers. AB - The use of thin-foil, self-propagating thermite reactions to bond components successfully depends on the ability to suppress gas generation and avoid pore formation during the exothermic production of brazes. To study the mechanisms of vapor production in diluted thermites, thin film multilayer Al-Cu-Cu2O-Cu foils are produced via magnetron sputtering, where the Cu layer thickness is systematically increased from 0 to 100 nm in 25 nm increments. The excess Cu layers act as diffusion barriers, limiting the transport of oxygen from the oxide to the Al fuel, as determined by slow heating differential scanning calorimetry experiments. Furthermore, by adding excess Cu to the system, the temperature of the self-propagating thermite reactions drops below the boiling point of Cu, eliminating the metal vapor production. It is determined that Cu vapor production can be eliminated by increasing the Cu interlayer thickness above 50 nm. However, the porous nature of the final products suggests that only metal vapor production is suppressed via dilution. Gas generation via oxygen release is still capable of producing a porous reaction product. PMID- 28589714 TI - Magnetic Field-Assisted Perovskite Film Preparation for Enhanced Performance of Solar Cells. AB - Perovskite solar cells (PSCs) are promising low-cost photovoltaic technologies with high power conversion efficiency (PCE). The crystalline quality of perovskite materials is crucial to the photovoltaic performance of the PSCs. Herein, a simple approach is introduced to prepare high-quality CH3NH3PbI3 perovskite films with larger crystalline grains and longer carriers lifetime by using magnetic field to control the nucleation and crystal growth. The fabricated planar CH3NH3PbI3 solar cells have an average PCE of 17.84% and the highest PCE of 18.56% using an optimized magnetic field at 80 mT. In contrast, the PSCs fabricated without the magnetic field give an average PCE of 15.52% and the highest PCE of 16.72%. The magnetic field action produces an ordered arrangement of the perovskite ions, improving the crystallinity of the perovskite films and resulting in a higher PCE. PMID- 28589712 TI - Inhibition of angiogenesis impairs bone healing in an in vivo murine rapid resynostosis model. AB - Biologics can improve bone formation, but may diffuse away from sites of therapeutic need. We developed a click-chemistry hydrogel that rapidly polymerizes in situ to control delivery of biologics during post-suturectomy resynostosis in 21-day-old male mice. Here, we used this model to determine the role of angiogenesis in post-suturectomy resynostosis and examine whether controlled release of angiogenesis inhibitors could delay bone regeneration. Hydrogels [DB-co-PEG/poly (TEGDMA)-co-(N3-TEGDMA)] were produced containing anti angiogenic compounds [anti-VEGFA-antibody or hypoxia inducible factor 1alpha inhibitor topotecan]. Bioactivity in vitro was assessed by tube length and branching points of endothelial cells in hydrogel-conditioned media. In vivo effects were examined 14 day post-suturectomy, based on the temporal analysis of angiogenic mRNAs during resynostosis following posterior frontal suture removal. MicroCT was used to quantify angiogenesis in contrast-agent-perfused blood vessels and bone defect size in defects receiving hydrogel, anti-VEGFA/hydrogel, or topotecan/hydrogel. Shorter endothelial tube length and less branching were seen in inhibitor-conditioned media (topotecan > AbVEGFA). In vivo, both compounds inhibited angiogenesis compared with hydrogel-only. Anti-VEGFA/hydrogel reduced resynostosis compared with empty defects, but topotecan/hydrogel blocked bone regeneration. We demonstrate that anti-angiogenic compounds can be incorporated into a spontaneously polymerizing hydrogel and remain active over 14 days in vitro and in vivo. Moreover, bone formation can be delayed by inhibiting neovascularization, suggesting possible use as a therapeutic to control resynostosis following suturectomies and potential applications in other conditions where rapid osteogenesis is not desired. (c) 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2742-2749, 2017. PMID- 28589715 TI - Self-Propagated Flaming Synthesis of Highly Active Layered CuO-delta-MnO2 Hybrid Composites for Catalytic Total Oxidation of Toluene Pollutant. AB - A new self-propagated flaming (SPF) technique was applied to the synthesis of highly active layered CuO-delta-MnO2 hybrid composites, for the de-polluting catalytic total oxidation of gaseous toluene vapor. Other transition metal oxide doped MnO2 hybrid composites were also successfully prepared and investigated, ensuring a feasible strategy for the fabrication of various layered MOx-delta MnO2 (M?Co, Ni, or Zn) hybrids. By changing the molar ratio of the precursors (KMnO4 and acetate salt) and the type of transition metal oxide introduced, it is possible to control the crystal structure and reducibility of the sheetlike hybrid composites as well as the catalytic activity for the total oxidation of toluene. The catalyst sample (CuO-delta-MnO2) with a Mn/Cu molar ratio of 10:1 exhibited the highest catalytic performance, with a lower reaction temperature of 300 degrees C for complete toluene removal, which was comparable to the reaction temperature for total toluene conversion by the Pt-based catalyst. The SPF technique provides an approach for developing highly efficient catalysts for the complete removal of volatile organic compounds, by allowing the facile and energy saving fabrication of large quantities of layered CuO-delta-MnO2 hybrids. PMID- 28589716 TI - Microfluidic Generation of High-Viscosity Droplets by Surface-Controlled Breakup of Segment Flow. AB - Fluids containing high concentration polymers, sols, nanoparticles, etc., usually have high viscosities, and high-viscosity fluids are difficult to be encapsulated into uniform droplets. Here we report a surface-controlled breakup method to generate droplets directly from various aqueous and nonaqueous fluids with viscosities of 1.0 to 11.9 Pa s and a dispersed-to-continuous viscosity ratio up to 1000, whereas the volume fraction of droplets up to 50% can be achieved. It provides a straightforward method to encapsulate high viscosity fluids, in a well controlled manner in the rapid developing droplet-based applications, including materials synthesis, drug delivery, cell assay, bioengineering, etc. PMID- 28589717 TI - Total Synthesis of Biselyngbyaside. AB - The first total synthesis of biselyngbyaside, an 18-membered macrolide glycoside, was achieved. The glycoside bond was introduced using the Schmidt method before construction of the 18-membered ring due to the instability of the conjugated diene and the beta-hydroxy ester moiety. The macrolactone ring was constructed using the Mitsunobu reaction followed by intramolecular the Stille coupling reaction. PMID- 28589718 TI - Quantitative Analysis of Electrochemical and Electrode Stability with Low Self Discharge Lithium-Sulfur Batteries. AB - The viability of employing high-capacity sulfur cathodes in building high-energy density lithium-sulfur batteries is limited by rapid self-discharge, short shelf life, and severe structural degradation during cell resting (static instability). Unfortunately, the static instability has largely been ignored in the literature. We present in this letter a long-term self-discharge study by quantitatively analyzing the control lithium-sulfur batteries with a conventional cathode configuration, which provides meaningful insights into the cathode failure mechanisms during resting. Utilizing the understanding obtained with the control cells, we design and present low self-discharge (LSD) lithium-sulfur batteries for investigating the long-term self-discharge effect and electrode stability. PMID- 28589719 TI - How Important is the Host (Semiconductor Nanoparticles) Identity and Absolute Band Gap in Host-Sensitized Dopant Photoluminescence? AB - This work reports the host (semiconductor nanoparticles) sensitized dopant (lanthanides, Ln) photoluminescence in near band gap matched Sn(Ln)O2 and Zn(Ln)S [Ln = Sm, Tb] nanoparticles to address the importance of the nanoparticle identity and absolute band gap in the underlying process. While the sensitization was evident in the Sn(Sm)O2 and Zn(Tb)S nanoparticles, the same was not observed in the Sn(Tb)O2 and Zn(Sm)S nanoparticles. This observation stresses the importance of nanoparticle identity as the determining factor in realizing the host-sensitized dopant photoluminescence and provides important insight into developing novel doped inorganic nanoparticle-based optical materials. PMID- 28589720 TI - Development of a sp2-sp3 Stille Cross-Coupling for Rapid Synthesis of HIV NNRTI Doravirine Analogues. AB - The development of a C(sp2)-C(sp3) cross-coupling reaction for rapid, parallel synthesis of analogues of two HIV NNRTI clinical candidates is described. This method allowed easy access to the C-ring space using a practical alkylation with commercially available tributyl(iodomethyl)stannane followed by a palladium catalyzed coupling with a variety of aryl halides (I, Br) in the presence of copper chloride. Optimization and scope of this method are reported. PMID- 28589721 TI - Graphene Oxide/Chitosan Aerogel Microspheres with Honeycomb-Cobweb and Radially Oriented Microchannel Structures for Broad-Spectrum and Rapid Adsorption of Water Contaminants. AB - Multifunctional graphene oxide (GO)/chitosan (CS) aerogel microspheres (GCAMs) with honeycomb-cobweb and radially oriented microchannel structures are prepared by combining electrospraying with freeze-casting to optimize adsorption performances of heavy metal ions and soluble organic pollutants. The GCAMs exhibit superior adsorption capacities of heavy metal ions of Pb(II), Cu(II), and Cr(VI), cationic dyes of methylene blue (MB) and Rhodamine B, anionic dyes of methyl orange and Eosin Y, and phenol. It takes only 5 min to reach 82 and 89% of equilibrium adsorption capacities for Cr(VI) (292.8 mg g-1) and MB (584.6 mg g 1), respectively, much shorter than the adsorption equilibrium time (75 h) of a GO/CS monolith. More importantly, the GCAMs maintain excellent adsorption capacity for six cycles of adsorption-desorption. The broad-spectrum, rapid, and reusable adsorption performance makes the GCAMs promising for highly efficient water treatments. PMID- 28589722 TI - Metal- and O2-Free Oxidative C-C Bond Cleavage of Aromatic Aldehydes. AB - An oxidative C-C cleavage of aldehydes requiring neither metals nor O2 was discovered. Homobenzylic aldehydes and alpha-substituted homobenzylic aldehydes were cleaved to benzylic aldehydes and ketones, respectively, using nitrosobenzene as an oxidant. This reaction is chemoselective for aromatic aldehydes, as an aliphatic aldehyde was unreactive under these conditions, and other reactive functionality such as ketones and free alcohols are tolerated. A mechanism accounting for the fate of the lost carbon is proposed. PMID- 28589723 TI - Molecular Interaction Between Salivary Proteins and Food Tannins. AB - Polyphenols interaction with salivary proteins (SP) has been related with organoleptic features such as astringency. The aim of this work was to study the interaction between some human SP and tannins through two spectroscopic techniques, fluorescence quenching, and saturation transfer difference-nuclear magnetic resonance (STD-NMR). Generally, the results showed a significant interaction between SP and both condensed tannins and ellagitannins. Herein, STD NMR proved to be a useful tool to map tannins' epitopes of binding, while fluorescence quenching allowed one to discriminate binding affinities. Ellagitannins showed the greatest binding constants values (KSV from 20.1 to 94.1 mM-1; KA from 0.7 to 8.3 mM-1) in comparison with procyanidins (KSV from 5.4 to 40.0 mM-1; KA from 1.1 to 2.7 mM-1). In fact, punicalagin was the tannin that demonstrated the highest affinity for all three SP. Regarding SP, P-B peptide was the one with higher affinity for ellagitannins. On the other hand, cystatins showed in general the lower KSV and KA values. In the case of condensed tannins, statherin was the SP with the highest affinity, contrasting with the other two SP. Altogether, these results are evidence that the distinct SP present in the oral cavity have different abilities to interact with food tannins class. PMID- 28589724 TI - C-H Trifluoromethylation of 2-Substituted/Unsubstituted Aminonaphthoquinones at Room Temperature with Bench-Stable (CF3SO2)2Zn: Synthesis and Antiproliferative Evaluation. AB - A direct C-H trifluoromethylation of 2-amino-1,4-naphthoquinone analogues is described. This reaction proceeds under mild conditions at open atmosphere, providing a range of CF3-containing naphthoquinones with good yield and functional group compatibility. All synthetic compounds were screened for antiproliferative activity against three human cancer cell lines. Notably, some of those trifluoromethyl analogs, such as 3a, 3g, 3j, and 3t, showed good antiproliferative profiles. PMID- 28589725 TI - Dual Targeting Nanoparticle Stimulates the Immune System To Inhibit Tumor Growth. AB - We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. Immunoswitch particles enhance effector target cell conjugation and bypass the requirement for a priori knowledge of tumor antigens. The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells. Changes in the T cell receptor repertoire against a single tumor antigen indicate immunoswitch particles expand an effective set of T cell clones. Our data show the potential of a signal-switching approach to cancer immunotherapy that simultaneously targets two stages of the cancer immunity cycle resulting in robust antitumor activity. PMID- 28589726 TI - Tri-Needle Coaxial Electrospray Engineering of Magnetic Polymer Yolk-Shell Particles Possessing Dual-Imaging Modality, Multiagent Compartments, and Trigger Release Potential. AB - Particulate platforms capable of delivering multiple actives as well as providing diagnostic features have gained considerable interest over the last few years. In this study, magnetic polymer yolk-shell particles (YSPs) were engineered using a tri-needle coaxial electrospraying technique enabling dual-mode (ultrasonic and magnetic resonance) imaging capability with specific multidrug compartments via an advanced single-step encapsulation process. YSPs comprised magnetic Fe3O4 nanoparticles (MNPs) embedded in the polymeric shell, an interfacing oil layer, and a polymeric core (i.e., composite shell-oil interface-polymeric core). The frequency of the ultrasound backscatter signal was modulated through YSP loading dosage, and both T1- and T2-weighted magnetic resonance imaging signal intensities were shown to decrease with increasing MNP content (YSP outer shell). Three fluorescent dyes (selected as model probes with varying hydrophobicities) were coencapsulated separately to confirm the YSP structure. Probe release profiles were tuned by varying power or frequency of an external auxiliary magnetic field (AMF, 0.7 mT (LAMF) or 1.4 mT (HAMF)). In addition, an "inversion" phenomenon for the AMF-enhanced drug release process was studied and is reported. A low YSP cytotoxicity (5 mg/mL) and biocompatibility (murine, L929) was confirmed. In summary, magnetic YSPs demonstrate timely potential as multifunctional theranostic agents for dual-imaging modality and magnetically controlled coactive delivery. PMID- 28589728 TI - Spectroscopic Characterization, Computational Investigation, and Comparisons of ECX- (E = As, P, and N; X = S and O) Anions. AB - Three newly synthesized [Na+(221-Kryptofix)] salts containing AsCO-, PCO-, and PCS- anions were successfully electrosprayed into a vacuum, and these three ECX- anions were investigated by negative ion photoelectron spectroscopy (NIPES) along with high-resolution photoelectron imaging spectroscopy. For each ECX- anion, a well-resolved NIPE spectrum was obtained, in which every major peak is split into a doublet. The splittings are attributed to spin-orbit coupling (SOC) in the ECX* radicals. Vibrational progressions in the NIPE spectra of ECX- were assigned to the symmetric and the antisymmetric stretching modes in ECX* radicals. The electron affinities (EAs) and SO splittings of ECX* are determined from the NIPE spectra to be AsCO*: EA = 2.414 +/- 0.002 eV, SO splitting = 988 cm-1; PCO*: EA = 2.670 +/- 0.005 eV, SO splitting = 175 cm-1; PCS*: EA = 2.850 +/- 0.005 eV, SO splitting = 300 cm-1. Calculations using the B3LYP, CASPT2, and CCSD(T) methods all predict linear geometries for both the anions and the neutral radicals. The calculated EAs and SO splittings for ECX* are in excellent agreement with the experimentally measured values. The simulated NIPE spectra, which are based on the calculated Franck-Condon factors, and the SO splittings nicely reproduce all of the observed spectral peaks, thus allowing unambiguous spectral assignments. The finding that PCS* has the greatest EA of the three triatomic molecules considered here is counterintuitive based upon simple electronegativity considerations, but this finding is understandable in terms of the movement of electron density from phosphorus in the HOMO of PCO- to sulfur in the HOMO of PCS . Comparisons of the EAs of PCO* and PCS* with the previously measured EA values for NCO* and NCS* are made and discussed. PMID- 28589729 TI - Copper-Catalyzed [2 + 2 + 3] Annulation of 1,6-Enynes with alpha-Bromo-1,3 Dicarbonyl Compounds: Synthesis of Dihydrooxepines. AB - Copper-catalyzed [2 + 2 + 3] annulation of 1,6-enynes with alpha-bromo-1,3 dicarbonyl compounds is described. This reaction provides facile access to seven membered dihydrooxepines for epidithiodiketopiperazines with two newly formed C-C bonds and one C-O bond. PMID- 28589730 TI - Variation in genital human papillomavirus infection prevalence and vaccination coverage among men and women in the USA. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection that causes majority of anogenital and oropharyngeal cancers. Prophylactic HPV vaccine is available for the primary prevention of cancer and HPV transmission. Here, we are going to discuss the variation of HPV prevalence, HPV vaccination coverage and potential risk factors of men and women, retrieved from the cross-sectional study of the National Health Nutrition Examination Survey, a representative sample of noninstitutionalized, civilian residents in the USA. The overall penile HPV prevalence in men was 45.2% and the high risk oncogenic HPV prevalence defined by DNA testing was 25.1% that appeared to be widespread among all the age groups, which contrasts the vaginal HPV prevalence of 26.8% in women. PMID- 28589727 TI - Identification of Microprotein-Protein Interactions via APEX Tagging. AB - Microproteins are peptides and small proteins encoded by small open reading frames (smORFs). Newer technologies have led to the recent discovery of hundreds to thousands of new microproteins. The biological functions of a few microproteins have been elucidated, and these microproteins have fundamental roles in biology ranging from limb development to muscle function, highlighting the value of characterizing these molecules. The identification of microprotein protein interactions (MPIs) has proven to be a successful approach to the functional characterization of these genes; however, traditional immunoprecipitation methods result in the enrichment of nonspecific interactions for microproteins. Here, we test and apply an in situ proximity tagging method that relies on an engineered ascorbate peroxidase 2 (APEX) to elucidate MPIs. The results demonstrate that APEX tagging is superior to traditional immunoprecipitation methods for microproteins. Furthermore, the application of APEX tagging to an uncharacterized microprotein called C11orf98 revealed that this microprotein interacts with nucleolar proteins nucleophosmin and nucleolin, demonstrating the ability of this approach to identify novel hypothesis generating MPIs. PMID- 28589731 TI - Next steps in Ewing sarcoma (epi-)genomics. PMID- 28589732 TI - Functional factors that are important correlates to physical activity in people with multiple sclerosis: a pilot study. AB - PURPOSE: Identify functional factors that are important correlates to physical activity levels among people with multiple sclerosis. METHODS: A total of eight functional tests were conducted and physical activity was objectively measured (Actigraph GT3X accelerometer) for one week in 34 people with multiple sclerosis. A corrected Akaike Information Criterion analysis was performed to identify the strongest correlates with moderate-to-vigorous physical activity, total activity and sedentary time. RESULTS: The multiple regression analysis converged on a model for moderate-to-vigorous physical activity (R2 = 0.31, F = 6.97, p= 0.003) that included total strength of the less-affected leg (partial r = 0.46, p = 0.007) and average peg test performance (partial r = -0.30, p = 0.087). The model for total activity (R2 = 0.40, F = 10.51, p < 0.001) included five times sit-to stand performance (partial r= -0.44, p = 0.010) and total strength of the less affected leg (partial r = 0.31, p = 0.077). The model for sedentary time (R2=0.22, F = 9.23, p = 0.005) only included total strength of the more affected leg (r= -0.47, p = 0.005). CONCLUSION: These results suggest that leg strength, manual dexterity and the ability to perform functional tasks may be important correlates with physical activity levels in people with multiple sclerosis. The findings of this pilot study can inform future investigations aiming to increase physical activity levels or develop improved rehabilitation protocols for people with multiple sclerosis. Implications for Rehabilitation Physical activity is an effective means of improving the symptoms associated with multiple sclerosis. Participation in physical activity by people with multiple sclerosis may be affected by functional factors such as leg strength, manual dexterity and the ability to rise from a seated position. Bilateral leg strength differences should be assessed and addressed in people with multiple sclerosis. PMID- 28589733 TI - Health and security: ethical principles for counter-terror policy and practice in protection crises and beyond. PMID- 28589734 TI - Cancer care in lesbian, gay, bisexual, transgender and queer populations. AB - Lesbian, gay, bisexual, transgender and queer (LGBTQ) populations experience health and healthcare disparities that may place them at higher risk for developing cancer. In addition, LGBTQ communities have psychosocial factors, such as fear of discrimination, that have substantial impacts on their medical care. As a result, these populations have specific needs with regard to cancer screening, treatment and support that must be addressed by cancer care providers. Although much has been done to address cancer care in the general population, more improvement is needed in the care of LGBTQ patients. We aim to present an overview of the current state of LGBTQ cancer care, opportunities for improvement and how cancer centers and providers can create a better future for the care of LGBTQ cancer patients. PMID- 28589735 TI - Prospective memory rehabilitation using smartphones in patients with TBI. AB - PURPOSE: The aim of the present study was to investigate the effectiveness of a prospective memory aid that combines smartphones with Internet-based calendars among community-dwelling patients with traumatic brain injury. METHOD: An uncontrolled pre- and post-assessment design was employed to study the use of unmodified, low-cost, off-the-shelf smartphones combined with Internet-calendars as a compensatory memory strategy in community-dwelling patients with traumatic brain injury. Thirteen participants received a 6-week group-based intervention with pre-, post- and 2-month follow-up-assessments by questionnaires and by daily assessment of target behaviors for 2-week periods. RESULTS: Participants reported significantly fewer retro- and prospective memory problems on questionnaires after the intervention and at follow-up with large effect sizes. The performance of target behaviors, however, improved insignificantly with moderate effect sizes. There were no changes in quality of life or symptoms of emotional distress. CONCLUSIONS: This study adds to a growing body of evidence that smartphones are a useful compensatory aid in rehabilitation of prospective memory that should routinely be considered in rehabilitation of traumatic brain injury patients. Implication for rehabilitation Smartphones are easy-to-use and accessible assistive technology for compensatory memory rehabilitation to most traumatic brain injury patients. By using low-cost, off-the-shelf devices, the technology becomes available to a broader range of patients. By combining smartphones with Internet-based and cross-platform services (e.g., calendars, contacts) the participants are less device-dependent and less vulnerable to data loss. Smartphones should routinely be considered as compensatory aid in rehabilitation of prospective memory of traumatic brain injured patients. PMID- 28589737 TI - Targeting ALK-rearranged non-small-cell lung cancer: an update. PMID- 28589736 TI - Development and in vitro characterization of self-emulsifying drug delivery system (SEDDS) for oral opioid peptide delivery. AB - AIM: In this study, self-emulsifying drug delivery system (SEDDS) for oral delivery of opioid peptide dalargin were developed and characterized in vitro. METHODS: Dalargin lipophilicity was increased by O-esterification of tyrosine OH group, hydrophobic ion pairing, or a combination thereof. Distribution coefficients (log D) of lipidized dalargin derivatives were determined. Then, dalargin was incorporated in chosen SEDDS, namely SEDDS-1, composed of 50% Capmul 907, 40% Cremophor EL, and 10% propylene glycol and comparatively more lipophilic SEDDS-2 composed of 30% Captex 8000, 30% Capmul MCM, 30% Cremophor EL, and 10% propylene glycol. Additionally, SEDDS were characterized regarding droplet size, polydispersity index (PDI), cloudy point, physical stability and stability against pancreatic lipase. Furthermore, mucus permeating properties of SEDDS and their ability to protect the incorporated dalargin against proteolysis by trypsin, alpha-chymotrypsin, elastase, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) were evaluated. RESULTS: The highest dalargin drug payload of 4.57% in SEDDS-2 was achieved when dalargin palmitate (pDAL) was ion paired with sodium dodecyl sulfate (SDS) in molar ratio 1:1. Moreover, SEDDS 1 and SEDDS-2 had a narrow droplet size distribution with average droplet sizes of 42.1 and 33.1 nm with PDI of 0.042 and 0.034, respectively. Lipolysis study showed that within 30 min 78.5% of SEDDS-1 and 92.1% of SEDDS-2 were digested. In addition, both SEDDS exhibited mucus permeating properties as well as a protective effect against enzymatic degradation by trypsin, alpha-chymotrypsin, elastase, SGF and SIF. CONCLUSION: The results of this study suggest that the developed SEDDS could be considered for oral opioid peptide delivery. PMID- 28589738 TI - Hemoglobin Variant Profiles among Brazilian Quilombola Communities. AB - Brazilian Quilombolas are communities composed of African-derived populations that have their territories guaranteed by the Brazilian Constitution. The present study investigated the hemoglobin (Hb) variants among these population groups. This study was conducted in a total of 2843 individuals of Brazilian Quilombola communities of the Bahia, Para, and Piaui states. All the participants had their Hb profiles evaluated. The Hb S (HBB: c.20A>T) variant was described in all the studied localities. However, the individuals in Bahia State had the highest frequency of the Hb C (HBB: c.19G>A) variant; individuals from Piaui State had a higher frequency of the Hb D-Punjab (HBB: c.364G>C) variant compared to the other states, and individuals from Para State only carried the Hb S variant. The present study revealed a specific distribution of Hb variants that could represent different waves of African influence in these Brazilian populations. PMID- 28589739 TI - Characteristics and functional outcomes of chordoma patients admitted for inpatient rehabilitation. AB - PURPOSE: To describe the population and functional changes observed after an inpatient rehabilitation facility stay in chordoma patients Materials and Methods: We conducted a consecutive series retrospective review of patients with chordoma, admitted to an academic inpatient rehabilitation facility after surgical resection from 2010 to 2015. Information regarding demographic, tumor- and surgery-specific data, lengths of stay, complications, admission and discharge functional independence measure scores was collected. RESULTS: A total of 40 patients with a diagnosis of chordoma were admitted to an inpatient rehabilitation facility postoperatively were included for analysis. Thirty-three patients had initial resection of chordoma, seven patients had resection of recurrent chordoma, and eight patients had metastatic disease on admission to an inpatient rehabilitation facility. The average change in total and motor functional independence measure scores after an inpatient rehabilitation facility stay was 33.7 and 26.1, respectively. The acute hospital transfer rate was 32.5% and the postoperative complication rate was 62.5%. CONCLUSIONS: This study is the first to describe the population and functional improvement in the chordoma population who are admitted to an inpatient rehabilitation facility postoperatively. While there is a high rate of acute hospital transfer and postoperative complications, these values are comparable to prior studies in this population. With the increasing prevalence of cancer survivors, improving function during and after cancer treatment is extremely important. Implications for Rehabilitation Chordoma patients who are admitted to inpatient rehabilitation facilities after surgical tumor resection experience improvement in multiple functional domains. Chordoma patients admitted to inpatient rehabilitation facilities experience a high rate of acute hospital transfer, but it is comparable to other cancer rehabilitation populations. Understanding the characteristics of the postoperative chordoma population is essential to direct future studies regarding cancer rehabilitation. PMID- 28589740 TI - A survey of scientists' awareness of and attitudes to the use of human blood products and alternatives in human assisted reproductive technology. AB - Scientists working in assisted reproduction [members of Scientists in Reproductive Technology (SIRT) Australia, and subscribers of the online forums EmbryoMail and Quartec] were invited to complete an online questionnaire on the use of human blood products in assisted reproductive technologies (ART). A total of 260 started the questionnaire, with 208 (80%) completing it. A total of 62% of respondents had worked in human ART >=8 years and 68% had post-graduate qualifications. The majority (82%) reported using products of animal or human origin, with 75% knowing why protein was added to culture media and 41% not worried by this. Almost half (49%) of respondents were unaware of regulations surrounding the use of human blood products in health care and 70% were unaware of adverse events involving human blood products in human ART. Most respondents (70%) indicated that they were not concerned about infections such as hepatitis, but agents such as prions were a cause for concern (57%). A total of 57% of respondents were unaware of alternatives, but 77% would use a suitable alternative. Using blood products in human ART is surrounded by a lack of awareness, often independent of respondents' qualifications or experience. A better understanding of these products and possible alternatives is required if informed decisions about their suitability are to be made. PMID- 28589741 TI - A content analysis of the consumer-facing online information about My Health Record: Implications for increasing knowledge and awareness to facilitate uptake and use. AB - BACKGROUND: Low health literacy, low levels of positive belief and privacy and security concerns have been identified as a significant barrier to personal electronic health record uptake and use. An important tool for overcoming these barriers is the consumer-facing information which accompanies the system. My Health Record (MyHR) is the Australian national e-health record system, for which a large suite of online resources exists to facilitate consumer registration and use. This study uses a number of different measures of health resource quality to assess the MyHR online consumer-facing information and identify any gaps or areas for improvement. OBJECTIVE: To analyse the quality and content of the online consumer-facing resources which support the uptake and use of MyHR. METHOD: Australian information resources aimed at healthcare consumers about the MyHR were included in this study. A comprehensive search using Internet search engines was conducted to locate all online consumer-facing resources about MyHR from both government and non-government sources. Readability (measured by Flesch-Kincaid grade level), year of publication/review, publishing organisation type, presentation style, linked websites, target audience, and themes were identified as important measures of health information quality, and these were recorded and reported on for each resource. RESULTS: Eighty resources met the inclusion criteria. The mean Flesch-Kincaid grade level was 11.8. Most resources were created by Australian government sources ( n = 55), and the most common target audience was the general public ( n = 65). Registration ( n = 51), privacy/security ( n = 49), and benefits of use ( n = 46) were the most common resource themes. CONCLUSION: The authors identified a number of gaps and areas for improvement in the provision of consumer-facing information about MyHR. Readability is too high for the general Australian population, and there are few translated resources, which means that the information provided does not cater to people with low literacy levels, communication disability, and/or difficulties in understanding written English. The target audiences for resources do not reflect priority groups that were identified during the MyHR development processes. There are also gaps in information provision about how consumers can use MyHR as a tool to meaningfully engage with health professionals and services to support their own person-centred care. PMID- 28589742 TI - Potential prognostic value of clinical characteristics, hormone status and major depressive disorder in breast cancer. AB - AIM: To identify independent factors predicting overall survival (OS) of breast cancer (BC) patients. PATIENTS & METHODS: Two hundred and eighty one women with BC were recruited and clinical characteristics including lymphovascular invasion, clinical stage of Tumor Node Metastasis and positive axillary lymph nodes were documented; immunohistochemistry/fluorescence in situ hybridization was used to examine the expression of estrogen receptor, progesterone receptor, HER2 and Ki 67; major depressive disorder was assessed with Diagnostic and Statistical Manual of Mental Disorders V. RESULTS: Multivariable analyses indicated that in BC patients, lymphovascular invasion, Tumor Node Metastasis, pN, Ki-67 and major depressive disorder were significantly negatively correlated with OS; estrogen receptor was significantly positively associated with OS. CONCLUSION: Early diagnostic approaches and effective psychologic intervention are indispensable for BC patients. PMID- 28589743 TI - Rapid and sensitive insulated isothermal PCR for point-of-need feline leukaemia virus detection. AB - Objectives Feline leukaemia virus (FeLV), a gamma retrovirus, causes diseases of the feline haematopoietic system that are invariably fatal. Rapid and accurate testing at the point-of-need (PON) supports prevention of virus spread and management of clinical disease. This study evaluated the performance of an insulated isothermal PCR (iiPCR) that detects proviral DNA, and a reverse transcription (RT)-iiPCR that detects both viral RNA and proviral DNA, for FeLV detection at the PON. Methods Mycoplasma haemofelis, feline coronavirus, feline herpesvirus, feline calicivirus and feline immunodeficiency virus were used to test analytical specificity. In vitro transcribed RNA, artificial plasmid, FeLV strain American Type Culture Collection VR-719 and a clinical FeLV isolate were used in the analytical sensitivity assays. A retrospective study including 116 clinical plasma and serum samples that had been tested with virus isolation, real time PCR and ELISA, and a prospective study including 150 clinical plasma and serum samples were implemented to evaluate the clinical performances of the iiPCR based methods for FeLV detection. Results Ninety-five percent assay limit of detection was calculated to be 16 RNA and five DNA copies for the RT-iiPCR, and six DNA copies for the iiPCR. Both reactions had analytical sensitivity comparable to a reference real-time PCR (qPCR) and did not detect five non-target feline pathogens. The clinical performance of the RT-iiPCR and iiPCR had 98.82% agreement (kappa[kappa] = 0.97) and 100% agreement (kappa = 1.0), respectively, with the qPCR (n = 85). The agreement between an automatic nucleic extraction/RT iiPCR system and virus isolation to detect FeLV in plasma or serum was 95.69% (kappa = 0.95) and 98.67% (kappa = 0.85) in a retrospective (n = 116) and a prospective (n = 150) study, respectively. Conclusions and relevance These results suggested that both RT-iiPCR and iiPCR assays can serve as reliable tools for PON FeLV detection. PMID- 28589744 TI - Circulating Vitamin D and Overall Survival in Breast Cancer Patients: A Dose Response Meta-Analysis of Cohort Studies. AB - Studies have shown that vitamin D could have a role in breast cancer survival; however, the evidence of the relationship between patients' vitamin D levels and their survival has been inconsistent. This meta-analysis explores possible dose response relationships between vitamin D levels and overall survival by allowing for differences in vitamin D levels among populations of the various studies. Studies relating vitamin D (25-OH-D [25-hydroxyvitamin D]) levels in breast cancer patients with their survival were identified by searching PubMed and Embase. A pooled HR (hazard ratio) comparing the highest with the lowest category of circulating 25-OH-D levels were synthesized using the Mantel-Haenszel method under a fixed-effects model. A two-stage fixed-effects dose-response model including both linear (a log-linear dose-response regression) and nonlinear (a restricted cubic spline regression) models were used to further explore possible dose-response relationships. Six studies with a total number of 5984 patients were identified. A pooled HR comparing the highest with the lowest category of circulating 25-OH-D levels under a fixed-effects model was 0.67 (95% confidence interval = 0.56-0.79, P < .001). Utilizing a dose-response meta-analysis, the pooled HR for overall survival in breast cancer patients was 0.994 (per 1 nmol/L), Pfor linear trend < .001. At or above a 23.3 nmol/L threshold, for a 10 nmol/L, 20 nmol/L, or 25 nmol/L increment in circulating 25-OH-D levels, the risk of breast cancer overall mortality decreased by 6%, 12%, and 14%, respectively. There was no significant nonlinearity in the relationship between overall survival and circulating 25-OH-D levels. Our findings suggest that there is a highly significant linear dose-response relationship between circulating 25-OH-D levels and overall survival in patients with breast cancer. However, better designed prospective cohort studies and clinical trials are needed to further confirm these findings. PMID- 28589745 TI - Green synthesis of tea Ag nanocomposite hydrogels via mint leaf extraction for effective antibacterial activity. AB - In this report, we investigated the swelling behavior and antibacterial property of nanosilver composite hydrogels made from tea with polyacrylamide via a free radical polymerization and green process technique. This is probably for the first time; tea-based nano silver composite hydrogels were developed. The composite hydrogels comprise embedded nano silver particles in the tea hydrogel matrix via a green process with mint leaf extract. The size of the nano silver particles in the hydrogel matrix was found to be < 10 nm. The nano silver composite hydrogels formed and their blank hydrogels from the mint leaf were characterized by using ultraviolet-visible spectroscopy, scanning electron microscopy with energy dispersive spectroscopy, transmission electron microscopy, thermogravimetric analysis and X-ray diffraction studies. The nano silver composite hydrogels developed exhibit eminent antibacterial activity against Escherichia coli and Staphylococcus aureus. This clearly indicates that the nano silver composite hydrogels are potential candidates for antimicrobial applications. PMID- 28589746 TI - A review of the use of human papilloma virus (HPV) in cervical screening. AB - Using key words online databases were searched to identify relevant publications to review the use of Human papilloma virus (HPV) in cervical screening. The mode of cervical screening in the UK has been decided but implementation plans have yet to be announced. The protracted uncertainty surrounding the initial announcement to move to HPV primary screening together with the lack of a national steer has resulted in a flight of staff which threatens the provision of the current and future service. The transition will be a challenging time but analysis of data from more than 176,000 women has shown clear evidence of a reduction in the incidence of cancer where HPV testing is used. There will however, be a population of women who are cytologically negative but high-risk HPV positive and the management of these women will be key to maximising the benefits of HPV primary screening. As cervical cytology becomes increasingly rare its effectiveness and role in cervical screening will come under scrutiny and we must ensure the specificity of reporting is maintained in order for it to survive. PMID- 28589747 TI - A novel bio electro active alginate-aniline tetramer/ agarose scaffold for tissue engineering: synthesis, characterization, drug release and cell culture study. AB - In this study, synthesis of a novel biocompatible stimuli-responsive conducting hydrogel based on agarose/alginate-aniline tetramer with the capability of a tailored electrically controlled drug-release for neuroregeneration is investigated. First, aniline tetramer is synthesized and grafted onto sodium alginate. Then, this material is added to agarose as an electrical conductivity modifier to obtain Agarose/alginate-aniline tetramer hydrogel. The synthesized materials are characterized by H NMR and FTIR. The hydrogels are prepared with varying content of aniline tetramer and their swelling-deswelling and shape memory behavior is evaluated. The electroactivity and ionic conductivity of hydrogels against temperature is measured. The sample with 10% aniline tetramer (AT10) reveals the highest ionic conductivity. In MTT and SEM assays, AT10 shows the best cell viability and cell proliferation due to its highest ionic conductivity highlighting the fact that electrical stimuli cell signaling. Hydrogels also represent great potentials for passive and electro-stimulated dexamethasone release. These results demonstrate that the newly developed conducting hydrogels are promising materials for neuroregenerative medicine. PMID- 28589748 TI - Challenges in management of left ventricular thrombus. AB - Left ventricular thrombus (LVT) complicates both ischemic and non-ischemic cardiomyopathies and is a potential cause of thromboembolic complications such as stroke. Management of LVT in the 21st century is primarily based on studies before the widespread use of potent pharmacological and interventional therapies such as primary percutaneous coronary intervention, especially in the setting of acute myocardial infarction. Though advances in diagnostic technology have improved detection of LVT, clinicians face several uncertainties in the management of LVT in daily practice. The aim of this paper is to examine several controversies in the diagnosis and management of LVT. Prospective studies are needed to advance therapy of LVT. PMID- 28589749 TI - Safety of parecoxib when used for more than 3 days for the management of postoperative pain. AB - AIM: To assess parecoxib safety when used for >3 days for postoperative pain management. METHODS: Treatment-emergent adverse event (TEAE) occurrence after day 3 was examined in a pooled analysis of three placebo-controlled trials of parecoxib following general or gynecologic surgery, or total hip arthroplasty. A total of 358 patients received parecoxib, and 318 placebo. RESULTS: Mean treatment duration was similar between treatment groups. The overall frequency of all TEAEs after day 3 was also similar between treatment groups. Most TEAEs occurred in <1% of patients after day 3; frequencies were similar between treatment groups. Most TEAEs were considered mild or moderate in severity. CONCLUSION: TEAE occurrence in patients receiving parecoxib for >3 days was low and similar to placebo after treatment day 3. PMID- 28589750 TI - A unified approach for assessing heterogeneity in age-period-cohort model parameters using random effects. AB - Age-period-cohort models are a popular tool for studying population-level rates; for example, trends in cancer incidence and mortality. Age-period-cohort models decompose observed trends into age effects that correlate with natural history, period effects that reveal factors impacting all ages simultaneously (e.g. innovations in screening), and birth cohort effects that reflect differential risk exposures that vary across birth years. Methodology for the analysis of multiple population strata (e.g. ethnicity, cancer registry) within the age period-cohort framework has not been thoroughly investigated. Here, we outline a general model for characterizing differences in age-period-cohort model parameters for a potentially large number of strata. Our model incorporates stratum-specific random effects for the intercept, the longitudinal age trend, and the model-based estimate of annual percent change (net drift), thereby enabling a comprehensive analysis of heterogeneity. We also extend the standard model to include quadratic terms for age, period, and cohort, along with the corresponding random effects, which quantify possible stratum-specific departures from global curvature. We illustrate the utility of our model with an application to metastatic prostate cancer incidence (2004-2013) in non-Hispanic white and black men, using 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results Program. PMID- 28589751 TI - Modelling disease activity in juvenile dermatomyositis: A Bayesian approach. AB - Juvenile dermatomyositis is the most common form of the juvenile idiopathic inflammatory myopathies characterised by muscle and skin inflammation, leading to symmetric proximal muscle weakness and cutaneous symptoms. It has a fluctuating course and varying prognosis. In a Bayesian framework, we develop a joint model for four longitudinal outcomes, which accounts for within individual variability as well as inter-individual variability. Correlations among the outcome variables are introduced through a subject-specific random effect. Moreover, we exploit an approach similar to a hurdle model to account for excess of a specific outcome in the response. Clinical markers and symptoms are used as covariates in a regression set-up. Data from an ongoing observational cohort study are available, providing information on 340 subjects, who contributed 2725 clinical visits. The model shows good performance and yields efficient estimations of model parameters, as well as accurate predictions of the disease activity parameters, corresponding well to observed clinical patterns over time. The posterior distribution of the by-subject random intercepts shows a substantial correlation between two of the outcome variables. A subset of clinical markers and symptoms are identified as associated with disease activity. These findings have the potential to influence clinical practice as they can be used to stratify patients according to their prognosis and guide treatment decisions, as well as contribute to on-going research about the most relevant outcome markers for patients affected by juvenile dermatomyositis. PMID- 28589752 TI - A framework for prospectively defining progression rules for internal pilot studies monitoring recruitment. AB - Just over half of publicly funded trials recruit their target sample size within the planned study duration. When recruitment targets are missed, the funder of a trial is faced with the decision of either committing further resources to the study or risk that a worthwhile treatment effect may be missed by an underpowered final analysis. To avoid this challenging situation, when there is insufficient prior evidence to support predicted recruitment rates, funders now require feasibility assessments to be performed in the early stages of trials. Progression criteria are usually specified and agreed with the funder ahead of time. To date, however, the progression rules used are typically ad hoc. In addition, rules routinely permit adaptations to recruitment strategies but do not stipulate criteria for evaluating their effectiveness. In this paper, we develop a framework for planning and designing internal pilot studies which permit a trial to be stopped early if recruitment is disappointing or to continue to full recruitment if enrolment during the feasibility phase is adequate. This framework enables a progression rule to be pre-specified and agreed upon prior to starting a trial. The novel two-stage designs stipulate that if neither of these situations arises, adaptations to recruitment should be made and subsequently evaluated to establish whether they have been successful. We derive optimal progression rules for internal pilot studies which minimise the expected trial overrun and maintain a high probability of completing the study when the recruitment rate is adequate. The advantages of this procedure are illustrated using a real trial example. PMID- 28589755 TI - Psychosocial and ergonomic survey of office and field jobs in a utility company. AB - INTRODUCTION: The effect of different kinds of work on the psychosocial assessment of workers under the same management and organizational environment is investigated. METHODS: A voluntary assessment in a utility company was carried out using the short version of the Copenhagen psychosocial questionnaire (CoPsoQ) on two occasions, 1.5 years apart. Initially, 25 office workers (11 men and 14 women) participated, while 14 of those workers (8 women and 6 men) participated in the second assessment together with 32 field workers. The sewage, water treatment and maintenance workers, totaling 32 men, also participated in a field ergonomics assessment using the Washington State Department of Labor and Industries field work ergonomic checklist. RESULTS: The longitudinal outlook was fairly stable, with sustained severe scores in many CoPsoQ subscales and intensification of severity of workers' control over work and esteem for men. A significantly higher esteem score resulted for field rather than office workers. Workers subjected to foul odors showed similar severity of psychosocial factors. DISCUSSION: For most psychosocial dimensions, the organizational design and management system in place, as well as the overall cultural environment in which it operates, create a much stronger and more decisive impact than job-specific factors. PMID- 28589754 TI - Participatory art-based research with children to gain their perspectives on designing healthcare environments. AB - BACKGROUND: A study was designed to understand the experiences and needs of children within the public spaces of the Outpatients Department of New Zealand's national children's hospital, Starship Childrens' Directorate. AIM: To find out from children what they thought about the outpatient environment. DESIGN: A participatory art based methodology was used. METHODS: Based around the key areas of the physical environment, wayfinding, noise, and uniforms, art-based methods (draw and tell and letter writing) were used to collect data from 175 children ages 5-16 whilst they attended outpatient clinics. The drawings and letters were analysed using descriptive/thematic analysis. RESULTS: The findings show that children are very aware of their environment and are able to clearly voice what is important to them. Children appreciate environments that are child friendly, and inclusive of colour and artwork; however, wayfinding remains a challenge for many families. Although the environment was seen as important, children placed significant value on the people who demonstrated warmth and care within these environments. CONCLUSION: Participatory art based approaches offer a child centred approach to finding out what children perceive is important in the design of hospital environments. PMID- 28589756 TI - Evaluating the impact of method bias in health behaviour research: a meta analytic examination of studies utilising the theories of reasoned action and planned behaviour. AB - The methods employed to measure behaviour in research testing the theories of reasoned action/planned behaviour (TRA/TPB) within the context of health behaviours have the potential to significantly bias findings. One bias yet to be examined in that literature is that due to common method variance (CMV). CMV introduces a variance in scores attributable to the method used to measure a construct, rather than the construct it represents. The primary aim of this study was to evaluate the impact of method bias on the associations of health behaviours with TRA/TPB variables. Data were sourced from four meta-analyses (177 studies). The method used to measure behaviour for each effect size was coded for susceptibility to bias. The moderating impact of method type was assessed using meta-regression. Method type significantly moderated the associations of intentions, attitudes and social norms with behaviour, but not that between perceived behavioural control and behaviour. The magnitude of the moderating effect of method type appeared consistent between cross-sectional and prospective studies, but varied across behaviours. The current findings strongly suggest that method bias significantly inflates associations in TRA/TPB research, and poses a potentially serious validity threat to the cumulative findings reported in that field. PMID- 28589753 TI - Evaluating the gray and white matter energy budgets of human brain function. AB - The insatiable appetite for energy to support human brain function is mainly supplied by glucose oxidation (CMRglc(ox)). But how much energy is consumed for signaling and nonsignaling processes in gray/white matter is highly debated. We examined this issue by combining metabolic measurements of gray/white matter and a theoretical calculation of bottom-up energy budget using biophysical properties of neuronal/glial cells in conjunction with species-exclusive electrophysiological and morphological data. We calculated a CMRglc(ox)-derived budget and confirmed it with experimental results measured by PET, autoradiography, 13C-MRS, and electrophysiology. Several conserved principles were observed regarding the energy costs for brain's signaling and nonsignaling components in both human and rat. The awake resting cortical signaling processes and mass-dependent nonsignaling processes, respectively, demand ~70% and ~30% of CMRglc(ox). Inhibitory neurons and glia need 15-20% of CMRglc(ox), with the rest demanded by excitatory neurons. Nonsignaling demands dominate in white matter, in near opposite contrast to gray matter demands. Comparison between 13C-MRS data and calculations suggests ~1.2 Hz glutamatergic signaling rate in the awake human cortex, which is ~4 times lower than signaling in the rat cortex. Top-down validated bottom-up budgets could allow computation of anatomy-based CMRglc(ox) maps and accurate cellular level interpretation of brain metabolic imaging. PMID- 28589757 TI - Quantitative Trait Loci for Slow-Rusting Resistance to Leaf Rust in Doubled Haploid Wheat Population CI13227 * Lakin. AB - CI13227 is a U.S. winter wheat line with adult-plant slow-rusting resistance that has been the subject of several studies on the characteristics and components of slow rusting. Previous genetic studies used different populations and approaches and came to different conclusions about the genetic basis of resistance in CI13227. To clarify the situation, a new doubled-haploid (DH) population of CI13227 * Lakin was produced and a linkage map was constructed using 5,570 single nucleotide polymorphism (SNP) markers derived from wheat 90K SNP assays and 84 simple sequence repeat markers. Three quantitative trait loci (QTL) were identified for three slow-rusting traits on chromosome arms 2DS, 7AL, and 7BL from CI13227. A fourth QTL mapped on chromosome 3BS was from Lakin. The QTL on 2DS, designated QLr.hwwg-2DS, explained 11.2 to 25.6% of the phenotypic variation. It was found in the same position as a slow-rusting QTL in the CI13227 * Suwon 92 population in a previous study and, thus, verified the 2DS QTL. The QTL on chromosome 7BL explained 8.1 and 19.3% of the phenotypic variation and is likely to be Lr68. The other two QTL showed a minor effect on some of the traits evaluated in a single experiment. Flanking SNP closely linked to all QTL were converted to Kompetitive allele-specific polymerase chain reaction markers that can be used in marker-assisted selection to transfer these QTL into adapted wheat cultivars. PMID- 28589758 TI - Identification of type I and type II inhibitors of c-Yes kinase using in silico and experimental techniques. AB - c-Yes kinase is considered as one of the attractive targets for anti-cancer drug design. The DFG (Asp-Phe-Gly) motif present in most of the kinases will adopt active and inactive conformations, known as DFG-in and DFG-out and their inhibitors are classified into type I and type II, respectively. In the present study, two screening protocols were followed for identification of c-Yes kinase inhibitors. (i) Structure-based virtual screening (SBVS) and (ii) Structure-based (SB) and Pharmacophore-based (PB) tandem screening. In SBVS, the c-Yes kinase structure was obtained from homology modeling and seven ensembles with different active site scaffolds through molecular dynamics (MD) simulations. For SB-PB tandem screening, we modeled ligand bound active and inactive conformations. Physicochemical properties of inhibitors of Src kinase family and c-Yes kinase were used to prepare target focused libraries for screenings. Our screening procedure along with docking showed 520 probable hits in SBVS and tandem screening (120 and 400, respectively). Out of 5000 compounds identified from different computational methods, 2410 were examined using kinase inhibition assays. It includes 266 compounds (5.32%) identified from our method. We observed that 14 compounds (12%) are identified by the present method out of 168 that showed > 30% inhibition. Among them, three compounds are novel, unique, and showed good inhibition. Further, we have studied the binding of these compounds at the DFG-in and DFG-out conformations and reported the probable class (type I or type II). Hence, we suggest that these compounds could be novel drug leads for regulation of colorectal cancer. PMID- 28589759 TI - Leukemic transformation in patients with myeloproliferative neoplasms: a population-based retrospective study. AB - AIM: This study determined the epidemiology of developing leukemic transformation in patients with myeloproliferative neoplasms (MPN). METHODS: We utilized the Surveillance, Epidemiology and End Results 13 database to identify 83 cases of leukemic transformation in MPN (n = 9335). RESULTS: The 5-year cumulative incidence of leukemic transformation was higher in male versus female (2.17 vs 1.09%; p < 0.001), and in myelofibrosis (2.19%; 95% CI: 1.36-3.34%), compared with essential thrombocythemia (0.37%; 95% CI: 0.19-0.65%) and polycythemia vera (0.72%; 95% CI: 0.46-1.07%; p < 0.001). Patients had a median survival of 2 months after leukemic transformation, worse in older patients and without any impact of prior MPN subtypes. CONCLUSION: Myelofibrosis has a higher risk of leukemic transformation. Overall survival is dismal regardless of MPN subtypes. PMID- 28589760 TI - The legacy of nuclear power. PMID- 28589761 TI - Colic: An Evolutionary Selective Pressure for Good Parents? PMID- 28589762 TI - Radial Head Subluxation Among Young Children in the United States Associated With Consumer Products and Recreational Activities. AB - This study investigated the epidemiology of children treated in US emergency departments for radial head subluxation (RHS) associated with consumer products and recreational activities using data from the National Electronic Injury Surveillance System. An estimated 430 766 (95% confidence interval: 341 194-520 339) children <=5 years of age were treated for RHS in US emergency departments from 1990 to 2011. The mean patient age was 2.1 years, and 56.5% of patients were girls. The most common mechanism of injury was a fall (43.2%), followed by arm pull (39.4%). The annual rate of RHS increased significantly by 190.1% during the 22-year study period. This is the largest study of RHS to date and the first to use a nationally representative sample to investigate secular trends and mechanisms of injury for RHS associated with consumer products and recreational activities. Events associated with consumer products and recreational activities are an important increasing source of RHS. PMID- 28589763 TI - Measuring Vaccine Hesitancy in a Minority Community. PMID- 28589764 TI - Perception, Awareness, and Acceptance of Human Papillomavirus Disease and Vaccine Among Parents of Boys Aged 9 to 18 Years. AB - Male human papillomavirus (HPV) vaccination rates remain very low. The study objective was to gain an understanding of the perceptions of HPV disease and acceptance/barriers to HPV vaccine by parents of boys aged 9 to 18 years. An anonymous, written survey was administered from January 1, 2011 to September 30, 2013 in private pediatric offices (PPOs) and public health clinics (PHCs) in Chicago, Illinois. A total of 230 PPO parents (PPOPs) and 286 PHC parents (PHCPs) completed the survey. Despite significant differences ( P < .0001) in education level, socioeconomic status, and HPV disease and vaccine knowledge/awareness between the PPOP and PHCP, there was no difference between PPOP and PHCP who would vaccinate their sons with HPV vaccine. For both groups, health care provider recommendation was the primary influence for vaccination. The major barrier to vaccination was lack of information on HPV disease/vaccine. Health care providers need to proactively discuss and use HPV vaccine in male patients. PMID- 28589765 TI - Prognostic value of Ki-67 expression in patients with extensive-stage small cell lung cancer. AB - AIM: To determine whether Ki-67 has prognostic significance in patients with extensive-stage small cell lung cancer. PATIENTS & METHODS: A retrospective review identified 159 consecutive patients with extensive-stage small cell lung cancer. Ki-67 expression level at the time of diagnosis was retrieved. Survival was assessed by Kaplan-Meier method and long-rank test. RESULTS: None of the clinical characteristics, including age, gender and lactate dehydrogenase, were significantly associated with Ki-67 expression level (p > 0.05). Patients with high Ki-67 expression had longer survival than patients with low Ki-67 expression (p = 0.078). Age, gender and lactate dehydrogenase were not significantly associated with survival (p > 0.05). CONCLUSION: Ki-67 expression level failed to have a markedly significant impact on survival in patients with extensive-stage small cell lung cancer. PMID- 28589766 TI - An update on genomic-guided therapies for pediatric solid tumors. AB - Currently, out of the 82 US FDA-approved targeted therapies for adult cancer treatments, only three are approved for use in children irrespective of their genomic status. Apart from leukemia, only a handful of genomic-based trials involving children with solid tumors are ongoing. Emerging genomic data for pediatric solid tumors may facilitate the development of precision medicine in pediatric patients. Here, we provide an up-to-date review of all reported genomic aberrations in the eight most common pediatric solid tumors with whole-exome sequencing or whole-genome sequencing data (from cBioPortal database, Pediatric Cancer Genome Project, Therapeutically Applicable Research to Generate Effective Treatments) and additional non-whole-exome sequencing studies. Potential druggable events are highlighted and discussed so as to facilitate preclinical and clinical research in this area. PMID- 28589770 TI - The emerging role of professional social media use in oncology. PMID- 28589771 TI - Imatinib mesylate in desmoplastic small round cell tumors. AB - AIM: To investigate the possible role of imatinib, an inhibitor of the tyrosine kinase activity of PDGF-R, in desmoplastic small round cell tumor (DSRCT). PATIENTS & METHODS: From August 2005 to June 2009, DSRCT patients refractory to conventional treatment were enrolled. Patients received imatinib 400 mg daily. Primary end point of this open label, prospective, Phase II trial was objective response rate. RESULTS: Of the 13 enrolled patients, eight were evaluable for response. Median age was 20 years (range: 9-32). Objective responses at 3 months were: stable disease in one patient and progressive disease in seven patients. CONCLUSION: Imatinib showed no efficacy in the treatment of DSRCT unresponsive to conventional therapy, despite molecular-based selection of patients. PMID- 28589773 TI - Estimating the spatial distribution of artificial groundwater recharge using multiple tracers. AB - Stable isotopes of water, organic micropollutants and hydrochemistry data are powerful tools for identifying different water types in areas where knowledge of the spatial distribution of different groundwater is critical for water resource management. An important question is how the assessments change if only one or a subset of these tracers is used. In this study, we estimate spatial artificial infiltration along an infiltration system with stage-discharge relationships and classify different water types based on the mentioned hydrochemistry data for a drinking water production area in Switzerland. Managed aquifer recharge via surface water that feeds into the aquifer creates a hydraulic barrier between contaminated groundwater and drinking water wells. We systematically compare the information from the aforementioned tracers and illustrate differences in distribution and mixing ratios. Despite uncertainties in the mixing ratios, we found that the overall spatial distribution of artificial infiltration is very similar for all the tracers. The highest infiltration occurred in the eastern part of the infiltration system, whereas infiltration in the western part was the lowest. More balanced infiltration within the infiltration system could cause the elevated groundwater mound to be distributed more evenly, preventing the natural inflow of contaminated groundwater. Dedicated to Professor Peter Fritz on the occasion of his 80th birthday. PMID- 28589772 TI - Report from European Association for the Study of the Liver: HCC Summit, Geneva, Switzerland, 2-5 February 2017. AB - The European Association for the Study of the Liver Hepatocellular Carcinoma (HCC) international meeting held in Geneva in February 2017 focused on the state of the art of HCC management, from diagnosis to treatment and the potential development of clinical research in this field. This report reviews some of the most interesting topics discussed at the meeting such as the role of hepatitis C viral infection treatment with direct-acting antivirals in enhancing HCC risk, current prognostic systems, early diagnosis techniques, curative therapies for early HCC and the systemic treatments for advanced disease with a look into future perspectives. PMID- 28589774 TI - Development of a multiplex qPCR in real time for quantification and differential diagnosis of Salmonella Gallinarum and Salmonella Pullorum. AB - Currently there are 2659 Salmonella serovars. The host-specific biovars Salmonella Pullorum and Salmonella Gallinarum cause systemic infections in food producing and wild birds. Fast diagnosis is crucial to control the dissemination in avian environments. The present work describes the development of a multiplex qPCR in real time using a low-cost DNA dye (SYBr Green) to identify and quantify these biovars. Primers were chosen based on genomic regions of difference (RoD) and optimized to control dimers. Primers pSGP detect both host-specific biovars but not other serovars and pSG and pSP differentiate biovars. Three amplicons showed different melting temperatures (Tm), allowing differentiation. The pSGP amplicon (97 bp) showed Tm of 78 degrees C for both biovars. The pSG amplicon (273 bp) showed a Tm of 86.2 degrees C for S. Gallinarum and pSP amplicon (260 bp) dissociated at 84.8 degrees C for S. Pullorum identification. The multiplex qPCR in real time showed high sensitivity and was capable of quantifying 108-101 CFU of these biovars. PMID- 28589775 TI - Opportunities to significantly reduce expenditure associated with cancer drugs. AB - AIM: To identify cancer drugs amenable to strategies for reducing expenditure and avoiding drug wastage. METHODS: Information was sourced from product information in 20 countries on parenteral cytotoxic agents, and cancer and noncancer monoclonal antibodies. Data were collected on vial sizes, overage, stability and presentation forms. RESULTS: Vial size availability varied significantly between countries, with often only single vial sizes for numerous medications. Overage was poorly reported. Stability data were inconsistent and variable between countries, with most drugs only having a 24 h expiry. Three cancer-indicated monoclonal antibodies, thought suitable for prefilled syringe administration, were only available as vials. CONCLUSION: Many expensive cancer drugs are suitable for global cost-reduction strategies. Collaboration is vital to affecting change and reducing expenditure. PMID- 28589776 TI - Early active motion after rigid internal fixation of unstable extra-articular fractures of the proximal phalanx. AB - : The purpose of this study is to describe active early rehabilitation in proximal phalanx fractures treated with rigid internal fixation. A total of 22 consecutive patients presenting with spiral, oblique or comminuted extra articular fractures of the proximal phalanx were included in the study. All fractures were rigidly stabilized with plate and screws or screws alone and subsequently entered an active early rehabilitation programme. The mean follow-up period was 15.4 months (SD 10.1). Mean visual analogue scale pain score was 0.3 (SD 0.5) and Disability of the Arm, Shoulder and Hand score was 9.2 (SD 4.1). Mean total active motion was 241.9 degrees (SD 18.3). According to the digital functional assessment, 86.3% of the patients had excellent results. Extension lags of the proximal interphalangeal joint were observed in seven fingers (mean lag, 3.4 degrees (SD 5.5)). The results of this study demonstrated high patient satisfaction and good outcomes after the surgical technique and postoperative rehabilitation protocol described in open reduction and rigid internal fixation of proximal phalangeal fractures. LEVEL OF EVIDENCE: IV. PMID- 28589777 TI - Social network, recovery attitudes and internal stigma among those with serious mental illness. AB - BACKGROUND: Social network size and strength is an important determinant of overall health. AIMS: This study describes the extent and strength of the social network among a sample of individuals with serious mental illness (SMI) and explores the relationship between an individual's social network and their experience of internal stigma and recovery attitudes. METHODS: Over a 2-year period, consecutive new patients with SMI attending two community mental health clinics were recruited and interviewed using a comprehensive battery of assessments including assessment of internalized stigma, recovery attitudes and symptom severity. RESULTS: Among the 271 patients interviewed, social network size was small across all diagnostic categories. In adjusted results, the number of friends and support from relatives and friends was significantly related to the personal confidence and hope recovery attitude ( p < .05). The number of relatives and friends and support from relatives was significantly related to internalized stigma ( p < .05). Frequency of contact with relatives or friends was not related to either recovery factors or internalized stigma. CONCLUSION: There is a significant positive relationship between the size and perceived strength of an individual's social network and internalized stigma and some recovery attitudes. Clinical programs that address any of these factors could potentially improve outcomes for this population. PMID- 28589778 TI - Relationship between musculoskeletal disorders and anthropometric indices among bus drivers in Zahedan city. AB - INTRODUCTION: Most work-related musculoskeletal disorders (MSDs) are associated with improper postures and poorly designed workstations. This study is an attempt to examine the prevalence and severity of MSDs as well as anthropometric dimensions among city bus drivers. METHODOLOGY: This cross-sectional study was carried out on 60 male bus drivers. A body discomfort chart was used to evaluate MSDs. Spearman correlation was employed to examine the relationship between body size and the severity of discomfort. RESULTS: Data analysis showed that discomfort reported in the lower back (33.3%), upper back (18.3%) and knee (15%) was severe and there was a direct and significant correlation between the body mass index and the severity of discomfort in the shoulder, arm and hip (p < 0.05). However, the results showed that eye sitting height and sitting height had significant inverse relationships with discomfort in the ankle and elbow (p < 0.05). CONCLUSION: The results of the study can be used to address ergonomic risk factors and reduce their associated disorders. The findings of the study can be used in training programs to educate drivers how to decrease the risk associated with work-related MSDs by adopting appropriate behavior strategies. PMID- 28589780 TI - Pelvic organ prolapse: the impact on quality of life and psychological well being. AB - The aim of this work is to propose a brief comment about the impact of pelvic organ prolapse on the quality of life and the psychological well-being of the affected women. PMID- 28589779 TI - Faking handedness: Individual differences in ability to fake handedness, social cognitions of the handedness of others, and a forensic application using Bayes' theorem. AB - People usually describe their handedness honestly, but that need not necessarily be the case. A legal case is described of a murder said by the pathologist to be committed by a left-hander but the defendant claimed to be right-handed, and the first author assessed the defendant's handedness as an expert witness. We know of no previous work on faking handedness, and so we tested 30 right-handers and 25 left-handers on various handedness tasks, and then asked the participants to repeat the tasks while faking being of opposite handedness. Social cognitions of handedness were assessed from participants' knowledge of how other right- and left-handers would answer handedness questionnaires. Fake handedness was best differentiated using cursive lower-case sentence writing, upper-case written letters being less good at distinguishing, as also were simple motor tasks. Participants differed in social cognitions of handedness, and those with more accurate social cognitions were better able to fake. Personality measures did not predict faking ability. For forensic purposes a Bayesian analysis was carried out to evaluate the likelihood of right and left hand performance being true rather than faked, and the cursive lower-case writing provided strong posterior odds that, as claimed, the particular defendant was a true right-hander. PMID- 28589781 TI - The effect of critical thinking education on nursing students' problem-solving skills. AB - THE AIM OF THE STUDY: The aim of this study is to examine the effect of critical thinking education on nursing students' problem-solving skills. MATERIALS AND METHOD: This study was conducted with 93 nursing students, 49 in the control group and 44 in the education group. The California Critical Thinking Disposition Inventory and the Problem-solving Inventory were administered to them before and after 12 weeks of critical thinking education. RESULTS: The education group's mean critical thinking score was 253.61 on the pretest and 268.72 on the posttest. This increase was statistically significant (p < .001). The posttest mean score of the control group fell to 258.18 on the posttest after a pretest mean score of 260.79, and this difference was statistically significant (p < .001). According to the posttest results, the problem-solving skills of education group increased significantly (p < .001), while the control group's score fell significantly (p < .001). CONCLUSION: This study determined that critical thinking education improves problem-solving skills. PMID- 28589782 TI - The Effect of Music on the Spirituality of Patients: A Systematic Review. AB - PURPOSE: Although some studies have suggested that music can positively affect physical and psychological variables, few have evaluated its effects on spirituality. This study aimed to evaluate the effects of musical interventions on the spirituality of patients, regardless of diagnoses. METHOD: This was a systematic literature review that followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations conducted through a relevant search of terms in six databases (PubMed, Web of Science, CINAHL, PsycINFO, ScienceDirect, and LILACS) without temporal delimitation. Experimental or quasi-experimental studies were included, involving participants regardless of diagnoses, to assess the effect of music on spirituality, either through musical intervention as music medicine or through music therapy. The methodological quality of included studies was evaluated using the Physiotherapy Evidence Database scale. RESULTS: A total of 147 studies were identified; 7 met the inclusion criteria. Five studies were randomized controlled trials involving six music therapists leading the musical intervention with the active participation of patients. The interventions used were heterogeneous. Three studies were associated with improved spirituality after the intervention. Four studies used measurements to evaluate spiritual well-being. CONCLUSION: This review did not allow ascertaining the positive impact of music intervention on spirituality in patients, which motivates further research. PMID- 28589783 TI - The pan occupational paradigm: development and key concepts. AB - BACKGROUND/AIM: Wilcock's Occupational Perspective of Health (OPH) aligns with the profession's re-discovery of its holistic, occupationally focused roots. Its dimensions of occupation-doing, being, becoming and belonging - resonate strongly with therapists on an intuitive, implicit level. However, its documented use in practice to date has been sparse, and several barriers to its implementation have been identified. The aim of this article is to present a renewal of the OPH - the Pan Occupational Paradigm (POP). Method of development: POP was developed using critical analysis, reflection and a comprehensive literature review. Each stage of development is described in detail, including the POP's inherent assumptions. Key concepts: POP retains the four dimensions of occupation, and shows their interdependent role within occupational entities (e.g. individuals, groups or communities). An entity can be approached by occupational therapy at any point and all the dimensions (either directly or indirectly) can be engaged. Occupational entities move along a continuum of wellbeing, and this movement can be in both positive and negative directions over a lifespan. CONCLUSION AND SIGNIFICANCE: POP is a distillation of occupational therapy's unique way of knowing about occupation and the promotion of wellbeing. It is put forward as an updated paradigm for occupational therapy in the 21st century. PMID- 28589784 TI - Resurrection of Mycteronastes (Monogenoidea: Monocotylidae), with Description of Mycteronastes caalusi n. sp. from Olfactory Sacs of the Smalltooth Sawfish, Pristis pectinata (Pristiformes: Pristidae), in the Gulf of Mexico off Florida. AB - Mycteronastes Kearn and Beverley-Burton, 1990 (Monogenoidea: Monocotylidae: Merizocotylinae) was resurrected from subjective synonymy with Merizocotyle Cerfontaine, 1894 , and its diagnosis was emended to include monocotylids with a haptor lacking a central loculus and having 5 peripheral (2 bilateral pairs and an unpaired anteromedial loculus), 1 interhamular, and 17 marginal loculi. The 3 species of Mycteronastes accepted herein are parasitic within the olfactory sacs of rays and sawfishes: Mycteronastes icopae ( Beverley-Burton and Williams, 1989 ) Kearn and Beverley-Burton, 1990 (type species) from the giant shovelnose ray, Glaucostegus typus (Anonymous (Bennett)) (Glaucostegidae), in the southwestern Pacific Ocean; Mycteronastes undulatae Kearn and Beverley-Burton, 1990 from the undulate ray, Raja undulata Lacepede (Rajidae), in the northeastern Atlantic Ocean; and Mycteronastes caalusi n. sp. from the smalltooth sawfish, Pristis pectinata Latham (Pristidae), in the Gulf of Mexico. Mycteronastes caalusi is most easily differentiated from its congeners by the combination of having 2 median cephalic papillae, an oval haptor that is wider than the body proper and lacks a deeply scalloped margin, a comparatively large anteromedial peripheral loculus, an unsclerotized male copulatory organ that is wholly anterior to the vaginal pores, a relatively small distal portion of the uterus (ootype chamber) that is mostly anterior to the vaginae, and a delicate uterus. The present study is the first report of a monocotylid from the olfactory sacs of P. pectinata and the first record of a species of Mycteronastes from the Gulf of Mexico. Notes on the taxonomy and systematics of some species assigned to Calicotyle Diesing, 1850 (Monocotylidae: Calicotylinae) are included. PMID- 28589785 TI - Revisiting beta thalassemia intermedia: past, present, and future prospects. AB - BACKGROUND: The spectrum of thalassemias is wide ranging from thalassemia minor, which consists of mild hypochromic microcytic anemia without obvious clinical manifestations, to thalassemia major (TM), which is characterized by severe anemia since the first years of life and is transfusion dependent. Thalassemia intermedia (TI) describes those patients with mild or moderate anemia. OBJECTIVE: To describe the genetic features and major clinical complications of TI, and the therapeutic approaches available in the management of this disease. METHODS: Publications from potentially relevant journals were searched on Medline. RESULTS AND DISCUSSION: Over the past decade, the understanding of TI has increased with regard to pathophysiology and molecular studies. It is now clear that clinical presentation and specific complications make TI different from TM. It is associated with greater morbidity, a wider spectrum of organ dysfunction and more complications than previously thought. CONCLUSION: TI is not a mild disease. The interplay of three hallmark pathophysiologic factors (ineffective erythropoiesis, chronic anemia, and iron overload) leads to the clinical presentations seen in TI. New treatment modalities are currently being investigated to broaden the options available for TI management. PMID- 28589786 TI - Mine rescuers' heat load during the expenditure of physical effort in a hot environment, using ventilated underwear and selected breathing apparatus. AB - Mine rescuers' heat load under the same physical effort load (25% of the maximal oxygen uptake), using three types of breathing apparatus, in newly developed heat removing underwear and outerwear was assessed for typical work conditions of mine rescuers, under milder and harsher ambient conditions of 32 and 38 degrees C, respectively, both at relative humidity of 85% and air velocity of 1.0 m/s. Expending physical effort at the same load while using different kinds of breathing apparatus resulted in a similar heat load. Under both milder and harsher ambient conditions, heat storage and sweating intensity were greater than the average limit value recommended by hygienic standards, which indicates that the use of breathing apparatus significantly hinders heat exchange with the environment. The developed clothing for mine rescuers was highly rated, and was considered by most people to be better than that used currently. PMID- 28589788 TI - Nurse's dedication helped us deal with our son's diabetes diagnosis. AB - When my son Luca was diagnosed with type 1 diabetes it was a massive shock. Our world was turned upside down. PMID- 28589790 TI - Staff fitness plan on track for raising team spirit. AB - Senior public heath nurse Jan Sinclair and her fitness team at Stepping Hill Hospital in Stockport walked, jogged and ran more than 1,000 miles at Easter. It took them nine days to cover a distance equivalent to a return trip from Glasgow to Plymouth, but no one had a day off work. PMID- 28589787 TI - Conditioned medium from the three-dimensional culture of human umbilical cord perivascular cells accelerate the migration and proliferation of human keratinocyte and fibroblast. AB - Previous studies have reported that the conditioned medium (CM) of bone marrow mesenchymal stem cells (BM-MSCs) stimulate the migration and proliferation of cell types involved in the wound healing process. However, these studies only show MSC-CM effects that were obtained using a two-dimensional (2D) culture. Recently, a three-dimensional (3D) culture has been considered to be a more physiologically appropriate system than the 2D culture. In addition, it has been shown that the procurement of BM-MSC is invasive, and other sources of MSC are thus being explored. Recently, perivascular cells (PVCs) have been considered as an alternative source of cells for dermal wound healing. Therefore, in this study, a PVC-conditioned medium (CM) was collected from a 3D culture (PVC-CM-3D) using highly porous polystyrene-based membranes and compared with PVC-CM from a 2D culture (PVC-CM-2D) to investigate the effects on the migration and proliferation of human keratinocytes and fibroblasts. Moreover, the PVC-CM components from the 2D and 3D cultures were identified using 2D gel electrophoresis. The migrations of the keratinocytes cells and fibroblasts were significantly higher with PVC-CM-3D than with the 2D culture; similarly, the proliferation of keratinocytes was also highly stimulated by PVC-CM-3D. Proteomic analyses of the PVC-CM revealed that type I collagen was highly expressed in the 3D-culture system. Microtubule-actin cross-linked factor 1 (KIAA0465), nebulin related anchoring protein, and thioredoxin were specifically expressed only in PVC-CM-3D. In addition, more EVs could be isolated from the PVC-CM-3D, and EVs were found to stimulate keratinocyte migration. Taken together, 3D-culture using a polystyrene scaffold is demonstrated to be a better system for providing better physiological conditions; therefore, PVC-CM-3D could be a promising option for skin-wound healing. PMID- 28589789 TI - Doctors' age linked to mortality risk for over-65s in hospital. AB - Patients aged 65 or over treated by older doctors in US hospitals were slightly more likely to die than those treated by younger doctors, except when high volumes of patients were being treated, a study has found. PMID- 28589791 TI - Number of older people with care needs 'to rise 25% by 2025'. AB - The number of older people with care needs is expected to grow by a quarter by 2025, research suggests. PMID- 28589792 TI - From treating need to creating wellness. AB - Six years ago I lost my job as a deputy director of commissioning due to compulsory redundancy. In the run-up to leaving the NHS I had been introduced to one of the most inspirational nurses I've ever met, Hazel Stuteley. PMID- 28589793 TI - Margaret Green - education pioneer. AB - Serving at the RCN for 24 years from 1966 to 1990, Margaret Green helped to set up the UKCC, the forerunner of the NMC, and introduce major changes to nurse education such as Project 2000 and PREP. PMID- 28589794 TI - Cognitive risk for overweight people with type 2 diabetes. AB - Obese and overweight people with type 2 diabetes are at increased risk of abnormal brain structure and cognitive problems, a study has found. PMID- 28589796 TI - Infants' cognition develops faster if dads play with them, study shows. AB - If fathers actively engage with their children and play with them in the first few months of life, it has a positive impact on cognitive development, research shows. PMID- 28589795 TI - Fertility preservation. AB - Essential facts [Figure: see text] Fertility preservation involves freezing and storing eggs, sperm, embryos and ovarian or testicular tissue for use in a person's future fertility treatment. Men and women may wish to preserve their fertility for a variety of reasons, including delaying parenthood and allowing treatment of a medical condition that may affect future fertility, including some cancer treatments. PMID- 28589799 TI - Campaign aims to boost profile of nurse leaders. AB - An ambitious global campaign to raise the profile of nursing across every continent has been announced at the International Council of Nurses (ICN) congress. PMID- 28589797 TI - Use of the wellness thermometer to improve consultations for patients with human immunodeficiency virus. AB - The care paradigm for patients with human immunodeficiency virus (HIV) has changed from managing an infectious condition with a suboptimal prognosis, to managing a long-term chronic disease. The wellness thermometer is a tool that was developed to assist with monitoring the biological, psychological, social and spiritual well-being of patients with HIV. Aim To evaluate the effectiveness of using the wellness thermometer in healthcare consultations with patients with HIV. Method This was a service evaluation that was undertaken in three UK HIV clinics in 2014. After using the wellness thermometer, patients and healthcare professionals completed a survey to indicate whether they felt the tool improved their consultations. Results A total of 231 patients completed the survey. It was found that 80% (n=185) of patients felt the wellness thermometer helped to identify their concerns, while 79% (n=182) of patients felt the wellness thermometer improved their conversation with the healthcare professional. Of the 12 healthcare professionals who completed the survey, most felt that the tool helped patients to identify their concerns (n=10) and that it was easy to use (n=11). Conclusion There are several benefits associated with using the wellness thermometer in healthcare consultations, and it may support patients with HIV to report any concerns they have in relation to their treatment and quality of life. The authors envisage that the tool will become a routine part of the care of these patients. PMID- 28589800 TI - Care of patients undergoing stoma formation: what the nurse needs to know. AB - Rationale and key points This article provides an overview of the various types of abdominal stoma and surgical procedures that result in stoma formation. It outlines the enhanced recovery pathway that is used to guide postoperative care, and some of the areas that should be incorporated in postoperative stoma care. These areas include training in the practical care of the stoma and its appliance, dietary advice and reintegrating lifestyle activities. In addition, the article briefly examines stoma reversal, and explores the role of the stoma specialist nurse. " Nurses require an understanding of the various surgical procedures that might result in the formation of a stoma. " An understanding of the stoma appliances that are available is essential to enable nurses to provide effective care for patients with a newly formed stoma. " Effective postoperative care that incorporates support and education enables patients to adapt quickly to having a stoma. " Enabling patients to understand changes that occur as a result of stoma formation will increase their confidence in managing their stoma alongside the effect on their quality of life. PMID- 28589801 TI - Call to champion health of refugees. AB - The highest-ranking nurse from the Obama administration has urged nurses around the world to help tackle migrant and refugee health challenges. PMID- 28589805 TI - Life expectancy rises for people with HIV, study finds. AB - Life expectancy for 20 year olds starting treatment for HIV has increased by ten years in Europe and the US since antiretroviral therapy began in the mid-1990s, an analysis shows. PMID- 28589804 TI - A royal turning point. AB - In disclosing the mental distress he experienced after the death of his mother Princess Diana, Prince Harry has joined a growing number of famous people who have felt enabled to make such issues public. PMID- 28589806 TI - Mobility care. AB - What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? I read the article because it was relevant to my practice as a nurse on a surgical unit, where many of the patients are older people. I wanted to improve my understanding of what an integrated approach to mobility care for older people might entail. The article stated that although this approach is aimed at older people living in nursing homes or residential care who require assistance with mobilising, it could also be applied to other care settings. PMID- 28589808 TI - Don't believe the bad press. AB - Never has media coverage put me off becoming a nurse (readers' panel, 31 May). I'm nearly qualified and couldn't be more proud to work for the NHS. PMID- 28589809 TI - 'I aim to inspire our new nurses'. AB - Isobel Mason is a nurse consultant in gastroenterology at the Royal Free London NHS Foundation Trust and inflammatory bowel disease (IBD) nurse development manager at the charity Crohn's & Colitis UK. Having qualified at the Royal Free in 1990 and worked in acute medicine before specialising in gastroenterology, she is now chair of the RCN Gastrointestinal Nursing Forum. PMID- 28589810 TI - When all is calm, please don't utter the 'q' word. AB - 'Labour will put a stop to bad language,' I heard in the run-up to the election. Quite right, I thought. All that effing and blinding; totally unnecessary. Then I realised they had said 'bad landlords'. Must make that audiology appointment.... PMID- 28589811 TI - Readers' panel - Should nurse handovers take place at the patient's bedside? AB - Our experts consider a hot topic of the day. PMID- 28589812 TI - I'm not married - will my partner get my pension? AB - Most occupational pension schemes, such as that for NHS employees, ask members to declare who they wish the benefits to be paid to if they die. These are known as 'expressions of interest' forms or something similar, and in them you state who you wish to receive your benefits. PMID- 28589813 TI - We are proud to be a four-country regulator. AB - The Nursing and Midwifery Council held its last next meeting in Cardiff. We are proud to be a four-country regulator, and once a year we hold the meeting outside London, giving us a chance to meet with our stakeholders in Wales, Northern Ireland and Scotland. PMID- 28589815 TI - Head of World Health Organization says nurses are key to universal healthcare. AB - The new director-general of the World Health Organization (WHO) has affirmed his support for nursing, promising to have a regular dialogue with nurse leaders. PMID- 28589814 TI - Nursing in the RAF: 'it's no ordinary job'. AB - Working in the military may not be an obvious choice for a nurse. but for Squadron Leader Ian Swain, a nursing officer at Royal Air Force College Cranwell, his job in the RAF has turned out to be 'varied, challenging, and exciting'. PMID- 28589816 TI - Two-way learning. AB - I have been a mentor for many years and believe it is a role all nurses should take on, as mentoring is a two-way process - we also learn from students. PMID- 28589818 TI - Language barriers. AB - I have worked with some overseas nurses who struggled to communicate at a basic level and it made for a stressful environment for staff and patients (NMC chief responds to concerns over language test review, news online, 26 May). PMID- 28589819 TI - Inpatients note nurse shortages, but say they have confidence in the profession. AB - Almost four in ten hospital inpatients believe there are not always enough nurses on duty to care for them, a survey reveals. PMID- 28589817 TI - Unfair expectations. AB - The International English Language Test System (IELTS) exam can be challenging even for native speakers. PMID- 28589820 TI - Missing out on good mentors. AB - My concern with the proposal to swap mentors for two new roles (news, 31 May) is that nurses who are good with students won't be able to help them if they are not on the approved list. PMID- 28589823 TI - Facing the challenges of providing leadership. AB - In the middle of a busy shift when patients or colleagues are looking to you for direction, you may find the demands of leadership overwhelming. PMID- 28589822 TI - Attacks on hospital employees' cars highlight workplace parking pressures. AB - Hospital staff members' cars were vandalised and angry notes left on their windscreens. PMID- 28589824 TI - Taking care to the patient: a rural outreach plan for men. AB - A staff nurse has turned her outpatients department into a health promotion hub, reaching across her community hospital and beyond to provide proactive, preventive and integrated services in rural communities. Anne Thomas, who works at Dolgellau Hospital in Gwynedd, north west Wales, won the Community Nursing category of the RCNi Nurse Awards 2017 for her work addressing health inequalities in men. PMID- 28589826 TI - Guidance row-back over PAYE for temporary staff. AB - Bank, agency and locum staff working in the NHS will not now automatically have their tax deducted at source. PMID- 28589825 TI - Effective communication with older adults. AB - Communication is an essential aspect of life, yet it can be taken for granted. Its centrality to being in the world and in professional practice often becomes evident when nurses and older adults encounter communication difficulties. The factors that can affect nurses' communication with older adults relate to the older adult, the nurse, sociocultural considerations and the environment, and the interactions between these factors. In adopting a person-centred approach to communicating with older adults, it is necessary to get to know the person as an individual and ensure communication meets their needs and abilities. Effective communication is essential in nursing practice and requires professional competence and engagement. This article can be used by nurses to support effective communication with older adults across the continuum of care. PMID- 28589828 TI - 'Tell your politicians to look at the safe staffing evidence'. AB - A nurse researcher who has led global studies on safe staffing said it is time for nurses and governments to act on the body of evidence. PMID- 28589829 TI - Royal Trinity Hospice. AB - Royal Trinity Hospice in south London has developed an app to help patients and carers navigate palliative care and access the support available to them. PMID- 28589830 TI - Swift response. AB - Healthcare leaders have praised the 'swift and heroic' actions of NHS staff in response to the terror attack in London last week. PMID- 28589831 TI - From downtrodden to influential: the global campaign to empower nurses. AB - Nurses have spent decades trying to shake off the image of being doctors' handmaidens, yet still the stereotype exists. In recent weeks their professionalism, skills and expertise have been highlighted by responses to terror attacks in Manchester and London, but dented by constant references in the general election campaign to nurses using food banks. PMID- 28589832 TI - Improving medicines management. AB - While on placement on a forensic learning disability ward in my third year as a mental health nursing student, I noticed that patients sometimes needed 'as required' (PRN) medication for distress associated with their mental health. PMID- 28589833 TI - The Skies I'm Under: The Rain and Shine of Parenting a Child with Complex Disabilities Wright Rachel The Skies I'm Under: The Rain and Shine of Parenting a Child with Complex Disabilities 204pp L6.99 Self-published ( www.theskiesimunder.co.uk ) 9780993491504 0993491502 [Formula: see text]. AB - This extraordinary book is one mother's heartfelt, inspiring story following the birth of her son. PMID- 28589834 TI - Doing & Writing Qualitative Research Holliday Adrian Doing & Writing Qualitative Research 216pp L28.99 Sage 9781473953277 1473953278 [Formula: see text]. AB - With a breadth of detail that will engage a variety of readers working in different research disciplines, this clear and concise introductory text handles difficult concepts with diverse and in-depth examples. PMID- 28589835 TI - Fears 'double dose of debt' is deterring mature students. AB - With the end of bursaries for nursing students in England a matter of weeks away, academics have told Nursing Standard of the need to ensure mature students are not put off by funding changes. About 6,000 fewer mature students have applied to start nursing courses this coming autumn compared with last year. Figures from the university admissions service UCAS show a 28% drop in the number of over-25s applying in England. PMID- 28589836 TI - Student life - No need to rush into a role. AB - Many students are in a rush to land a job as soon as they qualify. Having spent at least three years with little income, this is understandable. PMID- 28589837 TI - Description of a New Quadrigyrid Acanthocephalan from Kashmir, with Notes on Metal Analysis and Histopathology, and a Key to Species of the Subgenus Acanthosentis from the Indian Subcontinent. AB - Acanthogyrus (Acanthosentis) kashmirensis n. sp. is described from recently collected acanthocephalan specimens in the Jhelum River in northern Kashmir that are conspecific with Neoechinorhynchus kashmirensis Fotedar and Dhar, 1977 originally described in a Ph.D. thesis in 1972 from 4 species of cyprinid fishes: Tor tor Hamilton, Bangana diplostoma (Heckel) (syn. Labeo diplostoma Heckel), Labeo rohita Hamilton, and Ptychobarbus sp. Steindachner. The poor unpublished diagnosis was followed by 1 uninformative abstract in a scientific meeting in 1977. The acanthocephalan was later designated as invalid because of the lack of a formal published description and absence of information on deposited type or voucher specimens. Recent collections of specimens of the same species were made from 2 other cyprinid species of cyprinid fishes, Schizothorax plagiostomus Heckel and Schizothorax labiatus (McClelland) from the Sandran River, a tributary of the Jhelum River, in southern Kashmir. It is now possible to provide a full description of these specimens and reassign them in the subgenus Acanthosentis Verma and Datta, 1929 based on the finding of circles of vestigial spines at the anterior end of the trunk of male and female specimens. These vestigial spines are barely visible and easy to miss with optical microscopy. The new species is also characterized by having (1) a para-receptacle structure in males and females, (2) unique double Saefftigen's pouches, (3) large round single-nucleated cells in the proboscis, and (4) the lemnisci being either equal or distinctly unequal with no intermediate states. A key to the species of Acanthosentis of the Indian subcontinent is provided. Histopathological sections show extensive damage to the host intestine with subsequent blood loss, cell necrosis, and attempted encapsulation. Results of the energy dispersive X-ray analysis (EDAX) study show hollow hooks high in sulfur but with limited calcium ions. Hooks of most acanthocephalans studied with X-ray scans are solid with high calcium and low sulfur ions. PMID- 28589838 TI - A Novel Symbiotic Ciliate (Ciliophora: Peritrichia) in the Hindgut of a Stag Beetle (Coleoptera: Lucanidae). AB - Bell-shaped ciliates of the subclass Peritrichia, such as Vorticella, Carchesium and Epistylis, are commonly found in freshwater and other aquatic environments, either solitary or colonial. Peritrichs attach to a substratum via a contractile or non-motile stalk, and collect food particles by water current using ciliary rows around the edge of the bell, called the peristome. Some peritrichs are epibiotic and ectocommensalistic associates of aquatic insects and other animals, settling on the surface of their specific hosts. Only a few peritrichs are known to establish a more internal association with their hosts, locating within the preoral cavity or esophagus of water beetles and presumably subsisting on food materials chewed and ingested by the insects. To date, no endoparasitic or endocommensalistic peritrichs have been reported from insects. Host insects reported to date have all been aquatic, and given the aquatic lifestyle of peritrichs, terrestrial hosts have been considered unlikely. In the present study, we report a dense population of bizarre microbes within the gut of a terrestrial insect, and histological, ultrastructural and molecular phylogenetic analyses identified it as a peritrich ciliate. The highly-developed hindgut of the stag beetle Aegus currani contained oval colonial peritrichs connected by branched stalks resembling grape clusters. Each zooid exhibited a reduced peristome without disc, a vestibulum with active ciliary movement inside, and an elongated macronucleus. These features are morphologically reminiscent of but distinct in some respects from those in Operculariella parasitica, known from the esophagus of dysticid diving beetles. Taxonomic, ecological and functional aspects of this gut-dwelling peritrich warrant future study. PMID- 28589840 TI - Characterization of a Sea Urchin IQ Motif Containing Protein D as a Coactivator of Nuclear Receptors. AB - Nuclear receptor (NR) interacting proteins, such as coactivators and corepressors, play a crucial role in specifying the transcriptional activity of the receptor. However, little is known about the functional features of the NR coregulators in marine invertebrates. Using the yeast two-hybrid screening method, a sea urchin oocyte cDNA library was screened for proteins that interact with the ligand-binding domain of human RXRalpha (hRXRalpha) as the bait protein in the presence of 9-cis retinoic acid. Here, we describe IQ motif containing protein D (IQCD) as an RXR-interacting coactivator. The open reading frame of Strongylocentrotus nudus IQCD (SnIQCD) cDNA contains 1464 bp encoding a protein of 487 amino acids. SnIQCD and the vertebrate IQCDs contain well-conserved C terminal IQ motifs and coiled-coil domains. The interactions between RXRalpha and IQCD were confirmed by an immunoprecipitation assay and a mammal two-hybrid assay. RXRalpha preferentially interacted with the C-terminal half including IQ motif than the N-terminal half of SnIQCD. The coactivator interacting LXXLL motif in SnIQCD is not directly involved in the interaction with RXRalpha. SnIQCD overexpression increased the basal RXR transactivation of a RXR-responsive reporter gene. Furthermore, SnIQCD enhanced the transcriptional activity of RXR heterodimeric partners such as RAR, PPAR, and the steroid hormone receptor family members from mammals, teleost fish, and sea urchin. Taken together, we suggest that IQCD orthologs are able to function as transcriptional coactivators cooperating with NRs. PMID- 28589839 TI - Estimation of Evolutionary Rates of Mitochondrial DNA in Two Japanese Wood Mouse Species Based on Calibrations with Quaternary Environmental Changes. AB - Reliable estimates of evolutionary rates of mitochondrial DNA might allow us to build realistic evolutionary scenarios covering broad time scales based on phylogenetic inferences. In the present study, we sought to obtain estimates of evolutionary rates in murine rodents using calibrations against historical biogeographic events. We first assumed that land-bridge-like structures that appeared intermittently at glacial maxima with 100,000-year intervals shaped the divergence patterns of cytochrome b (Cytb) sequences (1140 bp) of the larger Japanese wood mouse Apodemus speciosus. The comparison of sequences from peripheral remote islands that are separated from one another by deep straits allowed us to estimate mitochondrial DNA evolutionary rates (substitutions/site/million years) to be 0.027 to 0.036, with presumed calibrations from 140,000, 250,000, 350,000, and 440,000 years ago. Second, we addressed rapid expansion events inferred from analyses of the Cytb sequences of the lesser Japanese wood mouse A. argenteus. We detected five expansion signals in the dataset and established three categories based on the expansion parameter tau values: 3.9, 5.6-5.7, and 7.8-8.1. Considering that the climate became warmer 15,000, 53,000, and 115,000 years ago after preceding periods of rapid cooling, we calculated evolutionary rates to be 0.114, 0.047, and 0.031, respectively. This preliminary concept of the evolutionary rates on a time scale from 15,000 to 440,000 years ago for the wood mouse should be refined and tested in other species of murine rodents, including mice and rats. PMID- 28589841 TI - Targeted Ablation of Pancreatic beta Cells in Medaka. AB - The pancreas plays important roles in the regulation of blood glucose, and is a well-studied organ in mammals because its dysfunction causes serious disorders, such as diabetes mellitus. However, mammals have the limited capacity for tissue regeneration in their organs, including pancreas. Fish may be an attractive model for regeneration studies, as fish exhibit a greater capacity for regeneration than do mammals. To elucidate the regenerative capacity of pancreatic beta cells in medaka, we generated transgenic lines, in which beta cells can be specifically ablated using the nitroreductase (NTR)/metronidazole (Mtz) system. We examined beta-cell regeneration at embryonic-larval stages after specific ablation of beta cells, and found that medaka rapidly regenerate beta cells. Furthermore, we found that teleost-specific secondary islet have a unique feature in that their size increases in response to beta-cell ablation in principal islets. PMID- 28589842 TI - Description of a New Species for Asian Populations of the "Cosmopolitan" Perinereis cultrifera (Annelida: Nereididae). AB - An Asian species of Perinereis, which has been regarded as a local population of a cosmopolitan species P. cultrifera ( Grube, 1840 ) (type locality: Italy), is described as a new species, P. euiini., based on Korean specimens. This new species is distinguishable from P. cultrifera and other similar species such as P. floridana ( Ehlers, 1868 ) (type locality: USA), P. anderssoni Kinberg, 1866 (type locality: Brazil), and P. helleri ( Grube, 1878 ) (type locality: Philippines) by the character combination of the absence of lateral group of paragnaths in area III on the proboscis, the presence of small notopodial prechaetal lobe in anterior parapodia, and the greatly expanded dorsal ligule in posterior parapodia. All previous records of "P. cultrifera" from eastern Asia (Taiwan, China, Japan, and Korea) are judged to belong to P. euiini sp. nov., leading to the conclusion that P. cultrifera is not a cosmopolitan species. Specimens previously identified as P. cultrifera var. floridana (or P. cultrifera floridana) in eastern Asia are also judged to belong to P. euiini sp. nov., although they have different paragnath number in area V (one instead of three). Their aberrant paragnath number was regarded as an intraspecific variation of P. euiini sp. nov. The comparison of DNA sequences of the mitochondrial cytochrome c oxidase subunit I (COI) between P. euiini sp. nov. and "P. cultrifera" from China and Portugal also supports the erection of the new species. PMID- 28589843 TI - Comparing the Survival Rate of Mangrove Clam, Polymesoda (Geloina) spp. (Solander 1876) Through Field Experiments in Mangrove Forests of Iriomote Island. AB - Polymesoda spp., which represent bivalves in the mangrove ecosystem, inhabit the mangrove forests of the Indo-Pacific region. They tend not to be broadly distributed across zones within the mangrove forest, but are instead typically encountered in the mesozone. We conducted field rearing experiments on four plots which were set across a mangrove forest along the Urauchi River of Iriomote Island, from the seaward to landward sides, over a period of 10 months. We compared the survival rates of clams at these plots with different environment for four months. Salinity was also measured during the study period, and we established a correlation between survival rate and change in salinity of each plot. The survival rate of the plot in the mesozone was 90%, that of two plots which were positioned in the seaward zone of the mesozone was 40%, and that of the plot on the landward side was 0%. In plot 4, the ambient water of the bivalves was fresh water. The salinity of the seaward zone changed rapidly in one day, or the salinity of the ambient water surrounding the bivalves was high for a long period of time. In Plot 3, salinity change was gradual, and the average salinity was lower than in Plots 1 and 2. This study indicates that salinity level affects bivalve survival rate and that area similar the mesozone, where gradual salinity change and average salinity were neither too high nor too low, are suitable for these species. PMID- 28589844 TI - Morpho-Molecular Evidence for Polymorphism in the Mushroom Coral Cycloseris hexagonalis (Scleractinia: Fungiidae), with a New Phylogenetic Position and the Establishment of a New Genus for the Species. AB - Mushroom corals are reef corals of the family Fungiidae, which live in the tropical and subtropical Indo-Pacific region. Recently, most species of this family have been revised taxonomically based on morphological and molecular analyses. However, the phylogenetic position of Cycloseris hexagonalis ( Milne Edwards and Haime, 1848 ) has not been analyzed and remains unclear. This species is believed to show allometric growth by changing its corallum shape from hexagonal in juveniles to irregularly circular with an undulated corallum margin in mature individuals. However, these morphological changes have not been monitored and their genetic basis has not been confirmed. In the present study morphological and molecular phylogenetic analyses were performed to evaluate the identity of the morpho-types in C. hexagonalis and to clarify the phylogenetic and taxonomic position of the species. In the morphological analysis, we used 20 specimens of C. hexagonalis collected from around Iriomote Island, Okinawa, Japan, and identified four morphotypes. Moreover, the molecular phylogenetic analyses using mitochondrial COI and nuclear ITS markers showed that all morpho types of C. hexagonalis together form an independent clade, indicating that they are all conspecific. Molecular phylogenetic comparison between this species and other fungiids revealed that the clade of C. hexagonalis is clearly distant from the Cycloseris clade as well as from clades representing other genera in the Fungiidae. Considering these data, we establish a monotypic new genus, Sinuorota, to accommodate C. hexagonalis. PMID- 28589845 TI - Deep Phylogeographic Breaks in Magpie Pica pica Across the Holarctic: Concordance with Bioacoustics and Phenotypes. AB - We examined sequences of the mitochondrial control region in magpies (Pica pica) from the entire distribution range and found deep genetic splits into four major lineages: (1) group West (Europe-Siberia), (2) group East (southern Far East), (3) P. p. mauritanica (North Africa), and (4) P. p. hudsonia (North America). These lineages show a geographic pattern corresponding to known subspecies or subspecies groups. Genetic variation within the widely-distributed group West is low and neutrality tests supported a recent expansion scenario. The haplotypes from Kamchatka, representing a separated sublineage with clear affinity to the European-Siberian group, are almost identical, implying a recent bottleneck. Group East contained two subclades without clear geographic pattern, presumably due to admixing of populations that had diverged in Pleistocene refuges. The homogeneity of the Kyushu population supports historical reports of introduction of the species from Korea. In contrast, the high variation in the recently established Hokkaido population may reflect an ongoing invasion from several populations of the Far Eastern mainland. Bioacoustic data based on chatter call differentiate groups of subspecies and reflect phylogeographic patterns, i.e., mitochondrial lineages. Furthermore, we report the fast spreading of P. p. jankowskii towards the west along the upper Amur River, and a slower shifting of P. p. leucoptera in the opposite direction thus yielding a new contact zone. Overall, our data support a scenario of divergence in geographic isolation, but the ongoing expansion of distribution ranges may lead to major changes in phylogeographic patterns. PMID- 28589846 TI - Low Genetic Variation of Red-Crowned Cranes on Hokkaido Island, Japan, Over the Hundred Years. AB - The red-crowned crane (Grus japonensis) is recognized internationally as an endangered species. Migratory populations breed in eastern Russia and northeastern China, whereas the resident population inhabits the island of Hokkaido, Japan. Although the population inhabiting Hokkaido had experienced a severe bottleneck by the end of the 19th century, the population size has recovered to about 1500 and continues to increase now thanks to conservation efforts. A previous study reported that no marked genetic differences were seen in the island population, and that the genetic variation of the whole population on Hokkaido was lower than that of the continental population. However, the precise genetic structure of the island population in the past or near present remains unclear. To better understand the spatiotemporal changes in the genetic structure of the island population, we performed mitochondrial DNA (mtDNA) analyses using stuffed specimens (years 1878-2001) and tissue or blood samples (years 1970-2014). We found three haplotypes in the island population, one of which was a novel mtDNA haplotype in 1997 and 2007 samples. In addition, there was no clear difference in the haplotype frequency through the time span. These results suggest that the low genetic variation of the island population persisted for the last hundred years. It is thus nearly impossible for the island population to recover its genetic variation in isolation. Conservation plans for this species should therefore include the promotion of genetic exchanges between the continental and island populations, such as through artificial introduction to Hokkaido. PMID- 28589847 TI - Comparison of the Inducing Effect of Indole Compounds on Medusa Formation in Different Classes of Medusozoa. AB - Scyphozoa, Cubozoa and Hydrozoa are classes in the phylum Cnidaria that undergo metagenesis involving a dramatic morphological transition. In Scyphozoa and Cubozoa, when exposed to species- or strain-specific transition-inducing stimuli, asexually reproducing benthic polyps transform into sexually reproducing planktonic medusae. In Hydrozoa, exposure to species- or strainspecific transition-inducing stimuli causes formation of medusa buds in the polyp's body. In Aurelia aurita (Linnaeus, 1758) (Scyphozoa, Semaeostomeae), polyp-to-jellyfish transition is induced by some simple indole compounds. However, whether indole compounds can induce polyp-to-jellyfish transition in Cubozoa and Hydrozoa remains unknown. In the present study, we show that an indole compound, 5-methoxy 2-methylindole, induces polyp-to-jellyfish transition in Scyphozoa and Cubozoa. This inducing action suggests that the downstream steps of polyp-to-jellyfish transition are regulated by the same biochemical reactions in Scyphozoa and Cubozoa, irrespective of the type of transition-inducing environmental stimuli. PMID- 28589848 TI - Factors Related to Altitudinal Body Size Variation in the Earthworm-Eating Ground Beetle Carabus japonicus. AB - To understand geographic body size variation in an insect species, various factors including habitat temperature, correlation between life history traits, and food availability must be examined. Carabus (Ohomopterus) japonicus is univoltine, feeds exclusively on earthworms during its larval stage, and shows a clinal body size variation along the habitat temperature gradient in northern Kyushu, Japan. Carabus japonicus occurs at both high and low altitudes; at high altitudes it coexists with a larger species, C. (O.) dehaanii. At low altitudes, C. japonicus shows larger body sizes. We sought to determine whether this increase in body size is only an adaptation to high habitat temperatures in the absence of C. dehaanii, and examined the life history of C. japonicus and seasonal trends in prey earthworms at six sites between altitudes of 30 and 980 m. While high-altitude populations used the entire warm season for reproduction and larval development, low-altitude populations showed shorter periods of reproductive activity and larval incidence coincided with seasonal trends in earthworm abundance. Thus, C. japonicus attained larger body sizes at lower altitudes without a notable extension of their juvenile period. At lower altitudes, earthworms grew faster and reached sizes, which may be too large for predation by small carabid larvae. Large females had higher fecundity, and laid larger eggs, from which larger first instar larvae hatch. The large body size of C. japonicus in warm habitats may thus be an adaptation not only for high fecundity, but also for producing large first instar larvae to more efficiently prey on large earthworms. PMID- 28589849 TI - Portal Vein Thrombosis and Nephrotic Syndrome After Liver Transplant. AB - Despite systemic thromboembolic complications being frequent, portal vein thrombosis is a rare complication of nephrotic syndrome. We report here a liver transplant recipient who presented a late extensive portal vein thrombosis related to nephrotic syndrome. During regular follow-up after liver transplant, the patient presented with diabetes, arterial hypertension, hypercholesterolemia, and progressive renal dysfunction. In addition, urine analysis showed isolated proteinuria, and the diagnosis of nephrotic syndrome was made 36 months after liver transplant. Sixty months after liver transplant, the patient presented with mild acute abdominal pain, and the diagnosis of portal vein thrombosis was made from a computed tomography scan. Other causes for portal vein thrombosis were excluded. Histologic examination of a liver biopsy disclosed only mild steatosis. Histologic examination of a kidney biopsy disclosed severe lesions, suggesting a multifactorial, advanced chronic nephropathy probably caused by nephroangiosclerosis, diabetes, and toxicity of calcineurin inhibitors. Anticoagulation therapy led to complete recanalization of the portal and splenic veins, which was maintained thereafter. In conclusion, the case we report here illustrates that portal vein thrombosis can occur after liver transplant in the context of nephrotic syndrome, complicating chronic kidney disease, which is a very frequent and multifactorial complication after liver transplant. PMID- 28589850 TI - EDITORIAL: Medicinal Chemistry of Molecular and Epigenetic Targets and Dug Development. PMID- 28589851 TI - Advances and New Perspectives in Medicinal Chemistry Engineering and Bioinformatics (from IWBBIO 2015). PMID- 28589852 TI - EDITORIAL: Medicinal Chemistry of Nanomaterials for Cancer Theranostics. PMID- 28589854 TI - A disease similarity matrix based on the uniqueness of shared genes. AB - BACKGROUND: Complex diseases involve many genes, and these genes are often associated with several different illnesses. Disease similarity measurement can be based on shared genotype or phenotype. Quantifying relationships between genes can reveal previously unknown connections and form a reference base for therapy development and drug repurposing. METHODS: Here we introduce a method to measure disease similarity that incorporates the uniqueness of shared genes. For each disease pair, we calculated the uniqueness score and constructed disease similarity matrices using OMIM and Disease Ontology annotation. RESULTS: Using the Disease Ontology-based matrix, we identified several interesting connections between cancer and other disease and conditions such as malaria, along with studies to support our findings. We also found several high scoring pairwise relationships for which there was little or no literature support, highlighting potentially interesting connections warranting additional study. CONCLUSIONS: We developed a co-occurrence matrix based on gene uniqueness to examine the relationships between diseases from OMIM and DORIF data. Our similarity matrix can be used to identify potential disease relationships and to motivate further studies investigating the causal mechanisms in diseases. PMID- 28589853 TI - N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes. AB - BACKGROUND: Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and down-regulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. RESULTS: We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. CONCLUSION: The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care. PMID- 28589855 TI - Identifying subtype-specific associations between gene expression and DNA methylation profiles in breast cancer. AB - BACKGROUND: Breast cancer is a complex disease in which different genomic patterns exists depending on different subtypes. Recent researches present that multiple subtypes of breast cancer occur at different rates, and play a crucial role in planning treatment. To better understand underlying biological mechanisms on breast cancer subtypes, investigating the specific gene regulatory system via different subtypes is desirable. METHODS: Gene expression, as an intermediate phenotype, is estimated based on methylation profiles to identify the impact of epigenomic features on transcriptomic changes in breast cancer. We propose a kernel weighted l1-regularized regression model to incorporate tumor subtype information and further reveal gene regulations affected by different breast cancer subtypes. For the proper control of subtype-specific estimation, samples from different breast cancer subtype are learned at different rate based on target estimates. Kolmogorov Smirnov test is conducted to determine learning rate of each sample from different subtype. RESULTS: It is observed that genes that might be sensitive to breast cancer subtype show prediction improvement when estimated using our proposed method. Comparing to a standard method, overall performance is also enhanced by incorporating tumor subtypes. In addition, we identified subtype-specific network structures based on the associations between gene expression and DNA methylation. CONCLUSIONS: In this study, kernel weighted lasso model is proposed for identifying subtype-specific associations between gene expressions and DNA methylation profiles. Identification of subtype-specific gene expression associated with epigenomic changes might be helpful for better planning treatment and developing new therapies. PMID- 28589856 TI - Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease. AB - BACKGROUND: The APOE epsilon4 allele is the most significant common genetic risk factor for late-onset Alzheimer's disease (LOAD). The region surrounding APOE on chromosome 19 has also shown consistent association with LOAD. However, no common variants in the region remain significant after adjusting for APOE genotype. We report a rare variant association analysis of genes in the vicinity of APOE with cerebrospinal fluid (CSF) and neuroimaging biomarkers of LOAD. METHODS: Whole genome sequencing (WGS) was performed on 817 blood DNA samples from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Sequence data from 757 non Hispanic Caucasian participants was used in the present analysis. We extracted all rare variants (MAF (minor allele frequency) < 0.05) within a 312 kb window in APOE's vicinity encompassing 12 genes. We assessed CSF and neuroimaging (MRI and PET) biomarkers as LOAD-related quantitative endophenotypes. Gene-based analyses of rare variants were performed using the optimal Sequence Kernel Association Test (SKAT-O). RESULTS: A total of 3,334 rare variants (MAF < 0.05) were found within the APOE region. Among them, 72 rare non-synonymous variants were observed. Eight genes spanning the APOE region were significantly associated with CSF Abeta1-42 (p < 1.0 * 10-3). After controlling for APOE genotype and adjusting for multiple comparisons, 4 genes (CBLC, BCAM, APOE, and RELB) remained significant. Whole-brain surface-based analysis identified highly significant clusters associated with rare variants of CBLC in the temporal lobe region including the entorhinal cortex, as well as frontal lobe regions. Whole-brain voxel-wise analysis of amyloid PET identified significant clusters in the bilateral frontal and parietal lobes showing associations of rare variants of RELB with cortical amyloid burden. CONCLUSIONS: Rare variants within genes spanning the APOE region are significantly associated with LOAD-related CSF Abeta1-42 and neuroimaging biomarkers after adjusting for APOE genotype. These findings warrant further investigation and illustrate the role of next generation sequencing and quantitative endophenotypes in assessing rare variants which may help explain missing heritability in AD and other complex diseases. PMID- 28589858 TI - Statistical analysis of fractionation resistance by functional category and expression. AB - BACKGROUND: The current literature establishes the importance of gene functional category and expression in promoting or suppressing duplicate gene loss after whole genome doubling in plants, a process known as fractionation. Inspired by studies that have reported gene expression to be the dominating factor in preventing duplicate gene loss, we analyzed the relative effect of functional category and expression. METHODS: We use multivariate methods to study data sets on gene retention, function and expression in rosids and asterids to estimate effects and assess their interaction. RESULTS: Our results suggest that the effect on duplicate gene retention fractionation by functional category and expression are independent and have no statistical interaction. CONCLUSION: In plants, functional category is the more dominant factor in explaining duplicate gene loss. PMID- 28589859 TI - Integrative information theoretic network analysis for genome-wide association study of aspirin exacerbated respiratory disease in Korean population. AB - BACKGROUND: Aspirin Exacerbated Respiratory Disease (AERD) is a chronic medical condition that encompasses asthma, nasal polyposis, and hypersensitivity to aspirin and other non-steroidal anti-inflammatory drugs. Several previous studies have shown that part of the genetic effects of the disease may be induced by the interaction of multiple genetic variants. However, heavy computational cost as well as the complexity of the underlying biological mechanism has prevented a thorough investigation of epistatic interactions and thus most previous studies have typically considered only a small number of genetic variants at a time. METHODS: In this study, we propose a gene network based analysis framework to identify genetic risk factors from a genome-wide association study dataset. We first derive multiple single nucleotide polymorphisms (SNP)-based epistasis networks that consider marginal and epistatic effects by using different information theoretic measures. Each SNP epistasis network is converted into a gene-gene interaction network, and the resulting gene networks are combined as one for downstream analysis. The integrated network is validated on existing knowledgebase of DisGeNET for known gene-disease associations and GeneMANIA for biological function prediction. RESULTS: We demonstrated our proposed method on a Korean GWAS dataset, which has genotype information of 440,094 SNPs for 188 cases and 247 controls. The topological properties of the generated networks are examined for scale-freeness, and we further performed various statistical analyses in the Allergy and Asthma Portal (AAP) using the selected genes from our integrated network. CONCLUSIONS: Our result reveals that there are several gene modules in the network that are of biological significance and have evidence for controlling susceptibility and being related to the treatment of AERD. PMID- 28589860 TI - GaussianCpG: a Gaussian model for detection of CpG island in human genome sequences. AB - BACKGROUND: As crucial markers in identifying biological elements and processes in mammalian genomes, CpG islands (CGI) play important roles in DNA methylation, gene regulation, epigenetic inheritance, gene mutation, chromosome inactivation and nuclesome retention. The generally accepted criteria of CGI rely on: (a) %G+C content is >= 50%, (b) the ratio of the observed CpG content and the expected CpG content is >= 0.6, and (c) the general length of CGI is greater than 200 nucleotides. Most existing computational methods for the prediction of CpG island are programmed on these rules. However, many experimentally verified CpG islands deviate from these artificial criteria. Experiments indicate that in many cases %G+C is < 50%, CpG obs /CpG exp varies, and the length of CGI ranges from eight nucleotides to a few thousand of nucleotides. It implies that CGI detection is not just a straightly statistical task and some unrevealed rules probably are hidden. RESULTS: A novel Gaussian model, GaussianCpG, is developed for detection of CpG islands on human genome. We analyze the energy distribution over genomic primary structure for each CpG site and adopt the parameters from statistics of Human genome. The evaluation results show that the new model can predict CpG islands efficiently by balancing both sensitivity and specificity over known human CGI data sets. Compared with other models, GaussianCpG can achieve better performance in CGI detection. CONCLUSIONS: Our Gaussian model aims to simplify the complex interaction between nucleotides. The model is computed not by the linear statistical method but by the Gaussian energy distribution and accumulation. The parameters of Gaussian function are not arbitrarily designated but deliberately chosen by optimizing the biological statistics. By using the pseudopotential analysis on CpG islands, the novel model is validated on both the real and artificial data sets. PMID- 28589857 TI - Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer. AB - BACKGROUND: One of the fundamental challenges in cancer is to detect the regulators of gene expression changes during cancer progression. Through transcriptional silencing of critical cancer-related genes, epigenetic change such as DNA methylation plays a crucial role in cancer. In addition, miRNA, another major component of epigenome, is also a regulator at the post transcriptional levels that modulate transcriptome changes. However, a mechanistic role of synergistic interactions between DNA methylation and miRNA as epigenetic regulators on transcriptomic changes and its association with clinical outcomes such as survival have remained largely unexplored in cancer. METHODS: In this study, we propose an integrative framework to identify epigenetic interactions between methylation and miRNA associated with transcriptomic changes. To test the utility of the proposed framework, the bladder cancer data set, including DNA methylation, miRNA expression, and gene expression data, from The Cancer Genome Atlas (TCGA) was analyzed for this study. RESULTS: First, we found 120 genes associated with interactions between the two epigenomic components. Then, 11 significant epigenetic interactions between miRNA and methylation, which target E2F3, CCND1, UTP6, CDADC1, SLC35E3, METRNL, TPCN2, NACC2, VGLL4, and PTEN, were found to be associated with survival. To this end, exploration of TCGA bladder cancer data identified epigenetic interactions that are associated with survival as potential prognostic markers in bladder cancer. CONCLUSIONS: Given the importance and prevalence of these interactions of epigenetic events in bladder cancer it is timely to understand further how different epigenetic components interact and influence each other. PMID- 28589861 TI - Evolution of Translational Bioinformatics: lessons learned from TBC 2016. PMID- 28589862 TI - Taking promoters out of enhancers in sequence based predictions of tissue specific mammalian enhancers. AB - BACKGROUND: Many genetic diseases are caused by mutations in non-coding regions of the genome. These mutations are frequently found in enhancer sequences, causing disruption to the regulatory program of the cell. Enhancers are short regulatory sequences in the non-coding part of the genome that are essential for the proper regulation of transcription. While the experimental methods for identification of such sequences are improving every year, our understanding of the rules behind the enhancer activity has not progressed much in the last decade. This is especially true in case of tissue-specific enhancers, where there are clear problems in predicting specificity of enhancer activity. RESULTS: We show a random-forest based machine learning approach capable of matching the performance of the current state-of-the-art methods for enhancer prediction. Then we show that it is, similarly to other published methods, frequently cross predicting enhancers as active in different tissues, making it less useful for predicting tissue specific activity. Then we proceed to show that the problem is related to the fact that the enhancer predicting models exhibit a bias towards predicting gene promoters as active enhancers. Then we show that using a two-step classifier can lead to lower cross-prediction between tissues. CONCLUSIONS: We provide whole-genome predictions of human heart and brain enhancers obtained with two-step classifier. PMID- 28589863 TI - A simple and economical method for improving whole genome alignment. AB - BACKGROUND: The recent advancement of whole genome alignment software has made it possible to align two genomes very efficiently and with only a small sacrifice in sensitivity. Yet it becomes very slow if the extra sensitivity is needed. This paper proposes a simple but effective method to improve the sensitivity of existing whole-genome alignment software without paying much extra running time. RESULTS AND CONCLUSIONS: We have applied our method to a popular whole genome alignment tool LAST, and we called the resulting tool LASTM. Experimental results showed that LASTM could find more high quality alignments with a little extra running time. For example, when comparing human and mouse genomes, to produce the similar number of alignments with similar average length and similarity, LASTM was about three times faster than LAST. We conclude that our method can be used to improve the sensitivity, and the extra time it takes is small, and thus it is worthwhile to be implemented in existing tools. PMID- 28589864 TI - Efficient detection of viral transmissions with Next-Generation Sequencing data. AB - BACKGROUND: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Molecular analysis has been frequently used in the study of HCV outbreaks and transmission chains; helping identify a cluster of sequences as linked by transmission if their genetic distances are below a previously defined threshold. However, HCV exists as a population of numerous variants in each infected individual and it has been observed that minority variants in the source are often the ones responsible for transmission, a situation that precludes the use of a single sequence per individual because many such transmissions would be missed. The use of Next-Generation Sequencing immensely increases the sensitivity of transmission detection but brings a considerable computational challenge because all sequences need to be compared among all pairs of samples. METHODS: We developed a three-step strategy that filters pairs of samples according to different criteria: (i) a k-mer bloom filter, (ii) a Levenhstein filter and (iii) a filter of identical sequences. We applied these three filters on a set of samples that cover the spectrum of genetic relationships among HCV cases, from being part of the same transmission cluster, to belonging to different subtypes. RESULTS: Our three-step filtering strategy rapidly removes 85.1% of all the pairwise sample comparisons and 91.0% of all pairwise sequence comparisons, accurately establishing which pairs of HCV samples are below the relatedness threshold. CONCLUSIONS: We present a fast and efficient three-step filtering strategy that removes most sequence comparisons and accurately establishes transmission links of any threshold-based method. This highly efficient workflow will allow a faster response and molecular detection capacity, improving the rate of detection of viral transmissions with molecular data. PMID- 28589865 TI - Estimation of the true evolutionary distance under the fragile breakage model. AB - BACKGROUND: The ability to estimate the evolutionary distance between extant genomes plays a crucial role in many phylogenomic studies. Often such estimation is based on the parsimony assumption, implying that the distance between two genomes can be estimated as the rearrangement distance equal the minimal number of genome rearrangements required to transform one genome into the other. However, in reality the parsimony assumption may not always hold, emphasizing the need for estimation that does not rely on the rearrangement distance. The distance that accounts for the actual (rather than minimal) number of rearrangements between two genomes is often referred to as the true evolutionary distance. While there exists a method for the true evolutionary distance estimation, it however assumes that genomes can be broken by rearrangements equally likely at any position in the course of evolution. This assumption, known as the random breakage model, has recently been refuted in favor of the more rigorous fragile breakage model postulating that only certain "fragile" genomic regions are prone to rearrangements. RESULTS: We propose a new method for estimating the true evolutionary distance between two genomes under the fragile breakage model. We evaluate the proposed method on simulated genomes, which show its high accuracy. We further apply the proposed method for estimation of evolutionary distances within a set of five yeast genomes and a set of two fish genomes. CONCLUSIONS: The true evolutionary distances between the five yeast genomes estimated with the proposed method reveals that some pairs of yeast genomes violate the parsimony assumption. The proposed method further demonstrates that the rearrangement distance between the two fish genomes underestimates their evolutionary distance by about 20%. These results demonstrate how drastically the two distances can differ and justify the use of true evolutionary distance in phylogenomic studies. PMID- 28589867 TI - [A motorcyclist with hematomas and tingling in his leg]. AB - A 30-year-old man presented with recurrent hematomas and tingling in his left leg, caused by a large femoral neck osteochondroma that induced multiple muscle ruptures and compressed the ischiadic nerve. There were no radiological signs of malignant transformation and symptoms disappeared without intervention. Hence, we chose a 'wait and see' approach instead of surgical removal of the osteochondroma. PMID- 28589866 TI - A scalable and memory-efficient algorithm for de novo transcriptome assembly of non-model organisms. AB - BACKGROUND: With increased availability of de novo assembly algorithms, it is feasible to study entire transcriptomes of non-model organisms. While algorithms are available that are specifically designed for performing transcriptome assembly from high-throughput sequencing data, they are very memory-intensive, limiting their applications to small data sets with few libraries. RESULTS: We develop a transcriptome assembly algorithm that recovers alternatively spliced isoforms and expression levels while utilizing as many RNA-Seq libraries as possible that contain hundreds of gigabases of data. New techniques are developed so that computations can be performed on a computing cluster with moderate amount of physical memory. CONCLUSIONS: Our strategy minimizes memory consumption while simultaneously obtaining comparable or improved accuracy over existing algorithms. It provides support for incremental updates of assemblies when new libraries become available. PMID- 28589868 TI - [Two-year follow-up of infants born at 24 weeks gestation; first outcomes following implementation of the new 'Guideline for perinatal policy in cases of extreme prematurity']. AB - OBJECTIVE: Since 2010 the guideline 'Guideline for perinatal policy in cases of extreme prematurity' has advised an active policy in infants born at 24 weeks gestation. We investigated how infants born at 24 and 25 weeks gestation in the first year following the implementation of the guideline had developed by the age of 2 years. DESIGN: Retrospective national cohort study. METHOD: The study population consisted of all surviving infants born in the Netherlands at 24 or 25 weeks gestation in the period from 1 October 2010 to 1 October 2011. At a corrected age of 2 years the children underwent a general physical and neurological examination, and their cognitive scores were determined on the 'Bayley scales of infant and toddler development' (Bayley III). Examinations took place in the 10 neonatal intensive care units (NICU's) in the Netherlands. RESULTS: Of 185 extremely premature infants, 166 were admitted to a NICU. A total of 95 survived to a corrected age of 2 years; 78 (82%) children were examined. Their average cognitive score on the Bayley III scale was 88 (SD: 16). Among the children born at 24 weeks gestation, 20% had mild disabilities and 20% had moderate to severe disabilities. Among the children born at 25 weeks gestation, 17% had mild disabilities and 12% had moderate to severe disabilities. CONCLUSION: Of the children born at 24 weeks gestation in the first year after the introduction of active policy in the Netherlands and surviving to 2 years of age (46%), more than half had developed without disabilities. This was comparable to children born at 25 weeks gestation. Of all children born at 24 weeks gestation, 25% survived to 2 years of age without disabilities. PMID- 28589869 TI - [Hepatopulmonary syndrome. A consideration in patients with liver disease accompanied by dyspnoea and hypoxaemia]. AB - BACKGROUND: Hepatopulmonary syndrome is a severe complication of liver disease, with greatly increased mortality. The syndrome is characterized by increased blood-flow, intrapulmonary vasodilatation and angiogenesis, leading to effects including the formation of shunts. This leads to a decrease in arterial oxygen pressure. Liver transplantation is the only effective treatment. CASE DESCRIPTION: A 74-year-old woman with cirrhosis of the liver attended the pulmonary outpatients' clinic with progressive dyspnoea, which worsened if she sat upright from a lying position (platypnoea). Contrast echocardiography confirmed the diagnosis 'hepatopulmonary syndrome'. The patient was not eligible for liver transplantation. She was given oxygen therapy and died from decompensated cirrhosis of the liver eighteen months later. CONCLUSION: Early recognition of hepatopulmonary syndrome is important, because patients may be given priority for liver transplantation. Contrast echocardiography is indicated in patients with liver disease and suffering from hypoxaemia for which there is no other explanation, to reveal the presence of intrapulmonary shunt. PMID- 28589870 TI - [Making better use of the clinical geneticist's expertise; treating physician could request a DNA test for most cancer patients]. AB - Eight university medical centres in the Netherlands have established clinical genetic services. Patients receive intensive, and therefore costly, genetic counselling before genetic testing takes place. In recent years the number of patients referred to clinical genetic services has risen dramatically, creating waiting-list backlogs. Knowing your carrier status in hereditary cancers, for instance for a BRCA1/2 mutation, can have consequences for surveillance, treatment, and prevention; however, 90% of patients with breast cancer do not have a mutation. We, therefore, argue that the pathway to genetic testing should be reconstructed in order to safeguard timely and adequate genetic testing for an increasing number of patients. The treating physician should be able to request a DNA test in carefully-selected patient-populations, and only refer patients for genetic counselling after a positive finding. Prerequisites for this 'mainstream pathway' are adequate training for medical specialists, good communication with genetics' departments, and guaranteed referral in uncertain or complex cases. PMID- 28589871 TI - Prevalence of cystic echinococcosis in Iran: a systematic review and meta analysis. AB - As a significant zoonosis, cystic echinococcosis (CE) is endemic in some parts of the world, such as the Middle East. There are studies on the prevalence of this infection in animal and human reservoirs in Iran; hence, we conducted this meta analysis to elucidate the prevalence of CE in Iran. English (PubMed, Scopus, Web of Science, Science Direct and Google Scholar) and Persian (Magiran, Iran Medex, Iran Doc and SID) databases were explored. In the case of definitive, animal and human intermediate hosts, 37, 90 and 33 studies, respectively, have been included in the current review from January 1990 to December 2015. According to outcomes of the heterogeneity test, either Der Simonian and Laird's random-effects method or Mantel-Haenszel's fixed-effects method were employed to pool the estimations. The pooled prevalence of Echinococcus granulosus infection in definitive hosts was calculated as 23.6% (95% confidence interval (CI) = 17.6-30.1%). The weighted prevalence of animal and human hydatidosis was calculated as 15.6% (95% CI = 14.2 17.1%) and 4.2% (95% CI = 3.0-5.5%), respectively. Meanwhile, most cases of human hydatidosis were in southern Iran, with a prevalence of 5.8% (3.2-9.2%). In terms of human hydatidosis, more infections were found in rural regions, and mostly in female individuals. Egger's regression test revealed publication bias, with a remarkable impact on total prevalence of the infection in animal intermediate hosts (P < 0.001), while it was not significant in human hosts (P = 0.4) and definitive hosts (P = 0.3). According to the weighted estimated prevalence of cystic echinococcosis and its financial burden, implementing appropriate control programmes should be compulsory to decrease the burden of the disease in Iran. PMID- 28589872 TI - Did the 'croaky voice' public health campaign have any impact on the stage of laryngeal cancer at presentation in 84 cases from the Humber and Yorkshire Coast Cancer Network? AB - BACKGROUND: A public health campaign on laryngeal cancer was conducted in 2011 in the Humber and Yorkshire Coast Cancer Network. This study evaluated its subsequent impact (if any) upon the stage of laryngeal cancer at presentation. METHODS: Cases of laryngeal cancer diagnosed in the Humber and Yorkshire Coast Cancer Network from January 2009 to July 2014 were identified from cancer registries and were dichotomised into early (tumour stage T1-2) and late (T3-4) disease. Statistical analysis using segmented regression analysis of interrupted time series data was performed. RESULTS: There were no statistically significant changes in laryngeal cancer cases immediately after the intervention for both early (p = 0.191) and late (p = 0.680) stage disease. There were also no significant changes to monthly detection rates in both groups on follow up. CONCLUSION: Findings of the first public health campaign on laryngeal cancer in the UK are described. Such processes are complex; the implications for future study are discussed. PMID- 28589875 TI - Secondary peritonitis associated with infective endocarditis and vertebral osteomyelitis in a peritoneal dialysis patient. PMID- 28589876 TI - Short-term results after arthroscopic resection of synovial plicae in the radiohumeral joint: a case series of 64 procedures. AB - INTRODUCTION: Painful Synovial Plicae (SP) in the posterolateral corner of the radiohumeral joint may be confused with lateral epicondylitis. The SP may impinge between the radial head and the humeral capitellum causing pain and snapping. The aim of this study was to evaluate the short-term results after arthroscopic plica resection of the elbow. METHODS: In this case series, we included a consecutive series of 64 arthroscopies (60 patients) with arthroscopic plica resection of the elbow. Inclusion criteria were six months of lateral elbow pain and unsuccessful conservative treatment. Patients had either ultrasonography verified plicae or pain on palpation of the plica. Patients were evaluated with an Oxford Elbow Score (OES) preoperatively, after three months and after mean 22 months (range: 12-31) of follow-up. Furthermore, baseline characteristics were recorded including, gender, age, body mass index (BMI), occupation, smoking and cartilage damage. RESULTS: The mean age was 44 years (range: 18-66). In 13 elbows, International Cartilage Repair Society (ICRS) grade 1 lesions were present in association with the plica. Preoperatively the mean OES was 19 (95% CI: 17-20). At three and 22 month follow-up the OES increased to 33 (95% CI: 30-36) and 35 (95% CI: 32-38), respectively (p < 0.001). Cartilage injury and gender did not affect the outcome. We reported no complications. DISCUSSION: Arthroscopic plica resection of the elbow indicates an improved OES after three and 22 months. A randomized prospective trial is needed to validate the effect of arthroscopic treatment of synovial elbow plicae. PMID- 28589873 TI - Human cytomegalovirus microRNAs are carried by virions and dense bodies and are delivered to target cells. AB - Human cytomegalovirus (HCMV) infection results in the production of virions, dense bodies (DBs) and non-infectious enveloped particles, all of which incorporate proteins and RNAs that can be transferred to host cells. Here, we investigated whether virions and DBs also carry microRNAs (miRNAs) and assessed their delivery and functionality in cells. Human lung fibroblasts (MRC-5) were infected with the HCMV strain AD169, and conditioned cell culture medium was collected and centrifuged. The pellets were treated with RNase-ONE, and the virions and DBs were purified with a potassium tartrate-glycerol gradient and dialysed. The virions and DBs were incubated with micrococcal nuclease, DNA and RNA were extracted and then analysed with TaqMan PCR assays, while the proteins were examined with Western blots. To assess the delivery of miRNAs to cells and their functionality, virions and DBs were irradiated with UV light. The purity of the virions and DBs was confirmed by typical morphology, the presence of the structural protein pp65 and the HCMV genome, the ability to infect MRC-5 cells and the absence of the host genome. RNA analysis revealed the presence of 14 HCMV encoded miRNAs (UL22A-5p, US25-1-5p, UL22A-3p, US5-2-3p, UL112-3p, US25-2-3p, US25-2-5p, US33-3p, US5-1, UL36-5p, US4-5p, UL36-3p, UL70-5p and US25-1-3p), HCMV immediate-early mRNA and long non-coding RNA2.7, moreover, two host-encoded miRNAs (hsa-miR-218-5p and hsa-miR-21-5p) and beta-2-microglobulin RNA. UV irradiated virions and DBs delivered viral miRNAs (US25-1-5p and UL112-3p) to the host cells, and miR-US25-1-5p was functional in a luciferase reporter assay. We conclude that virions and DBs carry miRNAs that are biologically functional and can be delivered to cells, which may affect cellular processes. PMID- 28589877 TI - Arthroscopic treatment of chondral defects in the hip: AMIC, MACI, microfragmented adipose tissue transplantation (MATT) and other options. AB - Chondral lesions are currently considered in the hip as a consequence of trauma, osteonecrosis, dysplasia, labral tears, loose bodies, dislocation, previous slipped capital femoral epiphysis and Femoro-Acetabular-Impingement (FAI). The management of chondral lesions is debated and several techniques are described. The physical examination must be carefully performed, followed by radiographs and magnetic resonance imaging (MRI). Differential diagnosis with other pathologies must be considered. Debridement is indicated in patients younger than 50 years with a chondropathy of 1st or 2nd degree. Microfractures are indicated in patients younger than 50 years with a chondropathy of 3rd or 4th degree less than 2 cm2. Matrix-Induced Autologous Chondrocyte Implantation (MACI) and Autologous Matrix-Induced Chondrogenesis (AMIC) procedures are indicated in patients with full-thickness symptomatic 3rd-4th degree chondral defects, extended 2 cm2 or more. The AMIC procedure has the advantage of a one-step procedure and much less expense. Microfragmented adipose tissue transplantation (MATT) is indicated for the treatment of delamination and 1st and 2nd degree chondral lesions, regardless of the age of the patient. Chondral defects are effective when the joint space is not compromised. When the Tonnis classification is two or greater, treatment of chondral lesions should be considered ineffective. PMID- 28589879 TI - Diabetes: a dynamic disease. PMID- 28589880 TI - Advancing LGBTIQ rights. PMID- 28589881 TI - Progress in environmental litigation. PMID- 28589882 TI - Antenatal milk expression for women with diabetes in pregnancy. PMID- 28589878 TI - Distinct Akt phosphorylation states are required for insulin regulated Glut4 and Glut1-mediated glucose uptake. AB - Insulin, downstream of Akt activation, promotes glucose uptake into fat and muscle cells to lower postprandial blood glucose, an enforced change in cellular metabolism to maintain glucose homeostasis. This effect is mediated by the Glut4 glucose transporter. Growth factors also enhance glucose uptake to fuel an anabolic metabolism required for tissue growth and repair. This activity is predominantly mediated by the Glut1. Akt is activated by phosphorylation of its kinase and hydrophobic motif (HM) domains. We show that insulin-stimulated Glut4 mediated glucose uptake requires PDPK1 phosphorylation of the kinase domain but not mTORC2 phosphorylation of the HM domain. Nonetheless, an intact HM domain is required for Glut4-mediated glucose uptake. Whereas, Glut1-mediated glucose uptake also requires mTORC2 phosphorylation of the HM domain, demonstrating both phosphorylation-dependent and independent roles of the HM domain in regulating glucose uptake. Thus, mTORC2 links Akt to the distinct physiologic programs related to Glut4 and Glut1-mediated glucose uptake. PMID- 28589883 TI - Novel influenza A viruses and pandemic threats. PMID- 28589884 TI - Warnings, uncertainty, and clinical practice. PMID- 28589885 TI - Cholera outbreak in the horn of Africa. PMID- 28589886 TI - Medical research in the UK party manifestos. PMID- 28589887 TI - Trump administration and the opioid epidemic in the USA. PMID- 28589888 TI - Elizabeth Mayer-Davis: leader in adolescent diabetes. PMID- 28589889 TI - Adequate clinical practice limited by the ethnic French taboo. PMID- 28589891 TI - Medical narratives: the patient is a 22-year-old black man.... PMID- 28589890 TI - The expansion of soil-transmitted helminth control strategies. PMID- 28589893 TI - Department of Error. PMID- 28589892 TI - The expansion of soil-transmitted helminth control strategies - Authors' reply. PMID- 28589894 TI - Advising women with diabetes in pregnancy to express breastmilk in late pregnancy (Diabetes and Antenatal Milk Expressing [DAME]): a multicentre, unblinded, randomised controlled trial. AB - BACKGROUND: Infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia, admission to a neonatal intensive care unit (NICU), and not being exclusively breastfed. Many clinicians encourage women with diabetes in pregnancy to express and store breastmilk in late pregnancy, yet no evidence exists for this practice. We aimed to determine the safety and efficacy of antenatal expressing in women with diabetes in pregnancy. METHODS: We did a multicentre, two-group, unblinded, randomised controlled trial in six hospitals in Victoria, Australia. We recruited women with pre-existing or gestational diabetes in a singleton pregnancy from 34 to 37 weeks' gestation and randomly assigned them (1:1) to either expressing breastmilk twice per day from 36 weeks' gestation (antenatal expressing) or standard care (usual midwifery and obstetric care, supplemented by support from a diabetes educator). Randomisation was done with a computerised random number generator in blocks of size two and four, and was stratified by site, parity, and diabetes type. Investigators were masked to block size but masking of caregivers was not possible. The primary outcome was the proportion of infants admitted to the NICU. We did the analyses by intention to treat; the data were obtained and analysed masked to group allocation. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000217909. FINDINGS: Between June 6, 2011, and Oct 29, 2015, we recruited and randomly assigned 635 women: 319 to antenatal expressing and 316 to standard care. Three were not included in the primary analysis (one withdrawal from the standard care group, and one post-randomisation exclusion and one withdrawal from the antenatal expressing group). The proportion of infants admitted to the NICU did not differ between groups (46 [15%] of 317 assigned to antenatal expressing vs 44 [14%] of 315 assigned to standard care; adjusted relative risk 1.06, 95% CI 0.66 to 1.46). In the antenatal expressing group, the most common serious adverse event for infants was admission to the NICU for respiratory support (for three [<1%] of 317. In the standard care group, the most common serious adverse event for infants was moderate to severe encephalopathy with or without seizures (for three [<1%] of 315). INTERPRETATION: There is no harm in advising women with diabetes in pregnancy at low risk of complications to express breastmilk from 36 weeks' gestation. FUNDING: Australian National Health and Medical Research Council. PMID- 28589896 TI - As white as ivory: sclerotic vertebra in POEMS syndrome. PMID- 28589895 TI - Type 2 diabetes in adolescents: a severe phenotype posing major clinical challenges and public health burden. AB - Type 2 diabetes in adolescence manifests as a severe progressive form of diabetes that frequently presents with complications, responds poorly to treatment, and results in rapid progression of microvascular and macrovascular complications. Although overall still a rare disease, adolescent type 2 diabetes now poses major challenges to paediatric and adult diabetes services in many countries. Therapeutic options are heavily curtailed by a dearth of knowledge about the condition, with low numbers of participants and poor trial recruitment impeding research. Together with lifestyle modification, metformin remains the first-line therapy for adolescents with type 2 diabetes, although the majority rapidly progress to treatment failure and insulin therapy. Early bariatric surgery is controversial but has great potential to transform outcomes. Health systems must respond by both concentrating patients in specialist clinical services integrated with translational research programmes, but also by joining up with local health and social care services to improve engagement and uptake of services. PMID- 28589912 TI - Epigenetic control of epileptogenesis by miR-146a. PMID- 28589911 TI - Comparative analyses of long non-coding RNA in lean and obese pig. AB - OBJECTIVES: Current studies have revealed that long non-coding RNA plays a crucial role in fat metabolism. However, the difference of lncRNA between lean (Duroc) and obese (Luchuan) pig remain undefined. Here, we investigated the expressional profile of lncRNA in these two pigs and discussed the relationship between lncRNA and fat deposition. MATERIALS AND METHODS: The Chinese Luchuan pig has a dramatic differences in backfat thickness as compared with Duroc pig. In this study, 4868 lncRNA transcripts (including 3235 novel transcripts) were identified. We determined that patterns of differently expressed lncRNAs and mRNAs are strongly tissue-specific. The differentially expressed lncRNAs in adipose tissue have 794 potential target genes, which are involved in adipocytokine signaling pathways, the PI3k-Akt signaling pathway, and calcium signaling pathways. In addition, differentially expressed lncRNAs were located to 13 adipose-related quantitative trait loci which include 65 QTL_ID. Subsequently, lncRNA and mRNA in the same QTL_ID were analyzed and their co-expression in two QTL_ID were confirmed by qPCR. CONCLUSIONS: Our study provides an insight into mechanism behind the fat metabolic differences between the two breeds and lays an important groundwork for further research regarding the regulatory role of lncRNA in obesity development. PMID- 28589914 TI - Comment on 'A geographical study of thyroid cancer incidence in north-west England following the Windscale nuclear reactor fire of 1957'. PMID- 28589915 TI - Doubling of the magnetic energy product in ferromagnetic nanowires at ambient temperature by capping their tips with an antiferromagnet. AB - We present an approach to prepare free-standing tips of micrometer-long nanowires electrodeposited in anodic aluminum oxide nanopores. Such open tips can be further processed, e.g. for vertical interconnects of functional layers or for tailoring the magnetization reversal of ferromagnetic nanowires. The magnetic switching of nanowires is usually initiated by vortex or domain formation at the nanowire tips. We show that coating the tips of Fe30Co70 nanowires (diameter 40 nm, length 16 MUm) with thin antiferromagnetic Fe50Mn50 capping layers (thickness ~10 nm) leads to magnetic hardening with a more than doubled energy product at ambient temperature. PMID- 28589916 TI - Design and fabrication of novel polymeric biodegradable stents for small caliber blood vessels by computer-aided wet-spinning. AB - Biodegradable stents have emerged as one of the most promising approaches in obstructive cardiovascular disease treatment due to their potential in providing mechanical support while it is needed and then leaving behind only the healed natural vessel. The aim of this study was to develop polymeric biodegradable stents for application in small caliber blood vessels. Poly[(R)-3-hydroxybutyrate co-(R)-3-hydroxyhexanoate] (PHBHHx), a renewable microbial aliphatic polyester, and poly(epsilon-caprolactone), a synthetic polyester approved by the US Food and Drug Administration for different biomedical applications, were investigated as suitable polymers for stent development. A novel manufacturing approach based on computer-aided wet-spinning of a polymeric solution was developed to fabricate polymeric stents. By tuning the fabrication parameters, it was possible to develop stents with different morphological characteristics (e.g. pore size and wall thickness). Thermal analysis results suggested that material processing did not cause changes in the molecular structure of the polymers. PHBHHx stents demonstrated great radial elasticity while PCL stents showed higher axial and radial mechanical strength. The developed stents resulted able to sustain proliferation of human umbilical vein endothelial cells within two weeks of in vitro culture and they showed excellent results in terms of thromboresistivity when in contact with human blood. PMID- 28589917 TI - Reply to Comment on 'A geographical study of thyroid cancer incidence in north west England following the Windscale nuclear reactor fire of 1957'. PMID- 28589918 TI - Cryogenic 3D printing for producing hierarchical porous and rhBMP-2-loaded Ca P/PLLA nanocomposite scaffolds for bone tissue engineering. AB - The performance of bone tissue engineering scaffolds can be assessed through cell responses to scaffolds, including cell attachment, infiltration, morphogenesis, proliferation, differentiation, etc, which are determined or heavily influenced by the composition, structure, mechanical properties, and biological properties (e.g. osteoconductivity and osteoinductivity) of scaffolds. Although some promising 3D printing techniques such as fused deposition modeling and selective laser sintering could be employed to produce biodegradable bone tissue engineering scaffolds with customized shapes and tailored interconnected pores, effective methods for fabricating scaffolds with well-designed hierarchical porous structure (both interconnected macropores and surface micropores) and tunable osteoconductivity/osteoinductivity still need to be developed. In this investigation, a novel cryogenic 3D printing technique was investigated and developed for producing hierarchical porous and recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded calcium phosphate (Ca-P) nanoparticle/poly(L-lactic acid) nanocomposite scaffolds, in which the Ca-P nanoparticle-incorporated scaffold layer and rhBMP-2-encapsulated scaffold layer were deposited alternatingly using different types of emulsions as printing inks. The mechanical properties of the as-printed scaffolds were comparable to those of human cancellous bone. Sustained releases of Ca2+ ions and rhBMP-2 were achieved and the biological activity of rhBMP-2 was well-preserved. Scaffolds with a desirable hierarchical porous structure and dual delivery of Ca2+ ions and rhBMP 2 exhibited superior performance in directing the behaviors of human bone marrow derived mesenchymal stem cells and caused improved cell viability, attachment, proliferation, and osteogenic differentiation, which has suggested their great potential for bone tissue engineering. PMID- 28589919 TI - Alternately plasma-roughened nanosurface of a hybrid scaffold for aligning myoblasts. AB - For successful skeletal muscle tissue regeneration, inducing alignment and fusion of myoblasts into multinucleated myotubes is critical. Many studies are ongoing to induce myoblast alignment using various micro/nanopatternings on scaffold surfaces, mechanically stretching scaffolds, or aligned micro/nanofibers. In this study, we have developed a simple method to induce myoblast alignment using a modified plasma treatment on a hybrid PCL scaffold consisting of melt-printed perpendicular PCL struts and an electrospun PCL fibrous mat. For the hybrid scaffold, the surface of the electrospun mat was selectively roughened with a plasma process supplemented with a template. The cell alignment of myoblasts using this system was enhanced significantly when compared to results from the use of a hybrid scaffold with a non-roughened electrospun fiber surface or a hybrid scaffold where the whole surface of the electrospun fibers was roughened. This new type of plasma-treated hybrid scaffold has strong potential as a biomaterial for use in muscle tissue regeneration. PMID- 28589920 TI - Systematic evaluation of the osteogenic capacity of low-melting bioactive glass reinforced 45S5 Bioglass porous scaffolds in rabbit femoral defects. AB - Due to the low strength and high brittleness of 45S5 Bioglass(r), it is still a great challenge for the three-dimensional porous 45S5 Bioglass(r) to treat mechanically required loaded bone defects. Therefore, 45S5 Bioglass(r)-derived bioactive glass-ceramic (BGC) porous scaffolds were fabricated at a low temperature sintering condition with and without the addition of 4% low-melting ZnO/B2O3 (ZB) bioactive glass as a reinforcing agent and using 350- or 500 MUm paraffin microspheres as a porogen. The pore structure characterization for the scaffolds indicated that the scaffolds containing 4% ZB had very good macroporous structures of ~313 and ~448 MUm in pore size and over 70% porosity with appreciable strength (>15 MPa), which was about four times higher than that those manufactured without ZB and with 350 MUm porogen scaffolds. The open porosity was decreased with the addition of 4% ZB but the interconnected pore percentage (>50 MUm) was increased with increasing the porogen size from 350 to 500 MUm. In vivo investigations revealed that the stronger scaffolds containing 4% ZB and 500 MUm porogen were particularly beneficial for osteogenic capacity in critical size femoral bone defects, accompanied with an accelerated bone ingrowth (6-18 weeks) and the material itself experiencing mild resorption. In contrast, both the scaffolds with smaller pore sizes exhibited a low level of new bone ingrowth (<32%) after 6-12 weeks implantation. These results suggest a promising application of such 45S5 Bioglass(r)-derived BGC scaffolds in a clinical setting, especially for mechanically loaded bone defects. PMID- 28589921 TI - Current and emerging applications of 3D printing in medicine. AB - Three-dimensional (3D) printing enables the production of anatomically matched and patient-specific devices and constructs with high tunability and complexity. It also allows on-demand fabrication with high productivity in a cost-effective manner. As a result, 3D printing has become a leading manufacturing technique in healthcare and medicine for a wide range of applications including dentistry, tissue engineering and regenerative medicine, engineered tissue models, medical devices, anatomical models and drug formulation. Today, 3D printing is widely adopted by the healthcare industry and academia. It provides commercially available medical products and a platform for emerging research areas including tissue and organ printing. In this review, our goal is to discuss the current and emerging applications of 3D printing in medicine. A brief summary on additive manufacturing technologies and available printable materials is also given. The technological and regulatory barriers that are slowing down the full implementation of 3D printing in the medical field are also discussed. PMID- 28589922 TI - Graphene oxide hydrogel as a restricted-area nanoreactor for synthesis of 3D graphene-supported ultrafine TiO2 nanorod nanocomposites for high-rate lithium ion battery anodes. AB - Three-dimensional graphene-supported TiO2 nanorod nanocomposites (3D GS-TNR) are prepared using graphene oxide hydrogel as a restricted-area nanoreactor in the hydrothermal process, in which well-distributed TiO2 nanorods with a width of approximately 5 nm and length of 30 nm are conformally embedded in the 3D interconnected graphene network. The 3D graphene oxide not only works as a restricted-area nanoreactor to constrain the size, distribution and morphology of the TiO2; it also work as a highly interconnected conducting network to facilitate electrochemical reactions and maintain good structural integration when the nanocomposites are used as anode materials in lithium-ion batteries. Benefiting from the nanostructure, the 3D GS-TNR nanocomposites show high capacity and excellent long-term cycling capability at high current rates. The 3D GS-TNR composites deliver a high initial charge capacity of 280 mAh g-1 at 0.2 C and maintain a reversible capacity of 115 mAh g-1, with a capacity retention of 83% at 20 C after 1000 cycles. Meanwhile, compared with that of previously reported TiO2-based materials, the 3D GS-TNR nanocomposites show much better performance, including higher capacity, better rate capability and long-term cycling stability. PMID- 28589923 TI - Electronic properties and morphology of copper oxide/n-type silicon heterostructures. AB - Silicon-based tandem heterojunction solar cells utilizing cuprous oxide (Cu2O) as the top absorber layer show promise for high-efficiency conversion and low production cost. In the present study, single phase Cu2O films have been realized on n-type Si substrates by reactive magnetron sputtering at 400 degrees C. The obtained Cu2O/Si heterostructures have subsequently been heat treated at temperatures in the 400-700 degrees C range in Ar flow and extensively characterized by x-ray diffraction (XRD) measurements, transmission electron microscopy (TEM) imaging and electrical techniques. The Cu2O/Si heterojunction exhibits a current rectification of ~5 orders of magnitude between forward and reverse bias voltages. High resolution cross-sectional TEM-images show the presence of a ~2 nm thick interfacial SiO2 layer between Cu2O and the Si substrate. Heat treatments below 550 degrees C result in gradual improvement of crystallinity, indicated by XRD. At and above 550 degrees C, partial phase transition to cupric oxide (CuO) occurs followed by a complete transition at 700 degrees C. No increase or decrease of the SiO2 layer is observed after the heat treatment at 550 degrees C. Finally, a thin Cu-silicide layer (Cu3Si) emerges below the SiO2 layer upon annealing at 550 degrees C. This silicide layer influences the lateral current and voltage distributions, as evidenced by an increasing effective area of the heterojunction diodes. PMID- 28589924 TI - Bo Lindell (1922-2016). PMID- 28589925 TI - Mesenchymal stem cells support growth and organization of host-liver colorectal tumor organoids and possibly resistance to chemotherapy. AB - Despite having yielded extensive breakthroughs in cancer research, traditional 2D cell cultures have limitations in studying cancer progression and metastasis and screening therapeutic candidates. 3D systems can allow cells to grow, migrate, and interact with each other and the surrounding matrix, resulting in more realistic constructs. Furthermore, interactions between host tissue and developing tumors influence the susceptibility of tumors to drug treatments. Host liver colorectal-tumor spheroids composed of primary human hepatocytes, mesenchymal stem cells (MSC) and colon carcinoma HCT116 cells were created in simulated microgravity rotating wall vessel (RWV) bioreactors. The cells were seeded on hyaluronic acid-based microcarriers, loaded with liver-specific growth factors and ECM components. Only in the presence of MSC, large tumor foci rapidly formed inside the spheroids and increased in size steadily over time, while not greatly impacting albumin secretion from hepatocytes. The presence of MSC appeared to drive self-organization and formation of a stroma-like tissue surrounding the tumor foci and hepatocytes. Exposure to a commonly used chemotherapeutic 5-FU showed a dose-dependent cytotoxicity. However, if tumor organoids were allowed to mature in the RWV, they were less sensitive to the drug treatment. These data demonstrate the potential utility of liver tumor organoids for cancer progression and drug response modeling. PMID- 28589926 TI - Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. AB - Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1beta levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease. PMID- 28589927 TI - The CaMKII holoenzyme structure in activation-competent conformations. AB - The Ca2+/calmodulin-dependent protein kinase II (CaMKII) assembles into large 12 meric holoenzymes, which is thought to enable regulatory processes required for synaptic plasticity underlying learning, memory and cognition. Here we used single particle electron microscopy (EM) to determine a pseudoatomic model of the CaMKIIalpha holoenzyme in an extended and activation-competent conformation. The holoenzyme is organized by a rigid central hub complex, while positioning of the kinase domains is highly flexible, revealing dynamic holoenzymes ranging from 15 35 nm in diameter. While most kinase domains are ordered independently, ~20% appear to form dimers and <3% are consistent with a compact conformation. An additional level of plasticity is revealed by a small fraction of bona-fide 14 mers (<4%) that may enable subunit exchange. Biochemical and cellular FRET studies confirm that the extended state of CaMKIIalpha resolved by EM is the predominant form of the holoenzyme, even under molecular crowding conditions. PMID- 28589928 TI - Dendro-dendritic cholinergic excitation controls dendritic spike initiation in retinal ganglion cells. AB - The retina processes visual images to compute features such as the direction of image motion. Starburst amacrine cells (SACs), axonless feed-forward interneurons, are essential components of the retinal direction-selective circuitry. Recent work has highlighted that SAC-mediated dendro-dendritic inhibition controls the action potential output of direction-selective ganglion cells (DSGCs) by vetoing dendritic spike initiation. However, SACs co-release GABA and the excitatory neurotransmitter acetylcholine at dendritic sites. Here we use direct dendritic recordings to show that preferred direction light stimuli evoke SAC-mediated acetylcholine release, which powerfully controls the stimulus sensitivity, receptive field size and action potential output of ON-DSGCs by acting as an excitatory drive for the initiation of dendritic spikes. Consistent with this, paired recordings reveal that the activation of single ON-SACs drove dendritic spike generation, because of predominate cholinergic excitation received on the preferred side of ON-DSGCs. Thus, dendro-dendritic release of neurotransmitters from SACs bi-directionally gate dendritic spike initiation to control the directionally selective action potential output of retinal ganglion cells. PMID- 28589929 TI - Type-2 innate lymphoid cells control the development of atherosclerosis in mice. AB - Type-2 innate lymphoid cells (ILC2) are a prominent source of type II cytokines and are found constitutively at mucosal surfaces and in visceral adipose tissue. Despite their role in limiting obesity, how ILC2s respond to high fat feeding is poorly understood, and their direct influence on the development of atherosclerosis has not been explored. Here, we show that ILC2 are present in para-aortic adipose tissue and lymph nodes and display an inflammatory-like phenotype atypical of adipose resident ILC2. High fat feeding alters both the number of ILC2 and their type II cytokine production. Selective genetic ablation of ILC2 in Ldlr-/- mice accelerates the development of atherosclerosis, which is prevented by reconstitution with wild type but not Il5-/- or Il13-/- ILC2. We conclude that ILC2 represent a major innate cell source of IL-5 and IL-13 required for mounting atheroprotective immunity, which can be altered by high fat diet. PMID- 28589931 TI - Inhomogeneous spatial distribution of the magnetic transition in an iron-rhodium thin film. AB - Monitoring a magnetic state using thermal or electrical activation is mandatory for the development of new magnetic devices, for instance in heat or electrically assisted magnetic recording or room-temperature memory resistor. Compounds such as FeRh, which undergoes a magnetic transition from an antiferromagnetic state to a ferromagnetic state around 100 degrees C, are thus highly desirable. However, the mechanisms involved in the transition are still under debate. Here we use in situ heating and cooling electron holography to quantitatively map at the nanometre scale the magnetization of a cross-sectional FeRh thin film through the antiferromagnetic-ferromagnetic transition. Our results provide a direct observation of an inhomogeneous spatial distribution of the transition temperature along the growth direction. Most interestingly, a regular spacing of the ferromagnetic domains nucleated upon monitoring of the transition is also observed. Beyond these findings on the fundamental transition mechanisms, our work also brings insights for in operando analysis of magnetic devices. PMID- 28589932 TI - Universal emulsion stabilization from the arrested adsorption of rough particles at liquid-liquid interfaces. AB - Surface heterogeneities, including roughness, significantly affect the adsorption, motion and interactions of particles at fluid interfaces. However, a systematic experimental study, linking surface roughness to particle wettability at a microscopic level, is currently missing. Here we synthesize a library of all silica microparticles with uniform surface chemistry, but tuneable surface roughness and study their spontaneous adsorption at oil-water interfaces. We demonstrate that surface roughness strongly pins the particles' contact lines and arrests their adsorption in long-lived metastable positions, and we directly measure the roughness-induced interface deformations around isolated particles. Pinning imparts tremendous contact angle hysteresis, which can practically invert the particle wettability for sufficient roughness, irrespective of their chemical nature. As a unique consequence, the same rough particles stabilize both water-in oil and oil-in-water emulsions depending on the phase they are initially dispersed in. These results both shed light on fundamental phenomena concerning particle adsorption at fluid interfaces and indicate future design rules for particle-based emulsifiers. PMID- 28589933 TI - Towards colloidal spintronics through Rashba spin-orbit interaction in lead sulphide nanosheets. AB - Employing the spin degree of freedom of charge carriers offers the possibility to extend the functionality of conventional electronic devices, while colloidal chemistry can be used to synthesize inexpensive and tunable nanomaterials. Here, in order to benefit from both concepts, we investigate Rashba spin-orbit interaction in colloidal lead sulphide nanosheets by electrical measurements on the circular photo-galvanic effect. Lead sulphide nanosheets possess rock salt crystal structure, which is centrosymmetric. The symmetry can be broken by quantum confinement, asymmetric vertical interfaces and a gate electric field leading to Rashba-type band splitting in momentum space at the M points, which results in an unconventional selection mechanism for the excitation of the carriers. The effect, which is supported by simulations of the band structure using density functional theory, can be tuned by the gate electric field and by the thickness of the sheets. Spin-related electrical transport phenomena in colloidal materials open a promising pathway towards future inexpensive spintronic devices. PMID- 28589930 TI - Dynamic alterations in decoy VEGF receptor-1 stability regulate angiogenesis. AB - Blood vessel expansion is driven by sprouting angiogenesis of endothelial cells, and is essential for development, wound healing and disease. Membrane-localized vascular endothelial growth factor receptor-1 (mVEGFR1) is an endothelial cell intrinsic decoy receptor that negatively modulates blood vessel morphogenesis. Here we show that dynamic regulation of mVEGFR1 stability and turnover in blood vessels impacts angiogenesis. mVEGFR1 is highly stable and constitutively internalizes from the plasma membrane. Post-translational palmitoylation of mVEGFR1 is a binary stabilization switch, and ligand engagement leads to depalmitoylation and lysosomal degradation. Trafficking of palmitoylation enzymes via Rab27a regulates mVEGFR1 stability, as reduced levels of Rab27a impaired palmitoylation of mVEGFR1, decreased its stability, and elevated blood vessel sprouting and in vivo angiogenesis. These findings identify a regulatory axis affecting blood vessel morphogenesis that highlights exquisite post-translational regulation of mVEGFR1 in its role as a molecular rheostat. PMID- 28589935 TI - Compressional pathways of alpha-cristobalite, structure of cristobalite X-I, and towards the understanding of seifertite formation. AB - In various shocked meteorites, low-pressure silica polymorph alpha-cristobalite is commonly found in close spatial relation with the densest known SiO2 polymorph seifertite, which is stable above ~80 GPa. We demonstrate that under hydrostatic pressure alpha-cristobalite remains untransformed up to at least 15 GPa. In quasi hydrostatic experiments, above 11 GPa cristobalite X-I forms-a monoclinic polymorph built out of silicon octahedra; the phase is not quenchable and back transforms to alpha-cristobalite on decompression. There are no other known silica polymorphs, which transform to an octahedra-based structure at such low pressures upon compression at room temperature. Further compression in non hydrostatic conditions of cristobalite X-I eventually leads to the formation of quenchable seifertite-like phase. Our results demonstrate that the presence of alpha-cristobalite in shocked meteorites or rocks does not exclude that materials experienced high pressure, nor is the presence of seifertite necessarily indicative of extremely high peak shock pressures. PMID- 28589934 TI - DNA vaccination protects mice against Zika virus-induced damage to the testes. AB - Zika virus (ZIKV) is an emerging pathogen causally associated with serious sequelae in fetuses, inducing fetal microcephaly and other neurodevelopment defects. ZIKV is primarily transmitted by mosquitoes, but can persist in human semen and sperm, and sexual transmission has been documented. Moreover, exposure of type-I interferon knockout mice to ZIKV results in severe damage to the testes, epididymis and sperm. Candidate ZIKV vaccines have shown protective efficacy in preclinical studies carried out in animal models, and several vaccines have entered clinical trials. Here, we report that administration of a synthetic DNA vaccine encoding ZIKV pre-membrane and envelope (prME) completely protects mice against ZIKV-associated damage to the testes and sperm and prevents viral persistence in the testes following challenge with a contemporary strain of ZIKV. These data suggest that DNA vaccination merits further investigation as a potential means to reduce ZIKV persistence in the male reproductive tract. PMID- 28589938 TI - Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice. AB - Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing. Moreover, systemic ASO injection into severely affected mice leads to reversal of muscle pathology within 2 weeks. Thus, ASO-mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease. PMID- 28589937 TI - Loss of Parkinson's disease-associated protein CHCHD2 affects mitochondrial crista structure and destabilizes cytochrome c. AB - Mutations in CHCHD2 have been identified in some Parkinson's disease (PD) cases. To understand the physiological and pathological roles of CHCHD2, we manipulated the expression of CHCHD2 in Drosophila and mammalian cells. The loss of CHCHD2 in Drosophila causes abnormal matrix structures and impaired oxygen respiration in mitochondria, leading to oxidative stress, dopaminergic neuron loss and motor dysfunction with age. These PD-associated phenotypes are rescued by the overexpression of the translation inhibitor 4E-BP and by the introduction of human CHCHD2 but not its PD-associated mutants. CHCHD2 is upregulated by various mitochondrial stresses, including the destabilization of mitochondrial genomes and unfolded protein stress, in Drosophila. CHCHD2 binds to cytochrome c along with a member of the Bax inhibitor-1 superfamily, MICS1, and modulated cell death signalling, suggesting that CHCHD2 dynamically regulates the functions of cytochrome c in both oxidative phosphorylation and cell death in response to mitochondrial stress. PMID- 28589936 TI - Variation in auxin sensing guides AUX/IAA transcriptional repressor ubiquitylation and destruction. AB - Auxin is a small molecule morphogen that bridges SCFTIR1/AFB-AUX/IAA co-receptor interactions leading to ubiquitylation and proteasome-dependent degradation of AUX/IAA transcriptional repressors. Here, we systematically dissect auxin sensing by SCFTIR1-IAA6 and SCFTIR1-IAA19 co-receptor complexes, and assess IAA6/IAA19 ubiquitylation in vitro and IAA6/IAA19 degradation in vivo. We show that TIR1 IAA19 and TIR1-IAA6 have distinct auxin affinities that correlate with ubiquitylation and turnover dynamics of the AUX/IAA. We establish a system to track AUX/IAA ubiquitylation in IAA6 and IAA19 in vitro and show that it occurs in flexible hotspots in degron-flanking regions adorned with specific Lys residues. We propose that this signature is exploited during auxin-mediated SCFTIR1-AUX/IAA interactions. We present evidence for an evolving AUX/IAA repertoire, typified by the IAA6/IAA19 ohnologues, that discriminates the range of auxin concentrations found in plants. We postulate that the intrinsic flexibility of AUX/IAAs might bias their ubiquitylation and destruction kinetics enabling specific auxin responses. PMID- 28589940 TI - Tightening of tropical ascent and high clouds key to precipitation change in a warmer climate. AB - The change of global-mean precipitation under global warming and interannual variability is predominantly controlled by the change of atmospheric longwave radiative cooling. Here we show that tightening of the ascending branch of the Hadley Circulation coupled with a decrease in tropical high cloud fraction is key in modulating precipitation response to surface warming. The magnitude of high cloud shrinkage is a primary contributor to the intermodel spread in the changes of tropical-mean outgoing longwave radiation (OLR) and global-mean precipitation per unit surface warming (dP/dTs) for both interannual variability and global warming. Compared to observations, most Coupled Model Inter-comparison Project Phase 5 models underestimate the rates of interannual tropical-mean dOLR/dTs and global-mean dP/dTs, consistent with the muted tropical high cloud shrinkage. We find that the five models that agree with the observation-based interannual dP/dTs all predict dP/dTs under global warming higher than the ensemble mean dP/dTs from the ~20 models analysed in this study. PMID- 28589939 TI - WASH maintains NKp46+ ILC3 cells by promoting AHR expression. AB - Innate lymphoid cells (ILCs) communicate with other haematopoietic and non haematopoietic cells to regulate immunity, inflammation and tissue homeostasis. How these ILC lineages develop and are maintained is not clear. Here we show that WASH is highly expressed in the nucleus of group 3 ILCs (ILC3s). WASH deletion impairs the cell pool of NKp46+ ILC3s. In NKp46+ ILC3s, WASH recruits Arid1a to the Ahr promoter thus activating AHR expression. WASH deletion in ILC3s decreases the number of NKp46+ ILC3s. Moreover, Arid1a deletion impedes AHR expression and impairs the maintenance of NKp46+ ILC3s. Therefore, WASH-mediated AHR expression has a critical function in the maintenance of NKp46+ ILC3s. PMID- 28589941 TI - Nanoimaging of resonating hyperbolic polaritons in linear boron nitride antennas. AB - Polaritons in layered materials-including van der Waals materials-exhibit hyperbolic dispersion and strong field confinement, which makes them highly attractive for applications including optical nanofocusing, sensing and control of spontaneous emission. Here we report a near-field study of polaritonic Fabry Perot resonances in linear antennas made of a hyperbolic material. Specifically, we study hyperbolic phonon-polaritons in rectangular waveguide antennas made of hexagonal boron nitride (h-BN, a prototypical van der Waals crystal). Infrared nanospectroscopy and nanoimaging experiments reveal sharp resonances with large quality factors around 100, exhibiting atypical modal near-field patterns that have no analogue in conventional linear antennas. By performing a detailed mode analysis, we can assign the antenna resonances to a single waveguide mode originating from the hybridization of hyperbolic surface phonon-polaritons (Dyakonov polaritons) that propagate along the edges of the h-BN waveguide. Our work establishes the basis for the understanding and design of linear waveguides, resonators, sensors and metasurface elements based on hyperbolic materials and metamaterials. PMID- 28589944 TI - Cerebellar hypoplasia with endosteal sclerosis is a POLR3-related disorder. AB - CHES (cerebellar hypoplasia with endosteal sclerosis) syndrome (OMIM#213002) associates hypomyelination, cerebellar atrophy, hypogonadism and hypodontia. So far, only five patients have been described. The condition is of neonatal onset. Patients have severe psychomotor delay and moderate to severe intellectual disability. Inheritance is assumed to be autosomal recessive due to recurrence in sibs, consanguinity of parents and absence of vertical transmission. CHES syndrome is reminiscent of 4H-leukodystrophy, a recessive-inherited affection due to variations in genes encoding subunits of the RNA polymerase III (POLR3A-POLR3B POLR1C). POLR3B variants have been identified in one CHES patient. Here we report on a novel CHES patient, carrying compound heterozygous variations in POLR3B. This report confirms affiliation of CHES to POLR3-related disorders and suggests that CHES syndrome represents a severe form of 4H-leukodystrophy. PMID- 28589942 TI - Misfolded polypeptides are selectively recognized and transported toward aggresomes by a CED complex. AB - Misfolded polypeptides are rapidly cleared from cells via the ubiquitin proteasome system (UPS). However, when the UPS is impaired, misfolded polypeptides form small cytoplasmic aggregates, which are sequestered into an aggresome and ultimately degraded by aggrephagy. Despite the relevance of the aggresome to neurodegenerative proteinopathies, the molecular mechanisms underlying aggresome formation remain unclear. Here we show that the CTIF-eEF1A1 DCTN1 (CED) complex functions in the surveillance of either pre-existing or newly synthesized polypeptides by linking two molecular events: selective recognition and aggresomal targeting of misfolded polypeptides. These events are accompanied by CTIF sequestration into the aggresome, preventing the additional synthesis of misfolded polypeptides from mRNAs bound by nuclear cap-binding complex. These events render cells more resistant to apoptosis induced by proteotoxic stresses. Collectively, our data provide compelling evidence for a previously unappreciated protein surveillance pathway and a regulatory gene expression network for coping with misfolded polypeptides. PMID- 28589943 TI - The signalling receptor MCAM coordinates apical-basal polarity and planar cell polarity during morphogenesis. AB - The apical-basal (AB) polarity and planar cell polarity (PCP) provide an animal cell population with different phenotypes during morphogenesis. However, how cells couple these two patterning systems remains unclear. Here we provide in vivo evidence that melanoma cell adhesion molecule (MCAM) coordinates AB polarity driven lumenogenesis and c-Jun N-terminal kinase (JNK)/PCP-dependent ciliogenesis. We identify that MCAM is an independent receptor of fibroblast growth factor 4 (FGF4), a membrane anchor of phospholipase C-gamma (PLC-gamma), an immediate upstream receptor of nuclear factor of activated T-cells (NFAT) and a constitutive activator of JNK. We find that MCAM-mediated vesicular trafficking towards FGF4, while generating a priority-grade transcriptional response of NFAT determines lumenogenesis. We demonstrate that MCAM plays indispensable roles in ciliogenesis through activating JNK independently of FGF signals. Furthermore, mcam-deficient zebrafish and Xenopus exhibit a global defect in left-right (LR) asymmetric establishment as a result of morphogenetic failure of their LR organizers. Therefore, MCAM coordination of AB polarity and PCP provides insight into the general mechanisms of morphogenesis. PMID- 28589945 TI - Dissemination of antibiotic resistance genes from antibiotic producers to pathogens. AB - It has been hypothesized that some antibiotic resistance genes (ARGs) found in pathogenic bacteria derive from antibiotic-producing actinobacteria. Here we provide bioinformatic and experimental evidence supporting this hypothesis. We identify genes in proteobacteria, including some pathogens, that appear to be closely related to actinobacterial ARGs known to confer resistance against clinically important antibiotics. Furthermore, we identify two potential examples of recent horizontal transfer of actinobacterial ARGs to proteobacterial pathogens. Based on this bioinformatic evidence, we propose and experimentally test a 'carry-back' mechanism for the transfer, involving conjugative transfer of a carrier sequence from proteobacteria to actinobacteria, recombination of the carrier sequence with the actinobacterial ARG, followed by natural transformation of proteobacteria with the carrier-sandwiched ARG. Our results support the existence of ancient and, possibly, recent transfers of ARGs from antibiotic producing actinobacteria to proteobacteria, and provide evidence for a defined mechanism. PMID- 28589946 TI - Elevated prostaglandin E2 post-bone marrow transplant mediates interleukin-1beta related lung injury. AB - Hematopoietic stem cell transplant (HSCT) treats or cures a variety of hematological and inherited disorders. Unfortunately, patients who undergo HSCT are susceptible to infections by a wide array of opportunistic pathogens. Pseudomonas aeruginosa bacteria can have life-threatening effects in HSCT patients by causing lung pathology that has been linked to high levels of the potent pro-inflammatory cytokine, interleukin-1beta (IL-1beta). Using a murine bone marrow transplant (BMT) model, we show that overexpression of prostaglandin E2 (PGE2) post-BMT signals via EP2 or EP4 to induce cyclic adenosine monophosphate (cAMP), which activates protein kinase A or the exchange protein activated by cAMP (Epac) to induce cAMP response element binding-dependent transcription of IL-1beta leading to exacerbated lung injury in BMT mice. Induction of IL-1beta by PGE2 is time and dose dependent. Interestingly, IL-1beta processing post-P. aeruginosa infection occurs via the enzymatic activity of either caspase-1 or caspase-8. Furthermore, PGE2 can limit autophagy-mediated killing of P. aeruginosa in alveolar macrophages, yet autophagy does not have a role in PGE2-mediated upregulation of IL-1beta. Reducing PGE2 levels with indomethacin improved bacterial clearance and reduced IL-1beta-mediated acute lung injury in P. aeruginosa-infected BMT mice. PMID- 28589949 TI - They say coconut oil can aid weight loss, but can it really? AB - There has in recent years, been much media speculation and consumer interest in the beneficial satiating properties of consuming coconut oil and its potential to aid weight loss. However, the media has primarily cited studies using medium chain triglycerides (MCT) oil. The current perspective looks at the research that is available on coconut oil. It examines if and how MCT-related research can be applied to coconut oil and if there is potential for coconut oil to aid weight loss. The current report indicates a lack of consistent evidence on the topic of coconut oil, satiety and weight loss. Given both the publicity and the increased consumption of coconut oil further research, particularly long-term clinical trials, in this area are warranted. PMID- 28589948 TI - Associations between fatty acids and low-grade inflammation in children from the LISAplus birth cohort study. AB - BACKGROUND/OBJECTIVES: Assessing fatty acid (FA) composition in relation to inflammatory markers can shed light on the role of different FA and their metabolism in low-grade inflammation. Existing exploratory studies in children are scarce, and findings inconsistent. We hence aim to analyse associations of FA with common inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), in 10-year-old children. SUBJECTS/METHODS: Complete data were available for 958 participants from the 10-year follow-up of the LISAplus (Influence of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus the Influence of Traffic Emissions and Genetics) birth cohort study. FA composition was assessed in serum glycerophospholipids. Hs-CRP and IL-6 were categorised into three levels. Associations of FA with inflammatory markers were assessed using multinomial logistic regression, adjusting for potential confounders. Additionally, sex stratified analyses were carried out. RESULTS: FA exposures associated with significantly higher low-grade inflammation, as indicated by higher hs-CRP or IL 6 levels, included: palmitic acid (PA) (IL-6: P<0.001, 95% confidence interval: 1.30; 2.43), arachidonic acid (AA) (hs-CRP: P=0.002, 1.07; 1.31), n-6 highly unsaturated FA (HUFA) (hs-CRP: P=0.002, 1.06; 1.27), ratio of AA to linoleic acid (AA/LA) (hs-CRP: P<0.001, 1.16; 1.62) and total saturated FA (SFA) (IL-6: P<0.001, 1.77; 3.15). FA exposures associated with reduced levels of inflammatory markers included LA (hs-CRP: P=0.001, 0.84; 0.96; IL-6: P<0.001, 0.69; 0.90) and total polyunsaturated FA (PUFA) (IL-6: P<0.001, 0.57; 0.78). CONCLUSIONS: These findings suggest that higher SFA and minor n-6 HUFA, namely PA and AA, are associated with increased low-grade inflammation in children, whereas the major dietary n-6 PUFA and total PUFA are associated with reduced inflammation. Elevated desaturase activity, estimated by the ratio AA/LA, may be associated with higher inflammation, particularly in boys. PMID- 28589947 TI - Gut microbiota composition in relation to the metabolic response to 12-week combined polyphenol supplementation in overweight men and women. AB - BACKGROUND/OBJECTIVES: The intestinal microbiota may have a profound impact on host metabolism. As evidence suggests that polyphenols affect substrate utilization, the present study aimed to investigate the effects of polyphenol supplementation on intestinal microbiota composition in humans. Furthermore, we examined whether (changes in) gut microbiota composition may determine the metabolic response to polyphenol supplementation. SUBJECTS/METHODS: In this randomized, double-blind, placebo (PLA)-controlled trial, 37 overweight and obese men and women (18 males/19 females, 37.8+/-1.6 years, body mass index: 29.6+/-0.5 kg/m2) received either epigallocatechin-3-gallate and resveratrol (EGCG+RES, 282 and 80 mg/day, respectively) or PLA for 12 weeks. Before and after intervention, feces samples were collected to determine microbiota composition. Fat oxidation was assessed by indirect calorimetry during a high-fat mixed meal test (2.6 MJ, 61 energy% fat) and skeletal muscle mitochondrial oxidative capacity by means of ex vivo respirometry on isolated skeletal muscle fibers. Body composition was measured by dual-energy X-ray absorptiometry. RESULTS: Fecal abundance of Bacteroidetes was higher in men as compared with women, whereas other assessed bacterial taxa were comparable. EGCG+RES supplementation significantly decreased Bacteroidetes and tended to reduce Faecalibacterium prausnitzii in men (P=0.05 and P=0.10, respectively) but not in women (P=0.15 and P=0.77, respectively). Strikingly, baseline Bacteroidetes abundance was predictive for the EGCG+RES induced increase in fat oxidation in men but not in women. Other bacterial genera and species were not affected by EGCG+RES supplementation. CONCLUSIONS: We demonstrated that 12-week EGCG+RES supplementation affected the gut microbiota composition in men but not in women. Baseline microbiota composition determined the increase in fat oxidation after EGCG+RES supplementation in men. PMID- 28589951 TI - Adiposity and blood pressure among 55 000 relatively lean rural adults in southwest of China. AB - This corrects the article DOI: 10.1038/jhh.2014.129. PMID- 28589950 TI - Mycelium-mediated transfer of water and nutrients stimulates bacterial activity in dry and oligotrophic environments. AB - Fungal-bacterial interactions are highly diverse and contribute to many ecosystem processes. Their emergence under common environmental stress scenarios however, remains elusive. Here we use a synthetic microbial ecosystem based on the germination of Bacillus subtilis spores to examine whether fungal and fungal-like (oomycete) mycelia reduce bacterial water and nutrient stress in an otherwise dry and nutrient-poor microhabitat. We find that the presence of mycelia enables the germination and subsequent growth of bacterial spores near the hyphae. Using a combination of time of flight- and nanoscale secondary ion mass spectrometry (ToF and nanoSIMS) coupled with stable isotope labelling, we link spore germination to hyphal transfer of water, carbon and nitrogen. Our study provides direct experimental evidence for the stimulation of bacterial activity by mycelial supply of scarce resources in dry and nutrient-free environments. We propose that mycelia may stimulate bacterial activity and thus contribute to sustaining ecosystem functioning in stressed habitats. PMID- 28589953 TI - Corrigendum: Fractional Solitons in Excitonic Josephson Junctions. AB - This corrects the article DOI: 10.1038/srep15796. PMID- 28589952 TI - Contrasting mechanisms of growth in two model rod-shaped bacteria. AB - How cells control their shape and size is a long-standing question in cell biology. Many rod-shaped bacteria elongate their sidewalls by the action of cell wall synthesizing machineries that are associated to actin-like MreB cortical patches. However, little is known about how elongation is regulated to enable varied growth rates and sizes. Here we use total internal reflection fluorescence microscopy and single-particle tracking to visualize MreB isoforms, as a proxy for cell wall synthesis, in Bacillus subtilis and Escherichia coli cells growing in different media and during nutrient upshift. We find that these two model organisms appear to use orthogonal strategies to adapt to growth regime variations: B. subtilis regulates MreB patch speed, while E. coli may mainly regulate the production capacity of MreB-associated cell wall machineries. We present numerical models that link MreB-mediated sidewall synthesis and cell elongation, and argue that the distinct regulatory mechanism employed might reflect the different cell wall integrity constraints in Gram-positive and Gram negative bacteria. PMID- 28589956 TI - Corrigendum: A reduced lymphocyte ratio as an early marker for predicting acute pancreatitis. AB - This corrects the article DOI: 10.1038/srep44087. PMID- 28589955 TI - Crystal structures of U6 snRNA-specific terminal uridylyltransferase. AB - The terminal uridylyltransferase, TUT1, builds or repairs the 3'-oligo uridylylated tail of U6 snRNA. The 3'-oligo-uridylylated tail is the Lsm-binding site for U4/U6 di-snRNP formation and U6 snRNA recycling for pre-mRNA splicing. Here, we report crystallographic and biochemical analyses of human TUT1, which revealed the mechanisms for the specific uridylylation of the 3'-end of U6 snRNA by TUT1. The O2 and O4 atoms of the UTP base form hydrogen bonds with the conserved His and Asn in the catalytic pocket, respectively, and TUT1 preferentially incorporates UMP onto the 3'-end of RNAs. TUT1 recognizes the entire U6 snRNA molecule by its catalytic domains, N-terminal RNA-recognition motifs and a previously unidentified C-terminal RNA-binding domain. Each domain recognizes specific regions within U6 snRNA, and the recognition is coupled with the domain movements and U6 snRNA structural changes. Hence, TUT1 functions as the U6 snRNA-specific terminal uridylyltransferase required for pre-mRNA splicing. PMID- 28589957 TI - Corrigendum: Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation. AB - This corrects the article DOI: 10.1038/srep39810. PMID- 28589954 TI - WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. AB - Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that beta catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that beta-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream beta-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients. PMID- 28589958 TI - Astronomical pacing of the global silica cycle recorded in Mesozoic bedded cherts. AB - The global silica cycle is an important component of the long-term climate system, yet its controlling factors are largely uncertain due to poorly constrained proxy records. Here we present a ~70 Myr-long record of early Mesozoic biogenic silica (BSi) flux from radiolarian chert in Japan. Average low mid-latitude BSi burial flux in the superocean Panthalassa is ~90% of that of the modern global ocean and relative amplitude varied by ~20-50% over the 100 kyr to 30 Myr orbital cycles during the early Mesozoic. We hypothesize that BSi in chert was a major sink for oceanic dissolved silica (DSi), with fluctuations proportional to DSi input from chemical weathering on timescales longer than the residence time of DSi (<~100 Kyr). Chemical weathering rates estimated by the GEOCARBSULFvolc model support these hypotheses, excluding the volcanism-driven oceanic anoxic events of the Early-Middle Triassic and Toarcian that exceed model limits. We propose that the Mega monsoon of the supercontinent Pangea nonlinearly amplified the orbitally paced chemical weathering that drove BSi burial during the early Mesozoic greenhouse world. PMID- 28589959 TI - Corrigendum: A dark green fluorescent protein as an acceptor for measurement of Forster resonance energy transfer. AB - This corrects the article DOI: 10.1038/srep15334. PMID- 28589960 TI - Ultra-bright and highly efficient inorganic based perovskite light-emitting diodes. AB - Inorganic perovskites such as CsPbX3 (X=Cl, Br, I) have attracted attention due to their excellent thermal stability and high photoluminescence quantum efficiency. However, the electroluminescence quantum efficiency of their light emitting diodes was <1%. We posited that this low efficiency was a result of high leakage current caused by poor perovskite morphology, high non-radiative recombination at interfaces and perovskite grain boundaries, and also charge injection imbalance. Here, we incorporated a small amount of methylammonium organic cation into the CsPbBr3 lattice and by depositing a hydrophilic and insulating polyvinyl pyrrolidine polymer atop the ZnO electron-injection layer to overcome these issues. As a result, we obtained light-emitting diodes exhibiting a high brightness of 91,000 cd m-2 and a high external quantum efficiency of 10.4% using a mixed-cation perovskite Cs0.87MA0.13PbBr3 as the emitting layer. To the best of our knowledge, this is the brightest and most-efficient green perovskite light-emitting diodes reported to date. PMID- 28589961 TI - River plastic emissions to the world's oceans. AB - Plastics in the marine environment have become a major concern because of their persistence at sea, and adverse consequences to marine life and potentially human health. Implementing mitigation strategies requires an understanding and quantification of marine plastic sources, taking spatial and temporal variability into account. Here we present a global model of plastic inputs from rivers into oceans based on waste management, population density and hydrological information. Our model is calibrated against measurements available in the literature. We estimate that between 1.15 and 2.41 million tonnes of plastic waste currently enters the ocean every year from rivers, with over 74% of emissions occurring between May and October. The top 20 polluting rivers, mostly located in Asia, account for 67% of the global total. The findings of this study provide baseline data for ocean plastic mass balance exercises, and assist in prioritizing future plastic debris monitoring and mitigation strategies. PMID- 28589962 TI - Seepage from an arctic shallow marine gas hydrate reservoir is insensitive to momentary ocean warming. AB - Arctic gas hydrate reservoirs located in shallow water and proximal to the sediment-water interface are thought to be sensitive to bottom water warming that may trigger gas hydrate dissociation and the release of methane. Here, we evaluate bottom water temperature as a potential driver for hydrate dissociation and methane release from a recently discovered, gas-hydrate-bearing system south of Spitsbergen (Storfjordrenna, ~380 m water depth). Modelling of the non-steady state porewater profiles and observations of distinct layers of methane-derived authigenic carbonate nodules in the sediments indicate centurial to millennial methane emissions in the region. Results of temperature modelling suggest limited impact of short-term warming on gas hydrates deeper than a few metres in the sediments. We conclude that the ongoing and past methane emission episodes at the investigated sites are likely due to the episodic ventilation of deep reservoirs rather than warming-induced gas hydrate dissociation in this shallow water seep site. PMID- 28589963 TI - Exposure to the Abused Inhalant Toluene Alters Medial Prefrontal Cortex Physiology. AB - Inhalants, including toluene, target the addiction neurocircuitry and are often one of the first drugs of abuse tried by adolescents. The medial prefrontal cortex (mPFC) is involved in regulating goal-directed/reward-motivated behaviors and different mPFC sub-regions have been proposed to promote (prelimbic, PRL) or inhibit (infralimbic, IL) these behaviors. While this dichotomy has been studied in the context of other drugs of abuse, it is not known whether toluene exposure differentially affects neurons within PRL and IL regions. To address this question, we used whole-cell electrophysiology and determined the intrinsic excitability of PRL and IL pyramidal neurons in adolescent rats 24 h following a brief exposure to air or toluene vapor (10 500 p.p.m.). Prior to exposure, fluorescent retrobeads were injected into the NAc core (NAcc) or shell (NAcs) sub regions to identify projection-specific mPFC neurons. In toluene treated adolescent rats, layer 5/6 NAcc projecting PRL (PRL5/6) neurons fired fewer action potentials and this was associated with increased rheobase, increased spike duration, and reductions in membrane resistance and amplitude of the Ih current. No changes in excitability were observed in layer 2/3 NAcc projecting PRL (PRL2/3) neurons. In contrast to PRL neurons, layer 5 IL (IL5) and layer 2/3 (IL2/3) NAcc projecting neurons showed enhanced firing in toluene-exposed animals and in IL5 neurons, this was associated with a reduction in rheobase and AHP. For NAcs projecting neurons, toluene exposure significantly decreased firing of IL5 neurons and this was accompanied by an increased rheobase, increased spike duration, and reduced Ih amplitude. The intrinsic excitability of PRL5, PRL2/3, and IL2/3 neurons projecting to the NAcs was not affected by exposure to toluene. The changes in excitability observed 24 h after toluene exposure were not observed when recordings were performed 7 days after the exposure. Finally, there were no changes in intrinsic excitability of any region in rats exposed to toluene as adults. These findings demonstrate that specific projections of the reward circuitry are uniquely susceptible to the effects of toluene during adolescence supporting the idea that adolescence is a critical period of the development that is vulnerable to drugs of abuse. PMID- 28589964 TI - HPA Axis Genes, and Their Interaction with Childhood Maltreatment, are Related to Cortisol Levels and Stress-Related Phenotypes. AB - Stress responses are controlled by the hypothalamus pituitary adrenal (HPA)-axis and maladaptive stress responses are associated with the onset and maintenance of stress-related disorders such as major depressive disorder (MDD). Genes that play a role in the HPA-axis regulation may likely contribute to the relation between relevant neurobiological substrates and stress-related disorders. Therefore, we performed gene-wide analyses for 30 a priori literature-based genes involved in HPA-axis regulation in 2014 subjects (34% male; mean age: 42.5) to study the relations with lifetime MDD diagnosis, cortisol awakening response, and dexamethasone suppression test (DST) levels (subsample N=1472) and hippocampal and amygdala volume (3T MR images; subsample N=225). Additionally, gene by childhood maltreatment (CM) interactions were investigated. Gene-wide significant results were found for dexamethasone suppression (CYP11A1, CYP17A1, POU1F1, AKR1D1), hippocampal volume (CYP17A1, CYP11A1, HSD3B2, PROP1, AVPRA1, SRD5A1), amygdala volume (POMC, CRH, HSD3B2), and lifetime MDD diagnosis (FKBP5 and CRH), all permutation p-values<0.05. Interactions with CM were found for several genes; the strongest interactions were found for NR3C2, where the minor allele of SNP rs17581262 was related to smaller hippocampal volume, smaller amygdala volume, higher DST levels, and higher odds of MDD diagnosis only in participants with CM. As hypothesized, several HPA-axis genes are associated with stress-related endophenotypes including cortisol response and reduced brain volumes. Furthermore, we found a pleiotropic interaction between CM and the mineralocorticoid receptor gene, suggesting that this gene plays an important moderating role in stress and stress-related disorders. PMID- 28589965 TI - Generalization of Extinguished Fear to Untreated Fear Stimuli after Exposure. AB - Exposure therapy is highly effective in treating excessive fear related to specific objects and/or situations. However, patients with anxiety disorders often display a generalization of fear responses toward conceptually and perceptually related stimuli and situations. It is unclear whether the beneficial effects of exposure on fear reduction toward treated fear stimuli can extend to untreated fear stimuli. Here, we investigated whether basic principles of extinction generalization apply to exposure. Spider-phobic participants were randomly assigned to either two sessions of exposure treatment (n=23) with spiders or no-treatment (n=24). Prior to and after treatment, behavioral approach tests (BATs) were conducted to examine avoidance, fear and disgust responses toward the treated phobic stimulus (spider as the extinction stimulus). Likewise, BATs with the untreated fear stimulus (cockroach) were conducted to dissect the generalization of treatment effects. Treatment was highly effective in increasing approach behavior toward both treated and untreated fear stimuli. Generalization of treatment effects were evident on the behavioral (approach distance during the BAT), subjective (fear levels during the BAT) and psychophysiological level (heart rate during the BAT). However, a stronger decline in disgust was only evident for the treated fear stimulus. Notably, the herein attained generalization effects were not context-dependent. Hence, exposure therapy for spider phobia was effective in reducing fear of untreated stimuli which share common fear-evoking characteristics with spiders but were never presented during the respective exposure treatment. These findings provide clinical evidence for extinction generalization across different fear-evoking stimuli mediated via exposure. PMID- 28589966 TI - Role of kappa-Opioid Receptors in the Bed Nucleus of Stria Terminalis in Reinstatement of Alcohol Seeking. AB - kappa-Opioid receptors (KORs) and their endogenous ligand dynorphin are involved in stress-induced alcohol seeking but the mechanisms involved are largely unknown. We previously showed that systemic injections of the KOR agonist U50,488, which induce stress-like aversive states, reinstate alcohol seeking after extinction of the alcohol-reinforced responding. Here, we used the neuronal activity marker Fos and site-specific injections of the KOR antagonist nor-BNI and U50,488 to study brain mechanisms of U50,488-induced reinstatement of alcohol seeking. We trained male Long-Evans rats to self-administer alcohol (12% w/v) for 23-30 days. After extinction of the alcohol-reinforced responding, we tested the effect of U50,488 (0, 1.25, 2.5, and 5 mg/kg) on reinstatement of alcohol seeking. Next, we correlated regional Fos expression with reinstatement induced by the most effective U50,488 dose (5 mg/kg). Based on the correlational Fos results, we determined the effect of bed nucleus of the stria terminalis (BNST) injections of nor-BNI (4 MUg/side) on U50,488-induced reinstatement of alcohol seeking, and reinstatement induced by injections of U50,488 (0, 0.3, 1, and 3 MUg/side) into the BNST. U50,488-induced reinstatement of alcohol seeking was associated with increased Fos expression in multiple brain areas, including the BNST, where it was significantly correlated with lever pressing. U50,488-induced reinstatement was blocked by BNST nor-BNI injections, and BNST U50,488 injections partially mimicked the drug's systemic effect on reinstatement. Our data indicate that the BNST is a critical site for U50,488-induced reinstatement of alcohol seeking and suggest that KOR/dynorphin mechanisms in this brain area play a key role in stress-induced alcohol seeking. PMID- 28589969 TI - Combined effects of NQO1 Pro187Ser or SULT1A1 Arg213His polymorphism and smoking on bladder cancer risk: Two meta-analyses. AB - OBJECTIVES: Objectives: Cigarette smoking is the major risk factor of bladder cancer via exposure to chemical carcinogens. Nicotinamide adenine dinucleotide phosphate (NADP+): quinine oxidoreductase 1 (NQO1) and sulfotransferase 1A1 (SULT1A1) have been reported to involve in the metabolism of polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Therefore, the risk of bladder cancer (BC) may be influenced by polymorphisms in the genes that modulate metabolic detoxification in particular by interacting with cigarette smoking. Considering the limited power by the individual studies with a relatively small sample size, especially when analyzing the combined effect of polymorphisms in NQO1 and SULT1A1 genes and smoking, these 2 meta-analyses have aimed to clarify the combined effects of them on BC risk by integrating related studies. MATERIAL AND METHODS: Two meta-analyses included 1341 cases and 1346 controls concerning NQO1 Pro187Ser and smoking, and 1921 cases and 1882 controls on SULT1A1 Arg213His and smoking were performed. Odds ratios (OR) and 95% confidence intervals (CI) were used for assessing the strength of the association. RESULTS: The result has demonstrated that smokers with NQO1 Pro/Ser or Ser/Ser genotypes have a prominent association with the risk of BC as compared with non-smokers with NQO1 Pro/Pro genotype, with OR equal to 3.71 (95% CI: 2.87-4.78, pheterogeneity = 0.376). Besides, smokers carrying SULT1A1 Arg/Arg genotypes were observed to confer 2.38 fold increased risk of BC (95% CI: 1.44-3.93, pheterogeneity = 0.001) when compared with non-smokers with SULT1A1 Arg/Arg or His/His genotypes. CONCLUSIONS: These findings have suggested that the NQO1 Pro187Ser or SULT1A1 Arg213His polymorphism combination with smoking significantly confer susceptibility to BC. Int J Occup Med Environ Health 2017;30(5):791-802. PMID- 28589967 TI - In Vivo Fiber Photometry Reveals Signature of Future Stress Susceptibility in Nucleus Accumbens. AB - Recognizing why chronic stress causes only a subset of individuals to become depressed is critical to understanding depression on a basic level and, also, to developing treatments that increase resilience. Stress-induced alterations in the activity of reward-related brain regions, such as the nucleus accumbens (NAc), are linked to the pathophysiology of depression. However, it has been difficult to determine if differences in stress susceptibility are pre-existing or merely an effect of chronic stress. The NAc consists largely of medium spiny neurons (MSNs), distinguished by their predominant expression of either D1 or D2 dopamine receptors. Mice that develop depressive-like symptoms after chronic social defeat stress show distinct changes in the activity of these two cell subtypes. Until now it has not been possible to determine whether such effects are merely a consequence of stress or in fact precede stress and, thus, have utility in pre identifying stress-susceptible individuals. The goal of this study was to define a cell-type specific signature of stress susceptibility and resilience. Using fiber photometry calcium imaging, we recorded calcium transients in NAc D1- and D2-MSNs in awake behaving mice and found that D1-MSN activity is a predictive marker of depression susceptibility: prior to stress, mice that will later become resilient had increased baseline D1- MSN activity, and increased calcium transients specific to social interaction. Differences in D2- MSN activity were not specific to social interaction. Our findings identify a pre-existing mechanism of stress-induced susceptibility, creating the potential to target preventative interventions to the most relevant populations. PMID- 28589970 TI - Electronic and optical properties of nanostructured MoS2 materials: influence of reduced spatial dimensions and edge effects. AB - We theoretically study the electronic and optical properties of nanostructured MoS2 systems focusing on the influence of reduced spatial dimensions and edge effects, which lead to the change in character from semiconducting to metallic. For nanowires, we identify edge types which lead to the creation of a bandgap, reflecting the effect of confinement: with increasing the size of the wire in lateral direction and/or number of MoS2 layers, the gap reduces. For nanodisks, we identify features in electronic properties that are universal; specifically, our calculations reveal presence of a local maximum in electronic density of states, insensitive on nanodisk's geometrical properties. By manipulating with sulfur and molybdenum atoms at the edges we tune position of Fermi energy with respect to the local maximum. We discuss total electronic density and partial electronic density for energy levels below Fermi energy, that could be used for mapping to STM images under negative bias. Our findings are extracted from a tight-binding (TB) model that includes non-orthogonal sp3d5 orbitals and spin orbit coupling. We benchmark our TB model by comparing our results to those extracted from density functional theory and quasiparticle self-consistent GW, test different TB parameter sets, establishing the range of their validity, and discuss limitations of our model. PMID- 28589971 TI - On the structures, spin states, and optical properties of titanium, platinum, and iron azacalixphyrins: a DFT study. AB - Azacalixphyrins (ACP) constitute a new class of macrocycles isoelectronic and isostructural to porphyrins. Herein, we report the first theoretical investigation of the properties of the ACP macrocycles metallated at their centre by titanium, platinum, and iron ions. We considered both the original phenyl-type ACP and new pyridyl-type forms. Our results indicate that the metallation greatly impacts the global structure of the macrocycle through pseudo Jahn-Teller effects, giving rise to a possible conformational transition between D2d and S4 structures. Such an effect could not be found in the metal-free ACPs. In addition, we find that, in contrast to the purely singlet platinum ACPs, and the purely triplet iron ACPs, several spin states are energetically close in the titanium ACPs, especially when weak field ligands are bound in axial positions to the metallic centre. According to TD-DFT calculations, metallation also tunes the optical properties. In particular, the absorption band in the near infrared region undergoes a hypsochromic shift of ca. 100-200 nm when going from the D2d to the S4 structures. We quantify how the addition of electroactive ligands in the axial position can increase or tune down these spectral changes. This contribution therefore supports the development of ACP coordination complexes. PMID- 28589968 TI - The 5-HTTLPR Polymorphism Affects Network-Based Functional Connectivity in the Visual-Limbic System in Healthy Adults. AB - The serotonin transporter-linked polymorphic region 5-HTTLPR is a key genetic regulator of 5-HTT expression in the human brain where the short allele S has been implicated in emotion dysregulation. However, the neural mechanism underlying the association between this variant and emotion processing is still unclear. Earlier studies suggested an effect of 5-HTTLPR on amygdala activation during emotional face processing. However, this association has been questioned in recent studies employing larger sample sizes and meta-analyses. Here, we examined a sample of 223 healthy subjects with a well-established fMRI emotional face processing task to (1) re-evaluate the association between 5-HTTLPR and amygdala activation, (2) explore potential network-based functional connectivity phenotypes for associations with 5-HTTLPR, and (3) probe the reliability, behavioral significance and potential structural confounds of the identified network phenotype. Our results revealed no significant effect of 5-HTTLPR on amygdala activation (P>0.79). However, the number of S alleles was significantly correlated with functional connectivity of a visual-limbic subnetwork (PFWE=0.03). The subnetwork cluster included brain regions that are pivotal to emotion regulation such as the hippocampus, orbitofrontal cortex, anterior cingulate gyrus, fusiform gyrus, and subcortex. Notably, individuals with lower subnetwork connectivity had significantly higher emotion suppression scores (P=0.01). Further, the connectivity metrics were test-retest reliable and independent from subnetwork gray matter volume and white matter anisotropy. Our data provide evidence for a functional network-based phenotype linking genetic variation in 5-HTTLPR to emotion regulation, and suggest that further critical evaluations of the association between 5-HTTLPR and amygdala activation are warranted. PMID- 28589974 TI - Multifunctional catalysis: stereoselective construction of alpha-methylidene gamma-lactams via an amidation/Rauhut-Currier sequence. AB - Mixing of acryloylchloride, dienone 2, N,N-diisopropylethylamine with chiral organocatalyst 5a, which could simultaneously act as Bronsted and Lewis base catalysts, led to a one-pot amidation/Rauhut-Currier sequence, affording alpha methylidene-gamma-lactams 4. Catalyst 5a could be recovered and reused by acid/base extraction without any loss of catalytic activity in the stepwise protocol. PMID- 28589972 TI - The influence of tumor-induced immune dysfunction on the immune cell distribution of gold nanoparticles in vivo. AB - Gold nanoparticles (AuNPs) have been extensively explored as a drug carrier and have been widely used to provide advanced biomedical research tools in diagnostic imaging and therapy for cancer. Although the mononuclear phagocyte system and immune system are known to play the main roles in the clearance of AuNPs during the circulation, the particle distribution within the immune cells under the condition of immune dysfunction caused by tumor growth has not been thoroughly studied. Here, the cellular distribution of Cy5 labeled AuNPs with diameters of 5, 30 and 50 nm is characterized within the immune populations of the blood, spleen and bone marrow from tumor free and tumor bearing mice using flow cytometry. Tumor-associated immune dysfunction was observed in all immune organs and cell lineages, and it changed with tumor growth. Furthermore, the particle cellular distribution significantly changed in the tumor bearing mice compared with the tumor free mice. Finally, the particle distribution in the immune cells was also different at different stages of the tumor. Overall, these results can help inform and influence future AuNP design criteria including the future applications for nanoparticle-mediated cancer therapy. PMID- 28589973 TI - The effect of a membrane-mimicking environment on the interactions of Cu2+ with an amyloidogenic fragment of chicken prion protein. AB - Prion proteins (PrP) from different species have the ability to tightly bind Cu2+ ions. Copper coordination sites are located in the disordered and flexible N terminal region which contains several His anchoring sites. Among them, two His residues are found in the so called amyloidogenic PrP region which is believed to play a key role in the process leading to oligomer and fibril formation. Both chicken and human amyloidogenic regions have a hydrophobic C-terminal region rich in Ala and Val amino acids. Recent findings revealed that this domain undergoes random coil to alpha-helix structuring upon interaction with membrane models. This interaction might strongly impact metal binding abilities either in terms of donor sets or affinity. In this study we investigated Cu2+ interaction with an amyloidogenic fragment, chPrP105-140, derived from chicken prion protein (chPrP), in different solution environments. The behavior of the peptide and its metal complexes was analyzed in water and in the presence of negative and positive charged membrane mimicking environments formed by sodium dodecyl sulfate (SDS) and dodecyl trimethyl ammonium chloride (DTAC) micelles. The metal coordination sphere, the metal binding affinity and stoichiometry were evaluated by combining spectroscopic and potentiometric methods. Finally we compare copper(ii) interactions with human and chicken amyloidogenic fragments. Our results indicate that the chicken amyloidogenic fragment is a stronger copper ligand than the human amyloidogenic fragment. PMID- 28589976 TI - Pd-Catalyzed regioselective sequential meta-, ortho-C-H functionalization of arenes: a predictable approach to the synthesis of polysubstituted beta arylethylamines. AB - With the assistance of the same bidentate directing group, the first example of sequential, controllable C-H functionalization of beta-arylethylamines at different positions for the construction of polysubstituted arenes is reported. Pd-Catalyzed highly regioselective ortho-C-H functionalization reactions of meta aryl substituted arylethylamines are performed, including alkynylation, iodination, acetoxylation and amination, which led to a concise approach to the synthesis of polysubstituted beta-arylethylamine derivatives. PMID- 28589975 TI - Non-stoichiometric MoO3-x quantum dots as a light-harvesting material for interfacial water evaporation. AB - We herein present oxygen-deficient molybdenum oxide quantum dots (MoO3-x QDs), which possess matching-absorption-spectrum to solar light in both visible and near infrared regions, for proof-of-concept of interfacial water evaporation. Theoretical modeling suggests that the unique optical property of MoO3-x QDs results from oxygen defect level, instead of localized surface plasmon resonance. PMID- 28589977 TI - Fingerprints of inter- and intramolecular hydrogen bonding in saligenin-water clusters revealed by mid- and far-infrared spectroscopy. AB - Saligenin (2-(hydroxymethyl)phenol) exhibits both strong and weak intramolecular electrostatic interactions. The bonds that result from these interactions compete with intermolecular hydrogen bonds once saligenin binds to one or more water molecules. Infrared (IR) ultraviolet (UV) ion-dip spectroscopy was used to study isolated saligenin-(H2O)n clusters (n = 1-3) in the far- and mid-IR regions of the spectrum. Both harmonic and anharmonic (coupled local modes and Born Oppenheimer molecular dynamics) quantum chemical calculations were applied to assign cluster geometries to the measured spectra, and to assign vibrational modes to all spectral features measured for each cluster. The hydrated clusters with n = 1 and 2 have geometries that are quite similar to benzyl alcohol-water clusters, whereas the larger clusters with n = 3 show structures equivalent to the isolated water pentamer. Systematic shifts in the frequencies of three hydrogen bond (H-bond) deforming modes, namely OH stretching, OH torsion and H bond stretching, were studied as a function of the hydrogen bond strength represented by either the OH bond length or the H-bond length. The shifts of the frequencies of these three modes correlate linearly to the OH length, despite both intra- and intermolecular H-bonds being included in this analysis. The OH torsion vibration displays the largest frequency shift when H-bonded, followed by the OH stretching vibrations and finally the H-bond stretching frequency. The frequency shifts of these H-bond deforming modes behave non-linearly as a function of the H-bond length, asymptotically approaching the frequency expected for the non H-bonded modes. The nonlinear behavior was quantified using exponential functions. PMID- 28589978 TI - Controlled ROS production by corannulene: the vehicle makes a difference. AB - Curved corannulene (Cor) can produce reactive oxygen species (ROS) in a controlled manner due to the large dipole moment. However, the poor aqueous solubility of Cor necessitates the employment of solubilization vehicles. This work revealed that PEGylation was less efficient than the cyclodextrin complexation regarding ROS production. PMID- 28589979 TI - From force curves to surface nanomechanical properties. AB - Surface science, which spans the fields of chemistry, physics, biology and materials science, requires information to be obtained on the local properties and property variations across a surface. This has resulted in the development of different scanning probe methods that allow the measurement of local chemical composition and local electrical and mechanical properties. These techniques have led to rapid advancement in fundamental science with applications in areas such as composite materials, corrosion protection and wear resistance. In this perspective article, we focussed on the branch of scanning probe methods that allows the determination of surface nanomechanical properties. We discussed some different AFM-based modes that were used for these measurements and provided illustrative examples of the type of information that could be obtained. We also discussed some of the difficulties encountered during such studies. PMID- 28589980 TI - Nitrogen-doped graphene: effect of graphite oxide precursors and nitrogen content on the electrochemical sensing properties. AB - Graphene, produced via chemical methods, has been widely applied for electrochemical sensing due to its structural and electrochemical properties as well as its ease of production in large quantity. While nitrogen-doped graphenes are widely studied materials, the literature showing an effect of graphene oxide preparation methods on nitrogen quantity and chemical states as well as on defects and, in turn, on electrochemical sensing is non-existent. In this study, the properties of nitrogen-doped graphene materials, prepared via hydrothermal synthesis using graphite oxide produced by various classical methods using permanganate or chlorate oxidants Staudenmaier, Hummers, Hofmann and Brodie oxidation methods, were studied; the resulting nitrogen-doped graphene oxides were labeled as ST-GO, HU-GO, HO-GO and BR-GO, respectively. The electrochemical oxidation of biomolecules, such as ascorbic acid, uric acid, dopamine, nicotinamide adenine nucleotide and DNA free bases, was carried out using cyclic voltammetry and differential pulse voltammetry techniques. The nitrogen content in doped graphene oxides increased in the order ST-GO < BR-GO < HO-GO < HU-GO. In the same way, the pyridinic form of nitrogen increased and the electrocatalytic effect of N-doped graphene followed this trend, as shown in the cyclic voltammograms. This is a very important finding that provides insight into the electrocatalytic effect of N-doped graphene. The nitrogen-doped graphene materials exhibited improved sensitivity over bare glassy carbon for ascorbic acid, uric acid and dopamine detection. These studies will enhance our understanding of the effects of graphite oxide precursors on the electrochemical sensing properties of nitrogen-doped graphene materials. PMID- 28589982 TI - Construction of thiazines and oxathianes via [3 + 3] annulation of N tosylaziridinedicarboxylates and oxiranes with 1,4-dithiane-2,5-diol: application towards the synthesis of bioactive molecules. AB - Lewis acid catalyzed [3 + 3] annulation of N-tosylaziridinedicarboxylates and oxiranes with in situ generated mercaptoaldehyde for the synthesis of functionalized thiazine and oxathiane derivatives has been developed. Additionally, this method facilitates the derivatization of thiazines by detosylation and Krapcho monodecarboxylation. PMID- 28589986 TI - Formation and dynamics of endoplasmic reticulum-like lipid nanotube networks. AB - We report on the self-organized formation and dynamics of artificial lipid nanotube networks, which, in terms of morphology and behavior, resemble the endoplasmic reticulum(ER) of biological cells. The networks, initially generated from a solid-supported planar phospholipid membrane, undergo a morphological transformation, triggered by the chelation and removal of Ca2+ from the environment surrounding the membrane. Calcium depletion gradually causes de pinning, thus de-wetting, at the membrane-substrate interface. We observe dynamic re-arrangements very similar to the ones reported for the cellular ER, such as sliding of tubes and formation of new junctions, and quantify these transformations. We also show occurrences of the dynamic replacement of lipidic particles on nanotubes as indicators for the existence of a tension gradient throughout the network, as well as the spontaneous formation of small vesicles from semi-free floating tubes. We propose that these artificial networks are suitable to serve as a bottom-up-generated structural model for the cellular ER, whose fascinating characteristic morphology is suggested to be tied to its biological function, but with respect to formation, dynamics, and functional details still incompletely understood. PMID- 28589987 TI - Emerging strategies in near-infrared light triggered drug delivery using organic nanomaterials. AB - Near-infrared light has significant advantages for light-triggered drug delivery systems within deep tissues. The use of inorganic nanomaterials raises concern over their long-term in vivo toxicities. Here we will highlight emerging near infrared light-triggered drug delivery using organic nanomaterials, as well as new photocleavage reactions mediated by near-infrared light. PMID- 28589988 TI - Development of non-oxide semiconductors as light harvesting materials in photocatalytic and photoelectrochemical water splitting. AB - Water splitting via photocatalysis and photoelectrolysis is a potential means to produce clean and renewable hydrogen as a storable high-density energy carrier. At present, the main concern is how to develop semiconductor materials for efficiently converting sunlight energy. The present perspective summarises recent developments in the use of new semiconductors as light-harvesting materials. Specifically, non-oxides, oxynitrides and oxysulfides have been demonstrated to be promising materials for water splitting under visible light. The design of such materials and their application to photocatalytic and photoelectrochemical water splitting are discussed. PMID- 28589989 TI - Monitoring focal adhesion kinase phosphorylation dynamics in live cells. AB - Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase essential for a diverse set of cellular functions. Current methods for monitoring FAK activity in response to an extracellular stimulus lack spatiotemporal resolution and/or the ability to perform multiplex detection. Here we report on a novel approach to monitor the real-time kinase phosphorylation activity of FAK in live single cells by fluorescence lifetime imaging. PMID- 28589990 TI - A novel self-activation mechanism of Candida antarctica lipase B. AB - Candida antarctica lipase B (CalB), resembling many other lipases structure-wise, contains a flexible lid that undergoes a surprisingly large conformational change when catalyzing hydrophobic substrates (e.g. triglycerides). Despite extensive and important applications in industry, it is so far still elusive whether CalB can be activated on a hydrophobic surface, like other lipases. From large-scale all-atom molecular dynamics simulations, we discovered an open state that strikingly shows a much wider and more stable entrance to the catalytic site than the one suggested by previous crystal structures. Simulations demonstrate that in the newly found open state CalB possesses a "lid-holder" structure that intimately harbors the lid of CalB, i.e. a remarkable self-activation mechanism. To account for the unusual interfacial activation of CALB revealed in a recent experiment, we further introduce a simple model: the activation occurs only when the binding free energy between the lid and a hydrophobic surface is larger than a critical value, 4.0 kcal mol-1 that is the one between the lid and the "lid holder". Our findings shed light on possible protein engineering of lipases to permit either self-activation with broadened catalytic targets (including water soluble ones) or surface activation with elevated activities. PMID- 28589993 TI - Photoperiodic time measurement and photoentrainment of a circadian locomotor activity rhythm in subtropical tree sparrows. AB - Experiments were performed on the subtropical tree sparrow (Passer montanus) to investigate the involvement of an endogenous circadian rhythm in photoperiodic time measurement during the initiation of gonadal growth and functions and also to study the photic entrainment of the circadian activity rhythm. Groups of photosensitive birds of both sexes were exposed to different "night-interruption" light-dark regimes of 24 h duration viz., G1 - 6L/5D/1L/12D, G2 - 6L/6D/1L/11D, G3 - 6L/7D/1L/10D, G4 - 6L/8D/1L/9D, G5 - 6L/10D/1L/7D, G6 - 6L/12D/1L/5D, G7 - 6L/14D/1L/3D and G8 - 6L/16D/1L/1D for 30 days in which 17 h long nights were interrupted by 1 h light pulse falling at different ZTs (i.e., 11, 12, 13, 14, 16, 18, 20 and 22). A control group, for each sex, was maintained under 7L/17D. The birds of all groups behaved as though they had been exposed to a stimulatory photoperiod except those of G1, G8 and the control. Furthermore, the serum levels of testosterone in males and estradiol-17beta in females ran almost parallel to changes in the gonadal size. Birds, when exposed to 12L/12D, showed entrainment of their locomotor activity rhythm with the activity confined mainly during the light phase. However, various characteristics of the activity rhythm differed significantly upon transfer of birds to various night interruption regimes. These results suggest the involvement of the endogenous circadian rhythm in photoperiodic time measurement during the induction of gonadal growth and functions in the tree sparrow. Also, there is photic entrainment of the locomotor activity rhythm that shows variations in various circadian characteristics under different night interruption cycles suggesting that the photoinducible phase is differentially sensitive to light. PMID- 28589994 TI - Rhenium-catalysed hydroboration of aldehydes and aldimines. AB - The first examples for the rhenium-catalysed hydroboration of aldehydes, ketones and aldimines, including heteroaromatic quinoline, are reported herein. Reactions are remarkably chemoselective and tolerant of several functional groups. A wide array of rhenium complexes were efficient pre-catalysts for these hydroborations, including new low-valent complexes of the formula [Re(N-N)(CO)3(L)]X (N-N = bipy derivative, L = labile ligand/solvent, and X = [BArF4]- and [B(3,5-di-tBu-cat)2] ), which have been characterized fully including an X-ray diffraction study for [Re(bipy)(CO)3(quin)][BArF4] (2). A new silver spiroboronate ester Ag[B(3,5-di tBu-cat)2](NCCH3)3 (3) was prepared and characterized fully, including an X-ray diffraction study, and used to make one of the new rhenium complexes. PMID- 28589995 TI - trans-Polydatin protects the mouse heart against ischemia/reperfusion injury via inhibition of the renin-angiotensin system (RAS) and Rho kinase (ROCK) activity. AB - BACKGROUND: Recent studies highlighted the protective benefits of a Chinese herb extract from polygonum cuspidatum, trans-polydatin, on cardiac disease. We investigated the therapeutic effect of trans-polydatin on myocardial ischemia/reperfusion (IR) injury and the underlying mechanisms related to the renin-angiotensin system (RAS) and RhoA kinase (ROCK) pathway. METHODS AND RESULTS: Experiments were performed on neonatal rats' ventricular myocytes that were subjected to hypoxia-reoxygenation (simulated IR, SIR) and on adult mice which were subjected to left anterior descending coronary artery occlusion for 45 min followed by a one-week reperfusion. trans-Polydatin significantly increased cell viability and reduced apoptosis in SIR cardiomyocytes. It was also observed to reduce the infarct size and increase the cardiac function in IR mice. trans Polydatin decreased the expression of angiotensin and inhibited the activities of renin and angiotensin-converting enzyme. Furthermore, trans-polydatin inhibited ROCK activity, especially the angiotensin I receptor-activated ROCK pathway. CONCLUSIONS: trans-Polydatin exerts a cardio-protection against myocardial IR injury likely through inhibiting both RAS and the downstream ROCK pathway. PMID- 28589996 TI - Implications of the Maillard reaction on bovine alpha-lactalbumin and its proteolysis during in vitro infant digestion. AB - This study investigated the functionality and digestibility of Maillard reaction products (MRPs) of alpha-lactalbumin (alpha-la), a major whey protein and component of infant formulas. The impact of different carbohydrates (glucose, galactose or galacto-oligosaccharides (GOS)) and heating duration was studied. SDS-PAGE, UV and color measurements monitored reaction extent, which varied between carbohydrates whereby galactose reacted more readily than glucose. Surface hydrophobicity and antioxidant capacity were found to be significantly (p < 0.05) higher following Maillard conjugation, with GOS-based MRPs elevating antioxidant capacity ~50-fold compared to alpha-la. In addition, the digestive proteolysis of MRPs was evaluated using an infant in vitro gastro-duodenal model. SDS-PAGE analyses of digesta revealed Maillard conjugation generally increased alpha-la's susceptibility to proteolysis. Interestingly, GOS-based MRPs presented an optimization challenge, since heating for 12 h delayed proteolysis, while extended heating resulted in the highest susceptibility to proteolysis. Proteomic analyses further demonstrated the differences in enzymatic cleavage patterns and helped identify bioactive peptides rendered bioaccessible during the digestion of alpha-la or its MRPs. Bioinformatic mining of the proteomic data using PeptideRanker also gave rise to two potentially novel bioactive peptides, FQINNKIW and GINYWLAHKALCS. Finally, antioxidant capacity of luminal contents, measured by DPPH, revealed Maillard conjugation increased the antioxidant capacity of both gastric and duodenal digesta. Overall, this work draws a link between the Maillard reaction, digestive proteolysis and the bioaccessibility of bioactive peptides and antioxidant species in the infant alimentary canal. This could help rationally process infant formulas towards improved nutritional and extra-nutritional benefits. PMID- 28589997 TI - How coffee affects metabolic syndrome and its components. AB - Metabolic syndrome, with its increasing prevalence, is becoming a major public health problem throughout the world. Many risk factors including nutrition play a role in the emergence of metabolic syndrome. Of the most-consumed beverages in the world, coffee contains more than 1000 components such as caffeine, chlorogenic acid, diterpenes and trigonelline. It has been proven in many studies that coffee consumption has a positive effect on chronic diseases. In this review, starting from the beneficial effects of coffee on health, the relationship between coffee consumption and metabolic syndrome and its components has been investigated. There are few studies investigating the relationship between coffee and metabolic syndrome, and the existing ones put forward different findings. The factors leading to the differences are thought to stem from coffee variety, the physiological effects of coffee elements, and the nutritional ingredients (such as milk and sugar) added to coffee. It is reported that consumption of coffee in adults up to three cups a day reduces the risk of Type-2 diabetes and metabolic syndrome. PMID- 28589998 TI - Magnetic field application or mechanical stimulation via magnetic microparticles does not enhance chondrogenesis in mesenchymal stem cell sheets. AB - Using a novel magnetic field bioreactor, this work evaluated the chondrogenesis of scaffold-free human mesenchymal stem cell sheets in response to static and variable magnetic fields, as well as mechanical stimulation via 4.4 MUm magnetic particles. Neither static nor variable magnetic fields generated by 1.44-1.45 T permanent magnets affected cartilage formation. Notably, magnetic field-induced mechanical stimulation by magnetic particles, which applied forces to the cells and ECM statically (4.39 pN) or cyclically (1.06-63.6 pN; 16.7 mHz), also did not affect cartilage formation. PMID- 28589999 TI - Thermodynamic analysis of alkali metal complex formation of polymer-bonded crown ether. AB - The complex formation of two crown ethers with colored alkali metal salts was investigated by UV/Vis spectroscopy. Complexation was accomplished with free benzo-15-crown-5 (B15C5) and 15-crown-5 bonded to a diblock copolymer (Poly15C5). The diblock copolymer was synthesized by two controlled polymerization techniques and copper(i)-catalyzed azide-alkyne cycloaddition. Depending on the inserted cation, 1 : 1- or 1 : 2-complexes are formed. A significant difference of the stability constants was determined by concentration dependence solvent extraction with sodium or potassium salt. For Poly15C5 the stability constants increase for both salts compared to the stability constants of B15C5, which suggests a more effective complexation. Evaluation of the thermodynamics (DeltaH, DeltaS, DeltaG) of cation complexation was achieved by temperature dependence phase extraction on the basis of established thermodynamic equations. Remarkably, in all cases the entropic gain seems to be the major propulsion facilitating the complexation between alkali metal salts and crown ethers. Indeed, by using Poly15C5 a more pronounced dependency of enthalpy and entropy on the complex formation is calculated. PMID- 28590000 TI - Incorporating spectroscopic on-line monitoring as a method of detection for a Lewis cell setup. AB - A Lewis cell was designed and constructed for investigating solvent extraction systems by spectrophotometrically monitoring both the organic and aqueous phases in real time. This new Lewis cell was tested and shown to perform well compared to other previously reported Lewis cell designs. The advantage of the new design is that the spectroscopic measurement allows determination of not only metal ion concentrations, but also information regarding chemical speciation - information not available with previous Lewis cell designs. For convenience, the new Lewis cell design was dubbed COSMOFLEX (COntinuous Spectroscopic MOnitoring of Forrest's Liquid-liquid EXtraction cell). After construction performance testing was done for establishing the ideal stir speed range, UV-Vis measured concentration and D value determination. Each one of these tests was satisfactorily passed. PMID- 28590001 TI - Signal enhancement and low oxidation potentials for miniaturized ECL biosensors via N-butyldiethanolamine. AB - We present studies on ruthenium-based electrochemiluminescence (ECL) focusing on conditions supporting signal enhancement and low oxidation potentials. Low oxidation potentials (LOPs) are especially attractive for miniaturized ECL biosensors, as microfabricated electrodes tend to detach from their support when used with high currents and operated at high potentials. Furthermore, high potentials or current densities can lead to damage of typical biosensor surface coatings and biological probes. The possibility of generating LOP ECL signals at a potential below 900 mV was therefore studied for Ru(bpy)32+ with two typical coreactants, i.e. 2-(dibutylamino)ethanol (DBAE) and tripropylamine (TPA), as well as with the tertiary amine N-butyldiethanolamine (NBEA). Furthermore, the effect of buffer components and pH values on ECL signal generation was investigated. We could show a significant LOP ECL signal for NBEA. We found that Tris buffer, with its ability to form complexes with transition metal ions, has a positive influence on this ECL signal in terms of signal strength and LOP capabilities. Specifically, at basic pH values significant increases in ECL signals were observed at 900 mV and at 1.2 V. In fact, the ECL signal at 1.2 V was three times higher than the signal observed in phosphate buffer at a pH of 7, and it was thirty times higher than the ECL signal for TPA under these conditions. The LOP signal for NBEA in Tris buffer at pH 8.5 was similar to the signal obtained for TPA in phosphate buffer at pH 8.5 but three times higher than for TPA at pH 7.0. Interestingly, the coreactant DBAE was neither significantly influenced by the buffer system or pH nor did it present a valuable LOP ECL signal. Finally, it was found that high peak currents in cyclic voltammograms are not the indicators for high ECL signals, which should be obvious because the ECL mechanism requires more complex electron transfers. Overall, the standard TPA ECL at 1.2 V in phosphate buffer at pH 7.0 can successfully be replaced by NBEA ECL at 900 mV in Tris at pH 8.5 providing significantly higher signals accompanied by more gentle electrochemical conditions. PMID- 28590003 TI - A [Ce21] keplerate. AB - The solvothermal reaction between Ce(NO3)3.6H2O, 2-amino-isobutyric acid, 2 hydroxy-1-naphthaldehyde and 2-amino-2-methyl-1,3-propanediol in MeOH, in the presence of base, leads to the formation of a unique [CeCe ] keplerate cage. PMID- 28590004 TI - Chemoenzymatic synthesis of optically active phenolic 3,4-dihydropyridin-2-ones: a way to access enantioenriched 1,4-dihydropyridine and benzodiazepine derivatives. AB - A chemoenzymatic approach for the synthesis of optically active 4-(3 acetoxyphenyl)-5-(alkoxycarbonyl)-6-methyl-3,4-dihydropyridin-2-ones (3,4-DHP-2 ones) and their hydroxyphenyl derivatives has been developed, the key step being a Candida rugosa lipase (CRL)-catalyzed hydrolysis reaction. As a result, different optically active 3,4-DHP-2-ones have been prepared with very high enantiomeric excesses (ee = 94-99%) and good yields. The enantioenriched 3,4-DHP 2-ones have easily been converted into highly functionalized (R)- and (S)-1,4 dihydropyridines (1,4-DHPs) by means of a Vilsmeier-Haack reaction. Finally, the coupling of the 1,4-DHPs with benzene-1,2-diamine using TFA as an acid promoter provided us the corresponding optically active hybrid 1,5-benzodiazepine-1,4 dihydropyridine (BZD-DHP) derivatives. No racemization took place in these processes and all optically active compounds were obtained in excellent yields. PMID- 28590005 TI - Synthesis, structures and thermal decomposition of ammine MxB12H12 complexes (M = Li, Na, Ca). AB - A series of ammine metal-dodecahydro-closo-dodecaboranes, MxB12H12.nNH3 (M = Li, Na, Ca) were synthesized and their structural and thermal properties studied with in situ time-resolved synchrotron radiation powder X-ray diffraction, thermal analysis, Fourier transformed infrared spectroscopy, and temperature-programmed photographic analysis. The synthesized compounds, Li2B12H12.7NH3, Na2B12H12.4NH3 and CaB12H12.6NH3, contain high amounts of NH3, 43.3, 26.6 and 35.9 wt% NH3, respectively, which can be released and absorbed reversibly at moderate conditions without decomposition, thereby making the closo-boranes favorable 'host' materials for ammonia or indirect hydrogen storage in the solid state. In this work, fifteen new ammine metal dodecahydro-closo-dodecaborane compounds are observed by powder X-ray diffraction, of which six are structurally characterized, Li2B12H12.4NH3, Li2B12H12.2NH3, Na2B12H12.4NH3, Na2B12H12.2NH3, CaB12H12.4NH3 and CaB12H12.3NH3. Li2B12H12.4NH3 and Na2B12H12.4NH3 are isostructural and monoclinic (P21/n) whereas Na2B12H12.2NH3 and CaB12H12.3NH3 are both trigonal with space groups P3[combining macron]m1 and R3[combining macron]c, respectively. Generally, coordination between the metal and the icosahedral closo borane anion is diverse and includes point sharing, edge sharing, or face sharing, while coordination of ammonia always occurs via the lone pair on nitrogen to the metal. Furthermore, a liquid intermediate is observed during heating of Li2B12H12.7NH3. This work provides deeper insight into the structural, physical, and chemical properties related to thermal decomposition and possible ammonia and hydrogen storage. PMID- 28590007 TI - Evidence for Auditory-Motor Impairment in Individuals With Hyperfunctional Voice Disorders. AB - Purpose: The vocal auditory-motor control of individuals with hyperfunctional voice disorders was examined using a sensorimotor adaptation paradigm. Method: Nine individuals with hyperfunctional voice disorders and 9 individuals with typical voices produced sustained vowels over 160 trials in 2 separate conditions: (a) while experiencing gradual upward perturbations in the fundamental frequency (fo) of their auditory feedback (shift-up) and (b) under no auditory perturbation (control). The shift-up condition consisted of 4 ordered (fixed) phases: baseline (no perturbation), ramp (gradual increases in heard fo), hold (a consistently higher heard fo), and after-effect (no perturbation). Adaptive responses were defined as the difference in produced fo during control and shift-up conditions. Results: Adaptive responses were significantly different between groups. Individuals with typical voices generally showed compensatory adaptive responses, with decreased fo during the ramp and hold phases. Conversely, many individuals with hyperfunctional voice disorders instead displayed the opposite effect by following the direction of the perturbation. When fo was experimentally increased, speakers further increased their fo. Conclusion: Results indicate that some individuals diagnosed with hyperfunctional voice disorders have disrupted auditory-motor control, suggesting atypical neurological function. These findings may eventually allow for the development of new interventions for hyperfunctional voice disorders. PMID- 28590008 TI - Time-limited environments affect the evolution of egg-body size allometry. AB - Initial offspring size is a fundamental component of absolute growth rate, where large offspring will reach a given adult body size faster than smaller offspring. Yet, our knowledge regarding the coevolution between offspring and adult size is limited. In time-constrained environments, organisms need to reproduce at a high rate and reach a reproductive size quickly. To rapidly attain a large adult body size, we hypothesize that, in seasonal habitats, large species are bound to having a large initial size, and consequently, the evolution of egg size will be tightly matched to that of body size, compared to less time-limited systems. We tested this hypothesis in killifishes, and found a significantly steeper allometric relationship between egg and body sizes in annual, compared to nonannual species. We also found higher rates of evolution of egg and body size in annual compared to nonannual species. Our results suggest that time constrained environments impose strong selection on rapidly reaching a species specific body size, and reproduce at a high rate, which in turn imposes constraints on the evolution of egg sizes. In combination, these distinct selection pressures result in different relationships between egg and body size among species in time-constrained versus permanent habitats. PMID- 28590009 TI - Effect of rMnSOD on Sodium Reabsorption in Renal Proximal Tubule in Ochratoxin A Treated Rats. AB - Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus and Penicillium that represent toxic real threat for human beings and animal health. In this study we evaluated the effect of a new recombinant mitochondrial manganese containing superoxide dismutase (rMnSOD) on oxidative stress and on the alterations of fluid reabsorption in renal proximal tubule (PT) as possible causes of OTA nephrotoxicity. Finally, we have measured the concentration of O2- in the kidney through dihydroethidium assay (DHE) and nitric oxide (NO) concentration through nitrites and nitrates assay. Male Sprague Dawley rats weighing 120-150 g were treated for 14 days by gavage, as follows: Control group, 12 rats received a corresponding amount of saline solution (including 10% DMSO); rMnSOD group, 12 rats treated with rMnSOD (10 ug/kg bw); OTA group, 12 rats treated with OTA (0.5 mg/kg bw) dissolved in 10% DMSO and then scaled to required volume with corn oil; rMnSOD + OTA, 12 rats treated with rMnSOD (10 ug/kg bw) plus OTA (0.5 mg/kg bw). Our results have shown that rMnSOD restores the alteration of reabsorption in PT in rats treated with OTA plus rMnSOD, probably through the response to pressure natriuresis, where nitric oxide plays a key role. Moreover, rMnSOD prevents the nephrotoxicity induced by OTA probably restoring the balance between superoxide and NO that is most probably the cause of hypertension and renal functional alterations through the inhibition of NO synthase. In conclusion these data provide important information for understanding of mechanism of toxic action of OTA. J. Cell. Biochem. 119: 424-430, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590010 TI - Proton Pump Inhibitors and Risk of Mild Cognitive Impairment and Dementia. AB - OBJECTIVES: To examine the risk associated with the use of proton pump inhibitors (PPIs) of conversion to mild cognitive impairment (MCI), dementia, and specifically Alzheimer's disease (AD). DESIGN: Observational, longitudinal study. SETTING: Tertiary academic Alzheimer's Disease Centers funded by the National Institute on Aging. PARTICIPANTS: Research volunteers aged 50 and older with two to six annual visits; 884 were taking PPIs at every visit, 1,925 took PPIs intermittently, and 7,677 never reported taking PPIs. All had baseline normal cognition or MCI. MEASUREMENTS: Multivariable Cox regression analyses evaluated the association between PPI use and annual conversion of baseline normal cognition to MCI or dementia or annual conversion of baseline MCI to dementia, controlling for demographic characteristics, vascular comorbidities, mood, and use of anticholinergics and histamine-2 receptor antagonists. RESULTS: Continuous (always vs never) PPI use was associated with lower risk of decline in cognitive function (hazard ratio (HR) = 0.78, 95% confidence interval (CI) =0.66-0.93, P = .005) and lower risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.69-0.98, P = .03). Intermittent use was also associated with lower risk of decline in cognitive function (HR = 0.84, 95% CI = 0.76-0.93, P = .001) and risk of conversion to MCI or AD (HR = 0.82, 95% CI = 0.74-0.91, P = .001). This lower risk was found for persons with normal cognition or MCI. CONCLUSION: Proton pump inhibitors were not associated with greater risk of dementia or of AD, in contrast to recent reports. Study limitations include reliance on self-reported PPI use and lack of dispensing data. Prospective studies are needed to confirm these results to guide empirically based clinical treatment recommendations. PMID- 28590012 TI - Swiprosin-1: Its Expression and Diverse Biological Functions. AB - Swiprosin-1/EFhd2 is a Ca2+ binding adapter protein involved in the various cellular functions. Swiprosin-1 is significantly upregulated in a number of pathological conditions of inflammation, neurodegeneration, and cancer. Swiprosin 1 associated with actin and its expression level amplifies the production of proinflammatory mediators and modulates the activation of transcription factor during immune cells activation. This review aims at providing an overview of the expression and function of swiprosin-1/EFhd2 in various pathophysiological conditions. We also discussed the key role of swiprosin-1 in immune cell activation, cell migration, apoptosis, humoral immunity, cancer invasion and metastasis, neuronal transport, and major signaling cascades. J. Cell. Biochem. 119: 150-156, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590011 TI - AKT as Locus of Hydrogen Bond Network in Cancer. AB - Generation and maintenance of a cancer complexity and robustness are impossible without hydrogen element. It is essential element for the cancer signaling through the AKT locus. Hyperactivated AKT locus by a positive feedback loops from the cancer hypoxic microenvironment generates a hydrogen bond network. Such network initiates protein-protein interaction at the AKT active site and at the same time stabilizes signal propagation. A hydrogen bond network conforms an entropy/enthalpy energetic process used for the interconversion of the AKT protein in metastasis formation and maintenance. Targeting the AKT locus by the redox balance change or hydrogen balance change or proton beam radiation disrupts a hydrogen bond network leading to the disappearance of a cancer complexity and robustness causing failure of the complex energy system in solid cancers and hematological malignancy. J. Cell. Biochem. 119: 130-133, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590013 TI - Prophage as a genetic reservoir: Promoting diversity and driving innovation in the host community. AB - Sequencing of bacterial genomes has revealed an abundance of prophage sequences in many bacterial species. Since these sequences are accessible, through recombination, to infecting phages, bacteria carry an arsenal of genetic material that can be used by these viruses. We develop a mathematical model to isolate the effects of this phenomenon on the coevolution of temperate phage and bacteria. The model predicts that prophage sequences may play a key role in maintaining the phage population in situations that would otherwise favor host cell resistance. In addition, prophage recombination facilitates the existence of multiple phage types, thus promoting diverse co-existence in the phage-host ecosystem. Finally, because the host carries an archive of previous phage strategies, prophage recombination can drive waves of innovation in the host cell population. PMID- 28590014 TI - Annular itchy rash in a woman with chronic pancreatitis. PMID- 28590016 TI - NHF and hypercapnia: How brief can you look? PMID- 28590015 TI - Mucinous adenocarcinoma of prostate and prostatic adenocarcinoma with mucinous components: a clinicopathological analysis of 143 cases. AB - AIM: The clinical significance of mucinous prostatic adenocarcinoma (PCa) remains uncertain. METHODS: From 6440 cases of PCa treated by radical prostatectomy from 2009 to 2014, mucinous components of 5-100% were found in 143 (2.2%) cases. RESULTS: The mean age was 61.4 years, mean pre-operative serum prostate-specific antigen (PSA) was 7.8 ng/ml and clinical stage category was cT1 in 81% and cT2 in 19% of cases. Cases were graded using the 2014 International Society of Urological Pathology recommendation of grading underlying architecture, and Gleason scores (GS) were 3 + 4 in 13.3%, 4 + 3 in 54.5%, 4 + 4 in 2.1%, 3 + 4 or 4 + 3 with tertiary 5 in 11.9% and 9-10 in 18.2%. The mucinous component invariably had a high-grade component. Extraprostatic extension was found in 46.8% of cases. In 21.6%, tumour volume was >=3 cm3 and 9.7% had surgical margin positivity. Seminal vesicle involvement was found in 6.9%. In 73 cases the mucinous component was >25%, and when cases were divided on the basis of the area of mucin present (<=25 versus >25%) there was no significant difference between clinical or pathological features. Similar findings were achieved when cases were compared with grade-matched non-mucinous carcinoma controls. The 5-year biochemical recurrence rates for mucinous versus non-mucinous cancer were 12.5 versus 17% (P = 0.15). CONCLUSION: PCa with mucinous components is often high grade; however, the prognosis appears to be similar to non-mucinous cancers of similar GS. PMID- 28590017 TI - Fibrotic focus: An important parameter for accurate prediction of a high level of tumor-associated macrophage infiltration in invasive ductal carcinoma of the breast. AB - Our group and others have previously reported that a fibrotic focus is a very useful histological factor for the accurate prediction of the outcome of patients with invasive ductal carcinoma of the breast. We classified 258 cases of invasive ductal carcinoma into those with and those without a fibrotic focus to investigate whether the presence of a fibrotic focus was significantly associated with the degree of tumor-associated macrophage (CD68, CD163 or CD204-positive) infiltration or whether the presence of tumor-associated macrophage infiltration heightened the malignant potential of invasive ductal carcinoma with a fibrotic focus. Multiple regression analyses demonstrated that a fibrotic focus was the only factor that was significantly associated with a high level of CD68-, CD163- or CD204-positive tumor-associated macrophage infiltration. The combined assessment of the presence or absence of a fibrotic focus and a high or a low level of CD204-positive tumor-associated macrophage infiltration clearly demonstrated that CD204-positive tumor-associated macrophage infiltration had a significant prognostic power only for patients with invasive ductal carcinoma with a fibrotic focus in multivariate analyses; CD204-positive tumor-associated macrophages might only exert a significant effect on tumor progression when a fibrotic focus is present within the invasive ductal carcinoma of the breast. PMID- 28590018 TI - Reply to "letter to the editor: Is obesity related to postexercise cardiac autonomic recovery?" PMID- 28590019 TI - Afatinib Decreases P-Glycoprotein Expression to Promote Adriamycin Toxicity of A549T Cells. AB - We investigated the reversal effect of afatinib (AFT) on activity of adriamycin (ADR) in A549T cells and clarified the related molecular mechanisms. A549T cells overexpressing P-glycoprotein (P-gp) were resistant to anticancer drug ADR. AFT significantly increased the antitumor activity of ADR in A549T cells. AFT increased the intracellular concentration of ADR by inhibiting the function and expression of P-gp at mRNA and protein levels in A549T cells. Additionally, the reversal effect of AFT on P-gp mediated multidrug resistance (MDR) might be related to the inhibition of PI3K/Akt pathway. Cotreatment with AFT and ADR could enhance ADR-induced apoptosis and autophagy in A549T cells. Meanwhile, the co treatment significantly induced cell apoptosis and autophagy accompanied by increased expression of cleaved caspase-3, PARP, LC3B-II, and beclin 1. Apoptosis inhibitors had no significant effect on cell activity, while autophagy inhibitors decreased cell viability, suggesting that autophagy may be a self protective mechanism of cell survival in the absence of chemotherapy drugs. Interestingly, when combined with AFT and ADR, inhibition of apoptosis and/or autophagy could enhance cell viability. These results indicated that in addition to inhibit P-gp, ADR-induced apoptosis, and autophagy promoted by AFT contributed to the antiproliferation effect of combined AFT and ADR on A549T cells. These findings provide evidence that AFT combined ADR may achieve a better therapeutic effect to lung cancer in clinic. J. Cell. Biochem. 119: 414-423, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590020 TI - Reply: QT interval measurements in patients with left bundle branch block. There is yet more to learn about repolarization. PMID- 28590021 TI - GLUT-1 expression of pulmonary mixed squamous cell and glandular papilloma may be associated with high SUVmax on fluorodeoxyglucose-positron emission tomography. PMID- 28590023 TI - Unravelling the impact of early life exposures on lung structure and function in the developmental origins of asthma. PMID- 28590022 TI - On the significance of craniosynostosis in a case of Kabuki syndrome with a concomitant KMT2D mutation and 3.2 Mbp de novo 10q22.3q23.1 deletion. AB - Craniosynostosis has rarely been described in patients with Kabuki syndrome. We report here a boy with facial asymmetry due to combined premature synostosis of the right coronal and sagittal sutures as well as several symptoms reminiscent of Kabuki syndrome (KS). Our case supports previous observations and suggests that craniosynostosis is a part of the KS phenotype. The uniqueness of our case is the sporadic co-occurrence of two genetic disorders, that is, a de novo frameshift variant in the KMT2D gene and a de novo 3.2 Mbp 10q22.3q23.1 deletion. Our findings emphasize the importance of the initial clinical assessment of children with craniosynostosis and that genomic and monogenic disorders, such as Kabuki syndrome, should be considered among the differential diagnoses of syndromic forms of craniosynostosis. PMID- 28590024 TI - One-pot synthesis of fluorescent nitrogen-doped carbon dots with good biocompatibility for cell labeling. AB - Here we report an easy and economical hydrothermal carbonization approach to synthesize the fluorescent nitrogen-doped carbon dots (N-CDs) that was developed using citric acid and triethanolamine as the precursors. The synthesis conditions were optimized to obtain the N-CDs with superior fluorescence performances. The as-prepared N-CDs are monodispersed sphere nanoparticles with good water solubility, and exhibited strong fluorescence, favourable photostability and excitation wavelength-dependent behavior. Furthermore, the in vitro cytotoxicity and cellular labeling of N-CDs were investigated using the rat glomerular mesangial cells. The results showed the N-CDs have more inconspicuous cytotoxicity and better biosafety in comparison with ZnSe quantum dots, although both targeted the cells successfully. Considering their admirable photostability, low toxicity and good compatibility, the as-obtained N-CDs could have potential applications in biosensors, cellular imaging, and other fields. PMID- 28590026 TI - Efficient approach for the extraction of proanthocyanidins from Cinnamomum longepaniculatum leaves using ultrasonic irradiation and an evaluation of their inhibition activity on digestive enzymes and antioxidant activity in vitro. AB - Proanthocyanidins were separated for the first time from Cinnamomum longepaniculatum leaves. An experiment-based extraction strategy was used to research the efficiency of an ultrasound-assisted method for proanthocyanidins extraction. The Plackett-Burman design results revealed that the ultrasonication time, ultrasonic power and liquid/solid ratio were the most significant parameters among the six variables in the extraction process. Upon further optimization of the Box-Behnken design, the optimal conditions were obtained as follows: extraction temperature, 100 degrees C; ethanol concentration, 70%; pH 5; ultrasonication power, 660 W; ultrasonication time, 44 min; liquid/solid ratio, 20 mL/g. Under the obtained conditions, the extraction yield of the proanthocyanidins using the ultrasonic-assisted method was 7.88 +/- 0.21 mg/g, which is higher than that obtained using traditional methods. The phloroglucinolysis products of the proanthocyanidins, including the terminal units and derivatives from the extension units, were tentatively identified using a liquid chromatography with tandem mass spectrometry analysis. Cinnamomum longepaniculatum proanthocyanidins have promising antioxidant and anti nutritional properties. In summary, an ultrasound-assisted method in combination with a response surface experimental design is an efficient methodology for the sufficient isolation of proanthocyanidins from Cinnamomum longepaniculatum leaves, and this method could be used for the separation of other bioactive compounds. PMID- 28590025 TI - APOBEC3G is increasingly expressed on the human uterine cervical intraepithelial neoplasia along with disease progression. AB - PROBLEM: APOBEC3G (A3G) is a cytidine deaminase that exhibits antiviral activity by introducing C-to-T hypermutation in viral DNA. We recently observed the distinct presence of C-to-T hypermutation of human papillomavirus DNA in uterine cervical intraepithelial neoplasia (CIN), suggesting the possible involvement of A3G in the mutation-inducing process. Consequently, we investigated the association of A3G expression with CIN progression in this study. METHOD OF STUDY: Patients who had undergone cervical conization due to CIN1 (n=11), CIN2 (n=9), CIN3 (n=12), and micro-invasive squamous cell carcinoma (n=2) were included. The expression profiles of A3G and p16 proteins in cervical lesions and A3G-positive immune cells around the lesions were examined by immunohistochemistry. RESULTS: Immunoreactive A3G protein was detected in the CIN and squamous cell carcinoma lesions. Its expression intensity and positive areas were increased and spread in accordance with the progression of CIN, respectively. The co-expression of p16 was observed on the A3G-positive atypical cells. The numbers of A3G-positive immune cells in CIN3 lesions were significantly higher than those of CIN1-2 lesions. CONCLUSION: These findings indicate that A3G is associated with CIN, suggesting its important roles in human papillomavirus-induced pathophysiological processes such as CIN progression and viral elimination. PMID- 28590027 TI - A colorimetric and fluorescent chemosensor for selective detection of Cu2+ based on a new diarylethene with a benzophenone hydrazone unit. AB - A new photochromic diarylethene based on benzophenone hydrazone has been synthesized. Its photochromic and fluorescent properties changed upon alternating irradiation with UV/Vis light and adding Cu2+ /EDTA in methanol, which showed that the diarylethene could be served as a colorimetric and fluorescent chemosensor for selective detection of Cu2+ based on internal charge transfer processes. The colorimetric and turn-off fluorescent selective detection of Cu2+ was attributed to the 2:1 complex of the diarylethene and Cu2+ . The binding constant (Ka) was 1.53 * 104 L mol-1 and the limit of detection of the diarylethene for Cu2+ was calculated to be 1.45 * 10-6 mol L-1 . In addition, the metal-responsive photochromic behavior of diarylethene was applied successfully to the construction of a molecular logic circuit. PMID- 28590028 TI - Phenotypic plasticity drives a depth gradient in male conspicuousness in threespine stickleback, Gasterosteus aculeatus. AB - Signal evolution is thought to depend on both a signal's detectability or conspicuousness (signal design) as well as any extractable information it may convey to a potential receiver (signal content). While theoretical and empirical work in sexual selection has largely focused on signal content, there has been a steady accrual of evidence that signal design is also important for trait evolution. Despite this, relatively little attention has been paid to spatial variation in the conspicuousness of a given signal, especially over small spatial scales (relative to an organism's dispersal distance). Here, we show that visual signals of male threespine stickleback vary in conspicuousness, depending on a male's nest depth within a given lake. Deeper nesting males were typically more chromatically conspicuous than shallow nesting males. This trend is partly because all male stickleback are more conspicuous in deep optical environments. However, deep males are even more conspicuous than environmentally driven null expectations, while shallow males tend to be disproportionally cryptic. Experimental manipulation of male nesting depth induced plastic changes in nuptial color that replicated the natural gradients in conspicuousness. We discuss a number of potential mechanisms that could produce depth gradients in conspicuousness in male stickleback, including concomitant depth gradients in diet, predation pressure, male/female density, female preference, and opportunity for sexual selection. PMID- 28590030 TI - Resonance Rayleigh scattering methods for the determination of chitosan with Congo red as probe. AB - Two methods were presented for the sensitive and selective determination of chitosan (CTS) with Congo red (CR) as probe based on resonance Rayleigh scattering (RRS) intensities in health products. In weakly acidic buffer solution, the binding of CTS to CR, could result in the enhancement of the RRS intensities. Moreover, after adding OP emulsifier (octyl-phenyl polyoxyethylene ether) to the system, the RRS intensities showed more significantly enhancement. The maximum RRS signals for the CTS-CR system and the CTS-CR-OP system were located at 380 nm and 376 nm, respectively. Under optimum experimental conditions, the increased RRS intensities (DeltaI) of these two systems were linear to CTS concentration in the range of 0.40-8.00 MUg/ml and 0.05-1.00 MUg/ml. Their limits of detection (LOD) were 44.81 ng/ml and 6.99 ng/ml, which indicated that the latter system was more sensitive than the former. In this work, the optimum conditions and the effects of some foreign substances on the determination were studied. In addition, the effect of the molecular weight of CTS and the reasons for the enhancement of resonance light scattering were discussed. Finally, these two methods were applied to the determination of chitosan in health products with satisfactory results. PMID- 28590029 TI - Treatment of heterotopic caesarean scar pregnancy complicated with post termination increase in size of residual mass and morbidly adherent placenta. AB - We report a case of a secundipara with heterotopic cesarean scar pregnancy (HCSP) treated with potassium chloride injection into the ectopic embryo followed by sac aspiration. The remaining "mass" increased in size threefold and was surrounded by a rich vascular network. An arteriovenous malformation was suspected; however, appropriate treatment was precluded because of the viability of the ectopic gestation. Sonographic examination revealed a morbidly adherent placenta, and attempt to resect the mass laparoscopically was complicated by bleeding that required hysterectomy. This case illustrates a complication of the intervention performed to preserve the intrauterine gestation in case of HCSP. (c) 2017 Wiley Periodicals, Inc. J Clin Ultrasound 46:227-230, 2018. PMID- 28590031 TI - Progress and Application of CRISPR/Cas Technology in Biological and Biomedical Investigation. AB - Based on the tremendous progress of the understanding on the CRISPR-Cas systems, the application CRISPR/Cas technology has been extended into increasing scenarios in biological and biomedical investigation. The potency of gene editing has been greatly improved by the rapid development of engineered Cas9 variants and modified CRISPR platforms. As advanced sequencing technology identified vast causative genetic basis for human diseases, CRISPR toolkits are now able to mediate precise genetic disruption or correction in vitro and in vivo. In this review, we have discussed the recent development of the CRISPR/Cas gene-editing technology and the extensive applications of the CRISPR platforms in biological and biomedical investigation, including disease modeling in animal and human cell line, development of gene therapy, as well as high-throughput genetic screening. J. Cell. Biochem. 118: 3061-3071, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28590033 TI - Radiological and pathological evaluation of the level of arterial division after colon cancer surgery. AB - AIM: In aiming to cure patients with colorectal cancer surgery, the surgeon must carefully dissect the mesocolon and mesorectum and divide the vascular pedicle near to its origin so as to include all local lymph nodes. This has been termed complete mesocolic excision. The distance from the distal vascular tie to the bowel wall in the fixed specimen is an indication as to the quality of surgery but this does not assess the length of the residual vascular pedicle and, by implication, residual lymph nodes. The aim of this study was to establish if our surgeons were carrying out complete mesocolic excision by assessing the length of the proximal arterial pedicle and relating this to arterial length in the fixed specimen. METHOD: This was a single centre prospective study of patients undergoing elective surgery for locally advanced colorectal cancer. An abdominal and pelvic CT scan was performed 2 days postoperatively and a radiologist blinded to the operative procedure measured the length of the residual arterial stump. Similarly, the length of the vessel in the fixed resected specimen and lymph node yield were also recorded. RESULTS: Fifty-two patients were recruited. The mean length of the residual arterial stump was 38 mm (95% CI: 33-43), which was significantly longer than the < 10 mm recommended in guidelines (P < 0.0001). The mean length was 31 mm (95% CI: 25-37) and 49 mm (95% CI: 40-57) for left and right sided resections respectively. There was no correlation between the residual arterial stump and the pathology. CONCLUSIONS: The residual arterial length was greater than suggested by guidelines and may indicate that our surgery is less radical than we planned. Caution should be taken when using pathological measurements of vascular ligation as it may not reflect the height of the pedicle division. PMID- 28590034 TI - Pigmented macular variant of chronic cutaneous lupus erythematosus: an under recognized subset in dark skin. PMID- 28590032 TI - Epithelial-mesenchymal transition in cancer metastasis through the lymphatic system. AB - It was already in the 18th century when the French surgeon LeDran first noted that breast cancer patients with spread of tumor cells to their axillary lymph nodes had a drastically worse prognosis than patients without spread (LeDran et al., ). Since then, metastatic spread of cancer cells to regional lymph nodes has been established as the most important prognostic factor in many types of cancer (Carter et al., ; Elston and Ellis, ). However, despite its clinical importance, lymph metastasis remains an underexplored area of tumor biology. Fundamental questions, such as when, how, and perhaps most importantly, why tumor cells disseminate through the lymphatic system, remain largely unanswered. Accordingly, no treatment strategies exist that specifically target lymph metastasis. The identification of epithelial-mesenchymal transition (EMT) as a mechanism, which allows cancer cells to dedifferentiate and acquire enhanced migratory and invasive properties, has been a game changer in cancer research. Conceptually, EMT provides an explanation for why epithelial cancers with poor differentiation status are generally more aggressive and prone to metastasize than more differentiated cancers. Inflammatory cytokines, such as TGF-beta, which are produced and secreted by tumor-infiltrating immune cells, are potent inducers of EMT. Thus, reactivation of EMT also links cancer-related inflammation to invasive and metastatic disease. Recently, we found that breast cancer cells undergoing TGF-beta-induced EMT acquire properties of immune cells allowing them to disseminate in a targeted fashion through the lymphatic system similar to activated dendritic cells during inflammation. Here, we review our current understanding of the mechanisms by which cancer cells spread through the lymphatic system and the links to inflammation and the immune system. We also emphasize how imaging techniques have the potential to further expand our knowledge of the mechanisms of lymph metastasis, and how lymph nodes serve as an interface between cancer and the immune system. PMID- 28590035 TI - Interindividual epigenetic variability: Sound or noise? AB - Interindividual variability is an inherent characteristic of biological systems. Whereas the underlying molecular sources of interindividual variability remain poorly understood, recent work by Ecker et al. (Ecker S, Chen L, Pancaldi V, Bagger FO, et al. 2017. Genome Biol 18: 18.) sheds light on the characterization of this phenomenon in a complex biological scenario. By combining data from the BLUEPRINT Epigenome Project with a novel analytical approach, these authors were able to measure the degree of transcriptional and epigenetic variability across a wide panel of samples and types of immune cell. Interestingly, neutrophils displayed increased variability compared to monocytes and T cells, which may be related to the crucial role of the former as an initial mediator of immune responses. Here we review recent literature in this area, and discuss some important issues raised by these innovative analyses. Furthermore, we summarize other potential sources of epigenetic variability, such as epigenetic drift and the epigenetic clock, as well as the current ongoing direction of the field. PMID- 28590036 TI - T regulatory cells and other lymphocyte subsets in patients with bullous pemphigoid. AB - BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune blistering disease, and is associated with autoantibodies to the hemidesmosomal BP autoantigens BPAG1 and BPAG2. AIM: We aimed to investigate the significance of T regulatory cells and other lymphocyte subsets in patients with BP. METHODS: In total, 31 inpatients with BP were treated with systemic prednisolone in a tapered dose regimen, while 28 healthy individuals matched for age and sex served as the healthy control (HC) group., Blood samples were taken at baseline and after treatment, and levels of inducer/helper and suppressor/cytotoxic T lymphocytes, B lymphocytes, natural killer cells, CD4+CD25++CD127- cells were assessed by flow cytometry, while CD4, CD8, and FOXP3 positivity were assessed by immunohistochemistry, and FOXP3 mRNA was assessed by reverse transcription (RT) PCR. RESULTS: Flow cytometry showed that numbers of CD8+ and CD4+CD25++CD127- cells were significantly increased, while the number of CD4+ cells and the CD4/CD8 ratio were significantly decreased at baseline and after therapy in patients with BP compared with HCs. Immunohistology revealed that CD4+, CD8+ and FOXP3+ cells were significantly increased at baseline and post-treatment in patients with BP compared with HCs. FOXP3 mRNA levels were significantly increased in the blood of patients with BP compared with HCs. CONCLUSION: These results indicate that increased numbers of CD8+, CD4+CD25++CD127- cells and FOXP3+ cells may play a pathogenetic role during the course of BP. PMID- 28590037 TI - Epigenetic Effects of an Adenosine Derivative in a Wistar Rat Model of Liver Cirrhosis. AB - The pathological characteristic of cirrhosis is scarring which results in a structurally distorted and dysfunctional liver. Previously, we demonstrated that Col1a1 and Pparg genes are deregulated in CCl4 -induced cirrhosis but their normal expression levels are recovered upon treatment with IFC-305, an adenosine derivative. We observed that adenosine was able to modulate S-adenosylmethionine dependent trans-methylation reactions, and recently, we found that IFC-305 modulates HDAC3 expression. Here, we investigated whether epigenetic mechanisms, involving DNA methylation processes and histone acetylation, could explain the re establishment of gene expression mediated by IFC-305 in cirrhosis. Therefore, Wistar rats were CCl4 treated and a sub-group received IFC-305 to reverse fibrosis. Global changes in DNA methylation, 5-hydroxymethylation, and histone H4 acetylation were observed after treatment with IFC-305. In particular, during cirrhosis, the Pparg gene promoter is depleted of histone H4 acetylation, whereas IFC-305 administration restores normal histone acetylation levels which correlates with an increase of Pparg transcript and protein levels. In contrast, the promoter of Col1a1 gene is hypomethylated during cirrhosis but gains DNA methylation upon treatment with IFC-305 which correlates with a reduction of Col1a1 transcript and protein levels. Our results suggest a model in which cirrhosis results in a general loss of permissive chromatin histone marks which triggers the repression of the Pparg gene and the upregulation of the Col1a1 gene. Treatment with IFC-305 restores epigenetic modifications globally and specifically at the promoters of Pparg and Col1a1 genes. These results reveal one of the mechanisms of action of IFC-305 and suggest a possible therapeutic function in cirrhosis. J. Cell. Biochem. 119: 401-413, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590038 TI - Effects of oestrogen and Cimicifuga racemosa on the cardiac noradrenaline pathway of ovariectomized rats. AB - NEW FINDINGS: What is the central question of this study? We investigated the effects of oestrogen and Cimicifuga racemosa on the stellate ganglion, cardiac noradrenaline pathway and Ca2+ -calmodulin-dependent protein kinase II in ovariectomized rats. What is the main finding and its importance? The right stellate ganglion, but not the left, may be associated with decreased left ventricular noradrenaline content in ovariectomized rats. Oestrogen can reverse all changes caused by ovariectomy. Cimicifuga racemosa did not affect left ventricular noradrenaline, but decreased protein expression of beta1 -adrenergic receptor and Ca2+ -calmodulin-dependent protein kinase II. The results might explain potential effects of C. racemosa on the cardiovascular system and provide new insights into cardiovascular protection. The aim of this study was to investigate the effects of oestrogen and Cimicifuga racemosa on the stellate ganglion, cardiac noradrenaline (NA) pathway and Ca2+ -calmodulin-dependent protein kinase II (CaMK II). Forty adult female Sprague-Dawley rats were randomly divided into the following four groups: sham operated (SHAM); ovariectomized (OVX); ovariectomized with oestrogen treatment (E2); and ovariectomized with C. racemosa treatment (iCR). After 4 weeks of treatment, the NA content was determined by high-performance liquid chromatography, and dopamine beta hydroxylase (DBH) and noradrenaline transporter (NET) expression were detected by immunohistochemistry. Western blotting was used to determine NET, beta1 adrenergic receptor (beta1 -AR) and CaMK II expression. Compared with the SHAM group, body weights, DBH and NET expression in the right stellate ganglia, and NET, beta1 -AR and CaMK II expression in the left ventricles of the OVX group were increased, whereas left ventricular NA content was decreased; DBH and NET expression in the left stellate ganglion was not significantly different. The indexes of the E2 group were similar to those of the SHAM group. Moreover, in the iCR group, DBH, NET, beta1 -AR and CaMK II expression was decreased; NET expression and NA content of the left ventricle remained unchanged. Our conclusions are as follows. First, the right stellate ganglion, but not the left, may be associated with decreased left ventricular NA content in OVX rats. Second, oestrogen increases the left ventricular NA content and adjusts the expression of DBH and NET in the right stellate ganglion and restores beta1 -AR and CaMK II protein expression to normal levels. Third, C. racemosa does not affect left ventricular NA, but decreases the protein expression of beta1 -AR and CaMK II. PMID- 28590040 TI - Orbital Analysis of Carbon-13 Chemical Shift Tensors Reveals Patterns to Distinguish Fischer and Schrock Carbenes. AB - Fischer and Schrock carbenes display highly deshielded carbon chemical shifts (>250 ppm), in particular Fischer carbenes (>300 ppm). Orbital analysis of the principal components of the chemical shift tensors determined by solid-state NMR spectroscopy and calculated by a 2-component DFT method shows specific patterns that act as fingerprints for each type of complex. The calculations highlight the role of the paramagnetic term in the shielding tensor especially in the two most deshielded components (sigma11 and sigma22 ). The paramagnetic term of sigma11 is dominated by coupling sigma(M=C) with pi*(M=C) through the angular momentum operator perpendicular to the sigma and pi M=C bonds. The highly deshielded carbon of Fischer carbenes results from the particularly low-lying pi*(M=C) associated with the CO ligand. A contribution of the coupling of pi(M=C) with sigma*(M=C) is found for Schrock and Ru-based carbenes, indicating similarities between them, despite their different electronic configurations (d0 vs. d6 ). PMID- 28590042 TI - Changes in arrhythmogenic properties and five-year prognosis after carbon-ion radiotherapy in patients with mediastinum cancer. AB - INTRODUCTION: Carbon-ion irradiation of rabbit hearts has improved left ventricular conduction abnormalities through upregulation of gap junctions. However, to date, there has been no investigation on the effect of carbon-ion irradiation on electrophysiological properties in human. We investigated this effect in patients with mediastinum extra-cardiac cancer treated with carbon-ion radiotherapy that included irradiating the heart. METHODS AND RESULTS: In April December 2009, eight patients were prospectively enrolled (including two male, aged 72.5 +/- 13.0 years). They were treated with 44-72 Gray equivalent (GyE), with their hearts exposed to 1.3-19.1 GyE. High-resolution ambulatory electrocardiography was performed before and after radiotherapy to investigate arrhythmic events, late potentials (LPs), and heart rate variability. Five patients had pre-existing premature ventricular contraction (PVC)/atrial contraction (PAC) or paroxysmal atrial fibrillation (PAF)/AF; after irradiation, this improved in four patients with PVC/PAF/AF and did not deteriorate in one patient with PAC. Ventricular LP findings did not deteriorate and improved in one patient. In eight cases with available atrial LP findings, there was no deterioration, and two patients showed improvements. The low frequency/high frequency ratio of heart rate variability improved or did not deteriorate in the six patients who received radiation exposure to the bilateral stellate ganglions. During the five-year follow-up for the prognosis, six of the eight patients died because of cancer; there was no history of hospitalization for cardiac events. CONCLUSION: Although this preliminary study has several limitations, carbon-ion beam irradiation to the heart is not immediately cardiotoxic and demonstrates consistent signals of arrhythmia reduction. PMID- 28590043 TI - Effects of intranasal kinetic oscillation stimulation on heart rate variability. AB - BACKGROUND: Kinetic oscillation stimulation in the nasal cavity (KOS) has been shown to have positive symptomatic effects in subjects with non-allergic rhinitis and in patients with migraine. METHODS: To evaluate the effect of KOS on autonomic function, we assessed heart rate variability (HRV) in this small exploratory study in 12 healthy subjects. KOS treatment was performed using a minimally invasive system with a single-use catheter inserted into the nasal cavity. During treatment, the tip was inflated and oscillated with a mean pressure of 95 millibar and amplitude of the oscillations of 100 millibar at a frequency of 68 Hz. Treatment was given for 15 minutes sequentially on each side. Heart rate variability was assessed during five 30-minutes periods before, during and immediately after KOS treatment and 3.5 hours thereafter. KOS resulted in a substantial reduction of HRV. RESULTS: As compared to baseline recorded during 30 minutes preceding treatment, VLF was reduced by 65%, LF by 55%, the ratio LF/HF by 44%, with somewhat smaller observed effects in the time domain; SDNN and RMSDD were reduced by of 36% and 18%, respectively. Heart rate remained stable during treatment with minimal mean changes from 68 +/- 7 bpm before to 68 +/- 9 and 69 +/- 9 bpm during and after treatment. Reduction of HRV parameters was consistently seen in all subjects, with rapid onset and return towards baseline values during post-treatment observation periods. CONCLUSIONS: KOS has an effect on the autonomic balance with pronounced heart-rate independent reduction on HRV. PMID- 28590041 TI - Evaluating the importance of social motor synchronization and motor skill for understanding autism. AB - Impairments in social interaction and communicating with others are core features of autism spectrum disorder (ASD), but the specific processes underlying such social competence impairments are not well understood. An important key for increasing our understanding of ASD-specific social deficits may lie with the social motor synchronization that takes place when we implicitly coordinate our bodies with others. Here, we tested whether dynamical measures of synchronization differentiate children with ASD from controls and further explored the relationships between synchronization ability and motor control problems. We found (a) that children with ASD exhibited different and less stable patterns of social synchronization ability than controls; (b) children with ASD performed motor movements that were slower and more variable in both spacing and timing; and (c) some social synchronization that involved motor timing was related to motor ability but less rhythmic synchronization was not. These findings raise the possibility that objective dynamical measures of synchronization ability and motor skill could provide new insights into understanding the social deficits in ASD that could ultimately aid clinical diagnosis and prognosis. Autism Res 2017, 10: 1687-1699. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28590044 TI - Is radiation indicated for young women with early stage, node-negative breast cancer after mastectomy? A multi-institution, retrospective review. AB - The role of post-mastectomy radiation for women with node negative, early stage disease is not well-defined. The purpose of this study is to more clearly define a subset of women who are <=40 years of age with T1-T2, node negative breast cancer who may benefit from post-mastectomy radiation. Using tumor registries at two institutions, we identified 219 women <=40 years of age with T1-T2, node negative breast cancer treated with mastectomy. Of these 219 patients, 38 received post-mastectomy radiation and 181 did not. Kaplan-Meier methods and cox proportional-hazards regression models were employed for statistical analysis. There were no locoregional failures in the women receiving post mastectomy radiation, which lead to a nonsignificant increase in freedom from locoregional recurrence (P=.08). For women not receiving post-mastectomy radiation, freedom from locoregional recurrence was 94.7% and 89.7% at 5- and 10-years. Lymphovascular space invasion (LVSI) was the only factor predictive of locoregional recurrence. For women without LVSI, freedom from locoregional recurrence was 96.0% and 93.3% at 5- and 10-years respectively. For women with LVSI who did not receive post mastectomy radiation, freedom from locoregional recurrence was 89.1% at 5-years. There were no failures in the women with LVSI who received post mastectomy radiation. For women <=40 years of age with T1-2, node negative breast cancer treated with mastectomy and no post-mastectomy radiation, locoregional control is excellent in the absence of LVSI, regardless of other risk factors. In the presence of LVSI (regardless of other risk factors), the risk of locoregional recurrence is high and appears to be decreased with post-mastectomy radiation. PMID- 28590039 TI - EMT: Present and future in clinical oncology. AB - Epithelial/mesenchymal transition (EMT) has emerged as a key regulator of metastasis by facilitating tumor cell invasion and dissemination to distant organs. Recent evidences support that the reverse mesenchymal/epithelial transition (MET) is required for metastatic outgrowth; moreover, the existence of hybrid epithelial/mesenchymal (E/M) phenotypes is increasingly being reported in different tumor contexts. The accumulated data strongly support that plasticity between epithelial and mesenchymal states underlies the dissemination and metastatic potential of carcinoma cells. However, the translation into the clinics of EMT and epithelial plasticity processes presents enormous challenges and still remains a controversial issue. In this review, we will evaluate current evidences for translational applicability of EMT and depict an overview of the most recent EMT in vivo models, EMT marker analyses in human samples as well as potential EMT therapeutic approaches and ongoing clinical trials. We foresee that standardized analyses of EMT markers in solid and liquid tumor biopsies in addition to innovative tools targeting the E/M states will become promising strategies for future translation to the clinical setting. PMID- 28590045 TI - Computer-aided design and synthesis of a highly selective molecularly imprinted polymer for the extraction and determination of buprenorphine in biological fluids. AB - Buprenorphine is widely used to aid the cessation of opioids in addicted patients. To the best of our knowledge, there is no selective extraction method for buprenorphine from biological fluids. Here, we describe the synthesis of a molecularly imprinted polymer with the aid of computational design and its application for selective extraction of buprenorphine from plasma and urine. Computational design was used to study intermolecular interactions in the pre polymerization mixture by the comparison of the binding energy between buprenorphine (template) and functional monomers. The largest interaction energy of template-monomers was obtained at ratio of 1:5 buprenorphine/acrylic acid monomers. Afterwards, the molecularly imprinted polymer was synthesized through precipitation polymerization technique and was employed for selective extraction of buprenorphine. Optimization of various parameters of the molecularly imprinted polymer solid-phase extraction of buprenorphine was carried out by a design of experiment approach using a central composite design and the analyte was determined by employing high-performance liquid chromatography with UV detection. Equilibrium isotherms were studied, and results revealed that the sorption process was in adoption with Langmuir model. Maximum enrichment capacity and Langmuir constant were calculated as 18.2 mg/g and 0.797 L/mg, respectively. Kinetic studies indicated the sorption process followed a pseudo-second-order model. PMID- 28590046 TI - Applying community ecological theory to maximize productivity of cultivated biocrusts. AB - Degraded rangelands around the world may benefit from the reestablishment of lost biological soil crusts (biocrusts, soil surface cryptogamic-microbial communities). Cultivation of biocrust organisms is the first step in this process, and may benefit from harnessing species interactions. Species interactions are a dominant force structuring ecological communities. One key element of community structure, species richness, is itself important because it can promote the productivity of the entire community. Here, we use biological soil crusts as a model to test the effects of species interactions on production of biocrust materials for use in ecosystem rehabilitation. We screened eight different moss and lichen species from semiarid rangelands of Montana, USA, for growth potential under two watering regimes. Mosses generally grew well, but we were unable to cultivate the selected lichen species. We produced a >400% increase in the biomass of one species (Ceratodon purpureus). We tested whether a parasite-host relationship between two lichens could be used to enhance productivity of the parasite species, but this also resulted in no net gain of lichen productivity. Finally, we constructed all possible community combinations from a pool of five moss species to test for overyielding (community productivity exceeding that expected from the growth of community members in monoculture), and to determine both if, and the mode in which, species richness increases productivity. Polycultures yielded more than would be expected based upon the production of community constituents in monoculture. Using structural equation models, we determined that there was a modest effect of species richness on community productivity (r = 0.24-0.25), which was independent of a stronger effect of the identity of species in the community (r = 0.41-0.50). These results will contribute to the optimization of biocrust cultivation, promoting the development of this emerging ecological rehabilitation technology. PMID- 28590047 TI - Cytopathologic findings of cell block materials from the vitreous: Diagnostic distinction between intraocular lymphoma and non-lymphomatous diseases. AB - Intraocular lymphoma is a rare neoplasm that occurs only in the eyes and/or central nervous system. Diagnosis of intraocular lymphoma is difficult because its clinical manifestations mimic chronic uveitis. Pathological examination of the vitreous is one of the main diagnostic tools for intraocular lymphoma, but this is challenging due to the sparse cellularity and specimen degeneration. Here, we reviewed 33 cell block preparations from vitreous perfusion fluid in order to examine the significance of cytopathological findings for differential diagnosis using vitreous samples. The cases comprised 12 intraocular lymphomas and 21 non-lymphomatous diseases. Cytologically, vitreous samples from non lymphoma cases showed lower cellularity than the lymphoma cases. Whereas vitreous material from cases with infectious endophthalmitis showed prominent neutrophilic infiltration, material from sarcoidosis cases showed infiltration of small lymphoid cells, especially CD4-positive T cells. On the other hand, lymphoma cases showed higher cellularity, with large, irregular and atypical lymphoid cells, frequent necrotic cells in the background, and less pronounced neutrophil infiltration. Immunocytochemically, 11 of the 12 lymphoma cases were of the B cell phenotype and the remaining case was of the T/NK-cell phenotype. In conclusion, careful cytopathological examination or immunocytochemistry of vitreous material facilitates appropriate diagnosis of intraocular lymphoma. PMID- 28590048 TI - Educational needs of nurses to provide genetic services in prenatal care: A cross sectional study from Turkey. AB - The latest advances in genetics/genomics have significantly impacted prenatal screening and diagnostic tests. This cross-sectional descriptive study was conducted in inpatient and outpatient obstetric clinics in 24 hospitals in Turkey to determine knowledge of genetics related to prenatal care and the educational needs of perinatal nurses. A total of 116 nurses working in these clinics agreed to participate. The results included the level of knowledge among nurses was not affected by sociodemographic factors. Also, there is a lack of knowledge and interest in genetics among prenatal nurses and in clinical practice to provide education and counseling related to genetics in prenatal settings as a part of prenatal care. PMID- 28590050 TI - A switch-off fluorescence probe towards Pb(II) and cu(II) ions based on a calix[4]pyrrole bearing amino-quinoline group. AB - A new fluorescence receptor calix[4]pyrrole-N-(quinoline-8-yl) acetamide (CAMQ) containing a pyrrolic ring connected via the meso-position was synthesized, purified and characterized by elemental analysis, NMR and mass spectroscopy. This compound was examined for its fluorescence properties towards different metal ions e.g. Ag(I), Hg(II), Co(II), Ca(II), Ni(II), Zn(II), Cr(II), Ba(II), Fe(II), Cu(II), Pb(II)and Mg(II) ions by spectrophotometry and spectrofluorometry. It was concluded that the compound (CAMQ) possessed significantly enhanced selectivity for Pb(II) and Cu(II) ions in dimethyl sulfoxide (DMSO) even at very low concentrations (1 MUM). It exhibit 'turn-on' fluorescence when exposed to Pb(II) and Cu(II) and did so in preference to other metal ions. The binding constants, stoichiometry and quantum yields have been determined. The quenching mechanism was assessed using the Stern-Volmer equation and was also discussed. PMID- 28590051 TI - A tricorn-rhodamine fluorescent chemosensor for detection of Co2+ ions. AB - A novel chemosensor TrisRh based on tris(2-aminoethyl)amine and rhodamine 6G is designed and synthesized as a fluorescence turn-on probe for Co2+ ions that is paramagnetic with a property of quenching fluorescence. Rhodamine spirolactam forms are nonfluorescent, whereas, ring-opening of corresponding spirocyclic induced by Co2+ results in strong fluorescence emission. Upon the addition of Co2+ ions, TrisRh can display significant enhancements in absorbance and fluorescence intensity as well as evident colorific transformation, which can be perceived by the naked eye. The association stoichiometry of TrisRh to Co2+ ions was inferred to be 1:1 through Job's plot and electrospray ionization mass spectrometry analysis. The binding model was speculated from Fourier transform infrared spectra and 1 H-nuclear magnetic resonance technologies. Significantly, the limit of detection was determined to be as low as 1.22 nmol. Furthermore, TrisRh can exhibit robust anti-jamming ability against other interference metal ions. PMID- 28590049 TI - Chromatographic analysis of tryptophan metabolites. AB - The kynurenine pathway generates multiple tryptophan metabolites called collectively kynurenines and leads to formation of the enzyme cofactor nicotinamide adenine dinucleotide. The first step in this pathway is tryptophan degradation, initiated by the rate-limiting enzymes indoleamine 2,3-dioxygenase, or tryptophan 2,3-dioxygenase, depending on the tissue. The balanced kynurenine metabolism, which has been a subject of multiple studies in last decades, plays an important role in several physiological and pathological conditions such as infections, autoimmunity, neurological disorders, cancer, cataracts, as well as pregnancy. Understanding the regulation of tryptophan depletion provide novel diagnostic and treatment opportunities, however it requires reliable methods for quantification of kynurenines in biological samples with complex composition (body fluids, tissues, or cells). Trace concentrations, interference of sample components, and instability of some tryptophan metabolites need to be addressed using analytical methods. The novel separation approaches and optimized extraction protocols help to overcome difficulties in analyzing kynurenines within the complex tissue material. Recent developments in chromatography coupled with mass spectrometry provide new opportunity for quantification of tryptophan and its degradation products in various biological samples. In this review, we present current accomplishments in the chromatographic methodologies proposed for detection of tryptophan metabolites and provide a guide for choosing the optimal approach. PMID- 28590052 TI - Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment. AB - Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis. PMID- 28590054 TI - pi-Extended Dihydrophenazines with Three-State NIR Electrochromism Involving Large Conformational Changes. AB - pi-Extended dihydrophenazines were successfully prepared by oxidation of 2-(N arylamino)anthracenes. Their roof-type conformations were revealed by X-ray diffraction analysis, and the analysis of the optical properties indicated the presence of intramolecular charge-transfer processes. Upon chemical oxidation, the electronic absorption dramatically changed in a two-step fashion. The electron spin resonance (ESR) analysis revealed that, depending on the amount of oxidant added, either a paramagnetic radical cation or a diamagnetic dication was generated. The NMR analysis revealed a conformational change upon oxidation, which was supported by theoretical calculations. A three-state electrochromic behavior was observed during the electrochemical oxidation and reduction cycles, showing sequential switching between visible and near-infrared (NIR) absorption properties upon application of electrochemical stimuli. PMID- 28590053 TI - Bryostatin and its synthetic analog, picolog rescue dermal fibroblasts from prolonged stress and contribute to survival and rejuvenation of human skin equivalents. AB - Skin health is associated with the day-to-day activity of fibroblasts. The primary function of fibroblasts is to synthesize structural proteins, such as collagen, extracellular matrix proteins, and other proteins that support the structural integrity of the skin and are associated with younger, firmer, and more elastic skin that is better able to resist and recover from injury. At sub nanomolar concentrations (0.03-0.3 nM), bryostatin-1 and its synthetic analog, picolog (0.1-10 nM) sustained the survival and activation of human dermal fibroblasts cultured under the stressful condition of prolonged serum deprivation. Bryostatin-1 treatment stabilized human skin equivalents (HSEs), a bioengineered combination of primary human skin cells (keratinocytes and dermal fibroblasts) on an extracellular matrix composed of mainly collagen. Fibroblasts activated by bryostatin-1 protected the structural integrity of HSEs. Bryostatin 1 and picolog prolonged activation of Erk in fibroblasts to promote cell survival. Chronic stress promotes the progression of apoptosis. Dermal fibroblasts constitutively express all components of Fas associated apoptosis, including caspase-8, an initiator enzyme of apoptosis. Prolong bryostatin-1 treatment reduced apoptosis by decreasing caspase-8 and protected dermal fibroblasts. Our data suggest that bryostatin-1 and picolog could be useful in anti-aging skincare, and could have applications in tissue engineering and regenerative medicine. PMID- 28590055 TI - Enhanced dissolution and bioavailability of Nateglinide by microenvironmental pH regulated ternary solid dispersion: in-vitro and in-vivo evaluation. AB - OBJECTIVES: Nateglinide, an Antidiabetic drug (BCS II), shows pH-dependent solubility and variable bioavailability. The purpose of study was to increase dissolution and bioavailability of Nateglinide by development of its microenvironmental pH-regulated ternary solid dispersion (MeSD). METHODS: MeSD formulation of Nateglinide, poloxamer-188 and Na2 CO3 was prepared by melt dispersion in 1 : 2 : 0.2 w/w ratio and further characterised for solubility, In vitro dissolution, microenvironmental pH, crystallinity/amorphism, physicochemical interactions, bioavailability in Wistar rats. KEY FINDINGS: Solubility of Nateglinide was increased notably in MeSD, and its in-vitro dissolution study showed fourfold increase in the dissolution, particularly in 1.2 pH buffer. Prominent reduction in the peak intensity of X-ray powder diffraction (XRPD) and absence of endotherm in DSC thermogram confirmed the amorphism of Nateglinide in MeSD. Attenuated total reflectance Fourier transform infrared spectra revealed the hydrogen bond interactions between Nateglinide and poloxamer-188. In-vivo study indicated that MeSD exhibited fourfold increase in area under curve over Nateglinide. Tmax of MeSD was observed at 0.25 h, which is beneficial for efficient management of postprandial sugar. Instead of mere transformation of the Nateglinide to its amorphous form as evidenced by DSC and XRPD, formation of a soluble carboxylate compound of Nateglinide in MeSD was predominantly responsible for dissolution and bioavailability enhancement. CONCLUSIONS: The study demonstrates the utility of MeSD in achieving pH independent dissolution, reduced Tmax and enhanced bioavailability of Nateglinide. PMID- 28590056 TI - R202Q/M694V as novel MEFV gene mutations in chronic periodontitis and familial Mediterranean fever. AB - BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) and chronic periodontitis are inflammatory diseases leading to an increase in the number of inflammasomes. To date, no published studies have reported on mutations in the Mediterranean fever (MEFV) gene in patients with chronic periodontitis, although the roles of MEFV gene mutations in FMF and FMF-associated amyloidosis (FMF-A) are well known. Therefore, the aim of this study was to evaluate the frequencies of MEFV gene mutations and serum amyloid A (SAA) and high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic periodontitis, FMF and FMF-A. MATERIAL AND METHODS: The study population included 122 patients with FMF and 128 subjects who were systemically healthy. Clinical periodontal parameters, including the plaque index, gingival index, probing pocket depth, clinical attachment level and percentage of bleeding on probing were recorded. Blood samples were obtained from patients with FMF and systemically healthy controls, and all mutations located on exons 2 and 10 of the MEFV gene were analyzed by DNA Sanger Sequencing, which is the gold standard. SAA and high-sensitive CRP levels were also assessed. RESULTS: Mean gingival index, percentage of bleeding on probing, probing pocket depth and clinical attachment level, and the levels of SAA and hs-CRP were higher in the FMF-A group than those in the FMF and control groups. The two most relevant mutations in patients with FMF were heterozygous M694V (46.2%), and heterozygous R202Q (32.7%). The frequencies of the homozygous M694V and R202Q mutations in the FMF-A group were 53.8% and 46.1%, respectively. The complex R202Q/M694V homozygous state led to an increased risk of chronic periodontitis (odds ratio: 3.6), and FMF-A (odds ratio: 7.6). CONCLUSION: This is the first study to report the R202Q mutation in patients with periodontitis. Furthermore, the MEFV gene-mediated inflammatory pathway increased serum acute phase reactants, and the changes in the R202Q and M694V could play a role in inflammatory-genetic diseases, such as FMF, FMF-associated amyloidosis and chronic periodontitis. PMID- 28590057 TI - Behavioral abnormalities in the Fmr1-KO2 mouse model of fragile X syndrome: The relevance of early life phases. AB - Fragile X syndrome (FXS) is a developmental disorder caused by a mutation in the X-linked FMR1 gene, coding for the FMRP protein which is largely involved in synaptic function. FXS patients present several behavioral abnormalities, including hyperactivity, anxiety, sensory hyper-responsiveness, and cognitive deficits. Autistic symptoms, e.g., altered social interaction and communication, are also often observed: FXS is indeed the most common monogenic cause of autism. Mouse models of FXS are therefore of great interest for research on both FXS and autistic pathologies. The Fmr1-KO2 mouse line is the most recent FXS model, widely used for brain studies; surprisingly, little is known about the face validity of this model, i.e., its FXS-like behavioral phenotype. Furthermore, no data are available for the age-related expression of the pathological phenotypes in this mouse line, a critical issue for modelling neurodevelopmental disorders. Here we performed an extensive behavioral characterization of the KO2 model at infancy, adolescent and adult ages. Hyperactivity, altered emotionality, sensory hyper-responsiveness and memory deficits were already present in KO mice at adolescence and remained evident at adulthood. Alterations in social behaviors were instead observed only in young KO animals: during the first 2 weeks of life, KOs emitted longer ultrasonic vocalizations compared to their WT littermates and as adolescents they displayed more aggressive behaviors towards a conspecific. These results strongly support the face validity of the KO2 mouse as a model for FXS, at the same time demonstrating that its ability to recapitulate social autistic-relevant phenotypes depends on early testing ages. Autism Res 2017, 10: 1584-1596. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 28590058 TI - Transgelin mediates transforming growth factor-beta1-induced proliferation of human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: Human periodontal ligament cells (HPDLCs) express transforming growth factor-beta1 (TGF-beta1) that regulates differentiation and proliferation, and plays key roles in homeostasis of PDL tissue. Transgelin is a cytoskeleton-associated protein with an Smad-binding element in its gene promoter region. In this study, we examined the localization and potential function of transgelin in PDL tissue and cells. MATERIAL AND METHODS: Microarray analysis of HPDLC lines (2-14, 2-23 and 2-52) was performed. Expression of transgelin in HPDLCs was examined by quantitative reverse transcription-polymerase chain reaction, immunofluorescence staining and western blot analysis. Effects of TGF beta1 and its signaling inhibitor, SB431542, on transgelin expression in HPDLCs were examined by western blot analysis. The effects of transgelin knockdown by small interfering RNA (siRNA) on HPDLC proliferation stimulated by TGF-beta1 were assessed by WST-1 assay. RESULTS: In microarray and quantitative reverse transcription-polymerase chain reaction analyses, the expression levels of transgelin (TAGLN) in 2-14 and 2-23 cells, which highly expressed PDL markers such as periostin (POSTN), tissue non-specific alkaline phosphatase (ALPL), alpha smooth muscle actin (ACTA2) and type I collagen A1 (COL1A1), was significantly higher than those in 2-52 cells that expressed PDL markers weakly. Immunohistochemical and immunofluorescence staining revealed expression of transgelin in rat PDL tissue and HPDLCs. In HPDLCs, TGF-beta1 treatment upregulated transgelin expression, whereas inhibition of the type 1 TGF-beta1 receptor by SB431542 suppressed this upregulation. Furthermore, TAGLN siRNA transfection did not promote the proliferation of HPDLCs treated with TGF-beta1. The expression levels of CCNA2 and CCNE1, which regulate DNA synthesis and mitosis through the cell cycle, were also not upregulated in HPDLCs transfected with TAGLN siRNA. CONCLUSION: Transgelin is expressed in PDL tissue and might have a role in HPDLC proliferation induced by TGF-beta1 stimulation. PMID- 28590060 TI - Structure-function relationships at the human spinal disc-vertebra interface. AB - Damage at the intervertebral disc-vertebra interface associates with back pain and disc herniation. However, the structural and biomechanical properties of the disc-vertebra interface remain underexplored. We sought to measure mechanical properties and failure mechanisms, quantify architectural features, and assess structure-function relationships at this vulnerable location. Vertebra-disc vertebra specimens from human cadaver thoracic spines were scanned with micro computed tomography (MUCT), surface speckle-coated, and loaded to failure in uniaxial tension. Digital image correlation (DIC) was used to calculate local surface strains. Failure surfaces were scanned using scanning electron microscopy (SEM), and adjacent sagittal slices were analyzed with histology and SEM. Seventy one percent of specimens failed initially at the cartilage endplate-bone interface of the inner annulus region. Histology and SEM both indicated a lack of structural integration between the cartilage endplate (CEP) and bone. The interface failure strength was increased in samples with higher trabecular bone volume fraction in the vertebral endplates. Furthermore, failure strength decreased with degeneration, and in discs with thicker CEPs. Our findings indicate that poor structural connectivity between the CEP and vertebra may explain the structural weakness at this region, and provide insight into structural features that may contribute to risk for disc-vertebra interface injury. The disc-vertebra interface is the site of failure in the majority of herniation injuries. Here we show new structure-function relationships at this interface that may motivate the development of diagnostics, prevention strategies, and treatments to improve the prognosis for many low back pain patients with disc-vertebra interface injuries. (c) 2017 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:192-201, 2018. PMID- 28590059 TI - Sympatholytic effect of intravascular ATP is independent of nitric oxide, prostaglandins, Na+ /K+ -ATPase and KIR channels in humans. AB - KEY POINTS: Intravascular ATP attenuates sympathetic vasoconstriction (sympatholysis) similar to what is observed in contracting skeletal muscle of humans, and may be an important contributor to exercise hyperaemia. Similar to exercise, ATP-mediated vasodilatation occurs via activation of inwardly rectifying potassium channels (KIR ), and synthesis of nitric oxide (NO) and prostaglandins (PG). However, recent evidence suggests that these dilatatory pathways are not obligatory for sympatholysis during exercise; therefore, we tested the hypothesis that the ability of ATP to blunt alpha1 -adrenergic vasoconstriction in resting skeletal muscle would be independent of KIR , NO, PGs and Na+ /K+ -ATPase activity. Blockade of KIR channels alone or in combination with NO, PGs and Na+ /K+ -ATPase significantly reduced the vasodilatatory response to ATP, although intravascular ATP maintained the ability to attenuate alpha1 -adrenergic vasoconstriction. This study highlights similarities in the vascular response to ATP and exercise, and further supports a potential role of intravascular ATP in blood flow regulation during exercise in humans. ABSTRACT: Exercise and intravascular ATP elicit vasodilatation that is dependent on activation of inwardly rectifying potassium (KIR ) channels, with a modest reliance on nitric oxide (NO) and prostaglandin (PG) synthesis. Both exercise and intravascular ATP attenuate sympathetic alpha-adrenergic vasoconstriction (sympatholysis). However, KIR channels, NO, PGs and Na+ /K+ -ATPase activity are not obligatory to observe sympatholysis during exercise. To further determine similarities between exercise and intravascular ATP, we tested the hypothesis that inhibition of KIR channels, NO and PG synthesis, and Na+ /K+ -ATPase would not alter the ability of ATP to blunt alpha1 -adrenergic vasoconstriction. In healthy subjects, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (FVC) to intra-arterial infusion of phenylephrine (PE; alpha1 -agonist) during ATP or control vasodilatator infusion, before and after KIR channel inhibition alone (barium chloride; n = 7; Protocol 1); NO (l-NMMA) and PG (ketorolac) inhibition alone, or combined NO, PGs, Na+ /K+ -ATPase (ouabain) and KIR channel inhibition (n = 6; Protocol 2). ATP attenuated PE-mediated vasoconstriction relative to adenosine (ADO) and sodium nitroprusside (SNP) (PE-mediated DeltaFVC: ATP: -16 +/- 2; ADO: -38 +/- 6; SNP: -59 +/- 6%; P < 0.05 vs. ADO and SNP). Blockade of KIR channels alone or combined with NO, PGs and Na+ /K+ -ATPase, attenuated ATP-mediated vasodilatation (~35 and ~60% respectively; P < 0.05 vs. control). However, ATP maintained the ability to blunt PE-mediated vasoconstriction (PE-mediated DeltaFVC: KIR blockade alone: -6 +/- 5%; combined blockade:-4 +/- 14%; P > 0.05 vs. control). These findings demonstrate that intravascular ATP modulates alpha1 -adrenergic vasoconstriction via pathways independent of KIR channels, NO, PGs and Na+ /K+ -ATPase in humans, consistent with a role for endothelium-derived hyperpolarization in functional sympatholysis. PMID- 28590062 TI - Sensitivity improvement of rapid Vibrio harveyi detection with an enhanced chemiluminescent-based dot blot. AB - : Vibrio harveyi is an opportunistic pathogen in seawater and can cause severe vibriosis. It is prevalent in hatcheries worldwide and can lead to severe economic losses. Therefore, there is an urgent need to develop a rapid detection method for monitoring this pathogen. In this study, to increase the detection sensitivity of our assay with monoclonal antibodies (Mabs) against V. harveyi, the conditions of the dot blot assay were optimized, and enhanced chemiluminescent (ECL) substrate replaced the traditional tetramethylbenzidine (TMB) substrate. Based on the optimization results, an ECL-based novel dot blot assay was developed for the rapid and sensitive detection of V. harveyi. Compared with the traditional dot blot assay, the incubation time was shortened from 8 to 2 h. The limit of detection (LOD) for V. harveyi was 2 * 105 CFU per ml (103 CFU per spot) in pure bacterial suspension, which was 50-fold more sensitive than the traditional dot blot assay (1 * 107 CFU per ml). Furthermore, when compared with indirect ELISA, the dot blot assay showed approximately 1000-fold higher sensitivity (CFU/CFU). After the test sample was pre-enriched in turbot homogenates for 6 h before the dot blot analysis, the LOD for V. harveyi was 10 CFU per ml. SIGNIFICANCE AND IMPACT OF THE STUDY: Vibrio harveyi is one of the most opportunistic pathogens that can cause high mortality in hatcheries worldwide. To detect this pathogen, a novel dot blot based on enhanced chemiluminescent (ECL) has been established. This ECL-based dot blot was found to be more sensitive and rapid for V. harveyi detection than traditional dot blot, and this technology is recommended as an applied protocol for monitoring V. harveyi in seawater to reduce economic losses. PMID- 28590063 TI - Highly Stable Three-Dimensional Porous Nickel-Iron Nitride Nanosheets for Full Water Splitting at High Current Densities. AB - A noble-metal-free and highly efficient bifunctional catalyst for overall water splitting is greatly desirable to generate clean and sustainable energy carriers such as hydrogen, but enormous challenges remain. Herein, porous interconnected iron-nickel nitride nanosheets are designed and grown on carbon fiber cloth (FeNi N/CFC); combining a facile electrodeposition method and in situ nitriding process. The as-synthesized FeNi-N/CFC, with a low mass loading of 0.25 mg cm-2 , exhibits excellent catalytic activities for both the oxygen evolution reaction (OER) with 20 mA cm-2 at an overpotential (eta) of 232 mV and also the hydrogen evolution reaction (HER) with 10 mA cm-2 at eta=106 mV. As a bifunctional electrocatalyst for overall water splitting FeNi-N/CFC only requires a cell voltage of 1.55 V to drive a current density (j) of 10 mA cm-2 and shows robust long-term durability at j>360 mA cm-2 with a negligible change in current density over 60 h; revealing its promising application in commercial electrolyzers. PMID- 28590061 TI - Porphyromonas gingivalis lipopolysaccharide regulates ephrin/Eph signalling in human periodontal ligament fibroblasts. AB - OBJECTIVE: EphrinA2-EphA2 and ephrinB2-EphB4 critically engage in bidirectional signalling to modulate alveolar bone remodelling. The present study aimed to investigate the effects of lipopolysaccharides (LPS) derived from Porphyromonas gingivalis on ephrin/Eph signalling in periodontal ligament fibroblasts (PDLFs). MATERIAL AND METHODS: The primary cultured PDLFs were incubated in the absence (as a control) or presence of P. gingivalisLPS at 0.001-10 MUg/mL for 24 hours. The PDLFs were then stimulated with P. gingivalisLPS at the optimal concentration (0.1 MUg/mL) for different periods (6-48 hours). The expression of ephrinA2, ephrinB2, EphA2 and EphB4 was assessed by quantitative reverse-transcription real time polymerase chain reaction and western blotting. The osteoblastic markers alkaline phosphatase, osteocalcin and Runt-related transcription factor 2 (Runx2), and the osteoclastogenesis-related factors receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin were also evaluated. RESULTS: The ephrinA2 and EphA2 expression was upregulated and EphB4 expression was downregulated by stimulation of P. gingivalisLPS. EphrinA2 mRNA expression in the PDLFs was significantly upregulated from 12 to 48 hours (P<.05), whereas EphA2 exhibited no change for the first 24 hours, after which there was a significant increase at 48 hours (P<.05). EphB4 exhibited lower mRNA expression at 12 and 24 hours than did the control (P<.05), but the change was insignificant at 48 hours. In contrast, the expression of ephrinB2 remained unchanged. The expressions of ephrinA2, EphA2, ephrinB2 and EphB4 at the protein level showed a similar pattern to that at the mRNA level. The expression of Runx2 and osteocalcin significantly decreased, whereas that of RANKL/osteoprotegerin increased. CONCLUSION: The present study suggest that P. gingivalisLPS would contribute to a dysregulation of bone remodelling, whereby ephrinA2/EphA2 expression is stimulated and EphB4 expression is inhibited. PMID- 28590064 TI - Breast Cancer Stem Cell Therapeutics, Multiple Strategies Versus Using Engineered Mesenchymal Stem Cells With Notch Inhibitory Properties: Possibilities and Perspectives. AB - Relapse cases of cancers are more vigorous and difficult to control due to the preponderance of cancer stem cells (CSCs). Such CSCs that had been otherwise dormant during the first incidence of cancer gradually appear as radiochemoresistant cancer cells. Hence, cancer therapeutics aimed at CSCs would be an effective strategy for mitigating the cancers during relapse. Alternatively, CSC therapy can also be proposed as an adjuvant therapy, along with the conventional therapies. As regenerative stem cells (RSCs) are known for their trophic effects, anti-tumorogenicity, and better migration toward an injury site, this review aims to address the use of adult stem cells such as dental pulp derived; cord blood derived pure populations of regenerative stem cells for targeting CSCs. Indeed, pro-tumorogenicity of RSCs is of concern and hence has also been dealt with in relation to breast CSC therapeutics. Furthermore, as notch signaling pathways are upregulated in breast cancers, and anti-notch antibody based and sh-RNA based therapies are already in the market, this review focuses the possibilities of engineering RSCs to express notch inhibitory proteins for breast CSC therapeutics. Also, we have drawn a comparison among various possibilities of breast CSC therapeutics, about, notch1 inhibition. J. Cell. Biochem. 119: 141-149, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590065 TI - Safety and efficacy of laryngeal mask airway ventilation in obese patients with airway stenosis. AB - OBJECTIVE: To assess the efficacy of laryngeal mask airway (LMA) ventilation in obese patients with airway stenosis. STUDY DESIGN: A retrospective chart review was conducted in an academic practice in a tertiary care center. METHODS: We retrospectively reviewed our experience using LMA ventilation in obese patients with airway stenosis. Lowest intraoperative O2 saturation and maximum-end tidal carbon dioxide (CO2 ) levels were recorded. Complications including intubation, unplanned admission, re-admission, postoperative pain, dysphonia, oral trauma, pneumothorax, pneumomediastinum, and tracheostomy were recorded. RESULTS: Fourteen bronchoscopies with laser incisions and dilation were performed in patients with airway stenosis exclusively using LMA ventilation. Thirteen of 14 procedures were performed on patients who had body mass index (BMI) > 30 kg/m2 . Mean BMI was noted to be 38 kg/m2 (range 25-54). All patients underwent successful laser incisions and dilation via LMA anesthesia without major or minor adverse events. The mean lowest O2 saturation level was noted to be 92%; the mean highest CO2 level was noted to be 56 mm Hg; and no patients required endotracheal intubation. CONCLUSION: In this small series of obese patients with airway stenosis, LMA anesthesia was effectively used without major or minor complications. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2582-2584, 2017. PMID- 28590066 TI - The roles of signaling pathways in bone repair and regeneration. AB - Regenerative medicine has sparked interest in potential strategies for bone repair. Bone defects are widespread and could be caused by trauma, congenital malformations, infections, and surgery. Although bone has a large self-healing capacity, some defects or fractures are too big to regenerate. To regenerate bone structures which can be used for treatment of patients, bone growth must be induced by a number of bioactive implantable materials, cell types and intracellular, and extracellular molecular signaling pathways. Since mesenchymal stem cells (MSCs) and their differentiation during remodeling processes have important roles in bone regeneration, it is believed that understanding molecular signaling pathways involved is crucial to the development of bone implants, bone substitute materials, and cell-based scaffolds for bone regeneration. In this review, we briefly introduce concepts in fracture repair and regeneration following bone injuries, and then discuss the current clinical methods in bone regeneration. In the next section, we review the involvement of the various key signaling pathways in bone regeneration. PMID- 28590067 TI - Detection of Tilapia Lake Virus in Egyptian fish farms experiencing high mortalities in 2015. PMID- 28590068 TI - Comparison of HIV-1 drug-resistance genotyping by ultra-deep sequencing and sanger sequencing using clinical samples. AB - Sanger population sequencing (SPS) is the reference technique to monitor HIV-1 infected patients' therapy. Ultra-deep sequencing (UDS), which allows quantitative detection of drug resistance mutations, may be an alternative method. The study aimed to compare reproducibility and predictions of UDS versus SPS in a routine setting. A control containing low-abundance variants was repeatedly tested and clinical plasma samples from 100 patients were prospectively assayed by SPS and UDS using the Roche 454 system. Complete analysis by UDS was available for 88% of samples with various viral loads and subtypes. Comparison of detection thresholds found that SPS sensitivity was variable. Variations found by UDS between 5% to >20% were detected by SPS in 25% to more than 80% of samples. At the 5% cut-off, disagreements were rare and in most cases UDS detected an additional protease secondary mutation, suggesting a possible resistance to a protease inhibitor according to the 2015 ANRS algorithm. Mutations found on reverse transcriptase by only UDS were often explained by previous therapy. UDS with a variant detection threshold at 5% might allow therapy management with minimal differences compared to population sequencing while providing additional information for further determination of pertinent cutoff values for specific resistance mutations. PMID- 28590069 TI - Controllable Dynamic Zigzag Pattern Formation in a Soft Helical Superstructure. AB - Zigzag pattern formation is a common and important phenomenon in nature serving a multitude of purposes. For example, the zigzag-shaped edge of green leaves boosts the transportation and absorption of nutrients. However, the elucidation of this complicated shape formation is challenging in fluid mechanics and soft condensed matter systems. Herein, a dynamically reconfigurable zigzag pattern deformation of a soft helical superstructure is demonstrated in a photoresponsive self organized cholesteric liquid crystal superstructure under the simultaneous influence of an applied electric field and light irradiation. The zigzag-shaped pattern can not only be generated and terminated repeatedly on demand, but can also be easily manipulated by alternating irradiation of ultraviolet and visible light while under the influence of a sustained electric field. This unique behavior results from a delicate balance among the variable experimental parameters. The evolution of the zigzag-shaped pattern is successfully modeled by numerical simulations and has been monitored through diffraction of a probe laser. Interestingly, this fascinating zigzag-shaped pattern yields crescent shaped diffraction pattern. The reversibly controllable dynamic zigzag pattern could enable the fabrication of novel photonic devices and architectures, besides greatly advancing the fundamental understanding of temporal behavior of ordered soft materials under combined stimuli. PMID- 28590071 TI - Synthesis and Characterization of Nitro-, Trinitromethyl-, and Fluorodinitromethyl-Substituted Triazolyl- and Tetrazolyl-trihydridoborate Anions. AB - The problem of preparing energetic, exclusively mono-azolyl substituted hydridoborate anions in high yield and purity from [BH4 ]- and nitroazoles by hydrogen elimination was overcome by reacting the corresponding nitroazolate anions with the BH3 adducts BH3 ?S(CH3 )2 or BH3 ?THF. The highly-energetic, nitro-, trinitromethyl-, and fluorodinitromethyl- substituted triazolyl- and tetrazolyl-trihydridoborate anions were synthesized in this manner and characterized by vibrational and multinuclear NMR spectroscopy and their crystal structures. The use of excess BH3 resulted in some cases in the addition of a second BH3 molecule bound more-weakly to one of the nitrogen atoms of the azole ring. All monoazolyl-trihydridoborates were thermally less stable than the parent azolate anions. A decomposition product of tetraphenylphosphonium (5 (trinitromethyl)-5H-2lambda4 -tetrazol-2-yl)trihydridoborate, the tetraphenyl phosphonium (dinitro-1H-tetrazol-5-yl)methanide monohydrate, was also structurally characterized, providing some insight into the decomposition pathways of the nitromethyl-substituted azolyltrihydridoborate anions. PMID- 28590070 TI - Chemical exchange rotation transfer imaging of intermediate-exchanging amines at 2 ppm. AB - Chemical exchange saturation transfer (CEST) imaging of amine protons exchanging at intermediate rates and whose chemical shift is around 2 ppm may provide a means of mapping creatine. However, the quantification of this effect may be compromised by the influence of overlapping CEST signals from fast-exchanging amines and hydroxyls. We aimed to investigate the exchange rate filtering effect of a variation of CEST, named chemical exchange rotation transfer (CERT), as a means of isolating creatine contributions at around 2 ppm from other overlapping signals. Simulations were performed to study the filtering effects of CERT for the selection of transfer effects from protons of specific exchange rates. Control samples containing the main metabolites in brain, bovine serum albumin (BSA) and egg white albumen (EWA) at their physiological concentrations and pH were used to study the ability of CERT to isolate molecules with amines at 2 ppm that exchange at intermediate rates, and corresponding methods were used for in vivo rat brain imaging. Simulations showed that exchange rate filtering can be combined with conventional filtering based on chemical shift. Studies on samples showed that signal contributions from creatine can be separated from those of other metabolites using this combined filter, but contributions from protein amines may still be significant. This exchange filtering can also be used for in vivo imaging. CERT provides more specific quantification of amines at 2 ppm that exchange at intermediate rates compared with conventional CEST imaging. PMID- 28590072 TI - Pyxipyrrolones: Structure Elucidation and Biosynthesis of Cytotoxic Myxobacterial Metabolites. AB - In the search for new secondary metabolites from myxobacteria, a strain from the genus Pyxidicoccus was investigated. This led to the identification of a new class of natural products showing structural novelty and interesting biological activity. Isolation and structure elucidation of two analogues led to the identification of pyxipyrrolone A and B, harboring the novel 3-methylene 2,3,4,5,6,7,8,9-octahydro-1H-benzo[e]isoindol-1-one scaffold. Mosher's ester analysis combined with NMR studies allowed the determination of all stereocenters but one. Genome sequencing of the producer strain led to the identification of a putative biosynthetic gene cluster for the pyxipyrrolones. The compounds showed activity against several cancer cell lines (MUm range) with pyxipyrrolone B having 2- to 11-fold higher activity than A, although they differ only by one methylene group. PMID- 28590073 TI - Water Transport with Ultralow Friction through Partially Exfoliated g-C3 N4 Nanosheet Membranes with Self-Supporting Spacers. AB - Two-dimensional (2D) graphitic carbon nitride (g-C3 N4 ) nanosheets show brilliant application potential in numerous fields. Herein, a membrane with artificial nanopores and self-supporting spacers was fabricated by assembly of 2D g-C3 N4 nanosheets in a stack with elaborate structures. In water purification the g-C3 N4 membrane shows a better separation performance than commercial membranes. The g-C3 N4 membrane has a water permeance of 29 L m-2 h-1 bar-1 and a rejection rate of 87 % for 3 nm molecules with a membrane thickness of 160 nm. The artificial nanopores in the g-C3 N4 nanosheets and the spacers between the partially exfoliated g-C3 N4 nanosheets provide nanochannels for water transport while bigger molecules are retained. The self-supported nanochannels in the g-C3 N4 membrane are very stable and rigid enough to resist environmental challenges, such as changes to pH and pressure conditions. Permeation experiments and molecular dynamics simulations indicate that a novel nanofluidics phenomenon takes place, whereby water transport through the g-C3 N4 nanosheet membrane occurs with ultralow friction. The findings provide new understanding of fluidics in nanochannels and illuminate a fabrication method by which rigid nanochannels may be obtained for applications in complex or harsh environments. PMID- 28590074 TI - Evolutionary bottlenecks in brackish water habitats drive the colonization of fresh water by stingrays. AB - Species richness in freshwater bony fishes depends on two main processes: the transition into and the diversification within freshwater habitats. In contrast to bony fishes, only few cartilaginous fishes, mostly stingrays (Myliobatoidei), were able to colonize fresh water. Respective transition processes have been mainly assessed from a physiological and morphological perspective, indicating that the freshwater lifestyle is strongly limited by the ability to perform osmoregulatory adaptations. However, the transition history and the effect of physiological constraints on the diversification in stingrays remain poorly understood. Herein, we estimated the geographic pathways of freshwater colonization and inferred the mode of habitat transitions. Further, we assessed habitat-related speciation rates in a time-calibrated phylogenetic framework to understand factors driving the transition of stingrays into and the diversification within fresh water. Using South American and Southeast Asian freshwater taxa as model organisms, we found one independent freshwater colonization event by stingrays in South America and at least three in Southeast Asia. We revealed that vicariant processes most likely caused freshwater transition during the time of major marine incursions. The habitat transition rates indicate that brackish water species switch preferably back into marine than forth into freshwater habitats. Moreover, our results showed significantly lower diversification rates in brackish water lineages, whereas freshwater and marine lineages exhibit similar rates. Thus, brackish water habitats may have functioned as evolutionary bottlenecks for the colonization of fresh water by stingrays, probably because of the higher variability of environmental conditions in brackish water. PMID- 28590076 TI - Solvent-Directed Helical Stereomutation Discloses Pathway Complexity on N Heterotriangulene-Based Organogelators. AB - The chiroptical features of supramolecular polymers formed from N heterotriangulenes 1-3 have been investigated by circular dichroism (ECD) and vibrational circular dichroism (VCD) techniques. In solution, the CD spectra demonstrate that the helicity of the aggregates depends on only the stereogenic centres located at the peripheral chains. In the gel state, the chiroptical features are conditioned by the point chirality of the stereogenic centres and by the achiral solvent utilised. Sonication of the gels formed in CCl4 reveals both kinetic and thermodynamic phases. These findings reveal the presence of pathway complexity in the gel state triggered by sonication. The described solvent induced helical stereomutation demonstrates that the gel state can be utilised as an outstanding benchmark for investigating uncommon chiroptical effects and to explore the rules of chirality transmission. PMID- 28590075 TI - MALAT1/miR-127-5p Regulates Osteopontin (OPN)-Mediated Proliferation of Human Chondrocytes Through PI3K/Akt Pathway. AB - Osteoarthritis (OA) is characterized by progressive destruction of articular cartilage, resulting in significant disability. Chondrocytes present in various types of cartilage and are responsible for the growth and maintenance of the tissue. Over-proliferation of human chondrocytes may contributes to OA pathological process. Previously, we revealed that miR-127-5p could inhibit the proliferation of human chondrocytes through osteopontin (OPN). In the present study, we used online tools to figure out several candidates lncRNAs which were potentially correlated with miR-127-5p. Through assessing the expression levels of the candidates lncRNAs, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was chosen as a further research subject. MALAT1 knockdown significantly repressed human OA chondrocyte proliferation, as well as the protein levels of OPN, p-PI3K, and p-Akt in OA chondrocytes. As verified by luciferase assays, MALAT1 directly bound to miR-127-5p to inhibit miR-127-5p expression. Then we achieved miR-127-5p inhibition through miR-127-5p inhibitor transfection; the miR 127-5p inhibition could promote chondrocyte proliferation, as well as the protein levels of OPN, p-PI3K, and p-Akt; in addition, the MALAT1 knockdown partially reversed the promotive effect of miR-127-5p inhibition on chondrocyte proliferation, OPN and PI3K/Akt signaling-related protein levels. Taken together, MALAT1 could directly bind to miR-127-5p to inhibit its expression, so as to rescue OPN expression and promote chondrocyte proliferation through PI3K/Akt pathway. Targeting MALAT1 so as to rescue miR-127-5p expression in OA might help to inhibit chondrocyte proliferation through miR-127-5p-mediated OPN regulation and downstream PI3K/Akt pathway. J. Cell. Biochem. 119: 431-439, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28590077 TI - (Electro)chemical Oxidation of 6,13-Bis[tri(isopropyl)silylethynyl]pentacene to its Radical Cation and Dication. AB - 6,13-Bis[tri(isopropyl)silylethynyl]pentacene is a prototypical molecule for organic semiconductor and photovoltaic materials, which makes its electrochemical (redox) properties highly interesting. However, previous cyclic voltammetric studies have provided only limited information. Kinetic and persistence information and identification of the oxidation product(s) and their further reaction or oxidation have not been reported. Thus, an extended electrochemical and spectroscopic investigation of this compound was conducted in CH2 Cl2 and THF electrolytes at Pt electrodes. The electrochemically and chemically generated radical cation of the title compound was characterized by using ESR and UV/Vis/NIR spectroscopy and quantum-chemical modeling. In CH2 Cl2 , further oxidation to a dication with chemical reversibility at fast timescales but follow up reactivity at slow timescales was observed. Pertinent parameters of the electron transfers (formal potentials E0 , electron transfer rate constants ks , electron stoichiometry n) were determined. The diffusion coefficients, D, in the two electrolytes were estimated from electrochemical and pulse gradient spin echo (PGSE) NMR spectroscopy data. Simulations of cyclic voltammograms supported the proposed oxidation mechanism and allowed the estimation of further reaction parameters. PMID- 28590078 TI - Separation of single-base sequential isomers of single-stranded DNA by capillary electrophoresis and its application in the discrimination of single-base DNA mutations. AB - Separation of single-base substitution sequential DNA isomers remains one of the most challenging tasks in DNA separation by capillary electrophoresis. We developed a simple, versatile capillary electrophoresis technique for the separation of single-base sequential isomers of DNA having the same chain length. This technique is based on charge differences resulting from the different protonation (acid dissociation) properties of the four DNA bases. A mixture of 13 single-base sequential isomers of 12-mer single-stranded DNA was separated by using an electrophoretic buffer solution containing 20 mM phosphoric acid (pH 2.0) and 8 M urea. We demonstrated that our method could separate all possible mutation patterns under identical experimental conditions. In addition, application of our method to the separation of the polymerase chain reaction product of a 68-mer gene fragment and its single-base isomers indicates that in combination with the appropriate genomic DNA extraction techniques, the method can detect single-base gene mutations. PMID- 28590080 TI - An assessment of interspecific competition between two introduced parasitoids of Diaphorina citri (Hemiptera: Liviidae) on caged citrus plants. AB - Two parasitoids attacking nymphs of Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Liviidae), Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae) and Diaphorencyrtus aligarhensis (Shafee, Alam & Agarwal) (Hymenoptera: Encyrtidae) are being released in California, USA in a classical biological control program. To evaluate the effect of multiple parasitoid species on D. citri mortality, we conducted mesocosm experiments under controlled conditions using a complete block design with 6 treatments (D. citri nymphs exposed to: no parasitoids; D. aligarhensis or T. radiata alone; D. aligarhensis or T. radiata released first (by 48 h); and both species released simultaneously). Parasitism of D. citri nymphs by T. radiata exceeded 60% and was unchanged when D. aligarhensis were present. Parasitism by D. aligarhensis was greatest when T. radiata was absent (~28%) and was reduced in all treatments with T. radiata present (<3%). D. citri mortality and parasitoid-related mortality of D. citri was consistent across parasitoid treatments. Laboratory results suggest that competition between D. aligarhensis and T. radiata is asymmetric and favors T. radiata. It may be difficult for D. aligarhensis to contribute significantly to D. citri biological control where T. radiata is present. However, results reported here suggest that competition between T. radiata and D. aligarhensis is not likely to reduce parasitism by T. radiata or reduce parasitoid-induced mortality of D. citri. PMID- 28590079 TI - Isohexide Dinitriles: A Versatile Family of Renewable Platform Chemicals. AB - Building blocks of isohexides extended by one carbon atom at the 2- or 5 positions are now synthetically accessible by a convenient, selective, base catalyzed epimerization of the corresponding dinitriles. Kinetic experiments using the strong organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) show that all three possible isohexide dinitrile isomers exist within a dynamic equilibrium. An epimerization mechanism based on density functional theory (DFT) calculations is proposed. Structural identification of all three possible isomers is based on NMR analysis and single crystal x-ray crystallography. DFT calculations confirm that the observed crystal structures are indeed the lowest energy conformers of these isohexide derivatives. PMID- 28590081 TI - Resilience as a mediator between cardiorespiratory fitness and mental health related quality of life: A cross-sectional study. AB - In this cross-sectional study, we analyzed the relationship between resilience, cardiorespiratory fitness, and mental health-related quality of life, and examined whether resilience acts as a mediator between the latter two. The study included 770 university students, aged 18-30 years, from Cuenca, Spain. Anthropometric, sociodemographic, cardiorespiratory fitness (20 m shuttle run test), biochemical parameters, resilience, and mental health-related quality of life measurements were analyzed. The results showed that mental health-related quality-of-life values were significantly higher in students who had good cardiorespiratory fitness and a high level of resilience. Moreover, resilience acted as a partial mediator between cardiorespiratory fitness and mental health related quality of life at 33.79%. Therefore, in young adults, resilience mediates the relationship between cardiorespiratory fitness and mental health related quality of life. These findings should be taken into account by nurses and other public health professionals, because in addition to the development of physical activity interventions to improve mental health-related quality of life, it is necessary to implement measures that increase resilience to achieve mental wellness. PMID- 28590082 TI - Mechanism of ion stacking in aqueous partition chromatographic processes. AB - It has been reported that ion enrichment phenomena are observed in liquid chromatographic processes with an aqueous mobile phase on the columns packed with nonionic materials. However, the mechanism of the ion enrichment is not at all well understood. In this study, we investigated the retention and enrichment behaviors of simple inorganic anions on a C18-bonded silica column and a cross linked hydroxylated methacrylic polymer gel column with pure aqueous mobile phases containing various electrolytes. We show that the stacking of ionic solutes can successfully be accounted for by the ion partition model, and it takes place due to the effect of the background coion in the eluent and/or sample solution on the distribution of the ions between the bulk water and the water incorporated in the packing material, which acts as the stationary phase. Using the ion exclusion effect of fixed anionic charges on a packing material as well as the ion stacking by partition, we developed a simple and versatile method for effective enrichment of anionic solutes in aqueous solutions. The enrichment factor and the elution time of the stacked ion zone can be predicted by the ion partition model. PMID- 28590083 TI - Novel strategy for quality consistency evaluation of Chinese medicine "YIQING" tablet that combines the simultaneous quantification and screening of ten bioactive constituents. AB - The UV characteristics for different categories compounds in complex traditional Chinese medicines and herbal preparations usually vary. Thus, to achieve the integral analysis of multiwavelength fingerprint characteristics, we introduced a novel strategy of multiwavelength total fusion profiling. The simultaneous separation and quantification of multiple components by reversed-phase high performance liquid chromatography coupled with diode array detection was developed in an effective, accurate, and reliable way. Furthermore, a 2,2 diphenyl-1-picrylhydrazyl radical (DPPH) scavenging assay was set up to detect and screen the bioactivity of similar-structure constituents (aloe-emodin, rhein, emodin, chrysophanol, baicalein, wogonin, baicalin, wogonoside, berberine hydrochloride, and jatrorrhizine hydrochloride). Moreover, the high-performance liquid chromatography DPPH assay was developed to monitor the relationship between the biological activity and the spatial structure, the number of hydroxyl groups, the concentration of the analytes in samples. The result of qualitative classification for 15 batches of "YIQING" tablets using principle component analysis was consistent with the quantitative fingerprint assessment using the average linear quantitative fingerprint method. Therefore, chemometrics, multiwavelength total fusion profiling in conjunction with average linear quantitative fingerprint method and antioxidant activity can control the quality of traditional Chinese medicines/herbal preparations comprehensively and practically. PMID- 28590085 TI - Diastolic dysfunction and older adults: heating up the conversation. PMID- 28590084 TI - Psychosocial Influences on Fruit and Vegetable Intake Following a NYC Supermarket Discount. AB - OBJECTIVE: To assess the effect of a 50% discount on fruits and vegetables (F&V) on the purchase and intake of F&V and on psychosocial determinants of F&V intake: self-efficacy (SE), stages of change (SOC), and perceived barriers (PB). METHODS: This randomized controlled trial was conducted in local supermarkets over 16 weeks, including a 4-week baseline, 8-week discount intervention, and 4-week follow-up. Shoppers with overweight or obesity (BMI > 25) were randomized to receive a discount or no discount via their reward scan card after the baseline. Twenty-four-hour recalls and psychosocial measures were obtained for each study period. RESULTS: Purchases (P < 0.0005) and intakes (P = 0.019) of F&V increased significantly during the intervention, while only F&V intake was sustained at follow-up. The discount intervention increased SE (P < 0.01) and SOC (P < 0.05) and did not decrease PB (P = 0.057) during the intervention. SOC mediated the discount intervention effect on F&V intake (P < 0.05) during the intervention, explaining 43% of variance. CONCLUSIONS: A supermarket discount intervention led to increases in purchases and intakes of F&V and increases in the psychosocial factors SE and SOC and did not decrease PB. The discount intervention prompted participants to move from the preparation to action stage of SOC, which acted as a mediator for increased F&V intake. PMID- 28590086 TI - Prevention of intestinal parasites in a tri-border area of Latin America: Children perceptions and an integral health education strategy. AB - To investigate knowledge of school-aged children and their perception on intestinal parasites, and to assess knowledge reconstruction on prevention practices after specific training in the subject. We performed an activity package that included the analysis of children's drawings of intestinal parasites, and information and communication technologies (ITCs) to transfer knowledge about these pathogens and prevention measures. Retrieval learning activities were performed to fixation of general and specific prevention and control measures.Overall, we found that there is a knowledge gap in many aspects of parasite biology and ecology, and therefore on the risk of infection and acquisition mechanisms. After ITCs, the children improved their knowledge over non-trained children.The approaches used to transfer knowledge and for learning, fixation were valuable tools for incorporating changes in misconceptions and in the deep-rooted habits that favour entero-parasitic diseases. This has important implications for the specific design of future education materials and campaigns. Understanding of perceptions helps to provide justifications and knowledge to achieve changes in unhealthy habits, and it constitutes the basis for the transformation of many risky practices. PMID- 28590088 TI - Trypsin inhibitor screening in traditional Chinese medicine by using an immobilized enzyme microreactor in capillary and molecular docking study. AB - A trypsin immobilized enzyme microreactor was successfully prepared in capillary for studying enzyme kinetics of trypsin and online screening of trypsin inhibitors from traditional Chinese medicine through capillary electrophoresis. Trypsin was immobilized on the inner wall at the inlet of the capillary treated with polydopamine. The rest of the capillary was used as a separation channel. The parameters including the separation efficiency and the activity of immobilized trypsin were comprehensively evaluated. Under the optimal conditions, online screening of trypsin inhibitors each time can be carried out within 6 min. The Michaelis-Menten constant of immobilized trypsin was calculated to be 0.50 mM, which indicated high affinity of the immobilized trypsin for the substrate. The half-maximal inhibitory concentration of known inhibitor of benzamidine hydrochloride hydrate as a model inhibitor was 13.32 mM. The proposed method was successfully applied to screen trypsin inhibitors from 15 compounds of traditional Chinese medicine. It has been found that baicalin showed inhibitory potency. Molecular docking study well supported the experimental result by exhibiting molecular interaction between enzyme and inhibitors. PMID- 28590087 TI - Structural States of RORgammat: X-ray Elucidation of Molecular Mechanisms and Binding Interactions for Natural and Synthetic Compounds. AB - The T-cell-specific retinoic acid receptor (RAR)-related orphan receptor-gamma (RORgammat) is a key transcription factor for the production of pro-inflammatory Th17 cytokines, which are implicated in the pathogenesis of autoimmune diseases. Over the years, several structurally diverse RORgammat inverse agonists have been reported, but combining high potency and good physicochemical properties has remained a challenging task. We recently reported a new series of inverse agonists based on an imidazopyridine core with good physicochemical properties and excellent selectivity. Herein we report eight new X-ray crystal structures for different classes of natural and synthetic compounds, including examples selected from the patent literature. Analysis of their respective binding modes revealed insight into the molecular mechanisms that lead to agonism, antagonism, or inverse agonism. We report new molecular mechanisms for RORgammat agonism and propose a separation of the inverse agonists into two classes: those that act via steric clash and those that act via other mechanisms (for the latter, co crystallization with a co-activator peptide and helix 12 in the agonist position is still possible). For the non-steric clash inverse agonists, we propose a new mechanism ("water trapping") which can be combined with other mechanisms (e.g., close contacts with H479). In addition, we compare the interactions made for selected compounds in the "back pocket" near S404 and in the "sulfate pocket" near R364 and R367. Taken together, these new mechanistic insights should prove useful for the design and optimization of further RORgammat modulators. PMID- 28590089 TI - An Exceptionally Water Stable Metal-Organic Framework with Amide-Functionalized Cages: Selective CO2 /CH4 Uptake and Removal of Antibiotics and Dyes from Water. AB - As the main organic pollutants in wastewater, antibiotics and organic dyes are harmful to the environment and public health, and their removal is important but challenging. In this work, highly porous 3D metal-organic frameworks (MOFs) [M2 (PDAD)(H2 O)]n (PCN-124-stu; M=Cu, Zn; H4 PDAD = 5,5'-(pyridine-3,5 dicarbonyl)bis(azanediyl)diisophthalic acid) were synthesized, and PCN-124 stu(Cu) shows excellent chemical and thermal stability. PCN-124-stu(Cu) was used as a host for efficient extraction of various organic dyes, especially the large molecule dye Coomassie brilliant blue, and fluoroquinolones from water, in comparison with five common MOFs, zeolite 13X, and activated carbon. PCN-124 stu(Cu) exhibits absolute predominance for fluoroquinolone adsorption among these microporous materials because of the H-bonds between fluoroquinolone molecules and the amide groups in the frameworks, except for MIL-100(Cr), which is a mesoporous MOF. Moreover, PCN-124-stu(Cu) could release fluoroquinolones slowly in physiological saline and retained its framework structure after four adsorption/desorption cycles. In addition, PCN-124-stu(Cu) can be used as a platform for selective adsorption of CO2 /CH4. PMID- 28590090 TI - Motile hepatocellular carcinoma cells preferentially secret sugar metabolism regulatory proteins via exosomes. AB - Exosomes are deliverers of critically functional proteins, capable of transforming target cells in numerous cancers, including hepatocellular carcinoma (HCC). We hypothesize that the motility of HCC cells can be featured by comparative proteome of exosomes. Hence, we performed the super-SILAC-based MS analysis on the exosomes secreted by three human HCC cell lines, including the non-motile Hep3B cell, and the motile 97H and LM3 cells. More than 1400 exosomal proteins were confidently quantified in each MS analysis with highly biological reproducibility. We justified that 469 and 443 exosomal proteins represented differentially expressed proteins (DEPs) in the 97H/Hep3B and LM3/Hep3B comparisons, respectively. These DEPs focused on sugar metabolism-centric canonical pathways per ingenuity pathway analysis, which was consistent with the gene ontology analysis on biological process enrichment. These pathways included glycolysis I, gluconeogenesis I and pentose phosphate pathways; and the DEPs enriched in these pathways could form a tightly connected network. By analyzing the relative abundance of proteins and translating mRNAs, we found significantly positive correlation between exosomes and cells. The involved exosomal proteins were again focusing on sugar metabolism. In conclusion, motile HCC cells tend to preferentially export more sugar metabolism-associated proteins via exosomes that differentiate them from non-motile HCC cells. PMID- 28590091 TI - An Update on the Protocols and Biologic Actions of Platelet Rich Fibrin in Dentistry. AB - Platelet rich fibrin (PRF) is a surgical biologic additive that is prepared by manipulation of autologous blood. It has now evolved to become one of the most widely used platelet concentrate in dentistry. It has almost replaced Platelet rich plasma (PRP) for usage owing to its advantages such as being 100% autogenous, easy technique, time and cost effectiveness, superior & prolonged growth factor release. It finds varied applications in dentistry including management of gingival recession, for guided bone regeneration in periodontal, peri-implant and endodontic bone defects. Since its inception in 2001 by Choukroun & co-workers, there has been in-depth research regarding its clinical applications, biologic actions, various technique modifications and optimizations. Several modifications of the conventional protocol like the advanced PRF, injectable PRF, PRF lysate and Titanium-prepared PRF. Hence, the aim of this article to review the biological properties of platelet rich fibrin and the advancement in the PRF technology since its inception. PMID- 28590092 TI - Additive Manufacturing: A Novel Method for Fabricating Cobalt-Chromium Removable Partial Denture Frameworks. AB - Additive manufacturing (AM) often referred to as 3D printing (3DP) has shown promise of being significantly viable in the construction of cobalt-chromium removable partial denture (RPD) frameworks. The current paper seeks to discuss AM technologies (photopolymerization processes and selective laser melting) and review their scope. The review also discusses the clinical relevance of cobalt chromium RPD frameworks. All relevant publications in English over the last 10 years, when the first 3D-printed RPD framework was reported, are examined. The review notes that AM offers significant benefits in terms of speed of the manufacturing processes however cost and other aspects of current technologies remain a hindrance. PMID- 28590094 TI - Optical Properties and Failure Load of Thin CAD/CAM Ceramic Veneers. AB - This study aimed to compare optical properties and failure load of leucite (IPS Empress CAD LT) and lithium disilicate glass ceramic (IPS e.max CAD LT) materials in incisor veneers. Four groups of veneers were made on 36 bovine incisors with Cerec 3D milling unit (n=9/group): 0.5 and 0.3 mm thick leucite glass and 0.5 and 0.3 mm lithium disilicate glass veneers. The optical features were measured with CM-700d spectrophotometer using white and yellow try-in pastes. Differences were determined by means of DeltaE value and luminance. The bovine teeth with veneers were mounted on acrylic resin blocks (Palapress, Heraeus Kulzer) and static loading test was conducted (LR30K plus, Lloyd Instruments). The color difference of veneers could be noticed with yellow and white cements when the material thickness increased from 0.3 to 0.5 mm (leucite DeltaE yellow 4.4, white 6.0; lithiumdisilicate DeltaE yellow 2.1, white 4.1). Both materials showed similar failure load with 0.5 mm veneers (leucite 1906 +/-319 N; lithiumdisilicate 2098 +/- 309 N). The failure load of 0.3 mm thick lithium dilisilicate veneers (2002 +/- 427 N) was comparable with the 0.5mm veneers. Ultrathin lithium disilicate glass ceramic veneers (0.3 mm) could be a potential option for clinical use. PMID- 28590093 TI - Marginal Adaptation and Internal Fit of Posterior 3-Unit Zirconia FPDs Fabricated with Different CAD/CAM Systems. AB - The purpose of this study was to compare the accuracy of zirconia FPDs fabricated by different laboratory CAD/CAM system. Thirty-six FPD zirconia frameworks were fabricated on corresponding epoxy resin models that were duplicated from a master model of mandibular second premolar and second molar mounted in an acrylic block to simulate missing first mandibular tooth. Frameworks were divided into groups (n = 12) of three laboratory CAD/CAM systems: Cercon, Amann Girrbach, and Zirkonzahn. For the two factors, system and abutment type, the absolute marginal discrepancy (AMD) was measured before cementation. Internal fit was also determined at three sites after cementation. The data were analyzed statistically (alpha = 0.05). The effects of system and tooth type were not significant for AMD (p ? 0.05). Both factors showed influence on the internal fit of FPDs (p ? 0.05). Molars showed larger gaps in axial and occlusal sites (p = 0.001 and p = 0.003), and Cercon led in better occlusal adaptation compared with Amann Girrbach (p = 0.013). The systems tested did not show differences in AMD, despite different incorporated components. However, internal fit was significantly different between tooth type and system. PMID- 28590095 TI - The Early Erosive and Abrasive Challenge: A Profilometric, Electron Microscopic and Microhardness Study Using Human, Bovine and Ovine Enamel. AB - AIM: This study aimed to test the null hypothesis that there are no significant differences in surface characteristics of eroded and abraded human, ovine and bovine enamel. DESIGN: Twenty enamel slabs were prepared from bovine, human and ovine incisor crowns, and randomly assigned to one of 4 treatments: 30 second/4 minute immersion at 1%/6% w/v citric acid. Post-erosion, an oscillatory brush was used for 20 seconds. Roughness parameters, height change and scanning electron microscopy were measured at each stage. RESULTS: Whilst the eroded surface became generally less rough after the abrasive challenge, there were significant tissue differences. Abraded microhardness was significantly increased compared to eroded values (P?0.001), Surface loss was also significantly different between tissue types (P?0.001). Bovine enamel showed similar trends to human enamel but was consistently harder and more resistant to surface change. Ovine enamel displayed little correlation with human enamel.Scanning electron microscopy images showed differences for each tissue that were consistent with the quantitative data. CONCLUSIONS: The null hypothesis was rejected; neither bovine nor ovine enamel can be reliably used interchangeably with human enamel for erosion/abrasion studies. PMID- 28590096 TI - Efficacy of Removable Partial Denture Treatment: A Retrospective Oral Health Related Quality of Life Evaluation. AB - : Successful removable partial dentures (RPDs) use may be influenced by patient and denture variables including age, denture experience and number or position of teeth being replaced. Influence of patient and denture variables on OHRQoL with RPDs was investigated using ordinal logistic regression analysis. METHODS: Participants provided with RPDs were invited to complete OHIP-20 at least 4 weeks after dentures were fitted. Clinical records were retrieved to identify a number of independent variables. Variables meeting a standard of statistical significance were included into regression analysis to quantify influence on OHIP 20 scores. RESULTS: 84 patients agreed to participate. No. of missing teeth, age, gender, replacement of anterior teeth and framework material were entered into the model, which was statistically significant, p?0.001, with pseudo R2 of 0.39. Significant variables were age (p?0.05), no. of missing teeth (p?0.01), gender (p?0.05) and replacement of anterior teeth (p?0.001). Replacing anterior teeth showed 9.68 point reduction in OHIP-20 score in patients with replaced anterior teeth. DISCUSSION: Replacing anterior teeth was associated better post-operative OHRQoL outcomes, suggesting RPDs address impacts on OHRQoL of missing anterior teeth. Success of RPDs in overcoming impacts of tooth loss on OHRQoL was worse as more teeth were lost. PMID- 28590097 TI - Five Year Clinical Evaluation of Restorations Placed in a Low Shrinkage Stress Composite in UK General Dental Practices. AB - : This paper evaluates the five year clinical evaluation of restorations formed in a low shrinkage stress resin composite material (3M ESPE Filtek Silorane, Seefeld, Germany) and placed in the general dental practices of five members of the PREP Panel, a group of UK practice-based researchers. Results indicated satisfactory performance of the material under evaluation, other than for marginal staining, which affected 60% of the restorations evaluated after five years, albeit with less than 10% of the circumference of the restorations being affected. CLINICAL RELEVANCE: The low shrinkage stress material, Filtek SiloraneTM, demonstrated good clinical performance in the majority of parameters which were assessed at five years. PMID- 28590099 TI - ? AB - Surgical injury of the biliary tract have increased in thelaparoscopic cholecystectomy era, anatomic variants of thebiliary ducts, mainly the type F, is likely to receive this kindof injury. Cholangiography helps to prevent such complications,so, we recommended the execution of this procedure ina routine way. Treatment usually is complex and requirestrained surgeons. PMID- 28590098 TI - ? AB - : In Argentina there are no multicenter studies evaluating themanagement of patients with acute pancreatitis (AP) nationwide. OBJECTIVES: The main objective of this study is toknow how the patients with AP are treated in Argentina.The secondary objective is to assess whether the results complywith the recommendation of the American College of GastroenterologyGuide. MATERIAL AND METHODS: Twenty threecenter participated in the study. They include in a databasehosted online consecutive patients with acute pancreatitisfrom june 2010 to june 2013. RESULTS: 854 patients enteredthe study. The average age was 46.6 years and 495(58%) belonged to the female sex. The most common cause(88.2%) of AP was biliary. Some prognostic system wasused in 99 % of patients and the most used was Ranson(74.5%). Were classified as mild 714 (83.6%) patientsand severe 140 (16.4%). Systemic complications occurredin 43 patients and local complications in 21. 86 patientsunderwent dynamic CT scans and 73 patients had pancreaticand / or peripancreatic necrosis. Mortality was1.5%. There was no difference in mortality in relation tothe size, complexity or affiliation of the center. The complyof key recommendations of the American College of Gastroenterology Guide was over 80%. CONCLUSIONS: The diagnosis and treatment of patients with AP in 23 healthcenters located throughout the country was optimal. Themanagement complied with most of the recommendationsof the American College of Gastroenterology Guide. PMID- 28590100 TI - ? AB - Colonic metastasis of breast cancer are extremely infrequent,being ductal subtype the most rarely affects the digestivetract, compared to lobular subtype. We present a case reportof a colonic metastasis of ductal breast cancer; found in thecontext of a screening colonoscopy. Besides we perform anarticle research about digestive tract metastasis of primarybreast cancer, finding very few published cases among theliterature about this ductal subtype behavior. PMID- 28590101 TI - ? AB - : The gastrointestinal commitment is the six most frequentlocation of extrapulmonary tuberculosis. Often its acutecomplications constitute the main presentation form due toa late diagnosis. OBJECTIVES: To review the presentation ofgastrointestinal tuberculosis as perforative acute abdomenand surgical resolution. MATERIAL AND METHOD: Case 1. A31 year old female, with newly diagnosed pulmonary tuberculosis,discontinuous treatment. Two month later presentswith peritonitis acute abdomen. Laparotomy is done beingstated intestinal perforations. They performed resection andanastomosis terminal. The treatment with ant tuberculosisstarts. Good evolution. Case 2. A 30 years male patient, HIVand pulmonary tuberculosis with discontinuous treatment.He was admitted with abdominal pain and generalizedperitoneal reaction. Intestinal perforations is found at laparotomy.Biopsy and raffia intestinal is performed. Fourdays later suture dehiscence and new intestinal perforationsare found. Resection and ileostomy is performed. It evolutionwith distress and death. In both cases histopathology confirmedintestinal tuberculosis. CONCLUSIONS: Because of thenonspecific symptoms of intestinal tuberculosis, is commonthe diagnosis through their acute complications and these are potentially lethalespecially in immunocompromised patients.The prompt treatment with anti tuberculosis drugs isthe limiting in elective surgery in selected cases. PMID- 28590102 TI - ? AB - Tuberculosis is the commonest cause of spinal infectionworldwide (9-46%). Tuberculosis spondylodiscitis causesmultifocal thoracic and lumbar spinal disease, and big paraspinaland psoas abscesses. It is more frequent in peopleunder 40 who had previous tuberculosis infection and fromcountries where the illness is endemic. Clinic is non-specificand sub-acute. We report the clinical case of a 29-year-oldpatient who suffered from pericardic tuberculosis in her childhoodand who presents a bilateral retroperitoneal abscessdue to tuberculosis spondylodiscitis. Her clinical debut beganwith left inguinal pain and an irreducible mass at this levelthat simulated an incarcerated inguinal hernia, whichis why surgery was indicated. Due to discrepancies betweenintraoperative findings and the initial diagnosis, the diagnosisand treatment strategy were changed. The purpose of thiscase report is to emphasize the challenge that the diagnosisof this pathology represents, due to low incidence in our environmentand poor clinical features, which results in latediagnosis and late management. PMID- 28590103 TI - Esophageal metalic stent migration. Case report of adislodged stent retrieval. AB - BACKGROUND: Metallic stent placing is the first choice in thetreatment of malign or benign strictures of the esophagus. Stentmigration is a well-known complication of this procedure. Wereport a case of stent migration in which surgical laparoscopicintervention was used to retrieve it. METHODS: An 85 yearsold man with unsuccessfully endoscopic retrieval of a migratedstent underwent laparoscopic gastrotomy for solution. The patientrecovered without incident. CONCLUSION: This case illustratesthat laparoscopic technique can be an optional way toretrieve migrated stents in selected patients. PMID- 28590104 TI - Time remaining in labor and probability of vaginal delivery as a function of the angle of progression in a low risk population with a normal first stage of labor. In-house observational study and comparison with the data in the literature. AB - BACKGROUND: The aim of the study was to investigate whether the angle of progression (AoP), as measured by transperineal ultrasound, was predictive of both the time remaining in labor and vaginal delivery. METHODS: This was a prospective observational cohort study involving 270 low-risk women with singleton pregnancies at term. The AoP, measured at the end of the first stage of labor, was used as a predictive variable of time remaining in labor and mode of delivery. The Kaplan Meier and Cox algorithms were used to evaluate the time elapsed between AoP measurement and delivery as a function of AoP. Instead, logistic regression was used to calculate the adjusted probability of vaginal delivery as a function of AoP. RESULTS: Of the 270 women enrolled, 15 (5.6%) delivered by cesarean section and 33 (12.1%) by vacuum or forceps. The AoP, stratified by quartiles, was a significant predictor of the time remaining in labor, even after adjustment for possible confounders (Body Mass Index [BMI], oxytocin administration and parity). The mean+/-SD second stage of labor length for each AoP quartile was 134+/-25, 126+/-18, 96+/-33 and 58+/-23 minutes (P value<0.001, ANOVA). The mean+/-SD probability of a vaginal delivery expressed as a function of the AoP quartile (adjusted for BMI) was 51.5+/-0.16%, 81.5+/-0.10%, 97.0+/-0.16% and 99.3+/-0.004% at the AoP of the 1st, 2nd, 3rd and 4th quartiles, respectively, (P value<0.001 ANOVA). CONCLUSIONS: The AoP was directly associated with the time remaining in labor and was predictive of a successful vaginal delivery; however, the impact on clinical practice seems low. PMID- 28590105 TI - ? AB - Intussusception is rare in adults and has different characteristicsfrom intussusceptions of children. Its clinical manifestationsare varied and often nonspecific, requiring a highindex of suspicion for diagnosis. Within the study methods,computed tomography has become fundamental in the studyof abdominal pain. This has a high sensitivity and specificityfor the diagnosis of intussusception. Most of the time thetreatment is surgical, and succeeded in identifying the underlyinglesions. We review the basics concepts, pathophysiology,imaging findings and frequent etiologies that can causeintussusception in adults. PMID- 28590106 TI - ? PMID- 28590107 TI - ? PMID- 28590108 TI - ? PMID- 28590109 TI - ? AB - : Celiac disease is an autoimmune enteropathy. The onlyknown treatment consists of a permanent adherence to a strictgluten-free diet, which represents an important challenge forpatients. Objective. To describe the gluten-free processedfood offer in food locals from 3 neighborhoods representativeof high, middle and low economic status in Buenos Aires,Argentina. METHODS: Cross sectional study. Specially trainedmonitors performed a standardized direct assessment offood locals. Whenever direct observation was not possible,we interviewed the personnel as an indirect assessment. Weclassified dish offer in different categories, and evaluated theprocesses of food elaboration, storage and distribution. RESULTS: We included 112 food locals. Results for neighborhoodsrepresentative of high, middle and low economic status were,respectively: no gluten free dish available in 27.5% (45/62),27.0% (27/37) and 30.8% (9/13), (p = 0.96); adequateelaboration in 17.7%, 13.5% and 7.7%, (p = 0.61); appropriate food storage in 12.9% (8), 13.5% (5) and 7.7%(1); (p = 0.85); adequate distribution in 8.1%, 8.1% and0% (0), (p = 0.56). Conclusion. In 1 out of 4 food localsthere was not even one gluten free dish. In addition, therewas a lack of compliance with safety measures to avoid glutencross-contamination. PMID- 28590111 TI - Synthesis of Water-Dispersible Single-Layer CoAl-Carbonate Layered Double Hydroxide. AB - Despite extensive study on single-layer layered double hydroxides (SL-LDHs) with NO3- counterions, SL-LDHs with CO32- counterions (CO32- SL-LDHs) have never been prepared before. Herein, a CoAl-CO32- SL-LDH which stays stable in water and powdery state is first synthesized using ethylene glycol as a reaction medium. The SL-LDH, with thickness of ~0.85 nm, is composed of one Co(Al)O6 layer sandwiched between two CO32- layers. The SL-LDH powder shows high specific surface area (~289 m2/g) and excellent electrocatalytic oxygen evolution efficiency. This work provides the first simple way to prepare CO32- SL-LDHs and will open an avenue for synthesizing other SL-LDHs. PMID- 28590110 TI - Modeling and Optimization of NLDH/PVDF Ultrafiltration Nanocomposite Membrane Using Artificial Neural Network-Genetic Algorithm Hybrid. AB - In this research, MgAl-CO32- nanolayered double hydroxide (NLDH) was synthesized through a facile coprecipitation method, followed by a hydrothermal treatment. The prepared NLDHs were used as a hydrophilic nanofiller for improving the performance of the PVDF-based ultrafiltration membranes. The main objective of this research was to obtain the optimized formula of NLDH/PVDF nanocomposite membrane presenting the best performance using computational techniques as a cost effective method. For this aim, an artificial neural network (ANN) model was developed for modeling and expressing the relationship between the performance of the nanocomposite membrane (pure water flux, protein flux and flux recovery ratio) and the affecting parameters including the NLDH, PVP 29000 and polymer concentrations. The effects of the mentioned parameters and the interaction between the parameters were investigated using the contour plot predicted with the developed model. Scanning electron microscopy (SEM), atomic force microscopy (AFM), and water contact angle techniques were applied to characterize the nanocomposite membranes and to interpret the predictions of the ANN model. The developed ANN model was introduced to genetic algorithm (GA) as a bioinspired optimizer to determine the optimum values of input parameters leading to high pure water flux, protein flux, and flux recovery ratio. The optimum values for NLDH, PVP 29000 and the PVDF concentration were determined to be 0.54, 1, and 18 wt %, respectively. The performance of the nanocomposite membrane prepared using the optimum values proposed by GA was investigated experimentally, in which the results were in good agreement with the values predicted by ANN model with error lower than 6%. This good agreement confirmed that the nanocomposite membranes prformance could be successfully modeled and optimized by ANN-GA system. PMID- 28590112 TI - Impurities in a 28Si-Enriched Single Crystal Produced for the Realization of the Redefined Kilogram. AB - The practical realization of the unit of mass is possible by manufacturing a perfect one-kilogram sphere from a 28Si-enriched single crystal. The mass of the sphere can be determined in terms of a fixed value of the Planck constant by counting the number of silicon atoms in the core of the single crystal. To reach the target 2.0 * 10-8 relative standard uncertainty, the mass of the surface layer and the mass deficit due to point defects such as impurities and vacancies must be investigated and corrected for. A sample of a 28Si-enriched single crystal produced to test the possibility of obtaining material at a scale useful to the dissemination of mass standards was measured by instrumental neutron activation analysis to check the purity with respect to a large number of possible contaminant elements. The results collected in a neutron activation experiment performed with the high thermal neutron flux available at the 20 MW OPAL research reactor are described. The data collected in this study showed that the produced material has a purity level never achieved with silicon used to manufacture previous one-kilogram spheres. PMID- 28590113 TI - Dacarbazine-Loaded Hollow Mesoporous Silica Nanoparticles Grafted with Folic Acid for Enhancing Antimetastatic Melanoma Response. AB - Dacarbazine (DTIC) is one of the most important chemotherapeutic agents for the treatment of melanoma; however, its poor solubility, photosensitivity, instability, and serious toxicity to normal cells limit its clinical applications. In this article, we present a rationally designed nanocarrier based on hollow mesoporous silica nanoparticles (HMSNs) for the encapsulation and targeted release of DTIC for eradicating melanoma. The nanocarrier (DTIC@HMLBFs) is prepared by modifying HMSNs with carboxyl groups to enhance the loading of DTIC, followed by further enveloping of folic acid-grafted liposomes, which act as a melanoma active target for controlled and targeted drug release. In vitro, DTIC@HMLBFs exhibited the strongest cytotoxicity to melanoma cells compared with DTIC@HMSNs and free DTIC. The in vivo investigations demonstrate that the rationally designed nanocarrier loaded with DTIC achieves significant improvement against lung metastasis of melanoma via targeting melanoma cells and tumor associated macrophages. This study provides a promising platform for the design and fabrication of multifunctional nanomedicines, which are potentially useful for the treatment of melanoma. PMID- 28590114 TI - Analysis of Nanoprecipitates in a Na-Doped PbTe-SrTe Thermoelectric Material with a High Figure of Merit. AB - The dimensionless figure of merit, ZT, of bulk thermoelectric materials depends mainly on the transport properties of charge carriers and heat-carrying phonons. PbTe-4 mol % SrTe doped with 2 mol % Na (Pb0.94Na0.02Sr0.04Te) is a nanostructured material system that exhibits a ZT higher than 2. The precipitate size distribution of SrTe precipitates is believed to play a key role. This raises the question of whether its performance is limited by precipitate coarsening (Ostwald ripening) at elevated temperatures. Herein, we utilize an atom-probe tomography (APT) to study the number density and mean radii of precipitates in concert with partial radial distribution functions (RDFs) of individual atoms. We find that the SrTe precipitates actually contain oxygen: SrTe1-xOx. We correlate this information with the overall ZT performance, specifically focusing on the electrical and lattice thermal conductivities after isothermal heat treatments at 300 and 400 degrees C for 7 days, followed by furnace cooling. Comparison of the samples annealed at 400 and 300 degrees C demonstrates significant coarsening of SrTe1-xOx precipitates as well as strong segregation of oxygen impurities in the SrTe1-xOx precipitates. Additionally, on the basis of the partial RDFs, the Na dopant atoms cluster with other Na atoms as well as with Pb, Te, and Sr atoms; clustering depends strongly on the annealing temperature and concomitantly affects the overall ZT values. We found that the coarsening slightly increases the lattice thermal conductivity and also increases the electrical conductivity, thereby having little or even a beneficial effect on the ZT values. Importantly, these findings demonstrate that APT enables quantitative analyses in three dimensions of the PbTe-4 mol % SrTe samples in addition to correlation of their properties with the thermoelectric performance. PMID- 28590116 TI - Facile and Selective Enrichment of Intact Sialoglycopeptides Using Graphitic Carbon Nitride. AB - Combining powerful selectivity, high stability, convenient operation, mild condition, and eco-friendliness, a novel graphitic carbon nitride (g-C3N4)-based enrichment method of intact sialoglycopeptides (SGs) was developed. The intact SGs could be simply enriched and separated from protein tryptic digests by hydrogen bonding without damage of glycan structures due to the specific structure of g-C3N4. By optimizing the enrichment and elution conditions, 45 and 38 SGs were detected from the tryptic digests of bovine fetuin and transferrin, respectively. Under the synergistic effect of hydrogen bonding and electrostatic adsorption, the SGs could be enriched simply in less than 2 h with a detection limit of 50 fmol. The method is repeatable due to the high stability of g-C3N4 and the simple protocol of the method, indicating the potential application of g C3N4 in efficient and selective enrichment of intact SGs. PMID- 28590115 TI - Aqueous Ligand-Stabilized Palladium Nanoparticle Catalysts for Parahydrogen Induced 13C Hyperpolarization. AB - Parahydrogen-induced polarization (PHIP) is a method for enhancing NMR sensitivity. The pairwise addition of parahydrogen in aqueous media by heterogeneous catalysts can lead to applications in chemical and biological systems. Polarization enhancement can be transferred from 1H to 13C for longer lifetimes by using zero field cycling. In this work, water-dispersible N acetylcysteine- and l-cysteine-stabilized palladium nanoparticles are introduced, and carbon polarizations up to 2 orders of magnitude higher than in previous aqueous heterogeneous PHIP systems are presented. P13C values of 1.2 and 0.2% are achieved for the formation of hydroxyethyl propionate from hydroxyethyl acrylate and ethyl acetate from vinyl acetate, respectively. Both nanoparticle systems are easily synthesized in open air, and TEM indicates an average size of 2.4 +/- 0.6 nm for NAC@Pd and 2.5 +/- 0.8 nm for LCys@Pd nanoparticles with 40 and 25% ligand coverage determined by thermogravimetric analysis, respectively. As a step toward biological relevance, results are presented for the unprotected amino acid allylglycine upon aqueous hydrogenation of propargylglycine. PMID- 28590117 TI - Nanotechnology-Enhanced No-Wash Biosensors for in Vitro Diagnostics of Cancer. AB - In vitro biosensors have been an integral component for early diagnosis of cancer in the clinic. Among them, no-wash biosensors, which only depend on the simple mixing of the signal generating probes and the sample solution without additional washing and separation steps, have been found to be particularly attractive. The outstanding advantages of facile, convenient, and rapid response of no-wash biosensors are especially suitable for point-of-care testing (POCT). One fast growing field of no-wash biosensor design involves the usage of nanomaterials as signal amplification carriers or direct signal generating elements. The analytical capacity of no-wash biosensors with respect to sensitivity or limit of detection, specificity, stability, and multiplexing detection capacity is largely improved because of their large surface area, excellent optical, electrical, catalytic, and magnetic properties. This review provides a comprehensive overview of various nanomaterial-enhanced no-wash biosensing technologies and focuses on the analysis of the underlying mechanism of these technologies applied for the early detection of cancer biomarkers ranging from small molecules to proteins, and even whole cancerous cells. Representative examples are selected to demonstrate the proof-of-concept with promising applications for in vitro diagnostics of cancer. Finally, a brief discussion of common unresolved issues and a perspective outlook on the field are provided. PMID- 28590118 TI - Measuring Rapid Time-Scale Reaction Kinetics Using Isothermal Titration Calorimetry. AB - Isothermal titration calorimetry (ITC) is a powerful tool for acquiring both thermodynamic and kinetic data for biological interactions including molecular recognition and enzymatic catalysis. ITC-based kinetics measurements typically focus on reactions taking place over long time scales (tens of minutes or hours) in order to avoid complications due to the finite length of time needed detect heat flow in the calorimeter cell. While progress has been made toward analyzing more rapid reaction kinetics by ITC, the capabilities and limitations of this approach have not been thoroughly tested to date. Here, we report that the time resolution of commercial instruments is on the order of 0.2 s or less. We successfully performed rapid ITC kinetics assays with durations of just tens of seconds using the enzyme trypsin. This is substantially shorter than previous ITC enzyme measurements. However, we noticed that for short reaction durations, standard assumptions regarding the ITC instrument response led to significant deviations between calculated and measured ITC peak shapes. To address this issue, we developed an ITC empirical response model (ITC-ERM) that quantitatively reproduces ITC peak shapes for all reaction durations. Applying the ITC-ERM approach to another enzyme (prolyl oligopeptidase), we unexpectedly discovered non-Michaelis-Menten kinetics in short time-scale measurements that are absent in more typical long time-scale experiments and are obscured in short time-scale experiments when standard assumptions regarding the instrument response are made. This highlights the potential of ITC measurements of rapid time scale kinetics in conjunction with the ITC-ERM approach to shed new light on biological dynamics. PMID- 28590119 TI - Parallel Evaluation of Melting Temperatures of DNAs in the Arrayed Droplets through the Fluorescence from DNA Intercalators. AB - Parallel evaluation of melting temperatures (Tm's) of DNA molecules in multiple floating droplets (20 MUm in diameter) was demonstrated. The Tm values were evaluated from the melting curves which were observed through the fluorescence from the DNA intercalators. The Tm values measured in the droplets corresponded well to those measured in the bulk, indicating the validity of the measurement. The parallel evaluation of Tm's was realized by observing melting curves of DNAs in the different droplets at the same time using the "droplet guide", which guided and fixed the floating droplets to the designated points in the observing plane. This demonstration would pave the way for the improvement of the precision of droplet digital PCR (ddPCR), whose state-of-the-art ascribes color and intensity of fluorescence to the base sequence of DNA in the droplet. PMID- 28590120 TI - Detection of Biosynthetic Precursors, Discovery of Glycosylated Forms, and Homeostasis of Calcitonin in Human Cancer Cells. AB - The peptide hormone calcitonin is intimately connected with human cancer development and proliferation. Its biosynthesis is reasoned to proceed via glycine-, alpha-hydroxyglycine-, glycyllysine-, and glycyllysyllysine-extended precursors; however, as a result of the limitations of current analytical methods, until now, there has been no procedure capable of detecting these individual species in cell or tissue samples. Therefore, their presence and dynamics in cancer had not been established. Here, we report the first methodology for the separation, detection, and quantification of calcitonin and each of its precursors in human cancer cells. We also report the discovery and characterization of O-glycosylated calcitonin and its analogous biosynthetic precursors. Through direct and simultaneous analysis of the glycosylated and nonglycosylated species, we interrogate the hormone biosynthesis. This shows that the cellular calcitonin level is maintained to mitigate effects of biosynthetic enzyme inhibitors that substantially change the proportions of calcitonin-related species released into the culture medium. PMID- 28590121 TI - Toward Multifunctional Materials Incorporating Stepladder Manganese(III) Inverse [9-MC-3]-Metallacrowns and Anti-Inflammatory Drugs. AB - The interaction of Mn(ClO4)2.6H2O with salicylaldoxime (H2sao) in the presence of nonsteroidal anti-inflammatory drug (NSAID) sodium diclofenac (Nadicl) or indomethacin (Hindo) leads to the formation of the hexanuclear Mn(III) clusters [Mn6(O)2(dicl)2(sao)6(CH3OH)6] (1) and [Mn6(O)2(indo)2(sao)6(H2O)4] (2) both characterized as stepladder inverse-9-metallacrown-3 accommodating dicl- or indo- ligands, respectively. When the interaction of MnCl2.4H2O with Nadicl or Hindo is in the absence of H2sao, the mononuclear Mn(II) complexes [Mn(dicl)2(CH3OH)4] (3) and [Mn(indo)2(CH3OH)4] (4) were isolated. The complexes were characterized by physicochemical and spectroscopic techniques, and the structure of complexes 1 and 2 was characterized by X-ray crystallography. Magnetic measurements (dc and ac) were carried out in order to investigate the nature of magnetic interactions between the magnetic ions and the overall magnetic behavior of the complexes. PMID- 28590122 TI - Total Synthesis and Stereochemical Revision of the 2-Formylpyrrole Alkaloid Hemerocallisamine I. AB - The first total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is reported. The convergent synthesis features a key Maillard-type condensation of a complex amine derived from cis-4-hydroxy-l-proline with a dihydropyranone, to directly furnish the 2-formylpyrrole ring system. The absolute configuration of hemerocallisamine I has been revised on the basis of optical rotation data obtained for the synthesized compound. PMID- 28590123 TI - Slow Magnetic Relaxation in a Lanthanide-[1]Metallocenophane Complex. AB - The first example of a lanthanide metallocenophane complex has been isolated as [Li(THF)4][DyFc3Li2(THF)2] (1). The molecular structure of complex 1 differs dramatically from those of main group and transition metal ferrocenophane complexes and features a distorted trigonal prismatic geometry around the Dy(III) ion and close intramolecular Dy...Fe distances. Furthermore, complex 1 exhibits all characteristics of a soft single-molecule magnet. PMID- 28590124 TI - Terpenoids from Euphorbia soongarica and Their Multidrug Resistance Reversal Activity. AB - Ten new terpenoids, including five diterpenoids (1-5), three nortriterpenoids (6 8), and two triterpenoids (9, 10), and 15 known terpenoids (11-25) were isolated from an acetone extract of Euphorbia soongarica. Sooneuphoramine (1) is the first example of a euphoractine B-type diterpenoid alkaloid, while sooneuphanones A-C (6-8) are rare nortriterpenoids from the Euphorbia genus. The isolated terpenoids were tested for their cytotoxicity and multidrug resistance (MDR) reversal activity, 10 of which showed moderate cytotoxicity against the KB and KBv200 cell lines, while 11 compounds exhibited P-gp modulating potential. The triterpenoid sooneuphanone D (9) possessed a remarkable MDR reversal activity much higher than the positive control, verapamil. PMID- 28590125 TI - Significant Increase of Aromatics-Derived Secondary Organic Aerosol during Fall to Winter in China. AB - Human activities release large amounts of anthropogenic pollutants into the air, and thereby produce substantial secondary organic aerosol (SOA). Aromatic hydrocarbons (AHs) that mainly emitted from coal combustion, transportation, solvent use and biofuel/biomass burning, are a major class of anthropogenic SOA precursors. At present, there are few field studies focusing on AH-derived SOA (SOAA) on a continental scale, especially in polluted regions of the world. In this study, a one-year concurrent observation of the SOAA tracer, 2,3-dihydroxy-4 oxopentanoic acid (C5H8O5, DHOPA) was carried out at 12 sites across six regions of China for the first time. The annual averages of DHOPA among the 12 sites ranged from 1.23 to 8.83 ng m-3 with a mean of 3.48 +/- 1.96 ng m-3. At all observation sites, the concentrations of DHOPA from fall to spring were significantly higher than those in summertime, and positive correlations were observed between DHOPA and the biomass burning tracer (levoglucosan). This indicated that such a nationwide increase of SOAA during the cold period was highly associated with the enhancement of biomass burning emission. In the northern China, the highest levels of DHOPA were observed in the coldest months during winter, probably due to the enhancement of biofuel and coal consumption for household heating. In the southern China, the highest levels of DHOPA were mostly observed in fall and spring, which were associated with the enhancement of open biomass burning. The apparent increases of DHOPA and levoglucosan levels during the cold period and the negative correlations of visibility with DHOPA and levoglucosan imply that the reduction of SOAA amount and biomass burning emission is an efficient way to reduce haze pollution during fall to winter in China. PMID- 28590126 TI - Epoxy and Oxidoannulene Oxidation Mechanisms of Fused-Pentagon Chlorofullerenes: Oxides Linked by a Pirouette-Type Transition State. AB - Recently, the oxidative functionalization of double-fused-pentagon (DFP) containing chlorofullerenes #271C50Cl10 and #913C56Cl10 was carried out, resulting in two monoepoxides with the oxygen atom added at the ortho site of pentalene on the DFP moiety. To uncover the reactivity of isolated-pentagon-rule violating fullerenes upon oxidation, two possible formation processes (ozone molecule and oxygen radical served as oxidation reagents) of these two oxides were systematically investigated through density functional theory calculations. For the ozone oxidation, two possible pathways were explored, and the results indicate that the biradical mechanism Pathos-RACDP is kinetically more favorable than Pathos-RABP, where R, A, and P represent reactants, ozonide intermediates, and oxidation products and B, C, and D represent another three oxygen-containing intermediates. The products obtained by ozone oxidation ([6,6]-55-closed epoxides P-C3-C29 for #271C50Cl10 and P-C42-C43 for #913C56Cl10 with oxygen atom added at the shortest and highest HOMO-contribution bonds) are consistent with experimental observations. However, the oxygen radical additions on these two chlorofullerenes favor generation of the [5,6]-66-open oxidoannulene adducts P-C3 C2 and P-C42-C54, respectively. Subsequent analyses of their geometrical features and structural stabilities suggest that these two oxidoannulene adducts are energetically unfavorable and could be converted to more stable epoxides mentioned above by undergoing a pirouette-type transition state. In these two diverse oxidation procedures, the favorable C-C bonds for ozone attacking and C atoms for oxygen-adsorption are rationalized in terms of their bond lengths and HOMO contributions as well as pyramidalization angles. PMID- 28590127 TI - Interwoven Aligned Conductive Nanofiber Yarn/Hydrogel Composite Scaffolds for Engineered 3D Cardiac Anisotropy. AB - Mimicking the anisotropic cardiac structure and guiding 3D cellular orientation play a critical role in designing scaffolds for cardiac tissue regeneration. Significant advances have been achieved to control cellular alignment and elongation, but it remains an ongoing challenge for engineering 3D cardiac anisotropy using these approaches. Here, we present a 3D hybrid scaffold based on aligned conductive nanofiber yarns network (NFYs-NET, composition: polycaprolactone, silk fibroin, and carbon nanotubes) within a hydrogel shell for mimicking the native cardiac tissue structure, and further demonstrate their great potential for engineering 3D cardiac anisotropy for cardiac tissue engineering. The NFYs-NET structures are shown to control cellular orientation and enhance cardiomyocytes (CMs) maturation. 3D hybrid scaffolds were then fabricated by encapsulating NFYs-NET layers within hydrogel shell, and these 3D scaffolds performed the ability to promote aligned and elongated CMs maturation on each layer and individually control cellular orientation on different layers in a 3D environment. Furthermore, endothelialized myocardium was constructed by using this hybrid strategy via the coculture of CMs on NFYs-NET layer and endothelial cells within hydrogel shell. Therefore, these 3D hybrid scaffolds, containing NFYs-NET layer inducing cellular orientation, maturation, and anisotropy and hydrogel shell providing a suitable 3D environment for endothelialization, has great potential in engineering 3D cardiac anisotropy. PMID- 28590128 TI - Antibacterial Actions of Glycinin Basic Peptide against Escherichia coli. AB - Glycinin basic peptide (GBP) is an antibacterial ingredient that occurs naturally in the basic parts of soybean glycinin. The antibacterial actions of GBP against Escherichia coli ATCC 8739 were investigated in this study. The minimum inhibitory concentration of GBP against E. coli was 200 MUg/mL. The exposure of E. coli cells to GBP induced significant cell damage and inactivated intracellular esterases (stressed and dead cells, 70.9% +/- 0.04 for 200 MUg/mL of GBP and 91.9% +/- 0.06 for 400 MUg/mL of GBP), as determined through dual staining in flow cytometry. GBP resulted in the exposure of phosphatidylserine in E. coli cells. The analyses of flow cytometry-manifested GBP treatment led to the shrinkage of the cell surface and the complication of cell granularity. The observations in transmission electron microscopy demonstrated that 400 MUg/mL of GBP severely disrupted the membrane integrity, resulting in ruptures or pores in the membrane, outflows of intracellular contents, or aggregation of the cytoplasm. Release of alkaline phosphatase, lipopolysaccharide, and reducing sugar further verified that the membrane damage was due to GBP. In addition, GBP treatment changed the helicity and base staking of DNA, as determined by circular dichroism spectroscopy. These results showed that GBP had strong antibacterial activity against E. coli via membrane damage and DNA perturbation. Additionally, GBP exhibited no cytotoxicity on the viability of human embryonic kidney cells. Thus, GBP may be a promising candidate as a natural antibacterial agent. PMID- 28590130 TI - Paying the Price of Desolvation in Solvent-Exposed Protein Pockets: Impact of Distal Solubilizing Groups on Affinity and Binding Thermodynamics in a Series of Thermolysin Inhibitors. AB - In lead optimization, open, solvent-exposed protein pockets are often disregarded as prospective binding sites. Because of bulk-solvent proximity, researchers are instead enticed to attach charged polar groups at inhibitor scaffolds to improve solubility and pharmacokinetic properties. It is rarely considered that solvent effects from water reorganization in the first hydration shell of protein-ligand complexes can have a significant impact on binding. We investigate the thermodynamic fingerprint of thermolysin inhibitors featuring terminal charged ammonium groups that are gradually pulled from a distal, solvent-exposed position into the flat, bowl-shaped S2' pocket. Even for the most remote attachment, costs for partial desolvation of the polar group next to the protein-solvent interface are difficult to compensate by interactions with the protein or surrounding water molecules. Through direct comparison with hydrophobic analogues, a significant 180-fold affinity loss was recorded, which questions popular strategies to attach polar ligand-solubilizing groups at the exposed terminus of substituents accommodated in flat open pockets. PMID- 28590129 TI - High-Level Production and Properties of the Cysteine-Depleted Cytochrome P450 3A4. AB - Human drug-metabolizing cytochrome P450 3A4 (CYP3A4) is a dynamic enzyme with a large and highly malleable active site that can fit structurally diverse compounds. Despite extensive investigations, structure-function relationships and conformational dynamics in CYP3A4 are not fully understood. This study was undertaken to engineer a well-expressed and functionally active cysteine-depleted CYP3A4 that can be used in biochemical and biophysical studies. cDNA codon optimization and screening mutagenesis were utilized to boost the level of bacterial expression of CYP3A4 and identify the least harmful substitutions for all six non-heme-ligating cysteines. The C58A/C64M/C98A/C239T/C377A/C468S (Cys less) mutant was found to be expressed as highly as the optimized wild-type (opt WT) CYP3A4. The high-resolution X-ray structures of opt-WT and Cys-less CYP3A4 revealed that gene optimization leads to a different folding in the Phe108 and Phe189 regions and promotes binding of the active site glycerol that interlocks Ser119 and Arg212, critical for ligand association, and the hydrophobic cluster adjacent to Phe108. Crowding and decreased flexibility of the active site, as well as structural alterations observed at the C64M, C239T, and C468S mutational sites, might be responsible for the distinct ligand binding behavior of opt-WT and Cys-less CYP3A4. Nonetheless, the Cys-less mutant could be used for structure function investigations because it orients bromoergocryptine and ritonavir (a high-affinity substrate and a high-potency inhibitor, respectively) like the WT and has a higher activity toward 7-benzyloxy(4-trifluoromethyl)coumarin. PMID- 28590131 TI - Iron(II)-Catalyzed Iron Atom Exchange and Mineralogical Changes in Iron-rich Organic Freshwater Flocs: An Iron Isotope Tracer Study. AB - In freshwater wetlands, organic flocs are often found enriched in trace metal(loid)s associated with poorly crystalline Fe(III)-(oxyhydr)oxides. Under reducing conditions, flocs may become exposed to aqueous Fe(II), triggering Fe(II)-catalyzed mineral transformations and trace metal(loid) release. In this study, pure ferrihydrite, a synthetic ferrihydrite-polygalacturonic acid coprecipitate (16.7 wt % C), and As- (1280 and 1230 mg/kg) and organic matter (OM)-rich (18.1 and 21.8 wt % C) freshwater flocs dominated by ferrihydrite and nanocrystalline lepidocrocite were reacted with an isotopically enriched 57Fe(II) solution (0.1 or 1.0 mM Fe(II)) at pH 5.5 and 7. Using a combination of wet chemistry, Fe isotope analysis, X-ray absorption spectroscopy (XAS), 57Fe Mossbauer spectroscopy and X-ray diffraction, we followed the Fe atom exchange kinetics and secondary mineral formation over 1 week. When reacted with Fe(II) at pH 7, pure ferrihydrite exhibited rapid Fe atom exchange at both Fe(II) concentrations, reaching 76 and 89% atom exchange in experiments with 0.1 and 1 mM Fe(II), respectively. XAS data revealed that it transformed into goethite (21%) at the lower Fe(II) concentration and into lepidocrocite (73%) and goethite (27%) at the higher Fe(II) concentration. Despite smaller Fe mineral particles in the coprecipitate and flocs as compared to pure ferrihydrite (inferred from Mossbauer-derived blocking temperatures), these samples showed reduced Fe atom exchange (9-30% at pH 7) and inhibited secondary mineral formation. No release of As was recorded for Fe(II)-reacted flocs. Our findings indicate that carbohydrate rich OM in flocs stabilizes poorly crystalline Fe minerals against Fe(II) catalyzed transformation by surface-site blockage and/or organic Fe(II) complexation. This hinders the extent of Fe atom exchange at mineral surfaces and secondary mineral formation, which may consequently impair Fe(II)-activated trace metal(loid) release. Thus, under short-term Fe(III)-reducing conditions facilitating the fast attainment of solid-solution equilibria (e.g., in stagnant waters), Fe-rich freshwater flocs are expected to remain an effective sink for trace elements. PMID- 28590132 TI - Origin of the Excited-State Absorption Spectrum of Polythiophene. AB - The excited states of conjugated polymers play a central role in their applications in organic solar photovoltaics. The delocalized excited states of conjugated polymers are short-lived (tau < 40 fs) but are imperative in the photovoltaic properties of these materials. Photoexcitation of poly(3 hexylthiophene) (P3HT) induces an excited-state absorption band, but the transitions that are involved are not well understood. In this work, calculations have been performed on P3HT analogues using nonlinear response time-dependent density functional theory to show that an increase in the oligomer length correlates with the dominance of the S1 -> S3 transition. Furthermore, the predicted transition energy shows an excellent agreement with experiment. The calculations also yielded results on intramolecular charge transfer in P3HT due to the S1 -> S3 transition, providing insight into the mechanism of exciton dissociation to form charge carriers. PMID- 28590133 TI - Hydration Repulsion Difference between Ordered and Disordered Membranes Due to Cancellation of Membrane-Membrane and Water-Mediated Interactions. AB - Hydration repulsion acts between all sufficiently polar surfaces in water at small separations and prevents dry adhesion up to kilobar pressures. Yet it remained unclear whether this ubiquitous force depends on surface structure or is a sole water property. We demonstrate that previous deviations among different experimental measurements of hydration pressures in phospholipid bilayer stacks disappear when plotting data consistently as a function of repeat distance or membrane surface distance. The resulting pressure versus distance curves agree quantitatively with our atomistic simulation results and exhibit different decay lengths in the ordered gel and the disordered fluid states. This suggests that hydration forces are not caused by water ordering effects alone. Splitting the simulated total pressure into membrane-membrane and water-mediated parts shows that these contributions are opposite in sign and of similar magnitude, thus they are equally important. The resulting net hydration pressure between membranes is what remains from the near-cancellation of these ambivalent contributions. PMID- 28590134 TI - Conical Nanopores for Efficient Ion Pumping and Desalination. AB - Previous experimental and theoretical studies have demonstrated that nanofabricated synthetic channels are able to pump ions using oscillating electric fields. We have recently proposed that conical pores with oscillating surface charges are particularly effective for pumping ions due to rectification that arises from their asymmetric structure. In this work, the energy and thermodynamic efficiency associated with salt pumping using the conical pore pump is studied, with emphasis on pumps needed to desalinate seawater. The energy efficiency is found to be as high as 0.60 to 0.83 mol/kJ when the radius of the tip side of the conical pore is two Debye lengths and the pump works with a concentration gradient smaller than 1.5. As a result, the energy consumption needed for seawater desalination with 20% salt rejection is 0.32 kJ/L. In addition, the energy consumption can be further reduced to 0.21 kJ/L (20% salt rejection) if the bias voltage is adaptively altered four times during the pump cycle while salt concentration is reduced. If the bias voltage is adaptively increased to higher values, then salt rejection can be improved to values that are needed to produce fresh water that satisfies standard requirements. Numerical analysis indicates that the energy consumption is 4.9 kJ/L for 98.6% salt rejection, which is smaller than the practical minimum energy requirement for RO based methods. In addition, the pumping efficiency can be further improved by tuning the pump structure, increasing the surface charge, and employing more adaptive bias voltages. The conical pores are also found to more efficiently counteract the concentration gradient compared to cylindrical counterparts. PMID- 28590135 TI - Evolution of the Uranium Chemical State in Mixed-Valence Oxides. AB - A fundamental question concerning the chemical state of uranium in the binary oxides UO2, U4O9, U3O7, U3O8, and UO3 is addressed. By utilizing high energy resolution fluorescence detection X-ray absorption near edge spectroscopy (HERFD XANES) at the uranium M4 edge, a novel technique in the tender X-ray region, we obtain the distribution of formal oxidation states in the mixed-valence oxides U4O9, U3O7, and U3O8. Moreover, we clearly identify a pivot from U(IV)-U(V) to U(V)-U(VI) charge compensation, corresponding with transition from a fluorite type structure (U3O7) to a layered structure (U3O8). Such physicochemical properties are of interest to a broad audience of researchers and engineers active in domains ranging from fundamental physics to nuclear industry and environmental science. PMID- 28590136 TI - Controlling Photocatalytic Activity and Size Selectivity of TiO2 Encapsulated in Hollow Silica Spheres by Tuning Silica Shell Structures Using Sacrificial Biomolecules. AB - Yolk-shell nanostructured photocatalyst which consists of inner core photocatalytic particles and outer silica shell exhibits high photocatalytic efficiency and molecular size selectivity due to the molecular sieving property of the outer shell. Creation of extended porosity in the shell endows it with improved adsorption properties and size selectivity toward targeted reactants. In this study, yolk-shell nanostructured photocatalyst consisting of TiO2 NPs core and porous silica shell with controllable pore size was fabricated through a facile single-step dual-templating approach utilizing oil-in-water (O/W) microemulsions and amphiphilic protein molecules. Addition of optimum amount of protein (ovalbumin) as a sacrificial template together with O/W microemulsion during the synthesis led to the expansion of average pore size from 2.0 to 3.6 nm, while retaining TiO2-encapsulated yolk-shell nanostructures. Photocatalytic degradation tests using gaseous 2-propanol and huge proteins as model substrates clearly revealed that the obtained material (TiO2@HSS_pro) showed superior photocatalytic performances with both improved photocatalytic efficiency and molecular size selectivity due to the increased surface area and expanded pore diameter. PMID- 28590138 TI - Vibrational Probes of Molybdenum Cofactor-Protein Interactions in Xanthine Dehydrogenase. AB - The pyranopterin dithiolene (PDT) ligand is an integral component of the molybdenum cofactor (Moco) found in all molybdoenzymes with the sole exception of nitrogenase. However, the roles of the PDT in catalysis are still unknown. The PDT is believed to be bound to the proteins by an extensive hydrogen-bonding network, and it has been suggested that these interactions may function to fine tune Moco for electron- and atom-transfer reactivity in catalysis. Here, we use resonance Raman (rR) spectroscopy to probe Moco-protein interactions using heavy atom congeners of lumazine, molecules that bind tightly to both wild-type xanthine dehydrogenase (wt-XDH) and its Q102G and Q197A variants following enzymatic hydroxylation to the corresponding violapterin product molecules. The resulting enzyme-product complexes possess intense near-IR absorption, allowing high-quality rR spectra to be collected on wt-XDH and the Q102G and Q197A variants. Small negative frequency shifts relative to wt-XDH are observed for the low-frequency Moco vibrations. These results are interpreted in the context of weak hydrogen-bonding and/or electrostatic interactions between Q102 and the -NH2 terminus of the PDT, and between Q197 and the terminal oxo of the Mo=O group. The Q102A, Q102G, Q197A, and Q197E variants do not appreciably affect the kinetic parameters kred and kred/KD, indicating that a primary role for these glutamine residues is to stabilize and coordinate Moco in the active site of XO family enzymes but to not directly affect the catalytic throughput. Raman frequency shifts between wt-XDH and its Q102G variant suggest that the changes in the electron density at the Mo ion that accompany Mo oxidation during electron transfer regeneration of the catalytically competent active site are manifest in distortions at the distant PDT amino terminus. This implies a primary role for the PDT as a conduit for facilitating enzymatic electron-transfer reactivity in xanthine oxidase family enzymes. PMID- 28590137 TI - Monitoring the Retention of Human Proliferating Cell Nuclear Antigen at Primer/Template Junctions by Proteins That Bind Single-Stranded DNA. AB - In humans, proliferating cell nuclear antigen (PCNA) sliding clamps encircling DNA coordinate various aspects of DNA metabolism throughout the cell cycle. A critical aspect of this is restricting PCNA to the vicinity of its DNA target site. For example, PCNA must be maintained at or near primer/template (P/T) junctions during DNA synthesis. With a diverse array of cellular factors implicated, many of which interact with PCNA, DNA, or both, it is unknown how this critical feat is achieved. Furthermore, current biochemical assays that examine the retention of PCNA near P/T junctions are inefficient, discontinuous, and qualitative and significantly deviate from physiologically relevant conditions. To overcome these challenges and limitations, we recently developed a novel and convenient Forster resonance energy transfer (FRET) assay that directly and continuously monitors the retention of human PCNA at a P/T junction. Here we describe in detail the design, methodology, interpretation, and limitations of this quantitative FRET assay using the single-stranded DNA-binding protein, SSB, from Escherichia coli as an example. This powerful tool is broadly applicable to any single-stranded DNA-binding protein and may be utilized and/or expanded upon to dissect DNA metabolic pathways that are dependent upon PCNA. PMID- 28590139 TI - Prehypertension and its optimal indicator among adults in Hubei Province, Central China, 2013-2015. AB - BACKGROUND: Hypertension accounts for 7% of the annual global disease burden, despite great efforts to counter this trend. Thus, interventions targeted at prehypertension might lead to a breakthrough for hypertension prevention. This study focused on the prevalence of prehypertension among adults in Central China and the best indicator of prehypertension, which would provide the basis for future interventions. METHODS: This cross-sectional study was conducted using multistage stratified random sampling in seven counties in Hubei Province. Data from 30,634 survey respondents were analyzed using logistic regression and receiver operating characteristic (ROC) curve statistical tests, for the prevalence of prehypertension and the predictive ability of body mass index (BMI), waist-to-height ratio (WHtR), and waist circumference (WC) for prehypertension. RESULTS: The prevalence of prehypertension in adults was 42.2%. The following factors contributed to the risk of prehypertension: male sex, elder age, divorce/separation, drinking, heavy labor intensity, and high BMI (p < 0.05). Being a farmer and exercise exhibited positive associations with prehypertension (p < 0.05). Compared with BMI and WHtR, WC had a higher predictive value for prehypertension (area under ROC curve, AUC = 0.630, 95% confidence interval: 0.623-0.637, p < 0.0001), especially for men. The optimal cutoffs of WC for prehypertension were 79.95 cm in men and 76.85 cm in women. CONCLUSIONS: The prehypertension rate in adults was high in Central China. Significant factors related to hypertension were identified. More interventions targeting individuals with WC above the cutoff level are needed for timely awareness of prehypertension and early prevention of hypertension. PMID- 28590140 TI - A case series comparison of semantically focused vs. phonologically focused cued naming treatment in aphasia. AB - There is a lack of clarity in the field regarding how to best predict which naming treatment will be most beneficial for a particular individual with aphasia. The purpose of this study was to elucidate whether or not semantic or phonological therapy differentially impacts on outcomes for people with a range of different aphasic profiles when given both therapies. A single-participant design, with multiple repeated baselines for naming, replicated across four participants, was used. Participants were provided with a counterbalanced order of Semantic Feature Analysis (SFA) and Phonological Components Analysis (PCA) treatment. Findings demonstrated differential effects across participants. This seemed to be influenced by factors such as severity of anomia, order of treatment presentation, and capacity limits. Clinical implications of these findings highlight the importance of expanding our picture of a participant's behaviours to consider what other important factors can inform intervention decisions. PMID- 28590141 TI - Amelioration of thioacetamide-induced liver toxicity in Wistar rats by rutin. AB - This study was designed to evaluate the effect of rutin on hepatotoxicity induced by thioacetamide (TAA) in rats. Four groups of male Wistar rats consisting of six rats each were used: Group I: control group; Group II: rats receiving single injection of 300 mg kg-1 body weight of TAA intraperitoneally; Group III: rats administered rutin (10 mg kg-1 body weight) dissolved in saline orally for 2 weeks; and Group IV: rats administered rutin (10 mg kg-1 body weight) dissolved in saline orally for 2 weeks followed by TAA injection last day of second week. All groups were sacrificed after 24 h of treatment and hepatic toxicity was analyzed with respect to liver toxicity markers, liver DNA fragmentation, and histology of liver tissue. Administration of TAA in Wistar rats resulted in significant increase of hepatic markers, DNA fragmentation in the hepatocytes, and changes in histology. Pretreatment of rats with rutin before 2 weeks of TAA assault resulted in the complete reversal of TAA-mediated hepatic toxicity ( P < 0.0001 to P < 0.01) with concomitant restoration of DNA fragmentation. This study suggests rutin as a protective agent for restoration of toxicity caused by TAA. PMID- 28590142 TI - Intra-Amniotic Soluble Endoglin Impairs Lung Development in Neonatal Rats. AB - Soluble endoglin (sENG) is increased in the amniotic fluid of women with preeclampsia and chorioamnionitis. Preterm infants born to women with these disorders have an increased risk of aberrant lung development. Whether this increased risk is secondary to elevated sENG levels is unclear. The objective of this study was to determine whether intrauterine exposure to an adenovirus overexpressing sENG impairs neonatal lung angiogenesis by modulating lung endothelial nitric oxide synthase (eNOS) signaling. Pregnant Sprague-Dawley rats were randomly assigned to receive ultrasound-guided intra-amniotic injections of adenovirus overexpressing sENG (Ad-sENG) or control adenovirus (Ad-control) on embryonic day 17. After this exposure, rat pups were maintained in normoxia and evaluated on postnatal day 14. Intra-amniotic Ad-sENG decreased lung vascular endothelial growth factor receptor 2 and eNOS expression in rat pups. This was accompanied by a marked decrease in lung angiogenesis and alveolarization. Ad sENG-exposed pups also had an increase in right ventricular systolic pressure, weight ratio of right ventricle to left ventricle plus septum, and pulmonary vascular remodeling. In addition, exposure of human pulmonary artery endothelial cells to recombinant sENG reduced endothelial tube formation and protein levels of eNOS, phosphorylated eNOS, and phosphorylated Smad1/5. Together, our findings demonstrate that intrauterine exposure to an adenovirus overexpressing sENG disrupts lung development by impairing Smad1/5-eNOS signaling. We speculate that sENG-mediated dysregulation of Smad1/5-eNOS signaling contributes to impaired lung development and potentially primes the developing lung for further postnatal insults. Further studies exploring the relationship between amniotic fluid sENG levels and preterm respiratory outcomes will be necessary. PMID- 28590144 TI - Pharmacological treatment of depression in geriatric chronic pain patients: a biopsychosocial approach integrating functional restoration. AB - INTRODUCTION: A recent literature review concluded that the comorbidity of chronic pain and depression in adults is approximately 50%-65%. Physical and cognitive declines, concurrent multiple health conditions, and complex medication regimens add to the unique and complex challenges of effectively treating pain in particularly geriatric populations. Interdisciplinary medical intervention and monitoring for psychiatric sequelae, such as depression, cognitive change, and synergistic physical side effects are necessary. Areas covered: This review covers an extensive multi-database wide search of the pharmacotherapy of pain and depression in older adults, including biopsychosocial approaches. One of these, on which this review focuses, is Functional Restoration, an interdisciplinary application of quantified physical rehabilitation, case management, and cognitive behavioral and educational therapies to achieve improved well- being and better physical functioning. The biopsychosocial model incorporates an overview of the overlapping and interactive dimensions of a patient's life and addresses them within a comprehensive plan of treatment. Expert commentary: A multifactorial, rather than a single factor approach to the treatment of complicated health care problems such as chronic pain in an elderly patient is emphasized as an important change in perspective for the health care provider. PMID- 28590143 TI - Combined exercise training reduces blood pressure, arterial stiffness, and insulin resistance in obese prehypertensive adolescent girls. AB - Childhood obesity is strongly linked to pathological processes for cardiovascular diseases in later adulthood. Obese adolescent girls with high blood pressure (BP) are reported to have increased arterial stiffness, which is associated with the development of hypertension and atherosclerosis. The present study sought to examine the impact of combined resistance and aerobic exercise (CRAE) training on BP, brachial-ankle pulse wave velocity (baPWV), insulin resistance (IR), and body composition in obese prehypertensive girls. Forty girls (age, 15 +/- 1 years; systolic BP, 132 +/- 2 mmHg, diastolic BP, 80 +/- 5 mmHg) were randomly assigned to either a combined exercise (EX, n = 20) or no exercise group (CON, n = 20). The EX group performed CRAE for 12 weeks, 3 times per week. BP, baPWV, blood nitrite/nitrate, endothelin-1 (ET-1), homeostasis model assessment for insulin resistance (HOMA-IR), and body composition were measured before and after the exercise intervention. BP (?-7.3 +/- 2.67 mmHg), baPWV (?-1.23 +/- 0.49 m/s), ET 1 (?-14.35 +/- 1.76 MUmol/mL), nitrite/nitrate (?0.5 +/- 0.09 MUM), HOMA-IR (? 1.4 +/- 0.07), percent body fat (?-1.35 +/- 0.9%), and waist circumference were significantly improved (P < 0.05) in the EX group after 12 weeks of training versus the CON group. These findings indicate that 12 weeks of CRAE improves BP, HOMA-IR, and arterial stiffness and reduces central adiposity in obese adolescent girls with prehypertension. Thus, this study provides evidence that CRAE can be a useful therapeutic treatment for high BP, IR, and central adiposity, thereby reducing the likelihood of pathological development for cardiovascular diseases in later adulthood. PMID- 28590146 TI - Insensitivity to verb conjugation patterns in French children with SLI. AB - Specific language impairment (SLI) is characterised by persistent difficulties that affect language abilities in otherwise normally developing children (Leonard, 2014). It remains challenging to identify young children affected by SLI in French. We tested oral production of the passe compose tense in 19 children in kindergarten and first grade with SLI aged from 5;6 to 7;4 years. All children were schooled in a French environment, but with different linguistic backgrounds. We used an Android application, Jeu de verbes (Marquis et al., 2012), with six verbs in each of four past participle categories (ending in -e, i, -u, and other irregulars). We compared their results and error types to those of control children (from Marquis, 2012-2014) matched for gender, age, languages spoken at home, and parental education. Results show that children with SLI do not master the passe compose in the same way as typical French children do, at later ages than previously shown in the literature. This task shows potential for oral language screening in French-speaking children in kindergarten and first grade, independently of language background. PMID- 28590145 TI - Hypertension and hyperglycemia and the combination thereof enhances the incidence of chronic kidney disease (CKD) in middle-aged and older males. AB - AIM: Chronic kidney disease (CKD) may be an etiologic cause of aging, hypertension, diabetes mellitus (DM), and metabolic syndrome. However, the influence of these cardiovascular risk factors and their combination on the development of CKD remains controversial. This retrospective study evaluated the influence of cardiovascular risk factors and their combination on the incidence of CKD during a 6-year follow-up period in middle-aged and older males. METHODS: The subjects were 303 males without a history of cardiovascular disease, stroke, renal dysfunction, or dialysis treatment. A biochemical analysis, blood pressure (BP) analysis, and anthropometry measurements were performed every year, and the classification of CKD was also assessed based on the estimated glomerular filtration rate (<60 ml/min/1.73 m2) and/or presence of proteinuria. RESULTS: After 6 years, the incidence of CKD was noted in 32 subjects. According to a multivariable analysis, hypertension (hazard ratio [HR]: 3.95, 95% confidence of interval [CI]: 1.64-9.49, p = 0.002) and hyperglycemia (HR: 3.27, 95% CI: 1.42 7.56, p = 0.006) were significantly associated with the incidence of CKD. According to a Cox proportional hazards model, the HR for the incidence of CKD was significantly higher in the combination of high-normal BP/hypertension and impaired fasting glucose/DM group than in the combination of normotensive and normal glucose tolerance group (HR: 7.16, 95% CI: 2.43-17.25, p = 0.001). CONCLUSIONS: These results suggest that the hypertension and hyperglycemia and their combination may be associated with the incidence of CKD. PMID- 28590147 TI - Screening of cardiovascular risk factors in patients with schizophrenia and patients treated with antipsychotic drugs: are we equally exhaustive as with the general population? AB - : Many studies have previously shown increased cardiovascular risk factors related to schizophrenia independently from the use of antipsychotic drugs. However, a poorer effort in clinical detection and management of cardiovascular risk in patients with severe mental illness could also explain these results. To test this hypothesis, we analyzed the differences in screening and incidence of cardiovascular risk factors between schizophrenia, non-schizophrenic patients on treatment with antipsychotic drugs (NS-TAD) and the general population. Data from adult subjects assessed by high-quality register general practitioners from 2006 to 2011 were extracted from the Catalonian SIDIAP database. The schizophrenia, NS TAD, and control groups were compared in terms of measurements and incidence of diabetes, dyslipidemia, obesity, hypertension, and smoking. A total of 4911 patients in the schizophrenia group, 4157 in NS-TAD group, and 98644 in the control group were included. Schizophrenia patients were screened for dyslipidemia and diabetes more frequently than the control group, while for obesity or hypertension, they were screened equal to controls. Also, as compared to the control group, the NS-TAD group was more frequently screened for obesity with no differences in dyslipidemia and diabetes and less frequently for hypertension. Smoking was less frequently screened in both study groups. The incidence of all risk factors studied in both study groups was higher than or equal to the control group, except for hypertension, which had lower incidence. The lack of screening of risk factors does not appear decisive in the increased cardiovascular risk of patients diagnosed with schizophrenia seen in primary care. Studies evaluating the possible under diagnosis of the risk factors are required. ABBREVIATIONS: Schizophrenia (SZ); Treatment with antipsychotic drugs (TAD); Cardiovascular risk factor/s (CVRF); Without schizophrenia but on therapy with antipsychotic drugs (NS-TAD); Defined Daily Dose (DDD). PMID- 28590148 TI - The phonological memory profile of preschool children who make atypical speech sound errors. AB - Previous research indicates that children with speech sound disorders (SSD) have underlying phonological memory deficits. The SSD population, however, is diverse. While children who make consistent atypical speech errors (phonological disorder/PhDis) are known to have executive function deficits in rule abstraction and cognitive flexibility, little is known about their memory profile. Sixteen monolingual preschool children with atypical speech errors (PhDis) were matched individually to age-and-gender peers with typically developing speech (TDS). The two groups were compared on forward recall of familiar words (pointing response), reverse recall of familiar words (pointing response), and reverse recall of digits (spoken response) and a receptive vocabulary task. There were no differences between children with TDS and children with PhDis on forward recall or vocabulary tasks. However, children with TDS significantly outperformed children with PhDis on the two reverse recall tasks. Findings suggest that atypical speech errors are associated with impaired phonological working memory, implicating executive function impairment in specific subtypes of SSD. PMID- 28590149 TI - Objective working hour characteristics and work-life conflict among hospital employees in the Finnish public sector study. AB - This epidemiological cohort study, based on Finnish public sector data, investigated the associations between objective working hour characteristics and work-life conflict in day and shift work. The comprehensive data of hospital workers (n = 8 931, 92% women, average age 45 years), consisted of survey responses from 2012, linked with the payroll data of working hour characteristics from 91 days preceding the survey. Logistic regression analysis was used to investigate the associations between working hour characteristics and experiencing work-life conflict often/very often. The analyses were adjusted for age (< 39, 40-49 and >50 years), sex, level of education, marital status, number of small (0-6 years) and school-aged (7-18 years) children, and the overall stressfulness of the life situation. We also conducted stratified analyses of age and sex on the basis of significant interactions. Difficulties in combining work and life were more often associated with shift work without night shifts and shift work with night shifts than with day work (41% and 34 versus 27%; OR for shift work with night shifts 1.78, 95% CI 1.59-2.00, OR for shift work without night shifts 1.42, 95% CI 1.26-1.60). A high proportion (> 25%) of long (> 40h, (OR 1.26, 95% 1.14-1.39) and very long (> 48h, OR 1.31, 95% CI 1.15-1.49) weekly working hours were associated with work-life conflict, and in the stratified analysis, the latter was also true among women (OR 1.54, 95% CI 1.25-1.89). Of the unsocial working hour characteristics, a relatively large amount (> 10% of all shifts) of evening (OR 1.56, 95% CI 1.41-1.72) and night shifts (OR 1.46, 95%CI 1.32-1.61), a high proportion (> 25% of all shifts) of quick returns (< 11h) (OR 1.46, 95% CI 1.31-1.63), and weekend work (OR 1.44, 95% CI 1.31-1.58) were associated with work-life conflict. A large amount of single days off (> 25% of all days off) was associated with work-life conflict among men (OR 1.90, 95% CI 1.11-3.25), but not in the whole sample. When the two types of shift work were analyzed separately, shift work without night shifts and very long work weeks had higher odds (OR 1.47, 95% CI 1.20-1.80) of work-life conflict than shift work with night shifts. Conversely, weekend work and evening shifts had higher odds of work-life conflict among shift workers with night shifts (OR 1.74, 95% 1.55-1.96; (OR 1.57, 95% CI 1.40-1.77) than among those without night shifts. To conclude, this study shows that shift workers with and without night shifts more often have difficulties combining work and life than day workers. Several unsocial working hour characteristics, including long work weeks, evening and night shifts, weekend work, and quick returns, are associated with work-life conflict. PMID- 28590150 TI - Impact of home-based, patient-centered support for people with advanced illness in an open health system: A retrospective claims analysis of health expenditures, utilization, and quality of care at end of life. AB - BACKGROUND: Home-based care coordination and support programs for people with advanced illness work alongside usual care to promote personal care goals, which usually include a preference for home-based end-of-life care. More research is needed to confirm the efficacy of these programs, especially when disseminated on a large scale. Advanced Illness Management is one such program, implemented within a large open health system in northern California, USA. AIM: To evaluate the impact of Advanced Illness Management on end-of-life resource utilization, cost of care, and care quality, as indicators of program success in supporting patient care goals. DESIGN: A retrospective-matched observational study analyzing medical claims in the final 3 months of life. SETTING/PARTICIPANTS: Medicare fee for-service 2010-2014 decedents in northern California, USA. RESULTS: Final month total expenditures for Advanced Illness Management enrollees ( N = 1352) were reduced by US$4824 (US$3379, US$6268) and inpatient payments by US$6127 (US$4874, US$7682). Enrollees also experienced 150 fewer hospitalizations/1000 (101, 198) and 1361 fewer hospital days/1000 (998, 1725). The percentage of hospice enrollees increased by 17.9 percentage points (14.7, 21.0), hospital deaths decreased by 8.2 percentage points (5.5, 10.8), and intensive care unit deaths decreased by 7.1 percentage points (5.2, 8.9). End-of-life chemotherapy use and non-inpatient expenditures in months 2 and 3 prior to death did not differ significantly from the control group. CONCLUSION: Advanced Illness Management has a positive impact on inpatient utilization, cost of care, hospice enrollment, and site of death. This suggests that home-based support programs for people with advanced illness can be successful on a large scale in supporting personal end-of life care choices. PMID- 28590151 TI - Characterization of a novel modification of a CHO-produced mAb: Evidence for the presence of tyrosine sulfation. AB - Herein we describe the investigation of a Chinese hamster ovary (CHO)-expressed human mAb molecule found partially modified by a +80 Da adduct. This mass difference, suggestive of a single sulfation or phosphorylation addition, was observed by mass analysis of the intact and reduced molecule by mass spectrometry (MS). The modification was located on tyrosine 31 (Y31) of the light chain in the complementarity-determining region 1 by liquid chromatography (LC)-MS peptide mapping and electron transfer dissociation fragmentation. The complete loss of the 80 Da modification moiety during collision induced dissociation fragmentation suggested this modification could not be a tyrosine phosphorylation. Treatment of the mAb with alkaline phosphatase confirmed our hypothesis. Western blot experiment using anti-tyrosine sulfation antibody and LC retention time correlation with corresponding synthetic sulfated peptides further confirmed the identification of tyrosine sulfation on the light chain. The unique sequence motif with neighboring acidic amino acids and local secondary structure might play a role to make Y31 a substrate residue for sulfation. This type of modification, to our knowledge, has not been previously reported for CHO-produced human IgG antibodies. PMID- 28590152 TI - Workers' sleep condition and related disorders in Japan: an analysis based on health insurance claim data and questionnaire. AB - The purpose of this study was to clarify the sleep disorders and sleep conditions among workers in a company through descriptive statistics. We analyzed the data of individuals with suspected sleep disorders based on the 1-year outpatient health insurance claim data of 2803 employees in a company in Japan. We conducted a questionnaire survey to determine the sleep condition and drug usage of the same participants. Claim data of 339 employees (12.1%) were selected for analysis, and the breakdown of diseases comprised 153 (5.5%) with sleep disorders, 149 (5.3%) with headache, 119 (4.2%) with depression and 17 (0.6%) with autonomic imbalance. We recovered 2608 questionnaire responses (93.0%) and found that 1852 subjects (71.0%) were aware of insomnia symptoms within 1 year. Our findings highlight the prevalence of sleep disorders and drug usage among workers in a company, and the conditions of these disorders, including awareness of insomnia. PMID- 28590154 TI - Practice parameters facilitating adoption of advanced technologies for enhancing neuropsychological assessment paradigms. AB - OBJECTIVE: Clinical neuropsychologists have long underutilized computer technologies for neuropsychological assessment. Given the rapid advances in technology (e.g. virtual reality; tablets; iPhones) and the increased accessibility in the past decade, there is an on-going need to identify optimal specifications for advanced technologies while minimizing potential sources of error. Herein, we discuss concerns raised by a joint American Academy of Clinical Neuropsychology/National Academy of Neuropsychology position paper. Moreover, we proffer parameters for the development and use of advanced technologies in neuropsychological assessments. METHOD: We aim to first describe software and hardware configurations that can impact a computerized neuropsychological assessment. This is followed by a description of best practices for developers and practicing neuropsychologists to minimize error in neuropsychological assessments using advanced technologies. We also discuss the relevance of weighing potential computer error in light of possible errors associated with traditional testing. Throughout there is an emphasis on the need for developers to provide bench test results for their software's performance on various devices and minimum specifications (documented in manuals) for the hardware (e.g. computer, monitor, input devices) in the neuropsychologist's practice. CONCLUSION: Advances in computerized assessment platforms offer both opportunities and challenges. The challenges can appear daunting but are a manageable and require informed consumers who can appreciate the issues and ask pertinent questions in evaluating their options. PMID- 28590153 TI - Is it acceptable to video-record palliative care consultations for research and training purposes? A qualitative interview study exploring the views of hospice patients, carers and clinical staff. AB - BACKGROUND: Research using video recordings can advance understanding of healthcare communication and improve care, but making and using video recordings carries risks. AIM: To explore views of hospice patients, carers and clinical staff about whether videoing patient-doctor consultations is acceptable for research and training purposes. DESIGN: We used semi-structured group and individual interviews to gather hospice patients, carers and clinical staff views. We used Braun and Clark's thematic analysis. SETTING/PARTICIPANTS: Interviews were conducted at one English hospice to inform the development of a larger video-based study. We invited patients with capacity to consent and whom the care team judged were neither acutely unwell nor severely distressed (11), carers of current or past patients (5), palliative medicine doctors (7), senior nurses (4) and communication skills educators (5). RESULTS: Participants viewed video-based research on communication as valuable because of its potential to improve communication, care and staff training. Video-based research raised concerns including its potential to affect the nature and content of the consultation and threats to confidentiality; however, these were not seen as sufficient grounds for rejecting video-based research. Video-based research was seen as acceptable and useful providing that measures are taken to reduce possible risks across the recruitment, recording and dissemination phases of the research process. CONCLUSION: Video-based research is an acceptable and worthwhile way of investigating communication in palliative medicine. Situated judgements should be made about when it is appropriate to involve individual patients and carers in video-based research on the basis of their level of vulnerability and ability to freely consent. PMID- 28590155 TI - Cardiopulmonary Exercise Testing and Metabolic Myopathies. AB - Skeletal muscle requires a large increase in its ATP production to meet the energy needs of exercise. Normally, most of this increase in ATP is supplied by the aerobic process of oxidative phosphorylation. The main defects in muscle metabolism that interfere with production of ATP are (1) disorders of glycogenolysis and glycolysis, which prevent both carbohydrate entering the tricarboxylic acid cycle and the production of lactic acid; (2) mitochondrial myopathies where the defect is usually within the electron transport chain, reducing the rate of oxidative phosphorylation; and (3) disorders of lipid metabolism. Gas exchange measurements derived from exhaled gas analysis during cardiopulmonary exercise testing can identify defects in muscle metabolism because [Formula: see text]o2 and [Formula: see text]co2 are abnormal at the level of the muscle. Cardiopulmonary exercise testing may thus suggest a likely diagnosis and guide additional investigation. Defects in glycogenolysis and glycolysis are identified by a low peak [Formula: see text]o2 and absence of excess [Formula: see text]co2 from buffering of lactic acid by bicarbonate. Defects in the electron transport chain also result in low peak [Formula: see text]o2, but because there is an overreliance on anaerobic processes, lactic acid accumulation and excess carbon dioxide from buffering occur early during exercise. Defects in lipid metabolism result in only minor abnormalities during cardiopulmonary exercise testing. In defects of glycogenolysis and glycolysis and in mitochondrial myopathies, other features may include an exaggerated cardiovascular response to exercise, a low oxygen-pulse, and excessive ammonia release. PMID- 28590156 TI - Hearing loss after platinum treatment is irreversible in noncranial irradiated childhood cancer survivors. AB - Cisplatin and carboplatin are effective antineoplastic agents. They are also considered to be potentially highly ototoxic. To date, no long-term follow-up data from well-documented cohorts with substantial numbers of childhood cancer survivors (CCS) with platinum-related hearing loss are available. Therefore, in this study, we studied the reversibility of ototoxicity from discontinuation of treatment onwards in a national cohort of platinum-treated survivors with hearing loss at the end of cancer treatment. Of the 168 CCS with follow-up audiograms, we longitudinally evaluated the course of hearing function in 61 CCS who showed hearing impairment at discontinuation of treatment according to the Munster criteria (>20 dB at >=4-8 kHz). Survivors were treated with platinum (median total cumulative dose cisplatin: 480 mg/m2 and median total cumulative dose carboplatin: 2520 mg/m2). Median follow-up time was 5.5 years (range: 1.0-28.8 years). The results showed that none of these survivors revealed improvement of hearing function even till 28.8 years after discontinuation of treatment (grade <2b during long-term follow-up). An increase in hearing loss with two or three Munster degrees was observed in five of 61 survivors after 1.6-19.6 years. Overall, this indicates that ototoxicity after platinum treatment may be irreversible and that longitudinal clinical audiological monitoring and care is required in long-term survivors of childhood cancer on a large scale. PMID- 28590157 TI - Pilot randomised controlled trial of focused narrative intervention for moderate to severe depression in palliative care patients: DISCERN trial. AB - BACKGROUND: Depression is poorly detected and sub-optimally managed in palliative care patients, and few trials of psychosocial interventions have been carried out in this group of patients. AIMS: A pilot trial to determine the effect of a focused narrative intervention on depression in palliative care patients when used in addition to usual care. DESIGN: Patients scoring 10 or higher on Patient Health Questionnaire-9 randomised to focused narrative intervention in addition to usual care or usual care only and followed up at 2, 4 and 6 weeks. A reduction of five points on Patient Health Questionnaire-9 was regarded as clinically significant response to treatment. SETTING/PARTICIPANTS: Palliative care patients aged over 18 recruited from hospice day care services - exclusion criteria included an estimated prognosis of 6 weeks or less, cognitive impairment and unable to understand written or spoken English. RESULTS: Out of 57 participating patients (71% female), with mean age 65.1 years (range 36-88 years), 33 patients were randomised to the intervention and 24 to usual care only. Mean Patient Health Questionnaire-9 score at baseline was 16.4. Patients receiving intervention had greater reduction in Patient Health Questionnaire-9 score at 6 week follow-up ( p = 0.04). Median survival was 157 days for intervention and 102 days for control group patients ( p = 0.07). CONCLUSION: This pilot trial suggests a focused narrative intervention in palliative care patients with moderate to severe depression can reduce depression scores more than usual care alone. Patients receiving intervention appeared to have longer survival. These results support the need for a fully powered trial. PMID- 28590158 TI - Relationship between total polar components and polycyclic aromatic hydrocarbons in fried edible oil. AB - Deep-fried dough sticks (a Chinese traditional breakfast) were fried individually in peanut, sunflower, rapeseed, rice bran, soybean and palm oil without any time lag for 32 h (64 batches fried, each for 30 min) and fried oil samples were obtained every 2 h. The frying-induced changes in the levels of total polar compounds (TPC) and polycyclic aromatic hydrocarbons (PAHs) were investigated by edible oil polar compounds (EOPC) fast separation chromatographic system and gas chromatography-mass spectrometry (GC-MS), respectively. The correlations were analysed of TPC with benzo[a]pyrene (BaP), TPC and PAH4 (benzo[a]anthracene, chrysene, benzo[b]fluoranthene and benzo[a]pyrene) as well as TPC with PAH16 (USEPA 16 PAHs). The results revealed that the levels of TPC and PAHs in fried oil considerably increased with frying time, and the type of oil affected their formation, which could inform the choice of oil for frying. The total BaP equivalents (?BaPeq) concentrations in fresh oil and in oil whose TPC exceeded 27% were 2.14-13.48 and 5.78-10.80 MUg kg-1, respectively, which means that the carcinogenic potency of frying oil was more pronounced than that of fresh oil. In addition, the TPC concentration was significantly correlated with the concentrations of the sum of the 16 PAHs, PAH4 and BaP, so that the levels of PAHs could be predicted according to the levels of TPC in fried oil. In European standards, the rejection point for TPC in frying oil should be recalculated when considered PAHs. In all, the concentration of PAHs is a vital factor for ensuring the safety of frying oil. PMID- 28590159 TI - Which patients die in their preferred place? A secondary analysis of questionnaire data from bereaved relatives. AB - BACKGROUND: Previous studies on factors influencing the place of death have focused on cancer patients dying at home. However, home is not always the preferred place. AIM: To provide insight into the extent to which patients with various diseases die in their preferred place and into factors associated with dying in the preferred place. DESIGN: A secondary analysis of the data set of the evaluation study of the National Quality Improvement Programme for Palliative Care was undertaken to explore factors related to 'dying in the preferred place'. SETTING/PARTICIPANTS: A total of 797 bereaved relatives filled in the Consumer Quality Index Palliative Care, a validated and reliable questionnaire. RESULTS: Two-thirds of the patients died in the preferred place. A preference for dying at home and having had a stroke decreased the likelihood of dying in the preferred place, while having a partner, dementia, contact with the general practitioner in the last week before death, and continuity of care between professionals increased the likelihood of dying in the preferred place. Furthermore, people who wanted to die at home and also had dementia were more likely to die elsewhere than people without dementia who wanted to die at home. CONCLUSION: Positive associations were found between continuity of care between healthcare professionals and contact with the general practitioner and the chance of people dying in their preferred place. Moreover, special attention for people who have had a stroke and for people with dementia who want to die at home seems indicated as their diagnosis is negatively associated with dying in their preferred place. PMID- 28590160 TI - The effect of caster types on global rolling resistance in manual wheelchairs on indoor and outdoor surfaces. AB - An important aspect of reducing the strain of wheeling is to decrease rolling resistance. Previous laboratory research, using a treadmill, determined that smaller casters significantly increased rolling resistance. The purpose of this study was to determine the effect of caster size on various indoor and outdoor surfaces on global wheelchair rolling resistance. Three caster types with sizes 4 in, 5 in, and 6 in, three indoor surfaces, and three outdoor surfaces were studied. A manual wheelchair was passively pulled along each surface at 1.11 m/s (3.64 ft/s) by a power wheelchair, and the global rolling resistance of the manual wheelchair was measured using a calibrated force transducer. A 3*3 repeated measures analysis of variance (ANOVA) was conducted for both indoor and outdoor environments. The 4-in casters resulted in the highest global rolling resistance on most surfaces. The 5-in casters had the least rolling resistance on most indoor surfaces, and the 6-in casters had the least rolling resistance on most outdoor surfaces. Although 4-in casters are more popular among active wheelchair users, larger casters were shown to have lower rolling resistance on most surfaces. This study may help users select the best caster size depending upon their daily activities and lifestyle. PMID- 28590161 TI - Nitrogen and phosphorus treatment of marine wastewater by a laboratory-scale sequencing batch reactor with eco-friendly marine high-efficiency sediment. AB - : We screened and identified a NH3-N-removing bacterial strain, Bacillus sp. KGN1, and a [Formula: see text] removing strain, Vibrio sp. KGP1, from 960 indigenous marine isolates from seawater and marine sediment from Tongyeong, South Korea. We developed eco-friendly high-efficiency marine sludge (eco-HEMS), and inoculated these marine bacterial strains into the marine sediment. A laboratory-scale sequencing batch reactor (SBR) system using the eco-HEMS for marine wastewater from land-based fish farms improved the treatment performance as indicated by 88.2% removal efficiency (RE) of total nitrogen (initial: 5.6 mg/L) and 90.6% RE of total phosphorus (initial: 1.2 mg/L) under the optimal operation conditions (food and microorganism (F/M) ratio, 0.35 g SCODCr/g mixed liquor volatile suspended solids (MLVSS).d; dissolved oxygen (DO) 1.0 +/- 0.2 mg/L; hydraulic retention time (HRT), 6.6 h; solids retention time (SRT), 12 d). The following kinetic parameters were obtained: cell yield (Y), 0.29 g MLVSS/g SCODCr; specific growth rate (u), 0.06 d-1; specific nitrification rate (SNR), 0.49 mg NH3-N/g MLVSS.h; specific denitrification rate (SDNR), 0.005 mg [Formula: see text]/g MLVSS.h; specific phosphorus uptake rate (SPUR), 0.12 mg [Formula: see text]/g MLVSS.h. The nitrogen- and phosphorus-removing bacterial strains comprised 18.4% of distribution rate in the microbial community of eco-HEMS under the optimal operation conditions. Therefore, eco-HEMS effectively removed nitrogen and phosphorus from highly saline marine wastewater from land-based fish farms with improving SNR, SDNR, and SPUR values in more diverse microbial communities. ABBREVIATIONS: DO: dissolved oxygen; Eco-HEMS: eco-friendly high efficiency marine sludge; F/M: food and microorganism ratio; HRT: hydraulic retention time; ML(V)SS: mixed liquor (volatile) suspended solids; NCBI: National Center for Biotechnology Information; ND: not determined; qPCR: quantitative real time polymerase chain reaction; RE: removal efficiency; SBR: sequencing batch reactor; SD: standard deviation; SDNR: specific denitrification rate; SNR: specific nitrification rate; SPUR: specific phosphate uptake rate; SRT: solids retention time; T-N: total nitrogen; T-P: total phosphorus; (V)SS: (volatile) suspended solids; w.w.: wet weight. PMID- 28590162 TI - Exercise Testing, Supplemental Oxygen, and Hypoxia. AB - Cardiopulmonary exercise testing (CPET) in hyperoxia and hypoxia has several applications, stemming from characterization of abnormal physiological response profiles associated with exercise intolerance. As altered oxygenation can impact the performance of gas-concentration and flow sensors and pulmonary gas exchange algorithms, integrated CPET system function requires validation under these conditions. Also, as oxygenation status can influence peak [Formula: see text]o2, care should be taken in the selection of work-rate incrementation rates when CPET performance is to be compared with normobaria at sea level. CPET has been used to evaluate the effects of supplemental O2 on exercise intolerance in chronic obstructive pulmonary disease, interstitial pulmonary fibrosis, and cystic fibrosis at sea level. However, identification of those CPET indices likely to be predictive of supplemental O2 outcomes for exercise tolerance at altitude in such patients is lacking. CPET performance with supplemental O2 in respiratory patients residing at high altitudes is also poorly studied. Finally, CPET has the potential to give physiological and clinical information about acute and chronic mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. It may also translate high-altitude acclimatization and adaptive processes in healthy individuals into intensive care medical practice. PMID- 28590163 TI - Merotelic kinetochore attachment in oocyte meiosis II causes sister chromatids segregation errors in aged mice. AB - Mammalian oocyte chromosomes undergo 2 meiotic divisions to generate haploid gametes. The frequency of chromosome segregation errors during meiosis I increase with age. However, little attention has been paid to the question of how aging affects sister chromatid segregation during oocyte meiosis II. More importantly, how aneuploid metaphase II (MII) oocytes from aged mice evade the spindle assembly checkpoint (SAC) mechanism to complete later meiosis II to form aneuploid embryos remains unknown. Here, we report that MII oocytes from naturally aged mice exhibited substantial errors in chromosome arrangement and configuration compared with young MII oocytes. Interestingly, these errors in aged oocytes had no impact on anaphase II onset and completion as well as 2-cell formation after parthenogenetic activation. Further study found that merotelic kinetochore attachment occurred more frequently and could stabilize the kinetochore-microtubule interaction to ensure SAC inactivation and anaphase II onset in aged MII oocytes. This orientation could persist largely during anaphase II in aged oocytes, leading to severe chromosome lagging and trailing as well as delay of anaphase II completion. Therefore, merotelic kinetochore attachment in oocyte meiosis II exacerbates age-related genetic instability and is a key source of age-dependent embryo aneuploidy and dysplasia. PMID- 28590164 TI - Care of the Critically Ill Burn Patient. An Overview from the Perspective of Optimizing Palliative Care. AB - Burn specialists have long recognized the need for and have role modeled a comprehensive approach incorporating relief of distress as part of care during critical illness. More recently, palliative care specialists have become part of the healthcare team in many U.S. hospitals, especially larger academic institutions that are more likely to have designated burn centers. No current literature describes the intersection of palliative care and burn care or integration of primary and specialist palliative care in this unique context. This Perspective gives an overview of burn care; focuses on pain and other symptoms in burn intensive care unit settings; addresses special needs of critically ill burned patients, their families, and clinicians for high-quality palliative care; and highlights potential benefits of integrating primary and specialist palliative care in burn critical care. MEDLINE and the Cumulative Index to Nursing and Allied Health Literature were searched, and an e-mail survey was used to obtain information from U.S. Burn Fellowship Program directors about palliative medicine training. The Improving Palliative Care in the Intensive Care Unit Project Advisory Board synthesized published evidence with their own research and clinical experience in preparing this article. Mortality and severe morbidity for critically ill burned patients remains high. American Burn Association guidelines lay the foundation for a robust system of palliative care delivery, embedding palliative care principles and processes in intensive care by burn providers. Understanding basic burn care, challenges for symptom management and communication, and the culture of the particular burn unit, can optimize quality and integration of primary and specialist palliative care in this distinctive setting. PMID- 28590165 TI - The complex relationship between household income of family caregivers, access to palliative care services and place of death: A national household population survey. AB - BACKGROUND: Previous work shows that more affluent patients with cancer are more likely to die at home, whereas those dying from non-cancer conditions are more likely to die in hospital. Family caregivers are an important factor in determining place of death. AIM: To investigate associations between family caregivers' household income, patients' access to specialist palliative care and place of patients' death, by level of personal end-of-life care. DESIGN: A cross sectional community household population survey. SETTING AND PARTICIPANTS: Respondents to the Household Survey for England. RESULTS: One-third of 1265 bereaved respondents had provided personal end-of-life care (caregivers) (30%). Just over half (55%) of decedents accessed palliative care services and 15% died in a hospice. Place of death and access to palliative care were strongly related ( p < 0.001). Palliative care services reduced the proportion of deaths in hospital ( p < 0.001), and decedents accessing palliative care were more likely to die at home than those who did not ( p < 0.001). Respondents' income was not associated with palliative care access ( p = 0.233). Overall, respondents' income and home death were not related ( p = 0.106), but decedents with caregivers in the highest income group were least likely to die at home ( p = 0.069). CONCLUSION: For people who had someone close to them die, decedents' access to palliative care services was associated with fewer deaths in hospital and more home deaths. Respondents' income was unrelated to care recipients' place of death when adjusted for palliative care access. When only caregivers were considered, decedents with caregivers from higher income quartiles were the least likely to die at home. Family caregivers from higher income brackets are likely to be powerful patient advocates. Caregiver information needs must be addressed especially with regard to stage of disease, aim of care and appropriate interventions at the end of life. PMID- 28590166 TI - Teduglutide-induced stem cell function in intestinal repair. AB - Malabsorption is a major and common clinical characteristics of short bowel syndrome (SBS) and inflammatory bowel diseases (IBD). Traditional treatment opportunities have focused on decreasing malabsorptive losses via dietary modifications and antisecretory/antidiarrheal agents. However, novel therapeutic modalities aim to enhance the absorptive capacity of the residual bowel by the administration of different intestinal growth factors including teduglutide. In a current study the existence of two distinct functional putative epithelial stem cell subpopulations (i.e. Lgr5+/Bmi1- and Lgr5-/Bmi1+) have been described in a rat model of ileal resection and anastomosis. The described epithelial stem cell subpopulations displayed distinct behaviour after surgical injury and teduglutide administration. Though teduglutide was found to be clinically effective, we must keep in mind that growth factors theoretically may provoke adenoma development and subsequent malignant transformation. The present results give us a better insight into the role of stem cell modulation in intestinal repair. Based on these results new perioperative adjuvant pharmacological approaches may be developed for SBS and IBD patients to reduce the clinical symptoms and complications of associated malabsorption. PMID- 28590167 TI - Effects of In Vivo and In Vitro Treatment of Ascaris suum Eggs with Anthelmintic Agents on Embryonation and Infectivity for Mice. AB - Ascaris suum is an important intestinal nematode causing economic losses in swine. Anthelminthic treatment is used to control A. suum infections and is part of normal production practices. Treatment with anthelminthic agents results in expulsion of adult worms from the intestinal tract and ends further contamination of the environment with eggs. The present study was conducted to determine the effects of drug treatment on the embryonation of A. suum eggs collected from worms obtained from pigs treated with 4 different commercially available anthelmintics. The effects of treatment with abamectin, doramectin, ivermectin, flubendazole, or no treatment on embryonation of A. suum eggs collected from female A. suum expelled in the feces was determined. The embryonation of eggs obtained from pigs treated with abamectin, doramectin, and ivermectin was not significantly (P > 0.05) different from eggs from non-treated control pigs. In contrast, the embryonation of A. suum eggs collected from worms from pigs treated with flubendazole demonstrated inhibited development, and most eggs remained in the 1-cell stage (85.5%) and only 6.3% of eggs developed larvae. In another experiment, we examined the direct effects of doramectin and flubendazole added to solutions of A. suum eggs collected from non-treated control pigs. Egg cultures were exposed to direct in vitro treatment with 0.04-parts per million (ppm) doramectin or 1.0-ppm flubendazole for 24 hr (highest concentrations [Cmax] of drugs in serum) and then embryonation and infectivity for mice was determined. Treatment of eggs in vitro did not significantly effect (P > 0.05) larval development or oral infectivity for mice. Our study demonstrates that flubendazole fed to pigs results in inhibited embryonation of A. suum eggs. However, direct treatment of A. suum eggs in culture for 24 hr with flubendazole did not inhibit embryonation or oral infectivity of in vitro treated eggs. Anthelmintic treatment of pigs in vivo with abamectin, doramectin, and ivermectin had no significant (P > 0.05) effect on embryonation of A. suum eggs, and 24 hr treatment with doramectin in vitro had no direct effects (P > 0.05) on embryonation or oral infectivity of A. suum eggs. PMID- 28590168 TI - Experimental Life-Cycle of Varestrongylus eleguneniensis (Nematoda: Protostrongylidae) in a Captive Reindeer (Rangifer tarandus tarandus) and a Muskox (Ovibos moschatus moschatus). AB - The life-cycle of a recently described protostrongylid lungworm, Varestrongylus eleguneniensis, which infects caribou, muskoxen, and moose from Arctic and boreal regions of North America, was completed experimentally for the first time. A native North American slug species, Deroceras laeve, was infected with the first stage larvae (L1) isolated from the feces of wild muskoxen to generate third stage larvae (L3). These were administered to a captive reindeer calf (250 L3) and an adult captive muskox (380 L3). The prepatent periods for the reindeer and muskox were 56 and 72 days, respectively. Patency lasted for only 19 days in the reindeer, and fecal larval counts were very low (0.09-1.53 larvae per gram of feces). Patency in the muskox was at least 210 days, and likely over 653 days, and the fecal larval counts were higher (0.06-17.8 larvae per gram of feces). This work provides the first experimental completion of the life-cycle of V. eleguneniensis. PMID- 28590202 TI - Editorial: Mental Health in Prisons. PMID- 28590201 TI - Improved sequence variant analysis strategy by automated false positive removal. AB - Sequence variant analysis (SVA) is critical in therapeutic protein development because it ensures the absence of genetic mutations of a production clone or high level misincorporations during cell culture. While software for searching sequence variants from mass spectrometry data are available, effectively distinguishing true positives from a large number of false positives in the reported hits or identifications found in the error tolerant search mode is a challenge. This verification process must be done manually and can take several days or even weeks to accomplish. We report here the use of a Perl-based script to evaluate every identified hit to remove the false positives from the search results of PepFinderTM (also known as MassAnalyzer) based on orthogonal criteria. Our data show that the false positives from PepFinderTM output were reduced ~4 fold without loss of accuracy in the detection of true identifications, representing a more than 70% reduction in time compared with the manual data verification process. PMID- 28590203 TI - Manifest Dream Content as a Predictor of Suicidality. AB - A number of behavioral, social, biological, and cultural factors are associated with suicide. However, the ability to predict an imminent suicide attempt remains problematic. Prior studies indicate that the manifest dream content of depressed, non-suicidal patients differs from that of depressed, suicidal patients. The dream imagery of depressed, suicidal patients contains themes of death, dying, violence, and departure. The dream imagery of depressed, non-suicidal patients contains themes of rejection, helplessness, hopelessness, humiliation, failure, and loss. In the present study, the dream reports of 52 depressed patients were collected and rated for various themes. Patients were divided into three groups: Depressed and non-suicidal; Depressed, with suicidal ideation; Depressed, with suicidal ideation and/or attempt(s). Themes of death and/or dying, and to a lesser extent, themes of violence, injury, and/or murder occurred with greater frequency in the dream reports of depressed patients with suicidal ideation and/or attempts, than in the dream reports of depressed patients without suicidal ideation or behavior. These observations correspond with the prevailing psychodynamic explanation of suicide; namely, that it is a murderous attack on the self that is identified with hated internalized objects. PMID- 28590204 TI - Differentiation Between Schizophreniform Configurations and Psychotic Personality Structures. AB - The symptom overlap between primary psychotic and severe personality disorders renders timely diagnosis challenging, which often results in ambiguous treatment and poorly defined outcomes. Kernberg's (1984) structural model of personality, treating symptoms as a non-pathognomonic higher order construct, has much contributed to our understanding of the nature of some severe disorders, highlighting fundamental facets of personality function. However, the model's main focus is on borderline personality organization and thus offers an incomplete formulation of psychotic structure. With regard to the psychotic structure, two distinct pathological disorders are currently confounded and need to be distinguished: (1) the authentic psychotic structures, mainly resulting from failures in early relational and affective development, and (2) schizophreniform configurations, mostly derived from a neurodevelopmental etiology. This differentiation, while specifying the notion of psychotic personality structure, takes into consideration: (a) the role of temperament bias, hypersensitity in particular; (b) dissimilar productions in response to projective testing, such as the Rorschach inkblot test; (c) differential processes in response to psychotherapy, including typical transferential manifestations; (d) differential symptom presentation. Key criteria to facilitate the differential diagnosis with severely regressed borderline structures are suggested. Clinical material illustrates the application of the proposed revised model. Therapeutic implications are discussed. PMID- 28590205 TI - Psychodynamic Treatment of the Criminal Offender: Making the Case for Longer-Term Treatment in a Longer-Term Setting. AB - In recent years, prisons and jails have become de facto psychiatric hospitals, responsible for the care and treatment of individuals with serious mental illness. Historically, cognitive-behaviorally informed therapeutic approaches have been the treatment of choice among mental health practitioners in correctional settings. However, inmate-clients often present with complex diagnostic issues that are arguably better served by long-term treatment options, such as psychodynamic psychotherapy. We first review the nature of psychotherapy in the correctional setting, as well as treatment barriers and challenges faced by both mental health providers and inmate-clients. We then review treatment studies that examine the efficacy of various therapeutic techniques in correctional/forensic contexts. Finally, we argue that, due to the complex nature of psychopathology, average length of time incarcerated, and treatment issues that arise in this multifaceted and challenging setting, mental health treatment providers should consider providing psychodynamic treatment modalities when working with incarcerated individuals. We also argue that more research is needed to examine the efficacy of these treatment approaches with inmate-clients. PMID- 28590206 TI - Letter to the Editor. PMID- 28590207 TI - An Integrative Approach to Treatment-Resistant Obsessive-Compulsive Disorder. AB - Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder that often runs a chronic unremitting course. Treatment outcomes can be unsatisfactory despite the availability of various somatic and psychological therapies. Psychodynamic psychotherapy in combination with cognitive behavioral therapy (CBT) with exposure and response prevention (ERP) could help patients with treatment-resistant OCD achieve better outcomes. An integrative approach can help patients gain insight, strengthen the therapeutic alliance, improve treatment adherence, and provide symptomatic relief when other treatments seem insufficient or have failed. We describe the treatment process of a person with treatment resistant OCD who received pharmacotherapy, concurrent CBT/ERP, and a brief course of psychodynamic psychotherapy. Case formulations from cognitive behavioral and psychodynamic perspectives are presented. The authors discuss the advantages of doing a psychodynamic assessment and formulation in treatment refractory cases and the wisdom of integrating psychotherapy interventions for OCD, as well as the unique clinical features of cases that warrant a multimodal treatment approach. PMID- 28590208 TI - Borderline Patients: 25 to 50 Years Later: With Commentary on Outcome Factors. AB - The current study concerns the long-term follow-up of 40 patients with borderline personality disorder. Sixteen were patients from the PI-500 study, formerly hospitalized at the New York State Psychiatric Institute. Twenty-four had been from the author's private practice 25 to 50 years ago. Twenty-one of the combined group had first been in treatment 50 years ago. This is believed to be the longest follow-up period recorded for borderline patients. The main results are that two-thirds of the patients eventually reached the level of either clinical remission or clinical recovery. Reaching recovery, in the patients now in their 60s and 70s, was associated with having life-long personality traits, as described in the Five-Factor Model, of Agreeableness and Conscientiousness. These traits conduced to better outcome in forming lasting relationships and in workplace success. In some of the patients, genetic vulnerability to mood disorder (recurrent unipolar depression; bipolar disorder) was associated with slower improvement or to poorer outcome. Incest by an older-generation relative appears as another negative prognostic factor. Psychotherapy for most of the patients had originally been psychoanalytically oriented ("expressive"), though circumstances and life crises often led to the use of supportive, psychopharmacological, and behavioral interventions as well. PMID- 28590209 TI - Psychodynamic Treatment of Combat Veterans with PTSD at Risk for Suicide. AB - Posttraumatic stress disorder is a condition associated with suicide in both military personnel and combat veterans. Most veterans with PTSD, however, are not at risk of suicide. The major factor distinguishing those who attempted or were preoccupied with suicide is persistent severe guilt over behavior in combat while emotionally out of control. A 12-session short-term, psychodynamic psychotherapy, presented here, showed promise of success in dissipating the guilt from combat related actions in veterans of the war in Vietnam. Preliminary work with combat veterans of the wars in Iraq and Afghanistan indicates it may be equally successful in treating them. Basic aspects of the psychodynamic approach could also be incorporated into current therapies and should improve their ability to treat veterans with PTSD at risk for suicide. Case examples are provided. PMID- 28590211 TI - A systematic review of the effectiveness of palliative interventions to treat rectal tenesmus in cancer. AB - BACKGROUND: Rectal tenesmus is a distressing symptom in patients with advanced cancer and challenging to treat. There is lack of consensus on the appropriate management of tenesmus in this patient population. AIM: To identify and examine the effectiveness of interventions to palliate rectal tenesmus caused by advanced cancer when surgery, radiotherapy or chemotherapy are no longer treatment options. DESIGN: A systematic review of the literature following standard systematic review methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. DATA SOURCES: A comprehensive search of the electronic databases MEDLINE, EMBASE and the Cochrane Library was conducted from date of inception to April 2016. PubMed 'related articles' search, grey literature search and hand-searches of the bibliographies of relevant papers and textbooks were also performed. Non-cancer patients were excluded. Any studies involving surgery or radiotherapy to treat tenesmus were excluded. Studies involving interventions to treat pelvic pain syndromes without specific outcome measures on severity of tenesmus were excluded. The quality of the studies was assessed using a National Institute for Health and Clinical Excellence recommended quality assessment tool. RESULTS: From 861 studies, 9 met full criteria and were selected. All were case series investigating the use of pharmacological interventions (diltiazem, nifedipine, methadone, mexiletine hydrochloride, lidocaine and bupivacaine), anaesthetic interventions (lumbar sympathectomy, neurolytic superior hypogastric plexus block), and endoscopic laser interventions. The included studies showed substantial heterogeneity, and therefore, a meta-analysis was not feasible. CONCLUSION: From this review, we identified a significant gap in research into the palliation of rectal tenesmus. A multimodal approach may be necessary due to the complexity of the pathophysiology of tenesmus. Future research should focus on randomised controlled trials of drug therapies whose potential effectiveness is suggested by case series. PMID- 28590214 TI - First Record of Aedes albopictus in Jordan. AB - The presence of Aedes albopictus in Jordan is reported for the 1st time based on collections of larvae and adults from 7 sites representing 3 governorates (Irbid, Ajloun, and Balqa). Adults were recovered from around houses, while larvae were collected from concrete reservoirs, water tanks for irrigation, small containers, and water barrels. Larvae of Ae. albopictus were found along with larvae of Culiseta longiareolata and Culex laticinctus. PMID- 28590212 TI - Evidence for intermolecular domain exchange in the Fab domains of dimer and oligomers of an IgG1 monoclonal antibody. AB - Recombinant protein therapeutics have become increasingly useful in combating human diseases, such as cancer and those of genetic origin. One quality concern for protein therapeutics is the content and the structure of the aggregated proteins in the product, due to the potential immunogenicity of these aggregates. Collective efforts have led to a better understanding of some types of protein aggregates, and have revealed the diversity in the structure and cause of protein aggregation. In this work we used a broad range of analytical techniques to characterize the quinary structure (complexes in which each composing unit maintains native quaternary structure) of the stable non-covalent dimer and oligomers of a monoclonal IgG1lambda antibody. The results supported a mechanism of intermolecular domain exchange involving the Fab domains of 2 or more IgG molecules. This mechanism can account for the native-like higher order (secondary, tertiary and disulfide bonding) structure, the stability of the non covalent multimers, and the previously observed partial loss of the antigen binding sites without changing the antigen-binding affinity and kinetics of the remaining sites (Luo et al., 2009, mAbs 1:491). Furthermore, the previously observed increase in the apparent affinity to various Fcgamma receptors (ibid), which may potentially promote immunogenicity, was also explained by the quinary structure proposed here. Several lines of evidence indicated that the formation of multimers by the mechanism of intermolecular domain exchange took place mostly during expression, not in the purified materials. The findings in this work will advance our knowledge of the mechanisms for aggregation in therapeutic monoclonal antibodies. PMID- 28590215 TI - Evaluation of the Trapping Performance of Four Biogents AG Traps and Two Lures for the Surveillance of Aedes albopictus and Other Host-Seeking Mosquitoes. AB - The BG-Sentinel(r) (BGS) trap has recently been redesigned for increased durability and ergonomic functionality, marketed as the BG-Sentinel 2(r) (BGS2). We evaluated the trapping performance of these 2 traps in addition to the BG Sentinel prototype (BGSP), a model similar to the BGS2 that was beta tested in several US states in 2014, and the BG-SNAP (SNAP), which is a prototype revision of the BG-MosquititoTM. We also evaluated 2 new Biogents AG lures: the BG-Lure cartridge and BG-SweetscentTM, as they are granular formulations replacing the original mesh BG-Lure(r). Evaluations were conducted between July and September 2015 under field conditions within a suburban area in southeastern Virginia. The 4 traps were compared with their respective lure systems (BGS, BGSP, and BGS2 with BG-Lure cartridge; SNAP with BG-Sweetscent). No significant differences were seen in total female mosquito collections among the 3 BG-Sentinel models. All 3 Sentinels collected significantly more female mosquitoes than the SNAP (P <= 0.009); BGS and BGS2 both collected significantly more Aedes albopictus females than the SNAP (P <= 0.02). The 2 lures were compared in both BGS2 and SNAP traps. Although both lures performed significantly better in the BGS2 trap (P <= 0.0003), there were no significant differences in number of mosquitoes or species composition collected with BG-Sweetscent and BG-Lure cartridge within the same trap type. PMID- 28590216 TI - Diagnostic Doses of Insecticides for Adult Aedes aegypti to Assess Insecticide Resistance in Cuba. AB - The objective of this study was to determine diagnostic doses (DDs) of 5 insecticides for the Rockefeller susceptible strain of Aedes aegypti , using the Centers for Disease Control and Prevention (CDC) bottle bioassay as a tool for monitoring insecticide resistance in the Cuban vector control program. The 30-min DD values determined in this study were 13.5 MUg/ml, 6.5 MUg/ml, 6 MUg/ml, 90.0 MUg/ml, and 15.0 MUg/ml for cypermethrin, deltamethrin, lambda-cyhalothrin, chlorpyrifos, and propoxur, respectively. To compare the reliability of CDC bottle bioassay with the World Health Organization susceptible test, 3 insecticide-resistant strains were evaluated for deltamethrin and lambda cyhalothrin. Results showed that the bottles can be used effectively from 21 to 25 days after treatment and reused up to 4 times, depending on the storage time. The CDC bottle bioassay is an effective tool to assess insecticide resistance in field populations of Ae. aegypti in Cuba and can be incorporated into vector management programs using the diagnostic doses determined in this study. PMID- 28590217 TI - Field Evaluation of Indoor Thermal Fog and Ultra-Low Volume Applications For Control of Aedes aegypti in Thailand. AB - Efficacies of a handheld thermal fogger (PatriotTM) and a backpack ultra-low volume (ULV) sprayer (TwisterTM) with combinations of 2 different adulticides (pyrethrin, deltamethrin) and an insect growth regulator (pyriproxyfen) were field-tested and compared for their impact on reducing indoor Aedes aegypti populations in Thailand. The effectiveness of the indoor space sprays was evaluated by sampling the natural Ae. aegypti population in houses and determining their physiological status, by monitoring mortality of sentinel caged mosquitoes (AFRIMS strain) and by assessing larval mortality in laboratory bioassays using water exposed to the spray. A total of 14,742 Ae. aegypti were collected from Biogents Sentinel traps in this study. The combination of ULD(r) BP-300 (3% pyrethrin) and NyGuard(r) (10% pyriproxyfen) sprayed either by the Patriot or Twister significantly reduced some Ae. aegypti populations up to 20 days postspray relative to the control clusters. The addition of pyriproxyfen to the adulticide extended how long household mosquito populations were suppressed. In 2 of the 4 products being compared, the Twister resulted in higher mortality of caged mosquitoes compared with the Patriot. However, neither machine was able to achieve high mortality among Ae. aegypti placed in hidden (protected) cages. The larval bioassay results demonstrated that the Twister ULV provided better adult emergence inhibition than the Patriot (thermal fogger), likely due to larger droplet size. PMID- 28590218 TI - Comparison of Mosquito Abundance From Biogents Sentinel 2.0 Traps With and Without Rain Covers. AB - Biogents Sentinel (BGS) traps have rapidly become a standard for adult Aedes aegypti surveillance. Several investigators have found that trap collections can be damaged easily by heavy dew or rain entering the trap intake port. In addition, water entering the trap may temporarily stop the fan, thus reducing the collection potential of the trap. We evaluated the effectiveness of a rain cover designed to minimize damage to mosquito trap collections from BGS 2.0 traps in a residential backyard in Jacksonville, FL. Rain covers consisted of white fiberglass 51-cm2 sheets positioned 19, 29, and 39 cm above the air intake of the traps. One BGS trap did not have a rain cover and was used as a control standard for comparison. All traps were baited with the BG-Lure. Generally, traps with rain covers resulted in higher mosquito counts when compared with collections from uncovered traps. Overall mosquito abundance was greater from traps with the rain cover positioned at 29 cm, but this difference was not significantly different when compared with the other cover heights. Covers spaced 29 or 39 cm collected significantly more Culex quinquefasciatus compared with traps at 19 cm and no cover. Species diversity was greatest for BGS traps with the rain cover positioned at 29 cm followed by 39 cm, 19 cm, and no cover; however, differences in diversity among the traps, with or without covers, were not significant. PMID- 28590220 TI - Effect of Common Species of Florida Landscaping Plants on the Efficacy of Attractive Toxic Sugar Baits Against Aedes albopictus. AB - Attractive toxic sugar bait (ATSB) was applied to 5 different types of commonly found plants in landscaping of northeastern Florida. The ATSB applications were assessed for possible plant effects and preference against Aedes albopictus in semifield evaluations. Positive and negative controls consisted of plants sprayed with attractive sugar bait (no toxicant) and plants with nothing applied. Bioassays were conducted on stems with leaf clippings and on full plants to assess any difference in mosquito mortality on the different plants. Plants utilized in these evaluations were Indian hawthorne, Yaupon holly, Japanese privet, Loropetalum ruby, and podocarpus. In both assays, no significant difference was observed in the effect of ATSBs on adult female mosquitoes based on the type of plant. ATSB could be applied to common landscape plants for adult Ae. albopictus control. PMID- 28590221 TI - Evaluation of Pyriproxyfen Dissemination via Aedes albopictus From a Point-Source Larvicide Application in Northeast Florida. AB - The Asian tiger mosquito, Aedes albopictus , ranks among the most important vectors of dengue fever, Zika virus, and chikungunya virus. With no specific medications or vaccines available, vector control is the only way to combat these diseases. Autodissemination of the insect growth regulator pyriproxyfen (NyGuard(r)) from a point-source treatment was evaluated in field settings in northeast Florida. The objective of this study was to investigate the possibility of pyriproxyfen dissemination from a treatment site to nontreated oviposition sites via the skip oviposition behavior of Ae. albopictus. A spray application was made to a tire pile using a Stihl(r) SR 420 backpack sprayer. Autodissemination oviposition vases containing oak infusion water were positioned in groups of five at 25 to 400 m in 4 transects surrounding the tire pile. Two sets of 5 control vases containing oak infusion water were placed 1,500 m from the tire pile and oak infusion water samples were collected directly from the tire pile. Fifty milliliter samples were extracted from each vase weekly and preserved for pyriproxyfen residue analysis. All vases were analyzed at week 0 (4 h post-treatment), 1, 2, 4, and 6. Overall, there were no differences in pupal mortality between the control and autodissemination vases. The tire pile samples had significantly more mortality (P < 0.0001) out to 4 wk when compared to autodissemination and control vases. PMID- 28590223 TI - 2017 AMCA Memorial Lecture Honoree: Dr. Jimmy Karl Olson 1942-2015. PMID- 28590222 TI - Phototaxis of Propsilocerus akamusi (Diptera: Chironomidae) From a Shallow Eutrophic Lake in Response to Led Lamps. AB - A study on the attraction of adult Propsilocerus akamusi midges to different colored light traps was carried out from October 21 to November 15, 2013. The 6 colored lights used in light-emitting diode (LED) lamps were white, green, red, blue, amber, and ultraviolet (UV). The UV lamp attracted the most P. akamusi, followed by green, white, blue, amber, and red. A white pulsed LED light attracted only half the number of midges as did a continuous-emission white LED light. The result indicated that manipulation of light color, considering that the red LED light and/or pulsed LED light are not as attractive as the other colors, may be appropriate for the development of an overall integrated strategy to control nuisance P. akamusi in the Lake Suwa area. PMID- 28590224 TI - Update on the Distribution of Aedes japonicus in Maine, 2001-15. AB - The first confirmed collection of Aedes japonicus in Maine was in Cumberland County in 2001. Since that initial collection, it has been found in 7 of Maine's 16 counties between 2001 and 2015. These collections include the northernmost collection of Ae. japonicus in the eastern USA, from Madawaska in Aroostook County. Though mosquito surveillance is limited in the state, it is evident that Ae. japonicus is more widely distributed in Maine than previously believed although its role in arboviral transmission in the region is unknown. PMID- 28590225 TI - Field Evaluation of Pyriproxyfen Against Mosquitoes in Catch Basins in Southern California. AB - In a field trial, pyriproxyfen (Sumilarv 0.5% G) applied at 10 g and 50 g per catch basin and S-methoprene (Altosid XR briquet 2.1%) at 1 briquet per catch basin at a local park provided 100% inhibition of adult emergence (IAE) of the test species, Culex quinquefasciatus , for the first 3 wk. The IAE dropped to 69% to 85% for pyriproxyfen and 68% for methoprene at 4 wk posttreatment. The IAE at 5 to 8 wk posttreatment, although remaining high, was overshadowed by high mortality in control catch basins. The high mortality in control could be attributed to autodissemination of pyriproxyfen by mosquitoes from treated to untreated catch basins. PMID- 28590227 TI - 2017 AMCA Presidential Address: Remarks On Leadership and the AMCA. PMID- 28590226 TI - Comparative Efficiency of Biogents Gravid Aedes Trap, Cdc Autocidal Gravid Ovitrap, and CDC Gravid Trap in Northeastern Florida. AB - We conducted a study to compare the effectiveness of the Biogents Gravid Aedes Trap (BG-GAT) and Centers for Disease Control and Prevention (CDC) Autocidal Gravid Ovitrap (AGO) with that of the CDC Gravid Trap (CDC-GT) (as a standard) for their proficiency to collect mosquitoes in an urban residential neighborhood in northeastern Florida. Aedes aegypti , Ae. albopictus, and Culex quinquefasciatus were collected from each trap, with the latter species being predominant. Significantly more Cx. quinquefasciatus were collected from CDC-GT traps compared with the other 2 traps. Pairwise comparison of the efficiency of the CDC-GT revealed that this trap collected 6.7- to 21.5-fold more mosquitoes than the BG-GAT, depending on species. The BG-GAT collected overall more mosquitoes (3- to 6-fold) than the AGO, with the exception of Ae. aegypti, where both traps were nearly equal in effectiveness. PMID- 28590228 TI - Phylogenetic Relationships Among Malaria Vectors and Closely Related Species in Thailand Using Multilocus DNA Sequences. AB - The evolutionary and taxonomic status is important for understanding speciation events and phylogenetic relationships between closely related vector and nonvector species. This information is useful for targeting important disease vector species groups for the development of novel genetic-based vector and pathogen control methods. In this study, different phylogenetic analyses were performed to reconstruct phylogenetic trees for the primary malaria vectors in Thailand based on sequence information of 4 DNA fragments from the nuclear and mitochondrial regions. The primary Anopheles species in the subgenus Cellia involved in malaria transmission in Thailand separate clearly into 3 distinct clades: the Leucosphyrus group, Minimus subgroup, and Maculatus group. The phylogenetic trees based on different reconstructed algorithms and different gene regions provided congruent phylogenetic status of the mosquito species studied. The phylogenetic relationships of malaria vector species examined followed similar patterns based on morphological characters. An estimate of the divergence time among the Anopheles species infers that they were present during the Eocene and Miocene periods (>41 million years ago). Congruent phylogenetic analysis of malaria vectors is presented with different algorithms and gene regions. The nuclear TOLL6 fragment appears useful for molecular phylogenetic, species DNA barcode, and Anopheles population genetic analyses. PMID- 28590229 TI - Editorial: New Avenues and Therapeutic Strategies for the Treatment of Neurodegenerative Diseases. PMID- 28590230 TI - Editorial: Conventional, Traditional and Alternative Therapies for Cardiovascular Disorders. Part 1: Conventional Therapy. PMID- 28590231 TI - Evaluation of phenolic profile, enzyme inhibitory and antimicrobial activities of Nigella sativa L. seed extracts. AB - Black cumin (Nigella sativa L. [N.sativa]) seed extracts demonstrated numerous beneficial biological effects including, among others, antidiabetic, anticancer, immunomodulatory, antimicrobial, anti-inflammatory, antihypertensive, and antioxidant activity. To better understand the phytochemical composition of N. sativa seeds, methanol seed extracts were analyzed for phenolic acid and flavonoid content. Furthermore, we tested N. sativa methanol, n-hexane, and aqueous seed extracts for their inhibitory activity against butyrylcholinesterase (BChE) and catalase (CAT) as well as for antimicrobial activity against several bacterial and a yeast strains. The phenolic content of N. sativa was analyzed using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The inhibition of BChE was assessed by modified Ellman's method, and the inhibition of CAT was determined by monitoring hydrogen peroxide consumption. The extracts were tested against Bacillus subtilis, Staphylococcus aureus, Salmonella enterica, and Escherichia coli using the agar diffusion method. The UHPLC-MS/MS method allowed the identification and quantification of 23 phenolic compounds within 15 minutes. The major components found in N. sativa seed extract were sinapinic acid (7.22 +/- 0.73 ug/mg) as a phenolic acid and kaempferol (11.74 +/- 0.92 ug/mg) as a flavonoid. All extracts showed inhibitory activity against BChE, with methanol seed extract demonstrating the highest inhibitory activity (inhibitory concentration 50% [IC50] 79.11 +/- 6.06 ug/ml). The methanol seed extract also showed strong inhibitory activity against CAT with an IC50 value of 6.61 +/- 0.27 ug/ml. Finally, the methanol extract exhibited considerable inhibitory activity against the tested microbial strains. Overall, this is the first study to investigate the ability of black cumin seed extracts to inhibit CAT. Our results indicate that N. sativa seed can be considered as an effective inhibitor of CAT activity. PMID- 28590232 TI - Anesthesia for patients with mucopolysaccharidoses: Comprehensive review of the literature with emphasis on airway management. AB - Mucopolysaccharidoses (MPS) are rare, inherited, lysosomal storage diseases that cause accumulation of glycosaminoglycans, resulting in anatomic abnormalities and organ dysfunction that can increase the risk of anesthesia complications. We conducted a systematic review of the literature in order to describe the anesthetic management and perioperative outcomes in patients with MPS. We reviewed English-language literature search using an OVID-based search strategy of the following databases: 1) PubMed (1946-present), 2) Medline (1946-present), 3) EMBASE (1946-present), and 4) Web of Science (1946-present), using the following search terms: mucopolysaccharidosis, Hurler, Scheie, Sanfilippo, Morquio, Maroteaux, anesthesia, perioperative, intubation, respiratory insufficiency, and airway. The review of the literature revealed nine case series and 27 case reports. A substantial number of patients have facial and oral abnormalities posing various challenges for airway management, however, evolving new technologies that include videolaryngoscopy appears to substantially facilitate airway management in these patients. The only type of MPS that appears to have less difficulty with airway management are MPS III patients, as the primary site of glycosaminoglycan deposition is in the central nervous system. All other MPS types have facial and oral characteristics that increase the risk of airway management. To mitigate these risks, anesthesia should be conducted by experienced anesthesiologists with expertise in using of advanced airway intubating devices. PMID- 28590233 TI - Mitoxantrone suppresses vascular smooth muscle cell (VSMC) proliferation and balloon injury-induced neointima formation: An in vitro and in vivo study. AB - Neointima formation, which occurs after vascular injury due to vascular disease or interventions such as angioplasty and stent placement, is a complex process that involves multiple molecular and cellular mechanisms. The inhibition of neointima formation is vital to prevent restenosis of blood vessels. In the present study, we investigated whether the systemic administration of mitoxantrone can inhibit neointima formation, and evaluated the underlying mechanisms under in vitro and in vivo experimental conditions. In vitro, rat and human vascular smooth muscle cells (RVSMCs and HVSMCs) were stimulated with platelet-derived growth factor-BB (PDGF-BB) and treated with mitoxantrone or DMSO as a control. In vivo, 54 male Sprague-Dawley rats were subjected to carotid artery balloon injury and then intravenously administered with mitoxantrone. Cell proliferation was determined using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry, and protein expression was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis. We used monoclonal mouse anti bromodeoxyuridine (BrdU) antibody for the detection of BrdU and anti Topoisomerase II antibody for staining Type II topoisomerase (Topo II), one week after the ballon injury. In both RVSMCs and HVSMCs, mitoxantrone treatment induced Topo II degradation, as well as suppressed DNA replication, cell cycle progression, and VSMC proliferation. A reduction in intimal hyperplasia, intimal to-medial area ratio, and Topo II level was observed in mitoxantrone-treated rats, as compared to the control (saline) group. Overall, our results indicate that systemic administration of mitoxantrone can reduce neointimal hyperplasia and, thus, represents a suitable option for restenosis treatment. PMID- 28590234 TI - A porcine enterovirus G associated with enteric disease contains a novel papain like cysteine protease. AB - Identification of unknown pathogens in pigs displaying enteric illness is difficult due to the large diversity of bacterial and viral species found within faecal samples. Current methods often require bacterial or viral isolation, or testing only a limited number of known species using quantitative PCR analysis. Herein, faeces from two 25-day-old piglets with diarrhoea from Texas, USA, were analysed by metagenomic next-generation sequencing to rapidly identify possible pathogens. Our analysis included a bioinformatics pipeline of rapid short-read classification and de novo genome assembly which resulted in the identification of a porcine enterovirus G (EV-G), a complete genome with substantial nucleotide differences (>30 %) among current sequences, and a novel non-structural protein similar in sequence to the Torovirus papain-like cysteine protease (PLpro). This discovery led to the identification and circulation of an EV-G with a novel PLpro in the USA that has not been previously reported. PMID- 28590235 TI - Chlorhexidine whole-body washing of patients reduces methicillin-resistant Staphylococcus aureus and has a direct effect on the distribution of the ST5-MRSA II (New York/Japan) clone. AB - PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) colonizes the skin of hospitalized patients and is associated with high morbidity and mortality. To prevent colonization and infection by S. aureus, better disinfection practices are required. Therefore, we evaluated the effect of chlorhexidine whole-body washing on hospital-acquired S. aureus infections among intensive care unit (ICU) patients in a tertiary hospital in Mexico. METHODOLOGY: The study was conducted over 18 months to evaluate the effect of 2 % chlorhexidine gluconate (CXG) whole body washing of ICU adult patients on chlorhexidine and antibiotic resistance, biofilm production and clonal distribution of S. aureus in a tertiary care hospital. Minimum inhibitory concentrations for CXG, antibiotic susceptibility and biofilm production by S. aureus isolates were determined. Pulsed-field gel electrophoresis, multilocus sequence typing (MLST) and PCR for Panton-Valentine leucocidin (PVL) were used for molecular typing of MRSA isolates.Results/Key findings. We included 158 isolates. A reduction in antibiotic resistance in the study period was observed for clindamycin, levofloxacin, norfloxacin, oxacillin and trimethoprim/sulfamethoxazole. None of the isolates showed reduced susceptibility to CXG. Most of the isolates were non-biofilm producers (147/158). The most commonly identified clone was a descendant of the ST5-MRSA-II (New York/Japan) clone. This clone decreased during the intervention period and reappeared markedly in the post-intervention period. During the post-intervention period, two isolates were related with the clone ST8-MRSA-IV (also known as USA300). CONCLUSION: Our findings suggest that the CXG bathing favored the reduction of healthcare-associated MRSA isolates and a temporary reduction of the predominant ST5-MRSA-II (New York/Japan) clone. PMID- 28590236 TI - Interaction between the New World begomovirus Euphorbia yellow mosaic virus and its associated alphasatellite: effects on infection and transmission by the whitefly Bemisia tabaci. AB - The majority of Old World monopartite begomoviruses (family Geminiviridae) are associated with satellite DNAs. Alphasatellites are capable of autonomous replication, but depend on the helper virus for movement, encapsidation and transmission by the insect vector. Recently, Euphorbia yellow mosaic alphasatellite (EuYMA) was found in association with Euphorbia yellow mosaic virus (EuYMV) infecting Euphorbia heterophylla plants in Brazil. The geographical range of EuYMA was assessed in a representative sampling of E. heterophylla plants collected in several states of Brazil from 2009 to 2014. Infectious clones were generated and used to assess the phenotype of viral infection in the presence or absence of the alphasatellite in tomato, E. heterophylla, Nicotiana benthamiana, Arabidopsis thaliana and Crotalaria juncea. Phenotypic differences of EuYMV infection in the presence or absence of EuYMA were observed in A. thaliana, N. benthamiana and E. heterophylla. Symptoms were more severe when EuYMV was inoculated in combination with EuYMA in N. benthamiana and E. heterophylla, and the presence of the alphasatellite was determinant for symptom development in A. thaliana. Quantification of EuYMV and EuYMA indicated that EuYMA affects the accumulation of EuYMV during infection on a host-dependent basis. Transmission assays indicated that EuYMA negatively affects the transmission of EuYMV by Bemisia tabaci MEAM1. Together, these results indicate that EuYMA is capable of modulating symptoms, viral accumulation and whitefly transmission of EuYMV, potentially interfering with virus dissemination in the field. PMID- 28590237 TI - Evaluation of self-collected rectal swabs for the detection of bacteria responsible for sexually transmitted infections in a cohort of HIV-1-infected patients. AB - PURPOSE: The standard approach to screening sexually transmitted infections (STIs) has often been restricted to urogenital specimens. Most current guidelines, however, also recommend testing extra-genital sites, including rectal locations, because asymptomatic rectal carriage of pathogens has often been reported. The aim of our study was to evaluate self-collected rectal swabs to screen bacterial STIs in HIV-infected patients in Marseille, France. METHODOLOGY: Between January 2014 and December 2015, 118 HIV-infected patients (93 males and 25 females) agreed to self-sample anal swabs for detection of bacterial STI. Detection of Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum, Mycoplasma genitalium and Haemophilus ducreyi was performed using in-house qPCR assay.Results/Key findings. Bacterial STIs were found in 8 % (9/118) of the patients. C. trachomatis was the most commonly detected bacterium (4.2 %) followed by N. gonorrhoeae (2.5 %), M. genitalium (1.7 %) and T. pallidum (0.8 %). All the positive patients were males. The rectal carriage of pathogenic bacteria was fortuitously discovered for seven men (78 %) who did not present rectal signs of STIs and was suspected for two men who presented proctitis (22 %). CONCLUSION: In conclusion, testing extra-genital sites is crucial for the diagnosis of STIs in men and women presenting or not concomitant urogenital infections in order to detect asymptomatic carriage with the aim of controlling and preventing transmission to their sexual partners. PMID- 28590238 TI - What were the risk factors and trends in antimicrobial resistance for enteric fever in London 2005-2012? AB - PURPOSE: A study was undertaken to determine the risk factors and trends in antimicrobial resistance for enteric fever. METHODOLOGY: Demographic, antimicrobial susceptibility, typing and epidemiological data were examined for 2005-2012 in patients with enteric fever in London. Single and multivariable logistic regression was used to determine the risk factors associated with antibiotic resistance. RESULTS: 453 cases with Salmonella enterica subsp. enterica serovar Paratyphi A, 17 with S. Paratyphi B and 611 with S. enterica subsp. enterica serovar Typhi were examined. For travellers, 335 (88 %) of S. Paratyphi A isolates were resistant to ciprofloxacin, but resistance to other antimicrobials was low. Almost 80 % (395) of the S. Typhi isolates were resistant to ciprofloxacin, 131 (26 %) to ampicillin, 131 (27 %) to chloramphenicol, 137 (28 %) to trimethoprim and 171 (28 %) to sulphonamide. None of the isolates were resistant to cephalosporins.A trend analysis for S. Typhi isolates showed no significant change in resistance to ampicillin, chloramphenicol, sulphonamide and trimethoprim or for multidrug resistance (P=0.38). Overall resistance to ciprofloxacin increased for S. Paratyphi A (P=0.018) and for S. Typhi (P<0.001) but fell for S. Typhi in 2011-2012. Resistance profiles were reflected by specific phage types and countries visited by the travellers. CONCLUSIONS: The proportion of S. Typhi strains resistant to ampicillin, chloramphenicol and cotrimoxazole remained steady for the period 2005-2012. There was a significant increase in a trend for resistance to ciprofloxacin which increased until 2010, followed by a fall in 2011-2012. S. Paratyphi resistance to ciprofloxacin increased until 2012. Specific phage types were associated with resistance to specific antimicrobials and travel abroad. PMID- 28590239 TI - Fish miR-146a promotes Singapore grouper iridovirus infection by regulating cell apoptosis and NF-kappaB activation. AB - miR-146a was reported to participate in various pathophysiological conditions in mammals, such as inflammation and immune responses, oncogenesis and cell damage. However, its function in low vertebrates has not been well elucidated. In this study, we characterized the expression profiles and functions of miR-146a in fish cells during iridovirus infection. We found that the reported fish miR-146a genes encoded an identical mature sequence, which shared high similarity with its mammalian orthologues, suggesting a putative functional conservation of miR-146a between fish and other vertebrates. Using a well-established infection model of Singapore grouper iridovirus (SGIV) in fathead minnow cells, we found that SGIV infection induced the expression of miR-146a to a dramatic extent. More importantly, we found that miR-146a promoted SGIV propagation, as demonstrated by higher expression of viral genes and increased virus titres in miR-146a overexpressing cells. Mechanistically, we found that miR-146a overexpression suppressed, while miR-146a knockdown promoted, NF-kappaB activation and SGIV induced cell apoptosis, two major cellular events involved in SGIV infection. Our study suggested that the induction of miR-146a by SGIV infection may function through a feed-forward mechanism to promote viral infection by restraining anti viral cellular responses. PMID- 28590240 TI - Epidemiology of culture-confirmed infections of Streptococcus pneumoniae (2012 2015) and nasopharyngeal carriage in children and households in Taiwan (2014 2015). AB - PURPOSE: An observational study was performed to investigate the carriage rate and serotypes of Streptococcus pneumoniae in the 13-valent pneumococcal conjugate vaccine (PCV13) era in Taiwan. METHODOLOGY: From March 2014 to March 2015 a total of 500 healthy children and their households (631 adults) were enrolled from two large medical centres for nasopharyngeal carriage survey. Clinical isolates were prospectively collected from June 2012 to May 2015 at Chang Gung Memorial Hospital. We applied a multiplex polymerase chain reaction in addition to culture to detect S. pneumoniae. RESULTS: S. pneumoniae was isolated from 12.0 % of the children and 3.6 % of the households. In the children's cohort only 23.3 % of the isolates could be assigned to PCV13 serotypes; non-vaccine serotypes were predominant (76.6 %) and the most frequently detected non-vaccine serotypes were 15A/F and 15B/C (both 13.3 %), followed by 23A (6.7 %). In the household cohort, 21.7 % belonged to PCV13 serotypes, and 78.3 % to non-vaccine serotypes. Clinical analysis of culture-confirmed pneumococcal infection showed that infection caused by PCV13 serotypes decreased by 47 % from 83 % in 2012-2013 to 44 % in 2014-2015, while infection caused by non-PCV13 serotypes increased from 17 to 56 %. Among the carriage isolates a significantly higher percentage belonged to serogroup 15 compared to serogroup 19 (26.6 vs 6.66 %, 2014-2015; P=0.003). Therefore, clinical isolates belonging to serogroup 15 were more prevalent than those belonging to serogroup 19 (44.1 vs 32.3 %, 2014-2015; P=0.318). CONCLUSION: The isolation of non-vaccine serotypes and unknown serotypes after the introduction of PCV13 in children highlights the importance of continued surveillance for emerging serotypes. PMID- 28590242 TI - Heterologous post-infection immunity against Egyptian avian influenza virus (AIV) H9N2 modulates the course of subsequent infection by highly pathogenic AIV H5N1, but vaccination immunity does not. AB - In Egypt, zoonotic A/goose/Guangdong/1/96 (gs/GD-like) highly pathogenic avian influenza virus (HPAIV) H5N1 of clade 2.2.1.2 is entrenched in poultry populations and has co-circulated with low-pathogenic avian influenza virus H9N2 of the G1 lineage since 2010. Here, the impact of H9N2 infection or vaccination on the course of consecutive infection with a lethal Egyptian HPAIV H5N1 is studied. Three-week-old chickens were infected with H9N2 or vaccinated with inactivated H9N2 or H5N1 antigens and challenged three weeks later by an HPAIV H5N1. Interestingly, pre-infection of chickens with H9N2 decreased the oral excretion of H5N1 to levels that were comparable to those of H5N1-immunized chickens, but vaccination with inactivated H9N2 did not. H9N2 pre-infection modulated but did not conceal clinical disease by HPAIV H5N1. By contrast, homologous H5 vaccination abolished clinical syndromic surveillance, although vaccinated clinical healthy birds were capable of spreading the virus. PMID- 28590241 TI - Natural history of human papillomavirus infection of sun-exposed healthy skin of immunocompetent individuals over three climatic seasons and identification of HPV209, a novel betapapillomavirus. AB - We present the first longitudinal study reporting the natural history of human papillomavirus (HPV) infection in sun-exposed skin of healthy individuals living in a geographical area in which solar UV radiation is influenced by the ozone content of the atmosphere. During three climatic seasons, skin swab samples were obtained from 78 healthy individuals and the prevalence of cutaneous HPVs was assessed with broad-spectrum FAP and CUT primers and determined at 54, 45 and 47 % in spring, summer and winter, respectively. Frequencies of mixed HPV infections were significantly higher in spring with respect to summer and winter (P=0.02). Seventy-one different HPV types/putative types were identified. While 62 volunteers were HPV-infected in at least one season, 23 had persistent infections. beta-PVs (beta-1) were the most prevalent and persistent. Age was associated with both the infection status (P=0.01) and the type of HPV infection (no infection, indeterminate/transient, persistent P=0.02). The molecular/phylogenetic analysis of the newly identified beta-PV, officially designated as HPV209, showed that the virus has a typical genomic organization of cutaneous HPVs with five early (E6, E7, E1, E2 and E4) and two late genes (L2 and L1), which clusters to the species beta-2. This provides useful data on cutaneous HPV infections in high UV-exposed regions. PMID- 28590243 TI - Detection of Actinomyces spp. in cervical exudates from women with cervical intraepithelial neoplasia or cervical cancer. AB - PURPOSE: Under certain circumstances, Actinomyces behaves as an opportunistic microorganism and can cause actinomycosis, a chronic and inflammatory granulomatous infection. The purpose of this project was to detect the presence of Actinomyces in cervical exudates from women with cervical intraepithelial neoplasia (CIN) and women with cervical cancer. METHODOLOGY: Cervical samples from 92 women were divided into three groups: CIN, cervical cancer and healthy women. Metagenomic DNA extraction was performed following the Qiagen QIAamp Mini Kit protocol. A specific fragment (675 bp) was amplified by PCR in order to detect the presence of Actinomycetales. Samples in which Actinomycetales was detected were subjected to separate amplification reactions with primer pairs for A. israelii, A. viscosus, A. meyeri and A. odontolyticus. Amplified products were observed by 2 % agarose gel electrophoresis. RESULTS: Actinomyces were found in 10 % of women with CIN, 36.6 % of women with cervical cancer and 9 % of healthy women. The species identified in this study were A. meyeri in 14/92 samples (15.2 %), A. viscosus in 10/92 samples (10.8 %), A. odontolyticus in 4/92 samples (4.3 %) and A. israelii in 6/92 samples (6.5 %). CONCLUSION: Patients with cervical cancer had a higher prevalence of the presence of Actinomyces compared to the CIN and control groups. This is the first study in which a deliberate search of this genus has been performed in women with cervical pathologies. The use of specific primers for each species facilitated their detection in comparison with traditional isolation methods. More information is necessary to understand the molecular mechanisms involved in the complex role that bacterial communities may play in the development of cancer (and vice versa). PMID- 28590244 TI - Tralokinumab pharmacokinetics and tolerability when administered by different subcutaneous injection methods and rates?. AB - OBJECTIVE: Tralokinumab, administered as two 1-mL subcutaneous injections every 2 weeks, at the target dose 300 mg, has been shown to improve lung function in patients with asthma. This study evaluated the pharmacokinetic (PK) and tolerability profile of tralokinumab 300 mg when administered by different rates of subcutaneous injection, as part of a pilot investigation of new injection regimens. METHODS: This phase I study randomized 60 healthy adults to receive 300 mg tralokinumab, as two 1-mL subcutaneous injections, each delivered over 10 seconds, or one 2-mL injection delivered over 10 seconds (12 mL/min), 1 minute (2 mL/min), or 12 minutes (0.167 mL/min). RESULTS: No differences in the PK profile of tralokinumab were observed between cohorts. Immediately following injection, injection-site pain intensity (mean (SD)) was lowest following 0.167 mL/min injection (5.1 mm (8.0) via visual analog scale (VAS)) and greatest following 12 mL/min injection (41 mm (27.7) via VAS); with mean injection-site pruritus intensity low for all participants. Two types of local injection-site reactions were observed: erythema (58.3%) and hematoma/bleeding (18.3%). All treatment emergent adverse events were mild. CONCLUSIONS: Tralokinumab 300 mg is well tolerated, with comparable PK, when administered by a single 2-mL injection at different rates of subcutaneous injection vs. two 1-mL injections.?. PMID- 28590245 TI - Collagen induces activation of DDR1 through lateral dimer association and phosphorylation between dimers. AB - The collagen-binding receptor tyrosine kinase DDR1 (discoidin domain receptor 1) is a drug target for a wide range of human diseases, but the molecular mechanism of DDR1 activation is poorly defined. Here we co-expressed different types of signalling-incompetent DDR1 mutants ('receiver') with functional DDR1 ('donor') and demonstrate phosphorylation of receiver DDR1 by donor DDR1 in response to collagen. Making use of enforced covalent DDR1 dimerisation, which does not affect receptor function, we show that receiver dimers are phosphorylated in trans by the donor; this process requires the kinase activity of the donor but not that of the receiver. The receiver ectodomain is not required, but phosphorylation in trans is abolished by mutation of the transmembrane domain. Finally, we show that mutant DDR1 that cannot bind collagen is recruited into DDR1 signalling clusters. Our results support an activation mechanism whereby collagen induces lateral association of DDR1 dimers and phosphorylation between dimers. PMID- 28590246 TI - Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria. AB - Cerebral malaria (CM) can be classified as retinopathy-positive or retinopathy negative, based on the presence or absence of characteristic retinal features. While malaria parasites are considered central to the pathogenesis of retinopathy positive CM, their contribution to retinopathy-negative CM is largely unknown. One theory is that malaria parasites are innocent bystanders in retinopathy negative CM and the etiology of the coma is entirely non-malarial. Because hospitals in malaria-endemic areas often lack diagnostic facilities to identify non-malarial causes of coma, it has not been possible to evaluate the contribution of malaria infection to retinopathy-negative CM. To overcome this barrier, we studied a natural experiment involving genetically inherited traits, and find evidence that malaria parasitemia does contribute to the pathogenesis of retinopathy-negative CM. A lower bound for the fraction of retinopathy-negative CM that would be prevented if malaria parasitemia were to be eliminated is estimated to be 0.93 (95% confidence interval: 0.68, 1). PMID- 28590248 TI - Volume-outcome relationship with transfemoral transcatheter aortic valve implantation (TAVI): insights from the compulsory German Quality Assurance Registry on Aortic Valve Replacement (AQUA). AB - AIMS: Previous studies have shown lower rates of in-hospital complications and mortality for patients undergoing surgical aortic valve replacement (sAVR) in high-volume compared with lower-volume hospitals. It was the aim of our study to analyse whether there is a similar volume-outcome relationship for transcatheter aortic valve implantation (TAVI), which is increasingly used in clinical practice. METHODS AND RESULTS: We analysed all patients with non-emergent transfemoral (TF) TAVI procedures performed in 2014 in 87 German hospitals. We used the German Aortic Valve score 2.0 to calculate the ratio of observed versus expected (O/E) in-hospital mortality. A total of 9,924 patients (age 81.4+/-1.1 years, 45.3% male, median log EuroSCORE 18.81%, IQR 4.55) were included. Average observed mortality was 4.3+/-3.3%, while the expected average mortality was 5.4+/ 1.4% (mean O/E ratio: 0.8). Average in-hospital mortality was 5.6+/-5.0% (range, 0 to 16.7%) in the lowest volume group of hospitals performing <50 TF-TAVI annually compared to 2.4+/-1.0% (range, 0.5 to 3.7%) in the highest volume hospitals with >=200 TF-TAVI procedures per year. There was a continuous, statistically significant association of lower O/E ratios with increasing TF-TAVI volumes (p<0.001), but without a clear-cut threshold. Major complications, neurologic events, and rates of new pacemaker implantation were not different between low- and high-volume hospitals. CONCLUSIONS: Across the spectrum of hospital volumes from 11 to 415 patients undergoing TF-TAVI per year in Germany, there was a continuous, statistically significant association of lower average observed as well as risk-adjusted in-hospital mortality with increasing TF-TAVI volumes. PMID- 28590247 TI - Repeated losses of PRDM9-directed recombination despite the conservation of PRDM9 across vertebrates. AB - Studies of highly diverged species have revealed two mechanisms by which meiotic recombination is directed to the genome-through PRDM9 binding or by targeting promoter-like features-that lead to dramatically different evolutionary dynamics of hotspots. Here, we identify PRDM9 orthologs from genome and transcriptome data in 225 species. We find the complete PRDM9 ortholog across distantly related vertebrates but, despite this broad conservation, infer a minimum of six partial and three complete losses. Strikingly, taxa carrying the complete ortholog of PRDM9 are precisely those with rapid evolution of its predicted binding affinity, suggesting that all domains are necessary for directing recombination. Indeed, as we show, swordtail fish carrying only a partial but conserved ortholog share recombination properties with PRDM9 knock-outs. PMID- 28590249 TI - Difference in haemodynamic microenvironment in vessels scaffolded with Absorb BVS and Mirage BRMS: insights from a preclinical endothelial shear stress study. AB - AIMS: In silico studies have provided robust evidence that stent design affects local haemodynamic forces, which appear as a major determinant of clinical outcomes following stent implantation. However, the implications of different stent/scaffold configurations on local haemodynamic forces have not yet been investigated in vivo in a comparative fashion. The aim of this study was to compare the ESS distribution in two differently shaped scaffolds using OCT-based modelling. METHODS AND RESULTS: Eight healthy mini pigs were implanted with six Absorb everolimus-eluting bioresorbable vascular scaffolds (Absorb BVS) and five Mirage sirolimus-eluting bioresorbable microfibre scaffolds (Mirage BRMS). Optical coherence tomography (OCT) was performed and strut protrusion was assessed post scaffold implantation. Following the reconstruction of coronary anatomy, blood flow simulation was performed and endothelial shear stress (ESS) was estimated on top of the struts and at luminal surface between the struts in each scaffold. The thicker struts in Absorb (152+/-140 MUm) resulted in an increased protruded distance compared to Mirage (117+/-123 MUm) (p=0.003). This had an effect on the local haemodynamic microenvironment. ESS at the top of the struts was higher in Absorb (1.69+/-1.20 Pa) than in Mirage (1.53+/-0.91 Pa) (p<0.001), but lower at inter-strut zones (0.60+/-0.51 Pa vs. 0.63+/-0.50 Pa; p<0.01) compared to Mirage. Both scaffold types revealed comparable percentages of vessel luminal surface exposed to recirculation. CONCLUSIONS: Absorb demonstrated higher shear stress on top of the struts compared to Mirage. However, in the inter-strut zones shear stress was higher in Mirage than in Absorb. Further research is required to examine the potential value of in vivo computational modelling in optimising scaffold configuration and clinical outcomes. PMID- 28590252 TI - The black hole information problem: past, present, and future. AB - We give a brief overview of the black hole information problem emphasizing fundamental issues and recent proposals for its resolution. The focus is on broad perspective and providing a guide to current literature rather than presenting full details. We concentrate on resolutions restoring naive unitarity. PMID- 28590253 TI - When lithography meets self-assembly: a review of recent advances in the directed assembly of complex metal nanostructures on planar and textured surfaces. AB - One of the foremost challenges in nanofabrication is the establishment of a processing science that integrates wafer-based materials, techniques, and devices with the extraordinary physicochemical properties accessible when materials are reduced to nanoscale dimensions. Such a merger would allow for exacting controls on nanostructure positioning, promote cooperative phenomenon between adjacent nanostructures and/or substrate materials, and allow for electrical contact to individual or groups of nanostructures. With neither self-assembly nor top-down lithographic processes being able to adequately meet this challenge, advancements have often relied on a hybrid strategy that utilizes lithographically-defined features to direct the assembly of nanostructures into organized patterns. While these so-called directed assembly techniques have proven viable, much of this effort has focused on the assembly of periodic arrays of spherical or near spherical nanostructures comprised of a single element. Work directed toward the fabrication of more complex nanostructures, while still at a nascent stage, has nevertheless demonstrated the possibility of forming arrays of nanocubes, nanorods, nanoprisms, nanoshells, nanocages, nanoframes, core-shell structures, Janus structures, and various alloys on the substrate surface. In this topical review, we describe the progress made in the directed assembly of periodic arrays of these complex metal nanostructures on planar and textured substrates. The review is divided into three broad strategies reliant on: (i) the deterministic positioning of colloidal structures, (ii) the reorganization of deposited metal films at elevated temperatures, and (iii) liquid-phase chemistry practiced directly on the substrate surface. These strategies collectively utilize a broad range of techniques including capillary assembly, microcontact printing, chemical surface modulation, templated dewetting, nanoimprint lithography, and dip-pen nanolithography and employ a wide scope of chemical processes including redox reactions, alloying, dealloying, phase separation, galvanic replacement, preferential etching, template-mediated reactions, and facet-selective capping agents. Taken together, they highlight the diverse toolset available when fabricating organized surfaces of substrate-supported nanostructures. PMID- 28590254 TI - Reconfigurable metamaterials for terahertz wave manipulation. AB - Reconfigurable metamaterials have emerged as promising platforms for manipulating the spectral and spatial properties of terahertz waves without being limited by the characteristics of naturally existing materials. Here, we present a comprehensive overview of various types of reconfigurable metamaterials that are utilized to manipulate the intensity, phase, polarization, and propagation direction of terahertz waves. We discuss various reconfiguration mechanisms based on optical, electrical, thermal, and mechanical stimuli while using semiconductors, superconductors, phase-change materials, graphene, and electromechanical structures. The advantages and disadvantages of different reconfigurable metamaterial designs in terms of modulation efficiency, modulation bandwidth, modulation speed, and system complexity are discussed in detail. PMID- 28590255 TI - Porous yolk-shell microspheres as N-doped carbon matrix for motivating the oxygen reduction activity of oxygen evolution oriented materials. AB - It is highly challenging to explore high-performance bi-functional oxygen electrode catalysts for their practical application in next-generation energy storage and conversion devices. In this work, we synthesize hierarchical N-doped carbon microspheres with porous yolk-shell structure (NCYS) as a metal-free electrocatalyst toward efficient oxygen reduction through a template-free route. The enhanced oxygen reduction performances in both alkaline and acid media profit well from the porous yolk-shell structure as well as abundant nitrogen functional groups. Furthermore, such yolk-shell microspheres can be used as precursor materials to motivate the oxygen reduction activity of oxygen evolution oriented materials to obtain a desirable bi-functional electrocatalyst. To verify its practical utility, Zn-air battery tests are conducted and exhibit satisfactory performance, indicating that this constructed concept for preparation of bi functional catalyst will afford a promising strategy for exploring novel metal air battery electrocatalysts. PMID- 28590257 TI - Critical care ultrasonography in circulatory shock. AB - PURPOSE OF REVIEW: The objective was to define the role of ultrasound in the diagnosis and the management of circulatory shock by critical appraisal of the literature. RECENT FINDINGS: Assessment of any patient's hemodynamic profile based on clinical examination can be sufficient in several cases, but many times unclarities remain. Arterial catheters and central venous lines are commonly used in critically ill patients for practical reasons, and offer an opportunity for advanced hemodynamic monitoring. Critical care ultrasonography may add to the understanding of the hemodynamic profile at hand. Improvements in ultrasound techniques, for example, smaller devices and improved image quality, may reduce limitations and increase its value as a complementary tool. Critical care ultrasonography has great potential to guide decisions in the management of shock, but operators should be aware of limitations and pitfalls as well. Current evidence comes from cohort studies with heterogeneous design and outcomes. SUMMARY: Use of ultrasonography for hemodynamic monitoring in critical care expands, probably because of absence of procedure-related adverse events. Easy applicability and the capacity of distinguishing different types of shock add to its increasing role, further supported by consensus statements promoting ultrasound as the preferred tool for diagnostics in circulatory shock. PMID- 28590256 TI - Thromboembolism prophylaxis in laparoscopic surgery for gynecologic benign diseases. Results of a single center experience in 922 procedures. AB - AIM: The aim of this study is to assess the role of preoperative evaluation risk for venous tromboembolism (VTE) in patients submitted to laparoscopic surgery for gynecologic benign diseases. METHODS: Date from nine hundred twenty-two women affected by adnexal benign diseases treated with laparoscopic procedures were collected and included in this study. VTE risk was assessed by "on line Caprini score calculator". Patients with one or more negative risk factors for Caprini's score underwent to venous thromboembolism prophylaxis (VTP). The remainign of the patients did not recived any VTP. A survey was conducted after three months from the discharge in order to collect the follow up date. RESULTS: In our study 160 patients had a Caprini's score major than 2 and they have been subjected to VTP. A total of 762 patients were considered at low risk for VTE and they did not receive any VTP. In these patients was not registered any event of VTE. DISCUSSION: The results of this study suggest that laparoscopic approach, when carried out in non-oncological patients and without any previous thromboembolic risk factor, is associated with a very low risk of VTE. This study also confirm what was reported by Ageno et al. 6, Nick et al. 7 and ACCP guidelines in 2012 8 in which routine thromboprophylaxis is recommended for patients with additional risk factors. CONCLUSIONS: Laparoscopic surgery in women for gynecologic benign diseases is associated with a very low risk of thromboembolism and therefore it does not require any mechanical or pharmacological thromboprophylaxis in the absence of risk factors. The systematic evaluation of VTE risk with the help of a standard calculator is highly recommended. KEY WORDS: Gynaecology, Laparoscopic surgery, Thromboprophylaxis. PMID- 28590251 TI - A Primer on Infectious Disease Bacterial Genomics. AB - The number of large-scale genomics projects is increasing due to the availability of affordable high-throughput sequencing (HTS) technologies. The use of HTS for bacterial infectious disease research is attractive because one whole-genome sequencing (WGS) run can replace multiple assays for bacterial typing, molecular epidemiology investigations, and more in-depth pathogenomic studies. The computational resources and bioinformatics expertise required to accommodate and analyze the large amounts of data pose new challenges for researchers embarking on genomics projects for the first time. Here, we present a comprehensive overview of a bacterial genomics projects from beginning to end, with a particular focus on the planning and computational requirements for HTS data, and provide a general understanding of the analytical concepts to develop a workflow that will meet the objectives and goals of HTS projects. PMID- 28590259 TI - Imaging of left-to-right shunt in adults. AB - PURPOSE OF REVIEW: Left-to-right shunts are commonly seen in congenital heart diseases. This review aims to review the anatomy, physiology, and imaging of the four most common left-to-right lesions in adults. RECENT FINDINGS: Reported late complications of left-to-right lesions provide guidance in follow-up imaging. Use of three-dimensional echocardiography helps not only in the diagnosis of these defects but also in assistance during device closure. SUMMARY: Noninvasive imaging plays a significant role in the diagnosis and management of left-to-right lesions. PMID- 28590258 TI - Opioid-induced hyperalgesia in clinical anesthesia practice: what has remained from theoretical concepts and experimental studies? AB - PURPOSE OF REVIEW: This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research. RECENT FINDINGS: Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral MU-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet. SUMMARY: Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended. PMID- 28590261 TI - Orthostatic hypotension and association of arterial compliance in elderly patients with hypertension: a pilot study. AB - BACKGROUNDS: Orthostatic hypotension (OH) is associated with cardiovascular diseases, heart failure, and increased mortality. We evaluated whether OH was affected by cardiac structure and function or autonomic function in elderly hypertensive outpatients. PATIENTS AND METHODS: In 64 hypertension patients (mean age 74.2+/-1.7 years old), we evaluated changes in blood pressure (BP) and heart rate variability before and after standing up using the MemCalc system. In addition, we retrospectively reviewed their medical records and echocardiographic data. RESULTS: Of the total patients, 28% had OH [decrease of systolic blood pressure (SBP) >=20 mmHg and/or diastolic BP >=10 mmHg]. Multivariate linear regression analysis showed that stroke volume (SV)/pulse pressure (PP) was associated independently with orthostatic change in SBP (P=0.007). The patients with OH tended to have a lower SV (57.3+/-13.1 vs. 68.1+/-16.3 ml, P=0.009) and lower SV/PP (1.02+/-0.26 vs. 1.33+/-0.45, P=0.001) than those without OH. The significance in difference in SV/PP remained even after adjustment for age, sex, BMI, estimated glomerular filtration rate, number of antihypertesive drugs, history of diabetes, and SBP at rest (P=0.036). However, there were no significant differences in change in the low frequency/high frequency ratio after standing up (P=0.899) between patients with and without OH. CONCLUSION: Elderly hypertensive patients with OH may have a reduced arterial compliance, measured as SV/PP, and may not have differences in sympathetic nerve activities, measured as the low frequency/high frequency ratio. PMID- 28590260 TI - Ghrelin and autophagy. AB - PURPOSE OF REVIEW: A compromised autophagy is associated with the onset of obesity, type 2 diabetes, nonalcoholic fatty liver disease, cardiovascular and neurodegenerative diseases. Our aim is to review the potential role of ghrelin, a gut hormone involved in energy homeostasis, in the regulation of autophagy. RECENT FINDINGS: In the recent years, it has been demonstrated that autophagy constitutes an important mechanism by which ghrelin exerts a plethora of central and peripheral actions. Ghrelin enhances autophagy through the activation of AMP activated protein kinase in different target organs to regulate lipid and glucose metabolism, the remodeling and protection of small intestine mucosa, protection against cardiac ischemia as well as higher brain functions such as learning and memory consolidation. Nonetheless, in inflammatory states, such as acute hepatitis, liver fibrosis or adipose tissue inflammation, ghrelin acts as an anti inflammatory factor reducing the autophagic flux to prevent further cell injury. Interestingly, several cardiometabolic disorders, including obesity, type 2 diabetes, nonalcoholic fatty liver disease or chronic heart failure are accompanied by low ghrelin levels in addition to altered autophagy. SUMMARY: Ghrelin represents an attractive target for development of therapeutics for prevention or treatment of metabolic, cardiac or neuronal disorders, in which autophagy is impaired. PMID- 28590262 TI - Prevention of betaeta-adrenergic-induced Adverse Cardiac Remodeling by Gonadectomy in Male but Not Female Spontaneously Hypertensive Rats. AB - Chronic beta-adrenergic stimulation induces left ventricular (LV) remodeling in male but not in female spontaneously hypertensive rats (SHRs). However, the role of sex steroids in mediating these effects has not been determined. The aim of the present study was to assess the impact of gonadectomy on isoproterenol (ISO) induced LV remodeling in SHR. Gonadectomy was performed on 9-month-old male and female SHR. LV remodeling was induced by daily ISO injection (0.04 mg/kg) for 6 months. LV dimensions and functions were determined in vivo by echocardiography and ex vivo using isolated perfused heart preparations. In males, ISO increased LV end diastolic (LVED) diameter in sham-operated (in millimeter, ISO: 8.12 +/- 0.26 vs. Con: 6.67 +/- 0.20, P = 0.0002) but not in castrated SHR (ISO: 6.97 +/- 0.31 vs. Con: 6.53 +/- 0.15, P = 0.66). Similarly, ISO increased the volume intercept of the LVED pressure-volume relationship in sham-operated (in milliliters, ISO: 0.26 +/- 0.02 vs. Con: 0.19 +/- 0.01, P = 0.01) but not in castrated SHR (ISO: 0.17 +/- 0.02 vs. Con: 0.17 +/- 0.01, P = 0.99). In females, ISO only increased LVED diameter (ISO: 6.43 +/- 0.13 vs. Con: 6.07 +/- 0.09, P = 0.027). However, ovariectomy did not modify any LV dimensions measured in vivo and ex vivo. In conclusion, testosterone may be responsible for the chronic beta adrenergic-induced LV dilation and eccentric remodeling observed in male but not female SHR. PMID- 28590263 TI - Why We Need to Enhance Suicide Postvention: Evaluating a Survey of Psychiatrists' Behaviors after the Suicide of a Patient. AB - Suicide prevention efforts are increasing to enhance capabilities and better understand risk factors and etiologies. Postvention, or how clinicians manage the postsuicide aftermath, strengthens suicide prevention, destigmatizes the tragedy, operationalizes the confusing aftermath, and promotes caregiver recovery. However, studies regarding its efficacy are minimal. The Psychopathology Committee of the Group for the Advancement for Psychiatry surveyed a convenience sample of psychiatrists to better understand postvention activities. Ninety psychiatrists completed the survey; they were predominantly men (72%) with an average of 24.6 years of experience (SD, 16.7 years). Most had contact with the patient's family within 6 months of the suicide, and most psychiatrists sought some form of support. Few psychiatrists used a suicide postvention procedure or toolkit (9%). No psychiatrists stopped clinical practice after a patient suicide, although 10% stopped accepting patients they deemed at risk of suicide. Postvention efforts, therefore, should be improved to better address survivor care. PMID- 28590264 TI - Traumatic Brain Injury, Sleep Quality, and Suicidal Ideation in Iraq/Afghanistan Era Veterans. AB - The objective of this study was to test the hypothesis that sleep quality mediates the association between traumatic brain injury (TBI) history and current suicidal ideation. Measures of TBI history, sleep quality, and suicidal ideation were administered to 130 Iraq/Afghanistan veterans. As expected, sleep quality mediated the effect of TBI history on current suicidal ideation (indirect effect, 0.0082; 95% confidence interval, 0.0019-0.0196), such that history of TBI was associated with worse sleep quality, which was, in turn, associated with increased suicidal ideation. These findings highlight the importance of assessing TBI history and sleep quality during suicide risk assessments for veterans. PMID- 28590265 TI - Expression of KGF-1 and KGF-2 in Skin Wounds and Its Application in Forensic Pathology. AB - The expression of keratinocyte growth factor-1 (KGF-1) and keratinocyte growth factor-2 (KGF-2) in skin wounds in mice was studied using multiple methods. The dynamic expression of KGF-1 and KGF-2 for antemortem and postmortem injuries as well as the examination of antemortem injuries after death under different temperature and over varying time periods was studied. It demonstrates that skin KGF-1 resulting from an antemortem injury starts to rise at 6 hours, reaches its peak at 1 day, and starts to drop at 5 days. The expression of skin KGF-2 resulting from an antemortem injury starts to rise at 12 hours, reaches its peak at 7 days, and begins to drop at 10 days. Skin KGF-1 and skin KGF-2 after death stabilize within 7 days at 4 degrees C and -20 degrees C, within 5 days at 20 degrees C, and within 1 day at 30 degrees C. The application of KGF-1 and KGF-2 indicators in skin wound age determination is both feasible and reliable. PMID- 28590266 TI - Sex differences in aortic augmentation index in adolescents. AB - BACKGROUND: Augmentation index (AIx) is a noninvasive measure of pulse wave reflection. AIx is associated with cardiovascular disease. Adult women have a higher AIx than men, but the factors determining this sex-related difference remain to be determined. METHODS: To examine factors associated with AIx in adolescents, participants in the Childhood Asthma Prevention Study, followed from birth, were assessed at age 14 years, with AIx standardized to a heart rate of 75/min (AIx_75) and pulse wave velocity. Associations of AIx_75 and pulse wave velocity with height, change in height, and measures of puberty were assessed. RESULTS: AIx_75 was higher in women compared to men [-24.5 (12.1) versus -32.3 (12.4)%; P < 0.001]. Lower AIx_75 was significantly related to greater change in height between 8 and 14 years, but not to achieved height. The sex difference in AIx was not independently related to puberty variables. Differences between sexes included early life weight gain, lipids, height, BMI-Z-score, change in height from 8 to 14 years, and age at peak height velocity. Change in AIx_75 from 8 to 14 years was highly associated with change in height (m) from 8 to 14 years (B = 88.8, 95% confidence interval -137.3 to -40.3, P = < 0.001). The difference between sexes established at 8 years was not amplified from 8 to 14 years. CONCLUSION: AIx is higher in girls than boys at 14 years and is closely associated with change in height between 8 and 14 years. Measures of puberty do not appear to independently influence the sex difference in AIx in adolescents. PMID- 28590267 TI - Reply. PMID- 28590268 TI - AR-v7 liquid biopsy for treatment stratification in prostate cancer: how close are we? AB - PURPOSE OF REVIEW: Recent clinical introduction of the novel antiandrogen, Enzalutamide (Enza), CYP17 inhibitor, Abiraterone (Abi), and the second generation chemotherapeutic, Cabazitaxel, has increased survival of patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). However, de novo and acquired resistance rates are high. A liquid biopsy that can rapidly, sensitively and robustly identify which patients will respond to treatment in a minimally invasive manner is urgently required to permit switch to a potentially more efficacious drug regimen, thus increasing survival whilst avoiding debilitating side effects associated with unnecessary treatment. This review will highlight recent developments in detection of AR-v7 in circulating mRNA/whole blood and circulating tumour cells (CTCs) as a liquid biopsy for patient stratification in mCRPC. RECENT FINDINGS: Continued androgen receptor (AR) activity in mCRPC has been linked to the expression of a number of truncated but constitutively active AR isoforms. One such variant, AR-v7, can drive drug resistance in preclinical models and is correlated with disease progression whilst showing dynamic response to AR-targeting treatments when assessed in blood. It has thus been proposed as an Abi/Enza treatment-response biomarker. SUMMARY: AR-v7 liquid biopsy has the potential to transform clinical management of mCRPC and increase patient survival. This review will explore recent efforts to validate AR-v7 as a robust, clinically informative biomarker. I will also address potential limitations of detection and quantification that could frustrate its adoption into routine clinical practise. PMID- 28590269 TI - Avoiding the Hughes flap in lower eyelid reconstruction. AB - PURPOSE OF REVIEW: To review current surgical practices of lower eyelid reconstruction with a focus on recent studies. RECENT FINDINGS: Combination techniques and new flap techniques offer efficacy comparable with existing reconstructive approaches, with the advantage of less local trauma. Inappropriate handling of posterior lamellar grafts, such as kerfing, may predispose to graft failures. Modified Hughes procedure is a favorable choice for large lower eyelid reconstruction; however, it requires temporary eye closure. Other surgical options have been developed to achieve a 1-stage procedure without the need of eye closure. These include the Smith-modified Kuhnt-Szymanowski procedure and the use of flaps. For posterior lamellar grafts, both nasal septal and ear cartilage donor tissue produce esthetically and functionally satisfactory outcomes and comparable efficacy. However, the ear cartilage carries a lower risk of donor site complications. SUMMARY: Lower eyelid reconstruction remains a challenge, especially for large or near total defects. Recent studies have explored modifications and alternatives to the conventional Hughes flap. New surgical procedures give surgeons more options. Taking into account the growing spectrum of reconstructive techniques, an individualized approach may facilitate better functional and esthetic outcomes. PMID- 28590270 TI - Employment Status of Depressed Individuals in an 11-Year Follow-up: Results From the Finnish Health 2011 Survey. AB - OBJECTIVES: The aim of this study was to describe the employment and mental health status of persons with depressive disorders after an 11-year follow-up, and identify individual and work-related factors that predict adverse outcomes. METHODS: Two nationally representative health surveys, Health 2000 and its follow up, Health 2011 were used, and persons with depressive disorders at baseline (n = 275) were re-interviewed after 11 years. RESULTS: Information on employment status was available for all 263 participants in 2011. About 15.7% had been granted disability pension by 2011, while 55.5% were employed and 18.2% on old age pension. High job control was the only statistically significant predictor of lower probability of disability pension (adjusted odds ratio 0.42, 95% confidence interval [95% CI] 0.23 to 0.77). Being unmarried (adjusted odds ratio 2.99, 95% CI 1.19 to 7.52) was associated with persistent depressive disorder. CONCLUSIONS: Job control emerged as an important predictor of long-term employment outcomes among depressed individuals. PMID- 28590271 TI - Impact of an Onsite Clinic on Utilization of Preventive Services. AB - OBJECTIVE: To assess impact of an onsite clinic on healthcare utilization of preventive services for employees of a public university and their dependents. METHOD: Descriptive statistics, logistic regression and classification tree techniques were used to assess health claim data to identify changes in patterns of healthcare utilization and factors impacting usage of onsite clinic. RESULT: Utilization of preventive services significantly increased for women and men employees by 9% and 14% one year after implementation of the onsite clinic. Hourly-paid employees, employees without diabetes, employees with spouse opt out or no coverage were more likely to go to the onsite clinic. CONCLUSION: Adapted framework for assessing performance of onsite clinics based on usage of health informatics would help to identify health utilization patterns and interaction between onsite clinic and offsite health providers. PMID- 28590272 TI - An Investigation of Self-reported Health-related Productivity Loss in Office Workers and Associations With Individual and Work-related Factors Using an Employer's Perspective. AB - OBJECTIVE: Office workers have a high prevalence of musculoskeletal conditions. This can be a significant economic burden due to health-related productivity loss. Individual and work-related factors related to office worker health-related productivity were investigated. METHODS: A survey including the Health and Work Performance Questionnaire, which estimated productivity loss, also recorded individual and work-related factors with potential associations with health related productivity. Muscle function and workstation ergonomics were examined through physical assessments. Linear models investigated the relationships between these factors and health-related productivity. RESULTS: Significant factors identified were occupational category (0.001 < P < 0.050), job satisfaction (P < 0.001), psychological wellbeing (P = 0.031), and musculoskeletal pain (P = 0.023). Health-related productivity loss was greater in office workers working as managers, with lower job satisfaction and psychological wellbeing, and those with musculoskeletal pain. CONCLUSION: Office worker health related productivity loss is represented by a combination of both individual and work-related factors. PMID- 28590273 TI - Incidence and survival of Hodgkin lymphoma patients in Girona (Spain) over three decades: a population-based study. AB - Hodgkin lymphoma (HL) is characterized by heterogeneous histologic findings, clinical presentation and outcomes. Using the Girona population-based cancer registry data we sought to explore the incidence of HL over three decades in Girona Province (Spain) and examine the relationship between clinical features at diagnosis and survival. From 1985 to 2013, 459 cases were recorded. Patients were stratified by sex, age group, stage at diagnosis, histological subtypes and the presence of B-symptoms. The crude incidence rate (CR) was 2.7 and the corresponding European age-adjusted rate was 2.6, being higher in men than in women (sex ratio=1.6). Incidence remained constant throughout the period of study. Nodular sclerosis was the most frequent histology and showed an increasing incidence over time [estimated annual percentage change=+2.4, 95% confidence interval (CI): 0.8-4.0]. The 5-year observed survival and relative survival of patients diagnosed with HL were 73.1% (95% CI: 69.0-77.5) and 74.6% (95% CI: 70.0 79.4), respectively. No statistical differences in observed survival were observed across the three decades of study (P=0.455). Clinical parameters negatively influencing 5-year relative survival in the multivariate analysis were as follows: age at diagnosis at least 65 years; clinical stage IV; and presence of B-symptoms. These current patterns of presentation and outcomes of HL help delineate key populations in order to explore risk factors for HL and strategies to improve treatment outcomes. PMID- 28590274 TI - Survival from cancer in the north region of Portugal: results from the first decade of the millennium. AB - The aim of this study was to evaluate net survival from cancer diagnosed during the period 2001-2010 in the north region of Portugal to identify the tumours that need actions to improve the outcomes. Data were retrieved from the North Region Cancer Registry of Portugal database. The top 20 cancer sites in adults were considered: oesophagus, stomach, colon, rectum, pancreas, liver, larynx, lung, skin melanoma, breast, cervix, corpus uteri, ovary, prostate, kidney, bladder, brain and central nervous system, thyroid, non-Hodgkin lymphoma and multiple myeloma. Net survival was estimated using the Pohar-Perme estimator. The effect of diagnosis period was evaluated using flexible parametric models adjusted for age and sex where appropriate. Thyroid and prostate cancers presented the best 5 year survival (>90%), whereas oesophagus, pancreas, liver and lung cancers the worst 5-year survival (<20%). The largest increase in survival was observed for the larynx. A significant decrease in age-adjusted and sex-adjusted excess mortality was observed for stomach, colon, pancreas, larynx, melanoma, breast, brain and central nervous system, thyroid, non-Hodgkin lymphoma and multiple myeloma. For the other cancer sites, no significant trends were observed. For some of these sites, the downward trend in excess mortality was only observed in the short term. An important picture of population-based cancer survival outcomes for the first decade of the millennium in the north region of Portugal was presented in this study. It has been shown that improvements in survival were not universal for all cancer sites. These results should be used to highlight tumours where intervention is needed the most. PMID- 28590275 TI - Endobronchial Ultrasound-guided Transbronchial Needle Injection of Liposomal Amphotericin B for the Treatment of Symptomatic Aspergilloma. AB - Surgical treatment with lung resection has traditionally been the treatment of choice for pulmonary cavities containing aspergillomas that cause hemoptysis. Endobronchial ultrasound (EBUS) is a minimally invasive bronchoscopic technique that is commonly used for transbronchial needle aspiration of hilar and mediastinal lymph nodes as well as centrally located parenchymal lesions. Here, we describe a case of a 71-year-old woman who was found to have a cavitary lesion in the lung containing aspergillomas. Under direct ultrasound visualization with EBUS, liposomal amphotericin B was injected into the aspergillomas. These aspergillomas regressed after treatment. To our knowledge, this is the first reported treatment of aspergilloma with EBUS-guided transbronchial needle injection of liposomal amphotericin B. PMID- 28590276 TI - Preface: State of the Art and Beyond: Anterior Segment Diagnostics. PMID- 28590277 TI - Corneal and Conjunctival Infectious Disease Diagnostics. PMID- 28590278 TI - State of the Art and Beyond: Anterior Segment Diagnostics Genetic Diagnostics in Corneal Disease. PMID- 28590279 TI - New Diagnostics in Ocular Surface Disease. PMID- 28590281 TI - New Diagnostics in Corneal Ectatic Disease. PMID- 28590280 TI - Updates in Ocular Surface Tumor Diagnostics. PMID- 28590283 TI - Perioperative Imaging in Corneal Surgery (Intraoperative and Postoperative). PMID- 28590284 TI - Advances in Preoperative Testing for Cataract Surgery. PMID- 28590285 TI - Updates in Biometry. PMID- 28590282 TI - Biomechanical Diagnostics of the Cornea. PMID- 28590286 TI - Diagnostic Imaging of the Anterior Segment in Glaucoma: An Update. PMID- 28590287 TI - Effect of Gender and Race on Ocular Biometry. PMID- 28590289 TI - Comparison of Inching Electrodiagnosis Method and Ultrasonographic Findings in the Determination of Median Nerve Entrapment Site in Carpal Tunnel Syndrome. AB - OBJECTIVE: The purpose of the study was to evaluate the diagnostic value of both inching method through the electrodiagnostic test and ultrasonographic assay in localizing the site of entrapment in patients with symptoms and signs of carpal tunnel syndrome. DESIGN: Thirty-two hands with confirmed carpal tunnel syndrome through electrodiagnostic test and 30 hands as control group were enrolled. For both groups, sensory and motor latencies by inching technique and cross-sectional area by ultrasonography were measured at the inching points. The statistical analysis was performed by SPSS software, and mean difference with 95% confidence interval was calculated. RESULTS: Mean of sensory peak latency with inching method and cross-sectional area by the ultrasonography was greater in case group compared with the control group (P < 0.05). We revealed a significant difference of antidromic sensory latency between two adjacent points belonging to the fifth and sixth segments. In orthodromic sensory and distal motor latency the sixth segment had statistically significant latency difference. Sixth and seventh points had the greatest cross-sectional area. Distal motor latency difference and cross-sectional area had the greatest sensitivity at the seventh point. CONCLUSIONS: In this study, we revealed the most sites of entrapment of the median nerve through carpal tunnel are 2- and 3-cm distal to the distal wrist crease. PMID- 28590291 TI - Bronchoscopic modalities to diagnose sarcoidosis. AB - PURPOSE OF REVIEW: Several studies have investigated different bronchoscopic techniques to obtain tissue diagnosis in patients with suspected sarcoidosis when the diagnosis cannot be based on clinicoradiographic findings alone. In this review, we will describe the most recent and relevant evidence from different bronchoscopic modalities to diagnose sarcoidosis. RECENT FINDINGS: Despite multiple available bronchoscopic modalities to procure tissue samples to diagnose sarcoidosis, the vast majority of evidence favors endobronchial ultrasound transbronchial needle aspiration to diagnose Scadding stages 1 and 2 sarcoidosis. Transbronchial lung cryobiopsy is a new technique that is mainly used to aid in the diagnosis of undifferentiated interstitial lung disease; however, we will discuss its potential use in sarcoidosis. SUMMARY: This review illustrates the limited information about the different bronchoscopic techniques to aid in the diagnosis of pulmonary sarcoidosis. However, it demonstrates that the combination of available bronchoscopic techniques increases the diagnostic yield for suspected sarcoidosis. PMID- 28590290 TI - Huge Hepatic Fungal Inflammatory Pseudotumor Misdiagnosed as Primary Hepatocellular Carcinoma. AB - Fungal inflammatory pseudotumor (FIPT) of the liver is a rare disease that may be mistaken for a malignant tumor. It is difficult to diagnose because of its nonspecific clinical and imaging features. We report the case of a 46-year-old Asian man who presented with a mass in the right upper quadrant of the abdomen. The patient had undergone transcatheter arterial chemoembolization therapy at another institution 6 months earlier, but the mass had continued to enlarge. He had no history of chronic hepatitis B, and the serum alpha-fetoprotein was negative. Contrast-enhanced ultrasonography and computed tomography images were suggestive of hepatocellular carcinoma. However, ultrasound-guided biopsy revealed features of chronic inflammation. The mass was resected and found to be an FIPT. We discuss the details of the case and review related articles. PMID- 28590293 TI - Pediatric pulmonary arterial hypertension: on the eve of growing up. AB - PURPOSE OF REVIEW: Current recommendations for diagnosis and treatment of pulmonary arterial hypertension (PAH) during childhood are expert opinion based, because of lacking pediatric data. In recent years, however, important pediatric data have emerged on PAH. RECENT FINDINGS: PAH in children shows similarities as well as differences compared to adults. Neonates and children know specific clinical presentations and a hemodynamic profile that differs from adults with PAH. Children identified as acute vasodilator responders according to the criteria proposed for adults rather than the pediatric criteria have better outcome when treated with calcium channel blockers. For nonresponders, combination PAH-targeted therapy leads to improved outcome compared to monotherapy. In pediatric PAH, WHO functional class, N-terminal pro-brain natriuretic peptide and tricuspid annular plane systolic excursion were identified as surrogates for survival and therefore qualify to be treatment goals in a goal-oriented treatment strategy. SUMMARY: In order to refine current pediatric treatment guidelines, data on efficacy of specific treatment regiments and strategies are needed. The recently validated composite endpoint of clinical worsening allows for trials that will provide these data. For the first time, evidence-based treatment goals have been identified that will allow for a goal oriented treatment strategy. Furthermore, various prognostic predictors have been identified that may prove treatment goals in future. PMID- 28590292 TI - Transcriptome profiles in sarcoidosis and their potential role in disease prediction. AB - PURPOSE OF REVIEW: Sarcoidosis is a systemic disease defined by the presence of nonnecrotizing granuloma in the absence of any known cause. Although the heterogeneity of sarcoidosis is well characterized clinically, the transcriptome of sarcoidosis and underlying molecular mechanisms are not. The signal of all transcripts, small and long noncoding RNAs, can be detected using microarrays or RNA-Sequencing. Analyzing the transcriptome of tissues that are directly affected by granulomas is of great importance to understand biology of the disease and may be predictive of disease and treatment outcome. RECENT FINDINGS: Multiple genome wide expression studies performed on sarcoidosis affected tissues were published in the last 11 years. Published studies focused on differences in gene expression between sarcoidosis vs. control tissues, stable vs. progressive sarcoidosis, as well as sarcoidosis vs. other diseases. Strikingly, all these transcriptomics data confirm the key role of TH1 immune response in sarcoidosis and particularly of interferon-gamma (IFN-gamma) and type I IFN-driven signaling pathways. SUMMARY: The steps toward transcriptomics of sarcoidosis in precision medicine highlight the potentials of this approach. Large prospective follow-up studies are required to identify signatures predictive of disease progression and outcome. PMID- 28590294 TI - Colonic Parasitic Infection Mimicking Peritoneal Seeding on 18F-FDG PET/CT. AB - A 77-year-old man with anorexia and weight loss for 6 months received a diagnosis of gastric cancer by endoscopy and referred for F-FDG PET/CT for initial staging. F-FDG PET/CT showed multiple foci of increased FDG uptake with diffuse wall thickening and multiple diverticula. The differential diagnoses were peritoneal seeding and multiple diverticulitis. The patient underwent curative total gastrectomy, and the lesion was diagnosed as poorly differentiated adenocarcinoma by histological examination. He underwent anterior resection of the sigmoid colon for exploration. The nodular lesions of the sigmoid colon were diagnosed by histopathologic examination as chronic diverticulitis caused by a parasitic infection. PMID- 28590295 TI - 68Ga-PSMA PET/MR-Positive Peritoneal Metastasis in the Falciform Ligament in Recurrent Prostate Cancer. AB - Synchronous or metachronous metastases develop in approximately one third of all prostate cancer (PCa) patients. Main sites of metastasis include lymph nodes, bone, lung and liver. Secondary peritoneal carcinomatosis is very rare in PCa, with only a few published cases. Ga-PSMA PET-based imaging is a promising tool for staging and restaging PCa. We report a case of Ga-PSMA PET/MR-positive peritoneal metastasis as site of primary relapse after definitive PCa treatment in a 58-year-old man with a prostate-specific antigen of 30 ng/mL at time of the study. Exploratory laparoscopy and subsequent histopathologic examination confirmed nonascitic peritoneal PCa carcinomatosis. PMID- 28590296 TI - 18F-FDG Superscan Caused by Extensive Bone Marrow Involvement in Hemophagocytic Lymphohistiocytosis. AB - An 82-year-old woman who initially presented with pulmonary infection had persistent pancytopenia, which presented a diagnostic dilemma requiring multiple bone marrow biopsies for eventual diagnosis of hemophagocytic lymphohistiocytosis. This case highlights the utility of FDG PET in (a) focusing attention on the bone marrow and reticuloendothelial system as the primary site of pathology and (b) excluding underlying malignancy and infection in this rare but potentially fatal hyperinflammatory condition caused by a highly stimulated but ineffective immune response. PMID- 28590297 TI - High Prevalence of Pneumothorax on PET-CT Studies Performed in Lung Cancer Patients Following Post-Transthoracic Needle Biopsy Mandates Careful Scrutiny. AB - In our practice, FDG PET-CT studies are frequently performed within days of transthoracic needle biopsy, often revealing presence of pneumothorax (PTX), a "critical finding" that should be reported expeditiously. In our experience, prevalence of PTX at PET-CT performed 1 day following biopsy is greater than 40%. Of these, approximately a third are not visible on the postprocedure chest radiography, as in a case we describe. A high level of vigilance is therefore recommended to identify PTX in patients who have undergone recent transthoracic needle biopsy, even when no PTX is present immediately following the biopsy procedure. PMID- 28590298 TI - Diagnostic and Prognostic Implications of Exercise Treadmill and Rest First-Pass Radionuclide Angiography in Patients With Pulmonary Hypertension. AB - PURPOSE: Pulmonary hypertension (PH) is characterized by abnormally increased pulmonary vascular pressure, leading to deteriorated right ventricular function and premature death. Pulmonary mean transit time (PMTT) and biventricular function response to exercise in first-pass radionuclide angiography (FP-RNA) may provide early detection and timely disease monitoring of PH. This study aimed to investigate the diagnostic and prognostic values of this imaging modality in PH patients. METHODS: Left and right ventricular ejection fraction (LVEF/RVEF) and PMTT at rest and immediately after exercise treadmill test were measured by FP RNA in 77 consecutive patients with clinical presentations suggestive of PH (aged 46 +/- 15 years, 33 men), mostly with symptoms of unexplained progressive dyspnea. These parameters, along with other clinical variables, were correlated with right-sided heart catheterization data and clinical outcomes. RESULTS: Fifty patients (64.9%) were diagnosed as having definite PH. Besides higher N-terminal pro-B-type natriuretic peptide levels, right atrial pressure, and pulmonary vascular resistance, PH patients had significantly longer PMTT, lower LVEF after exercise and rest, and lower poststress RVEF (all P < 0.05), compared with non-PH subjects. Moreover, PH patients exhibited stress-induced right ventricular dysfunction and stationary poststress PMTT. Poststress PMTT and echocardiography had comparable diagnostic utility (area under the curve, 0.80 vs 0.84, respectively). Eighteen patients died during a median follow-up period of 380 days. Failure of exercise treadmill test, lower peak heart rate response, and stress/rest LVEF ratio of less than 90% using exercise treadmill FP-RNA were independent predictors of mortality in PH patients. CONCLUSIONS: Exercise treadmill and rest FP-RNA provided diagnostic value and had prognostic implications in patients with PH. PMID- 28590299 TI - 18F-FDG PET/CT in the Detection of Undifferentiated Carcinoma With Osteoclast like Giant Cells of the Pancreas. AB - Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas (UCOGCP) is a rare nonendocrine pancreatic tumor. We present a case of a very small UCOGCP. F-FDG PET/CT revealed a solid mass measuring 1.0 * 0.8 cm on CT images with an SUVmax of 5.0 in the body of the pancreas. CT revealed a solid mass with significant enhancement. The histopathologic and immunohistochemical studies confirmed the diagnosis. Our findings indicate F-FDG PET/CT is a useful imaging modality for UCOGCP diagnosis. PMID- 28590300 TI - 18F-FDOPA PET Imaging in Prolactinoma. AB - Pituitary macroadenoma constitutes a frequently misdiagnosed benign tumor. We report herein a case where such macroadenoma, a prolactinoma, was incidentally discovered in a 63-year-old man who had been referred to F-FDG PET and F-FDOPA PET imaging for a pharmacoresistant epilepsy. An increased uptake was documented for both radiotracers within the sellar region, although with a much higher contrast for F-FDOPA than for F-FDG. This case presents an increased uptake documented within a prolactinoma owing to the high contrast and image quality provided by F-FDOPA PET. PMID- 28590301 TI - Epstein-Barr Virus-Positive Mucocutaneous Ulcer Mimicking Rectal Carcinoma at 18F FDG PET/CT. AB - We report focally intense F-FDG PET/CT rectal activity (SUVmax = 25) with a horseshoe distribution in an 81-year-old man with B-cell chronic lymphocytic leukemia and suspected Richter transformation. While imaging findings were typical for rectal adenocarcinoma, histology revealed Epstein-Barr virus-positive mucocutaneous ulcer. PMID- 28590303 TI - The immunomodulatory tellurium compound ammonium trichloro (dioxoethylene-O,O') tellurate reduces anxiety-like behavior and corticosterone levels of submissive mice. AB - Ammonium trichloro (dioxoethylene-O,O') tellurate (AS101) is a synthetic organotellurium compound with potent immunomodulatory and neuroprotective properties shown to inhibit the function of integrin alphavbeta3, a presynaptic cell-surface-adhesion receptor. As partial deletion of alphavbeta3 downregulated reuptake of serotonin by the serotonin transporter, we hypothesized that AS101 may influence pathways regulating anxiety. AS101 was tested in the modulation of anxiety-like behavior using the selectively bred Submissive (Sub) mouse strain that develop anxiety-like behavior in response to an i.p. injection. Mice were treated daily with AS101 (i.p., 125 or 200 MUg/kg) or vehicle for 3 weeks, after which their anxiety-like behavior was measured in the elevated plus maze. Animals were then culled for the measurement of serum corticosterone levels by ELISA and hippocampal expression of brain-derived neurotrophic factor (BDNF) by RT-PCR. Chronic administration of AS101 significantly reduced anxiety-like behavior of Sub mice in the elevated plus maze, according to both time spent and entries to open arms, relative to vehicle-treated controls. AS101 also markedly reduced serum corticosterone levels of the treated mice and increased their hippocampal BDNF expression. Anxiolytic-like effects of AS101 may be attributed to the modulation of the regulatory influence integrin of alphavbeta3 upon the serotonin transporter, suggesting a multifaceted mechanism by which AS101 buffers the hypothalamic-pituitary-adrenal axis response to injection stress, enabling recovery of hippocampal BDNF expression and anxiety-like behavior in Sub mice. Further studies should advance the potential of AS101 in the context of anxiety related disorders. PMID- 28590304 TI - Antinociceptive effect of (-)-epicatechin in inflammatory and neuropathic pain in rats. AB - The aim of this study was to investigate the antinociceptive potential of (-) epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (-)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (-)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5 HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL 15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (MU opioid receptor), nor-binaltorphimine (kappa opioid receptor), and 7 benzylidenenaltrexone (delta1 opioid receptor). The effect of (-)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4 aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (-)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5 HT1A/1B/1D/5A serotonergic receptors, and MU/kappa/delta opioid receptors. PMID- 28590302 TI - A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits. AB - BACKGROUND: The efficacy of opioid administration to reduce postoperative pain is limited by respiratory depression. We investigated whether clinically relevant opioid concentrations altered the respiratory pattern in the parabrachial nucleus, a pontine region contributing to respiratory pattern generation, and compared these effects with a medullary respiratory site, the pre-Botzinger complex. METHODS: Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjections elicited tachypnea. Two protocols were performed in separate sets of animals. First, bilateral microinjections of the MU-opioid receptor agonist [D Ala, N-MePhe, Gly-ol]-enkephalin (100 MUM) into the "tachypneic area" determined the effect of maximal MU-opioid receptor activation. Second, respiratory rate was decreased with continuous IV infusions of remifentanil. The opioid antagonist naloxone (1 mM) was then microinjected bilaterally into the "tachypneic area" of the parabrachial nucleus to determine whether the respiratory rate depression could be locally reversed. RESULTS: Average respiratory rate was 27 +/- 10 breaths/min. First, [D-Ala, N-MePhe, Gly-ol]-enkephalin injections decreased respiratory rate by 62 +/- 20% in young and 45 +/- 26% in adult rabbits (both P < 0.001). Second, during IV remifentanil infusion, bilateral naloxone injections into the "tachypneic area" of the parabrachial nucleus reversed respiratory rate depression from 55 +/- 9% to 20 +/- 14% in young and from 46 +/- 20% to 18 +/- 27% in adult rabbits (both P < 0.001). The effects of bilateral [D-Ala, N-MePhe, Gly-ol]-enkephalin injection and IV remifentanil on respiratory phase duration in the "tachypneic area" of the parabrachial nucleus was significantly different from the pre-Botzinger complex. CONCLUSIONS: The "tachypneic area" of the parabrachial nucleus is highly sensitive to MU-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids. PMID- 28590305 TI - Management of diabetic patients hospitalized for acute coronary syndromes: a prospective multicenter registry. AB - BACKGROUND: Patients with diabetes mellitus and acute coronary syndrome (ACS) present an increased risk of adverse cardiovascular events. An Italian Consensus Document indicated 'three specific must' to obtain in this subgroup of patients: optimal oral antiplatelet therapy, early invasive approach and a tailored strategy of revascularization for unstable angina/non-ST-elevation-myocardial infarction (UA/NSTEMI); furthermore, glycemia at admission should be managed with dedicated protocols. AIM: To investigate if previous recommendations are followed, the present multicenter prospective observational registry was carried out in Lombardia during a 9-week period between March and May 2015. METHODS AND RESULTS: A total of 559 consecutive ACS patients (mean age 68.7 +/- 11.3 years, 35% >=75 years, 50% STEMI), with 'known DM' (56%) or 'hyperglycemia', this last defined as blood glucose value >= 126 mg/dl at admission, were included in the registry at 29 hospitals with an on-site 24/7 catheterization laboratory. Patients with known diabetes mellitus received clopidogrel in 51% of the cases, whereas most patients with hyperglycemia (72%) received a new P2Y12 inhibitor: according to clinical presentation in case STEMI prasugrel/ticagrelor were more prescribed than clopidogrel (70 vs. 30%, P < 0.001); on the contrary, no significant difference was found in case of UA/NSTEMI (48 vs. 52%, P = 0.57).Overall, 96% of the patients underwent coronary angiography and 85% received a myocardial revascularization (with percutaneous coronary intervention in 92% of cases) that was however performed in fewer patients with known diabetes mellitus compared with hyperglycemia (79 vs. 90%, P = 0.001).Among UA/NSTEMI, 85% of patients received an initial invasive approach, less than 72 h in 80% of the cases (51% <24 h); no difference was reported comparing known diabetes mellitus to hyperglycemia. Despite similar SYNTAX score, patients with known diabetes mellitus had a higher rate of Heart Team discussion (29 vs. 12%, P = 0.03) and received a surgical revascularization in numerically more cases.Most investigators (85%) followed a local protocol for glycemia management at admission, but insulin was used in fewer than half of the cases; diabetes consulting was performed in 25% of the patients and mainly in case of known diabetes mellitus. CONCLUSION: Based on data of the present real world prospective registry, patients with ACS and known diabetes mellitus are treated with an early invasive approach in case of UA/NSTEMI and with a tailored revascularization strategy, but with clopidogrel in more cases; glycemia management is taken into account at admission. PMID- 28590306 TI - Pancreatic stellate cells: what's new? AB - PURPOSE OF REVIEW: Pancreatic stellate cells (PSCs) play an integral role in the pathogenesis of pancreatitis and pancreatic cancer. With the developing knowledge of this important cell type, we are at the cusp of developing effective therapies for the above diseases based upon targeting the PSC and modulating its function. RECENT FINDINGS: The major themes of the recent PSC literature include: PSC interactions with the extracellular matrix and other stromal components; intracellular calcium physiology as drivers of mechanical interactions and necrosis; the relationship between proinflammatory, protumoural, angiogenic, and metabolic pathways in pancreatic necrosis, fibrosis, and carcinogenesis; and targeting of the stroma for antitumoural and antifibrotic effects. SUMMARY: Traditionally, there have been few treatment options for pancreatitis and pancreatic cancer. The elucidation of the wide-ranging functions of PSCs provide an opportunity for treatments based on stromal reprogramming. PMID- 28590307 TI - Enterococcus durans Endocarditis. PMID- 28590308 TI - Perioperative factors related to the severity of vocal cord paralysis after thoracic cardiovascular surgery: A retrospective review. AB - BACKGROUND: Vocal cord paralysis (VCP) is a rare complication of thoracic cardiovascular surgery. In severe cases, life-threatening airway obstruction may occur. OBJECTIVE: To evaluate the incidence and severity of VCP among patients who underwent thoracic cardiovascular surgery and to identify possible risk factors. DESIGN: Single-centre retrospective review of adult patients. SETTING: Osaka University Hospital, Suita, Japan, from January 2013 to August 2015. PATIENTS: We included 688 patients in the final analysis. Preoperative, intraoperative and postoperative data were collected from medical records. Patients with preoperative VCP or tracheostomy prior to extubation were excluded. The VCP severity in relation to functional recovery was graded using the following categories: absent; mild, remission at 6 months; moderate, partial or persistent VCP at 6 months; or severe, airway obstruction after extubation requiring reintubation. An otolaryngologist diagnosed all VCP cases. MAIN OUTCOME MEASURES: The incidence and severity of VCP after extubation. RESULTS: The incidence (number) of VCP was 4.7% (32), with those of mild, moderate and severe VCP being 1.7% (12), 1.5% (10) and 1.5% (10), respectively. The ICU stay was significantly longer in patients with severe VCP than in patients without VCP [12.5 days (interquartile range 5.5 to 25.5) vs. 3 days (interquartile range 2 to 5), P = 0.0002]. In our multivariable analysis, type 2 diabetes mellitus [odds ratio (OR) 1.853, P = 0.009], intubation period (OR per 24 h 1.136, P = 0.014), ascending aortic arch surgery with brachiocephalic artery reconstruction (OR 8.708, P < 0.001) and ventricular assist device implantation (OR 3.460, P = 0.005) were independent predictors for VCP. CONCLUSION: The identification of these risk factors may facilitate screening for VCP before extubation and possibly help anaesthesia personnel to be prepared to treat VCP-related airway obstruction should it occur. PMID- 28590309 TI - Comparison of laryngeal mask airway insertion methods, including the external larynx lift with pre-inflated cuff, on postoperative pharyngolaryngeal complications: A randomised clinical trial. AB - BACKGROUND: Postoperative pharyngolaryngeal complications are commonly reported following laryngeal mask airway (LMA) insertion. After induction of anaesthesia, the airway structures fall backwards under the influence of gravity, and this may contribute to difficulty in placement of a LMA. External airway alignment by lifting the larynx during insertion of an airway may avoid collision of the airway with laryngeal structures. OBJECTIVE(S): To compare pharyngolaryngeal complications after either conventional airway insertion with or without cuff semi-inflation and a method, including an external larynx lift. DESIGN: Randomised controlled, double-blind, clinical trial. SETTING: Ambulatory surgical operating rooms of a university hospital. PATIENTS: American Society of Anaesthesiologists class 1 to 3 patients undergoing ambulatory surgery scheduled to receive general anaesthesia for which a LMA was not contraindicated. INTERVENTIONS: Patients were randomised into three groups for LMA placement: G1, deflated airway; G2, pre-inflated cuff; G3, pre-inflated cuff with external lifting of the larynx. Assessment of pharyngolaryngeal complications (blinded assessor) was made at the time of LMA removal and again at 1, 2 and 24 h. MAIN OUTCOME MEASURES: A pharyngolaryngeal complication, defined as a composite of one or more of sore throat, dysphonia or dysphagia at any time point, or blood on the airway at removal. RESULTS: Of the 450 consecutive patients, 441 were studied. There were no differences in insertion times or number of insertion attempts among the groups. There was no difference in pharyngolaryngeal complications among the groups: G1, 57%; G2, 55%; G3, 52%, (P = 0.77). Blood on the airway was observed less frequently in G3 (9%) compared with G1 and G2 combined (17%): difference -8% (95% confidence interval of the difference -0.8 to -16%, P = 0.01). CONCLUSION: The external larynx lift technique was associated with a lower incidence of blood on the airway at removal, suggesting that the method may decrease trauma to the tissues of the upper airway during insertion. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01749033. PMID- 28590311 TI - Aspirin challenge and desensitization: how, when and why. AB - PURPOSE OF REVIEW: To investigate the current approach to aspirin challenge (drug provocation) and/or desensitization in patients with histories of hypersensitivity reactions to it, particularly in those with cardiovascular diseases. RECENT FINDINGS: The literature indicates that patients with coronary artery disease (CAD), including those with an acute coronary syndrome, may safely undergo low-dose aspirin challenge and/or desensitization. Recently, flowcharts regarding challenge/desensitization procedures with aspirin in patients with CAD and histories of aspirin hypersensitivity reactions have become available. Aspirin desensitization and continuous aspirin therapy constitute an effective option in patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory diseases (NERD) who have suboptimally controlled asthma or rhinosinusitis, or require multiple revision polypectomies. SUMMARY: The use of aspirin has proven to reduce morbidity and mortality associated with CAD. There is a general consensus on aspirin's effectiveness in secondary prevention of CAD. Therefore, aspirin desensitization is necessary in patients with CAD and histories of hypersensitivity reactions to it. The effectiveness of aspirin desensitization and continuous therapy in patients with NERD has been shown in numerous studies. However, shared selection criteria of candidates for aspirin challenge/desensitization procedures, and simple and homogeneous protocols are necessary. Moreover, preventive safety measures are still needed in order to reduce the potential risks of these procedures. PMID- 28590310 TI - Medical Management of Endometriosis. AB - Endometriosis is a chronic medical condition that affects around 6% to 10% of reproductive age women. Pelvic pain, dysmenorrhea, and infertility are the most common presenting symptoms. The disease is characterized by estrogen-dependent growth of the endometrial glands and stroma outside the endometrial cavity. The diagnosis requires a high degree of suspicion and can be only confirmed on histopathology. Treatment includes medical and surgical options. Both hormonal and nonhormonal medical options are available and are tried at first with a goal to control pain and stop the growth of the endometriotic lesions. Nonsteroidal anti-inflammatory drugs, oral contraceptive pills, gonadotropin-releasing hormone (GnRH) agonists, aromatase inhibitors are some of the commonly used medications. With more research on the molecular and biochemical aspects of endometriosis, newer targets of therapy are being developed like selective progesterone receptor modulators, antiangiogenic factors and immunomodulators. In women who do not respond to medical therapy or have severe symptoms, surgical excision of the endometrial lesions and adhesions is often helpful and offers confirmatory diagnosis by histopathology. PMID- 28590313 TI - Current management of metastatic renal cell carcinoma: evolving new therapies. AB - PURPOSE OF REVIEW: Targeted therapies have recently replaced cytokine treatments as the gold standard for management of metastatic renal cell carcinoma (mRCC). Currently approved treatments include the tyrosine kinase inhibitors sunitinib, pazopanib, axitinib, sorafenib, cabozantinib and lenvatinib; the vascular endothelial growth factor (VEGF) inhibitor bevacizumab; the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus; and the immunologic nivolumab. The purpose of this review is to provide an updated analysis of the clinical data supporting the use of these agents in the first-line and second line setting. RECENT FINDINGS: In the first-line setting, pazopanib may be better tolerated than sunitinib, an individualized dosing sunitinib regimen based on toxicity might improve survival and cabozantinib appears to be an emerging option. In the second-line setting, three new therapies (cabozantinib, lenvatinib/everolimus and nivolumab) have shown superiority against everolimus, the previous standard therapy. The International Metastatic RCC Database Consortium prognostic model may be useful in guiding the selection of subsequent therapy and patients eligible for metastasectomy. SUMMARY: Targeted therapies are the standard treatment for mRCC. Despite advancements in survival, progression free survival and tolerability, these targeted therapies remain largely noncurative. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the management of mRCC. PMID- 28590314 TI - Novel imaging in advanced prostate cancer. AB - PURPOSE OF REVIEW: Prostate cancer (PCa) is the most commonly diagnosed noncutaneous cancer and second leading cause of death in men. Imaging evaluation of PCa is challenging because of the prostate's deep pelvic location, its complex zonal anatomy and its multifocal nature. Novel imaging modalities are needed to improve detection, reassessment in biochemical relapse, and disease progression in advanced metastatic stages. RECENT FINDINGS: Current imaging modalities have distinct strengths. However, all lack the ability to diagnose micrometastases, differentiate high from low-grade disease and diagnose advanced disease, especially at low prostate specific antigen values. There is a need to combine the existing imaging methods with concepts utilizing tumor biology to differentiate biologically aggressive from indolent tumors. PET imaging with novel tracers facilitate improved imaging of PCa, but also usher in new compounds that could be useful for directing treatment as well. Most tracers have limited sensitivity, with the exception of prostate-specific membrane antigen (PSMA) targeting tracers, that offer relatively higher sensitivity and specificity. SUMMARY: PSMA-PET appears promising in improving the imaging yield particularly in recurrent and advanced disease states. Incorporating PSMA-PET in these settings could open or prolong windows along the trajectory of the disease that could allow new treatments or more effective use of currently existing treatments. Prospective studies focusing on novel imaging enhancement and integration with therapeutic applications are needed. PMID- 28590315 TI - Revision ACL Reconstruction: A Critical Analysis Review. PMID- 28590316 TI - RECURRENCE OF CHOROIDAL NEOVASCULARIZATION LESION ACTIVITY AFTER AFLIBERCEPT TREATMENT FOR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To examine the recurrence rate of choroidal neovascularization (CNV) lesion activity in age-related macular degeneration (AMD) and associated factors after 1-year aflibercept treatment. METHODS: Age-related macular degeneration eyes with 1-year aflibercept fixed-regimen treatment and a follow-up period of at least 18 months from the initial aflibercept injection for treatment-naive exudative AMD were retrospectively evaluated. The recurrence rate was examined. Age, gender, visual acuity, AMD subtype, greatest linear dimension, and retinal and choroidal thicknesses at the 12th month examination were compared between eyes with and without recurrence. Presence of remnant polyps and pigment epithelial detachment (PED) morphology were also compared in polypoidal choroidal vasculopathy (PCV) eyes. RESULTS: Of the 98 eyes studied, 69 displayed a dry macula at the 12th month examination; 43.7% exhibited recurrence during the subsequent 12-month period in Kaplan-Meier analysis. Although no factors associated with recurrence were detected in AMD, remnant polyps and pigment epithelial detachment morphology at the 12th month examination were significantly associated with recurrence in polypoidal choroidal vasculopathy (P = 0.018 and 0.048, respectively). CONCLUSION: Continuous, proactive treatment would be considered overtreatment for more than half of the AMD eyes that achieved a dry macula. Angiography and optical coherence tomography analyses may be useful for predicting recurrence in polypoidal choroidal vasculopathy eyes. PMID- 28590317 TI - NEOVASCULARIZATION SECONDARY TO HIGH MYOPIA IMAGED BY OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY. AB - PURPOSE: To describe the optical coherence tomography angiography (OCTA) characteristics of active myopic choroidal neovascularization (CNV) and to compare its sensitivity versus fluorescein angiography and spectral-domain optical coherence tomography. METHODS: Consecutive highly myopic patients complicated with active myopic CNV were prospectively included. The OCTA features were analyzed and correlated with the findings of conventional imaging (spectral domain optical coherence tomography and fluorescein angiography). RESULTS: Twenty eyes of 19 patients (mean age: 59.6 +/- 12.1 years, mean spherical equivalent: 13.5 +/- 3.6 diopters) presenting with both treatment-naive CNV and recurrent CNV were included in the analysis. The OCTA showed a 90% sensitivity for myopic CNV detection in 18 of 20 eyes, revealing a high-flow neovascular network accurately visible using a 30-MUm manual segmentation underneath Bruch membrane. Mean selected area of myopic CNV on OCTA images was 0.34 +/- 0.45 mm, whereas the mean vessel area was 0.22 +/- 0.27 mm. Two neovascular phenotypes prevailed in our series: disorganized vascular loops and organized interlacing patterns. CONCLUSION: The OCTA seems to be a valuable tool in detecting myopic CNV with a high sensitivity. However, its specificity needs to be investigated in further studies. PMID- 28590318 TI - FIVE-YEAR OUTCOMES OF INTRAVITREAL INJECTION OF RANIBIZUMAB FOR THE TREATMENT OF MYOPIC CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To evaluate the 5-year outcomes, efficacy, and safety of intravitreal ranibizumab injections for the treatment of myopic choroidal neovascularization. METHODS: The medical records of 18 consecutive eyes of 14 patients who received intravitreal injections of ranibizumab for myopic choroidal neovascularization with a follow-up of 5 years were retrospectively reviewed. Outcomes included best corrected visual acuity, total number of treatments, and complications. RESULTS: The average number of injections over 5 years was 4.56 +/- 3.52. Ten eyes (55.56%) had no need for treatment after the first year. Mean best-corrected visual acuity improved from 0.59 +/- 0.47 logarithm of the minimum angle of resolution (Snellen equivalent, 6/24) at baseline to 0.32 +/- 0.35 logarithm of the minimum angle of resolution (Snellen equivalent, 6/13) at 1 year, and to 0.38 +/- 0.42 logarithm of the minimum angle of resolution (Snellen equivalent, 6/15) at 2 years (P = 0.001 and 0.020, respectively; paired t-test). After 2 years, although mean best-corrected visual acuity remained better than baseline, the difference was not statistically significant. At 5 years, vision improved by at least 1 line for 61.11% of eyes and by more than 3 lines for 33.33%. The final visual acuity of 2 eyes was worse than baseline because of disease activity and profound chorioretinal atrophy, which increased in six eyes. No complications were noted. CONCLUSION: Intravitreal ranibizumab was safe and effective for treating myopic choroidal neovascularization. Only 44% of eyes required retreatment after the first year, and vision improved in more than 60% of eyes over 5 years. PMID- 28590319 TI - SURGICAL OUTCOMES OF 27-GAUGE VITRECTOMY FOR A CONSECUTIVE SERIES OF 163 EYES WITH VARIOUS VITREOUS DISEASES. AB - PURPOSE: To evaluate the safety and efficacy of 27-gauge vitrectomy for various vitreoretinal disorders. METHODS: In this retrospective comparative study, 163 consecutive eyes with various diseases that underwent 27-gauge pars plana vitrectomy with or without ultraspeed transformer by a single surgeon from June 2012 through December 2014 were analyzed in regard to best-corrected visual acuity, intraocular pressure, intraoperative and postoperative complications, and surgery time. RESULTS: In 2 eyes (1.2%), peripheral retina breaks were encountered intraoperatively, yet no other complications were found in those eyes. No cases required larger-gauge vitrectomy. Mean best-corrected visual acuity improved from 20/58 (logarithm of the minimum angle of resolution, 0.46 +/ 0.64) preoperatively to 20/32 (logarithm of the minimum angle of resolution, 0.20 +/- 0.40) postoperatively (P < 0.001). Mean follow-up was 16.7 months (range, 6-33 months). Intraocular pressure remained stable throughout the postoperative course. Hypotony was seen in 15 eyes (9.2%) at 1-day postoperative, yet that spontaneously improved within 1 week. No case of retinal detachment or endophthalmitis was recorded. In macular surgeries, such as idiopathic epiretinal membrane and macular hole combined with cataract surgery, the mean surgery time was 32.1 +/- 6.9 minutes with ultraspeed transformer (n = 38) and 37.1 +/- 7.7 minutes without ultraspeed transformer (n = 40) (P = 0.004). CONCLUSION: The 27 gauge pars plana vitrectomy was found to be safe and effective for treating various vitreoretinal disorders. PMID- 28590320 TI - STICKY SILICONE OIL. AB - OBJECTIVE: To report and analyze the phenomenon of sticky silicone oil on the retina at the time of its removal. BACKGROUND: Silicone oil has been used for more than 25 years as a long-term retinal tamponade in the surgical management of patients with complex retinal detachments. When a decision to remove silicone oil was made at the end of the tamponade period, the system involved a number of different materials: silicone oil, aqueous solution with or without remnants of perfluorocarbon liquid plus the material of the cannula used to aspirate Silicone oil. This, in effect, may lead to an abnormal adherence of large bubbles of residual silicone oil to the posterior pole of the retina. PATIENTS AND METHODS: A retrospective, interventional case study was performed. We consecutively reviewed 796 patients of silicone oil removal (5,000 or 5,500 centistokes) after primary pars plana vitrectomy at one vitreoretinal center operated by a single surgeon (HG). Chart review was performed to identify potential patients or procedural factors that could predispose to sticky silicone oil formation at the macular area. RESULTS: Large silicone oil bubbles were sticky to the macula in eight out of 796 silicone oil removal procedures between January 2014 and August 2015. The use of perfluorooctane was related to the occurrence of the phenomenon (P < 0.001). CONCLUSION: The sticky silicone oil bubble at the macular region was not related to internal limiting membrane peeling, epiretinal membrane, viscosity, duration, or brand of silicone oil used, but to the use of perfluorooctane. PMID- 28590322 TI - Off-pump Versus On-pump Coronary Artery Bypass Surgery: Graft Patency Assessment With Coronary Computed Tomographic Angiography: A Prospective Multicenter Randomized Controlled Pilot Study. AB - PURPOSE: A large multicenter randomized trial (RCT) is needed to assess off-pump coronary artery bypass graft (CABG) patency when performed by skilled surgeons. This prospective multicenter randomized pilot study compares graft patency after on-pump and off-pump techniques and addresses the feasibility of such an RCT. MATERIALS AND METHODS: Consecutive patients were prospectively recruited for >=64 slice computed tomography angiography graft patency assessment 1 year after randomization to off-pump or on-pump CABG. Blinded assessment of graft patency was performed, and the results were categorized as normal, >=50% stenosis, or occlusion. A multilevel model with random effects on the patient was used to account for correlation of results in patients with multiple grafts. RESULTS: A total of 157 patients (3 centers, 84 off-pump and 73 on-pump patients, 512 grafts, assessability rate 98.4%) were included. Patency index (% nonoccluded grafts) was 89% for the off-pump technique and 95% for the on-pump technique (P=0.09). Patency was similar for arterial and vein grafts (both 92%; P=0.88), as well as between target territories (89% to 94%; P=0.53). CONCLUSIONS: In this pilot study, 1-year graft patency results after off-pump and on-pump surgery were similar. This feasibility trial demonstrates that a large multicenter RCT to compare CABG patency after on-pump with that after off-pump techniques is feasible and can be reliably undertaken using computed tomography angiography. PMID- 28590323 TI - Oxytocin and potential benefits for obesity treatment. AB - PURPOSE OF REVIEW: Laboratory animal experiments have consistently shown that oxytocin causes early termination of food intake, thereby promoting a decrease in body weight in a long term. Recent studies have also assessed some of oxytocin's effects on appetite and energy balance in humans. The present study examines the findings of the key basic research and of the few clinical studies published thus far in the context of potential benefits and challenges stemming from the use of oxytocin in obese patients. RECENT FINDINGS: Basic research indicates the involvement of oxytocin in satiety, processing, in reducing a drive to eat for pleasure and because of psychosocial factors. Although the results of clinical studies are very scarce, they suggest that oxytocin administered intranasally in humans decreases energy-induced and reward-induced eating, supports cognitive control of food choices, and improves glucose homeostasis, and its effectiveness may be BMI dependent. SUMMARY: Despite the wealth of basic research showing broad anorexigenic effects of oxytocin, clinical studies on oxytocin's therapeutic potential in obesity, are still in their infancy. Future implementation of oxytocin-based pharmacological strategies in controlling energy balance will likely depend on our ability to integrate diverse behavioral and metabolic effects of oxytocin in obesity treatment regimens. PMID- 28590324 TI - Is There a Relationship Between Treatment With Direct Antiviral Agents for HCV Infection and the Development of Malignancies? AB - BACKGROUND AND AIMS: Direct antiviral agents (DAAs) have become the treatment of choice for patients with chronic hepatitis C virus (HCV) infection. As these drugs are new, it is important to learn the adverse events of these drugs in the short and long terms. We report on 7 patients who developed malignancies during treatment with DAAs or a short time after finishing treatment. METHODS: We treated 133 patients with DAAs in our unit between January 2015 and June 2016, 100 (75%) of whom were treated with the combination of paritaprevir/ritonavir/ombitasvir with/without dasabuvir (PrOD). The distribution of HCV genotypes was as follow: G1b 114 (85.7%), G1a 3 (2.2%), G2 3 (2.2%), G3 10 (7.5%), G4 2 (1.5%). One hundred ten (82.7%) patients finished treatment. Adverse events were recorded during treatment and after finishing treatment. Efficacy was determined by assessment of serum HCV RNA. RESULTS: We observed malignancies in 7 patients: 1 developed laryngeal carcinoma, 1 developed pancreatic adenocarcinoma, 1 developed oropharyngeal lymphoma, 1 developed recurrent aggressive transitional cell carcinoma of the urinary bladder, 1 developed recurrent aggressive hepatocellular carcinoma, and 2 patients developed de novo hepatocellular carcinoma. All of these patients had advanced liver disease. CONCLUSIONS: This report raises questions about DAAs and the possible development of malignancies. It will be important to look at large clinical trial data and real-world experience to determine if this relationship is real. PMID- 28590325 TI - Uptake of and Factors Associated With Direct-acting Antiviral Therapy Among Patients in the Chronic Hepatitis Cohort Study, 2014 to 2015. AB - BACKGROUND: Limited information is available describing the uptake of direct acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection among patients in general US health care settings. We determined the proportion of HCV infected patients in the Chronic Hepatitis Cohort Study prescribed DAAs in 2014, who initiated treatment and identified characteristics associated with treatment initiation. METHODS: Uptake was defined as the proportion of HCV-infected patients with at least 1 clinical encounter in 2013 who were prescribed a DAA regimen during 2014 and initiated the regimen by August 2015. Using multivariable analysis, we examined demographic and clinical characteristics associated with receipt of DAAs. RESULTS: The cohort comprised 9508 patients; 544 (5.7%) started a DAA regimen. Higher annual income [adjusted odds ratios (aOR) 2.3 for income>$50K vs. <$30K], higher Fibrosis-4 score (aORs, 2.1, 2.0, and 1.4 for Fibrosis-4, >5.88, 3.25 to 5.88, 2.0 to 3.25, respectively, vs. <2.0), genotype 2 infection (aOR 2.2 vs. genotype 1), pre-2014 treatment failure (aOR 2.0 vs. treatment-naive), and human immunodeficiency virus (HIV) coinfection (aOR 1.8 vs. HCV monoinfection) were associated with DAA initiation. Black race/ethnicity (aOR 0.7 vs. whites) and Medicaid coverage (aOR 0.5 vs. private insurance) were associated with noninitiation. Sex, age, comorbidity, previous liver transplant, and duration of follow-up were not associated with receipt of DAAs. CONCLUSIONS: Among patients in these general US health care settings, uptake of DAA therapy was low in 2014, and especially so among minority and Medicaid patients. Systemic efforts to improve access to DAAs for all patients are essential to reduce morbidity and mortality from HCV infection. PMID- 28590326 TI - Improving HIV test uptake and case finding with assisted partner notification services. AB - OBJECTIVE: Despite the enormous expansion of HIV testing services (HTS), an estimated 40% of people with HIV infection remain undiagnosed. To enhance the efficiency of HTS, new approaches are needed. The WHO conducted a systematic review on the effectiveness of assisted partner notification in improving HIV test uptake and diagnosis, and the occurrence of adverse events, to inform the development of normative guidelines. METHODS: We systematically searched five electronic databases through June 2016. We also contacted experts in the field and study authors for additional information where needed. Eligible studies compared assisted HIV partner notification services to passive or no notification. Where multiple studies reported comparable outcomes, meta-analysis was conducted using a random-effects model to produce relative risks (RRs) or risk ratios and 95% confidence intervals (CIs). RESULTS: Of 1742 citations identified, four randomized controlled trials and six observational studies totalling 5150 index patients from eight countries were included. Meta-analysis of three individually randomized trials showed that assisted partner notification services resulted in a 1.5-fold increase in HTS uptake among partners compared with passive referral (RR = 1.46; 95% CI: 1.22-1.75; I = 0%). The proportion of HIV-positive partners was 1.5 times higher with assisted partner notification than with passive referral (RR = 1.47; 95% CI: 1.12-1.92; I = 0%). Few instances of violence or harm occurred. CONCLUSION: Assisted partner notification improved partner testing and diagnosis of HIV-positive partners, with few reports of harm. WHO strongly recommends voluntary assisted HIV partner notification services to be offered as part of a comprehensive package of testing and care. PMID- 28590327 TI - Pregnancy incidence and outcomes in women with perinatal HIV infection. AB - OBJECTIVES: To estimate the incidence of first pregnancy in women living with perinatally acquired HIV (PHIV) in the United Kingdom and to compare pregnancy management and outcomes with age-matched women with behaviourally acquired HIV (BHIV). DESIGN: The National Study of HIV in Pregnancy and Childhood is a comprehensive, population-based surveillance study that collects demographic and clinical data on all pregnant women living with HIV, their children, and all HIV infected children in the United Kingdom and Ireland. METHODS: The incident rate ratio of first pregnancy was calculated for all women of reproductive age who had been reported to the National Study of HIV in Pregnancy and Childhood as vertically infected children. These women and their pregnancies were compared to age-matched pregnant women with BHIV. RESULTS: Of the 630 women with PHIV reported in the United Kingdom as children, 7% (45) went on to have at least one pregnancy, with 70 pregnancies reported. The incident rate ratio of first pregnancy was 13/1000 woman-years. The BHIV comparison group comprised 118 women (184 pregnancies). Women with PHIV were more likely to be on combined antiretroviral therapy at conception and have a lower baseline CD4 cell count (P < 0.01 for both). In adjusted analysis, PHIV and a low baseline CD4 cell count were risk factors for detectable viral load near delivery; older age at conception and being on combined antiretroviral therapy at conception reduced this risk. CONCLUSION: Women with PHIV in the United Kingdom have a low pregnancy incidence, but those who become pregnant are at risk of detectable viral load near delivery, reflecting their often complex clinical history, adherence, and drug resistance issues. PMID- 28590328 TI - Sexual partnership age pairings and risk of HIV acquisition in rural South Africa. AB - OBJECTIVE: To quantify the contribution of specific sexual partner age groups to the risk of HIV acquisition in men and women in a hyperendemic region of South Africa. DESIGN: We conducted a population-based cohort study among women (15-49 years of age) and men (15-55 years of age) between 2004 and 2015 in KwaZulu Natal, South Africa. METHODS: Generalized additive models were used to estimate smoothed HIV incidence rates across partnership age pairings in men and women. Cox proportional hazards regression was used to estimate the relative risk of HIV acquisition by partner age group. RESULTS: A total of 882 HIV seroconversions were observed in 15 935 person-years for women, incidence rate = 5.5 per 100 person-years [95% confidence interval (CI), 5.2-5.9] and 270 HIV seroconversions were observed in 9372 person-years for men, incidence rate = 2.9 per 100 person years (95% CI, 2.6-3.2). HIV incidence was highest among 15-24-year-old women reporting partnerships with 30-34-year-old men, incidence rate = 9.7 per 100 person-years (95% CI, 7.2-13.1). Risk of HIV acquisition in women was associated with male partners aged 25-29 years (adjusted hazard ratio; aHR = 1.44, 95% CI, 1.02-2.04) and 30-34 years (aHR = 1.50, 95% CI, 1.08-2.09) relative to male partners aged 35 and above. Risk of HIV acquisition in men was associated with 25 29-year-old (aHR = 1.72, 95% CI, 1.02-2.90) and 30-34-year-old women (aHR = 2.12, 95% CI, 1.03-4.39) compared to partnerships with women aged 15-19 years. CONCLUSION: Age of sexual partner is a major risk factor for HIV acquisition in both men and women, independent of one's own age. Partner age pairings play a critical role in driving the cycle of HIV transmission. PMID- 28590330 TI - HIV birth testing and linkage to care for HIV-infected infants. AB - : On 5-6 May 2016, the division of AIDS of the National Institute of Allergy and Infectious Diseases convened a workshop on 'HIV Birth Testing and Linkage to Care for HIV Infected Infants.' The goal of the workshop was to evaluate birth testing for early infant diagnosis (EID) of HIV, delineate technological resources for advancing a point-of-care (POC) HIV test implementable at birth and chart out the implementation hurdles for initiating early antiretroviral therapy to HIV infected infants diagnosed at birth. The workshop addressed research and regulatory needs involved in the optimization of POC EID testing and challenges associated with implementation of EID, focusing on testing at birth. Scientific gaps and areas of intervention to accelerate and scale-up EID initiatives and birth testing were identified. These include discussion of the evidence supporting an early mortality peak among HIV-infected infant and justifying a role for birth HIV testing, including POC testing; evaluation of the current POC EID technology pipeline and test performance characteristics required for effective programmatic uptake; mathematical modeling of different testing scenarios and solutions with inclusion of birth testing; the adoption of setting specific EID testing algorithms to achieve efficient linkage to care including early antiretroviral therapy initiation; the development of appropriate quality assurance programs to ensure accuracy of test results and enable sustainability of the testing program. Addressing these gaps and answering these challenges will be important in helping improve outcomes for HIV-infected infants and accelerate achieving the Joint United Nations Program for HIV and AIDS 90-90-90 targets in children. PMID- 28590329 TI - Antiretroviral initiation is associated with increased skeletal muscle area and fat content. AB - OBJECTIVE: A greater burden of physical function impairment occurs in HIV infected adults; the impact of antiretroviral therapy (ART) initiation on muscle density (less dense = more fat), a measure of muscle quality, is unknown. DESIGN: AIDS Clinical Trials Group Study A5260s, a cardiometabolic substudy of A5257, randomized HIV-infected, ART-naive adults to ritonavir-boosted atazanavir, darunavir, or raltegravir with tenofovir/emtricitabine backbone. Single-slice abdominal computed tomography scans from baseline and week 96 were reanalyzed for total and lean muscle area and density. METHODS: Two-sample t-tests described the differences between baseline and week 96 variables. Linear regression analysis was used to explore the role of a priori identified variables and potential confounders. RESULTS: Participants (n = 235) were mostly men (90%); 31% were Black non-Hispanic; 21% were Hispanic. Over 96 weeks, small but significant increases were seen in oblique/transverse abdominal, rectus, and psoas muscle total area (range 0.21-0.83 cm; P < 0.05) but not the lean muscle component (all P >= 0.33). Significant decreases in overall density, consistent with increases in fat, were seen in all muscle groups (range -0.87 to -2.4 HU; P < 0.01); for the lean muscle component, only decreases in oblique/transverse abdominal and rectus reached statistical significance (P < 0.05). In multivariable analyses, Black race was associated with increased muscle density and female sex with decreased density; treatment arm was not associated with changes in mass or density. CONCLUSION: The ART-associated increase in muscle area, regardless of regimen, is likely a reflection of increased fat within the muscle. The consequences of fatty infiltration of muscle on subsequent muscle function require further investigation. PMID- 28590331 TI - Multimodal analysis of drug transporter expression in gastrointestinal tissue. AB - OBJECTIVES: Drug transporters affect antiretroviral therapy (ART) tissue disposition, but quantitative measures of drug transporter protein expression across preclinical species are not available. Our objective was to use proteomics to obtain absolute transporter concentrations and assess agreement with corresponding gene and immunometric protein data. DESIGN: In order to make interspecies comparisons, two humanized mouse [hu-HSC-Rag (n = 41); bone marrow liver-thymus (n = 13)] and one primate [rhesus macaque (nonhuman primate, n = 12)] models were dosed to steady state with combination ART. Ileum and rectum were collected at necropsy and snap frozen for analysis. METHODS: Tissues were analyzed for gene (quantitative PCR) and protein [liquid chromatography-mass spectrometry (LC-MS) proteomics and western blot] expression and localization (immunohistochemistry) of ART efflux and uptake transporters. Drug concentrations were measured by LC-MS/MS. Multivariable regression was used to determine the ability of transporter data to predict tissue ART penetration. RESULTS: Analytical methods did not agree, with different trends observed for gene and protein expression. For example, quantitative PCR analysis showed a two-fold increase in permeability glycoprotein expression in nonhuman primates versus mice; however, proteomics showed a 200-fold difference in the opposite direction. Proteomics results were supported by immunohistochemistry staining showing extensive efflux transporter localization on the luminal surface of these tissues. ART tissue concentration was variable between species, and multivariable regression showed poor predictive power of transporter data. CONCLUSION: Lack of agreement between analytical techniques suggests that resources should be focused on generating downstream measures of protein expression to predict drug exposure. Taken together, these data inform the use of preclinical models for studying ART distribution and the design of targeted therapies for HIV eradication. PMID- 28590334 TI - A decade of learning about the HIV reservoir: new insights into latent infection. PMID- 28590333 TI - Impact of long-term antiretroviral therapy interruption and resumption on viral reservoir in HIV-1 infected patients. AB - : We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV 1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation. These data suggest that the increase in reservoir after long-term ART discontinuation might not be reversible at midterm. PMID- 28590332 TI - HIV-positive youth who are perinatally infected have impaired endothelial function. AB - OBJECTIVE: Evaluating cardiovascular disease risk in children and youth 13 to 24 years old who are facing a life time exposure to both HIV and antiretroviral therapy is a research priority. This study compares endothelial function measured by peripheral arterial tonometry in HIV-positive youth infected perinatally and behaviorally as well as HIV-negative controls. METHODS: Three groups of participants aged 8-30 year were enrolled; HIV-positive perinatally infected, HIV positive behaviorally infected on antiretroviral therapy with HIV-1 RNA less than 1000 copies/ml, and HIV-negative controls. We measured the reactive hyperemic index, a measure of endothelial function, using endoPAT (Caesarea, Israel). Markers of systemic inflammation, monocyte activation, and gut integrity were also assessed. Spearman correlations and regression analyses were used to explore relationships between endothelial function measures and other measured variables. RESULTS: Overall, 119 participants were enrolled: 53 HIV-positive behaviorally infected, 18 HIV-positive perinatally infected, and 48 controls. Overall, 71% were men; 77% African Americans and median age was 22 years old. Median (interquartile range) reactive hyperemic index was lower in the HIV-positive perinatally infected group [1.34 (1.20, 1.42)], compared with the behaviorally infected group [1.52 (1.34, 1.75)] and the control group [1.52 (1.27, 1.80; P < 0.01)]. Soluble CD14, a marker of monocyte activation, intestinal fatty acid binding protein, a marker of gut integrity and soluble vascular cell adhesion molecule, a marker of vascular dysfunction, were different among the three groups (P <= 0.01). CONCLUSION: HIV-positive youth infected perinatally appear to have higher levels of endothelial dysfunction and immune activation when compared with behaviorally infected youth. Further longitudinal studies are needed to determine whether perinatally infected youth have higher risks of cardiovascular disease. PMID- 28590335 TI - Technological methods to measure adherence to antiretroviral therapy and preexposure prophylaxis. AB - PURPOSE OF REVIEW: The WHO's Consolidated Guidelines (2016) call for research on improved methods to proactively monitor adherence and identify those individuals who have the greatest needs for adherence support. This review aims to elucidate the latest technologies available to measure adherence to HIV antiretroviral therapy and preexposure prophylaxis against HIV infection and present their utility in various settings and populations. RECENT FINDINGS: Within the last few years, advances have been made in the features of existing technology to measure adherence (real-time electronic adherence measurements), additional approaches have been developed (digital medicine systems) and improved (short message service surveys), and point of care testing for pharmacokinetic measures are under development. SUMMARY: Technology advances in adherence measurement are promising for improved accuracy and, in some cases, the ability to intervene with adherence challenges in real time. This progress will greatly further our understanding of adherence behavior, as well as the ability to effectively link interventions with individuals who need them, thus maximizing the clinical and public health benefits of both antiretroviral therapy and preexposure prophylaxis. PMID- 28590338 TI - Surgery as part of radical treatment for malignant pleural mesothelioma. AB - PURPOSE OF REVIEW: To review the latest developments in surgery for malignant pleural mesothelioma both in patient selection, surgical technique, and strategy. RECENT FINDINGS: The International Association for the Study of Lung Cancer mesothelioma staging project has produced data to inform the 8th tumour node metastasis revision. The difficulty in clinical N staging and clinical T staging are highlighted and the importance of tumour volume is recognized. New imaging techniques can be utilized to assess tumour volume. The transition from extrapleural pneumonectomy to lung-sparing pleurectomy/decortication has extended the role of cancer-directed surgery into a more elderly population. More aggressive multimodality regimes, including induction radiotherapy are available to a selected population and adjuvant radiotherapy and chemotherapy are feasible in the elderly majority. Additional chemotherapy should not be delayed in those with poorer prognosis node positive, nonepithelioid disease. SUMMARY: Radical surgery for malignant pleural mesothelioma can achieve significant survival when targeted in those with the best prognosis by careful staging. It can be made more accessible by lung preservation without compromising outcome. It should be part of multimodality therapy. PMID- 28590339 TI - Improving adherence to asthma medications: current knowledge and future perspectives: Erratum. PMID- 28590337 TI - Spontaneous pneumothorax in diffuse cystic lung diseases. AB - PURPOSE OF REVIEW: Diffuse cystic lung diseases (DCLDs) are a heterogeneous group of disorders with varying pathophysiologic mechanisms that are characterized by the presence of air-filled lung cysts. These cysts are prone to rupture, leading to the development of recurrent spontaneous pneumothoraces. In this article, we review the epidemiology, clinical features, and management DCLD-associated spontaneous pneumothorax, with a focus on lymphangioleiomyomatosis, Birt-Hogg Dube syndrome, and pulmonary Langerhans cell histiocytosis. RECENT FINDINGS: DCLDs are responsible for approximately 10% of apparent primary spontaneous pneumothoraces. Computed tomography screening for DCLDs (Birt-Hogg-Dube syndrome, lymphangioleiomyomatosis, and pulmonary Langerhans cell histiocytosis) following the first spontaneous pneumothorax has recently been shown to be cost-effective and can help facilitate early diagnosis of the underlying disorders. Patients with DCLD-associated spontaneous pneumothorax have a very high rate of recurrence, and thus pleurodesis should be considered following the first episode of spontaneous pneumothorax in these patients, rather than waiting for a recurrent episode. Prior pleurodesis is not a contraindication to future lung transplant. SUMMARY: Although DCLDs are uncommon, spontaneous pneumothorax is often the sentinel event that provides an opportunity for diagnosis. By understanding the burden and implications of pneumothoraces in DCLDs, clinicians can facilitate early diagnosis and appropriate management of the underlying disorders. PMID- 28590340 TI - Colonic Phenotypes Are Associated with Poorer Response to Anti-TNF Therapies in Patients with IBD. AB - BACKGROUND: Although anti-tumor necrosis factor (TNF) agents are effective in patients with inflammatory bowel disease (IBD), many patients either do not respond to anti-TNF treatment or lose response over time. The aim of this study was to determine factors associated with response to anti-TNF therapy in IBD. METHODS: Patients with Crohn's disease (CD) or ulcerative colitis who had consented to participate in a genetics registry and been treated with anti-TNF agents were evaluated retrospectively and categorized as primary nonresponders or secondary nonresponders. We evaluated clinical, serological, and genetic characteristics associated with primary nonresponse or time to loss of response to anti-TNF agents. RESULTS: We included 314 CD (51 [16.2%] primary nonresponders and 179 [57.0%] secondary nonresponders) and 145 subjects with ulcerative colitis (43 [29.7%] primary nonresponders and 74 [51.0%] secondary nonresponders). Colonic involvement (P = 0.017; odds ratio = 8.0) and anti-TNF monotherapy (P = 0.017; odds ratio = 4.9) were associated in a multivariate analysis with primary nonresponse to anti-TNF agents in CD. In addition, higher anti-nuclear cytoplasmic antibody levels (P = 0.019; hazard ratio = 1.01) in CD, anti-nuclear cytoplasmic antibody positivity (P = 0.038; hazard ratio = 1.6) in ulcerative colitis, and a positive family history of IBD (P = 0.044; hazard ratio = 1.3) in all patients with IBD were associated with time to loss of response to anti-TNF agents. Furthermore, various known IBD susceptibility single-nucleotide polymorphisms and additional variants in immune-mediated genes were shown to be associated with primary nonresponse or time to loss of response. CONCLUSIONS: Our results may help to optimize the use of anti-TNF agents in clinical practice and position these therapies appropriately as clinicians strive for a more personalized approach to managing IBD. PMID- 28590341 TI - Fecal Calprotectin Levels Predict Histological Healing in Ulcerative Colitis. AB - BACKGROUND: Mucosal healing as measured by endoscopic activity is the therapeutic target for ulcerative colitis (UC) and associated with improved outcomes. We investigated the clinical utility of fecal calprotectin (FC) levels to predict depth of remission, including histological remission in patients with UC. METHODS: We performed a retrospective chart review of patients with UC who underwent a full colonoscopy and FC measured within 6 weeks before colonoscopy at a tertiary inflammatory bowel disease center. Clinical, endoscopic, and histological disease activity was assessed by Patient Reported Outcomes (PRO2), Mayo endoscopic score (0-3), and Nancy score (0-4), respectively. Outcomes of interest included (1) deep remission (PRO2 remission and Mayo score 0) and (2) deeper remission (deep remission plus Nancy score 0/1). Mann-Whitney U and Kruskal-Wallis tests and area under the curve-receiver operating characteristic curve analysis were used to evaluate accuracy of the predictive values. RESULTS: In 68 patients, increasing FC levels were significantly associated with disease extent (P = 0.006), Mayo score (P = 0.001), and Nancy scores (P < 0.001). Patients with Mayo score 0/1 and Nancy score <=1 (n = 20) had significantly lower FC levels compared with Mayo 0/1 and Nancy >= 2 (31 versus 231; P < 0.001). FC level of <=60 MUg/g predicted deep remission (area under the curve = 0.92, sensitivity 86%, and specificity 87%) and deeper remission (area under the curve = 0.91, sensitivity 83%, and specificity 90%). CONCLUSIONS: FC levels significantly correlated with endoscopic extent, mucosal healing, and histological activity, and reflect microscopic disease activity even in the face of macroscopic healing. An FC level of <=60 MUg/g robustly predicted depth of remission, suggesting that FC can be used instead of colonoscopy in a treat-to target paradigm in patients with UC. PMID- 28590342 TI - Supplementation of Low- and High-fat Diets with Fermentable Fiber Exacerbates Severity of DSS-induced Acute Colitis. AB - BACKGROUND: Lack of dietary fiber has been suggested to increase the risk of developing various chronic inflammatory diseases, whereas supplementation of diets with fiber might offer an array of health-promoting benefits. Consistent with this theme, we recently reported that in mice, compositionally defined diets that are made with purified ingredients and lack fermentable fiber promote low grade inflammation and metabolic syndrome, both of which could be ameliorated by supplementation of such diets with the fermentable fiber inulin. METHODS: Herein, we examined if, relative to a grain-based mouse diet (chow), compositionally defined diet consumption would impact development of intestinal inflammation induced by dextran sulfate sodium (DSS) and moreover, whether DSS-induced colitis might also be attenuated by diets supplemented with inulin. RESULTS: Analogous to their promotion of low-grade inflammation, compositionally defined diet of high- and low-fat content with cellulose increased the severity of DSS-induced colitis relative to chow. However, in contrast to the case of low-grade inflammation, addition of inulin, but not the insoluble fiber cellulose, further exacerbated the severity of colitis and its associated clinical manifestations (weight loss and bleeding) in both low- and high-fat diets. CONCLUSIONS: While inulin, and perhaps other fermentable fibers, can ameliorate low-grade inflammation and associated metabolic disease, it also has the potential to exacerbate disease severity in response to inducers of acute colitis. PMID- 28590345 TI - Two cases of epithelioid trophoblastic tumors in postmenopausal women. AB - OBJECTIVE: Epithelioid trophoblastic tumor is a rare gestational trophoblastic neoplasm usually presenting in women of reproductive age, with a history of a prior gestational event. Its presentation in postmenopausal women is extremely rare. Immunohistochemical staining is a helpful aid to distinguish epithelioid trophoblastic tumor from other gestational trophoblastic neoplasms. Correct diagnosis is crucial for clinical management that can vary according to the type of gestational trophoblastic neoplasm. METHODS: We report the case of a 63-year old postmenopausal woman 33 years after her last full-term pregnancy and another case of a 57-year-old postmenopausal woman who had had a first-trimester abortion 30 years previously as her last gestational event, both presenting cervical epithelioid trophoblastic tumors. In both cases, immunohistochemistry played an important role in differentiating this entity from other gestational trophoblastic neoplasms. Surgery was the primary treatment in both cases. The first patient remained disease-free and died 5 years later due to a rectal adenocarcinoma, and the second patient remains disease-free at publication. RESULTS: In both cases, the hysterectomy specimen confirmed the presence of two large epithelioid trophoblastic tumors arising in the endocervix and lower uterine segment with no extrauterine disease. Nuclear positivity for p63 allowed differentiation from a placental site trophoblastic tumor. The Ki67 proliferative index was 20% and 35%, respectively. CONCLUSIONS: Epithelioid trophoblastic tumors may occur a long time after a prior gestational event and should even be excluded in postmenopausal women with uterine masses. Immunohistochemical staining is helpful to make the differential diagnosis with other gestational trophoblastic neoplasms. PMID- 28590343 TI - Impact of Infliximab and Cyclosporine on the Risk of Colectomy in Hospitalized Patients with Ulcerative Colitis Complicated by Cytomegalovirus-A Multicenter Retrospective Study. AB - BACKGROUND: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA]). METHODS: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months. RESULTS: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy. CONCLUSIONS: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV positive patients with UC. PMID- 28590344 TI - The Characteristics and Long-term Outcomes of Pediatric Crohn's Disease Patients with Perianal Disease. AB - BACKGROUND: Data on the outcomes of children with perianal Crohn's disease are limited. We aimed to assess phenotypic features at diagnosis and long-term disease-specific outcomes of this phenotype. METHODS: The medical records of 296 pediatric onset patients with Crohn's disease, diagnosed from 2001 to 2015, were reviewed retrospectively. Baseline characteristics included age, sex, severity indices, laboratory data, endoscopic findings, and anthropometric measurements. Main outcome measures included time to first flare, hospitalization, surgery, and biological therapy. RESULTS: Of the 296 included patients (median age 14.2 years), 70 (24%) had nonfistulizing perianal findings, whereas only 40 (13%) had fistulizing perianal disease at diagnosis. Perianal involvement was associated with female sex (P = 0.01), whereas fistulizing perianal disease resulted in a greater use of immunomodulators (P = 0.01). Time to hospitalization was shorter for both nonfistulizing and fistulizing perianal disease (hazard ratio [HR] 1.66 and 1.34, respectively, P = 0.027) and time to biological therapy (HR 2.1 and 1.7, respectively, P = 0.002). There were no differences in time to first flare or surgery. During a median follow-up of 8.5 years, additional 26 patients (10%) developed fistulizing perianal disease after a median time of 3.5 years. The presence of nonfistulizing disease at diagnosis was a significant risk factor for the development of fistulizing perianal disease (HR 3.4, P = 0.002). At the end of follow-up, complicated disease was more common in patients with any perianal involvement (P = 0.01). CONCLUSIONS: Pediatric patients with Crohn's disease with both nonfistulizing and fistulizing disease have worse clinical outcomes. Nonfistulizing disease is a risk factor for the development of fistulizing disease over time. PMID- 28590346 TI - Associations between high-risk alcohol consumption and sarcopenia among postmenopausal women. AB - OBJECTIVE: Sarcopenia is an age-related process, leading to cardio-metabolic diseases and disabilities. High-risk drinking is also closely related to diabetes, hypertension, and dyslipidemia, which are modifiable risk factors for sarcopenia. In the present study, we aimed to investigate the association between alcohol-drinking patterns and sarcopenia in Korean postmenopausal women. METHODS: Data from 2,373 postmenopausal women were analyzed from the 2008 to 2011 Korean National Health and Nutrition Examination Survey. We defined sarcopenia as two standard deviations below the sex-specific means of the appendicular skeletal muscle/weight (percentage) values of a young reference group. Participants were categorized into three groups according to alcohol-drinking patterns, as assessed by the Alcohol Use Disorders Identification Test questionnaire. The odds ratios and 95% confidence intervals for sarcopenia were calculated using multiple logistic regression analyses. RESULTS: In total, 8.2% of Korean postmenopausal women met criteria for sarcopenia. The prevalence of sarcopenia increased from low-risk to high-risk alcohol-drinking groups as follows: 7.6, 11.0, and 22.7%, respectively. Compared with the low-risk group, the odds ratio (95% confidence interval) for the high-risk group was 4.29 (1.87-9.82) after adjusting for age, body mass index, systolic blood pressure, total cholesterol, fasting blood glucose, household income, education level, daily calorie intake, current smoking and regular exercise, and household food security status CONCLUSIONS:: High-risk alcohol drinking was associated with a higher risk of sarcopenia in postmenopausal Korean women. PMID- 28590347 TI - Focused assessment with sonography for trauma in children after blunt abdominal trauma: A multi-institutional analysis. AB - INTRODUCTION: The utility of focused assessment with sonography for trauma (FAST) in children is poorly defined with considerable practice variation. Our purpose was to investigate the role of FAST for intra-abdominal injury (IAI) and IAI requiring acute intervention (IAI-I) in children after blunt abdominal trauma (BAT). METHODS: We prospectively enrolled children younger than 16 years after BAT at 14 Level I pediatric trauma centers over a 1-year period. Patients who underwent FAST were compared with those that did not, using descriptive statistics and univariate analysis; p value less than 0.05 was considered significant. FAST test characteristics were performed using computed tomography (CT) and/or intraoperative findings as the gold standard. RESULTS: Two thousand one hundred eighty-eight children (age, 7.8 +/- 4.6 years) were included. Eight hundred twenty-nine (37.9%) received a FAST, 340 of whom underwent an abdominal CT. Ninety-seven (29%) of these 340 patients had an IAI and 27 (7.9%) received an acute intervention. CT scan utilization after FAST was 41% versus 46% among those who did not receive FAST. The frequency of FAST among centers ranged from 0.84% to 94.1%. There was low correlation between FAST and CT utilization (r = -0.050, p < 0.001). Centers that performed FAST at a higher frequency did not have improved accuracy. The test performance of FAST for IAI was sensitivity, 27.8%; specificity, 91.4%; positive predictive value, 56.2%; negative predictive value, 76.0%; and accuracy, 73.2%. There were 81 injuries among the 70 false-negative FAST. The test performance of FAST for IAI-I was sensitivity, 44.4%; specificity, 88.5%; positive predictive value, 25.0%; negative predictive value, 94.9%; and accuracy, 85.0%. Fifteen children with a negative FAST received acute interventions. Among the 27 patients with true positive FAST examinations, 12 received intervention. All had an abnormal abdominal physical examination. No patient underwent intervention before CT scan. CONCLUSION: As currently used, FAST has a low sensitivity for IAI, misses IAI-I and rarely impacts management in pediatric BAT. LEVEL OF EVIDENCE: Prognostic and epidemiologic study, level II; diagnostic tests or criteria study, level II; therapeutic/care management study, level III. PMID- 28590348 TI - Incidence of adult respiratory distress syndrome in trauma patients: A systematic review and meta-analysis over a period of three decades. AB - BACKGROUND: In trauma patients, acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality. Changes in diagnostics, management, and treatment may have influenced the incidence of ARDS. Therefore, the purpose of this article is to evaluate whether there is a difference in the incidence of posttraumatic ARDS (1) over time, (2) attributable to geographic distribution, and 3) related to admitting surgical subspecialities. METHODS: A comprehensive search of articles published in English and German language was conducted using PubMed, MEDLINE, and the ISI Web of Science. Search terms included ARDS, acute respiratory distress syndrome, multiple trauma, polytrauma, and surgery. A meta regression was performed to analyze differences between several decades of patient recruitment (decade 1, 1981-1990; decade 2, 1991-2000; decade 3, 2001 2010), geographic location (North America and Europe), and the type of admitting surgical service (general vs. orthopedic trauma), respectively. Statistical analyses were performed with R (version 3.1.2, metafor package). RESULTS: The search included studies between January 1, 1980, and December 31, 2015 and revealed 43 trials from 40 publications (117,951 patients, 7,816 with posttraumatic ARDS). The median incidences over the last three decades were similar between decade 1 (10.4%), decade 2 (7.7%), and decade 3 (8.0%) (p = 0.8322). Geographical observations comparing central Europe and North America revealed no statistically significant difference (Europe 13.0%) and North America (6.9%), (p = 0.0696). The ARDS incidence in patients published based on a general surgery service (9.8%) was comparable to those published by orthopedic trauma surgeons (7.0%) (p = 0.3436). CONCLUSION: The results of this meta-analysis discard the assumption that the following factors have influenced the incidence of posttraumatic ARDS: There was neither a change in the incidence over the last decades, nor a geographical difference within western societies, nor associated with the admitting surgical subspeciality. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 28590350 TI - Does prehospital management by doctors affect outcome in major trauma? A systematic review. AB - BACKGROUND: There is substantial variation worldwide in prehospital management of trauma and the role of doctors is controversial. The objective of this review was to determine whether prehospital management by doctors affects outcomes in major trauma, including the prespecified subgroup of severe traumatic brain injuries when compared with management by other advanced life support providers. METHODS: EMBASE, MEDLINE(R), PubMed, SciELO, Trip, Web of Science, and Zetoc were searched for published articles. HSRProj, OpenGrey, and the World Health Organization International Clinical Trials Registry Platform were searched for unpublished data. Relevant reference lists were hand-searched. There were no limits on publication year, but articles were limited to the English language. Authors were contacted for further information as required. Quality was assessed using the Downs and Black criteria. Mortality was the primary outcome, and disability was the secondary outcome of interest. Studies were subjected to a descriptive analysis alone without a meta-analysis due to significant study heterogeneity. All searches, quality assessment, data abstraction, and data analysis was performed by two reviewers independently. RESULTS: Two thousand thirty-seven articles were identified, 49 full-text articles assessed and eight studies included. The included studies consisted of one randomized controlled trial with 375 participants and seven observational studies with over 4,451 participants. All included studies were at a moderate to high risk of bias. Six of the eight included studies showed an improved outcome with prehospital management by doctors, five in terms of mortality and one in terms of disability. Two studies found no significant difference. CONCLUSION: There appears to be an association between prehospital management by doctors and improved survival in major trauma. There may also be an association with improved survival and better functional outcomes in severe traumatic brain injury. Further high-quality evidence is needed to confirm these findings. LEVEL OF EVIDENCE: Systematic review, level III. PMID- 28590351 TI - A novel approach to optimal placement of new trauma centers within an existing trauma system using geospatial mapping. AB - BACKGROUND: Trauma system expansion is a complex process often governed by financial and health care system imperatives. We sought to propose a new, informed approach to trauma system expansion through the use of geospatial mapping. We hypothesized that geospatial mapping set to specific parameters could effectively identify optimal placement of new trauma centers (TC) within an existing trauma system. METHODS: We used Pennsylvania Trauma Systems Foundation registry data of adult (age, >= 15 years) trauma for calendar years 2003 to 2015 (n = 408,432), hospital demographics, road networks, and US Census data files. We included TCs and zip codes outside of Pennsylvania to account for edge effects with trauma cases aggregated to the zip code centroid of residence. Our model assumptions included existing Pennsylvania Trauma Systems Foundation Level I and II TCs, a maximum travel time of 60 minutes to the TC, capacity based on mean statewide ratios of trauma cases per hospital bed size, Injury Severity Score, candidate hospitals with 200 or more licensed beds and 30 minutes or longer or 15 minutes or longer from an existing TC in nonurban/urban areas, respectively. We used the Network Analyst Location-Allocation function in ArcGIS Desktop to generate spatial models. RESULTS: Of the 130 candidate sites, only 14 met the bed size and travel time criteria from an existing TC. Approximately 70% of zip codes and 91% of cases were within 60 minutes of an existing TC. Adding one to six new optimally paced TCs increased to a maximum of 82% of zip codes and 96% of cases within 60 minutes of an existing TC. Changes to model assumptions had an impact on which candidate sites were selected. CONCLUSION: Intelligent trauma system design should include an objective process like geospatial to determine the optimum locations for new TCs within existing trauma networks. LEVEL OF EVIDENCE: Epidemiological study, level III. PMID- 28590352 TI - Big for small: Validating brain injury guidelines in pediatric traumatic brain injury. AB - BACKGROUND: Brain injury guidelines (BIG) were developed to reduce overutilization of neurosurgical consultation (NC) as well as computed tomography (CT) imaging. Currently, BIG have been successfully applied to adult populations, but the value of implementing these guidelines among pediatric patients remains unassessed. Therefore, the aim of this study was to evaluate the established BIG (BIG-1 category) for managing pediatric traumatic brain injury (TBI) patients with intracranial hemorrhage (ICH) without NC (no-NC). METHODS: We prospectively implemented the BIG-1 category (normal neurologic examination, ICH <= 4 mm limited to one location, no skull fracture) to identify pediatric TBI patients (age, <= 21 years) that were to be managed no-NC. Propensity score matching was performed to match these no-NC patients to a similar cohort of patients managed with NC before the implementation of BIG in a 1:1 ratio for demographics, severity of injury, and type as well as size of ICH. Our primary outcome measure was need for neurosurgical intervention. RESULTS: A total of 405 pediatric TBI patients were enrolled, of which 160 (NC, 80; no-NC, 80) were propensity score matched. The mean age was 9.03 +/- 7.47 years, 62.1% (n = 85) were male, the median Glasgow Coma Scale score was 15 (13-15), and the median head Abbreviated Injury Scale score was 2 (2-3). A subanalysis based on stratifying patients by age groups showed a decreased in the use of repeat head CT (p = 0.02) in the no NC group, with no difference in progression (p = 0.34) and the need for neurosurgical intervention (p = 0.9) compared with the NC group. CONCLUSION: The BIG can be safely and effectively implemented in pediatric TBI patients. Reducing repeat head CT in pediatric patients has long-term sequelae. Likewise, adhering to the guidelines helps in reducing radiation exposure across all age groups. LEVEL OF EVIDENCE: Therapeutic/care management, level III. PMID- 28590354 TI - Optimal timing for repair of peripheral nerve injuries. AB - BACKGROUND: Data regarding outcomes after peripheral nerve injuries is limited, and the optimal management strategy for an acute injury is unclear. The aim of this study was to examine timing of repair and specific factors that impact motor sensory outcomes after peripheral nerve injury. METHODS: This was a single center, retrospective study. Patients with traumatic peripheral nerve injury from January 2010 to June 2015 were included. Patients who died, required amputation, suffered brachial plexus injury, or had missing motor-sensory examinations were excluded. Motor-sensory examinations were graded 0 to 5 by the Modified British Medical Research Council system. Operative repair of peripheral nerves was analyzed for patient characteristics, anatomic nerve injured, level of injury, associated injuries, days until repair, and repair method. RESULTS: Three hundred eleven patients met inclusion criteria. Two hundred fifty-eight (83%) patients underwent operative management, and 53 (17%) underwent nonoperative management. Those who required operative intervention had significantly more penetrating injuries 85.7% versus 64.2% (p < 0.001), worse initial motor scores 1.19 versus 2.23 (p = 0.004), and worse initial sensory examination scores 1.75 versus 2.28 (p = 0.029). Predictors of improved operative motor outcomes on univariate analysis were Injury Severity Score less than 15 (p = 0.013) and male sex (p = 0.006). Upper arm level of injury was a predictor of poor outcome (p = 0.041). Multivariate analysis confirmed male sex as a predictor of good motor outcome (p = 0.014; Adjusted Odds Ratio, 3.88 [1.28-11.80]). Univariate analysis identified distal forearm level of injury (p = 0.026) and autograft repair (p = 0.048) as predictors of poor sensory outcome. Damage control surgery for unstable patients undergoing laparotomy (p = 0.257) and days to nerve repair (p = 0.834) did not influence motor-sensory outcome. Outcomes did not differ significantly in patients who underwent repair 24 hours or longer versus those who were repaired later. CONCLUSION: Outcomes were primarily influenced by patient characteristics and injury level rather than operative characteristics. Peripheral nerve injuries can be repaired after damage control surgery without detriment to outcomes. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28590358 TI - Erythropoietin in patients with traumatic brain injury and extracranial injury-A post hoc analysis of the erythropoietin traumatic brain injury trial. AB - BACKGROUND: Erythropoietin (EPO) may reduce mortality after traumatic brain injury (TBI). Secondary brain injury is exacerbated by multiple trauma, and possibly modifiable by EPO. We hypothesized that EPO decreases mortality more in TBI patients with multiple trauma, than in patients with TBI alone. METHODS: A post hoc analysis of the EPO-TBI randomized controlled trial conducted in 2009 to 2014. To evaluate the impact of injuries outside the brain, we calculated an extracranial Injury Severity Score (ISS) that included the same components of the ISS, excluding head and face components. We defined multiple trauma as two injured body regions with an Abbreviated Injury Scale (AIS) score of 3 or higher. Cox regression analyses, allowing for potential differential responses per the presence or absence of extracranial injury defined by these injury scores, were used to assess the effect of EPO on time to mortality. RESULTS: Of 603 included patients, the median extracranial ISS was 6 (interquartile range, 1-13) and 258 (43%) had an AIS score of 3 or higher in at least two body regions. On Cox regression, EPO was associated with decreased mortality in patients with greater extracranial ISS (interaction p = 0.048) and weakly associated with differential mortality with multiple trauma (AIS score > 3 or in two regions, interaction p = 0.17). At 6 months in patients with extracranial ISS higher than 6, 10 (6.8%) of 147 EPO-treated patients compared with 26 (17%) of 154 placebo-treated patients died (risk reduction, 10%; 95% confidence interval, 2.9-17%; p = 0.007). CONCLUSION: In this post hoc analysis, EPO administration was associated with a potential differential improvement in 6-month mortality in TBI patients with more severe extracranial injury. These findings need confirmation in future clinical and experimental studies. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 28590356 TI - Plasma succinate is a predictor of mortality in critically injured patients. AB - BACKGROUND: Trauma is the leading cause of mortality under the age of 40 years. Recent observations on metabolic reprogramming during hypoxia and ischemia indicate that hypoxic mitochondrial uncoupling promotes the generation of succinate, which in turn mediates reperfusion injury and inflammatory sequelae upon reoxygenation. Plasma levels of succinate significantly increase in response to trauma and hemorrhage in experimental models and clinical samples, suggesting that succinate may represent a candidate marker of systemic perfusion in trauma. METHODS: Quantitative mass spectrometry-based metabolomics was used to quantify succinate and lactate in 595 plasma samples from severely injured patients enrolled at the Denver Health Medical Center, a Level I trauma center in Denver, Colorado. RESULTS: A total of 95 severely injured patients were sampled for up to 10 time points (595 total samples), from field blood to 7 days postinjury. Results indicate that plasma levels of succinate increased up to 25.9-fold in deceased patients versus the median of the surviving patients (p = 2.75e-100; receiver operating characteristic area under the curve, 0.911). On the other hand, only 2.4-fold changes increases in lactate were observed (p = 5.8e-21; area under the curve, 0.874). CONCLUSION: Succinate represents a uniquely sensitive biomarker of postshock metabolic derangement and may be an important mediator of sequelae. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 28590359 TI - Laparoscopic Sleeve Gastrectomy Then and Now: An Updated Systematic Review of the Progress and Short-term Outcomes Over the Last 5 Years. AB - INTRODUCTION AND AIM: Laparoscopic sleeve gastrectomy (LSG) is considered one of the most popular bariatric surgeries of the present time. This review aimed to evaluate the progress and short-term outcomes of LSG over the last 5 years. METHODS: The systematic review of electronic databases revealed 27 relevant articles, which were carefully assessed. The data extracted from the studies were analyzed and compared with data reported by a previous review published in 2010. RESULTS: A total of 5218 patients were included in this review with a mean age of 41.1. The average preoperative body mass index (43.8+/-8) significantly dropped at 12 months to 30.7+/-3.9. The average percentage of excess weight loss at 1 year was 67.3. The mean rates of remission of diabetes mellitus, hypertension, and dyslipidemia were 81.9%, 66.5%, and 64.1%, respectively. The mean complication rate across the studies was 8.7% and the average mortality rate was 0.3%. A significant drop in postoperative body mass index, higher percentage of excess weight loss, and significantly lower overall complication rate were observed in comparison with the previous systematic review. CONCLUSIONS: LSG continues to achieve satisfactory weight loss and improvement of obesity-related comorbidities with acceptably low morbidity and mortality rates. PMID- 28590360 TI - Laparoscopic Total Extraperitoneal (TEP) Inguinal Hernia Repair Using 3 dimensional Mesh Without Mesh Fixation. AB - BACKGROUND: Approximately one fifth of patients suffer from inguinal pain after laparoscopic total extraperitoneal (TEP) inguinal hernia repair. There is existing literature suggesting that the staples used to fix the mesh can cause postoperative inguinal pain. In this study, we describe our experience with laparoscopic TEP inguinal hernia surgery using 3-dimensional mesh without mesh fixation, in our institution. MATERIALS AND METHODS: A total of 300 patients who had undergone laparoscopic TEP inguinal hernia repair with 3-dimensional mesh in VKV American Hospital, Istanbul from November 2006 to November 2015 were studied retrospectively. Using the hospital's electronic archive, we studied patients' selected parameters, which are demographic features (age, sex), body mass index, hernia locations and types, duration of operations, preoperative and postoperative complications, duration of hospital stays, cost of surgery, need for analgesics, time elapsed until returning to daily activities and work. RESULTS: A total of 300 patients underwent laparoscopic TEP hernia repair of 437 inguinal hernias from November 2006 to November 2015. Of the 185 patients, 140 were symptomatic. Mean duration of follow-up was 48 months (range, 6 to 104 mo). The mean duration of surgery was 55 minutes for bilateral hernia repair, and 38 minutes for unilateral hernia repair. The mean duration of hospital stay was 0.9 day. There was no conversion to open surgery. In none of the cases the mesh was fixated with either staples or fibrin glue. Six patients (2%) developed seroma that were treated conservatively. One patient had inguinal hernia recurrence. One patient had preperitoneal hematoma. One patient operated due to indirect right sided hernia developed right-sided hydrocele. One patient had wound dehiscence at the umbilical port entry site. Chronic pain developed postoperatively in 1 patient. Ileus developed in 1 patient. CONCLUSIONS: Laparoscopic TEP inguinal repair with 3-dimensional mesh without mesh fixation can be performed as safe as repair with tack fixation. PMID- 28590362 TI - A Randomized Clinical Trial of Oxytocin or Galantamine for the Treatment of Negative Symptoms and Cognitive Impairments in People With Schizophrenia. AB - PURPOSE/BACKGROUND: Negative symptoms and cognitive impairments tend to co-occur in people with schizophrenia. If their association with each other is due, in part, to shared pathophysiology, then this suggests that a single drug could potentially be effective for both domains. The current study was designed to examine this hypothesis. METHODS/PROCEDURES: Fifty-eight participants with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision schizophrenia or schizoaffective disorder entered into a 6-week double blind, placebo-controlled, double-dummy, randomized clinical trial of intranasal oxytocin and galantamine. Seventeen participants were randomized to intranasal oxytocin, 20 were randomized to galantamine, and 21 were randomized to placebo. The Scale for the Assessment of Negative Symptoms total score was used to assess change in negative symptoms (the primary outcome measure for oxytocin). The MATRICS Consensus Cognitive Battery composite score was used to assess cognition (the primary outcome measure for galantamine). FINDINGS/RESULTS: There were no significant group differences for negative symptoms (oxytocin vs placebo: F2,47.4 = 0.19, P = 0.83; galantamine vs placebo: F2,52.5 = 0.41, P = 0.67). There were no significant group differences for cognitive impairments (galantamine vs placebo: t40 = 0.71, P = 0.48; oxytocin vs placebo: t40 = 0.50, P = 0.62). There were also no significant group differences for the functional capacity or ancillary symptom measures. IMPLICATIONS/CONCLUSIONS: The lack of an efficacy signal for either compound precluded our ability to test whether pharmacological treatment pathways for negative symptoms and cognitive impairments overlap or are independent. PMID- 28590364 TI - Neurophysiological Effects of Bitopertin in Schizophrenia. AB - PURPOSE/BACKGROUND: Deficits in N-methyl-D-aspartate receptor (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia and are associated with impaired generation of event-related potential measures including auditory mismatch negativity. Parallel studies of the NMDAR agonist D-serine have suggested that sensitivity of these measures to glutamate-based interventions is related to symptomatic and cognitive response. Bitopertin is a selective inhibitor of glycine transport. This study investigates effects of bitopertin on NMDAR-related event-related potential deficits in schizophrenia. METHODS/PROCEDURES: Patients with schizophrenia/schizoaffective disorder were treated with bitopertin (10 mg, n = 29), in a double-blind, parallel group investigation. Auditory mismatch negativity served as primary outcome measures. Secondary measures included clinical symptoms and neurocognitive performance. FINDINGS/RESULTS: No significant changes were seen with bitopertin for neurophysiological, clinical, or neurocognitive assessments. IMPLICATIONS/CONCLUSIONS: These findings represent the first assessment of the effect of bitopertin on neurophysiological biomarkers. Bitopertin did not significantly affect either symptoms or NMDAR-related biomarkers at the dose tested (10 mg). Mismatch negativity showed high test-retest reliability, supporting its use as a target engagement measure. PMID- 28590363 TI - Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers. AB - BACKGROUND/PURPOSE: Ethanol coadministered with immediate-release dl methylphenidate (dl-MPH) or dexmethylphenidate (d-MPH) significantly increases the geomean maximum plasma concentration (Cmax) of d-MPH 22% and 15%, respectively, and elevates overall drug exposure and psychostimulant effects. We asked the question: Are these ethanol-MPH interactions based more fundamentally on (1) inhibition of postabsorption d-MPH metabolism or (2) acceleration of MPH formulation gastric dissolution by ethanol in the stomach? This was investigated using the pulsatile, distinctly biphasic, spheroidal oral drug absorption systems of dl-MPH and d-MPH. METHODS: In a randomized, 4-way crossover study, 14 healthy subjects received pulsatile dl-MPH (40 mg) or d-MPH (20 mg), with or without ethanol (0.6 g/kg), dosed 4 hours later. These 4 hours allowed the delayed release second MPH pulse to reach a more distal region of the gut to preclude gastric biopharmaceutical influences. Plasma was analyzed using a highly sensitive chiral method. Subjective/physiological effects were recorded. FINDINGS/RESULTS: Ethanol increased the second pulse of d-MPH Cmax for dl-MPH by 35% (P < 0.01) and the partial area under the plasma concentration curve from 4 to 8 hours by 25% (P < 0.05). The respective values for enantiopure d-MPH were 27% (P = 0.001) and 20% (P < 0.01). The carboxylesterase 1-mediated transesterification metabolite ethylphenidate served as a biomarker for coexposure. Ethanol significantly potentiated stimulant responses to either formulation. IMPLICATIONS/CONCLUSIONS: These findings support drug dispositional interactions between ethanol and MPH as dominant over potential biopharmaceutical considerations. Understanding the pharmacology underlying the frequent coabuse of MPH-ethanol provides rational guidance in the selection of first-line pharmacotherapy for comorbid attention-deficit/hyperactivity disorder-alcohol use disorder. PMID- 28590366 TI - Effect of GWAS-Identified Genetic Variants on Maximum QT Interval in Patients With Schizophrenia Receiving Antipsychotic Agents: A 24-Hour Holter ECG Study. AB - BACKGROUND: Users of antipsychotics (APs) have a risk of sudden cardiac death (SCD). Sudden cardiac death in such patients is thought to be largely due to drug induced QT prolongation. It has been reported that many subjects with drug induced torsades de pointes (TdP) have risk alleles associated with subclinical congenital long QT syndrome. METHODS: We investigated the effects of the risk alleles associated with long QT on the QT interval in patients receiving APs using 24-hour Holter electrocardiograms to take into account the circadian fluctuation of QT intervals. We investigated 8 single-nucleotide polymorphisms identified on a GWAS. RESULTS: We found that increased numbers of risk alleles at rs7188697 in NDRG4 and rs11970286 in PLN were the major predictors of an increased maximum QT interval over 24 hours in users of APs. CONCLUSIONS: It could be useful to perform a DNA-based analysis before the initiation of APs to reduce the risk of drug-induced torsades de pointes and SCD. PMID- 28590365 TI - The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Psychostimulants are frequently prescribed off-label for adults with major depressive disorder or bipolar disorder. The frequent and increasing usage of stimulants in mood disorders warrants a careful appraisal of the efficacy of this class of agents. Herein, we aim to estimate the efficacy of psychostimulants in adults with unipolar or bipolar depression. METHODS: The PubMed/Medline database was searched from inception to January 16, 2016 for randomized, placebo controlled clinical trials investigating the antidepressant efficacy of psychostimulants in the treatment of adults with unipolar or bipolar depression. RESULTS: Psychostimulants were associated with statistically significant improvement in depressive symptoms in major depressive disorder (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.13-1.78; P = 0.003) and bipolar disorder (OR, 1.42; 95% CI, 1.13-1.78; P = 0.003). Efficacy outcomes differed across the psychostimulants evaluated as a function of response rates: ar/modafinil (OR, 1.47; 95% CI, 1.20-1.81; P = 0.0002); dextroamphetamine (OR, 7.11; 95% CI, 1.09 46.44; P = 0.04); lisdexamfetamine dimesylate (OR, 1.21; 95% CI, 0.94-1.56; P = ns); methylphenidate (OR, 1.49; 95% CI, 0.88-2.54; P = ns). Efficacy outcomes also differed between agents used as adjunctive therapy (OR, 1.39; 95% CI, 1.19 1.64) or monotherapy (OR, 2.25; 95% CI, 0.67-7.52). CONCLUSIONS: Psychostimulants are insufficiently studied as adjunctive or monotherapy in adults with mood disorders. Most published studies have significant methodological limitations (eg, heterogeneous samples, dependent measures, type/dose of agent). In addition to improvements in methodological factors, a testable hypothesis is that psychostimulants may be more appropriately tested in select domains of psychopathology (eg, cognitive emotional processing), rather than as "broad spectrum" antidepressants. PMID- 28590367 TI - Statistics Commentary Series: Commentary No. 21: Using Diagnostic Tests; or the Search for Universal Truths. PMID- 28590368 TI - Priapism Associated With Antipsychotic Medication Use: Case Report. PMID- 28590369 TI - Adverse Events With Sustained-Release Donepezil in Alzheimer Disease: Relation to Body Mass Index. AB - PURPOSE/BACKGROUND: Sustained-release, high-dose (23 mg/d) donepezil has been approved for treatment of moderate to severe Alzheimer disease (AD). Based on a previous clinical trial, body weight of less than 55 kg is a risk factor for adverse events with donepezil 23 mg/d treatment in global population. METHODS/PROCEDURES: To clarify whether this finding is consistent across ethnic groups that vary in absolute body mass, we recruited Korean patients aged 45 to 90 years with moderate to severe AD who had been receiving standard donepezil immediate release 10 mg/d for at least 3 months. After screening, we analyzed a final cohort of 166 patients who received donepezil 23 mg/d for 24 weeks to compare the occurrence of treatment-emergent adverse events (TEAEs) between patients with high versus low body mass index (BMI) based on the World Health Organization overweight criteria for Asian populations (23 kg/m). FINDINGS/RESULTS: Treatment-emergent adverse events were reported by 79.45% of patients in the lower BMI group and 58.06% of patients in the higher BMI group (odds ratio, 2.79; 95% confidence interval, 1.39-5.63; chi = 7.58, P = 0.006). In a multivariable survival analysis, the group with lower BMI showed a higher occurrence of TEAEs (hazard ratio, 1.83; 95% confidence interval, 1.25-2.68; P = 0.002). IMPLICATIONS/CONCLUSIONS: In Korean patients with moderate to severe AD receiving high-dose donepezil over 24 weeks, TEAEs were significantly more common in those with lower BMI (not clinically overweight), especially nausea. This finding may inform clinical practice for Asian patients. PMID- 28590370 TI - Early Improvement Predicts Treatment Outcomes for Patients With Acute Mania: A Naturalistic Study in Taiwan. AB - BACKGROUND: Bipolar disorder is a serious mental disorder. This study investigated whether early improvement at week 1 or 2 could predict treatment outcomes at week 4 in clinical populations with acute mania. METHODS: We conducted a naturalistic study, recruiting inpatients with bipolar mania for acute treatment. Symptom severity was assessed using the Young Mania Rating Scale (YMRS) at weeks 0, 1, 2, 3, and 4. Early improvement was defined as a reduction in the YMRS score of at least 20% or 25%, assessed at weeks 1 and 2. Response was defined as a reduction of 50% or more in the YMRS score, and remission was defined as an end-point YMRS score of 12 or less. Receiver operating characteristic curves were used to determine whether week 1 or week 2 had better discriminative capacity. Sensitivity, specificity, and predictive values were calculated for the different definitions of early improvement. RESULTS: Of the 350 patients, 32.9% (n = 115) and 16.6% (n = 58) of the subjects were classified as responders and remitters at week 4, respectively. Early improvement at week 2 showed better discriminative capacity, with areas under the receiver operating characteristic curve greater than 0.8. It had high sensitivity and high negative predictive value for 2 cutoffs in predicting response and remission. CONCLUSIONS: Relatively lower response and remission rates were observed. Response and remission could be predicted by early improvement at week 2, whereas patients without early improvement were unlikely to reach response and remission at week 4. PMID- 28590371 TI - Cocaine Abuse, Traumatic Brain Injury, and Preexisting Brain Lesions as Risk Factors for Bupropion-Associated Psychosis. AB - BACKGROUND AND OBJECTIVE: Bupropion is generally considered safe and is widely used both as a monotherapy and as an augmentation agent for the treatment of major depression. Concerns have been raised about bupropion's propensity to precipitate new psychosis and worsen existing psychotic symptoms, although the mechanism is poorly understood. Three cases are reported in which bupropion use was associated with psychosis. The aim of the study was to explore the risk factors and possible mechanisms of psychosis in each case. CASE REPORTS: Case 1 describes the interaction of cocaine abuse sensitization in a patient who developed psychosis with a lower dosage of bupropion. Cases 2 and 3 discuss the role of traumatic brain injury and structural brain lesions in increasing the risk of psychosis when using bupropion. CONCLUSIONS: Cocaine abuse, traumatic brain injury, and preexisting brain lesions appear to be risk factors for developing psychosis in persons taking bupropion. In such cases, clinicians should carefully assess the risks and benefits and closely monitor patients for symptoms of psychosis. PMID- 28590372 TI - Changes in Neutrophil Count After Antipsychotic Prescription Among a Retrospective Cohort of Patients With Benign Neutropenia. AB - BACKGROUND: There is a paucity of literature regarding the effect of antipsychotics on absolute neutrophil count (ANC) of patients with benign neutropenia (BN). We evaluated the change in ANC after atypical antipsychotic prescription (excluding clozapine) in a retrospective cohort of 22 patients with BN. METHODS/PROCEDURES: Records of all patients with BN who were prescribed antipsychotics and who had ANC measured before and during antipsychotic treatment were obtained from Bronx VA Medical Center between 2005 and 2015 (inclusive). Twenty-two patients met criteria for inclusion. Individual and group mean ANC were calculated before treatment and during treatment. A paired, two-tailed t test was performed on the group ANC means. RESULTS: The group mean pretreatment ANC was 1.24 +/- 0.220 K/cmm, and the mean ANC during the time of antipsychotic prescription increased to 1.40 +/- 0.230 K/cmm, with a P value of 0.0045, t value of 3.18, degrees of freedom equal to 21, and 95% confidence interval of 1.30 to 1.49 K/cmm. CONCLUSIONS: There was a statistically significant increase in ANC among our cohort during the time of antipsychotic prescription. All BN patients who were prescribed antipsychotics maintained a stable neutrophil count, with none of the 22 patients with BN in this study developing agranulocytosis during treatment. Although this study is limited by a low patient count as well as other demographic factors, these findings provide initial evidence regarding the safety of prescribing atypical antipsychotics to BN patients. Further studies are needed to replicate these findings and assess for effects of individual medications. PMID- 28590373 TI - Nature as a Trialist?: Deconstructing the Analogy Between Mendelian Randomization and Randomized Trials. AB - Mendelian randomization (MR) studies are often described as naturally occurring randomized trials in which genetic factors are randomly assigned by nature. Conceptualizing MR studies as randomized trials has profound implications for their design, conduct, reporting, and interpretation. For example, analytic practices that are discouraged in randomized trials should also be discouraged in MR studies. Here, we deconstruct the oft-made analogy between MR and randomized trials. We describe four key threats to the analogy between MR studies and randomized trials: (1) exchangeability is not guaranteed; (2) time zero (and therefore the time for setting eligibility criteria) is unclear; (3) the treatment assignment is often measured with error; and (4) adherence is poorly defined. By precisely defining the causal effects being estimated, we underscore that MR estimates are often vaguely analogous to per-protocol effects in randomized trials, and that current MR methods for estimating analogues of per protocol effects could be biased in practice. We conclude that the analogy between randomized trials and MR studies provides further perspective on both the strengths and the limitations of MR studies as currently implemented, as well as future directions for MR methodology development and application. In particular, the analogy highlights potential future directions for some MR studies to produce more interpretable and informative numerical estimates. PMID- 28590374 TI - Return to Sport After Pediatric Anterior Cruciate Ligament Reconstruction and Its Effect on Subsequent Anterior Cruciate Ligament Injury. AB - BACKGROUND: Anterior cruciate ligament (ACL) graft failure and contralateral ACL tears are more frequent in children and adolescents than adults. The reasons for higher subsequent injury rates in this population are incompletely understood. METHODS: We analyzed a continuous cohort of patients who were <18 years of age. Subjects underwent isolated, primary ACL reconstruction with autograft between 2006 and January 1, 2014, and had a minimum 2-year follow-up. Return-to-sport characteristics were described, and multivariable Cox regression modeling was used to identify predictors of a second ACL injury. Candidate variables included patient factors (age, sex, physeal status, tibial slope, notch width index), surgical characteristics (graft type, surgical technique), measures of recovery (time to return to sport, duration of physical therapy), and patients' preoperative and postoperative sports involvement (primary and secondary sports, number of sports). RESULTS: A total of 112 subjects met inclusion criteria; of these patients, 85 (76%) had complete follow-up data and were analyzed. The mean age (and standard deviation) was 13.9 +/- 2.1 years (range, 6 to 17 years); 77% had open physes. The mean follow-up was 48.3 +/- 15.3 months. Seventy-seven patients (91%) returned to sports, and 84% returned to the same sport. The mean Marx activity score at the time of the latest follow-up was 13.7 +/- 3.5 points. Patients were involved in fewer sports after ACL reconstruction, 1.48 +/- 0.92 compared with 1.83 +/- 1.01 sports before reconstruction (p = 0.002). Sixteen patients (19%) sustained an ACL graft rupture, 11 patients (13%) sustained a contralateral ACL tear, and 1 of these patients (1%) sustained both. The overall prevalence of a second ACL injury was 32%. Time to return to sport was the only significant predictor of a second ACL injury, with a slower return being protective (hazard ratio per month, 0.87 [95% confidence interval, 0.73 to 0.99]; p = 0.04). CONCLUSIONS: Pediatric athletes return to sports at a high rate (91%) after ACL reconstruction. Unfortunately, the prevalence of a second ACL injury is high at 32%. Within this population, an earlier return to sport is predictive of a second ACL injury. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590376 TI - Outcomes of After-Hours Hip Fracture Surgery. AB - BACKGROUND: Given single-institution studies showing trends between after-hours hip fracture surgical procedures and adverse outcomes, as well as fixation time targets that may increasingly compel after-hours operations, we investigated the relationship between after-hours hip fracture surgical procedures and adverse outcomes in a large, population-based cohort. METHODS: All Ontarians who were >=60 years of age and underwent a hip fracture surgical procedure between April 2002 and March 2014 were eligible for study inclusion. Data were obtained from linked health administrative databases. The primary exposure was after-hours provision of surgical procedures, occurring weekday evenings between the hours of 5 P.M. and 12 A.M. or over the weekend, but not overnight (after 12 A.M. to 7 A.M.). Surgical complications up to 6 months following a hip fracture surgical procedure comprised the primary outcome. Medical complications, including mortality, up to 90 days postoperatively were also assessed. Odds ratios (ORs) were calculated using a logistic regression model that accounted for clustering at the hospital level and adjusted for patient, provider, and fracture characteristics previously shown to explain the majority of variance in hip fracture outcomes. RESULTS: During the study period, 87,647 patients underwent an isolated hip fracture surgical procedure; 51.2% of these patients had femoral neck fractures, 44.1% had intertrochanteric fractures, and 4.7% had subtrochanteric fractures. The surgical procedure occurred after hours in 59,562 patients (68.0%), and 27,240 patients (31.1%) underwent a surgical procedure during normal hours (7 A.M. to 5 P.M.). Only 845 patients (1%) underwent a surgical procedure overnight. We observed no significant relationships between timing of the surgical procedure and adverse outcomes, except for patients who had undergone an after-hours surgical procedure and had fewer inpatient surgical complications (OR, 0.90 [95% confidence interval, 0.83 to 0.99]; p = 0.01). CONCLUSIONS: Adverse outcomes following a hip fracture surgical procedure were similar whether a surgical procedure occurred during normal hours or after hours. Concerns regarding the quality of after-hours surgical procedures should not influence hip fracture prioritization policy. However, given that the great majority of hip fracture surgical procedures occurred after hours, future research should examine other potential consequences of this practice, such as financial impact and surgeon burnout. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590375 TI - Familial Clustering Identified in Periprosthetic Joint Infection Following Primary Total Joint Arthroplasty: A Population-Based Cohort Study. AB - BACKGROUND: It is estimated that the cost to treat periprosthetic joint infection in the United States will approach $1.62 billion by 2020. Thus, the need to better understand the pathogenesis of periprosthetic joint infection is evident. We performed a population-based, retrospective cohort study to determine if familial clustering of periprosthetic joint infection was observed. METHODS: Analyses were conducted using software developed at the Utah Population Database (UPDB) in conjunction with the software package R. The cohort was obtained by querying the UPDB for all patients undergoing total joint arthroplasty and for those patients who had subsequent periprosthetic joint infection. The magnitude of familial risk was estimated by hazard ratios (HRs) from Cox regression models to assess the relative risk of periprosthetic joint infection in relatives and spouses. Using percentiles for age strata, we adjusted for sex, body mass index (BMI) of >=30 kg/m, and a history of smoking, diabetes, and/or end-stage renal disease. Additionally, we identified families with excess clustering of periprosthetic joint infection above that expected in the population using the familial standardized incidence ratio. RESULTS: A total of 66,985 patients underwent total joint arthroplasty and 1,530 patients (2.3%) had a periprosthetic joint infection. The risk of periprosthetic joint infection following total joint arthroplasty was elevated in first-degree relatives (HR, 2.16 [95% confidence interval (CI), 1.29 to 3.59]) and combined first and second-degree relatives (HR, 1.79 [95% CI, 1.22 to 2.62]). Further, 116 high-risk pedigrees with a familial standardized incidence ratio of >2 and a p value of <0.05 were identified and 9 were selected for genotyping studies based on the observed periprosthetic joint infection/total joint arthroplasty ratio and visual inspection of the pedigrees for lack of excessive comorbidities. CONCLUSIONS: Although preliminary, these data may help to guide further genetic research associated with periprosthetic joint infections. An understanding of familial risks could lead to new discoveries in creating patient-centered pathways for infection prevention in patients at risk. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590377 TI - Brace Success Is Related to Curve Type in Patients with Adolescent Idiopathic Scoliosis. AB - BACKGROUND: Curve magnitude and skeletal maturity are important factors in determining the efficacy of bracing for the treatment of adolescent idiopathic scoliosis, but curve morphology may also affect brace success. The purpose of this study was to determine the influence of curve morphology on the response to bracing with a thoracolumbosacral orthosis (TLSO). METHODS: A retrospective review of patients managed with an orthosis for the treatment of adolescent idiopathic scoliosis who were prospectively enrolled at the initiation of brace wear and followed through completion of bracing or surgery was performed. Inclusion criteria were main curves of 25 degrees to 45 degrees and a Risser stage of 0, 1, or 2 at the time of brace prescription. Compliance with bracing was measured with Maxim Integrated Thermochrons. Radiographs made at brace initiation, brace cessation, and final follow-up were used to retrospectively categorize curves with use of the modified Lenke (mLenke) classification system and more broadly to categorize them as main thoracic or main lumbar. The effect of morphology on outcome was evaluated using chi-square and Fisher exact tests. RESULTS: One hundred and sixty-eight patients were included. There was no difference in curve magnitude at the time of brace initiation (p = 0.798) or in average hours of daily brace wear (p = 0.146) between groups. The rate of surgery or progression of the curve to >=50 degrees was 34.5% (29 of 84) in mLenke-I curves, 54.5% (6 of 11) in mLenke-II curves, 29.4% (10 of 34) in mLenke-III curves, 17.6% (3 of 17) in mLenke-V curves, and 13.6% (3 of 22) in mLenke-VI curves. There were no mLenke-IV curves at the time of brace initiation. The rate of surgery or progression to >=50 degrees was 34.1% (44 of 129) in the combined thoracic group and 15.4% (6 of 39) in the combined lumbar group (p = 0.0277). In brace-compliant patients (>12.9 hours/day), the rate of surgery or progression to >=50 degrees was 30.3% (20 of 66) in main thoracic curves and 5.3% (1 of 19) in main lumbar curves (p = 0.0239). One-tenth of curves changed morphology during bracing. The rate of surgery or progression to >=50 degrees was 35.8% (43 of 120) in persistent main thoracic curves, 20.0% (6 of 30) in persistent main lumbar curves, 12.5% (1 of 8) in main thoracic curves that became main lumbar curves, and 0% (0 of 9) in main lumbar curves that became main thoracic curves (p = 0.0383). CONCLUSIONS: Thoracic curves are at greater risk for brace failure than lumbar curves are despite similar initial curve magnitudes and average amount of daily brace wear. A change in curve pattern may imply flexibility and is associated with brace success. Patients with thoracic curves should be counseled accordingly. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590379 TI - Bisphosphonate Use and the Risk of Undergoing Total Knee Arthroplasty in Osteoporotic Patients with Osteoarthritis: A Nationwide Cohort Study in Taiwan. AB - BACKGROUND: The use of bisphosphonates has been reported to have potential beneficial effects on knee osteoarthritis, but existing studies have limitations. The purpose of this study was to examine the association of bisphosphonate use with the risk of undergoing total knee arthroplasty and with the consumption of pain medication among osteoporotic patients with knee osteoarthritis. METHODS: We identified patients who were newly diagnosed with knee osteoarthritis among a cohort of patients with osteoporosis from 2009 to 2012 in the National Health Insurance Research Database in Taiwan. We further categorized these patients into 2 groups: those who were treated with bisphosphonates (bisphosphonate users) and those who were not treated with any anti-osteoporosis drug (nonusers). Bisphosphonate treatment adherence was calculated by the medication possession ratio (MPR) as the proportion of days of bisphosphonate treatment within a fixed duration; an MPR of >=80% was considered high adherence. The primary and secondary outcomes of interest were undergoing total knee arthroplasty and the use of pain medication, respectively. Analyses using Cox proportional hazard models with propensity-score adjustment were performed to estimate the association between bisphosphonate use and the risk of undergoing total knee arthroplasty. The incremental change in the mean accumulated defined daily doses of pain medications among both bisphosphonate users and nonusers was calculated. RESULTS: We identified 16,276 bisphosphonate users and 123,791 nonusers of any anti-osteoporosis drug among the patients with osteoporosis who were newly diagnosed with osteoarthritis. Bisphosphonate use was significantly associated with a decreased risk of total knee arthroplasty (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.69 to 0.83; p < 0.001). In patients with a follow-up period of >=24 months and an MPR of >=80%, the effect size was significantly greater (adjusted HR, 0.66; p = 0.048). Over the 5 years of follow up, we found a significantly greater decrease in the use of pain medication among bisphosphonate users than among nonusers (p < 0.001; Chow test). CONCLUSIONS: Among patients with osteoporosis and osteoarthritis, bisphosphonate use was associated with a significantly lower risk of total knee arthroplasty, especially in patients with high adherence and longer treatment duration. A lower consumption of pain medication was also found for bisphosphonate users among the patients with osteoporosis and osteoarthritis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590378 TI - Increasing Body Mass Index Is Associated with Worse Outcomes After Shoulder Arthroplasty. AB - BACKGROUND: Although obesity is associated with increased complication rates after lower-extremity arthroplasty, there is a relative paucity of studies examining the effect of body mass index (BMI) on shoulder arthroplasty. The purpose of this investigation was to evaluate the effect of BMI on implant survival and the rate of complications after shoulder arthroplasty. METHODS: Using an institutional total joint registry, 4,567 consecutive shoulder arthroplasty cases from 1970 to 2013 were studied. The mean BMI was 29.7 kg/m (range, 14 to 66 kg/m), with 1,622 patients (36%) with a BMI of 30 to 40 kg/m and 297 patients (7%) with a BMI of >40 kg/m. There were 2,493 female patients (55%). BMI was dichotomized after examination of the smoothing spline curve. The associations of factors and complications were assessed using Cox proportional hazard regression analysis. RESULTS: Increasing BMI was associated with an increased risk of a revision surgical procedure, reoperation, revision for mechanical failure, and superficial infection, and it was negatively associated with risk of a periprosthetic fracture. The risk of a revision surgical procedure increased in a linear fashion with increasing BMI (hazard ratio [HR], 1.05, or a 5% increased risk per 1 unit of BMI; p = 0.03). Increased BMI was also associated with an increased risk of revision for mechanical failure (HR, 1.05; p = 0.004). In a multivariate model, the association of BMI and risk of a revision for any reason, revision for mechanical failure, and reoperation maintained significance (p <= 0.02). The most marked association between increasing BMI and any complication in shoulder arthroplasty was its association with superficial wound infection (HR, 1.09; p = 0.03). CONCLUSIONS: Increasing BMI is strongly associated with increased rates of revision surgical procedures and postoperative complications after shoulder arthroplasty. It is important to consider these findings when counseling patients, estimating risks, and estimating complication risks in policy decisions. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590380 TI - Surgical Treatment for Hemophilic Pseudotumor: Twenty-three Cases with an Average Follow-up of 5 Years. AB - BACKGROUND: Hemophilic pseudotumor (HPT) is a rare disease with many challenges. Only a few reports on surgical treatment for HPT have been published. METHODS: The cases of 23 patients with HPT who had surgical treatment from July 1996 to December 2014 were retrospectively reviewed. Demographic data, blood loss and transfusion during surgery, outcomes, and complications after surgery were analyzed. RESULTS: Eleven patients underwent HPT resection; 4 underwent HPT excision, allograft transplantation, and absorbable screw fixation; 3 had HPT resection and metallic internal fixation; 2 had HPT resection, autogenous fibular grafting, and absorbable screw fixation; 2 underwent curettage and bone-grafting; and 1 patient received above-the-knee amputation. The average age (and standard deviation) of the patients at the time of surgery was 31.9 +/- 12.8 years (range, 6 to 54 years) with an average follow-up of 5.3 +/- 4.7 years (range, 1.1 to 19.6 years). The median duration of the surgery was 157 minutes (range, 90 to 315 minutes). The median amount of blood loss during surgery was 800 mL (range, 100 to 4,000 mL). Three patients (13%) had a postoperative infection, 2 (8.7%) had recurrence of HPT, and another 2 patients had fracture nonunion. CONCLUSIONS: Surgical treatment of HPT with a modified protocol of coagulation factor replacement is safe and effective. It should be recommended for patients with HPT who have progressive enlargement of the mass, recurrent and massive bleeding, spontaneous perforation, bone erosion, or compression of surrounding tissues or who have had failure of conservative treatment. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590381 TI - Performance of PROMIS for Healthy Patients Undergoing Meniscal Surgery. AB - BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed as an extensive question bank with multiple health domains that could be utilized for computerized adaptive testing (CAT). In the present study, we investigated the use of the PROMIS Physical Function CAT (PROMIS PF CAT) in an otherwise healthy population scheduled to undergo surgery for meniscal injury with the hypotheses that (1) the PROMIS PF CAT would correlate strongly with patient-reported outcome instruments that measure physical function and would not correlate strongly with those that measure other health domains, (2) there would be no ceiling effects, and (3) the test burden would be significantly less than that of the traditional measures. METHODS: Patients scheduled to undergo meniscal surgery completed the PROMIS PF CAT, Knee injury and Osteoarthritis Outcome Score (KOOS), Marx Knee Activity Rating Scale, Short Form-36 (SF-36), and EuroQol-5 Dimension (EQ-5D) questionnaires. Correlations were defined as high (>=0.7), high moderate (0.61 to 0.69), moderate (0.4 to 0.6), moderate-weak (0.31 to 0.39), or weak (<=0.3). If >=15% respondents to a patient-reported outcome measure obtained the highest or lowest possible score, the instrument was determined to have a significant ceiling or floor effect. RESULTS: A total of 107 participants were analyzed. The PROMIS PF CAT had a high correlation with the SF-36 Physical Functioning (PF) (r = 0.82, p < 0.01) and KOOS Sport (r = 0.76, p < 0.01) scores; a high-moderate correlation with the KOOS Quality-of-Life (QOL) (r = 0.63, p < 0.01) and EQ-5D (r = 0.62, p < 0.01) instruments; and a moderate correlation with the SF-36 Pain (r = 0.60, p < 0.01), KOOS Symptoms (r = 0.57, p < 0.01), KOOS Activities of Daily Living (ADL) (r = 0.60, p < 0.01), and KOOS Pain (r = 0.60, p < 0.01) scores. The majority (89%) of the patients completed the PROMIS PF CAT after answering only 4 items. The PROMIS PF CAT had no floor or ceiling effects, with 0% of the participants achieving the lowest and highest score, respectively. CONCLUSIONS: The PROMIS PF CAT correlates strongly with currently used patient reported outcome measures of physical function and demonstrates no ceiling effects for patients with meniscal injury requiring surgery. It may be a reasonable alternative to more burdensome patient-reported outcome measures. PMID- 28590382 TI - Venous Thromboembolism Following Hip and Knee Arthroplasty: The Role of Aspirin. PMID- 28590383 TI - What's Important: Science, Faith, and Grace. PMID- 28590384 TI - Thoracic Idiopathic Scoliosis Severity Is Highly Correlated with 3D Measures of Thoracic Kyphosis. AB - BACKGROUND: Loss of thoracic kyphosis has been associated with thoracic idiopathic scoliosis. Modern 3-dimensional (3D) imaging systems allow more accurate characterization of the scoliotic deformity than traditional radiographs. In this study, we utilized 3D calculations to characterize the association between increasing scoliosis severity and changes in the sagittal and axial planes. METHODS: Patients evaluated in a scoliosis clinic and determined to have either a normal spine or idiopathic scoliosis were included in the analysis. All underwent upright, biplanar radiography with 3D reconstructions. Two dimensional (2D) measurements of the magnitude of the thoracic major curve and the thoracic kyphosis were recorded. Image processing and MATLAB analysis were utilized to produce a 3D calculation of thoracic kyphosis and apical vertebral axial rotation. Regression analysis was performed to determine the correlation of 2D kyphosis, 3D kyphosis, and apical axial rotation with the magnitude of the thoracic major curve. RESULTS: The 442 patients for whom 2D and 3D data were collected had a main thoracic curve magnitude ranging from 1 degrees to 118 degrees . Linear regression analysis of the 2D and 3D T5-T12 kyphosis versus main thoracic curve magnitude yielded significant models (p < 0.05). The 2D model had a minimally negative slope (-0.07), a small R value (0.02), and a poor correlation coefficient (-0.14). In contrast, the 3D model had a strongly negative slope (-0.54), a high R value (0.56), and a strong correlation coefficient (-0.75). Curve magnitude also had a strong correlation with loss of 3D T1-T12 kyphosis and increasing apical axial rotation. CONCLUSIONS: Segmentally calculated 3D thoracic kyphosis had a strongly negative correlation with the magnitude of the main thoracic curve. With near uniformity, 3D thoracic kyphosis progressively decreased as scoliosis magnitude increased, at a rate of more than half the increase in the main thoracic curve magnitude. Analysis confirmed a surprisingly strong correlation between scoliosis severity and loss of 3D kyphosis that was absent in the 2D analysis. A similarly strong correlation between curve magnitude and apical axial rotation was evident. These findings lend further credence to the concept that scoliosis progresses in the coronal, sagittal, and axial planes simultaneously. CLINICAL RELEVANCE: The findings of this study suggest that 3D assessment is critical for adequate characterization of the multiplanar deformity of idiopathic scoliosis and deformity in the sagittal plane is linked to deformity in the coronal plane. Increasing severity of coronal plane curvature is associated with a progressive loss of thoracic kyphosis that should be anticipated so that the appropriate intraoperative techniques for correction of idiopathic scoliosis can be applied in all 3 planes. PMID- 28590385 TI - Post-Discharge Care Duration, Charges, and Outcomes Among Medicare Patients After Primary Total Hip and Knee Arthroplasty. AB - BACKGROUND: In April 2016, the U.S. Centers for Medicare & Medicaid Services initiated mandatory 90-day bundled payments for total hip and knee arthroplasty for much of the country. Our goal was to determine duration of care, 90-day charges, and readmission rates by discharge disposition and U.S. region after hip or knee arthroplasty. METHODS: Using the 2008 Medicare Provider Analysis and Review database 100% sample, we identified patients who had undergone elective primary total hip or knee arthroplasty. We collected data on patient age, sex, comorbidities, U.S. Census region, discharge disposition, duration of care, 90 day charges, and readmission. Multivariate regression was used to assess factors associated with readmission (logistic) and charges (linear). Significance was set at p < 0.01. RESULTS: Patients undergoing 138,842 total hip arthroplasties were discharged to home (18%), home health care (34%), extended-care facilities (35%), and inpatient rehabilitation (13%); patients undergoing 329,233 total knee arthroplasties were discharged to home (21%), home health care (38%), extended care facilities (31%), and inpatient rehabilitation (10%). Patients in the Northeast were more likely to be discharged to extended-care facilities or inpatient rehabilitation than patients in other regions. Patients in the West had the highest 90-day charges. Approximately 70% of patients were discharged home from extended-care facilities, whereas after inpatient rehabilitation, >50% of patients received home health care. Among those discharged to home, 90-day readmission rates were highest in the South (9.6%) for patients undergoing total hip arthroplasty and in the Midwest (8.7%) and the South (8.5%) for patients undergoing total knee arthroplasty. Having >=4 comorbidities, followed by discharge to inpatient rehabilitation or an extended-care facility, had the strongest associations with readmission, whereas the region of the West and the discharge disposition to inpatient rehabilitation had the strongest association with higher charges. CONCLUSIONS: Among Medicare patients, discharge disposition and number of comorbidities were most strongly associated with readmission. Inpatient rehabilitation and the West region had the strongest associations with higher charges. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 28590386 TI - Can We Agree on Expectations and Assessments of Graduating Residents?: 2016 AOA Critical Issues Symposium. AB - Orthopaedic educators are responsible for training a prepared and competent workforce that will provide effective care for a growing number of patients with musculoskeletal conditions. Currently, there are both internal and external forces that pose substantial challenges to medical students, residents, program directors, faculty members, and chairs in achieving this goal. One area of particular concern is the education of surgeons, whose knowledge and professional behavior must be matched by their ability to acquire procedural skills. In order to address this issue, many training systems have implemented a competency-based training approach into their curricula. This article discusses the efforts that orthopaedic training bodies in Canada and Australia have taken toward competency based education and what steps the American Board of Orthopaedic Surgery (ABOS), the Council of Orthopaedic Residency Directors (CORD), the American Orthopaedic Association (AOA), the American Academy of Orthopaedic Surgeons (AAOS), and the Accreditation Council for Graduate Medical Education (ACGME) are considering to improve residency education in the current and future environments. PMID- 28590387 TI - The 2016 American Orthopaedic Association-Japanese Orthopaedic Association Traveling Fellowship. AB - The American Orthopaedic Association-Japanese Orthopaedic Association (AOA-JOA) Traveling Fellowship, which began in 1992 as a collaborative effort between the 2 orthopaedic communities, is aimed at fostering leadership among early-career surgeons through clinical, academic, and cultural exchange. Over 3 weeks, we experienced an extraordinary journey that led us across nearly 800 miles of the picturesque Japanese countryside, with stops at 6 distinguished academic centers. The opportunity to become personally acquainted with orthopaedic leaders in Japan, learn from their experiences, and immerse ourselves in the ancient and storied culture of a beautiful country was one that we will not soon forget. Along the way, we accumulated a wealth of information while enjoying the legendary hospitality of the Japanese people. There is a ubiquitous challenge in delivering cost-effective, accessible health care while maintaining a commitment to education and research. The U.S. orthopaedic community may take solace in the fact that our Japanese colleagues stand with us as partners in this pursuit, and our relationship with them continues to grow stronger through endeavors such as the AOA-JOA Traveling Fellowship. We look forward to honoring our Japanese colleagues in 2017 when we host them in the United States. PMID- 28590388 TI - The Quandary of Treating Anterior Cruciate Ligament Tears in Children and Adolescents: Commentary on an article by Travis J. Dekker, MD, et al.: "Return to Sport After Pediatric Anterior Cruciate Ligament Reconstruction and Its Effect on Subsequent Anterior Cruciate Ligament Injury". PMID- 28590389 TI - Brace Success as Related to Curve Type, Compliance, and Maturity in Adolescents with Idiopathic Scoliosis: Commentary on an article by Rachel M. Thompson, MD, et al.: "Brace Success Is Related to Curve Type in Patients with Adolescent Idiopathic Scoliosis". PMID- 28590391 TI - Misuse of Novel Synthetic Opioids: A Deadly New Trend. AB - : Novel synthetic opioids (NSOs) include various analogs of fentanyl and newly emerging non-fentanyl compounds. Together with illicitly manufactured fentanyl (IMF), these drugs have caused a recent spike in overdose deaths, whereas deaths from prescription opioids have stabilized. NSOs are used as stand-alone products, as adulterants in heroin, or as constituents of counterfeit prescription medications. During 2015 alone, there were 9580 deaths from synthetic opioids other than methadone. Most of these fatalities were associated with IMF rather than diverted pharmaceutical fentanyl. In opioid overdose cases, where the presence of fentanyl analogs was examined, analogs were implicated in 17% of fatalities. Recent data from law enforcement sources show increasing confiscation of acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to non fentanyl compounds such as U-47700. Since 2013, deaths from NSOs in the United States were 52 for acetylfentanyl, 40 for butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All of these substances induce a classic opioid toxidrome, which can be reversed with the competitive antagonist naloxone. However, due to the putative high potency of NSOs and their growing prevalence, it is recommended to forgo the 0.4 mg initial dose of naloxone and start with 2 mg. Because NSOs offer enormous profit potential, and there is strong demand for their use, these drugs are being trafficked by organized crime. NSOs present major challenges for medical professionals, law enforcement agencies, and policymakers. Resources must be distributed equitably to enhance harm reduction though public education, medication-assisted therapies, and improved access to naloxone. PMID- 28590392 TI - Pilot Studies Examining Feasibility of Substance Use Disorder Screening and Treatment Linkage at Urban Sexually Transmitted Disease Clinics. AB - BACKGROUND: Sexually transmitted disease (STD) clinics provide critical public health services for screening and treatment of sexually transmitted infections throughout the United States. These settings serve high-risk populations, often on a walk-in basis, and may be promising venues for integrating substance use disorder (SUD) services. METHODS: We report findings from 2 pilot studies conducted at Baltimore City Health Department's STD clinics. The screening study characterized rates of SUDs among STD clinic patients. Patients waiting for services completed a diagnostic interview mapping to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition SUD criteria (n = 100). The Treatment Linkage Feasibility study examined the feasibility of linking STD clinic patients with opioid and/or cocaine use disorders to SUD treatment in the community (n = 21), using SUD-focused Patient Navigation services for 1 month after the STD clinic visit. Assessments were conducted at baseline and 1-month follow-up. RESULTS: In the screening study, the majority of STD clinic patients met diagnostic criteria for alcohol and/or drug SUD (57%). Substance-specific SUD rates among patients were 35% for alcohol, 31% for cannabis, 11% for opioids, and 8% for stimulants (cocaine/amphetamines). In the Treatment Linkage Feasibility study, 57% (12/21) of participants attended at least 1 SUD service, and 38% (8/21) were actively enrolled in SUD treatment by 1-month follow-up. The sample reported significant reductions in past 30-day cocaine use from baseline to follow-up (P = 0.01). CONCLUSIONS: SUD rates are high among STD clinic patients. STD clinics are viable settings for initiating SUD treatment linkage services. Larger-scale research on integrating SUD services in these settings is needed. PMID- 28590393 TI - Addiction Research Training Programs: Four Case Studies and Recommendations for Evaluation. AB - : The presence of structured addiction research training programs helps to ensure that the scientific workforce includes well-trained, diverse scientists necessary to reduce the negative impact of alcohol, drug, and tobacco use disorders. Although the field has made significant progress in the development of standards for clinical training in addiction medicine, there remains significant room for improvement in the training of addiction researchers, and also opportunities to synergize across addiction research training programs. The purpose of this commentary is to describe 4 National Institutes of Health (NIH)-sponsored addiction research training programs, highlight critical components, and provide recommendations for more comprehensive and effective program evaluation. Moving forward, evaluation of addiction research training programs would be enhanced by the use of conceptual models to inform process and outcome evaluations, the application of innovative methods to ensure long-term data collection, the improvement of mentorship evaluation measures, and the integration of training methods from other fields of study. We encourage NIH and others in the field to be proactive in establishing core metrics for evaluation across programs. Furthermore, centralized tracking of NIH-funded addiction research trainees, analysis of aggregate data across programs, and innovative methods to effectively disseminate program materials and processes are recommended. PMID- 28590395 TI - Relation Between the Type of Hospitals and the Decision of Adenotonsillectomy Indication. AB - OBJECTIVE: This study aims to apply tonsillectomy criteria, symptoms and outcomes proposed in earlier studies to investigate patients who were given tonsillectomy indications at different clinical centers but were treated in our clinical center. METHODS: The prospective sample of patients at the ear, nose, and throat clinic within our hospital consisted of 855 male patients and 684 female patients (1539 in total) with ages between 3 and 16 years old who had been given a tonsillectomy or adenotonsillectomy indication. The patients were allocated to 1 of 3 groups, depending on whether they had been treated in a public hospital, a private hospital, or a university/training research hospital. RESULTS: Of the total of 1539 patients, tonsillectomy indication criteria were exhibited by 966 of them (62.8%) but were absent in the rest of 573 patients (37.2%). Most of the 966 patients with tonsillectomy indication criteria had been treated in private hospitals (n = 546; 56.5%), while the others were treated in public hospitals (n = 309; 31.9%) or in university/training research hospitals (n = 111; 15.9%). Furthermore, the majority of the 966 patients (84.1%) received the tonsillectomy indication in just 1 examination, while some of them (n = 154; 15.9%) received it after follow-up appointments. CONCLUSION: Tonsillectomy decisions can pose difficulties for ear, nose, and throat specialists. Therefore, such decisions should be made based on assessment of clinical evaluation and follow-up, information from patients' parents, and the results of examination against the criteria outlined in the literature. PMID- 28590394 TI - The Outcome of Endoscopic Optic Nerve Decompression for Bilateral Traumatic Optic Neuropathy. AB - OBJECTIVE: To investigate the outcomes of endoscopic optic nerve decompression (EOND) for bilateral traumatic optic neuropathy (TON). METHODS: A retrospective analysis was conducted in 5 patients with bilateral TON, between January 2003 and December 2013. All the patients underwent preoperative ophthalmological evaluation, flash visual-evoked potentials, computed tomography scan, and systemic corticosteroid therapy. All the patients required an EOND surgery, due to poor response to medical therapy, and the remainder one was only treated with corticosteroid due to operative contraindication. RESULTS: Of the 5 patients (10 eyes) undergoing EOND, visual acuity improved in 30% of eyes (n = 3) with a mean follow-up of 3 months. The remainder 7 eyes still had no light perception. All of the 5 patients undergoing EOND had no operative complications. CONCLUSION: Treatment for bilateral TON should not be limited on the length of time to injury and visual-evoked potentials results. If surgical conditions permit and with no contraindications, patients should receive active surgical treatment as soon as possible. PMID- 28590396 TI - Botulinum Toxin Conjugated With Silk Fibroin and 4-Hexylresorcinol. AB - PURPOSE: The objective of this study was to evaluate whether silk fibroin (SF) incorporated into 4-hexylresorcinol (4HR) could increase botulinum toxin-A (BTX A) activity. MATERIAL AND METHODS: In total, 30 rats were used for this study. The animals were divided into 6 groups according to the injected materials (SA: saline only; SF; 4HR; B2: 2 units of BTX-A; B2 + SF + 4HR: combination of B2, SF, and 4HR; B5: 5 units of BTX-A). Serial sonography was used for the evaluation of muscle thickness after injection. Immunohistochemical staining was used for the evaluation of myosin type II (myo2) and Bcl-2 protein expression. RESULTS: The relative thickness of the masseter muscle in B2 group was 66.14% +/- 4.55% to the preinjection level; in B2 + SF + 4HR group was 54.59% +/- 4.83%, and in B5 group was 56.19% +/- 8.28%. Any BTX-injected group showed significantly lower value of the relative muscle thickness compared to SA, SF, or 4HR group (P < 0.001 for all). The difference of relative muscle thickness between B2 group and B2 + SF + 4HR group was statistically significant (P < 0.001). The intensity of myo2 immunostaining in B5, B2, and B2 + SF + 4HR group was significantly higher than those in the other groups (P < 0.05). CONCLUSIONS: When 2 units of BTX was incorporated to SF and 4HR, combination formula showed similar activity to those of 5 units of BTX. PMID- 28590397 TI - Normal Nasopharyngeal Measurement by Computed Tomography in Adult. AB - BACKGROUND: This study aims to investigate the detailed computed tomography (CT) measurement of the nasopharynx (NP) in normal adult detecting mean of its dimension and relation of that measurement to that of the sphenoid sinus. METHODOLOGY/PRINCIPAL: A normal paranasal CT scan and a straight nasal septum of 128 individuals (256 sphenoid sinuses) were included in the study. Axial images were acquired with multiplanar reformates to obtain delicate details in coronal and sagittal planes for all subjects. Measurement of the width, length, and anteroposterior dimensions of the NP and sphenoid sinuses were taken separately. RESULTS: In 128 studied CT of adult subjects, the mean height of the NP was 19.4619 +/- 4.52661 and mean depth was 21.80714 +/- 4.62324 while the mean width was 25.31951 +/- 3.80521. No significant relations between diameters of NP and sphenoid sinuses were found. CONCLUSION: The detailed CT measurement of the NP in normal adult is an easy and reliable measurement. This study put the base of CT measurement of NP for further work to describe changes in such measures in patients with nasal and paranasal sinus anomalies. PMID- 28590398 TI - Bilateral Coronoid Hyperplasia in a 43-Year-Old Patient Treated With Intraoral Coronoidectomy. AB - The mandibular coronoid hyperplasia can be classified as a congenital or development change of the temporomandibular joint. This condition occurs due to a no-neoplasic growth of the coronoid process to the infratemporal fossa. Thus, this part of the bone impacts in the posterior face of the zygomatic bone causing limitation of the mouth opening. The aim of this paper is to report a clinical case of a 43-year-old male with mouth-opening limitation 28 years ago. After clinical and computed tomographic examinations, he was diagnosed with bilateral mandibular coronoid hyperplasia. The treatment proposed was a bilateral coronoidectomy by intraoral approach. In a 1-month postoperative period, the patient reported improvement of the painful complaints and mouth opening. After 1 year, the patient recovered the mouth opening improving his quality of life and there were no more complaints. PMID- 28590399 TI - Displacement of Dental Implant Into the Submental Space After Surgical Integration. AB - Osseointegrated dental implants are common and widely used to treat edentulism. Implant displacement into the maxillofacial spaces during surgery or after a period of use is a complication recognized in the literature. Foreign objects such as titanium dental implants in the maxillofacial region must be removed because they cause infection due to tissue reaction. In this report, the authors present the case of a patient whose dental implant slipped into the submental space after surgical integration and describe the surgical removal of the implant via an extraoral approach. PMID- 28590400 TI - Reply: Evidence-Based Medicine: A Graded Approach to Lower Lid Blepharoplasty. PMID- 28590401 TI - Psychological Outcomes of Labiaplasty: A Prospective Study. PMID- 28590402 TI - Evidence-Based Medicine: A Graded Approach to Lower Lid Blepharoplasty. PMID- 28590403 TI - Revision Buttock Implantation: Indications, Procedures, and Recommendations. PMID- 28590404 TI - Reply: Psychological Outcomes of Labiaplasty: A Prospective Study. PMID- 28590405 TI - Breast Tissue Metabolism by Magnetic Resonance Spectroscopy. AB - Metabolic alterations are known to occur with oncogenesis and tumor progression. During malignant transformation, the metabolism of cells and tissues is altered. Cancer metabolism can be studied using advanced technologies that detect both metabolites and metabolic activities. Identification, characterization, and quantification of metabolites (metabolomics) are important for metabolic analysis and are usually done by nuclear magnetic resonance (NMR) or by mass spectrometry. In contrast to the magnetic resonance imaging that is used to monitor the tumor morphology during progression of the disease and during therapy, in vivo NMR spectroscopy is used to study and monitor tumor metabolism of cells/tissues by detection of various biochemicals or metabolites involved in various metabolic pathways. Several in vivo, in vitro and ex vivo NMR studies using 1H and 31P magnetic resonance spectroscopy (MRS) nuclei have documented increased levels of total choline containing compounds, phosphomonoesters and phosphodiesters in human breast cancer tissues, which is indicative of altered choline and phospholipid metabolism. These levels get reversed with successful treatment. Another method that increases the sensitivity of substrate detection by using nuclear spin hyperpolarization of 13C-lableled substrates by dynamic nuclear polarization has revived a great interest in the study of cancer metabolism. This review discusses breast tissue metabolism studied by various NMR/MRS methods. PMID- 28590407 TI - Family Communication about End-of-Life Decisions and the Enactment of the Decision-Maker Role. AB - End-of-life (EOL) decisions in families are complex and emotional sites of family interaction necessitating family members coordinate roles in the EOL decision making process. How family members in the United States enact the decision-maker role in EOL decision situations was examined through in-depth interviews with 22 individuals who participated in EOL decision-making for a family member. A number of themes emerged from the data with regard to the enactment of the decision maker role. Families varied in how decision makers enacted the role in relation to collective family input, with consulting, informing and collaborating as different patterns of behavior. Formal family roles along with gender- and age based roles shaped who took on the decision-maker role. Additionally, both family members and medical professionals facilitated or undermined the decision-maker's role enactment. Understanding the structure and enactment of the decision-maker role in family interaction provides insight into how individuals and/or family members perform the decision-making role within a cultural context that values autonomy and self-determination in combination with collective family action in EOL decision-making. PMID- 28590406 TI - De Novo Transcriptome Sequencing and the Hypothetical Cold Response Mode of Saussurea involucrata in Extreme Cold Environments. AB - Saussurea involucrata grows in high mountain areas covered by snow throughout the year. The temperature of this habitat can change drastically in one day. To gain a better understanding of the cold response signaling pathways and molecular metabolic reactions involved in cold stress tolerance, genome-wide transcriptional analyses were performed using RNA-Seq technologies. A total of 199,758 transcripts were assembled, producing 138,540 unigenes with 46.8 Gb clean data. Overall, 184,416 (92.32%) transcripts were successfully annotated. The 365 transcription factors identified (292 unigenes) belonged to 49 transcription factor families associated with cold stress responses. A total of 343 transcripts on the signal transduction (132 upregulated and 212 downregulated in at least any one of the conditions) were strongly affected by cold temperature, such as the CBL-interacting serine/threonine-protein kinase (CIPKs), receptor-like protein kinases, and protein kinases. The circadian rhythm pathway was activated by cold adaptation, which was necessary to endure the severe temperature changes within a day. There were 346 differentially expressed genes (DEGs) related to transport, of which 138 were upregulated and 22 were downregulated in at least any one of the conditions. Under cold stress conditions, transcriptional regulation, molecular transport, and signal transduction were involved in the adaptation to low temperature in S. involucrata. These findings contribute to our understanding of the adaptation of plants to harsh environments and the survival traits of S. involucrata. In addition, the present study provides insight into the molecular mechanisms of chilling and freezing tolerance. PMID- 28590408 TI - Tdrd12 Is Essential for Germ Cell Development and Maintenance in Zebrafish. AB - The regularity of Piwi-interacting RNA (piRNA) biogenesis is crucial to germline development. Functioning as Piwi-interacting proteins, Tudor domain-related proteins (Tdrds) have been demonstrated to be involved in spermatogenesis and the piRNA pathway. In this study, zebrafish tdrd12 was identified, and the maternal and germ cell-specific expression patterns of zebrafish tdrd12 were observed. Utilizing TALEN (transcription activator-like effector nuclease) techniques, two independent tdrd12 mutant zebrafish lines were generated. Although no defects were found during the generation of the primordial germ cells (PGCs) in the tdrd12-null fish progenies obtained from the heterozygous tdrd12 mutant parents, all Tdrd12-deficient fish developed into infertile males. The reduced numbers and eventually loss of the germ cells by 35 days post fertilization (dpf) led to masculinization and infertility of the Tdrd12-deficient fish. Meiosis defects of the germ cells in the tdrd12 mutants during the gonad-transitioning period were observed, revealing the indispensable functions of Tdrd12 in gametogenesis. Our studies demonstrated that zebrafish Tdrd12 is essential for germ cell development and maintenance. PMID- 28590410 TI - Depigmenting Effect of Resveratrol Is Dependent on FOXO3a Activation without SIRT1 Activation. AB - Resveratrol exhibits not only anti-melanogenic property by inhibiting microphthalmia-associated transcription factor (MITF), but also anti-aging property by activating sirtuin-1 (SIRT1). In this study, the relationship between depigmenting effect of resveratrol and SIRT1/forkhead box O (FOXO) 3a activation and was investigated. Resveratrol suppressed melanogenesis by the downregulation of MITF and tyrosinase via ERK pathway. Results showed that the expression of both SIRT1 and FOXO3a were increased. It is reported that SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. However in our study, FOXO3a activation appeared earlier than that of SIRT1. Furthermore, the effect of resveratrol on the levels of MITF and tyrosinase was suppressed when melanocytes were pre-treated with SP600125 (JNK inhibitor). However, pre treatment with SIRT1 inhibitor (EX527, or sirtinol) did not affect the levels of MITF and tyrosinase. Therefore, resveratrol inhibits melanogenesis through the activation of FOXO3a but not by the activation of SIRT1. Although SIRT1 activation by resveratrol is a well-known mechanism of resveratrol-induced antiaging effects, our study showed that not SIRT1 but FOXO3a activation is involved in depigmenting effects of resveratrol. PMID- 28590411 TI - A Conjugate of Pentamethine Cyanine and 18F as a Positron Emission Tomography/Near-Infrared Fluorescence Probe for Multimodality Tumor Imaging. AB - The novel synthesis of a dual-modality, pentamethine cyanine (Cy5) fluorescent, 18F positron emission tomography (PET) imaging probe is reported. The probe shows a large extinction coefficient and large quantum yield in the biologically transparent, near-infrared window (650-900 nm) for in vivo fluorescent imaging. This fluorophore bears the isotope, 18F, giving a 18F-PET/near-infrared fluorescent (NIRF), bi-modal imaging probe, that combines the long-term stability of NIRF and the unlimited penetration depth of PET imaging. The bi-modal probe is labeled with 18F in a quick, one-step reaction, which is important in working with the rapid decay of 18F. The bi-modal probe bears a free carboxyl group, highlighting a PET/NIRF synthon that can be conjugated onto many advanced biomolecules for biomarker-specific in vivo dual-modal PET/NIR tumor imaging, confocal histology, and utility in multi-fluorophore, fluorescence-guided surgery. Its potential in vivo biocompatibility is explored in a quick proof-of principal in vivo study. The dye is delivered to A549 xenograft flank-tumors to generate PET and NIRF signals at the tumor site. The tumor distribution is confirmed in ex vivo gamma counting and imaging. Pentamethine cyanine (Cy5) has the ability to preferentially accumulate in tumor xenografts. We substitute the PET/NIRF probe for Cy5, and explore this phenomenon. PMID- 28590409 TI - The Spleen: A Hub Connecting Nervous and Immune Systems in Cardiovascular and Metabolic Diseases. AB - Metabolic disorders have been identified as major health problems affecting a large portion of the world population. In addition, obesity and insulin resistance are principal risk factors for the development of cardiovascular diseases. Altered immune responses are common features of both hypertension and obesity and, moreover, the involvement of the nervous system in the modulation of immune system is gaining even more attention in both pathophysiological contexts. For these reasons, during the last decades, researches focused their efforts on the comprehension of the molecular mechanisms connecting immune system to cardiovascular and metabolic diseases. On the other hand, it has been reported that in these pathological conditions, central neural pathways modulate the activity of the peripheral nervous system, which is strongly involved in onset and progression of the disease. It is interesting to notice that neural reflex can also participate in the modulation of immune functions. In this scenario, the spleen becomes the crucial hub allowing the interaction of different systems differently involved in metabolic and cardiovascular diseases. Here, we summarize the major findings that dissect the role of the immune system in disorders related to metabolic and cardiovascular dysfunctions, and how this could also be influenced by neural reflexes. PMID- 28590413 TI - An Empirical Study of the Transmission Power Setting for Bluetooth-Based Indoor Localization Mechanisms. AB - Nowadays, there is a great interest in developing accurate wireless indoor localization mechanisms enabling the implementation of many consumer-oriented services. Among the many proposals, wireless indoor localization mechanisms based on the Received Signal Strength Indication (RSSI) are being widely explored. Most studies have focused on the evaluation of the capabilities of different mobile device brands and wireless network technologies. Furthermore, different parameters and algorithms have been proposed as a means of improving the accuracy of wireless-based localization mechanisms. In this paper, we focus on the tuning of the RSSI fingerprint to be used in the implementation of a Bluetooth Low Energy 4.0 (BLE4.0) Bluetooth localization mechanism. Following a holistic approach, we start by assessing the capabilities of two Bluetooth sensor/receiver devices. We then evaluate the relevance of the RSSI fingerprint reported by each BLE4.0 beacon operating at various transmission power levels using feature selection techniques. Based on our findings, we use two classification algorithms in order to improve the setting of the transmission power levels of each of the BLE4.0 beacons. Our main findings show that our proposal can greatly improve the localization accuracy by setting a custom transmission power level for each BLE4.0 beacon. PMID- 28590412 TI - Changes in Smoking Behavior over Family Transitions: Evidence for Anticipation and Adaptation Effects. AB - The study of changes in smoking behaviors over the life course is a promising line of research. This paper aims to analyze the temporal relation between family transitions (partnership formation, first childbirth, separation) and changes in smoking initiation and cessation. We propose a discrete-time logistic model to explore the timing of changes in terms of leads and lags effects up to three years around the event in order to measure both anticipation and adaptation mechanisms. Retrospective biographical data from the Sante et Itineraires Professionnels (SIP) survey conducted in France in 2006 are used. Partnership formation was followed for both genders by a fall in smoking initiation and an immediate rise in smoking cessation. Childbirth was associated with increased smoking cessation immediately around childbirth, and additionally, females showed an anticipatory increase in smoking cessation up to two years before childbirth. Couple separation was accompanied by an anticipatory increase in smoking initiation for females up to two years prior to the separation, but this effect only occurred in males during separation. Our findings highlight opportunities for more targeted interventions over the life course to reduce smoking, and therefore have relevance for general practitioners and public policy elaboration. PMID- 28590414 TI - mtDNA as a Mediator for Expression of Hypoxia-Inducible Factor 1alpha and ROS in Hypoxic Neuroblastoma Cells. AB - Mitochondria consume O2 to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1alpha pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (rho0) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia inducible factor 1alpha (HIF-1alpha) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1alpha, which was additionally influenced by level of generated ROS within the cytosol. Moreover, elevation of HIF-1alpha also resulted in increases of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1) in both hypoxic cells. The expression of mitochondrial biogenesis related proteins and metabolic components were noted to increase significantly in hypoxic SK-N-AS cells, indicating that mtDNA was involved in mitochondrial retrograde signaling and metabolic pathways. An analysis of dynamic proteins found elevated levels of HIF-1alpha causing an increased expression of dynamin-related protein 1 (DRP1) during hypoxia; further, the existence of mtDNA also resulted in higher expression of DRP1 during hypoxia. By using siRNA of HIF-1alpha or DRP1, expression of DRP1 decreased after suppression of HIF-1alpha; moreover, the expression of HIF-1alpha was also affected by the suppression of DRP1. In this study, we demonstrated that mtDNA is a mediator of HIF-1alpha in eliciting metabolic reprogramming, and mitochondrial biogenesis. Identification of a mutual relationship between HIF-1alpha and DRP1 may be a critical tool in the future development of clinical applications. PMID- 28590416 TI - Response to a Comment by Albert et al. (Nutrients 2017, 9, 137) Entitled "Concerns with the Study on Australian and New Zealand Fish Oil Products" by Nichols et al. (Nutrients 2016, 8, 703). AB - n/a. PMID- 28590417 TI - Facile Synthesis of Flower-Like Copper-Cobalt Sulfide as Binder-Free Faradaic Electrodes for Supercapacitors with Improved Electrochemical Properties. AB - Supercapacitors have been one of the highest potential candidates for energy storage because of their significant advantages beyond rechargeable batteries in terms of large power density, short recharging time, and long cycle lifespan. In this work, Cu-Co sulfides with uniform flower-like structure have been successfully obtained via a traditional two-step hydrothermal method. The as fabricated Cu-Co sulfide vulcanized from precursor (P-Cu-Co sulfide) is able to deliver superior specific capacitance of 592 F g-1 at 1 A g-1 and 518 F g-1 at 10 A g-1 which are surprisingly about 1.44 times and 2.39 times higher than those of Cu-Co oxide electrode, respectively. At the same time, excellent cycling stability of P-Cu-Co sulfide is indicated by 90.4% capacitance retention at high current density of 10 A g-1 after 3000 cycles. Because of the introduction of sulfur during the vulcanization process, these new developed sulfides can get more flexible structure and larger reaction surface area, and will own richer redox reaction sites between the interfaces of active material/electrolyte. The uniform flower-like P-Cu-Co sulfide electrode materials will have more potential alternatives for oxides electrode materials in the future. PMID- 28590418 TI - Enhancement of X-ray Induced Apoptosis by Mobile Phone-Like Radio-Frequency Electromagnetic Fields in Mouse Spermatocyte-Derived Cells. AB - To explore the combined effects of environmental radio-frequency (RF) field and X ray, mouse spermatocyte-derived (GC-1) cells were exposed to 1950 MHz RF field at specific absorption rate (SAR) of 3 W/kg for 24 h combined with or without X-ray irradiation at 6 Gy. After treatment, the cell proliferation level was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) Assay and 5-Bromo-2-deoxy Uridine (BrdU) enzyme linked immunosorbent (ELISA) Assay. The apoptosis level was detected by annexin V flow cytometry assay, transferase mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) Assay and Caspase-3 Activity Assay. It was found that the proliferation and apoptosis level did not change in GC-1 cells after RF exposure alone. However, compared with the X-ray group, the proliferation level significantly decreased and the apoptotic rate significantly increased in the RF+X-ray group. Moreover, a significant decrease in Bcl-2 protein expression and increase in Bax protein expression were observed. The findings suggested that RF exposure at SAR of 3 W/kg did not affect apoptosis and proliferation in GC-1 cells by itself, but that it did enhance the effects of X-ray induced proliferation inhibition and apoptosis, in which B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) might be involved. PMID- 28590415 TI - The Dual Roles of MYC in Genomic Instability and Cancer Chemoresistance. AB - Cancer is associated with genomic instability and aging. Genomic instability stimulates tumorigenesis, whereas deregulation of oncogenes accelerates DNA replication and increases genomic instability. It is therefore reasonable to assume a positive feedback loop between genomic instability and oncogenic stress. Consistent with this premise, overexpression of the MYC transcription factor increases the phosphorylation of serine 139 in histone H2AX (member X of the core histone H2A family), which forms so-called gammaH2AX, the most widely recognized surrogate biomarker of double-stranded DNA breaks (DSBs). Paradoxically, oncogenic MYC can also promote the resistance of cancer cells to chemotherapeutic DNA-damaging agents such as cisplatin, clearly implying an antagonistic role of MYC in genomic instability. In this review, we summarize the underlying mechanisms of the conflicting functions of MYC in genomic instability and discuss when and how the oncoprotein exerts the contradictory roles in induction of DSBs and protection of cancer-cell genomes. PMID- 28590420 TI - Anti-Inflammatory and Antioxidant Properties of Peptides Released from beta Lactoglobulin by High Hydrostatic Pressure-Assisted Enzymatic Hydrolysis. AB - BACKGROUND: beta-lactoglobulin hydrolysates (BLGH) have shown antioxidant, antihypertensive, antimicrobial, and opioid activity. In the current study, an innovative combination of high hydrostatic pressure and enzymatic hydrolysis (HHP EH) was used to increase the yield of short bioactive peptides, and evaluate the anti-inflammatory and antioxidant properties of the BLGH produced by the HHP-EH process. METHOD: BLG was enzymatically hydrolyzed by different proteases at an enzyme-to-substrate ratio of 1:100 under HHP (100 MPa) and compared with hydrolysates obtained under atmospheric pressure (AP-EH at 0.1 MPa). The degree of hydrolysis (DH), molecular weight distribution, and the antioxidant and anti inflammatory properties of hydrolysates in chemical and cellular models were evaluated. RESULTS: BLGH obtained under HHP-EH showed higher DH than the hydrolysates obtained under AP-EH. Free radical scavenging and the reducing capacity were also significantly stronger in HHP-BLGH compared to AP-BLGH. The BLGH produced by alcalase (Alc) (BLG-Alc) showed significantly higher antioxidant properties among the six enzymes examined in this study. The anti-inflammatory properties of BLG-HHP-Alc were observed in lipopolysaccharide-stimulated macrophage cells by a lower level of nitric oxide production and the suppression of the synthesis of pro-inflammatory cytokines. Peptide sequencing revealed that 38% of the amino acids in BLG-HHP-Alc are hydrophobic and aromatic residues, which contribute to its anti-inflammatory properties. CONCLUSIONS: Enzymatic hydrolysis of BLG under HHP produces a higher yield of short bioactive peptides with potential antioxidant and anti-inflammatory effects. PMID- 28590421 TI - Characterization of Asian Corn Borer Resistance to Bt Toxin Cry1Ie. AB - A strain of the Asian corn borer (ACB), Ostrinia furnacalis (Guenee), has evolved >800-fold resistance to Cry1Ie (ACB-IeR) after 49 generations of selection. The inheritance pattern of resistance to Cry1Ie in ACB-IeR strain and its cross resistance to other Bt toxins were determined through bioassay by exposing neonates from genetic-crosses to toxins incorporated into the diet. The response of progenies from reciprocal F1 crosses were similar (LC50s: 76.07 vs. 74.32 MUg/g), which suggested the resistance was autosomal. The effective dominance (h) decreased as concentration of Cry1Ie increased. h was nearly recessive or incompletely recessive on Cry1Ie maize leaf tissue (h = 0.02), but nearly dominant or incompletely dominant (h = 0.98) on Cry1Ie maize silk. Bioassay of the backcross suggested that the resistance was controlled by more than one locus. In addition, the resistant strain did not perform cross-resistance to Cry1Ab (0.8-fold), Cry1Ac (0.8-fold), Cry1F (0.9-fold), and Cry1Ah (1.0-fold). The present study not only offers the manifestation for resistance management, but also recommends that Cry1Ie will be an appropriate candidate for expression with Cry1Ab, Cry1Ac, Cry1F, or Cry1Ah for the development of Bt maize. PMID- 28590422 TI - Wearable Sensor Data Classification for Human Activity Recognition Based on an Iterative Learning Framework. AB - The design of multiple human activity recognition applications in areas such as healthcare, sports and safety relies on wearable sensor technologies. However, when making decisions based on the data acquired by such sensors in practical situations, several factors related to sensor data alignment, data losses, and noise, among other experimental constraints, deteriorate data quality and model accuracy. To tackle these issues, this paper presents a data-driven iterative learning framework to classify human locomotion activities such as walk, stand, lie, and sit, extracted from the Opportunity dataset. Data acquired by twelve 3 axial acceleration sensors and seven inertial measurement units are initially de noised using a two-stage consecutive filtering approach combining a band-pass Finite Impulse Response (FIR) and a wavelet filter. A series of statistical parameters are extracted from the kinematical features, including the principal components and singular value decomposition of roll, pitch, yaw and the norm of the axial components. The novel interactive learning procedure is then applied in order to minimize the number of samples required to classify human locomotion activities. Only those samples that are most distant from the centroids of data clusters, according to a measure presented in the paper, are selected as candidates for the training dataset. The newly built dataset is then used to train an SVM multi-class classifier. The latter will produce the lowest prediction error. The proposed learning framework ensures a high level of robustness to variations in the quality of input data, while only using a much lower number of training samples and therefore a much shorter training time, which is an important consideration given the large size of the dataset. PMID- 28590423 TI - A Novel Technique for Sterilization Using a Power Self-Regulated Single-Mode Microwave Cavity. AB - In this paper, a novel technique to achieve precise temperatures in food sterilization has been proposed. An accurate temperature profile is needed in order to reach a commitment between the total removal of pathogens inside the product and the preservation of nutritional and organoleptic characteristics. The minimal variation of the target temperature in the sample by means of a monitoring and control software platform, allowing temperature stabilization over 100 degrees C, is the main goal of this work. A cylindrical microwave oven, under pressure conditions and continuous control of the microwave supply power as function of the final temperature inside the sample, has been designed and developed with conditions of single-mode resonance. The uniform heating in the product is achieved by means of sample movement and the self-regulated power control using the measured temperature. Finally, for testing the sterilization of food with this technology, specific biological validation based on Bacillus cereus as a biosensor of heat inactivation has been incorporated as a distribution along the sample in the experimental process to measure the colony forming units (CFUs) for different food samples (laboratory medium, soup, or fish based animal by-products). The obtained results allow the validation of this new technology for food sterilization with precise control of the microwave system to ensure the uniform elimination of pathogens using high temperatures. PMID- 28590424 TI - Development of High Sensitivity Humidity Sensor Based on Gray TiO2/SrTiO3 Composite. AB - A gray TiO2/SrTiO3 composite nanocrystalline sensor with narrow band-gap was successfully prepared through a facile wet chemical method. The precursor was calcined in N2 flow under atmospheric pressure and thereafter, a humidity sensor based on the composite was fabricated. The sensor showed high resistive sensitivity and varied by more than four orders of magnitude with an increase in relative humidity (RH) from 11% to 95%. The response and recovery time were about 3.1 s and 76 s, respectively with maximum hysteresis at 1% RH. In comparison with pure SrTiO3 and black TiO2, the gray composite based device exhibits a higher sensitivity. These results demonstrate the potential of gray TiO2/SrTiO3 for humidity sensing applications. PMID- 28590425 TI - A Capacitance-To-Digital Converter for MEMS Sensors for Smart Applications. AB - The use of MEMS sensors has been increasing in recent years. To cover all the applications, many different readout circuits are needed. To reduce the cost and time to market, a generic capacitance-to-digital converter (CDC) seems to be the logical next step. This work presents a configurable CDC designed for capacitive MEMS sensors. The sensor is built with a bridge of MEMS, where some of them function with pressure. Then, the capacitive to digital conversion is realized using two steps. First, a switched-capacitor (SC) preamplifier is used to make the capacitive to voltage (C-V) conversion. Second, a self-oscillated noise shaping integrating dual-slope (DS) converter is used to digitize this magnitude. The proposed converter uses time instead of amplitude resolution to generate a multibit digital output stream. In addition it performs noise shaping of the quantization error to reduce measurement time. This article shows the effectiveness of this method by measurements performed on a prototype, designed and fabricated using standard 0.13 um CMOS technology. Experimental measurements show that the CDC achieves a resolution of 17 bits, with an effective area of 0.317 mm2, which means a pressure resolution of 1 Pa, while consuming 146 uA from a 1.5 V power supply. PMID- 28590419 TI - Melatonin and Fertoprotective Adjuvants: Prevention against Premature Ovarian Failure during Chemotherapy. AB - Premature ovarian failure is one of the side effects of chemotherapy in pre menopausal cancer patients. Preservation of fertility has become increasingly important in improving the quality of life of completely recovered cancer patients. Among the possible strategies for preserving fertility such as ovarian tissue cryopreservation, co-treatment with a pharmacological adjuvant is highly effective and poses less of a burden on the human body. Melatonin is generally produced in various tissues and acts as a universally acting antioxidant in cells. Melatonin is now more widely used in various biological processes including treating insomnia and an adjuvant during chemotherapy. In this review, we summarize the information indicating that melatonin may be useful for reducing and preventing premature ovarian failure in chemotherapy-treated female patients. We also mention that many adjuvants other than melatonin are developed and used to inhibit chemotherapy-induced infertility. This information will give us novel insights on the clinical use of melatonin and other agents as fertoprotective adjuvants for female cancer patients. PMID- 28590428 TI - Building Relations with Radiology Administrators. AB - In some radiology departments, the lack of alignment between administrators and radiologists can pose significant challenges. This article describes how differences in background and priorities between administrators and radiologists can contribute to conflict and presents strategies on how to manage the conflict in a way that can leverage positive change. Strategies to build relations between radiologists and radiology administrators are described. PMID- 28590427 TI - Integral Design Methodology of Photocatalytic Reactors for Air Pollution Remediation. AB - An integral reactor design methodology was developed to address the optimal design of photocatalytic wall reactors to be used in air pollution control. For a target pollutant to be eliminated from an air stream, the proposed methodology is initiated with a mechanistic derived reaction rate. The determination of intrinsic kinetic parameters is associated with the use of a simple geometry laboratory scale reactor, operation under kinetic control and a uniform incident radiation flux, which allows computing the local superficial rate of photon absorption. Thus, a simple model can describe the mass balance and a solution may be obtained. The kinetic parameters may be estimated by the combination of the mathematical model and the experimental results. The validated intrinsic kinetics obtained may be directly used in the scaling-up of any reactor configuration and size. The bench scale reactor may require the use of complex computational software to obtain the fields of velocity, radiation absorption and species concentration. The complete methodology was successfully applied to the elimination of airborne formaldehyde. The kinetic parameters were determined in a flat plate reactor, whilst a bench scale corrugated wall reactor was used to illustrate the scaling-up methodology. In addition, an optimal folding angle of the corrugated reactor was found using computational fluid dynamics tools. PMID- 28590426 TI - Down's Syndrome and Triple Negative Breast Cancer: A Rare Occurrence of Distinctive Clinical Relationship. AB - Down's syndrome (DS), the most common genetic cause of significant intellectual disability in children and adults is caused by the trisomy of either all or a part of human chromosome 21 (HSA21). Patients with DS mostly suffer from characteristic tumor types. Although individual patients of DS are at a higher risk for acute leukemia and testicular cancers, other types of solid tumors including breast cancers are mostly uncommon and have significantly lower-than expected age-adjusted incidence rates. Except for an increased risk of retinoblastomas, and lymphomas, the risk of developing solid tumors has been found to be lower in both children and adults, and breast cancer was found to be almost absent (Hasle H., The Lancet Oncology, 2001). A study conducted in the United States found only one death when 11.65 were expected (Scholl T et al., Dev Med Child Neurol. 1982). A recent study examined mammogram reports of women with DS treated in the largest medical facility specifically serving adults with DS in the United States. It was found that only 0.7% women with DS had been diagnosed with breast cancers (Chicoine B et al., Intellect Dev Disabil. 2015). Here we describe a case of breast cancer in a 25-year-old patient with DS. The disease was presented as lymph node positive carcinoma with alterations of tumor suppressor genes characteristic to the triple negative breast cancer subtype. Comprehensive Genomic Profiling (CGP) revealed a wild-type status for BRCA1. The CGP report showed a frameshift mutation, A359fs*10 of the tumor suppressor gene INPP4B and another frameshift mutation, R282fs*63 of tumor suppressor gene TP53 in the tumor biopsy as characteristically found in triple-negative breast cancers. The VUS (Variance of Unknown Significance) alteration(s) were identified in ASXL1 (L1395V), NTRK1 (G18E), DDR2 (I159T), RUNX1 (amplification), ERG (amplification), SOX2 (T26A), FAM123B (G1031D), and HNF1A (A301T). Bonafide cancer-related genes of chromosome 21 amplified in the patient's tumor are RUNX1 and ERG genes. After the completion of the radiation, the patient was placed on everolimus which was based on the result of her CGP report. Thus, post-mastectomy radiation therapy was completed with a recommendation for everolimus for one year. During the time of writing of this report, no metastatic lesions were identified. The patient currently has no evidence of disease. PMID- 28590429 TI - Spatial Characterization of Radio Propagation Channel in Urban Vehicle-to Infrastructure Environments to Support WSNs Deployment. AB - Vehicular ad hoc Networks (VANETs) enable vehicles to communicate with each other as well as with roadside units (RSUs). Although there is a significant research effort in radio channel modeling focused on vehicle-to-vehicle (V2V), not much work has been done for vehicle-to-infrastructure (V2I) using 3D ray-tracing tools. This work evaluates some important parameters of a V2I wireless channel link such as large-scale path loss and multipath metrics in a typical urban scenario using a deterministic simulation model based on an in-house 3D Ray Launching (3D-RL) algorithm at 5.9 GHz. Results show the high impact that the spatial distance; link frequency; placement of RSUs; and factors such as roundabout, geometry and relative position of the obstacles have in V2I propagation channel. A detailed spatial path loss characterization of the V2I channel along the streets and avenues is presented. The 3D-RL results show high accuracy when compared with measurements, and represent more reliably the propagation phenomena when compared with analytical path loss models. Performance metrics for a real test scenario implemented with a VANET wireless sensor network implemented ad-hoc are also described. These results constitute a starting point in the design phase of Wireless Sensor Networks (WSNs) radio-planning in the urban V2I deployment in terms of coverage. PMID- 28590430 TI - Design and Fabrication of a Ratiometric Planar Optode for Simultaneous Imaging of pH and Oxygen. AB - This paper presents a simple, high resolution imaging approach utilizing ratiometric planar optode for simultaneous measurement of dissolved oxygen (DO) and pH. The planar optode comprises a plastic optical film coated with oxygen indicator Platinum(II) octaethylporphyrin (PtOEP) and reference quantum dots (QDs) embedded in polystyrene (PS), pH indicator 5-Hexadecanoylamino-fluorescein (5-Fluorescein) embedded in Hydromed D4 matrix. The indicator and reference dyes are excited by utilizing an LED (Light Emitting Diode) source with a central wavelength of 405 nm, the emission respectively matches the different channels (red, green, and blue) of a 3CCD camera after eliminating the excitation source by utilizing the color filter. The result shows that there is low cross sensitivity between the two analytes dissolved oxygen and pH, and it shows good performance in the dynamic response ranges of 0-12 mg/L and a dynamic range of pH 6-8. The optode has been tested with regard to the response times, accuracy, photostability and stability. The applied experiment for detecting pH/Oxygen of sea-water under the influence of the rain drops is demonstrated. It is shown that the planar optode measuring system provides a simple method with low cross-talk for pH/Oxygen imaging in aqueous applications. PMID- 28590431 TI - Food and Nutrients Intake in the School Lunch Program among School Children in Shanghai, China. AB - This study aimed to evaluate the intake of food and nutrients among primary, middle, and high schools students in Shanghai, and provide recommendations for possible amendments in new school lunch standards of Shanghai. Twenty schools were included in the school lunch menu survey. Of those, seven schools enrolled 5389 students and conducted physical measurement of plate waste and a questionnaire survey. The amount of food and nutrients was compared according to the new China National Dietary Guideline for School Children (2016) and Chinese Dietary Reference Intakes (2013). The provision of livestock and poultry meat in menus was almost 5-8 times the recommended amount. The amount of seafood was less than the recommended amount, and mostly came from half-processed food. The average percentage of energy from fat was more than 30% in students of all grades. The greatest amount of food wasted was vegetables with 53%, 42%, and 31%, respectively, among primary, middle and high school students. Intake of Vitamin A, Vitamin B2, calcium, and iron was about 50% of the recommended proportion. Only 24.0% students were satisfied with the taste of school lunches. Higher proportions of livestock and poultry meat and low intake of vegetables have become integral problems in school lunch programs. Additionally, more attention needs to be paid to the serving size in primary schools with five age groups. PMID- 28590433 TI - Adaptive Grouping Distributed Compressive Sensing Reconstruction of Plant Hyperspectral Data. AB - With the development of hyperspectral technology, to establish an effective spectral data compressive reconstruction method that can improve data storage, transmission, and maintaining spectral information is critical for quantitative remote sensing research and application in vegetation. The spectral adaptive grouping distributed compressive sensing (AGDCS) algorithm is proposed, which enables a distributed compressed sensing reconstruction of plant hyperspectral data. The spectral characteristics of hyperspectral data are analyzed and the joint sparse model is constructed. The spectral bands are adaptively grouped and the hyperspectral data are compressed and reconstructed on the basis of grouping. The experimental results showed that, compared with orthogonal matching pursuit (OMP) and gradient projection for sparse reconstruction (GPSR), AGDCS can significantly improve the visual effect of image reconstruction in the spatial domain. The peak signal-to-noise ratio (PSNR) at a low sampling rate (the sampling rate is lower than 0.2) increases by 13.72 dB than OMP and 1.66 dB than GPSR. In the spectral domain, the average normalized root mean square error, the mean absolute percentage error, and the mean absolute error of AGDCS is 35.38%, 31.83%, and 33.33% lower than GPSR, respectively. Additionally, AGDCS can achieve relatively high reconstructed efficiency. PMID- 28590434 TI - A Reliable Data Transmission Model for IEEE 802.15.4e Enabled Wireless Sensor Network under WiFi Interference. AB - The IEEE 802.15.4e standard proposes Medium Access Control (MAC) to support collision-free wireless channel access mechanisms for industrial, commercial and healthcare applications. However, unnecessary wastage of energy and bandwidth consumption occur due to inefficient backoff management and collisions. In this paper, a new channel access mechanism is designed for the buffer constraint sensor devices to reduce the packet drop rate, energy consumption and collisions. In order to avoid collision due to the hidden terminal problem, a new frame structure is designed for the data transmission. A new superframe structure is proposed to mitigate the problems due to WiFi and ZigBee interference. A modified superframe structure with a new retransmission opportunity for failure devices is proposed to reduce the collisions and retransmission delay with high reliability. Performance evaluation and validation of our scheme indicate that the packet drop rate, throughput, reliability, energy consumption and average delay of the nodes can be improved significantly. PMID- 28590432 TI - Faller Classification in Older Adults Using Wearable Sensors Based on Turn and Straight-Walking Accelerometer-Based Features. AB - Faller classification in elderly populations can facilitate preventative care before a fall occurs. A novel wearable-sensor based faller classification method for the elderly was developed using accelerometer-based features from straight walking and turns. Seventy-six older individuals (74.15 +/- 7.0 years), categorized as prospective fallers and non-fallers, completed a six-minute walk test with accelerometers attached to their lower legs and pelvis. After segmenting straight and turn sections, cross validation tests were conducted on straight and turn walking features to assess classification performance. The best "classifier model-feature selector" combination used turn data, random forest classifier, and select-5-best feature selector (73.4% accuracy, 60.5% sensitivity, 82.0% specificity, and 0.44 Matthew's Correlation Coefficient (MCC)). Using only the most frequently occurring features, a feature subset (minimum of anterior-posterior ratio of even/odd harmonics for right shank, standard deviation (SD) of anterior left shank acceleration SD, SD of mean anterior left shank acceleration, maximum of medial-lateral first quartile of Fourier transform (FQFFT) for lower back, maximum of anterior-posterior FQFFT for lower back) achieved better classification results, with 77.3% accuracy, 66.1% sensitivity, 84.7% specificity, and 0.52 MCC score. All classification performance metrics improved when turn data was used for faller classification, compared to straight walking data. Combining turn and straight walking features decreased performance metrics compared to turn features for similar classifier model-feature selector combinations. PMID- 28590435 TI - Effects of Perceived Neighbourhood Environments on Self-Rated Health among Community-Dwelling Older Chinese. AB - In response to the growing number of older people living in cities, the World Health Organization (WHO) introduced the concept of "Age-Friendly Cities" (AFC) to guide the way in designing physical and social environments to encourage active ageing. Limited research has studied the effects of neighbourhood age friendliness on elderly health outcomes. Using the example of a highly urbanized city in Asia, this study examined the effects of perceived age-friendliness of neighbourhood environments on self-rated health (SRH) among community-dwelling older Chinese. A multi-stage sampling method was used to collect views of community-dwelling older people from two local districts of Hong Kong. A structured questionnaire covering the WHO's eight AFC domains was developed to collect information on the perceived neighbourhood environments, SRH and individual characteristics. Age-friendliness of neighbourhood was assessed by mean scores of AFC domains, which was used to predict SRH with adjustment for individual and objective neighbourhood characteristics. Furthermore, 719 respondents aged >=60 years completed the questionnaire, of which 44.5% reported good SRH. Independent of individual and objective neighbourhood characteristics, multiple logistics regressions showed that higher satisfaction on outdoor spaces and buildings, transportation, housing, social participation, and respect and social inclusion was significantly associated with increased odds of reporting good SRH by more than 20% (p < 0.05). Individuals aged 70-79 years, being female, lower education and residents of public or subsidized housing were less likely to report good SRH, after controlling for individual and neighbourhood characteristics. In addition to age, gender, education and housing type, AFC environments have important contributive influence on SRH, after controlling for individual and objective neighbourhood characteristics. PMID- 28590436 TI - Volatile Organic Compounds in Anatomical Pathology Wards: Comparative and Qualitative Assessment of Indoor Airborne Pollution. AB - The impact of volatile organic compounds (VOCs) on indoor air quality and on human health is widely recognized. However, VOC contamination in hospital indoor air is rarely studied and chemical compounds that singularly do not show high toxicity are not submitted to any regulation. This study aimed to compare VOC contamination in two different anatomical pathology wards in the same hospital. Hydrocarbons, alcohols, and terpenes were sampled by passive diffusive samplers. Analytical tests were performed by thermal desorption coupled with gas chromatography and mass spectrometry detector. Results highlighted a different VOC pollution in the two wards, due to the structural difference of the buildings and different organizational systems. The scarcity of similar data in the literature shows that the presence of VOCs in pathology wards is an underestimated problem. We believe that, because of the adverse effects that VOCs may have on the human health, this topic is worth exploring further. PMID- 28590437 TI - The Value of In Vitro Tests to DiminishDrug Challenges. AB - Drug hypersensitivity reactions have multiple implications for patient safety and health system costs, thus it is important to perform an accurate diagnosis. The diagnostic procedure includes a detailed clinical history, often unreliable; followed by skin tests, sometimes with low sensitivity or unavailable; and drug provocation testing, which is not risk-free for the patient, especially in severe reactions. In vitro tests could help to identify correctly the responsible agent, thus improving the diagnosis of these reactions, helping the physician to find safe alternatives, and reducing the need to perform drug provocation testing. However, it is necessary to confirm the sensitivity, specificity, negative and positive predictive values for these in vitro tests to enable their implementation in clinical practice. In this review, we have analyzed these parameters from different studies that have used in vitro test for evaluating drug hypersensitivity reactions and estimated the added value of these tests to the in vivo diagnosis. PMID- 28590438 TI - High Manifestations of Mental Distress in Arabic Asylum Seekers Accommodated in Collective Centers for Refugees in Germany. AB - The number of asylum seekers in Germany has significantly increased in the last two years. Coming from regions of political conflict and war, the refugees have often experienced traumatic events which designate them as a high risk group for mental disorders. In a sample of Arabic speaking asylum seekers in collective accommodation centers in Erlangen, Germany, we estimated the extent of posttraumatic stress, depression, and anxiety. A further objective of the study was to test the comprehensibility and cultural appropriateness of the Arabic translations of the questionnaires in this sample. Between August and September 2016, 56 Arabic speaking asylum seekers placed among three collective accommodation centers in Erlangen completed self-report questionnaires assessing posttraumatic stress disorder (Essen Trauma-Inventory, ETI), and symptoms of depression (Patient Health Questionnaire-depression module, PHQ-9) and anxiety (Generalized Anxiety Disorder, GAD-7). The prevalence of participants with personally and/or witnessed traumatic events was 80.4% (n = 45). About one-third of the examinees (35.7%, n = 20) endorsed symptoms of PTSD (posttraumatic stress disorder). The total score for depression in this sample was M = 11.9 (SD = 7.9, range: 0-27). Moderate to severe depression (PHQ-9 score >= 15) was found in 35.7% (n = 20) of our sample and severe depression (PHQ-9 score >= 20) was found in 23.2% (n = 13). The total score for anxiety was M = 8.8 (SD = 6.9, range: 0 21), with 26.8% (n = 15) of the sample showing symptoms of severe anxiety (GAD-7 score >= 15). No significant difference between women and men with respect to frequency and symptom scores of PTSD, depression, and anxiety was found. Amongst asylum seekers of the presented sample, the rates of traumatic events as well as the prevalence of possible PTSD, depression, and anxiety were significantly higher than in the German population. This indicates that the refugee population is in need of culturally sensitive psychological interventions. However, more studies are required to improve the understanding of mental health among this particularly vulnerable population. PMID- 28590439 TI - Reclassifying Anaphylaxis to Neuromuscular Blocking Agents Based on the Presumed Patho-Mechanism: IgE-Mediated, Pharmacological Adverse Reaction or "Innate Hypersensitivity"? AB - Approximately 60% of perioperative anaphylactic reactions are thought to be immunoglobulin IgE mediated, whereas 40% are thought to be non-IgE mediated hypersensitivity reactions (both considered non-dose-related type B adverse drug reactions). In both cases, symptoms are elicited by mast cell degranulation. Also, pharmacological reactions to drugs (type A, dose-related) may sometimes mimic symptoms triggered by mast cell degranulation. In case of hypotension, bronchospasm, or urticarial rash due to mast cell degranulation, identification of the responsible mechanism is complicated. However, determination of the type of the underlying adverse drug reaction is of paramount interest for the decision of whether the culprit drug may be re-administered. Neuromuscular blocking agents (NMBA) are among the most frequent cause of perioperative anaphylaxis. Recently, it has been shown that NMBA may activate mast cells independently from IgE antibodies via the human Mas-related G-protein-coupled receptor member X2 (MRGPRX2). In light of this new insight into the patho-mechanism of pseudo allergic adverse drug reactions, in which as drug-receptor interaction results in anaphylaxis like symptoms, we critically reviewed the literature on NMBA-induced perioperative anaphylaxis. We challenge the dogma that NMBA mainly cause IgE mediated anaphylaxis via an IgE-mediated mechanism, which is based on studies that consider positive skin test to be specific for IgE-mediated hypersensitivity. Finally, we discuss the question whether MRGPRX2 mediated pseudo-allergic reactions should be re-classified as type A adverse reactions. PMID- 28590442 TI - Joint Estimation of Source Range and Depth Using a Bottom-Deployed Vertical Line Array in Deep Water. AB - This paper presents a joint estimation method of source range and depth using a bottom-deployed vertical line array (VLA). The method utilizes the information on the arrival angle of direct (D) path in space domain and the interference characteristic of D and surface-reflected (SR) paths in frequency domain. The former is related to a ray tracing technique to backpropagate the rays and produces an ambiguity surface of source range. The latter utilizes Lloyd's mirror principle to obtain an ambiguity surface of source depth. The acoustic transmission duct is the well-known reliable acoustic path (RAP). The ambiguity surface of the combined estimation is a dimensionless ad hoc function. Numerical efficiency and experimental verification show that the proposed method is a good candidate for initial coarse estimation of source position. PMID- 28590440 TI - The Impact of Integrated Infant and Young Child Feeding and Micronutrient Powder Intervention on Feeding Practices and Anemia in Children Aged 6-23 Months in Madagascar. AB - This study assesses the impact of an integrated infant and young child feeding (IYCF) and micronutrient powder (MNP) intervention on children's risk of anemia and IYCF practices in Madagascar. Quantitative baseline and endline surveys were conducted in representative households with children 6-23 months from two districts, where an 18-month IYCF-MNP intervention was implemented. Relative risks comparing children's risk of anemia and maternal IYCF knowledge and practices at baseline versus endline, and also at endline among MNP-users versus non-users were estimated using log-binomial regression models. 372 and 475 children aged 6-23 months were assessed at baseline and endline respectively. Prevalence of anemia fell from 75.3% to 64.9% from baseline to endline (p = 0.002); the reduction in the risk of anemia remained significant in models adjusting for sociodemographic characteristics (ARR (95% CI): 0.86 (0.78, 0.95), p = 0.003). In endline assessments, 229 out of 474 (48.3%) of children had consumed MNPs. MNP-users had a lower risk of anemia (ARR (95% CI): 0.86 (0.74, 0.99), p = 0.04) than non-users, after controlling for child's dietary diversity and morbidity, maternal counseling by community-health-workers, and sociodemographic characteristics. Mothers interviewed at endline also had greater nutrition knowledge and were more likely to feed their children >=4 food groups (ARR (95% CI): 2.92 (2.24, 3.80), p < 0.001), and the minimum acceptable diet (ARR (95% CI): 2.88 (2.17, 3.82), p < 0.001) than mothers interviewed at baseline. Integration of MNP into IYCF interventions is a viable strategy for improving children's consumption of micronutrients and reducing risk of anemia. The addition of MNP does not negatively impact, and may improve, IYCF practices. PMID- 28590441 TI - Origins, Phytochemistry, Pharmacology, Analytical Methods and Safety of Cortex Moutan (Paeonia suffruticosa Andrew): A Systematic Review. AB - Cortex Moutan (CM), a well-known traditional Chinese medicine, is commonly used for treating various diseases in China and other eastern Asian countries. Recorded in Pharmacopeias of several countries, CM is now drawing increasing attention and under extensive studies in various fields. Phytochemical studies indicate that CM contains many valuable secondary metabolites, such as monoterpene glycosides and phenols. Ample evidence from pharmacological researches suggest that CM has a wide spectrum of activities, such as anti inflammatory, anti-oxidant, anti-tumor, anti-diabetic, cardiovascular protective, neuroprotective, hepatoprotective effects. Moreover, various analytical methods were established for the quality evaluation and safety control of CM. This review synopsizes updated information concerning the origins, phytochemistry, pharmacology, analytical method and safety of CM, aiming to provide favorable references for modern CM research and application. In conclusion, continuing pharmacological investigations concerning CM should be conducted to unravel its pharmacological mechanisms. Further researches are necessary to obtain comprehensive and applicable analytical approach for quality evaluation and establish harmonized criteria of CM. PMID- 28590443 TI - Interaction of Candida Species with the Skin. AB - The human skin is commonly colonized by diverse fungal species. Some Candida species, especially C. albicans, do not only reside on the skin surface as commensals, but also cause infections by growing into the colonized tissue. However, defense mechanisms at the skin barrier level are very efficient, involving residential non-immune and immune cells as well as immune cells specifically recruited to the site of infection. Therefore, the skin is an effective barrier against fungal infection. While most studies about commensal and pathogenic interaction of Candida species with host epithelia focus on the interaction with mucosal surfaces such as the vaginal and gastrointestinal epithelia, less is known about the mechanisms underlying Candida interaction with the skin. In this review, we focus on the ecology and molecular pathogenesis of Candida species on the skin and give an overview of defense mechanisms against C. albicans in this context. We also discuss new research avenues in dermal infection, including the involvement of neurons, fibroblasts, and commensal bacteria in both mouse and human model systems. PMID- 28590445 TI - Surface-Modification of Carbonate Apatite Nanoparticles Enhances Delivery and Cytotoxicity of Gemcitabine and Anastrozole in Breast Cancer Cells. AB - pH sensitive nanoparticles of carbonate apatite (CA) have been proven to be effective delivery vehicles for DNA, siRNAs and proteins. More recently, conventional anti-cancer drugs, such as doxorubicin, methotrexate and cyclophosphamide have been successfully incorporated into CA for intracellular delivery to breast cancer cells. However, physical and chemical properties of drug molecules appeared to affect their interactions with CA, with hydrophillic drug so far exhibiting better binding affinity and cellular uptakes compared to hydrophobic drugs. In this study, anastrozole, a non-steroidal aromatase inhibitor which is largely hydrophobic, and gemcitabine, a hydrophilic nucleoside inhibitor were used as solubility models of chemotherapy drug. Aggregation tendency of poorly soluble drugs resulting in larger particle-drug complex size might be the main factor hindering their delivery effectiveness. For the first time, surface modification of CA with poly(ethylene glycol) (PEG) has shown promising result to drastically reduce anastrozole- loaded CA particle size, from approximately 1000 to 500 nm based on zeta sizer analysis. Besides PEG, a cell specific ligand, in this case fibronectin, was attached to the particles in order to facilitate receptor mediated endocytosis based on fibronectin-integrin interaction. High-performance liquid chromatography (HPLC) was performed to measure uptake of the drugs by breast cancer cells, revealing that surface modification increased the drug uptake, especially for the hydrophobic drug, compared to the uncoated particles and the free drug. In vitro chemosensitivity assay and in vivo tumor regression study also showed that coated apatite/drug nanoparticle complexes presented higher cytotoxicity and tumor regression effects than uncoated apatite/drug nanoparticles and free drugs, indicating that surface modification successfully created optimum particles size with the consequence of more effective uptake along with favorable pharmacokinetics of the particles. PMID- 28590444 TI - Consumers' Preferences for Electronic Nicotine Delivery System Product Features: A Structured Content Analysis. AB - To inform potential governmental regulations, we aimed to develop a list of electronic nicotine delivery system (ENDS) product features important to U.S. consumers by age and gender. We employed qualitative data methods. Participants were eligible if they had used an ENDS at least once. Groups were selected by age and gender (young adult group aged 18-25, n = 11; middle-age group aged 26-64, n = 9; and women's group aged 26-64, n = 9). We conducted five individual older adult interviews (aged 68-80). Participants discussed important ENDS features. We conducted a structured content analysis of the group and interview responses. Of 34 participants, 68% were white and 56% were female. Participants mentioned 12 important ENDS features, including: (1) user experience; (2) social acceptability; (3) cost; (4) health risks/benefits; (5) ease of use; (6) flavors; (7) smoking cessation aid; (8) nicotine content; (9) modifiability; (10) ENDS regulation; (11) bridge between tobacco cigarettes; (12) collectability. The most frequently mentioned ENDS feature was modifiability for young adults, user experience for middle-age and older adults, and flavor for the women's group. This study identified multiple features important to ENDS consumers. Groups differed in how they viewed various features by age and gender. These results can inform ongoing regulatory efforts. PMID- 28590447 TI - Left-Right Asymmetry in Spectral Characteristics of Lung Sounds Detected Using a Dual-Channel Auscultation System in Healthy Young Adults. AB - Though lung sounds auscultation is important for the diagnosis and monitoring of lung diseases, the spectral characteristics of lung sounds have not been fully understood. This study compared the spectral characteristics of lung sounds between the right and left lungs and between healthy male and female subjects using a dual-channel auscultation system. Forty-two subjects aged 18-22 years without smoking habits and any known pulmonary diseases participated in this study. The lung sounds were recorded from seven pairs of auscultation sites on the chest wall simultaneously. We found that in four out of seven auscultation pairs, the lung sounds from the left lung had a higher total power (PT) than those from the right lung. The PT of male subjects was higher than that of female ones in most auscultation pairs. The ratio of inspiration power to expiration power (RI/E) of lung sounds from the right lung was greater than that from the left lung at auscultation pairs on the anterior chest wall, while this phenomenon was reversed at auscultation pairs on the posterior chest wall in combined subjects, and similarly in both male and female subjects. Though the frequency corresponding to maximum power density of lung sounds (FMPD) from the left and right lungs was not significantly different, the frequency that equally divided the power spectrum of lung sounds (F50) from the left lung was significantly smaller than that from the right lung at auscultation site on the anterior and lateral chest walls, while it was significantly larger than that of from the right lung at auscultation site on the posterior chest walls. In conclusion, significant differences in the PT, FMPD, F50, and RI/E between the left and right lungs at some auscultation pairs were observed by using a dual-channel auscultation system in this study. Structural differences between the left and the right lungs, between the female and male subjects, and between anterior and posterior lungs might account for the observed differences in the spectral characteristics of lung sounds. The dual-channel auscultation system might be useful for future development of digital stethoscopes and power spectral analysis of lung sounds in patients with various kinds of cardiopulmonary diseases. PMID- 28590446 TI - Fruits of Black Chokeberry Aronia melanocarpa in the Prevention of Chronic Diseases. AB - In recent years, growing attention has been focused on the utilization of natural sources of antioxidants in the prevention of chronic diseases. Black chokeberry (Aronia melanocarpa) represents a lesser known fruit species utilized mainly as juices, purees, jams, jellies and wine, as important food colorants or nutritional supplements. The fruit is valued as a great source of antioxidants, especially polyphenols, such as phenolic acids (neochlorogenic and chlorogenic acids) and flavonoids (anthocyanins, proanthocyanidins, flavanols and flavonols), particularly cyanidin-3-galactoside and cyanidin-3-arabinoside, as well as (-) epicatechin units. The berries of A. melanocarpa, due to the presence and the high content of these bioactive components, exhibit a wide range of positive effects, such as strong antioxidant activity and potential medicinal and therapeutic benefits (gastroprotective, hepatoprotective, antiproliferative or anti-inflammatory activities). They could be also contributory toward the prevention of chronic diseases including metabolic disorders, diabetes and cardiovascular diseases, because of supportive impacts on lipid profiles, fasting plasma glucose and blood pressure levels. PMID- 28590449 TI - Development of Laser Scanner for Full Cross-Sectional Deformation Monitoring of Underground Gateroads. AB - The deformation of underground gateroads tends to be asymmetric and complex. Traditional instrumentation fails to accurately and conveniently monitor the full cross-sectional deformation of underground gateroads. Here, a full cross sectional laser scanner was developed, together with a visualization software package. The developed system used a polar coordinate measuring method and the full cross-sectional measurement was shown by 360 degrees rotation of a laser sensor driven by an electrical motor. Later on, the potential impact of gateroad wall flatness, roughness, and geometrical profile, as well as coal dust environment on the performance of the developed laser scanner will be evaluated. The study shows that high-level flatness is favorable in the application of the developed full cross-sectional deformation monitoring system. For a smooth surface of gateroad, the sensor cannot receive reflected light when the incidence angle of laser beam is large, causing data loss. Conversely, the roughness surface shows its nature as the diffuse reflection light can be received by the sensor. With regards to coal dust in the measurement environment, fine particles of floating coal dust in the air can lead to the loss of measurement data to some extent, due to scattering of the laser beam. PMID- 28590450 TI - Improving Multidimensional Wireless Sensor Network Lifetime Using Pearson Correlation and Fractal Clustering. AB - An efficient strategy for reducing message transmission in a wireless sensor network (WSN) is to group sensors by means of an abstraction denoted cluster. The key idea behind the cluster formation process is to identify a set of sensors whose sensed values present some data correlation. Nowadays, sensors are able to simultaneously sense multiple different physical phenomena, yielding in this way multidimensional data. This paper presents three methods for clustering sensors in WSNs whose sensors collect multidimensional data. The proposed approaches implement the concept of multidimensional behavioral clustering. To show the benefits introduced by the proposed methods, a prototype has been implemented and experiments have been carried out on real data. The results prove that the proposed methods decrease the amount of data flowing in the network and present low root-mean-square error (RMSE). PMID- 28590451 TI - Environmental Factors Associated with Type 1 Diabetes Development: A Case Control Study in Egypt. AB - Uncertainty still exists regarding the role of some environmental risk in the development of type 1 diabetes mellitus (T1DM) both globally and in Egypt. The objective here was to explore the potential environmental risk factors associated with the development of T1DM among children in Egypt. A case-controlled study of 204 T1DM children and an equal number of age and sex-matched controls was conducted in Assiut, Egypt. Data regarding the parental, gestational, neonatal, and childhood possible risk factors for T1DM were evaluated. The final sex adjusted multivariable logistic regression model revealed that the risk for T1DM was significantly higher among rural residents (aOR = 2.03, 95% CI: 1.30-4.25), those with parental history of T1DM (aOR = 9.03, 95% CI: 1.02-83.32), birth through cesarean section (aOR = 2.13, 95% CI: 1.09-5.03), and having history of early introduction of cow milk in the first year of life (aOR = 19.49, 95% CI: 8.73-45.53). On the other hand, a protective effect was observed between at least six months' breastfeeding, vitamin D supplementation in the first year of life, high physical activity, and the development of T1DM. Educational programs should be adopted to improve awareness and knowledge of the parents to avoid the increased risk factors and encourage protective practices. PMID- 28590448 TI - Striatal Vulnerability in Huntington's Disease: Neuroprotection Versus Neurotoxicity. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection. PMID- 28590453 TI - Tyrosinase-Based Biosensors for Selective Dopamine Detection. AB - A novel tyrosinase-based biosensor was developed for the detection of dopamine (DA). For increased selectivity, gold electrodes were previously modified with cobalt (II)-porphyrin (CoP) film with electrocatalytic activity, to act both as an electrochemical mediator and an enzyme support, upon which the enzyme tyrosinase (Tyr) was cross-linked. Differential pulse voltammetry was used for electrochemical detection and the reduction current of dopamine-quinone was measured as a function of dopamine concentration. Our experiments demonstrated that the presence of CoP improves the selectivity of the electrode towards dopamine in the presence of ascorbic acid (AA), with a linear trend of concentration dependence in the range of 2-30 uM. By optimizing the conditioning parameters, a separation of 130 mV between the peak potentials for ascorbic acid AA and DA was obtained, allowing the selective detection of DA. The biosensor had a sensitivity of 1.22 +/- 0.02 uA.cm-2.uM-1 and a detection limit of 0.43 uM. Biosensor performances were tested in the presence of dopamine medication, with satisfactory results in terms of recovery (96%), and relative standard deviation values below 5%. These results confirmed the applicability of the biosensors in real samples such as human urine and blood serum. PMID- 28590452 TI - Genistein Supplementation and Cardiac Function in Postmenopausal Women with Metabolic Syndrome: Results from a Pilot Strain-Echo Study. AB - Genistein, a soy-derived isoflavone, may improve cardiovascular risk profile in postmenopausal women with metabolic syndrome (MetS), but few literature data on its cardiac effects in humans are available. The aim of this sub-study of a randomized double-blind case-control study was to analyze the effect on cardiac function of one-year genistein dietary supplementation in 22 post-menopausal patients with MetS. Participants received 54 mg/day of genistein (n = 11) or placebo (n = 11) in combination with a Mediterranean-style diet and regular exercise. Left ventricular (LV) systolic function was assessed as the primary endpoint, according to conventional and strain-echocardiography measurements. Also, left atrial (LA) morphofunctional indices were investigated at baseline and at the final visit. Results were expressed as median with interquartile range (IQ). A significant improvement of LV ejection fraction (20.3 (IQ 12.5) vs. -1.67 (IQ 24.8); p = 0.040)), and LA area fractional change (11.1 (IQ 22.6) vs. 2.8 (9.5); p = 0.034)) were observed in genistein patients compared to the controls, following 12 months of treatment. In addition, body surface area indexed LA systolic volume and peak LA longitudinal strain significantly changed from basal to the end of the study in genistein-treated patients. One-year supplementation with 54 mg/day of pure genistein improved both LV ejection fraction and LA remodeling and function in postmenopausal women with MetS. PMID- 28590456 TI - Artificial Neural Network-Based Early-Age Concrete Strength Monitoring Using Dynamic Response Signals. AB - Concrete is one of the most common materials used to construct a variety of civil infrastructures. However, since concrete might be susceptible to brittle fracture, it is essential to confirm the strength of concrete at the early-age stage of the curing process to prevent unexpected collapse. To address this issue, this study proposes a novel method to estimate the early-age strength of concrete, by integrating an artificial neural network algorithm with a dynamic response measurement of the concrete material. The dynamic response signals of the concrete, including both electromechanical impedances and guided ultrasonic waves, are obtained from an embedded piezoelectric sensor module. The cross correlation coefficient of the electromechanical impedance signals and the amplitude of the guided ultrasonic wave signals are selected to quantify the variation in dynamic responses according to the strength of the concrete. Furthermore, an artificial neural network algorithm is used to verify a relationship between the variation in dynamic response signals and concrete strength. The results of an experimental study confirm that the proposed approach can be effectively applied to estimate the strength of concrete material from the early-age stage of the curing process. PMID- 28590454 TI - Lignins and Their Derivatives with Beneficial Effects on Human Health. AB - A review of the pharmacological applications of lignins provides evidence of their protective role against the development of different diseases. In many cases, the effects of lignins could be explained by their antioxidant capacity. Here, we present a systematic review of the literature from the period 2010-2016 which provides information concerning new applications of lignins derived from recent research. The most promising findings are reported, including the methodologies employed and results obtained with lignins or their derivatives which may improve human health. We highlight potential applications in the treatment of obesity, diabetes, thrombosis, viral infections and cancer. Moreover, we report both that lignins can be used in the preparation of nanoparticles to deliver different drugs and also their use in photoprotection. PMID- 28590457 TI - Highlights in myeloproliferative neoplasms from the 2016 American Society of Hematology annual meeting and exposition. PMID- 28590455 TI - Machine-Learned Data Structures of Lipid Marker Serum Concentrations in Multiple Sclerosis Patients Differ from Those in Healthy Subjects. AB - Lipid metabolism has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS). With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research. We used unsupervised machine-learning to analyze lipid marker serum concentrations, pursuing the hypothesis that for the most relevant markers the emerging data structures will coincide with the diagnosis of MS. Machine learning was implemented as emergent self-organizing feature maps (ESOM) combined with the U*-matrix visualization technique. The data space consisted of serum concentrations of three main classes of lipid markers comprising eicosanoids (d = 11 markers), ceramides (d = 10), and lyosophosphatidic acids (d = 6). They were analyzed in cohorts of MS patients (n = 102) and healthy subjects (n = 301). Clear data structures in the high-dimensional data space were observed in eicosanoid and ceramides serum concentrations whereas no clear structure could be found in lysophosphatidic acid concentrations. With ceramide concentrations, the structures that had emerged from unsupervised machine-learning almost completely overlapped with the known grouping of MS patients versus healthy subjects. This was only partly provided by eicosanoid serum concentrations. Thus, unsupervised machine-learning identified distinct data structures of bioactive lipid serum concentrations. These structures could be superimposed with the known grouping of MS patients versus healthy subjects, which was almost completely possible with ceramides. Therefore, based on the present analysis, ceramides are first-line candidates for further exploration as drug-gable targets or biomarkers in MS. PMID- 28590458 TI - Highlights in myeloproliferative neoplasms from the 2016 American Society of Hematology meeting: Commentary. PMID- 28590461 TI - Advances in lymphoma and leukemia from the 2016 American Society of Hematology annual meeting and exposition. PMID- 28590460 TI - Highlights in lymphoma from the 2016 American Society of Hematology annual meeting and exposition: Commentary. PMID- 28590462 TI - Advances in lymphoma and leukemia from the 2016 American Society of Hematology annual meeting and exposition: Commentary. PMID- 28590464 TI - Policy solutions to recruiting and retaining minority children in research. PMID- 28590463 TI - Prediction and association mapping of agronomic traits in maize using multiple omic data. AB - Genomic selection holds a great promise to accelerate plant breeding via early selection before phenotypes are measured, and it offers major advantages over marker-assisted selection for highly polygenic traits. In addition to genomic data, metabolome and transcriptome are increasingly receiving attention as new data sources for phenotype prediction. We used data available from maize as a model to compare the predictive abilities of three different omic data sources using eight representative methods for six traits. We found that the best linear unbiased prediction overall performs better than other methods across different traits and different omic data, and genomic prediction performs better than transcriptomic and metabolomic predictions. For the same maize data, we also conducted genome-wide association study, transcriptome-wide association studies and metabolome-wide association studies for the six agronomic traits using both the genome-wide efficient mixed model association (GEMMA) method and a modified least absolute shrinkage and selection operator (LASSO) method. The new LASSO method has the ability to perform statistical tests. Simulation studies show that the modified LASSO performs better than GEMMA in terms of high power and low Type 1 error. PMID- 28590466 TI - Ethylperoxy radical: approaching spectroscopic accuracy via coupled-cluster theory. AB - Interest in peroxy radicals derives from their central role in tropospheric and low-temperature combustion processes; however, their transient nature limits the scope of possible experimental characterization. As a result, theoretical methods (notably, coupled-cluster theory) have become indispensable in the reliable prediction of properties of such ephemeral open-shell systems. Herein, the X[combining tilde] and A state conformers of ethylperoxy radical (C2H5O2) have been structurally optimized at the CCSD(T)/ANO2 level of theory. Relative enthalpies at 0 K [including A <- X[combining tilde] transition origins (T0)] are reported, incorporating CCSD(T) electronic energies extrapolated to the complete basis set limit via the focal point approach. Higher-level computations, employing basis sets as large as cc-pV5Z and post-HF methods up to CCSDT(Q), prove essential in achieving predictions to within 10 cm-1 for experimental T0; we predict 7363 and 7583 cm-1 for the trans and gauche conformers, respectively. Furthermore, predictions of X[combining tilde] state fundamental transitions incorporating CCSD(T)/ANO0 anharmonic contributions are given. For each conformer, all 21 modes were characterized, improving upon the 16 modes reported in the experimental literature, and providing predictions for the 5 remaining modes. PMID- 28590468 TI - The influence of cation ordering, oxygen vacancy distribution and proton siting on observed properties in ceramic electrolytes: the case of scandium substituted barium titanate. AB - The origin of the 2-order of magnitude difference in the proton conductivity of the hydrated forms of hexagonal and cubic oxygen deficient BaScxTi1-xO3-delta (x = 0.2 and x = 0.7) was probed using a combination of neutron diffraction and density functional theory techniques to support published X-ray diffraction, conductivity, thermogravimetric and differential scanning calorimetry studies. Cation ordering is found in the 6H structure type (space group P63/mmc) adopted by BaSc0.2Ti0.8O3-delta with scandium preferentially substituting in the vertex sharing octahedra (2a crystallographic site) and avoiding the face-sharing octahedra (4f site). This is coupled with oxygen vacancy ordering in the central plane of the face-sharing octahedra (O1 site). In BaSc0.7Ti0.3O3-delta a simple cubic perovskite (space group Pm3[combining macron]m) best represents the average structure from Rietveld analysis with no evidence of either cation ordering or oxygen vacancy ordering. Significant diffuse scattering is observed, indicative of local order. Hydration in both cases leads to complete filling of the available oxygen vacancies and permits definition of the proton sites. We suggest that the more localised nature of the proton sites in the 6H structure is responsible for the significantly lower proton conduction observed in the literature. Within the 6H structure type final model, proton diffusion requires a 3-step process via higher energy proton sites that are unoccupied at room temperature and is also likely to be anisotropic whereas the highly disordered cubic perovskite proton position allows 3-dimensional diffusion by well-described modes. Finally, we propose how this knowledge can be used to further materials design for ceramic electrolytes for proton conducting fuel cells. PMID- 28590469 TI - Elasticity of particle-loaded liquid foams. AB - Mixing solid particles with liquid foam is a common process used in industry for manufacturing aerated materials. Desire for improvement of involved industrial processes and optimization of resulting foamed materials stimulates fundamental research on those complex mixtures of grains, bubbles and liquid. In this paper, we generate well-controlled particle-loaded liquid foams and we determine their elastic behavior as a function of particle size (6-3000 MUm) and particle volume fraction (0-6%). We focus on both the elastic modulus exhibited by the material at small strain and the strain marking the end of the linear elastic regime. Results reveal the existence of a critical particle-to-bubble size ratio triggering a sharp transition between two well-defined regimes. For small size ratios, the behavior is governed by the mechanical properties of the solid grains, which have been proved to pack in the shape of a foam-embedded granular skeleton. In contrast, bubbles elasticity prevails in the second regime, where isolated large particles contribute only weakly to the rheological behavior of the foamed material. The modeling of elasticity for each regime allows for this transition to be normalized and compared with previously reported particle size induced effects for foam drainage (Haffner et al. J. Colloid Interface Sci., 2015, 458, 200-208) and solid foam mechanics (Khidas et al., Compos. Sci. Technol., 2015, 119, 62-67). This highlights that rheology and the other properties of particle-loaded foams are subjected to the same size-induced morphological transition. PMID- 28590470 TI - An engineering design approach to systems biology. AB - Measuring and modeling the integrated behavior of biomolecular-cellular networks is central to systems biology. Over several decades, systems biology has been shaped by quantitative biologists, physicists, mathematicians, and engineers in different ways. However, the basic and applied versions of systems biology are not typically distinguished, which blurs the separate aspirations of the field and its potential for real-world impact. Here, we articulate an engineering approach to systems biology, which applies educational philosophy, engineering design, and predictive models to solve contemporary problems in an age of biomedical Big Data. A concerted effort to train systems bioengineers will provide a versatile workforce capable of tackling the diverse challenges faced by the biotechnological and pharmaceutical sectors in a modern, information-dense economy. PMID- 28590471 TI - Seedless synthesis and SERS characterization of multi-branched gold nanoflowers using water soluble polymers. AB - We report for the first time, the aqueous-based synthesis of multibranched, monodispersed gold nanoflowers (AuNFs) using pyromellitic dianhydride-p-phenylene diamine - PPDDs at room temperature. AuNF synthesis was achieved using PPDDs that converts Au precursor (Au3+) into AuNFs while serving as both the reducing and directional agent. The resulting branched AuNFs exhibited different degrees of anisotropy and protuberance lengths obtained by modulating the ratio of PPDDs and HAuCl4.3H2O. The surface roughness obtained ranged from small bud-like protuberances to elongated spikes, which enabled the tuning of the optical properties of the nanoparticles from ~450 to 1100 nm. Systematic analysis revealed that the generation of urchin-like particles as well as their size depended on the PPDDs/HAuCl4.3H2O ratio. At a medium concentration of the precursor, spherical nanoparticles were formed. Whereas at lower precursor concentrations, urchin-like nanoparticles were obtained with their size and protuberances length increasing at even lower HAuCl4.3H2O concentration. Increasing the temperature to 100 degrees C resulted in the enhancement of the anisotropy of the AuNFs. The resulting gold nanoflowers exhibited an enhanced performance in surface-enhanced Raman scattering (SERS). This work provides a unique approach for anisotropic particle synthesis using water soluble polymer and greener approaches. The fabricated AuNFs exhibited variable UV-vis absorption and SERS enhancement as a function of branch morphology, indicating their potential application in biolabeling, biosensing, imaging, and therapeutic applications. PMID- 28590472 TI - Gram-scale free radical polymerization of an azaborine vinyl monomer. AB - The gram-scale polymerization of a novel azaborine vinyl monomer is reported. We describe an efficient and high-yielding synthesis of B-vinyl-2,1 borazanaphthalene. Homopolymers and co-polymers with 2-vinylnaphthalene are characterized by heteronuclear NMR and absorbance spectroscopy. PMID- 28590473 TI - Is more better? A comparison of tri- and tetrapeptidic catalysts. AB - From an enzymatic perspective, there is a general notion that the bigger and more complex a catalytically active peptide is the more enzyme-like and the better it should become. But is this really true? We have tackled this question firstly by screening split-and-mix-libraries of tri- and tetrapeptides for members that catalyze aldol reactions. Then, the catalytic performance of all possible diastereoisomers of related tri- and tetrapeptidic catalysts of the type H-Pro Pro-Glu/Asp-NH2 and H-Pro-Pro-Glu/Asp-Pro-NH2 in aldol and conjugate addition reactions was compared. PMID- 28590474 TI - Conducting microhelices from self-assembly of protein fibrils. AB - Herein we utilize insulin to prepare amyloid based chiral helices with either right or left handed helicity. We demonstrate that the helices can be utilized as structural templates for the conducting polymer alkoxysulfonate poly(ethylenedioxythiophene) (PEDOT-S). The chirality of the helical assembly is transferred to PEDOT-S as demonstrated by polarized optical microscopy (POM) and Circular Dichroism (CD). Analysis of the helices by conductive atomic force microscopy (c-AFM) shows significant conductivity. In addition, the morphology of the template structure is stabilized by PEDOT-S. These conductive helical structures represent promising candidates in our quest for THz resonators. PMID- 28590475 TI - A NbO type Cu(ii) metal-organic framework showing efficient catalytic activity in the Friedlander and Henry reactions. AB - A three-dimensional NbO type porous metal-organic framework 1 containing both tertiary amine groups and paddle wheel dinuclear Cu2(COO)4 secondary building units as the active centre was synthesized at room temperature. The activated framework 1' can be used as an efficient heterogeneous catalyst for the synthesis of quinoline derivatives by the Friedlander reaction and for the synthesis of beta-nitroalcohols by the Henry (nitroaldol) reaction. This MOF-based heterogeneous catalyst is easily recycled and reused further without losing its structural integrity and catalytic activity. PMID- 28590476 TI - Boron-doped graphitic carbon nitride nanosheets for enhanced visible light photocatalytic water splitting. AB - A new type of boron-doped graphitic carbon nitride (B-g-C3N4) nanosheets was prepared by a benign one-pot thermal polycondensation process. Systematic studies revealed that a B-doping amount of 1 at% into g-C3N4 (1at%B-g-C3N4) showed the best photocatalytic H2 evolution activity of 1880 MUmol h-1 g-1 under visible light irradiation (>400 nm), which is more than 12 times that of the pristine g C3N4 bulk. Detailed characterizations revealed that the high photocatalytic performance could be attributed to the combination of band structure engineering and morphological control. B-doping not only reduces the band gap to absorb more visible light but also exhibits a higher surface area of B-g-C3N4 (49.47 m2 g-1) as compared to that of g-C3N4 bulk (8.24 m2 g-1), which subsequently improve the photocatalytic performance drastically. This work demonstrates a synergistic strategy to prepare efficient metal-free B-g-C3N4 nanosheets as a promising photocatalyst for H2 evolution under visible light with good stability. PMID- 28590477 TI - Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41. AB - Small molecule inhibitors of glycoprotein-41 (gp41) are able to prevent HIV infection by binding to a hydrophobic pocket (HP) contained within the gp41 ectodomain, and preventing progression of fusion. There is little structural information on gp41-ligand complexes, owing to hydrophobicity of the ligands, occlusion of the HP in folded gp41 ectodomain, and failure to form crystals of complexes. Here we used an engineered gp41 ectodomain protein containing an exposed HP and a small molecule designed to bind with weak affinity to the HP. We evaluated NMR methods, including WaterLOGSY, Saturation Transfer Difference spectroscopy (STD-NMR) and 1H relaxation rate difference spectroscopy with and without target irradiation (DIRECTION) for their ability to probe complex formation and structure. WaterLOGSY was the most sensitive technique for monitoring formation of the complex. STD-NMR and DIRECTION experiments gave similar pharmacophore mapping profiles, although the low dynamic range of the DIRECTION experiment limited its discrimination and sensitivity. A unique binding pose was identified from the STD data and provided clues for future optimization. Advantages and disadvantages of the techniques are discussed. This is the first example of the use of STD for structural analysis of a gp41-small molecule complex. PMID- 28590478 TI - Investigation of interfacial thermal transport across graphene and an organic semiconductor using molecular dynamics simulations. AB - The interfacial thermal transport across graphene and an organic semiconductor, dinaphtho[2,3-b:2',3'-f]thieno[3,2-b]thiophene (DNTT), is investigated using molecular dynamics simulations. The average thermal boundary resistance (TBR) of graphene and DNTT is 4.88 +/- 0.12 * 10-8 m2 K W-1 at 300 K. We find that TBR of a graphene-DNTT heterostructure possesses as high as 83.4% reduction after the hydrogenation of graphene. Moreover, as the graphene vacancy increases from 0% to 6%, the TBR drops up to 39.6%. The reduction of TBR is mainly attributed to the coupling enhancement of graphene and DNTT phonons as evaluated from the phonon density of states. On the other hand, TBR keeps a constant value while the vacancy in the DNTT layer increases. The TBR would decrease when the temperature and coupling strength increase. These findings provide a useful guideline for the thermal management of the graphene-based organic electronic devices, especially the large area transistor arrays or sensors. PMID- 28590479 TI - Tip-enhanced Raman spectroscopy for surfaces and interfaces. AB - Surface and interfaces play key roles in heterogeneous catalysis, electrochemistry and photo(electro)chemistry. Tip-enhanced Raman spectroscopy (TERS) combines plasmon-enhanced Raman spectroscopy with scanning probe microscopy to simultaneously provide a chemical fingerprint and morphological information for the sample at the nanometer spatial resolution. It is an ideal tool for achieving an in-depth understanding of the surface and interfacial processes, so that the relationship between structure and chemical performance can be established. We begin with the background of surfaces and interfaces and TERS, followed by a detailed discussion on some issues in experimental TERS, including tip preparation and TERS instrument configuration. We then focus on the progress of TERS for studying the surfaces and interfaces under different conditions, from ambient, to UHV, solid-liquid and electrochemical environments, followed by a brief introduction to the current understanding of the unprecedented high spatial resolution and surface selection rules. We conclude by discussing the future challenges for TERS practical applications in surfaces and interfaces. PMID- 28590480 TI - Dynamic glass transition of the rigid amorphous fraction in polyurethane urea/SiO2 nanocomposites. AB - We report molecular dynamics in the rigid amorphous fraction (RAF) of the polymer bound at the interfaces with nanoparticles in polymer nanocomposites and calculate the glass transition temperature, Tg, for this bound layer of polymer. We follow the '3-phase-model' for semicrystalline polymers where the polymer matrix consists of the crystalline fraction (CF), the mobile amorphous fraction (MAF) and the RAF. While the amorphous polymer bound by crystallites is completely rigid, neither contributing to the glass transition, nor displaying molecular dynamics, the amorphous polymer bound at the interfaces with filler displays decelerated dynamics, as compared to the bulk polymer. Reports in the literature suggest a discrepancy between Tg values obtained by Differential Scanning Calorimetry (DSC) and by Dielectric Relaxation Spectroscopy (DRS). As a plausible explanation we suggest that DRS results in Tg values taking into account the bound polymer, whereas DSC does not. For this investigation we use semicrystalline polyurethane-urea/SiO2 nanocomposites and employ, next to DSC and DRS, SEM, SAXS and WAXS for morphological characterization. It is our intention to use DRS as a tool for investigating the RAF. PMID- 28590481 TI - Polymorphism of a chiral iron(ii) complex: spin-crossover and ferroelectric properties. AB - Two solvent-free polymorphs of a chiral iron(ii) complex have been obtained, and their polymorphism dependent spin-crossover and ferroelectric properties have been demonstrated. Polymorph I shows a gradual spin-crossover behavior, whereas polymorph II remains in a high-spin state but shows a typical ferroelectric feature. PMID- 28590482 TI - Thickness control of 3-dimensional mesoporous silica ultrathin films by wet etching. AB - The thickness of 3-dimensional (3D) mesoporous silica ultrathin films was controlled at a single-nanometer scale by wet-etching. A drop casting method with an aqueous etchant of ammonium fluoride was effective in etching the surfaces of films in the direction perpendicular to their substrates. The decrease in the film thickness depends on the interface tension of etching solutions. The wettability of thin films also influences the etching. CoPt nanodots were electrodeposited within ultrathin silica films on Ru substrates to form CoPt nanodot patterns. PMID- 28590484 TI - Normal-to-abnormal rearrangement of an N-heterocyclic carbene with a silylene transition metal complex. AB - The synthesis and characterization of the N-heterocyclic carbene (NHC) stabilized dichlorosilylene Group 6 metal complexes {(IPr)SiCl2}W(CO)5 (3-W), {(IPr)SiCl2}2Cr(CO)4 (4-Cr), and {(IPr)SiCl2}2W(CO)4 (4-W) (IPr = 1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene) are reported. Treatment of 3-W with CsOH in the presence of IPr leads to the formation of an abnormal-NHC (aNHC) metal complex (aIPrH)W(CO)5 (6-W) (aIPrH = 1,3-bis(2,6-diisopropylphenyl)imidazol-4 ylidene), unveiling an unprecedented normal-to-abnormal transformation route of an NHC. DFT calculations support the proposed mechanism that involves CsOH mediated deprotonation of the IPr-backbone of 3-W to yield a ditopic carbanionic NHC (dcNHC) complex 5a-W. Subsequent 1,4-migration of the W(CO)5 moiety and hydrolysis of the unmasked SiCl2 rationalize the formation of 6-W. The desired H2O molecule is generated in the initial step on deprotonation of IPr with CsOH. In contrast to the literature precedents, the calculations indicate that the abnormal complex 6-W is 13.5 kcal mol-1 thermodynamically higher in energy than the normal counterpart (IPr)W(CO)5 (8-W). Interestingly, as the aNHC-compounds reported so far are more stable than their normal counterparts, this finding showcases an opposite trend. Moreover, reaction pathways to the synthesized and related complexes have been investigated by DFT calculations. PMID- 28590485 TI - Intermolecular charge fluxes and far-infrared spectral intensities of liquid formamide. AB - The intensity generation mechanisms of the far-infrared (far-IR) [or terahertz (THz)] spectrum of liquid formamide, particularly with regard to the behavior of electrons induced by modulations of the hydrogen-bonding conditions of the molecules, are examined theoretically. The theoretical analysis is done in the following two steps. First, density functional theory (DFT) calculations are carried out for the dimers and larger clusters of formamide to analyze the change in the dipole derivative (the square of which is proportional to the IR intensity) induced by hydrogen-bond formation. Then, by using the information derived in the first step, molecular dynamics-based spectral simulations are carried out. It is shown that, upon formation of a hydrogen bond, a change in the dipole derivative is induced along the direction of the hydrogen bond, and is reasonably modeled by the intermolecular charge flux mechanism, where a certain amount of electron density is transferred between molecules according to the modulation of the hydrogen-bond length, similarly to the case of liquid water. This model is in a form that is suitable for use in molecular dynamics-based spectral simulations. From these spectral simulations, it is found that the observed spectral features of the far-IR spectrum of liquid formamide are reasonably reproduced, and that the inclusion of the effect of intermolecular charge flux is essential for it. Contrary to the case of liquid water, the molecular libration band (rather than the molecular translation band) is significantly enhanced by the intermolecular charge flux. It is discussed that this difference is related to the geometrical relation between the hydrogen bonds and the atomic displacements in the molecular translations and librations (rotations). It is considered that, in general, in hydrogen-bonding liquids, modulations of hydrogen-bond lengths occurring upon dynamics of molecules give rise to intermolecular charge fluxes, significantly affecting the dipole derivatives, and hence, the IR intensity distributions in the spectra. PMID- 28590486 TI - Correction: A review of carrier thermoelectric-transport theory in organic semiconductors. AB - Correction for 'A review of carrier thermoelectric-transport theory in organic semiconductors' by Nianduan Lu et al., Phys. Chem. Chem. Phys., 2016, 18, 19503 19525. PMID- 28590488 TI - Correction: Statistical theory of polarizable target compound impregnation into a polymer coil under the influence of an electric field. AB - Correction for 'Statistical theory of polarizable target compound impregnation into a polymer coil under the influence of an electric field' by A. L. Kolesnikov et al., Soft Matter, 2017, DOI: 10.1039/c7sm00417f. PMID- 28590491 TI - 4,5-Substituted C^C* cyclometalated thiazol-2-ylidene platinum(ii) complexes - synthesis and photophysical properties. AB - We report the synthesis of seven novel backbone functionalized N-phenyl-1,3 thiazol-2-ylidene platinum(ii) complexes and their photophysical properties. Electronically diverse N-phenyl-1,3-thiazol-2-thiones were prepared by a reaction of aniline with carbon disulfide and different alpha-haloketone compounds. Oxidative desulfuration and salt metathesis yielded the desired NHC-precursors with hexafluorophosphate counterions. In addition, a new route for the synthesis of N-phenyl-1,3-benzo[d]thiazole tetrafluoroborate via N-arylation using hypervalent iodine species is presented. All complexes were prepared from the corresponding NHC precursor in a one-pot process using silver(i)oxide, transmetalation to platinum and reaction with the beta-diketone acetylacetone under basic conditions. These complexes exhibit strong phosphorescence with quantum yields up to 72% in 2 wt% PMMA films with decay lifetimes of 8.8-12.3 MUs. The influence of methyl- and phenyl-groups, and an ester-substituent at the 4- and/or 5-position of the 1,3-thiazole moiety, as well as the N-phenyl-1,3 benzo[d]thiazole-derived motif is discussed. The 4,5-unsubstituted-N-phenyl-1,3 thiazol-2-ylidene platinum(ii) acetylacetonato complex served as a reference in this study to evaluate the electronic effects originating from the backbone substitution. All complexes emit in a narrow range of the bluish-green spectrum of the visible light (510 +/- 10 nm). PMID- 28590489 TI - Biocompatible and label-free separation of cancer cells from cell culture lines from white blood cells in ferrofluids. AB - This paper reports a biocompatible and label-free cell separation method using ferrofluids that can separate a variety of low-concentration cancer cells from cell culture lines (~100 cancer cells per mL) from undiluted white blood cells, with a throughput of 1.2 mL h-1 and an average separation efficiency of 82.2%. The separation is based on the size difference of the cancer cells and white blood cells, and is conducted in a custom-made biocompatible ferrofluid that retains not only excellent short-term viabilities but also normal proliferations of 7 commonly used cancer cell lines. A microfluidic device is designed and optimized specifically to shorten the time of live cells' exposure to ferrofluids from hours to seconds, by eliminating time-consuming off-chip sample preparation and extraction steps and integrating them on-chip to achieve a one-step process. As a proof-of-concept demonstration, a ferrofluid with 0.26% volume fraction was used in this microfluidic device to separate spiked cancer cells from cell lines at a concentration of ~100 cells per mL from white blood cells with a throughput of 1.2 mL h-1. The separation efficiencies were 80 +/- 3%, 81 +/- 5%, 82 +/- 5%, 82 +/- 4%, and 86 +/- 6% for A549 lung cancer, H1299 lung cancer, MCF-7 breast cancer, MDA-MB-231 breast cancer, and PC-3 prostate cancer cell lines, respectively. The separated cancer cells' purity was between 25.3% and 28.8%. In addition, the separated cancer cells from this strategy showed an average short term viability of 94.4 +/- 1.3%, and these separated cells were cultured and demonstrated normal proliferation to confluence even after the separation process. Owing to its excellent biocompatibility and label-free operation and its ability to recover low concentrations of cancer cells from white blood cells, this method could lead to a promising tool for rare cell separation. PMID- 28590490 TI - Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate. AB - The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for assessing cholinergic dysfunction associated with dementia. We recently reported three new potent and selective carbon-11 labeled VAChT radiotracers. Herein, we report the resolution with a Chiralcel OD column of three additional fluorine containing VAChT ligands in which a fluoroethoxy or fluoroethylamino moiety was substituted for the methoxy group. An in vitro competitive binding assay showed that (-)-7 had high potency for VAChT (Ki-VAChT = 0.31 +/- 0.03 nM) and excellent selectivity for VAChT versus sigma receptors (Ki-sigma1 = 1870 +/- 250 nM, Ki sigma2 = 5480 +/- 140 nM). Three different radiolabeling approaches were explored; the radiosynthesis of (-)-[18F]7 was successfully accomplished via a stepwise two-pot, three-step method with moderate yield (11 +/- 2%) and high radiochemical purity (>98%). PET imaging studies in a nonhuman primate indicated that (-)-[18F]7 rapidly entered the brain and accumulated in the VAChT-enriched striatum. The uptake of (-)-[18F]7 in the target striatal area peaked at 10 min and displayed improved clearance kinetics compared to the VAChT tracer [18F]VAT, which has been approved by the Food and Drug Administration (FDA) for first-in man studies. These studies justify further investigation of (-)-[18F]7 and exploration of the structure-activity relationships of these fluoroethoxy and fluoroethylamino analogs. PMID- 28590493 TI - Novel properties of 0D metal-organic polyhedra bonded to the surfaces of 2D graphene and 1D single-walled carbon nanotubes. AB - A strategy for the stabilization of metal-organic polyhedra (MOP) cages on graphene (Gr) and single-walled carbon nanotubes (NT) is reported. The surface area of the composites, MOPGr and MOPNT increases by an order of magnitude with a significant increase in pore volume in comparison to bulk MOP. The composites show an enhancement in the catalytic activity of up to ~80% relative to bulk MOP in the conversion of propylene oxide into propylene carbonate. Depositing individual MOP cages on graphene or SWNT surfaces is beneficial in terms of gas adsorption and catalytic properties and provides a good example for useful effects of bonding materials of different dimensionalities. PMID- 28590494 TI - Tris(2-pyridyl)phosphine as a versatile ligand for pnictogen acceptors. AB - We report cationic complexes of arsenic and antimony with the tris(2 pyridyl)phosphine ligand. Chloride ion abstraction from AsCl3 using TMSOTf in the presence of the ligand gives [P(Pyr)3As][OTf]3, in which the trication adopts a C3v symmetric cage structure. The reaction proceeds via the intermediate [P(Pyr)3AsCl][OTf]2, which undergoes chloride exchange to give [P(Pyr)3As][OTf]3 and [P(Pyr)3AsCl2][OTf]. The rearrangement reaction has been supported by the isolation of the antimony mono fluoride derivative [P(Pyr)3SbF][OTf]2. The asymmetric axial lone pairs in derivatives of [P(Pyr)3Pn]3+ are electronically separated. The HOMO-1 (for arsenic) and HOMO (for antimony) represent the major contribution to the phosphine lone pair indicating the possibility for nucleophilic behaviour despite the +3 charge. Less accessible is the HOMO-7, which represents the lone pair at arsenic or antimony, respectively. PMID- 28590496 TI - Artefact suppression in 5-pulse double electron electron resonance for distance distribution measurements. AB - A 5-pulse version of the Double Electron Electron Resonance (DEER) experiment with Carr-Purcell delays and an additional pump pulse has been shown to significantly extend the experimentally accessible distance range in cases where nuclear spin diffusion dominates electron spin phase memory loss [Borbat et al., J. Phys. Chem. Lett., 2013, 4, 170]. We show that the sequence also prolongs coherence decay for spin labels in or near lipid bilayers, where this decay is mono-exponential. Compared to 4-pulse DEER, 5-pulse DEER suffers from additional artefacts that stem from pulse imperfection and excitation band overlap. Only some of these artefacts can be suppressed by phase cycling and the remaining ones have hindered widespread utilization of the method. Here, we report previously unknown additional artefact contributions stemming from overlap between the excitation bands of the microwave pulses that introduce additional dipolar evolution pathways. Experimental conditions are analyzed in detail that suppress these as well as the already known artefacts. Such suppression results in data that contain at most the partial excitation artefact, which can be deliberately shifted in time by a change in pulse timing without affecting the wanted contribution. PMID- 28590495 TI - Structure-based design of novel combinatorially generated NBTIs as potential DNA gyrase inhibitors against various Staphylococcus aureus mutant strains. AB - Although intercalating agents such as quinolones have had proven therapeutic success as antibacterial agents for more than 40 years, new forms of quinolone based resistance in bacteria are continually emerging. To alleviate this problem, a new class of antibacterials is urgently needed; recently, novel bacterial topoisomerase inhibitors (NBTIs) have been found to be particularly important. Based on 67 experimentally evaluated NBTIs against wild-type (WT) DNA gyrase originating from Staphylococcus aureus, a predictive QSAR model was initially constructed and validated and was later used for in silico prediction of biological activities for an in house designed compound library of 548 novel drug like NBTI combinatorial analogs. To evaluate the influence of gyrA alterations on NBTI resistance, various mutant homology models were constructed; meanwhile, their resistance profiles were assessed and validated relative to that of WT enzyme by structure-based virtual screening (VS) of known NBTIs. Surprisingly, the M121K mutant model was recognized as the most selective due to an additional established cation-pi interaction between K121-NH3+ (not found in the WT) and the aromatic moiety of the NBTI right-hand site (RHS) fragment; this finding was additionally supported by VS of our combinatorially generated NBTIs. Moreover, we identified several attractive, synthetically feasible RHS building blocks that may enable the development of new NBTIs. PMID- 28590497 TI - Iodine-catalyzed sulfenylation of pyrazolones using dimethyl sulfoxide as an oxidant. AB - An iodine catalyzed sulfenylation of pyrazolones with a diverse range of heterocyclic thiols, heterocyclic thiones and disulfides has been described using dimethyl sulfoxide as an oxidant, which is an inexpensive, readily available and green oxidant. The present methodology exhibits a wide range of substrate scope and targeted products were obtained in good to excellent yields under metal-free conditions in a short duration. This methodology provides a simple process for the formation of C-S bonds through the thioetherification of pyrazolones. PMID- 28590498 TI - A Multi-way Multi-task Learning Approach for Multinomial Logistic Regression*. An Application in Joint Prediction of Appointment Miss-opportunities across Multiple Clinics. AB - OBJECTIVES: Whether they have been engineered for it or not, most healthcare systems experience a variety of unexpected events such as appointment miss opportunities that can have significant impact on their revenue, cost and resource utilization. In this paper, a multi-way multi-task learning model based on multinomial logistic regression is proposed to jointly predict the occurrence of different types of miss-opportunities at multiple clinics. METHODS: An extension of L1 / L2 regularization is proposed to enable transfer of information among various types of miss-opportunities as well as different clinics. A proximal algorithm is developed to transform the convex but non-smooth likelihood function of the multi-way multi-task learning model into a convex and smooth optimization problem solvable using gradient descent algorithm. RESULTS: A dataset of real attendance records of patients at four different clinics of a VA medical center is used to verify the performance of the proposed multi-task learning approach. Additionally, a simulation study, investigating more general data situations is provided to highlight the specific aspects of the proposed approach. Various individual and integrated multinomial logistic regression models with/without LASSO penalty along with a number of other common classification algorithms are fitted and compared against the proposed multi-way multi-task learning approach. Fivefold cross validation is used to estimate comparing models parameters and their predictive accuracy. The multi-way multi task learning framework enables the proposed approach to achieve a considerable rate of parameter shrinkage and superior prediction accuracy across various types of miss-opportunities and clinics. CONCLUSIONS: The proposed approach provides an integrated structure to effectively transfer knowledge among different miss opportunities and clinics to reduce model size, increase estimation efficacy, and more importantly improve predictions results. The proposed framework can be effectively applied to medical centers with multiple clinics, especially those suffering from information scarcity on some type of disruptions and/or clinics. PMID- 28590499 TI - Can Statistical Machine Learning Algorithms Help for Classification of Obstructive Sleep Apnea Severity to Optimal Utilization of Polysomnography Resources? AB - OBJECTIVES: The goal of this study is to evaluate the results of machine learning methods for the classification of OSA severity of patients with suspected sleep disorder breathing as normal, mild, moderate and severe based on non polysomnographic variables: 1) clinical data, 2) symptoms and 3) physical examination. METHODS: In order to produce classification models for OSA severity, five different machine learning methods (Bayesian network, Decision Tree, Random Forest, Neural Networks and Logistic Regression) were trained while relevant variables and their relationships were derived empirically from observed data. Each model was trained and evaluated using 10-fold cross-validation and to evaluate classification performances of all methods, true positive rate (TPR), false positive rate (FPR), Positive Predictive Value (PPV), F measure and Area Under Receiver Operating Characteristics curve (ROC-AUC) were used. RESULTS: Results of 10-fold cross validated tests with different variable settings promisingly indicated that the OSA severity of suspected OSA patients can be classified, using non-polysomnographic features, with 0.71 true positive rate as the highest and, 0.15 false positive rate as the lowest, respectively. Moreover, the test results of different variables settings revealed that the accuracy of the classification models was significantly improved when physical examination variables were added to the model. CONCLUSIONS: Study results showed that machine learning methods can be used to estimate the probabilities of no, mild, moderate, and severe obstructive sleep apnea and such approaches may improve accurate initial OSA screening and help referring only the suspected moderate or severe OSA patients to sleep laboratories for the expensive tests. PMID- 28590500 TI - Genetic diversity of Morato's Digger Toad, Proceratophrys moratoi: spatial structure, gene flow, effective size and the need for differential management strategies of populations. AB - The Morato's Digger Toad, Proceratophrys moratoi, is a critically endangered toad species with a marked population decline in southern Brazilian Cerrado. Despite this, new populations are being discovered, primarily in the northern part of the distribution range, which raises a number of questions with regard to the conservation status of the species. The present study analyzed the genetic diversity of the species based on microsatellite markers. Our findings permitted the identification of two distinct management units. We found profound genetic structuring between the southern populations, on the left margin of the Tiete River, and all other populations. A marked reduction was observed in the contemporary gene flow among the central populations that are most affected by anthropogenic impacts, such as extensive sugar cane plantations, which presumably decreases habitat connectivity. The results indicated reduced diversity in the southern populations which, combined with a smaller effective population size, may make these populations more susceptible to extinction. We recommend the reclassification of P. moratoi as vulnerable and the establishment of a special protection program for the southern populations. Our results provide important insights about the local extinction of southern populations of this toad. PMID- 28590501 TI - Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family. AB - Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A (p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships. PMID- 28590502 TI - A SNP in 5' untranslated region of CD40 gene is associated with an increased risk of ischemic stroke in a Chinese population: a case-control study. AB - Cluster of differentiation 40 (CD40), the receptor for CD154, is a member of the tumor necrosis factor (TNF) receptor superfamily. Several studies have been conducted to investigate the effect of the CD40 rs1883832 polymorphism on atherosclerotic disease in different population; however, inconsistent results were obtained. In this study, we investigated the association of four polymorphisms (rs1883832, rs13040307, rs752118 and rs3765459) of CD40 gene and their effect on CD40 expression with the risk of ischemic stroke (IS) in a Chinese population. Three hundred and eighty patients with IS and 450 control subjects were included in the study. The CD40 polymorphisms were discriminated by Snapshot SNP genotyping assay. Serum soluble CD40 (sCD40) levels were detected by ELISA. We found that the rs1883832CT and rs1883832TT genotypes were associated with an increased risk of IS compared with the rs1883832CC genotype (OR = 1.42, 95% CI: 1.03-1.95, p = 0.030 and OR = 1.91, 95% CI: 1.29-2.82, P = 0.001, respectively), and the rs1883832T allele was associated with a significantly increased risk of IS compared with rs1883832C allele (OR = 1.40, 95% CI: 1.15 1.70, P = 0.001). Elevated serum sCD40 levels were observed in patients with IS compared with the control gropu (P < 0.01). Individuals carrying the rs1883832TT or rs1883832CT genotypes showed significantly higher sCD40 levels compared with the rs1883832CC genotype in the IS group [(64.8 +/- 25.4 pg/mL, TT = 94); (63.9 +/- 24.3 pg/mL, CT = 185) vs (53.3 +/- 22.5 pg/mL, CC = 101), P < 0.01]. The TCCA haplotype was associated with an increased risk of IS compared with the control group (OR = 2.10, 95% CI: 1.23-3.58, p = 0.005). However, we did not find a significant association between the other three polymorphisms and IS risk. In conclusion, after a comprehensive comparison with other studies, we confirmed that the rs1883832T allele but not the rs1883832C allele is associated with an increased risk of IS. The rs1883832 polymorphism may exert influences on abnormal CD40 expression in IS patients among the Chinese population. PMID- 28590503 TI - Growth hormone insensitivity with immune dysfunction caused by a STAT5B mutation in the south of Brazil: evidence for a founder effect. AB - Homozygous STAT5B mutations causing growth hormone insensitivity with immune dysfunction were described in 10 patients since 2003, including two Brazilian brothers from the south of Brazil. Our objectives were to evaluate the prevalence of their STAT5B mutation in this region and to analyze the presence of a founder effect. We obtained DNA samples from 1,205 local inhabitants, 48 relatives of the homozygous patients and four individuals of another affected family. Genotyping for STAT5B c.424_427del mutation and for two polymorphic markers around it was done through fragment analysis technique. We also determined Y-chromosome and mtDNA haplotypes and genomic ancestry in heterozygous carriers. We identified seven families with STAT5B c.424_427del mutation, with 33 heterozygous individuals. The minor allelic frequency of this mutation was 0.29% in this population (confidence interval 95% 0.08-0.5%), which is significantly higher than the frequency of other pathogenic STAT5B allele variants observed in public databases (p < 0.001). All heterozygous carriers had the same haplotype present in the homozygous patients, found in only 9.4% of non-carriers (p < 0.001), supporting the existence of a founder effect. The Y-chromosome haplotype, mtDNA and genomic ancestry analysis indicated a European origin of this mutation. Our results provide compelling evidence for a founder effect of STAT5B c.424_427del mutation. PMID- 28590504 TI - Identifying Mazama gouazoubira (Artiodactyla; Cervidae) chromosomes involved in rearrangements induced by doxorubicin. AB - The process of karyotype evolution in Cervidae from a common ancestor (2n = 70, FN = 70) has been marked by complex chromosomal rearrangements. This ancestral karyotype has been retained by the current species Mazama gouazoubira (Fischer 1814), for which a chromosomal polymorphism (Robertsonian translocations and the presence of B chromosomes) has been described, presumably caused by a chromosome fragility. Thus, this study has identified doxorubicin-induced chromosome aberrations and mapped the regions involved in breaks, which may be related to the chromosome evolution process. G-banding pattern showed that 21 pairs of chromosomes presented chromosomal aberrations, 60% of the total chromosome number of the species M. gouazoubira. Among chromosomes that carry aberrations, the region where they were most frequently concentrated was distal relative to the centromere. These data suggest that certain chromosomal regions may be more susceptible to chromosome fragility and consequently could be involved in karyotype differentiation in species of the family Cervidae. PMID- 28590505 TI - Carotid endarterectomy for symptomatic carotid stenosis. AB - BACKGROUND: Stroke is the third leading cause of death and the most common cause of long-term disability. Severe narrowing (stenosis) of the carotid artery is an important cause of stroke. Surgical treatment (carotid endarterectomy) may reduce the risk of stroke, but carries a risk of operative complications. This is an update of the Cochrane Review, originally published in 1999, and most recently updated in 2011. OBJECTIVES: To determine the balance of benefit versus risk of endarterectomy plus best medical management compared with best medical management alone, in people with a recent symptomatic carotid stenosis (i.e. transient ischaemic attack (TIA) or non-disabling stroke). SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (last searched in July 2016), CENTRAL (2016, Issue 7), MEDLINE (1966 to July 2016), Embase (1990 to July 2016), Web of Science Core Collection, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) portal, and handsearched relevant journals and reference lists. SELECTION CRITERIA: We included randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias, and extracted the data. MAIN RESULTS: We included three trials involving 6343 participants. As the trials differed in the methods of measurement of carotid stenosis and in the definition of stroke, we did a pooled analysis of individual patient data on 6092 participants (35,000 patient years of follow-up), after reassessing the carotid angiograms and outcomes from all three trials using the primary electronic data files, and redefined outcome events where necessary, to achieve comparability.On re-analysis, there were no significant differences between the trials in the risks of any of the main outcomes in either of the treatment groups, or in the effects of surgery. Surgery increased the five-year risk of ipsilateral ischaemic stroke in participants with less than 30% stenosis (N = 1746, risk ratio (RR) 1.27, 95% confidence interval (CI) 0.80 to 2.01), had no significant effect in participants with 30% to 49% stenosis (N = 1429, RR 0.93, 95%CI 0.62 to 1.38), was of benefit in participants with 50% to 69% stenosis (N = 1549, RR 0.84, 95%CI 0.60 to 1.18), and was highly beneficial in participants with 70% to 99% stenosis without near-occlusion (N = 1095, RR 0.47, 95%CI 0.25 to 0.88). However, there was no evidence of benefit (N = 271, RR 1.03, 95%CI 0.57 to 1.84) in participants with near-occlusions. Ipsilateral ischaemic stroke describes insufficient blood flow to the cerebral hemisphere, secondary to same side severe stenosis of the internal carotid artery. AUTHORS' CONCLUSIONS: Endarterectomy was of some benefit for participants with 50% to 69% symptomatic stenosis (moderate-quality evidence), and highly beneficial for those with 70% to 99% stenosis without near-occlusion (moderate quality evidence). We found no benefit in people with carotid near-occlusion (high-quality evidence). PMID- 28590506 TI - Subcutaneous emphysema related to air-powder tooth polishing: a report of three cases. AB - Subcutaneous emphysema is a rare complication of dental procedures and can occasionally give rise to potentially life-threatening complications. We describe three cases of subcutaneous emphysema diagnosed in the same dental clinic. All cases occurred during tooth or implant cleaning using air polishing (KavoProphyflex(r) ) with a sodium bicarbonate powder (Air-N-Go Classic(r) ). The diagnosis was based on clinical findings and was confirmed radiologically. The cervical and facial regions were affected in all three cases, and spread to the mediastinum occurred in one case. All the episodes resolved within 3-5 days. Tooth cleaning using air polishing combined with an abrasive powder is a risk factor for subcutaneous emphysema, especially when the powder and device are from different manufacturers. Radiological assessment must be performed to rule out involvement of deep tissue planes. PMID- 28590507 TI - Roles of partitioning-defective protein 6 (Par6) and its complexes in the proliferation, migration and invasion of cancer cells. AB - A pivotal regulator of cell polarity and homeostasis, partitioning-defective protein 6 (Par6) forms multicomponent complexes that not only regulate cell polarity and stabilize cell morphology, but have also been demonstrated to participate in the proliferation, migration and invasion of cancer cells. The transforming growth factor (TGF)-beta and extracellular signal-regulated kinase (Erk) 1/2 pathways are the most thoroughly studied pathways involving Par6 in many cancers. Aurothiomalate has been used to disrupt the interaction between Par6 and atypical protein kinase C within the multicomponent complexes, and has been shown to effectively block transformed growth and metastasis in vitro and/or in vivo in a variety of cancers, including pancreatic, prostate and lung cancers, as well as alveolar rhabdomyosarcoma. It is likely that with further revelations regarding the critical roles of Par6 in cancer initiation, progression and metastasis, targeted therapies against Par6 will be discovered and prove effective preclinically, and hopefully clinically, in cancer treatment. PMID- 28590509 TI - MRI measures of brainstem in Parkinsonian syndromes: Where we stand and where we need to go. PMID- 28590508 TI - Pyramidal tract activation due to subthalamic deep brain stimulation in Parkinson's disease. AB - BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is an effective treatment for Parkinson's disease (PD), but can have side effects caused by stimulus spread to structures outside the target volume such as the pyramidal tract. OBJECTIVES: To assess the relevance of pyramidal tract activation with STN DBS in PD. METHODS: In a multimodal, blinded study in 20 STN-DBS patients, we measured stimulation thresholds for evoking electromyographic activity in orbicularis oris and first dorsal interosseous muscles at each of 150 electrode sites. We also modeled the electric field spread and calculated its overlap with the estimated anatomical location of corticospinal and corticobulbar tracts from primary motor cortex using 3 Tesla MRI probabilistic tractography. RESULTS: Mean resting motor thresholds were significantly lower for the contralateral orbicularis oris (3.5 +/- 1.0 mA) compared with ipsilaterally (4.1 +/- 1.1 mA) and with the contralateral first dorsal interosseous (4.0 +/- 1.2 mA). The modeled volumes of corticobulbar and corticospinal tract activated correlated inversely with the resting motor threshold of the contralateral orbicularis oris and first dorsal interosseous, respectively. Active motor thresholds were significantly lower compared with resting motor thresholds by around 30% to 35% and correlated with the clinically used stimulation amplitude. Backward multiple regression in 12 individuals with a "lateral-type" speech showed that stimulation amplitude, levodopa equivalent dose reduction postsurgery, preoperative speech intelligibility, and first dorsal interosseous resting motor thresholds explained 79.9% of the variance in postoperative speech intelligibility. CONCLUSIONS: Direct pyramidal tract activation can occur at stimulation thresholds that are within the range used in clinical routine. This spread of current compromises increase in stimulation strengths and is related to the development of side effects such as speech disturbances with chronic stimulation. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28590510 TI - 3D Printing by Multiphase Silicone/Water Capillary Inks. AB - 3D printing of polymers is accomplished easily with thermoplastics as the extruded hot melt solidifies rapidly during the printing process. Printing with liquid polymer precursors is more challenging due to their longer curing times. One curable liquid polymer of specific interest is polydimethylsiloxane (PDMS). This study demonstrates a new efficient technique for 3D printing with PDMS by using a capillary suspension ink containing PDMS in the form of both precured microbeads and uncured liquid precursor, dispersed in water as continuous medium. The PDMS microbeads are held together in thixotropic granular paste by capillary attraction induced by the liquid precursor. These capillary suspensions possess high storage moduli and yield stresses that are needed for direct ink writing. They could be 3D printed and cured both in air and under water. The resulting PDMS structures are remarkably elastic, flexible, and extensible. As the ink is made of porous, biocompatible silicone that can be printed directly inside aqueous medium, it can be used in 3D printed biomedical products, or in applications such as direct printing of bioscaffolds on live tissue. This study demonstrates a number of examples using the high softness, elasticity, and resilience of these 3D printed structures. PMID- 28590511 TI - Variation in Maternal Co-morbidities and Obstetric Interventions across Area Level Socio-economic Status: A Cross-Sectional Study. AB - BACKGROUND: Multiple studies indicate a significant association between area level socio-economic status (SES) and adverse maternal health outcomes; however, the impact of area-level SES on maternal co-morbidities and obstetric interventions has not been examined. OBJECTIVE: To examine the variation in maternal co-morbidities and obstetric interventions across area-level SES. METHODS: This study used data from the Discharge Abstract Database that comprised birth data in Alberta between 2005-2007 (n = 120 285). Co-morbidities and obstetric interventions were identified using validated case-definitions. Material deprivation index was obtained for each dissemination area through linkage of hospitalisation and census data. Multilevel logistic regression was used to analyse the data adjusting for potential confounding variables. RESULTS: The prevalence of any co-morbidity varied across area-level SES. Drug abuse odds ratio (OR) 2.5 (95% confidence interval (CI) 1.8, 3.5), pre-existing diabetes OR 1.7 (95% CI 1.1, 2.6), and prolonged hospital stay OR 1.5 (95% CI 1.4, 1.6) were significantly more likely to occur in the most deprived areas compared to the least deprived areas. In contrast, caesarean delivery OR 0.9 (95% CI 0.8, 0.9) was less likely to occur in the most deprived areas compared to the least deprived areas. Area-level deprivation explained area-level variance of drug abuse, HIV, and other mental diseases only. CONCLUSION: Many co-morbidities and obstetric interventions vary at the area-level, but only some are associated with area-level SES, and few of them vary due to the area-level SES. This indicates that other area-level factors, in addition to area-level SES, need to be considered when investigating maternal health and use of health interventions. PMID- 28590512 TI - Tissue-specific turnover and diet-tissue discrimination factors of carbon and nitrogen isotopes of a common forage fish held at two temperatures. AB - RATIONALE: The application of stable isotopes to foraging ecology is dependent on understanding life-history and environmental factors unrelated to diet that may influence isotopic composition. Diet-tissue discrimination factors (DTDFs) and turnover rates will increase the accuracy of isotope-based studies. Furthermore, little consideration has been given to the effects of temperature or life-history stage on isotopic ratios despite the prevalence of variation in temperature and growth rates throughout life. METHODS: We measured delta13 C and delta15 N values with an elemental analyzer coupled to a continuous flow isotope ratio mass spectrometer. These values were used to estimate turnover and DTDFs for Emerald Shiners (Notropis atherinoides), a common North American freshwater forage fish. Fish were assigned to a temperature treatment, either 10 degrees C (Low) or 20 degrees C (High), and provided one of three diets (commercial pellet, Artemia salina, or Hemimysis anomala). At regular intervals fish were sampled and the isotopic compositions of whole body and liver tissues were determined. RESULTS: Tissue turnover rates for fish fed Artemia were faster for liver than for whole body, but were also influenced by temperature. Turnover occurred faster at higher temperatures for body and liver delta15 N values, but not for delta13 C values. The pellet and Hemimysis treatments were in isotopic equilibrium from the start of the experiment and estimated DTDFs based on these treatments were lower than assumed for Delta15 N (+0.6 to 2.70/00) and variable, but within expected ranges for Delta13 C (-1.9 to +1.50/00). CONCLUSIONS: The results for Emerald Shiners differed from commonly made assumptions for applying stable isotopes to ecological questions, possibly related to a bias in the use of juveniles in studies of turnover and DTDFs and assumptions regarding thermal-independence of isotopic relationships. The species-specific DTDF and tissue turnover estimates provided here will inform interpretations of stable isotope data for smaller fish species and improve food-web studies. PMID- 28590513 TI - Diagnostic accuracy of increased urinary cortisol/cortisone ratio to differentiate ACTH-dependent Cushing's syndrome. AB - BACKGROUND AND AIM: Differential diagnosis between Cushing's Disease (CD) and Ectopic ACTH Syndrome (EAS) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol (UFF) and cortisone (UFE). We have recently observed that cortisol to cortisone ratio (FEr) was higher in a small series of EAS; in this study we collected a larger number of ACTH-dependent Cushing's Syndrome (CS) to study the role of FEr to characterize the source of corticotropin secretion. MATERIALS AND METHODS: High-pressure liquid chromatography with UV detection (HPLC-UV, n=35) or liquid chromatography-tandem mass spectrometry (LC-MS/MS, n=72) were used to measure UFF, UFE and FEr in 83 patients with CD and 24 with EAS. RESULTS: UFF, UFE and FEr levels were higher in EAS than in CD (UFF: 6671 vs 549 nmol/24 hours; UFE: 2069 vs 464 nmol/24 hours; FEr: 4.13 vs 0.97; all P<.001). FEr >1.15 (the best ROC-based threshold) was able to distinguish CD from EAS with 75% sensitivity (SE) and 75% specificity (SP), AUC 0.811; results were similar between HPLC-UV (SE 73%, SP 79%, AUC 0.708) and LC-MS/MS (SE 77%, SP 73%, AUC 0.834; P=.727). The diagnostic accuracy of FEr was similar to that of CRH test or high-dose dexamethasone suppression test (respectively P=.171 and P=.683), also combined. Finally, FEr was able to increase the number of correct diagnosis in patients with discordant dynamic tests. CONCLUSIONS: Urinary FEr >1.15 was able to suggest EAS, with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH-dependent CS. PMID- 28590515 TI - Tailor-made Molecular Cobalt Catalyst System for the Selective Transformation of Carbon Dioxide to Dialkoxymethane Ethers. AB - Herein a non-precious transition-metal catalyst system for the selective synthesis of dialkoxymethane ethers from carbon dioxide and molecular hydrogen is presented. The development of a tailored catalyst system based on cobalt salts in combination with selected Triphos ligands and acidic co-catalysts enabled a synthetic pathway, avoiding the oxidation of methanol to attain the formaldehyde level of the central CH2 unit. This unprecedented productivity based on the molecular cobalt catalyst is the first example of a non-precious transition-metal system for this transformation utilizing renewable carbon dioxide sources. PMID- 28590514 TI - Altered white matter microarchitecture in the cingulum bundle in women with primary dysmenorrhea: A tract-based analysis study. AB - Primary dysmenorrhea (PD), as characterized by painful menstrual cramps without organic causes, is associated with central sensitization and brain function changes. Previous studies showed the integrated role of the default mode network (DMN) in the pain connectome and its key contribution on how an individual perceives and copes with pain disorders. Here, we aimed to investigate whether the cingulum bundle connecting hub regions of the DMN was disrupted in young women with PD. Diffusion tensor imaging was obtained in 41 PD patients and 41 matched healthy controls (HC) during their periovulatory phase. The production of prostaglandins (PGs) was obtained in PD patients during their pain-free and pain phases. As compared with HC, PD patients had similar scores of pain intensity, anxiety, and depression in their pain-free phase. However, altered white matter properties mainly located in the posterior section of the cingulum bundle were observed in PD. Besides PGs being related to menstrual pain, a close relationship was found between the white matter properties of the cingulum bundle during the pain-free phase and the severity of the menstrual pain in PD patients. Our study suggested that PD had trait changes of white matter integrities in the cingulum bundle that persisted beyond the time of menstruation. We inferred that altered anatomical connections may lead to less-flexible communication within the DMN, and/or between the DMN and other pain-related brain networks, which may result in the central susceptibility to develop chronic pain conditions in PD's later life. Hum Brain Mapp 38:4430-4443, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28590516 TI - 1,3-Bis(aryloxy)propan-2-ols as potential antileishmanial agents. AB - We describe herein the synthesis and antileishmanial activity of 1,3 bis(aryloxy)propan-2-ols. Five compounds (2, 3, 13, 17, and 18) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC50 < 15.0 MUm), and an influence of compound lipophilicity on activity was suggested. Most of the compounds were poorly selective, as they showed toxicity toward murine macrophages, except 17 and 18, which presented good selective indexes (SI >= 10.0). The five more active compounds (2, 3, 13, 17, and 18) were selected for the treatment of infected macrophages, and all of them were able to reduce the number of internalized parasites by more than 80%, as well as the number of infected macrophages by more than 70% in at least one of the tested concentrations. Altogether, these results demonstrate the potential of these compounds as new hits of antileishmanial agents and open future possibilities for them to be tested in in vivo studies. PMID- 28590517 TI - Flower specialisation: the occluded corolla of snapdragons (Antirrhinum) exhibits two pollinator niches of large long-tongued bees. AB - Flower specialisation of angiosperms includes the occluded corollas of snapdragons (Antirrhinum and some relatives), which have been postulated to be one of the most efficient structures to physical limit access to pollinators. The Iberian Peninsula harbours the highest number of species (18 Iberian of the 20 species of Antirrhinum) that potentially share similar pollinator fauna. Crossing experiments with 18 Iberian species from this study and literature revealed a general pattern of self-incompatibility (SI) - failure in this SI system has been also observed in a few plants - which indicates the need for pollinator agents in Antirrhinum pollination. Field surveys in natural conditions (304 h) found flower visitation (>85%) almost exclusively by 11 species of bee (Anthophora fulvitarsis, Anthophora plumipes, Anthidium sticticum, Apis mellifera, Bombus hortorum, Bombus pascuorum, Bombus ruderatus, Bombus terrestris, Chalicodoma lefebvrei, Chalicodoma pyrenaica and Xylocopa violacea). This result covering the majority of Antirrhinum species suggests that large bees of the two long-tongued bee families (Megachilidae, Apidae) are the major pollinators of Antirrhinum. A bipartite modularity analysis revealed two pollinator systems of long-tongued bees: (i) the long-studied system of bumblebees (Bombus spp.) associated with nine primarily northern species of Antirrhinum; and (ii) a newly proposed pollinator system involving other large bees associated with seven species primarily distributed in southern Mediterranean areas. PMID- 28590518 TI - Barbier Continuous Flow Preparation and Reactions of Carbamoyllithiums for Nucleophilic Amidation. AB - An ambient temperature continuous flow method for nucleophilic amidation and thioamidation is described. Deprotonation of formamides by lithium diisopropylamine (LDA) affords carbamoyllithium intermediates that are quenched in situ with various electrophiles such as ketones, allyl bromides, Weinreb and morpholino amides. The nature of the reactive lithium intermediates and the thermodynamics of the metalation were further investigated by ab initio calculations and kinetic experiments. PMID- 28590520 TI - Developing multicenter consortia in liver disease in Latin America: Challenges and opportunities. AB - The development of consortia has been useful for exploring challenging scenarios and uncharted territories in liver disease treatments. Several consortia already developed in the United States and Europe have become key factors in patient care decision-making processes and medical education, and they have also impacted policy makers' decisions. In Latin America, the situation is different. As a result of a combination of different factors, our region has not been able to develop networking advantages in research and education in liver diseases. Thus far, most of the initial experiences focused on the development of collaborative groups established to investigate a particular topic, which were dissolved once the questions were answered. It is the aim of this review to describe those difficulties we confront in developing multicenter liver consortia in Latin America, to identify those challenges we face, and also to describe the opportunities we have for improvement. Liver Transplantation 23 1210-1215 2017 AASLD. PMID- 28590519 TI - Probiotic Bifidobacterium bifidum G9-1 attenuates 5-fluorouracil-induced intestinal mucositis in mice via suppression of dysbiosis-related secondary inflammatory responses. AB - Bifidobacterium, a major component of the intestinal microbiota, has been clinically used for the treatment of diarrhoea and constipation. 5-Fluorouracil (5-FU), widely used for cancer chemotherapy, is known to frequently induce intestinal mucositis accompanied by severe diarrhoea. The present study examined the effect of Bifidobacterium bifidum G9-1 (BBG9-1) on 5-FU-induced intestinal mucositis in mice. Intestinal mucositis was induced by repeated administration of 5-FU for 6 days. BBG9-1 was administered orally once daily for 9 days, beginning 3 days before the onset of 5-FU treatment. Repeated administration of 5-FU caused severe intestinal mucositis, characterised by shortening of villi and destruction of crypts, accompanied by increases in intestinal myeloperoxidase activity and inflammatory cytokine expression, body weight loss, and diarrhoea on day 6. Daily administration of BBG9-1 significantly reduced the severity of intestinal mucositis and inflammatory responses and tended to attenuate clinical symptoms. In contrast, BBG9-1 failed to prevent apoptosis induction on day 1 after the first 5-FU administration. The structure of the intestinal microbiota, as analysed by weighted UniFrac distance, was largely altered by 5-FU treatment, but this change was mitigated by daily administration of BBG9-1. Moreover, 5-FU treatment decreased the abundance of Firmicutes and increased the abundance of Bacteroidetes, but these responses were also significantly inhibited by daily administration of BBG9-1. These results suggest that BBG9-1 has an ameliorative effect against 5-FU-induced intestinal mucositis through the attenuation of inflammatory responses via improve dysbiosis. BBG9-1 could be useful for the prevention of intestinal mucositis during cancer chemotherapy. PMID- 28590521 TI - Seventy years of pallidotomy for movement disorders. AB - The year 2017 marks the 70th anniversary of the birth of human stereotactic neurosurgery. The first procedure was a pallidotomy for Huntington's disease. However, it was for Parkinson's disease that pallidotomy was soon adopted worldwide. Pallidotomy was abandoned in the late 1950s in favor of thalamotomy because of the latter's more striking effect on tremor. The advent of levodopa put a halt to all surgery for PD. In the mid-1980s, Laitinen reintroduced the posteroventral pallidotomy of Leksell, and this procedure spread worldwide thanks to its efficacy on most parkinsonian symptoms including levodopa-induced dyskinesias and thanks to basic scientific work confirming the role of the globus pallidus internus in the pathophysiology of PD. With the advent of deep brain stimulation of the subthalamic nucleus, pallidotomy was again abandoned, and even DBS of the GPi has been overshadowed by STN DBS. The GPi reemerged in the late 1990s as a major stereotactic target for DBS in dystonia and, recently, in Tourette syndrome. Lately, lesioning of the GPI is being proposed to treat refractory status dystonicus or to treat DBS withdrawal syndrome in PD patients. Hence, the pallidum as a stereotactic target for either lesioning or DBS has been the phoenix of functional stereotactic neurosurgery, constantly abandoned and then rising again from its ashes. This review is a tribute to the pallidum on its 70th anniversary as a surgical target for movement disorders, analyzing its ebbs and flows and highlighting its merits, its versatility, and its resilience. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28590522 TI - Adolescents' smokeless tobacco susceptibility by perceived professional baseball players' use. AB - OBJECTIVE: Measure associations between adolescent baseball players' perceptions of smokeless tobacco (ST) use by professional baseball players and those adolescents' actual ST use and susceptibility. METHODS: Male baseball players (N = 360) at 25 rural California high schools completed tobacco behavior surveys and reported how likely they believed it was their favorite major league baseball player used ST. We compared ST use and, among ST never-users, willingness and expectations to use ST, according to perceived favorite player's use. RESULTS: Adolescents responding that their favorite player definitely or probably used ST were significantly more likely to use ST themselves. High school ST never-users who perceived that their favorite player definitely used ST were 2.5 to 3-times more likely to be susceptible to ST initiation than participants responding that their favorite player definitely did not use ST. CONCLUSIONS: Adolescents' ST behaviors and intentions were correlated with their perceptions of professional baseball players' ST use. PMID- 28590524 TI - Work-related carpal tunnel syndrome: What's important? PMID- 28590523 TI - Hepatic artery reconstruction in living donor liver transplantation using surgical loupes: Achieving low rate of hepatic arterial thrombosis in 741 consecutive recipients-tips and tricks to overcome the poor hepatic arterial flow. PMID- 28590526 TI - Gas-phase fragmentation of 1-adamantylbisimidazolium salts and their complexes with cucurbit[7]uril studied using selectively 2 H-labeled guest molecules. AB - RATIONALE: Bisimidazolium salts (BIMs) represent an interesting family of ditopic ligands that are used in the construction of supramolecular systems with hosts based on cyclodextrins or cucurbit[n]urils. Understanding the fragmentation mechanism of individual BIMs and how this mechanism changes after complexation with cucurbit[n]urils can bring new insight into the intrinsic host-guest relationship, thereby allowing utilization of mass spectrometry to describe binding behavior. METHODS: Selectively 2 H-labeled bisimidazolium salts were prepared and fully characterized by spectroscopic methods. All MSn experiments were conducted in the positive-ion mode using an electrospray ionization (ESI) ion-trap mass spectrometer. The structures of the proposed fragments were supported by theoretical optimizations performed at the B3LYP/6-31G(d) level of density functional theory (DFT) using the Spartan'14 program. RESULTS: Using selectively deuterium-labeled isotopologues of two adamantylated bisimidazolium salts and DFT calculations, we describe the fragmentation pathways of bisimidazolium salts. The release of two important adamantane moieties, [C11 H17 ]+ and C11 H16 , from M2+ was determined, although the former was strongly preferred. In contrast, when M2+ was complexed with CB7, the neutral loss of the C11 H16 fragment was favored. The fragmentation pattern strongly depended on the steric hindrance of the M2+ guest against slippage of the CB7 unit over the guest molecular axle. CONCLUSIONS: The structures of two adamantane-based fragments and the mechanisms of their formation were rationalized. Two distinct geometric arrangements for the adamantane cage inside the CB7 cavity were hypothesized to explain the differences in the fragmentation patterns for guests with minimal, moderate, and high steric hindrance. This finding brings new insight into the understanding of intrinsic behavior of the adamantane-based guests inside the CB7 cavity. PMID- 28590525 TI - Effects of repeated abobotulinumtoxinA injections in upper limb spasticity. AB - INTRODUCTION: The efficacy of single injections of abobotulinumtoxinA (Dysport) is established in adults with upper limb spasticity. In this study we assessed the effects of repeated injections of abobotulinumtoxinA over 1 year. METHODS: Patients (n = 258, safety population) received 500 U, 1,000 U, or 1,500 U (1,500 U dose included 500-U shoulder injections) for up to 4 or 5 treatment cycles. Assessments included treatment-emergent adverse events (TEAEs), muscle tone, passive and active range of motion (XV1, XA ), angle of catch (XV3 ), Disability Assessment Scale (DAS) score, Modified Frenchay Scale (MFS) score, and Physician Global Assessment (PGA) score. RESULTS: The incidence of TEAEs decreased across cycles. Muscle tone reduction and XV1 remained stable across cycles, whereas XV3 and XA continued to improve at the finger, wrist, and elbow flexors. DAS and PGA improved across cycles. MFS improved best with 1,500 U. DISCUSSION: A favorable safety profile and continuous improvements in active movements and perceived and active function were associated with repeated abobotulinumtoxinA injections in upper limb muscles. Muscle Nerve 57: 245-254, 2018. PMID- 28590527 TI - Phase-Transformation Ductilization of Brittle High-Entropy Alloys via Metastability Engineering. AB - High-entropy alloys (HEAs) in which interesting physical, chemical, and structural properties are being continuously revealed have recently attracted extensive attention. Body-centered cubic (bcc) HEAs, particularly those based on refractory elements are promising for high-temperature application but generally fail by early cracking with limited plasticity at room temperature, which limits their malleability and widespread uses. Here, the "metastability-engineering" strategy is exploited in brittle bcc HEAs via tailoring the stability of the constituent phases, and transformation-induced ductility and work-hardening capability are successfully achieved. This not only sheds new insights on the development of HEAs with excellent combination of strength and ductility, but also has great implications on overcoming the long-standing strength-ductility tradeoff of metallic materials in general. PMID- 28590529 TI - Twinning causative origin investigated by Sartwell's biometrical method. AB - Sartwell's biometrical model is useful to test potential causal factors at the origin of biological phenomena of unknown etiology. It postulates a lognormal distribution of the incubation time. The method has been applied in the past to infectious and neoplastic diseases and, only lately, to genetic diseases. We report here an application to unlike-sex and like-sex twins in an attempt to infer causal origin from a family of potentially related factors. Two hypotheses are tested: the maternal prenatal origin of unlike-sex twins, and the menopausal basis of like-sex twins. The hypotheses are respectively grounded in the presumed genetic origin of DZ twinning, and in the ovarian-dysfunction origin of MZ twinning. The study is population-based; it proceeds from a matched control group and considers various time windows (induction periods) of possible etiologic significance-namely, age at onset of twins, the time window from the first birth to the twin birth, and the time window from the twin birth to the last birth. The study of lognormality has been carried out with the Box-Cox transformations, Fisher's cumulants method, and the normal probability plots. Results show clearly that unlike-sex (presumably DZ) twins have their causal origin in the maternal prenatal period as age of onset is definitely lognormal. Median induction time is 31 +/- 6 years. This is interpreted as a multiplicative age-related causal process involving hypophyseal hormones. The menopausal origin of like-sex twins, a mixture of MZ and DZ, is less clear-cut, as the fit of the distribution of the time window until last birth to a lognormal model is less than perfect. In spite of the heterogeneity of the like-sex twin group, there is evidence that some cases of MZ twins may be menopause-related. But this complex question needs more study. PMID- 28590530 TI - Stress, migration, and blood pressure in Kiribati. AB - Investigation into the relationship between essential hypertension and migration and modernization typically conclude that modernized, urban migrants have more elevated blood pressures with age and are more at risk from hypertension than are their traditional rural sedentary compatriots. These differences are often attributed to greater stresses on the migrating or modernizing segment of the population. In contrast, this study of rural sedentes and urban migrants in Kiribati (Gilbert Islands) indicates that hypertension and elevation of pressure with age have appeared in this modernizing population which was free of essential hypertension less than twenty years previously. Yet there are no significant differences in blood pressure or the incidence of hypertension of migrants and sedentes. This similarity of rural and urban islanders' health status is traced to the stress-relieving nature of migration and the urban experience in Kiribati. PMID- 28590531 TI - Human biology council: Poster abstracts. PMID- 28590532 TI - Pubertal growth spurt in the female rhesus monkey: Relation to menarche and skeletal maturation. AB - Three-monthly measurements of tibia length, crown-rump length (CRL), and body wieght have been made on nine indoor-housed and six outdoor-housed female rhesus monkeys (Macaca mulatta) from ages 17 to 41 months. In the indoor-housed there were clear pubertal growth spurts, identifiable in individual curves, with average peaks at 22.5 months for tibia length, 23.5 months for CRL, and 24.5 for weight. Menarche occurred on average at 26.0 months. In both skeletal dimensions the amount of acceleration exceeded that which occurs in man. The relative timing of the spurts and of menarche was similar to that in man. The outdoor-housed monkeys showed a similar spurt in tibia length, although a less easily identifiable one in crown-rump length. The peak velocity of tibia length in these monkeys occurred on average at 30.5 months, with menarche at 32.5 months. We conclude that the pubertal growth spurt in female rhesus is very little different from that in man. PMID- 28590533 TI - Effects of maternal drinking, smoking, size, and parity on parent-offspring birth weight correlations. AB - Parent-offspring birth weight correlations are presented by sex of parent and infant. They range from .14 to .16, except for the mother-daughter correlation, which is .32. This pattern of parent-offspring correlations varies when the parity of the infant, the size of the mother, and the mother's drinking and smoking status are considered. All parent-offspring correlations are higher when the infant is parity 2 or more. The mother-daughter correlations are significantly higher than mother-son correlations when the mother is above average in usual weight, height, or pregnancy weight gain. When the mother smoked before conception, all birth weight correlations except mother-daughter are essentially zero. The mother-son correlation is also very small if the mother was a regular drinker, independent of her smoking status. The complex relationships in this sample demonstrate that interactions with environmental variables must be taken into account in studies of familial aggregation of human birth weight. PMID- 28590535 TI - Program. PMID- 28590534 TI - New approach for estimating excess body fat from changes in abdominal girth. AB - A new method is proposed for determining changes in percent body fat (%BF) based on the difference between an initial value for abdominal girth (AG) and a calculated "target" AG based on a desired %BF. Group data from large-scale anthropometric surveys in the military were used to derive specific reference values for Q, defined as the ratio of AG at a desired %BF to F(?BMkg /Htm ). For an individual, Q*F resulted in an AG that corresponded to a desired %BF (set at approximately 20% for males and 30% for females). The method was applied to professional football players, longshoremen, shot-put and weight-lifting athletes, and obese males and females who reduced body mass and altered their body composition. The results showed that changes in AG with body mass loss were proportional to percentage changes in total body fat loss. These relationships permitted extrapolation to a projected target AG that corresponded to a desired %BF. The proposed method differs from the traditional approach that first determines %BF, and then the individual attempts to achieve a desired change in body mass or body composition. The objective of the new method is straightforward; the individual endeavors to attain a target AG that corresponds to a desired %BF. PMID- 28590536 TI - Dispersal, effective population size, and the genetic structure of the contemporary United States. AB - I estimate effective population size (Ne ) and the inbreeding coefficient (FST ) for contemporary United States using Wright's isolation by distance model (Wright: Genetics 28:114-138, 1943) and parent-offspring dispersal distances obtained from individuals surveyed as part of a study of modern dispersal patterns. Ne is estimated to be minimally 3.61 * 107 and more likely closer to 8.05 * 107 ; based on these values, FST is between 1.59 * 10-7 and 9.28 * 10-9 , depending on whether it is measured relative to the United States population or the world at large. Not all the assumptions of the isolation by distance model are met by modern populations, and thus the results must be interpreted with caution. They suggest, however, that both mobility within and immigration into contemporary United States are great enough to make the probability of inbreeding and random genetic drift negligible factors in producing future evolutionary change. In contrast, gene flow, acting as both a constraint against geographic differentiation within the United States and by introducing new genes via international immigration, is likely to be a dominant evolutionary force in this population. PMID- 28590537 TI - Body circumferences as measures of body fat distribution in 10-14-year-old schoolchildren. AB - In this paper the hypothesis is tested that circumferences are as useful as skinfolds in children aged 10-14 years to detect variation in regional fat distribution. This would be confirmed by the appearance of a significant canonical correlation between a vector of appropriately selected circumferences and an analogous vector of skinfolds, producing a weighted pattern suggestive of centralized obesity (that is a series of mathematical weights of different signs for central versus peripheral regions of the body). The hypothesis is confirmed (P < 0.01) in this sample of 378 children of both sexes. The association occurs in the second canonical correlation after a strong first canonical correlation providing information about fatness level (0.83-0.87). The canonical correlations are low (0.29 in boys, 0.36 in girls), lower than has previously been reported in a similar study of adults. The circumferences most heavily weighted in opposite directions are the waist and thigh. These results are in accord with adult studies. This study did not support the use of the waist-hip circumference combination, the measures currently used in most epidemiologic studies of body fat distribution. PMID- 28590538 TI - Council officers and committees. PMID- 28590539 TI - Nutritional status and morbidity on an irrigation project in Turkana District, Kenya. AB - The research reported on here was undertaken to identify the most important contributors to continuing high mortality on a small-scale irrigation project at Nakwamoru in Turkana District, Kenya. The health status of project settlers had not been assessed prior to the present study, which was undertaken in 1978-79, a decade after the project was started. The purpose of the study was to estimate the nutritional status of project children and the major causes of morbidity in the Nakwamoru area. Nutritional status was derived from cross-sectional anthropometric measurements, including weights, heights, triceps skinfolds, and upper arm circumferences, taken on approximately 60% of project children (n = 236) aged 1-10 years. The major causes of morbidity in project settlers of all ages for the period 1973-78 were estimated from outpatient records from the local primary care facility. Age/sex patterns of clinic use were obtained through interviews. Stunting was found to be prevalent, especially in children aged 1-4, while wasting was only observed in a small proportion of the sample, indicating a seasonal pattern of malnutrition. Derived cross-sectional areas of upper arm muscle and fat were found to be low by comparison with U.S. standards, suggesting both energy and protein deficits in project children. Malaria and acute respiratory infections were found to be the major causes of illness in the local population, and both are likely to have contributed to the generally poor nutritional status of project children. Despite free biomedical care, 15% of the local population in general and 23% of adult females had never used clinic services. PMID- 28590541 TI - A Conceptual Model and Clinical Framework for Integrating Mindfulness into Family Therapy with Adolescents. AB - Individual and group-based psychotherapeutic interventions increasingly incorporate mindfulness-based principles and practices. These practices include a versatile set of skills such as labeling and attending to present-moment experiences, acting with awareness, and avoiding automatic reactivity. A primary motivation for integrating mindfulness into these therapies is compelling evidence that it enhances emotion regulation. Research also demonstrates that family relationships have a profound influence on emotion regulation capacities, which are central to family functioning and prosocial behavior more broadly. Despite this evidence, no framework exists to describe how mindfulness might integrate into family therapy. This paper describes the benefits of mindfulness based interventions, highlighting how and why informal mindfulness practices might enhance emotion regulation when integrated with family therapy. We provide a clinical framework for integrating mindfulness into family therapy, particularly as it applies to families with adolescents. A brief case example details sample methods showing how incorporating mindfulness practices into family therapy may enhance treatment outcomes. A range of assessment modalities from biological to behavioral demonstrates the breadth with which the benefits of a family-based mindfulness intervention might be evaluated. PMID- 28590542 TI - The donor risk index: A decade of experience. AB - In 2006, derivation of the donor risk index (DRI) highlighted the importance of donor factors for successful liver transplantation. Over the last decade, the DRI has served as a useful metric of donor quality and has enhanced our understanding of donor factors and their impact upon recipients with hepatitis C virus, those with low Model for End-Stage Liver Disease (MELD) score, and individuals undergoing retransplantation. DRI has provided the transplant community with a common language for describing donor organ characteristics and has served as the foundation for several tools for organ risk assessment. It is a useful tool in assessing the interactions of donor factors with recipient factors and their impact on posttransplant outcomes. However, limitations of statistical modeling, choice of donor factors, exclusion of unaccounted donor and geographic factors, and the changing face of the liver transplant recipient have tempered its widespread use. In addition, the DRI was derived from data before the MELD era but is currently being applied to expand the donor pool while concurrently meeting the demands of a dynamic allocation system. A decade after its introduction, DRI remains relevant but may benefit from being updated to provide guidance in the use of extended criteria donors by accounting for the impact of geography and unmeasured donor characteristics. DRI could be better adapted for recipients with nonalcoholic fatty liver disease by examining and including recipient factors unique to this population. Liver Transplantation 23 1216-1225 2017 AASLD. PMID- 28590543 TI - Association of the -449GC and -1151AC polymorphisms in the DDAH2 gene with asymmetric dimethylarginine and erythropoietin resistance in Chinese patients on maintenance hemodialysis. AB - We investigated the association of the -449G/C and -1151A/C polymorphisms in the DDAH2 gene with plasma asymmetric dimethylarginine (ADMA) concentration and erythropoietin resistance in 131 Chinese patients on maintenance hemodialysis (MHD). The -449G allele was in complete linkage disequilibrium with the -1151A allele and so were their corresponding C alleles. The -449GG/-1151AA genotype had the highest plasma ADMA concentration, erythropoietin resistance index (EPI) and serum malondialdehyde level, compared to either the -449GC/-1151AC or -449CC/ 1151CC variation. The genetic effect on the ADMA and EPI was separately confirmed by multivariate regression analysis. Our findings suggested that complex genetic variations in the DDAH2 gene may influence the ADMA concentration and erythropoietin resistance in MHD patients, in which altered oxidative stress was likely involved. PMID- 28590540 TI - Bicyclic Peptides as Next-Generation Therapeutics. AB - Bicyclic peptides have greater conformational rigidity and metabolic stability than linear and monocyclic peptides and are capable of binding to challenging drug targets with antibody-like affinity and specificity. Powerful combinatorial library technologies have recently been developed to rapidly synthesize and screen large bicyclic peptide libraries for ligands against enzymes, receptors, and protein-protein interaction targets. Bicyclic peptides have been developed as potential therapeutics against a wide range of diseases, drug targeting agents, imaging/diagnostic probes, and research tools. In this Minireview, we provide a summary of the recent progresses on the synthesis and applications of bicyclic peptides. PMID- 28590544 TI - Optically Triggered Melting of DNA on Individual Semiconducting Carbon Nanotubes. AB - Optical excitation of nanostructures is known to induce local heating, a phenomenon that has been intensely exploited for drug release, gene delivery, cancer thermotherapy, and energy harvesting. However, the effect is typically small requiring collective heating of a large concentration or aggregates of particles. Herein, we show that optical excitation of individual semiconducting single-walled carbon nanotubes triggers strongly localized heating adequate to melt non-covalently attached double-stranded oligonucleotides in solution. In contrast to conventional thermal dehybridization, this optically triggered DNA melting occurs at a solution temperature that is 22 degrees C lower than the DNA melting temperature. This unexpectedly large localized optical heating effect provides important new insights to design selective optical nanoheaters at the single particle level. PMID- 28590545 TI - The utility of a single simple question in the evaluation of patients with myasthenia gravis. AB - INTRODUCTION: Assessing myasthenia gravis (MG) can be challenging, and multiple scales are available to evaluate disease severity. We evaluated the utility of a single, simple question, as part of the MG evaluation: "What percentage of normal do you feel regarding your MG, 0%-100% normal?" METHODS: A retrospective chart review of patients attending the neuromuscular clinic from January 2014 to December 2015 was performed. Responses were correlated with symptoms and signs, the Quantitative Myasthenia Gravis Score (QMGS), the Myasthenia Gravis Impairment Index (MGII), and the 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15). RESULTS: The total cohort included 169 patients. The percentage of normal correlated strongly with limb muscle weakness and MG scales, moderately with bulbar and respiratory symptoms, and weakly with ocular manifestations. DISCUSSION: The question, "What percentage of normal do you feel regarding your MG?" is feasible and valid, and can be incorporated easily into routine clinical evaluation. Muscle Nerve 57: 240-244, 2018. PMID- 28590546 TI - Non a Priori Automatic Discovery of 3D Chemical Patterns: Application to Mutagenicity. AB - This article introduces a new type of structural fragment called a geometrical pattern. Such geometrical patterns are defined as molecular graphs that include a labelling of atoms together with constraints on interatomic distances. The discovery of geometrical patterns in a chemical dataset relies on the induction of multiple decision trees combined in random forests. Each computational step corresponds to a refinement of a preceding set of constraints, extending a previous geometrical pattern. This paper focuses on the mutagenicity of chemicals via the definition of structural alerts in relation with these geometrical patterns. It follows an experimental assessment of the main geometrical patterns to show how they can efficiently originate the definition of a chemical feature related to a chemical function or a chemical property. Geometrical patterns have provided a valuable and innovative approach to bring new pieces of information for discovering and assessing structural characteristics in relation to a particular biological phenotype. PMID- 28590547 TI - Geraniin suppresses ovarian cancer growth through inhibition of NF-kappaB activation and downregulation of Mcl-1 expression. AB - This study investigated the anticancer effects of geraniin on ovarian cancer cells and the signaling pathways involved. Ovarian cancer cells were treated with different concentrations of geraniin for 48 h and examined for viability, apoptosis, mitochondrial membrane depolarization, and gene expression. Xenograft tumor studies were performed to determine the anticancer activity of geraniin in vivo. Geraniin significantly decreased cancer cell viability in a concentration dependent fashion. Geraniin significantly triggered apoptosis, which was accompanied by loss of mitochondrial membrane potential and increased cytochrome c release and caspsase-3 activity. Mechanistically, geraniin significantly downregulated Mcl-1 and impaired NF-kappaB p65 binding to the mcl-1 promoter. Overexpression of Mcl-1 significantly reversed geraniin-induced apoptosis in OVCAR3 cells. In addition, geraniin retarded ovarian cancer growth and reduced expression of phospho-p65 and Mcl-1. Collectively, geraniin elicits growth suppression in ovarian cancer through inhibition of NF-kappaB and Mcl-1 and may provide therapeutic benefits for this malignancy. PMID- 28590548 TI - Living and Conducting: Coating Individual Bacterial Cells with In Situ Formed Polypyrrole. AB - Coating individual bacterial cells with conjugated polymers to endow them with more functionalities is highly desirable. Here, we developed an in situ polymerization method to coat polypyrrole on the surface of individual Shewanella oneidensis MR-1, Escherichia coli, Ochrobacterium anthropic or Streptococcus thermophilus. All of these as-coated cells from different bacterial species displayed enhanced conductivities without affecting viability, suggesting the generality of our coating method. Because of their excellent conductivity, we employed polypyrrole-coated Shewanella oneidensis MR-1 as an anode in microbial fuel cells (MFCs) and found that not only direct contact-based extracellular electron transfer is dramatically enhanced, but also the viability of bacterial cells in MFCs is improved. Our results indicate that coating individual bacteria with conjugated polymers could be a promising strategy to enhance their performance or enrich them with more functionalities. PMID- 28590549 TI - Association between Breast Feeding and Paediatric Sleep Disordered Breathing: a Systematic Review. AB - BACKGROUND: Breast feeding has been suggested as a potential protective factor against childhood snoring and sleep disordered breathing (SDB). SDB can have major health consequences. The objective of this systematic review is to synthesise the available literature concerning any potential association between infant feeding methods and SDB in young children. METHODS: Five electronic databases were searched. All searches were inclusive until August 5, 2016. Two authors independently reviewed potentially relevant articles for eligibility. Any prospective or retrospective study, case-control study, cohort study, clinical trial, and cross-sectional study that evaluated the association between infant feeding methods and SDB were included. Data on study design, aim of study, sample size, study population, assessment tool, infant feeding methods, and outcome measures were extracted. RESULTS: Nine studies fulfilled the criteria to be finally included in this review, only cohorts and cross-sectional studies were identified. While seven of the selected studies reported a statistically significant association between breast feeding and reduced risk of SDB, the remaining two studies did not report any association. The main methodological limitation was high heterogeneity in the diagnostic criteria and assessment tools to identify SDB and limited data collection on infant feeding methods. CONCLUSIONS: The current evidence may point to a protective association, however, as uncertainty is moderate, any suggestion that breast feeding may or may not decrease the risk of SDB is currently unwarranted. More research on the topic is required to resolve some of the contradictions between included studies. PMID- 28590550 TI - OSI-027 modulates acute graft-versus-host disease after liver transplantation in a rat model. AB - Despite its rarity (1%-2%), acute graft-versus-host disease after liver transplantation (LT-aGVHD) has a high mortality rate (85%). A gradual decrease in regulatory T cells (Tregs) correlates with disease progression in a rat LT-GVHD model, and treatments which increase Tregs exert therapeutic effects on LT-aGVHD. In this study, LT-aGVHD model rats were treated with rapamycin (RAPA), OSI-027, or an equal quantity of vehicle. Rats treated with OSI-027 survived longer (>100 days) than those in the RAPA (70 +/- 8 days) or control (24 +/- 3 days) groups. Flow cytometric analysis showed that the Treg ratios in peripheral blood mononuclear cells in the OSI-027 group were higher than those in the RAPA or control groups. The proportions of donor-derived lymphocytes in the OSI-027 group were lower than those in the RAPA or control groups. Hematoxylin-eosin staining of skin tissue demonstrated less severe lymphocyte infiltration in the OSI-027 group than that in the RAPA or control groups. In vitro, OSI-027 induced differentiation of CD4+ CD25- T cells into CD4+ CD25+ forkhead box P3+ Tregs. Furthermore, injection of OSI-027-induced donor-derived CD4+ CD25+ T cells into the peripheral blood of LT-aGVHD model rats prevented LT-aGVHD. Thus, OSI-027 is implicated as a novel method for the treatment of LT-aGVHD. Liver Transplantation 23 1186-1198 2017 AASLD. PMID- 28590552 TI - Direct Functionalization of C-H Bonds by Iron, Nickel, and Cobalt Catalysis. AB - Non-precious-metal-catalyzed reactions are of increasing importance in chemistry due to the outstanding ecological and economic properties of these metals. In the subfield of metal-catalyzed direct C-H functionalization reactions, recent years have shown an increasing number of publications dedicated to this topic. Nickel, cobalt, and last but not least iron, have started to enter a field which was long dominated by precious metals such as palladium, rhodium, ruthenium, and iridium. The present review article summarizes the development of iron-, nickel-, and cobalt-catalyzed C-H functionalization reactions until the end of 2016, and discusses the scope and limitations of these transformations. PMID- 28590551 TI - Ozone-induced dissociation on a traveling wave high-resolution mass spectrometer for determination of double-bond position in lipids. AB - RATIONALE: The position of C=C within fatty acyl chains affects the biological function of lipids. Ozone-induced dissociation mass spectrometry (OzID-MS) has great potential in determination of lipid double-bond position, but has generally been implemented on low-resolution ion trap mass spectrometers. In addition, most of the OzID-MS experiments carried out so far were focused on the sodiated adducts of lipids; fragmentation of the most commonly observed protonated ions generated in LC/MS-based lipidomics workflow has been less explored. METHODS: Ozone generated in line from an ozone generator was connected to the trap and transfer gas supply line of a Synapt G2 high-resolution mass spectrometer. Protonated ions of different phosphatidylcholines (PC) were generated by electrospray ionization through direct infusion. Different parameters, including traveling wave height and velocity, trap entrance and DC potential, were adjusted to maximize the OzID efficiency. sn-positional isomers and cis/trans isomers of lipids were compared for their reactivity with ozone. RESULTS: Traveling wave height and velocity were tuned to prolong the encounter time between lipid ions and ozone, and resulted in improved OzID efficiency, as did increasing trapping region DC and entrance potential. Under optimized settings, at least 1000 times enhancement in OzID efficiency was achieved compared to that under default settings for monounsaturated PC standards. Monounsaturated C=C in the sn-2 PC isomer reacted faster with ozone than the sn-1 isomer. Similarly, the C=C in trans PC reacted faster than in cis PC. CONCLUSIONS: This is the first implementation of OzID in the trap and transfer region of a traveling wave enabled high-resolution mass spectrometer. The OzID reaction efficiency is significantly improved by slowing down ions in the trap region for their prolonged interaction with ozone. This will facilitate application of high resolution OzID-MS in lipidomics. PMID- 28590554 TI - Wet years have more caterpillars: interacting roles of plant litter and predation by ants. AB - Climate is widely recognized as an important factor that affects temporal and spatial patterns of occurrence and abundance of herbivorous insects, although the ecological mechanisms responsible are poorly understood. We found that precipitation and standing water were positively correlated with locations and years of high abundance of caterpillars of the ranchman's tiger moth, Platyprepia virginalis. We analyzed 30 years of survey data and found that the number of large rainfall events was a better predictor of caterpillar abundance than total annual accumulation. We considered three ecological mechanisms that could drive this relationship and conducted observations and manipulative experiments to evaluate these mechanisms. (1) Rainfall facilitates more plant growth, although we found no evidence that increased food quality or quantity was causing the positive association between precipitation and caterpillar abundance. (2) Large rainfall events cause predatory ground-nesting ants to be less abundant and we found that the number of ants that recruited to local sites was negatively associated with survival and abundance of caterpillars. (3) We found that litter from wet sites provided a refuge from ant predation; litter from wet sites was not beneficial to caterpillars in the absence of ants. Both abiotic factors (precipitation) and biotic factors (predatory ants) affected the temporal and spatial abundance of caterpillars directly and interactively. Climate models predict that rainfall will become more variable, suggesting that populations of this caterpillar may also become more variable in the future. PMID- 28590555 TI - 750 Reasons To Celebrate Chemistry! AB - Time to reflect: This issue marks the 750th issue of Chemistry-A European Journal. The journal has played a significant role in changing chemistry. Its history has featured top papers from top authors for more than 20 years. PMID- 28590553 TI - Transgenerational effects of mild heat in Arabidopsis thaliana show strong genotype specificity that is explained by climate at origin. AB - Transgenerational environmental effects can trigger strong phenotypic variation. However, it is unclear how cues from different preceding generations interact. Also, little is known about the genetic variation for these life history traits. Here, we present the effects of grandparental and parental mild heat, and their combination, on four traits of the third-generation phenotype of 14 Arabidopsis thaliana genotypes. We tested for correlations of these effects with climate and constructed a conceptual model to identify the environmental conditions that favour the parental effect on flowering time. We observed strong evidence for genotype-specific transgenerational effects. On average, A. thaliana accustomed to mild heat produced more seeds after two generations. Parental effects overruled grandparental effects in all traits except reproductive biomass. Flowering was generally accelerated by all transgenerational effects. Notably, the parental effect triggered earliest flowering in genotypes adapted to dry summers. Accordingly, this parental effect was favoured in the model when early summer heat terminated the growing season and environments were correlated across generations. Our results suggest that A. thaliana can partly accustom to mild heat over two generations and genotype-specific parental effects show non-random evolutionary divergence across populations that may support climate change adaptation in the Mediterranean. PMID- 28590556 TI - Breast cysts rapidly enlarging with replacement of breast parenchyma and asymmetry. PMID- 28590558 TI - Tangential Extraperitoneal Retrorenal approach: a specified uniform technique for renal transplant biopsy. PMID- 28590559 TI - DOSY Analysis of Micromolar Analytes: Resolving Dilute Mixtures by SABRE Hyperpolarization. AB - DOSY is an NMR spectroscopy technique that resolves resonances according to the analytes' diffusion coefficients. It has found use in correlating NMR signals and estimating the number of components in mixtures. Applications of DOSY in dilute mixtures are, however, held back by excessively long measurement times. We demonstrate herein, how the enhanced NMR sensitivity provided by SABRE hyperpolarization allows DOSY analysis of low-micromolar mixtures, thus reducing the concentration requirements by at least 100-fold. PMID- 28590557 TI - Declines in plant palatability from polar to tropical latitudes depend on herbivore and plant identity. AB - Long-standing theory predicts that the intensity of consumer-prey interactions declines with increasing latitude, yet for plant-herbivore interactions, latitudinal changes in herbivory rates and plant palatability have received variable support. The topic is of growing interest given that lower-latitude species are moving poleward at an accelerating rate due to climate change, and predicting local interactions will depend partly on whether latitudinal gradients occur in these critical biotic interactions. Here, we assayed the palatability of 50 seaweeds collected from polar (Antarctica), temperate (northeastern Pacific; California), and tropical (central Pacific; Fiji) locations to two herbivores native to the tropical and subtropical Atlantic, the generalist crab Mithraculus sculptus and sea urchin Echinometra lucunter. Red seaweeds (Rhodophyta) of polar and temperate origin were more readily consumed by urchins than were tropical reds. The decline in palatability with decreasing latitude is explained by shifts in tissue organic content along with the quantity and quality of secondary metabolites, degree of calcification or both. We detected no latitudinal shift in palatability of red seaweeds to crabs, nor any latitudinal shifts in palatability of brown seaweeds (Phaeophyta) to either crabs or urchins. Our results suggest that evolutionary pressure from tropical herbivores favored red seaweeds with lower palatability, either through the production of greater levels of chemical defenses, calcification, or both. Moreover, our results tentatively suggest that the "tropicalization" of temperate habitats is facilitated by the migration of tropical herbivores into temperate areas dominated by weakly defended and more nutritious foods, and that the removal of these competing seaweeds may facilitate the invasion of better-defended tropical seaweeds. PMID- 28590560 TI - Routine provision of intrauterine contraception at elective cesarean section in a national public health service: a service evaluation. AB - INTRODUCTION: We conducted a prospective health service evaluation to assess the feasibility and acceptability of routinely offering insertion of intrauterine contraception at cesarean section in a maternity setting in the UK. MATERIAL AND METHODS: One month before scheduled cesarean section, women were sent information about postpartum contraception including the option of insertion of an intrauterine contraception at cesarean. Women choosing intrauterine contraception (copper intrauterine device or levonorgestrel intrauterine system) were followed up in person at six weeks, and telephone contact was made at three, six and 12 months postpartum. Our main outcome measures were uptake of intrauterine contraception and complications by six weeks. Secondary outcomes were continuation and satisfaction with intrauterine contraception at 12 months. RESULTS: 120/877 women opted to have intrauterine contraception (13.7%), of which 114 were fitted. By six weeks, there were seven expulsions (6.1%). The expulsion rate by one year was 8.8%. There were no cases of uterine perforations and one case of infection (0.8%). Follow-up rates were 82.5% at 12 months, and continuation rates with intrauterine contraception at 12 months were 84.8% of those contacted. At 12 months, 92.7% of respondents asked were either 'very' or 'fairly' happy with their intrauterine contraception. CONCLUSIONS: Routine provision of intrauterine contraception at elective cesarean for women in a public maternity service is feasible and acceptable to women. It is associated with good uptake and good continuation rates for the first year. This could be an important strategy to increase use of intrauterine contraception and prevent short inter-pregnancy intervals and unintended pregnancies. PMID- 28590561 TI - Reprogramming the striatal stars: A new treatment option for Parkinson's disease. PMID- 28590562 TI - Robust EPI Nyquist ghost removal by incorporating phase error correction with sensitivity encoding (PEC-SENSE). AB - PURPOSE: The existing approach of Nyquist ghost correction by parallel imaging in echo planar imaging (EPI) can suffer from image noise amplification. We propose a method that estimates a phase error map from multi-channel data itself and incorporates it into the sensitivity encoding (SENSE) reconstruction for Nyquist ghost correction without compromising the image SNR. METHODS: This method first reconstructs two ghost-free images from positive and negative echoes using SENSE, respectively, from which the phase error map is computed. This map is then incorporated into the coil sensitivity maps for the negative echo image during the joint SENSE reconstruction of all k-space data to obtain the final ghost-free image. Phantom and in vivo EPI experiments at 7 T and 3 T were performed to evaluate the proposed method. RESULTS: Nyquist ghost was effectively removed in all images even under oblique imaging and poor eddy current conditions. Resulting image signal-to-noise ratio (SNR) was comparable to that by the traditional linear phase error correction method and higher than that by a previous SENSE based parallel imaging correction approach. CONCLUSION: The proposed correction method can robustly eliminate Nyquist ghost while preserving the image SNR. This approach requires no additional calibration data beyond standard coil sensitivity maps and can be readily applied to all EPI applications. Magn Reson Med 79:943 951, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28590563 TI - A multi-state initiative to implement pediatric oral health in primary care practice and clinical education. AB - OBJECTIVES: To implement and study the effect of improving pediatric oral health by training primary care practices and training programs. METHOD: In six New England States, primary care practices and clinical training programs (medical schools, residencies, physician assistant programs) were recruited and trained to incorporate pediatric oral health into medical practice. We measured the results of varying practice recruitment approaches and measured training outcomes based on self-reported implementation and state reported EPSDT CMS oral health claims. RESULTS: We trained 415 practices across six states with a 74 percent average retention rate of providing services at 6 months. This resulted in 136,963 preventive oral health services (fluoride varnish, oral health assessment, or screening). Thirty-five of 52 health education programs established pediatric oral health curricula. The average cost of recruitment, training, and follow-up for an office or an educational program is approximately $1,000/site. CONCLUSION: We have created an enduring infrastructure and model for primary care practices and education programs for training in pediatric oral health. PMID- 28590564 TI - Beta-blockers in patients with advanced liver disease: Has the dust settled? AB - Nonselective beta-blockers (NSBBs) have been the backbone for the treatment of portal hypertension in cirrhosis for the last 3 decades. A publication in 2010 of a prospective observational study suggested that NSBBs could increase mortality in patients with refractory ascites. This opened a controversy about the safety and efficacy of NSBBs in patients with advanced liver disease and led to the publication of a large corpus of observational data assessing the safety of NSBBs in patients with advanced cirrhosis. In this article, we briefly review the clinical pharmacology of NSBBs, the pathophysiological basis for the underlying benefits and harms of NSBBs in advanced cirrhosis, and the evidence in favor and against the use of NSBBs in specific scenarios. Finally, we summarize the current recommendations and propose areas of opportunity for future research. Liver Transplantation 23 1058-1069 2017 AASLD. PMID- 28590565 TI - Three-dimensional MR reconstruction of high-contrast magnetic susceptibility by the variational born iterative method based on the magnetic field volume integral equation. AB - PURPOSE: To provide high-quality and high-contrast magnetic susceptibility mapping, a 3D MR reconstruction method for magnetic susceptibility based on the magnetic field volume integral equation with the variational Born iterative method (VBIM) is developed. METHODS: Three-dimensional magnetic susceptibility is reconstructed from the positive rotating magnetic field component H1+ of the radiofrequency field acquired by B1 mapping. The stabilized biconjugate gradient fast Fourier transform (BCGS-FFT) method is implemented in the forward problem to solve for the magnetic field, and the conjugate gradient fast Fourier transform method is implemented in the inverse problem to reconstruct the magnetic susceptibility distribution. RESULTS: Numerical results demonstrated that good effectiveness and high accuracy can be achieved for both the forward solver of the stabilized biconjugate gradient fast Fourier transform method and the inverse solver of the VBIM method. The method proved to be robust under noise contamination. Moreover, the magnetic susceptibilities with much higher contrasts than that of the non-full wave methods can also be efficiently reconstructed. CONCLUSIONS: The proposed method can reconstruct the magnetic susceptibility of not only human head, but also other human tissues or materials such as magnetic contrast agents with high magnetic susceptibilities. It has promising applications in high-contrast magnetic susceptibility mapping. Magn Reson Med 79:923-932, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28590566 TI - Phenotypic switching prevention and proliferation/migration inhibition of vascular smooth muscle cells by the ruthenium nitrosyl complex trans [Ru(NO)Cl(cyclam](PF6 )2. AB - OBJECTIVES: Vascular smooth muscle cell (VSMC) migration and proliferation at sites of vascular injury are both critical steps in the development of intimal hyperplasia (IH). Local delivery of nitric oxide (NO) largely prevents these events. Among the NO donors, tetraazamacrocyclic nitrosyl complexes, such as trans-[Ru(NO)Cl(cyclam)](PF6 )2 (cyclamNO), gained attention for their features, which include the possibility of being embedded in solid matrices, and ability to participate in a nitrite/NO catalytic conversion cycle. METHODS: Methods used to evaluate cyclamNO activity: safety margin by NR and MTT; cell proliferation by 3H thymidine incorporation and proliferating cell nuclear antigen (PCNA) expression; antimigratory properties by transwell and wound healing; prevention of cell phenotypic switching under platelet-derived growth factor type BB (PDGF-BB) stimuli by analysis of alpha smooth muscle actin (alpha-SMA) expression. KEY FINDINGS: Cell proliferation and migration induced by PDGF-BB were significantly inhibited by cyclamNO. The ~60% reduction on expression of contractile protein alpha-SMA induced by PDGF-BB revealed VSMC phenotypic switching which is significantly prevented by cyclamNO. Compared to the NO donor sodium nitroprusside, cyclamNO showed to be significantly less cytotoxic. CONCLUSIONS: With great potential to maintain VSMC functionality and prevent IH-associated events, cyclamNO might be a promissory drug for several applications in cardiovascular medicine, as in stents. PMID- 28590568 TI - Age at menarche and an analysis of secular trends in menarcheal age of South African urban and rural black females. AB - Age at menarche was estimated using status quo techniques on a sample of 230 rural South African females aged 11 to 17 years. Mean age of menarche was 14.03 years (SD = 1.25 years). Compared with contemporary rural and well-off urban samples, these females experienced menarche 0.6 years earlier than did the rural sample and 0.8 years later than the well-off urban group. Data from 11 previously reported studies of menarcheal age in urban and rural girls were analyzed with these data to determine the existence and magnitude of secular trends and whether rates differed between urban and rural environments. Regression analysis demonstrated a clear secular trend in both urban and rural females since 1943. Menarcheal age decreased at a rate of 0.34, 0.73, and 0.46 years per decade for rural, urban, and combined groups, respectively. The decline in menarcheal age over the last 40 years is thought to be due to improving socioeconomic conditions, but differences between urban and rural groups remain. Within rural groups there appears to be considerable variation in menarcheal age. PMID- 28590567 TI - Vitamin D insufficiency, preterm delivery and preeclampsia in women with type 1 diabetes - an observational study. AB - INTRODUCTION: The aim of this study was to evaluate whether vitamin D insufficiency is associated with preterm delivery and preeclampsia in women with type 1 diabetes. MATERIAL AND METHODS: An observational study of 198 pregnant women with type 1 diabetes. 25-Hydroxy-Vitamin D and HbA1c were measured in blood samples in early (median 8 weeks, range 5-14) and late (34 weeks, range 32-36) pregnancy. Kidney involvement (microalbuminuria or nephropathy) at inclusion, smoking status at inclusion, preterm delivery (<37 weeks) and preeclampsia (blood pressure >=140/90 mmHg and proteinuria) were registered. Vitamin D supplementation of 10 MUg daily was routinely recommended. RESULTS: Thirty-nine (20%) of the 198 women delivered preterm and 16 (8%) developed preeclampsia. Vitamin D insufficiency (<50 nmol/L) was present in 68 women (34%) in early pregnancy and in 73 women (37%) in late pregnancy. Preterm delivery occurred more frequently in women with vitamin D insufficiency in late pregnancy (27% vs. 15%, crude odds ratio 2.1; 95% confidence interval 1.0-4.3, p = 0.04). After adjustment for preexisting kidney involvement, HbA1c in late pregnancy and smoking the association became nonsignificant (adjusted odds ratio 1.8; 95% confidence interval 0.8-3.7). Preeclampsia developed in 11% of women with vitamin D insufficiency vs. 6% of the remaining women (crude odds ratio 1.8; 95% confidence interval 0.9-4.1, p = 0.25). CONCLUSION: In women with type 1 diabetes, preterm delivery was twice as frequent in women with vitamin D insufficiency in late pregnancy in crude analysis, but in this small study, low vitamin D was not independently associated with preterm birth or preeclampsia. PMID- 28590569 TI - Causes of death and the components of mortality: Testing the biological interpretations of a competing hazards model. PMID- 28590570 TI - Anthropometric assessment of nutritional status among highland Kashmiri children: Reevaluating the assumption of female nutritional disadvantage. AB - As part of a larger project investigating the health of rural villagers in Kashmir, India anthropometric data were collected from 132 residents of the highland village of Basmina. Here data for 70 children (53% of the total sample) less than 10 years old are examined and compared to United States reference data and presented as a percentage of the median and Z-scores to describe nutritional status differences by age and sex. Overall, these children maintain indices of weight/age, stature/age, and arm circumference (AC)/age at almost -2.0 Z-scores or more below reference medians. Weight/height and triceps skinfold/age approximate -1.4 and -1.3 Z-scores below the median, respectively. These data along with clinical observations suggest that the Basmina sample is low normal to mildly malnourished. However, preschool children show evidence of moderate and severe malnutrition. The entire child sample shows a higher prevalence of malnutrition when compared to other populations living under similar conditions. The results are contrary to the belief that Indian girls are at a nutritional disadvantage when compared to boys. In fact, preschool girls maintain higher, though not significant, percentages of weight/age, weight/height, and AC/age. Girls between 5 and 10 years old also maintain a higher triceps/age index. On the other hand, boys between 5 and 10 years old maintain a higher stature/age index, but the difference is not statistically significant. PMID- 28590571 TI - Somatic comparisons: Baiga and Gond males of Madhya Pradesh, India. AB - Data were collected during 1987 on 84 Baiga and 146 Gond males, ages 7 years to 18 years, living in rural regions of Madhya Pradesh State (India). Comparisons are made between Baiga and Gond males for 11 measures of body size, one measure of body form, and the body mass index (BMI). Somatic comparisons (standing height, body weight, and skelic index) were made at 5 ages with earlier samples of rural Indian males. Across all ages Gond males exceed their Baiga peers in standing height, sitting height, shoulder width, and body weight. Skelic index values (lower limb height expressed relative to sitting height) are similar for both ethnic groups through late childhood, but thereafter values are higher for Baiga males. Through age 15 years, Gond males exceed other rural Indian males from various tribes in standing height and body weight; lower limb height expressed relative to sitting height is highest for Baiga males. PMID- 28590572 TI - Sources of measurement variation in child anthropometry in the Malawi maternal and child nutrition study. AB - An examination of intra- and inter-observer error in child anthropometry and variation between two skinfold calipers was conducted as part of a large prospective study of maternal and child nutrition in Malawi, Central Africa. Measurements include length, weight, head and arm circumferences, triceps and subscapular skinfolds, and estimated cross-sectional arm fat and arm muscle areas. Total observer error, expressed as a percentage of total variance in each trait, is ?3.2% for length, weight, and head circumference; 7% for arm circumference; 10% for arm fat area; and 16-20% for skinfolds and arm muscle area. When total observer error is divided into the two additive components studied, intraobserver error represents approximately 50% or more of total observer error for most traits. An exception is the subscapular skinfold for which intra-observer represents 38% of total observer error. Errors of this magnitude will cause an attenuation of approximately 10% in the correlation coefficients between anthropometric and other variables, and a loss of power in attempting to detect associations between anthropometric variables and either their determinants or outcomes. However, the effects of errors of this magnitude are minor compared to those encountered in studies correlating nutrient intake with other variables. This study also finds that the SlimGuide caliper systematically overestimates skinfolds at low readings and underestimates skinfolds at high readingss relative to the Lange caliper. PMID- 28590573 TI - PC program for analyzing one-sample longitudinal data sets which satisfy the two stage polynomial growth curve model. AB - The two-stage polynomial growth curve model is described and a GAUSS program to perform the associated computations is documented and made available to interested readers. The two-stage model is similar to that considered by us earlier (Schneiderman and Kowalski: American Journal of Physical Anthropology 67:323-333, 1985; American Journal of Human Biology 1:31-42, 1989), i.e., it is appropriate for the analysis of one-sample longitudinal data collected at either equal or unequal time intervals. Here, however, the covariance matrix, Sigma, instead of being considered arbitrary, is now assumed to have the special structure Sigma = W A W' + sigma2 I. We show the conditions under which this special structure may be expected to arise and how it may be exploited to produce sharper results in certain situations. The method and the program are illustrated and the results are contrasted to those obtained when Sigma is arbitrary. It is suggested that the two-stage model is more efficient when the same degree polynomial is adequate to model the data in the two situations, but that, should a higher degree be necessary for the two-stage model, confidence intervals and/or bands may be wider than those corresponding to Sigma arbitrary. PMID- 28590574 TI - Genetic and environmental contributions to the variance of the body mass index in a Norwegian sample of first- and second-degree relatives. AB - Height and weight were measured in a health screening of the population in Nord Trondelag, Norway. Correlations for the body mass index were computed for 23,936 pairs of spouses, 43,586 pairs of parents and offspring, 19,151 pairs of siblings, 1,251 pairs of grandparents and grandchildren, 1,146 cognate avuncular pairs, 801 noncognate avuncular pairs, 168 pairs of same-sexed twins, and smaller groups of other types of relatives. Correlations were largely independent of age and age difference within pairs of relatives, suggesting a stable effect of the same set of genes and familial environment throughout adulthood. No effect of convergence during marriage could be detected. Correlations were approximately .20 for parents and offspring, .26 for same-sexed siblings, .20 for opposite sexed siblings, .58 for monozygotic twins, and close to zero for most second order relatives. Results from structural equation model-fitting indicate a broad heritability of .4, much of which is due to genetic dominance or other genetic nonadditivity. PMID- 28590576 TI - Do women with dense breasts have higher radiation dose during screening mammography? AB - Radiation dose during screening mammography is a concern among women. The purpose of this study was to evaluate the relative contribution of breast density to the radiation dose from screening mammography. This IRB approved retrospective study involved collecting patient age, weight, height, compressed breast thickness, and average glandular dose for each exposure for 434 sequential patients undergoing screening mammography at our institution. Automated volumetric density software was used to quantify breast density. The relationship of predictors was evaluated by univariate and multivariate analysis. Median patient age was 58 years and median body mass index (BMI) was 26.8. Median volumetric breast density was 5.8% (range 1.7-30.5%). Median compressed breast thickness was 63.4 mm (range 24.5 111.5 mm). Univariate analysis showed positive associations between radiation dose and both breast thickness and BMI, an inverse association with age, and no association with density. Multivariate regression analysis demonstrated a significant association between dose and age (P=.021), laterality (P<.001), BMI (P=.038), density (P<.001), and breast thickness (P<.001). Decomposition of the multivariate regression model coefficient of determination showed that breast thickness was the primary determinant of dose, accounting for 76% of the 58% of the dose variability, followed by density (8%), laterality (4%), age (<1%), and BMI (<1%). Compressed breast thickness had the greatest effect on average glandular dose. Breast density has a minor impact, while BMI and age have minimal impact on dose. PMID- 28590575 TI - Reply to: MRI measures of brainstem in parkinsonian syndromes: Where we stand and where we need to go. PMID- 28590577 TI - Non-neural androgen receptors affect sexual differentiation of brain and behaviour. AB - Although gonadal testosterone is the principal endocrine factor that promotes masculine traits in mammals, the development of a male phenotype requires local production of both androgenic and oestrogenic signals within target tissues. Much of our knowledge concerning androgenic components of testosterone signalling in sexual differentiation comes from studies of androgen receptor (Ar) loss of function mutants. Here, we review these studies of loss of Ar function and of AR overexpression either globally or selectively in the nervous system of mice. Global and neural mutations affect socio-sexual behaviour and the neuroanatomy of these mice in a sexually differentiated manner. Some masculine traits are affected by both global and neural mutation, indicative of neural mediation, whereas other masculine traits are affected only by global mutation, indicative of an obligatory non-neural androgen target. These results support a model in which multiple sites of androgen action coordinate to produce masculine phenotypes. Furthermore, AR overexpression does not always have a phenotype opposite to that of loss of Ar function mutants, indicative of a nonlinear relationship between androgen dose and masculine phenotype in some cases. Potential mechanisms of Ar gene function in non-neural targets in producing masculine phenotypes are discussed. PMID- 28590578 TI - Acute inhibitory effect of alpha-mangostin on sarcoplasmic reticulum calcium ATPase and myocardial relaxation. AB - The benefits of alpha-mangostin for various tissues have been reported, but its effect on the heart has not been clarified. This study aimed to evaluate the effects of alpha-mangostin on cardiac function. Using a cardiac sarcoplasmic reticulum (SR) membrane preparation, alpha-mangostin inhibited SR Ca2+ -ATPase activity in a dose-dependent manner (IC50 of 6.47 +/- 0.7 MUM). Its suppressive effect was specific to SR Ca2+ -ATPase but not to myofibrillar Ca2+ -ATPase. Using isolated cardiomyocytes, 50 MUM of alpha-mangostin significantly increased the duration of cell relengthening and increased the duration of Ca2+ transient decay, suggesting altered myocyte relaxation. The relaxation effect of alpha mangostin was also supported in vivo after intravenous infusion. A significant suppression of both peak pressure and rate of ventricular relaxation (-dP/dt) relative to DMSO infusion was observed. The results from the present study demonstrated that alpha-mangostin exerts specific inhibitory action on SR Ca2+ ATPase activity, leading to myocardial relaxation dysfunction. PMID- 28590579 TI - Flexible mate choice may contribute to ecotype assortative mating in pumpkinseed sunfish (Lepomis gibbosus). AB - Gene flow is expected to limit adaptive divergence, but the ecological and behavioural factors that govern gene flow are still poorly understood, particularly at the earliest stages of population divergence. Reduced gene flow through mate choice (sexual isolation) can evolve even under conditions of subtle population divergence if intermediate phenotypes have reduced fitness. We indirectly tested the hypothesis that mate choice has evolved between coexisting littoral and pelagic ecotypes of polyphenic pumpkinseed sunfish (Lepomis gibbosus) that have diverged in morphology and resource use and where intermediate phenotypes have reduced performance. We assessed the ecotype of nesting males and females using stable isotope estimates of diet and a divergent male morphological trait, oral jaw width. We found positive assortative mating between ecotypes in a common spawning habitat along exposed lake shorelines, but contrary to expectations, assortative mating was variably expressed between two sampling years. Although the factors that influence variable assortative mating remain unclear, our results are consistent with mate choice being expressed by ecotypes. Despite being variably expressed, mate choice will reduce gene flow between ecotypes and could contribute to further adaptive divergence depending on its frequency and strength in the population. Our findings add to a growing body of evidence indicating mate choice behaviour can be a plastic trait, an idea that should be more explicitly considered in empirical studies of mate choice as well as conceptual frameworks of mate choice evolution and adaptive divergence. PMID- 28590581 TI - Bilateral intra-areolar polythelia. PMID- 28590580 TI - Projection of the prevalence of Parkinson's disease in the coming decades: Revisited. AB - OBJECTIVE: Previous studies have estimated future PD prevalence based on population aging. This study revisits that projection by accounting for the potential impact of declining rates of smoking. METHODS: The age- and gender stratified smoking prevalence in the United States from 2000 to 2040 were obtained from the U.S. Census Bureau and the U.S. Surgeon General's Smoking Report. PD prevalence was estimated based on population aging with and without an account of the impact of declining smoking rates. Relative risks of 0.56 and 0.78 were applied for current and former smokers, respectively. RESULTS: Accounting for aging alone, ~700,000 PD cases are predicted by 2040. After accounting for the declining smoking prevalence, ~770,000 cases, an increase of ~10% over the estimate without smoking, is predicted. CONCLUSIONS: If the epidemiological association of smoking and PD is causal, projecting future cases without considering smoking may underestimate disease burden, underscoring the urgency of adequate resource allocation. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28590582 TI - Remarkable Modulation of Self-Assembly in Short gamma-Peptides by Neighboring Ions and Orthogonal H-Bonding. AB - Gabapentin, an antiepileptic drug, is known to form stable helical structures in short peptides. Distinctly, we report on the newly synthesized gamma-analogue of gabapentin, that is, gamma-gabapentin (gamma-Gpn), which manifests beta-sheet character at molecular and nanofibrous hydrogels at the supramolecular level. We investigated the influence of proximally immobilized cationic amino acids (lysine and arginine) on the self-assembly of backbone-expanded tripeptide motif. Interestingly, arginine was found to be superior, both physically and mechanically, over lysine in driving hydrogelation. We have concluded that intrinsic and biochemically distinct properties of the guanidinium ion of arginine (compared to ammonium ion of lysine) have contributed towards this effect. Furthermore, similar to pyroglutamyl (pGlu) modified amyloid beta peptides, N-pGlu modification of our self-assembling tripeptide motif exerts a dramatic influence on aggregation and exhibits enhanced beta-sheet character, accelerated self-assembly kinetics, improved optical transparency and provides higher mechanical stiffness to the peptide hydrogel. PMID- 28590584 TI - Free-water and free-water corrected fractional anisotropy in primary and premotor corticospinal tracts in chronic stroke. AB - Measures from diffusion MRI have been used to characterize the corticospinal tract in chronic stroke. However, diffusivity can be influenced by partial volume effects from free-water, region of interest placement, and lesion masking. We collected diffusion MRI from a cohort of chronic stroke patients and controls and used a bitensor model to calculate free-water corrected fractional anisotropy (FAT ) and free water (FW) in the primary motor corticospinal tract (M1-CST) and the dorsal premotor corticospinal tract (PMd-CST). Region of interest analyses and whole-tract slice-by-slice analyses were used to assess between-group differences in FAT and FW in each tract. Correlations between FAT and FW and grip strength were also examined. Following lesion masking and correction for multiple comparisons, relative increases in FW were found for the stroke group in large portions of the M1-CST and PMd-CST in the lesioned hemisphere. FW in cortical regions was the strongest predictor of grip strength in the stroke group. Our findings also demonstrated that FAT is sensitive to the direct effects of the lesion itself, thus after controlling for the lesion, differences in FAT in nonlesioned tissue were small and generally similar between hemispheres and groups. Our observations suggest that FW may be a robust biological measurement that can be used to assess microstructure in residual white matter after stroke. Hum Brain Mapp 38:4546-4562, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28590583 TI - 3R MoS2 with Broken Inversion Symmetry: A Promising Ultrathin Nonlinear Optical Device. AB - Nonlinear 2D layered crystals provide ideal platforms for applications and fundamental studies in ultrathin nonlinear optical (NLO) devices. However, the NLO frequency conversion efficiency constrained by lattice symmetry is still limited by layer numbers of 2D crystals. In this work, 3R MoS2 with broken inversion symmetry structure are grown and proved to be excellent NLO 2D crystals from monolayer (0.65 nm) toward bulk-like (300 nm) dimension. Thickness and wavelength-dependent second harmonic generation spectra offer the selection rules of appropriate working conditions. A model comprising of bulk nonlinear contribution and interface interaction is proposed to interpret the observed nonlinear behavior. Polarization enhancement with two petals along staggered stacking direction appears in 3R MoS2 is first observed and the robust polarization of 3R MoS2 crystal is caused by the retained broken inversion symmetry. The results provide a new arena for realizing ultrathin NLO devices for 2D layered materials. PMID- 28590586 TI - Beyond the Hammett Effect: Using Strain to Alter the Landscape of Electrochemical Potentials. AB - The substitution of sterically bulky groups at precise locations along the periphery of fused-ring aromatic systems is demonstrated to increase electrochemical oxidation potentials by preventing relaxation events in the oxidized state. Phenothiazines, which undergo significant geometric relaxation upon oxidation, are used as fused-ring models to showcase that electron-donating methyl groups, which would generally be expected to lower oxidation potential, can lead to increased oxidation potentials when used as the steric drivers. Reduction events remain inaccessible through this molecular design route, a critical characteristic for electrochemical systems where high oxidation potentials are required and in which reductive decomposition must be prevented, as in high-voltage lithium-ion batteries. This study reveals a new avenue to alter the redox characteristics of fused-ring systems that find wide use as electroactive elements across a number of developing technologies. PMID- 28590585 TI - Comparison of the c-MET gene amplification between primary tumor and metastatic lymph nodes in non-small cell lung cancer. AB - BACKGROUND: c-MET has recently been identified as a promising novel target in non small cell lung cancer (NSCLC). We detected the consistency of c-MET gene amplification in metastatic lymph nodes and tumor tissues of NSCLC patients and discuss the clinical application value of c-MET gene amplification in metastatic lymph nodes. METHODS: Real-time fluorescent quantitative PCR was used to test tumor tissues in 368 NSCLC patients and 178 paired metastatic lymph node samples. The amplification consistency in metastatic lymph nodes and tissue samples were compared and the correlation between c-MET gene amplification and the clinical characteristics of patients was analyzed. RESULTS: The c-MET gene amplification rate was 8.97% (33/368) in tumor tissues. Of the 178 paired cases, c-MET gene amplification was positive in 7.95% (15/178) of cancerous tissues and 18.54% (33/178) of metastatic lymph nodes. c-MET gene amplification was detected more frequently in metastatic lymph nodes than in primary cancerous tissue. When metastatic lymph nodes were used as surrogate samples of primary cancerous tissues, the sensitivity was 86.67% (13/15) and the specificity was 87.69% (143/163). CONCLUSIONS: Screening for c-MET gene amplification in lymph node metastases could determine which patients are eligible for tyrosine kinase inhibitor therapy. Lymph node metastasis can predict c-MET gene amplification in a primary tumor and guide the clinical use of c-MET gene targeted drugs. PMID- 28590589 TI - Living donor liver transplantation for post-Kasai biliary atresia: Analysis of pretransplant predictors of outcomes in infants. AB - After decades of dramatic surgical innovations in pediatric living donor liver transplantation (LDLT), LDLT for biliary atresia (BA) still poses various challenges. This study reviewed our experience with LDLT for children with post Kasai BA and evaluated outcomes and prognostic factors. From 2005 to 2016, 168 post-Kasai BA LDLT patients were enrolled and divided into 3 groups by age. Patient characteristics and perioperative data were compared. Predictors of morbidity and mortality following LDLT were analyzed in 93 infants. Outcome was relatively worse in infants than older children, with overall survival at 1 and 5 years of 94.5% and 93.2%, respectively, and graft survival at 1 and 5 years of 91.1% each. Incidence of vascular complications was not significantly higher in infants. High Pediatric End-Stage Liver Disease (PELD) score (odds ratio [OR], 3.72; 95% confidence interval [CI], 1.30-10.67; P = 0.02) and portal vein (PV) hypoplasia (OR, 3.23; 95% CI, 1.10-9.52; P = 0.03) were independent risk factors for morbidity. Low weight-for-age z score (hazard ratio, 5.76; 95% CI, 1.05 31.47; P = 0.03) was identified as a significant risk factor for mortality after LDLT, but not age or absolute body weight (BW). Infants with BW deficit had a significantly smaller PV diameter (P = 0.005), greater blood loss (P = 0.001), and higher incidence of postoperative bacteremia (P = 0.01). In conclusion, high PELD score and PV hypoplasia were independent risk factors for morbidity, and BW deficit was associated with poor survival in infants with post-Kasai BA after LDLT. However, LDLT in these infants at the earliest possible time after referral is a feasible option with excellent patient survival in an experienced center. Liver Transplantation 23 1199-1209 2017 AASLD. PMID- 28590590 TI - Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases. AB - Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell-surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target-based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids. PMID- 28590587 TI - Genetic variants in 5-HTTLPR, BDNF, HTR1A, COMT, and FKBP5 and risk for treated depression after cancer diagnosis. AB - BACKGROUND: The role of gene-environment interactions in the pathogenesis of depression is unclear. Previous studies addressed vulnerability for depression after childhood adversity and stressful life events among carriers of numerous specific genetic variants; however, the importance of individual genetic variants, the environmental exposures with which they interact, and the magnitude of the risk conveyed by these interactions remain elusive. METHODS: We included 7,320 people with a first primary cancer identified in the prospective Diet, Cancer and Health study in an exposed-only cohort study. The mean age of the individuals was 68 years (5th, 95th percentiles: 58, 78) at cancer diagnosis. Using Cox regression models and cumulative incidence plots, we analyzed the associations between genetic variants in 5-HTTLPR, BDNF, HTR1A, COMT, and FKBP5 and use of antidepressants as well as hospital contact for depression after diagnosis of cancer. RESULTS: Overall, we observed no statistically significant associations, with nonsignificant hazard ratio estimates for use of antidepressants of 0.95-1.07. CONCLUSIONS: This study of elderly people indicates that it is unlikely that the investigated genetic variants are clinically relevantly associated with depression after diagnosis of cancer. The mechanisms for gene-environment interactions in younger individuals are probably different, and we advise caution in extrapolating our results to early life stress. However, conclusion from the present study might be generalizable to elderly persons exposed to other stressful life events. PMID- 28590591 TI - Hot Off the Press: Which Febrile Children With Sickle Cell Disease Need a Chest X ray? PMID- 28590592 TI - Decadal changes in habitat characteristics influence population trajectories of southern elephant seals. AB - Understanding divergent biological responses to climate change is important for predicting ecosystem level consequences. We use species habitat models to predict the winter foraging habitats of female southern elephant seals and investigate how changes in environmental variables within these habitats may be related to observed decreases in the Macquarie Island population. There were three main groups of seals that specialized in different ocean realms (the sub-Antarctic, the Ross Sea and the Victoria Land Coast). The physical and climate attributes (e.g. wind strength, sea surface height, ocean current strength) varied amongst the realms and also displayed different temporal trends over the last two to four decades. Most notably, sea ice extent increased on average in the Victoria Land realm while it decreased overall in the Ross Sea realm. Using a species distribution model relating mean residence times (time spent in each 50 * 50 km grid cell) to 9 climate and physical co-variates, we developed spatial predictions of residence time to identify the core regions used by the seals across the Southern Ocean from 120 degrees E to 120 degrees W. Population size at Macquarie Island was negatively correlated with ice concentration within the core habitat of seals using the Victoria Land Coast and the Ross Sea. Sea ice extent and concentration is predicted to continue to change in the Southern Ocean, having unknown consequences for the biota of the region. The proportion of Macquarie Island females (40%) utilizing the relatively stable sub-Antarctic region, may buffer this population against longer-term regional changes in habitat quality, but the Macquarie Island population has persistently decreased ( 1.45% per annum) over seven decades indicating that environmental changes in the Antarctic are acting on the remaining 60% of the population to impose a long-term population decline in a top Southern Ocean predator. PMID- 28590594 TI - Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: II. Cephalosporins and penicillins update. PMID- 28590593 TI - The proteasome enters the meiotic prophase fray. AB - The segregation of homologous chromosomes in meiosis depends on their ability to locate one another in the nucleus and establish a physical association through crossing over. A tightly regulated number of crossovers (COs) emerges following repair of induced DNA double-strand breaks by homologous recombination (HR), but the process of how HR intermediates transition into COs is still poorly understood. Two recent studies by Ahuja et al. and Rao et al. have revealed a role for chromosomally localized proteasomes in choreographing both homologous chromosome pairing and the evolution of HR intermediates into segregation competent COs. Using chemical inhibition of the proteasome and mutant analysis, the collective data reveal conserved functions for both the proteasome and a family of E3 ligases that can direct or compete with its activity in ensuring CO formation. Here, we review these findings and the impact of the discovery that protein modification dynamics and proteasomal activity cooperate to regulate key meiotic processes. PMID- 28590595 TI - Obstructive sleep apnea syndrome in children: Risk assessment. PMID- 28590596 TI - Alternating Copolymer of Double Four Ring Silicate and Dimethyl Silicone Monomer PSS-1. AB - A new copolymer consisting of double four ring (D4R) silicate units linked by dimethylsilicone monomer referred to as polyoligosiloxysilicone number one (PSS 1) was synthesized. The D4R building unit is provided by hexamethyleneimine cyclosilicate hydrate crystals, which were dehydrated and reacted with dichlorodimethylsilane. The local structure of D4R silicate units and dimethyl silicone monomers was revealed by multidimensional solid-state NMR, FTIR and modeling. On average, D4R silicate units have 6.8 silicone linkages. Evidence for preferential unidirectional growth and chain ordering within the PSS-1 copolymer was provided by STEM and TEM. The structure of PSS-1 copolymer consists of twisted columns of D4R silicate units with or without cross-linking. Both models are consistent with the spectroscopic, microscopic and physical properties. PSS-1 chains are predicted to be mechanically strong compared to silicones such as PDMS, yet more flexible than rigid silica materials such as zeolites. PMID- 28590597 TI - Height at Ages 7-13 Years in Relation to Developing Type 2 Diabetes Throughout Adult Life. AB - BACKGROUND: Short adults have an increased risk of type 2 diabetes. Although adult height results from childhood growth, the effects of height and growth trajectories during childhood are sparsely investigated. We investigated sex specific associations between childhood height, growth and adult type 2 diabetes, including potential influences of birthweight and childhood body mass index (BMI). METHODS: We followed 292 827 individuals, born 1930-83, from the Copenhagen School Health Records Register in national registers for type 2 diabetes (11 548 men; 7472 women). Weights and heights were measured at ages 7-13 years. Hazard ratios (HR) of type 2 diabetes (age >=30 years) were estimated without and with adjustment for birthweight and BMI. RESULTS: In men, associations between height and type 2 diabetes changed from inverse for below average heights at age 7 years to positive for above-average heights at 13 years. No consistent associations were observed among women. These associations were not affected by birthweight. After adjustment for BMI, below-average childhood heights were inversely associated with type 2 diabetes among men (HR range: 0.91 0.93 per z-score) but above-average heights were not. Among women, after adjustment for BMI, below- and above-average heights in childhood were inversely associated with type 2 diabetes (HR range: 0.91-0.95). Greater height growth from 7 to 13 years was positively associated with type 2 diabetes in men and women. CONCLUSIONS: After adjustment for BMI, short childhood height at all ages and greater growth during childhood are associated with an increased risk of type 2 diabetes, suggesting that this period of life warrants mechanistic investigations. PMID- 28590599 TI - Reply. PMID- 28590598 TI - The 28-year incidence of de novo malignancies after liver transplantation: A single-center analysis of risk factors and mortality in 1616 patients. AB - De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD. PMID- 28590600 TI - A Case of Caffeine Intolerance With Long-Term Use of Fluoxetine. PMID- 28590601 TI - Patient Characteristics Associated With Use of Lurasidone Versus Other Atypical Antipsychotics in Patients With Bipolar Disorder: Analysis From a Claims Database in the United States. AB - Objective: To compare patient characteristics, medical comorbidities, health care utilization, and health care costs among patients with bipolar disorder who initiated lurasidone versus other atypical antipsychotics in usual clinical practice. Methods: A retrospective analysis of administrative claims data was conducted using the US Optum Research Database (December 30, 2012, through February 27, 2014). Adult, commercially insured patients with bipolar disorder with an atypical antipsychotic prescription between June 28, 2013, and November 30, 2013, were included. The lurasidone cohort first included any patients with a lurasidone prescription; remaining patients were assigned to their first atypical antipsychotic (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). Preindex patient characteristics comparisons to lurasidone were conducted with t tests (continuous variables) and chi2 or Fisher exact tests (categorical variables). Results: A total of 3,329 patients were included in this database analysis. A higher percentage of the lurasidone cohort (31.1%) had bipolar depression compared with the other cohorts (23.5%-28.0%). The lurasidone cohort had a statistically significantly higher percentage of patients with prior diabetes mellitus (13.3%) and lipid metabolism disorders (23.2%) than did the quetiapine cohort (8.4% and 16.3%, P < .01). In addition, the lurasidone cohort had significantly more prior antipsychotic polypharmacy (23.0% vs 6.7%-12.9%, P < .01) and atypical antipsychotic use (55.6% vs 11.8%-26.3%, P < .01) than other cohorts. The lurasidone cohort had a statistically significantly higher mean number of prior all-cause and mental health office visits (P < .001) and higher mean prior pharmacy costs than most cohorts (P < .01). Conclusions: Lurasidone treated patients with bipolar disorder tended to have a more complex clinical profile, comorbidities, and prior treatment history compared to patients initiated with other atypical antipsychotics in this claims database study. This pattern of treatment may have reflected the overall clinical profile of lurasidone, the role perceived for lurasidone in the therapeutic armamentarium by practitioners, and the recent introduction of lurasidone into clinical practice during the study period. PMID- 28590602 TI - ? AB - INTRODUCTION: XSome authors have assessed the link betweenobesity and colon adenoma risk. Moreover, it has been reportedthat obesity could increase the risk of proximal adenomadevelopment. Accordingly, obese patients may have a distinctivepattern of adenoma recurrence. AIM: To determinewhether metachronous adenoma features differ between obeseand non-obese subjects submitted to colonoscopy surveillance. MATERIALS AND METHODS: We prospectively evaluated all patientsover 18 years old that underwent surveillance colonoscopyat our institution between June 2013 and June 2014.Date of prior colonoscopy was registered. A body mass index>= 30 was used to define obesity. Analysis looking for variablessignificantly associated with metachronous adenoma was performed.Metachronous adenoma rate was compared betweenobese and non-obese subjects, as well as size, location, morphologicaland histopathological characteristics. RESULTS: Overall,825 subjects were enrolled. Median time of surveillance colonoscopywas 38.9 months. Obesity was statistically more frequentin those subjects with metachronous adenomas (40% vs25.71%, p < 0.001). On multivariate analysis, obesity [OR1.7 (1.01-2.9)] and age [OR 1.02 (1-1.05)] were independentlyassociated with metachronous adenoma presence. Obesitywas also significantly associated with a higher risk of rightcolon adenomas [OR 2.4 (1.76 3.26)] and advanced adenoma[OR 1.99 (1.29-3.06)]. The risk is significantly higherin men and in those with a family history of colorectal cancer/adenoma. CONCLUSION: Obesity was associated with a higherrisk of metachronous adenomas on surveillance colonoscopy. Ahigher risk of right-sided lesions and advanced adenomas wasalso found in this population. PMID- 28590603 TI - Aldosterone increases oxygen consumption of rectalepithelia of normal, sodium deprived and sodiumloadedrats. AB - INTRODUCTION: The colonic epithelium is a classical aldosteronetarget, but the effect of the hormone on the oxygenconsumption rate (QO2 ) of this tissue is unknown. Objectives.We aimed at assessing, in the rectal epithelium ofrats fed with diets of different sodium content, the effect ofepithelial sodium channel (ENaC) blockade on short-circuitcurrent (ISC ) and QO2 , and the acute effect of aldosteroneincubation on ISC and QO2 . METHODS: Adult male ratswere fed with normal, low or high-sodium diets for 8 days.Plasma sodium and serum aldosterone were measured. Isolatedmucosa preparations from the rectal portion of the colonwere mounted in Ussing chambers modified to measureISC and QO2. RESULTS: Baseline ISC and QO2 were highestin sodium-deprived rats. Both were proportionally reducedby amiloride (0.1 mM) in this group and in the normalsodium group, but not in sodium-loaded rats. In separateexperiments, incubation with aldosterone (10 nM) for 7 hincreased ISC and QO2 in all groups; increases were larger inthe normal and sodium-loaded groups. Amiloride decreasedboth ISC and QO2 , abolishing the differences between groups.Linear regression of the decrease in QO2 and ISC after amilorideshowed the steepest slope for the sodium-deprived groupand the flattest one for the sodium-loaded group. CONCLUSIONS: Baseline epithelial QO2 of sodium-deprived and controlrats is reduced by ENaC blockade. Aldosterone increasedQO2 proportionally to ISC augmentation in all groups, butthe coupling between aerobic metabolism and electrogenictransport seems more efficient in sodium-deprived animals. PMID- 28590604 TI - Total gastrectomy due to ferric chloride intoxication. AB - INTRODUCTION: The ferric chloride intoxication is frequentlycaused by accident. Its toxicity is generally underrated,which can lead to fatal evolution or irreversible consequences.In this case, the caustic condition of the substance isrelated to the toxic properties of iron. CASE PRESENTATION: A 36-year-old male patient arrives by ambulance indicatingsensory deterioration. He presents erosive injuries in thebuccal cavity and in the oropharynx, brownish teeth andmetabolic acidosis. Toxicology tests and ferritin blood dosageare requested, which show a result from 1400 mg/dl. Thesymptoms are interpreted as acute iron intoxication. Due tothe unfavorable evolution of his condition, an abdominaland pelvic CT scan are performed, which show extensivepneumoperitoneum and free fluid in the abdominal cavity.An exploratory laparotomy, a total gastrectomy with esophagostomyand feeding jejunostomy, washing and drainagedue to perforated gastric necrosis caused by caustic ingestionare performed. DISCUSSION: In our country, there is a highrate of intoxication caused by iron compounds, although itis not statistically measured. Nevertheless, the ferric chlorideintoxication is extremely infrequent. The ingestion of thisproduct leads to complications, which are associated with theiron concentration and its condition as a caustic agent. CONCLUSIONS: The surgical indications in the presence of intoxicationcaused by iron compounds are: stomach evacuationof iron, gastric necrosis, perforation or peritonitis and stenosis.Early or prophylactic gastrectomy is contraindicated.However, if complications that require immediate surgicalintervention arise, there should be no hesitation and the correspondingprocedure should be performed. PMID- 28590605 TI - ? AB - In this case we present a patient with chronic abdominalpain of a year of evolution, three months before being admittedto hospital the patient presented melaena and anaemia.Within the surgery antecedents it appears a caesarean 2 yearsbefore and a cholecystectomy a year before. In the endoscopystudy a textiloma was observed coming up from the posterosiorside of the antrum which, after its endoscopic removal,showed a gastro-duodenal fistula with a non-patent pylorus. PMID- 28590606 TI - ? AB - It is presented a 48 year-old male patient with antecedent ofa foreign body intake (a beer metallic top) 4 years ago, whorejected surgery at first previous a failed attempt of endoscopicextraction. Four years later he was admitted in the ThoraxNational Institute in an emergency, with acute respiratoryfailure and sepsis signs that were corrected quickly; lateron after failed surgical attempts of trachea-esophageal fistulacorrection and extraction of the foreign body, the patient wassent to BJIG where the endoscopic extraction of the foreignbody located in the trachea was carried out together with thecorrection of the trachea esophageal fistula by means of implantation,in esophagus, of covered self expanding prosthesis. PMID- 28590607 TI - ? AB - The intestinal pneumatosis is a clinical entity that is describedas the presence of gas within the intestinal wall andportomesenteric venous complex as an air cysts without surroundedor no epithelial lining by a granulomatous infiltratewith giant cells multinucleic.1 It is a extremely rareclinical entity that has been characteristically associated withintestinal ischemia and high mortality. We present two casesof intestinal pneumatosis tomographic reports, admittedwith clinical symptoms of intestinal obstruction. Recent advancesin imaging techniques, mainly in multislice computedtomography (MSCT), allow a reliable and accurate earlydiagnosis of these findings. PMID- 28590608 TI - ? AB - Syphilis is a chronic systemic infection mainly transmittedthrough sexual contact that shows a great variety of clinicalmanifestations. Liver involvement is an unusual complicationmainly reported in HIV patients. In this case reportwe present a case of a 42-year-old immunocompent manwith acute cholestatic hepatitis who was finally diagnosed ofluetic hepatitis. Liver disease was the only manifestation ofsyphilis infection difficulty it's diagnostic. We emphasize theimportance of including syphilis in the differential diagnosisof abnormal liver function tests in patients at risk of sexuallytransmitted diseases due to its resolution with appropriateantibiotic treatment. PMID- 28590710 TI - ? AB - Neurophysiological studies of anorectal function provide usefulinformation about the integrity of innervation and neuromuscularfunction. This information helps to understand the pathophysiological mechanisms leading to severe anorectaldisorders function, such as fecal incontinence, pelvic floordisorders and dyssynergic defecation. These tests are commonlyperformed in patients referred to third level medicalcenters having negative evaluations or no response to conventionaltherapy. Proper use of these tests may reveal significantnew knowledge of the underlying mechanisms that can leadto better management of these disorders. These techniques arecomplementary to other types of research such as imaging ofthe pelvic floor. In this review, the most accomplished neurophysiologicalstudies, indications and clinical utility areanalyzed. Several techniques are emerging and provide uswith a better understanding of the brain-gut interactions. PMID- 28590709 TI - ? AB - One of the greatest achievements in gastroenterology and surgeryof the last 50 years has been the capability to transplantdifferent abdominal organs of the digestive system separatelyor as a whole. The complexity of the intestinal transplantationdemands a multidisciplinary team engaged in the managementof patients with intestinal failure responsible fordefining the need for nutritional support, rehabilitation, orintestinal transplantation. This team should include a basicresearch area to provide answers to unresolved clinical problems.The aim of this work is to update the current status ofintestinal transplantation, and to show the progress and resultsof our center; emphasizing our achievements in the clinicalarea, and the contributions of the translational researchand mucosal immunology studies as part of the integral unitof intestinal failure, rehabilitation and transplantation. Thedata reported here demonstrate that the intestinal transplantationhas been established as a therapeutic option in ourcountry and Latin America, with long term results that haveranked our service at the level of the best centers in the worldpositioning us as referent in the specialty. PMID- 28590711 TI - ? AB - During the last twenty years Eosinophilic Esophagitis has becomeone the most important causes of esophageal disfunctionin children, food impactation in adolescents and youngadults, therapeutic failure in patients with gastroesophagealreflux disease (GERD) and the most frecuent eosinophilicdisease of the gastrointestinal tract. We present recommendationsfor the diagnosis and treatment of the disease based ina systematic review of the literature. PMID- 28590712 TI - Structural Characterization of Intermetallic Compounds by 27Al Solid State NMR Spectroscopy. AB - Intermetallic compounds are of broad interest for solid state chemists, condensed matter physicists, and material scientists due to their intriguing crystal chemistry, their physical properties, and their potential applications, ranging from lab curiosities to everyday objects. To characterize and understand the properties of new compounds and novel materials, the availability of structural information, particularly single-crystal X-ray diffraction data, is a mandatory prerequisite. Especially when it comes to the formation of compounds with deficient or mixed site occupancies, superstructures, or representatives crystallizing in other, thus far unknown structure types, a complementary method for structural analysis is of great value. Solid state nuclear magnetic resonance spectroscopy has been a valuable tool in many areas of chemistry, being an element-selective, site-specific, and inherently quantitative tool for detailed structural characterization. Magic-angle spinning conditions eliminate or reduce the effect of anisotropic interactions in the solid state, producing high resolution spectra. Until recently, 27Al NMR studies of intermetallic aluminum compounds have been relatively sparse and mostly limited to binary systems. In this Account, we will summarize the current state of the art of high-resolution 27Al NMR in intermetallic compounds focusing on recent research efforts in our laboratories and the interpretation of NMR parameters in terms of the structural details of the compounds investigated. Besides theoretical aspects of 27Al NMR spectroscopy, short paragraphs on experimental details and the crystal chemistry of the discussed compounds are given. In the main part of this Account, we focus on three key aspects: (i) crystal structure validation, (ii) structural disorder and mixed site occupancies, and (iii) the electronic structure, all of which can be investigated by spectroscopic means. For the first part, we have chosen the ternary equiatomic compounds CaAuAl (TiNiSi type), BaAuAl (LaIrSi type), and Ba3Pt4Al4 (own type). Structural disorder and mixed site occupancies have been probed in the ScTAl series (T = Cr, Ru, Ag, Re) crystallizing in the TiNiSi, HfRhSn, and MgZn2-type structures. Also Na2Au3Al and the Heusler compounds, Sc(T0.5T'0.5)2Al (T = T' = Ni, Pd, Pt, Cu, Ag, Au), have been used for structure validation purposes, based on the number and signal area ratios of the resonances observed and on the comparison between experimental and theoretically calculated nuclear electric quadrupolar interaction parameters. Electronic structure information available from 27Al magnetic shielding will be discussed based on experimental data obtained for the RET5Al2 series (RE = Y, Lu; T = Pd, Pt), the extended RE10TAl3 series (RE = Y, Lu; T = Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt), and the ordered Heusler compounds ScT2Al (T = Ni, Pd, Pt, Cu, Ag, Au). PMID- 28590713 TI - High Photovoltaic Quantum Efficiency in Ultrathin van der Waals Heterostructures. AB - We report experimental measurements for ultrathin (<15 nm) van der Waals heterostructures exhibiting external quantum efficiencies exceeding 50% and show that these structures can achieve experimental absorbance >90%. By coupling electromagnetic simulations and experimental measurements, we show that pn WSe2/MoS2 heterojunctions with vertical carrier collection can have internal photocarrier collection efficiencies exceeding 70%. PMID- 28590714 TI - Reaching out for Sensitive Evaluation of the Mu Opioid Receptor in Vivo: Positron Emission Tomography Imaging of the Agonist [11C]AH7921. AB - Imaging of the mu opioid receptor (MOR) availability with positron emission tomography (PET) is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioral phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioantagonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo. We investigated a moderately potent, selective MOR agonist in rat to test if a radiotracer design paradigm tailored to competition with endogeneous opioids leads to viable imaging results. The benzamide 3,4-dichlorobenzenecarboxylic acid (dimethylamino)cyclohexyl)methyl amide (AH-7921, 1) was synthesized and characterized in rat brain using autoradiography and positron emission tomography. Compound 1 was found to activate with low nanomolar potency the MOR and to a lesser extent KOR as a full agonist. Concentration dependent binding studies with agonist and antagonist radioligands were conducted to assess competition behavior and obtain inhibition constants. Kinetic analysis of 3,4 dichlorobenzene[11C]carboxylic acid (dimethylamino)cyclohexyl)methyl amide binding in rat brain resulted in low but reproducible binding potential in the thalamus (0.8 +/- 0.1). A radioactive metabolite was detected in brain (17%, after 15 min). Nonetheless, we conclude that quantitative imaging of MOR availability is possible when using a moderate affinity radiotracer. PMID- 28590715 TI - Enhanced Immune Adjuvant Activity of Aluminum Oxyhydroxide Nanorods through Cationic Surface Functionalization. AB - Aluminum-salt-based vaccine adjuvants are prevailingly used in FDA-approved vaccines for the prevention of infectious diseases for over eighty years. Despite their safe applications, the mechanisms regarding how the material characteristics affect the interactions at nano-bio interface and immunogenicity remain unclear. Recently, studies have indicated that the activation of NLRP3 inflammasome plays a critical role in inducing adjuvant effects that are controlled by the inherent shape and hydroxyl contents of aluminum oxyhydroxide (AlOOH) nanoparticles; however, the detailed relationship between surface properties and adjuvant effects for these materials remains unknown. Thus, we engineered AlOOH nanorods (ALNRs) with controlled surface functionalization and charge to assess their effects on the activation of NLRP3 inflammasome in vitro and the potentiation of immunogenicity in vivo. It is demonstrated that NH2 functionalized ALNRs exhibited higher levels of cellular uptake, lysosomal damage, oxidative stress, and NLRP3 inflammasome activation than pristine and SO3H-functionalized ALNRs in cells. This structure-activity relationship also correlates with the adjuvant activity of the material using ovalbumin (OVA) in a mouse vaccination model. This study demonstrates that surface functionalization of ALNRs is critical for rational design of aluminum-based adjuvants to boost antigen-specific immune responses for more effective and long-lasting vaccination. PMID- 28590716 TI - Multiwavelength Light-Responsive Au/B-TiO2 Janus Micromotors. AB - Conventional photocatalytic micromotors are limited to the use of specific wavelengths of light due to their narrow light absorption spectrum, which limits their effectiveness for applications in biomedicine and environmental remediation. We present a multiwavelength light-responsive Janus micromotor consisting of a black TiO2 microsphere asymmetrically coated with a thin Au layer. The black TiO2 microspheres exhibit absorption ranges between 300 and 800 nm. The Janus micromotors are propelled by light, both in H2O2 solutions and in pure H2O over a broad range of wavelengths including UV, blue, cyan, green, and red light. An analysis of the particles' motion shows that the motor speed decreases with increasing wavelength, which has not been previously realized. A significant increase in motor speed is observed when exploiting the entire visible light spectrum (>400 nm), suggesting a potential use of solar energy, which contains a great portion of visible light. Finally, stop-go motion is also demonstrated by controlling the visible light illumination, a necessary feature for the steerability of micro- and nanomachines. PMID- 28590717 TI - Sensitive and Selective NO2 Sensing Based on Alkyl- and Alkylthio-Thiophene Polymer Conductance and Conductance Ratio Changes from Differential Chemical Doping. AB - NO2-responsive polymer-based organic field-effect transistors (OFETs) are described, and room-temperature detection with high sensitivity entirely from the semiconductor was achieved. Two thiophene polymers, poly(bisdodecylquaterthiophene) and poly(bisdodecylthioquaterthiophene) (PQT12 and PQTS12, respectively), were used as active layers to detect a concentration at least as low as 1 ppm of NO2. The proportional on-current change of OFETs using these polymers reached over 400% for PQTS12, which is among the highest sensitivities reported for a NO2-responsive device based on an organic semiconducting film. From measurements of cyclic voltammetry and the electronic characteristics, we found that the introduction of sulfurs into the side chains induces traps in films of the PQTS12 and also decreases domain sizes, both of which could contribute to the higher sensitivity of PQTS12 to NO2 gas compared with PQT12. The ratio of responses of PQTS12 and PQT12 is higher for exposures to lower concentrations, making this parameter a means of distinguishing responses to low concentrations for extended times from exposures to high concentrations from shorter times. The responses to nonoxidizing vapors were much lower, indicating good selectivity to NO2 of two polymers. This work demonstrates the capability of increasing selectivity and calibration of OFET sensors by modulating redox and aggregation properties of polymer semiconductors. PMID- 28590718 TI - Tuning Supramolecular Structure and Functions of Peptide bola-Amphiphile by Solvent Evaporation-Dissolution. AB - Solvent molecules significantly affect the supramolecular self-assembly, for example, in forming solvent-bridged hydrogen bonding networks. Even small changes in solvent composition can have dramatic impact on supramolecular assembly. Herein, we demonstrate the use of trace solvents (as low as 0.04%) to tune the morphology and consequent functions of supramolecular nanostructures based on an aromatic peptide bola-amphiphile. Specifically, perylene bisimide-(di)glycine tyrosine (PBI-[GY]2) bola-amphiphile was shown to give rise to red-emitting nanofibers when assembled in water, while exposure to trace organic solvents such as tetrahydrofuran (THF) and others via solvent-evaporation followed by aqueous assembly gave rise to white-light-emitting nanospheres. Differential hydrogen bonding between water (donor and acceptor) and THF (acceptor only) impacts supramolecular organization, which was verified using a density functional theory (DFT) simulation. The tunable consequent surface hydrophobicity was utilized in staining the cytoplasm and membrane of cells, respectively. The trace-solvent effect achieved through evaporation-dissolution provides a methodology to mediate the morphologies and consequent functions for supramolecular biomaterials controlled by the self-assembly pathway. PMID- 28590719 TI - Strongly Coupled High-Quality Graphene/2D Superconducting Mo2C Vertical Heterostructures with Aligned Orientation. AB - Vertical heterostructures of two-dimensional (2D) crystals have led to the observations of numerous exciting physical phenomena and presented the possibilities for technological applications, which strongly depend on the quality, interface, relative alignment, and interaction of the neighboring 2D crystals. The heterostructures or hybrids of graphene and superconductors offer a very interesting platform to study mesoscopic superconductivity and the interplay of the quantum Hall effect with superconductivity. However, so far the heterostructures of graphene and 2D superconductors are fabricated by stacking, and consequently suffer from random relative alignment, weak interfacial interaction, and unavoidable interface contaminants. Here we report the direct growth of high-quality graphene/2D superconductor (nonlayered ultrathin alpha Mo2C crystal) vertical heterostructures with uniformly well-aligned lattice orientation and strong interface coupling by chemical vapor deposition. In the heterostructure, both graphene and 2D alpha-Mo2C crystal show no defect, and the graphene is strongly compressed. Different from the previously reported graphene/superconductor heterostructures or hybrids, the strong interface coupling leads to a phase diagram of superconducting transition with multiple voltage steps being observed in the transition regime. Furthermore, we demonstrate the realization of highly transparent Josephson junction devices based on these strongly coupled high-quality heterostructures, in which a clear magnetic-field-induced Fraunhofer pattern of the critical supercurrent is observed. PMID- 28590720 TI - ZnS-Sb2S3@C Core-Double Shell Polyhedron Structure Derived from Metal-Organic Framework as Anodes for High Performance Sodium Ion Batteries. AB - Taking advantage of zeolitic imidazolate framework (ZIF-8), ZnS-Sb2S3@C core double shell polyhedron structure is synthesized through a sulfurization reaction between Zn2+ dissociated from ZIF-8 and S2- from thioacetamide (TAA), and subsequently a metal cation exchange process between Zn2+ and Sb3+, in which carbon layer is introduced from polymeric resorcinol-formaldehyde to prevent the collapse of the polyhedron. The polyhedron composite with a ZnS inner-core and Sb2S3/C double-shell as anode for sodium ion batteries (SIBs) shows us a significantly improved electrochemical performance with stable cycle stability, high Coulombic efficiency and specific capacity. Peculiarly, introducing a carbon shell not only acts as an important protective layer to form a rigid construction and accommodate the volume changes, but also improves the electronic conductivity to optimize the stable cycle performance and the excellent rate property. The architecture composed of ZnS inner core and a complex Sb2S3/C shell not only facilitates the facile electrolyte infiltration to reduce the Na-ion diffusion length to improve the electrochemical reaction kinetics, but also prevents the structure pulverization caused by Na-ion insertion/extraction. This approach to prepare metal sulfides based on MOFs can be further extended to design other nanostructured systems for high performance energy storage devices. PMID- 28590721 TI - Biocompatible Iron Phthalocyanine-Albumin Assemblies as Photoacoustic and Thermal Theranostics in Living Mice. AB - Exploring novel and versatile nanomaterials for the construction of personalized multifunctional phototheranostics with significant potentials in bioimaging guided tumor phototherapies has attracted considerable attention. Herein, the phototheranostic agent human serum albumin-iron (II) phthalocyanine FePc nanoparticles (HSA-FePc NPs) were fabricated for photoacoustic (PA) imaging guided photothermal therapy (PTT) of cancer in vivo. The prepared HSA-FePc NPs exhibited high stability, efficient NIR absorption, good capability and stability of photothermal behavior with a high photothermal conversion efficiency of ~44.4%, high contrast and spatial resolution of PA imaging, efficient cancer therapy, and low long-term toxicity. This potent multifunctional phototheranostic is, therefore, very promising and favorable for effective, precise, and safe antitumor treatment in clinical application. PMID- 28590722 TI - Injectable Fullerenol/Alginate Hydrogel for Suppression of Oxidative Stress Damage in Brown Adipose-Derived Stem Cells and Cardiac Repair. AB - Stem cell implantation strategy has exhibited potential to treat the myocardial infarction (MI), however, the low retention and survival limit their applications due to the reactive oxygen species (ROS) microenvironment after MI. In this study, the fullerenol nanoparticles are introduced into alginate hydrogel to create an injectable cell delivery vehicle with antioxidant activity. Results suggest that the prepared hydrogels exhibit excellent injectable and mechanical strength. In addition, the fullerenol/alginate hydrogel can effectively scavenge the superoxide anion and hydroxyl radicals. Based on these results, the biological behaviors of brown adipose-derived stem cells (BADSCs) seeded in fullerenol/alginate hydrogel were investigated in the presence of H2O2. Results suggest that the fullerenol/alginate hydrogels have no cytotoxicity effects on BADSCs. Moreover, they can suppress the oxidative stress damage of BADSCs and improve their survival capacity under ROS microenvironment via activating the ERK and p38 pathways while inhibiting JNK pathway. Further, the addition of fullerenol can improve the cardiomyogenic differentiation of BADSCs even under ROS microenvironment. To assess its therapeutic effects in vivo, the fullerenol/alginate hydrogel loaded with BADSCs were implanted in the MI area in rats. Results suggest that the fullerenol/alginate hydrogel can effectively decrease ROS level in MI zone, improve the retention and survival of implanted BADSCs, and induce angiogenesis, which in turn promote cardiac functional recovery. Therefore, the fullerenol/alginate hydrogel can act as injectable cell delivery vehicles for cardiac repair. PMID- 28590723 TI - Terpene Cyclizations inside a Supramolecular Catalyst: Leaving-Group-Controlled Product Selectivity and Mechanistic Studies. AB - The tail-to-head terpene cyclization is arguably one of the most complex reactions found in nature. The hydrogen-bond-based resorcinarene capsule represents the first man-made enzyme-like catalyst that is capable of catalyzing this reaction. Based on noncovalent interactions between the capsule and the substrate, the product selectivity can be tuned by using different leaving groups. A detailed mechanistic investigation was performed to elucidate the reaction mechanism. For the cyclization of geranyl acetate, it was found that the cleavage of the leaving group is the rate-determining step. Furthermore, the studies revealed that trace amounts of acid are required as cocatalyst. A series of control experiments demonstrate that a synergistic interplay between the supramolecular capsule and the acid traces is required for catalytic activity. PMID- 28590724 TI - An Ultraviolet Nonlinear Optic Borate with 13-Ring Channels Constructed from Different Building Units. AB - Under solvothermal conditions, a chair open-framework borate, Na2B9O15(H2O)(H3O) (1), has been synthesized. Compound 1 shows regular pores of zeolites as well as nonlinear optical (NLO) properties of borates. The large 13-ring channels of the boron oxide framework are constructed from different cluster units of B3O7 and B6O13 with three-ring units. The second harmonic generation (SHG) signal intensity of 1 is similar to that of KH2PO4 (KDP) and gradually increased with larger particle size. Compound 1 is a potential UV NLO material for its short wavelength absorption edge. PMID- 28590726 TI - Anion- and Solvent-Induced Rotary Dynamics and Sensing in a Perylene Diimide [3]Catenane. AB - A novel dynamic [3]catenane consisting of a large four-station central macrocycle which incorporates a bay tetrachloro-functionalized perylene diimide (PDI) unit and two triazolium anion-binding motifs, mechanically bonded with two smaller isophthalamide-containing macrocycles, is constructed using an anion template synthetic methodology. Proton NMR, electronic absorption, and fluorescence emission spectroscopies together with molecular dynamics simulations are used to investigate the anion recognition- and solvent-dependent dynamic properties of the higher-order mechanically interlocked molecule. Importantly, unprecedented solvent-dependent and anion-binding-induced circumrotatory motion in a hetero[3]catenane system is demonstrated where the exotic dual rotary switching behavior provides a unique and sophisticated mechanism for optical anion sensing in competitive protic organic and aqueous-organic media. PMID- 28590725 TI - Discovery of a Cryptic Antifungal Compound from Streptomyces albus J1074 Using High-Throughput Elicitor Screens. AB - An important unresolved issue in microbial secondary metabolite production is the abundance of biosynthetic gene clusters that are not expressed under typical laboratory growth conditions. These so-called silent or cryptic gene clusters are sources of new natural products, but how they are silenced, and how they may be rationally activated are areas of ongoing investigation. We recently devised a chemogenetic high-throughput screening approach ("HiTES") to discover small molecule elicitors of silent biosynthetic gene clusters. This method was successfully applied to a Gram-negative bacterium; it has yet to be implemented in the prolific antibiotic-producing streptomycetes. Herein we have developed a high-throughput transcriptional assay format in Streptomyces spp. by leveraging eGFP, inserted both at a neutral site and inside the biosynthetic cluster of interest, as a read-out for secondary metabolite synthesis. Using this approach, we successfully used HiTES to activate a silent gene cluster in Streptomyces albus J1074. Our results revealed the cytotoxins etoposide and ivermectin as potent inducers, allowing us to isolate and structurally characterize 14 novel small molecule products of the chosen cluster. One of these molecules is a novel antifungal, while several others inhibit a cysteine protease implicated in cancer. Studies addressing the mechanism of induction by the two elicitors led to the identification of a pathway-specific transcriptional repressor that silences the gene cluster under standard growth conditions. The successful application of HiTES will allow future interrogations of the biological regulation and chemical output of the countless silent gene clusters in Streptomyces spp. PMID- 28590727 TI - Capturing Chemistry in Action with Electrons: Realization of Atomically Resolved Reaction Dynamics. AB - One of the grand challenges in chemistry has been to directly observe atomic motions during chemical processes. The depiction of the nuclear configurations in space-time to understand barrier crossing events has served as a unifying intellectual theme connecting the different disciplines of chemistry. This challenge has been cast as an imaging problem in which the technical issues reduce to achieving not only sufficient simultaneous space-time resolution but also brightness for sufficient image contrast to capture the atomic motions. This objective has been met with electrons as the imaging source. The review chronicles the first use of electron structural probes to study reactive intermediates, to the development of high bunch charge electron pulses with sufficient combined spatial-temporal resolution and intensity to literally light up atomic motions, as well as the means to characterize the electron pulses in terms of temporal brightness and image reconstruction. The use of femtosecond Rydberg spectroscopy as a novel means to use internal electron scattering within the molecular reference frame to obtain similar information on reaction dynamics is also discussed. The focus is on atomically resolved chemical reaction dynamics with pertinent references to work in other areas and forms of spectroscopy that provide additional information. Effectively, we can now directly observe the far from-equilibrium atomic motions involved in barrier crossing and categorize chemistry in terms of a power spectrum of a few dominant reaction modes. It is this reduction in dimensionality that makes chemical reaction mechanisms transferrable to seemingly arbitrarily complex (large N) systems, up to molecules as large as biological macromolecules (N > 1000 atoms). We now have a new way to reformulate reaction mechanisms using an experimentally determined dynamic mode basis that in combination with recent theoretical advances has the potential to lead to a new conceptual basis for chemistry that forms a natural link between structure and dynamics. PMID- 28590728 TI - Switchable Chiral Selection of Aspartic Acids by Dynamic States of Brushite. AB - We herein show the chiral recognition and separation of aspartic acid (Asp) enantiomers by achiral brushite due to the asymmetries of their dynamical steps in its nonequilibrium states. Growing brushite has a higher adsorption affinity to d-Asp, while l-Asp is predominant on the dissolving brushite surface. Microstructural characterization reveals that chiral selection is mainly attributed to brushite [101] steps, which exhibit two different configurations during crystal growth and dissolution, respectively, with each preferring a distinct enantiomer due to this asymmetry. Because these transition step configurations have different stabilities, they subsequently result in asymmetric adsorption. By varying free energy barriers through solution thermodynamic driving force (i.e., supersaturation), the dominant nonequilibrium intermediate states can be switched and chiral selection regulated. This finding highlights that the dynamic steps can be vital for chiral selection, which may provide a potential pathway for chirality generation through the dynamic nature. PMID- 28590729 TI - Synthetic Modularity of Protein-Metal-Organic Frameworks. AB - Previously, we adopted the construction principles of metal-organic frameworks (MOFs) to design a 3D crystalline protein lattice in which pseudospherical ferritin nodes decorated on their C3 symmetric vertices with Zn coordination sites were connected via a ditopic benzene-dihydroxamate linker. In this work, we have systematically varied both the metal ions presented at the vertices of the ferritin nodes (Zn(II), Ni(II), and Co(II)) and the synthetic dihydroxamate linkers, which yielded an expanded library of 15 ferritin-MOFs with the expected body-centered (cubic or tetragonal) lattice arrangements. Crystallographic and small-angle X-ray scattering (SAXS) analyses indicate that lattice symmetries and dimensions of ferritin-MOFs can be dictated by both the metal and linker components. SAXS measurements on bulk crystalline samples reveal that some ferritin-MOFs can adopt multiple lattice conformations, suggesting dynamic behavior. This work establishes that the self-assembly of ferritin-MOFs is highly robust and that the synthetic modularity that underlies the structural diversity of conventional MOFs can also be applied to the self-assembly of protein-based crystalline materials. PMID- 28590730 TI - Three-Coordinate Copper(II) Aryls: Key Intermediates in C-O Bond Formation. AB - Copper(II) aryl species are proposed key intermediates in Cu-catalyzed cross coupling reactions. Novel three-coordinate copper(II) aryls [CuII]-C6F5 supported by ancillary beta-diketiminate ligands form in reactions between copper(II) alkoxides [CuII]-OtBu and B(C6F5)3. Crystallographic, spectroscopic, and DFT studies reveal geometric and electronic structures of these Cu(II) organometallic complexes. Reaction of [CuII]-C6F5 with the free radical NO(g) results in C-N bond formation to give [Cu](eta2-ONC6F5). Remarkably, addition of the phenolate anion PhO- to [CuII]-C6F5 directly affords diaryl ether PhO-C6F5 with concomitant generation of the copper(I) species [CuI](solvent) and {[CuI]-C6F5}-. Experimental and computational analysis supports redox disproportionation between [CuII]-C6F5 and {[CuII](C6F5)(OPh)}- to give {[CuI]-C6F5}- and [CuIII](C6F5)(OPh) unstable toward reductive elimination to [CuI](solvent) and PhO-C6F5. PMID- 28590731 TI - Synthesis, Transient Absorption, and Transient Resonance Raman Spectroscopy of Novel Electron Donor-Acceptor Complexes: [5,15-Bis[(4'-nitrophenyl)ethynyl] 10,20- diphenylporphinato]copper(II) and [5-[[4'-(Dimethylamino)phenyl]ethynyl] 15-[(4''-nitrophenyl)ethynyl]-10,20-diphenylporphinato]copper(II). AB - We report the synthesis, transient absorption, FT Raman, resonance Raman, time resolved resonance Raman, and transient resonance Raman spectra of pseudo-D 2h symmetric [5,15-bis[(4'-nitrophenyl)ethynyl]-10,20-diphenylporphinato]copper(II) (I) and electronically asymmetric [5-[4'-(dimethylamino)phenyl]ethynyl]-15-[(4'' nitrophenyl)ethynyl]-10,20-diphenylporphinato]copper(II) (II), which bears both electron-releasing and electron-withdrawing groups conjugated directly to the porphyrin periphery. The spectroscopic results suggest extensive electronic communication between the 5- and 15-arylethynyl groups and the porphyrin core. Relative to the parent compound, (tetraphenylporphinato)copper(II) (CuTPP), the arylethynyl substituents increase the lifetime of the excited trip-multiplet states. CuTPP, as well as compounds I and II, however, shows similar solvent dependent dynamics: the trip-multiplet lifetimes are longer in a noncoordinating solvent such as benzene than in a coordinating solvent such as THF. This behavior is consistent with the existence of a quenching state whose effect is more pronounced upon coordination of solvent. The time-resolved resonance Raman spectrum of compound II shows features commonly associated with the relatively long-lived triplet excited states of copper(II) porphyrins. The transient resonance Raman spectrum of a short-lived excited state present in both compounds I and II is characterized by marked shifts in the nitro and porphyrin stretching frequencies relative to that observed for the ground states of both (4 nitrophenyl)ethyne and (tetraphenylporphinato)copper(II). We interpret these results for the compounds I and II as arising from (i) a short-lived excited state present at early time that possesses enhanced porphyrin-to-nitro charge transfer character with respect to the ground state and (ii) a longer-lived excited state deriving from this initially probed charge-transfer state that is largely porphyrin localized. PMID- 28590732 TI - Study of Substituted Ester Formation in Red Wine by the Development of a New Method for Quantitative Determination and Enantiomeric Separation of Their Corresponding Acids. AB - A new method was developed for quantifying substituted acids including, where applicable, their various unexplored enantiomeric forms. A new step was added to acids' usual quantification methods, consisting of extraction, derivatization to methyl esters, and gas chromatography analysis: preliminary extraction was performed at basic pH to eliminate ethyl esters, thus avoiding their transesterification during derivatization. Quantitation and enantiomeric distribution of some substituted esters and their corresponding acids were established in 31 commercial Bordeaux red wines from 0 to 20 years old. A strong positive correlation was observed between the age of wine and levels of ethyl 2 methylpropanoate, ethyl 3-methylbutanoate, ethyl 2-methylbutanoate, ethyl (3R)-3 hydroxybutanoate, both enantiomeric forms of ethyl 2-hydroxy-3-methylbutanoate, and ethyl (2S)-2-hydroxy-4-methylpentanoate, but not ethyl (3S)-3 hydroxybutanoate. However, the standard deviations of average concentrations for the corresponding substituted acids were so large that only few correlations between concentrations and age were observed. Concentrations of (2S)-2-hydroxy-3 methylbutanoic acid and (2S)-2-hydroxy-4-methylpentanoic acid increased slightly over time, while (2R)-2-hydroxy-4-methylpentanoic acid levels decreased slightly with the age. Variations in the ratio of substituted ethyl esters to their corresponding acids over time detected thanks to these analytical advances suggested that, in general, acids were continuously esterified during aging. PMID- 28590733 TI - Resonance Destabilization in N-Acylanilines (Anilides): Electronically-Activated Planar Amides of Relevance in N-C(O) Cross-Coupling. AB - Transition-metal-catalyzed activation of amide N-C(O) bonds proceeds via selective metal insertion into the carbon-nitrogen amide bond. Herein, we demonstrate that N-acylanilines (anilides), the first class of planar amides that have been shown to undergo selective amide N-C cross-coupling reactions, feature a significantly decreased barrier to rotation around the amide N-C(O) bond. Most significantly, we demonstrate that amide nN -> pi*C?O resonance in simple anilides can be varied by as much as 10 kcal/mol. The data have important implications for the design of N-C(O) amide cross-coupling reactions and control of the molecular conformation of anilides by resonance effects. PMID- 28590734 TI - Derivatives of the Lignan 7'-Hydroxymatairesinol with Antioxidant Properties and Enhanced Lipophilicity. AB - The lignan 7'-hydroxymatairesinol (1), extracted from the knotwoods of fir (Abies alba), spruce (Picea abies), and Douglas fir (Pseudotsuga menziesii), exhibited unexpected reactivity when esterification reactions were attempted on the hydroxy group at position C-7'. To circumvent the rapid intramolecular cyclization procedure, leading quantitatively to the lignan conidendrin (7), a simple strategy for 7'-esterification of 1 under mild conditions (three steps, up to 80% overall yield) was developed. Compared to hydroxymatairesinol (1) (log K'w = 1.49), the derivatives (2-5) had increased lipophilicity with log K'w > 3.1, as determined by a UHPLC method. Compounds 1-5 exhibited potent antioxidant properties in the same range as the standards ascorbic acid and alpha-tocopherol (IC50 = 20-25 MUM) and higher than that of BHT using a DPPH radical-scavenging assay. PMID- 28590735 TI - Peptidyl-Prolyl Model Study: How Does the Electronic Effect Influence the Amide Bond Conformation? AB - The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2 allylamino)acrylic acid derivatives. Subsequent pKa studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The trans/cis amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a trans-amide is extraordinary, and in this regard, 2,4-methanoproline is closer to primary alpha-amino acids than to proline. At the same time the amide rotation velocities were 3-4 orders of magnitude higher when compared to N-acetylprolyl. Finally, our results indicate that the electronic effect of the 4-substituent only affects the kinetics of the amide isomerization but not the thermodynamic prevalence for the trans-rotamer. PMID- 28590736 TI - Ozone and Other 1,3-Dipoles: Toward a Quantitative Measure of Diradical Character. AB - Ozone and its sulfur-substituted isomers are studied by means of the Breathing Orbital Valence Bond ab initio method, with the objective of estimating their controversial diradical characters. The calculated weights of the various VB structures and their individual diabatic energies are found to be consistent with each other. All 1,3-dipoles can be described in terms of three major VB structures, one diradical and two zwitterionic ones, out of the six structures, forming a complete basis. Ozone has a rather large diradical character, estimated to 44%-49%. SOO and SOS are even more diradicalar, whereas SSO and especially OSO are better described as closed-shell zwitterions. Moreover, the description of 1,3-dipoles, in terms of the three major structures, yields VB weights in full agreement with simple chemical wisdom, i.e., a diradical weight of 33% when the three structures are quasi-degenerate, and a smaller (larger) value when the diradical structure is higher (lower) in energy than the zwitterionic ones. Therefore, the VB-calculated weight of the diradical structure of a molecule qualifies itself as a quantitative measure of diradical character, and not only as an indicator of tendencies. Other definitions of the diradical character, based on molecular orbital/configuration interaction methods, are discussed. PMID- 28590737 TI - Reagent-Free Quantification of Aqueous Free Chlorine via Electrical Readout of Colorimetrically Functionalized Pencil Lines. AB - Colorimetric methods are commonly used to quantify free chlorine in drinking water. However, these methods are not suitable for reagent-free, continuous, and autonomous applications. Here, we demonstrate how functionalization of a pencil drawn film with phenyl-capped aniline tetramer (PCAT) can be used for quantitative electric readout of free chlorine concentrations. The functionalized film can be implemented in a simple fluidic device for continuous sensing of aqueous free chlorine concentrations. The sensor is selective to free chlorine and can undergo a reagent-free reset for further measurements. Our sensor is superior to electrochemical methods in that it does not require a reference electrode. It is capable of quantification of free chlorine in the range of 0.1 12 ppm with higher precision than colorimetric (absorptivity) methods. The interactions of PCAT with the pencil-drawn film upon exposure to hypochlorite were characterized spectroscopically. A previously reported detection mechanism relied on the measurement of a baseline shift to quantify free chlorine concentrations. The new method demonstrated here measures initial spike size upon exposure to free chlorine. It relies on a fast charge built up on the sensor film due to intermittent PCAT salt formation. It has the advantage of being significantly faster than the measurement of baseline shift, but it cannot be used to detect gradual changes in free chlorine concentration without the use of frequent reset pulses. The stability of PCAT was examined in the presence of free chlorine as a function of pH. While most ions commonly present in drinking water do not interfere with the free chlorine detection, other oxidants may contribute to the signal. Our sensor is easy to fabricate and robust, operates reagent-free, and has very low power requirements and is thus suitable for remote deployment. PMID- 28590738 TI - Tyrosine as a Non-perturbing Site-Specific Vibrational Reporter for Protein Dynamics. AB - The ability to detect changes in the local environment of proteins is pivotal to determining their dynamic nature during many biological processes. For this purpose, the utility of the tyrosine ring breathing vibration as a sensitive infrared reporter for measuring the local electric field in protein is investigated. Variations in the bandwidth of this vibrational transition in a variety of solvents indicate differences in microenvironment affect the inhomogeneous broadening and thus the frequency distribution. The ring mode is influenced by direct and indirect interactions associated with the charge distribution of the surrounding solvent molecules. Molecular dynamics simulations were implemented to obtain a correlation between the electric field induced by the solvent on the mode and the observed vibrational bandwidth. Moreover, the Trp cage was synthesized as a model peptide system to access the efficacy of the correlation to predict the electric field strength within the hydrophobic core of the native and denatured states of the protein. The 2D IR spectra of tyrosine in dimethyl sulfoxide (DMSO) and water (D2O) show a two-fold difference in the time constant of the vibrational dynamics alluding to the dephasing mechanisms of the vibration and supporting the model put forth about the solvachromatic nature of the transition. PMID- 28590740 TI - C-H Alkylations of (Hetero)Arenes by Maleimides and Maleate Esters through Cobalt(III) Catalysis. AB - Efficient cobalt(III)-catalyzed (hetero)aryl and alkenyl C-H hydroarylations of maleimides and maleate esters have been achieved under remarkably mild reaction conditions. Thus, the versatile cobalt(III) catalyst [Cp*CoI2(CO)] showed excellent atom-and step-economy as well as high chemo- and site-selectivity providing expedient access to pharmacologically useful succinimides with wide functional group tolerance. PMID- 28590741 TI - Bu4NI-Catalyzed Oxygen-Centered Radical Addition between Acyl Peroxides and Isocyanides. AB - A novel oxygen-centered radical addition between acyl peroxides and isocyanides has been developed. A diverse collection of valuable arylcarboxyamides were easily synthesized by this protocol. From the preliminary mechanistic study, the elimination of carbon dioxide affords the product via an intramolecular rearrangement. PMID- 28590739 TI - Development of 1-((1,4-trans)-4-Aryloxycyclohexyl)-3-arylurea Activators of Heme Regulated Inhibitor as Selective Activators of the Eukaryotic Initiation Factor 2 Alpha (eIF2alpha) Phosphorylation Arm of the Integrated Endoplasmic Reticulum Stress Response. AB - Heme-regulated inhibitor (HRI), an eukaryotic translation initiation factor 2 alpha (eIF2alpha) kinase, plays critical roles in cell proliferation, differentiation, adaptation to stress, and hemoglobin disorders. HRI phosphorylates eIF2alpha, which couples cellular signals, including endoplasmic reticulum (ER) stress, to translation. We previously identified 1,3-diarylureas and 1-((1,4-trans)-4-aryloxycyclohexyl)-3-arylureas (cHAUs) as specific activators of HRI that trigger the eIF2alpha phosphorylation arm of ER stress response as molecular probes for studying HRI biology and its potential as a druggable target. To develop drug-like cHAUs needed for in vivo studies, we undertook bioassay-guided structure-activity relationship studies and tested them in the surrogate eIF2alpha phosphorylation and cell proliferation assays. We further evaluated some of these cHAUs in endogenous eIF2alpha phosphorylation and in the expression of the transcription factor C/EBP homologous protein (CHOP) and its mRNA, demonstrating significantly improved solubility and/or potencies. These cHAUs are excellent candidates for lead optimization for development of investigational new drugs that potently and specifically activate HRI. PMID- 28590742 TI - Enantio- and Diastereoselective Cyclopropanation of beta,gamma-Unsaturated alpha Ketoester by a Chiral Phosphate/Indium(III) Complex. AB - We report herein an enantioselective cyclopropanation of beta,gamma-unsaturated alpha-ketoesters with diazoesters by the complexes of InBr3 and chiral calcium phosphate. The reaction proceeds via a Michael addition-cyclization pathway to afford highly functionalized chiral cyclopropanes with excellent enantioselectivities (up to >99% ee) as a single diastereoisomer. PMID- 28590743 TI - Nanoscale Surface Curvature Effects on Ligand-Nanoparticle Interactions: A Plasmon-Enhanced Spectroscopic Study of Thiolated Ligand Adsorption, Desorption, and Exchange on Gold Nanoparticles. AB - The interfacial adsorption, desorption, and exchange behaviors of thiolated ligands on nanotextured Au nanoparticle surfaces exhibit phenomenal site-to-site variations essentially dictated by the local surface curvatures, resulting in heterogeneous thermodynamic and kinetic profiles remarkably more sophisticated than those associated with the self-assembly of organothiol ligand monolayers on atomically flat Au surfaces. Here we use plasmon-enhanced Raman scattering as a spectroscopic tool combining time-resolving and molecular fingerprinting capabilities to quantitatively correlate the ligand dynamics with detailed molecular structures in real time under a diverse set of ligand adsorption, desorption, and exchange conditions at both equilibrium and nonequilibrium states, which enables us to delineate the effects of nanoscale surface curvature on the binding affinity, cooperativity, structural ordering, and the adsorption/desorption/exchange kinetics of organothiol ligands on colloidal Au nanoparticles. This work provides mechanistic insights on the key thermodynamic, kinetic, and geometric factors underpinning the surface curvature-dependent interfacial ligand behaviors, which serve as a central knowledge framework guiding the site-selective incorporation of desired surface functionalities into individual metallic nanoparticles for specific applications. PMID- 28590744 TI - Inhibiting Low-Frequency Vibrations Explains Exceptionally High Electron Mobility in 2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F2-TCNQ) Single Crystals. AB - Organic electronics requires materials with high charge mobility. Despite decades of intensive research, charge transport in high-mobility organic semiconductors has not been well understood. In this Letter, we address the physical mechanism underlying the exceptionally high band-like electron mobility in F2-TCNQ (2,5 difluoro-7,7,8,8-tetracyanoquinodimethane) single crystals among a crystal family of similar compounds Fn-TCNQ (n = 0, 2, 4) using a combined experimental and theoretical approach. While electron transfer integrals and reorganization energies did not show outstanding features for F2-TCNQ, Raman spectroscopy and solid-state DFT indicated that the frequency of the lowest vibrational mode is nearly twice higher in the F2-TCNQ crystal than in TCNQ and F4-TCNQ. This phenomenon is explained by the specific packing motif of F2-TCNQ with only one molecule per primitive cell so that electron-phonon interaction decreases and the electron mobility increases. We anticipate that our findings will encourage investigators for the search and design of organic semiconductors with one molecule per primitive cell and/or the poor low-frequency vibrational spectrum. PMID- 28590745 TI - Sensitive Detection of Staphylococcus aureus with Vancomycin-Conjugated Magnetic Beads as Enrichment Carriers Combined with Flow Cytometry. AB - A novel sandwich strategy was designed to detect Staphylococcus aureus. The strategy is based on an antibacterial agent that captures bacterial cells and a fluorescein-labeled antibody that acts as the signal-output probe. Vancomycin (Van), which exerts a strong antibacterial effect on Gram-positive bacteria, was utilized as a molecular recognition agent to detect pathogenic bacteria. To effectively concentrate S. aureus, we used bovine serum albumin (BSA) as the amplification carrier to modify magnetic beads (MBs), which were then functionalized with Van. To improve the specificity of the method for S. aureus detection, we adopted fluorescein isothiocyanate (FITC)-tagged pig immunoglobulin G (FITC-pig IgG) as the signal probe and the second recognition agent that bound between the Fc fragment of pig IgG and protein A in the surface of S. aureus. To quantify S. aureus, we measured the fluorescence signal by flow cytometry (FCM). The use of multivalent magnetic nanoprobes (Van-BSA-MBs) showed a high concentration efficiency (>98%) at bacterial concentrations of only 33 colony forming units (CFU)/mL. Furthermore, the sandwich mode (FITC-pig IgG/SA/Van-BSA MBs) also showed ideal specificity because Van and IgG bound with S. aureus at two distinct sites. The detection limit for S. aureus was 3.3 * 101 CFU/mL and the total detection process could be completed within 120 min. Other Gram positive bacteria and Gram-negative bacteria, including Listeria monocytogenes, Bacillus cereus, Cronobacter sakazakii, Escherichia coli O157:H7, and Salmonella Enteritidis, negligibly interfered with S. aureus detection. The proposed detection strategy for S. aureus possesses attractive characteristics, such as high sensitivity, simple operation, short testing time, and low cost. PMID- 28590746 TI - Iminoxyl Radical-Promoted Oxycyanation and Aminocyanation of Unactivated Alkenes: Synthesis of Cyano-Featured Isoxazolines and Cyclic Nitrones. AB - A novel and facile approach to vicinal oxycyanation and aminocyanation of internal unactivated alkenes is developed. This method utilizes the dichotomous reactivity of iminoxyl radical derived from the initiation of beta,gamma- and gamma,delta-unsaturated ketoximes to provide the general difunctionalization of internal alkenes using tert-butyl hydroperoxide (TBHP) as the environmentally friendly oxidant, CuCN as the commercially available cyanating reagent, and pentamethyldiethylenetriamine (PMDETA) as the ligand. By using this protocol, a series of useful cyano-featured isoxazolines and cyclic nitrones were efficiently prepared. PMID- 28590747 TI - Synthesis of pi-Extended Fluoranthenes via a KHMDS-Promoted Anionic-Radical Reaction Cascade. AB - An unprecedented KHMDS-promoted domino reaction to furnish hydroxyfluoranthenes is described. Biaryl compounds bearing acyl and naphthylalkenyl moieties are transformed into 9-hydroxydibenzo[j,l]fluoranthenes in a single step through the formation of an aromatic and a pentagonal ring system. A variety of fluoranthenes including those with extended pi-conjugation, a heteroaromatic ring, and unsymmetrical substituents could be synthesized. Mechanistic studies reveal a unique reaction cascade where KHMDS acts as both a base and a single-electron donor. PMID- 28590748 TI - Huygens' Metasurfaces Enabled by Magnetic Dipole Resonance Tuning in Split Dielectric Nanoresonators. AB - Dielectric metasurfaces that exploit the different Mie resonances of nanoscale dielectric resonators are a powerful platform for manipulating electromagnetic fields and can provide novel optical behavior. In this work, we experimentally demonstrate independent tuning of the magnetic dipole resonances relative to the electric dipole resonances of split dielectric resonators (SDRs). By increasing the split dimension, we observe a blue shift of the magnetic dipole resonance toward the electric dipole resonance. Therefore, SDRs provide the ability to directly control the interaction between the two dipole resonances within the same resonator. For example, we achieve the first Kerker condition by spectrally overlapping the electric and magnetic dipole resonances and observe significantly suppressed backward scattering. Moreover, we show that a single SDR can be used as an optical nanoantenna that provides strong unidirectional emission from an electric dipole source. PMID- 28590749 TI - Copper-Catalyzed Asymmetric Hydroboration of 1,1-Disubstituted Alkenes. AB - A mild and efficient approach for highly regio- and enantioselective copper catalyzed hydroboration of 1,1-diaryl substituted alkenes with bis(pinacolato)diboron (B2Pin2) was developed for the first time, providing facile access to a series of valuable beta,beta-diaryl substituted boronic esters with high enantiomeric purity. Moreover, this approach could also be suitable for hydroboration of alpha-alkyl styrenes for the synthesis of enantioenriched beta,beta-arylalkyl substituted boronic esters. Gram-scale reaction, stereospecific derivatizations, and the application of important antimuscarinic drug (R)-tolterodine for concise enantioselective synthesis further highlighted the attractiveness of this new approach. PMID- 28590751 TI - Correction to Biochemical and Spectroscopic Characterization of the Non-Heme Fe(II)- and 2-Oxoglutarate-Dependent Ethylene-Forming Enzyme from Pseudomonas syringae pv. phaseolicola PK2. PMID- 28590750 TI - On-Chip Single-Plasmon Nanocircuit Driven by a Self-Assembled Quantum Dot. AB - Quantum photonics holds great promise for future technologies such as secure communication, quantum computation, quantum simulation, and quantum metrology. An outstanding challenge for quantum photonics is to develop scalable miniature circuits that integrate single-photon sources, linear optical components, and detectors on a chip. Plasmonic nanocircuits will play essential roles in such developments. However, for quantum plasmonic circuits, integration of stable, bright, and narrow-band single photon sources in the structure has so far not been reported. Here we present a plasmonic nanocircuit driven by a self-assembled GaAs quantum dot. Through a planar dielectric-plasmonic hybrid waveguide, the quantum dot efficiently excites narrow-band single plasmons that are guided in a two-wire transmission line until they are converted into single photons by an optical antenna. Our work demonstrates the feasibility of fully on-chip plasmonic nanocircuits for quantum optical applications. PMID- 28590752 TI - Optimization of an Enzymatic Antibody-Drug Conjugation Approach Based on Coenzyme A Analogs. AB - Phosphopantetheine transferases (PPTases) can be used to efficiently prepare site specific antibody-drug conjugates (ADCs) by enzymatically coupling coenzyme A (CoA)-linker payloads to 11-12 amino acid peptide substrates inserted into antibodies. Here, a two-step strategy is established wherein in a first step, CoA analogs with various bioorthogonal reactivities are enzymatically installed on the antibody for chemical conjugation with a cytotoxic payload in a second step. Because of the high structural similarity of these CoA analogs to the natural PPTase substrate CoA-SH, the first step proceeds very efficiently and enables the use of peptide tags as short as 6 amino acids compared to the 11-12 amino acids required for efficient one-step coupling of the payload molecule. Furthermore, two-step conjugation provides access to diverse linker chemistries and spacers of varying lengths. The potency of the ADCs was largely independent of linker architecture. In mice, proteolytic cleavage was observed for some C-terminally linked auristatin payloads. The in vivo stability of these ADCs was significantly improved by reduction of the linker length. In addition, linker stability was found to be modulated by attachment site, and this, together with linker length, provides an opportunity for maximizing ADC stability without sacrificing potency. PMID- 28590753 TI - The 1,2,4-Triazolo[4,3-a]pyrazin-3-one as a Versatile Scaffold for the Design of Potent Adenosine Human Receptor Antagonists. Structural Investigations to Target the A2A Receptor Subtype. AB - In this work, we describe the identification of the 1,2,4-triazolo[4,3-a]pyrazin 3-one as a new versatile scaffold for the development of adenosine human (h) receptor antagonists. The new chemotype ensued from a molecular simplification approach applied to our previously reported 1,2,4-triazolo[4,3-a]quinoxalin-1-one series. Hence, a set of novel 8-amino-2-aryl-1,2,4-triazolopyrazin-3-one derivatives, featured by different substituents on the 2-phenyl ring (R) and at position 6 (R6), was synthesized with the main purpose of targeting the hA2A adenosine receptor (AR). Several compounds possessed nanomolar affinity for the hA2A AR (Ki = 2.9-10 nM) and some, very interestingly, also showed high selectivity for the target. One selected potent hA2A AR antagonist (12, R = H, R6 = 4-methoxyphenyl) demonstrated some ability to counteract MPP+-induced neurotoxicity in cultured human neuroblastoma SH-SY5Y cells, a widely used in vitro Parkinson's disease model. Docking studies at hAR structures were performed to rationalize the observed affinity data. PMID- 28590754 TI - Multilevel Approaches within the Local Pair Natural Orbital Framework. AB - The linear-scaling local coupled cluster method DLPNO-CCSD(T) allows calculations on systems containing hundreds of atoms to be performed while reproducing canonical CCSD(T) energies typically with chemical accuracy (<1 kcal/mol). The accuracy of the method is determined by two main truncation thresholds that control the number of electron pairs included in the CCSD iterations and the size of the pair natural orbital virtual space for each electron pair, respectively. While the results of DLPNO-CCSD(T) calculations converge smoothly toward their canonical counterparts as the thresholds are tightened, the improved accuracy is accompanied by a fairly steep increase of the computational cost. Many applications study events that are confined to a relatively small region of the system of interest. Hence, it is viable to develop methods that allow the user to treat different parts of a large system at various levels of accuracy. In this work we present an extension to the native DLPNO method that fragments the system into preselected molecular parts and uses different thresholds or even different levels of theory for the interaction between individual fragments. Thereby chemical intuition can be used to focus computational resources on a more accurate evaluation of the properties at the center of interest, while permitting a less demanding description of the surrounding moieties. The strategy was implemented within the DLPNO-CCSD(T) framework. We tested the scheme for a series of realistic quantum chemical applications such as the calculation of the dimerization energies, potential energy surfaces, enantiomeric excess in organometallic catalysis, and the binding energy of the anticancer drug ellipticine to DNA. This work demonstrates the power of the approach and offers guidance to its setup. PMID- 28590755 TI - Morphology Evolution of Polymer Blends under Intense Shear During High Speed Thin Wall Injection Molding. AB - The morphology evolution under shear during different processing is indeed an important issue regarding the phase morphology control as well as final physical properties of immiscible polymer blends. High-speed thin wall injection molding (HSTWIM) has recently been demonstrated as an effective method to prepare alternating multilayered structure. To understand the formation mechanism better and explore possible phase morphology for different blends under HSTWIM, the relationship between the morphology evolution of polymer blends based on polypropylene (PP) under HSTWIM and some intrinsic properties of polymer blends, including viscosity ratio, interfacial tension, and melt elasticity, is systematically investigated in this study. Blends based on PP containing polyethylene (PE), ethylene vinyl alcohol copolymer (EVOH), and polylactic acid (PLA) are used as examples. Compatibilizer has also been added into respective blends to alter their interfacial interaction. It is demonstrated that dispersed phase can be deformed into a layered-like structure if interfacial tension, viscosity ratio, and melt elasticity are relatively small. While some of these values are relatively large, these dispersed droplets are not easily deformed under HSTWIM, forming ellipsoidal or fiber-like structure. The addition of a moderate amount of compatibilizer into these blends is shown to be able to reduce interfacial tension and the size of dispersed phase, thus, allowing more deformation on the dispersed phase. Such a study could provide some guidelines on phase morphology control of immiscible polymer blends under shear during various processing methods. PMID- 28590756 TI - Lattice Model of an Ionic Liquid at an Electrified Interface. AB - We study ionic liquids interacting with electrified interfaces. The ionic fluid is modeled as a Coulomb lattice gas. We compare the ionic density profiles calculated using a popular modified Poisson-Boltzmann equation with the explicit Monte Carlo simulations. The modified Poisson-Boltzmann theory fails to capture the structural features of the double layer and is also unable to correctly predict the ionic density at the electrified interface. The lattice Monte Carlo simulations qualitatively capture the coarse-grained structure of the double layer in the continuum. We propose a convolution relation that semiquantitatively relates the ionic density profiles of a continuum ionic liquid and its lattice counterpart near an electrified interface. PMID- 28590758 TI - Cross-Coupling Reactions of Aryldiazonium Salts with Allylsilanes under Merged Gold/Visible-Light Photoredox Catalysis. AB - A method for the cross-coupling reactions of aryldiazonium salts with trialkylallylsilanes via merged gold/photoredox catalysis is described. The reaction is proposed to proceed through a photoredox-promoted generation of an electrophilic arylgold(III) intermediate that undergoes transmetalation with allyltrimethylsilane to form allylarenes. PMID- 28590757 TI - Donor-sigma-Acceptor Molecules for Green Thermally Activated Delayed Fluorescence by Spatially Approaching Spiro Conformation. AB - By separating donor/acceptor with a sigma linker while keeping them in contact through space interactions, new oxygen-bridged triphenylamine/fluorene-based donor-sigma-acceptor (D-sigma-A) type thermally activated delayed fluorescence (TADF) emitters are developed. X-ray structural analyses and time-dependent density functional theory reveal that tilted configuration of spiro skeleton, extended delocalization of the highest occupied molecular orbital (HOMO), and lowest triplet state of charge transfer property (3CT) play key roles in the TADF mechanism. OLEDs fabricated with these D-sigma-A emitters achieved good external quantum efficiency of 20.4% and long operating durability of 18000 h at 100 cd m 2. PMID- 28590759 TI - Effects of Nozzle Geometry on the Fluid Dynamics of Thin Liquid Films Flowing down Vertical Strings in the Rayleigh-Plateau Regime. AB - Thin-liquid films flowing down vertical strings undergo instability, creating wavy film profiles and traveling beads. Previous studies assumed that the liquid film thickness and velocity profiles within the healing length from a nozzle were specified by the Nusselt solution, independent of the nozzle geometry. As a result, the influence of the nozzle diameter on the flow characteristics, such as the liquid bead size, spacing, and traveling speed, was largely overlooked. We report an experimental and numerical simulation study on liquid-film flows in the Rayleigh-Plateau regime while systematically varying the nozzle diameter from 0.5 to 3.2 mm at different mass flow rates (0.02, 0.04, 0.06, and 0.08 g/s). We find that the nozzle diameter does have a strong influence on the flow regime and the flow characteristics. We identify the thickness of a nearly flat portion of a liquid film that precedes the onset of instability, which we term the preinstability thickness, as a critical flow parameter that governs the size, spacing, and frequency of liquid beads that develop downstream. By defining the liquid film aspect ratio alpha in terms of the preinstability thickness, we capture a flow transition from the Rayleigh-Plateau (RP) instability regime to the isolated droplet regime. Improved understanding of the flow regimes and characteristics assists in the systematic design and optimization of a wide variety of processes and devices, including fiber coating and direct contact heat and mass exchangers. PMID- 28590760 TI - Oscillating Ferrofluid Droplet Microrheology of Liquid-Immersed Sessile Droplets. AB - The damped oscillations of liquid-immersed ferrofluid sessile droplets were studied with high-speed imaging experiments and analytical modeling to develop a novel microrheology technique. Droplet oscillations were induced with an external magnetic field, thereby avoiding transients in the resulting vibrational response of the droplet. By following the droplet relaxation with a high-speed camera, the frequency and relaxation time of the damped harmonic oscillations were measured. We extend upon existing analytical theories to describe our liquid-immersed sessile droplet system, and directly quantify the droplet relaxation with the viscosity of the internal and external fluid as well as the interfacial tension between these. The easily controllable magnetic droplets make our oscillating ferrofluid droplet technique a potential candidate for high-throughput microrheology and tensiometry in the future. PMID- 28590763 TI - Helically Chiral 1-Sulfur-Functionalized [6]Helicene: Synthesis, Optical Resolution, and Functionalization. AB - The synthesis and optical resolution of helically chiral 5,6,9,10-tetrahydro-1 [6]helicenethiol and its subsequent transformations to enantiopure 1-sulfur functionalized [6]helicenes are reported. A novel enantiopure [7]thiahelicene having a thiophene ring at the terminal position of the [6]helicene skeleton was synthesized. PMID- 28590762 TI - Direct Oxidative Cleavage of Multiple Csp3-H Bonds and a C-C Bond in 2-(Pyridin-2 yl)acetate Derivatives: Formal [3 + 1 + 1] Synthesis of 3-(Pyridin-2 yl)indolizine Skeletons. AB - A novel iodine-promoted oxidative cross-coupling/cyclization of 2-(pyridin-2 yl)acetate derivatives and methyl ketones via the cleavage of multiple Csp3-H bonds has been developed, which also achieved efficient cleavage of a C-C bond in the 2-(pyridin-2-yl)acetate derivatives. This protocol represents an elegant molecular fragment assembly of diverse 3-(pyridin-2-yl)indolizines via a formal [3 + 1 + 1] annulation. Notably, the pyridine derivatives serve two pivotal roles to provide two fragments to construct 3-(pyridin-2-yl)indolizine skeletons, rather than the single role in building common indolizines. PMID- 28590761 TI - Proteome-wide Adaptations of Mouse Skeletal Muscles during a Full Month in Space. AB - The safety of space flight is challenged by a severe loss of skeletal muscle mass, strength, and endurance that may compromise the health and performance of astronauts. The molecular mechanisms underpinning muscle atrophy and decreased performance have been studied mostly after short duration flights and are still not fully elucidated. By deciphering the muscle proteome changes elicited in mice after a full month aboard the BION-M1 biosatellite, we observed that the antigravity soleus incurred the greatest changes compared with locomotor muscles. Proteomics data notably suggested mitochondrial dysfunction, metabolic and fiber type switching toward glycolytic type II fibers, structural alterations, and calcium signaling-related defects to be the main causes for decreased muscle performance in flown mice. Alterations of the protein balance, mTOR pathway, myogenesis, and apoptosis were expected to contribute to muscle atrophy. Moreover, several signs reflecting alteration of telomere maintenance, oxidative stress, and insulin resistance were found as possible additional deleterious effects. Finally, 8 days of recovery post flight were not sufficient to restore completely flight-induced changes. Thus in-depth proteomics analysis unraveled the complex and multifactorial remodeling of skeletal muscle structure and function during long-term space flight, which should help define combined sets of countermeasures before, during, and after the flight. PMID- 28590764 TI - An Entirely Solid Phase Peptide Synthesis-Based Strategy for Synthesis of Gelatinase Biosynthesis-Activating Pheromone (GBAP) Analogue Libraries: Investigating the Structure-Activity Relationships of the Enterococcus faecalis Quorum Sensing Signal. AB - The development of an entirely solid-phase peptide synthesis (SPPS)-based synthesis of the quorum sensing signal gelatinase biosynthesis-activating pheromone (GBAP) from Enterococcus faecalis is reported. The method was used to prepare three libraries of analogues to investigate the structure-activity relationships (SARs) of the GBAP signal. The SAR studies revealed new characteristics of the GBAP signal and uncovered the most potent quorum sensing activator in E. faecalis known to date. PMID- 28590765 TI - Ultrasonographic Evaluation of Acupuncture Effect on Common Extensor Tendon Thickness in Patients with Lateral Epicondylitis: A Randomized Controlled Study. AB - OBJECTIVE: To explore the effect of acupuncture on common extensor tendon (CET) thickness in patients with lateral epicondylitis (LE). Additionally, to identify whether clinical and ultrasonographic changes showed any correlation. METHODS: Forty-one patients were randomly assigned to acupuncture and control groups. Conventional treatment (rest, NSAII, bracing, exercise) methods for LE were applied to all patients. In addition to this, the acupuncture treatment was applied to the acupuncture group. The visual analog scale (VAS) for pain, the Duruoz Hand Index (DHI) for functioning of the affected limb, the pressure pain threshold, and CET thickness (via ultrasound imaging) were assessed before and end of the treatment in both groups. RESULTS: The VAS and DHI scores in both groups decreased. The pressure pain threshold and CET thickness only demonstrated improvement in the acupuncture group. CONCLUSION: These findings show that the CET thickness was reduced after 10 sessions of acupuncture treatment in LE patients. PMID- 28590766 TI - Examining Burnout, Depression, and Self-Compassion in Veterans Affairs Mental Health Staff. AB - OBJECTIVES: Burnout, a state of emotional exhaustion associated with negative personal and occupational outcomes, is prevalent among healthcare providers. A better understanding of the psychological factors that may be associated with resilience to burnout is essential to develop effective interventions. Self compassion, which includes kindness toward oneself, recognition of suffering as part of shared human experience, mindfulness, and nonjudgment toward inadequacies and failures, may be one such factor. The purpose of this study was to examine the relationships between burnout, depression, and self-compassion in Veterans Affairs (VA) mental health staff. DESIGN: Cross-sectional study. SETTING: VA medical center and affiliated community-based clinics. PARTICIPANTS: VA mental health staff. OUTCOME MEASURES: The 19-item Copenhagen Burnout Inventory, the 26 item Self-Compassion Scale, and the Patient Health Questionnaire 2-item depression screen. Demographic information included age, sex, years worked in current position, and number of staff supervised. RESULTS: One hundred and twenty eight of a potential 379 individuals (33.8%) responded. Clerical support, nursing, social work, psychology, and psychiatry were the major professions represented. Self-compassion was inversely correlated with burnout (r = -0.41, p < 0.001), and inversely correlated with depression (rpb = -0.39, p < 0.001). The inverse relationship between self-compassion and burnout remained significant even after accounting for depressive symptoms and demographic variables in a multiple linear regression model. Of all the variables examined, self-compassion was the strongest predictor of burnout. CONCLUSIONS: The results of this study support the hypothesis that self-compassion may be associated with resilience to burnout. Alternatively, decreased self-compassion may be a downstream effect of increased burnout. Prospective, longitudinal studies are needed to determine the directional relationship between these factors, and whether interventions that cultivate self-compassion may decrease burnout and/or protect against its negative personal and professional outcomes. PMID- 28590767 TI - Effects of Biodanza on Stress, Depression, and Sleep Quality in University Students. AB - BACKGROUND: The existing literature shows dance to be an innovative and successful form of stress management. Previous research indicates that Biodanza is able to increase well-being and personal resources and prevent stress. However, Biodanza has not yet been empirically tested as a possible therapy for application outside the clinical context in young adults with perceived stress. OBJECTIVES: This study aimed to determine the effectiveness of Biodanza in reducing symptoms of perceived stress and depression and in promoting sleep quality in young adults, comparing the changes with those observed in a control group. DESIGN: Randomized controlled trial. SETTINGS/LOCATION: This study was carried out at the Faculty of Health Sciences of the University of Almeria. SUBJECTS: One hundred and twenty-one university students with perceived stress were randomly placed into either a Biodanza group or a wait-list control group. INTERVENTION: Study participants attended Biodanza sessions for 90 min a week, over a period of 4 weeks. OUTCOME MEASURES: Depression, perceived stress, and sleep quality were assessed both before and after intervention. RESULTS: Ninety five participants completed the program and were included in the statistical analysis. Significant differences in perceived stress [t (93) = 2.136; p = 0.015] and depression [t (93) = 2.738; p = 0.000] were observed after the Biodanza period. Pre/post analysis found that Biodanza also had a significant effect on depression (Cohen d = 1.88; p < 0.05) and perceived stress (Cohen d = 0.79; p < 0.05). CONCLUSION: The Biodanza program is an effective stress management strategy for students. The results of this study showed Biodanza to have a positive effect on perceived stress and depression in young adults. This demonstrates how artistic, collaborative, and psychophysical interventions are an effective means of preventing and managing these problems in university students. PMID- 28590768 TI - Effect of Hydroalcoholic Extract of Capsella bursa pastoris on Early Postpartum Hemorrhage: A Clinical Trial Study. AB - OBJECTIVES: Postpartum hemorrhage (PPH) is one of three main causes of maternal mortality and a life-threatening condition throughout the world. PPH can have irreversible complications for the mother even if it does not lead to death. This study was conducted to determine the effect of hydroalcoholic extract of Capsella bursa pastoris on early PPH. DESIGN: The present study was a single-blinded, randomized, clinical trial. SETTING: The study was conducted in Afzalipour Hospital of Kerman in 2015. SUBJECTS: The subjects included 100 women who had given vaginal birth and met the study inclusion criteria. INTERVENTION: The participants were selected and randomly assigned into an intervention group (n = 50) and a placebo group (n = 50). Immediately after placental expulsion, the intervention group was given 10 sublingual drops of the hydroalcoholic extract of Capsella bursa pastoris plus an infusion of 20 U of oxytocin in 1 L of Ringer's solution, and the control group was given 10 sublingual drops of the placebo plus an infusion of 20 U of oxytocin in 1 L of Ringer's solution. OUTCOME MEASURES: The amount of bleeding was assessed in both groups. Hemoglobin and hematocrit levels were measured in all the participants 6 h after childbirth. The statistical analysis of the data was performed in SPSS-17 using the following tests: independent t, paired t, repeated measures ANOVA, Friedman's, Wilcoxon, Mann-Whitney, Fisher's exact, and chi square. P-value <0.05 was considered statistically significant. RESULTS: There were no significant differences between groups in baseline characteristics (p > 0.05). After the intervention, there was significant decrease in the amount of postpartum bleeding in both groups. However, the mean decrease in the amount of bleeding was significantly more in the Capsella bursa pastoris group (p < 0.001). CONCLUSION: Compared with the mere administration of oxytocin, sublingual Capsella bursa drops appear to be effective in reducing PPH in this study. Further research regarding the efficacy and safety of various doses of Capsella bursa pastoris is required. PMID- 28590769 TI - Associations of Genetic Polymorphisms Relevant to Metabolic Pathway of Vitamin D3 with Development and Prognosis of Childhood Bronchial Asthma. AB - This study was aimed at investigating the correlation between genetic polymorphisms relevant to metabolic pathway of vitamin D3 (VD3) and susceptibility to childhood bronchial asthma. Altogether 143 childhood patients with bronchial asthma and 143 healthy children of Chinese Han ethnicity were enrolled in this study. The key single-nucleotide polymorphisms (SNPs) were identified by HaploView 4.2 software and selected from previous investigations. Genomic DNAs were isolated from peripheral blood samples by using TaqMan Blood DNA kits. The genotyping of SNPs was performed by TaqMan SNPs genotyping assay. Odds ratios and corresponding 95% confidence intervals were calculated to evaluate the association between SNPs and susceptibility to bronchial asthma. Statistical analyses were conducted by using SPSS 13.0 software. Rs10766197 of CYP2R1, rs7041 and rs4588 of CG, rs4646536 of CYP27B1, rs2228570, rs7975232, and rs1544410 of VDR, as well as rs1805192 and rs10865710 of PPAR were shown to be significantly associated with increased risk of bronchial asthma. Besides, prognosis of childhood bronchial asthma, which was represented as Saint George Respiratory Questionnaire (SGRQ) scoring, was closely linked with CYP2R1 rs10766197, CYP27B1 rs4646536, VDR rs7975232, VDR rs1544410, PPAR rs1805192, and PPAR rs10865710. The haplotype analysis suggested that TA and CG of CG rs7041/rs4588, CA and AG of VDR rs7975232/rs1544410, and CC of PPAR rs1805192/rs10865710 were, respectively, correlated with levels of VD, IL-4, and IL-5. And only haplotypes of VDR showed associations with risk of bronchial asthma during childhood, whereas hardly any significance could be observed between the haplotypes and behavior of quality-of-life (SGRQ) scoring. Significant associations were found between rs10766197 of CYP2R1, rs7041 and rs4588 of CG, rs4646536 of CYP27B1, rs2228570, rs7975232, and rs1544410 of VDR, as well as rs1805192 and rs10865710 of PPAR and susceptibility to and prognosis of childhood bronchial asthma, providing novel targets for treating the disorder. PMID- 28590770 TI - Pediatric Abdominal Radiographs: Common and Less Common Errors. AB - OBJECTIVE: Interpretation of abdominal radiographs of children benefits from a firm knowledge of the congenital anomalies and pathologies unique to this patient population, leveraged by a systematic approach. Interpretive errors place the patients and their families at risk for a delay in diagnosis, unnecessary additional imaging, a potential increase in the radiation burden, and possible psychologic trauma. CONCLUSION: In this article, we describe the common and uncommon potential pitfalls in pediatric abdominal radiography, using several of our own interpretive errors as a framework while providing teaching points to help avoid these mistakes. PMID- 28590771 TI - Non-contrast MR angiography using three-dimensional balanced steady-state free precession imaging for evaluation of stenosis in the celiac trunk and superior mesenteric artery: a preliminary comparative study with computed tomography angiography. AB - OBJECTIVE: Although non-contrast MR angiography (NC-MRA) is well established for the evaluation of renal artery stenosis, its usefulness in the evaluation of other abdominal aortic branches remains to be studied. This study aimed at evaluating the image quality and diagnostic accuracy of NC-MRA using a three dimensional balanced steady-state free-precession sequence in identifying stenosis in the celiac trunk (CTR) and superior mesenteric artery (SMA) as compared with CT angiography (CTA) as the reference standard. METHODS: 41 patients underwent both NC-MRA and CTA of the abdominal aorta. Two radiologists analyzed the quality of the images (diagnostic vs non-diagnostic) and the performance (accuracy, sensitivity and specificity) of NC-MRA for the identification of arterial stenosis. Kappa tests were used to determine the interobserver agreement and the intermethod agreement between NC-MRA and CTA. RESULTS: NC-MRA provided diagnostic quality images of the CTR and SMA in 87.8% and 90.2% of cases, respectively, with high interobserver agreement (kappa 0.95 and 0.80, respectively). For stenosis assessment, NC-MRA had a sensitivity of 100%, a positive-predictive value of 50% and a negative-predictive value of 100% for both segments, with accuracies of 88.8% for the CTR and 94.5% for the SMA. CONCLUSION: NC-MRA is an accurate method for detecting stenosis in the CTR and SMA. Advances in knowledge: Data from this study suggest that MR angiography with balanced steady-state free-precession sequence is a viable non-contrast alternative for stenosis evaluation of these branches in patients for whom a contrast-enhanced examination is contraindicated. PMID- 28590772 TI - Arterial stiffness in fertile women with metabolic syndrome. AB - INTRODUCTION: Although metabolic syndrome (MetS) is evidently associated with the risk of cardiovascular disease (CVD), recently its use has been questioned. We studied the utility of MetS diagnosis when estimating individual CVD risk. METHODS: We compared 27 fertile women with MetS and 27 counterparts without the syndrome, matched pairwise according to well-known risk factors of CVD. Pulse wave velocity (PWV) and central blood pressure (cBP) were determined noninvasively via a SphygmoCor device. Arterial compliance was measured noninvasively with an HDI/PulseWaveTMCR-2000 arterial tonometer. RESULTS: PWV (7.1 +/- 2.5 versus 6.5 +/- 1.1 m/s, p = .037), and both systolic (120.9 +/- 12.2 versus 111.5 +/- 16.0 mmHg, p = .031) and diastolic cBP (81.3 +/- 8.5 versus 74.1 +/- 11.2 mmHg, p = .035) were higher in the MetS group. Systemic arterial compliance values were lower in both large (15.1 +/- 8.0 versus 16.1 +/- 4.4 mL/mmHg * 10, p = .034) and small arteries (7.1 +/- 2.5 versus 9.3 +/- 3.2 mL/mmHg *100, p = .010) in women with MetS. CONCLUSIONS: Fertile women with MetS had increased arterial stiffness, as measured by three different methods. Our results highlight the utility of MetS when revealing increased individual CVD risks in fertile-aged women. Key messages Women with MetS have increased arterial stiffness when measured by different methods. MetS is a useful clinical tool to assess increased cardiovascular risk, particularly among fertile-aged women. PMID- 28590773 TI - Factors influencing brown fat activation in FDG PET/CT: a retrospective analysis of 15,000+ cases. AB - OBJECTIVE: Brown fat can exhibit high uptake of fluorine-18 fludeoxyglucose (18F FDG) on positron emission tomography (PET) and interferes with interpretation of the scan. The goal of this study was to identify factors that may influence brown adipose tissue (BAT) activation. METHODS: A retrospective study of 18F-FDG PET scans was performed using a database of 15,109 PET/CT reports. BAT activation reported by nuclear medicine physicians and factors influencing BAT activation were gathered. The data were analyzed using in-house software. RESULTS: The total reported BAT activation was 3.6%. BAT activation was reported significantly more often in patients who were female (p < 0.0001), younger (p < 0.0001), with lower body mass index (p < 0.0001), with lower blood glucose levels (p = 0.01), indicated for breast cancer (p = 0.004), not administered chemotherapy recently before the scan (p < 0.0001) and shown to have BAT activation in a previous scan (p < 0.0001). BAT activation was also reported significantly more for lower outdoor temperatures (p < 0.0001) and for late morning scans than for afternoon (p = 0.005) and early morning (p = 0.001) scans. CONCLUSION: This retrospective study of 15,109 scans highlights multiple factors contributing to BAT activation on 18F-FDG PET. The identification of new factors influencing BAT and confirmation of previously identified factors with a larger data set can be used to more accurately identify patients at risk for BAT activation so that prevention strategies can be implemented. Advances in knowledge: This study presents new factors associated with higher incidence of BAT activation, such as time of day, previous BAT activation and breast cancer. Conversely, recent chemotherapy was associated with reduced incidence of BAT activation. PMID- 28590774 TI - Fluorine-18 fluorodeoxyglucose positron emission tomography in the management of solitary pulmonary nodule: a review. AB - Solitary pulmonary nodules are common radiologic findings and their detection has increased due to the introduction and improvement of diagnostics. Since a nodule can be an expression of early lung cancers, a proper classification and management are required because its treatment might lead to decreased morbidity and mortality. In this regard, prominent guidelines are available although they are characterized sometimes by discordant and misleading evidences. Furthermore, the same results of studies in the literature appear conflicting. Aim of this work is to evaluate the role of imaging through an extensive literature review but focusing on 18-fluorine fluorodeoxyglucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) in order to assess the limits and future perspectives of solitary pulmonary nodule characterization in early detection of lung cancer. Key messages Detection of solitary pulmonary nodules has increased. Management of solitary pulmonary nodules is still debated. Future perspectives of early solitary pulmonary nodule characterization. PMID- 28590775 TI - MDCT Angiography With 3D Rendering: A Novel Cinematic Rendering Algorithm for Enhanced Anatomic Detail. AB - OBJECTIVE: The two most widely used postprocessing 3D tools in clinical practice are volume rendering (VR) and maximum intensity projection (MIP). With the use of current-generation MDCT, these techniques enable accurate characterization of arterial anatomy and pathology in all anatomic regions. Recently, the VR algorithm has been enhanced by the incorporation of a new lighting model. This new technique-called cinematic rendering-generates photorealistic images with the potential to more accurately depict anatomic detail. CONCLUSION: As an enhancement of the technology championed in VR, cinematic rendering promises to provide additional anatomic detail for MDCT interpretation and display. Future investigations must be conducted to evaluate the diagnostic accuracy of cinematic rendering and determine whether interpretative pitfalls result from its unique lighting model in practice. PMID- 28590777 TI - Reply: Response to Risks and Cough-Aggravating Factors in Prolonged Cough. PMID- 28590776 TI - Clinical effects of chemoradiotherapy in pursuit of optimal treatment of locally advanced unresectable pancreatic cancer. AB - OBJECTIVE: The treatment of locally advanced unresectable pancreatic cancer remains extremely challenging, particularly as the efficacy of concurrent chemoradiotherapy (CRT) remains unclear. METHODS: We studied 93 patients (8.0%) with locally advanced unresectable pancreatic cancer without distant metastases from among a total group of 1168 patients who were diagnosed with pancreatic cancer from March 2005 to November 2015 at the Kochi Health Sciences Center, Kochi, Japan. We therefore evaluated the clinical efficacy of CRT in patients with locally advanced unresectable pancreatic cancer. RESULTS: Of the 93 patients with locally advanced unresectable pancreatic cancer, 35 patients (37.6%) were subsequently classified as having resectable disease following CRT. The median overall survival of patients who received CRT alone for locally advanced unresectable pancreatic cancer was 8.0 months, and all died within 3 years. On the other hand, the overall 1-, 3- and 5-year survival rates in patients who were reclassified as having resectable tumour after CRT were 71.3%, 39.2% and 23.5%, respectively. Our pathological assessments after surgical resection suggested that CRT might be associated with a significant reduction in the risk of lymph node metastases in patients with locally advanced unresectable pancreatic cancer. CONCLUSION: The results of this study suggested that CRT is clinically effective in improving survival, particularly in association with the resultant possibility of curative resection. Advances in knowledge: The best treatment strategy for patients with locally advanced unresectable pancreatic cancer is the subject of considerable debate, and CRT is only recommended if cancer has only grown around the pancreas without any distant metastases. PMID- 28590778 TI - Accounts for Unprotected Sex with Partners Met Online from Heterosexual Men and Women from Large US Metropolitan Areas. AB - For about 30 years, soon after the onset of the AIDS epidemic, sexual-health messaging has emphasized personal responsibility for using condoms to protect from acquiring or transmitting HIV or other sexually transmitted infections. Those who did not use condoms during casual sexual encounters may therefore feel compelled to offer to others aware of their behavior what sociologists have called "accounts," an impression-management strategy to avoid unfavorable judgment. We analyzed accounts-excuses and justifications-from qualitative interviews with 150 adults who had unprotected sex in the past 3 months with at least two different partners met online (ages 18-50, mean: 33.7, equally divided among black, Hispanic, and white men and women, over half were college educated and the median yearly household income range was $50-$75,000). Many participants made excuses that aimed to defer responsibility for unprotected sex: they claimed that consistently practicing safer sex was impossible, that they got carried away by sexual passion, that they were inebriated, that they were influenced by emotional or psychological problems, or they put fault on their partners. Participants also provided justifications, claiming that unsafe sex had been acceptable because the risks taken were likely minimal or negotiated with their partner. Understanding the accounts heterosexual adults offer to excuse and justify condomless sex with partners met online can be helpful in developing prevention messages that debunk these explanations for their behavior. PMID- 28590779 TI - Oculopharyngeal Muscular Dystrophy and Inherited Retinal Dystrophy in Bukhara Jews Due to Linked Mutations in the PABPN1 and NRL Genes. AB - AIM: We have previously described two unrelated Bukhara Jews (BJs) with a combination of oculopharyngeal muscular dystrophy (OPMD) and inherited retinal dystrophy (IRD), because of mutations in two linked genes: PABPN1 and NRL. Here we investigated the prevalence of the NRL mutation among BJs with OPMD. MATERIALS AND METHODS: PABPN1 and NRL mutation testing were performed by polymerase chain reaction amplification and direct sequencing on two cohorts of Bukhara Jewish patients: OPMD patients (with or without IRD) and IRD patients (without OPMD). RESULTS: Of 24 unrelated chromosomes from Bukhara Jewish OPMD patients, 19 (79%) harbored the NRL mutation. In contrast, the NRL mutation was not detected in Bukhara Jewish patients diagnosed with IRD but without OPMD. CONCLUSIONS: Our findings provide an explanation for the reoccurrence of IRD in Bukhara Jewish OPMD homozygotes. Moreover, they indicate that Bukhara Jewish OPMD patients are at high risk for carrying the NRL mutation, and should be offered appropriate genetic counseling and testing. PMID- 28590780 TI - Intravoxel incoherent motion and dynamic contrast-enhanced MRI for differentiation between hepatocellular adenoma and focal nodular hyperplasia. AB - OBJECTIVE: To examine if intravoxel incoherent motion (IVIM) and dynamic contrast enhanced MRI (DCE-MRI) can be used as new and supplemental MRI techniques to differentiate hepatocellular adenomas (HCAs) from focal nodular hyperplasias (FNHs) and analyse if diffusion parameter apparent diffusion coefficient (ADC) and IVIM parameter true diffusion coefficient (D) differ in doing so. METHODS: This prospective study included 21 patients (8 HCAs and 13 FNHs) who underwent a specifically designed MRI scanning protocol, including series for analysis of IVIM (four b-values 0, 10, 150 and 800 s mm-2) and DCE-MRI. On a dedicated workstation, identical regions of interest were placed in parametric maps of Ktrans, Ve, D and ADC in each lesion for quantification. Diagnostic accuracy was assessed using receiver operating characteristics analysis. Time-intensity curves (TICs) were classified in different types. RESULTS: HCAs had significantly lower values for Ktrans (mean 1.45 vs 2.68 min-1; p = 0.029) and D (mean 1.02 * 10-3 vs 1.22 * 10-3 mm2 s-1; p = 0.033). Both parameters showed good diagnostic accuracy of 76%. TIC analysis could not differentiate between HCAs and FNHs. CONCLUSION: In this exploratory study, Ktrans and D were able to differentiate HCAs from FNHs in most cases, whereas Ve, ADC and TIC analysis were not. Advances in knowledge: Histological differences between HCAs and FNHs can be quantified on MRI using Ktrans and D. PMID- 28590782 TI - Rhabdomyosarcoma in Children and Adolescents: Patterns and Risk Factors of Distant Metastasis. AB - OBJECTIVE: The objective of this study is to evaluate patterns of distant metastasis and identified factors that may increase the risk of distant metastasis in pediatric patients with rhabdomyosarcoma. MATERIALS AND METHODS: This retrospective study included 69 patients (age, <= 20 years) who had rhabdomyosarcoma diagnosed between January 2000 and February 2016. Various imaging features, including distant metastasis, were evaluated on initial and follow-up imaging studies. Differences in the distribution of distant metastasis on the basis of the primary location were analyzed. Logistic regression analysis was performed to identify factors associated with distant metastasis. RESULTS: Twenty-six of the 69 patients (37.7%) had distant metastasis. Nineteen of the 26 patients had distant metastasis noted at initial presentation, and 15 of the 26 patients had new metastasis noted during follow-up. The most common site of metastasis was bone (n = 14), followed by lung (n = 12) and distant lymph nodes (n = 9). Lymph node metastasis more frequently developed in patients with primary rhabdomyosarcoma in an extremity than in patients with primary rhabdomyosarcoma that developed at other sites (p = 0.003). Of 15 patients who had metastasis during follow-up, nine (60%) did not appear to have simultaneous locoregional recurrence at the time of the discovery of distant metastasis. Older age at presentation and unfavorable sites of the primary tumor were significantly associated with distant metastasis in multivariate analysis. CONCLUSION: Distant metastasis of rhabdomyosarcomas in pediatric patients showed different patterns according to the location of the primary tumor and even occurred without local recurrence. PMID- 28590781 TI - Cognitive impairment in liver transplanted patients with transthyretin-related hereditary amyloid polyneuropathy. AB - INTRODUCTION AND AIM: Hereditary transthyretin-related amyloidosis (ATTR-FAP) is characterized by a progressive neuropathy, cardiomyopathy, nephropathy and ocular disease. More than 90% of amyloidogenic transthyretin is produced by the liver; however, this protein is also synthesized in the choroid plexus. Although some patients have transitory neurologic events, the impact on cognition is still unknown. The aim was to study the cognitive performance of ATTR-FAP V30M patients with long disease course. METHODS: A prospective observational study of a consecutive sample of patients with 10 or more years of disease duration was conducted. All patients underwent an extensive neuropsychological evaluation. RESULTS: Sixteen patients were included, with a mean age of 53 years and mean duration of disease of 18 years. All had been submitted to liver transplantation. The functional status was not incapacitating in the majority, with 75% needing at most a stick to walk and 38% still actively working. The neuropsychological evaluation disclosed episodic memory impairments in 31% and executive dysfunction in 25% of patients. CONCLUSIONS: These novel findings suggest that cognitive dysfunction can be a delayed manifestation of hereditary transthyretin-related amyloidosis. The putative relation of cognitive dysfunction with transthyretin amyloid deposition can provide another model to study the amyloid hypothesis of cognitive impairment. PMID- 28590783 TI - Efficacy of intradermal mesotherapy in cellulite reduction - Conventional and high-frequency ultrasound monitoring results. AB - BACKGROUND: Cellulite affects the majority of women and is an unacceptable cosmetic defect. Therefore, effective methods for cellulite reduction are being sought. Intradermal mesotherapy is one of such methods. OBJECTIVE: The aim of the study was to assess the efficacy of intradermal mesotherapy in cellulite reduction, using conventional and high-frequency ultrasound. METHODS: Twenty-one women with cellulite underwent a series of intradermal mesotherapy procedures. The following parameters were assessed: thickness of epidermis, dermis and hypodermis, echogenicity of dermis and the surface area of serrated hypodermis dermis junction. Furthermore, the thigh circumference was measured; body mass index and cellulite severity were assessed based on photographs using Nurnberger Muller's scale. RESULTS: Intradermal mesotherapy reduced severity of cellulite. The surface area of serrated hypodermis-dermis junction and hypodermis thickness decreased significantly as compared to baseline. Cellulite reduction was also confirmed by palpation, decreased thigh circumference and the Nurnberger-Muller's grade. There were no statistically significant changes in epidermis or dermis thickness, body weight and the BMI. CONCLUSION: Intradermal mesotherapy offers effective cellulite reduction. It is a simple and safe treatment, which makes it popular. Further research in mesotherapy is essential due to a limited number of published studies. Ultrasound is a useful method to monitor intradermal mesotherapy and assess its efficacy. PMID- 28590784 TI - Acetabular Chondral Lesions in Hip Arthroscopy: Relationships Between Grade, Topography, and Demographics. AB - BACKGROUND: Hip pain remains a challenge given the multiple factors that can cause damage to the articular cartilage, such as traumatic injury, metabolic damage, and morphologic variations such as femoroacetabular impingement (FAI) and that can contribute to progression of osteoarthritis. However, a direct relationship between patient characteristics, the extent of acetabular chondral damage, and topologic characteristics of chondral lesions has not been established. PURPOSE: To compare the grade of acetabular chondral damage, measured in terms of acetabular labrum articular disruption (ALAD) classification, to the size and position of the chondral lesions, matching patients' demographic factors such as age and body mass index (BMI). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: This study included all hip arthroscopies performed by the corresponding author from August 7, 2008, to November 19, 2014, in which acetabular chondral lesions were intraoperatively identified and measured in terms of ALAD grade, clockface location, and size. Bivariate analyses and multiple logistic regression were used to identify the demographic factors, characteristics of the acetabular chondral lesion, and other anatomic characteristics that were related to the ALAD grade of the acetabular chondral lesion. RESULTS: Acetabular chondral lesions were measured in 1502 patients during the study period. Multivariate analysis showed that higher ALAD grade of acetabular chondral damage was significantly related to male sex, more advanced age, the area of the acetabular chondral lesion, anterior extension of the acetabular chondral lesion within the anterosuperior quadrant, labral detachment from the acetabular cartilage, and posterior extension of the labral tear. CONCLUSION: Higher grades of acetabular chondral damage were related to male sex, increased age, height, weight, BMI, and the size of the lesion. Chondral lesions were generally found in the anterosuperior region of the acetabulum, consistent with labral lesions and the weightbearing area of the acetabulum. PMID- 28590785 TI - Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real-world evidence. AB - OBJECTIVES: Renal dysfunction is associated with increased risk of cardiovascular disease and is an independent predictor of stroke and systemic embolism. Nonvalvular atrial fibrillation (NVAF) patients with renal dysfunction may face a particularly high risk of thromboembolism and bleeding. The current retrospective cohort study was designed to assess the impact of renal function on ischemic stroke and major bleeding rates in NVAF patients in the real-world setting (outside a clinical trial). METHODS: Medical claims and Electronic Health Records were retrieved retrospectively from Optum's Integrated Claims-Clinical de identified dataset from May 2011 to August 2014. Patients with NVAF treated with warfarin (2468) or rivaroxaban (1290) were selected. Each treatment cohort was stratified by baseline estimated creatinine clearance (eCrCl) levels. Confounding adjustments were made using inverse probability of treatment weights (IPTWs). Incidence rates and hazard ratios of ischemic stroke and major bleeding events were calculated for both cohorts. RESULTS: Overall, patients treated with rivaroxaban had an ischemic stroke incidence rate of 1.9 per 100 person-years (PY) while patients treated with warfarin had a rate of 4.2 per 100 PY (HR = 0.41 [0.21-0.80], p = .009). Rivaroxaban patients with an eCrCl below 50 mL/min (N = 229) had an ischemic stroke rate of 0.8 per 100 PY, while the rate for the warfarin cohort (N = 647) was 6.0 per 100 PY (HR = 0.09 [0.01-0.72], p = .02). For the other renal function levels (i.e. eCrCl 50-80 and >=80 mL/min) HRs indicated no statistically significant differences in ischemic stroke risks. Bleeding events did not differ significantly between cohorts stratified by renal function. CONCLUSIONS: Ischemic stroke rates were significantly lower in the overall NVAF population for rivaroxaban vs. warfarin users, including patients with eCrCl below 50 mL/min. For all renal function groups, major bleeding risks were not statistically different between treatment groups. PMID- 28590786 TI - Liver Fibrosis Associated With Crigler-Najjar Syndrome in a Compound Heterozygote: A Case Report. AB - Crigler-Najjar syndrome is a hereditary unconjugated hyperbilirubinemia. Two forms of the disease are recognized. Type I is more severe and results in kernicterus if left untreated, and Type II is less severe and responds to phenobarbital. While Crigler-Najjar syndrome is thought by many to have normal liver histology, few reports of the liver pathology exist. Herein, we present a 19-year-old patient with Crigler-Najjar who underwent liver transplantation. The liver showed marked canalicular cholestasis with portal and variable, delicate, bridging fibrosis. Correlation of the patient's genetic test results and clinical phenotype is presented. PMID- 28590787 TI - "In the physio we trust": A qualitative study on patients' preferences for physiotherapy. AB - BACKGROUND: Patients' preferences should be integrated in evidence-based practice. This study aimed to explore patients' preferences for physiotherapy treatment and participation in decision making. METHODS: A qualitative study set in an urban physiotherapy clinic in Gothenburg, Sweden. Individual, semi structured interviews were conducted with 20 individuals who sought physiotherapy for musculoskeletal disorders. The interviews were recorded, transcribed, and analyzed with qualitative content analysis. RESULTS: An overarching theme, embracing six categories, was conceptualized: Trust in the physiotherapist fosters active engagement in therapy. The participants preferred active treatment strategies such as exercise and advice for self-management, allowing them to actively engage in their therapy. Some preferred passive treatments. Key influencers on treatment preferences were previous experiences and media. All participants wanted to be involved in the clinical decision making, but to varying extents. Some expressed a preference for an active role and wanting to share decisions while others were content with a passive role. Expectations for a professional management were reflected in trust and confidence in physiotherapists' skills and competence, expectations for good outcomes, and believing that treatment methods should be evidence-based. CONCLUSION: Trust in the physiotherapist's competence, as well as a desire to participate in clinical decision making, fosters active engagement in physiotherapy. PMID- 28590789 TI - Addressing weight stigma in physiotherapy: Development of a theory-driven approach to (re)thinking weight-related interactions. AB - In this article, we propose a theory-driven approach to developing interventions for reducing weight stigma in physiotherapy and discuss the design and exploratory trial of such an intervention. Weight stigma has been identified in physiotherapists in empirical investigations. However, there has been little consideration of how this stigma might be addressed. We highlight Goffman's work on stigma that provides social and embodied understandings of stigma. Goffman's approach, however, is notably apolitical, ahistorical and lacks mechanisms for understanding power. We suggest that post-structuralist perspectives can provide insight into these areas. Drawing on these theories, we critically examine the literature on weight stigma reduction, finding that trials have largely been unsuccessful. We argue that this may be due to overly passive and simplistic intervention designs. As context-specific understandings are desirable, we examine the nature of physiotherapy to determine what might be relevant to (re)thinking weight in this profession. We then discuss the development of a multifactorial, active weight stigma intervention we trialed with eight physiotherapists. Supported by theory, the outcomes of the exploratory study suggest that physiotherapy-specific factors such as fostering professional reflexivity and improving understandings of stigma need to be incorporated into an active intervention that considers the complex determinants of weight stigma. PMID- 28590788 TI - Thermo-responsive magnetic liposomes for hyperthermia-triggered local drug delivery. AB - We prepared and characterised thermo-responsive magnetic liposomes, which were designed to combine features of magnetic targeting and thermo-responsive control release for hyperthermia-triggered local drug delivery. The particle size and zeta-potential of the thermo-responsive magnetic ammonium bicarbonate (MagABC) liposomes were about 210 nm and -14 mV, respectively. The MagABC liposomes showed encapsulation efficiencies of about 15% and 82% for magnetic nanoparticles (mean crystallite size 12 nm) and doxorubicin (DOX), respectively. The morphology of the MagABC liposomes was visualised using transmission electron microscope (TEM). The MagABC liposomes showed desired thermo-responsive release. The MagABC liposomes, when physically targeted to tumour cells in culture by a permanent magnetic field yielded a substantial increase in intracellular accumulation of DOX as compared to non-magnetic ammonium bicarbonate (ABC) liposomes. This resulted in a parallel increase in cytotoxicity for DOX loaded MagABC liposomes over DOX loaded ABC liposomes in tumour cells. PMID- 28590790 TI - The Effect of Ascorbic Acid (Vitamin C) on Transepithelial Corneal Cross-Linking in Rabbits. AB - PURPOSE: To evaluate the effects of ascorbic acid (vitamin C), the main antioxidant agent in the cornea on transepithelial corneal cross-linking (CXL) where the main mechanism is oxidation. METHODS: Twenty eyes of 20 rabbits were divided into 3 groups: Group 1 (7 eyes) had transepithelial corneal CXL after being fed with normal diet; Group 2 (7 eyes) had corneal CXL after once-daily subcutaneous injections of 200 mg of ascorbic acid in addition to normal diet; and the control group (6 eyes) was fed with normal diet but did not have corneal CXL performed. Ascorbic acid levels were measured in aqueous humor and plasma, and biomechanical measurements were applied to the cornea. RESULTS: There was a significant difference in ascorbic acid levels of plasma (P = 0.008) and aqueous humor (P = 0.006) between group 1 and 2. The Young's modulus values of group 1 and 2 were similar (P = 0.741) and were significantly higher than the control group (P = 0.02 and P = 0.01). The increase rate in Young's modulus values was 37.3% in group 1 and 43.9% in group 2 compared to control group. The ultimate strain values in group 1 and 2 were similar (P = 0.632) and were significantly higher than control group (P = 0.04, P = 0.03). The ultimate stress values in group 1 and 2 were similar (P = 0.836) and were significantly lower than control group (P = 0.001, P = 0.001). CONCLUSIONS: Systemic vitamin C does not appear to decrease effectiveness of transepithelial corneal CXL. Therefore, there is no reason to stop or reduce vitamin C supplementation before corneal CXL therapy. PMID- 28590791 TI - Using an exercise program to improve activity tolerance in a female with postural orthostatic tachycardia syndrome: A case report. AB - The incidence of postural orthostatic tachycardia syndrome (POTS) is estimated to be at least 500,000 in the United States and is most commonly found in premenopausal females. This syndrome shares clinical features with orthostatic hypotension (OH); however, the inclusion criteria and clinical features for POTS are not well known. The purposes of this case report are to: 1) describe the common clinical features of POTS and highlight the differences to orthostatic hypotension and 2) discuss physical therapy management of patients with POTS using exercise. A 34-year-old female with a POTS exacerbation completed a 4-week physical therapy endurance and strengthening 'reconditioning' program. Initial symptoms included the following: dyspnea with mild exertion, light-headedness, fatigue, leg "heaviness," and the inability to perform normal work duties. One mile track walk test (1-MWT) estimated VO2max improved from the 45-50th percentile to the 65-70th percentile at 8 weeks post-discharge. She returned to work full-time and resumed all previous fitness activities. The patient demonstrated clinically meaningful improvements in estimated VO2max after the "reconditioning" training. Physical therapists should be able to recognize the clinical features and inclusion criteria for POTS as part of a differential diagnosing process for patients complaining of orthostatic symptoms. PMID- 28590792 TI - Antibiotic prescribing and dispensing for acute respiratory infections in children: effectiveness of a multi-faceted intervention for health-care providers in Vietnam. AB - BACKGROUND: Appropriate antibiotic use is vital to effectively contain antibiotic resistance and improve global health. Acute respiratory infections (ARIs) remain the leading cause of disease and death in children under five in low-income countries. OBJECTIVE: To evaluate a multi-faceted intervention targeting health care-providers' (HCPs) knowledge, practical competences and practices regarding antibiotic use for ARIs. METHODS: A multi-faceted educational intervention with a two-armed randomised controlled design targeting HCPs treating ARIs in children was conducted in Bavi district, a rural district in Northern Vietnam in 2010 2011. Thirty-two communes of the district were randomized into two arms, with 144 HCPs in the intervention arm and 160 in the control arm. The intervention, conducted over seven months, comprised: (i) education regarding appropriate antibiotic use, (ii) case scenario discussion and (iii) poster distribution. Questionnaires to assess knowledge and dispensing/prescribing forms to assess practice were completed before-and after interventions. The main outcome measures were differences in improvement in knowledge and practice in the intervention and control group, respectively. RESULTS: Knowledge improved in the intervention group for ARI aetiology by 28% (DeltaDecrement control arm 10%), antibiotic use for mild ARIs by 15% (DeltaDecrement control arm 13%) and for severe ARIs by 14% (DeltaImprovement control arm 29%). Practical competence for a mild ARI case scenario improved in the intervention and control groups by 20% and 11%, respectively. Total knowledge score increased statistically in the intervention group (Deltamean improvement 1.17); less so in the control group (Deltamean improvement 0.48). Practice regarding antibiotics for mild ARIs improved by 28% in the intervention group (DeltaDecrement control arm 3%). CONCLUSIONS: The intervention significantly improved HCPs' knowledge of ARIs and practice of antibiotic use in treatment of ARIs. We suggest mixed method assessment and long term follow-up of these interventions to enable better appreciation of the effects and effect sizes of our interventions. PMID- 28590793 TI - Effective Legislative Advocacy - Lessons from Successful Medical Trainee Campaigns. PMID- 28590794 TI - Transforming Practices Through the Oncology Care Model: Financial Toxicity and Counseling. PMID- 28590795 TI - A recombinant live attenuated tetravalent vaccine for the prevention of dengue. AB - INTRODUCTION: Dengue is an important and still growing public health problem associated with substantial morbidity, as well as significant social and economic impact. The present review describes the main features and development of the first dengue vaccine (CYD-TDV, Dengvaxia(r)), which has been licensed by several dengue-endemic countries in Asia and Latin America for use in populations above 9 years of age. Areas covered: The review focuses on the large clinical development of CYD-TDV, which includes in particular two pivotal phase III efficacy trials conducted in Asia and Latin America and supported vaccine licensure. Based on these clinical data, the WHO Strategic Advisory Group of Experts (SAGE) on Immunization recommended considering introduction of the vaccine in geographic settings (national or subnational) with high burden of disease. Long-term safety follow-up studies of the efficacy trials are currently ongoing, and post licensure studies will evaluate the vaccine effectiveness and safety in 'real life' following vaccine introduction. Expert commentary: During vaccine development, a number of complexities were tackled, innovation pursued, and risk managed. These aspects, as well as the potential impact of CYD-TDV on public health are also discussed. PMID- 28590797 TI - Using the electronic medical record to study the association of child and environmental characteristics on the type of physical therapy services delivered to individuals with cerebral palsy. AB - The purpose of this study was to characterize the intervention type delivered to individuals with cerebral palsy (CP) in a pediatric outpatient medical setting and to identify factors associated with the total amount of service within each type. Four hundred and twenty-five individuals with CP (1-33 years) Gross Motor Function Classification System (GMFCS): Level I (n = 152); II (n = 63); III (n = 55); IV (n = 80); and V (n = 75). Billing code data was extracted retrospectively from 2008 medical records and categorized to reflect four types: body structures and function (BSF), activity (ACT), environment (ENV), and examination (EXAM). Age at first visit, type of insurance at first visit and GMFCS level was also collected. The majority (47%) of the PT delivered was categorized as activity based units, 25% as body structure and function, 21% as environment, and 7% as examination. Significant differences were found in: total BSF therapy units among GMFCS (p = 0.008) and insurance type (p < 0.001), ACT units among GMFCS (p < 0.001), age groups (p < 0.001), and insurance type (p = 0.008), and ENV units among GMFCS (p = 0.04). The amount of variability (R2) explained by the model for each category BSF, ACT, and ENV was 0.09 (p < 0.0001), 0.15 (p < 0.0001) and 0.02 (p = 0.04), respectively. Variations in amount of services received among types of intervention are associated with child and environmental characteristics. Low R2 values indicate the need to collect information on other factors that influence service delivery. Data that are standardized and reliably collected should be validated and compared across institutions to support larger studies of service delivery patterns. PMID- 28590796 TI - Noninvasive Therapy for Osteoid Osteoma: A Prospective Developmental Study with MR Imaging-guided High-Intensity Focused Ultrasound. AB - Purpose To demonstrate that magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) is a safe, effective, and durable treatment option for the management of osteoid osteoma in children and young adults. Materials and Methods This prospective study was institutional review board approved and is registered with clinicaltrials.gov (identification number NCT02302651). Written informed consent was obtained from patients or their parents. Patients who had both clinical and radiologic findings that were diagnostic for nonvertebral osteoid osteoma and no contraindications to MR imaging-guided HIFU were enrolled between June 2010 and June 2013. The feasibility, safety, and clinical effectiveness of MR imaging-guided HIFU were considered primary outcomes; tumor control at imaging was considered a secondary outcome. Analyses were conducted on a per-protocol basis. Results Forty-five of the 50 recruited patients underwent MR imaging-guided HIFU. All patients were discharged without treatment-related complications. The median visual analog scale (VAS) pain score (scale, 0-10) decreased from 8 before treatment to 0 at 1-week and 1- , 6- , 12- , 24- , and 36 month follow-up. Similarly, median VAS scores for the degree to which pain interfered with sleep and physical and daily activities decreased to 0 within the 1st month after treatment and remained stable at subsequent follow-up. Overall, 39 (87%) of the 45 patients achieved and maintained a VAS score of 0 during the 3 year observation period. Quality of life, as assessed by using Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) scores (scale, 0-60 points), improved, with the median FACT-BP score of 28 (points) before treatment increasing to a median score of 55 at 1-week follow-up and 60 at 6-month and subsequent follow-ups. At (final) 36-month follow-up, MR imaging depicted an absence of residual nidus vascularity in 32 (76%) of the 42 patients who were treated with MR imaging-guided HIFU only. Conclusion The durable clinical efficacy and safety of MR imaging-guided HIFU were demonstrated. These features are evidence of the potential of MR imaging-guided HIFU to be part of a routine strategy for the treatment of osteoid osteoma. (c) RSNA, 2017. PMID- 28590798 TI - Beyond Ketamine and Phencyclidine: Analytically Confirmed Use of Multiple Novel Arylcyclohexylamines. AB - BACKGROUND: Methoxetamine and 3-methoxy-phencyclidine are novel arylcyclohexylamines whose use and clinical toxicity are poorly reported in the medical literature. We report a case of analytically confirmed use of both methoxetamine and 3-methoxy-phencyclidine. CASE REPORT: A 27-year-old male presented 10 hours after insufflating an Internet-obtained powder. He was hypertensive, tachycardic, and demonstrated dissociated affect, a delayed verbal response to questions, ataxia, and vertical nystagmus. A urine drug screen was positive for phencyclidine and 11-nor-delta9-THC-9-carboxylic acid. He was admitted and his mental status and blood pressure normalized eight hours later. Blood samples (0, 2, and 3 hours from arrival) and the powders were analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry. Methoxetamine and 3-methoxy-phencyclidine were detected in all samples (279 ng/ml, 205 ng/ml, and 180 ng/ml for methoxetamine; 167 ng/mL, 131 ng/mL, and 90 ng/ml for 3-methoxy phencyclidine at 0, 2, and 3 hours, respectively). No phencyclidine or tetrahydrocannabinol was detected. Two powders contained methoxetamine while one contained 3-methoxy-phencyclidine. CONCLUSION: The literature regarding methoxetamine and 3-methoxy-phencyclidine toxicity is limited. Methoxetamine use is associated with altered mental status, ataxia, and hypertension. Toxicity from 3-methoxy-phencyclidine is poorly described. There is no prior case describing serial qualitative analysis. Health care providers should be aware of the novel arylcyclohexylamines and their toxicity. PMID- 28590800 TI - Response to Risks and Cough-Aggravating Factors in Prolonged Cough. PMID- 28590801 TI - Don't Let Funding Caps to NIH Researchers Harm Highly Collaborative HIV Cure Research. PMID- 28590802 TI - Upcoming Implementation of NIH Funding Caps Invites Researcher Feedback. PMID- 28590799 TI - Development of short-form measures to assess four types of elder mistreatment: Findings from an evidence-based study of APS elder abuse substantiation decisions. AB - Improving the standardization and efficiency of adult protective services (APS) investigations is a top priority in APS practice. Using data from the Elder Abuse Decision Support System (EADSS), we developed short-form measures of four types of elder abuse: financial, emotional/psychological, physical, and neglect. The EADSS data set contains 948 elder abuse cases (age 60+) with yes/no abuse substantiation decisions for each abuse type following a 30-day investigation. Item sensitivity/specificity analyses were conducted on long-form items with the substantiation decision for each abuse type as the criterion. Validity was further tested using receiver-operator characteristic (ROC) curve analysis, correlation with long forms and internal consistency. The four resulting short form measures, containing 36 of the 82 original items, have validity similar to the original long forms. These short forms can be used to standardize and increase efficiency of APS investigations, and may also offer researchers new options for brief elder abuse assessments. PMID- 28590804 TI - Vaccine Uncertainty: Preventing Progress of Public Health. PMID- 28590803 TI - Up Front. PMID- 28590806 TI - Editorial. PMID- 28590807 TI - Prescriptions. PMID- 28590809 TI - Radiology and Ethics Education. AB - OBJECTIVE: The purpose of this study is to assess medical ethics knowledge among trainees and practicing radiologists through an online survey that included questions about the American College of Radiology Code of Ethics and the American Medical Association Code of Medical Ethics. CONCLUSION: Most survey respondents reported that they had never read the American Medical Association Code of Medical Ethics or the American College of Radiology Code of Ethics (77.2% and 67.4% of respondents, respectively). With regard to ethics education during medical school and residency, 57.3% and 70.0% of respondents, respectively, found such education to be insufficient. Medical ethics training should be highlighted during residency, at specialty society meetings, and in journals and online resources for radiologists. PMID- 28590810 TI - Worth the Wait? Leisure Can Be Just as Enjoyable With Work Left Undone. AB - Four studies reveal that (a) people hold a robust intuition about the order of work and leisure and that (b) this intuition is sometimes mistaken. People prefer saving leisure for last, believing they would otherwise be distracted by looming work (Study 1). In controlled experiments, however, although subjects thought their enjoyment would be spoiled when they played a game before rather than after a laborious problem-solving task, got a massage before rather than after midterms, and consumed snacks and watched videos before rather than after a stressful performance, in reality these experiences were similarly enjoyable regardless of order (Studies 2 through 4). This misprediction was indeed mediated by anticipated distraction and was therefore attenuated after people were reminded of the absorbing nature of enjoyable activities (Studies 3 and 4). These studies highlight the power of hedonic experience within the moment of consumption, which has implications for managing (or mismanaging) everyday work and leisure. People might postpone leisure and overwork for future rewards that could be just as pleasurable in the present. PMID- 28590812 TI - Depression in the barrio: An analysis of the risk and protective nature of cultural values among Mexican American substance users. AB - Understanding the effect of cultural values on depression and how social networks influence these relationships may be important in the treatment of substance using, Mexican American populations. Latino cultural values, familismo, personalismo, fatalismo, and machismo, may be associated with depression among Latinos. The current study identified the association of traditional Latino values on depressive symptomatology among a sample of Mexican American heroin injectors. A cross-sectional research design and field-intensive outreach methodology were utilized to recruit 227 Mexican American men. Participants were categorized into depressed and nondepressed groups. Relations among cultural values and depression were examined using logistic regression. Findings indicate that drug-using men with higher familismo and fatalismo scores are protected against depressive symptomatology. Relations between familismo and depression seem to be moderated by having a drug use network. In addition, findings reveal that age is inversely related to depressive symptomatology. Young Mexican American heroin users who do not ascribe to traditional Latino values may be highly associated with depression and therefore more vulnerable to riskier drug use behaviors. Moreover, drug-using social networks may affect the protective nature of certain cultural values. Further research is needed to identify whether culturally tailored treatments can cultivate these values while simultaneously undermining the effect of substance-using social networks in order to reduce depression symptoms among this group of high-risk substance users. PMID- 28590815 TI - The evaluation of a strength and balance exercise program for falls prevention in community primary care. AB - We aimed to evaluate a strength and balance program delivered in the community. There is little evidence of implementation of evidence-based exercise in practice. The program was a step-down model, designed to encourage long-term exercise in community classes. The program consisted of a fully funded referral only evidence-based 12-week strength and balance (Community Otago) class, followed by an evidence-based continuous open-access community strength and balance class (Active Always). The program was offered to patients: 1) after formal falls rehabilitation (falls and fracture service); 2) after falls rehabilitation in intermediate care; and 3) referred by a GP who were not eligible for rehabilitation (preventative measure). Outcome evaluation used descriptive statistics to report changes in function, confidence in balance, hospital attendance/admission for falls/fractures and transition to community classes. Focus groups established participant experience/satisfaction. Seventy nine participants were included, aged 56-96, and 53 (67%) were women. About 63.3% of patients transitioned to Active Always classes, demonstrating improvement in maintenance. Follow-up scores from baseline attendance at falls and fracture service to 12-weeks follow-up (24 weeks) in Community Otago showed the majority of patients improved their function (Timed up and Go), confidence (ConfBal) and lowered their falls risk (Tinetti). Follow-up of participants from Community Otago baseline to the end of 12-weeks showed improvement in function and confidence, but only a third of participants lowered their falls risk. Focus groups data suggest that continuity of delivery, the role of the instructor, health professional, and social and physical outcomes were essential for maintenance. A supportive environment can be created which encourages older adults' continued participation in group-based strength and balance, helping the delivery of evidence-based practice. PMID- 28590816 TI - Found in Transition. AB - The journey to adulthood is complex and multi-dimensional. Young people may be independent in some spheres of their lives, but dependent in others. For young people with a disability, long-term condition, or mental health problem there are additional hurdles. As they move between health and social care services, they will find significant differences in expectations, delivery, and culture. At the same time, their own needs will be evolving. Despite a great deal of guidance on effective transition support, in 2014, England's Care Quality Commission highlighted a shortfall between policy and practice. The result is confusion and frustration for young people, their families, and the staff caring for them. Seamless transition to adult services is by no means a universal experience. Here the authors offer two case studies that triangulate inter-related perspectives: those of young people, parents and carers, and the professionals involved in successful models of transition support. The case studies illustrate how the challenge of transitioning to adult services is actually experienced and how, despite some concerns held by young people, parents, and carers, well-planned and coordinated transitions can have positive outcomes for the families involved. PMID- 28590814 TI - A dosimetric parameter to limit chest wall toxicity in SABR of NSCLC. AB - OBJECTIVE: Chest wall (CW) toxicity (rib fracture and/or pain) is a recognized complication of stereotactic ablative radiotherapy (SABR) for non-small-cell lung cancer. The aim of this study was to evaluate the frequency of CW toxicity following SABR and to propose a new dosimetric parameter. METHODS: We reviewed the charts and SABR plans from patients treated for T1-T2N0 peripheral non-small cell lung cancer between 2009 and 2015. The CW structure was created through a 3 cm expansion of the lung. The median dose delivered to the planning target volume was 60 Gy. SABR was delivered in three fractions for patients with CW V30 < 30 cm3. If the CW V30 exceeded 30 cm3, five fractions were used, and the plan was optimized based on CW V37 (biologically equivalent to the V30 of three-fraction plans). RESULTS: In 6 years, 361 lesions from 356 patients were treated (3 fractions: 297; 5 fractions: 64). The median follow-up was 16 months. 23 patients (6.5%) developed CW toxicity after a median time of 10 months following treatment. The mean CW V30/V37 was 21 cm3 for patients with CW toxicity and 17 cm3 for patients without toxicity (p < 0.05). The 2-year local control and the CW toxicity rates were similar, whether patients received three or five fractions (97% vs 96% and 7% vs 5%). CONCLUSION: When the CW V30 is >30 cm3, altered fractionation combined with V37 optimization can limit CW toxicity. Advances in knowledge: The CW V37 is a suggested dosimetric parameter adapted to fractionation that may potentially limit CW toxicity after lung SABR. PMID- 28590813 TI - Imaging features of solid renal masses. AB - The widespread use of abdominal imaging techniques has increased the detection of solid renal masses over the past years. Imaging plays a crucial role in the management and surveillance and in determining which lesions need treatment. The "classical angiomyolipoma" is the only benign solid renal mass that can be characterized with confidence by imaging through the detection of a fat containing lesion without calcifications. There is a large overlap of imaging features between benign and malignant renal masses that often makes difficult a correct characterization of these lesions. In this review, we discuss the imaging features of the main solid renal masses that may suggest a likely benign diagnosis. PMID- 28590817 TI - Long-Term Surveillance and Timeline of Progression of Presumed Low-Risk Intraductal Papillary Mucinous Neoplasms. AB - OBJECTIVE: The purpose of this study was to assess risk of progression and rate of growth of presumed low-risk branch duct intraductal papillary mucinous neoplasms surveyed for more than 4 years. MATERIALS AND METHODS: A keyword search of electronic medical charts was performed for the years 2001-2013. Cystic lesions that met the criteria for clinical branch duct intraductal papillary mucinous neoplasm, lacked baseline high-risk or worrisome features, and had more than 4 years of surveillance were included in this study. Two radiologists performed cyst size measurements to assess interreader variability. Cyst progression was defined either as 2-mm or greater or 20% or greater increase in diameter or as development of worrisome features. Kaplan-Meier curves were generated to evaluate cyst progression time and linear mixed models to evaluate growth rates. RESULTS: The search revealed 2423 patients with cystic pancreatic lesions. Among these patients 228 had imaging follow-up for 4 or more years, and 131 met the clinical criteria for branch duct intraductal papillary mucinous neoplasms. Among the 131 cysts, 73 (55.7%) progressed: 61 (46.6%) increased in size, 10 (7.6%) increased in size and developed worrisome features, and two (1.5%) developed worrisome features only. Of the 71 cysts that increased in size, 50 (70.4%) did so within the first 5 years, and 21 (29.6%) grew after 5 years. No patient had adenocarcinoma. There was no significant difference in growth rate based on cyst size within the first 50 months. After 50 months, cysts larger than 20 mm continued to increase in size (p < 0.05) and had faster growth rates. CONCLUSION: Among presumed low-risk branch duct intraductal papillary mucinous neoplasms, most increased in size, approximately 30% after 5 years. Cysts with baseline size larger than 20 mm continued to grow beyond 5 years at a faster rate. PMID- 28590818 TI - Work ability is influenced by kinesiophobia among patients with persistent pain. AB - The purpose of this study was to investigate how kinesiophobia fluctuates in patients over a four weeks multimodal rehabilitation program and to study the relationship between work ability and kinesiophobia. The study included 112 patients (94 women, 18 men). Measurements were made before, directly after, 2 months after, and 12 months after the program. The level of work ability was rated by the patients on a scale from 0% to 100%, and kinesiophobia was measured by the Swedish version of the Tampa Scale for Kinesiophobia (TSK-SV). Kinesiophobia decreased between the start of the multimodal rehabilitation program and the follow-up periods. Work ability increased over time, but not between baseline and the 2-month follow-up. Decreases in the TSK-SV score between baseline and the 2-month follow-up were related to the increased probability of improved work ability at the 12-month follow-up. In conclusion, a decrease in kinesiophobia seems to be related to increased work ability of patients participating in a 4-week multimodal rehabilitation program. PMID- 28590819 TI - Pattern and Distribution of Distant Metastases in Anaplastic Prostate Carcinoma: A Single-Institute Experience With 101 Patients. AB - OBJECTIVE: The aim of this study was to evaluate the sites and frequencies of distant metastases in patients with anaplastic prostate carcinoma and to correlate those findings with prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: Patients with anaplastic prostate carcinoma (n = 101) underwent CT and bone scans before platinum-based chemotherapy. CT findings were retrospectively reviewed to identify the sites of metastases. CT findings were correlated with baseline PSA levels. The Wilcoxon rank sum test was used to correlate PSA levels between patients with metastases at osseous and nonosseous sites. The Wilcoxon rank sum test was also used to correlate the type of bone metastases (blastic vs lytic) and the PSA levels. RESULTS: Eighty-three of 101 patients (82%) had osseous metastases. PSA levels were significantly higher in patients with bone metastases than in patients without osseous metastases. However, 23 of the 83 patients (28%) with bone metastases had PSA levels in the normal range (i.e., < 4 ng/mL). The type of bone metastases (blastic vs lytic) did not show any statistically significant correlation to the PSA levels. Overall, 63 of 101 patients (62%) had nonosseous distant metastases at one or more sites, including the liver (n = 34), lung (n = 24), mediastinum (n = 31), pleura (n = 7), brain (n = 9), adrenal glands (n = 6), peritoneum (n = 4), and spleen (n = 1). PSA levels were not significantly elevated in patients with nonosseous distant metastases. Twenty-six of the 63 patients (41%) with nonosseous metastases had PSA levels in the normal range (< 4 ng/mL). CONCLUSION: Patients with the anaplastic clinical variant of prostate cancer have a high frequency of typical and atypical sites of metastases. Common sites of nonosseous distant metastases include the liver, lung, mediastinum, pleura, brain, and adrenal glands. PSA levels are unreliable and may be disproportionately low, despite the presence of multifocal large-volume metastases. CT of the chest, abdomen, and pelvis should be considered in routine staging and follow-up of patients with anaplastic prostate carcinoma regardless of their PSA levels. PMID- 28590821 TI - T2 Mapping of the Sacroiliac Joints With 3-T MRI: A Preliminary Study. AB - OBJECTIVE: The objective of this study was to assess the feasibility of T2 relaxation time measurements of the sacroiliac joints. SUBJECTS AND METHODS: The sacroiliac joints of 40 patients were imaged by 3-T MRI using an oblique axial multislice multiecho spin-echo T2-weighted sequence. Manual plotting and automatic subdivision of ROIs allowed us to obtain T2 values for up to 48 different areas per patient (posterior and anterior parts, sacral, intermediate, and iliac parts). Intraand interobserver reproducibility of T2 values were calculated after independent assessment by two musculoskeletal radiologists. RESULTS: A total of 1656 measurement sites could be analyzed. Mean (+/- SD) T2 values were 40.6 +/- 6.7 ms and 41.2 +/- 6.3 ms for observer 1 and 39.9 +/- 6.6 ms for observer 2. The intraobserver intraclass correlation coefficient was 0.72 (95% CI, 0.70-0.74), and the interobserver intraclass correlation coefficient was 0.71 (95% CI, 0.68-0.72). CONCLUSION: Our study shows the feasibility of T2 relaxation time measurements at the sacroiliac joints. PMID- 28590822 TI - Evaluation of an Improved U.S. Food and Drug Administration Method for the Detection of Cyclospora cayetanensis in Produce Using Real-Time PCR. AB - Cyclospora cayetanensis is a protozoan parasite that causes human diarrheal disease associated with the consumption of fresh produce or water contaminated with C. cayetanensis oocysts. In the United States, foodborne outbreaks of cyclosporiasis have been linked to various types of imported fresh produce, including cilantro and raspberries. An improved method was developed for identification of C. cayetanensis in produce at the U.S. Food and Drug Administration. The method relies on a 0.1% Alconox produce wash solution for efficient recovery of oocysts, a commercial kit for DNA template preparation, and an optimized TaqMan real-time PCR assay with an internal amplification control for molecular detection of the parasite. A single laboratory validation study was performed to assess the method's performance and compare the optimized TaqMan real-time PCR assay and a reference nested PCR assay by examining 128 samples. The samples consisted of 25 g of cilantro or 50 g of raspberries seeded with 0, 5, 10, or 200 C. cayetanensis oocysts. Detection rates for cilantro seeded with 5 and 10 oocysts were 50.0 and 87.5%, respectively, with the real-time PCR assay and 43.7 and 94.8%, respectively, with the nested PCR assay. Detection rates for raspberries seeded with 5 and 10 oocysts were 25.0 and 75.0%, respectively, with the real-time PCR assay and 18.8 and 68.8%, respectively, with the nested PCR assay. All unseeded samples were negative, and all samples seeded with 200 oocysts were positive. Detection rates using the two PCR methods were statistically similar, but the real-time PCR assay is less laborious and less prone to amplicon contamination and allows monitoring of amplification and analysis of results, making it more attractive to diagnostic testing laboratories. The improved sample preparation steps and the TaqMan real-time PCR assay provide a robust, streamlined, and rapid analytical procedure for surveillance, outbreak response, and regulatory testing of foods for detection of C. cayetanensis. PMID- 28590820 TI - Activity of Ceftazidime-Avibactam Against Clinical Isolates of Klebsiella pneumoniae, Including KPC-Carrying Isolates, Endemic to New York City. AB - In this report, we examined the (1) activity of ceftazidime-avibactam against clinical isolates Klebsiella pneumoniae, including those harboring blaKPC, (2) potential mechanisms leading to reduced susceptibility, and (3) activity of ceftazidime-avibactam when combined with other agents. Of 802 carbapenem resistant isolates of K. pneumoniae gathered from New York City from 1999 to 2014, all were susceptible to ceftazidime-avibactam. Minimum inhibitory concentrations (MICs) were higher in isolates with K. pneumoniae, with the carbapenemase (KPC)-3 (compared to KPC-2), and those with a frameshift mutation in ompK35. MICs did not appear to be affected by changes in ompK36 or by expression of acrB. Time-kill experiments demonstrated synergy between either polymyxin B or amikacin and ceftazidime-avibactam in a minority of isolates. In conclusion, ceftazidime-avibactam is active against K. pneumoniae, including blaKPC isolates, in our region, but activity is affected by KPC subtype and by mutations in ompK35. Synergy can occur when combined with polymyxin B or amikacin, but is unpredictable. PMID- 28590823 TI - Understanding death, suicide and self-injury among adherents of the emo youth subculture: A qualitative study. AB - Emo youth subculture bases its subcultural identification mostly on symbols of death, dying, suicide, and other kinds of morbid content. The main goal of the present study was to explore attitudes toward suicidal behavior and self-injury in emo adolescents. Semistructured in-depth qualitative interviews were conducted with 14 emo adherents, accompanied by the analysis of emo Web discussion forums. Participants reported attitudes including high acceptance for suicidal behavior and self-injury. The identification with the emo youth subculture is considered to be a factor strengthening vulnerability towards risky behaviors. PMID- 28590824 TI - Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review. AB - There has been a noticeable shift from pharmaceutical batch processing towards a more continuous mode of manufacture for solid oral dosage forms. Continuous solid oral dose processes would not be possible in the absence of a highly accurate feeding system. The performance of feeders defines the content of formulations and is therefore a critical operation in continuous manufacturing of solid dosage forms. It was the purpose of this review to review the role of the initial powder feeding step in a continuous manufacturing process. Different feeding mechanisms are discussed with a particular emphasis on screw controlled loss in weight (LIW) feeding. The importance of understanding the physical properties of the raw materials and its impact on the feeding process is reviewed. Prior knowledge of materials provides an initial indication of how the powders will behave through processing and facilitates in the selection of the most suitable (i) feeder (capacity), (ii) feeding mechanism, and (iii) in the case of screw feeder - screw type. The studies identified in this review focus on the impact of material on powder feeding performance. PMID- 28590825 TI - The effects of smart phone gaming duration on muscle activation and spinal posture: Pilot study. AB - This study investigates changes in the posture angles of the neck and trunk, together with changes in the muscle activation of users, at the start of and at 5, 10, and 15 minutes of smartphone use. Eighteen males participated in this study. Surface electromyography (EMG) and a digital camera were used to measure the muscle activation and angular changes of the neck and trunk of participants during smartphone use for a period of 16 minutes. Neck and trunk flexion significantly increased at 5, 10, and 15 minutes (p < 0.05) in comparison with the neck and trunk flexion of participants at the start of smartphone usage. The EMG activation and 10th%amplitude probability distribution function (APDF) values of the bilateral cervical erector spinae at 5-6, 10-11, and 15-16 minutes of usage (p < 0.05) were also significantly greater than at the start of usage. The EMG activation of the bilateral thoracic erector spinae and lower trapezius was significantly decreased at 5-6, 10-11, and 15-16 minutes of usage (p < 0.05). Smartphone use induced more flexed posture on the neck and trunk than other visual display terminal (VDT) work. Smartphone use also changed posture and muscle activation within a relatively short amount of time, just 5 minutes. Pain after 16 minutes of smartphone use was also observed. Thus, clinicians should consider the influences of smartphone use in posture and muscle activity in evaluation, intervention, and prevention of neck and trunk conditions. PMID- 28590826 TI - Minimally Invasive Treatment of Pediatric Extrinsic Ureteropelvic Junction Obstruction by Crossing Polar Vessels: Is Vascular Hitching a Definitive Solution? Report of a Multicenter Survey. AB - BACKGROUND: This article aimed to evaluate the outcome of laparoscopic vascular hitch (VH) as an effective alternative to dismembered pyeloplasty in the treatment of children with extrinsic ureteropelvic junction obstruction (UPJO) by crossing vessels (CVs), by reporting the experience of three Italian centers of Pediatric Surgery. METHODS: From 2006 to 2014, 54 children (18 girls and 36 boys, average age 10.7 years) affected by suspected extrinsic UPJO by CV were treated in three different institutions: 51 patients underwent laparoscopic VH, while 3 patients, in which a coexisting intrinsic etiology of UPJO was doubtful, underwent laparoscopic dismembered pyeloplasty. Preoperative diagnostic workup included: ultrasound (US)/Doppler scan, mercaptoacetyltriglycine (MAG3)-renal scan, and functional-magnetic-resonance-urography (fMRU). Symptoms at presentation were recurrent abdominal/flank pain and hematuria. All patients presented intermittent hydronephrosis (range 18-100 mm) on US and an obstructive pattern on MAG3 renogram. RESULTS: Average operative time was 108 minutes, and average hospital stay was 1.8 days. As for complications, we reported a small abdominal wall hematoma and a high UPJ distortion without obstruction in 2 patients, not requiring reintervention (grade I Clavien-Dindo). At follow-up (range 12-96 months), all patients reported resolution of symptoms, decrease in the hydronephrosis grade, and improved drainage on MAG3 renogram. CONCLUSIONS: Our results demonstrated the safety and efficacy of laparoscopic VH for treatment of extrinsic UPJO by CV, registering excellent outcomes in a very selected patient population. The careful selection of patients through intraoperative assessment of anatomical and functional aspects is a crucial step to confirm indications for VH and maintain a high success rate with the procedure. We believe that any concerns regarding the coexistence of intrinsic stenosis should certainly lead to opening the collecting system and to performing a classic dismembered pyeloplasty. PMID- 28590827 TI - Extracorporeal shockwave: mechanisms of action and physiological aspects for cellulite, body shaping, and localized fat-Systematic review. AB - Extracorporeal Shockwave Therapy (ESWT) has had a wide use in rehabilitation, and has presented positive effects in the treatment of unaesthetic affections. The objective of the present study was to search, in the literature, the mechanisms of action and the physiological aspects of shockwaves acting on the biological tissue to improve the condition of cellulite and localized fat. The systematic review of the literature was carried out in the period of September 2016 to February 2017 based on the bibliographic databases such as Lilacs, Medline, PubMed, and SciELO. Fifteen articles were identified in that systematic review, three of which were excluded as they did not make the complete access to the article available or the theme investigated did not encompass the objective of the study. The revision demonstrated that extracorporeal shockwaves present relevant effects on the biological tissue, which leads to the restructuring of skin properties and subcutaneous tissue, thus clinically improving the aspects of cellulite and localized fat. PMID- 28590828 TI - Daily use of sildenafil 50mg at night effectively ameliorates nocturia in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia: an exploratory multicenter, double-blind, randomized, placebo controlled study. AB - PURPOSE: To compare the efficacy and safety of sildenafil 25 mg qd, 25 mg bid or 50 mg qd - on treating lower urinary tract symptoms with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: Men aged > 45 years with LUTS/BPH were randomly assigned to receive sildenafil 25 mg qd (n = 42), bid (n = 41), 50 mg qd (n = 38) or placebo (n = 41) for 8 weeks. Changes from baseline in International Prostate Symptom Score (I-PSS), maximum urinary flow rate (Qmax) and postvoid residual urine volume (PVR) were assessed at week 4 and week 8. RESULTS: Sildenafil 25 mg qd (-7.3 +/- 5.8) and 25 mg bid (-7.0 +/- 5.7) exhibited significant improvements of I-PSS compared to placebo (-5.2 +/- 6.4) (p = 0.020, 0.025, respectively). In particular, voiding domain was more affected than storage domain. Only sildenafil 50 mg qd improved nocturia significantly (versus placebo, p = 0.027). Quality of life score was improved in all treatment groups. Qmax and PVR did not change significantly in all groups. All regimens were well tolerated. CONCLUSIONS: Sildenafil 25 mg qd, 25 mg bid and 50 mg qd are safe and effective to improve LUTS/BPH in long term, along with coexisting ED. In particular, nocturia is most well-controlled by 50 mg qd. PMID- 28590829 TI - Aging and sexual health: getting to the problem. AB - Erectile dysfunction (ED) is one of the most common disorders in male and is often associated with other age-related comorbidities. The aging process affects the structural organization and function of penile erectile components such as smooth muscle cell and vascular architecture. These modifications affect penile hemodynamics by impairing cavernosal smooth muscle cell relaxation, reducing penile elasticity, compliance and promoting fibrosis. This review aims to identify the mechanisms of ED in the penile aging process in experimental and clinical data. It also highlights areas that are in need of more research. The search strategies yielded total records screened from PubMed. Clarification of the molecular mechanisms that accompanies corpus cavernosum aging and aging associated ED will aid new perspectives in the development of novel mechanism based therapeutic approaches. Age is not a limiting factor for ED medical management, and it is never too late to treat. Hypogonadism should be managed regardless of age, and synergistic effects have been found during testosterone (T) replacement therapy when used along with oral phosphodiesterase-5 (PDE-5) inhibitors. Therefore, the clinical management of ED related to aging can be done by therapeutic interventions that include PDE-5 inhibitors, and other pharmacological treatments. PMID- 28590830 TI - Association of elevated interleukin-17 and angiopoietin-2 with prostate size in benign prostatic hyperplasia. AB - INTRODUCTION: Inflammation and angiogenesis are known to play a role in the development prostate tumors. The present study was designed to assess the levels of markers of inflammation and angiogenesis like interleukin-17 (IL-17) and angiopoietin-2 (ANGPT2) levels and their association with prostate size in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: 42 BPH cases and 42 controls were enrolled in the study. IL-17 and ANGPT2 were estimated in both the groups. RESULTS: IL-17 and ANGPT2 were significantly increased in BPH cases when compared with controls. Multivariate analysis showed that ANGPT2 predicts the prostate size in patients with BPH (R2 = 0.203, beta = 0.355, p = 0.028). Linear regression analysis showed that IL-17 was significantly associated with ANGPT2 in BPH cases (R2 = 0.129, beta - 0.359, p = 0.020). CONCLUSIONS: We conclude that IL-17 and ANGPT2 are elevated in BPH cases and ANGPT2 was associated with IL-17 and prostate size. PMID- 28590831 TI - Effects of testosterone administration on liver structure and function in aging rats. AB - : Aging males have a decrease in testosterone levels, by which the testosterone treatment may influence in a negatively fashion the liver. AIM: This study aimed to analyze the effects of aging with or without testosterone administration on the liver components of animals. METHODS: Wistar rats were divided into three groups: 20 months' group (G20), 24 months' group (G24), group treated with testosterone for 16 weeks (GT). All groups were sacrificed at 24 months except for G20 that was sacrificed at 20 months. RESULTS: Aging and testosterone treatment alters the body weight (BW), liver weight (LW) and relative liver weight. Besides, testosterone increased the mitogen capacity of hepatocytes. Nonetheless, we reinforce the negative effects of testosterone on old animals' liver as chronic hepatic congestion and/or cholestasis. In addition, we observed that testosterone plays an important role on hepatic glycogen stores. CONCLUSIONS: Our study showed many implications for the knowledge about the effects of aging with or without testosterone administration on old animals' liver. PMID- 28590833 TI - Evaluation of a Decision Aid for Women with Epilepsy Who Are Considering Pregnancy: A Randomized Controlled Trial. AB - BACKGROUND: For many women with epilepsy (WWE), decision making about pregnancy is complicated by considerations such as the potential teratogenicity of antiepileptic drugs, offspring risk of epilepsy, seizure occurrence during pregnancy, and the challenges of parenting amidst poorly controlled seizures. OBJECTIVE: This proof-of-concept, randomized controlled trial aimed to evaluate a decision aid (DA) developed to help WWE decide if they should start or enlarge their families. METHODS: Seventy-nine WWE of childbearing age were recruited from Epilepsy Action Australia between October and November 2013 and randomized to receive the intervention (the DA) or not, and to complete a set of questionnaires pre- and post- intervention. The DA, delivered as a PDF booklet, provided balanced evidence-based information about options, risks and benefits, including probabilities; as well as steps for clarifying values and considering options within one's personal situation. RESULTS: Compared with the control group, the DA group had statistically significant improvements in knowledge about pregnancy and epilepsy (Cohen's d = 1.24; 95%CI = 0.77 to 1.83) and reduced decisional conflict (Cohen's d = 0.59; 95%CI = 0.21 to 0.99). Changes in decision self-efficacy, certainty of choice, patient-practitioner communication abilities and value congruence with choice were comparable between the DA and control group. Importantly, women's decisions about motherhood were not biased towards either direction, and there were no adverse effects on depression or anxiety. All women who received the DA indicated they would recommend it to other WWE. CONCLUSIONS: The DA has the potential to serve as a useful support tool for WWE who are considering motherhood. Future research is needed to test the DA in clinical settings with guidance from a health professional. The trial was registered with the Australian New Zealand Clinical Trials Registry (ID ACTRN12613001082796). PMID- 28590832 TI - Association of the modified frailty index with adverse outcomes after penile prosthesis implantation. AB - OBJECTIVES: To investigate frailty as a predictor of surgical outcome in elderly patients undergoing penile prosthesis implantation. MATERIAL AND METHODS: A total of 54 elderly patients, above 60 years of age, underwent penile prosthesis implantation between 2012 and 2014. Their data were collected and retrospectively analyzed. A modified frailty index (mFI) was calculated for each patient based on 11 risk factors from the Canadian Study of Health and Aging Frailty Index. The 1 year adverse outcomes were correlated with mFI, patients' and procedure's risk factors. RESULTS: Mean age was 64.9 +/- 5.2 years. No mortality was reported in our patients, however, one-year adverse outcomes were encountered in 43 (79.6%) patients. Among all studied variables, the 1-year adverse outcomes was not significantly association with mFI, but with preoperative glycosylated hemoglobin A1c (HbA1c) (p = 0.031) and associated Peyronie's disease (PD) (p = 0.000). HbA1c, dyslipidemia, hypertension, PD and duration of the procedure were predictive of infection complications (p < 0.05). Only PD and HbA1c sustained an independent significant impact. CONCLUSIONS: mFI is not a predictive of post penile prosthesis implantation adverse outcomes in elderly patients with impotence. Degree of diabetic control and association with PD was associated with the 1-year adverse outcomes and infection complications. PMID- 28590834 TI - Comparison of the Effects of a Pharmaceutical Industry Decision Guide and Decision Aids on Patient Choice to Intensify Therapy in Rheumatoid Arthritis. AB - OBJECTIVE: To compare the effects a pharmaceutical industry decision guide and International Patient Decision Aids Standard (IPDAS) compliant patient decision aids (PtDA) on patient medication beliefs and choice to intensify therapy. METHODS: Rheumatoid arthritis (RA) patients, who had never taken etanercept (Enbrel), took part in a mail survey. They were presented with a hypothetical decision scenario where they were asked to consider adding etanercept to their current regimen. Each patient was randomized to review 1 of 3 forms of an etanercept-specific decision support: a long PtDA (LONG DA), a short PtDA (SHORT DA), or the manufacturer's Enbrel decision guide (Pharm Booklet). RESULTS: We had 402 RA patients participate in the study (response rate, 52%). Of the patients randomized to the Pharm Booklet, 30.6% elected to initiate etanercept. Only 14.6% and 14.0% of patients who reviewed the LONG DA or SHORT DA choose to take etanercept (chi2 = 15.7; P < 0.001). Patients who reviewed the LONG DA or SHORT DA had a greater increase in knowledge about etanercept than those who reviewed the Pharm Booklet. There was no difference in decisional conflict among the groups. A logistic regression model explained 44.2% (R2 = 0.442) of patient choice to intensify therapy by initiating etanercept. The strongest predictor of choice to intensify therapy were beliefs about etanercept's ability to improve symptoms (OR = 2.56, 96%CI [1.71, 3.80]), and its use by others like the respondent (OR = 2.24, 95%CI [1.49, 3.35]). Mediation analysis confirmed the presence of a partial mediating effect of decision support on patients' intent to take etanercept (OR = 0.59, 95%CI [0.39, 0.89]). CONCLUSIONS: Patients supported by the Pharm Booklet were twice as likely to choose to intensify therapy. The Pharm Booklet's effects are partially mediated through persuasive communication techniques that influence patients' beliefs that symptoms will improve, and increase social normative beliefs, rather than by increasing the relevant knowledge, clarifying patient values about positive or negative treatment outcomes, or increasing their self-efficacy. PMID- 28590835 TI - A Pilot Study on the Evaluation of Physicians' Laser Delivery Performance Using a Laser Beam Detection Kit. AB - BACKGROUND AND OBJECTIVE: Many laser devices have been developed over the past decades for various skin conditions. However, variations in the technical skill of physicians for laser skin treatment delivery have not yet been evaluated. This study evaluates the differences in omission and overlap percentages during simulated laser hair removal treatments among physicians at two clinics. MATERIALS AND METHODS: A laser beam detection kit was developed to record and collect laser irradiation from a diode laser device. Eight physicians (primary private clinic 4, tertiary referral hospital 4) were recruited to perform 80 trials of laser delivery simulation. The simulation process was captured in video frames by a camera built inside of the detection kit. The laser distribution map was reconstructed, and each physician's performance result was determined by a computer calculation. RESULTS: Various assumption tests showed that each physician had different laser delivery skills. Four physicians from clinic A had an average omission rate of 13.4%, and four physicians from clinic B had an average omission rate of 19.7%. Regarding the average overlap rate of the two clinics, clinic A had a higher rate than clinic B (26.1% vs. 14.6%). CONCLUSIONS: The study's findings confirmed the differences of the technical skills among the physicians and between the two clinics. The proposed computer-assisted evaluation of technical skill is useful for assessing physicians' performance during laser skin treatments. PMID- 28590836 TI - Photoselective Vaporization of the Prostate Using 120 W High Performance System: A Prospective Evaluation of Results Over 2 Years. AB - PURPOSE: This study evaluated the safety and efficacy of photoselective vaporization of prostate using the 120 W High Performance System for management of symptomatic benign prostatic hyperplasia (BPH). METHODS: We prospectively obtained data from 229 patients between January 2009 and December 2012. We evaluated the serum prostate specific antigen level, International Prostate Symptom Score (IPSS), prostate volume; maximum urine flow rate (Qmax); and postvoid residual urine volume (PVR) in the patients at presentation and on follow-up at 1, 6, 12, and 24 months. The mean duration of the surgery, energy used, hospital stay, and intra- and postoperative complications were assessed. RESULTS: The mean age of the patients was 71.2 +/- 9.6 years, and the mean preoperative size of the prostate was 59.41 +/- 28.1 mL. The mean duration of the surgery was 47.35 +/- 16.14 min, and the mean energy use was 184.39 +/- 101.3 kJ. The mean time to removal of the urinary catheter was 21.45 +/- 11.06 h, while the mean duration of hospital stay was 24.82 +/- 11.5 h. The IPSS declined and mean Qmax increased by over twofold within the first month. The PVR also declined significantly in all groups up to 6 months after the surgery and increased slightly thereafter. Urinary urgency and incontinence occurred in two patients, while four patients developed urinary strictures. Between 12 and 24 months after the surgery, four patients underwent repeat surgery. CONCLUSIONS: Our findings show that photoselective vaporization is safe and effective for the management of BPH and resulted in few complications. It yielded improvements in all parameters that were sustained even up to 2 years after the surgery. PMID- 28590837 TI - Regulation and Measurement of the Heat Generated by Automatic Tooth Preparation in a Confined Space. AB - OBJECTIVE: The aim of this study was to assess and regulate heat generation in the dental pulp cavity and circumambient temperature around a tooth during laser ablation with a femtosecond laser in a confined space. BACKGROUND DATA: The automatic tooth preparing technique is one of the traditional oral clinical technology innovations. In this technique, a robot controlled an ultrashort pulse laser to automatically complete the three-dimensional teeth preparing in a confined space. The temperature control is the main measure for protecting the tooth nerve. METHODS: Ten tooth specimens were irradiated with a femtosecond laser controlled by a robot in a confined space to generate 10 teeth preparation. During the process, four thermocouple sensors were used to record the pulp cavity and circumambient environment temperatures with or without air cooling. A statistical analysis of the temperatures was performed between the conditions with and without air cooling (p < 0.05). RESULTS: The recordings showed that the temperature with air cooling was lower than that without air cooling and that the heat generated in the pulp cavity was lower than the threshold for dental pulp damage. CONCLUSIONS: These results indicate that femtosecond laser ablation with air cooling might be an appropriate method for automatic tooth preparing. PMID- 28590838 TI - Comparative Evaluation of Effects of Laser Modalities on Shear Bond Strengths of Veneering Porcelains to Laser Sintered Substructures: An In Vitro Study. AB - OBJECTIVE: Laser modalities and direct metal laser sintering (DMLS) have a potential to enhance micromechanical bonding between dental super- and infrastructures. However, the effect of different manufacturing methods on the metal-ceramic bond strength needs further evaluation. We investigated the effect of surface treatment with Er:YAG, Nd:YAG, and Ho:YAG lasers on the shear bond strength (SBS) of high-fusion dental porcelains (Vita and G-Ceram) to infrastructures prepared with DMLS in vitro settings. MATERIALS AND METHODS: Study specimens (n = 128) were randomly divided into study subsets (n = 8), considering treatment types applied on the surface of infrastructures, including sandblasting and selected laser modalities; infrastructure types as direct laser sintered (DLS) and Ni-Cr based; and superstructure porcelains as Vita and G Ceram. The SBS test was performed to assess the effectiveness of surface modifications that were also examined with a stereo microscope. RESULTS: Considering laser procedure types, the highest SBS values were obtained by Er:YAG laser, followed by, with a decreasing efficiency, Ho:YAG laser and sandblasting procedures, and Nd:YAG laser procedure (p < 0.05). Nd:YAG laser decreases the bonding of Vita and G-Ceram in all the infrastructures compared with sandblasting. Considering porcelains, the highest SBS values were obtained by Vita (p < 0.05). Considering infrastructures, the highest SBS values were obtained by DMLS procedure (p < 0.05). The laser procedures caused surface irregularities as revealed by the stereo microscopic examination. CONCLUSIONS: In current experimental settings, Er:YAG laser applied to DLS infrastructure veneered with Vita porcelain increases bonding strength more distinctly, and Nd:YAG laser applied to Ni-Cr-based infrastructure veneered with G-Ceram porcelain alters bonding strength unfavorably. PMID- 28590839 TI - Contractility, differential tension and membrane removal lead zebrafish epiboly biomechanics. AB - Precise tissue remodeling during development is essential for shaping embryos and optimal organ function. Epiboly is an early gastrulation event by which the blastoderm expands around the yolk to engulf it. Three different layers are involved in this process, an epithelial layer (the enveloping layer, EVL), the embryo proper, constituted by the deep cells (DCs), and the yolk cell. Although teleost epiboly has been studied for many years, a clear understanding of its mechanics was still missing. Here we present new information on the cellular, molecular and mechanical elements involved in epiboly that, together with some other recent data and upon comparison with previous biomechanical models, lets conclude that the expansion of the epithelia is passive and driven by active cortical contraction and membrane removal in the adjacent layer, the External Yolk Syncytial Layer (E-YSL). The isotropic actomyosin contraction of the E-YSL cortex generates an anisotropic stress pattern and a directional net movement consequence of the differences in the deformation response of the 2 opposites adjacent domains (EVL and the Yolk Cytoplasmic Layer - YCL). Contractility is accompanied by the local formation of membrane folds and its removal by Rab5ab dependent macropinocytosis. The increase in area of the epithelia during the expansion is achieved by cell-shape changes (flattening) responding to spherical geometrical cues. The counterbalance between the geometry of the embryo and forces dissipation among different elements is therefore essential for epiboly global coordination. PMID- 28590840 TI - Addressing child under nutrition: can traditional practices offer a solution? AB - Child under nutrition continues to be a challenge to global development, especially in resource-poor contexts. In the multifaceted attempts to address this challenge, popular traditional practices, although closely linked to infant health, remain neglected and less researched. The World Health Organization's recent strategy on traditional medicine systems provides overarching guidance in this regard. In this commentary, we attempt to exemplify this. We highlight the importance of traditional child care practices with regard to child nutrition and the need for trans-disciplinary research to explore the potential of these for public health. Infant oil massage appears to be a potentially beneficial practice for child nutrition. Rigorous trans-disciplinary research on traditional infant massage can provide simple solutions to address child under nutrition and nurture human capabilities globally. PMID- 28590841 TI - Rapid Prediction of Hematologic Acute Radiation Syndrome in Radiation Injury Patients Using Peripheral Blood Cell Counts. AB - Rapid clinical triage of radiation injury patients is essential for determining appropriate diagnostic and therapeutic interventions. We examined the utility of blood cell counts (BCCs) in the first three days postirradiation to predict clinical outcome, specifically for hematologic acute radiation syndrome (HARS). We analyzed BCC test samples from radiation accident victims (n = 135) along with their clinical outcome HARS severity scores (H1-4) using the System for Evaluation and Archiving of Radiation Accidents based on Case Histories (SEARCH) database. Data from nonirradiated individuals (H0, n = 132) were collected from an outpatient facility. We created binary categories for severity scores, i.e., 1 (H0 vs. H1-4), 2 (H0-1 vs. H2-4) and 3 (H0-2 vs. H3-4), to assess the discrimination ability of BCCs using unconditional logistic regression analysis. The test sample contained 454 BCCs from 267 individuals. We validated the discrimination ability on a second independent group comprised of 275 BCCs from 252 individuals originating from SEARCH (HARS 1-4), an outpatient facility (H0) and hospitals (e.g., leukemia patients, H4). Individuals with a score of H0 were easily separated from exposed individuals based on developing lymphopenia and granulocytosis. The separation of H0 and H1-4 became more prominent with increasing hematologic severity scores and time. On day 1, lymphocyte counts were most predictive for discriminating binary categories, followed by granulocytes and thrombocytes. For days 2 and 3, an almost complete separation was achieved when BCCs from different days were combined, supporting the measurement of sequential BCC. We found an almost complete discrimination of H0 vs. irradiated individuals during model validation (negative predictive value, NPV > 94%) for all three days, while the correct prediction of exposed individuals increased from day 1 (positive predictive value, PPV 78-89%) to day 3 (PPV > 90%). The models were unable to provide predictions for 10.9% of the test samples, because the PPVs or NPVs did not reach a 95% likelihood defined as the lower limit for a prediction. We developed a prediction model spreadsheet to provide early and prompt diagnostic predictions and therapeutic recommendations including identification of the worried well, requirement of hospitalization or development of severe hematopoietic syndrome. These results improve the provisional classification of HARS. For the final diagnosis, further procedures (sequential diagnosis, retrospective dosimetry, clinical follow-up, etc.) must be taken into account. Clinical outcome of radiation injury patients can be rapidly predicted within the first three days postirradiation using peripheral BCC. PMID- 28590843 TI - Introduction to Dual Diagnosis Special Issue. PMID- 28590842 TI - Suicide-Related Internet Use Among Suicidal Young People in the UK: Characteristics of Users, Effects of Use, and Barriers to Offline Help-Seeking. AB - The study replicates earlier research using a UK sample to examine differences between suicidal people who go online for suicide-related reasons and suicidal people who do not, perceived effects of suicide-related Internet use, and perceived barriers to offline help-seeking. A total of 72 UK citizens (18-24 years old) who had contemplated killing themselves or deliberately harmed themselves with the intention of dying within the past 12 months participated in an anonymous online survey. Results indicate that suicidal young people who use the Internet for suicide-related purposes are a high-risk group characterized by higher levels of social anxiety. The main purposes of suicide-related Internet use were to connect with others and seek information. Both positive and negative effects were found. PMID- 28590844 TI - Impulsivity and cue reactivity in smokers with comorbid depression and anxiety: Possible implications for smoking cessation treatment strategies. AB - Smoking remains one of the most preventable causes of morbidity and mortality in the United States (1). A number of factors contribute to the initiation and maintenance of smoking behavior, including psychosocial influences (2,3), neurobehavioral traits (4), and genetic susceptibility (5-7). Prevalence rates of tobacco dependence among individuals with mental health issues are strikingly high when compared to the general population, particularly among individuals with depression and anxiety disorders (8). There are well-established relationships between impulsivity, cue reactivity, and tobacco use in the literature (9). However, the interaction between these relationships remains unclear. The primary goal of this paper is to provide an overview of the existing literature across these domains and explore their interrelationship and subsequent impact on smoking initiation and tobacco dependence. Further, the clinical implications regarding the development of potential targeted smoking cessation strategies for this population are presented. PMID- 28590845 TI - Epilogue to Dual Diagnosis Special Issue. PMID- 28590846 TI - Preface: Selected Papers from RECOMB 2016. PMID- 28590847 TI - New Genome Similarity Measures based on Conserved Gene Adjacencies. AB - Many important questions in molecular biology, evolution, and biomedicine can be addressed by comparative genomic approaches. One of the basic tasks when comparing genomes is the definition of measures of similarity (or dissimilarity) between two genomes, for example, to elucidate the phylogenetic relationships between species. The power of different genome comparison methods varies with the underlying formal model of a genome. The simplest models impose the strong restriction that each genome under study must contain the same genes, each in exactly one copy. More realistic models allow several copies of a gene in a genome. One speaks of gene families, and comparative genomic methods that allow this kind of input are called gene family-based. The most powerful-but also most complex-models avoid this preprocessing of the input data and instead integrate the family assignment within the comparative analysis. Such methods are called gene family-free. In this article, we study an intermediate approach between family-based and family-free genomic similarity measures. Introducing this simpler model, called gene connections, we focus on the combinatorial aspects of gene family-free genome comparison. While in most cases, the computational costs to the general family-free case are the same, we also find an instance where the gene connections model has lower complexity. Within the gene connections model, we define three variants of genomic similarity measures that have different expression powers. We give polynomial-time algorithms for two of them, while we show NP-hardness for the third, most powerful one. We also generalize the measures and algorithms to make them more robust against recent local disruptions in gene order. Our theoretical findings are supported by experimental results, proving the applicability and performance of our newly defined similarity measures. PMID- 28590851 TI - Injury Mortality in Autism. PMID- 28590852 TI - Fostering a Public Health of Consequence: Practical Skills and Lessons Learned. PMID- 28590848 TI - Exploring the QSAR's predictive truthfulness of the novel N-tuple discrete derivative indices on benchmark datasets. AB - Graph derivative indices (GDIs) have recently been defined over N-atoms (N = 2, 3 and 4) simultaneously, which are based on the concept of derivatives in discrete mathematics (finite difference), metaphorical to the derivative concept in classical mathematical analysis. These molecular descriptors (MDs) codify topo chemical and topo-structural information based on the concept of the derivative of a molecular graph with respect to a given event (S) over duplex, triplex and quadruplex relations of atoms (vertices). These GDIs have been successfully applied in the description of physicochemical properties like reactivity, solubility and chemical shift, among others, and in several comparative quantitative structure activity/property relationship (QSAR/QSPR) studies. Although satisfactory results have been obtained in previous modelling studies with the aforementioned indices, it is necessary to develop new, more rigorous analysis to assess the true predictive performance of the novel structure codification. So, in the present paper, an assessment and statistical validation of the performance of these novel approaches in QSAR studies are executed, as well as a comparison with those of other QSAR procedures reported in the literature. To achieve the main aim of this research, QSARs were developed on eight chemical datasets widely used as benchmarks in the evaluation/validation of several QSAR methods and/or many different MDs (fundamentally 3D MDs). Three to seven variable QSAR models were built for each chemical dataset, according to the original dissection into training/test sets. The models were developed by using multiple linear regression (MLR) coupled with a genetic algorithm as the feature wrapper selection technique in the MobyDigs software. Each family of GDIs (for duplex, triplex and quadruplex) behaves similarly in all modelling, although there were some exceptions. However, when all families were used in combination, the results achieved were quantitatively higher than those reported by other authors in similar experiments. Comparisons with respect to external correlation coefficients (q2ext) revealed that the models based on GDIs possess superior predictive ability in seven of the eight datasets analysed, outperforming methodologies based on similar or more complex techniques and confirming the good predictive power of the obtained models. For the q2ext values, the non-parametric comparison revealed significantly different results to those reported so far, which demonstrated that the models based on DIVATI's indices presented the best global performance and yielded significantly better predictions than the 12 0-3D QSAR procedures used in the comparison. Therefore, GDIs are suitable for structure codification of the molecules and constitute a good alternative to build QSARs for the prediction of physicochemical, biological and environmental endpoints. PMID- 28590854 TI - Donald Trump, the Police, and Mental Health in US Cities. PMID- 28590855 TI - "Alien" Health Care. PMID- 28590856 TI - Educational Disparities in Adult Disability: Person, Place, Policies, and Family. PMID- 28590858 TI - The Lead Battery: A Growing Global Public Health Challenge. PMID- 28590857 TI - Public Health Research Priorities to Address US Human Trafficking. PMID- 28590859 TI - Trauma, Psychopathology, and the Refugee Crisis: A Call to Action. PMID- 28590861 TI - Applewhite and Sherman Respond. PMID- 28590860 TI - Inclusion of Disability Status in Investigations of Child Maltreatment Lifetime Prevalence. PMID- 28590862 TI - Potential Issues With Naloxone Distribution in the Community. PMID- 28590863 TI - Soda Consumption Among Adolescents: Implications for Low- and Middle-Income Countries. PMID- 28590864 TI - Hosting Syrian Refugees: Resources Exist in Our Communities. PMID- 28590867 TI - AJPH Global News. PMID- 28590866 TI - Toward Creation of the Oral Physician. PMID- 28590868 TI - Guan and Li Respond. PMID- 28590865 TI - Evaluating Public Health Interventions: 6. Modeling Ratios or Differences? Let the Data Tell Us. AB - We provide an overview of the relative merits of ratio measures (relative risks, risk ratios, and rate ratios) compared with difference measures (risk and rate differences). We discuss evidence that the multiplicative model often fits the data well, so that rarely are interactions with other risk factors for the outcome observed when one uses a logistic, relative risk, or Cox regression model to estimate the intervention effect. As a consequence, additive models, which estimate the risk or rate difference, will often exhibit interactions. Under these circumstances, absolute measures of effect, such as years of life lost, disability- or quality-adjusted years of life lost, and number needed to treat, will not be externally generalizable to populations other than those with similar risk factor distributions as the population in which the intervention effect was estimated. Nevertheless, these absolute measures are often of the greatest importance in public health decision-making. When studies of high-risk study populations are used to more efficiently estimate effects, these populations will not be representative of the general population's risk factor distribution. The relative homogeneity of ratio versus absolute measures will thus have important implications for the generalizability of results across populations. PMID- 28590869 TI - What Public Health Practitioners Need to Know About Unhealthy Industry Tactics. PMID- 28590870 TI - The Relentless Enemies of Science. PMID- 28590871 TI - A Public Health of Consequence: Review of the July 2017 Issue of AJPH. PMID- 28590872 TI - Risk Analysis in the 21st Century: Adapting to New Challenges and Opportunities. PMID- 28590873 TI - Physical Activity and Physical and Mental Well-Being in Church Settings. PMID- 28590874 TI - US Hospital Awards and Community Health Improvement. PMID- 28590875 TI - Increasing Availability of Prevention to Communities Disproportionately Affected by HIV. PMID- 28590876 TI - Cucumber green mottle mosaic virus: Rapidly Increasing Global Distribution, Etiology, Epidemiology, and Management. AB - Cucumber green mottle mosaic virus (CGMMV) was first described in 1935 infecting cucumber, making it one of the first plant viruses to be studied. Its initial distribution occurred out of England to other countries. This was followed by its distribution from England and these other countries to additional countries. This process increased slowly between 1935 and 1985, faster between 1986 and 2006, and rapidly between 2007 and 2016. The discovery that it diminished cucurbit fruit yields and quality, especially of watermelon, prompted a substantial research effort in worst-affected countries. These efforts included obtaining insight into its particle and genome characteristics, evolution, and epidemiology. CGMMV's particle stability, ease of contact transmission, and seed transmissibility, which are typical tobamovirus characteristics, explained its complex disease cycle and its ability to spread locally or over long distances without a vector. Knowledge of its disease etiology and epidemiology enabled development of integrated disease management approaches that rely heavily on diverse phytosanitary measures. Dispersal of seed-borne infection through the international seed trade following cucurbit seed crop production in tropical or subtropical countries explains its recent rapid dispersion worldwide. PMID- 28590877 TI - Genome Evolution of Plant-Parasitic Nematodes. AB - Plant parasitism has evolved independently on at least four separate occasions in the phylum Nematoda. The application of next-generation sequencing (NGS) to plant parasitic nematodes has allowed a wide range of genome- or transcriptome-level comparisons, and these have identified genome adaptations that enable parasitism of plants. Current genome data suggest that horizontal gene transfer, gene family expansions, evolution of new genes that mediate interactions with the host, and parasitism-specific gene regulation are important adaptations that allow nematodes to parasitize plants. Sequencing of a larger number of nematode genomes, including plant parasites that show different modes of parasitism or that have evolved in currently unsampled clades, and using free-living taxa as comparators would allow more detailed analysis and a better understanding of the organization of key genes within the genomes. This would facilitate a more complete understanding of the way in which parasitism has shaped the genomes of plant-parasitic nematodes. PMID- 28590878 TI - Tick Tock: Circadian Regulation of Plant Innate Immunity. AB - Many living organisms on Earth have evolved the ability to integrate environmental and internal signals to determine time and thereafter adjust appropriately their metabolism, physiology, and behavior. The circadian clock is the endogenous timekeeper critical for multiple biological processes in many organisms. A growing body of evidence supports the importance of the circadian clock for plant health. Plants activate timed defense with various strategies to anticipate daily attacks of pathogens and pests and to modulate responses to specific invaders in a time-of-day-dependent manner (gating). Pathogen infection is also known to reciprocally modulate clock activity. Such a cross talk likely reflects the adaptive nature of plants to coordinate limited resources for growth, development, and defense. This review summarizes recent progress in circadian regulation of plant innate immunity with a focus on the molecular events linking the circadian clock and defense. More and better knowledge of clock-defense cross talk could help to improve disease resistance and productivity in economically important crops. PMID- 28590879 TI - Tritrophic Interactions: Microbe-Mediated Plant Effects on Insect Herbivores. AB - It is becoming abundantly clear that the microbes associated with plants and insects can profoundly influence plant-insect interactions. Here, we focus on recent findings and propose directions for future research that involve microbe induced changes to plant defenses and nutritive quality as well as the consequences of these changes for the behavior and fitness of insect herbivores. Insect (herbivore and parasitoid)-associated microbes can favor or improve insect fitness by suppressing plant defenses and detoxifying defensive phytochemicals. Phytopathogens can influence or manipulate insect behavior and fitness by altering plant quality and defense. Plant-beneficial microbes can promote plant growth and influence plant nutritional and phytochemical composition that can positively or negatively influence insect fitness. Lastly, we suggest that entomopathogens have the potential to influence plant defenses directly as endophytes or indirectly by altering insect physiology. PMID- 28590880 TI - Development and Validation of a Measure Assessing Child Diabetes Behavior: The Diabetes Behavior Checklist. AB - Previous research in pediatric diabetes management has focused on general child behavior, which is linked with treatment adherence and health outcomes in children with type 1 diabetes. Little is known about child diabetes behavior problems specifically. The current study aimed to develop and validate a measure of diabetes-specific child behavior problems, and parents' confidence in managing these behaviors. Participants were a community sample of 186 parents of children aged 2-10 years with type 1 diabetes, recruited via online parenting forums and advertisements placed in school and childcare newsletters throughout Australia. The measure demonstrated excellent internal consistency and evidence of construct validity, and factor analyses revealed a 3-factor and a 1-factor structure for the Extent and Confidence scales, respectively. This study provides preliminary evidence of validity of the Diabetes Behavior Checklist. The implications of these findings for intervention development are discussed. PMID- 28590881 TI - Effects of irrelevant background speech on eye movements during reading. AB - The irrelevant speech effect (ISE) refers to the impairment of visual information processing by background speech. Prior research on the ISE has focused on short term memory for visually presented word lists. The present research extends this work by using measurements of eye movements to examine effects of irrelevant background speech during Chinese reading. This enabled an examination of the ISE for a language in which access to semantic representations is not strongly mediated by phonology. Participants read sentences while exposed to meaningful irrelevant speech, meaningless speech (scrambled meaningful speech) or silence. A target word of high or low lexical frequency was embedded in each sentence. The results show that meaningful, but not meaningless, background speech produced increased re-reading. In addition, the appearance of a normal word frequency effect, characterised by longer fixation times on low- compared to high-frequency words, was delayed when meaningful or meaningless speech was present in the background. These findings show that irrelevant background speech can disrupt normal processes of reading comprehension and, in addition, that background noise can interfere with the early processing of words. The findings add to evidence showing that normal reading processes can be disrupted by environmental noise such as irrelevant background speech. PMID- 28590882 TI - Item response theory analysis of the Lichtenberg Financial Decision Screening Scale. AB - The focus of these analyses was to examine the psychometric properties of the Lichtenberg Financial Decision Screening Scale (LFDSS). The purpose of the screen was to evaluate the decisional abilities and vulnerability to exploitation of older adults. Adults aged 60 and over were interviewed by social, legal, financial, or health services professionals who underwent in-person training on the administration and scoring of the scale. Professionals provided a rating of the decision-making abilities of the older adult. The analytic sample included 213 individuals with an average age of 76.9 (SD = 10.1). The majority (57%) were female. Data were analyzed using item response theory (IRT) methodology. The results supported the unidimensionality of the item set. Several IRT models were tested. Ten ordinal and binary items evidenced a slightly higher reliability estimate (0.85) than other versions and better coverage in terms of the range of reliable measurement across the continuum of financial incapacity. PMID- 28590883 TI - What's in a name? Group fitness class names and women's reasons for exercising. AB - The benefits of intrinsic exercise motivation are well recognized, yet extrinsically focused group-fitness class names/descriptions dominate the fitness industry. To explore the impact of how fitness classes are marketed, women (N = 389) were asked to indicate their preference for either intrinsically or extrinsically focused fitness classes based on title/description. Participants who favored intrinsic class names/descriptions were more likely to report greater interest/enjoyment, perceived competence, and greater effort and report exercising for health/fitness-related reasons. Those favoring extrinsic class names/descriptions were more likely to experience tension/pressure when exercising and report exercising for appearance/weight-related reasons. The results demonstrate the importance of wording when marketing fitness classes. PMID- 28590884 TI - Milk, juice, or cola? Exploring the effect of product placement on children's attitudes and behavior. AB - Childhood obesity is a significant public health concern, and scholars and academicians have proposed the use of successful marketing and advertising tactics as a means of influencing healthy behaviors. This research investigates product placement to assess its potential effects on attitudes and behavior when utilized in an animated children's television show. Results from an experiment suggest that multiple product placements may affect children's attitudes toward certain drinks, but also suggest that a child's existing favorite drink is a stronger predictor of actual beverage choice. Implications are provided. PMID- 28590886 TI - Bioconversion of Isoflavones into Bioactive Equol: State of the Art. AB - BACKGROUND: Soy isoflavones, an important class of phytoestrogens, are suggested to be responsible for a number of biological activities associated with health benefits, including defense against various chronic diseases, including breast and prostate cancer, cardiovascular disorders, and osteoporosis, and they may alleviate the symptoms of menopause. METHODS: However, current researches (including patents) have shown that the clinical efficacy of these phenolic compounds is related to the ability of an individual to biotransform isoflavones into equol, which is a metabolite of daidzein formed exclusively by the intestinal microbiota. RESULTS: This biologically active metabolite presents greater effects than other isoflavones; however, only about 30-50 % of people have a microbiota that is able to produce equol from dietary daidzein. Concern has recently grown about applications to improve the production of this metabolite. CONCLUSION: This paper summarizes the metabolism of equol, its production, and clinical implications. PMID- 28590885 TI - Optimistic bias, advertising skepticism, and consumer intentions for seeking information about the health risks of prescription medicine. AB - Based on a survey of prescription drug users (N = 408), this study revealed that: (a) the frequency of consumers' personal experience of prescription medicine adverse reactions negatively related to the extent of their optimistic bias about the chances of such events, (b) consumers' perceived personal control over adverse reactions positively related to optimistic bias, and (c) optimistic bias related more negatively to intentions to seek risk information when consumer skepticism toward direct-to-consumer advertising was high. When skepticism was low to average, optimistic bias did not inhibit such intentions. Implications and recommendations for the practice of direct-to-consumer advertising are provided. PMID- 28590887 TI - Editorial (Thematic Issue: Thyroid Cancer in Children and Adolescents). PMID- 28590888 TI - Editorial: Chromatographic Enantioseparations in Pharmaceutical Analysis: From the Analytical to the Preparative-Scale. PMID- 28590889 TI - DOK3 Degradation is Required for the Development of LPS-induced ARDS in Mice. AB - It has been reported that DOK3 protein negatively regulates LPS responses and endotoxin tolerance in mice. However, the role of DOK3 in the development of acute respiratory distress syndrome (ARDS) remains unknown. In this study, we showed that DOK3 is degraded in the lung tissues of LPS-induced ARDS. Through lentivirus transduction containing DOK3(K27R) via the intranasal route, we created a mice model, in which DOK3 maintains stable expression. We found that the forced DOK3 expression significantly attenuated LPS-induced pulmonary histological alterations, inflammatory cells infiltration, lung edema, as well as the generation of inflammatory cytokines TNFalpha, IL- 1beta and IL-6 in BALF of LPS-induced ARDS mice. In addition, DOK3 expression apparently suppressed LPS induced NF-kappaB and ERK activation. These data suggested that DOK3 expression negatively regulates the development of LPS-induced ARDS in mice. PMID- 28590890 TI - Editorial. PMID- 28590892 TI - Be a Teacher. PMID- 28590891 TI - Preface. PMID- 28590893 TI - Acoustic Reflexes in Normal-Hearing Adults, Typically Developing Children, and Children with Suspected Auditory Processing Disorder: Thresholds, Real-Ear Corrections, and the Role of Static Compliance on Estimates. AB - BACKGROUND: Previous studies have suggested elevated reflex thresholds in children with auditory processing disorders (APDs). However, some aspects of the child's ear such as ear canal volume and static compliance of the middle ear could possibly affect the measurements of reflex thresholds and thus impact its interpretation. Sound levels used to elicit reflexes in a child's ear may be higher than predicted by calibration in a standard 2-cc coupler, and lower static compliance could make visualization of very small changes in impedance at threshold difficult. For this purpose, it is important to evaluate threshold data with consideration of differences between children and adults. PURPOSE: A set of studies were conducted. The first compared reflex thresholds obtained using standard clinical procedures in children with suspected APD to that of typically developing children and adults to test the replicability of previous studies. The second study examined the impact of ear canal volume on estimates of reflex thresholds by applying real-ear corrections. Lastly, the relationship between static compliance and reflex threshold estimates was explored. RESEARCH DESIGN: The research is a set of case-control studies with a repeated measures design. STUDY SAMPLE: The first study included data from 20 normal-hearing adults, 28 typically developing children, and 66 children suspected of having an APD. The second study included 28 normal-hearing adults and 30 typically developing children. DATA COLLECTION AND ANALYSIS: In the first study, crossed and uncrossed reflex thresholds were measured in 5-dB step size. Reflex thresholds were analyzed using repeated measures analysis of variance (RM-ANOVA). In the second study, uncrossed reflex thresholds, real-ear correction, ear canal volume, and static compliance were measured. Reflex thresholds were measured using a 1-dB step size. The effect of real-ear correction and static compliance on reflex threshold was examined using RM-ANOVA and Pearson correlation coefficient, respectively. RESULTS: Study 1 replicated previous studies showing elevated reflex thresholds in many children with suspected APD when compared to data from adults using standard clinical procedures, especially in the crossed condition. The thresholds measured in children with suspected APD tended to be higher than those measured in the typically developing children. There were no significant differences between the typically developing children and adults. However, when real-ear calibrated stimulus levels were used, it was found that children's thresholds were elicited at higher levels than in the adults. A significant relationship between reflex thresholds and static compliance was found in the adult data, showing a trend for higher thresholds in ears with lower static compliance, but no such relationship was found in the data from the children. CONCLUSIONS: This study suggests that reflex measures in children should be adjusted for real-ear-to-coupler differences before interpretation. The data in children with suspected APD support previous studies suggesting abnormalities in reflex thresholds. The lack of correlation between threshold and static compliance estimates in children as was observed in the adults may suggest a nonmechanical explanation for age and clinically related effects. PMID- 28590894 TI - Hearing Characteristics of Stroke Patients: Prevalence and Characteristics of Hearing Impairment and Auditory Processing Disorders in Stroke Patients. AB - BACKGROUND: Stroke survivors may suffer from a range of hearing impairments that may restrict their participation in postacute rehabilitation programs. Hearing impairment may have a significant impact on listening, linguistic skills, and overall communication of the affected stroke patient. However, no studies sought to systematically characterize auditory function of stroke patients in detail, to establish the different types of hearing impairments in this cohort of patients. Such information would be clinically useful in understanding and addressing the hearing needs of stroke survivors. PURPOSE: The present study aimed to characterize and classify the hearing impairments, using a detailed audiological assessment test battery, in order to determine the level of clinical need and inform appropriate rehabilitation for this patient population. RESEARCH DESIGN: A case-control study. STUDY SAMPLE: Forty-two recruited stroke patients who were discharged from a stroke unit and 40 control participants matched for age. DATA COLLECTION AND ANALYSIS: All participants underwent pure-tone audiometry and immittance measurements including acoustic reflex threshold, transient-evoked otoacoustic emissions, auditory-evoked brainstem response, and a central auditory processing assessment battery, performed in a single session. Hearing impairments were classified as peripheral hearing loss (cochlear and neural type), central auditory processing disorder (CAPD), and as a combination of CAPD and peripheral hearing loss. RESULTS: Overall mean hearing thresholds were not significantly different between the control and stroke groups. The most common type of hearing impairment in stroke patients was the combination type, "peripheral and CAPD," in the 61- to 80-yr-old subgroup (in 55%), and auditory processing deficits in 18- to 60-yr-olds (in 40%), which were both significantly higher than in controls. CONCLUSIONS: This is the first study to examine hearing function in detail in stroke patients. Given the importance of hearing for the efficiency of communication, it is essential to identify hearing impairments and differentiate peripheral and central deficits to define an appropriate intervention plan. PMID- 28590895 TI - A Qualitative Case Study of Smartphone-Connected Hearing Aids: Influences on Patients, Clinicians, and Patient-Clinician Interactions. AB - BACKGROUND: Innovations in hearing aid technology influence clinicians and individuals who use hearing aids. Little research, to date, explains the innovation adoption experiences and perspectives of clinicians and patients, which matter to a field like audiology, wherein technology innovation is constant. By understanding clinician and patient experiences with such innovations, the field of audiology may develop technologies and ways of practicing in a manner more responsive to patients' needs, and attentive to society's influence. PURPOSE: The authors aimed to understand how new innovations influence clinician and patient experiences, through a study focusing on connected hearing aids. "Connected" refers to the wireless functional connection of hearing aids with everyday technologies like mobile phones and tablets. RESEARCH DESIGN: The authors used a qualitative collective case study methodology, borrowing from constructivist grounded theory for data collection and analysis methods. Specifically, the authors designed a collective case study of a connected hearing aid and smartphone application, composed of two cases of experience with the innovation: the case of clinician experiences, and the case of patient experiences. STUDY SAMPLE: The qualitative sampling methods employed were case sampling, purposive within-case sampling, and theoretical sampling, and culminated in a total collective case n = 19 (clinician case n = 8; patient case n = 11). These data were triangulated with a supplementary sample of ten documents: relevant news and popular media collected during the study time frame. DATA COLLECTION AND ANALYSIS: The authors conducted interviews with the patients and clinicians, and analyzed the interview and document data using the constant comparative method. The authors compared their two cases by looking at trends within, between, and across cases. RESULTS: The clinician case highlighted clinicians' heuristic-based candidacy judgments in response to the adoption of the connected hearing aids into their practice. The patient case revealed patients' perceptions of themselves as technologically competent or incompetent, and descriptions of how they learned to use the new technology. Between cases, the study found a difference in the response to how the connected hearing aid changed the clinician-patient relationship. While clinicians valued the increased time they spent "getting to know" their patients, patients experienced some frustration specific to the additional troubleshooting related to Bluetooth connectivity. Across cases, there was a resounding theme of "normalization" of hearing aids via their integration with a "normal" technology (mobile phones) and general lack of concern about privacy in relation to the smartphone application and its tracking and geotagging features. Both audiologists and patients credited the connected hearing aids with increased opportunities to participate more fully in everyday life. CONCLUSIONS: The introduction of smartphone-connected hearing aids influenced the identities and candidate profiles of hearing aid users, and the nature of time spent in clinical interactions, in important and interesting ways. The influence of connected hearing aids on patient experience and audiology practice calls for continued research and clinical consideration, with implications for clinical decision-making regarding hearing aid candidacy. Further study should look critically at normalization and possible unintended stigmatizing effects of making hearing aids increasingly discreet. PMID- 28590896 TI - Social Representation of "Loud Music" in Young Adults: A Cross-Cultural Study. AB - BACKGROUND: Exposure to recreational noise, particularly music exposure, is considered one of the biggest public health hazards of our time. Some important influencing factors such as socioeconomic status, educational background, and cross-cultural perspectives have previously been found to be associated with attitudes toward loud music and the use of hearing protection. Although culture seems to play an important role, there is relatively little known about how it influences perceptions regarding loud music exposure in young adults. PURPOSE: The present study was aimed to explore cross-cultural perceptions of and reactions to loud music in young adults (18-25 yr) using the theory of social representations. RESEARCH DESIGN: The study used a cross-sectional survey design. STUDY SAMPLE: The study sample included young adults (n = 534) from five different countries (India, Iran, Portugal, the United States, and the United Kingdom) who were recruited using convenience sampling. DATA COLLECTION AND ANALYSIS: Data were collected using a questionnaire. Data were analyzed using a content analysis, co-occurrence analysis, and also chi2 analysis. RESULTS: Fairly equal numbers of positive and negative connotations (~40%) were noted in all countries. However, the chi2 analysis showed significant differences between the countries (most positive connotations were found in India and Iran, whereas the most negative connotations were found in the United Kingdom and Portugal) regarding the informants' perception of loud music. The co-occurrence analysis results generally indicate that the category "negative emotions and actions" occurred most frequently, immediately followed by the category "positive emotions and actions." The other most frequently occurring categories included "acoustics," "physical aliment," "location," and "ear and hearing problems." These six categories formed the central nodes of the social representation of loud music exposure in the global index. Although some similarities and differences were noted among the social representations toward loud music among countries, it is noteworthy that more similarities than differences were noted among countries. CONCLUSIONS: The study results suggest that "loud music" is perceived to have both positive and negative aspects within society and culture. We suggest that the health promotion strategies should focus on changing societal norms and regulations to be more effective in decreasing the noise- and/or music induced auditory symptoms among young adults. PMID- 28590897 TI - Cortical Auditory-Evoked Potential and Behavioral Evidence for Differences in Auditory Processing between Good and Poor Readers. AB - BACKGROUND: The relationship between auditory processing (AP) and reading is thought to be significant; however our understanding of this relationship is somewhat limited. Previous studies have investigated the relation between certain electrophysiological and behavioral measures of AP and reading abilities in children. This study attempts to further understand that relation. PURPOSE: Differences in AP between good and poor readers were investigated using electrophysiological and behavioral measures. STUDY SAMPLE: Thirty-two children (15 female) aged 9-11 yr were placed in either a good reader group or poor reader group, based on the scores of a nationally normed reading test in New Zealand. RESEARCH DESIGN: Children were initially tested using an automated behavioral measuring system that runs through a tablet computer known as "Feather Squadron." Following the administration of Feather Squadron, cortical auditory-evoked potentials (CAEPs) were recorded using a speech stimulus (/m/) with the HEARLab(r) Cortical Auditory Evoked Potential Analyzer. DATA COLLECTION AND ANALYSIS: The children were evaluated on eight subsections of the Feather Squadron, and CAEP waveform peaks were visually identified and averaged. Separate Kruskal-Wallis analyses were performed for the behavioral and electrophysiological variables, with group (good versus poor readers) serving as the between-group independent variable and scores from the Feather Squadron AP tasks as well as CAEP latencies and amplitudes as dependent variables. After the children's AP status was determined, the entire group was further divided into three groups: typically developing, auditory processing disorder + reading difficulty (APD + RD), and RDs only. Statistical analyses were repeated for these subgroups. RESULTS: Poorer readers showed significantly worse scores than the good readers for the Tonal Pattern 1, Tonal Pattern 2, and Word Double Dichotic Right tasks. CAEP differences observed across groups indicated comorbid effects of RD and AP difficulties. N2 amplitude was significantly smaller for the poor readers. CONCLUSIONS: The current study found altered AP in poor readers using behavioral Feather Squadron measures and speech-evoked cortical potentials. These results provide further evidence that intact central auditory function is fundamental for reading development. PMID- 28590898 TI - Tinnitus Management: Randomized Controlled Trial Comparing Extended-Wear Hearing Aids, Conventional Hearing Aids, and Combination Instruments. AB - BACKGROUND: Whereas hearing aids have long been considered effective for providing relief from tinnitus, controlled clinical studies evaluating this premise have been very limited. PURPOSE: The purpose of this study was to systematically determine the relative efficacy of conventional receiver-in-the canal hearing aids (HA), the same hearing aids with a sound generator (HA+SG), and extended-wear, deep fit hearing aids (EWHA), to provide relief from tinnitus through a randomized controlled trial. Each of these ear-level devices was a product of Phonak, LLC. RESEARCH DESIGN: Participants were randomized to HA, HA+SG, or EWHA and wore bilaterally fit devices for about 4 months. Fittings, adjustments, and follow-up appointments were conducted to comply with company guidelines and to ensure that all participants attended appointments on the same schedule. At 4-5 months, participants returned to complete final outcome measures, which concluded their study participation. STUDY SAMPLE: Participants were 55 individuals (mean age: 63.1 years) with mild to moderately-severe hearing loss who: (a) did not currently use hearing aids; (b) reported tinnitus that was sufficiently bothersome to warrant intervention; and (c) were suitable candidates for each of the study devices. DATA COLLECTION AND ANALYSIS: The primary outcome measure was the Tinnitus Functional Index (TFI). Secondary outcome measures included hearing-specific questionnaires and the Quick Speech in Noise test (QuickSIN). The goal of the analysis was to evaluate efficacy of the EWHA and HA+SG devices versus the HA standard device. RESULTS: There were 18 participants in each of the HA and EWHA groups and 19 in the HA+SG group. Gender, age, and baseline TFI severity were balanced across treatment groups. Nearly all participants had a reduction in tinnitus symptoms during the study. The average TFI change (improvement) from baseline was 21 points in the HA group, 31 points in the EWHA group, and 33 points in the HA+SG group. A "clinically significant" improvement in reaction to tinnitus (at least 13-point reduction in TFI score) was seen by 67% of HA, 82% of EWHA, and 79% of HA+SG participants. There were no statistically significant differences in the extent to which the devices reduced TFI scores. Likewise, the hearing-specific questionnaires and QuickSIN showed improvements following use of the hearing aids but these improvements did not differ across device groups. CONCLUSIONS: There is insufficient evidence to conclude that any of these devices offers greater relief from tinnitus than any other one tested. However, all devices appear to offer some improvement in the functional effects of tinnitus. PMID- 28590899 TI - The Potential in Preparing Community Health Workers to Address Hearing Loss. AB - BACKGROUND: In underserved areas, it is crucial to investigate ways of increasing access to hearing health care. The community health worker (CHW) is a model that has been applied to increase access in various health arenas. This article proposes further investigation into the application of this model to audiology. PURPOSE: To assess the feasibility of training CHWs about hearing loss as a possible approach to increase accessibility of hearing health support services in an underserved area. RESEARCH DESIGN: A specialized three-phase training process for CHWs was developed, implemented, and evaluated by audiologists and public health researchers. The training process included (1) focus groups with CHWs and residents from the community to raise awareness of hearing loss among CHWs and the community; (2) a 3-hr workshop training to introduce basic topics to prepare CHWs to identify signs of hearing loss among community members and use effective communication strategies; and (3) a 24-hr multisession, interactive training >6 weeks for CHWs who would become facilitators of educational and peer-support groups for individuals with hearing loss and family members. STUDY SAMPLE: Twelve Spanish-speaking local CHWs employed by a federally qualified health center participated in a focus group, twelve received the general training, and four individuals with prior experience as health educators received further in-person training as facilitators of peer-education groups on hearing loss and communication. DATA COLLECTION AND ANALYSIS: Data was collected from each step of the three-phase training process. Thematic analysis was completed for the focus group data. Pre- and posttraining assessments and case study discussions were used to analyze results for the general workshop and the in-depth training sessions. RESULTS: CHWs increased their knowledge base and confidence in effective communication strategies and developed skills in facilitating hearing education and peer-support groups. Through case study practice, CHWs demonstrated competencies and applied their learning to specific situations related to effective communication with hearing loss, family support, availability of assistive technology, use of hearing protection, and making referrals for hearing health care. Needs were identified for ongoing training in the area of use of assistive technology and addressing situations of more severe hearing loss and its effects. CONCLUSIONS: Initial results suggest it is feasible to train CHWs to engage community members regarding hearing loss and facilitate culturally relevant peer-health education and peer-support groups for individuals with hearing loss and their family members. In efforts to increase access to audiological services in rural or underserved communities, application of the CHW model with a partnership of audiologists deserves further consideration as a viable approach. PMID- 28590900 TI - The Association between Hearing Loss, Postural Control, and Mobility in Older Adults: A Systematic Review. AB - BACKGROUND: Degraded hearing in older adults has been associated with reduced postural control and higher risk of falls. Both hearing loss (HL) and falls have dramatic effects on older persons' quality of life (QoL). A large body of research explored the comorbidity between the two domains. PURPOSE: The aim of the current review is to describe the comorbidity between HL and objective measures of postural control, to offer potential mechanisms underlying this relationship, and to discuss the clinical implications of this comorbidity. DATA COLLECTION AND ANALYSIS: PubMed and Google Scholar were systematically searched for articles published in English up until October 15, 2015, using combinations of the following strings and search words: for hearing: Hearing loss, "Hearing loss," hearing, presbycusis; for postural control: postural control, gait, postural balance, fall, walking; and for age: elderly, older adults. RESULTS: Of 211 screened articles, 7 were included in the systematic review. A significant, positive association between HL and several objective measures of postural control was found in all seven studies, even after controlling for major covariates. Severity of hearing impairment was connected to higher prevalence of difficulties in walking and falls. Physiological, cognitive, and behavioral processes that may influence auditory system and postural control were suggested as potential explanations for the association between HL and postural control. CONCLUSIONS: There is evidence for the independent relationship between HL and objective measures of postural control in the elderly. However, a more comprehensive understanding of the mechanisms underlying this relationship is yet to be elucidated. Concurrent diagnosis, treatment, and rehabilitation of these two modalities may reduce falls and increase QoL in older adults. PMID- 28590902 TI - Attentional modulation of neuronal variability in circuit models of cortex. AB - The circuit mechanisms behind shared neural variability (noise correlation) and its dependence on neural state are poorly understood. Visual attention is well suited to constrain cortical models of response variability because attention both increases firing rates and their stimulus sensitivity, as well as decreases noise correlations. We provide a novel analysis of population recordings in rhesus primate visual area V4 showing that a single biophysical mechanism may underlie these diverse neural correlates of attention. We explore model cortical networks where top-down mediated increases in excitability, distributed across excitatory and inhibitory targets, capture the key neuronal correlates of attention. Our models predict that top-down signals primarily affect inhibitory neurons, whereas excitatory neurons are more sensitive to stimulus specific bottom-up inputs. Accounting for trial variability in models of state dependent modulation of neuronal activity is a critical step in building a mechanistic theory of neuronal cognition. PMID- 28590905 TI - The bioguided fractionation and pharmacological activity of an endemic Salix canariensis species. AB - The present study was designed to confirm the wide traditional use of treating pain with Salix canariensis, an endemic species of the Macaronesian region. The active compounds were identified. Pharmacological activities were explored in experimental animals by acetic acid-induced writhing, formalin and Levy's tests, and bioactive compounds were identified after a bio-guided fractionation of the most active organic extract. S. canariensis extract, orally administrated at different doses, led to a significant reduction in writhing, caused a moderate decrease of formalin-induced pain and revealed an excellent dose-dependent anti inflammatory effect. Bioassay-guided fractionation of the ethyl acetate extract suggested the possible presence of pentacyclic triterpenes from oleanane and ursane series. These findings allow the conclusion that S. canariensis exerts analgesic and anti-inflammatory activities, documenting its traditional use in the treatment of pain and inflammatory diseases. PMID- 28590906 TI - Influence of concentration and type of microcrystalline cellulose on the physical properties of tablets containing Cornelian cherry fruits. AB - The aim of this study was to find the optimal tablet composition with maximum content of dried fruits (Cornus mas L.). The effect of three different concentrations (12.5, 25 and 50 %) of two types of microcrystalline cellulose (Avicel(r) PH 101 and Avicel(r) PH 200) and three different compression pressures (20, 60 and 100 MPa) on the physical properties of tablet blends and tablets was studied. Tablets containing 50 % Avicel(r) PH 101 compressed under 100 MPa were found to have the best physical properties. This combination of composition and compression pressure resulted in stable tablets even after storage under accelerated stability conditions (6 months, 40 degrees C and 75 % RH). PMID- 28590904 TI - Niemann-Pick type C proteins promote microautophagy by expanding raft-like membrane domains in the yeast vacuole. AB - Niemann-Pick type C is a storage disease caused by dysfunction of NPC proteins, which transport cholesterol from the lumen of lysosomes to the limiting membrane of that compartment. Using freeze fracture electron microscopy, we show here that the yeast NPC orthologs, Ncr1p and Npc2p, are essential for formation and expansion of raft-like domains in the vacuolar (lysosome) membrane, both in stationary phase and in acute nitrogen starvation. Moreover, the expanded raft like domains engulf lipid droplets by a microautophagic mechanism. We also found that the multivesicular body pathway plays a crucial role in microautophagy in acute nitrogen starvation by delivering sterol to the vacuole. These data show that NPC proteins promote microautophagy in stationary phase and under nitrogen starvation conditions, likely by increasing sterol in the limiting membrane of the vacuole. PMID- 28590903 TI - Contributions of local speech encoding and functional connectivity to audio visual speech perception. AB - Seeing a speaker's face enhances speech intelligibility in adverse environments. We investigated the underlying network mechanisms by quantifying local speech representations and directed connectivity in MEG data obtained while human participants listened to speech of varying acoustic SNR and visual context. During high acoustic SNR speech encoding by temporally entrained brain activity was strong in temporal and inferior frontal cortex, while during low SNR strong entrainment emerged in premotor and superior frontal cortex. These changes in local encoding were accompanied by changes in directed connectivity along the ventral stream and the auditory-premotor axis. Importantly, the behavioral benefit arising from seeing the speaker's face was not predicted by changes in local encoding but rather by enhanced functional connectivity between temporal and inferior frontal cortex. Our results demonstrate a role of auditory-frontal interactions in visual speech representations and suggest that functional connectivity along the ventral pathway facilitates speech comprehension in multisensory environments. PMID- 28590907 TI - Real-practice thromboprophylaxis in atrial fibrillation. AB - This retrospective observational study was based on databases of the Local Health Authority of Treviso, Italy. It evaluated the prevalence and the effectiveness of oral anticoagulation treatment (OAT) for the management of nonvalvular atrial fibrillation (NVAF) in everyday clinical practice. Out of 6,138 NVAF patients, only 3,024 received vitamin K antagonist (VKA). Potential barriers decreasing the probability of being treated with VKA were female sex, older age, antiplatelet treatment and history of bleeding. In addition, VKA-treatment was not in line with current ESC and AIAC guidelines, since the patients at high or low risk of stroke were under- or over-treated, resp. Among VKAtreated patients, 73 % of subjects were not at target with anticoagulation. OAT resulted to be effective in reducing stroke risk. However, stroke events were significantly influenced also by previous stroke or transient ischemic attack (hazard ratio, HR = 2.99, p < 0.001) and by previous bleeding events (HR = 1.60, p < 0.001). PMID- 28590908 TI - Biomimetic insulin-imprinted polymer nanoparticles as a potential oral drug delivery system. AB - In this study, we investigate molecularly imprinted polymers (MIPs), which form a three-dimensional image of the region at and around the active binding sites of pharmaceutically active insulin or are analogous to b cells bound to insulin. This approach was employed to create a welldefined structure within the nanospace cavities that make up functional monomers by cross-linking. The obtained MIPs exhibited a high adsorption capacity for the target insulin, which showed a significantly higher release of insulin in solution at pH 7.4 than at pH 1.2. In vivo studies on diabetic Wistar rats showed that the fast onset within 2 h is similar to subcutaneous injection with a maximum at 4 h, giving an engaged function responsible for the duration of glucose reduction for up to 24 h. These MIPs, prepared as nanosized material, may open a new horizon for oral insulin delivery. PMID- 28590909 TI - Comparing monolithic and fused core HPLC columns for fast chromatographic analysis of fat-soluble vitamins. AB - HPLC stationary phases of monolithic and fused core type can be used to achieve fast chromatographic separation as an alternative to UPLC. In this study, monolithic and fused core stationary phases are compared for fast separation of four fat-soluble vitamins. Three new methods on the first and second generation monolithic silica RP-18e columns and a fused core pentafluoro-phenyl propyl column were developed. Application of three fused core columns offered comparable separations of retinyl palmitate, DL-alpha-tocopheryl acetate, cholecalciferol and menadione in terms of elution speed and separation efficiency. Separation was achieved in approx. 5 min with good resolution (Rs > 5) and precision (RSD <= 0.6 %). Monolithic columns showed, however, a higher number of theoretical plates, better precision and lower column backpressure than the fused core column. The three developed methods were successfully applied to separate and quantitate fat soluble vitamins in commercial products. PMID- 28590910 TI - Application of SeDeM expert systems in preformulation studies of pediatric ibuprofen ODT tablets. AB - Pediatric, ibuprofen containing orodispersible tablets (ODTs) were prepared using the SeDeM expert system methodology. In order to facilitate formulation, directly compressible ibuprofen was employed (Ibuprofen DC 8TM) and characterized using its SeDeM profile. The mannitol based superdisintegrant Ludiflash(r) was characterized by the SeDeM-ODT expert system, which also allowed calculation of the optimal excipient concentration in order to obtain suitable tablet hardness and disintegration time. After adding a sweetener and a standard combination of lubricants, the optimized formulation was directly compressed into tablets and evaluated in terms of tablet hardness, friability, disintegration time and dissolution profile. The SeDeM method was applied to determine the amount of corrective excipient (Ludiflash(r)) required for the compression of Ibuprofen DC 85TM in order to achieve suitable ODTs. Adequate tablet hardness, disintegration time, friability and dissolution profiles were found during tablet evaluation. PMID- 28590911 TI - Effect of gamma-ethyl-gamma-phenyl-butyrolactone (EFBL), anticonvulsant and hypnotic drug, on mouse brain catecholamine levels. AB - gamma-Ethyl-gamma-phenyl-butyrolactone (EFBL) is a structural combination of the anticonvulsant gamma-hydroxy-gamma-ethyl-gamma-phenylbutyramide (HEPB) and the hypnotic gamma-butyrolactone (GBL), which inherits both properties. To clarify its mechanism of action, the effects of EFBL, GBL and HEPB on dopamine (DA) and noradrenaline (NA) brain levels were investigated. Influences of chlorpromazine, phenelzine and aminooxyacetic acid were also studied. EFBL increased DA in a dose dependent manner, remaining enhanced by 80 % over a period of 24 h and augmented NA by 54 % one hour after treatment. HEPB increased DA and NA approximately 2 fold after the first hour. GBL raised DA and NA after three and 24 h, resp. EFBL reversed chlorpromazine effects but potentiated those of phenelzine on DA. Amino oxyacetic modified neither DA nor NA brain levels, not even in the presence of EFBL. The anticonvulsant and hypnotic properties of EFBL are attributed to its effect on presynaptic dopaminergic receptors and its lasting effect on ethyl and phenyl radicals that hinder its degradation. The results support the role of DA and NA in regulating seizure activity in the brain and indicate that EFBL offers a potential treatment for refractory epilepsy without complementary drugs and Parkinson's disease, without the drawbacks of oral therapies. PMID- 28590912 TI - Quantitative analysis of povidone-iodine thin films by X-ray photoelectron spectroscopy and their physicochemical properties. AB - In this study, povidone-iodine (PVP-I) has been formulated as a topical spray to produce a thin film for the controlled release of I2. By means of experimental design, 27 formulations containing glycerol, ethanol, PEG 400, copovidone and HFA 134a as a propellant were prepared. The pH values of all formulations were in the range of 6-7. The viscosity was within the range of 11.9-85.9 mPa s. The surface tensions were 20.3 to 24.6 mN m-1 and the contact angles were between 19.3 and 38.7 degrees . The assays for the iodine contents were within acceptable range (80-120 %). X-ray photoelectron spectroscopy analysis revealed the ionized form of iodine was much higher than the unionized form. The MIC and MBC values of the PVP-I sprays against Staphylococcus aureus, S. epidermidis and Pseudomonas aeruginosa were higher than that of commercial PVP-I solution. The cytotoxicity study confirmed that the PVP-I spray had lower toxic effects on keratinocytes and fibroblasts compared to the commercial PVP-I solution. The formulation containing 59 % ethanol, 18 % copovidone and 12 % PEG 400 showed good antibacterial activity. PMID- 28590913 TI - Testing of resveratrol microemulsion photostability and protective effect against UV induced oxidative stress. AB - Resveratrol is well known for its antioxidant activity and susceptibility to ultraviolet radiation. Development of formulations providing improved stability and relevant drug delivery of resveratrol is still a challenging task. The aim of this study was to determine protective characteristics of formulated microemulsions by evaluating photoisomerization of resveratrol and to investigate the effects of resveratrol on human keratinocyte cells under oxidative stress caused by ultraviolet radiation. Incorporation of resveratrol into microemulsions resulted in increased photostability of active compounds and the results demonstrated that photodegradation of resveratrol was significantly delayed. Results of biopharmaceutical evaluation in vitro demonstrated that up to 60 % of resveratrol was released from microemulsions within 6 hours under a constant release rate profile. In vivo biological testing confirmed the ability of resveratrol to protect cells from oxidative stress and to increase cell viability. It was concluded that microemulsions might be considered in the development of UV light sensitive compounds. PMID- 28590914 TI - Porphyra-334, a mycosporine-like amino acid, attenuates UV-induced apoptosis in HaCaT cells. AB - The main aim of the current research was to study the effect of porphyra-334, one of mycosporine-like amino acids (MAAs), well known as UV-absorbing compounds, on UVinduced apoptosis in human immortalized keratinocyte (HaCaT) cells. Due to their UV-screening capacity and ability to prevent UV-induced DNA damage, MAAs have recently attracted considerable attention in both industry and research in pharmacology. Herein, human HaCaT cells were used to determine the biological activities of porphyra- 334 by various in vitro assays, including proliferation, apoptosis and Western blot assays. The proliferation rate of UV-irradiated HaCaT cells was significantly decreased compared to the control group. Pretreatment with porphyra- 334 markedly attenuated the inhibitory effect of UV and induced a dramatic decrease in the apoptotic rate. Expression of active caspase-3 protein was increased in response to UV irradiation, while caspase-3 levels were similar between cells treated with porphyra-334 and the non-irradiated control group. Taken together, our data suggest that porphyra-334 inhibits UV-induced apoptosis in HaCaT cells through attenuation of the caspase pathway. PMID- 28590915 TI - Cancer sniffer dogs: how can we translate this peculiarity in laboratory medicine? Results of a pilot study on gastrointestinal cancers. AB - BACKGROUND: Identification of cancer biomarkers to allow early diagnosis is an urgent need for many types of tumors, whose prognosis strongly depends on the stage of the disease. Canine olfactory testing for detecting cancer is an emerging field of investigation. As an alternative, here we propose to use GC Olfactometry (GC/O), which enables the speeding up of targeted biomarker identification and analysis. A pilot study was conducted in order to determine odor-active compounds in urine that discriminate patients with gastrointestinal cancers from control samples (healthy people). METHODS: Headspace solid phase microextraction (HS-SPME)-GC/MS and GC-olfactometry (GC/O) analysis were performed on urine samples obtained from gastrointestinal cancer patients and healthy controls. RESULTS: In total, 91 key odor-active compounds were found in the urine samples. Although no odor-active biomarkers present were found in cancer carrier's urine, significant differences were discovered in the odor activities of 11 compounds in the urine of healthy and diseased people. Seven of above mentioned compounds were identified: thiophene, 2-methoxythiophene, dimethyl disulphide, 3-methyl-2-pentanone, 4-(or 5-)methyl-3-hexanone, 4-ethyl guaiacol and phenylacetic acid. The other four compounds remained unknown. CONCLUSIONS: GC/O has a big potential to identify compounds not detectable using untargeted GC/MS approach. This paves the way for further research aimed at improving and validating the performance of this technique so that the identified cancer-associated compounds may be introduced as biomarkers in clinical practice to support early cancer diagnosis. PMID- 28590917 TI - Serum levels of nitrite/nitrate, lipid profile, and Fasting Plasma Glucose and their associations in subclinical hypothyroid women before and after a two month treatment by levothyroxine. AB - BACKGROUND: Subclinical hypothyroidism (sHT) is a condition defined by elevated TSH values with normal levels of free thyroid hormones. Altered metabolic status is one of the consequences of sHT which can affect serum levels of FPG, lipid profile, and nitric oxide which propounds cardiovascular consequences per se. The aim of this study was to determine the possible effects of sHT on nitrite/nitrate levels, as a marker of endothelial performance. MATERIALS AND METHODS: 50 females were enrolled in this study, 25 women as control group and 25 women as case group (evaluated two times: before and after levothyroxine therapy). Blood samples were collected and levels of FPG, lipid profile components, and nitric oxide were measured spectrophotometrically. The data were analyzed using SPSS version 18 software. RESULTS: The levels of lipid profile (except for TG between before and after group, p < 0.05) and nitric oxide did not differ in groups while FPG was significantly higher in case groups in comparison to control group (p < 0.001). Nitric oxide had no correlations with any of variables except for LDL in after treatment group (p < 0.05 and r = 0.397). CONCLUSION: Nitric oxide does not have correlation with components of lipid profile (except for LDL) or FPG and has no differences in subclinical hypothyroid patients and control group. Levothyroxine therapy during 2 months cannot alter the levels of nitric oxide in subclinical hypothyroid patients. PMID- 28590918 TI - ERRATUM for the paper Erfani A. Liver Fibrosis: Causes and Methods of Assessment, A Review. Rom J Intern Med. 2015; 53(4):304-14. PMID- 28590916 TI - Anti-stress effects of a GSK-3beta inhibitor, AR-A014418, in immobilization stress of variable duration in mice. AB - BACKGROUND: The present study was designed to explore the anti-stress role of AR A014418, a selective glycogen synthase kinase-3beta inhibitor (GSK-3beta), on changes provoked by immobilization stress of varying duration. METHODS: Acute stress of varying degree was induced by subjecting mice to immobilization stress of short duration (30 min) or long duration (120 min). Thereafter, these animals were exposed to the same stressor for 5 days to induce stress adaptation. The behavioral alterations were assessed using an actophotometer, a hole-board, and the open field and social interaction tests. The serum corticosterone levels were assessed as markers of the hypothalamic-pituitary-adrenal (HPA) axis activity. The levels of total GSK-3beta and p-GSK-3beta-S9 were determined in the prefrontal cortex. RESULTS: A single exposure to short or long immobilization stress produced behavioral and biochemical changes and the levels of p-GSK-3beta S9 decreased without affecting the total GSK-3beta levels in the brain. However, repeated exposure to both short and long stress reversed the behavioral and biochemical changes along with the normalization of p-GSK-3beta-S9 levels. The administration of AR-A014418, a selective GSK-3beta inhibitor, diminished acute stress-induced behavioral and biochemical changes. Furthermore, AR-A014418 normalized acute stress-induced alterations in p-GSK-3beta-S9 levels without changing total GSK-3beta levels. CONCLUSIONS: Our study suggests that acute stress-induced decrease in p-GSK-3beta-S9 levels in the brain contributes to the development of behavioral and biochemical alterations and the normalization of GSK-3beta signaling may contribute to stress adaptive behavior in mice which have been subjected to repeated immobilization stress. PMID- 28590939 TI - Monte Carlo study of the exchange bias effect in Co/CoO core-shell nanowires. AB - We study the magnetic properties of cylindrical ferromagnetic core antiferromagnetic shell nanowires using Monte Carlo simulations and a classical Heisenberg Hamiltonian in order to elucidate the impact of the oxidized shell on the magnetic properties and the magnetization reversal mechanism. We find that the coupling to the antiferromagnetic shell leads to suppression of the coercivity and emergence of a weak exchange bias effect. Comparison of the magnetization reversal mechanism in the bare and the surface-oxidized nanowire reveals that the domain wall propagation and annihilation remains the dominant reversal mechanism in surface oxidized nanowires as in their ferromagnetic counterparts. However, the interface exchange coupling introduces a secondary reversal mechanism activated in the central part of the wire with characteristics of coherent rotation, which acts in synergy to wall propagation leading to enhancement of the wall mobility. This effect is more pronounced in nanowires with large exchange bias values and is attributed to the uncompensated interface moments that act as nucleation centers for magnetization reversal. Our results are in good agreement with recent measurements in Co and Co/CoO nanowires. PMID- 28590940 TI - SimDoseCT: dose reporting software based on Monte Carlo simulation for a 320 detector-row cone-beam CT scanner and ICRP computational adult phantoms. AB - This study aims to develop and test software for assessing and reporting doses for standard patients undergoing computed tomography (CT) examinations in a 320 detector-row cone-beam scanner. The software, called SimDoseCT, is based on the Monte Carlo (MC) simulation code, which was developed to calculate organ doses and effective doses in ICRP anthropomorphic adult reference computational phantoms for acquisitions with the Aquilion ONE CT scanner (Toshiba). MC simulation was validated by comparing CTDI measurements within standard CT dose phantoms with results from simulation under the same conditions. SimDoseCT consists of a graphical user interface connected to a MySQL database, which contains the look-up-tables that were generated with MC simulations for volumetric acquisitions at different scan positions along the phantom using any tube voltage, bow tie filter, focal spot and nine different beam widths. Two different methods were developed to estimate organ doses and effective doses from acquisitions using other available beam widths in the scanner. A correction factor was used to estimate doses in helical acquisitions. Hence, the user can select any available protocol in the Aquilion ONE scanner for a standard adult male or female and obtain the dose results through the software interface. Agreement within 9% between CTDI measurements and simulations allowed the validation of the MC program. Additionally, the algorithm for dose reporting in SimDoseCT was validated by comparing dose results from this tool with those obtained from MC simulations for three volumetric acquisitions (head, thorax and abdomen). The comparison was repeated using eight different collimations and also for another collimation in a helical abdomen examination. The results showed differences of 0.1 mSv or less for absolute dose in most organs and also in the effective dose calculation. The software provides a suitable tool for dose assessment in standard adult patients undergoing CT examinations in a 320 detector-row cone-beam scanner. PMID- 28590938 TI - Combined passive acoustic mapping and magnetic resonance thermometry for monitoring phase-shift nanoemulsion enhanced focused ultrasound therapy. AB - Focused ultrasound (FUS) has the potential to enable precise, image-guided noninvasive surgery for the treatment of cancer in which tumors are identified and destroyed in a single integrated procedure. However, success of the method in highly vascular organs has been limited due to heat losses to perfusion, requiring development of techniques to locally enhance energy absorption and heating. In addition, FUS procedures are conventionally monitored using MRI, which provides excellent anatomical images and can map temperature, but is not capable of capturing the full gamut of available data such as the acoustic emissions generated during this inherently acoustically-driven procedure. Here, we employed phase-shift nanoemulsions (PSNE) embedded in tissue phantoms to promote cavitation and hence temperature rise induced by FUS. In addition, we incorporated passive acoustic mapping (PAM) alongside simultaneous MR thermometry in order to visualize both acoustic emissions and temperature rise, within the bore of a full scale clinical MRI scanner. Focal cavitation of PSNE could be resolved using PAM and resulted in accelerated heating and increased the maximum elevated temperature measured via MR thermometry compared to experiments without nanoemulsions. Over time, the simultaneously acquired acoustic and temperature maps show translation of the focus of activity towards the FUS transducer, and the magnitude of the increase in cavitation and focal shift both increased with nanoemulsion concentration. PAM results were well correlated with MRI thermometry and demonstrated greater sensitivity, with the ability to detect cavitation before enhanced heating was observed. The results suggest that PSNE could be beneficial for enhancement of thermal focused ultrasound therapies and that PAM could be a critical tool for monitoring this process. PMID- 28590941 TI - TTC-Pluronic 3D radiochromic gel dosimetry of ionizing radiation. AB - This work reports the first results obtained using a new 3D radiochromic gel dosimeter. The dosimeter is an aqueous physical gel matrix made of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127, PEO-PPO-PEO) doped with a representative of tetrazolium salts, 2, 3, 5 triphenyltetrazolium chloride (TTC). There were several reasons for the choice of Pluronic as a gel forming substrate: (i) the high degree of transparency and colourlessness; (ii) the possibility of gel dosimeter preparation at both high and low temperatures due to the phase behaviour of Pluronic; (iii) the broad temperature range over which the TTC-Pluronic dosimeter is stable; and (iv) the non-toxicity of Pluronic. A reason for the choice of TTC was its ionising radiation-induced transformation to water-insoluble formazan, which was assumed to impact beneficially on the spatial stability of the dose distribution. If irradiated, the TTC-Pluronic gels become red but transparent in the irradiated part, while the non-irradiated part remains crystal clear. The best obtained composition is characterised by <4 Gy dose threshold, a dose sensitivity of 0.002 31 (Gy * cm)-1, a large linear dose range of >500 Gy and a dynamic dose response much greater than 500 Gy (7.5% TTC, 25% Pluronic F-127, 50 mmol dm-3 tetrakis). Temporal and spatial stability studies revealed that the TTC-Pluronic gels (7.5% TTC, 25% Pluronic F-127) were stable for more than one week. The addition of compounds boosting the gels' dose performance caused deterioration of the gels' temporal stability but did not impact the stability of the 3D dose distribution. The proposed method of preparation allows for the repeatable manufacture of the gels. There were no differences observed between gels irradiated fractionally and non-fractionally. The TTC-Pluronic dose response might be affected by the radiation source dose rate-this, however, requires further examination. PMID- 28590942 TI - A visualization method for probing grain boundaries of single layer graphene via molecular beam epitaxy. AB - Graphene, a member of layered two-dimensional (2D) materials, possesses high carrier mobility, mechanical flexibility, and optical transparency, as well as enjoying a wide range of promising applications in electronics. Adopting the chemical vaporization deposition method, the majority of investigators have ubiquitously grown single layer graphene (SLG), which inevitably involves polycrystalline properties. Here we demonstrate a simple method for the direct visualization of arbitrarily large-size SLG domains by synthesizing one-hundred nm-scale MoS2 single crystals via a high-vacuum molecular beam epitaxy process. The present study based on epitaxial growth provides a guide for probing the grain boundaries of various 2D materials and implements higher potentials for the next-generation electronic devices. PMID- 28590944 TI - Simulation Fellowship Programs in Graduate Medical Education. PMID- 28590943 TI - Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid. AB - To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29-34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD. PMID- 28590945 TI - Addressing the Global Zika Epidemic Locally: An Interprofessional Model of Universal Screening at One Center. AB - Escalating evidence for the fetal impact of Zika virus infection required a change in care by all prenatal providers. This article describes an effective model of rapid implementation of universal prenatal screening at one hospital and its network of community health centers for a large and diverse immigrant population exploring the challenges, experiences, and lessons learned. Implementation of national recommendations required a workflow change, challenging a system with a heterogeneity of settings and providers. Using a physician clinical champion and advanced practice nurses in the roles of logistical coordinator and liaison to the network, Zika screening was embedded into prenatal intake visits at both the hospital and community health centers. Challenges addressed include varied medical record systems, acceptance by patients, providers, and community health center leadership, as well as culturally appropriate outreach to diverse ethnic and linguistic communities. In 6 months, the prenatal screening rates increased from 20% to 88%, which resulted in the identification of more than 300 pregnant patients at risk of exposure to Zika virus. This model offers key lessons for emergency preparedness in heterogeneous, safety net hospital settings. PMID- 28590946 TI - Hospitalization Among Individuals Waitlisted For Kidney Transplant. AB - BACKGROUND: For patients waitlisted for a deceased-donor kidney, hospitalization is associated with a lower likelihood of transplantation and worse posttransplant outcomes. However, individual-, neighborhood-, and regional-level risk factors for hospitalization throughout the waitlist period and specific causes of hospitalization in this population are unknown. METHODS: We used United States Renal Data System Medicare-linked data on patients waitlisted between 2005 and 2013 with continuous enrollment in Medicare parts A and B (n = 53 810) to examine the association between annual hospitalization rate and a variety of demographic, clinical, and social factors. We used multilevel multivariable ordinal logistic regression to estimate odds ratios. RESULTS: Factors associated with significantly increased hospitalization rates among waitlisted individuals included older age, female sex, more years on dialysis before waitlisting, tobacco use, panel-reactive antibody greater than 0, public insurance or no insurance at end-stage renal disease diagnosis, more regional acute care hospital beds, and urban residence (all P < 0.05). Among patients dialysis-dependent when waitlisted, individuals with arteriovenous fistulas were significantly less likely than individuals with indwelling catheters or grafts to be hospitalized (odds ratios, 0.79 and 0.82, respectively, both P < 0.001). The most common causes of hospitalization were complications related to devices, implants, and grafts; hypertension; and sepsis. CONCLUSIONS: Individual- and regional-level variables were significantly associated with hospitalization while waitlisted, suggesting that personal, health system, and geographic factors may impact patients' risk. Conditions related to dialysis access and comorbidities were common hospitalization causes, underscoring the importance proper access management and care for additional chronic health conditions. PMID- 28590947 TI - The Conundrum of Equitable Organ Allocation in Heart Transplantation: The Moving Target of Candidate Risk Score. PMID- 28590948 TI - Proximal Blockade of Complement: A "Neoclassical" Approach to Prevent Antibody Mediated Rejection. PMID- 28590949 TI - Quantitative Assessment of Statistical Reviews of Patient Safety Research Articles. AB - OBJECTIVES: For 8.5 consecutive years, all patient safety articles of a journal underwent statistical review before publication. We sought to establish the prevalence of statistical themes in the statistical reviews, consideration of contemporary statistical methods, and their associations with time to journal receipt of authors' revision. METHODS: An initial set of statistical themes was created using the statistical editor's notes. For example, for the statistical theme of "CONSORT checklist," the search term needed was "CONSORT." A complete (exhaustive) list of additional themes was obtained inductively. RESULTS: Among the 273 subsequent reviews for manuscripts that were ultimately accepted, the number of paragraphs that included a theme of a statistical method was only weakly associated with longer revision times (Kendall tau = 0.139 +/- 0.039, P = 0.0004). Among the total 3274 paragraphs of statistical reviews, 72.2% did not include a theme of a statistical method (e.g., the editor instead asked the authors to clarify what statistical method had been used) (95% confidence interval [CI] = 70.6%-73.7%, P < 0.0001 versus 50%).Among the 207 manuscripts with a review that included a statistical method, 47.3% included a contemporary topic (e.g., generalized pivotal methods) (95% CI = 40.4%-54.4%). However, among the 911 corresponding paragraphs of statistical review comments, only 16.0% included a contemporary theme (95% CI = 13.7%-18.6%). CONCLUSIONS: The revised versions of patient safety articles, which are eventually to be accepted for publication, have many statistical limitations especially in the reporting (writing) of basic statistical methods and results. The results suggest a need for education of patient safety investigators to include statistical writing. PMID- 28590951 TI - Cutaneous Squamous Cell Carcinoma: Review of the Eighth Edition of the American Joint Committee on Cancer Staging Guidelines, Prognostic Factors, and Histopathologic Variants. AB - Cutaneous squamous cell carcinoma is the second most common form of nonmelanoma skin cancer after basal cell carcinoma and accounts for the majority of nonmelanoma skin cancer-related deaths. In 2017, the American Joint Committee on Cancer revised the staging guidelines of cutaneous squamous cell carcinoma to reflect recent evidence concerning high-risk clinicopathologic features. This update reviews the literature on prognostic features and staging, including the eighth edition of the American Joint Committee on Cancer Staging Manual. A wide range of histopathologic variants of cutaneous squamous cell carcinoma exists, several of which are associated with aggressive behavior. A review of cutaneous squamous cell carcinoma variants, emphasizing diagnostic pitfalls, immuhistochemical findings and prognostic significance, is included. Of note, the eighth edition of the American Joint Committee on Cancer Staging Manual refers to squamous cell carcinoma of the head and neck only. PMID- 28590952 TI - Role of Human Papillomavirus in Vulvar Cancer. AB - Human papillomavirus (HPV) is involved in one of the at least 2 pathways leading to vulvar squamous cell carcinoma (VSCC). Inactivation of p53 and retinoblastoma by the viral products E6 and E7 is involved in malignant transformation. The percentage of HPV-positive VSCCs ranges from 18% to 75%, depending on the geographical area. HPV-associated tumors affect relatively young women and arise from high-grade intraepithelial lesions, identical to other HPV-associated premalignant lesions of the anogenital tract. HPV-independent tumors tend to affect older women and usually arise in a background of inflammatory skin disorders and a subtle variant of in situ lesion called differentiated vulvar intraepithelial neoplasia. HPV-positive tumors tend to be of basaloid or warty types, whereas HPV-independent tumors tend to be of keratinizing type, but there is frequent overlap between histologic types. There is no conclusive evidence yet on the best strategy in terms of determining HPV attribution. HPV DNA detection is generally considered the gold standard although there is some concern about misclassification when using this technique alone. p16 immunostaining has shown to be an excellent surrogate marker of HPV infection. Positive results for both techniques are considered the best evidence for HPV-association. The prognostic role of HPV in VSCC is still contradictory, but increasing evidence suggests that HPV-associated tumors are less aggressive. Currently, there are no differences in treatment between HPV-associated and HPV-independent VSCC, but novel immunological strategies based on anti-HPV antigens are being evaluated in clinical trials. PMID- 28590950 TI - Systematic Review: The Impact of Cancer Treatment on the Gut and Vaginal Microbiome in Women With a Gynecological Malignancy. AB - BACKGROUND AND AIM: Worldwide, 1,470,900 women are diagnosed yearly with a gynecological malignancy (21,000 in the UK). Some patients treated with pelvic radiotherapy develop chronic changes in their bowel function. This systematic review summarizes current research on the impact of cancer treatment on the gut and vaginal microbiome in women with a gynecological malignancy. METHODS: The Preferred reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews were used to ensure transparent and complete reporting. Quantitative studies exploring the gut or vaginal microbiome in this patient cohort were included. Animal studies were excluded. There were no language restrictions. RESULTS: No studies examined the possible effects of surgery or chemotherapy for gynecological cancers on the gut or vaginal microbiome.Three prospective cohort studies were identified using sequencing of changes in the gut microbiome reporting on a total of 23 women treated for gynecological cancer. All studies included patients treated with radiotherapy with a dosage ranging from 43.0 to 54.0 Gy. Two studies assessed gastrointestinal toxicity formally; 8 women (57%) developed grade 2 or 3 diarrhea during radiotherapy. The outcomes suggest a correlation between changes in the intestinal microbiome and receiving radiotherapy and showed a decrease in abundance and diversity of the intestinal bacterial species. Before radiotherapy, those who developed diarrhea had an increased abundance of Bacteroides, Dialister, and Veillonella (P < 0.01), and a decreased abundance of Clostridium XI and XVIII, Faecalibacterium, Oscillibacter, Parabacteroides, Prevotella, and unclassified bacteria (P < 0.05). CONCLUSION: The limited evidence to date implies that larger studies including both the vaginal and gut microbiome in women treated for a gynecological malignancy are warranted to explore the impact of cancer treatments on the microbiome and its relation to developing long-term gastrointestinal toxicity. This may lead to new avenues to stratify those at risk and explore personalized treatment options and prevention of gastrointestinal consequences of cancer treatments. PMID- 28590953 TI - Clinical Applications of Whole-slide Imaging in Anatomic Pathology. AB - The development of whole-slide imaging has paved the way for digitizing of glass slides that are the basis for surgical pathology. This transformative technology has changed the landscape in research applications and education but despite its tremendous potential, its adoption for clinical use has been slow. We review the various niche applications that initiated awareness of this technology, provide examples of clinical use cases, and discuss the requirements and challenges for full adoption in clinical diagnosis. The opportunities for applications of image analysis tools in a workflow will be changed by integration of whole-slide imaging into routine diagnosis. PMID- 28590955 TI - Determining the Effects of Simulation on Intercultural Competency in Undergraduate Nursing Students. PMID- 28590954 TI - Current Valuation of Pathology Service. AB - Health care reform has accelerated as the existing health care system undergoes continuing financial stress. Medicare's new value-based payment system, commonly referred to as MACRA, provides opportunities for physicians to participate in this new system in a variety of ways. However, many of the value-based adjustments are based on existing valuations of services through traditional mechanisms. To achieve appropriate valuation of pathologist's services in the new payment models, it is imperative that we continue to achieve proper valuation of services through the traditional mechanisms. PMID- 28590956 TI - Assessment of Nursing Student Confidence Using the Clinical Skills Self-Efficacy Scale. AB - Student self-efficacy related to clinical skills is important to successful performance in the clinical setting. This pilot study was designed to evaluate the confidence levels of junior and senior nursing students in performing selected nursing skills, using the Clinical Skills Self-Efficacy Scale. A descriptive cross-sectional design was used in which participants completed an online survey. Findings indicate that senior students demonstrated higher self efficacy than juniors; their experiences and confidence related to performing specific clinical skills varied across groups. Strategies to improve students' clinical skills learning specific to the laboratory and clinical settings are addressed. PMID- 28590959 TI - Go public with nursing expertise. PMID- 28590958 TI - Constructing a Measure of Private-pay Nursing Home Days. AB - BACKGROUND: Nursing home (NH) care is financed through multiple sources. Although Medicaid is the predominant payer for NH care, over 20% of residents pay out-of pocket for their care. Despite this large percentage, an accepted measure of private-pay NH occupancy has not been established and little is known about the types of facilities and the long-term care markets that cater to this population. OBJECTIVES: To describe 2 novel measures of private-pay utilization in the NH setting, including the proportion of privately financed residents and resident days, and examine their construct validity. DESIGN: Retrospective descriptive analysis of US NHs in 2007-2009. MEASURES: We used Medicare claims, Medicare Enrollment records, and the Minimum Data Set to create measures of private-pay resident prevalence and proportion of privately financed NH days. We compared our estimates of private-pay utilization to payer data collected in the NH annual certification survey and evaluated the relationships of our measures with facility characteristics. RESULTS: Our measures of private-pay resident prevalence and private-pay days are highly correlated (r=0.83, P<0.001 and r=0.83, P<0.001, respectively) with the rate of "other payer" reported in the annual certification survey. We also observed a significantly higher proportion of private-pay residents and days in higher quality facilities. CONCLUSIONS: This new methodology provides estimates of private-pay resident prevalence and resident days. These measures were correlated with estimates using other data sources and validated against measures of facility quality. These data set the stage for additional work to examine questions related to NH payment, quality of care, and responses to changes in the long-term care market. PMID- 28590957 TI - Genetic moderation of cocaine subjective effects by variation in the TPH1, TPH2, and SLC6A4 serotonin genes. AB - OBJECTIVE: This study investigated variants of tryptophan hydroxylase (TPH)1, TPH2, and SLC6A4 in the moderation of the subjective effects of cocaine. METHODS: Non-treatment-seeking cocaine-dependent individuals (N=66) were intravenously administered saline and cocaine (40 mg) in a randomized order. Participants self reported subjective effects of cocaine using a visual analog scale starting before administration of saline or cocaine (-15 min) to up to 20 min after infusion. Self-report ratings on the visual analog scale ranged from 0 (no effect) to 100 (greatest effect). Participants were genotyped for the TPH1 rs1799913, TPH2 rs4290270, and SLC6A4 5-HTTLPR variants. Repeated-measures analysis of covariance was used to examine changes in subjective effect scores over time while controlling for population structure. RESULTS: Participants carrying the TPH1 rs1799913 A allele reported greater subjective response to cocaine for 'stimulated' and 'access' relative to the CC genotype group. Those carrying the TPH2 rs4290270 A allele reported higher 'good effect' and lower 'depressed' effect relative to the TT genotype group. Those carrying the SLC6A4 5 HTTLPR S' allele reported greater 'desire' and 'access' compared with the L'L' genotype group. CONCLUSION: These findings indicate that TPH1, TPH2, and SLC6A4 variants moderate the subjective effects of cocaine in non-treatment-seeking cocaine-dependent participants. PMID- 28590960 TI - NewDrugs 2017, part 2. PMID- 28590961 TI - NORMAL ELECTROOCULOGRAPHY IN BEST DISEASE AND AUTOSOMAL RECESSIVE BESTROPHINOPATHY. AB - PURPOSE: To evaluate the electrooculogram (EOG) in a large series of patients with Best disease and autosomal recessive bestrophinopathy. METHODS: A retrospective review of consecutive cases at Moorfields Eye Hospital, London, United Kingdom. Patients with Best disease or autosomal recessive bestrophinopathy who, after electrophysiologic testing, had a normal or atypical EOG light rise were identified. Main outcome measure was EOG amplitude, clinical phenotype and genotype. RESULTS: One hundred thirteen patients were identified with likely disease-causing sequence variants in BEST1 (99 Best disease and 14 autosomal recessive bestrophinopathy). Electrooculograms had been performed in 75 patients. Twenty patients (27%) had no detectable light rise (Arden ratio of 100%) and 49 (65%) had Arden ratios of between 100% to 165%. Six patients (8%) were found to have an EOG light rise of >165%. No cases demonstrated significant interocular asymmetry in EOG amplitude. CONCLUSION: The current work provides significant clinical evidence that the EOG phenotype in Best disease and autosomal recessive bestrophinopathy is more variable than currently appreciated. As a normal EOG may occur in the presence of a classical fundus appearance, the consequences of BEST1 mutation may be independently expressed, possibly mediated through differential effects on intracellular calcium homeostasis. PMID- 28590962 TI - LONGITUDINAL CHANGES IN THICKNESSES OF THE MACULA, GANGLION CELL-INNER PLEXIFORM LAYER, AND RETINAL NERVE FIBER LAYER AFTER VITRECTOMY: A 12-Month Observational Study. AB - PURPOSE: To analyze longitudinal changes in the thicknesses of the macula, ganglion cell-inner plexiform layer (GC-IPL), and peripapillary retinal nerve fiber layer (RNFL) after vitrectomy. METHODS: Thirty-eight patients diagnosed with intraocular lens (IOL) dislocation without evidence of other vitreoretinal diseases were included. They underwent conventional vitrectomy and IOL transscleral fixation, with a follow-up of 12 months. Using spectral domain optical coherence tomography, the thicknesses of the macula, GC-IPL, and peripapillary RNFL in the vitrectomized and fellow control eyes were measured. Various optic nerve head parameters were also determined. RESULTS: Optical coherence tomography showed that there were no significant differences in postoperative central macular thickness compared with baseline values. The average GC-IPL thickness increased 1 month after surgery from baseline (P = 0.038). The average RNFL thickness increased from baseline at 1 month (P = 0.001) and 3 months (P = 0.011) after vitrectomy. The mean foveal, GC-IPL, and RNFL thicknesses of the study eyes compared with the fellow control eyes increased at 1 month (P = 0.034), 1 month (P = 0.048), and 1 month (P = 0.013) to 3 months (P = 0.038), respectively, after surgery. However, no significant differences were found in intraocular pressure or optic nerve head parameters between the study and fellow control eyes at 12 months after surgery. CONCLUSION: Transient increases in the thickness of the macula and GC-IPL were observed at 1 month after vitrectomy, and the postoperative RNFL thickness increased until 3 months after surgery, after which it returned to preoperative levels. There was no significant change in intraocular pressure or optic nerve head parameters before and after surgery. PMID- 28590964 TI - OVERVIEW OF THE COMPLICATIONS OF HIGH MYOPIA. AB - : High myopia is very common and one of the major causes of social blindness, especially in East Asian countries. It is characterized by axial length elongation, and induces various specific complications, including cataract formation, retinal detachment from peripheral retinal tears, myopic foveoschisis, macular hole with or without retinal detachment, peripapillary deformation, dome shaped macula, choroidal/scleral thinning, myopic choroidal neovascularization, and glaucoma. This article will review these complications and discuss the current concepts relating to these complications and their treatments. CONCLUSION: This information will be helpful for the daily practice of treating myopic eyes. PMID- 28590963 TI - ACUTE ZONAL OCCULT OUTER RETINOPATHY: Structural and Functional Analysis Across the Transition Zone Between Healthy and Diseased Retina. AB - PURPOSE: To assess structure and function across the transition zone (TZ) between relatively healthy and diseased retina in acute zonal occult outer retinopathy. METHODS: Six patients (6 eyes; age 22-71 years) with acute zonal occult outer retinopathy were studied. Spectral-domain optical coherence tomography, fundus autofluorescence, near-infrared reflectance, color fundus photography, and fundus perimetry were performed and images were registered to each other. The retinal layers of the spectral-domain optical coherence tomography scans were segmented and the thicknesses of two outer retinal layers, that is, the total receptor and outer segment plus layers, and the retinal nerve fiber layer were measured. RESULTS: All eyes showed a TZ on multimodal imaging. On spectral-domain optical coherence tomography, the TZ was in the nasal retina at varying distances from the fovea. For all eyes, it was associated with loss of the ellipsoid zone band, significant thinning of the two outer retinal layers, and in three eyes with thickening of the retinal nerve fiber layer. On fundus autofluorescence, all eyes had a clearly demarcated peripapillary area of abnormal fundus autofluorescence delimited by a border of high autofluorescence; the latter was associated with loss of the ellipsoid zone band and with a change from relatively normal to markedly decreased or nonrecordable visual sensitivity on fundus perimetry. CONCLUSION: The results of multimodal imaging clarified the TZ in acute zonal occult outer retinopathy. The TZ was outlined by a distinct high autofluorescence border that correlated with loss of the ellipsoid zone band on spectral-domain optical coherence tomography. However, in fundus areas that seemed healthy on fundus autofluorescence, thinning of the outer retinal layers and thickening of the retinal nerve fiber layer were observed near the TZ. The TZ was also characterized by a decrease in visual sensitivity. PMID- 28590965 TI - POSTTRAUMATIC ENDOPHTHALMITIS: An 18-Year Case Series. AB - PURPOSE: To describe the demographics, characteristics, management, and visual outcomes of eyes diagnosed with endophthalmitis after open globe injury. METHODS: Retrospective cohort analysis of all patients diagnosed with endophthalmitis after open globe injury from 1997 to 2015 at University Hospital, Newark, NJ. RESULTS: Twenty-six eyes were identified (all male patients; mean age: 37 +/- 15 years). Cultures were positive in 16 eyes (62%), with Staphylococcus species (7 eyes, 44%) being the most common organism. Twelve eyes (46%) presented with open globe injury and concurrent endophthalmitis; 14 eyes (54%) developed endophthalmitis a mean of 14 days after open globe repair (OGR; 1 outlier of 98 days excluded). All eyes were managed with systemic and intravitreal antibiotics. The presence of intraocular foreign body (P < 0.05) and delayed primary OGR (P < 0.03) were significantly more common with concurrent versus post-OGR endophthalmitis. Four (29%) eyes in the post-OGR endophthalmitis group had corneal wound leak after OGR. Four (15%) eyes with no light perception vision were enucleated. Ten (40%) of 25 eyes with documented best-corrected visual acuity had final best-corrected visual acuity >=20/200; final best-corrected visual acuity ranged from no light perception to 20/20. CONCLUSION: The presence of intraocular foreign body and delayed presentation were significantly more common with concurrent endophthalmitis. Twenty-nine percent of eyes that presented with endophthalmitis after OGR had a wound leak. Final best-corrected visual acuity >=20/200 was achieved in 40% of cases. PMID- 28590966 TI - CHARACTERISTICS OF EPIRETINAL MEMBRANE REMNANT EDGE BY OPTICAL COHERENCE TOMOGRAPHY AFTER PARS PLANA VITRECTOMY. AB - PURPOSE: To evaluate the incidence, characteristics, and the progression of epiretinal membrane (ERM) remnant edge seen by optical coherence tomography after ERM peeling. METHODS: A retrospective chart review was conducted for 86 eyes of 85 consecutive patients who were diagnosed with ERM and underwent pars plana vitrectomy for epiretinal membrane peeling between 2013 and 2014. Data collected and analyzed included age, gender, preoperative and postoperative visual acuity, use of indocyanine green dye to stain internal limiting membrane, tamponade used after vitrectomy, ERM edge boundaries, presence of cystoid macular edema, and central foveal thickness. RESULTS: An ERM remnant edge was detected in 33/86 study eyes (38.4%) at the first postoperative optical coherence tomography scan. Compared with those without an ERM remnant, patients with an ERM remnant after surgery were significantly older at baseline and had a higher incidence of ERM recurrence at their last visit. They were not significantly different in terms of gender, preoperative and postoperative visual acuity, reduction of central foveal thickness from baseline, proportion of eyes with preoperative ERM elevation on optical coherence tomography, presence of macular edema before surgery, intraoperative use of indocyanine green staining for ILM peeling, or tamponade used. Based on the edge morphology, we classified the ERM remnant into three types: Type 1 was flat and blended with the retina (14/33 eyes, 42.4%), Type 2 was flat but stepped (17/33 eyes, 51.5%), and Type 3 was elevated (2/33 eyes, 6.0%). A significantly higher risk of ERM recurrence was seen in Type 2 and Type 3 ERM remnants (75% and 100%, respectively) than Type 1 ERM remnants (10%). CONCLUSION: An ERM remnant edge was detected by optical coherence tomography after ERM peeling in 38.4% of eyes. The presence of a postoperative ERM edge was associated with a higher risk of ERM recurrence, particularly in Type 2 and Type 3 ERM remnants. PMID- 28590967 TI - PERIPHERAL RETINOSCHISIS IN INTERMEDIATE UVEITIS. AB - PURPOSE: To examine cases of intermediate uveitis complicated by retinoschisis and review the pathogenetic hypothesis. METHODS: A retrospective chart review of patients with intermediate uveitis. Data were collected at three uveitis referral centers on sex, age, best-corrected visual acuity, degree of vitritis, extent and location of snowbanking, presence of hard exudates, neovascularization, vitreous hemorrhage, and extent and nature of retinal elevations. RESULTS: A series of 23 eyes of 20 patients were examined; patient's age ranged from 10 years to 70 years and follow-up period from 8 months to 6 years. Twenty-two eyes had retinoschisis (95.6%), and 1 had retinoschisis associated with serous retinal detachment (4.3%). Extensive inferior pars plana exudates with snowbanking were present in 12 eyes (52.2%), whereas 3 eyes had inferior snowballs over the elevated retina. Neovascularization of the vitreous base accompanied by vitreous hemorrhage occurred in one eye. There was no coexisting macular pathology in 16 eyes, whereas 4 eyes had cystoid macular edema. CONCLUSION: The appearance of peripheral retinoschisis in this series of uncontrolled intermediate uveitis patients seems to be secondary to a complex balance between the persistent fluorescein leakage, a subclinical peripheral ischemia, and the constant low grade vitreous inflammation that causes vitreous shrinkage and traction. The results of this study suggest that the absence of macroscopic changes in the retina does not preclude ischemic peripheral abnormalities, and the detection of a peripheral retinoschisis in an intermediate uveitis patient with active fluorescein leakage must suggest the need for a more aggressive form of treatment despite the good visual acuity. PMID- 28590968 TI - Mechanically Isolated Stromal Vascular Fraction by Nanofat Emulsification Techniques. PMID- 28590969 TI - Comparison of Endothelial Differentiation Capacities of Human and Rat Adipose Derived Stem Cells. PMID- 28590971 TI - Reply: Mechanical Micronization of Lipoaspirates: Squeeze and Emulsification Techniques. PMID- 28590970 TI - Crowdsourcing as a Novel Method to Evaluate Aesthetic Outcomes of Treatment for Unilateral Cleft Lip. PMID- 28590972 TI - Reply: Crowdsourcing as a Novel Method to Evaluate Aesthetic Outcomes of Treatment for Unilateral Cleft Lip. PMID- 28590973 TI - Reply: Comparison of Endothelial Differentiation Capacities of Human and Rat Adipose-Derived Stem Cells. PMID- 28590974 TI - Successful Breast Reconstruction with a Free Muscle-Sparing TRAM Flap in a Patient with Prior Ligation of the Bilateral Deep Inferior Epigastric Vessels. PMID- 28590975 TI - A Safe and Inexpensive Technique for Turbinate Cauterization Surgery. PMID- 28590976 TI - The Graduated Coupler Sizer: An Innovative Design Associated with Improved Accuracy. PMID- 28590977 TI - Reply: Very Low Prevalence of Intracranial Hypertension in Trigonocephaly. PMID- 28590978 TI - The Cosmetic Ladder: Familiar Structure, New Commitment. PMID- 28590980 TI - Outcomes of Prosthetic Reconstruction of Irradiated and Nonirradiated Breasts with Fat Grafting. PMID- 28590981 TI - Reply: Late Seromas in Natrelle 410 Form-Stable Silicone Breast Implants. PMID- 28590982 TI - Reply: Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects Receiving Natrelle 410 Form-Stable Silicone Breast Implants. PMID- 28590983 TI - Late Seromas in Natrelle 410 Form-Stable Silicone Breast Implants. PMID- 28590984 TI - Risk Factor Analysis for Capsular Contracture, Malposition, and Late Seroma in Subjects Receiving Natrelle 410 Form-Stable Silicone Breast Implants. PMID- 28590985 TI - Reply: Outcomes of Prosthetic Reconstruction of Irradiated and Nonirradiated Breasts with Fat Grafting. PMID- 28590986 TI - Functional movement disorders. AB - PURPOSE OF REVIEW: The review highlights the clinical presentation of functional movement disorders (FMDs) and presents current evidence on bedside signs and paraclinical tests to differentiate them from other neurological disorders. RECENT FINDINGS: FMDs are diagnosed by the presence of positive clinical signs as emphasized in the new Diagnostic and Statistical Manual of Mental Disorders-5 classification criteria. Bedside signs are numerous, and a subset of them has been validated in controlled studies. This review summarizes evidence from the literature on specificity and sensibility of positive clinical signs for FMDs. The value of rule-in paraclinical tests to confirm the diagnosis is also presented. Recent developments in neuroscience with pathophysiological mechanisms and current treatment strategies are also discussed. SUMMARY: FMDs represent a field of neurology that is currently rapidly growing in terms of research. Clinicians should be aware that highly reliable signs exist for the diagnosis and that early multidisciplinary treatment should be offered. PMID- 28590987 TI - "Chaotic Arrhythmia" During Successful Resuscitation After Ingestion of Yew (Taxus baccata) Needles. AB - OBJECTIVE: The study aims to describe the management of a case of life threatening yew (Taxus baccata) intoxication. BACKGROUND: The needles of the yew tree contain highly cardiotoxic taxines. Intoxication with taxines, typically as part of suicide attempts, may lead to potentially lethal arrhythmias which often require prolonged cardiopulmonary resuscitation and other supportive measures. No specific therapy has been described. In some cases, extracorporeal life support has been used. CASE: After an attempted suicide with yew needles and out-of hospital cardiac arrest, a female adolescent was resuscitated for 6 hours according to Advanced Cardiovascular Life Support guidelines. Complex ventricular tachycardias were treated by repeated direct current shocks and broad complex bradycardia managed with transvenous cardiac pacing. Antiarrhythmic drugs (amiodarone, lidocaine), magnesium sulfate, and supportive measures (intravenous lipids, sodium bicarbonate) were provided. The arrhythmias finally resolved, and the patient did not show any significant neurological or cardiac short-term sequelae after 24 hours. RESULTS: The authors describe the successful management of a case of severe taxine intoxication by prolonged conventional advanced cardiac life support lasting for more than 6 hours. CONCLUSIONS: In life threatening yew intoxication, prolonged cardiopulmonary resuscitation is absolutely essential owing to the long duration of the cardiotoxic action of taxines and can lead to an outcome without cardiac or neurological sequelae. PMID- 28590989 TI - "It's Not a Tumor": A Rare Case of Symptomatic Cerebellar Developmental Venous Anomaly. AB - Cerebral developmental venous anomalies (DVAs) are benign anatomical variants of the venous system and are commonly described as an incidental finding without clinical significance. Neurologic symptoms or abnormal examination findings are rare and usually attributed to hemorrhagic complications related to coexisting cavernous malformations. There have been limited case reports of symptomatic, uncomplicated DVAs described in the literature. The following case describes a previously healthy child who presented to the emergency department with an acute onset of altered mental status, headache, and focal neurologic examination abnormalities. Magnetic resonance imaging revealed a prominent cerebellar DVA. There was no evidence of a cavernous angioma, hemorrhage, or acute parenchymal injury. This case report illustrates a clinically symptomatic, uncomplicated posterior fossa DVA. It provides additional evidence regarding the potential for a cerebral venous malformation in causing focal neurologic deficits. PMID- 28590988 TI - Seizures After Pediatric Vilazodone Ingestion: A Case Series. AB - Vilazodone hydrochloride is the first member in a new class of antidepressants called indolealkylamines and was approved for use in the United States in 2011 for major depressive disorder. It has a combined mechanism of action of a selective serotonin reuptake inhibitor and a partial agonist of serotonin 5-HT1A receptors. It has not been approved for use in the pediatric population, and toxicity from exploratory vilazodone ingestion has been rarely described to date. We describe 2 children with laboratory-confirmed vilazodone ingestions that led to significant toxicity including refractory status epilepticus in 1 patient and likely transient seizure activity in the other. Both patients required multiple doses of benzodiazepines; in the more severe case, barbiturates were added to control seizure activity. These children returned to baseline and had no prolonged neurologic complications. Pediatric experience with vilazodone is limited; however, the literature demonstrates 3 additional case reports of children experiencing seizure after vilazodone ingestion. With the 2 new cases presented here, it seems prudent to educate prescribers and families of the potential dangers of ingestion of vilazodone tablets by young children. PMID- 28590990 TI - Delirium Upon Presentation to the Pediatric Emergency Department: A Case Series. AB - The following cases describe children who presented to the emergency department (ED) with a constellation of symptoms consistent with delirium. In each case, there was no identified inciting cause (eg, fever, medications) other than the presence of influenza. All children had variable workups, with 2 children undergoing extensive neurologic evaluation and testing. Clinical recognition of delirium in the pediatric acute care setting can be challenging, but heightened awareness by ED and primary care physicians may lead to earlier diagnosis, prevent unwarranted investigations, and decrease hospitalization. Children with influenza may be at increased risk of developing delirium. A prospective study to assess the prevalence of delirium in pediatric patients presenting to the ED with influenza is warranted. PMID- 28590991 TI - Risk Factors Associated With Emergency Department Return Visits Following Trauma System Discharge. AB - OBJECTIVES: Little evidence exists in the pediatric trauma literature regarding what factors are associated with re-presentation to the hospital for patients discharged from the emergency department (ED). METHODS: This was a retrospective cohort study of trauma system activations at a pediatric trauma center from June 30, 2007, through June 30, 2013, who were subsequently discharged from the ED or after a brief inpatient stay. Returns within 30 days were reviewed. chi, Student t test, and univariate logistical regression were used to compare predictive factors for those returning and not. RESULTS: One thousand eight hundred sixty three patient encounters were included in the cohort. Seventy-two patients (3.9%) had at least 1 return visit that was related to the original trauma activation. Age, sex, language, race/ethnicity, ED length of stay, arrival mode, level of trauma activation, and transfer from an outside hospital did not vary significantly between the groups. Patients with public insurance were almost 2 times more likely to return compared with those with private insurance (odds ratio, 1.92; 95% confidence interval, 1.11-3.35). Income by zip code was associated with the risk of a return visit, with patients in neighborhoods at less than the 50th percentile income twice as likely to return to the ED (odds ratio, 2.15; 95% confidence interval, 1.30-3.54). CONCLUSIONS: Patients with public insurance and those from low-income neighborhoods were significantly more likely to return to the ED after trauma system activation. These data can be used to target interventions to decrease returns in high-risk trauma patients. PMID- 28590992 TI - Montelukast Treatment of Acute Asthma Exacerbations in Children Aged 2 to 5 Years: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Although montelukast has an established role in the management of chronic asthma in children, its efficacy in acute asthma exacerbations (AAEs) in children aged 2 to 5 years is not fully known. This study aimed to evaluate the effectiveness and safety of montelukast for treating AAE in children aged 2 to 5 years in China. METHODS: In total, 120 Chinese children with AAE, aged 2 to 5 years, were randomly divided into 2 groups, each with 60 patients. All patients received either montelukast or placebo along with standard therapy for acute asthma between January 2011 and December 2015. The outcome measurements included the difference in peak expiratory flow and lung function improvements, as well as adverse events. RESULTS: A total of 117 patients completed the study. Montelukast showed no greater effectiveness than did placebo in increasing the peak expiratory flow during the period of hospital stay (P = 0.92 at day 2, P = 0.86 at day 3, and P = 0.82 at day 4) and at discharge (P = 0.84). Similarly, the forced expiratory volume in 1 second at discharge also did not show significant difference between the 2 groups (P = 0.80). In addition, no serious adverse events were found during the intervention period of the study. CONCLUSIONS: The results of this study demonstrate no benefit of montelukast over placebo in the treatment of AAE in a cohort of 2- to 5-year-old children. PMID- 28590993 TI - Childhood Falls With Occipital Impacts. AB - OBJECTIVES: Falls are commonly reported in children who present with both accidental and inflicted brain injuries. Short falls rarely result in serious or life-threatening injuries. Our purpose is to describe a series of cases of short falls with occipital impact leading to subdural hemorrhage (SDH). METHODS: We present a series of 8 witnessed accounts of young children diagnosed as having SDHs after striking the back of their heads during a short fall. Child-abuse physicians were surveyed to determine if they had evaluated a child younger than 24 months diagnosed as having SDH, with or without retinal hemorrhages, following a witnessed fall with occipital impact. Submitted cases were analyzed. RESULTS: The median age of the children was 12.5 months. All fell backward from a standing or seated position onto a hard surface and immediately developed symptoms. There was an average of 4 witnesses per case. Physical examinations were normal; however, the majority of children had enlarged head circumferences. All were previously healthy. Six of 8 children had unilateral convexity SDH. All children had varying degrees of retinal hemorrhage but no retinoschisis. The majority of children had returned to their baseline within 24 hours of hospitalization. CONCLUSIONS: Although a larger study is needed to identify the full spectrum of injuries, we postulate that, if a history of a fall with an occipital impact is elicited during a trauma workup, accidental injury should be considered. PMID- 28590994 TI - A Collaborative Behavioral Model for Psychiatric Visits in a Pediatric Emergency Department. AB - OBJECTIVES: Psychiatric pediatric emergency department (PED) visits are associated with extended length of stay (LOS) compared with nonpsychiatric visits. To address delays in definitive care, our PED incorporated a Collaborative Behavioral Model for patients with a psychiatric complaint. We evaluated LOS and 6-month readmission by comparing patients who received a psychiatric consultation through the model with a control group of nonpsychiatric patients. In addition, we assessed the utilization of laboratory tests and imaging and the impact of testing on final patient disposition. METHODS: A matched-pair retrospective chart review of psychiatric PED visits was conducted for visits from January 1, 2009, to December 31, 2013. Patients who received a psychiatric diagnosis and consultation through the Collaborative Behavioral Model were included. Participants were matched with a control group of similar patients who did not receive a psychiatric diagnosis. RESULTS: One hundred forty-seven patients met all the inclusion criteria. There was no statistical difference in median LOS for patients who received a psychiatric consultation versus nonpsychiatric visits (204 vs 200 minutes; P = 0.35). The 6-month PED readmission rate for psychiatric visits was significantly less than that in the control group (18% vs 32%; P = 0.003). Of the laboratory and imaging studies performed, 1 abnormal laboratory test (1%) and no imaging studies resulted in a change in patient management. CONCLUSIONS: Collaborative models, with specialized psychiatric components, can better coordinate the care of mental health visits by providing focused interventions that promote efficient disposition. In addition, laboratory and imaging studies resulted in few changes in management or final disposition. PMID- 28590995 TI - Mental Health Problems in Children and Adolescents in the Emergency Department: "The Times They Are A-Changin'". PMID- 28590996 TI - Helicopter Transport From the Scene of Injury: Are There Improved Outcomes for Pediatric Trauma Patients? AB - BACKGROUND: There is conflicting data to support the routine use of helicopter transport (HT) for the transfer of trauma patients. The purpose of this study was to evaluate outcomes for trauma patients transported via helicopter from the scene of injury to a regional pediatric trauma center. METHODS: The institutional trauma registry was queried for trauma patients presenting from January 2000 through March 2012. Of 9119 patients, 1709 patients who presented from the scene were selected for further evaluation. This cohort was stratified into HT and ground transport (GT) for analysis. Associations between mode of transport and outcomes were estimated using odds ratios and 95% confidence intervals from multivariable logistic regression models. RESULTS: Seven hundred twenty-five patients (42.4%) presented via HT, whereas 984 (57.6%) presented via GT. Patients arriving by HT had a higher Injury Severity Score, lower Glasgow Coma Scale, were less likely to undergo surgery within 3 hours, more likely to present after motorized trauma, and had longer intensive care unit (ICU) and hospital length of stay (LOS). Multivariate analysis controlling for Injury Severity Score, Glasgow Coma Scale, mechanism of injury, scene distance, and time to arrive to the hospital revealed that patients arriving by HT were more likely to have longer hospital LOS compared with those arriving by GT (odds ratios = 2.3, 95% confidence interval = 1.00-5.28, P = 0.049). However, no statistically significant association was observed for prehospital intubation, surgery within 3 hours, ICU admissions, or ICU LOS. CONCLUSIONS: Although patients arriving by helicopter are more severely injured and arrive from greater distances, when controlling for injuries, scene distance, and time to hospital arrival, only hospital LOS was significantly affected by HT. PMID- 28590997 TI - Is Radiography Necessary for Pediatric Emergency Department Clinicians to Safely Manage Ankle Injuries? AB - OBJECTIVES: Ankle radiography in the pediatric emergency department exposes a radiosensitive population to harmful ionizing radiation and is costly to health care systems. This study aimed to determine if ankle injuries in children could be managed safely and effectively without radiography. METHODS: This prospective study enrolled 94 patients with ankle injuries between July 14, 2015, and December 16, 2015. Participating clinicians filled out a tick-box questionnaire describing their predicted diagnosis and management. In March 2016, we looked retrospectively at TRAK to determine how these patients were actually managed and compared this with the predictions. RESULTS: Agreement was calculated for the predicted and actual presence of a fracture, with a kappa value of 0.433. The intraclass correlation coefficient was calculated to determine interrater reliability between predicted management and actual management, showing an average score of 0.801. Of the 16 patients found to be Low Risk Ankle Rule positive, none were found to have high-risk fractures. CONCLUSIONS: This study found that radiographs are necessary for the management of pediatric ankle injuries. However, there is scope to reduce radiography by implementing the Low Risk Ankle Rule. PMID- 28590998 TI - A Comparison of Direct Laryngoscopy and Videolaryngoscopy for Endotracheal Intubation by Inexperienced Users: A Pediatric Manikin Study. AB - OBJECTIVE: Direct laryngoscopy (DL) is the most common technique for endotracheal intubation, whereas videolaryngoscopy provides an indirect view of the glottis without the need to align the oral, pharyngeal, and tracheal axes. The current study compares videolaryngoscopy with DL among experienced and inexperienced users for endotracheal intubation using a pediatric manikin. METHODS: Participants performed DL using Miller and Macintosh laryngoscopes and videolaryngoscopy using CMAC and GlideScope devices on a manikin (SimBaby; Laerdel, Wappingers Falls, NY). Time to endotracheal intubation, number of attempts, and successful intubation within 120 seconds were recorded. RESULTS: Among 31 experienced users, time to endotracheal intubation with the CMAC (20 +/- 13 seconds) did not differ from DL with either the Miller (30 +/- 28 seconds) or Macintosh (27 +/- 23 seconds) laryngoscopes. However, with the GlideScope, time to endotracheal intubation (85 +/- 38 seconds) was longer. The results were similar among 12 inexperienced users, as time to endotracheal intubation with the CMAC (61 +/- 34 seconds) was comparable with the Miller (72 +/- 45 seconds) or Macintosh (72 +/- 45 seconds) laryngoscopes but was longer with the GlideScope (118 +/- 6 seconds) for each comparison. CONCLUSIONS: The standard straight or curved laryngoscope blades including the CMAC were associated with shorter procedural time and higher success rate when compared with indirect videolaryngoscopy with an unconventional blade design such as the GlideScope in both experienced and inexperienced users. However, the current study demonstrates that results may be influenced by the anatomical design of the manikin. PMID- 28591000 TI - Middle Ear Aural Polyp Mimicking Glomus Tympanicum in a Male Adolescent. PMID- 28590999 TI - Surgical Management of a Persistent Stapedial Artery: A Review. AB - OBJECTIVE: To evaluate the outcome and per- and postoperative complications of the surgical management of patients with a persistent stapedial artery (PSA). METHODS: A systemic literature search for reports on patients treated for pulsatile tinnitus and/or conductive hearing loss caused by a PSA was conducted of the PubMed and Embase databases using the terms "stapedial" and "artery." Inclusion criteria were adequate description of the intervention and pre- and postoperative signs and symptoms. In addition, one case of a PSA, treated at VU University Medical Center Amsterdam, The Netherlands, was included in this series. INTERVENTION: Middle ear surgery consisting of stapedotomy or stapedectomy, and/or transection of the PSA. MAIN OUTCOME MEASURES: Pre- and postoperative hearing levels, pre- and postoperative pulsatile tinnitus, and per- and postoperative complications. RESULTS: Seventeen patients and 18 operated ears were evaluated (16 patients described in 14 articles and our case). Twelve out of 14 ears in which a stapedotomy or stapedectomy was initiated experienced improvement in hearing. In four cases pulsatile tinnitus was described pre- and postoperatively. In all four, pulsatile tinnitus subsided after transection of the PSA. Peroperative bleeding from the PSA was described in four patients, which could be controlled during the procedure. No significant postoperative sequelae were reported. CONCLUSIONS: In case of a PSA, improvement of conductive hearing loss is best achieved by stapes surgery, while pulsatile tinnitus is effectively treated with transection of the PSA. To date no long-term postoperative complications have been reported. PMID- 28591001 TI - Multiple Unilateral Skull Base Defects in a Child With Conductive Hearing Loss. PMID- 28591002 TI - The Role of Radiation in Tympanojugular Paragangliomas Needs to be Objectively Re evaluated. PMID- 28591003 TI - Gender Differences in Anxiety and Complications Early After Acute Myocardial Infarction. AB - BACKGROUND: Anxiety is the earliest psychological response to acute myocardial infarction. When anxiety persists or becomes severe, it has negative consequences including increased risk for in-hospital complications. Therefore, it is necessary to determine which groups of people are at risk for high anxiety after acute myocardial infarction. OBJECTIVE: The aim of this study was to determine whether there is a difference in anxiety levels and rate of complications based on gender early after acute myocardial infarction. METHODS: A comparative design was used. Patients with acute myocardial infarction were interviewed within 72 hours (mean [SD], 40 [18] hours) of admission to the hospital and completed a sociodemographic and clinical questionnaire and the Anxiety Subscale of Hospital Anxiety and Depression Scale. In addition, clinical data were abstracted from the participants' medical record after discharge. RESULTS: A total of 250 patients, with a confirmed diagnosis of acute myocardial infarction, participated in this study: 163 men and 87 women. Female patients were more anxious (15.5 [3.6] vs 8.1 [2.9], P < .01) and had more complications (1.1 [1.9] vs 0.6 [0.08], P < .05) than male patients did. CONCLUSIONS: Anxiety is a global problem after acute myocardial infarction. Exploration of reasons why women of different cultures are at a higher risk for anxiety after acute myocardial infarction is necessary. It is of high clinical importance to determine strategies for managing anxiety in patients with or suspected to have acute myocardial infarction, especially women. PMID- 28591005 TI - Implant Strategy-Specific Changes in Symptoms in Response to Left Ventricular Assist Devices. AB - BACKGROUND: Although we know that the quality of life generally improves after left ventricular assist device (LVAD) implantation, we know little about how symptoms change in response to LVAD. METHODS: The purpose of this study was to compare the changes in symptoms between bridge and destination therapy patients as part of a prospective cohort study. Physical (dyspnea and wake disturbances) and affective symptoms (depression and anxiety) were measured before LVAD and at 1, 3, and 6 months after LVAD. Multiphase growth modeling was used to capture the 2 major phases of change: initial improvements between preimplant and 1 month after LVAD and subsequent improvements between 1 and 6 months after LVAD. RESULTS: The sample included 64 bridge and 22 destination therapy patients as the preimplant strategy. Destination patients had worse preimplant dyspnea and wake disturbances, and they experienced greater initial improvements in these symptoms compared with bridge patients (all P < .05); subsequent change in both symptoms were similar between groups (both P > .05). Destination patients had worse preimplant depression (P = .042) but experienced similar initial and subsequent improvements in depression in response to LVAD compared with bridge patients (both P > .05). Destination patients had similar preimplant anxiety (P = .279) but experienced less initial and greater subsequent improvements in anxiety after LVAD compared with bridge patients (both P < .05). CONCLUSION: There are many differences in the magnitude and timing of change in symptom responses to LVAD between bridge and destination therapy patients. Detailed information on changes in specific symptoms may better inform shared decision-making regarding LVAD. PMID- 28591004 TI - Medication Adherence Mediates the Relationship Between Heart Failure Symptoms and Cardiac Event-Free Survival in Patients With Heart Failure. AB - BACKGROUND: Heart failure (HF) symptoms such as dyspnea are common and may precipitate hospitalization. Medication nonadherence is presumed to be associated with symptom exacerbations, yet how HF symptoms, medication adherence, and hospitalization/death are related remains unclear. OBJECTIVE: The aim of this study was to explore the relationships among HF symptoms, medication adherence, and cardiac event-free survival in patients with HF. METHODS: At baseline, patient demographics, clinical data, and HF symptoms were collected in 219 patients with HF. Medication adherence was monitored using the Medication Event Monitoring System. Patients were followed for up to 3.5 years to collect hospitalization and survival data. Logistic regression and survival analyses were used for the analyses. RESULTS: Patients reporting dyspnea or ankle swelling were more likely to have poor medication adherence (P = .05). Poor medication adherence was associated with worse cardiac event-free survival (P = .006). In Cox regression, patients with HF symptoms had 2 times greater risk for a cardiac event than patients without HF symptoms (P = .042). Heart failure symptoms were not a significant predictor of cardiac event-free survival after entering medication adherence in the model (P = .091), indicating mediation. CONCLUSIONS: Medication adherence was associated with fewer HF symptoms and lower rates of hospitalization and death. It is important to develop interventions to improve medication adherence that may reduce HF symptoms and high hospitalization and mortality in patients with HF. PMID- 28591007 TI - The relationship between body adiposity index and pregnancy-induced hypertension in third-trimester pregnant women. AB - The aim of this study was to evaluate the relationship between body adiposity index (BAI) and pregnancy-induced hypertension (PIH) in third-trimester pregnant women. This study included 126 women in the third trimester of pregnancy. All participants completed anthropometric measurements and ultrasonic testing. The formula of BAI was hip circumference (cm)/height (m)-18. The frequency of PIH were significantly higher in the upper tertile group (31.0%) than in the low tertile group (7.1%) and the middle tertile group (4.8%) (P<0.01). The area under curve values for the accuracy of BAI in identifying PIH were 0.784. The optimal threshold of BAI for identifying PIH was 36.0. The sensitivity was 72.2% and the specificity was 85.1%. BAI was correlated with PIH. The performance of BAI for identifying third-trimester pregnant women with PIH was moderately accurate. PMID- 28591006 TI - Assessment of functional liver reserve: old and new in 99mTc-sulfur colloid scintigraphy. AB - PURPOSE: A semiquantitative assessment of hepatic reticuloendothelial system function using colloidal particles scintigraphy has been proposed previously as a surrogate for liver function evaluation. In this article, we present an updated method for the overall assessment of technetium-99m (Tc)-sulfur colloid (SC) biodistribution that combines information from planar and attenuation-corrected Tc-SC single-photon emission computed tomography (SPECT) images. The imaging protocol described here was developed as an easy-to-implement method to assess overall and regional liver function changes associated with chronic liver disease. PATIENTS AND METHODS: Thirty patients with chronic liver disease and primary liver cancers underwent Tc-SC whole-body planar imaging and upper-abdomen SPECT/computed tomography (CT) imaging before external beam radiation therapy. Liver plus spleen and bone marrow counts as a fraction of whole-body total counts were calculated from SC planar imaging. Attenuation correction Tc-SC images were rigidly coregistered with treatment planning CT images that contained liver and spleen regions-of-interest. Ratios of total liver counts to total spleen counts were obtained from the aligned Tc-SC SPECT and CT images, and were subsequently used to separate liver plus spleen counts obtained on the planar images. This hybrid SPECT/CT and planar scintigraphy approach yielded an updated estimation of whole-body SC distribution. These biodistribution estimates were compared with historical data for reference. Statistical associations of Tc-SC biodistribution to liver function parameters and liver disease scoring systems (Child-Pugh) were evaluated by Spearman rank correlation. RESULTS: Percentages of Tc-SC uptake ranged from 19.3 to 77.3% for the liver; 3.4 to 40.7% for the spleen; and 19.0 to 56.7% for the bone marrow. Spearman's correlation coefficient showed a significant statistical association between Child-Pugh score and bone marrow uptake at 0.55 (P<=0.05), liver uptake at 0.71 (P<=0.001), spleen uptake at 0.56 (P<=0.05), and spleen plus bone marrow uptake at 0.71 (P<=0.001). There was also a good correlation of SC uptake percentages with individual quantitative liver function components such as albumin and total bilirubin, and qualitative liver function components (varices, portal hypertension, ascites). For albumin: r=0.64 (P<0.001) compared with liver uptake percentage from the whole-body counts, r=0.49 (P<0.001) compared with splenic uptake percentage, and r=0.45 (P<=0.05) compared with bone marrow uptake percentage. CONCLUSION: We describe a novel liver function quantitative assessment method that combines whole-body planar images and SPECT/CT attenuation-corrected images of Tc-SC distribution. Attenuation-corrected SC images provide valuable regional liver function information, which is a unique feature compared with other imaging methods available. The results of our study indicate that the Tc-SC uptake by the liver, spleen, and bone marrow correlates with liver function parameters in patients with diffuse liver disease and the correlation with liver disease severity is slightly better for liver uptake percentages than for individual values of bone marrow and spleen uptake percentages. PMID- 28591008 TI - Plasma Resuscitation Improved Survival in a Cecal Ligation and Puncture Rat Model of Sepsis. AB - BACKGROUND: The paradigm shift from crystalloid to plasma resuscitation of traumatic hemorrhagic shock has improved patient outcomes due in part to plasma mediated reversal of catecholamine and inflammation-induced endothelial injury, decreasing vascular permeability and attenuating organ injury. Since sepsis induces a similar endothelial injury as seen in hemorrhage, we hypothesized that plasma resuscitation would increase 48-h survival in a rat sepsis model. METHODS: Adult male Sprague-Dawley rats (375-425 g) were subjected to 35% cecal ligation and puncture (CLP) (t = 0 h). Twenty-two hours post-CLP and prior to resuscitation (t = 22 h), animals were randomized to resuscitation with normal saline (NS, 10 cc/kg/h) or pooled rat fresh frozen plasma (FFP, 3.33 cc/kg/h). Resuscitation under general anesthesia proceeded for the next 6 h (t = 22 h to t = 28 h); lactate was checked every 2 h, and fluid volumes were titrated based on lactate clearance. Blood samples were obtained before (t = 22 h) and after resuscitation (t = 28 h), and at death or study conclusion. Lung specimens were obtained for calculation of wet-to-dry weight ratio. Fisher exact test was used to analyze the primary outcome of 48-h survival. ANOVA with repeated measures was used to analyze the effect of FFP versus NS resuscitation on blood gas, electrolytes, blood urea nitrogen (BUN), creatinine, interleukin (IL)-6, IL-10, catecholamines, and syndecan-1 (marker for endothelial injury). A two-tailed alpha level of <0.05 was used for all statistical tests. RESULTS: Thirty-three animals were studied: 14 FFP, 14 NS, and 5 sham. Post-CLP but preresuscitation (t = 22 h) variables between FFP and NS animals were similar and significantly deranged compared with sham animals. FFP significantly increased 48-h survival compared to NS (n = 8 [57%] vs n = 2 [14%]), attenuated the post-resuscitation (t = 28 h) levels of epinephrine (mean 2.2 vs 7.0 ng/mL), norepinephrine, (3.8 vs 8.9 ng/mL), IL-6 (3.8 vs 18.7 ng/mL), and syndecan-1 (21.8 vs 31.0 ng/mL) (all P < 0.05), improved the post-resuscitation PO2 to FiO2 ratio (353 vs 151), and reduced the pulmonary wet-to-dry weight ratio (5.28 vs 5.94) (all P < 0.05). CONCLUSION: Compared to crystalloid, plasma resuscitation increased 48-h survival in a rat sepsis model, improved pulmonary function and decreased pulmonary edema, and attenuated markers for inflammation, endothelial injury, and catecholamines. PMID- 28591009 TI - Surfactant Proteins-A and -D Attenuate LPS-Induced Apoptosis in Primary Intestinal Epithelial Cells (IECs). AB - INTRODUCTION: SP-A/D KO mice with sepsis demonstrate more severe lung, kidney, and gut injury/apoptosis than WT controls. We hypothesize SP-A and SP-D directly regulate lipopolysaccharide (LPS)-induced P38 mitogen-activated protein kinase (MAPK) activation and gut apoptosis during sepsis. METHODS: Primary IECs were established from SP-A/D KO or C57BL/6 WT mice, stimulated with LPS and harvested at 24 h. IECs from WT mice were treated with SP-A, SP-D, or vehicle for 20 h, then LPS for 24 h. Apoptosis, cleaved caspase-3 levels and the ratio of BAX/Bcl-2 were assayed. The role of P38 MAPK was examined using the P38 MAPK-agonist U46619 and inhibitor SB203580 in LPS-treated cells. p-P38 MAPK/t-P38 MAPK, TLR4, and CD14 were measured by Western Blot. RESULTS: LPS-induced apoptosis, caspase-3 levels, BAX/Bcl-2, and p-P38/t-P38 MAPK were increased in SP-A/D KO IECs. SP-A and SP-D attenuate LPS-induced increase in apoptosis, cleaved caspase-3, BAX/Bcl 2, and p-P38/t-P38 MAPK in WT IECs. U46619 increased apoptosis, caspase-3, and BAX/Bcl-2 in IECs which was attenuated by SP-A/D. SB203580 attenuates the LPS induced increase in apoptosis, caspase-3, and BAX/Bcl-2 in WT IECs. Addition of SP-A or SP-D to SB203580 completely ameliorates LPS-induced apoptosis. The LPS induced increase in TLR4 and CD14 expression is greater in IECs from SP-A/D KO mice and treatment of WT IECs with SP-A or SP-D prevents the LPS-induced increase in TLR4 and CD14. CONCLUSIONS: SP-A and SP-D attenuate LPS-induced increases in apoptosis, caspase-3, and BAX/Bcl-2 in IECs. Attenuation of LPS-induced activation of TLR4 and P38 MAPK signaling pathways represents potential mechanisms for the protective effects of SP-A/D on apoptosis. PMID- 28591010 TI - The Impact of a Mother's Emotional Strains and Disclosure of Cancer on Her Child's Defensiveness and Adjustment to Cancer. AB - BACKGROUND: Defensiveness is one of the strategies that children with cancer use against psychosocial difficulties, yet it remains unclear what factors may impact children's use of defensiveness. OBJECTIVE: The aim of this study was to explore the psychological adjustment, including use of defensive behaviors, in children who may or may not be told about the diagnosis of cancer. METHODS: A total of 58 children and 51 mothers participated in the study. Children answered questionnaires about defensiveness, anxiety, and depression, whereas mothers completed a questionnaire of anxiety, depression, and stress and a question about disclosure of cancer to child. RESULTS: Significant differences were found in the defensiveness and depression scores between children with full disclosure and those with no disclosure about their cancer. Although children's adjustment has been directly related to that of their mother's adjustment, we did not find this variable to be a predictor of child's adjustment. The child's defensiveness scores were a strong predictor of child's anxiety and eventually for a high risk for depression. CONCLUSIONS: Mothers' emotional strains and lack of open disclosure about cancer significantly affect the psychosocial well-being of children. IMPLICATIONS FOR PRACTICE: It is essential for nurses to assess the emotional adjustment and defensiveness strategies that children with cancer use. We believe that nurses caring for children with cancer have a professional responsibility to identify and understand defensive behaviors and other characteristics of psychosocial distress and advocate for psychological interventions that will help mothers and their children cope with cancer. PMID- 28591011 TI - Being Fully Present: Gains Patients Attribute to a Telephone-Delivered Parenting Program for Child-Rearing Mothers With Cancer. AB - BACKGROUND: Oncology nurses can assist patients in gaining skills and confidence in multiple areas of illness self-management, including parenting skills. Child rearing parents with cancer are a unique population because they must self-manage their illness and also help their child manage the intrusion of cancer on everyday life. The telephone offers an inexpensive channel for nurses to assist mothers in developing competencies to parent their child. The acceptability and attributed gains from such telephone services are unknown. OBJECTIVE: The aims of this study were to (1) describe the gains child-rearing mothers attribute to participation in a nurse-delivered telephone cancer parenting program and (2) assess mothers' evaluation of the telephone as a channel for delivering the program. METHODS: Study participants were child-rearing mothers diagnosed with cancer (N = 31) who had completed a manualized telephone-delivered cancer parenting program by a nurse. Mothers were interviewed 1 month after exiting the program by a specially trained interviewer masked on the content of the program. RESULTS: Most mothers were white (74%), highly educated, and had breast cancer (93.5%). Mothers attributed gains from the program in 3 areas: (1) being fully present for my child, (2) communicating in new ways, and (3) putting away my assumptions. CONCLUSIONS: Communication skills learned from nurses can assist mothers to self-manage the impact of the cancer on their own well-being and add to their parenting skills and competencies to help their children. IMPLICATIONS FOR PRACTICE: The telephone is an effective and indeed preferred channel for delivering services to child-rearing parents impacted by cancer. PMID- 28591012 TI - Is Antibiotic Alternative to Appendectomy? PMID- 28591013 TI - Response to Letter: Is Antibiotic Alternative to Appendectomy? PMID- 28591014 TI - Is an RCT the Best Way to Investigate the Effectiveness of Nonoperative Management of Pediatric Appendicitis? PMID- 28591015 TI - Design of Studies for Antibiotic Treatment of Acute Appendicitis in Children: In Support of RCTs. PMID- 28591016 TI - Hey, I Just Did a Better Operation! Toward an IDEAL Innovation Model. PMID- 28591017 TI - Reply to Letter: "Hey, I Just Did a Better Operation! Toward an IDEAL Innovation Model". PMID- 28591018 TI - Factors Associated With Recurrence and Survival in N0 Gastric Cancer. PMID- 28591019 TI - The Comparison of Surgical Approaches in Locally Advanced Esophageal Cancer: Significant Insights but Clinical Fidelity Still to Be Delivered. PMID- 28591020 TI - Emergency and Trauma Surgery: A Hard Jazz Solo. PMID- 28591021 TI - Error Management in Emergency Surgery and Music: Fight, Flight, or Freeze. PMID- 28591022 TI - Synbiotic Therapy With Surgery for Chronic Pancreatitis. PMID- 28591023 TI - Synbiotics in Surgery for Chronic Pancreatitis - A Hobson's Choice? PMID- 28591026 TI - Imaging diagnosis of orbital Wegener granulomatosis: A rare case report. AB - INTRODUCTION: Wegener granulomatosis (WG) is a rare idiopathic autoimmune disease causing necrotizing granulomatous vasculitis. Whether as the first symptom or as part of systemic changes, ocular manifestations in WG patients are not specific. Any part of the eyes can be affected, with the anterior segment and orbit most commonly involved. So, early diagnosis and treatment are essential for controlling the progression of the disease and improving the quality of life for patients. CLINICAL FINDINGS/PATIENT CONCERNS: Here we present a rare case of orbital WG of a 22-year-old woman was admitted to the hospital because of intense pain associated with decreased visual acuity in her right eye since 1 day. She had been previously diagnosed with WG at our hospital. IMAGING DIAGNOSIS: Orbital computed tomography imaging showed diffuse swelling of intraorbital muscles, and space-occupying lesions were present in both eyes. Most postnasal anatomical structures were absent, appearing as a massive cavity shadow. Orbital magnetic resonance imaging showed a shadow of orbital soft tissues. CONCLUSION: WG is a serious, fatal disease. Early diagnosis and treatment are essential for controlling the progression of the disease and improving the quality of life for patients. PMID- 28591025 TI - Neurocognitive development in HIV-positive children is correlated with plasma viral loads in early childhood. AB - Because of neurocognitive impairments in perinatally human immunodeficiency virus (HIV)-infected children and adolescents, this study aimed to demonstrate the effect of plasma viral loads and early initiation of sufficient combined antiretroviral therapy (cART) on neurocognitive development.In total, 14 perinatally infected HIV-positive children (median age 8.24 years [range: 6.0 16.74]) receiving lopinavir/ritonavir (LPV/r)-based ART underwent neurocognitive testing using the Wechsler Intelligence Score for Children, 4th Edition (WISC IV). All 14 patients participated in a pharmacokinetic study in which they were hospitalized for an entire day. As a child's ability to concentrate varies over the course of the day, all tests were performed in the morning.The patients' neurocognitive development did not significantly differ from the normative collective pattern for any of the following composite scores that were examined: full-scale intelligence quotient (IQ) (mean: 106.5, P = .1060), verbal comprehension index (mean: 106.0, P = .1356), perceptual reasoning index (mean: 106.0, P = .1357), working memory index (mean: 106.3, P = .1171), and processing speed index (mean: 98.1, P = .6313). The overall full-scale IQ scores were significantly higher in children who began ART within the first year of life (P = .0379), whereas low lopinavir/r plasma levels (P = .0070) and high viral load area under the curves (AUCs) in the first 3 years of life, but not later, significantly correlated with reduced neurocognitive performance (Spearman r = 0.64, P = .0278).In this cohort of cART treated HIV-positive children and adolescents, neurocognitive performance correlated with early and sufficient viral load suppression within the first 3 years of life. PMID- 28591027 TI - Necrotizing fasciitis-A catastrophic complication following routine tibia fracture surgery: A case report and literature review. AB - RATIONALE: Necrotizing fasciitis (NF) is defined as a rare, life-threatening, rapidly spreading soft tissue infection resulting from a polymicrobial origin, with a predominance of anaerobic organisms that presents with necrosis of the muscle, fascia, and surrounding soft tissue. PATIENT CONCERNS AND DIAGNOSES: A 64 year-old male who sustained tibia fracture caused by falling from a height underwent a tibia surgery with minimally invasive plate osteosynthesis technique in another institution. Postoperatively, the patient had development of a very uncommon NF at the site of the tibia procedure. When the patient was transferred to our unit, he rapidly processed to toxic shock and coagulopathy. INTERVENTIONS AND OUTCOMES: Although the patient underwent antibiotics treatment in the emergency room and was transferred to the operating room for surgery promptly, the patient's condition deteriorated rapidly and he died of septic shock and multiple organ failure unfortunately. LESSONS: Our study aims to highlight the risk of NF in the elderly with diabetes during the perioperative period even if the injury is a simple closed fracture. Physicians must be vigilant to early inflammatory signs and pain in immunosuppressed patients. PMID- 28591029 TI - Observational report: Improved outcomes of transscleral cyclophotocoagulation for glaucoma patients. AB - The purpose of this article is to evaluate the improved safety and efficacy of transscleral cyclophotocoagulation (TSCPC) by performing it in the operating room.This is a retrospective review of 17 eyes of 16 patients who received TSCPC for uncontrolled glaucoma on maximum tolerated medication.Mean intraocular pressure (IOP) prior to surgery was 30.85 +/- 6.24 mm Hg and was reduced to 14.48 +/- 3.53 mm Hg after treatment for an average reduction in IOP of 48.56% at the final visit (P < .001). Visual acuity was measured at the final follow-up visit and was stable in 13 eyes (76.47%), improved in 2 eyes (11.75%), and decreased in 2 eyes (11.75%). Nine of the eyes (52.94%) saw a reduction in the number of medications taken, whereas 8 had no change. Two eyes had resolved complications of cystoid macular edema (CME) and subconjunctival hemorrhages. The overall success rate is determined to be 88%.TSCPC performed in the operating room may have greater safety and efficacy for patients with uncontrolled glaucoma. PMID- 28591030 TI - Pancreatic carcinosarcoma mimics malignant intraductal papillary mucinous neoplasm: A rare case report and literature review. AB - RATIONALE: Carcinosarcoma, an extremely rare pancreatic primary tumor, is characterized by coexistence of both carcinomatous and sarcomatous components. Due to its rarity, the clinical manifestation and imaging features have not been recognized. An accurate diagnostic method has not been available and a widely accepted guidelines instructing treatment has not been established. PATIENT CONCERNS: We present an uncommon case of pancreatic carcinosarcoma (PCS) which has been preoperatively diagnosed as pancreatic malignant intraductal papillary mucinous neoplasm. A radical resection, including total pancreatectomy (TP) and splenectomy, was performed. DIAGNOSIS: The diagnosis of PCS was confirmed by postoperative pathology. INTERVENTIONS: A radical resection, including TP and splenectomy, was performed. The patient was followed up by abdominal contrast enhanced computed tomography scan and blood tumor marker examination. OUTCOMES: The patient is still alive and self-sufficient 7 months after the surgery. No evidence of tumor recurrence is found during follow-up. LESSONS: Although, until recently, there are no widely accepted guidelines instructing treatment for PCS, a radical resection is still a possible way. All the pancreatic neoplastic patients with high surgical risk should be transferred to a specialized high volume pancreatic center to get precise preoperative evaluation, fine operation technique, and careful postoperative management. PMID- 28591028 TI - Haplotype-based interaction of the PPARGC1A and UCP1 genes is associated with impaired fasting glucose or type 2 diabetes mellitus. AB - The aim of this study is to evaluate the effect of single-nucleotide polymorphisms (SNPs) of the PPARGC1A and UCP1 genes on impaired fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) and the haplotype-based interaction between these genes.A cross-sectional study was conducted by cluster sampling in Henan province, China. Based on the level of fasting plasma glucose (FPG) and the history of T2DM, the participants were divided into 2 groups; 83 individuals were in the IFG+DM group (those with IFG or T2DM) and 445 individuals were in the NFPG group (those with normal FPG). Kernel canonical correlation analysis (KCCA), a haplotype-based gene-gene interaction method, which can increase the biological interpretability and extract nonlinear characteristics of SNPs, was used to analyze the correlation and interaction between PPARGC1A and UCP1 genes.The age, BMI, total cholesterol and triglycerides were statistically different between 2 groups (P <= .001). Haplotype analysis showed no significant difference in frequency distribution between the 2 groups when the PPARGC1A or UCP1 gene was tested (P > .05). KCCA analysis showed that the maximum kernel canonical correlation coefficient of the PPARGC1A and UCP1 genes was 0.9977 and 0.9995 in the IFG+DM and NPFG groups, respectively. A haplotype-based gene-gene interaction was observed significantly (U = -6.28, P < .001), indicating the possibility of an interaction between haplotype AAG of the PPARGC1A gene and haplotypes CTCG (odds ratio [OR] = 1.745, 95% confidence interval [95% CI] 1.069-2.847) and CTCA (OR = 0.239, 95% CI 0.060-0.958) of the UCP1 gene.Haplotype-based interaction between the PPARGC1A and UCP1 genes is associated with IFG or T2DM among residents in Henan, China. PMID- 28591031 TI - CT evaluation of living liver donor: Can 100-kVp plus iterative reconstruction protocol provide accurate liver volume and vascular anatomy for liver transplantation with reduced radiation and contrast dose? AB - We evaluated whether donor computed tomography (CT) with a combined technique of lower tube voltage and iterative reconstruction (IR) can provide sufficient preoperative information for liver transplantation.We retrospectively reviewed CT of 113 liver donor candidates. Dynamic contrast-enhanced CT of the liver was performed on the following protocol: protocol A (n = 70), 120-kVp with filtered back projection (FBP); protocol B (n = 43), 100-kVp with IR. To equalize the background covariates, one-to-one propensity-matched analysis was used. We visually compared the score of the hepatic artery (A-score), portal vein (P score), and hepatic vein (V-score) of the 2 protocols and quantitatively correlated the graft volume obtained by CT volumetry (graft-CTv) under the 2 protocols with the actual graft weight.In total, 39 protocol-A and protocol-B candidates showed comparable preoperative clinical characteristics with propensity matching. For protocols A and B, the A-score was 3.87 +/- 0.73 and 4.51 +/- 0.56 (P < .01), the P-score was 4.92 +/- 0.27 and 5.0 +/- 0.0 (P = .07), and the V-score was 4.23 +/- 0.78 and 4.82 +/- 0.39 (P < .01), respectively. Correlations between the actual graft weight and graft-CTv of protocols A and B were 0.97 and 0.96, respectively.Liver-donor CT imaging under 100-kVp plus IR protocol provides better visualization for vascular structures than that under 120-kVp plus FBP protocol with comparable accuracy for graft-CTv, while lowering radiation exposure by more than 40% and reducing contrast-medium dose by 20%. PMID- 28591032 TI - Prognostic impact of hyponatremia occurring at various time points during hospitalization on mortality in patients with acute myocardial infarction. AB - We investigated the incidence and prognostic impact of hyponatremia occurring at various time points during hospitalization on long-term mortality in acute myocardial infarction (AMI) survivors. We retrospectively studied 1863 patients diagnosed with AMI. Baseline, nadir, and discharge sodium levels during hospitalization were recorded and analyzed. Hyponatremia was defined as a serum sodium level <135 mEq/L. On the basis of baseline, nadir, and discharge sodium levels during hospitalization, hyponatremia was diagnosed in 309 (16.6%), 518 (27.8%), and 147 (7.9%) patients, respectively. In a multivariate Cox proportional regression analysis, discharge sodium level had the strongest significant relationship with long-term mortality (hazard ratio [HR] as continuous variable = 1.06, 95% confidence interval [CI]: 1.01-1.11, P = .026; HR as categorical variable = 1.71; 95% CI: 1.06-2.75; P = .028), but baseline and nadir sodium had no prognostic impact on long-term mortality after adjustment. The serum sodium level and incidence of hyponatremia varied at different time points during hospitalization. In addition, the association between sodium level and long-term mortality differed at these various time points. The discharge sodium level, among the various time points, seems the best predictor of long term mortality in AMI survivors. PMID- 28591033 TI - Vitamin D supplementation and disease activity in patients with immune-mediated rheumatic diseases: A systematic review and meta-analysis. AB - BACKGROUND: Vitamin D serum levels and the presence and activity of rheumatic conditions have been associated. However, many studies are merely observational, and the existent randomized clinical trials were never systematically analyzed. Therefore, this study aims to provide a systematic review and meta-analysis of such a topic. METHODS: MEDLINE, EMBASE, LILACS, COCHRANE, and CINAHL were explored to identify randomized trials that investigated clinical repercussions of vitamin D (or analogs) supplementation for at least 3 months in rheumatic diseases. Standardized clinical and/or laboratorial outcomes related to disease activity were analyzed according to each disease before and after supplementation. RESULTS: Database searches rendered 668 results; 9 were included 5 on rheumatoid arthritis, 3 on systemic lupus erythematosus, and 1 on systemic sclerosis. Seven of the studies were meta-analyzed. After vitamin D supplementation, rheumatoid arthritis recurrence decreased; however, not significantly (risk difference = -0.10, 95% CI = -0.21, 0.00, P = .05). No statistical significance was observed regarding visual analog scale (mean difference = 2.79, 95% CI = -1.87, 7.44, P = .24) and disease activity score28 (mean difference = -0.31, 95% CI = -0.86, 0.25, P = .28). Regarding systemic lupus erythematosus, anti-dsDNA positivity was significantly reduced (risk difference = -0.10, 95% CI = -0.18, -0.03; P = .005). CONCLUSION: Vitamin D supplementation reduced anti-dsDNA positivity on systemic lupus erythematosus and could possibly reduce rheumatoid arthritis recurrence, although novel randomized clinical trials are needed to confirm and extend the benefits of this hormone in immune-mediated rheumatic diseases. PMID- 28591034 TI - Surgical performance of large loop excision of the transformation zone in a training model: A prospective cohort study. AB - Large loop excision of the transformation zone (LLETZ) is one of the most common procedures in operative gynecology and it is a routine part of the surgical training program of residents. There is, however, no established and standardized method of teaching residents how to perform LLETZ. Here, we present a surgical training model and assessed the improvement of surgical skills during repeated hands-on trainings of LLETZ in this model.Surgical novices and experts were recruited and were shown a LLETZ training video and then performed 3 LLETZ training sessions on consecutive days. Surgical skills were assessed by Objective Structured Assessment of Technical Skills (OSATS). Global rating scale (GRS), confidence (CON), fragmentation rate (FR), performance time (PT), and OSATS scores were calculated. Intra- and interobserver variabilities were determined. The construct validity of OSATS was assessed comparing metric scores of novices with those of experts.Sixty-eight probands (58 novices, 10 experts) were recruited. GRS, 2.3 +/- 1.3 (median +/- SD) versus 1.4 +/- 0.6, P < .001; CON, 2.7 +/- 0.9 versus 1.6 +/- 0.6, P < .001; FR, 81% versus 100%, P < .001; PT, 152 +/- 33 versus 120 +/- 27 seconds, P = .006; and OSATS scores, 18.8 +/- 1.3 versus 19.1 +/- 1.1, P = .16 of novices improved from session 1 to session 3. OSATS showed construct validity with metric scores (GRS, 1.1 +/- 0.3 vs 2.3 +/- 0.8, P < .001; CON, 1.0 +/- 0.0 vs 2.7 +/- 0.9, P < .001; PT 125 +/- 30 vs 152 +/- 33 seconds, P = .02; OSATS scores, 19.6 +/- 0.7 vs. 18.8 +/- 1.3, P = .02) reliably discriminating between experts and novices. Intra- and interobserver variabilities across probands were 0.99 +/- 0.03 and 0.64 +/- 0.10, respectively. OSATS scores were independent of handedness, sex, and regular sports activity in univariate and multivariate analyses.Repeated hands-on trainings improve surgical performance of LLETZ in a surgical training model with construct validity. PMID- 28591035 TI - A case report of lymphoid intestitial pneumonia in common variable immunodeficiency: Oligoclonal expansion of effector lymphocytes with preferential cytomegalovirus-specific immune response and lymphoproliferative disease promotion. AB - RATIONALE: Lymphoid interstitial pneumonia (LIP) is a rare disease with lymphocytic infiltration of the alveolar interstitial and air spaces, sometimes classified as a clonal lymphoproliferative disease (LPD) with high prevalence in patients with immunodysregulation. Although association of mucosa-associated lymphoid tissue (MALT) lymphoma development with infectious agents has been well described, it is not so in the case of LIP. Attempts to demonstrate an infective cause by direct microbe detection have failed, but association with atypical specific immune response to opportunistic infectious agent has not been studied. PATIENT CONCERNS AND DIAGNOSES: We performed clinical, biochemical, and immunologic analysis of patients LIP that arises primarily from the common variable immune deficiency (CVID) with normal immunoglobulin class M (IgM) level and mild infectious course as a result of immunodysregulation. At the age of 13 multiple nodules, areas of consolidation were observed and LIP was confirmed by histological examination. The progression of the disease with massive splenomegaly (17->27 cm), lymphadenopathy soft tissue infiltration coincides with high standardized uptake value (SUV was 3.1-5.2), regulatory T cells decrease (CD4+25FoxP3+ level -0.02%, i.e., 8 cells per 100 MUL), oligoclonal gammapathy: very high IgM (3340 mg/dL) and beta2-microglobulin (18.8 mg/L) level observed 10 years later.Immune response polarization was observed in humoral and cellular compartment -Th and Tc-dependent: 10.8% of lymphocytes are CD8high+CMV pp65 pentamer positive cells (Epstein-Barr virus-specific not observed). Specific immune response polarization correlates with negative immunofixation, light chains kappa/lambda = 2.84 and narrow, but non-monoclonal T cell receptor (TCR)/ B cell receptor (BCR) repertoire. LESSONS: Taking everything into account, this case report shows that LIP is a consequence of immune-dysregulation in CVID, that is, Treg deficiency, narrow lymphocyte repertoire, and abnormal ability to respond to cytomegalovirus (CMV) antigens. It may be visualized by positron emission tomography (PET) and monitored by CMV-specific immune response, beta2 microglobulin level, and IgM paraproteinaemia, but not by immunofixation and kappa/lambda ratio. PMID- 28591036 TI - The impact of dual-source parallel radiofrequency transmission with patient adaptive shimming on the cardiac magnetic resonance in children at 3.0 T. AB - The cardiac magnetic resonance (CMR) of children at 3.0 T presents a unique set of technical challenges because of their small cardiac anatomical structures, fast heart rates, and the limited ability to keep motionless and hold breathe, which could cause problems associated with field inhomogeneity and degrade the image quality. The aim of our study was to evaluate the effect of dual-source parallel radiofrequency (RF) transmission on the B1 homogeneity and image quality in children with CMR at 3.0 T. The study was approved by the institutional ethics committee and written informed consent was obtained. A total of 30 free-breathing children and 30 breath-hold children performed CMR examinations with dual-source and single-source RF transmission. The B1 homogeneity, contrast ratio (CR) of cine images, and off-resonance artifacts in cine images between dual-source and single-source RF transmission were assessed in free-breathing and breath-hold groups, respectively. In both free-breathing and breath-hold groups, higher mean percentage of flip angle (free-breathing group: 104.2 +/- 4.6 vs 95.5 +/- 6.3, P < .001; breath-hold group: 101.5 +/- 5.1 vs 92.5 +/- 6.3, P < .001) and lower coefficient of variation (free-breathing group: 0.06 +/- 0.02 vs 0.09 +/- 0.03, P < .001; breath-hold group: 0.07 +/- 0.03 vs 0.10 +/- 0.04, P = .005) were found with dual-source than with single-source RF transmission. Both the CRs in the horizontal long axis (HLA) and short axis of cine images with dual-source RF transmission was improved (P < .05 for all). The scores of off-resonance artifacts in the HLA with dual-source RF transmission were higher in both free breathing and breath-hold groups (P < .05 for all), with substantial interreader agreement (kappa values from 0.68 to 0.74). Compared with conventional single source, dual-source parallel RF transmission could significantly improve the B1 homogeneity and image quality for CMR in children at 3.0 T. This technology could be taken into account in CMR for children with cardiac diseases. PMID- 28591037 TI - Different surgical approaches for the treatment of adjacent segment diseases after anterior cervical fusion: A retrospective study of 49 patients. AB - Studies in the literature have not delineated the surgical approaches of symptomatic adjacent segment diseases (ASDs) in patients undergoing reoperation after an initial anterior cervical fusion (ACF). The purpose of this study was to determine the optimal surgical approaches of ASD and the incidence of the dysphagia after reoperation.This was a retrospective study of 49 patients with ASD after an initial ACF surgery, which had undergone a reoperation at our medical center between January 2010 and December 2014. The surgical approaches were used by anterior cervical discectomy and fusion (ACDF), ACDF with the Zero profile device, laminoplasty, and laminectomy with internal fixation. Patients were classified according to the different surgical approaches of anterior (n = 38) versus posterior (n = 11) groups and ACDF (n = 25) versus Zero-P (n = 13) groups. Clinical evaluations were performed preoperatively and repeated in 24 months after operation.This retrospective study included 26 men and 23 women with a mean age at revision surgery of 54.3 years and ASD onset time of 7.3 years. The patients were followed up with an average of 4.1 years. The reoperation rate was 5.4% in this study. The Japanese Orthopaedic Association (JOA), Neck Disability Index (NDI), and visual analogue scale (VAS) scores demonstrated significant improvements compared with preoperative in both anterior and posterior groups (P < .05). However, there were no differences between the 2 groups (P > .05). The operation time of ACDF group was more than Zero-P group, with significant differences (P < .05). However, there were no differences in JOA, NDI, and VAS scores between the ACDF and Zero-P groups pre- and postoperative (P > .05). A total of 12 (24.5%) patients had dysphagia after reoperation. The incidence of dysphagia in Zero-P group (1/13) was less than ACDF group (11/25), with significant differences (P < .05). There were no cases of major neurological or vascular complications, and wound complications.The clinical situation, initial operation, and secondary preoperative imaging findings were analyzed comprehensively, anterior or posterior approach were chosen, which can effectively relieve spinal cord compression and improve spinal cord function. In ACDF with the Zero-profile device surgery, there was no need to remove the previous internal fixation, shorten the operation time, and reduce the incidence of postoperative dysphagia. PMID- 28591038 TI - Indication for hypertrophy posterior longitudinal ligament removal in anterior decompression for cervical spondylotic myelopathy. AB - The retrospective study aimed to investigate the indication for hypertrophy posterior longitudinal ligament (HPLL) removal in anterior decompression for cervical spondylotic myelopathy (CSM). A total of 138 consecutive patients with CSM were divided into 2 groups with developmental cervical stenosis (DCS) (group S) and non-DCS (group N), according to the Pavlov ratio. These 2 groups were subdivided into 2 further subgroups, according to whether HPLL was removed or preserved: group SR (49 patients) and group SP (32 patients) in group S, group NR (21 patients) and group NP (36 patients) in group N. The modified Japanese Orthopedic Association score (mJOA), the modified recovery rate (mRR), quality of life (QoL), and relevant clinical data were used for clinical and radiological evaluation. The mJOA scores improved from 7.3 +/- 2.2 to 15.0 +/- 1.8 in the SR group and from 7.9 +/- 2.3 to 14.2 +/- 1.5 in the SP group (P = .036), with postoperative QoL significantly higher in the SR group than the SP group. A reduction in the diameter of enlarged spinal canals occurred at a significantly faster rate in the SP group compared with the SR group (P = .002). Multivariate regression analyses showed removal of HPLL correlated with mJOA scores (coefficient = 7.337, P = .002), mRR (%) (coefficient = 9.117, P = .005), PCS (coefficient = 12.129, P < .001), and MCS (coefficient = 14.31, P < .001) in the S group at 24 months postoperatively, while removal of HPLL did not correlate with clinical outcomes in the N group. The HPLL should, therefore, be removed when mobility was reduced and the spinal cord remained compressed after anterior decompression procedures in the patients with DCS. However, in non-DCS patients, it remains unclear as to whether removal of HPLL provides any clinical benefit, thus, HPLL removal may not be necessary. PMID- 28591039 TI - Genetic polymorphism of methylenetetrahydrofolate reductase as a potential risk factor for congenital heart disease: A meta-analysis in Chinese pediatric population. AB - BACKGROUND: A meta-analysis of polymorphism C677T (rs1801133) of the methylene tetrahydrofolate reductase (MTHFR) gene as a potential risk factor for congenital heart disease (CHD) in Chinese paediatric population was studied in view of the previously reported controversial results. METHODS: We searched literature including PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases that resulted in the identification of a total of 21 separate studies with 6414 subjects that met the inclusion criteria in the Chinese population. The quality assessment of the included studies was preformed and relevant information was collected. We chose the fixed-effect model or random-effect model to calculate the pooled odds ratio (ORs) and its corresponding 95% confidence interval (95% CI) where appropriate. Begg test was used to measure publication bias and sensitivity analyses were done to ensure authenticity of the outcome. RESULTS: We observed a significant association between MTHFR C677T polymorphism and CHD development in all the genetic models evaluated. The pooled ORs and 95% CIs in all genetic models indicated that children's MTHFR C677T polymorphism was significantly associated with CHD. CONCLUSION: Our study results indicate that MTHFR gene 677T polymorphism is a genetic risk factor in the development of CHD in Chinese paediatric population. PMID- 28591040 TI - An uncommon cause of gastric outlet obstruction: A case report. AB - RATIONALE: Metastatic involvement of the gastrointestinal tract is an uncommon scenario encountered in the clinical practice. Our case represents a gastric outlet obstruction (GOO) as a consequence of distant Transitional cell carcinoma (TCC) metastasis without any lymph node involvement in association with inflammatory stranding leading to extrinsic duodenal obstruction. PATIENT CONCERNS: We report an unusual case of a 73-year-old male presented with a five week history of nausea, vomiting and abdominal pain due to the metastatic extension from TCC that had been considered in remission. DIAGNOSES: Computed tomography (CT) of the abdomen and pelvis revealed new circumferential thickening and inflammatory stranding involving the ascending colon extending to the hepatic flexure. Based on the imaging findings, colonoscopy was pursued which demonstrated a mass at the hepatic flexure and biopsies obtained confirmed invasive transitional cell cancer. INTERVENTION: Patient underwent a Wall Flex (22 mm * 120 mm) metal stent to help alleviate the gastric outlet obstruction. Chemotherapy was planned by oncology. LESSONS: Our case highlights the importance of ruling out distant metastases in the evaluation of new gastrointestinal tract pathology, for instance, Gastric Outlet Obstruction in our patient; with a prior history of TCC without any lymph node involvement under remission. PMID- 28591041 TI - Relationship of Treg/Th17 balance with HBeAg change in HBeAg-positive chronic hepatitis B patients receiving telbivudine antiviral treatment: A longitudinal observational study. AB - Telbivudine (LdT) is an orally L-nucleoside with potent and specific antihepatitis B virus (HBV) activity. The higher rate of hepatitis B e antigen (HBeAg) seroconversion of LdT treatment than other anti-HBV agents suggests a potential immunomodulatory effect. The aim of the study was to investigate the changes of regulatory T cell (Treg)/interleukin (IL)-17-producing CD4+T helper (Th17) balance during LdT treatment and to discuss the relationship of Treg/Th17 balance with HBeAg change in HBeAg-positive chronic hepatitis B (CHB) patients receiving LdT antiviral treatment. Twenty-seven HBeAg-positive CHB patients received LdT for 24 weeks and the percentages of Tregs and cells (Th17 cells) in peripheral blood as well as the serum TGF-beta1 and IL-17 levels in these patients were longitudinally analyzed. We found that the frequencies of Tregs and Th17 cells in peripheral blood as well as the serum TGF-beta1 and IL-17 levels increased significantly in CHB patients compared with healthy controls. During the LdT treatment, the Tregs frequency and TGF-beta1 level tended to decrease, and Th17 cells frequency and IL-17 level showed a reverse "V"-type change. The frequency of Tregs and the ratio of Treg/Th17 were significantly lower in the HBeAg loss group than those in the HBeAg no-loss group at the baseline. More important, the Tregs frequency and TGF-beta1 level were both positively correlated with HBeAg level during the LdT treatment for 24 weeks. Our data suggest that the lower Tregs frequency and Treg/Th17 ratio at the baseline of LdT treatment, the more likely to get the HBeAg loss. HBeAg negative can be predicted using changes in Tregs frequency and TGF-beta1 level during LdT treatment in CHB patients. Maybe we could provide the immunology marker for exploring the mechanism of the higher HBeAg seroconversion rate of LdT therapy. PMID- 28591042 TI - Acupuncture for polycystic ovarian syndrome: A systematic review and meta analysis. AB - BACKGROUND: This systematic review aimed at summarizing and evaluating the evidence from randomized controlled trials (RCTs) using acupuncture to treat polycystic ovarian syndrome (PCOS), specifically focusing on ovulation rate, menstrual rate, and related hormones. METHODS: Fifteen databases were searched electronically through February 2016. Our review included RCTs of women with PCOS; these RCTs compared acupuncture with sham acupuncture, medication, or no treatment. Two reviewers independently extracted data. Data were pooled and expressed as mean differences (MDs) for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals (CIs) using a random-effects model. RESULTS: We found a low level of evidence that acupuncture is more likely to improve ovulation rate (MD 0.35, 95% CI: 0.14-0.56) and menstruation rate (MD 0.50, 95% CI: 0.32-0.68) compared with no acupuncture. We found statistically significant pooled benefits of acupuncture treatment as an adjunct to medication in luteinizing hormone (LH), LH/follicular stimulating hormone (FSH) ratio, testosterone, fasting insulin, and pregnancy rates, but the level of evidence was low/very low. CONCLUSION: There is limited evidence to judge the efficacy and safety of acupuncture on key reproductive outcomes in women with PCOS. Large scale, long-term RCTs with rigorous methodological input are needed. PMID- 28591043 TI - Diabetes self-assessment score and the development of diabetes: A 10-year prospective study. AB - To verify that the Korean Diabetes Score (KDS), a self-assessment, predicts the risk of diabetes in various comprehensive risk models, and to investigate factors that enhance its predictive ability in a large cohort. We analyzed 8735 adults without diabetes in the Korean Genome and Epidemiology Study, an ongoing large community-based 10-year cohort study. Incident diabetes was defined as fasting blood glucose >=126 mg/dL or postload 2-hour glucose >=200 mg/dL by 75 g oral glucose tolerance test conducted biennually, or currently taking medication for diabetes. Hazard ratios (HRs) using Cox regression were calculated for relative risk of developing diabetes as associated with the KDS, and performance of risk models was assessed by area under the receiver-operating characteristic curve (AUC). Of 8735 participants, 1497 (17.1%) developed diabetes over 10 years. The prevalence of incident diabetes was 10.3% in people with a KDS <5 and was 21.8% in those with KDS >=5 (P < .001). Increasing KDS was significantly associated with developing diabetes (adjusted HR: 1.13; 95% confidence interval:1.09,1.18). The comprehensive prediction model with KDS added to fasting glucose, glycated hemoglobin, postload 2-hour glucose, and triglyceride showed a markedly higher AUC (0.782) compared to KDS alone (0.641). A low insulinogenic index (IGI) level, but not insulin resistance, was a significant determinant of developing diabetes in subjects who had baseline KDS < 5. We confirmed that KDS as a 10-year risk model to predict diabetes becomes more potent when added to relevant laboratory parameters. Beta-cell function as assessed by IGI should be taken into account when predicting diabetes using the KDS. PMID- 28591044 TI - Factors associated with chronic musculoskeletal pain in Japanese community dwelling older adults: A cross-sectional study. AB - Identifying older adults with chronic musculoskeletal pain (CMP) earlier is urgent because CMP is reportedly associated with deterioration in physical function, poor psychological status, and low physical activity level. The objective of this study was to identify factors that were most strongly associated with CMP in Japanese community-dwelling older adults.Using a cross sectional design, we assessed 263 older adults (mean age = 79.1 +/- 5.9 years, 85.9% women) who participated in community exercise classes. Participants' physical function, psychological status, and activity levels were evaluated as outcome measures using a variety of tests and instruments. These assessments were conducted prior to beginning the exercise intervention program and compared participants with and without CMP. Additionally, relevant participant characteristics were collected and analyzed. In this study, CMP was defined as the presence of related symptoms within the past month that continued for at least 6 months and corresponded to a numerical rating scale of at least 5 or more at the site of maximum pain.A total of 143 (54.4%) participants met the criteria for CMP, and a high number of them had chronic lower back pain (64.3%). Outcome measures for the CMP group were significantly worse than for the non-CMP group (P < .05). Logistic regression analysis revealed that the Pain Catastrophizing Scale helplessness domain scores (odds ratio: 1.20, 95% confidence interval: 1.09-1.32) with an estimated value of 10 points was the factor most significantly associated with the presence of CMP.These findings suggest that assessment of the helplessness associated with pain-related catastrophizing is important for identification and the creation of interventions for older adults with CMP. PMID- 28591045 TI - The efficiency and safety of tranexamic acid for reducing blood loss in open myomectomy: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: This meta-analysis aimed to perform a meta-analysis including randomized controlled trials (RCTs) to assess the efficiency and safety of tranexamic acid (TXA) for reducing blood loss and transfusion requirements in patients undergoing open myomectomy. METHODS: A systematic search was performed in Medline (1966-2017.03), PubMed (1966-2017.03), Embase (1980-2017.03), ScienceDirect (1985-2017.03,) and the Cochrane Library. Study evaluated the efficiency and safety of TXA in myomectomy was selected. Meta-analysis was performed using Stata 11.0 software. RESULTS: Four RCTs including 328 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of total blood loss (standard mean difference [SMD] = -1.512, 95% confidence interval [CI]: -2.746 to -0.278, P = .016), postoperative hemoglobin level (SMD = 0.650, 95% CI: 0.045-1.255, P = .035), transfusion requirements (SMD = -0.102, 95% CI: -0.199 to -0.006, P = .038), and duration of surgery (SMD = -0.514, 95% CI: -0.749 to -0.280, P = .000). In addition, no adverse effect was identified in treatment groups. CONCLUSIONS: Intravenous administration of TXA in open myomectomy was associated with significantly reduced total blood loss, postoperative hemoglobin decline, duration of surgery, and transfusion requirements. Based on the limitations of the current meta-analysis, high-quality RCTs with long-term follow-up are still required. PMID- 28591047 TI - Inverted gastric adenocarcinoma of fundic gland mucosa type colliding with well differentiated adenocarcinoma: A case report. AB - RATIONALE: Gastric adenocarcinoma of fundic gland mucosa type (GA-FGM) is a rare tumor composed of atypical cells with differentiation toward the fundic gland as well as the foveolar epithelium. Including our case, only 9 cases of GA-FGMs were reported from 2010 to 2016. CONCERNS OF THE PATIENT: An 87-year-old man was referred to our institution for endoscopic resection of a gastric lesion. The tumor was classified as type 0-I + IIa according to the Paris classification. Magnifying endoscopy with narrow band imaging (ME-NBI) revealed different structures of crypts and vessels among the components, illustrating the collision of 2 types of gastric cancer. INTERVENTIONS: We performed endoscopic submucosal dissection and successfully removed the tumor en bloc. OUTCOMES: The histological findings differed markedly between the 0-I lesion and the 0-IIa lesion. The superficial part of the 0-I lesion consisted of a papillary structure, and the deeper part consisted of a tubular structure that showed inverted downward growth to the submucosal layer with the lamina muscularis mucosae. Immunohistochemically, the superficial part of the 0-I lesion was positive for MUC5AC, which had differentiated to foveolar epithelium. The deeper part was positive for pepsinogen-I and MUC6, which had differentiated to fundic gland. The 0-I lesion was diagnosed as gastric phenotype of adenocarcinoma differentiated to fundic gland mucosa with upward growth in the superficial part and downward growth in the deeper part. The 0-IIa lesion was composed of a tubular structure positive for MUC2, and it was diagnosed as an intestinal phenotype of well differentiated adenocarcinoma. The boundary was clear, and no transitional tissue was observed between the 0-I and 0-IIa lesions, suggesting that the 0-I + IIa lesion was a gastric collision tumor of GA-FGM and well differentiated adenocarcinoma. LESSONS: We herein report the first case of inverted GA-FGM colliding with well differentiated adenocarcinoma. ME-NBI can be used to diagnose GA-FGM even if the lesion collides with other types of adenocarcinoma. PMID- 28591046 TI - Immunogenicity study to investigate the interchangeability among three different types of polio vaccine: A cohort study in Japan. AB - In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naive infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer >=1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer >=1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer >=1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order. PMID- 28591048 TI - Effects of dexmedetomidine on sleep quality of patients after surgery without mechanical ventilation in ICU. AB - Sleep quality of patients in intensive care unit (ICU) has been recently recognized as an important aspect of the intensive care. Dexmedetomidine is one of the most recently introduced for sedation in the ICU. This study was designed to evaluate the effect of dexmedetomidine on sleep quality of patients without mechanical ventilation in ICU.The patients who were included in this study were divided into two groups. In the sedation group, dexmedetomidine was given by a continuous infusion targeting a sedation level -1 to -2 on the score of RASS (Richmond Agitation-Sedation Scale). In the no sedation group, the patients slept by themselves. No other sedatives were given. Bispectral Index (BIS) was performed on these hemodynamically stable critically ill patients for 12 consecutive hours. Sleep time and sleep depth were recorded.Twenty patients were studied. Compared to no sedation group, sleep efficiency and sleep time of patients in the sedation group was significantly higher during the night. Moreover, there was no significantly difference between the changes of blood pressure, heart rate, and respiratory rate.Dexmedetomidine is a clinically effective and safe sedative for the highly selected critically ill patients without endotracheal tube and mechanical ventilation in the ICU to increases total sleep time and improve sleep efficiency. PMID- 28591049 TI - Impact of serum SP-A and SP-D levels on comparison and prognosis of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis in general; however, it is heterogeneous to detect relative biomarkers for predicting the disease progression. Serum biomarkers can be conveniently collected to detect and help to differentially diagnose IPF and predict IPF prognosis. This meta-analysis aimed to evaluate the use of serum surfactant proteins A and D (SP-A and SP-D) for differential diagnosis and prognosis of IPF. METHODS: Relevant articles were searched in PubMed, Embase, and Chinese National Knowledge Infrastructure databases and reviewed by 2 independent readers. Standard mean difference (SMD) and 95% confidence interval (CI) were calculated to assess the difference in serum levels of SP-A/D among patients with IPF, when compared to patients with non-IPF interstitial lung disease (ILD), pulmonary infection, and healthy control. Hazard ratio (HR) and 95% CI were used to compare the relative risk of mortality. RESULTS: Twenty-one articles (totalling 1289 IPF patients) were included in final meta-analysis. Serum SP-A levels were significantly higher in patients with IPF than in patients with non-IPF ILD (SMD: 1.108 [0.584, 1.632], P < .001), or pulmonary infection (SMD: 1.320 [0.999, 1.640], P < .001) and healthy controls (SMD: 2.802 [1.901, 3.702], P < .001). There was no significant difference in serum SP-D levels between patients with IPF and those with non-IPF ILD patients (SMD: 0.459 [-0.000, 0.919], P = .050). Serum SP-D levels were significantly higher in patients with IPF than in patients with pulmonary infection (SMD: 1.308 [0.813, 1.803], P < .001) and healthy controls (SMD: 2.235 [1.739, 2.731], P < .001). Risk of death in patients with IPF and elevated serum SP-A was increased 39% compared to patients with low SP-A groups. Elevated SP-D increased risk by 111% when compared to low SP-D. In acute exacerbation of IPF, serum SP-A/D were higher than those in stable stage. The comparisons and prognosis might be different in Asian and Caucasian patients. CONCLUSIONS: Serum SP-A/D detection might be useful for differential diagnosis and prediction of survival in patients with IPF. PMID- 28591051 TI - Association between red blood cell distribution width and Henoch-Schonlein purpura nephritis. AB - To investigate whether red blood cell distribution width (RDW) is a marker of the risk of Henoch-Schonlein purpura (HSP) nephritis (HSPN), a total of 669 HSP patients and 168 healthy controls were included in this retrospective study. Two hundred fifty-six (38.3%) of the patients had kidney involvement. Compared with the HSP group, RDW was significantly higher in the HSPN group (P < .001). Binary logistic regression identified that HSPN was independently associated with age, RDW, platelet, and total cholesterol (odds ratio = 1.409, 1.353, 0.996, and 2.019, respectively). In addition, RDW values of HSPN patients with crescents on histopathology (classes III, IV, and V) were higher compared with those of HSPN without crescents (classes I and II) (P = .019). The receiver-operating characteristic curve analysis showed that the RDW at a cut-off point of 13.25 has 61% sensitivity and 79% specificity in predicting the presence of crescents on histopathology. It was first shown that RDW levels in HSPN are significantly higher than those in HSP without nephritis and healthy controls. RDW can be an independent predictor of HSPN and its levels greater than 13.25 were useful in the predicting the presence of crescents on histopathology. PMID- 28591052 TI - Effects of multidisciplinary team on emergency care for colorectal cancer patients: A nationwide-matched cohort study. AB - The literature describing the effectiveness of multidisciplinary team (MDT) for the care of colorectal cancer remains unclear. We investigated the effects of MDT care on the quality of colorectal cancer treatment, and the emergency department visit number was used as an indicator. In total, 45,418 patients newly diagnosed with colorectal cancer from the Taiwan National Health Insurance Research Database (2005-2009) were included. Propensity score matching with a ratio of 1:3 was adopted to reduce differences in characteristics between MDT care participants and non-MDT care participants. After matching, 3039 participation MDT care groups and 9117 nonparticipation groups were included and analyzed with chi and t tests, determine the distribution was similar. Without the control of variables, the percentage difference between participation and nonparticipation MDT care groups in utilization of emergency care was 0.03% (P > .05). The logistic regression model involving controlled variables demonstrated that odds ratio (OR) by probability of emergency care used for participation MDT care groups within a year of cancer diagnosis was less than that for nonparticipation (OR = 0.87, 95% confidence interval: 0.78-0.96). Large amount data were used and confirmed significant benefits of MDT in colorectal cancer care. PMID- 28591050 TI - Clinicopathological and prognostic significance of homeobox transcript antisense RNA expression in various cancers: A meta-analysis. AB - BACKGROUND: Increased expression of the homeobox (HOX) transcript antisense RNA (HOTAIR) has been reported in multiple types of malignancies and enhances the proliferation and migration of cancer cells. However, the association between HOTAIR expression and tumor progression and prognosis remains controversial. We performed a meta-analysis to clarify the association between the expression of HOTAIR and the clinicopathological features and prognosis in different cancers. METHODS: A systematic search of the PubMed, Web of Science, EMBASE, and Ovid databases was conducted, up to September 2016, for eligible studies involving HOTAIR expression and malignancies. The odds ratios (ORs), hazard ratios (HRs), and corresponding 95% confidence intervals (CIs) were calculated using fixed- or random-effect models. Any publication bias was evaluated using Begg and Egger tests, and adjusted using the trim and fill method if a bias existed. RESULTS: A total of 4116 patients from 44 studies were included in our meta-analysis. The results showed that high HOTAIR expression was associated with an advanced clinical tumor stage (OR = 3.90, 95% CI = 3.02-5.03, P < .001), lymph node metastasis (OR = 3.11, 95% CI = 2.15-4.49, P < .001), poor differentiation of the tumor (OR = 1.56, 95% CI = 1.01-2.41, P = .03), and worse prognosis (HR = 2.16, 95% CI = 1.73-2.69, P < .001) in different cancer types. HOTAIR expression was more predictive in monitoring the clinical tumor stage of patients and there was no significant heterogeneity or publication bias found in the analysis. CONCLUSION: Our meta-analysis suggests that HOTAIR is positively correlated with tumor development and negatively correlated with clinical outcome. Thus, an increase in HOTAIR expression may be a potential biomarker for tumor progression and evaluation of prognosis. PMID- 28591053 TI - Use of sugammadex in a patient with progressive muscular atrophy and in a patient with amyotrophic lateral sclerosis: Case report. AB - INTRODUCTION: We herein present 2 cases involving the combination of rocuronium and sugammadex in patients with motor neuron disease. The patients were a 54-year old man with progressive muscular atrophy who underwent removal of internal fixators in the arm and leg, and a 66-year-old woman with amyotrophic lateral sclerosis who underwent skin grafting in the left lower leg. General anesthesia was induced with propofol, rocuronium, and remifentanil and maintained with desflurane and remifentanil. At the end of the surgical procedure, we administered sugammadex. Three or 4 minutes after administration of sugammadex, the patients began to breathe spontaneously and were extubated without complications. CONCLUSION: Sugammadex can be used successfully to reverse neuromuscular blockade in patients with motor neuron disease. PMID- 28591054 TI - Thromboelastometry: Relation to the severity of liver cirrhosis in patients considered for liver transplantation. AB - The severity of liver disease is assessed by scoring systems, which include the conventional coagulation test prothrombin time-the international normalized ratio (PT-INR). However, PT-INR is not predictive of bleeding in liver disease and thromboelastometry (ROTEM) has been suggested to give a better overview of the coagulation system in these patients. It has now been suggested that coagulation as reflected by tromboelastomety may also be used for prognostic purposes. The objective of our study was to investigate whether thrombelastometry may discriminate the degree of liver insufficiency according to the scoring systems Child Pugh and Model for End-stage Liver Disease (MELD).Forty patients with chronic liver disease of different etiologies and stages were included in this observational cross-sectional study. The severity of liver disease was evaluated using the Child-Pugh score and the MELD score, and blood samples for biochemistry, conventional coagulation tests, and ROTEM were collected at the time of the final assessment for liver transplantation. Statistical comparisons for the studied parameters with scores of severity were made using Spearman correlation test and receiver-operating characteristic (ROC) curves.Spearman correlation coefficients indicated that the thromboelastometric parameters did not correlate with Child-Pugh or MELD scores. The ROC curves of the thromboelastometric parameters could not differentiate advanced stages from early stages of liver cirrhosis.Standard ROTEM cannot discriminate the stage of chronic liver disease in patients with severe chronic liver disease. PMID- 28591055 TI - Stereoelectroencephalography based on the Leksell stereotactic frame and Neurotech operation planning software. AB - This study aimed to introduce a new stereoelectroencephalography (SEEG) system based on Leksell stereotactic frame (L-SEEG) as well as Neurotech operation planning software, and to investigate its safety, applicability, and reliability.L-SEEG, without the help of navigation, includes SEEG operation planning software (Neurotech), Leksell stereotactic frame, and corresponding surgical instruments. Neurotech operation planning software can be used to display three-dimensional images of the cortex and cortical vessels and to plan the intracranial electrode implantation. In 44 refractory epilepsy patients, 364 intracranial electrodes were implanted through the L-SEEG system, and the postoperative complications such as bleeding, cerebral spinal fluid (CSF) leakage, infection, and electrode-related problems were also investigated.All electrodes were implanted accurately as preoperatively planned shown by postoperative lamina computed tomography and preoperative lamina magnetic resonance imaging. There was no severe complication after intracranial electrode implantation through the L-SEEG system. There were no electrode-related problems, no CSF leakage and no infection after surgery. All the patients recovered favorably after SEEG electrode implantation, and only 1 patient had asymptomatic frontal lateral ventricle hematoma (3 mL).The L-SEEG system with Neurotech operation planning software can be used for safe, accurate, and reliable intracranial electrode implantation for SEEG. PMID- 28591056 TI - Epidemiology and clinical analysis of critical patients with child maltreatment admitted to the intensive care units. AB - Children with abuse who are admitted to the intensive care unit (ICU) may have high mortality and morbidity and commonly require critical care immediately. It is important to understand the epidemiology and clinical characteristics of these critical cases of child maltreatment.We retrospectively evaluated the data for 355 children with maltreatments admitted to the ICU between 2001 and 2015. Clinical factors were analyzed and compared between the abuse and the neglect groups, including age, gender, season of admission, identifying settings, injury severity score (ISS), etiologies, length of stay (LOS) in the ICU, clinical outcomes, and mortality. In addition, neurologic assessments were conducted with the Pediatric Cerebral Performance Category (PCPC) scale.The most common type of child maltreatments was neglect (n = 259), followed by physical abuse (n = 96). The mean age of the abuse group was less than that of the neglect group (P < .05). Infants accounted for the majority of the abuse group, and the most common etiology of abuse was injury of the central nervous system (CNS). In the neglect group, most were of the preschool age and the most common etiologies of abuse were injury of the CNS and musculoskeletal system (P < .001). The mortality rate in the ICU was 9.86%. The ISS was significantly associated with mortality in both the 2 groups (both P < .05), whereas the LOS in the ICU and injuries of the CNS, musculoskeletal system, and respiratory system were all associated with mortality in the neglect group (all P < .05). The PCPC scale showed poor prognosis in the abuse group as compared to the neglect group (P < .01).In the ICU, children in the abuse group had younger age, higher ISS, and worse neurologic outcome than those in the neglect group. The ISS was a predictor for mortality in the abuse and neglect groups but the LOS in the ICUs, injuries of the CNS, musculoskeletal system, and respiratory system were indicators for mortality in the neglect group. Most importantly, identifying the epidemiological information may provide further strategies to reduce the harm, lower the medical costs, and improve clinical care quality and outcomes in children with abuse. PMID- 28591057 TI - Increase the risk of intellectual disability in children with scabies: A nationwide population-based cohort study. AB - Scabies is a common and distressing disease caused by the mite Sarcoptes scabiei var. hominis. Psychiatric disorder in childhood is an important disease and easily neglected. There are several similarities in scabies and psychiatric disorders in childhood (PDC). Both of them may present with pruritus. They are relatively common in patients with lower socioeconomic status and crowded environment. Furthermore, immune-mediated inflammatory processes play a role in the pathophysiology in both diseases. An association between scabies and psychiatric disorders may exist. This nationwide population-based cohort study utilized data from the National Health Insurance Research Database to investigate the relationship between scabies and PDC. A total of 2137 children with scabies were identified as the study group and 8548 age- and sex-matched children were selected as the control group. A total of 607 (5.68%) children developed PDC during the 7-year follow-up period. The overall incidences of PDC are similar but patients with scabies had a higher risk of developing intellectual disability (ID) (scabies group vs control group: 1.3% vs 0.6%, adjusted hazard ratio: 2.04 and 95% confidence interval: 1.25-3.32). The immune-mediated inflammatory processes of both diseases were reviewed and may contribute to the 104% increased risk of interleukin in patients with scabies. We suggest a more comprehensive management in treating patients with scabies or ID. Early and comprehensive treatment of scabies and other risk factors may decrease the risk of subsequent ID. When we approach patients with ID, concurrent evaluation of scabies and other risk factors may contribute to successful management. PMID- 28591059 TI - Left sinus of valsalva aneurysm ruptured into left ventricle: A case report of 320-multidetector CT findings. AB - RATIONALE: Ruptured aneurysm originating from the left coronary sinus of Valsalva into the left ventricle (LV) is extremely rare. Imaging features of sinus aneurysm has been commonly reported using echocardiography or angiography. Here, we report multidetector computed tomography (MDCT) findings of left sinus of Valsalva aneurysm extending into the LV and caused severe aortic regurgitation (AR) in a 44-year-old male with latent infective endocarditis. The role of MDCT in preoperative surgical planning was also emphasized. PATIENT CONCERNS: The patient visited our hospital due to worsening exertional dyspnea for 3 months. DIAGNOSES: On cardiac computed tomography (CT) using 320-MDCT, a saccular aneurysm arising from the left coronary sinus of Valsalva extending into the LV was diagnosed as the cause of severe AR. INTERVENTIONS: The patient underwent resection of the aneurysm, aortic root reconstruction, and aortic valve replacement. OUTCOMES: The patient made an uneventful recovery. Follow-up echocardiography showed no paravalvular leakage with improved LV function. LESSONS: MDCT with wide coverage and high temporal resolution can provide exact and comprehensive information about complicated conditions, leading to confident surgical planning and successful management. PMID- 28591058 TI - Primary hepatic malignant fibrous histiocytoma combined with invasion of inferior vena cava: A case report and literature review. AB - RATIONALE: Malignant fibrous histiocytoma (MFH), primary presented in liver, was very rare and displayed a poor prognosis because of high aggression. As a few of cases had been reported merely, we shared the case of primary hepatic MFH combined with invasion of inferior vena cava (IVC). PATIENTS CONCERNS: A 69-year old women presented with abdominal pain. DIAGNOSES: Abdominal computed tomography and magnetic resonance imaging indicated a soft mass about 5.4 * 4.2 cm in the caudate lobe, accompanied with IVC invaded. INTERVENTIONS: After the multidisciplinary consultation, laparotomy was performed, followed by chemotherapy and radiotherapy. Primary hepatic MFH was demonstrated pathologically. Till now, the patient was alive for >22 months after surgery and no evidence of recurrence or distant metastasis was suspected. OUTCOMES: We discussed the integrated procedure of diagnosis and treatment, combined with data from literature review. LESSONS: To our knowledge, the primary hepatic MFH combined with invasion of IVC was hardly reported. Despite the poor prognosis, the comprehensive treatment integrating the surgery, chemotherapy, and radiotherapy showed the satisfactory disease-free and overall survival. However, further investigations are definitely warranted. PMID- 28591060 TI - Body mass index is a practical preoperative nutritional index for postoperative infectious complications after intestinal resection in patients with Crohn's disease. AB - The patients with Crohn's disease (CD) are often accompanied with nutritional deficiencies. Compared with other intestinal benign disease, patients with CD have the higher risk of developing postoperative complications following intestinal resection. The aim of this study was to investigate the risk factors for postoperative infectious complications (PICs) after intestinal resection for CD, as well as search a practical preoperative nutritional index for PICs in patients with CD. A total of 122 patients who underwent intestinal resection for CD during 2011 to 2015 were retrospectively analyzed. After operation, 28 (22.95%) patients experienced PICs. Compared with the non-PICs group, the patients with PICs have the lower preoperative body mass index (BMI) (16.96 +/- 2.33 vs 19.53 +/- 2.49 kg/m, P < .001), lower albumin (ALB) (33.64 +/- 5.58 vs 36.55 +/- 5.69 g/L, P = .013), higher C-reactive protein (CRP) level (30.44 +/- 37.06 vs 15.99 +/- 33.30 mg/L, P = .052), and longer hospital stay (22.64 +/- 9.93 vs 8.90 +/- 4.32 days, P < .001). By analyzing the receiver-operating characteristic (ROC) curve, BMI have better value in predicting the occurrence of PICs than ALB. The areas under the ROC curves of BMI for PICs was 0.784 (95% confidence interval 0.690-0.878, P < .001) with an optimal diagnostic cut-off value of 17.5 kg/m. In the univariate and multivariate analysis, BMI < 17.5 kg/m (P = .001), ALB < 33.6 g/L (P = .024), CRP >= 10 mg/L (P = .026) were risk factors for PICs. Patients with a lower preoperative BMI (BMI < 17.5 kg/m) had a 7.35 times greater risk of PICs. Therefore, preoperative BMI could be regarded as a practical preoperative nutritional index for evaluating the nutritional preparation sufficiency before CD operations. Preoperative treatment with the aim of reducing CRP level and improving the patient's nutritional status may be helpful to reduce the rate of PICs. PMID- 28591061 TI - Effects of elastic resistance exercise on body composition and physical capacity in older women with sarcopenic obesity: A CONSORT-compliant prospective randomized controlled trial. AB - BACKGROUND: Sarcopenia is associated with loss of muscle mass and an increased risk of physical disability in elderly people. However, the prevalence of sarcopenia has increased in obese elderly populations. The purpose of this study was to identify the clinical efficacy of elastic resistance exercise training (RET) in patients with sarcopenic obesity. METHODS: This study was conducted at the rehabilitation center of a university-based teaching hospital and was designed as a prospective and randomized controlled trial with an intention-to treat analysis. A total of 46 women aged 67.3 (5.2) years were randomly assigned to an experimental group (EG) and control group (CG). The EG underwent elastic RET for 12 weeks, and the CG received no RET intervention. All outcome measures were assessed at the baseline and posttest, including body composition measured using dual-energy X-ray absorptiometry, muscle quality (MQ) defined as a ratio of muscular strength to muscle mass, and physical capacity assessed using functional mobility tests. One-way analysis of covariance and Pearson correlation were used to compare outcomes between the 2 groups and to identify the relationship between changes in body composition and physical outcomes, respectively. A chi-square test was performed to identify differences in qualitative data between the 2 groups. RESULTS: At the posttest, a significant between-group difference was observed in fat-free mass, MQ, and physical capacity (all P < .05); and a significant correlation was found between leg-lean-mass change and gait speed (r = 0.36; P < .05). After 12 weeks of elastic RET intervention, the EG had significantly fewer patients exhibiting sarcopenia (P < .05) and experiencing physical difficulty (P < .001) than the CG. CONCLUSION: The present data suggest that elastic resistance exercise exerted benefits on the body composition, MQ, and physical function in patients with sarcopenic obesity. Regular exercise incorporating elastic RET should be used to attenuate muscle mass loss and prevent physical difficulty in obese older adults with sarcopenia on reconditioning therapy. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-15006069. PMID- 28591062 TI - Extracranial bone metastases from recurrent anaplastic astrocytoma on FDG PET/CT: A case report a care-compliant article. AB - OBJECTIVE: Extracranial bone metastases from astrocytoma are rare and frequently detected as part of multiorgan metastases. It is extremely rare for astrocytoma to have extracranial bone metastases alone. The importance of whole-body fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging in evaluating extracranial metastasis (ECMs) has not been described effectively due to the rarity of this event. The purpose of our case report is to emphasize the role of FDG PET/CT in the assessment of tumor recurrence and extracranial bone metastases from anaplastic astrocytoma. METHODS AND MATERIALS: A 25-year-old woman was firstly admitted with a 4-month history of progressive blurred vision, and 2-month history of intermittent headache. Presurgical MRI imaging revealed a large mass in the left trigone of lateral ventricle. Subsequently, she underwent tumor resection, radiotherapy and chemotherapy. A final pathological diagnosis of anaplastic astrocytoma (WHO III) was made. Nearly 12 months after the surgery, the follow-up brain MR imaging revealed a contrast enhanced lesion in the site of operative region. Whole-body FDG PET/CT imaging was performed to evaluate the situation. RESULTS: Postoperative brain FDG PET/CT showed an abnormal focal FDG uptake corresponding to the contrast-enhanced lesion in the operative area, suggesting a tumor recurrence. Whole-body FDG PET/CT also showed multiple FDG-avid osteosclerotic lesions in the body. It was highly suggestive of extracranial bone metastases. A subsequent open bone biopsy of FDG avid lesion in right iliac crest was performed. Histopathological and immunohistochemical findings indicated characteristic of glioma. The patient died 1 month later, nearly 13 months after the initial diagnosis. CONCLUSIONS: ECMs from anaplastic astrocytoma are extremely rare but they do occur. Whole-body FDG PET/CT imaging with inclusion of brain was valuable in differentiating tumor recurrence from radiation necrosis and in detecting uncommon extracranial bone metastases from anaplastic astrocytoma, which were closely related to prognosis of this disease. PMID- 28591063 TI - A new technique for lipid core plaque detection by optical coherence tomography for prevention of peri-procedural myocardial infarction: A case report. AB - RATIONALE: Percutaneous coronary intervention (PCI) provides effective revascularization of atherosclerotic coronary arteries but the invasive nature of treatment can result in complications. PATIENT CONCERNS: A 53-year old man underwent coronary angiography due to chest pain with minimal ST-segment elevation in the inferior leads of the electrocardiogram. DIAGNOSIS: We proceeded directly to coronary angiography and delineated a moderate stenosis with haziness in the mid right coronary artery (RCA). INTERVENTIONS: Expert analysis of the pre intervention OCT imaging demonstrated a large lipid core plaque (LCP), upstream of the culprit site, with minimal thrombus burden. Subsequent implantation of a bioresorbable vascular scaffold, protected with distal deployment of a filter protection device provided an excellent result with retrieval of plaque material. Post-hoc attenuation analysis confirmed the presence of large LCP. OUTCOMES: A post-procedural transthoracic echocardiogram confirmed good left ventricular function with no regional wall motion abnormality. An excellent clinical outcome was achieved. LESSONS: Optical coherence tomography (OCT) derived attenuation analysis can provide with qualitative and quantitative detailed evaluation of the underlying plaque substrate. Our case shows OCT can provide the interventionist with qualitative and qualitative assessment of large LCP for prevention of periprocedural complications, which may improve outcome for PCI. PMID- 28591064 TI - Clinical Documentation Improvement and Nursing Informatics. PMID- 28591065 TI - The Evolution of the TIGER Initiative. PMID- 28591066 TI - Understanding Nurses' Strategies to Handle (Un)wanted Nurse Calls: A Resilience Perspective. PMID- 28591068 TI - World Gastroenterology Organisation News and Events. PMID- 28591067 TI - Bergamot Polyphenolic Fraction Supplementation Improves Cognitive Functioning in Schizophrenia: Data From an 8-Week, Open-Label Pilot Study. AB - BACKGROUND: Novel treatment strategies for cognitive dysfunctions may prevent long-term disability in patients with schizophrenia, and polyphenolic compounds might be a promising strategy. Bergamot (Citrus bergamia), a citrus fruit characterized by a high amount of flavonoids and flavonoid glycosides, may represent a potential nutraceutical approach to cognitive dysfunction. The present study was aimed to explore the efficacy of bergamot polyphenolic fraction (BPF) supplementation on cognitive/executive functioning in a sample of patients with schizophrenia receiving second-generation antipsychotics. METHODS: Twenty outpatients treated with second-generation antipsychotics assumed BPF at an oral daily dose of 1000 mg/d for 8 weeks. Brief Psychiatric Rating Scale, Wisconsin Card Sorting Test (WCST), Verbal Fluency Task-Controlled Oral Word Association Test, and Stroop Color-Word Test were administered. RESULTS: At end point, (week 8) BPF supplementation significantly improved WCST "perseverative errors" (P = 0.004) and semantic fluency test (P = 0.004). Moreover, a trend for other cognitive variable (WCST "categories," phonemic fluency, and Stroop Color-Word Test) improvement was observed. CONCLUSIONS: The findings provide evidence that BPF administration may be proposed as a potential supplementation strategy to improve cognitive outcome in schizophrenia. Further clinical trials with adequately powered and well-designed methodology are needed to better explore the BPF effectiveness on cognitive impairments in patients with schizophrenia. PMID- 28591069 TI - World Gastroenterology Organisation Global Guidelines: GERD Global Perspective on Gastroesophageal Reflux Disease. PMID- 28591071 TI - Comparison of Intra-articular Thoracic Facet Joint Steroid Injection and Thoracic Medial Branch Block for the Management of Thoracic Facet Joint Pain. AB - STUDY DESIGN: A prospective observational study. OBJECTIVE: The aim of this study was to show the effect of intra-articular (IA) thoracic facet joint (TFJ) steroid injection for the management of TFJ pain, and to compare it with the effect of therapeutic thoracic medial branch block (MBB) with a local anesthetic and steroid. SUMMARY OF BACKGROUND DATA: Several studies have shown the effects of thoracic MBB with local anesthetics with or without steroids and radiofrequency neurotomy in managing TFJ pain, but thus far, the effectiveness of IA TFJ steroid injection has not been studied. METHODS: Forty patients with TFJ pain were recruited and randomly assigned to one of two groups, the IA steroid injection and the MBB group, each with 20 patients. For IA TFJ steroid injection and therapeutic MBB, we injected 0.5 mL of 0.5% bupivacaine, mixed with 10 mg (0.25 mL) of dexamethasone. We assessed the severity of TFJ pain using a numeric rating scale (NRS) before treatment and at 1, 3, and 6 months after treatment. RESULTS: Compared to the pretreatment NRS scores, the NRS scores at 1, 3, and 6 months after each treatment showed a significant decrease in patients in both the groups. Intergroup changes in the NRS scores were not significantly different over time. Six months after the treatment, 65% of the patients in the IA steroid injection group reported successful pain relief (pain relief >=50%), and 40% of the patients in the MBB group showed successful pain relief. CONCLUSION: In the present study, both IA TFJ steroid injection and therapeutic MBB significantly relieved TFJ pain. Their effects persisted for at least 6 months after the procedure. Thus, we think that both IA TFJ steroid injection and therapeutic thoracic MBB are useful treatment options for managing TFJ pain. LEVEL OF EVIDENCE: 2. PMID- 28591070 TI - Emerging Gastrointestinal and Liver Diseases in Asia Pacific: Implications to Health Care in the Region (World Gastroenterology Organization: Asian Pacific Association of Gastroenterology Distinguished Global Lecture 2015). AB - Colorectal cancer (CRC), gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), and nonalcoholic fatty liver disease are considered important emerging diseases in the Asia Pacific (AP) region. The incidence rate of CRC is the highest among gastrointestinal cancers in the region surpassing that of gastric cancer. However, population CRC screening is limited by availability of adequate health resources and financing. GERD is a highly prevalent disease in AP with the prevalence of GERD symptoms and reflux esophagitis reported to be increasing. The usage of proton pump inhibitors has also been reported to be high. The incidence and prevalence of IBD is not as high as in the west but is now an increasingly recognizable disease in the AP region. Being a complicated disease, IBD will pose a huge financial burden with the increasing use of expensive biological drugs. In tandem with the exponential increase in obesity and diabetes mellitus in AP, nonalcoholic fatty liver disease will become the most important liver disease in the region in the coming years. These emerging diseases reflect the continued fast-paced socioeconomic development in the region with marked lifestyle changes and increasing affluence. PMID- 28591072 TI - Incremental Hospital Cost and Length-of-stay Associated With Treating Adverse Events Among Medicare Beneficiaries Undergoing Cervical Spinal Fusion During Fiscal Year 2013 and 2014. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To report the incremental hospital resources consumed with treating adverse events experienced by Medicare beneficiaries undergoing a two or three vertebrae level cervical spinal fusion. SUMMARY OF BACKGROUND DATA: Hospitals are increasingly at financial risk for patients experiencing adverse events due "pay for performance." Little is known about incremental resources consumed when treating patients who experienced an adverse event after cervical spinal fusions. METHODS: Fiscal years 2013 and 2014 Medicare Provider Analysis and Review file was used to identify 86,265 beneficiaries who underwent 2 or 3 vertebrae level cervical spinal fusion. International Classification of Diseases 9th Clinical Modification diagnostic and procedure codes were used to identify 10 adverse events. This study estimated both the observed and risk-adjusted incremental hospital resources consumed (cost [2014 US $] and length-of-stay) in treating beneficiaries experiencing each adverse event. RESULTS: Overall, 6.2% of beneficiaries undergoing cervical spinal fusion experienced at least one of the study's adverse events. Beneficiaries experiencing any complication consumed significantly more hospital resources (incremental cost of $28,638) and had longer length-of-stay (incremental stays of 9.1 days). After adjusting for patient demographics and comorbid conditions, incremental cost of treating adverse events ranged from $42,358 (infection) to $10,100 (dural tear). CONCLUSION: Adverse events frequently occur and add substantially to the hospital costs of patients undergoing cervical spinal fusion. Shared decision-making instruments should clearly provide these risk estimates to the patient before surgical consideration. Investment in activities that have been shown to reduce specific adverse events is warranted, and this study may allow health systems to prioritize performance improvement areas. LEVEL OF EVIDENCE: 3. PMID- 28591073 TI - Predictors of Persistent Axial Neck Pain After Cervical Laminoplasty. AB - STUDY DESIGN: Retrospective analysis of prospective data. OBJECTIVE: The aim of this study was to reveal baseline predictors of persistent postlaminoplasty neck pain. SUMMARY OF BACKGROUND DATA: Axial neck pain is one of the most common complications after cervical laminoplasty; however, baseline predictors of persistent postlaminoplasty neck pain are unclear. METHODS: We analyzed data from 156 patients who completed a 2-year follow-up after double-door laminoplasty for degenerative cervical myelopathy. Patients rated the average intensity of axial neck pain in the last month using an 11-point numerical rating scale preoperatively and at the 2-year follow-up. The dependent variable was the presence of moderate-to-severe neck pain (numerical rating scale >=4) at the 2 year follow-up. The independent variables included patient characteristics, baseline radiological parameters, surgical variables, baseline axial neck pain intensity, and baseline functions, which were measured by the Japanese Orthopaedic Association score and the Short Form-36 survey (SF-36). Logistic regression analysis was performed to identify independent predictors of moderate to-severe neck pain after laminoplasty. RESULTS: At the 2-year follow-up, 51 patients (32%) had moderate-to-severe neck pain, and 106 patients (68%) had no or mild pain. Univariate analysis revealed that the ratio of cervical anterolisthesis, ratio of current smoking, baseline neck pain intensity, and baseline SF-36 Mental Component Summary differed significantly between the groups. Multivariate logistic regression analysis showed that independent predictors of moderate-to-severe neck pain at the 2-year follow-up include the presence of anterolisthesis, current smoking, moderate-to-severe baseline neck pain, and lower SF-36 Mental Component Summary. The presence of anterolisthesis and moderate-to-severe baseline neck pain were also associated with significantly poorer physical function after surgery. CONCLUSION: The presence of anterolisthesis was associated not only with the highest odds ratio of persistent neck pain but also with significantly poorer functional outcomes. Indications for cervical laminoplasty should be carefully determined in patients with cervical anterolisthesis. LEVEL OF EVIDENCE: 4. PMID- 28591074 TI - Different Fusion Approaches for Single-level Lumbar Spondylolysis Have Similar Perioperative Outcomes. AB - STUDY DESIGN: Retrospective cohort study OBJECTIVE.: The aim of this study was to compare perioperative adverse events for patients with lumbar spondylolysis treated with transforaminal lumbar interbody fusion (TLIF), posterior spinal fusion (PSF), combined anterior and posterior fusion (AP fusion), or anterior lumbar interbody fusion (ALIF). SUMMARY OF BACKGROUND DATA: Previous cohort studies have shown similar long-term outcomes for different surgical approaches for this indication, but potential differences in 30-day perioperative adverse events have not been well characterized. METHODS: The present study uses data extracted from the American College of Surgeons National Surgical Quality Improvement Database. Patients undergoing fusion with different approaches for lumbar spondylolysis were identified. Propensity score matching was utilized to account for potential differences in demographic and comorbidity factors. Comparisons among perioperative outcomes were then made among the propensity score-matched study groups. RESULTS: Of 1077 cases of spondylolysis identified, 556 underwent TLIF, 327 underwent PSF, 108 underwent AP fusion, and 86 underwent ALIF. After propensity score matching, there were no differences in the rates of any of the 30-day individual adverse events studied and no differences in the aggregated groupings of any adverse event, serious adverse event, or minor adverse event. There was a significantly increased operative time in the AP fusion group, but there were no differences in hospital length of stay or readmission rates. CONCLUSION: Because perioperative adverse event rates were similar, even with a slightly longer operative time in the AP fusion group, these findings suggest that surgeon preference and long-term outcomes are better used to determine the recommendation of one surgical approach over another for single level fusions for lumbar spondylolysis. LEVEL OF EVIDENCE: 3. PMID- 28591075 TI - Comparison of the Vacuum Mattress versus the Spine Board Alone for Immobilization of the Cervical Spine Injured Patient: A Biomechanical Cadaveric Study. AB - STUDY DESIGN: A biomechanical cadaveric study. OBJECTIVE: We sought to determine the amount of motion generated in an unstable cervical spine fracture with use of the vacuum mattress versus the spine board alone. Our hypothesis is that the vacuum mattress will better immobilize an unstable cervical fracture. SUMMARY OF BACKGROUND DATA: Trauma patients in the United States are immobilized on a rigid spine board, whereas in many other places, vacuum mattresses are used with the proposed advantages of improved comfort and better immobilization of the spine. METHODS: Unstable subaxial cervical injuries were surgically created in five fresh whole human cadavers. The amount of motion at the injured motion segment during testing was measured using a Fastrak, three-dimensional, electromagnetic motion analysis device (Polhemus Inc.). The measurements recorded in this investigation included maximum displacements during application and removal of the device, while tilting to 90 degrees , during a bed transfer, and a lift onto a gurney. Linear and angular displacements were compared using the Generalized Linear Model analysis of variance for repeated measures for each of the six dependent variables (three planes of angulations and three axes of displacement). RESULTS: There was more motion in all six planes of motion during the application process with use of the spine board alone, and this was statistically significant for axial rotation (P = 0.011), axial distraction (P = 0.035), medial-lateral translation (P = 0.027), and anteroposterior translation (P = 0.026). During tilting, there was more motion with just the spine board, but this was only statistically significant for anteroposterior translation (P = 0.033). With lifting onto the gurney, there was more motion with the spine board in all planes with statistical significance, except lateral bending. During the removal process, there was more motion with the spine board alone, and this was statistically significant for axial rotation (P = 0.035), lateral bending (P = 0.044), and axial distraction (P = 0.023). CONCLUSION: There was more motion when using a spine board alone during typical maneuvers performed during early management of the spine injured patient than the vacuum mattress. There may be benefit of use of the vacuum mattress versus the spine board alone in preventing motion at an unstable, subaxial cervical spine injury. LEVEL OF EVIDENCE: 2. PMID- 28591076 TI - Is Traditional Closed Thoracic Drainage Necessary to Treat Pleural Tears After Posterior Approach Thoracic Spine Surgery? AB - STUDY DESIGN: A prospective study. OBJECTIVE: The aim of this study was to evaluate the outcomes and efficacy of using a 10Fr elastic tube with a regular negative pressure ball to treat the operative pleural tear in the complicated single-stage posterior approach thoracic spine surgeries. SUMMARY OF BACKGROUND DATA: In some complicated single-stage posterior approach thoracic spine surgeries, such as total en bloc spondylectomy, pleural tear is quite inevitable. Traditional chest tube with a water-sealed bottle has many shortcomings, as pain, inconvenience, and other complications. In many thoracic surgeries, a smaller caliber elastic tube has been used to avoid such complications and achieve quick recovery. However, there are concerns about the efficacy and safety of the smaller-caliber elastic tube. METHODS: A prospective trial was performed in 72 patients between April 2008 and March 2012. Pleural tear occurred in 19 patients, among whom 10 patients were inserted a 10Fr elastic tube with a regular negative pressure ball (Group I), and nine were inserted a 28Fr chest tube with a water sealed bottle (Group II). Comparative evaluation of the clinical and radiographic data was carried out. RESULTS: The basic condition of two groups did not differ significantly. The oxygen saturation monitor, hospital length of stay, average volume, and failure rate of drainage between two groups were not statistically significant. The difference of the visual analog score was significant (1.10 +/- 0.35 vs. 3.89 +/- 0.59, P < 0.001). CONCLUSION: Patients who received a 10Fr elastic tube with a regular negative pressure ball experienced less pain and a tendency of quicker recovery than those who received a 28Fr chest tube with a water-sealed bottle. The complication rate in Group I was not higher than Group II, indicating an equally good drainage efficacy. LEVEL OF EVIDENCE: 2. PMID- 28591077 TI - Progressive Bone Formation After Cervical Disc Replacement: Minimum of 5-Year Follow-up. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: Our objective was to examine the prevalence, clinical significance, ramifications, and possible etiology of postoperative bone formation at the index level after cervical disc replacement (CDR) with a minimum of 5 years of follow-up. SUMMARY OF BACKGROUND DATA: CDR can be complicated by postoperative ossification and unwanted ankylosis at the index level, which some authors have termed "heterotopic ossification." This terminology may be inaccurate as it assumes the postoperative bone formation is unnatural and a consequence of the CDR surgery. We advocate that this phenomenon has more to do with individual patient factors rather than the surgery. METHODS: Patients who underwent Bryan CDR for cervical myelopathy or radiculopathy between 12/2003 and 8/2008 with a minimum of 5-years follow-up were analyzed. They were divided into two groups, those with and without postoperative bone formation. Patient-reported outcomes (Japanese Orthopaedic Association score, Neck Disability Index, Visual Analogue Scale for neck and arm pain) and radiographic parameters were collected pre- and postoperatively and compared between groups. RESULTS: Sixty-one patients (76 levels) were identified (mean follow-up 94.2 mo). The overall incidence of postoperative ossification was 50%. Both groups had sustained significant improvements across all patient-reported outcome measures at final follow-up. Notably, patients with more severe preoperative cervical spondylosis had higher rates of postoperative ossification (P = 0.036) and adjacent segment degeneration (P = 0.010). CONCLUSION: Although the long-term incidence of postoperative bone formation after CDR was relatively high, this did not adversely affect patient outcomes. Patients with more severe preoperative spondylosis had higher rates of postoperative ossification, suggesting that postoperative ossification at the CDR segment is likely one of progressive bone formation in individuals already predisposed to forming bone rather than one of alleged heterotopic ossification as a consequence of the surgery. LEVEL OF EVIDENCE: 3. PMID- 28591078 TI - Proximal Junctional Kyphosis: Inter- and Intra-observer Reliability of Radiographic Measurements in Adult Spinal Deformity. AB - STUDY DESIGN: Reliability study of radiographic measures of proximal junctional kyphosis in adult spinal deformity patients. OBJECTIVE: Assess impacts of level of proximal endpoint and vertebral fracture on reliability of measurement of junctional kyphosis. SUMMARY OF BACKGROUND DATA: Radiographic assessment is important in determining management of patients with Proximal Junctional Kyphosis (PJK) or Proximal Junctional Failure (PJF). No study to date has evaluated the reliability of radiographic measurement of the junctional kyphotic angle after surgery for Adult Spinal Deformity (ASD). METHODS: Post-operative radiographs from 52 ASD patients were divided into four categories based on the level of the upper instrumented vertebra (UIV) and the presence or absence of PJF: upper thoracic without failure (UT), thoracolumbar without failure (TL), upper thoracic with PJF (UTF) and thoracolumbar with PJF (TLF). Nine surgeon reviewers performed radiographic measurements of kyphosis between UIV+2 and UIV twice at least 4 weeks apart. Intraclass correlation coefficients (ICC) were calculated to determine inter- and intra-observer reliability. RESULTS: Inter-observer reliability for measurements of UT, TL, UTF, TLF were all "almost perfect" with ICC scores of 0.917, 0.965, 0.956, 0.882, and 0.932, 0.975, 0958, 0.989, for sessions 1 and 2 respectively. Similarly, ICC's for kyphosis measurements for the TL and TLF group had "almost perfect" agreement with means of 0.898 (range: 0.817 0.969) and 0.976 (range: 0.931-0.995), respectively. ICC's for measurements for the UT and UTF groups all had "substantial" or "almost perfect" agreement with means of 0.801 (range: 0.662-0.942) and 0.879 (range: 0.760-0.988), respectively. CONCLUSION: This study demonstrates high inter- and intra-observer reliability of proximal junctional kyphosis measurement following instrumented fusion for ASD, independent of the presence or absence of PJF. Although slightly lower for upper thoracic than for thoracolumbar proximal endpoints, all ICC's consistently reached at least "substantial agreement" and "near perfect agreement" for most. LEVEL OF EVIDENCE: 4. PMID- 28591080 TI - Muscle Pain Induces a Shift of the Spatial Distribution of Upper Trapezius Muscle Activity During a Repetitive Task: A Mechanism for Perpetuation of Pain With Repetitive Activity? AB - OBJECTIVE: An association exists between repetitive movements and the development or perpetuation of neck-shoulder muscle pain. The mechanisms underlying this association remain unclear. This observational study investigated the effect of upper trapezius muscle pain on the distribution of upper trapezius activity during repetitive lifting. It was hypothesized that nociception would change the distribution of activity resulting in activation of muscle regions which would not normally be active during the task. MATERIALS AND METHODS: Healthy men repeatedly lifted a box with a cycle time of 3 seconds for 50 cycles, at baseline, following injection of isotonic and hypertonic saline into the upper trapezius muscle and 15 minutes after the last injection. High-density surface electromyography (EMG) was recorded from the upper trapezius using a grid of 64 electrodes. The EMG amplitude was computed for each location to form a map of the EMG amplitude distribution. RESULTS: During the painful condition, the overall EMG amplitude was lower compared with all other conditions (P<0.05) and in addition, the center of upper trapezius activity was shifted toward the caudal region of the muscle (P<0.01), a region not normally active during the task. The described alterations of muscle activity likely play an important role in the perpetuation of pain during repetitive activity. DISCUSSION: Novel mapping of the spatial distribution of upper trapezius muscle activity showed that nociception induced a redistribution of activity during repetitive lifting. This knowledge provides new insights into the mechanisms underlying the perpetuation of pain with repetitive activity. PMID- 28591081 TI - Pain-related Activity Management Patterns and Function in Patients With Fibromyalgia Syndrome. AB - OBJECTIVES: To clarify the importance of avoidance, pacing, and overdoing pain related activity management patterns as predictors of adjustment in patients with fibromyalgia syndrome. METHODS: A total of 119 tertiary care patients with fibromyalgia syndrome who agreed to be part of an activity management pain program completed a survey, which requested information about demographics, pain intensity and pain interference, psychological and physical function, and pain related activity management patterns. Hierarchical regression analyses were used to identify the unique contributions of the 3 different pain-related activity management patterns (avoidance, pacing, and overdoing) to the prediction of pain interference, psychological function, and physical function. RESULTS: The avoidance pattern was a significant and unique predictor of worse psychological and physical function as well as greater pain interference. Pacing was significantly associated with less pain interference and better psychological function, whereas overdoing was not found to predict patient functioning. DISCUSSION: The findings confirm the importance of pain-related activity management patterns as predictors of patient function, and support the necessity of addressing these factors in chronic pain treatment. In addition, the results suggest that targeting increases in activity pacing and decreases in pain avoidance, specifically, might yield the best patient outcomes. However, further research to evaluate this possibility is necessary. PMID- 28591082 TI - Opioid-sparing Effects of SoluMatrix Indomethacin in a Phase 3 Study in Patients With Acute Postoperative Pain. AB - OBJECTIVES: To report the opioid-sparing effects of SoluMatrix indomethacin, developed using SoluMatrix Fine Particle Technology, in a phase 3 study in patients with acute pain following bunionectomy. METHODS: This phase 3, placebo controlled study randomized 462 patients with moderate-to-severe pain following bunionectomy surgery to receive SoluMatrix indomethacin 40 mg 3 times daily, SoluMatrix indomethacin 40 mg twice daily, SoluMatrix indomethacin 20 mg 3 times daily, celecoxib 400-mg loading dose followed by 200 mg twice daily, or placebo. Patients were permitted to receive opioid-containing rescue medication throughout the study. The proportion of patients who used rescue medication and the amount of rescue medication used on the first (0 to 24 h) and second (>24 to 48 h) days following initial dose of study medication, as well as time to first rescue medication use, were assessed. RESULTS: Significantly fewer patients who received SoluMatrix indomethacin 40 or 20 mg 3 times daily used opioid-containing rescue medication on day 1 compared with those receiving placebo (P<=0.034), and fewer patients in all active treatment groups used rescue medication during the second day compared with those in the placebo group (P<0.001). All active treatment groups used significantly fewer rescue medication tablets on days 1 and 2 following randomization compared with placebo (P<0.001). The most common adverse events were nausea, postprocedural edema, and headache. DISCUSSION: SoluMatrix indomethacin was associated with opioid-sparing effects in patients with acute postoperative pain. PMID- 28591079 TI - Genetic analyses of HIV env associated with uveitis in antiretroviral-naive individuals. AB - OBJECTIVE: To analyze and compare HIV-1 env sequences from the eye to those from the blood of individuals with uveitis attributed to HIV with the goal of gaining insight into the pathogenesis of HIV-associated eye disease. DESIGN: A prospective case series of five HIV-infected antiretroviral-naive individuals with uveitis negative for other pathogens. METHODS: RNA from blood plasma and ocular aqueous humor was reverse transcribed using random hexamers. HIV env C2-V5 (HXB2: 6990-7668) sequences were generated by single-genome amplification using nested polymerase chain reaction followed by bidirectional Sanger sequencing. Sequence analyses by Geneious, Geno2Pheno, N-GLYCOSITE, DIVEIN, and HyPhy evaluated relationships between HIV in plasma and aqueous humor. RESULTS: A median of 20 (range: 13-22) plasma and 15 (range: 9-18) aqueous humor sequences were generated from each individual. The frequencies of sequences with predicted N-linked-glycosylation sites and C-X-C chemokine receptor type 4 were comparable in aqueous humor and plasma of all five patients. Aqueous humor sequences had lower median genetic diversity compared with plasma across all patients, but similar divergence, in four of five patients. Aqueous humor HIV sequences were compartmentalized from plasma across subjects by Critchlow correlation coefficient, Slatkin and Maddison, nearest-neighbor statistic, and Fixation index. CONCLUSION: Among antiretroviral-naive individuals with uveitis attributed to HIV, the universal compartmentalization and decreased diversity of eye compared with blood sequences suggests time-limited passage of a small subset of variants from each patient's viral population into the eye tissues, followed by limited immune selection despite the inflammatory uveitis. PMID- 28591083 TI - Investigating the Fear Avoidance Model in People With Whiplash: The Association Between Fear of Movement and In Vivo Activity. AB - OBJECTIVES: The aims of this study were to examine the relationship between fear of movement and activity levels in people with whiplash-associated disorders (WAD) over the first 3 months postinjury, to determine the mediating effect of: fear of movement on the relationship between catastrophizing and activity levels, and activity levels on the relationship between fear of movement and disability in patients with WAD. MATERIALS AND METHODS: Ambulatory monitoring of physical activity was conducted for a minimum of 8 waking hours on 2 consecutive days within 4 weeks postinjury and at 12 weeks postinjury for 103 (74 female) people with WAD. Time spent in upright postures (uptime) and time in motion (TIM) were collected along with measures of pain, disability, pain catastrophizing, and fear of movement. The association of self-report outcome measures with uptime and TIM were examined. Mediation analyses were performed to determine the mediating effect of: fear of movement on the relationship between catastrophizing and activity, and activity levels on the relationship between fear of movement and disability. RESULTS: Fear of movement was significantly related to uptime but not TIM. Mediation analyses showed that the relationship between fear of movement and disability was not mediated by activity levels, and that the relationship between catastrophizing and activity levels was not mediated by fear of movement. DISCUSSION: Our data suggests measures of Fear Avoidance Model are not related to general physical activity in people with WAD. Investigation of movements specific to the cervical spine and alternative explanatory models may be required. PMID- 28591084 TI - Efficacy of Postoperative Analgesia of Local Ketamine Wound Instillation Following Total Thyroidectomy: A Randomized, Double-blind, Controlled Clinical Trial. AB - BACKGROUND: Total thyroidectomy is recommended as a line of management of thyroid cancer in many cases. Our aim was to compare postoperative analgesic effect of local ketamine 1 mg/kg instilled in the wound to that of intramuscular (IM) ketamine and placebo after total thyroidectomy. METHODS: A total of 90 patients aged 18 to 60 years, American Society of Anesthesiologists (ASA) class I to II, with a body weight of 50 to 90 kg, scheduled for total thyroidectomy were enrolled after ethics committee approval in this prospective, randomized, double blind, controlled study and divided randomly into 3 groups to receive treatment after hemostasis. Group (I) received 1 mg/kg ketamine in a total volume of 10 mL normal saline instilled in the wound. Group (II) received 1 mg/kg of IM ketamine. Group (III) received 10 mL of normal saline instilled in the wound. Total amount of morphine consumption, first request of analgesia, and side effects were recorded. Visual analog scale at rest and movement and hemodynamics were assessed immediately, 1, 2, 4, 6, 12, and 24 hours postoperatively. RESULTS: Total morphine consumption was reduced and first request of analgesia was delayed in group I compared with that in groups II and III, and in group II compared with that in group III (P=0.000). Visual analog scale at rest and movement were decreased immediately postoperatively in groups I and II in comparison with their values in group III; group II had higher sedation scores. CONCLUSIONS: Local wound ketamine instillation provided superior postoperative analgesia with lower incidence of side effects in comparison with IM ketamine and placebo following total thyroidectomy. PMID- 28591085 TI - Influence of OPRM1 Polymorphism on Postoperative Pain After Intrathecal Morphine Administration in Italian Patients Undergoing Elective Cesarean Section. AB - OBJECTIVES: The aim of this prospective observational study was to evaluate the influence of OPRM1 polymorphism on the analgesic efficacy (including visual analog scale [VAS] scores and requirement for rescue analgesia) of a standard dose of intrathecal morphine. MATERIALS AND METHODS: An Italian cohort of 63 parturients, scheduled for elective cesarean section at a tertiary University Hospital, received spinal anesthesia with hyperbaric bupivacaine and morphine 100 mcg. For the first 48 hours in the postoperative period the patients received acetaminophen 1 g IV q6hr. Incident pain was treated with ketorolac 30 mg IV. Every 6 hours the following parameters were registered: VAS at rest, VAS during movements, postoperative nausea and vomiting, pruritus, and rescue analgesic medications requirements. Age and anthropometric data, number of pregnancies, educational level, OPRM1 genotype, were also obtained. RESULTS: Of the 63 patients enrolled, 45 (71%) were homozygous genotype A/A (118A group), whereas 18 carried the G variants of OPRM1 (A/G or G/G) (118G group). No significant differences in analgesic rescue doses' administration and in incidence of moderate/severe postoperative pain (VAS>3) between the 2 groups were observed. Pruritus was more frequent in the 118A group than in the 118G group in the first 24 hours of the postoperative period. DISCUSSION: In the Italian population participating in this study there was a different incidence of pruritus in the postcesarean period in response to intrathecal opioids related to OPRM1 gene polymorphism, but not of postoperative pain. PMID- 28591086 TI - Dexamethasone Injected Perineurally is More Effective than Administered Intravenously for Peripheral Nerve Blocks: A Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION: Peripheral nerve blocks (PNBs) are widely and increasingly used for better acute perioperative pain control for a variety of procedures. Clinically preservative-free dexamethasone is arguably the most commonly used adjuvant and offers the most optimization effects on PNBs yet with the least side-effects noted. Our aim was to compare the effectiveness of intravenous versus perineural dexamethasone on the effectiveness and safety of PNBs. METHODS: Major databases (PubMed, EMBASE, Cochrane library, ISI Web of Science, Google Scholar) were systematically searched for randomized controlled trials comparing the effectiveness of intravenous versus perineural dexamethasone on PNBs. Study characteristics, intraoperative events, and postoperative outcomes including duration of analgesia, duration of sensory block, duration of motor block, pain score at 24 hours, opioid consumption, and postoperative nausea and vomiting, were extracted from the articles. Meta-analysis was performed using random-effect models. RESULTS: Thirteen randomized controlled trials comprising a total of 937 patients (intravenous: 464 patients; perineural: 473 patients) were included in this meta-analysis. Perineural dexamethasone significantly prolonged the duration of analgesia (standardized mean difference [SMD], 0.48 h; 95% confidence interval [CI], 0.18-0.79) and sensory block (SMD, 0.74; 95% CI, 0.53-0.94). In subgroup of studies that used 4 to 5 mg we found that perineural dexamethasone was universally more effective to prolong analgesia as compared with intravenous dexamethasone (SMD, 0.48 h; 95% CI, 0.24-0.72), but there was no significant difference between intravenous versus perineural dexamethasone when using a dose of dexamethasone >=8 mg (SMD, 0.33 h; 95% CI, -0.11 to 0.77). Perineural dexamethasone had similarly more benefits in terms of prolongation of motor block duration, decreasing pain score, reducing opioid consumption, and less postoperative nausea and vomiting. CONCLUSIONS: This investigation not only confirmed the better analgesic effects of perineurally administered dexamethasone as compared with its intravenous injection, but also implicitly supported the hypothesis of local interaction between dexamethasone and the nerve as one of the pain modulation mechanisms of dexamethasone, because systemic absorption alone could not explain the superior quality of PNBs. PMID- 28591089 TI - Recent advances in understanding glucocorticoid receptor function in cancer. PMID- 28591087 TI - Hyperhomocysteinemia as a Metabolic Risk Factor for Glucose Intolerance Among High-Risk Groups of Chinese Adults. AB - BACKGROUND Impaired glucose tolerance (IGT) is characterized by insulin resistance and causes atherosclerosis. Hyperhomocysteinemia is associated with insulin resistance and predicts cardiovascular diseases. In this study, we assessed the possible association between homocysteine and IGT. MATERIAL AND METHODS This was a cross-sectional study of 118 consecutive subjects with IGT (IGT group) and 128 consecutive subjects with normal glucose tolerance (NGT group). Homocysteine and clinical characteristics were measured. RESULTS The IGT group had higher homocysteine than the NGT group [18.00 (14.00, 22.25) vs. 12.50 (9.00, 15.00) MUmol/L, p<0.001]. Homocysteine was positively associated with body mass index (BMI) (r=0.178, p=0.005), triglycerides (r=0.306, p<0.001), fasting blood glucose (FBG) (r=0.312, p<0.001), 2-hour postchallenge glucose (2hPG) (r=0.363, p<0.001), fasting insulin (FINS) (r=0.655, p<0.001), and homeostasis model assessment for insulin resistance (HOMA-IR) (r=0.643, p<0.001), and was negatively correlated with high-density lipoprotein cholesterol (HDL-C) (r= 0.250, p<0.001). After controlling for confounders, hyperinsulinemia (beta=7.430, p<0.001) was independently related to hyperhomocysteinemia. In a logistic regression analysis, high triglycerides (OR=1.177, p<0.001) and homocysteine (OR=1.508, p=0.007), and low HDL-C (OR=0.315, p=0.026) were associated with IGT. CONCLUSIONS Patients with IGT have higher homocysteine levels compared with subjects with normal glucose tolerance, and hyperhomocysteinemia might be correlated with IGT. PMID- 28591090 TI - Common fungal infections in patients with leukemia. PMID- 28591091 TI - Antifibrinolytic agents in acquired bleeding disorders. PMID- 28591092 TI - The role of radiation therapy in upper gastrointestinal cancers. AB - Upper gastrointestinal cancers are common and account for a high proportion of cases of cancer-related morbidity and mortality. Combined-modality therapy with surgery, chemotherapy, and radiation therapy is standard treatment for esophageal and gastroesophageal junction cancers. For gastric cancer, the need to include radiation therapy appears to depend on the quality of the surgery performed. Radiation therapy plays an uncertain role in the surgical management of pancreatic cancer, and the results of ongoing clinical trials are awaited. Retrospective studies support the inclusion of radiotherapy in the surgical management of biliary tract cancers. The development of more effective systemic therapy for upper gastrointestinal cancers may ultimately lead to a greater survival benefit due to the potential for improved local tumor control achieved with radiotherapy. PMID- 28591093 TI - Testicular cancer update. AB - The advances seen in the treatment of testicular cancer are among the great achievements in modern medicine. These advances were made possible by the collaborative efforts of cancer researchers around the world. Investigators have been able to address many questions regarding the treatment of patients with disease limited to the testis, those with metastasis to the retroperitoneum only, and those with advanced metastatic disease. Questions answered include the chemotherapeutic agents to be used and in what combinations, the proper intensity of treatment and appropriate dosing, the optimal number of cycles of chemotherapy according to validated risk stratification, appropriate surgical approaches that preserve sexual function, the treatment of relapsed disease, what supportive care measures to take, and survivorship issues following treatment of testicular cancer. Today, cure is achievable in 95% of all patients with testicular cancer and 80% of those who have metastatic disease. Despite remarkable results with frontline and salvage combination chemotherapy, metastatic testicular cancer remains incurable in approximately 10% of patients, and novel treatment approaches are warranted. This review highlights past and recent discoveries in the treatment of patients with testicular cancer. PMID- 28591094 TI - Non-clear cell renal cell carcinomas: biological insights and therapeutic challenges and opportunities. AB - The non-clear cell renal cell carcinomas (nccRCCs) are a diverse group of rare variant renal carcinomas. Each subtype harbors a distinct cell of origin and exhibits a distinct clinical behavior and response to therapy. The advent of next generation sequencing has drastically advanced our understanding of key genetic and epigenetic drivers in these tumors, although mechanistic studies are needed to elucidate pathogenesis. The only 2 randomized clinical trials in nccRCC included patients with diverse histologic subtypes. Both of these trials compared everolimus with sunitinib and provided evidence suggesting that frontline sunitinib is superior to everolimus in terms of progression-free survival. Renal medullary and collecting duct carcinomas do not respond to targeted agents, supporting the use of platinum-based chemotherapy as frontline therapy. Clinical evidence is currently emerging on the efficacy of c-MET inhibitors in patients with papillary type 1 RCC harboring germline c-MET mutations. Data on the activity of immune checkpoint inhibitors in this setting are lacking; however, several trials are ongoing in this space. The management of patients with nccRCC likely will improve in the future with histology-driven trials, which may pave the way for personalized therapies based on the molecular characterization of these orphan kidney cancer subtypes. Efforts must also be made to establish in vitro and animal models for testing hypotheses generated through extensive genomic analysis. Ultimately, collaborative national and international studies are urgently needed to improve therapeutic strategies in patients with metastatic disease. PMID- 28591096 TI - Genetic conditions associated with a predisposition to kidney cancer. PMID- 28591097 TI - The best treatments to use after checkpoint inhibition in melanoma. PMID- 28591098 TI - The use of CAR T cells in diffuse large B-cell lymphoma and mantle cell lymphoma. PMID- 28591100 TI - Antibody-drug conjugates in breast cancer. PMID- 28591101 TI - Advances in the management of patients with carcinoid syndrome. PMID- 28591102 TI - How direct-to-patient research can improve interest in clinical trials. PMID- 28591103 TI - Treatment of acute lymphoblastic leukemia in older adults: now and the future. AB - Acute lymphoblastic leukemia (ALL) is an uncommon disease with poor outcomes in older patients. Although intensive chemotherapy can induce complete responses in older patients, the mortality rate is unacceptably high. The 5-year survival rate for patients achieving a remission ranges from 17% to 23%. ALL is usually more aggressive in older patients, and these patients' reduced functional capacity renders them less able to tolerate treatment. The need for less-intensive, more efficient treatment modalities in this population of frail and high-risk patients is evident. Clinicians should strongly consider treatment in clinical trials for their older patients. If such trials are not available on site, physicians should refer older patients to tertiary centers for possible enrollment in a study. Significant advances have been made in the past decade toward understanding the biology of ALL and in developing novel therapeutic agents. Blinatumomab, inotuzumab ozogamicin, and newer-generation tyrosine kinase inhibitors appear to be promising agents. Clinical studies show remarkable results with these agents, either alone or in combination with low-dose chemotherapy. Now that clinical trials are being designed with less-intensive treatment regimens and broad entry criteria, older age is less likely to be an exclusionary factor. However, clinical trials that enroll older patients with ALL should include detailed documentation of their underlying comorbidities, cognitive function, and performance status. PMID- 28591104 TI - Myeloma bone disease: pathogenesis and treatment. AB - Bone involvement manifesting as osteolytic bone disease (OBD) or osteopenia is one of the defining features of multiple myeloma (MM). Osteolytic lesions develop in nearly 90% of patients with MM, and these are frequently complicated by skeleton-related events (SREs) such as severe bone pain, pathologic fractures, vertebral collapse, hypercalcemia, and spinal cord compression. SREs have a negative effect on patients' quality of life and affect their long-term outcomes, including survival. In MM, the delicate balance between bone formation and bone destruction is perturbed. OBD is a consequence of increased osteoclast activation along with osteoblast inhibition, which alter bone remodeling. Although MM remains incurable, tremendous progress has been made in the treatment of the disease. As such, there is a need to address the symptoms of the disease that affect quality of life and, ultimately, overall survival. Novel agents targeting OBD are promising therapeutic strategies not only for the treatment of MM OBD but also for the treatment of MM itself. In addition to bisphosphonates, several novel agents are currently under investigation for their positive effect on bone remodeling via osteoclast inhibition or osteoblast stimulation. Future studies will look to combine or sequence all of these agents to improve quality of life, decrease the symptoms of MM OBD, and enhance antitumor activity. PMID- 28591105 TI - Everything old is new again: the case for imatinib as frontline therapy in 2017. PMID- 28591107 TI - Industry 'road tests' new wave of immune checkpoints. PMID- 28591106 TI - The biology of CML supports second-generation TKIs as frontline treatment. PMID- 28591109 TI - Interest rekindles in drug cocktails that reprogram cells. PMID- 28591110 TI - Patents as collateral for securitization. PMID- 28591111 TI - Verily chases a perfectly healthy human. PMID- 28591113 TI - Recent patents in microbiomes and microbial genomics. PMID- 28591114 TI - First deuterated drug approved. PMID- 28591115 TI - Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics. PMID- 28591116 TI - A synthetic biology approach to integrative high school STEM training. PMID- 28591117 TI - The illusion of control in germline-engineering policy. PMID- 28591118 TI - Hanging on a thread. PMID- 28591112 TI - The promise of organ and tissue preservation to transform medicine. AB - The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science. PMID- 28591119 TI - Manufacture of CAR-T cells in the body. PMID- 28591121 TI - A spring collection of designer yeast chromosomes. PMID- 28591122 TI - CAR-T death strikes Kite. PMID- 28591123 TI - Building the human inner ear in an organoid. PMID- 28591124 TI - Patient-centered drug manufacture. PMID- 28591126 TI - Around the world in a month. PMID- 28591127 TI - Eat a water bottle or two. PMID- 28591128 TI - After Glybera's withdrawal, what's next for gene therapy? PMID- 28591125 TI - Open-source, community-driven microfluidics with Metafluidics. AB - Microfluidic devices have the potential to automate and miniaturize biological experiments, but open-source sharing of device designs has lagged behind sharing of other resources such as software. Synthetic biologists have used microfluidics for DNA assembly, cell-free expression, and cell culture, but a combination of expense, device complexity, and reliance on custom set-ups hampers their widespread adoption. We present Metafluidics, an open-source, community-driven repository that hosts digital design files, assembly specifications, and open source software to enable users to build, configure, and operate a microfluidic device. We use Metafluidics to share designs and fabrication instructions for both a microfluidic ring-mixer device and a 32-channel tabletop microfluidic controller. This device and controller are applied to build genetic circuits using standard DNA assembly methods including ligation, Gateway, Gibson, and Golden Gate. Metafluidics is intended to enable a broad community of engineers, DIY enthusiasts, and other nontraditional participants with limited fabrication skills to contribute to microfluidic research. PMID- 28591129 TI - The shallow water equation and the vorticity equation for a change in height of the topography. AB - We consider the shallow water equation and the vorticity equations for a variable height of topography. On the assumptions that the atmosphere is incompressible and a constant density, we simplify the coupled dynamic equations. The change in topographic height is handled as the sum of the inherent and changing topography using the perturbation method, together with appropriate boundary conditions of the atmosphere, to obtain the relationship between the relative height of the flow, the inherent topography and the changing topography. We generalize the conservation of the function of relative position, and quantify the relationship between the height of the topography and the relative position of a fluid element. If the height of the topography increases (decreases), the relative position of a fluid element descends (ascends). On this basis, we also study the relationship between the vorticity and the topography to find the vorticity decreasing (increasing) for an increasing (decreasing) height of the topography. PMID- 28591130 TI - Natal and breeding philopatry of female Steller sea lions in southeastern Alaska. AB - Information on drivers of dispersal is critical for wildlife conservation but is rare for long-lived marine mammal species with large geographic ranges. We fit multi-state mark-recapture models to resighting data of 369 known-aged Steller sea lion (Eumetopias jubatus) females marked as pups on their natal rookeries in southeastern Alaska from 1994-2005 and monitored from 2001-15. We estimated probabilities of females being first observed parous at their natal site (natal philopatry), and of not moving breeding sites among years (breeding philopatry) at large (> 400 km, all five rookeries in southeastern Alaska) and small (< 4 km, all islands within the largest rookery, Forrester Island Complex, F) spatial scales. At the rookery scale, natal philopatry was moderately high (0.776-0.859) for most rookeries and breeding philopatry was nearly 1, with < 3% of females switching breeding rookeries between years. At more populous islands at F, natal philopatry was 0.500-0.684 versus 0.295-0.437 at less populous islands, and breeding philopatry was 0.919-0.926 versus 0.604-0.858. At both spatial scales, the probability of pupping at a non-natal site increased with population size of, and declined with distance from, the destination site. Natal philopatry of < 1 would increase gene flow, improve population resilience, and promote population recovery after decline in a heterogeneous environment. Very high breeding philopatry suggests that familiarity with neighboring females and knowledge of the breeding site (the topography of pupping sites and nearby foraging locations) may be a critical component to reproductive strategies of sea lions. PMID- 28591131 TI - Visualization of early influenza A virus trafficking in human dendritic cells using STED microscopy. AB - Influenza A viruses (IAV) primarily target respiratory epithelial cells, but can also replicate in immune cells, including human dendritic cells (DCs). Super resolution microscopy provides a novel method of visualizing viral trafficking by overcoming the resolution limit imposed by conventional light microscopy, without the laborious sample preparation of electron microscopy. Using three-color Stimulated Emission Depletion (STED) microscopy, we visualized input IAV nucleoprotein (NP), early and late endosomal compartments (EEA1 and LAMP1 respectively), and HLA-DR (DC membrane/cytosol) by immunofluorescence in human DCs. Surface bound IAV were internalized within 5 min of infection. The association of virus particles with early endosomes peaked at 5 min when 50% of NP+ signals were also EEA1+. Peak association with late endosomes occurred at 15 min when 60% of NP+ signals were LAMP1+. At 30 min of infection, the majority of NP signals were in the nucleus. Our findings illustrate that early IAV trafficking in human DCs proceeds via the classical endocytic pathway. PMID- 28591132 TI - Early menarche: A systematic review of its effect on sexual and reproductive health in low- and middle-income countries. AB - BACKGROUND: Adolescent girls aged 15-19 bear a disproportionate burden of negative sexual and reproductive health outcomes in low- and middle-income countries. Research from several high-income countries suggests that early age at menarche is an important determinant of sexual and reproductive health. We conducted this systematic review to better understand whether and how early menarche is associated with various negative sexual and reproductive health outcomes in low- and middle-income countries and the implications of such associations. METHODS: We systematically searched eight health and social sciences databases for peer-reviewed literature on menarche and sexual and reproductive health in low- and middle-income countries. Two reviewers independently assessed all studies for inclusion, overall quality and risk of bias, and performed data extraction on all included studies. RESULTS: Twenty-four articles met all inclusion criteria-nine of moderate quality and fifteen with several methodological weaknesses. Our review of the minimal existing literature showed that early menarche is associated with early sexual initiation, early pregnancy and some sexually transmitted infections in low- and middle-income countries, similar to what has been observed in high-income countries. Early menarche is also associated with early marriage-an association that may have particularly important implications for countries with high child marriage rates. CONCLUSIONS: Early age at menarche may be an important factor affecting the sexual and reproductive health of adolescent girls and young women in low- and middle-income countries. More research is needed to confirm the existence of the identified associations across different settings and to better understand the process through which early menarche and other markers of early pubertal development may contribute to the increased vulnerability of girls to negative sexual and reproductive health outcomes in low- and middle-income countries. Given the association of early menarche with early marriage, ongoing efforts to reduce child marriage may benefit from targeting efforts to early maturing girls. PMID- 28591133 TI - Combined Red Clover isoflavones and probiotics potently reduce menopausal vasomotor symptoms. AB - BACKGROUND: Natural estrogen decline leads to vasomotor symptoms (VMS). Hormone therapy alleviates symptoms but increases cancer risk. Effective treatments against VMS with minimal cancer risks are needed. We investigate the effects of a highly bioavailable aglycone rich Red Clover isoflavone treatment to alleviate existing menopausal VMS, assessed for the first time by 24hour ambulatory skin conductance (SC). METHODS AND RESULTS: We conducted a parallel, double blind, randomised control trial of 62 peri-menopausal women aged 40-65, reporting >= 5 hot flushes/day and follicle stimulating hormone >=35 IU/L. Participants received either twice daily treatment with bioavailable RC extract (RCE), providing 34 mg/d isoflavones and probiotics, or masked placebo formulation for 12 weeks. The primary outcome was change in daily hot flush frequency (HFF) from baseline to 12 weeks using 24hr SC. Secondary outcomes were change in SC determined hot flush intensity (HFI), self-reported HFF (rHFF) and hot flush severity (rHFS), blood pressure and plasma lipids. A significant decrease in 24hr HFF (P < 0.01) and HFI (P<0.05) was found when comparing change from baseline to 12 months of the RCE ( 4.3 HF/24hr, CI -6.8 to -2.3; -12956 MUS s-1, CI -20175 to -5737) with placebo (0.79 HF/24hr, CI -1.56 to 3.15; 515 MUS s-1, CI -5465 to 6496). rHFF was also significantly reduced (P <0.05)in the RCE (-2.97 HFs/d, CI -4.77 to -1.17) group compared to placebo (0.036 HFs/d, CI -2.42 to 2.49). Other parameters were non significant. RCE was well tolerated. CONCLUSION: Results suggest that moderate doses of RCE were more effective and superior to placebo in reducing physiological and self-reported VMS. Findings support that objective physiological symptom assessment methods should be used together with self-report measures in future studies on menopausal VMS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02028702. PMID- 28591134 TI - Global gene expression profiling and antibiotic susceptibility after repeated exposure to the carbon monoxide-releasing molecule-2 (CORM-2) in multidrug resistant ESBL-producing uropathogenic Escherichia coli. AB - Treatment of urinary tract infections is today a challenge due to the increasing prevalence of multidrug-resistant ESBL-producing uropathogenic Escherichia coli (UPEC). There is an urgent need for new treatment strategies for multidrug resistant UPEC and preferably with targets that have low potential for development of resistance. Carbon monoxide-releasing molecules (CORMs) are novel and potent antibacterial agents. The present study examines the transcriptomic targets of CORM-2 in a multidrug-resistant ESBL-producing UPEC isolate in response to a single exposure to CORM-2 and after repeated exposure to CORM-2. The bacterial viability and minimal inhibitory concentration (MIC) were also examined after repeated exposure to CORM-2. Microarray analysis revealed that a wide range of processes were affected by CORM-2, including a general trend of down-regulation in energy metabolism and biosynthesis pathways and up-regulation of the SOS response and DNA repair. Several genes involved in virulence (ibpB), antibiotic resistance (marAB, mdtABC) and biofilm formation (bhsA, yfgF) were up regulated, while some genes involved in virulence (kpsC, fepCEG, entABE), antibiotic resistance (evgA) and biofilm formation (artIP) were down-regulated. Repeated exposure to CORM-2 did not alter the gene expression patterns, the growth inhibitory response to CORM-2 or the MIC values for CORM-2, cefotaxime, ciprofloxacin and trimethoprim. This study identifies several enriched gene ontologies, modified pathways and single genes that are targeted by CORM-2 in a multidrug-resistant UPEC isolate. Repeated exposure to CORM-2 did not change the gene expression patterns or fold changes and the susceptibility to CORM-2 remained after repeated exposure. PMID- 28591136 TI - Breeding chronology and social interactions affect ungulate foraging behavior at a concentrated food resource. AB - Prey species must balance predator avoidance behavior with other essential activities including foraging, breeding, and social interactions. Anti-predator behaviors such as vigilance can impede resource acquisition rates by altering foraging behavior. However, in addition to predation risk, foraging behavior may also be affected by socio-sexual factors including breeding chronology and social interactions. Therefore, we investigated how time-of-day, distance-to-forest, group size, social interactions (presence of different sex-age class), and breeding chronology (pre-breeding, breeding, post-breeding seasons) affected probability of feeding (hereafter: feeding) for different sex and age-classes (mature males, immature males, adult females, and juveniles) of white-tailed deer at feed sites. We developed a set of candidate models consisting of social, habitat, reproductive, and abiotic factors and combinations of these factors. We then used generalized linear mixed models (GLMMs) to estimate the probability of feeding and used model averaging of competing models for multimodel inference. Each adult sex-age class' feeding was influenced by breeding chronology. Juveniles were more likely to be feeding than adults in all seasons. Feeding increased with group size for all sex-age classes. The presence of a mature male negatively influenced the feeding of immature males and juveniles were more likely to be feeding when an adult female was present. Feeding decreased with increasing distance-to-forest for mature males but not for other sex-age classes. Our results indicate that each sex-age class modulates vigilance levels in response to socio-sexual factors according to the unique pressures placed upon them by their reproductive status and social rank. PMID- 28591135 TI - Bioelectrical impedance vector analysis (BIVA) for measuring the hydration status in young elite synchronized swimmers. AB - PURPOSE: The assessment of body hydration is a complex process, and no measurement is valid for all situations. Bioelectrical impedance vector analysis (BIVA) has emerged as a relatively novel technique for assessing hydration status in sports. We applied BIVA a) to determine hydration changes evoked by an intense synchronized swimming (SS) training session; b) to characterize the sample of young elite swimmers in relation with a nonathletic reference population; and c) to generate its 50%, 75% and 95% percentiles of the bioelectrical variables. METHODS: Forty-nine elite SS female swimmers of two age categories, comen (Co: 13.9 +/- 0.9 years, n = 34) and junior (Jr: 16.3 +/- 0.6 years, n = 15), performed a long, high intensity training session. Body mass (BM) and bioelectrical variables (R, resistance; Xc, reactance; PA, phase angle; and Z, impedance module) were assessed pre- and post-training. BIVA was used to characterize 1) the distribution pattern of the bioelectrical vector (BIA vector) for both age groups, and 2) pre- to post-training BIA vector migration. Bioelectrical variables were also correlated with BM change values. RESULTS: Most swimmers were mostly located outside the 75% and some beyond the 95% percentile of the bioelectrical tolerance ellipses of the general population. The BIA vector showed statistically significant differences in both Co (T2 = 134.7, p = 0.0001) and Jr (T2 = 126.2, p < 0.001). Both groups were also bioelectrically different (T2 = 17.6, p < 0.001). After the training session, a decrease in BM (p = 0.0001) and an increase in BIA variables (p = 0.01) was observed. BIVA also showed a significant pre-post vector migration both in Co (T2 = 82.1; p < 0.001) and Jr (T2 = 41.8; p < 0.001). No correlations were observed between BM changes and bioelectrical variables. CONCLUSIONS: BIVA showed specific bioelectrical characteristics in young elite SS athletes. Considering the decrease in BM and the migration of the BIA vector, we conclude that the homeostatic hydration status of these young elite female swimmers was affected by the execution of intense training sessions. From a methodological perspective, BIVA appears to be sensitive enough to detect subtle hydration changes, but further research is needed to ensure its validity and reliability. Moreover, these findings highlight the importance of ensuring adequate fluid intake during training in young SS athletes. PMID- 28591137 TI - Increasing medication adherence and income assistance access for first-episode psychosis patients. AB - BACKGROUND: Assertive community treatment for first-episode psychosis programs have been shown to improve symptoms and reduce service use. There is little or no evidence on whether these programs can increase access to income assistance and improve medication adherence in first episode psychosis patients. This research examines the impact of the Early Psychosis Prevention and Intervention Service (EPPIS) on these outcomes. METHODS: We extracted data on EPPIS patients held in the Data Repository at the Manitoba Centre for Health Policy. The Repository is a comprehensive collection of person-level de-identified administrative records, including data from Manitoba's health services. We compared income assistance use and antipsychotic medication adherence in EPPIS patients to a historical cohort matched on pattern of diagnosis. Confounders were adjusted through propensity score weighting with asymmetrical trimming. Odds ratios (OR), hazard ratios (HR) and 95% confidence intervals were calculated. RESULTS: We identified a matched sample of 244 patients and 449 controls. EPPIS patients had a higher rate of income assistance use during the program (67.4% vs. 38.7%; p< 0.0001). EPPIS patients were more likely to have been prescribed at least one antipsychotic medication than the control cohort, both during the program (OR = 15.05; 95%CI 10.81 to 20.94) and after the program ended (OR = 5.20; 95%CI: 4.50 to 6.02). Patients in EPPIS were also more likely to adhere to their medication during the program (OR = 4.71; 95%CI 3.75 to 5.92), and after the program (OR = 2.54; 95%CI 2.04 to 3.16). CONCLUSION: Enrolment in the EPPIS program was associated with increased adherence to antipsychotic medication treatment and improved uptake of income assistance. PMID- 28591138 TI - Understanding the dynamics of terrorism events with multiple-discipline datasets and machine learning approach. AB - Terror events can cause profound consequences for the whole society. Finding out the regularity of terrorist attacks has important meaning for the global counter terrorism strategy. In the present study, we demonstrate a novel method using relatively popular and robust machine learning methods to simulate the risk of terrorist attacks at a global scale based on multiple resources, long time series and globally distributed datasets. Historical data from 1970 to 2015 was adopted to train and evaluate machine learning models. The model performed fairly well in predicting the places where terror events might occur in 2015, with a success rate of 96.6%. Moreover, it is noteworthy that the model with optimized tuning parameter values successfully predicted 2,037 terrorism event locations where a terrorist attack had never happened before. PMID- 28591140 TI - Correction: Pleiotropic Mechanisms Indicated for Sex Differences in Autism. AB - [This corrects the article DOI: 10.1371/journal.pgen.1006425.]. PMID- 28591139 TI - Physical education policy compliance and Latino children's fitness: Does the association vary by school neighborhood socioeconomic advantage? AB - OBJECTIVES: To investigate the contribution of school neighborhood socioeconomic advantage to the association between school-district physical education policy compliance in California public schools and Latino students' physical fitness. METHODS: Cross-sectional Fitnessgram data for public-school students were linked with school- and district-level information, district-level physical education policy compliance from 2004-2005 and 2005-2006, and 2000 United States Census data. Multilevel logistic regression models examined whether income and education levels in school neighborhoods moderated the effects of district-level physical education policy compliance on Latino fifth-graders' fitness levels. RESULTS: Physical education compliance data were available for 48 California school districts, which included 64,073 Latino fifth-graders. Fewer than half (23, or 46%) of these districts were found to be in compliance, and only 16% of Latino fifth-graders attended schools in compliant districts. Overall, there was a positive association between district compliance with physical education policy and fitness (OR, 95%CI: 1.38, 1.07, 1.78) adjusted for covariates. There was no significant interaction between school neighborhood socioeconomic advantage and physical education policy compliance (p>.05): there was a positive pattern in the association between school district compliance with physical education policy and student fitness levels across levels of socioeconomic advantage, though the association was not always significant. CONCLUSIONS: Across neighborhoods with varying levels of socioeconomic advantage, increasing physical education policy compliance in elementary schools may be an effective strategy for improving fitness among Latino children. PMID- 28591141 TI - Floodplain farm fields provide novel rearing habitat for Chinook salmon. AB - When inundated by floodwaters, river floodplains provide critical habitat for many species of fish and wildlife, but many river valleys have been extensively leveed and floodplain wetlands drained for flood control and agriculture. In the Central Valley of California, USA, where less than 5% of floodplain wetland habitats remain, a critical conservation question is how can farmland occupying the historical floodplains be better managed to improve benefits for native fish and wildlife. In this study fields on the Sacramento River floodplain were intentionally flooded after the autumn rice harvest to determine if they could provide shallow-water rearing habitat for Sacramento River fall-run Chinook salmon (Oncorhynchus tshawytscha). Approximately 10,000 juvenile fish (ca. 48 mm, 1.1 g) were reared on two hectares for six weeks (Feb-March) between the fall harvest and spring planting. A subsample of the fish were uniquely tagged to allow tracking of individual growth rates (average 0.76 mm/day) which were among the highest recorded in fresh water in California. Zooplankton sampled from the water column of the fields were compared to fish stomach contents. The primary prey was zooplankton in the order Cladocera, commonly called water fleas. The compatibility, on the same farm fields, of summer crop production and native fish habitat during winter demonstrates that land management combining agriculture with conservation ecology may benefit recovery of native fish species, such as endangered Chinook salmon. PMID- 28591142 TI - Collective phenomena in crowds-Where pedestrian dynamics need social psychology. AB - This article is on collective phenomena in pedestrian dynamics during the assembling and dispersal of gatherings. To date pedestrian dynamics have been primarily studied in the natural and engineering sciences. Pedestrians are analyzed and modeled as driven particles revealing self-organizing phenomena and complex transport characteristics. However, pedestrians in crowds also behave as living beings according to stimulus-response mechanisms or act as human subjects on the basis of social norms, social identities or strategies. To show where pedestrian dynamics need social psychology in addition to the natural sciences we propose the application of three categories-phenomena, behavior and action. They permit a clear discrimination between situations in which minimal models from the natural sciences are appropriate and those in which sociological and psychological concepts are needed. To demonstrate the necessity of this framework, an experiment in which a large group of people (n = 270) enters a concert hall through two different spatial barrier structures is analyzed. These two structures correspond to everyday situations such as boarding trains and access to immigration desks. Methods from the natural and social sciences are applied. Firstly, physical measurements show the influence of the spatial structure on the dynamics of the entrance procedure. Density, waiting time and speed of progress show large variations. Secondly, a questionnaire study (n = 60) reveals how people perceive and evaluate these entrance situations. Markedly different expectations, social norms and strategies are associated with the two spatial structures. The results from the questionnaire study do not always conform to objective physical measures, indicating the limitations of models which are based on objective physical measures alone and which neglect subjective perspectives. PMID- 28591143 TI - The Weapons Identification Task: Recommendations for adequately powered research. AB - This article synthesizes the extant literature on the Weapons Identification Task (WIT), a sequential priming paradigm developed to investigate the impact of racial priming on identification of stereotype-congruent and stereotype irrelevant objects. Given recent controversy over the replicability of and statistical power required to detect priming effects, the aim of this synthesis is to systematically assess the literature in order to develop recommendations for statistical power in future research with the WIT paradigm. To develop these recommendations, the present article first quantitatively ascertains the magnitude of publication bias in the extant literature. Next, expected effect sizes and power recommendations are generated from the extant literature. Finally, a close conceptual replication of the WIT paradigm is conducted to prospectively test these recommendations. Racial priming effects are detected in this prospective test providing increased confidence in the WIT priming effect and credibility to the proposed recommendations for power. PMID- 28591144 TI - ERRalpha negatively regulates type I interferon induction by inhibiting TBK1-IRF3 interaction. AB - Estrogen-related receptor alpha (ERRalpha) is a member of the nuclear receptor superfamily controlling energy homeostasis; however, its precise role in regulating antiviral innate immunity remains to be clarified. Here, we showed that ERRalpha deficiency conferred resistance to viral infection both in vivo and in vitro. Mechanistically, ERRalpha inhibited the production of type-I interferon (IFN-I) and the expression of multiple interferon-stimulated genes (ISGs). Furthermore, we found that viral infection induced TBK1-dependent ERRalpha stabilization, which in turn associated with TBK1 and IRF3 to impede the formation of TBK1-IRF3, IRF3 phosphorylation, IRF3 dimerization, and the DNA binding affinity of IRF3. The effect of ERRalpha on IFN-I production was independent of its transcriptional activity and PCG-1alpha. Notably, ERRalpha chemical inhibitor XCT790 has broad antiviral potency. This work not only identifies ERRalpha as a critical negative regulator of antiviral signaling, but also provides a potential target for future antiviral therapy. PMID- 28591146 TI - Recent tree cover increases in eastern China linked to low, declining human pressure, steep topography, and climatic conditions favoring tree growth. AB - Globally, the extent of forest continues to decline, however, some countries have increased their forest extent in recent years. China is one of these countries and has managed to increase their tree cover through huge reforestation and afforestation programs during recent decades as well as land abandonment dynamics. This study investigates tree cover change in the eastern half of China between 2000 and 2010 on three different scales, using random forest modeling of remote sensing data for tree cover in relation to environmental and anthropogenic predictor variables. Our results show that between the years 2000 and 2010 2,667,875 km2 experienced an increase in tree cover while 1,854,900 km2 experienced a decline in tree cover. The area experiencing >=10% increase in tree cover is almost twice as large as the area with >=10% drop in tree cover. There is a clear relation between topography and tree cover change with steeper and mid elevation areas having a larger response on tree cover increase than other areas. Furthermore, human influence, change in population density, and actual evapotranspiration are also important factors in explaining where tree cover has changed. This study adds to the understanding of tree cover change in China, as it has focus on the entire eastern half of China on three different scales and how tree cover change is linked to topography and anthropogenic pressure. Though, our results show an increase in tree cover in China, this study emphasizes the importance of incorporating anthropogenic factors together with biodiversity protection into the reforestation and afforestation programs in the future. PMID- 28591145 TI - Successful implementation of Helping Babies Survive and Helping Mothers Survive programs-An Utstein formula for newborn and maternal survival. AB - Globally, the burden of deaths and illness is still unacceptably high at the day of birth. Annually, approximately 300.000 women die related to childbirth, 2.7 million babies die within their first month of life, and 2.6 million babies are stillborn. Many of these fatalities could be avoided by basic, but prompt care, if birth attendants around the world had the necessary skills and competencies to manage life-threatening complications around the time of birth. Thus, the innovative Helping Babies Survive (HBS) and Helping Mothers Survive (HMS) programs emerged to meet the need for more practical, low-cost, and low-tech simulation-based training. This paper provides users of HBS and HMS programs a 10 point list of key implementation steps to create sustained impact, leading to increased survival of mothers and babies. The list evolved through an Utstein consensus process, involving a broad spectrum of international experts within the field, and can be used as a means to guide processes in low-resourced countries. Successful implementation of HBS and HMS training programs require country-led commitment, readiness, and follow-up to create local accountability and ownership. Each country has to identify its own gaps and define realistic service delivery standards and patient outcome goals depending on available financial resources for dissemination and sustainment. PMID- 28591147 TI - Jaccard distance based weighted sparse representation for coarse-to-fine plant species recognition. AB - Leaf based plant species recognition plays an important role in ecological protection, however its application to large and modern leaf databases has been a long-standing obstacle due to the computational cost and feasibility. Recognizing such limitations, we propose a Jaccard distance based sparse representation (JDSR) method which adopts a two-stage, coarse to fine strategy for plant species recognition. In the first stage, we use the Jaccard distance between the test sample and each training sample to coarsely determine the candidate classes of the test sample. The second stage includes a Jaccard distance based weighted sparse representation based classification(WSRC), which aims to approximately represent the test sample in the training space, and classify it by the approximation residuals. Since the training model of our JDSR method involves much fewer but more informative representatives, this method is expected to overcome the limitation of high computational and memory costs in traditional sparse representation based classification. Comparative experimental results on a public leaf image database demonstrate that the proposed method outperforms other existing feature extraction and SRC based plant recognition methods in terms of both accuracy and computational speed. PMID- 28591148 TI - Natural disasters and indicators of social cohesion. AB - Do adversarial environmental conditions create social cohesion? We provide new answers to this question by exploiting spatial and temporal variation in exposure to earthquakes across Chile. Using a variety of methods and controlling for a number of socio-economic variables, we find that exposure to earthquakes has a positive effect on several indicators of social cohesion. Social cohesion increases after a big earthquake and slowly erodes in periods where environmental conditions are less adverse. Our results contribute to the current debate on whether and how environmental conditions shape formal and informal institutions. PMID- 28591149 TI - Greater HbA1c variability is associated with increased cardiovascular events in type 2 diabetes patients with preserved renal function, but not in moderate to advanced chronic kidney disease. AB - Emerging evidence suggests that glycemic variability may be a more reliable measure of glycemic control than mean HbA1c in type 2 diabetes mellitus. This study aimed to determine if HbA1c variability is associated with cardiovascular events in type 2 diabetic patients and if different renal functions affect such association. This longitudinal study enrolled 8259 diabetic patients from the Kaohsiung Medical University Research Database in 2009 and were followed-up until 2015. Intra-individual HbA1C variability was defined as the standard deviation (SD) of HbA1c and cardiovascular events were defined as hospitalization for coronary artery disease, unstable angina, myocardial infarction, stroke, peripheral artery disease, and cardiovascular death. The patients were grouped into two based on their estimated glomerular filtration rate (eGFR) >= 60 or < 60 min/ml/1.73m2. In a mean follow-up period of 6.3 years, cardiovascular events were recorded in 8.9% of the patients. In an adjusted Cox model, high HbA1c SD (hazard ratio, 1.290; 95% confidence interval, 1.008-1.650; p = 0.043), but not mean HbA1c, was associated with significantly increased risk of cardiovascular events in patients with eGFR >= 60 min/ml/1.73m2. This association was not seen in patients with eGFR < 60 min/ml/1.73m2. In this study, greater HbA1c variability is associated with increased risk of cardiovascular among patients with preserved renal function, but not in those with moderate to advanced chronic kidney disease. PMID- 28591150 TI - More than one fungus in the pepper pot: Integrative taxonomy unmasks hidden species within Myriostoma coliforme (Geastraceae, Basidiomycota). AB - Since the nineteenth century, Myriostoma has been regarded as a monotypic genus with a widespread distribution in north temperate and subtropical regions. However, on the basis of morphological characters and phylogenetic evidence of DNA sequences of the internal transcribed spacer (ITS) regions and the large subunit nuclear ribosomal RNA gene (LSU), four species are now delimited: M. areolatum comb. & stat. nov., M. calongei sp. nov., M. capillisporum comb. & stat. nov., and M. coliforme. Myriostoma coliforme is typified by selecting a lectotype (iconotype) and a modern sequenced collection as an epitype. The four species can be discriminated by a combination of morphological characters, such as stomatal form, endoperidial surface texture, and basidiospore size and ornamentation. PMID- 28591151 TI - Cardiac glycosides use and the risk and mortality of cancer; systematic review and meta-analysis of observational studies. AB - BACKGROUND: Cardiac glycosides (CGs) including digitalis, digoxin and digitoxin are used in the treatment of congestive heart failure and atrial fibrillation. Pre-clinical studies have investigated the anti-neoplastic properties of CGs since 1960s. Epidemiological studies concerning the association between CGs use and cancer risk yielded inconsistent results. We have performed a systematic review and meta-analysis to summarize the effects of CGs on cancer risk and mortality. METHODS: PubMed, Scopus, Cochrane library, Medline and Web of Knowledge were searched for identifying relevant studies. Summary relative risks (RR) and 95% confidence intervals (CI) were calculated using random-effects model. RESULTS: We included 14 case-control studies and 15 cohort studies published between 1976 and 2016 including 13 cancer types. Twenty-four studies reported the association between CGs and cancer risk and six reported the association between CGs and mortality of cancer patients. Using CGs was associated with a higher risk of breast cancer (RR = 1.330, 95% CI: 1.247-1.419). Subgroup analysis showed that using CGs increased the risk of ER+ve breast cancer but not ER-ve. Using CGs wasn't associated with prostate cancer risk (RR = 1.015, 95% CI: 0.868-1.87). However, CGs decreased the risk in long term users and showed a protective role in decreasing the risk of advanced stages. CGs use was associated with increased all-cause mortality (HR = 1.35, 95% CI: 1.248-1.46) but not cancer-specific mortality (HR = 1.075, 95% CI: 0.968-1.194). CONCLUSION: The anti-tumor activity of CGs observed in pre-clinical studies requires high concentrations which can't be normally tolerated in humans. However, the estrogen like activity of CGs could be responsible for increasing the risk of certain types of tumors. PMID- 28591152 TI - Increased risk of deep vein thrombosis and pulmonary thromboembolism in patients with aortic aneurysms: A nationwide cohort study. AB - Studies on the association between aortic aneurysm (AA) and the subsequent risk of venous thromboembolism (VTE) are limited to a few case reports and investigations which only focused on surgical effects. Therefore, we used the National Health Insurance Research Database to clarify whether patients with AAs have a heightened risk of subsequent VTEs, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Our retrospective cohort study comprised patients aged >= 18 years who received a diagnosis of an AA and were hospitalized at any point during 2000-2010 (n = 16,630). Each AA patient was frequency-matched to 4 non-AA hospitalized patients based on age, sex, and index year (n = 66,453). The Cox proportional hazard regressions model was used to estimate the adjusted effect of AAs on VTE risk. The overall incidence of DVT and PE was higher in the patients with AA than in the non-AA group patients (23.5 versus 13.2 and 13.5 versus 7.98/1,000 person-years). After adjustment for age, sex, duration of hospitalization in the study period, and comorbidities, patients with AAs were associated with a 1.88-fold higher risk of DVT and 1.90-fold higher risk of PE compared to the non-AA cohort. Patients with abdominal AAs were more likely to develop DVT, whereas thoracic AA patients were more likely to develop PE. A diagnosis of a ruptured AA was associated with a substantially increased risk of DVT. Surgical treatment of AAs was associated with a heightened risk of VTE within 6-months post-operation. Our study demonstrates that AAs are associated with an increased risk of subsequent VTE. Future investigations are encouraged to delineate the mechanisms underlying this association and to evaluate the cost effectiveness of screening for VTEs in patients with AAs. PMID- 28591153 TI - Effects of gravity changes on gene expression of BDNF and serotonin receptors in the mouse brain. AB - Spaceflight entails various stressful environmental factors including microgravity. The effects of gravity changes have been studied extensively on skeletal, muscular, cardiovascular, immune and vestibular systems, but those on the nervous system are not well studied. The alteration of gravity in ground based animal experiments is one of the approaches taken to address this issue. Here we investigated the effects of centrifugation-induced gravity changes on gene expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors (5-HTRs) in the mouse brain. Exposure to 2g hypergravity for 14 days showed differential modulation of gene expression depending on regions of the brain. BDNF expression was decreased in the ventral hippocampus and hypothalamus, whereas increased in the cerebellum. 5-HT1BR expression was decreased in the cerebellum, whereas increased in the ventral hippocampus and caudate putamen. In contrast, hypergravity did not affect gene expression of 5-HT1AR, 5-HT2AR, 5 HT2CR, 5-HT4R and 5-HT7R. In addition to hypergravity, decelerating gravity change from 2g hypergravity to 1g normal gravity affected gene expression of BDNF, 5-HT1AR, 5-HT1BR, and 5-HT2AR in various regions of the brain. We also examined involvement of the vestibular organ in the effects of hypergravity. Surgical lesions of the inner ear's vestibular organ removed the effects induced by hypergravity on gene expression, which suggests that the effects of hypergravity are mediated through the vestibular organ. In summary, we showed that gravity changes induced differential modulation of gene expression of BDNF and 5-HTRs (5-HT1AR, 5-HT1BR and 5-HT2AR) in some brain regions. The modulation of gene expression may constitute molecular bases that underlie behavioral alteration induced by gravity changes. PMID- 28591154 TI - Prediction of in-hospital mortality after pancreatic resection in pancreatic cancer patients: A boosting approach via a population-based study using health administrative data. AB - BACKGROUND: One reason for the aggressiveness of the pancreatic cancer is that it is diagnosed late, which often limits both the therapeutic options that are available and patient survival. The long-term survival of pancreatic cancer patients is not possible if the tumor is not resected, even among patients who receive chemotherapy in the earliest stages. The main objective of this study was to create a prediction model for in-hospital mortality after a pancreatectomy in pancreatic cancer patients. METHODS: We performed a retrospective study of all pancreatic resections in pancreatic cancer patients in Spanish public hospitals (2013). Data were obtained from records in the Minimum Basic Data Set. To develop the prediction model, we used a boosting method. RESULTS: The in-hospital mortality of pancreatic resections in pancreatic cancer patients was 8.48% in Spain. Our model showed high predictive accuracy, with an AUC of 0.91 and a Brier score of 0.09, which indicated that the probabilities were well calibrated. In addition, a sensitivity analysis of the information available prior to the surgery revealed that our model has high predictive accuracy, with an AUC of 0.802. CONCLUSIONS: In this study, we developed a nation-wide system that is capable of generating accurate and reliable predictions of in-hospital mortality after pancreatic resection in patients with pancreatic cancer. Our model could help surgeons understand the importance of the patients' characteristics prior to surgery and the health effects that may follow resection. PMID- 28591155 TI - Electroacupuncture prevents endothelial dysfunction induced by ischemia reperfusion injury via a cyclooxygenase-2-dependent mechanism: A randomized controlled crossover trial. AB - OBJECTIVE: Exploring clinically effective methods to reduce ischemia-reperfusion (IR) injury in humans is critical. Several drugs have shown protective effects, but studies using other interventions have been rare. Electroacupuncture (EA) has induced similar protection in several animal studies but no study has investigated how the effects could be translated and reproduced in humans. This study aimed to explore the potential effect and mechanisms of EA in IR-induced endothelial dysfunction in humans. METHODS: This is a prospective, randomized, crossover, sham-controlled trial consisting of two protocols. Protocol 1 was a crossover study to investigate the effect of EA on IR-induced endothelial dysfunction. Twenty healthy volunteers were randomly assigned to EA or sham EA (sham). Flow mediated dilation (FMD) of the brachial artery (BA), nitroglycerin mediated endothelial independent dilation, blood pressure before and after IR were measured. In protocol 2, seven volunteers were administered COX-2 inhibitor celecoxib (200 mg orally twice daily) for five days. After consumption, volunteers underwent FMD before and after IR identical to protocol 1. RESULTS: In protocol 1, baseline BA diameter, Pre-IR BA diameter and FMD were similar between the two groups (p = NS). After IR, sham group showed significantly blunted FMD (Pre-IR: 11.41 +/- 3.10%, Post-IR: 4.49 +/- 2.04%, p < 0.001). However, EA protected this blunted FMD (Pre-IR: 10.96 +/- 5.30%, Post-IR: 9.47 +/- 5.23%, p = NS, p < 0.05 compared with sham EA after IR). In protocol 2, this protective effect was completely abolished by pre-treatment with celecoxib (Pre-IR: 11.05 +/ 3.27%; Post-IR: 4.20 +/- 1.68%, p = 0.001). CONCLUSION: EA may prevent IR induced endothelial dysfunction via a COX-2 dependent mechanism. PMID- 28591156 TI - Dark eyes in female sand gobies indicate readiness to spawn. AB - In animals, colorful and conspicuous ornaments enhance individual attractiveness to potential mates, but are typically tempered by natural selection for crypsis and predator protection. In species where males compete for females, this can lead to highly ornamented males competing for mating opportunities with choosy females, and vice versa. However, even where males compete for mating opportunities, females may exhibit conspicuous displays. These female displays are often poorly understood and it may be unclear whether they declare mating intent, signal intrasexual aggression or form a target for male mate preference. We examined the function of the conspicuous dark eyes that female sand gobies temporarily display during courtship by experimentally testing if males preferred to associate with females with artificially darkened eyes and if dark eyes are displayed during female aggression. By observing interactions between a male and two females freely associating in an aquarium we also investigated in which context females naturally displayed dark eyes. We found that dark eyes were more likely to be displayed by more gravid females than less gravid females and possibly ahead of spawning, but that males did not respond behaviorally to dark eyes or prefer dark-eyed females. Females behaving aggressively did not display dark eyes. We suggest that dark eyes are not a signal per se but may be an aspect of female mate choice, possibly related to vision. PMID- 28591157 TI - The impact of de novo liver metastasis on clinical outcome in patients with advanced non-small-cell lung cancer. AB - Liver metastasis has been found to affect outcome in prostate cancer and colorectal cancer, but its role in lung cancer is unclear. The current study aimed to evaluate the impact of de novo liver metastasis (DLM) on stage IV non small cell lung cancer (NSCLC) outcomes and to examine whether tyrosine kinase inhibitors (TKI) reverse poor prognosis in patients with DLM and epidermal growth factor receptor (EGFR)-mutant NSCLC. Among 1392 newly diagnosed NSCLC patients, 490 patients with stage IV disease treated between November 2010 and March 2014 at Kaohsiung Chang Gung Memorial Hospital were included. Patients were divided into two groups according to DLM status. There were 75 patients in the DLM group and 415 patients in the non-DLM group. The DLM group included more patients with bone metastasis, fewer patients with a lymphocyte-to-monocyte ratio (LMR) > 3.1, and fewer patients with pleural metastasis. In the DLM group, Eastern Cooperative Oncology Group performance status 3-4 and LMR ?3.1 were associated with poor outcome. In patients without DLM, overall survival (OS) was longer in patients with EGFR-mutant NSCLC than in those without (20.2 vs. 7.3 months, p < 0.001). Among DLM patients, OS was similar between the EGFR-mutant and wild-type EGFR tumor subgroups (11.9 vs. 7.7 months, p = 0.155). We found that DLM was a significant poor prognostic factor in the EGFR-mutant patients treated with EGFR TKIs, whereas DLM did not affect the prognosis of EGFR-wild-type patients. PMID- 28591159 TI - Technological variability during the Early Middle Palaeolithic in Western Europe. Reduction systems and predetermined products at the Bau de l'Aubesier and Payre (South-East France). AB - The study of the lithic assemblages of two French sites, the Bau de l'Aubesier and Payre, contributes new knowledge of the earliest Neanderthal techno-cultural variability. In this paper we present the results of a detailed technological analysis of Early Middle Palaeolithic lithic assemblages of MIS 8 and 7 age from the two sites, which are located on opposite sides of the Rhone Valley in the south-east of France. The MIS 9-7 period is considered in Europe to be a time of new behaviours, especially concerning lithic strategies. The shift from the Lower Palaeolithic to the Early Middle Palaeolithic is "classically" defined by an increase in the number of core technologies, including standardized ones, which are stabilized in the full Middle Palaeolithic (MIS 5-3), associated with the decline of the "Acheulean" biface. Applying a common technological approach to the analysis of the two assemblages highlights their technological variability with respect to reduction systems and end products. Differences between Payre and the Bau de l'Aubesier concerning raw material procurement and faunal exploitation only partially explain this multifaceted technological variability, which in our opinion also reflects the existence of distinct technological strategies within the same restricted geographic area, which are related to distinct traditions, site uses, and/or as yet unknown parameters. PMID- 28591158 TI - Mitochondrial function of immune cells in septic shock: A prospective observational cohort study. AB - BACKGROUND: Reduced cellular ATP synthesis due to impaired mitochondrial function of immune cells may be a factor influencing the immune response in septic shock. We investigate changes in mitochondrial function and bioenergetics of human monocytes and lymphocyte subsets. METHODS: Thirty patients with septic shock were studied at ICU admission, after 24 and 48 hours, and after resolution of shock. Enzymatic activities of citrate synthase and mitochondrial complexes I, IV, and ATP synthase and ATP content of monocytes, T-cells and B-cells and pro inflammatory (IL-1beta and IL-6) and anti-inflammatory (IL-10) cytokine plasma concentrations were compared to samples from 20 healthy volunteers. RESULTS: Large variations in mitochondrial enzymatic activities of immune cells of septic patients were detected. In monocytes, maximum levels of citrate synthase activity in sepsis were significantly lower when compared to controls (p = 0.021). Maximum relative enzymatic activity (ratio relative to citrate synthase activity) of complex I (p<0.001), complex IV (p = 0.017) and ATP synthase (p<0.001) were significantly higher. In T-cells, maximum levels of citrate synthase (p = 0.583) and relative complex IV (p = 0.602) activity did not differ between patients and controls, whereas levels of relative complex I (p = 0.006) and ATP synthase (p = 0.032) were significantly higher in septic patients. In B-cells of patients, maximum levels of citrate synthase activity (p = 0.004) and relative complex I (p<0.001) were significantly higher, and mean levels of relative complex IV (p = 0.042) lower than the control values, whereas relative ATP synthase activity did not differ (p = 1.0). No significant difference in cellular ATP content was detected in any cell line (p = 0.142-0.519). No significant correlations between specific cytokines and parameters of mitochondrial enzymatic activities or ATP content were observed. CONCLUSIONS: Significant changes of mitochondrial enzymatic activities occur in human peripheral blood immune cells in septic shock when compared to healthy controls. Assessed sub-types of immune cells showed differing patterns of regulation. Total ATP-content of human immune cells did not differ between patients in septic shock and healthy volunteers. PMID- 28591160 TI - The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: The English longitudinal study of ageing. AB - BACKGROUND: Ferritin constitutes a sensitive iron-storage index and multi functional protein. Evidence on its association with mortality in general population is scarce and conflicting. We investigated the sex-specific associations of ferritin levels with all-cause and cardiovascular mortality in a population-based cohort. METHODS: Data came from the English Longitudinal Study of Ageing and the national mortality registry. The sample comprised 5,471 participants aged >=52 years. Blood concentration of ferritin was measured at baseline in 2004-05. Sex-specific Cox proportional hazards models were estimated with adjustment for age, major chronic diseases, marital status, educational attainment, total net household wealth, anemia, inflammatory markers, body mass index, smoking, and physical activity. Stratified analyses by chronic disease status were also performed. RESULTS: We categorized ferritin in sex-specific quartiles. In men, we used, the following categorization: lowest (2-69ng/ml), second lowest (70-118ng/ml), second highest (reference category) (119-193ng/ml) and highest (194-598ng/ml) ferritin quartiles. In women, ferritin was categorized as follows: lowest (2-44ng/ml), second lowest (45-73ng/ml), second highest (reference category) (74-115ng/ml) and highest (116-341ng/ml) ferritin quartiles. 841 deaths of which 262 cardiovascular disease-related were recorded over a mean follow-up time of 7.7 years. Risk for all-cause mortality was found increased in men with hyperferritinemia (194-598ng/ml) and no history of major chronic diseases compared with the reference group [fully-adjusted HR: 1.49 (95%CI 1.03 2.16)]. Among women, those in the lowest ferritin quartile (2-44ng/ml) had increased risk for all-cause mortality [fully-adjusted HR: 1.59 (95%CI 1.18 2.13)] compared with the reference group after adjustment for all covariates. Regarding cardiovascular mortality, we observed a positive association with ferritin levels in men, which was blunted after adjustment for inflammatory markers and lifestyle parameters. Men with no major chronic diseases who were in the highest ferritin quartile had a significantly increased risk of cardiovascular mortality. No association between ferritin levels and cardiovascular mortality was detected in women. CONCLUSION: Circulating ferritin levels showed sex-specific prognostic patterns. High ferritin levels in men with no major chronic disease and low ferritin levels in all women were associated with increased all-cause mortality after adjusting for covariates. High ferritin levels in men with no major chronic diseases were also independently associated with an increased risk of cardiovascular mortality. Future research is needed to clarify the prognostic role of ferritin. PMID- 28591162 TI - Whether weather matters: Evidence of association between in utero meteorological exposures and foetal growth among Indigenous and non-Indigenous mothers in rural Uganda. AB - Pregnancy and birth outcomes have been found to be sensitive to meteorological variation, yet few studies explore this relationship in sub-Saharan Africa where infant mortality rates are the highest in the world. We address this research gap by examining the association between meteorological factors and birth weight in a rural population in southwestern Uganda. Our study included hospital birth records (n = 3197) from 2012 to 2015, for which we extracted meteorological exposure data for the three trimesters preceding each birth. We used linear regression, controlling for key covariates, to estimate the timing, strength, and direction of meteorological effects on birth weight. Our results indicated that precipitation during the third trimester had a positive association with birth weight, with more frequent days of precipitation associated with higher birth weight: we observed a 3.1g (95% CI: 1.0-5.3g) increase in birth weight per additional day of exposure to rainfall over 5mm. Increases in average daily temperature during the third trimester were also associated with birth weight, with an increase of 41.8g (95% CI: 0.6-82.9g) per additional degree Celsius. When the sample was stratified by season of birth, only infants born between June and November experienced a significant associated between meteorological exposures and birth weight. The association of meteorological variation with foetal growth seemed to differ by ethnicity; effect sizes of meteorological were greater among an Indigenous subset of the population, in particular for variation in temperature. Effects in all populations in this study are higher than estimates of the African continental average, highlighting the heterogeneity in the vulnerability of infant health to meteorological variation in different contexts. Our results indicate that while there is an association between meteorological variation and birth weight, the magnitude of these associations may vary across ethnic groups with differential socioeconomic resources, with implications for interventions to reduce these gradients and offset the health impacts predicted under climate change. PMID- 28591161 TI - Health-related quality of life among military HIV patients on antiretroviral therapy. AB - OBJECTIVE: The aims of this study were: (i) to determine the factors associated with HRQOL at baseline in our cohort, and (ii) to evaluate if there are differences in baseline HRQOL measures by antiretroviral treatment. METHODS: The Short Form 36 (SF-36) was administered between 2006 and 2010 among members of the United States HIV Natural History Study cohort (NHS), and participants who completed the SF-36 were included in the study. Physical component summary (PCS) and mental component summary (MCS) scores were computed based on standard algorithms. Multivariate linear regression models were constructed for PCS and MCS to estimate the association between selected variables and HRQOL scores. RESULTS: Antiretroviral therapy (ART) was not independently associated with HRQOL scores. Factors associated with PCS were CD4+ count < 200 cells/mm3 (beta = 5.84, 95% CI: -7.63, -4.06), mental comorbidity (beta = -2.82, 95% CI: -3.79, 1.85), medical comorbidity (beta = -2.51, 95% CI: -3.75, -1.27), AIDS diagnosis (beta = -2.38, 95% CI: -3.79, -0.98). Others were gender, military rank, marital status, and age. Factors independently associated with MCS were CD4+ count < 200 cells/mm3 (beta = -1.93, 95% CI: -3.85, -0.02), mental comorbidity (beta = -6.25, 95% CI: -7.25, -5.25), age (beta = 0.37, 95% CI: 0.14, 0.60), and being African American (beta = 1.55, 95% CI: 0.63, 2.47). CONCLUSION: Among military active duty and beneficiaries with HIV, modifiable factors associated with HRQOL measures included advanced HIV disease, and mental or medical comorbidity. Addressing these factors may improve quality of life of HIV-infected individuals in the NHS cohort. PMID- 28591163 TI - Strong influence of livestock environments on the emergence and dissemination of distinct multidrug-resistant phenotypes among the population of non-typhoidal Salmonella. AB - The problem of emergence and dissemination of multidrug resistance, especially among Gram-negative bacteria, has reached alarming levels. This increases the need to develop surveillance methods that more effectively and accurately provide information about the emergence and spread of multidrug-resistant organisms. In this study, using a well-defined population of non-typhoidal Salmonella (NTS) isolates associated with avian, bovine and porcine hosts, we found that the livestock environments had a specific (P < 0.005) and profound (P < 0.005) effect on the evolution of multidrug-resistant phenotypes among population of NTS isolates. The MDR pattern containing penicillins, tetracyclines and macrolides and the evolving counterparts (i.e., penicillins, tetracyclines and macrolides + other antibiotic classes) were significantly (P < 0.005) associated with NTS isolates of porcine origin. Similarly, MDR patterns containing folate pathway inhibitors, macrolides and aminocyclitol or containing penicillins, cephalosporins, tetracyclines, phenicols and macrolides were significantly associated with avian (P < 0.005) and bovine (P < 0.005) NTS isolates, respectively. Furthermore, STRUCTURE, an evolutionary analysis, clearly showed that the host origin (i.e., livestock environment), and not the genetic background of different NTS serovars, was the most determinative factor for acquisition and spread of MDR phenotypes. In addition, we described a novel non synonymous mutation, located outside of the QRDR at position 864 of GyrA, that was likely associated with fluoroquinolone resistance. PMID- 28591164 TI - Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue. AB - OBJECTIVE: Obesity is associated with an increased risk of diabetes mellitus, hypertension, and renal dysfunction. Angiotensin 1-7 and alamandine are heptameric renin angiotensin system peptide hormones. Further, alamandine levels increase with renal dysfunction. In the cardiovascular system, angiotensin 1-7 and alamandine produce similar improvements and counterbalance angiotensin II in regulating vascular function. We aimed to determine whether the effect of alamandine on leptin expression and secretion in adipocytes was similar to that of angiotensin 1-7. APPROACH AND RESULTS: We studied isolated peri-renal visceral adipose tissue and peri-renal isolated visceral adipocytes from male Wistar rats. Angiotensin II from 0.01 to 10nM had no effect on leptin expression. Angiotensin 1-7 (1 nM) increased leptin secretion and expression, whereas alamandine (1 nM) decreased leptin secretion and expression in adipose tissue and isolated adipocytes and reduced blood leptin levels in vivo. These effects were mediated by Gq, c-Src, p38 mitogen-activated protein, and IkappaB activation. Additionally, alamandine induced nitric oxide expression via inducible nitric oxidase synthase and plasminogen activator inhibitor 1 expression in adipose tissue and isolated adipocytes. CONCLUSIONS: Angiotensin 1-7 and alamandine produced opposing effects on leptin expression and secretion in adipose tissue. This result suggests that the action of Mas (angiotensin 1-7 receptor) and Mas related G-protein coupled receptor D in adipocytes exhibited opposing actions similar to angiotensin II type 1 and type 2 receptors. PMID- 28591166 TI - Assessment of the effectiveness of a small quantity lipid-based nutrient supplement on reducing anaemia and stunting in refugee populations in the Horn of Africa: Secondary data analysis. AB - Stunting and micronutrient malnutrition are persistent public health problems in refugee populations. UNHCR and its partner organisations implement blanket supplementary feeding programmes using a range of special nutritional products as one approach to address these issues. The evidence base for the efficacy and effectiveness of a small quantity lipid-based nutrient supplement, Nutributter(r), in reducing stunting and anaemia is limited. Secondary data analysis was used to assess the effectiveness of Nutributter(r) distribution on anaemia and stunting in children aged 6-23 months (programme target group) and 6 59 months (the standard age group sampled in routine nutrition surveys). Analysis was conducted using routine pre and post-intervention cross-sectional nutrition survey data collected between 2008-2011 in five refugee camps in Kenya and Djibouti. Changes in total anaemia (Haemoglobin<110g/L), anaemia categories (mild, moderate and severe), and stunting (height-for-age z-score <-2) were explored using available data on the Nutributter(r) programme and contextual factors. A significant reduction in the prevalence of anaemia in children aged 6 23 months and 6-59 months was seen in four of five, and in all five camps, respectively (p<0.05). Reductions ranged from 12.4 to 23.0, and 18.3 to 29.3 percentage points in each age group. Improvements were largely due to reductions in moderate and severe anaemia and occurred where the prevalence of acute malnutrition was stable or increasing. No change in stunting was observed in four of five camps. The replicability of findings across five sites strongly suggests that Nutributter(r) distribution was associated with a reduction in anaemia, but not stunting, among refugee children in the Horn of Africa. Benefits were not restricted to the 6-23 month target group targeted by the nutrition programme. However, even following this intervention anaemia remained a serious public health problem and additional work to define and evaluate an effective intervention package is warranted. PMID- 28591165 TI - Dichloroacetate affects proliferation but not apoptosis in canine mammary cell lines. AB - Targeting mitochondrial energy metabolism is a novel approach in cancer research and can be traced back to the description of the Warburg effect. Dichloroacetate, a controversially discussed subject of many studies in cancer research, is a pyruvate dehydrogenase kinase inhibitor. Dichloroacetate causes metabolic changes in cancerous glycolysis towards oxidative phosphorylation via indirect activation of pyruvate dehydrogenase in mitochondria. Canine mammary cancer is frequently diagnosed but after therapy prognosis still remains poor. In this study, canine mammary carcinoma, adenoma and non-neoplastic mammary gland cell lines were treated using 10 mM Dichloroacetate. The effect on cell number, lactate release and PDH expression and cell respiration was investigated. Further, the effect on apoptosis and several apoptotic proteins, proliferation, and microRNA expression was evaluated. Dichloroacetate was found to reduce cell proliferation without inducing apoptosis in all examined cell lines. PMID- 28591167 TI - Genomic analysis of stayability in Nellore cattle. AB - Stayability, which can be defined as the probability of a cow calving at a certain age when given the opportunity, is an important reproductive trait in beef cattle because it is directly related to herd profitability. The objective of this study was to estimate genetic parameters and to identify possible genomic regions associated with the phenotypic expression of stayability in Nellore cows. The variance components were estimated by Bayesian inference using a threshold animal model that included the systematic effects of contemporary group and sexual precocity and the random effects of animal and residual. The SNP effects were estimated by the single-step genomic BLUP method using information of 2,838 animals (2,020 females and 930 sires) genotyped with the Illumina High-Density BeadChip Array (San Diego, CA, USA). The variance explained by windows formed by 200 consecutive SNPs was used to identify genomic regions of largest effect on the expression of stayability. The heritability was 0.11 +/- 0.01 when A matrix (pedigree) was used and 0.14 +/- 0.01 when H matrix (relationship matrix that combines pedigree information and SNP data) was used. A total of 147 candidate genes for stayability were identified on chromosomes 1, 2, 5, 6, 9 and 20 and on the X chromosome. New candidate regions for stayability were detected, most of them related to reproductive, immunological and central nervous system functions. PMID- 28591168 TI - Exploiting repetitive sequences and BAC clones in Festuca pratensis karyotyping. AB - The Festuca genus is thought to be the most numerous genus of the Poaceae family. One of the most agronomically important forage grasses, Festuca pratensis Huds. is treated as a model plant to study the molecular mechanisms associated with tolerance to winter stresses, including frost. However, the precise mapping of the genes governing stress tolerance in this species is difficult as its karyotype remains unrecognized. Only two F. pratensis chromosomes with 35S and 5S rDNA sequences can be easily identified, but its remaining chromosomes have not been distinguished to date. Here, two libraries derived from F. pratensis nuclear DNA with various contents of repetitive DNA sequences were used as sources of molecular probes for fluorescent in situ hybridisation (FISH), a BAC library and a library representing sequences most frequently present in the F. pratensis genome. Using FISH, six groups of DNA sequences were revealed in chromosomes on the basis of their signal position, including dispersed-like sequences, chromosome painting-like sequences, centromeric-like sequences, knob-like sequences, a group without hybridization signals, and single locus-like sequences. The last group was exploited to develop cytogenetic maps of diploid and tetraploid F. pratensis, which are presented here for the first time and provide a remarkable progress in karyotype characterization. PMID- 28591170 TI - A potential role of microRNAs in protein accumulation in cellular senescence analyzed by bioinformatics. AB - Cellular senescence is an important protective mechanism against cell proliferation and has critical roles in aging and aging-related disease. Recently, one interesting observation is that the protein abundance is higher in senescent cells than that in young cells. So far, some factors were presented to interpret this observation, such as active protein synthesis linked with autophagy, mTOR, and oxidative stress. Here, applying bioinformatic analysis of microRNA profiles in young cells and aging cells, we revealed that globally senescent cells show lower miRNA abundance than that in young cells, suggesting that the repression of protein synthesis by miRNA in senescent cells could be largely attenuated. This finding provides clues that protein accumulation in cellular senescence could be associated with lower miRNA abundance in aging cells. PMID- 28591169 TI - Exposure of bighorn sheep to domestic goats colonized with Mycoplasma ovipneumoniae induces sub-lethal pneumonia. AB - BACKGROUND: Bronchopneumonia is a population limiting disease of bighorn sheep (Ovis canadensis) that has been associated with contact with domestic Caprinae. The disease is polymicrobial but is initiated by Mycoplasma ovipneumoniae, which is commonly carried by both domestic sheep (O. aries) and goats (Capra aegagrus hircus). However, while previous bighorn sheep comingling studies with domestic sheep have resulted in nearly 100% pneumonia mortality, only sporadic occurrence of fatal pneumonia was reported from previous comingling studies with domestic goats. Here, we evaluated the ability of domestic goats of defined M. ovipneumoniae carriage status to induce pneumonia in comingled bighorn sheep. METHODOLOGY/PRINCIPAL FINDINGS: In experiment 1, three bighorn sheep naive to M. ovipneumoniae developed non-fatal respiratory disease (coughing, nasal discharge) following comingling with three naturally M. ovipneumoniae-colonized domestic goats. Gross and histological lesions of pneumonia, limited to small areas on the ventral and lateral edges of the anterior and middle lung lobes, were observed at necropsies conducted at the end of the experiment. A control group of three bighorn sheep from the same source housed in isolation during experiment 1 remained free of observed respiratory disease. In experiment 2, three bighorn sheep remained free of observed respiratory disease while comingled with three M. ovipneumoniae-free domestic goats. In experiment 3, introduction of a domestic goat-origin strain of M. ovipneumoniae to the same comingled goats and bighorn sheep used in experiment 2 resulted in clinical signs of respiratory disease (coughing, nasal discharge) in both host species. At the end of experiment 3, gross and histological evidence of pneumonia similar to that observed in experiment 1 bighorn sheep was observed in both affected bighorn sheep and domestic goats. CONCLUSIONS/SIGNIFICANCE: M. ovipneumoniae strains carried by domestic goats were transmitted to comingled bighorn sheep, triggering development of pneumonia. However, the severity of the disease was markedly milder than that seen in similar experiments with domestic sheep strains of the bacterium. PMID- 28591171 TI - Mixed-mode oscillations in pyramidal neurons under antiepileptic drug conditions. AB - Subthreshold oscillations in combination with large-amplitude oscillations generate mixed-mode oscillations (MMOs), which mediate various spatial and temporal cognition and memory processes and behavioral motor tasks. Although many studies have shown that canard theory is a reliable method to investigate the properties underlying the MMOs phenomena, the relationship between the results obtained by applying canard theory and conductance-based models of neurons and their electrophysiological mechanisms are still not well understood. The goal of this study was to apply canard theory to the conductance-based model of pyramidal neurons in layer V of the Entorhinal Cortex to investigate the properties of MMOs under antiepileptic drug conditions (i.e., when persistent sodium current is inhibited). We investigated not only the mathematical properties of MMOs in these neurons, but also the electrophysiological mechanisms that shape spike clustering. Our results show that pyramidal neurons can display two types of MMOs and the magnitude of the slow potassium current determines whether MMOs of type I or type II would emerge. Our results also indicate that slow potassium currents with large time constant have significant impact on generating the MMOs, as opposed to fast inward currents. Our results provide complete characterization of the subthreshold activities in MMOs in pyramidal neurons and provide explanation to experimental studies that showed MMOs of type I or type II in pyramidal neurons under antiepileptic drug conditions. PMID- 28591172 TI - Multi-state modelling of heart failure care path: A population-based investigation from Italy. AB - BACKGROUND: How different risk profiles of heart failure (HF) patients can influence multiple readmissions and outpatient management is largely unknown. We propose the application of two multi-state models in real world setting to jointly evaluate the impact of different risk factors on multiple hospital admissions, Integrated Home Care (IHC) activations, Intermediate Care Unit (ICU) admissions and death. METHODS AND FINDINGS: The first model (model 1) concerns only hospitalizations as possible events and aims at detecting the determinants of repeated hospitalizations. The second model (model 2) considers both hospitalizations and ICU/IHC events and aims at evaluating which profiles are associated with transitions in intermediate care with respect to repeated hospitalizations or death. Both are characterized by transition specific covariates, adjusting for risk factors. We identified 4,904 patients (4,129 de novo and 775 worsening heart failure, WHF) hospitalized for HF from 2009 to 2014. 2,714 (55%) patients died. Advanced age and higher morbidity load increased the rate of dying and of being rehospitalized (model 1), decreased the rate of being discharged from hospital (models 1 and 2) and increased the rate of inactivation of IHC (model 2). WHF was an important risk factor associated with hospital readmission. CONCLUSION: Multi-state models enable a better identification of two patterns of HF patients. Once adjusted for age and comorbidity load, the WHF condition identifies patients who are more likely to be readmitted to hospital, but does not represent an increasing risk factor for activating ICU/IHC. This highlights different ways to manage specific patients' patterns of care. These results provide useful healthcare support to patients' management in real world context. Our study suggests that the epidemiology of the considered clinical characteristics is more nuanced than traditionally presented through a single event. PMID- 28591173 TI - Overinterpretation is common in pathological diagnosis of appendix cancer during patient referral for oncologic care. AB - CONTEXT: Low-grade appendiceal mucinous neoplasm (LAMN) and appendiceal adenocarcinoma are known to cause the majority of pseudomyxoma peritonei (PMP, i.e. mucinous ascites); however, recognition and proper classification of these neoplasms can be difficult despite established diagnostic criteria. OBJECTIVE: To determine the pathological diagnostic concordance for appendix neoplasia and related lesions during patient referral to an academic medical center specialized in treating patients with PMP. DESIGN: The anatomic pathology laboratory information system was searched to identify cases over a two-year period containing appendix specimens with mucinous neoplasia evaluated by an outside pathology group and by in-house slide review at a single large academic medical center during patient referral. RESULTS: 161 cases containing appendix specimens were identified over this period. Forty-six of 161 cases (28.6%) contained appendiceal primary neoplasia or lesions. Of these, the originating pathologist diagnosed 23 cases (50%) as adenocarcinoma and 23 cases (50%) as LAMN; however, the reference pathologist diagnosed 29 cases (63.0%) as LAMN, 13 cases (28.3%) as adenocarcinoma, and 4 cases (8.7%) as ruptured simple mucocele. Importantly, for cases in which the originating pathologist rendered a diagnosis of adenocarcinoma, the reference pathologist rendered a diagnosis of adenocarcinoma (56.5%, 13 of 23), LAMN (39.1%, 9 of 23), or simple mucocele (4.3%, 1 of 23). The overall diagnostic concordance rate for these major classifications was 71.7% (33 of 46) with an unweighted observed kappa value of 0.48 (95% CI, 0.27-0.69), consistent with moderate interobserver agreement. All of the observed discordance (28.3%) for major classifications could be attributed to over-interpretation. In addition, the majority of LAMN cases (65.5%) had potential diagnostic deficiencies including over-interpretation as adenocarcinoma and lacking or discordant risk stratification (i.e. documentation of extra-appendiceal neoplastic epithelium). CONCLUSIONS: Appendiceal mucinous lesions remain a difficult area for appropriate pathological classification with substantial discordance due to over-interpretation in this study. The findings highlight the critical need for recognition and application of diagnostic criteria regarding these tumors. Recently published consensus guidelines and a checklist provided herein may help facilitate improvement of diagnostic concordance and thereby reduce over-interpretation and potential overtreatment. Further studies are needed to determine the extent of this phenomenon and its potential clinical impact. PMID- 28591174 TI - The acute effects of lower limb intermittent negative pressure on foot macro- and microcirculation in patients with peripheral arterial disease. AB - BACKGROUND: Intermittent negative pressure (INP) applied to the lower leg and foot increases foot perfusion in healthy volunteers. The aim of the present study was to describe the effects of INP to the lower leg and foot on foot macro- and microcirculation in patients with lower extremity peripheral arterial disease (PAD). METHODS: In this experimental study, we analyzed foot circulation during INP in 20 patients [median (range): 75 (63-84yrs)] with PAD. One leg was placed inside an air-tight vacuum chamber connected to an INP-generator. During application of INP (alternating 10s of -40mmHg/7s of atmospheric pressure), we continuously recorded blood flow velocity in a distal foot artery (ultrasound Doppler), skin blood flow on the pulp of the first toes (laser Doppler), heart rate (ECG), and systemic blood pressure (Finometer). After a 5-min baseline sequence (no pressure), a 10-min INP sequence was applied, followed by 5-min post INP (no pressure). To compare and quantify blood flow fluctuations between sequences, we calculated cumulative up-and-down fluctuations in arterial blood flow velocity per minute. RESULTS: Onset of INP induced an increase in arterial flow velocity and skin blood flow. Peak blood flow velocity was reached 3s after the onset of negative pressure, and increased 46% [(95% CI 36-57), P<0.001] above baseline. Peak skin blood flow was reached 2s after the onset of negative pressure, and increased 89% (95% CI 48-130), P<0.001) above baseline. Cumulative fluctuations per minute were significantly higher during INP-sequences compared to baseline [21 (95% CI 12-30)cm/s/min to 41 (95% CI 32-51)cm/s/min, P<0.001]. Mean INP blood flow velocity increased significantly ~12% above mean baseline blood flow velocity [(6.7 (95% CI 5.2-8.3)cm/s to 7.5 (95% CI 5.9-9.1)cm/s, P = 0.03)]. CONCLUSION: INP increases foot macro- and microcirculatory flow pulsatility in patients with PAD. Additionally, application of INP resulted in increased mean arterial blood flow velocity. PMID- 28591176 TI - Moxibustion treatment for primary osteoporosis: A systematic review of randomized controlled trials. AB - Primary osteoporosis (POP) has a serious impact on quality of life for middle aged and elderly, which particularly increase the risk of fracture. We conducted the systematic review to evaluate the effects of moxibustion for POP in randomized controlled trials (RCTs).Eight databases were searched from their inception to July 30, 2016. The RCTs reporting the moxibustion as a monotherapy or in combination with conventional therapy for POP were enrolled. The outcomes might be fracture incidence, quality of life, clinical symptoms, death attributed to osteoporosis, adverse effect, bone mineral density (BMD), and biochemical indicators. Literature selection, data abstraction, quality evaluation, and data analysis were in accordance with Cochrane standards.Thirteen trials including 808 patients were included. Meta-analysis was not conducted because of the obvious clinical or statistical heterogeneity. Limited evidence suggested that moxibustion plus anti-osteoporosis medicine might be more effective in relieving the pain (visual analogue scale scores average changed 2 scores between groups, 4 trials), increasing the BMD of femoral neck (average changed 0.4 g/cm2 between groups, 3 trials), and improving the level of bone gla protein, osteoprotegerin and bone alkaline phosphatase (2 trials) compared with anti-osteoporosis medicine alone. However, the quality of previous studies was evaluated as generally poor. The safety evidence of moxibustion was still insufficient. Due to the paucity of high-quality studies, there was no definite conclusion about the efficacy and safety of moxibustion treating POP although parts of positive results were presented. Future research should pay attention to the dose-response relation and fracture incidence of moxibustion for POP. PMID- 28591175 TI - Tigers in the Terai: Strong evidence for meta-population dynamics contributing to tiger recovery and conservation in the Terai Arc Landscape. AB - The source populations of tigers are mostly confined to protected areas, which are now becoming isolated. A landscape scale conservation strategy should strive to facilitate dispersal and survival of dispersing tigers by managing habitat corridors that enable tigers to traverse the matrix with minimal conflict. We present evidence for tiger dispersal along transboundary protected areas complexes in the Terai Arc Landscape, a priority tiger landscape in Nepal and India, by comparing camera trap data, and through population models applied to the long term camera trap data sets. The former showed that 11 individual tigers used the corridors that connected the transboundary protected areas. The estimated population growth rates using the minimum observed population size in two protected areas in Nepal, Bardia National Park and Suklaphanta National Park showed that the increases were higher than expected from growth rates due to in situ reproduction alone. These lines of evidence suggests that tigers are recolonizing Nepal's protected areas from India, after a period of population decline, and that the tiger populations in the transboundary protected areas complexes may be maintained as meta-population. Our results demonstrate the importance of adopting a landscape-scale approach to tiger conservation, especially to improve population recovery and long term population persistence. PMID- 28591177 TI - Identification and characterization of CONSTANS-like (COL) gene family in upland cotton (Gossypium hirsutum L.). AB - The CONSTANS/FLOWERING LOCUS T (CO/FT) regulon plays a central role in the control of flowering time in photoperiod-sensitive plants. Flowering time in wild cotton (Gossypium spp.) has strict photoperiod sensitivity, but domesticated cotton is day-neutral. Information on the molecular characterization of the CO and CO-like (COL) genes in cotton is very limited. In this study, we identified 42 COL homologs (GhCOLs) in the G. hirsutum genome, and many of them were previously unreported. We studied their chromosome distribution, phylogenetic relationships, and structures of genes and proteins. Our results showed that GhCOLs were classified into three groups, and 14 COLs in group I showed conserved structure when compared with other plants. Two homoeologous pairs, GhCOL1-A and GhCOL1-D in Group I, showed the highest sequence similarity to Arabidopsis thaliana CO and rice CO homologous gene Heading date1 (Hd1). Tissue-specific expression showed that 42 GhCOL genes may function as tissue-specific regulators in different cells or organs. We cloned and sequenced the 14 GhCOL genes in Group I related to flowering induction to study their diurnal expression pattern, and found that their expression showed distinct circadian regulation. Most of them peaked at dawn and decreased rapidly to their minima at dusk, then started to accumulate until following dawn under long- or short-day conditions. Transgenic study in the Arabidopsis co-2 mutant demonstrated that GhCOL1-A and GhCOL1-D fully rescued the late-flowering phenotype, whereas GhCOL3-A, GhCOL3-D, GhCOL7-A, and GhCOL7-D partially rescued the late-flowering phenotype, and the other five homoeologous pairs in Group I did not promote flowering. These results indicate that GhCOL1-A and GhCOL1-D were potential flowering inducers, and are candidate genes for research in flowering regulation in cotton. PMID- 28591178 TI - Unfolded protein response plays a critical role in heart damage after myocardial ischemia/reperfusion in rats. AB - The unfolded protein response (UPR) plays a critical role in cell death mediated by ischemia/reperfusion (I/R) injury. However, little is known about the exact mechanism of UPR signaling pathways after myocardial I/R injury in rats. An attempt was therefore made to assess whether the myocardial I/R induced UPR, and which branch of UPR (ATF6, IRE1 and PERK) signal pathway was activated. Sprague Dawley rats were pretreated with UPR stimulator dithiothreitol (DTT) and UPR inhibitor 4-phenylbutyrate (4PBA) and then subjected to myocardial I/R surgery. Compared with sham-operated group, the expression of GRP78, ATF6, CHOP and sXBP1 in the I/R injured group is significantly increased at transcript and protein levels, which indicated that all the three signal pathways of UPR were activated in the myocardial I/R injury. Compared with the I/R injured group, treatment with 4PBA effectively decreased myocardium infarct size, reduced myocardial apoptosis, down-regulated caspase-12 expression, diminished serum creatine kinase and lactate dehydrogenase levels. In contrast, these effects were reversed in DTT treated group. In summary, these results demonstrated that myocardial I/R injury activates UPR and inhibiting cell UPR possesses a cardioprotective effect through the suppression of ER stress-induced apoptosis. Therefore, inhibition of UPR might be used as a therapeutic target during myocardial I/R injury. PMID- 28591179 TI - A systematic review of elephant impact across Africa. AB - Contradictory findings among scientific studies that address a particular issue may impede the conversion of science to management implementation. A systematic review of peer-reviewed studies to generate a single outcome may overcome this problem. The contentious topic of the impact that a megaherbivore such as the savanna elephant have for other species and their environment can benefit from such an approach. After some 68 years, 367 peer-reviewed papers covered the topic and 51 of these papers provided sufficient data to be included in a meta analysis. We separated the direct impact that elephants had on trees and herbs from the indirect effects on other vertebrates, invertebrates, and soil properties. Elephants have an impact on tree structure and abundance but no overall negative cascading effects for species that share space with them. Primary productivity explained a small amount of variation of elephant impact on vegetation. Elephant numbers (density), study duration, rainfall, tree cover, and the presence of artificial water and fences failed to describe patterns of impact. We conclude that published information do not support the calls made for artificially manipulating elephant numbers to ameliorate elephant impact, and call for the management of space use by elephants to maintain savanna heterogeneity. PMID- 28591180 TI - The oldest fossil mushroom. AB - A new fossil mushroom is described and illustrated from the Lower Cretaceous Crato Formation of northeast Brazil. Gondwanagaricites magnificus gen. et sp. nov. is remarkable for its exceptional preservation as a mineralized replacement in laminated limestone, as all other fossil mushrooms are known from amber inclusions. Gondwanagaricites represents the oldest fossil mushroom to date and the first fossil mushroom from Gondwana. PMID- 28591181 TI - Combined use of tri-axial accelerometers and GPS reveals the flexible foraging strategy of a bird in relation to weather conditions. AB - Tri-axial accelerometry has proved to be a useful technique to study animal behavior with little direct observation, and also an effective way to measure energy expenditure, allowing a refreshing revisit to optimal foraging theory. This theory predicts that individuals should gain the most energy for the lowest cost in terms of time and energy when foraging, in order to maximize their fitness. However, during a foraging trip, central-place foragers could face different trade-offs during the commuting and searching parts of the trip, influencing behavioral decisions. Using the lesser kestrel (Falco naumanni) as an example we study the time and energy costs of different behaviors during the commuting and searching parts of a foraging trip. Lesser kestrels are small insectivorous falcons that behave as central-place foragers during the breeding season. They can commute by adopting either time-saving flapping flights or energy-saving soaring-gliding flights, and capture prey by using either time saving active hovering flights or energy-saving perch-hunting. We tracked 6 lesser kestrels using GPS and tri-axial accelerometers during the breeding season. Our results indicate that males devoted more time and energy to flight behaviors than females in agreement with being the sex responsible for food provisioning to the nest. During the commuting flights, kestrels replaced flapping with soaring-gliding flights as solar radiation increased and thermal updrafts got stronger. In the searching part, they replaced perch-hunting with hovering as wind speed increased and they experienced a stronger lift. But also, they increased the use of hovering as air temperature increased, which has a positive influence on the activity level of the preferred prey (large grasshoppers). Kestrels maintained a constant energy expenditure per foraging trip, although flight and hunting strategies changed dramatically with weather conditions, suggesting a fixed energy budget per trip to which they adjusted their commuting and searching strategies in response to weather conditions. PMID- 28591182 TI - An integrated calcium imaging processing toolbox for the analysis of neuronal population dynamics. AB - The development of new imaging and optogenetics techniques to study the dynamics of large neuronal circuits is generating datasets of unprecedented volume and complexity, demanding the development of appropriate analysis tools. We present a comprehensive computational workflow for the analysis of neuronal population calcium dynamics. The toolbox includes newly developed algorithms and interactive tools for image pre-processing and segmentation, estimation of significant single neuron single-trial signals, mapping event-related neuronal responses, detection of activity-correlated neuronal clusters, exploration of population dynamics, and analysis of clusters' features against surrogate control datasets. The modules are integrated in a modular and versatile processing pipeline, adaptable to different needs. The clustering module is capable of detecting flexible, dynamically activated neuronal assemblies, consistent with the distributed population coding of the brain. We demonstrate the suitability of the toolbox for a variety of calcium imaging datasets. The toolbox open-source code, a step-by step tutorial and a case study dataset are available at https://github.com/zebrain-lab/Toolbox-Romano-et-al. PMID- 28591183 TI - Acanthamoeba castellanii is not be an adequate model to study human adenovirus interactions with macrophagic cells. AB - Free living amoebae (FLA) including Acanthamoeba castellanii, are protozoa that feed on different microorganisms including viruses. These microorganisms show remarkable similarities with macrophages in cellular structures, physiology or ability to phagocyte preys, and some authors have therefore wondered whether Acanthamoeba and macrophages are evolutionary related. It has been considered that this amoeba may be an in vitro model to investigate relationships between pathogens and macrophagic cells. So, we intended in this study to compare the interactions between a human adenovirus strain and A. castellanii or THP-1 macrophagic cells. The results of molecular and microscopy techniques following co-cultures experiments have shown that the presence of the adenovirus decreased the viability of macrophages, while it has no effect on amoebic viability. On another hand, the viral replication occurred only in macrophages. These results showed that this amoebal model is not relevant to explore the relationships between adenoviruses and macrophages in in vitro experiments. PMID- 28591184 TI - Occult hepatitis B virus infection in HIV positive patients at a tertiary healthcare unit in eastern India. AB - Occult HBV infection (OBI), defined by the presence of HBV DNA in absence of hepatitis B surface antigen (HBsAg), is a significant concern in the HIV-infected population. Of 441 HIV+/HBsAg- patients analyzed, the overall prevalence of OBI was 6.3% (28/441). OBI was identified in 21 anti-HBc positives (17.8%), as well as among those who lacked any HBV-specific serological markers (2.2%). Comparison with HIV/HBV co-infection revealed that the levels of CD4, ALT, and HBV DNA were significantly lower during occult infection. Discrete differences were also observed with respect to quasispecies divergence. Additionally, subgenotype D1 was most frequent in occult infection, while D2 was widespread during chronic infection. The majority (~90%) of occult D1 sequences had the sQ129R mutation in the surface gene. This study highlights several distinct features of OBI in India and underscores the need for additional HBV DNA screening in HIV-positive individuals. PMID- 28591185 TI - Selection of suitable endogenous reference genes for qPCR in kidney and hypothalamus of rats under testosterone influence. AB - Real-time quantitative PCR (qPCR) is the most reliable and accurate technique for analyses of gene expression. Endogenous reference genes are being used to normalize qPCR data even though their expression may vary under different conditions and in different tissues. Nonetheless, verification of expression of reference genes in selected studied tissue is essential in order to accurately assess the level of expression of target genes of interest. Therefore, in this study, we attempted to examine six commonly used reference genes in order to identify the gene being expressed most constantly under the influence of testosterone in the kidneys and hypothalamus. The reference genes include glyceraldehyde-3-phosphate dehydrogenase (GAPDH), actin beta (ACTB), beta-2 microglobulin (B2m), hypoxanthine phosphoribosyltransferase 1 (HPRT), peptidylprolylisomerase A (Ppia) and hydroxymethylbilane synthase (Hmbs). The cycle threshold (Ct) value for each gene was determined and data obtained were analyzed using the software programs NormFinder, geNorm, BestKeeper, and rank aggregation. Results showed that Hmbs and Ppia genes were the most stably expressed in the hypothalamus. Meanwhile, in kidneys, Hmbs and GAPDH appeared to be the most constant genes. In conclusion, variations in expression levels of reference genes occur in kidneys and hypothalamus under similar conditions; thus, it is important to verify reference gene levels in these tissues prior to commencing any studies. PMID- 28591187 TI - Male suicide rates in German prisons and the role of citizenship. AB - PURPOSE: Prisoners are at a particularly high risk of suicide. In contrast to other psychosocial risk factors it remains unclear to what degree the risk of suicide differs between prisoners with local citizenship and foreigners. In order to provide more detailed information for suicide prevention in prisons, this study aims to compare suicide rates (SR) between these populations in German criminal custody. METHODS: Based on a German national database of completed suicide in custody, suicides by prisoners were analysed and compared with epidemiological data of the prison population and the general population, stratified for German and foreign citizenship. Data analysis was adjusted for differences in the age distribution of both populations by calculating standard mortality ratios (SMR) for suicide. RESULTS: SR were higher in prisoners with German citizenship than those with foreign citizenship (SR = 76.5 vs. SR = 42.8, P<0.01). This association was not specific to the prison population, as the higher SR in citizens compared to non-citizens (SR = 19.3 vs. SR = 9.0, P<0.01) were also found in the general population. The association between prison suicide and citizenship was comparable in juvenile and adult prisoners, indicating its relevance to both the juvenile and adult detention systems. CONCLUSION: Imprisonment is associated with a substantially increased risk of suicide in both German and non-German citizens, a finding which needs to be taken into consideration by the justice system. The lower suicide risk in non-German citizens is independent of whether or not they are in custody. PMID- 28591188 TI - A constrained multinomial Probit route choice model in the metro network: Formulation, estimation and application. AB - Considering that metro network expansion brings us with more alternative routes, it is attractive to integrate the impacts of routes set and the interdependency among alternative routes on route choice probability into route choice modeling. Therefore, the formulation, estimation and application of a constrained multinomial probit (CMNP) route choice model in the metro network are carried out in this paper. The utility function is formulated as three components: the compensatory component is a function of influencing factors; the non-compensatory component measures the impacts of routes set on utility; following a multivariate normal distribution, the covariance of error component is structured into three parts, representing the correlation among routes, the transfer variance of route, and the unobserved variance respectively. Considering multidimensional integrals of the multivariate normal probability density function, the CMNP model is rewritten as Hierarchical Bayes formula and M-H sampling algorithm based Monte Carlo Markov Chain approach is constructed to estimate all parameters. Based on Guangzhou Metro data, reliable estimation results are gained. Furthermore, the proposed CMNP model also shows a good forecasting performance for the route choice probabilities calculation and a good application performance for transfer flow volume prediction. PMID- 28591186 TI - Increasing incidence of mucormycosis in a large Spanish hospital from 2007 to 2015: Epidemiology and microbiological characterization of the isolates. AB - We studied 19 cases of proven/probable mucormycosis diagnosed from 2007 to 2015 in our hospital and assessed the microbiological characteristics of the isolates. We recorded the incidence of mucormycosis and clinical and microbiological data of infected patients. Isolates were identified to molecular level and tested for their antifungal susceptibility to azoles, amphotericin B, and liposomal amphotericin B according to the CLSI M-38 A2 procedure. The incidence of mucormycosis in cases/100,000 hospital admissions during 2007-2015 increased significantly with respect to that reported in 1988-2006 (3.3 vs. 1.2; P<0.05). Patients mainly had hematological malignancies (52.6%) and/or trauma/surgical wounds (52.6%) and had received antifungal agents before the diagnosis of mucormycosis in 68% of cases. Diagnosis was by isolation (n = 17/19) and/or direct staining (n = 17/18) of Mucorales fungi in clinical samples. Identification was by panfungal PCR in patients with negative results in culture and in direct staining. The microorganisms identified were Lichtheimia spp. (42%), Rhizopus spp. (21%), Cunninghamella bertholletiae (16%), and others (21%). Liposomal amphotericin B was always more active than the other drugs against all the microorganisms except C. bertholletiae. All patients received antifungal treatment with 1 or more antifungal agents, mainly liposomal amphotericin B (17/19). Mortality was 47.4%, although this was significantly lower in the 11 patients in whom debridement was performed (18% vs. 87.5%) (P = 0.015). The incidence of mucormycosis has risen in recent years. The proportion of cases with soft tissue involvement was high, and Lichtheimia was the most frequently involved species. The highest antifungal activity was observed with liposomal amphotericin B. PMID- 28591190 TI - Statistical methods used in the public health literature and implications for training of public health professionals. AB - Statistical literacy and knowledge is needed to read and understand the public health literature. The purpose of this study was to quantify basic and advanced statistical methods used in public health research. We randomly sampled 216 published articles from seven top tier general public health journals. Studies were reviewed by two readers and a standardized data collection form completed for each article. Data were analyzed with descriptive statistics and frequency distributions. Results were summarized for statistical methods used in the literature, including descriptive and inferential statistics, modeling, advanced statistical techniques, and statistical software used. Approximately 81.9% of articles reported an observational study design and 93.1% of articles were substantively focused. Descriptive statistics in table or graphical form were reported in more than 95% of the articles, and statistical inference reported in more than 76% of the studies reviewed. These results reveal the types of statistical methods currently used in the public health literature. Although this study did not obtain information on what should be taught, information on statistical methods being used is useful for curriculum development in graduate health sciences education, as well as making informed decisions about continuing education for public health professionals. PMID- 28591189 TI - Shift from slow- to fast-water habitats accelerates lineage and phenotype evolution in a clade of Neotropical suckermouth catfishes (Loricariidae: Hypoptopomatinae). AB - Identifying habitat characteristics that accelerate organismal evolution is essential to understanding both the origins of life on Earth and the ecosystem properties that are most critical to maintaining life into the future. Searching for these characteristics on a large scale has only recently become possible via advances in phylogenetic reconstruction, time-calibration, and comparative analyses. In this study, we combine these tools with habitat and phenotype data for 105 species in a clade of Neotropical suckermouth catfishes commonly known as cascudinhos. Our goal was to determine whether riverine mesohabitats defined by different flow rates (i.e., pools vs. rapids) and substrates (plants vs. rocks) have affected rates of cascudinho cladogenesis and morphological diversification. In contrast to predictions based on general theory related to life in fast flowing, rocky riverine habitats, Neoplecostomini lineages associated with these habitats exhibited increased body size, head shape diversity, and lineage and phenotype diversification rates. These findings are consistent with a growing understanding of river rapids as incubators of biological diversification and specialization. They also highlight the urgent need to conserve rapids habitats throughout the major rivers of the world. PMID- 28591191 TI - Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability. AB - While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways. PMID- 28591192 TI - Perinatal outcomes and congenital heart defect prognosis in 53313 non-selected perinatal infants. AB - OBJECTIVE: To evaluate perinatal outcomes and congenital heart defect (CHD) prognosis in a non-selected population. METHODS: The population-based surveillance data used in this assessment of CHDs were based on birth defect surveillance data collected from 2010-2012 in Liuyang City, China. Infants living with CHDs were followed up for 5 years to determine their prognosis. Prevalence, prenatal diagnosis, perinatal outcomes, and total and type-specific prognosis data were assessed using SPSS 18.0. RESULTS: In total, 190 CHD cases were identified among the 53313 included perinatal infants (PIs), indicating a CHD prevalence of 35.64 per 10000 PIs in this non-selected population. The five most frequently identified types of CHDs were ventricular septal defects (VSDs, 38.95%), atrial septal defects (ASDs, 15.79%), cardiomegaly (7.89%), tetralogy of Fallot (TOF, 5.79%), and atrioventricular septal defects (AVSDs, 5.26%). Of the 190 CHD cases, 110 (57.89%) were diagnosed prenatally, 30 (15.79%) were diagnosed with associated malformations, and 69 (36.32%) resulted in termination of pregnancy (TOP). Moreover, 15 (7.89%) PIs died within 7 days after delivery, and 42 (22.10%) died within 1 year. In contrast, 79 (41.58%) were still alive after 5 years. When TOP cases were included, the 5-year survival rate of PIs with prenatally detected CHDs was lower than that of PIs with postnatally detected CHDs (25.45% vs. 63.75%). The CHD subtype associated with the highest rate of infant (less than 1 year old) mortality was transposition of the great arteries (100%). The subtypes associated with higher 5-year survival rates were patent ductus arteriosus (80%), ASD (63.33%), VSD (52.70%) and AVSD (50%). CONCLUSIONS: The rates of prenatal CHD detection and TOP were high in this study population, and the 5-year survival rate of PIs with CHDs was low. The government should strengthen efforts to educate pediatricians regarding this issue and provide financial assistance to improve the prognosis of infants living with CHDs, especially during the first year of life. PMID- 28591193 TI - Differential effects of formaldehyde exposure on airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice. AB - Epidemiological evidence suggests that formaldehyde (FA) exposure may influence the prevalence and severity of allergic asthma. However, the role of genetic background in FA-induced asthma-like responses is poorly understood. In the present study, we investigated the nature and severity of asthma-like responses triggered by exposure to different doses of FA together with or without ovalbumin (OVA) in two genetically different mouse strains-BALB/c and C57BL/6. Both mouse strains were divided into two main groups: the non-sensitized group and the OVA sensitized group. All the groups were exposed to 0, 0.5 or 3.0 mg/m3 FA for 6 h/day over 25 consecutive days. At 24 h after the final FA exposure, the pulmonary parameters were evaluated. We found that FA exposure induced Th2-type allergic responses in non-sensitized BALB/c and C57BL/6 mice. In addition, FA induced allergic responses were significantly more prominent in BALB/c mice than in C57BL/6 mice. In sensitized BALB/c mice, however, FA exposure suppressed the development of OVA-induced allergic responses. Exposure to 3.0 mg/m3 FA in sensitized C57BL/6 mice also led to suppressed allergic responses, whereas exposure to 0.5 mg/m3 FA resulted in exacerbated allergic responses to OVA. Our findings suggest that FA exposure can induce differential airway inflammation and bronchial hyperresponsiveness in BALB/c and C57BL/6 mice. PMID- 28591194 TI - Regulation of neural stem cell proliferation and differentiation by Kinesin family member 2a. AB - In the developing neocortex, cells in the ventricular/subventricular zone are largely multipotent neural stem cells and neural progenitor cells. These cells undergo self-renewal at the early stage of embryonic development to amplify the progenitor pool and subsequently differentiate into neurons. It is thus of considerable interest to investigate mechanisms controlling the switch from neural stem cells or neural progenitor cells to neurons. Here, we present evidence that Kif2a, a member of the Kinesin-13 family, plays a role in regulating the proliferation and differentiation of neural stem cells or neural progenitor cells at embryonic day 13.5. Silencing Kif2a by use of in utero electroporation of Kif2a shRNA reduced neural stem cells proliferation or self renewal but increased neuronal differentiation. We further found that knockdown of Kif2a decreased the protein level of beta-catenin, which is a critical molecule for neocortical neurogenesis. Together, these results reveal an important function of Kif2a in embryonic neocortical neurogenesis. PMID- 28591195 TI - Hyponatremia and increased risk of dementia: A population-based retrospective cohort study. AB - Hyponatremia is the most common electrolyte disorder and also a predictor of mild cognition impairment. However, the association between hyponatremia and dementia in long follow up periods is rarely investigated. A retrospective cohort study was performed using the claims data of all insured residents who were covered by Taiwan's universal health insurance from 2000 to 2011. A total of 4900 hyponatremia patients and 19545 matched comparisons were recruited for the analysis. The incidences of hyponatremia and dementia were diagnosed with clinical protocol and defined using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Cox proportional hazard regression and Kaplan-Meier curves were used for the analyses. Independent of adjusting factors, hyponatremia patients had 2.36-fold higher chances of suffering dementia, including Alzheimer's disease (AD) and non-AD dementia, than the comparisons. Severe hyponatremia patients had higher risks of suffering dementia than the non-severe hyponatremia patients (adjusted hazard ratio: 4.29 (95% CI: 3.47-5.31) versus 2.08 (95% CI: 1.83-2.37)). A dose response relationship was observed between hyponatremia and dementia. Those hyponatremia patients with baseline or incident stroke had significantly higher chances of suffering dementia compared with those patients without hyponatremia and stroke. Stroke is a significant modifier of the relationship between hyponatremia and dementia. Cerebrovascular disease after incident hyponatremia must be prevented to reduce the incidence of dementia. PMID- 28591196 TI - Trajectories of dementia-related cognitive decline in a large mental health records derived patient cohort. AB - BACKGROUND: Modeling trajectories of decline can help describe the variability in progression of cognitive impairment in dementia. Better characterisation of these trajectories has significant implications for understanding disease progression, trial design and care planning. METHODS: Patients with at least three Mini-mental State Examination (MMSE) scores recorded in the South London and Maudsley NHS Foundation Trust Electronic Health Records, UK were selected (N = 3441) to form a retrospective cohort. Trajectories of cognitive decline were identified through latent class growth analysis of longitudinal MMSE scores. Demographics, Health of Nation Outcome Scales and medications were compared across trajectories identified. RESULTS: Four of the six trajectories showed increased rate of decline with lower baseline MMSE. Two trajectories had similar initial MMSE scores but different rates of decline. In the faster declining trajectory of the two, a higher incidence of both behavioral problems and sertraline prescription were present. CONCLUSIONS: We find suggestive evidence for association of behavioral problems and sertraline prescription with rate of decline. Further work is needed to determine whether trajectories replicate in other datasets. PMID- 28591197 TI - Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity. AB - METHODS: The in vitro activity of kinase inhibitors targeting mTOR (RAD001), EGFR, HER2/neu, VEGFR (AEE788) and IGF-1R (AEW541) alone or in combination with cisplatin was tested in the cisplatin sensitive TGCT cell lines H12.1 and GCT72 as well as in the resistant cell lines H12.1RA, H12.1D, 1411HP and 1777NRpmet using the sulforhodamin-B-(SRB)-cytotoxicity-assay. To evaluate the activity of the kinase inhibitors, western blot analysis of the targeted receptors and their phosphorylated state was performed before and after exposure to each substance. RESULTS: The different kinase inhibitors demonstrated significant cell growth inhibition in both cisplatin sensitive and resistant cell lines. The examined cell lines showed different protein expression levels of the targeted receptors. However there was no correlation between the targeted receptor expression and phosphorylation level and the antiproliferative effect of the respective agent. Furthermore, the combination of cisplatin and the kinase inhibitors exerted both additive and antagonistic effects in the studied cell lines. CONCLUSION: Our data suggest potential activity of the investigated kinase inhibitors in both cisplatin sensitive and resistant TGCT cell lines as a single agent. However, when combined with cisplatin they did not demonstrate any promising ability to overcome cisplatin resistance in TGCTs. PMID- 28591200 TI - Correction: Use of molecular markers in identification and characterization of resistance to rice blast in India. AB - [This corrects the article DOI: 10.1371/journal.pone.0176236.]. PMID- 28591198 TI - Single dose primaquine to reduce gametocyte carriage and Plasmodium falciparum transmission in Cambodia: An open-label randomized trial. AB - BACKGROUND: Single low dose primaquine (SLD PQ, 0.25mg/kg) is recommended in combination with artemisinin-based combination therapy (ACT) as a gametocytocide to prevent Plasmodium falciparum transmission in areas threatened by artemisinin resistance. To date, no randomized controlled trials have measured primaquine's effect on infectiousness to Anopheline mosquitoes in Southeast Asia. METHODS: Cambodian adults with uncomplicated falciparum malaria were randomized to receive a single 45mg dose of primaquine (equivalent to three SLD PQ) or no primaquine after the third dose of dihydroartemisin-piperaquine (DHP) therapy. A membrane feeding assay measured infectiousness to Anopheles dirus on days 0, 3, 7, and 14 of blood-stage therapy. Gametocytemia was evaluated by microscopy and reverse transcriptase PCR. RESULTS: Prior to trial halt for poor DHP treatment efficacy, 101 participants were randomized and 50 received primaquine. Overall microscopic gametocyte prevalence was low (9%), but gametocytemic subjects given primaquine were gametocyte-free by day 14, and significantly less likely to harbor gametocytes by day 7 compared to those treated with DHP-alone, who remained gametocytemic for a median of two weeks. Only one infectious subject was randomized to the primaquine group, precluding assessment of transmission blocking efficacy. However, he showed a two-fold reduction in oocyst density of infected mosquitoes less than 24 hours after primaquine dosing. In the DHP-alone group, four subjects remained infectious through day 14, infecting roughly the same number of mosquitoes pre and post-treatment. Overall, microscopic gametocytemia was an excellent predictor of infectiousness, and performed better than submicroscopic gametocytemia post-treatment, with none of 474 mosquitoes infected post-treatment arising from submicroscopic gametocytes. CONCLUSIONS: In a setting of established ACT resistance, a single dose of 45mg primaquine added to DHP rapidly and significantly reduced gametocytemia, while DHP-alone failed to reduce gametocytemia and prevent malaria transmission to mosquitoes. Continued efforts to make single dose primaquine widely available are needed to help achieve malaria elimination. PMID- 28591199 TI - Sperm DNA fragmentation index does not correlate with blastocyst aneuploidy or morphological grading. AB - High DNA fragmentation index (DFI) may be associated with poor outcome after IVF. Our aim was to determine whether DFI impacts blastocyst quality or clinical outcome. This retrospective study included 134 couples who underwent 177 IVF-ICSI and pre-implantation genetic screening (PGS) cycles during January 1st, 2014 March 31st, 2016 and had documented previous DFI. Group 1 (DFI>30%) encompassed 25 couples who underwent 36 cycles; Group 2 (DFI 15-30%) included 45 couples and 57 cycles; group 3 (DFI<15%) included 64 couples and 83 cycles. Male partners within group 1 were older (45.1 compared to 40.6 and 38.3 years, respectively, p<0.05), had higher BMI (32.4 compared to 26.6 and 25.8 respectively, p<0.05) and lower sperm count and motility (46*106/ml and 35.5%, respectively) compared to groups 2 (61.8*106/ml and 46.6%, respectively) and 3 (75.8*106/ml and 55.1%, respectively, p<0.05). Female parameters including ovarian reserve and response and embryo development were similar. Total numbers of biopsied blastocysts were 116, 175 and 259 in groups 1, 2 and 3, respectively. PGS for 24 chromosomes revealed comparable euploidy rate of 46-50.4%, with a similar morphological classification. No significant differences were found regarding pregnancy rates or pregnancy loss. It seems that DFI doesn't correlate with blastocyst aneuploidy or morphological grading. PMID- 28591202 TI - Epidemiological features of influenza circulation in swine populations: A systematic review and meta-analysis. AB - BACKGROUND: The emergence of the 2009 influenza pandemic virus with a swine origin stressed the importance of improving influenza surveillance in swine populations. The objectives of this systematic review and meta-analysis were to describe epidemiological features of swine influenza (SI) across the world and identify factors impacting swine influenza virus surveillance. METHODS: The systematic review followed the PRISMA guidelines. Articles published after 1990 containing data on SI on pig and herd-level seroprevalence, isolation and detection rates, and risk factors were included. Meta-regression analyses using seroprevalence and virological rates were performed. RESULTS: A total of 217 articles were included. Low avian influenza (AI) seroprevalence (means pig = 4.1%; herd = 15%) was found, showing that AIV do not readily establish themselves in swine while SIV seroprevalence was usually high across continents (influenza A means pig = 32.6-87.8%; herd = 29.3-100%). Higher pig density and number of pigs per farm were shown by the meta-regression analyses and/or the risk factor articles to be associated with higher SI seroprevalence. Lower seroprevalence levels were observed for countries with low-to-medium GDP. These results suggest that larger industrial farms could be more at risk of SIV circulation. Sampling swine with influenza-like illness (ILI) was positively associated with higher isolation rates; most studies in Europe, Latin and North America were targeting swine with ILI. CONCLUSIONS: To improve understanding of SI epidemiology, standardization of the design and reporting of SI epidemiological studies is desirable. Performance of SI surveillance systems in low-to-medium GDP countries should be evaluated to rule out technical issues linked to lower observed SIV prevalence. Targeting certain swine age groups, farming systems and swine with ILI may improve the surveillance cost-effectiveness. However, focusing on pigs with ILI may bias virus detection against strains less virulent for swine but which may be important as pandemic threats. PMID- 28591203 TI - Positive mental health among health professionals working at a psychiatric hospital. AB - BACKGROUND: Positive mental health (PMH) is a combination of emotional, psychological and social well-being that is necessary for an individual to be mentally healthy. The current study aims to examine the socio-demographic differences of PMH among mental health professionals and to explore the association between job satisfaction and total PMH. METHODS: Doctors, nurses and allied health staff (n = 462) completed the online survey which included the multidimensional 47-item PMH instrument as well as a single item job satisfaction question. Associations of PMH with job satisfaction were investigated via linear regression models. RESULTS: Significant differences in PMH total and domain specific scores were observed across socio-demographic characteristics. Age and ethnicity were significantly correlated with PMH total scores as well as various domain scores, while gender, marital and residency status and the staff's position were only significantly correlated with domain specific scores. Job satisfaction was also found to be a significantly associated with total PMH. CONCLUSION: The workplace is a key environment that affects the mental health and well-being of working adults. In order to promote and foster PMH, workplaces need to consider the importance of psychosocial well-being and the wellness of staff whilst providing an environment that supports and maintains overall health and work efficiency. PMID- 28591201 TI - Hippocampal neurogenesis and volume in migrating and wintering semipalmated sandpipers (Calidris pusilla). AB - Long distance migratory birds find their way by sensing and integrating information from a large number of cues in their environment. These cues are essential to navigate over thousands of kilometers and reach the same breeding, stopover, and wintering sites every year. The semipalmated sandpiper (Calidris pusilla) is a long-distance migrant that breeds in the arctic tundra of Canada and Alaska and winters on the northeast coast of South America. Its fall migration includes a 5,300-kilometer nonstop flight over the Atlantic Ocean. The avian hippocampus has been proposed to play a central role in the integration of multisensory spatial information for navigation. Hippocampal neurogenesis may contribute to hippocampal function and a variety of factors including cognitive activity, exercise, enrichment, diet and stress influence neurogenesis in the hippocampus. We quantified hippocampal neurogenesis and volume in adult migrating and wintering semipalmated sandpipers using stereological counts of doublecortin (DCX) immunolabeled immature neurons. We found that birds captured in the coastal region of Braganca, Brazil during the wintering period had more DCX positive neurons and larger volume in the hippocampus than individuals captured in the Bay of Fundy, Canada during fall migration. We also estimate the number of NeuN immunolabeled cells in migrating and wintering birds and found no significant differences between them. These findings suggest that, at this time window, neurogenesis just replaced neurons that might be lost during the transatlantic flight. Our findings also show that in active fall migrating birds, a lower level of adult hippocampal neurogenesis is associated with a smaller hippocampal formation. High levels of adult hippocampal neurogenesis and a larger hippocampal formation found in wintering birds may be late occurring effects of long distance migratory flight or the result of conditions the birds experienced while wintering. PMID- 28591205 TI - Shift in tuna catches due to ocean warming. AB - Ocean warming is already affecting global fisheries with an increasing dominance of catches of warmer water species at higher latitudes and lower catches of tropical and subtropical species in the tropics. Tuna distributions are highly conditioned by sea temperature, for this reason and their worldwide distribution, their populations may be a good indicator of the effect of climate change on global fisheries. This study shows the shift of tuna catches in subtropical latitudes on a global scale. From 1965 to 2011, the percentage of tropical tuna in longliner catches exhibited a significantly increasing trend in a study area that included subtropical regions of the Atlantic and western Pacific Oceans and partially the Indian Ocean. This may indicate a movement of tropical tuna populations toward the poles in response to ocean warming. Such an increase in the proportion of tropical tuna in the catches does not seem to be due to a shift of the target species, since the trends in Atlantic and Indian Oceans of tropical tuna catches are decreasing. Our results indicate that as populations shift towards higher latitudes the catches of these tropical species did not increase. Thus, at least in the Atlantic and Indian Oceans, tropical tuna catches have reduced in tropical areas. PMID- 28591204 TI - Feeding toxicity and impact of imidacloprid formulation and mixtures with six representative pesticides at residue concentrations on honey bee physiology (Apis mellifera). AB - Imidacloprid is the most widely used insecticide in agriculture. In this study, we used feeding methods to simulate in-hive exposures of formulated imidacloprid (Advise(r) 2FL) alone and mixtures with six representative pesticides for different classes. Advise, fed at 4.3 mg/L (equal to maximal residue detection of 912 ppb active ingredient [a.i.] in pollen) induced 36% mortality and 56% feeding suppression after 2-week feeding. Treatments with individual Bracket (acephate), Karate (lambda-cyhalothrin), Vydate (oxamyl), Domark (tetraconazole), and Roundup (glyphosate) at residue level had a mortality range of 1.3-13.3%, statistically similar to that of control (P>0.05). The additive/synergistic toxicity was not detected from binary mixtures of Advise with different classes of pesticides at residue levels. The feeding of the mixture of all seven pesticides increased mortality to 53%, significantly higher than Advise only but still without synergism. Enzymatic data showed that activities of invertase, glutathione S transferase, and acetylcholinesterase activities in imidacloprid-treated survivors were mostly similar to those found in control. Esterase activity mostly increased, but was significantly suppressed by Bracket (acephate). The immunity related phenoloxidase activity in imidacloprid-treated survivors tended to be lower, but most treatments were statistically similar to the control. Increase of cytochrome P450 activity was correlated with Advise concentrations and reached significant difference at 56 mg/L (12 ppm a.i.). Our data demonstrated that residue levels of seven pesticide in pollens/hive may not adversely affect honey bees, but long term exclusive ingestion of the maximal residue levels of imidacloprid (912 ppb) and sulfoxaflor (3 ppm a.i.) may induce substantial bee mortality. Rotating with other insecticides is a necessary and practical way to reduce the residue level of any given pesticide. PMID- 28591207 TI - Long-term growth comparison studies of FBS and FBS alternatives in six head and neck cell lines. AB - Fetal bovine serum (FBS) is depended upon by investigators as an indispensable supplement in cell and tissue culture systems. Due to increased demand and limited availability, the price of FBS has increased by greater than 300% in the past few years. In addition, there are ethical and scientific controversies about the collection and use of FBS in culture systems. In response to the shortage of FBS, many FBS alternative serum products have been developed. Although many have claimed comparable performance to FBS, their support of long-term cell growth and effects on cell phenotype have not been revealed. In this study, we examined the performances of six bovine calf serum-based FBS alternatives in six head and neck cell lines and compared them with FBS. The results indicate that some of these sera had growth promoting capabilities comparable or superior to that of FBS. Additionally, these alternative sera supported long-term (30 passages) growth of tested cells and exhibited plating efficiencies comparable to that of FBS. Cells cultured in alternative sera also exhibited comparable anchorage-independent growth and similar drug inhibition responses in FBS. Still, caution should be taken in choosing suitable sera given that changes in cell morphology and variations in chemotactic responses were noted for cells maintained in certain sera. These FBS alternatives are more readily available, cost less, and are associated with less ethical concerns, thus making them attractive alternatives to FBS in cell culture systems. PMID- 28591208 TI - AKT and its related molecular feature in aged mice skin. AB - Previous studies suggest that Akt signaling promotes tissue regeneration and decreased Akt activities are found in aged tissues. However, this study finds that the expression and activation levels of Akt in the mice skin increased with age. Additionally, the expression levels of Pten, p16, p21 and p53 also elevated with increased age. Immuno-fluorescence analysis showed that Akt phosphorylation found in the epidermal cells (with increased levels of NF-kappaB activation) were also found. In vivo inhibition of AKT activity result in reduced NF-kappaB activation. Our results suggest that increasing Akt/ NF-kappaB is a crucial mediator of skin aging, which can increase the susceptibility of cell transformation. PMID- 28591209 TI - Sexual function and postpartum depression 6 months after attempted operative vaginal delivery according to fetal head station: A prospective population-based cohort study. AB - OBJECTIVE: To evaluate the effect of the fetal head station at attempted operative vaginal delivery (aOVD), and specifically midpelvic or low aOVD, on female and male sexual function and symptoms of postpartum depression (PPD) at 6 months. DESIGN: Prospective population-based cohort study. SETTING: 1,941 women with singleton term fetuses in vertex presentation with midpelvic or low aOVD between 2008 and 2013 in a tertiary care university hospital. METHODS: Symptoms of female sexual dysfunction using the Pelvic Organ Prolapse/Urinary Incontinence/Sexual Function Short Form Questionnaire (PISQ-12), symptoms of PPD using the Edinburgh Postnatal Depression Scale (EPDS) score, symptoms of male sexual dysfunction using the International Index of Erectile Function (IIEF-15) and perineal pain were assessed 6 months after aOVD. We measured the association between midpelvic or low aOVD and symptoms of female and male sexual function and symptoms of PPD at 6 months using multiple regression and adjusting for demographics, and risk factors of sexual dysfunction, symptoms of PPD and perineal pain with adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). RESULTS: The study included 907 women (46.7%) who responded to the questionnaire; 18.4% (167/907) had midpelvic aOVD, and 81.6% (740/907) low. Most women (873/907 [96.3%]) of those with partners reported sexual activity at 6 months. No significant difference was observed for PISQ-12, EPDS, IIEF-15 scores and perineal pain between mid and low pelvic groups. Compared with low pelvic aOVD, midpelvic aOVD was not significantly associated with either female or male sexual dysfunction (p = 0.89 and p = 0.76, respectively), or maternal symptoms of PPD (p = 0.83). Perineal pain significantly increased the risk of male and female sexual dysfunction and maternal symptoms of PPD at 6 months (p = 0.02, p = 0.006, and p = 0.02, respectively). CONCLUSION: Midpelvic compared with low pelvic aOVD was not associated with an increase in sexual dysfunction, nor with symptoms of PPD at 6 months. PMID- 28591210 TI - The dual role of friendship and antipathy relations in the marginalization of overweight children in their peer networks: The TRAILS Study. AB - Weight-based stigma compromises the social networks of overweight children. To date, research on the position of overweight children in their peer network has focused only on friendship relations, and not on negative relationship dimensions. This study examined how overweight was associated with relations of friendship and dislike (antipathies) in the peer group. Exponential random graph models (ERGM) were used to examine friendship and antipathy relations among overweight children and their classmates, using a sub-sample from the TRacking Adolescents' Individual Lives Survey (N = 504, M age 11.4). Findings showed that overweight children were less likely to receive friendship nominations, and were more likely to receive dislike nominations. Overweight children were also more likely than their non-overweight peers to nominate classmates that they disliked. Together, the results indicate that positive and negative peer relations are impacted by children's weight status, and are relevant to addressing the social marginalization of overweight children. PMID- 28591206 TI - ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1). AB - Devil Facial Tumour 1 (DFT1) is one of two transmissible neoplasms of Tasmanian devils (Sarcophilus harrisii) predominantly affecting their facial regions. DFT1's cellular origin is that of Schwann cell lineage where lesions are evident macroscopically late in the disease. Conversely, the pre-clinical timeframe from cellular transmission to appearance of DFT1 remains uncertain demonstrating the importance of an effective pre-clinical biomarker. We show that ERBB3, a marker expressed normally by the developing neural crest and Schwann cells, is immunohistohemically expressed by DFT1, therefore the potential of ERBB3 as a biomarker was explored. Under the hypothesis that serum ERBB3 levels may increase as DFT1 invades local and distant tissues our pilot study determined serum ERBB3 levels in normal Tasmanian devils and Tasmanian devils with DFT1. Compared to the baseline serum ERBB3 levels in unaffected Tasmanian devils, Tasmanian devils with DFT1 showed significant elevation of serum ERBB3 levels. Interestingly Tasmanian devils with cutaneous lymphoma (CL) also showed elevation of serum ERBB3 levels when compared to the baseline serum levels of Tasmanian devils without DFT1. Thus, elevated serum ERBB3 levels in otherwise healthy looking devils could predict possible DFT1 or CL in captive or wild devil populations and would have implications on the management, welfare and survival of Tasmanian devils. ERBB3 is also a therapeutic target and therefore the potential exists to consider modes of administration that may eradicate DFT1 from the wild. PMID- 28591211 TI - Dispersal strategies in the highly polygynous ant Crematogaster (Orthocrema) pygmaea Forel (Formicidae: Myrmicinae). AB - In ants, dispersal strategies and morphology of female sexuals are generally linked to the mode of colony founding. In species using long-range dispersal tactics, queen/worker dimorphism is generally high and young queens are able to initiate new colonies by themselves, using their metabolic reserves. By contrast, in species using short-range dispersal strategies, queen/worker dimorphism is generally low and, due to their limited metabolic reserves, queens have lost the capacity to raise their brood alone and to found their colony independently. Moreover, polygyny is also often associated with short-range dispersal strategies, although the relationship between the number of queens and the dispersal strategy in ants is not clear-cut. Here, dispersal strategies were investigated in C. pygmaea, a highly polygynous and polydomous ant species from northeastern Brazil. Field observations and laboratory experiments show that this ant exhibits a suite of traits that are more commonly associated with long-range dispersal and independent colony foundation: functional wings in both males and females, high queen/worker dimorphism, strong weight loss in mature queens, nuptial flights and, in the lab, ability of young queens to found new colonies in haplometrotic conditions. On the other hand, this species shows a high degree of polygyny with a strong seasonal component, and, at least under laboratory conditions, mature queens seem able to develop propagules if they are accompanied by at least 10 workers. These features strongly suggest that (1) some of the gynes do not engage in a long-range dispersal but become new queens in their mother colony and (2) that budding events are possible in this species. We therefore speculate that C. pygmaea has a dual dispersal strategy probably related to environmental conditions: some gynes engage in long-range dispersal followed by independent colony foundation at the beginning of rainy season, while others mate in the parental colony and are re-adopted leading to high polygyny. During the rainy season, budding events can lead to colony extension and increased polydomy. Polydomy is commonly thought to improve resource discovery and exploitation through decentralized foraging behavior, a significant advantage during the rainy season when food ressources (mainly floral/extrafloral nectaries and hemipteran honeydew) are more abundant and when colony needs for food supplies are highest. PMID- 28591212 TI - Reduced ADAMTS13 levels in patients with acute and chronic cerebrovascular disease. AB - Von Willebrand Factor (VWF) plays a major role in thrombosis and hemostasis and its thrombogenicity is controlled by ADAMTS13. Whereas increasing evidence shows a clear association between VWF levels and acute ischemic stroke, little is known about a correlation with ADAMTS13. Therefore, the aim of this study was to compare plasma levels of ADAMTS13 between 85 healthy volunteers (HV), 104 patients with acute ischemic stroke and 112 patients with a chronic cerebrovascular disease (CCD). In this case-control study, plasma ADAMTS13 antigen levels were measured by ELISA and plasma VWF levels, measured previously, were next used to calculate VWF:ADAMTS13 ratios. ADAMTS13 levels and VWF:ADAMTS13 ratios were subsequently correlated with key demographic and clinical parameters. ADAMTS13 levels were significantly lower in acute ischemic stroke patients (82.6 +/- 21.0%) compared with HV (110.6 +/- 26.9%). Also, CCD patients (99.6 +/- 24.5%) had significantly lower ADAMTS13 levels compared with HV however these were still higher than in acute stroke patients. Furthermore, when assessing the VWF:ADAMTS13 ratios, an even greater difference was revealed between stroke patients (2.7 +/- 1.9), HV (1.1 +/- 0.5) and CCD patients (1.7 +/- 0.7). The VWF:ADAMTS13 ratio was significantly associated with stroke severity and modality. In conclusion, both in acute and chronic cerebrovascular disease patients, ADAMTS13 levels were significantly decreased, with the lowest ADAMTS13 levels found in acute stroke patients. This difference was even more distinct when the ratio of VWF:ADAMTS13 was considered. These results demonstrate the potentially important involvement of the VWF/ADAMTS13 axis in ischemic stroke. PMID- 28591214 TI - 'The Devil has entered you': A qualitative study of Men Who Have Sex With Men (MSM) and the stigma and discrimination they experience from healthcare professionals and the general community in Bosnia and Herzegovina. AB - Men who have sex with men (MSM) are often exposed to unequal treatment in societies worldwide as well as to various forms of stigma and discrimination in healthcare services. Bosnia and Herzegovina (B&H) is a postconflict developing country located in Southeast Europe and the Western Balkans, where little is known about the experiences of MSM regarding their communities and interactions with healthcare services. The aim of this study was to explore the types of experiences MSM face and to assess the level of stigma and discrimination they are exposed to in this setting. We conducted twelve in-depth face-to-face interviews with MSM who were 16 to 45 years old and residing in B&H. The main findings indicated that they all experienced various levels of stigma, discrimination, prejudice and inequities in treatment and attitudes from different segments of society, including the health care sector, that prevented them from fully developing their human and health potential. Additionally, these experiences were adversely related to opportunities to receive good quality health care services due to the insufficiently educated and old-fashioned health professionals who sometimes believed in black magic practices. The findings present numerous opportunities for educational trainings and structural reform to create a society that provides and guarantees equal opportunities for all. PMID- 28591213 TI - Flight of the bumble bee: Buzzes predict pollination services. AB - Multiple interacting factors drive recent declines in wild and managed bees, threatening their pollination services. Widespread and intensive monitoring could lead to more effective management of wild and managed bees. However, tracking their dynamic populations is costly. We tested the effectiveness of an inexpensive, noninvasive and passive acoustic survey technique for monitoring bumble bee behavior and pollination services. First, we assessed the relationship between the first harmonic of the flight buzz (characteristic frequency) and pollinator functional traits that influence pollination success using flight cage experiments and a literature search. We analyzed passive acoustic survey data from three locations on Pennsylvania Mountain, Colorado to estimate bumble bee activity. We developed an algorithm based on Computational Auditory Scene Analysis that identified and quantified the number of buzzes recorded in each location. We then compared visual and acoustic estimates of bumble bee activity. Using pollinator exclusion experiments, we tested the power of buzz density to predict pollination services at the landscape scale for two bumble bee pollinated alpine forbs (Trifolium dasyphyllum and T. parryi). We found that the characteristic frequency was correlated with traits known to affect pollination efficacy, explaining 30-52% of variation in body size and tongue length. Buzz density was highly correlated with visual estimates of bumble bee density (r = 0.97), indicating that acoustic signals are predictive of bumble bee activity. Buzz density predicted seed set in two alpine forbs when bumble bees were permitted access to the flowers, but not when they were excluded from visiting. Our results indicate that acoustic signatures of flight can be deciphered to monitor bee activity and pollination services to bumble bee pollinated plants. We propose that applications of this technique could assist scientists and farmers in rapidly detecting and responding to bee population declines. PMID- 28591215 TI - Application of environmental DNA to detect an endangered marine skate species in the wild. AB - Environmental DNA (eDNA) techniques have only recently been applied in the marine environment to detect the presence of marine species. Species-specific primers and probes were designed to detect the eDNA of the endangered Maugean skate (Zearaja maugeana) from as little as 1 L of water collected at depth (10-15 m) in Macquarie Harbour (MH), Tasmania. The identity of the eDNA was confirmed as Z. maugeana by sequencing the qPCR products and aligning these with the target sequence for a 100% match. This result has validated the use of this eDNA technique for detecting a rare species, Z. maugeana, in the wild. Being able to investigate the presence, and possibly the abundance, of Z. maugeana in MH and Bathurst harbour (BH), would be addressing a conservation imperative for the endangered Z. maugeana. For future application of this technique in the field, the rate of decay was determined for Z. maugeana eDNA under ambient dissolved oxygen (DO) levels (55% saturation) and lower DO (20% saturation) levels, revealing that the eDNA can be detected for 4 and 16 hours respectively, after which eDNA concentration drops below the detection threshold of the assay. With the rate of decay being influenced by starting eDNA concentrations, it is recommended that samples be filtered as soon as possible after collection to minimize further loss of eDNA prior to and during sample processing. PMID- 28591216 TI - Modification effects of genetic polymorphisms in FTO, IL-6, and HSPD1 on the associations of diabetes with breast cancer risk and survival. AB - The contribution of diabetes to breast cancer remains uncertain among Chinese females, which may result from different genetic factors. We evaluated the associations of diabetes, combined with the polymorphisms in the genes of fat mass and obesity-associated gene (FTO), interleukin 6 (IL-6), and heat shock protein 60 (HSPD1), with breast cancer risk and survival in a Chinese Han population. The information on the history of diabetes was collected from 1551 incident breast cancer cases and 1605 age-frequency matched controls in Guangzhou, China. In total, 1168 cases were followed up. Diabetes was associated with both an increased risk of breast cancer [OR (95%CI): 1.67 (1.11, 2.52)] and a poor overall survival and progression free survival for breast cancer patients [HRs (95%CIs): 2.66 (1.10, 6.44) and 2.46 (1.29, 4.70), respectively]. IL-6 rs1800796 and HSPD1 rs2605039 had interactions with diabetes on breast cancer risk. Among women with CC genotype of IL-6 rs1800796 or GG genotype of HSPD1 rs2605039, diabetic individuals had a remarkably increased risk of breast cancer compared to non-diabetic women with ORs and 95%CIs of 2.53 (1.45, 4.41) and 6.40 (2.29, 17.87), respectively. GT/TT genotypes of HSPD1 rs2605039 was also associated with a better progression free survival for breast cancer patients [HR (95%CI): 0.70 (0.49, 0.99)]. Our results suggest that the contribution of diabetes to breast cancer risk might be modified by IL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 might also influence breast cancer prognosis. PMID- 28591217 TI - Effects of bevacizumab on endoplasmic reticulum stress in hypoxic retinal pigment epithelial cells. AB - PURPOSE: To investigate the effects of bevacizumab on endoplasmic reticulum (ER) stress in human retinal pigment epithelial (RPE) cells cultured under hypoxic conditions. METHODS: RPE cells (ARPE-19) were cultured under hypoxic conditions (1% O2) with or without bevacizumab (0.3125 mg/mL) for 24 and 48 h. Cell viability was measured by a PrestoBlue assay. The expression of vascular endothelial growth factor (VEGF), binding protein/glucose-regulated protein 78 (BiP/GRP78), and C/EBP homologous protein-10 (CHOP) mRNA was measured by quantitative real-time polymerase chain reaction (qRT-PCR). BiP/GRP78 and CHOP protein levels in the cells were assessed by western blot. VEGF protein in the media was quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Under hypoxic conditions, cell viability decreased and mRNA and protein levels of VEGF, BiP/GRP78, and CHOP increased compared to those under normoxic conditions. Bevacizumab improved cell viability and reduced the expression of VEGF mRNA under hypoxic conditions. Bevacizumab also reduced the expression of both mRNA and protein of two ER stress indicators, BiP/GRP78 and CHOP, under hypoxic conditions. CONCLUSIONS: Bevacizumab mitigated ER stress in human RPE cells cultured under hypoxic conditions. This effect may be involved in the improved cell viability and reduction of VEGF expression after bevacizumab treatment of hypoxic RPE cells in vitro. However, the effects of bevacizumab on RPE cells under experimental conditions are unlikely to be clinically equivalent to those in the human eye. PMID- 28591218 TI - When is genetic modification socially acceptable? When used to advance human health through avenues other than food. AB - Given the potential for genetic modification (GM) to impact human health, via food and health mechanisms, a greater understanding of the social acceptance of GM is necessary to facilitate improved health outcomes. This analysis sought to quantify U.S. residents' acceptance of GM across five potential uses (grain production, fruit or vegetable production, livestock production, human medicine, and human health, i.e. disease vector control) and provides an in-depth analysis of a timely case study-the Zika virus (ZIKV). The two categories with the highest levels of acceptance for GM use were human medicine (62% acceptance) and human health (68% acceptance); the proportions agreeing with the use of GM for these two categories were statistically different from all other categories. Acceptance of GM in food uses revealed 44% of the sample accepted the use of GM in livestock production while grain production and fruit and vegetable production showed similar levels of agreement with 49% and 48% of responses, respectively. Two variables were significant in all five models predicting GM acceptance; namely, being male and GM awareness. Being male was significant and positive for all models; respondents who reported being male were more likely (than those who reported female) to agree with all five of the uses of GM studied. Those who were reportedly aware of GM mosquito technology were also more likely to agree with all uses of GM technology investigated. The potential relationship between awareness of GM technology uses and acceptance of other uses could help inform rates of acceptance of new technologies by various population segments. PMID- 28591219 TI - Mechanisms underlying a thalamocortical transformation during active tactile sensation. AB - During active somatosensation, neural signals expected from movement of the sensors are suppressed in the cortex, whereas information related to touch is enhanced. This tactile suppression underlies low-noise encoding of relevant tactile features and the brain's ability to make fine tactile discriminations. Layer (L) 4 excitatory neurons in the barrel cortex, the major target of the somatosensory thalamus (VPM), respond to touch, but have low spike rates and low sensitivity to the movement of whiskers. Most neurons in VPM respond to touch and also show an increase in spike rate with whisker movement. Therefore, signals related to self-movement are suppressed in L4. Fast-spiking (FS) interneurons in L4 show similar dynamics to VPM neurons. Stimulation of halorhodopsin in FS interneurons causes a reduction in FS neuron activity and an increase in L4 excitatory neuron activity. This decrease of activity of L4 FS neurons contradicts the "paradoxical effect" predicted in networks stabilized by inhibition and in strongly-coupled networks. To explain these observations, we constructed a model of the L4 circuit, with connectivity constrained by in vitro measurements. The model explores the various synaptic conductance strengths for which L4 FS neurons actively suppress baseline and movement-related activity in layer 4 excitatory neurons. Feedforward inhibition, in concert with recurrent intracortical circuitry, produces tactile suppression. Synaptic delays in feedforward inhibition allow transmission of temporally brief volleys of activity associated with touch. Our model provides a mechanistic explanation of a behavior related computation implemented by the thalamocortical circuit. PMID- 28591220 TI - Comparative transcriptomics of genetically divergent lines of chickens in response to Marek's disease virus challenge at cytolytic phase. AB - Marek's disease (MD), caused by Marek's disease virus (MDV), remains an economically significant threat to the poultry industry worldwide. Genetic resistance to MD is a promising alternative strategy to augment current control measures (vaccination and management). However, only a few functional genes reportedly conferring MD resistance have been identified. Here, we performed a comparative transcriptomics analysis of two highly inbred yet genetically divergent lines of chickens (line 63 and 72) that are resistant and susceptible to MD, respectively, in response to a very virulent plus strain of MDV (vv+MDV) challenge at cytolytic phase. A total of 203 DEGs in response to MDV challenge were identified in the two lines. Of these, 96 DEGs were in common for both lines, in addition to 36 and 71 DEGs that were specific for line 63 and 72, respectively. Functional enrichment analysis results showed the DEGs were significantly enriched in GO terms and pathways associated with immune response. Especially, the four DEGs, FGA, ALB, FN1, and F13A1 that reportedly facilitate virus invasion or immunosuppression, were found to be significantly up-regulated in the susceptible line 72 but down-regulated in the resistant line 63 birds. These results provide new resources for future studies to further elucidate the genetic mechanism conferring MD resistance. PMID- 28591221 TI - Loci associated with resistance to stripe rust (Puccinia striiformis f. sp. tritici) in a core collection of spring wheat (Triticum aestivum). AB - Stripe rust, caused by Puccinia striiformis Westend. f. sp. tritici Erikss. (Pst) remains one of the most significant diseases of wheat worldwide. We investigated stripe rust resistance by genome-wide association analysis (GWAS) in 959 spring wheat accessions from the United States Department of Agriculture-Agricultural Research Service National Small Grains Collection, representing major global production environments. The panel was characterized for field resistance in multi-environment field trials and seedling resistance under greenhouse conditions. A genome-wide set of 5,619 informative SNP markers were used to examine the population structure, linkage disequilibrium and marker-trait associations in the germplasm panel. Based on model-based analysis of population structure and hierarchical Ward clustering algorithm, the accessions were clustered into two major subgroups. These subgroups were largely separated according to geographic origin and improvement status of the accessions. A significant correlation was observed between the population sub-clusters and response to stripe rust infection. We identified 11 and 7 genomic regions with significant associations with stripe rust resistance at adult plant and seedling stages, respectively, based on a false discovery rate multiple correction method. The regions harboring all, except three, of the QTL identified from the field and greenhouse studies overlap with positions of previously reported QTL. Further work should aim at validating the identified QTL using proper germplasm and populations to enhance their utility in marker assisted breeding. PMID- 28591222 TI - Ecological impact of the end-Cretaceous extinction on lamniform sharks. AB - Lamniform sharks are apex marine predators undergoing dramatic local and regional decline worldwide, with consequences for marine ecosystems that are difficult to predict. Through their long history, lamniform sharks have faced widespread extinction, and understanding those 'natural experiments' may help constrain predictions, placing the current crisis in evolutionary context. Here we show, using novel morphometric analyses of fossil shark teeth, that the end-Cretaceous extinction of many sharks had major ecological consequences. Post-extinction ecosystems supported lower diversity and disparity of lamniforms, and were dominated by significantly smaller sharks with slimmer, smoother and less robust teeth. Tooth shape is intimately associated with ecology, feeding and prey type, and by integrating data from extant sharks we show that latest Cretaceous sharks occupied similar niches to modern lamniforms, implying similar ecosystem structure and function. By comparison, species in the depauperate post-extinction community occupied niches most similar to those of juvenile sand tigers (Carcharias taurus). Our data show that quantitative tooth morphometrics can distinguish lamniform sharks due to dietary differences, providing critical insights into ecological consequences of past extinction episodes. PMID- 28591224 TI - Low-dose glucocorticoids suppresses ovarian tumor growth and metastasis in an immunocompetent syngeneic mouse model. AB - Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 MUg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1beta and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment. PMID- 28591223 TI - Why do authors derive new cardiovascular clinical prediction rules in the presence of existing rules? A mixed methods study. AB - BACKGROUND: Researchers should examine existing evidence to determine the need for a new study. It is unknown whether developers evaluate existing evidence to justify new cardiovascular clinical prediction rules (CPRs). OBJECTIVE: We aimed to assess whether authors of cardiovascular CPRs cited existing CPRs, why some authors did not cite existing CPRs, and why they thought existing CPRs were insufficient. METHOD: Derivation studies of cardiovascular CPRs from the International Register of Clinical Prediction Rules for Primary Care were evaluated. We reviewed the introduction sections to determine whether existing CPRs were cited. Using thematic content analysis, the stated reasons for determining existing cardiovascular CPRs insufficient were explored. Study authors were surveyed via e-mail and post. We asked whether they were aware of any existing cardiovascular CPRs at the time of derivation, how they searched for existing CPRs, and whether they thought it was important to cite existing CPRs. RESULTS: Of 85 derivation studies included, 48 (56.5%) cited existing CPRs, 33 (38.8%) did not cite any CPR, and four (4.7%) declared there was none to cite. Content analysis identified five categories of existing CPRs insufficiency related to: (1) derivation (5 studies; 11.4% of 44), (2) construct (31 studies; 70.5%), (3) performance (10 studies; 22.7%), (4) transferability (13 studies; 29.5%), and (5) evidence (8 studies; 18.2%). Authors of 54 derivation studies (71.1% of 76 authors contacted) responded to the survey. Twenty-five authors (46.3%) reported they were aware of existing CPR at the time of derivation. Twenty-nine authors (53.7%) declared they conducted a systematic search to identify existing CPRs. Most authors (90.7%) indicated citing existing CPRs was important. CONCLUSION: Cardiovascular CPRs are often developed without citing existing CPRs although most authors agree it is important. Common justifications for new CPRs concerned construct, including choice of predictor variables or relevance of outcomes. Developers should clearly justify why new CPRs are needed with reference to existing CPRs to avoid unnecessary duplication. PMID- 28591225 TI - Trends in food insecurity for adults with cardiometabolic disease in the United States: 2005-2012. AB - BACKGROUND: Food insecurity, the uncertain ability to access adequate food, can limit adherence to dietary measures needed to prevent and manage cardiometabolic conditions. However, little is known about temporal trends in food insecurity among those with diet-sensitive cardiometabolic conditions. METHODS: We used data from the Continuous National Health and Nutrition Examination Survey (NHANES) 2005-2012, analyzed in 2015-2016, to calculate trends in age-standardized rates of food insecurity for those with and without the following diet-sensitive cardiometabolic conditions: diabetes mellitus, hypertension, coronary heart disease, congestive heart failure, and obesity. RESULTS: 21,196 NHANES participants were included from 4 waves (4,408 in 2005-2006, 5,607 in 2007-2008, 5,934 in 2009-2010, and 5,247 in 2011-2012). 56.2% had at least one cardiometabolic condition, 24.4% had 2 or more, and 8.5% had 3 or more. The overall age-standardized rate of food insecurity doubled during the study period, from 9.06% in 2005-2006 to 10.82% in 2007-2008 to 15.22% in 2009-2010 to 18.33% in 2011-2012 (p for trend < .001). The average annual percentage change in food insecurity for those with a cardiometabolic condition during the study period was 13.0% (95% CI 7.5% to 18.6%), compared with 5.8% (95% CI 1.8% to 10.0%) for those without a cardiometabolic condition, (parallelism test p = .13). Comparing those with and without the condition, age-standardized rates of food insecurity were greater in participants with diabetes (19.5% vs. 11.5%, p < .0001), hypertension (14.1% vs. 11.1%, p = .0003), coronary heart disease (20.5% vs. 11.9%, p < .001), congestive heart failure (18.4% vs. 12.1%, p = .004), and obesity (14.3% vs. 11.1%, p < .001). CONCLUSIONS: Food insecurity doubled to historic highs from 2005-2012, particularly affecting those with diet-sensitive cardiometabolic conditions. Since adherence to specific dietary recommendations is a foundation of the prevention and treatment of cardiometabolic disease, these results have important implications for clinical management and public health. PMID- 28591226 TI - Interval to vascularization development in cirrhotic precursor nodules in patients with hepatitis B and C virus co-infections. AB - With the widespread use of gadoxetic acid-enhanced magnetic resonance imaging, liver nodules appearing as hypovascular in the arterial phase and hypointense in the hepatobiliary phase, defined as hypovascular hypointense nodules, are increasingly detected in patients with cirrhosis and are considered precursor nodules. We sought to evaluate the interval to vascularization development in hepatitis C virus/hepatitis B virus co-infected-associated precursor nodules (BC HHN group) compared with that in hepatitis C virus mono-infected-associated precursor nodules (C-HHN group) in the hepatobiliary phase of gadoxetic acid enhanced magnetic resonance imaging. The interval to vascularization development was estimated by the Kaplan-Meier method and compared using the Cox proportional hazards model. The mean intervals to vascularization development in the BC-HHN and C-HHN groups were 272.9+/-31.1 and 603.8+/-47.6 days, respectively (p<0.001). The cumulative vascularization development incidence at 6, 12, and 18 months was 44.9%, 73.5%, and 91.8%, respectively, in the BC-HHN group and 16.9%, 39.0%, and 55.8%, respectively, in the C-HHN group (p<0.001). The multivariate analysis showed that the presence of hepatitis B virus co-infection (hazard ratio: 1.819; 95% confidence interval: 1.222-2.707; p = 0.003) and male sex (hazard ratio: 1.753; 95% confidence interval: 1.029-2.985; p = 0.039) were predictors of vascularization development. More than half of the hypovascular hypointense nodules showed high-signal changes on T2-weighted imaging, and almost half of them showed restricted diffusion on diffusion-weighted images, but these did not predict vascularization development. In a hepatitis C virus- and hepatitis B virus-endemic area, such as Taiwan, precursor nodules in the BC-HHN group tended to have shorter intervals to vascularization development, especially in male patients. PMID- 28591227 TI - Correction: Resource Availability Modulates the Cooperative and Competitive Nature of a Microbial Cross-Feeding Mutualism. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002540.]. PMID- 28591229 TI - Expanded view of ecosystem stability: A grazed grassland case study. AB - Analysis of stability under linearized dynamics is central to ecology. We highlight two key limitations of the widely used traditional analysis. First, we note that while stability at fixed points is often the focus, ecological systems may spend less time near fixed points, and more time responding to stochastic environmental forcing by exhibiting wide zero-mean fluctuations about those states. If non-steady, uniquely precarious states along the nonlinear flow are analyzed instead of fixed points, transient growth is possible and indeed common for ecosystems with stable attractive fixed points. Second, we show that in either steady or non-steady states, eigenvalue based analysis can misleadingly suggest stability while eigenvector geometry arising from the non-self adjointness of the linearized operator can yield large finite-time instabilities. We offer a simple alternative to eigenvalue based stability analysis that naturally and straightforwardly overcome these limitations. PMID- 28591228 TI - A secondary wave of neutrophil infiltration causes necrosis and ulceration in lesions of experimental American cutaneous leishmaniasis. AB - We evaluated the importance of neutrophils in the development of chronic lesions caused by L. Viannia spp. using the hamster as experimental model of American Cutaneous Leishmaniasis (ACL). Neutrophils infiltrated the lesion within the first six hours post-infection. Inhibition of this early infiltration using a polyclonal antibody or cyclophosphamide was associated with transient parasite control but the protective effect vanished when lesions became clinically apparent. At lesion onset (approximately 10 days p.i.), there was an increased proportion of both uninfected and infected macrophages, and subsequently a second wave of neutrophils infiltrated the lesion (after 19 days p.i.) This second neutrophil infiltration was associated with lesion necrosis and ulceration (R2 = 0.75) and maximum parasite burden. Intradermal delivery of N-formylmethionyl leucyl-phenylalanine (fMLP), aimed to increase neutrophil infiltration, resulted in larger lesions with marked necrosis and higher parasite burden than in mock treated groups (p<0.001 each). In contrast, reduced neutrophil infiltration via cyclophosphamide-mediated depletion led to more benign lesions and lower parasite loads compared to controls (p<0.001 each). Neutrophils of the second wave expressed significantly lower GM-CSF, reactive oxygen species and nitric oxide than those of the first wave, suggesting that they had less efficient anti leishmania activity. However, there was increased inflammatory cytokines and expression of neutrophil proteases (myeloperoxidase, cathepsin G and elastase) in lesions during the second wave of neutrophil infiltration compared with the levels reached during the first wave (6h p.i.). This suggests that augmented neutrophil proteases and inflammatory cytokines during the secondary wave of neutrophils could contribute to skin inflammation, ulceration and necrosis in ACL. The overall results indicate that neutrophils were unable to clear the infection in this model, and that the second wave of neutrophils played an important role in the severity of ACL. PMID- 28591236 TI - Predictors of success for mandibular repositioning appliance in obstructive sleep apnea syndrome. AB - The characteristics of non-obese patients with mild to moderate Obstructive Sleep Apnea Syndrome (OSAS) who will present with a good response to Mandibular Repositioning Appliance (MRA) treatment have not yet been well established in the literature. The aim of this study is to assess whether polysomnographic (PSG), demographic, anthropometric, cephalometric, and otorhinolaryngological parameters predict MRA success in the treatment of OSAS. Forty (40) males with mild and moderate OSAS were assessed pretreatment and 2-months post-treatment after wearing an MRA. Demographic, anthropometric, otorhinolaryngological (ENT), cephalometric, and polysomnographic parameters, including continuous positive airway pressure (CPAP) titrated pressure, dental models, Epworth Sleepiness Scale, quality of life (Short Form SF-36), and mood state (Profile of Mood States - POMS), were assessed. The responders exhibited fewer oropharyngeal alterations, increased upper pharyngeal space, reduced lower airway space, and increased mandibular intercanine width, and they had milder disease. Nevertheless, no predictive factors of MRA success could be found. MRA was more successful among men with a more pervious airway, a larger interdental width and milder OSAS. However, a combined [1] functional and structural assessment is needed to successfully predict the [2] effectiveness of MRA treatment of OSA. PMID- 28591230 TI - Frequency of respiratory virus infections and next-generation analysis of influenza A/H1N1pdm09 dynamics in the lower respiratory tract of patients admitted to the ICU. AB - Recent molecular diagnostic methods have significantly improved the diagnosis of viral pneumonia in intensive care units (ICUs). It has been observed that 222G/N changes in the HA gene of H1N1pdm09 are associated with increased lower respiratory tract (LRT) replication and worse clinical outcome. In the present study, the frequency of respiratory viruses was assessed in respiratory samples from 88 patients admitted to 16 ICUs during the 2014-2015 winter-spring season in Lombardy. Sixty-nine out of 88 (78.4%) patients were positive for a respiratory viral infection at admission. Of these, 57/69 (82.6%) were positive for influenza A (41 A/H1N1pdm09 and 15 A/H3N2), 8/69 (11.6%) for HRV, 2/69 (2.9%) for RSV and 2/69 (2.9%) for influenza B. Phylogenetic analysis of influenza A/H1N1pdm09 strains from 28/41 ICU-patients and 21 patients with mild respiratory syndrome not requiring hospitalization, showed the clear predominance of subgroup 6B strains. The median influenza A load in LRT samples of ICU patients was higher than that observed in the upper respiratory tract (URT) (p<0.05). Overall, a greater number of H1N1pdm09 virus variants were observed using next generation sequencing on partial HA sequences (codons 180-286) in clinical samples from the LRT as compared to URT. In addition, 222G/N/A mutations were observed in 30% of LRT samples from ICU patients. Finally, intra-host evolution analysis showed the presence of different dynamics of viral population in LRT of patients hospitalized in ICU with a severe influenza infection. PMID- 28591237 TI - Association between pathogens from tracheal aspirate and oral biofilm of patients on mechanical ventilation. AB - The aim of this study was to detect possible associations between respiratory pathogens from tracheal aspirate and oral biofilm samples in intubated patients in an intensive care unit (ICU), and to identify the most common respiratory pathogens in oral biofilm, particularly in patients that developed ventilator associated pneumonia (VAP). Two oral biofilm samples were collected from the tongue of intubated patients (at admission and after 48 hours) and analyzed by culture with the Antibiotic Sensitivity Test. The results from the tongue biofilm samples were compared with the tracheal secretions samples. A total of 59.37% of patients exhibited the same species of pathogens in their tracheal aspirate and oral biofilm, of which 8 (42.1%) developed VAP, 10 (52.63%) did not develop pneumonia and one (5.26%) had aspiration pneumonia. There was a statistically significant association between presence of microorganisms in the tracheal and mouth samples for the following pathogens: Klebsiella pneumoniae, Candida albicans, Pseudomonas aeruginosa, Enterobacter gergoviae, Streptococcus spp and Serratia marcescens (p < 0.05). Pathogens that are present in tracheal aspirates of intubated patients can be detected in their oral cavity, especially in those who developed VAP or aspiration pneumonia. Thus, the results indicate that an improved oral care in these patients could decrease ICU pneumonia rates. PMID- 28591231 TI - Association of blood pressure variability with orthostatic intolerance symptoms. AB - The short-term blood pressure variability (BPV) reflects autonomic regulatory mechanisms. However, the influence of BPV in orthostatic intolerance (OI) is unknown. Herein, we assessed BPV profiles in patients with OI and determined their association with orthostatic symptoms. In this cross-sectional study, we prospectively enrolled 126 patients presenting with OI at the Seoul National University Hospital from December 2014 to August 2016. Among them, those with other neurological diseases (n = 8) and insufficient BP measurements (n = 15) were excluded. The degree of OI symptoms were measured using the self administered orthostatic intolerance questionnaire (OIQ). All patients underwent ambulatory BP monitoring and we calculated the standard deviation and coefficient of variation as a measure of BPV. The mean age was 48.6 years and the average of the total OIQ score was 11.6. The severe OI group had higher BPV values than the mild group, although mean BP profiles did not differ significantly. Correlation analysis demonstrated that the orthostatic symptoms were positively correlated with diastolic BPV for the total and awake periods. Multiple linear regression analysis revealed that diastolic BPV (B = 0.46, p = 0.031) and current smoking (B = 4.687, p = 0.018) were independent factors for higher OI symptom scores after adjusting for covariates. The results of the current study demonstrated that a positive correlation exists between BPV and OI symptoms. Further studies are required to confirm the present findings and understand the neural mechanisms contributing to the excessive BPV in patients with OI. PMID- 28591238 TI - Salivary protein polymorphisms and risk of dental caries: a systematic review. AB - Dental caries is an oral pathology associated with both lifestyle and genetic factors. The caries process can be influenced by salivary composition, which includes ions and proteins. Studies have described associations between salivary protein polymorphisms and dental caries experience, while others have shown no association with salivary proteins genetic variability. The aim of this study is to assess the influence of salivary protein polymorphisms on the risk of dental caries by means of a systematic review of the current literature. An electronic search was performed in PubMed, Scopus, and Virtual Health Library. The following search terms were used: "dental caries susceptibility," "dental caries," "polymorphism, genetics," "saliva," "proteins," and "peptides." Related MeSH headings and free terms were included. The inclusion criteria comprised clinical investigations of subjects with and without caries. After application of these eligibility criteria, the selected articles were qualified by assessing their methodological quality. Initially, 338 articles were identified from the electronic databases after exclusion of duplicates. Exclusion criteria eliminated 322 articles, and 16 remained for evaluation. Eleven articles found a consistent association between salivary protein polymorphisms and risk of dental caries, for proteins related to antimicrobial activity (beta defensin 1 and lysozyme-like protein), pH control (carbonic anhydrase VI), and bacterial colonization/adhesion (lactotransferrin, mucin, and proline-rich protein Db). This systematic review demonstrated an association between genetic polymorphisms and risk of dental caries for most of the salivary proteins. PMID- 28591239 TI - Association between crack cocaine use and reduced salivary flow. AB - Crack cocaine use appears to have an impact on oral conditions. However, changes in the salivary flow among crack users have not been fully clarified. The aim of this study was to compare stimulated salivary flow and the occurrence of hyposalivation between crack users and non-users. A cross-sectional study was conducted involving 40 crack users and 40 controls matched for sex, age, and smoking habits. Interviews were conducted to acquire data on the perception of dry mouth (xerostomia) and drug use. Stimulated salivary flow was determined using the spitting method. A significant reduction in stimulated salivary flow was found among crack users in comparison to non-users (1.02 vs. 1.59 ml/min). A total of 42.5% and 15% of crack users had very low and low stimulated salivary flow, respectively. Moreover, 65% of users reported xerostomia in comparison to 37.5% non-users (p < 0.012). No significant association was found between xerostomia and hyposalivation (p = 0.384). A multivariate analysis revealed that individuals older than 26 years of age, those with a low household income, and crack users (prevalence ratio: 2.59) had a significant association with the occurrence of hyposalivation. A significant association was found between the use of crack and reduced salivary flow. The use of crack was associated with the occurrence of hyposalivation in the multivariate analysis. PMID- 28591240 TI - A randomized clinical trial on the sealing of occlusal carious lesions: 3-4-year results. AB - This randomized clinical trial aimed to assess the efficacy of sealing occlusal carious lesions in permanent teeth. The sample consisted of 54 occlusal carious lesions in permanent molars and premolars of 49 patients aged 8-43 years (median: 19 years). The inclusion criteria comprised the presence of a cavity with no access allowing biofilm control. The maximum depth of the lesion was the middle third of the dentin thickness, as assessed by bitewing radiography. The teeth were randomly assigned to sealant treatment (n = 28) or restorative treatment (n = 26). Clinical and radiographic examinations were performed after 1 year and after 3-4 years. The outcomes depended on the clinical performance of the sealant/restoration and the control of caries progression observed radiographically. Survival analysis was performed to assess success rates. Over the 3-4 years of monitoring, 2 sealants were totally lost, 1 needed repair, and 1 showed caries progression, totaling 4 failures in the sealant group. In the restoration group, 1 failure was observed (in need of repair). The success rates were 76% and 94% in the sealant and the restoration groups, respectively (p > 0.05). The sealing of occlusal carious lesions in permanent teeth succeeded in controlling caries over a 3-4-year period. However, sealed carious lesions require patient compliance in attending regular follow-ups to control the occurrence of clinical failures of the sealants. PMID- 28591241 TI - The anti-caries activity and toxicity of an experimental propolis-containing varnish. AB - We investigated the anti-caries effects of an experimental propolis varnish in vivo, and further tested its toxicity against fibroblasts. Fifty-six SPF female Wistar rats were infected with Streptococcus mutans UA159 (SM) and allocated into four groups (n = 14/group): G1, propolis varnish (15%/PV); G2, chitosan varnish (CV/vehicle); G3, gold standard (GS/Duraphat(r)); and G4, untreated. The animals received a single varnish application on their molars and were submitted to a high cariogenic challenge (Diet-2000, 56% sucrose, and 5% sucrose-added water, ad libitum) for 4 weeks. Total cultivable microbiota and SM were counted, and smooth surface and sulcal caries were scored. PV, CV and GS cytotoxic effects were tested against fibroblasts. The data were analyzed using ANOVA with the Tukey Kramer test (p <= 0.05). Total microbiota and SM counts did not differ among the treatments (p = 0.78), or in relation to the untreated group (p = 0.52). PV reduced development of smooth-surface enamel caries compared with the untreated group (p = 0.0018), with no significant difference from GS (p = 0.92); however, the PV effects were no longer observed when the dentin was affected. Neither PV nor GS prevented enamel sulcal lesion onset, but GS significantly reduced the severity of dentinal sulcal lesions (p < 0.0001). No significant difference was observed in fibroblast viability between PV and GS (p < 0.0001). In conclusion, PV prevented smooth-surface enamel caries and showed low cell toxicity. Nevertheless, due to the high cariogenic challenge, its effects were not sustained throughout the experiment. Further studies are encouraged to establish a protocol to sustain the long-term anti-caries activity of PV in the oral cavity. PMID- 28591242 TI - 3D analysis of effects of primary surgeries in cleft lip/palate children during the first two years of life. AB - This study aimed at monitoring the maxillary growth of children with cleft lip/palate in the first two years of life, and to evaluate the effects of primary surgeries on dental arch dimensions. The sample consisted of the three dimensional digital models of 25 subjects with unilateral complete cleft lip and palate (UCLP) and 29 subjects with isolated cleft palate (CP). Maxillary arch dimensions were measured at 3 months (before lip repair), 1 year (before palate repair), and at 2 years of age. Student's ttest was used for comparison between the groups. Repeated measures ANOVA followed by Tukey's test was used to compare different treatment phases in the UCLP group. Paired ttest was used to compare different treatment phases in the CP group. P<0.05 was considered statistically significant. Decreased intercanine distance and anterior arch length were observed after lip repair in UCLP. After palate repair, maxillary dimensions increased significantly, except for the intercanine distance in UCLP and the intertuberosity distance in both groups. At the time of palate repair and at two years of age, the maxillary dimensions were very similar in both groups. It can be concluded that the maxillary arches of children with UCLP and CP changed as a result of primary surgery. PMID- 28591243 TI - PLATELET COUNT SQUARED/SPLEEN DIAMETER-ASPARTATE AMINOTRANSFERASE RATIO: NON INVASIVE METHOD TO PREDICT ESOPHAGEAL VARICES. AB - BACKGROUND: - Variceal bleeding has a high mortality among cirrhotics, and screening with endoscopy is indicated at the diagnosis of cirrhosis. Screening with endoscopy implies discomfort, risks and considerable costs. OBJECTIVE: - To evaluate platelet count squared/spleen diameter-aspartate aminotransferase ratio (PS/SA), as a non-invasive predictor of esophageal varices in cirrhotics. METHODS: - This cross-sectional study evaluated cirrhotics for PS/SA and presence of esophageal varices. Outpatient records of cirrhotic patients were reviewed for the abovementioned data. Sensitivity, specificity, negative and positive predictive values of PS/SA were calculated. After the univariate analysis, variables with P<0.10 were submitted to a logistic regression. RESULTS: - The study included 164 cirrhotics, 59.70% male, with a mean age of 56.7 years. Hepatitis C was the most frequent cause of cirrhosis, being present in 90 patients. Patients were classified as Child-Pugh A in 52.44% and as Child-Pugh B or C in 47.56%. Esophageal varices were present in 72.56% of the patients at endoscopy. PS/SA, with a cutoff of 3x108, had a sensitivity of 95.80% (confidence interval of 95% - 95%CI=0.92-0.99), a specificity of 22.70% (95%CI=0.10-0.35), a positive predictive value of 77.20% (95%CI=0.70-0.84) and a negative predictive value of 66.70% (95%CI=0.42-0.91). In the logistic regression, only platelet count and Child-Pugh score were associated to esophageal varices (P<0.05). CONCLUSION: - PS/SA has an excellent sensitivity to predict esophageal varices, allowing almost one fourth of patients without esophageal varices to spare endoscopy. Nevertheless, PS/SA is not independently associated to esophageal varices. PMID- 28591244 TI - INFLUENCE OF DRINKING A PROBIOTIC FERMENTED MILK BEVERAGE CONTAINING BIFIDOBACTERIUM ANIMALIS ON THE SYMPTOMS OF CONSTIPATION. AB - BACKGROUND: Constipation is a chronic problem in many patients all over the world. OBJECTIVE: - To evaluate the effect of consumption of a probiotic fermented milk beverage containing Bifidobacterium animalis on the symptoms of constipation. METHODS: - This randomized, double-blind controlled trial included 49 female patients aged 20 to 50 years and diagnosed with constipation according to the ROME III criteria (Diagnostic Criteria for Functional Gastrointestinal Disorders) and the Bristol Stool Form Scale. The patients were randomized into two groups: the intervention group received the probiotic fermented milk beverage and the control group received non-probiotic milk. Participants were instructed to ingest 150 mL of the beverages during 60 days. At the end of this period, patients were assessed again by the ROME III criteria and Bristol scale. The Wilcoxon test was used to evaluate pre and post-intervention results of the ROME III criteria and Bristol scale. The statistical significance level was considered as 5% ( P <=0.05). RESULTS: - The intervention group showed improvement in the following criteria: straining during a bowel movement ( P <0.001), feeling of incomplete evacuation ( P <0.001) and difficulty in passing stool ( P <0.014), in addition to Bristol scale results ( P <0.001). In the control group, improvements were observed in the following criteria: straining during a bowel movement ( P <0.001), feeling of incomplete evacuation ( P <0.001) and difficulty in passing stool ( P <0.025), in addition to Bristol scale results ( P <0.001). No statistically significant post-intervention differences were observed between the two groups for the Rome III criteria and Bristol scale. CONCLUSION: - The results show that the consumption of milk resulted in the improvement of constipation symptoms, regardless of the probiotic culture. PMID- 28591246 TI - Translation and adaptation of "Perception of Severity of Chronic Illness" to the Brazilian culture for adolescents. AB - Objective: To translate, adapt, and evaluate the applicability of the "Perception of Severity of Chronic Illness" questionnaire to the Brazilian culture for diabetic adolescents. Methods: This is a methodological study consisting of the stages of translation, synthesis of translations, back translation, review by an expert committee, and pre-test. The expert judges evaluated semantic, idiomatic, conceptual, and cultural equivalences. The judges' concordance was quantified using the Content Validity Index. Results: The translation and back translation were performed successfully. After the synthesised translation was reviewed by the committee, the items were altered to ensure equivalence between the original and translated instrument. After the pre-test, some statements were reformulated to make them clearer and easier to understand. The preliminary data of the instrument's reliability calculated using Cronbach's alpha was 0.66. Conclusion: The Brazilian version of the instrument Perception of Severity of Chronic Illness proved satisfactory in terms of the translation, cultural adaptation, and practicality, and it was considered an easily applicable and viable tool for clinical practice. PMID- 28591245 TI - AGREEMENT BETWEEN DIFFERENT PATHOLOGISTS IN HISTOPATHOLOGIC DIAGNOSIS OF 128 GASTRIC POLYPS. AB - BACKGROUND: - Gastric polyps are elevated mucosal lesions. Most of them are less than 1 cm and when larger than 2 cm, has a high malignancy probability. The histopathological types are mainly fundic gland polyps, hyperplastic polyps and adenomatous polyps. OBJECTIVE: - To evaluate the agreement between three different pathologists in the histopathological diagnosis of 128 biopsied gastric polyps in Digestive Endoscopy Unit from Walter Cantideo University Hospital, between May 2010 to May 2012. METHODS: - To describe the intensity of agreement between observers, we use kappa index that is based on the number of concordant measures between them. RESULTS: - There was substantial agreement in the diagnosis of adenoma (kappa=0.799, CI: 0.899-0.698) and fundic glands (kappa=0.655, CI: 0.755-0.555). Regarding to hyperplastic polyps (kappa=0.415, CI: 0.515-0.315) and inflammatory (kappa=0.401, CI: 0.501-0.301), we obtained a moderate agreement. Regarding the presence of Helicobacter pylori in biopsy of the polyp, there was a low agreement (kappa=0.219, CI: 0.319-0.119). CONCLUSION: It is clear that the agreement between pathologists depends on the histological type of the biopsied polyp and this agreement is more substantial in adenoma, or fundic gland polyps. PMID- 28591247 TI - Mental health care network: the views of coordinators of the Family Health Strategy (FHS). AB - Objective: This study aimed to analyze the opinions of the coordinators of the Family Health Strategy (FHS) on the mental health care network in the city of Pelotas/RS. Method: Descriptive and exploratory study with a qualitative approach, carried out with six FHS coordinators, in 2012. Semi-structured interview was used in data collection, and the results were evaluated using the thematic analysis. Results: The network designed by the coordinators consists of few formal services and is focused on the Psychosocial Care Centers (CAPS). The informal network has a greater number of care units. Exchange of information related to joint responsibilities in the care is scarce, with lack of dialogue. Conclusion: The coordinators have scarce knowledge on the formal care network and on care focused on the ESF and CAPS. They also recognize the importance public policies that value and expand the informal care spaces in the territory. PMID- 28591248 TI - Communication of scientific production and knowledge visibility in nursing. PMID- 28591249 TI - [RETRACTED ARTICLE] GASTRIC AND JEJUNAL HISTOPATHOLOGICAL CHANGES IN PATIENTS UNDERGOING BARIATRIC SURGERY. AB - [This retracts the article DOI: 10.1590/s0004-2803.2017v54n1-15.]. PMID- 28591250 TI - Erratum. AB - [This corrects the article DOI: 10.1590/S0004-28032015000500004.]. PMID- 28591251 TI - Analysis of the Economic Impact of Cardiovascular Diseases in the Last Five Years in Brazil. AB - Background: There is growing concern about the economic impact of cardiovascular diseases (CVD) in Brazil and worldwide. Objective: To estimate the economic impact of CVD in Brazil in the last five years. Methods: The information to estimate CVD costs was taken from national databases, adding the direct costs with hospitalizations, outpatient visits and benefits granted by social security. Indirect costs were added to the calculation, such as loss of income caused by CVD morbidity or mortality. Results: CVD mortality accounts for 28% of all deaths in Brazil in the last five years and for 38% of deaths in the productive age range (18 to 65 years). The estimated costs of CVD were R$ 37.1 billion in 2015, a 17% increase in the period from 2010 to 2015. The estimated costs of premature death due to CVD represent 61% of the total cost of CVD, Direct costs with hospitalizations and consultations were 22%, and costs related to the loss of productivity related to the disease were 15% of the total. Health expenditures in Brazil are estimated at 9.5% of GDP and the average cost of CVD was estimated at 0.7% of GDP. Conclusion: CVD costs have increased significantly in the last five years. It is estimated that CVD costs increase as the Brazilian population ages and the prevalence of CVD increases. PMID- 28591252 TI - Impact of the Use of Different Diagnostic Criteria in the Prevalence of Dyslipidemia in Pregnant Women. AB - Background: There is a physiologic elevation of total cholesterol (TC) and triglycerides (TG) during pregnancy. Some authors define dyslipidemia (DLP) in pregnant women when TC, LDL and TG concentrations are above the 95th percentile (p95%) and HDL concentration is below the 5th percentile (P5%) for gestational age (GA). Objective: To compare the prevalence of DLP in pregnant women using percentiles criteria with the V Brazilian Guidelines on Dyslipidemia and the association with maternal and fetal outcomes. Results: Pregnant women with high risk conditions, aged 18-50 years, and at least one lipid profile during pregnancy was classified as the presence of DLP by two diagnostic criteria. Clinical and laboratorial data of mothers and newborns were evaluated. Conclusion: 433 pregnant women aged 32.9 +/- 6.5 years were studied. Most (54.6%) had lipid profile collected during third trimester. The prevalence of any lipid abnormalities according to the criteria of the National Guidelines was 83.8%: TC >= 200 mg/dL was found in 49.9%; LDL >= 160 mg/dL, in 14.3%, HDL <= 50 mg/dL in 44.4% and TG >= 150 mg/dL in 65.3%. Any changes of lipid according to percentiles criteria was found in 19.6%: elevation above the P95% for TC was found in 0.7%; for LDL, 1.7%; for TG 6.4% and HDL lower than the P5% in 13%. The frequency of comorbidity: hypertension, diabetes, smoking, obesity and preeclampsia was similar among pregnant women when DLP was compared by both criteria. Conclusion: The prevalence of DLP during pregnancy varies significantly depending on the criteria used, however none demonstrated superiority in association with comorbidities. PMID- 28591254 TI - Bacteremia caused by Elizabethkingia meningoseptica in a mechanically ventilated patient successfully treated with imipenem-cilastatin and ciprofloxacin. PMID- 28591253 TI - Acute kidney injury complicating bee stings - a review. AB - Bee stings can cause severe reactions and have caused many victims in the last years. Allergic reactions can be triggered by a single sting and the greater the number of stings, the worse the prognosis. The poisoning effects can be systemic and can eventually cause death. The poison components are melitin, apamin, peptide 401, phospholipase A2, hyaluronidase, histamine, dopamine, and norepinephrine, with melitin being the main lethal component. Acute kidney injury (AKI) can be observed in patients suffering from bee stings and this is due to multiple factors, such as intravascular hemolysis, rhabdomyolysis, hypotension and direct toxicity of the venom components to the renal tubules. Arterial hypotension plays an important role in this type of AKI, leading to ischemic renal lesion. The most commonly identified biopsy finding in these cases is acute tubular necrosis, which can occur due to both, ischemic injury and the nephrotoxicity of venom components. Hemolysis and rhabdomyolysis reported in many cases in the literature, were demonstrated by elevated serum levels of indirect bilirubin and creatine kinase. The severity of AKI seems to be associated with the number of stings, since creatinine levels were higher, in most cases, when there were more than 1,000 stings. The aim of this study is to present an updated review of AKI associated with bee stings, including the currently advised clinical approach. PMID- 28591255 TI - Entomological survey in the state of Piaui, Northeastern Brazil, reveals intradomiciliary colonization of Triatoma brasiliensis macromelasoma. AB - This survey aimed to assess the presence of triatomine vectors of Chagas disease within the rural communities of Sao Joao do Piaui, Northeast Brazil. Intradomiciliary and peridomiciliary collection strategies were implemented wherein 279 specimens of Triatoma brasiliensis macromelasoma, both nymph and adult were found in 15 (50%) of the studied homes. Of the intradomiciliary insects, 73 (67.6%) were identified as nymph instars (1st instar [N1]= 6, N2= 14, N3= 28, N4= 7 and N5= 18). In the studied communities, a continuous interaction between triatomine bugs and humans could be shown. It is therefore urgent that suitable strategies for the control of the triatomine vector are implemented in this area. PMID- 28591256 TI - Association of outcomes with comprehension, adherence and behavioral characteristics of tuberculosis patients using fixed-dose combination therapy in Contagem, Minas Gerais, Brazil. AB - The present study aimed to assess the association of outcomes with comprehension, adherence and behavioral characteristics of tuberculosis (TB) patients using fixed-dose combination (FDC) therapy in the city of Contagem, MG, Brazil. This study used standardized questionnaires to collect data. Outcomes included cure in 77.2% (64/ 83), noncompliance with treatment in 20.4% (17/ 83), and absence of organ failure or death cases. The rate of adherence to treatment was high (71.1% 59/ 83), while the level of comprehension of the treatment was insufficient for the majority of patients (72.3% - 60/ 83). When a greater number of medicines was used, the chance of noncompliance with treatment increased exponentially (p = 0.00 - OR 1.72). Light-skinned black patients, alcoholics and those who live with HIV/ AIDS showed a significant association with noncompliance with treatment (p=0.039 - OR 3.38, p=0.002 - OR 4.68, and p=0.001 - OR 9.68, respectively). Comprehension also presented a significant association with noncompliance with treatment (p=0.01 and OR 5.76 and CI 1.49-22.29). The probability of noncompliance with treatment in the first few months was greater than in the subsequent months. This study demonstrates that if the TB patients had a better understanding of the treatment, the outcome would have been more favorable as regards a proper cure. PMID- 28591257 TI - Oral Candida spp carriage and periodontal diseases in HIV-infected patients in Ribeirao Preto, Brazil. AB - The majority of HIV-infected patients develop Candida spp-associated clinical oral lesions. Studies have shown that asymptomatic oral colonization of Candida spp may lead to oral lesions or become a source of disseminated infections. The aim of this study was to verify the effects of periodontal conditions on Candida spp prevalence and Candida spp carriage in the oral cavity of HIV-infected patients compared to non-infected patients. Twenty-five patients not infected with HIV and 48 HIV-infected patients were classified according to periodontal conditions as being periodontal healthy or with periodontal disease. Candida spp carriage and classification were performed in oral rinse samples. Viral load and CD4+ T lymphocyte (CD4+L) counts were performed in blood samples from HIV infected patients. No differences in Candida spp prevalence related to HIV status or periodontal condition were detected. However, Candida spp carriage was increased in periodontally affected HIV-infected patients when compared to periodontally healthy HIV-infected patients (p= 0.04). Periodontally healthy HIV infected patients presented Candida spp carriage in similar levels as healthy or periodontally affected non-HIV-infected patients. Candida spp carriage was correlated with CD4+L counting in HIV-infected patients. We concluded that periodontal disease is associated with increased Candida spp carriage in HIV infected patients and may be a predisposing factor to clinical manifestations of candidiasis. PMID- 28591258 TI - Immune development in HIV-exposed uninfected children born to HIV-infected women. AB - Immunological and clinical findings suggestive of some immune dysfunction have been reported among HIV-exposed uninfected (HEU) children and adolescents. Whether these defects are persistent or transitory is still unknown. HEU pediatric population at birth, 12 months, 6-12 years were evaluated in comparison to healthy age-matched HIV-unexposed controls. Plasma levels of LPS, sCD14, cytokines, lymphocyte immunophenotyping and T-cell receptor excision circles (TREC) were assessed. HEU and controls had similar LPS levels, which remained low from birth to 6-12 years; for plasma sCD14, IL-2, IL-6, IL-7, IL-10, IL-12p70, IL 13, IL-17, IFN-gamma, TNF-alpha, G-CSF, GM-CSF and MCP-1, which increased from birth to 12 months and then decreased at 6-12 years; and for TREC/106 PBMC at birth in HEU and controls. By contrast, plasma MIP-1beta levels were lower in HEU than in controls (p=0.009) at 12 months, and IL-4 levels were higher in HEU than controls (p=0.04) at 6-12 years. Immune activation was higher in HEU at 12 months and at 6-12 years than controls based on frequencies of CD38+HLA-DR+CD8+T cells (p=0.05) and of CD38+HLA-DR+CD4+T cells (p=0.006). Resting memory and activated mature B cells increased from birth to 6-12 years in both groups. The development of the immune system in vertically HEU individuals is comparable to the general population in most parameters, but subtle or transient differences exist. Their role in influencing clinical incidences in HEU is unknown. PMID- 28591259 TI - Knowledge and perceptions on toxoplasmosis among pregnant women and nurses who provide prenatal in primary care. AB - Background: Toxoplasmosis is an infection that affects almost a third of the world population. In adults, it is often asymptomatic, although having important manifestation in children- infected by placental transmission. The prenatal is an important moment, requiring actions in women's care during pregnancy, in order to prevent diseases that could compromise the mother and the child's life. Methods: This is a descriptive study of qualitative approach aimed to understand the perception of nurses and pregnant women about toxoplasmosis during primary - prenatal care. The study was conducted in five selected primary health care units, in the municipality of Sao Luis - MA. The sample consisted of 15 nurses working in nursing consultation and 15 pregnant women attended in prenatal care. For data collection, a semi-structured questionnaire and an interview guide covering issues related to knowledge and conduct on toxoplasmosis were used. For analysis, the content analysis technique was used. Results: The answers were transcribed, organized and grouped thematically, where the following categories emerged: knowledge about examination requests; knowledge about toxoplasmosis; guidance during prenatal consultation; knowledge of nurses about the avidity test; procedures and guidelines on reagent cases. Pregnant women showed unawareness about toxoplasmosis and its effects. Nurses, although having basic knowledge about the subject, showed little applicability regarding pregnant women's guidance. Conclusion: The nurse plays an important role in educational activities regarding pregnant women, contributing to the quality of prenatal care. Pregnant women were shown to have some knowledge about toxoplasmosis, although they said they did not have assurance about prevention. PMID- 28591260 TI - Presence of rotavirus and free-living amoebae in the water supplies of Karachi, Pakistan. AB - Rotavirus and pathogenic free-living amoebae are causative agents of important health problems, especially for developing countries like Pakistan where the population has limited access to clean water supplies. Here, we evaluated the prevalence of rotavirus and free-living amoebae (Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri) in drinking water supplies of Karachi, Pakistan. Six water filtration plants that supply drinking water to the population of Karachi were investigated. Additionally, drinking water samples from households were analyzed for the presence of rotavirus and free-living amoebae. Rotavirus was present in 35% of the water samples collected from water filtration plants; however, domestic tap water samples had a prevalence of only 5%. Out of 20 water samples from filtration plants, 13 (65%) were positive for Acanthamoeba spp., and one (5%) was positive for B. mandrillaris. Out of 20 drinking water samples collected from different areas of Karachi, 35% were positive for Acanthamoeba spp. Rotavirus was detected in 5% of the drinking water samples tested. Overall, these findings showed for the first time the presence of rotavirus, in addition to pathogenic free-living amoebae in drinking water supplies of Karachi that could be an important public health risk for the affected population. PMID- 28591262 TI - Fatal Cryptococcus gattii genotype VGI infection in an HIV-positive patient in Barranquilla, Colombia. AB - Cryptococcosis is a major invasive fungal disease related worldwide with the AIDS population. New reports of HIV/AIDS cases to the national public health surveillance system (SIVIGILA) in Colombia have shown that there is a growing community at risk of contracting cryptococcosis throughout the country who do not have access to ART. Even though the most prevalent species Cryptococcus neoformans is mainly associated with the HIV population, we report a fatal case of cryptococcosis in an AIDS patient in Barranquilla, associated with Cryptococcus gattii VGI, isolated from blood culture. PMID- 28591261 TI - Sporotrichoid leishmaniasis: a cross-sectional clinical, epidemiological and laboratory study in Rio de Janeiro State, Brazil. AB - Background: Atypical presentations of cutaneous leishmaniasis include sporotrichoid leishmaniasis (SL), which is clinically described as a primary ulcer combined with lymphangitis and nodules and/or ulcerated lesions along its pathway. Aims: To assess the differences between patients with sporotrichoid leishmaniasis and typical cutaneous leishmaniasis (CL). Methods: From January 2004 to December 2010, 23 cases of SL (4.7%) were detected among 494 CL patients diagnosed at a reference center for the disease in Rio de Janeiro State, Brazil. These 23 cases were compared with the remaining 471 patients presenting CL. Results: SL predominated in female patients (60.9%, p = 0.024), with older age (p = 0.032) and with lesions in upper limbs (52.2%, p = 0.028). CL affected more men (64.5%), at younger age, and with a higher number of lesions exclusively in lower limbs (34.8%). Conclusions: Differences in clinical and epidemiological presentation were found between SL patients as compared to CL ones, in a region with a known predominance of Leishmania (Viannia) braziliensis. The results are similar to the features of most of the sporotrichosis patients as described in literature, making the differential diagnosis between ATL and sporotrichosis more important in overlapping areas for both diseases, like in Rio de Janeiro State. PMID- 28591263 TI - Myiasis associated with an invasive ductal carcinoma of the left breast: case study. AB - Most breast cancers originate in the ductal epithelium and are referred to as invasive ductal carcinoma. In this study we report on the clinical procedures adopted to diagnose myiasis in association with infiltrating metastatic breast carcinoma in a female patient. A 41 years old woman came to the Federal Hospital of Andarai complaining of intense itching, warmth, redness and hardening of the breast, which had acquired the aspect of an orange peel. A lesion in the left breast was cavitated, dimpled, had fetid odor, and had fibrotic and infected air nodules filled with exudate and Dipteran larvae. The tissue was cleaned and 33 larvae were extracted. The patient was hospitalized and received Ivermectin. Eighteen of the larvae extracted from the patient were placed in 70% alcohol, and twelve were placed in a container with sterile wood shavings under controlled conditions until they metamorphosed into adults. The taxonomic identification of the flies revealed that the culprit was Cochliomyia hominivorax. A histopathological exam conducted three months earlier had revealed infiltrating ductal carcinoma. Two months after the myiasis treatment, the breast tissue had healed. The patient had waited ten days from the onset of the myiasis to seek treatment, and that delay interfered negatively in the prognosis of both the neoplasm and the myiasis. This study is relevant to public health in view of the strong social impact of myiasis. PMID- 28591264 TI - Sarcoid-like cutaneous lesions in chronic adult paracoccidioidomycosis: report of two cases. AB - This study reports two cases of chronic paracoccidioidomycosis with sarcoid-like cutaneous lesions. The patients began the treatment in 2013 at Hospital Universitario Clementino Fraga Filho (HUCFF) of the Universidade Federal do Rio de Janeiro (UFRJ). The first case (mild form) was treated with trimethoprim sulfamethoxazole (8 mg /kg per day, orally) for three months and, then, with half the dose for nine months; the second (moderate form), with itraconazole (200 mg per day, orally) for 12 months. We point out the rareness of the sarcoid-like cutaneous lesions and the differential diagnoses for other granulomatous diseases. PMID- 28591265 TI - Disseminated cutaneous leishmaniasis caused by Leishmania braziliensis in Southern Brazil. AB - The authors report a case of disseminated cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis, in a 55 years old patient with 1,119 lesions distributed throughout the body. The patient resides in Sabaudia municipality, North of Parana State, Southern Brazil, where there was no previous report of this form of leishmaniasis. Treatment with meglumine antimoniate was successful, although the diagnosis was made only five months later. PMID- 28591266 TI - Efficiency of noninvasive sampling methods (swab) together with Polymerase Chain Reaction (PCR) for diagnosing American Tegumentary Leishmaniasis. AB - Traditional diagnostic methods used to detect American Tegumentary Leishmaniasis, such as histopathology using biopsy samples, culture techniques, and direct search for parasites, have low sensitivity and require invasive collection procedures. This study evaluates the efficiency of noninvasive sampling methods (swab) along with Polymerase Chain Reaction (PCR) for diagnosing American Tegumentary Leishmaniasis using skin and mucous samples from 25 patients who had tested positive for leishmaniasis. The outcome of the tests performance on swab samples was compatible with PCR results on biopsy samples. The findings have also shown that PCR-kDNA test is more efficient than PCR-HSP70 and qPCR tests (sensitivity of 92.3%, 40.7%, and 41%, respectively). Given the high sensitivity of the tests and the fact that the sampling method using swabs affords greater patient comfort and safety, it could be said that this method is a promising alternative to conventional biopsy-based methods for the molecular diagnosis of leishmaniasis. PMID- 28591267 TI - The performance of serological tests for Leishmania infantum infection screening in dogs depends on the prevalence of the disease. AB - Dogs are considered the main reservoir of Leishmania infantum. This protozoan causes visceral leishmaniasis (VL), an uncontrolled urban zoonosis in Brazil. Serological tests and polymerase chain reaction (PCR) on peripheral blood were performed to identify infected dogs in scenarios of higher and lower prevalence of the disease (Teresina and Vitoria). One-hundred infected and 57 non-infected animals from Teresina and 100 non-infected animals from Vitoria were studied. Animal selection was not dependent on previous serology. The sensitivity (Teresina) and specificity (Teresina and Vitoria) were as follows: indirect antibody fluorescence (IFAT) cut-off of 1:40 (IFAT 1:40): 96%, 18%, and 76%; IFAT 1:80: 90%, 33%, and 93%; direct agglutination test (DAT): 96%, 33%, and 98%; fast agglutination screening test (FAST): 93%, 68%, and 100%; immunochromatographic assay with a recombinant rK39 antigen (rK39): 88%, 74%, and 98%; enzyme linked immunosorbent assay (ELISA): 91%, 79%, and 98%; rapid dual-path platform test (TR DPP(r)): 98%, 60%, and 98%; and blood PCR: 29%, 93%, and 97%, respectively. In the high transmission area, none of the tests adequately discriminated L. infantum-infected from non-infected dogs. However, in the high transmission city, the area under the receiver operating characteristic (ROC) curve of FAST, DAT, ICrK39, ELISA and TR DPP(r) was high. PMID- 28591269 TI - What can BDNF genotype tell us about our memory? PMID- 28591270 TI - Staging in bipolar disorder: one step closer to precision psychiatry. PMID- 28591268 TI - Diagnosis of mycobacteria in bovine milk: an overview. AB - Tuberculosis remains as the world's biggest threat. In 2014, human tuberculosis ranked as a major infectious disease by the first time, overcoming HIV death rates. Bovine tuberculosis is a chronic disease of global distribution that affects animals and can be transmitted to humans by the consumption of raw milk, representing a serious public health concern. Despite the efforts of different countries to control and eradicate bovine tuberculosis, the high negative economic impact on meat and milk production chains remains, given the decreased production efficiency (approximately 25%), the high number of condemned carcasses, and increased animal culling rates. This scenario has motivated the establishment of official programs based on regulations and diagnostic procedures. Although Mycobacterium tuberculosis and Mycobacterium bovis are the major pathogenic species to humans and bovines, respectively, nontuberculous mycobacteria within the Mycobacterium genus have become increasingly important in recent decades due to human infections, including the ones that occur in immunocompetent people. Diagnosis of mycobacteria can be performed by microbiological culture from tissue samples (lymph nodes, lungs) and secretions (sputum, milk). In general, these pathogens demand special nutrient requirements for isolation/growth, and the use of selective and rich culture media. Indeed, within these genera, mycobacteria are classified as either fast- or slow-growth microorganisms. Regarding the latter ones, incubation times can vary from 45 to 90 days. Although microbiological culture is still considered the gold standard method for diagnosis, molecular approaches have been increasingly used. We describe here an overview of the diagnosis of Mycobacterium species in bovine milk. PMID- 28591271 TI - A case of bleach addiction associated with severe obsessive-compulsive disorder. PMID- 28591272 TI - S-(+)-ketamine-induced dissociative symptoms as a traumatic experience in patients with treatment-resistant depression. PMID- 28591273 TI - An index to examine the sexual HIV risk of psychiatric service users based on sexual partners. PMID- 28591274 TI - Current inpatient prescription practices for the treatment of schizophrenia in public hospitals of Minas Gerais, Brazil. PMID- 28591275 TI - A new season for the Arquivos Brasileiros de Oftalmologia (ABO). PMID- 28591276 TI - Comparison of optical coherence tomographic findings between Behcet disease patients with and without ocular involvement and healthy subjects. AB - Purpose:: We aimed to compare the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, and the choroid thickness between patients with Behcet disease and healthy subjects by using spectral domain optical coherence tomography (SD-OCT). Methods:: Ninety eyes of 45 healthy subjects and 104 eyes of 52 patients with Behcet disease were included in this study. Rheumatoid factor and C-reactive protein levels were measured by blood testing in the patients. Results:: The mean thickness of the retinal nerve fiber layer, ganglion cells layer, and inner plexiform layer were significantly lower in patients with Behcet's disease than in the healthy subjects. The mean choroidal thickness was significantly higher in the patients than in the healthy subjects. Conclusions:: SD-OCT was a useful and non-invasive tool for the detection of retinal nerve degeneration and choroidal changes in patients with Behcet disease even in the absence of ocular involvement. PMID- 28591277 TI - Evaluation of nicotinamide as an anti-inflammatory and anti-angiogenic agent in uveal melanoma cell lines. AB - Purpose:: To investigate the effect of nicotinamide on the secretion of pro-an giogenic and pro-inflammatory cytokines in uveal melanoma cell lines. Methods:: Two human uveal melanoma cell lines (92.1 and OCM-1) were treated with nicotinamide (10 mmol/L) or control media for 48 hours in culture. The su perna tant from each culture was used in sandwich enzyme-linked immuno sorbent assay based angiogenesis and inflammation arrays to evaluate the effects of exogenously administered nicotinamide on the secretion of a total of 20 pro-an gio genic and pro-inflammatory proteins. Results:: Seven pro-angiogenic cytokines were detected under control conditions for both uveal melanoma cell lines. Treatment with nicotinamide resulted in a significant decrease in secretion of the following pro angiogenic cytokines: angiogenin, angiopoietin-2, epidermal growth factor, and vascular epithelial growth factor-A in the 92.1 cells; basic fibroblast growth factor in the OCM-1 cells; and placenta growth factor in both cell lines. Among the pro-inflammatory proteins, monocyte chemotactic protein-1 and interleukin-8 were expressed in both untreated cell lines and both were significantly reduced when treated with nicotinamide. Conclusions:: Results from this in vitro model suggest that nicotinamide may have anti-inflammatory and anti-angiogenic properties, which may open the possibility of using it as a chemopreventive agent for uveal melanoma; however, further studies including animal models are warranted. PMID- 28591278 TI - Comparisons of choroidal nevus measurements obtained using 10- and 20-MHz ultrasound and spectral domain optical coherence tomography. AB - Purpose:: To compare measurements of lesions clinically diagnosed as choroidal nevi using spectral domain optical coherence tomography (SD-OCT) and 10- and 20 MHz ultrasound (US). Methods:: This prospective study, which was conducted between May 2011 and December 2011, evaluated eyes diagnosed with choroidal nevus via photographic documentation using 10- or 20-MHz A- and B-mode US (experienced examiner using both the transpalpebral technique and direct contact) or SD-OCT in the enhanced depth imaging mode (performed by a different examiner blinded to the US results). Anteroposterior (AP) and transverse (T) US sections corresponded to sections adjusted perpendicularly on SD-OCT. Results:: We evaluated 14 eyes from 12 patients (six males, mean patient age= 64.5 years) diagnosed with choroidal nevus. The choroidal nevi of all samples had a melanocytic profile. Moreover, eight nevi were located at the equator, five nevi were located in the posterior pole (peripapillary in one sample), and one nevus shifted from the equator to the periphery. On SD-OCT, the maximum measurable dimension was 9 mm. The lesions in the posterior pole were easier to evaluate, and image acquisition of lesions located more peripherally was possible depending on patient cooperation. The accurate assessment of height was difficult. Baseline dimensions on 10- and 20 MHz US were larger than those determined via OCT. No significant differences in height were observed between US and SD-OCT. All parameters were statistically similar between 10- and 20-MHz US measurements. Conclusions:: No significant difference in the AP and T diameters was observed between 10- and 20-MHz US measurements; however, these measurements (AP and T) were significantly higher than those obtained using OCT. No significant differences in height were observed among the techniques adopted. PMID- 28591279 TI - Detection of herpes simplex-1 and -2 and varicella zoster virus by quantitative real-time polymerase chain reaction in corneas from patients with bacterial keratitis. AB - Objective:: Bacterial keratitis occurs worldwide, and despite recent developments, it remains a potentially blinding condition. This study assesses the presence of herpes simplex virus (HSV-1 and -2) and varicella zoster virus (VZV) by quantitative real-time polymerase chain reaction (qPCR) in corneal scrapings from patients with bacterial keratitis. Methods:: A total of 65 patients with clinical diagnoses of infectious corneal ulcers prospectively underwent clinical eye examinations. Corneal scrapings were investigated by Gram staining, Giemsa staining, culture, and qPCR (the study group). Risk factors and epidemiological data were recorded. The control group comprising 25 eyes with typical herpes dendritic keratitis was also analyzed by qPCR. Results:: From the study group (n=65), nine patients (13.8%) had negative smears, cultures, and qPCR findings. Fifty-six (86.2%) patients had positive cultures: 51 for bacteria, 4 for fungi, and 1 for amoebae. Of the patients who had positive bacterial cultures, qPCR identified 10 patients who were also positive for virus: one for VZV and nine for HSV-1. Of the 25 patients in the control group, 21 tested positive for HSV-1 by qPCR analysis. Conclusions:: Herpes may be present in patients with bacterial corneal ulcers, and qPCR may be useful in its detection. PMID- 28591280 TI - Keratoconus progression is not inhibited by reducing eyelid muscular force with botulinum toxin A treatment: a randomized trial. AB - Purpose:: To evaluate whether reducing eyelid muscular force through the administration of botulinum toxin type A (BTX-A) to the orbicularis oculi muscles of patients with keratoconus affected corneal parameters indicative of disease progression. Methods:: In this prospective parallel randomized clinical trial, 40 eyes of 40 patients with keratoconus were randomized into equally sized control and BTX-A groups. Patients in the BTX-A group received subcutaneous BTX-A injections into the orbicularis muscle. The control group received no intervention. Palpebral fissure height, best spectacle-corrected visual acuity (BSCVA), and corneal topographic parameters were evaluated at baseline and at 3-, 6-, 12-, and 18-month follow-ups. Results:: The mean +/- standard deviation vertical palpebral fissure heights were 9.74 +/- 1.87 mm and 9.45 +/- 1.47 mm at baseline in the control and BTX-A groups, respectively, and 10.0 +/- 1.49 mm and 9.62 +/- 1.73 mm at 18 months, with no significant difference between the groups (p=0.337). BSCVA values were 0.63 +/- 0.56 and 0.60 +/- 0.27 at baseline in the control and BTX-A groups (p=0.643), and 0.52 +/- 0.59 and 0.45 +/- 0.26 at 18 months, again with no significant difference between the groups (p=0.452). In addition, there were no statistical differences between the groups at 18 months for the three keratometry topographic parameters: flattest (K1), steepest (K2), and mean (Km) keratometry (p=0.562). Conclusion:: BTX-A inhibition of eyelid force generation did not result in detectable changes in corneal parameters in keratoconic patients during 18 months of follow-up. PMID- 28591281 TI - Topographic outcomes after corneal collagen crosslinking in progressive keratoconus: 1-year follow-up. AB - Purpose:: We aimed to report and analyze topographic and refractive outcomes following corneal collagen crosslinking (CXL) in patients with progressive keratoconus (KC). Methods:: We performed a retrospective, analytical, and observational study of 100 eyes from 74 progressive KC patients who underwent CXL at the Eye Hospital of Parana. Keratometric values were analyzed preoperatively as well as 3 and 12 months postoperatively. Results:: For a total of 100 eyes, 68 belonged to male patients. The mean age of our study population was 19.9 +/- 5.61 years. The average visual acuity and topographic parameters overall were stable after 1 year (p<0.05). After 3 months, steepest keratometry reading (K2) and maximum keratometry (Kmax) were significantly decreased (p<0.05). Regarding topographic astigmatism (dK), there was no significant difference between the 3 month and 12-month follow-ups. When we made comparisons between genders following CXL, there were no significant differences related to the changes in Kmax, K2, and spectacle-corrected distance visual acuity (SCDVA). Conclusions:: CXL promoted stabilization or improvement of keratometric values and visual acuity. We found that keratoconus apex stability may be achieved 3 months after the procedure. There was no significant difference in keratometric and refractive values measured between male and female patients. PMID- 28591282 TI - Incidence of anterior segment neovascularization during intravitreal treatment for macular edema secondary to central retinal vein occlusion. AB - Purpose:: To analyze the effects of injections of intravitreal triamcinolone acetonide (IVTA) and intravitreal bevacizumab (IVB) on the incidence rates of anterior segment neovascularization (ASN) and neovascular glaucoma (NVG) in patients with macular edema secondary to central retinal vein occlusion (CRVO). Methods:: In this prospective, randomized, double-masked, sham-controlled study, 35 patients with macular edema following CRVO were randomized to intravitreal bevacizumab, intravitreal triamcinolone acetonide, or sham injections during the first 6 months of the study. The primary outcome was the incidence rate of ASN at month 6. The secondary outcomes were the mean changes from baseline in best corrected visual acuity (BCVA) and central foveal thickness (CFT) on optical coherence tomography over time to month 12. Results:: ASN developed in 8 (22.86%) eyes, including 5 (62.50%) eyes in the sham group and 3 (37.50%) eyes in the IVTA group, during 12 months of fol low-up (p=0.009). BCVA differed significantly (p<0.05) among the groups only at month 1. CFT did not differ significantly (p<0.05) among the groups over 12 months. NVG required surgery and developed in one eye despite laser treatment. Conclusion:: Early treatment with intravitreal antivascular endothelial growth factor therapy decreases the rates of ASN and NVG after CRVO. PMID- 28591283 TI - Outcomes of phacoemulsification in patients with uveitis at a tertiary center in Sao Paulo, Brazil: a review of cases from 2007 to 2012. AB - Purpose:: To evaluate the outcomes of phacoemulsification with intraocular lens (IOL) implantation in eyes with uveitis. Methods:: Consecutive patients with uveitis and cataracts who had phacoemulsification and acrylic IOL implantation during 2007-2012 were evaluated for visual outcomes, etiology, and complications. Inflammation was controlled for at least 3 months before surgery, and oral prednisone (0.5 mg/kg/day) was administered to patients with non-infectious uveitis. Results:: This study investigated 45 eyes in 38 patients with a mean age of 52 +/- 12.5 years. The most common etiologies among non-infectious causes (n=32; 73.3%) were Vogt-Koyanagi-Harada disease (n=9), Fuchs heterochromic iridocyclitis (n=4), and sympathetic ophthalmia (n=3). Four cases were idiopathic. Among infectious cases (n=13; 28.9%), the most common causes were toxoplasmosis (n=6) and presumed ocular tuberculosis (n=4). An acrylic IOL was implanted in-the-bag in all cases. After 1-year follow-up, an improvement in visual acuity of two or more lines was observed in 38 eyes (84.4%), and 28 eyes (62.2%) achieved a postoperative visual acuity of >=0.5. Posterior capsule opacification was observed in 10 eyes (22.2%). Persistent postoperative inflammation (of >6 months) was observed in seven eyes (15.5%) and recurrence occurred in four eyes (8.8%). IOL was explanted in one eye. Intraocular hypertension was observed in six eyes (13.3%). Conclusions:: Phacoemulsification with IOL implantation improved vision in most patients with coexisting cataracts and uveitis. Good preoperative and postoperative control of inflammation plays an important role in achieving favorable visual outcomes. Furthermore, the final visual outcome depends on the posterior segment status. PMID- 28591285 TI - Iris-claw intraocular lens implantation in children with ectopia lentis. AB - Purpose:: Artisan iris-claw lens implantation (AICLI) is a surgical technique for treating ectopia lentis. We aimed to compare visual outcomes and possible long term complications of AICLI surgery in pediatric patients with ectopia lentis with or without a diagnosable hereditary disease. Methods:: Seventeen children with non-traumatic ectopia lentis were retros pectively classified into two groups: group 1 included children with a diagnosable hereditary disease (11 patients, 65%), and group 2 included children without any definable hereditary disease (six patients, 35%). Patients were evaluated for post-surgical refraction, best-corrected visual acuity, and clinical follow-up complications. Results:: The average follow-up time was 38 months, and the average age of the patients was 103 +/- 53 months (30-196 months). Best-corrected visual acuity values were significantly increased in both groups after surgery (p<0.05). Target refraction values were achieved at a rate of 47% in group 1 and 22% in group 2. Post-surgery complications, such as lens dislocation (36%, 11 eyes of 10 patients) and hypotonia (10%, three eyes of three patients) were observed in both groups, and retinal detachments (10%, three eyes of three patients) were observed in three patients from group 1. Conclusions:: Compared with previous similar studies, this study utilized the largest pediatric patient group and had the longest post-surgery follow-up time. Moreover, it is advisable that pediatric patients with non-traumatic ectopia lentis be carefully screened for any underlying hereditary disease, especially diseases related to connective tissue metabolism. PMID- 28591284 TI - Quality of bevacizumab (Avastin(r)) repacked in single-use glass vials for intravitreal administration. AB - Purpose:: Avastin(r) (bevacizumab) is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody given as an off-label drug by intravitreal administration for treatment of ocular diseases. The drug's clinical application and its cost-benefit profile has generated demand for its division into single use vials to meet the low volume and low-cost doses necessary for intraocular administration. However, the safety of compounding the drug in single-use vials is still under discussion. In this study, the stability and efficacy of Avastin(r) repacked in individual single-use glass vials and glass ampoules by external compounding pharmacies were evaluated. Methods:: Polyacrylamide gel electrophoresis (PAGE), size-exclusion chromatography (SEC), dynamic light scattering (DLS), and turbidimetry were selected to detect the formation of aggregates of various sizes. Changes in bevacizumab biological efficacy were investigated by using an enzyme-linked immunosorbent assay (ELISA). Results:: Repacked and reference bevacizumab showed similar results when analyzed by PAGE. By SEC, a slight increase in high molecular weight aggregates and a reduction in bevacizumab monomers were observed in the products of the three compounding pharmacies relative to those in the reference bevacizumab. A comparison of repacked and reference SEC chromatograms showed that the mean monomer loss was <=1% for all compounding pharmacies. Protein aggregates in the nanometer- and micrometer-size ranges were not detected by DLS and turbidimetry. In the efficacy assay, the biological function of repacked bevacizumab was preserved, with <3% loss of VEGF binding capacity relative to that of the reference. Conclusion:: The results showed that bevacizumab remained stable after compounding in ampoules and single-use glass vials; no significant aggregation, fragmentation, or loss of biological activity was observed. PMID- 28591286 TI - Structure-functional correlation using adaptive optics, OCT, and microperimetry in a case of occult macular dystrophy. AB - We report retinal functional and structural changes of a 40-year-old man diagnosed with occult macular dystrophy. Comprehensive ophthalmological evaluation was performed, followed by spectral-domain optical coherence tomography (SD-OC - Heidelberg) and image acquisition using an adaptive optics (AO) camera (RTX1, Imagine Eyes) for photoreceptor density analysis. Functional tests included full-field ERG (ERG) and multifocal electroretinography (mfERG) (Diagnosys, LLC) and microperimetry with scanning laser ophthalmoscope (SLO) fixation controlled (MAIA, CenterVUE). OCT revealed a line of discontinuity corresponding to cone outer-segment photoreceptors associated with a loss of cone density, highlighted by a dark blue spot on the AO co ne-density map on the fovea in both eyes. Loss of central sensitivity was revealed using microperimetry; ERG was within the normal range, although the mfERG showed a reduced central response amplitude. PMID- 28591287 TI - Large colloid drusen analyzed with structural en face optical coherence tomography. AB - Drusen are extracellular deposits between the basal lamina of the retinal pigment epithelium (RPE) and the inner collagenous layer of Bruch's membrane. Large colloid drusen (LCD) are located below the RPE and are characterized by multiple, large, dome-shaped RPE detachments, with marked attenuation of the ellipsoid zone overlaying the drusen. This report presents the structural en face optical coherence tomography (OCT) findings of LCD and relates them to findings from fluorescein and indocyanine green angiography. We describe the case of a 55-year old woman who presented with the chief complaint of a 5-year history of progressively worsening vision. Her best-corrected visual acuities were 20/40 and 20/400 in the right eye and the left eye, respectively. Fundus examination showed large bilateral, symmetrical, sub-retinal, yellowish lesions compatible with LCD. We describe the structural en face OCT characteristics and angiographic findings from this patient. PMID- 28591288 TI - Ocular sarcoidosis masked by positive IgM for toxoplasmosis. AB - We report a case of ocular sarcoidosis with positive immunoglobulin (Ig) M and IgG serology for toxoplasmosis. The patient was a young female with red painful eyes, bilateral eyelid edema, and panuveitis with periphlebitis. In laboratory testing, she was IgM and IgG positive for toxoplasmosis and anergic in the tuberculin test. Topical treatment for anterior uveitis and oral antibiotics for toxoplasmosis were started, without improvement. Orbit tomography showed increased lacrimal glands bilaterally, and chest X-ray radiographic findings were consistent with pulmonary sarcoidosis, which supported the presumed ocular sarcoidosis diagnosis. The patient was treated with oral prednisone and methotrexate without antibiotics. She showed clinical and vision improvement without recurrences during the 1-year follow-up. Ocular sarcoidosis is an important differential diagnosis requiring careful anamnesis and ophthalmological examinations. Ancillary tests, such as X-ray radiography, tomography, and clinical and laboratory evaluations may help rule out other causes. Treatment mainly consists of corticosteroids and immunosuppression. PMID- 28591289 TI - Oncocytoma of the lacrimal gland: a case report. AB - Here we describe a rare case of a benign tumor in the lacrimal gland of a healthy 4-year-old girl. Mild proptosis was the only abnormality observed on clinical examination. Magnetic resonance imaging of the right orbit revealed an oval, solid, well-circumscribed, homogeneous mass extending from the lacrimal gland and measuring 2.5 * 2.3 * 1.7 cm without any evidence of invasion into adjacent bones. The lesion was surgically excised and histological analyses defined the diagnosis of oncocytoma of the lacrimal gland. Although rare, oncocytoma should be included in the differential diagnosis of lacrimal gland tumors. PMID- 28591291 TI - Macular atrophy and Zika virus infectionResponse: macular atrophy and Zika virus infection. PMID- 28591292 TI - Optical coherence tomography in congenital Zika syndrome. PMID- 28591290 TI - Adjuvant treatment or primary topical monotherapy for ocular surface squamous neoplasia: a systematic review. AB - In this systematic review, we evaluated studies involving adjuvant and primary topical treatment for ocular surface squamous neoplasia (OSSN). The findings were: (i) adjuvant 5-fluorouracil (5-FU) reduces the risk of relapse after surgical excision with mild side effects [level Ib, grade of recommendation (GR) A]. (ii) Primary topical mitomycin (MMC) produces a high rate of complete response, low recurrence rate, and mild side effects (level Ib, GR A). (iii) Primary chemotherapy versus adjuvant chemotherapy produce similar rates of recurrence, with no significant difference (level IIb, GR B). (iv) Adjuvant 5-FU versus MMC showed no significant differences, with mild side effects in both groups and a better toxicity profile for MMC (level III, GR C). (v) Primary topical 5-FU versus MMC versus interferon (IFN) showed similar rates of tumor recurrence, mild side effects for all drugs, and more severe side effects in the 5-FU arm, followed successively by MMC and IFN (level III, GR C). PMID- 28591293 TI - Evaluation metrics in science: current status and prospects. PMID- 28591294 TI - Impact of critical care environment on burnout, perceived quality of care and safety attitude of the nursing team. AB - Objective:: assess the perception of the nursing team about the environment of practice in critical care services and its relation with the safety attitude, perceived quality of care and burnout level. Method:: cross-sectional study involving 114 nursing professionals from the intensive care unit of a teaching hospital. The following instruments were used: Nursing Work Index-Revised, Maslach Burnout Inventory and the Safety Attitude Questionnaire. Results:: the professionals who perceived greater autonomy, good relationships with the medical team and better control over the work environment presented lower levels of burnout, assessed the quality of care as good and reported a positive perception on the safety attitude for the domain job satisfaction. Conclusion:: the findings evidenced that environments favorable to these professionals' practice result in lower levels of burnout, a better perceived quality of care and attitudes favorable to patient safety. Objetivo:: avaliar a percepcao da equipe de enfermagem sobre o ambiente da pratica em unidades de cuidados criticos e sua relacao com atitude de seguranca, percepcao da qualidade do cuidado e nivel de burnout. Metodo:: estudo transversal com a participacao de 114 profissionais de enfermagem da unidade de terapia intensiva de um hospital de ensino. Foram utilizados os instrumentos: Nursing Work Index-Revised, Inventario de Burnout de Maslach e o Questionario de Atitudes de Seguranca. Resultados:: os profissionais que perceberam maior autonomia, boas relacoes com a equipe medica e melhor controle sobre o ambiente de trabalho, apresentaram menores niveis de burnout, avaliaram como boa a qualidade do cuidado e relataram uma percepcao positiva da atitude de seguranca para o dominio satisfacao no trabalho. Conclusao:: os achados evidenciaram que ambientes favoraveis a pratica desses profissionais resultam em menores niveis de burnout, melhor percepcao da qualidade do cuidado e atitudes favoraveis a seguranca do paciente. Objetivo:: evaluar la percepcion del equipo de enfermeria sobre el ambiente de la practica en unidades de cuidados criticos y su relacion con actitud de seguridad, percepcion de la calidad del cuidado y nivel de burnout. Metodo:: estudio trasversal con la participacion de 114 profesionales de enfermeria de la unidad de terapia intensiva de un hospital de ensenanza. Fueron utilizados los instrumentos: Nursing Work Index-Revised, Inventario de Burnout de Maslach y el Cuestionario de Actitudes de Seguridad. Resultados:: los profesionales que percibieron mayor autonomia, buenas relaciones con el equipo medico y mejor control sobre el ambiente de trabajo presentaron menores niveles de burnout, evaluaron como buena la calidad del cuidado y relataron percepcion positiva de la actitud de seguridad para el dominio satisfaccion en el trabajo. Conclusion:: los hallazgos evidenciaron que ambientes favorables a la practica de esos profesionales resultan en menores niveles de burnout, mejor percepcion de la calidad del cuidado y actitudes favorables a la seguridad del paciente. PMID- 28591295 TI - Associations between frailty syndrome and sociodemographic characteristics in long-lived individuals of a community. AB - Objective: investigating the association between frailty syndrome and sociodemographic characteristics in long-lived individuals of a community. Method: a cross-sectional study with a proportional stratified sample consisting of 243 long-lived individuals. A structured instrument, scales and tests that comprise evaluating frailty were applied for data collection. Univariate and multivariate analyzes were performed by logistic regression (p<0.05) by Statistica 10(r) software and Odds Ratio (95% Confidence Interval) were calculated for the predictive models. Results: of the 243 long-lived individuals evaluated, 36 (14.8%) were frail, 55 (63.8%) were pre-frail and 52 (21.4%) were not frail. A predominance of females (n=161; 66.3%), widows/widowers (n=158; 65%), who lived with family members (n=144; 59.3%) and in a self-reported satisfactory financial situation (n=108; 44.5%) was observed. A significant association was found between the demographic variable of age (p=0.043) and frailty syndrome. The best predictor model for the syndrome included the variables: gender, age and household companion. Conclusion: the variable of age contributed most to the fragilization process of long-lived individuals residing in the community. It is essential that gerontological nursing care contemplates early detection of this syndrome, considering age as being indicative of care needs. PMID- 28591296 TI - Spatial distribution of tuberculosis in a municipality in the interior of Sao Paulo, 2008-2013. AB - Objective:: to describe the epidemiological clinical profile of tuberculosis and analyze the spatial distribution of cases in a municipality in the state of Sao Paulo. Method:: descriptive and ecological study of cases of tuberculosis through the records in an information system. Descriptive statistics were used to calculate central tendency (mean) and chi-square test, with Yates correction or Fisher exact test, when necessary. The Kernel technique was also used to calculate the occurrence densities of tuberculosis cases, using a radius of 1000 meters. Type I error was set at 5%. Results:: 299 cases of tuberculosis were identified, with 290 (96.98%) being geocoded. The majority of these were male (n = 212; 70.91%), median age 40 years, and the pulmonary clinical form was predominant (n = 244, 81.60%). The distribution occurred in a non-random manner, observing important areas of the municipality with a higher density of cases of the disease. Conclusion:: the study evidenced an epidemiological profile of tuberculosis cases similar to those in the literature; however, their distribution does not occur in a random manner, pointing to specific population groups that require greater management and planning of health services for the control of tuberculosis. Objetivo:: caracterizar o perfil clinico epidemiologico da tuberculose (TB) e analisar a distribuicao espacial dos casos em municipio paulista. Metodo:: estudo descritivo e ecologico dos casos de tuberculose registrados em um sistema de informacao. Recorreu-se a estatistica descritiva com calculo de medidas de tendencia central (media) e aplicacao do teste qui quadrado, com correcao de Yates ou teste exato de Fisher, quando necessarios. Aplicou-se ainda a tecnica de Kernel para o calculo das densidades de ocorrencia dos casos da TB, utilizando um raio de 1000 metros. Fixou-se o erro tipo I em 5%. Resultados:: identificou-se 299 casos de TB, sendo geocodificados 290 (96,98%). A maioria destes foi do sexo masculino (n=212; 70,91%), idade mediana 40 anos, sendo a forma clinica pulmonar predominante (n=244; 81,60%). A distribuicao ocorreu de forma nao aleatoria, observando-se areas importantes do municipio com maior densidade de casos da doenca. Conclusao:: o estudo evidenciou perfil epidemiologico dos casos de tuberculose semelhante ao da literatura, no entanto, a distribuicao dos mesmos nao ocorre de forma aleatoria, apontando grupos especificos da populacao que necessitam de maior gestao e planejamento dos servicos de saude para o controle da tuberculose. Objetivo:: caracterizar el perfil epidemiologico clinico de tuberculosis y analizar la distribucion espacial de casos en un municipio paulista. Metodos:: Estudio descriptivo y ecologico de casos de tuberculosis registrados en un sistema de informacion. Se utilizo estadistica descriptiva con medidas de tendencia central (media) y aplicacion de chi-cuadrado, con correlacion de Yates o prueba exacta de Fisher segun necesidad. Para el calcular la densidad en la ocurrencia de casos de tuberculosis, se aplico la tecnica uniforme Kernel utilizando una distancia de 1000 metros. El error de tipo I fue fijado en 5%. Resultados:: Se identificaron 299 casos de tuberculosis, siendo geocodificados 290 (96.98%). La mayoria de los casos fueron de sexo masculino (n=212; 70,91%), con edad mediana de 40 anos, siendo la forma pulmonar la mas predominante (n=244; 81,60%). La distribucion de casos fue forma no aleatoria, identificando areas del municipio con mayor densidad de casos con esta patologia. Conclusion:: el perfil epidemiologico de casos de tuberculosis observado fue similar a lo observado en la literatura, aunque la distribucion de estos no ocurre de manera aleatoria, identificando grupos especificos de la poblacion los cuales requieren de mayores gestion y planificacion en los servicios de salud para el control de la tuberculosis. PMID- 28591297 TI - Organization of professional practices against intrafamily violence against children and adolescents in the institutional context. AB - Objective: to analyze based on the practitioners' discourse, the way they organize their practices confronting situations of intra-family violence against children and adolescents. Method: qualitative research carried out with 15 professionals who work in social and health services located in the southernmost of Brazil. Data were collected through semi-structured interviews, performed at the participants' workplace. We used a theoretical matrix to analyze the data, based on Institutional Ethnography and the technique of discursive textual analysis. Results: the practitioners' practices developed in situations of intra family violence against children and adolescents are organized on the basis of: power relations that take place in services that respond to violence situations; routines instituted to meet the demands of care in services; and the interplay between the conception of violence as a public health problem and the conception of violence as a social problem. Conclusion: the way these practices are organized is reflected in actions that are not protective against situations of intra-family violence against children and adolescents. PMID- 28591298 TI - Construction and validation of the Self-care Assessment Instrument for patients with type 2 diabetes mellitus. AB - Objective: to construct and validate the contents of the Self-care Assessment instrument for patients with type 2 diabetes mellitus. Method: methodological study, based on Orem's General Theory of Nursing. The empirical categories and the items of the instrument were elucidated through a focus group. The content validation process was performed by seven specialists and the semantic analysis by 14 patients. The Content Validity Indices of the items, >=0.78, and of the scale, >=0.90, were considered excellent. Results: the instrument contains 131 items in six dimensions corresponding to the health deviation self-care requisites. Regarding the maintenance, a Content Validity Index of 0.98 was obtained for the full set of items, and, regarding the relevance, Content Validity Indices >=0.80 were obtained for the majority of the assessed psychometric criteria. Conclusion: the instrument showed evidence of content validity. PMID- 28591299 TI - Anxiety and coping in women with breast cancer in chemotherapy. AB - Objective: to identify the coping strategies used by women with breast cancer in chemotherapy and to verify the association with the anxiety profile presented by them. Method: cross-sectional study of the analytical type. We used a random sample of 307 women with cancer in previous chemotherapy, adjuvant or palliative treatment. The data was collected using an interview technique with form registration, active search in medical records, Scale of Mode of Confronting Problems and Inventory of Anxiety and State. The Statistical Package for Social Sciences 19.0, Pearson correlation coefficient and the test Mann-Whitney were used. Results: there was a significant association of the anxiety trait and problem-focused coping strategies with a focus on emotion (p<0,000) and the anxiety state with problem-focused coping (p=0,001) and with focus on emotion (p=0,004). The results demonstrate weak associations between different coping strategies. Conclusion: the coping strategy chosen by women with breast cancer is directly related to anxiety. Patients with low-level anxiety tend to use problem solving strategies while emotion-focused coping is applied if the level is medium to high. PMID- 28591300 TI - Risk factors for unstable blood glucose level: integrative review of the risk factors related to the nursing diagnosis. AB - Objective: to identify evidence in the literature on the possible risk factors for the risk of unstable blood glucose diagnosis in individuals with type 2 diabetes mellitus, and to compare them with the risk factors described by NANDA International. Method: an integrative literature review guided by the question: what are the risk factors for unstable blood glucose level in people with type 2 diabetes mellitus? Primary studies were included whose outcomes were variations in glycemic levels, published in English, Portuguese or Spanish, in PubMed or CINAHL between 2010 and 2015. Results: altered levels of glycated hemoglobin, body mass index>31 kg/m2, previous history of hypoglycemia, cognitive deficit/dementia, autonomic cardiovascular neuropathy, comorbidities and weight loss corresponded to risk factors described in NANDA International. Other risk factors identified were: advanced age, black skin color, longer length of diabetes diagnosis, daytime sleepiness, macroalbuminuria, genetic polymorphisms, insulin therapy, use of oral antidiabetics, and use of metoclopramide, inadequate physical activity and low fasting glycemia. Conclusions: risk factors for the diagnosis, risk for unstable blood glucose level, for persons with type 2 diabetes mellitus were identified, and 42% of them corresponded to those of NANDA International. These findings may contribute to the practice of clinical nurses in preventing the deleterious effects of glycemic variation. PMID- 28591301 TI - A Grounded theory study of the intention of nurses to leave the profession. AB - Objective: this study explores the process of the development of an intention to leave bedside nursing. Method: the process was studied from the perspective of 21 nurses using the grounded theory method. Data were collected using semi structured interviews and the constant comparative method of Corbin and Strauss was used for data analysis. Results: according to the participants, the two main categories, "social image of nursing", and "culture and structure of the bedside", were the contextual factors that influence why nurses are leaving bedside care provision. Disappointment with a perceived lack of progress or improvement in the clinical experience formed primary psychosocial concerns for the participants. Competence and a process of self-control were steps taken by the participants. These, associated with interventional conditions produced the outcomes of the loss of professional commitment and desire to leave bedside nursing. "Failure to integrate personal expectations with organizational expectations: in search of escape" was the central category of the study that linked the categories together. Conclusion: the findings of this study provide useful information about the needs of nurses for overcoming the intention to leave bedside care. The identification of this process can help in recognizing emerging problems and providing solutions for them. PMID- 28591302 TI - Translation and adaptation of the Competencias Esenciales en Salud Publica para los recursos humanos en salud. AB - Objective:: to perform the translation and cultural adaptation of the document named Marco Regional de Competencias Esenciales en Salud Publica para los Recursos Humanos en Salud de la Region de las Americas (Regional Framework of Core Competencies in Public Health for Health Human Resources in the Region of Americas) from Spanish to Brazilian Portuguese. Method:: a methodological study comprising the following phases: authorization for translation; initial translation; synthesis of translations and consensus; back-translation and formation of an expert committee. Result:: in the translation of domain names, there was no difference in 66.7% (N = 4); in the translation of domain description and competencies there were divergences in 100% of them (N = 6, N = 56). A consensus of more than 80% was obtained in the translation and improvement in the expert committee by the change of words and expressions for approximation of meanings to the Brazilian context. Conclusion:: the translated and adapted document has the potential of application in research, and use in the practice of collective/public health care in Brazil. Objetivo:: realizar a traducao e adaptacao cultural do Marco Regional de Competencias Esenciales en Salud Publica para los Recursos Humanos en Salud de la Region de las Americas, do espanhol para a lingua portuguesa do Brasil. Metodo:: pesquisa metodologica, que seguiu as fases: autorizacao para traducao; traducao inicial; sintese das traducoes e consenso; retrotraducao e composicao de um comite de especialistas. Resultado:: na traducao dos nomes dos dominios, nao houve diferenca em 66,7 % (N=4); na traducao da descricao dos dominios e das competencias ocorreram divergencias em 100 % destes (N=6, N=56), obteve-se consenso acima de 80% ainda na traducao, e aprimoramento no comite de especialistas pela alteracao de palavras e expressoes para aproximar os significados ao contexto brasileiro. Conclusao:: o documento traduzido e adaptado possui potencial de aplicacao em pesquisas e utilizacao na pratica da atencao a saude publica/coletiva no Brasil. Objetivo:: realizar la traduccion y adaptacion cultural del Marco Regional de Competencias Esenciales en Salud Publica para los Recursos Humanos en Salud de la Region de las Americas, del espanol para el idioma portugues de Brasil. Metodo:: investigacion metodologica, que siguio las fases: autorizacion para traduccion; traduccion inicial; sintesis de las traducciones y consenso; y, retrotraduccion y composicion de un comite de especialistas. Resultado:: en la traduccion de los nombres de los dominios, no hubo diferencia en 66,7 % (N=4); en la traduccion de la descripcion de los dominios y de las competencias ocurrieron divergencias en 100 % de estos (N=6, N=56), se obtuvo consenso arriba de 80%, durante la traduccion y perfeccionamiento, en el comite de especialistas, en la alteracion de palabras y expresiones para aproximar los significados al contexto brasileno. Conclusion:: el documento traducido y adaptado posee potencial de aplicacion en investigaciones y de utilizacion en la practica de la atencion a la salud publica/colectiva en Brasil. PMID- 28591303 TI - Translation and cross-cultural adaptation of the Clinical Competence Questionnaire for use in Brazil. AB - Objective: translating and transculturally adapting the Clinical Competence Questionnaire to Brazilian senior undergraduate Nursing students, as well as measuring psychometric properties of the questionnaire. Method: a methodological study carried out in six steps: translation of the Clinical Competence Questionnaire instrument, consensus of the translations, back-translation, analysis by an expert committee, pre-testing and then presentation of the cross cultural adaptation process to the developers. Psychometric properties were measured using Cronbach's alpha, intraclass correlation coefficient and content validity index. Results: the instrument was translated, transculturally adapted and its final version consisted of 48 items. Cronbach's alpha coefficient was 0.90, and the agreement index of the items was 99% for students and 98% for evaluators. Conclusion: the Clinical Competence Questionnaire was translated and adapted to Brazilian students, and the psychometric properties of the Portuguese version of the questionnaire presented satisfactory internal consistency regarding the studied sample. PMID- 28591304 TI - Association between poor clinical prognosis and sleep duration among breast cancer patients. AB - Objective:: to investigate the association between clinical progression and the quality and duration of sleep in women with breast cancer. Method:: longitudinal study, with 114 participants, conducted in a hospital in Brazil. The instruments used were: questionnaire for sociodemographic and clinical characterization, Pittsburgh Sleep Quality Index; Beck Depression Inventory and Herth Hope Scale. Data were analyzed through descriptive statistics and survival analyses (outcome: poor clinical progression), using the Kaplan-Meier curve, Log-rank test and Cox proportional model. Results:: a higher probability of poor clinical progression was verified in women with sleep durations of less than six hours or nine hours and over (p=.0173). Conclusion:: the results suggest the importance of further studies that seek to verify whether the quantitative management of sleep disorders would have an impact on the progression of breast cancer. Women should be encouraged to report sleep problems to nurses. Objetivo:: mensurar a associacao entre evolucao clinica e qualidade e duracao do sono em mulheres com cancer de mama. Metodo:: estudo longitudinal, com 114 participantes, realizado em um hospital do Brasil. Os instrumentos utilizados foram: questionario para caracterizacao sociodemografica e clinica, Indice de Qualidade do Sono de Pittsburgh; Inventario de Depressao de Beck e Escala de Esperanca de Herth. Os dados foram analisados via analises descritivas e de sobrevivencia (resultado: evolucao clinica desfavoravel), utilizando-se a curva de Kaplan-Meier, o teste log-rank e o modelo proporcional de Cox. Resultados:: verificou-se maior probabilidade de evolucao clinica desfavoravel em mulheres com duracao de sono inferior a seis ou mais de nove horas (p = 0,0173). Conclusao:: os resultados sugerem a importancia de mais estudos que buscam verificar se a gestao quantitativa dos disturbios do sono teria um impacto sobre a evolucao do cancer de mama. As mulheres devem ser encorajadas a relatar isso espontaneamente aos enfermeiros. Objetivo:: medir la asociacion entre progresion clinica y calidad y duracion del sueno en mujeres con cancer de mama. Metodo:: estudio longitudinal, con 114 participantes, realizado en un hospital de Brasil. Los instrumentos utilizados fueron: cuestionario para caracterizacion sociodemografica y clinica; indice de calidad del sueno de Pittsburgh; Inventario de Depresion de Beck; y Escala de esperanza de Herth. Los datos se analizaron a traves de analisis descriptivo y de supervivencia (resultado: evolucion clinica desfavorable), utilizando la curva de Kaplan-Meier, la prueba log-rank y el modelo proporcional de Cox. Resultados:: se comprobo una mayor probabilidad de progresion clinica desfavorable en mujeres con duracion de sueno inferior a seis horas o mas de nueve horas (p = 0,0173). Conclusion:: los resultados sugieren la importancia de realizar mas estudios que busquen verificar si la gestion cuantitativa de los trastornos del sueno tendria un impacto en la progresion del cancer de mama. Las mujeres deben ser alentadas a informar esto espontaneamente a las enfermeras. PMID- 28591305 TI - Association between domestic violence and women's quality of life. AB - Objective: to analyze the association between domestic violence against women and quality of life. Method: a cross-sectional population-based household survey conducted with women 18 years and older, using a stratified sample by neighborhoods. For analysis, prevalence of domestic violence and quality of life index was verified and logistic regression was used to determine associations, with a significance level of 5%. Results: 424 women who had a prevalence of domestic violence of 54.4% and a quality of life index of 61.59 participated in this study. It was verified, through logistic regression, that domestic violence is associated with women's quality of life (p=0,017). The observed variables that influence the occurrence of domestic violence were in the social relations domain (p=0,000), provision of medical treatment for women (p=0,019) and safety (p=0,006). Conclusion: the study confirmed the evidence of an association between domestic violence against women and quality of life, a situation that reaffirms the importance of constructing public policies focused on gender emancipation. PMID- 28591306 TI - Psychometric properties of the Exercise Benefits/Barriers Scale in Mexican elderly women. AB - Objective: analyze and assess the psychometric properties of the subscales in the Spanish version of the Exercise Benefits/Barriers Scale in an elderly population in the Northeast of Mexico. Method: methodological study. The sample consisted of 329 elderly associated with one of the five public centers for senior citizens in the metropolitan area of Northeast Mexico. The psychometric properties included the assessment of the Cronbach's alpha coefficient, the Kaiser Meyer Olkin coefficient, the inter-item correlation, exploratory and confirmatory factor analysis. Results: in the principal components analysis, two components were identified based on the 43 items in the scale. The item-total correlation coefficient of the exercise benefits subscale was good. Nevertheless, the coefficient for the exercise barriers subscale revealed inconsistencies. The reliability and validity were acceptable. The confirmatory factor analysis revealed that the elimination of items improved the goodness of fit of the baseline scale, without affecting its validity or reliability. Conclusion: the Exercise Benefits/Barriers subscale presented satisfactory psychometric properties for the Mexican context. A 15-item short version is presented with factorial structure, validity and reliability similar to the complete scale. PMID- 28591307 TI - Schistosomiasis and hepatopulmonary syndrome: the role of concomitant liver cirrhosis. AB - BACKGROUND: Hepatopulmonary syndrome (HPS) is defined as an oxygenation defect induced by intrapulmonary vasodilation in patients with liver disease or portal hypertension. It is investigated in patients with liver cirrhosis and less frequently in those with portal hypertension without liver cirrhosis, as may occur in hepatosplenic schistosomiasis (HSS). OBJECTIVES: To investigate the prevalence of HPS in patients with HSS, and to determine whether the occurrence of HPS is influenced by concomitant cirrhosis. METHODS: We evaluated patients with HSS with or without concomitant liver cirrhosis. All patients underwent laboratory testing, ultrasound, endoscopy, contrast echocardiography, and arterial blood gas analysis. FINDINGS: Of the 121 patients with HSS, 64 were also diagnosed with liver cirrhosis. HPS was diagnosed in 42 patients (35%) and was more frequent among patients with concomitant liver cirrhosis than in those without cirrhosis (42% vs. 26%), but the difference was not significant (p = 0.069). HPS was more common in those with spider naevi, Child-Pugh classes B or C and high model for end stage liver disease (MELD) scores (p < 0.05 each). MAIN CONCLUSIONS: The prevalence of HPS was 35% in this study. The occurrence of liver cirrhosis concomitantly with HSS may have influenced the frequency of patients presenting with HPS. PMID- 28591308 TI - Prevalence of tuberculosis respiratory symptoms and associated factors in the indigenous populations of Paraguay (2012). AB - BACKGROUND: The prevalence of respiratory symptoms and confirmed tuberculosis (TB) among indigenous groups in Paraguay is unknown. METHODS: This study assessed the prevalence of respiratory symptoms, confirmed pulmonary TB, and associated socio-economic factors among indigenous Paraguayan populations. Indigenous persons residing in selected communities were included in the study. A total of 24,352 participants were interviewed at home between October and December 2012. Respiratory symptomatic individuals were defined as those with respiratory symptoms of TB. A hierarchical Poisson regression analysis was performed with four levels: individual characteristics, living conditions and environmental characteristics, source of food, and type of nutrition. FINDINGS: In this study, 1,383 participants had respiratory symptoms (5.7%), but only 10 had culture confirmed TB (41/100,000 inhabitants). The small number of cases did not allow evaluation of the risk factors for TB. Age older than 37 years was associated with a two-fold increased risk of symptoms. Female sex; family history of TB; type of housing; home heating; a lack of hunting, fishing, or purchasing food; and a lack of vegetable consumption were also associated with the presence of symptoms. A lack of cereal consumption had a protective effect. Members of the Ayoreo or Manjui ethnic groups had a three-fold increased risk of symptoms. MAIN CONCLUSION: Individual characteristics, dietary habits, and belonging to specific ethnic groups were associated with respiratory symptoms. PMID- 28591309 TI - Detection and molecular characterisation of a diagnosis escape variant associated with occult hepatitis B virus in Brazil. AB - BACKGROUND: Many studies have identified mutations in the hepatitis B surface antigen (HBsAg) as important factors limiting the ability of commercial serological assays to detect this viral antigen. However, an association between mutations in the HBsAg gene and the occurrence of occult HBV infection (OBI) in patients has not been established. OBJECTIVES: To detect hepatitis B virus (HBV) DNA in patients with anti-HBc as a unique serological marker, a previously published, cost-effective TaqMan-based real-time polymerase chain reaction (PCR) test with minor groove binding probes was adapted for use in this study. The current study also aimed to investigate HBsAg mutations and genotypes of HBV in OBI at the Viral Hepatitis Ambulatory Clinic in Rio de Janeiro to determine any possible association. METHODS: Intra-assay and inter-assay reproducibility were determined, and the mean coefficient of variation values obtained were 2.07 and 3.5, respectively. Probit analysis indicated that the 95% detection level was 25 IU/mL. The prevalence of OBI was investigated in 35 serum samples with an 'anti HBc alone' profile from individuals who attended our clinic between 2011 and 2013. FINDINGS: HBV DNA was detected in only one sample, resulting in an OBI rate of 2.9%. Nucleotide sequencing of the pre-S/S region was performed to genotype and analyse mutations within the HBsAg gene of this HBV DNA. The HBV in the OBI case was classified as sub-genotype A1, and a sequence analysis of the small S gene revealed 12 mutations in the major hydrophilic region compared to the consensus A1 sequence. Most of these mutations occurred in amino acid residues that have been reported as clinically relevant because they have been implicated in vaccine escape and/or inability to detect HBsAg by commercial serological assays. MAIN CONCLUSIONS: Our study suggests the importance of specific HBsAg mutations, different from those in D, B, and C genotypes, in sub-genotype A1 HBV associated with OBI. PMID- 28591311 TI - Participation of the arcRACME protein in self-activation of the arc operon located in the arginine catabolism mobile element in pandemic clone USA300. AB - Staphylococcus aureus pandemic clone USA300 has, in addition to its constitutive arginine catabolism (arc) gene cluster, an arginine catabolism mobile element (ACME) carrying another such cluster, which gives this clone advantages in colonisation and infection. Gene arcR, which encodes an oxygen-sensitive transcriptional regulator, is inside ACME and downstream of the constitutive arc gene cluster, and this situation may have an impact on its activation. Different relative expression behaviours are proven here for arcRACME and the arcACME operon compared to the constitutive ones. We also show that the artificially expressed recombinant ArcRACME protein binds to the promoter region of the arcACME operon; this mechanism can be related to a positive feedback model, which may be responsible for increased anaerobic survival of the USA300 clone during infection-related processes. PMID- 28591310 TI - Human papillomavirus type distribution and HPV16 intratype diversity in southern Brazil in women with and without cervical lesions. AB - BACKGROUND: Increasing evidence suggests that human papillomavirus (HPV) intratype variants (specific lineages and sublineages) are associated with pathogenesis and progression from HPV infection to persistence and the development of cervical cancer. OBJECTIVES: This study aimed to verify the prevalence of HPV infection and distribution of HPV types and HPV16 variants in southern Brazil in women with normal cytology or intraepithelial lesions. METHODS: HPV typing was determined by L1 gene sequencing. To identify HPV16 variants, the LCR and E6 regions were sequenced, and characteristic single nucleotide variants were identified. FINDINGS: A total of 445 samples were studied, with 355 from cervical scrapes and 90 from cervical biopsies. HPV was detected in 24% and 91% of these samples, respectively. The most prevalent HPV types observed were 16 (cervical, 24%; biopsies, 57%) and 58 (cervical, 12%; biopsies, 12%). Seventy-five percent of the HPV16-positive samples were classified into lineages, with 88% defined as lineage A, 10% as lineage D, and 2% as lineage B. MAIN CONCLUSIONS: This study identified a high frequency of European and North American HPV16 lineages, consistent with the genetic background of the human population in southern Brazil. PMID- 28591312 TI - Identification of a type I nitroreductase gene in non-virulent Trypanosoma rangeli. AB - Trypanosomatid type I nitroreductases (NTRs), i.e., mitochondrial enzymes that metabolise nitroaromatic pro-drugs, are essential for parasite growth, infection, and survival. Here, a type I NTR of non-virulent protozoan Trypanosoma rangeli is described and compared to those of other trypanosomatids. The NTR gene was isolated from KP1(+) and KP1(-) strains, and its corresponding transcript and 5' untranslated region (5'UTR) were determined. Bioinformatics analyses and nitro drug activation assays were also performed. The results indicated that the type I NTR gene is present in both KP1(-) and KP1(+) strains, with 98% identity. However, the predicted subcellular localisation of the protein differed among the strains (predicted as mitochondrial in the KP1(+) strain). Comparisons of the domains and 3D structures of the NTRs with those of orthologs demonstrated that the nitroreductase domain of T. rangeli NTR is conserved across all the strains, including the residues involved in the interaction with the FMN cofactor and in the tertiary structure characteristics of this oxidoreductase protein family. mRNA processing and expression were also observed. In addition, T. rangeli was shown to be sensitive to benznidazole and nifurtimox in a concentration-dependent manner. In summary, T. rangeli appears to have a newly discovered functional type I NTR. PMID- 28591313 TI - Multiplexed reverse transcription real-time polymerase chain reaction for simultaneous detection of Mayaro, Oropouche, and Oropouche-like viruses. AB - We describe a sensitive method for simultaneous detection of Oropouche and Oropouche-like viruses carrying the Oropouche S segment, as well as the Mayaro virus, using a multiplexed one-step reverse transcription real-time polymerase chain reaction (RT-qPCR). A chimeric plasmid containing both Mayaro and Oropouche targets was designed and evaluated for the in vitro production of transcribed RNA, which could be easily used as a non-infectious external control. To track false-negative results due to PCR inhibition or equipment malfunction, the MS2 bacteriophage was also included in the multiplex assay as an internal positive control. The specificity of the multiplex assay was evaluated by Primer-Blast analysis against the entire GenBank database, and further against a panel of 17 RNA arboviruses. The results indicated an accurate and highly sensitive assay with amplification efficiency greater than 98% for both targets, and a limit of detection between two and 20 copies per reaction. We believe that the assay described here will provide a tool for Mayaro and Oropouche virus detection, especially in areas where differential diagnosis of Dengue, Zika and Chikungunya viruses should be performed. PMID- 28591314 TI - Complete plasmid sequence carrying type IV-like and type VII secretion systems from an atypical mycobacteria strain. AB - The genus Mycobacterium is highly diverse and ubiquitous in nature, comprehending fast- and slow-growing species with distinct impact in public health. The plasmid mediated horizontal gene transfer represents one of the major events in bacteria evolution. Here, we report the complete sequence of a 160,489 bp circular plasmid (pCBMA213_2) from an atypical and fast-growing environmental mycobacteria. This is a unique plasmid, in comparison with the characterised mycobacteria plasmids, harboring a type IV-like and ESX-P2 type VII secretion systems. pCBMA213_2 can be further explored for evolutionary and conjugation studies as well as a tool to manipulate DNA within this bacteria genus. PMID- 28591315 TI - Trichophoromyia auraensis is a putative vector AB - The sandfly Trichophoromyia auraensis has recently evolved as a proven vector of Leishmania (Viannia) endemic to state of Acre in the north of Brazil. This note is intended to propose a correction in the report of the first occurrence of natural infection of Leishmania (Viannia) in this species. We and the other scientific groups reinforced that Tr. auraensis is a possible vector involved in the transmission of American cutaneous leishmaniasis in Acre, Brazil. PMID- 28591316 TI - Molecular detection of mixed infections with multiple dengue virus serotypes in suspected dengue samples in Tamaulipas, Mexico. AB - This study aimed to detect dengue virus (DENV) serotypes in serum samples obtained in Matamoros Tamaulipas, Mexico, and to determine the concordance of conventional nested reverse transcriptase polymerase chain reaction (RT-PCR) and a serological test [enzyme-linked immunosorbent assay (ELISA NS1)]. Here, we detected mixed infections consisting of four serotypes of DENV. The most prevalent serotype was DENV-1, followed by DENV-4. This is the first report of DENV-4 in our region. Mixed infections were also detected in 21.5% of samples, and the predominant coinfection consisted of DENV-1 and DENV-2. Therefore, continuous epidemiological surveillance of DENV in this area is required to predict future forms of dengue heterologous infections and the effect of this on health care. PMID- 28591317 TI - Challenges of Translational Science. PMID- 28591319 TI - Self-Reported High-Cholesterol Prevalence in the Brazilian Population: Analysis of the 2013 National Health Survey. AB - Background:: Data on the prevalence of dyslipidemia in Brazil are scarce, with surveys available only for some towns. Objective:: To evaluate the prevalence of the self-reported medical diagnosis of high cholesterol in the Brazilian adult population by use of the 2013 National Health Survey data. Methods:: Descriptive study assessing the 2013 National Health Survey data, a household-based epidemiological survey with a nationally representative sample and self-reported information. The sample consisted of 60,202 individuals who reported a medical diagnosis of dyslipidemia. The point prevalence and 95% confidence interval (95%CI) for the medical diagnosis of high cholesterol/triglyceride by gender, age, race/ethnicity, geographic region and educational level were calculated. Adjusted odds ratio was calculated. Results:: Of the 60,202 participants, 14.3% (95%CI=13.7-14.8) never had their cholesterol or triglyceride levels tested, but a higher frequency of women, white individuals, elderly and those with higher educational level had their cholesterol levels tested within the last year. The prevalence of the medical diagnosis of high cholesterol was 12.5% (9.7% in men and 15.1% in women), and women had 60% higher probability of a diagnosis of high cholesterol than men. The frequency of the medical diagnosis of high cholesterol increased up to the age of 59 years, being higher in white individuals or those of Asian heritage, in those with higher educational level and in residents of the Southern and Southeastern regions. Conclusion:: The importance of dyslipidemia awareness in the present Brazilian epidemiological context must be emphasized to guide actions to control and prevent coronary heart disease, the leading cause of death in Brazil and worldwide. Fundamento:: A prevalencia de hipercolesterolemia no Brasil nao e conhecida para todo o pais, havendo somente inqueritos em algumas cidades. Objetivo: : Avaliar a prevalencia de diagnostico medico de colesterol alto autorreferido na populacao adulta brasileira, utilizando-se dos dados da Pesquisa Nacional de Saude (PNS) de 2013. Metodos: : Estudo descritivo que avaliou os dados da PNS de 2013, um inquerito epidemiologico de base domiciliar, representativo para o Brasil, com informacoes autorreferidas. A amostra compreendeu 60.202 individuos entrevistados com autorrelato de diagnostico medico de colesterol. Calculou-se a prevalencia de ponto e o intervalo de confianca de 95% (IC95%) para diagnostico medico de colesterol/triglicerideos alto(s) por sexo, idade, cor da pele, regiao geografica, escolaridade. Foram calculadas as razoes de chance ajustadas. Resultados: : Dos 60.202 participantes adultos, 14,3% (IC95%=13,7-14,8) nunca tiveram colesterol ou triglicerideos dosados, sendo que um maior numero de mulheres, idosos, individuos com instrucao superior completa e de raca branca relatou afericao ha menos de um ano. A prevalencia de diagnostico medico de colesterol alto foi de 12,5%, maior nas mulheres (15,1%) do que nos homens (9,7%). A frequencia de diagnostico medico de colesterol alto foi maior naqueles com idade ate 59 anos, em brancos ou aqueles de origem asiatica, em pessoas com maior escolaridade e entre os moradores das macrorregioes Sul e Sudeste do pais. Conclusao: : A importancia do conhecimento da dislipidemia no atual contexto epidemiologico brasileiro deve ser ressaltada para orientar as acoes de prevencao das doencas coronarianas, que representam a primeira causa de obito no Brasil e no mundo. PMID- 28591318 TI - Data Sharing: A New Editorial Initiative of the International Committee of Medical Journal Editors. Implications for the Editors' Network. AB - The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology. Resumo O Comite Internacional de Editores de Revistas Medicas (ICMJE) fornece recomendacoes para aprimorar o padrao editorial e a qualidade cientifica das revistas biomedicas. Tais recomendacoes variam desde requisitos tecnicos de uniformizacao ate assuntos editoriais mais complexos e elusivos, como os aspectos eticos do processo cientifico. Recentemente, foram propostos registro de ensaios clinicos, divulgacao de conflitos de interesse e novos criterios de autoria, enfatizando a importancia da responsabilidade e da responsabilizacao. No ultimo ano, lancou-se uma nova iniciativa editorial para fomentar o compartilhamento dos dados de ensaios clinicos. Esta revisao discute essa nova iniciativa visando a aumentar a conscientizacao de leitores, investigadores, autores e editores filiados a Rede de Editores da Sociedade Europeia de Cardiologia. PMID- 28591320 TI - Degree of Agreement between Cardiovascular Risk Stratification Tools. AB - Background:: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in Brazil, and primary prevention care may be guided by risk stratification tools. The Framingham (FRS) and QRISK-2 (QRS) risk scores estimate 10-year overall cardiovascular risk in asymptomatic individuals, but the instrument of choice may lead to different therapeutic strategies. Objective:: To evaluate the degree of agreement between FRS and QRS in 10-year overall cardiovascular risk stratification in disease-free individuals. Methods:: Cross sectional, observational, descriptive and analytical study in a convenience sample of 74 individuals attending the outpatient care service of a university hospital in Brazil between January 2014 and January 2015. After application of FRS and QRS, patients were classified in low/moderate risk (< 20%) or high risk (>= 20%). Results:: The proportion of individuals classified as at high risk was higher in FRS than in QRS (33.7% vs 21.6%). A synergic effect of male gender with systemic arterial hypertension was observed in both tools, and with for geriatric age group in QRS (p < 0.05) in high-risk stratum. The Kappa index was 0.519 (95%CI = 0.386-0.652; p < 0.001) between both instruments. Conclusion:: There was a moderate agreement between FRS and QRS in estimating 10-year overall cardiovascular risk. The risk scores used in this study can identify synergism between variables, and their behavior is influenced by the population in which it was derived. It is important to recognize the need for calibrating risk scores for the Brazilian population. Fundamento:: A doenca cardiovascular (DCV) e a principal causa de morbimortalidade no Brasil, e a prevencao primaria pode ser direcionada com ferramentas que estratificam o risco. Os escores de Framingham (ERF) e QRISK-2 (ERQ) estimam o risco cardiovascular (RCV) global em 10 anos em individuos assintomaticos, mas a escolha do instrumento pode implicar em terapeuticas distintas. Objetivo:: Observar o grau de concordancia entre o ERF e o ERQ, na estratificacao do risco cardiovascular global em 10 anos, nos individuos livres da doenca. Metodos:: Estudo transversal, observacional, descritivo e analitico, com uma amostra de conveniencia de 74 individuos, atendidos em um ambulatorio de ensino de um hospital universitario brasileiro, no sul do pais, de janeiro de 2014 a janeiro de 2015. O ERF e o ERQ foram aplicados nos pacientes, que foram classificados em baixo/moderado (< 20%) ou alto risco (>= 20%). Resultados:: A proporcao de individuos classificados no estrato de alto risco foi superior no ERF que no ERQ (33,7% vs 21,6%), sendo identificado efeito sinergico do genero masculino com hipertensao arterial sistemica nas duas ferramentas, e com faixa etaria geriatrica no ERQ (p < 0,05) nesse estrato de risco. O indice de concordancia Kappa entre os dois escores foi igual a 0,519 (IC95% = 0,386-0,652; p < 0,001). Conclusao:: Houve concordancia moderada entre o ERF e o ERQ, na estimativa de RCV global em 10 anos. Os escores utilizados podem identificar sinergismo entre as variaveis, e tem comportamento influenciado pela populacao na qual foram originados. E importante reconhecer a necessidade de escores calibrados para a populacao brasileira. PMID- 28591321 TI - Effects of a Single Bout of Resistance Exercise in Different Volumes on Endothelium Adaptations in Healthy Animals. AB - Background:: Resistance exercise (RE) has been recommended for patients with cardiovascular diseases. Recently, a few studies have demonstrated that the intensity of a single bout of RE has an effect on endothelial adaptations to exercise. However, there is no data about the effects of different volumes of RE on endothelium function. Objective:: The aim of the study was to evaluate the effects of different volumes of RE in a single bout on endothelium-dependent vasodilatation and nitric oxide (NO) synthesis in the mesenteric artery of healthy animals. Methods:: Male Wistar rats were divided into three groups: Control (Ct); low-volume RE (LV, 5 sets x 10 repetitions) and high-volume RE (HV, 15 sets x 10 repetitions). The established intensity was 70% of the maximal repetition test. After the exercise protocol, rings of mesenteric artery were used for assessment of vascular reactivity, and other mesenteric arteries were prepared for detection of measure NO production by DAF-FM fluorescence. Insulin responsiveness on NO synthesis was evaluated by stimulating the vascular rings with insulin (10 nM). Results:: The maximal relaxation response to insulin increased in the HV group only as compared with the Ct group. Moreover, the inhibition of nitric oxide synthesis (L-NAME) completely abolished the insulin induced vasorelaxation in exercised rats. NO production showed a volume-dependent increase in the endothelial and smooth muscle layer. In endothelial layer, only Ct and LV groups showed a significant increase in NO synthesis when compared to their respective group under basal condition. On the other hand, in smooth muscle layer, NO fluorescence increased in all groups when compared to their respective group under basal condition. Conclusions:: Our results suggest that a single bout of RE promotes vascular endothelium changes in a volume-dependent manner. The 15 sets x 10 repetitions exercise plan induced the greatest levels of NO synthesis. Fundamentos:: O exercicio resistido (ER) tem sido recomendado para pacientes com doencas cardiovasculares. Recentemente, alguns estudos demonstraram que a intensidade de uma sessao de ER exerce um efeito sobre a disfuncao endotelial. No entanto, nao ha dados sobre os efeitos de diferentes volumes de ER sobre a funcao endotelial. Objetivo:: O objetivo deste estudo foi avaliar os efeitos de diferentes volumes de ER, realizados em uma unica sessao, sobre a vasodilatacao dependente do endotelio e sintese de oxido nitrico (NO) em arteria mesenterica de animais saudaveis. Metodos:: Ratos Wistar machos foram divididos em tres grupos: Controle (Ct); baixo volume (BV, 5 series x 10 repeticoes) e alto volume de ER (AV, 15 series x 10 repeticoes). Foi estabelecida a intensidade de 70% do teste de repeticao maxima. Apos o protocolo de exercicio, aneis de arteria mesenterica foram utilizados na avaliacao da reatividade vascular, e outras arterias mesentericas foram preparadas para a deteccao da producao de NO por fluorescencia com para do DAF-FM. A resposta a insulina pela sintese de NO foi avaliada estimulando-se os aneis vasculares com insulina (10nM). Resultados:: A resposta maxima do relaxamento induzido por insulina foi aumentada somente no grupo AV em comparacao ao grupo Ct. Alem disso, a inibicao da sintese do NO (L-NAME), aboliu completamente o relaxamento vascular induzido por insulina em ratos exercitados. A producao de NO mostrou um aumento dependente do volume no endotelio e no musculo liso. No endotelio, apenas os grupos Ct e BV mostraram aumento significativo na sintese de NO quando comparado aos seus respectivos grupos sob condicao basal. No entanto, no musculo liso, a fluorescencia foi aumentada em todos os grupos quando comparados aos seus respectivos grupos sob a condicao basal. Conclusoes:: Nossos resultados sugerem que uma unica sessao de ER foi capaz de promover adaptacoes no endotelio vascular. Alem disso, nos observamos que este efeito e volume-dependente e o volume de 15 series x10 repeticoes induziu o maior aumento na sintese de NO. PMID- 28591323 TI - Prediction Models for Decision-Making on Chagas Disease. PMID- 28591322 TI - Myocardial Viability on Cardiac Magnetic Resonance. AB - The study of myocardial viability is of great importance in the orientation and management of patients requiring myocardial revascularization or angioplasty. The technique of delayed enhancement (DE) is accurate and has transformed the study of viability into an easy test, not only for the detection of fibrosis but also as a binary test detecting what is viable or not. On DE, fibrosis equal to or greater than 50% of the segmental area is considered as non-viable, whereas that below 50% is considered viable. During the same evaluation, cardiac magnetic resonance (CMR) may also use other techniques for functional and perfusion studies to obtain a global evaluation of ischemic heart disease. This study aims to highlight the current concepts and broadly emphasize the use of CMR as a method that over the last 20 years has become a reference in the detection of infarction and assessment of myocardial viability. Resumo O estudo de viabilidade miocardica e de grande importancia para a orientacao e manejo de pacientes que necessitam de cirurgia de revascularizacao miocardica ou angioplastia. A tecnica de realce tardio (RT) e precisa e transformou o estudo de viabilidade em um teste facil, nao so para a deteccao de fibrose, mas tambem como um modelo binario para a deteccao do que e ou nao e viavel. Uma fibrose identificada pelo RT e considerada como nao viavel quando igual ou maior do que 50% da area segmentar e como viavel quando menor que 50%. A ressonancia magnetica cardiaca (RMC) tambem pode lancar mao de outras tecnicas para estudo funcional e de perfusao para uma avaliacao global da doenca isquemica do coracao no mesmo exame. Este estudo tem como objetivo destacar os conceitos atuais e enfatizar amplamente o uso da RMC como um metodo que nos ultimos 20 anos se tornou referencia na deteccao de infarto e avaliacao de viabilidade miocardica. PMID- 28591325 TI - Myocardial Deformation by Echocardiogram after Transcatheter Aortic Valve Implantation. PMID- 28591324 TI - Case 2/2017 - 56-Year-Old Male with Refractory Heart Failure, Systemic Arterial Hypertension and Aortic Valve Stenosis That Led to Heart Transplantation. PMID- 28591326 TI - Three-Dimensional Printing Model-Guided Percutaneous Closure of Atrial Septal Defect. PMID- 28591327 TI - [Strategy to improve access to etiological treatment of Chagas disease at the first level of care in Argentina]. AB - Objective: Improve distribution of etiological treatment of Chagas disease by identifying barriers to the decentralization of treatment to the first level of care in Argentina. Methods: A qualitative, exploratory, and descriptive study was conducted using semi-structured interviews of key actors belonging to the National Chagas Program and members of health teams at the first level of care, for the purpose of identifying barriers to diagnosis and treatment of Chagas disease at different levels (administrative, health agents, and community) that could affect a decentralized distribution strategy. Additionally, pilot decentralization was instituted in 10 primary health care centers in an Argentine province. Results: Semi-structured interviews were conducted with 22 program heads and health professionals. Principal obstacles found were lack of systematic case-finding, poor coordination among levels of care and health system actors, lack of health team training on treatment, patient monitoring, and patient related barriers. A pilot decentralization program was carried out and strategies were evaluated to optimize large-scale intervention. Conclusions: The results made it possible to improve implementation of the plan to decentralize treatment through better inter-program coordination, capitalization on existing monitoring and communication tools, and sensitization of health teams. Furthermore, recommendations were developed to improve diagnosis and treatment of Chagas disease. PMID- 28591328 TI - [Health-worker barriers to syphilis screening in pregnant women in Bolivia's Los Andes network]. AB - Objective: Identify health-worker barriers that keep pregnant women who receive prenatal care from being screened for syphilis (Los Andes Health Network, Bolivia). Methods: Semi-structured interviews were done with 46 health care providers and 249 clinical health records of pregnant women were analyzed in eight public health facilities in the Los Andes network. Results: Health-worker barriers to syphilis screening in pregnant women included lack of time by personnel to raise awareness of the benefit of syphilis screening; some mentioned that syphilis tests should only be done in facilities that attend deliveries and have a laboratory; lack of communication between clinicians and laboratory personnel; and problems with provision of supplies and reagents. The clinical record review found that only 55.4% contained syphilis laboratory results and only 37.4% of perinatal clinical histories had records of laboratory results. The interviews found that providers believe that syphilis screening is done in 100% of pregnant women receiving prenatal care. Conclusion: Syphilis screening is not being done according to Bolivia's strategy for the elimination of congenital syphilis, and is not done on more than half of pregnant women in prenatal care with perinatal clinical history records. This is not perceived by health professionals and can become a barrier to syphilis screening in pregnant women. PMID- 28591329 TI - [Evaluation of the teleconsultation process from the perspective of the provider (Oaxaca Telehealth Program, Mexico)]. AB - Objective: Identify barriers to implementation of the teleconsultation process in order to develop strategies to improve the program's operation. Methods: A process evaluation strategy was used to study the implementation of the teleconsultation service. The program's operating manuals were compared with the qualitative and quantitative information compiled on the practical implementation of the teleconsultation process. Results: The factors reported as obstacles to the teleconsultation process were: slow Internet connection, the hours available to the public, the specialized services offered, and insufficient clinical history included in teleconsultation requests. It was determined that 60% of internal medicine patients received two or more teleconsultations in the study period, as did 44% of patients of the gynecology service. Four consulting medical units accounted for 75% of the teleconsultations and the rest were distributed among 12 medical units. Conclusions: The barriers identified in the teleconsultation process mainly affect consulting physicians; even so, productivity is on an upward trend. Despite the existing barriers, it was determined that some patients receive follow-up through the program, which favors access to care. It is necessary to standardize implementation and to conduct subsequent research on patients' health condition. PMID- 28591331 TI - [CYTED-RITMOS network: toward the search for solutions to promote mobile health in Latin America]. AB - The area of mobile technologies applied to health (mHealth) is a growing worldwide trend that has generated enormous expectations for the mitigation of problems related to medical services delivery and public health stemming from a lack of resources and the limited number of specialists. The numerous opportunities offered by mobile technologies, together with their ease of use, have attracted the interest both of governments and universities. This is the case of the Ibero-American Mobile Technologies and Health Network (CYTED-RITMOS, Spanish acronym). As a result of the network's first year of activity, in October 2015 the RITMOS International Workshop was held in Barcelona to present the priority areas in Latin America where research, development, and innovation (R&D+i) projects on mobile health could be carried out and possible solutions found. The objective of this article is to present the potentialities and applicability of mHealth in the Region of the Americas. PMID- 28591330 TI - [Access barriers to comprehensive care for people affected by tuberculosis and human immunodeficiency virus coinfection in Peru, 2010-2015]. AB - Objective: Identify the programmatic barriers that hinder access to comprehensive care of patients with tuberculosis and human immunodeficiency virus (TB/HIV) coinfection. Methods: This is a mixed-method study. Qualitative research was conducted via in-depth interviews with key actors and the quantitative component involved cross-sectional descriptive analysis of programmatic data from 2010-2015 on tuberculosis and HIV programs at health facilities in the cities of Lima and Iquitos. Results: Twenty-two key actors in seven establishments were interviewed. The identified barriers were: little or no coordination between tuberculosis and HIV teams, separate management of tuberculosis and HIV cases at different levels of care, insufficient financing, limited or poorly trained human resources, and lack of an integrated information system. It was found that HIV screening in TB patients increased (from 18.8% in 2011 to 95.2% in 2015), isoniazid coverage of HIV patients declined (from 62% to 9%), and the proportion of deaths among TB/HIV coinfection cases averaged 20%. Conclusions: There is poor coordination between HIV and TB health strategies. Management of TB/HIV coinfection is fragmented into different levels of care, which has an impact on comprehensive patient care. As a result of this research, a technical document was prepared to establish joint procedures that should be implemented to improve comprehensive care of TB/HIV coinfection. PMID- 28591332 TI - Prevalence of bullying by gender and education in a city with high violence and migration in Mexico. AB - Objective: To understand the prevalence of bullying, by gender and educational level, in Ciudad Juarez, Mexico, a city with high rates of violence and migration. Methods: This was a cross-sectional, observational study conducted in 2012 - 2014 using a questionnaire known as the Bullying-Mexican. A probabilistic multistage cluster-sampling method obtained a study sample of 2 347 students (10 27 years of age) from the 400 000 enrolled in grade 5 - university level at the 611 public schools in Ciudad Juarez. Bullying prevalence and frequency (never, rarely, sometimes, often, every day) were analyzed with descriptive statistics. The statistical differences between males and females was assessed using a chi square test; associations between frequency and academic level were determined by correspondence analysis and the Spearman Rho correlation. A multinomial logistic regression was performed to analyze whether gender and academic level acted independently in the frequency of bullying. Results: Bullying prevalence was reported by 38% of females and 47% of males: 'only victim' represented 8.7%; 'only aggressor,' 13.2%; and 'victim and aggressor,' 21%. At higher levels of education, bullying prevalence declined; however, at the university, prevalence increased in the last semesters. Mockery and social exclusion were the two most dominant types of bullying, followed by beating, threats, and punishment. Conclusions: The prevalence of bullying in Ciudad Juarez public schools is among the highest compared to other random studies and surveys. Bullying diminishes with age and educational level. PMID- 28591333 TI - [Regionalization of perinatal health care in the province of Santa Fe, Argentina]. AB - Objective: Improve the performance of the regionalization policy in the province of Santa Fe, Argentina, as a strategy to improve perinatal health care by analyzing implementation processes and building consensus among decision makers and stakeholders around an action plan. Methods: Implementation research was conducted using mixed methodology. A needs assessment established tracer indicators to measure adherence to the components of the policy. Actors were studied to identify the barriers and facilitators of implementation. Training was provided on the development of consensus- and evidence-based policies, through workshops in which policy briefs were prepared and through a deliberative dialogue. Results: There were improvements in the number of births in appropriate hospitals and in the number of births in maternity hospitals with Essential Obstetric and Neonatal Care (CONE). Barriers were identified in the referral systems and in communication on policy, which resulted in an initial agreement on the need for guidelines and specific technical training on the transfer of babies and mothers. Conclusions: The participation of health workers in identifying barriers and strategies to overcome them, and the use of tools to report this to management, permit the adoption of consensus- and evidence-based strategies to improve policy implementation. PMID- 28591334 TI - [Evaluation of implementation of the protocol for managing tuberculosis/ human immunodeficiency virus coinfection in specialized care services in ceara state]. AB - Objectives: Identify barriers and strategies for implementation of the protocol for managing tuberculosis/ human immunodeficiency virus (TB/HIV) coinfection in specialized care services in Ceara state, through evaluation research. Methods: The study followed iPIER methodology, a new initiative to help improve the implementation of health programs through the use of research that is conducted as a part of the implementation process. Data were collected on the structure and processes of 22 services and barriers were explored in four focus groups with 28 participants, from the standpoint of the health team, administrators, and users. The discussions were transcribed and interpreted with regard to the objectives of the study. Results: The information on structure and process revealed that six services manage TB/HIV coinfection and 16 do not. The barriers were: team members were unaware of the protocol; lack of clinical practice guidelines in the services; specialized care services working at all three levels of the health system; inadequate spaces for treatment of airborne diseases; and lack of communication with primary health care sectors for patient transfers. The results were discussed with teams and administrators in seminars held in the services and with program managers for sexually transmitted infections, human immunodeficiency virus, AIDS, hepatitis, and tuberculosis. Conclusions: Direct dialogue between administrators, implementers, users, and researchers generated knowledge about the services and led to joint preparation of modifications in workflow aimed at acceptance and use of the protocol; however, users continue to resist adherence to treatment. PMID- 28591335 TI - [Evaluation of tools for the implementation of clinical practice guidelines on sexually transmitted infections]. AB - Objective: Determine the acceptability, perceived usefulness, and adoption of implementation tools and technical assistance provided by the Health Technology Assessment Institute (IETS) in hospitals in two regions of Colombia. Methods: Assistance was provided for implementation of clinical practice guidelines (CPGs) in 24 hospitals (17 in Antioquia and seven in Cundinamarca) in areas with high prevalence of sexually transmitted infections, and for use of the implementation tools. Health professionals were given surveys and medical specialists were interviewed. Results: Overall, 86% of respondents are familiar with the GPGs, 86% with the tracer recommendations, 79% with the interactive flow charts, and 82% with the evidence sheets, while 41% never used the implementation tools. Of the respondents who used the tools, 55% did so on their work computer, while 24% used their personal telephone. The most useful tools were the evidence sheets and flow charts (98%) and the tracer recommendations (92%). The least useful were the budgetary impact tools (81%). Conclusions: The implementation tools and technical assistance provided in hospitals in two regions of Colombia are perceived as useful and acceptable, although the degree of implementation is low. The findings of this research will help the different actors, such as the Ministry of Health and Social Protection, the IETS, and the Administrative Department of Science, Technology and Innovation (Colciencias), among others, improve their programs for the implementation of clinical practice guidelines. PMID- 28591336 TI - Prognostic factors affecting outcomes in multivisceral en bloc resection for colorectal cancer. AB - OBJECTIVES:: This study sought to determine the clinical and pathological factors associated with perioperative morbidity, mortality and oncological outcomes after multivisceral en bloc resection in patients with colorectal cancer. METHODS:: Between January 2009 and February 2014, 105 patients with primary colorectal cancer selected for multivisceral resection were identified from a prospective database. Clinical and pathological factors, perioperative morbidity and mortality and outcomes were obtained from medical records. Estimated local recurrence and overall survival were compared using the log-rank method, and Cox regression analysis was used to determine the independence of the studied parameters. ClinicalTrials.gov: NCT02859155. RESULTS:: The median age of the patients was 60 (range 23-86) years, 66.7% were female, 80% of tumors were located in the rectum, 11.4% had stage-IV disease, and 54.3% received neoadjuvant chemoradiotherapy. The organs most frequently resected were ovaries and annexes (37%). Additionally, 30.5% of patients received abdominoperineal resection. Invasion of other organs was confirmed histologically in 53.5% of patients, and R0 resection was obtained in 72% of patients. The overall morbidity rate of patients in this study was 37.1%. Ureter resection and intraoperative blood transfusion were independently associated with an increased number of complications. The 30-day postoperative mortality rate was 1.9%. After 27 (range 5-57) months of follow-up, the mortality and local recurrence rates were 23% and 15%, respectively. Positive margins were associated with a higher recurrence rate. Positive margins, lymph node involvement, stage III/IV disease, and stage IV disease alone were associated with lower overall survival rates. On multivariate analysis, the only factor associated with reduced survival was lymph node involvement. CONCLUSIONS:: Multivisceral en bloc resection for primary colorectal cancer can be performed with acceptable rates of morbidity and mortality and may lead to favorable oncological outcomes. PMID- 28591338 TI - Muscle strength and body composition in severe obesity. AB - OBJECTIVE:: The aim of our study was to evaluate associations between maximum voluntary contraction torques of the lower limbs and body composition for subjects with severe obesity. METHODS:: Body composition was evaluated by bioelectrical impedance analysis, and maximum voluntary contraction torques of the lower limbs were measured using an isokinetic dynamometer. One hundred thirty two patients were enrolled (100 females and 32 males). Eighty-seven patients had a body mass index between 40 and 49.9 kg/m2 (the A group), and 45 patients had a body mass index between 50 and 59.9 kg/m2 (the B group). RESULTS:: Absolute extension and flexion torques had weak associations with fat-free mass but a moderate association with absolute extension torque and fat-free mass of the lower limbs. There were no significant differences between the A and B groups with respect to absolute extension and flexion torques. For the A group, absolute extension and flexion torques were moderately associated with fat-free mass and with fat-free mass of the lower limbs. For the B group, there were only moderate associations between absolute extension and flexion torques with fat-free mass of the lower limbs. CONCLUSIONS:: Our findings demonstrate that both groups exhibited similar absolute torque values. There were weak to moderate associations between absolute extension and flexion torques and fat-free mass but a moderate association with fat-free mass of the lower limbs. Individuals with severe obesity should strive for greater absolute torques, fat-free mass and especially fat-free mass of the lower limbs to prevent functional limitations and physical incapacity. PMID- 28591337 TI - Placental weight and birth weight to placental weight ratio in monochorionic and dichorionic growth-restricted and non-growth-restricted twins. AB - OBJECTIVE:: The aim of the present study was to compare the placental weight and birth weight/placental weight ratio for intrauterine growth-restricted and non intrauterine growth-restricted monochorionic and dichorionic twins. METHODS:: This was a retrospective analysis of placentas from twin pregnancies. Placental weight and the birth weight/placental weight ratio were compared in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins. The association between cord insertion type and placental lesions in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins was also investigated. RESULTS:: A total of 105 monochorionic (intrauterine growth restriction=40; non-intrauterine growth restriction=65) and 219 dichorionic (intrauterine growth restriction=57; non intrauterine growth restriction=162) placentas were analyzed. A significantly lower placental weight was observed in intrauterine growth-restricted monochorionic (p=0.022) and dichorionic (p<0.001) twins compared to non intrauterine growth-restricted twins. There was no difference in the birth weight/placental weight ratio between the intrauterine growth restriction and non intrauterine growth restriction groups for either monochorionic (p=0.36) or dichorionic (p=0.68) twins. Placental weight and the birth weight/placental weight ratio were not associated with cord insertion type or with placental lesions. CONCLUSION:: Low placental weight, and consequently reduced functional mass, appears to be involved in fetal growth restriction in monochorionic and dichorionic twins. The mechanism by which low placental weight influences the birth weight/placental weight ratio in intrauterine growth-restricted monochorionic and dichorionic twins needs to be determined in larger prospective studies. PMID- 28591339 TI - Oral motor and electromyographic characterization of adults with facial fractures: a comparison between different fracture severities. AB - OBJECTIVES:: To characterize the oral motor system of adults with facial injuries and to compare the oral motor performance/function between two different groups. METHODS:: An observational, descriptive, cross-sectional study was conducted in 38 patients presenting with facial trauma who were assigned to the Division of Orofacial Myology of a Brazilian School Hospital. Patients were divided into two groups: Group 1 (G1) consisted of 19 patients who were submitted to open reduction of at least one facial fracture, and Group 2 (G2) consisted of 19 individuals who were submitted to closed fracture reduction with maxillomandibular fixation. For comparison purposes, a group of 19 healthy volunteers was recruited. All participants underwent a clinical assessment that included an oral motor evaluation, assessment of the mandibular range of motions, and electromyographic assessment of the masticatory muscles. RESULTS:: Clinical assessment of the oral motor organs indicated that G1 and G2 presented deficits related to the posture, position, and mobility of the oral motor organs. Patients also presented limited mandibular ranges of movement. Deficits were greater for individuals in G1, especially for maximal incisor opening. Additionally, patients in G1 and G2 presented a similar electromyographic profile of the masticatory muscles (i.e., patients with facial fractures presented lower overall muscle activity and significant asymmetrical activity of the masseter muscle during maximum voluntary teeth clenching). CONCLUSION:: Patients in G1 and G2 presented similar functional deficits after fracture treatment. The severity of facial fractures did not influence muscle function/performance 4 months after the correction of fractures. PMID- 28591340 TI - Uterine artery Doppler flow velocimetry parameters for predicting gestational trophoblastic neoplasia after complete hydatidiform mole, a prospective cohort study. AB - OBJECTIVES:: Doppler ultrasonography can be used to assess neoangiogenesis, a characteristic feature of postmolar gestational trophoblastic neoplasia. However, there is limited information on whether uterine artery Doppler flow velocimetry parameters can predict gestational trophoblastic neoplasia following a complete hydatidiform mole. The purpose of this study was as follows: 1) to compare uterine blood flow before and after complete mole evacuation between women who developed postmolar gestational trophoblastic neoplasia and those who achieved spontaneous remission, 2) to assess the usefulness of uterine Doppler parameters as predictors of postmolar gestational trophoblastic neoplasia and to determine the best parameters and cutoff values for predicting postmolar gestational trophoblastic neoplasia. METHODS:: This prospective cohort study included 246 patients with a complete mole who were treated at three different trophoblastic diseases centers between 2013 and 2014. The pulsatility index, resistivity index, and systolic/diastolic ratio were measured by Doppler flow velocimetry before and 4-6 weeks after molar evacuation. Statistical analysis was performed using Wilcoxon's test, logistic regression, and ROC analysis. RESULTS:: No differences in pre- and post-evacuation Doppler measurements were observed in patients who developed postmolar gestational trophoblastic neoplasia. In those with spontaneous remission, the pulsatility index and systolic/diastolic ratio were increased after evacuation. The pre- and post-evacuation pulsatility indices were significantly lower in patients with gestational trophoblastic neoplasia (odds ratio of 13.9-30.5). A pre-evacuation pulsatility index <=1.38 (77% sensitivity and 82% specificity) and post-evacuation pulsatility index <=1.77 (79% sensitivity and 86% specificity) were significantly predictive of gestational trophoblastic neoplasia. CONCLUSIONS:: Uterine Doppler flow velocimetry measurements, particularly pre- and post-molar evacuation pulsatility indices, can be useful for predicting postmolar gestational trophoblastic neoplasia. PMID- 28591341 TI - The Effect of FRAX on the Prediction of Osteoporotic Fractures in Urban Middle aged and Elderly Healthy Chinese Adults. AB - OBJECTIVE:: We aimed to analyze the applicability of a fracture risk assessment tool for the prediction of osteoporotic fractures in middle-aged and elderly healthy Chinese adults. METHODS:: A standard questionnaire was administered, and bone mineral density was measured in residents visiting the Dongliu Street Community Health Service Center. Paired t-tests were used to compare the FRAX based probabilities of fractures estimated with and without consideration of bone mineral density. Risk stratification and partial correlation analyses were applied to analyze the associations between FRAX-based probabilities and body mass index or bone mineral density at different sites. RESULTS:: A total of 444 subjects were included in this study. Of these subjects, 175 (39.59%) were diagnosed as osteoporotic, and 208 (47.06%) were diagnosed as osteopenic. The Kappa value for the detection of osteoporosis at the L1-L4 lumbar spine and femoral neck was 0.314. The FRAX-based 10-year major osteoporotic fracture probability and hip osteoporotic fracture probability estimated without considering bone mineral density were 4.93% and 1.64%, respectively; when estimated while considering bone mineral density, these probabilities were 4.97% and 1.54%, respectively. A significant positive association was observed between the FRAX-based fracture probabilities estimated with and without consideration of bone mineral density, while significant negative associations between body mass index and the estimated FRAX-based fracture probabilities after adjustment for age and the estimated FRAX-based fracture probabilities and femoral neck bone mineral density were identified. These results remained the same after controlling for lumbar spine bone mineral density. CONCLUSIONS:: The Chinese FRAX model could predict osteoporotic fracture risk regardless of whether bone mineral density was considered and was especially appropriate for predicting osteoporotic fractures of the femoral neck. PMID- 28591342 TI - Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases. AB - OBJECTIVES:: In this study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma. METHODS:: We analyzed forty patients with medulloblastoma who underwent surgical resection at our center between January 2004 and June 2014. Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed by Kaplan-Meier survival curves. RESULTS:: Factors associated with overall survival included M stage (p=0.014), calcification (p=0.012), postoperative treatment, postoperative Karnofsky Performance Scale (KPS) score (p=0.015), and molecular subtype (p=0.005 for WNT and p=0.008 for SHH). Number of symptoms (p=0.029), M stage (p<0.001), and postoperative radiotherapy (p=0.033) were associated with disease progression. Patients with the WNT or SHH subtype had better survival outcomes than patients with non-WNT/SHH subtypes. Risk factors for disease progression-free survival were symptoms >2 and >=M1 stage without postoperative radiotherapy. The risk of recurrence increased with advanced M stage. Protective factors for recurrence included M0 stage and a combination of chemotherapy and radiotherapy. CONCLUSION:: We identified the risk factors associated with survival, disease progression and recurrence of medulloblastoma patients. This information is helpful for understanding the prognostic factors related to medulloblastoma. PMID- 28591343 TI - Burnout syndrome in health-care professionals in a university hospital. AB - OBJECTIVE:: To evaluate professional achievement and factors associated with occupational burnout among health professionals. METHODS:: An institution-based cross-sectional study was conducted on 436 healthcare providers, consisting of 101 nurses, 81 doctors and 254 nursing technicians, all meeting pre-established inclusion criteria. Occupational burnout was detected using the Maslach occupational burnout inventory tool. Data were collected by self-administered questionnaires comprising questions concerning socio-demographics, education and training, and the Maslach occupational burnout inventory was used to identify levels of emotional exhaustion, depersonalization and professional achievement. RESULTS:: Emotional exhaustion was associated with education level and work place for nursing technicians. Depersonalization was associated with gender in nursing technicians. For nurses, depersonalization showed a significant association with education level, whereas this factor was associated with number of jobs for doctors. Lower levels of professional achievement were observed for unspecialized doctors compared to those with further training. Higher levels of professional achievement were associated with professionals with postgraduate training compared to those without. CONCLUSIONS:: High levels of emotional exhaustion were found in professionals from the maternity unit as well as in professionals with lower educational levels. Depersonalization was higher in physicians with several jobs and in female nurses. Low professional achievement was found in unspecialized doctors, while high professional achievement was associated with postgraduate training. PMID- 28591344 TI - Aerobic Swim Training Restores Aortic Endothelial Function by Decreasing Superoxide Levels in Spontaneously Hypertensive Rats. AB - OBJECTIVE:: We aimed to determine whether aerobic training decreases superoxide levels, increases nitric oxide levels, and improves endothelium-dependent vasodilation in the aortas of spontaneously hypertensive rats. METHODS:: Spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were distributed into 2 groups: sedentary (SHRsd and WKYsd, n=10 each) and swimming trained (SHRtr, n=10 and WKYtr, n=10, respectively). The trained group participated in training sessions 5 days/week for 1 h/day with an additional work load of 4% of the animal's body weight. After a 10-week sedentary or aerobic training period, the rats were euthanized. The thoracic aortas were removed to evaluate the vasodilator response to acetylcholine (10-10 to 10-4 M) with or without preincubation with L-NG-nitro-L-arginine methyl ester hydrochloride (L NAME; 10-4 M) in vitro. The aortic tissue was also used to assess the levels of the endothelial nitric oxide synthase and nicotinamide adenine dinucleotide oxidase subunit isoforms 1 and 4 proteins, as well as the superoxide and nitrite contents. Blood pressure was measured using a computerized tail-cuff system. RESULTS:: Aerobic training significantly increased the acetylcholine-induced maximum vasodilation observed in the SHRtr group compared with the SHRsd group (85.9+/-4.3 vs. 71.6+/-5.2%). Additionally, in the SHRtr group, superoxide levels were significantly decreased, nitric oxide bioavailability was improved, and the levels of the nicotinamide adenine dinucleotide oxidase subunit isoform 4 protein were decreased compared to the SHRsd group. Moreover, after training, the blood pressure of the SHRtr group decreased compared to the SHRsd group. Exercise training had no effect on the blood pressure of the WKYtr group. CONCLUSIONS:: In SHR, aerobic swim training decreased vascular superoxide generation by nicotinamide adenine dinucleotide oxidase subunit isoform 4 and increased nitric oxide bioavailability, thereby improving endothelial function. PMID- 28591346 TI - Prevalence of and factors associated with self-reported high blood pressure in Brazilian adults. AB - OBJECTIVE: To analyze factors associated with self-reported high blood pressure among adults in Brazilian state capitals. METHODS: The study uses data from Sistema de Vigilancia de Fatores de Risco e Protecao para Doencas Cronicas por Inquerito Telefonico (Vigitel - Surveillance System of Risk and Protection Factors of Noncommunicable Diseases by Telephone Survey) collected in 2013. Prevalence rates and their respective 95% confidence intervals by gender were estimated according to sociodemographic variables, lifestyle, reported noncommunicable diseases and self-rated health status. Multivariate logistic regression modeling was used to identify variables associated with self-reported high blood pressure with alpha < 0.05. RESULTS: Prevalence of self-reported high blood pressure among adults living in Brazilian state capitals and the Federal District was 24.1%. The following variables were associated with self-reported high blood pressure: age group, taking 18-24 as reference (all age groups presented increased risk - from 25-34 years [OR = 2.6; 95%CI 2.0-3.4] up to 65 years or more [OR = 28.1; 95%CI 21.7-36.4]); low education level (9 to 11 years of study [OR = 0.8; 95%CI 0.7-0.9] and 12 years or more [OR = 0.6; 95%CI 0.6 0.7]); Black race or skin color (OR = 1.3; 95%CI 1.1-1.5); being a former smoker (OR = 1.2; 95%CI 1.1-1.3); obesity (OR = 2.7; 95%CI 2.4-3.0); diabetes (OR = 2.9; 95%CI 2.5-3.5%), and high cholesterol (OR = 1.9; 95%CI 1.8-2.2). CONCLUSIONS: Approximately one quarter of the adult population living in Brazilian state capitals reported having high blood pressure. Information from Vigitel is useful to monitor high blood pressure and identity its associated factors, supporting public policies for health promotion, surveillance and care. PMID- 28591345 TI - Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients. AB - The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (>=180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status. PMID- 28591347 TI - Factors associated with self-reported diabetes according to the 2013 National Health Survey. AB - OBJECTIVES: To analyze the factors associated with self-reported diabetes among adult participants of the National Health Survey (PNS). METHODS: Cross-sectional study using data of the PNS carried out in 2013, from interviews with adults (>= 18 years) of 64,348 Brazilian households. The prevalence of self-reported diabetes, assessed by the question "Has a doctor ever told you that you have diabetes?," was related to sociodemographic characteristics, lifestyle, self reported chronic disease, and self-evaluation of the health condition. Prevalence ratios were adjusted according to age, sex, and schooling by Poisson regression with robust variance. RESULTS: The diagnosis of diabetes was reported by 6.2% of respondents. Its crude prevalence was higher in women (7.0% vs. 5.4%), and among older adults, reaching 19.8% in the elderly. Black adults who received less schooling showed higher prevalence. Among those classified as obese, 11.8% reported having diabetes. Ex-smokers, those insufficiently active and those who consume alcohol abusively reported diabetes more often. Differences were not verified in eating habits among adults who reported, or did not, diabetes. A relation between diabetes and hypertension was found. CONCLUSIONS: After adjustment according to age, schooling and sex, diabetes was shown to be associated with higher age, lower schooling, past smoking, overweight and obesity, and hypertension, as well as with a self-declared poor state of health, indicating a pattern of risk factors common to many chronic non-communicable diseases and the association of the disease with morbidity. PMID- 28591348 TI - Informal and paid care for Brazilian older adults (National Health Survey, 2013). AB - OBJECTIVE: To describe the prevalence and sociodemographic factors associated with informal and paid care for Brazilian older adults with functional limitations. METHODS: Of the 23,815 participants of the National Health Survey aged 60 or older, 5,978 reported needing help to perform activities of daily living and were included in this analysis. The dependent variable was the source of care, categorized as exclusively informal (unpaid), exclusively formal (paid), mixed or none. The socio-demographic variables were age (60-64, 65-74, >= 75 years old), gender and number of residents in the household (1, 2, >= 3). The multivariate analysis was based on binomial and multinomial logistic regressions. RESULTS: Informal care predominated (81.8%), followed by paid (5.8%) or mixed (6.8%) and no care (5.7%). The receipt of care from any source increased gradually with the number of residents in a same household, regardless of age and gender (OR = 4.85 and 9.74 for 2 and >= 3, respectively). Age was positively associated with receiving any care while the male gender showed a negative association. The number of residents in the household showed the strongest association with informal care (OR = 10.94 for >= 3 residents), compared with paid (OR = 5.48) and mixed (OR = 4.16) care. CONCLUSIONS: Informal care is the main source of help for community-dwelling older adults with functional limitations. In a context of rapid population aging and decline in family size, the results reinforce the need for policies to support long-term care for older Brazilians. PMID- 28591349 TI - Family influence on the consumption of sugary drinks by children under two years old. AB - OBJECTIVE: To evaluate the influence of family habits and household characteristics on the consumption of sugary drinks by Brazilian children under two years old. METHODS: This was a cross-sectional study that used secondary data generated by the National Health Survey (PNS) in 2013. We studied 4,839 pairs of children under two years old and adults living in the same house. We estimated the prevalence of the indicator of sugary drinks consumption for the total sample of children and according to family and household variables. We applied multiple logistic regression analysis to evaluate the influence of family habits and household characteristics on the consumption of sugary drinks by the children. RESULTS: The consumption of sugary drinks was identified in 32% of the studied children (95%CI 30.6-33.3) and was independently associated with the following family and household characteristics: regular consumption of sugary drinks by the adult living in the house (OR = 1.78; 95%CI 1.51-2.10), watching TV for more than three hours per day (OR = 1.22; 95%CI 1.03-1.45), older age (OR = 3.10; 95%CI 1.54-6.26), greater education level (OR = 0.70; 95%CI 0.53-0.91), house located in the Northeast region (OR = 0.65; 95%CI 1.54-6.26), and number of family members (OR = 1.05; 95%CI 1.00-1.09). CONCLUSIONS: Our findings indicate the high prevalence of sugary drinks consumption by Brazilian children under two years old and show that sociodemographic characteristics and family habits affect this feeding practice not recommended in childhood. PMID- 28591350 TI - Factors associated with chronic back pain in adults in Brazil. AB - OBJECTIVE: To identify associations of chronic back pain with sociodemographic characteristics, lifestyles, body mass index, self-reported chronic diseases and health assessment, according to sex. METHODS: We analyzed data from the 2013 National Health Survey, estimated the prevalence and their respective 95% confidence intervals (95%CI) of chronic back pain, according to selected variables and performed adjustment by age and education. RESULTS: 18.5% of the Brazilian population reported chronic back pain, 15.5% (95%CI 14.7-16.4) of them being men and 21.1% (95%CI 20.2-22.0) being women. The characteristics that remained associated and statistically significant (p < 0.05) after adjustment, in men, were: age group, higher in men with 65 years or older (ORa = 6.06); low education level; living in rural area; history of smoking, high salt intake, increase in the time of heavy physical activity at work and at home; being overweight (ORa = 1.18) or obese (ORa = 1.26); diagnostic of hypertension (ORa = 1.42), high cholesterol (ORa = 1.60); and worse health assessment in comparison with very good (good [ORa = 1.48]; regular [ORa = 3.22]; poor [ORa = 5.00], very poor [ORa = 8.60]). Among women, they were: increase with age, higher among women with 55-64 years (ORa = 3.64); low education level; history of smoking, regular candy consumption, high salt intake, heavy physical activity at work and at home and increase in the time of these activities; being overweight (ORa = 1.23) or obese (ORa = 1.32); diagnosis of hypertension (ORa = 1.50), high cholesterol (ORa = 1.84); and worse health assessment than very good (good [ORa = 1.43]; regular [ORa = 3.16]; poor [ORa = 5.44], very poor [ORa = 8.19]). CONCLUSIONS: Our findings point out differences by sex and contribute to the knowledge of the panorama of chronic back pain, which, besides affecting individuals, generate negative socioeconomic impacts, by causing work-related disabilities and hindering everyday activities. PMID- 28591351 TI - Use of and access to health services in Brazil, 2013 National Health Survey. AB - OBJECTIVE: To analyze the use of health services in the Brazilian population by sociodemographic factors, according to data from the 2013 Brazilian National Health Survey. METHODS: The study analyzed data from 205,000 Brazilian citizens in all age groups who participated in the Brazilian National Health Survey, a cross-sectional study carried out in 2013. Prevalence and confidence intervals were estimated for indicators related to access to and use of health services according to age group, level of education of head of household, and Brazilian macroregions. RESULTS: Among individuals who sought health services in the two weeks prior to the survey, 95.3% (95%CI 94.9-95.8) received care in their first visit. Percentages were higher in the following groups: 60 years of age and over; head of household with complete tertiary education; living in the South and Southeast regions. In addition, 82.5% (95%CI 81.2-83.7) of individuals who received health care and prescriptions were able to obtain all the necessary medicines, 1/3 of them from SUS. Less than half the Brazilian population (44.4%; 95%CI 43.8-45.1) visited a dentist in the 12 months prior to the survey, with smaller percentages among the following groups: 60 years of age or older; head of household with no education or up to incomplete elementary; living in the North region of Brazil. CONCLUSIONS: People living in the South and Southeast regions still have greater access to health services, as do those whose head of household has a higher level of education. The (re)formulation of health policies to reduce disparities should consider differences encountered between regions and social levels. OBJETIVO: Descrever o uso de servicos de saude na populacao brasileira segundo fatores sociodemograficos, de acordo com dados da Pesquisa Nacional de Saude, 2013. METODOS: Foram analisados dados referentes a 205 mil brasileiros, de todas as faixas etarias, que participaram da Pesquisa Nacional de Saude, estudo transversal conduzido em 2013. Calcularam-se as prevalencias e seus intervalos de confianca para indicadores referentes ao acesso e a utilizacao dos servicos de saude, segundo grupos de idade, nivel de instrucao do chefe da familia e macrorregioes do pais. RESULTADOS: Dentre os individuos que procuraram o servico de saude nas duas semanas previas a pesquisa, 95,3% (IC95% 94,9-95,8) conseguiu usa-lo na primeira vez que procurou. As proporcoes foram maiores: no grupo de 60 anos ou mais; cujo chefe da familia tinha nivel superior completo; e nas regioes Sul e Sudeste. Ainda, dos individuos atendidos e que tiveram medicamentos receitados, 82,5% (IC95% 81,2-83,7) conseguiram obter todos os medicamentos, sendo 1/3 pelo SUS. Menos da metade da populacao brasileira (44,4%; IC95% 43,8 45,1) consultou um dentista nos 12 meses anteriores a pesquisa, com proporcoes menores entre: individuos com 60 anos ou mais; cujo chefe da familia nao possuia nivel de instrucao ou tinha ate o fundamental incompleto; e individuos que residiam na regiao Norte do pais. CONCLUSOES: Pessoas que residem nas regioes Sul e Sudeste ainda possuem maior acesso aos servicos de saude, bem como aquelas cujo chefe da familia tem maior nivel de instrucao. A (re)formulacao de politicas de saude no intuito de reduzir disparidades deve considerar as diferencas regionais e entre niveis sociais encontradas. PMID- 28591352 TI - Depression and health behaviors in Brazilian adults - PNS 2013. AB - OBJECTIVE: To evaluate the prevalence of health-related behaviors according to presence and type of depression in Brazilian adults. METHODS: Based on a sample of 49,025 adults (18 to 59 years) from the National Survey on Health 2013 (PNS 2013), we estimated the prevalence of health-related behaviors (smoking; passive smoking; frequent or risky alcohol consumption; leisure time physical activity; time watching TV; and eating pattern indicators), according to the presence of depression (minor and major), evaluated by the Patient Health Questionnaire - 9 (PHQ-9), and the report of depressive mood (in up to seven days or more than seven days) over a two-week period. Prevalence ratios were estimated by Poisson regression. RESULTS: Evaluated by the PHQ-9 scale, 9.7% of the Brazilian adults had depression and 3.9% presented major depression. About 21.0% reported depressive mood and, in 34.9% of them, that feeling has been present for more than seven days. In individuals with major depression (PHQ-9), higher prevalence was found in almost all unhealthy behaviors analyzed, in particular, smoking (PR = 1.65), passive smoking (PR = 1.55), risk alcohol consumption (PR = 1.72), TV for >= 5 hours/day (PR = 2.13), consumption of fat meat (PR = 1.43) and soft drink (PR = 1.42). The prevalence ratios tended to be lower in those with minor depression. Similar results were observed in adults with depressive mood. CONCLUSIONS: This study detected relevant association between depression and health behaviors, in particular for smoking and physical activity. The associations found with the PHQ were similar to those observed with the application of a single question about depressive mood. Our results indicate the importance of assessing the presence of depression and the frequency and severity of symptoms when implementing actions for the promotion of healthy behaviors. PMID- 28591353 TI - Noncommunicable diseases and the use of health services: analysis of the National Health Survey in Brazil. AB - OBJECTIVE: To assess whether sex, education level, and health insurance affect the use of health services among the adult Brazilian population with chronic noncommunicable diseases (NCD). METHODS: Data from a cross-sectional survey were analyzed, the National Health Survey (PNS). Frequency of use of services in the population that referred at least one NCD were compared with the frequency from a population that did not report NCD, according to sex, education level, health insurance, and NCD number (1, 2, 3, 4, or more). The prevalence and prevalence ratios were calculated crude and adjusted for sex, age, region, and 95% confidence intervals. RESULTS: The presence of a noncommunicable disease was associated with increase in hospitalizations in the last 12 months, in 1.7 times (95%CI 1.53-1.9). Failing to perform usual activities in the last two weeks for health reasons was 3.1 times higher in NCD carriers (95%CI 2.78-3.46); while the prevalence of medical consultation in the last 12 months was 1.26 times higher (95%CI 1.24-1.28). NCD carriers make more use of health services, as well as women, people with higher number of comorbidities, with health insurance, and higher education level. CONCLUSIONS: NCD carriers make more use of health services, as well as women, people with higher number of comorbidities, with health insurance, and higher education level. PMID- 28591354 TI - Inequalities in healthy life expectancy by Federated States. AB - OBJECTIVES: To estimate the healthy life expectancy at 60 years by sex and Federated States and to investigate geographical inequalities by socioeconomic status. METHODS: Healthy life expectancy was estimated by the Sullivan method, based on the information of the National Survey on Health, 2013. Three criteria were adopted for the definition of "unhealthy state": self-assessment of bad health, functionality for performing the activities of daily living, and the presence of noncommunicable disease with intense degree of limitation. The indicator of socioeconomic status was built based on the number of goods at household and educational level of the head of household. To analyze the geographical inequalities and socioeconomic level, inequality measures were calculated, such as the ratio, the difference, and the angular coefficient. RESULTS: Healthy life expectancy among men ranged from 13.8 (Alagoas) to 20.9 (Espirito Santo) for the self-assessment criterion of bad health. Among women, the corresponding estimates were always higher and ranged from 14.9 (Maranhao) to 22.2 (Sao Paulo). As to the ratio of inequality by Federated State, the medians were always higher for healthy life expectancy than for life expectancy, regardless of the definition adopted for healthy state. Regarding the differences per Federated State, the healthy life expectancy was seven years higher in one state than in another. By socioeconomic status, differences of three and four years were found, approximately, between the last and first fifth, for men and women, respectively. CONCLUSIONS: Despite the association of the mortality indicators with living conditions, the inequalities are even more pronounced when the welfare and the limitations in usual activities are considered, showing the necessity to promote actions and programs to reduce the socio-spatial gradient. PMID- 28591355 TI - Effect of the inclusion of mobile phone interviews to Vigitel. AB - OBJECTIVE: To evaluate the impact on the prevalence changes of risk factors for chronic diseases, published in the Surveillance System of Risk and Protection Factors for Chronic Diseases by Telephone Survey (Vigitel), after the inclusion of data from the population only with mobile phone. METHODS: Our study used data from the 26 State capitals and Federal District of Brazil obtained by the National Survey on Health (PNS) and Vigitel, both held in 2013. In each capital, we added a subsample of 200 adults living in households with only mobile phones, extracted from PNS, to the Vigitel 2013 database, with approximately 1,900 households, named Vigitel dual frame. RESULTS: Vigitel results showed absolute relative biases between 0.18% and 14.85%. The system underestimated the frequency of adult smokers (10.77%), whole milk consumption (52.82%), and soft drink consumption (22.22%). Additionally, it overestimated the prevalence of hypertension (25.46%). In the simulations using Vigitel dual frame, with inclusion of the sample of adults living in households with only mobile phones, the bias of estimates was reduced in five out of eight analyzed indicators, with greater effects in regions with lower rates of landline coverage. In comparing regions, we observed negative correlation (rho = -0.91) between the percentage of indicators with presence of bias and the percentage of households with only mobile phone. CONCLUSIONS: The results of this study indicate the benefits of including a subsample of 200 adults with only mobile phone on the Vigitel sample, especially in the capitals of the North and Northeast regions. OBJETIVO: Avaliar o impacto nas mudancas das prevalencias de fatores de risco de doencas cronicas, divulgadas no Vigitel, apos a inclusao de dados provenientes da populacao com somente telefone celular. METODOS: O estudo utilizou os dados das capitais obtidos da Pesquisa Nacional de Saude e do Vigitel, que foram realizados em 2013. Em cada capital, acrescentou-se uma subamostra de 200 adultos residentes em domicilios com somente celular, extraida da PNS, a base de dados do Vigitel 2013, com aproximadamente 1.900 domicilios, denominado Vigitel cadastro duplo. RESULTADOS: Os resultados do Vigitel mostraram vicios relativos absolutos entre 0,18% e 14,85%. O sistema subestimou a frequencia de adultos fumantes (10,77%), o consumo de leite com teor integral de gordura (52,82%) e o consumo de refrigerante (22,22%). Adicionalmente, superestimou a prevalencia de hipertensao (25,46%). Nas simulacoes utilizando o Vigitel cadastro duplo, com inclusao da amostra de adultos residentes em domicilios com somente celular, o vicio das estimativas foi reduzido em cinco de oito indicadores analisados, com maiores efeitos nas regioes com menores taxas de cobertura de telefonia fixa. Na comparacao entre as regioes, observa-se correlacao negativa (rho = -0,91) entre o percentual de indicadores com presenca de vicio e o percentual de cobertura de domicilios com somente celular. CONCLUSOES: Os resultados do presente estudo indicam os beneficios da inclusao de uma subamostra de 200 adultos com somente celular na amostra do Vigitel, especialmente nas capitais das regioes Norte e Nordeste. PMID- 28591356 TI - Early detection of breast cancer in Brazil: data from the National Health Survey, 2013. AB - OBJECTIVE: To analyze whether the actions of early detection of breast cancer, initiated with the medical request for mammography, differ between users of the Brazilian Unified Health System (SUS) and those who have private health insurance. METHODS: From the data collected in the National Health Survey, we estimated the proportions of women who had medical request for mammography according to presence or absence of private health insurance. For assessing the factors related to having mammography medical request, we estimated crude and adjusted odds ratios and respective 95%CI by logistic regression. We also analyzed the main reasons reported for not having performed mammography after medical request, as well as the time between examination and result. RESULTS: Of the women interviewed, 66.7% had a medical request for mammography (59.4% among SUS users and 83.9% among those with private health insurance). Having private health insurance, higher education level, and being white were positively associated with having the medical request. Only 5.4% (95%CI 4.8-6.0) of women who received medical request failed to perform mammography - 7.6% were SUS users and 1.7% had health insurance. The most reported reasons for not being able to perform the examination were: not thinking it was necessary; having the test scheduled, but not yet performed; and not being able to schedule it. More than 70% of women received the result with less than one month from its execution. CONCLUSIONS: The barriers to access a medical request for mammographic screening for breast cancer are higher among women who depend exclusively on SUS. PMID- 28591357 TI - Use of health services by Brazilian older adults with and without functional limitation. AB - OBJECTIVE: To analyze the use of health services and the quality of medical care received by Brazilian older adults with and without functional limitation. METHODS: The main analyses were based on a national sample representing 23,815 participants of the National Survey on Health (PNS) aged 60 years or older. Functional limitation was defined by the difficulty to perform at least one out of ten basic or instrumental activities of daily living. Potential confounding variables included predisposing and enabling factors of the use of health services. RESULTS: The prevalence of functional limitation was 30.1% (95%CI 29.2 31.4). The number of doctor visits and hospitalizations in the past 12 months showed statistically significant associations with functional limitation, both for users of the public system (OR = 2.48 [95%CI 2.13-2.88] for three or more doctor visits and OR = 2.58 [95%CI 2.15-3.09] for one or more hospitalizations) and of the private system (OR = 2.56 [95%CI 1.50-4.36] and OR = 2.22 [95%CI 1.64 3.00], respectively). The propensity to use basic health units was higher among users of the private system with functional limitations (OR = 2.01 [95%CI 1.12 3.59]). Only two out of seven indicators of the quality of medical care received were associated with functional limitation, in the perception of users of public and private systems. The public system users with functional limitations did worse evaluation of the freedom for choosing the doctor and waiting time for an appointment, when compared with users of the same system without these limitations (OR = 0.81 [95%CI 0.67-0.99] and OR = 0.76 [95%CI 0.62-0.93], respectively). CONCLUSIONS: Older adults with functional limitations use more health services in comparison with those without such limitations. The magnitude of the association between functional limitation and number of doctor visits and hospitalizations was similar in the public and private health systems. PMID- 28591358 TI - Factor associated with self-reported work-related musculoskeletal disorders in Brazilian adults. AB - OBJECTIVE: To describe the prevalence of work-related musculoskeletal disorder (WMSD) and analyze the factors associated with this outcome in the Brazilian population. METHODS: In this cross-sectional, population-based study, we use data from the National Survey on Health (PNS) of 2013. The sample was composed of 60,202 Brazilians aged 18 years or older. The outcome variable was the occurrence of self-reported WMSD. Sociodemographic and occupational characteristics, personal resources, and health conditions were investigated as explanatory variables. Analyses were performed with the software Stata 12.0 and considered the weighting imposed by the sampling design of the study. Then, univariate and multivariate binary logistic models were carried out, considering a significance level of 5%. RESULTS: The results obtained indicated that the prevalence of WMSD in the Brazilian population was of 2.5%, ranging from 0.2% (Acre) to 4.2% (Santa Catarina). The factors associated with a greater chance of occurrence of WMSD were: female sex (OR = 2.33; 95%CI 1.72-3.15); be temporarily away from work (OR = 2.44; 95%CI 1.41-4.23); be exposed to noise at the workplace (OR = 2.16; 95%CI 1.68-2.77); seniority equal to or greater than 4.5 years at the current job (OR = 1.37; 95%CI 1.09-1.72); participate in volunteer work (OR = 1.65; 95%CI 1.25 2.17); report medical diagnosis of arthritis or rheumatism (OR = 2.40; 95%CI 1.68 3.44); and depression (OR = 2.48; 95%CI 1.86-3.31). On the other hand, factors associated with less chance of WMSD were: not having a partner (OR = 0.73; 95%CI 0.37-0.71) and working in an open environment (OR = 0.51; 95%CI 0.37-0.71). CONCLUSIONS: The associated factors and the prevalence found indicate regional and gender differences. Special attention to comorbidities and environmental noise monitoring would benefit the health of workers in the Country. PMID- 28591359 TI - Population-based surveys and monitoring of noncommunicable diseases. PMID- 28591360 TI - Chronic noncommunicable diseases and population surveys. PMID- 28591361 TI - Doppler velocimetry in fetal rats exposed to enoxaparin and unfractionated heparin (UFH) during pregnancy. AB - Purpose: : To evaluate the effects of enoxaparin and unfractionated heparin (UFH) administered in prophylactic and therapeutic doses on fetal vessels in healthy pregnant Wistar rats, according to Doppler velocimetry measurements. Methods: : Fifty animals were assigned to one of five groups: controls (saline), prophylactic and therapeutic enoxaparin (1 and 2 mg/kg/day, respectively), and prophylactic and therapeutic UFH (72 and 400 UI/kg/day, respectively). Uterine horns were examined by ultrasound for identification of live fetuses. A sample of these fetuses underwent Doppler velocimetry. Spectral curves, peak systolic velocity (PSV), pulsatility index (PI), and resistance index (RI) of the middle cerebral artery, ductus venosus, and umbilical artery were investigated. Differences were considered statistically significant when p<0.05. Results: : No significant differences in PSV, PI, or RI values were observed among the groups. Conclusion: : Doppler velocimetry measurements revealed no significant effects of enoxaparin or unfractionated heparin on fetal vessels in pregnant Wistar rats. PMID- 28591362 TI - The relationship between renal warm ischemia time and glomerular loss. An experimental study in a pig model. AB - Purpose: : To investigate the glomerular number after different warm ischemia times. Methods: : Thirty two pigs were assigned into four groups. Three groups (G10, G20, and G30) were treated with 10, 20, and 30 minutes of left renal warm ischemia. The sham group underwent the same surgery without renal ischemia. The animals were euthanized after 3 weeks, and the kidneys were collected. Right kidneys were used as controls. The kidney weight, volume, cortical-medullar ratio, glomerular volumetric density, volume-weighted mean glomerular volume, and the total number of glomeruli per kidney were obtained. Serum creatinine levels were assessed pre and postoperatively. Results: : Serum creatinine levels did not differ among the groups. All parameters were similar for the sham, G10, and G20 groups upon comparison of the right and left organs. The G30 group pigs' left kidneys had lower weight, volume, and cortical-medullar ratio and 24.6% less glomeruli compared to the right kidney. A negative correlation was found between warm ischemia time and glomerular number. Conclusions: : About one quarter of glomeruli was lost after 30 minutes of renal warm ischemia. No glomeruli loss was detected before 20 minutes of warm ischemia. However, progressive glomerular loss was associated with increasing warm ischemia time. PMID- 28591363 TI - Effects of chronic consumption of green tea on weight and body fat distribution of Wistar rats evaluated by computed tomography. AB - Purpose: : To evaluate the effects of chronic consumption of green tea on body weight and distribution of visceral fat by Computed tomography in female Wistar rats. Methods: : Wistar rats were divided into control group (n = 5), which received water and feed ad libitum, and green tea group (n = 8), in which water has been replaced by green tea. The animals were weighed weekly and Computed Tomography was used at the beginning (1st week) and end (18th week) of the experiment for evaluating the distribution of visceral fat. The animals were followed for 18 weeks. Results: : There was no significant difference in body weight between the groups. However, there was significant difference in visceral fat area. The green tea group had less visceral fat area at the end of the experiment, 3.67 +/- 1.2 cm2, while the control group showed an area of 6.25 +/- 2.2 cm (p = 0.00). Conclusions: : Chronic consumption of green tea leads to decreased visceral adipose tissue area. PMID- 28591365 TI - Expression dynamics of caveolin-1 in fibroblasts of newborn rats with chronic lung disease and its impact on lung fibroblast proliferation. AB - Purpose:: To evaluate the changes of caveolin-1 in lung fibroblasts in newborn Wistar rats when exposed to hyperoxic conditions, as well as lung fibroblasts cell cycle. Methods: : One hundred newborn Wistar rats were randomly divided (50 rats/group) into experimental and control groups, exposed to hyperoxic conditions or normal air, respectively. The fraction of inspired oxygen (FiO2) in the experimental group was 90%, whereas this value was 21% in the control group. Lung fibroblasts were collected on days 3, 7, and 14 of the experiment. Caveolin-1 expression dynamics in lung fibroblasts was assayed in each group by immunofluorescence and Western blot analyses. Flow cytometry (FCM) was used to assess the proportions of lung fibroblasts at different stages of the cell cycle. Results:: On day 3, no significant difference in caveolin-1 expression was observed between the hyperoxic and control groups; however, on days 7 and 14, caveolin-1 expression was significantly lower in the hyperoxic group than in the control (P<0.05). No apparent differences were observed in caveolin-1 expression in the control group at the different time points. Using FCM analysis, we showed that the proportion of lung fibroblasts in G0/G1 phase in the hyperoxic group decreased compared to that of the control group on day 7, while the proportion of S-phase cells increased (P<0.05). These differences were more significant when the groups were compared on day 14 (P<0.01). Conclusion:: After seven days the exposure to hyperoxic conditions, lung fibroblasts proliferated and caveolin-1 expression decreased. PMID- 28591364 TI - Roles of the ERK1/2 and PI3K/PKB signaling pathways in regulating the expression of extracellular matrix genes in rat pulmonary artery smooth muscle cells. AB - Purpose: : To investigate the mechanisms by which PD98059 and LY294002 interfere with the abnormal deposition of extracellular matrix regulated by connective tissue growth factor (CTGF) of rat pulmonary artery smooth muscle cells (PASMCs). Methods: : Rat PASMCs were cultured and separated into a control group. Real-time fluorescence quantitative PCR was performed to detect the expression of collagen III and fibronectin mRNA. Immunohistochemistry and western blot analyses were performed to detect the expression of collagen III protein. Results: : The expression of collagen III and fibronectin mRNA was greater in PASMCs stimulated with CTGF for 48 h, than in the control group. After 72h of stimulation, the expression of collagen III protein in the PASMCs was greater than in the control. The equivalent gene and protein expression of the CPL group were much more significant. Conclusions: : CTGF can stimulate the gene expression of collagen III and fibronectin in PASMCs, which may be one of the factors that promote pulmonary vascular remodeling (PVR) under the conditions of pulmonary arterial hypertension (PAH). PD98059 and LY294002 can inhibit the ERK1/2 and PI3K/PKB signaling pathways, respectively, thus interfering with the biological effects of CTGF. This may be a new way to reduce PAH-PVR. PMID- 28591366 TI - Creation of a contusion injury method for skeletal muscle in rats with differing impacts. AB - Purpose:: To realize a morphological examination of the musculoskeletal tissue, assessing the effect of a contusion method for the production in rat gastrocnemius, comparing the inflammatory responses generated by different impacts. Methods: : For the analysis of a contusion method, twelve female Wistar rats were distributed into four groups. The lesion was generated by 324 g of mass that was dropped from different predetermined heights for each group (30, 45, 60 and 70 cm). Results: : In the analysis of musculoskeletal tissue, the response to injury varied according to the mass of the height drop onto the muscle. Only the group that was injured from 70 cm responded with uniform and severe inflammation, whereas the groups 30, 45 and 60 cm showed inflammation in some regions of the tissue with mild and moderate infiltrates. Conclusion: : The method with the 324 gram mass dropped from a 70-cm height onto the gastrocnemius muscle of rats seems to be the most suitable for the production of muscle injury in these animals after 72 hours, showing an important inflammatory infiltrate. PMID- 28591367 TI - Myocardial ischemic post-conditioning protects the lung against myocardial ischemia/reperfusion-induced damage by activating GSK-3beta. AB - Purpose:: To investigate whether modulating GSK-3beta could attenuate myocardial ischemia reperfusion injury (MIRI) induced acute lung injury (ALI) and analyze the underlying mechanism. Methods:: Male SD rats were subjected to MIRI with or without myocardial ischemic post-conditioning in the presence or absence of GSK 3beta inhibitor. GSK-3beta inhibitor was injected peritoneally 10min before MIRI. Lung W/D weight ratio, MPO, PMNs, histopathological changes, TUNEL, Bax, Bcl-2, IL-6, IL-8, IL-10, GSK-3beta, and caspase-3 were evaluated in the lung tissues of all rats. Results:: After MIRI, lung injury was significantly increased manifested as significant morphological changes and increased leukocytes in the interstitial capillaries, Lung W/D ratio, MPO, and PMN in BALF, which was associated with enhanced inflammation evidenced by increased expressions of IL-6, IL-8 and reduced expression of IL-10. MIRI significantly increased cell apoptosis in the lung as increased levels of apoptotosis, Bax, cleaved caspase-3, and reduced expression of Bcl-2 was observed, which was concomitant with reduced p GSK-3beta. All these changes were reversed/prevented by ischemic post conditioning, while these beneficial effects of ischemic post-conditioning were abolished by GSK-3beta inhibition. Conclusion:: Myocardial ischemia reperfusion injury induces acute lung injury by induction of inflammation and cell apoptosis. Ischemic post-conditioning protects the lung from ALI following MIRI by increasing p-GSK-3beta. PMID- 28591368 TI - DNA damage in Wistar Kyoto rats exercised during pregnancy. AB - Purpose: : To evaluate DNA damage levels in pregnant rats undergoing a treadmill exercise program. Methods:: Wistar Kyoto rats were allocated into two groups (n= 5 animals/group): non-exercise and exercise. The pregnant rats were underwent an exercise protocol on a treadmill throughout pregnancy. Exercise intensity was set at 50% of maximal capacity during maximal exercise testing performed before mating. Body weight, blood pressure and glucose levels, and triglyceride concentration were measured during pregnancy. At day 10 post-natal, the animals were euthanized and maternal blood samples were collected for DNA damage. Results:: Blood pressure and glucose levels and biochemical measurements showed no significant differences. Increased DNA damage levels were found in exercise group compared to those of non-exercise group (p<0.05). Conclusion: : The exercise intensity protocol used in the study might have been exhaustive leading to maternal increased DNA damage levels, demonstrating the relevance of an adequate protocol of physical exercise. PMID- 28591369 TI - Propofol attenuates cytokine-mediated upregulation of expression of inducible nitric oxide synthase and apoptosis during regeneration post-partial hepatectomy. AB - Purpose: : To determine the effects of propofol and ketamine anesthesia on liver regeneration in rats after partial hepatectomy (PHT). Methods: : Male Wistar albino rats were assigned randomly to four groups of 10. Anesthesia was induced and maintained with propofol in groups 1 and 2, and with ketamine in groups 3 and 4. PHT was undertaken in groups 1 and 3. Rats in groups 2 and 4 (control groups) underwent an identical surgical procedure, but without PHT. At postoperative day 5, rats were killed. Regenerated liver was removed, weighed, and evaluated (by immunohistochemical means) for expression of inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), apoptosis protease-activating factor (APAF)-1, and proliferating cell nuclear antigen (PCNA). Also, blood samples were collected for measurement of levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Results: : Between groups 2 and 4, there were no differences in tissue levels of iNOS, eNOS, and APAF-1 or plasma levels of TNF-alpha and IL-6. eNOS expression was similar in group 1 and group 3. Expression of iNOS and APAF-1 was mild-to-moderate in group 1, but significantly higher in group 3. Groups 1 and 3 showed an increase in PCNA expression, but expression in both groups was comparable. Plasma levels of TNF-alpha and IL-6 increased to a lesser degree in group 1 than in group 3. Conclusion:: Propofol, as an anesthetic agent, may attenuate cytokine-mediated upregulation of iNOS expression and apoptosis in an animal model of liver regeneration after partial hepatectomy. PMID- 28591370 TI - Relating family satisfaction to the care provided in intensive care units: quality outcomes in Saudi accredited hospitals. AB - OBJECTIVES: This study aims to identify the satisfaction levels of the family members of patients in intensive care units. METHODS: This is a cross-sectional analytical study. General intensive care units offer a variety of services to clinical and surgical patients. For the purpose of this study, a trained interviewer communicated with the families of patients, either before or after visiting hours. RESULTS: The study included 208 participants: 119 (57.2%) males and 89 (42.8%) females. Seventy-three (35.1%) of the patients attended a private hospital, and 135 (64.9%) attended a public hospital in the city of Al Madinah Al Munawarah. All of the participants were either family members or friends of patients admitted to the intensive care units at the hospitals. The responses of both groups yielded low scores on the satisfaction index. However, a relatively high score was noted in response to questions 2, 6, and 10, which concerned the care that was extended by the hospital staff to their patients, the courteous attitude of intensive care unit staff members towards patients, and patients' satisfaction with the medical care provided, respectively. A very low score was obtained for item 11, which was related to the possibility for improvements to the medical care that the patients received. Overall, greater satisfaction with the services offered by the public intensive care units was reported compared to the satisfaction with the services offered by the private intensive care units. CONCLUSION: An overall low score on the satisfaction index was obtained, and further studies are recommended to assess the current situation and improve the satisfaction and quality of care provided by intensive care units. PMID- 28591371 TI - [Food insecurity in rural communities in Northeast Brazil: does belonging to a slave-descendent community make a difference?] AB - This study aimed to measure the prevalence of food insecurity in a rural area of Northeast Brazil and investigate this outcome according to residence in quilombola communities (descendants of African slaves) versus non-quilombola communities. This was a cross-sectional study in 21 rural communities, 9 of which quilombolas, in 2014, using the Brazilian Food Insecurity Scale (EBIA). Prevalence rates and prevalence ratios were estimated for food insecurity, and Poisson multiple regression analysis with robust variance was performed. Food insecurity was found in 52.1% of the families: 64.9% in quilombola communities and 42% in the others. Food insecurity was associated with belonging to a quilombola community (PR = 1.25), lower economic status (PR = 1.89; 2.98, and 3.22 for status C2, D, and E, respectively), beneficiaries of Bolsa Familia program (PR = 1.52), and four or more household members (PR = 1.20). Food insecurity prevalence was high in the entire population, but it was even higher in quilombola communities, even though they belonged to the same coverage area. The results emphasize this population's vulnerability. PMID- 28591372 TI - [Factors associated with cross-nursing in two cities in Southeast Brazil]. AB - The objective was to estimate the prevalence of cross-nursing in two Brazilian cities and analyze factors associated with the practice. This was a cross sectional study nested in a cohort of pregnant women recruited at public health services that offered prenatal care in two medium-sized cities in the State of Rio de Janeiro: one in Greater Metropolitan Rio and the other in the Mountainous Region, conducted from 2008 to 2010. The current study included women interviewed when their infants were six months old. Adjusted prevalence ratios were obtained with a Poisson regression model, and exposure variables that reached p <= 0.05 comprised the final model. Cross-nursing was practiced by 43.4% of the mothers in Greater Metropolitan Rio de Janeiro and 34.5% in Mountainous Region. Low socioeconomic status was associated with cross-nursing in both cities. In addition, in Mountainous Region the outcome was directly associated with adolescent motherhood, maternal schooling less than or equal to complete primary, and fewer than six prenatal visits. In Greater Metropolitan Rio de Janeiro, in addition to socioeconomic status, only multiparity was associated (inversely) with cross-nursing. Cross-nursing, although contraindicated by the Brazilian Ministry of Health, showed high prevalence among the mothers in the sample and was more frequent among the more vulnerable population groups. PMID- 28591373 TI - [Vulnerability to HIV infection in serodiscordant couples in Rio de Janeiro, Brazil]. AB - A new era in HIV/AIDS treatment began in 1996 with the advent of highly active antiretroviral therapy (HAART). The advent of these new medicines expanded the treatment resources and improved life expectancy and quality of life for persons living with HIV and AIDS, favoring the maintenance and initiation of relationships between partners with discordant HIV serological status. The main objective of this study with serodiscordant couples was to understand the three dimensions of vulnerability - programmatic, social, and individual - in these couples. The study, belonging to the field of social constructionism, used analysis of discursive practices and production of meanings. Forty in-depth interviews were conducted with couples followed in a clinical research institute. The main results include the lack of information on sexuality in the family and in schools, distorted knowledge on HIV prevention and transmission, inadequacies in HIV testing, and flaws in communicating test results. PMID- 28591374 TI - [Health agents' perspective on the incorporation of self-collected samples in HPV screening programs]. AB - The objective of this study was to analyze health agents' perception of self collecting of samples for HPV testing among women and the degree of agreement by the agents to incorporate this approach into their daily tasks. A self administered questionnaire was applied to 127/191 health agents that participated in the EMA Project (Proyecto Evaluacion Modalidad Autotoma) in the province of Jujuy, Argentina, in 2012-2013. The health agents with and without the experience of offering self-collected sampling expressed a high degree of agreement towards adoption of the strategy (78.7%), given its potential to prevent cervical cancer and its contribution to health care for the women under their coverage. However, the health agents identified the extra work and problems linking to the formal health system as the main barriers to offering this modality in the future. The study found that self-collecting of samples is a practice that can be adopted by health agents in the province of Jujuy, but that it should be accompanied by support measures from the formal health system. PMID- 28591375 TI - [Barriers to the search for female sterilization among women in the Bolsa Familia Program]. AB - Poor women in the Bolsa Familia program are accused of having more children in order to enroll or remain in the program. In an ethnographic study (2012-2014), we analyzed reports by five beneficiaries of the program and found exactly the opposite. The women reported that they had gone to public health services in Recife, Pernambuco State, Brazil, in hopes of avoiding more children, but that they had encountered various obstacles. Such barriers included difficulties in obtaining reversible contraception and restrictions in the supply of sterilization in these services, which increases the demand for cesarean sections. Their argument that they are beneficiaries of Bolsa Familia aims to emphasize their poverty and increase the odds of obtaining sterilization (not always successful). Only two of the women had succeeded in obtaining sterilization, which they attributed to "luck" and "the grace of God" rather than as a right. The study's findings suggest that poor women increase their offspring not because they are enrolled in Bolsa Familia, but due to the lack of access to reproductive rights. PMID- 28591376 TI - [Vulnerabilities and recognition: a life story approach to links between youth and violence in marginalized neighborhoods in Buenos Aires, Argentina]. AB - We present the results of a study analyzing the experience of young people with violence in marginalized neighborhoods, examining the links to processes of vulnerability and recognition. We used the methodological strategy of life story reports, built on semi-structured interviews with ten young people 18 to 26 years of age, with their spaces of sociability in marginalized neighborhoods in Greater Metropolitan Buenos Aires, Argentina. Following the theory's lines, we simultaneously built, coded, and analyzed the data, using the Atlas.ti package. Recording the young people's experiences with violence allows visualizing the dynamic and multidimensional nature of their processes of vulnerability, identifying the links to forms of recognition (affective, legal-moral, and ethical-social), the denial of which at different moments in their lives generates situations of disparagement or social invisibility. PMID- 28591377 TI - Effects of heme oxygenase-1 recombinant Lactococcus lactis on the intestinal barrier of hemorrhagic shock rats. AB - This study aimed to investigate the effects of heme oxygenase-1 recombinant Lactococcus lactis (LL-HO-1) on the intestinal barrier of rats with hemorrhagic shock. One hundred Sprague-Dawley male rats (280-320 g) were randomly divided into healthy control group (N group) and hemorrhagic shock group (H group). Each group was subdivided into HO1t, HO2t, HO3t, PBS and LL groups in which rats were intragastrically injected with LL-HO-1 once, twice and three times, PBS and L. lactis (LL), respectively. The mortality, intestinal myeloperoxidase (MPO) activity, intestinal contents of TNF-alpha, IL-10 and HO-1, and intestinal Chiu's score were determined. Results showed that in N group, the HO-1 content increased after LL-HO-1 treatment, and significant difference was observed in HO1t group and HO2t group (P<0.05). In H groups, MPO activity and Chiu's score decreased, but IL-10 content increased in LL-HO-1-treated groups when compared with PBS and LL groups (P<0.05). When compared with N group, the MPO activity reduced dramatically in LL-HO-1-treated groups. Thus, in healthy rats (N group), intragastrical LL-HO-1 treatment may increase the intestinal HO-1 expression, but has no influence on the intestinal barrier. In hemorrhagic shock rats, LL-HO-1 may significantly protect the intestinal barrier, and repeating the intragastrical LL-HO-1 treatments twice has the most obvious protection. PMID- 28591378 TI - Is there a role for voltage-gated Na+ channels in the aggressiveness of breast cancer? AB - Breast cancer is the most common cancer among women and its metastatic potential is responsible for numerous deaths. Thus, the need to find new targets for improving treatment, and even finding the cure, becomes increasingly greater. Ion channels are known to participate in several physiological functions, such as muscle contraction, cell volume regulation, immune response and cell proliferation. In breast cancer, different types of ion channels have been associated with tumorigenesis. Recently, voltage-gated Na+ channels (VGSC) have been implicated in the processes that lead to increased tumor aggressiveness. To explain this relationship, different theories, associated with pH changes, gene expression and intracellular Ca2+, have been proposed in an attempt to better understand the role of these ion channels in breast cancer. However, these theories are having difficulty being accepted because most of the findings are contrary to the present scientific knowledge. Several studies have shown that VGSC are related to different types of cancer, making them a promising pharmacological target against this debilitating disease. Molecular biology and cell electrophysiology have been used to look for new forms of treatment aiming to reduce aggressiveness and the disease progress. PMID- 28591379 TI - An ontogenic study of the behavioral effects of chronic intermittent exposure to ayahuasca in mice. AB - Ayahuasca is a beverage obtained from decoctions of the Banisteriopsis caapi plus Psychotria viridis. In religious contexts, ayahuasca is used by different age groups. However, little is known of the effects of ayahuasca during ontogenic development, particularly with regard to the functional characteristics of the central nervous system. Animal models are useful for studying the ontogenic effects of ayahuasca because they allow exclusion of the behavioral influence associated with the ritualistic use. We investigated the effects of exposure to ayahuasca (1.5 mL/kg, orally, twice a week) on memory and anxiety in C57BL/6 mice, with the post-natal day (PND) being used as the ontogenic criterion for classification: childhood (PND21 to PND35), adolescence (PND35 to PND63), adulthood (PND90-PND118), childhood-adolescence (PND21 to PND63), childhood adulthood (PND21 to PND118) and adolescence-adulthood (PND35 to PND118). One day after the last ayahuasca exposure, the mice were subjected to the Morris water maze (MWM), open field and elevated plus maze tasks (EPM). Ayahuasca did not affect locomotion in the open field or open arms exploration in the EPM, but increased the risk assessment behavior in the childhood group. Ayahuasca did not cause any change in acquisition of spatial reference memory in the MWM task, but decreased the time spent on the platform quadrant during the test session in the adolescence group. These results suggest that, in mice, exposure to ayahuasca in childhood and adolescence promoted anxiety and memory impairment, respectively. However, these behavioral changes were not long-lasting since they were not observed in the childhood-adulthood and adolescence-adulthood groups. PMID- 28591380 TI - Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice. AB - The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old) received ayahuasca or water (1.5 mL/kg, orally) twice a week for 12 months and were tested in the Morris water maze (MWM), open field and elevated plus maze (EPM) tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition) of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice. PMID- 28591381 TI - Presence of t(14;18) translocation in healthy individuals varies according to ethnic background in the Brazilian population. AB - Several groups have demonstrated that healthy individuals can present the t(14;18) translocation. In this report, the presence of the translocation was examined in healthy blood donors in Brazil, a country considered an ethnic melting pot. The translocation was detected by nested PCR in 227 peripheral blood samples from individuals with different ethnic backgrounds. The t(14;18) translocation was found in 45 of 85 White individuals (52.94%); in 57 of 72 Black individuals (79.17%); and in 68 of 70 individuals (97.14%) of Japanese-descent. In conclusion, the frequency of the t(14;18) translocation in the Brazilian population varies according to the ethnic background. PMID- 28591382 TI - Quality of life goes beyond the medical priorities in multiple sclerosis: assessing the impact of social support network. PMID- 28591383 TI - Revealing the microstructural brain damage in amyotrophic lateral sclerosis: the relentless pursuit to approach an imaging biomarker. PMID- 28591384 TI - Social support network and quality of life in multiple sclerosis patients. AB - Objective: To analyse the relationship between the social support network (SSN) and health related quality of life (HRQOL) in multiple sclerosis (MS) patients. Methods: The sample comprised 150 consecutive MS patients attending our MS clinic. To assess the socio-demographic data, a specifically designed questionnaire was applied. The HRQOL dimensions were measured with the Short-Form Health Survey Questionnaire-SF36 and the SSN with the Medical Outcomes Study Social Support Survey. Spearman's correlation was used to compare the magnitude of the relationship between the SSN and HRQOL. Results: The mean patient age was 41.7 years (+/- 10.4; range: 18-70 yr); the mean Expanded Disability Status Score was 2.5 (+/-2.4; range: 0-9). There was a statistically significant correlation between the structure of the SSN and the HRQOL. Conclusion: The composition of the SSN, social group membership and participation in voluntary work have an important role in the HRQOL of patients with MS. PMID- 28591385 TI - Usefulness of diffusion tensor imaging in amyotrophic lateral sclerosis: potential biomarker and association with the cognitive profile. AB - Methods: This was a case-control study conducted from December 1, 2012 to December 1, 2014. Clinical and demographic data were recorded. A neuropsychological test battery adapted to ALS patients was used. An MRI with DTI was performed in all patients and fractional anisotropy (FA) was analyzed in the white matter using the tract based spatial statistics program. Results: Twenty four patients with ALS (15 females, mean age 66.9 + -2.3) and 13 healthy controls (four females, average age 66.9 + - 2) were included. The DTI showed white matter damage in ALS patients vs. healthy controls (p < 0.001). Discussion: In our preliminary study the alterations of white matter in DTI were significantly associated with cognitive impairment in patients with ALS. PMID- 28591386 TI - Impact of insomnia on self-perceived health in the elderly. AB - Objective: To investigate the association between self-perceived health, and sociodemographic and clinical factors in a sample of elderly outpatients in Rio de Janeiro. Methods: A sample of 345 elderly patients was assessed with an anamnesis, Lawton and Brody's Scale, Katz Index, Geriatric Depression Scale, Timed Up and Go Test, and Study of Osteoporotic Fracture Index. Logistic regression analyses were performed to investigate the predictors of self perceived health. Results: Risk of falls, frailty, functional performance on the Instrumental Activities of Daily Living, insomnia, and familial support were related to self-perceived health. Insomnia was the variable that strongly influenced self-perceived health (OR = 0.47, CI 95%: 0.28-0.80, p = 0.01) in our sample. Conclusions: The investigation of insomnia in the elderly should be routinely performed in primary care, because of the negative impact it imposes on the health of this population. PMID- 28591387 TI - Treatment of drooling with sublingual atropine sulfate in children and adolescents with cerebral palsy. AB - Objective: To report the effect of sublingual atropine sulfate to treat drooling in children with cerebral palsy by comparing the results of the Drooling Impact Scale in a non-controlled open clinical trial. Results: Twenty-five children were assessed. The difference in the mean scores of the pre- and post-treatment scales reached statistical significance. There was a low frequency of side effects compared to studies with other anticholinergics. Conclusion: The use of sublingual atropine sulfate seems to be safe and there is a reduction in the Drooling Impact Scale score, which suggests efficacy in the treatment of drooling in children and adolescents with cerebral palsy. Our results should be replicated in randomized, placebo-controlled studies with larger numbers of participants. PMID- 28591388 TI - Incidence and functional outcome of atrial fibrillation and non-atrial fibrillation- related cardioembolic stroke in Joinville, Brazil: a population based study. AB - Among ischemic strokes, cardioembolic (CE) stroke has the worst outcome. We measured the incidence of atrial fibrillation (AF) and non-AF related CE strokes, previous anticoagulant use, and the 90-day functional outcome. Using multiple overlapping sources, we included all CE strokes that occurred in 2015 in Joinville, Brazil. Of the 374 ischemic strokes, 23% (84) were CE. The CE age adjusted incidence, per 1,000 person-years, was 0.14 (0.11-0.17). Of the 26 patients with known prior AF, 73% (19) were not anticoagulated, 77% (20) had a CHA2DS2VASc score >= 3 and 81% (21) had a HAS-BLED score < 3. After three months, approximately one third of those 26 patients died or became disabled. The incidence of CE stroke in our sample was lower than in other population-based studies. The opportunity for anticoagulation was missed in one third of cases. PMID- 28591390 TI - Long term follow-up of growth hormone-secreting pituitary adenomas submitted to endoscopic endonasal surgery. AB - Objective: The aim of this study was to evaluate the results of the endoscopic transsphenoidal technique for growth hormone (GH)-secreting adenomas. Methods: A retrospective analysis based on medical records of 23 acromegalic patients submitted to endoscopic transsphenoidal surgery. Biochemical control was defined as basal GH < 1ng/ml, nadir GH < 0.4ng/ml after glucose load and age-adjusted IGF 1 normal at the last follow-up. Results: The overall endocrinological remission rate was 39.1%. While all microademonas achieved a cure, just one third of macroadenomas went into remission. Suprasellar extension, cavernous sinus invasion and high GH levels were associated with lower rates of disease control. The most common complication was diabetes insipidus and the most severe was an ischemic stroke. Conclusion: The endoscopic transsphenoidal approach is a safe and effective technique to control GH-secreting adenomas. The transcavernous approach may increase the risk of complications. Suprasellar and cavernous sinus extensions may preclude gross total resection of these tumors. PMID- 28591389 TI - Cranial venous sinus dominance: what to expect? Analysis of 100 cerebral angiographies. AB - Methods: Data of 100 cerebral angiographies were retrospectively analyzed (p = 0.05). Results: Mean age was 56.3 years, 62% female and 38% male. Measurements and dominance are shown in the Tables. There was no association between age or gender and dominance. Right parasagittal division of the superior sagittal sinus was associated with right dominance of the transverse sinus, sigmoid sinus and internal jugular vein; and left parasagittal division of the superior sagittal sinus was associated with left dominance of the transverse sinus, sigmoid sinus and internal jugular vein. Conclusion: A dominance pattern of cranial venous sinuses was found. Age and gender did not influence this pattern. Angiographic findings, such as division of the superior sagittal sinus, were associated with a pattern of cranial venous dominance. We hope this article can add information and assist in preoperative venous analysis for neurosurgeons and neuroradiologists. PMID- 28591391 TI - Evolving story: trepanation and self-trepanation to enhance brain function. AB - Trepanation has been performed by people interested in enhancing mental power and well-being since the early 1960s. The pioneers and main proponents of the procedure are described here. The phenomenon appeared in Europe after a Dutch former medical student published a psychoactive drug-friendly scroll suggesting trepanation as a form of permanently increasing cerebral blood volume and function. He trepanned himself in 1965. Three of his friends became enthusiasts. They also submitted themselves to the procedure and published films and books describing their experiences. Two of them coauthored papers, in collaboration with Russian researchers, and created institutions to promote discussion on trepanation. One of these institutions organized trips to Central and South America to get the operation done. Dozens of people nowadays look for trepanation as a method of spiritualization and increasing well-being and mental power. The phenomenon has an uncertain future, however, as the main proponents and supporters are aging. PMID- 28591392 TI - Andrew Lees, a visionary mentored by a madman. AB - Andrew Lees, Professor of Neurology at the National Hospital Queen Square (London, UK), has been recognized as the world's most highly-cited researcher over the 200-year history of Parkinson's Disease. Although he remains actively involved in the investigation of movement disorders, Prof. Lees embarked on a literary career that started in 2011 with the publication of a social history of his native Liverpool. His last work is Mentored by a Madman: The William Burroughs Experiment, which is reviewed here. PMID- 28591393 TI - The relationship between the First World War and neurology: 100 years of "Shell Shock". AB - The First World War was a global war, beginning on 28 July 1914, until 11 November 1918. Soon after the beginning of the war, there was an "epidemic" of neurological conversion symptoms. Soldiers on both sides started to present in large numbers with neurological symptoms, such as dizziness, tremor, paraplegia, tinnitus, amnesia, weakness, headache and mutism of psychosomatic origin. This condition was known as shell shock, or "war neurosis". Because medically unexplained symptoms remain a major challenge, and considering the close relationship of symptoms described in shell shock with clinical neurology, we should study their history in order to improve future care. PMID- 28591394 TI - Charcot's famous secretaries. AB - At the pinnacle of his career, Professor Charcot had four secretaries: Charles Fere, Pierre Marie, Georges Gilles de la Tourette and Georges Guinon. They helped the great founder of neurology with his activities at La Salpetriere Hospital and his private clinic, examining patients before he made the final diagnosis. PMID- 28591395 TI - The many faces of demyelinating diseases: acute disseminated encephalomyelitis and Guillain-Barre syndrome in the same patient. PMID- 28591396 TI - Neurological manifestations of Chikungunya. PMID- 28591397 TI - Ophthalmological findings in myotonic dystrophy. PMID- 28591398 TI - High prevalence of norovirus in children with sporadic acute gastroenteritis in Manaus, Amazon Region, northern Brazil. AB - BACKGROUND: Norovirus (NoV) is a major cause of acute gastroenteritis (AGE) worldwide, especially in children under five years. Studies involving the detection and molecular characterisation of NoV have been performed in Brazil, demonstrating its importance as an etiological agent of AGE. OBJECTIVES: The objectives of this study were to investigate the frequency of human NoV and to genotype the strains isolated from 0-14-year-old patients of AGE in Manaus, Brazil, over a period of two years. METHODS: A total of 426 faecal samples were collected between January 2010 and December 2011. All samples were tested for the presence of NoV antigens using a commercial enzyme immunoassay kit. RNA was extracted from all faecal suspensions and reverse transcription-polymerase chain reaction (RT-PCR) for the NoV-polymerase partial region was performed as a trial test. Positive samples were then subjected to PCR with specific primers for partial capsid genes, which were then sequenced. FINDINGS: NoV was detected in 150 (35.2%) faecal samples, for at least one of the two techniques used. NoV was detected in children from all age groups, with the highest positivity observed among the group of 1-2 years old. Clinically, fever was verified in 43% of the positive cases and 46.3% of the negative cases, and vomiting was observed in 75.8% and 70.8% cases in these groups, respectively. Monthly distribution showed that the highest positivity was observed in January 2010 (81.2%), followed by February and April 2010 and March 2011, when the positivity rate reached almost 50%. Phylogenetic analyses performed with 65 positive strains demonstrated that 58 (89.2%) cases of NoV belonged to genotype GII.4, five (7.7%) to GII.6, and one (1.5%) each to GII.7 and GII.3. MAIN CONCLUSIONS: This research revealed a high circulation of NoV GII.4 in Manaus and contributed to the understanding of the importance of this virus in the aetiology of AGE cases, especially in a region with such few studies available. PMID- 28591399 TI - Detection of tuberculosis drug resistance: a comparison by Mycobacterium tuberculosis MLPA assay versus Genotype(r)MTBDRplus. AB - BACKGROUND: To cope with the emergence of multidrug-resistant tuberculosis (MDR TB), new molecular methods that can routinely be used to screen for a wide range of drug resistance related genetic markers in the Mycobacterium tuberculosis genome are urgently needed. OBJECTIVE: To evaluate the performance of multiplex ligaton-dependent probe amplification (MLPA) against Genotype(r) MTBDRplus to detect resistance to isoniazid (INHr) and rifampicin (RIFr). METHOD: 96 culture isolates characterised for identification, drug susceptibility testing (DST) and sequencing of rpoB, katG, and inhA genes were evaluated by the MLPA and Genotype(r)MTBDRplus assays. RESULTS: With sequencing as a reference standard, sensitivity (SE) to detect INHr was 92.8% and 85.7%, and specificity (SP) was 100% and 97.5%, for MLPA and Genotype(r)MTBDRplus, respectively. In relation to RIFr, SE was 87.5% and 100%, and SP was 100% and 98.8%, respectively. Kappa value was identical between Genotype(r)MTBDRplus and MLPA compared with the standard DST and sequencing for detection of INHr [0.83 (0.75-0.91)] and RIFr [0.93 (0.88 0.98)]. CONCLUSION: Compared to Genotype(r)MTBDRplus, MLPA showed similar sensitivity to detect INH and RIF resistance. The results obtained by the MLPA and Genotype(r)MTBDRplus assays indicate that both molecular tests can be used for the rapid detection of drug-resistant TB with high accuracy. MLPA has the added value of providing information on the circulating M. tuberculosis lineages. PMID- 28591400 TI - Enterocytozoon bieneusi detected by molecular methods in raw sewage and treated effluent from a combined system in Brazil. AB - BACKGROUND: Enterocytozoon bieneusi are the most common microsporidia associated with different clinical manifestations such as diarrhoea, respiratory tract inflammation and acalculous cholecystitis, especially in immunocompromised patients. Infection usually occurs by ingestion of food and water contaminated with spores, but can also result from direct contact with spores through broken skin, eye lesions, and sexual transmission, depending on the microsporidian species. Although there are reports of E. bieneusi found in humans and animals in Brazil, there are no published studies of environmental samples examined by molecular methods. OBJECTIVES: The purpose of this study was to verify the presence of E. bieneusi in raw sewage and treated effluent from a combined system by molecular methods. METHODS: Raw sewage and treated effluent samples collected from a combined system were analysed for the presence of E. bieneusi using the internal transcriber spacer (ITS) region of E. bieneusi by nested polymerase chain reaction. FINDINGS: The analysis revealed E. bieneusi presence and a novel genotype (EbRB) in one raw sewage sample and one treated effluent. MAIN CONCLUSIONS: The presence of E. bieneusi in final effluent indicates that the combined system may not remove microsporidian spores. This study is the first report of E. bieneusi in environmental samples in Brazil. PMID- 28591401 TI - An overview of the molecular and epidemiological features of HIV-1 infection in two major cities of Bahia state, Brazil. AB - BACKGROUND: The high mutation rate of the human immunodeficiency virus (HIV) has created a public health challenge because the use of antiretroviral drugs can generate selective pressure that drives resistance in these viruses. OBJECTIVE: The aim of this work was to characterise the molecular and epidemiological profile of HIV in Bahia, Brazil. METHODS: DNA sequences from regions of HIV gag, pol, and env genes were obtained from previous studies performed in this area between 2002 and 2012. Their genotype and drug-resistance mutations were identified using bioinformatics tools. Clinical and epidemiological data were analysed. FINDINGS: Among 263 individuals (46.4% male), 97.5% were asymptomatic and 49.1% were receiving treatment. Most of the individuals were 31 to 40 years old (36.9%) and infected through heterosexual contact (40.7%). The predominant genotype was B (68.1%) followed by BF recombinants (18.6%). Among the individuals infected with either F or BF genotypes, 68.4% were women and 76.8% were infected through heterosexual transmission. The prevalence of associated mutations conferring antiretroviral resistance was 14.2%, with 3.8% of all mutations conferring resistance to protease inhibitors, 9.43% to nucleoside reverse transcriptase inhibitors, and 8.5% to non-nucleoside reverse transcriptase inhibitors. Drug resistance was higher in individuals receiving treatment (26.1%) than in the drug-naive (4.3%) individuals. MAIN CONCLUSIONS: This study will contribute to the understanding and monitoring of HIV epidemic in this Brazilian region. PMID- 28591402 TI - Towards leprosy elimination by 2020: forecasts of epidemiological indicators of leprosy in Corrientes, a province of northeastern Argentina that is a pioneer in leprosy elimination. AB - BACKGROUND: Corrientes, a province of northeastern Argentina with endemic leprosy, has improved its epidemiological indicators, however, a study of the dynamics over time is lacking. OBJECTIVES: We analysed data of 1308 leprosy patients between 1991 to 2014, and the forecast for 2020. METHODS: Descriptive statistics and stepwise Bayesian model selection were performed. Forecasts were made using the median of 100,000 projections using the parameters calculated via Monte Carlo methods. RESULTS: We found a decreasing number of new leprosy cases ( 2.04 cases/year); this decrease is expected to continue by an estimated 20.28 +/- 10.00 cases by 2020, evidenced by a sustained decline in detection rate (from 11 to 2.9/100,000 inhabitants). Age groups that were most affected were 15-44 (40.13%) and 45-64 (38.83%) year olds. Multibacillary forms (MB) predominated (70.35%) and while gradually declining, between 10 and 30% developed disability grade 2 (DG2) (0.175 (0.110 - 0.337) DG2/MB cases), with a time delay between 0 to 15 years (median = 0). The proportion of MB clinic forms and DG2 increased and will continuously increase in the short term (0.036 +/- 0.018 logit (MB/total of cases). MAIN CONCLUSIONS: Corrientes is on the way to eliminating leprosy by 2020, however the increased proportion of MB clinical forms and DG2 signals a warning for disease control efforts. PMID- 28591403 TI - Preliminary multiplex microarray IgG immunoassay for the diagnosis of toxoplasmosis and rubella. AB - BACKGROUND: During pregnancy, toxoplasmosis and rubella can cause serious damage to the mother and the foetus through vertical transmission. Early diagnosis enables implementation of health measures aimed at preventing vertical transmission and minimising damage caused by these diseases. OBJECTIVE: Here, we report the development of a multiplex assay for simultaneous detection of IgG antibodies produced during toxoplasmosis and rubella infection. METHODS: This assay is based on xMap technology. Initially, by singleplex assays, we evaluated the following antigens: one Toxoplasma gondii lysate; two antigenic extracts of T. gondii (TOX8131 and TOX8122); fragments of T. gondii antigens [SAG-1 (amino acids 45-198), GRA-7 (24-100), GRA-1 (57-149), ROP-4, and MIC-3 (234-306)]; two chimeric antigens composed of fragments of SAG-1, GRA-7, and P35 (CTOX and CTOXH); and fragments of Rubella virus antigens [E-1 (157-176, 213-239, 374-390), E-2 (31-105), and C (1-123)]. FINDINGS: A multiplex assay to simultaneously diagnose toxoplasmosis and rubella was designed with the best-performing antigens in singleplex and multiplex assays, which included CTOXH, T. gondii lysate, TOX8131, E-1, and E-2. The multiplex assay showed 100% sensitivity and specificity for anti-T. gondii IgG detection and 95.6% sensitivity and 100% specificity for anti-R. virus IgG detection. MAIN CONCLUSIONS: We found that, despite the difficulties related to developing multiplex systems, different types of antigens (extracts and recombinant proteins) can be used to develop high performance diagnostic tests. The assay developed is suitable to screen for prior T. gondii and R. virus infections, because it is a rapid, high-throughput, low cost alternative to the current standard diagnostic tools, which require multiple individual tests. PMID- 28591404 TI - Sexual transmission of American trypanosomiasis in humans: a new potential pandemic route for Chagas parasites. AB - BACKGROUND: The Trypanosoma cruzi infection endemic in Latin America has now spread to several countries across four continents; this endemic involves triatomine vector-free protists. We hypothesised that the sexual transmission of T. cruzi contributes to the ongoing spread of Chagas disease. OBJECTIVES: A short term longitudinal study was conducted to evaluate this hypothesis. METHODS: The study population comprised 109 subjects from four families, among whom 21 had been diagnosed with acute Chagas disease by direct parasitological analysis. Blood mononuclear cells and serum samples were obtained from each study subject once per year for three consecutive years. Enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence serological examinations were used to detect specific T. cruzi antibodies. Polymerase chain reaction of T. cruzi DNA revealed 188-nucleotide bands, which hybridised to a specific radiolabelled probe and were confirmed by cloning and sequencing. RESULTS: Three independent assessments at different time points revealed T. cruzi nuclear DNA footprints in 76% (83/109) of the study population with active infection. In contrast, the ELISA and indirect immunofluorescence assays detected the T. cruzi antibody in 28.4% (31/109) of the study samples. Moreover, the semen from 82.6% (19/23) of subjects people revealed harboured the 188- bp base pair T. cruzi footprint. Interestingly, the ejaculates of nuclear DNA-positive Chagas patient transmitted the T. cruzi upon peritoneal injection or infusion in the vagina of mice, and amastigotes were detected in the skeletal muscle, myocardium, vas deferens, and uterine tube. MAIN CONCLUSIONS: T. cruzi infections can be transmitted from females or males to naive mates through intercourse, and progeny showed discrepancies between the ratios of nuclear DNA footprints and specific antibody that can be explained by the tolerance attained during early embryo growth. Additional studies are needed to develop drugs to eradicate the infections. Additionally, the importance of a vigorous education, information, and communication program to prevent sexually transmitted Chagas disease in humans cannot be underemphasised. PMID- 28591405 TI - Genome analysis of yellow fever virus of the ongoing outbreak in Brazil reveals polymorphisms. AB - The current yellow fever outbreak in Brazil is the most severe one in the country in recent times. It has rapidly spread to areas where YF virus (YFV) activity has not been observed for more than 70 years and vaccine coverage is almost null. Here, we sequenced the whole YFV genome of two naturally infected howler-monkeys (Alouatta clamitans) obtained from the Municipality of Domingos Martins, state of Espirito Santo, Brazil. These two ongoing-outbreak genome sequences are identical. They clustered in the 1E sub-clade (South America genotype I) along with the Brazilian and Venezuelan strains recently characterised from infections in humans and non-human primates that have been described in the last 20 years. However, we detected eight unique amino acid changes in the viral proteins, including the structural capsid protein (one change), and the components of the viral replicase complex, the NS3 (two changes) and NS5 (five changes) proteins, that could impact the capacity of viral infection in vertebrate and/or invertebrate hosts and spreading of the ongoing outbreak. PMID- 28591406 TI - The use of circulating cathodic antigen rapid test and serology for diagnosis of active Schistosoma mansoni infection in migrants in Italy, a non-endemic country: a cross sectional study. AB - Diagnosis of schistosomiasis in migrants coming from endemic areas can be difficult, especially in asymptomatic subjects. Light-intensity disease, in fact, may be missed due to the low sensitivity of the stool microscopy and serologic testing cannot distinguish between a resolved infection and an active infection in patients who have been infected and treated in the past, because specific antibodies can persist despite cure. We describe a cross-sectional study conducted on 82 migrants tested for Schistosoma mansoni on single blood (anti schistosome antibodies, total IgE) and urine [point-of-care (POC) circulating cathodic-antigen (CCA) test] samples. A positive POC-CCA test (active infection) resulted in two untreated patients with a positive serology while all patients (n = 66) with a past infection showed a negative POC-CCA test. POC-CCA urine test in combination with serology may be helpful in rapidly differentiate active from past S. mansoni infection in migrants coming from endemic areas. PMID- 28591407 TI - Insights from tissue-specific transcriptome sequencing analysis of Triatoma infestans. AB - Triatoma infestans is an insect of subfamily Triatominae (Hemiptera: Reduviidae) and an important vector of Trypanosoma cruzi, the etiologic agent of human Chagas disease. In this work we reported a transcriptome assembly and annotation of T. infestans heads obtained by Next Generation Sequencing (NGS) technologies. PMID- 28591410 TI - Competitive Energy and Electron Transfer in beta-Functionalized Free-Base Porphyrin-Zinc Porphyrin Dimer Axially Coordinated to C60 : Synthesis, Supramolecular Formation and Excited-State Processes. AB - Simultaneous occurrence of energy and electron transfer events involving different acceptor sites in a newly assembled supramolecular triad comprised of covalently linked free-base porphyrin-zinc porphyrin dyad, H2 P-ZnP axially coordinated to electron acceptor fullerene, has been successfully demonstrated. The dyad was connected through the beta-pyrrole positions of the porphyrin macrocycle instead of the traditionally used meso-positions for better electronic communication. Interestingly, the beta-pyrrole functionalization modulated the optical properties to such an extent that it was possible to almost exclusively excite the zinc porphyrin entity in the supramolecular triad. The measured binding constant for the complex with 1:1 molecular stoichiometry was in the order of 104 m-1 revealing moderately stable complex formation. An energy level diagram constructed using optical, electrochemical and computational results suggested that both the anticipated energy and electron events are thermodynamically feasible in the triad. Consequently, it was possible to demonstrate occurrence of excited state energy transfer to the covalently linked H2 P, and electron transfer to the coordinated ImC60 from studies involving steady-state and time-resolved emission, and femto- and nanosecond transient absorption studies. The estimated energy transfer was around 67 % in the dyad with a rate constant of 1.1*109 s-1 . In the supramolecular triad, the charge separated state was rather long-lived although it was difficult to arrive the exact lifetime of charge separated state from nanosecond transient spectral studies due to overlap of strong triplet excited signals of porphyrin in the monitoring wavelength window. Nevertheless, simultaneous occurrence of energy and electron transfer in the appropriately positioned energy and electron acceptor entities in a supramolecular triad was possible to demonstrate in the present study, a step forward to unraveling the complex photochemical events occurring in natural photosynthesis and its implications in building light energy harvesting devices. PMID- 28591408 TI - Decrease in Dengue virus-2 infection and reduction of cytokine/chemokine production by Uncaria guianensis in human hepatocyte cell line Huh-7. AB - BACKGROUND: Dengue fever may present hemorrhages and cavitary effusions as result of exacerbated immune responses. We investigated hydro-alcoholic extracts from leaves (UGL) and bark (UGB) of the medicinal species Uncaria guinanensis with respect to antiviral effects in Dengue virus (DENV) infection and in immunological parameters associated with in vivo physiopathological features. METHODS: Chemical profiles from UGB or UGL were compared in thin layer chromatography and 1H nuclear magnetic resonance using flavonoid compounds and a pentacyclic oxindole alkaloid-enriched fraction as references. DENV-2-infected hepatocytes (Huh-7) were treated with extracts. Cell viability, DENV antigens and immunological factors were detected by enzyme-linked immunosorbent assay (ELISA) or flow cytometry. FINDINGS: The UGL mainly differed from UGB by selectively containing the flavonoid kaempferitrin. UGB and UGL improved hepatocyte viability. Both extracts reduced intracellular viral antigen and inhibited the secretion of viral non-structural protein (NS1), which is indicative of viral replication. Reduction in secretion of macrophage migration inhibitory factor was achieved by UGB, of interleukin-6 by UGL, and of interleukin-8 by both UGB and UGL. MAIN. CONCLUSIONS: The U. guianensis extracts presented, antiviral and immunomodulatory effects for DENV and possibly a hepatocyte-protective activity. Further studies may be performed to consider these products as potential candidates for the development of an herbal product for the future treatment of dengue. PMID- 28591409 TI - Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma. AB - Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45.5%, 63.9%, and 47.5%, respectively, with 5.3%, 11.0%, and 9.6% grade >=3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50.1%, 63.9%, and 48.3%, respectively, with 4.2%, 11.0%, and 8.6% grade >=3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. PMID- 28591411 TI - Late sequelae in Hodgkin lymphoma survivors. PMID- 28591412 TI - Management of aggressive lymphoma in very elderly patients. PMID- 28591413 TI - Pathology and classification of aggressive mature B-cell lymphomas. PMID- 28591414 TI - The costs of care in haematological cancers: Health economic issues. PMID- 28591415 TI - Response-adapted therapy in Hodgkin lymphoma. PMID- 28591417 TI - Molecular genetics of aggressive B-cell lymphoma. PMID- 28591416 TI - Disease-oriented treatment of T-cell lymphoma. PMID- 28591418 TI - Role and timing of new drugs in CLL. PMID- 28591419 TI - The multiple faces of marginal zone lymphomas. PMID- 28591420 TI - Anaplastic large-cell lymphoma and peripheral T-cell lymphoma: What can pediatricians and adult oncologists learn from each other? PMID- 28591421 TI - Immunotherapy in lymphoma. PMID- 28591423 TI - Preliminars and Program. PMID- 28591422 TI - The role of stem cell transplant for lymphoma in 2017. PMID- 28591424 TI - Clinical applications of genome studies. PMID- 28591425 TI - Treatment of aggressive B-cell lymphomas. PMID- 28591426 TI - Chemotherapy free treatment of indolent lymphoma. PMID- 28591427 TI - The 2016 updated WHO classification of lymphoid neoplasias. PMID- 28591428 TI - Does disestablishment lead to religious vitality? The case of Switzerland. AB - Economists and sociologists of religion have claimed that religious establishment dampens religious vitality, leading to lower recruitment efforts, low attendance, declining membership within established congregations, and the 'crowding out' of non-established congregations. Conversely, these authors have told us, disestablishment will lead to more religious vitality. Remarkably, even though these claims rest on the connection between establishment and the organizational and membership behaviour of local religious congregations, no research has directly examined that connection. We use the 2008 Swiss National Congregations Study as well as historical data to assess the effect of different levels of religious establishment on both established and non-established congregations. We find that established congregations do indeed show less religious vitality than non-established congregations. Contrary to the claims of the economic literature, however, these covariations are not caused by differences in religious establishment on the cantonal level. Both our quantitative and historical analyses show that disestablishment has not led to religious vitality for either established or non-established congregations. The only clear effect of disestablishment is a dramatic decrease of income for established congregations. Based on quantitative and historical evidence, we suggest that differences between established and non-established congregations are produced by differences in religious tradition and immigration flows, not by differences in levels of establishment. PMID- 28591429 TI - Impacts of Seasonal Pumping on Stream-Aquifer Interactions in Miryang, Korea. AB - Large agricultural fields in South Korea are located mostly on alluvial plains, where a significant amount of groundwater is used for heating of water-curtain insulated greenhouses. Such greenhouses are commonly used for crop cultivation during the winter dry season from November to March. After use the groundwater is discharged directly into streams, causing groundwater depletion. A hydrogeological study was carried out in a typical agricultural area of this type, located on an alluvial aquifer near the Nakdong River. Groundwater levels, chemical characteristics, and temperatures from 68 observation wells were analyzed to determine the impacts of seasonal groundwater pumping on the groundwater system and stream-aquifer interactions. Our results show that the groundwater system has not yet reached a state of dynamic equilibrium. Decades of excessive seasonal pumping have caused a gradual decline of groundwater levels, leading to groundwater depletion, especially in areas further from the river. Seasonal pumping has also significantly affected groundwater quality in the aquifer near the river. Groundwater temperature is decreasing (in this case a disadvantage), and saline groundwater is being diluted by induced recharge. The results of this study provide a basic outline for effective integrated water management that is widely applicable in South Korea. PMID- 28591430 TI - Qualitative HPLC-DAD/ESI-TOF-MS Analysis, Cytotoxic, and Apoptotic Effects of Croatian Endemic Centaurea ragusina L. Aqueous Extracts. AB - Centaurea ragusina L., an endemic Croatian plant species, revealed a good cytotoxic activity of aqueous extracts (AE) on human bladder (T24) and human glioblastoma (A1235) cancer cell lines. The chemical constituents were tentatively identified using high performance liquid chromatography HPLC-DAD/ESI TOF-MS in negative ionization mode. The main compounds of herba extract were sesquiterpene lactones: solstitialin A 3,13-diacetate and epoxyrepdiolide; organic acid: quinic acid. The main compounds of flower extract were organic acids: quinic acid, citric acid, and malic acid; sesquiterpene lactone: cynaropicrin; phenolic compounds: chlorogenic acid and phenylpropanoid: syringin. The AE of C. ragusina were investigated for correlation of their effects on human bladder (T24) and human glioblastoma (A1235) cancer cell lines using the MTT assay. Although both extracts showed significant dose- and time-dependent cytotoxic activity against both cancer cell lines, the flower extract exhibited slightly higher activity. In order to determine type of cell death induced by treatment, cell lines were exposed subsequently to a treatment with both flower and herba AE. The majority of the cells died by induced apoptosis treatment. Flower AE (26.25%), compared to a leaf AE (22.15%) showed slightly higher percentage of an apoptosis in T24 cells, when compared to a non-treated cells (0.04%). PMID- 28591432 TI - Pyoderma gangraenosum bei einer schwangeren Patientin unter Behandlung mit G-CSF (Lenograstim). PMID- 28591431 TI - Autumn senescence in aspen is not triggered by day length. AB - Autumn senescence in mature aspens, grown under natural conditions, is initiated at almost the same date every year. The mechanism of such precise timing is not understood but we have previously shown that the signal must be derived from light. We studied variation in bud set and autumn senescence in a collection of 116 natural Eurasian aspen (Populus tremula) genotypes, from 12 populations in Sweden and planted in one northern and one southern common garden, to test the hypothesis that onset of autumn senescence is triggered by day length. We confirmed that, although bud set seemed to be triggered by a critical photoperiod/day length, other factors may influence it. The data on initiation of autumn senescence, on the other hand, were incompatible with the trigger being the day length per se, hence the trigger must be some other light-dependent factor. PMID- 28591433 TI - Perianale weiche, leicht druckdolente Knoten. PMID- 28591434 TI - Pustulobullose Variante eines SDRIFE (symmetrical drug-related intertriginous and flexural exanthema). PMID- 28591435 TI - Pseudoaneurysma der Arteria temporalis superficialis als seltene Komplikation nach chirurgischer Tumorentfernung im Schlafenbereich. PMID- 28591436 TI - Atrophodermia Pasini-Pierini entlang der Blaschko-Linien. PMID- 28591437 TI - Aquagene Hauterkrankungen. PMID- 28591438 TI - Dermatologische Erkrankungen bei Palliativpatienten: eine prospektive Studie an 271 Patienten. PMID- 28591439 TI - Retrospective evaluation of exposure to natural UV radiation: experiences with the online UV history tool in a field study. AB - BACKGROUND: Cutaneous squamous cell carcinoma and multiple actinic keratoses can be recognized as occupational diseases if the site affected has been subjected to additional occupational UV exposure of at least 40 %. An online UV history tool that allows for the quantification of occupational and recreational UV doses was now tested in a field study. PATIENTS AND METHODS: Ninety-nine patients with nonmelanoma skin cancer were examined. Patient history with respect to UV exposure was obtained using the online UV history tool. Initial validation was carried out with data from ten additional patients. In the context of a pilot study, the applicability of the tool was assessed using a questionnaire. RESULTS: Overall, patient history revealed a UV exposure between 3,792 and 53,163 SEDs. Patients with squamous cell carcinoma, actinic keratoses, or Bowen's disease (n = 22) had significantly higher SED values and were significantly older (73 vs. 66 years) than patients with basal cell carcinoma (n = 77). Occupational UV exposure was reported by 19 patients, two of whom showed an additional occupational UV exposure of more than 40 %, which prompted the filing of a (suspected) occupational disease report. With respect to validation, there was evidence of good inter-investigator reliability. The applicability of the tool was rated as good. CONCLUSIONS: The online UV history tool enables quick retrospective quantification of occupational and recreational UV exposure in case of suspicion of the occupational disease "cutaneous squamous cell carcinoma or multiple actinic keratoses caused by natural UV radiation". PMID- 28591440 TI - Ulzerierende Plaque innerhalb einer Tatowierung bei einem 49-jahrigen Mann. PMID- 28591441 TI - Kongresskalender 2017. PMID- 28591442 TI - Schnell wachsende Plaque im Nacken eines gesunden Patienten. PMID- 28591443 TI - Low-dose isotretinoin prevents digital amputation in loricrin keratoderma (Vohwinkel syndrome with ichthyosis). PMID- 28591444 TI - S3-Leitlinie Diagnostik, Therapie und Nachsorge des Melanoms - Update 2015/2016, Kurzversion 2.0. PMID- 28591445 TI - Retrospektive Expositionsabschatzung der naturlichen UV-Strahlendosis: Erfahrungen mit dem Online-UV-Anamnese-Instrument im Feldversuch. PMID- 28591447 TI - Niedrig dosiertes Isotretinoin verhindert Amputation bei Loricrin Palmoplantarkeratose (Vohwinkel-Syndrom mit Ichthyose). PMID- 28591446 TI - Kutane Sarkome. AB - Cutaneous sarcomas comprise a heterogeneous group of mesenchymal spindle cell tumors of the dermis and subcutis, one of the best-known entities being dermatofibrosarcoma protuberans. Other sarcomas addressed in this review include a typical fibroxanthoma, cutaneous undifferentiated pleomorphic sarcoma, leiomyosarcoma, liposarcoma, and angiosarcoma. With the exception of dermatofibrosarcoma protuberans, which has its peak incidence in middle-aged adults, cutaneous sarcomas usually occur in elderly individuals starting in the sixth or seventh decade of life. The pathogenesis of the various disease entities is not uniform and has not been definitively ascertained. Histology is the key to arriving at a correct diagnosis, and should always include ruling out other dermal neoplasms such as melanoma. In recent years, molecular genetic methods have provided greater insight into the pathogenesis, thus paving the way for new targeted therapies. Treatment of choice for cutaneous sarcomas is excision with sufficient surgical margins. Adjuvant and neoadjuvant therapeutic concepts include radiation therapy and the use of targeted therapies or chemotherapies. Local recurrences have frequently been reported in cutaneous sarcomas. Unlike soft tissue sarcomas, the prognosis in terms of survival - with the exception of angiosarcoma - is very good if treated adequately, a fact that should be emphasized to patients. PMID- 28591449 TI - 2. Fortbildungsveranstaltung der AG Biologika der OGDV, 25. Marz 2017, Wien. PMID- 28591448 TI - Anaphylaktischer Schock bei Intrakutantestung auf Cefuroxim. PMID- 28591450 TI - Unilaterale navoide Teleangiektasien bei zwei Jugendlichen. PMID- 28591451 TI - UV-Schutzbundnis verabschiedet ein neues Grundsatzpapier zur Verhaltnispravention: Vorbeugung gesundheitlicher Schaden der Sonne - Verhaltnispravention in der Stadt und auf dem Land. PMID- 28591453 TI - "Water Stress": selten, unverstanden und unlosbar - und doch relevant. PMID- 28591454 TI - Pseudoaneurysm of the superficial temporal artery: a rare complication following tumor surgery in the temporal region. PMID- 28591456 TI - Pyoderma gangrenosum on G-CSF (lenograstim) treatment during pregnancy. PMID- 28591457 TI - Cutaneous sarcomas. AB - Cutaneous sarcomas comprise a heterogeneous group of mesenchymal spindle cell tumors of the dermis and subcutis, one of the best-known entities being dermatofibrosarcoma protuberans. Other sarcomas addressed in this review include atypical fibroxanthoma, cutaneous undifferentiated pleomorphic sarcoma, leiomyosarcoma, liposarcoma, and angiosarcoma. With the exception of dermatofibrosarcoma protuberans, which has its peak incidence in middle-aged adults, cutaneous sarcomas usually occur in elderly individuals starting in the sixth or seventh decade of life. The pathogenesis of the various disease entities is not uniform and has not been definitively ascertained. Histology is the key to arriving at a correct diagnosis, and should always include ruling out other dermal neoplasms such as melanoma. In recent years, molecular genetic methods have provided greater insight into the pathogenesis, thus paving the way for new targeted therapies. Treatment of choice for cutaneous sarcomas is excision with sufficient surgical margins. Adjuvant and neoadjuvant therapeutic concepts include radiation therapy and the use of targeted therapies or chemotherapies. Local recurrences have frequently been reported in cutaneous sarcomas. Unlike soft tissue sarcomas, the prognosis in terms of survival - with the exception of angiosarcoma - is very good if treated adequately, a fact that should be emphasized to patients. PMID- 28591458 TI - Program Abstracts: The 59th Annual American Headache Society Meeting. PMID- 28591459 TI - Simulating Head Recovery and Intermittent Discharge in Free Flowing Wells. AB - Modeling of the head recovery (buildup) in and intermittent operation of flowing wells lacks rigorous analytical tools. Presently different methods are applied in discharging and recovery phases. The presented reliable approximate solution considers a continuous free flow process and time variant screen loss parameters. The latter are temporarily set to large value to prevent inflow into the well bore during the single recovery or in repeated shut down periods. This method is called as screen loss control or SLC technique and is verified by means of comparative analysis with the constant rate pumping-recovery test simulated in leaky aquifer. The evaluation of the free flow and recovery test in the free flowing well 28 (Artesia Heights) concluded with calibrated parameters close to those obtained in the earlier analyses based on split well flow process. The simulation of intermittent flowing well operation also underwent successful validation resulting in reasonable values of the Qw and s response functions. PMID- 28591460 TI - Editorial: The Expanding World of Couple and Family Therapy. PMID- 28591461 TI - Changes in Families' Caregiving Experiences through Involvement as Participants then Facilitators in a Family Peer-Education Program for Mental Disorders in Japan. AB - A family peer-education program for mental disorders was developed in Japan, similar to existing programs in the United States and Hong Kong. Families that serve as facilitators in such programs may enhance their caregiving processes and, thereby, their well-being. This study's aim was to describe how families' caregiving experiences change, beginning with the onset of a family member's mental illness, through their involvement in a family group or peer-education program as participants then facilitators. Thus, this study was conducted in a family peer-education program for mental disorders in Japan. Group interviews were conducted with 27 facilitators from seven program sites about their experiences before, during, and after becoming facilitators. Interview data were coded and categorized into five stages of caregiving processes: (1) withdrawing and suppressing negative experiences with difficulty and regret; (2) finding comfort through being listened to about negative experiences; (3) supporting participants' sharing as facilitators; (4) understanding and affirming oneself through repeated sharing of experiences; and (5) finding value and social roles in one's experiences. The third, fourth, and fifth stages were experienced by the facilitators. The value that the facilitators placed on their caregiving experiences changed from negative to positive, which participants regarded as helpful and supportive. We conclude that serving as facilitators may improve families' caregiving processes. PMID- 28591462 TI - Preliminary Validation of a Korean Version of the Acquired Capability for Suicide Scale-Fearlessness About Death. AB - The interpersonal-psychological theory of suicide proposes that the desire for suicide must be accompanied by the capability to do so in order for an individual to engage in suicidal behavior. The Acquired Capability for Suicide Scale Fearlessness about Death (ACSS-FAD) measures fearlessness about death, a core component of the capability for suicide. This study aimed to validate a Korean version of the ACSS-FAD in a college student sample. We administered the ACSS-FAD and measures of suicide ideation, fear of suicide, death anxiety, pain anxiety, and depression in a sample of Korean college students (N = 301) and analyzed its reliability, factor structure, invariance across genders, convergent validity, and discriminant validity. The one-factor model achieved satisfactory model fit. Across genders, partial metric invariance and partial scalar invariance were established. The results also revealed that the ACSS-FAD has good internal consistency, convergent validity (positive correlations with fear of suicide, death anxiety, and pain anxiety), and discriminant validity (no relation with depression). The Korean version of the ACSS-FAD presents adequate psychometric properties and may be considered to be a promising instrument for measuring fearlessness about death in college students. PMID- 28591463 TI - Immunosuppression-associated Kaposi sarcoma following stem cell transplantation. PMID- 28591466 TI - Tanner Awards for the Most Cited Articles of 2014. PMID- 28591464 TI - Risk of low bone mineral density in testicular germ cell cancer survivors: association with hypogonadism and treatment modality. AB - The cure rate of testicular cancer exceeds 95%, but testicular cancer survivors (TCS) are at increased risk of hypogonadism (HG). It has been suggested that TCS have reduced bone mineral density (BMD), but it is unclear whether this is related to HG or a direct effect of cancer therapy. The aim of this study was to evaluate whether TCS have decreased BMD, and if BMD is related to HG and/or the cancer treatment given. We investigated 91 TCS (mean age at diagnosis: 31 years; mean 9.3 years follow-up) and equal number of age matched controls (mean age at inclusion 40.3 years and 41.2 years, respectively). Total testosterone and LH were measured. BMD was determined using dual-energy X-ray absorptiometry (DXA). Low BMD (LBD) was defined as Z-score <-1. Compared to eugonadal TCS, both TCS with untreated HG (mean difference: -0.063 g/cm2 ; 95% CI: -0.122; -0.004 p = 0.037) and TCS receiving androgen replacement (mean difference -0.085 g/cm2 ; 95% CI: -0.168; -0.003; p = 0.043) presented with statistically significantly 6-8% lower hip BMD. At the spine, L1-L4, an 8% difference reached the level of statistical significance only for those with untreated HG (mean difference: 0.097 g/cm2 ; 95% CI: -0.179; -0.014; p = 0.022). TCS with untreated HG had significantly increased OR for spine L1-L4 LBD (OR = 4.1; 95% CI: 1.3; 13; p = 0.020). The associations between the treatment given and BMD were statistically non-significant, both with and without adjustment for HG. In conclusion, TCS with HG are at increased risk of impaired bone health. Prevention of osteoporosis should be considered as an important part in future follow up of these men. PMID- 28591467 TI - The Effect of Impella CP on Cardiopulmonary Physiology During Venoarterial Extracorporeal Membrane Oxygenation Support. AB - Left ventricle (LV) distension is a complication of venoarterial extracorporeal membrane oxygenation (VA-ECMO) support. The effects of Impella on the pulmonary circulatory physiology were studied in a single-center study of six consecutive patients on VA-ECMO support who had LV unloading with Impella. Right ventricular stroke volume, pulmonary hemodynamics, and partial pressure of end-tidal CO2 (PETCO2 ) were measured on echocardiogram, pulmonary artery catheter, and capnography, respectively. The addition of Impella CP increased total blood flow and reduced pulmonary artery wedge pressure. There was a small reduction in arterial oxygen saturation as Impella increased LV output. The increase in pulmonary artery capacitance (PCap) exceeded the reduction in pulmonary vascular resistance (PVR), thereby increasing the pulmonary artery time constant (product of PCap and PVR). The right ventricular stroke volume increased and the improvement in pulmonary hemodynamics and blood flow were associated with reduced arterial-PETCO2 gradient. The Impella CP unloads the LV during VA-ECMO support, increasing total flow, reducing RV afterload, and facilitating RV output and pulmonary blood flow with improvement in gas exchange. PMID- 28591468 TI - What is it all about? PMID- 28591469 TI - Continued decline in blood collection and transfusion in the United States-2015. AB - BACKGROUND: In 2011 and 2013, the National Blood Collection and Utilization Survey (NBCUS) revealed declines in blood collection and transfusion in the United States. The objective of this study was to describe blood services in 2015. STUDY DESIGN AND METHODS: The 2015 NBCUS was distributed to all US blood collection centers, all hospitals performing at least 1000 surgeries annually, and a 40% random sample of hospitals performing 100 to 999 surgeries annually. Weighting and imputation were used to generate national estimates for units of blood and components collected, deferred, distributed, transfused, and outdated. RESULTS: Response rates for the 2015 NBCUS were 78.4% for blood collection centers and 73.9% for transfusing hospitals. In 2015, 12,591,000 units of red blood cells (RBCs) (95% confidence interval [CI], 11,985,000-13,197,000 units of RBCs) were collected, and 11,349,000 (95% CI, 10,592,000-11,747,000) were transfused, representing declines since 2013 of 11.6% and 13.9%, respectively. Total platelet units distributed (2,436,000; 95% CI, 2,230,000-2,642,000) and transfused (1,983,000; 95% CI, 1,816,000 = 2,151,000) declined by 0.5% and 13.1%, respectively, since 2013. Plasma distributions (3,714,000; 95% CI, 3,306,000 4,121,000) and transfusions (2,727,000; 95% CI, 2,594,000-2,859,000) in 2015 declined since 2013. The median price paid per unit in 2015-$211 for leukocyte reduced RBCs, $524 for apheresis platelets, and $54 for fresh frozen plasma-was less for all components than in 2013. CONCLUSIONS: The 2015 NBCUS findings suggest that continued declines in demand for blood products resulted in fewer units collected and distributed Maintaining a blood inventory sufficient to meet routine and emergent demands will require further monitoring and understanding of these trends. PMID- 28591470 TI - Cost projections for implementation of safety interventions to prevent transfusion-transmitted Zika virus infection in the United States. AB - BACKGROUND: In August 2016, the Food and Drug Administration advised US blood centers to screen all whole blood and apheresis donations for Zika virus (ZIKV) with an individual-donor nucleic acid test (ID-NAT) or to use approved pathogen reduction technology (PRT). The cost of implementing this guidance nationally has not been assessed. STUDY DESIGN AND METHODS: Scenarios were constructed to characterize approaches to ZIKV screening, including universal ID-NAT, risk-based seasonal allowance of minipool (MP) NAT by state, and universal MP-NAT. Data from the 2015 National Blood Collection and Utilization Survey (NBCUS) were used to characterize the number of donations nationally and by state. For each scenario, the estimated cost per donor ($3-$9 for MP-NAT, $7-$13 for ID-NAT) was multiplied by the estimated number of relevant donations from the NBCUS. Cost of PRT was calculated by multiplying the cost per unit ($50-$125) by the number of units approved for PRT. Prediction intervals for costs were generated using Monte Carlo simulation methods. RESULTS: Screening all donations in the 50 states and DC for ZIKV by ID-NAT would cost $137 million (95% confidence interval [CI], $109-$167) annually. Allowing seasonal MP-NAT in states with lower ZIKV risk could reduce NAT screening costs by 18% to 25%. Application of PRT to all platelet (PLT) and plasma units would cost $213 million (95% CI, $156-$304). CONCLUSION: Universal ID-NAT screening for ZIKV will cost US blood centers more than $100 million annually. The high cost of PRT for apheresis PLTs and plasma could be mitigated if, once validated, testing for transfusion transmissible pathogens could be eliminated. PMID- 28591471 TI - Supplemental findings from the National Blood Collection and Utilization Surveys, 2013 and 2015. PMID- 28591472 TI - Response to: Finding clinical efficacy with balloon sinus dilation in pediatric chronic rhinosinusitis patients. PMID- 28591473 TI - Olfactory loss in chronic rhinosinusitis. PMID- 28591474 TI - Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls. AB - The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality. PMID- 28591475 TI - Gamma Knife radiosurgery for hypothalamic hamartoma preserves endocrine functions. AB - Gamma Knife radiosurgery (GK) is an effective treatment for hypothalamic hamartoma. No precise data are available on the risk of endocrine side effects of this treatment. In this study, 34 patients with hypothalamic hamartoma (HH) were followed prospectively at the Department of Endocrinology, La Timone Hospital, Marseille, France, for a mean follow-up of >2 years (mean +/- standard deviation [SD] 3.6 +/- 2 years). Initial pre- and post-GK radiosurgery evaluations were performed, including weight, body mass index (BMI), and a complete endocrinological workup. At diagnosis, eight patients presented with central precocious puberty at a mean age of 5.4 +/- 2.4 years. At the time of GK (mean age 18.2 +/- 11.1 years), two patients previously treated with surgery presented with luteinizing hormone/follicle-stimulating hormone (LH/FSH) deficiency. After GK, only one patient presented with a new thyrotropin-stimulating hormone (TSH) deficiency, 2 years after the procedure. The other pituitary axes remained normal in all but two patients (who had LH/FSH deficiency prior to GK). There was no significant difference between pre- and post-GK mean BMI (26.9 vs. 25.1 kg/m2 , p = 0.59). To conclude, in this group of 34 patients, GK did not induce major endocrinologic side effects reported with all the other surgical techniques in the literature. It is, thus, a safe and effective procedure in the treatment of hypothalamic hamartoma. PMID- 28591476 TI - Clinical features and evolution of the gelastic seizures-hypothalamic hamartoma syndrome. AB - Gelastic seizures, usually with onset in early infancy, are the hallmark manifestation of hypothalamic hamartoma. This seizure type is directly generated by hamartoma itself, intrinsically epileptogenic because of its anatomofunctional organization. Other types of seizures, focal or generalized, may appear during the evolution, probably resulting from mechanisms of secondary epileptogenesis. Nevertheless, the clinical expression and the severity of the syndrome, ranging from a focal drug-resistant epilepsy to a catastrophic generalized encephalopathy with severe cognitive and behavioral impairments, depends on the size and the site of attachment of the hamartoma. Early suspicion, timely diagnosis, and appropriate treatment are mandatory to reverse a potential catastrophic evolution of this condition. PMID- 28591477 TI - Reduced glucose metabolism in neocortical network nodes remote from hypothalamic hamartomas reflects cognitive impairment. AB - The clinical appearance of patients with hypothalamic hamartomas is very heterogeneous, and interindividual variability of intellectual abilities is not completely understood. We retrospectively investigated cerebral dysfunction as indicated by reduced regional glucose metabolism in 29 patients (age range 7-49 years) with epilepsy due to hypothalamic hamartomas. Brain metabolism assessed by [18 F]FDG-PET was compared between patients with and without cognitive impairment controlled for unevenly distributed hamartoma lateralization seen on magnetic resonance imaging (MRI). Due to the broad age range, the variable "age" was included in the imaging analyses as a covariate. Additional voxel-wise analysis with hamartoma volume, disease duration, seizure severity, seizure frequency, and antiepileptic drug (AED) load as well as dosage and gender as further covariates was accomplished. Furthermore, global visual ratings on laterality of hypometabolism patterns were assessed according to clinical standards and related to hamartoma lateralization on MRI as well as lateralization of electroencephalography (EEG) abnormalities. Cognitively impaired patients showed significantly reduced glucose metabolism in bilateral frontal as well as right parietal and posterior midline cortices (p < 0.005), irrespective of hamartoma lateralization seen on MRI. Additional voxel-wise analysis with the above mentioned further covariates revealed comparable results. FDG uptake values within the main right frontal cluster obtained from group comparison were not associated with hamartoma volume, disease duration, or AED load. Irrespective of cognitive functioning, lateralization of reduced FDG uptake in global visual ratings was associated with lateralization of hypothalamic hamartomas seen on MRI (p < 0.01), but not with EEG abnormalities. We found regions of reduced glucose metabolism in cognitively impaired patients remote from the hypothalamic hamartomas in frontal and parietal regions, which have been identified as important network nodes in the human brain and are linked to higher cognitive functions. PMID- 28591478 TI - Hypothalamic hamartoma: Neuropathology and epileptogenesis. AB - Hypothalamic hamartomas (HHs) are congenital malformations of the ventral hypothalamus resulting in treatment-resistant epilepsy and are intrinsically epileptogenic for the gelastic seizures that are the hallmark symptom of this disorder. This paper reviews the neuropathologic features of HHs associated with epilepsy, with an emphasis on characterizing neuron phenotypes and an ultimate goal of understanding the cellular model of ictogenesis occurring locally within this tissue. We also present previously unpublished findings on Golgi staining of HH. The microarchitecture of HH is relatively simple, with nodular clusters of neurons that vary in size and abundance with poorly defined boundaries. Approximately 80-90% of HH neurons have an interneuron-like phenotype with small, round soma and short, unbranched processes that lack spines. These neurons express glutamic acid decarboxylase and likely utilize gamma-aminobutyric acid (GABA) as their primary neurotransmitter. They have intrinsic membrane properties that lead to spontaneous pacemaker-like firing activity. The remaining HH neurons are large cells with pleomorphic, often pyramidal, soma and dendrites that are more likely to be branched and have spines. These neurons appear to be excitatory, projection-type neurons, and have the functionally immature behavior of depolarizing and firing in response to GABA ligands. We hypothesize that the irregular neuronal clusters are the functional unit for ictogenesis. Further research to define and characterize these local networks is required to fully understand the cellular mechanisms responsible for gelastic seizures. PMID- 28591481 TI - Achieving a cure for hypothalamic hamartomas: a Sisyphean quest? PMID- 28591480 TI - Laser interstitial thermal therapy: A first line treatment for seizures due to hypothalamic hamartoma? AB - Successful treatment of hypothalamic hamartoma (HH) can result in the resolution of its sequelae including epilepsy and rage attacks. Risks and morbidity of open surgical management of this lesion have motivated the development of laser interstitial thermal therapy (LITT) as a less invasive treatment approach to the disease. Although overall morbidity and risk would appear to be lower, complications related to LITT therapy have been reported, and the longer-term follow-up that is now possible after initial experience helps address the question of whether LITT provides equivalent efficacy compared to other treatment options. We conducted a retrospective analysis of clinical outcomes in eight patients undergoing LITT for HH at our center using the Visualase/Medtronic device. Five patients had refractory epilepsy, one had rage attacks, and two had both. We also compared the published seizure-free outcomes over time and the complication rates for different interventional approaches to the treatment of epilepsy due to HH including open craniotomy, neuroendoscopic, radiosurgical, and radiofrequency approaches. With a mean follow-up of 19.1 months in our series of eight patients, six of seven epilepsy patients achieved seizure freedom, whereas the one patient with rage attacks only did not have improvement of his symptoms. A length of hospital stay of 2.6 days reflects low morbidity and rapid postoperative recuperation with LITT. Considering other reported series and case reports, the overall published seizure freedom rate of 21 of 25 patients is superior to published outcomes of HH cases treated by stereotactic radiosurgery (SRS), craniotomy, or neuroendoscopy, and comparable to radiofrequency ablation. The cumulative experience of our center with other published series supports relatively lower operative morbidity than more invasive approaches and efficacy that is as good or better than open craniotomy procedures and SRS. Although morbidity appears to be lower than other open approaches, complications related to LITT and their avoidance should be considered carefully. PMID- 28591482 TI - Hypothalamic hamartoma: Epileptogenesis beyond the lesion? AB - The discovery of intrinsic epileptogenicity of the hypothalamic hamartoma (HH) marked a new area in understanding the associated clinical syndrome, often manifesting as progressive epileptic encephalopathy. However, therapeutic procedures targeting the HH proved to be inefficient to cure seizures in up to 50% of cases, whereas in cases with partial improvement, the electroclinical patterns of persisting seizures suggest an involvement of distant cortical regions. The concept of kindling-like secondary epileptogenesis has been suggested as a possible underlying mechanism. Yet the role of the hypothalamic lesion in the pathophysiology of the syndrome remains debatable. In the Strasbourg-Kork series, the best outcomes were obtained when the duration of epilepsy before endoscopic HH surgery did not exceed 10 years. In two patients with HH ablation followed at a later time by a temporal lobectomy, only this second surgical step allowed complete seizure freedom. These findings suggest the existence of an independent, third stage of secondary epileptogenesis in human. In the Grenoble series, stereotactic intracerebral recordings (stereo electroencephalography [SEEG]) of five HH cases demonstrated that gelastic/dacrystic seizures were correlated with discharges within the HH, whereas other seizure types were related to discharges affecting cortical regions, which sometimes seemed to be triggered by HH. In the Marseille series, two cases explored by SEEG provided evidence of extended epileptogenicity outside the limits of the HH, forming complex epileptogenic networks, with HH still triggering clusters of neocortical seizures in the first, but not obligatory involved in spontaneous seizures in the second case. Taken together, our data argue for the existence of dynamic ictal network organization, with possible "kindling-like" relationships between the HH and the neocortex or widespread epileptogenesis. Despite the existence of secondary epileptogenesis, the epileptogenic zone could still be limited to the hamartoma, for which early surgical treatment should be pragmatically considered as a first surgical step. PMID- 28591479 TI - Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity. AB - The most common, and usually the only, endocrine disturbance in patients with hypothalamic hamartoma (HH) and epilepsy is central precocious puberty (CPP). The mechanism for CPP associated with HH may relate to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) from the HH, but this remains an unproven hypothesis. Possible regulators of GnRH release that are intrinsic to HH tissue include the following: (1) glial factors (such as transforming growth factor alpha[TGFalpha) and (2) gamma-aminobutyric acid (GABA) mediated excitation. Both are known to be present in surgically-resected HH tissue, but are present in patients with and without a history of CPP, suggesting the possibility that symptoms related to HH are directly associated with the region of anatomic attachment of the HH to the hypothalamus, which determines functional network connections, rather than to differences in HH tissue expression or pathophysiology. CPP associated with HH presents with isosexual development prior to the age of 8 years in girls and 9 years in boys. It is not uncommon for CPP with HH to present in children at an earlier age in comparison to other causes of CPP, including in infancy. Surgical resection of the HH can be effective for treating CPP, but is reserved for patients with intractable epilepsy, since GnRH agonists are widely available and effective treatment. Other endocrine disturbances with HH are rare, but can include growth hormone deficiency, hypothyroidism, and adrenal insufficiency. Diabetes insipidus is commonly encountered postoperatively, but is not observed with HH prior to surgical intervention. PMID- 28591483 TI - Cognition in epilepsy patients with hypothalamic hamartomas. AB - Many patients with epilepsy caused by hypothalamic hamartomas (HHs) have cognitive impairments during the course of the disease or following neurosurgical treatment. The purpose of this study was to assess cognitive function in these patients, as well as factors influencing preoperative cognitive performance and cognitive outcome after neurosurgical treatment. Using the two largest and most detailed neuropsychology datasets on HH and epilepsy from two centers, we retrospectively report on cognitive functions in 48 patients with structural epilepsy due to HH (mean age +/- standard deviation [SD] 20 +/- 12 years, range 5 53 years, median 16 years; disease duration mean 17 +/- 11 years). Intelligence, verbal learning and recall, and speed and executive functions (processing speed and cognitive flexibility) were assessed before and on average 19 (+/-11) months after surgery (interstitial radiosurgery: N = 22; neurosurgical resection/disconnection: N = 26). Prior to neurosurgical treatment, 52% of patients showed impaired executive and 62% showed reduced verbal memory functions. A trend for a detrimental effect of higher drug load on cognitive functioning was found. After neurosurgical treatment, intellectual functions for the entire cohort tended to increase. This correlated with improved seizure frequency and decreased number of antiepileptic drugs (AEDs). However, postoperative outcomes for individual patients were highly variable, with significant deteriorations in 17% (processing speed) to 34% (cognitive flexibility and verbal learning), and performance increases in 17% (intellectual functioning) up to 39% (processing speed) of the patients. Higher levels of presurgical performance were significant predictors of cognitive decline after surgery. These results are highly relevant for patient consultation and may help with therapeutic decisions. PMID- 28591484 TI - Safety and efficacy of Gamma Knife radiosurgery in hypothalamic hamartomas with severe epilepsies: A prospective trial in 48 patients and review of the literature. AB - Epilepsies associated with hypothalamic hamartomas (HHs) are frequently drug resistant with severe psychiatric and cognitive comorbidities. We performed a prospective trial to evaluate the safety and efficacy of Gamma Knife radiosurgery (GKS). Between October 1999 and October 2007, a total of 57 patients were investigated, included and treated by GKS in Timone University Hospital. Preoperative workup and 3-year postoperative evaluation consisted of seizure diary, neuropsychological, psychiatric, endocrinologic, visual field, and visual acuity examinations. Follow-up of >3 years was available for 48 patients. Topologic type was type I in 11 patients, type II in 15, type III in 17, type IV in one, type V in one, type VI in one, and mixed type in 2. The median marginal dose was 17 Gy (min 14 and max 25 Gy). The median target volume was 398 mm3 (28 1,600 mm3 ). Due to partial results, 28 patients (58.3%) required a second treatment. The median follow-up was 71 months (36-153 months). At last follow-up, the rate of Engel class I outcome was 39.6%, Engel class II was 29.2% (I+II 68.8%), and Engel class III was 20%. Global psychiatric comorbidity was considered cured in 28%, improved in 56%, stable in 8%, and continued to worsen in 8%. No permanent neurologic side effect was reported (in particular, no memory deficit). Nondisabling transient poikilothermia was observed in three patients (6.2%). A transient increase of seizure frequency was reported in 8 patients (16.6%) with a median duration of 30 days (9-90 days). Microsurgery was proposed because of insufficient efficacy of GKS in seven patients (14.5%) with a postoperative Engel class I-II in 28.6%. This prospective trial demonstrates very good long-term safety and efficacy of GKS for 2 patients. Beyond seizure reduction, the improvement of psychiatric and cognitive comorbidities along with better school performance and social functioning, being better socially integrated, having friends having a social life, working, participating to group activities turn out to be major benefits of GKS in this group of patients with frequently catastrophic epilepsy. PMID- 28591485 TI - Medical management and antiepileptic drugs in hypothalamic hamartoma. AB - Hypothalamic hamartoma may present with epilepsy, specifically gelastic or dacrystic seizures, or endocrine dysfunction, commonly precocious puberty. The epilepsy in many patients is drug resistant, and has a high association with progressive cognitive, learning and behavioral difficulty. Medical treatment of seizures remains problematic, with many resistant to drug treatment. Surgical resection, or disconnection of the hamartoma provides the optimal chance of seizure control but with a relatively high risk of endocrine dysfunction, the result of interference with the hypothalamic-pituitary axis in many. Careful assessment and monitoring by specialist centers with discussion of optimal intervention is required for individual cases. PMID- 28591486 TI - Computational Fluid Dynamic Analysis of the Hemodialysis Plastic Cannula. AB - The jet of fluid returning to the patient through a hemodialysis venous needle has previously been reported as a potential source of endothelial damage which can lead to intimal hyperplasia (IH) in arteriovenous fistulae (AVF). Metal needles are the current standard practice for accessing the vascular system in hemodialysis. However, plastic cannulae have been used in Japan for 30 years. This study utilized computational fluid dynamics to analyze the hemodynamics of blood exiting a plastic cannula and determined the optimal placement and blood flow rate. Transient simulations were run using a 15G Argyle Safety Fistula Cannula with Anti-Reflux Valve inserted into an idealized cephalic vein. The cannula tip was fixed at three different locations within the vein (upper third, middle, and lower third) with blood flow rates of 200 mL/min, 300 mL/min, and 400 mL/min imposed. The high degree of jet break down immediately after exiting the cannula was attributed to the staggered side hole arrangement, position of the cannula in the vein, and the imposed blood flow rate. Elevated levels of wall shear stress which may lead to IH were identified at the site of jet impingement on the vein floor as well as regions of high residency time. The risk of IH may be minimized by enhancing the breakdown of the jet through the use of optimal blood flow rates between 300 and 400 mL/min and ensuring the cannula tip is placed away from the walls of the vein. PMID- 28591488 TI - Salvage of fetal karyotype information from SNP array data obtained from products of conception with maternal cell contamination. AB - OBJECTIVE: Maternal cell contamination (MCC) is known to increase the risk of misdiagnosis in prenatal diagnosis as well as in diagnostic tests for the products of conception (POC) from miscarriages. We aimed to develop a data correction method to salvage fetal karyotype information from single-nucleotide polymorphism (SNP) array data for POC with MCC when parental genotype data are available. METHODS: We obtained SNP array data from mixed genomic DNAs of a mother-child pair and used the dataset to assess the accuracy of data correction. We subsequently applied our method to miscarriage specimens with MCC. RESULTS: We adopted a linear interpolation model as a data correction method and implemented the method in an R package, snpsal. We successfully determined the fetal karyotypes of two miscarriage specimens that were previously undiagnosed due to MCC to be normal in one case and trisomy 16 in the other case using snpsal. CONCLUSION: The R package, snpsal, developed in this study facilitates rapid and accurate estimation of the fetal karyotype from SNP array data for POC with MCC. (c) 2017 John Wiley & Sons, Ltd. PMID- 28591487 TI - Deciphering the Nature of Enzymatic Modifications of Bacterial Cell Walls. AB - The major constituent of bacterial cell walls is peptidoglycan, which, in its crosslinked form, is a polymer of considerable complexity that encases the entire bacterium. A functional cell wall is indispensable for survival of the organism. There are several dozen enzymes that assemble and disassemble the peptidoglycan dynamically within each bacterial generation. Understanding of the nature of these transformations is critical knowledge for these events. Octasaccharide peptidoglycans were prepared and studied with seven recombinant cell-wall-active enzymes (SltB1, MltB, RlpA, mutanolysin, AmpDh2, AmpDh3, and PBP5). With the use of highly sensitive mass spectrometry methods, we described the breadth of reactions that these enzymes catalyzed with peptidoglycan and shed light on the nature of the cell wall alteration performed by these enzymes. The enzymes exhibit broadly distinct preferences for their substrate peptidoglycans in the reactions that they catalyze. PMID- 28591489 TI - Association of microalbuminuria with diabetes is stronger in people with prehypertension compared to those with ideal blood pressure. AB - AIM: Microalbuminuria (MA) has been demonstrated as a biomarker for microvascular dysfunction. This study is aimed to evaluate the association of glycaemic status with MA in prehypertensive and ideal BP subjects and to evaluate the interaction between glycaemic and blood pressure status as risk factors for MA prevalence. METHODS: 1059 subjects aged 40-70 with non-hypertension who were recruited from six districts of Tianjin were divided into a prehypertensive group (622 cases) and an ideal blood BP group (437 cases). Subjects of the prehypertensive group and the ideal BP group were divided respectively into three subgroups: normoglycaemia subgroup, prediabetes subgroup and diabetes subgroup. The prevalence of MA in the above three subgroups of subjects with prehypertension and ideal BP were assessed. We performed a statistical analysis for interaction test between glycaemia and BP status on microalbuminuria in the overall study sample by a multivariate logistic regression model. The association of glycaemic status (defined as normoglycaemia, prediabetes, and diabetes) with MA was evaluated separately in prehypertensive and ideal BP subjects. RESULTS: Results showed that the prevalence of MA in both prehypertensive and ideal BP groups rose with the increasing of classification of glycaemic level of subgroups (32.6%, 18.3%, 14.8% vs. 23.1%, 16.2%, 13.4%), the differences in prehypertensive group were statistically significant (Pearson chi2 = 15.24, P < 0.001). The ORs (95% CI) of MA were 1.25 (0.86-1.83) for prediabetes and 2.56 (1.62-4.03) for diabetes in the fully adjusted model. There was no interaction between prediabetes and BP status regarding MA (P = 0.237) but we found a significant interaction between diabetes and BP status (P < 0.001). In the prehypertensive group, multivariate logistic regression models showed that the diabetes subgroup had a significant association with MA, and the adjusted odds ratio of the diabetes subgroup to the normoglycaemia subgroup was 2.68 (95%CI 1.54-4.67) (P < 0.001). However, there was no significant association of glycaemic status with MA in the ideal BP group. Stratified analysis by a multivariate logistic regression model in the whole study population showed that people with both prehypertension and diabetes had the highest risk of MA (adjusted OR = 2.50, 95%CI 1.16-5.36; P = 0.019), compared with those with ideal BP and normoglycaemia (reference group). CONCLUSIONS: Our findings suggest that there was a statistically significant association between diabetes and microalbuminuria only in prehypertensive subjects. In addition, our study highlights the interaction between prehypertension and diabetes as a risk factor for MA. PMID- 28591490 TI - Region-specific atrophy of precentral gyrus in patients with amyotrophic lateral sclerosis. AB - PURPOSE: To assess the region-specific atrophy of precentral gyrus (PrCG) and its correlation to clinical function score in amyotrophic lateral sclerosis (ALS). MATERIALS AND METHODS: Twenty-eight patients with sporadic ALS and 28 healthy controls underwent high-resolution 3D T1-BRAVO magnetic resonance imaging at 3T. The bilateral PrCG segmentations were automatically obtained from a validated segmentation pipeline based on diffeomorphic multi-atlas likelihood fusion. Patients with ALS were further subclassified into early-stage (ALS-e, n = 22) and late-stage (ALS-l, n = 6) groups, with 12 months as a disease duration cutoff. Vertex-based shape analysis was performed to quantify the region-specific abnormalities of PrCG in ALS subgroups as compared to controls. In addition, we tested the statistical association between altered PrCG morphometry and clinical disability in ALS as evaluated by the revised ALS Functional Rating Scale (ALSFRS r). RESULTS: Compared to controls, vertex-wise analysis showed that both ALS-e and ALS-l had significant atrophy of the dorsal-lateral part of PrCG (P < 0.05, uncorrected). Importantly, atrophy in ALS-e was not as widespread as that in ALS l; while atrophy in ALS-e was mostly confined to the dorsal-lateral region (P < 0.05, uncorrected, surface areas exhibiting significant difference at a level of P = 0.05: left 613.88 mm2 , right 937.80 mm2 ), atrophy in ALS-l occurred at the dorsal-medial and ventral region as well (P < 0.05, uncorrected, surface areas exhibiting significant difference at a level of P = 0.05: left 1465.98 mm2 , right 1253.89 mm2 ). Partial correlation analysis showed that the significant surface area atrophy of PrCG in ALS, especially that of the dorsal-lateral portion, was found to link tightly with ALSFRS-r (P < 0.05, uncorrected, surface areas exhibiting significant correlation: left 723.08 mm2 , right 474.24 mm2 ). CONCLUSION: Our findings suggest that an altered PrCG morphometry, especially atrophy of the surface area in the dorsal-lateral portion, may be associated with the dysfunction that characterizes ALS. This study is an initial attempt to apply a validated statistical shape analysis pipeline to cortical gray matter structure like PrCG. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2018;47:115-122. PMID- 28591492 TI - [Ethics and methodology: the importance of promoting, evaluating and implementing education and humanities research in health]. AB - In this editorial we initially expose the agreements that have set the mechanisms to guarantee safety and fair treatment to human subjects in research. Later on, we offer alternatives from translational and multidisciplinary research to promote education and humanities research in health. PMID- 28591493 TI - [Perception of quality of life related with health and depression in patients with hemophilia]. AB - BACKGROUND: Hemophilia is a hemorrhagic disease characterized by the deficiency of either coagulation factor VIII or IX. It impacts negatively in people's quality of life and it causes side effects, such as depression. The objective was to describe and analyze the health-related quality of life (HRQoL) and depression levels in a group of 50 pediatric patients with hemophilia (PPwH) and their parents. The specific objectives were: to analyze the correlation between HRQoL levels reported by patients and their parents, and to analyze the correlation between HRQoL levels and depression in PPwH. METHODS: Descriptive, cross sectional and correlational study with a group of 50 PPwH and their parents. The Pediatric Life Quality Questionnaire [PedsQLTM 4.0] was completed by PPwH and their parents and the Children's Depression Inventory (CDI) was answered only by PPwH. RESULTS: The average age of PPwH was 10.66 years (SD = 2.61) and that of parents was 36.28 years (SD = 6.4). 82% suffered from hemophilia A and 70% suffered from severe hemophilia. 78% of participants felt at risk or at high risk with regards to their quality of life, and, concerning their depression levels, we found moderate symptoms in 54% and severe symptoms in 10%. CONCLUSIONS: The HRQoL and depression levels we found are alarming. They show the importance of evaluating objective and subjective indicators; in addition, we emphasize the need of assisting the severe cases detected and suggest the activities to face these health issues. PMID- 28591494 TI - [Sepsis: the hidden enemy between the lines]. PMID- 28591495 TI - [Risk factors associated with preterm birth in a second level hospital]. AB - BACKGROUND: Preterm birth is one of the biggest problems in obstetrics and gynecology, given that it has an incidence of 10-11%. The objective was to identify the risk factors associated with a preterm birth. METHODS: A retrospective, observational, transversal and analytic case-control study was made. All premature birth incidences were determined as study objects and controls were integrated with term deliveries. A sample size of 344 patients with a control per case was calculated. A total of 688 patients were studied. Statistical analysis was descriptive, univariate and bivariate and we used the Pearson chi square test, with a p < 0.05, odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: The risk factors associated with a preterm labor were placenta praevia: OR = 10.2 (p = 0.005); previous preterm delivery: OR = 10.2 (p = 0.005); preeclampsia: OR = 6.38 (p = 0.00); twin pregnancy: OR = 5.8 (p = 0.000); oligohydramnios: OR = 5.8 (p = 0.000); tobacco use: OR = 4.6 (p = 0.002); premature rupture of membranes (PROM): OR = 4.1 (p = 0.000); cervicovaginitis: OR = 3 (p = 0.000); urinary tract infections (UTI): OR = 1.5 (p = 0.010). CONCLUSION: Maternal history of prenatal care, preclampsia, PROM, twin pregnancy, placenta praevia, cervicovaginitis, previous preterm delivery and UTI are risk factors with statistical significance associated with preterm delivery. PMID- 28591496 TI - [Answer to comment "Sepsis: The hidden enemy between the lines"]. PMID- 28591497 TI - [ANCA-associated vasculitides at Mexico City's metropolitan Eastern area]. AB - BACKGROUND: The anti-neutrophil cytoplasmic antibody-associated (ANCA) vasculitides includes granulomatosis with polyangiitis (Wegener's) (GPW), Chrug Strauss syndrome (CSS) and microscopic polyangiitis (MPA). Since it has low incidence in our field, there are a few published papers. The aim of this study was to report the clinical characteristics, activity and damage of these vasculitides in Mexico City's metropolitan eastern area. METHODS: We studied 28 cases with ANCA-associated vasculitis in the aforementioned area. The classification was made according to the ACR 1990 criteria, the Chapel Hill 2012 consensus, and the EULAR 2007 recommendations. We collected demographic data, as well as data of clinical manifestations, laboratory, management and outcomes. The activity was established using the Birmingham Vasculitis Activity Score (BVAS) and the damage using the Vasculitis Damage Index (VDI). We used paired t test and 95% confidence intervals (95% CI). RESULTS: 15 females and 13 males were included, 20 with GPW and 8 with CCS. The mean age was 50.1 +/- 12.7 years, and the evolution time was 69 +/- 49.6 months. We didn't find cases of MAP. 23 patients (82.1%) had general symptoms. The initial and final BVAS means were 10.5 and 1.5 (p < 0.001) and the global VDI was 2.4. CONCLUSIONS: The presence of ANCA associated vasculitides is rare in the eastern Metropolitan area of Mexico City. GPW was predominant over CCS, and MPA was absent. They are multi-system vasculitides with high scores of initial activity and moderate damage. PMID- 28591498 TI - [Methodologies for estimating the indirect costs of traffic accidents]. AB - BACKGROUND: Traffic accidents generate multiple costs to society, including those associated with the loss of productivity. However, there is no consensus about the most appropriate methodology for estimating those costs. The aim of this study was to review methods for estimating indirect costs applied in crash cost studies. METHODS: A thematic review of the literature was carried out between 1995 and 2012 in PubMed with the terms cost of illness, indirect cost, road traffic injuries, productivity loss. RESULTS: For the assessment of costs we used the the human capital method, on the basis of the wage-income lost during the time of treatment and recovery of patients and caregivers. In the case of premature death or total disability, the discount rate was applied to obtain the present value of lost future earnings. The computed years arose by subtracting to life expectancy at birth the average age of those affected who are not incorporated into the economically active life. CONCLUSIONS: The interest in minimizing the problem is reflected in the evolution of the implemented methodologies. We expect that this review is useful to estimate efficiently the real indirect costs of traffic accidents. PMID- 28591499 TI - [Dienogest usefulness in pelvic pain due to endometriosis. A meta-analysis of its effectiveness]. AB - BACKGROUND: Endometriosis is the presence of functional endometrial tissue in the pelvic peritoneum and it affects several age groups. That is why the impact of endometriosis in quality of life is considerable. The objective of this study was to evaluate the effectiveness of dienogest in patients with pelvic pain associated to endometriosis (PPAE). METHODS: The evaluation of the effectiveness was carried out through a systematic review using the Cochrane methodology. It was used Markov model, which considers two states of health (with and without PPAE), with the possibility of weekly transition. Women between 18 and 45 years with PPAE were included, in a temporary horizon of 26 weeks. A level of statistical significance of 95% was used for a p < 0.05, with a multivariate probabilistic analysis of sensibility, as well as a univariate analysis of sensibility in several scenarios. RESULTS: The probability that the female patient did not experience PPAE with the initial treatment was 87.91% with dienogest, 80.07% with danazol, 84.93% with medroxyprogesterone (injectable and oral) and 89.17% with gosereline. The probability that the female patient abandoned her initial treatment was 9% with dienogest, 12.07% with danazol, 9.6 and 6.75% with medroxyprogesterone injectable and oral, respectively, and 10.8 and 3.6% 3-monthly and monthly with gosereline. CONCLUSION: Compared to danazol, medroxiprogesterone and gosereline, dienogest is the most efficient alternative to treat PPAE. PMID- 28591500 TI - [Optimism, family cohesion and treatment as predictors of quality of life in blood cancer diseases]. AB - BACKGROUND: Quality of life must be a part of the goals of care given to blood cancer patients and it must be used to assess the effectiveness of their treatment. The objective was to evaluate the quality of life of patients with leukemia and its relationship with psychological, familial and disease-related aspects. METHODS: An analytic cross-sectional study was carried out in patients with acute leukemia at different stages of treatment. We used SF-36, Optimism and Family Cohesion scales. RESULTS: Quality of life was affected physically and mentally in the treatment phases aimed to mitigate the active, and the advanced stage of this disease (50.6 +/- 25.6, 62 +/- 14.3; 46 +/- 23.2, 53.8 +/- 23.4, respectively), regardless of gender, age, level of optimism and family cohesion. Patients could carry out basic functions of self-care (bathing, feeding, etcetera), but not activities of daily living (shopping, household chores, etcetera), which require a greater effort. Although the patients perceived having been affected in the emotional health area-by the presence of anxiety and depression-they did not consider that these alterations limited their ability to carry out work and everyday activities. CONCLUSIONS: Quality of life was most affected at mental dimension and physical dimension, mainly in patients at induction and palliative treatment. The results showed that the objectives of care aimed to reduce symptoms and maintain patient comfort are not achieved. PMID- 28591501 TI - [Implementation of a clinical prediction tool in renal transplant recipients]. AB - BACKGROUND: Kasiske developed a tool for predicting the risk of 5-year graft loss. We analyzed our results using this model. METHODS: 109 deceased donor kidney transplants were included. 5-year probability of graft survival was calculated during transplantation, seven days after transplantation and 1-year after transplantation. Z-test and ROC curves were used for proportion differences and discrimination ability. RESULTS: Mean age of donor and recipient was 33.7 and 33.9 years, respectively. 59.6% died due to trauma. Mean of years on dialysis was 3.7. 22.9% of patients had delayed graft function (DGF). Calculated 5-year probability of graft survival during transplantation time was 74.1%; 7 days after transplantation, 74.9%; and one year after transplantation, 76.4%. 5-year death censored graft survival was 64.9%. There were no differences between death censored graft survival and calculated probabilities (Z-test), with a C-statistic value of 0.54 +/- 0.6 (95%CI 0.42-0.65, p = 0.5) and 0.51 +/- 0.6 (0.39-0.63, 95% CI, p = 0. 7) for transplant time and seven days after. C-statistic value 1-year after transplantation was 0.68 +/- 0.8 (95%CI 0.52-0.84, p = 0.02). CONCLUSION: Only calculated 5-year graft survival one year after transplantation had modest prediction ability. PMID- 28591502 TI - [Factors associated with physical activity and body mass index among schoolchildren from Arandas, Jalisco, Mexico]. AB - BACKGROUND: In 2015, Mexico was the top country for childhood obesity. The objective was to identify the association between physical activity and sedentary lifestyle with the social and demographic characteristics of families of schoolchildren in Arandas, Jalisco, Mexico. METHODS: In a cross-sectional study, 192 schoolchildren were randomly selected. Body mass index (BMI), active and sedentary behaviors, and socio-demographic characteristics of families were obtained. Logistic regression models with the included variables were constructed. RESULTS: Males living in not-crowding houses [OR 6.12 (2.17-17.25), p = 0.001], whose mothers were housewives [OR 2.44 (1.00, 5.94), p = 0.05], practiced more physical activity. Active transport to school was more common in schoolchildren whose fathers had lower income [OR 3.13 (1.27, 7.7), p = 0.013] and employment as peasant or mason [OR 5.12 (1.13, 23.3), p = 0.034]. Schoolchildren of nuclear families spent more hours watching television [OR 2.69 (1.10, 6.58), p = 0.03]. The frequency of outdoor playing was higher in males whose fathers had unstable employment [OR 2.93 (1.06, 8.1), p = 0.038] and low education [OR 2.94 (0.96, 8.98), p = 0.059]. CONCLUSION: Families with lower socioeconomic strata (less educated parents, unstable employment and family overcrowding) are more associated with active activities that do not require active economic spending. PMID- 28591503 TI - [Cytogenetics of myelodysplastic syndromes and its impact as prognostic factor]. AB - Myelodysplastic syndromes (MDS) are a group of disorders of the hematopoietic stem cell. They are characterized by cytopenia(s), dysplasia of one or more cell lines, ineffective hematopoiesis, and an increased risk for developing acute myelogenous leukemia. The classification of MDS has been complicated due to the great heterogeneity in clinical phenotype as well as in the morphological and cytogenetic characteristics. The prognostic value of cytogenetic abnormalities in MDS has been analyzed in multicenter studies. This approach raised the development of the revised International Prognostic Scoring System (IPSS-R), which analyzes five prognostic variables, among which the cytogenetic study stands out. According to the cytogenetic findings, a classification of MDS in five subgroups was developed. Knowledge of the cytogenetic abnormalities has led to the study of genes involved in various chromosomal rearrangements. Moreover, DNA sequencing has helped to identify mutations in approximately 50 genes related to signal transduction, DNA methylation, transcriptional regulation, and RNA splicing. Therefore, the cytogenetic study should be used to improve the classification and therapeutic management of MDS. This approach will be an essential tool for the development of targeted therapy protocols. PMID- 28591504 TI - [Cellular senescence as a common denominator in age-related diseases]. AB - Cellular senescence has been traditionally characterized by cell cycle arrest of pot-mitotic cells as a response to a cellular damage. Now is known that senescent cells secret a diverse array of cytokines, chemokines, growth factors and other that altogether are called senescence associates secretory phenotype (SASP), which might have beneficial or deleterious effects on neighbor cells. This review describes those effects as well as the relationship between the SASP and several age related diseases. We also analyze the direction that recent investigations are turning in order to modulate or avoid the effect of the SASP in those pathologies. PMID- 28591505 TI - [The ENARM and the schools and faculties of medicine. An analysis that nobody will like]. AB - In Mexico, the career of Doctor of Medicine has been considered as a prerequisite stage to access the specialization. Of course the majority of medical graduates aspire to undertake postgraduate courses in the different institutions that have a university program. The Examen Nacional de Aspirantes a Residencias Medicas (ENARM) (National Evaluation for Medical Residency Applicants) has become for the supporters a gap between the possibility of practicing the profession in a decent way and with a regular remuneration or exercising it in very limited conditions and with low economic income or even without exercising it. For educational institutions, the ENARM and the percentages of selection of their graduates are indicators of efficiency and a source of prestige and even of propaganda among the aspirants to study medicine. In this study, we carried out an analysis of the results of the ENARM in the last 15 years. For this we refer to the reports of the Postgraduate and Continuing Education Committee of the CIFRHS of the Directorate of Health Education of the General Directorate of Quality and Health Education Of the Undersecretariat of Innovation and Quality of the Ministry of Health, from the examination carried out in 2001 to the one carried out in 2016. PMID- 28591506 TI - [Persists the controversy concerning the rutinary use of diagnostic tests in asymptomatic persons]. AB - Currently, in medicine there is an environment replete with controversy and debate, partially due to the popular concept Evidence-Based Medicine, and to the development of technological advances and, apparently, better therapeutic resources. This has led to the establishment of an over-diagnosis epidemic and to an excess of therapeutic interventions, which do not necessarily lead to a longer life expectancy. Some medical controversies, which have called the attention of physicians and even of common people are those related with dislipoproteinemias, pre-diabetes and detection of cancer in asymptomatic persons. The debate and the controversy will surely continue and that is why it is very important to emphasize that clinical practice should be personalized, taking into account risks and implied benefits. PMID- 28591507 TI - [Regarding surface ablation as an ethically superior option when compared to LASIK: primum non nocere]. AB - Refractive surgery is an extremely safe surgical intervention, with excellent profiles of clinical improvement and satisfaction. The ethical responsibility of the refractive surgeon is to look for diminishing the patients' exposure to unnecessary risks. Therefore, surface ablation would be a preferable option over LASIK as the former has a better safety profile than the latter, without compromising final visual acuity. Ethically, surface ablation should be considered as the first choice in those patients undergoing Excimer laser refractive surgery. PMID- 28591508 TI - [Considerations concerning medical knowledge inherited in Mexico from 19th century: the diabetes mellitus case]. AB - In Mexico, as in the entire Western world, during the 19th century and the beginnings of the 20th century, medical knowledge developed in a remarkable way and the case of diabetes mellitus was not the exception. This situation, which arose on the basis of the antique paradigm, and which in turn was overthrown by the positivism as the emergent paradigm (with its clinical and anatomical, as well as physiopathological and etiopathological viewpoints), was reflected during the 19th the century through its actors and the communications that opened the access of Mexican medicine to the modernity. PMID- 28591510 TI - [Overlap syndrome. LEOPARD and neurofibromatosis. A case report]. AB - We expose a clinical case of a 43-year-old patient who was attended at the Dermatology service in a general hospital of the Instituto Mexicano del Seguro Social, with a disseminated pattern of lentigines, psychomotor retardation and electrocardiographic abnormalities. Afterwards, we made an analysis of the literature. PMID- 28591509 TI - [Double pneumotorax secondary to single proyectile weapon: One case report and review of literature]. AB - BACKGROUND: The 25% of traumatic deaths are due to chest trauma with a mortality of 28%, and closed trauma is the most common mechanism of injury. The use of firearms increases the relative risk of death. The five more frequent specific chest injuries are lung contusion (31.8%), hemothorax/pneumothorax (19.4%), rib fractures (13.2%), and diaphragmatic injury (7.5%). CLINICAL CASE: Patient of 25 years with a single firearm projectile wound in the chest who assisted to the emergency room (ER) with significant respiratory distress and meriting surgical emergency airway, documenting double pneumothorax, aortic laceration and rupture of the trachea, which required management in the ER with bilateral chest tube placement and subsequent surgical repair. CONCLUSION: Anatomical and pathophysiological knowledge and the standardized management of the international guidelines are the key to keep a high level of suspect with a patient with chest penetrating trauma. Besides they improve the possibility of diagnosis and timely treatment. PMID- 28591511 TI - Electrodeposition of Amorphous Molybdenum Chalcogenides from Ionic Liquids and Their Activity for the Hydrogen Evolution Reaction. AB - This work reports on the general electrodeposition mechanism of tetrachalcogenmetallates from 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide. Both tetrathio- and tetraselenomolybdate underwent anodic electrodeposition and cathodic corrosion reactions as determined by UV-vis spectroelectrochemistry. Electrodeposition was carried out by cycling the potential between the anodic and cathodic regimes. This resulted in a film of densely packed nanoparticles of amorphous MoSx or MoSex as determined by SEM, Raman, and XPS. The films were shown to have high activity for the hydrogen evolution reaction. The onset potential (J = 1 mA/cm2) of the MoSx film was E = 0.208 V vs RHE, and that of MoSex was E = -0.230 V vs RHE. The Tafel slope of MoSx was 42 mV/decade, and that of MoSex was 59 mV/decade. PMID- 28591512 TI - Discovery of a Highly Selective Tankyrase Inhibitor Displaying Growth Inhibition Effects against a Diverse Range of Tumor Derived Cell Lines. AB - The availability of high quality probes for specific protein targets is fundamental to the investigation of their function and their validation as therapeutic targets. We report the utilization of a dedicated chemoproteomic assay platform combining affinity enrichment technology with high-resolution protein mass spectrometry to the discovery of a novel nicotinamide isoster, the tetrazoloquinoxaline 41, a highly potent and selective tankyrase inhibitor. We also describe the use of 41 to investigate the biology of tankyrase, revealing the compound induced growth inhibition of a number of tumor derived cell lines, demonstrating the potential of tankyrase inhibitors in oncology. PMID- 28591514 TI - Elastin-like Polypeptide Linkers for Single-Molecule Force Spectroscopy. AB - Single-molecule force spectroscopy (SMFS) is by now well established as a standard technique in biophysics and mechanobiology. In recent years, the technique has benefitted greatly from new approaches to bioconjugation of proteins to surfaces. Indeed, optimized immobilization strategies for biomolecules and refined purification schemes are being steadily adapted and improved, which in turn has enhanced data quality. In many previously reported SMFS studies, poly(ethylene glycol) (PEG) was used to anchor molecules of interest to surfaces and/or cantilever tips. The limitation, however, is that PEG exhibits a well-known trans-trans-gauche to all-trans transition, which results in marked deviation from standard polymer elasticity models such as the worm-like chain, particularly at elevated forces. As a result, the assignment of unfolding events to protein domains based on their corresponding amino acid chain lengths is significantly obscured. Here, we provide a solution to this problem by implementing unstructured elastin-like polypeptides as linkers to replace PEG. We investigate the suitability of tailored elastin-like polypeptides linkers and perform direct comparisons to PEG, focusing on attributes that are critical for single-molecule force experiments such as linker length, monodispersity, and bioorthogonal conjugation tags. Our results demonstrate that by avoiding the ambiguous elastic response of mixed PEG/peptide systems and instead building the molecular mechanical systems with only a single bond type with uniform elastic properties, we improve data quality and facilitate data analysis and interpretation in force spectroscopy experiments. The use of all-peptide linkers allows alternative approaches for precisely defining elastic properties of proteins linked to surfaces. PMID- 28591513 TI - Unravelling the Molecular Basis of High Affinity Nanobodies against HIV p24: In Vitro Functional, Structural, and in Silico Insights. AB - Preventing the spread of infectious diseases remains an urgent priority worldwide, and this is driving the development of advanced nanotechnology to diagnose infections at the point of care. Herein, we report the creation of a library of novel nanobody capture ligands to detect p24, one of the earliest markers of HIV infection. We demonstrate that these nanobodies, one tenth the size of conventional antibodies, exhibit high sensitivity and broad specificity to global HIV-1 subtypes. Biophysical characterization indicates strong 690 pM binding constants and fast kinetic on-rates, 1 to 2 orders of magnitude better than monoclonal antibody comparators. A crystal structure of the lead nanobody and p24 was obtained and used alongside molecular dynamics simulations to elucidate the molecular basis of these enhanced performance characteristics. They indicate that binding occurs at C-terminal helices 10 and 11 of p24, a negatively charged region of p24 complemented by the positive surface of the nanobody binding interface involving CDR1, CDR2, and CDR3 loops. Our findings have broad implications on the design of novel antibodies and a wide range of advanced biomedical applications. PMID- 28591515 TI - ROC'n'Ribo: Characterizing a Riboswitching Expression System by Modeling Single Cell Data. AB - RNA-engineered systems offer simple and versatile control over gene expression in many organisms. In particular, the design and implementation of riboswitches presents a unique opportunity to manipulate any reporter device in cis, executing tight temporal and spatial control at low metabolic costs. Assembled to higher order genetic circuits, such riboswitch-regulated devices may efficiently process logical operations. Here, we propose a hierarchical stochastic modeling approach to characterize an in silico repressor gate based on neomycin- and tetracycline sensitive riboswitches. The model was calibrated on rich, transient in vivo single-cell data to account for cell-to-cell variability. To capture the effect of this variability on gate performance we employed the well-known ROC-analysis and derived a novel performance indicator for logic gates. Introduction of such a performance measure is necessary, since we aimed to assess the correct functionality of the gate at the single-cell level-a prerequisite for its further adaption to a genetic circuitry. Our results may be applied to other genetic devices to analyze their efficiency and ensure their correct performance in the light of cell-to-cell variability. PMID- 28591516 TI - Impact of Drug-Rich Colloids of Itraconazole and HPMCAS on Membrane Flux in Vitro and Oral Bioavailability in Rats. AB - Improving the oral absorption of compounds with low aqueous solubility is a common challenge that often requires an enabling technology. Frequently, oral absorption can be improved by formulating the compound as an amorphous solid dispersion (ASD). Upon dissolution, an ASD can reach a higher concentration of unbound drug than the crystalline form, and often generates a large number of sub micrometer, rapidly dissolving drug-rich colloids. These drug-rich colloids have the potential to decrease the diffusional resistance across the unstirred water layer of the intestinal tract (UWL) by acting as rapidly diffusing shuttles for unbound drug. In a prior study utilizing a membrane flux assay, we demonstrated that, for itraconazole, increasing the concentration of drug-rich colloids increased membrane flux in vitro. In this study, we evaluate spray-dried amorphous solid dispersions (SDDs) of itraconazole with hydroxypropyl methylcellulose acetate succinate (HPMCAS) to study the impact of varying concentrations of drug-rich colloids on the oral absorption of itraconazole in rats, and to quantify their impact on in vitro flux as a function of bile salt concentration. When Sporanox and itraconazole/AFFINISOL High Productivity HPMCAS SDDs were dosed in rats, the maximum absorption rate for each formulation rank ordered with membrane flux in vitro. The relative maximum absorption rate in vivo correlated well with the in vitro flux measured in 2% SIF (26.8 mM bile acid concentration), a representative bile acid concentration for rats. In vitro it was found that as the bile salt concentration increases, the importance of colloids for improving UWL permeability is diminished. We demonstrate that drug containing micelles and colloids both contribute to aqueous boundary layer diffusion in proportion to their diffusion coefficient and drug loading. These data suggest that, for compounds with very low aqueous solubility and high epithelial permeability, designing amorphous formulations that produce colloids on dissolution may be a viable approach to improve oral bioavailability. PMID- 28591517 TI - An ATP-Responsive Codelivery System of Doxorubicin and MiR-34a To Synergistically Inhibit Cell Proliferation and Migration. AB - Establishing stimulus-responsive nanosystems for the codelivery of anticancer drug and oligonucleotide is a promising strategy in cancer treatment owing to the combination of chemotherapy and gene therapy in a synergistic manner. Herein, an ATP aptamer and its cDNA sequence were first hybridized to produce the duplex, into which chemotherapeutic agent doxorubicin (DOX) interacted through the GC rich motif of duplex, and PEI25K was then employed as a carrier to condense the DOX-loading duplex and miR-34a to construct the ternary nanocomplex PEI/DOX Duplex/miR-34a. The nanocomplex exhibited a favorable drug release profile through the response to high concentration of ATP in the cytosol. The ATP responsive delivery system was demonstrated to possess higher antiproliferative effect (cell viability of <40%) than the single cargo delivery, which could be attributed to the synergistic induction of cell apoptosis and cell cycle arrest from DOX and miR-34a. Furthermore, wound healing and Transwell assay elucidated the higher antimigration effect of ternary nanocomplex than DOX-Duplex or miR-34a delivery. Overall, the combinatorial delivery of DOX and miR-34a through an ATP responsive manner could trigger the rapid release of cargoes in the cytosol and enhance the inhibition of cell proliferation and migration through the synergistic manner of these two components. PMID- 28591518 TI - Intra-operative mapping of the atria: the first step towards individualization of atrial fibrillation therapy? AB - INTRODUCTION: Atrial fibrillation (AF), an age-related progressive disease, is becoming a worldwide epidemic with a prevalence rate of 33 million. Areas covered: In this expert review, an overview of important results obtained from previous intra-operative mapping studies is provided. In addition, our novel intra-operative high resolution mapping studies, its surgical considerations and data analyses are discussed. Furthermore, the importance of high resolution mapping studies of both sinus rhythm and AF for the development of future AF therapy is underlined by our most recent results. Expert commentary: Progression of AF is determined by the extensiveness of electropathology which is defined as conduction disorders caused by structural damage of atrial tissue. The severity of electropathology is a major determinant of therapy failure. At present, we do not have any diagnostic tool to determine the degree of electropathology in the individual patient and we can thus not select the most optimal treatment modality for the individual patient. An intra-operative, high resolution scale, epicardial mapping approach combined with quantification of electrical parameters may serve as a diagnostic tool to stage AF in the individual patient and to provide patient tailored therapy. PMID- 28591519 TI - Cyberattack on Britain's National Health Service - A Wake-up Call for Modern Medicine. PMID- 28591520 TI - Targeting Unconscionable Prescription-Drug Prices - Maryland's Anti-Price-Gouging Law. PMID- 28591521 TI - Changes in face-specific neural processing explain reduced cuteness and approachability of infants with cleft lip. AB - The current study investigated whether changes in the neural processing of faces of infants with a facial abnormality - a cleft lip - mediate effects of the cleft lip on judgments of infant cuteness and approachability. Event-related potentials (ERPs) in response to pictures of faces of healthy infants and infants with a cleft lip, and ratings of cuteness and approachability of these infant faces, were obtained from 30 females. Infants with a cleft lip were rated as less attractive (less cute and approachable) than healthy infants, and both the N170 and P2 components of the ERP were of reduced amplitude in response to pictures of infants with a cleft lip. Importantly, decreased configural processing of infant faces with a cleft lip, as evidenced by reduced N170 amplitudes, mediated the reduced attractiveness ratings for infants with a cleft lip compared to healthy infants. Our findings help elucidate the mechanisms behind the less favorable responses to infants with a cleft lip, highlighting the role of face-specific rather than domain-general neural processes. PMID- 28591522 TI - Health Effects of Dramatic Societal Events - Ramifications of the Recent Presidential Election. PMID- 28591524 TI - Pembrolizumab for Advanced Urothelial Carcinoma. PMID- 28591525 TI - Pembrolizumab for Advanced Urothelial Carcinoma. PMID- 28591526 TI - Pembrolizumab for Advanced Urothelial Carcinoma. PMID- 28591529 TI - Are Small Breast Cancers Good because They Are Small or Small because They Are Good? PMID- 28591530 TI - Tight Glycemic Control in Critically Ill Children. PMID- 28591527 TI - Case 17-2017. A 14-Year-Old Boy with Acute Fear of Choking while Swallowing. PMID- 28591523 TI - Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. AB - BACKGROUND: Sentinel-lymph-node biopsy is associated with increased melanoma specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. METHODS: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. RESULTS: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (+/ SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86+/-1.3% and 86+/-1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68+/-1.7% and 63+/-1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92+/-1.0% vs. 77+/-1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group. CONCLUSIONS: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .). PMID- 28591531 TI - Large Arachnoid Cyst. PMID- 28591532 TI - Mondor's Disease. PMID- 28591533 TI - Management of Septic Shock. PMID- 28591534 TI - The Enigma of Regional Lymph Nodes in Melanoma. PMID- 28591535 TI - Acute Lower Gastrointestinal Bleeding. PMID- 28591536 TI - Income and Cancer Overdiagnosis - When Too Much Care Is Harmful. PMID- 28591537 TI - Blinatumomab for Acute Lymphoblastic Leukemia. PMID- 28591538 TI - Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor. PMID- 28591539 TI - Data-Sharing Models. PMID- 28591540 TI - Reviving a Drug for Tuberculosis? PMID- 28591542 TI - Social Anxiety Disorder. PMID- 28591541 TI - Lithium Use in Pregnancy and the Risk of Cardiac Malformations. AB - BACKGROUND: There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein's anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited. METHODS: We conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders. RESULTS: Cardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group. CONCLUSIONS: Maternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein's anomaly; the magnitude of this effect was smaller than had been previously postulated. (Funded by the National Institute of Mental Health.). PMID- 28591544 TI - Erratum. PMID- 28591545 TI - Reply to F. Liang et al. PMID- 28591547 TI - Population estimates and characteristics of Australians potentially eligible for bariatric surgery: findings from the 2011?13 Australian Health Survey. AB - Objective The aim of the present study was to determine the potential demand for publicly and privately funded bariatric surgery in Australia.Methods Nationally representative data from the 2011-13 Australian Health Survey were used to estimate the numbers and characteristics of Australians meeting specific eligibility criteria as recommended in National Health and Medical Research Council guidelines for the management of overweight and obesity.Results Of the 3352037 adult Australians (aged 18-65 years) estimated to be obese in 2011-13, 882441 (26.3%; 95% confidence interval (CI) 23.0-29.6) were potentially eligible for bariatric surgery (accounting for 6.2% (95% CI 5.4-7.1) of the adult population aged 18-65 years (n=14122020)). Of these, 396856 (45.0%; 95% CI 40.4 49.5) had Class 3 obesity (body mass index (BMI) >=40kgm-2), 470945 (53.4%; 95% CI 49.0-57.7) had Class 2 obesity (BMI 35-39.9kgm-2) with obesity-related comorbidities or risk factors and 14640 (1.7%; 95% CI 0.6-2.7) had Class 1 obesity (BMI 30-34.9kgm-2) with poorly controlled type 2 diabetes and increased cardiovascular risk; 458869 (52.0%; 95% CI 46.4-57.6) were female, 404594 (45.8%; 95% CI 37.3-54.4) had no private health insurance and 309983 (35.1%; 95% CI 28.8 41.4) resided outside a major city.Conclusion Even if only 5% of Australian adults estimated to be eligible for bariatric surgery sought this intervention, the demand, particularly in the public health system and outside major cities, would far outstrip current capacity. Better guidance on patient prioritisation and greater resourcing of public surgery are needed.What is known about this topic? In the period 2011-13, 4million Australian adults were estimated to be obese, with obesity disproportionately more prevalent in areas of socioeconomic disadvantage. Bariatric surgery is considered to be cost-effective and the most effective treatment for adults with obesity, but is mainly privately funded in Australia (>90%), with 16650 primary privately funded procedures performed in 2015. The extent to which the supply of bariatric surgery is falling short of demand in Australia is unknown.What does this paper add? The present study provides important information for health service planners. For the first time, population estimates and characteristics of those potentially eligible for bariatric surgery in Australia have been described based on the best available evidence, using categories that best approximate the national recommended eligibility criteria.What are the implications for practitioners? Even if only 5% of those estimated to be potentially eligible for bariatric surgery in Australia sought a surgical pathway (44122 of 882441), the potential demand, particularly in the public health system and outside major cities, would still far outstrip current capacity, underscoring the immediate need for better guidance on patient prioritisation. The findings of the present study provide a strong signal that more funding of public surgery and other effective interventions to assist this population group are necessary. PMID- 28591543 TI - Influence of polyphenol-rich diet on exercise-induced immunomodulation in male endurance athletes. AB - Stress is associated with increased susceptibility to infection. We investigated if the mechanism involves immunomodulation of dendritic cells and whether this can be inhibited by a polyphenol-rich diet. Blood samples were taken from a total of 100 male endurance athletes at 5 time points around a marathon run: 4 weeks before; 1 week before; and immediately, 24 h, and 72 h after. Participants were randomized into 2 double-blinded groups. One group received a polyphenol-rich beverage during a 3-week training phase before marathon while the other group received a placebo beverage. Flow cytometric analysis of dendritic cell (DC) counts and subpopulation counts (myeloid, plasmocytoid DCs) was performed. Levels of viral antigen presenting toll-like receptor (TLR) 7 messenger RNA was measured by real-time polymerase chain reaction. Marathon running induced a significant increase of circulating myeloid DCs (0.2% vs. 0.33% of whole-blood leukocytes (wbl); p < 0.01) and a significant decrease of plasmozytoid DCs (0.12% vs. 0.03% of wbl; p < 0.01) and TLR7 expression (decline of 60%; p < 0.01). Polyphenol supplementation did not significantly affect mobilization of dendritic cells but showed beneficial effects on regeneration of TLR7 expression in wbl at 3 days postmarathon (decline of 40% vs. increase of 1000%; p < 0.05). In conclusion, physical stress affects circulating DCs, with an increase of myeloid and a decrease of plasmozytoid DCs. This may partially explain the susceptibility to viral infections after strenuous exercise. These detrimental effects are not attenuated by polyphenol supplementation. However, polyphenols support regeneration of viral antigen presenting TLR7 after strenuous exercise. PMID- 28591546 TI - Problematic Landmark Analysis Has Led to a Problematic Conclusion. PMID- 28591548 TI - UK healthcare professionals' uncertainties, barriers and facilitators to the introduction of targeted human papillomavirus vaccination for men who have sex with men. AB - BACKGROUND: Female-only human papillomavirus (HPV) vaccination will fail to protect men who have sex with men (MSM) against HPV and its sequelae (i.e. genital warts and anal cancers). In the absence of gender-neutral HPV vaccination, targeted vaccination at sexual health clinics for MSM offers a valuable preventive opportunity. This study aimed to identify sexual healthcare professionals' (HCPs) perceived barriers and facilitators for MSM-targeted HPV vaccination. METHODS: Nineteen telephone interviews with UK-based self-referred HCPs (13 doctors, three nurses, three health advisers) were conducted in October and November 2014. The interviews were recorded and transcribed verbatim. Data were analysed thematically by two researchers. RESULTS: HCPs were unsure about selection criteria, acceptable healthcare settings and the source of vaccination funding for the introduction of MSM-targeted HPV vaccination. Lack of political and public support, MSMs' limited access to HPV vaccination and disclosure of sexual orientation to HCPs, identification of eligible MSM, patients' poor HPV awareness and motivation to complete HPV vaccination were perceived as significant barriers. HCPs believed that the introduction of official guidelines on HPV vaccination for MSM, awareness campaigns and integrated clinic procedures could improve vaccination coverage. CONCLUSION: HCPs recognised a need to protect MSM against HPV. However, several challenges and obstacles associated with the introduction of MSM-targeted HPV vaccination in the UK were reported. HCPs' perspectives and concerns need to be addressed when developing policies and guidelines for a potential MSM-targeted HPV vaccination. Future research needs to examine whether negative views of HCPs towards MSM-targeted HPV vaccination are associated with lower HPV vaccine uptake and completion rates in MSM. PMID- 28591549 TI - Prevalence and correlates of condom use among sexually active men who have sex with men in the United States: findings from the National Survey of Family Growth, 2002, 2006-10 and 2011-13. AB - BACKGROUND: Men who have sex with men (MSM) are disproportionately at risk of contracting HIV and other sexually transmissible infections (STIs). Correct and consistent condom use is the most effective method to prevent HIV and other STIs among sexually active MSM. METHODS: Using data from the 2002, 2006-10, 2011-13 cycles of the National Survey of Family Growth (NSFG), the overall prevalence of condom use at last sex and by sexual risk behaviours (sex with >=2 same-sex partners, sex with >=2 opposite sex partners, sex with a person who injects drugs, sex with an HIV-positive person and exchanged sex for money or drugs) among sexually active MSM (reported oral or anal sex with a male in the preceding 12 months) was estimated. The association between condom use at last sex and demographic and sexual behaviour variables was also evaluated. RESULTS: Approximately 31% of all respondents (n=618; weighted n=1596702) reported condom use at last sex. Among MSM who reported >=1 sexual risk behaviour in the past year, prevalence of condom use at last sex ranged from 30 to 38%. After adjusting for covariates, Hispanic MSM [adjusted prevalence ratio (APR)=1.81, 95%CI=1.27 2.58] were more likely than White MSM to report condom use at last sex; MSM with a recently diagnosed STI (APR=1.71, 95%CI=1.04-2.80) were more likely than MSM without a recently diagnosed STI to report condom use at last sex; and married or cohabitating MSM (APR=0.29, 95%CI=0.13-0.66) were less likely than unmarried and not cohabitating MSM to report condom use at last sex. There was no difference in temporal trends in condom use at last sex across the three NSFG cycles [2002 (33.8%); 2006-10 (25.6%); 2011-13 (40.6%), P=0.926]. CONCLUSIONS: This study data suggest that prevalence of condom use among MSM is low, even among MSM who report sexual risk behaviours. The continued promotion of consistent condom use as an effective primary HIV/STI risk-reduction strategy is important because it mitigates HIV and STI risk and also complements the effectiveness of newer HIV prevention approaches such as pre-exposure prophylaxis. PMID- 28591550 TI - Investigation of P120catenin Expression in Human Basal Cell Carcinoma of the Skin. AB - BACKGROUND: P120(ctn) is a specific membranous adhesion protein, that maintains the stability of intercellular junctions. An altered expression of p120(ctn), either reduced in the cell membrane or increase in the cytoplasm, plays a crucial role in carcinogenesis. No research has analysed the expression of p120(ctn) in basal cell carcinoma (BCC) of the skin so far. Therefore, we immunohistochemically studied p120(ctn) in a set of cutaneous BCCs in order to determine, whether there is difference in the expression pattern related to the histologic subtypes and tumor growth characteristics. MATERIAL AND METHODS: The study group consisted of 38 BCCs cathegorized into low-risk (non-infiltrative) subroup (8 superficial and 12 nodular subtypes) and high-risk (infiltrative) subgroup (10 nodular-infiltrative and 8 infiltrative subtypes). Specific monoclonal antibody against p120(ctn) was used for staining. RESULTS: Overall, there were 12 cases (31.6%) with normal preserved and 26 cases (68.4%) with abnormal p120(ctn) expression. In superficial, nodular, nodular-infiltrative and infiltrative subtypes, abnormal p120(ctn) immunoreactivity was found in 37.5% (3/8), 41.7% (5/12), 100% (10/10) and 100% (8/8), respectively. We have confirmed a strong correlation between the expression of p120(ctn) and both given, non infiltrative and infiltrative BCC growth phenotypes. In the latter subgroup, almost all lesions showed diffusely reduced membranous staining, of which five also manifested an aberrant immunoreactivity in the cytoplasm. This cytoplasmic positivity occurred solely at the invasive front of the infiltrative tumor formations. CONCLUSION: Our results showed that decreased membranous expression of p120(ctn) was a frequent event in human cutaneous BCC and it was associated with infiltrative growth phenotype. Considering that nearly half of the BCCs with non-infiltrative growth pattern also exhibited reduced membranous expression, aberrant cytoplasmic immunoreactivity of p120(ctn), which was found exclusively in the high-risk BCC variants, can more reliably reflect and predict biological behaviour and malignant potential. PMID- 28591552 TI - Aberrant Cutaneous Nerve Loops in the Axilla. AB - During routine dissection classes, conducted for first year undergraduate medical students, we encountered a rare anatomical variation in relation to the intercostobrachial nerve (ICBN). The ICBN represents the lateral undivided cutaneous branch of second intercostal nerve. In this case, the ICBN formed nerve loops with branches of the lateral cutaneous branch of the third intercostal nerve. These loops eventually gave branches that probably supplied the floor of the axilla and proximal arm. Nowadays, this ICBN is gaining clinical importance during the axillary lymph node dissections and mammary gland surgeries. Damage to the ICBN, may results in the sensory deficits in patients undergoing surgery. In our case report, ICBN was making aberrant nerve loop along with the branches from the third intercostal nerve. Knowledge regarding the origin, formation and route of ICBN is of clinical significance to axillary surgeons, radiologist and anesthesiologists. PMID- 28591551 TI - Papillary Thyroid Carcinoma: Analysis of the Central Compartment's Lymph Nodes Metastases. AB - BACKGROUND: Papillary thyroid carcinoma is typical by regional lymph nodes metastases. Therefore we decided to analyse associated risk factors. OBJECTIVE: In this retrospective study we focused on the incidence of metastatic involvement of the central compartment's lymph nodes correlated with age, size of the primary tumour, infiltration of thyroid gland capsule, positive lymphangioinvasion in order to assess risk factors. METHOD: We analysed group of 156 patients with papillary carcinoma, who have undergone total thyroidectomy and bilateral elective central compartment neck dissection. We evaluated the occurrence of metastases, size, infiltration and lymphangioinvasion based on definitive histology of the whole group and separately for subgroups of patients under and over 45 years. RESULT: We found metastatic involvement in 88 (56.4%) patients. When comparing the subgroups of patients under (73 patients) and over 45 years (83 patients), we found metastases in 56 vs. 32 (76.7% vs. 38.6%) patients. In the subgroup of younger patients we found significant higher incidence of metastases compared with the group of over 45 years, P < 0.001 (P = 0.000027). We found significant higher incidence of metastases in patients with positive capsule infiltration in the whole group, P < 0.001 (P = 0.00049); in the subgroup of under 45 years, P < 0.001 (P = 0.00091) and in patients with positive lymphangioinvasion in the whole group, P < 0.01 (P = 0.00177); in the subgroup of over 45 years, P < 0.001 (P = 0.0002). In patients with metastases we found tumour size >=1cm more frequently in all groups. CONCLUSION: We recorded higher incidence of regional metastases in patients under 45 years, positive capsule infiltration, lymphangioinvasion. Age under 45 years itself does not correlate with less aggressive disease, to the contrary some of other analysed risk factors correlate with more aggressive disease. PMID- 28591553 TI - Familial Adenomatous Polyposis Registry in Czech Republic - History, Present and Future. PMID- 28591554 TI - NLRP3 participates in the regulation of EMT in bleomycin-induced pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and irreversible lung disease. Studies have shown that epithelial-mesenchymal transition (EMT) plays an important role in the development of IPF. The NLRP3 inflammasome is reported to be activated and play an important role in many respiratory diseases. However, whether the NLRP3 inflammasome is activated in alveolar epithelial cells as well as the regulatory role of NLRP3 in EMT have not been reported. In this study, we transfected NLRP3 siRNA into A549 and RLE-6TN cells and treated them with bleomycin (BLM) for 24h. Then, we detected the expression of NLRP3 inflammasome-related proteins, EMT-related proteins and transforming growth factor-beta1 (TGF-beta1) via western blotting, immunofluorescence and real-time quantitative PCR. The mRNA and protein level of NLRP3, ASC and caspase-1 increased after treatment with BLM. The IL-1beta levels were significantly decreased after inhibition of NLRP3 and caspase-1. E-cadherin expression increased and alpha-SMA was reduced in the BLM group when inhibited by NLRP3. The level of TGF-beta1 was reduced after NLRP3 silencing. These results indicated that the NLRP3 inflammasome was activated in alveolar epithelial cells and that NLRP3 may regulate EMT through TGF-beta1. These results may extend our understanding of the mechanism of pulmonary fibrosis and provide a new therapeutic target for pulmonary fibrosis. PMID- 28591556 TI - Regulation of USP7: A High Incidence of E3 Complexes. AB - Ubiquitin (Ub) conjugation is a critical signalling process in eukaryotic cells. The precise regulation of deubiquitination is an important component of this signalling cascade. Here, we discuss how USP7 (or Herpes-Associated Ubiquitin Specific Protease, HAUSP), one of the most abundant deubiquitinating enzymes, is regulated by complex formation with regulatory proteins and targets. Full activity of USP7 requires that its C-terminal Ub-like domains fold back onto the catalytic domain, to allow the remodelling of the active site to a catalytically competent state by the very C-terminal peptide. This regulatory mode can be modulated by complex formation with other proteins. USP7 is found in a large number of relatively stable complexes with different possible functions. Complex formation can provide recruitment of a target, bring in an E3 Ub ligase, or modulate the activation of the deubiquitinating enzyme activity. These complexes make up potential cellular "switches", using their (de)ubiquitination ability to switch pathways on or off upon cellular signals. Here, we summarize what is known for USP7 complexes, focussing on the prevalence of E3 Ub ligases and how complex formation can affect Ub switches. PMID- 28591555 TI - Seroepidemiological study and associated risk factors of Toxocara canis infection among preschool children in Osun State, Nigeria. AB - Human toxocariasis is caused by the nematode, Toxocara canis and it is a poorly understood phenomenon in Nigeria. Seroepidemiological studies have not been previously carried out among the preschool aged children in Nigeria. A cross sectional study was conducted in pre-school children in four communities from Osun State, Nigeria between January and July 2016. A total of 308 children Aged 9 months and 5 years were studied comprising 53.2% (164/308) male and 46.8% (144/308) female. Blood samples were collected and screened for the presence of anti-Toxocara IgG antibodies by Western blot analysis based on the excretory secretory antigens of larva T. canis (TcES), targeting low molecular weight bands of 24 - 35kDa specific for T. canis. Questionnaires were given to parents/guardians of the studied children to collect information regarding relationship between infection and host factors. The overall seroprevalence of Toxocara infection was 37.3%. The seroprevalence in the studied preschool children ranged from 18.2% in children less than one year old to a max of 57.6% in children aged 3 years and above. The logistic regression analysis of risk factors showed that children's age (odds ratio (OR)=6.12, 95% confidence interval (CI)=1.25-29.90, p=0.02), contact with dogs (OR=3.17, 95% CI=1.40-7.20, p=0.01) and parent's religion (OR=0.54, 95% CI=0.32-0.91, p=0.02) were the risk factors associated with Toxocara infection. However, after adjustment by multivariate logistic regression analysis, contact with dogs (p=0.02) remained the only statistically significant risk factor. Preschool children were exposed early in life to T. canis infection as 18.18% of children less than one year old were infected. This is the first serological investigation of T. canis infection among preschool children in Nigeria. The results show high levels of exposure to T. canis infection among the studied group and contact with the dog plays the predominant risk factor. It indicates high transmission with the consequent of visceral or ocular larva migrans and neurologic disorder in these children. The results also provide baseline data for effective prevention strategies of toxocariasis in Southwest Nigeria and the study recommends prompt interventional measures, particularly health education on personal hygiene. PMID- 28591557 TI - Characterization of badnaviruses infecting Dioscorea spp. in the Pacific reveals two putative novel species and the first report of dioscorea bacilliform RT virus 2. AB - The complete genome sequences of three new badnaviruses associated with yam (Dioscorea spp.) originating from Fiji, Papua New Guinea and Samoa were determined following rolling circle amplification of the virus genomes. The full length genomes consisted of a single molecule of circular double-stranded DNA of 8106bp for isolate FJ14, 7871bp for isolate PNG10 and 7426bp for isolate SAM01. FJ14 and PNG10 contained three open reading frames while SAM01 had an additional open reading frame which partially overlapped the 3' end of ORF 3. Amino acid sequence analysis of ORF 3 from the three isolates confirmed the presence of conserved motifs typical of other badnaviruses. Phylogenetic analysis revealed the sequences to be closely related to other Dioscorea-infecting badnaviruses. FJ14 and PNG10 appear to be new species, which we have tentatively named dioscorea bacilliform ES virus (DBESV) and dioscorea bacilliform AL virus 2 (DBALV2), respectively, while SAM01 represents a Pacific isolate of the recently published dioscorea bacilliform RT virus 2 and is described as dioscorea bacilliform RT virus 2-[4RT] (DBRTV2-[4RT]). PMID- 28591558 TI - Validation of a new proposal to avoid donor resuscitation in controlled donation after circulatory death with normothermic regional perfusion. AB - AIM: The use of abdominal normothermic regional perfusion (nRP) and premortem interventions in controlled donation after circulatory death (cDCD) may represent a significant advance to increase the number and quality of grafts recovered in cDCD. The main limitation for the widespread acceptance of nRP in cDCD is the concerns of restoring circulation to the brain once death has been declared should the thoracic aorta not be adequately blocked. METHODS: We describe and validate a specific methodology to ensure an appropriate blocking of the thoracic aorta in a multicenter study using this technique. RESULTS: A total of 78 procedures with premortem cannulation and abdominal nRP were performed in four different hospitals. No case of heart or brain resuscitation was observed after nRP CONCLUSION: The use of premortem interventions before nRP and the aortic occlusion balloon may increase the number of grafts recovered in cDCD. Our proposed methodology avoids the ethical problem of resuscitation by guaranteeing that circulation to the heart and brain is not restored after nRP. PMID- 28591559 TI - Repetition suppression in aging: A near-infrared spectroscopy study on the size congruity effect. AB - Age-related changes in the hemodynamic response regarding inhibition capacity and repetition suppression were examined using a modified version of the numerical Stroop task. Young (20-38 yrs; M = 28 yrs; N = 18), middle-aged (47-59 yrs; M = 52 yrs; N = 17), and older participants (60-78 yrs; M = 69 yrs; N = 19) solved a physical and numerical version of the size-congruity task, in which trials from the same experimental condition were presented in triplets. Response times revealed a strong Stroop effect in both tasks (faster reaction times during neutral than during incongruent trials) and increased with participants' age. Reaction times decreased with item repetition. In line with previous studies, the hemodynamic response (relative concentration changes in oxygenated and deoxygenated hemoglobin) assessed with near-infrared spectroscopy was comparable across incongruent and neutral trials. Strong repetition suppression of the oxygenated hemoglobin response was observed in frontal brain regions as well as in the left parietal region in all age groups. In middle and right parietal regions, repetition suppression decreased with age and was absent among older participants. These results indicate a reduced adaptation of the hemodynamic response in middle and right parietal regions of older individuals' brains in response to repeated interference control. PMID- 28591560 TI - Implications of the lysophosphatidic acid signaling axis in liver cancer. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death in western countries. The major risk factors for HCC are hepatitis C or B viruses, alcohol and metabolic disorders. The increasing risk of HCC in patients with metabolic disorders (i.e. obesity, diabetes and non-alcoholic steatohepatitis/NASH) regardless of the presence of liver cirrhosis is becoming relevant. Nevertheless, molecular mechanisms linking these risk factors to liver oncogenesis are unclear. This review focuses on the pathogenic role of the lysophosphatidic acid (LPA) pathway in HCC, highlighting the implications of this bioactive phospholipid in liver cancer biology and metabolism and as potential therapeutic target. PMID- 28591561 TI - Over expression of GroESL in Cupriavidus necator for heterotrophic and autotrophic isopropanol production. AB - We previously reported a metabolic engineering strategy to develop an isopropanol producing strain of Cupriavidus necator leading to production of 3.4gL-1 isopropanol. In order to reach higher titers, isopropanol toxicity to the cells has to be considered. A toxic effect of isopropanol on the growth of C. necator has been indeed observed above a critical value of 15gL-1. GroESL chaperones were first searched and identified in the genome of C. necator. Native groEL and groES genes from C. necator were over-expressed in a strain deleted for PHA synthesis. We demonstrated that over-expressing groESL genes led to a better tolerance of the strain towards exogenous isopropanol. GroESL genes were then over-expressed within the best engineered isopropanol producing strain. A final isopropanol concentration of 9.8gL-1 was achieved in fed-batch culture on fructose as the sole carbon source (equivalent to 16gL-1 after taking into account evaporation). Cell viability was slightly improved by the chaperone over-expression, particularly at the end of the fermentation when the isopropanol concentration was the highest. Moreover, the strain over-expressing the chaperones showed higher enzyme activity levels of the 2 heterologous enzymes (acetoacetate carboxylase and alcohol dehydrogenase) of the isopropanol synthetic operon, translating to a higher specific production rate of isopropanol at the expense of the specific production rate of acetone. Over-expressing the native chaperones led to a 9-18% increase in the isopropanol yield on fructose. PMID- 28591562 TI - Identification of Histone Deacetylase (HDAC) as a drug target against MRSA via interolog method of protein-protein interaction prediction. AB - Patently, Protein-Protein Interactions (PPIs) lie at the core of significant biological functions and make the foundation of host-pathogen relationships. Hence, the current study is aimed to use computational biology techniques to predict host-pathogen Protein-Protein Interactions (HP-PPIs) between MRSA and Humans as potential drug targets ultimately proposing new possible inhibitors against them. As a matter of fact this study is based on the Interolog method which implies that homologous proteins retain their ability to interact. A distant homolog approach based on Interolog method was employed to speculate MRSA protein homologs in Humans using PSI-BLAST. In addition the protein interaction partners of these homologs as listed in Database of Interacting Proteins (DIP) were predicted to interact with MRSA as well. Moreover, a direct approach using BLAST was also applied so as to attain further confidence in the strategy. Consequently, the common HP-PPIs predicted by both approaches are suggested as potential drug targets (22%) whereas, the unique HP-PPIs estimated only through distant homolog approach are presented as novel drug targets (12%). Furthermore, the most repeated entry in our results was found to be MRSA Histone Deacetylase (HDAC) which was then modeled using SWISS-MODEL. Eventually, small molecules from ZINC, selected randomly, were docked against HDAC using Auto Dock and are suggested as potential binders (inhibitors) based on their energetic profiles. Thus the current study provides basis for further in-depth analysis of such data which not only include MRSA but other deadly pathogens as well. PMID- 28591563 TI - Evaluation of the cytotoxicity and intestinal absorption of a self-emulsifying drug delivery system containing sodium taurocholate. AB - Currently, many surfactants used in self-emulsifying drug delivery systems (SMEDDS) can cause gastrointestinal mucosal irritation and systemic toxicity. In the present study, SMEDDS were loaded with pueraria flavones, using sodium taurocholate to replace polyoxyl 40 dydrogenated castor oil (Cremophor(r) RH 40) as the surfactant (PF-SMEDDSNR) to reduce the toxicity of SMEDDS using Cremophor(r) RH 40 as the surfactant (PF-SMEDDSR). The absorption rate constants (Ka) and intestinal permeability coefficients (Peff) were measured. The effects of P-glycoprotein inhibitor (verapamil), adenosine triphosphate (ATP) inhibitor (2,4-dinitrophenol), and carrier inhibitor on Ka and Peff values in the ileum were determined. Biological safety was also evaluated. The Ka and Peff values increased for PF-solution concentrations of 200MUg/ml>100MUg/ml>400MUg/ml in individual segments of the intestines. The results indicated that Peff values of PF-SMEDDSNR were distinctly higher than those of SMEDDS loaded with pueraria flavones using Cremophor(r)RH 40 as the surfactant (PF-SMEDDSR) and PF-solution in four intestinal segments. However, the Ka values of PF-SMEDDSNR were higher only in the jejunum and ileum segments compared with those of PF-SMEDDSR and PF solution. The Ka and Peff values without verapamil were significantly lower than those with verapamil. 2,4-Dinitrophenol had no effect on Ka and Peff values. The Ka and Peff values of PF-SMEDDSNR significantly decreased after perfusing B SMEDDSNR for 1h prior to the study. The cell viabilities after exposure to SMEDDSNR were higher than those of SMEDDSR in the range of 81-324MUg/ml. Lactate dehydrogenase release from cells treated with PF-SMEDDSNR or B-SMEDDSNR was significantly lower than that from cells treated with PF-SMEDDSR or B-SMEDDSR at surfactant concentrations of 243 and 324MUg/ml. However, there were no differences with SMEDDS treatment at surfactant concentrations of 0-162MUg/ml. Hence, we conclude that SMEDDS using sodium taurocholate as the surfactant can reduce the toxicity of SMEDDS, meanwhile, maintain the characteristics of SMEDDS, and enhance intestinal absorption. PMID- 28591565 TI - Quantitative proteomic analysis of the fall armyworm saliva. AB - Lepidopteran larvae secrete saliva on plant tissues during feeding. Components in the saliva may aid in food digestion, whereas other components are recognized by plants as cues to elicit defense responses. Despite the ecological and economical importance of these plant-feeding insects, knowledge of their saliva composition is limited to a few species. In this study, we identified the salivary proteins of larvae of the fall armyworm (FAW), Spodoptera frugiperda; determined qualitative and quantitative differences in the salivary proteome of the two host races-corn and rice strains-of this insect; and identified changes in total protein concentration and relative protein abundance in the saliva of FAW larvae associated with different host plants. Quantitative proteomic analyses were performed using labeling with isobaric tags for relative and absolute quantification followed by liquid chromatography-tandem mass spectrometry. In total, 98 proteins were identified (>99% confidence) in the FAW saliva. These proteins were further categorized into five functional groups: proteins potentially involved in (1) plant defense regulation, (2) herbivore offense, (3) insect immunity, (4) detoxification, (5) digestion, and (6) other functions. Moreover, there were differences in the salivary proteome between the FAW strains that were identified by label-free proteomic analyses. Thirteen differentially identified proteins were present in each strain. There were also differences in the relative abundance of eleven salivary proteins between the two FAW host strains as well as differences within each strain associated with different diets. The total salivary protein concentration was also different for the two strains reared on different host plants. Based on these results, we conclude that the FAW saliva contains a complex mixture of proteins involved in different functions that are specific for each strain and its composition can change plastically in response to diet type. PMID- 28591566 TI - Regulation of clustered protocadherin genes in individual neurons. AB - Individual neurons are basic functional units in the complex system of the brain. One aspect of neuronal individuality is generated by stochastic and combinatorial expression of diverse clustered protocadherins (Pcdhs), encoded by the Pcdha, Pcdhb, and Pcdhg gene clusters, that are critical for several aspects of neural circuit formation. Each clustered Pcdh gene has its own promoter containing conserved sequences and is transcribed by a promoter choice mechanism involving interaction between the promoter and enhancers. A CTCF/Cohesin complex induces this interaction by configuration of DNA-looping in the chromatin structure. At the same time, the semi-stochastic expression of clustered Pcdh genes is regulated in individual neurons by DNA methylation: the methyltransferase Dnmt3b regulates methylation state of individual clustered Pcdh genes during early embryonic stages prior to the establishment of neural stem cells. Several other factors, including Smchd1, also contribute to the regulation of clustered Pcdh gene expression. In addition, psychiatric diseases and early life experiences of individuals can influence expression of clustered Pcdh genes in the brain, through epigenetic alterations. Clustered Pcdh gene expression is thus a significant and highly regulated step in establishing neuronal individuality and generating functional neural circuits in the brain. PMID- 28591564 TI - Effect of a model consultation informed by guidelines on recorded quality of care of osteoarthritis (MOSAICS): a cluster randomised controlled trial in primary care. AB - OBJECTIVE: To determine the effect of a model osteoarthritis (OA) consultation (MOAC) informed by National Institute for Health and Care Excellence (NICE) recommendations compared with usual care on recorded quality of care of clinical OA in general practice. DESIGN: Two-arm cluster randomised controlled trial. SETTING: Eight general practices in Cheshire, Shropshire, or Staffordshire UK. PARTICIPANTS: General practitioners and nurses with patients consulting with clinical OA. INTERVENTION: Following six-month baseline period practices were randomised to intervention (n = 4) or usual care (n = 4). Intervention practices delivered MOAC (enhanced initial GP consultation, nurse-led clinic, OA guidebook) to patients aged >=45 years consulting with clinical OA. An electronic (e )template for consultations was used in all practices to record OA quality care indicators. OUTCOMES: Quality of OA care over six months recorded in the medical record. RESULTS: 1851 patients consulted in baseline period (1015 intervention; 836 control); 1960 consulted following randomisation (1118 intervention; 842 control). At baseline wide variations in quality of care were noted. Post randomisation increases were found for written advice on OA (4-28%), exercise (4 22%) and weight loss (1-15%) in intervention practices but not controls (1-3%). Intervention practices were more likely to refer to physiotherapy (10% vs 2%, odds ratio 5.30; 95% CI 2.11, 13.34), and prescribe paracetamol (22% vs 14%, 1.74; 95% CI 1.27, 2.38). CONCLUSIONS: The intervention did not improve all aspects of care but increased core NICE recommendations of written advice on OA, exercise and weight management. There remains a need to reduce variation and uniformly enhance improvement in recorded OA care. TRIAL REGISTRATION NUMBER: ISRCTN06984617. PMID- 28591567 TI - A role for dystroglycan in the pathophysiology of acute leukemic cells. AB - AIMS: Previous reports have demonstrated that alterations or reduced expression of Dystroglycan (Dg) complex (alphaDg and betaDg subunits) are related to progression and severity of neoplastic solid tissues. Therefore we determined the expression pattern and subcellular distribution of Dg complex in Acute Myeloid Leukemia (AML) primary blasts (M1, M2, and M3 phenotypes), as well as HL-60 and Kasumi-1 leukemia cell lines. Additionally, we evaluated the relative expression of the main enzymes controlling alpha-Dg glycosylation to ascertain the post translational modifications in the leukemia cell phenotype. MAIN METHODS: Primary leukemia blasts and leukemia cell lines were processed by confocal analysis to determine the subcellular distribution of alpha-Dg, beta-Dg, and phosphorylated beta-Dg (Y892), to evaluate the expression pattern of the different Dg species we performed Western Blot (WB) assays, while the messenger RNA (mRNA) expression of enzymes involved in alpha-Dg glycosylation, such as POMGnT1, POMT1, POMT2, LARGE, FKTN, and FKRP, were evaluated by qualitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). Finally, in an attempt to ameliorate the leukemia cell phenotype, we transfected leukemia cells with a plasmid expressing the Dg complex. KEY FINDINGS: The Dg complex was altered in leukemia cells, including decreased mRNA, protein, and alpha-Dg glycosylated levels, mislocalization of beta-Dg, and a diminution of mRNA expression of LARGE in patients leukemia blasts and in cell lines. Interestingly, the exogenous expression of Dg complex promoted filopodial formation, differentiation, and diminished proliferation, attenuating some HL-60 and Kasumi cells characteristics. SIGNIFICANCE: Dg complex integrity and balance are required for a proper hematopoietic cell function, in that its disruption might contribute to leukemia pathophysiology. PMID- 28591568 TI - Nicotinamide induces mitochondrial-mediated apoptosis through oxidative stress in human cervical cancer HeLa cells. AB - AIMS: Nicotinamide participates in energy metabolism and influences cellular redox status and modulates multiple pathways related with both cellular survival and death. Recent studies have shown that it induced proliferation inhibition and apoptosis in many cancer cells. However, little is known about the effects of nicotinamide on human cervical cancer cells. We aimed to evaluate the effects of the indicated concentrations nicotinamide on cell proliferation, apoptosis and redox-related parameters in HeLa cells and investigated the apoptotic mechanism. MATERIALS AND METHODS: After the treatment of the indicated concentrations nicotinamide, HeLa cell proliferation was evaluated by the CCK-8 assay and the production of ROS (reactive oxygen species) was measured using 2',7' Dichlorofluorescin diacetate. The apoptotic effect was confirmed by observing the cellular and nuclear morphologies with fluorescence microscope and apoptotic rate of HeLa cell apoptosis was measured by flow cytometry using Annexin-V method. Moreover, we examined the mitochondrial membrane potential by JC-1 method and measured the expression of apoptosis related genes using qRT-PCR and immunoblotting. KEY FINDINGS: Nicotinamide restrained the HeLa cell proliferation and significantly increased the accumulation of ROS and depletion of GSH at relatively high concentrations. Furthermore, nicotinamide promoted HeLa cell apoptosis via the intrinsic mitochondrial apoptotic pathway. SIGNIFICANCE: Our study revealed that nicotinamide induced the apoptosis through oxidative stress and intrinsic mitochondrial apoptotic pathways in HeLa cell. The results emerge that nicotinamide may be an inexpensive, safe and promising therapeutic agent or a neoadjuvant chemotherapy for cervical cancer patients, as well useful to find new drugs for cervical cancer therapy. PMID- 28591569 TI - The Alzheimer's Disease gamma-Secretase Generates Higher 42:40 Ratios for beta Amyloid Than for p3 Peptides. AB - Alzheimer's disease is characterized by intracerebral deposition of beta-amyloid (Abeta). While Abeta40 is the most abundant form, neurotoxicity is mainly mediated by Abeta42. Sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases gives rise to full-length Abeta (Abeta1-x) and N terminally truncated Abeta' (Abeta11-x) whereas cleavage by alpha- and gamma secretases leads to the shorter p3 peptides (Abeta17-x). We uncovered significantly higher ratios of 42- versus 40-ending variants for Abeta and Abeta' than for p3 secreted by mouse neurons and human induced pluripotent stem cell (iPSC)-derived neurons or produced in a cell-free gamma-secretase assay with recombinant APP-CTFs. The 42:40 ratio was highest for Abeta', followed by Abeta and then p3. Mass spectrometry analysis of APP intracellular domains revealed differential processing of APP-C83, APP-C89, and APP-C99 by gamma-secretase already at the epsilon-cleavage stage. This mechanistic insight could aid in developing substrate-targeted modulators of APP-C99 processing to specifically lower the Abeta42:Abeta40 ratio without compromising gamma-secretase function. PMID- 28591570 TI - Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRalpha1 or RET Impairs Normal Cerebellar Motor Learning. AB - The role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRalpha1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning. PMID- 28591571 TI - Global Hypertranscription in the Mouse Embryonic Germline. AB - Primordial germ cells (PGCs) are vital for inheritance and evolution. Their transcriptional program has been extensively studied and is assumed to be well known. We report here a remarkable global upregulation of the transcriptome of mouse PGCs compared to somatic cells. Using cell-number-normalized genome-wide analyses, we uncover significant transcriptional amplification in PGCs, including mRNAs, rRNA, and transposable elements. Hypertranscription preserves tissue specific gene expression patterns, correlates with cell size, and can still be detected in E15.5 male germ cells when proliferation has ceased. PGC hypertranscription occurs at the level of nascent transcription, is accompanied by increased translation rates, and is driven by Myc factors n-Myc and l-Myc (but not c-Myc) and by P-TEFb. This study provides a paradigm for transcriptional analyses during development and reveals a major global hyperactivity of the germline transcriptome. PMID- 28591572 TI - Hepatic Diacylglycerol-Associated Protein Kinase Cepsilon Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. AB - Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKCepsilon activation, as reflected by PKCepsilon translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol-induced PKCepsilon activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans. PMID- 28591573 TI - Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin. AB - Growth factors, such as insulin, can induce both acute and long-term glucose uptake into cells. Apart from the rapid, insulin-induced fusion of glucose transporter (GLUT)4 storage vesicles with the cell surface that occurs in muscle and adipose tissues, the mechanism behind acute induction has been unclear in other systems. Thioredoxin interacting protein (TXNIP) has been shown to be a negative regulator of cellular glucose uptake. TXNIP is transcriptionally induced by glucose and reduces glucose influx by promoting GLUT1 endocytosis. Here, we report that TXNIP is a direct substrate of protein kinase B (AKT) and is responsible for mediating AKT-dependent acute glucose influx after growth factor stimulation. Furthermore, TXNIP functions as an adaptor for the basal endocytosis of GLUT4 in vivo, its absence allows excess glucose uptake in muscle and adipose tissues, causing hypoglycemia during fasting. Altogether, TXNIP serves as a key node of signal regulation and response for modulating glucose influx through GLUT1 and GLUT4. PMID- 28591574 TI - mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss. AB - It is unknown whether and how very-low density lipoprotein receptors (VLDLRs) impact skeletal homeostasis. Here, we report that maternal and offspring VLDLRs play opposite roles in osteoclastogenesis and bone resorption. VLDLR deletion in the offspring augments osteoclast differentiation by enhancing RANKL signaling, leading to osteoporosis. In contrast, VLDLR deletion in the mother alters milk metabolism, which inhibits osteoclast differentiation and causes osteopetrosis in the offspring. The maternal effects are dominant. VLDLR-null lactating mammary gland exhibits higher mTORC1 signaling and cholesterol biosynthesis. Pharmacological probing reveals that rapamycin, but not statin, treatment of the VLDLR-null mother can prevent both the low bone resorption and our previously described inflammatory fur loss in their offspring. Genetic rescue reveals that maternal mTORC1 attenuation in adipocytes, but not in myeloid cells, prevents offspring osteopetrosis and fur loss. Our studies uncover functions of VLDLR and mTORC1 in lactation and osteoclastogenesis, illuminating key mechanisms and therapeutic insights for bone and metabolic diseases. PMID- 28591575 TI - MicroRNA-Mediated Dynamic Bidirectional Shift between the Subclasses of Glioblastoma Stem-like Cells. AB - Large-scale transcriptomic profiling of glioblastoma (GBM) into subtypes has provided remarkable insight into the pathobiology and heterogeneous nature of this disease. The mechanisms of speciation and inter-subtype transitions of these molecular subtypes require better characterization to facilitate the development of subtype-specific targeting strategies. The deregulation of microRNA expression among GBM subtypes and their subtype-specific targeting mechanisms are poorly understood. To reveal the underlying basis of microRNA-driven complex subpopulation dynamics within the heterogeneous intra-tumoral ecosystem, we characterized the expression of the subtype-enriched microRNA-128 (miR-128) in transcriptionally and phenotypically diverse subpopulations of patient-derived glioblastoma stem-like cells. Because microRNAs are capable of re-arranging the molecular landscape in a cell-type-specific manner, we argue that alterations in miR-128 levels are a potent mechanism of bidirectional transitions between GBM subpopulations, resulting in intermediate hybrid stages and emphasizing highly intricate intra-tumoral networking. PMID- 28591576 TI - Regulation of Rvb1/Rvb2 by a Domain within the INO80 Chromatin Remodeling Complex Implicates the Yeast Rvbs as Protein Assembly Chaperones. AB - The hexameric AAA+ ATPases Rvb1 and Rvb2 (Rvbs) are essential for diverse processes ranging from metabolic signaling to chromatin remodeling, but their functions are unknown. While originally thought to act as helicases, recent proposals suggest that Rvbs act as protein assembly chaperones. However, experimental evidence for chaperone-like behavior is lacking. Here, we identify a potent protein activator of the Rvbs, a domain in the Ino80 ATPase subunit of the INO80 chromatin-remodeling complex, termed Ino80INS. Ino80INS stimulates Rvbs' ATPase activity by 16-fold while concomitantly promoting their dodecamerization. Using mass spectrometry, cryo-EM, and integrative modeling, we find that Ino80INS binds asymmetrically along the dodecamerization interface, resulting in a conformationally flexible dodecamer that collapses into hexamers upon ATP addition. Our results demonstrate the chaperone-like potential of Rvb1/Rvb2 and suggest a model where binding of multiple clients such as Ino80 stimulates ATP driven cycling between hexamers and dodecamers, providing iterative opportunities for correct subunit assembly. PMID- 28591578 TI - PLK1 Activation in Late G2 Sets Up Commitment to Mitosis. AB - Commitment to mitosis must be tightly coordinated with DNA replication to preserve genome integrity. While we have previously established that the timely activation of CyclinB1-Cdk1 in late G2 triggers mitotic entry, the upstream regulatory mechanisms remain unclear. Here, we report that Polo-like kinase 1 (Plk1) is required for entry into mitosis during an unperturbed cell cycle and is rapidly activated shortly before CyclinB1-Cdk1. We determine that Plk1 associates with the Cdc25C1 phosphatase and induces its phosphorylation before mitotic entry. Plk1-dependent Cdc25C1 phosphosites are sufficient to promote mitotic entry, even when Plk1 activity is inhibited. Furthermore, we find that activation of Plk1 during G2 relies on CyclinA2-Cdk activity levels. Our findings thus elucidate a critical role for Plk1 in CyclinB1-Cdk1 activation and mitotic entry and outline how CyclinA2-Cdk, an S-promoting factor, poises cells for commitment to mitosis. PMID- 28591577 TI - Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer. AB - Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses. PMID- 28591579 TI - Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation. AB - The G protein-coupled receptor Smoothened (Smo) is the signal transducer of the Sonic Hedgehog (Shh) pathway. Smo signals through G protein-dependent and independent routes, with G protein-independent canonical signaling to Gli effectors requiring Smo accumulation in the primary cilium. The mechanisms controlling Smo activation and trafficking are not yet clear but likely entail small-molecule binding to pockets in its extracellular cysteine-rich domain (CRD) and/or transmembrane bundle. Here, we demonstrate that the cytosolic phospholipase cPLA2alpha is activated through Gbetagamma downstream of Smo to release arachidonic acid. Arachidonic acid binds Smo and synergizes with CRD binding agonists, promoting Smo ciliary trafficking and high-level signaling. Chemical or genetic cPLA2alpha inhibition dampens Smo signaling to Gli, revealing an unexpected contribution of G protein-dependent signaling to canonical pathway activity. Arachidonic acid displaces the Smo transmembrane domain inhibitor cyclopamine to rescue CRD agonist-induced signaling, suggesting that arachidonic acid may target the transmembrane bundle to allosterically enhance signaling by CRD agonist-bound Smo. PMID- 28591581 TI - Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6. AB - Nuclear actin (N-actin) is known to participate in the regulation of gene expression. We showed previously that N-actin levels mediate the growth and quiescence of mouse epithelial cells in response to laminin-111 (LN1), a component of the mammary basement membrane (BM). We know that BM is defective in malignant cells, and we show here that it is the LN1/N-actin pathway that is aberrant in human breast cancer cells, leading to continuous growth. Photobleaching assays revealed that N-actin exit in nonmalignant cells begins as early as 30 min after LN1 treatment. LN1 attenuates the PI3K pathway leading to upregulation of exportin-6 (XPO6) activity and shuttles actin out of the nucleus. Silencing XPO6 prevents quiescence. Malignant cells are impervious to LN1 signaling. These results shed light on the crucial role of LN1 in quiescence and differentiation and how defects in the LN1/PI3K/XPO6/N-actin axis explain the loss of tissue homeostasis and growth control that contributes to malignant progression. PMID- 28591580 TI - MYO6 Regulates Spatial Organization of Signaling Endosomes Driving AKT Activation and Actin Dynamics. AB - APPL1- and RAB5-positive signaling endosomes play a crucial role in the activation of AKT in response to extracellular stimuli. Myosin VI (MYO6) and two of its cargo adaptor proteins, GIPC and TOM1/TOM1L2, localize to these peripheral endosomes and mediate endosome association with cortical actin filaments. Loss of MYO6 leads to the displacement of these endosomes from the cell cortex and accumulation in the perinuclear space. Depletion of this myosin not only affects endosome positioning, but also induces actin and lipid remodeling consistent with endosome maturation, including accumulation of F-actin and the endosomal lipid PI(3)P. These processes acutely perturb endosome function, as both AKT phosphorylation and RAC-dependent membrane ruffling were markedly reduced by depletion of either APPL1 or MYO6. These results place MYO6 and its binding partners at a central nexus in cellular signaling linking actin dynamics at the cell surface and endosomal signaling in the cell cortex. PMID- 28591582 TI - Hepatocyte ABCA1 Deletion Impairs Liver Insulin Signaling and Lipogenesis. AB - Plasma membrane (PM) free cholesterol (FC) is emerging as an important modulator of signal transduction. Here, we show that hepatocyte-specific knockout (HSKO) of the cellular FC exporter, ATP-binding cassette transporter A1 (ABCA1), leads to decreased PM FC content and defective trafficking of lysosomal FC to the PM. Compared with controls, chow-fed HSKO mice had reduced hepatic (1) insulin stimulated Akt phosphorylation, (2) activation of the lipogenic transcription factor Sterol Regulatory Element Binding Protein (SREBP)-1c, and (3) lipogenic gene expression. Consequently, Western-type diet-fed HSKO mice were protected from steatosis. Surprisingly, HSKO mice had intact glucose metabolism; they showed normal gluconeogenic gene suppression in response to re-feeding and normal glucose and insulin tolerance. We conclude that: (1) ABCA1 maintains optimal hepatocyte PM FC, through intracellular FC trafficking, for efficient insulin signaling; and (2) hepatocyte ABCA1 deletion produces a form of selective insulin resistance so that lipogenesis is suppressed but glucose metabolism remains normal. PMID- 28591583 TI - Distinct Thalamic Reticular Cell Types Differentially Modulate Normal and Pathological Cortical Rhythms. AB - Integrative brain functions depend on widely distributed, rhythmically coordinated computations. Through its long-ranging connections with cortex and most senses, the thalamus orchestrates the flow of cognitive and sensory information. Essential in this process, the nucleus reticularis thalami (nRT) gates different information streams through its extensive inhibition onto other thalamic nuclei, however, we lack an understanding of how different inhibitory neuron subpopulations in nRT function as gatekeepers. We dissociated the connectivity, physiology, and circuit functions of neurons within rodent nRT, based on parvalbumin (PV) and somatostatin (SOM) expression, and validated the existence of such populations in human nRT. We found that PV, but not SOM, cells are rhythmogenic, and that PV and SOM neurons are connected to and modulate distinct thalamocortical circuits. Notably, PV, but not SOM, neurons modulate somatosensory behavior and disrupt seizures. These results provide a conceptual framework for how nRT may gate incoming information to modulate brain-wide rhythms. PMID- 28591584 TI - Dorsal-CA1 Hippocampal Neuronal Ensembles Encode Nicotine-Reward Contextual Associations. AB - Natural and drug rewards increase the motivational valence of stimuli in the environment that, through Pavlovian learning mechanisms, become conditioned stimuli that directly motivate behavior in the absence of the original unconditioned stimulus. While the hippocampus has received extensive attention for its role in learning and memory processes, less is known regarding its role in drug-reward associations. We used in vivo Ca2+ imaging in freely moving mice during the formation of nicotine preference behavior to examine the role of the dorsal-CA1 region of the hippocampus in encoding contextual reward-seeking behavior. We show the development of specific neuronal ensembles whose activity encodes nicotine-reward contextual memories and that are necessary for the expression of place preference. Our findings increase our understanding of CA1 hippocampal function in general and as it relates to reward processing by identifying a critical role for CA1 neuronal ensembles in nicotine place preference. PMID- 28591586 TI - Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense. PMID- 28591585 TI - Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire. AB - Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd gene segments share the Tcra-Tcrd locus, with interspersed Valpha and Vdelta segments undergoing Vdelta-Ddelta-Jdelta rearrangement in CD4-CD8- thymocytes and then multiple rounds of Valpha-Jalpha rearrangement in CD4+CD8+ thymocytes. We document stepwise, highly coordinated proximal-to-distal progressions of Valpha and Jalpha use on individual Tcra alleles, limiting combinatorial diversity. This behavior is supported by an extended chromatin conformation in CD4+CD8+ thymocytes, with only nearby Valpha and Jalpha segments contacting each other. Tcrd rearrangements can use distal Vdelta segments due to a contracted Tcra-Tcrd conformation in CD4-CD8- thymocytes. These rearrangements expand the Tcra repertoire by truncating the Valpha array to permit otherwise disfavored Valpha-Jalpha combinations. Therefore, recombination events at two developmental stages with distinct chromatin conformations synergize to promote Tcra repertoire diversity. PMID- 28591587 TI - NLRP6 Protects Il10-/- Mice from Colitis by Limiting Colonization of Akkermansia muciniphila. PMID- 28591588 TI - Hyaluronic acid in complexes with surfactants: The efficient tool for reduction of the cytotoxic effect of surfactants on human cell types. AB - The cationic surfactants carbethoxypendecinium bromide (Septonex) and cetyltrimethylammonium bromide (CTAB) are known to be harmful for certain cell types (bacteria, fungi, mammal cells, etc.). Colloidal complexes of these surfactants with negatively-charged hyaluronic acid (HyA) were prepared for potential drug and/or universal delivery applications. The complexes were tested for their cytotoxic effect on different human cell types - osteoblasts, keratinocytes and fibroblasts. Both the CTAB-HyA and Septonex-HyA complexes were found to reduce the cytotoxicity induced by surfactants alone concerning all the tested concentrations. Moreover, we suggested the limits of HyA protection provided by the surfactant-HyA complexes, e.g. the importance of the amount of HyA applied. We also determined the specific sensitivity of different cell types to surfactant treatment. Keratinocytes were more sensitive to CTAB, while osteoblasts and fibroblasts were more sensitive to Septonex. Moreover, it was indirectly shown that CTAB combines lethal toxicity with cell metabolism induction, while Septonex predominantly causes lethal toxicity concerning fibroblasts. This comprehensive study of the effect of surfactant-HyA complexes on various human cell types revealed that HyA represents a useful CTAB or Septonex cytotoxic effect modulator at diverse levels. Potential applications for these complexes include drug and/or nucleic acid delivery systems, diagnostic dye carriers and cosmetics production. PMID- 28591590 TI - Salt-regulated reversible fibrillation of Mycobacterium tuberculosis isocitrate lyase: Concurrent restoration of structure and activity. AB - Protein fibrillation is associated with a number of neurodegenerative diseases. Nevertheless, several proteins not related to disease can also form fibrils in vitro under specific conditions. In the present study, we demonstrate the reversible fibrillation of a globular protein that is modulated by salt under physiological pH. Mycobacterium tuberculosis Isocitrate lyase (MtbICL) is a crucial enzyme involved in the glyoxylate shunt and a potential drug target against M. tuberculosis infection. Under physiological pH, the enzyme self assembles into a fibrillar structure in the absence of salt in vitro. The mature fibrillar structure of MtbICL is dynamic and restores its tetrameric structure as well as activity with the addition of salt. The kinetics of fibril formation was investigated spectroscopically using 8-Anilinonaphthalene-1-sulfonic acid (ANS). Further, Transmission electron microscopy (TEM) and Atomic force microscopy (AFM) imaging also confirmed the formation of elongated fibrils in the absence of salt. The results indicate the balance between stabilizing forces and the localized electrostatic repulsions destabilizing the tetrameric MtbICL is adjusted via ion shielding. Our result is in congruence of the hypothesis that amyloid formation is an intrinsic property of most, if not all natural proteins under an appropriate set of conditions. PMID- 28591589 TI - Can gamma-radiation modulate hemagglutinating and anticoagulant activities of PpyLL, a lectin from Phthirusa pyrifolia? AB - Blood coagulation and platelet-dependent primary homeostasis are important defense mechanisms against bleeding and novel inhibitors have been researched to obtain pharmacological and clinical applications. In this work, the PpyLL, a lectin obtained from Phthirusa pyrifolia, was characterized in terms of its molecular structure and biological functions (anticoagulant, antiplatelet agreggation and hemagglutinating activities) in presence or absence of Gamma radiation exposure. Results revealed a lectin with secondary-structure content by approximately 49% of beta-sheet, 20% of beta-turn and 31% of disordered structure. Irradiation effect demonstrated possible different sites of function by lectin on anticoagulant and hemagglutinating activities, once a decrease about 80% was observed when compared the activities under 0.5kGy of exposition to gamma radiation. An emphatic discussion about the use of gamma radiation as a possible modulator of the lectin activity was made, and once the ionizing radiation affected differently the anticoagulation and hemagglutinating activities, we speculated that the results are determined by selective molecular damages in different binding sites. PpyLL biological activities and gamma radiation modulation could be considered for future researches in biomedical field aiming possible medical applications. PMID- 28591591 TI - Activation of sodium channel by a novel alpha-scorpion toxin, BmK NT2, stimulates ERK1/2 and CERB phosphorylation through a Ca2+ dependent pathway in neocortical neurons. AB - Neuronal excitability controls the expression of a variety of genes and proteins and therefore regulates neurite outgrowth and synapse formation, fundamental physiological processes controlling learning and memory. Scorpion venom contains many neurotoxins which alter ion channel activities that influence neuronal excitability. In this study, a novel scorpion peptide termed BmK NT2 was purified from venom of Chinese scorpion Buthus martensii Karsch by combining mass spectrum mapping and intracellular Ca2+ concentration measurement in primary cultured neocortical neurons. Electrophysiological experiments demonstrated that BmK NT2 concentration-dependently delayed inactivation of voltage-gated sodium channels (VGSCs) with an EC50 value of 0.91MUM, and shifted the steady-state activation and inactivation of VGSCs to hyperpolarized direction. The effects of BmK NT2 on electrophysiological characteristics of VGSCs were similar to that of alpha scorpion toxins. BmK NT2 altered Ca2+ dynamics and increased phosphorylation of extracellular-regulated protein kinases (ERK) 1/2 and cAMP-response element binding (CREB) proteins, which were eliminated by the VGSC blocker, tetrodotoxin. These data demonstrate that BmK NT2 is a novel VGSC alpha-scorpion toxin which is sufficient to increase the phosphorylation of ERK1/2 and CREB proteins, suggesting that modulation of VGSC function by alpha-scorpion toxin exerts neurotrophic effect in primary cultured neocortical neurons. PMID- 28591592 TI - Recombinant thermo-alkali-stable endoglucanase of Myceliopthora thermophila BJA (rMt-egl): Biochemical characteristics and applicability in enzymatic saccharification of agro-residues. AB - Codon adaptation index (CAI) of a 1263bp long endoglucanase encoding gene from the thermophilic mould Myceliopthora thermophile BJA has been improved from 0.44 to 0.76 by in vitro gene synthesis. The codon optimized endoglucanase gene (Mt egl) has been constitutively expressed in Pichia pastoris under the regulation of GAP promoter. Recombinant endoglucanase (rMt-egl), purified by size exclusion chromatography, has been confirmed to be a monomeric protein of ~47kDa. rMt-egl is optimally active at pH 10 and 50 degrees C, displaying stability in broad pH and temperature ranges, with a t1/2 of 60 and 15min at 90 and 100 degrees C, respectively. This retained ~70% of activity after 3h incubation at pH 5-12. The Km, Vmax, kcat and kcat/Km of rMt-egl were 5mgmL-1, 20MUmolesmin-1mg-1, 1.02*103s 1 and 204s-1mg-1mL-1, respectively. Homology modeling and bioinformatics analysis confirmed catalytically important role of glutamate 234 and 344. rMt-egl released high amounts of reducing sugars from wheat bran and corn cobs (421 and 382mgg-1), thus making it a useful biocatalyst for producing bioethanol and fine chemicals from agro-residues. PMID- 28591593 TI - Hydrogel beads bio-nanocomposite based on Kappa-Carrageenan and green synthesized silver nanoparticles for biomedical applications. AB - This paper describes the fabrication and characterization of bio-nanocomposite hydrogel beads based on Kappa-Carrageenan (kappa-Carrageenan) and bio-synthesized silver nanoparticles (Ag-NPs). The silver nanoparticles were prepared in aqueous Citrullus colocynthis seed extract as both reducing and capping agent. Cross linked kappa-Carrageenan/Ag-NPs hydrogel beads were prepared using potassium chloride as the cross-linker. The hydrogel beads were characterized using XRD and FESEM. Moreover, swelling property of the hydrogel beads was investigated. The Ag release profile of the hydrogels was obtained by fitting the experimental data to power law equation. The direct visualization of the green synthesized Ag-NPs using TEM shows particle size in the range of 23+/-2nm. The bio-nanocomposite hydrogels showed lesser swelling behavior in comparison with pure kappa Carrageenan hydrogel. Regardless the slow Ag release, kappa-Carrageenan/Ag-NPs presented good antibacterial activities against Staphylococcus aureus, Methicilin Resistant Staphylococcus aurous, Peseudomonas aeruginosa and Escherichia coli with maximum zones of inhibition 11+/-2mm. Cytotoxicity study showed that the bio nanocomposite hydrogels with non-toxic effect of concentration below 1000MUg/mL have great pharmacological potential and a suitable level of safety for use in the biological systems. PMID- 28591595 TI - Mapping the effect of the X chromosome on the human brain: Neuroimaging evidence from Turner syndrome. AB - In addition to determining sex, the X chromosome has long been considered to play a crucial role in brain development and intelligence. Turner syndrome (TS) is caused by the congenital absence of all or part of one of the X chromosomes in females. Thus, Turner syndrome provides a unique "knock-out model" for investigating how the X chromosome influences the human brain in vivo. Numerous cutting-edge neuroimaging techniques and analyses have been applied to investigate various brain phenotypes in women with TS, which have yielded valuable evidence toward elucidating the causal relationship between the X chromosome and human brain structure and function. In this review, we comprehensively summarize the recent progress made in TS-related neuroimaging studies and emphasize how these findings have enhanced our understanding of X chromosome function with respect to the human brain. Future investigations are encouraged to address the issues of previous TS neuroimaging studies and to further identify the biological mechanisms that underlie the function of specific X-linked genes in the human brain. PMID- 28591596 TI - Measuring the Invisible: Determining the Size of Growing Nanodomains Using the "Inverse FCS". PMID- 28591594 TI - Oleanolic-bioenhancer coloaded chitosan modified nanocarriers attenuate breast cancer cells by multimode mechanism and preserve female fertility. AB - Addressing multidrug resistant stage of breast cancer is an impediment for chemotherapy. Moreover, breast cancer chemotherapy has potential enduring confrontations i.e. related toxicity including effect on fertility of young female patients. The co-delivery of polyphenolic bio-enhancers with oleanolic acid in chitosan coated PLGA nanoparticles was designed for oral delivery with enhanced antitumor effect consecutively preserving the female fertility. The optimized oleanolic- bio-enhancer nano formulation CH-OA-B-PLGA with particle size was 342.2+/-3.7nm and zeta potential of 34.2+/-3.1mV was capable of lowering viability in MDAMB 231 cell line 16 times than OA. Further, mechanistic studies in MDAMB-231 cells revealed that CH-OA-PLGA induces apoptosis by mitochondrial membrane disruption; follows ROS mediated and caspase dependent apoptosis. The antitumor effect studied in 4-T1 induced Balb/c mice mammary tumor model displayed augmented antitumor potency by CH-OA-B-PLGA in comparison to OA. In the in vivo toxicity on Sprague-Dawley rat model, CH-OA-B-PLGA significantly displayed the safe profile and also preserves fertility in female rats. The experiment result suggests co-delivery of oleanolic acid with bio-enhancers as a breakthrough for developing safe chemotherapy for hormone independent breast cancer therapy countering the toxicity issues. PMID- 28591597 TI - Single-Molecule Threshold of HIV Fate Decision. AB - During early infection, the HIV virus makes a key decision between two states: lytic and lysogenic fate. Deterministic bistability requires combination of positive feedback and ultrasensitivity. Although HIV circuity includes positive feedback activation of the Tat transactivator, it lacks ultrasensitivity. How does the HIV circuit allow for multiple fates without ultrasensitivity? A new article suggests that HIV bistability is a result of a transient threshold that allows the kinetic trapping of the inactive state. Interestingly, the model shows that the transient threshold is a result of a single molecule threshold that occurs when the promoter toggles between inactive and active states. PMID- 28591598 TI - Mechanism of NTP Binding to the Active Site of T7 RNA Polymerase Revealed by Free Energy Simulation. AB - In genetic transcription, molecular dynamic details and energetics of NTP binding to the active site of RNA polymerase (RNAP) are poorly understood. In this article, we investigated the NTP binding process in T7 RNAP using all-atom MD simulation combined with the umbrella sampling technique. Based on our simulations, a two-step mechanism was proposed to explain NTP binding: first, substrate NTP in aqueous solution, which carries a magnesium ion, diffuses through a secondary channel of RNAP to attain a pore region, where it undergoes conformational changes to give a correct orientation; next, the NTP establishes initial basepairing contacts with the template nucleoside (TN). Our free-energy calculations suggest that both steps are spontaneous. This mechanism can easily explain the problem of NTP binding with different orientations. Moreover, it is found that the nascent NTP:TN basepair is fragile and easily broken by thermal disturbance. Therefore, we speculate that the fingers domain will be triggered to close, so as to create a steady environment for the next chemical step. The observations from the work provide valuable information for comprehensively understanding the mechanism of the basic step in genetic transcription. PMID- 28591599 TI - DNA Internal Motion Likely Accelerates Protein Target Search in a Packed Nucleoid. AB - Transcription factors must diffuse through densely packed and coiled DNA to find their binding sites. Using a coarse-grained model of DNA and lac repressor (LacI) in the Escherichia coli nucleoid, simulations were performed to examine how LacI diffuses in such a space. Despite the canonical picture of LacI diffusing rather freely, in reality the DNA is densely packed, is not rigid but highly mobile, and the dynamics of DNA dictates to a great extent the LacI motion. A possibly better picture of unbound LacI motion is that of gated diffusion, where DNA confines LacI in a cage, but LacI can move between cages when hindering DNA strands move out of the way. Three-dimensional diffusion constants for unbound LacI computed from simulations closely match those for unbound LacI in vivo reported in the literature. The internal motions of DNA appear to be governed by strong internal forces arising from being crowded into the small space of the nucleoid. A consequence of the DNA internal motion is that protein target search may be accelerated. PMID- 28591600 TI - Elastic-Fluid Model for DNA Damage and Mutation from Nuclear Fluid Segregation Due to Cell Migration. AB - When cells migrate through constricting pores, they incur DNA damage and develop genomic variation. Experiments show that this damage is not due to DNA breakage from mechanical stress on chromatin in the deformed nucleus. Here we propose a model for a mechanism by which nuclear deformation can lead to DNA damage. We treat the nucleus as an elastic-fluid system with an elastic component (chromatin) and fluid component that can be squeezed out when the nucleus is deformed. We couple the elastic-fluid model to the kinetics of DNA breakage and repair by assuming that the local volume fraction of the elastic component controls the rate of damage per unit volume due to naturally occurring DNA breaks, whereas the volume fraction of the fluid component controls the rate of repair of DNA breaks per unit volume by repair factors, which are soluble in the fluid. By comparing our results to a number of experiments on controlled migration through pores, we show that squeeze-out of the fluid, and hence of the mobile repair factors, is sufficient to account for the extent of DNA damage and genomic variation observed experimentally. We also use our model for migration through a cylindrical pore to estimate the variation with tissue stiffness of the mutation rate in tumors. PMID- 28591601 TI - Origin of Ion Specificity of Telomeric DNA G-Quadruplexes Investigated by Free Energy Simulations. AB - Telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) that form G quadruplex structures made of stacked guanines with monovalent cations bound at a central cavity. Although different ions can stabilize a G-quadruplex structure, the preferred bound ions are typically K+ or Na+. Several different strand folding topologies have been reported for Q-quadruplexes formed from telomeric repeats depending on DNA length and ion solution condition. This suggests a possible dependence of the ion selectivity of the central pore on the folding topology of the quadruplex. Molecular dynamics free energy perturbation has been employed to systematically study the relative affinity of the central quadruplex pore for different cation types and the associated energetic and solvation contributions to ion selectivity. The calculations have been performed on two different common quadruplex folding topologies. For both topologies, the same ion selectivity was found with a preference for K+ followed by Rb+ and Na+, which agrees with the experimentally determined preference for most investigated quadruplexes. The selectivity is determined by a balance between attractive Coulomb interactions and loss of hydration but also modulated by van der Waals contributions. Specificity is mediated by the central guanines and no significant contribution of the nucleic acid backbone. The simulations indicate that different topologies might be stabilized by ions bound at the surface or alternative sites of the quadruplex because the ion specificity of the central pore does not depend on the strand folding topology. PMID- 28591602 TI - Configurational Preference of the Glutamate Receptor Ligand Binding Domain Dimers. AB - Ionotropic glutamate receptors are a family of tetrameric ion channels with functional states consisting of nonconducting, conducting, and desensitized states that are starting to become well characterized by electrophysiological and biophysical studies. However, the structure and relative energetics of these states beyond the general structure of the receptor are still not well understood. It is known that the interface between monomeric subunits of the tetramer plays a major role in distinguishing these functional states. We have used umbrella sampling and multimicrosecond molecular dynamics simulations of the GluA2 AMPA subtype glutamate receptor ligand-binding domain (LBD) dimers to characterize a natural propensity of the LBD dimers for various configurational states. Our results show a proposed desensitized conformation of the LBD dimer is a highly preferable conformation of the LBD dimer without the influence of other receptor domains or crystallographic conditions. This has been demonstrated by both free protein simulations of 5 MUs duration, as well as by computed free energy difference between the active and desensitized states. At the same time, the simulations performed using the same protocols revealed that for the LBD mutant L483Y, known to lack desensitization, the postulated active state of the LBD dimer is indeed the preferred configurational state, which remained stable in the simulations. Our findings pave the path for developing more detailed hypotheses of the full receptor activation mechanism. Combined with the energetics of glutamate binding to the LBD and the energy required to open the transmembrane pore helices, our results strongly support a hypothesis that the low absolute free-energy state is the desensitized state of the intact AMPA receptor. PMID- 28591603 TI - One-Dimensional Search Dynamics of Tumor Suppressor p53 Regulated by a Disordered C-Terminal Domain. AB - Tumor suppressor p53 slides along DNA and finds its target sequence in drastically different and changing cellular conditions. To elucidate how p53 maintains efficient target search at different concentrations of divalent cations such as Ca2+ and Mg2+, we prepared two mutants of p53, each possessing one of its two DNA-binding domains, the CoreTet mutant having the structured core domain plus the tetramerization (Tet) domain, and the TetCT mutant having Tet plus the disordered C-terminal domain. We investigated their equilibrium and kinetic dissociation from DNA and search dynamics along DNA at various [Mg2+]. Although binding of CoreTet to DNA becomes markedly weaker at higher [Mg2+], binding of TetCT depends slightly on [Mg2+]. Single-molecule fluorescence measurements revealed that the one-dimensional diffusion of CoreTet along DNA consists of fast and slow search modes, the ratio of which depends strongly on [Mg2+]. In contrast, diffusion of TetCT consisted of only the fast mode. The disordered C terminal domain can associate with DNA irrespective of [Mg2+], and can maintain an equilibrium balance of the two search modes and the p53 search distance. These results suggest that p53 modulates the quaternary structure of the complex between p53 and DNA under different [Mg2+] and that it maintains the target search along DNA. PMID- 28591605 TI - Blocking of Single alpha-Hemolysin Pore by Rhodamine Derivatives. AB - Measurements of ion conductance through alpha-hemolysin pore in a bilayer lipid membrane revealed blocking of the ion channel by a series of rhodamine 19 and rhodamine B esters. The longest dwell closed time of the blocking was observed with rhodamine 19 butyl ester (C4R1), whereas the octyl ester (C8R1) was of poor effect. Voltage asymmetry in the binding kinetics indicated that rhodamine derivatives bound to the stem part of the aqueous pore lumen. The binding frequency was proportional to a quadratic function of rhodamine concentrations, thereby showing that the dominant binding species were rhodamine dimers. Two levels of the pore conductance and two dwell closed times of the pore were found. The dwell closed times lengthened as the voltage increased, suggesting impermeability of the channel for the ligands. Molecular docking analysis revealed two distinct binding sites within the lumen of the stem of the alpha hemolysin pore for the C4R1 dimer, but only one binding site for the C8R1 dimer. The blocking of the alpha-hemolysin nanopore by rhodamines could be utilized in DNA sequencing as additional optical sensing owing to bright fluorescence of rhodamines if used for DNA labeling. PMID- 28591604 TI - G Protein-Coupled Receptors Contain Two Conserved Packing Clusters. AB - G protein-coupled receptors (GPCRs) have evolved a seven-transmembrane helix framework that is responsive to a wide range of extracellular signals. An analysis of the interior packing of family A GPCR crystal structures reveals two clusters of highly packed residues that facilitate tight transmembrane helix association. These clusters are centered on amino acid positions 2.47 and 4.53, which are highly conserved as alanine and serine, respectively. Ala2.47 mediates the interaction between helices H1 and H2, while Ser4.53 mediates the interaction between helices H3 and H4. The helical interfaces outside of these clusters are lined with residues that are more loosely packed, a structural feature that facilitates motion of helices H5, H6, and H7, which is required for receptor activation. Mutation of the conserved small side chain at position 4.53 within packing cluster 2 is shown to disrupt the structure of the visual receptor rhodopsin, whereas sites in packing cluster 1 (e.g., positions 1.46 and 2.47) are more tolerant to mutation but affect the overall stability of the protein. These findings reveal a common structural scaffold of GPCRs that is important for receptor folding and activation. PMID- 28591606 TI - Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations. AB - Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane. Our simulations show strong overall agreement with published experimental data, reproducing the shapes of experimental oximetry curves with high accuracy. We calculate the upper limit transmembrane oxygen permeability of a 1-palmitoyl,2 oleoylphosphatidylcholine phospholipid bilayer to be 52 +/- 2 cm/s, close to the permeability of a water layer of the same thickness. With addition of cholesterol, the permeability decreases somewhat, reaching 40 +/- 2 cm/s at the near-saturating level of 62.5 mol % cholesterol and 10 +/- 2 cm/s in a 100% cholesterol mimic of the experimentally observed noncrystalline cholesterol bilayer domain. These reductions in permeability can only be biologically consequential in contexts where the diffusional path of oxygen is not water dominated. In our simulations, cholesterol reduces the overall solubility of oxygen within the membrane but enhances the oxygen transport parameter (solubility-diffusion product) near the membrane center. Given relatively low barriers to passing from membrane to membrane, our findings support hydrophobic channeling within membranes as a means of cellular and tissue-level oxygen transport. In such a membrane-dominated diffusional scheme, the influence of cholesterol on oxygen permeability is large enough to warrant further attention. PMID- 28591607 TI - SNARE-Mediated Single-Vesicle Fusion Events with Supported and Freestanding Lipid Membranes. AB - In vitro single-vesicle fusion assays are important tools to analyze the details of SNARE-mediated fusion processes. In this study, we employed planar pore spanning membranes (PSMs) prepared on porous silicon substrates with large pore diameters of 5 MUm, allowing us to compare the process of vesicle docking and fusion on the supported parts of the PSMs (s-PSMs) with that on the freestanding membrane parts (f-PSM) under the exact same experimental conditions. The PSMs harbor the t-SNARE DeltaN49-complex to investigate the dynamics and fusogenicity of single large unilamellar vesicles doped with the v-SNARE synaptobrevin 2 by means of spinning-disc confocal microscopy with a time resolution of 10 ms. Our results demonstrate that vesicles docked to the s-PSM were fully immobile, whereas those docked to the f-PSM were mobile with a mean diffusion coefficient of 0.42 MUm2/s. Despite the different dynamics of the vesicles on the two membrane types, similar fusion kinetics were observed, giving rise to a common fusion mechanism. Further investigations of individual lipid mixing events on the s-PSMs revealed semi-stable post-fusion structures. PMID- 28591608 TI - Ceramide-C16 Is a Versatile Modulator of Phosphatidylethanolamine Polymorphism. AB - Ceramide-C16 (CerC16) is a sphingolipid associated with several diseases like diabetes, obesity, Parkinson disease, and certain types of cancers. As a consequence, research efforts are devoted to identify the impact of CerC16 on the behavior of membranes, and to understand how it is involved in these diseases. In this work, we investigated the impacts of CerC16 (up to 20 mol %) on the lipid polymorphism of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), using differential scanning calorimetry, and sequential 2H and 31P solid-state nuclear magnetic resonance spectroscopy. A partial phase diagram is proposed. The results indicate that the presence of CerC16 leads to an upshift of the temperature of the gel-to-liquid crystalline (Lbeta - Lalpha) phase transition, leading to a large Lbeta/Lalpha phase coexistence region where gel-phase domains contain ~35 mol % CerC16. It also leads to a downshift of the temperature of the lamellar-to-inverted hexagonal (L - HII) phase transition of POPE. The opposite influence on the two-phase transitions of POPE brings a three-phase coexistence line when the two transitions overlap. The resulting HII phase can be ceramide enriched, coexisting with a Lalpha phase, or ceramide depleted, coexisting with a Lbeta phase, depending on the CerC16 proportions. The uncommon capability of CerC16 to modulate the membrane fluidity, its curvature propensity, and the membrane interface properties highlights its potential as a versatile messenger in cell membrane events. PMID- 28591609 TI - Investigation of Nanoscopic Phase Separations in Lipid Membranes Using Inverse FCS. AB - Measurement of the sizes of nanoscopic particles is a difficult challenge, especially in two-dimensional systems such as cell membranes. We have extended inverse fluorescence correlation spectroscopy (iFCS) to endow it with unique advantages for measuring particle size from the nano- to the microscale. We have augmented iFCS with an analysis of moments of fluorescence fluctuations and used it to measure stages of phase separation in model lipid bilayer membranes. We observed two different pathways for the growth of phase domains. In one, nanoscopic gel domains appeared first and then gradually grew to micrometer size. In the other, the domains reached micrometer size quickly, and their number gradually increased. These measurements demonstrate the value of iFCS measurements through their ability, to our knowledge, to provide new information about the mechanism of lipid phase separation and potentially about the physical basis of naturally occurring nanodomains such as lipid rafts. PMID- 28591610 TI - A Dynamic Biochemomechanical Model of Geometry-Confined Cell Spreading. AB - Cell spreading is involved in many physiological and pathological processes. The spreading behavior of a cell significantly depends on its microenvironment, but the biochemomechanical mechanisms of geometry-confined cell spreading remain unclear. A dynamic model is here established to investigate the spreading of cells confined in a finite region with different geometries, e.g., rectangle, ellipse, triangle, and L-shape. This model incorporates both biophysical and biochemical mechanisms, including actin polymerization, integrin-mediated binding, plasma viscoelasticity, and the elasticity of membranes and microtubules. We simulate the dynamic configurational evolution of a cell under different geometric microenvironments, including the angular distribution of microtubule forces and the deformation of the nucleus. The results indicate that the positioning of the cell-division plane is affected by its boundary confinement: a cell divides in a plane perpendicular to its minimal principal axis of inertia of area. In addition, the effects of such physical factors as the adhesive bond density, membrane tension, and microtubule number are examined on the cell spreading dynamics. The theoretical predictions show a good agreement with relevant experimental results. This work sheds light on the geometry confined spreading dynamics of cells and holds potential applications in regulating cell division and designing cell-based sensors. PMID- 28591611 TI - Concise Whole-Cell Modeling of BKCa-CaV Activity Controlled by Local Coupling and Stoichiometry. AB - Large-conductance Ca2+-dependent K+ (BKCa) channels are important regulators of electrical activity. These channels colocalize and form ion channel complexes with voltage-dependent Ca2+ (CaV) channels. Recent stochastic simulations of the BKCa-CaV complex with 1:1 stoichiometry have given important insight into the local control of BKCa channels by fluctuating nanodomains of Ca2+. However, such Monte Carlo simulations are computationally expensive, and are therefore not suitable for large-scale simulations of cellular electrical activity. In this work we extend the stochastic model to more realistic BKCa-CaV complexes with 1:n stoichiometry, and analyze the single-complex model with Markov chain theory. From the description of a single BKCa-CaV complex, using arguments based on timescale analysis, we derive a concise model of whole-cell BKCa currents, which can readily be analyzed and inserted into models of cellular electrical activity. We illustrate the usefulness of our results by inserting our BKCa description into previously published whole-cell models, and perform simulations of electrical activity in various cell types, which show that BKCa-CaV stoichiometry can affect whole-cell behavior substantially. Our work provides a simple formulation for the whole-cell BKCa current that respects local interactions in BKCa-CaV complexes, and indicates how local-global coupling of ion channels may affect cell behavior. PMID- 28591612 TI - Role of Ambient Gas Composition on Cold Physical Plasma-Elicited Cell Signaling in Keratinocytes. AB - A particularly promising medical application of cold physical plasma is the support of wound healing. This is presumably achieved by modulating inflammation as well as skin cell signaling and migration. Plasma-derived reactive oxygen and nitrogen species (ROS/RNS) are assumed the central biologically active plasma components. We hypothesized that modulating the environmental plasma conditions from pure nitrogen (N2) to pure oxygen (O2) in an atmospheric pressure argon plasma jet (kINPen) will change type and concentration of ROS/RNS and effectively tune the behavior of human skin cells. To investigate this, HaCaT keratinocytes were studied in vitro with regard to cell metabolism, viability, growth, gene expression signature, and cytokine secretion. Flow cytometry demonstrated only slight effects on cytotoxicity. O2 shielding provided stronger apoptotic effects trough caspase-3 activation compared to N2 shielding. Gene array technology revealed induction of signaling and communication proteins such as immunomodulatory interleukin 6 as well as antioxidative and proproliferative molecules (HMOX1, VEGFA, HBEGF, CSF2, and MAPK) in response to different plasma shielding gas compositions. Cell response was correlated to reactive species: oxygen-shielding plasma induces a cell response more efficiently despite an apparent decrease of hydrogen peroxide (H2O2), which was previously shown to be a major player in plasma-cell regulation, emphasizing the role of non-H2O2 ROS like singlet oxygen. Our results suggest differential effects of ROS- and RNS-rich plasma, and may have a role in optimizing clinical plasma applications in chronic wounds. PMID- 28591613 TI - Analysis of Noise Mechanisms in Cell-Size Control. AB - At the single-cell level, noise arises from multiple sources, such as inherent stochasticity of biomolecular processes, random partitioning of resources at division, and fluctuations in cellular growth rates. How these diverse noise mechanisms combine to drive variations in cell size within an isoclonal population is not well understood. Here, we investigate the contributions of different noise sources in well-known paradigms of cell-size control, such as adder (division occurs after adding a fixed size from birth), sizer (division occurs after reaching a size threshold), and timer (division occurs after a fixed time from birth). Analysis reveals that variation in cell size is most sensitive to errors in partitioning of volume among daughter cells, and not surprisingly, this process is well regulated among microbes. Moreover, depending on the dominant noise mechanism, different size-control strategies (or a combination of them) provide efficient buffering of size variations. We further explore mixer models of size control, where a timer phase precedes/follows an adder, as has been proposed in Caulobacter crescentus. Although mixing a timer and an adder can sometimes attenuate size variations, it invariably leads to higher-order moments growing unboundedly over time. This results in a power-law distribution for the cell size, with an exponent that depends inversely on the noise in the timer phase. Consistent with theory, we find evidence of power-law statistics in the tail of C. crescentus cell-size distribution, although there is a discrepancy between the observed power-law exponent and that predicted from the noise parameters. The discrepancy, however, is removed after data reveal that the size added by individual newborns in the adder phase itself exhibits power-law statistics. Taken together, this study provides key insights into the role of noise mechanisms in size homeostasis, and suggests an inextricable link between timer-based models of size control and heavy-tailed cell-size distributions. PMID- 28591614 TI - Cell Division Induces and Switches Coherent Angular Motion within Bounded Cellular Collectives. AB - Collective cell migration underlies many biological processes, including embryonic development, wound healing, and cancer progression. In the embryo, cells have been observed to move collectively in vortices using a mode of collective migration known as coherent angular motion (CAM). To determine how CAM arises within a population and changes over time, here, we study the motion of mammary epithelial cells within engineered monolayers, in which the cells move collectively about a central axis in the tissue. Using quantitative image analysis, we find that CAM is significantly reduced when mitosis is suppressed. Particle-based simulations recreate the observed trends, suggesting that cell divisions drive the robust emergence of CAM and facilitate switches in the direction of collective rotation. Our simulations predict that the location of a dividing cell, rather than the orientation of the division axis, facilitates the onset of this motion. These predictions agree with experimental observations, thereby providing, to our knowledge, new insight into how cell divisions influence CAM within a tissue. Overall, these findings highlight the dynamic nature of CAM and suggest that regulating cell division is crucial for tuning emergent collective migratory behaviors, such as vortical motions observed in vivo. PMID- 28591615 TI - Transient Thresholding: A Mechanism Enabling Noncooperative Transcriptional Circuitry to Form a Switch. AB - Threshold generation in fate-selection circuits is often achieved through deterministic bistability, which requires cooperativity (i.e., nonlinear activation) and associated hysteresis. However, the Tat positive-feedback loop that controls HIV's fate decision between replication and proviral latency lacks self-cooperativity and deterministic bistability. Absent cooperativity, it is unclear how HIV can temporarily remain in an off-state long enough for the kinetically slower epigenetic silencing mechanisms to act-expression fluctuations should rapidly trigger active positive feedback and replication, precluding establishment of latency. Here, using flow cytometry and single-cell imaging, we find that the Tat circuit exhibits a transient activation threshold. This threshold largely disappears after ~40 h-accounting for the lack of deterministic bistability-and promoter activation shortens the lifetime of this transient threshold. Continuous differential equation models do not recapitulate this phenomenon. However, chemical reaction (master equation) models where the transcriptional transactivator and promoter toggle between inactive and active states can recapitulate the phenomenon because they intrinsically create a single molecule threshold transiently requiring excess molecules in the inactive state to achieve at least one molecule (rather than a continuous fractional value) in the active state. Given the widespread nature of promoter toggling and transcription factor modifications, transient thresholds may be a general feature of inducible promoters. PMID- 28591617 TI - Neuronal activity-regulated alternative mRNA splicing. AB - Activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. Numerous genes whose expression is induced by different neuronal plasticity inducing pathways have been identified, but the alteration of gene expression levels represents only part of the complexity of the activity-regulated transcriptional program. Alternative splicing of precursor mRNA is an additional mechanism that modulates the activity-dependent transcriptional signature. Recently developed splicing sensitive transcriptome wide analyses improve our understanding of the underlying mechanisms and demonstrate to what extend the activity regulated transcriptome is alternatively spliced. So far, only for a small group of differentially spliced mRNAs of synaptic proteins, the functional implications have been studied in detail. These include examples in which differential exon usage can result in the expression of alternative proteins which interfere with or alter the function of preexisting proteins and cause a dominant negative functional block of constitutively expressed variants. Such altered proteins contribute to the structural and functional reorganization of pre- and postsynaptic terminals and to the maintenance and formation of synapses. In addition, activity-induced alternative splicing can affect the untranslated regions (UTRs) and generates mRNAs harboring different cis-regulatory elements. Such differential UTRs can influence mRNA stability, translation, and can change the targeting of mRNAs to subcellular compartments. Here, we summarize different categories of alternative splicing which are thought to contribute to synaptic remodeling, give an overview of activity-regulated alternatively spliced mRNAs of synaptic proteins that impact synaptic functions, and discuss splicing factors and epigenetic modifications as regulatory determinants. PMID- 28591618 TI - Exploring drug solubility in fasted human intestinal fluid aspirates: Impact of inter-individual variability, sampling site and dilution. AB - One of the main factors defining intestinal drug absorption is the solubility of the compound in the gastrointestinal environment. This study reports the solubility of a series of 27 commonly used acidic, neutral and basic drugs in human intestinal fluid samples collected from the duodenum or jejunum of healthy volunteers under fasted state conditions. The interindividual variability as well as the impact of factors such as pH, sampling site and bile salts on the solubility in human intestinal fluids was investigated. The solubility measurements were evaluated using a statistical experimental design. Variability in solubility across volunteers and sampling sites was highly compound-specific and appeared to be substantial for weak acids and bases and for lipophilic drugs. Both pH of the samples and the abundance of amphiphilic components were responsible for the variability observed in the solubility values obtained. The results confirm strong interindividual differences in intraluminal solubility, especially for compounds with high lipophilicity and/or compounds with a pKa value within the physiological pH range. It is important to recognize this variability in intestinal drug solubility as it may considerably influence the therapeutic outcome among patients. PMID- 28591616 TI - Focal Adhesion Kinase: The Reversible Molecular Mechanosensor. AB - Sensors are the first element of the pathways that control the response of cells to their environment. Protein complexes that produce or enable a chemical signal in response to a mechanical stimulus are called "mechanosensors". In this work, we develop a theoretical model describing the physical mechanism of a reversible single-molecule stiffness sensor. Although this has the potential for general application, here we apply the model to focal adhesion kinase, which initiates the chemical signal in its active phosphorylated conformation, but can spontaneously return to its closed folded conformation. We find how the rates of conformation changes depend on the substrate stiffness and the pulling force applied from the cell cytoskeleton. We find the sensor is homeostatic, spontaneously self-adjusting to reach a state where its range of maximum sensitivity matches the substrate stiffness. The results compare well with the phenotype observations of cells on different substrates. PMID- 28591621 TI - RBR Ubiquitin Transfer: Not Simply an "Open" and "Closed" Case? AB - The three distinct types of E3 ubiquitin ligases, RING, HECT, and RBR, employ different modes of ubiquitin transfer including E2~Ub conjugate type and conformation. In this issue of Structure, Dove et al. (2017) provide a structural rationale for the preference and conformation of the UbcH7~Ub conjugate by the RBR E3 ligase HHARI. PMID- 28591620 TI - The effects of mechanical and hydrothermal aging on microstructure and biaxial flexural strength of an anterior and a posterior monolithic zirconia. AB - OBJECTIVES: To evaluate the effect of hydrothermal aging (H), mechanical cycling (M), and the combination of hydrothermal plus mechanical cycling (H+M) on biaxial flexural strength (BFS) and microstructure of two monolithic zirconias, indicated for anterior (AMZ) or posterior restorations (PMZ) and a conventional zirconia (IZr). METHODS: Disc specimens of each material (n=12) were submitted to: i) H (8h in autoclave at 134 degrees C); ii) M (106 cycles, at 40% of BFS); and iii) H+M. BFS was measured (ISO-6872) and Weibull modulus (m) and the characteristic strength (sigma0) were calculated. crystalline phase composition analyzed by XRD, and grain size measured by MEV analysis. RESULTS: XRD analysis showed AMZ was not susceptible to monoclinic transformation in any treatment. Conventional zirconia (IZr) and PMZ had monoclinic transformation only after H and H+M. BFS of AMZ was lower than PMZ and IZr. Cubic phase was found in all conditions for AMZ and IZr, while it was identified in PMZ only after H and H+M. BFS of AMZ was affected by M and H+M. For IZr and PMZ the unique difference detected in BFS was in the comparison of H to M. H treatment induced lower Weibull modulus, but characteristic strength was compatible with the BFS results. AMZ grain size (MUm2) was 8.6 times larger than PMZ grains, and 13.6 times larger than IZr grains. CONCLUSIONS: AMZ showed the largest mean grain size, had the lowest BFS values, and was affected when mechanical cycling was involved. Monoclinic transformation was not found in any treatment for AMZ, but was found in IZr and PMZ when hydrothermal aging was used alone or when combined with mechanical cycling. PMZ showed similar behavior to the IZr. H induced to higher fracture probability. CLINICAL SIGNIFICANCE: Translucent monolithic dental zirconia available on the market may behave differently under simulated oral aging. The relationship between composition and microstructure determines their properties presumably, and clinical performance. PMID- 28591619 TI - High hydrostatic pressure encapsulation of doxorubicin in ferritin nanocages with enhanced efficiency. AB - Human ferritin (HFn) nanocaging is becoming an appealing platform for anticancer drugs delivery. However, protein aggregation always occurs during the encapsulation process, resulting in low production efficiency. A new approach using high hydrostatic pressure (HHP) was explored in this study to overcome the problem of loading doxorubicin (DOX) in HFn. At the pressure of 500MPa and pH 5.5, DOX molecules were found to be encapsulated into HFn. Meanwhile, combining it with an additive of 20mM arginine completely inhibited precipitation and aggregation, resulting in highly monodispersed nanoparticles with almost 100% protein recovery. Furthermore, stepwise decompression and incubation of the complex in atmospheric pressure at pH 7.4 for another period could further increase the DOX encapsulation ratio. The HFn-DOX nanoparticles (NPs) showed similar morphology and structural features to the hollow cage and no notable drug leakage occurred for HFn-DOX NPs when stored at 4 degrees C and pH 7.4 for two weeks. HFn-DOX NPs prepared through HHP also showed significant cytotoxicity in vitro and higher antitumor bioactivity in vivo than naked DOX. Moreover, This HHP encapsulation strategy could economize on DOX that was greatly wasted during the conventional preparation process simply through a desalting column. These results indicated that HHP could offer a feasible approach with high efficiency for the production of HFn-DOX NPs. PMID- 28591622 TI - Structural Insight into the Core of CAD. AB - The CAD complex catalyzes the first four reactions of the pyrimidine biosynthetic pathway. CAD exhibits allosteric regulaton, both negative and positive, covalent regulation by phosphorylation, and metabolite channeling. In this issue of Structure, Moreno-Morcillo et al. (2017) show that the dihydroorotase domain plays a crucial role in the establishment of the quaternary structure of this complex. PMID- 28591623 TI - Multiple Motifs Compete for EB-Dependent Microtubule Plus End Binding. AB - Microtubule (MT) dynamics are regulated by a plethora of microtubule-associated proteins (MAPs). An important MT regulator is the end binding protein EB, which serves as a scaffold to recruit other MAPs to MT plus ends. In this issue of Structure, Kumar et al. (2017) describe LxxPTPh, a new linear sequence motif that can bind EBs. The finding opens up the possibility of discovering new MT regulators. PMID- 28591624 TI - Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex. AB - Cullin RING E3 ubiquitin ligases (CRLs) function in the ubiquitin proteasome system to catalyze the transfer of ubiquitin from E2 conjugating enzymes to specific substrate proteins. CRLs are large dynamic complexes and attractive drug targets for the development of small-molecule inhibitors and chemical inducers of protein degradation. The atomic details of whole CRL assembly and interactions that dictate subunit specificity remain elusive. Here we present the crystal structure of a pentameric CRL2VHL complex, composed of Cul2, Rbx1, Elongin B, Elongin C, and pVHL. The structure traps a closed state of full-length Cul2 and a new pose of Rbx1 in a trajectory from closed to open conformation. We characterize hotspots and binding thermodynamics at the interface between Cul2 and pVHL-EloBC and identify mutations that contribute toward a selectivity switch for Cul2 versus Cul5 recognition. Our findings provide structural and biophysical insights into the whole Cul2 complex that could aid future drug targeting. PMID- 28591625 TI - Functional comparison of versatile carbohydrate esterases from families CE1, CE6 and CE16 on acetyl-4-O-methylglucuronoxylan and acetyl-galactoglucomannan. AB - BACKGROUND: The backbone structure of many hemicelluloses is acetylated, which presents a challenge when the objective is to convert corresponding polysaccharides to fermentable sugars or else recover hemicelluloses for biomaterial applications. Carbohydrate esterases (CE) can be harnessed to overcome these challenges. METHODS: Enzymes from different CE families, AnAcXE (CE1), OsAcXE (CE6), and MtAcE (CE16) were compared based on action and position preference towards acetyl-4-O-methylglucuronoxylan (MGX) and acetyl galactoglucomannan (GGM). To determine corresponding positional preferences, the relative rate of acetyl group released by each enzyme was analyzed by real time 1H NMR. RESULTS: AnAcXE (CE1) showed lowest specific activity towards MGX, where OsAcXE (CE6) and MtAcE were approximately four times more active than AnAcXE (CE1). MtAcE (CE16) was further distinguished by demonstrating 100 times higher activity on GGM compared to AnAcXE (CE1) and OsAcXE (CE6), and five times higher activity on GGM than MGX. Following 24h incubation, all enzymes removed between 78 and 93% of total acetyl content from MGX and GGM, where MtAcE performed best on both substrates. MAJOR CONCLUSIONS: Considering action on MGX, all esterases showed preference for doubly substituted xylopyranosyl residues (2,3-O-acetyl Xylp). Considering action on GGM, OsAcXE (CE6) preferentially targeted 2-O-acetyl mannopyranosyl residues (2-O-acetyl-Manp) whereas AnAcXE (CE1) demonstrated highest activity towards 3-O-acetyl-Manp positions; regiopreference of MtAcE (CE16) on GGM was less clear. GENERAL SIGNIFICANCE: The current comparative analysis identifies options to control the position of acetyl group release at initial stages of reaction, and enzyme combinations likely to accelerate deacetylation of major hemicellulose sources. PMID- 28591627 TI - Triglyceride Metabolism under Attack. AB - Hydrolysis of circulating triglycerides is carried out by the enzyme lipoprotein lipase, which is transported and anchored to the capillary wall by the protein GPIHBP1. Recent evidence indicates that certain individuals develop autoantibodies against GPIHBP1, impairing lipoprotein lipase function and leading to markedly elevated plasma triglyceride levels (Beigneux et al., 2017). PMID- 28591628 TI - Type I Interferons Interfere with Liver Glucose Metabolism. AB - The specific immunological components linking metabolic stresses to liver inflammation and systemic metabolic pathologies in obesity are not entirely known. A recent study (Ghazarian et al., 2017) reveals that obesity-induced type I interferon signaling drives the accumulation and activation of intrahepatic CD8+ T cells, leading to systemic metabolic deterioration. PMID- 28591626 TI - Multi-omics analysis provides insight to the Ignicoccus hospitalis-Nanoarchaeum equitans association. AB - BACKGROUND: Studies of interspecies interactions are inherently difficult due to the complex mechanisms which enable these relationships. A model system for studying interspecies interactions is the marine hyperthermophiles Ignicoccus hospitalis and Nanoarchaeum equitans. Recent independently-conducted 'omics' analyses have generated insights into the molecular factors modulating this association. However, significant questions remain about the nature of the interactions between these archaea. METHODS: We jointly analyzed multiple levels of omics datasets obtained from published, independent transcriptomics, proteomics, and metabolomics analyses. DAVID identified functionally-related groups enriched when I. hospitalis is grown alone or in co-culture with N. equitans. Enriched molecular pathways were subsequently visualized using interaction maps generated using STRING. RESULTS: Key findings of our multi-level omics analysis indicated that I. hospitalis provides precursors to N. equitans for energy metabolism. Analysis indicated an overall reduction in diversity of metabolic precursors in the I. hospitalis-N. equitans co-culture, which has been connected to the differential use of ribosomal subunits and was previously unnoticed. We also identified differences in precursors linked to amino acid metabolism, NADH metabolism, and carbon fixation, providing new insights into the metabolic adaptions of I. hospitalis enabling the growth of N. equitans. CONCLUSIONS: This multi-omics analysis builds upon previously identified cellular patterns while offering new insights into mechanisms that enable the I. hospitalis-N. equitans association. GENERAL SIGNIFICANCE: Our study applies statistical and visualization techniques to a mixed-source omics dataset to yield a more global insight into a complex system, that was not readily discernable from separate omics studies. PMID- 28591629 TI - Treg Cells Survive and Thrive in Inhospitable Environments. AB - Immune responses are dangerous by nature and require regulation to prevent inflammatory and/or autoimmune sequelae and allow healing. CD4+Foxp3+ T cells (Treg cells) play a crucial role in this process, and in this edition of Cell Metabolism, Angelin et al. (2017) describe how these cells are metabolically adapted to the job. PMID- 28591631 TI - Gut-Brain Glucose Signaling in Energy Homeostasis. AB - Intestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection. PMID- 28591630 TI - A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism. AB - In animal models, the physiological systems involved in metabolic homeostasis exhibit a sex difference. Investigators often use male rodents because they show metabolic disease better than females. Thus, females are not used precisely because of an acknowledged sex difference that represents an opportunity to understand novel factors reducing metabolic disease more in one sex than the other. The National Institutes of Health (NIH) mandate to consider sex as a biological variable in preclinical research places new demands on investigators and peer reviewers who often lack expertise in model systems and experimental paradigms used in the study of sex differences. This Perspective discusses experimental design and interpretation in studies addressing the mechanisms of sex differences in metabolic homeostasis and disease, using animal models and cells. We also highlight current limitations in research tools and attitudes that threaten to delay progress in studies of sex differences in basic animal research. PMID- 28591632 TI - Bread Affects Clinical Parameters and Induces Gut Microbiome-Associated Personal Glycemic Responses. AB - Bread is consumed daily by billions of people, yet evidence regarding its clinical effects is contradicting. Here, we performed a randomized crossover trial of two 1-week-long dietary interventions comprising consumption of either traditionally made sourdough-leavened whole-grain bread or industrially made white bread. We found no significant differential effects of bread type on multiple clinical parameters. The gut microbiota composition remained person specific throughout this trial and was generally resilient to the intervention. We demonstrate statistically significant interpersonal variability in the glycemic response to different bread types, suggesting that the lack of phenotypic difference between the bread types stems from a person-specific effect. We further show that the type of bread that induces the lower glycemic response in each person can be predicted based solely on microbiome data prior to the intervention. Together, we present marked personalization in both bread metabolism and the gut microbiome, suggesting that understanding dietary effects requires integration of person-specific factors. PMID- 28591633 TI - Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation. AB - T cells undergo metabolic reprogramming with major changes in cellular energy metabolism during activation. In patients with mitochondrial disease, clinical data were marked by frequent infections and immunodeficiency, prompting us to explore the consequences of oxidative phosphorylation dysfunction in T cells. Since cytochrome c oxidase (COX) is a critical regulator of OXPHOS, we created a mouse model with isolated dysfunction in T cells by targeting a gene, COX10, that produces mitochondrial disease in humans. COX dysfunction resulted in increased apoptosis following activation in vitro and immunodeficiency in vivo. Select T cell effector subsets were particularly affected; this could be traced to their bioenergetic requirements. In summary, the findings presented herein emphasize the role of COX particularly in T cells as a metabolic checkpoint for cell fate decisions following T cell activation, with heterogeneous effects in T cell subsets. In addition, our studies highlight the utility of translational models that recapitulate human mitochondrial disease for understanding immunometabolism. PMID- 28591634 TI - A Cell-Autonomous Mammalian 12 hr Clock Coordinates Metabolic and Stress Rhythms. AB - Besides circadian rhythms, oscillations cycling with a 12 hr period exist. However, the prevalence, origin, regulation, and function of mammalian 12 hr rhythms remain elusive. Utilizing an unbiased mathematical approach identifying all superimposed oscillations, we uncovered prevalent 12 hr gene expression and metabolic rhythms in mouse liver, coupled with a physiological 12 hr unfolded protein response oscillation. The mammalian 12 hr rhythm is cell autonomous, driven by a dedicated 12 hr pacemaker distinct from the circadian clock, and can be entrained in vitro by metabolic and ER stress cues. Mechanistically, we identified XBP1s as a transcriptional regulator of the mammalian 12 hr clock. Downregulation of the 12 hr gene expression strongly correlates with human hepatic steatosis and steatohepatitis, implying its importance in maintaining metabolic homeostasis. The mammalian 12 hr rhythm of gene expression also is conserved in nematodes and crustaceans, indicating an ancient origin of the 12 hr clock. Our work sheds new light on how perturbed biological rhythms contribute to human disease. PMID- 28591636 TI - N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking beta Cell Dysfunction in Type 2 Diabetes. AB - The processes contributing to beta cell dysfunction in type 2 diabetes (T2D) are uncertain, largely because it is difficult to access beta cells in their intact immediate environment. We examined the pathophysiology of beta cells under T2D progression directly in pancreatic tissues. We used MALDI imaging of Langerhans islets (LHIs) within mouse tissues or from human tissues to generate in situ omics data, which we supported with in vitro experiments. Molecular interaction networks provided information on functional pathways and molecules. We found that stearoylcarnitine accumulated in beta cells, leading to arrest of insulin synthesis and energy deficiency via excessive beta-oxidation and depletion of TCA cycle and oxidative phosphorylation metabolites. Acetylcarnitine and an accumulation of N-acyl taurines, a group not previously detected in beta cells, provoked insulin secretion. Thus, beta cell dysfunction results from enhanced insulin secretion combined with an arrest of insulin synthesis. PMID- 28591637 TI - Amino Acid Transporter Slc38a5 Controls Glucagon Receptor Inhibition-Induced Pancreatic alpha Cell Hyperplasia in Mice. AB - Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids and compensatory glucagon hypersecretion involving expansion of pancreatic alpha cell mass. Recent findings indicate that hyperaminoacidemia triggers pancreatic alpha cell proliferation via an mTOR dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative alpha cells and that Slc38a5 controls the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased alpha cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino-acid-dependent regulation of pancreatic alpha cell mass in mice. PMID- 28591635 TI - Hypothalamic-Pituitary Axis Regulates Hydrogen Sulfide Production. AB - Decreased growth hormone (GH) and thyroid hormone (TH) signaling are associated with longevity and metabolic fitness. The mechanisms underlying these benefits are poorly understood, but may overlap with those of dietary restriction (DR), which imparts similar benefits. Recently we discovered that hydrogen sulfide (H2S) is increased upon DR and plays an essential role in mediating DR benefits across evolutionary boundaries. Here we found increased hepatic H2S production in long-lived mouse strains of reduced GH and/or TH action, and in a cell-autonomous manner upon serum withdrawal in vitro. Negative regulation of hepatic H2S production by GH and TH was additive and occurred via distinct mechanisms, namely direct transcriptional repression of the H2S-producing enzyme cystathionine gamma lyase (CGL) by TH, and substrate-level control of H2S production by GH. Mice lacking CGL failed to downregulate systemic T4 metabolism and circulating IGF-1, revealing an essential role for H2S in the regulation of key longevity-associated hormones. PMID- 28591640 TI - Effects of atmospheric ageing under different temperatures on surface properties of sludge-derived biochar and metal/metalloid stabilization. AB - Ageing is a common phenomenon during biochar storage and its soil application. In this study, we exposed sludge-derived biochar (SDBC) in the air under 4 degrees C, 22 degrees C, and 45 degrees C for 30-120 d to imitate the ageing process after SDBC production. The aged SDBC was characterized and its sorption capacities for Pb(II), Cr(V) and As(III) were compared with the fresh ones in batch sorption experiments. The results showed an increase in acidity, cation exchange capacity, and carboxyl groups of SDBC surface, but a decrease in alkalinity and Fe(III) species during ageing, indicating the oxidation. In addition, ageing for more than 30 d was found to favor the Pb(II) and As(III) sorption, because of higher density of available oxygen-containing groups. The Cr(VI) sorption was found to be compromised by the ageing, because some reducing agents for Cr(VI) reduction was consumed there. Higher temperatures accelerated the above-mentioned ageing effect. Yet, when the SDBC was applied in the heavy metal contaminated soil, its performance would be affected by both ageing of SDBC itself as well as long-term interactions among soil components, such as colloids and solution, heavy metals, and SDBC, which require further investigation. PMID- 28591638 TI - Interrupted Glucagon Signaling Reveals Hepatic alpha Cell Axis and Role for L Glutamine in alpha Cell Proliferation. AB - Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to alpha cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for alpha cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human alpha cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated alpha cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. alpha cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in alpha cell proliferation. These results indicate a hepatic alpha islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate alpha cell proliferation and mass via mTOR-dependent nutrient sensing. PMID- 28591641 TI - Cardiac stem cells for myocardial regeneration: promising but not ready for prime time. AB - Remarkable strides have been made in the treatment of ischemic heart disease in decades. As the initial loss of cardiomyocytes associated with myocardial infarction serves as an impetus for myocardial remodeling, the ability to replace these cells with healthy counterparts would represent an effective treatment for many forms of cardiovascular disease. The discovery of cardiac stem cells (that can differentiate into multiple lineages) highlighted the possibility for development of cell-based therapeutics to achieve this ultimate goal. Recent research features cardiac stem cell maintenance, proliferation, and differentiation, as well as direct reprogramming of various somatic cells into cardiomyocytes, all within the context of the holy grail of regeneration of the injured heart. Much work remains to be done, but the future looks bright! PMID- 28591639 TI - Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control. AB - Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic beta cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release. PMID- 28591642 TI - Effects of amplitude and predictability of perturbations to the arm on anticipatory and reactionary muscle responses to maintain balance. AB - Disturbances to balance arising from forces applied to the upper limb have received relatively little attention compared to disturbances arising from support surface perturbations. In this study we applied fast ramp perturbations to the hand in anterior, posterior, medial and lateral directions. The effects of perturbation predictability and amplitude on the postural response of upper limb, trunk and lower limb muscles were investigated. Perturbations were applied either in blocks of constant amplitude and direction (predictable) or with direction and amplitude varying randomly (random) from trial to trial. The spatial-temporal patterns of anticipatory muscle activation under the predictable condition and the reactionary responses following the perturbation under both conditions were similarly organized. The size of the response increased systematically with the perturbation magnitude for both anticipatory and reactionary changes in muscle activation. However, the slope of the relation between perturbation amplitude and the magnitude of the change in muscle activation was greater when perturbations were predictable than when they were randomly selected. The timing of both the anticipatory and reactionary increases in muscle activation was invariant across perturbation amplitudes. The characteristics of the reactionary responses have a similar organization to the long latency muscle responses to support surface perturbations. PMID- 28591643 TI - Female choice, male dominance and condition-related traits in the polygynous subterranean rodent Ctenomys talarum. AB - Ctenomys talarum is a solitary and highly territorial species in which dominant males aggressively deter other males and monopolize reproductive activity. Female preference for dominant males is not easy to assess due to coercive mating by males. Hence, we aimed to answer if behavioural dominance and several condition related traits like testosterone and cortisol levels, endoparasite load, and hematocrit volume may affect female preference when they have the opportunity to exert it. We designed a laboratory experiment using wild-caught C. talarum and employed a combined approach involving behavioural observations and the measurements of parameters of physical condition. We staged dyadic encounters between males to determine dominance index and then analyzed female preference towards tethered males (n=15) or their odours (n=18). Male dominance did not affect female preferences when odours were presented. When two tethered males were offered, females preferred those with higher dominance index. Preference of females for dominant males would mainly represent indirect benefits. Females did not show preference for males in relation to any physiological trait evaluated. Dominance was found negatively related to cortisol levels, probably avoiding the glucocorticoids-related costs, and positively related to parasite diversity, since they could tolerate it without impairing their health. PMID- 28591645 TI - Fast method for the determination of short-chain-length polyhydroxyalkanoates (scl-PHAs) in bacterial samples by In Vial-Thermolysis (IVT). AB - A new method based on the GC-MS analysis of thermolysis products obtained by treating bacterial samples at a high temperature (above 270 degrees C) has been developed. This method, here named "In-Vial-Thermolysis" (IVT), allowed for the simultaneous determination of short-chain-length polyhydroxyalkanoates (scl-PHA) content and composition. The method was applied to both single strains and microbial mixed cultures (MMC) fed with different carbon sources. The IVT procedure provided similar analytical performances compared to previous Py-GC-MS and Py-GC-FID methods, suggesting a similar application for PHA quantitation in bacterial cells. Results from the IVT procedure and the traditional methanolysis method were compared; the correlation between the two datasets was fit for the purpose, giving a R2 of 0.975. In search of further simplification, the rationale of IVT was exploited for the development of a "field method" based on the titration of thermolyzed samples with sodium hydrogen carbonate to quantify PHA inside bacterial cells. The accuracy of the IVT method was fit for the purpose. These results lead to the possibility for the on-line measurement of PHA productivity. Moreover, they allow for the fast and inexpensive quantification/characterization of PHA for biotechnological process control, as well as investigation over various bacterial communities and/or feeding strategies. PMID- 28591644 TI - Co-expression of glucose-6-phosphate dehydrogenase and acyl-CoA binding protein enhances lipid accumulation in the yeast Yarrowia lipolytica. AB - The oleaginous yeast Yarrowia lipolytica is a convenient model for investigating lipid biosynthesis and for engineering high lipid accumulated strains. In this organism, the pentose phosphate pathway is the major source of NADPH for lipid biosynthesis. Thus, we over-expressed gene encoding NADP+-dependent glucose-6 phosphate dehydrogenase (ZWF1) in a strain deficient in peroxisome biogenesis. However, this strategy suppressed growth during cultivation under lipogenic conditions and did not significantly increase lipid accumulation. Remarkably, co expression of gene encoding acyl-CoA binding protein (ACBP), which functions as an intracellular acyl-CoA transporter and acyl-CoA-pool former, restored growth. Co-expression of ZWF1 and ACBP increased the lipid content to 30% of dry cell weight via de novo lipid synthesis. In comparison to wild type, the engineered strain accumulated 41% more lipids with a higher ratio of saturated to unsaturated fatty acids. PMID- 28591646 TI - Cultivating a Robust Stem Cell Field. PMID- 28591648 TI - Using Zebrafish to Study Pathways that Regulate Hematopoietic Stem Cell Self Renewal and Migration. AB - This perspective describes the usefulness of zebrafish as a model to study interaction of hematopoietic stem cells with the associated niche in vivo, explains how such interactions influence regeneration, migration, and clonality of HSCs, and defines their fate during differentiation. PMID- 28591647 TI - The Art of Capturing Pluripotency: Creating the Right Culture. AB - Embryonic stem cells (ESCs) are a unique tool for genetic perturbation of mammalian cellular and organismal processes additionally in humans offer unprecedented opportunities for disease modeling and cell therapy. Furthermore, ESCs are a powerful system for exploring the fundamental biology of pluripotency. Indeed understanding the control of self-renewal and differentiation is key to realizing the potential of ESCs. Building on previous observations, we found that mouse ESCs can be derived and maintained with high efficiency through insulation from differentiation cues combined with consolidation of an innate cell proliferation program. This finding of a pluripotent ground state has led to conceptual and practical advances, including the establishment of germline competent ESCs from recalcitrant mouse strains and for the first time from the rat. Here, we summarize historical and recent progress in defining the signaling environment that supports self-renewal. We compare the contrasting requirements of two types of pluripotent stem cell, naive ESCs and primed post-implantation epiblast stem cells (EpiSCs), and consider the outstanding challenge of generating naive pluripotent stem cells from different mammals. PMID- 28591649 TI - Activation of Lineage Regulators and Transposable Elements across a Pluripotent Spectrum. AB - Embryonic stem cells (ESCs) are characterized by the pluripotent capacity to generate all embryonic lineages. Here, we show that ESCs can occupy a spectrum of distinct transcriptional and epigenetic states in response to varied extrinsic conditions. This spectrum broadly corresponds to a developmental continuum of pluripotency and is coupled with a gradient of increasing global DNA methylation. Each pluripotent state is linked with activation of distinct classes of transposable elements (TEs), which in turn influence ESCs through generating chimeric transcripts. Moreover, varied ESC culture parameters differentially license heterogeneous activation of master lineage regulators, including Sox1, Gata4, or Blimp1, and influence differentiation. Activation of Blimp1 is prevalent in 2i (without LIF) conditions, and marks a dynamic primordial germ cell (PGC)-like sub-state that is directly repressed by Klf4 downstream of LIF/STAT3 signaling. Thus, extrinsic cues establish a spectrum of pluripotent states, in part by modulating sub-populations, as well as directing the transcriptome, epigenome, and TE. PMID- 28591650 TI - Long-Term Culture of Self-renewing Pancreatic Progenitors Derived from Human Pluripotent Stem Cells. AB - Pluripotent stem cells have been proposed as an unlimited source of pancreatic beta cells for studying and treating diabetes. However, the long, multi-step differentiation protocols used to generate functional beta cells inevitably exhibit considerable variability, particularly when applied to pluripotent cells from diverse genetic backgrounds. We have developed culture conditions that support long-term self-renewal of human multipotent pancreatic progenitors, which are developmentally more proximal to the specialized cells of the adult pancreas. These cultured pancreatic progenitor (cPP) cells express key pancreatic transcription factors, including PDX1 and SOX9, and exhibit transcriptomes closely related to their in vivo counterparts. Upon exposure to differentiation cues, cPP cells give rise to pancreatic endocrine, acinar, and ductal lineages, indicating multilineage potency. Furthermore, cPP cells generate insulin+ beta like cells in vitro and in vivo, suggesting that they offer a convenient alternative to pluripotent cells as a source of adult cell types for modeling pancreatic development and diabetes. PMID- 28591651 TI - Transplantation of Human Pancreatic Endoderm Cells Reverses Diabetes Post Transplantation in a Prevascularized Subcutaneous Site. AB - Beta-cell replacement therapy is an effective means to restore glucose homeostasis in select humans with autoimmune diabetes. The scarcity of "healthy" human donor pancreata restricts the broader application of this effective curative therapy. "beta-Like" cells derived from human embryonic stem cells (hESC), with the capacity to secrete insulin in a glucose-regulated manner, have been developed in vitro, with limitless capacity for expansion. Here we report long-term diabetes correction in mice transplanted with hESC-derived pancreatic endoderm cells (PECs) in a prevascularized subcutaneous site. This advancement mitigates chronic foreign-body response, utilizes a device- and growth factor free approach, facilitates in vivo differentiation of PECs into glucose responsive insulin-producing cells, and reliably restores glycemic control. Basal and stimulated human C-peptide secretion was detected throughout the study, which was abolished upon graft removal. Recipient mice demonstrated physiological clearance of glucose in response to metabolic challenge and safely retrieved grafts contained viable glucose regulatory cells. PMID- 28591652 TI - Fetal Therapy Model of Myelomeningocele with Three-Dimensional Skin Using Amniotic Fluid Cell-Derived Induced Pluripotent Stem Cells. AB - Myelomeningocele (MMC) is a congenital disease without genetic abnormalities. Neurological symptoms are irreversibly impaired after birth, and no effective treatment has been reported to date. Only surgical repairs have been reported so far. In this study, we performed antenatal treatment of MMC with an artificial skin using induced pluripotent stem cells (iPSCs) generated from a patient with Down syndrome (AF-T21-iPSCs) and twin-twin transfusion syndrome (AF-TTTS-iPSCs) to a rat model. We manufactured three-dimensional skin with epidermis generated from keratinocytes derived from AF-T21-iPSCs and AF-TTTS-iPSCs and dermis of human fibroblasts and collagen type I. For generation of epidermis, we developed a protocol using Y-27632 and epidermal growth factor. The artificial skin was successfully covered over MMC defect sites during pregnancy, implying a possible antenatal surgical treatment with iPSC technology. PMID- 28591653 TI - A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. AB - Microglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology. PMID- 28591654 TI - Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells. AB - Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia inducible factor 1alpha and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders. PMID- 28591656 TI - Taming Human Genetic Variability: Transcriptomic Meta-Analysis Guides the Experimental Design and Interpretation of iPSC-Based Disease Modeling. AB - Both the promises and pitfalls of the cell reprogramming research platform rest on human genetic variation, making the measurement of its impact one of the most urgent issues in the field. Harnessing large transcriptomics datasets of induced pluripotent stem cells (iPSC), we investigate the implications of this variability for iPSC-based disease modeling. In particular, we show that the widespread use of more than one clone per individual in combination with current analytical practices is detrimental to the robustness of the findings. We then proceed to identify methods to address this challenge and leverage multiple clones per individual. Finally, we evaluate the specificity and sensitivity of different sample sizes and experimental designs, presenting computational tools for power analysis. These findings and tools reframe the nature of replicates used in disease modeling and provide important resources for the design, analysis, and interpretation of iPSC-based studies. PMID- 28591657 TI - AGC kinases, mechanisms of regulation and innovative drug development. AB - The group of AGC kinases consists of 63 evolutionarily related serine/threonine protein kinases comprising PDK1, PKB/Akt, SGK, PKC, PRK/PKN, MSK, RSK, S6K, PKA, PKG, DMPK, MRCK, ROCK, NDR, LATS, CRIK, MAST, GRK, Sgk494, and YANK, while two other families, Aurora and PLK, are the most closely related to the group. Eight of these families are physiologically activated downstream of growth factor signalling, while other AGC kinases are downstream effectors of a wide range of signals. The different AGC kinase families share aspects of their mechanisms of inhibition and activation. In the present review, we update the knowledge of the mechanisms of regulation of different AGC kinases. The conformation of the catalytic domain of many AGC kinases is regulated allosterically through the modulation of the conformation of a regulatory site on the small lobe of the kinase domain, the PIF-pocket. The PIF-pocket acts like an ON-OFF switch in AGC kinases with different modes of regulation, i.e. PDK1, PKB/Akt, LATS and Aurora kinases. In this review, we make emphasis on how the knowledge of the molecular mechanisms of regulation can guide the discovery and development of small allosteric modulators. Molecular probes stabilizing the PIF-pocket in the active conformation are activators, while compounds stabilizing the disrupted site are allosteric inhibitors. One challenge for the rational development of allosteric modulators is the lack of complete structural information of the inhibited forms of full-length AGC kinases. On the other hand, we suggest that the available information derived from molecular biology and biochemical studies can already guide screening strategies for the identification of innovative mode of action molecular probes and the development of selective allosteric drugs for the treatment of human diseases. PMID- 28591658 TI - Cutaneous leishmaniasis in immigrant workers returning to Bangladesh - An emerging problem. PMID- 28591655 TI - Differentiation of Inflammation-Responsive Astrocytes from Glial Progenitors Generated from Human Induced Pluripotent Stem Cells. AB - Astrocyte dysfunction and neuroinflammation are detrimental features in multiple pathologies of the CNS. Therefore, the development of methods that produce functional human astrocytes represents an advance in the study of neurological diseases. Here we report an efficient method for inflammation-responsive astrocyte generation from induced pluripotent stem cells (iPSCs) and embryonic stem cells. This protocol uses an intermediate glial progenitor stage and generates functional astrocytes that show levels of glutamate uptake and calcium activation comparable with those observed in human primary astrocytes. Stimulation of stem cell-derived astrocytes with interleukin-1beta or tumor necrosis factor alpha elicits a strong and rapid pro-inflammatory response. RNA sequencing transcriptome profiling confirmed that similar gene expression changes occurred in iPSC-derived and primary astrocytes upon stimulation with interleukin 1beta. This protocol represents an important tool for modeling in-a-dish neurological diseases with an inflammatory component, allowing for the investigation of the role of diseased astrocytes in neuronal degeneration. PMID- 28591659 TI - Decreased levels of matrix metalloproteinase-2 in root-canal exudates during root canal treatment. AB - OBJECTIVE: To determine the matrix metalloproteinase-2 (MMP-2) levels in root canal exudates from teeth undergoing root-canal treatment. MATERIAL AND METHODS: The root-canal exudates from six teeth with normal pulp and periradicular tissues that required intentional root canal treatment for prosthodontic reasons and from twelve teeth with pulp necrosis and asymptomatic apical periodontitis (AAP) were sampled with paper points for bacterial culture and aspirated for the detection of proMMP-2 and active MMP-2 by gelatin zymography and the quantification of MMP 2 levels by ELISA. RESULTS: By gelatin zymography, both proMMP-2 and active MMP-2 were detected in the first collection of root-canal exudates from teeth with pulp necrosis and AAP, but not from teeth with normal pulp, and their levels gradually decreased and disappeared at the last collection. Consistently, ELISA demonstrated a significant decrease in MMP-2 levels in the root-canal exudates of teeth with pulp necrosis and AAP following root canal procedures (p<0.05). Furthermore, the MMP-2 levels were significantly lower in the negative bacterial culture than those in the positive bacterial culture (p<0.001). CONCLUSIONS: The levels of MMP-2 in root-canal exudates from teeth with pulp necrosis and AAP were gradually reduced during root canal procedures. Future studies are required to determine if MMP-2 levels may be used as a biomolecule for the healing of apical lesions, similar to the clinical application of MMP-8 as a biomarker. PMID- 28591660 TI - The effect of advanced secondary municipal wastewater treatment on the molecular composition of dissolved organic matter. AB - There is a growing interest in water reuse and in recovery of nutrients from wastewater. Because many advanced treatment processes are designed to remove organic matter, a better understanding of the composition of dissolved organic matter (DOM) in wastewater is needed. To that end, we assessed DOM in the Nine Springs Wastewater Treatment Plant in Madison, Wisconsin by UV-visible spectroscopy and Fourier transform-ion cyclotron resonance mass spectrometry. Samples were collected from the influent and effluent of two different secondary treatment processes and their respective secondary clarifiers, the UV disinfection unit, and an Ostara treatment system, which produces struvite via chemical precipitation. The optical properties reveal that DOM throughout the plant is relatively aliphatic and is low in molecular weight compared to DOM in freshwater systems. Furthermore, the DOM is rich in heteroatoms (e.g., N, S, P, and Cl) and its molecular formulas are present in the lipid-, protein-, carbohydrate-, and lignin-like regions of van Krevelen diagrams. Secondary treatment produces DOM that is more aromatic and more complex, as shown by the loss of highly saturated formulas and the increase in the number of CHO, CHON, and CHOP formulas. The two secondary treatment processes produce DOM with distinct molecular compositions, while the secondary clarifiers and UV disinfection unit result in minimal changes in DOM composition. The Ostara process decreases the molecular weight of DOM, but does not otherwise alter its composition. The optical properties agree with trends in the molecular composition of DOM within the main treatment train of the Nine Springs plant. PMID- 28591661 TI - Characterisation of plastic microbeads in facial scrubs and their estimated emissions in Mainland China. AB - Plastic microbeads are often added to personal care and cosmetic products (PCCPs) as an abrasive agent in exfoliants. These beads have been reported to contaminate the aquatic environment and are sufficiently small to be readily ingested by aquatic organisms. Plastic microbeads can be directly released into the aquatic environment with domestic sewage if no sewage treatment is provided, and they can also escape from wastewater treatment plants (WWTPs) because of incomplete removal. However, the emissions of microbeads from these two sources have never been estimated for China, and no regulation has been imposed on the use of plastic microbeads in PCCPs. Therefore, in this study, we aimed to estimate the annual microbead emissions in Mainland China from both direct emissions and WWTP emissions. Nine facial scrubs were purchased, and the microbeads in the scrubs were extracted and enumerated. The microbead density in those products ranged from 5219 to 50,391 particles/g, with an average of 20,860 particles/g. Direct emissions arising from the use of facial scrubs were estimated using this average density number, population data, facial scrub usage rate, sewage treatment rate, and a few conservative assumptions. WWTP emissions were calculated by multiplying the annual treated sewage volume and estimated microbead density in treated sewage. We estimated that, on average, 209.7 trillion microbeads (306.9 tonnes) are emitted into the aquatic environment in Mainland China every year. More than 80% of the emissions originate from incomplete removal in WWTPs, and the remaining 20% are derived from direct emissions. Although the weight of the emitted microbeads only accounts for approximately 0.03% of the plastic waste input into the ocean from China, the number of microbeads emitted far exceeds the previous estimate of plastic debris (>330 MUm) on the world's sea surface. Immediate actions are required to prevent plastic microbeads from entering the aquatic environment. PMID- 28591662 TI - A loop-mediated isothermal amplification (LAMP) assay for the rapid detection of Enterococcus spp. in water. AB - Faecal pollution of water and the resulting potential presence of human enteric pathogens is a predominant threat to public health. Microbiological water quality can be assessed by the detection of standard faecal indicator bacteria (SFIB) such as E. coli or certain Enterococcus species. In recent years, isothermal amplification methods have become a useful alternative to polymerase chain reaction (PCR), allowing molecular diagnostics with simple or no instrumentation. In this study, a novel screening method for the molecular detection of Enterococcus spp. by loop-mediated isothermal amplification (LAMP) is described. A set of six specific LAMP primers was designed to amplify a diagnostic fragment of the Enterococcus 23S rRNA gene, which is present in several enterococcal species targeted by quantitative PCR (qPCR), which is the standard technique recommended by the US Environmental Protection Agency. Sensitivity and specificity tests were performed using a set of 30 Enterococcus and non-target bacterial reference strains. It is shown that LAMP is equally sensitive and even more specific than the qPCR assay. A dilution series of Enterococcus faecalis DNA revealed that the LAMP method can reliably detect 130 DNA target copies per reaction within 45 min. Additionally, enterococci isolated from Austrian surface waterbodies, as well as a set of DNA extracts from environmental waters, were tested. Contingency analysis demonstrated a highly significant correlation between the results of the developed LAMP assay and the reference qPCR method. Furthermore, a simple staining procedure with a fluorescence dye demonstrated the identification of amplified products by eye. In conclusion, this method is an important component for the efficient screening and testing of water samples in low-resource settings lacking sophisticated laboratory equipment and highly trained personnel, requiring only a simple heating block. PMID- 28591663 TI - An application of cellular organic matter to coagulation of cyanobacterial cells (Merismopedia tenuissima). AB - Algae affect the performance of drinking water treatment significantly when they decay and release considerable amounts of cellular organic matter (COM). The study describes the cyanobacterium Merismopedia tenuissima and its COM and investigates the effect of their simultaneous coagulation. As COM is highly complex mixture, we characterised it in terms of hydrophobicity, protein content and molecular weights (MWs). To describe the coagulation mechanisms and molecular interactions in the system, we determined both COM and cell surface charge by means of potentiometric titration and zeta potential analysis, respectively, and performed the jar tests with single components and their mixtures with and without a coagulant (ferric sulphate). The coagulation tests performed with the individual components or with their mixtures proved efficient cell removals (up to 99%) but relatively low COM removals (37 / 57%). This disproportion can be attributed to the prevalence of hydrophilic compounds and to the high portion of low-MW organics in COM. Coagulation of COM/cell mixtures achieved comparable efficacy with single component tests, using even lower coagulant doses. Furthermore, COM presence substantially deviated the pH optimum for cell removal and thus altered coagulation mechanisms. While single cells interacted prevailingly through adsorption onto Fe-oxide-hydroxides at about neutral pH (6.0 7.7), the COM/cell mixtures succumbed to charge neutralisation by Fe hydroxopolymers within moderately acidic pH range (5.0-6.5). Moreover, COM initiated cell flocculation also at acidic pH in both the presence (pH 3.4-3.9) and the absence of a coagulant (pH 3.6-4.6). This supportive effect is ascribed to relatively high-MW COM (>10 kDa), serving as a natural flocculant through inter-particle bridging mechanism and exhibiting nearly the same COM/cell removals as ferric sulphate. PMID- 28591664 TI - Retinoic acid in developmental toxicology: Teratogen, morphogen and biomarker. AB - This review explores the usefulness retinoic acid (RA) related physiological factors as possible biomarkers of embryotoxicity. RA is involved in the morphogenesis of the early embryo as well as in the development and maturation of a wide variety of organ anlagen. The region-specific homeostasis of RA in the embryo is in many ways the driving force determining developmental cell proliferation versus differentiation. As a consequence, RA concentrations are carefully controlled in time and space in the developing embryo. RA deficiency and overdosing both result in characteristic patterns of malformations that may involve many different organ systems. The central role of RA in embryo development provides us with a set of sensitive biomarkers that may be employed in developmental toxicity testing. This includes the synthesizing and metabolizing enzymes of RA, but also a myriad of related morphogenetic factors and their genes, of which the expression may be affected by changes in RA balance. Several examples of embryotoxicants interfering with the homeostasis of RA and related parameters have been described. A preliminary adverse outcome pathway framework for RA mediated malformations has been published. Expansion of this framework and its application in developmental toxicity testing may allow the detection of a large variety of embryotoxicants with diverse modes of action. RA homeostasis therefore provides a promising set of molecular tools that may be employed in the advancement of mode of action driven animal-free developmental toxicity testing. PMID- 28591665 TI - Inhibition of Pseudomonas aeruginosa quorum sensing by subinhibitory concentrations of curcumin with gentamicin and azithromycin. AB - OBJECTIVES: Pseudomonas aeruginosa quorum sensing (QS) circuits regulate virulence factors and co-ordinate bacterial pathogenicity. This study aimed to investigate the inhibitory activity of subinhibitory concentrations of curcumin with azithromycin and gentamicin against P. aeruginosa QS-related genes and virulence factors. METHODS: The minimum inhibitory concentrations (MICs) and synergistic activity of curcumin with azithromycin and gentamicin against P. aeruginosa PAO1 were determined using broth microdilution and checkerboard titration methods, respectively. The activity of sub-MICs (1/4* and 1/16* MIC) of curcumin on the QS signal molecules was assessed using a reporter strain assay. The influence of sub-MICs of curcumin, azithromycin and gentamicin alone and in combination on motility and biofilm formation was also determined and was confirmed by RT-PCR to test the expression of the QS regulatory genes lasI, lasR, rhlI and rhlR. RESULTS: Addition of curcumin drastically decreased the MIC of azithromycin and gentamicin. Curcumin showed synergistic effects with azithromycin and gentamicin. Treated PAO1 cultures in the presence of curcumin showed a significant reduction of signals C12-HSL and C4-HSL (P<0.05). Sub-MICs (1/4* and 1/16* MIC) of curcumin, azithromycin and gentamicin alone and in combination significantly reduced swarming and twitching motilities as well as biofilm formation. Expression of QS regulatory genes lasI, lasR, rhlI and rhlR using 1/4* MIC of curcumin, azithromycin and gentamicin alone and in combination was decreased significantly compared with untreated PAO1. CONCLUSIONS: These results indicate that a combination of sub-MIC of curcumin with azithromycin and gentamicin exhibited synergism against P. aeruginosa QS systems. PMID- 28591666 TI - Characterization of the chemicals used in hydraulic fracturing fluids for wells located in the Marcellus Shale Play. AB - Hydraulic fracturing, coupled with the advances in horizontal drilling, has been used for recovering oil and natural gas from shale formations and has aided in increasing the production of these energy resources. The large volumes of hydraulic fracturing fluids used in this technology contain chemical additives, which may be toxic organics or produce toxic degradation byproducts. This paper investigated the chemicals introduced into the hydraulic fracturing fluids for completed wells located in Pennsylvania and West Virginia from data provided by the well operators. The results showed a total of 5071 wells, with average water volumes of 5,383,743 +/- 2,789,077 gal (mean +/- standard deviation). A total of 517 chemicals was introduced into the formulated hydraulic fracturing fluids. Of the 517 chemicals listed by the operators, 96 were inorganic compounds, 358 chemicals were organic species, and the remaining 63 cannot be identified. Many toxic organics were used in the hydraulic fracturing fluids. Some of them are carcinogenic, including formaldehyde, naphthalene, and acrylamide. The degradation of alkylphenol ethoxylates would produce more toxic, persistent, and estrogenic intermediates. Acrylamide monomer as a primary degradation intermediate of polyacrylamides is carcinogenic. Most of the chemicals appearing in the hydraulic fracturing fluids can be removed when adopting the appropriate treatments. PMID- 28591667 TI - Exposure to residential road traffic noise prior to conception and time to pregnancy. AB - OBJECTIVES: To examine the association between residential road traffic noise and fecundity estimated by time to pregnancy (TTP). DESIGN: We identified 65,201 mothers from the Danish National Birth Cohort with self-reported information on TTP collected through computer assisted telephone interviews. Road traffic noise was modelled at all historical addresses and expressed as time-weighted means for periods corresponding to individual TTP. Associations were analyzed using logistic regression for analyses of dichotomous outcomes and ordinal logistic regression for TTP in four categories, adjusting for maternal age at conception, disposable household income, education and air pollution (NOx). RESULTS: Ordinal logistic regression showed a 10dB increase in road traffic noise to be associated with a 8% increased risk of 6-12month TTP (95% CI:1.03; 1.12) whereas we found no statistically significant associations for >=12months TTP (OR=1.04, 95% CI: 0.99; 1.09) when compared to 0-2months TTP. Similarly, when exploring TTP as a binary outcome we found a 10dB higher road traffic noise to be associated with a 5% higher risk of TTP of 6months or more (95% CI: 1.01; 1.08) as compared with <6months TTP, whereas when the cut-point was 12months TTP no association was found. CONCLUSION: Road traffic noise was associated with an increased risk of 6 12month TTP, but not with risk of longer TTP, indicating that noise may have a small impact on sub-fecundity. PMID- 28591668 TI - The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen improve ANP levels and decrease nuclear translocation of NF-kB in estrogen deficient rats. AB - BACKGROUND: The selective estrogen receptor modulators (SERMs) raloxifene and tamoxifen are used for the treatment of osteoporosis and cancer, respectively, in women. The impairment of both the Atrial Natriuretic Peptide (ANP) cell signaling system and the translocation of nuclear factor-kappa B (NF-kB) to the cell nucleus are associated with detrimental cardiovascular effects and inflammation. The effects of SERMs on these parameters in the cardiac tissue of estrogen deficient rats has not been reported. METHODS: We investigated the effects of raloxifene and tamoxifen on ANP signaling, p65 NF-kB nuclear translocation, cardiac histology and contractility. Female rats were divided into five groups: control (SHAM), ovariectomized (OVX), OVX-treated 17-beta-estradiol (E), OVX treated raloxifene (RLX) and OVX-treated tamoxifen (TAM). The treatments started 21days after ovariectomy and continued for 14days. RESULTS: Ovariectomy reduced ANP mRNA in the left atrium (LA), decreased the content of ANP protein in the LA and in plasma, and increased the level of p65 NF-kB nuclear translocation in the left ventricle. Both 17-beta-estradiol and SERMs were able to reverse these alterations, which were induced by the estrogen deficient state. The hemodynamic and cardiac structural parameters analyzed in the present work were not modified by the interventions. CONCLUSIONS: Our study demonstrates, for the first time, the additional benefits of raloxifene and tamoxifen in an estrogen-deficient state. These include the normalization of plasmatic and cardiac ANP levels and cardiac p65 NF-kB translocation. Therefore, these treatments promote cardiovascular protection and may contribute to the prevention of cardiac dysfunction observed long-term in postmenopausal women. PMID- 28591669 TI - Bupropion induces social anxiety in adolescent mice: Influence of housing conditions. AB - BACKGROUND: The antidepressant bupropion has received increasing attention as a pharmacological tool to treat addiction although little is known about its effects on social behaviour in adolescents. The present study aimed to evaluate if environmental housing conditions influence bupropion's actions on social behaviour of adolescent mice. METHODS: Mice were either group- or individually housed for 2-weeks and then randomly divided into 2 cohorts: half of the mice remained in the initial housing condition and the other half were changed to isolated conditions for further 2-weeks. The following groups were compared: isolated/isolated (ISO/ISO), isolated/group-housed (ISO/GR), group housed/isolated (GR/ISO), and group-housed/group-housed (GR/GR). The effects of bupropion (40, 20, 10mg/kg) or saline on social interaction were assessed for each housing condition. Social encounters were evaluated using ethological analysis. RESULTS: Data showed significant effects of bupropion on grooming and digging. This drug diminished time mice allocated to these behavioural categories in all housing conditions. In ISO/GR and GR/ISO conditions, bupropion increased environmental exploration (non-social exploration and exploration from a distance), reduced social investigation and increased avoidance/flee and defence/submission behaviours. An augment of avoidance/flee during social interactions was observed in bupropion-treated mice in GR/GR housing condition. CONCLUSION: These results suggest that this drug exhibits anxiogenic-like properties in social encounters between adolescent mice, especially when a transition in housing conditions has been experienced during this period. Changes in housing conditions may be a useful model for evaluating the effects of bupropion on social behaviour and the role of environmental housing conditions. PMID- 28591670 TI - Novel synthetic analogs of diallyl disulfide triggers cell cycle arrest and apoptosis via ROS generation in MIA PaCa-2 cells. AB - BACKGROUND: Diallyl disulfide (DADS), a principal organosulfur component of garlic, is known for its medicinal properties including anti-cancer activity. Prior studies have demonstrated that the compounds containing Diallyl disulfide moieties exhibited diverse therapeutic potential with promising biological activities. In the present study, we have investigated the in vitro anticancer activity of Diallyl disulfide derivatives (5a-5l and 7e-7m) against human cancer cell lines. METHODS: The effect of DADS analogs on different cancer cell lines was measured through MTT assay. Cell cycle progression, apoptosis, DNA fragmentation and levels of ROS were analyzed through FACS and confocal imaging. RESULTS: Bis[3-(3-fluorophenyl)prop-2-ene]disulfide (compound 5b) was the most potent compound among the tested DADS derivatives. FACS analysis revealed that increase in ROS generation by compound 5b was accompanied by cell cycle arrest in the G2/M phase and apoptosis in MIA PaCa-2 cells. Further, the apoptosis was confirmed by TUNEL assay. Western blot analysis showed that compound 5b induces G2/M phase arrest via ROS mediated DNA-damage, which in turn, induces phosphorylation of Chk1/Cdc25c/Cdc2 pathway. Furthermore, altered levels of ROS triggers intrinsic apoptotic cascade, as evidenced by dissipated mitochondrial membrane potential (psi), decrease in Bcl-2/Bax ratio, cytochrome c release and cleavage of procaspase-3. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the compound 5b induced augmented intracellular ROS levels and cell death. CONCLUSION: Taken together, the anti-proliferative effects of compound 5b were attributed to intracellular ROS accumulation, which in turn, triggers apoptosis by mediating DNA damage-induced G2/M phase arrest and evoking mitochondrial apoptotic pathway in MIA PaCa-2 cells. PMID- 28591671 TI - Mille viae in eukaryotic mRNA decapping. AB - Cellular mRNA levels are regulated via rates of transcription and decay. Since the removal of the mRNA 5'-cap by the decapping enzyme DCP2 is generally an irreversible step towards decay, it requires regulation. Control of DCP2 activity is likely effected by two interdependent means: by conformational control of the DCP2-DCP1 complex, and by assembly control of the decapping network, an array of mutually interacting effector proteins. Here, we compare three recent and conformationally distinct crystal structures of the DCP2-DCP1 decapping complex in the presence of substrate analogs and decapping enhancers and we discuss alternative substrate recognition modes for the catalytic domain of DCP2. Together with structure-based insight into decapping network assembly, we propose that DCP2-mediated decapping follows more than one path. PMID- 28591672 TI - Global variation in pregnancy complications in women with epilepsy: A meta analysis. AB - OBJECTIVE: Women with epilepsy are at risk of pregnancy complications. Whether these vary globally is unknown. We undertook a systematic review to assess the overall rates of obstetric outcomes in women with epilepsy, and variations in estimates across geographical region, economic status of country, and over time. STUDY DESIGN: We searched Medline, Embase, Cochrane, AMED and CINAHL, (January 1, 1990 and November 29, 2016), without any language restrictions for studies reporting core maternal and fetal outcomes in women with epilepsy. We pooled the results using Freeman-Tukey Transformation random effectsanalysis, and reported our findings as rates of complications per 100 pregnancies with 95% confidence intervals (CI). We assessed for differences in risk across World Health Organisation (WHO) regions, income status, and year of publication. RESULTS: From the 7420 articles screened, we included 60 studies (62 articles). In women with epilepsy (116,105 pregnancies), the commonest complications were caesarean section (29.2 per 100 pregnancies; 95% CI 25.4-33.1, I2=98.44%), and admission to the neonatal intensive care unit (12.5 per 100 pregnancies; 95% CI 9.6-15.8, I2=60.63%). There were significant differences across the WHO regions, with the highest rates of caesarean section (37%, 95% CI 32%-42%); spontaneous miscarriage (39%, 95% CI 35%-44%) and preterm birth (10%, 95% CI 8%-12%) in the Americas; postpartum haemorrhage (9%, 95% CI 7%-12%), hypertensive disorders (14%, 95% CI 8%-21%) and perinatal death (2%, 95% CI 1%-7%) in the Western Pacific; induction of labour (30%, 95% CI 19%-41%) in South East Asia and antepartum haemorrhage (10%, 95% CI 5%-17%) in the Eastern Mediterranean. The reported rates of antepartum haemorrhage, caesarean section, gestational diabetes and spontaneous miscarriage were highest in high income and high-middle income countries. Over time, there was a significant increase in caesarean section, and reduction in stillbirths, perinatal deaths and admission to the neonatal intensive care unit in women with epilepsy. CONCLUSION: There is significant variation in reported maternal and offspring outcomes in pregnant women with epilepsy across geographical regions, economic status of country and over time, which needs to be considered in setting priorities for clinical management and research. PMID- 28591673 TI - The Windmill technique avoids manual removal of the retained placenta-A new solution for an old problem. AB - OBJECTIVE: The primary objective is to assess the reduction in manual removal of placenta with the Windmill technique of placenta delivery in patients with retained placenta. DESIGN: The Windmill technique involves the application of continuous 360 degrees umbilical cord traction and rotation in such a manner as to be perpendicular to the direction of the birth canal at the level of the introitus. This rotation through 360 degrees is repeated slowly with movement akin to the motion of the blades of a windmill. We performed a 3-year retrospective case-control study at the Charite University Hospital in Berlin. Patients with a retained placenta more than 30min following failed traditional interventions were consented and offered the Windmill technique of placenta delivery. Study cases were compared to controls where an operative manual removal of placenta was performed. Patients with suspected placenta implantation problems, uterine atony, bleeding due to vaginal tract injury and coagulation disturbances were excluded. RESULTS: Over the study period 14 patients were recruited to the study arm and 17 patients were in the control group. With the Windmill technique for retained placenta, 86% (12/14, p<0.001) of patients avoided invasive operative manual removal of the placenta in theatre. There was a statistically significant reduction in mean blood loss (429ml vs 724ml, p=0.001) and mean postoperative fall in hemoglobin values (1.3g/dl vs 2.5g/dl, p=0.04). There was a reduction in the time to delivery of the placenta, antibiotic prophylaxis and use of general anesthesia. CONCLUSION: The Windmill technique for the delivery of the retained placenta is a simple, safe, effective and easy to teach technique that reduces invasive operative manual removal of the placenta, postpartum blood loss and delay in the placenta delivery. This innovative technique can also be a lifesaving intervention especially in areas with limited or no access to operative facilities. PMID- 28591674 TI - High-frequency power within the QRS complex in ischemic cardiomyopathy patients with ventricular arrhythmias: Insights from a clinical study and computer simulation of cardiac fibrous tissue. AB - BACKGROUND: The distribution of frequency power (DFP) within the QRS complex (QRS) is unclear. This study aimed to investigate the DFP within the QRS in ischemic cardiomyopathy (ICM) with lethal ventricular arrhythmias (L-VA). A computer simulation was performed to explore the mechanism of abnormal frequency power. METHODS: The study included 31 ICM patients with and without L-VA (n = 10 and 21, respectively). We applied the continuous wavelet transform to measure the time-frequency power within the QRS. Integrated time-frequency power (ITFP) was measured within the frequency range of 5-300 Hz. The simulation model consisted of two-dimensional myocardial tissues intermingled with fibroblasts. We examined the relation between frequency power calculated from the simulated QRS and the fibroblast-to-myocyte ratio (r) of the model. RESULTS: The frequency powers significantly increased from 180 to 300 Hz and from 5 to 15 Hz, and also decreased from 45 to 80 Hz in patients with ICM and L-VA compared with the normal individuals. They increased from 110 Hz to 250 Hz in ICM alone. In the simulation, the high-frequency power increased when the ratio (r) were 2.0-2.5. Functional reentry was initiated if the ratio (r) increased to 2.0. CONCLUSIONS: Abnormal higher-frequency power (180-300 Hz) may provide arrhythmogenic signals in ICM with L-VA that may be associated with the fibrous tissue proliferation. PMID- 28591676 TI - Evolution of commensal bacteria in the intestinal tract of mice. AB - Hundreds of different bacterial species inhabit our intestines and contribute to our health status, with significant loss of species diversity typically observed in disease conditions. Within each microbial species a great deal of diversity is hidden and such intra-specific variation is also key to the proper homeostasis between the host and its microbial inhabitants. Indeed, it is at this level that new mechanisms of antibiotic resistance emerge and pathogenic characteristics evolve. Yet, our knowledge on intra-species variation in the gut is still limited and an understanding of the evolutionary mechanisms acting on it is extremely reduced. Here we review recent work that has begun to reveal that adaptation of commensal bacteria to the mammalian intestine may be fast and highly repeatable, and that the time scales of evolutionary and ecological change can be very similar in these ecosystems. PMID- 28591675 TI - Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient-focused outcome results from the randomised phase III REACH study. AB - PURPOSE: To report patient-focused outcomes as measured by quality of life (QoL) and performance status (PS) in REACH, a phase III placebo-controlled randomised study, assessing ramucirumab in advanced hepatocellular carcinoma (HCC) patients who received prior sorafenib. METHODS: Eligible patients had advanced HCC, Child Pugh A, PS 0 or 1 and prior sorafenib. Patients received ramucirumab (8 mg/kg) or placebo (1:1) on day 1 of a 2-week cycle. QoL was assessed by FACT Hepatobiliary Symptom Index (FHSI)-8 and EuroQoL (EQ-5D) at baseline; cycles 4, 10, and 16; and end of treatment. PS was assessed at baseline, each cycle, and end of treatment. Deterioration in FHSI-8 was defined as a >=3-point decrease from baseline and PS deterioration was defined as a change of >=2. Both intention-to-treat and pre specified subgroup of patients with baseline serum alpha-fetoprotein (AFP) >=400 ng/mL were assessed. RESULTS: There were 565 patients randomised to ramucirumab and placebo. Compliance with FHSI and EQ-5D was high and similar between groups. In the ITT population, deterioration in FHSI-8, EQ-5D, and PS was similar between ramucirumab and placebo. In patients with baseline AFP >=400 ng/mL, ramucirumab significantly reduced deterioration in FHSI-8 at the end of treatment compared with placebo (P = 0.0381), and there was a trend towards a delay in the deterioration of symptoms in FHSI-8 (HR 0.690; P = 0.054) and PS (HR 0.642; P = 0.057) in favour of ramucirumab. CONCLUSIONS: We report one of the most comprehensive data sets of QoL and symptom burden in patients undergoing systemic therapy for advanced HCC. Ramucirumab was associated with no worsening of QoL. In patients with baseline AFP >=400 ng/mL, the significant survival benefit observed in patients treated with ramucirumab was coupled with a trend in patient-focused outcome benefits. CLINICAL TRIAL REGISTRATION: NCT01140347. PMID- 28591677 TI - A highly sensitive and selective fluorimetric probe for intracellular peroxynitrite based on photoinduced electron transfer from ferrocene to carbon dots. AB - Herein, a highly sensitive and selective fluorimetric nanoprobe for peroxynitrite (ONOO-) detection based on photoinduced electron transfer (PET) from ferrocene (Fc) to carbon dots (CDs) is reported. The nanoprobe (named CDs-Fc) can be facilely constructed through covalently conjugating CDs and ferrocenecarboxylic acid. Further studies reveal that the energy level of highest occupied molecular orbital (HOMO) of the CDs is lowered with the addition of ONOO- due to its oxidation and nitration capabilities. Thus, an efficient electron transfer from Fc to the excited states of CDs could occur, leading to obvious fluorescence quenching. The fluorescence quenching of the nanoprobe was determined to be peroxynitrite concentrations dependence with a linear range between 4nM to 0.12MUM. Thanks to the excellent optical properties of the CDs and efficient electron transfer efficiency from Fc to the excited CDs, the nanoprobe exhibits very high sensitivity to ONOO- with a limit of detection (LOD) of 2.9nM. To the best of our knowledge, this LOD is the highest reported value till today for the detection of peroxynitrite. Besides, the nanoprobe also shows excellent selectivity to ONOO- among a broad range of substances, even including other reactive oxygen/nitrogen species (ROS/RNS). Finally, the nanoprobe was verified to be very low cytotoxicity, and was successfully applied for intracellular ONOO- detection. This work would provide a promising tool for the research of ONOO- in cytobiology and disease diagnosis. PMID- 28591678 TI - Treatment outcomes after implementation of an adapted WHO protocol for severe sepsis and septic shock in Haiti. AB - PURPOSE: The World Health Organization (WHO) has developed a simplified algorithm specific to resource-limited settings for the treatment of severe sepsis emphasizing early fluids and antibiotics. However, this protocol's clinical effectiveness is unknown. We describe patient outcomes before and after implementation of an adapted WHO severe sepsis protocol at a community hospital in Haiti. MATERIALS AND METHODS: Using a before-and-after study design, we retrospectively enrolled 99 adult Emergency Department patients with severe sepsis from January through March 2012. After protocol implementation in January 2014, we compared outcomes to 67 patients with severe sepsis retrospectively enrolled from February to April 2014. We defined sepsis according to the WHO's Integrated Management of Adult Illness guidelines and severe sepsis as sepsis plus organ dysfunction. RESULTS: After protocol implementation, quantity of fluid administered increased and the physician's differential diagnoses more often included sepsis. Patients were more likely to have follow-up vital signs taken sooner, a radiograph performed, and a lactic acid tested. There were no improvements in mortality, time to fluids or antimicrobials. CONCLUSIONS: Use of a simplified sepsis protocol based primarily on physiologic parameters allows for substantial improvements in process measures in the care of severely septic patients in a resource-constrained setting. PMID- 28591679 TI - Serial blood lactate measurements and its prognostic significance in intensive care unit management of aneurysmal subarachnoid hemorrhage patients. AB - PURPOSE: This study assesses the behavior of serial blood lactate measurements during intensive care unit (ICU) stay to identify prognostic factors of unfavorable neurological outcomes (UO) in patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: We retrospectively reviewed all patients who were consecutively hospitalized with SAH between 2009 and 2016. Arterial blood lactate levels were routinely obtained on admission and every 6h in the ICU. Univariate/multivariate analyses were performed to identify independent predictors of UO (modified Rankin scale of 3-6 upon hospital discharge). RESULTS: There were 145 patients with 46% of UO. Initially, increased lactate levels reached maximum levels during the first 24h and then decreased to within the normal range. Then, the levels slightly increased again to within the normal range for the next 24h, especially in UO. On multiple regression analysis, lactate levels measured at 24h, and 48h after admission were strong predictors of UO. Lactate level measured at 48h after admission demonstrated the greatest accuracy and the highest specificity (area under the curve, 0.716; sensitivity, 40%; specificity, 92.1%). CONCLUSIONS: The lactate level at 48h after admission was the most accurate predictor of UO with a high specificity in SAH patients. PMID- 28591680 TI - Clinical research in small genomically stratified patient populations. AB - The paradigm of early drug development in cancer is shifting from 'histology oriented' to 'molecularly oriented' clinical trials. This change can be attributed to the vast amount of tumour biology knowledge generated by large international research initiatives such as The Cancer Genome Atlas (TCGA) and the use of next generation sequencing (NGS) techniques developed in recent years. However, targeting infrequent molecular alterations entails a series of special challenges. The optimal molecular profiling method, the lack of standardised biological thresholds, inter- and intra-tumor heterogeneity, availability of enough tumour material, correct clinical trials design, attrition rate, logistics or costs are only some of the issues that need to be taken into consideration in clinical research in small genomically stratified patient populations. This article examines the most relevant challenges inherent to clinical research in these populations. Moreover, perspectives from the Academia point of view are reviewed as well as initiatives to be taken in forthcoming years. PMID- 28591682 TI - Misdiagnosis of epilepsy: A patient's perspective on Maria Oto's review. PMID- 28591681 TI - Structural features of glycan recognition among viral pathogens. AB - Recognition and binding to host glycans present on cellular surfaces is an initial and critical step in viral entry. Diverse families of host glycans such as histo-blood group antigens, sialoglycans and glycosaminoglycans are recognized by viruses. Glycan binding determines virus-host specificity, tissue tropism, pathogenesis and potential for interspecies transmission. Viruses including noroviruses, rotaviruses, enteroviruses, influenza, and papillomaviruses have evolved novel strategies to bind specific glycans often in a strain-specific manner. Structural studies have been instrumental in elucidating the molecular determinants of these virus-glycan interactions, aiding in developing vaccines and antivirals targeting this key interaction. Our review focuses on these key structural aspects of virus-glycan interactions, particularly highlighting the different strain-specific strategies employed by viruses to bind host glycans. PMID- 28591683 TI - A quantitative risk-assessment system (QR-AS) evaluating operation safety of Organic Rankine Cycle using flammable mixture working fluid. AB - Mixture of hydrocarbon and carbon dioxide shows excellent cycle performance in Organic Rankine Cycle (ORC) used for engine waste heat recovery, but the unavoidable leakage in practical application is a threat for safety due to its flammability. In this work, a quantitative risk assessment system (QR-AS) is established aiming at providing a general method of risk assessment for flammable working fluid leakage. The QR-AS covers three main aspects: analysis of concentration distribution based on CFD simulations, explosive risk assessment based on the TNT equivalent method and risk mitigation based on evaluation results. A typical case of propane/carbon dioxide mixture leaking from ORC is investigated to illustrate the application of QR-AS. According to the assessment results, proper ventilation speed, safe mixture ratio and location of gas detecting devices have been proposed to guarantee the security in case of leakage. The results revealed that this presented QR-AS was reliable for the practical application and the evaluation results could provide valuable guidance for the design of mitigation measures to improve the safe performance of ORC system. PMID- 28591684 TI - Environmental performance, mechanical and microstructure analysis of concrete containing oil-based drilling cuttings pyrolysis residues of shale gas. AB - The overall objective of this research project is to investigate the feasibility of incorporating oil-based drilling cuttings pyrolysis residues (ODPR) and fly ash serve as replacements for fine aggregates and cementitious materials in concrete. Mechanical and physical properties, detailed environmental performances, and microstructure analysis were carried out. Meanwhile, the early hydration process and hydrated products of ODPR concrete were analyzed with X-ray diffraction (XRD), Fourier transform infrared (FT-IR), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). The results indicated that ODPR could not be categorize into hazardous wastes. ODPR had specific pozzolanic characteristic and the use of ODPR had certain influence on slump and compressive strength of concrete. The best workability and optimal compressive strength were achieved with the help of 35% ODPR. Environmental performance tests came to conclusion that ODPR as recycled aggregates and admixture for the preparation of concrete, from the technique perspective, were the substance of mere environmental contamination. PMID- 28591685 TI - Identification of a consistent polyene component of purple pigment in diseased sclerites of Caribbean corals across region, species, and insult agent. AB - Gorgonians respond to insult (damage and disease) by producing sclerites containing a purple pigment as opposed to the normal white sclerites. Raman microscopy is used to study the purple areas of three species of diseased coral, Gorgonia ventalina, Pseudoplexaura porosa, and Eunicea laciniata obtained from Puerto Rico. These spectra were compared to Gorgonia ventalina samples previously reported that were obtained from San Salvador, Bahamas. Spectra from two samples of G. ventalina that had been infected by different agents, Aspergillus sydowii and a slime mold, were also obtained. The results indicate that the purple compounds (polyenes) generated by the coral in response to infection are similar regardless of region from which the coral were harvested, of species of coral, and of the infective agent. A discussion of the Raman spectra of G. ventalina and the other coral species is presented. PMID- 28591686 TI - The role of topically applied l-ascorbic acid in ex-vivo examination of burn injured human skin. AB - Wound treatment and healing is complex and is comprised of an elaborate set of processes including cellular, spectroscopic and biochemical ones as well as the "reaction" of local tissue to thermal injury. Vitamin C as l-ascorbic acid (LA) prevents injurious effects of oxidants because it reduces reactive oxygen species to stable molecules, it becomes oxidized to the short-lived ascorbyl radical. As a result, antioxidant treatment may contribute to minimizing injury in burn patients. The aim of this study is to assess changes in molecular structure of collagen extracted from human epidermis burn wound scab during incubation of the epidermis in l-ascorbic acid solution. The study will be performed using FTIR and FT Raman spectroscopies. During this research it was observed that the intensity of Raman peaks increased where healing was being modified by LA. The intensity of the amide III band at 1247cm-1 relative to the intensity at 1326cm-1 was used to test tissue repair degree at the incision site. FTIR spectra were recorded from frozen specimens of serum modified by LA; an analysis of shifts in the amide I band position was conducted. The appearance of a new band for frozen samples modified by LA was observed around 1149-1220cm-1. The above conclusions confirmed the creation of hydrogen bonds between NH stretch and CO. Samples being incubated in solutions of l-ascorbic acid demonstrated the absence of electrophoretic bands of albumin. Alterations in the surface of the skin incubated in l-ascorbic acid were investigated with the use of Scanning Electron Microscopy (SEM). A decrease in external symptoms of burn injury was noted in the damaged epidermis incubated in l-ascorbic acid. PMID- 28591687 TI - mTOR-mediated Na+/Ca2+ exchange affects cell proliferation and metastasis of melanoma cells. AB - Melanoma is a common malignant tumor, which is associated with high mortality rate. The multiple-drug resistance of tumor cells often results in failure of chemotherapy. The aim of our study is to investigate the expression of Nav 1.6 in human melanoma cells and human epidermal melanocytes. Additionally, the effect of Na+channels on Ca+ current and mTOR activity in melanoma cells were also analyzed. The protein expression levels of Nav1.6 in human melanocyte PIG1, WM266 and WM115 cells were investigated by western blot. After treatment of Na+ channel inhibitor Tetroadotoxin (TTX) or mTOR inhibitor rapamycin (RAPA), the electrophysiological activity (Na+ current and Ca2+ current) in WM266 and WM115 cells was detected by patch clamp technique. The expression of mTORC1 phosphorylates S6 kinase (p-S6), cell invasion and migration, cell proliferation and cell apoptosis were also performed. Results shown that Nav 1.6 was overexpressed in WM266 and WM115 cells, and the inhibition of Na+ channel by TTX reduced Na+ current. Both TTX and RAPA suppressed Ca2+ current and the expression of p-S6, thus inducing Na+ channel which activates the mTOR-Ca2+ signaling pathway. Both TTX and RAPA suppressed cell invasion, migration and proliferation, and promoted cell apoptosis of WM266 cells. Thus, the Nav1.6 sodium channel promotes cell proliferation and invasion through mTOR-mediated Na+/Ca2+ exchange in melanoma. The observations will provide a new perspective for understanding the malignant biological behavior of melanoma cells, and potentially provide a new drug target. PMID- 28591688 TI - Qa-2 expression levels is related with tumor-infiltrating lymphocytes profile during solid Ehrlich tumor development. AB - The Qa-2 has been described as Human Leucocyte Antigen G (HLA-G) murine homolog. This homology is well accepted to gene and protein structure, in different pathology process and embryos implantation. However, in some neoplasm, this homology is questioned, where Qa-2 has been proposed as an immunogenic molecule, associated to tumor rejection. In this way, the aim of this study was to describe the pattern of Qa-2 expression and its relationship with the profile of tumor infiltrating lymphocytes in solid Ehrlich tumor. The Ehrlich tumor growth was evaluated in Balb/c female mice in different tumor stages. The inflammatory infiltration features were determined by histopathology and, both lymphocyte type and tissue Qa-2 expression by immunohistochemistry. ELISA kit was used to determine soluble Qa-2 in the serum from the animals. We observed that Qa-2 in neoplastic cells increases in intermediate tumor development stages, while, serum Qa-2 increases in the late stage. Qa-2 increasing is correlated with CD3+ increase. Our results suggest that Qa-2 has a role opposite to HLA-G in Ehrlich solid carcinoma, and may be modulating the immune response by attracting the inflammatory infiltrate, especially T CD8+ Lymphocytes. PMID- 28591689 TI - Detrimental effects of atherogenic and high fat diet on bone and aortic calcification rescued by an isoflavonoid Caviunin beta-d-glucopyranoside. AB - OBJECTIVE: Atherogenic diet (AD) and high fat diet (HFD) cause deleterious effect on bone micro-architecture and this phenomenon prompts aortic calcification. This study aims to show the effects of Caviunin beta-d-glucopyranoside (CAFG), against bone loss and its associated aortic calcification in presence of AD and HFD challenged diets. METHODS: Five groups of C57BL/6 male mice with 8 animals in each group, comprising of chow, AD, HFD, AD+CAFG and HFD+CAFG were fed with respective diets for 16 weeks. At the end of the treatment period, preventive effects of CAFG on bone tissue were analyzed by assessing the osteogenic potential of bone marrow cells, bone micro-architecture, ability of new bone formation and histomorphometry studies. Aortic calcification was assessed by transcription and translation analysis of osteogenic key markers in aortic tissue and assessment of aortic endothelial function. Plasma lipid profiling was done to assess the effects of diets as its role in both bone loss and aortic calcification. RESULTS: Bone marrow stromal cell (BMSC's) dynamics showed that AD and HFD decreased osteoblast number that led to bone loss, deterioration in bone micro-architecture with up-regulated bone resorptive genes that lead to increase in aortic calcification. CAFG treatment rescued the bone health by modulating BMSC's towards osteogenic lineage. It increased the osteogenic gene expression with simultaneous decrease in osteoclastic genes thus stabilized the receptor activator of nuclear factor-kappa-B ligand/osteoprotegerin ratio that eventually reduced the amount of calcification in aorta. Biochemical studies showed that CAFG reduced the TC, TG and LDL-C content with no marked changes in HDL-C. Moreover, CAFG decreased the osteogenic key markers in the aortic tissue and enhanced endothelial function. CONCLUSION: Overall, this study indicates that CAFG protected against physiologically challenged diet induced bone loss with associated vascular calcification in mice. Moreover, data revealed that atherogenic diet is more detrimental as compared to the excess fatty acid diet to the bone and aorta. PMID- 28591691 TI - Naringenin protects keratinocytes from oxidative stress injury via inhibition of the NOD2-mediated NF-kappaB pathway in pemphigus vulgaris. AB - Naringenin is known to have anti-oxidative activity; however, the effect of naringenin on the progression of pemphigus vulgaris (PV) still remains unclear. This study aims to analyze the effect of naringenin on HaCaT cell apoptosis and oxidative damage under the treatment of PV serum. The results showed that PV serum significantly induced cell apoptosis compared with the control group; whereas, comparing with PV group, naringenin inhibited cell apoptosis. Moreover, PV serum increased the expression of bax and caspase-3, and decreased the expression of bcl-2; but naringenin significantly suppressed the expression of bax and caspase-3, induced the expression of bcl-2. Naringenin inhibited PV serum induced disruption of cell-cell contacts. Naringenin also down-regulated the expression of Dsg1, Dsg3 and E-cadherin compared with the PV group. Additionally, naringenin noticeably decreased the PV serum-induced ROS production and alleviated PV serum induced the drop of mitochondrial membrane potential. Furthermore, naringenin increased the activity of SOD, GSH-Px and TAC under the treatment of PV serum. Naringenin also decreased the expression of NOD2, RIPK2 and NF-kappaB p-p65, but this effect could be reversed by muramyl dipeptide (MDP). In conclusion, these results suggested that naringenin protected keratinocytes from apoptosis and oxidative stress injury through inhibition of the NOD2-mediated NF-kappaB pathway. PMID- 28591690 TI - A Review on Phytoconstituents and Biological activities of Cuscuta species. AB - The genus Cuscuta belonging to the Cuscutaceae family comprises of about 100-170 species spread around the world. Although several species have been studied for their phytochemical characterization and biological activities but still many species are yet unexplored till date. Cuscuta are parasitic plants generally of yellow, orange, red or rarely green color. The Cuscuta species were reported rich in flavonoid and glycosidic constituents along with alkaloids, fatty acids, fixed oil, minerals, essential oil and others phytomolecules also etc. Flavonoids and other molecules of Cuscuta species were reported for different types of biological activities such as antiproliferative activity, antioxidant activity, anti-inflammatory, hepatoprotective, antimicrobial and anxiolytic activity, while some other flavonoids have exhibited potential antiviral and anticancer especially in ovarian and breast cancer activities. This review is an attempt to compile all the available data for the 24 different of Cuscuta species on the basis of different types of phytochemical constituents and biological studies as above. PMID- 28591692 TI - The effect of 1800MHz radio-frequency radiation on NMDA receptor subunit NR1 expression and peroxidation in the rat brain in healthy and inflammatory states. AB - BACKGROUND: The aim of this study was to evaluate the effect of repeated exposure (5 times for 15min) of 1800MHz radio-frequency radiation (RFR) on N-methyl-d aspartate receptor subunit NR1 (NMDA-NR1) expression in the brains of rats in a persistent inflammatory state. We also measured the effect of RFR combined with tramadol (TRAM) to determine the potential antioxidant capacity of this agent. METHODS: The effects of the Global System for Mobile Communication (GSM) modulated 1800MHz RFR exposure on the expression and activity of glutamate receptor channels with antioxidative activity in brain tissue was measured using oxygen radical absorbance capacity (ORAC) and electron spin resonance (ESR) detection of the hydroxyl radical generated by the Fenton reaction. NMDA-NR1 was measured in the cerebral tissue of rats with inflammation (complete Freund's adjuvent) and those injected with tramadol after RFR exposure (RFR, RFR/TRAM) and in non-exposed (baseline, TRAM) rats. RESULTS: No differences between the baseline group and the exposed group (RFR) were observed. NMDA-NR1 expression decreased after CFA injection and RFR exposure, and an elevated expression of NMDA-NR1 was observed in healthy control rats of both groups: TRAM/RFR and RFR. CONCLUSIONS: ORAC assessment revealed a robust effect of RFR, however the other experiments revealed equivocal effects. Further studies examining the combination of ORAC with NMDA are warranted to elucidate more clearly the effect of RFR on the brain. PMID- 28591695 TI - Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for lung squamous carcinomas harboring EGFR mutation: A multicenter study and pooled analysis of published reports. AB - Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinoma (ADC) but rare in squamous cell carcinoma (SQC). The efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for SQC with EGFR mutations is unclear. The aim of this study was to evaluate the efficacy of EGFR-TKIs for these patients. We performed a retrospective matched-pair case-control study from 3 cancer centers, including 44 SQC and 44 ADC patients with EGFR mutation who were treated with EGFR-TKI. Subsequently, we performed a pooled analysis on the efficacy of EGFR-TKIs for EGFR-mutant SQC in 115 patients, including 71 patients selected from 25 published reports. In our multicenter study, EGFR-mutant SQC and ADC patients had similar objective response rate (ORR) (43.2% vs. 54.5%, p = 0.290), but SQC patients had lower disease control rate (DCR) (71.3% vs. 100%, p = 0.001), significant shorter median progression free survival (PFS) (5.1 vs. 13.0 months, p = 0.000) and median overall survival (OS) (17.2 vs. 23.6 months, p = 0.027). In pooled analysis, the ORR, DCR, PFS and OS of SQC patients were 39.1%, 71.3%, 5.6 months and 15.0 months, respectively. Performance status was the only independent predictor of PFS and erlotinib treatment was associated with a better survival. In conclusion, EGFR-TKI was less effective in EGFR-mutant SQC than in ADC but still has clinical benefit for SQC patients. Further study is need to evaluate the using of EGFR-TKIs in these SQC patients. PMID- 28591694 TI - The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-beta antagonizing mechanism: attenuation of PACT-mediated RIG-I/ MDA5 activation. AB - Coronaviruses (CoVs) are a huge threat to both humans and animals and have evolved elaborate mechanisms to antagonize interferons (IFNs). Nucleocapsid (N) protein is the most abundant viral protein in CoV-infected cells, and has been identified as an innate immunity antagonist in several CoVs, including mouse hepatitis virus (MHV) and severe acute respiratory syndrome (SARS)-CoV. However, the underlying molecular mechanism(s) remain unclear. In this study, we found that MHV N protein inhibited Sendai virus and poly(I:C)-induced IFN-beta production by targeting a molecule upstream of retinoic acid-induced gene I (RIG I) and melanoma differentiation gene 5 (MDA5). Further studies showed that both MHV and SARS-CoV N proteins directly interacted with protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein that can bind to RIG-I and MDA5 to activate IFN production. The N-PACT interaction sequestered the association of PACT and RIG-I/MDA5, which in turn inhibited IFN-beta production. However, the N proteins from porcine epidemic diarrhea virus (PEDV) and porcine reproductive and respiratory syndrome virus (PRRSV), which are also classified in the order Nidovirales, did not interact and counteract with PACT. Taken together, our present study confirms that both MHV and SARS-CoV N proteins can perturb the function of cellular PACT to circumvent the innate antiviral response. However, this strategy does not appear to be used by all CoVs N proteins. PMID- 28591696 TI - Clinical evaluation of integrated panel testing by next-generation sequencing for somatic mutations in neuroblastomas with MYCN unamplification. AB - Neuroblastomas (NBs) exhibit heterogeneity and show clinically significant prognosis classified by genetic alterations. Among prognostic genes or genome factors, MYCN amplification (MNA) is the most established genomic marker of poor prognosis in patients with NB. However, the prognostic classification of more than 60% of patients without MNA has yet to be clarified. In this study, the application of target next-generation sequencing (NGS) was extended on the basis of a comprehensive panel of regions where copy number variations (CNVs) or point mutations occurred to improve the prognostic evaluation of these patients and obtain the sequence of 33 patients without MNA. A mean coverage depth of 887* was determined in the target regions in all of the samples, and the mapped read percentage was more than 99%. Somatic mutations in patients without MNA could be precisely defined on the basis of these findings, and 17 unique somatic aberrations, including 14 genes, were identified in 11 patients. Among these variations, most were CNVs with a number of 13. The 3-year event-free survival (EFS) of CNV(-) patients was 60.0% compared with the EFS (16.7%) of CNV(+) patients (P = 0.015, HR = 0.1344, 95%, CI = 0.027 to 0.678). CNVs were also associated with unfavorable histological characteristics (P = 0.003) and likely to occur in stage 4 (P = 0.041). These results might further indicate the role of CNVs in NB chemotherapy resistance (P = 0.059) and show CNVs as a therapeutic target. In multivariate analysis, the presence of CNVs was a clinically negative prognostic marker that impaired the outcome of patients without MNA and associated with poor prognosis in this tumor subset. Comprehensive genetic/genomic profiling instead of focusing on single genetic marker should be performed through in-depth NGS that could reveal prognostic information, improve NB target therapy, and provide a basis for investigations on NB pathogenesis. PMID- 28591698 TI - Bevacizumab for ramucirumab refractory malignant pleural effusion in non-small cell lung cancer: a case report and review of the literature. AB - Malignant pleural effusion (MPE) is a major problem associated with advanced non small cell lung cancer for which an optimum treatment strategy has yet to be determined. Notably, vascular endothelial growth factor (VEGF) signaling has been found to influence MPE, and bevacizumab, a VEGF ligand inhibitor, can effectively control MPE. Ramucirumab, a human monoclonal antibody specific for VEGF receptor 2, has recently been approved for advanced non-small cell lung cancer. However, it remains unclear which of these agents more effectively control MPE.We describe a case of a 68-year-old man with advanced non-small cell lung cancer in whom ramucirumab plus docetaxel-refractory MPE was responsive to bevacizumab plus docetaxel combination therapy. The patient's MPE progressed after two cycles of ramucirumab plus docetaxel second-line chemotherapy. After switching to bevacizumab plus docetaxel, a computed tomography scan revealed a decreased MPE after two cycles of treatment.Bevacizumab may be more effective for treating MPE. However, further investigations are still warranted to determine the optimal VEGF targeted agent for this condition. PMID- 28591697 TI - Relationship between expression of PD-L1 and tumor angiogenesis, proliferation, and invasion in glioma. AB - Programmed death ligand 1 (PD-L1) is highly expressed in many cancers. We investigated the expression of PD-L1 and its relationship with vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 and KI-67 expression in 64 patients with primary glioma. The expression rate of PD-L1 in glioma patients was 78.12%. PD-L1 levels correlated with the tumor grade (p = 0.013), VEGF status (p = 0.002) and KI-67 status (p = 0.002). In addition, PD-L1 levels correlated positively with VEGF (r = 0.314, p = 0.011) and KI-67 (r = 0.391, p = 0.001) levels when the data were treated as continuous variables. This is the first report suggesting that PD-L1 is important for glioma angiogenesis and proliferation. Thus, further research should be conducted to assess the combination of targeted VEGF therapy and anti-PD-L1 immunotherapy for the treatment of glioma. PMID- 28591701 TI - DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors. AB - BACKGROUND: PanNETs shows heterogeneous biological behaviors. The aim was to investigate prognostic markers based on most frequently mutated genes in PanNETs. RESULTS: There was a total of 76 patients (M: 39, F: 37) with pathologically proven PanNETs. ATRX/DAXX and MEN1 protein expression was detected in 16 (21%) and 31 (41%) patients, respectively. The mean OS of the total study patients was 16 years, and DFS was 17 years among the 68 patients with curative resections. PanNETs presented with distant metastasis or loss of ATRX/DAXX protein expression was the independent prognostic factors associated with poor OS. In curative resected PanNETs, there was no significant difference in the mean DFS according to ATRX/DAXX or MEN1 protein. However, there was statistically significant difference in survival after the recurrence according to the expression of ATRX/DAXX protein; Y/N: 10 vs. 15 years, p < 0.001. In metastatic PanNETs, we could find out OS was significantly longer in negative protein expression of ATRX/DAXX and MEN1 groups; 7 vs. 1 years, p < 0.001, 6 vs. 2 years, p = 0.02, respectively. MATERIALS AND METHODS: The histologically proven PanNETs were enrolled and the clinicopathologic and genetic alterations were evaluated. CONCLUSIONS: Protein expression of MEN1 and DAXX/ATRX can be prognostic markers for PanNETs. Further investigation in genetic alterations of PanNETs may give us insights understanding the behavior of PanNETs. PMID- 28591699 TI - Genetic heterogeneity in leiomyomas of deep soft tissue. AB - Leiomyoma of deep soft tissue is a rare type of benign smooth muscle tumor that mostly occurs in the retroperitoneum or abdominal cavity of women, and about which very little genetic information exists. In the present study, eight leiomyomas of deep soft tissue were genetically analyzed. G-banding showed that three tumors carried rearrangements of the long arm of chromosome 12, three others had 8q rearrangements, the 7th tumor had deletion of the long arm of chromosome 7, del(7)(q22), and the 8th had aberrations of chromosome bands 3q21~23 and 11q21~22. The target genes of the 12q and 8q aberrations were HMGA2 and PLAG1, respectively. In the leiomyomas with 12q rearrangements, both HMGA2 and PLAG1 were expressed whereas in the tumors with 8q aberrations, only PLAG1 was expressed. In the cases without 12q or 8q aberrations, the expression of HMGA2 was very low and PLAG1 was expressed only in the case with del(7)(q22). All eight leiomyomas of deep soft tissue expressed MED12 but none of them had mutation in exon 2 of that gene. In two tumors with 12q rearrangements, RPSAP52 on 12q14.3 was fused with non-coding RNA (accession number XR_944195) from 14q32.2 or ZFP36L1 from14q24.1. In a tumor with inv(12), exon 3 of HMGA2 was fused to a sequence in intron 1 of the CRADD gene from 12q22. The present data together with those of our two previous studies in which the fusions KAT6B-KANSL1 and EWSR1-PBX3 were described in two retroperitoneal leiomyomas carrying a t(10;17)(q22;q21) and a t(9;22)(q33;q12) translocation, respectively, show that leiomyomas of deep soft tissue are genetically heterogenous but have marked similarities to uterine leiomyomas. PMID- 28591702 TI - FGF21 functions as a sensitive biomarker of APAP-treated patients and mice. AB - Acetaminophen (APAP) is a common medication that induces hepatocellular damage in a time- or dose-dependent manner. Fibroblast growth factor 21 (FGF21) exerts a series of biological effects, including cellular repair. Compared to clinical diagnosis parameters, we aimed to evaluate whether FGF21 can serve as a sensitive biomarker for APAP-induced liver impairment. In the present study, we discussed comparable data from APAP-treated patients and parallelly established APAP exposed mice for investigation. The resulting human serological data showed that APAP-treated patients have a visible reduction of FGF21 expression in undetected liver impairment of clinical diagnosis. In the animal study, APAP-exposed livers exhibited normal metabolic functions and liver functions, as revealed by biochemical test and histopathological examination. Endogenous FGF21 concentrations in APAP-treated mice were decreased in sera and liver cells. Moreover, comparable immunoassay data showed that hepatocellular FGF21 expression was reduced in a time-dependent manner. Taken together, these findings elucidate the involvement of abnormal FGF21 expression in early APAP-induced liver impairment. Interestingly, FGF21 may be a promising biomarker of APAP-exposed livers. PMID- 28591704 TI - Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway. AB - Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR 196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo. Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC. PMID- 28591705 TI - M2 tumor-associated macrophages produce interleukin-17 to suppress oxaliplatin induced apoptosis in hepatocellular carcinoma. AB - M2 macrophages are a major component of the tumor microenvironment and are important promoters of tumor occurrence and progression. In this study, we detected large numbers of M2 macrophages in hepatocellular carcinoma tissues using immunohistochemistry and immunofluorescence. Moreover, upon oxaliplatin treatment, the M2 macrophages overexpressed interleukin-17, an important inflammatory cytokine, and thus inhibited oxaliplatin-induced apoptosis. By knocking down the interleukin-17 receptor and lysosome-associated membrane protein 2A (a key protein in chaperone-mediated autophagy) in hepatocellular carcinoma cells, we found that interleukin-17 stimulated chaperone-mediated autophagy, which further suppressed apoptosis upon oxaliplatin treatment. Chaperone-mediated autophagy induced tolerance to oxaliplatin treatment by reducing cyclin D1 expression; thus, cyclin D1 overexpression stimulated oxaliplatin-induced apoptosis. In addition, cyclin D1 expression was inhibited by interleukin-17, but increased when the interleukin-17 receptor was knocked down. Thus M2 macrophages in the hepatocellular carcinoma microenvironment generate large amounts of interleukin-17, which suppress oxaliplatin-induced tumor cell apoptosis by activating chaperone-mediated autophagy and in turn reducing cyclin D1 expression. These findings may facilitate the development of novel therapeutic strategies for chemorefractory liver cancer. PMID- 28591703 TI - Vitamin D receptor activation reduces VCaP xenograft tumor growth and counteracts ERG activity despite induction of TMPRSS2:ERG. AB - Whether vitamin D is chemopreventive and/or has potential therapeutically in prostate cancer is unresolved. One confounding factor is that many prostate cancers express a TMPRSS2:ERG fusion gene whose expression is increased both by androgens and by vitamin D receptor (VDR) activation. Two challenges that limit VDR agonist use clinically are hypercalcemia and the cooperation of VDR with ERG to hyper-induce the 1alpha,25-dihydroxyvitamin D3 metabolizing enzyme, CYP24A1, thus reducing VDR activity. Using the VCaP TMPRSS2:ERG positive cell line as a model, we found that a nonsecosteroidal CYP24A1 resistant VDR agonist, VDRM2, substantially reduces growth of xenograft tumors without inducing hypercalcemia. Utilizing next generation RNA sequencing, we found a very high overlap of 1,25D(OH)2D3 and VDRM2 regulated genes and by drawing upon previously published datasets to create an ERG signature, we found activation of VDR does not induce ERG activity above the already high basal levels present in VCaP cells. Moreover, we found VDR activation opposes 8 of the 10 most significant ERG regulated Hallmark gene set collection pathways from Gene Set Enrichment Analysis (GSEA). Thus, a CYP24A1 resistant VDR agonist may be beneficial for treatment of TMPRSS2:ERG positive prostate cancer; one negative consequence of TMPRSS2:ERG expression is inactivation of VDR signaling. PMID- 28591713 TI - Nomogram predicts survival benefit from preoperative radiotherapy for non metastatic breast cancer: A SEER-based study. AB - BACKGROUND: To estimate survival in non-metastatic breast cancer patients who failed to achieve a pathological complete response (pCR) more effectively, we combined the clinicpathological characteristics after preoperative radiation therapy (pRT) and established a novel nomogram. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 2,545 non-metastatic breast cancer patients who underwent pRT between 1998 and 2013. Based on the registries of patients, the primary cohort divided into training set (n = 1,692) and validation set (n = 853). Nomograms were established by training set and validated by validation set. RESULTS: According to the multivariate analysis of training set, nomogram which combined age at diagnosed, marital status, location, grade, ER status, yp-T status, yp-N status and whether received breast conservation surgery (BCS) was developed. Calibration plots of the nomograms showed that the probability of DSS corresponded to actual observation closely. The C-index was 0.78 in validation set, which was significantly higher than that of yp-TNM staging system (0.75, p = 0.004). CONCLUSIONS: The proposed nomogram resulted in more-reliable DSS prediction for non-metastatic breast cancer patients in general population, it would be helpful in individualized survival prediction and better treatment allocation after pRT. PMID- 28591712 TI - An esophageal squamous cell carcinoma classification system that reveals potential targets for therapy. AB - ESCC (Esophageal squamous cell carcinoma) is a heterogeneous cancer with diverse prognosis. Here, to explore the biological diversity of ESCC, we employed gene expression profiles from 360 ESCC tumors from East Asians to establish a comprehensive molecular classification and characterization of ESCC. Using the specific 185-gene signature generated by unsupervised consensus clustering of gene expression data, we defined four subtypes associated with distinct clinical metrics: tumors with high metastasis associated with EMT (epithelial to mesenchymal transition) and active MAP4K4/JNK signaling pathway; tumors with high chromosomal instability with up regulated MYC targes; well differentiated tumors with less aggressive and moderated tumors. The clinical relevance of these subtypes was stated by significant differences in prognosis. Importantly, 24% of all ESCCs (n = 360) were classified into the high metastasis subtype associated with poorly differentiation and unfavorable prognosis. We provided evidence that this subtype relates to tumor microenvironment. Collectively, these results might contribute to more precise personalized therapeutic strategies for each subtype of ESCC patients in the near future. PMID- 28591715 TI - BRCA2, EGFR, and NTRK mutations in mismatch repair-deficient colorectal cancers with MSH2 or MLH1 mutations. AB - Deficient mismatch repair (MMR) and microsatellite instability (MSI) contribute to ~15% of colorectal cancer (CRCs). We hypothesized MSI leads to mutations in DNA repair proteins including BRCA2 and cancer drivers including EGFR. We analyzed mutations among a discovery cohort of 26 MSI-High (MSI-H) and 558 non MSI-H CRCs profiled at Caris Life Sciences. Caris-profiled MSI-H CRCs had high mutation rates (50% vs 14% in non-MSI-H, P < 0.0001) in BRCA2. Of 1104 profiled CRCs from a second cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 compared to non-MSH2/MLH1-mutant tumors (38% vs 6%, P < 0.0000001). BRCA2 mutations in MSH2/MLH1-mutant CRCs included 75 unique mutations not known to occur in breast or pancreatic cancer per COSMIC v73. Only 5 deleterious BRCA2 mutations in CRC were previously reported in the BIC database as germ-line mutations in breast cancer. Some BRCA2 mutations were predicted to disrupt interactions with partner proteins DSS1 and RAD51. Some CRCs harbored multiple BRCA2 mutations. EGFR was mutated in 45.5% of MSH2/MLH1-mutant and 6.5% of non-MSH2/MLH1-mutant tumors (P < 0.0000001). Approximately 15% of EGFR mutations found may be actionable through TKI therapy, including N700D, G719D, T725M, T790M, and E884K. NTRK gene mutations were identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L. Our findings have clinical relevance regarding therapeutic targeting of BRCA2 vulnerabilities, EGFR mutations or other identified oncogenic drivers such as NTRK in MSH2/MLH1-mutant CRCs or other tumors with mismatch repair deficiency. PMID- 28591716 TI - Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. AB - Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor kappaB (NF kappaB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-kappaB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future. PMID- 28591717 TI - Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet. AB - The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We established an atherogenic and high-fat diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and liver tumors at a high frequency. Using two NASH-HCC mouse models, we showed that peretinoin, an acyclic retinoid, significantly improved liver histology and reduced the incidence of liver tumors. Interestingly, we found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of microtubule-associated protein light chain 3B-II and lysosome-associated membrane protein 2, and increased autophagosome formation and autophagy flux in the liver. These findings were confirmed using primary mouse hepatocytes. Among representative autophagy pathways, the autophagy related (Atg) 5-Atg12-Atg16L1 pathway was impaired; especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Promoter analysis revealed that peretinoin activated the promoter of Atg16L1 by increasing the expression of CCAAT/enhancer-binding-protein-alpha. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and interleukin-6 induced STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated-STAT3 (Tyr705) levels, and this process might be independent of autophagy function. Thus, peretinoin prevents the progression of NASH and the development of HCC through activating the autophagy pathway by increased Atg16L1 expression, which is an essential regulator of autophagy and anti-inflammatory proteins. PMID- 28591718 TI - Riluzole exerts distinct antitumor effects from a metabotropic glutamate receptor 1-specific inhibitor on breast cancer cells. AB - Recent evidence suggests that glutamate signaling plays an important role in cancer. Riluzole is a glutamate release inhibitor and FDA-approved drug for the treatment of amyotrophic lateral sclerosis. It has been investigated as an inhibitor of cancer cell growth and tumorigenesis with the intention of repurposing it for the treatment of cancer. Riluzole is thought to act by indirectly inhibiting glutamate signaling. However, the specific effects of riluzole in breast cancer cells are not well understood. In this study, the anti cancer effects of riluzole were explored in a panel of breast cancer cell lines in comparison to the metabotropic glutamate receptor 1-specific inhibitor BAY 36 7620. While both drugs inhibited breast cancer cell proliferation, there were distinct functional effects suggesting that riluzole action may be metabotropic glutamate receptor 1-independent. Riluzole induced mitotic arrest independent of oxidative stress while BAY 36-7620 had no measurable effect on mitosis. BAY 36 7620 had a more pronounced and significant effect on DNA damage than riluzole. Riluzole altered cellular metabolism as demonstrated by changes in oxidative phosphorylation and cellular metabolite levels. These results provide a better understanding of the functional action of riluzole in the treatment of breast cancer. PMID- 28591719 TI - Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer. AB - Two decades ago, Galectin-8 was described as a prostate carcinoma biomarker since it is only expressed in the neoplastic prostate, but not in the healthy tissue. To date, no biological function has been attributed to Galectin-8 that could explain this differential expression. In this study we silenced Galectin-8 in two human prostate cancer cell lines, PC3 and IGR-CaP1, and designed a pre-clinical experimental model that allows monitoring the pathology from its early steps to the long-term metastatic stages. We show for the first time that the natural and conserved expression of Gal-8 in tumour cells is responsible for the metastatic evolution of prostate cancer. In fact, Gal-8 controls the rearrangement of the cytoskeleton and E-Cadherin expression, with a major impact on anoikis and homotypic aggregation of tumour cells, both being essential processes for the survival of circulating tumour cells during metastasis. While localized prostate cancer can be cured, metastatic and advanced disease remains a significant therapeutic challenge, urging for the identification of prognostic markers of the metastatic process. Collectively, our results highlight Galectin-8 as a potential target for anti-metastatic therapy against prostate cancer. PMID- 28591720 TI - BRSK2 induced by nutrient deprivation promotes Akt activity in pancreatic cancer via downregulation of mTOR activity. AB - Neoplastic cells in pancreatic ductual adenocarcinoma (PDAC) survive in an energy deprived milieu, and hyper-activation of Akt is thought to contribute to the neoplastic cell survival in PDAC. Kras activating mutations, common in PDAC, was believed to be the major driver of Akt activation. However, the inhibitor to Kras was not therapeutic for PDAC patients. This implied that PDAC cells might harbor an intrinsic merit that strengthens Akt activity. Here we showed that BRSK2, a serine/threonine-protein kinase of AMPK family, was induced by nutrient deprivation in PDAC cells and suppressed mTORC1 activity via phosphorylation of tuberous sclerosis complex 2 (TSC2). The suppression of mTORC1 activity in PDAC results in a dominant loss of feedback inhibition on Akt activity by mTORC1, consequently enhancing cell survival. This finding indicates that the intrinsic molecular merit that BRSK2 provides is a survival advantage to PDAC cells and strengthens the invasiveness of these neoplastic cells in energy-deprived environments. PMID- 28591721 TI - Ginkgolide K attenuates neuronal injury after ischemic stroke by inhibiting mitochondrial fission and GSK-3beta-dependent increases in mitochondrial membrane permeability. AB - Ginkgolide K (GK) belongs to the ginkgolide family of natural compounds found in Ginkgo biloba leaves, which have been used for centuries to treat cerebrovascular and cardiovascular diseases. We evaluated the protective effects of GK against neuronal apoptosis by assessing its ability to sustain mitochondrial integrity and function. Co-immunoprecipitation showed that Drp1 binding to GSK-3beta was increased after an oxygen-glucose deprivation/reperfusion (OGD/R) insult in cultured neuroblastoma cells. This induced Drp1 and GSK-3beta translocation to mitochondria and mitochondrial dysfunction, which was attenuated by GK. GK also reduced mitochondrial fission by increasing Drp1 phosphorylation at Ser637 and inhibiting mitochondrial Drp1 recruitment. In addition, GK exposure induced GSK 3beta phosphorylation at Ser9 and enhanced the interaction between adenine nucleotide translocator (ANT) and p-GSK-3beta. This interaction suppressed the interaction between ANT and cyclophilin D (CypD), which inhibited mitochondrial permeability transition pore (mPTP) opening. Similarly, suppression of mitochondrial fission by Mdivi-1 also inhibited GSK-3beta-induced mPTP opening. Treating mice with GK prevented GSK-3beta and Drp1 translocation to mitochondria and attenuated mitochondrial dysfunction after middle cerebral artery occlusion. We therefore propose that by inhibiting mitochondrial fission and attenuating mPTP opening, GK exerts neuroprotective effects that mitigate or prevent neuronal damage secondary to ischemic stroke. PMID- 28591723 TI - RIP1 is a central signaling protein in regulation of TNF-alpha/TRAIL mediated apoptosis and necroptosis during Newcastle disease virus infection. AB - Newcastle disease virus (NDV) is an oncolytic virus which selectively replicates in tumor cells and exerts anti-tumor cytotoxic activity by promoting cell death. In this study, we focus on characterization of the underlying mechanisms of NDV induced cell death in HeLa cells. We find that NDV Herts/33 strain triggers both extrinsic and intrinsic apoptosis at late infection times. The activation of NF DoB pathway and subsequent up-regulation of TNF-alpha/TRAIL initiates extrinsic apoptosis, leading to activation of caspase 8 and cleavage of Bid into tBid. tBid transmits the extrinsic apoptotic signals to mitochondria and mediates intrinsic apoptosis, which is hallmarked by cleavage of caspase 9. Moreover, RIP1 is cleaved into RIP1-N and RIP1-C at D324 by caspase 8, and this cleavage promotes apoptosis. Surprisingly, over expression of RIP1 reduces apoptosis and depletion of RIP1 promotes apoptosis, suggesting full length RIP1 is anti-apoptotic. Moreover, necroptosis hallmark protein MLKL is activated by phosphorylation at 12 24 h.p.i., and RIP1 regulates the level of phosphor-MLKL. Immunostaining shows that RIP1 aggregates to stress granules (SGs) at 8-24 h.p.i., and phosphor-MLKL is also recruited to SGs, instead of migrating to plasma membrane to exert its necrotic function. Immunoprecipitation study demonstrates that RIP1 bind to phosphor-MLKL, and depletion of RIP1 reduces the aggregation of MLKL to SGs, suggesting that RIP1 recruits MLKL to SGs. Altogether, NDV infection initiates extrinsic apoptosis via activation of NF-DoB and secretion of TNF-alpha/TRAIL. Activation of caspase 8 by TNF-alpha/TRAIL and subsequent cleavage of Bid and RIP1 transmit the death signals to mitochondria. Meanwhile, virus subverts the host defensive necroptosis via recruiting phosphor-MLKL by RIP1 to SGs. Thus, RIP1 is a central signaling protein in regulation of apoptosis and necroptosis during NDV infection. PMID- 28591725 TI - FOXP3 inhibits cancer stem cell self-renewal via transcriptional repression of COX2 in colorectal cancer cells. AB - Colon cancer stem cell (cCSC) is considered as the seed cell of colon cancer initiation and metastasis. Cyclooxygenase-2 (COX2), a downstream target of NFkappaB, is found to be essential in promoting cancer stem cell renewal. However, how COX2 is dysregulated in cCSCs is largely unknown. In this study, we found that the expression of transcription factor FOXP3 was much lower in the spheroids than that in the parental tumor cells. Overexpression of FOXP3 significantly decreased the numbers of spheres, reduced the side population. Accordingly, FOXP3 expression decreased the tumor size and weight in the xenograft model. The tumor inhibitory effects of FOXP3 were rarely seen when COX2 was additionally knocked down. Mechanically, FOXP3 transcriptionally repressed COX2 expression via interacting with and thus inhibiting p65 activity on the putative NFkappaB response elements in COX2 promoter. Taken together, we here revealed possible involvement of FOXP3 in regulating cCSC self-renewal via tuning COX2 expression, and thus providing a new target for the eradication of colon cancer stem cells. PMID- 28591727 TI - VEGF-C expression attributes the risk for lymphatic metastases to ovarian cancer patients. AB - BACKGROUND: Peritoneal dissemination and retroperitoneal lymph node involvement are main routes for progression of epithelial ovarian cancer (EOC). Vascular endothelial growth factor (VEGF) mediated angiogenesis has been identified as an important mechanism promoting tumour progression. METHODS: Tumour tissue of 100 patients with EOC was analysed for protein expression of vascular endothelial growth factor (VEGF)-A, -C, -D by Western Blot analysis. Expression patterns in patients with 'extensive intraperitoneal' metastases (pT3c pN1 and pT3b-pT3c pN0, n=80) were compared to patients with 'predominantly retroperitoneal' metastases (pT1a-pT3b, pN1, n=20). Overall and progression-free survival was analysed by Kaplan-Meier method. RESULTS: While no significant differences in expression levels among the different modes of metastases were noted for VEGF-A and -D, VEGF C expression was significantly higher in the group of predominantly retroperitoneal metastases compared to the group with extensive intraperitoneal metastases. Patients with high VEGF-C expression had a significantly worse overall survival compared to patients with low expression levels. CONCLUSIONS: Retroperitoneal tumour progression in EOC patients is associated with high VEGF-C expression. VEGF-C may serve as a molecular marker to identify patients with assumed high risk for lymphatic metastases, who might benefit from specific treatment strategies. PMID- 28591732 TI - Spindle cell carcinoma: the general demographics, basic clinico-pathologic characteristics, treatment, outcome and prognostic factors. AB - BACKGROUND: Owing to the rarity, the general demographics, basic clinico pathologic features, management, outcome and prognostic factors of spindle cell carcinoma (SpCC) were unexplored. METHODS: A SEER analysis was performed with 2336 cases (1973-2016). RESULTS: A peak incidence occurred at 70~80 years without any gender predominance and 83.13% occurred in white people. The respiratory system was mostly affected tumor site (35%). Significant overall survival (OS) and disease specific survival (DSS) were found differentiated in gender, age, marital status, primary tumor location, AJCC stage, T stage, N stage, M stage, pathologic grade and treatment modality. In the multivariate Cox model, the age > 69 years (Hazard ratio [HR] = 1.427 for OS, P = 0.01 and HR = 1.491 for DSS, P = 0.003; Reference [Ref] age <= 69 years), tumor location in respiratory system (HR = 1.550 for OS, P = 0.041 and HR = 1.561 for DSS, P = 0.04; Ref: digestive system), N2 stage (HR = 1.962 for OS, P = 0.006 and HR = 1.982 for DSS, P = 0.004; Ref: N0 stage) and AJCC stage IV (HR = 4.601 for OS, P = 0.000 and HR = 5.107 for DSS, P = 0.000; Ref: stage I) were independently associated with worse OS and DSS. CONCLUSIONS: SpCC mostly occurred in white people at 70~80 years old without predominance in any gender. The respiratory system was mostly affected site. The patient's age, primary tumor location, AJCC stage were independent prognostic indicators for both DSS and OS of SpCC. PMID- 28591733 TI - ABCG2 downregulation in glioma stem cells enhances the therapeutic efficacy of demethoxycurcumin. AB - We analyzed the role of ABCG2, a drug transporter, in determining the sensitivity of glioma stem cells (GSCs) to demethoxycurcumin (DMC). We first demonstrated that ABCG2 is more highly expressed in GSCs than primary astrocytes. Modulation of ABCG2 levels in GSCs by transfection of ABCG2 shRNA or a lentiviral vector encoding ABCG2 revealed an inverse relation between ABCG2 levels and DMC-induced GSC growth inhibition. Suppressing ABCG2 increased DMC-induced apoptosis and G0/G1 cell cycle arrest in GSCs. It also increased levels reactive oxygen species (ROS) in GSCs treated with DMC, resulting in increased cytochrome C and caspase-3 activity. When GSCs transfected with ABCG2 shRNA or overexpressing ABCG2 were xenografted and the tumor-bearing, immunodeficient mice were treated with DMC, ABCG2 expression suppressed the tumor proliferation rate (T/C %). These findings demonstrate that ABCG2 expression is critical for DMC resistance in GSCs and is a potential therapeutic target for GBM. PMID- 28591751 TI - Prognostic Accuracy of Mild Cognitive Impairment Subtypes at Different Cut-Off Levels. AB - BACKGROUND/AIMS: The prognostic accuracy of mild cognitive impairment (MCI) in clinical settings is debated, variable across criteria, cut-offs, subtypes, and follow-up time. We aimed to estimate the prognostic accuracy of MCI and the MCI subtypes for dementia using three different cut-off levels. METHODS: Memory clinic patients were followed for 2 (n = 317, age 63.7 +/- 7.8) and 4-6 (n = 168, age 62.6 +/- 7.4) years. We used 2.0, 1.5, and 1.0 standard deviations (SD) below the mean of normal controls (n = 120, age 64.1 +/- 6.6) to categorize MCI and the MCI subtypes. Prognostic accuracy for dementia syndrome at follow-up was estimated. RESULTS: Amnestic multi-domain MCI (aMCI-md) significantly predicted dementia under all conditions, most markedly when speed/attention, language, or executive function was impaired alongside memory. For aMCI-md, sensitivity increased and specificity decreased when the cut-off was lowered from 2.0 to 1.5 and 1.0 SD. Non-subtyped MCI had a high sensitivity and a low specificity. CONCLUSION: Our results suggest that aMCI-md is the only viable subtype for predicting dementia for both follow-up times. Lowering the cut-off decreases the positive predictive value and increases the negative predictive value of aMCI-md. The results are important for understanding the clinical prognostic utility of MCI, and MCI as a non-progressive disorder. PMID- 28591735 TI - Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells. AB - The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis.We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF 2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas.These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer. PMID- 28591752 TI - Physical Activity in End-Stage Renal Disease Patients: The Effects of Starting Dialysis in the First 6 Months after the Transition Period. AB - OBJECTIVES: Physical inactivity in end-stage renal disease (ESRD) patients is associated with increased mortality, and might be related to abnormalities in body composition (BC) and physical performance. It is uncertain to what extent starting dialysis influences the effects of ESRD on physical activity (PA). This study aimed to compare PA and physical performance between stage 5 chronic kidney disease (CKD-5) non-dialysis and dialysis patients, and healthy controls, to assess alterations in PA during the transition from CKD-5 non-dialysis to dialysis, and to relate PA to BC. METHODS: For the cross-sectional analyses 44 CKD-5 non-dialysis patients, 29 dialysis patients, and 20 healthy controls were included. PA was measured by the SenseWearTM pro3. Also, the walking speed and handgrip strength (HGS) were measured. BC was measured by the Body Composition Monitor(c). Longitudinally, these parameters were assessed in 42 CKD-5 non dialysis patients (who were also part of the cross-sectional analysis), before the start of dialysis and 6 months thereafter. RESULTS: PA was significantly lower in CKD-5 non-dialysis patients as compared to that in healthy controls but not as compared to that in dialysis patients. HGS was significantly lower in dialysis patients as compared to that in healthy controls. Walking speed was significantly lower in CKD-5 non-dialysis patients as compared to that in healthy controls but not as compared to that in dialysis patients. Six months after starting dialysis, activity related energy expenditure (AEE) and walking speed significantly increased. CONCLUSIONS: PA is already lower in CKD-5 non-dialysis patients as compared to that in healthy controls and does not differ from that of dialysis patients. However, the transition phase from CKD-5 non-dialysis to dialysis is associated only with a modest improvement in AEE. PMID- 28591753 TI - Antinociceptive Activity of Methanol Extract of Tabebuia hypoleuca (C. Wright ex Sauvalle) Urb. Stems. AB - OBJECTIVE: The aim of this study was to evaluate the antinociceptive activity of the methanol extract of Tabebuia hypoleuca stems (THME). MATERIALS AND METHODS: The animals were divided into 5 groups of 8 mice for each test (negative controls, positive controls, and 3 groups treated with THME at doses of 150, 300, and 500 mg/kg, p.o.). The antinociceptive effect of THME was evaluated using the writhing, formalin, tail flick, and hot plate models in mice. RESULTS: In the writhing test, THME (150, 300, and 500 mg/kg) produced significantly (p < 0.001) fewer writhes induced by acetic acid than in the control group. In the formalin test, the licking time for THME at doses of 300 and 500 mg/kg was significantly shorter (p < 0.001) compared to the control group in the first phase of the formalin test, whereas in the second phase only the dose of 500 mg/kg showed an antinociceptive effect. In addition, THME at doses of 300 and 500 mg/kg significantly increased the latency time in the tail flick test (p < 0.05 and p < 0.001, respectively) and in the hot plate test (p < 0.01 and p < 0.001, respectively) compared to the control group. CONCLUSIONS: These results show that THME had antinociceptive activity using several models of nociception, and they suggest that the effect is mediated by the participation of both peripheral and central antinociceptive mechanisms. PMID- 28591754 TI - Changes in Sleep Architecture under Sustained Pain in Adult Male Rats Subjected to Neonatal Short-Lasting Local Inflammatory Insult. AB - Neonatal, short-lasting, local, nociceptive insult by carrageenan can cause long term alterations in somatosensory and neurohumoral systems. We previously revealed hyporesponsiveness of the autonomic nervous system (ANS) after painful stimulation of adult rats in a neonatal carrageenan-induced pain model. Sleep disturbance has been highly correlated with pain and ANS activity. In the present study, adult rats that had received an intraplantar injection of carrageenan on postnatal day 1 were investigated to determine if there were alterations in their sleep architecture upon the stimulation of pain. Polysomnographic and heart rate variability recordings were carried out, with a wireless transmission of data, for 24 h under baseline conditions and after an intraplantar injection of complete Freund's adjuvant to induce sustained nociception. Increased active awake (AW) and decreased quiet sleep (QS) and paradoxical sleep (PS) times were noted in the control animals. In the carrageenan-treated rats, the AW time increased but with decreased alertness, as revealed by decreases in beta and increases in theta power. The QS time did not decrease. The PS time decreased during the first 12 h, then increased during the following 12 h, suggesting an early rebound of formerly deprived PS time. Sympathetic activation under sustained pain was not apparent in any stage of sleep in carrageenan-treated rats and was even suppressed in AW time. An impaired sympathetic reaction to pain may have contributed to the atypical changes in sleep architecture in these rats. In conclusion, pain in early life has a long-term effect on the cardiovascular autonomic-electroencephalographic responses to pain later in life. The physiological relevance of these results remains undetermined. PMID- 28591756 TI - The "Fetal Reserve Index": Re-Engineering the Interpretation and Responses to Fetal Heart Rate Patterns. AB - OBJECTIVE: Electronic fetal monitoring (EFM) correlates poorly with neonatal outcome. We present a new metric: the "Fetal Reserve Index" (FRI), formally incorporating EFM with maternal, obstetrical, fetal risk factors, and excessive uterine activity for assessment of risk for cerebral palsy (CP). METHODS: We performed a retrospective, case-control series of 50 term CP cases with apparent intrapartum neurological injury and 200 controls. All were deemed neurologically normal on admission. We compared the FRI against ACOG Category (I-III) system and long-term outcome parameters against ACOG monograph (NEACP) requirements for labor-induced fetal neurological injury. RESULTS: Abnormal FRI's identified 100% of CP cases and did so hours before injury. ACOG Category III identified only 44% and much later. Retrospective ACOG monograph criteria were found in at most 30% of intrapartum-acquired CP patients; only 27% had umbilical or neonatal pH <7.0. CONCLUSIONS: In this initial, retrospective trial, an abnormal FRI identified all cases of labor-related neurological injury more reliably and earlier than Category III, which may allow fetal therapy by intrauterine resuscitation. The combination of traditional EFM with maternal, obstetrical, and fetal risk factors creating the FRI performed much better as a screening test than EFM alone. Our quantified screening system needs further evaluation in prospective trials. PMID- 28591755 TI - A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family. AB - Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans. PMID- 28591757 TI - Special Issue Dedicated to Susan J. Vannucci and Robert C. Vannucci. PMID- 28591758 TI - Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab? AB - BACKGROUND: The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed. METHODS: We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years. RESULTS: Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (<10%). There was no association of BKPyV or JCPyV with CMV reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death. CONCLUSION: We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding. PMID- 28591759 TI - PPARgamma-Coactivator-1alpha, Nicotinamide Adenine Dinucleotide and Renal Stress Resistance. AB - With one of the highest mitochondrial densities in the body, the kidneys consume approximately 10% of total oxygen while constituting 0.5% of body mass. Renal respiration is linear to solute extraction, linking oxidative metabolism directly to tubular function. This fundamental role of mitochondria in renal health may become an "Achilles heel" under duress. Acute kidney injury (AKI) related to each major class of stressor - inflammation, ischemia, and toxins - exhibits early and prominent mitochondrial injury. The mitochondrial biogenesis regulator, PPARgamma coactivator-1alpha (PGC1alpha), may confer tubular protection against these stressors. Recent work proposes that renal PGC1alpha directly increases levels of nicotinamide adenine dinucleotide (NAD+), an essential co-factor for energy metabolism that has lately been proposed as an anti-aging factor. This mini review summarizes recent studies on AKI, PGC1alpha, and NAD+ that identify a direct mechanism between the regulation of metabolic health and the ability to resist renal stressors. PMID- 28591760 TI - Cultural Challenges in the Care of Refugees with End-Stage Renal Disease: What Western Nephrologists Should Know. AB - Forced migration is on the rise, mainly from the Middle East to western countries, resulting in unprecedented moral, political, and economic challenges for both refugees and host communities. Recent research showed that refugees represent around 1.5% of the dialysis population in several European and Middle Eastern countries surveyed. Despite the fact that refugees represent a small percentage of all dialysis patients in these countries, adequate care for this population is challenging. There are cultural differences between refugee patients with end-stage renal disease hailing from the Middle East, who are predominantly Muslims, and people from the western host countries. These differences may present a major obstacle in ensuring adequate patient care. In this study, we identify several of these issues that we believe western renal providers should be aware of. PMID- 28591762 TI - Current Trends in Breast Augmentation: An International Analysis. AB - Background: Breast augmentation surgery remains the most frequently performed aesthetic surgical procedure worldwide. However, many variations exist regarding preoperative planning, surgical management, and postoperative care. Objectives: The goal was to evaluate current trends and practices in breast augmentation, with a focus on international variability. Methods: A questionnaire was sent to over 5000 active breast surgeons in 44 countries worldwide. The survey inquired about current controversies, new technologies, common practices, secondary procedures, and surgeon demographics. The findings and variations were evaluated and correlated to evidence-based literature. Results: There were a total 628 respondents equaling a response rate of approximately 18%. While certain approaches and common practices prevail also on an international basis, there exist several geographic controversies. For example, while almost fifty percent of surgeons in the United States and Latin America never use anatomically shaped implants, in Europe and Oceania most surgeons use them. Similarly, in Latin America, Europe, Asia, and Oceania, over 80% of surgeons use silicone implants only, whereas in the United States only 20% use them - meanwhile US surgeons use the largest implants (78% > 300 cc). Internationally dominant practice preferences include preoperative sizing with silicone implants, as well as the use of inframammary incisions and partial submuscular pockets. Conclusions: Significant differences exist when comparing most common surgical breast augmentation approaches on an international basis. While certain techniques seem to be universal standards, there still remain several controversies. Further standardizing this most common aesthetic surgical procedure according to evidence based guidelines will help to improve outcomes. PMID- 28591761 TI - Prospective Cohort Study of Uterine Fibroids and Miscarriage Risk. AB - We sought to determine the relationship of fibroids to pregnancy loss in a prospective cohort in which fibroid status was uniformly documented in early pregnancy. Participants had an intake interview, transvaginal ultrasonography, computer-assisted telephone interview, and follow-up assessment of outcomes. We recruited diverse participants for the Right From the Start study from 8 metropolitan areas in 3 states in the United States during 2000-2012. Participants were at least 18 years of age, trying to become pregnant or at less than 12 weeks' gestation, not using fertility treatments, fluent in English or Spanish, and available for telephone interviews. Miscarriage was defined as loss before 20 weeks' gestation. Fibroid presence, number, type, and volume were assessed using standardized ultrasonography methods. We used proportional hazards models to estimate associations. Among 5,512 participants, 10.4% had at least 1 fibroid, and 10.8% experienced a miscarriage. Twenty-three percent had experienced a prior miscarriage and 52% prior births. Presence of fibroids was associated with miscarriage in models without adjustments. Adjusting for key confounders indicated no increase in risk (adjusted hazard ratio = 0.83, 95% confidence interval: 0.63, 1.08). No characteristic of fibroids was associated with risk. Prior evidence attributing miscarriage to fibroids is potentially biased. These findings imply that surgical removal of fibroids to reduce risk of miscarriage deserves careful scrutiny. PMID- 28591763 TI - Non-Linear Formation of EtG and FAEEs after Controlled Administration of Low to Moderate Doses of Ethanol. AB - Aims: Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) are non oxidative metabolites of alcohol that can be detected in conventional and non conventional biological matrices for longer periods than alcohol. The aim was to describe the time courses of both biomarkers after ingestion of acute low moderate doses of ethanol. Methods: The study design was double-blind, randomized, crossover and controlled with placebo. Participants were distributed in three different cohorts: (a) Cohort-1: two doses of 18 and 30 g of ethanol and placebo were administered to 12 subjects; (b) Cohort-2: two doses of 6 and 12 g of ethanol and placebo were administered to six subjects and (c) Cohort-3: two doses of 24 and 42 g of ethanol and placebo were administered to six subjects. Each participant received two doses of ethanol and placebo. Plasma concentrations (0-6 h) of ethanol and specific FAEEs (palmitic, stearic, linoleic and oleic acid ethyl esters) and urinary concentrations of EtG (0-24 h) were measured. Results: A dose-dependent increase in blood ethanol concentrations was observed. EtG excretion and FAEEs plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. Area under the curve (AUC0-6h) of ethanol concentrations showed a linear trend with non-oxidative metabolites' concentrations. Conclusion: The formation rate of ethanol non-oxidative biomarkers does not follow a linear trend, explained mainly by a disproportionate increase in AUC0-6h of ethanol concentrations in relation to dose. This observation should be taken into account when interpreting results in biological matrices in clinical and forensic settings. Short summary: A double-blind, randomized, crossover and controlled study was conducted administering ethanol (6 42 g). Ethyl glucuronide (EtG) excretion and fatty acid ethyl esters (FAEEs) plasmatic concentrations showed a disproportionate increase with the ethanol dose suggesting non-linearity. This observation should be taken into account when interpreting biomarker concentrations in clinical settings. PMID- 28591765 TI - Corticotomy affects both the modus and magnitude of orthodontic tooth movement. AB - Objective: To analyze whether the decreased bone density due to the manipulation of bone remodeling rate has an influence on the type of the planned tooth movement. Materials and methods: A finite element model of a lower incisor has been developed. The density of the alveolar bone surrounding the tooth has been assumed to simulate the one occurring after corticotomy to increase tooth movement rate. Moment-to-force ratios corresponding to three different types of movements have been simulated; uncontrolled tipping, translation, and root movement. The three tooth movements have been analyzed in both corticotomized and non-corticotomized simulations, and the final effects on the amount and type of tooth movement analyzed. The stress and strain levels in the periodontal ligament have been analyzed too. Results: The amount of tooth movement obtained in case of lower bone density is higher in all types of movement simulations. The centre of rotation of the movement shifts more apically in case of translation, controlled and uncontrolled tipping. In the corticotomy simulations, the compressive stresses in the periodontal ligament decreased while the tensile stresses increased. Conclusion: A decreased bone density influences not only the amount of tooth movement, but also its type. This study suggests that the moment-to-force ratios used in conventional orthodontics should be modified in case of techniques that decrease bone density to enhance tooth movement rate. PMID- 28591764 TI - A Randomized Controlled Pilot Trial of Interventions to Improve Functional Recovery After Hospitalization in Older Adults: Feasibility and Adherence. AB - Background: Hospitalization is a major risk factor for functional decline, disability, loss of independence, and mortality in older adults. Evidence-based interventions to improve functional recovery from hospitalization are difficult to evaluate and implement in geriatric patients. The goal of this pilot study was to test the feasibility of recruiting geriatric inpatients and implementing pragmatic interventions to improve physical function following hospitalization. Methods: Enrolled subjects were randomized to one of five 30-day posthospitalization interventions: isocaloric placebo (P), whey protein supplement (W), in-home rehabilitation+placebo (R+P), rehabilitation+whey protein (R+W), or testosterone (T). Data were collected from a single-site university hospital to determine: (i) institution-based feasibility (nonmodifiable factors including number of patients screened, eligible, contacted) and (ii) patient based feasibility (modifiable factors including number of patients refusing, enrolled, randomized, intervention adherence, and withdrawal). Results: From January 2014 to July 2016, 4,533 patients were chart screened; 594 (13.1%) were eligible to participate; 384 eligible subjects were contacted; 113 were enrolled; and 100 were randomized. Supplement adherence was 75% and was not different by age, education, level of independence, depression, supplement type, or dual intervention, but was significantly higher in subjects who completed the intervention (p < .01). Rehabilitation session adherence was 77% and did not vary significantly by age, education, level of independence, depression, or supplement type, but was significantly higher for sessions directly supervised (p < .01). Adherence was 100% in the testosterone arm with 94.7% of injections given within 24 hours of discharge. Conclusions: Findings from this clinical trial indicate that posthospitalization interventions in geriatric patients are feasible at both the institution and patient level. PMID- 28591767 TI - An amber signal lights up before the red: do not dismiss it. PMID- 28591766 TI - Elective frozen elephant trunk procedure using the E-Vita Open Plus prosthesis in 94 patients: a multicentre French registry. AB - OBJECTIVES: Our goal was to evaluate the operative outcomes of the frozen elephant trunk technique using the E-Vita Open Plus(r) hybrid prosthesis in chronic aortic arch diseases and report clinical and radiological outcomes at the 1-year follow-up. METHODS: As determined from a prospective multicentre registry, 94 patients underwent frozen elephant trunk procedures using the E-Vita Open Plus hybrid device for the treatment of chronic aortic conditions, including 50% chronic aortic dissections, 40% degenerative aneurysms and 10% miscellaneous indications. Fifty percent of the cases were reoperations. RESULTS: The perioperative mortality rate was 11.7%. Spinal cord ischaemia and stroke rates were 4% and 9.6%, respectively. The mean cardiopulmonary bypass time was 252 +/- 97 min, cardiac ischaemia time was 152 +/- 53 min and cerebral perfusion time was 82 +/- 22 min. Concomitant procedures were observed in 15% of patients. Among the 83 surviving patients, the survival rate after the 1-year follow-up was 98%. Eleven percent of patients underwent endovascular completion, whereas 4% of patients required aortic reintervention at 1 year. CONCLUSIONS: The E-Vita Open Plus hybrid device confirms the favourable short- and mid-term outcomes offered by its predecessor in frozen elephant trunk procedures in patients with chronic aortic arch disease. Implantation of the E-Vita Open Plus is associated with good 1-year survival rates, good rates of favourable aortic remodelling in both chronic dissection and degenerative aneurysms and a reproducible technique in a multicentre registry. Continued follow-up is required due to the risk of evolution at the downstream aorta. PMID- 28591768 TI - Adipose-Derived Stem Cells in Aesthetic Surgery: A Mixed Methods Evaluation of the Current Clinical Trial, Intellectual Property, and Regulatory Landscape. AB - Background: Adipose tissue, which can be readily harvested via a number of liposuction techniques, offers an easily accessible and abundant source of adipose-derived stem cells (ASCs). Consequently, ASCs have become an increasingly popular reconstructive option and a novel means of aesthetic soft tissue augmentation. Objectives: This paper examines recent advances in the aesthetic surgery field, extending beyond traditional review formats to incorporate a comprehensive analysis of current clinical trials, adoption status, and the commercialization pathway. Methods: Keyword searches were carried out on clinical trial databases to search for trials using ASCs for aesthetic indications. An intellectual property landscape was created using commercial software (Thomson Reuters Thomson Innovation, New York, NY). Analysis of who is claiming what in respect of ASC use in aesthetic surgery for commercial purposes was analyzed by reviewing the patent landscape in relation to these techniques. Key international regulatory guidelines were also summarized. Results: Completed clinical trials lacked robust controls, employed small sample sizes, and lacked long-term follow up data. Ongoing clinical trials still do not address such issues. In recent years, claims to intellectual property ownership have increased in the "aesthetic stem cell" domain, reflecting commercial interest in the area. However, significant translational barriers remain including regulatory challenges and ethical considerations. Conclusions: Further rigorous randomized controlled trials are required to delineate long-term clinical efficacy and safety. Providers should consider the introduction of patient reported outcome metrics to facilitate clinical adoption. Robust regulatory and ethical policies concerning stem cells and aesthetic surgery should be devised to discourage further growth of "stem cell tourism." PMID- 28591769 TI - Functional Characterization of Xenopus Thyroid Hormone Transporters mct8 and oatp1c1. AB - Xenopus is an excellent model for studying thyroid hormone signaling as it undergoes thyroid hormone-dependent metamorphosis. Despite the fact that receptors and deiodinases have been described in Xenopus, membrane transporters for these hormones are yet to be characterized. We cloned Xenopus monocarboxylate transporter 8 (mct8) and organic anion-transporting polypeptide 1C1 (oatpc1c1), focusing on these two transporters given their importance for vertebrate brain development. Protein alignment and bootstrap analysis showed that Xenopus mct8 and oatp1c1 are closer to their mammalian orthologs than their teleost counterparts. We functionally characterized the two transporters using a radiolabeled hormones in vitro uptake assay in COS-1 cells. Xenopus mct8 was found to actively transport both T3 and T4 bidirectionally. As to the thyroid precursor molecules, diiodotyrosine (DIT) and monoiodotyrosine (MIT), both human and Xenopus mct8, showed active efflux, but no influx. Again similar to humans, Xenopus oatp1c1 transported T4 but not T3, MIT, or DIT. We used reverse transcription quantitative polymerase chain reaction and in situ hybridization to characterize the temporal and spatial expression of mct8 and oatp1c1 in Xenopus. Specific expression of the transporter was observed in the brain, with increasingly strong expression as development progressed. In conclusion, these results show that Xenopus thyroid hormone transporters are functional and display marked spatiotemporal expression patterns. These features make them interesting targets to elucidate their roles in determining thyroid hormone availability during embryonic development. PMID- 28591770 TI - Inferolateral early repolarization among non-ischaemic sudden cardiac death victims. AB - Aim: Inferolateral early repolarization (ER) has been associated with an increased risk of sudden cardiac death (SCD). However, this association is thought to be mainly due to ischaemic SCD. The association of ER and non ischaemic SCD has not been studied. The aim was to evaluate whether inferolateral ER is associated with non-ischaemic SCD. Methods and results: Study population consists of 275 consecutive victims of non-ischaemic SCD with 12-lead ECG and control group of general population cohort with 10 864 subjects. Sudden cardiac deaths were verified as non-ischaemic by medicolegal autopsy. Hypertensive cardiomyopathy (HTCMP) (25%), alcohol related dilated cardiomyopathy (ACMP) (24%), obesity associated cardiomyopathy (OCMP) (23%), and idiopathic myocardial fibrosis (IMF) (15%) were the most common causes of non-ischaemic SCD. A structurally normal heart was seen in only 1.5%. The prevalence of inferolateral ER was 20.7% among patients with non-ischaemic SCD compared to 5.3% in the general population (P < 0.001). The ECG pattern was accompanied with a horizontal/descending ST segment in 95% of the cases. The prevalence of inferolateral ER was slightly higher in the HTCMP group (26%) and the ACMP group (24%) than in the IMF group (20%) and the OCMP group (13%). The history of previously diagnosed cardiac diseases was not higher among subjects with ER (55%) than those without (59%, P = 0.59). Conclusion: The prevalence of inferolateral ER among non-ischaemic SCD victims is high. Almost all ER patterns are accompanied with the malignant horizontal/descending ST segment morphology suggesting that inferolateral ER is not only associated with an ischaemic SCD but also a non-ischaemic SCD. PMID- 28591771 TI - The use of Twitter to facilitate sharing of clinical expertise in urology. AB - The use of social media in the urologic community is common and increasing. Although the potential benefits of platforms like Twitter have been described in the literature, the use of social media in the clinical context of Urology has not been explored.In this case report, we describe how we used Twitter to share ideas about the clinical management of a complex urologic patient. By posting a clinical scenario, a timely discussion was generated with global participation and expert suggestions. This knowledge was applied to the surgical management of a patient with positive clinical outcomes.The ability of Twitter to facilitate rapid communication with a wide network of contributors makes it a potentially useful tool for clinical decision making. Care must be taken to ensure patient confidentiality and caution used appropriately when evaluating the sources and content of the clinical information shared. PMID- 28591773 TI - Ethyl Glucuronide Elimination Kinetics in Fingernails and Comparison to Levels in Hair. AB - Aims: Measurement of ethyl glucuronide (EtG) in nail, as a biomarker for alcohol intake, has recently been suggested as alternative to measurement in hair. The aim of this study was to compare levels of EtG in nail and hair, and to investigate the elimination kinetics of EtG in fingernails during an alcohol abstinent period. Methods: Overall, 40 subjects (median estimated daily intake of ethanol (EDI) 92.5 g/day) were recruited from an alcohol rehabilitation clinic. Nail and hair samples were collected at inclusion and nail clippings were collected every 7-10th day for up to 12 weeks. Results: All patients showed higher nail EtG/EDI ratios compared to hair EtG/EDI ratios (P < 0.001). The median value of the ratios between EtG in nail and EtG in hair was 5.0 (range: 1.07-56.1). There was a significant correlation between nail EtG/EDI and hair EtG/EDI (Spearman's rho = 0.638, P < 0.001). EtG disappeared from nails after ~2 months of abstinence and the median calculated EtG half-life in nail clippings was 13.3 days (range: 5.5-29.0). There was a significant correlation between the time elapsed to last positive sample for nail EtG and nail EtG levels at time of inclusion (Spearman's rho = 0.449, P = 0.004). Conclusion: The present data indicate that EtG cut-off levels in nails should be higher compared to the established 30 pg/mg EtG cut-off in hair representing heavy drinking. EtG may disappear faster from nail than expected from nail growth physiology. Short summary: Nails are an alternative matrix to hair when measuring ethyl glucuronide (EtG). The present study indicate that EtG cut-off levels in nails should be higher compared to the established 30 pg/mg EtG cut-off in hair representing heavy drinking, and EtG may disappear faster from nail than expected. PMID- 28591774 TI - Host Plants of the Wheat Stem Sawfly (Hymenoptera: Cephidae). AB - Wheat stem sawfly (Cephus cinctus Norton) is a pest of economic importance across much of the wheat (Triticum aestivum L.)-growing areas of the western Great Plains of North America as well as an ecologically important insect owing to its wide range of grass hosts. Little research has been published regarding the noncultivated native and invasive grasses attacked by this insect. Knowledge of the complete host range of C. cinctus can inform future research about potential new sources of genetic resistance, improve understanding of the biology and spread of natural enemies, and better define this insect's role in grassland and agricultural systems. The aim of this review is to compile a checklist of reported host plants of C. cinctus and present data from an extensive survey of noncultivated hosts used by C. cinctus. PMID- 28591772 TI - Biological Evaluation of a Fluorescent-Imaging Agent for Medullary Thyroid Cancer in an Orthotopic Model. AB - Context: The primary and definitive treatment of medullary thyroid cancer (MTC) is surgical resection. Recurrent or residual disease is typically a result of incomplete surgical removal. Objective: Our objective is to develop a compound that assists in intraoperative visualization of cancer, which would have the potential to improve surgical cure rates and outcomes. Results: We report the biological characterization of Compound-17, which is labeled with IRdye800, allowing fluorescent visualization of MTC mouse models. We found that the agent has high affinity for two human MTC cell lines (TT and MZ-CRC1) in vitro and in vivo. We further tested the affinity of the compound in a newly developed MTC orthotopic xenograft model and found that Compound-17 produces fluorescent signals within MTC-derived orthotopic xenografts in comparison with a sequence jumbled control compound and surrounding normal tissues. Conclusions: Compound-17 is a unique and effective molecule for MTC identification that may have therapeutic potential. PMID- 28591775 TI - Parainfluenza Virus in the Hospitalized Adult. AB - Parainfluenza virus (PIV) is a negative-sense single-stranded RNA virus in the Paramyxoviridae family. There are 4 serotypes that follow seasonal patterns with varying rates of infection for each serotype. PIV is an established cause of disease and death in the pediatric and immunocompromised populations, and its impact on the hospitalized adult is becoming more apparent with the increased use of multiplex molecular assays in the clinical setting. The clinical presentation of PIV in hospitalized adults varies widely and includes upper respiratory tract infections, severe lower respiratory tract infections, and exacerbations of underlying disease; 0.2%-11.5% of hospitalized patients with pneumonia have been found to have PIV infection. Currently no licensed treatment is available for PIV infection. Ribavirin has been used, but case studies show no impact on mortality rates. DAS181, an inhaled sialidase, is undergoing clinical development for the treatment of PIV in adults and children. PMID- 28591777 TI - miR-582-5p inhibits invasion and migration of salivary adenoid cystic carcinoma cells by targeting FOXC1. AB - Objective: Neurotropism of salivary adenoid cystic carcinoma (SACC) and pulmonary metastasis may lead to in treatment failure. miR-582-5p plays important roles in tumorigenesis, invasion and migration. Here, we aim to determine the effect of miR-582-5p and its role in SACC invasion and metastasis. Methods: Six primary human SACC samples and matching adjacent normal tissues were analyzed by microarray analysis. Next, quantitative real-time PCR was carried out to evaluate miR-582-5p expression in 16 primary human SACC samples and matching adjacent normal tissues. Cell invasion and migration were also analyzed, and a luciferase reporter assay and western analysis were conducted. Cell growth and apoptosis assay were performed to confirm the effect of miR-582-5p and Forkhead box C1 (FOXC1) siRNA in cell proliferation and apoptosis. SACC tumorigenesis and metastasis were investigated in vivo experiment. Clinical samples from 110 patients were analyzed using in situ hybridization and immunohistochemistry. Results: Microarray analysis revealed that miR-582-5p was significantly downregulated in the SACC samples compared with the matching adjacent normal tissues. Regulation of miR-582-5p expression significantly influenced the migration, invasion and proliferation ability of SACC cells by targeting FOXC1. E cadherin was increased, while vimentin and snail were decreased with downregulation of FOXC1, suggesting that FOXC1 may regulate the epithelial-to mesenchymal transition (EMT) of SACC cells by transactivating snail. In vivo, miR 582-5p overexpression suppressed the tumorigenesis and pulmonary metastasis of SACC. Lower expression of miR-582-5p expression predicts unfavorable prognoses and high rates of metastasis. Conclusions: miR-582-5p could suppress effect on the process of invasion and migration in SACC cell lines, and this could occur through its target gene FOXC1. PMID- 28591776 TI - Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults With Type 1 Diabetes. AB - Context: Standard treatment of hypoglycemia is oral carbohydrate, but it often results in hyperglycemia and entails extra caloric intake. Objective: To evaluate low-dose glucagon to treat mild hypoglycemia in ambulatory adults with type 1 diabetes (T1D). Design: Randomized crossover trial (two 3-week periods). Setting: Five U.S. diabetes clinics. Patients: Twenty adults with T1D using an insulin pump and continuous glucose monitor (CGM) and experiencing frequent mild hypoglycemia. Intervention: Nonaqueous mini-dose glucagon (MDG) (150 ug) to treat nonsevere hypoglycemia. Main Outcome Measures: Successful treatment was defined as blood glucose (BG) >=50 mg/dL 15 minutes and >=70 mg/dL 30 minutes after intervention, on the study meter. Two authors, blinded to treatment arm, independently judged each event as a clinical success or failure. Results: Sixteen participants (mean age 39 years, 75% female, mean diabetes duration 23 years, mean hemoglobin A1c 7.2%) had 118 analyzable events with initial BG of 50 to 69 mg/dL. Successful treatment criteria were met for 58 (94%) of 62 events during the MDG period and 53 (95%) of 56 events during the glucose tablets (TABS) period (adjusted P = 0.99). Clinical assessments of success for these events were 97% and 96%, respectively. CGM-measured time in range did not differ between treatment groups during the 2 hours after events, but TABS resulted in higher maximum glucose (116 vs 102 mg/dL; P = 0.01) over the first hour. Conclusions: Low-dose glucagon can successfully treat mild hypoglycemia and may be a useful alternative to treatment with oral carbohydrate when trying to avoid unnecessary caloric intake. PMID- 28591779 TI - Elucidating the Biological Roles of Insulin and Its Receptor in Murine Intestinal Growth and Function. AB - The role of the intestinal insulin receptor (IR) is not well understood. We therefore explored the effect of insulin (300 nmol/kg per day for 12 days) on the intestine in sex-matched C57Bl/6J mice. The intestinal and metabolic profiles were also characterized in male and female intestinal-epithelial IR knockout (IE irKO) mice compared with all genetic controls on a chow diet or Western diet (WD) for 4 to 12 weeks. Insulin treatment did not affect intestinal size, intestinal resistance, or metabolic genes, but it reduced proximal-colon crypt depth and acutely increased colonic serine/threonine-specific protein kinase B (AKT) activation. Feeding with a WD increased body weight and fasting insulin level and decreased oral glucose tolerance in C57Bl/6J and IE-irKO mice. However, although the overall responses of the IE-irKO mice were not different from those of Villin Cre (Vil-Cre):IRfl/+ and IRfl/fl controls, profound differences were found for female control Vil-Cre mice, which demonstrated reduced food intake, body weight, jejunal glucose transport, oral glucose tolerance, and fasting insulin and cholesterol levels. Vil-Cre mice also had smaller intestines compared with those of IE-irKO and IRfl/fl mice and greater insulin-mediated activation of jejunal IR and AKT. In summary, gain- and loss-of-function studies, with and without caloric overload, indicate that insulin did not exert remarkable effects on intestinal metabolic or morphologic phenotype except for a small effect on the colon. However, the transgenic control Vil-Cre mice displayed a distinct phenotype compared with other control and knockout animals, emphasizing the importance of thoroughly characterizing genetically modified mouse models. PMID- 28591778 TI - Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial. AB - Background: We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9-14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15-25 years. Here, we report the results at study end (month 36 [M36]). Methods: Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety. Results: At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36. Conclusions: Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls. PMID- 28591781 TI - Global Spinal Alignment in Cervical Kyphotic Deformity: The Importance of Head Position and Thoracolumbar Alignment in the Compensatory Mechanism. AB - BACKGROUND: Previous studies have evaluated cervical kyphosis (C-kypho) using cervical curvature or chin-brow vertical angle, but the relationship between C kypho and global spinal alignment is currently unknown. OBJECTIVE: To elucidate global spinal alignment and compensatory mechanisms in primary symptomatic C kypho using full-spine radiography. METHODS: In this retrospective multicenter study, symptomatic primary C-kypho patients (Cerv group; n = 103) and adult thoracolumbar deformity patients (TL group; n = 119) were compared. We subanalyzed Cerv subgroups according to sagittal vertical axis (SVA) values of C7 (SVAC7 positive or negative [C7P or C7N]). Various Cobb angles ( degrees ) and SVAs (mm) were evaluated. RESULTS: SVAC7 values were -20.2 and 63.6 mm in the Cerv group and TL group, respectively (P < .0001). Various statistically significant compensatory curvatures were observed in the Cerv group, namely larger lumbar lordosis (LL) and thoracic kyphosis. The C7N group had significantly lower SVACOG (center of gravity of the head) and SVAC7 (32.9 and 49.5 mm) values than the C7P group (115.9 and 45.1 mm). Sagittal curvatures were also different in T4-12, T10-L2, LL4-S, and LL. The value of pelvic incidence (PI)-LL was different (C7N vs C7P; -2.2 degrees vs 9.9 degrees ; P < .0003). Compensatory sagittal curvatures were associated with potential for shifting of SVAC7 posteriorly to adjust head position. PI-LL affected these compensatory mechanisms. CONCLUSION: Compensation in symptomatic primary C-kypho was via posterior shifting of SVAC7, small T1 slope, and large LL. However, even in C kypho patients, lumbar degeneration might affect global spinal alignment. Thus, global spinal alignment with cervical kyphosis is characterized as head balanced or trunk balanced. PMID- 28591780 TI - Position-dependent effects of regioisomeric methylated adenine and guanine ribonucleosides on translation. AB - Reversible methylation of the N6 or N1 position of adenine in RNA has recently been shown to play significant roles in regulating the functions of RNA. RNA can also be alkylated upon exposure to endogenous and exogenous alkylating agents. Here we examined how regio-specific methylation at the hydrogen bonding edge of adenine and guanine in mRNA affects translation. When situated at the third codon position, the methylated nucleosides did not compromise the speed or accuracy of translation under most circumstances. When located at the first or second codon position, N1-methyladenosine (m1A) and m1G constituted robust blocks to both Escherichia coli and wheat germ extract translation systems, whereas N2 methylguanosine (m2G) moderately impeded translation. While m1A, m2G and N6 methyladenosine (m6A) did not perturb translational fidelity, O6-methylguanosine (m6G) at the first and second codon positions was strongly and moderately miscoding, respectively, and it was decoded as an adenosine in both systems. The effects of methylated ribonucleosides on translation could be attributed to the methylation-elicited alterations in base pairing properties of the nucleobases, and the mechanisms of ribosomal decoding contributed to the position-dependent effects. Together, our study afforded important new knowledge about the modulation of translation by methylation of purine nucleobases in mRNA. PMID- 28591783 TI - Risk Factors for Ineffectiveness of Posterior Decompression and Dekyphotic Corrective Fusion with Instrumentation for Beak-Type Thoracic Ossification of the Posterior Longitudinal Ligament: A Single Institute Study. PMID- 28591784 TI - Trends in Informal Care for Disabled Older Americans, 1982-2012. AB - Background and Objectives: We examine trends in informal care from the perspective of both community-dwelling disabled older Americans and their caregivers from 1982 to 2012. We decompose hours of care received from spouses and children according to changes in: (a) the number of potential spousal and child caregivers ("family structure"), (b) the likelihood that existing spouses and children are caregivers ("caregiving propensity"), and (c) the amount of care provided by individual caregivers ("time burden"). Research Design and Methods: We examine two sets of time trends based on distinct samples of community dwelling disabled older Americans from the 1982-2004 waves of the National Long Term Care Survey (NLTCS) and the 2000-2012 waves of the Health and Retirement Study (HRS). Results: Existing spouses' and children's decreasing likelihood of being caregivers led to fewer spousal and child caregivers per disabled older person in the 2004 NLTCS than the 1982 NLTCS. However, the NLTCS and HRS time trends suggest that the amount of care provided by individual caregivers was similar from 1989 to 2012. Discussion and Implications: Because individual caregivers' time burden has remained fairly constant since at least 1989, advocacy on behalf of policies that promote more and better support for caregivers is appropriate. PMID- 28591782 TI - Sex-Dependent Effects of Stress on Immobility Behavior and VTA Dopamine Neuron Activity: Modulation by Ketamine. AB - Background: Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine system underactivation is implicated in the pathophysiology of depression, little is known about the female dopamine system at baseline and post-stress. Methods: The effects of chronic mild stress were examined on ventral tegmental area dopamine neuron activity and forced swim test immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10 mg/kg, i.p.) on forced swim test immobility and ventral tegmental area function was then tested. Results: Baseline ventral tegmental area dopamine activity was comparable in both sexes. At baseline, females exhibited roughly double the forced swim test immobility duration than males, which corresponded to ~50% decrease in ventral tegmental area dopamine population activity compared with similarly treated (i.e., post forced swim test) males. Following chronic mild stress, there was greater immobility duration in both sexes and reduced ventral tegmental area dopamine neuron activity by approximately 50% in males and nearly 75% in females. Ketamine restored behavior and post-forced swim test ventral tegmental area dopamine activity for up to 7 days in females as well as in both male and female chronic mild stress-exposed rats. Conclusions: These data suggest increased female susceptibility to depression-like phenotypes (i.e., greater immobility, ventral tegmental area hypofunction) is associated with higher dopamine system sensitivity to both acute and repeated stress relative to males. Understanding the neural underpinnings of sex differences in stress vulnerability will provide insight into mechanisms of disease and optimizing therapeutic approaches in both sexes. PMID- 28591785 TI - Results from more than 20 years of surgical pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Denmark. AB - OBJECTIVES: Chronic thromboembolic pulmonary hypertension is a fatal disease if left untreated, and pulmonary endarterectomy (PEA) is the potentially curable treatment of choice. We aimed to estimate the current in-hospital mortality rate, complication rate and long-term survival for patients with chronic thromboembolic pulmonary hypertension undergoing PEA in Denmark. METHODS: All chronic thromboembolic pulmonary hypertension patients who underwent PEA in the period 1994 till 2016 were consecutively enrolled in our single-centre study. All patients were followed from PEA until death or end of study. Kaplan-Meier survival analysis was used to estimate the 3-, 5- and 10-year survival rates with 95% confidence interval (CI). RESULTS: In total, 239 patients were operated in the study period. A significant reduction in mean pulmonary arterial pressure from 48 mmHg to 33 mmHg, and pulmonary vascular resistance from 800 dynes s cm-5 to 289 dynes s cm-5, was observed during the first postoperative day after PEA. Overall, in-hospital mortality rate was 8.4%. A significantly lower mortality rate in the late decade (2005-2016) compared with the early decade (1994-2004) was observed (4.3% vs 22.6%, P < 0.001). In-hospital mortality during the last 5 years (n = 80) was 2.5%. Three-, 5- and 10-year survival rates were 84% (CI: 77.8 88), 77% (CI: 70.7-82.7) and 62% (CI: 53-69.1), respectively. The majority of patients improved in World Health Organization functional class from III/IV to I/II and significantly increased their 6-min walking distance. CONCLUSIONS: PEA in Denmark is associated with a low in-hospital mortality rate and significant improvements in both haemodynamics and exercise capacity. Long-term survival is excellent and similar to high-volume international centres. PMID- 28591786 TI - Dietary intake and habits of South Asian immigrants living in Western countries. AB - Previous reviews have indicated that immigration from South Asian to Western countries leads to unhealthy changes in diet; however, these reviews have been limited by the methods used in some included studies. This critical narrative review summarizes findings from original research articles that performed appropriate statistical analyses on diet data obtained using culturally appropriate diet assessment measures. All studies quantitatively compared the diets of South Asian immigrants with those of residents of Western or South Asian countries or with those of South Asian immigrants who had varying periods of time since immigration. Most studies examined total energy and nutrient intake among adults. Total energy intake tended to decrease with increasing duration of residence and immigrant generation, and immigrants consumed less protein and monounsaturated fat compared with Westerners. However, findings for intakes of carbohydrate, total fat, saturated fat, polyunsaturated fat, and micronutrients were mixed. Studies that examine food group intake and include South Asians living in South Asia as a comparison population are needed. PMID- 28591787 TI - Optimizing Antimicrobial Utilization: Job of a Steward, or Time for a Pilot? PMID- 28591788 TI - Electronic Cigarette: A Longitudinal Study of Regular Vapers. AB - Introduction: It is unclear how vaping behavior changes over time in regular vapers, and what occurs when vapers relapse to smoking or when they stop vaping. We assessed change in vaping and smoking behaviors over 12 months in regular vapers. Methods: A longitudinal study of 3868 regular vapers enrolled on the Internet in 2012-2015 ("baseline"), followed after one (n = 1631, 42%), three (n = 1337, 35%), six (n = 1148, 30%), and 12 months (n = 893, 23%). Results: Participants had been vaping for a median of five months at baseline. Most (77%) were former smokers, who had not smoked for a median of three months at baseline. Over 12 months, enjoyment gradually became the most frequently cited reason to vape (93%), and vaping to deal with craving for tobacco gradually decreased (from 87% to 56%). In exclusive vapers (ex-smokers), nicotine concentration in e liquids decreased over time (from 12 to 9 mg/mL), but puffs/day remained stable (200 puffs/day). After 12 months, 9% of 687 former smokers relapsed to smoking and 28% of 64 daily smokers (dual users) stopped smoking. After 12 months, when participants stopped vaping, they tended to relapse to smoking (+18% daily smokers among those who stopped vaping versus -2% in permanent vapers, p < .001). When ex-smokers relapsed to smoking, they tended to stop vaping. Conclusions: After 12 months, enjoyment and relapse prevention were the most important reasons to vape. Rates of relapse to smoking were low in former smokers and quit rates were high in current smokers. Stopping vaping was associated with relapsing to smoking. Implications: Even in established vapers, vaping behavior and reasons to vape change over time. This should be taken into account by clinicians, manufacturers and regulators. Results from this non-representative sample can help generate hypotheses that can later be tested in representative samples of vapers. PMID- 28591789 TI - Vancomycin Taper and Pulse Regimen With Careful Follow-up for Patients With Recurrent Clostridium difficile Infection. AB - We retrospectively studied vancomycin taper and pulse treatment on 100 consecutive, evaluable patients with recurrent Clostridium difficile infection. Following taper to once-daily vancomycin dosing, 22 of 36 patients (61%) who received every-other-day dosing (QOD) and 50 of 64 (81%) who received QOD followed by every-third-day dosing were cured (P = .03). PMID- 28591790 TI - Asian G6PD-Mahidol Reticulocytes Sustain Normal Plasmodium Vivax Development. AB - Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder in humans and appears to be protective against falciparum severe malaria. Controversially, it is also thought that Plasmodium vivax has driven the recent selection of G6PD alleles. We use an experimental approach to determine whether G6PD-MahidolG487A variant, a widespread cause of severe G6PD deficiency in Southeast Asia, provides a barrier against vivax malaria. Our results show that the immature reticulocytes (CD71+) targeted by P. vivax invasion are enzymatically normal, even in hemizygous G6PD-Mahidol G487A mutants; thus, allowing the normal growth, development, and high parasite density in severely deficient samples. PMID- 28591792 TI - Corporate sponsorship of physical activity promotion programmes: part of the solution or part of the problem? AB - Background: Parklives is a programme intended to raise levels of physical activity across the UK, funded by Coca-Cola GB and delivered in association with Local Authorities and other organizations. Such public-private partnerships have been advocated by many however critics suggest that the conflict between stakeholder motives is too great. Methods: This study conducted a content analysis of twitter content related to the ParkLives physical activity programme. Images and text were analysed from two separate weeks, one from the school vacation period and one during school term time. Results: Three hundred and eighteen tweets were analysed. Content analysis revealed 79% of images contained children and 45% of these images contained prominent Coca-Cola branding, a level of exposure that suggests ParkLives simultaneously provides opportunities for children's physical activity and for targeted marketing. Content analysis also demonstrated that the programme allowed increased access to policy-makers. Conclusions: The sponsorship of a physical activity promotion campaign can allow a corporation to target its marketing at children and gain access to health related policy development networks. This study reinforces the need for independent evaluation of all potential impacts of such a partnership and calls on those responsible for community health to fully consider the ethical implications of such relationships. PMID- 28591791 TI - 5?-Vinylphosphonate improves tissue accumulation and efficacy of conjugated siRNAs in vivo. AB - 5?-Vinylphosphonate modification of siRNAs protects them from phosphatases, and improves silencing activity. Here, we show that 5?-vinylphosphonate confers novel properties to siRNAs. Specifically, 5?-vinylphosphonate (i) increases siRNA accumulation in tissues, (ii) extends duration of silencing in multiple organs and (iii) protects siRNAs from 5?-to-3? exonucleases. Delivery of conjugated siRNAs requires extensive chemical modifications to achieve stability in vivo. Because chemically modified siRNAs are poor substrates for phosphorylation by kinases, and 5?-phosphate is required for loading into RNA-induced silencing complex, the synthetic addition of a 5?-phosphate on a fully modified siRNA guide strand is expected to be beneficial. Here, we show that synthetic phosphorylation of fully modified cholesterol-conjugated siRNAs increases their potency and efficacy in vitro, but when delivered systemically to mice, the 5?-phosphate is removed within 2 hours. The 5?-phosphate mimic 5?-(E)-vinylphosphonate stabilizes the 5? end of the guide strand by protecting it from phosphatases and 5?-to-3? exonucleases. The improved stability increases guide strand accumulation and retention in tissues, which significantly enhances the efficacy of cholesterol conjugated siRNAs and the duration of silencing in vivo. Moreover, we show that 5?-(E)-vinylphosphonate stabilizes 5? phosphate, thereby enabling systemic delivery to and silencing in kidney and heart. PMID- 28591794 TI - Does the Centers for Disease Control and Prevention's Ventilator-Associated Event Definition Unintentionally Contradict Its Antimicrobial Stewardship Initiative? PMID- 28591793 TI - Dynamics of Bile Acid Profiles, GLP-1, and FGF19 After Laparoscopic Gastric Banding. AB - Context: An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective: To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed. Design and Setting: Observational study at the University Hospital Innsbruck. Patients: Twenty obese patients. Interventions: Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively. Main Outcome Measures: BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined. Results: Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes. Conclusions: Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19. PMID- 28591796 TI - Histamine Enhances Theta-Coupled Spiking and Gamma Oscillations in the Medial Entorhinal Cortex Consistent With Successful Spatial Recognition. AB - Encoding of spatial information in the superficial layers of the medial entorhinal cortex (sMEC) involves theta-modulated spiking and gamma oscillations, as well as spatially tuned grid cells and border cells. Little is known about the role of the arousal-promoting histaminergic system in the modification of information encoded in the sMEC in vivo, and how such histamine-regulated information correlates with behavioral functions. Here, we show that histamine upregulates the neural excitability of a significant proportion of neurons (16.32%, 39.18%, and 52.94% at 30 MUM, 300 MUM, and 3 mM, respectively) and increases local theta (4-12 Hz) and gamma power (low: 25-48 Hz; high: 60-120 Hz) in the sMEC, through activation of histamine receptor types 1 and 3. During spatial exploration, the strength of theta-modulated firing of putative principal neurons and high gamma oscillations is enhanced about 2-fold by histamine. The histamine-mediated increase of theta phase-locking of spikes and high gamma power is consistent with successful spatial recognition. These results, for the first time, reveal possible mechanisms involving the arousal-promoting histaminergic system in the modulation of spatial cognition. PMID- 28591795 TI - Socioeconomic Status and Reading Disability: Neuroanatomy and Plasticity in Response to Intervention. AB - Although reading disability (RD) and socioeconomic status (SES) are independently associated with variation in reading ability and brain structure/function, the joint influence of SES and RD on neuroanatomy and/or response to intervention is unknown. In total, 65 children with RD (ages 6-9) with diverse SES were assigned to an intensive, 6-week summer reading intervention (n = 40) or to a waiting-list control group (n = 25). Before and after, all children completed standardized reading assessments and magnetic resonance imaging to measure cortical thickness. At baseline, higher SES correlated with greater vocabulary and greater cortical thickness in bilateral perisylvian and supramarginal regions-especially in left pars opercularis. Within the intervention group, lower SES was associated with both greater reading improvement and greater cortical thickening across broad, bilateral occipitotemporal and temporoparietal regions following the intervention. Additionally, treatment responders (n = 20), compared with treatment nonresponders (n = 19), exhibited significantly greater cortical thickening within similar regions. The waiting control and nonresponder groups exhibited developmentally typical, nonsignificant cortical thinning during this time period. These findings indicate that effective summer reading intervention is coupled with cortical growth, and is especially beneficial for children with RD who come from lower-SES home environments. PMID- 28591797 TI - Cell Class-Dependent Intracortical Connectivity and Output Dynamics of Layer 6 Projection Neurons of the Rat Primary Visual Cortex. AB - Neocortical information processing is powerfully influenced by the activity of layer 6 projection neurons through control of local intracortical and subcortical circuitry. Morphologically distinct classes of layer 6 projection neuron have been identified in the mammalian visual cortex, which exhibit contrasting receptive field properties, but little information is available on their functional specificity. To address this we combined anatomical tracing techniques with high-resolution patch-clamp recording to identify morphological and functional distinct classes of layer 6 projection neurons in the rat primary visual cortex, which innervated separable subcortical territories. Multisite whole-cell recordings in brain slices revealed that corticoclaustral and corticothalamic layer 6 projection neurons exhibited similar somatically recorded electrophysiological properties. These classes of layer 6 projection neurons were sparsely and reciprocally synaptically interconnected, but could be differentiated by cell-class, but not target-cell-dependent rules of use dependent depression and facilitation of unitary excitatory synaptic output. Corticoclaustral and corticothalamic layer 6 projection neurons were differentially innervated by columnar excitatory circuitry, with corticoclaustral, but not corticothalamic, neurons powerfully driven by layer 4 pyramidal neurons, and long-range pathways conveyed in neocortical layer 1. Our results therefore reveal projection target-specific, functionally distinct, streams of layer 6 output in the rodent neocortex. PMID- 28591800 TI - Cerebral Revascularization for Aneurysms in the Flow-Diverter Era. PMID- 28591799 TI - Incentivizing universal safe delivery in Nepal: 10 years of experience. AB - Payments to users and providers of health services are an important ingredient in attempts to promote universal health coverage in low resource settings. The maternal health programme in Nepal explicitly recognizes that ensuring universal access to safe delivery care requires policies that both ensure effective services and overcome demand-side barriers. The programme has used three innovative financing initiatives to stimulate an increase in the use of facility based delivery: the maternity incentive scheme (2005) reimbursing women for accessing a facility, activity payments in poor districts (2006) and universal free-delivery (2009). We examine the impact of these mechanisms on access to safe delivery services. Multiple waves of the Demographic and Health Survey were merged to provide household-level cross-sectional data on maternity services. A multilevel logit model was used to investigate the roll-out of the three policies across ecological zones assuming a district-wide treatment effect. An interrupted time-series approach that includes cross sectional data on deliveries at each period is used to detect the association between outcomes and policy. The maternal Incentive programme was associated with an increase in service delivery in hill and tarai areas. A positive effect in mountain areas was detectable as a result of the supply side payments made to facilities for delivery. Although use among the non-poor increased across the country, a positive effect on the poorest population was only present in mountain areas. The beneficial impact of maternal financing policies in Nepal is skewed towards areas and households that are geographically more accessible and wealthy. Inferior services in remote areas reduce the impact of financing policies. Policy may need to be refocused on poorer, less accessible areas if improvements in access to maternal health services are to continue. PMID- 28591798 TI - Associations among body size across the life course, adult height and endometriosis. AB - STUDY QUESTION: Are body size across the life course and adult height associated with endometriosis? SUMMARY ANSWER: Endometriosis is associated with lean body size during childhood, adolescence and adulthood; tall total adult height; and tall sitting height. WHAT IS KNOWN ALREADY: The literature suggests that both adult body size and height are associated with endometriosis risk, but few studies have investigated the role of body size across the life course. Additionally, no study has investigated the relationships between components of height and endometriosis. STUDY DESIGN, SIZE, DURATION: We used a nested case control design within E3N (Etude Epidemiologique aupres de femmes de l'Education Nationale), a prospective cohort of French women. Data were updated every 2-3 years through self-administered questionnaires. Odds ratios (ORs) and 95% CIs were computed using logistic regression models adjusted for a priori confounding factors. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 2416 endometriosis cases were reported as surgically ascertained among the 61 208 included women. MAIN RESULTS AND THE ROLE OF CHANCE: The odds of endometriosis were lower among women who reported having a large versus lean body size at 8 years (P for trend = 0.003), at menarche (P for trend < 0.0001) and at ages 20-25 years (P for trend < 0.0001). Women in the highest quartiles of height had statistically significantly increased odds of endometriosis compared to those in the lowest (<158 cm) (162 164 cm: OR = 1.28, 95% CI = 1.12-1.46; >=165 cm: OR = 1.33, 95% CI = 1.18-1.49, P for trend < 0.0001). Statistically significantly increased odds were also observed among women with a taller sitting height (OR = 1.24, 95% CI = 1.05-1.47, P for trend = 0.01). Leg length was not statistically significantly associated with endometriosis. LIMITATIONS REASONS FOR CAUTION: Endometriosis cases may be prone to misclassification; however, we restricted our case definition to surgically-confirmed cases, which showed a high validation rate. Body size is based on retrospective self-report, which may be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study suggest that endometriosis is positively associated with lean body size across the life course and total adult height. They also suggest that components of height are associated with endometriosis, which should be investigated further. STUDY FUNDING/COMPETING INTEREST(S): The Mutuelle Generale de l'Education Nationale (MGEN); the European Community; the French League against Cancer (LNCC); Gustave Roussy; the French Institute of Health and Medical Research (Inserm). L.V.F. was supported by a T32 grant (#HD060454) in reproductive, perinatal and pediatric epidemiology from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Cancer Institute (3R25CA057711) National Institutes of Health. M.K. was supported by a Marie Curie Fellowship within the seventh European Community Framework Programme (#PIOF-GA-2011-302078). The authors have no conflicts of interest to declare. PMID- 28591801 TI - Systematic Review of Guidelines on Managing Patients with Harmful Use of Alcohol in Primary Healthcare Settings. AB - Aim: To appraise existing alcohol guidelines for identifying and managing harmful alcohol use in primary healthcare settings. Methods: Seven databases and 18 health organization or medical society websites were systematically searched from inception to 31 October 2016. Guidelines in English language, developed by a national or international medical specialty society, government or health organization, and containing recommendations for identifying and managing harmful use of alcohol in primary healthcare settings, were included. The Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument was used to appraise the guidelines. Results: Of the 970 literature identified, 17 were included for review, with 13 guidelines developed for use in Western countries and 4 for international use. The AGREE II scores ranged from 2.0 to 5.3, out of 7. Variations in terminology of harmful alcohol use were seen, with 'harmful drinking' and 'problem drinking' being mostly used. All guidelines were in favor of screening and brief interventions due to their effectiveness and cost effectiveness. Potential benefits and costs of applying screening and brief interventions were found, but there was a lack of evidence for long-term effects or specific populations. Conclusions: All 17 guidelines recommended screening and brief interventions due to its associated health and financial benefits. Policy makers are highly encouraged to integrate these practices into primary healthcare settings taking the drinking status, culture and resources into account. Short summary: Screening and brief interventions were recommended by all 17 guidelines on managing patients with harmful use of alcohol in primary healthcare settings. Policy makers and healthcare practitioners are highly encouraged to implement these recommendations. PMID- 28591802 TI - Systemic Inflammatory and Th17 Immune Activation among Patients Treated for Lumbar Radiculopathy Exceeds that of Patients Treated for Persistent Postoperative Neuropathic Pain. AB - BACKGROUND: The pathophysiology of lumbar radiculopathy includes both mechanical compression and biochemical irritation of apposed neural elements. Inflammatory and immune cytokines have been implicated, induced by systemic exposure of immune privileged intervertebral disc tissue. Surgical intervention provides improved symptoms and quality of life, but persistent postoperative neuropathic pain (PPNP) afflicts a significant fraction of patients. OBJECTIVE: To compare the inflammatory and immune phenotypes among patients undergoing structural surgery for lumbar radiculopathy and spinal cord stimulation for neuropathic pain. METHODS: Consecutive patients undergoing surgical intervention for lumbar radiculopathy or neuropathic pain were studied. Demographic data included age, gender, and VAS and neuropathic pain scores. Serum was evaluated for cytokine levels (IL-6, Il-17, TNF-alpha) and cellular content [white blood cell (WBC)/differential, lymphocyte subtypes]. The primary analysis differentiated molecular and cellular profiles between radiculopathy and neuropathic pain patients. Subgroup analysis within the surgical radiculopathy population compared those patients achieving relief of symptoms and those with PPNP. RESULTS: Heightened IL-6, Il-17, and TNF-alpha levels were observed for the lumbar radiculopathy group compared with the neuropathic pain group. This was complemented by higher WBC count and a greater fraction of Th17 lymphocytes among radiculopathy patients. In the lumbar discectomy subgroup, pain relief was seen among patients with preoperatively elevated IL-17 levels. Those patients with PPNP refractory to surgical discectomy exhibited normal cytokine levels. CONCLUSION: Differences in Th17 immune activation are seen among radiculopathy and neuropathic pain patients. These cellular and molecular profiles may be translated into biomarkers to improve patient selection for structural spine surgery. PMID- 28591804 TI - Arrhythmias and sudden cardiac death: substrates, monitoring, and prevention. PMID- 28591803 TI - Temporally Segmented Directionality in the Motor Cortex. AB - Developing models of the dynamic and complex patterns of information processing that take place during behavior is a major thrust of systems neuroscience. An underlying assumption of many models is that the same set of rules applies across different conditions. This has been the case for directional tuning during volitional movement; a single cosine function has been remarkably robust for describing the encoding of movement direction in different types of neurons, in many locations of the nervous system, and even across species. However, detailed examination of the tuning time course in motor cortex suggests that direction coding may be labile. Here, we show that there are discrete time epochs within single reaches, between which individual neurons change their tuning. Our findings suggest that motor cortical activity patterns may reflect consistent changes in the state of the control system during center-out reaching. These transitions are likely linked to different behavioral components, suggesting that the task defines changes in the operational structure of the control system. PMID- 28591806 TI - Quantitative Proteomics of Intestinal Mucosa From Male Mice Lacking Intestinal Epithelial Insulin Receptors. AB - The goal of the present study was to determine whether loss of the insulin receptor alters the molecular landscape of the intestinal mucosa, using intestinal-epithelial insulin receptor knockout (IE-irKO) mice and both genetic (IRfl/fl and Villin-cre) controls. Quantitative proteomic analysis by liquid chromatography mass spectrometry was applied to jejunal and colonic mucosa from mice fed a normal chow diet and mice fed a Western diet (WD). Jejunal mucosa from IE-irKO mice demonstrated alterations in all intestinal cell lineages: Paneth, goblet, absorptive, and enteroendocrine cells. Only goblet and absorptive cells were affected in the colon. Also, a marked effect of WD consumption was found on the gut proteome. A substantial reduction was detected in Paneth cell proteins with antimicrobial activity, including lysozyme C-1, angiogenin-4, cryptdin related sequence 1C-3 and -2, alpha-defensin 17, and intelectin-1a. The key protein expressed by goblet cells, mucin-2, was also reduced in the IE-irKO mice. Proteins involved in lipid metabolism, including aldose reductase-related protein 1, 15-hydroxyprostaglandin dehydrogenase, apolipoprotein A-II, and pyruvate dehydrogenase kinase isozyme 4, were increased in the mucosa of WD-fed IE-irKO mice compared with controls. In contrast, expression of the nutrient-responsive gut hormones, glucose-dependent insulinotropic polypeptide and neurotensin, was reduced in the jejunal mucosa of IE-irKO mice, and the expression of proteins of the P-type adenosine triphosphatases and the solute carrier-transporter family was reduced in the colon of WD-fed IE-irKO mice. In conclusion, IE-irKO mice display a distinct molecular phenotype, suggesting a biological role of insulin and its receptor in determining differentiated cell specificity in the intestinal epithelium. PMID- 28591805 TI - Two DELLA-interacting proteins bHLH48 and bHLH60 regulate flowering under long day conditions in Arabidopsis thaliana. AB - Gibberellin (GA) regulates many developmental transitions in the plant life cycle. Although great progress has been made, the GA signaling pathways have not been fully elucidated. Identifying and characterizing new targets of DELLA proteins is an effective approach to reveal the complicated GA signaling networks. In this study, two novel DELLA-interacting transcription factors, bHLH48 and bHLH60, were identified. Their overexpression caused plants to flower early under long-day conditions, whereas their functional repression resulted in the opposite result. The constitutive expression of bHLH48 and bHLH60 upregulated the transcription of the FLOWERING LOCUS T (FT) gene. Chromatin immunoprecipitation experiments confirmed that bHLH48 bound to the promoter of FT and that GA promoted the DNA-binding activity of bHLH48. Genetic analyses indicated that the early flowering phenotype of plants overexpressing bHLH48 and bHLH60 depended on FT and that the overexpression of bHLH48 and bHLH60 could rescue the late-flowering phenotypes of RGL1 overexpressing plants. Transient expression assays suggested that RGL1 inhibited the transcription activation ability of bHLH48 and bHLH60. Taken together, this study confirmed that bHLH48 and bHLH60 positively regulate GA-mediated flowering. PMID- 28591807 TI - Improving the quality and impact of public health social media activity in Scotland during 2016: #ScotPublicHealth. AB - Background: Social media, including Twitter, potentially provides a route to communicate public health messages to a large audience. Simple measures can boost onward broadcast to other users ('retweeting'). This study compares the impact of a structured programme of social media activity in Scotland during 2016 (using #ScotPublicHealth hashtag) with previous years. Methods: The Twitter search function was used to identify tweets between 2014 and 2016 inclusive. The first three tweets from each Twitter user were selected for each period. The number of retweets was used as a measure of impact. The quality of tweets was assessed by recording use of image, weblink (uniform resource locator or URL), mention of another Twitter user and/or hashtag, each of which have been shown to boost number of retweets. Results: The percentage of tweets with an image, URL and/or mention of another Twitter user increased during the period of study. The percentage of tweets retweeted during Scottish Public Health conferences increased from 43% in 2014 to 70% in 2016. The volume of tweeting also increased. Conclusions: The quality and impact of tweets sent by the Scottish Public Health community was higher during 2016 than previous years. Conference tweeting remains an area for improvement. PMID- 28591808 TI - Relationship between beta-lactamase production and resistance phenotype in Klebsiella pneumoniae strains. AB - This study was designed to evaluate the resistance phenotypes of beta-lactamases producing Klebsiella pneumoniae strains. The antibiotic susceptibility and beta lactamase activity of K. pneumoniae strains, including antibiotic-sensitive K. pneumoniae (KPWT), ciprofloxacin-induced resistant K. pneumoniae (KPCIP) and clinically isolated K. pneumoniae strains (KPCI237, KPCI263 and KPCI272) were determined in the absence and presence of beta-lactamase inhibitors (BLI 489, sulbactam, clavulanate and tazobactam). All strains were highly resistant to ampicillin in the absence of beta-lactamase inhibitors (MIC>= 512 MUg mL-1). In the presence of clavulanate, the MICs of ampicillin and piperacillin against KPWT were decreased by > 64-fold and 4-fold, respectively. The resistance of KPCI263 to cefotaxime, ceftazidime, ceftriaxone and piperacillin were increased in the presence of BLI-489. The antibiotic susceptibility of KPCI237 to beta-lactams was not noticeably changed in the presence of beta-lactamase inhibitor (clavulanate, sulbactam or tazobactam). KPWT, KPCIP and KPCI272 were positive for blaSHV, blaAmpC and blaFOX/MOX; KPCI237 for blaSHV and blaAmpC; and KPCI263 for blaSHV and blaOXA-48. The antibiotic susceptibility corresponded well with the results obtained from dual disc diffusion assay, which was in good agreement with the beta-lactamase production. The results provide useful information for understanding the resistance phenotypes in association with beta-lactamase production. PMID- 28591809 TI - Cpx-dependent expression of YqjA requires cations at elevated pH. AB - Under alkaline pH conditions, Escherichia coli must maintain a stable cytoplasmic pH of about 7.6 that is acidic relative to the environment. Bacteria employ various mechanisms to survive alkaline pH; however, membrane cation/H+ antiporters play a primary role by facilitating inward transport of protons. Escherichia coli YqjA belongs to the DedA/Tvp38 membrane protein family and, along with its paralog YghB, is required for growth at 42 degrees C, proper cell division and antibiotic resistance. YqjA is required for viability at alkaline pH, requiring cations sodium or potassium to support growth under these conditions, suggesting it may be a transporter. We measured yqjA expression at different pHs and cation concentrations using a yqjA promoter-lacZ fusion. We found that yqjA promoter activity was highest at alkaline pH. Increased activity of the yqjA promoter required both the transcriptional regulator CpxR, in agreement with previous results, and sodium or potassium salts at alkaline pH. Extracellular cations are also required for activity of cpxP and degP promoters at alkaline pH, suggesting this is a general property of the Cpx regulon. To our knowledge, this is the first demonstration of cation-dependent expression of Cpx regulated genes at alkaline pH. PMID- 28591810 TI - Hessian Fly (Diptera: Cecidomyiidae) Attraction to Different Wavelengths and Intensities of Light-Emitting Diodes in the Laboratory. AB - Monitoring of Hessian fly, Mayetiola destructor (Say) (Diptera: Cecidomyiidae), populations is important for targeted management methods. Also, effectiveness of monitoring efforts is critical to surveillance efforts in regions of the world without this pest. Current Hessian fly monitoring traps rely purely on a single attractant, the female sex pheromone, which is ineffective for monitoring females in the population. Our objective was to examine another attractant targeting vision of both males and females. To do this, we evaluated emitted light of various wavelengths and intensities produced by light-emitting diodes (LEDs). Hessian flies were released in the center of a four-leaf clover-shaped arena, which contained an LED within each collection cup at the apex of each of the four cloverleaves. Initially, we examined a range of colors, including red, amber, green, and blue, with wavelengths of 624, 590, 527, and 472 nm, respectively. Both sexes of Hessian fly preferred green LEDs; therefore, we examined specific wavelengths within the green spectrum (502, 525, and 565 nm), and varied light intensities (4, 8, 12, and 16 W/m2). Specifically, females preferred wavelengths in the lower region of the green spectrum (502 and 525 nm), and both sexes preferred high intensity light (16 W/m2). This is the first report of Hessian fly attraction to select emitted wavelengths and intensities from LEDs under controlled conditions. Leveraging these results into new trap designs will add a second sensory modality to the existing trap; however, future studies are needed to assess attraction to LED traps under field conditions. PMID- 28591811 TI - Massive relaxation of the diaphragm. PMID- 28591812 TI - Corrigendum. PMID- 28591813 TI - The energy expenditure benefits of reallocating sedentary time with physical activity: a systematic review and meta-analysis. AB - Background: We compared direct and daily cumulative energy expenditure (EE) differences associated with reallocating sedentary time to physical activity in adults for meaningful EE changes. Methods: Peer-reviewed studies in PubMed, Medline, EMBASE, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched from inception to March 2017. Randomized and non-randomized interventions with sedentary time and EE outcomes in adults were included. Study quality was assessed by the National Heart Lung and Blood Institute tool, and summarized using random-effects meta analysis and meta-regression. Results: In total, 26 studies were reviewed, and 24 studies examined by meta-analysis. Reallocating 6-9 h of sedentary time to light intensity physical activity (LIPA) (standardized mean difference [SMD], 2.501 [CI: 1.204-5.363]) had lower cumulative EE than 6-9 h of combined LIPA and moderate-vigorous intensity physical activity (LIPA and moderate-vigorous physical activity [MVPA]) (SMD, 5.218 [CI: 3.822-6.613]). Reallocating 1 h of MVPA resulted in greater cumulative EE than 3-5 h of LIPA and MVPA, but <6-9 h of LIPA and MVPA. Conclusions: Comparable EE can be achieved by different strategies, and promoting MVPA might be effective for those individuals where a combination of MVPA and LIPA is challenging. PMID- 28591814 TI - Abnormal Gray Matter Shape, Thickness, and Volume in the Motor Cortico Subcortical Loop in Idiopathic Rapid Eye Movement Sleep Behavior Disorder: Association with Clinical and Motor Features. AB - Idiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for Parkinson's disease and dementia with Lewy bodies. Anatomical gray matter abnormalities in the motor cortico-subcortical loop areas remain under studied in iRBD patients. We acquired T1-weighted images and administrated quantitative motor tasks in 41 patients with polysomnography-confirmed iRBD and 41 healthy subjects. Cortical thickness and voxel-based morphometry (VBM) analyses were performed to investigate local cortical thickness and gray matter volume changes, vertex-based shape analysis to investigate shape of subcortical structures, and structure-based volumetric analyses to investigate volumes of subcortical and brainstem structures. Cortical thickness analysis revealed thinning in iRBD patients in bilateral medial superior frontal, orbitofrontal, anterior cingulate cortices, and the right dorsolateral primary motor cortex. VBM results showed lower gray matter volume in iRBD patients in the frontal lobes, anterior cingulate gyri, and caudate nucleus. Shape analysis revealed extensive surface contraction in the external and internal segments of the left pallidum. Clinical and motor impaired features in iRBD were associated with anomalies of the motor cortico-subcortical loop. In summary, iRBD patients showed numerous gray matter structural abnormalities in the motor cortico-subcortical loop, which are associated with lower motor performance and clinical manifestations of iRBD. PMID- 28591815 TI - Reply to Sopirala. PMID- 28591816 TI - Is preoperative spirometry a predictive marker for postoperative complications after colorectal cancer surgery? AB - Background: Spirometry is a basic test that provides much information about pulmonary function; it is performed preoperatively in almost all patients undergoing colorectal cancer (CRC) surgery in our hospital. However, the value of spirometry as a preoperative test for CRC surgery remains unknown. The aim of this study was to determine whether spirometry is useful to predict postoperative complications (PCs) after CRC surgery. Methods: The medical records of 1236 patients who had preoperative spirometry tests and underwent CRC surgery between 2005 and 2014 were reviewed. Preoperative spirometry results, such as forced vital capacity (FVC), one-second forced expiratory volume (FEV1), %VC (FVC/predicted VC) and FEV1/FVC (%FEV1), were analyzed with regard to PCs, including pneumonia. Results: PCs were found in 383 (30.9%) patients, including 218 (56%) with surgical site infections, 67 (17%) with bowel obstruction, 62 (16%) with leakage and 20 (5.2%) with pneumonia. Of the spirometry results, %VC was correlated with PC according to logistic regression analysis (odds ratio, OR = 0.99, 95% confidence interval, CI = 0.98-0.99; P = 0.034). Multivariate analysis after adjusting for male sex, age, laparoscopic surgery, tumor location, operation time and blood loss showed that a lower %VC tends to be a risk factor for PC (OR = 0.99, 95% CI = 0.98-1.002; P = 0.159) and %VC was an independent risk factor for postoperative pneumonia in PCs (OR = 0.97, 95% CI = 0.94-0.99; P = 0.049). Conclusions: In CRC surgery, %VC may be a predictor of postoperative complications, especially pneumonia. PMID- 28591817 TI - Efficacy of radiotherapy for primary tumor in patients with unresectable pancreatic neuroendocrine tumors. AB - Background: Detailed information regarding the clinical efficacy of radiotherapy (RT) for primary tumor in patients with unresectable pancreatic neuroendocrine tumors (pNETs) is unknown. We therefore performed a retrospective study to evaluate the efficacy and safety of RT for primary pancreatic tumors in patients with pNETs. Methods: We investigated 11 patients with pNETs who received RT to the primary site between January 1997 and June 2015. Seven patients had Grade 2 neuroendocrine tumors (NET-G2) and four had neuroendocrine carcinoma (NEC) according to the 2010 WHO histopathological classification. Results: The tumor response and control rates were 27.2% and 100%, respectively (3: partial response, 8: stable disease). Among patients with NET-G2 tumors, the response rate was 28.5% (2/7 patients) and symptomatic improvement was noted in 33.3% of the patients (1/3 patients). The response rate for patients with NEC were 25% (1/4), one NEC patients with symptoms exhibited symptomatic improvement. The median overall survival and median progression-free survival were 35.9 months and 5.5 months, respectively. Grade 3 diarrhea as an acute toxicity and Grade 3 gastrointestinal hemorrhage as a late toxicity were observed. Conclusions: RT to the primary cancer site in patients with pNETs was an effective modality for local disease control and the treated patients had good outcomes. If metastatic tumors are under control, RT to the primary site may be beneficial for patients with pNETs. PMID- 28591818 TI - Yokukansan for the treatment of preoperative anxiety and postoperative delirium in colorectal cancer patients: a retrospective study. AB - Background: Yokukansan (YKS), a Japanese traditional herbal medicine for neurosis and insomnia, is speculated to be useful for perioperative psychiatric symptoms in cancer patients, but there exists little empirical evidence. This study provides preliminary data about the efficacy, feasibility, and side effects of YKS for the treatment of preoperative anxiety and postoperative delirium in cancer patients. Methods: We retrospectively reviewed the medical records of colorectal cancer patients who took YKS for preoperative anxiety, evaluating the following: (1) patient characteristics, (2) feasibility of taking YKS, (3) changes in preoperative anxiety based on the Clinical Global Impression (CGI) scale and Edmonton Symptom Assessment System-revised (ESAS-r-anxiety), (4) incidence of postoperative delirium and (5) YKS-related side effects. Results: We reviewed 19 medical records. There was a significant difference between ESAS-r anxiety scores (P = 0.028) before and after taking YKS, but no difference between CGI scores (P = 0.056). The incidence of postoperative delirium was 5.2% (95% CI = 0.0-14.5). One patient could not complete the course of YKS during the perioperative administration period, but there were no side effects of Grade 2 or worse according to the Common Terminology Criteria for Adverse Events v4. Conclusions: Cancer patients could safely take YKS before surgery. There was a significant improvement in preoperative anxiety after taking YKS, and the incident rate of postoperative delirium was lower than in previous studies. These results suggest that YKS may be useful for perioperative psychiatric symptoms in cancer patients. Further well-designed studies are needed to substantiate our results. PMID- 28591819 TI - Comparison of phenotypic and WGS-derived antimicrobial resistance profiles of Shigella sonnei isolated from cases of diarrhoeal disease in England and Wales, 2015. AB - Objectives: Phenotypic and genotypic methods for the detection of antimicrobial resistance (AMR) in Shigella sonnei in England and Wales were compared and evaluated. Methods: WGS data from 341 isolates of S. sonnei isolated between June 2015 and January 2016 were mapped to genes known to be associated with phenotypic AMR. Antimicrobial susceptibility testing was performed on all viable isolates (n = 335). Results: Fifteen of 335 isolates had a discrepancy between phenotypic and genotypic testing for 1 of the 10 antimicrobial classes tested, equating to 15 (0.45%) discordant results out of a possible 3350 isolate/antimicrobial combinations. All 15 mismatched results were genotypically resistant but phenotypically susceptible. Eleven of the 15 discrepancies were observed in streptomycin resistance profiles. The most common resistance profile was trimethoprim, sulphonamides, tetracyclines and streptomycin, occurring in 97 (28.4%) isolates. Resistances to ciprofloxacin and the third-generation cephalosporins, not detected in England and Wales prior to 2002, were identified in 18.2% and 12% of isolates, respectively. Three hundred and four (89.1%) isolates were MDR. There was no significant association between any of the AMR determinants tested and recent foreign travel in male or female cases. The number of isolates of S. sonnei harbouring blaTEM-1 and ermB/mphA was significantly higher in men who reported no recent travel outside the UK. Conclusions: The use of WGS for routine public health surveillance is a reliable method for rapid detection of emerging AMR in isolates of S. sonnei. PMID- 28591820 TI - Proton Pump Inhibitors, Nephropathy, and Cardiovascular Disease in Type 2 Diabetes: The Fremantle Diabetes Study. AB - Context: There is emerging evidence of various adverse effects of chronic proton pump inhibitor (PPI) therapy. Objective: To assess the impact of PPI use on nephropathy and cardiovascular disease (CVD) risk in type 2 diabetes. Design: Longitudinal observational study. Setting: Urban-dwelling community. Patients: Patients with type 2 diabetes from the Fremantle Diabetes Study Phase II and on stable renin-angiotensin system blocking therapy were divided into those remaining untreated with a PPI (group 1, n = 686), on PPI therapy throughout (group 2, n = 174), and commencing (group 3, n = 109) or discontinuing regular PPI therapy (group 4, n = 67) during the 2 years between assessments. Main Outcome Measures: Changes (Delta) in urinary albumin/creatinine ratio (uACR), estimated glomerular filtration rate (eGFR), and predicted 5-year CVD risk. Results: There were no statistically significant differences in DeltauACR between groups [analysis of variance (ANOVA), P = 0.36], but DeltaeGFR was different (ANOVA, P = 0.002), with group 3 exhibiting a greater reduction than group 1 [adjusted mean difference (95% confidence interval), -2.7 (-4.5 to -0.8) mL/min/1.73 m2; P = 0.005]. The Delta5-year CVD risk showed a similar pattern (ANOVA, P < 0.001), with group 3 having a greater increase than group 1 [adjusted mean difference (95% confidence interval), 1.7% (0.6% to 2.8%); P = 0.002]. Conclusions: Although PPI use was not associated with a sustained adverse effect on uACR, the association between PPI initiation and both worsening nephropathy and increasing 5-year CVD risk has potential clinical implications in type 2 diabetes. PMID- 28591821 TI - Effect of prosthesis patient mismatch in mitral position on pulmonary hypertension. AB - OBJECTIVES: Pulmonary arterial hypertension (PAH) is associated with poor outcome after mitral valve replacement (MVR). We proposed to evaluate the effect of valve prosthesis patient mismatch (PPM) on pulmonary arterial (PA) pressure following MVR. METHODS: Five hundred patients who have undergone MVR were studied retrospectively. Postoperative PA systolic pressure (PASP) measured 6 months postoperatively by Doppler echocardiography was compared with preoperative values. PASP >= 40 mmHg was defined as PAH. Mitral valve effective orifice area was calculated by the continuity equation and indexed for body surface area. PPM was defined as indexed effective orifice area <= 1.2 cm2/m2. A multivariate model was constructed to ascertain the independent determinants of systolic PA pressure. Also, a propensity score model was constructed to overcome the baseline differences between the PPM and no PPM groups. RESULTS: The incidence of PPM in this study was 37.2%. The average postoperative PASPs were 30.49 and 42.35 mmHg in the no PPM and PPM groups, respectively; (P < 0.001). Regression of PAH in the PPM and no PPM groups was 76.26% and 20.64%, respectively; (P < 0.001). The indexed effective orifice area correlated well with postoperative PASP (r = 0.71). The overall survival and freedom from cardiac death at 10 years were 79.8% and 85.3%; and at 20 years were 66.5% and 74.3%, respectively. Both, overall survival and the freedom from cardiac death were higher in the no PPM group than in the PPM group; (P < 0.001). Propensity score matching analysis yielded 112 pairs of the PPM and no PPM cohorts, which revealed higher overall survival and freedom from cardiac death in the no PPM group; (P = 0.028 and 0.012, respectively). CONCLUSIONS: Mitral PPM is an independent predictor of persistent PAH after MVR along with associated morbidity and reduced survival. PMID- 28591823 TI - The Survival Advantage of "Supratotal" Resection of Glioblastoma Using Selective Cortical Mapping and the Subpial technique. PMID- 28591822 TI - Neural Sources and Underlying Mechanisms of Neural Responses to Heartbeats, and their Role in Bodily Self-consciousness: An Intracranial EEG Study. AB - Recent research has shown that heartbeat-evoked potentials (HEPs), brain activity in response to heartbeats, are a useful neural measure for investigating the functional role of brain-body interactions in cognitive processes including self consciousness. In 2 experiments, using intracranial electroencephalography (EEG), we investigated (1) the neural sources of HEPs, (2) the underlying mechanisms for HEP generation, and (3) the functional role of HEPs in bodily self-consciousness. In Experiment-1, we found that shortly after the heartbeat onset, phase distributions across single trials were significantly concentrated in 10% of the recording sites, mainly in the insula and the operculum, but also in other regions including the amygdala and fronto-temporal cortex. Such phase concentration was not accompanied by increased spectral power, and did not correlate with spectral power changes, suggesting that a phase resetting, rather than an additive "evoked potential" mechanism, underlies HEP generation. In Experiment-2, we further aimed to anatomically refine previous scalp EEG data that linked HEPs with bodily self-consciousness. We found that HEP modulations in the insula reflected an experimentally induced altered sense of self identification. Collectively, these results provide novel and solid electrophysiological evidence on the neural sources and underlying mechanisms of HEPs, and their functional role in self-consciousness. PMID- 28591824 TI - LOW-DOSE CT PROTOCOL OPTIMIZATION FOR THE ASSESSMENT OF ACUTE APPENDICITIS: THE OPTICAP PHANTOM STUDY. AB - : The aim was to evaluate effects of voltage, noise input (NI) and iterative reconstruction (IR) on radiation dose and image quality in order to establish a contrast enhanced low-dose protocol for assessment of acute appendicitis. An anthropomorphic abdominal phantom mimicking contrast enhanced abdomen was scanned with 80, 100 and 120 kV, standard and strong IR and 11 NIs (66 protocols). A total of 14 test tubes of increasing iodine dilutions and one tube with an appendicolith were evaluated within the phantom. The dose, HUs, noise, contrast to-noise ratio (CNR) and figure of merit (FOM) were determined. Visual quality scores were assessed by two readers. A clinically used voltage-IR combination (120 kV, standard IR) was used as a reference. Overall, 100 kV with standard IR (p = 0.002) and 80 kV with both IRs (p < 0.001) showed higher CNR than the reference, but noise was most pronounced at 80 kV (p < 0.001). The highest FOM was found in the 100 kV protocols (p < 0.001). The reference and 100 kV with standard IR had highest image quality scores, where the 100 kV protocol enabled a distinct dose reduction. Lowering the voltage seems to be a more favorable tool than IR changes in optimizing the dose in contrast enhanced abdominal CT. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01022567. PMID- 28591825 TI - Corticotrophin-releasing hormone and corticosterone impair development of preimplantation embryos by inducing oviductal cell apoptosis via activating the Fas system: an in vitro study. AB - STUDY QUESTION: What are the mechanisms by which corticotrophin-releasing hormone (CRH) and corticosterone impair the development of preimplantation embryos in the oviduct. SUMMARY ANSWER: CRH and corticosterone do not affect preimplantation embryos directly, but impair their development indirectly by triggering apoptosis of oviductal epithelial cells (OECs) through activation of the Fas system. WHAT IS KNOWN ALREADY: Studies report that stress impairs embryo development with facilitated secretion of CRH and glucocorticoids. Although an in vivo study demonstrated that preimplantation stress impaired embryo development in conjunction with oviductal apoptosis and activation of the Fas system, whether CRH or glucocorticoids damage embryos directly or indirectly by way of oviductal cells remains to be clarified. STUDY DESIGN, SIZE, DURATION: Mice of Kunming strain, the generalized lymphoproliferative disorder (gld) mice with a germline mutation F273L in Fas ligand in a C57BL/6J genomic background and the wild-type C57BL/6J mice were used. Female mice were used 8-10 weeks after birth. PARTICIPANTS/MATERIALS, SETTING, METHODS: While some female mice were killed 48 h after being injected with equine CG to collect oviducts and prepare OECs, others were killed to recover zygotes after mating with males following superovulation with eCG and hCG. The zygotes obtained were cultured with or without CRH or corticosterone (CRH/Cort) either in Chatot-Ziomek-Bavister (CZB) medium with or without OECs or in conditioned medium (CM) conditioned with OECs pretreated or not with CRH/Cort. Preimplantation development, levels of redox potential and apoptosis, and expression of CRH receptor 1 (CRHR1), glucocorticoid receptor (GR), Fas and 11beta-hydroxysteroid dehydrogenase (HSD) were observed in embryos recovered at different times of in vitro culture. After culture of OECs with or without CRH/Cort, levels of redox potential and apoptosis, mRNA and protein expression of growth factors, and protein expression of CRHR1, GR and Fas were examined in OECs and the level of FasL was measured in CM. The gld mice were used to confirm a role for the Fas system in triggering apoptosis of embryos and oviducts. MAIN RESULTS AND THE ROLE OF CHANCE: This study showed that blastocyst development was unaffected when mouse zygotes were cultured in CZB medium containing various concentrations of CRH/Cort but was impaired when embryos were cultured with CRH/Cort plus OECs or in CM conditioned with OECs pretreated with CRH/Cort (treatment CM). Culture in treatment-CM induced oxidative stress and apoptosis in embryos. Preimplantation embryos expressed GR and Fas at all stages and CRHR1 at the blastocyst stage only. Mouse 4-cell embryos and blastocysts expressed HSD2 but not HSD1. Culture of OECs with CRH/Cort increased their oxidative stress, apoptosis, CRHR1, Fas and FasL while decreasing their GR and growth factors. Blastocyst development in treatment-CM conditioned with OECs from gld mice harboring FasL mutations was superior to treatment-CM conditioned with wild-type mouse OECs. The results suggest that CRH/Cort impairs embryo development indirectly by inducing oviductal apoptosis via activating the Fas system. The insensitivity of preimplantation embryos to CRH and corticosterone is due to, respectively, a lack of CRHR and the exclusive expression of HSD2 that inactivate corticosterone. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: Although significant, the conclusions were drawn from limited results obtained using mice and thus they need further verification in other species. For example, bovine embryos express both HSD1 and HSD2 at all the preimplantation stages whereas mouse preimplantation embryos express HSD2 exclusively without HSD1. WIDER IMPLICATIONS OF THE FINDINGS: The data are important for our understanding of the mechanisms by which stress affects female reproduction in both human and animals, as early stages of pregnancy are considered more vulnerable to stress than the late stages. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by grants from the National Basic Research Program of China (Nos. 2014CB138503 and 2012CB944403), the China National Natural Science Foundation (Nos. 31272444 and 30972096) and the Animal breeding improvement program of Shandong Province. All authors declare that their participation in the study did not involve factual or potential conflicts of interests. PMID- 28591826 TI - STUDY ON THE SHIELDING AND DOSE RATE DISTRIBUTIONS OF THERAPEUTIC PROTON SYNCHROTRON ACCELERATOR BASED ON FLUKA. AB - Some therapeutic proton synchrotron accelerators will be built for cancer treatment in China. The radiation produced by proton must be carefully evaluated and shielded for occupational disease hazard assessment and environmental impact assessment. Adopting the FLUKA code, a therapeutic room model, a synchrotron hall model and a high energy transport line tunnel model are constructed to get the ambient dose equivalent rate distributions. The ambient dose equivalent rates are also calculated with an empirical formula in some regions. The results calculated by the two ways are consistent with each other. The advantages and disadvantages of the two methods have been analyzed. The ambient dose equivalent rates are no more than 2.5 MUSv/h at 30 cm beyond the shielding wall and the maze door. The dose rates are <25 MUSv/h at 30 cm beyond the roof of the therapeutic room. These results comply with the National Occupational Health Standard requirements. PMID- 28591828 TI - Measuring Successful Aging With Respect for Preferences of Older Persons. AB - Objectives: This paper explores how to measure successful aging in a manner consistent with the preferences of older persons about what matters in their lives. Method: To overcome the fact that existing objective and subjective measures of successful aging may not reflect the preferences of older persons about what matters in their lives, a new preference-based measure of successful aging is proposed. To implement the measure, the preferences of older persons are estimated using a statistical life satisfaction model, which is estimated with data from 11 European countries from the Survey of Health, Ageing and Retirement in Europe (SHARE). Results: The proposed measure is found to yield different results compared to objective and subjective measures in terms of how successful aging has evolved between 2007 and 2013 and how countries are ranked for successful aging. Successful aging measured by a subjective measure is highest in 2011 compared to 2007 and 2013, for instance, whereas the ranking is reversed for the objective- and preference-based measures. Discussion: The findings highlight the relevance of the degree of importance we attribute to the preferences of older persons in the measurement of successful aging, methodologically as well as empirically. PMID- 28591829 TI - Benzoate transport in Pseudomonas putida CSV86. AB - Pseudomonas putida strain CSV86 metabolizes variety of aromatic compounds as the sole carbon source. Genome analysis revealed the presence of genes encoding putative transporters for benzoate, p-hydroxybenzoate, phenylacetate, p hydroxyphenylacetate and vanillate. Bioinformatic analysis revealed that benzoate transport and metabolism genes are clustered at the ben locus as benK-catA-benE benF. Protein topology prediction suggests that BenK (aromatic acid-H+ symporter of major facilitator superfamily) has 12 transmembrane alpha-helices with the conserved motif LADRXGRKX in loop 2, while BenE (benzoate-H+ symporter protein) has 11 predicted transmembrane alpha-helices. benF and catA encode benzoate specific porin, OprD and catechol 1,2-dioxygenase, respectively. Biochemical studies suggest that benzoate was transported by an inducible and active process. Inhibition (90%-100%) in the presence of dinitrophenol suggests that the energy for the transport process is derived from the proton motive force. The maximum rate of benzoate transport was 484 pmole min-1 mg-1 cells with an affinity constant, Kmof 4.5 MUM. Transcriptional analysis of the benzoate and glucose grown cells showed inducible expression of benF, benK and benE, suggesting that besides outer membrane porin, both inner membrane transporters probably contribute for the benzoate transport in P. putida strain CSV86. PMID- 28591827 TI - Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes. AB - The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls the expression of extensive gene networks, driving both up- and down regulation. GR utilizes multiple DNA-binding-dependent and -independent mechanisms to achieve context-specific transcriptional outcomes. The DNA-binding independent mechanism involves tethering of GR to the pro-inflammatory transcription factor activator protein-1 (AP-1) through protein-protein interactions. This mechanism has served as the predominant model of GR-mediated transrepression of inflammatory genes. However, ChIP-seq data have consistently shown GR to occupy AP-1 response elements (TREs), even in the absence of AP-1. Therefore, the current model is insufficient to explain GR action at these sites. Here, we show that GR regulates a subset of inflammatory genes in a DNA-binding dependent manner. Using structural biology and biochemical approaches, we show that GR binds directly to TREs via sequence-specific contacts to a GR-binding sequence (GBS) half-site found embedded within the TRE motif. Furthermore, we show that GR-mediated transrepression observed at TRE sites to be DNA-binding dependent. This represents a paradigm shift in the field, showing that GR uses multiple mechanisms to suppress inflammatory gene expression. This work further expands our understanding of this complex multifaceted transcription factor. PMID- 28591830 TI - Letter: Factors Predicting Recurrence after Resection of Clival Chordoma Using Variable Surgical Approaches and Radiation Modalities. PMID- 28591832 TI - Reply to Bush and Kaye. PMID- 28591831 TI - The Gut Metagenome Changes in Parallel to Waist Circumference, Brain Iron Deposition, and Cognitive Function. AB - Context: Microbiota perturbations seem to exert modulatory effects on emotional behavior, stress-, and pain-modulation systems in adult animals; however, limited information is available in humans. Objective: To study potential relationships among the gut metagenome, brain microstructure, and cognitive performance in middle-aged, apparently healthy, obese and nonobese subjects after weight changes. Design: This is a longitudinal study over a 2-year period. Setting: A tertiary public hospital. Patients or Other Participants: Thirty-five (18 obese) apparently healthy subjects. Intervention(s): Diet counseling was provided to all subjects. Obese subjects were followed every 6 months. Main Outcome Measure(s): Brain relaxometry (using magnetic resonance R2*), cognitive performance (by means of cognitive tests), and gut microbiome composition (shotgun). Results: R2* increased in both obese and nonobese subjects, independent of weight variations. Changes in waist circumference, but not in body mass index, were associated with brain iron deposition (R2*) in the striatum, amygdala, and hippocampus in parallel to visual-spatial constructional ability and circulating beta amyloid Abeta42 levels. These changes were linked to shifts in gut microbiome in which the relative abundance of bacteria belonging to Caldiserica and Thermodesulfobacteria phyla were reciprocally associated with raised R2* in different brain nuclei. Of note, the increase in bacteria belonging to Tenericutes phylum was parallel to decreased R2* gain in the striatum, serum Abeta42 levels, and spared visual-spatial constructional ability. Interestingly, metagenome functions associated with circulating and brain iron stores are involved in bacterial generation of siderophores. Conclusions: Changes in the gut metagenome are associated longitudinally with cognitive function and brain iron deposition. PMID- 28591834 TI - Cholinergic Grb2-Associated-Binding Protein 1 Regulates Cognitive Function. AB - Grb2-associated-binding protein 1 (Gab1) is a docking/scaffolding molecule known to play an important role in cell growth and survival. Here, we report that Gab1 is decreased in cholinergic neurons in Alzheimer's disease (AD) patients and in a mouse model of AD. In mice, selective ablation of Gab1 in cholinergic neurons in the medial septum impaired learning and memory and hippocampal long-term potentiation. Gab1 ablation also inhibited SK channels, leading to an increase in firing in septal cholinergic neurons. Gab1 overexpression, on the other hand, improved cognitive function and restored hippocampal CaMKII autorphosphorylation in AD mice. These results suggest that Gab1 plays an important role in the pathophysiology of AD and may represent a novel therapeutic target for diseases involving cholinergic dysfunction. PMID- 28591835 TI - Assessing phagotrophy in the mixotrophic ciliate Paramecium bursaria using GFP expressing yeast cells. AB - We used cells of the yeast Saccharomyces cerevisiae expressing green fluorescent protein (GFP) as fluorescently labelled prey to assess the phagocytic activities of the mixotrophic ciliate Paramecium bursaria, which harbours symbiotic Chlorella-like algae. Because of different fluorescence spectra of GFP and algal chlorophyll, ingested GFP-expressing yeast cells can be distinguished from endosymbiotic algal cells and directly counted in individual P. bursaria cells using fluorescence microscopy. By using GFP-expressing yeast cells, we found that P. bursaria altered ingestion activities under different physiological conditions, such as different growth phases or the presence/absence of endosymbionts. Use of GFP-expressing yeast cells allowed us to estimate the digestion rates of live prey of the ciliate. In contrast to the ingestion activities, the digestion rate within food vacuoles was not affected by the presence of endosymbionts, consistent with previous findings that food and perialgal vacuoles are spatially and functionally separated in P. bursaria. Thus, GFP-expressing yeast may provide a valuable tool to assess both ingestion and digestion activities of ciliates that feed on eukaryotic organisms. PMID- 28591833 TI - A new fully human recombinant FSH (follitropin epsilon): two phase I randomized placebo and comparator-controlled pharmacokinetic and pharmacodynamic trials. AB - STUDY QUESTION: What are the differences and similarities of pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the novel recombinant human FSH follitropin epsilon expressed in the human cell line GlycoExpress compared with a Chinese hamster ovary (CHO) derived compound and a urinary derived product? SUMMARY ANSWER: Overall follitropin epsilon, with a fully human glycosylation, shows a comparable PK profile at single-dose as well as multiple-dose administration compared to recombinant CHO-derived FSH as well as urinary derived FSH, whereas the PD properties differ from product to product with follitropin epsilon being most active in PD parameters. WHAT IS KNOWN ALREADY: Recombinant FSH produced in CHO and FSH obtained from the urine of postmenopausal women show comparable PK and PD properties. However, more recently a comparative study of a recombinant FSH produced in the human cell line PerC6 and a CHO-derived FSH preparation revealed differences in PK and PD properties of the molecule. STUDY DESIGN, SIZE, DURATION: Both studies were randomized, placebo- and comparator controlled, single-blind phase I studies in healthy pituitary-suppressed female volunteers aged 18 and 40 years. The single-dose, dose escalation study included 19 women (April 2011 to September 2011) with three ascending dose levels per subject or placebo/comparators with a 14-day washout phase between dosings. The multiple-dose study included 57 women (October 2011 to April 2012) in five cohorts with three dose levels versus placebo and two comparators. Randomization to the respective treatment was performed after successful downregulation of the pituitary gland prior to Investigational Medicinal Product dosing. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the single-dose study, 12 subjects received follitropin epsilon (25, 75, 150 and 300 IU) in three of four possible ascending doses and seven subjects received one dose of two comparators (150 IU Bravelle and 150 IU Gonal-f) and placebo in random order in each treatment period. In the multiple-dose study, 30 subjects received follitropin epsilon (75 IU or 150 IU once daily [QD], or 150 IU every other day [QAD], 10 subjects each) and 27 subjects received 150 IU Gonal-f, 150 IU Bravelle, or placebo for 7 days (11/10/6 subjects). Blood samples for measuring PK as well as PD parameters were collected systematically before, during and after dosing. Adverse events (AEs) and other relevant safety parameters were recorded. Data were summarized using descriptive statistics. MAIN RESULTS AND THE ROLE OF CHANCE: The single- and multiple-dose PK parameters maximum concentration (Cmax) and area under the concentration-time curve (AUC0-last) increased in a linear fashion with increasing dose levels of follitropin epsilon. Follitropin epsilon showed PK characteristics comparable to the comparators indicating that well established treatment schemes could be applied. There was a dose-response effect of single and multiple doses of follitropin epsilon on follicular growth, which was shown for the biomarker inhibin B as well as for the mean number and size of follicles. Multiple doses of 75 IU follitropin epsilon given daily, as well as 150 IU follitropin epsilon every second day, showed a follicle growth comparable with 150 IU Gonal-f given daily, while in case of daily administration of 150 IU Bravelle only weak follicle stimulation was observed. Multiple doses of 150 IU follitropin epsilon induced a much higher follicle growth compared to the same dose of Gonal-f. All single and multiple follitropin epsilon doses tested were safe and well tolerated, and overall there were no relevant differences between follitropin epsilon and the comparators in terms of safety. The average number of AEs increased with increasing dose levels. No clinically relevant abnormalities were reported for any of the other safety parameters assessed. No follitropin epsilon anti-drug antibodies were observed. LIMITATIONS, REASONS FOR CAUTION: The studies were conducted as a single-blind design. Hormone levels or other parameters assessed in serum are generally not considered as being subject to bias. Other assessments directly performed by the investigators, such as transvaginal ultrasound assessments, may have been subject to personal bias. No prospective calculations of statistical power had been made, as is common practice for first in human and early phase I studies in healthy volunteers. WIDER IMPLICATIONS OF THE FINDINGS: These early development studies showed that follitropin epsilon exhibits comparable PK characteristics, as well as inducing stronger PD effects in terms of follicle growth and serum inhibin B, than the comparators. Follitropin epsilon induced a dose-dependent increase in follicular growth. The results warrant further studies with this new fully human recombinant FSH. STUDY FUNDING/COMPETING INTEREST(S): The studies were sponsored by GLYCOTOPE GmbH, Berlin, Germany. K.A-E. is an employee of QPS-Netherlands, B.V., which received funding for the studies from Glycotope GmbH; I.D. and C.K. are employees of Dinox B.V., which received funding for the studies from Glycotope GmbH; L.S. and S.G. are employees and shareholders of Glycotope GmbH; B.D. and K.E. are employees of Glycotope GmbH. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov: NCT01354886 (single-dose); NCT01477073 (multiple-dose). TRIAL REGISTRATION DATE: The single-dose trial was registered on 11 May 2011 while the multiple-dose trial was registered on 09 November 2011. DATE OF FIRST SUBJECT'S ENROLMENT: First subject was enroled in the single-dose trial in 27 April 2011 and in the multiple dose trial in 02 October 2011. PMID- 28591836 TI - Focal Cortical Anomalies and Language Impairment in 16p11.2 Deletion and Duplication Syndrome. AB - Individuals with copy number variants (CNV) in the 16p11.2 chromosomal region are at high risk for language disorders. We investigate whether the extent and location of focal cortical anomalies are associated with language impairment in individuals with 16p11.2 CNVs. High-resolution T1-weighted MRI scans from 30 16p11.2 deletion (16p-del), 25 16p11.2 duplication (16p-dup), and 90 noncarrier controls (NCC) were analyzed to derive personalized cortical anomaly maps through single-case cortical thickness (CT) comparison to age-matched normative samples. Focal cortical anomalies were elevated in both 16p-del and 16p-dup and their total extent was inversely correlated with Full-Scale IQ. Clusters of abnormally thick cortex were more extensive in the 16p-del group and clusters of abnormally thin cortex were more extensive in the 16p-dup group. Abnormally thick clusters were more extensive in left lateral temporal and bilateral postcentral and mesial occipital regions in 16p-del. Focal cortical anomalies in the left middle temporal region and pars opercularis (Broca's region) of children with 16-del were associated with lower scores on a comprehensive language evaluation. Results extend neuroanatomical findings in 16p11.2 syndrome to include spatially heterogenous focal cortical anomalies that appear to disrupt language ability in accordance with the functional specialization of left frontotemporal regions. PMID- 28591838 TI - Errata. PMID- 28591839 TI - Errata. PMID- 28591837 TI - Attention Selectively Reshapes the Geometry of Distributed Semantic Representation. AB - Humans prioritize different semantic qualities of a complex stimulus depending on their behavioral goals. These semantic features are encoded in distributed neural populations, yet it is unclear how attention might operate across these distributed representations. To address this, we presented participants with naturalistic video clips of animals behaving in their natural environments while the participants attended to either behavior or taxonomy. We used models of representational geometry to investigate how attentional allocation affects the distributed neural representation of animal behavior and taxonomy. Attending to animal behavior transiently increased the discriminability of distributed population codes for observed actions in anterior intraparietal, pericentral, and ventral temporal cortices. Attending to animal taxonomy while viewing the same stimuli increased the discriminability of distributed animal category representations in ventral temporal cortex. For both tasks, attention selectively enhanced the discriminability of response patterns along behaviorally relevant dimensions. These findings suggest that behavioral goals alter how the brain extracts semantic features from the visual world. Attention effectively disentangles population responses for downstream read-out by sculpting representational geometry in late-stage perceptual areas. PMID- 28591841 TI - RSAT matrix-clustering: dynamic exploration and redundancy reduction of transcription factor binding motif collections. AB - Transcription factor (TF) databases contain multitudes of binding motifs (TFBMs) from various sources, from which non-redundant collections are derived by manual curation. The advent of high-throughput methods stimulated the production of novel collections with increasing numbers of motifs. Meta-databases, built by merging these collections, contain redundant versions, because available tools are not suited to automatically identify and explore biologically relevant clusters among thousands of motifs. Motif discovery from genome-scale data sets (e.g. ChIP-seq) also produces redundant motifs, hampering the interpretation of results. We present matrix-clustering, a versatile tool that clusters similar TFBMs into multiple trees, and automatically creates non-redundant TFBM collections. A feature unique to matrix-clustering is its dynamic visualisation of aligned TFBMs, and its capability to simultaneously treat multiple collections from various sources. We demonstrate that matrix-clustering considerably simplifies the interpretation of combined results from multiple motif discovery tools, and highlights biologically relevant variations of similar motifs. We also ran a large-scale application to cluster ~11 000 motifs from 24 entire databases, showing that matrix-clustering correctly groups motifs belonging to the same TF families, and drastically reduced motif redundancy. matrix-clustering is integrated within the RSAT suite (http://rsat.eu/), accessible through a user friendly web interface or command-line for its integration in pipelines. PMID- 28591840 TI - Novel approaches in function-driven single-cell genomics. AB - Deeper sequencing and improved bioinformatics in conjunction with single-cell and metagenomic approaches continue to illuminate undercharacterized environmental microbial communities. This has propelled the 'who is there, and what might they be doing' paradigm to the uncultivated and has already radically changed the topology of the tree of life and provided key insights into the microbial contribution to biogeochemistry. While characterization of 'who' based on marker genes can describe a large fraction of the community, answering 'what are they doing' remains the elusive pinnacle for microbiology. Function-driven single-cell genomics provides a solution by using a function-based screen to subsample complex microbial communities in a targeted manner for the isolation and genome sequencing of single cells. This enables single-cell sequencing to be focused on cells with specific phenotypic or metabolic characteristics of interest. Recovered genomes are conclusively implicated for both encoding and exhibiting the feature of interest, improving downstream annotation and revealing activity levels within that environment. This emerging approach has already improved our understanding of microbial community functioning and facilitated the experimental analysis of uncharacterized gene product space. Here we provide a comprehensive review of strategies that have been applied for function-driven single-cell genomics and the future directions we envision. PMID- 28591842 TI - Children with Cerebral Palsy Hyper-Gate Somatosensory Stimulations of the Foot. AB - We currently have a substantial knowledge gap in our understanding of the neurophysiological underpinnings of the sensory perception deficits often reported in the clinic for children with cerebral palsy (CP). In this investigation, we have begun to address this knowledge gap by using magnetoencephalography (MEG) brain imaging to evaluate the sensory gating of neural oscillations in the somatosensory cortices. A cohort of children with CP (Gross Motor Function Classification System II-III) and typically developing children underwent paired-pulse electrical stimulation of the tibial nerve during MEG. Advanced beamforming methods were used to image significant oscillatory responses, and subsequently the time series of neural activity was extracted from peak voxels. Our experimental results showed that somatosensory cortical oscillations (10-75 Hz) were weaker in the children with CP for both stimulations. Despite this reduction, the children with CP actually exhibited a hyper-gating response to the second, redundant peripheral stimulation applied to the foot. These results have further established the nexus of the cortical somatosensory processing deficits that are likely responsible for the degraded sensory perceptions reported in the clinic for children with CP. PMID- 28591843 TI - The First Evidence of Nanism in Ixodes (Ixodes) scapularis (Acari: Ixodidae), Found Parasitizing a Human Host. AB - Ixodes scapularis Say 1821, the primary vector of several human pathogens in the northeastern and upper Midwestern United States, has considerable genetic and morphological variation throughout its range. Recently, developmental or teratological abnormalities have been observed in this species for the first time, further complicating morphological identification. Here, we report the first evidence of nanism (dwarfism) in I. scapularis, found parasitizing a human host. We used molecular methods and scanning electron microscopy to identify the specimen. Morphological identification confirmed that the specimen is substantially smaller, approximately half the size, than a typical I. scapularis female. Here we discuss the recent reports of teratological abnormalities in I. scapularis, particularly from the Hudson River valley region of the northeastern United States, and highlight the need for additional studies of teratology in this important species and its potential implications in disease transmission. PMID- 28591844 TI - New insights into a classic aptamer: binding sites, cooperativity and more sensitive adenosine detection. AB - The DNA aptamer for adenosine (also for AMP and ATP) is a highly conserved sequence that has recurred in a few selections. It it a widely used model aptamer for biosensor development, and its nuclear magnetic resonance structure shows that each aptamer binds two AMP molecules. In this work, each binding site was individually removed by rational sequence design, while the remaining site still retained a similar binding affinity and specificity as confirmed by isothermal titration calorimetry. The thermodynamic parameters of binding are presented, and its biochemical implications are discussed. The number of binding sites can also be increased, and up to four sites are introduced in a single DNA sequence. Finally, the different sequences are made into fluorescent biosensors based on the structure-switching signaling aptamer design. The one-site aptamer has 3.8 fold higher sensitivity at lower adenosine concentration with a limit of detection of 9.1 MUM adenosine, but weaker fluorescence signal at higher adenosine concentrations, consistent with a moderate cooperativity in the original aptamer. This work has offered insights into a classic aptamer for the relationship between the number of binding sites and sensitivity, and a shorter aptamer for improved biosensor design. PMID- 28591845 TI - Severe esophagitis associated with cytomegalovirus during concurrent chemoradiotherapy for esophageal cancer. AB - Although radiation esophagitis is one of the most common adverse events that occurs during chemoradiotherapy (CRT) in patients with esophageal cancer, CRT associated cytomegalovirus (CMV) esophagitis is rare. CMV esophagitis typically occurs in patients with an immunosuppressed status. Here we report a case of CMV esophagitis during CRT initially treated as radiation esophagitis. A 64-year-old man with mid-thoracic esophageal cancer was admitted to our hospital with clinical stage cT4bN1M1 (supraclavicular lymph node metastasis) Stage IV according to the UICC ver. 7 guidelines, and he was administered definitive concurrent CRT. From the 39th day of CRT onwards, he presented with a sustained fever and severe odynophagia that was resistant to antibiotic therapy. An esophagoscopy revealed severe esophagitis with a circumferential ulcer throughout the entire esophagus, and CMV esophagitis was clinically suspected because of positive result of CMV antigenemia. Subsequently, antiviral therapy for CMV provided dramatic relief of his symptoms. Later, CMV DNA was confirmed with a polymerase chain reaction in the biopsy specimen.The symptoms of CMV esophagitis resemble those of radiation esophagitis and can make the diagnosis difficult. Thus, CMV esophagitis associated CRT may be overlooked or masked by radiation esophagitis and can cause a delay in healing. Therefore, CMV esophagitis may be considered when severe intractable esophagitis is observed during CRT. PMID- 28591846 TI - Visualization of conformational variability in the domains of long single stranded RNA molecules. AB - We demonstrate an application of atomic force microscopy (AFM) for the structural analysis of long single-stranded RNA (>1 kb), focusing on 28S ribosomal RNA (rRNA). Generally, optimization of the conditions required to obtain three dimensional (3D) structures of long RNA molecules is a challenging or nearly impossible process. In this study, we overcome these limitations by developing a method using AFM imaging combined with automated, MATLAB-based image analysis algorithms for extracting information about the domain organization of single RNA molecules. We examined the 5 kb human 28S rRNA since it is the largest RNA molecule for which a 3D structure is available. As a proof of concept, we determined a domain structure that is in accordance with previously described secondary structural models. Importantly, we identified four additional small (200-300 nt), previously unreported domains present in these molecules. Moreover, the single-molecule nature of our method enabled us to report on the relative conformational variability of each domain structure identified, and inter-domain associations within subsets of molecules leading to molecular compaction, which may shed light on the process of how these molecules fold into the final tertiary structure. PMID- 28591847 TI - Implementing targeted expectant management in fertility care using prognostic modelling: a cluster randomized trial with a multifaceted strategy. AB - STUDY QUESTION: What is the effectiveness of a multifaceted implementation strategy compared to usual care on improving the adherence to guideline recommendations on expectant management for couples with unexplained infertility? SUMMARY ANSWER: The multifaceted implementation strategy did not significantly increase adherence to guideline recommendations on expectant management compared to care as usual. WHAT IS KNOWN ALREADY: Intrauterine insemination (IUI) with or without ovarian hyperstimulation has no beneficial effect compared to no treatment for 6 months after the fertility work-up for couples with unexplained infertility and a good prognosis of natural conception. Therefore, various professionals and policy makers have advocated the use of prognostic profiles and expectant management in guideline recommendations. STUDY DESIGN, SIZE, DURATION: A cluster randomized controlled trial in 25 clinics in the Netherlands was conducted between March 2013 and May 2014. Clinics were randomized between the implementation strategy (intervention, n = 13) and care as usual (control, n = 12). The effect of the implementation strategy was evaluated by comparing baseline and effect measurement data. Data collection was retrospective and obtained from medical record research and a patient questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 544 couples were included at baseline and 485 at the effect measurement (247 intervention group/238 control group). MAIN RESULTS AND THE ROLE OF CHANCE: Guideline adherence increased from 49 to 69% (OR 2.66; 95% CI 1.45-4.89) in the intervention group, and from 49 to 61% (OR 2.03; 95% CI 1.38-3.00) in the control group. Multilevel analysis with case-mix adjustment showed that the difference of 8% was not statistically significant (OR 1.31; 95% CI 0.67-2.59). The ongoing pregnancy rate within six months after fertility work-up did not significantly differ between intervention and control group (25% versus 27%: OR 0.72; 95% CI 0.40-1.27). LIMITATIONS REASONS FOR CAUTION: There is a possible selection bias, couples included in the study had a higher socio-economic status than non-responders. How this affects guideline adherence is unclear. Furthermore, when powering for this study we did not take into account the unexpected improvement of adherence in the control group. WIDER IMPLICATIONS OF THE FINDINGS: Generalization of our results to other countries with recommendations on expectant management might be questionable because barriers for expectant management can be very different in other countries. Furthermore, due to a large variation in improved adherence rate in the intervention group it will be interesting to further analyse the process of implementation in each clinic with a process evaluation on professionals and couples' exposure to and experiences with the strategy. STUDY FUNDING/COMPETING INTEREST(S): Supported by Netherlands Organisation for Health Research and Development (ZonMW, project number 171203005). No competing interests. TRIAL REGISTRATION NUMBER: Dutch trial Register, www.trialregister.nl NTR3405. TRIAL REGISTRATION DATE: 19 April 2012. DATE OF FIRST PATIENT'S ENROLMENT: 10 July 2012. PMID- 28591848 TI - Comparative genomics of free-living Gammaproteobacteria: pathogenesis-related genes or interaction-related genes? AB - Bacteria have numerous strategies to interact with themselves and with their environment, but genes associated with these interactions are usually cataloged as pathogenic. To understand the role that these genes have not only in pathogenesis but also in bacterial interactions, we compared the genomes of eight bacteria from human-impacted environments with those of free-living bacteria from the Cuatro Cienegas Basin (CCB), a relatively pristine oligotrophic site. Fifty one genomes from CCB bacteria, including Pseudomonas, Vibrio, Photobacterium and Aeromonas, were analyzed. We found that the CCB strains had several virulence related genes, 15 of which were common to all strains and were related to flagella and chemotaxis. We also identified the presence of Type III and VI secretion systems, which leads us to propose that these systems play an important role in interactions among bacterial communities beyond pathogenesis. None of the CCB strains had pathogenicity islands, despite having genes associated with antibiotics. Integrons were rare, while CRISPR elements were common. The idea that pathogenicity-related genes in many cases form part of a wider strategy used by bacteria to interact with other organisms could help us to understand the role of pathogenicity-related elements in an ecological and evolutionary framework leading toward a more inclusive One Health concept. PMID- 28591849 TI - Pseudomonas aeruginosa quorum-sensing response in the absence of functional LasR and LasI proteins: the case of strain 148, a virulent dolphin isolate. AB - Pseudomonas aeruginosa is an opportunistic pathogen that presents a complex regulatory network called 'quorum-sensing', which is responsible for the transcription of genes coding for several traits implicated in its pathogenicity. Strain 148 is a dolphin isolate that has been shown to produce quorum-sensing regulated virulence traits and to be virulent in a mouse model, despite the fact that it contains a 20-kbp deletion that eliminates from the chromosome the lasR gene and the lasI promoter. LasR is a key quorum-sensing transcriptional regulator that, when coupled with the autoinducer 3-oxo-dodecanoyl homoserine lactone (3O-C12-HSL) produced by LasI, activates transcription of genes coding for some virulence-associated traits such as elastase, lasI, rhlI and rhlR. RhlR is also a key quorum-sensing transcriptional regulator that, when interacting with the autoinducer butanoyl homoserine lactone (C4-HSL) that is produced by the synthase RhlI, activates the genes involved in the synthesis of some virulence associated traits, as rhamnolipids and pyocyanin. We describe that in P. aeruginosa 148, the LasR/3O-C12-HSL-independent rhlR transcriptional activation is due to the release of the negative effect of Vfr (a CRP-ortholog) caused by the insertion of an IS element in vfr, and that rhlI transcription is driven from the rhlR promoter, forming the rhlR-I operon. PMID- 28591851 TI - Reduced Fidelity of Neural Representation Underlies Episodic Memory Decline in Normal Aging. AB - Emerging studies have emphasized the importance of the fidelity of cortical representation in forming enduring episodic memory. No study, however, has examined whether there are age-related reductions in representation fidelity that can explain memory declines in normal aging. Using functional MRI and multivariate pattern analysis, we found that older adults showed reduced representation fidelity in the visual cortex, which accounted for their decreased memory performance even after controlling for the contribution of reduced activation level. This reduced fidelity was specifically due to older adults' poorer item-specific representation, not due to their lower activation level and variance, greater variability in neuro-vascular coupling, or decreased selectivity of categorical representation (i.e., dedifferentiation). Older adults also showed an enhanced subsequent memory effect in the prefrontal cortex based on activation level, and their prefrontal activation was associated with greater fidelity of representation in the visual cortex and better memory performance. The fidelity of cortical representation thus may serve as a promising neural index for better mechanistic understanding of the memory declines and its compensation in normal aging. PMID- 28591850 TI - Acrolein Exposure in Hookah Smokers and Non-Smokers Exposed to Hookah Tobacco Secondhand Smoke: Implications for Regulating Hookah Tobacco Products. AB - Introduction: Acrolein is a highly ciliatoxic agent, a toxic respiratory irritant, a cardiotoxicant, and a possible carcinogen present in tobacco smoke including hookah tobacco. Methods: 105 hookah smokers and 103 non-smokers attended exclusively hookah smoking social events at either a hookah lounge or private home, and provided urine samples the morning of and the morning after the event. Samples were analyzed for 3-hydroxypropylmercapturic acid (3-HPMA), a metabolite of acrolein. Results: Geometric mean (GM) urinary 3-HPMA levels in hookah smokers and non-smokers exposed to secondhand smoke (SHS) increased significantly, 1.41 times, 95% CI = 1.15 to 1.74 and 1.39 times, 95% CI = 1.16 to 1.67, respectively, following a hookah social event. The highest increase (1.68 times, 95% CI = 1.15 to 2.45; p = 0.007) in 3-HPMA post a hookah social event was among daily hookah smokers (GM, from 1991 pmol/mg to 3348 pmol/mg). Pre-to-post event change in urinary 3-HPMA was significantly positively correlated with pre to-post event change in urinary cotinine among hookah smokers at either location of hookah event, (rho = 0.359, p = 0.001), and among non-smokers in hookah lounges (rho = 0.369, p = 0.012). Conclusions: Hookah tobacco smoke is a source of acrolein exposure. Findings support regulating hookah tobacco products including reducing humectants and sugar additives, which are precursors of acrolein under certain pyrolysis conditions. We suggest posting health warning signs for indoor smoking in hookah lounges, and encouraging voluntary bans of smoking hookah tobacco in private homes. Implications: Our study is the first to quantify the increase in acrolein exposure in hookah smokers and non-smokers exposed to exclusively hookah tobacco SHS at hookah social events in homes or hookah lounges. Our findings provide additional support for regulating hookah tobacco product content, protecting non-smokers' health by posting health warning signs for indoor smoking in hookah lounges, and encouraging home bans on hookah tobacco smoking to safeguard vulnerable residents. PMID- 28591852 TI - Morbidity and mortality in opioid dependent patients after entering an opioid pharmacotherapy compared with a cohort of non-dependent controls. AB - Aims: To compare morbidity and mortality in opioid dependence patients following the commencement of treatment with the general population. Methods: Morbidity and mortality in all patients treated with methadone, buprenorphine or implant naltrexone for opioid dependence for the first time between 2001 and 2010 in Western Australia was compared to a cohort of age and gender matched controls using state health records. Results: Compared to community controls rates of all cause mortality, hospital admissions and Emergency Department attendances are significantly elevated in opioid dependent persons following the commencement of their first treatment. Not surprisingly, rates of opioid and non-opioid drug poisoning, and intentional self-harm/suicide mortality and hospital admissions were significantly elevated in opioid dependent patients compared with non dependent controls. However, significant increases in mortality and hospital admissions for conditions which are not generally associated with opioid use were also identified including cardiovascular, respiratory and traffic accidents. Life time prevalence of both HBV and HCV were significantly elevated in opioid dependent patients compared with non-dependent patients. Conclusions: Even after the commencement of treatment, opioid dependent patients are at a high risk of morbidity and mortality compared with non-dependent age and gender matched controls. PMID- 28591855 TI - Corrigendum. PMID- 28591854 TI - CORRECTION FACTORS FOR ATTENUATION AND SCATTERING OF THE WALL OF A CYLINDRICAL IONIZATION CHAMBER IN THE 6-7 MeV HIGH-ENERGY PHOTON REFERENCE FIELD. AB - In high-energy photon reference fields the value of the air kerma rate is determined by using ionization chambers (ICs). From the charge collected inside the IC the dose can be calculated using a set of calibration and correction factors according to ISO 4037-2. A crucial parameter is the correction for the attenuation and scattering of the primary radiation due to the chamber wall. This parameter can be determined using Monte Carlo calculations. The evaluation of the factor was performed for a commercially available IC of the type Victoreen 550-3 under different build-up conditions. The results were verified by measurements in the R-F high-energy photon fields according to ISO 4037-1 at the Physikalisch Technische Bundesanstalt (PTB) and the Japan Atomic Energy Agency (JAEA). PMID- 28591856 TI - A BRIEF OVERVIEW OF COMPARTMENTAL MODELING FOR INTAKE OF PLUTONIUM VIA WOUNDS. AB - The aim of this study is to present several approaches that have been used to model the behavior of radioactive materials (specifically Pu) in contaminated wounds. We also review some attempts by the health physics community to validate and revise the National Council on Radiation Protection and Measurements (NCRP) 156 biokinetic model for wounds, and present some general recommendations based on the review. Modeling of intake via the wound pathway is complicated because of a large array of wound characteristics (e.g. solubility and chemistry of the material, type and depth of the tissue injury, anatomical location of injury). Moreover, because a majority of the documented wound cases in humans are medically treated (excised or treated with chelation), the data to develop biokinetic models for unperturbed wound exposures are limited. Since the NCRP wound model was largely developed from animal data, it is important to continue to validate and improve the model using human data whenever plausible. PMID- 28591853 TI - Neisseria genomics: current status and future perspectives. AB - High-throughput whole genome sequencing has unlocked a multitude of possibilities enabling members of the Neisseria genus to be examined with unprecedented detail, including the human pathogens Neisseria meningitidis and Neisseria gonorrhoeae. To maximise the potential benefit of this for public health, it is becoming increasingly important to ensure that this plethora of data are adequately stored, disseminated and made readily accessible. Investigations facilitating cross-species comparisons as well as the analysis of global datasets will allow differences among and within species and across geographic locations and different times to be identified, improving our understanding of the distinct phenotypes observed. Recent advances in high-throughput platforms that measure the transcriptome, proteome and/or epigenome are also becoming increasingly employed to explore the complexities of Neisseria biology. An integrated approach to the analysis of these is essential to fully understand the impact these may have in the Neisseria genus. This article reviews the current status of some of the tools available for next generation sequence analysis at the dawn of the 'post-genomic' era. PMID- 28591857 TI - Adaptive Patterns of Mitogenome Evolution Are Associated with the Loss of Shell Scutes in Turtles. AB - The mitochondrial genome encodes several protein components of the oxidative phosphorylation (OXPHOS) pathway and is critical for aerobic respiration. These proteins have evolved adaptively in many taxa, but linking molecular-level patterns with higher-level attributes (e.g., morphology, physiology) remains a challenge. Turtles are a promising system for exploring mitochondrial genome evolution as different species face distinct respiratory challenges and employ multiple strategies for ensuring efficient respiration. One prominent adaptation to a highly aquatic lifestyle in turtles is the secondary loss of keratenized shell scutes (i.e., soft-shells), which is associated with enhanced swimming ability and, in some species, cutaneous respiration. We used codon models to examine patterns of selection on mitochondrial protein-coding genes along the three turtle lineages that independently evolved soft-shells. We found strong evidence for positive selection along the branches leading to the pig-nosed turtle (Carettochelys insculpta) and the softshells clade (Trionychidae), but only weak evidence for the leatherback (Dermochelys coriacea) branch. Positively selected sites were found to be particularly prevalent in OXPHOS Complex I proteins, especially subunit ND2, along both positively selected lineages, consistent with convergent adaptive evolution. Structural analysis showed that many of the identified sites are within key regions or near residues involved in proton transport, indicating that positive selection may have precipitated substantial changes in mitochondrial function. Overall, our study provides evidence that physiological challenges associated with adaptation to a highly aquatic lifestyle have shaped the evolution of the turtle mitochondrial genome in a lineage-specific manner. PMID- 28591858 TI - The Geographic Distribution of Ixodes scapularis (Acari: Ixodidae) Revisited: The Importance of Assumptions About Error Balance. AB - The black-legged tick, Ixodes scapularis Say, is the primary vector of Borrelia burgdorferi, a spirochete that causes Lyme disease, in eastern North America. Lyme disease risk has generally been considered to be focused in the Northeast and the northern Midwest in the United States, yet the distribution of the vector extends considerably more broadly. A recent analysis of the distribution of the species using ecological niche modeling approaches painted an odd biogeographic picture, in which the species is distributed in a "rimming" distribution across the northern Midwest and Northeast, and along the Atlantic and Gulf coasts of the eastern United States, but not broadly in the interior of eastern North America. Here, we reanalyze the situation for this species, and demonstrate that the distribution estimated in the previous study was a consequence of assumptions about relative weights applied to different error types. A more appropriate error weighting scheme for niche modeling analyses, in which omission error is prioritized over commission error, shows a simpler distribution, in which the species ranges continuously across eastern North America; this distributional pattern is supported by independent occurrence data from the eastern Great Plains, in Kansas. We discuss implications for public health planning and intervention across the region, as well as for developing effective and predictive maps of vector distributions and pathogen transmission risk. PMID- 28591859 TI - Rhipicephalus microplus and Dermacentor nitens (Acari: Ixodidae) Coparasitize White-Tailed Deer on St. John, U.S. Virgin Islands. AB - Ticks parasitizing introduced white-tailed deer, Odocoileus virginianus (Zimmermann), on St. John, U.S. Virgin Islands, were recorded during and after drought conditions. Tick infestation prevalences were 22% at the start of the drought (July 2015), 66% at the height of the drought (March 2016), and 35% after the drought had ended (July 2016; n = 67 deer). Samples of ticks from 22 tranquilized deer in July 2016 revealed the presence of two species, the southern cattle tick, Rhipicephalus (Boophilus) microplus (Canestrini), and the tropical horse tick, Dermacentor (Anocentor) nitens Neumann. Both tick species have considerable veterinary importance, especially for cattle and horses, respectively, as nuisance biters and also as vectors of parasitic piroplasms or of Anaplasma marginale Theiler. All 22 deer examined were infested by R. microplus, whereas 14 (64%) of the samples also included specimens of D. nitens. Because of the large numbers of ticks recorded, wild deer on St. John could develop associated health problems (pruritis, alopecia, anemia, low weight gain, tick-borne pathogens and parasites) and could also serve as a source of these ticks for cattle and horses. PMID- 28591860 TI - Suggestions for clinical studies on percutaneous left atrial appendage occlusion: authors' reply. PMID- 28591861 TI - DIAGNOSTIC REFERENCE LEVELS IN CARDIAC COMPUTED TOMOGRAPHY ANGIOGRAPHY: A SYSTEMATIC REVIEW. AB - Cardiac computed tomography angiography (CCTA) is a commonly used diagnostic tool for cardiovascular disease. Despite constant improvements to imaging technologies, the radiation dose to patients from CCTA remains a concern when using this procedure. There remains a need for optimisation of CCTA procedures and accurate dose monitoring to reduce the potential risk of cancer. Establishing diagnostic reference levels (DRLs) allows for the assessment of radiation dose variations, enabling strategies aimed at standardising doses across radiological centres. This systematic review explores the literature on CCTA methodologies that have been used to establish DRLs. A search was carried out using the Web of Science, SCOPUS, Medline, CINAHL and EMBASE databases. Reference lists of published articles were also assessed to identify further articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was employed to evaluate articles for relevance. Articles were included if they assessed DRLs in CCTA. The search resulted in 448 articles, of which, six were included after a thorough screening process. The literature demonstrates a wide dose variation in reported CCTA DRLs ranging from 671 to 1510 mGy cm in DLP. Where reported, CTDIvol DRLs ranged from 26 to 70 mGy. Differences were found in the methodologies used for establishing CCTA DRLs, including the sampling methodology used for identifying suitable patients and scanning protocols. This current review emphasises the need for an international standardisation for DRLs establishment methods, to provide a more comparable global measurement of dose variations across CT sites. PMID- 28591862 TI - ASSESSMENT OF BODY POTASSIUM LEVEL BY GENDER AND AGE IN KOREAN ADULT GROUP. AB - Most internal radiation dose resulting from natural radionuclides is due to radon and radioactive potassium. Total body potassium (TBK) in human body may vary by ethnic group, gender and age. The objective of this study was to measure TBK and body potassium concentration in Korean subjects. Body potassium concentrations of the subjects were measured with a whole-body counter for 283 adult males and 181 adult females. Average TBK value and body potassium level were 111.2 g and 1.5 g kg-1 for males, while for females they were 71.7 g and 1.4 g kg-1. TBK increased with increasing body weight. Body potassium level per body weight was inversely proportional to age in both genders. The annual effective doses due to 40K in the human body of Korean population were calculated to be 0.15 and 0.13 mSv for males and females, respectively. PMID- 28591863 TI - MEASUREMENT OF THE CONTRALATERAL BREAST PHOTON AND THERMAL NEUTRON DOSES IN BREAST CANCER RADIOTHERAPY: A COMPARISON BETWEEN PHYSICAL AND DYNAMIC WEDGES. AB - This research aimed to measure the received photon and thermal neutron doses to contralateral breast (CB) in breast cancer radiotherapy for various field sizes in presence of physical and dynamic wedges. The measurement of photon and thermal neutron doses was carried out on right breast region of RANDO phantom (as CB) for 18 MV photon beams. The dose measurements were performed by thermoluminescent dosimeter chips. These measurements obtained for various field sizes in presence of physical and dynamic wedges. The findings of this study showed that the received doses (both of the photon and thermal neutron) to CB in presence of physical wedge for 11 * 13, 11 * 17 and 11 * 21 cm2 field sizes were 5.92, 6.36 and 6.77% of the prescribed dose, respectively as well as for dynamic wedge were 2.92, 4.63 and 5.60% of the prescribed dose, respectively. The results showed that the received photon and thermal neutron doses to CB increase with increment of field sizes. The received photon and thermal neutron doses to CB in presence of physical wedge were more than dynamic wedge. According to obtained findings, it is suggested that using a dynamic wedge is preferable than physical wedge, especially for medial tangential field. PMID- 28591864 TI - Optimism, pessimism and self-efficacy in female cancer patients. AB - Objective: The aim of this examination was to study whether psychological resource variables (optimism and self-efficacy) decrease when cancer is present and to test the predictive power of these variables for anxiety, depression and quality of life (QoL). Methods: The patient sample was comprised of 354 German women suffering from breast cancer or gynecological cancer. Participants filled in the resource assessment tools Life Orientation Test-Revised and the General Self-Efficacy Scale as well as the Hospital Anxiety and Depression Scale, the Patient Health Questionnaire-4 and the QoL instrument EORTC QLQ-C30 at two time points: (t1) during patients' hospital stay and (t2) 3 months later. Results: The mean scores for optimism (total score: M = 16.2) and self-efficacy (M = 29.8) were even somewhat higher than the corresponding means of the general population. Optimism and self-efficacy were positively correlated with QoL (r between 0.15 and 0.17, P < 0.01) and negatively associated with anxiety and depression (r between -0.17 and -0.36, P < 0.01). However, only optimism was predictive of the t2 anxiety, depression and QoL scores when statistically taking into account the baseline levels of the outcome variables. Conclusions: Having cancer does not generally reduce optimism and self-efficacy on the level of patients' mean scores. Cancer patients with a high level of habitual optimism will adapt to their disease better than pessimistic patients, even if the baseline levels of the outcome variables have been accounted for. PMID- 28591865 TI - Reliability and Accuracy of MRI Laminar Angle Measurements to Determine Intraprocedural Contralateral Oblique View Angle for Cervical or Thoracic Interlaminar Epidural Steroid Injections-Safety Before Accuracy. PMID- 28591866 TI - Effectiveness of Influenza Vaccines in Asthma: A Systematic Review and Meta Analysis. AB - There is uncertainty about the effectiveness of influenza vaccination in persons with asthma and its impact on asthma outcomes, which may contribute to the suboptimal vaccination rates in persons with asthma. This systematic review and meta-analysis involved searching 12 international databases for randomized controlled trials (RCTs) and high-quality quasi-experimental and epidemiological studies (1970-2016). The risk of bias was low for 3 included RCTs. The quality of 3 included observational studies was moderate. The quality of evidence was very low for all study outcomes. Pooled vaccine effectiveness in 1825 persons with asthma from 2 test-negative design case-control studies was 45% (95% confidence interval [CI], 31%-56%) for laboratory-confirmed influenza. Pooled efficacy of live vaccines in reducing influenza was 81% (95% CI, 33%- 94%). Live vaccine reduced febrile illness by 72% (95% CI, 20%-90%). Influenza vaccine prevented 59% 78% of asthma attacks leading to emergency visits and/or hospitalizations. For persons with asthma, influenza vaccination may be effective in both reducing influenza infection and asthma attacks. PMID- 28591868 TI - Video-assisted thoracoscopic thymectomy for non-thymomatous myasthenia gravis: a right-sided or left-sided approach? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was in [patients undergoing video-assisted thoracoscopic thymectomy for myasthenia gravis (MG)] is a [left-sided approach] superior to a [right-sided approach] in terms of [clinical outcome]? Two hundred and fifty-nine papers were found using the reported search. In looking at both procedures, we selected studies with a sizeable number of patients performing or studying both procedures and comparing their outcome. Hence, only 4 studies represented the best evidence to answer the clinical question. The authors, journal, date, country, study type, patient group, relevant outcomes and results of these papers are tabulated. Two studies compared their clinical experience with a right-sided versus a left-sided video assisted thoracoscopic surgery thymectomy approach, while 1 study compared using a bilateral versus a unilateral right-sided approach in patients with non-thymomatous MG. The number of patients studied included 31, 107 and 103 patients, respectively. All 3 studies demonstrated no difference regarding surgical time, intraoperative blood loss, postoperative hospital stay, postoperative complications and therapeutic effects (the last study compared the 5-year complete stable remission rate). All 3 studies concluded that both approaches are feasible, effective and comparable in operative and long-term results for the treatment of non-thymomatous MG. One anatomical study compared both approaches in 10 cadavers, 5 in each group. They studied the size of the specimen resected and visualization of different anatomic sites via each approach. Visualization was superior using the left-sided approach, while a right-sided approach resulted in slightly higher chances of an incomplete resection. The study concluded that a left-sided approach achieves a better chance of radical thoracoscopic thymectomy due to anatomic considerations. In conclusion, despite 1 cadaveric study suggesting that a left-sided approach may achieve more complete resection, possibly due to anatomical considerations, there are no differences in outcomes with either unilateral approach in terms of complications, hospital stay or long-term symptom relief. PMID- 28591871 TI - [Relevance of Heat Health Actions Plans for Preventive Public Health in Germany]. AB - BACKGROUND: Heat waves are among the extreme weather events and represent a growing health hazard for the population in Europe. According to the current climate studies, the probability of an increase and intensification of heat waves has been increasing for years. Particularly affected by exposure to unusually high heat are people whose organism is already weakened by age or illness. As the share of senior citizens in Germany continues to rise as a result of demographic change, the health effects of heat waves are gaining in importance. OBJECTIVE: Heat-induced morbidity and mortality can be effectively countered by information provision and timely initiation of preventive measures. The heat wave of the summer of 2003, which killed around 70000 people across Europe, led to the establishment of national heat warning systems and / or hot weather plans in much of Europe. In Germany, the heat warning system of the German Weather Service was set up nationwide in 2005. Thus, a 2-stage warning process can be comprehensively and timely inform people of an imminent heat wave, whereupon appropriate preventive measures can be initiated. In addition, it is recommended to establish a heat action plan which, in addition to heat warning, also takes into account comprehensive health intervention measures. MATERIALS AND METHODS: This article outlines the background, significance and structure of a heat action plan according to the World Health Organization (WHO). This is based on the guidance document prepared in 2008 and the supplementary documents of the years 2009 and 2011. RESULTS AND DISCUSSION: In order to ensure sustainable protection against heat-related health hazards, the World Health Organization (WHO) recommends the introduction of a national heat action plan for its Member States. There are fundamental differences between a heat warning system and a heat action plan. While the warning of a brief heat period is the central task of the heat warning system, the heat action plan follows an integrative approach that combines short, medium and long-term health protection measures within a common framework. PMID- 28591869 TI - Alternative splicing of CNOT7 diversifies CCR4-NOT functions. AB - The CCR4-associated factor CAF1, also called CNOT7, is a catalytic subunit of the CCR4-NOT complex, which has been implicated in all aspects of the mRNA life cycle, from mRNA synthesis in the nucleus to degradation in the cytoplasm. In human cells, alternative splicing of the CNOT7 gene yields a second CNOT7 transcript leading to the formation of a shorter protein, CNOT7 variant 2 (CNOT7v2). Biochemical characterization indicates that CNOT7v2 interacts with CCR4-NOT subunits, although it does not bind to BTG proteins. We report that CNOT7v2 displays a distinct expression profile in human tissues, as well as a nuclear sub-cellular localization compared to CNOT7v1. Despite a conserved DEDD nuclease domain, CNOT7v2 is unable to degrade a poly(A) tail in vitro and preferentially associates with the protein arginine methyltransferase PRMT1 to regulate its activity. Using both in vitro and in cellulo systems, we have also demonstrated that CNOT7v2 regulates the inclusion of CD44 variable exons. Altogether, our findings suggest a preferential involvement of CNOT7v2 in nuclear processes, such as arginine methylation and alternative splicing, rather than mRNA turnover. These observations illustrate how the integration of a splicing variant inside CCR4-NOT can diversify its cell- and tissue-specific functions. PMID- 28591872 TI - [The role of immunooncology in the treatment of urothelial cancer]. AB - Data published in November 2016 showed a significant survival benefit for the PD 1 antibody Pembrolizumab in the second-line treatment of metastatic urothelial cancer in comparison to standard chemotherapy. Other PD-1/PD-L1 antibodies are being tested in advanced clinical trials. This class of substances will become standard of care from the time of their approval which is expected for 2017 and will replace vinflunine, which is currently recommended in the German guideline. PD-1/PD-L1 directed substances are also being tested as a first line treatment of metastatic urothelial carcinoma. Monotherapy is evaluated as well as combination treatments with CTLA-4 inhibitors of conventional chemotherapy. First data are expected at the end of 2017.A new strategy is the application of PD-1/PD-L1 directed substances in the perioperative treatment of patients with a muscle invasive urothelial carcinoma after complete surgical resection (cystectomy or nephroureterectomy). Two international phase III trials evaluate an adjuvant immunotherapy with nivolumab and atezolizumab. Recruitment will be completed in 2018. PMID- 28591870 TI - Editor's Highlight: Transcriptome Profiling Reveals Bisphenol A Alternatives Activate Estrogen Receptor Alpha in Human Breast Cancer Cells. AB - Plasticizers with estrogenic activity, such as bisphenol A (BPA), have potential adverse health effects in humans. Due to mounting evidence of these health effects, BPA is being phased out and replaced by other bisphenol variants in "BPA free" products. We have compared estrogenic activity of BPA with 6 bisphenol analogues [bisphenol S (BPS); bisphenol F (BPF); bisphenol AP (BPAP); bisphenol AF (BPAF); bisphenol Z (BPZ); bisphenol B (BPB)] in 3 human breast cancer cell lines. Estrogenicity was assessed (10-11-10-4 M) by cell growth in an estrogen receptor (ER)-mediated cell proliferation assay, and by the induction of estrogen response element-mediated transcription in a luciferase assay. BPAF was the most potent bisphenol, followed by BPB > BPZ ~ BPA > BPF ~ BPAP > BPS. The addition of ICI 182,780 antagonized the activation of ERs. Data mining of ToxCast high throughput screening assays confirm our results but also show divergence in the sensitivities of the assays. Gene expression profiles were determined in MCF-7 cells by microarray analysis. The comparison of transcriptome profile alterations resulting from BPA alternatives with an ERalpha gene expression biomarker further indicates that all BPA alternatives act as ERalpha agonists in MCF-7 cells. These results were confirmed by Illumina-based RNA sequencing. In conclusion, BPA alternatives are not necessarily less estrogenic than BPA in human breast cancer cells. BPAF, BPB, and BPZ were more estrogenic than BPA. These findings point to the importance of better understanding the risk of adverse effects from exposure to BPA alternatives, including hormone-dependent breast cancer. PMID- 28591873 TI - [Non-infectious Causes for Digital Bone Marrow Edema]. PMID- 28591867 TI - Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG). AB - Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37 0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity. PMID- 28591885 TI - Uterine Artery Embolization (UAE) for Fibroid Treatment: Results of the 6th Radiological Gynecological Expert Meeting. PMID- 28591884 TI - Consensus meetings regarding uterine artery embolization and focused ultrasound in fibroid treatment: an analysis. PMID- 28591886 TI - MR-Guided Focused Ultrasound in Fibroid Treatment - Results of the 3rd Radiological-Gynecological Expert Meeting. PMID- 28591887 TI - Accuracy of High-Field Intraoperative MRI in the Detectability of Residual Tumor in Glioma Grade IV Resections. AB - Objective To assess the sensitivity/specificity of tumor detection by T1 contrast enhancement in intraoperative MRI (ioMRI) in comparison to histopathological assessment as the gold standard in patients receiving surgical resection of grade IV glioblastoma. Materials and Methods 68 patients with a primary or a recurrent glioblastoma scheduled for surgery including fluorescence guidance and neuronavigation were included (mean age: 59 years, 26 female, 42 male patients). The ioMRI after the first resection included transverse FLAIR, DWI, T2-FFE and T1 - 3 d FFE +/- GD-DPTA. The second resection was performed whenever residual contrast-enhancing tissue was detected on ioMRI. Resected tissue samples were histopathologically evaluated (gold standard). Additionally, we evaluated the early postoperative MRI scan acquired within 48 h post-OP for remaining enhancing tissue and compared them with the ioMRI scan. Results In 43 patients ioMRI indicated residual tumorous tissue, which could be confirmed in the histological specimens of the second resection. In 16 (4 with recurrent, 12 with primary glioblastoma) cases, ioMRI revealed truly negative results without residual tumor and follow-up MRI confirmed complete resection. In 7 cases (3 with recurrent, 4 with primary glioblastoma) ioMRI revealed a suspicious result without tumorous tissue in the histopathological workup. In 2 (1 for each group) patients, residual tumorous tissue was detected in spite of negative ioMRI. IoMRI had a sensitivity of 95 % (94 % recurrent and 96 % for primary glioblastoma) and a specificity of 69.5 % (57 % and 75 %, respectively). The positive predictive value was 86 % (84 % for recurrent and 87 % for primary glioblastoma), and the negative predictive value was 88 % (80 % and 92 %, respectively). Conclusion ioMRI is effective for detecting remaining tumorous tissue after glioma resection. However, scars and leakage of contrast agent can be misleading and limit specificity. Key points . Intraoperative MRI (ioMRI) presents with a high sensitivity for residual contrast-enhancing tumorous tissue during glioma resection.. . Contrast leakage due to bleeding and scars with reactive contrast enhancement can cause possible misleading artifacts in ioMRI, leading to a limited specificity of ioMRI.. . Bleeding control in glioma resection is crucial for successful usage of ioMRO for glioma resection.. Citation Format . Hebetaelmann V, Mager A, Goetz C et al. Accuracy of High-Field Intraoperative MRI in the Detectability of Residual Tumor in Glioma Grade IV Resections. Fortschr Rontgenstr 2017; 189: 519 - 526. PMID- 28591888 TI - ? PMID- 28591889 TI - ? PMID- 28591893 TI - ? PMID- 28591895 TI - ? PMID- 28591898 TI - ? PMID- 28591900 TI - ["Morbus Google" vs. e-Health: A Qualitative Study of Acceptance and Implementation of Online-Aftercare in Inpatient Rehabilitation]. AB - INTRODUCTION: Internet- and mobile-based health interventions (IMIs) e. g. in the form of internet-based aftercare can supplement existing treatments of inpatient rehabilitation. Acceptance presents a key precondition to the utilization and clinical implementation of new technologies and was examined in patients and health professionals with qualitative research methods. METHODS: In 3 inpatient rehabilitation clinics with various diagnostic and age groups, we interviewed n=15 patients individually and n=29 health professionals of various occupational groups in focus groups based on the 'Unified Theory of Acceptance and Use of Technology'. RESULTS: Benefits of online-aftercare were seen in the access to health information, motivation to health promotion or in monitoring or correcting health behavior. Occupational stress was not seen as an area of application. Reservations were expressed in terms of lack of trust in online contact. Overall, acceptance was higher in patients in comparison to health professionals. CONCLUSION: Barriers of uptake or application of IMIs in rehabilitation exceed technical and demographic aspects and provide important information for specific facilitation of acceptance of patients as well as health professionals. PMID- 28591901 TI - [Determinants for the Access to Follow-Up Rehabilitation Concerning Cardiological Patients after Surgery]. AB - OBJECTIVE: The aim was to analyze individual and environmental factors influencing the access to follow-up rehabilitation of cardiological patients after surgery. METHODS: An exploratory, cross-sectional study without intervention was conducted. A standardized questionnaire was used for data collection in two acute care clinics at cardiological and cardiosurgical wards. Multivariate logistic regression was used to measure the influence of different factors on the access to follow-up rehabilitation. In 61.0% of the patients a follow-up rehabilitation was granted. RESULTS: 210 patients were included. The average age was 52.1 years, 81.0% were male. There were significant differences between the groups with and without follow-up rehabilitation concerning age (p=0.018), sex (p=0.007), the PAREMO-scales "Anderungsbereitschaft" (p=0.011) and "Skepsis" (p=0.005) and the aim of rehabilitation to learn skills in dealing with the disease (p=0.043). The Barthel-Index was not significant different between the two groups. The chance to get a follow-up rehabilitation was significantly increased by indications corresponding to the "AHB-Indikationskatalog" (p=0.001; OR=5.76) and after request of the patients to get a follow-up rehabilitation (p<0.001; OR=17.91). DISCUSSION: The access to follow-up rehabilitation was predominantly indication-specific and depended on patients' request of cardiological patients after surgery. A follow-up rehabilitation requires an adequate rehabilitation capacity (Barthel-Index). However the effect of the Barthel-Index on the access to follow-up rehabilitation was not significant. CONCLUSION: It is still in question, to what extent the personal patient's wish can be linked to parameters of rehabilitation capacity. Furthermore it is necessary to develop concepts which increase the influence of rehabilitation capacity on the decision of a follow-up rehabilitation. PMID- 28591902 TI - [The Need for Psychosocial Support of Parents of Children in Neonatal Care]. AB - Background Advances in neonatal care have reduced mortality but increased morbidity in babies born pre-maturely or after high-risk pregnancies. However, this often increases the burden on the family and the parents in particular. A systematic review of the literature was conducted that demonstrated the importance of psychosocial support for parents of children in neonatal care. Methods A systematic search of Pubmed, Psyndex, CINAHI and medpilot was conducted. Reference lists of the included articles were also searched for relevant publications. A free-text search found further publications. Together, 78 publications (from 1975-2015) were included in our review. Results A shift from a biomedical model and child-centred treatment to family-centred care has already taken place in neonatal care. However, there is still a considerable gap between theory and practice. Although there is awareness of the need for psychosocial support of parents, the focus of day-to-day care is still on medical interventions and life-supporting treatment for the child. In particular, while the importance of an assessment of needs as a basis for family-centred psychosocial support appears to be well-known, validated screening instruments are rarely used. In addition, the demand for psychosocial support of parents is not just solely determined by the child's medical risk. Conclusions The results highlight the challenges of delivering individualised psychosocial support to families within a healthcare system of limited resources, with practitioners having to take into account the developing parent-child relationship as well as health economics. In future, psychosocial support should be based on evidence rather than intuition. Attachment theory and research, and health psychology can contribute to this development. PMID- 28591903 TI - Relationship between Partial Uterine Cervical Tissue Excision and Preterm Birth: An Experimental Animal Study. PMID- 28591905 TI - Management of the Third Stage of Labor: How Delayed Umbilical Cord Clamping Can Affect Neonatal Outcome. PMID- 28591904 TI - Racial Disparities in Delivery Gestational Age among Twin Pregnancies. PMID- 28591906 TI - Improving patient information - are the new media already requested? - A questionnaire study at a gastroenterology outpatient clinic. AB - Background Information provided for patients is an essential factor for communication between patients and health-care professionals. To analyze the most used sources of medical information and requested media for patient information, a questionnaire study was initiated. Methods A single-center questionnaire study at an outpatient clinic at a tertiary care hospital. Two hundred participating patients, average age 54.4 years (1:1.5 m:f). Results were displayed in total and as count per participant (i. e., how often is a medium mentioned per participant). Results As a source for general information, printed media are mentioned 112 times (0.56 counts per participant), the Internet 125 (0.62), and television 124 (0.62). As a source for medical information, printed media were mentioned 84 times (0.42) and the Internet 133 (0.67). As the most requested source for additional patient information, printed media were mentioned 105 times (0.53) and medical apps 63 (0.32). Conclusion A majority of our patients regularly use the Internet for medical information. Paper-print media are still highly requested by patients. New media are more often requested in younger patients but still reach the ages for screening programs and therefore offer big opportunities towards patient-doctor communication. By a good mixture of media provided a higher patient satisfaction and adherence could be ensured by the health-care professionals. PMID- 28591907 TI - [Ultrasound in palliative care medicine, Part II]. AB - Complementary to part 1, this review summarizes indications, opportunities and applications of ultrasounds in palliative care medicine. In particular, the following topics are discussed: . Ultrasound as a non-invasive, low-threshold, bedside technique, which uniquely combines diagnostic efficacy and empathy.. . Sonographic surveillance of patients with malignant disease.. . Point-of-care application of ultrasound in palliative care services.. . Ultrasound-guided palliative interventions (drainage of effusions and other therapeutic procedures).. PMID- 28591908 TI - [Unplanned hospitalization in the end stage of liver cirrhosis: predictable or not?] PMID- 28591909 TI - [Testosterone treatment for patients with sarcopenia and liver cirrhosis]. PMID- 28591910 TI - ? PMID- 28591911 TI - ? PMID- 28591912 TI - ? PMID- 28591913 TI - ? PMID- 28591914 TI - ? PMID- 28591915 TI - ? PMID- 28591916 TI - ? PMID- 28591917 TI - ? PMID- 28591918 TI - ? PMID- 28591919 TI - ? PMID- 28591920 TI - ? PMID- 28591921 TI - ? PMID- 28591922 TI - ? PMID- 28591923 TI - ? PMID- 28591925 TI - ? PMID- 28591924 TI - ? PMID- 28591926 TI - ? PMID- 28591927 TI - ? PMID- 28591929 TI - Erratum: Highly Variable Femoral Morphology in Osteoarthritic Chinese: Are Prostheses Today Sufficiently Suitable? PMID- 28591928 TI - [Does Sports Activity Influence Total Knee Arthroplasty Durability? Analysis with a Follow-Up of 12 Years]. AB - Background Total knee replacement is the only surgical option to treat painful degenerative osteoarthritis, restore knee function, improve quality of life, and enable patients to return to sports activity. With an aging population expecting an active life after retirement, patients' expectations of improvement after surgery are increasing as well. In view of the growing demand for higher performance, exercise and athletic activity, clinicians have been increasingly forced to question how much athletic activity a patient may resume after total knee replacement, and what types of athletic activity seem to be acceptable. However, there is currently no consensus on the appropriate intensity of physical activity after total knee arthroplasty or how activity levels affect the rate of revision surgery. Patients, material and methods In a retrospective study with a follow-up period of 12 years, 130 patients were asked about their sport activities 22 months before and after total knee replacement. Based on their answers, the patients were divided into one sports group (group A) and one group without any sports activity (group B). Seven years after surgery the same patients were asked about their sports activity again, and 12 years postoperatively they were additionally asked about whether or not they underwent revision surgery. Results Twenty-two months after total knee replacement 88 (67.7 %) of the 130 patients practiced sports for a minimum of 3 times a week (group A), whereas 42 (32.3 %) patients reported that they practiced no sports (group B). In 2010 - 7 years postoperatively - 60 patients of group A and 27 patients of group B took part in the survey; their levels of sports activity had not changed over the previous 7 years. In 2015, 46 patients out of group A and 21 patients out of group B were questioned. We saw a revision rate of 15.2 % (7 out of 46 patients) in the group with continuous sports activity, whereas we found an increased revision rate of 23.8 % (5 out of 21 patients) in the group without any sports activity 12 years after total knee arthroplasty. Conclusion Our study showed that sports activity after total knee replacement led to a reduced revision rate in the sports group compared with the non-sports group. Therefore, more liberal recommendations should be given to patients regarding athletic activity after total knee arthroplasty. We conclude that moderate sports activities have no negative influence on total knee arthroplasty and may even lead to improved osteointegration with a decrease in osteolytic changes and less prosthesis loosening. PMID- 28591931 TI - High Tibial Osteotomy for the Correction of Varus Knee Deformity. PMID- 28591930 TI - Unusually High Rate of Early Failure of Tibial Component in ATTUNE Total Knee Arthroplasty System at Implant-Cement Interface. PMID- 28591932 TI - The Rationale of Osteotomy around the Knee. PMID- 28591933 TI - Possible involvement of chemokine C-C receptor 7- programmed cell death-1+ follicular helper T-cell subset in the pathogenesis of autoimmune hepatitis. AB - BACKGROUND AND AIM: Recent studies have demonstrated that B cells and follicular helper T (Tfh) cells, which are central regulators of humoral immune response, contribute to the development and progression of autoimmune diseases. Because Tfh cells can be divided into several subsets with distinct functional properties, this study aimed to examine the roles of different subsets of circulating Tfh cells in the immune pathogenesis of autoimmune hepatitis (AIH). METHODS: Thirty five patients with AIH, 28 patients with primary biliary cholangitis, 22 patients with chronic hepatitis B (CHB), and 44 health controls (HC) were enrolled. The frequencies of different Tfh subsets in the blood and liver were examined by flow cytometry and immunohistochemical staining. The function of circulating Tfh subsets was examined after in vitro stimulation. RESULTS: In newly diagnosed AIH patients, the frequency of circulating chemokine C-C receptor 7- programmed cell death-1+ Tfh subset was significantly increased compared with that in CHB patients and HC, significantly correlated with clinical parameters, including serum IgG, prothrombin time and albumin levels, and significantly decreased after corticosteroid treatment. In the liver of AIH patients, the frequencies of activated Tfh subsets were significantly increased and positively correlated with those in the blood. Moreover, the ability to produce interleukin-21 and interleukin-17 from circulating Tfh cells was significantly increased in AIH patients compared with HC. CONCLUSIONS: These results significantly extend our understanding of Tfh subsets in AIH and suggest a potential role of dysregulated chemokine C-C receptor 7- programmed cell death-1+ Tfh subset in the pathogenesis and disease progression of AIH. PMID- 28591936 TI - Corrigendum. PMID- 28591934 TI - Long-term adverse effects after retropubic and robot-assisted radical prostatectomy. Nationwide, population-based study. AB - BACKGROUND AND OBJECTIVES: Surgery for prostate cancer is associated with adverse effects. We studied long-term risk of adverse effects after retropubic (RRP) and robot-assisted radical prostatectomy (RARP). METHODS: In the National Prostate Cancer Register of Sweden, men who had undergone radical prostatectomy (RP) between 2004 and 2014 were identified. Diagnoses and procedures indicating adverse postoperative effects were retrieved from the National Patient Register. Relative risk (RR) of adverse effects after RARP versus RRP was calculated in multivariable analyses adjusting for year of surgery, hospital surgical volume, T stage, Gleason grade, PSA level at diagnosis, patient age, comorbidity, and educational level. RESULTS: A total of 11 212 men underwent RRP and 8500 RARP. Risk of anastomotic stricture was lower after RARP than RRP, RR for diagnoses 0.51 (95%CI = 0.42-0.63) and RR for procedures 0.46 (95%CI = 0.38-0.55). Risk of inguinal hernia was similar after RARP and RRP but risk of incisional hernia was higher after RARP, RR for diagnoses 1.48 (95%CI = 1.01-2.16), and RR for procedures 1.52 (95%CI = 1.02-2.26). CONCLUSIONS: The postoperative risk profile for RARP and RRP was quite similar. However, risk of anastomotic stricture was lower and risk of incisional hernia higher after RARP. PMID- 28591935 TI - Cost analysis of postmastectomy reconstruction: A comparison of two staged implant reconstruction using tissue expander and acellular dermal matrix with abdominal based perforator free flaps. PMID- 28591938 TI - Variants in MODY genes associated with maternal lipids profiles in second trimester of pregnancy. AB - BACKGROUND: Dyslipidemia during pregnancy increases the risk of complications of pregnancy. Lipid profiles have a strong genetic determinant and numerous susceptibility loci have been identified. However, very few studies have focused on the association of lipid-related loci and maternal serum lipids during pregnancy. For the first time, we investigated the association of common variants in three maturity onset diabetes of the young (MODY) genes (HNF1A, HNF4A and HNF1B) with serum lipid concentrations and glucose metabolism related quantitative traits in the second trimester of pregnancy. METHODS: A total of 1797 unrelated Han Chinese pregnant women were included. Three variants in 3'-UTR were selected and genotyped using TaqMan allelic discrimination assays. Multiple linear regression adjusted for age and body mass index was applied for analysis. RESULTS: We found that T allele of rs1169309 in MODY3-HNF1A gene was significantly associated with increased levels of total cholesterol [beta = 0.123 (0.057-0.189); p = 2.7 * 10-4 ] and LDL-C [beta = 0.075 (0.018-0.132); p = 1.0 * 10-2 ]. Rs1169309-TT genotype carriers exhibited with higher levels of apolipoprotein A1 (p = 4.2 * 10-2 ) and ApoB (p = 6.0 * 10-3 ). In addition, correlations between minor C allele of HNF1B-rs2688 and decreased levels of HOMA B (p = 1.4 * 10-2 ), fasting insulin (p = 2.7 * 10-2 ) and HOMA-IR (p = 3.8 * 10 2 ) were identified. The minor C allele of HNF4A-rs6130615 was marginally associated with decreased fasting insulin levels (p = 0.050) and HOMA-IR (p = 0.048). CONCLUSIONS: Variants in MODY genes playe a critical role in lipid and glucose homeostasis. Future studies will be required to further clarify the molecular mechanisms underlying these observed associations. PMID- 28591939 TI - Current and future therapies for advanced pancreatic cancer. AB - Pancreatic cancer remains a deadly disease with a 5-year survival rate of only 8%. Even after surgical resection, most patients have recurrence of their cancer. Over the last 10 years, improvements in chemotherapy regimens led to a doubling in median overall survival. Here we review the management of advanced pancreatic cancer and highlight vaccine therapy as a novel modality of treatment. PMID- 28591940 TI - Cost analysis of postmastectomy reconstruction: A comparison of two staged implant reconstruction using tissue expander and acellular dermal matrix with abdominal-based perforator free flaps. AB - BACKGROUND AND OBJECTIVES: Two staged tissue expander-implant with acellular dermal matrix (TE/I + ADM) and deep inferior epigastric perforator (DIEP) flap are the most common implant and autologous methods of reconstruction in the U.S. Implant-based techniques are disproportionally more popular, partially due to its presumed cost effectiveness. We performed a comprehensive cost analysis to compare TE/I + ADM and DIEP flap. METHODS: A comparative cost analysis of TE/I + ADM and DIEP flap was performed. Medicare reimbursement costs for each procedure and their associated complications were calculated. Pooled probabilities of complications including cellulitis, seroma, skin necrosis, implant removal, flap loss, partial flap loss, and fat necrosis, were calculated using published studies from 2010 to 2016. RESULTS: Average actual cost for successful TE/I + ADM and DIEP flap were $13 304.55 and $10 237.13, respectively. Incorporating pooled complication data from published literature resulted in an increase in cost to $13 963.46 for TE/I + ADM and $12 624.29 for DIEP flap. The expected costs for successful TE/I + ADM and DIEP flap were $9700.35 and $8644.23, which are lower than the actual costs. CONCLUSIONS: DIEP flap breast reconstruction incurs lower costs compared to TE/I + ADM. These costs are lower at baseline and when additional costs from pooled complications are incorporated. PMID- 28591941 TI - [Study on the Effect of Overexpression of miR-18a on Cellular Proliferation and Migration by Targeting ATM in Human Colorectal Cancer Cells]. AB - OBJECTIVES: To study the regulation to colon cancer cellular biological properties through miR-18a targeting ataxia-telangiectasia mutated gene (ATM). METHODS: A target of miR-18a was predicted by using bioinformatics tools. The miR 18a mimics and inhibitors were designed and synthesized. The expression of endogenous miR-18a in colon cancer cell line HCT116 was up-regulated or down regulated by transfection. The effect of overexpression of miR-18a on cellular proliferation, invasion and migration via regulation of ATM gene expression was confirmed in vitro by using qRT-PCR, Western blot, MTT assay, clone forming assay and Transwell method, respectively. RESULTS: ATM was identified as a potential target gene of miR-18a in the bioinformatics analysis. In addition, through transient transfection leading to the overexpression of miR-18a in HCT116 cell, the expression level of ATM was decreased. Down-regulation of HCT116 cell proliferation activity while significantly reducing HCT116 cell clone forming ability, lateral migration ability and longitudinal invasion ability were observed after transfected with miR-18a mimics. All of the changes were related to the overexpression of miR-18a. CONCLUSIONS: miR-18a inhibited the proliferation and migration of colon cance cell HCT116 through negative regulation of ATM expression. PMID- 28591942 TI - [Effects of Sialidase Inhibitor on Proliferation and Apoptosis of Endometrial Cancer Cells]. AB - OBJECTIVES: To explore the effects of sialidase inhibitor on the proliferation and apoptosis of endometrial cancer Ishikawa cells. METHODS: Ishikawa cells were cultured and divided into 2 groups: control group and sialidase inhibitor N Acetyl-2, 3-dehydro-2-deoxyneuraminic acid (DANA) treated group. After the sialidase activity was compared between the two groups, the expression level of matrix metalloproteinases (MMPs), proliferating cell nuclear antigen (PCNA), apoptosis rate and proliferation ability were detected by immunofluorescence staining, flow cytometry or MTT assay. RESULTS: With the treatment of DANA, the activity of sialidase in the cell culture supernatant was suppressed while MMPs expression levels and apoptosis rate of Ishikawa cells were decreased. The expression level of PCNA and cell proliferation showed no statistical differences in two groups. CONCLUSIONS: Sialidase could affect the invasive ability and apoptosis rate of Ishikawa cells, but it seems no effect on cell proliferation. PMID- 28591943 TI - [Heregulin-beta1-induced Glycolysis Promotes Migration of Breast Cancer Cell Line MCF7]. AB - OBJECTIVES: To explore whether heregulin-beta1 (HRG-beta1) can induce glycolysis and the role of HRG-beta1-induced glycolysis in the migration of human breast cancer cell line MCF7. METHODS: MCF7 cells were treated with PBS (PBS group) or HRG-beta1 for 12, 24 and 48 h. Culture media were harvested for glucose uptake and lactate production assays, and cells were collected and lactate dehydrogenase A (LDHA) protein levels were detected by using Western blot. MCF7 cells were treated with PBS (PBS group), HRG-beta1 or HRG-beta1 plus oxamate (OX) for 24 h. Culture media were harvested for glucose uptake and lactate production assays, and cells were harvested and the protein levels of LDHA was detected by Western blot. The wound healing assay was used to detect the migration of MCF7 cells treated with PBS (PBS group), HRG-beta1 or HRG-beta1 plus OX for 48 h. RESULTS: MCF7 cells treated with HRG-beta1 for 12, 24 and 48 h displayed higher levels of glucose uptake, lactate production and LDHA protein levels when the levels reached the peak at 24 h. The differences of glucose uptake, lactate production and LDHA protein levels between PBS group and HRG-beta1 group were statistically significant ( P<0.05). Compared to HRG-beta1 group, the glucose uptake of HRG beta1 plus OX treated group was not significantly different ( P>0.05), but the statistically significant decrease of lactate production and LDHA protein levels were noticed ( P<0.01 and P<0.05). When MCF7 cells were scratched for 48 h, the wound healing rate of control group, HRG-beta1 group and HRG-beta1 plus OX group was (49+/-5.09)%, (100+/-2.21)% and (51+/-4.10)% respectively. The difference of each group was statistically significant ( P<0.001). CONCLUSIONS: HRG-beta1 induces glycolysis via upregualtion of LDHA and HRG-beta1-induced glycolysis promotes the migration of breast cancer cells line MCF7. PMID- 28591944 TI - [MiRNA224 Regulation Role on RKIP Gene Expression and Methylation of miRNA224 Gene Promoter Region in Esophageal Squamous Cell Carcinoma]. AB - OBJECTIVES: To study the expression levels of tumor suppressor gene RIKP and miRNA224 in esophageal squamous cell carcinoma (ESCC) tissues. To determine whether miRNA224 targets RKIP and the methylation status of miRNA224 gene promoter region in esophageal carcinoma. METHODS: The expression levels of RKIP and miRNA224 in ESCC and normal tissue were detected by using immunohistochemistry and real-time qPCR, respectively. Luciferase assay was used to determine the targeting of miRNA224 to RKIP. The methylation status of miRNA224 promoter region was studied by bisulfite sequencing PCR (BSP). RESULTS: In 40 cases of ESCC, RKIP expression was significantly lower than that of normal tissue; miRNA224 expression was higher in ESCC than in paracancerous tissue. Luciferase assay showed that miRNA224 targets RKIP 3'UTR thus inhibit its expression. The miRNA224 gene promoter region was hypomethylated in ESCC. CONCLUSIONS: Compared with normal tissue, in ESCC, RKIP was downregulated, while miRNA224 was upregulated, and the promoter region of miRNA224 gene was hypomethylated. RKIP is the target of miRNA224, which may be closely related to esophageal squamous cell carcinoma. PMID- 28591946 TI - [The Effects of All-trans Retinoic Acid on the Expression of Inflammatory Cytokines and Cartilage Damage Related Protease in Rats with Collagen Induced Arthritis]. AB - OBJECTIVES: To investigate the effects of all-trans retinoic acid (ATRA) on arthritis and the expressions of inflammatory cytokines and cartilage damage related proteases of the collagen-induced arthritis model (CIA) rats in vivo. METHODS: The CIA model of rheumatoid arthritis was induced with C2 and incomplete Freund's adjuvant. The rats were randomly divided into control group, CIA model group and two ATRA dose groups (ATRA 0.50 mg/kg group and ATRA 1.00 mg/kg group). ATRA were given three times per week for six weeks in ATRA groups. Morphological changes, arthritis index (AI) scores, the semi-quantitative scores of pathology damage, the protein expressions of cartilage damage related proteases and the serum levels of TNF-alpha, IL-17A, IFN-gamma, IL-4, IL-10 were observed. RESULTS: The AI scores of ATRA groups were similar to CIA model group ( P<0.05). Apparent morphological disorders in knee and ankle joints were observed in the CIA model group and ATRA 1.00 mg/kg group. The structure of knee joint was improved slightly in ATRA 0.50 mg/kg group. The serum levels of TNF-alpha, IFN-gamma and IL-17A were decreased in both ATRA groups; ATRA also can increase the serum level of IL-4. Compared to CIA model group, the protein expressions of ADAMTS-4, MMP3, MMP1 were decreased in both ATRA groups ( P<0.05). CONCLUSIONS: ATRA, which was able to inhibit pro-inflammatory cytokines secretion, could correct the imbalance of Th1/Th2 and Th17/Treg. ATRA also can reduce the expressions of cartilage damage related proteases, which proved that ATRA may have a beneficial effect on rheumatoid arthritis. PMID- 28591945 TI - [Effect of IFN-alpha2b on COX-2 and Angiogenesis in JAK2V617F Mutation Myeloproliferative Neoplasms]. AB - OBJECTIVES: To investigate the influence of interferon-alpha-2b (IFN-alpha2b) with JAK2 kinase, COX-2 and microvessel density in patients of MPN and the relation of JAK2V617F and COX-2 in human erythroleukemia cell line (HEL) cells. METHODS: Forty-two cases of MPN patients with JAK2V617F mutation of initial treatment were collected from the Frist hospital of Baoding, including the IFN alpha2b treatment group with 17 cases and untreated group with 25 cases. 10 cases of idiopathic immune thrombocytopenic purpura (ITP) patients synchronization were enrolled as controls. JAK2V617F/JAK2 mutation burden of MPN patients was detected by real time PCR (qRT-PCR);the expression levels of p-JAK2, COX-2 and microvascular density (MVD) marked with CD105 inpathological tissues of bone marrow in patients of MPN and ITP were detected by immunohistochemistry. The HEL cells were treated with different concentrations of IFN-alpha2b. The cell proliferation inhibition rate was calculated by CCK-8 test;the apoptosis rate was detected by flow cytometry; cell migration ability was tested by transwell chambers. JAK2 and COX-2 mRNA were detected by semi-quantitative PCR; p-JAK2 and COX-2 protein in HEL cells were detected by Western blotting. RESULTS: The expression levels of p-JAK2, COX-2 protein and MVD in untreated group were significantly higher than those of control groups. p-JAK2, COX-2 and MVD levels were significantly reduced in patients treated with IFN-alpha2b. Cell growth inhibition rates and apoptosis rates raise up by dose of IFN-alpha2b in HEL cells at 48 h.The mRNA expression levels of JAK2 and COX-2 as well as protein expression levels of p-JAK2 and COX-2 had a decreasing tendency with the increase of IFN-alpha2b concentration at 48 h.The migration capacity level of HEL cells which treated with 0.5*10 4 U/L IFN-alpha2b after 24 h was lower than that of control group. CONCLUSIONS: Angiogenesis of MPN and COX-2 were inhibited by IFN alpha2b which regulates JAK2 signal pathway. PMID- 28591947 TI - [Inhibition of Cigarettes Smoke-induced Epithelial to Mesenchymal Transition by the SMO Inhibitor PF-5274857 in Beas-2b Epithelial Cells]. AB - OBJECTIVES: To explore the effects of the Smoothened (Smo) inhibitor PF-5274857 on cigarette smoke (CS)-induced epithelial-mesenchymal transition (EMT) and apply a new idea fororal squamous cell carcinoma (OSCC) treatment. METHODS: Beas-2b cells were used to investigate the CS-induced EMT. Both pretreat and post-treat were performed in the study. In pretreat group, after being pretreated with 3 MUmol/L PF-5274857 for 2 h, cells were cultured with CS for 8 d; In post-treat group, cells were treated by 3 MUmol/L PF-5274857 for 4 d after CS cultrue. Western blot and immunofluorescence were applied to examine the EMT markers E cadherin, vimentin, and smooth muscle actin alpha (alpha-SMA) in Beas-2b epithelial cells. The transwell culture system was used in migration assays. RESULTS: Pretreat Beas-2b cells with PF-5274857 for 2 h can prevent the CS induced EMT for epithelial and mesenchymal markers, as well as migration capacity. Up regulated E-cadherin and down regulated vimentin and alpha-SMA were observed by Western blot. Furthermore Beas-2b cells induced by CS that underwent EMT showed increased E-cadherin and decreased vimentin and alpha-SMA after treatment with PF-5274857 for 4 d. Importantly, the elevated migration capacity level was also decreased. CONCLUSIONS: The Smo inhibitor PF-5274857 has both preventive effect and therapeutic potential against CS-induced EMT. PMID- 28591948 TI - [The Role of HMGN2 in the Development of Periodontitis Dental Plaque]. AB - OBJECTIVES: To determine the role of high mobility group chromosomal protein N2 (HMGN2) in the development of periodontitis plaque biofilm. METHODS: Saliva samples were collected before clinical interventions in patients with periodontitis (25 Mild periodontitis, 25 Moderate periodontitis and 25 Severe periodontitis) and healthy controls ( n=25).Following an estimation of dental plaque index, the level of HMGN2 in saliva was determined by enzyme-linked immunosorbent assay (ELISA).The recombinant human HMGN2 protein was purified and tested, its inhibitive effects on Porphyromonas gingivalis (P.g)growth and formation of P.g bioflim were detected by K-B antibacterial annulus and crystal violet staining, respectively. RESULTS: The healthy controls had lower levels of HMGN2 in saliva than those with periodontitis, especially those with severe periodontitis ( P<0.01).The level of HMGN2 was negatively correlated with dental plaque index ( r=-0.363, P<0.05). HMGN2 inhibited the development of main periodontal bacteria biofilm ( P<0.05). CONCLUSIONS: HMGN2 is involved in the development of periodontitis plaque biofilm and plays an important role in the development of periodontitis. PMID- 28591949 TI - [Detection and Analysis the HPV16 Integration in the Specimens of the Cervical Carcinoma and the Cell Line Siha]. AB - OBJECTIVES: To build the viral integration sites map and verify the integration sites at or near the fragile site. METHODS: PCR method were applied to screen single HPV16 infected cervical carcinoma specimen and the viral integration sites in the specimens of cervical carcinomas and the cell line cells were detected by detection of integrated papillomavirus seguences by ligation-mediated PCR (DIPS PCR). RESULTS: The integration site in cell line Siha was 13q22. The integration sites in the specimens of the cervical cancinomas were randomly located in chromosome 1, 3, 5, 6, 8, 10, 11, 13, 14, 15, 17, 19 as well as in X, but the sites were most likely at or near the chromosome fragile site. The location of the integration sites were at 1p35.1, 5p15.3, 10q24, 13q21-q22 and Xp11.4. By using the softwares CBS prediction servers and BDGP Neural Network Promoter prediction we found that the integration sites were located at the promoter like sequences. CONCLUSIONS: DIPS-PCR can detect the viral integration sites, and the sites are at or near the chromosome fragile sites, and the integration sites may including the promoter to amplify the virus oncogene. PMID- 28591950 TI - [Functional Analysis of DNA Damage Repair Factor WDR70 and Its Mutation in Ovarian Cancer]. AB - OBJECTIVES: To analyze the cellular function of the newly discovered DNA damage repair factor WDR70, and investigate the mutation in ovarian cancer to verify if function loss of the WDR70gene was associated with ovarian cancer. METHODS: The WDR70 gene was silenced by using siRNA technique or overexpressed its wild and mutation type by with lentivirus and plasmid in hunman cells. The subcellular localization and biochemical function of WDR70 was analyzes by indirect immunofluorescence and immunoblotting. The expression level of WDR70 and the mutations of its cDNA was checked with RT-PCR sequencing for 1 normal ovarian tissue and 16 ovarian cancer specimen. RESULTS: We found gene silencing of WDR70 or overexpression of WDR70 mutation type disrupts the phosphorylation level of homologous recombination functional protein RPA32 and the ability of recruitment at DNA damage site of recombinase RAD51, the loss of function of WDR70 also causes the elevation of the chromosome breakage in metaphase. Meanwhile, we also noticed that the existence of multiple mutations in genomic WDR70 in ovarian cancer specimen. CONCLUSIONS: Our results defined that in vitro system, WDR70 is a DNA damage repair gene, silencing of WDR70 or overexpression of WDR70 mutation type disrupts homologous recombination and chromosomal instability; the frequent mutations of WDR70 gene in genome of ovarian cancer specimens could also lead to DNA repair defeat and gene instability. Consequently WDR70 gene could represent an anti-cancer mechanism for ovarian cancer. PMID- 28591951 TI - [Expressions and Significance of PTEN and LKB1 in Non-small Cell Lung Cancer]. AB - OBJECTIVES: To analyze the correlation between the expression of PTEN and LKB1 in non-small cell lung cancer (NSCLC). METHODS: Paraffin blocks of 74 cases of NSCLC patients were collected, and the expression of LKB1 and PTEN were detected by immunohistochemistry. The clinical related index and the correlation with the expression of PTEN and LKB1 were analyzed to explore the expression clinical significance of them. RESULTS: The PTEN and LKB1 expression positive rate were 47.3% and 70.3%, respectively. LKB1 expression negative samples were mostly associated with PTEN negative expression. Statistical analysis showed that LKB1 was positively correlated with PTEN expression ( r=0.287, P=0.017). The expression of PTEN and LKB1 in NSCLC had no relationship with gender, age and pathology type ( P>0.05). The expression of PTEN is closely associated with lymph node metastasis (LNM, P=0.017), invasion ( P=0.008) and clinical stage ( P=0.019). And lack expression of LKB1 was closely associated with tissue invasion ( P=0.043) and clinical stage ( P=0.003). Patients with PTEN and LKB1 positive showed more LNM and/or invasion than those with them negative. CONCLUSIONS: The expression of PTEN and LKB1 may be related to the occurrence and progression of NSCLC, and may have a synergistic effect, and it can be used as a judgment of the prognosis of NSCLC. PMID- 28591952 TI - [Expressions of Livin and PTEN in Cancerous Tissues of Ovary Endometriosis]. AB - OBJECTIVES: To investigate the expressions of Livin and phosphate and tension homology deleted on chromsome ten (PTEN) protein in the cancerous tissues of ovary endometriosis. METHODS: Immunohistochemistry EliVision was used to examine the expressions of Livin and PETN protein in 19 samples of ovary endometriosis cancerous tissues, 30 samples of ovary endometriosis tissues and 30 samples of ovarian benign tumor tissues. RESULTS: The positive expression rate of Livin in ovary endometriosis cancerous tissues (68%) was obviously higher than that in ovary endometriosis tissues (36%) and benign tumor tissues (13%)( P<0.05). The positive expression rate of PTEN in ovary endometriosis cancerous tissues (16%) was obviously lower than that in ovary endometriosis tissues (65%) and benign tumor tissues (80%)( P<0.01). There was no correlations between positive expressions of Livin and age, clinical stage, grading, histological type and lymphatic metastasis of ovary endometriosis cancer ( P>0.05), the same result was also found for PTEN. Livin and PTEN expression presented an obviously negative correlation in ovary endometriosis cancer ( r=-0.559, P=0.001). CONCLUSIONS: Up regulation of Livin expression and down-regulation of PTEN may be involved in the occurrence and development of ovary endometriosis cancerization. PMID- 28591953 TI - [Magnetic Resonance Imaging Tracing the Biodistribution of SPIO-shRNA Molecular Probe in vivo]. AB - OBJECTIVES: To investigate the biodistribution of superparamagnetic iron oxide (SPIO)-shRNA molecular probe by magnetic resonance imaging (MRI) in vivo. METHODS: Six New Zealand white rabbits were injected intravenously with SPIO shRNA molecular probe (9.6 mg Fe/kg) via ear edge vein. The blood samples were collected to analyse the pharmacokinetic parameters through measuring the iron content by atomic absorption spectrometry (AAS) method at 30 min before and 1 min, 3 min, 5 min, 10 min, 15 min, 30 min and at 1, 2, 3, 6, 12, and 24 h after the injection. Six Kun Ming (KM) mice were injected intravenously with SPIO-shRNA molecular probe (4.8 mg Fe/kg). The biodistribution of SPIO-shRNA molecular probe was traced by MRI in vivo. Ninety six KM mice were randomly divided into control group and experimental group: each mouse in experimental group was injected intravenously with SPIO-shRNA molecular probe (4.8 mg Fe/kg). The liver, spleen, kidney, brain and muscle of the control group and the experimental group on 1, 3, 5, 7, 9, 11 and 14 d after the injection were collected. The organ iron content were measured by AAS method and Prussian blue staining in order to observe the distribution of the SPIO-shRNA molecular probe in the main organ. RESULTS: Our results demonstrated that the pharmacokinetics of the molecular probe complied with two-compartment model, and the blood half-life was (3.692+/-0.196) h. The data of MRI showed that the probe were distributed in liver and spleen, and the signs were reduced in accord with the increase of probe's doses in liver and spleen. The probe's metabolism was slow, and the probe was cleared from liver and spleen at 2 weeks after the injection. The results of AAS and Prussian blue staining further testified the results of MRI. CONCLUSIONS: Our data showed the biodistribution of SPIO-shRNA molecular probe in main organs can be traced by MRI in vivo. Meanwhile, it provides important information for the effectiveness of the probe by MRI at tumor in vivo. PMID- 28591954 TI - [The Effect of Emulsified Sevofluran on Muscular Relaxation through Selective Blockage of Peripheral Nerves]. AB - OBJECTIVES: To identify the site that emulsified sevoflurane influences in the nerve system. METHODS: Thirty-six healthy New Zealand rabbits were randomly and equally divided into low concentration emulsified sevoflurane group [4 mL/(kg.h)], medium concentration [6 mL/(kg.h)]group, high concentration group[10 mL/(kg.h)]and intralipid control group. Emulsified sevoflurane was infused through arterial to selectively block peripheral nerves, neuro-muscular junctions and muscle fibers. The anterior tibial muscle resting tensions and muscle contraction forces were compared before and after the infusions. RESULTS: Significant differences of blood sevoflurane pressure between femoral veins and internal jugular veins appeared in rabbits in all the groups ( P<0.05). No significant changes in the resting tension of anterior tibia muscles were found in terms of single contractions and tetanic forces with the low and medium levels of infusion of sevoflurane compared to the base values. High level of infusion of sevoflurane resulted in decreased single contraction forces and tetanic forces of anterior tibia muscles ( P<0.05). CONCLUSIONS: A rabbit model with selective blockage of peripheral nerves was established. Peripheral nerves are not the primary site which low and medium levels of emulsified sevoflurane influence skeletal muscle relaxations. PMID- 28591955 TI - [Analyzing Colonization of Bifidobacteria in Infants with Real-time Fluorescent Quantitative PCR]. AB - OBJECTIVES: In order to know how intestinal Bifidobacteria community could be built in the infants and whether the environmental factors could affect them, the present study was conducted to characterizethe species composition and trace the quantitative changes of intestinal Bifidobacteria of the infants in their early stages with non-culture dependent molecular method. The possible association of Bifidobacteria community of the infants with their health was also discussed. METHODS: Total 16 of full-term newborn infants born between March and April 2013 were recruited for the present study. Fecal samples were collected from them at 1 day, 2 days, 4 days, 7 days, 10 days, 14 days, 28 days, 3 months, 6 months and 1 year after birth. Real-time fluorescent quantitative PCR with genus and species specific premiers was used to detect Bifidobacteria and 8 predominate species in human intestine qualitatively and quantitatively present in these collected fecal samples. RESULTS: Total 136 fecal sample were collected and Bifidobacteria were detected from 93.4% (127/136) of them with the concentration of 1.0*10 5 to 1.0*10 11 CFU/g. Bifidobacteria were found in 83.3% of the fecal samples collected from the first day after birth with more than about 10 5 CFU/g. However, Bifidobacteria were detected relative low until 14 days and were taxonomically belonged only to one or two species. Bifidobacteria were found in almost 100% of the fecal samples collected after birth 28 days with more than 108 CFU/g, and the detected species of Bifidobacteria was increased to 3 species after 28 days to 6 months. All of the fecal samples collected from one year had more than 3 species of Bifidobacteria with high cell counts. Among the detected Bifidobacteria were B.breve 92.1%, B.infantis 66.1%, B. catenulatum 59.8%, B. bifidum 25.2%, B. longum 24.4%, B.dentium 13.4%, B.angulatum 5.5% and B.adolescentis 1.6%, respectively. CONCLUSIONS: The detected Bifidobacteria greatly varied qualitatively and quantitatively after birth to one year which could be considered as the important and sensitive period for Bifidobacteria to colonize and built its communityin the infants. Different from previous studies, the colonization of Bifidobacteria in the tested infants was found delayed and the composition and diversity of Bifidobacteria species was different from other studies. These might result from different deliveryway, feeding pattern and other environmental factors related to the tested infants. PMID- 28591956 TI - [Effects of Human Acellular Amniotic Membrane on Postsurgical Recovery of Nail Beds]. AB - OBJECTIVES: To determine the effects of human acellular amniotic membrane(HAAM) on postsurgical recovery of nail beds. METHODS: Patients undergoing nail surgery were randomly divided into two groups: 19 in the experimental and 19 in the control groups. Patients in the experimental group were given HAAM before the wounds were covered with vaseline gauze the next day after surgery; whereas those in the control group received vaseline gauze dressing only. Ratings of pain were recorded when 1, 4, 8, 12, 24, 36, 48 and 72 h after the dressing was changed. The time when the wounds healed and the nail grew thoroughly were observed. RESULTS: The characteristics of patients in the two groups were similar. The patients in the experimental group reported significantly less pain at 4 h and 48 h than those in the control group ( P<0.05). After dress changing 24 h, pain disappear in the experimental group. The wounds of the patients in the experimental group also healed quicker [(12.37+/-2.48) d] than those in the control group [(17.68+/-2.86) d, P<0.05]. It took (13.95+/-1.72) weeks for the patients in the experimental group to have their nails grown completely, compared with (15.63+/-2.00) weeks for those in the control group ( P=0.016). The experimental group had a similar degree of satisfaction (7.61+/-1.38) towards the cosmetic appearance of their nails compare the control group (7.58+/-1.18, P=0.919). CONCLUSIONS: HAAM can promote healing of surgical wounds on nail beds. PMID- 28591957 TI - [Correlates of Fatigue in Patients with Neuromyelitis Optica]. AB - OBJECTIVES: To determine clinical characteristics associated with fatigue in patients with neuromyelitis optica (NMO). METHODS: A questionnaire survey was conducted in NMO patients, measuring fatigue using the fatigue impact scale (FIS). RESULTS: A total of 64 NMO patients (mean age: 50.0 years; male/female: 3/61) completed the survey: 71.9% were NMO-IgG seropositive and 43 (67.2%) received immunosuppressive treatments. The patients obtained a global FIS score of 64.8+/-36.1, with 13.2+/-8.5, 20.6+/-11.6 and 31.0+/-18.7 for the cognitive, physical and social dimensions, respectively. No significant differences were found in global FIS scores ( P=0.294 9), and cognitive ( P=0.467 1), physical ( P=0.472 2) and social ( P=0.212 6) dimensional scores between those with and without immunosuppressive treatments. Age, sex, serum NMO-IgG, duration of disease and annual relapse rates were neither correlated with global FIS scores ( P>0.05), nor with the three dimensional scores ( P>0.05). The Expanded Disability Status Scale score was positively associated with global FIS scores ( P=0.000 5)and cognitive( P=0.018 7), physical( P=0.000 4) and social ( P=0.000 5)dimensional scores. The frequency of attack was also positively correlated with cognitive dimensional scores ( P=0.007 9). CONCLUSIONS: Disability is associated with cognitive, physical and social dimensions of fatigue. High frequency of attack is positively correlated with the cognitive dimension of fatigues. PMID- 28591958 TI - [Survival of Patients with Metastatic Recurrent Triple-negative Breast Cancer]. AB - OBJECTIVES: To determine factors associated with the survival of patients with metastatic recurrent triple-negative breast cancer (mrTNBC). METHODS: Initial metastatic recurrent (during or after therapy) patients with triple-negative breast cancer (TNBC) confirmed by post-operate pathology in the West China Hospital of Sichuan University were followed up. The accumulative survival rates after recurrence were calculated using Kaplan-Meier method and differences were tested using log-rank tests. Cox proportional hazards regression analyses were performed to identify independent predictors of survival rates. RESULTS: A total of 142 patients were included in this study. They were followed up on average 41.9 months (range: 5.1-189.5 months), and had median post-recurrence survival time of 22.0 months.Tumor diameter, lymph node status, TNM stage, disease-free interval (DFI), numbers of recurrent lesions, brain metastasis, liver metastasis and the rapeutic patterns were associated with the survival of patients. The Cox proportional hazards regression model identified multi-lesions recurrence ( P=0.004), DFI<=12 months ( P=0.010), brain metastasis ( P=0.037) and single-modal therapy (SMT) ( P<0.001) as independent risk predictors of post-recurrence survival. In the patients with local recurrence, multi-modal therapy (MMT) had 53.0%post-recurrence 3-year survival rate compared with 11.4% of SMT ( P=0.024). Similar results were also found in the patients with distant metastases (post recurrence 3-year survival rate 58.1% for MMT versus 29.3% for SMT, P=0.003). CONCLUSIONS: Multi-lesions recurrence, short DFI and brain metastasis are independent risk predictors, while MMT is a protective factor for the survival of patients with mrTNBC. PMID- 28591959 TI - [Learning Curve of Retroperitoneal Laparoscopic Donor Nephrectomy and Risk Analysis of Intraoperative Complications]. AB - OBJECTIVES: To investigate the learning curve of retroperitoneal laparoscopic donor nephrectomy (LDN) and evaluate the risk factors of intraoperative complications with data from a single center. METHODS: We evaluated perioperative data of 527 consecutive kidney donors who received retroperitoneal LDN between April 2009 and April 2014. The patients were divided into two groups according to the learning curve which was determined by the operation time:group 1 (on the learning curve) and group 2 (learning curve completed). RESULTS: The mean operation time was (88.4+/-38.07) min. The asymptote of the surgeon's learning curve for retroperitoneal LDN was achieved at the 100th case. The operation time and the incidence of intraoperative complications in group 1 were significantly higher than those of group 2. When cases completed, body mass index (BMI) and intraoperative complications were correlated to operative time. The incidence of intraoperative complications was 1.90% and BMI was correlated to the incidence of intraoperative complications. When the learning curve was completed, renal artery numbers and right kidney were found being correlated to operative time. CONCLUSIONS: Retroperitoneal LDN is a safe and effective operation method with a low incidence of complications. Technical proficiency in retroperitoneal LDN could be achieved after 100 surgeries. PMID- 28591960 TI - [Diagnostic Value of Immunofixation Electrophoresis and KAP/LAM Ratio in Multiple Myeloma Patients with Renal Injury]. AB - OBJECTIVES: To explore the diagnostic value of immunofixation electrophoresis and Kappa/Lambda (KAP/LAM) ratio in multiple myeloma patients with renal injury. METHODS: The serum of 822 patients of renal disease were collected for the examnation of immunofixation electrophoresis, KAP/LAM ratio, serum immunoglobulin levels and renal function, including serum urea nitrogen (BUN), serum creatinine (Crea), cystatin C (Cys-C) and estimated glomerular filtration rate (eGFR). To analyze the diagnostic value of immunofixation and KAP/LAM ratio in the differentiation of renal injury of multiple myeloma from primary renal injury diseases. RESULTS: M protein was observed in 75 patients (9.1%). The ratio of each type was IgG 49.3%(37/75), IgA 34.7%(26/75), IgM 5.3%(4/75) and LAM 10.7%(8/75). There was significant difference of KAP/LAM ratio between M protein group and non-M protein group. The KAP/LAM ratio was significant higher in KAP group, compared to non-M protein group. Reverse result was obtained in LAM group. There were higher Crea level and lower eGFR value in pure LAM light chain group, compared with IgG, IgA and IgM groups. CONCLUSIONS: Immunofixation electrophoresis and KAP/LAM ratio may play an important role in the diagnosis of multiple myeloma patients with renal injury, so could be early screening markers. PMID- 28591961 TI - [Diagnostic Value of Cystain C in Contrast Associated Acute Kidney Injury after Transcatheter Closure for Children with Congenital Heart Disease]. AB - OBJECTIVES: To investigate the diagnostic value of cystain C (SCys-C) in contrast associated acute kidney injury (AKI) after transcatheter closure for children with congenital heart disease. METHODS: There were 128 children with congenital heart disease (interventricular septal defect or patent ductus arteriosus) underwent transcatheter closure in West China Second University Hospital during 2013. Blood urea nitrogen (BUN), serum creatinine (SCr) and SCys-C were examined before surgery and at 24 and 48 h after surgery. The incidence of AKI was calculated. The children were divided into two groups according to glomerular filtration rate: AKI group (renal function stage 1, renal function stage 2 subgroups) and non-AKI group. Differences in renal function indexes and SCys-C were compared between AKI group ( n=16) and non-AKI group ( n=112), renal function stage 1 and stage 2 subgroups. ROC curve analysis was used to calculate the cut-off value of SCys-C in the diagnosis of AKI . RESULTS: The levels of SCr and SCys-C in AKI group were significantly higher than those in non-AKI group ( P<0.05). However, there was no significant difference in BUN between the two groups ( P>0.05). Only SCys-C had a significant difference between renal function stage 1 and stage 2 subgroups ( P<0.05). The cut-off value of 24 h SCys-C in the diagnosis of AKI was 1.055 mg/L according to area under curve (AUC). AUC indicated that AKI could be diagnosed earlier with SCys-C than SCr ( P<0.05). CONCLUSIONS: The contrast agent could increase the risk of child AKI after transcatheter closure for congenital disease children.SCys-C is an important index for this risk with its cut-off value of 1.055 mg/L at 24 h post-surgery. PMID- 28591962 TI - [Clinical Application of Cardiac Magnetic Resonance Imaging in a Tertiary Referral Hospital in China]. AB - OBJECTIVES: To review clinical application of cardiac magnetic resonace (CMR) imaging in a tertiary hospital. METHODS: A total of 344 medical records were reviewed in relation to the use of CMR imaging over one year period in a tertiary hospital in China. Data regarding indications for CMR imaging, cardiac structure and function, late gadolinium enhancement (LGE), and diagnoses made from CMR imaging were extracted and examined. RESULTS: Detection of heart failure and cardiomyopathies was the most common reason for CMR imaging requests [164 (47.7%) of requests], which was followed by diagnoses of coronary artery disease [79 (23.0%) of requests] and ventricular arrhythmia [65 (18.9%) of requests]. Quantitative analyses were made in 319 (92.7%) cases, with 208 (65.2%) patients being identified with ventricular dilatation and 46 (14.4%) patients being identified with right ventricular dilatation. Apart from 74 (21.5%) cases for which a confirmed diagnosis could not be obtained, CMR imaging assessment corrected 21.2% (73 patients) and confirmed 57.3% (197 patients) of initial referral diagnoses. CONCLUSIONS: CMR imaging is mainly used for structural and functional assessments of hearts, which can help identify abnormalities that are not detected by other imaging modalities. It can provide incremental diagnostic, therapeutic, and prognostic information. PMID- 28591963 TI - [Extensively Porous-coated Distal Fixation Long Stem Prosthesis for Unstable Proximal Femur Fracture with Complex Hip Disease]. AB - OBJECTIVES: To evaluate the clinical results of femoral proximal fracture with complex hip diseases using an uncemented extensively porous-coated long femoral stems. METHODS: 15 cases of femoral proximal fracture with complex hip diseases treated with the uncemented extensively porous-coated long femoral stem were retrospectively reviewed. All patients were followed up at 1, 3, 6, 12 months in the first year postoperatively and once a year from the second year on.Radiological evaluations were conducted using the related criteria, including anteropostierior radiograph of pelvis, anteropostierior and lateral radiograph of proximal femur, and flat tomography of lower limbs.The bone union of the femur fracture, the fixation of prosthesis, and periprosthetic bone loss were evaluated by above-mentioned radiography.The subsidence of femoral prosthesis was compared between 1 month postoperatively and the last follow-up. Complications during the follow-up period was recorded.Clinical outcomes were assessed with Harris Hip Score the last follow-up, including excellent (90-100), good (80-89), moderate (70-79) and bad (<70). RESULTS: The average follow-up period was (45.5+/-21.7) months. All fractures were united at mean 12.6 weeks. There were no femoral stem subsidence and evidence of loosening both radiologically and clinically. The reconstructive offset for femoral fracture was 35.8 mm, while the contralateral offset was 34.8 mm. The average Harris Hip Score was 89.5 at the last follow-up. Moreover, no loosening, dislocation or infection were observed. CONCLUSIONS: Total hip arthroplasty with extensively porous-coated long femoral stem provides a good fracture stability that promotes fracture healing and offers a successful solution for femoral proximal fracture with complex hip diseases. PMID- 28591964 TI - [New Concept for Surviving Sepsis: from Phenomenon to Essence]. AB - Sepsis is a critical clinical syndrome which keep puzzling the medical profession for many years. Recently, the results from several large-scale trials challenged the necessity of early goal directed therapy (EGDT) in surviving sepsis bundle, These trials were not opposed to EGDT but bring new concept that it is essential to utilize therapy with multiple monitoring measures in order to minimize injury while guarantee the safety . Deeper understanding in the pathogenesis of sepsis gives rise to the update of its definition based on vital organ dysfunction. The importance of dynamic monitoring in defining sepsis also need to be emphasized. Developing more effective monitoring measures could provide better treatments, thus improve the prognosis of septic patients. PMID- 28591965 TI - [Predictive Value of Early Changes in Sublingual Microcirculation on Organ Failure of Patients with Septic Shock]. AB - OBJECTIVES: To determine the predictive value of early changes in sublingual microcirculation on organ failure of patients with septic shock. METHODS: Side streamdark field imaging (SDF) videomicroscopy was performed to assess sublingual microcirculation of 34 adult patients at 0 h, 6 h and 24 h after they were diagnosed with septic shock.The patients were subject to sequential organ failure assessment (SOFA24 h-0 h). The patients with DeltaSOFA24 h-0 h>=1 (deteriorated conditions) were compared with those with DeltaSOFA24 h-0 h<1 in regard to sublingual microcirculation and the traditional hemodynamic indicators such as heart rate, mean arterial pressure, central venous pressure, urine output and lactate. RESULTS: No significant baseline differences were found between the two groups of patients in age, sex and acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ), nor any differences in the traditional hemodynamic indicators, as well as dose of vasopressor, infusion of crystalloids, and colloids after septic shock was diagnosed. The patients with deteriorated conditions had lower proportion of perfused small vessels (PPVs) compared with the non-deteriorated patients at 0 h [(75.96+/-10.55)% vs.(84.03+/-10.16)%, P=0.032] and 24 h [(79.43+/-9.23)% vs.(86.32+/-9.02)%, P=0.037]. The ROC analysis showed a greater area under the curve (AUC) for PPVs at 0 h [0.750 (95%CI, 0.586 0.914)] compared with the AUC for Lac at 0 h [0.588 (95%CI, 0.370-0.805) ], albeit a lack of statistical significance ( P>0.05). The incidence of organ failure in the patients with a lower than optimal cut-off point (81.5%) of PPVs was significantly higher than that of those above the cut-off point (71.4% vs. 20.0%). CONCLUSIONS: Changes in sublingual microcirculation (e.g. PPVs) can predict the development of organ failure earlier than systemic hemodynamic indicators in patients with septic shock. PMID- 28591966 TI - [The Value of Early Diastolic Transmitral Velocity to Early Mitral Anulus Diastolic Velocity Ratio for Pulmonary Edema in Severe Sepsis Patients]. AB - OBJECTIVES: To determine the association between the value of early diastolic transmitral velocity to early mitral anulus diastolic velocity ratio (E/E')measured by bedside ultrasound and pulmonary edema in severe sepsis (including septic shock) patients. METHODS: Data were obtained from the critical ultrasound database between November 2014 and August 2015. The severe sepsis (including septic shock) patients were eligible, but those with chronic heart disease or acute heart failure were excluded. Pulmonary edema was quantified by lung ultrasound score. The patients were divided into two groups according to lateral E/E'. E/E'-high group was defined as the lateral E/E'>8, and the others were in E/E'-low group. The severity and distribution of pulmonary edema were compared between the two groups. The correlation analysis and logistic regression analysis were performed to determine whether E/E' was the independent risk factor of pulmonary edma. RESULTS: There were 82 cases included. The lung ultrasound score of E/E'-high group was significantly higher than that of E/E'-low group ( P=0.007). There was no statistic difference of pulmonary edema severity in the bilateral 5 th and 6 th ultrasound exam areas, but E/E'-high group were more severe in the bilateral 1 th to 4 th ultrasound exam areas ( P=0.004). Linear regression analysis demonstrated that E/E' and inferior vena cava diameter were independent risk factors of pulmonary edema (standardized regression coefficients were 0.425 and 0.249, respectively, P<0.05). CONCLUSIONS: E/E' is the independent risk factor of pulmonary edema in severe sepsis and septic shock patients. PMID- 28591967 TI - [Effects of Blood Glucose Levels on Liver Functions in Sepsis Patients]. AB - OBJECTIVES: To explore the effects of blood glucose levels on liver functions in patients with sepsis treated in intensive care unit (ICU). METHODS: We performed a retrospective study on 93 patients with sepsis between March 2014 to January 2015. Patients were divided into two groups according to the initial blood glucose levels when admitted to ICU: high glucose group (blood glucose>10 mmol/L) and normal glucose group(blood glucose<=10 mmol/L). Routine blood test results, liver functions and coagulations function were compared between the two groups. RESULTS: On the first day of ICU admission, patients in normal glucose group had lower blood platelet count, higher total bilirubin (TB) and direct bilirubin (DB) levels, lower high density lipoprotein cholesterol (HDL-C) level, lower low density lipoprotein cholesterol (LDL-C) level, longer prothrombin time (PT), longer international normalized ratio (INR), longer activated partial thromboplastin time (APTT) and lower antithrombin Ⅲ (AT Ⅲ) level ( P<0.05). However, seven days after ICU admission, there were no significant differences between the two groups ( P>0.05). CONCLUSIONS: In patients with sepsis, normal blood glucose level might represent severe liver damage. PMID- 28591968 TI - [Risk Factors for Mortality among Patients with Sepsis Complicated with Active Tuberculosis]. AB - OBJECTIVES: To determine risk factors associated with mortality of patients with sepsis complicated with active tuberculosis (TB) in intensive care units (ICU). METHODS: We reviewed medical records of 61 TB patients whom were admitted to the ICU in West China Hospital of Sichuan University, among whom 19 were dead. Logistic regression models were established to determine predictors of mortality. RESULTS: The acute physiology and chronic health evaluation (APACHE Ⅱ) score, smear-positive sputum, delayed treatment of active TB and acute kidney dysfunction were independent predictors of mortality. CONCLUSIONS: Mortality of patients with sepsis complicated with active tuberculosis is high. APACHE Ⅱ score, smear-positive sputum, delayed treatment of active TB and acute kidney dysfunction are independent predictors of mortality. PMID- 28591969 TI - [Clinical Presentations and Prognostic Factors in Systemic Lupus Erythematosus Patients with Sepsis Admitted to Intensive Care Unit]. AB - OBJECTIVES: To explore the characteristics and prognostic factors associated with the death of systemic lupus erythematosus (SLE) with sepsis in intensive care unit(ICU). METHODS: Clinical and laboratory documents of SLE patients with sepsis from Jan 2010 to Dec 2014 were retrospectively analyzed, including active organ involvement, systemic lupus erythematosus disease activity index (SLEDAI) score, acute physiology and chronic health evaluation (APACHE) Ⅱ score, sites of infection and organisms cultured. Prognostic factors were analyzed by multivariate logistic regression analysis. RESULTS: Included patients were mainly females (86%, 43/50). For all patients, SLEDAI was 15.8+/-6.3; APACHE Ⅱ was 25.8+/-6.5; the mortality rate during ICU hospitalization was 46%. The most common causes of death and admission were multiple organ dysfunction syndrome and respiratory failure, respectively. The most common pathogen was Gram-negative bacteria.Multivariate logistic regression analysis suggested that gastrointestinal bleeding, septic shock and high APACHE Ⅱ score were independent risks for mortality. CONCLUSIONS: Gastrointestinal bleeding, septic shock and high APACHE Ⅱ score were risk factors in SLE patients with sepsis in ICU. PMID- 28591970 TI - [Reference Values for Left Ventricular Myocardial Strains Measured by Feature tracking Magnetic Resonance Imaging in Chinese Han Population]. AB - OBJECTIVES: To establish reference values for left ventricular (LV) myocardial strains in a cohort of healthy Chinese volunteers with feature tracking cardiac magnetic resonance imaging. METHODS: A total of 60 healthy volunteers were recruited, receiving a cardiac magnetic resonance imaging (CMR) examination at 3.0T scanner (Tim Trio, Magnetum, Siemens, Germany). A new feature tracking CMR software (Trufisp-strain, Siemens) was used to analyze left ventricular myocardial strain parameters, including radial, circumferential, longitudinal strain, systolic strain rate, and early diastolic strain rate. RESULTS: The image quality was sufficient to perform strain analysis.The reference values of global strain, global strain rate and segmental strains were obtained. A good inter- and intra-observer agreement was achieved in global strain analysis (except circumferential straininter-observer in apical level), with (37.7+/-9.6)% for LV global mean radial strain, (-18.4+/-3.3)% for circumferential strain and (-15.2+/ 2.3%) for longitudinal strain, respectively.Age was positively correlated with global mean radial strain ( r=0.416, P<0.001) and negatively correlated with early diastolic strain rate (circumferential or longitudinal) and circumferential strain( r=-0.436, P<0.001; r=-0.326, P=0.011; r=-0.273, P=0.035, respectively). Women showed higher circumferential and longituinal strain values and lower systolic circumferential strain rate than men. The strain parameters were correlated with left ventricular ejection fraction (LVEF) ( P<0.05). CONCLUSIONS: FT-CMR (Trufisp-strain software) is a fast, convenient and highly reproducible method for analyzing left ventricular myocardial strains, which can sensitively detect gender and age differences. The reference values of LV myocardial strains can support further studies in the future. PMID- 28591971 TI - [Preparing Bifidobacteria for Quantitative Detections]. AB - OBJECTIVES: To compare different preparation methods for quantitative real-time PCR (qPCR) detection of Bifidobacteria. METHODS: Standard strains of Bifidobacteria were prepared with concentration gradients using strain DNA, PCR product amplification and purification, and plasmid DNA methods. The concentrations of Bifidobacteria were determined with ultraviolet spectrophotometer and real-time quantitative PCR. RESULTS: Greater than 0.99 R 2 in values of standard curves were achieved by all three preparation methods. The plasmid DNA method obtained a higher level of concentration and purity of Bifidobacteria than the other two methods ( P<0.01). CONCLUSIONS: The plasmid DNA method produces high quality preparations and is more suitable for real-time quantitative PCR, which can provide a reference for the molecular biological detection of Bifidobacteria. PMID- 28591972 TI - [One Carrier of Robinsoniella peoriensis in China]. AB - OBJECTIVES: To study morphological feature, biochemical characteristic and antibiotic resistance of Robinsoniella peoriensis (R.peoriensis) strain. METHODS: The clinical R.peoriensis strain was isolated from ananus swab samples being screened in ICU. Biochemical characteristic of the strain was completed by fully automatic microbial identification and drug susceptibility analysis system (BioMerieux, Marcy-l'eE toile, France) with the ANC Vitek2. Antibiotic susceptibility in vitro was performed using agar dilution. RESULTS: The organism was found to be positive to saccharose, beta-galactopyr anosidase indoxyl, alpha arabinosidase and so on, while negative to the others. The susceptibility test in vitro showed that this strain was resistant to clindamycin, rifampicin, moxifloxacin, while sensitive to vancomycin, metronidazole and tetracycline. CONCLUSIONS: R.peoriensis is positive to many biochemical products such as saccharose. The clinical isolate of R.peoriensis strain is resistant to clindamycin, rifampicin and moxifloxacin. PMID- 28591974 TI - Schedules of Controlled Substances: Placement of Acetyl Fentanyl Into Schedule I. Final order. AB - With the issuance of this final order, the Administrator of the Drug Enforcement Administration will maintain the placement of the substance acetyl fentanyl (N-(1 phenethylpiperidin-4-yl)-N-phenylacetamide), including its isomers, esters, ethers, salts, and salts of isomers, esters and ethers, in schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act and is required in order for the United States to discharge its obligations under the Single Convention on Narcotic Drugs, 1961. This action continues to impose the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, acetyl fentanyl. PMID- 28591973 TI - [The Application of Internal Iliac Artery Balloon Occlusion in Pernicious Placenta Previa]. AB - OBJECTIVES: To evaluate the clinical application value of internal iliac artery balloon occlusion in pernicious placenta previa. METHODS: We retrospectively reviewed the medical records of the patients of pernicious placenta previa in a single center from Jan, 2010 to Jan, 2015. The patients were divided into two groups, internal iliac artery balloon occlusion group and the control group without endovascular intervention. Blood loss in operation, volume of transfused blood products, caesarean hysterectomy, operating time, hospital days after operation and postoperative morbidity were compared between the two groups. RESULTS: The balloon occlusion group had significantly less blood loss, the volume of transfused blood products, caesarean hysterectomy, hospital day after operation than the control group had. There was no statistical difference in operating time, intensive care units (ICU), hypotension, infection, hypoxemia, bladder injury, bowel obstruction, neonatal asphyxia between the two groups. The balloon occlusion group had significantly higher rate in coagulopathy, hypoalbuminemia, electrolyte imbalance. Among the patients whose uterus were preserved, the blood loss was not significantly difference between the two groups. Among the patients with the complication of placenta accreta, caesarean hysterectomy was less in balloon group, and blood loss between the two groups was not significantly different. Among the patients without placenta accrete, the blood loss was less in balloon group, and caesarean hysterectomy between the two groups was not significantly different. The risk of hysterectomy in balloon group was related to placenta accreta, uterine arteries engorgement, placental invasive serosa, taking placenta by hand, placental invasive bladder, barrel-shaped thickening of lower uterine segment, unable to remove placenta. CONCLUSIONS: Internal iliac artery balloon occlusion is an effective treatment for pernicious placenta previa. PMID- 28591976 TI - Do Drug Monitoring Programs Reduce the Misuse of Opioids? PMID- 28591975 TI - An Overview of Home-Based Primary Care: Learning from the Field. AB - ISSUE: Homebound and functionally limited individuals are often unable to access office-based primary care, leading to unmet needs and increased health care spending. GOAL: Show how home-based primary care affects outcomes and costs for Medicare and Medicaid beneficiaries with complex care needs.METHODS: Qualitative synthesis of expert perspectives and the experiences of six case-study sites. FINDINGS AND CONCLUSIONS: Successful home-based primary care practices optimize care by: fielding interdisciplinary teams, incorporating behavioral care and social supports into primary care, responding rapidly to urgent and acute care needs, offering palliative care, and supporting family members and caregivers. Practices participating in Medicare's Independence at Home Demonstration saved $3,070 per beneficiary on average in the first year, primarily by reducing hospital use under this shared-savings program. The experience of a risk-based medical group that contracts with health plans and health systems to provide home based care suggests similar potential to reduce health care spending under capitated or value-based payment arrangements. Making effective home-based primary care more widely available would require a better-prepared workforce, appropriate financial incentives to encourage more clinicians to provide house calls to their home-limited patients, and relevant quality measures to ensure that value-based payment is calibrated to meet the needs of patients and their families. PMID- 28591977 TI - Fragmentation in the Delivery of Health Care. PMID- 28591978 TI - How Nurses Affect Health Care Delivery and Patient Health. PMID- 28591979 TI - Investigation into the antimicrobial action and mechanism of a novel endogenous peptide beta-casein 197 from human milk. AB - A novel endogenous peptide cleaved from 197-213 AA of beta-casein, named beta casein 197, was identified by tandem mass spectrometry. beta-casein 197 constituted a significant proportion of the peptide content in preterm milk. This study investigated the antibacterial effects and mechanisms against common pathogenic bacteria. Six bacterial strains were selected for this study: Escherichia coli, Staphylococcus aureus, Yersinia enterocolitica, Listeria monocytogenes, Klebsiella pneumonia and Bacillus subtilis. After synthesis, serial twofold dilutions of beta-casein 197 were added to select for sensitive bacteria. The disk diffusion method and analysis of bacterial staining were used to identify antibacterial effect, while DNA-binding, scanning electron microscopy and transmission electron microscopy were used to explore antimicrobial mechanisms. Disk diffusion showed that E. coli, S. aureus and Y. enterocolitica were sensitive to the beta-casein 197. In addition, live/dead fluorescent staining also confirmed antibacterial effects. Scanning electron and transmission electron microscopy revealed affected extracellular and intracellular structure for three species of bacteria, while a DNA-binding assay showed that the antimicrobial activity did not occur through DNA binding. This study suggests that beta-casein 197 has antimicrobial activity against common pathogenic bacteria in newborns with infection. The peptide induced membrane permeabilization but did not bind to genomic DNA. Based on our findings, beta casein 197 has potential clinical value for preventing infections of premature infants. PMID- 28591980 TI - Dip-Coating Process Engineering and Performance Optimization for Three-State Electrochromic Devices. AB - Titanium dioxide (TiO2) nanoparticles were modified onto fluorine-doped tin oxide (FTO) via dip-coating technique with different nanoparticle sizes, lifting speeds, precursor concentrations, and dipping numbers. Electrodeposition-based electrochromic device with reversible three-state optical transformation (transparent, mirror, and black) was fabricated subsequently by sandwiching a suitable amount of gel electrolyte between modified FTO electrode and flat FTO electrode. Correlation between dip-coating process engineering, morphological features of TiO2 thin films, i.e., thickness and roughness, as well as performance of electrochromic devices, i.e., optical contrast, switching time, and cycling stability, were investigated. The modified device exhibits high optical contrast of 57%, the short coloration/bleaching switching time of 6 and 20 s, and excellent cycling stability after 1500 cycles of only 27% decrement rate by adjusting dip-coating processes engineering. The results in this study will provide valuable guidance for rational design of the electrochromic device with satisfactory performance. PMID- 28591981 TI - [Chinese consensus statement for the management of clinical cardiovascular specimens]. PMID- 28591982 TI - [Clinicopathologic characteristics and prognosis of early onset prostate cancer]. AB - Objective: To observe the clinicopathologic features and prognosis of prostate cancer (PCa) in young men. Methods: Twenty-eight early onset (<=55 years) patients with PCa pathologically confirmed in the Peking University Third Hospital and Peking University Shougang Hospital from January 1st 2000 to August 31st 2016 were collected. There were 18 radical prostatectomy (RP) cases and 10 transrectal prostatic biopsy cases. Contemporaneously, 445 elderly (>55 years) patients were collected, of which 385 had detailed pathological information, were chosen as control group. The mean age of young group was 51 years (29-55 years). Follow-up data for 22 cases were available (1-110 months). The correlation of the clinicopathological features and prognosis were analyzed retrospectively. Results: Presurgical prostatic specific antigen (PSA) level was abnormal in young patients, with 18 cases (64.3%) had elevated fPSA level, 26 (92.9%) had increased tPSA level, and 26 (92.9%) had decreased fPSA/tPSA ratio. Gleason score (GS) was 8 in 10.7% (3/28) of cases, and 9 in 42.9% (12/28) of cases. Of the 18 patients with RP, 17 (94.4%) had pT stage >=pT2c. PSA level (P=0.006) and GS (P=0.001) were positively correlated with pT stage. Family history of PCa in 1st degree relatives was found in 9.1% of the cases. During follow-up, 2 patients died of PCa, 7 patients showed progression within 24 months. There were no significant differences in PSA level and GS between young patients and elderly patients, while the former group was more likely to have incontinence (P=0.023), higher PSA levels (P=0.001), and lower overall survival (P=0.049). Only postsurgical PSA level was found to be negatively associated with overall survival (P=0.030) and cancer specific survival (P=0.021) in young patients. Conclusions: Presurgical PSA level and GS are positively correlated with pT stage of early onset PCa. Compared with elderly patients, young patients are more likely to have incontinence, higher postsurgical PSA level, and lower overall survival. Among all the parameters, only postsurgical PSA level shows an adverse impact on prognosis of early onset PCa. Young patients, especially those with family history, may benefit from studies on the susceptibility loci and phenotype of PCa. PMID- 28591983 TI - [Clinical and pathologic analysis of 414 cases of renal angiomyolipomain in a single institution]. AB - Objective: To study the different clinicopathological characteristics between classic and epithelioid renal angiomyolipoma, and the relationships between clinicopathological characteristics and biological behaviors as basis for clinical treatment. Methods: The clinicopathological and follow-up data for the patients diagnosed with renal angiomyolipoma between 2004 and 2011 were retrospectively reviewed and analyzed. Results: There were 414 cases of renal angiomyolipoma diagnosed over 8 years ago, accounting for 8.1% (414/5 287) of all renal parenchymal tumors. The patients included 122 male and 292 female (male-to female ratio of 1.0?2.4), mean age 44.0 years (range 15-74 years). Of these, 195(47.1%) tumors occurred in the left kidney, 212(51.2%) in the right kidney and seven (1.7%) were bilateral. Clinically, some cases presented with hypochondrial pain, hematuria or palpable masses. Histologically, 394(95.2%) were classic angiomyolipoma, 20(4.8%) were epithelioid angiomyolipoma; 54, 23 and 7 cases had hemorrhage, necrosis and cystic degeneration, respectively; and 5, 30 and 14 cases had perirenal fat invasion, atypical cells and polymorphic/giant tumor cell. There was a positive correlation between atypical cells and epithelioid tumor type, respectively. The other clinicopathological parameters did not correlate with histological type. Follow-up data was available in 360 patients, with follow-up period of 3 to 99 months. One case died from other causes. The remaining patients were free of disease. Conclusions: Angiomyolipoma is a common renal parenchyma tumor. Clinically, it is usually biologically benign. Histologically, it can be either classic or epithelioid types. The epithelioid type should be differentiated from the classic renal cell carcinoma, Mit family translocation renal tumor and renal hemangioblastoma. Atypical cells, more commonly found in the epithelioid angiomyolipoma, do not affect the clinical prognosis of patients. PMID- 28591984 TI - [Clinicopathologic features and expression of OCT4 protein in testicular diffuse large B cell lymphoma]. AB - Objective: To evaluate the expression of OCT4 and SALL4 in testicular diffuse large B-cell lymphoma (DLBCL), and the utility of an immunohistochemical (IHC) panel of OCT4, SALL4 and CD20 in the differential diagnosis of DLBCL and GCT of the testis. Methods: Eighteen cases of testicular DLBCL were selected.IHC method was used to detect the protein expression of CD20, CD3, CD5, CD10, bcl-6, MUM1, Ki-67, bcl-2, c-MYC, OCT4 and SALL4. Results: Among the 18 cases, CD20 and PAX5 were strongly and diffusely expressed in all cases, while CD21, CD3, cyclinD1, SALL4, CD117 and PLAP were all negative. CD5, bcl-2 and c-myc were expressed in 3, 16 and 8 cases, respectively. Ki-67 proliferation index ranged from 40%-95%. Bcl-2 and c-MYC were co-expressed in seven cases. Four cases were GCB-DLBCL and the remaining 14 cases were non-GCB-DLBCL, according to Hans algorithm. Nuclear OCT4 expression was present in two cases, which demonstrated moderate expression in >50% of neoplastic cells. Univariate analysis showed that clinical stage, CD5 and OCT4 expression were relevant to prognosis. Multivariate Cox regression analysis further confirmed that clinical stage, CD5 and OCT4 were independent prognostic factors in patients with testicular DLBCL. Conclusions: Care should be exercised in using OCT4 as the sole marker of germ cell differentiation in the testis. The association of OCT4 and CD5, bcl-2 co-expression raises the question of whether OCT4 expression in DLBCL may reflect more aggressive biology. PMID- 28591985 TI - [Application of immunohistochemistry for p16 and GATA3 and molecular HPV typing in diagnosis of secondary bladder involvement by cervical carcinoma]. AB - Objective: To investigate the expression of p16 and GATA3 and the detection of human papillomavirus (HPV) in secondary bladder involvement by cervical carcinomas. Methods: Sixteen cases of cervical carcinoma with bladder involvement diagnosed from December 2008 to March 2016 were collected and evaluated by light microscopy, immunohistochemistry for p16 and GATA3 detection and PCR-reverse dot blot for molecular typing of HPV. Results: The age of the patients ranged from 25 to 76 years with median of 52 years. Morphologically, 14 cases(14/16) showed tumor nests infiltrating lamina propria or muscle bundles of the bladder. By immunohistochemistry, 15 cases (15/16) were found to be diffusely and strongly positive for p16, and 1 showed patchy staining pattern. Seven cases (7/7) of corresponding original cervical cancers were also diffusely and strongly positive for p16. GATA3 staining was negative in 13 cases (13/16), and focal weak to moderate positivity was detected in 3 cases.Three cases (3/7) of corresponding original cervical cancers showed focal weak to moderate positivity of GATA3. Fifteen cases (15/16) showed concordant high risk HPV-positivity, including HPV16 in 8 cases and HPV31 in one case. Five cases showed co-infection of HPV16 and HPV18. One case showed co-infection with HPV18 and HPV45. Conclusion: Differential diagnosis by p16 or GATA3 alone is of limited value. Combination of immunohistochemistry for p16 and GATA3 and molecular typing for HPV detection are useful to distinguish primary bladder carcinoma from the secondary involvement by cervical carcinoma. PMID- 28591986 TI - [Accurate grading of pancreatic neuroendocrine tumors with Ki-67 index in fine needle aspiration specimens: a comparative cytologic and histologic study]. AB - Objective: To study the cytomorphologic features and determine whether pancreatic neuroendocrine tumors (PanNET) sampled by fine-needle aspiration (FNA) can be accurately graded based on the Ki-67 index when compared to surgical samples. Methods: Corresponding intraoperative (19 cases) or endoscopic ultrasound-guided (3 cases) FNA cytology and surgical tissue specimens were obtained from 22 tumors, which were reviewed and stained for Ki-67 proliferation marker. The cytological samples included more than 200 tumor cells. Samples were graded by scoring the Ki-67 positive index in accordance with the 2010 WHO criteria. The grading scores assigned to the FNA cytology samples were compared with the scores assigned to the corresponding histological samples. Concordance was achieved by using 5% (instead of 2%) as a cut-off value for defining G2 tumors. One cytological sample included less than 500 tumor cells was excluded in the concordance calculation. Results: The cytological smears consisted of uniform, monotonous and isolated cells, loose cellular aggregates and rosette-like formations. Some tumor cells clustered around segments of capillaries. The cells demonstrated distinct cytoplasmic and nuclear features. Mitoses and necrosis were rarely seen. When traditional 2% Ki-67 index cut-off value were used to classify G2 tumors, the majority (86.4%, kappa=0.812, P<0.01) of FNA cytology samples and corresponding surgical tissue specimens demonstrated concordance. When a 5% cut off value was adopted, the concordance rate was 95.5% (21/22, kappa=1.000, P<0.01). Similar concordance rates between the cytological and histological grades were achieved with threshold value of cytological assessment material set at more than 500 or 200 cells. Conclusions: The cytological Ki-67 index in adequate material (>200 tumor cells) is useful in grading pancreatic neuroendocrine tumors, and a cut-off value of 5% showed better predictive value compared with that of 2%. Accurate grading of PanNET is critical for predicting tumor biology, patient prognosis, and making informed decisions regarding patient management and treatment. PMID- 28591987 TI - [Notch signaling pathway participates in the differentiation of hepatic progenitor cells into bile duct epithelial cells and progression of hepatic fibrosis in cholestatic liver fibrosis rat]. AB - Objective: To investigate differentiation direction of hepatic progenitor cells (HPCs) in cholestatic liver fibrosis (CLF), and the role of Notch signaling pathway in the differentiation of HPCs. Methods: A CLF rat model was established by bile duct ligation (BDL) followed by monitoring changes of Notch signal pathway and the cellular origin of proliferating cholangiocytes. After intraperitoneal injection of DAPT (a Notch signaling inhibitor) after bile duct ligation, the progress of liver fibrosis and the proliferation of cholangiocytes after inhibition of the Notch pathway were analyzed. Results: Data showed that bile duct proliferation gradually increased along with inflammatory cell infiltration and proliferating bile duct cells surrounded by abundant collagen in the BDL group. Immunostaining confirmed markedly increased expression of CK19, OV6, Sox9 and EpCAM. In addition, RT-PCR results showed that Notch signaling pathway was activated significantly. Once the Notch signaling pathway was inhibited by DAPT, bile duct proliferation markedly suppressed along with significantly decreased the mRNA expression of CK19, OV6, Sox9 and EpCAM, compared with BDL group [(10.2+/-0.7) vs. (22.3+/-0.8), (7.6+/-1.5) vs. (18.1+/ 3.7), (1.4+/-0.4) vs. (4.1+/-1.1), (1.3+/-0.3) vs. (5.0+/-1.4), respectively, P<0.01]. Moreover, liver fibrosis was also reduced significantly. Conclusion: Notch signaling activation is required for HPCs differentiation into cholangiocytes in CLF and inhibition of the Notch signaling pathway may offer a therapeutic option for treating CLF. PMID- 28591989 TI - [Clinicopathologic characteristics of light chain proximal tubulopathy]. PMID- 28591988 TI - [Correlation between Mic60 haploid insufficiency and cardiac aging in mouse]. AB - Objective: To investigate the role of Mic60 in cardiac aging. Methods: Wild-type and Mic60(+ /-) male mice at age of 4-6 months (young group, n=6) and 18-20 months (aged group, n=9) were used. H&E and Masson staining of frozen and paraffin sections were subjected to morphologic evaluation of the cardiac tissue samples. SA-beta-Gal staining was utilized to detect the activity of senescence associated beta-galactosidase. Western blot was performed to detect the expression of Mic60 and p21 in cardiac tissues. Results: Expression of Mic60 in mouse cardiac tissue increased in an age-dependent manner. Haploid insufficiency of Mic60 resulted in an increased left ventricular wall thickness [(1.32+/-0.09) mm vs.(1.12+/-0.09) mm, P<0.05], cardiomyocyte hypertrophy[(474.9+/-27.6) MUm(2) vs.(358.8+/-48.7) MUm(2), P<0.05] and interstitial fibrosis [ (38.24+/-7.58) *10(3)MUm(2) vs.(25.81+/-4.12)*10(3)MUm(2,) P<0.05], increased activity of SA beta-Gal (2.26+/-0.24 vs.0.25+/-0.05, P<0.01) and higher expression of p21 (P<0.01) in aged mouse cardiac tissue, but not in young mice. Conclusion: Haploid insufficiency of Mic60 leads to cardiac hypertrophy, interstitial fibrosis, increased activity of SA-beta-Gal and higher expression of p21 in aged cardiac tissue in mice, suggesting that Mic60 may prevent cardiac aging. PMID- 28591990 TI - [Histiocytoid breast carcinoma: a clinicopathologic analysis of 4 cases]. PMID- 28591991 TI - [Solitary rectal ulcer syndrome: a clinicopathologic analysis of 2 cases]. PMID- 28591992 TI - [Spindle cell hemangioma: a clinicopathologic analysis of 3 cases]. PMID- 28591993 TI - [Application of three methods of periodic acid-silver-methenamine staining in renal biopsy]. PMID- 28591994 TI - [Introduction of a simple polarization microscope]. PMID- 28591995 TI - [Extrarenal Wilms' tumor: report of a case]. PMID- 28591996 TI - [Multilocular ductal cystadenocarcinoma of prostate: report of a case]. PMID- 28591997 TI - [Hepatic cavernous hemangioma with intravascular large B cell lymphoma: report of a case]. PMID- 28591999 TI - [Microcystic/reticular schwannoma of hard palate mimicking salivary grand tumor: report of a case]. PMID- 28591998 TI - [TFE3 translocation associated epithelioid hemangioendothelioma: report of a case]. PMID- 28592000 TI - [Bronchopulmonary foregut malformation: report of a case]. PMID- 28592001 TI - [Updates on diagnosis and classification of testicular germ cell tumors]. PMID- 28592002 TI - [Research progress in molecular classification of muscle invasive bladder cancer]. PMID- 28592003 TI - [Research progress of Rosai-Dorfman disease]. PMID- 28592004 TI - [Children and adolescents with type 2 diabetes: challenges and opportunities]. PMID- 28592005 TI - [Type 2 diabetes in the child and adolescent: consensus in China]. PMID- 28592006 TI - [Consensus statement on neonatal screening, diagnosis and treatment for glucose-6 phosphate dehydrogenase deficiency]. PMID- 28592007 TI - [Effect of the use of antibiotics controlled by clinical pharmacist in patients with diabetic ketoacidosis]. AB - Objective: To analyze the effect of the use of antibiotics intervened by clinical pharmacist in diabetic ketoacidosis (DKA) patients. Method: This was a prospective clinical study with a historical control group.The group 1 was the control group which was not intervened for antibiotics use from January 2010 to November 2012. The group 2 was the intervention group treated from December 2012 to June 2016. Group 1 was divided into group 1a which included newly-onset diabetes patients and group 1b which included long standing diabetes patients. Group 2 was divided into the similar group 2a and group 2b.Clinical pharmacist supervised the implementation of terms to restrict the use of antibiotics.Changes of the rate of antibiotics use, the length of time of antibiotics use, hospital stay, the cost of antibiotics, etc.were compared. Result: In group 1a and group 2a, the rate of antibiotics use was 85%(107/126) and 31%(58/190)(chi(2)=25.787), the length of time of antibiotics use was 11(7-18)d and 6(4-10)d (U=1 507), the hospital stay was 23(18-27)and 20(6-24)d(U=8 177) , the cost of antibiotics was 1 615(1 000-2 970)and 1 080(504-1 932) yuan ( U=1 783), the differences had statistical significance(P<0.05). In group 1b and group 2b, the rate of antibiotics use was 97% (33/34) and 48% (23/48)(chi(2)=14.222), the length of time of antibiotics use was 8(6-12)d and 5(4-7)d (U=180), the hospital stay was 15(10-21)and 12(8-16)d (U=580), the cost of antibiotics was 2 200(1 356-3 100)and 1 600(705-2 200) yuan (U=223), the differences had statistical significance(P<0.05). Conclusion: Clinical pharmacist intervened use of antibiotics was effective in reducing the use of antibiotics and financial burden. PMID- 28592008 TI - [Analysis of the influence of iron overload in glucose metabolism in thalassemia major patients]. AB - Objective: This study aimed at determining the characteristics of the glucose homeostasis and its relationship with iron overload of the patients with beta thalassemia major (beta-TM). Method: From Sun Yat-sen Memorial Hospital between January 2014 and December 2015, a total of 57 transfusion-dependent beta-TM patients with 5-18 years old were enrolled in this study and fasting blood glucose(FBG) and insulin level, serum ferritin (SF), serum iron, transferrin, total iron binding capacity, unsaturated iron binding capacity were determined.Insulin resistance index (IRI), insulin sensitivity index and beta cell function index (BFI) were also estimated. Besides, in 36 patients cardiac T2* and liver T2* were estimated. Result: (1) Four patients(7%) with beta-TM were diagnosed diabetes mellitus, and 14(24%) had impaired fasting glucose. (2) The incidence of abnormal glucose metabolism was significantly different according to levels of SF and degrees of the cardiac iron overload(chi(2)=9.737, P<0.05; chi(2)=17.027, P<0.05). It rose while the level of SF increased and the degree of cardiac iron overload aggravated. (3) The incidence of abnormal glucose level was not significantly different in cases with different degree of liver iron overload.The severe group of liver iron overload had significantly higher levels of INS, HOMA-betaFI, HOMA-ISI, HOMA-betaFI than the non-severe group (Z=-2.434, 2.515, F=8.658, all P<0.05), while no differences were found in the level of FBG, HOMA-betaFI between two groups. (4) The result of logistic regression analysis indicated that the cardiac T2* was a significant predictor for the incidence of abnormal glucose metabolism in TM patients (P=0.035, OR=1.182%, 95%CI=1.048 to 1.332). Conclusion: The high prevalence of abnormal glucose metabolism in beta-TM patients was mainly closely related with the internal iron overload, especially in organs.The cardiac T2* was an independent risk factor for the incidence of abnormal glucose metabolism in TM patients. PMID- 28592009 TI - [Clinical and gene mutation analysis of three children with late-onset glycogen storage disease type II with hypertrophic cardiomyopathy]. AB - Objective: To investigate the clinical and laboratory features of three children with late-onset type II glycogen storage disease(GSD) who presented with hypertrophic cardiomyopathy and to analyze the effect of five mutations identified on the acid-alpha-glucosidase (GAA) activity and stability. Method: Three cases of children with muscle weakness were included in this study.GAA activity was analyzed in Dried Blood Spot of the patients.DNA was extracted from peripheral blood in all the patients and their parents and subjected to polymerase chain reaction and directly sequencing of GAA gene.Five mutant pcDNA3.1-myc-his-GAA expression plasmids(p.G478R, p.P361L, p.P266S, p.Q323X, p.R672Q) were constructed and transient instantaneously transfected into 293T cells to analyze the enzyme activity and stability of GAA. Result: All the three children had the onset of disease at 3 years or 1.5 years of age.They presented with developmental delay, muscle weakness and hypertrophic cardiomyopathy.GAA activity of 3 patients was 2.65, 3.55 and 1.51 pmol(punch.h)(8.00 98.02)respectively. Genetic analysis found 5 mutations (p.G478R, p. P361L, p. P266S, p. Q323X, p. R672Q), and all of these 3 cases had clinical manifestations and were diagnosed as late-onset type II glycogen storage disease.Five mutant pcDNA3.1-myc-his-GAA expression plasmids were transfected into 293T cells.Five mutant enzyme activities were found to be only 9.9%-22.5% of the wild-type enzyme activity and the protein expression of the five mutants was 32.0%-63.9% compared with the wild type. Conclusion: This study reports 3 children with late-onset GSD II accompanied by hypertrophic cardiomyopathy and compensatory stage of cardiac function in addition to limb muscle weakness.Five pathogenic mutations were identified, and these 5 mutations result in decreased GAA activity and GAA expression by in vitro functional analysis. PMID- 28592010 TI - [Clinical diagnosis and treatment of three cases with hyperornithinemia hyperammonemia-homocitrullinuria syndrome]. AB - Objective: To study the clinical characteristics, methods of diagnosis and treatment of hyperornithinemia-hyperammonemia- homocitrullinuria (HHH) syndrome. Method: From July 2011 to August 2016, 3 Chinese patients with HHH syndrome were enrolled in this study. The clinical course, biochemical features, brain MRI findings, and gene mutations were analyzed. Result: The three patients' age at onset of symptoms was 3 months to 7 years, and the age of diagonosis was 3 years and 10 months to 9 years and 10 months. All of them presented with intolerance to protein-rich foods from the infant period, development retardation and abnormal posture. Case 1 and 2 had moderate mental retardation. Serum ammonia 25-276 MUmol/L (reference range<60 MUmol/L), alanine aminotransferase (ALT) 20-139 IU/L (reference range 9-50 IU/L), ornithine 29.12-99.44 MUmol/L(reference range 15-100 MUmol/L), urinary orotic acid 1.49-29.75 mmol/mol Cr (reference range 0-7 mmol/mol Cr), uracil 6.09-103.97 mmol/mol Cr (reference range 0-1.5 mmol/mol Cr). The cranial MRI revealed lesions in the basal ganglia, abnormal white matter signal, progressive demyelination and cerebral atrophy. On their SLC25A15 gene, a novel homozygous missense mutation c. 416A>G (p.E139G) was identified in case 1, a known pathogenic homozygous nonsense mutation c. 535C>T was found in case 2 and 3. Liver transplantation had been performed when case 1 was 6 years old. Significant improvements were observed in dietary habit, mental and motor functions, and biochemical parameters. After the dietary intervention with the supplements of arginine, L-carnitine, case 2 was improved, spastic paraplegia of case 3 had no mitigation. Liver transplant was recommended. Conclusion: HHH syndrome has an aversion to protein-rich food, and the patients have recurrent vomiting and progressive neurological dysfunction. Clinical diagnosis of HHH syndrome is difficult and patients may present with incomplete biochemical phenotype. The genetic analysis is key for the diagnosis. Depending on their condition, individuals with HHH syndrome can be treated with a low-protein diet, drugs and liver transplantation. PMID- 28592011 TI - [Gas chromatography-mass spectrometry based urinary metabolomics in very low birth weight premature infants]. AB - Objective: To investigate the urinary metabolic spectrum and pathways in very low birth weight (VLBW) premature infants. Method: A prospective case-control study was conducted to collect and compare the data of VLBW premature infants and full term infants from the Sixth Affiliated Hospital of Sun Yet-Sen University in 2014. Within 24 hours after birth, urine specimens in each group were collected. Metabolites of urine samples including amino acid, fatty acid and organic acid were detected using the urease pre-processing and gas chromatography mass spectrometry (GC-MS) technology. Using the orthogonal partial least squares discriminant analysis (OPLS-DA), the biomarkers and differences between the two groups were found. The online metabolic pathway website was explored and multivariable analysis was conducted to investigate the valuable pathways and biomarkers related to the prematurity. Result: A total of 20 VLBW premature infants were enrolled, among whom 11 were male, 9 were female; and 20 full term infants were enrolled, among whom 9 were male, 11 were female. The urinary metabolites were established and compared between the VLBW premature and term infants. The investigation showed that the following nine pathways were enriched: amino-acyl-tRNA biosynthesis(P=0.000), lysine degradation(P=0.007), fatty acid biosynthesis(P=0.008), pyrimidine metabolism(P=0.014), pantothenate and CoA biosynthesis(P=0.022), valine, leucine and isoleucine biosynthesis(P=0.022), lysine biosynthesis(P=0.031), glycerolipid metabolism(P=0.046), and valine, leucine and isoleucine degradation(P=0.031). Almost all the metabolites decreased except for the glyceric acid exhibiting a higher content in the VLBW premature infant. 12 potential biomarkers were explored with the most significant covariance and correlation, within which stearic acid, palmiticacid, myristic acid, beta-amino-isobutyric acid, and uric acid were lower, while myo-inositol, mannitol, glycine, glucose1, glucose2, glyceric acid and N-acetyl-tyrosine were higher in the VLBW premature group compared with the control group. Conclusion: There is a significant difference between the VLBW premature infants and full term infants in the metabolic state and pathways. The urease pre-processing and GC-MS technology followed by the OPLS-DA and multivariable analysis to investigate VLBW premature infants' urinary metabolites is a valuable method to evaluate the patients' metabolism. PMID- 28592012 TI - [Investigation of dose-dependent association between bedtime routines and sleep outcomes in infants and toddlers]. AB - Objective: To investigate the current bedtime routine among Chinese children less than 3 years of age and explore its dose-dependent association with sleep duration and sleep quality. Method: Healthy full-term born children aged 0-35 months were selected by stratified cluster random sampling method from 8 provinces in China following the "Hospital of Province-City-County" sampling technical route during 2012-2013.Brief Infant Sleep Questionnaire(BISQ) was used to assess sleep conditions of these children.Children's personal and family information was obtained by Shanghai Children's Medical Center Socio-demographic Questionnaire.Both of these questionnaires were filled in by parents. The effects of bedtime routine on children's sleep duration and quality were analyzed by multivariate analysis of variance. Result: The children's average age was(12+/ 10) months(n=1 304), of whom 689 were males (52.8%, 689/1 304). There were 48.5%(632/1 304)of the parents reported that their children had not established regular sleep routines. There was a consistent dose-dependent association between bedtime routine and sleep duration, as well as other indicators for sleep quality (all P<0.05). The more regular the sleep routines, the longer the sleep duration, the earlier the children went to sleep, the shorter the sleep onset latency, the fewer the nighttime wakeup and the shorter the nighttime waking.The nighttime sleep duration was significantly longer for those with a bedtime routine 'every night' than those who 'never' had a bedtime routine (9.5(95%CI: 9.4-9.6)vs. 8.9(95%CI: 8.6-9.3)h, t=3.345, P=0.001). Compared with children who never had bedtime routines, children with regular bedtime routines had fewer night wakeup (1.3(95%CI: 1.2-1.4) vs. 2.4( 95%CI: 2.0-2.9), t=3.182, P=0.001) and shorter night waking duration(16.6(95%CI: 14.6-18.8) vs. 59.2 (95%CI: 47.0-72.7)min, t=6.383, P<0.01). Conclusion: The percentage of children who have established regular bedtime routine is low in China. There is significant dose-dependent association between regular bedtime routine and sleep outcomes, especially sleep quality. The more regular the sleep routines, the better the sleep quality. PMID- 28592013 TI - [Reliability and validity of warning signs checklist for screening psychological, behavioral and developmental problems of children]. AB - Objective: To evaluate the reliability and validity of warning signs checklist developed by the National Health and Family Planning Commission of the People's Republic of China (NHFPC), so as to determine the screening effectiveness of warning signs on developmental problems of early childhood. Method: Stratified random sampling method was used to assess the reliability and validity of checklist of warning sign and 2 110 children 0 to 6 years of age(1 513 low-risk subjects and 597 high-risk subjects) were recruited from 11 provinces of China. The reliability evaluation for the warning signs included the test-retest reliability and interrater reliability. With the use of Age and Stage Questionnaire (ASQ) and Gesell Development Diagnosis Scale (GESELL) as the criterion scales, criterion validity was assessed by determining the correlation and consistency between the screening results of warning signs and the criterion scales. Result: In terms of the warning signs, the screening positive rates at different ages ranged from 10.8%(21/141) to 26.2%(51/137). The median (interquartile) testing time for each subject was 1(0.6) minute. Both the test retest reliability and interrater reliability of warning signs reached 0.7 or above, indicating that the stability was good. In terms of validity assessment, there was remarkable consistency between ASQ and warning signs, with the Kappa value of 0.63. With the use of GESELL as criterion, it was determined that the sensitivity of warning signs in children with suspected developmental delay was 82.2%, and the specificity was 77.7%. The overall Youden index was 0.6. Conclusion: The reliability and validity of warning signs checklist for screening early childhood developmental problems have met the basic requirements of psychological screening scales, with the characteristics of short testing time and easy operation. Thus, this warning signs checklist can be used for screening psychological and behavioral problems of early childhood, especially in community settings. PMID- 28592014 TI - [Clinical characteristics of new-onset organ dysfunction in pediatric intensive care unit]. AB - Objective: To investigate the incidence and clinical characteristics of new-onset organ dysfunction of patients in pediatric intensive care unit (PICU). Method: A retrospective observational study identified all patients admitted to the PICU of Shengjing Hospital Affiliated to China Medical University from January 2015 to January 2016. The functional status score (FSS) was evaluated at admission and hospital discharge respectively, and the difference defined as DeltaFSS between the FSS at hospital discharge and the FSS at admission was calculated. According to the initial FSS, the patients were divided into normal group (6-7 scores), mildly abnormal group (8-9 scores), moderate abnormal group (10-15 scores), severe abnormal group (16-21 scores) and extreme severe abnormal group (22-30 scores). According to the primary disease, all cases were divided into cardiovascular disease group, urinary disease group, surgery group, digestive disease group, neurological disease group, respiratory disease group, hematological disease group, poisoning group and other group. According to the FSS domain, all cases were divided into mental status group, sensory group, communication group, motor group, feeding group, respiratory group. The incidence of new-onset organ dysfunction, the case fatality rate and the FSS of each group were calculated. Comparisons were performed using a chi-square test, t test and analysis of variance. Result: The study population included 928 patients (561(60.5%) male, mean age (31.1+/-1.3) months). The incidence of new-onset organ dysfunction was 8.8%(82/928) and the case fatality rate was 1.3%(12/928). The FSS at hospital discharge(scores), DeltaFSS (scores) and the incidence of new-onset organ dysfunction were significantly less in patients in the normal group (6.38+/ 0.17, -0.20+/-0.17 and 1.3%(3/229), respectively) compared to patients in the mildly abnormal group (7.09+/-0.27, -1.39+/-0.27 and 7.2%(12/170), respectively, t=2.36, 3.93, chi(2)=7.39, all P<0.05), patients in the moderately abnormal group (8.86+/-0.28, -2.76+/-0.28 and 10.6%(38/359), t=6.56, 6.91, chi(2)=17.14, all P<0.05), patients in the severely abnormal group(13.56+/-0.88, -4.39+/-0.88 and 24.6%(19/79), t=12.29, 7.13, chi(2)=42.43, all P<0.05) and patients in the extreme severely abnormal group(18.68+/-0.99, -6.59+/-0.91 and 10.9%(10/91), t=18.15, 10.10, chi(2)=13.27, all P<0.05). Significant difference was found regarding the incidence of new-onset organ dysfunction among patients in cardiovascular disease group (27.3%, 24/88), surgery group (9.2%, 6/65), digestive disease group (8.2%, 8/97), neurological disease group (7.7%, 23/299), respiratory disease group (6.9%, 17/248), hematological disease group (3.9%, 2/51) and toxic group (0, 0/61) (chi(2)=37.75, all P<0.05). There were significant differences among primary disease groups regarding the FSS at admission, the FSS at hospital discharge, DeltaFSS, Deltamental status FSS, Deltasensory FSS, Deltacommunication FSS, Deltamotor FSS, Deltafeeding FSS, and Deltarespiratory FSS (F=13.56, 8.97, 10.84, 6.30, 7.37, 7.84, 7.47, 9.97, 10.50, all P<0.05). Conclusion: The incidence of new-onset organ dysfunction in PICU was high. The case fatality rate in patients with new-onset organ dysfunction was high. The functional status at hospital discharge was strongly associated with the functional status at admission. Patients in the cardiovascular disease group had the highest incidence of new-onset organ dysfunction and the most severe deterioration of functional status.More attention must be paid to motor function and respiratory function in cardiovascular disease, respiratory disease and hematological disease. PMID- 28592015 TI - [Clinical manifestations of three cases of surfactant protein C p. V39L mutation]. AB - Objective: To investigate the clinical manifestations of surfactant protein C gene (SFTPC) exon-2 c. 115G>G/T (p.V39L). Method: Patients were screened for the entire coding sequence of SFTPC. Three cases from three children's hospital with mutation in p. V39L were reported. Result: All the three cases were females. The age of onset ranged from 2 months to 7 years. Two cases had recurrent lower respiratory tract infection and failed to thrive. One had chronic anoxia and clubbing fingers. Chest computed tomography (CT) showed diffused ground glass pattern, localized emphysema and intralobular septal thickening. In one case, early sign of cyst formation was also shown on CT. Two were lost to follow-up after alleviation of acute respiratory infection. One was treated with oral low dose azithromycin and nebulized budesonide and terbutaline. She had recurrent lower respiratory tract infection in more than one year of follow-up. Conclusion: Mutations in SFTPC p. V39L cause interstitial lung diseases. Clinical manifestations included recurrent respiratory tract infections, chronic lung disease. Chest CT showing diffused ground glass pattern, localized emphysema, intralobular septal thickening and early sign of cyst formation. The treatment and prognosis need further study. PMID- 28592016 TI - [Efficacy and safety of oseltamivir in children with suspected influenza: a multicenter randomized open-label trial]. AB - Objective: To evaluate the efficacy and safety of oseltamivir in the treatment of suspected influenza in children. Method: A multicenter, randomized and open-label trial was conducted among 229 individuals with suspected influenza which were collected from the clinic of 5 hospitals in Guangdong province (Guangzhou Women and Children's Medical Center, Shenzhen Baoan District Maternity and Child Care Service Center, the Second Affiliated Hospital of Shantou University Medical College, Dongguan Maternity and Child Care Service Centre, Yuexiu District Children's Hospital of Guangzhou) from April to July 2015. They were randomized either to oseltamivir group (oseltamivir 30-75 mg, twice daily for 5 days) or control group who were given symptom relief medicines for 5 days. Result: No significant difference was found between two groups in influenza symptoms of the patients before the treatment(P>0.05). Altogether 229 individuals (114 in oseltamivir group, 115 in control group) were analyzed for efficacy, in which 73 individuals (42 oseltamivir, 31 control), 31.9%, were identified as influenza infected through laboratory test. No significant difference was found between the two groups in the duration of fever although shortened. In the 229 individuals , the cumulative alleviation proportion between oseltamivir and control group was not significantly different (P>0.05): the median duration of illness was 69.9 hours (95% CI 65.3-91.5) in oseltamivir group and 75.4 hours (95%CI 63.9-91. 7) in control group; the median duration of fever was 40.4 hours (95%CI 31.5-53.4) in oseltamivir group and 44.0 hours (95%CI 33.2-50.0) in control group. In the 73 individuals, the cumulative alleviation proportion between oseltamivir and control group was significantly different (P<0.05). The median duration of illness was 61.2 hours (95%CI 48.0-121. 0) in oseltamivir group, being significantly shorter than that of 116.0 hours (95%CI 91.5-175.0) in control group. But it was not significantly different that the median duration of fever was 32.8 hours (95%CI 24.0-47.0 ) in oseltamivir group and 55.8 hours (95%CI 43.6 78.3 ) in control group (P>0.05). And the median duration of fever in 60 individuals (38 oseltamivir, 22 control) was significantly different between two groups(P<0.05), who had finished a course of taking oseltamivir in the 73 individuals, 34.8 hours (95%CI 24.0-48.5 ) in oseltamivir group being significantly shorter than that of 53.3 hours (95%CI 43.6-104.0 ) in control group. There was certain difference in side effects rate between the two groups (oseltamivir 10%, control 2%, P<0.05). The main side-effects were gastrointestinal symptoms (stomachache, diarrhea, poor appetite, vomiting). Conclusion: The duration of illness and fever in suspected influenza patients treated with oseltamivir was shorter than those in the patients treated with no oseltamivir, the difference was not statistically significant, when 31.9% was confirmed with positive result of virus test in suspected influenza in children. But in these patients with positive result of virus test, the duration of illness was significantly shortened with treatment with oseltamivir as compared with no treatment with oseltamivir, and it would be better if full oseltamivir course was completed for reducing the duration of fever. Oseltamivir treatment was safe with mild side effects. PMID- 28592017 TI - [A case of severe congential neutropenia induced by ELA2 gene mutation]. PMID- 28592018 TI - [A case report of anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma characterized by skin panniculitis in children]. PMID- 28592019 TI - [Progres of diagnosis and treatment of congenital lung malformations]. PMID- 28592020 TI - [Research progress of RLR signal transduction pathways blocked by enterovirus 71]. PMID- 28592021 TI - [Primary immunodeficiency diseases with eosinophilia]. PMID- 28592022 TI - [Development and prospects of interventional pulmonology in China]. PMID- 28592023 TI - [Revival and application of rigid bronchoscopy]. PMID- 28592024 TI - [Training and competency in interventional pulmonology--the foundation of professional development]. PMID- 28592025 TI - [Comparison of two quantitative methods of endobronchial ultrasound real-time elastography for evaluating intrathoracic lymph nodes]. AB - Objective: To compare the clinical value of two quantitative methods in analyzing endobronchial ultrasound real-time elastography (EBUS-RTE) images for evaluating intrathoracic lymph nodes. Methods: From January 2014 to April 2014, EBUS-RTE examination was performed in patients who received EBUS-TBNA examination in Shanghai Chest Hospital. Each intrathoracic lymph node had a selected EBUS-RTE image. Stiff area ratio and mean hue value of region of interest (ROI) in each image were calculated respectively. The final diagnosis of lymph node was based on the pathologic/microbiologic results of EBUS-TBNA, pathologic/microbiologic results of other examinations and clinical following-up. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy were evaluated for distinguishing malignant and benign lesions. Results: Fifty six patients and 68 lymph nodes were enrolled in this study, of which 35 lymph nodes were malignant and 33 lymph nodes were benign. The stiff area ratio and mean hue value of benign and malignant lesions were 0.32+/-0.29, 0.62+/-0.20 and 109.99+/-28.13, 141.62+/-17.52, respectively, and statistical differences were found in both of those two methods (t=-5.14, P<0.01; t=-5.53, P<0.01). The area under curves was 0.813, 0.814 in stiff area ratio and mean hue value, respectively. The optimal diagnostic cut-off value of stiff area ratio was 0.48, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.86%, 81.82%, 82.86%, 81.82% and 82.35%, respectively. The optimal diagnostic cut-off value of mean hue value was 126.28, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 85.71%, 75.76%, 78.95%, 83.33% and 80.88%, respectively. Conclusion: Both the stiff area ratio and mean hue value methods can be used for analyzing EBUS-RTE images quantitatively, having the value of differentiating benign and malignant intrathoracic lymph nodes, and the stiff area ratio is better than the mean hue value between the two methods. PMID- 28592026 TI - [Clinical analysis of therapeutic bronchoscopy for tracheal neoplasm]. AB - Objective: To analyze the clinical features in adults with tracheal neoplasm and to evaluate the efficacy of interventional bronchoscopic treatment. Methods: We retrospectively analyzed the clinical features of 43 adults undergoing therapeutic bronchoscopy for tracheal neoplasm diagnosed in Changhai Hospital affiliated to the Second Military Medical University from January 2004 to July 2014.The degree of stenosis, the grade of dyspnea, and Karnofsky performance status scale were evaluated before and after the last procedure. All cases were followed up for 2 years. Results: The 43 cases took (4.6+/-3.9) months on average to be diagnosed since initial symptom. The initial misdiagnosis rate was 41.9%(18/43), and 11 cases were mistaken for asthma (11/43). Malignant tumors were more common than benign tumors for tracheal neoplasm in adults. Squamous cell carcinoma and adenoid cystic carcinoma were the top 2 histological types. Central airway obstruction was completely or partially alleviated with significant relief of dyspnea after the procedures, and all 6 cases of tracheal benign tumors got complete alleviation (the overall response rate was 100%). The grade of dyspnea was 3.2+/-0.7 before and 1.5+/-0.8 after the procedures(t=6.63, P<0.05). The value of KPS was 63+/-12 before and 83+/-11 after the procedures(t=5.78, P<0.05). The 2-year survival rate of 6 cases of tracheal benign tumors was 100.0%, and 1 case of papillomatosis had a relapse. The 1-year survival rate and 2-year survival rate of 37 cases of tracheal malignant tumors were 59.5% and 43.2% respectively with a median survival of 13.6 months. Conclusion: Therapeutic bronchoscopic interventions provide significantly alleviation of central airway obstruction and result in improvement in shortness of breath and quality of life for tracheal neoplasm. PMID- 28592027 TI - [Glyburide prevents pulmonary artery smooth muscle cell proliferation and migration via inhibiting NLRP3 activation]. AB - Objective: To investigate whether glyburide prevents platelet-derived growth factor (PDGF) induced pulmonary artery smooth muscle cells(PASMCs) proliferation and migration via inhibiting nucleotide binding domain leucine-rich repeat containing receptors protein 3(NLRP3) inflammasome activation. Methods: PASMCs were divided into 4 groups: control group, glyburide group, PDGF group and PDGF+ glyburide group. Cell proliferation and migration were assessed by MTT and Transwell respectively. The NLRP3 inflammasome activation was assessed by Western blot. Results: Compared with the control group, the protein expressions of NLRP3, caspase-1 and IL-1beta in PASMCs were increased to (1.38+/-0.09, t=3.998, P<0.001), (1.32+/-0.1, t=3.268, P<0.01)and(1.43+/-0.19) (t=2.096, P<0.05) folds in the PDGF group. Glyburide had no effect on NLRP3, caspase-1 and IL-1beta expression as compared with the control group, while the NLRP3, caspase-1 and IL 1beta were decreased by(20.49+/-7.6)% (t=2.862, P<0.01), (32.94+/-3.44)% (t=4.154, P<0.001) and (24.67+/-5.29)% (t=2.335, P<0.05) in the PDGF+ glyburide group, respectively, as compared with the PDGF group. Compared with the control group, the PASMCs proliferation and migration in the PDGF group were significantly increased to (1.74+/-0.23, t=4.717, P<0.001) and (3.12+/-0.8, t=5.249, P<0.001) folds, respectively. Compared with the control group, glyburide had no effect on PASMCs proliferation and migration. In PDGF+ glyburide group, cell proliferation was reduced by (50.5+/-4.27)% (t=4.462, P<0.001) and cell migration count was lower than in the PDGF group (42.77+/-2.84)% (t=3.716, P<0.001). Conclusion: Glyburide could ameliorate PDGF-induced PASMCs proliferation and migration by inhibiting NLRP3 inflammasome activation. PMID- 28592029 TI - [Effects of noninvasive proportional assist vs pressure support ventilation on respiratory work in chronic obstructive pulmonary disease patients with hypercapnia]. AB - Objective: To investigate the effect of noninvasive proportional assist ventilation (PAV) on respiratory work in chronic obstructive pulmonary disease(COPD) patients, in comparison to noninvasive pressure support ventilation(PSV). Methods: Ten severe COPD patients with hypercapnia during acute exacerbation were examined. The baseline inspiratory pressure of PSV (PS) and the assistance level of PAV(PA) were titrated by patients' tolerance. In addition to the baseline PS and PA, an additional decrease by 25% (PS-=75% PS, PA-=75% PA) or increase by 25% (PS+ =125% PS, PA+ =125% PA) of the assist level were applied to the patients. After the assessment of unassisted spontaneous breathing (SB), the patient was placed on the 6 levels of noninvasive-PSV and noninvasive-PAV in random sequence. Each level lasted at least 20 minutes. Respiratory rate (RR), tidal volume (Vt), and respiratory work(Wex, Wip and Wv) were measured. Asynchrony index (AI) was calculated. Results: During ventilation, Vt was significantly higher with each assist level than with SB. The Vt was significant increased with PS+ than with PA+ . An increase in expiratory work(Wex) and decrease in inspiratory work(Wip) were observed respectively, with the increasing assist level. The inspiratory muscles assessed by Wip were more unloaded at PS compared with PA [PS: (1.59+/-1.27) J/min vs PA: (4.99+/-3.48) J/min P<0.01]. However, the Wex was significantly higher with PS+ than with PA+ [PS+ : (1.17+/ 0.54) J/min vs PA+ : (0.49+/-0.56)J/min, P<0.01]. The AI was increased with the increasing assist level of PSV [PS-: (0.46+/-0.57)%, PS: (1.36+/-1.24)% PS+ : (5.26+/-4.77)]. No asynchrony events were observed at PA- and PA. "Runaway" (expiratory asynchrony) was observed during PA+ [AI: (2.62+/-2.72)%]. Conclusions: Noninvasive-PAV can increase the Vt and decrease the Wip of the COPD patients with hypercapnia and avoid the over-assistance. The "Runaway" will occur at assist level higher than that set by tolerance. Physiological data can monitor the patient's responses and the ventilator-patient interaction, which may provide objective criteria for ventilator setting. PMID- 28592028 TI - [Analysis of 12 cases of exogenous lipoid pneumonia confirmed by pathology]. AB - Objective: To study the etiological, clinical, radiological, diagnostic, therapeutic, and prognostic manifestations of exogenous lipoid pneumonia (ELP), and therefore to improve the diagnosis and treatment of this disease. Methods: The clinical data of 12 cases of ELP confirmed by pathology were retrospectively analyzed. Results: The patients consisted of 9 males and 3 females, with an average age of 73.8 years (range, 44 to 100 years). The underlying diseases were variable, including diseases affecting the general condition (multiple organ failure, chronic heart and renal insufficiency, pemphigoid, etc) and conditions with increased risk of aspiration (sequelae of cerebrovascular disease, Alzheimer's disease, advanced stage of nasopharyngeal carcinoma, paralytic ileus, etc). The 12 cases were all caused by Inhalation of mineral oil. Common symptoms included cough, sputum production and dyspnea. ELP had no special physical signs. Inflammation indexes, such as white blood cell, neutrophil percentage, ESR, C reactive protein, procalcitonin, D-Dimer, and blood lipid levels were usually normal. Radiological features of ELP mainly included consolidation, mass or nodules, with a little ground-glass opacity. Some patients had ventilation and/or diffusion dysfunction. The diagnostic methods included CT-guided percutaneous lung biopsy, thoracoscopy, thoracotomy or autopsy. Histopathological findings showed accumulation of large foamy macrophages in the alveolar spaces, with a few lipid deposition and polykaryocytes. The main treatment of ELP was cessation of lipid material contact. One case died of ELP, 6 died of other coexisting diseases, and the rest 6 improved with treatment and were discharged. The survival patients were all stable during a follow-up of 2-4.5 years. Conclusions: ELP was rare and its clinical manifestation was atypical. Its radiological manifestations were indistinguishable from pneumonia, lung cancer, interstitial lung diseases, etc. Pathological examination was the gold standard for diagnosis, and the preferred means of sampling was bronchoscopy. In cases whose diagnosis could not be confirmed by BALF, CT-guided percutaneous lung biopsy might be considered. The most important treatment is cessation of lipid material contact. The prognosis is good. PMID- 28592030 TI - [Follicular bronchiolitis: report of 3 cases and literature review]. AB - Objective: To improve understanding of the characteristics of follicular bronchiolitis(FB). Methods: The clinical data of 3 patients with FB confirmed by thoracoscopic lung biopsy were retrospectively analyzed. A literature search was performed with "follicular bronchiolitis" as the key word in China Knowledge Resource Integrated Database, Wanfang and PubMed, Ovid Database. The time interval was from January 1947 to December 2015. Related articles of FB were retrieved and the clinical, radiographic characteristics and prognosis were analyzed. Results: Among the 3 patients, 1 was male and 2 were female, aging 32 55 years. Two patients were asymptomatic, and 1 patient presented with fever, cough and dyspnea. Two patients showed normal pulmonary ventilatory function with decreased diffusive function, and 1 patient showed normal pulmonary function. The predominant HRCT findings were bilateral multiple small nodules and cystic opacities, patchy ground-glass opacities, reticular opacities and traction bronchiectasis. The pathological examination by thoracoscopic biopsy revealed bronchiolar and peribronchiolar lymphoid follicles. All patients were treated with corticosteroids, with 2 patients receiving immunosuppressants. Follow-up HRCT after 1-2 months showed no improvement, and further follow-up HRCT after 2-4 years revealed no change in 2 patients while the other patient had increased pulmonary nodules and cystic opacities. Seventeen articles concerning FB with complete records were included in the literature review. A total of 64 patients were reported in these articles. The typical images were bilateral multiple small nodules and ground-glass opacities, reticular opacities, and cystic opacities. The majority of patients improved after treatment of corticosteroids and (or) immunosuppressants. But our 3 cases showed no improvement. Conclusions: FB is a rare small airway disease which has non-specific clinical manifestations and pulmonary function. The most common imaging findings are bilateral multiple small nodules, with cystic opacities, ground-glass opacities, and reticular opacities. Surgical thoracoscopic biopsy can get ideal specimen which is useful for diagnosis. The curative effects of corticosteroids or immunosuppressants on FB need to be further clinically investigated. PMID- 28592031 TI - [The stimulation of human pulmonary artery endothelial cells by cigarette smoke extract contributed to cell senescence and induced human pulmonary artery smooth cell migration]. AB - Objective: To observe the senescent effect of human pulmonary arterial endothelial cells (HPAEC) stimulated by cigarette smoke extract (CSE) and the effect of secretion of senescent cells on human pulmonary arterial smooth muscles cell (HPASMC) proliferation and migration. Methods: HPAEC was treated with different concentrations of CSE in vitro and cell proliferation was determined by CCK8, senescence cells analyzed by detecting the beta-gal activity, and the senescent proteins of cells measured by Western blot. The concentration of senescence-associated secretory phenotype (SASP) was detected by ELISA and the expression of MCP-1 and TGF-beta1 was measured by Real-time PCR. The number of the proliferated cells was measured by Transwell assay and immunoflurescence. Results: The HPAEC was aging with the stimulation concentration of CSE increasing and the stimulation time prolonging (P<0.05). Western blot indicated that the senescent associated protein p53 or p21 increased markedly after 48 h and 72 h CSE-exposure (n=3, P<0.05). The SA-beta-Gal staining showed that the number of senescent cells increased as the exposure time prolonged. Compared with the control group, cell viability of 48 h group(1.8+/-0.1) and 72 h group (1.8+/-0.1) decreased significantly. The flow cytometry showed a significant difference between the CSE group(14.1+/-1.2) and the control group(28.5+/-1.8) in S phase(P<0.01), indicating cell cycle arrest. The SASP was increasing as the CSE exposure prolonged. Compared with the control group(177+/-39), the 48 h group(460+/-43) and the 72 h group(609+/-64) showed a marked increase in MCP 1(P<0.05). For TGF-beta1, it had a same tendency and a significant difference between the control group(121+/-18) and the 48 h group(413+/-32) or 72 h group(606+/-67, both P<0.05). In the meantime, the bFGF increased after 48 h stimulation(291+/-13, P<0.05). Besides MCP-1, TGF-beta1 showed a significant difference between the control group and the 72 h CSE-exposure group (P<0.01). Premature cells could secrete SASP which induced HPASMC proliferation. After different times of conditioned medium stimulation, HPASMC proliferated especially at 72 h(P<0.05) . The immnoflorescence and Transwell assay confirmed this finding. Conclusion: CSE could induce senescence of HPAEC and SASP production which improved HPASMC proliferation and migration. PMID- 28592032 TI - [Tracheobronchomalacia and excessive dynamic airway collapse]. PMID- 28592033 TI - [Advances in chronic obstructive pulmonary disease and epigenetics]. PMID- 28592034 TI - [Chemokines and tuberculosis]. PMID- 28592035 TI - [Evaluate the role of the guidelines from the development of "Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers" in China]. PMID- 28592036 TI - [Undefined invasive fungal disease: a perspectie from the Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers]. PMID- 28592037 TI - [A prospective control study of Saccharomyces boulardii in prevention of antibiotic-associated diarrhea in the older inpatients]. AB - Objective: To study the value of Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in older inpatients. Methods: A total of 163 older patients who were treated with wide-spectrum antibiotics at least three days during January 2014 to December 2015 were randomly divided into control and study group. In study group, 81 patients were administrated with oral Saccharomyces boulardii 500 mg twice a day for 21 days. The control group was of no intervention. Morbidity rate of antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea, frequency and duration of diarrhea were recorded. Results: The incidence of antibiotic-associated diarrhea in study group was significantly lower than that in control group [14.8%(12/81) vs 28.0%(23/82), P<0.05], whereas no difference was seen in the incidence of Clostridium difficile associated diarrhea [3.7%(3/81) vs 4.9%(4/82), P>0.05] in two groups. The frequency and duration of diarrhea in the study group were significantly lower and shorter than those in control group[(4.3+/-1.7) times/day vs (6.9+/-2.0) times/day; (3.0+/-1.1) days vs (5.7+/-1.8) days, both P<0.01]. Conclusion:Saccharomyces boulardii may reduce the incidence of antibiotic associated diarrhea therefore improving the symptom of diarrhea in older inpatients. PMID- 28592038 TI - [The application of captopril challenge test in the diagnosis of primary aldosteronism]. AB - Objective: To evaluate the value of captopril challenge test (CCT) in the diagnosis of primary aldosteronism (PA). Methods: A total of 674 patients [(45.0+/-13.7) years, men 341, women 333] admitted to Peking Union Medical College Hospital from 2000 to 2015 were analyzed. Among them, 222 subjects were with essential hypertension (EH), 28 were with pheochromocytoma (PHEO), 246 were with idiopathic hyperaldosteronism (IHA) and 178 were with aldosterone producing adenoma (APA). All patients received CCT. 24 h urine sodium was measured in partial patients. Plasma renin activity (PRA), aldosterone (ALD) were detected. Results: Compared with EH [PRA: before 0.5(0.2, 0.9) MUg.L(-1).h(-1,) after 0.8(0.4, 1.5) MUg.L(-1).h(-1;) ALD: before (393+/-122) pmol/L, after (360+/-97) pmol/L] and PHEO [PRA: before 0.3(0.1, 0.9) MUg.L(-1).h(-1,) after 0.4(0.1, 1.6) MUg.L(-1).h(-1;) ALD: before (396+/-108) pmol/L, after (374+/-114) pmol/L], lower levels of PRA and higher levels of ALD before and after CCT were observed in PA patients [PRA: before 0.1 (0.1, 0.2) MUg.L(-1).h(-1,) after 0.1 (0.1, 0.2) MUg.L( 1).h(-1;) ALD: before (468+/-216) pmol/L; after (457+/-199) pmol/L]. After CCT, the suppression rate of ALD [2.8% (-8.8%, 15.4%) vs 6.6% (-4.3%, 17.6%)] and increasing rate of PRA [0(0, 50%) vs 50%(0, 200%)] in PA patients were lower than those in EH patients. The ALD/PRA ratio (ARR) were higher in PA than that in EH or PHEO patients. In the EH subjects, ALD levels of seated posture were higher than those of recumbent posture both before and after receiving captopril, but with no changes in ARR after CCT. No significant differences in ALD and ARR (before and after receiving captopril) were observed between seated and recumbent position in the PA group. The ARR after CCT tended to decrease in EH subjects with elevated urine-sodium compared with those with normal urine-sodium. No changes could be viewed in ALD and PRA levels between normal urine-sodium and elevated urine-sodium groups among APA, IHA and EH patients either before or after CCT. Among patients with APA, the ALD levels before CCT and the ARR after CCT were lower in the patients with AngiotensionII(AngII) reactive than those without. A ROC curve analysis suggested that the optimal cutoff value was 46.2 (ALD unit: ng/dl; PRA unit: MUg.L(-1).h(-1)) for ARR after challenge in diagnosing PA, with the sensitivity of 88.7% and specificity of 84.8%. Conclusions: ARR after 25 mg captopril had high sensitivity and specificity in diagnosis of PA with the cutoff of 46.2. Seated CCT could replace recumbent CCT as a more confirmatory test. The PRA increasing rate should be taken into consideration when diagnosis of PA. PMID- 28592039 TI - [The prevalence of metabolic syndrome among adults in rural areas of Ningxia Hui autonomous region]. AB - Objective: To investigate the prevalence of metabolic syndrome (MS) among adults in rural areas of Ningxia Hui autonomous region. Methods: A cross-sectional study was conducted in 10 639 adults enrolled with a multistage method from Jingyuan County. The MS was identified according to Chinese type 2 diabetes prevention guide (2013). Results: Among all the subjects, 17.4% of them met the MS definition with the standardized prevalence of 14.7% after adjustment of sex and age. The prevalence and standardized rate of MS in men were 19.9% and 17.3%, and in women were 15.3% and 13.5%.The prevalence of MS in men was higher than that in women(P<0.001) and increased with aging in both genders. The prevalence and standardized rate of abdominal obesity, hyperglycemia, hypertension, high triglycerides, and low HDL-C were 19.5% and 16.7%, 15.0% and 12.9%, 42.0% and 37.1%, 25.8% and 23.1%, 28.5% and 27.7%, respectively. The rate of abdominal obesity was higher in women than in men (20.5% vs 18.2%, P=0.004), whereas the rate of hypertension, high triglycerides, and low HDL-C were higher in men than in women (all P<0.01). The prevalence of having one parameter of the MS was 68.4%. Conclusion: The prevalence of MS is higher in rural areas of Ningxia Hui autonomous region, suggesting that a series of comprehensive prevention measures should be carried out to prevent and control the MS so as to improve the public health conditions in rural areas. PMID- 28592040 TI - [Surgical treatment of severe, refractory hemorrhagic cystitis following allogeneic hematopoietic stem cell transplantation: a report of 17 patients]. AB - Objective: To investigate the clinical effect and safety of surgical treatment for severe, refractory hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Patients with severe HC, who were admitted to Peking University Institute of Hematology from January 2010 to December 2015, were enrolled in this study.All patients were refractory to medical managements and received bladder surgery including mucous electrocoagulation and/or selective transcatheter arterial embolization. Results: A total of 17 patients with severe HC (grade III, n=5; grade IV, n=12) received surgical treatment, including 11 embolization and 18 mucous electrocoagulation.The median time from allo-HSCT to surgery was 107 d (46-179 d) and 75 d after HC.Eight patients only received embolization.Four patients only received mucous electrocoagulation.Five patients were given combined embolization and electrocoagulation.HC was cured in 11 patients, improved in 1 patient, which corresponded to a response rate of 70.6% and complete remission rate of 64.7%.Five patients didn't respond to these methods.In patients with response, macroscopic hematuria disappeared 3 to 10 days after treatments whereas microscopic hematuria vanished after 25 to 32 days.Both procedures were well tolerated and no severe adverse effects were observed. Conclusion: Surgery of bladder mucous electrocoagulation and/or selective arterial embolization are safe and effective for severe HC. PMID- 28592042 TI - [The significances of peripheral neutrophils CD(55) and myeloperoxidase expression in patients with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody associated vasculitis]. AB - Objective: To investigate the expression of CD(55) and myeloperoxidase (MPO) on neutrophils in patients with MPO-specific anti-neutrophil cytoplasmic antibody associated vasculitis(MPO-AAV), and analyze the relationship between the expression and clinical manifestation. Methods: Forty untreated patients with active MPO-AAV (patient group) and 30 healthy volunteers (control group) were enrolled in this study. The CD(55) on neutrophils and both membrane and cytoplasmic MPO were detected by flow cytometry. Serum fragment-from the activated complement factor B(Ba) and MPO were measured by ELISA. The clinical activity of vasculitis was valued by Birmingham vasculitis activity score-version 3(BVAS-V3). The significance of laboratory data was evaluated by Spearman correlation test and multivariate linear regression analysis. Results: (1)The mean fluorescence intensity(MFI) of CD(55) expressed on neutrophils was significantly higher than that in control group[4 068.6+/-2 306.0 vs 2 999.5+/-1 504.9, P=0.033]. Similar results of serum MPO and Ba in patient group were found compared to controls [500.0(381.0, 612.7) IU/L vs 286.9(225.5, 329.1) IU/L, P<0.001; 35.2(25.2, 79.5) ng/L vs 18.0(15.0, 28.0) ng/L, P<0.001], respectively. However, MIF of cytoplasmic MPO in patients was significantly lower than that of control group(1 577.1+/-1 175.9 vs 3 105.3+/-2 323.0, P=0.003) . (2) In patient group, cytoplasmic intensity of MPO was negatively associated with the serum levels of MPO(r=-0.710, P<0.001) and Ba (r=-0.589, P=0.001). Moreover, serum MPO was positively associated with serum Ba(r=0.691, P<0.001). Membrane intensity of CD(55) on neutrophils was positively correlated with patient age (r=0.514, P=0.001), C reactive protein (r=0.376, P=0.018), peripheral neutrophils count (r=0.485, P=0.001) and BVAS-V3 (r=0.484, P=0.002), whereas negative correlation between membrane CD(55) and disease duration was seen (r=-0.403, P=0.01). (3) The result of multiple linear regression analysis showed there was statistically significant positive correlation between MFI of CD(55) expressed on neutrophils and BVAS-V3 (beta=0.001, P=0.027). Conclusions: In MPO-AAV, CD(55) expression on neutrophils is markedly enhanced, which is one of the independent risk factors related to disease activity. It might protect neutrophils from attacking AAV, CD(55) expression on neutrophils is markedly enhanced, which is one of the independent risk factors related to disease activity. It might protect neutrophils from attacking by complement alternative pathway. Activated neutrophils release more MPO and lysosome to intensify the inflammation reaction and aggravate the disease. Thus CD(55) might become a new potential target for the treatment of this disease in the future. PMID- 28592041 TI - [The effects of different tidal volume ventilation on right ventricular function in critical respiratory failure patients]. AB - Objective: To observe and explore the effects of different tidal volume (VT) ventilation on right ventricular (RV) function in patients with critical respiratory failure. Methods: Consecutive respiratory failure patients who were treated with invasive ventilator over 24 h in the Department of Critical Care Medicine at the Fourth Hospital of Hebei Medical University from June to December in 2015 were enrolled in this study.Clinical data including patients' vital signs, ventilator parameters and RV echocardiography were collected within 6 h (D0), day1(D1), day2 (D2) and day3 (D3) after ventilation started.According to the VT, patients with acute respiratory distress syndrome (ARDS) were assigned to low VT group [S6, <=6 ml/kg predicted body weight (PBW)] and high VT group (L6, >6 ml/kg PBW), while non-ARDS patients were also assigned to low VT group (S8, <=8 ml/kg PBW) and high VT group (L8, >8 ml/kg PBW). Results: A total of 84 patients were enrolled in this study.44.2% ARDS patients and 58.5% non-ARDS patients were in low VT groups.After ventilation, tricuspid annulus plane systolic excursion(TAPSE)decreased progressively in S6 [from 18.30(16.70, 20.70) mm to 17.55(15.70, 19.50) mm, P=0.001], L6 [from 19.50(17.00, 21.00) mm to 16.30(15.00, 18.00) mm P=0.001], S8[from 18.00(16.00, 21.00) mm to 16.50(15.50, 18.00) mm, P=0.001] and L8 [from 19.00(17.50, 21.50) mm to 16.35(15.15, 17.00) mm, P=0.001] groups.However, TAPSE decreased less in small VT groups (S6 and S8) than those of in large VT groups (S8 and L8) without significant differences.There were not statistical differences between different VT groups in terms of ventilation days, including right ventricle area/left ventricle area (RV(area)/LV(area)), TAPSE, peak mitral flow velocity of the early rapid filling wave (E), peak mitral flow velocity of the late rapid filling wave (A), early diastolic velocity of the tricuspid annulus (e'), pulmonary artery systolic pressure, inferior vena cava diameter (all P>0.05). Compared to L6 group, low VT (S6 group) resulted in decreased mortality at 28 days [1/19 vs 37.5%(9/24), P=0.014]. There were not statistical differences between different VT groups in terms of ventilation days, length of intensive care unit stay, length of hospital stay (all P>0.05). Logistic regression analysis showed that VT could be the independent factor of TAPSE (OR=1.104, 95%CI 0.100-1.003, P=0.049). Conclusions: Positive pressure mechanical ventilation resulted in RV systolic dysfunction .Lower VT may have the protective effect on RV function. Trial registration: Chinese Clinical Trial Registry, ChiCTR-POC-15007563. PMID- 28592044 TI - [Dermatomyositis associated with glycogen storage disease type II: a case report]. PMID- 28592043 TI - [A report of atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum caused by a de novo mutation in tubulin beta 4A (TUBB4A) gene and literature review]. AB - Objective: To explore the clinical symptoms and neuroimaging features of a patient with atypical hypomyelinating leukodystrophy with atrophy of the basal ganglia and cerebellum (H-ABC) caused by a novel TUBB4A mutation. Methods: We analyzed the clinical data, imaging features and the result of genetic testing of a case diagnosed as atypical H-ABC. Results: The initial symptoms were progressive spasticity, mild cerebellar ataxia and mild cognitive impairment. MRI showed regional blurring of slight high signal on T(2)-weight and FLAIR image in white matter of the bilateral midbrain ventral, internal capsule, posteior horn of lateral ventricle and centrum semiovale, with normal bilateral cerebellar and caudoputamen nucleus. Compared with normal subjects of the same age and gender, hypometabolism was found by (18)F-FDG-PET in brainstem, cerebellar and caudoputamen nucleus in the patient. Genetic testing revealed a de novo pathogenic exome missense heterozygous mutations c. 70G>A in TUBB4A, which was not reported in the human gene mutation database (HGMDpro) and was assessed to be a pathogenic mutation by pathogenic mutation prediction software. Conclusions: The diversity of TUBB4A gene mutations may cause different functional and/or structural impairment in subcortical white matter, cerebellar and caudoputamen nucleus, leading to atypical symptoms and neuroimaging features. Genetic testing for pathogenic mutation in TUBB4A gene is a key for the diagnosis of H-ABC. PMID- 28592045 TI - [Standardized diagnosis and treatment of diabetes: a talk from an event that should not have happened]. PMID- 28592046 TI - [The application of selectie granulocyte and monocyte apheresis in the treatment of ulcerative colitis]. PMID- 28592047 TI - [The update of emerging targeted therapies of lung cancer]. PMID- 28592048 TI - [The development of the epidemiology in osteoarthritis]. PMID- 28592049 TI - [The Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers (the fifth revision)]. AB - Invasive fungal disease(IFD) is a common yet highly lethal complication in patients with hematological malignancies receiving chemotherapy or stem cell transplantation, as well as immune suppressive conditions including aplastic anemia and other malignancies. According to the diagnostic criteria, patients are defined as proven, probable, possible and undefined IFD based on the evidence provided by histopathologic/cytologic, culture, radiographic and biomarker examinations. For the management of IFD, the major treatment strategies consist of prophylaxis, empirical, diagnostic-driven and target therapy. The Chinese Invasive Fungal Infection Working Group has developed the Chinese consensus for the diagnosis and treatment of invasive fungal disease based on international guidelines and local experience. Recently, the working group revises the consensus by update international guidelines and clinical studies in China. PMID- 28592050 TI - [The Chinese guidelines for the evaluation and management of cerebral collateral circulation in ischemic stroke (2017)]. AB - Precise evaluation of the structure and function of collateral circulation is vital for individualized management in stroke. By summarizing the most up-to-date evidence, the new concepts and clinical significance of cerebral collaterals are highlighted in the guideline, and clinical recommendations for the evaluation and management strategies of cerebral collateral circulation are provided. PMID- 28592051 TI - [Expert consensus for the prevention of cardiovascular disease in Chinese women]. AB - Cardiovascular disease is the leading cause of death for Chinese women, which has not been paid enough attention at present. Chinese women account for 20 percent of 3.5 billion women all over the world. Health promotion and prevention are facing the rigorous challenge. The pathophysiological characteristics, clinical manifestations, disease diagnosis, drug metabolism and prevention strategies of woman cardiovascular diseases are different from those of men in some respects and require special attention. "Consensus for the prevention of cardiovascular diseases in Chinese women" is developed by Women Physician Committee of Chinese College Cardiovascular Physicians and Women's Health Work Group of Chinese Society of Cardiology, which is aimed at strengthening and promoting prevention of cardiovascular diseases in Chinese women. PMID- 28592053 TI - [Improving the management and prognosis of renal hypertension]. PMID- 28592052 TI - [The 457th case: polyarthralgia, back pain and subcutaneous masses]. AB - A 54-year-old man was admitted to the Department of Rheumatology in Peking Union Medical College Hospital due to polyarthritis, back pain and multiple subcutaneous masses. He had symmetrical polyarthritis at onset, which was diagnosed as rheumatoid arthritis. His follow-up and treatment were irregular. Back pain and multiple subcutaneous masses developed 2 year ago. Erythrocyte sedimentation rate and C-reactive protein were elevated. Rheumatoid factor and Anti-cyclic citrullinated peptide antibody were positive. No evidence of infection or malignancy was detected. Chest CT suggested pulmonary fibrosis and osteolytic lesions of sternum. Spinal MRI showed paravertebral soft tissue. Biopsy of the soft tissue suggested the pathological finding of a rheumatoid nodule. The patient was diagnosed as rheumatoid arthritis complicated with multiple rheumatoid bursal cysts.Combination therapy of methylprednisolone(40mg/d) and cyclophosphamide(0.4 g/w) lead to a rapid improvement of clinical symptoms and laboratory parameters.The patient was still in remission at 6-month follow-up. PMID- 28592054 TI - [Focus on promoting the standardization of the clinical oxygen therapy in China]. PMID- 28592055 TI - [Shortcomings of CORAL trial and prospect of treatments in the future]. PMID- 28592056 TI - [Special Forums:Standardization of Oxygen Therapy Side effects of hyperoxia for respiratory critically ill patients and oxygen therapy criteria]. PMID- 28592057 TI - [Rational oxygen therapy in patients with chronic obstructive pulmonary disease]. PMID- 28592059 TI - [Hyperoxia induced injury and its pathological mechanisms]. PMID- 28592058 TI - [Hazards of hyperoxia in patients with myocardial infarction and heart failure]. PMID- 28592060 TI - [Introduction and interpretation of oxygen therapy guidelines in various countries]. PMID- 28592061 TI - [Value of forced expiratory volume in 6 seconds (FEV(6)) in the evaluation of pulmonary function in Chinese elderly males]. AB - Objective: To evaluate the value of forced expiratory volume in 6 seconds (FEV(6)) in the evaluation of pulmonary function in Chinese elderly males. Methods: Pulmonary function tests of elderly who had received regular physical examination in Beijing Hospital from July 2003 to April 2015 were analyzed on subjects with the following characteristics: aged 60 years or older, completion of bronchial dilation test and able to exhale for at least six seconds. The included subjects were divided into 2 groups: 60-<80 years group and >=80 years group. The association of FEV(6) with forced vital capacity (FVC), FEV(1)/FEV(6) with FEV(1)/FVC, the diagnostic efficiency and influencing factor of FEV(6) and FEV(1)/FEV(6) were analyzed; the value of FEV(6) in the evaluation of pulmonary function in the study population was evaluated. Results: A total of 475 elderly men aged 60 years or older were enrolled, with a mean age of (77.13+/-9.53) years. Totally there were 269 subjects in 60-<80 years group, which accounted for 56.6%; 206 subjects were in >=80 years group, which accounted for 43.4%. There were 292 subjects with irreversible airflow obstruction, accounting for 61.5%. In all the included subjects, FEV(6) was significantly correlated with FVC and post bronchodilator FEV(1)/FEV(6) was significantly correlated with post bronchodilator FEV(1)/FVC(r=0.971, 0.978; both P<0.001), which were similar in 60 <80 years group and >=80 years group (r=0.967, 0.974 and r=0.955, 0.967; all P<0.001). FEV(1)/FEV(6) showed excellent accuracy in diagnosing airflow obstruction[area under curve (AUC)=0.990(95%CI: 0.983-0.996); P<0.001]. Using FEV(1)/FVC<0.70 as a reference, FEV(1)/FEV(6)<0.73 had the best sensitivity (0.952) and specificity (0.945), and there was excellent agreement between the two diagnostic cutoffs (kappa=0.891; P<0.001). When difference between before and after bronchial dilation test was analyzed, no correlation was observed between FEV(6) improvement and the improvement of forced expiratory time (r=0.089; P=0.053), but FVC improvement was significantly correlated with the improvement of forced expiratory time (r=0.460; P<0.001). Similar results were also found in subjects with irreversible airflow obstruction. Subjects with FEV(1)/FEV(6)>=0.70 and FEV(1)/FVC<0.70 were categorized as pulmonary function middle group, a total of 73 cases, which included 20 cases >=80 years old. The proportion of middle group among >=80 years group was significantly less than that of the 60-<80 years group (chi(2)=8.958; P=0.003). In pulmonary function middle group, FEV(1)/FEV(6) or FEV(1)/FVC had no correlation with inspiratory capacity or residual volume/total lung capacity (all P>0.05). Conclusions: FEV(6) and FEV(1)/FEV(6) are strongly correlated with FVC and FEV(1)/FVC, and there is excellent agreement between FEV(1)/FEV(6) and FEV(1)/FVC. FEV(6) is simple, easy to operate and with less influencing factors, which can be used as a valid alternative for FVC in diagnosing airflow obstruction in elderly males. PMID- 28592062 TI - [Glucose excursion in senior patients with type 2 diabetes mellitus and coronary artery disease]. AB - Objectives: To explore glucose excursion and incidence of hypoglycemia in senior patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) with different hemoglobin A1c (HbA1c) values. Methods: Eighty-nine outpatients [58 male, 31 female, aged 69.0 (66.0, 73.0) years] diagnosed with T2DM and CAD in Beijing Anzhen Hospital between June 2013 and March 2016 were divided into group A (HbA1c<6.5%, n=25) and group B (HbA1c>=6.5%, n=64). Every patient wore continuous glucose monitoring system (CGMS) for 72 h. Glucose excursion parameters and incidence of hypoglycemia from CGMS readings were calculated. Results: Compared with group B, patients in group A experienced shorter diabetes duration [8.0 (3.5, 15.0) vs 15.0 (8.0, 20.0) years, Z=-2.222, P=0.026], lower standard deviation (SD) of blood glucose from CGMS, mean amplitude of glycemic excursions(MAGE) and mean of the daily differences(MODD) (P=0.001, 0.003, 0.001). However, incidence of hypoglycemia was significantly increased [56.0% (14/25) vs 32.8% (21/64), chi(2)=4.051, P=0.044] in group A. Compared to those who had not experienced hypoglycemia, patients with hypoglycemia had higher SD [1.8(1.4, 2.4) mmol/L vs 1.4(1.1, 1.8) mmol/L, Z=-3.198, P=0.001] and MAGE [6.0(3.2, 7.4) mmol/L vs 3.9(2.7, 4.8 )mmol/L, Z=-2.768, P=0.006] which were appropriate tools for assessing intraday glycemic variability. No statistical difference were found in MODD which was the index for estimating interday glycemic variability. Conclusions: Intensive glycemic control in senior patients with T2DM and CAD had higher incidence of hypoglycemia. Those with hypoglycemia experienced greater intraday glucose excursion. PMID- 28592064 TI - [Clinical analysis on monitoring and comprehensive treatment after carotid endarterectomy]. AB - Objective: To discuss the therapeutic effect of management of carotid endarterectomy in care unit. Methods: A total of 315 patients with carotid atherosclerotic stenosis were enrolled. All of the patients were taken into care unit under tracheal intubation anesthesia after carotid endarterectomy. Then the patients were managed with a breathing machine, continuous sedation, strict monitoring of hemodynamics and pupil change, strict control of heart rate and blood pressure, atomization inhalation therapy, treatment of anticoagulation and antiplatelet therapy and classification management of airway. Results: All patients were recovered well and no death was documented, among which cranial nerve injury occurred in 2 cases, incision bleeding was observed in 6 patients, endotracheal intubation were performed again in 4 cases due to postoperative airway obstruction, pneumonia was found in 2 cases, aphasia and homolateral hemiplegia were observed in one case, while disturbance of consciousness and contralateral hemiplegia occurred in 1 case, psychiatric symptoms occurred temporarily after operation in 8 cases, and one case suffered from acute myocardial infarction. Conclusion: The present study suggests that the comprehensive measures, including continuous sedation, strict control of heart rate and blood pressure, classification management of airway and so on, can be beneficial to postoperative anesthesia recovery and ideal blood pressure, and prevent the occurrence of cerebral hyperperfusion syndrome effectively. PMID- 28592063 TI - [Effect of cisatracurium on entropy index of children undergoing sevoflurane anesthesia]. AB - Objective: To investigate the effect of cisatracurium on entropy index of children undergoing sevoflurane anesthesia. Methods: Forty-five child patients (ASAI-II) who underwent cleft lip and palate repair surgery in Beijing Stomatological Hospital were selected from June to November in 2015. They aged from 8 to 24 months and were randomly divided into 3 groups, as well as maintained at different end-tidal sevoflurane concentrations (C(ET)Sev), respectively. The C(ET)Sev in Group I was 2.5%, with a total number of 15 cases. The C(ET)Sev in Group II was 3.0%, with a total number of 16 cases. The C(ET)Sev in Group III was 3.5%, with a total number of 14 cases. After the child patients were sent into operating room, their ulnar nerves underwent train-of-four stimulation (TOF) inspection using Datex-Ohmeda anesthesia workstation. The four muscle twitches orderly occurring on abductor pollicis muscle were recorded as T(1,)T(2,)T(3) and T(4,)respectively. The level of state entropy (SE) and reactive entropy (RE) was monitored by the entropy index module. 6% of sevoflurane high-flow inhalation was used to induce children's sleep, and the oxygen flow was adjusted to 2 L/min. Also, the C(ET)Sev in 3 groups maintained at 2.5%, 3.0% and 3.5%, respectively, which lasted for more than 10 min. Then, they were administered with 0.15 mg/kg cisatracurium, and the level of SE and RE in 3 groups was recorded when they were before the drug delivery of cisatracurium (t(1)), 50% inhibition of T(1) (t(2)), 75% inhibition of T(1) (t(3)) and 100% inhibition of T(1) (t(4)), respectively. Results: At the time of t(1,)t(2,)t(3) and t(4,)the SE values in Group I were (55+/-19), (53+/-20), (48+/-18) and (43+/ 16), respectively, and the differences were statistically significant (F=3.881, P<0.05). The SE values in Group II were (42+/-19), (41+/-21), (39+/-18), (31+/ 13), and the differences were statistically significant (F=3.463, P<0.05). The SE values in Group III were (34+/-11), (33+/-16), (33+/-14) and (32+/-13), respectively. The differences were not statistically significant (F=0.162, P>0.05). At the time of t(1,)t(2,)t(3) and t(4,)the RE values in Group I were (54+/-13), (48+/-11), (34+/-13) and (30+/-13) respectively, and the differences were statistically significant (F=36.975, P<0.01). The RE values in Group II were (43+/-13), (38+/-13), (33+/-12) and (28+/-11) respectively, the differences were statistically significant (F=12.438, P<0.01). The RE values in Group III were (34+/-10), (33+/-11), (31+/-12) and (25+/-11) respectively, and the differences were statistically significant (F=6.019, P<0.01). The RE values of child patients in Group I, II and III decreased after the drug delivery of cisatracurium. Conclusion: The muscle relaxants (cisatracurium) will decrease the entropy index of children undergoing sevoflurane anesthesia, but will not affect their SE values under deep anesthesia. PMID- 28592065 TI - [Impact of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease after neoadjuvant chemotherapy]. AB - Objective: To explore the influence of adjuvant chemotherapy on the prognosis of hormone receptor negative breast cancer with residual lymph node disease(RLND)after neoadjuvant chemotherapy. Methods: A total of 110 hormone receptor negative breast cancer patients treated with 4-8 cycles of neoadjuvant chemotherapy were respectively analysed between 2002 and 2012. Residual lymph node disease was comfirmed by subsequent radical mastectomy. Then all these patients were classified into two groups: patients treated with adjuvant chemotherapy(group A) and patients untreated with adjuvant chemotherapy(group B). Results: All patients were female, the median age was 54.5 years old(IQR: 47-59 years). The median follow-up time was 61 months(IQR: 51-88 months). There were 82 patients (74.5%) in group A, and 28 patients (25.5%) in group B. The five-year disease-free survival (DFS) rate was 76.2% in group A and 57.6% in group B. The distant disease-free survival (DDFS) rate was 78.9% in group A and 60.4% in group B. Overall survival (OS) rate was 81.0% in group A and 60.0% in group B. Multivariate analysis showed that there were significant differences for DDFS rate (group A vs group B, P=0.033; hazard ratio [HR], 5.256; 95% confidence interval [95%CI], 1.14-24.17) and OS rates (group A vs group B, P=0.011; HR, 7.478; 95%CI, 1.58-35.30) between two groups. Conclusion: The patients who have hormone receptor negative breast cancer with RLND after neoadjuvant chemotherapy, may benefit from postoperative adjuvant chemotherapy. PMID- 28592066 TI - [Analysis of haematological phenotype and mutation spectrum of delta-globin gene from Guangdong area in Chinese Han prenatal population]. AB - Objective: To analyze the genotype-phenotype correlations among southern Chinese Han prenatal population in Guangdong area with delta-globin gene mutation, so as to enrich the delta-thalassemia gene mutations data. Methods: A total of 33 cases were selected in 7 580 patients during prenatal thalassemia trait screening, from January 2012 to May 2015(including 10 males and 23 females, aged 22-48 years old). Complete blood cell count was performed on a XE 4000i automatic hemocyte analyzer. Hb, HbF and HbA2 were tested by high performance liquid chromatography (HPLC). Genomic DNA was extracted from whole blood samples using a whole blood genomic DNA extraction kit. Polymerase chain reaction (PCR) was used to amplify three different fragments corresponding to the exons and the regulatory sequences using three different couples of primers for the delta-globin gene. Results: Twenty one of the 33 samples were positive for the delta-globin gene defects. Four previously known mutations were detected: including 12 cases for 77(T>C)[HBD c. -127 (T>C)](57.14%), 4 cases for -30 (T>C)[HBD c. -80 (T>C)](19.05%), 1 case for codon 10 (-G) (HBD c. 31delG)(4.76%), and 1 case for HBD c. 244 C>T(4.76%). Three new delta-globin gene defects which had not yet been reported in database were detected, including 1 case for HBD c. 22_24delGAG(4.76%), 1 case for HBD c. 347 C>T(4.76%), and one case for HBD c. 349 C>G(4.76%). Conclusions: -77 (T>C) is the most common mutation in Chinese southern prenatal population. Three new HBD gene mutations are referred in this report, which provide the valuable information for genetic counseling and prenatal diagnosis in Guangdong area. PMID- 28592067 TI - [Combination of PP242 and dasatinib suppresses the progression of acute myeloid leukemia in a mouse model]. AB - Objective: To establish the acute myeloid leukemia (AML) mouse model, and to preliminarily investigate the efficiency of dasatinib, a tryosine kinase inhibitor, and PP242, an inhibitor of PI3K/Akt/mTOR signaling pathway in the development of AML. Methods: The lineage(-) (Lin(-)) cells of C57BL/6J were transduced with retrovirus carrying MSCV-MLL-AF9-IRES-GFP fusion gene. The transduced cells were transplanted into lethally irradiated recipient mice to induce AML, and then the AML mouse model were established. The leukemia mice were treated with vehicle, dasatinib, PP242, dasatinib+ PP242, separately. The survival of the recipient mice was observed and the percentage of leukemia cells in peripheral blood (PB) and bone marrow (BM) was examined every four days. The apoptosis rates and cell cycle status of leukemia cells were also examined by FLOW. The leukemia cells in different group were sorted, the mRNA of these leukemia were extracted and reverse transcripted for related gene expression by qRT-PCR. The molecular mechanism of supression of leukemia cells growth was studied via RNA-Seq experiments. Results: Compared with control group, either PP242 or dasatinib could prolong the survival rate of recipient mice, however, the combination treatment AML mice with PP242 and dasatinib prolonged the life span of AML mice more significantly. The combination of PP242 and dasatinib could decrease the percentage of leukemia cells in PB and BM more significantly, arresting more leukemia cells in G0 phase, inducing more apoptosis of leukemia cells. Conclusion: Combination of tryosine kinase inhibitor-dasatinib and PI3K/Akt/mTOR signaling pathway inhibitor- PP242 could delay the progression of AML by inducing more leukemia to apoptosis and arrest more leukemia cells in the cell cycle G0 phase, it may be provied a new method for clinical therapy. PMID- 28592068 TI - [Reoperation for residual aneurysm of coronary anastomosis after Bentall procedure]. AB - Objective: To introduce a new operative method for residual aneurysm of coronary anastomosis after Bentall procedure. Methods: Between March 2011 and December 2012, six patients in Beijing Anzhen Hospital with residual aneurysm of coronary anastomosis (CT showed goldfish eye sign at the openings of coronary) after Bentall procedure underwent the operation of concentric circular patch procedure under cardiopulmonary bypass. Femoral artery, right atrium and upper right pulmonary artery cannulation were used for cardiopulmonary bypass, and the artificial vessel was transected after cardiac arrest. A concentric circular patch was pruned, whose outside diameter was slightly larger than the aneurysm and the inside diameter was equal to the openings of coronary. The outer edge of the patch was anastomosed to the outer edge of the aneurysm (opening of artificial vessel in primary surgery) with 4-0 prolene. The inner edge of the patch was anastomosed to the openings of coronary with 5-0 prolene. Results: All patients had clinical recovery. Postoperative CT demonstrated the disappearance of residual aneurysm during follow-up (the goldfish eye sign disappeared). Conclusion: The concentric circular patch procedure is a feasible treatment for residual aneurysm of coronary anastomosis. PMID- 28592069 TI - [The mobile application of patient management in education and follow-up for patients following total knee arthroplasty]. AB - Objective: To apply themobile application of patient management in education and follow-up for patients following total knee arthroplasty, and evaluate the clinical outcomes. Methods: A total of 150 patients following total knee arthroplasty were chosen from May to October 2016 in orthopaedics department of our hospital, and they were randomly divided into two groups. On the basis of the traditional education, the observation group combined with the APP education, guidance of functional exercise and follow-up. While traditional face-to-face and telephone education were combined to control group. The activity, compliance and satisfaction score of the two groups were observed. Results: Finally, 132 patients were included in the study. The postoperative range of motion of the two groups in February were respectively (110.83+/-6.83) degrees and (105.45+/-7.53) degrees , the difference was statistically significant (P<0.05); the range of motion in March were respectively (110+/-6.33) degrees and (103.26+/-7.57) degrees , the difference was statistically significant too (P<0.05); Patients's compliance and satisfaction score in observation group were significantly better than control group(P<0.05). Conclusion: Combination of traditional face-to-face education with mobile application will improve effects of functional training, compliance, and hospital-discharge satisfaction, it will also both shorten the education time and increase the education efficiency. To sum up, it's worth being widely applied clinically. PMID- 28592070 TI - [The progression of tumor liquid biopsy and its applications in precision medicine]. AB - Malignant tumor is the most heterogeneous human disease, and it has been gradually reached the consensus in clinical oncology that the personalized treatment of tumor patients should be directed by molecular diagnostics. However, the ever-changing characteristic of tumor in heterogeneity and the fact that tissue samples are usually unavailable highlight the function and significant of liquid biopsy. The material that could be used in liquid biopsy are mainly the circulating tumor DNA, circulating tumor cells and extracellular vesicles, which though have their own advantages and disadvantages, but could complement to each other, thus accurately and comprehensively reflecting the characteristic of the tumor and gave the best direction for patient's individualized therapy. This article reviewed the recent advances of liquid biopsy and explained its importance in tumor precision medicine. PMID- 28592071 TI - [Progress in methodological characteristics of clinical practice guideline for osteoarthritis]. AB - At present, several clinical practice guidelines for the treatment of osteoarthritis have been developed by institutes or societies. The ultimate purpose of developing clinical practice guidelines is to formulate the process in the treatment of osteoarthritis effectively. However, the methodologies used in developing clinical practice guidelines may place an influence on the transformation and application of that in treating osteoarthritis. The present study summarized the methodological features of individual clinical practice guideline and presented the tools for quality evaluation of clinical practice guideline. The limitations of current osteoarthritis guidelines of China are also indicated. The review article might help relevant institutions improve the quality in developing guide and clinical transformation. PMID- 28592072 TI - [Effects of trabecular metal augments for the reconstruction of Paprosky type III acetabulum bone defects]. AB - Objective: To investigate the methods and short-time clinical results of reconstruction of Paprosky type III acetabulum bone defects by using tantalum augments. Methods: A total of 17 patients (17 hips) with Paprosky type III acetabulum bone defects, treated with tantalum augments in revision of total hip arthroplasty at Department of Orthopedics Surgery in General Hospital of Chinese People's Liberation Army were retrospectively analyzed from March 2014 to May 2016.There were 6 males and 11 females aged from 23 to 74 years with an average of (50.2+/-16.3) years. Tantalum augments or TM-Cup augment (the cup-on-cup technique) were used to reconstruct the defects.The TM-Cup augment was the tantalum revision cup which was removed titanium ring. The cup-on-cup technique combined TM-Cup augment and biological acetabulum cup. Augments were served as the nonresorptive structural allograft in revision of total hip arthroplasty. Harris hip score was used to evaluate clinical effects. The vertical position of the rotation center was measured and analyzed. Radiographic assessments of the acetabular components were performed by DeLee-Charnley and the Anderson criteria and recorded postoperative complications. Results: All the patients were followed up from 3 to 29 months with an average of (16.2+/-5.4) months, tantalum augments and biological acetabulum cup were used in 13 patients, the TM-Cup augment and biological acetabulum cup were used in 4 patients. At the time of the latest follow-up, the mean Harris hip score increased compared to preoperatively (86.8+/ 8.3 vs. 30.0+/-12.0) (t=12.78, P<0.01), the average vertical location of the center of rotation was decreased ((25.3+/-9.8) mm vs.(47.6+/-10.5)) mm (t=4.95, P<0.01). All the tantalum augments and biological acetabulum cups were stable, there were no infection, dislocation and other complications. Conclusions: The use of tantalum augments could be considered as an effective management of Paprosky type III defects providing good clinical and radiographic outcomes in the short term.The cup-on-cup technique which was used in reconstruction of severe superior-invagination acetabular bone defects and restoration relatively normal center of rotation had special application value. PMID- 28592074 TI - [Effects of iASSIST navigation system and personal specific instrument assisted total knee arthroplasty in the treatment of osteoarthritis]. AB - Objective: To compare the application of iASSIST assisted total knee arthroplasty (TKA) and three-dimentional(3D) printing personal specific instrument (PSI) assist TKA in the treatment of osteoarthritis (OA). Methods: Clinical data of 47 patients with OA admitted at Department of Orthopaedic Surgery in Nanjing Medical University Nanjing Hospital between April and September 2016 were retrospectively reviewed, including 20 males and 27 females, aging from 57 to 77 years with mean age of (63.8+/-8.2) years. They were randomly divided into iASSIST-TKA group (23 patients) and PSI-TKA group (24 patients). The data such as hip knee ankle (HKA) angle, frontal femoral component (FFC) angle, frontal tibial component (FTC) angle, lateral femoral component (LFC) angle, lateral tibial component (LTC) angle, time of operation, post-operative wound drainage, period of hospitalization, visual analog scale (VAS) and Knee Society Score (KSS) at 1 day, 7 days, 14 days, 1 month and 3 months were recorded and compared between the two groups. T test was used to compare measurement data, Fisher exact test and chi(2) test were applied to enumeration data in comparison among groups, and Kruskal Wallis test was applied to ranked data. Results: The deviation values of HKA, FFC, LFC, FTC and LTC angles were all below 3 degrees (-2 degrees to 2 degrees ), and there were no significant difference between iASSIST-TKA group and PSI-TKA group (Z=-0.610 to 0.000, P=0.542 to 1.000). Compared to PSI-TKA group, the time of operation was long((80.7+/-8.8) minutes vs.(60.2+/-7.8) minutes), the amount of post-operative wound drainage was increased((210.7+/-32.1) ml vs.(185.5+/ 30.2)ml) and the period of hospitalization decreased((5.4+/-2.4) d vs.(6.7+/-1.6) d) in iASSIST-TKA group, there were significant difference(t=-2.190 to 8.460, P=0.000 to 0.033). There were no significant difference in intra-operative blood drainage((18.4+/-5.4) ml vs.(17.3+/-6.2) ml) between the two groups(t=0.650, P=0.521). PSI-TKA group had a superior VAS score(4.8+/-0.6 vs. 5.5+/-0.9, 3.6+/ 0.8 vs. 4.3+/-0.9), KSS clinical score(49.3+/-5.5 vs. 44.2+/-6.4, 54.9+/-4.0 vs. 50.8+/-4.2) and KSS function score(44.1+/-2.9 vs. 41.2+/-3.5, 49.6+/-3.8 vs. 46.6+/-3.2) in 1 day and 7 days post-operation(t=-3.420 to 3.150, P=0.001 to 0.007). There were no significant difference in VAS and KSS score in 14 days, 1 month and 3 months post-operation(t=-1.390 to 0.530, P=0.170 to 1.000) between the two groups. Conclusions: The iASSIST-TKA and PSI-TKA can help to make TKA procedure more accurately. iASSIST-TKA may take longer time of operation and have slower recovery, PSI-TKA may need more X-ray input and longer period of hospitalization. The long-term research of both techniques may be valuable for the further clinical usage. PMID- 28592075 TI - [Influence of tibial component slope on short-term clinical outcome for Oxford unicompartmental knee arthroplasty]. AB - Objective: To investigate the effects of tibial component slope change after microplasty (MP) Oxford unicompartmental knee arthroplasty (UKA) on short-term clinical outcome. Methods: A total of 116 patients(128 UKAs)underwent UKA in Department of Orthopaedic Surgery of China-Japan Friendship Hospital between January 2014 and December 2015 were retrospectively reviewed. Totally 100 patients (108 UKAs) were finally included in the study. There were 31 males and 69 females, aging from 47 to 90 years (mean 67.2 years). The mean height was (161.9+/-8.4) cm and the mean body mass index (BMI) was (26.2+/-3.3) kg/m(2). The posterior tibial slope (PTS) at preoperative and postoperative were measured on the lateral radiograph. The postoperative PTS were divided into five groups (<3 degrees , 3 degrees to 5 degrees , 5 degrees to 7 degrees , 7 degrees to 9 degrees and>9 degrees ). The Oxford Knee Score (OKS) was recorded. Pearson correlation analysis, ANOVA and t test were used to analyze data. Results: All operations were successfully accomplished and there were no transfusion, infection, thrombus and other complications. There was 1 patient accepted revision because of bearing dislocation. Compared to preoperative, the PTS decreased (6.5 degrees +/-2.2 degrees vs.9.6 degrees +/-3.4 degrees ) postoperative, there was statistical difference (t=9.053, P<0.01). Only 3 patients were beyond the recommended range (2 degrees to 12 degrees ). A total of 82 patients (86 UKAs) were followed up. The follow-up time was 1 to 2.9 years (mean 2 years). The OKS was 43.0+/-4.1 (mean 31 to 48). The PTS increased in 12 patients (12 UKAs) postoperative, the mean OKS was 40.5+/-5.2. The PTS decreased in 70 patients (74 UKAs), the mean OKS was 43.4+/-3.8. There were significant difference in OKS (t=2.347, P=0.021). There were no significant difference in OKS between the five groups. There were positive correlation between postoperative PTS and preoperative PTS (r=0.201, 95%CI: 0.001 to 0.396, P=0.037), there were no correlations between postoperative PTS and hight and BMI. There were negative correlations between OKS and postoperative PTS (r=-0.255, 95%CI: -0.063 to 0.427, P=0.018) and PTS change (r=-0.292, 95%CI: -0.08 to -0.475, P<0.01). Conclusions: Satisfying PTS can be obtained by use of Oxford MP instrumentation. The clinical outcome of the postoperative PTS decreased was relatively better. Too large posterior slope of the tibial implant should be avoided. PMID- 28592073 TI - [Influence of patellofemoral joint degeneration on outcome of medial unicompartmental knee arthroplasty]. AB - Objective: To evaluate the influence of patellofemoral joint degeneration and pre operative pain location on the outcome of medial Oxford unicompartmental knee arthroplasty (UKA). Methods: A total of 58 patients (58 knees) with medial Oxford UKA had been performed for medial osteoarthritis from March 2013 to July 2014 in Department of Orthopaedic Surgery at First Teaching Hospital of Xinjiang Medical University were retrospective reviewed. There were 24 males and 34 females, the age from 43 to 87 years with the mean age was 68.5 years. The mean body mass index was 25.2 kg/m(2) ranging from 19.7 to 31.5 kg/m(2). Patients were divided into anterior-medial pain group (35 knees), anterior knee pain group (17 knees) and general knee pain group (6 knees) according to pre-operative pain location. Pre-operative radiological statuses of the patellefemoral joint were defined by Ahlback system and divided into patellofemoral joint degeneration group (16 knees) and normal group (42 knees). Patients were also divided into medial patellofemoral degeneration group (20 knees), lateral patellofemoral degeneration group (12 knees) and normal group (26 knees) according to Altman scoring system. Outerbridge system was used intraoperatively and the patients were divided into patellofemoral joint degeneration group (21 knees) and normal group (37 knees). Pre- and post-operative outcomes were evaluated with Oxford Knee Score (OKS), Western Ontario and MacMaster (WOMAC) and patellofemoral score system of Lonner. T test and ANOVA were used to analyze the data. Results: The average duration of follow-up was 33 months (from 26 to 42 months). There were no patients had complications of infection, deep vein thrombosis, dislocation or loosing at the last follow-up. Compared to pre-operation, OKS (18.9+/-3.5 vs. 38.9+/-4.7, 19.3+/ 4.2 vs. 39.6+/-4.6, 18.1+/-3.2 vs. 38.1+/-3.7)(t=5.64 to 7.08, all P<0.01) and WOMAC (10.9+/-2.3 vs.53.2+/-4.5, 10.4+/-2.1 vs.54.6+/-3.4, 11.7+/-1.8 vs.52.8+/ 3.7)(t=14.50 to 19.16, all P<0.01) decreased, and the Lonner score (88.9+/-3.4 vs.38.6+/-2.8, 87.5+/-4.1 vs.38.2+/-2.3, 88.2+/-3.2 vs. 37.6+/-3.5)(t=-19.78 to 18.16, all P<0.01) increased significantly in anterior-medial pain group, anterior knee pain group and general knee pain group. According to Ahlback scoring system, compared to pre-operation, OKS (18.3+/-2.4 vs. 38.7+/-4.4, 19.6+/ 1.8 vs. 38.4+/-3.1)(t=7.05, 9.08, both P<0.01) and WOMAC (10.6 +/-2.6 vs.53.2+/ 4.5, 12.1+/-1.4 vs.52.4+/-3.3)(t=14.21, 19.52, both P<0.01) decreased, the Lonner score (88.1+/-3.1 vs.38.3+/-3.3, 86.9+/-2.6 vs.39.1+/-2.4)(t=-18.90, -23.40, both P<0.01) increased significantly in patellofemoral joint degeneration group and normal group, the outcomes were the same according to Altman and Outerbridge scoring system. There was no significant difference between patellofemoral joint degeneration group and normal group based on Ahlback grading system. According to Altman classification, compared to normal group, there was no statistically differences in OKS, WOMAC and Lonner scoring system between patients with degeneration in the medial patellofemoral joint group, OKS and WOMAC increased (20.2+/-1.4 vs.18.2+/-2.7, 12.5+/-1.7 vs.10.5+/-2.5) (t=-4.30, P=0.03; t=-4.80, P=0.02), the Lonner score decreased (84.3+/-2.8 vs.87.4+/-3.2) (t=-6.20, P=0.01) in lateral patellofemoral degeneration group. According to Outerbridge scoring system, there were no statistically differences in patients in patellofemoral joint degeneration group and normal group. Conclusions: There is a good evidence that neither mild to moderate degree of patellofemoral joint degeneration nor pre operative pain location will compromise the short-term outcome of medial Oxford UKA, and should not be considered as contraindications. The situation is less clear for lateral patellofemoral degeneration, and more cautious option is advised. PMID- 28592076 TI - [Effects of different pelvic incidence minus lumbar lordosis mismatch after long posterior instrumentation and fusion for adult degenerative scoliosis]. AB - Objective: To evaluate the influence of PI-LL (pelvic incidence minus lumbar lordosis mismatch) on scoliosis correction, living quality and internal fixation related complications for adult degenerative scoliosis (ASD) after long posterior instrumentation and fusion. Methods: A total of 79 patients with ADS underwent long posterior instrumentation and fusion in the Department of Orthopedics at Beijing Chao Yang Hospital from January 2010 to January 2014 were retrospectively reviewed.There were 21 males and 58 females aging from 55 to 72 years with the mean age (63.4+/-4.8)years. The patients were divided into three groups according to immediately postoperative PI-LL: PI-LL<10 degrees , 10 degrees <=PI-LL<=20 degrees , PI-LL>20 degrees .Compare the Cobb's angles, PI-LL, Japanese Orthopaedic Association (JOA) score, Oswestry Disability Index (ODI), Visual Analog Scale (VAS) and Lumbar Stiffness Disability Index (LSDI). Measurement data were compared via t test and ANOVA, enumeration data were compared via Kruskal Wallis test, noncontiguous data was performed by chi(2) test. Univariate linear regression equation was performed to investigate the relative influences of postoperative PI-LL on postoperative radiographic parameters and clinical outcome. Results: All the operations were successful without intraoperative complications. The operation time was 145-310 minutes (235.3+/-42.0) minutes, the intraoperative blood loss was 300-5 300 ml (1 021+/-787) ml, the duration of hospital was 12-18 d (14.5+/-1.3) d. A total of 4 to 10 (7.0+/-1.1) vertebra levels were fused. Compared to preoperative, the Cobb's angle of scoliosis ((4.2+/-1.8) degrees vs. (20.1+/-2.7) degrees ), PI-LL ((16.1+/-8.6) degrees vs. (36.0+/-4.3) degrees ), JOA (3.0+/-1.3 vs. 5.5+/-1.2), ODI (24.4+/-8.1 vs. 62.9+/-2.7), VAS (3.0+/-1.0 vs. 6.8+/-1.3) were significantly decreased postoperative (t=18.539~53.826, P<0.01). Compared to preoperative, postoperative Cobb's angle of scoliosis ((4.1+/-2.7) degrees vs. (19.5+/-2.7) degrees , (4.0+/ 1.4) degrees vs. (20.2+/-2.4) degrees , (4.7+/-0.9) degrees vs. (20.6+/-3.0) degrees ) (t=21.148-45.355, P<0.01) and PI-LL ((5.2+/-2.8) degrees vs. (35.8+/ 4.9) degrees , (17.9+/-2.9) degrees vs. (37.2+/-3.9) degrees , (25.8+/-2.7) degrees vs. (34.5+/-4.0) degrees ) (t=7.227-38.250, P<0.01) were significantly reduced postoperative in PI-LL<10 degrees group, 10 degrees <=PI-LL<=20 degrees group and PI-LL>20 degrees group. Compared to preoperative, ODI (27.7+/-4.9 vs. 63.3+/-2.6, 17.7+/-5.9 vs. 63.1+/-2.8, 30.6+/-6.5 vs. 62.3+/-2.5) (t=21.218~50.858, P<0.01), JOA (2.8+/-1.2 vs. 5.2+/-1.2, 3.3+/-1.1 vs. 5.7+/-1.1, 2.8+/-1.7 vs. 5.7+/-1.2) (t=9.042-16.025, P<0.01) and VAS (2.9+/-1.2 vs.7.0+/ 1.3, 3.3+/-0.9 vs.7.0+/-1.4, 2.9+/-0.8 vs. 6.3+/-1.2) (t=16.073-22.214, P<0.01) were all significantly reduced at last follow-up. There were statistic differences in ODI and LSDI (F=38.477, P<0.01; F=37.063, P<0.01) at the last follow-up among the three groups. There was a negative correlation in PI-LL and LSDI according to linear regression (B=-5.838, P<0.01) in the last follow-up. All the patients were followed up, the follow-up duration were 2 to 5 years with the mean (3.1+/-0.7) years. The internal fixation failure related complications in 3 years included proximal junctional kyphosis (PJK) in 19 cases, internal fixation loosening in 6 cases. Eight patients received reoperation for severe local pain and low extremity symptoms. PJK occurrences were significantly different among PI LL<10 degrees group, 10 degrees <=PI-LL<=20 degrees group and PI-LL>20 degrees group. Conclusions: The PI-LL between 10 degrees and 20 degrees may be the best choice in ADS patients after long posterior instrumentation and fusion for its better clinical outcome and less proximal junctional kyphosis (PJK). The overcorrection of LL may lead to more serious postoperative lumbar stiffness. PMID- 28592077 TI - [Clinical effects of microsurgery in spinal cord anaplastic astrocytoma]. AB - Objective: To investigate the surgical outcomes and prognosis of spinal cord anaplastic astrocytoma (AA). Methods: A total of 27 consecutive patients diagnosed as spinal cord AA between January 2008 and May 2015 in Department of Neurosurgery of Beijing Tiantan Hospital were retrospectively reviewed. There were 18 males and 9 females, the mean age was (30.7+/-13.0) years (ranging from 5 to 52 years). The lesions were located at cervical level in 8 patients, at thoracic level in 9 patients, at cervicothoracic level in 3 patients, and at thoracolumbar level in 7 patients, the average number of vertebral was 3.3+/ 1.3.The median time from onset of symptom to surgery was 4 months, ranging from 3 days to 48 months. The clinical presentations were weakness (23 cases), paresthesia (22 cases), pain (20 cases), sphincter disorder (15 cases) and paralysis (7 cases). The preoperative modified McCormick scale was as follows: grade II for 6 cases, grade III for 7 cases, grade IV for 7 cases, grade V for 7 cases. The tumors were surgically removed via posterior median approach with the monitoring of the somatosensory-evoked potentials to minimize the neurological injury. All of the patients were recommonded to receive adjuvant chemotherapy and radiotherapy postoperatively after pothological verified and followed up by clinic interview or telephone postoperatively. Log-rank test was used to calculate the survival rate. Results: Gross total resection and subtotal resection were achieved in 18 patients and partial resection in 9. Twenty patients received adjuvant chemotherapy and (or) radiotherapy, 7 patients did not received chemoradiation postoperatively. Nineteen patients died and 8 were alive at the last follow-up. The median survival time was 23 months with 1 and 2-year survival rates of 85.2% and 50.0%.There was no statistical significance between subtotal resection group and partial resection group(chi(2)=0.089, P=0.880), the survival rates of patients in chemotherapy group and radiotherapy group were increased significantly(chi(2)=6.687, P=0.001; chi(2)=14.887, P=0.002). Conclusions: Spinal cord AA is a rare spinal high-grade astrocytoma with aggressive nature, the prognosis remains poor even after comprehensive treatments. Microsurgery followed by adjuvant chemoradiation is recommended for the treatment. PMID- 28592078 TI - [Treatment of single one-stage posterior atlantoaxial fixation in Chiari malformation]. AB - Objective: To explore the effects of surgical technique of single one-stage posterior C(1-2) screw rod fixation of Chiari malformation (CM) associated with occipitalization and without atlantoaxial dislocation. Methods: A total of 23 patients with CM treated between January 2014 and October 2015 in Department of Neurosurgery of Chinese People's Liberation Army General Hospital were retrospective reviewed. All of them were diagnosis with CM associated with occipitalization and without atlantoaxial dislocation, including 8 males and 15 females, aging from 11 to 57 years (mean (35.5+/-10.52) years). Single one-stage posterior C(1-2) screw rod fixation with bone grafting fusion was performed. Operation time and intraoperative blood loss were recorded. Japanese Orthopaedic Association (JOA) scores and Odom rating were used to evaluate the clinical effects at pre- and post-operative. Regression of the cerebellar tonsillar was measured by MRI. The results were analyzed by paired samples t test. Results: Twenty-three patients were implanted screws successfully, the vertebral artery injury and cerebrospinal fluid leakage were not found. The mean operation time was (172.7+/-19.9) minutes, the intraoperative blood loss was (153.9+/-49.3) ml. Compared to preoperative, the JOA score increased (13.7+/-1.6 vs. 11.5+/-1.4) and the tonsillar herniation decreased ((0.8+/-0.6)cm vs. (1.9+/-0.6) cm) in the last follow-up, there were statistical difference (t=13.386, P<0.01; t=17.995, P<0.01). The results of the postoperative Odom grading were as follows: 6 cases were perfect (26.1%), 13 cases were good (56.5%), 4 cases were moderate (17.4%) and no case was poor.No signs of instrument loosen or screw broken was noticed. 100% bony fusion rate was achieved. The follow-up time was 6 to 23 months (mean (10.5+/-3.2) months). One case developed internal fixator related discomfort, the symptom was relieved by internal fixator removal surgery performed 4 months after the operation when osseous fusion had already been achieved. No new neurologic symptoms were observed in other 22 patients. Conclusions: The results of the study substantiates the effectiveness of single one-stage posterior fixation strategy for CM, which is associated with occipitalization and without atlantoaxial dislocation. This technique could be an alternative choice for this type of CM. PMID- 28592079 TI - [Endovascular aortic repair of abdominal aortic aneurysm of short neck with Endurant stent graft]. AB - Objective: To evaluate the safety and effectiveness of the Endurant stent graft for abdominal aortic aneurysm cases with proximal neck length <10 mm. Methods: This study was a retrospective analysis. From January 2010 to May 2015, 22 consecutive abdominal aortic aneurysm patients with proximal neck length <10 mm were treated with endovascular aortic repair by Endurant stent graft in Department of Vascular Surgery, Zhongshan Hospital, Fudan University. There were 19 (86.3%) male cases, aging from 57 to 84 years. All patients underwent preoperative CT angiography and the anatomic parameters of abdominal aortic aneurysm were measured. All patients performed standard endovascular aortic repair first and if there was obvious proximal typeI endoleak, the CUFF or the chimney technology were applied to observed the perioperative technical and the clinical success rate. During follow-up, the incidence of adverse events and the reintervention rate were observed. Results: These 22 cases had proximal neck length 5 to 9 mm with the average of (7.2+/-1.4) mm. Immediate endoleak occurred in 5 patients with 4 cases of proximal typeI endoleak, 3 cases were implanted proximal CUFF, 1 case implanted CUFF and left renal artery chimney. One case died perioperatively, the clinical success rate was 95.4%, the technical success rate was 77.3%. During the follow-up of 6 to 54 months, there was 1 case with delayed proximal type-1 endoleak, during operation the patient had no endoleak, but disappeared 6 months later without further intervention. So the incidence of adverse event was 4.5% and reintervention rate was 0. Conclusion: The Endurant stent graft for abdominal aortic aneurysm cases with proximal neck length < 10 mm is safe and effective. PMID- 28592080 TI - [Complete revascularization for multi-vessel coronary diseases through lower ministernotomy on beating heart off-pump surgery]. AB - Objective: To discuss a novel method of complete revascularization for multi vessel coronary diseases on beating heart off-pump surgery through lower ministernotomy. Methods: Clinical data of 79 patients underwent ministernotomy off-pump coronary artery bypass from January 2015 to May 2016 at Department of Cardiac Surgery, Heart Center, Beijing Friendship Hospital, Capital Medical University were analyzed retrospectively. There were 62 male and 17 female patients, with an average age of (65+/-9) years. All the patients were multi vessel coronary diseases and planned to receive coronary artery bypass grafting. Left internal mammary artery, radial artery and great saphenous veins were harvested and prepared, respectively. The perioperative clinical data was observed and collected. Postoperative ventilator-assisted time, intensive care time, and 24-hour thoracic mediastinal drainage volume were recorded. Postoperative cardiac function was evaluated by echocardiography. The data were compared between pre- and post-operative using paired t test. Results: Cardiopulmonary bypass was used in 2 patients during operation because of unstable hemodynamic status, but the incision was not needed to extend for those 2 patients. The lower ministernotomy was converted to traditional full sternotomy in 2 patients due to limited space for proximal anastomosis. In total, 79 patients had an average of (2.8+/-0.6) grafts. One proximal anastomosis was performed in 75 patients and 2 anastomoses in 4 patients. Distal target vessels consisted of left descending arteries for 79 patients, posterior descending artery for 60 patients, obtuse marginal branch and intermediate branch for 56 patients and diagonal branches for 25 patients, respectively. Average postoperative ventilation time was (19.0+/-2.2) hours and ICU stay was (60+/-20) hours. One patient developed postoperative myocardial infarction and needed temporary intra-aortic balloon pump support. One patient was subjected to incision infection. None of patient died in this study. There were no significant differences in left ventricular end-diastolic diameter and left ventricular end systolic diameter between pre- and post-operative. The post-operative ejection fraction was significantly higher than that pre-operative (66.5%+/-1.6% vs. 61.2%+/-2.3%, t=4.30, P=0.00). Conclusion: With lower ministernotomy, the various sites of distal target vessels could be reached and complete revascularization could be achieved for selected patients with triple vessel diseases, although the procedure is technical demanding. PMID- 28592081 TI - [Comparison of transthoracic or percutaneous balloon pulmonary valvuloplasty in the therapy of pulmonary valve stenosis]. AB - Objective: To compare the clinical outcome of patients with pulmonary valve stenosis underwent transthoracic and percutaneous balloon pulmonary valvuloplasty. Methods: Clinical data of 806 patients diagnosed as pulmonary valve stenosis underwent transthoracic(171 patients as group A)or percutaneous balloon pulmonary valvuloplasty (635 patients as Group B) in Fuwai Hospital from February 2006 to January 2016 were analyzed retrospectively. There were 72 males in group A (42.1%) and 344 males in group B (54.2%). The average age was (1.6+/ 1.1) years in group A and (21.0+/-18.5) years in group B. The median weight was 7.65 (7.68) kg (M(Q(R))) in group A and 43.75 (47.38) kg in group B. There were 732 (90.9%) patients followed up from 3 months to 10 years, with an average interval of (6.3+/-3.6) years. Sixty cases were ligated patent ductus arteriosus simultaneously, and 20 cases got Blalock-Taussig shunt at the same time of valvuloplasty in group A. There were 47 cases of transcatheter closure of atrial septal defect and 6 cases of transcatheter closure of patent ductus arteriosus in group B. The t test, rank sum test and chi(2) test were used to compare data of two groups. Results: There were no hospital death or cardiac tamponade and other serious complications for all patients. The postoperative hospital stayin group A was significantly longer than that in group B (8(5) days vs. 2(2) days, Z=-9.404, P=0.000). In every further consultation, patients were reviewed with transthoracic echocardiography to assess transpulmonary gradient and pulmonary regurgitation. There were significant difference between group A and B of preoperative transpulmonary pressure gradient ((80.6+/-22.4) mmHg vs.(72.6+/ 20.5) mmHg, t=1.611, P=0.032, 1 mmHg=0.133 kPa) and so as transpulmonary pressure gradient reduction value ((55.9+/-21.0) mmHg vs. (46.6+/-23.4) mmHg, t=-1.710, P=0.026). Patients in both groups had good cardiac function during follow-up interval. One patient needed surgical valvuloplasty 10 months after percutaneous balloon pulmonary valvuloplasty and 1 case occurred moderate to severe tricuspid regurgitation in group B. During follow-up period, there was no significant difference between group A and B of transpulmonary pressure gradient ((22.3+/ 6.5) mmHg vs. (25.2+/-12.6) mmHg, t=1.320, P=0.072), the incidence of pulmonary valve regurgitation in patients of group A was significantly lower than patients of group B (56.1% vs.65.2%, chi(2)=4.755, P=0.029). Conclusions: The clinical outcome and complications are similar between patients underwent two different routes of balloon pulmonary valvuloplasty. Transthoracic balloon pulmonary valvuloplasty is more suitable for infant and underweight children patients with pulmonary valve stenosis. Percutaneous balloon pulmonary valvuloplasty is more suitable for the treatment of the elder children or adults. PMID- 28592082 TI - [Expression of nucleolar protein 14 and CD31 in pancreatic cancer mouse model and its correlation with tumor progression]. AB - Objective: To investigate expression of nucleolar protein 14(NOP14) and CD31 in pancreatic cancer mouse model and its correlation with tumor progression. Methods: Clinicopathological data of 5 patients with pathologically confirmed pancreatic ductal adenocarcinoma(PDAC) and hepatic metastasis between January 2013 and December 2015 was collected in Department of General Surgery, Peking Union Medical College Hospital. Immunohistochemistry staining was employed to detect the expression of NOP14 in matched primary PDAC and relevant metastasis.Pancreatic cancer cells with NOP14 stably knocked down were established by transfecting lentivirus with NOP14 targeted silencing RNA.The inhibition efficacy was detected by quantitative real time PCR and western blot.Microvascular density(MVD) in pancreatic cancer transplantation mouse model was determined by CD31 immunohistochemistry staining analysis and correlated with NOP14 expression and tumor progression. Results: NOP14 had a significant higher expression in liver metastasis than primary pancreatic adenocarcinoma (2.09+/ 0.45 vs. 1.31+/-0.27, P=0.028). NOP14 was knocked down 86 percent on mRNA level determined by qPCR and 78 percents on protein level detected by western blot. MVD was significantly decreased in NOP14-inhibited tumor from both pancreatic cancer cells subcutaneously and orthotopically grafted tumor mouse model with the value of 61.40+/-13.85 vs. 85.53+/-14.59 (P=0.041) and 38.33+/-10.91 vs. 59.33+/ 15.37(P =0.037), respectively. Besides, MVD was positively associated with tumor volume(r=0.842, P<0.01) and metastasis (r=0.726, P=0.008). Conclusion: NOP14 presents higher expression in hepatic metastasis of pancreatic adenocarcinoma and might promote tumor progression by increasing microvascular density. PMID- 28592083 TI - [Correlation between miR-1178 expression and clinicopathological significance in human pancreatic cancer]. AB - Objective: To test the expression of miR-1178 in pancreatic cancer and study its clinicopathological significance and mechanism. Methods: The expression of miR 1178 in 87 paired paraffin pancreatic ductal adenocarcinoma specimens and adjacent non- cancerous pancreatic tissue diagnosed by Pathology Department of Peking Union Medical College Hospital was detected by hybridization in situ. The relationship between the expression of miR-1178 and clinicopathological characters was analyzed.miR-1178 mimics and inhibitor were used to further detect the close relationship among miR-1178 and cancer invasion. Establish a nude mice subcutaneously transplanted tumor model, 4 weeks after vaccination for tumor volume and weight measurement.Student t-test, rank sum test, and chi(2) test was used respectively to compare the data between two groups. Cox regression was adopted to improve the single factor and multiple factors analysis. Results: The results of hybridization in situ showed the expression of miR-1178 was increased in 72 cases with pancreatic cancer compared to that in paired normal pancreatic tissues (50/72 vs. 11/72, chi(2)=43.26, P<0.05). miR-1178 expression was positively associated with tumor lymph node stage (chi(2)=4.189, P=0.041). Univariate and multivariate analysis revealed that miR-1178 was an independent adverse prognostic indicator for patients with pancreatic cancer (HR=2.364, 95%CI: 1.114-5.019, P=0.025). Transwell assay indicated the over-expression of miR-1178 increased the number of AsPC-1 cells that penetrated the ECM-coated membrane (177.0+/-19.8 vs. 119.7+/-15.9)(chi(2)=8.21, P<0.05). For the in vivo experiment, overexpression of miR-1178 significantly promoted tumor growth, compared with control group (tumor volume: (5 122.4+/-760.2)mm(3) vs. (1 976.8+/ 601.8)mm(3), t=2.413, P<0.05; tumor weight: (1.55+/-0.21)g vs. (0.67+/-0.17)g, t=2.960, P<0.05). Over-expression of miR-1178 down-regulated the expression of Stub1 and elevated the expression of FAK/MMP-9 signal pathway(P<0.05). Conclusions: MiR-1178 is overexpressed in pancreatic cancer, and is effective for predicting patients' prognosis. MiR-1178 regulate Stub1/FAK/MMP-9 signal pathway and promote the invasion of AsPC-1 cells. PMID- 28592085 TI - [The review and significance of national seroepidemiological surveys on viral hepatitis in China]. PMID- 28592084 TI - [Modified capsular arthroplasty for young patients with developmental dislocation of the hip]. AB - Developmental dislocation of the hip(DDH) is one of the most serious hip diseases. Patients with unilateral DDH are prone to secondary osteoarthritis, low back pain, gait disturbance and compensatory scoliosis because of the leg length discrepancy. Total hip arthroplasty(THA) is the highly effective treatment for patients with hip pain or dysfunction caused by unilateral DDH, thus decrease the demand for hip-preserving surgeries such as capsular arthroplasty which may postpone or avoid hip replacement. However, the failure rate of THA for young patients is high and the majority of young patients may require one or more revision arthroplasties throughout their lifetime. The basic principle of capsular arthroplasty is that the femoral head wrapped by capsule is placed into a newly reamed socket on the location of true acetabulum. Therefore, hip replacement for patients with previous capsular arthroplasty becomes easier and safer than primary THA. However, the early capsular arthroplasty have been abandoned due to the relatively high rates of femoral head necrosis and hip stiffness. Ganz modified the early procedure with the technique of surgical hip dislocation in 2012, and emphasized the importance of postoperative rehabilitation. The incidence of complication, therefore, decreased greatly due to the preservation of main blood supply of femoral head as well as the proper postoperative management. In order to improve the clinical outcomes of this modified procedure, the selection of indications and surgeons' experience should also be taken into consideration. PMID- 28592086 TI - [Comparative analyze on hepatitis B seroepidemiological surveys among population aged 1-29 years in different epidemic regions of China in 1992 and 2014]. AB - Objective: To evaluate the effect of hepatitis B prevention and control by comparative analysis on the results of HBsAg, anti-HBs and anti-HBc prevalence from national hepatitis B seroepidemiological surveys in 1992 and 2014 in different epidemic regions of China. Methods: Data was from the national seroepidemiological surveys of hepatitis B conducted in 1992 and 2014. The survey in 1992 was conducted in 145 disease surveillance points of 30 provinces (excluding Hong Kong, Macao Special Administrative Region and Taiwan province) in China. The survey in 2016 was conducted in 160 disease surveillance points of 31 provinces (excluding Hong Kong, Macao Special Administrative Region and Taiwan province) in China. In the two surveys, face-to-face interviews with the subject by door to door or on the investigation site were conducted by trained staff using standard questionnaires to obtain basic information including birth date, gender, ethnicity, resident place and so on. And then 5 ml venous blood was collected to test the sero-markers of HBsAg, anti-HBs and anti-HBc. We analyzed unweighted point prevalence and 95% CI of HBsAg, anti-HBs and anti-HBc in 1992 which had no design weighting, and analyzed weighted point prevalence and 95%CI of HBsAg, anti-HBs and anti-HBc in 2014 which had design weighting. Results: 34 291 and 31 713 people aged 1-29 years were involved in 1992 and 2014 national serosurveys of China, respectively. For the people aged 1-29 years, HBsAg prevalence was 2.64% (95%CI: 2.28%-3.06%) in 2014 and decreased by 73.92% as compared with the rate 10.13% (95% CI: 9.81%-10.45%) in 1992. Anti-HBc prevalence was 13.01% (95%CI: 12.09%-14.00%) in 2014 and decreased by 71.61% as compared with the rate 45.84% (95% CI: 45.31%-46.37%) in 1992. Anti-HBs prevalence was 57.79% (95%CI: 56.33%-59.25%) in 2014 and ascended by 127.41% as compared with the rate 25.41% (95% CI: 24.95%-25.87%) in 1992. In high, medium and low epidemic region, for the people who born during 1992-2001 when hepatitis B vaccine was introduced in routine immunization management, HBsAg prevalence was 4.74% (95%CI: 3.79%-5.69%), 1.59% (95%CI: 1.09%-2.10%) and 2.53% (95%CI: 1.66%-3.39%), respectively, and anti-HBs prevalence was 64.25% (95% CI: 62.11%-66.39%), 56.34% (95% CI: 54.50%-58.57%), 54.49% (95%CI: 51.75%-57.23%), respectively, and anti HBc prevalence was 15.16% (95%CI: 13.56%-16.76%), 11.07% (95%CI: 9.80%-12.33%), 7.61% (95%CI: 6.15%-9.07%), respectively. In high, medium and low epidemic region, for the people who born during 2002-2013 the duration which hepatitis B vaccine was integrated in expanded immunization program born during when HBsAg prevalence was 0.88% (95%CI: 0.66%-1.11%), 0.37% (95%CI: 0.24%-0.49%)and 0.71% (95%CI: 0.48%-0.94%), respectively, and anti-HBs prevalence was 60.74% (95%CI: 59.57%-61.90%), 59.46% (95%CI: 58.44%-60.49%), 52.56% (95% CI: 51.20%-53.92%), respectively, and anti-HBc prevalence was 3.30% (95% CI: 2.87%-3.72%), 1.91% (95%CI: 1.63%-2.20%), 2.25% (95%CI: 1.85%-2.66%), respectively. Conclusion: China had made great achievement in hepatitis B prevention and control. HBsAg prevalence among people aged 1-29 years old in 2014 decreased dramatically as compared with that in 1992. Since hepatitis B vaccine was integrated into expanded immunization program, China reduced HBsAg prevalence to less than 1% among people aged 1-12 years in 2014 in different epidemic region. PMID- 28592087 TI - [Analysis on sero-epidemiological characteristics of hepatitis B virus among people born during 1994-2001 before and after hepatitis B vaccine catch-up vaccination, China]. AB - Objective: To analyze the sero-epidemiological characteristics of hepatitis B virus among people born during 1994-2001, conducted by the national hepatitis B sero-epidemiological surveys in 2006 and 2014. Methods: Based on the data of the two national hepatitis B sero-epidemiological surveys in 2006 and 2014, people born during 1994-2001 were included into our analysis as this study subjects. The two surveys were conducted in 160 disease surveillance points of 31 provinces (not including Hong Kong, Macao and Taiwan) in China. Face-to-face interviews with the subject by door to door or on the investigation site were conducted by trained staff using standard questionnaires to obtain basic information including birth date, sex, ethnicity, resident place and so on. And then 5 ml venous blood was collected. Enzyme-linked immunosorbent assay (ELISA) reagents were used for HBsAg, anti-HBs and anti-HBc measurements and Abbott micro-particle enzyme immunoassay (MEIA) reagents was used to confirm test. We analyzed HBsAg, anti-HBs and anti-HBc positive rate by gender, ethnicity, urban/rural, eastern/central/western region, birth years and compared the distribution of serum epidemiological characteristics in 2006 and 2014. Results: 19 821 and 4 712 people born during 1994-2001 were involved in 2006 and 2014 national serosurveys of China, respectively. For the people born during 1994-2001, HBsAg positive rate were 2.02% (95% CI: 1.82%-2.21%) in 2014 and 1.95% (95% CI: 1.56%-2.35%) in 2006. Anti-HBc positive rate were 7.94% (95%CI: 7.17%-8.71%) in 2014 and higher than that in 2006 (6.49%, 95%CI: 6.15%-6.83%), especially for the female (8.31%, 95% CI: 7.20%-9.43%), urban (7.45%, 95% CI: 6.38%-8.52%), western region (11.25%, 95%CI: 9.79%-12.71%), minority people (16.02%, 95%CI: 13.47%-18.57%) in 2014 were higher than that of the female (6.29%, 95% CI: 5.81%-6.78%), urban (4.82%, 95% CI: 4.40%-5.24%), western region (7.97%, 95% CI: 7.31%-8.63%), minority people (11.88%, 95% CI: 10.66%-13.00%) in 2006 respectively. Anti-HBs positive rate were 57.80% (95%CI: 57.11%-58.48%) in 2014 and 59.13% (95%CI: 57.72%-60.53%) in 2006. Anti-HBs positive rate of rural (58.80%, 95% CI: 56.83%-60.78%),western region (58.50%, 95% CI: 56.23%-60.78%), minority people (57.20%, 95% CI: 53.76%-60.63%) in 2014 was higher than of rural (52.62%, 95% CI: 51.64%-53.61%),western region (51.73%, 95% CI: 50.54%-52.96%),minority people (41.14%, 95%CI: 39.28%-43.00%) in 2006. Conclusion: Anti-HBc positive rate among people born during 1994-2001 in 2014 survey showed a rising tendency than in 2006. The risk of HBV infection was existed. Hepatitis B vaccine catch-up in childhood was necessary. PMID- 28592088 TI - [Hepatitis B prevalence among women in child-bearing age in Shandong Province, China, 2014]. AB - Objective: To know the prevalence of hepatitis B virus (HBV) among women in child bearing age in Shandong Province, China, providing references to the improvement of HBV control strategy. Methods: The participants were randomly selected by two stage sampling method from 12 counties which were representative for the whole province. Firstly two townships were selected from each county by probability proportional to size sampling (PPS) method. Then participants aged 1-4 years, 5 14 years, 15-29 years and 30-59 years were selected by stratified random sampling method. The women in child-bearing age (20-49 years) were involved in this study. Questionnaire survey and 5 ml blood collection were conducted among all participants. Blood samples were detected for hepatitis B surface antigen (HBsAg), antibody against HBsAg (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc). Those who were positive for HBsAg were further detected for hepatitis e antigen (HBeAg), antibody against HBeAg (anti-HBe) and the load of HBV DNA. The basic information of the participants including age, gender, occupation, nationality and residence place were collected. The prevalence of HBV infection indicators after weight adjustment were calculated and compared between participants with different demographic characteristics. Results: A total of 1 151 women in child-bearing age were involved in this study. Twenty-seven participants were positive for HBsAg and the prevalence rate was 2.10% (95% CI: 0.97%-3.23%). Five participants were positive for both HBsAg and HBeAg and the prevalence rate was 0.36% (95% CI: 0-0.84%). There were 567 and 291 participants who were positive for anti-HBs and anti-HBc respectively and the corresponding prevalence rates were 47.72% (95%CI: 41.68%-53.75%) and 24.40% (95% CI: 18.50% 30.30%). The number of participants susceptible for HBV was 527 and the percentage of HBV susceptible women was 47.55% (95% CI: 41.63%-53.47%). Conclusion: HBV infection among women in child-bearing age has attained very low level in Shandong Province, China. However, the high proportion of women in child bearing age were still susceptible for HBV and hepatitis B immunization should be improved among them. PMID- 28592089 TI - [Prevalence of hepatitis A antibody among population covered by different hepatitis A immunization strategies in Shandong Province, 2015, China]. AB - Objective: To evaluate prevalence of hepatitis A antibody (anti-HAV IgG) among population covered by different hepatitis A vaccine immunization strategies in Shandong Province in 2015. Methods: In October 2015, according to the geographical location of Shandong Province, the stratified random sampling method was used to stratify the 17 municipal distrcts, and the random number table method was used for sampling, First, two eastern cites (Qingdao, Rizhao), two western cities (Liaocheng, Zaozhuang) and three central cities (Jinan, Zibo and Laiwu) were selected; secondly, one county was drawn from each city. Finally, the participants were divided into five age groups including <=7 years (age group covered by free hepatitis A vaccination strategy), 8-11 years (age group who receive hepatitis A vaccination at their own charge), 12-24 years (age group covered by catch-up vaccination of hepatitis A), 25-34 years (age group born before hepatitis A vaccine was used) and >=35 years (age group born before hepatitis A vaccine was used). After all the paticipants or their guardians asked and registered basic information such as age, gender, home address, blood samples were collected from them and anti-HAV IgG was detected by ELISA method. The positive rate of anti-HAV IgG and 95%CI were calculated. Results: A total of 1 654 participants were involved in the final analysis, including 856 males (51.75%) and 798 females (48.25%) whose mean age was (13.44+/-13.06) years. The crude positive rate of anti-HAV IgG was 91.41% (1 512/1 654, 95%CI: 89.96% 92.72%) and the age-adjusted rate was 90.93% (95%CI: 90.92%-90.94%). The positive rates of anti-HAV IgG was at the highest level in the age group of <=7 years (95.90%, 95%CI: 95.88%-95.91%) and was at the lowest level in the age group of 25 34 years (83.23%, 95%CI: 83.21%-83.25%). The age-specific positive rates of anti HAV IgG in eastern areas (96.79%, 95%CI: 96.78%-96.80%) were higher than those in both middle areas (86.66%, 95%CI: 86.65%-86.67%) and western areas (91.96%, 95%CI: 91.95%-91.97%). Conclusion: The positive rate of anti-HAV IgG was high among the general population in Shandong Province, but relatively low among young and middle-aged adults. Besides the routine immunization of hepatitis A among the children, more efforts should be taken for the prevention and control of hepatitis A among young and middle-aged adults in Shandong Province, especially in central and western areas. PMID- 28592090 TI - [A cross-sectional study of seroepidemiology of viral hepatitis among Uighurs in Shufu of Xinjiang]. AB - Objective: To explore the status of seroepidemiology on hepatitis A, B and C among students and residents aged equal or greater than 18 years in south Xinjiang, and to provide scientific evidence for prevention and control of viral hepatitis. Methods: Uyghur students in four towns and villages were selected by cluster random sampling from Feb to May, 2015, and Uyghur residents aged 18 to 69 years were selected by stratified cluster sampling from May to September, 2016. 4 507 middle and primary Uygur students and 4 833 Uyghur resides equal or greater than 18 years attended this survey. Self-designed questionnaire was used to collect the demographic information. And Elisa test was adopted to detect HAV IgG, HBsAg, HBsAb and HCV-IgG. Chi-square test was used to calculate the difference on antibody positive rate of three types of hepatitis among the participants. Results: The overall HAV-IgG positive rate was 99.45% (9 289/9 340). The positive rates were 99.70% (4 006/4 018) in male and 99.27% (5 283/5 322) in female (chi(2)=7.95, P=0.005). The HAV-IgG positive rate among people aged 10 to 14 years was the highest (99.91%, 2 233/2 235), and the difference between the age specific HAV-IgG positive rates was statistical significant (chi(2)=38.21, P<0.001). The overall HBsAg positive rate was 4.11% (384 cases), with 4.55% (183 cases) for male and 3.78% (201 cases) for female. The HBsAg positive rate among participants 19 to 24 years old was the highest (9.46%, 21/222) and the differences between the age specific HBsAg was statistically significant (chi(2)=116.22, P<0.001). The HBsAb positive rate was 35.03% (3 272 cases), with 35.59% (1 430 cases) for male and 34.61% (1 842 cases) for female, and the HBsAb positive rate among participants aged 15 to 18 years was the highest, which was 69.12% (696/1 007). The differences between the age specific HBsAb rates appeared statistically significant (chi(2)=671.80, P<0.001). The overall HCV-IgG positive rate was 0.65%(61 cases). The HCV-IgG positive rate in female was 0.86% (46 cases) and 0.37% (15 cases) in male (chi(2)=8.51, P=0.004).The HCV-IgG positive rate among participants aged over 70 years was the highest (3.78%,9/238) , and the difference between the age specific HCV-IgG positive rates had statistic significance (chi(2)=70.30, P<0.001). The HAV-IgG positive rate in hepatitis A vaccinees (100%, 876/876) was higher than that among the non-vaccinees (99.40%, 8 413/8 464) (chi(2)=4.26, P=0.039). The HBsAb positive rate in hepatitis B vaccinees was 39.32% (1 816/4 619) which was higher than that among the non-vaccinees (30.84%, 1 456/4 721) (chi(2)=73.68, P<0.001). Conclusion: The positive rate of overall HAV-IgG was high, male and participants aged between 10 to 14 had higher probability to be infected. But the infection rates of hepatitis B and C were low, with the low vaccination rate and the poor protective effectiveness of hepatitis B. PMID- 28592091 TI - [Anti-HBs persistence after revaccination with three doses of hepatitis B vaccine among low-responder infants following primary vaccination: 4-year of follow-up]. AB - Objective: Assess the 4-year antibody against hepatitis B surface antigen (anti HBs) persistence after revaccination with 3-dose of hepatitis B vaccine (HepB) among low-responder infants following primary vaccination. Methods: According to stratified cluster sampling, a total of 4 147 infants were enrolled and primarily vaccinated with 5 MUg HepB derived in Saccharomyces Cerevisiae (HepB-SC) at 0-1-6 months schedule from 75 towns of Jinan, Weifang, Yantai, Weihai prefectures, Shandong Province, China in Aug and Sep 2009. Blood samples were collected one to six months after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). 717 infants who appeared low response (10 mU/ml <= anti-HBs<100 mU/ml) were revaccinated with 3 dose of HepB. Blood samples were collected from a total of 315 infants one month (T(0)), four years (T(1)) after revaccination and anti-HBs, antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (HBsAg) were detected by CMIA. Information about their birth, primary vaccination were collected. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple non-conditional logistic regression analysis and multifactor linear regression model analysis, respectively. Results: Among 315 children, 165 (52.38%) were male and 150 (47.62%) were female. The positive rate was 83.81% (264/315) at T(0) and it decreased to 16.51% (149/529) at T(1). The corresponding GMC decreased from 473.15 mU/ml to 17.37 mU/ml. The average annual decreasing rate of positive rate and GMC was 33.38% and 56.23% from T(0) to T(1). Multivariable analysis showed the positive rate and GMC among those whose anti-HBs titer higher at T(0) were significantly higher at T(1). The positive rate at T(1) among those whose anti-HBs titer 400-<600, 600-<800, 800-<1 000, >=1 000 mU/ml at T(0) were significantly higher than those whose anti-HBs titer less than 200 mU/ml. The OR (95%CI) of the positive rate was 4.29 (1.03 17.84), 4.53 (1.25-16.47), 4.19 (1.10-15.97) and 9.13 (2.91-28.63), respectively. The GMC at T(1) among those whose anti-HBs titer 400-<600, 600-<800, 800-<1 000 mU/ml and those whose anti-HBs titer >=1 000 mU/ml at T(0) were higher than those whose anti-HBs titer<200 mU/ml. The b value (95% CI) of GMC was 0.84 (0.06-1.62), 1.13 (0.46-1.79), 1.33 (0.65-2.01) and 1.88 (1.33-2.44), respectively. GMC among full-term infants were significantly higher than premature infants at T(1). The b value (95% CI) of GMC was 0.86 (0.04-1.68). Conclusion: Anti-HBs GMC decreased rapidly 4 years after revaccination among low-responder infants, but still kept good protection. The anti-HBs persistence after revaccination was associated with anti-HBs level of titer one month after revaccination. PMID- 28592092 TI - [Early physical growth and disease analysis among children born delivered by HBsAg-positive mothers]. AB - Objective: To estimate the early physical growth and disease in children born to HBsAg-positive mothers. Methods: This was a retrospective cohort study. Three areas as Xihu in Hangzhou, Lanxi in Jinhua, and Haiyan in Jiaxing in Zhejiang province were selected by cluster sampling. The growth outcomes of children born to HBsAg-positive mothers (exposure group) and matched 1?1 women uninfected with HBV (control group) in 2014 were investigated and compared at birth, 6, 9, 12, and 18 months, respectively. There were totally 342 children in each group. Results: The incidences of low birth weight (LBW) for children born to exposure and control group were 1.8% (6/342), and 2.6% (9/342), respectively (P=0.433); and, rates of preterm birth were 2.3% (8/342), and 2.0% (7/342), respectively (P=0.794). The mean birth weight of children born to mothers without HBV infection (3.4+/-0.4) kg was dramatically higher than children in exposure group (3.3+/-0.4) kg (P=0.019). At 18 months, the average head circumference was significantly greater among children in control group (47.3+/-1.3) cm than children in exposure group (47.0+/-2.0) cm (P=0.038). Additional, mean birth weeks, height, weight, increases in height/weight/head circumference each month, weight/height/head circumference for age Z scores, proportion of growth retardation and low weight, disease prevalence were not observed statistically differences between two groups (P>0.05). All children born to HBsAg-positive mothers were received three-dose HBV vaccination. The rate of hepatitis B immunoglobulin for births born to HBsAg-positive was 98.8% (338/342). Mother to children transmission of HBV at 18 months was 1.0% (1/97). Conclusion: No significant differences in growth development and disease prevalence were found among children born to HBsAg-positive women and women without HBV infection. PMID- 28592093 TI - [Comparative analysis of hepatitis B virus large protein, hepatitis B virus-DNA and Pre-S1 antigen in evaluating serum hepatitis B virus replication]. AB - Objective: To investigate the comparative study of serum hepatitis B virus (HBV) large protein (HBV-LP) , HBV-DNA, and Pre S1 antigen (Pre S1-Ag) detection in the evaluation of serum HBV replication in patients with chronic hepatitis B. Methods: A total of 482 patients infected with chronic hepatitis B virus (CHB) were enrolled and the serums were collected in a hospital of Hefei city in Anhui province from June 2013 to March 2015. The serum HBV-LP, HBV markers(HBV-M) and Pre S1-Ag were detected using ELISA, and HBV-DNA were quantified using quantitative real-time PCR. The positive detection rate difference of HBV-DNA, HBV-LP and Pre S1-Ag were compared, the correlation between the logarithm of HBV DNA copies number and the absorbance value of HBV-LP was analyzed using Spearman rank correlation. Results: The positive rates of HBV DNA, HBV-LP, and Pre S1-Ag were 67.22% (324/482), 73.86% (356/482), and 37.34% (180/482), respectively (P<0.01). The positive rates of the three markers were 54.57% (185/339), 64.90% (220/339), and 27.73% (94/339), respectively, in 339 HBeAg-negative CHB patients (P<0.01). In HBeAg negative patients, the positive rate of HBV-LP in 185 cases of HBV-DNA positive samples was 90.81% (168/185), which was higher than that of Pre S1-Ag with rate of 39.46% (73/185) (P<0.01).The positive rate of HBV-LP was 33.77% (52/154) in 154 cases of patients with negative HBV-DNA whose positive rate was higher than Pre S1-Ag with positive rate of 13.64% (21/154)(P<0.01). The positive rates of HBV-DNA, HBV-LP and Pre S1-Ag in HBsAg, HBeAg and HBcAb positive groups were 97.04% (131/135), 94.81% (128/135), and 60.00% (81/135), (P<0.01); The positive rates of three indexes of HBsAg, HBeAb, HBcAb positive group were 53.74% (122/227), 63.88% (145/227), and 27.31% (62/227); The positive rates of three indexes of HBsAg and HBcAb positive group were 55.79% (53/95), 67.37% (64/95), and 28.42% (27/95) (P<0.01). The absorbance value of HBV-LP was positively related with the logarithm of HBV-DNA copies number (Spearman rank correlation coefficient was 0.908, P<0.01). Conclusion: There was a good correlation between HBV-LP and HBV-DNA load value, and could be used as an effective complement for the detection of HBV-DNA and HBV-M. Compared with Pre S1 Ag. PMID- 28592095 TI - [The epidemic status of metabolic syndrome among Chinese adolescents aged 10-17 years in 2010-2012]. AB - Objective: To invesigate the epidemic status of the metabolic syndrome (MS) among mainland Chinese adolescents aged 10-17 in 2010-2012. Methods: Data were collected from Chinese Nutrition and Health Surveillance in 2010-2012. Multi stage stratified proportion to the population cluster random sampling method was conducted to determine 16 872 adolescents in 150 counties from 31 provinces in mainland China. The epidemic status of metabolic syndrome was analyzed by China criterion (defined by Chinese Pediatric Society, Chinese Medical Association) and Cook criterion, respectively. The prevalence of MS and 95%CI were calculated through weighted complex sampling processing by population data released by the National Bureau of Statistics in 2009. Results: Based on China criterion, the weighted prevalence of MS was 2.4% (95% CI: 2.1%-2.6%) among Chinese adolescents aged 10-17. Prevalence in urban was higher than in rural (2.8%, 95%CI: 2.4%-3.2% and 1.9%, 95%CI:1.6%-2.3%, respectively). Prevalence in boys and girls were 2.7% (95% CI: 2.3%-3.0%), and 2.0% (95% CI: 1.7%-2.4%), respectively. Based on Cook criterion, the weighted prevalence was 4.3% (95% CI: 4.0%-4.7%) . The highest weighted prevalence of the components of the metabolic syndrome was low high density lipoprotein cholesterol (26.8%, 95% CI: 26.0%-27.5%), followed by high fasting glucose (11.5%, 95% CI: 11.0%-12.0%), abdominal obesity (11.1%, 95%CI: 10.6%-11.7%) , hypertriglyceridemia (8.8%, 95%CI: 8.4%-9.3%) , and high blood pressure (6.4%, 95% CI: 6.0%-6.8%). Conclusion: Among the five indicators of metabolic syndrome, the prevalence of central obesity and hypertriglyceridemia were relative high in Chinese adolescents aged 10-17 years, though the prevalence of metabolic syndrome was not high. PMID- 28592094 TI - [Epidemiological characteristics of waist circumference and abdominal obesity among Chinese adults in 2010-2012]. AB - Objective: To investigate the epidemiological characteristics of waist circumference (WC) and abdominal obesity (AO) among Chinese adults aged 18 and above. Methods: Data were collected from China National Nutrition and Health Surveillance in 2010-2012. Multi-stage stratifies proportion to the population cluster random sampling method was conducted to determine 120 265 subjects aged 18 and above at 150 counties in 31 provinces in China mainland. WC was determined for all subjects, and AO was judged according to the "Healthy Adult Weight Determination" (WS/T 428-2013). Using the demographic data published by the National Bureau of Statistics of China in 2009, we performed complex sampling weighted treatment to calculate the WC, AO rate and 95%CI. Results: The mean WC of Chinese men aged 18 and above was 82.8 cm, which of urban men (84.1 cm) was higher than that of rural men (81.4 cm) (P<0.001). The average WC of women was 78.5 cm. There was no statistical difference between urban (78.7 cm) and rural women (78.4 cm) (P=0.965). With the increase of education level, the mean WC of male increased gradually from 81.2 cm to 84.3 cm (P<0.001), and the mean WC of female decreased from 80.3 cm to 74.3 cm (P<0.001). With the family income rose, the mean WC of men increased gradually from 81.9 cm to 84.7 cm (P<0.001), and the mean of WC of women decreased from 78.8 cm to 77.6 cm (P<0.001). The AO rate was 25.7% (95% CI: 23.7%-27.7%) in adults aged 18 years and older. The AO rate in urban males (29.8% (95%CI: 26.5%-33.1%)) was significantly higher than that of rural males (22.3% (95%CI: 19.3%-25.2%)) (P=0.001). There was no significant difference in the female AO rate between urban (25.6% (95%CI: 22.8%-28.4%)) and rural areas (25.1% (95%CI: 22.2%-27.9%)) (P=0.772). With the increase of the educational level, the AO rate of men increased from 20.1% (95%CI: 18.0%-22.1%) to 32.6% (95%CI: 28.6%-36.6%) (P<0.001), the rate of women decreased gradually from 31.3% (95%CI: 28.7%-33.9%) to 13.5% (95%CI: 10.9%-16.1%) (P<0.001). With the increase of family income, the AO rate of male increased gradually from 23.3% (95%CI: 20.7%-25.9%) to 31.8% (95%CI: 27.6%-36.1%) (P<0.001), the rate of female decreased from 26.5% (95% CI: 24.2%-28.7%) to 20.0% (95% CI: 17.2%-22.8%) (P<0.001). Conclusion: The prevalence of AO among Chinese residents aged 18 years and above was high, and there were significant differences in WC and AO rate between men and women under different age, region, educational level and family income level. PMID- 28592096 TI - [Survey on dietary nutrients intake of Chinese residents between 2010 and 2012]. AB - Objective: To investigate the average dietary nutrients intake status among Chinese residents between 2010-2012, and to compare the difference between rural and urban areas. Methods: Data were collected from Chinese Nutrition and Health Surveillance between 2010-2012. Based on regional features and economic development levels, China's county-level divisions were classified into four types: big city, medium and small city, ordinary rural area and poor rural area. A total of 62 857 valid subjects, including 14 017, 16 539, 19 910 and 12 391 respondents in each group separately, were enrolled by Multi-stage stratified proportion to the population cluster random sampling method. The dietary survey was conducted by recalling the 24 h diet in 3 consecutive days and weighting condiment. The daily dietary intake of energy, macronutrient, dietary fiber, vitamin, and mineral substance per resident were calculated based on China Food Composition. Results: The average energy intake per resident in Mainland China was 9 047.1 kJ, with highest (9 719.3 kJ) in poor rural area and lowest (8 490.4 kJ) in medium and small city. The average dietary protein intake was 64.2 g, with highest (73.9 g) in big city and lowest (60.7 g) in poor rural area. The average dietary fat intake was 79.7 g, with highest (89.4 g) in big city and lowest (70.6 g) in poor rural area. The average intake of micronutrients of vitamin A, vitamin B(2), vitamin C, calcium, iron, phosphorus, zinc was separately 441.9 MUg, 0.8 mg, 80.1 mg, 364.3 mg, and 21.4 mg; which were lower than Chinese Dietary Reference Intakes. The percentage of population whose average intake of vitamin A, vitamin B(2), vitamin C, calcium were lower than estimated average requirement was separately 77.0%, 90.2%, 67.7%, and 96.6%. Conclusion: The supply of 3 macronutrient was sufficient in mainland China. However, it was a common issue that there was excessive intake of fat but deficient intake of micronutrients such as vitamin, calcium, iron and zinc. There were differences in nutrition intake among big city, medium and small city, ordinary rural area and poor rural area. PMID- 28592097 TI - [Study on breakfast consumption of children aged from 6-17 in China in 2010 2012]. AB - Objective: To investigate breakfast status and influencing factors among children aged 6-17 in China in 2010-2012. Methods: Data were collected from China National Nutrition and Health Surveillance in 2010-2012. By using multi-stage stratified sampling and population proportional stratified random sampling method, the research objects were 29 393 children, who aged 6 to 17 y from 150 sites in 31 provinces in mainland China. The information of breakfast frequency and the numbers of breakfast dinning out (in restaurant and at schools) in the past week with seven days were collected by questionnaire; and compared by different ages, genders and areas. Results: During the past week, 91.1% (26 776/29 393) of the children aged 6 to 17 y had their breakfast daily, and 94.6% (13 457/14 221) of children aged 6 to 11 y was higher than 87.8% (13 319/15 172) of children aged 12 to 17 y, the highest proportion of the children never eat breakfast (0 time in the past week) found in poor rural areas was 3.6% (189/5 261), the ratio of big cities, small-medium cities and normal rural areas was 1.1% (77/7 104), 0.6% (51/8 361), and 0.6% (54/8 667), respectively (P<0.001). The rate of boys and girls ate their breakfast daily in the past week were 91.3% (13 481/14 761), and 90.9% (13 295/14 632), respectively (P>0.05). Totally 42.2% (12 398/29 393) of children ate breakfast outside-home (the restaurant and the school) in the past week, the percentage of children aged 12 to 17 y and poor rural areas was higher, 50.9% (7 722/15 172), and 52.4% (2 756/5 261), respectively (P<0.001). 42.1% (6 208/14 761) boys and 42.3% (6 190/14 632) girls ate their breakfast outside-home (P>0.05). The place of most school-age children eat outside-home was school, the ratio was 32.2% (9 477/29 393). Conclusion: It was common for school-aged children in China to skip breakfast during their daily lives, especially in poor rural areas and older children, lots of school-aged children ate breakfast outside-home, and most of them ate breakfast in school. PMID- 28592098 TI - [The effect of short-term exposure to ambient NO(2) on lung function and fractional exhaled nitric oxide in 33 chronic obstructive pulmonary disease patients]. AB - Objectives: To investigate the effect of short-term exposure to ambient NO(2) has influence on lung function and fractional exhaled nitric oxide (FeNO) in chronic obstructive pulmonary disease (COPD) patients. Methods: A panel of doctor diagnosed stable COPD patients (n=33) were recruited and repeatedly measured for lung function and FeNO from December 2013 to October 2014. The patients who lived in Beijing for more than one year and aged between 60 and 85 years old were included in the study. We excluded patients with asthma, bronchial tensor, lung cancer and other respiratory disorders other than chronic obstructive pulmonary disease and occupational exposure and chest trauma surgery patients. Because the frequency of each subject visiting to the hospital was different, a total of 170 times of lung function measurements and 215 times of FeNO measurements were conducted. At the same time, the atmospheric NO(2) data of Beijing environmental monitoring station near the residence of each patient during the study period were collected from 1 day to 7 days lag before the measurement. Effects of short term NO(2) exposure on lung function and FeNO in COPD patients were estimated by linear mixed-effects models. Results: The subjects' forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), peak expiratory flow (PEF), and exhaled NO of subjects were (3.26+/-0.83) L, (1.66+/-0.61) L, (4.13+/-1.77) L/s, and (48.99+/-14.30) MUg/m(3), respectively. The concentration of NO(2) was (70.3+/-34.2) MUg/m(3) and the interquartile range (IQR) was 39.0 MUg/m(3). Short term exposure to NO(2) resulted in a significant decrease in FVC among COPD patients' which was most obvious in 2 days lag. Every quartile range increased in NO(2) (39 MUg/m(3), 2 day) would cause a 1.84% (95%CI: -3.20%- -0.48%) reduction in FVC. The effects of exposure to higher concentration of NO(2) (>=58.0 MUg/m(3)) on FVC estimate was -2.32% (95%CI: -4.15%- -0.48%)(P=0.02). No significant relevance of FeNO and NO(2) was observed in this study. Conclusions: Short term exposure to ambient NO(2) may bring down pulmonary function in COPD patients. PMID- 28592099 TI - [Study of the association between polymorphism of persistent obesity, human leptin gene/leptin receptor gene and molecular subtypes of breast cancer]. AB - Objectives: To explore the association between the polymorphism of persistent obesity and genetic variations in the LEP (human leptin gene, LEP) and LEPR (leptin receptor gene, LEPR) genes and different molecular subtypes of breast cancer. Methods: All 703 female patients of breast cancer diagnosed by histopathology in the Sichuan Cancer Hospital or the West China Hospital, excluding patients with metastatic breast cancer or mental disease, were selected as cases from April 2014 to May 2015. At the same time, 805 healthy women received physical examination in medical examination center of Sichuan People Hospital or Shuangliu maternal and child health care hospital, excluding those with therioma, breast disease, and mental disease, were enrolled in control group. A uniform questionnaire was used to collect general information including demographic characteristic, reproductive history height, weight, and so on. And the obesity status in recent 10 years was judged. Time of Flight Mass Spectrometer was used to determine the genotypes of LEP rs7799039, LEPR rs1137100 and LEPR rs1137101, while the multinomial logistic regression analysis was conducted to estimate the effect of risk factors related to breast cancer in different molecular subtypes; and then, the association between polymorphism of persistent obesity, the LEP, LEPR genes and breast cancer of different molecular subtypes was analyzed by binary logistic regression models. Results: The average age of controls was (48.98+/-8.83) years old, while the age of cases of TNBC, Luminal A, Luminal B, and HER-2+ were (51.43+/-11.33), (49.94+/-10.10), (49.73+/ 9.38), (50.50+/-9.04) years old, respectively. The frequency of genotype LEP rs7799039, LEPR rs1137100 and LEPR rs1137101 in control group was separately 74.8%(1 157/1 546), 83.6%(1 339/1 602) and 88.4%(1 416/1 602); while 77.6% (1 074/1 384), 82.4% (1 155/1 402) and 87.9% (1 232/1 402) respectively in case group. Compared with non-persistent obesity subjects, the persistent obesity ones showed an increased risk in TNBC (OR=3.58, 95%CI: 1.90-6.72), Luminal A (OR=2.65, 95%CI: 1.35-5.21) and Luminal B (OR=1.90, 95%CI: 1.26-2.89) breast cancer. LEP rs7799039-AA was relevant with the upward risk of Luminal B independently (OR=1.30, 95%CI: 1.00-1.69). Besides, persistent obesity was found to have a combined effect on Luminal B (beta=3.34, 95% CI: 1.00-11.12) with LEPR rs1137101 GG. Conclusion: Persistent obesity could increase the potential risk of TNBC, Luminal A and Luminal B breast cancer. Women who were suffered from persistent obesity with a genotype of LEPR rs1137101-GG were more susceptible to Luminal B breast cancer. PMID- 28592100 TI - [The association between aflatoxin exposure and primary hepatocellular carcinoma risks: a case-control study in Chongqing]. AB - Objective: To investigate the association between aflatoxin exposure and primary hepatocellular carcinoma (PHC) development. Methods: From December 2013 to May 2016, we selected 214 patients newly diagnosed with PHC as cases, and 214 patients as controls from three hospitals in Chongqing. Cases were confirmed with PHC diagnosis standard. And cases caused by clear reasons such as drug-induced liver injury, alcoholic liver damage, fatty liver and gallstones etiology, were excluded. Controls were included with no cancer and no digestive system disease, and recruited simultaneously with cases. Cases and controls were frequency matched (1?1) by same gender and age (+/-3 years). Peripheral blood and random urine samples were collected and analyzed for serum HBsAg status by biochemistry analyzer, and serum AFB(1)-ALB adduct and urinary AFB(1)-N(7)-GUA adduct by ELISA. Basic information, living habits and history of disease for patients were obtained by questionnaires. We used wilcoxon rank sum test to compare the median of serum AFB(1)-ALB adduct and urinary AFB(1)-N(7)-GUA adduct in cases and controls. Logistic regression analyses were performed to assess risk factors for PHC, and synergism index (S) of aflatoxin with other factors was estimated by the method of Andersson. Results: There was no significant difference in age between PHC cases (50.74+/-9.67) years and controls (51.15+/-9.90) years. Logistic regression showed that the odds ratio of HBV infection for PHC development was 46.3 (95% CI: 23.3-88.0). There was a significant difference in median concentrations of serum AFB(1)-ALB adduct (cases vs controls: 146.23 vs 74.42 ng/g albumin, P<0.001), but no difference in median concentrations of urinary AFB(1)-N(7)-GUA adduct was observed (cases vs controls: 0.17 vs 0.14 ng/mg creatinine, P<0.210). The odd ratios for PHC risk after adjustment were 1.9 (95%CI: 1.1-3.4) for AFB(1)-ALB adduct, and 2.1 (95%CI: 1.0-4.2) for AFB(1)-N(7) GUA adduct. Moreover, we observed a positive interaction of aflatoxin exposure with HBV, alcohol drinking, and diabetes. The S was 4.7 (95%CI: 2.8-7.9), 3.5 (95%CI: 1.0-12.0), and 12.4 (95%CI: 1.8-84.2), respectively for serum AFB(1)-ALB adduct with each of the three factors mentioned, and was 1.9 (95%CI:1.1-3.1), 2.0 (95%CI: 1.1-3.6), and 2.0 (95%CI: 1.1-3.6), respectively for urinary AFB(1)-N(7) GUA adduct with each of the three factors mentioned. Conclusion: HBV was still the main risk factor, and AFB(1) exposure was also an independent risk factor for PHC in Chongqing. There was a positive interaction of aflatoxin with HBV, alcohol drinking, and diabetes. PMID- 28592101 TI - [Analysis of related factors for primary hepatic carcinoma caused by chronic hepatitis B and hepatitis C]. AB - Objective: To explore the related factors for primary hepatic carcinoma (PHC) caused by chronic hepatitis B (CHB) and hepatitis C (CHC). Methods: According to the principle of cross-sectional study, a cluster random sample method was used, a total of 366 chronic hepatitis patients in hospitals were recruited from three provincial tertiary hospitals in Shanxi, Henan and Jilin between July 2016 and October 2016, respectively. Using a self-designed unified questionnaire, face-to face interviews was conducted on subjects, including sex, age, alcohol consumption, coffee consumption, green tea consumption, fish consumption, smoking, HBV/HCV diagnosis and treatment, diabetes mellitus, family history of PHC (whether PHC in first-degree relatives), etc. Multivariate unconditional logistic regression were performed to identify the related factors for PHC with CHB and CHC. According to the clinical diagnosis the patients were divided into a chronic hepatitis group (not developing to PHC) and a PHC group. Results: Among 366 cases patients, 287 (78.4%) cases were male, 79 cases were female (21.6%), average age was (52.7+/-9.3) years. 202 cases were chronic hepatitis group, 164 cases were PHC group. Multivariate unconditional logistics regression analysis indicated that alcohol consumption (odds ratio (OR)=2.11, 95%CI: 1.18-3.75), family history of PHC (OR=5.12, 95%CI: 2.60-10.08) were positively correlated with the development of PHC in chronic b, green tea consumption (OR=0.45, 95%CI: 0.23-0.88), antiviral treatment (OR=0.19, 95%CI: 0.11-0.32) were negatively correlated. Alcohol consumption (OR=3.98, 95%CI: 1.14-13.85) was positively correlated with the development of PHC in chronic c, antiviral treatment (OR=0.14, 95%CI: 0.04-0.50) was negatively correlated. Conclusion: Alcohol consumption, family history of PHC, green tea consumption and antiviral treatment were the related factors for the development of PHC in chronic hepatitis b. Alcohol consumption and antiviral treatment were the related factors for the development of PHC in chronic hepatitis c. PMID- 28592102 TI - [Assessment of comprehensive nutritional status and eating behavior among 311 middle aged and aged women with osteoporosis in Chengdu]. AB - Objective: To investigate the comprehensive nutritional status and diet behavior of middle aged and elderly women with osteoporosis, and thereby to explore the relationship between diet behavior and comprehensive nutritional status. Methods: 311 middle-aged and elderly women with osteoporosis in Chengdu were included in this study. Mini Nutritional Assessment (MNA) was applied to assess their comprehensive nutritional status. Information of social-demographic characteristics and diet behavior (about meals, snacks and water drinking, etc.) of the subjects was collected by questionnaire. Chi square test was used to assess the differences in nutritional status among patients who have different eating behaviors. Logistic regression analysis was performed to evaluate the relationship between diet behaviors and comprehensive nutritional status. Results: The mean MNA score of subjects was 25.8+/-2.5. 20.3% (63/311) of the subjets were at risk of potential malnutrition, but there was no malnourished subjects found. 46.9% (46/311) of the subjects were in good appetite. 95.2% (296/311) of them had a fixed food intake each meal. 65.8% (198/311) of them had snacks every day, and the most common choice was fruit (86.4% (248/287)). 54.8% (165/311) of them had initiative drinking water habits, and the most common choice was plain boiled water (79.9%, 246/308). 76.5% (238/311) of them had daily portable water less than 1 500 ml. After adjusting the effects of age, occupation and education level, bad appetite (OR=3.50, 95%CI: 1.18-10.62), unfixed food intake (OR=7.27, 95%CI: 1.40-35.83), and seldom or never intake of snack (OR=3.71, 95%CI: 1.42-9.72) were risk factors for malnutrition risk, while tea drinking was protective factor(OR=0.31, 95%CI: 0.11-0.93). Conclusion: Risk of potential malnutrition and unhealthy diet behavior among the middle aged and elderly women with osteoporosis should be paid more attention. Unhealtghy diet behavior has a negative effect on their comprehensive nutritional status. PMID- 28592105 TI - [Prevalence and associated factors of postpartum depression of 1 355 puerperas in Shenzhen]. PMID- 28592104 TI - [Loop-mediated isothermal amplification technique in the diagnosis of hepatitis B virus infection: a Meta-analysis]. AB - Objective: To evaluate the diagnostic performance of Loop-mediated isothermal amplification (LAMP) in the diagnosis of Hepatitis B Virus (HBV) infection using Meta-analysis. Methods: Literatures about LAMP in the diagnosis of HBV throughPubMed database of the National Library of Medicine, the EMBASE database of the Dutch Medical Digest, the Cochrane Clinical Trials Database, China Science Periodical Database, CSPD and the China National Knowledge Infrastructure (CNKI) were searched from 2000 to 2016, and the Language limited to Chinese and English. English search terms include: LAMP, Loop-mediated isothermal amplification, HBV, hepatitis B virus; Chinese search terms include: loop-mediated isothermal amplification technology, HBV, hepatitis B virus. The keywords and free words are combined to search the literature, and the references mentioned in the retrieval literature are searched twice. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR), Q index as well as area under summary receiver operating characteristic curve (SROC) were calculated with Stata 12.0 software. Results: A total of 12 literatures with 1 494 cases were included. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.922 (95%CI: 0.905-0.937), 0.860 (95%CI: 0.818-0.896), 0.093 (95%CI: 0.048-0.182), and 15.400 (95%CI: 2.003 118.380), respectively. The DOR, area under SROC and Q index were 311.090 (95%CI: 95.841-1 009.800), 0.986 (95%CI: 0.974-0.998) and 0.949 (95%CI: 0.922-0.976), respectively. Deek's test indicates that no publication bias were found (P=0.140). Conclusion: LAMP is worth to be popularized in field tests and primary level hospitals tests. PMID- 28592103 TI - [Association of etheno-DNA adduct and DNA methylation level among workers exposed to diesel engine exhaust]. AB - Objective: To investigate the association between etheno-DNA adduct and the promoter of DNA methylation levels of cyclin dependent kinase inhibitor 2A (P16), Ras association domain family 1 (RASSF1A) and O-6-methylguanine-DNA methyltransferase (MGMT) in workers with occupational exposure to diesel engine exhaust (DEE). Methods: We recruited 124 diesel engine testing workers as DEE exposure group and 112 water pump operator in the same area as control group in Henan province in 2012 using cluster sampling. The demographic data were obtained by questionnaire survey; urine after work and venous blood samples were collected from each subject. The urinary etheno-DNA adducts were detected using UPLC-MS/MS, including 1,N6-etheno-2'-deoxyadenosine (epsilondA) and 3,N4-etheno-2' deoxycytidine(epsilondC). The DNA methylation levels of P16, RASSF1A, and MGMT were evaluated using bisulfite-pyrosequencing assay. The percentage of methylation was expressed as the 5-methylcytosine (5mC) over the sum of cytosines (%5mC). Spearman correlation and multiple linear regression were applied to analyze the association between etheno-DNA adducts and DNA methylation of P16, RASSF1A, and MGMT. Results: The median (P(25)-P(75)) of urinary epsilondA level was 230.00 (98.04-470.91) pmol/g creatinine in DEE exposure group, and 102.10 (49.95-194.48) creatinine in control group. The level of epsilondA was higher in DEE exposure group than control group (P<0.001). DNA methylation levels of P16, RASSF1A and MGMT were 2.04+/-0.41, 2.19 (1.94-2.51), 2.22 (1.94-2.46)%5mC in exposure group, and 2.19+/-0.40, 2.41 (2.11-2.67), 2.44 (2.15-2.91)%5mC in control group. DNA methylation levels were lower in exposure group (P values were 0.005, 0.002 and 0.001, respectively). Spearman correlation analysis showed that DNA methylation levels of P16, RASSF1A, and MGMT were negative associated with urinary epsilondA level (r values were -0.155, -0.137, and -0.198, respectively, P<0.05). No significant correlation was observed between the epsilondC level and any measured DNA methylation levels (P>0.05) . Multiple linear regression confirmed the negative correlation between epsilondA and DNA methylation levels of P16, RASSF1A, and MGMT in non-smoking group (beta (95%CI) was -0.068 (-0.132- 0.003), -0.082 (-0.159--0.004) and -0.048 (-0.090--0.007), P values were 0.039, 0.039 and 0.024, respectively). Moreover, epsilondC was negative associated with DNA methylation level of MGMT in non-smoking group (beta (95%CI) was -0.094 ( 0.179--0.008), P=0.032). Conclusion: DEE exposure could induce the increased of epsilondA and decreased of DNA methylation levels of P16, RASSF1A and MGMT. PMID- 28592106 TI - [Progress in environmental exposure of organophosphate flame retardants]. AB - Organophosphate flame retardants (OPFRs), which have both great properties of flame retardation and plasticization, are currently widely used as additive flame retardants. Due to the restriction and phase-out of brominated flame retardants (BFRs), the market demand for OPFRs as excellent alternatives of BFRs has been rapid increasing. OPFRs can be slowly released into the environment during production and application. Some OPFRs might be persistent in the environment. As a result, OPFRs have been detected in various matrices in the environment and are expected to accumulate in human body through various pathways. OPFRs may cause adverse effects to human health as some of them have been identified as neurotoxicants, reproductive toxicants and potential carcinogens. The article summarized the occurrence and patterns of OPFRs in various environmental matrices such as air, dust, water, food and so on, and in human specimens, estimates the exposure status through different pathways and body burdens of OPFRs. The expected hotspots of OPFRs were also discussed in the future. PMID- 28592107 TI - Retraction of "Preorganized Chromophores Facilitate Triplet Energy Migration, Annihilation and Upconverted Singlet Energy Collection". PMID- 28592108 TI - Geometrical Effect in 2D Nanopores. AB - A long-standing problem in the application of solid-state nanopores is the lack of the precise control over the geometry of artificially formed pores compared to the well-defined geometry in their biological counterpart, that is, protein nanopores. To date, experimentally investigated solid-state nanopores have been shown to adopt an approximately circular shape. In this Letter, we investigate the geometrical effect of the nanopore shape on ionic blockage induced by DNA translocation using triangular h-BN nanopores and approximately circular molybdenum disulfide (MoS2) nanopores. We observe a striking geometry-dependent ion scattering effect, which is further corroborated by a modified ionic blockage model. The well-acknowledged ionic blockage model is derived from uniform ion permeability through the 2D nanopore plane and hemisphere like access region in the nanopore vicinity. On the basis of our experimental results, we propose a modified ionic blockage model, which is highly related to the ionic profile caused by geometrical variations. Our findings shed light on the rational design of 2D nanopores and should be applicable to arbitrary nanopore shapes. PMID- 28592109 TI - Roles of the Active Site Zn(II) and Residues in Substrate Discrimination by Threonyl-tRNA Synthetase: An MD and QM/MM Investigation. AB - Threonyl-tRNA synthetase (ThrRS) is a Zn(II) containing enzyme that catalyzes the activation of threonine and its subsequent transfer to the cognate tRNA. This process is accomplished with remarkable fidelity, with ThrRS being able to discriminate its cognate substrate from similar analogues such as serine and valine. Molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) methods have been used to elucidate the role of Zn(II) in the aminoacylation mechanism of ThrRS. More specifically, the role of Zn(II) and active site residues in ThrRS's ability to discriminate between its cognate substrate l-threonine and the noncognate l-serine, l-valine, and d-threonine has been examined. The present results suggest that a role of the Zn(II) ion, with its Lewis acidity, is to facilitate deprotonation of the side chain hydroxyl groups of the aminoacyl moieties of cognate Thr-AMP and noncognate Ser-AMP substrates. In their deprotonated forms, these substrates are able to adopt a conformation preferable for aminoacyl transfer from aa-AMP onto the Ado 3'OH of the tRNAThr cosubstrate. Relative to the neutral substrates, when the substrates are first deprotonated with the assistance of the Zn(II) ion, the barrier for the rate-limiting step is decreased significantly by 42.0 and 39.2 kJ mol-1 for l-Thr-AMP and l-Ser-AMP, respectively. An active site arginyl also plays a key role in stabilizing the buildup of negative charge on the substrate's bridging phosphate oxygen during the mechanism. For the enantiomeric substrate analogue d-Thr-AMP, product formation is highly disfavored, and as a result, the reverse reaction has a very low barrier of 16.0 kJ mol-1. PMID- 28592110 TI - Mechanism of Photocatalytic Water Splitting with Graphitic Carbon Nitride: Photochemistry of the Heptazine-Water Complex. AB - Impressive progress has recently been achieved in photocatalytic hydrogen evolution with polymeric carbon nitride materials consisting of heptazine building blocks. However, the fundamental mechanistic principles of the catalytic cycle are as yet poorly understood. Here, we provide first-principles computational evidence that water splitting with heptazine-based materials can be understood as a molecular excited-state reaction taking place in hydrogen-bonded heptazine-water complexes. The oxidation of water occurs homolytically via an electron/proton transfer from water to heptazine, resulting in ground-state heptazinyl and OH radicals. It is shown that the excess hydrogen atom of the heptazinyl radical can be photodetached by a second photon, which regenerates the heptazine molecule. Alternatively to the photodetachment reaction, two heptazinyl radicals can recombine in a dark reaction to form H2, thereby regenerating two heptazine molecules. The proposed molecular photochemical reaction scheme within hydrogen-bonded chromophore-water complexes is complementary to the traditional paradigm of photocatalytic water splitting, which assumes the separation of electrons and holes over substantial time scales and distances. PMID- 28592111 TI - Tip-Specific Functionalization of Gold Nanorods for Plasmonic Biosensing: Effect of Linker Chain Length. AB - Gold nanorods are promising platforms for label-free biosensing. We have functionalized gold nanorods with biotin thiol linkers of increasing chain length and evaluated their ability in the molecular detection of streptavidin. We have found an unexpected effect of the increase in linker length, which resulted in a substantial improvement of the plasmon response at surface saturation. The plasmon peak shift increased from 5 to 14 nm, i.e., more than twice the response, between the short and long biotin linkers. This effect is observed only for site selective tip functionalization, whereas for a full biotin coating there is no improvement observed with the linker length. The improved plasmon response for tip functionalization is attributed to low biotin coverage but is directed to the most sensitive regions, which, combined with a longer chain linker, reduces the steric hindrance for streptavidin binding on the rod's surface. The model sensors were further characterized by measuring their dose-response curves and binding kinetic assays. Simulations of the discrete dipole approximation give theoretical plasmon shifts that compare well with the experimental ones for the long linker but not with those of the short linker, thus suggesting that steric hindrance affects the latter. Our results highlight the importance of specifically functionalizing the plasmonic hot spots in nanoparticle sensors with the adequate density of receptors in order to maximize their response. PMID- 28592112 TI - Characterization and cellular studies of molecular nanoparticle of iron (III) tannic complexes; toward a low cost magnetic resonance imaging agent. AB - Herein, a new magnetic resonance imaging (MRI) agent based on molecular nanoparticles of iron(III)-tannic complexes (Fe-TA NPs) is reported. The paramagnetic and molecularlike Fe-TA NPs were successfully synthesized at room temperature within a few minutes without the use of any toxic agents or expensive equipment. The coordination states of the Fe-TA NPs were pH-dependent. The r1 relaxivity values of the bis-dominated and tris-dominated structures of the Fe-TA NPs were determined to be 6.31 and 5.24 mM-1 s-1, respectively, by using a Philips Achieva 1.5T MRI scanner. The Fe-TA NPs were 177 +/- 12 nm in diameter (hydrodynamic size) with a zeta potential value of -28 +/- 0.9 mV, dispersing very well in aqueous solution and were highly stable in phosphate buffered saline buffer (pH 7.4) containing competitive ligands and metals. From in vitro studies, it was evident that the Fe-TA NPs exhibited good biocompatibility, with high cellular uptake in HepG2 cells. Clearly, the Fe-TA NPs were found to induce signal enhancement in the T1-weighted image of the HepG2 cells. As a result, it can be stated that the Fe-TA NPs may have the potential for being developed as low-cost and clinically translatable magnetic resonance imaging agents in the near future. PMID- 28592114 TI - Oleanolic acid derivative SZC014 inhibit cell proliferation and induce apoptosis of human breast cancer cells in a ROS-dependent way. AB - Oleanolic acid (OA) and its derivatives are a novel emerging class of compounds. Although OA exhibits potent anticancer and anti-inflammatory function, the potential effect of its new derivatives (SZC014) in human breast cancers has not been understood yet. In this investigation, we demonstrated the anticancer effect of SZC014, a novel OA derivative and identified the possible mechanisms by which SZC014 induced MCF-7 cell death. The biological functions of SZC014 were validated by MTT, migration and colony formation assays in breast cancer cells. Cell apoptosis was monitored by Annexin V- FITC assay. Intracellular ROS and cell cycle were measured by flow cytometric analysis. Western blot was used to detect protein expression level. Our present results fully demonstrated that SZC014 inhibits breast cancer cells proliferation, colony formation, and cell migration. Further investigation verified that ROS generation, apoptosis induction and G0/G1 phase arrest was observed in SZC014-treated MCF-7 cells. However, pretreatment with N-acetyl- L-cysteine (NAC), a ROS scavenger, increased the expression of procaspase-3. Additionally, SZC014 treatment suppressed the levels of Akt, phosphorylated-Akt (p-Akt), COX-2, p-p65 in the cytoplasmic and p65 in nuclear. Furthermore, the inhibition of p65 nuclear translocation was confirmed by immunofluorescence staining. These data show that SZC014 is an effectively selective anticancer agent against breast cancer cells, highlighting the potential use of this derivative as a breast cancer therapeutic agent. PMID- 28592113 TI - pH-dependent lipid vesicle interactions with plasma polymerized thin films. AB - Model lipid vesicle and supported lipid bilayer (SLB) systems are used in a variety of applications including biosensing, cell membrane mimics, and drug delivery. Exposure of a surface to a vesicle solution provides a straightforward method for creating such systems via vesicle adsorption and collapse. However, this process is complex and the relationship between the surface physicochemical properties and vesicle collapse is poorly understood. Plasma polymers are thin conformal films that can be applied to a variety of materials to modify surface properties. This paper uses quartz crystal microbalance with dissipation and fluorescence recovery after photobleaching (FRAP) to explore lipid vesicle interactions with plasma polymerized acrylic acid (ppAAc), allylamine (ppAAm), and ppAAc/ppAAm micropatterns. Vesicle interactions were dependent on plasma polymer chemistry and pH of the buffer solution. Vesicles readily and stably adsorbed to ppAAm over a wide pH range. ppAAc demonstrated limited interactions at pH 7 and vesicle adsorption at pH 4. Vesicle collapse and SLB formation could be induced using a pH change. FRAP was used to explore the fluidity of the lipid structures on both the patterned and unpatterned plasma polymer films. On ppAAm/ppAAc micropatterns, pH transitions combined with the presence of chemically distinct regions on the same substrate enabled immobile lipid islands on ppAAc to be surrounded by fluid lipid regions on ppAAm. This work demonstrates that plasma polymer films could enable spatially controlled vesicle adsorption and SLB formation on a wide variety of different substrates. PMID- 28592115 TI - Identification of chemokine CXCL10 in tumor microenvironment by antibody array as a prognostic marker in hepatocellular carcinoma. AB - Immunological microenvironment is not only composed of multiple immune cells, but also deposited various inflammation factors that regulate immune response to tumor cells. To ascertain the crucial immune factors presented in hepatocellular carcinoma microenvironment (HCM), tumor tissue culture supernatant (TCS) and the corresponding non-tumor tissue culture supernatant (NCS) from patient with hepatocellular carcinoma (HCC) were analyzed by antibody array technology. Among the inflammation-associated cytokines assayed, high level of chemokines CXCL8/IL 8 (6.82-fold increase) and CXCL10/IP-10 (16.45-fold increase) in TCS than that in paired NCS were evidently identified. And low expression of IL-16 (0.14-fold decrease) and RANTES/CCL5 (0.17-fold decrease) in TCS were also uncovered. Especially, overexpression of CXCL10 in primary HCC compared with their non-tumor counterparts was significantly associated with serum AFP level (P = 0.004), tumor size (P = 0.021), tumor number (P < 0.001) and TNM stage (P = 0.027). In addition, Kaplan-Meier curves demonstrated that patients with higher CXCL10 expression levels had significantly poorer overall survival (P = 0.016) and disease-free survival (P = 0.022) than those with lower CXCL10 expression levels. Univariate and multivariate analyses revealed that the level of CXCL10 expression was an independent prognostic factor for overall survival in HCC patients. In summary, high concentration of CXCL10 is deposited in HCM identified by antibody array, which may contribute to the prediction of clinical outcome of HCC patients. PMID- 28592116 TI - Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy? AB - For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included. PMID- 28592117 TI - Mechanisms regulating radiosensitivity of glioma stem cells. AB - Malignant glioblastoma (GBM) has become a very common and difficult brain tumor given its low cure rate and high recurrence rate. GBMs are resistant to treatments because glioma stem cells (GSCs)/glioma-initiating cells (GICs), a specific subpopulation of GBM, possess properties of tumor stem cells, such as unlimited proficiency, self-renewal, differentiation and resistance to chemotherapy and radiotherapy, and exhibit a very strong DNA repair capability. Radiotherapy has become a preponderant treatment, and researchers have found many significant tumor microenvironmental factors and valuable signaling pathways regulating the GSC radioresistance, including NOTCH, Wnt/beta-catenin, Hedgehog, STAT3, and PI3K/AKT/mTOR. Therefore, we seek to boost GSC radiosensitivity through activating or inactivating pathways alone or together to eliminate the likely source of glioma and prolong survival of patients. PMID- 28592118 TI - MiR-99a-5p regulates proliferation, migration and invasion abilities of human oral carcinoma cells by targeting NOX4. AB - Previous research has showed that miR-99a-5p was a tumor suppressor. The aim of our study was to explore the effect of miR-99a-5p on the vitality and proliferation, migration together with the invasion of oral tumor cells via inhibiting the expression of NOX4. QRT-PCR and Western blot were applied to examine the expression level of miR-99a-5p and NOX4 in human oral tumorous and adjacent tissues. Dual luciferase reporter gene assay was applied to confirm that miR-99a-5p negatively regulated directly on NOX4 in TSCC1 cells. Cell transfection and lentiviral vectors were used to up-regulate expression of miR 99a-5p and NOX4, respectively. Cell proliferation, cell cycle, apoptosis and invasion along with the migration in different groups were assessed using MTT assay, colony formation assay, the flow cytometry, transwell assay and the wound healing assay, respectively. MiR-99a-5p was under-expressed in human oral tumor, while NOX4 was over-expressed. There was a negative relationship between miR-99a 5p and NOX4. Up-regulating miR-99a-5p or down-regulating NOX4 suppressed the vitality, proliferation, migration together with invasion of TSCC1 cells. MiR-99a 5p affected the vitality and proliferation, migration together with the invasion of oral tumor cells through targeting NOX4. PMID- 28592119 TI - Tea Polyphenol inhibits autophagy to sensitize Epirubicin-induced apoptosis in human bladder cancer cells. AB - Resistance to anticancer agents such as Epirubicin (EPI) becomes a great challenge for treating bladder cancer. However, the mechanism by which chemoresistance arised is still elusive. In the present study, we showed evidence that EPI induced cytoprotective autophagy in bladder cancer cell lines T24 and BIU87. In addition, EPI robustly activated JNK-mediated phosphorylation of Bcl-2 and disruption of Bcl-2/Beclin-1 complex. Furthermore, the green tea derivative tea polyphenol (TP) inhibited EPI-induced autophagy and promoted apoptosis induced by EPI in bladder cancer cells. These results revealed a pathway for EPI induced autophagy that involved in JNK/Bcl-2/Beclin-1 in bladder cancer cells, and that TP synergistically promoted EPI-induced apoptosis at least partly through autophagy inhibition. Thus, TP could be utilized in combination with EPI to improve EPI-based bladder cancer therapy. PMID- 28592120 TI - Downregulated vimentin and upregulated E-cadherin in T1 stage non-small-cell lung cancer: does it suggest a mesenchymal-epithelial transition? AB - Lung cancer has been a major threat to human health worldwide. Vimentin (VIM) and E-cadherin (E-cad) are molecular markers that play important roles in epithelial mesenchymal transition (EMT), which has been shown to be correlated with tumor progression. Herein, we investigated the associations between clinicopathological parameters and VIM/E-cad expression in primary T1 stage non-small cell lung cancer (NSCLC). Real-time PCR was performed on RNA extracted from tumor tissue isolated from 54 patients with T1 stage NSCLC. Immunohistochemistry was used to measure the protein levels of VIM and E-cad. The paired-samples t-test, independent-samples t- test, Kappa test, and nonparametric test were used to perform statistical analyses. The expression of VIM were lower (P<0.001) and that of E-cad was higher (P<0.001) in tumor tissue when compared with the normal tissue at the transcriptional level. The RNA of VIM in adenocarcinomas was significantly higher than that found in squamous cell carcinomas (P<0.01). Moreover, the level of metastasis observed in the lymph node was significantly higher than that observed in metastasis outside of the lymph node (P<0.05). Vimentin protein had a lower profile in the tumor tissue, and the protein level of E-cad was higher in the tumor tissue. The IHC score of VIM in tumor tissue was found associated with both the pathological type and smoke index, and the score of E-cad was found to be related to visceral pleura involvement. In conclusions, VIM is downregulated and E-cad is upregulated in T1 stage NSCLC. Our study results suggest that a mesenchymal-epithelial transition may take place in the early-stage of tumor development, and that EMT occurs when the tumor develops into a certain stage. PMID- 28592121 TI - Inhibition of JMJD6 expression reduces the proliferation, migration and invasion of neuroglioma stem cells. AB - Neuroglioma is the most common form of human primary malignant brain tumor, more and more studies recently showed only a small subpopulation of glioma cells which called glioma stem cells have true tumorigenic potential. Meanwhile, it was reported the overexpression of JMJD6 protein is closely involvement with the occurrence and development of multiple tumors, and JMJD6 is required for the differentiation of multiple organ, tissues and cells during embryogenesis. However, the influence of JMJD6 overexpression on neuroglioma development is unclear now. Hence, to explore the effects of JMJD6 expression on neuroglioma, we firstly isolated glioma stem cells by using CD133 MicroBead Kit, and identified via neurosphere-forming assay and Immunofluorescence staining. At the same time, we investigated the effects and mechanism of JMJD6 on the proliferation, migration and invasion of glioma stem cells through MTT, transwell assays and the Cignal finder cancer 10-pathway reporter array. The results demonstrated that the glioma neurosphere cells positively expressed stem cell marker SOX2, neuroectodermal stem cell marker Nestin, and also expressed astrocytes marker GFAP and neurons marker beta-tubulin III fter FBS-induced differentiation for a week, which proved the glioma neurosphere cells have the self-renewal and multipotential differentiation capacity. Moreover, shRNA lentiviral vector mediated knockdown of JMJD6 in glioma stem cells led to decreased proliferation, migration and invasion, the underlying molecular mechanism is related to the weaken of Wnt signaling pathway and strengthen of p53 signaling pathway. PMID- 28592122 TI - Knockdown of CFTR enhances sensitivity of prostate cancer cells to cisplatin via inhibition of autophagy. AB - Prostate cancer is one of the most lethal diseases in men worldwide. Although the survival rate of men diagnosed with prostate cancer has increased with the improvement of treatments, drug resistance still remains a big challenge for improving overall survival. Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated anion channel, has been reported to have a pivotal role in the pathogenesis of various cancers, but its role in chemoresistance of prostate cancer cells is poorly understood. In our study, we found that CFTR expression was significantly increased in prostate cancer tissues associated the chemoresistance, and in the cisplatin-resistant cell line LNCaP/CP compared with their respective parental cells. Cisplatin treatment inhibited CFTR expression in a concentration-dependent manner, which was correlated with a decrease in cell viability. Moreover, inhibition of CFTR by transfection of small interfering RNA enhanced cisplatin-induced the decrease of cell viability. Autophagy was dramatically increased in LNCaP/CP cells, as evidenced by autopaphgic markers as well as fluorescence microscopy analysis of GFP-LC3, MDC and AO staining. Of note, inhibiting autophagy by 3MA induced LNCaP/CP cell apoptosis, showed by MTT assay and Hoechst 33258 staining. In addition, blockade of CFTR also inhibited LNCaP/CP cell viability and autophagy. Furthermore, the dephosphorylation of AKT and mTOR was reversed by CFTR inhibition, indicating the knockdown of CFTR might inhibit autophagy in LNCaP/CP cells via activation of AKT/mTOR signaling. Altogether, these results provide a novel understanding of the mechanism for acquired cisplatin. Inhibition of CFTR may be a useful strategy to increase the efficacy of cisplatin to treat prostate cancer by preventing the protective response of autophagy. PMID- 28592124 TI - Long non-coding RNA MALAT1 promotes cholangiocarcinoma cell proliferation and invasion by activating PI3K/Akt pathway. AB - Increasing evidence indicated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a key regulator in the proliferation and invasion of several cancers. However, the function of MALAT1 in the development of cholangiocarcinoma has not been experimentally established. In the present study, the expression levels of MALAT1 in cholangiocarcinoma cell lines were detected by quantitative real-time PCR. The effects of MALAT1 knockdown on the cell proliferation and invasion of cholangiocarcinoma cells were detected with Cell Counting Kit-8 (CCK-8), colony formation assay and Trans-well assay, respectively. The expressions of epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, Vimentin) were evaluated to discover whether the process of EMT was involved. We also evaluated the expression of phos-phatidylinositol-3 kinase/serine/threonine kinase (PI3K/Akt) signaling pathway proteins (PI3K, p PI3K, Akt, p-Akt) to determine the associated molecular mechanism. And we discovered that MALAT1 was up-regulated in cholangiocarcinoma cancer cells. CCK 8, colony formation and trans-well assay showed that the proliferation and invasion of QBC-939 and RBE with MALAT1 knockdown were inhibited. Moreover, MALAT1 could promote EMT in cholangiocarcinoma cells. In addition, MALAT1 may activate PI3K/Akt pathway. These results indicated that MALAT1 promoted cholangiocarcinoma cell proliferation and invasion. The effects of MALAT1 on cholangiocarcinoma cells might be through activating the PI3K/Akt signaling pathway. These investigations may facilitate a better understanding of MALAT1 and it might be a potential therapeutic target for the treatment of cholangiocarcinoma. PMID- 28592123 TI - Sorafenib inhibits growth of hepatoma with hypoxia and hypoxia-driven angiogenesis in nude mice. AB - The study aimed to investigate the effects of sorafenib on growth of hepatoma with hypoxia and angiogenesis. Green fluorescent protein (GFP)-expressing SMMC 7721 hepatoma cells were established via transfection with a lentiviral vector carrying GFP. GFP-labelled cells were treated with CoCl2 for 24 h with or without pretreatment of sorafenib for 30 min, and then injected subcutaneously into nude mice to induce hepatoma xenografts. This study used 16 BALB/c nude mice, which were divided into 4 groups: control group (GFP-labelled cells), CoCl2 group (GFP labelled cells treated with CoCl2), CoCl2 plus sorafenib group (GFP-labelled cells pretreated with sorafenib and then treated with CoCl2) and CoCl2 plus sorafenib (cell+i.g.) group (GFP-labelled cells pretreated with sorafenib and then treated with CoCl2). After injection, CoCl2 plus sorafenib (cell+i.g.) group received intragastrical administration of sorafenib daily for 40 days. Tumor volume and weight were measured for each mouse. Cy5.5-annexinV and in vivo bioluminescence imaging were used for in vivo detection of cell apoptosis in tumor. Vascular endothelial growth factor (VEGF) and CD 34 were detected by immunohistochemistry. The results showed that, under the hypoxia condition induced by CoCl2, sorafenib pretreatment combined with intragastric administration of sorafenib more obviously suppressed tumor growth and decreased VEGF expression and MVD compared to sorafenib pretreatment alone, and induced cell apoptosis as well. Sorafenib pretreatment combined with intragastric administration is more effective than sorafenib pretreatment alone in the therapy of hepatoma. PMID- 28592125 TI - Correlation of Gankyrin oncoprotein overexpression with histopathological grade in prostate cancer. AB - Prostate cancer is the second most commonly diagnosed cancer among men worldwide. Identifying new prognostic and predictive biomarkers will help stratification of prostate cancer patients for a better treatment. Gankyrin is a novel oncoprotein which regulates cell cycle and protein degradation. Gankyrin overexpression correlated with the malignant phenotypes and promotes the tumorigenicity and metastasis in many cancers. However, there are not any reports on the role of Gankyrin in prostate cancer. Therefore, this study was designed to investigate the expression of Gankyrin in prostate cancer and analyze its correlation with some clinicopathological characteristics. We characterized the expression of gankyrin in fifty five prostate cancer specimens and twenty non-cancerous tissues by immunohistochemical staining and the results were correlated with clinical characteristics and pathological parameters.Results showed that Gankyrin was expressed in 41 of 55 (74%) prostate cancer patients and its expression was significantly higher than corresponding adjacent normal tissues (p<0.001). Gankyrin overexpression was significantly correlated with histopathological tumor grade, Gleason score and tumor differentiation (P=0.002). These findings showed that Gankyrin is mainly overexpressed in high grade prostate tumors so it may have a significant role in prostate cancer progress and it May serve as a useful biomarker for the identification of aggressive prostate cancers. PMID- 28592126 TI - Autologous hematopoietic stem cell transplantation for acute myeloid leukemia - single center experience. AB - We aimed to determine the effect of autologous hematopoietic stem cell transplantation (auto-HSCT) on acute myeloid leukemia (AML) patients as a valid alternative therapeutic option for patients without HLA-compatible donor. This retrospective single center study included 79 patients with AML older than 18 years. In this report, we describe the patient characteristics, engraftment, toxicity of treatment, complications, overall survival, and relapse incidence of 79 patients treated chemotherapy and followed by auto-HSCT. The descriptive statistics was used, and the method of Kaplan and Meier was applied to calculate the actuarial rate of overall survival. The patients achieved an absolute neutrophile count (ANC) of >= 0.5 x109/l in between 10 to 40 days; median was 14 days after auto-HSCT. The patients achieved platelet count >= 20 x109/l in between 10 to 209 days; median was 19 days after auto-HSCT. Hundred-day mortality after autologous transplant was 6.57% (5/76). The relapse rate was 39.5% (32 patients) and 7 patients (8.6%) were lost from follow-up. On the date of evaluation (April 30, 2016), 48 patients (60.8%) were alive, including 7 (8.6%) patients who are lost from follow-up (not responding to check-up request). The 5 year overall survival (OS) was 60.8%; median overall survival was not reached. The present clinical study has demonstrated safety and efficacy of myeloablative chemotherapy followed by auto-HSCT in the treatment of AML in first remission. PMID- 28592127 TI - Methylation of SOX1 and VIM promoters in serum as potential biomarkers for hepatocellular carcinoma. AB - Aberrant methylation of tumor-related genes has been identified as a promising biomarker for hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic value of SRY (sex determining region Y)-box 1 (SOX1) and Vimentin (VIM) promoter methylation for HCC. The study included 360 subjects, 240 patients with HCC, 29 with liver cirrhosis (LC), 66 with chronic hepatitis B (CHB) and 25 healthy controls (HCs). The methylation status of SOX1 and VIM promoters in the serum was detected by methylation-specific polymerase chain reaction (MSP). The methylation frequencies of SOX1 and VIM promoters in HCC patients were significantly higher than those in LC (p<0.001 and p<0.001), CHB (p<0.001 and p<0.001) and HC (p<0.001 and p<0.001) subjects. Furthermore, hypermethylation of SOX1 and VIM promoters were found in patients with advanced TNM stage (III-IV) and larger tumor size (>=5 cm) compared with early stage (I-II) (p<0.001 and p=0.004) patients with smaller tumor size (<3 cm) (p=0.018 and p=0.001). Moreover, the VIM promoter methylation frequency was higher in patients with portal vein tumor thrombosis (PVTT) (p=0.006) and vascular invasion (p=0.003). In addition, the combination of alpha-fetoprotein (>=20 ng/ml) with SOX1 and VIM promoter methylation significantly improved their diagnostic value. In conclusions, aberrant methylation of SOX1 and VIM promoters may be potential biomarkers for noninvasive detection of HCC and HCC metastasis. PMID- 28592128 TI - Association of nuclear FOXP3 expression with low Ki67 index and better prognosis in patients with breast invasive ductal carcinoma. AB - Recent studies have provided clear evidence that some types of human cancer cells expressed Forkhead Box Protein 3 (FOXP3). However, the presence and role of FOXP3 in breast cancer are still contradictory up to now. In this study, we detected the expression of FOXP3 protein by immunohistochemistry in 123 cases of breast invasive ductal carcinoma. It exhibited that the subcellular localization of FOXP3 expression in breast cancer cells is heterogeneous. In nucleus, FOXP3 expression ratio was 47.97% (59/123) and the nuclear FOXP3 expression was significantly associated with lower Ki67 index (P=0.041), negative vessel tumor embolus (P=0.024). It was also significantly correlated with the molecular subtypes of breast cancer (P=0.002), displaying the highest ratio in the Luminal A subtype (68.18%). Kaplan-Meier analysis indicated that high nuclear FOXP3 expression was associated with better overall survival (OS) (94.92% vs. 82.81%, P=0.022) and disease-free survival (DFS) (91.53% vs. 76.56%, P=0.026). Moreover, nuclear FOXP3 represented an independent prognostic factor for OS (P =0.033) in multivariate analysis. However, in cytoplasm, FOXP3 expression ratio was 63.41% (78/123) and no statistic prognostic significance was found. Thus, our data demonstrated that nuclear FOXP3 expression correlated with low Ki-67 index and better outcome in breast invasive ductal carcinoma, indicating that FOXP3 acted as a potential prognostic marker for breast cancer. PMID- 28592129 TI - Allogeneic stem cell transplantation after fludarabine, melphalan and thymoglobulin followed by early withdrawal of prophylactic immunosuppression in patients with acute lymphoblastic leukemia - update of single center study. AB - Presented are updated results of allogeneic hematopoietic stem cell transplantations (HSCTs) in 25 adult patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) after a reduced intensity conditioning (RIC) combining fludarabine (150 mg/m2) and melphalan (140 mg/m2) with thymoglobulin (4.5 mg/kg or recently 4.0 mg/kg) followed by early initiation of reduction and withdrawal of prophylactic posttransplant immunosuppression. The median post transplant follow-up was 32 (range, 4-87) months. Stable engraftment of donor's hematopoiesis was achieved in all patients. Acute graft versus host disease (GVHD) as well as the chronic one were equally observed in four cases (16%). Five patients (20%) relapsed with ALL in the median of 9 (range, 3-15) months after HSCT. During the above post-transplant follow-up, 4 recipients (16%) died. Disease progression and posttransplant complications were the cause of death in three (12%) and one (4%) of them, respectively. The probabilities of 2-year event free (EFS) and overall survival (OS) were 70.3% (95% CI 51.9-88.7%) and 86.1% (95% CI 71.6-100%), respectively. Presented study confirmed our previously reported promising results and this approach may be considered as an alternative to traditional HSCTs performed in high-risk patients with ALL. PMID- 28592130 TI - The miR-93 promotes proliferation by directly targeting PDCD4 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. Although advances have made in treatment of HCC, the overall survival rate remains low and the molecular pathogenesis of HCC is still poorly understood. The purpose of this study was to explore the molecular pathogenesis of HCC. A total of 89 patients were involved in the study. MicroRNA-93 (miR-93) was aberrantly up-regulated in HCC tissues as determined by qRT-PCR. The high level of miR-93 was closely associated with larger tumor size (p < 0.05) and poor overall survival (p < 0.05). In in vitro and in vivo assays, we demonstrated that high miR-93 levels enhanced cell growth of HCC. The luciferase activity assay showed that PDCD4 was a direct target of miR-93 and its expression was down regulated by miR-93. Re-expression of PDCD4 inversely correlated with the level of miR-93 and attenuated the miR-93-induced promotion of cell growth in HCC. Taken together, our data indicate that miR-93 may function as an oncogenic factor in HCC, and promotes HCC cell proliferation by targeting PDCD4. PMID- 28592131 TI - Phosphorylated 4E-BP1 is associated with tumor progression and adverse prognosis in colorectal cancer. AB - Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E)- binding protein (4E-BP1) results in release of eIF4E, relieving translational repression and enhancing cancerigenic protein synthesis. This study aim to evaluate the level of phosphorylated 4E-BP1 (p-4E-BP1) in colorectal cancer (CRC) and to assess the cor-relation with clinicopathological factors and patient survival. The level of p-4E-BP1 was detected by immunohistochemistry and western bolt in patients with CRC. Then Cox regression model was used to evaluate the prognostic value of all covariates. Among 164 assessed patients, 95 (57.9%) patients showed high level of p-4E-BP1. We noted that the level of p-4E-BP1 was significantly associated with tumor differentiation, invasive depth, lymph node metastasis and TNM stage. Then we compared the mRNA and protein expressions of 4E-BP1 in tumor regions and paired adjacent normal colorectal mucosal tissues in CRC patients. mRNA and protein expressions of 4E-BP1 did not differ between colorectal cancer and corresponding normal tissues, while the phosphorylation level of 4E-BP1 was markedly increased in CRC. Survival analysis and Cox proportional hazards model revealed that p-4E-BP1 was an independent adverse prognostic factor for both overall survival (OS) (HR = 5.414, p = 0.029) and progression-free survival (PFS) (HR = 4.754, p = 0.042). Herein, our results indicate that high p-4E-BP1 level is associated with tumor progression and adverse prognosis. p-4E-BP1 might be a novel biomarker to predict the clinical outcome of patients with CRC. PMID- 28592132 TI - Combination of LINE-1 hypomethylation and RASSF1A promoter hypermethylation in serum DNA is a non-invasion prognostic biomarker for early recurrence of hepatocellular carcinoma after curative resection. AB - Hepatocarcinogenesis, a multistep process, involves not only genetic mutations but also epigenetic alterations. Widespread of global DNA hypomethylation is accompanied with specific regional hypermethylation especially at tumor suppressor genes' promoters. The aim of this study is to determine the efficacy of combined DNA methylation analysis of a global DNA methylation marker - LINE-1 and a tumor suppressor gene highly associated with the malignancy of HCC- RASSF1A in serum as a novel prognostic marker for diagnosis of early recurrence after curative resection.LINE-1 was hypomethylated in 66.7% (70/105) and RASSF1A promoter was hypermethylated in 73.3% (77/105) of HCC serum DNA samples by methylation specific PCR, but in none of the healthy controls: LINE-1 hypometylation (0/50) and RASSF1A hypermethylation (0/50). A significant association was found between LINE-1 hypomethylation and clinical pathologic features including HBsAg positivity (p=0.009), tumor size (p=0.001) and AFP levels (p<0.001). Besides, significant correlation was detected between RASSF1A promoter hypermethylation and lymph nodes metastasis (p=0.045).The results of Kaplan-Meier estimates of survival suggested that LINE-1 hypomethylation was highly associated with poor survival of patients (disease-free survival p=0.002, overall survival p=0.0123). More importantly, co-evaluation of LINE-1 hypomethylation and RASSF1A promoter hypermethylation was found to be significantly correlated to early recurrence and poor prognosis (disease-free survival p=0.0001, overall survival p=0.05) in patients after curative resection.In conclusion, our study showed that the combined examination of LINE-1 hypomethylation and RASSF1A promoter hypermethylation was effective in predicting early recurrence of HCC after curative resection. Patients with dual positivity of LINE-1 hypomethylation and RASSF1A promoter hypermethylation should be supplied with more intensive care and close follow-up after they undergo tumor resection. PMID- 28592133 TI - Concurrent hyperthermia and re-irradiation for recurrent high-grade gliomas. AB - Salvage therapy for recurrent high grade gliomas (HGG) includes surgery, radiotherapy and chemotherapy, however, standard treatment does not exist. We evaluated the tolerability and efficacy of re-irradiation (re-RT) with hyperthermia (HT) for patients with recurrent HGG. From September 2010 to July 2015, 20 patients with recurrent HGG were treated with re-RT and HT. The radiotherapy dose of 30 Gray (Gy) was delivered with 2 Gy per fraction daily, and HT was performed twice weekly. Primary endpoints were treatment compliance and toxicity. Second endpoints were overall survival (OS) and progression free survival (PFS). The median interval between initial RT and re-RT was 11 months. During re-RT with HT, there were no significant acute morbidities over grade 3. Median overall survival (OS) from re-irradiation was 8.4 months and the 6 and 12 months survival rate were 67% and 30%, respectively. The median progression free survival (PFS) from re-irradiation was 4.1 month. Our findings suggested that concurrent re-RT with HT was a safe and well-tolerated. In addition, the combination re-RT and HT could be a valuable salvage treatment option for selected recurrent HGG patients with poor performance status. PMID- 28592134 TI - Circulating annexin A5 levels are associated with carotid intima-media thickness but not coronary plaque composition. AB - BACKGROUND: Annexin A5 (anxA5) is involved in processes which are crucial in atherogenesis. However, anxA5's relationship with atherosclerotic lesion extension and plaque composition in high-risk patients with type 2 diabetes remains unclear. Thus, we characterized the association between circulating anxA5 levels with atherosclerotic burden and coronary plaque composition in diabetes mellitus patients. METHODS: Intima-media thickness was determined in 96 diabetes mellitus patients with stable coronary artery disease. Furthermore, intracoronary optical coherence tomography was performed in 106 lesions to determine plaque composition. RESULTS: AnxA5 plasma levels of patients with intima-media thickening were higher (3.49 +/- 2.19 ng/mL) compared to patients with normal intima-media thickness (2.24 +/- 1.67 ng/mL, p = 0.002). Furthermore, anxA5 was associated with intima-media thickening on univariable [odds ratio = 1.445 (1.106 1.889), p = 0.007] and multivariable [odds ratio = 1.643 (1.166-2.314), p = 0.005] logistic regression analysis when adjusted for multiple cardiovascular risk factors and biomarkers. Furthermore, receiver operating characteristic analysis demonstrated that anxA5 predicted intima-media thickening with low moderate diagnostic efficiency [area under the curve = 0.700 (0.592-0.808)]. In contrast, there was no association between anxA5 levels and coronary plaque composition as assessed by optical coherence tomography including the presence of lipid, calcified, fibrous plaque or the minimal thickness of the fibrous cap overlying the necrotic lipid core ( p = ns). CONCLUSION: Circulating anxA5 levels are associated with carotid intima-media thickness but not coronary plaque composition in high-risk patients with diabetes mellitus. PMID- 28592135 TI - Low-Pressure, Low-Flow Voiding Dysfunction in an Elderly Male Treated Through Ayurveda: A Case Report. AB - INTRODUCTION: Neurogenic bladder is a common urological condition among elderly. It results in incontinence or retention of the urine depending on the synergy of bladder smooth muscles and urethral sphincter. There can also be a condition where retention causes overflow incontinence. Retention of urine in this condition is caused by relative lack of contractility of bladder smooth muscles in response to the stretch reflex. As a result, there is no urge and therefore the bladder remains over-distended causing retention of urine. Currently, there are no absolute ways to deal with such a situation except that the patients are advised for self-help techniques of regularly evacuating the bladder. Pharmacotherapy for such condition is not promising. As the patients of neurogenic bladder are often healthy otherwise (with manageable conditions such as diabetes), a bladder dysfunction is considered as a disability that they do not want to share. In this state, any approach that offers a regeneration of bladder reflex and restoration of its functions is more than one can expect for. METHODS: An elderly male suffering with chronic urinary retention recommended for indwelling catheterization after the failure of voiding trial following the possible conventional pharmacotherapy was treated with Ayurvedic therapy. RESULTS: There was a complete symptom reversal after about 45 days of Ayurvedic therapy. The changes were stable after 3-month follow-up of the patient. CONCLUSION: This case report presents the complete symptom reversal in a case of chronic urine retention as an outcome of Ayurvedic therapy. Seeing the importance of this clinical condition and unavailability of sufficient means in conventional medicine, it requires a serious note and enquiry into its applicability in similar cases. PMID- 28592137 TI - Defining Research: The Effect of Linguistic Choices on the Intentions to Participate in Clinical Research. AB - Significant barriers to participant recruitment for clinical research (CR) are related to effective communication, and nurse coordinators are entrusted with being knowledge brokers between investigators and prospective participants. This prospective cohort study sought to identify linguistic choices that could inform and facilitate recruitment efforts. Healthy adults ( N = 204) were invited to join an online survey to assess the likelihood of participation in CR based on short and extended definitions of CR. Five short definitions included clinical trial, clinical study, health-related research study, community participatory study, and quality improvement study. The likelihood of participation in CR was the lowest for clinical trial and the highest for health-related research study. However, when only an extended definition was provided, those differences were not observed. A linguistic change from trial to study could lead to positive attitude toward CR and improvements in recruitment. However, ethical implications of linguistic choices should be considered. PMID- 28592136 TI - Relationship of Depression With Executive Functions and Visuospatial Memory in Elderly. AB - Cognitive deficits are a potential part of the clinical picture of depression, especially when it comes to late-life depression. The present study was carried out to establish whether distinctive cognitive deficiencies can be linked with depression in the late-life period, especially in executive functioning, working memory, and visuospatial memory. Our sample consisted of 71 seniors in the age range between 69 and 85 years. A battery of neurocognitive tests was used, including tests of executive functioning (Trail Making Test [TMT], part B, Stroop color word test, semantic word fluency test, and partially Rey-Osterrieth Complex Figure test [ROCF]), tests of attention and working memory (TMT, part A and digit span), and test of visuospatil ability and memory (ROCF). Results demonstrated that depression scores were significantly negatively correlated with scores on Verbal Fluency test, Stroop test, and ROCF immediate copy and recall. Depression was also linked to slower functioning on Trail Making A and Trail Making B subtest. In general, higher depression scores were correlated with lower performance on neuropsychological tests. However, digit span showed no significant correlation with depression. In addition, results of regression analyses revealed that the strongest predictors of depression were performance on the Rey-Osterrieth test-immediate recall and Stroop test. Thus, we could ascertain that difficulties in executive functioning and visuospatial memory are the best predictors of depression in elderly. PMID- 28592138 TI - The effects of perceived social norms on handwashing behaviour in students. AB - Handwashing is widely considered the most effective method of preventing the spread of infectious illness. Exploring the determinants of handwashing is vital to the development of interventions to increase this behaviour. A survey based on Social Norms Theory assessed handwashing frequency and perceptions of peer handwashing in 255 university students. Participants reported their own handwashing frequency, and how often they thought their peers washed their hands in particular circumstances, to determine whether misperceptions around handwashing exist, and whether these influence the behaviour of individuals. Gender was found to be a significant determinant of handwashing frequency as females reported washing their hands significantly more often than males. Participants also believed they washed their hands significantly more frequently than their peers. Perceived peer handwashing frequency was significantly correlated with participants' own behaviour. This effect was seen in overall handwashing and in food, waste and illness-related hand washing. These results suggest perceived social norms around hand washing have a clear association with individual behaviour. Future research might test the effectiveness of a social norms intervention in other settings which carry an increased risk of infection spread. PMID- 28592139 TI - Adjuvant chemotherapy for elderly patients with non-small-cell lung cancer. AB - Background Adjuvant chemotherapy after complete surgical resection is currently the standard of care for patients with stage IB, II, or IIIA non-small-cell lung cancer. However, the generalizability of this treatment to elderly patients is controversial. We investigated the effects of adjuvant chemotherapy in patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer. Methods We retrospectively analyzed 246 consecutive patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer who underwent standard lung cancer surgery between January 2001 and December 2015. They were divided into 102 who had adjuvant chemotherapy and 144 who had none (control group). The outcomes were compared between the two groups, and prognostic factors were evaluated. Results Relapse-free survival and overall survival were significantly shorter in the control group than the chemotherapy group ( p = 0.006 and p = 0.008, respectively). In multivariable analyses, adjuvant chemotherapy was found to be an independent prognostic factor for relapse-free survival and overall survival (hazard ratio = 0.594, 95% confidence interval: 0.396-0.893, p = 0.012; and hazard ratio = 0.616, 95% confidence interval: 0.397-0.957, p = 0.031, respectively). After inverse-probability-of-treatment weighting adjustment using the propensity score for baseline characteristics, chemotherapy almost improved relapse-free survival and overall survival (hazard ratio = 0.652, 95% confidence interval: 0.433-0.981, p = 0.040; and hazard ratio = 0.657, 95% confidence interval: 0.429-1.004, p = 0.052, respectively). Conclusions Adjuvant chemotherapy improved the prognosis after standard lung cancer surgery in patients aged over 75 years with stage IB-IIIA non-small-cell lung cancer. PMID- 28592140 TI - Surgical treatment for double-chambered right ventricle in a septuagenarian. AB - The majority of patients with double-chambered right ventricle present during childhood; it is rarely treated in adults. We report the case of a 71-year-old woman who presented with mild fatigue for 2 years. Investigation of an ejection systolic murmur revealed a double-chambered right ventricle with a peak gradient of 147 mm Hg across the right ventricular outflow tract. Substantial right ventricular muscle bundle resection and augmentation of the right ventricular outflow tract with a bovine pericardial patch were performed after a right ventriculotomy. PMID- 28592141 TI - A case of supernumerary intrathoracic rib. PMID- 28592142 TI - Valved patch closure of aortopulmonary window. AB - The case of an 8-year-old boy with an aortopulmonary window who underwent unidirectional valved patch closure of the window is described. The advantages of unidirectional valved patch closure in this setting are discussed. PMID- 28592143 TI - Three new polyketides from the marine sponge-derived fungus Trichoderma sp. SCSIO41004. AB - Three new polyketides named trichbenzoisochromen A (1), 5,7-dihydroxy-3-methyl -2 (2-oxopropyl)naphthalene-1,4-dione (2) and 7-acetyl-1,3,6-trihydroxyanthracene 9,10- dione (3) together with six known compounds (4-9) were isolated from a sponge-derived fungus Trichoderma sp. SCSIO41004. The structures of three new polyketides (1-3) were determined by the extensive spectroscopic analysis, including 1D, 2D NMR and HRESIMS data. The absolute configuration of compound 1 was confirmed by the specific optical rotation value and CD spectra analyses. Compound 4 exhibited significant inhibitory activity against EV71 with the IC50 value of 25.7 MUM. PMID- 28592144 TI - Cancer-type OATP1B3 mRNA has the potential to become a detection and prognostic biomarker for human colorectal cancer. AB - AIM: We aimed to clarify diagnostic and prognostic biomarker potentials of cancer type organic anion transporting polypeptide 1B3 (Ct-OATP1B3) mRNA in colorectal cancer (CRC) patients. PATIENTS & METHODS: Ct-OATP1B3 mRNA levels in 97 CRC and adjacent normal colon tissues were measured by real-time PCR. The receiver operating characteristic curve analysis and the Kaplan-Meier curve analysis were performed to characterize its biomarker potentials. RESULTS: Ct-OATP1B3 mRNA showed noticeable diagnostic power (the area under the receiver operating characteristic = 0.91) in the CRC patients. Additionally, the higher/lower mRNA expression was clearly associated with better/poorer overall survival in the CRC patients (p < 0.05). CONCLUSION: Ct-OATP1B3 mRNA has the potential to be a tissue based biomarker for definitive diagnosis and prognostic stratification in CRC. PMID- 28592145 TI - High expression of COX5B is associated with poor prognosis in breast cancer. AB - BACKGROUND: Cytochrome c oxidase subunit VB (COX5B), a subunit of mammalian COX, takes roles in COX assembling and functions. Online database predicts high COX5B transcription may be associated with worse disease-free survival (DFS). However, the clinical implications of COX5B in breast cancer remain unclear. METHODS: We carried out immunohistochemistry on tissue microarrays of 244 patients with invasive ductal breast carcinoma to detected COX5B expression. RESULTS: Our results suggest that COX5B protein level might be associated with tumor size. COX5B overexpression indicated a worse DFS (p < 0.05) in breast cancer. Furthermore, high COX5B expression may act as an independent factor for worse DFS in breast cancer. CONCLUSIONS: Cumulatively, our findings suggest that COX5B might serve as an important prognostic factor for breast cancer. PMID- 28592146 TI - Drug Use, the Drug Environment, and Child Physical Abuse and Neglect. AB - Although drug use is considered a risk factor for child maltreatment, very little work has examined how the drug environment may affect physical abuse and neglect by parents. Utilizing information from a telephone survey with 2,597 respondents from 43 cities with valid police data on narcotics incidents, we analyzed the relationship between drug use, drug availability, and child maltreatment using multilevel models. City-level rates of drug abuse and dependence were related to more frequent physical abuse. Parents who use drugs in areas with greater availability of drugs reported more physical abuse and physical neglect. Emotional support was protective of all types of maltreatment. While most child welfare interventions focus on reducing parental drug use in order to reduce child abuse, these findings suggest environmental prevention or neighborhood strengthening approaches designed to reduce the supply of illicit drugs may also reduce child abuse through multiple mechanisms. PMID- 28592148 TI - Use of Intravenous Lidocaine for the Treatment of Acute Pain in the Emergency Department. PMID- 28592147 TI - Efficiency of three treatment strategies on occupational and quality of life impairments for chronic low back pain patients: is the multidisciplinary approach the key feature to success? AB - OBJECTIVE: To compare the effectiveness of three treatment strategies for chronic low back pain with varying biomechanical intensity and multidisciplinary approach. METHODS: A monocentric randomized controlled trial with a 12-months follow-up, conducted in the French Valley Loire region from May 2009 to April 2013. Participants were working-aged patients with chronic low back pain referred to a French chronic low back pain care-network to support medical and occupational issues. Three treatment strategies, each for five weeks were compared: (i) intensive and multidisciplinary program conducted in a rehabilitation center; (ii) less intensive outpatient program conducted by a trained private physiotherapist; (iii) mixed strategy combining the same outpatient program associated with a weekly multidisciplinary intervention. The effects of treatment conditions were compared using an "intention to treat" approach: Number of days' sick leave during the 12-months following treatment, and quality of life and social ability assessed by auto-questionnaires. RESULTS: A total of 159 patients (58.9% men, 41.5 +/- 10.3 years old, median duration of sick leave = 221.0 days (127.5-319.0)) were included. Sick leave duration significantly decreased during the 12-months following treatment in the three groups. There was no significant difference for the evolution of participants' quality of life, social ability, and personal beliefs between the three groups. CONCLUSION: This study confirms that disparate treatments might show similar effectiveness because they could all work through concomitant changes in beliefs, attitudes, and coping mechanisms. The original mixed strategy can treat a larger number of chronic low back pain patients, at a lower cost and provide local community-based care. CLINICAL TRIAL REGISTRATION: NCT02030171. PMID- 28592149 TI - The Comparison of Angiographic Scoring Systems With the Predictors of Atherosclerosis. AB - Syntax score (SS) and Gensini score (GS) are used to determine the complexity and severity of coronary artery disease. Although there are some studies indicating the individual relationship of these scoring systems with the carotid intima media thickness (cIMT) and epicardial fat tissue (EFT), there was no previous study that compared the SS and GS in that respect. We aimed to assess the relationship of SS and GS with predictors of atherosclerosis. We enrolled 522 patients. There were positive correlations between GS and SS tertiles with cIMT and EFT. According to multivariate linear regression analysis for GS, EFT (beta: 0.035, t: 2.63, and P = .49) and cIMT (beta: 0.339, t: 2.97, and P = .053) were not independently associated. For SS, EFT (beta: 0.009, t: 6.5, and P = .006) and cIMT (beta: 1.2, t: 10.1, and P = .001) were independently and significantly associated. We showed that the SS is significantly associated more with surrogate markers of atherosclerosis such as EFT and cIMT than the GS. PMID- 28592151 TI - Non-diagnostic thyroid nodules after application of the Bethesda system: a study evaluating the interval for repeat aspiration for non-diagnostic results. AB - Background The non-diagnostic category of the Bethesda system has a low malignancy rate; nevertheless, repeat ultrasonography-guided fine needle aspiration (US-FNA) is recommended with no consensus for follow-up intervals. Purpose To investigate whether a six-month time interval for repeat US-FNA is appropriate for non-diagnostic thyroid nodules after applying the Bethesda system. Material and Methods From January 2010 to January 2014, 322 thyroid nodules >=10 mm with non-diagnostic results on initial US-FNA with any follow-up with US or US-FNA were included (mean age = 52.2 years +/- 12.4). Clinical and US features were compared according to size change (increase, no change, decrease) and follow-up interval (<6 months and >=6 months after initial US-FNA), and the minimal time interval observed in nodules with size increase on follow-up. The outcome of non-diagnostic nodules according to follow-up interval and size change were evaluated. Results Of the 322 nodules, 13 (4.0%) were malignant and 309 (96.0%) were benign. None of the 82 nodules with decreased size were malignant and 90.2% nodules with decreased size were found after six months. Of 175 nodules with repeat US-FNA, repeat cytology results did not differ significantly between the groups with follow-up US-FNA before and after six months ( P = 0.337). No significant differences were seen in size or extrathyroidal extension among the 13 malignant nodules according to the six-month interval (all P > 0.05), and no lateral lymph node metastasis was present. Conclusion Repeat US-FNA for initially non-diagnostic thyroid nodules can be performed at a six-month interval after initial procedure without tumor progression. PMID- 28592150 TI - Atrial Fibrillation in Patients Hospitalized With Heart Failure: Patient Characteristics and Outcomes From the HEARTS Registry. AB - Effect of atrial fibrillation (AF) on short- and long-term outcomes in heart failure (HF) is controversial. Accordingly, we examined this relationship in a national multicenter project using data from the Hearts Function Assessment Registry Trial in Saudi Arabia that studied the clinical features and outcomes of patients admitted with de novo and acute on chronic HF. Out of 2593 patients with HF, 449 (17.8%) had AF at presentation. Patients with AF were more likely to be males and older (mean age 65.2 +/- 15.0 vs 60.5 +/- 14.8 years) to have a history of ventricular tachycardia/ventricular fibrillation (3.1% vs 1.9%) or cerebrovascular accident (15.0% vs 8.5%). However, they were less likely to have diabetes (66.0% vs 55.9%) or coronary artery disease (55.6% vs 42.3%). The 1-, 2 , and 3-year crude mortality rates were significantly higher in patients with AF (23.2% vs 18.3%, 27.4% vs 22.3%, and 27.8% vs 23.2%, respectively). However, there was no significant difference in mortality after adjusting for covariates. Thus, in patients admitted with HF, AF upon presentation was not associated with increased mortality. PMID- 28592152 TI - The relationship between myocardial and hepatic T2 and T2* at 1.5T and 3T MRI in normal and iron-overloaded patients. AB - Background Cardiac and liver iron assessment using magnetic resonance imaging (MRI) is non-invasive and used as a preclinical "endpoint" in asymptomatic patients and for serial iron measurements in iron-overloaded patients. Purpose To compare iron measurements between hepatic and myocardial T2* and T2 at 1.5T and 3T MRI in normal and iron-overloaded patients. Material and Methods The T2 and T2* values from the regions of interest (ROIs) at mid-left ventricle and mid hepatic slices were evaluated by 1.5T and 3T MRI scans for healthy and iron overloaded patients. Results For iron-overloaded patients, the myocardial T2 (1.5T) and myocardial T2 (3T) values were 60.3 ms (range = 56.2-64.8 ms) and 55 ms (range = 51.6-60.1 ms) (rho = 0.3679) while the myocardial T2* (3T) 20.5 ms (range = 18.4-25.9 ms) was shorter than the myocardial T2* (1.5T) 35.9 ms (range = 31.4-39.5 ms) (rho = 0.6454). The hepatic T2 at 1.5T and 3T were 19.1 ms (range = 14.8-27.9 ms) and 15.5 ms (14.6-20.4 ms) (rho = 0.9444) and the hepatic T2* at 1.5T and 3T were 2.7 ms (range = 1.8-5.6 ms) and 1.8 ms (range = 1.1-2.9 ms) (rho = 0.9826). The line of best fit exhibiting the linearity of the hepatic T2* (1.5T) and hepatic T2* (3T) had a slope of 2 and an intercept of -0.387 ms (R = 0.984). Conclusion Our study found myocardial T2 (1.5T) nearly equal to T2 (3T) with myocardial T2* (3T) 1.75 shorter than myocardial T2* (1.5T). The relationship of hepatic T2* (1.5T) and hepatic T2* (3T) was linear with T2* (1.5T) approximately double to T2* (3T) in iron-overloaded patients. This linear relationship between hepatic T2* (1.5T) and hepatic T2 (3T) could be an alternative method for estimating liver iron concentration (LIC) from 3T. PMID- 28592153 TI - Does Level of Hospital Matter? A Study of Mortality of Acute Myocardial Infarction Patients in Shanxi, China. AB - This study compares risk-standardized mortality rates (RSMRs) of patients with acute myocardial infarction among tertiary A (typically, advanced urban hospitals with more than 800 beds), tertiary B (urban hospitals with more than 500 beds), and secondary A hospitals (rural and urban hospitals with less than 500 beds) in Shanxi, China. In all, 43 500 acute myocardial infarction inpatient records from 93 hospitals were included. Hierarchical logistic regression was used to estimate RSMRs, and Dunn's post hoc test was used to make pairwise comparisons of RSMR between hospital levels. It was found that the median RSMRs of secondary A hospitals were significantly lower than those of tertiary A and tertiary B hospitals (at 1% and 10% significance level, respectively), while there was no significant difference between the median RSMRs in tertiary A and tertiary B hospitals. The reasons for significant disparity in quality of care among different hospital levels requires further exploration. PMID- 28592155 TI - Future perspectives for personalized immunotherapy in renal cell carcinoma. PMID- 28592154 TI - "I just had to be flexible and show good patience": management of interactional approaches to enact mentoring roles by peer mentors with developmental disabilities. AB - PURPOSE: Peer mentoring may be an effective approach for fostering skill development for mentors and mentees with developmental disabilities. However, little is known about how mentors with developmental disabilities perceive and enact their roles. RESEARCH QUESTIONS: (1) How do young adults with developmental disabilities describe their role as a peer mentor in the context of instrumental peer mentoring? (2) How do they enact their perceived roles? METHODS: Thematic analysis of semi-structured reflections completed by six mentors with developmental disabilities (ages 17-35) with multiple mentoring experiences. RESULTS: Mentors perceived themselves as professionals with a primary role of teaching, and for some mentoring relationships, a secondary role of developing an interpersonal relationship. To enact these roles, mentors used a supportive interactional approach characterized by actions such as encouragement and sharing examples and dispositions, such as flexibility and patience. Mentors monitored mentee learning and engagement within the mentoring session and, as needed, adjusted their approach to optimize mentee learning and engagement. To successfully manage their interactional approach, mentors used supports such as peer mentoring scripts, tip sheets, and supervisors. CONCLUSIONS: While mentors reported several actions for teaching, they may benefit from training to learn approaches to facilitate more consistent development of interpersonal relationships. Implications for Rehabilitation Peer mentoring may be an effective approach for fostering skill development for young adult mentors and mentees with developmental disabilities. In this study, young adult peer mentors with developmental disabilities perceived themselves as professionals with a primary role of teaching and a secondary role of developing an interpersonal relationship. Peer mentors used actions and dispositions that matched their perceived roles and supported mentees with developmental disabilities to engage in instrumental mentoring. With supports and training, young adults with developmental disabilities can successfully execute the complex relational and teaching tasks required of peer mentoring. PMID- 28592156 TI - Diagnosis and management of smoldering multiple myeloma: the razor's edge between clonality and cancer. AB - Smoldering multiple myeloma (SMM) is a rare plasma cell disorder, and as the disease is asymptomatic, diagnosis is often incidental. SMM is characterized by increased marrow infiltration by clonal plasma cells and/or elevated serum M protein in the absence of a myeloma-defining event (MDE). In recent years, SMM has gained increased attention owing to a broadening of the criteria for MDE, which include apart from the CRAB criteria, three additional parameters. Survival advantage may be offered by early treatment in the high-risk subset, based on a single trial. In this review, we assess the risk factors and models for progression to multiple myeloma. A review of our diagnostic and management approaches to SMM is presented. PMID- 28592158 TI - Phase Ib study of the mTOR inhibitor everolimus with low dose cytarabine in elderly acute myeloid leukemia. PMID- 28592157 TI - Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity. AB - This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure-activity relationships. Intranasal administration of PTP1B inhibitors at >=0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action. PMID- 28592159 TI - Taurine prevents ultraviolet B induced apoptosis in retinal ganglion cells. AB - BACKGROUND: Compatible osmolytes accumulation is an active resistance response in retina under ultraviolet (UV) radiation and hypertonicity conditions. OBJECTIVE: The purpose of this research is to investigate the protective role of taurine on retina under UVB radiation. METHODS: Osmolytes transporters were measured by quantitative realtime PCR. Osmolytes uptake was estimated by radioimmunoassay. Cell viability was calculated by MTT assay. Cell apoptosis was measured by flow cytometry analysis. RESULTS: Hypertonicity accelerated osmolytes uptake into retinal ganglion cells (RGCs) including taurine, betadine, and myoinositol. UVB radiation increased osmolytes transporter expression and osmolytes uptake. In addition, osmolyte taurine remarkably prevented UVB radiation induced cell apoptosis in RGCs. CONCLUSIONS: The effect of compatible osmolyte taurine on cell survival rate may play an important role in cell resistance and adaption to UVB exposure. PMID- 28592160 TI - Using Virtual Reality to investigate multitasking ability in individuals with frontal lobe lesions. AB - Individuals with lesions in the prefrontal cortex often show impairments with the organisation of their behaviour in everyday life. These difficulties can be hard to detect using structured formal tests. The objective of this study was to use Virtual Reality (VR) to explore the multitasking performance of individuals with focal frontal lobe lesions, specifically using the Jansari assessment of Executive Functions (JEF(c)). Nineteen individuals with frontal lobe lesions were compared with 19 matched controls on the test and a group of commonly used clinical measures of neuropsychological functioning, as well as questionnaire measures of everyday activity, anxiety and depression. There was a significant difference between groups on the overall JEF(c) score and on five of the eight individual constructs, namely the planning, creative thinking, adaptive thinking, event-based Prospective Memory (PM) and time-based PM constructs. There were no differences between groups on the non-VR EF individual measures apart from on one EF control measure, Trail Making A. These results demonstrate the potential clinical utility of the JEF(c) and highlight the value of ecologically valid VR measures in detecting impairments in EF in individuals with frontal lobe lesions. PMID- 28592161 TI - Preparing for the future: multi-stakeholder perspectives on autonomous goal setting for adolescents with autism spectrum disorders. AB - PURPOSE: Self-determination is linked to numerous positive outcomes including improved social inclusion and quality of life for adolescents with autism spectrum disorder. Autonomous participation in therapeutic goal setting is an important component of self-determination. This study examined perceptions of, and barriers to, autonomous goal setting as perceived by: (1) adolescents with autism spectrum disorder, (2) parents of adolescents with autism spectrum disorder, and (3) interdisciplinary professionals. METHOD: Three focus groups (one with each of the key stakeholders) and one joint parent and child interview were conducted. All discussions were audio-recorded, transcribed verbatim and thematically analyzed based on the methods outlined by Braun and Clarke (2006). RESULTS: A total of 7 parents (6 mothers, 1 father), 4 youth with autism spectrum disorder, and 10 professionals participated in the study. Three themes related to current experiences with goal setting emerged: (1) purpose, (2) barriers, and (3) types. CONCLUSIONS: Currently, adolescents with autism spectrum disorder are rarely active participants in the goal setting process. This study provides novel data, from the perspectives of multiple stakeholders, about barriers, perceptions, and actualities related to autonomous goal setting for adolescents with autism spectrum disorder. Implications for rehabilitation Adolescent participation in autonomous goal setting is an important component of self determination. Rehabilitation professionals, parents, and adolescents with autism spectrum disorder identified similar barriers to autonomous goal setting. Adolescents with autism spectrum disorder described goals as short-term, concrete tasks, whereas parents perceived involvement in goal setting as a gateway to long term self-determination. Rehabilitation professionals and parents acknowledged the benefits and advocated for increased involvement of adolescents with autism spectrum disorder in the goal setting process. Similar to the paradigm shift toward family-centered care, rehabilitation professionals need to shift to include the involvement and participation of individuals with autism spectrum disorder. PMID- 28592163 TI - Updating Probability in Sex Offender Risk Assessment. AB - Actuarial scales like the Static-99R are widely used to predict an individual's risk of sexual recidivism. However, current actuarial scales only provide rates of detected sex offenses over 10-year follow-up and do not account for all recidivism risk factors. Therefore, some forensic evaluators extrapolate, adjust, or override recidivism rates derived from actuarial scales to predict the lifetime risk of committed offenses that accounts for external risk factors, those not addressed by the actuarial scales. However, critics contend that altering rates from actuarial scales degrades their predictive validity. This article makes the case for extrapolating risk for time of exposure and for evidence-based external risk factors. It proposes using odds ratios (ORs) from case-control studies to adjust predictions from follow-up cohort studies. Finally, it shows how evaluators can apply ORs and their margins of error to sex offender risk assessment. PMID- 28592162 TI - Natural and synthetic products used for the treatment of smoke inhalation: a patent review. AB - INTRODUCTION: Inhalation injury is the leading cause of death in burn patients and is usually caused by the uninhibited absorption of smoke, which has an extremely toxic effect on the respiratory system. The physiopathology of inhalation injury covers multiple factors and the injured respiratory system may present deterioration in a few hours. Areas covered: In this present review, we analyzed patents based on both natural and synthetic products developed for the treatment of smoke inhalation. We found 14 patents in Espacenet, 25 in WIPO and none in the USPTO data search. Expert opinion: Several previous reports on treatments used for smoke inhalation are discussed. Although there are a number of research based products for this injury, there has been no review of the patents dealing with treatments for smoke inhalation. The development of novel natural or synthetic products are discussed in detail in the review. PMID- 28592164 TI - What Did Latino Family Caregivers Expect and Learn From Education Intervention "Caregivers Like Me"? AB - OBJECTIVE: US Latinos historically have underutilized end-of-life (EOL) resources. This study reports the views of family caregivers before and after education intervention Caregivers Like Me geared to improve knowledge and attitudes regarding EOL resources among Latino caregivers. METHODS: This is a qualitative substudy within a multicentered cross-sectional study design. Educational intervention was offered to family caregivers of Latino elders from 3 different communities, using an audiovisual presentation, including a case-based video telenovela and pre-posttest questionnaires with open-ended questions. This study pertains to the qualitative results for the open-ended questions before and after education intervention. RESULTS: Participants (N = 145) were mostly females (79%) with a mean age of 56 +/- 15 years and reported (92%) active learning from intervention. The pretest open-ended question on expected learning identified 2 themes, care for the sick and self-care. It included 5 subthemes and the most common one was how to help the sick. The posttest question on actual learning identified the same 2 themes and 4 subthemes that were similar but different from the pretest. Accepting help and knowledge of services available were the most common. CONCLUSION: The education intervention Caregivers Like Me was able to improve attitudes toward EOL care because participants who wanted to help their loved ones realized that they need to accept professional help and were made aware of the services available. PMID- 28592165 TI - Self-Concealment Mediates the Relationship Between Perfectionism and Attitudes Toward Seeking Psychological Help Among Adolescents. AB - One of the biggest barriers in treating adolescents with mental health problems is their refusing to seek psychological help. This study was designed to examine the relationships between two forms of perfectionism, self-concealment and attitudes toward seeking psychological help and to test the mediating role of self-concealment in the relationship between perfectionism and attitudes toward seeking psychological help among Malaysian high school students. The participants were 475 Malaysian high school students from four high schools in Kuala Lumpur, Malaysia. Structural equation modelling results indicated that high school students with high levels of socially prescribed perfectionism, high levels of self-concealment, and low levels of self-oriented perfectionism reported negative attitudes toward seeking psychological help. Bootstrapping analysis showed that self-concealment emerged as a significant, full mediator in the link between socially prescribed perfectionism and attitudes toward seeking psychological help. Moderated mediation analysis also examined whether the results generalized across men and women. The results revealed that male students with socially prescribed perfectionism are more likely to engage in self-concealment, which in turn, leads to negative attitudes toward seeking psychological help more than their female counterparts. The results suggested that students high in socially prescribed perfectionism were more likely to engage in self-concealment and be less inclined to seek psychological help. PMID- 28592166 TI - Continuous bilateral thoracic paravertebral blockade for analgesia after cardiac surgery: a randomised, controlled trial. AB - BACKGROUND: Continuous bilateral thoracic paravertebral blockade has been used for analgesia after cardiac surgery, but its efficacy has never been formally tested. METHOD: Fifty adult patients were enrolled in a double-blind, randomised, controlled study of continuous bilateral thoracic paravertebral infusion of 0.5% lidocaine (1 mg.kg-1.hr-1) for analgesia after coronary surgery. Control patients received a subcutaneous infusion of lidocaine at the same rate through catheters inserted at the same locations as the study group. The primary outcome was morphine consumption at 48 hours using patient-controlled analgesia (PCA). Secondary outcomes included pain, respiratory function, nausea and vomiting. Serum lidocaine concentrations were measured on the first two post-operative days. RESULTS: There was no difference in morphine consumption or in any other outcome measure between the groups. Serum lidocaine concentrations increased during the study, with a maximum of 5.9 mg.l-1. There were no adverse events as a consequence of the study. CONCLUSION: Bilateral paravertebral infusion of lidocaine confers no advantage over systemic lidocaine infusion after cardiac surgery. CLINICAL TRIAL REGISTRATION: ISRCTN13424423 ( https://www.isrctn.com ). PMID- 28592167 TI - Friction forces and patient-centredness: Understanding how established logics endure during infrastructure transformation. AB - In this article, we examine three cases of e-health solutions for patients in Norway. For the analysis of the three cases, we focused on friction forces that come into play when different established arrangements need to change to accommodate novelty. We argue that the design of new technologies was shaped by friction related to institutionalised practices, regulatory regimes and entrenched patient roles. These friction forces connect the past with the present, come into action when aiming for novelty and result to the perpetuation of constituents of the past during change processes. Specifically, the e-health solutions under study were strongly influenced by established healthcare provision logics. All three initiatives expanded the healthcare information infrastructure towards the patients with as little disruption to established arrangements as possible. PMID- 28592168 TI - Homozygous Mutation on the beta-Globin Polyadenylation Signal in a Tunisian Patient with beta-Thalassemia Intermedia and Coinheritance of Gilbert's Syndrome. AB - We report here the clinical, hematological and molecular data in a 50-year-old patient with beta-thalassemia intermedia (beta-TI) caused by a homozygous beta+ mutation on the beta-globin gene polyadenylation (polyA) signal (AATAAA>AAAAAA). beta Haplotype analysis was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Haplotype and framework analysis showed that this mutation is associated with the [- - - - + + +] beta haplotype and framework 1 (CCGCT) (FW1). This mutation was previously reported in the heterozygous state in association with the codon 9 (+TA) mutation in a beta-TI patient originating from Tunisia. To the best of our knowledge, this is the first report describing this mutation in the homozygous state. The case reported here, coinherited Gilbert's syndrome, which is characterized by hyperbilirubinemia. This conclusion was reached by the investigation of the promoter region [A(TA)nTAA] motif of the UGT1A1 gene, showing the (TA)6/(TA)7 genotype. PMID- 28592169 TI - Clinical and radiological control of highly active relapsing-remitting multiple sclerosis with first-line natalizumab. AB - A 33-year-old man with gait instability, weakness of the left lower extremity, decreased visual acuity in the left eye, and urgency and urine incontinence was diagnosed of relapsing-remitting multiple sclerosis. He was treated with natalizumab (300 mg intravenously every 4 weeks) as first-line therapy, which reached at 6 months a favorable clinical evolution and dramatic radiological improvement (T2-weighted lesion load decreased by 50% and no gadolinium-enhancing T1 lesions) sustained over the course of 8 years. This clinical case shows the efficacy of natalizumab in a real-world setting and, particularly, the sustained effect of this drug in the long term as demonstrated by persistent radiological improvement. Natalizumab can be considered as the treatment of choice in relapsing-remitting multiple sclerosis forms presenting with two relapses and gadolinium-enhancing (Gd+) lesions. PMID- 28592170 TI - Current options to manage Waldenstrom's macroglobulinemia. AB - INTRODUCTION: Waldenstrom's macroglobulinemia (WM) is a rare, incurable B-cell lymphoma, with a median survival of 5-10 years in symptomatic patients. There is no consensus on the standard of care and several agents are currently used in these patients. Areas covered: In this article, we will review the use of standard therapies and new drugs investigated such as monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, Bruton's tyrosine kinase inhibitors and novel agents in early-stage development. Expert commentary: RCD (Rituximab/Cyclophosphamide/Dexamethasone) is an effective and safe treatment in first line in WM. BR (Bendamustine/Rituximab) or BRD (Bortezomib/Rituximab/Dexamethasone) provide durable responses, and are still indicated in most patients. Ibrutinib is a new option and it was approved as primary therapy and for relapse. Carfilzomib based therapy represents an emerging option for proteasome-inhibitor based therapy for WM. Despite encouraging results, WM remains an incurable disease; therefore, new treatment options are needed. For this reason, continued participation in clinical trials should be encouraged. PMID- 28592172 TI - Hydrogen Storage Technologies for Future Energy Systems. AB - Future energy systems will be determined by the increasing relevance of solar and wind energy. Crude oil and gas prices are expected to increase in the long run, and penalties for CO2 emissions will become a relevant economic factor. Solar- and wind-powered electricity will become significantly cheaper, such that hydrogen produced from electrolysis will be competitively priced against hydrogen manufactured from natural gas. However, to handle the unsteadiness of system input from fluctuating energy sources, energy storage technologies that cover the full scale of power (in megawatts) and energy storage amounts (in megawatt hours) are required. Hydrogen, in particular, is a promising secondary energy vector for storing, transporting, and distributing large and very large amounts of energy at the gigawatt-hour and terawatt-hour scales. However, we also discuss energy storage at the 120-200-kWh scale, for example, for onboard hydrogen storage in fuel cell vehicles using compressed hydrogen storage. This article focuses on the characteristics and development potential of hydrogen storage technologies in light of such a changing energy system and its related challenges. Technological factors that influence the dynamics, flexibility, and operating costs of unsteady operation are therefore highlighted in particular. Moreover, the potential for using renewable hydrogen in the mobility sector, industrial production, and the heat market is discussed, as this potential may determine to a significant extent the future economic value of hydrogen storage technology as it applies to other industries. This evaluation elucidates known and well-established options for hydrogen storage and may guide the development and direction of newer, less developed technologies. PMID- 28592173 TI - Algae to Economically Viable Low-Carbon-Footprint Oil. AB - Algal oil as an alternative to fossil fuel has attracted attention since the 1940s, when it was discovered that many microalgae species can produce large amounts of lipids. Economics and energy security were the motivational factors for a spurt in algae research during the 1970s, 1990s, and early 2000s. Whenever crude prices declined, research on algae stopped. The scenario today is different. Even given low and volatile crude prices ($30-$50/barrel), interest in algae continues all over the world. Algae, with their cure-all characteristics, have the potential to provide sustainable solutions to problems in the energy food-climate nexus. However, after years of effort, there are no signs of algae to-biofuel technology being commercialized. This article critically reviews past work; summarizes the current status of the technology; and based on the lessons learned, provides a balanced perspective on a potential path toward commercialization of algae-to-oil technology. PMID- 28592171 TI - Next generation human skin constructs as advanced tools for drug development. AB - Many diseases, as well as side effects of drugs, manifest themselves through skin symptoms. Skin is a complex tissue that hosts various specialized cell types and performs many roles including physical barrier, immune and sensory functions. Therefore, modeling skin in vitro presents technical challenges for tissue engineering. Since the first attempts at engineering human epidermis in 1970s, there has been a growing interest in generating full-thickness skin constructs mimicking physiological functions by incorporating various skin components, such as vasculature and melanocytes for pigmentation. Development of biomimetic in vitro human skin models with these physiological functions provides a new tool for drug discovery, disease modeling, regenerative medicine and basic research for skin biology. This goal, however, has long been delayed by the limited availability of different cell types, the challenges in establishing co-culture conditions, and the ability to recapitulate the 3D anatomy of the skin. Recent breakthroughs in induced pluripotent stem cell (iPSC) technology and microfabrication techniques such as 3D-printing have allowed for building more reliable and complex in vitro skin models for pharmaceutical screening. In this review, we focus on the current developments and prevailing challenges in generating skin constructs with vasculature, skin appendages such as hair follicles, pigmentation, immune response, innervation, and hypodermis. Furthermore, we discuss the promising advances that iPSC technology offers in order to generate in vitro models of genetic skin diseases, such as epidermolysis bullosa and psoriasis. We also discuss how future integration of the next generation human skin constructs onto microfluidic platforms along with other tissues could revolutionize the early stages of drug development by creating reliable evaluation of patient-specific effects of pharmaceutical agents. Impact statement Skin is a complex tissue that hosts various specialized cell types and performs many roles including barrier, immune, and sensory functions. For human relevant drug testing, there has been a growing interest in building more physiological skin constructs by incorporating different skin components, such as vasculature, appendages, pigment, innervation, and adipose tissue. This paper provides an overview of the strategies to build complex human skin constructs that can faithfully recapitulate human skin and thus can be used in drug development targeting skin diseases. In particular, we discuss recent developments and remaining challenges in incorporating various skin components, availability of iPSC-derived skin cell types and in vitro skin disease models. In addition, we provide insights on the future integration of these complex skin models with other organs on microfluidic platforms as well as potential readout technologies for high-throughput drug screening. PMID- 28592175 TI - Magnetic Resonance Imaging and Velocity Mapping in Chemical Engineering Applications. AB - This review aims to illustrate the diversity of measurements that can be made using magnetic resonance techniques, which have the potential to provide insights into chemical engineering systems that cannot readily be achieved using any other method. Perhaps the most notable advantage in using magnetic resonance methods is that both chemistry and transport can be followed in three dimensions, in optically opaque systems, and without the need for tracers to be introduced into the system. Here we focus on hydrodynamics and, in particular, applications to rheology, pipe flow, and fixed-bed and gas-solid fluidized bed reactors. With increasing development of industrially relevant sample environments and undersampling data acquisition strategies that can reduce acquisition times to <1 s, magnetic resonance is finding increasing application in chemical engineering research. PMID- 28592176 TI - Introduction. PMID- 28592177 TI - Biocatalytic Nanocomposites for Combating Bacterial Pathogens. AB - Bacterial infections remain a major public health concern. However, broad spectrum antibiotics largely target redundant mechanisms of bacterial survival and lead to gained resistance owing to microbial evolution. New methods are needed to attack bacterial infections, and we have only begun to seek out nature's vast arsenal of antimicrobial weapons. Enzymes offer one such weapon, and their diversity has been exploited to kill bacteria selectively through unique targets, particularly in bacterial cell walls, as well as nonselectively through generation of bactericidal molecules. In both approaches, microbial resistance has largely been absent, which bodes well for its potential use in human therapeutics. Furthermore, enzyme stabilization through conjugation to nanoscale materials and incorporation into polymeric composites enable their use on surfaces to endow them with antimicrobial properties. Here, we highlight the use of enzymes as antimicrobial agents, including applications that may prove effective in new therapeutics and through control of key societal infrastructures. PMID- 28592178 TI - Artificially Engineered Protein Polymers. AB - Modern polymer science increasingly requires precise control over macromolecular structure and properties for engineering advanced materials and biomedical systems. The application of biological processes to design and synthesize artificial protein polymers offers a means for furthering macromolecular tunability, enabling polymers with dispersities of ~1.0 and monomer-level sequence control. Taking inspiration from materials evolved in nature, scientists have created modular building blocks with simplified monomer sequences that replicate the function of natural systems. The corresponding protein engineering toolbox has enabled the systematic development of complex functional polymeric materials across areas as diverse as adhesives, responsive polymers, and medical materials. This review discusses the natural proteins that have inspired the development of key building blocks for protein polymer engineering and the function of these elements in material design. The prospects and progress for scalable commercialization of protein polymers are reviewed, discussing both technology needs and opportunities. PMID- 28592174 TI - At Light Speed: Advances in Optogenetic Systems for Regulating Cell Signaling and Behavior. AB - Cells are bombarded by extrinsic signals that dynamically change in time and space. Such dynamic variations can exert profound effects on behaviors, including cellular signaling, organismal development, stem cell differentiation, normal tissue function, and disease processes such as cancer. Although classical genetic tools are well suited to introduce binary perturbations, new approaches have been necessary to investigate how dynamic signal variation may regulate cell behavior. This fundamental question is increasingly being addressed with optogenetics, a field focused on engineering and harnessing light-sensitive proteins to interface with cellular signaling pathways. Channelrhodopsins initially defined optogenetics; however, through recent use of light-responsive proteins with myriad spectral and functional properties, practical applications of optogenetics currently encompass cell signaling, subcellular localization, and gene regulation. Now, important questions regarding signal integration within branch points of signaling networks, asymmetric cell responses to spatially restricted signals, and effects of signal dosage versus duration can be addressed. This review summarizes emerging technologies and applications within the expanding field of optogenetics. PMID- 28592179 TI - Driving Forces for Nonnative Protein Aggregation and Approaches to Predict Aggregation-Prone Regions. AB - Nonnative protein aggregation is the process by which otherwise folded, monomeric proteins are converted to stable aggregates composed of protein chains that have undergone some degree of unfolding. Often, a conformational change is needed to allow certain sequences of amino acids-so-called aggregation-prone regions (APRs) to form stable interprotein contacts such as beta-sheet structures. In addition to APRs that are needed to stabilize aggregates, other factors or driving forces are also important in inducing aggregation in practice. This review focuses first on the overall process and mechanistic drivers for nonnative aggregation, followed by a more detailed summary of the factors currently thought to be important for determining which amino acid sequences most greatly stabilize nonnative protein aggregates, as well as a survey of many of the existing algorithms that are publicly available to attempt to predict APRs. Challenges with experimental validation of predicted APRs for proteins are briefly discussed. PMID- 28592180 TI - Characteristics and demographics of reversible cerebral vasoconstriction syndrome: A large prospective series of Korean patients. AB - Objectives To report demographics and characteristics of reversible cerebral vasoconstriction syndrome (RCVS) in the Korean cohort. Methods We prospectively recruited patients with definite (imaging-proven) RCVS and probable (imaging negative) RCVS who visited Samsung Medical Center between June 2012 and September 2016. Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of RCVS without typical causes ("idiopathic RCVS") were compared with those of RCVS with identifiable causes ("secondary RCVS"). International Classification of Headache Disorders (ICHD)-3 beta criteria for 6.7.3 RCVS and 6.7.3.1 probable RCVS were tested. Results A total of 138 patients (104 definite and 34 probable RCVS) were included in this study. Patients with definite RCVS were predominantly female (85.6%) and middle aged (mean, 50.7 [range, 23-82] years). Probable RCVS was associated with less female predominance (70.6%, p = 0.049), more typical manifestations ( p < 0.001), and none of neurological complications. One-hundred and one (97.1%) patients with definite RCVS had headache, but the typical "recurrent and/or triggered" thunderclap headache was reported in only 83 (82.2%). In most patients with definite RCVS (84.6%), RCVS was idiopathic, while only 16 (15.4%) had secondary causes. Compared to those with secondary RCVS, patients with idiopathic RCVS were older (52.8 +/- 11.42 vs. 39.1 +/- 9.55 years, p < 0.001). Patients with secondary RCVS had more complications than those with idiopathic RCVS (40.5% vs. 12.5%, p = 0.018). Among idiopathic RCVS patients, 33 (37.5%) reported a preceding event or a change in lifestyle, environment, health, or medication within one month before onset. Conclusion In our cohort, RCVS was benign and idiopathic in most patients, and occurred frequently in middle-aged women. Manifestations of RCVS were more diverse than previously recognized, and forms without any headache existed. Different genetic, social, and environmental factors should be taken into account to unveil the spectrum and pathophysiology of RCVS. PMID- 28592181 TI - Grappling with the future: The messiness of pilot implementation in information systems design. AB - Pilot implementation is a method for avoiding unintended consequences of healthcare information systems. This study investigates how learning from pilot implementations is situated, messy, and therefore difficult. We analyze two pilot implementations by means of observation and interviews. In the first pilot implementation, the involved porters saw their improved overview of pending patient transports as an opportunity for more self-organization, but this opportunity hinged on the unclear prospects of extending the system with functionality for the porters to reply to transport requests. In the second pilot implementation, the involved paramedics had to print the data they had entered into the system because it had not yet been integrated with the electronic patient record. This extra work prolonged every dispatch and influenced the paramedics' experience of the entire system. We discuss how pilot implementations, in spite of their realism, leave room for uncertainty about the implications of the new system. PMID- 28592182 TI - Perioperative and Anesthetic Considerations in Atrioventricular Septal Defect. AB - Atrioventricular septal defect results from a failure of normal endocardial cushion fusion during embryologic cardiac development. This developmental aberration results in defects in the atrial and/or ventricular septum and malformation of the atrioventricular valves. The pathophysiology of atrioventricular septal defect is variable, and ranges from mild left to right shunting similar to a simple atrial septal defect to complex single-ventricle heart disease. This review focuses on the spectrum of atrioventricular septal defect from partial to complete, without associated cardiac defects. PMID- 28592184 TI - Don't think twice it's all right: tamoxifen and CYP2D6 genotyping in the treatment of breast cancer patients. AB - Letter in resonse to: Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17(18), 1967 1969 (2016). PMID- 28592185 TI - Gendering of day center occupations as perceived by people with psychiatric disabilities in Sweden. AB - BACKGROUND: The aim was to explore the experiences and views of people attending day centers for people with psychiatric disabilities concerning the occurrence and nature of gendering of the occupations performed there. METHODS: Twenty-five day center attendees were interviewed regarding occupational choices at the day centers, whether they would describe day center occupations as gendered, and if so what the consequences were of the gendering of occupations. The transcribed texts were analyzed by thematic analysis. RESULTS: Three main themes were identified: Thinking and doing gender; Understandings of gendering of day center occupations; and Consequences of gendered occupation. The participants were more open-minded in their reasoning than in what they were doing. They understood gendering to be a result of traditions, role models from childhood, ideas about typically male and female innate capacities, lack of knowledge and low self confidence. Doing seemed to reproduce gender, but being in a group of the same sex could shape unity and a relaxed atmosphere. CONCLUSIONS: The findings could be understood as a set of gender frames, which might prevent either of the sexes from developing their full potentials and transgress into e.g. the employment market. Gendering should be highlighted and debated in psychosocial rehabilitation. PMID- 28592183 TI - Vaginal film for prevention of HIV: using visual and tactile evaluations among potential users to inform product design. AB - Topical prevention of HIV and other STIs is a global health priority. To provide options for users, developers have worked to design safe, effective and acceptable vaginal dissolving film formulations. We aimed to characterize user experiences of vaginal film size, texture and color, and their role in product elicited sensory perceptions (i.e. perceptibility), acceptability and willingness to use. In the context of a user-centered product evaluation study, we elicited users' 'first impressions' of various vaginal film formulation designs via visual and tactile prototype inspection during a qualitative user evaluation interview. Twenty-four women evaluated prototypes. Participants considered size and texture to be important for easy insertion. Color was more important following dissolution than prior to insertion. When asked to combine and balance all properties to arrive at an ideal film, previously stated priorities for individual characteristics sometimes shifted, with the salience of some individual characteristics lessening when multiple characteristics were weighted in combination. While first impressions alone may not drive product uptake, users' willingness to initially try a product is likely impacted by such impressions. Developers should consider potential users' experiences and preferences in vaginal film design. This user-focused approach is useful for characterizing user sensory perceptions and experiences relevant to early design of prevention technologies. PMID- 28592186 TI - The role of the MTHFR C677T polymorphism in methotrexate-induced toxicity in pediatric osteosarcoma patients. AB - AIM: Osteosarcoma patients receive high doses of methotrexate (MTX). However, pharmacogenetic information remains limited and has mainly been investigated in leukemia so far. PATIENTS & METHODS: We investigated the link between the MTHFR C677T genotype, toxicity levels (mucositis, MTX plasma level, hematological toxicity and hepatotoxicity) and survival of 48 pediatric osteosarcoma patients. RESULTS: The TT genotype did not show more toxicity compared with the CC/CT genotype. However, plasma MTX levels were related with mucositis, but not with hematological toxicity, nor hepatotoxicity. Survival rates did not differ between homozygous and non-homozygous patients. Yet, homozygous patients had higher relapse risk. CONCLUSION: The MTHFR C667T polymorphism is not predictive for toxicity or overall survival, but could be used for relapse risk stratification. PMID- 28592187 TI - Outcomes of organ donation in brain-dead patient's families: Ethical perspective. AB - BACKGROUND: The families of brain-dead patients have a significant role in the process of decision making for organ donation. Organ donation is a traumatic experience. The ethical responsibility of healthcare systems respecting organ donation is far beyond the phase of decision making for donation. The principles of donation-related ethics require healthcare providers and organ procurement organizations to respect donor families and protect them against any probable harm. Given the difficult and traumatic nature of donation-related experience, understanding the outcomes of donation appears crucial. OBJECTIVE: The aim of this study was to explore the outcomes of organ donation for the families of brain-dead patients. METHODS: This was a qualitative descriptive study to which a purposeful sample of 19 donor family members were recruited. Data were collected through holding in-depth semi-structured interviews with the participants. Data analysis was performed by following the qualitative content analysis approach developed by Elo and Kyngas. FINDINGS: The main category of the data was "Decision to organ donation: a challenge from conflict to transcendence." This main category consisted of 10 subcategories and 3 general categories. The general categories were "challenging outcomes," "reassuring outcomes," and "transcending outcomes." Ethical considerations: The study was approved by the regional ethical review board. The ethical principles of informed consent, confidentiality, and non-identification were used. CONCLUSION: Donor families experience different challenges which range from conflict and doubtfulness to confidence, satisfaction, and transcendence. Healthcare providers and organ procurers should not discontinue care and support provision to donor families after obtaining their consent to donate because the post-decision phase is also associated with different complexities and difficulties with which donor families may not be able to cope effectively. In order to help donor families achieve positive outcomes from the tragedy of significant loss, healthcare professionals need to facilitate the process of achieving confidence and transcendence by them. PMID- 28592189 TI - Perceiving rejection by others: Relationship between rejection sensitivity and the spontaneous neuronal activity of the brain. AB - Rejection sensitivity (RS) can be defined as the disposition of a person to anxiously expect, readily perceive, and intensely react to rejection. Individuals with high RS are likely to suffer from mental disorders. The association between individual differences in RS and spontaneous neuronal activity at resting state has not yet been investigated. In this study, resting state data were used to investigate the relationship between RS and spontaneous neuronal activity in a large sample of healthy men (137) and women (172). The participants completed the rejection sensitivity questionnaire and underwent resting-state magnetic resonance imaging scan. Multiple regression analysis was conducted to examine the correlation between the regional amplitude of low-frequency fluctuations (ALFF) and rejection sensitivity scores adjusted for age and sex. Results showed that the ALFF value in the subgenual anterior cingulate cortex (sgACC) was positively associated with RS. Furthermore, functional connectivity with the middle frontal gyrus was negatively correlated with RS when sgACC was used as the seed region. These findings suggest that the spontaneous neuronal activity of sgACC and its functional connectivity with the lateral prefrontal cortex which are involved in experiencing social exclusion and regulating negative emotions are associated with individual differences in RS. PMID- 28592188 TI - Polymer-coated cardiopulmonary bypass circuit attenuates upregulation of both proteases/protease inhibitors and platelet degranulation in pigs. AB - INTRODUCTION: Interaction of blood with a cardiopulmonary bypass (CPB) circuit activates the coagulation-fibrinolysis, complement and kinin-kallikrein systems that are mainly supported by proteases and their inhibitors. METHODS: Biocompatibility of a new polymer-coated (SEC-coated) CPB circuit was globally evaluated and compared with that of a non-coated CPB circuit by quantitative proteomics, using isobaric tags for relative and absolute quantification labeling tandem mass spectrometry. Plasma samples were taken three times (5 min after initiation of CPB, just before declamping and just before termination of CPB) in 12 pigs undergoing 120 min of CPB with the SEC-coated CPB circuit or a non-coated CPB circuit (n = 6, respectively). RESULTS: Identified were 224 proteins having high protein confidence (>99%) and false discovery rate (FDR) <5%. Among these proteins, there were 25 significantly upregulated proteins in the non-coated CPB group compared to those in the SEC-coated CPB group. Dominant protein functions were platelet degranulation, serine-type (cysteine-type) endopeptidase inhibitor activity and serine-type endopeptidase activity in the 25 proteins. Bioinformatics analysis similarly revealed upregulation of proteins belonging to platelet degranulation and negative regulation of endopeptidase activity in the non-coated CPB group; these upregulations were effectively attenuated in the SEC coated CPB group. CONCLUSION: The new polymer (SEC)-coated CPB circuit effectively attenuated upregulation of proteins compared to the non-coated CPB circuit. These proteins were associated with both proteases/protease inhibitors and platelet degranulation. PMID- 28592190 TI - Genetic variants associated with warfarin dosage in Kuwaiti population. AB - Assessing the distinct prevalence or absence of genetic variants associated with differential response to the anticoagulant medication of warfarin in different population groups is actively pursued by pharmacogenomics community. Populations from Arabian Peninsula are underrepresented in such studies. By way of examining exome- and genome-wide genotype data from 1395 Arab individuals in Kuwait, we report distinct occurrence of warfarin response-related variants rs12460590_A/CYP2A7, rs2108622_T/CYP4F2, rs2884737_C/VKORC1 and distinct absence of rs11150606_C/PRSS53 in Kuwaiti population. The presented results in conjunction with similar literature reports on Qatari population enhance the worldwide understanding on population-specific distributions of genetic variants associated with warfarin drug dosage. PMID- 28592192 TI - Pyridine influence on a sequential anaerobic-anoxic-aerobic FMBR system for phenol, thiocyanate and ammonia removal. AB - A synthetic wastewater containing various pyridine concentrations (25-250 mg/L) was treated in a sequential anaerobic(B1)-anoxic(B2)-aerobic(B3) fed batch moving bed reactor (FMBR) system. Pyridine was associated with phenol (1500 mg/L), SCN- (800 mg/L), chemical oxygen demand (COD) (5400-5430 mg/L) and NH4+-N (500 mg/L) at hydraulic retention time (HRT) of 6 (B1: 3 days; B2 and B3: 1.5 days each) days. In B1, pyridine removal was 10-12% from influent concentration of 25-100 mg/L and beyond that, it was zero. Removal of phenol (53-39%) and COD (33-22%) occurred in B1, but pyridine above 50 mg/L inhibited both. In B2, 68-90% of pyridine removal occurred along with phenol (>98%), COD (>67%), SCN- (>85%) removal and denitrification. In B2, with an increase in pyridine loading removal rate of phenol, COD and nitrate increased, whereas SCN- removal decreased beyond pyridine loading of 0.031g/L day. In B3, nitrification decreased with high generation of free ammonia. Pyridine degradation in B1, B2 and B3 follows the Stover-Kincannon model with a maximum substrate removal rate of 111.1, 333.3 and 23.81 g/L day, respectively. Thiocyanate removal in B2 and ammonia removal in B3 follows the Bhatia inhibition model with a maximum substrate removal rate of 0.641 and 0.528/day, respectively. The overall efficiency of the FMBR system remained unaffected up to 250 mg pyridine/L at 6 days HRT. PMID- 28592191 TI - Influence of two variants of CYP450 oxidoreductase on the stable dose of acenocoumarol in a Spanish population. AB - AIM: To evaluate the influence of two variants of P450 oxidoreductase (POR), rs2868177 and POR*28, on the stable dosage of acenocoumarol. PATIENTS & METHODS: For this observational, cross-sectional study, patients were undergone stable anticoagulant treatment with acenocoumarol. Univariate and multiple regression analyses were performed to assess the influence of POR polymorphisms. RESULTS: About 340 patients were enrolled. Multiple regression had a coefficient of determination (R2) of 51.5% and an Akaike information criterion of 234.22. The inclusion of POR*28 polymorphisms increased the R2 to 52.0% and reduced the Akaike information criteria to 230.58. The POR*28 heterozygote showed statistical significance in the algorithm. CONCLUSION: The POR*28 heterozygote appears to be associated with the stable dose of acenocoumarol, but its clinical contribution to the prediction of the dosing of this drug is minimal. PMID- 28592193 TI - Permanent chronotropic impairment after closure of atrial or ventricular septal defect. AB - OBJECTIVES: Atrial and ventricular septal defects are commonly closed surgically with low rates of post-operative morbidity, and the long-term outcome has widely been described as benign. Nevertheless, there is an increasing understanding of late morbidity, and the possibility of postoperative chronotropic impairment is continuously questioned. Furthermore, potentially abnormal chronotropic responses may be associated with the recently demonstrated overrepresentation of late arrhythmias. We conducted this review to methodically describe the potential effects of surgical defect closure on the chronotropic response to exercise. METHODS: We performed a search protocol based on the 'Preferred Reporting Items for Systematic Reviews and Meta- Analyses' (PRISMA) guidelines. A data collection form was specifically developed and data were extracted from the included studies by a primary reviewer and crosschecked by a secondary reviewer. RESULTS: A search of electronic databases revealed 16 publications, which consistently reported an abnormal heart rate responses to exercise after surgical closure. In contrast, these and other studies convincingly showed normal chronotropic response in un operated patients as well as after percutaneous closure. Potential mechanisms include disturbances in the sinoatrial or atrioventricular conduction system and denervation in the proximity of the aorta during the surgical procedure. DISCUSSION: ASD and VSD patients have abnormal heart rate responses to exercise after surgical closure, which indicates a need of change in the preoperative information given to these patients and their parents before surgical defect closure. Although there may not be any alternatives to surgery, patients should still be informed about potential long-term consequences, including the risk of chronotropic incompetence. Moreover, this review suggests that 'specialized', long-term follow up may be indicated. PMID- 28592194 TI - 2,3',4,4',5-Pentachlorobiphenyl impairs insulin-induced NO production partly through excessive ROS production in endothelial cells. AB - Polychlorinated biphenyls (PCBs) have been reported to be associated with increased risk to hypertension, atherosclerosis, cardiovascular disease, etc. 2,3',4,4',5-Pentachlorobiphenyl, known as PCB-118, is a member of coplanar PCBs which renders their structure similar to polychlorinated dibenzo-p-dioxins (PCDDs) and has dioxin-like activity. In our current study, we investigated the effect of PCB-118 exposure on nitric oxide (NO) production and the underlying mechanisms in vitro. Exposure of PCB-118 impaired insulin-induced NO production and endothelial nitric oxide synthase (eNOS) activity in human umbilical vein endothelial cells (HUVECs) with no significant effect on cell viability. Furthermore, PCB-118 treatment induced oxidative stress. In addition, scavenging of reactive oxygen species (ROS) by 10 MUM N-acetyl-l-cysteine (NAC) partly rescued impaired insulin-induced eNOS activities and NO productions induced by PCB-118 in HUVECs. Taken together, these results indicate that PCB-118 mediates lower eNOS activity and impairs insulin-induced NO production partly through excessive ROS production in endothelial cells. PMID- 28592195 TI - Objective multicentre performance of the automated assays for AMH and estimation of established critical concentrations. AB - The measurement of AMH has now become widespread practice within the field of fertility treatment and research, despite technical issues with some of the original assays. The two new automated assays, with their potentially improved technical performance, require detailed examination and comparison under different conditions. In addition, the determination of categories of responses to ovarian stimulation, require re-evaluation for these new tests. The performance of the assays across numerous laboratories, and over a protracted timeframe, has been examined through the UK NEQAS published results. The automated assays show high quality performance figures over a broad concentration range, with exceptionally low variance figures, and they also yield very similar absolute concentration values. Critical response diagnostic concentrations have been re-evaluated by determination of age-related concentrations from within large population datasets. PMID- 28592196 TI - The Use of Self-Directed Relapse Prevention Booklets to Assist in Maintaining Abstinence After a 6-Week Group Smoking Cessation Treatment Program: A Randomized Controlled Trial. AB - BACKGROUND: Identifying effective relapse prevention interventions is a vital step to help smokers maintain abstinence for the long term. AIMS: The purpose of this study is to determine if providing recently quit smokers with self-directed relapse prevention booklets is effective at maintaining abstinence after intensive group smoking cessation treatment. METHOD: Two hundred and twenty-five participants were randomized to receive Forever Free (FF) relapse prevention booklets or a control booklet (Surgeon General's report, SG) at the end of a 6 week group treatment program. Participants were then contacted by phone to assess whether they had read the materials. Smoking status was assessed 6 months after their target quit date. Primary analyses focused on the 115 participants who quit at the end of treatment. RESULTS: There was no difference in the 6-month quit rate between groups (40.7% quit FF vs. 44.6% quit SG, p = .67). The FF group read a significantly smaller proportion of the materials versus the control booklet (20.0% read most or all of FF vs. 72.0% of SG, p < .001). CONCLUSION: Forever Free self-directed relapse prevention booklets did not reduce relapse or enhance cessation over general tobacco and health information when added to intensive group smoking cessation treatment. However, this study lacked power to detect a small but clinically meaningful positive effect. PMID- 28592197 TI - Cardiovascular effects of the addition of nilotinib to standard therapy for acute myeloid leukemia. PMID- 28592198 TI - Reversible drug-induced antiphospholipid syndrome. AB - We report an original case of reversible antiphospholipid syndrome (APS) due to minocycline in a young male patient who experienced recurrent strokes while taking minocycline. He started minocycline therapy (50 mg twice daily) at 15 years old for acne. After three years of treatment, the patient experienced a lateral medullary syndrome. He was treated with aspirin while minocycline was continued. Eighteen months later, the patient complained about horizontal binocular diplopia. MRI revealed an infarct of the oculomotor nerve nucleus. Laboratory investigations revealed high titers of anti-beta 2 glycoprotein 1 (antibeta2GP1) antibodies of 470 U/ml (normal range <15 U/ml) and antiphosphatidylethanolamine antibodies of 137.4 U/ml (normal range <18 U/ml). Other laboratory tests were normal. Six weeks after discontinuation of minocycline, anti-beta2GP1 antibodies decreased to 335 U/ml and to 36 U/ml at six months and then remained negative for six years. Many drugs have been considered as possibly causing APS but only in a limited number of patients. To our knowledge this is the first case of drug-induced APS with complete disappearance of high titers of anti-beta2GP1 antibodies after minocycline withdrawal. This case also illustrates the need to monitor the levels of antiphospholipid antibodies, even though initial values are high and confirmed after 12 weeks. PMID- 28592199 TI - Diffuse alveolar haemorrage as initial presentation of systemic lupus erythematosus: a case report. AB - Diffuse alveolar haemorrhage (DAH) is a rare life-threatening complication of systemic lupus erythematosus (SLE), associated with high mortality rates. It usually occurs in patients with an established diagnosis of SLE. It has been reported as the initial presentation of SLE in 11-20% of cases. It occurs most frequently in females. We describe the case of a child, aged 14 years, with fever, asthenia, haemoptysis, dyspnea, anaemia, increased inflammatory markers, positivity to ANA, nDNA, direct Coombs tests, anticardiolipin antibodies and complement factors consumption. Computed tomography (CTscan) of the chest showed bilateral pulmonary alveolar infiltrates. He also developed renal involvement with nephritis later in the course of the disease. He was started on the treatment approved by the Euro Lupus Protocol for critical patients. After starting Mycophenolate Mofetil the clinical and radiological features were improved as was the survival outcome. PMID- 28592200 TI - Anti-carbamylated protein antibodies in systemic lupus erythematosus patients with articular involvement. AB - Objective Several studies have evaluated the prevalence of rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA) in systemic lupus erythematosus (SLE) patients but no data are available on the anti-carbamylated proteins (anti CarP), a new biomarker for rheumatoid arthritis (RA). We evaluated the anti-CarP prevalence in SLE patients with joint involvement and the associations with different phenotypes. Methods Seventy-eight SLE patients with joint involvement were enrolled (F/M 73/5; mean +/- SD age 47.6 +/- 11.2 years; mean +/- SD disease duration 214.3 +/- 115.6 months). As control groups, we evaluated SLE patients without joint manifestations ( N = 15), RA ( N = 78) and healthy individuals (HS, N = 98). Anti-CarP were assessed by home-made ELISA in all patients and controls, RF and ACPA in SLE patients with joint involvement (commercial ELISA kit). Results The prevalence of anti-CarP in SLE patients with joint involvement was similar to RA ( p = NS) and significantly higher compared with SLE without joint involvement and HS ( p < 0.0001, p < 0.0001, respectively). Four patients were positive for all three antibodies: seventy-five percent of these showed Jaccoud arthropathy. Fourty-five percent of ACPA-ve/RF-ve patients were anti-CarP + ve. Conclusions The evaluation of anti-CarP in SLE joint involvement demonstrated a prevalence of almost 50%, similar to RA and significantly higher than SLE without joint involvement and HS. PMID- 28592201 TI - Comparative efficacy and safety of intravenous or subcutaneous belimumab in combination with standard therapy in patients with active systemic lupus erythematosus: a Bayesian network meta-analysis of randomized controlled trials. AB - Objective In this study, we aimed to assess the relative efficacy and safety of intravenous (IV) or subcutaneous (SC) belimumab compared with those of placebo in patients with active systemic lupus erythematosus (SLE). Methods We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of belimumab 1 mg/kg and 10 mg/kg IV administration, and belimumab 200 mg SC injection, and placebo in patients with active SLE despite having received standard therapy. Results Five RCTs (3460 patients) met the inclusion criteria. The SLE Responder Index (SRI) response rate at week 52 was significantly higher in the belimumab 10 mg/kg group than in the placebo group (OR 2.63, 95% CrI 2.14 3.23). Similarly, the SRI response rates were significantly higher in the belimumab 1 mg/kg, and belimumab 200 mg SC groups than in the placebo group (OR 2.42, 95% CrI 1.90-3.09; OR 1.71, 95% CrI 1.27-2.29). Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that belimumab 10 mg/kg had the highest probability of being the best treatment for achieving the SRI response (SUCRA = 0.9174), followed by belimumab 1 mg/kg (SUCRA = 0.7338), belimumab 200 mg SC (SUCRA = 0.3487), and placebo (SUCRA = 0.0000). However, a sensitivity test by omitting one outlier study showing low SRI response rate compared with the other three studies (11% vs. 33%, 40%, 48%) showed that belimumab 200 mg SC and belimumab 10 mg/kg had the highest probability of being the best treatment for achieving the SRI response (SUCRA = 0.7903, SUCRA = 0.7456), followed by belimumab 1 mg/kg, and placebo. The number of serious adverse events (SAEs) did not differ significantly among the four treatment options. Conclusions Belimumab at 1 and 10 mg/kg IV and belimumab 200 mg SC in combination with standard therapy was an efficacious intervention for active SLE, and was not associated with a significant risk of SAEs. PMID- 28592202 TI - Pharmacogenetics and aromatase inhibitor induced side effects in breast cancer patients. AB - This paper reviews genetic variations mainly related to the onset of adverse events during aromatase inhibitors in early breast cancer. Genetic variability could occur at different steps. The analysis included studies that involved breast cancer patients, treated with an aromatase inhibitor, genotyped for CYP19A1 and/or CYP17A1 and/or CYP27B1 and/or TCLA1, and/or RANK/RANKL/OPG and/or ESR1/ESR2, and assessed for toxicity profile. Twenty-two articles were included for the analysis. Three studies evaluated outcomes and adverse events; 19 studies assessed only side effects. Functional variations may be useful in predicting the onset of toxicities. The identification of polymorphisms at increased risk of toxicity may enable patient management. However, more data are needed to be applied in the individualization of treatment in daily practice. PMID- 28592203 TI - The use of an online support group for neuromuscular disorders: a thematic analysis of message postings. AB - PURPOSE: People affected by neuromuscular disorders can experience adverse psychosocial consequences and difficulties accessing information and support. Online support groups provide new opportunities for peer support. The aim of this study was to understand how contributors used the message board function of a newly available neuromuscular disorders online support group. METHODS: Message postings (n = 1951) from the first five months of the message board of a newly formed online support group for neuromuscular disorders hosted by a charitable organization were analyzed using inductive thematic analysis. RESULTS: Members created a sense of community through disclosing personal information, connecting with people with similar illness experiences or interests, welcoming others and sharing aspirations for the development of a resourceful community. Experiences, emotional reactions and support were shared in relation to: delayed diagnosis; symptom interpretation; illness management and progression; the isolating impact of rare disorders; and the influence of social and political factors on illness experiences. CONCLUSIONS: This study provided a novel insight into individuals' experiences of accessing a newly available online support group for rare conditions hosted by a charitable organization. The findings highlight how the online support group provided an important peer support environment for members to connect with others, exchange information and support and engender discussion on political and social issues unique to living with often-rare neuromuscular disorders. Online support groups may therefore provide an important and easily accessible support outlet for people with neuromuscular disorders as well as a platform for empowering members to raise awareness about the impact of living with these conditions. Further research is needed to examine member motivations for using such groups and any effects of participation in greater detail. Implications for rehabilitation Online support groups may provide a unique forum for information sharing and peer support between people affected by often rare, neuromuscular conditions. Rehabilitation professionals may wish to signpost those affected by neuromuscular disorders to such groups. An advantage is that these groups are freely available and can be accessed from anywhere and at any time. Members may be able to learn about the diagnosis and symptom experiences of others, discuss coping strategies, validate illness experiences and discuss social and political issues relating to living with these conditions. Further research is needed before researchers and clinicians can fully understand participants' motivations for, and experiences of, using such groups and any potential psychosocial benefits. PMID- 28592204 TI - Factor Structure and Measurement Invariance of the Need-Supportive Teaching Style Scale for Physical Education. AB - The purpose of the current study was to examine the factor structure and measurement invariance of a scale measuring students' perceptions of need supportive teaching (Need-Supportive Teaching Style Scale in Physical Education; NSTSSPE). We sampled 615 secondary school students in Hong Kong, 200 of whom also completed a follow-up assessment two months later. Factor structure of the scale was examined through exploratory structural equation modeling (ESEM). Further, nomological validity of the NSTSSPE was evaluated by examining the relationships between need-supportive teaching style and student satisfaction of psychological needs. Finally, four measurement models-configural, metric invariance, scalar invariance, and item uniqueness invariance-were assessed using multiple group ESEM to test the measurement invariance of the scale across gender, grade, and time. ESEM results suggested a three-factor structure of the NSTSSPE. Nomological validity was supported, and weak, strong, and strict measurement invariance of the NSTSSPE was evidenced across gender, grade, and time. The current study provides initial psychometric support for the NSTSSPE to assess student perceptions of teachers' need-supportive teaching style in physical education classes. PMID- 28592206 TI - Molecular modeling and SPRi investigations of interleukin 6 (IL6) protein and DNA aptamers. AB - Interleukin 6 (IL6), an inflammatory response protein has major implications in immune-related inflammatory diseases. Identification of aptamers for the IL6 protein aids in diagnostic, therapeutic, and theranostic applications. Three different DNA aptamers and their interactions with IL6 protein were extensively investigated in a phosphate buffed saline (PBS) solution. Molecular-level modeling through molecular dynamics provided insights of structural, conformational changes and specific binding domains of these protein-aptamer complexes. Multiple simulations reveal consistent binding region for all protein aptamer complexes. Conformational changes coupled with quantitative analysis of center of mass (COM) distance, radius of gyration (Rg), and number of intermolecular hydrogen bonds in each IL6 protein-aptamer complex was used to determine their binding performance strength and obtain molecular configurations with strong binding. A similarity comparison of the molecular configurations with strong binding from molecular-level modeling concurred with Surface Plasmon Resonance imaging (SPRi) for these three aptamer complexes, thus corroborating molecular modeling analysis findings. Insights from the natural progression of IL6 protein-aptamer binding modeled in this work has identified key features such as the orientation and location of the aptamer in the binding event. These key features are not readily feasible from wet lab experiments and impact the efficacy of the aptamers in diagnostic and theranostic applications. PMID- 28592207 TI - Corrigendum. PMID- 28592205 TI - Pilot Feasibility Study of a Digital Storytelling Intervention for Immigrant and Refugee Adults With Diabetes. AB - Purpose The purpose of this pilot feasibility project was to examine the potential effectiveness of a digital storytelling intervention designed through a community-based participatory research (CBPR) approach for immigrants and refugees with type 2 diabetes mellitus (T2DM). Methods The intervention was a 12 minute culturally and linguistically tailored video consisting of an introduction, 4 stories, and a concluding educational message. A structured interview was used to assess the intervention for acceptability, interest level, and usefulness among 25 participants with T2DM (15 Latino, 10 Somali) across 5 primary care clinical sites. After watching the video, participants rated their confidence and motivation about managing T2DM as a result of the intervention. Baseline A1C and follow-up values (up to 6 months) were abstracted from medical records. Results All participants reported that the intervention got their attention, was interesting, and was useful; 96% reported that they were more confident about managing their T2DM than before they watched the video, and 92% reported that the video motivated them to change a specific behavior related to T2DM self-management. The mean baseline A1C level for the intervention participants was 9.3% (78 mmol/mol). The change from baseline to first follow-up A1C level was -0.8% (-10 mmol/mol) ( P < .05). Conclusions Implementation of a digital storytelling intervention for T2DM among immigrant populations in primary care settings is feasible and resulted in self-rated improvement in psychosocial constructs that are associated with healthy T2DM self-management behaviors, and there was some evidence of improvement in glycemic control. A large-scale efficacy trial of the intervention is warranted. PMID- 28592208 TI - Is a polygenic predictor of antidepressant response a possibility? PMID- 28592209 TI - Breastfeeding Patterns Among Employees at a Land Grant University. AB - Exclusive breastfeeding is recommended for the first 6 months of life, and up to 1 year with complementary food. Breastfeeding rates have improved over the last 20 years, but exclusive breastfeeding, and breastfeeding to 6 months have not yet met Healthy People 2020 goals. Given that the majority of women return to work shortly after delivery, workplace support for breastfeeding could facilitate breastfeeding continuance. The Patient Protection and Affordable Care Act (ACA) was the first federal legislation to address breastfeeding in the workplace. This article examines employee breastfeeding behavior before and after implementation of workplace breastfeeding support policies and practices. Breastfeeding behavior change over time was assessed by comparing employees' responses by age of their youngest children. Results indicated that breastfeeding among employees and breastfeeding after returning to work improved after initiation of breastfeeding support policies in this university setting. PMID- 28592210 TI - Incidence of disseminated Mycobacterium avium-complex infection in HIV patients receiving antiretroviral therapy with use of Mycobacterium avium-complex prophylaxis. AB - The incidence of disseminated Mycobacterium avium complex (MAC) infection in HIV patients has fallen markedly since the introduction of effective antiretroviral therapy (ART). However, current guidelines still recommend primary prophylaxis. We conducted a retrospective cohort study in a university-affiliated hospital from January 1998 to January 2014. During that period, HIV patients who had at least one CD4 cell count below 50 cells/mm3 and had been treated with ART were enrolled. We compared incidence of disseminated MAC infection in the 12 months after the first CD4 cell count below 50 cells/mm3 between prophylaxis and nonprophylaxis groups. A total of 157 patients were enrolled and the total observation period was 144 patient-years (PY). Thirty-three patients (21%) received primary MAC prophylaxis. The initial CD4 cell count of the prophylaxis group was lower than that of the nonprophylaxis group ( P = 0.024), but the proportion of patients who reached a CD4 cell count >100 cells/mm3 ( P = 0.234) and were virologically suppressed ( P = 0.513) 12 months after ART commencement was not different in the prophylaxis and nonprophylaxis groups. The incidence of MAC did not differ significantly between the groups (3.4/100 PY versus 0.8/100 PY, P = 0.368). Routine MAC prophylaxis may be not required in the era of effective ART. PMID- 28592211 TI - Calmodulin-like skin protein is downregulated in human cerebrospinal fluids of Alzheimer's disease patients with apolipoprotein E4; a pilot study using postmortem samples. AB - OBJECTIVE: Calmodulin-like skin protein (CLSP) is a secreted peptide that inhibits neuronal cell death, linked to Alzheimer's disease (AD), by binding to the heterotrimeric humanin receptor and activating an intracellular survival pathway. CLSP is only expressed in skin keratinocytes and related epithelial cells, circulates in the blood stream, and passes the blood-cerebrospinal fluid (CSF) barrier. In the current study, we addressed the issues as to whether CLSP functions in the central nervous system and whether the concentration of CLSP is reduced in the CSFs of AD patients. METHODS: Mice were intraperitoneally injected with 5 nmol of recombinant human CLSP. At 1h after the injection, the mice were sacrificed for the analysis of the existence of human CLSP in blood and interstitial fluid (ISF)-containing brain samples. Using postmortem CSF samples, we next determined the concentrations of CLSP in CSFs of human AD and control cases. RESULTS: Intraperitoneally administered recombinant human CLSP circulated in the blood stream and reached the brain interstitial fluid. The concentrations of CLSP in CSFs of human AD and control cases are sufficient to exhibit the CLSP activity. Although the concentrations of CLSP in CSFs were not significantly different between AD and control cases, the concentrations of CLSP are lower in the AD cases with the apolipoprotein E4 genotype than in the AD cases without the apolipoprotein E4 genotype. DISCUSSION: The first result indicates that CLSP enters the central nervous system through the blood-brain barrier. The second result suggests that CLSP functions in the human brains. The third result may exclude the possibility that the downregulation of the CLSP level is involved in the AD pathogenesis. The last result may contribute to the better understanding of the AD pathogenesis from the standpoint of the apolipoprotein E genotype. PMID- 28592212 TI - Low dose versus high dose anti-snake venom therapy in the treatment of haematotoxic snake bite in South India. AB - Most of the studies on the appropriate dose of anti-snake venom (ASV) are from tertiary hospitals and the guidelines are unclear. Our observational study compared the outcomes of two prevalent treatment regimes for haematotoxic snake bite in a secondary care hospital in South India. The time to normalisation of whole blood clotting time, mortality and complications were not different between the groups. The average dose of ASV required in the low and high dose groups were 106 mL and 246 mL, respectively. Consequently, patients who received low dose ASV incurred approximately 50% less expense. Urticarial rashes were also significantly fewer in the low dose group. PMID- 28592213 TI - Proton Grid Therapy. AB - In this work, we studied the possibility of merging proton therapy with grid therapy. We hypothesized that patients with larger targets containing solid tumor growth could benefit from being treated with this method, proton grid therapy. We performed treatment planning for 2 patients with abdominal cancer with the suggested proton grid therapy technique. The proton beam arrays were cross-fired over the target volume. Circular or rectangular beam element shapes (building up the beam grids) were evaluated in the planning. An optimization was performed to calculate the fluence from each beam grid element. The optimization objectives were set to create a homogeneous dose inside the target volume with the constraint of maintaining the grid structure of the dose distribution in the surrounding tissue. The proton beam elements constituting the grid remained narrow and parallel down to large depths in the tissue. The calculation results showed that it is possible to produce target doses ranging between 100% and 130% of the prescribed dose by cross-firing beam grids, incident from 4 directions. A sensitivity test showed that a small rotation or translation of one of the used grids, due to setup errors, had only a limited influence on the dose distribution produced in the target, if 4 beam arrays were used for the irradiation. Proton grid therapy is technically feasible at proton therapy centers equipped with spot scanning systems using existing tools. By cross-firing the proton beam grids, a low tissue dose in between the paths of the elemental beams can be maintained down to the vicinity of a deep-seated target. With proton grid therapy, it is possible to produce a dose distribution inside the target volume of similar uniformity as can be created with current clinical methods. PMID- 28592214 TI - Multinozzle Multichannel Temperature Deposition System for Construction of a Blood Vessel. AB - 3D bioprinting is an emerging technology that drives us to construct the complicated tissues and organs consisting of various materials and cells, which has been in widespread use in tissue engineering and organ regeneration. However, the protection and accurate distribution of cells are the most urgent problems to achieve tissue and organ reconstruction. In this article, a multinozzle multichannel temperature deposition and manufacturing (MTDM) system is proposed to fabricate a blood vessel with heterogeneous materials and gradient hierarchical porous structures, which enables not only the reconstruction of a blood vessel with an accurate 3D model structure but also the capacity to distribute bioactive materials such as growth factors, nutrient substance, and so on. In addition, a coaxial focusing nozzle is proposed and designed to extrude the biomaterial and encapsulation material, which can protect the cell from damage. In the MTDM system, the tubular structure of a blood vessel was successfully fabricated with the different biomaterials, which proved that the MTDM system has a potential application prospect in tissue engineering and organ regeneration. PMID- 28592215 TI - Commentary: Toward an EVAR Prevention Strategy for Type II Endoleak. PMID- 28592216 TI - Benzoates intakes from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. AB - Food consumption data from national dietary surveys were combined with brand specific-use levels reported by beverage manufacturers to calculate the exposure to benzoic acid and its salts (INS Nos 210-213) from non-alcoholic beverages in Brazil, Canada, Mexico and the United States. These four jurisdictions were identified as having some of the most prevalent use of benzoates in beverages globally. Use levels were weighted according to the brand's market volume share in the respective countries. Benzoates were reported to be used primarily in 'water-based flavoured drinks' (Codex General Standard for Food Additives (GSFA) category 14.1.4). As such, the assessments focused only on intakes from these beverage types. Two different models were established to determine exposure: probabilistic (representing non-brand loyal consumers) and distributional (representing brand-loyal consumers). All reported-use levels were incorporated into both models, including those above the Codex interim maximum benzoate use level (250 mg kg-1). The exception to this was in the brand-loyal models for consumers of regular carbonated soft drinks (brand loyal category) which used (1) the interim maximum use level for beverages with a pH <= 3.5 and (2) all reported use levels for beverages pH > 3.5 (up to 438 mg kg-1). The estimated exposure levels using both models were significantly lower than the ADI established for benzoates at the mean level of intake (4-40% ADI) and lower than - or at the ADI only for toddlers/children - at the 95th percentile (23-110% ADI). The results rendered in the models do not indicate a safety concern in these jurisdictions, and as such provide support for maintaining the current Codex interim maximum benzoate level of 250 mg kg-1 in water-based beverages. PMID- 28592217 TI - Screening of trace metal supplementation for black water anaerobic digestion. AB - Community on-site separation of wastewater is a treatment approach that leads to more efficient processes. Black water has high organic matter content and can be a suitable feedstock for anaerobic treatment systems. Biological methane production (BMP) tests were conducted using Plackett-Burman design to screen the effects of adding Fe, Ni, Cu, Co, Mn, Ba and Se, with simulated black water (SBW) as the substrate. In the inoculum, most metals were found mainly in the organic matter/sulfide and residual fractions except for Mn, which was present at 12.3% in the bioavailable fractions (exchangeable and carbonates), and Ba, which was evenly distributed among all the fractions. Ba had a significant negative effect on methane production and Mn addition enhanced the toxic effect. A specific methanogenic activity (SMA) between 18% and 27% lower than the control, was predicted at a total Ba concentration of approximately 1000-1200 mg L-1. Similar SMA was predicted at Ba concentration between 400 and 600 mg L-1 when 0.55 mg L-1 of Mn is added. Se and Cu additions demonstrate the potential to improve the methane production from SBW. The SMA was predicted to reach 12 mLCH4 gCOD-1 d-1 when Cu and Se are supplied at total concentrations of 3.0 mg L-1 and 0.98 mg L 1, respectively. PMID- 28592218 TI - First-line use of contact aspiration for thrombectomy versus a stent retriever for recanalization in acute cerebral infarction: The randomized ASTER study protocol. AB - Rationale Mechanical thrombectomy with a stent retriever is now the standard of care in anterior circulation ischemic stroke caused by large vessel occlusion. New techniques for mechanical thrombectomy, such as contact aspiration, appear promising to increase reperfusion status and improve clinical outcome. Aim We aim at ascertaining whether contact aspiration is more efficient than the stent retriever as a first-line endovascular procedure. Sample size estimates With a two-sided test (alpha = 5%, power = 90%) and an anticipated rate of spontaneous recanalization and catheterization failures of 15%, we estimate that a sample size of 380 patients will be necessary to detect an absolute difference of 15% in primary outcome (superiority design). Methods and design The ASTER trial is a prospective, randomized, multicenter, controlled, open-label, blinded end-point clinical trial. Patients admitted with suspected ischemic anterior circulation stroke secondary to large vessel occlusion, with onset of symptoms <6 h, will be randomly assigned to contact aspiration or stent retriever in a 1:1 ratio; stratified by center and prior IV thrombolysis. If the assigned treatment technique is not successful after three attempts, another technique will be applied, at the operator's discretion. Study outcomes The primary outcome will be successful recanalization (modified Thrombolysis in Cerebral Infarction score 2b 3) at the end of the endovascular procedures. Secondary outcome will include successful recanalization after the assigned first-line treatment technique alone, procedural times, the need for a rescue technique, complications and modified Rankin Scale at three months. Discussion No previous head to head randomized trials have directly compared contact aspiration versus stent retriever reperfusion techniques. This prospective trial aims to provide further evidence of benefit of contact aspiration versus stent retriever techniques among patients with ischemic stroke. PMID- 28592220 TI - Increased inflammatory status in chronic venous insufficiency patients. PMID- 28592219 TI - Early risk of recurrent stroke in patients with symptomatic carotid near occlusion: Results from CAOS, a multicenter registry study. AB - Background The risk of recurrent stroke among patients with symptomatic carotid near-occlusion is not well established, and management of the condition remains controversial. Symptomatic carotid near-occlusion with full collapse has been identified as a strong predictor of early recurrence. We aimed to analyze the 90 day risk of recurrent ipsilateral ischemic stroke in medically treated patients with symptomatic carotid near-occlusion. Methods We performed a multicenter, nationwide, prospective study from January 2010 to May 2016. Patients with angiography-confirmed symptomatic carotid near-occlusion were included. The primary endpoint was ipsilateral ischemic stroke or transient ischemic attack (TIA) within 90 days after the presenting event. For this analysis, patients who underwent revascularization within 90 days after stroke were excluded. Results The study population comprised 141 patients from 17 Spanish centers; 83 patients were treated medically. Primary endpoint occurred in eight patients, resulting in a cumulative rate of 10.6% (95% CI, 3.7-17.5). Previous history of stroke or transient ischemic attack was identified as an independent predictor for recurrence in the multivariate Cox regression analysis (HR, 4.37 [95% CI, 1.05 18.18]; p = 0.043), while the presence of full collapse was not associated with an increased risk (HR, 0.81 [95% CI, 0.17-3.92]; p = 0.793). The risk of recurrence was also not affected by the presence of significant stenosis or occlusion of the contralateral carotid artery, or by the collateral circulation. Conclusions Patients with symptomatic carotid near-occlusion seem to have an increased risk of early ipsilateral recurrent stroke. Our results contrast with the low risk of symptomatic carotid near-occlusion reported to date. Full collapse did not increase the risk of recurrent stroke in our study. PMID- 28592221 TI - News & Views. PMID- 28592222 TI - The feline blood film. AB - Practical relevance: Many veterinary practices have invested in quality automated hematology instruments for use in-house. However, regardless of their specific choice of analyzer, there are important hematology findings that can only be determined by microscopic examination of stained blood films. For this reason, and also for the purpose of quality control for the analyzer, a quick blood film review should be performed alongside every automated complete blood count. Even those practices that submit their blood samples to outside diagnostic laboratories for evaluation, still require the capability to examine stained blood films in emergency situations. Series outline: This is the second of a two part article series that aims to familiarize the practitioner with normal findings on feline blood films, with a particular focus on unique features in the cat, as well as to assist with interpretation of common abnormalities. Part 2 focuses on the morphology of feline leukocytes and platelets in health and disease. Evidence base: The information and guidance offered is based on the published literature and the author's own extensive clinical pathology research. PMID- 28592224 TI - Postoperative complications associated with external skeletal fixators in cats. AB - OBJECTIVES: The objective of this study was to quantify complications associated with external skeletal fixators (ESFs) in cats and to identify potential risk factors. METHODS: A retrospective review of medical records and radiographs following ESF placement was performed. RESULTS: Case records of 140 cats were reviewed; fixator-associated complications (FACs) occurred in 19% of cats. The region of ESF placement was significantly associated with complication development. Complications developed most frequently in the femur (50%), tarsus (35%) and radius/ulna (33%). Superficial pin tract infection (SPTI) and implant failure accounted for 45% and 41% of all FACs, respectively. SPTI occurred more frequently in the femur, humerus and tibia, with implant failure more frequent in the tarsus. No association between breed, age, sex, weight, fracture type (open vs closed), ESF classification, number of pins per bone segment, degree of fracture load sharing, and the incidence or type of FAC was identified. No association between region of placement, breed, age, sex, weight, fracture type (open vs closed), ESF classification, number of pins per bone segment, fracture load sharing and the time to complication development was identified. CONCLUSIONS AND RELEVANCE: Complication development is not uncommon in cats following ESF placement. The higher complication rate in the femur, tarsus and radius/ulna should be considered when reviewing options for fracture management. However, cats appear to have a lower rate of pin tract infections than dogs. PMID- 28592223 TI - Feline leprosy due to Mycobacterium lepraemurium. AB - OBJECTIVES: This paper, the second in a series of three on 'feline leprosy', provides a detailed description of disease referable to Mycobacterium lepraemurium, the most common cause of feline leprosy worldwide. METHODS: Cases were sourced retrospectively and prospectively for this observational study, describing clinical, geographical and molecular microbiological data for cats definitively diagnosed with M lepraemurium infection. RESULTS: A total of 145 cases of feline leprosy were scrutinised; 114 'new' cases were sourced from the Victorian Infectious Diseases Reference Laboratory records, veterinary pathology laboratories or veterinarians, and 31 cases were derived from six published studies. Sixty-five cats were definitively diagnosed with M lepraemurium infection. Typically, cats were 1-3 years of age when first infected, with a male gender predilection. Affected cats were generally systemically well. All had outdoor access. Lesions tended to consist of one or more cutaneous/subcutaneous nodules, typically located on the head and/or forelimbs, possibly reflecting the most likely locations for a rodent bite as the site of inoculation for organisms. Nodules had the propensity to ulcerate at some stage in the clinical course. The cytological and histological picture varied from tuberculoid, with relatively low bacterial numbers, to lepromatous with moderate to high bacterial numbers. Treatment was varied, although most cats underwent surgical resection of lesions with adjunctive medical therapy, most often using a combination of oral clarithromycin and rifampicin. Prognosis for recovery was generally good, and in two cases there was spontaneous remission without the requirement for medical intervention. Untreated cats continued to enjoy an acceptable quality of life despite persistence of the disease, which extended locally but had no apparent tendency to disseminate to internal organs. CONCLUSIONS AND RELEVANCE: M lepraemurium causes high bacterial index (lepromatous) or low bacterial index (tuberculoid) feline leprosy. The infection typically causes nodules of the skin and/or subcutis (which tend towards ulceration) on the head and/or forelimbs. The disease usually has an indolent clinical course and infected cats have a generally favourable response to therapeutic interventions, with rare cases undergoing spontaneous resolution. Genomic analysis may yield clues as to the environmental niche and culture requirements of this elusive organism. Prospective treatment trials and/or additional drug susceptibility testing in specialised systems would further inform treatment recommendations. PMID- 28592225 TI - Diagnostic bone marrow sampling in cats. AB - : Practical relevance: Hematologic disorders are relatively common in cats, as inflammatory, immune-mediated and infectious diseases have the potential to impact erythroid, myeloid and thrombopoietic lines within the bone marrow. Clinical challenges: Clinicians often benefit from information obtained from bone marrow cytology and histopathology in diagnosing hematologic disorders in feline patients. However, these sampling procedures are ones that many veterinarians are intimidated by and thus not comfortably performing in clinical practice. AUDIENCE: This review, aimed at all veterinarians who treat cats, highlights the reasons a clinician may elect to sample bone marrow, and details the collection of bone marrow for both cytology and histopathology. Potential complications and limitations of each procedure are also reviewed. Evidence base: The collection of bone marrow for cytology and histopathology is not new to feline medicine and several research studies have investigated various sampling modalities in cats. This article offers a comprehensive review of the currently accepted best practices. PMID- 28592226 TI - Removal of sulfate and heavy metals by sulfate-reducing bacteria in an expanded granular sludge bed reactor. AB - The objective of this study is to utilize an expanded granular sludge bed reactor for removing heavy metals and sulfate from synthetic acid-mine drainage (AMD) using sewage sludge fermentation centrate as the substrate. The reactor was bioaugmented with an enriched consortium of sulfate-reducing bacteria (SRB). The bioreactor performance was studied with different chemical oxygen demand [Formula: see text] ratios, liquid upflow velocity (Vup), hydraulic retention time (HRT) and influent pH. The highest COD, sulfate and heavy metal removal efficiencies were achieved at a [Formula: see text] ratio of 1.5, Vup of 4.0 m/h, HRT of 15 h and influent pH of 6.0 (68.2%, 92.1% and 100%, respectively). The activity of SRB greatly increases the effluent pH. Even at an influent pH of 3.0, 60.8% of sulfate, 41.3% of COD and 91.2% of heavy metals could be removed, and the effluent quality can meet the national discharge standard of China. The activity tests demonstrate that the sludge fermentation centrate is an excellent carbon source for SRB. This study shows the potential of synchronous treatment of residual sewage sludge and treatment of AMD. PMID- 28592227 TI - Long-term outcome of bioresorbable vascular scaffolds for the treatment of coronary artery disease: a meta-analysis of RCTs. AB - BACKGROUND: Coronary bioresorbable scaffolds (BRS) were developed to overcome the limitations of standard metallic stents, especially to address late events after percutaneous coronary interventions. The aim of this meta-analysis was to evaluate the efficacy and safety of BRS, compared with Everolimus-eluting stents (EES), using the data available from randomized trials, with a focus on long-term outcomes. METHODS: Published randomized trials comparing BRS to EES for the treatment of coronary artery disease were searched for within PubMed, Cochrane Library and Scopus electronic databases up to April 4th 2017. The summary measure used was odds ratio (OR) with 95% confidence intervals. RESULTS: A total of 5 studies were eligible, including 5219 patients. At 2 years, BRS was associated with higher rates of target lesion failure (9.4% vs 7.2%; OR = 1.33; 95% CI 1.07 to 1.63; p = 0.008) and device thrombosis (2.3% vs 0.7%; OR = 3.22; 95% CI 1.86 to 5.57; p < 0.0001) compared with EES. The incidence of both early (within 30 days after implantation, 1.1% vs 0.5%, OR 1.97, 95% CI 1.02 to 3.81; p = 0.05) and very-late device thrombosis (>1 year, 0.6% vs 0.1%, OR 4.03, 95% CI 1.37 to 11.82; p = 0.01) was higher with BRS compared with EES. CONCLUSIONS: BRS may be associated with worse two-years clinical outcomes compared with EES in patients with coronary artery disease. PMID- 28592228 TI - Anti-fibrogenic effect of PPAR-gamma agonists in human intestinal myofibroblasts. AB - BACKGROUND: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- gamma (PPAR-gamma) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-gamma agonists on human primary intestinal myofibroblasts (HIFs). METHODS: HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-beta1 and co-incubated with or without one of two synthetic PPAR-gamma agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and alpha-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-beta1 induced expression of procollagen1A1, fibronectin, and alpha-smooth muscle actin in HIFs. The irreversible PPAR-gamma antagonist GW9662 was used to investigate whether the effect of PPAR-gamma agonists was PPAR-gamma dependent. RESULTS: Both PPAR-gamma agonists reduced the TGF-beta1-induced expression of alpha-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and alpha-smooth muscle actin-specific immunocytochemistry. PPAR-gamma agonists also inhibited TGF-beta1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and alpha-smooth muscle actin. TGF-beta1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-beta1 induced synthesis of procollagen1A1, fibronectin, and alpha-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-gamma agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-gamma independent. CONCLUSIONS: Troglitazone and rosiglitazone suppress TGF-beta1 induced synthesis of procollagen1A1, fibronectin, and alpha-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis. PMID- 28592229 TI - The intention of Dutch general practitioners to offer vaccination against pneumococcal disease, herpes zoster and pertussis to people aged 60 years and older. AB - BACKGROUND: Increasing life expectancy results in a larger proportion of older people susceptible to vaccine preventable diseases (VPDs). In the Netherlands, influenza vaccination is routinely offered to people aged 60 years and older. Vaccination against pneumococcal disease, herpes zoster and pertussis is rarely used. These vaccines will be evaluated by the Dutch Health Council and might be routinely offered to older people in the near future. Possible expansion of the program depends partly on the willingness of general practitioners (GPs) to endorse additional vaccinations. In this study, we assessed predictors of GPs' attitude and intention to vaccinate people aged 60 years and older. METHODS: GPs (N = 12.194) were invited to fill in an online questionnaire consisting of questions about social cognitive factors that can influence the willingness of GPs to vaccinate people aged 60 years and older, including underlying beliefs, practical considerations of adding more vaccines to the national program, demographics, and GPs' patient population characteristics. The questionnaire was filled in by 732 GPs. RESULTS: GPs were positive both about vaccination as a preventive tool and the influenza vaccination program, but somewhat less positive about expanding the current program. Prediction analysis showed that the intention of GPs to offer additional vaccination was predicted by their attitude towards offering additional vaccination, towards vaccination as a preventive tool, towards offering vaccination during an outbreak and on GPs opinion regarding suitability to offer additional vaccination (R2 = 0.60). The attitude of GPs towards offering additional vaccination was predicted by the perceived severity of herpes zoster and pneumonia, as well as the perceived incidence of herpes zoster. Severity of diseases was ranked as important argument to recommend vaccination, followed by effectiveness and health benefits of vaccines. CONCLUSION: Providing GPs with evidence-based information about the severity and prevalence of diseases, and effectiveness and health benefits of the vaccines, together with an active role of GPs in informing older people about vaccines, could modify the intention towards additional vaccination of people 60 years and older. PMID- 28592230 TI - Evaluation of targeted antimicrobial prophylaxis for transrectal ultrasound guided prostate biopsy: a prospective cohort trial. AB - BACKGROUND: We evaluated the effectiveness of targeted antimicrobial prophylaxis in transrectal ultrasound guided prostate biopsy (TRUSP). METHODS: A prospective, non-randomized cohort study was conducted. Rectal swab cultures plated on non selective blood agar and on selective MacConkey agar supplemented with ciprofloxacin identified ciprofloxacin-susceptible and -resistant gram-negative bacteria (CS-GNB and CR-GNB). Patients with CS-GNB received ciprofloxacin while those with CR-GNB received directed prophylaxis. Infectious complications were defined clinically and microbiologically within 30 days after TRUSP. Data were derived at 7 and 30 days post procedure by questionnaires and electronic medical records. We hypothesized that there would be no difference in the infectious outcomes among the CS and CR groups. RESULTS: From November 1, 2012 to March 31, 2015, 510 men completed the study; 430 (84.3%) had CS-GNB and 80 (15.7%) had CR GNB. 484 (94.9%) completed the study per protocol, while 26 (5.1%) had an intention-to-treat (ITT) analysis. Of the 484, 475 (98.1%) had no infections, nine (1.9%) had infections, six of which (1.2%) were culture-proven (CP). The nine infections were as follows: five (1.0%) uncomplicated UTIs, one (0.2%) complicated UTI, and three (0.6%) urosepsis. One case of uncomplicated UTI and two cases of urosepsis were not CP, but were diagnosed clinically. ITT outcomes were similar. The infection rates were not statistically different between the CS and CR-GNB patients (p-value = 0.314; 95% CI 0.8-3.3). The four patients with complicated UTIs or sepsis were hospitalized for a mean of 2.6 days and discharged without sequelae. Of the nine infections, three were antimicrobial prophylaxis failures (two ciprofloxacin and one amikacin); three were likely due to failure of the collection or processing of the rectal swab or increasing bacterial resistance between the time of swab collection and biopsy, and three developed clinical infections with no isolate recovered. CONCLUSIONS: Targeted antimicrobial prophylaxis follows the principles of antimicrobial stewardship and achieved a low rate of infectious complications with limited morbidity and no sequelae. This individualized method of prophylaxis may be widely applied. Further studies are needed to explore reasons for targeted prophylaxis failure and to determine comparative efficacy of non-ciprofloxacin-containing targeted prophylaxis regimens. TRIAL REGISTRATION: ClinicalTrials.gov. NCT01659866 . Registered 9 July 2012. First patient enrolled 1 November 2012. PMID- 28592231 TI - High burden of complicated skin and soft tissue infections in the Indigenous population of Central Australia due to dominant Panton Valentine leucocidin clones ST93-MRSA and CC121-MSSA. AB - BACKGROUND: Superficial skin and soft tissue infections (SSTIs) are common among the Indigenous population of the desert regions of Central Australia. However, the overall burden of disease and molecular epidemiology of Staphylococcus aureus complicated SSTIs has yet to be described in this unique population. METHODS: Alice Springs Hospital (ASH) admission data was interrogated to establish the population incidence of SSTIs. A prospective observational study was conducted on a subset of S. aureus complicated SSTIs (carbuncles and furuncles requiring surgical intervention) presenting during a one month period to further characterize the clinical and molecular epidemiology. High resolution melting analysis was used for clonal complex discrimination. Real-time polymerase chain reaction identifying the lukF component of the Panton Valentine leucocidin (pvl) gene determined pvl status. Clinical and outcome data was obtained from the ASH medical and Northern Territory shared electronic health records. RESULTS: SSTIs represented 2.1% of ASH admissions during 2014. 82.6% occurred in Indigenous patients (n = 382) with an estimated incidence of 18.9 per 1, 000 people years compared to the non-Indigenous population of 2.9 per 1000, with an incident rate ratio of 6.6 (95% confidence interval 5.1-8.5). Clinical and molecular analysis was performed on 50 isolates from 47 patients. Community-associated methicillin resistant S. aureus (CA-MRSA) predominated (57% of isolates). The high burden of SSTIs is partly explained by the prevalence of pvl positive strains of S. aureus (90% isolates) for both CA-MRSA and methicillin-susceptible S. aureus (MSSA). ST93-MRSA and CC121-MSSA were the most prevalent clones. SSTIs due to ST93-MRSA were more likely to require further debridement (p = 0.039), however they also more frequently received inactive antimicrobial therapy (p < 0.001). CONCLUSIONS: ST93-MRSA and CC121-MSSA are the dominant causes of carbuncles and furuncles in Central Australia. Both of these virulent clones harbor pvl but the impact on clinical outcomes remains uncertain. The high prevalence of CA-MRSA supports empiric vancomycin use in this population when antimicrobial therapy is indicated. Prompt surgical intervention remains the cornerstone of treatment. PMID- 28592233 TI - Single-fiber electromyography in the orbicularis oculi muscle in patients with ocular myasthenia gravis symptoms: does abnormal jitter predict response to treatment? AB - BACKGROUND: Seronegative ocular myasthenia gravis (OMG) is diagnosed by ocular symptoms with supporting SFEMG, typically of frontalis or extensor digitorum muscles. We aimed to determine the sensitivity and specificity of orbicularis oculi SFEMG to diagnose and exclude myasthenia gravis and predict response to therapy. METHODS: Orbicularis oculi SFEMG studies were conducted in 142 consecutive patients with symptoms and/or findings of OMG and negative AChR antibody during the period of 5 years. Retrospective chart review was conducted 2 years after the SFEMG to determine whether treatments were given and responses to treatment. RESULTS: Orbicularis oculi SFEMG was abnormal in 31 patients and normal in 111 patients. Twenty-nine patients with abnormal SFEMG were treated, and 25 had a good response. Twenty-four patients with normal SFEMG received treatment; none responded to treatment or developed generalized myasthenia. CONCLUSION: An abnormal orbicularis oculi SFEMG in patients with seronegative OMG has a high predictive value for response to therapy. Our study findings may affect the treatment decisions in practice and aid better management of myasthenic patients. PMID- 28592232 TI - Association of frontal plane knee alignment with foot posture in patients with medial knee osteoarthritis. AB - BACKGROUND: To examine the association of radiographic frontal plane knee alignment with three-dimensional foot posture in patients with medial knee osteoarthritis (OA). METHODS: Participants in orthopedic clinics with Kellgren/Lawrence (K/L) grade >=1 (88 patients and 88 knees; age, 61-91 years; 65.9% female) were enrolled. An anteroposterior radiographic view was used to assess the anatomical axis angle (AAA) after subtracting a sex-specific correction factor. The three-dimensional foot posture was also evaluated. RESULTS: Multiple regression analyses showed that increased corrected AAA (i.e., valgus direction) was independently associated with a decrease in the hallux valgus angle (regression coefficient: -0.40 per degree, 95% confidence interval [CI]: -0.72, -0.09; P = 0.013) and increase in the pronation angle of the calcaneus relative to floor (regression coefficient: 0.33 per degree, 95% CI: 0.10, 0.56; P = 0.005) adjusted for age, sex, and body mass index. The relationship between the corrected AAA and hallux valgus angle strengthened (regression coefficient: -0.60 per degree, 95% CI: -1.08, -0.13; P = 0.014) in varus-aligned knees examined separately (63 knees). The other foot postures (navicular height, navicular height/foot length, and rearfoot angle) were not significantly associated with corrected AAA. CONCLUSIONS: Radiographic frontal plane knee alignment was associated with hallux valgus angle and calcaneus angle relative to the floor in patients with medial knee OA, particularly in varus aligned knees. These results indicate a connection between altered frontal knee alignment and foot posture, which may be helpful in understanding the pathogenesis of altered foot posture observed in patients with knee OA. PMID- 28592234 TI - Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil. AB - BACKGROUND: Warfarin is a commonly used anticoagulant. Whether a given dose of the different formulations of Brazilian warfarin will result in the same effect on the international normalized ratio (INR) is uncertain. The aim of the WARFA trial is to determine whether the branded and two generic warfarins available in Brazil differ in their effect on the INR. METHODS: WARFA is a cross-over RCT comparing three warfarins. The formulations tested are the branded Marevan(r) (Uniao Quimica/Farmoquimica) and two generic warfarin (manufactured respectively by Uniao Quimica Farmaceutica Nacional and Laboratorio Teuto Brasileiro). All of them were manufactured in Brazil, are available in all settings of the Brazilian healthcare system and were purchased from retail drugstores. Eligible participants had atrial fibrillation or flutter, had been using warfarin for at least 2 months with a therapeutic range of 2.0-3.0 and had low variability in INR results during the 1st period of the trial. Our primary outcome, for which we have an equality hypothesis, is the difference between warfarins in the mean absolute difference between two INR results, obtained after three and 4 weeks with each drug. Our secondary outcomes, that will be tested for inequality (except for the mean INR, which will be tested for equality), include the difference in the warfarin dose, and time in therapeutic range. Clinical events and adherence were also recorded and will be reported. DISCUSSION: To our knowledge, WARFA will be the first comparison of the more readily applicable INR results between branded and generic warfarins in Brazil. WARFA is important because warfarins are commonly switched between in the course of a chronic treatment in Brazil. Final results of WARFA are expected in May 2017. TRIAL REGISTRATION: ClinicalTrials.gov NCT02017197 . Registered 11 December 2013. PMID- 28592235 TI - Gene-centromere mapping in meiotic gynogenetic European seabass. AB - BACKGROUND: Fully isogenic lines in fish can be developed using "mitotic" gynogenesis (suppression of first zygotic mitosis following inactivation of the sperm genome). However, genome-wide verification of the steps in this process has seldom been applied. We used ddRADseq to generate SNP markers in a meiotic gynogenetic family of European seabass (Dicentrarchus labrax): (i) to verify the lack of paternal contribution in a meiotic gynogenetic family; (ii) to generate a gene-centromere map from this family; (iii) to identify telomeric markers that could distinguish mitotic gynogenetics from meiotic gynogenetics, which sometimes arise spontaneously in mitotic gynogenetic families. RESULTS: From a single meiotic gynogenetic family consisting of 79 progeny, 42 million sequencing reads (Illumina, trimmed to 148 bases) resolved 6866 unique RAD-tags. The 340 male informative SNP markers that were identified confirmed the lack of paternal contribution. A gene-centromere map was constructed based on 804 female informative SNPs in 24 linkage groups (2n = 48) with a total length of 1251.02 cM (initial LG assignment was based on the seabass genome assembly, dicLab v1). Chromosome arm structure could be clearly discerned from the pattern of heterozygosity in each linkage group in 18 out of 24 LGs: the other six showed anomalies that appeared to be related to issues in the genome assembly. CONCLUSION: Genome-wide screening enabled substantive verification of the production of the gynogenetic family used in this study. The large number of telomeric and subtelomeric markers with high heterozygosity values in the meiotic gynogenetic family indicate that such markers could be used to clearly distinguish between meiotic and mitotic gynogenetics. PMID- 28592237 TI - Labour management guidelines for a Tanzanian referral hospital: The participatory development process and birth attendants' perceptions. AB - BACKGROUND: While international guidelines for intrapartum care appear to have increased rapidly since 2000, literature suggests that it has only in few instances been matched with reviews of local modifications, use, and impact at the targeted low resource facilities. At a Tanzanian referral hospital, this paper describes the development process of locally achievable, partograph associated, and peer-reviewed labour management guidelines, and it presents an assessment of professional birth attendants' perceptions. METHODS: Part 1: Modification of evidence-based international guidelines through repeated evaluation cycles by local staff and seven external specialists in midwifery/obstetrics. Part 2: Questionnaire evaluation 12 months post implementation of perceptions and use among professional birth attendants. RESULTS: Part 1: After the development process, including three rounds of evaluation by staff and two external peer-review cycles, there were no major concerns with the guidelines internally nor externally. Thereby, international recommendations were condensed to the eight-paged 'PartoMa guidelines (c)'. This pocket booklet includes routine assessments, supportive care, and management of common abnormalities in foetal heart rate, labour progress, and maternal condition. It uses colour codes indicating urgency. Compared to international guidelines, reductions were made in frequency of assessments, information load, and ambiguity. Part 2: Response rate of 84% (n = 84). The majority of staff (93%) agreed that the guidelines helped to improve care. They found the guidelines achievable (89%), and the graphics worked well (90%). Doctors more often than nurse-midwives (89% versus 74%) responded to use the guidelines daily. CONCLUSIONS: The PartoMa guidelines ensure readily available, locally achievable, and acceptable support for intrapartum surveillance, triage, and management. This is a crucial example of adapting evidence-based international recommendations to local reality. TRIAL REGISTRATION: This paper describes the intervention of the PartoMa trial, which is registered on ClinicalTrials.org ( NCT02318420 , 4th November 2014). PMID- 28592236 TI - Prevalence of frailty among community dwelling older adults in receipt of low level home support: a cross-sectional analysis of the North Dublin Cohort. AB - BACKGROUND: There is increasing demand for formal government funded home help services to support community-dwelling older people in Ireland, yet limited information exists on the health profiles of this group, especially regarding frailty. Our aim was to profile a large cohort of adults in receipt of low level home help and to determine the prevalence of frailty. METHODS: A total 1312 older adults, (>= 65 years) in receipt of low level home help (< 5 h per week) were reviewed by community nurses and frailty was assessed using the Clinical Frailty Scale (CFS) in this cross-sectional study. Characteristics of the group were compared between males and females and prevalence of frailty was reported according to gender and principal care. Associations between frailty and a number of variables were explored using bivariate and regression analysis. RESULTS: The cohort of low level home-help users was a mean age of 82.1 (SD 7.3) years, predominantly female (70.6%) and over half (69.2%) lived alone. The prevalence of frailty in this population was 41.5%, with subjects primarily considered mildly (23.2%) or moderately frail (14.5%) by the CFS. A further 38.4% were classed as vulnerable. The degree of frailty did not differ significantly across the younger categories aged 65-84 years. However, in the oldest age groups, namely 90-94 and >95 years, moderate frailty was significantly higher relative to the younger groups (21% and 34%, p < 0.05, p < 0.01 respectively). Home help hours significantly correlated with frailty (rs = 0.371, p < 0.001) and functional dependency (rs = 0.609, p < 0.001), but only weakly with age (rs = 0.101, p = 0.034). Based on regression analysis, determinants of frailty included greater dependency (Barthel score), higher home help hours, non-self-caring and communication difficulty, all of which significantly contributed to the model, with a r squared value of 0.508. CONCLUSION: A high prevalence of frailty (41.5%) was documented in this population which associated with higher home help utilisation. Frailty was associated with greater functional dependency, but not strongly with chronological age, until after 90 years. These findings highlight opportunities for developing intervention strategies targeted at ageing in place among home help users. PMID- 28592238 TI - A survey of palliative medicine education in Japan's undergraduate medical curriculum. AB - BACKGROUND: This study aimed to examine the status of undergraduate palliative care education among Japanese medical students using data from a survey conducted in 2015. METHODS: A questionnaire was originally developed, and the survey forms were sent to universities. The study's objectives, methods, disclosure of results, and anonymity were explained to participating universities in writing. Responses returned by the universities were considered to indicate consent to participate. Descriptive statistical methodology was employed. RESULTS: The response rate was 82.5% (66 of 80 medical faculties and colleges). Palliative care lectures were implemented in 98.5% of the institutions. Regarding lecture titles, "palliative medicine," "palliative care," and "terminal care" accounted for 42.4, 30.3, and 9.1% of the lectures, respectively. Teachers from the Department of Anesthesia, Palliative Care, and Psychiatry administered 51.5, 47.0, and 28.8% of lectures, respectively. Subjects of lectures included general palliative care (81.8%), pain management (87.9%), and symptom management (63.6%). Clinical clerkship on palliative care was a compulsory and non-compulsory course in 43.9 and 25.8% of the schools, respectively; 30.3% had no clinical clerkship curriculum. CONCLUSIONS: Undergraduate palliative care education is implemented in many Japanese universities. Clinical clerkship combined with participation in actual medical practice should be further improved by establishing a medical education certification system in compliance with the international standards. PMID- 28592239 TI - Oral health knowledge, behaviors and parental practices among rural-urban migrant children in Guangzhou: a follow-up study. AB - BACKGROUND: Despite the growing number of rural-urban migrant children in China, follow-up observation on the oral health of migrant children is still scarce. This study described the changes of oral health knowledge, behaviors and parental practices in migrant children over a period of one year. Possible factors affecting changes were also investigated. METHODS: The study used purposive sampling to select five private schools of migrant children in Guangzhou. A total of 1900 students in Grades 3 and 4 were recruited. A self-administered questionnaire was used in November 2011 to understand their basic situations, including oral health knowledge, behaviors and parental practices. A final survey was conducted in April 2013 to detect any changes. RESULTS: The mean accuracy of oral health knowledge was 53.17% and 59.42% in 2011 and 2013, respectively (p < 0.001). For migrant children, the total score of oral hygiene, dietary habits and parental practices increased at the follow-up evaluation (p < 0.05). Children with less oral health knowledge were more likely to achieve significantly positive changes in score of knowledge (p < 0.001) in the final survey. Migrant children who had worse performance on oral hygiene (beta estimate = 0.68, p < 0.001), dietary habits (beta estimate = 0.58, p < 0.001) and good parental practices in the baseline survey were more likely to obtain beneficial changes. No significant associations between demographic characteristics and changes of oral health knowledge and behaviors (p > 0.05) were observed. CONCLUSION: Oral health knowledge, behaviors and parental practices among migrant children significantly improved at the follow-up assessment. However, the overall situation was still poor. Positive and effective health education and prevention programs tailored to rural-urban migrant children with varying levels of oral health knowledge, behaviors and parental practices will be needed. PMID- 28592240 TI - Randomized controlled trial of piperacillin-tazobactam, cefepime and ertapenem for the treatment of urinary tract infection caused by extended-spectrum beta lactamase-producing Escherichia coli. AB - BACKGROUND: Due to limited therapeutic options, the spread of extended-spectrum beta-lactamases (ESBLs) have become a major public health concern. We conducted a prospective, randomized, open-label comparison of the therapeutic efficacy of piperacillin-tazobactam (PTZ), cefepime, and ertapenem in febrile nosocomial urinary tract infection with ESBL-producing Escherichia coli (ESBL-EC). METHODS: This study was conducted at three university hospitals between January 2013 and August 2015. Hospitalized adult patients presenting with fever were screened for healthcare-associated urinary tract infection (HA-UTI). When ESBL-EC was solely detected and susceptible to a randomized antibiotic in vitro, the case was included in the final analysis. Participants were treated for 10-14 days with PTZ, cefepime, or ertapenem. RESULTS: A total of 66 participants were evenly assigned to the PTZ and ertapenem treatment groups. After the recruitment of six participants, assignment to the cefepime treatment group was stopped because of an unexpectedly high treatment failure rate. The baseline characteristics of these participants did not differ from participants in other treatment groups. The clinical and microbiological response to PTZ treatment was estimated to be 94% and was similar to the response to ertapenem treatment. The efficacy of cefepime was 33.3%. In the cefepime group, age, Charlson comorbidity index, genotype, and minimal inhibitory concentration (MIC) did not significantly affect the success of treatment. Similarly, genotype seemed to be irrelevant with respect to clinical outcome in the PTZ group. Expired cases tended to involve septic shock with a high Charlson comorbidity index and high MIC. CONCLUSION: Results from this study suggest that PTZ is effective in the treatment of urinary tract infection caused by ESBL-EC when the in vitro test indicates susceptibility. In addition, cefepime should not be used as an alternative treatment for urinary tract infection caused by ESBL-EC. TRIAL REGISTRATION: The trial was registered with the Clinical Research Information Service of Korea Centers for Disease Control and Prevention. (KCT0001895). PMID- 28592241 TI - Effect of major school playground reconstruction on physical activity and sedentary behaviour: Camden active spaces. AB - BACKGROUND: The physical school environment is a promising setting to increase children's physical activity although robust evidence is sparse. We examined the effects of major playground reconstruction on physical activity and sedentary time in primary schools using a quasi-experimental design (comparison group pre test/post-test design). METHODS: Five experimental and two control schools from deprived areas of inner city London were recruited at baseline. Main outcome was physical activity and sedentary time measured from objective monitoring (Actigraph accelerometer) at one year follow up. Pupils' impressions of the new playground were qualitatively assessed post construction. RESULTS: A total of 347 pupils (mean age = 8 years, 55% boys; 36% Caucasian) were recruited into the study at baseline; 303 provided valid baseline Actigraph data. Of those, 231 (76%) completed follow-up (n = 169 intervention; n = 62 control) and 77.4% of the sample recorded at least 4 days of Actigraph wear. In mixed models adjusted for age, sex, ethnicity, ratio activity or sedentary/wear time at baseline, wear time at follow up, and school, no differences were observed in total moderate - vigorous activity (B = -1.4, 95% CI, -7.1, 4.2 min/d), light activity (B = 4.1, 95% CI, -17.9, 26.1), or sedentary time (B = -3.8, 95% CI, -29.2, 21.6 min/d) between groups. There were significant age interactions for sedentary (p = 0.002) and light intensity physical activity (p = 0.008). We observed significant reductions in total sedentary (-28.0, 95% CI, -1.9, -54.1 min/d, p = 0.037) and increases in total light intensity activity (24.6, 95% CI, 0.3, 48.9 min/d, p = 0.047) for children aged under 9 yrs. old in the intervention. CONCLUSION: Major playground reconstruction had limited effects on physical activity, but reduced sedentary time was observed in younger children. Qualitative data suggested that the children enjoyed the new playgrounds and experienced a perceived positive change in well-being and social interactions. PMID- 28592242 TI - An avirulent Burkholderia pseudomallei ?purM strain with atypical type B LPS: expansion of the toolkit for biosafe studies of melioidosis. AB - BACKGROUND: The work was undertaken to expand the tools available for researching Burkholderia pseudomallei (Bp), the etiological agent of the tropical disease melioidosis. Melioidosis has the potential to pose a severe threat to public health and safety. In the United States, Bp is listed as a Tier-1 select agent by the Centers for Disease Control and Prevention (CDC), thus requiring high levels of regulation and biosafety level 3 (BSL3) facilities for experimental manipulation of live organisms. An avirulent ?purM derivative of strain 1026b (Bp82) has proven to be a valuable tool for biosafe research as a select-agent excluded strain, but the high level of genetic diversity between Bp strains necessitates an expansion of the biosafe toolset. RESULTS: The ?purM mutation was recapitulated in the Bp 576a strain, a serotype B background. An important difference between strains 1026b and 576a is the lipopolysaccharide (LPS), a major virulence factor and protective antigen. Polyclonal sera from 1026b challenged non-human primates showed no cross reactivity with strain 576a LPS and low reactivity with whole cell lysate. Strain 576a replicates to higher levels in mouse organs and induces more TNF-alpha in the lungs of BALB/c mice compared to 1026b. The newly created Bp 576a ?purM strain, designated 576mn, was auxotrophic for adenine in minimal media, capable of wild-type growth in rich media with addition of adenine, and auxotrophy was abrogated with single-copy complementation. Bp 576mn was unable to replicate in human cells and was avirulent in BALB/c mice following high-dose intranasal inoculation, similar to Bp82. Organ loads indicated a significant reduction in bacterial replication. CONCLUSIONS: In this work, the new biosafe strain 576mn with atypical type B LPS was generated. This strain should prove a valuable addition to the toolkit for biosafe studies of Bp and development of therapeutic and preventative strategies aimed at combatting melioidosis. Strain 576mn is an ideal candidate for select agent exclusion. PMID- 28592243 TI - Reduced Kidney Function, Albuminuria, and Risks for All-cause and Cardiovascular Mortality in China: A Population-based Cohort Study. AB - BACKGROUND: Previous studies have indicated that reduced kidney function and albuminuria are associated with increased risk of mortality and adverse cardiovascular outcomes, however, the evidence from the Asian population is limited. We investigated the association between the indicators of chronic kidney disease (CKD) and all-cause mortality, as well as cardiovascular mortality among a general population in China. METHODS: We conducted an observational study among 47,204 Chinese adults, from a cross-sectional survey, whose survival status is identified through December 31, 2013. Estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) were used as indicators of CKD. We determined the rates of all-cause and cardiovascular mortality. RESULTS: The incidence rates for both all-cause and cardiovascular mortality increased with the advanced stages of reduced eGFR or elevated ACR. Elevated ACR levels were found to be significantly associated with increased risk of both all-cause and cardiovascular mortality, as shown in the Cox proportional hazards regression model. The multivariable adjusted hazard ratios (HR) associated with all-cause mortality were 1.26 (95% confidence interval [CI]: 1.04-1.53) for those with ACR 30-299 mg/g and 2.07 (95% CI: 1.40-3.04) with ACR >= 300 mg/g, compared to those with ACR <30 mg/g. The corresponding HRs for the above ACR levels associated with cardiovascular mortality were 1.08 (95% CI: 0.77-1.50) and 2.32 (95% CI: 1.31 4.12), respectively. We did not identify reduced eGFR as a risk predictor in the multivariable adjusted model for the adverse outcomes in the population, however, an interaction between eGFR and age were detected. Stratified analyses revealed that the associations of reduced eGFR (<60 mL/min/1.73 m2) with all-cause mortality were prominent among participants aged less than 65 years. CONCLUSIONS: Albuminuria was associated with an elevated risk of all-cause and cardiovascular mortality among the Chinese population, however, the association of reduced kidney function with all-cause mortality was not clear. PMID- 28592244 TI - Optimising child outcomes from parenting interventions: fathers' experiences, preferences and barriers to participation. AB - BACKGROUND: Early childhood interventions can have both immediate and long-term positive effects on cognitive, behavioural, health and education outcomes. Fathers are underrepresented in interventions focusing on the well-being of children. However, father participation may be critical for intervention effectiveness, especially for parenting interventions for child externalising problems. To date, there has been very little research conducted to understand the low rates of father participation and to facilitate the development of interventions to meet the needs of fathers. This study examined fathers' experiences of, and preferences for, parenting interventions as well as perceptions of barriers to participation. It also examined how these factors were associated with child externalising behaviour problems, and explored the predictors of participation in parenting interventions. METHODS: A community sample of 1001 fathers of children aged 2-16 years completed an online survey about experiences with parenting interventions, perceived barriers to participation, the importance of different factors in their decision to attend, and preferred content and delivery methods. They also completed ratings of their child's behaviour using the Strengths and Difficulties Questionnaire. RESULTS: Overall, 15% of fathers had participated in a parenting intervention or treatment for child behaviour, with significantly higher rates of participation for fathers of children with high versus low levels of externalising problems. Fathers rated understanding what is involved in the program and knowing that the facilitator is trained as the two most important factors in their decision to participate. There were several barriers to participation that fathers of children with high-level externalising problems were more likely to endorse, across practical barriers and help-seeking attitudes, compared to fathers of children with low-level externalising problems. Almost two-thirds of fathers of children with high-level externalising behaviour had not participated in a parenting intervention or treatment. The only significant predictors of intervention participation were severity of child externalising behaviour problems and child age. CONCLUSIONS: The findings have important implications for services seeking to increase father engagement and highlight a number of strategies to enhance the promotion and delivery of parenting interventions to fathers. These strategies include more public health messaging about parenting programs and the importance of father participation. PMID- 28592246 TI - Using a programmatic mapping approach to plan for HIV prevention and harm reduction interventions for people who inject drugs in three South African cities. AB - BACKGROUND: Stigma, criminalisation and a lack of data on drug use contribute to the "invisibility" of people who inject drugs (PWID) and make HIV prevention and treatment service delivery challenging. We aimed to confirm locations where PWID congregate in Cape Town, eThekwini and Tshwane (South Africa) and to estimate PWID population sizes within selected electoral wards in these areas to inform South Africa's first multi-site HIV prevention project for PWID. METHODS: Field workers (including PWID peers) interviewed community informants to identify suspected injecting locations in selected electoral wards in each city and then visited these locations and interviewed PWID. Interviews were used to gather information about the accessibility of sterile injecting equipment, location coordinates and movement patterns. We used the Delphi method to obtain final population size estimates for the mapped wards based on estimates from wisdom of the crowd methods, the literature and programmatic data. RESULTS: Between January and April 2015, we mapped 45 wards. Tshwane teams interviewed 39 PWID in 12 wards, resulting in an estimated number of accessible PWID ranging from 568 to 1431. In eThekwini, teams interviewed 40 PWID in 15 wards with an estimated number of accessible PWID ranging from 184 to 350. The Cape Town team interviewed 61 PWID in 18 wards with an estimated number of accessible PWID ranging between 398 and 503. Sterile needles were only available at one location. Almost all needles were bought from pharmacies. Between 80 and 86% of PWID frequented more than one location per day. PWID who reported movement visited a median of three locations a day. CONCLUSIONS: Programmatic mapping led by PWID peers can be used effectively to identify and reach PWID and build relationships where access to HIV prevention commodities for PWID is limited. PWID reported limited access to sterile injecting equipment, highlighting an important HIV prevention need. Programmatic mapping data show that outreach programmes should be flexible and account for the mobile nature of PWID populations. The PWID population size estimates can be used to develop service delivery targets and as baseline measures. PMID- 28592245 TI - In silico identification of potential key regulatory factors in smoking-induced lung cancer. AB - BACKGROUND: Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. METHODS: We used a systems biology approach to identify potential key regulatory factors in smoking-induced lung cancer. We first identified genes that were differentially expressed between smokers with normal lungs and those with cancerous lungs, then integrated these differentially expressed genes (DEGs) with data from a protein-protein interaction database to build a network model with functional modules for pathway analysis. We also carried out a gene set enrichment analysis of DEG lists using the Kinase Enrichment Analysis (KEA), Protein-Protein Interaction (PPI) hubs, and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. RESULTS: Twelve transcription factors were identified as having potential significance in lung cancer (CREB1, NUCKS1, HOXB4, MYCN, MYC, PHF8, TRIM28, WT1, CUX1, CRX, GABP, and TCF3); three of these (CRX, GABP, and TCF) have not been previously implicated in lung carcinogenesis. In addition, 11 kinases were found to be potentially related to lung cancer (MAPK1, IGF1R, RPS6KA1, ATR, MAPK14, MAPK3, MAPK4, MAPK8, PRKCZ, and INSR, and PRKAA1). However, PRKAA1 is reported here for the first time. MEPCE, CDK1, PRKCA, COPS5, GSK3B, BRCA1, EP300, and PIN1 were identified as potential hubs in lung cancer-associated signaling. In addition, we found 18 pathways that were potentially related to lung carcinogenesis, of which 12 (mitogen-activated protein kinase, gonadotropin-releasing hormone, Toll-like receptor, ErbB, and insulin signaling; purine and ether lipid metabolism; adherens junctions; regulation of autophagy; snare interactions in vesicular transport; and cell cycle) have been previously identified. CONCLUSION: Our systems-based approach identified potential key molecules in lung carcinogenesis and provides a basis for investigations of tumor development as well as novel drug targets for lung cancer treatment. PMID- 28592248 TI - Impact of poor muscle strength on clinical and service outcomes of older people during both acute illness and after recovery. AB - BACKGROUND: Although Low muscle strength is an important predictor of functional decline in older people, however information on its impact on clinical and service outcomes in acute care settings is still lacking. The aim of this study is to measure the impact of low muscle strength on clinical and service outcomes in older adults during both acute illness and recovery. METHODS: Randomly selected 432 hospitalised older patients had their clinical characteristics and nutritional status assessed within 72 h of admission, at 6 weeks and at 6 months. Low muscle strength-hand grip was defined using the European Working Group criteria. Health outcome measures including nutritional status, length of hospital stay, disability, discharge destination, readmission and mortality were also measured. RESULTS: Among the 432 patients recruited, 308 (79%) had low muscle strength at baseline. Corresponding figures at 6 weeks and at 6 months were 140 (73%) and 158 (75%). Patients with poor muscle strength were significantly older, increasingly disabled, malnourished and stayed longer in hospital compared with those with normal muscle strength. A significantly higher number of patients with normal muscle strength discharged home independently compared with those with poor muscle strength (p < 0.05). One-year death rate was lower in patients with normal muscle strength 5(6%), compared with those with poor muscle strength 52(15%), however, results were not statistically significant after adjusting for other poor prognostic indicators [adjusted hazard ratio 0.74 (95% CI: 0.14-3.87), p = 0.722]. CONCLUSION: Poor muscle strength in older people is associated with poor clinical service outcomes during both acute illness and recovery. PMID- 28592247 TI - Immunization with a DNA vaccine encoding Toxoplasma gondii Superoxide dismutase (TgSOD) induces partial immune protection against acute toxoplasmosis in BALB/c mice. AB - BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that infects all warm-blooded animals including humans and causes toxoplasmosis. An effective vaccine could be an ideal choice for preventing and controlling toxoplasmosis. T. gondii Superoxide dismutase (TgSOD) might participate in affecting the intracellular growth of both bradyzoite and tachyzoite forms. In the present study, the TgSOD gene was used to construct a DNA vaccine (pEGFP-SOD). METHODS: TgSOD gene was amplified and inserted into eukaryotic vector pEGFP-C1 and formed the DNA vaccine pEGFP-SOD. Then the BALB/c mice were immunized intramuscularly with the DNA vaccine and those injected with pEGFP-C1, PBS or nothing were treated as controls. Four weeks after the last immunization, all mouse groups followed by challenging intraperitoneally with tachyzoites of T. gondii ME49 strain. RESULTS: Results showed higher levels of total IgG, IgG2alpha in the sera and interferon gamma (IFN-gamma) in the splenocytes from pEGFP-SOD inoculated mice than those unvaccinated, or inoculated with either empty plasmid vector or PBS. The proportions of CD4+ T cells and CD8+ T cells in the spleen from pEGFP-SOD inoculated mice were significantly (p < 0.05) increased compared to control groups. In addition, the survival time of mice immunized with pEGFP-SOD was significantly prolonged as compared to the controls (p < 0.05) although all the mice died. CONCLUSION: The present study revealed that the DNA vaccine triggered strong humoral and cellular immune responses, and aroused partial protective immunity against acute T. gondii infection in BALB/c mice. The collective data suggests the SOD may be a potential vaccine candidate for further development. PMID- 28592249 TI - Ixora (Rubiaceae) on the Philippines - crossroad or cradle? AB - BACKGROUND: The Philippine archipelago is globally one of the most important model island systems for studying evolutionary processes. However, most plant species on this archipelago have not yet been studied in sufficient detail. The main aim of this study is to unravel the evolutionary history and biogeographic relationships of the Philippine members of the pantropical genus Ixora. RESULTS: The complex plastid and nuclear divergence patterns in Philippine Ixora, documented using tree and network approaches, reveal a highly dynamic evolution in Ixora, involving several phases of radiation and recolonization. Philippine Ixora comprises at least five lineages, of which one is most closely related to species from Wallacea, and the remaining four to species from Asia. CONCLUSIONS: Our study highlights the importance of Philippine species for understanding phytogeographic patterns in the Indomalayan-Australasian eco-region. The overall genetic differentiation, as well as the incongruence between genealogies based on the biparentally inherited nucleome and the maternally inherited plastome in Ixora, reflect the complex tectonic history of the Philippine archipelago. The Ixora lineage related to Wallacean species supports the delimitation of different ecozones along Huxley's line, because it is absent from Palawan. The remaining four lineages are all allied with Asian taxa, reflecting several waves of colonization. Close relationships between some widespread Philippine species and locally adapted narrow endemics suggest that the widespread, genetically diverse species act as pools for the formation of new species in a process of ongoing speciation. Our results suggest that the species concepts of some of the more widespread taxa need to be revised. PMID- 28592250 TI - Community-based intermittent mass testing and treatment for malaria in an area of high transmission intensity, western Kenya: study design and methodology for a cluster randomized controlled trial. AB - Most human Plasmodium infections in western Kenya are asymptomatic and are believed to contribute importantly to malaria transmission. Elimination of asymptomatic infections requires active treatment approaches, such as mass testing and treatment (MTaT) or mass drug administration (MDA), as infected persons do not seek care for their infection. Evaluations of community-based approaches that are designed to reduce malaria transmission require careful attention to study design to ensure that important effects can be measured accurately. This manuscript describes the study design and methodology of a cluster-randomized controlled trial to evaluate a MTaT approach for malaria transmission reduction in an area of high malaria transmission. Ten health facilities in western Kenya were purposively selected for inclusion. The communities within 3 km of each health facility were divided into three clusters of approximately equal population size. Two clusters around each health facility were randomly assigned to the control arm, and one to the intervention arm. Three times per year for 2 years, after the long and short rains, and again before the long rains, teams of community health volunteers visited every household within the intervention arm, tested all consenting individuals with malaria rapid diagnostic tests, and treated all positive individuals with an effective anti malarial. The effect of mass testing and treatment on malaria transmission was measured through population-based longitudinal cohorts, outpatient visits for clinical malaria, periodic population-based cross-sectional surveys, and entomological indices. PMID- 28592252 TI - A questionnaire for assessing breastfeeding intentions and practices in Nigeria: validity, reliability and translation. AB - BACKGROUND: Validating a questionnaire/instrument (whether developed or adapted) before proceeding to the field for data collection is important. This article presents the modification of an Irish questionnaire for a Nigerian setting. The validation process and reliability testing of this questionnaire (which was used in assessing previous breastfeeding practices and breastfeeding intentions of pregnant women in English and Hausa languages) were also presented. METHOD: Five experts in the field of breastfeeding and infant feeding voluntarily and independently evaluated the instrument. The experts evaluated the various items of the questionnaire based on relevance, clarity, simplicity and ambiguity on a Likert scale of 4. The analysis was performed to determine the content validity index (CVI).Two language experts performed the translation and back-translation. Ten pregnant women completed questionnaires which were evaluated for internal consistency. Two other pregnant women completed the questionnaire twice at an interval of two weeks to test the reliability. SPSS version 21 was used to calculate the coefficient of reliability. RESULTS: The content validity index was high (0.94 for relevance, clarity and ambiguity and 0.96 for simplicity). The analysis suggested that four of the seventy one items should be removed. Cronbach's Alpha was 0.81, while the reliability coefficient was 0.76. The emerged validated questionnaire was translated from English to Hausa, then, back translated into English and compared for accuracy. CONCLUSION: The final instrument is reliable and valid for data collection on breastfeeding in Nigeria among English and Hausa speakers. Therefore, the instrument is recommended for use in assessing breastfeeding intention and practices in Nigeria. PMID- 28592251 TI - Distinct expression profile of HCMV encoded miRNAs in plasma from oral lichen planus patients. AB - BACKGROUND: Oral lichen planus (OLP) is a T cell-mediated autoimmune disease. The aetiology and molecular mechanisms of OLP remain unclear. Human cytomegalovirus (HCMV) infection is a causal factor in the development of various diseases, but the clinical relevance of HCMV in OLP has not been thoroughly investigated. METHODS: In the present study, we firstly examined twenty-three HCMV-encoded microRNA (miRNA) expression profiles in plasma from training set that including 21 OLP patients and 18 healthy controls using RT-qPCR technology. Dysregulated miRNAs were subsequently confirmed in another larger cohort refereed as validation set consisting of 40 OLP patients and 33 healthy controls. HCMV DNA in peripheral blood leukocytes (PBLs) was also measured in an additional cohort of 13 OLP patients and 12 control subjects. Furthermore, bioinformatics analyses, luciferase reporter assay and western blotting were also performed to predict and verify the direct potential targets of HCMV-encoded miRNAs. RESULTS: The RT-qPCR results showed that the plasma levels of five HCMV-encoded miRNAs including hcmv miR-UL112-3p, hcmv-miR-UL22a-5p, hcmv-miR-UL148d, hcmv-miR-UL36-5p and hcmv-miR UL59 were significantly increased in OLP patients in both training and validation sets. HCMV DNA in PBLs was also significantly higher in OLP patients than in control subjects. Additionally, by using a combination of luciferase reporter assay and western blotting, we demonstrated that cytomegalovirus UL16-binding protein 1, a molecule that mediates the killing of virus-infected cells by natural killer cells, is a direct target of hcmv-miR-UL59. CONCLUSIONS: Our results demonstrate a distinct expression pattern of HCMV-encoded miRNAs in OLP patients, which may provide insight into the relationship between HCMV infection and OLP, and warrants additional study in the diagnosis and aetiology of OLP. PMID- 28592253 TI - iTRAQ-based proteome profile analysis of superior and inferior Spikelets at early grain filling stage in japonica Rice. AB - BACKGROUND: Large-panicle rice varieties often fail to achieve their yield potential due to poor grain filling of late-flowering inferior spikelets (IS). The physiological and molecular mechanisms of poor IS grain filling, and whether an increase in assimilate supply could regulate protein abundance and consequently improve IS grain filling for japonica rice with large panicles is still partially understood. RESULTS: A field experiment was performed with two spikelet removal treatments at anthesis in the large-panicle japonica rice line W1844, including removal of the top 1/3 of spikelets (T1) and removal of the top 2/3 of spikelets (T2), with no spikelet removal as a control (T0). The size, weight, setting rate, and grain filling rate of IS were significantly increased after spikelet removing. The biological functions of the differentially expressed proteins (DEPs) between superior and inferior spikelets as well as the response of IS to the removal of superior spikelets (SS) were investigated by using iTRAQ at 10 days post anthesis. A total of 159, 87, and 28 DEPs were identified from group A (T0-SS/T0-IS), group B (T0-SS/T2-IS), and group C (T2-IS/T0-IS), respectively. Among these, 104, 63, and 22 proteins were up-regulated, and 55, 24, and 6 proteins were down-regulated, respectively. Approximately half of these DEPs were involved in carbohydrate metabolism (sucrose-to-starch metabolism and energy metabolism) and protein metabolism (protein synthesis, folding, degradation, and storage). CONCLUSIONS: Reduced endosperm cell division and decreased activities of key enzymes associated with sucrose-starch metabolism and nitrogen metabolism are mainly attributed to the poor sink strength of IS. In addition, due to weakened photosynthesis and respiration, IS are unable to obtain a timely supply of materials and energy after fertilization, which might be resulted in the stagnation of IS development. Finally, an increased abundance of 14-3-3 protein in IS could be involved in the inhibition of starch synthesis. The removal of SS contributed to transfer of assimilates to IS and enhanced enzymatic activities of carbon metabolism (sucrose synthase, starch branching enzyme, soluble starch synthase, and pullulanase) and nitrogen metabolism (aspartate amino transferase and alanine amino transferase), promoting starch and protein synthesis in IS. In addition, improvements in energy metabolism (greater abundance of pyrophosphate-fructose 6-phosphate 1-phosphotransferase) might be played a vital role in inducing the initiation of grain filling. These results collectively demonstrate that carbohydrate supply is the main cause of poor IS grain filling. PMID- 28592254 TI - CKD.QLD: establishment of a chronic kidney disease [CKD] registry in Queensland, Australia. AB - BACKGROUND: Chronic kidney disease [CKD] is recognised as a global public health problem. Until recently, the majority of information informing on CKD has been generated from renal registries reporting on patients with end-stage kidney disease [ESKD] and on renal replacement therapy [RRT]. There has been a paucity of information on pre-dialysis CKD cohorts, and many issues related to these poorly described populations are unresolved. To this end, international organizations have called for CKD surveillance systems across all countries. DESCRIPTION: In Australia, we have responded by developing the Chronic Kidney Disease in Queensland [CKD.QLD] with three main platforms consisting of CKD Registry, clinical trials and development of biobank. This registry which is the core component of CKD surveillance was conceptualized specifically for the pre dialysis population in the public health system in Queensland, Australia. Recruitment started in May 2011, and to date the Registry has evolved as one of the largest CKD cohorts in the world with recruitment close to 7000 patients. The Registry has had many outcomes, including being the nidus for Australia's first National Health and Medical Research Council [NHMRC] CKD Centre of Research Excellence [CKD.CRE]. CONCLUSIONS: The Registry, with its linkage to Queensland Health datasets, is reporting, and is expected to continue generating, significant information on multiple aspects of CKD, its trajectory, management and patient outcomes. Intent of the CKD.CRE is to facilitate an expanded Registry network that has representation from health services, both public and private, across Australia. PMID- 28592255 TI - Developing a data-driven spatial approach to assessment of neighbourhood influences on the spatial distribution of myocardial infarction. AB - BACKGROUND: There is a growing understanding of the role played by 'neighbourhood' in influencing health status. Various neighbourhood characteristics-such as socioeconomic environment, availability of amenities, and social cohesion, may be combined-and this could contribute to rising health inequalities. This study aims to combine a data-driven approach with clustering analysis techniques, to investigate neighbourhood characteristics that may explain the geographical distribution of the onset of myocardial infarction (MI) risk. METHODS: All MI events in patients aged 35-74 years occurring in the Strasbourg metropolitan area (SMA), from January 1, 2000 to December 31, 2007 were obtained from the Bas-Rhin coronary heart disease register. All cases were geocoded to the census block for the residential address. Each areal unit, characterized by contextual neighbourhood profile, included socioeconomic environment, availability of amenities (including leisure centres, libraries and parks, and transport) and psychosocial environment as well as specific annual rates standardized (per 100,000 inhabitants). A spatial scan statistic implemented in SaTScan was then used to identify statistically significant spatial clusters of high and low risk of MI. RESULT: MI incidence was non randomly spatially distributed, with a cluster of high risk of MI in the northern part of the SMA [relative risk (RR) = 1.70, p = 0.001] and a cluster of low risk of MI located in the first and second periphery of SMA (RR 0.04, p value = 0.001). Our findings suggest that the location of low MI risk is characterized by a high socioeconomic level and a low level of access to various amenities; conversely, the location of high MI risk is characterized by a high level of socioeconomic deprivation-despite the fact that inhabitants have good access to the local recreational and leisure infrastructure. CONCLUSION: Our data-driven approach highlights how the different contextual dimensions were inter-combined in the SMA. Our spatial approach allowed us to identify the neighbourhood characteristics of inhabitants living within a cluster of high versus low MI risk. Therefore, spatial data-driven analyses of routinely-collected data georeferenced by various sources may serve to guide policymakers in defining and promoting targeted actions at fine spatial level. PMID- 28592257 TI - Clinical safety and efficacy of vitamin D3 analog ointment for treatment of obstructive meibomian gland dysfunction. AB - BACKGROUND: Hyperkeratinization is a major cause of obstructive meibomian gland dysfunction (oMGD) and results in degenerative gland dilation and atrophy without inflammation. Ointment containing 1,25-dihydroxy-22-oxavitamin D3 (maxacalcitol), a noncalcemic analog of the active form of vitamin D3, is applied for the treatment of hyperkeratotic cutaneous conditions such as psoriasis and ichtyosis because it suppresses the proliferation and promotes the differentiation of keratinocytes through interaction with the vitamin D receptor. The aim of the present study was to evaluate the safety and efficacy of maxacalcitol ointment for the treatment of oMGD. METHODS: Six eyes of six healthy male subjects (mean age +/- SD, 36.4 +/- 10.8 years) and 12 eyes of eight oMGD patients (five men and three women; mean age +/- SD, 55.6 +/- 13.2 years) were enrolled in the study. Maxacalcitol ointment was applied to the upper and lower lid margins twice a day for 8 weeks. Subjective symptoms, lid margin abnormalities, tear film breakup time (BUT), ocular surface staining, meibum grade, Schirmer test value, and meibomian gland area were evaluated in the oMGD patients before, during, and after the treatment period. RESULTS: Severe adverse effects of ointment application were not observed in the healthy subjects or oMGD patients. The clinical scores for plugging of meibomian gland orifices and lid margin vascularity as well as BUT, meibum grade, and meibomian gland area were significantly improved in oMGD patients after the 8-week treatment period compared with pretreatment values (P values of <0.001, 0.020, 0.030, 0.020, and 0.017, respectively). CONCLUSIONS: Topical eyelid application of an analog of the active form of vitamin D3 was found to be safe as well as to improve the condition of patients with oMGD. Such ointment thus warrants further evaluation as a potential new treatment option for this condition. TRIAL REGISTRATION: This study was registered with the UMIN database (ID: UMIN000016230 ) on 16 January 2015. PMID- 28592256 TI - High prevalence of complementary and alternative medicine use among patients with sickle cell disease in a tertiary hospital in Lagos, South West, Nigeria. AB - BACKGROUND: Attention and interest in the use of complementary and alternative medicine (CAM) has been reignited globally, most especially in patients with chronic diseases. Sickle cell disease (SCD) is one of such chronic diseases associated with devastating clinical and psychosocial consequences, thus leading those affected to seek alternative treatment apart from orthodox medicine. Hence, this study aimed to determine the prevalence, pattern and tolerability of the use of CAM in patients with SCD in the Lagos University Teaching Hospital (LUTH). METHODS: This was a cross-sectional survey of 200 respondents with SCD attending the hematology clinics of the Lagos University Teaching Hospital over a period of 3 months. Data on socio-demographic characteristic, clinical profile, the types and sources of CAM used were collected using a well structured pretested questionnaire. The data obtained were analyzed using Statistical Package for Social Sciences (SPSS(r)) version 17. RESULT: Of the 200 patients who participated in the study, 113; 56.5% were males and 87; 43.5% were females. Majority of the SCD patients were 1-10 years old and their mean age was 18.8 +/- 14.39 years. CAM was reportedly used by 88.5% of the respondents. Biological (herbal) products 156; 62.9% were the most commonly used CAM, followed by alternative medical systems 52; 20.9% and mind-body interventions 30; 12.1%. Relations, friends and neighbors influenced 85.2% of CAM users by recommending CAM to them. Tolerability of CAM was perceived to be excellent as only 33 (18.6%) of the respondents abandoned the use of CAM. Comparing CAM users and CAM non users, there was no statistical significant difference in the proportion of those >18 years (45.76% vs 52.17%; p = 0.658), those who experienced two or more crises (51.41% vs 34.78%; p = 0.183), and those with stable haemoglobin concentration of >7 g/dL (15.81% vs 8.69%; p = 0.539) More patients among CAM non-users (91.30%) significantly spend over 3000 Naira (USD 15) per month on medicine than CAM users (4.51%) (p < 0.001). CONCLUSION: CAM use is highly prevalent among adults with sickle cell diseases in Nigeria. CAM is well tolerated and relatively affordable by these patients. Clinician awareness and understanding of the factors influencing the use of CAM and the potential herbal-orthodox medicine interaction are crucial during hospital treatment of these patients. PMID- 28592258 TI - Pathways linking car transport for young adults and the public health in Northern Ireland: a qualitative study to inform the evaluation of graduated driver licensing. AB - BACKGROUND: Novice drivers are at relatively high risk of road traffic injury. There is good evidence that Graduated Driving Licensing (GDL) schemes reduce collisions rates, by reducing exposure to risk and by extending learning periods. Legislation for a proposed scheme in Northern Ireland was passed in 2016, providing an opportunity for future evaluation of the full public health impacts of a scheme in a European context within a natural experiment. This qualitative study was designed to inform the logic model for such an evaluation, and provide baseline qualitative data on the role of private cars in health and wellbeing. METHODS: Nine group interviews with young people aged 16-23 (N = 43) and two group interviews with parents of young people (N = 8) were conducted in a range of settings in Northern Ireland in 2015. Data were analysed using thematic content analysis. RESULTS: Informal car-pooling within and beyond households led to routine expectations of lift provision and uptake. Experiences of risky driving situations were widespread. In rural areas, extensive use of farm vehicles for transport needs meant many learner drivers had both early driving experience and expectations that legislation may have to be locally adapted to meet social needs. Cars were used as a site for socialising, as well as essential means of transport. Alternative modes (public transport, walking and cycling) were held in low esteem, even where available. Recall of other transport-related public health messages and parents' existing use of GDL-type restrictions suggested GDL schemes were acceptable in principle. There was growing awareness and use of in-car technologies (telematics) used by insurance companies to reward good driving. CONCLUSIONS: Key issues to consider in evaluating the broader public health impact of GDL will include: changes in injury rates for licensed car occupants and other populations and modes; changes in exposure to risk in the licensed and general population; and impact on transport exclusion. We suggest an important pathway will be change in social norms around offering and accepting lifts and to risk-taking. The growing adoption of in-car telematics will have implications for future GDL programmes and for evaluation. PMID- 28592259 TI - Safety of low-molecular-weight heparin compared to unfractionated heparin in hemodialysis: a systematic review and meta-analysis. AB - BACKGROUND: Low molecular weight heparins (LMWH) have been extensively studied and became the treatment of choice for several indications including pulmonary embolism. While their efficacy in hemodialysis is considered similar to unfractionated heparin (UFH), their safety remains controversial mainly due to a risk of bioaccumulation in patients with renal impairment. The aim of this systematic review was to evaluate the safety of LMWH when compared to UFH for extracorporeal circuit (ECC) anticoagulation. METHODS: We used Pubmed, Embase, Cochrane central register of controlled trials, Trip database and NICE to retrieve relevant studies with no language restriction. We looked for controlled experimental trials comparing LMWH to UFH for ECC anticoagulation among end-stage renal disease patients undergoing chronic hemodialysis. Studies were kept if they reported at least one of the following outcomes: bleeding, lipid profile, cardiovascular events, osteoporosis or heparin-induced thrombocytopenia. Two independent reviewers conducted studies selection, quality assessment and data extraction with discrepancies solved by a third reviewer. Relative risk and 95% CI was calculated for dichotomous outcomes and mean weighted difference (MWD) with 95% CI was used to pool continuous variables. RESULTS: Seventeen studies were selected as part of the systematic. The relative risk for total bleeding was 0.76 (95% CI 0.26-2.22). The WMD calculated for total cholesterol was -28.70 mg/dl (95% CI -51.43 to -5.98), a WMD for triglycerides of -55.57 mg/dl (95% CI 94.49 to -16.66) was estimated, and finally LDL-cholesterol had a WMD of -14.88 mg/dl (95% CI -36.27 to 6.51). CONCLUSIONS: LMWH showed to be at least as safe as UFH for ECC anticoagulation in chronic hemodialysis. The limited number of studies reporting on osteoporosis and HIT does not allow any conclusion for these outcomes. Larger studies are needed to evaluate properly the safety of LMWH in chronic hemodialysis. PMID- 28592261 TI - TREM2 protects against cerebral ischemia/reperfusion injury. AB - Although post-ischemic inflammation induced by the innate immune response is considered an essential step in the progression of cerebral ischemia injury, the role of triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of ischemic stroke remains to be elucidated. Here, we found that the transcriptional and post-transcriptional levels of TREM2 were increased in cultured primary microglia after oxygen-glucose deprivation and reoxygenation and in the ischemic penumbra of the cerebral cortex after middle cerebral artery occlusion (MCAO) and reperfusion in mice. TREM2 was mainly expressed in microglia, but not in astrocytes, neurons, or oligodendrocytes in mice subjected to MCAO. Manipulating TREM2 expression levels in vitro and in vivo significantly regulated the production of pro- and anti-inflammatory mediators after ischemic stroke. TREM2 overexpression markedly suppressed the inflammatory response and neuronal apoptosis. By contrast, TREM2 gene silencing intensified the inflammatory response, increased neuronal apoptosis and infarct volume, and further exacerbated neurological dysfunction. Our study demonstrated that TREM2 protects against cerebral ischemia/reperfusion injury through the aspect of post ischemic inflammatory response and neuronal apoptosis. Pharmacological targeting of TREM2 to suppress the inflammatory response may provide a new approach for developing therapeutic strategies in the treatment of ischemic stroke and other cerebrovascular diseases. PMID- 28592260 TI - Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development. AB - Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients' prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies. PMID- 28592262 TI - Port site recurrence after laparoscopic radical nephrectomy: a case report. AB - BACKGROUND: Due to the recent development of laparoscopic devices, laparoscopic radical nephrectomy is the standard procedure for localized renal cell carcinoma. However, some studies have reported postoperative port site metastasis in several cancers. CASE PRESENTATION: A 68-year-old Asian-Japanese man was referred to our hospital for a further examination of his right renal tumor in 2009. Due to a clinical suspicion of renal cell carcinoma, laparoscopic nephrectomy was performed. The histopathological diagnosis was clear cell renal cell carcinoma. Follow-up computed tomography revealed a mass between the internal oblique muscle of his abdomen and the transverse muscle of his abdomen in 2014. The tumor size gradually increased, and positron emission tomography-computed tomography revealed the accumulation of fludeoxyglucose in that tumor with maximum standardized uptake value of 2.7. Based on these findings, port site recurrence was suspected, and tumor resection was performed in 2017. The pathological diagnosis was metastatic clear cell renal cell carcinoma. CONCLUSIONS: Here we report a rare case of port site metastasis that was successfully treated 7 years after laparoscopic nephrectomy. PMID- 28592263 TI - Radiologic findings as a determinant and no effect of macrolide resistance on clinical course of Mycoplasma pneumoniae pneumonia. AB - BACKGROUND: With the emergence of macrolide resistance, concerns about the efficacy of macrolides for the treatment of Mycoplasma pneumoniae (MP) pneumonia in children have been raised. This study aimed to determine the effect of macrolide resistance on the outcome of children who were hospitalized with MP pneumonia. METHODS: Between 2010 and 2015, we performed culture of MP from nasopharyngeal samples obtained from children who were hospitalized with pneumonia at five hospitals in Korea. Macrolide resistance was determined by the analysis of 23S rRNA gene transition and the minimal inhibitory concentrations of four macrolides. Medical records were reviewed to analyze the clinical response to treatment with macrolides. RESULTS: MP was detected in 116 (4.8%) of the 2436 children with pneumonia. MP pneumonia was prevalent in 2011 and 2015. Of the 116 patients with MP pneumonia, 82 (70.7%) were macrolide-resistant. There were no differences in the age distribution, total duration of fever, and chest x-ray patterns between the macrolide-susceptible and macrolide-resistant groups. After macrolide initiation, mean days to defervescence were longer in the macrolide resistant group than in macrolide-susceptible group (5.7 days vs. 4.1 days, P = 0.021). However, logistic regression analysis revealed that the presence of extrapulmonary signs (P = 0.039), homogeneous lobar consolidation (P = 0.004), or parapneumonic effusion (P < 0.001) were associated with fever duration of >=7 days after the initiation of macrolides, regardless of macrolide resistance. CONCLUSIONS: This study demonstrated that fever duration in MP pneumonia was determined by the radiologic findings of chest x-ray, not by the presence of macrolide resistance. The results highlight the need for future studies to assess therapeutic benefit from macrolides in the treatment of children with MP pneumonia. PMID- 28592264 TI - Adaptation to new nutritional environments: larval performance, foraging decisions, and adult oviposition choices in Drosophila suzukii. AB - BACKGROUND: Understanding how species adapt to new niches is a central issue in evolutionary ecology. Nutrition is vital for the survival of all organisms and impacts species fitness and distribution. While most Drosophila species exploit rotting plant parts, some species have diversified to use ripe fruit, allowing earlier colonization. The decomposition of plant material is facilitated by yeast colonization and proliferation. These yeasts serve as the main protein source for Drosophila larvae. This dynamic rotting process entails changes in the nutritional composition of the food and other properties, and animals feeding on material at different stages of decay are expected to have behavioural and nutritional adaptations. RESULTS: We compared larval performance, feeding behaviour and adult oviposition site choice between the ripe fruit colonizer and invasive pest Drosophila suzukii, and a closely-related rotting fruit colonizer, Drosophila biarmipes. Through the manipulation of protein:carbohydrate ratios in artificial diets, we found that D. suzukii larvae perform better at lower protein concentrations and consume less protein rich diets relative to D. biarmipes. For adult oviposition, these species differed in preference for substrate hardness, but not for the substrate nutritional composition. CONCLUSIONS: Our findings highlight that rather than being an exclusive specialist on ripe fruit, D. suzukii's adaptation to use ripening fruit allow it to colonize a wider range of food substrates than D. biarmipes, which is limited to soft foods with higher protein concentrations. Our results underscore the importance of nutritional performance and feeding behaviours in the colonization of new food niches. PMID- 28592265 TI - Building freeways: piloting communication skills in additional languages to health service personnel in Cape Town, South Africa. AB - BACKGROUND: This study reflects on the development and teaching of communication skills courses in additional national languages to health care staff within two primary health care facilities in Cape Town, South Africa. These courses were aimed at addressing the language disparities that recent research has identified globally between patients and health care staff. Communication skills courses were offered to staff at two Metropolitan District Health Services clinics to strengthen patient access to health care services. This study reflects on the communicative proficiency in the additional languages that were offered to health care staff. METHODS: A mixed-method approach was utilised during this case study with quantitative data-gathering through surveys and qualitative analysis of assessment results. The language profiles of the respective communities were assessed through data obtained from the South African National census, while staff language profiles were obtained at the health care centres. Quantitative measuring, by means of a patient survey at the centres, occurred on a randomly chosen day to ascertain the language profile of the patient population. Participating staff performed assessments at different phases of the training courses to determine their skill levels by the end of the course. RESULTS: The performances of the participating staff during the Xhosa and Afrikaans language courses were assessed, and the development of the staff communicative competencies was measured. Health care staff learning the additional languages could develop Basic or Intermediate Xhosa and Afrikaans that enables communication with patients. CONCLUSIONS: In multilingual countries such as South Africa, language has been recognised as a health care barrier preventing patients from receiving quality care. Equipping health care staff with communication skills in the additional languages, represents an attempt to bridge a vital barrier in the South African health care system. The study proves that offering communication skills courses in additional languages, begins to equip health care staff to be multilingual, that allows patients to communicate about their illnesses within their mother tongues. PMID- 28592266 TI - Urgent needs in fostering neglected tropical diseases (NTDs) laboratory capacity in WHO Western Pacific Region: results from the external quality assessment on NTDs diagnosis in 2012-2015. AB - BACKGROUND: Neglected tropical diseases (NTDs) are a heterogeneous group of mainly chronic, debilitating and often stigmatizing diseases that largely affects low-income and politically marginalized populations, causing a large burden of public health, social and economies in the NTDs endemic countries. NTDs are caused by infections with a range of pathogen, including bacteria, parasites, protozoa and viruses. The accurate diagnosis of NTDs is important for reducing morbidity, preventing mortality and for monitoring of control programs. External Quality Assessment (EQA), a component of laboratory quality assurance, aims to assess the performance of participating laboratories in detecting parasitic infections. The aim of this paper is to report the findings and put forward the recommendations on capacity build from the EQA results of participating NTDs laboratories in selected countries in the WHO Western Pacific Region from 2012 to 2015. METHODS: Reference or public health laboratories at national level working on NTDs in 6 countries participated in EQAs organized by the National Institute of Parasitic Diseases (NIPD) of Chinese Center for Disease Control and Prevention (CDC) based in Shanghai, China. Two representatives of each participating laboratory were invited to NIPD to detect NTDs' parasitic infections using the same prepared samples for serological tests (IHA and ELISA) and helminth eggs' morphological tests (Direct smear and Kato-Katz). All of the results were scored and analyzed by using SPSS statistics 19.0 software. RESULTS: The percentage of participants who had EQA score >= 60 during 2012-2015 for direct smear test were 80.00% (2012), 71.43% (2013), 100% (2014) and 75.00% (2015), whereas for Kato Katz test were 80.00% (2012), 57.14% (2013), 100% (2014) and 37.50% (2015), respectively. The detection rate of helminth eggs varied in different species, with Ascaris lumbricoides being the highest at 94.07% in average. All laboratories did very well with ELISA tests as shown by the high scores in all four years except Lab A in the first and last EQA. For the positive or negative judgments of serum samples, the total coincidence rates of ELISA between 2012 and 2015 were 90.00%, 99.29%, 94.29% and 98.75%, respectively. While the total coincidence rates of IHA were respectively 100%, 95.00%, 90.00% and 97.50%. However, detecting low levels of serum antibody remained problematic for IHA when the titres of samples were taken into consideration. CONCLUSION: This study demonstrate that EQA scheme have been beneficial to the participating laboratories. The EQA programme identifies certain deficiencies which were needed to overcome and improved the laboratories' performance in helminthiasis diagnosis. However, further optimization of accuracy and uniformity in NTDs diagnosis remains a big challenge. PMID- 28592267 TI - A vaccine with Abeta oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer's disease. AB - BACKGROUND: beta-Amyloid peptide (Abeta) oligomers are initial factors used to induce Alzheimer's disease (AD) development, and Abeta monomers have normal physiological function. The antibodies or vaccines against Abeta monomers have serious problems, such as side effects and low curative effects. Therefore, it is essential to specifically target Abeta oligomers rather than monomers for the treatment of AD. METHODS: The mimotopes of Abeta oligomers were obtained by panning the phage-displayed random peptide libraries using oligomer-specific antibodies as targets and expressed on the surface of EBY100 Saccharomyces cerevisiae to generate yeast cell base vaccines. One vaccine (AOE1) induced antibodies specifically against Abeta oligomers and was selected for further study. The APP/PS1 mice were subcutaneously immunized with AOE1 eight times. The levels and characteristics of antibodies induced by AOE1 were determined by enzyme-linked immunosorbent assay. The effect of AOE1 on the cognitive deficits of AD mice was tested by novel object recognition (NOR) and Y-maze. Dot blot analysis, Western blot analysis, and immunohistochemistry were applied to measure the effects of AOE1 on Abeta pathologies, neuroinflammation, and microhemorrhages in the brains of AD mice. RESULTS: Eight mimotope candidates of Abeta oligomers were selected and expressed on EBY100 S. cerevisiae. Only AOE1 vaccine containing mimotope L2 induced antibodies that specifically recognized Abeta42 oligomers rather than monomers. AOE1 immunization significantly increased the AD mice's exploration times for the novel object in the NOR test and the choices for new arms in the Y-maze test, and it reduced levels of Abeta oligomers and glial activation in the AD mouse brains. No activation of Abeta-specific T cells and microhemorrhages was observed in their brains following AOE1 vaccination. CONCLUSIONS: AOE1 is the first vaccine applying the oligomer-specific mimotope as an immunogen, which could induce antibodies with high specificity to Abeta oligomers. AOE1 immunization attenuated Abeta pathologies and cognitive deficits in AD mice, decreased the overactivation of glial cells, and did not induce microhemorrhage in the brains of AD mice. These findings suggest that AOE1 may be a safer and more effective vaccine for AD treatment. PMID- 28592268 TI - Prevalence, perceptions and predictors of alcohol consumption and abstinence among South Australian school students: a cross-sectional analysis. AB - BACKGROUND: Alcohol consumption by young people (particularly early initiation) is a predictor for poorer health in later life. In addition, evidence now clearly shows a causal link between alcohol and cancer. This study investigated prevalence, predictors of alcohol consumption among adolescents including perceptions of the link between alcohol and cancer, and the role of parents and peers. METHODS: A sample of Australian school students aged 12-17 years participated in a survey (n = 2885). Logistic regression analysis was undertaken to determine predictors. RESULTS: Alcohol use increased with age and by 16, most had tried alcohol with 33.1% of students aged 12-17 reporting that they drank at least occasionally (95% CI = 31.0-35.2). Awareness of the link between alcohol and cancer was low (28.5%). Smoking status and friends' approval were predictive of drinking, whereas parental disapproval was protective. Those aged 14-17 who did not think the link between alcohol and cancer was important were more likely to drink, as were those living in areas of least disadvantage. The only factors that predicted recent drinking were smoking and the perception that alcohol was easy to purchase. CONCLUSIONS: An education campaign highlighting the link between alcohol and cancer may have positive flow-on effects for young people, and schools should incorporate this messaging into any alcohol education programs. Consideration should be given to factors that serve to regulate under aged accessibility of alcohol. PMID- 28592269 TI - The health and healthcare impact of providing insurance coverage to uninsured children: A prospective observational study. AB - BACKGROUND: Of the 4.8 million uninsured children in America, 62-72% are eligible for but not enrolled in Medicaid or CHIP. Not enough is known, however, about the impact of health insurance on outcomes and costs for previously uninsured children, which has never been examined prospectively. METHODS: This prospective observational study of uninsured Medicaid/CHIP-eligible minority children compared children obtaining coverage vs. those remaining uninsured. Subjects were recruited at 97 community sites, and 11 outcomes monitored monthly for 1 year. RESULTS: In this sample of 237 children, those obtaining coverage were significantly (P < .05) less likely than the uninsured to have suboptimal health (27% vs. 46%); no PCP (7% vs. 40%); experienced never/sometimes getting immediate care from the PCP (7% vs. 40%); no usual source of preventive (1% vs. 20%) or sick (3% vs. 12%) care; and unmet medical (13% vs. 48%), preventive (6% vs. 50%), and dental (18% vs. 62%) care needs. The uninsured had higher out-of-pocket doctor-visit costs (mean = $70 vs. $29), and proportions of parents not recommending the child's healthcare provider to friends (24% vs. 8%) and reporting the child's health caused family financial problems (29% vs. 5%), and lower well-child-care-visit quality ratings. In bivariate analyses, older age, birth outside of the US, and lacking health insurance for >6 months at baseline were associated with remaining uninsured for the entire year. In multivariable analysis, children who had been uninsured for >6 months at baseline (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.4-10.3) and African-American children (OR, 2.8; 95% CI, 1.1-7.3) had significantly higher odds of remaining uninsured for the entire year. Insurance saved $2886/insured child/year, with mean healthcare costs = $5155/uninsured vs. $2269/insured child (P = .04). CONCLUSIONS: Providing health insurance to Medicaid/CHIP-eligible uninsured children improves health, healthcare access and quality, and parental satisfaction; reduces unmet needs and out-of-pocket costs; and saves $2886/insured child/year. African-American children and those who have been uninsured for >6 months are at greatest risk for remaining uninsured. Extrapolation of the savings realized by insuring uninsured, Medicaid/CHIP eligible children suggests that America potentially could save $8.7-$10.1 billion annually by providing health insurance to all Medicaid/CHIP-eligible uninsured children. PMID- 28592270 TI - Waist-to-height ratio and its associations with body mass index in a sample of Tuscan children in primary school. AB - BACKGROUND: Visceral obesity in children increases the risk of developing cardiovascular diseases. To evaluate overweight children, in addition to Body Mass Index (BMI), waist-to-height ratio (WHtR) can be used to predict cardiometabolic risk. The goal of this study is to describe WHtR in a sample of Tuscan children. METHODS: A sample of children living in the province of Pistoia, Tuscany, was measured for the following anthropometric parameters: weight, height, and waist circumference. BMI and WHtR were calculated. For the latter indicator, a threshold of 0.5 was considered as a cardiovascular risk predictor. The subjects were classified into underweight, normal weight, overweight, and obese using Cole's cut-offs. RESULTS: The number of children enrolled were 1575 (821 males; 754 females), aged 6-11 years. Of them, 64.3% were normal weight, 4.9% underweight, 22.3% overweight, and 8.5% obese. Moreover, 12.8% had a WHtR >=0.5 (85.7% males; 88.7% females). The average WHtR value was 0.45 +/- 0.045, and was significantly different as per gender (F = 0.45 vs. M = 0.46). WHtR was significantly correlated with BMI (r = 0.766). CONCLUSION: The average WHtR value was in line with previous studies conducted among children of similar age groups. Large-scale perspective studies are needed to validate the Italian WHtR cut-offs for children. PMID- 28592271 TI - Simulating therapeutic drug monitoring results for dose individualisation to maintain investigator blinding in a randomised controlled trial. AB - BACKGROUND: Therapeutic drug monitoring (TDM) is essential practice when dosing drugs with a narrow therapeutic index in order to achieve a plasma drug concentration within a narrow target range above the efficacy concentration but below the toxicity concentration. However, TDM with dose individualisation is challenging during a double-blind clinical trial with laboratory staff and investigators blinded to treatment arm allocation. METHODS: Drug concentrations were simulated for participants in the placebo arm by an unblinded independent statistician, utilising the measured values from the treatment arm participants. Simulated and actual concentrations were re-blinded and passed on to a dose adjusting investigator, who made dose adjustment recommendations but was not directly responsible for clinical care of participants. RESULTS: A total of 257 sham lithium plasma concentrations were simulated utilising 242 true lithium plasma concentrations in real time as the trial progressed. The simulated values had a median (interquartile range) of 0.59 (0.46, 0.72) compared to 0.53 (0.39, 0.72) in the treatment arm. Blinding of the laboratory staff and dose-adjusting investigator was maintained successfully. CONCLUSIONS: We succeeded in simulating sham lithium plasma concentrations while maintaining blinding. Our simulated values have a smaller range than the observed data, which can be explained by the challenges with respect to drug adherence and dose timing that were experienced. TRIAL REGISTRATION: Pan African Clinical Trials Registry, PACTR201310000635418 . Registered on 30 August 2013. PMID- 28592273 TI - Research on subgroups is not research on equity attributes: Evidence from an overview of systematic reviews on vaccination. AB - BACKGROUND: Equity remains a priority in the international health development agenda. However, major inequities in vaccination coverage jeopardise the achievement of the Sustainable Development Goals. We aim at comprehensively describing how research has addressed equity issues related to vaccination. METHODS: We carried out an overview of systematic reviews (SRs) that explicitly explored the effects of interventions to improve vaccination in any context; for any vaccine and, in any language. We followed standard research synthesis methods to systematically search for SR, assess them for inclusion and extracting relevant data, particularly on vaccination related outcomes. To gather evidence on equity issues addressed in the SR, we used the PROGRESS-plus framework. FINDINGS: Our search obtained 2,003 hits which resulted in 54 included SRs, published between 1994 and 2014. The quality of SRs was generally poor, with less than half complying with most of the quality criteria. Reported vaccines included, by order of frequency, influenza and Expanded Programme on Immunisation vaccines. The types of interventions more frequently reported were related to vaccination delivery strategies, financial support and information, education and communication. Most of the SRs suggested effects favouring intervention groups as opposed to comparison groups. The most frequently reported equity attribute was 'place of residence' and the least reported equity attributes were sexual orientation and religion. Very few estimates of effects actually measured differences or changes between groups having those attributes and all of them referred to the place of residence. No data was found about reducing equity gaps for vulnerable groups or minorities, or attributes such as sexual orientation, education or specific religious groups. CONCLUSIONS: Although research on vulnerable populations as a subgroup is abundant, it fails to report on the interventions that will actually reduce inequities and consider how redistribution of health care resources could shrink the gap between the privileged and most vulnerable groups including minorities. Research, if aiming at being responsive to global health policy trends, needs to report not only on specific attributes but also on how a better redistribution of health care resources could contribute to alleviating the unjust situation of the most vulnerable populations. PMID- 28592274 TI - The magnitude and correlates of Parvovirus B19 infection among pregnant women attending antenatal clinics in Mwanza, Tanzania. AB - BACKGROUND: Human parvovirus B19 (B19) infection has been associated with congenital infection which may result into a number of the adverse pregnancy outcomes. The epidemiology and the magnitude of B19 infections among pregnant women have been poorly studied in developing countries. This study was done to establish preliminary information about the magnitude of B19 among pregnant women attending antenatal clinics in the city of Mwanza, Tanzania. METHODS: A cross sectional study was conducted between December 2014 and June 2015 among 258 pregnant women attending two antenatal clinics representing rural and urban areas in the city of Mwanza. Socio-demographic data were collected using structured data collection tool. Specific B19 IgM and IgG antibodies were determined using indirect enzyme linked immunosorbent assay kits (DRG Instruments GmbH, Germany). Data were analyzed using STATA version 11 software. RESULTS: The median age of study participants was 21 IQR (19-25) years. Of 253 pregnant women; 116(44.96%), 109(42.25%) and 33(12.79%) were in the first, second and third trimester respectively. The majority 168(66.4%) of women were from urban areas. Of 253 pregnant women, the overall prevalence of IgM was 83(32.8%) while that of IgG was 142(55.0%) among 258 women tested. A total of 50(19.4%) women were positive for both IgG and IgM indicating true IgM positive. History of baby with low birth weight (OR: 10, 95% CI: 1.82-58.05, P = 0.01) was independent predictor of B19 IgG seropositivity and being at the third trimester was protective (OR: 0.38, 95% CI: 0.16-0.92, P = 0.03). The IgG titers were found to decrease significantly as gestational age increases (Spearman's rho = -0.2939, p = 0.0004) CONCLUSION: More than a half of pregnant women in Mwanza city are B19 IgG sero-positive with about one third of these being B19 IgM seropositive. Further studies to determine the impact of B19 infections among pregnant women and their newborns are recommended in developing countries. PMID- 28592272 TI - Betaine promotes cell differentiation of human osteoblasts in primary culture. AB - BACKGROUND: Betaine (BET), a component of many foods, is an essential osmolyte and a source of methyl groups; it also shows an antioxidant activity. Moreover, BET stimulates muscle differentiation via insulin like growth factor I (IGF-I). The processes of myogenesis and osteogenesis involve common mechanisms with skeletal muscle cells and osteoblasts sharing the same precursor. Therefore, we have hypothesized that BET might be effective on osteoblast cell differentiation. METHODS: The effect of BET was tested in human osteoblasts (hObs) derived from trabecular bone samples obtained from waste material of orthopedic surgery. Cells were treated with 10 mM BET at 5, 15, 60 min and 3, 6 and 24 h. The possible effects of BET on hObs differentiation were evaluated by real time PCR, western blot and immunofluorescence analysis. Calcium imaging was used to monitor intracellular calcium changes. RESULTS: Real time PCR results showed that BET stimulated significantly the expression of RUNX2, osterix, bone sialoprotein and osteopontin. Western blot and immunofluorescence confirmed BET stimulation of osteopontin protein synthesis. BET stimulated ERK signaling, key pathway involved in osteoblastogenesis and calcium signaling. BET induced a rise of intracellular calcium by means of the calcium ions influx from the extracellular milieu through the L-type calcium channels and CaMKII signaling activation. A significant rise in IGF-I mRNA at 3 and 6 h and a significant increase of IGF-I protein at 6 and 24 h after BET stimulus was detected. Furthermore, BET was able to increase significantly both SOD2 gene expression and protein content. CONCLUSIONS: Our study showed that three signaling pathways, i.e. cytosolic calcium influx, ERK activation and IGF-I production, are enhanced by BET in human osteoblasts. These pathways could have synergistic effects on osteogenic gene expression and protein synthesis, thus potentially leading to enhanced bone formation. Taken together, these results suggest that BET could be a promising nutraceutical therapeutic agent in the strategy to counteract the concomitant and interacting impact of sarcopenia and osteoporosis, i.e. the major determinants of senile frailty and related mortality. PMID- 28592275 TI - NCBO Ontology Recommender 2.0: an enhanced approach for biomedical ontology recommendation. AB - BACKGROUND: Ontologies and controlled terminologies have become increasingly important in biomedical research. Researchers use ontologies to annotate their data with ontology terms, enabling better data integration and interoperability across disparate datasets. However, the number, variety and complexity of current biomedical ontologies make it cumbersome for researchers to determine which ones to reuse for their specific needs. To overcome this problem, in 2010 the National Center for Biomedical Ontology (NCBO) released the Ontology Recommender, which is a service that receives a biomedical text corpus or a list of keywords and suggests ontologies appropriate for referencing the indicated terms. METHODS: We developed a new version of the NCBO Ontology Recommender. Called Ontology Recommender 2.0, it uses a novel recommendation approach that evaluates the relevance of an ontology to biomedical text data according to four different criteria: (1) the extent to which the ontology covers the input data; (2) the acceptance of the ontology in the biomedical community; (3) the level of detail of the ontology classes that cover the input data; and (4) the specialization of the ontology to the domain of the input data. RESULTS: Our evaluation shows that the enhanced recommender provides higher quality suggestions than the original approach, providing better coverage of the input data, more detailed information about their concepts, increased specialization for the domain of the input data, and greater acceptance and use in the community. In addition, it provides users with more explanatory information, along with suggestions of not only individual ontologies but also groups of ontologies to use together. It also can be customized to fit the needs of different ontology recommendation scenarios. CONCLUSIONS: Ontology Recommender 2.0 suggests relevant ontologies for annotating biomedical text data. It combines the strengths of its predecessor with a range of adjustments and new features that improve its reliability and usefulness. Ontology Recommender 2.0 recommends over 500 biomedical ontologies from the NCBO BioPortal platform, where it is openly available (both via the user interface at http://bioportal.bioontology.org/recommender , and via a Web service API). PMID- 28592277 TI - Perceived barriers to effective implementation of public reporting of hospital performance data in Australia: a qualitative study. AB - BACKGROUND: Public reporting of government funded (public) hospital performance data was mandated in Australia in 2011. Studies suggest some benefit associated with such public reporting, but also considerable scope to improve reporting systems. METHODS: In 2015, a purposive sample of 41 expert informants were interviewed, representing consumer, provider and purchasers perspectives across Australia's public and private health sectors, to ascertain expert opinion on the utility and impact of public reporting of health service performance. Qualitative data was thematically analysed with a focus on reporting perceived strengths and barriers to public reporting of hospital performance data (PR). RESULTS: Many more weaknesses and barriers to PR were identified than strengths. Barriers were: conceptual (unclear objective, audience and reporting framework); systems-level (including lack of consumer choice, lack of consumer and clinician involvement, jurisdictional barriers, lack of mandate for private sector reporting); technical and resource related (including data complexity, lack of data relevance consistency, rigour); and socio-cultural (including provider resistance to public reporting, poor consumer health literacy, lack of consumer empowerment). CONCLUSIONS: Perceptions of the Australian experience of PR highlight important issues in its implementation that can provide lessons for Australia and elsewhere. A considerable weakness of PR in Australia is that the public are often not considered its major audience, resulting in information ineffectually framed to meet the objective of PR informing consumer decision-making about treatment options. Greater alignment is needed between the primary objective of PR, its audience and audience needs; more than one system of PR might be necessary to meet different audience needs and objectives. Further research is required to assess objectively the potency of the barriers to PR suggested by our panel of informants. PMID- 28592276 TI - Different strategies for mechanical VENTilation during CardioPulmonary Bypass (CPBVENT 2014): study protocol for a randomized controlled trial. AB - BACKGROUND: There is no consensus on which lung-protective strategies should be used in cardiac surgery patients. Sparse and small randomized clinical and animal trials suggest that maintaining mechanical ventilation during cardiopulmonary bypass is protective on the lungs. Unfortunately, such evidence is weak as it comes from surrogate and minor clinical endpoints mainly limited to elective coronary surgery. According to the available data in the academic literature, an unquestionable standardized strategy of lung protection during cardiopulmonary bypass cannot be recommended. The purpose of the CPBVENT study is to investigate the effectiveness of different strategies of mechanical ventilation during cardiopulmonary bypass on postoperative pulmonary function and complications. METHODS/DESIGN: The CPBVENT study is a single-blind, multicenter, randomized controlled trial. We are going to enroll 870 patients undergoing elective cardiac surgery with planned use of cardiopulmonary bypass. Patients will be randomized into three groups: (1) no mechanical ventilation during cardiopulmonary bypass, (2) continuous positive airway pressure of 5 cmH2O during cardiopulmonary bypass, (3) respiratory rate of 5 acts/min with a tidal volume of 2-3 ml/Kg of ideal body weight and positive end-expiratory pressure of 3-5 cmH2O during cardiopulmonary bypass. The primary endpoint will be the incidence of a PaO2/FiO2 ratio <200 until the time of discharge from the intensive care unit. The secondary endpoints will be the incidence of postoperative pulmonary complications and 30-day mortality. Patients will be followed-up for 12 months after the date of randomization. DISCUSSION: The CPBVENT trial will establish whether, and how, different ventilator strategies during cardiopulmonary bypass will have an impact on postoperative pulmonary complications and outcomes of patients undergoing cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02090205 . Registered on 8 March 2014. PMID- 28592278 TI - Effects of oil quality and antioxidant supplementation on sow performance, milk composition and oxidative status in serum and placenta. AB - BACKGROUND: The aim of this study was to determine the effects of oil quality and antioxidant (AOX) supplementation on sow performance, milk composition and oxidative status. METHODS: A total of 80 PIC (PIC breeding, 3 ~ 5 parities) sows with similar body condition were allocated to four groups (n = 20), receiving diets including fresh corn oil, oxidized corn oil, fresh corn oil plus AOX and oxidized corn oil plus AOX, respectively, from d 85 of gestation to d 21 of lactation. AOX was provided at 200 mg/kg diet and mixed with corn oil prior to dietary formulation. RESULTS: The results showed that sows fed oxidized corn oil had significantly lower feed intake (P < 0.05) during lactation period. Feeding oxidized corn oil markedly decreased (P < 0.05) the contents of protein and fat in colostrums and milk, but the addition of AOX in oxidized corn oil prevented the decrease on protein content of colostrums. Moreover, sows fed oxidized corn oil had significantly lower serum activities of total SOD and Mn-SOD across lactation (P < 0.05). In contrast, addition of AOX to oxidized corn oil tended to inhibit the production of MDA (P = 0.08) in sows across lactation relative to fresh oil. Intriguingly, the placental oxidative status was affected by oil quality and AOX supplementation, as indicated by the markedly increased placental gene expression of GPX and SOD (P < 0.05) in sows fed oxidized corn oil but normalized by supplementation of AOX. CONCLUSION: In conclusion, feeding oxidized corn oil did not markedly affect reproductive performance in addition to decreasing feed intake during lactation. Milk composition and systemic oxidative status were deteriorated in sows fed oxidized corn oil and partially improved by AOX supplementation. Moreover, placental antioxidant system of sows may have an adaptive response to oxidative stress, but normalized by AOX. PMID- 28592279 TI - The effect of post-traumatic-stress-disorder on intra-operative analgesia in a veteran population during cataract procedures carried out using retrobulbar or topical anesthesia: a retrospective study. AB - BACKGROUND: A growing proportion of veterans treated at the Veterans Health Administration (VA) have a history of post-traumatic-stress-disorder (PTSD), and there exists a higher rate of PTSD amongst veterans than the general population. The purpose of this study is to determine the correlation between PTSD and intra operative analgesia, intra-operative time, and anesthesia type for cataract surgery in a veteran population. Secondary objectives are to determine if patient age, and first or second eye surgery affect intra-operative pain control or are correlated with type of anesthesia modality. METHODS: A retrospective study of 330 cataract surgeries performed by resident physicians between January and September 2012 at the Veterans Affairs Medical Center Tennessee Valley Healthcare System, Nashville and Murfreesboro Campuses was completed. Three hundred and thirty veteran patients were selected if their cataract surgery was performed between January and September 2012. Combined cases were excluded. The primary outcome evaluated was intra-operative analgesia. Secondary outcomes included history of post-traumatic-stress-disorder, anesthesia type, first or second eye, pain control, intra-operative heart rate and blood pressure, age, and case complexity. Data was analyzed using an unpaired two-sample Welch's t-test assuming unequal variance and Z test of comparison of proportions. RESULTS: Patients with post-traumatic-stress-disorder reported higher pain scores, had longer operative times, and were more likely to have received a retrobulbar block. Operative time was not associated with an increased pain score, irrespective of anesthesia type, when controlled for PTSD. Complex cases had longer operative times, more sedation, and higher pain scores. P < 0.05 was used consistently. CONCLUSIONS: Post-traumatic stress disorder and anxiety are more prevalent in the veteran population. Our data suggests that a history of post traumatic-stress-disorder was correlated with higher pain scores, longer operative times, and with having received a retrobulbar block. Patients without a history of PTSD were more likely to have received topical anesthesia with or without sedation. The veteran population requires more sedation to allay anxiety and perceptions of discomfort, which may account for longer surgical times. The veteran population is a special population and it is important to investigate how PTSD in the veteran population affects intra-operative analgesia. PMID- 28592280 TI - White blood cell count predicts the odds of kidney function decline in a Chinese community-based population. AB - BACKGROUND: Inflammatory processes are very important in the development of kidney disease. Nevertheless, the association between white blood cell (WBC) count and the risk of renal dysfunction has not been well-established, especially in subjects without chronic kidney disease (CKD). Our study investigated the association between WBC count and kidney function decline in a Chinese community based population with baseline estimated glomerular filtration rate (eGFR) >=60 mL/min/1.73 m2. METHODS: A total of 3768 subjects who were enrolled in an atherosclerosis cohort in Beijing were included in this study. EGFRs were calculated at baseline and follow-up using the CKD-EPI formula. The outcomes of this study were renal function decline (RFD) (a drop in eGFR stage along with a decline in eGFR of 25% or exceeding 5 mL/min/1.73 m2/year), rapid eGFR decline (an annual decrease in eGFR exceeding 3 mL/min/1.73 m2), and incident CKD (eGFR <60 min/1.73 m2 at follow-up). Multivariate logistic regression models were used to evaluate the associations between WBC count and each outcome. RESULTS: On average, the subjects were 56.6 +/- 8.5 years old, and 35.9% were male. Of the participants, 48.6% had hypertension and 17.4% had diabetes. The mean (SD) WBC count at baseline was 6.1 +/- 1.5 * 109/L. The mean (SD) eGFR at baseline was 101.1 +/- 10.6 mL/min/1.73 m2. After 2.3 years follow-up, the incidence rates of RFD, rapid eGFR decline and new CKD were 7.7, 20.9, and 0.8%, respectively. WBC count was significantly related to RFD, rapid eGFR decline and new CKD in the univariate analyses. Even after adjustment for demographic variables, comorbidities, medications and baseline eGFR, these associations remained. Moreover, similar trends in RFD were observed in nearly all subgroups stratified by each confounding variable. The increase in the odds of RFD associated with each 109/L increase in WBC count was significantly greater in subjects not undergoing treatment with lipid-lowering drugs than those not undergoing this treatment (P-interaction: 0.05). CONCLUSIONS: In conclusion, elevated WBC count served as a predictor of the odds of kidney function decline in this population, which supports the hypothesis that systemic inflammation may serve as a risk factor for CKD development. PMID- 28592281 TI - Influence of Plantago ovata husk (dietary fiber) on the bioavailability and other pharmacokinetic parameters of metformin in diabetic rabbits. AB - BACKGROUND: Metformin is an oral hypoglycemic agent frequently used in patients with type 2 diabetes. In this study, we have investigated the influence of the dietary fiber Plantago ovata husk on the pharmacokinetics of this drug when included in the diet, as well as when administered at the same time as metformin. METHODS: Six groups of 6 rabbits were used. Groups 1 to 3 were fed with standard chow and groups 4 to 6 with chow supplemented with fiber (3.5 mg/kg/day). Groups 1 and 4 received metformin intravenously (30 mg/kg). Groups 2 and 5 received metfomin orally (30 mg/kg), and number 3 and 6 were treated orally with metformin (30 mg/kg) and fiber (300 mg/kg). RESULTS: The changes caused by the inclusion of fiber in the feeding were more important in groups that received oral metformin. In this way, metformin oral bioavailability showed an increase of 34.42% when rabbits were fed with supplemented chow. CONCLUSIONS: Plantago ovata husk increased the amount of absorbed metformin when included in the diet (significant increase in AUC), and delayed its absorption when administered at the same time (significant increase in tmax). PMID- 28592283 TI - Health systems research in fragile and conflict affected states: a qualitative study of associated challenges. AB - BACKGROUND: High quality health systems research (HSR) in fragile and conflict affected states (FCAS) is essential to guiding the policies and programmes that will improve access to health services and, ultimately, health outcomes. Yet, conducting HSR in FCAS is challenging. An understanding of these challenges is essential to tackling them and to supporting research conducted in these complex environments. Led by the Thematic Working Group on Health Systems in FCAS, the primary aim of this study was to develop a research agenda on HSR in FCAS. The secondary aim was to identify the challenges associated with conducting HSR in these contexts. This paper presents these challenges. METHODS: Guided by a purposely-selected steering group, this qualitative study collected respondents' perspectives through an online survey (n = 61) and a group discussion at the Third Global Symposium on HSR in September 2014 (n = 11). Respondents with knowledge and/or experience of HSR in FCAS were intentionally recruited. RESULTS: Of those ever involved in HSR in FCAS (45/61, 75%), almost all (98%) experienced challenges in conducting their research. Challenges fall under three broad thematic areas: (1) lack of appropriate support; (2) complex local research environment, including access constraints, weak local research capacity, collaboration challenges and lack of trust in the research process; and (3) limited research application, including rapidly outdated findings and lack of engagement with the research process and results. CONCLUSIONS: This study shows that those familiar with HSR in FCAS face many challenges in gaining support for and in conducting and applying high-quality research. There is a need for more sustainable support, including commitment to and long-term funding of HSR in FCAS; investment in capacity building within FCAS to meet the challenges related to implementation of research in these complex environments; relationship and trust building among stakeholders involved in HSR, particularly between local and international researchers and between researchers and participants; and innovative and flexible approaches to research design and implementation in these insecure and rapidly changing contexts. PMID- 28592284 TI - Biogenic selenium nanoparticles induce ROS-mediated necroptosis in PC-3 cancer cells through TNF activation. AB - BACKGROUND: Selenium is well documented to inhibit cancer at higher doses; however, the mechanism behind this inhibition varies widely depending on the cell type and selenium species. Previously, we have demonstrated that Bacillus licheniformis JS2 derived biogenic selenium nanoparticles (SeNPs) induce non apoptotic cell death in prostate adenocarcinoma cell line, PC-3, at a minimal concentration of 2 ug Se/ml, without causing toxicity to the primary cells. However, the mechanism behind its anticancer activity was elusive. RESULTS: Our results have shown that these SeNPs at a concentration of 2 ug Se/ml were able to induce reactive oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1. CONCLUSION: Data suggest that our biogenic SeNPs induce cell death in PC-3 cells by the ROS-mediated activation of necroptosis, independent to RIP3 and MLKL, regulated by a RIP1 kinase. PMID- 28592282 TI - The role of virtual reality in improving motor performance as revealed by EEG: a randomized clinical trial. AB - BACKGROUND: Many studies have demonstrated the usefulness of repetitive task practice by using robotic-assisted gait training (RAGT) devices, including Lokomat, for the treatment of lower limb paresis. Virtual reality (VR) has proved to be a valuable tool to improve neurorehabilitation training. The aim of our pilot randomized clinical trial was to understand the neurophysiological basis of motor function recovery induced by the association between RAGT (by using Lokomat device) and VR (an animated avatar in a 2D VR) by studying electroencephalographic (EEG) oscillations. METHODS: Twenty-four patients suffering from a first unilateral ischemic stroke in the chronic phase were randomized into two groups. One group performed 40 sessions of Lokomat with VR (RAGT + VR), whereas the other group underwent Lokomat without VR (RAGT-VR). The outcomes (clinical, kinematic, and EEG) were measured before and after the robotic intervention. RESULTS: As compared to the RAGT-VR group, all the patients of the RAGT + VR group improved in the Rivermead Mobility Index and Tinetti Performance Oriented Mobility Assessment. Moreover, they showed stronger event related spectral perturbations in the high-gamma and beta bands and larger fronto central cortical activations in the affected hemisphere. CONCLUSIONS: The robotic based rehabilitation combined with VR in patients with chronic hemiparesis induced an improvement in gait and balance. EEG data suggest that the use of VR may entrain several brain areas (probably encompassing the mirror neuron system) involved in motor planning and learning, thus leading to an enhanced motor performance. TRIAL REGISTRATION: Retrospectively registered in Clinical Trials on 21-11-2016, n. NCT02971371 . PMID- 28592285 TI - Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma. AB - BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model. RESULTS: Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1alpha, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4+Foxp3+ regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4+ Foxp3+ Tregs and enhanced the anti-tumor response of CD8+ T cells. CONCLUSIONS: These results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy. PMID- 28592286 TI - Immunological effect of local ablation combined with immunotherapy on solid malignancies. AB - Recent comprehensive investigations clarified that immune microenvironment surrounding tumor cells are deeply involved in tumor progression, metastasis, and response to treatment. Furthermore, several immunotherapeutic trials have achieved successful results, and the immunotherapeutic agents are available in clinical practice. To enhance their demonstrated efficacy, combination of immunotherapy and ablation has begun to emerge. Local ablations have considerable advantages as an alternative therapeutic option, especially its minimal invasiveness. In addition, local ablations have shown immune-regulatory effect in preclinical and clinical studies. Although the corresponding mechanisms are still unclear, the local ablations combined with immunotherapy have been suggested in the treatment of several solid malignancies. This article aims to review the published data on the immune-regulatory effects of local ablations including stereotactic body radiotherapy, cryoablation, radiofrequency ablation, and high intensity-focused ultrasound. We also discuss the value of local ablations combined with immunotherapy. Local ablations have the potential to improve future patient outcomes; however, the effectiveness and safety of local ablations combined with immunotherapy should be further investigated. PMID- 28592287 TI - Naloxone and the Inner City Youth Experience (NICYE): a community-based participatory research study examining young people's perceptions of the BC take home naloxone program. AB - BACKGROUND: Take home naloxone (THN) programs reduce mortality by training bystanders to respond to opioid overdoses. Clinical observation by the health care team at the Inner City Youth (ICY) program indicated that young adults appeared to enthusiastically participate in the THN program and developed improved relationships with staff after THN training. However, we found a dearth of literature exploring the experiences of young adults with THN programs. This study set out to address this gap and identify suggestions from the young adults for program improvement. The primary research question was "How do street involved young people experience the THN Program in Vancouver, BC?" METHODS: The study was undertaken at the ICY Program. Two peer researchers with lived experience of THN were recruited from ICY and were involved in all phases of the study. The peer researchers and a graduate student facilitated two focus groups and five individual interviews with ICY program participants using a semi structured interview guide. Audio recordings were transcribed verbatim. The cut up-and-put-in-folders approach was used to identify emerging themes. RESULTS: The themes that emerged were perceptions of risk, altruism, strengthening relationship with staff, access to training, empowerment, and confidence in ability to respond, and suggestions for youth-friendly training. These themes were then situated within the framework of the health belief model to provide additional context. Participants viewed themselves as vulnerable to overdose and spoke of the importance of expanding access to THN training. Following training, participants reported an increase in internal locus of control, an improved sense of safety among the community of people who use drugs, improved self-esteem, and strengthened relationships with ICY staff. Overall, participants found THN training engaging, which appeared to enhance participation in other ICY programming. CONCLUSIONS: Young people perceived THN training as a positive experience that improved relationships with staff. Participant recommendations for quality improvement were implemented within the provincial program. PMID- 28592288 TI - Stool frequency recording in severe acute malnutrition ('StoolSAM'); an agreement study comparing maternal recall versus direct observation using diapers. AB - BACKGROUND: Approximately 50% of the deaths of children under the age of 5 can be attributed to undernutrition, which also encompasses severe acute malnutrition (SAM). Diarrhoea is strongly associated with these deaths and is commonly diagnosed solely based on stool frequency and consistency obtained through maternal recall. This trial aims to determine whether this approach is equivalent to a 'directly observed method' in which a health care worker directly observed stool frequency using diapers in hospitalised children with complicated SAM. METHODS: This study was conducted at 'Moyo' Nutritional Rehabilitation Unit, Queen Elizabeth Central Hospital, Malawi. Participants were children aged 5-59 months admitted with SAM. We compared 2 days of stool frequency data obtained with next-day maternal-recall versus a 'gold standard' in which a health care worker observed stool frequency every 2 h using diapers. After study completion, guardians were asked their preferred method and their level of education. RESULTS: We found poor agreement between maternal recall and the 'gold standard' of directly observed diapers. The sensitivity to detect diarrhoea based on maternal recall was poor, with only 75 and 56% of diarrhoea cases identified on days 1 and 2, respectively. However, the specificity was higher with more than 80% of children correctly classified as not having diarrhoea. On day 1, the mean stool frequency difference between the two methods was -0.17 (SD; 1.68) with limits of agreement (of stool frequency) of -3.55 and 3.20 and, similarly on day 2, the mean difference was -0.2 (SD; 1.59) with limits of agreement of -3.38 and 2.98. These limits extend beyond the pre-specified 'acceptable' limits of agreement (+/-1.5 stool per day) and indicate that the 2 methods are non equivalent. The higher the stool frequency, the more discrepant the two methods were. Most primary care givers strongly preferred using diapers. CONCLUSIONS: This study shows lack of agreement between the assessment of stool frequency in SAM patients using maternal recall and direct observation of diapers. When designing studies, one should consider using diapers to determining diarrhoea incidence/prevalence in SAM patients especially when accuracy is essential. TRIAL REGISTRATION NUMBER: ISRCTN11571116 (registered 29/11/2013). PMID- 28592290 TI - DNA methylation-based chromatin compartments and ChIP-seq profiles reveal transcriptional drivers of prostate carcinogenesis. AB - BACKGROUND: Profiles of DNA methylation of many tissues relevant in human disease have been obtained from microarrays and are publicly available. These can be used to generate maps of chromatin compartmentalization, demarcating open and closed chromatin across the genome. Additionally, large sets of genome-wide transcription factor binding profiles have been made available thanks to ChIP-seq technology. METHODS: We have identified genomic regions with altered chromatin compartmentalization in prostate adenocarcinoma tissue relative to normal prostate tissue, using DNA methylation microarray data from The Cancer Genome Atlas. DNA binding profiles from the Encyclopedia of DNA Elements (ENCODE) ChIP seq studies have been systematically screened to find transcription factors with inferred DNA binding sites located in discordantly open/closed chromatin in malignant tissue (compared with non-cancer control tissue). We have combined this with tests for corresponding up-/downregulation of the transcription factors' putative target genes to obtain an integrated measure of cancer-specific regulatory activity to identify likely transcriptional drivers of prostate cancer. RESULTS: Generally, we find that the degree to which transcription factors preferentially bind regions of chromatin that become more accessible during prostate carcinogenesis is significantly associated to the level of systematic upregulation of their targets, at the level of gene expression. Our approach has yielded 11 transcription factors that show strong cancer-specific transcriptional activation of targets, including the novel candidates KAT2A and TRIM28, alongside established drivers of prostate cancer MYC, ETS1, GABP and YY1. CONCLUSIONS: This approach to integrated epigenetic and transcriptional profiling using publicly available data represents a cheap and powerful technique for identifying potential drivers of human disease. In our application to prostate adenocarcinoma data, the fact that well-known drivers are amongst the top candidates suggests that the discovery of novel candidate drivers may unlock pathways to future medicines. Data download instructions and code to reproduce this work are available at GitHub under 'edcurry/PRAD-compartments'. PMID- 28592289 TI - Weight-for-length, early weight-gain velocity and atopic dermatitis in infancy and at two years of age: a cohort study. AB - BACKGROUND: Overweight and atopic dermatitis (AD) are major health problems in most industrialised countries, but the relationship between overweight and AD in infants and young children is unclear. We investigated if weight-for-length at birth, in infancy and at two years, as well as early weight-gain velocity, are associated with the development of AD in early life. METHODS: Cohort study of infants (n = 642), all living in south-east Norway, hospitalized with acute bronchiolitis (n = 404) or recruited from the general population (n = 238), examined at mean age 5.1 months (enrolment) and at a two-year follow-up visit (n = 499; 78%) at mean age 24.6 months. Exposures were weight-for-length (g/cm) at birth, enrolment and two-year follow-up, and early weight-gain velocity (gram/month from birth to enrolment). Excessive weight-for-length was defined as weight-for-length >95th percentile of WHO child-growth standards. Data on weight for-length at the three time points were obtained for 435, 428 and 473 children. AD was diagnosed according to the Hanifin & Rajka criteria or from a history of physician-diagnosed AD. We performed multivariate analyses with weight-for-length at birth, at enrolment and at the two-year follow-up visit and with early weight gain velocity for the endpoint AD at each visit. RESULTS: In adjusted analyses, excessive weight-for-length at enrolment was associated with concurrent AD (OR 3.03; 95% CI 1.23-7.50) and with AD at two years (OR 2.40; 1.11-5.17). In infants without AD, weight-for-length at enrolment increased the risk of AD at two years, with OR being 1.02 (95% CI 1.00-1.04) per increased gram/cm. AD at two years was not associated with concurrent excessive weight-for-length, nor was AD at any time associated with weight-for-length at birth or with early weight-gain velocity. CONCLUSIONS: The results suggest that overweight in infancy may contribute to the development of AD in early life, highlighting the need for child health-care professionals to address potential overweight and atopic disease when advising infants' caregivers. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00817466 , EudraCT number, 2009-012667-34. PMID- 28592291 TI - Tightly controlled MRTF-A activity regulates epithelial differentiation during formation of mammary acini. AB - BACKGROUND: Myocardin-related transcription factors (MRTF) A and B link actin dynamics and mechanotransduction to gene expression. In mice, MRTF-A is involved in mammary gland differentiation, but its role in human mammary epithelial cells remains unclear. METHODS: Three-dimensional cultures of human mammary epithelial MCF10A cells were used to model acinar morphogenesis. Stable MRTF-A knockdown, MRTF-A/B rescue and MRTF-A/B overexpression was established to characterize the functional role during morphogenesis using confocal microscopy and expression analysis. Breast cancer patient databases were analyzed for MRTF-A expression. RESULTS: We showed that a precise temporal control of MRTFs is required for normal morphogenesis of MCF10A mammary acini. MRTF transcriptional activity, but not their protein amounts, is transiently induced during 3D acini formation. MRTF A knockdown dramatically reduces acini size and prevents lumen formation. These effects are rescued by re-expression of MRTF-A, and partially by MRTF-B. Conversely, overexpression of MRTF-A and MRTF-B increases acini size, resulting in irregular spheroids without lumen and defective apico-basal polarity. These phenotypes correlate with deregulated expression of cell cycle inhibitors p21/Waf1, p27/Kip1 and altered phosphorylation of retinoblastoma protein. In MRTF overexpressing spheroids, proliferation and apoptosis are simultaneously increased at late stages, whilst neither occurs in control acini. MRTFs interfere with anoikis of the inner cells and cause an integrin switch from alpha6 to alpha5, repression of E-cadherin and induction of mesenchymal markers vimentin, Snai2 and Zeb1. Moreover, MRTF-overexpressing spheroids are insensitive to alteration in matrix stiffness. In two breast cancer cohorts, high expression of MRTF-A and known target genes was associated with decreased patient survival. CONCLUSION: MRTF-A is required for proliferation and formation of mammary acini from luminal epithelial cells. Conversely, elevated MRTF activity results in pre malignant spheroid formation due to defective proliferation, polarity loss and epithelial-mesenchymal transition. PMID- 28592292 TI - Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study. AB - BACKGROUND: Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (I K1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3. METHODS: The ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate I K1 formulations based on experimental data of Kir2.1 channels (including WT, WT D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry. RESULTS: Amiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (deltaV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue's temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue. CONCLUSIONS: At the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients. PMID- 28592293 TI - Plasmobase: a comparative database of predicted domain architectures for Plasmodium genomes. AB - BACKGROUND: With the availability of complete genome sequences of both human and non-human Plasmodium parasites, it is now possible to use comparative genomics to look for orthology across Plasmodium species and for species specific genes. This comparative analyses could provide important clues for the development of new strategies to prevent and treat malaria in humans, however, the number of functionally annotated proteins is still low for all Plasmodium species. In the context of genomes that are hard to annotate because of sequence divergence, such as Plasmodium, domain co-occurrence becomes particularly important to trust predictions. In particular, domain architecture prediction can be used to improve the performance of existing annotation methods since homologous proteins might share their architectural context. RESULTS: Plasmobase is a unique database designed for the comparative study of Plasmodium genomes. Domain architecture reconstruction in Plasmobase relies on DAMA, the state-of-the-art method in architecture prediction, while domain annotation is realised with CLADE, a novel annotation tool based on a multi-source strategy. Plasmobase significantly increases the Pfam domain coverage of all Plasmodium genomes, it proposes new domain architectures as well as new domain families that have never been reported before for these genomes. It proposes a visualization of domain architectures and allows for an easy comparison among architectures within Plasmodium species and with other species, described in UniProt. CONCLUSIONS: Plasmobase is a valuable new resource for domain annotation in Plasmodium genomes. Its graphical presentation of protein sequences, based on domain architectures, will hopefully be of interest for comparative genomic studies. It should help to discover species-specific genes, possibly underlying important phenotypic differences between parasites, and orthologous gene families for deciphering the biology of these complex and important Apicomplexan organisms. In conclusion, Plasmobase is a flexible and rich site where any biologist can find something of his/her own interest. AVAILABILITY: Plasmobase is accessible at http://genome.lcqb.upmc.fr/plasmobase/ . PMID- 28592294 TI - Exercise in claudicants increase or decrease walking ability and the response relates to mitochondrial function. AB - BACKGROUND: Exercise of patients with intermittent claudication improves walking performance. Exercise does not usually increase blood flow, but seems to increase muscle mitochondrial enzyme activities. Although exercise is beneficial in most patients, it might be harmful in some. The mitochondrial response to exercise might therefore differ between patients. Our hypothesis was that changes in walking performance relate to changes in mitochondrial function after 8 weeks of exercise. At a subgroup level, negative responders decrease and positive responders increase mitochondrial capacity. METHODS: Two types of exercise were studied, calf raising and walking (n = 28). We wanted to see whether there were negative and positive responders, independent of type of exercise. Measurements of walking performance, peripheral hemodynamics, mitochondrial respiration and content (citrate synthase activity) were obtained on each patient before and after the intervention period. Multiple linear regression was used to test whether changes in peak walking time relate to mitochondrial function. Subgroups of negative (n = 8) and positive responders (n = 8) were defined as those that either decreased or increased peak walking time following exercise. Paired t test and analysis of covariance was used to test changes within and between subgroups. RESULTS: Changes in peak walking time were related to changes in mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.004), complex I (CI + ETF)P (p = 0.003), complex I + complex II (CI + CII + ETF)P (p = 0.037) and OXPHOS coupling efficiency (p = 0.046) in the whole group. Negative responders had more advanced peripheral arterial disease. Mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.0013), complex I (CI + ETF)P (p = 0.0005), complex I + complex II (CI + CII + ETF)P (p = 0.011) and electron transfer system capacity (CI + CII + ETF)E (p = 0.021) and OXPHOS coupling efficiency decreased in negative responders (p = 0.0007) after exercise. Positive responders increased citrate synthase activity (p = 0.010). CONCLUSIONS: Changes in walking performance seem to relate to changes in mitochondrial function after exercise. Negative responders have more advanced peripheral arterial disease and decrease, while positive responders increase mitochondrial capacity. Trial registration ClinicalTrials.gov ID: NCT023110256. PMID- 28592295 TI - Angiostrongylus vasorum infection in dogs from a cardiopulmonary dirofilariosis endemic area of Northwestern Italy: a case study and a retrospective data analysis. AB - BACKGROUND: In Italy, Angiostrongylus vasorum, an emergent parasite, is being diagnosed in dogs from areas considered free of infection so far. As clinical signs are multiple and common to other diseases, its diagnosis can be challenging. In particular, in areas where angiostrongylosis and dirofilariosis overlap, a misleading diagnosis of cardiopulmonary dirofilariosis might occur even on the basis of possible misleading outcomes from diagnostic kits. CASE PRESENTATION: Two Cavalier King Charles spaniel dogs from an Italian breeding in the Northwest were referred to a private veterinary hospital with respiratory signs. A cardiopulmonary dirofilariosis was diagnosed and the dogs treated with ivermectin, but one of them died. At necropsy, pulmonary oedema, enlargement of tracheo-bronchial lymphnodes and of cardiac right side were detected. Within the right ventricle lumen, adults of A. vasorum were found. All dogs from the same kennel were subjected to faecal examination by FLOTAC and Baermann's techniques to detect A. vasorum first stage larvae; blood analysis by Knott's for Dirofilaria immitis microfilariae, and antigenic tests for both A. vasorum (Angio DetectTM) and D.immitis (DiroCHEK(r) Heartworm, Witness(r)Dirofilaria). The surviving dog with respiratory signs resulted positive for A. vasorum both at serum antigens and larval detection. Its Witness(r) test was low positive similarly to other four dogs from the same kennel, but false positive results due to cross reactions with A. vasorum were also considered. No dogs were found infected by A. vasorum. Eventually, the investigation was deepened by browsing the pathological database of Veterinary Pathology Laboratories at Veterinary School of Milan University through 1998-2016, where 11 cases of angiostrongylosis were described. Two out of 11 dogs had a mixed infection with Crenosoma vulpis. CONCLUSION: The study demonstrates the need for accurate surveys to acquire proper epidemiological data on A. vasorum infection in Northwestern Italy and for appropriate diagnostic methods. Veterinary clinicians should be warned about the occurrence of this canine parasite and the connected risk of a misleading diagnosis, particularly in areas endemic for cardiopulmonary dirofilariosis. PMID- 28592296 TI - Pigsties near dwellings as a potential risk factor for the prevalence of Japanese encephalitis virus in adult in Shanxi, China. AB - BACKGROUND: The increasing trend of adult cases of Japanese encephalitis (JE) in China, particularly in northern China, has become an important public health issue. We conducted an epidemiological investigation in the south of Shanxi Province to examine the relationships between mosquitoes, Japanese encephalitis virus (JEV), and adult JE cases. METHODS: Mosquito specimens were collected from the courtyards of farmers' households and pig farms in Shanxi Province. Mosquitoes were pooled, homogenized, and centrifuged. Reverse transcription polymerase chain reaction (RT-PCR) was used to detect mosquito-borne arbovirus genes in homogenates. Specimens positive for these genes were inoculated into the baby hamster kidney cell line (BHK-21) to isolate virus. Minimum infection rate was calculated and phylogenetic analyses were performed. RESULTS: A total of 7 943 mosquitoes belonging to six species in four genera were collected; Culex tritaeniorhynchus accounted for 73.08% (5 805/7 943), C. pipiens pallens for 24.75% (1 966/7 943), and the remaining 3% (104/ 7943) consisted of Anopheles sinensis, Aedes vexans, Ae. dorsalis, and Armigeres subalbatus. Sixteen pools were positive for JEV based on RT-PCR using JEV pre-membrane gene nested primers. Phylogenetic analyses showed that all JEVs belonged to genotype I; two pools were positive using Getah Virus (GETV) gene primers. In addition, one JEV strain (SXYC1523) was isolated from C. pipiens pallens specimens. These results indicate that the minimum infection rate of JEV in mosquito specimens collected from the courtyards of farmers' households with pigsties was 7.39/1 000; the rate for pig farms was 2.68/1 000; and the rate for farmers' courtyards without pigsties was zero. CONCLUSIONS: The high-prevalence regions of adult JE investigated in this study are still the natural epidemic focus of JEV. Having pigsties near dwellings is a potential risk factor contributing to the prevalence of adult JE. To prevent the occurrence of local adult JE cases, a recommendation was raised that, besides continuing to implement the Expanded Program on Immunization for children, the government should urge local farmers to cease raising pigs in their own courtyards to reduce the probability of infection with JEV. PMID- 28592297 TI - Negative anti-neutrophil cytoplasm antibody at switch to maintenance therapy is associated with a reduced risk of relapse. AB - BACKGROUND: Relapse of disease is frequent in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). It is unclear whether persistent ANCA when starting maintenance therapy increases the risk of relapse. We examined the association between ANCA status and relapse in two randomised controlled trials. METHODS: ANCA-positive patients in two trials, CYCLOPS and IMPROVE, were switched from cyclophosphamide to maintenance therapy after achieving clinical remission. We classified patients as being either ANCA-positive or ANCA-negative at the time they started maintenance therapy. We compared the risk of relapse in ANCA positive and ANCA-negative patients. RESULTS: Of 252 patients included, 102 (40%) experienced at least one relapse during the follow-up period. At the time of the switch from induction to maintenance therapy, 111 were ANCA-positive, of whom 55 (50%) relapsed, compared to 141 patients who were ANCA-negative, of whom 47 (33%) relapsed. In multivariable time-to-event analysis, a reduced risk of relapse was associated with having become ANCA-negative at the time of switching to maintenance therapy (hazard ratio 0.63, 95% confidence interval 0.42-0.95; p = 0.026). In addition, initial proteinase 3 (PR3)-ANCA, younger age, lower serum creatinine, pulsed cyclophosphamide for remission induction, and mycophenolate mofetil for remission maintenance were all associated with an increased risk of relapse. CONCLUSIONS: Becoming ANCA-negative before the switch to maintenance is associated with a reduced risk of relapse. TRIAL REGISTRATION: CYCLOPS: ClinicalTrials.gov, NCT00430105 . Registered retrospectively on 31 January 2007. IMPROVE: ClinicalTrials.gov, NCT00307645 . Registered retrospectively on 27 March 2006. PMID- 28592298 TI - Exploring breast cancer preventive lifestyle and social support of Iranian women: a study protocol for a mixed-methods approach. AB - BACKGROUND: It is widely accepted that a healthy lifestyle may decrease the probability of developing cancer. This study aimed to describe a study protocol that makes it possible to explore preventive health lifestyles of Iranian women and their received social support for the purpose of developing cultural strategies to increase breast cancer prevention. METHODS: A mixed-methods study will be accomplished in two sequential parts. First, a cross-sectional study will be conducted in which 2,250 Iranian women are recruited by using a random multistage cluster sampling of 20 health care centers. Structured face-to-face interviews will be conducted to obtain information on the participants' health lifestyle and perceived social support. Data will be analyzed using both multivariate regression and structural equation modeling techniques. Then, a qualitative study will be conducted among employed women using a purposive sampling design. Data will be collected by means of focus groups and semi structured interviews and will be analyzed using a conventional content analysis approach. The results of the quantitative and qualitative study will be used to develop breast cancer preventive strategies. DISCUSSION: Researchers need to acquire knowledge regarding the lifestyle and perceived social support of Iranian women that will foster culturally competent approaches to promote healthy lifestyles to develop breast cancer preventive strategies. Examining breast cancer preventive lifestyles provides valuable information for designing applicable intervention programs for improving women's health. PMID- 28592300 TI - Factors influencing treatment success of negative pressure wound therapy in patients with postoperative infections after Osteosynthetic fracture fixation. AB - BACKGROUND: Negative Pressure Wound Therapy (NPWT) is being increasingly used to treat postoperative infections after osteosynthetic fracture fixation. The aim of the present study was to analyze the influence of epidemiological and microbiological parameters on outcome. METHODS: Infections following operative fracture fixation were registered in a comprehensive Critical Incidence Reporting System and subsequently analyzed retrospectively for characteristics of patients including comorbidity, bacteria, and clinical factors. The influence of the investigated parameters was analyzed using logistic regression models based on data from 106 patients. RESULTS: Staged wound lavage in combination with NPWT allowed implant preservation in 44% and led to successful healing in 73% of patients. Fermentation characteristics, load and behavior after gram staining revealed no statistically significant correlation with either healing or implant preservation. Infecting bacteria were successfully isolated in 87% of patients. 20% of all infections were caused by bacterial combinations. We observed a change in the infecting bacterial species under therapy in 23%. Age, gender, metabolic diseases or comorbidities did not influence the probability of implant preservation or healing. The delayed manifestation of infection (>4 weeks) correlated with a higher risk for implant loss (OR 5.1 [95% CI 1.41-17.92]) as did the presence of bacterial mixture (OR 5.0 [95% CI 1.41-17.92]) and open soft tissue damage >= grade 3 (OR 10.2 [CI 1.88-55.28]). Wounds were less likely to heal in conjunction with high CRP blood levels (>20 mg/l) at the time of discharge (OR 3.6 [95% CI 1.31-10.08]) or following a change of the infecting bacterial species under therapy (OR 3.2 [95% CI, 1.13-8.99]). CONCLUSIONS: These results indicate that the delayed manifestation of infection, high CRP blood levels at discharge, and alterations in the infecting bacterial species under therapy raise the risk of NPWT failure. PMID- 28592299 TI - Real versus sham proximal biofield therapy in the treatment of warts of the hands and feet in adults: study protocol for a randomized controlled trial (MAGNETIK study). AB - BACKGROUND: Despite the lack of scientific studies on biofield therapies, they are widely acclaimed by patients. The mechanisms of action are not explained by current allopathic medical approaches. Warts are common and contagious viral lesions that may be refractory to standard dermatologic treatments such as cryotherapy, laser therapy, and keratolytic ointments. Biofield therapies are efficient in various pathologies. Their ability to treat warts has never been demonstrated in a scientific study with a robust methodology. Patients with refractory warts often place their trust in these alternative therapies because of the poor results obtained from traditional medicine. We propose a prospective, randomized, single-blind, assessor-blind trial to evaluate the efficacy of treatment of warts by biofield therapy. METHODS/DESIGN: Subjects with warts on their feet or hands will be randomized into two groups: real biofield therapy versus sham therapy. The diagnosis will be made at the time of inclusion, and follow-up will take place in week 3. Comparison of pictures of the warts at baseline and after 3 weeks will be used as the primary outcome measure. The hypothesis is that the extent of the disappearance of the original wart in the group treated by real biofield therapy will be 70% and that it will be 30% in the group treated by sham therapy. Using 90% power and an alpha risk of 5%, 31 subjects are required in each group for a two-tailed proportion comparison test. DISCUSSION: To our knowledge, this is the first study to evaluate the efficacy of biofield therapy on warts. Therefore, the aim of this study is to extend knowledge of biofield therapy to another area of medicine such as dermatology and to propose complementary or alternative practices to improve patient well-being. The main strength of the study is that it is a randomized, single-blind, assessor blind, placebo-controlled study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02773719 . Registered on 22 April 2016. PMID- 28592301 TI - Pneumococcal meningitis with normal cerebrospinal biochemistry and no pneumococci at microscopy, mimicking a stroke: a case report. AB - BACKGROUND: Bacterial meningitis commonly presents with symptoms such as headache, impaired consciousness, neck stiffness, and fever. In most cases, cerebrospinal fluid analysis will yield white cell counts >100/mm3. Atypical presentations occur, especially in the very young or very elderly and the immunocompromised. We report an unusual case of pneumococcal meningitis in a healthy 78-year-old Danish woman who presented with clinical features mimicking a stroke with normal cerebrospinal fluid parameters and without microscopic evidence of bacteria. CASE PRESENTATION: The patient was admitted after being found unconscious on her bed. Upon admittance, she was considered confused, with a temperature of 39.4 degrees C and slight neutrophilic leukocytosis, but no neck stiffness. A neurological examination revealed bilateral horizontal nystagmus, unstable eye movements, and suspected right-sided gaze paralysis. Cerebrospinal fluid analysis revealed normal parameters, and the microscopy result was negative for bacteria. The most likely diagnosis was considered to be stroke with concomitant infection. However, cerebrospinal fluid and blood cultures subsequently were rapidly positive for pneumococci. Neither immunodeficiency nor blood contamination was considered a likely cause of this discrepancy. CONCLUSIONS: This case emphasizes the need to consider a multidisciplinary approach and empirical meningitis treatment until diagnostic results from microbiological cultures are obtained. PMID- 28592302 TI - Fourth Surviving Sepsis Campaign's hemodynamic recommendations: a step forward or a return to chaos? PMID- 28592303 TI - Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya. AB - BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121 193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease. PMID- 28592305 TI - Incremental diagnostic utility of systematic double-bed SPECT/CT for bone scintigraphy in initial staging of cancer patients. AB - BACKGROUND: SPECT/CT has been shown to increase the diagnostic performance of bone scintigraphy for staging of malignancies. A systematic double-bed SPECT/CT of the trunk may allow further improvement. However, this would be balanced by higher dosimetry and longer acquisition time. The objective was to assess the incremental diagnostic utility of a systematic double-bed SPECT/CT acquisition for bone scintigraphy in initial staging of cancer patients, especially compared with the usual approach consisting in a whole body planar scan (WBS) plus one single-bed targeted SPECT/CT. METHODS: One hundred two consecutive patients referred for bone scintigraphy for initial staging of malignancy were analyzed. All patients underwent a double-bed SPECT/CT acquisition of the trunk. Images were interpreted by two nuclear medicine physicians in a 3-step procedure. Firstly, only WBS planar images were used; secondly, one additional single-bed SPECT/CT chosen based on planar images was used; finally, WBS planar and double bed SPECT/CT images were interpreted. Lesions were classified as benign, equivocal or suspicious for metastasis. A per-lesion, per-anatomical region and per-patient analysis was performed. RESULTS: In a per-lesion analysis, the number of equivocal and suspicious lesions was 91 and 241 using WBS planar images, 17 and 259 using a single-bed SPECT/CT acquisition and 11 and 269 using double-bed SPECT/CT images, respectively. In a per-patient analysis, the diagnostic conclusion was negative, equivocal or suspicious for malignancy in 35, 53 and 14 patients using WB planar images, 77, 6 and 19 patients using an additional single bed SPECT/CT and 76, 7 and 19 using double-bed SPECT/CT images, respectively. Seventeen lesions unseen on WBS images were interpreted as suspicious (n = 12) or equivocal (n = 5) on double-bed SPECT/CT images. Six lesions unseen on "WBS + targeted single-bed SPECT/CT" were interpreted as suspicious on double-bed SPECT/CT, with no shift in the metastatic status of patients. CONCLUSION: A systematic double-bed SPECT/CT acquisition has a limited incremental diagnostic value over an oriented single-bed SPECT/CT in terms of specificity and conclusiveness of bone scintigraphy in the initial staging of cancer patients. However, it slightly improved the sensitivity of the test by detecting unseen lesions on WBS, which may be of value for initial staging of cancer. PMID- 28592306 TI - Priorities and strategies for improving Roma women's access to primary health care services in cases on intimate partner violence: a concept mapping study. AB - BACKGROUND: With an explicit focus on Roma women in Spain (Kale/Spanish Gypsies), this study aims to integrate key informants' opinions about the main actions needed to improve primary health care services' and professionals' responses to Roma women in an Intimate Partner Violence (IPV) situation. METHODS: Concept mapping study. A total of 50 (brainstorming phase), 36 (sorting and rating phase) and 16 (interpretation phase) participants from Roma civil society groups, primary health care professionals and other related stakeholders (social services, academic experts and other IPV NGOs representatives) from different cities in Spain were involved in the different study phases. RESULTS: Among the 55 action proposals generated, ten priority actions were identified through consensus as most important for improving primary health care's response to Romani women in an IPV situation, and these included primary, secondary and tertiary prevention activities. CONCLUSION: Results indicated that efforts to address this challenge should take an integrated approach that reinforces the primary health care response to IPV in general, while also promoting more specific actions to address barriers to access that affect all Roma women and those who experience IPV in particular. PMID- 28592304 TI - Post translational changes to alpha-synuclein control iron and dopamine trafficking; a concept for neuron vulnerability in Parkinson's disease. AB - Parkinson's disease is a multifactorial neurodegenerative disorder, the aetiology of which remains elusive. The primary clinical feature of progressively impaired motor control is caused by a loss of midbrain substantia nigra dopamine neurons that have a high alpha-synuclein (alpha-syn) and iron content. alpha-Syn is a neuronal protein that is highly modified post-translationally and central to the Lewy body neuropathology of the disease. This review provides an overview of findings on the role post translational modifications to alpha-syn have in membrane binding and intracellular vesicle trafficking. Furthermore, we propose a concept in which acetylation and phosphorylation of alpha-syn modulate endocytic import of iron and vesicle transport of dopamine during normal physiology. Disregulated phosphorylation and oxidation of alpha-syn mediate iron and dopamine dependent oxidative stress through impaired cellular location and increase propensity for alpha-syn aggregation. The proposition highlights a connection between alpha-syn, iron and dopamine, three pathological components associated with disease progression in sporadic Parkinson's disease. PMID- 28592307 TI - Global gene expression in muscle from fasted/refed trout reveals up-regulation of genes promoting myofibre hypertrophy but not myofibre production. AB - BACKGROUND: Compensatory growth is a phase of rapid growth, greater than the growth rate of control animals, that occurs after a period of growth-stunting conditions. Fish show a capacity for compensatory growth after alleviation of dietary restriction, but the underlying cellular mechanisms are unknown. To learn more about the contribution of genes regulating hypertrophy (an increase in muscle fibre size) and hyperplasia (the generation of new muscle fibres) in the compensatory muscle growth response in fish, we used high-density microarray analysis to investigate the global gene expression in muscle of trout during a fasting-refeeding schedule and in muscle of control-fed trout displaying normal growth. RESULTS: The compensatory muscle growth signature, as defined by genes up regulated in muscles of refed trout compared with control-fed trout, showed enrichment in functional categories related to protein biosynthesis and maturation, such as RNA processing, ribonucleoprotein complex biogenesis, ribosome biogenesis, translation and protein folding. This signature was also enriched in chromatin-remodelling factors of the protein arginine N-methyl transferase family. Unexpectedly, functional categories related to cell division and DNA replication were not inferred from the molecular signature of compensatory muscle growth, and this signature contained virtually none of the genes previously reported to be up-regulated in hyperplastic growth zones of the late trout embryo myotome and to potentially be involved in production of new myofibres, notably genes encoding myogenic regulatory factors, transmembrane receptors essential for myoblast fusion or myofibrillar proteins predominant in nascent myofibres. CONCLUSION: Genes promoting myofibre growth, but not myofibre formation, were up-regulated in muscles of refed trout compared with continually fed trout. This suggests that a compensatory muscle growth response, resulting from the stimulation of hypertrophy but not the stimulation of hyperplasia, occurs in trout after refeeding. The generation of a large set of genes up regulated in muscle of refed trout may yield insights into the molecular and cellular mechanisms controlling skeletal muscle mass in teleost and serve as a useful list of potential molecular markers of muscle growth in fish. PMID- 28592309 TI - Machine learning techniques for diabetic macular edema (DME) classification on SD OCT images. AB - BACKGROUND: Spectral domain optical coherence tomography (OCT) (SD-OCT) is most widely imaging equipment used in ophthalmology to detect diabetic macular edema (DME). Indeed, it offers an accurate visualization of the morphology of the retina as well as the retina layers. METHODS: The dataset used in this study has been acquired by the Singapore Eye Research Institute (SERI), using CIRRUS TM (Carl Zeiss Meditec, Inc., Dublin, CA, USA) SD-OCT device. The dataset consists of 32 OCT volumes (16 DME and 16 normal cases). Each volume contains 128 B-scans with resolution of 1024 px * 512 px, resulting in more than 3800 images being processed. All SD-OCT volumes are read and assessed by trained graders and identified as normal or DME cases based on evaluation of retinal thickening, hard exudates, intraretinal cystoid space formation, and subretinal fluid. Within the DME sub-set, a large number of lesions has been selected to create a rather complete and diverse DME dataset. This paper presents an automatic classification framework for SD-OCT volumes in order to identify DME versus normal volumes. In this regard, a generic pipeline including pre-processing, feature detection, feature representation, and classification was investigated. More precisely, extraction of histogram of oriented gradients and local binary pattern (LBP) features within a multiresolution approach is used as well as principal component analysis (PCA) and bag of words (BoW) representations. RESULTS AND CONCLUSION: Besides comparing individual and combined features, different representation approaches and different classifiers are evaluated. The best results are obtained for LBP[Formula: see text] vectors while represented and classified using PCA and a linear-support vector machine (SVM), leading to a sensitivity(SE) and specificity (SP) of 87.5 and 87.5%, respectively. PMID- 28592310 TI - Validation of the Spanish version of the Amsterdam Preoperative Anxiety and Information Scale (APAIS). AB - BACKGROUND: Preoperative anxiety is a frequent and challenging problem with deleterious effects on the development of surgical procedures and postoperative outcomes. To prevent and treat preoperative anxiety effectively, the level of anxiety of patients needs to be assessed through valid and reliable measuring instruments. One such measurement tool is the Amsterdam Preoperative Anxiety and Information Scale (APAIS), of which a Spanish version has not been validated yet. OBJECTIVE: To perform a Spanish cultural adaptation and empirical validation of the APAIS for assessing preoperative anxiety in the Spanish population. METHODS: A two-step forward/back translation of the APAIS scale was performed to ensure a reliable Spanish cultural adaptation. The final Spanish version of the APAIS questionnaire was administered to 529 patients between the ages of 18 to 70 undergoing elective surgery at hospitals of the Agencia Sanitaria Costa del Sol (Spain). Cronbach's alpha, homogeneity index, intra-class correlation coefficient, and confirmatory factor analysis were calculated to assess internal consistency and criteria and construct validity. RESULTS: Confirmatory factor analysis showed that a one-factor model was better fitted than a two-factor model, with good fitting patterns (root mean square error of approximation: 0.05, normed-fit index: 0.99, goodness-of-fit statistic: 0.99). The questionnaire showed high internal consistency (Cronbach's alpha: 0.84) and a good correlation with the Goldberg Anxiety Scale (CCI: 0.62 (95% CI: 0.55 to 0.68). CONCLUSIONS: The Spanish version of the APAIS is a valid and reliable preoperative anxiety measurement tool and shows psychometric properties similar to those obtained by similar previous studies. PMID- 28592308 TI - Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and D-lactic acidosis: a systematic review. AB - BACKGROUND: The pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of D-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of D-lactic acidosis (D-la). METHODS: D-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high D-lactate levels. Fifty-nine D-la episodes were included in the qualitative synthesis comparing D la symptoms with ME/CFS diagnostic criteria. A narrative review of D-la mechanisms and relevance for ME/CFS was provided. RESULTS: The majority of neurological disturbances reported in D-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported D-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS. LIMITATIONS: Interpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for D-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined. CONCLUSIONS: Shared symptomatology and underlying microbiota-gut-brain interactions raise the possibility of a continuum of acute (D-la) versus chronic (ME/CFS) presentations related to D-lactate absorption. Measurement of D-lactate in ME/CFS is needed to effectively evaluate whether subclinical D-lactate levels affect neurological symptoms in this clinical population. PMID- 28592311 TI - The effects of green cardamom on blood glucose indices, lipids, inflammatory factors, paraxonase-1, sirtuin-1, and irisin in patients with nonalcoholic fatty liver disease and obesity: study protocol for a randomized controlled trial. AB - BACKGROUND: The relationship between dietary components and nonalcoholic fatty liver disease (NAFLD) needs to be further investigated. The potential health benefits of cardamom have been found in some studies. Cardamom showed beneficial effect on hepatomegaly, dyslipidemia, and fasting hyperglycemia in animals. However, some adverse effects of cardamom have been reported in animals. No previous human study had been conducted on the effects of cardamom in NAFLD. This study aims to determine the effects of green cardamom (Elettaria cardamomum) supplementation on blood glucose indices, lipids, inflammatory profiles, and liver function, especially by examining irisin, paraxonase-1 (PON1) and sirtuin-1 (Sirt1) in obese patients with NAFLD. METHODS: This trial is to be conducted at the polyclinic of the National Iranian Oil Company (NIOC) Central Hospital, Tehran. Eighty obese patients with NAFLD will be selected according to the eligibility criteria. The NAFLD diagnosis method is ultrasonography. Patients will be randomly divided into two groups by a random-number table (cardamom and placebo groups, two 500-mg capsules, three times/day, taken with meals for 3 months, follow-up monthly). General characteristics, dietary intakes (at the beginning, middle, and end), and physical activity (at the beginning and end) will be assessed using a general, 24-h food recall, and short-form International Physical Activity Questionnaires (IPAQ), respectively. Lifestyle advice will be presented to both groups identically. At the beginning and the end, anthropometrics (weight, height, and waist circumference), blood pressure, extent of fatty liver, and blood biomarkers, including serum glucose indices (fasting blood sugar (FBS)) and insulin (FBI), homeostasis model assessment-insulin resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI)), lipids (triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), high density lipoprotein-cholesterol (HDL-c), total cholesterol (TC)), inflammatory markers (highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6)), liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST)), irisin, PON1, and Sirt1, will be determined. DISCUSSION: This trial would be the first to assess the effects of green cardamom on several blood factors, including glucose indices, lipids, inflammatory markers, liver enzymes, irisin, PON1, and Sirt1, and blood pressure and anthropometry in obese patients with NAFLD. Further study of cardamom's potential in improving NAFLD is suggested. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), ID number: IRCT2015121317254N4 . Registered on 27 December 2015. PMID- 28592312 TI - Vertical bone regeneration using rhBMP-2 and VEGF. AB - BACKGROUND: Sufficient vertical and lateral bone supply and a competent osteogenic healing process are prerequisities for the successful osseointegration of dental implants in the alveolar bone. Several techniques including autologous bone grafts and guided bone regeneration are applied to improve quality and quantity of bone at the implantation site. Depending on the amount of lacking bone one- or two-stage procedures are required. Vertical bone augmentation has proven to be a challenge particularly in terms of bone volume stability. This study focuses on the three dimensional vertical bone generation in a one stage procedure in vivo. Therefore, a collagenous disc-shaped scaffold (ICBM = Insoluble Collagenous Bone Matrix) containing rhBMP-2 (Bone Morphogenetic Protein 2) and/or VEGF (Vascular Endothelial Growth Factor) was applied around the coronal part of a dental implant during insertion. RhBMP-2 and VEGF released directly at the implantation site were assumed to induce the generation of new vertical bone around the implant. METHODS: One hundred eight titanium implants were inserted into the mandible and the tibia of 12 mini pigs. Four experimental groups were formed: Control group, ICBM, ICBM + BMP-2, and ICBM + BMP-2 + VEGF. After 1, 4 and 12 weeks the animals were sacrificed and bone generation was investigated histologically and histomorphometrically. RESULTS: After 12 weeks the combination of ICBM + rhBMP2 + VEGF showed significantly more bone volume density (BVD%), a higher vertical bone gain (VBG) and more vertical bone gain around the implant (PVBG) in comparison to the control group. CONCLUSION: By using collagenous disc-shaped matrices in combination with rhBMP-2 and VEGF vertical bone can be generated in a one stage procedure without donor site morbidity. The results of the presenting study suggest that the combination of rhBMP-2 and VEGF applied locally by using a collagenous carrier improves vertical bone generation in vivo. Further research is needed to establish whether this technique is applicable in clinical routines. PMID- 28592313 TI - Impact of community-initiated Kangaroo Mother Care on survival of low birth weight infants: study protocol for a randomized controlled trial. AB - BACKGROUND: Around 70% neonatal deaths occur in low birth weight (LBW) babies. Globally, 15% of babies are born with LBW. Kangaroo Mother Care (KMC) appears to be an effective way to reduce mortality and morbidity among LBW babies. KMC comprises of early and continuous skin-to-skin contact between mother and baby as well as exclusive breastfeeding. Evidence derived from hospital-based studies shows that KMC results in a 40% relative reduction in mortality, a 58% relative reduction in the risk of nosocomial infections or sepsis, shorter hospital stay, and a lower risk of lower respiratory tract infections in babies with birth weight <2000 g. There has been considerable interest in KMC initiated outside health facilities for LBW babies born at home or discharged early. Currently, there is insufficient evidence to support initiation of KMC in the community (cKMC). Formative research in our study setting, where 24% of babies are born with LBW, demonstrated that KMC is feasible and acceptable when initiated at home for LBW babies. The aim of this trial is to determine the impact of cKMC on the survival of these babies. METHODS/DESIGN: This randomized controlled trial is being undertaken in the Palwal and Faridabad districts in the State of Haryana, India. Neonates weighing 1500-2250 g identified within 3 days of birth and their mothers are being enrolled. Other inclusion criteria are that the family is likely to be available in the study area over the next 6 months, that KMC was not initiated in the delivery facility, and that the infant does not have an illness requiring hospitalization. Eligible neonates are randomized into intervention and control groups. The intervention is delivered through home visits during the first month of life by study workers with a background and education similar to that of workers in the government health system. An independent study team collects mortality and morbidity data as well as anthropometric measurements during periodic home visits. The primary outcomes of the study are postenrollment neonatal mortality and mortality between enrollment and 6 months of age. The secondary outcomes are breastfeeding practices; prevalence of illnesses and care seeking practices for the same; hospitalizations; weight and length gain; and, in a subsample, neurodevelopment. DISCUSSION: This efficacy trial will answer the question whether the benefits of KMC observed in hospital settings can also be observed when KMC is started in the community. The formative research used for intervention development suggests that the necessary high level of KMC adoption can be reached in the community, addressing a problem that seriously constrained conclusions in the only other trial in which researchers examined the benefits of cKMC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02653534 . Registered on 26 December 2015 (retrospectively registered). PMID- 28592314 TI - Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study. AB - BACKGROUND: Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. METHODS: Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. RESULTS: Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. CONCLUSIONS: Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism. PMID- 28592315 TI - Efficacy and safety of enzyme-replacement-therapy with agalsidase alfa in 36 treatment-naive Fabry disease patients. AB - BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from the alpha-galactosidase A gene mutations. Enzyme-replacement therapy (ERT) products for FD currently used include agalsidase alfa and agalsidase beta. There are many reports on efficacy and safety of ERT. However, most of the previous studies are done as a retrospective medical records analysis. METHODS: The Japan Fabry Research - 002 (JFR-002) was a prospective observational clinical study of 36 ERT-naive FD patients (14 men and 22 women) at baseline (BL) and after initiation of ERT with agalsidase alfa 0.2 mg/kg every two weeks, a median period 62.5 months. The parameters measured included globotriaosylceramide (Gb3), globotriaosylsphingosine (Lyso-Gb3), left ventricular mass index (LVMI), brain natriuretic peptide (BNP), high-sensitivity troponin I (hs-Trop I), estimated glomerular filtration rate (eGFR), and anti agalsidase alfa IgG antibody formation. RESULTS: All parameters remained steady during ERT treatment period. BNP levels in 14 patients whose BL levels were within the normal range (<19.5 pg/mL) remained within the same range, while 22 patients whose BL levels were abnormally high (>=19.5 pg/mL) gradually showed decreased levels after start of ERT. Gb3 and Lyso-Gb3 levels remarkably decreased after the initiation of ERT and remained low. CONCLUSION: The JFR-002 suggests that agalsidase alfa is effective in maintaining organ function in FD patients, and that the incidence of infusion reactions related to the treatment with agalsidase alfa is low, indicating the good tolerability to this ERT. TRIAL REGISTRATION: The JFR-002 was retrospectively registered at Japan Medical Association Center for Clinical Trials (Registration number: JMA-IIA00291 ) on May 19th, 2017. PMID- 28592316 TI - The influence of climatic factors on the development of hemorrhagic fever with renal syndrome and leptospirosis during the peak season in Korea: an ecologic study. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) and leptospirosis are seasonal rodent-borne infections in the Republic of Korea (Korea). The occurrences of HFRS and leptospirosis are influenced by climatic variability. However, few studies have examined the effects of local climatic variables on the development of these infections. The purpose of this study was to estimate the effect of climatic factors on the occurrence of HFRS and leptospirosis in Korea. METHODS: Daily records on human cases of HFRS and leptospirosis between January 2001 to December 2009 were analyzed. The associations of climatic factors with these cases in high incidence provinces were estimated using the time-series method and multivariate generalized linear Poisson models with a maximal lag of 12 weeks. RESULTS: From 2001 to 2009, a total of 2912 HFRS and 889 leptospirosis cases were reported, with overall incidences of 0.67 and 0.21 cases per 100,000, respectively, in the study areas. The increase in minimum temperature (1 degrees C) at a lag of 11 weeks was associated with 17.8% [95% confidence interval (CI): 15.1, 20.6%] and 22.7% (95% CI: 16.5, 29.3%) increases in HFRS and leptospirosis cases, respectively. A 1-h increase in the daily sunshine was related to a 27.5% (95% CI: 18.2, 37.6%) increase in HFRS at a lag of 0 week. A 1% increase in daily minimum relative humidity and a 1 mm increase in daily rainfall were associated with 4.0% (95% CI:1.8, 6.1) and 2.0% (95% CI: 1.2, 2.8%) increases in weekly leptospirosis cases at 11 and 6 weeks later, respectively. A 1 mJ/m2 increase in daily solar radiation was associated with a 13.7% (95% CI: 4.9, 23.2%) increase in leptospirosis cases, maximized at a 2-week lag. CONCLUSIONS: During the peak season in Korea, climatic factors play a significant role in the development of HFRS and leptospirosis. The findings of this study may be applicable to the forecasting and prediction of disease outbreaks. PMID- 28592317 TI - Modeling the spatio-temporal dynamics of porcine reproductive & respiratory syndrome cases at farm level using geographical distance and pig trade network matrices. AB - BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically devastating infectious diseases for the swine industry. A better understanding of the disease dynamics and the transmission pathways under diverse epidemiological scenarios is a key for the successful PRRS control and elimination in endemic settings. In this paper we used a two step parameter driven (PD) Bayesian approach to model the spatio-temporal dynamics of PRRS and predict the PRRS status on farm in subsequent time periods in an endemic setting in the US. For such purpose we used information from a production system with 124 pig sites that reported 237 PRRS cases from 2012 to 2015 and from which the pig trade network and geographical location of farms (i.e., distance was used as a proxy of airborne transmission) was available. We estimated five PD models with different weights namely: (i) geographical distance weight which contains the inverse distance between each pair of farms in kilometers, (ii) pig trade weight (PT ji ) which contains the absolute number of pig movements between each pair of farms, (iii) the product between the distance weight and the standardized relative pig trade weight, (iv) the product between the standardized distance weight and the standardized relative pig trade weight, and (v) the product of the distance weight and the pig trade weight. RESULTS: The model that included the pig trade weight matrix provided the best fit to model the dynamics of PRRS cases on a 6-month basis from 2012 to 2015 and was able to predict PRRS outbreaks in the subsequent time period with an area under the ROC curve (AUC) of 0.88 and the accuracy of 85% (105/124). CONCLUSION: The result of this study reinforces the importance of pig trade in PRRS transmission in the US. Methods and results of this study may be easily adapted to any production system to characterize the PRRS dynamics under diverse epidemic settings to more timely support decision making. PMID- 28592319 TI - High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K2, A pre-post intervention clinical trial. AB - BACKGROUND: Vascular calcifications are highly prevalent in hemodialysis patients. Dephosphorylated-uncarboxylated MGP (dp-ucMGP) was found to increase in vitamin K-deficient patients and may be associated with vascular calcifications. Supplementation of hemodialysis patients with vitamin K2 (menaquinone-7) has been studied in Europe with a maximum 61% drop of dp-ucMGP levels. The aim of this study is to assess first the drop of dp-ucMGP in an Eastern Mediterranean cohort after vitamin K2 treatment and second the correlation between baseline dp-ucMGP and vascular calcification score. METHODS: This is a prospective, pre-post intervention clinical trial involving 50 hemodialysis patients who received daily 360 MUg of menaquinone-7 for 4 weeks. At baseline they were assessed for plasma dp-ucMGP levels and vascular calcification scores (AC-24) as well as for other demographic, clinical and biological variables. Dp-ucMGP levels were measured a second time at 4 weeks. RESULTS: At baseline, dp-ucMGP levels were extremely elevated with a median of 3179.15 (1825.25; 4339.50) pM and correlated significantly with AC-24 (Spearman's rho = 0.43, P = 0.002). Using a bivariate regression analysis, the association between dp-ucMGP levels and AC-24 was most significant when comparing dp-ucMGP levels less than 1000 to those more than 1000 pM (P = 0.02). Dp-ucMGP levels higher than 5000 pM were significantly associated with females, patients with recent fracture and patients with lower serum albumin (respectively P = 0.02, 0.004 and 0.046). The average drop of dp-ucMGP at 4 weeks of treatment was found to be 86% with diabetics having the lowest drop rate (P = 0.01). CONCLUSION: Vitamin K deficiency, as assessed by high dp-ucMGP levels, is profound in hemodialysis patients from the Eastern Mediterranean region and it is significantly correlated with vascular calcifications. Daily 360 MUg of menaquinone-7, given for 4 weeks, effectively reduces dp-ucMGP in this population. Future studies are needed to assess the changes in vascular calcifications in hemodialysis patients treated with vitamin K2 over a longer follow-up period. TRIAL REGISTRATION: The clinical trial was registered on clinicaltrials.gov (Identification number NCT02876354 , on August 11, 2016). PMID- 28592318 TI - Potential survival benefit of polymyxin B hemoperfusion in patients with septic shock: a propensity-matched cohort study. AB - BACKGROUND: The purpose of this study was to investigate whether polymyxin B hemoperfusion (PMX-HP) improves the survival of patients with septic shock. METHODS: This was a retrospective, multicenter study conducted on patients treated during a 3-year period. We performed propensity-score analyses of the Japan Septic Disseminated Intravascular Coagulation (JSEPTIC DIC) study database. The study included data on 1723 patients with septic shock aged 16 years or older. Furthermore, we divided patients into to PMX-HP- and non-PMX-HP-treated groups. The primary endpoint was all-cause hospital mortality; secondary endpoints included intensive care unit (ICU) mortality and number of ICU-free days (ICUFDs) in the first 28 days. RESULTS: Of 1,723 eligible patients, 522 had received PMX-HP. Propensity score matching created 262 matched pairs (i.e., 262 patients in each of the non-PMX-HP and PMX-HP groups). The proportion of all cause hospital mortality was significantly lower in the PMX-HP group than in the non-PMX-HP group (32.8% vs. 41.2%; odds ratio (OR): 0.681; 95% confidence interval (CI): 0.470-0.987; P = 0.042). The number of ICUFD in the first 28 days was significantly higher in the PMX-HP group than in the non-PMX-HP group (18 (0 22) vs. 14 (0-22) days, respectively; P = 0.045). On the other hand, there was no significant difference in ICU mortality between the two groups (21.8% vs. 24.4%; OR: 0.844; CI: 0.548-1.300; P = 0.443). CONCLUSIONS: Our results strongly suggest that PMX-HP reduces all-cause hospital mortality and length of ICU stay in patients with septic shock. PMID- 28592320 TI - Infectivity, transmission and pathogenicity of H5 highly pathogenic avian influenza clade 2.3.4.4 (H5N8 and H5N2) United States index viruses in Pekin ducks and Chinese geese. AB - In late 2014, a H5N8 highly pathogenic avian influenza (HPAI) virus, clade 2.3.4.4, spread by migratory waterfowl into North America reassorting with low pathogenicity AI viruses to produce a H5N2 HPAI virus. Since domestic waterfowl are common backyard poultry frequently in contact with wild waterfowl, the infectivity, transmissibility, and pathogenicity of the United States H5 HPAI index viruses (H5N8 and H5N2) was investigated in domestic ducks and geese. Ducks infected with the viruses had an increase in body temperature but no or mild clinical signs. Infected geese did not show increase in body temperature and most only had mild clinical signs; however, some geese presented severe neurological signs. Ducks became infected and transmitted the viruses to contacts when inoculated with high virus doses [(104 and 106 50% embryo infective dose (EID50)], but not with a lower dose (102 EID50). Geese inoculated with the H5N8 virus became infected regardless of the virus dose given, and transmitted the virus to direct contacts. Only geese inoculated with the higher doses of the H5N2 and their contacts became infected, indicating differences in infectivity between the two viruses and the two waterfowl species. Geese shed higher titers of virus and for a longer period of time than ducks. In conclusion, the H5 HPAI viruses can infect domestic waterfowl and easily transmit to contact birds, with geese being more susceptible to infection and disease than ducks. The disease is mostly asymptomatic, but infected birds shed virus for several days representing a risk to other poultry species. PMID- 28592321 TI - Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. AB - Uterine smooth muscle tumors range from benign leiomyomas to malignant leiomyosarcomas. Based on numerous molecular studies, leiomyomas and leiomyosarcomas mostly lack shared mutations and the majority of tumors are believed to develop through distinct mechanisms. To further characterize the molecular variability among uterine smooth muscle tumors, and simultaneously insinuate their potential malignant progression, we examined the frequency of known genetic leiomyoma driver alterations (MED12 mutations, HMGA2 overexpression, biallelic FH inactivation) in 65 conventional leiomyomas, 94 histopathological leiomyoma variants (18 leiomyomas with bizarre nuclei, 22 cellular, 29 highly cellular, and 25 mitotically active leiomyomas), and 51 leiomyosarcomas. Of the 210 tumors analyzed, 107 had mutations in one of the three driver genes. No tumor had more than one mutation confirming that all alterations are mutually exclusive. MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression. Highly cellular leiomyomas displayed the least amount of alterations leaving the majority of tumors with no known driver aberration. Our results indicate that based on the molecular background, histopathological leiomyoma subtypes do not only differ from conventional leiomyomas, but also from each other. The presence of leiomyoma driver alterations in nearly one third of leiomyosarcomas suggests that some tumors arise through leiomyoma precursor lesion or that these mutations provide growth advantage also to highly aggressive cancers. It is clinically relevant to understand the molecular background of various smooth muscle tumor subtypes, as it may lead to improved diagnosis and personalized treatments in the future. PMID- 28592322 TI - Potential for rapid antibody detection to identify tuberculous cattle with non reactive tuberculin skin test results. AB - BACKGROUND: Bovine tuberculosis (TB) control programs generally rely on the tuberculin skin test (TST) for ante-mortem detection of Mycobacterium bovis infected cattle. RESULTS: Present findings demonstrate that a rapid antibody test based on Dual-Path Platform (DPP(r)) technology, when applied 1-3 weeks after TST, detected 9 of 11 and 34 of 52 TST non-reactive yet M. bovis-infected cattle from the US and GB, respectively. The specificity of the assay ranged from 98.9% (n = 92, US) to 96.0% (n = 50, GB) with samples from TB-free herds. Multi-antigen print immunoassay (MAPIA) revealed the presence of antibodies to multiple antigens of M. bovis in sera from TST non-reactors diagnosed with TB. CONCLUSIONS: Thus, use of serologic assays in series with TST can identify a significant number of TST non-reactive tuberculous cattle for more efficient removal from TB-affected herds. PMID- 28592323 TI - Antibacterial and anticancer activities of acetone extracts from in vitro cultured lichen-forming fungi. AB - BACKGROUND: Lichens that were used in traditional medicine for ages produce numerous secondary metabolites, however our knowledge about biological activities of substances secreted by separated bionts is scarce. The main objectives of this study were to isolate and find optimal conditions for the growth of mycelia from three common lichen-forming fungi, i.e. Caloplaca pusilla, Protoparmeliopsis muralis and Xanthoria parietina and to evaluate antibacterial and antiproliferative activities of their acetone extracts. METHODS: Agar disc diffusion and broth microdilution methods were used to test antimicrobial activity against six species of bacteria. MTT method, flow cytometry assay and DAPI staining were applied to test antiproliferative activity of selected extracts against MCF-7 (human breast adenocarcinoma), PC-3 (human prostate cancer) and HeLa (human cervix adenocarcinoma) cancer cells. RESULTS: P. muralis strongly inhibited the growth of Gram-positive bacteria, i.e. Bacillus subtilis, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis (MICs from 6.67 to 100.00 MUg mL-1). X. parietina grown on PDA and G-LBM media decreased HeLa or MCF-7 cancer cells viability with IC50 values of about 8 MUg mL 1, while C. pusilla grown on G-LBM medium showed the highest potency in decreasing MCF-7 (7.29 MUg mL-1), PC-3 (7.96 MUg mL-1) and HeLa (6.57 MUg mL-1) cancer cells viability. We also showed induction of apoptosis in HeLa, PC-3 and MCF-7 cell lines treated with increasing concentrations of C. pusilla extract. CONCLUSION: We showed that selected acetone extracts demonstrated a strong antimicrobial and anticancer effects that suggests that aposymbiotically cultured lichen-forming fungi can be a source of antibacterial and antiproliferative compounds. PMID- 28592324 TI - Comparison of local infiltration analgesia and sciatic nerve block for pain control after total knee arthroplasty: a systematic review and meta-analysis. AB - BACKGROUND: This meta-analysis aimed to perform a meta-analysis to evaluate the efficiency and safety between local infiltration analgesia (LIA) and sciatic nerve block (SNB) when combined with femoral nerve block (FNB) after total knee arthroplasty (TKA). METHODS: A systematic search was performed in MEDLINE (1966 2017.04), PubMed (1966-2017.04), Embase (1980-2017.04), ScienceDirect (1985 2017.04), and the Cochrane Library. Only high-quality studies were selected. Meta analysis was performed using Stata 11.0 software. RESULTS: Four randomized controlled trials (RCTs) and two non-randomized controlled trials (non-RCTs), including 273 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of visual analogue scale (VAS) score at 12 h (SMD = -0.303, 95% CI -0.543 to -0.064, P = 0.013), VAS score at 24 h (SMD = -0.395, 95% CI -0.636 to -0.154, P = 0.001), morphine equivalent consumption at 24 h (SMD = -0.395, 95% CI -0.636 to -0.154, P = 0.001), and incidence of nausea (RD = 0.233, 95% CI 0.107 to 0.360, P = 0.000) and vomiting (RD = 0.131, 95% CI 0.025 to 0.237, P = 0.015). CONCLUSION: FNB combined SNB provides superior pain relief and less morphine consumption within the first 24 h compared FNB-combined LIA in total knee arthroplasty. In addition, there were fewer side effects associated with SNB. Because the sample size and the number of included studies were limited, a multicenter RCT is needed to identify the effects of the two kinds of methods and further work must include range of motion analyses and functional test. PMID- 28592325 TI - Isolation and characterization of the first phage infecting ecologically important marine bacteria Erythrobacter. AB - BACKGROUND: Erythrobacter comprises a widespread and ecologically significant genus of marine bacteria. However, no phage infecting Erythrobacter spp. has been reported to date. This study describes the isolation and characterization of phage vB_EliS-R6L from Erythrobacter. METHODS: Standard virus enrichment and double-layer agar methods were used to isolate and characterize the phage. Morphology was observed by transmission electron microscopy, and a one-step growth curve assay was performed. The phage genome was sequenced using the Illumina Miseq platform and annotated using standard bioinformatics tools. Phylogenetic analyses were performed based on the deduced amino acid sequences of terminase, endolysin, portal protein, and major capsid protein, and genome recruitment analysis was conducted using Jiulong River Estuary Virome, Pacific Ocean Virome and Global Ocean Survey databases. RESULTS: A novel phage, vB_EliS R6L, from coastal waters of Xiamen, China, was isolated and found to infect the marine bacterium Erythrobacter litoralis DSM 8509. Morphological observation and genome analysis revealed that phage vB_EliS-R6L is a siphovirus with a 65.7-kb genome that encodes 108 putative gene products. The phage exhibits growth at a wide range of temperature and pH conditions. Genes encoding five methylase related proteins were found in the genome, and recognition site predictions suggested its resistance to restriction-modification host systems. Genomic comparisons and phylogenetic analyses indicate that phage vB_EliS-R6L is distinct from other known phages. Metagenomic recruitment analysis revealed that vB_EliS R6L-like phages are widespread in marine environments, with likely distribution in coastal waters. CONCLUSIONS: Isolation of the first Erythrobacter phage (vB_EliS-R6L) will contribute to our understanding of host-phage interactions, the ecology of marine Erythrobacter and viral metagenome annotation efforts. PMID- 28592326 TI - The genomic road to invasion-examining the similarities and differences in the genomes of associated oral pre-cancer and cancer samples. AB - BACKGROUND: It is frequently assumed that pre-invasive lesions are simpler precursors of cancer and will contain a limited subset of the genomic changes seen in their associated invasive disease. Driver mutations are thought to occur early, but it is not known how many of these are present in pre-invasive lesions. These assumptions need to be tested with the increasing focus on both personalised cancer treatments and early detection methodologies. METHODS: We examined genomic copy number changes in 256 pre-invasive and invasive samples from 69 oral cancer patients. Forty-eight samples from 16 patients were further examined using exome sequencing. RESULTS: Evidence of a shared ancestor of both dysplasia and carcinoma was seen in all but one patient. One-third of dysplasias showed independent copy number events. The remainder had a copy number pattern that was similar to or simpler than that of the carcinoma. All dysplasias examined contained somatic mutations absent in the related carcinoma. Previously observed copy number changes and TP53 mutations were very frequently observed, and almost always shared between dysplasia and carcinoma. Other gene changes were more sporadic. Pathway analysis confirmed that each patient's disease developed in a different way. Examining the numbers of shared mutations and the rate of accumulation of mutations showed evidence that all samples contain a population of sub-clones, with little evidence of selective advantage of a subset of these. CONCLUSIONS: These findings suggest that most of the genomic changes driving oral cancer occur in the pre-cancerous state by way of gradual random accumulation rather than a dramatic single event. PMID- 28592327 TI - Is detection of intraperitoneal exfoliated tumor cells after surgical resection of rectal cancer a prognostic factor of survival? AB - BACKGROUND: The prognostic significance of free cancer cells detected in peritoneal fluid at the time of rectal surgery remains unclear. A substantial number of patients will develop metastatic disease even with successful local treatment. This prospective non-randomized study investigated the prognostic value of intraperitoneal free cancer cells harvested in peritoneal lavage after surgery for rectal cancer. Mutational hotspots in mitochondrial DNA were examined as potential molecular signatures to detect circulating intraperitoneal free cancer cells when present in primary tumor and in lavage. METHODS: Point mutations in mitochondrial DNA amplifications were determined in primary tumors and corresponding exfoliated intraperitoneal free cancer cells in lavage from 191 patients with locally advanced rectal cancer scheduled for radical treatment. Mitochondrial DNA target sequences were amplified by polymerase chain reaction and base substitutions were detected by denaturant, cycling temperature capillary electrophoresis. Detection of intraperitoneal free cancer cells was correlated to survival. RESULTS: Of 191patients analyzed, 138 (72%) were identified with somatic mitochondrial point mutations in rectal cancer tumors. From this fraction, 45 patients (33%) had positive lavage fluid with corresponding somatic mtDNA point mutations in lavage representing circulating intraperitoneal free cancer cells. There was no significant survival difference between patients identified with or without somatic mitochondrial DNA point mutations in the corresponding lavage. CONCLUSION: Somatic mitochondrial DNA point mutations identified in primary rectal tumors enable detection of circulating intraperitoneal free cancer cells in lavage fluid. Intraperitoneal free cancer cells harvested from lavage immediately after surgery for rectal cancer does not represent an independent prognostic factor on survival. PMID- 28592329 TI - Autoimmune antibody decline in Parkinson's disease and Multiple System Atrophy; a step towards immunotherapeutic strategies. AB - BACKGROUND: Parkinson's' disease (PD) and Multiple System Atrophy (MSA) are progressive brain disorders characterized by intracellular accumulations of alpha synuclein and nerve cell loss in specific brain areas. This loss causes problems with movement, balance and/or autonomic functions. Naturally occurring autoantibodies (NAbs) play potentially an important role in clearing or/and blocking circulating pathological proteins. Little is known about the functional properties of anti-alpha-synuclein NAbs in PD and MSA, and there have been opposing reports regarding their plasma concentrations in these disorders. METHODS: We have investigated the apparent affinity of anti-alpha-synuclein NAbs in plasma samples from 46 PD patients, 18 MSA patients and 41 controls using competitive enzyme-linked immunosorbent assay (ELISA) and Meso Scale Discovery (MSD) set-ups. RESULTS: We found that the occurrence of high affinity anti-alpha synuclein NAbs in plasma from PD patients is reduced compared to healthy controls, and nearly absent in plasma from MSA patients. Also, levels of alpha synuclein/NAbs immunocomplexes is substantially reduced in plasma from both patient groups. Further, cross binding of anti-alpha-synuclein NAbs with beta- and gamma-synuclein monomers suggest, the high affinity anti-alpha-synuclein plasma component, seen in healthy individuals, is directed mainly against C terminal epitopes. Furthermore, we also observed reduced occurrence of high affinity anti-phosphorylated-alpha-synuclein NAbs in plasma from PD and MSA patients. CONCLUSIONS: One interpretation implies that these patients may have impaired ability to clear and/or block the effects of pathological alpha synuclein due to insufficient/absent concentration of NAbs and as such provides a rationale for testing immune-based therapeutic strategies directed against pathological alpha-synuclein. Following this interpretation, we can hypothesize that high affinity autoantibodies efficiently bind and clear potentially pathological species of alpha-synuclein in healthy brain, and that this mechanism is impaired or absent in PD and MSA patients. PMID- 28592328 TI - Severe varicella-zoster virus pneumonia: a multicenter cohort study. AB - BACKGROUND: Pneumonia is a dreaded complication of varicella-zoster virus (VZV) infection in adults; however, the data are limited. Our objective was to investigate the clinical features, management, and outcomes of critically ill patients with VZV-related community-acquired pneumonia (VZV-CAP). METHODS: This was an observational study of patients with VZV-CAP admitted to 29 intensive care units (ICUs) from January 1996 to January 2015. RESULTS: One hundred and two patients with VZV-CAP were included. Patients were young (age 39 years (interquartile range 32-51)) and 53 (52%) were immunocompromised. Time since respiratory symptom onset was 2 (1-3) days. There was a seasonal distribution of the disease, with more cases during spring and winter time. All but four patients presented with typical skin rash on ICU admission. Half the patients received mechanical ventilation within 1 (1-2) day following ICU admission (the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) = 150 (80-284), 80% with acute respiratory distress syndrome (ARDS)). Sequential Organ Failure Assessment (SOFA) score on day 1 (odds ratio (OR) 1.90 (1.33-2.70); p < 0.001), oxygen flow at ICU admission (OR 1.25 (1.08-1.45); p = 0.004), and early bacterial co-infection (OR 14.94 (2.00-111.8); p = 0.009) were independently associated with the need for mechanical ventilation. Duration of mechanical ventilation was 14 (7-21) days. ICU and hospital mortality rates were 17% and 24%, respectively. All patients were treated with aciclovir and 10 received adjunctive therapy with steroids. Compared to 60 matched steroid-free controls, patients treated with steroids had a longer mechanical ventilation duration, ICU length of stay, and a similar hospital mortality, but experienced more ICU acquired infections. CONCLUSIONS: Severe VZV-CAP is responsible for an acute pulmonary involvement associated with a significant morbidity and mortality. Steroid therapy did not influence mortality, but increased the risk of superinfection. PMID- 28592331 TI - Thyroid nodule recognition in computed tomography using first order statistics. AB - BACKGROUND: Computed tomography (CT) is one of the popular tools for early detection of thyroid nodule. The pixel intensity of thyroid in CT image is very important information to distinguish nodule from normal thyroid tissue. The pixel intensity in normal thyroid tissues is homogeneous and smooth. In the benign or malignant nodules, the pixel intensity is heterogeneous. Several studies have shown that the first order features in ultrasound image can be used as imaging biomarkers in nodule recognition. METHODS: In this paper, we investigate the feasibility of utilizing the first order texture features to identify nodule from normal thyroid tissue in CT image. A total of 284 thyroid CT images from 113 patients were collected in this study. We used 150 healthy controlled thyroid CT images from 55 patients and 134 nodule images (50 malignant and 84 benign nodules) from 58 patients who have undergone thyroid surgery. The final diagnosis was confirmed by histopathological examinations. In the presented method, first, regions of interest (ROIs) from axial non-enhancement CT images were delineated manually by a radiologist. Second, average, median, and wiener filter were applied to reduce photon noise before feature extraction. The first-order texture features, including entropy, uniformity, average intensity, standard deviation, kurtosis and skewness were calculated from each ROI. Third, support vector machine analysis was applied for classification. Several statistical values were calculated to evaluate the performance of the presented method, which includes accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area of under receiver operating characteristic curve (AUC). RESULTS: The entropy, uniformity, mean intensity, standard deviation, skewness (P < 0.05), except kurtosis (P = 0.104) of thyroid tissue with nodules have a significant difference from those of normal thyroid tissue. The optimal classification was obtained from the presented method. The accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) are 0.880, 0.821, 0.933, 0.917, 0.854, and 0.953 respectively. CONCLUSION: First order texture features can be used as imaging biomarkers, and the presented system can be used to assist radiologists to recognize the nodules in CT image. PMID- 28592332 TI - The negative effect of initial high-dose methylprednisolone and tapering regimen for acute respiratory distress syndrome: a retrospective propensity matched cohort study. AB - BACKGROUND: The efficacy of corticosteroid use in acute respiratory distress syndrome (ARDS) remains controversial. Generally, short-term high-dose corticosteroid therapy is considered to be ineffective in ARDS. On the other hand, low-dose, long-term use of corticosteroids has been reported to be effective since they provide continued inhibition of the systemic inflammatory response syndrome (SIRS) that accompanies ARDS. Thus far, no reports have been published on the efficacy of initiating treatment with a high-dose corticosteroid regimen with tapering. METHODS: We conducted a retrospective observational study involving 186 patients treated at a teaching hospital (68% had sepsis, pneumonia, or aspiration pneumonia). ARDS was diagnosed according to the Berlin definition. Patients were divided into a high-dose (n = 21) or low-dose corticosteroid group (n = 165) to compare the effectiveness of a down-titration regimen. The primary medical team chose which treatment a patient would receive. We were careful to conduct a differential diagnosis of interstitial pneumonia (e.g., acute eosinophilic pneumonia) since corticosteroid treatment has been proven effective in that patient population. The primary outcome was the 60-day mortality rate. The secondary outcome was the number of ventilator-free days (VFD). RESULTS: Those started on a high-dose regimen had a significantly higher 60-day mortality rate (P = 0.031) with significantly fewer VFD (P = 0.021). Propensity scores were used to adjust patient backgrounds in a variable analysis that also showed the high-dose regimen was a factor in decreasing VFD (OR, 95.63; 95% CI, 1.74 5271.07; P = 0.026) and worsening the 60-day mortality rate (OR, 2.54; 95% CI, 0.92-7.02; P = 0.072). CONCLUSIONS: A tapering regimen after high-dose corticosteroids is likely to increase ventilator dependency and might aggravate the prognosis of patients with ARDS diagnosed according to the Berlin definition. PMID- 28592333 TI - Effect of Cessation of Contact Isolation for Endemic Methicillin-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci. PMID- 28592330 TI - State of play and clinical prospects of antibody gene transfer. AB - Recombinant monoclonal antibodies (mAbs) are one of today's most successful therapeutic classes in inflammatory diseases and oncology. A wider accessibility and implementation, however, is hampered by the high product cost and prolonged need for frequent administration. The surge in more effective mAb combination therapies further adds to the costs and risk of toxicity. To address these issues, antibody gene transfer seeks to administer to patients the mAb-encoding nucleotide sequence, rather than the mAb protein. This allows the body to produce its own medicine in a cost- and labor-effective manner, for a prolonged period of time. Expressed mAbs can be secreted systemically or locally, depending on the production site. The current review outlines the state of play and clinical prospects of antibody gene transfer, thereby highlighting recent innovations, opportunities and remaining hurdles. Different expression platforms and a multitude of administration sites have been pursued. Viral vector-mediated mAb expression thereby made the most significant strides. Therapeutic proof of concept has been demonstrated in mice and non-human primates, and intramuscular vectored mAb therapy is under clinical evaluation. However, viral vectors face limitations, particularly in terms of immunogenicity. In recent years, naked DNA has gained ground as an alternative. Attained serum mAb titers in mice, however, remain far below those obtained with viral vectors, and robust pharmacokinetic data in larger animals is limited. The broad translatability of DNA-based antibody therapy remains uncertain, despite ongoing evaluation in patients. RNA presents another emerging platform for antibody gene transfer. Early reports in mice show that mRNA may be able to rival with viral vectors in terms of generated serum mAb titers, although expression appears more short-lived. Overall, substantial progress has been made in the clinical translation of antibody gene transfer. While challenges persist, clinical prospects are amplified by ongoing innovations and the versatility of antibody gene transfer. Clinical introduction can be expedited by selecting the platform approach currently best suited for the mAb or disease of interest. Innovations in expression platform, administration and antibody technology are expected to further improve overall safety and efficacy, and unlock the vast clinical potential of antibody gene transfer. PMID- 28592335 TI - Disaster Management Structure of Universities: Case Study of the Central Campus of the University of Tehran. AB - OBJECTIVE: Research on the disaster management plans of renowned universities worldwide shows that such plans are generally compiled in 3 categories: structural, nonstructural, and organizational sections. The importance of earthquakes in Tehran and the high vulnerability of the University of Tehran to earthquakes encouraged us to challenge the university's plans concerning disaster management. METHODS: An initial attempt was made to analyze the disaster management of 23 renowned universities worldwide and their structure compared with the present organizational structure of the University of Tehran. Then an expert opinion study was done to determine the appropriate management structure of the Incident Command System. RESULTS: These efforts resulted in an adhocratic system as the proper one for emergency situations after an earthquake. Furthermore, the results of the comparative study led to a general management structure that may be considered as a global pattern. CONCLUSIONS: An appropriate organizational structure is proposed for the disaster management of the University of Tehran, which may be used as an appropriate disaster management structure for other universities. (Disaster Med Public Health Preparedness. 2017;11:681-693). PMID- 28592334 TI - Impact of oocyte-secreted factors on its developmental competence in buffalo. AB - Oocyte-secreted factors (OSFs) play an important role in the acquisition of oocyte developmental competence through bidirectional cross-talk between oocyte and cumulus cells via gap junctions. Thus, the present study was designed to investigate the effect of two OSFs, growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15), on the developmental competence of buffalo oocytes derived from two different follicle sizes. Cumulus-oocyte complexes (COCs) from large follicles (LF, >6 mm) or small follicles (SF, 0.05) between DOs and combination groups. Relative mRNA analysis revealed significantly higher (P > 0.05) expression of the cumulus cell marker genes EGFR, HAS2, and CD44 in LF derived than SF-derived oocyte; the expression of these markers was significantly higher (P > 0.05) in DOs and combination groups, irrespective of the follicle size. These results suggested that LF-derived oocytes have a higher developmental competence than SF-derived oocytes and that supplementation of GDF9 and BMP15 modulates the developmental competence of buffalo oocytes by increasing the relative abundance of cumulus-enabling factors and thereby increasing cleavage and the quality of blastocyst production. PMID- 28592336 TI - Changing Tradition in the Humanitarian Sector: The Business Model Approach of the Kenya Red Cross. PMID- 28592337 TI - Phylogenetic relationships among European and Asian representatives of the genus Aspidogaster Baer, 1827 (Trematoda: Aspidogastrea) inferred from molecular data. AB - In the present study, phylogenetic relationships of European and Far Eastern representatives of the genus Aspidogaster Baer, 1827 were analysed: A. conchicola Baer, 1827, A. limacoides Diesing, 1834, A. ijimai Kawamura, 1915 and A. chongqingensis Wei, Huang & Dai, 2001. Based on ITS1-5.8S-ITS2 rDNA sequence data, an obvious differentiation was seen between specimens of A. limacoides sensu stricto from the European part of Russia and A. limacoides sensu Chen et al., 2010 from China (13.7%); the latter parasites were recognized as A. chongqingensis. Aspidogaster chongqingensis was more closely related to A. ijimai than to A. limacoides s. str. Specimens of A. ijimai from the Amur River, Khanka Lake (Russian Far East) and China were grouped into a single clade with low intra specific molecular differentiation (d = 0-0.3%). Specimens of A. conchicola from the European part of Russia, the Russian Far East and China also formed a single distinct clade. Genetic differentiation between European and Chinese samples of this species was two times lower (d = 0.45%) than between Russian Far East and European or Chinese samples (d = 0.96%), suggesting a long-term separate existence of A. conchicola in the Russian Far East. PMID- 28592338 TI - Prenatal diagnosis of isolated total anomalous systemic venous connection to the left atrium. AB - We report the prenatal diagnosis and the neonatal follow-up of a patient with isolated total abnormal systemic venous connection to the left atrium. Right sided and left-sided superior caval veins and the inferior caval vein were all connected to the left atrium. Pulmonary venous return was normal. This was associated with some right ventricular underdevelopment. To our knowledge, this is the first fetal description of this very rare congenital cardiac malformation. PMID- 28592339 TI - Mass Casualty Incidents in the Underground Mining Industry: Applying the Haddon Matrix on an Integrative Literature Review. AB - OBJECTIVE: Underground mining is associated with obvious risks that can lead to mass casualty incidents. Information about such incidents was analyzed in an integrated literature review. METHODS: A literature search (1980-2015) identified 564 modern-era underground mining reports from countries sharing similar occupational health legislation. These reports were condensed to 31 reports after consideration of quality grading and appropriateness to the aim. The Haddon matrix was used for structure, separating human factors from technical and environmental details, and timing. RESULTS: Most of the reports were descriptive regarding injury-creating technical and environmental factors. The influence of rock characteristics was an important pre-event environmental factor. The organic nature of coal adds risks not shared in hard-rock mines. A sequence of mechanisms is commonly described, often initiated by a human factor in interaction with technology and step-wise escalation to involve environmental circumstances. Socioeconomic factors introduce heterogeneity. In the Haddon matrix, emergency medical services are mainly a post-event environmental issue, which were not well described in the available literature. The US Quecreek Coal Mine incident of 2002 stands out as a well-planned rescue mission. CONCLUSION: Evaluation of the preparedness to handle underground mining incidents deserves further scientific attention. Preparedness must include the medical aspects of rescue operations. (Disaster Med Public Health Preparedness. 2018;12:138-146). PMID- 28592341 TI - Intensive Care Unit Probiotic Utilization Rates: When Committee Recommendations and Physician Utilization Diverge. PMID- 28592340 TI - Influence of gonadotropins on ovarian follicle growth and development in vivo and in vitro. AB - Gonadotropins are the key regulators of ovarian follicles development. They are applied in therapeutic practice in assisted reproductive technology clinics. In the present review we discuss the basic gonadotropic hormones - recombinant human follicle-stimulating hormone, its derivatives, luteinizing hormone and gonadotropin serum of pregnant mares, their origin, and application in ovarian follicle systems in in vitro culture systems. PMID- 28592342 TI - Treatment of Obsessive Compulsive Disorder and Excessive Reassurance Seeking in an Older Adult: A Single Case Quasi-Experimental Design. AB - BACKGROUND: Cognitive behavioural interventions for excessive reassurance seeking (ERS) typically focus on encouraging individuals to refrain from seeking any reassurance and in some cases banning caregivers (e.g. family members) from providing it. However, this blanket consideration that reassurance is a bad thing that should simply be stopped may not always be appropriate or helpful. Cognitive behavioural treatment (CBT) targeting ERS by helping the sufferer to shift from seeking reassurance to seeking support may be a promising treatment intervention. AIMS: This study aims to examine the targeted treatment of ERS in an older adult who has been suffering from severe obsessive compulsive disorder (OCD) for seven decades. METHOD: Using a single case quasi-experimental design (ABCD), the frequency of reassurance seeking, urges to seek reassurance, OCD beliefs and anxiety were measured daily for almost a year in addition to standard symptom measures. RESULTS: At the end of treatment, visual inspection showed that reassurance seeking was no longer considered excessive and OCD severity fell from the severe to non-clinical range across the treatment sessions. All treatment gains were maintained at follow-up. CONCLUSIONS: This study illustrates how CBT can be successfully applied to treat long-standing OCD and ERS in an older adult. Engendering support as an alternative to reassurance seeking in CBT may be a particularly promising intervention for ERS. PMID- 28592343 TI - External Validation of Three Prediction Tools for Patients at Risk of a Complicated Course of Clostridium difficile Infection: Disappointing in an Outbreak Setting. AB - OBJECTIVE Estimating the risk of a complicated course of Clostridium difficile infection (CDI) might help doctors guide treatment. We aimed to validate 3 published prediction models: Hensgens (2014), Na (2015), and Welfare (2011). METHODS The validation cohort comprised 148 patients diagnosed with CDI between May 2013 and March 2014. During this period, 70 endemic cases of CDI occurred as well as 78 cases of CDI related to an outbreak of C. difficile ribotype 027. Model calibration and discrimination were assessed for the 3 prediction rules. RESULTS A complicated course (ie, death, colectomy, or ICU admission due to CDI) was observed in 31 patients (21%), and 23 patients (16%) died within 30 days of CDI diagnosis. The performance of all 3 prediction models was poor when applied to the total validation cohort with an estimated area under the curve (AUC) of 0.68 for the Hensgens model, 0.54 for the Na model, and 0.61 for the Welfare model. For those patients diagnosed with CDI due to non-outbreak strains, the prediction model developed by Hensgens performed the best, with an AUC of 0.78. CONCLUSION All 3 prediction models performed poorly when using our total cohort, which included CDI cases from an outbreak as well as endemic cases. The prediction model of Hensgens performed relatively well for patients diagnosed with CDI due to non-outbreak strains, and this model may be useful in endemic settings. Infect Control Hosp Epidemiol 2017;38:897-905. PMID- 28592344 TI - Whole grain intake of Australians estimated from a cross-sectional analysis of dietary intake data from the 2011-13 Australian Health Survey. AB - OBJECTIVE: The Australian Dietary Guidelines recommend Australians choose mostly whole-grain and/or high-fibre varieties within the grains (cereal) foods category, with other groups specifying a whole grain Daily Target Intake of 48 g for Australians aged 9 years or above. The USA and UK report estimates of whole grain intake that are low and declining, and no comprehensive studies on whole grain intake in the Australian population are available. The present study aimed to determine national estimates of whole grain intake, compared with current recommendations. DESIGN: A recently updated whole grain database was applied to the most current population dietary intake data. Single 24 h dietary recall intake data were reviewed against age group, sex, relative to energy intake and whole grain recommendations. SETTING: Australia. SUBJECTS: Australians (2-85 years) participating in the 2011-13 Australian Health Survey (n 12 153). RESULTS: The median daily whole grain intake was 21 g for adults (19-85 years) and 17 g for children/adolescents (2-18 years), or 28 and 23 g/10 MJ per d, respectively. Approximately 30 % of children/adolescents consumed no whole grains on the day of the survey. Whole grain intake was lowest for the age group 14-18 years (8.7 g/d). Of all participants aged >=9 years, 73 % did not reach the recommended Daily Target Intake of 48 g. CONCLUSIONS: Whole grain intake in Australia is below recommendations in all age groups. Adolescents may be a key target for campaigns to increase whole grain consumption. This study provides the first quantification of absolute whole grain intake from all food sources in a national sample of Australians. PMID- 28592345 TI - The effect of kinetic heat shock on bovine oocyte maturation and subsequent gene expression of targeted genes. AB - The exposure of oocytes to heat stress during the maturation process results in harmful effects to their internal organelles, low fertilization capability and higher embryonic losses. In the present experiment the effect of heat shock (HS) during the maturation process was assessed. In Assay 1, oocytes from winter (December-March; n = 100) and summer (June-September; n = 100) months were collected and matured to analyse their HS tolerance. Total RNA was extracted from matured oocytes and cDNA synthesis was performed, followed by qPCR for selected genes (Cx43, CDH1, DNMT1, HSPA14), compared with two reference genes (GAPDH and SDHA). In Assay 2, oocytes collected during the winter were subjected to kinetic HS by stressing them at 39.5 degrees C for 6, 12, 18 or 24 h and were afterwards matured at control temperature (38.5 degrees C), and subsequently subjected to the previously described gene analysis procedure. Results of Assay 1 show that summer-collected oocytes exhibited lower maturation rate than winter-collected oocytes, which may be due to the down-regulation of the HSPA 14 gene. Assay 2 showed that 6 h of HS had no effect on gene regulation. CDH1 and DNMT1 up regulation was observed starting at 12 h, which may represent the effect of heat shock on oocyte development. PMID- 28592346 TI - Analysing Tuberculosis Cases Among Healthcare Workers to Inform Infection Control Policy and Practices. AB - OBJECTIVE To determine the number and proportion of healthcare worker (HCW) tuberculosis (TB) cases infected while working in healthcare institutions in the Netherlands and to learn from circumstances that led to these infections. DESIGN Cohort analysis. METHODS We included all HCW TB patients reported to the Netherlands TB Register from 2000 to 2015. Using data from this register, including DNA fingerprints of the bacteria profile and additional information from public health clinics, HCW TB cases were classified into 4 categories: (1) infected during work in the Netherlands, (2) infected in the community, (3) infected outside the Netherlands, or (4) outside these 3 categories. An in-depth analysis of category 1 cases was performed to identify factors contributing to patient-to-HCW transmission. RESULTS In total, 131 HCW TB cases were identified: 32 cases (24%) in category 1; 13 cases (10%) in category 2; 42 cases (32%) in category 3; and 44 cases (34%) in category 4. The annual number of HCW TB cases (P<.05), the proportion among reported cases (P<.01), and the number of category 1 HCW TB cases (P=.12) all declined over the study period. Delayed diagnosis in a TB patient was the predominant underlying factor of nosocomial transmission in 47% of category 1 HCW TB patients, most of whom were subsequently identified in a contact investigation. Performing high-risk procedures was the main contributing factor in the other 53% of cases. CONCLUSION In low-incidence countries, every HCW TB case should warrant timely and thorough investigation to help further define and fine-tune the HCW screening policy and to monitor its proper implementation. Infect Control Hosp Epidemiol 2017;38:976-982. PMID- 28592348 TI - Distinguishing Clostridium difficile Recurrence From Reinfection: Independent Validation of Current Recommendations. AB - OBJECTIVE Distinguishing recurrent Clostridium difficile infection (CDI), defined as CDI caused by the same genotype, from reinfection with a different genotype, has important implications for surveillance and clinical trials investigating treatment effectiveness. We validated the proposed 8-week period for distinguishing "same genotype CDI" from "different genotype CDI," and we aimed to identify clinical variables with distinctiveness to propose an improved definition. METHODS From January 2004 to December 2013, a cohort of all inpatients with CDI at the University Hospital Basel, Switzerland, was established, and respective strains were collected. In patients with a second episode of CDI, both strains were compared using polymerase chain reaction (PCR) ribotyping. The standard definition of recurrence (within 8 weeks after initial diagnosis) was evaluated for its performance to predict CDI caused by the same genotype. RESULTS Among 750 patients with CDI, 130 (17.3%) were diagnosed with recurrence or reinfection. Strains from both episodes were available from 106 patients. Identical strains were identified in 36 patients with recurrence (36 of 47) and 27 patients with reinfection (27 of 59). Sensitivity, specificity, and negative and positive predictive values of the standard definition were 56%, 74%, 53%, and 76%, respectively. An extended period of 20 weeks resulted in the best match for both sensitivity and specificity (83% and 58%, respectively), while none of the clinical characteristics revealed independent distinctive power. CONCLUSIONS Our results challenge the utility of the 8-week cutoff for distinguishing recurrent CDI from reinfection. An extended period of 20 weeks may result in improved overall performance characteristics, but this finding requires external validation. Infect Control Hosp Epidemiol 2017;38:891-896. PMID- 28592347 TI - Management of the thyroid gland during laryngectomy. AB - OBJECTIVES: This study aimed to: describe the incidence of thyroid gland involvement in advanced laryngeal cancer, analyse patterns of spread to the thyroid and elucidate predictors of thyroid involvement. METHODS: A retrospective review was performed on patients who underwent laryngectomy from 1991 to 2015 as a primary or salvage treatment for squamous cell carcinoma of the larynx, hypopharynx or base of tongue. The incidence of thyroidectomy during total laryngectomy, type of thyroidectomy, incidence of gland involvement, route of spread, and positive predictors of spread were analysed and reported. RESULTS: A total of 188 patients fit the inclusion criteria. Of these, 125 (66 per cent) underwent thyroidectomy. The thyroid was involved in 10 of the 125 patients (8 per cent), 9 by direct extension and 1 by metastasis. Cartilage invasion was a predictor of thyroid gland involvement, with a positive predictive value of 26 per cent. CONCLUSION: There is a low incidence of thyroid gland involvement in laryngeal carcinoma. Most cases of gland involvement occurred by direct extension. Thyroidectomy during laryngectomy should be considered for advanced stage tumours with cartilage invasion. PMID- 28592349 TI - Development of a video-delivered relaxation treatment of late-life anxiety for veterans. AB - BACKGROUND: Behavioral treatments reduce anxiety, yet many older adults may not have access to these efficacious treatments. To address this need, we developed and evaluated the feasibility and acceptability of a video-delivered anxiety treatment for older Veterans. This treatment program, BREATHE (Breathing, Relaxation, and Education for Anxiety Treatment in the Home Environment), combines psychoeducation, diaphragmatic breathing, and progressive muscle relaxation training with engagement in activities. METHODS: A mixed methods concurrent study design was used to examine the clarity of the treatment videos. We conducted semi-structured interviews with 20 Veterans (M age = 69.5, SD = 7.3 years; 55% White, Non-Hispanic) and collected ratings of video clarity. RESULTS: Quantitative ratings revealed that 100% of participants generally or definitely could follow breathing and relaxation video instructions. Qualitative findings, however, demonstrated more variability in the extent to which each video segment was clear. Participants identified both immediate benefits and motivation challenges associated with a video-delivered treatment. Participants suggested that some patients may need encouragement, whereas others need face-to-face therapy. CONCLUSIONS: Quantitative ratings of video clarity and qualitative findings highlight the feasibility of a video-delivered treatment for older Veterans with anxiety. Our findings demonstrate the importance of ensuring patients can follow instructions provided in self-directed treatments and the role that an iterative testing process has in addressing these issues. Next steps include testing the treatment videos with older Veterans with anxiety disorders. PMID- 28592351 TI - Actual expense associated with patients with Alzheimer's disease in Colombia. AB - BACKGROUND: There is paucity in the level of knowledge on the actual insurer expenses associated with patients suffering with dementia in the developing world. Less is known about direct costs by severity and how costs vary because of the presence of other comorbidities. METHODS: Using claims data from an insurer for three years, we identified patients with AD with an algorithm that takes advantage of information on age, primary diagnosis, and services and drugs provided. RESULTS: Distribution by dementia stage was as follows: mild 21%, moderate 53%, severe 17%, and undetermined 9%. Expenses paid for all causes by the insurer were at least double than estimated in the literature and were increasing annually at rates higher than 30%. Also, 92% of patients have at least another chronic condition. CONCLUSIONS: Worldwide costs of dementia estimates maybe underestimating the actual costs to health systems in the developing world. PMID- 28592350 TI - Vitamin D status in renal transplant recipients living in a low-latitude city: association with body fat, cardiovascular risk factors, estimated glomerular filtration rate and proteinuria. AB - Recent evidence suggests that vitamin D deficiency is associated with CVD, impaired kidney function and proteinuria. To date, no study has evaluated these associations in renal transplant recipients (RTR) adjusting for body adiposity assessed by a 'gold standard' method. This study aimed to evaluate the vitamin D status and its association with body adiposity, CVD risk factors, estimated glomerular filtration rate (eGFR) and proteinuria in RTR, living in Rio de Janeiro, Brazil (a low-latitude city (22 degrees 54'10"S)), taking into account body adiposity evaluated by dual-energy X-ray absorptiometry (DXA). This cross sectional study included 195 RTR (114 men) aged 47.6 (sd 11.2) years. Nutritional evaluation included anthropometry and DXA. Risk factors for CVD were hypertension, diabetes mellitus, dyslipidaemia and the metabolic syndrome. eGFR was evaluated using the Chronic Kidney Disease Epidemiology Collaboration equation. Serum 25-hydroxyvitamin D (25(OH)D) concentration was used to define vitamin D status as follows: 10 % (n 19) had vitamin D deficiency (30 ng/ml). Percentage of body fat (DXA) was significantly associated with vitamin D deficiency independently of age, sex and eGFR. Lower 25(OH)D was associated with higher odds of the metabolic syndrome and dyslipidaemia after adjustment for age, sex and eGFR, but not after additional adjustment for body fat. Hypertension and diabetes were not related to 25(OH)D. Lower serum 25(OH)D was associated with increasing proteinuria and decreasing eGFR even after adjustments for age, sex and percentage of body fat. This study suggests that in RTR of a low-latitude city hypovitaminosis D is common, and is associated with excessive body fat, decreased eGFR and increased proteinuria. PMID- 28592352 TI - The health and health preparation of long-term Australian travellers. AB - A growing number of Australians are travelling domestically for extended periods. This creates challenges in both continuity of health care and burdens on health services. This paper reports a cross-sectional survey aimed to explore the health needs and health planning of long-term travellers. In total, 316 respondents who had travelled for more than 3 months consecutively in the last year participated. Most respondents were retired (n=197; 62.3%); however, ages ranged from 26 to 89 years. Nearly half of the respondents or their travel companion had a long-term illness that affected their daily life (n=135; 42.7%). Nearly half of respondents visited a GP (n=133; 42.1%), nearly one-quarter visited an Emergency Department (n=72; 22.8%) and 19.9% (n=63) visited another health provider while travelling. The level of preparation around health while travelling varied between participants. This study highlights that long-term travellers have significant health needs and are likely to require health services during their extended travel. Additionally, it identifies that currently few strategies are used to plan for health care during travel. This raises issues for rural and remote health services in terms of both capacity and continuity of care. PMID- 28592353 TI - Role of information and communication technology in promoting oral health at residential aged care facilities. AB - Information and communication technology (ICT) can provide knowledge and clinical support to those working in residential aged care facilities (RACFs). This paper aims to: (1) review literature on ICT targeted at residents, staff and external providers in RACFs including general practitioners, dental and allied health professionals on improving residents' oral health; (2) identify barriers and enablers to using ICT in promoting oral health at RACFs; and (3) investigate evidence of effectiveness of these approaches in promoting oral health. Findings from this narrative literature review indicate that ICT is not widely used in RACFs, with barriers to usage identified as limited training for staff, difficulties accessing the Internet, limited computer literacy particularly in older staff, cost and competing work demands. Residents also faced barriers including impaired cognitive and psychosocial functioning, limited computer literacy and Internet use. Findings suggest that more education and training in ICT to upskill staff and residents is needed to effectively promote oral health through this medium. PMID- 28592355 TI - Why intensity is not a bad word - Benefits and practical aspects of high effort resistance training to the older. PMID- 28592354 TI - Post wall fixation by lag screw only in associated both column fractures with posterior wall involvement. AB - PURPOSE: To evaluate the quality of reduction, clinical outcomes and complications of associated both column acetabular fractures with posterior wall involvement that are treated through single ilioinguinal approach and fixation of posterior wall by lag screws only. METHODS: We conducted a retrospective review involving ninety-nine consecutive patients with associated both column fractures of acetabulum treated through single ilioinguinal approach. Patients were divided into two groups. The first group consisted of 35 patients presented with both column fractures with posterior wall involvement that fixation performed with lag screws. This group was compared to a second group of 64 patients with both column fractures without posterior wall involvement. The quality of reduction was assessed using criteria described by Matta. The size of posterior wall fragment was measured. Functional outcome was evaluated using Modified Postel Merle D'Aubigne score. Radiographs at the latest follow up were analyzed for arthritis (Kellgren-Lawrence classification), and femoral head avascular necrosis (Ficat/Arlet classification). RESULTS: The study showed no significant differences in all preoperative variables (P>0.05). While intraoperative blood loss and operative time in group 1 were increased compared to group 2, the difference was not statistically significant (P>0.05). The height, relative depth and peripheral length of posterior wall respectively were 27.8+/-2.5mm (range: 24 35mm), 71.5+/-5.4% (range: 65-88%), 23.0+/-2.3mm (range: 17-28mm). The mean posterior wall fracture displacement is 5.0+/-3.2mm (range: 0-11mm). There was no difference regarding the quality of reduction between the two groups (P>0.05). The excellent to good clinical outcome was around 71.4% in the group 1 versus 73.4% in the group 2 at the final follow-up, this difference was not statistically significant (P>0.05). There was no difference in rate of complications between the two groups (P>0.05). CONCLUSIONS: Lag screws fixation of posterior wall through single ilioinguinal approach in associated both column fractures of acetabulum is a safe and effective method. Our results shown that the presence of posterior wall fracture in cases of associated both column fractures does not compromise the clinical outcomes. PMID- 28592356 TI - Use of health resources and healthcare costs associated with nutritional risk: The FRADEA study. AB - BACKGROUND: In spite of its high prevalence and its clinical relevance, the economic impact of malnutrition has not been sufficiently explored. OBJECTIVE: To study whether malnutrition predicts total hospital healthcare costs and costs related to specialist visits, emergency department visits and hospitalization in older adults. METHODS: Concurrent cohort study in Albacete City, Spain. The study sample included 827 subjects aged 70 and over from the FRADEA Study. Mini Nutritional Assessment(r)-Short Form (MNA(r)-SF) was recorded at baseline. Use of hospital resources (hospital admissions, emergency visits, and specialist visits), and hospital healthcare costs were recorded at follow-up. Generalized linear models (GLM) adjusted for age, sex, comorbidity, polypharmacy, and disability in basic activities of daily living were used to estimate the impact of nutritional factors on total healthcare costs per person/year (? base year 2013) as well as specialist visit costs, emergency department visit costs and hospitalization costs. RESULTS: The average cost associated with the use of health resources was 1922?/year. Subjects with MNA(r)-SF between 0 and 7 had an average total health cost of 3492?/year, 2744?/year in those with MNA(r)-SF between 8 and 11, and 1542?/year in those with MNA(r)-SF between 12 and 14. Of the total health cost, 67.2% was associated with hospital admission costs. Adjusted healthcare costs were 714?/year greater in subjects with malnutrition or nutritional risk. Subjects with malnutrition or nutritional risk presented an increased adjusted risk of hospitalization (OR1.72, 95% CI 1.22-2.43). CONCLUSIONS: Malnutrition assessed by MNA(r)-SF is a prognostic factor of high healthcare cost and use of resources in older adults. PMID- 28592358 TI - Engineering waterborne Pseudomonas aeruginosa out of a critical care unit. AB - OBJECTIVE: To describe engineering and holistic interventions on water outlets contaminated with Pseudomonas aeruginosa and the observed impact on clinical P. aeruginosa patient isolates in a large Intensive Care Unit (ICU). DESIGN: Descriptive study. SETTING: Queen Elizabeth Hospital Birmingham (QEHB), part of University Hospitals Birmingham (UHB) NHS Foundation Trust is a tertiary referral teaching hospital in Birmingham, UK and provides clinical services to nearly 1 million patients every year. METHODS: Breakpoint models were used to detect any significant changes in the cumulative yearly rates of clinical P. aeruginosa patient isolates from August 2013-December 2016 across QEHB. RESULTS: Water sampling undertaken on the ICU indicated 30% of the outlets were positive for P. aeruginosa at any one time. Molecular typing of patient and water isolates via Pulsed Field Gel Electrophoresis suggested there was a 30% transmission rate of P. aeruginosa from the water to patients on the ICU. From, February 2014, QEHB implemented engineering interventions, consisting of new tap outlets and PALL point-of-use filters; as well as holistic measures, from February 2016 including a revised tap cleaning method and appropriate disposal of patient waste water. Breakpoint models indicated the engineering and holistic interventions resulted in a significant (p<0.001) 50% reduction in the number of P. aeruginosa clinical patient isolates over a year. CONCLUSION: Here we demonstrate that the role of waterborne transmission of P. aeruginosa in an ICU cannot be overlooked. We suggest both holistic and environmental factors are important in reducing transmission. PMID- 28592357 TI - Physicochemical parameters affecting the perception of borehole water quality in Ghana. AB - Rural Ghanaian communities continue using microbiologically contaminated surface water sources due in part to undesirable organoleptic characteristics of groundwater from boreholes. Our objective was to identify thresholds of physical and chemical parameters associated with consumer complaints related to groundwater. Water samples from 94 boreholes in the dry season and 68 boreholes in the rainy season were analyzed for 18 parameters. Interviews of consumers were conducted at each borehole regarding five commonly expressed water quality problems (salty taste, presence of particles, unfavorable scent, oily sheen formation on the water surface, and staining of starchy foods during cooking). Threshold levels of water quality parameters predictive of complaints were determined using the Youden index maximizing the sum of sensitivity and specificity. The probability of complaints at various parameter concentrations was estimated using logistic regression. Exceedances of WHO guidelines were detected for pH, turbidity, chloride, iron, and manganese. Concentrations of total dissolved solids (TDS) above 172mg/L were associated with salty taste complaints. Although the WHO guideline is 1000mg/L, even at half the guideline, the likelihood of salty taste complaint was 75%. Iron concentrations above 0.11, 0.14 and 0.43mg/L (WHO guideline value 0.3mg/L) were associated with complaints of unfavorable scent, oily sheen, and food staining, respectively. Iron and TDS concentrations exhibited strong spatial clustering associated with specific geological formations. Improved groundwater sources in rural African communities that technically meet WHO water quality guidelines may be underutilized in preference of unimproved sources for drinking and domestic uses, compromising human health and sustainability of improved water infrastructure. PMID- 28592360 TI - Clinical study of a new Modified Early Warning System scoring system, some lingering doubts. PMID- 28592359 TI - Mercury accumulation in Lethrinus nebulosus from the marine waters of the Qatar EEZ. AB - Total mercury (THg) and methylmercury (MeHg) were recorded in the commercial demersal fish Lethrinus nebulosus, caught from six locations in Qatar EEZ (Exclusive Economic Zone). Concentrations of THg decreased in the order: liver?muscle?gonad. THg concentrations in fish tissue ranged from 0.016ppm in gonad to 0.855ppm (mgkg-1w/w) in liver tissues, while concentrations in muscle tissue ranged from 0.24 to 0.49ppm (mgkg-1w/w) among sampling sites. MeHg concentrations were used to validate food web transfer rate calculations. Intake rates were calculated to assess the potential health impact of the fish consumption. There is no major threat to human health from the presence of Hg in L. nebulosus, based upon reasonable consumption patterns, limited to no more than three meals of L. nebulosus per week. PMID- 28592361 TI - CT imaging of solid renal masses: pitfalls and solutions. AB - Computed tomography (CT) remains the first-line imaging test for the characterisation of renal masses; however, CT has inherent limitations, which if unrecognised, may result in errors. The purpose of this manuscript is to present 10 pitfalls in the CT evaluation of solid renal masses. Thin section non-contrast enhanced CT (NECT) is required to confirm the presence of macroscopic fat and diagnosis of angiomyolipoma (AML). Renal cell carcinoma (RCC) can mimic renal cysts at NECT when measuring <20 HU, but are usually heterogeneous with irregular margins. Haemorrhagic cysts (HC) may simulate solid lesions at NECT; however, a homogeneous lesion measuring >70 HU is essentially diagnostic of HC. Homogeneous lesions measuring 20-70 HU at NECT or >20 HU at contrast-enhanced (CE) CT, are indeterminate, requiring further evaluation. Dual-energy CT (DECT) can accurately characterise these lesions at baseline through virtual NECT, iodine overlay images, or quantitative iodine concentration analysis without recalling the patient. A minority of hypo-enhancing renal masses (most commonly papillary RCC) show indeterminate or absent enhancement at multiphase CT. Follow-up, CE ultrasound or magnetic resonance imaging (MRI) is required to further characterise these lesions. Small (<3 cm) endophytic cysts commonly show pseudo enhancement, which may simulate RCC; this can be overcome with DECT or MRI. In small (<4 cm) solid renal masses, 20% of lesions are benign, chiefly AML without visible fat or oncocytoma. Low-dose techniques may simulate lesion heterogeneity due to increased image noise, which can be ameliorated through the appropriate use of iterative reconstruction algorithms. PMID- 28592362 TI - In vitro treatment of Toxoplasma gondii with copper(II) complexes induces apoptosis-like and cellular division alterations. AB - Toxoplasma gondii is the causative agent of toxoplasmosis, which is one of the most common parasitic diseases in the world. This pathogen causes severe damage to immunocompromised hosts, and the most frequently used therapy is the combination of pyrimethamine and sulfadiazine, which has side effects. Thus, there is a need for new therapies that target T. gondii. Herein, we present the anti-Toxoplasma effect of two new copper(II) complexes: [(H2L1) Cu (MU-Cl)2 Cu(H2L1)] Cl2.5H2O (1) and [(H2L2) Cu (MU-Cl)2 Cu(H2L2)] Cl2.6H2O (2). Complexes (1) and (2) irreversibly controlled parasite growth in vitro, with IC50 values of 0.78MUM and 3.57MUM, respectively, after 48h. These complexes induced part of the tachyzoite population to convert to bradyzoites, which eventually die. The cell death mechanism was unknown, but signs of apoptosis, such as membrane blebs and nuclear fragmentation, and necrosis, such as plasma membrane disruption, intense cytoplasm vesiculation and the release of cellular contents, were seen. In addition, complex (2) interfered with the correct disposition of the inner membrane complex of the parasite, affecting cell division. These results indicate that these copper complexes have potential effects against T. gondii and may be used as drugs in the future or serve as prototypes for the development of new drugs to treat toxoplasmosis. PMID- 28592363 TI - LDL apheresis as it relates to nursing practice. AB - Nurses are an essential partner in the treatment of complex diseases and they have extensive influence on patient outcomes. Connecting a patient to a machine takes courage, skill, and a whole lot of trust. Anyone who has earned the title of "nurse" has shown courage. Skill comes with hours and hours of practice. Trust is earned and ongoing. Combine these three attributes and you get the "care" that goes into nursing care. Low-density lipoprotein (LDL) apheresis is a well established therapy for hypercholesterolemia. This article will focused on the Liposorber(r) MA-03 system in a brief conversation of LDL apheresis as it relates to nursing practice. PMID- 28592365 TI - Assisted baseline subtraction in complex chromatograms using the BEADS algorithm. AB - The data processing step of complex signals in high-performance liquid chromatography may constitute a bottleneck to obtain significant information from chromatograms. Data pre-processing should be preferably done with little (or no) user supervision, for a maximal benefit and highest speed. In this work, a tool for the configuration of a state-of-the-art baseline subtraction algorithm, called BEADS (Baseline Estimation And Denoising using Sparsity) is developed and verified. A quality criterion based on the measurement of the autocorrelation level was designed to select the most suitable working parameters to obtain the best baseline. The use of a log transformation of the signal attenuated artifacts associated to a large disparity in signal size between sample constituents. Conventional BEADS makes use of trial-and-error strategies to set up the working parameters, which makes the process slow and inconsistent. This constitutes a major drawback in its successful application. In contrast, the assisted BEADS simplifies the setup, shortens the processing time and makes the baseline subtraction more reliable. The assisted algorithm was tested on several complex chromatograms corresponding to extracts of medicinal herbs analysed with acetonitrile-water gradients, and a mixture of sulphonamides eluted with acetonitrile gradients in the presence of the non-ionic surfactant Brij-35 under micellar conditions. PMID- 28592364 TI - Erratum to "Characteristics and prognosis of Japanese colorectal cancer patients: The BioBank Japan Project" [J Epidemiol 27(3S) (2017) S36-S42]. PMID- 28592367 TI - Corrigendum to "Safety assessment and attenuation of cisplatin induced nephrotoxicity by tuberous roots of Boerhaavia diffusa" [Regul. Toxicol. and Pharmacol. 81 (2016) 341-352]. PMID- 28592366 TI - Unmet needs for information and psychosocial support in relation to quality of life and emotional distress: A comparison between gynecological and breast cancer patients. AB - OBJECTIVE: We compared gynecological and breast cancer patients regarding their needs for information and psychosocial support, quality of life (QoL), and emotional distress and the relationship among these constructs. METHODS: In a multicenter, cross-sectional study in Germany, we evaluated 1214 female cancer patients (317 with gynecological cancer, 897 with breast cancer). We obtained self-reports of unmet needs, using a self-developed measure. We measured QoL with the EORTC QLQ-C30, symptoms of depression with the Patient Health Questionnaire (PHQ-9), and symptoms of anxiety with the Generalized Anxiety Disorder Scale (GAD 7). RESULTS: Compared to breast cancer patients, gynecological cancer patients felt less informed about several aspects of their disease, particularly regarding psychological support (p<0.001), tended to have more unmet information needs, and reported lower QoL levels. Lower emotional functioning, but higher physical functioning were independent correlates of the level of unmet information needs. Depressive symptoms and higher physical functioning (only in breast cancer) were independent correlates of higher needs for psychosocial support. CONCLUSION: Compared to breast cancer, gynecological cancer patients were less satisfied with the information received and reported lower levels of QoL. PRACTICE IMPLICATIONS: Both clinicians and policy makers should take efforts to address the higher needs of gynecological cancer patients. PMID- 28592368 TI - Plant Breeding Goes Microbial. AB - Plant breeding has traditionally improved traits encoded in the plant genome. Here we propose an alternative framework reaching novel phenotypes by modifying together genomic information and plant-associated microbiota. This concept is made possible by a novel technology that enables the transmission of endophytic microbiota to the next plant generation. PMID- 28592370 TI - Smoking-epigenetics interaction: What do microRNAs tell us about susceptibility to atherosclerotic disease in smokers? PMID- 28592369 TI - Preliminary study of histamine H4 receptor expressed on human CD4+ T cells and its immunomodulatory potency in the IL-17 pathway of psoriasis. AB - BACKGROUND: Previous studies have shown the expression of histamine H4 receptor (H4R) on CD4+ T cells, especially human CD4+ Th2-polarized T cells. OBJECTIVE: This study aimed to investigate the role of H4R on these effector T cells in psoriasis. METHODS: We enrolled three patients each with active psoriasis, inactive psoriasis, scalp seborrheic dermatitis, and three normal controls, and compared the basal expression of H4R mRNA in their peripheral blood CD4+ T cells. Then, we identified H4R expression in dermal CD4+ T cells. Furthermore, we investigated H4R expression after stimulating separated peripheral blood CD4+ T cells with several inflammatory cytokines. RESULTS: The results showed higher H4R expression in the active psoriasis group compared to the inactive psoriasis group. It was interesting that interleukin (IL)-23, which is a representative cytokine contributing to Th17 cell differentiation, stimulated H4R expression significantly. After adding a selective H4R antagonist (JNJ-7777120) while the CD4+ T cells were polarized into Th17 cells, we observed a tendency toward suppressed IL-17 secretion. CONCLUSIONS: Histamine stimulation influences the IL 17 pathway in psoriasis via the fourth histamine receptor subtype, H4R, on CD4+ T cells. The immunomodulatory roles of H4R suggest its potency as a new therapeutic target for obstinate psoriasis. PMID- 28592371 TI - Low yield of blood and wound cultures in patients with skin and soft-tissue infections. AB - BACKGROUND: Current guidelines recommend blood cultures in skin and soft-tissue infection (SSTI) patients only with signs of systemic toxicity and wound cultures for severe purulent infections. Our objectives were to determine: 1) blood and wound culture yields in patients admitted with SSTIs; 2) whether injection drug users (IDUs) and febrile patients had higher blood culture yields; and 3) whether blood and wound cultures grew organisms sensitive to typical SSTI empiric antibiotics. METHODS: We prospectively enrolled adult patients admitted from the ED with SSTIs at an urban hospital. We recorded patient characteristics, including IDU, comorbidities and temperatures, and followed admitted patients throughout their hospital course. RESULTS: Of 734 SSTI patients enrolled, 246 (33.5%) were admitted. Of 86 (35.0%) patients who had blood cultures, six had positive cultures (yield=7.0%; 95% confidence intervals [CIs] 3.2-14.4); 4 were methicillin sensitive Staphylococcus aureus (MSSA) and 2 were methicillin resistant (MRSA). Of 29 febrile patients, 1 had a positive culture (yield=3.5%; 95% CI 0.6-17.2). Of 101 admitted IDU patients, 46 (46%) received blood cultures, and 4 had positive cultures (yield=8.7%; 95% CI 3.4-20.3). Of 89 patients with purulent wounds, 44 (49.4%) patients had ED wound cultures. Thirteen had positive cultures (yield=29.6%; 95% CI 18.2-44.2%). Most were MRSA, MSSA, and group A Streptococcus species - all sensitive to Vancomycin. CONCLUSIONS: Febrile and IDU patients had low yields of blood cultures similar to yields in non-IDU and afebrile patients. All blood and wound culture species were adequately covered by currently recommended empiric antibiotic regimens. PMID- 28592373 TI - "What's the next step?" Improving interfacility emergency department transfer handoff communication. PMID- 28592372 TI - Scene time interval and good neurological recovery in out-of-hospital cardiac arrest. AB - OBJECTIVES: It is unclear whether scene time interval (STI) is associated with better neurological recovery in the emergency medical service (EMS) system with intermediate service level. METHODS: Adult out-of-hospital cardiac arrest (OHCA) patients with presumed cardiac etiology (2012 to 2014) were analyzed, excluding patients not-resuscitated, occurred in ambulance/medical/nursing facility, unknown STI or extremely longer STI (>60 min), and unknown outcomes. STI was classified into short (0.0-3.9 min), middle (4.0-7.9 min), long (8.0-11.9 min), and very-long (12.0-59.9 min), respectively. The end point was a good cerebral performance category (CPC) 1 or 2. Multivariable logistic regression by STI group (reference=short) was performed to calculate adjusted odds ratios (AORs) with 95% confidence intervals (95% CIs) for outcomes with or without interaction term (STI*prehospital return of spontaneous circulation, (PROSC)). RESULTS: Of 79,832 OHCA patients, 41,054 cases were analyzed; good CPC in the short (3.0%), middle (3.2%), long (3.0%), and very-long (2.9%) STI groups were similar, respectively (p=0.55). The AORs (95% CI) for good CPC in the final model without interaction term were 0.74 (0.58-0.95) for the middle, 0.51 (0.39-0.67) for the long, and 0.45 (0.33-0.61) for the very-long STI group (reference=short STI). The AORs in PROSC group were 1.18 (0.97-1.44) for middle STI group, 0.72 (0.57-0.92) for long group, and 0.56 (0.42-0.77) for very-long group. The AORs in non-PROSC group were 1.22 (1.06-1.40) for middle STI group, 0.82 (0.70-0.96) for long group, and 0.70 (0.57-0.85) for very-long group. CONCLUSION: The middle STI (4-7min) was associated with the highest odds of neurological recovery for patients who could not be restored in the field. The STI may be a clinically useful predictor of good neurology outcome in victims of cardiac arrest. PMID- 28592374 TI - Characteristics and outcomes of acute pediatric blunt torso trauma based on injury intent. AB - INTRODUCTION: Blunt trauma is a leading cause of pediatric morbidity. We compared injuries, interventions and outcomes of acute pediatric blunt torso trauma based on intent. METHODS: We analyzed de-identified data from a prospective, multi center emergency department (ED)-based observational cohort of children under age eighteen. Injuries were classified based on intent (unintentional/inflicted). We compared demographic, physical and laboratory findings, ED disposition, hospitalization, need for surgery, 30-day mortality, and cause of death between groups using Chi-squared or Fisher's test for categorical variables, and Mann Whitney test for non-normal continuous factors comparing median values and interquartile ranges (IQR). RESULTS: There were 12,044 children who sustained blunt torso trauma: Inflicted=720 (6%); Unintentional=9563 (79.4%); Indeterminate=148 (1.2%); Missing=1613 (13.4%). Patients with unintentional torso injuries significantly differed from those with inflicted injuries in median age in years (IQR) [10 (5, 15) vs. 14 (8, 16); p-value<0.001], race, presence of pelvic fractures, hospitalization and need for non-abdominal surgery. Mortality rates did not differ based on intent. Further adjustment using binary, logistic regression revealed that the risk of pelvic fractures in the inflicted group was 96% less than the unintentional group (OR: 0.04; 95%CI: 0.01-0.26; p value=0.001). CONCLUSIONS: Children who sustain acute blunt torso trauma due to unintentional causes have a significantly higher risk of pelvic fractures and are more likely to be hospitalized compared to those with inflicted injuries. PMID- 28592375 TI - An educational intervention allows for greater prehospital recognition of acute stroke. PMID- 28592376 TI - Post-operative fatal blood aspiration after routine lung surgery. AB - A routine question encountered in medicolegal practice is whether the death of a patient in proximity to a surgical procedure is due to medical malpractice. The case of a 62-year-old man who died two weeks after undergoing a VATS sleeve resection of the upper right lung lobe in conjunction with radical lymphadenectomy, a routine surgical procedure, is reported. To address the issue of medical malpractice, a forensic autopsy was ordered by the investigative authority. During the autopsy, the lungs were removed as a whole and fixed in formalin and were later dissected in cooperation with a thoracic surgeon. In the course of this dissection, a bronchovascular fistula, which had led to the occlusion of the bronchial system with clotted blood, was discovered. Bronchovascular fistulas are a rare complication of bronchial sleeve resections. Because this surgical complication is essentially always fatal, it is highly pertinent to medicolegal practice. The presented case report also lists other important complications associated with bronchial anastomosis and elucidates a pragmatic approach to obtaining an expert clinical assessment of possible medical malpractice after operations through the example of a dissection performed in cooperation with a thoracic surgeon. PMID- 28592377 TI - Normative Values of Short-Term Heart Rate Variability Parameters in Koreans and Their Clinical Value for the Prediction of Mortality. AB - BACKGROUND: Heart rate variability (HRV) analysis is an important clinical tool for characterising cardiac autonomic status. We sought to determine the normative values and characteristics of the HRV parameters derived from a short-term study in Koreans and to determine their clinical role in predicting mortality. METHODS: A total of 1828 consecutive patients (range 20-84 years, men 64.8%) with no serious comorbid conditions were recruited. The RR intervals from 10-minute electrocardiograms were used for computation of the following HRV parameters: conventional time- and frequency-domain measures and nonlinear measures. RESULTS: A greater age-dependence of most conventional parameters, including the low frequency (LF) and high frequency (HF) powers, was observed than that of the Shannon entropy (ShanEn), approximate entropy (ApEn), and sample entropy. Fifty four patients (14 cardiac deaths) died during a 10-year follow-up period. The LF/HF ratio (odds ratio [OR], 0.876; p=0.025), ShanEn (OR, 0.372; p=0.028), and ApEn (OR, 0.093; p=0.030) were found to be predictors of all-cause mortality in the multivariate regression analysis. Age was also a powerful risk factor for all cause mortality (OR, 1.141; p<0.001). CONCLUSIONS: We presented the normative values and characterised the short-term HRV parameters in Koreans. Among the short-term nonlinear parameters, the ShanEn and ApEn were adjunctive parameters for predicting the all-cause mortality in the general population. PMID- 28592378 TI - No FAD, No CRY: Redox and Circadian Rhythms. AB - There is growing evidence of reciprocal interactions between the endogenous circadian clock and subcellular redox pathways. Recently, researchers at the University of California unearthed another possible link between redox metabolism and the mammalian circadian clock: the redox cofactor FAD stabilises the clock protein cryptochrome (CRY), modifying rhythmic clock gene expression. PMID- 28592379 TI - Comprehensive Geriatric Assessment in Men Aged 70 Years or Older with Localised Prostate Cancer Undergoing Radical Radiotherapy. AB - AIMS: Treatment decisions for men aged 70 years or over with localised prostate cancer need to take into account the risk of death from competing causes and fitness for the proposed treatment. Objective assessments such as those included in a comprehensive geriatric assessment (CGA) might help to inform the decision making process. The aim of this study was to describe the CGA scores of a cohort of older men with prostate cancer, evaluate potential screening tools in this population and assess whether any CGA component predicts significant acute radiotherapy toxicity. MATERIALS AND METHODS: This was a prospective cohort study undertaking pretreatment CGA, Vulnerable Elders Survey (VES-13) and G8 assessment in patients aged 70 years and over with localised prostate cancer planned to undergo radical external beam radiotherapy. RESULTS: In total, 178 participants were recruited over a 3 year period and underwent a CGA. Fifty-five (30.1%) participants were defined as having health needs identified by their CGA. Both VES-13 and G8 screening tools showed a statistically significant association with CGA needs (P < 0.001 and X2 = 15.02, P < 0.001, respectively), but their sensitivity was disappointing. There was no association between a CGA (or its components) and significant acute radiotherapy toxicity. CONCLUSIONS: Many older men with localised prostate cancer are vulnerable according to a CGA. The screening tools evaluated were not sufficiently sensitive to identify this group. CGA outcome does not predict for significant acute radiotherapy toxicity. PMID- 28592380 TI - Good practices of publishing AYUSH research: A practical checklist for authors. AB - Since its inception, Journal of Ayurveda and Integrative Medicine (J-AIM) has been constantly striving to create an environment that inculcates and strengthens "Good Publication Practices (GPP)" amongst students, practitioners and researchers in AYUSH community. The J-AIM has been doing this in the form of conducting workshops on scientific writing and research methods on different platforms. This article is based on our experiences and varied discussions that we have had with students, teachers, practitioners and researchers during these interactive sessions, and is intended at addressing the gap that prevails in the domain. The need for such awareness is felt even more strongly ever since the Beall's list of predatory journals has been unpublished. This article tries to fill the void this disappearance has created. We analyze the current scenario of AYUSH publications, enumerate the common perceptions and concerns among the workers in the field, and consider the periodicals where the doctoral and postgraduate level of Ayurveda research works are being published at present. The article also presents a practical checklist that will be helpful for students and teachers to refer authentic resources and submit their work to an appropriate scholarly journal. PMID- 28592381 TI - Getting under the skin. PMID- 28592382 TI - Incidence of MRI-detected brain lesions and neurocognitive function after electrical cardioversion in anticoagulated patients with persistent atrial fibrillation. AB - BACKGROUND: After electrical cardioversion (eCV) in patients with atrial fibrillation (AF), the risk for clinically apparent cerebral thromboembolism is increased in the subsequent weeks. To date, there is little evidence on the incidence of acute brain lesions (ABL) detected with cerebral magnetic resonance imaging (MRI) after eCV, in particular in patients treated with the Non-Vitamin K Antagonist oral anticoagulants (NOAC). AIMS: The aim of this pilot study was to evaluate the incidence of MRI-detected ABL, as well as the neuro-cognitive function after eCV in patients with persistent AF using NOACs as compared to phenprocoumon. METHODS AND RESULTS: 50 consecutive patients with persistent AF (mean age 69.6+/-3.5years, 26 male) were evaluated in this prospective study. Cerebral 3Tesla MRI and neuro-cognitive assessment using the National Institutes of Health Stroke Scale (NIHSS) score and the Montreal Cognitive Assessment Test (MoCA) were performed in all patients within 24h before eCV and after a median follow-up duration of 14days (Q1: 13, Q3: 19days). Patients were treated with an OAC for at least 4weeks after eCV and according to the CHA2DS2-Vasc-score thereafter. Thirty-nine patients were treated with NOACs (Dabigatran 10/50 [20%], Apixaban 21/50 [42%] and Rivaroxaban 8/50 [16]) and 11/50 patients with Phenprocoumon (22%). No patient developed ABL on cerebral MRI at the 2-week follow-up. Neurological as well as cognitive function were similar before and 2weeks after eCV (NIHSS-score: p=0.35; MoCa score: p=0.21). CONCLUSION: Electrical CV in patients with persistent AF, in particular when treated with NOACs, carries a low risk for the development of MRI-detected ABL or neurocognitive decline. CLINICAL TRIALS REGISTRATION: GermanClinicalTrialsRegister number: DRKS00010460. PMID- 28592383 TI - Long-term outcome prediction by functional parameters derived from coronary computed tomography angiography. AB - BACKGROUND: Estimation of hemodynamic relevance of a coronary stenosis from coronary computed angiography (CCTA) has raised substantial interest. Recently, the corrected coronary opacification (CCO) decrease and the transluminal attenuation gradient (TAG) have been suggested as faster alternatives to the FFRCT. The aim of the study was to evaluate whether the diagnostic accuracy of CCO decrease and TAG translates into an added prognostic value in patients evaluated for coronary artery disease (CAD). METHODS: This retrospective study consists of 162 consecutive patients referred for evaluation of known or suspected CAD by CCTA. CCO decrease was defined as difference of mean luminal coronary attenuation normalized to aorta attenuation proximal-distal of a stenosis. To calculate TAG, mean attenuation was measured at 5-mm intervals from the ostium to a distal segment with a minimal cross-sectional area of 2.0mm2. Death, myocardial infarction, unstable angina requiring hospitalization, and coronary revascularization were defined as major adverse cardiac events (MACE). Multivariate analysis included covariates age, sex, >=3 cardiovascular risk factors and stenosis severity. RESULTS: Follow-up was completed in 154 patients, CAD was found in 72. During median follow-up of 6.1years (interquartile range, 5.8-6.9years), 55 patients experienced a MACE. Among CAD patients, the presence of an abnormal CCO decrease (p<0.05) but not TAG (p=0.894) was associated with a worse MACE-free survival. In multivariate analysis, CCO decrease was an independent predictor of MACE (HR, 2.27; 95% CI, 1.14-4.52; p=0.02) while TAG was not predictive (p=0.895). CONCLUSION: In CAD patients, CCO decrease adds long term prognostic value over clinical characteristics and stenosis severity while TAG does not. PMID- 28592384 TI - Gender differences in long-term clinical outcomes and prognostic factors in patients with vasospastic angina. AB - BACKGROUND: Men are more likely to suffer from vasospastic angina (VSA) than women; however, gender differences in the long-term prognosis of VSA patients have not been fully elucidated. We sought to investigate clinical outcomes and predictive factors of VSA patients according to gender. METHODS: A total of 986 patients (838 men and 148 women) with a positive result on intracoronary ergonovine provocation test between January 2003 and December 2014 were analyzed. The primary outcome was major adverse cardiac events (MACE), defined as a composite of cardiac death, acute myocardial infarction, revascularization, or rehospitalization due to recurrent angina. RESULTS: Women were younger and showed a lower prevalence of smoking or fixed coronary stenosis than men. The risk for MACE was similar between male and female patients (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.65-1.39; p=0.79). In multivariable prediction models for MACE, high-sensitivity C-reactive protein (hs-CRP) level was a significant predictor of MACE in male patients (HR, 1.95; 95% CI, 1.25-3.06; p=0.003), but there was no significant predictor in female patients. There was a significant interaction between hs-CRP level and MACE rate across genders (interaction p=0.02). CONCLUSIONS: Long-term clinical outcome was not different between genders. Hs-CRP was an important predictor of long-term clinical outcomes in male patients with VSA, but not in female patients. PMID- 28592385 TI - Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) modulates T1DM susceptibility by gut microbiota. AB - Nucleotide-binding oligomerization domain-containing protein 2 (Nod2) is an innate immune receptor. To investigate the role of Nod2 in susceptibility to the autoimmune disease, type 1 diabetes mellitus (T1DM), we generated Nod2-/- non obese diabetic (NOD) mice. The Nod2-/-NOD mice had different composition of the gut microbiota compared to Nod2+/+NOD mice and were significantly protected from diabetes, but only when housed separately from Nod2+/+NOD mice. This suggested that T1DM susceptibility in Nod2-/-NOD mice is dependent on the alteration of gut microbiota, which modulated the frequency and function of IgA-secreting B-cells and IL-10 promoting T-regulatory cells. Finally, colonizing germ-free NOD mice with Nod2-/-NOD gut microbiota significantly reduced pro-inflammatory cytokine secreting immune cells but increased T-regulatory cells. Thus, gut microbiota modulate the immune system and T1D susceptibility. Importantly, our study raises a critical question about the housing mode in the interpretation of the disease phenotype of genetically-modified mouse strains in T1DM studies. PMID- 28592389 TI - Spaces of well-being among young adults with physical disabilities transitioning from pediatric to adult healthcare. AB - BACKGROUND: Youth with disabilities are at risk of poor health outcomes as they transition to adult healthcare. Although space and place play an important role in accessing healthcare little is known about the spatial aspects of youth's transition from pediatric to adult healthcare. OBJECTIVE: To understand the spaces of well-being as youth with physical disabilities transition from pediatric to adult healthcare. METHODS: This study draws on a qualitative design involving 63 in-depth interviews with young adults (n = 22), parents (n = 17), and clinicians (n = 24) involved in preparing young adults for transition. All participants were recruited from a pediatric rehabilitation hospital within a metropolitan area of Ontario, Canada. Data were analyzed using an inductive content analysis approach that was informed by the spaces of well-being framework. RESULTS: The results highlight that within the 'spaces of capability' those with more disability-related complications and/or those using a mobility device encountered challenges in their transition to adult care. The 'spaces of security' influencing youth's well-being during their transition included: temporary (in)security while they were away at college, and health (in)security. Most of the focus on youth's transition included 'integrative spaces', which can enhance or hinder their well-being. Such spaces included: spatial (dis)connections (distance to access care), embeddedness (family and community), physical access, and distance. Meanwhile, therapeutic spaces involved having spaces that youth were satisfied with and enhanced their well-being as they transitioned to adult care. CONCLUSIONS: In applying the spaces of well-being framework, the findings showed that youth had varied experiences regarding spaces of capability, security, integrative, and therapeutic spaces. PMID- 28592387 TI - Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. AB - BACKGROUND: Dabrafenib plus trametinib improves clinical outcomes in BRAFV600 mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases. METHODS: This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAFV600E-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAFV600E-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAFV600D/K/R-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAFV600D/E/K/R-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. FINDINGS: Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8.5 months (IQR 5.5-14.0), 44 (58%; 95% CI 46-69) of 76 patients in cohort A achieved an intracranial response. Intracranial response by investigator assessment was also achieved in nine (56%; 95% CI 30-80) of 16 patients in cohort B, seven (44%; 20-70) of 16 patients in cohort C, and ten (59%; 33-82) of 17 patients in cohort D. The most common serious adverse events related to study treatment were pyrexia for dabrafenib (eight [6%] of 125 patients) and decreased ejection fraction (five [4%]) for trametinib. The most common grade 3 or worse adverse events, regardless of study drug relationship, were pyrexia (four [3%] of 125) and headache (three [2%]). INTERPRETATION: Dabrafenib plus trametinib was active with a manageable safety profile in this melanoma population that was consistent with previous dabrafenib plus trametinib studies in patients with BRAFV600-mutant melanoma without brain metastases, but the median duration of response was relatively short. These results provide evidence of clinical benefit with dabrafenib plus trametinib and support the need for additional research to further improve outcomes in patients with melanoma brain metastases. FUNDING: Novartis. PMID- 28592386 TI - CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial. AB - BACKGROUND: CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. METHODS: In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m2 on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m2], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m2]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0.15 to 0.15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. FINDINGS: Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46.8%; 95% CI 40.4-53.2] of 248 patients) and reference trastuzumab (129 [50.4%; 44.1-56.7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0.04% [95% CI -0.12 to 0.05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). INTERPRETATION: CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. FUNDING: Celltrion Inc. PMID- 28592388 TI - Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. AB - BACKGROUND: Papillary renal cell carcinoma (PRCC) is a rare subset of RCC. The Cancer Genome Atlas (TCGA) data largely reflect localized disease, and there are limited data for advanced PRCC. OBJECTIVE: To characterize the frequency of genomic alterations (GAs) in patients with advanced PRCC for whom comprehensive genomic profiling (CGP) was performed in the context of routine clinical care. DESIGN, SETTING, AND PARTICIPANTS: Formalin-fixed, paraffin-embedded tissue was obtained for 169 consecutive patients with confirmed PRCC. DNA was extracted and comprehensive genomic profiling was performed in a certified central laboratory. MEASUREMENTS: Hybrid-capture, adaptor ligation-based libraries of up to 315 genes were sequenced to a median coverage of 648*. All classes of GAs were identified, including substitutions, insertions/deletions, copy number alterations, and rearrangements. RESULTS AND LIMITATIONS: From 169 patients, either primary tumor tissue (102 patients, 60%) or metastatic tissue (67 patients, 40%) was collected. In patients with type 1 PRCC, commonly altered genes were MET (33%; 8 activating mutations, 5 amplifications at >6 copies), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In patients with type 2 PRCC, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%), and FH (13%); MET GAs (5 mutations, 3 amplifications) were observed in 7% of type 2 cases. Notable differences from TCGA data include higher frequencies of MET, NF2, and CDKN2A/B GAs, association of alterations in SWI/SNF complex genes with type 2 PRCC, and observation of frequent CDKN2A/B alterations in both type 1 and type 2 disease. CONCLUSIONS: Both the current study and the TCGA experience represent similarly sized cohorts of patients with PRCC. Key differences in GA frequency probably underscore the marked difference in stage distribution between these data sets. These results may inform planned precision medicine trials for metastatic PRCC. PATIENT SUMMARY: Papillary renal cell carcinoma (PRCC) is a rare subtype of kidney cancer, and understanding of the biology of advanced PRCC is limited. This report highlights some of the unique biologic features of PRCC that may inform on future use of targeted therapies for the treatment of metastatic disease. PMID- 28592390 TI - Greywater characterization and loadings - Physicochemical treatment to promote onsite reuse. AB - Greywater is the wastewater produced in bathtubs, showers, hand basins, kitchen sinks, dishwashers and laundry machines. Segregation of greywater and blackwater and on site greywater treatment in order to promote its reuse for toilet flushing and/or garden irrigation is an interesting option especially in water deficient areas. The objective of this study was to characterize the different greywater sources in Greek households and to evaluate the performance of alternative physicochemical treatment systems to treat several types of greywater. Based on the results average daily greywater production was equal to 98 L per person per day and accounts for approximately 70-75% of the total household wastewater production (135 L per person per day). Among the different sources, laundry and kitchen sink are the main contributors to the total greywater load of organic carbon, suspended solids and surfactants, whereas dishwasher and bathroom greywater are the main sources of phosphorus and endocrine disrupting chemicals respectively. Depending on sources, greywater accounts for as low as 15% of the total wastewater load of organic carbon (in the case of light greywater sources), to as high as 74% of the total load organic load (in the case of the heavy greywater sources). On the other hand, the nutrients load of greywater is limited. The application of a physical treatment system consisting of coagulation, sedimentation, sand filtration, granular activated carbon filtration and disinfection can provide for a final effluent with high quality characteristics for onsite reuse, especially when treating light greywater. PMID- 28592391 TI - Long-term fate of the upper tracts following complete primary repair of bladder exstrophy. AB - INTRODUCTION: Complete primary repair of bladder exstrophy (CPRE) is widely used for classic bladder exstrophy (CBE) closure. Long-term renal function with or without dilation in these patients is poorly characterized and may be impacted by bladder storage parameters or recurrent urinary tract infections (UTIs). OBJECTIVE: We sought to assess our long-term experience with CPRE and investigate factors that may influence upper-tract deterioration. STUDY DESIGN: A retrospective review of patients at our institution with CBE undergoing CPRE from 1990 to 2015 was performed. Patients were considered included if age at the last renal ultrasound was at least 5 years. Renal imaging and renal function were reviewed. The Society of Fetal Urology (SFU) and Upper Tract Dilation (UTD) grades were retrospectively assigned to all available ultrasounds with hydronephrosis (HN). Additionally, outcomes related to vesicoureteral reflux and lower urinary tract function were assessed. Descriptive and comparative statistical analyses were performed to assess factors influencing HN and renal function at follow-up. RESULTS: Thirty patients (57% male) had a median follow-up of 9.7 (3.9-22.3) years. The table shows the HN status and grade for the entire group, stratified by gender, continence, and surgical reconstruction in. The mean creatinine was 0.50 mg/dL (0.2-1.0) and the mean estimated glomerular filtration rate (eGFR) was 106.8 mL/min/1.73 m2. No patient had greater than stage 2 chronic kidney disease. Male gender was associated with worse renal outcomes, including overall rate of HN (p < 0.001), severity of HN (p = 0.004) and worse eGFR (p = 0.05). Lower tract reconstruction, urodynamic parameters, and continence were not associated with differences in upper-tract outcomes. Ureteral reimplantation was performed in 22 patients (73%) at a mean age of 22 months for indications of persistent VUR (10), worsening HN (1), or recurrent UTI (11). DISCUSSION: HN is common following CPRE, although severe HN is seen infrequently. Overall long-term renal outcomes are similar to those of other techniques presented in the literature. However, male gender portends a higher risk for long-term upper-tract deterioration as measured by HN and eGFR. Ureteral reimplantation and the status of the lower urinary tract were not associated with differences in upper-tract outcomes. CONCLUSIONS: Prospective, standardized approaches to characterize upper tract outcomes are needed to follow children with bladder exstrophy into adulthood. We believe higher-risk patients should be assessed early and managed more aggressively with attention paid towards accurately assessing renal function and lower tract anatomy. PMID- 28592392 TI - Code Krishna: an innovative practice respecting death, dying and beyond. AB - In moments of grief, human beings seek solace and attempt to discover the meaning of life and death by reaching out to wider and deeper dimensions of existence that stem from their religious, cultural and spiritual beliefs. Conventional patient care fails to consider this vital aspect of our lives. Many hold the view that life and its experiences do not end with death; the body is but a sheath which holds the soul that inhabits it. The use of a protocol-based practice to create a solemn atmosphere around the departed individual can bridge the gap between the materialistic and non-materialistic perceptions of the dimensions of care. The innovative practice, "Code Krishna", is aimed at institutionalising a practice which sensitises and empowers the treating team to address the grief of the relatives of deceased patients, and respect the departed in consonance with the family's cultural, religious and spiritual beliefs. The practice entails the creation of a solemn atmosphere amidst the action-packed environment of the critical care unit at the time of the patient's death, offering of collective prayer and floral tributes, and observation of silence both by the healthcare team and family members. Code Krishna attempts to blend current care practices with spirituality, ensuring that the treating team is the first to commiserate with the grieving family, with warmth and openness. In this piece, we briefly report our first-hand experiences of practising Code Krishna in our hospital [Shree Krishna Hospital, Karamsad, Central Gujarat]. PMID- 28592393 TI - Enhancing the autonomy of Indian nurses. AB - With additional training and qualification, nurses in several countries are recognised as independent professionals. Evidence from several countries shows that capacitating nurses to practise independently could contribute to better health outcomes. Recently, the idea of nurses practising independently has been gaining momentum in Indian health policy circles as well, and the Ministry of Health and Family Welfare is contemplating the introduction of nurse practitioners (NPs) in primary healthcare. We briefly assess the policy environment for the role of NPs in India. We argue for the need to conceptualise health stewardship anew, keeping the nursing profession in mind, within the currently doctor-centred health system in India. We argue that, in the current policy environment, conditions for independent nursing practice or for the introduction of a robust NP in primary healthcare do not yet exist. PMID- 28592395 TI - Using Social Media to Characterize Public Sentiment Toward Medical Interventions Commonly Used for Cancer Screening: An Observational Study. AB - BACKGROUND: Although cancer screening reduces morbidity and mortality, millions of people worldwide remain unscreened. Social media provide a unique platform to understand public sentiment toward tools that are commonly used for cancer screening. OBJECTIVE: The objective of our study was to examine public sentiment toward colonoscopy, mammography, and Pap smear and how this sentiment spreads by analyzing discourse on Twitter. METHODS: In this observational study, we classified 32,847 tweets (online postings on Twitter) related to colonoscopy, mammography, or Pap smears using a naive Bayes algorithm as containing positive, negative, or neutral sentiment. Additionally, we characterized the spread of sentiment on Twitter using an established model to study contagion. RESULTS: Colonoscopy-related tweets were more likely to express negative than positive sentiment (negative to positive ratio 1.65, 95% CI 1.51-1.80, P<.001), in contrast to the more positive sentiment expressed regarding mammography (negative to positive ratio 0.43, 95% CI 0.39-0.47, P<.001). The proportions of negative versus positive tweets about Pap smear were not significantly different (negative to positive ratio 0.95, 95% CI 0.87-1.04, P=.18). Positive and negative tweets tended to share lexical features across screening modalities. Positive tweets expressed resonance with the benefits of early detection. Fear and pain were the principal lexical features seen in negative tweets. Negative sentiment for colonoscopy and mammography spread more than positive sentiment; no correlation with sentiment and spread was seen for Pap smear. CONCLUSIONS: Analysis of social media data provides a unique, quantitative framework to better understand the public's perception of medical interventions that are commonly used for cancer screening. Given the growing use of social media, public health interventions to improve cancer screening should use the health perceptions of the population as expressed in social network postings about tests that are frequently used for cancer screening, as well as other people they may influence with such postings. PMID- 28592394 TI - Social Media Use and Access to Digital Technology in US Young Adults in 2016. AB - BACKGROUND: In 2015, 90% of US young adults with Internet access used social media. Digital and social media are highly prevalent modalities through which young adults explore identity formation, and by extension, learn and transmit norms about health and risk behaviors during this developmental life stage. OBJECTIVE: The purpose of this study was to provide updated estimates of social media use from 2014 to 2016 and correlates of social media use and access to digital technology in data collected from a national sample of US young adults in 2016. METHODS: Young adult participants aged 18-24 years in Wave 7 (October 2014, N=1259) and Wave 9 (February 2016, N=989) of the Truth Initiative Young Adult Cohort Study were asked about use frequency for 11 social media sites and access to digital devices, in addition to sociodemographic characteristics. Regular use was defined as using a given social media site at least weekly. Weighted analyses estimated the prevalence of use of each social media site, overlap between regular use of specific sites, and correlates of using a greater number of social media sites regularly. Bivariate analyses identified sociodemographic correlates of access to specific digital devices. RESULTS: In 2014, 89.42% (weighted n, 1126/1298) of young adults reported regular use of at least one social media site. This increased to 97.5% (weighted n, 965/989) of young adults in 2016. Among regular users of social media sites in 2016, the top five sites were Tumblr (85.5%), Vine (84.7%), Snapchat (81.7%), Instagram (80.7%), and LinkedIn (78.9%). Respondents reported regularly using an average of 7.6 social media sites, with 85% using 6 or more sites regularly. Overall, 87% of young adults reported access or use of a smartphone with Internet access, 74% a desktop or laptop computer with Internet access, 41% a tablet with Internet access, 29% a smart TV or video game console with Internet access, 11% a cell phone without Internet access, and 3% none of these. Access to all digital devices with Internet was lower in those reporting a lower subjective financial situation; there were also significant differences in access to specific digital devices with Internet by race, ethnicity, and education. CONCLUSIONS: The high mean number of social media sites used regularly and the substantial overlap in use of multiple social media sites reflect the rapidly changing social media environment. Mobile devices are a primary channel for social media, and our study highlights disparities in access to digital technologies with Internet access among US young adults by race/ethnicity, education, and subjective financial status. Findings from this study may guide the development and implementation of future health interventions for young adults delivered via the Internet or social media sites. PMID- 28592396 TI - Prevalence of and Risk Factors for Childhood Asthma, Rhinitis, and Eczema in Hong Kong: Proposal for a Cross-Sectional Survey. AB - BACKGROUND: Previous studies have shown that particulate matter is a major problem in indoor air quality in Hong Kong schools, but little has been done to assess its relationship with health indicators in the children attending those schools. Our study aims to address this research gap by collecting aerosol data in schools to examine the link between different air pollutants with childhood respiratory health. It is important to explore whether or not the prevalence of asthma, allergic rhinoconjunctivitis, and eczema are increasing in local children. OBJECTIVE: Our aim is to (1) examine the prevalence of asthma, allergic rhinitis, and eczema in school children aged 6-7 years in Hong Kong between 2001 and 2017, and (2) measure air quality at primary schools and explore its relationship with health outcomes measured by the International Study of Asthma and Allergies in Childhood (ISAAC) survey. METHODS: This is a cross-sectional study consisting of an ISAAC questionnaire and aerosol data collection. We have recruited over 2000 parents of primary school students aged 6-7 years old for the questionnaire, and so far 19 schools have completed aerosol data collection. RESULTS: The study is expected to be completed this year. CONCLUSIONS: We predict that our study will show a significant change in the prevalence of asthma, allergic rhinitis, and eczema in school children aged 6-7 years old in recent years. In addition, we expect to show a significant association between air quality at school and health outcomes measured by the ISAAC survey. PMID- 28592399 TI - Dacomitinib Beats Gefitinib for EGFR+ NSCLC. AB - The irreversible EGFR inhibitor dacomitinib reduced the chance of lung cancer progression compared with an older, first-generation EGFR inhibitor, gefitinib, in a phase III trial. As reported at the 2017 American Society of Clinical Oncology Annual Meeting, the experimental drug also increased toxicity, which could limit its use, especially with a safer, more effective third-generation EGFR inhibitor not far behind in the development pipeline. PMID- 28592397 TI - Gamification in Stress Management Apps: A Critical App Review. AB - BACKGROUND: In today's society, stress is more and more often a cause of disease. This makes stress management an important target of behavior change programs. Gamification has been suggested as one way to support health behavior change. However, it remains unclear to which extend available gamification techniques are integrated in stress management apps, and if their occurrence is linked to the use of elements from behavior change theory. OBJECTIVE: The aim of this study was to investigate the use of gamification techniques in stress management apps and the cooccurrence of these techniques with evidence-based stress management methods and behavior change techniques. METHODS: A total of 62 stress management apps from the Google Play Store were reviewed on their inclusion of 17 gamification techniques, 15 stress management methods, and 26 behavior change techniques. For this purpose, an extended taxonomy of gamification techniques was constructed and applied by 2 trained, independent raters. RESULTS: Interrater reliability was high, with agreement coefficient (AC)=.97. Results show an average of 0.5 gamification techniques for the tested apps and reveal no correlations between the use of gamification techniques and behavior change techniques (r=.17, P=.20), or stress management methods (r=.14, P=.26). CONCLUSIONS: This leads to the conclusion that designers of stress management apps do not use gamification techniques to influence the user's behaviors and reactions. Moreover, app designers do not exploit the potential of combining gamification techniques with behavior change theory. PMID- 28592400 TI - Dual Checkpoint Blockade Takes Aim at Relapsed Mesothelioma. AB - In the largest clinical trial to date of immune checkpoint inhibitors for mesothelioma, patients treated with nivolumab-either alone or in combination with ipilimumab-posted impressive response rates and survival outcomes, according to data presented at the 2017 American Society of Clinical Oncology Annual Meeting. However, the combination, although more effective, was also more toxic. PMID- 28592403 TI - Saliha Mahmood: Junior doctor, master chef. PMID- 28592401 TI - Transgenic tomatoes expressing the 6F peptide and ezetimibe prevent diet-induced increases of IFN-beta and cholesterol 25-hydroxylase in jejunum. AB - Feeding LDL receptor (LDLR)-null mice a Western diet (WD) increased the expression of IFN-beta in jejunum as determined by quantitative RT-PCR (RT-qPCR), immunohistochemistry (IHC), and ELISA (all P < 0.0001). WD also increased the expression of cholesterol 25-hydroxylase (CH25H) as measured by RT-qPCR (P < 0.0001), IHC (P = 0.0019), and ELISA (P < 0.0001), resulting in increased levels of 25-hydroxycholesterol (25-OHC) in jejunum as determined by LC-MS/MS (P < 0.0001). Adding ezetimibe at 10 mg/kg/day or adding a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) at 0.06% by weight of diet substantially ameliorated these changes. Adding either ezetimibe or Tg6F to WD also ameliorated WD-induced changes in plasma lipids, serum amyloid A, and HDL cholesterol. Adding the same doses of ezetimibe and Tg6F together to WD (combined formulation) was generally more efficacious compared with adding either agent alone. Surprisingly, adding ezetimibe during the preparation of Tg6F, but before addition to WD, was more effective than the combined formulation for all parameters measured in jejunum (P = 0.0329 to P < 0.0001). We conclude the following: i) WD induces IFN-beta, CH25H, and 25-OHC in jejunum; and ii) Tg6F and ezetimibe partially ameliorate WD-induced inflammation by preventing WD-induced increases in IFN-beta, CH25H, and 25-OHC. PMID- 28592404 TI - Alcohol-flavoured tobacco products. AB - BACKGROUND: In 2009, the Food and Drug Administration (FDA) banned characterising flavours in cigarettes (except for menthol) due to their appeal to teen starter smokers. In August 2016, the agency deemed all tobacco products to be under its authority and a more comprehensive flavour ban is under consideration. OBJECTIVES: To determine the scope and scale of alcohol-flavoured tobacco products among cigars & cigarillos, hookahs and electronic cigarettes (e cigarettes). METHODS: Alcohol-flavoured tobacco products were identified by online search of tobacco purveyors' product lines and via Google search cross referencing the various tobacco product types versus a list of alcoholic beverage flavours (eg, wine, beer, appletini, margarita). RESULTS: 48 types of alcohol flavoured tobacco products marketed by 409 tobacco brands were identified. Alcohol flavours included mixed drinks (n=25), spirits (11), liqueurs (7) and wine/beer (5). Sweet and fruity tropical mixed drink flavours were marketed by the most brands: pina colada (96), mojito (66) and margarita (50). Wine flavours were common with 104 brands. Among the tobacco product categories, brands offering alcohol-flavoured e-cigarettes (280) were most numerous, but alcohol flavoured products were also marketed by cigars & cigarillos (88) and hookah brands (41). Brands by major tobacco companies (eg, Philip Morris, Imperial Tobacco) were well represented among alcohol-flavoured cigars & cigarillos with five companies offering a total of 17 brands. CONCLUSIONS: The widespread availability of alcohol-flavoured tobacco products illustrates the need to regulate characterising flavours on all tobacco products. PMID- 28592406 TI - Factors influencing practice variation in the management of nephrotic syndrome: a qualitative study of pediatric nephrology care providers. AB - BACKGROUND: Treatment protocols for childhood nephrotic syndrome are highly variable between providers and care centres. We conducted a qualitative study to understand the complex multilevel processes that lead to practice variation and influence provider management of nephrotic syndrome. METHODS: Focus groups with multidisciplinary pediatric nephrology care providers (n = 67) from 10 Canadian pediatric nephrology centres that had more than 1 pediatric nephrologist were conducted between September 2013 and April 2015. Focus group discussions were guided by the Ottawa Model for Research Use. We used a semistructured interview guide to elicit participants' perspectives regarding 1) the work setting and context of the clinical environment, 2) reasons for variation at the provider level and 3) clinical practice guidelines for nephrotic syndrome. Focus group discussions were transcribed and analyzed concurrently with the use of qualitative content analysis. RESULTS: Emerging themes were grouped into 2 categories: centre-level factors and provider-level factors. At the centre level, the type of care model used, clinic structures and resources, and lack of communication and collaboration within and between Canadian centres influenced care variation. At the provider level, use of experiential knowledge versus empirical knowledge and interpretation of patient characteristics influenced provider management of nephrotic syndrome. INTERPRETATION: Centre- and provider level factors play an important role in shaping practice differences in the management of childhood nephrotic syndrome. Further research is needed to determine whether variation in care is associated with disparities in outcomes. PMID- 28592410 TI - Ernest Walton. PMID- 28592408 TI - Recovery of Corneal Sensitivity and Increase in Nerve Density and Wound Healing in Diabetic Mice After PEDF Plus DHA Treatment. AB - Diabetic keratopathy decreases corneal sensation and tear secretion and delays wound healing after injury. In the current study, we tested the effect of treatment with pigment epithelium-derived factor (PEDF) in combination with docosahexaenoic acid (DHA) on corneal nerve regeneration in a mouse model of diabetes with or without corneal injury. The study was performed in streptozotocin-induced diabetic mice (C57BL/6). Ten weeks after streptozotocin injection, diabetic mice showed significant decreases of corneal sensitivity, tear production, and epithelial subbasal nerve density when compared with age matched normal mice. After diabetic mice were wounded in the right eye and treated in both eyes with PEDF+DHA for 2 weeks, there was a significant increase in corneal epithelial nerve regeneration and substance P-positive nerve density in both wounded and unwounded eyes compared with vehicle-treated corneas. There also was elevated corneal sensitivity and tear production in the treated corneas compared with vehicle. In addition, PEDF+DHA accelerated corneal wound healing, selectively recruited type 2 macrophages, and prevented neutrophil infiltration in diabetic wounded corneas. These results suggest that topical treatment with PEDF+DHA promotes corneal nerve regeneration and wound healing in diabetic mice and could potentially be exploited as a therapeutic option for the treatment of diabetic keratopathy. PMID- 28592409 TI - Undergraduate and Medical School Physiology Education in the United States. PMID- 28592412 TI - Polypill is not just for cardiovascular disease. PMID- 28592414 TI - Effects of sarcolipin deletion on skeletal muscle adaptive responses to functional overload and unload. AB - Overexpression of sarcolipin (SLN), a regulator of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs), stimulates calcineurin signaling to enhance skeletal muscle oxidative capacity. Some studies have shown that calcineurin may also control skeletal muscle mass and remodeling in response to functional overload and unload stimuli by increasing myofiber size and the proportion of slow fibers. To examine whether SLN might mediate these adaptive responses, we performed soleus and gastrocnemius tenotomy in wild-type (WT) and Sln-null (Sln-/-) mice and examined the overloaded plantaris and unloaded/tenotomized soleus muscles. In the WT overloaded plantaris, we observed ectopic expression of SLN, myofiber hypertrophy, increased fiber number, and a fast-to-slow fiber type shift, which were associated with increased calcineurin signaling (NFAT dephosphorylation and increased stabilin-2 protein content) and reduced SERCA activity. In the WT tenotomized soleus, we observed a 14-fold increase in SLN protein, myofiber atrophy, decreased fiber number, and a slow-to-fast fiber type shift, which were also associated with increased calcineurin signaling and reduced SERCA activity. Genetic deletion of Sln altered these physiological outcomes, with the overloaded plantaris myofibers failing to grow in size and number, and transition towards the slow fiber type, while the unloaded soleus muscles exhibited greater reductions in fiber size and number, and an accelerated slow-to-fast fiber type shift. In both the Sln-/- overloaded and unloaded muscles, these findings were associated with elevated SERCA activity and blunted calcineurin signaling. Thus, SLN plays an important role in adaptive muscle remodeling potentially through calcineurin stimulation, which could have important implications for other muscle diseases and conditions. PMID- 28592413 TI - Recruitment of endosomal signaling mediates the forskolin modulation of guinea pig cardiac neuron excitability. AB - Forskolin, a selective activator of adenylyl cyclase (AC), commonly is used to establish actions of G protein-coupled receptors (GPCRs) that are initiated primarily through activation of AC/cAMP signaling pathways. In the present study, forskolin was used to evaluate the potential role of AC/cAMP, which is a major signaling mechanism for the pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor, in the regulation of guinea pig cardiac neuronal excitability. Forskolin (5-10 uM) increases excitability in ~60% of the cardiac neurons. The forskolin-mediated increase in excitability was considered related to cAMP regulation of a cyclic nucleotide gated channel or via protein kinase A (PKA)/ERK signaling, mechanisms that have been linked to PAC1 receptor activation. However, unlike PACAP mechanisms, forskolin enhancement of excitability was not significantly reduced by treatment with cesium to block currents through hyperpolarization-activated nonselective cation channels (Ih) or by treatment with PD98059 to block MEK/ERK signaling. In contrast, treatment with the clathrin inhibitor Pitstop2 or the dynamin inhibitor dynasore eliminated the forskolin-induced increase in excitability; treatments with the inactive Pitstop analog or PP2 treatment to inhibit Src-mediated endocytosis mechanisms were ineffective. The PKA inhibitor KT5702 significantly suppressed the forskolin induced change in excitability; further, KT5702 and Pitstop2 reduced the forskolin-stimulated MEK/ERK activation in cardiac neurons. Collectively, the present results suggest that forskolin activation of AC/cAMP/PKA signaling leads to the recruitment of clathrin/dynamin-dependent endosomal transduction cascades, including MEK/ERK signaling, and that endosomal signaling is the critical mechanism underlying the forskolin-induced increase in cardiac neuron excitability. PMID- 28592416 TI - Understanding the American healthcare reform debate. PMID- 28592417 TI - Electrophysiological findings show generalised post-photoreceptoral deficiency in macular telangiectasia type 2. AB - BACKGROUND: Photoreceptor damage, reported in single observations, has been suggested to contribute to the disease pathogenesis in macular telangiectasia type 2 (MacTel2). The purpose of this study was to ascertain whether the photoreceptor or post-photoreceptoral function is affected in MacTel2 and could be detected using electrophysiological examination. METHODS: Thirty-five eyes from 18 patients (15 men, aged 60.1+/-9.6 years, range 38-77 years) with MacTel2 were included in the study. All patients underwent standard ophthalmic examination followed by pattern electroretinography (PERG) and full-field ERG. The data were compared against 22 normal control subjects (10 men, age 59.83+/ 6.28 years, range 48-76). RESULTS: Mean PERG P50 amplitude and peak time in patients with MacTel2 did not differ significantly from control values (p>0.2) but P50 amplitude was subnormal in three patients. The mean scotopic rod b-wave amplitude was significantly lower in patients than in healthy controls (p=0.027). A lower dark-adapted 10.0 b-wave (p=0.06) but not a-wave amplitude (p=0.58) was present in patients with MacTel2. Photopic single-flash a-wave and b-wave amplitudes did not differ between patient and control groups (p=0.2 and 0.3), but 30 Hz flicker peak time was significantly later in patients with MacTel2 with no effect on amplitude (p=0.04 and 0.7). CONCLUSION: Both scotopic (rod system dominated) and photopic ERGs (cone system) are consistent with post photoreceptoral dysfunction. There was no electrophysiological evidence of dysfunction at the level of the photoreceptor. PMID- 28592405 TI - Current and Emerging Topical Antibacterials and Antiseptics: Agents, Action, and Resistance Patterns. AB - Bacterial skin infections represent some of the most common infectious diseases globally. Prevention and treatment of skin infections can involve application of a topical antimicrobial, which may be an antibiotic (such as mupirocin or fusidic acid) or an antiseptic (such as chlorhexidine or alcohol). However, there is limited evidence to support the widespread prophylactic or therapeutic use of topical agents. Challenges involved in the use of topical antimicrobials include increasing rates of bacterial resistance, local hypersensitivity reactions (particularly to older agents, such as bacitracin), and concerns about the indiscriminate use of antiseptics potentially coselecting for antibiotic resistance. We review the evidence for the major clinical uses of topical antibiotics and antiseptics. In addition, we review the mechanisms of action of common topical agents and define the clinical and molecular epidemiology of antimicrobial resistance in these agents. Moreover, we review the potential use of newer and emerging agents, such as retapamulin and ebselen, and discuss the role of antiseptic agents in preventing bacterial skin infections. A comprehensive understanding of the clinical efficacy and drivers of resistance to topical agents will inform the optimal use of these agents to preserve their activity in the future. PMID- 28592415 TI - Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction. AB - RATIONALE: Pathological increases in cardiac afterload result in myocyte hypertrophy with changes in myocyte electrical and mechanical phenotype. Remodeling of contractile and signaling Ca2+ occurs in pathological hypertrophy and is central to myocyte remodeling. STIM1 (stromal interaction molecule 1) regulates Ca2+ signaling in many cell types by sensing low endoplasmic reticular Ca2+ levels and then coupling to plasma membrane Orai channels to induce a Ca2+ influx pathway. Previous reports suggest that STIM1 may play a role in cardiac hypertrophy, but its role in electrical and mechanical phenotypic alterations is not well understood. OBJECTIVE: To define the contributions of STIM1-mediated Ca2+ influx on electrical and mechanical properties of normal and diseased myocytes, and to determine whether Orai channels are obligatory partners for STIM1 in these processes using a clinically relevant large animal model of hypertrophy. METHODS AND RESULTS: Cardiac hypertrophy was induced by slow progressive pressure overload in adult cats. Hypertrophied myocytes had increased STIM1 expression and activity, which correlated with altered Ca2+-handling and action potential (AP) prolongation. Exposure of hypertrophied myocytes to the Orai channel blocker BTP2 caused a reduction of AP duration and reduced diastolic Ca2+ spark rate. BTP2 had no effect on normal myocytes. Forced expression of STIM1 in cultured adult feline ventricular myocytes increased diastolic spark rate and prolonged AP duration. STIM1 expression produced an increase in the amount of Ca2+ stored within the sarcoplasmic reticulum and activated Ca2+/calmodulin-dependent protein kinase II. STIM1 expression also increased spark rates and induced spontaneous APs. STIM1 effects were eliminated by either BTP2 or by coexpression of a dominant negative Orai construct. CONCLUSIONS: STIM1 can associate with Orai in cardiac myocytes to produce a Ca2+ influx pathway that can prolong the AP duration and load the sarcoplasmic reticulum and likely contributes to the altered electromechanical properties of the hypertrophied heart. PMID- 28592418 TI - Growth of meibomian gland tissue after intraductal meibomian gland probing in patients with obstructive meibomian gland dysfunction. AB - PURPOSE: To investigate the impact of meibomian gland probing (MGP) on meibomian gland (MG) area from the upper lids of patients with obstructive meibomian gland dysfunction (o-MGD). METHODS: Retrospective study comparing pre-MGP/post-MGP non contact infrared meibography results in patients with o-MGD, viewing signs of MG growth within total measurement field. RESULTS: Post-MGP meibography of 34 lids (19 patients, >=4.5 to <=12 months' follow-up) showed 41.2% with MG growth. Ten lids had meibographies suitable for analysis, showing significant collective (116 glands) increase in mean individual glandular area (MIGA) of 4.87% (p=0.0145). Four of 10 lids independently showed significant increase in MIGA, ranging from 10.70% to 21.13% (p<0.0001, p=0.0277, p=0.0292, p=0.0345), while six did not.At >12 and <25 months' follow-up, 16 lids (9 additional patients) had follow-up showing 25% with signs of MG growth. Analysis of three lids showed a significant collective (33 glands) increase in MIGA of 11.19% (p=0.0004). Two of three lids independently showed significant increase in MIGA of 13.73% and 20.00% (p=0.0097, p=0.0001). Collectively, for all 13 analysed lids (149 glands), there was a significant increase of 6.38% in total glandular area (p=0.0447) and a significant increase of 6.23% in MIGA (p=0.0003). CONCLUSION: MGP was associated with increased MG tissue area and growth of atrophied MGs as viewed on meibography. MGP provides unequivocal physical proof of a patent meibum outflow tract through the natural orifice, and may promote glandular growth in part by direct mechanical establishment of a patent duct/orifice system. PMID- 28592420 TI - Patterns of cannabis use during adolescence and their association with harmful substance use behaviour: findings from a UK birth cohort. AB - BACKGROUND: Evidence on the role of cannabis as a gateway drug is inconsistent. We characterise patterns of cannabis use among UK teenagers aged 13-18 years, and assess their influence on problematic substance use at age 21 years. METHODS: We used longitudinal latent class analysis to derive trajectories of cannabis use from self-report measures in a UK birth cohort. We investigated (1) factors associated with latent class membership and (2) whether latent class membership predicted subsequent nicotine dependence, harmful alcohol use and recent use of other illicit drugs at age 21 years. RESULTS: 5315 adolescents had three or more measures of cannabis use from age 13 to 18 years. Cannabis use patterns were captured as four latent classes corresponding to 'non-users' (80.1%), 'late-onset occasional' (14.2%), 'early-onset occasional' (2.3%) and 'regular' users (3.4%). Sex, mother's substance use, and child's tobacco use, alcohol consumption and conduct problems were strongly associated with cannabis use. At age 21 years, compared with the non-user class, late-onset occasional, early-onset occasional and regular cannabis user classes had higher odds of nicotine dependence (OR=3.5, 95% CI 0.7 to 17.9; OR=12.1, 95% CI 1.0 to 150.3; and OR=37.2, 95% CI 9.5 to 144.8, respectively); harmful alcohol consumption (OR=2.6, 95% CI 1.5 to 4.3; OR=5.0, 95% CI 2.1 to 12.1; and OR=2.6, 95% CI 1.0 to 7.1, respectively); and other illicit drug use (OR=22.7, 95% CI 11.3 to 45.7; OR=15.9, 95% CI 3.9 to 64.4; and OR=47.9, 95% CI 47.9 to 337.0, respectively). CONCLUSIONS: One-fifth of the adolescents in our sample followed a pattern of occasional or regular cannabis use, and these young people were more likely to progress to harmful substance use behaviours in early adulthood. PMID- 28592419 TI - Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies. AB - Objective To map the diverse health outcomes associated with serum uric acid (SUA) levels.Design Umbrella review.Data sources Medline, Embase, Cochrane Database of Systematic Reviews, and screening of citations and references.Eligibility criteria Systematic reviews and meta-analyses of observational studies that examined associations between SUA level and health outcomes, meta-analyses of randomised controlled trials that investigated health outcomes related to SUA lowering treatment, and Mendelian randomisation studies that explored the causal associations of SUA level with health outcomes.Results 57 articles reporting 15 systematic reviews and144 meta-analyses of observational studies (76 unique outcomes), 8 articles reporting 31 meta-analyses of randomised controlled trials (20 unique outcomes), and 36 articles reporting 107 Mendelian randomisation studies (56 unique outcomes) met the eligibility criteria. Across all three study types, 136 unique health outcomes were reported. 16 unique outcomes in meta-analyses of observational studies had P<10-6, 8 unique outcomes in meta-analyses of randomised controlled trials had P<0.001, and 4 unique outcomes in Mendelian randomisation studies had P<0.01. Large between study heterogeneity was common (80% and 45% in meta-analyses of observational studies and of randomised controlled trials, respectively). 42 (55%) meta-analyses of observational studies and 7 (35%) meta-analyses of randomised controlled trials showed evidence of small study effects or excess significance bias. No associations from meta-analyses of observational studies were classified as convincing; five associations were classified as highly suggestive (increased risk of heart failure, hypertension, impaired fasting glucose or diabetes, chronic kidney disease, coronary heart disease mortality with high SUA levels). Only one outcome from randomised controlled trials (decreased risk of nephrolithiasis recurrence with SUA lowering treatment) had P<0.001, a 95% prediction interval excluding the null, and no large heterogeneity or bias. Only one outcome from Mendelian randomisation studies (increased risk of gout with high SUA levels) presented convincing evidence. Hypertension and chronic kidney disease showed concordant evidence in meta-analyses of observational studies, and in some (but not all) meta-analyses of randomised controlled trials with respective intermediate or surrogate outcomes, but they were not statistically significant in Mendelian randomisation studies.Conclusion Despite a few hundred systematic reviews, meta-analyses, and Mendelian randomisation studies exploring 136 unique health outcomes, convincing evidence of a clear role of SUA level only exists for gout and nephrolithiasis. PMID- 28592422 TI - Association of Sex with Risk of Kidney Graft Failure Differs by Age. AB - Prior studies of sex differences in kidney graft survival showed conflicting results. We hypothesized that the association between recipient sex and kidney graft failure risk differs by recipient age and donor sex. We evaluated 159,417 patients recorded in the Scientific Registry of Transplant Recipients database who received a first deceased-donor kidney transplant (1995-2013). We used time varying Cox models to estimate the association between recipient sex and death censored graft failure. Models, stratified on donor sex and adjusted for potential confounders, included a recipient sex by current age interaction term. Among recipients of male donors, females of all ages had significantly higher graft failure risks than males (adjusted hazard ratios 0-14 years: 1.51 [95% confidence intervals 1.19 to 1.90]; 15-24 years: 1.37 [1.18 to 1.59]; 25-44 years: 1.14 [1.03 to 1.26]; 45 years: 1.05 [1.01 to 1.09]). Among recipients of female-donor grafts, only female recipients aged 15-24 years had a significantly higher graft failure risk than their male counterparts had (1.28 [1.06 to 1.53]). Indeed, female recipients aged >=45 years had a significantly lower graft failure risk than their male counterparts had (0.95 [0.91 to 0.99]). These observations might be explained by the combined influence of several factors, including recognition of sex-determined minor histocompatibility antigens, influence of sex hormones on immune activation, sex- and age-related differences in medication adherence, and sex-related differences in body size. Additional studies should determine whether sex- and age-specific immunosuppression strategies are warranted for kidney graft recipients. PMID- 28592421 TI - Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. AB - Interstitial cells of Cajal (ICC) in the myenteric plexus region (ICC-MY) of the small intestine are pacemakers that generate rhythmic depolarizations known as slow waves. Slow waves depend on activation of Ca2+-activated Cl- channels (ANO1) in ICC, propagate actively within networks of ICC-MY, and conduct to smooth muscle cells where they generate action potentials and phasic contractions. Thus, mechanisms of Ca2+ regulation in ICC are fundamental to the motor patterns of the bowel. Here, we characterize the nature of Ca2+ transients in ICC-MY within intact muscles, using mice expressing a genetically encoded Ca2+ sensor, GCaMP3, in ICC. Ca2+ transients in ICC-MY display a complex firing pattern caused by localized Ca2+ release events arising from multiple sites in cell somata and processes. Ca2+ transients are clustered within the time course of slow waves but fire asynchronously during these clusters. The durations of Ca2+ transient clusters (CTCs) correspond to slow wave durations (plateau phase). Simultaneous imaging and intracellular electrical recordings revealed that the upstroke depolarization of slow waves precedes clusters of Ca2+ transients. Summation of CTCs results in relatively uniform Ca2+ responses from one slow wave to another. These Ca2+ transients are caused by Ca2+ release from intracellular stores and depend on ryanodine receptors as well as amplification from IP3 receptors. Reduced extracellular Ca2+ concentrations and T-type Ca2+ channel blockers decreased the number of firing sites and firing probability of Ca2+ transients. In summary, the fundamental electrical events of small intestinal muscles generated by ICC-MY depend on asynchronous firing of Ca2+ transients from multiple intracellular release sites. These events are organized into clusters by Ca2+ influx through T-type Ca2+ channels to sustain activation of ANO1 channels and generate the plateau phase of slow waves. PMID- 28592423 TI - Remission of Hematuria Improves Renal Survival in IgA Nephropathy. AB - Hematuria is a cardinal symptom in IgA nephropathy, but its influence on the risk of disease progression has been scarcely investigated. We followed a cohort of 112 patients with IgA nephropathy for a mean+/-SEM period of 14+/-10.2 years, during which clinical and analytic risk factors (including urine sediment examination) were regularly recorded. According to the magnitude of time-averaged hematuria, we classified patients as those with persistent hematuria and those with negative or minimal hematuria. We also classified patients according to the magnitude of time-averaged proteinuria (>0.75 or <=0.75 g/d). The proportion of patients reaching ESRD or a 50% reduction of renal function was significantly greater among patients with persistent hematuria than patients with minimal or negative hematuria (30.4% and 37.0% versus 10.6% and 15.2%, respectively; P=0.01). Multivariable analysis revealed time-averaged hematuria, time-averaged proteinuria, renal function at baseline, and the presence of tubulointerstitial fibrosis on renal biopsy as independent predictors of ESRD. After hematuria disappearance, which occurred in 46% of the patients, the rate of renal function decline changed from -6.45+/-14.66 to -0.18+/-2.56 ml/min per 1.73 m2 per year (P=0.001). Patients with time-averaged proteinuria >0.75 g/d had significantly poorer renal survival than those with time-averaged proteinuria <=0.75 g/d. However, on further classification by time-averaged hematuria, only those patients with time-averaged proteinuria >0.75 g/d and persistent hematuria had significantly worse renal survival than those in the other three groups. In conclusion, remission of hematuria may have a significant favorable effect on IgA nephropathy outcomes. PMID- 28592424 TI - Uromodulin in the Bloodstream: Old Wine in a New Wineskin. PMID- 28592425 TI - Targeting Plasma Cells with Proteasome Inhibitors: Principles from Primates. PMID- 28592426 TI - A Nonadjuvanted IgG2a Monoclonal Antibody against Nucleosomes Elicits Potent T Cell-Dependent, Idiotype-Specific IgG1 Responses and Glomerular IgG1/IgG2a Deposits in Normal Mice. AB - Idiotypes (Ids) are unique epitopes of Ab V regions and can trigger anti-Id immune responses, but immunization with several nonadjuvanted isologous IgG mAbs has induced tolerance to their Ids. We immunized non-lupus-prone mice with 11 allotype "a" of IgG2a (IgG2aa) and 4 IgG2c nonadjuvanted, isologous mAbs purified from serum-free medium. Of five IgG2aa mAbs with specificity for nucleosomes, the repeating histone-DNA subunit of chromatin, four elicited an IgG1 anti-mAb response and one mAb was nonimmunogenic. In contrast, none of six IgG2aa mAbs with unknown specificity triggered anti-mAb responses. The data suggested a link between immunogenicity and specificity for nucleosomes. One anti-nucleosome IgG2aa mAb, termed 3F7.A10, copurified with self-histones and was a potent immunogen for BALB/c mice. The response against IgG2aa 3F7.A10 was CD4+ Th cell dependent, dominated by the IgG1 subclass, and Id specific. Ultracentrifugation converted the purified 3F7.A10 mAb into a weak immunogen, suggesting that the mAb had formed immunogenicity-enhancing immune complexes (ICs) with nucleosomal Ags during cell culture. BALB/c mice injected with viable MHC-incompatible 3F7.A10 hybridoma cells grown in serum-free medium mounted strong anti-Id responses. TLR9 deficient mice responded significantly weaker to Id-3F7.A10 than did TLR9 sufficient mice, suggesting that the cognate BCR efficiently internalizes the Id in an IC with nucleosomes. Passive transfer of IgG2aa 3F7.A10 to BALB/c mice with high titers of IgG1 anti-3F7.A10 led to glomerular deposits of IgG1/IgG2a complexes. The immunogenicity of Id-3F7.A10 raises the possibility that diverse Ids of nucleosome-specific Abs form ICs with nucleosomes released from dying cells and elicit spontaneous formation of anti-Id Abs in vivo. PMID- 28592427 TI - Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin alpha4beta1 Expressing Immune Cells. AB - Positron emission tomography and computed tomography imaging (PET/CT) is an increasingly valuable tool for diagnosing tuberculosis (TB). The glucose analog [18F]fluoro-2-deoxy-2-d-glucose ([18F]-FDG) is commonly used in PET/CT that is retained by metabolically active inflammatory cells in granulomas, but lacks specificity for particular cell types. A PET probe that could identify recruitment and differentiation of different cell populations in granulomas would be a useful research tool and could improve TB diagnosis and treatment. We used the Mycobacterium-antigen murine inflammation model and macaques with TB to identify [64Cu]-labeled CB-TE1A1P-PEG4-LLP2A ([64Cu]-LLP2A), a high affinity peptidomimetic ligand for very late Ag-4 (VLA-4; also called integrin alpha4beta1) binding cells in granulomas, and compared [64Cu]-LLP2A with [18F] FDG over the course of infection. We found that [64Cu]-LLP2A retention was driven by macrophages and T cells, with less contribution from neutrophils and B cells. In macaques, granulomas had higher [64Cu]-LLP2A uptake than uninfected tissues, and immunohistochemical analysis of granulomas with known [64Cu]-LLP2A uptake identified significant correlations between LLP2A signal and macrophage and T cell numbers. The same cells coexpressed integrin alpha4 and beta1, further supporting that macrophages and T cells drive [64Cu]-LLP2A avidity in granulomas. Over the course of infection, granulomas and thoracic lymph nodes experienced dynamic changes in affinity for both probes, suggesting metabolic changes and cell differentiation or recruitment occurs throughout granuloma development. These results indicate [64Cu]-LLP2A is a PET probe for VLA-4, which when used in conjunction with [18F]-FDG, may be a useful tool for understanding granuloma biology in TB. PMID- 28592428 TI - EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis. AB - The efficacy of B cell depletion therapy in multiple sclerosis indicates their central pathogenic role in disease pathogenesis. The B lymphotropic EBV is a major risk factor in multiple sclerosis, via as yet unclear mechanisms. We reported in a nonhuman primate experimental autoimmune encephalomyelitis model that an EBV-related lymphocryptovirus enables B cells to protect a proteolysis sensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) epitope (residues 40-48) against destructive processing. This facilitates its cross presentation to autoaggressive cytotoxic MHC-E-restricted CD8+CD56+ T cells. The present study extends these observations to intact human B cells and identifies a key role of autophagy. EBV infection upregulated APC-related markers on B cells and activated the cross-presentation machinery. Although human MOG protein was degraded less in EBV-infected than in uninfected B cells, induction of cathepsin G activity by EBV led to total degradation of the immunodominant peptides MOG35 55 and MOG1-20 Inhibition of cathepsin G or citrullination of the arginine residue within an LC3-interacting region motif of immunodominant MOG peptides abrogated their degradation. Internalized MOG colocalized with autophagosomes, which can protect from destructive processing. In conclusion, EBV infection switches MOG processing in B cells from destructive to productive and facilitates cross-presentation of disease-relevant epitopes to CD8+ T cells. PMID- 28592429 TI - A centennial gift from Einstein. PMID- 28592431 TI - Psychiatrist who kicked back at patient is suspended for six months. PMID- 28592430 TI - Relativistic deflection of background starlight measures the mass of a nearby white dwarf star. AB - Gravitational deflection of starlight around the Sun during the 1919 total solar eclipse provided measurements that confirmed Einstein's general theory of relativity. We have used the Hubble Space Telescope to measure the analogous process of astrometric microlensing caused by a nearby star, the white dwarf Stein 2051 B. As Stein 2051 B passed closely in front of a background star, the background star's position was deflected. Measurement of this deflection at multiple epochs allowed us to determine the mass of Stein 2051 B-the sixth nearest white dwarf to the Sun-as 0.675 +/- 0.051 solar masses. This mass determination provides confirmation of the physics of degenerate matter and lends support to white dwarf evolutionary theory. PMID- 28592432 TI - Upregulation of lysyl oxidase and adhesion to collagen of human megakaryocytes and platelets in primary myelofibrosis. PMID- 28592435 TI - Sex differences in renin-angiotensin-aldosterone system affect extracellular volume in healthy subjects. AB - Several studies reported sex differences in aldosterone. It is unknown whether these differences are associated with differences in volume regulation. Therefore we studied both aldosterone and extracellular volume in men and women on different sodium intakes. In healthy normotensive men ( n = 18) and premenopausal women ( n = 18) we investigated plasma aldosterone, blood pressure, and extracellular volume (125I-iothalamate), during both low (target intake 50 mmol Na+/day) and high sodium intake (target intake 200 mmol Na+/day) in a crossover setup. Furthermore, we studied the adrenal response to angiotensin II infusion (0.3, 1.0, and 3.0 ng.kg-1.min-1 for 1 h) on both sodium intakes. Men had a significantly higher plasma aldosterone, extracellular volume, and systolic blood pressure than women during high sodium intake ( P < 0.05). During low sodium intake, extracellular volume and blood pressure were higher in men as well ( P < 0.05), whereas the difference in plasma aldosterone was no longer significant ( P = 0.252). The adrenal response to exogenous angiotensin II was significantly lower in men than in women on both sodium intakes. Constitutive sex differences in the regulation of aldosterone, characterized by a higher aldosterone and a lower adrenal response to exogenous angiotensin II infusion in men, are associated with a higher extracellular volume and blood pressure in men. These findings suggest that sex differences in the regulation of aldosterone contribute to differences in volume regulation between men and women. PMID- 28592434 TI - Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label). AB - BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. METHODS: Children with HeFH (age, 6-<18 years) and low-density lipoprotein cholesterol >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6-<10 years) or 20 mg (age, 10-<18 years). Carotid IMT was assessed by ultrasonography at baseline and 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model was used to evaluate differences in carotid IMT between children with HeFH and the unaffected siblings. P values were adjusted for age, sex, carotid artery site, and family relations. RESULTS: At baseline, mean+/-SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397+/-0.049 and 0.377+/-0.045 mm, respectively; P=0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030-0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095-0.0192) in unaffected siblings (P=0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408+/ 0.043 and 0.402+/-0.042 mm, respectively; P=0.2). CONCLUSIONS: In children with HeFH who were >=6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low density lipoprotein cholesterol reduction in children with HeFH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01078675. PMID- 28592433 TI - Bifurcated BACH2 control coordinates mantle cell lymphoma survival and dispersal during hypoxia. AB - BACH2, a B-cell-specific transcription factor, plays a critical role in oxidative stress-mediated drug resistance in mantle cell lymphoma (MCL); however, the biological functions of BACH2 and its regulation of B-cell malignancies in chronic hypoxic microenvironment have not been studied. Here, we found that silencing BACH2 led to not only increased tumor formation and colony formation but also increased tumor dispersal to spleen and bone marrow. Decreased BACH2 levels in patients were also correlated with bone marrow and gastrointestinal dispersal of MCL and blastoid subtypes of MCL. Unexpectedly, decreased BACH2 levels in dispersed MCL cells were due to direct transcriptional repression by hypoxia-induced factor 1alpha (HIF-1alpha) and increased heme-mediated protein degradation. In normoxic conditions, BACH2 was able to modulate HIF-1alpha degradation by suppressing prolyl hydroxylase 3 expression. Bifurcated BACH2 controls during hypoxia and normoxia coordinate not only MCL tumor dispersal but also drug resistance, including bortezomib resistance, via plasmacytic differentiation. Our data highlight an interactive relationship between tumor cells and local microenvironment and the mechanisms of B-cell transcription factor in the regulation of MCL dispersal. PMID- 28592437 TI - Characterization of the transport activity of SGLT2/MAP17, the renal low-affinity Na+-glucose cotransporter. AB - The cotransporter SGLT2 is responsible for 90% of renal glucose reabsorption, and we recently showed that MAP17 appears to work as a required beta-subunit. We report in the present study a detailed functional characterization of human SGLT2 in coexpression with human MAP17 in Xenopus laevis oocytes. Addition of external glucose generates a large inward current in the presence of Na, confirming an electrogenic transport mechanism. At a membrane potential of -50 mV, SGLT2 affinity constants for glucose and Na are 3.4 +/- 0.4 and 18 +/- 6 mM, respectively. The change in the reversal potential of the cotransport current as a function of external glucose concentration clearly confirms a 1:1 Na-to-glucose transport stoichiometry. SGLT2 is selective for glucose and alpha-methylglucose but also transports, to a lesser extent, galactose and 3-O-methylglucose. SGLT2 can be inhibited in a competitive manner by phlorizin (Ki = 31 +/- 4 nM) and by dapagliflozin (Ki = 0.75 +/- 0.3 nM). Similarly to SGLT1, SGLT2 can be activated by Na, Li, and protons. Pre-steady-state currents for SGLT2 do exist but are small in amplitude and relatively fast (a time constant of ~2 ms). The leak current defined as the phlorizin-sensitive current in the absence of substrate was extremely small in the case of SGLT2. In summary, in comparison with SGLT1, SGLT2 has a lower affinity for glucose, a transport stoichiometry of 1:1, very small pre-steady-state and leak currents, a 10-fold higher affinity for phlorizin, and an affinity for dapagliflozin in the subnanomolar range. PMID- 28592436 TI - Bladder fibrosis during outlet obstruction is triggered through the NLRP3 inflammasome and the production of IL-1beta. AB - Bladder outlet obstruction (BOO) triggers inflammation in the bladder through the NLRP3 inflammasome. BOO also activates fibrosis, which is largely responsible for the decompensation of the bladder in the chronic state. Because fibrosis can be driven by inflammation, we have explored a role for NLRP3 (and IL-1beta produced by NLRP3) in the activation and progression of BOO-induced fibrosis. Female rats were divided into five groups: 1) control, 2) sham, 3) BOO + vehicle, 4) BOO + the NLRP3 inhibitor glyburide, or 5) BOO + the IL-1beta receptor antagonist anakinra. Fibrosis was assessed by Masson's trichrome stain, collagen secretion via Sirius Red, and protein localization by immunofluorescence. BOO increased collagen production in the bladder, which was blocked by glyburide and anakinra, clearly implicating the NLRP3/IL-1beta pathway in fibrosis. The collagen was primarily found in the lamina propria and the smooth muscle, while IL-1 receptor 1 and prolyl 4-hydroylase (an enzyme involved in the intracellular modification of collagen) both localized to the urothelium and the smooth muscle. Lysyl oxidase, the enzyme involved in the final extracellular assembly of mature collagen fibrils, was found to some extent in the lamina propria where its expression was greatly enhanced during BOO. In vitro studies demonstrated isolated urothelial cells from BOO rats secreted substantially more collagen than controls, and collagen expression in control cultures could be directly stimulated by IL-1beta. In summary, NLRP3-derived-IL-1beta triggers fibrosis during BOO, most likely through an autocrine loop in which IL-1beta acts on urothelia to drive collagen production. PMID- 28592439 TI - High body mass index and the risk of hepatocellular carcinoma. PMID- 28592438 TI - CD14+ CD15- HLA-DR- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure. AB - OBJECTIVE: Immune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR- myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses. DESIGN: Patients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15-CD11b+HLA-DR- cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques. RESULTS: Circulating CD14+CD15-CD11b+HLA-DR- M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo. CONCLUSION: Immunosuppressive CD14+HLA-DR- M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent. PMID- 28592440 TI - Rome Foundation-Asian working team report: Asian functional gastrointestinal disorder symptom clusters. AB - OBJECTIVE: Functional gastrointestinal disorders (FGIDs) are diagnosed by the presence of a characteristic set of symptoms. However, the current criteria-based diagnostic approach is to some extent subjective and largely derived from observations in English-speaking Western patients. We aimed to identify latent symptom clusters in Asian patients with FGID. DESIGN: 1805 consecutive unselected patients with FGID who presented for primary or secondary care to 11 centres across Asia completed a cultural and linguistic adaptation of the Rome III Diagnostic Questionnaire that was translated to the local languages. Principal components factor analysis with varimax rotation was used to identify symptom clusters. RESULTS: Nine symptom clusters were identified, consisting of two oesophageal factors (F6: globus, odynophagia and dysphagia; F9: chest pain and heartburn), two gastroduodenal factors (F5: bloating, fullness, belching and flatulence; F8 regurgitation, nausea and vomiting), three bowel factors (F2: abdominal pain and diarrhoea; F3: meal-related bowel symptoms; F7: upper abdominal pain and constipation) and two anorectal factors (F1: anorectal pain and constipation; F4: diarrhoea, urgency and incontinence). CONCLUSION: We found that the broad categorisation used both in clinical practice and in the Rome system, that is, broad anatomical divisions, and certain diagnoses with long historical records, that is, IBS with diarrhoea, and chronic constipation, are still valid in our Asian societies. In addition, we found a bowel symptom cluster with meal trigger and a gas cluster that suggests a different emphasis in our populations. Future studies to compare a non-Asian cohort and to match to putative pathophysiology will help to verify our findings. PMID- 28592441 TI - FOXAI: a phase II trial evaluating the efficacy and safety of hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin for advanced hepatocellular carcinoma. PMID- 28592442 TI - The low FODMAP diet: recent advances in understanding its mechanisms and efficacy in IBS. AB - There is an intensifying interest in the interaction between diet and the functional GI symptoms experienced in IBS. Recent studies have used MRI to demonstrate that short-chain fermentable carbohydrates increase small intestinal water volume and colonic gas production that, in those with visceral hypersensitivity, induces functional GI symptoms. Dietary restriction of short chain fermentable carbohydrates (the low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet) is now increasingly used in the clinical setting. Initial research evaluating the efficacy of the low FODMAP diet was limited by retrospective study design and lack of comparator groups, but more recently well-designed clinical trials have been published. There are currently at least 10 randomised controlled trials or randomised comparative trials showing the low FODMAP diet leads to clinical response in 50% 80% of patients with IBS, in particular with improvements in bloating, flatulence, diarrhoea and global symptoms. However, in conjunction with the beneficial clinical impact, recent studies have also demonstrated that the low FODMAP diet leads to profound changes in the microbiota and metabolome, the duration and clinical relevance of which are as yet unknown. This review aims to present recent advances in the understanding of the mechanisms by which the low FODMAP diet impacts on symptoms in IBS, recent evidence for its efficacy, current findings regarding the consequences of the diet on the microbiome and recommendations for areas for future research. PMID- 28592448 TI - Correction. PMID- 28592443 TI - ESCRT-mediated vesicle concatenation in plant endosomes. AB - Ubiquitinated plasma membrane proteins (cargo) are delivered to endosomes and sorted by endosomal sorting complex required for transport (ESCRT) machinery into endosome intralumenal vesicles (ILVs) for degradation. In contrast to the current model that postulates that ILVs form individually from inward budding of the endosomal limiting membrane, plant ILVs form as networks of concatenated vesicle buds by a novel vesiculation mechanism. We ran computational simulations based on experimentally derived diffusion coefficients of an ESCRT cargo protein and electron tomograms of Arabidopsis thaliana endosomes to measure cargo escape from budding ILVs. We found that 50% of the ESCRT cargo would escape from a single budding profile in 5-20 ms and from three concatenated ILVs in 80-200 ms. These short cargo escape times predict the need for strong diffusion barriers in ILVs. Consistent with a potential role as a diffusion barrier, we find that the ESCRT III protein SNF7 remains associated with ILVs and is delivered to the vacuole for degradation. PMID- 28592444 TI - Cellular differentiation state modulates the mRNA export activity of SR proteins. AB - SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells. PMID- 28592445 TI - Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease. AB - BACKGROUND: Deficiency of the lysosomal enzyme galactosylcerebrosidase (GALC) causes Krabbe disease. Newborn screening for Krabbe disease is ongoing, but improved methods for follow-up analysis of screen-positive babies are needed to better advise families and to optimize treatment. We report a new assay for the enzymatic activity of GALC in lymphocytes. METHODS: T lymphocytes were isolated from venous blood by magnetic bead technology. The assay used a close structural analog of the natural substrate and LC-MS/MS to quantify the amount of product with the aid of a chemically identical internal standard. RESULTS: The analytical range of the assay (ratio of assay response for the QC high standard to that from all non-enzymatic-dependent processes) was 20-fold greater than that for the conventional radiometric GALC assay. The LC-MS/MS could distinguish cells that were null in GALC from those that contained traces of active enzyme (down to 0.3% of normal). There was a good correlation between the level of residual GALC activity in lymphocytes and the severity of Krabbe disease. CONCLUSIONS: The new assay can measure small amounts of residual GALC activity in leukocytes with high accuracy compared to previous assays and can contribute, along with genotyping, biomarker analysis, and neurological imaging, a better plan for post-newborn screening follow-up for Krabbe disease. PMID- 28592449 TI - SUDEP: An important cause of premature mortality in epilepsy across the life spectrum. PMID- 28592450 TI - A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis. AB - OBJECTIVE: We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET). METHODS: Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome. RESULTS: A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests. CONCLUSIONS: Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy. PMID- 28592451 TI - Baseline motor findings and Parkinson disease prognostic subtypes. AB - OBJECTIVE: To identify the significance of baseline motor features to the lifelong prognostic motor subtypes in a Parkinson disease (PD) cohort. METHODS: In a previous study of 166 PD cases, we observed different prognosis in tremor dominant, akinetic-rigid, and mixed subtypes. This study includes the same cases, but we excluded 10 cases with symptoms of >=15 years duration at baseline. Relative severity of tremor, bradykinesia/akinesia, and rigidity at baseline were evaluated as predictors of the motor subtypes, which are known to have different prognosis. RESULTS: The most common motor subtype was mixed, followed by akinetic rigid and then the tremor-dominant. Seventy cases were not receiving antiparkinsonian drugs at baseline. The prognostic subtypes could be predicted at baseline in 85% of all and in 91% of the treatment-naive cases. Sensitivity, specificity, and positive predictive values were strong for the mixed and the akinetic-rigid but weak for the tremor-dominant subtype. CONCLUSIONS: Our data show that motor profile at baseline can predict prognosis in most PD cases. These findings can be incorporated into clinical practice. PMID- 28592452 TI - Dementia with Lewy bodies advances: A new consensus report. PMID- 28592454 TI - Coated-platelets predict stroke at 30 days following TIA. AB - OBJECTIVE: To examine the potential for coated-platelets, a subset of highly procoagulant platelets observed on dual agonist stimulation with collagen and thrombin, for predicting stroke at 30 days in patients with TIA. METHODS: Consecutive patients with TIA were enrolled and followed up prospectively. ABCD2 scores were obtained for each patient. Coated-platelet levels, reported as percent of cells converted to coated-platelets, were determined at baseline. The primary endpoint was the occurrence of stroke at 30 days. Receiver operator characteristic (ROC) analysis was used to calculate area under the curve (AUC) values for a model including coated-platelets to predict incident stroke at 30 days. RESULTS: A total of 171 patients with TIA were enrolled, and 10 strokes were observed at 30 days. A cutoff of 51.1% for coated-platelet levels yielded a sensitivity of 0.80 (95% confidence interval [CI] 0.55-1.0), specificity of 0.73 (95% CI 0.66-0.80), positive predictive value of 0.16 (95% CI 0.06-0.26), and negative predictive value of 0.98 (95% CI 0.96-1.0). The adjusted hazard ratio of incident stroke in patients with coated-platelet levels >=51.1% was 10.72 compared to those with levels <51.1%. ROC analysis showed significant improvement in the predictive ability of the coated-platelet model compared to ABCD2 score (AUC 0.78 +/- 0.07 vs 0.54 +/- 0.07, p = 0.01). CONCLUSIONS: These findings suggest a role for coated-platelets in risk stratification for stroke at 30 days after TIA. PMID- 28592455 TI - The incidence of SUDEP: A nationwide population-based cohort study. AB - OBJECTIVE: To identify all cases of sudden unexpected death in epilepsy (SUDEP) among people in Sweden during 1 year and to determine the SUDEP incidence in relation to age, sex, and psychiatric comorbidity. METHODS: We included all individuals with a hospital-based ambulatory care or hospital discharge diagnosis of epilepsy in the Swedish National Patient Registry during 1998-2005 who were alive on January 1, 2008. Deaths during 2008 were identified by linkage to the National Cause of Death Registry. Death certificates, medical charts, and police and autopsy reports were extensively reviewed to identify SUDEP cases. RESULTS: Of 57,775 epilepsy patients alive on January 1, 2008, 1,890 died (3.3%) during 2008. Of these, 99 met the Annegers SUDEP criteria (49 definite, 19 probable, and 31 possible). SUDEP accounted for 5.2% of all deaths and 36% of deaths in the 0 15 years age group. The incidence of definite/probable SUDEP was 1.20/1,000 person-years, and higher in men (1.41) than in women (0.96). All SUDEP cases <16 years were in boys. SUDEP incidence at ages <16, 16-50, and >50 years was 1.11, 1.13, and 1.29, respectively, per 1,000 person-years. The incidence was 5-fold increased among female patients with psychiatric comorbidities compared to those without. Epilepsy was mentioned on the death certificate in only 62 of the 99 (63%) SUDEP cases. CONCLUSIONS: Methods relying on death certificates underestimate SUDEP incidence. SUDEP risk has been underestimated especially in boys and in older people regardless of sex. Patients with psychiatric comorbidities, women in particular, are at increased SUDEP risk. PMID- 28592453 TI - Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. AB - The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support. PMID- 28592456 TI - CSF sAPPbeta, YKL-40, and neurofilament light in frontotemporal lobar degeneration. AB - OBJECTIVE: To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD). METHODS: We analyzed 3 CSF biomarkers (YKL-40, soluble beta fragment of amyloid precursor protein [sAPPbeta], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (beta-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility. RESULTS: Patients with FTLD-related syndromes had lower levels of sAPPbeta than CN and patients with AD. The levels of sAPPbeta showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPbeta/YKL-40 and NfL/sAPPbeta ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD. CONCLUSIONS: The combination of sAPPbeta with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that CSF levels of sAPPbeta, YKL-40, and NfL are useful to identify patients with FTLD related syndromes. PMID- 28592458 TI - Localized and systemic variations in central motor drive at different local skin and muscle temperatures. AB - This study investigated the ability to sustain quadriceps central motor drive while subjected to localized heat and metaboreceptive feedback from the contralateral leg. Eight active males each completed two counter-balanced trials, in which muscle temperature (Tm) of a single-leg (TEMP-LEG) was altered to 29.4 degrees C (COOL) or 37.6 degrees C (WARM), while the contralateral leg (CL-LEG) remained thermoneutral: 35.3 degrees C and 35.2 degrees C Tm in COOL and WARM, respectively. To activate metaboreceptive feedback, participants first performed one 120-s isometric maximal voluntary contraction (MVC) of the knee extensors in the TEMP-LEG, immediately followed by postexercise muscle ischemia (PEMI) via femoral blood flow occlusion. To assess central motor drive of a remote muscle group immediately following PEMI, another 120-s MVC was subsequently performed in the CL-LEG. Voluntary muscle activation (VA) was assessed using the twitch interpolation method. Perceived mental effort and limb discomfort were also recorded. In a cooled muscle, a significant increase in mean force output and mean VA (force, P < 0.001; VA, P < 0.05), as well as a significant decrease in limb discomfort (P < 0.05) occurred during the sustained MVC in the TEMP-LEG. However, no differences between Tm were observed in mean force output, mean VA, or limb discomfort during the sustained MVC in the CL-LEG (force, P = 0.33; VA, P > 0.68; and limb discomfort, P = 0.73). The present findings suggest that elevated local skin temperature and Tm can increase limb discomfort and decrease central motor drive, but this does not limit systemic motor activation of a thermoneutral muscle group. PMID- 28592459 TI - Effects of 10 days of separate heat and hypoxic exposure on heat acclimation and temperate exercise performance. AB - Adaptations to heat and hypoxia are typically studied in isolation but are often encountered in combination. Whether the adaptive response to multiple stressors affords the same response as when examined in isolation is unclear. We examined 1) the influence of overnight moderate normobaric hypoxia on the time course and magnitude of adaptation to daily heat exposure and 2) whether heat acclimation (HA) was ergogenic and whether this was influenced by an additional hypoxic stimulus. Eight males [Vo2max = 58.5 (8.3) ml.kg-1.min-1] undertook two 11-day HA programs (balanced-crossover design), once with overnight normobaric hypoxia (HAHyp): 8 (1) h per night for 10 nights [[Formula: see text] = 0.156; SpO2 = 91 (2)%] and once without (HACon). Days 1, 6, and 11 were exercise-heat stress tests [HST (40 degrees C, 50% relative humidity, RH)]; days 2-5 and 7-10 were isothermal strain [target rectal temperature (Tre) ~38.5 degrees C], exercise heat sessions. A graded exercise test and 30-min cycle trial were undertaken pre , post-, and 14 days after HA in temperate normoxia (22 degrees C, 55% RH; FIO2 = 0.209). HA was evident on day 6 (e.g., reduced Tre, mean skin temperature (Tsk), heart rate, and sweat [Na+], P < 0.05) with additional adaptations on day 11 (further reduced Tsk and heart rate). HA increased plasma volume [+5.9 (7.3)%] and erythropoietin concentration [+1.8 (2.4) mIU/ml]; total hemoglobin mass was unchanged. Peak power output [+12 (20) W], lactate threshold [+15 (18) W] and work done [+12 (20) kJ] increased following HA. The additional hypoxic stressor did not affect these adaptations. In conclusion, a separate moderate overnight normobaric hypoxic stimulus does not affect the time course or magnitude of HA. Performance may be improved in temperate normoxia following HA, but this is unaffected by an additional hypoxic stressor. PMID- 28592457 TI - Functional network integrity presages cognitive decline in preclinical Alzheimer disease. AB - OBJECTIVE: To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD). METHODS: A total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline beta-amyloid (Abeta) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Abeta burden. Median neuropsychological follow-up was 3 years. RESULTS: Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Abeta burden in predicting decline, with combined higher Abeta and lower connectivity predicting the steepest curvilinear decline in PACC performance. CONCLUSIONS: In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Abeta burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings. PMID- 28592460 TI - Heads you gain, tails you lose. PMID- 28592461 TI - RBM24 promotes U1 snRNP recognition of the mutated 5' splice site in the IKBKAP gene of familial dysautonomia. AB - The 5' splice site mutation (IVS20+6T>C) of the inhibitor of kappa light polypeptide gene enhancer in B cells, kinase complex-associated protein (IKBKAP) gene in familial dysautonomia (FD) is at the sixth intronic nucleotide of the 5' splice site. It is known to weaken U1 snRNP recognition and result in an aberrantly spliced mRNA product in neuronal tissue, but normally spliced mRNA in other tissues. Aberrantly spliced IKBKAP mRNA abrogates IKK complex-associated protein (IKAP)/elongator protein 1 (ELP1) expression and results in a defect of neuronal cell development in FD. To elucidate the tissue-dependent regulatory mechanism, we screened an expression library of major RNA-binding proteins (RBPs) with our mammalian dual-color splicing reporter system and identified RBM24 as a regulator. RBM24 functioned as a cryptic intronic splicing enhancer binding to an element (IVS20+13-29) downstream from the intronic 5' splice site mutation in the IKBKAP gene and promoted U1 snRNP recognition only to the mutated 5' splice site (and not the wild-type 5' splice site). Our results show that tissue-specific expression of RBM24 can explain the neuron-specific aberrant splicing of IKBKAP exon 20 in familial dysautonomia, and that ectopic expression of RBM24 in neuronal tissue could be a novel therapeutic target of the disease. PMID- 28592462 TI - Ten-Year (2001-2011) Trends in the Incidence Rates and Short-Term Outcomes of Early Versus Late Onset Cardiogenic Shock After Hospitalization for Acute Myocardial Infarction. AB - BACKGROUND: Cardiogenic shock (CS) is a serious complication of acute myocardial infarction, and the time of onset of CS has a potential role in influencing its prognosis. Limited contemporary data exist on this complication, however, especially from a population-based perspective. Our study objectives were to describe decade-long trends in the incidence, in-hospital mortality, and factors associated with the development of CS in 3 temporal contexts: (1) before hospital arrival for acute myocardial infarction (prehospital CS); (2) within 24 hours of hospitalization (early CS); and (3) >=24 hours after hospitalization (late CS). METHODS AND RESULTS: The study population consisted of 5782 patients with an acute myocardial infarction who were admitted to all 11 hospitals in central Massachusetts on a biennial basis between 2001 and 2011. The overall proportion of patients who developed CS was 5.2%. The proportion of patients with prehospital CS (1.6%) and late CS (1.5%) remained stable over time, whereas the proportion of patients with early CS declined from 2.2% in 2001-2003 to 1.2% in 2009-2011. In-hospital mortality for prehospital CS increased from 38.9% in 2001 2003 to 53.6% in 2009-2011, whereas in-hospital mortality for early and late CS decreased over time (35.9% and 64.7% in 2001-2003 to 15.8% and 39.1% in 2009 2011, respectively). CONCLUSIONS: Development of prehospital and in-hospital CS was associated with poor short-term survival and the in-hospital death rates among those with prehospital CS increased over time. Interventions focused on preventing or treating prehospital and late CS are needed to improve in-hospital survival after acute myocardial infarction. PMID- 28592465 TI - Closing the Science-Health Gap With Technology: Evidence-Based Living. PMID- 28592464 TI - Pharmacokinetic Changes in Liver Failure and Impact on Drug Therapy. PMID- 28592463 TI - Associations of Glycemic Control With Cardiovascular Outcomes Among US Hemodialysis Patients With Diabetes Mellitus. AB - BACKGROUND: There is a lack of data on the relationship between glycemic control and cardiovascular end points in hemodialysis patients with diabetes mellitus. METHODS AND RESULTS: We included adult Medicare-insured patients with diabetes mellitus who initiated in-center hemodialysis treatment from 2006 to 2008 and survived for >90 days. Quarterly mean time-averaged glycated hemoglobin (HbA1c) values were categorized into <48 mmol/mol (<6.5%) (reference), 48 to <58 mmol/mol (6.5% to <7.5%), 58 to <69 mmol/mol (7.5% to <8.5%), and >=69 mmol/mol (>=8.5%). Medicare claims were used to identify outcomes of cardiovascular mortality, nonfatal myocardial infarction (MI), fatal or nonfatal MI, stroke, and peripheral arterial disease. We used Cox models as a function of time-varying exposure to estimate multivariable adjusted hazard ratios and 95%CI for the associations between HbA1c and time to study outcomes in a cohort of 16 387 eligible patients. Patients with HbA1c 58 to <69 mmol/mol (7.5% to <8.5%) and >=69 mmol/mol (>=8.5%) had 16% (CI, 2%, 32%) and 18% (CI, 1%, 37%) higher rates of cardiovascular mortality (P-trend=0.01) and 16% (CI, 1%, 33%) and 15% (CI, 1%, 32%) higher rates of nonfatal MI (P-trend=0.05), respectively, compared with those in the reference group. Patients with HbA1c >=69 mmol/mol (>=8.5%) had a 20% (CI, 2%, 41%) higher rate of fatal or nonfatal MI (P-trend=0.02), compared with those in the reference group. HbA1c was not associated with stroke, peripheral arterial disease, or all cause mortality. CONCLUSIONS: Higher HbA1c levels were significantly associated with higher rates of cardiovascular mortality and MI but not with stroke, peripheral arterial disease, or all-cause mortality in this large cohort of hemodialysis patients with diabetes mellitus. PMID- 28592466 TI - Adults in the Pediatric Intensive Care Unit: A Pediatric Nurse's Perspective. PMID- 28592467 TI - Supplementing Intensivist Staffing With Nurse Practitioners: Literature Review. AB - In the United States, providing health care to critically ill patients is a challenge. An increase in patients older than 65 years, a decrease in critical care physicians, and a decrease in work hours for residents cause intensivist staffing issues. In this article, use of nurse practictioners to fill the intensive care unit intensivist staffing gap is assessed and evidence-based recommendations are identified to better incorporate nurse practitioners as part of intensive care unit intensivist staffing. The literature reveals that when nurse practitioners are part of a staffing model, outcomes are either positively impacted or no different from physician outcomes. However, successfully integrating nurse practitioners into an intensive care unit team is not adequately discussed in the literature. This gap is addressed and 3 mechanisms to integrate nurse practitioners into the intensive care unit are identified: (1) use of a multidisciplinary staffing model, (2) completion of onboarding programs, and (3) evaluation of nurse practitioner productivity. PMID- 28592468 TI - Improving Health Care Provider Communication in End-of-Life Decision-Making. AB - Critical care providers are responsible for many aspects of patient care, primarily focusing on preserving life. However, nearly 40% of patients who are admitted to an adult critical care unit will not survive. Initiating a conversation about end-of-life decision-making is a daunting task. Often, health care providers are not trained, experienced, or comfortable facilitating these conversations. This article describes a quality improvement project that identified current views on end-of-life communication in the intensive care unit and potential barriers that obstruct open discussion, and offering strategies for improvement. PMID- 28592469 TI - Letters to the Editor. PMID- 28592470 TI - Letters to the Editor. PMID- 28592471 TI - Letters to the Editor. PMID- 28592472 TI - Family-Centered Care. PMID- 28592473 TI - Implementing the SCCM Family-Centered Care Guidelines in Critical Care Nursing Practice. AB - Family-centered care is an important component of holistic nursing practice, particularly in critical care, where the impact on families of admitted patients can be physiologically and psychologically burdensome. Family-centered care guidelines, developed by an international group of nursing, medical, and academic experts for the American College of Critical Care Medicine/Society of Critical Care Medicine, explore the evidence base in 5 key areas of family-centered care. Evidence in each of the guideline areas is outlined and recommendations are made about how critical care nurses can use this information in family-centered care practice. PMID- 28592474 TI - Implementing Intensive Care Unit Family-Centered Care: Resources to Identify and Address Gaps. AB - During creation of the 2017 Society of Critical Care Medicine Guidelines for Family-Centered Care in the Intensive Care Unit, 2 implementation tools were developed to assist intensive care unit clinicians in incorporating the new recommendations into local practice: a gap analysis tool and a work tools document. The gap analysis tool helps intensive care unit teams rapidly develop unit- or organization-specific recommendations to enhance family-centered care and assess local barriers to implementation. The work tools document identifies readily available and tested resources that may further assist with action planning for change. The goal of these implementation tools is to promote rapid translation of the SCCM Guideline recommendations into practice, thereby streamlining the process of enacting meaningful evidence-based practice change. PMID- 28592475 TI - Promoting Patient- and Family-Centered Care in the Intensive Care Unit: A Dissemination Project. AB - Awareness of patient-centered and family-centered care research can assist clinicians to promote patient and family engagement in the intensive care unit. Project Dispatch (Disseminating Patient-Centered Outcomes Research to Healthcare Professionals) was developed to disseminate patient- and family-centered care research and encourage its application in clinical practice. The 3-year project involved the development of an interactive website platform, online educational programming, social media channels, a podcast and webcast series, and electronic and print media. The project's webpages received more than 5200 page views with over 4000 unique visitors from 36 countries. The podcast series has download numbers ranging from 35 596 for "Family Presence in the ICU" to 25 843 for "Improving Patient and Family satisfaction in the ICU" and 22 148 for "Family Satisfaction in the ICU." The project therefore successfully developed resources for critical care health care professionals to promote the patient- and family centric perspective. PMID- 28592477 TI - Sleep in the Intensive Care Unit in a Model of Family-Centered Care. AB - The desire for families to be physically present to support their loved ones in the intensive care unit, and guidelines in favor of this open visitation approach, require that clinicians consider both patient and family sleep. This article reviews the causes of poor sleep for patients and their family members in the intensive care unit as well as the expected changes in cognition and emotion that can result from sleep deprivation. Measures are proposed to improve the intensive care unit environment to promote family sleep. A framework to educate family members and engage them in preservation of their and their loved one's circadian rhythm is also presented. Although further research is needed, the proposed framework has the potential to improve outcomes for patients and their families in the intensive care unit. PMID- 28592476 TI - Factors Influencing Active Family Engagement in Care Among Critical Care Nurses. AB - Critical care nurses are vital to promoting family engagement in the intensive care unit. However, nurses have varying perceptions about how much family members should be involved. The Questionnaire on Factors That Influence Family Engagement was given to a national sample of 433 critical care nurses. This correlational study explored the impact of nurse and organizational characteristics on barriers and facilitators to family engagement. Study results indicate that (1) nurses were most likely to invite family caregivers to provide simple daily care; (2) age, degree earned, critical care experience, hospital location, unit type, and staffing ratios influenced the scores; and (3) nursing work-flow partially mediated the relationships between the intensive care unit environment and nurses' attitudes and between patient acuity and nurses' attitudes. These results help inform nursing leaders on ways to promote nurse support of active family engagement in the intensive care unit. PMID- 28592478 TI - Measuring Outcomes of an Intensive Care Unit Family Diary Program. AB - Patients discharged from intensive care units are at risk of short- and long-term physical, cognitive, and emotional symptoms known as post-intensive care syndrome. Family members of intensive care unit patients are at risk of similar symptoms known as post-intensive care syndrome-family. Both syndromes are common, and strategies to reduce risk factors should be employed. An intensive care unit diary project to help reduce these syndromes was implemented in 2 intensive care units using an evidence-based framework. The effects of these diaries were studied using the Family Satisfaction with Care in the Intensive Care Unit survey. Rates of referrals to a postintensive care unit recovery clinic were also observed in relation to the diaries. Although preliminary data did not reveal a significant increase in family satisfaction, the surveys provided important staff feedback. The diaries fostered feelings of compassion and caring as well as built trust between staff and family members of intensive care unit patients. The diaries increased referrals to the postintensive care unit recovery clinic. PMID- 28592479 TI - Innovation and Technology: Electronic Intensive Care Unit Diaries. AB - Hospitalization in the intensive care unit can be a stressful time for patients and their family members. Patients' family members often have difficulty processing all of the information that is given to them. Therefore, an intensive care unit diary can serve as a conduit for synthesizing information, maintaining connection with patients, and maintaining a connection with family members outside the intensive care unit. Paper intensive care unit diaries have been used outside the United States for many years. This article explores the development of an electronic intensive care unit diary using a rapid prototyping model to accelerate the process. Initial results of design testing demonstrate that it is feasible, useful, and desirable to consider the implementation of electronic intensive care unit diaries for patients at risk for post-intensive care syndrome. PMID- 28592480 TI - Implementing Family-Centered Care Through Facilitated Sensemaking. AB - The Society of Critical Care Medicine has released updated recommendations for care of the family in neonatal, pediatric, and adult intensive care units. Translation of the recommendations into practice may benefit from a supporting theoretical framework. Facilitated sensemaking is a mid-range theory built from the same literature that formed the basis for recommendations within the guidelines. The process of facilitated sensemaking may be used to help nurses adopt the SCCM recommendations into practice through the development of caring relationships, promoting family presence, teaching family engagement strategies, and supporting families with communication, information gathering, and participation in decision-making. PMID- 28592481 TI - Creating Clinical Research Protocols in Advanced Practice: Part IV, Designing Research to Fit Practice. PMID- 28592482 TI - Aid in Dying: The Role of the Critical Care Nurse. PMID- 28592483 TI - Atrioventricular Reentrant Tachycardia. PMID- 28592484 TI - Analysis of neointima development in flow diverters using optical coherence tomography imaging. AB - BACKGROUND: Flow diverters are used for the treatment of intracranial aneurysms. Surface modification may decrease the thrombogenicity of flow diverters but the details are unknown. Optical coherence tomography (OCT) is an intravascular imaging test with high resolution which identifies neointimal growth over stents. We compared the development of neointima in a flow diverter and stents with and without surface modification in a swine model. METHODS: In this study we implanted four devices (two in each carotid artery) in four pigs. The devices used were the Pipeline Flex embolization device (PED Flex, n=6), PED with Shield technology (PED Shield, n=6), and Solitaire AB (n=4). Serial carotid angiographic and OCT images were obtained on days 0, 7, 14, and 21. The data analyzed included: neointimal area (lumen area - stent area), neointimal ratio ([lumen area - stent area]/stent area), and the neointimal thickness ratio (minimum neointimal thickness/maximum neointimal thickness). RESULTS: There was no significant difference in where neointima formation was initiated in relation to the implanted device (distal vs middle vs proximal). The PED Shield had a trend towards earlier endothelial formation at day 7. By day 21 the neointimal ratio was significantly higher for the PED Flex and PED Shield devices than for Solitaire (p<0.05 and p<0.01, respectively). The neointimal thickness ratio was significantly higher with PED Shield than with PED Flex and Solitaire (p<0.05 and p<0.01, respectively). CONCLUSIONS: OCT enabled us to follow and compare in vivo the development of neointima over implants. PED Shield showed a similar neointimal volume to PED Flex and more concentric neointima. PMID- 28592485 TI - Energetics of side-chain partitioning of beta-signal residues in unassisted folding of a transmembrane beta-barrel protein. AB - The free energy of water-to-interface amino acid partitioning is a major contributing factor in membrane protein folding and stability. The interface residues at the C terminus of transmembrane beta-barrels form the beta-signal motif required for assisted beta-barrel assembly in vivo but are believed to be less important for beta-barrel assembly in vitro Here, we experimentally measured the thermodynamic contribution of all 20 amino acids at the beta-signal motif to the unassisted folding of the model beta-barrel protein PagP. We obtained the partitioning free energy for all 20 amino acids at the lipid-facing interface (DeltaDeltaG0w,i(phi)) and the protein-facing interface (DeltaDeltaG0w,i(pi)) residues and found that hydrophobic amino acids are most favorably transferred to the lipid-facing interface, whereas charged and polar groups display the highest partitioning energy. Furthermore, the change in non-polar surface area correlated directly with the partitioning free energy for the lipid-facing residue and inversely with the protein-facing residue. We also demonstrate that the interface residues of the beta-signal motif are vital for in vitro barrel assembly, because they exhibit a side chain-specific energetic contribution determined by the change in nonpolar accessible surface. We further establish that folding cooperativity and hydrophobic collapse are balanced at the membrane interface for optimal stability of the PagP beta-barrel scaffold. We conclude that the PagP C terminal beta-signal motif influences the folding cooperativity and stability of the folded beta-barrel and that the thermodynamic contributions of the lipid- and protein-facing residues in the transmembrane protein beta-signal motif depend on the nature of the amino acid side chain. PMID- 28592486 TI - Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM). AB - Metabolic reprogramming is a hallmark of cancer. The changes in metabolism are adaptive to permit proliferation, survival, and eventually metastasis in a harsh environment. Stable isotope-resolved metabolomics (SIRM) is an approach that uses advanced approaches of NMR and mass spectrometry to analyze the fate of individual atoms from stable isotope-enriched precursors to products to deduce metabolic pathways and networks. The approach can be applied to a wide range of biological systems, including human subjects. This review focuses on the applications of SIRM to cancer metabolism and its use in understanding drug actions. PMID- 28592487 TI - Electrostatic control of DNA intersegmental translocation by the ETS transcription factor ETV6. AB - To find their DNA target sites in complex solution environments containing excess heterogeneous DNA, sequence-specific DNA-binding proteins execute various translocation mechanisms known collectively as facilitated diffusion. For proteins harboring a single DNA contact surface, long-range translocation occurs by jumping between widely spaced DNA segments. We have configured biosensor-based surface plasmon resonance to directly measure the affinity and kinetics of this intersegmental jumping by the ETS-family transcription factor ETS variant 6 (ETV6). To isolate intersegmental target binding in a functionally defined manner, we pre-equilibrated ETV6 with excess salmon sperm DNA, a heterogeneous polymer, before exposing the nonspecifically bound protein to immobilized oligomeric DNA harboring a high-affinity ETV6 site. In this way, the mechanism of ETV6-target association could be toggled electrostatically through varying NaCl concentration in the bulk solution. Direct measurements of association and dissociation kinetics of the site-specific complex indicated that 1) freely diffusive binding by ETV6 proceeds through a nonspecific-like intermediate, 2) intersegmental jumping is rate-limited by dissociation from the nonspecific polymer, and 3) dissociation of the specific complex is independent of the history of complex formation. These results show that target searches by proteins with an ETS domain, such as ETV6, whose single DNA-binding domain cannot contact both source and destination sites simultaneously, are nonetheless strongly modulated by intersegmental jumping in heterogeneous site environments. Our findings establish biosensors as a general technique for directly and specifically measuring target site search by DNA-binding proteins via intersegmental translocation. PMID- 28592488 TI - DNA damage-induced ATM- and Rad-3-related (ATR) kinase activation in non replicating cells is regulated by the XPB subunit of transcription factor IIH (TFIIH). AB - The role of the DNA damage response protein kinase ataxia telangiectasia-mutated (ATM)- and Rad-3-related (ATR) in the cellular response to DNA damage during the replicative phase of the cell cycle has been extensively studied. However, little is known about ATR kinase function in cells that are not actively replicating DNA and that constitute most cells in the human body. Using small-molecule inhibitors of ATR kinase and overexpression of a kinase-inactive form of the enzyme, I show here that ATR promotes cell death in non-replicating/non-cycling cultured human cells exposed to N-acetoxy-2-acetylaminofluorene (NA-AAF), which generates bulky DNA adducts that block RNA polymerase movement. Immunoblot analyses of soluble protein extracts revealed that ATR and other cellular proteins containing SQ motifs become rapidly and robustly phosphorylated in non-cycling cells exposed to NA-AAF in a manner largely dependent on ATR kinase activity but independent of the essential nucleotide excision repair factor XPA. Although the topoisomerase I inhibitor camptothecin also activated ATR in non-cycling cells, other transcription inhibitors that do not directly damage DNA failed to do so. Interestingly, genetic and pharmacological inhibition of the XPB subunit of transcription factor IIH prevented the accumulation of the single-stranded DNA binding protein replication protein A (RPA) on damaged chromatin and severely abrogated ATR signaling in response to NA-AAF and camptothecin. Together, these results reveal a previously unknown role for transcription factor IIH in ATR kinase activation in non-replicating, non-cycling cells. PMID- 28592489 TI - Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome. AB - Individuals with Hajdu-Cheney syndrome (HCS) present with osteoporosis, and HCS is associated with NOTCH2 mutations causing deletions of the proline-, glutamic acid-, serine-, and threonine-rich (PEST) domain that are predicted to enhance NOTCH2 stability and cause gain-of-function. Previously, we demonstrated that mice harboring Notch2 mutations analogous to those in HCS (Notch2HCS) are severely osteopenic because of enhanced bone resorption. We attributed this phenotype to osteoclastic sensitization to the receptor activator of nuclear factor-kappaB ligand and increased osteoblastic tumor necrosis factor superfamily member 11 (Tnfsf11) expression. Here, to determine the individual contributions of osteoclasts and osteoblasts to HCS osteopenia, we created a conditional-by inversion (Notch2COIN ) model in which Cre recombination generates a Notch2DeltaPEST allele expressing a Notch2 mutant lacking the PEST domain. Germ line Notch2COIN inversion phenocopied the Notch2HCS mutant, validating the model. To activate Notch2 in osteoclasts or osteoblasts, Notch2COIN mice were bred with mice expressing Cre from the Lyz2 or the BGLAP promoter, respectively. These crosses created experimental mice harboring a Notch2DeltaPEST allele in Cre expressing cells and control littermates expressing a wild-type Notch2 transcript. Notch2COIN inversion in Lyz2-expressing cells had no skeletal consequences and did not affect the capacity of bone marrow macrophages to form osteoclasts in vitro In contrast, Notch2COIN inversion in osteoblasts led to generalized osteopenia associated with enhanced bone resorption in the cancellous bone compartment and with suppressed endocortical mineral apposition rate. Accordingly, Notch2 activation in osteoblast-enriched cultures from Notch2COIN mice induced Tnfsf11 expression. In conclusion, introduction of the HCS mutation in osteoblasts, but not in osteoclasts, causes osteopenia. PMID- 28592490 TI - Functional analyses yield detailed insight into the mechanism of thrombin inhibition by the antihemostatic salivary protein cE5 from Anopheles gambiae. AB - Saliva of blood-feeding arthropods carries several antihemostatic compounds whose physiological role is to facilitate successful acquisition of blood. The identification of novel natural anticoagulants and the understanding of their mechanism of action may offer opportunities for designing new antithrombotics disrupting blood clotting. We report here an in-depth structural and functional analysis of the anophelin family member cE5, a salivary protein from the major African malaria vector Anopheles gambiae that specifically, tightly, and quickly binds and inhibits thrombin. Using calorimetry, functional assays, and complementary structural techniques, we show that the central region of the protein, encompassing amino acids Asp-31-Arg-62, is the region mainly responsible for alpha-thrombin binding and inhibition. As previously reported for the Anopheles albimanus orthologue anophelin, cE5 binds both thrombin exosite I with segment Glu-35-Asp-47 and the catalytic site with the region Pro-49-Arg-56, which includes the highly conserved DPGR tetrapeptide. Moreover, the N-terminal Ala-1 Ser-30 region of cE5 (which includes an RGD tripeptide) and the additional C terminal serine-rich Asn-63-Glu-82 region (absent in orthologues from anophelines of the New World species A. albimanus and Anopheles darlingi) also played some functionally relevant role. Indeed, we observed decreased thrombin binding and inhibitory properties even when using the central cE5 fragment (Asp-31-Arg-62) alone. In summary, these results shed additional light on the mechanism of thrombin binding and inhibition by this family of salivary anticoagulants from anopheline mosquitoes. PMID- 28592493 TI - Back to the Future: Multiparent Populations Provide the Key to Unlocking the Genetic Basis of Complex Traits. PMID- 28592492 TI - Heterogeneous nuclear ribonucleoprotein K inhibits heat shock-induced transcriptional activity of heat shock factor 1. AB - When cells are exposed to heat shock and various other stresses, heat shock factor 1 (HSF1) is activated, and the heat shock response (HSR) is elicited. To better understand the molecular regulation of the HSR, we used 2D-PAGE-based proteome analysis to screen for heat shock-induced post-translationally modified cellular proteins. Our analysis revealed that two protein spots typically present on 2D-PAGE gels and containing heterogeneous nuclear ribonucleoprotein K (hnRNP K) with trioxidized Cys132 disappeared after the heat shock treatment and reappeared during recovery, but the total amount of hnRNP K protein remained unchanged. We next tested whether hnRNP K plays a role in HSR by regulating HSF1 and found that hnRNP K inhibits HSF1 activity, resulting in reduced expression of hsp70 and hsp27 mRNAs. hnRNP K also reduced binding affinity of HSF1 to the heat shock element by directly interacting with HSF1 but did not affect HSF1 phosphorylation-dependent activation or nuclear localization. hnRNP K lost its ability to induce these effects when its Cys132 was substituted with Ser, Asp, or Glu. These findings suggest that hnRNP K inhibits transcriptional activity of HSF1 by inhibiting its binding to heat shock element and that the oxidation status of Cys132 in hnRNP K is critical for this inhibition. PMID- 28592491 TI - Exploiting fine-scale genetic and physiological variation of closely related microbes to reveal unknown enzyme functions. AB - Polysaccharide degradation by marine microbes represents one of the largest and most rapid heterotrophic transformations of organic matter in the environment. Microbes employ systems of complementary carbohydrate-specific enzymes to deconstruct algal or plant polysaccharides (glycans) into monosaccharides. Because of the high diversity of glycan substrates, the functions of these enzymes are often difficult to establish. One solution to this problem may lie within naturally occurring microdiversity; varying numbers of enzymes, due to gene loss, duplication, or transfer, among closely related environmental microbes create metabolic differences akin to those generated by knock-out strains engineered in the laboratory used to establish the functions of unknown genes. Inspired by this natural fine-scale microbial diversity, we show here that it can be used to develop hypotheses guiding biochemical experiments for establishing the role of these enzymes in nature. In this work, we investigated alginate degradation among closely related strains of the marine bacterium Vibrio splendidus One strain, V. splendidus 13B01, exhibited high extracellular alginate lyase activity compared with other V. splendidus strains. To identify the enzymes responsible for this high extracellular activity, we compared V. splendidus 13B01 with the previously characterized V. splendidus 12B01, which has low extracellular activity and lacks two alginate lyase genes present in V. splendidus 13B01. Using a combination of genomics, proteomics, biochemical, and functional screening, we identified a polysaccharide lyase family 7 enzyme that is unique to V. splendidus 13B01, secreted, and responsible for the rapid digestion of extracellular alginate. These results demonstrate the value of querying the enzymatic repertoires of closely related microbes to rapidly pinpoint key proteins with beneficial functions. PMID- 28592494 TI - Epistasis: Searching for Interacting Genetic Variants Using Crosses. PMID- 28592495 TI - Genomes of the Mouse Collaborative Cross. AB - The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30* coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 +/- 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources. PMID- 28592496 TI - Male Infertility Is Responsible for Nearly Half of the Extinction Observed in the Mouse Collaborative Cross. AB - The goal of the Collaborative Cross (CC) project was to generate and distribute over 1000 independent mouse recombinant inbred strains derived from eight inbred founders. With inbreeding nearly complete, we estimated the extinction rate among CC lines at a remarkable 95%, which is substantially higher than in the derivation of other mouse recombinant inbred populations. Here, we report genome wide allele frequencies in 347 extinct CC lines. Contrary to expectations, autosomes had equal allelic contributions from the eight founders, but chromosome X had significantly lower allelic contributions from the two inbred founders with underrepresented subspecific origins (PWK/PhJ and CAST/EiJ). By comparing extinct CC lines to living CC strains, we conclude that a complex genetic architecture is driving extinction, and selection pressures are different on the autosomes and chromosome X Male infertility played a large role in extinction as 47% of extinct lines had males that were infertile. Males from extinct lines had high variability in reproductive organ size, low sperm counts, low sperm motility, and a high rate of vacuolization of seminiferous tubules. We performed QTL mapping and identified nine genomic regions associated with male fertility and reproductive phenotypes. Many of the allelic effects in the QTL were driven by the two founders with underrepresented subspecific origins, including a QTL on chromosome X for infertility that was driven by the PWK/PhJ haplotype. We also performed the first example of cross validation using complementary CC resources to verify the effect of sperm curvilinear velocity from the PWK/PhJ haplotype on chromosome 2 in an independent population across multiple generations. While selection typically constrains the examination of reproductive traits toward the more fertile alleles, the CC extinct lines provided a unique opportunity to study the genetic architecture of fertility in a widely genetically variable population. We hypothesize that incompatibilities between alleles with different subspecific origins is a key driver of infertility. These results help clarify the factors that drove strain extinction in the CC, reveal the genetic regions associated with poor fertility in the CC, and serve as a resource to further study mammalian infertility. PMID- 28592497 TI - Increased Power To Dissect Adaptive Traits in Global Sorghum Diversity Using a Nested Association Mapping Population. AB - Adaptation of domesticated species to diverse agroclimatic regions has led to abundant trait diversity. However, the resulting population structure and genetic heterogeneity confounds association mapping of adaptive traits. To address this challenge in sorghum [Sorghum bicolor (L.) Moench]-a widely adapted cereal crop we developed a nested association mapping (NAM) population using 10 diverse global lines crossed with an elite reference line RTx430. We characterized the population of 2214 recombinant inbred lines at 90,000 SNPs using genotyping-by sequencing. The population captures ~70% of known global SNP variation in sorghum, and 57,411 recombination events. Notably, recombination events were four to fivefold enriched in coding sequences and 5' untranslated regions of genes. To test the power of the NAM population for trait dissection, we conducted joint linkage mapping for two major adaptive traits, flowering time and plant height. We precisely mapped several known genes for these two traits, and identified several additional QTL. Considering all SNPs simultaneously, genetic variation accounted for 65% of flowering time variance and 75% of plant height variance. Further, we directly compared NAM to genome-wide association mapping (using panels of the same size) and found that flowering time and plant height QTL were more consistently identified with the NAM population. Finally, for simulated QTL under strong selection in diversity panels, the power of QTL detection was up to three times greater for NAM vs. association mapping with a diverse panel. These findings validate the NAM resource for trait mapping in sorghum, and demonstrate the value of NAM for dissection of adaptive traits. PMID- 28592498 TI - Genetic Dissection of Nutrition-Induced Plasticity in Insulin/Insulin-Like Growth Factor Signaling and Median Life Span in a Drosophila Multiparent Population. AB - The nutritional environments that organisms experience are inherently variable, requiring tight coordination of how resources are allocated to different functions relative to the total amount of resources available. A growing body of evidence supports the hypothesis that key endocrine pathways play a fundamental role in this coordination. In particular, the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways have been implicated in nutrition-dependent changes in metabolism and nutrient allocation. However, little is known about the genetic basis of standing variation in IIS/TOR or how diet-dependent changes in expression in this pathway influence phenotypes related to resource allocation. To characterize natural genetic variation in the IIS/TOR pathway, we used >250 recombinant inbred lines (RILs) derived from a multiparental mapping population, the Drosophila Synthetic Population Resource, to map transcript-level QTL of genes encoding 52 core IIS/TOR components in three different nutritional environments [dietary restriction (DR), control (C), and high sugar (HS)]. Nearly all genes, 87%, were significantly differentially expressed between diets, though not always in ways predicted by loss-of-function mutants. We identified cis (i.e., local) expression QTL (eQTL) for six genes, all of which are significant in multiple nutrient environments. Further, we identified trans (i.e., distant) eQTL for two genes, specific to a single nutrient environment. Our results are consistent with many small changes in the IIS/TOR pathways. A discriminant function analysis for the C and DR treatments identified a pattern of gene expression associated with the diet treatment. Mapping the composite discriminant function scores revealed a significant global eQTL within the DR diet. A correlation between the discriminant function scores and the median life span (r = 0.46) provides evidence that gene expression changes in response to diet are associated with longevity in these RILs. PMID- 28592499 TI - Structural Variation Shapes the Landscape of Recombination in Mouse. AB - Meiotic recombination is an essential feature of sexual reproduction that ensures faithful segregation of chromosomes and redistributes genetic variants in populations. Multiparent populations such as the Diversity Outbred (DO) mouse stock accumulate large numbers of crossover (CO) events between founder haplotypes, and thus present a unique opportunity to study the role of genetic variation in shaping the recombination landscape. We obtained high-density genotype data from [Formula: see text] DO mice, and localized 2.2 million CO events to intervals with a median size of 28 kb. The resulting sex-averaged genetic map of the DO population is highly concordant with large-scale (order 10 Mb) features of previously reported genetic maps for mouse. To examine fine-scale (order 10 kb) patterns of recombination in the DO, we overlaid putative recombination hotspots onto our CO intervals. We found that CO intervals are enriched in hotspots compared to the genomic background. However, as many as [Formula: see text] of CO intervals do not overlap any putative hotspots, suggesting that our understanding of hotspots is incomplete. We also identified coldspots encompassing 329 Mb, or [Formula: see text] of observable genome, in which there is little or no recombination. In contrast to hotspots, which are a few kilobases in size, and widely scattered throughout the genome, coldspots have a median size of 2.1 Mb and are spatially clustered. Coldspots are strongly associated with copy-number variant (CNV) regions, especially multi-allelic clusters, identified from whole-genome sequencing of 228 DO mice. Genes in these regions have reduced expression, and epigenetic features of closed chromatin in male germ cells, which suggests that CNVs may repress recombination by altering chromatin structure in meiosis. Our findings demonstrate how multiparent populations, by bridging the gap between large-scale and fine-scale genetic mapping, can reveal new features of the recombination landscape. PMID- 28592501 TI - A Physicist's Quest in Biology: Max Delbruck and "Complementarity". AB - Max Delbruck was trained as a physicist but made his major contribution in biology and ultimately shared a Nobel Prize in Physiology or Medicine. He was the acknowledged leader of the founders of molecular biology, yet he failed to achieve his key scientific goals. His ultimate scientific aim was to find evidence for physical laws unique to biology: so-called "complementarity." He never did. The specific problem he initially wanted to solve was the nature of biological replication but the discovery of the mechanism of replication was made by others, in large part because of his disdain for the details of biochemistry. His later career was spent investigating the effect of light on the fungus Phycomyces, a topic that turned out to be of limited general interest. He was known both for his informality but also for his legendary displays of devastating criticism. His life and that of some of his closest colleagues was acted out against a background of a world in conflict. This essay describes the man and his career and searches for an explanation of his profound influence. PMID- 28592500 TI - Epistatic Networks Jointly Influence Phenotypes Related to Metabolic Disease and Gene Expression in Diversity Outbred Mice. AB - Genetic studies of multidimensional phenotypes can potentially link genetic variation, gene expression, and physiological data to create multi-scale models of complex traits. The challenge of reducing these data to specific hypotheses has become increasingly acute with the advent of genome-scale data resources. Multi-parent populations derived from model organisms provide a resource for developing methods to understand this complexity. In this study, we simultaneously modeled body composition, serum biomarkers, and liver transcript abundances from 474 Diversity Outbred mice. This population contained both sexes and two dietary cohorts. Transcript data were reduced to functional gene modules with weighted gene coexpression network analysis (WGCNA), which were used as summary phenotypes representing enriched biological processes. These module phenotypes were jointly analyzed with body composition and serum biomarkers in a combined analysis of pleiotropy and epistasis (CAPE), which inferred networks of epistatic interactions between quantitative trait loci that affect one or more traits. This network frequently mapped interactions between alleles of different ancestries, providing evidence of both genetic synergy and redundancy between haplotypes. Furthermore, a number of loci interacted with sex and diet to yield sex-specific genetic effects and alleles that potentially protect individuals from the effects of a high-fat diet. Although the epistatic interactions explained small amounts of trait variance, the combination of directional interactions, allelic specificity, and high genomic resolution provided context to generate hypotheses for the roles of specific genes in complex traits. Our approach moves beyond the cataloging of single loci to infer genetic networks that map genetic etiology by simultaneously modeling all phenotypes. PMID- 28592503 TI - A Short History and Description of Drosophila melanogaster Classical Genetics: Chromosome Aberrations, Forward Genetic Screens, and the Nature of Mutations. AB - The purpose of this chapter in FlyBook is to acquaint the reader with the Drosophila genome and the ways in which it can be altered by mutation. Much of what follows will be familiar to the experienced Fly Pusher but hopefully will be useful to those just entering the field and are thus unfamiliar with the genome, the history of how it has been and can be altered, and the consequences of those alterations. I will begin with the structure, content, and organization of the genome, followed by the kinds of structural alterations (karyotypic aberrations), how they affect the behavior of chromosomes in meiotic cell division, and how that behavior can be used. Finally, screens for mutations as they have been performed will be discussed. There are several excellent sources of detailed information on Drosophila husbandry and screening that are recommended for those interested in further expanding their familiarity with Drosophila as a research tool and model organism. These are a book by Ralph Greenspan and a review article by John Roote and Andreas Prokop, which should be required reading for any new student entering a fly lab for the first time. PMID- 28592502 TI - The Mouse Lemur, a Genetic Model Organism for Primate Biology, Behavior, and Health. AB - Systematic genetic studies of a handful of diverse organisms over the past 50 years have transformed our understanding of biology. However, many aspects of primate biology, behavior, and disease are absent or poorly modeled in any of the current genetic model organisms including mice. We surveyed the animal kingdom to find other animals with advantages similar to mice that might better exemplify primate biology, and identified mouse lemurs (Microcebus spp.) as the outstanding candidate. Mouse lemurs are prosimian primates, roughly half the genetic distance between mice and humans. They are the smallest, fastest developing, and among the most prolific and abundant primates in the world, distributed throughout the island of Madagascar, many in separate breeding populations due to habitat destruction. Their physiology, behavior, and phylogeny have been studied for decades in laboratory colonies in Europe and in field studies in Malagasy rainforests, and a high quality reference genome sequence has recently been completed. To initiate a classical genetic approach, we developed a deep phenotyping protocol and have screened hundreds of laboratory and wild mouse lemurs for interesting phenotypes and begun mapping the underlying mutations, in collaboration with leading mouse lemur biologists. We also seek to establish a mouse lemur gene "knockout" library by sequencing the genomes of thousands of mouse lemurs to identify null alleles in most genes from the large pool of natural genetic variants. As part of this effort, we have begun a citizen science project in which students across Madagascar explore the remarkable biology around their schools, including longitudinal studies of the local mouse lemurs. We hope this work spawns a new model organism and cultivates a deep genetic understanding of primate biology and health. We also hope it establishes a new and ethical method of genetics that bridges biological, behavioral, medical, and conservation disciplines, while providing an example of how hands-on science education can help transform developing countries. PMID- 28592506 TI - An Extraordinary Sex Determination Mechanism in a Book Louse. PMID- 28592507 TI - Alternative Poly(A) Tails Meet miRNA Targeting in Caenorhabditis elegans. PMID- 28592510 TI - Methodological utility of chemerin as a novel biomarker of immunity and metabolism. AB - Chemerin is a recently discovered adipokine with inflammatory and metabolic actions relevant for chronic disease development. However, evidence from human research on the role of chemerin in chronic disease risk is still lacking. We assessed the reliability of plasma chemerin concentrations measured on two occasions over a 4-month period in 207 apparently healthy participants. In addition, we explored the cross-sectional associations between chemerin and inflammatory biomarkers using Spearman partial correlation and multivariable linear regression analyses. Intra-individual reproducibility of chemerin measurements was assessed by calculating intraclass correlation coefficients (ICCs) and exploration of Bland-Altman plots. Reliability analyses revealed good reproducibility of chemerin measurements (ICC: 0.72 (95%-CI 0.65, 0.78)). Visual inspection of Bland-Altman plots confirmed that the two time point measurements had a high level of agreement. In correlation analyses, chemerin was positively correlated with adiposity measures (body mass index and waist circumference). In addition, independent of adiposity measures, chemerin was correlated with the biomarkers C-reactive protein, fatty acid-binding protein 4 and progranulin (Rho s ranging from 0.23 to 0.37). In multivariable linear regression analysis, a combination of correlated factors including body mass index, waist circumference, C-reactive protein, progranulin and fatty acid-binding protein-4 explained 28.0% of chemerin concentrations. These findings demonstrate methodological utility of chemerin concentrations in population-based research setting. Human studies are highly warranted in order to provide further insights into the role of chemerin as a biomarker linking immunity and metabolism in relation to chronic disease risk. PMID- 28592509 TI - Comparative functional genomic screens of three yeast deletion collections reveal unexpected effects of genotype in response to diverse stress. AB - The Yeast Knockout (YKO) collection has provided a wealth of functional annotations from genome-wide screens. An unintended consequence is that 76% of gene annotations derive from one genotype. The nutritional auxotrophies in the YKO, in particular, have phenotypic consequences. To address this issue, 'prototrophic' versions of the YKO collection have been constructed, either by introducing a plasmid carrying wild-type copies of the auxotrophic markers (Plasmid-Borne, PBprot) or by backcrossing (Backcrossed, BCprot) to a wild-type strain. To systematically assess the impact of the auxotrophies, genome-wide fitness profiles of prototrophic and auxotrophic collections were compared across diverse drug and environmental conditions in 250 experiments. Our quantitative profiles uncovered broad impacts of genotype on phenotype for three deletion collections, and revealed genotypic and strain-construction-specific phenotypes. The PBprot collection exhibited fitness defects associated with plasmid maintenance, while BCprot fitness profiles were compromised due to strain loss from nutrient selection steps during strain construction. The repaired prototrophic versions of the YKO collection did not restore wild-type behaviour nor did they clarify gaps in gene annotation resulting from the auxotrophic background. To remove marker bias and expand the experimental scope of deletion libraries, construction of a bona fide prototrophic collection from a wild-type strain will be required. PMID- 28592504 TI - Experimental Evolution with Caenorhabditis Nematodes. AB - The hermaphroditic nematode Caenorhabditis elegans has been one of the primary model systems in biology since the 1970s, but only within the last two decades has this nematode also become a useful model for experimental evolution. Here, we outline the goals and major foci of experimental evolution with C. elegans and related species, such as C. briggsae and C. remanei, by discussing the principles of experimental design, and highlighting the strengths and limitations of Caenorhabditis as model systems. We then review three exemplars of Caenorhabditis experimental evolution studies, underlining representative evolution experiments that have addressed the: (1) maintenance of genetic variation; (2) role of natural selection during transitions from outcrossing to selfing, as well as the maintenance of mixed breeding modes during evolution; and (3) evolution of phenotypic plasticity and its role in adaptation to variable environments, including host-pathogen coevolution. We conclude by suggesting some future directions for which experimental evolution with Caenorhabditis would be particularly informative. PMID- 28592511 TI - Androgenic potential of human fetal adrenals at the end of the first trimester. AB - The onset of steroidogenesis in human fetal adrenal glands (HFA) during the first trimester is poorly investigated. An unresolved question is the capacity of the HFA to produce potent androgen DHT via conventional and/or the backdoor pathway(s) at the end of first trimester, when androgen-responsive organs are developed. Our aim was to explore steroidogenesis and the expression of steroidogenic enzymes and transcription factors in HFA at gestational weeks (GW) 9-12 with focus on their androgenic potential. Steroids in the HFA were analyzed by gas chromatography/mass spectrometry. The expression of steroidogenic enzymes and transcription factors in the HFA at GW9-12 was investigated by qPCR, automated Western blotting and immunohistochemistry. We demonstrated that during GW9-12 HFA produced steroids of the ?5, ?4 and the backdoor pathways of the biosynthesis of DHT, though the latter was limited to production of 17alpha-OH dihydroprogesterone, androsterone and androstanedione without further conversion to DHT. The only androgens identified in the HFA were testosterone and androsterone, a precursor in the biosynthesis of DHT. We also observed higher levels of CYP17A1 but low expression of 3betaHSD2 at GW11-12 in the HFA. Elevated levels of CYP17A1 were associated with an increased expression of SF-1 and GATA 6. Altogether, our data demonstrate that of those steroids analyzed, the only potent androgen directly produced by the HFA at GW9-12 was testosterone. The onset of steroidogenesis in the HFA is a complex process that is regulated by the coordinated action of related transcription factors. PMID- 28592505 TI - Genome Diversity and Evolution in the Budding Yeasts (Saccharomycotina). AB - Considerable progress in our understanding of yeast genomes and their evolution has been made over the last decade with the sequencing, analysis, and comparisons of numerous species, strains, or isolates of diverse origins. The role played by yeasts in natural environments as well as in artificial manufactures, combined with the importance of some species as model experimental systems sustained this effort. At the same time, their enormous evolutionary diversity (there are yeast species in every subphylum of Dikarya) sparked curiosity but necessitated further efforts to obtain appropriate reference genomes. Today, yeast genomes have been very informative about basic mechanisms of evolution, speciation, hybridization, domestication, as well as about the molecular machineries underlying them. They are also irreplaceable to investigate in detail the complex relationship between genotypes and phenotypes with both theoretical and practical implications. This review examines these questions at two distinct levels offered by the broad evolutionary range of yeasts: inside the best-studied Saccharomyces species complex, and across the entire and diversified subphylum of Saccharomycotina. While obviously revealing evolutionary histories at different scales, data converge to a remarkably coherent picture in which one can estimate the relative importance of intrinsic genome dynamics, including gene birth and loss, vs. horizontal genetic accidents in the making of populations. The facility with which novel yeast genomes can now be studied, combined with the already numerous available reference genomes, offer privileged perspectives to further examine these fundamental biological questions using yeasts both as eukaryotic models and as fungi of practical importance. PMID- 28592512 TI - Higher Maternal Protein Intake during Pregnancy Is Associated with Lower Cord Blood Concentrations of Insulin-like Growth Factor (IGF)-II, IGF Binding Protein 3, and Insulin, but Not IGF-I, in a Cohort of Women with High Protein Intake. AB - Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment.Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin.Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity.Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean +/- SD protein intake was 1.35 +/- 0.35 g ? kg-1 ? d-1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 MUU/mL (95% CI: 1.45, -0.37 MUU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls (P-interaction = 0.04) and multiparous mothers (P interaction = 0.05), and with IGFBP-3 in multiparous mothers (P-interaction = 0.04).Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth promoting hormones in cord blood, suggesting a pathway that may link higher protein intake to lower fetal growth. This trial was registered at clinicaltrials.gov as NCT02820402. PMID- 28592513 TI - Iron, Zinc, Folate, and Vitamin B-12 Status Increased among Women and Children in Yaounde and Douala, Cameroon, 1 Year after Introducing Fortified Wheat Flour. AB - Background: Few data are available on the effectiveness of large-scale food fortification programs.Objective: We assessed the impact of mandatory wheat flour fortification on micronutrient status in Yaounde and Douala, Cameroon.Methods: We conducted representative surveys 2 y before and 1 y after the introduction of fortified wheat flour. In each survey, 10 households were selected within each of the same 30 clusters (n = ~300 households). Indicators of inflammation, malaria, anemia, and micronutrient status [plasma ferritin, soluble transferrin receptor (sTfR), zinc, folate, and vitamin B-12] were assessed among women aged 15-49 y and children 12-59 mo of age.Results: Wheat flour was consumed in the past 7 d by >=90% of participants. Postfortification, mean total iron and zinc concentrations of flour samples were 46.2 and 73.6 mg/kg (target added amounts were 60 and 95 mg/kg, respectively). Maternal anemia prevalence was significantly lower postfortification (46.7% compared with 39.1%; adjusted P = 0.01), but mean hemoglobin concentrations and child anemia prevalence did not differ. For both women and children postfortification, mean plasma concentrations were greater for ferritin and lower for sTfR after adjustments for potential confounders. Mean plasma zinc concentrations were greater postfortification and the prevalence of low plasma zinc concentration in women after fortification (21%) was lower than before fortification (39%, P < 0.001); likewise in children, the prevalence postfortification (28%) was lower than prefortification (47%, P < 0.001). Mean plasma total folate concentrations were ~250% greater postfortification among women (47 compared with 15 nmol/L) and children (56 compared with 20 nmol/L), and the prevalence of low plasma folate values was <1% after fortification in both population subgroups. In a nonrepresentative subset of plasma samples, folic acid was detected in 77% of women (73% of those fasting) and 93% of children. Mean plasma and breast-milk vitamin B-12 concentrations were >50% greater postfortification.Conclusion: Although the pre-post survey design limits causal inference, iron, zinc, folate, and vitamin B-12 status increased among women and children in urban Cameroon after mandatory wheat flour fortification. PMID- 28592514 TI - A Western Diet Pattern Is Associated with Higher Concentrations of Blood and Bone Lead among Middle-Aged and Elderly Men. AB - Background: Little is known about the effects of overall dietary pattern on lead concentration.Objective: We examined the association of overall dietary patterns, derived from a semiquantitative food frequency questionnaire, with bone and blood lead concentrations.Methods: These longitudinal analyses included mostly non Hispanic white, middle-aged-to-elderly men from the Veterans Affairs Normative Aging Study. Long-term lead exposures were measured as tibia and patella lead concentrations by using K-shell-X-ray fluorescence. Short-term lead exposures were measured as blood lead concentrations by using graphite furnace atomic absorption spectroscopy. Dietary pattern scores were derived by using factor analysis. Linear mixed-effects models were utilized to predict blood lead concentrations among 983 men, aged 44-92 y at baseline, with a total of 3273 observations (during 1987-2008). We constructed linear regression models to determine the relations between dietary patterns and bone lead concentrations among 649 participants with an age range of 49-93 y.Results: Two major dietary patterns were identified: a prudent dietary pattern, characterized by high intakes of fruit, legumes, vegetables, whole grains, poultry, and seafood; and a Western dietary pattern, characterized by high intakes of processed meat, red meat, refined grains, high-fat dairy products, French fries, butter, and eggs. After adjusting for age, smoking status, body mass index, total energy intake, education, occupation, neighborhood-based education and income level, men in the highest tertile of the Western pattern score (compared with the lowest) had 0.91 MUg/dL (95% CI: 0.41, 1.42 MUg/dL) higher blood lead, 5.96 MUg/g (95% CI: 1.76, 10.16 MUg/g) higher patella lead, and 3.83 MUg/g (95% CI: 0.97, 6.70 MUg/g) higher tibia lead. No significant association was detected with the prudent dietary pattern in the adjusted model.Conclusions: These findings suggest that the Western diet is associated with a greater lead body burden among the middle aged-to-elderly men. More studies are needed to examine the underlying mechanisms by which dietary patterns are associated with lead concentrations. PMID- 28592515 TI - Intragastric Lysine Lowers the Circulating Glucose and Insulin Responses to a Mixed-Nutrient Drink without Slowing Gastric Emptying in Healthy Adults. AB - Background: Lysine is reported to lower the glycemic response to oral glucose in humans and, albeit at high loads, to slow gastric emptying of glucose and decrease food intake in rats.Objective: We investigated the effects of intragastrically administered lysine on early (15 min) and later (60 min) blood glucose and insulin responses to and gastric emptying of a mixed-nutrient drink, and effects on subsequent energy intake.Methods: Twelve healthy volunteers (7 men and 5 women; mean +/- SEM age: 24 +/- 2 y) received intragastric infusions (200 mL) containing 5 or 10 g l-lysine or a control solution within 2 min on 3 different occasions in randomized order. Fifteen minutes later, participants consumed a mixed-nutrient drink (300 mL, 400 kcal, and 56 g carbohydrates) within 1 min. For the next hour (t = 0-60 min), we collected blood samples every 15 min (to measure blood glucose, plasma insulin, and plasma glucagon) and breath samples every 5 min (to measure gastric emptying via a 13C-acetate breath test). We then quantified subjects' energy intake from a buffet-style meal (t = 60-90 min).Results: There were no differences between the 2 lysine treatments; hence, data were pooled for further analysis. Lysine did not affect blood glucose at 15 min or the blood glucose area under the curve from 0 to 60 min (AUC0-60min) but it decreased blood glucose at 60 min compared with the control solution (-9.1% +/ 3.1%, P < 0.01). Similarly, the early insulin response and insulin AUC0-60min were not affected by lysine, but plasma insulin at 60 min was 20.9% +/- 5.6% lower than after the control (P < 0.05). Plasma glucagon at both 15 min (20.7% +/ 4.7%, P < 0.001) and 60 min (14.1% +/- 5.4%, P < 0.05) and the glucagon AUC0 60min (P < 0.01) were greater after lysine than after the control. Lysine did not slow gastric emptying, and there was no effect on energy intake.Conclusion: In healthy adults, lysine slightly reduced the glycemic response to an oral mixed macronutrient drink, an effect that was apparently independent of insulin or slowing of gastric emptying. This trial was registered at www.anzctr.orgau as 12614000837628. PMID- 28592516 TI - Maternal Night-Fasting Interval during Pregnancy Is Directly Associated with Neonatal Head Circumference and Adiposity in Girls but Not Boys. AB - Background: Synchrony between daily feeding-fasting signals and circadian rhythms has been shown to improve metabolic health in animals and adult humans, but the potential programming effect on fetal growth is unknown.Objective: We examined the associations of the maternal night-fasting interval during pregnancy with offspring birth size and adiposity.Methods: This was a cross-sectional study of mother-offspring dyads within the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. For 384 mothers aged 30.8 +/- 4.8 y (mean +/- SD), the night-fasting interval at 26-28 wk of gestation was determined from a 3-d food diary based on the average of the fasting duration at night (1900-0659). Offspring birth weight, length, and head circumference were measured and converted to weight-for-gestational age (GA), length-for-GA, and head circumference-for-GA z scores, respectively, by using local customized percentile charts. The percentage of neonatal total body fat (TBF) was derived by using a validated prediction equation. Multivariable general linear models, stratified by child sex, were performed.Results: The mean +/- SD maternal night-fasting interval was 9.9 +/- 1.3 h. In infant girls, each 1-h increase in the maternal night-fasting interval was associated with a 0.22-SD (95% CI: 0.05-, 0.40-SD; P = 0.013) increase in birth head circumference-for-GA and a 0.84% (95% CI: 0.19%, 1.49%; P = 0.012) increase in TBF at birth, after adjustment for confounders. In infant boys, no associations were observed between the maternal night-fasting interval and birth size or TBF.Conclusions: An increased maternal night-fasting interval in the late second trimester of pregnancy is associated with increased birth head circumference and TBF in girls but not boys. Our findings are in accordance with previous observations that suggest that there are sex-specific responses in fetal brain growth and adiposity, and raise the possibility of the maternal night-fasting interval as an underlying influence. This trial was registered at clinicaltrials.gov as NCT01174875. PMID- 28592518 TI - Zinc Supplementation Does Not Alter Indicators of Insulin Secretion and Sensitivity in Black and White Female Adolescents. AB - Background: Zinc is a micronutrient involved in the production of, and peripheral sensitivity to, pancreatic beta cell-derived insulin. To our knowledge, the effect of zinc supplementation on insulin outcomes, and potential risk of diabetes, in otherwise healthy children in the United States has not been investigated.Objective: The objective of this study was to determine the influence of zinc supplementation on insulin outcomes in black and white girls in the early stages of adolescence. A secondary objective was to determine relations between baseline zinc concentrations and insulin outcomes.Methods: Healthy black and white girls aged 9-11 y were randomly assigned to daily supplementation of zinc (9 mg elemental Zn/d; n = 75; blacks: n = 35) or placebo (n = 72; blacks: n = 32) for 4 wk. Fasting serum insulin, glucose, and C-peptide were assessed at baseline and at 4 wk. C-peptide and glucose values were used to calculate the computer model-derived homeostatic model assessment of insulin resistance (HOMA2 IR). Changes in outcome measures were compared by using repeated-measures, mixed model ANOVA.Results: Baseline plasma zinc was not correlated with C-peptide (r = 0.07), insulin (r = -0.06), or HOMA2-IR (r = -0.09) (all P > 0.05) after controlling for race and age. Treatment * time interactions for C-peptide and HOMA2-IR were not significant (both P > 0.05). Although the treatment * race * time interactions for C-peptide and HOMA2-IR were not significant (both P = 0.08), black girls who received the placebo experienced slight increases in C peptide (15.7%) and HOMA2-IR (17.7%) (P = 0.06).Conclusions: Four weeks of zinc supplementation had no effect on insulin outcomes in healthy black and white early-adolescent girls, although C-peptide and HOMA2-IR tended to increase in black girls who received placebo. Additional trials that are appropriately powered should further explore the effect of zinc on markers of diabetes risk, and whether race affects this relation. This trial was registered at clinicaltrials.gov as NCT01892098. PMID- 28592517 TI - Consumption of Fish Is Not Associated with Risk of Differentiated Thyroid Carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. AB - Background: Differentiated thyroid cancer (TC) is the most common endocrine cancer. Fish can be an important source of iodine and other micronutrients and contaminants that may affect the thyroid gland and TC risk.Objective: We prospectively evaluated the relations between the consumption of total fish and different fish types and shellfish and TC risk in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.Methods: EPIC is a cohort of >500,000 men and women, mostly aged 35-70 y, who were recruited in 10 European countries. After a mean follow-up of 14 y, 748 primary differentiated TC cases were diagnosed; 666 were in women and 601 were papillary TC. Data on intakes of lean fish, fatty fish, fish products, and shellfish were collected by using country-specific validated dietary questionnaires at recruitment. Multivariable Cox regression was used to calculate HRs and 95% CIs adjusted for many potential confounders, including dietary and nondietary factors.Results: No significant association was observed between total fish consumption and differentiated TC risk for the highest compared with the lowest quartile (HR: 1.03; 95% CI: 0.81, 1.32; P-trend = 0.67). Likewise, no significant association was observed with the intake of any specific type of fish, fish product, or shellfish. No significant heterogeneity was found by TC subtype (papillary or follicular tumors), by sex, or between countries with low and high TC incidence.Conclusion: This large study shows that the intake of fish and shellfish was not associated with differentiated TC risk in Europe, a region in which iodine deficiency or excess is rare. PMID- 28592520 TI - Tyrannosauroid integument reveals conflicting patterns of gigantism and feather evolution. AB - Recent evidence for feathers in theropods has led to speculations that the largest tyrannosaurids, including Tyrannosaurus rex, were extensively feathered. We describe fossil integument from Tyrannosaurus and other tyrannosaurids (Albertosaurus, Daspletosaurus, Gorgosaurus and Tarbosaurus), confirming that these large-bodied forms possessed scaly, reptilian-like skin. Body size evolution in tyrannosauroids reveals two independent occurrences of gigantism; specifically, the large sizes in Yutyrannus and tyrannosaurids were independently derived. These new findings demonstrate that extensive feather coverings observed in some early tyrannosauroids were lost by the Albian, basal to Tyrannosauridae. This loss is unrelated to palaeoclimate but possibly tied to the evolution of gigantism, although other mechanisms exist. PMID- 28592521 TI - No evidence for extrinsic post-zygotic isolation in a wild Saccharomyces yeast system. AB - Although microorganisms account for the largest fraction of Earth's biodiversity, we know little about how their reproductive barriers evolve. Sexual microorganisms such as Saccharomyces yeasts rapidly develop strong intrinsic post zygotic isolation, but the role of extrinsic isolation in the early speciation process remains to be investigated. We measured the growth of F1 hybrids between two incipient species of Saccharomyces paradoxus to assess the presence of extrinsic post-zygotic isolation across 32 environments. More than 80% of hybrids showed either partial dominance of the best parent or over-dominance for growth, revealing no fitness defects in F1 hybrids. Extrinsic reproductive isolation therefore likely plays little role in limiting gene flow between incipient yeast species and is not a requirement for speciation. PMID- 28592519 TI - Mechanistic Target of Rapamycin Is a Novel Molecular Mechanism Linking Folate Availability and Cell Function. AB - Folate deficiency has been linked to a wide range of disorders, including cancer, neural tube defects, and fetal growth restriction. Folate regulates cellular function mediated by its involvement in the synthesis of nucleotides, which are needed for DNA synthesis, and its function as a methyl donor, which is critical for DNA methylation. Here we review current data showing that folate sensing by mechanistic target of rapamycin (mTOR) constitutes a novel and distinct pathway by which folate modulates cell functions such as nutrient transport, protein synthesis, and mitochondrial respiration. The mTOR signaling pathway responds to growth factors and changes in nutrient availability to control cell growth, proliferation, and metabolism. mTOR exists in 2 complexes, mTOR complex (mTORC) 1 and mTORC2, which have distinct upstream regulators and downstream targets. Folate deficiency in pregnant mice caused a marked inhibition of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues, downregulation of placental amino acid transporters, and fetal growth restriction. In addition, folate deficiency in primary human trophoblast (PHT) cells resulted in inhibition of mTORC1 and mTORC2 signaling and decreased the activity of key amino acid transporters. Folate sensing by mTOR in PHT cells is independent of the accumulation of homocysteine and requires the proton-coupled folate transporter (PCFT; solute carrier 46A1). Furthermore, mTORC1 and mTORC2 regulate trophoblast folate uptake by modulating the cell surface expression of folate receptor alpha and the reduced folate carrier. These findings, which provide a novel link between folate availability and cell function, growth, and proliferation, may have broad biological significance given the critical role of folate in normal cell function and the multiple diseases that have been associated with decreased or excessive folate availability. Low maternal folate concentrations are linked to restricted fetal growth, and we propose that the underlying mechanisms involve trophoblast mTOR folate sensing resulting in inhibition of mTORC1 and mTORC2 and downregulation of placental amino acid transporters. PMID- 28592522 TI - Feasibility of physiologist-led stress echocardiography for the assessment of coronary artery disease. AB - BACKGROUND: Physiologist-led stress echocardiography (PLSE) services provide potential for expansion of SE services and increased productivity for cardiologists. There are however no published data on the feasibility of PLSE. We sought to assess the feasibility, safety and robustness of PLSE and cardiologist led stress echocardiography (CLSE) for coronary artery disease (CAD) assessment. METHODS: Retrospective analysis of 898 patients undergoing PLSE or CLSE for CAD assessment using exercise or dobutamine stress over 24 months. PLSE involved 2 cardiac physiologists (exercise) or 1 physiologist plus 1 cardiac nurse (dobutamine). A cardiology registrar was present in the echocardiography department during PLSE in case of medical complications. CLSE involved 1 physiologist and 1 trainee cardiologist who analysed the study and reviewed findings with an imaging cardiologist. Sixteen-segment wall motion scoring (WMS, WMSI) analysis was performed. Feasibility (stressor, image quality, proportion of completed studies, agreement with imaging cardiologist analysis) and safety (complication rate) were compared for PLSE and CLSE. RESULTS: The majority of studies were CLSE (56.2%) and used dobutamine (68.7%). PLSE more commonly used exercise (69.2%). Overall, 96% of studies were successfully completed (>14 diagnostic segments in 98%, P = 0.899 PLSE vs CLSE). Commencement of PLSE was associated with an increase in annual SE's performed for CAD assessment. Complication rates were comparably very low for PLSE and CLSE (0.8% vs 1.8%, P = 0.187). There was excellent agreement between PLSE and CLSE WMS interpretation of 480 myocardial segments at rest (kappa = 0.87) and stress (kappa = 0.70) and WMSI (ICCs and Pearson's r >0.90, zero Bland-Altman mean bias). CONCLUSION: This to our knowledge is the first study of the feasibility of PLSE. PLSE performed by well-trained physiologists is feasible and safe in contemporary practice. PLSE and CLSE interpretation of stress echocardiography for CAD agree very closely. PMID- 28592523 TI - Germline CDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma. AB - BACKGROUND: Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly understood; both environmental and genetic risk factors could contribute to their aetiology. METHODS AND RESULTS: We performed whole-exome sequencing (WES) in a familial aggregation of three individuals affected with soft-tissue sarcoma (STS) without TP53 mutation (Li-Fraumeni-like, LFL) and found a shared pathogenic mutation in CDKN2A tumour suppressor gene. We searched for individuals with sarcoma among 474 melanoma-prone families with a CDKN2A-/+ genotype and for CDKN2A mutations in 190 TP53-negative LFL families where the index case was a sarcoma. Including the initial family, eight independent sarcoma cases carried a germline mutation in the CDKN2A/p16INK4A gene. In five out of seven formalin fixed paraffin-embedded sarcomas, heterozygosity was lost at germline CDKN2A mutations sites demonstrating complete loss of function. As sarcomas are rare in CDKN2A/p16INK4A carriers, we searched in constitutional WES of nine carriers for potential modifying rare variants and identified three in platelet-derived growth factor receptor (PDGFRA) gene. Molecular modelling showed that two never described variants could impact the PDGFRA extracellular domain structure. CONCLUSION: Germline mutations in CDKN2A/P16INK4A, a gene known to predispose to hereditary melanoma, pancreatic cancer and tobacco-related cancers, account also for a subset of hereditary sarcoma. In addition, we identified PDGFRA as a candidate modifier gene. PMID- 28592524 TI - Loss of function in ROBO1 is associated with tetralogy of Fallot and septal defects. AB - BACKGROUND: Congenital heart disease (CHD) is a common birth defect affecting approximately 1% of newborns. Great progress has been made in elucidating the genetic aetiology of CHD with advances in genomic technology, which we leveraged in recovering a new pathway affecting heart development in humans previously known to affect heart development in an animal model. METHODS: Four hundred and sixteen individuals from Thailand and the USA diagnosed with CHD and/or congenital diaphragmatic hernia were evaluated with chromosomal microarray and whole exome sequencing. The DECIPHER Consortium and medical literature were searched for additional patients. Murine hearts from ENU-induced mouse mutants and transgenic mice were evaluated using both episcopic confocal histopathology and troponin I stained sections. RESULTS: Loss of function ROBO1 variants were identified in three families; each proband had a ventricular septal defect, and one proband had tetralogy of Fallot. Additionally, a microdeletion in an individual with CHD was found in the medical literature. Mouse models showed perturbation of the Slit-Robo signalling pathway, causing septation and outflow tract defects and craniofacial anomalies. Two probands had variable facial features consistent with the mouse model. CONCLUSION: Our findings identify Slit Robo as a significant pathway in human heart development and CHD. PMID- 28592525 TI - Association of Glycemic Status During Progression of Chronic Kidney Disease With Early Dialysis Mortality in Patients With Diabetes. AB - OBJECTIVE: Although early trials suggested that intensive glycemic targets reduce the number of complications with diabetes, contemporary trials indicate no cardiovascular benefit and potentially higher mortality risk. As patients with advanced chronic kidney disease (CKD) transitioning to treatment with dialysis were excluded from these studies, the optimal glycemic level in this population remains uncertain. We hypothesized that glycemic status, defined by hemoglobin A1c (HbA--1c) and random glucose levels, in the pre-end-stage renal disease (ESRD) period is associated with higher 1-year post-ESRD mortality among patients with incident diabetes who have ESRD. RESEARCH DESIGN AND METHODS: Among 17,819 U.S. veterans with diabetic CKD transitioning to dialysis from October 2007 to September 2011, we examined the association of mean HbA--1c and random glucose levels averaged over the 1-year pre-ESRD transition period with mortality in the first year after dialysis initiation. All-cause mortality hazard ratios (HRs) were estimated using multivariable survival models. Secondary analyses examined cardiovascular mortality using competing risks methods. RESULTS: HbA--1c levels >=8% (>=64 mmol/mol) were associated with higher mortality in the first year after dialysis initiation (reference value 6% to <7% [42-53 mmol/mol]): adjusted HRs [aHRs] 1.19 [95% CI 1.07-1.32] and 1.48 (1.31-1.67) for HbA--1c 8% to <9% [64 75 mmol/mol] and >=9% [>=75 mmol/mol], respectively). Random glucose levels >=200 mg/dL were associated with higher mortality (reference value 100 to <125 mg/dL): aHR 1.34 [95% CI 1.20-1.49]). Cumulative incidence curves showed that incrementally higher mean HbA--1c and random glucose levels were associated with increasingly higher cardiovascular mortality. CONCLUSIONS: In patients with diabetes and CKD transitioning to dialysis, higher mean HbA--1c and random glucose levels during the pre-ESRD prelude period were associated with higher 1 year post-ESRD mortality. Clinical trials are warranted to examine whether modulating glycemic status improves survival in this population. PMID- 28592527 TI - Zika virus hijacks stress granule proteins and modulates the host stress response. AB - Zika virus (ZIKV), a member of the Flaviviridae family, has recently emerged as an important human pathogen with increasing economic and health impact worldwide. Because of its teratogenic nature and association with the serious neurological condition Guillain-Barre syndrome, a tremendous amount of effort has focused on understanding ZIKV pathogenesis. To gain further insights into ZIKV interaction with host cells, we investigated how this pathogen affects stress response pathways. While ZIKV infection induces stress signaling that leads to phosphorylation of eIF2alpha and cellular translational arrest, stress granule (SG) formation was inhibited. Further analysis revealed that the viral proteins NS3 and NS4A are linked to translational repression, whereas expression of the capsid protein, NS3/NS2B-3 and NS4A interfered with SG formation. Some but not all flavivirus capsid proteins also blocked SG assembly, indicating differential interactions between flaviviruses and SG biogenesis pathways. Depletion of the SG components G3BP1, TIAR and Caprin-1, but not TIA-1 reduced ZIKV replication. Both G3BP1 and Caprin-1 formed complexes with capsid whereas viral genomic RNA stably interacted with G3BP1 during ZIKV infection. Taken together, these results are consistent with a scenario in which ZIKV uses multiple viral components to hijack key SG proteins to benefit viral replication.IMPORTANCE There is a pressing need to understand ZIKV pathogenesis in order to advance the development of vaccine and therapeutics. The cellular stress response constitutes one of the first lines of defense against viral infection and therefore, understanding how ZIKV evades this antiviral system will provide key insights into ZIKV biology and potentially pathogenesis. Herein, we show that ZIKV induces the stress response through activation of the UPR (unfolded protein response) and PKR (protein kinase R), leading to host translational arrest, a process likely mediated by the viral proteins NS3 and NS4A. Despite the activation of translational shut-off, formation of SG is strongly inhibited by the virus. Specifically, ZIKV hijacks the core SG proteins G3BP1, TIAR and Caprin-1 to facilitate viral replication, resulting in impaired SG assembly. This process is potentially facilitated by the interactions of the viral RNA with G3BP1 as well as the viral capsid protein with G3BP1 and Caprin-1. Interestingly, expression of capsid proteins from several other flaviviruses also inhibited SG formation. Taken together, the present study provides novel insights into how ZIKV modulates cellular stress response pathways during replication. PMID- 28592526 TI - Novel Cross-Reactive Monoclonal Antibodies against Ebolavirus Glycoproteins Show Protection in a Murine Challenge Model. AB - Out of an estimated 31,100 cases since their discovery in 1976, ebolaviruses have caused approximately 13,000 deaths. The vast majority (~11,000) of these occurred during the 2013-2016 West African epidemic. Three out of five species in the genus are known to cause Ebola Virus Disease in humans. Several monoclonal antibodies against the ebolavirus glycoprotein are currently in development as therapeutics. However, there is still a paucity of monoclonal antibodies that can cross-react between the glycoproteins of different ebolavirus species, and the mechanism of these monoclonal antibody therapeutics is still not understood in detail. Here, we generated a panel of eight murine monoclonal antibodies (MAbs) utilizing a prime-boost vaccination regimen with a Zaire ebolavirus glycoprotein expression plasmid followed by infection with a vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein. We tested the binding breadth of the resulting monoclonal antibodies using a set of recombinant surface glycoproteins from Reston, Tai Forest, Bundibugyo, Zaire, Sudan, and Marburg viruses and found two antibodies that showed pan-ebolavirus binding. An in vivo Stat2-/- mouse model was utilized to test the ability of these MAbs to protect from infection with a vesicular stomatitis virus expressing the Zaire ebolavirus glycoprotein. Several of our antibodies, including the broadly binding ones, protected mice from mortality despite lacking neutralization capability in vitro, suggesting their protection may be mediated by Fc-FcR interactions. Indeed, three antibodies displayed cellular phagocytosis and/or antibody-dependent cell mediated cytotoxicity in vitro Our antibodies, specifically the two identified cross-reactive monoclonal antibodies (KL-2E5 and KL-2H7), might add to the understanding of anti-ebolavirus humoral immunity.IMPORTANCE This study describes the generation of a panel of novel anti-ebolavirus glycoprotein monoclonal antibodies, including two antibodies with broad cross-reactivity to all known ebolavirus species. The antibodies were raised using a heterologous DNA-viral vector prime-boost regimen, resulting in a high proportion of cross-reactive antibodies (25%). Similar vaccination regimens have been used successfully to induce broad protection against influenza viruses in humans, and our limited data indicate that this might be a useful strategy for filovirus vaccines as well. Several of our antibodies showed protective efficacy when tested in a novel murine challenge model and may be developed into future therapeutics. PMID- 28592528 TI - HDM2 Promotes NEDDylation of Hepatitis B Virus HBx To Enhance Its Stability and Function. AB - Hepatitis B virus (HBV)-encoded X protein (HBx) plays a critical role in HBV related hepatocarcinoma development. In this study, we demonstrate that HBx is specifically modified by NEDD8. We found that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability by preventing its ubiquitination-mediated degradation. Consistently, analysis of 160 hepatocellular carcinoma patient specimens indicated that the amount of HDM2 protein correlates with HBx protein level. We identified that HBx K91 and K95 as the key HBx NEDDylation sites and observed that the NEDDylation-deficient HBx has shorter half-life. We generated Huh7 cell lines which ectopically express wild-type and NEDDylation-deficient HBx and found that NEDDylation-deficient HBx showed less chromatin localization and less DDB1 binding. Consistently, the expression of HBx-regulated genes (IL-8, MMP9, and YAP) and HBV transcription (the activity of HBV enhancer and the amount of pgRNA transcribed from cccDNA) were significantly higher in cells expressing wild-type (WT) HBx than that in cells expressing mutant HBx. In addition, HBx expressing cells proliferated faster than control and mutant HBx-expressing cells. We also showed that the ability of WT HBx-expressing cells to form tumors in nude mice was significantly higher than that of mutant HBx-expressing cells. In conclusion, we revealed that E3 ligase HDM2 promotes NEDDylation of HBx to enhance HBx stability and chromatin localization, which in turn favors HBx dependent transcriptional regulation, cell proliferation, and HBV-driven tumor growth.IMPORTANCE Hepatitis B virus (HBV) HBx protein plays a critical role in viral replication and hepatocarcinogenesis. However, the regulation of HBx stability is not well understood. We found that HBx is modified by NEDD8 and that the HDM2 E3 ligase promotes HBx NEDDylation to enhance HBx stability by inhibiting its ubiquitination. We provide a new evidence to show the positive correlation between HDM2 and HBx in clinical hepatocellular carcinoma (HCC) samples. We also identified the major NEDDylation sites on HBx. Our studies indicate that the defective NEDDylation of HBx negatively affects its ability to activate the transcription of downstream genes and promote cell proliferation and tumor growth in vivo Taken together, our findings reveal a novel posttranslational modification of HBx by HDM2 which regulates its stability, subcellular localization, and functions. These findings indicate that HDM2 is an important regulator on HBx and a potential diagnosis/therapeutic marker for HBV associated HCC. PMID- 28592529 TI - Guanylate-Binding Protein 1 Inhibits Nuclear Delivery of Kaposi's Sarcoma Associated Herpesvirus Virions by Disrupting Formation of Actin Filament. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a typical gammaherpesvirus that establishes persistent lifelong infection in host cells. In order to establish successful infection, KSHV has evolved numerous immune evasion strategies to bypass or hijack the host immune system. However, host cells still produce immune cytokines abundantly during primary KSHV infection. Whether the immune effectors produced are able to inhibit viral infection and how KSHV successfully conquers these immune effectors remain largely unknown. The guanylate-binding protein 1 (GBP1) gene is an interferon-stimulated gene and exerts antiviral functions on several RNA viruses; however, its function in DNA virus infection is less well understood. In this study, we found that KSHV infection increases both the transcriptional and protein levels of GBP1 at the early stage of primary infection by activating the NF-kappaB pathway. The overexpression of GBP1 significantly inhibited KSHV infection, while the knockdown of GBP1 promoted KSHV infection. The GTPase activity and dimerization of GBP1 were demonstrated to be responsible for its anti-KSHV activity. Furthermore, we found that GBP1 inhibited the nuclear delivery of KSHV virions by disrupting the formation of actin filaments. Finally, we demonstrated that replication and transcription activator (RTA) promotes the degradation of GBP1 through a proteasome pathway. Taken together, these results provide a new understanding of the antiviral mechanism of GBP1, which possesses potent anti-KSHV activity, and suggest the critical role of RTA in the evasion of the innate immune response during primary infection by KSHV.IMPORTANCE GBP1 can be induced by various cytokines and exerts antiviral activities against several RNA viruses. Our study demonstrated that GBP1 can exert anti-KSHV function by inhibiting the nuclear delivery of KSHV virions via the disruption of actin filaments. Moreover, we found that KSHV RTA can promote the degradation of GBP1 through a proteasome-mediated pathway. Taken together, our results elucidate a novel mechanism of GBP1 anti-KSHV activity and emphasize the critical role of RTA in KSHV evasion of the host immune system during primary infection. PMID- 28592530 TI - Kaposi's Sarcoma-Associated Herpesvirus Utilizes and Manipulates RNA N6-Adenosine Methylation To Promote Lytic Replication. AB - N6-adenosine methylation (m6A) is the most common posttranscriptional RNA modification in mammalian cells. We found that most transcripts encoded by the Kaposi's sarcoma-associated herpesvirus (KSHV) genome undergo m6A modification. The levels of m6A-modified mRNAs increased substantially upon stimulation for lytic replication. The blockage of m6A inhibited splicing of the pre-mRNA encoding the replication transcription activator (RTA), a key KSHV lytic switch protein, and halted viral lytic replication. We identified several m6A sites in RTA pre-mRNA crucial for splicing through interactions with YTH domain containing 1 (YTHDC1), an m6A nuclear reader protein, in conjunction with serine/arginine rich splicing factor 3 (SRSF3) and SRSF10. Interestingly, RTA induced m6A and enhanced its own pre-mRNA splicing. Our results not only demonstrate an essential role of m6A in regulating RTA pre-mRNA splicing but also suggest that KSHV has evolved a mechanism to manipulate the host m6A machinery to its advantage in promoting lytic replication.IMPORTANCE KSHV productive lytic replication plays a pivotal role in the initiation and progression of Kaposi's sarcoma tumors. Previous studies suggested that the KSHV switch from latency to lytic replication is primarily controlled at the chromatin level through histone and DNA modifications. The present work reports for the first time that KSHV genome encoded mRNAs undergo m6A modification, which represents a new mechanism at the posttranscriptional level in the control of viral replication. PMID- 28592531 TI - Use of a Recombinant Gamma-2 Herpesvirus Vaccine Vector against Dengue Virus in Rhesus Monkeys. AB - Research on vaccine approaches that can provide long-term protection against dengue virus infection is needed. Here we describe the construction, immunogenicity, and preliminary information on the protective capacity of recombinant, replication-competent rhesus monkey rhadinovirus (RRV), a persisting herpesvirus. One RRV construct expressed nonstructural protein 5 (NS5), while a second recombinant expressed a soluble variant of the E protein (E85) of dengue virus 2 (DENV2). Four rhesus macaques received a single vaccination with a mixture of both recombinant RRVs and were subsequently challenged 19 weeks later with 1 * 105 PFU of DENV2. During the vaccine phase, plasma of all vaccinated monkeys showed neutralizing activity against DENV2. Cellular immune responses against NS5 were also elicited, as evidenced by major histocompatibility complex class I (MHC-I) tetramer staining in the one vaccinated monkey that was Mamu-A*01 positive. Unlike two of two unvaccinated controls, two of the four vaccinated monkeys showed no detectable viral RNA sequences in plasma after challenge. One of these two monkeys also showed no anamnestic increases in antibody levels following challenge and thus appeared to be protected against the acquisition of DENV2 following high-dose challenge. Continued study will be needed to evaluate the performance of herpesviral and other persisting vectors for achieving long term protection against dengue virus infection.IMPORTANCE Continuing studies of vaccine approaches against dengue virus (DENV) infection are warranted, particularly ones that may provide long-term immunity against all four serotypes. Here we investigated whether recombinant rhesus monkey rhadinovirus (RRV) could be used as a vaccine against DENV2 infection in rhesus monkeys. Upon vaccination, all animals generated antibodies capable of neutralizing DENV2. Two of four vaccinated monkeys showed no detectable viral RNA after subsequent high-dose DENV2 challenge at 19 weeks postvaccination. Furthermore, one of these vaccinated monkeys appeared to be protected against the acquisition of DENV2 infection on the basis of undetectable viral loads and the lack of an anamnestic antibody response. These findings underscore the potential utility of recombinant herpesviruses as vaccine vectors. PMID- 28592532 TI - Voltage-Dependent Anion Channel 1 Interacts with Ribonucleoprotein Complexes To Enhance Infectious Bursal Disease Virus Polymerase Activity. AB - Infectious bursal disease virus (IBDV) is a double-stranded RNA (dsRNA) virus. Segment A contains two overlapping open reading frames (ORFs), which encode viral proteins VP2, VP3, VP4, and VP5. Segment B contains one ORF and encodes the viral RNA-dependent RNA polymerase, VP1. IBDV ribonucleoprotein complexes are composed of VP1, VP3, and dsRNA and play a critical role in mediating viral replication and transcription during the virus life cycle. In the present study, we identified a cellular factor, VDAC1, which was upregulated during IBDV infection and found to mediate IBDV polymerase activity. VDAC1 senses IBDV infection by interacting with viral proteins VP1 and VP3. This association is caused by RNA bridging, and all three proteins colocalize in the cytoplasm. Furthermore, small interfering RNA (siRNA)-mediated downregulation of VDAC1 resulted in a reduction in viral polymerase activity and a subsequent decrease in viral yield. Moreover, overexpression of VDAC1 enhanced IBDV polymerase activity. We also found that the viral protein VP3 can replace segment A to execute polymerase activity. A previous study showed that mutations in the C terminus of VP3 directly influence the formation of VP1-VP3 complexes. Our immunoprecipitation experiments demonstrated that protein-protein interactions between VDAC1 and VP3 and between VDAC1 and VP1 play a role in stabilizing the interaction between VP3 and VP1, further promoting IBDV polymerase activity.IMPORTANCE The cellular factor VDAC1 controls the entry and exit of mitochondrial metabolites and plays a pivotal role during intrinsic apoptosis by mediating the release of many apoptogenic molecules. Here we identify a novel role of VDAC1, showing that VDAC1 interacts with IBDV ribonucleoproteins (RNPs) and facilitates IBDV replication by enhancing IBDV polymerase activity through its ability to stabilize interactions in RNP complexes. To our knowledge, this is the first report that VDAC1 is specifically involved in regulating IBDV RNA polymerase activity, providing novel insight into virus-host interactions. PMID- 28592533 TI - MicroRNAs of Epstein-Barr Virus Control Innate and Adaptive Antiviral Immunity. AB - Epstein-Barr virus (EBV) has established lifelong infection in more than 90% of humanity. While infection is usually controlled by the immune system, the human host fails to completely eliminate the pathogen. Several herpesviral proteins are known to act as immunoevasins, preventing or reducing recognition of EBV-infected cells. Only recently were microRNAs of EBV identified to reduce immune recognition further. This Gem summarizes what we know about immunomodulatory microRNAs of herpesviruses. PMID- 28592534 TI - Comprehensive Cross-Clade Characterization of Antibody-Mediated Recognition, Complement-Mediated Lysis, and Cell-Mediated Cytotoxicity of HIV-1 Envelope Specific Antibodies toward Eradication of the HIV-1 Reservoir. AB - Immunotherapy with passive administration of broadly neutralizing HIV-1 envelope specific antibodies (bnAbs) in the setting of established infection in vivo has yielded mixed results. The contribution of different antibodies toward the direct elimination of infected cells is poorly understood. In this study, we determined the ability of 12 well-characterized anti-HIV-1 neutralizing antibodies to recognize and eliminate primary CD4 T cells infected with HIV-1 belonging to clades A, B, C, and D, via antibody-dependent complement-mediated lysis (ADCML) and antibody-dependent cell-mediated cytotoxicity (ADCC), in vitro We further tested unique combinations of these antibodies to determine the optimal antibody cocktails to be tested in future clinical trials. We report that antibody binding to infected CD4 T cells is highly variable and correlates with ADCML and ADCC processes. Particularly, antibodies targeting the envelope glycan shield (2G12) and V1/V2 site (PG9, PG16, and PGT145) are best at recognizing HIV-1-infected CD4 T cells. However, only PG9 and PG16 and their combinations with other bnAbs sufficiently induced the elimination of HIV-1-infected CD4 T cells by ADCML, ADCC, or both. Notably, CD4 binding site antibodies VRC01, 3BNC117, and NIH45-46 G54W did not exhibit recognition of infected cells and were unable to induce their killing. Future trials geared toward the development of a cure for HIV/AIDS should incorporate V1/V2 antibodies for maximal clearance of infected cells. With the use of only primary immune cells, we conducted a comprehensive cross-clade physiological analysis to aid the direction of antibodies as therapeutics toward the development of a cure for HIV/AIDS.IMPORTANCE Several antibodies capable of neutralizing the majority of circulating HIV-1 strains have been identified to date and have been shown to prevent infection in animal models. However, the use of combinations of such broadly neutralizing antibodies (bnAbs) for the treatment and eradication of HIV-1 in infected humans remains uncertain. In this study, we tested the ability of bnAbs to directly recognize and eliminate primary human CD4 T cells infected with diverse HIV-1 strains representative of the global epidemic by antibody-dependent pathways. We also tested several combinations of bnAbs in our assays in order to maximize the clearance of infected cells. We show that the ability of bnAbs to identify and kill infected cells is highly variable and that only a few of them are able to exert this function. Our data will help guide the formulation of bnAbs to test in future human trials aimed at the development of a cure. PMID- 28592536 TI - Evasion of the STING DNA-Sensing Pathway by VP11/12 of Herpes Simplex Virus 1. AB - The stimulator of interferon (IFN) genes (STING) is a broad antimicrobial factor that restricts herpes simplex virus (HSV) by activating type I interferon and proinflammatory responses upon sensing of foreign DNA. UL46 is one of the most abundant tegument proteins of HSV-1, but a well-established function has yet to be found. We found that the HSV-1 UL46 protein interacts with and colocalizes with STING. A DeltaUL46 virus displayed growth defects and activated innate immunity, but both effects were alleviated in STING knockdown cells. UL46 was also required for the inhibition of the 2',3'-cyclic GMP-AMP (cGAMP)-dependent immune responses during infection. In cells expressing UL46, out of the context of the infection, innate immunity to a DeltaICP0 virus was largely compromised, and that permitted ICP0-deficient mutants to replicate. The UL46-expressing cell lines also rescued the defects of the DeltaUL46 virus and enhanced wild-type virus infection. The UL46-expressing cell lines did not activate interferon stimulated gene (ISG) transcription following treatment with the noncanonical cyclic dinucleotide 2',3'-cGAMP, suggesting that the STING pathway may be compromised. Indeed, we found that both proteins STING and IFI16 were eliminated in cells constitutively expressing UL46 and that the accumulation of their transcripts was blocked. Finally, we demonstrated that UL46 via its N terminus binds to STING and, via its C terminus, to TBK1. These interactions appear to modulate the functions of STING during HSV-1 infection. Taken together, our studies describe a novel function for one of the least-studied proteins of HSV, the tegument protein UL46, and that function involves the evasion of foreign DNA sensing pathways.IMPORTANCE Herpes simplex virus 1 (HSV-1) afflicts 80% of the population worldwide, causing various diseases. After initial infection, the virus establishes latent reservoirs in sensory neurons and persists for life. Here we describe novel interactions between HSV-1 and the DNA sensor STING. We found that (i) HSV-1 tegument protein UL46 interacts with and colocalizes with STING; (ii) UL46 expressed out of the context of the infection blocks type I interferon triggered by STING stimuli, through the elimination of STING and of interferon-inducible protein 16 (IFI16); (iii) a DeltaUL46 virus displayed growth defects, which were rescued in STING knockdown cells; (iv) the DeltaUL46 virus failed to block innate immunity triggered by ligands of STING such as 2',3'-cGAMP and also activated IFN-beta and ISG expression; and (v) UL46 binds to both STING and TBK1 through different domains. We conclude that UL46 counteracts the actions of STING during HSV-1 infection. PMID- 28592535 TI - Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro: Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase. AB - Newcastle disease virus (NDV) is an oncolytic virus being developed for the treatment of cancer. Following infection of a human ovarian cancer cell line (OVCAR3) with a recombinant low-pathogenic NDV, persistent infection was established in a subset of tumor cells. Persistently infected (PI) cells exhibited resistance to superinfection with NDV and established an antiviral state, as demonstrated by upregulation of interferon and interferon-induced genes such as myxoma resistance gene 1 (Mx1) and retinoic acid-inducing gene-I (RIG-I). Viruses released from PI cells induced higher cell-to-cell fusion than the parental virus following infection in two tumor cell lines tested, HT1080 and HeLa, and remained attenuated in chickens. Two mutations, one in the fusion (F) protein cleavage site, F117S (F117S), and another in hemagglutinin-neuraminidase (HN), G169R (HN169R), located in the second sialic acid binding region, were responsible for the hyperfusogenic phenotype. F117S improves F protein cleavage efficiency, facilitating cell-to-cell fusion, while HN169R possesses a multifaceted role in contributing to higher fusion, reduced receptor binding, and lower neuraminidase activity, which together result in increased fusion and reduced viral replication. Thus, establishment of persistent infection in vitro involves viral genetic changes that facilitate efficient viral spread from cell to cell as a potential mechanism to escape host antiviral responses. The results of our study also demonstrate a critical role in the viral life cycle for the second receptor binding region of the HN protein, which is conserved in several paramyxoviruses.IMPORTANCE Oncolytic Newcastle disease virus (NDV) could establish persistent infection in a tumor cell line, resulting in a steady antiviral state reflected by constitutively expressed interferon. Viruses isolated from persistently infected cells are highly fusogenic, and this phenotype has been mapped to two mutations, one each in the fusion (F) and hemagglutinin-neuraminidase (HN) proteins. The F117S mutation in the F protein cleavage site improved F protein cleavage efficiency while the HN169R mutation located at the second receptor binding site of the HN protein contributed to a complex phenotype consisting of a modest increase in fusion and cell killing, lower neuraminidase activity, and reduced viral growth. This study highlights the intricate nature of these two mutations in the glycoproteins of NDV in the establishment of persistent infection. The data also shed light on the critical balance between the F and HN proteins required for efficient NDV infection and their role in avian pathogenicity. PMID- 28592537 TI - Role of Autophagy in HIV-1 Matrix Protein p17-Driven Lymphangiogenesis. AB - AIDS-related lymphomas (ARLs) are expected to increase in the future since combined antiretroviral therapy (cART) enhances the life expectancy of HIV-1 infected (HIV+) patients but does not affect the occurrence of ARLs to the same extent as that of other tumors. Lymphangiogenesis is essential in supporting growth and metastatic spreading of ARLs. HIV-1 does not infect the neoplastic B cells, but HIV-1 proteins have been hypothesized to play a key role in sustaining a prolymphangiogenic microenvironment in lymphoid organs. The HIV-1 matrix protein p17 is detected in blood and accumulates in the germinal centers of lymph nodes of HIV+ patients under successful cART. The viral protein displays potent lymphangiogenic activity in vitro and in vivo This is, at least in part, mediated by the secretion of the lymphangiogenic factor endothelin-1, suggesting that activation of a secretory pathway sustains the lymphangiogenic activity of p17. Here, we show that the p17 lymphangiogenic activity occurs on human lymph node derived lymphatic endothelial cells (LN-LECs) under stress conditions only and relies entirely on activation of an autophagy-based pathway. In fact, induction of autophagy by p17 promotes lymphangiogenesis, whereas pharmacological and genetic inhibition of autophagy inhibits p17-triggered lymphangiogenesis. Similarly, the vasculogenic activity of p17 was totally inhibited in autophagy incompetent mice. Our findings reveal a previously unrecognized role of autophagy in lymphangiogenesis and open the way to identify novel treatment strategies aimed at inhibiting aberrant tumor-driven lymphangiogenesis in HIV+ patients.IMPORTANCE AIDS-related lymphomas (ARLs) are the most common malignancies in HIV-1-infected (HIV+) patients after the introduction of combined antiretroviral therapy (cART). Lymphangiogenesis is of critical importance in sustaining growth and metastasis of ARLs. Indeed, enhanced lymphangiogenesis occurs in the lymph nodes of HIV+ patients under successful cART. The HIV-1 matrix protein p17 is detected in blood and accumulates in the lymph node germinal centers even in the absence of virus replication. Several findings suggest a key role for p17 as a microenvironmental factor capable of promoting lymphangiogenesis. Here, we show that p17 promotes lymphangiogenesis of human lymph node-derived lymphatic endothelial cells (LN-LECs). The lymphangiogenic activity of p17 is sustained by an autophagy-based pathway that enables LN-LECs to release prolymphangiogenic factors into the extracellular microenvironment. Our findings indicate that specific targeting of autophagy may provide an important new tool for treating ARLs. PMID- 28592538 TI - Identification of Interleukin-27 (IL-27)/IL-27 Receptor Subunit Alpha as a Critical Immune Axis for In Vivo HIV Control. AB - Intact and broad immune cell effector functions and specific individual cytokines have been linked to HIV disease outcome, but their relative contribution to HIV control remains unclear. We asked whether the proteome of secreted cytokines and signaling factors in peripheral blood can be used to discover specific pathways critical for host viral control. A custom glass-based microarray, able to measure >600 plasma proteins involved in cell-to-cell communication, was used to measure plasma protein profiles in 96 HIV-infected, treatment-naive individuals with high (>50,000) or low (<10,000 HIV RNA copies/ml) viral loads. Univariate and regression model analysis demonstrate that plasma levels of soluble interleukin 27 (IL-27) are significantly elevated in individuals with high plasma viremia (P < 0.0001) and are positively correlated with proviral HIV-DNA copy numbers in peripheral blood mononuclear cells (PBMC) (Rho = 0.4011; P = 0.0027). Moreover, soluble IL-27 plasma levels are negatively associated with the breadth and magnitude of the total virus-specific T-cell responses and directly with plasma levels of molecules involved in Wnt/beta-catenin signaling. In addition to IL-27, gene expression levels of the specific IL-27 receptor (IL27RA) in PBMC correlated directly with both plasma viral load (Rho = 0.3531; P = 0.0218) and the proviral copy number in the peripheral blood as an indirect measure of partial viral reservoir (Rho = 0.4580; P = 0.0030). These results were validated in unrelated cohorts of early infected subjects as well as subjects before and after initiation of antiretroviral treatment, and they identify IL-27 and its specific receptor as a critical immune axis for the antiviral immune response and as robust correlates of viral load and proviral reservoir size in PBMC.IMPORTANCE The detailed knowledge of immune mechanisms that contribute to HIV control is a prerequisite for the design of effective treatment strategies to achieve HIV cure. Cells communicate with each other by secreting signaling proteins, and the blood is a key conduit for transporting such factors. Investigating the communication factors promoting effective immune responses and having potentially antiviral functions against HIV using a novel focused omics approach ("communicome") has the potential to significantly improve our knowledge of effective host immunity and accelerate the HIV cure agenda. Including 140 subjects with variable viral loads and measuring the plasma levels of >600 soluble proteins, our data highlight the importance of Th17 cells and Wnt/beta catenin signaling in HIV control and especially identify the IL-27/IL-27 receptor subunit alpha (IL-27RA) axis as a predictor of plasma viral load and proviral copy number in the peripheral blood. These data may provide important guidance to therapeutic approaches in the HIV cure agenda. PMID- 28592539 TI - HIV-1 Epitope Variability Is Associated with T Cell Receptor Repertoire Instability and Breadth. AB - Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier for effective immune control. Each epitope typically is targeted by multiple clones with distinct T cell receptors (TCRs). While the clonal repertoire may be important for containing epitope variation, determinants of its composition are poorly understood. We investigate the clonal repertoire of 29 CTL responses against 23 HIV-1 epitopes longitudinally in nine chronically infected untreated subjects with plasma viremia of <3,000 RNA copies/ml over 17 to 179 weeks. The composition of TCRs targeting each epitope varied considerably in stability over time, although clonal stability (Sorensen index) was not significantly time dependent within this interval. However, TCR stability inversely correlated with epitope variability in the Los Alamos HIV-1 Sequence Database, consistent with TCR evolution being driven by epitope variation. Finally, a robust inverse correlation of TCR breadth against each epitope versus epitope variability further suggested that this variability drives TCR repertoire diversification. In the context of studies demonstrating rapidly shifting HIV-1 sequences in vivo, our findings support a variably dynamic process of shifting CTL clonality lagging in tandem with viral evolution and suggest that preventing escape of HIV-1 may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways.IMPORTANCE Mutational escape of HIV-1 from HIV-1-specific CD8+ T lymphocytes (CTLs) is a major barrier to effective immune control. The number of distinct CTL clones targeting each epitope is proposed to be an important factor, but the determinants are poorly understood. Here, we demonstrate that the clonal stability and number of clones for the CTL response against an epitope are inversely associated with the general variability of the epitope. These results show that CTLs constantly lag epitope mutation, suggesting that preventing HIV-1 escape may require coordinated direction of the CTL clonal repertoire to simultaneously block escape pathways. PMID- 28592540 TI - Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses. AB - We have demonstrated that a liposomal array of well-ordered trimers enhances B cell activation, germinal center formation, and the elicitation of tier-2 autologous neutralizing antibodies. Previously, we coupled well-ordered cleavage independent NFL trimers via their C-terminal polyhistidine tails to nickel lipids integrated into the lipid bilayer. Despite favorable in vivo effects, concern remained over the potentially longer-term in vivo instability of noncovalent linkage of the trimers to the liposomes. Accordingly, we tested both cobalt coupling and covalent linkage of the trimers to the liposomes by reengineering the polyhistidine tail to include a free cysteine on each protomer of model BG505 NFL trimers to allow covalent linkage. Both cobalt and cysteine coupling resulted in a high-density array of NFL trimers that was stable in both 20% mouse serum and 100 mM EDTA, whereas the nickel-conjugated trimers were not stable under these conditions. Binding analysis and calcium flux with anti-Env-specific B cells confirmed that the trimers maintained conformational integrity following coupling. Following immunization of mice, serologic analysis demonstrated that the covalently coupled trimers elicited Env-directed antibodies in a manner statistically significantly improved compared to soluble trimers and nickel conjugated trimers. Importantly, the covalent coupling not only enhanced gp120 directed responses compared to soluble trimers, it also completely eliminated antibodies directed to the C-terminal His tag located at the "bottom" of the spike. In contrast, soluble and noncovalent formats efficiently elicited anti-His tag antibodies. These data indicate that covalent linkage of well-ordered trimers to liposomes in high-density array displays multiple advantages in vitro and in vivoIMPORTANCE Enveloped viruses typically encode a surface-bound glycoprotein that mediates viral entry into host cells and is a primary target for vaccine design. Liposomes with modified lipid head groups have a unique feature of capturing and displaying antigens on their surfaces, mimicking the native pathogens. Our first-generation nickel-based liposomes captured HIV-1 Env glycoprotein trimers via a noncovalent linkage with improved efficacy over soluble glycoprotein in activating germinal center B cells and eliciting tier-2 autologous neutralizing antibodies. In this study, we report the development of second-generation cobalt- and maleimide-based liposomes that have improved in vitro stability over nickel-based liposomes. In particular, the maleimide liposomes captured HIV-1 Env trimers via a more stable covalent bond, resulting in enhanced germinal center B cell responses that generated higher antibody titers than the soluble trimers and liposome-bearing trimers via noncovalent linkages. We further demonstrate that covalent coupling prevents release of the trimers prior to recognition by B cells and masks a nonneutralizing determinant located at the bottom of the trimer. PMID- 28592542 TI - Gender parity trends for invited speakers at four prominent virology conference series. AB - Scientific conferences are most beneficial to participants when they showcase significant new experimental developments, accurately summarize the current state of the field, and provide strong opportunities for collaborative networking. A top-notch slate of invited speakers, assembled by conference organizers or committees, is key to achieving these goals. The perceived underrepresentation of female speakers at prominent scientific meetings is currently a popular topic for discussion, but one that often lacks supportive data. We compiled the full rosters of invited speakers over the last 35 years for four prominent international virology conferences, the American Society for Virology Annual Meeting (ASV), the International Herpesvirus Workshop (IHW), the Positive-Strand RNA Virus Symposium (PSR), and the Gordon Research Conference on Viruses & Cells (GRC). The rosters were cross-indexed by unique names, gender, year, and repeat invitations. When plotted as gender-dependent trends over time, all four conferences showed a clear proclivity for male-dominated invited speaker lists. Encouragingly, shifts toward parity are emerging within all units, but at different rates. Not surprisingly, both selection of a larger percentage of first time participants and the presence of a woman on the speaker selection committee correlated with improved parity. Session chair information was also collected for the IHW and GRC. These visible positions also displayed a strong male dominance over time that is eroding slowly. We offer our personal interpretation of these data to aid future organizers achieve improved equity among the limited number of available positions for session moderators and invited speakers.IMPORTANCE Politicians and media members have a tendency to cite anecdotes as conclusions without any supporting data. This happens so frequently now, that a name for it has emerged: fake news. Good science proceeds otherwise. The under representation of women as invited speakers at international scientific conferences exemplifies a present-day discussion topic usually occurring without facts to support or refute the arguments. We now provide records profiling four prominent virology conferences over the years 1982 to 2017 with the intention that the trends and accompanying analyses of the gender parity of invited speakers may allow the ongoing discussions to be informed. PMID- 28592541 TI - Dimerization Efficiency of Canine Distemper Virus Matrix Protein Regulates Membrane-Budding Activity. AB - Paramyxoviruses rely on the matrix (M) protein to orchestrate viral assembly and budding at the plasma membrane. Although the mechanistic details remain largely unknown, structural data suggested that M dimers and/or higher-order oligomers may facilitate membrane budding. To gain functional insights, we employed a structure-guided mutagenesis approach to investigate the role of canine distemper virus (CDV) M protein self-assembly in membrane-budding activity. Three six alanine-block (6A-block) mutants with mutations located at strategic oligomeric positions were initially designed. While the first one includes residues potentially residing at the protomer-protomer interface, the other two display amino acids located within two distal surface-exposed alpha-helices proposed to be involved in dimer-dimer contacts. We further focused on the core of the dimeric interface by mutating asparagine 138 (N138) to several nonconservative amino acids. Cellular localization combined with dimerization and coimmunopurification assays, performed under various denaturing conditions, revealed that all 6A-block mutants were impaired in self-assembly and cell periphery accumulation. These phenotypes correlated with deficiencies in relocating CDV nucleocapsid proteins to the cell periphery and in virus-like particle (VLP) production. Conversely, all M-N138 mutants remained capable of self-assembly, though to various extents, which correlated with proper accumulation and redistribution of nucleocapsid proteins at the plasma membrane. However, membrane deformation and VLP assays indicated that the M-N138 variants exhibiting the most reduced dimerization propensity were also defective in triggering membrane remodeling and budding, despite proper plasma membrane accumulation. Overall, our data provide mechanistic evidence that the efficiency of CDV M dimerization/oligomerization governs both cell periphery localization and membrane-budding activity.IMPORTANCE Despite the availability of effective vaccines, both measles virus (MeV) and canine distemper virus (CDV) still lead to significant human and animal mortality worldwide. It is assumed that postexposure prophylaxis with specific antiviral compounds may synergize with vaccination campaigns to better control ongoing epidemics. Targeting the matrix (M) protein of MeV/CDV is attractive, because M coordinates viral assembly and egress through interaction with multiple cellular and viral components. However, the lack of basic molecular knowledge of how M orchestrates these functions precludes the rational design of antivirals. Here we combined structure-guided mutagenesis with cellular, biochemical, and functional assays to investigate a potential correlation between CDV M self-assembly and virus-like particle (VLP) formation. Altogether, our findings provide evidence that stable M dimers at the cell periphery are required to productively trigger VLPs. Such stabilized M dimeric units may facilitate further assembly into robust higher-order oligomers necessary to promote plasma membrane-budding activity. PMID- 28592543 TI - Mapping of Transcription Termination within the S Segment of SFTS Phlebovirus Facilitated Generation of NSs Deletant Viruses. AB - SFTS phlebovirus (SFTSV) is an emerging tick-borne bunyavirus that was first reported in China in 2009. Here we report the generation of a recombinant SFTSV (rHB29NSsKO) that cannot express the viral nonstructural protein (NSs) upon infection of cells in culture. We show that rHB29NSsKO replication kinetics are greater in interferon (IFN)-incompetent cells and that the virus is unable to suppress IFN induced in response to viral replication. The data confirm for the first time in the context of virus infection that NSs acts as a virally encoded IFN antagonist and that NSs is dispensable for virus replication. Using 3' rapid amplification of cDNA ends (RACE), we mapped the 3' end of the N and NSs mRNAs, showing that the mRNAs terminate within the coding region of the opposite open reading frame. We show that the 3' end of the N mRNA terminates upstream of a 5' GCCAGCC-3' motif present in the viral genomic RNA. With this knowledge, and using virus-like particles, we could demonstrate that the last 36 nucleotides of the NSs open reading frame (ORF) were needed to ensure the efficient termination of the N mRNA and were required for recombinant virus rescue. We demonstrate that it is possible to recover viruses lacking NSs (expressing just a 12-amino-acid NSs peptide or encoding enhanced green fluorescent protein [eGFP]) or an NSs-eGFP fusion protein in the NSs locus. This opens the possibility for further studies of NSs and potentially the design of attenuated viruses for vaccination studies.IMPORTANCE SFTS phlebovirus (SFTSV) and related tick-borne viruses have emerged globally since 2009. SFTSV has been shown to cause severe disease in humans. For bunyaviruses, it has been well documented that the nonstructural protein (NSs) enables the virus to counteract the human innate antiviral defenses and that NSs is one of the major determinants of virulence in infection. Therefore, the use of reverse genetics systems to engineer viruses lacking NSs is an attractive strategy to rationally attenuate bunyaviruses. Here we report the generation of several recombinant SFTS viruses that cannot express the NSs protein or have the NSs open reading frame replaced with a reporter gene. These viruses cannot antagonize the mammalian interferon (IFN) response mounted to virus infection. The generation of NSs-lacking viruses was achieved by mapping the transcriptional termination of two S-segment-derived subgenomic mRNAs, which revealed that transcription termination occurs upstream of a 5'-GCCAGCC-3' motif present in the virus genomic S RNA. PMID- 28592544 TI - Time-Sampled Population Sequencing Reveals the Interplay of Selection and Genetic Drift in Experimental Evolution of Potato Virus Y. AB - RNA viruses are one of the fastest-evolving biological entities. Within their hosts, they exist as genetically diverse populations (i.e., viral mutant swarms), which are sculpted by different evolutionary mechanisms, such as mutation, natural selection, and genetic drift, and also the interactions between genetic variants within the mutant swarms. To elucidate the mechanisms that modulate the population diversity of an important plant-pathogenic virus, we performed evolution experiments with Potato virus Y (PVY) in potato genotypes that differ in their defense response against the virus. Using deep sequencing of small RNAs, we followed the temporal dynamics of standing and newly generated variations in the evolving viral lineages. A time-sampled approach allowed us to (i) reconstruct theoretical haplotypes in the starting population by using clustering of single nucleotide polymorphisms' trajectories and (ii) use quantitative population genetics approaches to estimate the contribution of selection and genetic drift, and their interplay, to the evolution of the virus. We detected imprints of strong selective sweeps and narrow genetic bottlenecks, followed by the shift in frequency of selected haplotypes. Comparison of patterns of viral evolution in differently susceptible host genotypes indicated possible diversifying evolution of PVY in the less-susceptible host (efficient in the accumulation of salicylic acid).IMPORTANCE High diversity of within-host populations of RNA viruses is an important aspect of their biology, since they represent a reservoir of genetic variants, which can enable quick adaptation of viruses to a changing environment. This study focuses on an important plant virus, Potato virus Y, and describes, at high resolution, temporal changes in the structure of viral populations within different potato genotypes. A novel and easy-to-implement computational approach was established to cluster single nucleotide polymorphisms into viral haplotypes from very short sequencing reads. During the experiment, a shift in the frequency of selected viral haplotypes was observed after a narrow genetic bottleneck, indicating an important role of the genetic drift in the evolution of the virus. On the other hand, a possible case of diversifying selection of the virus was observed in less susceptible host genotypes. PMID- 28592545 TI - Development of a Web Tool for Escherichia coli Subtyping Based on fimH Alleles. AB - The aim of this study was to construct a valid publicly available method for in silico fimH subtyping of Escherichia coli particularly suitable for differentiation of fine-resolution subgroups within clonal groups defined by standard multilocus sequence typing (MLST). FimTyper was constructed as a FASTA database containing all currently known fimH alleles. The software source code is publicly available at https://bitbucket.org/genomicepidemiology/fimtyper, the database is freely available at https://bitbucket.org/genomicepidemiology/fimtyper_db, and a service implementing the software is available at https://cge.cbs.dtu.dk/services/FimTyper FimTyper was validated on three data sets: one containing Sanger sequences of fimH alleles of 42 E. coli isolates generated prior to the current study (data set 1), one containing whole-genome sequence (WGS) data of 243 third-generation-cephalosporin resistant E. coli isolates (data set 2), and one containing a randomly chosen subset of 40 E. coli isolates from data set 2 that were subjected to conventional fimH subtyping (data set 3). The combination of the three data sets enabled an evaluation and comparison of FimTyper on both Sanger sequences and WGS data. FimTyper correctly predicted all 42 fimH subtypes from the Sanger sequences from data set 1 and successfully analyzed all 243 draft genomes from data set 2. FimTyper subtyping of the Sanger sequences and WGS data from data set 3 were in complete agreement. Additionally, fimH subtyping was evaluated on a phylogenetic network of 122 sequence type 131 (ST131) E. coli isolates. There was perfect concordance between the typology and fimH-based subclones within ST131, with accurate identification of the pandemic multidrug-resistant clonal subgroup ST131 H30. FimTyper provides a standardized tool, as a rapid alternative to conventional fimH subtyping, highly suitable for surveillance and outbreak detection. PMID- 28592546 TI - Rapid and Robust Identification of the Agents of Black-Grain Mycetoma by Matrix Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry. AB - Eumycetoma, a chronic fungal infection endemic in India, Indonesia, and parts of Africa and South and Central America, follows traumatic implantation of saprophytic fungi and frequently requires radical surgery or amputation in the absence of appropriate treatment. Fungal species that can cause black-grain mycetomas include Madurella spp., Falciformispora spp., Trematosphaeria grisea, Nigrograna mackinnonii, Pseudochaetosphaeronema larense, Medicopsis romeroi, and Emarellia spp. Rhytidhysteron rufulum and Parathyridaria percutanea cause similar subcutaneous infections, but these infections lack the draining sinuses and fungal grains characteristic of eumycetoma. Accurate identification of the agents of subcutaneous fungal infection is essential to guide appropriate antifungal therapy. Since phenotypic identification of the causative fungi is often difficult, time-consuming molecular approaches are currently required. In the study described here we evaluated whether matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry might allow the accurate identification of eumycetoma agents and related fungi. A panel of 57 organisms corresponding to 10 different species from confirmed cases of eumycetoma and subcutaneous pedal masses, previously formally identified by PCR amplification and sequencing of internal transcribed spacer 1 (ITS1), was employed. Representative isolates of each species were used to create reference MALDI-TOF spectra, which were then used for the identification of the remaining isolates in a user-blinded manner. Here, we demonstrate that MALDI-TOF mass spectrometry accurately identified all of the test isolates, with 100%, 90.4%, and 67.3% of isolates achieving log scores greater than 1.8, 1.9, and 2.0, respectively. PMID- 28592548 TI - Evaluation of the Aptima HIV-1 Quant Dx Assay for HIV-1 RNA Quantitation in Different Biological Specimen Types. AB - The search for a cure for HIV infection has highlighted the need for increasingly sensitive and precise assays to measure viral burden in various tissues and body fluids. We describe the application of a standardized assay for HIV-1 RNA in multiple specimen types. The fully automated Aptima HIV-1 Quant Dx assay (Aptima assay) is FDA cleared for blood plasma HIV-1 RNA quantitation. In this study, the Aptima assay was applied for the quantitation of HIV RNA in peripheral blood mononuclear cells (PBMCs; n = 72), seminal plasma (n = 20), cerebrospinal fluid (CSF; n = 36), dried blood spots (DBS; n = 104), and dried plasma spots (DPS; n = 104). The Aptima assay was equivalent to or better than commercial assays or validated in-house assays for the quantitation of HIV RNA in CSF and seminal plasma. For PBMC specimens, the sensitivity of the Aptima assay in the detection of HIV RNA decayed as background uninfected PBMC counts increased; proteinase K treatment demonstrated some benefit in restoring signal at higher levels of background PBMCs. Finally, the Aptima assay yielded 100% detection rates of DBS in participants with plasma HIV RNA levels of >=35 copies/ml and 100% detection rates of DPS in participants with plasma HIV RNA levels of >=394 copies/ml. The Aptima assay can be applied to a variety of specimens from HIV-infected subjects to measure HIV RNA for studies of viral persistence and cure strategies. It can also detect HIV in dried blood and plasma specimens, which may be of benefit in resource-limited settings. PMID- 28592547 TI - Performance of the Abbott RealTime MTB and MTB RIF/INH Assays in a Setting of High Tuberculosis and HIV Coinfection in South Africa. AB - South Africa is a country with a high incidence of tuberculosis (TB), complicated by coinfection with human immunodeficiency virus (HIV). The Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is used in South Africa as the test for the initial diagnosis of TB, and other molecular platforms such as the m2000 (Abbott Molecular, Des Plaines, IL, USA) are widely used for molecular monitoring of HIV load. The latter platform is now also equipped with the RealTime (RT) MTB and RealTime MTB RIF/INH assays for TB and first-line drug resistance screening but has not been evaluated in settings of HIV and TB coinfection. A prospective clinical validation study was conducted at a community health center in Johannesburg, South Africa, and consenting individuals with presumptive pulmonary TB were enrolled. The performance of the Abbott assays was compared with those of the Xpert MTB/RIF, liquid culture, drug susceptibility testing, and clinical case definitions. A statistical analysis was performed on 206 individuals (73% were HIV positive). The sensitivity and specificity of the RT MTB were 82.5% (confidence interval [CI], 67.2 to 92.7) and 93.1% (CI, 86.2 to 97.2) on raw sputum and 77.5% (CI, 61.5 to 89.2) and 95.1% (CI, 88.9 to 98.4) on concentrated sputum, respectively, compared with those from liquid culture. The RT MTB correctly identified 17/35 more smear-negative culture-positive specimens than the Xpert MTB/RIF. Both the RT MTB and the Xpert MTB/RIF displayed sensitivities >70% and specificities >90% in HIV-positive individuals. The available drug resistance results concurred with MTBDRplus and drug susceptibility profiles. The RT MTB assay has similar diagnostic performance to the Xpert MTB/RIF and is suited to testing presumptive TB patients coinfected with HIV. The existing laboratory information system connectivity, training, and technical support make this a viable polyvalent option to scale up TB alongside HIV laboratory testing services in South Africa. PMID- 28592549 TI - Emergence of a Staphylococcus aureus Clone Resistant to Mupirocin and Fusidic Acid Carrying Exotoxin Genes and Causing Mainly Skin Infections. AB - Skin and soft tissue infections (SSTIs) caused by mupirocin-resistant Staphylococcus aureus strains have recently increased in number in our settings. We sought to evaluate the characteristics of these cases over a 43-month period. Data for all community-acquired staphylococcal infections caused by mupirocin resistant strains were retrospectively reviewed. Genes encoding products producing high-level resistance (HLR) to mupirocin (mupA), fusidic acid resistance (fusB), resistance to macrolides and lincosamides (ermC and ermA), Panton-Valentine leukocidin (PVL) (lukS/lukF-PV), exfoliative toxins (eta and etb), and fibronectin binding protein A (fnbA) were investigated by PCRs in 102 selected preserved strains. Genotyping was performed by SCCmec and agr typing, whereas clonality was determined by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). A total of 437 cases among 2,137 staphylococcal infections were recorded in 2013 to 2016; they were all SSTIs with the exception of 1 case of primary bacteremia. Impetigo was the predominant clinical entity (371 cases [84.9%]), followed by staphylococcal scalded skin syndrome (21 cases [4.8%]), and there were no abscesses. The number of infections detected annually increased during the study years. All except 3 isolates were methicillin susceptible. The rates of HLR to mupirocin and constitutive resistance to clindamycin were 99% and 20.1%, respectively. Among the 102 tested strains, 100 (98%) were mupA positive and 97 (95%) were fusB positive, 26/27 clindamycin-resistant strains (96.3%) were ermA positive, 83 strains (81.4%) were lukS/lukF positive, 95 (93%) carried both eta and etb genes, and 99 (97%) were fnbA positive. Genotyping of methicillin-sensitive S. aureus (MSSA) strains revealed that 96/99 (96.7%) belonged to one main pulsotype, pulsotype 1, classified as sequence type 121 (ST121). The emergence of a single MSSA clone (ST121) causing impetigo was documented. Resistance to topical antimicrobials and a rich toxinogenic profile confer to this clone adaptability for spread in the community. PMID- 28592551 TI - Molecular Identification of Saprochaete capitata in Human Blood and Paraffinized Tissue Samples. PMID- 28592550 TI - Validation and Implementation of Clinical Laboratory Improvements Act-Compliant Whole-Genome Sequencing in the Public Health Microbiology Laboratory. AB - Public health microbiology laboratories (PHLs) are on the cusp of unprecedented improvements in pathogen identification, antibiotic resistance detection, and outbreak investigation by using whole-genome sequencing (WGS). However, considerable challenges remain due to the lack of common standards. Here, we describe the validation of WGS on the Illumina platform for routine use in PHLs according to Clinical Laboratory Improvements Act (CLIA) guidelines for laboratory-developed tests (LDTs). We developed a validation panel comprising 10 Enterobacteriaceae isolates, 5 Gram-positive cocci, 5 Gram-negative nonfermenting species, 9 Mycobacterium tuberculosis isolates, and 5 miscellaneous bacteria. The genome coverage range was 15.71* to 216.4* (average, 79.72*; median, 71.55*); the limit of detection (LOD) for single nucleotide polymorphisms (SNPs) was 60*. The accuracy, reproducibility, and repeatability of base calling were >99.9%. The accuracy of phylogenetic analysis was 100%. The specificity and sensitivity inferred from multilocus sequence typing (MLST) and genome-wide SNP-based phylogenetic assays were 100%. The following objectives were accomplished: (i) the establishment of the performance specifications for WGS applications in PHLs according to CLIA guidelines, (ii) the development of quality assurance and quality control measures, (iii) the development of a reporting format for end users with or without WGS expertise, (iv) the availability of a validation set of microorganisms, and (v) the creation of a modular template for the validation of WGS processes in PHLs. The validation panel, sequencing analytics, and raw sequences could facilitate multilaboratory comparisons of WGS data. Additionally, the WGS performance specifications and modular template are adaptable for the validation of other platforms and reagent kits. PMID- 28592552 TI - Colistin and Polymyxin B Susceptibility Testing for Carbapenem-Resistant and mcr Positive Enterobacteriaceae: Comparison of Sensititre, MicroScan, Vitek 2, and Etest with Broth Microdilution. AB - Colistin and polymyxin B remain part of the last line of antibiotics for multidrug-resistant Gram-negative bacteria, such as carbapenem-resistant Enterobacteriaceae Current joint EUCAST-CLSI recommendations are for broth microdilution (BMD) to be performed for MIC testing of colistin. Commercial susceptibility testing methods were evaluated and compared against the reference BMD, using a susceptibility breakpoint of <=2 mg/liter for both colistin and polymyxin B. Seventy-six Enterobacteriaceae were included, of which 21 were mcr-1 positive (18 Escherichia coli isolates, 2 Klebsiella pneumoniae isolates, and 1 Enterobacter aerogenes isolate). Rates of essential agreement (EA) of colistin test results between BMD and Vitek 2, Sensititre, and Etest were 93.4%, 89.5%, and 75.0%, respectively. Rates of EA of polymyxin B test results between BMD and Vitek 2, Sensititre, and Etest were 96.1%, 96.1%, and 48.7%, respectively. A positive MIC correlation with a categorical agreement of >90% was achieved for Sensititre (colistin Spearman's rho = 0.863, and polymyxin B Spearman's rho = 0.877) and Vitek 2 (polymyxin B [only] Spearman's rho = 0.8917). Although a positive MIC correlation (Spearman's rho = 0.873) with the reference method was achieved for colistin testing with Vitek 2, categorical agreement was <90%, with very major error rates of 36%. Correlation with the Etest MIC was lower, with very major error rates of 12% (colistin) and 26.1% (polymyxin B). MicroScan (colistin) categorical agreement was 88.2%, with a very major error rate of 4%. Colistin MICs for 15 of the 21 mcr-1-positive isolates were >2 mg/liter, and polymyxin MICs for 17 of them were >2 mg/liter by broth microdilution. The use of a lower breakpoint of <=1 mg/liter further improves detection of mcr-1 for all testing methods. However, further data on the correlation between MICs and clinical outcome are required to determine the most suitable breakpoint to guide clinical management. PMID- 28592553 TI - Accurate and Rapid Differentiation of Acinetobacter baumannii Strains by Raman Spectroscopy: a Comparative Study. AB - In recent years, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has become the standard for routine bacterial species identification due to its rapidity and low costs for consumables compared to those of traditional DNA-based methods. However, it has been observed that strains of some bacterial species, such as Acinetobacter baumannii strains, cannot be reliably identified using mass spectrometry (MS). Raman spectroscopy is a rapid technique, as fast as MALDI-TOF, and has been shown to accurately identify bacterial strains and species. In this study, we compared hierarchical clustering results for MS, genomic, and antimicrobial susceptibility test data to hierarchical clustering results from Raman spectroscopic data for 31 A. baumannii clinical isolates labeled according to their pulsed-field gel electrophoresis data for strain differentiation. In addition to performing hierarchical cluster analysis (HCA), multiple chemometric methods of analysis, including principal component analysis (PCA) and partial least-squares discriminant analysis (PLSDA), were performed on the MS and Raman spectral data, along with a variety of spectral preprocessing techniques for best discriminative results. Finally, simple HCA algorithms were performed on all of the data sets to explore the relationships between, and natural groupings of, the strains and to compare results for the four data sets. To obtain numerical comparison values of the clustering results, the external cluster evaluation criteria of the Rand index of the HCA dendrograms were calculated. With a Rand index value of 0.88, Raman spectroscopy outperformed the other techniques, including MS (with a Rand index value of 0.58). PMID- 28592554 TI - Urinary glycated uromodulin in diabetic kidney disease. AB - Advanced glycation end-products (AGEs) form during oxidative stress, which is increased in diabetes mellitus (DM). Uromodulin is a protein with a renal protective effect, and may be subject to glycation. The implications of uromodulin glycation and AGEs in the urine are not understood. Here, immunoprecipitation and liquid chromatography-mass spectrometry identified glycated uromodulin (glcUMOD) in the urine of 62.5% of patients with diabetic kidney disease (DKD), 20.0% of patients with non-diabetic chronic kidney disease (CKD), and no DM patients with normal renal function or healthy control participants; a finding replicated in a larger cohort of 84 patients with CKD in a case-control study (35 with DM, 49 without). Uromodulin forms high molecular weight polymers that associate with microvesicles and exosomes. Differential centrifugation identified uromodulin in the supernatant, microvesicles, and exosomes of the urine of healthy participants, but only in the supernatant of samples from patients with DKD, suggesting that glycation influences uromodulin function. Finally, the diagnostic and prognostic utility of measuring urinary glcUMOD concentration was examined. Urinary glcUMOD concentration was substantially higher in DKD patients than non-diabetic CKD patients. Urinary glcUMOD concentration predicted DKD status, particularly in patients with CKD stages 1-3a aged <65 years and with urine glcUMOD concentration >=9,000 arbitrary units (AU). Urinary uromodulin is apparently glycated in DKD and forms AGEs, and glcUMOD may serve as a biomarker for DKD. PMID- 28592555 TI - Genetic Dissection of Morphometric Traits Reveals That Phytochrome B Affects Nucleus Size and Heterochromatin Organization in Arabidopsis thaliana. AB - Microscopically visible chromatin is partitioned into two major components in Arabidopsis thaliana nuclei. On one hand, chromocenters are conspicuous foci of highly condensed "heterochromatic" domains that contain mostly repeated sequences. On the other hand, less condensed and gene-rich "euchromatin" emanates from these chromocenters. This differentiation, together with the dynamic nature of chromatin compaction in response to developmental and environmental stimuli, makes Arabidopsis a powerful system for studying chromatin organization and dynamics. Heterochromatin dynamics can be monitored by measuring the Heterochromatin Index, i.e., the proportion of nuclei displaying well-defined chromocenters, or the DNA fraction of chromocenters (relative heterochromatin fraction). Both measures are composite traits, thus their values represent the sum of effects of various underlying morphometric properties. We exploited genetic variation between natural occurring accessions to determine the genetic basis of individual nucleus and chromocenter morphometric parameters (area, perimeter, density, roundness, and heterogeneity) that together determine chromatin compaction. Our novel reductionist genetic approach revealed quantitative trait loci (QTL) for all measured traits. Genomic colocalization among QTL was limited, which suggests a complex genetic regulation of chromatin compaction. Yet genomic intervals of QTL for nucleus size (area and perimeter) both overlap with a known QTL for heterochromatin compaction that is explained by natural polymorphism in the red/far-red light and temperature receptor Phytochrome B. Mutant analyses and genetic complementation assays show that Phytochrome B is a negative regulator of nucleus size, revealing that perception of climatic conditions by a Phytochrome-mediated hub is a major determinant for coordinating nucleus size and heterochromatin compaction. PMID- 28592556 TI - Whole-Genome Resequencing Identifies the Molecular Genetic Cause for the Absence of a Gy5 Glycinin Protein in Soybean PI 603408. AB - During ongoing proteomic analysis of the soybean (Glycine max (L.) Merr) germplasm collection, PI 603408 was identified as a landrace whose seeds lack accumulation of one of the major seed storage glycinin protein subunits. Whole genomic resequencing was used to identify a two-base deletion affecting glycinin 5 The newly discovered deletion was confirmed to be causative through immunological, genetic, and proteomic analysis, and no significant differences in total seed protein content were found to be due to the glycinin 5 loss-of function mutation per se In addition to focused studies on this one specific glycinin subunit-encoding gene, a total of 1,858,185 nucleotide variants were identified, of which 39,344 were predicted to affect protein coding regions. In order to semiautomate analysis of a large number of soybean gene variants, a new SIFT 4G (Sorting Intolerant From Tolerated 4 Genomes) database was designed to predict the impact of nonsynonymous single nucleotide soybean gene variants, potentially enabling more rapid analysis of soybean resequencing data in the future. PMID- 28592557 TI - Comparative Mapping of Seed Dormancy Loci Between Tropical and Temperate Ecotypes of Weedy Rice (Oryza sativa L.). AB - Genotypic variation at multiple loci for seed dormancy (SD) contributes to plant adaptation to diverse ecosystems. Weedy rice (Oryza sativa) was used as a model to address the similarity of SD genes between distinct ecotypes. A total of 12 quantitative trait loci (QTL) for SD were identified in one primary and two advanced backcross (BC) populations derived from a temperate ecotype of weedy rice (34.3 degrees N Lat.). Nine (75%) of the 12 loci were mapped to the same positions as those identified from a tropical ecotype of weedy rice (7.1 degrees N Lat.). The high similarity suggested that the majority of SD genes were conserved during the ecotype differentiation. These common loci are largely those collocated/linked with the awn, hull color, pericarp color, or plant height loci. Phenotypic correlations observed in the populations support the notion that indirect selections for the wild-type morphological characteristics, together with direct selections for germination time, were major factors influencing allelic distributions of SD genes across ecotypes. Indirect selections for crop mimic traits (e.g., plant height and flowering time) could also alter allelic frequencies for some SD genes in agroecosystems. In addition, 3 of the 12 loci were collocated with segregation distortion loci, indicating that some gametophyte development genes could also influence the genetic equilibria of SD loci in hybrid populations. The SD genes with a major effect on germination across ecotypes could be used as silencing targets to develop transgene mitigation (TM) strategies to reduce the risk of gene flow from genetically modified crops into weed/wild relatives. PMID- 28592559 TI - Time-dependent inhibition of PHD2. AB - Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2 oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time. PMID- 28592558 TI - Duplication and Loss of Function of Genes Encoding RNA Polymerase III Subunit C4 Causes Hybrid Incompatibility in Rice. AB - Reproductive barriers are commonly observed in both animals and plants, in which they maintain species integrity and contribute to speciation. This report shows that a combination of loss-of-function alleles at two duplicated loci, DUPLICATED GAMETOPHYTIC STERILITY 1 (DGS1) on chromosome 4 and DGS2 on chromosome 7, causes pollen sterility in hybrid progeny derived from an interspecific cross between cultivated rice, Oryza sativa, and an Asian annual wild rice, O. nivara Male gametes carrying the DGS1 allele from O. nivara (DGS1-nivaras ) and the DGS2 allele from O. sativa (DGS2-T65s ) were sterile, but female gametes carrying the same genotype were fertile. We isolated the causal gene, which encodes a protein homologous to DNA-dependent RNA polymerase (RNAP) III subunit C4 (RPC4). RPC4 facilitates the transcription of 5S rRNAs and tRNAs. The loss-of-function alleles at DGS1-nivaras and DGS2-T65s were caused by weak or nonexpression of RPC4 and an absence of RPC4, respectively. Phylogenetic analysis demonstrated that gene duplication of RPC4 at DGS1 and DGS2 was a recent event that occurred after divergence of the ancestral population of Oryza from other Poaceae or during diversification of AA-genome species. PMID- 28592560 TI - Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. AB - Biallelic mutations in ABCC6 cause pseudoxanthoma elasticum (PXE), a disease characterized by calcification in the skin, eyes, and blood vessels. The function of ATP-binding cassette C6 (ABCC6) and the pathogenesis of PXE remain unclear. We used mouse models and patient fibroblasts to demonstrate genetic interaction and shared biochemical and cellular mechanisms underlying ectopic calcification in PXE and related disorders caused by defined perturbations in extracellular adenosine 5'-triphosphate catabolism. Under osteogenic culture conditions, ABCC6 mutant cells calcified, suggesting a provoked cell-autonomous defect. Using a conditional Abcc6 knockout mouse model, we excluded the prevailing pathogenic hypothesis that singularly invokes failure of hepatic secretion of an endocrine inhibitor of calcification. Instead, deficiency of Abcc6 in both local and distant cells was necessary to achieve the early onset and penetrant ectopic calcification observed upon constitutive gene targeting. ABCC6 mutant cells additionally had increased expression and activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme that degrades pyrophosphate, a major inhibitor of calcification. A selective and orally bioavailable TNAP inhibitor prevented calcification in ABCC6 mutant cells in vitro and attenuated both the development and progression of calcification in Abcc6-/- mice in vivo, without the deleterious effects on bone associated with other proposed treatment strategies. PMID- 28592563 TI - The effects of treatment failure generalize across different routes of drug administration. AB - Failure of medical treatments can hamper responses to subsequent treatments. It has been suggested that changing the route of drug administration could reduce such negative carry-over effects, but direct evidence for this approach is lacking. We therefore investigated in 211 healthy volunteers whether changes in drug administration route reduce such carry-over effects. A positive or negative treatment history with topical analgesic treatments was induced experimentally in a mock clinical trial setting. Subsequently, a different inert drug was introduced via the same (topical) or another (oral) route of administration and its analgesic efficacy was tested. Changing the route of drug administration induced expectations of positive treatment effects in the subjects but did not actually counteract the negative carry-over effects on treatment efficacy. These findings indicate that learned carry-over effects generalize over time and across routes of drug administration-independent of conscious expectations. Other strategies are needed to prevent negative carry-over effects of treatment failure from influencing the results of subsequent treatment attempts. PMID- 28592564 TI - Modeling human brain development. AB - Human forebrain spheroids enable in vitro observation of region-specific neural migration and circuit formation during brain development. PMID- 28592561 TI - Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant mediated antigen uptake. AB - The innate immune mechanisms by which adjuvants enhance the potency and protection of vaccine-induced adaptive immunity are largely unknown. We introduce a model to delineate the steps of how adjuvant-driven innate immune activation leads to priming of vaccine responses using rhesus macaques. Fluorescently labeled HIV-1 envelope glycoprotein (Env) was administered together with the conventional aluminum salt (alum) adjuvant. This was compared to Env given with alum with preabsorbed Toll-like receptor 7 (TLR7) ligand (alum-TLR7) or the emulsion MF59 because they show superiority over alum for qualitatively and quantitatively improved vaccine responses. All adjuvants induced rapid and robust immune cell infiltration to the injection site in the muscle. This resulted in substantial uptake of Env by neutrophils, monocytes, and myeloid and plasmacytoid dendritic cells (DCs) and migration exclusively to the vaccine-draining lymph nodes (LNs). Although less proficient than monocytes and DCs, neutrophils were capable of presenting Env to memory CD4+ T cells. MF59 and alum-TLR7 showed more pronounced cell activation and overall higher numbers of Env+ cells compared to alum. This resulted in priming of higher numbers of Env-specific CD4+ T cells in the vaccine-draining LNs, which directly correlated with increased T follicular helper cell differentiation and germinal center formation. Thus, strong innate immune activation promoting efficient vaccine antigen delivery to infiltrating antigen-presenting cells in draining LNs is an important mechanism by which superior adjuvants enhance vaccine responses. PMID- 28592565 TI - Anti-VEGF AAV2 injections: The fewer the better. AB - A single intravitreal injection of AAV2 provides sustained delivery of anti-VEGF protein for the treatment of neovascular AMD. PMID- 28592562 TI - Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD. PMID- 28592567 TI - Driver mutations take the wheel in invasive yet nonmalignant disease. AB - Despite their low risk for malignant transformation, infiltrating endometriotic lesions harbor cancer-associated mutations. PMID- 28592568 TI - Congenital Zika virus infection: More than just microcephaly. AB - A nonhuman primate model demonstrates efficient vertical transmission of Zika virus. PMID- 28592569 TI - Rett syndrome modeling goes simian. AB - Rett syndrome modeling in monkey mirrors the human disorder. PMID- 28592566 TI - Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. AB - Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model. BRCA1-mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including PDCD1 (PD-1) and CTLA4, when compared to TNBCs from BRCA1-wild-type patients. Cisplatin treatment combined with dual anti-programmed death-1 and anti-cytotoxic T lymphocyte associated antigen 4 therapy substantially augmented antitumor immunity in Brca1 deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3+ regulatory T cells, and concomitant increase in the activation of tumor infiltrating cytotoxic CD8+ and CD4+ T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of Brca1 deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in BRCA1 associated TNBC. PMID- 28592570 TI - Editorial retraction. PMID- 28592571 TI - Evaluating the short-term and long-term effects of an internet-based aural rehabilitation programme for hearing aid users in general clinical practice: a randomised controlled trial. AB - OBJECTIVE: Guided internet-based intervention beyond hearing aid (HA) fitting has been shown to be efficacious in randomised controlled trials (RCTs). However, internet interventions have rarely been applied clinically as a part of regular aural rehabilitation (AR). Our aim was to evaluate the effectiveness of internet based AR for HA users from a clinical population. OUTCOME MEASURES: The Hearing Handicap Inventory for the Elderly (HHIE) was used as the primary outcome measure, and the Communication Strategies Scale (CSS) and the Hospital Anxiety and Depression Scale were used as secondary outcome measures. All questionnaires were administered before and directly after the intervention and at 6 months postintervention. METHODS: We used a parallel group design (RCT). The data were collected in 2013-2014 at three different clinics. Seventy-four HA users were randomly assigned to receive either full internet-based AR (intervention group, n=37) or one element of the internet-based AR (control group, n=37). RESULTS: Data were analysed following the intention-to-treat principle. Each group showed improved HHIE scores over time and did not differ significantly from each other. The intervention group showed significantly greater improvement compared with the control group for the CSS total and the non-verbal subscale scores. The intervention group and control group were also subdivided into two age groups: 20 59 years and 60-80 years. Significantly better improvement on the CSS total and non-verbal subscale scores was found in the older group compared with the younger participants. CONCLUSIONS: This study indicates that participants in an internet based intervention applied in general clinical practice showed improved self reported communication skills compared with a control group. Receiving a full intervention was not more effective in improving self-reported hearing problems than receiving just one element of the internet-based intervention. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrals.gov, NCT01837550; results. PMID- 28592572 TI - Impact of iron fortification on the geospatial patterns of malaria and non malaria infection risk among young children: a secondary spatial analysis of clinical trial data from Ghana. AB - OBJECTIVES: Patterns of infection among children with varying levels of iron status in a malaria endemic area may vary spatially in ways requiring integrated infection and iron deficiency control programmes. The objective of this secondary analysis was to determine the geospatial factors associated with malaria and non malaria infection status among young Ghanaian children at the end of a 5-month iron intervention trial. DESIGN: Cluster-randomised controlled trial. SETTING: Rural Ghana PARTICIPANTS: 1943 children (6-35 months of age) with geocoded compounds. INTERVENTIONS: Point-of-use fortification with micronutrient powders containing vitamins and minerals with or without iron. PRIMARY AND SECONDARY OUTCOME MEASURES: Generalised linear geostatistical models with a Matern spatial correlation function were used to analyse four infection response variables, defined using different combinations of inflammation (C-reactive protein, CRP >5 mg/L) and malaria parasitaemia. Analyses were also stratified by treatment group to assess the independent effects of the iron intervention. RESULTS: The by-group and combined-group analyses both showed that baseline infection status was the most consistent predictor of endline infection risk, particularly when infection was defined using parasitaemia. In the No-iron group, age above 24 months and weight-for-length z-score at baseline were associated with high CRP at endline. Higher asset score was associated with a 12% decreased odds of endline infection, defined as CRP >5 mg/L and/or parasitaemia (OR 0.88, 95% credible interval 0.78 to 0.98), regardless of group. Maps of the predicted risk and spatial random effects showed a defined low-risk area around the District centre, regardless of how infection was defined. CONCLUSION: In a clinical trial setting of iron fortification, where all children receive treated bed nets and access to malaria treatment, there may be geographical variation in the risk of infection with distinct high-risk and low-risk areas, particularly around municipal centres. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT01001871. PMID- 28592573 TI - Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial). AB - INTRODUCTION: The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A1c (HbA1c)39-47 mmol/mol / 5.7%-6.4%). The secondary aims are to investigate the effects of the interventions on body composition and cardiometabolic risk factors. METHODS AND ANALYSIS: The Pre-D Trial is an investigator-initiated, randomised, controlled, parallel, open-label, superiority trial. The study aims to assign 120 participants in a 1:1:1:1 ratio to receive one of four interventions for 13 weeks: (1) dapagliflozin (10 mg once daily); (2) metformin (850 mg twice daily); (3) exercise (interval training, 5 days a week, 30 min per session); or (4) control (lifestyle advice). After the 13 weeks of intervention, a follow-up period of 13 weeks will follow to study the long-term effects of the interventions. The primary endpoint is reduction from baseline to end-of treatment (13 weeks) in mean amplitude of glycaemic excursions measured by continuous glucose monitoring. The secondary endpoints include concomitant changes in various measures of glucose metabolism, body weight, cardiorespiratory fitness, blood pressure, plasma lipids, objectively measured physical activity and dietary intake. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the Capital Region and the Danish Medicines Agency. Approval of data and biobank storage has been obtained from the Danish Data Protection Board. The study will be carried out according to the Declaration of Helsinki and to the regulations for good clinical practice. The results from this trial will allow a number of research questions concerning the effect of exercise versus dapagliflozin or metformin in HbA1c-defined prediabetes to be addressed. TRIAL REGISTRATION: NCT02695810. PMID- 28592574 TI - Dyspnoea-12: a translation and linguistic validation study in a Swedish setting. AB - BACKGROUND: Dyspnoea consists of multiple dimensions including the intensity, unpleasantness, sensory qualities and emotional responses which may differ between patient groups, settings and in relation to treatment. The Dyspnoea-12 is a validated and convenient instrument for multidimensional measurement in English. We aimed to take forward a Swedish version of the Dyspnoea-12. METHODS: The linguistic validation of the Dyspnoea-12 was performed (Mapi Language Services, Lyon, France). The standardised procedure involved forward and backward translations by three independent certified translators and revisions after feedback from an in-country linguistic consultant, the developerand three native physicians. The understanding and convenience of the translated version was evaluated using qualitative in-depth interviews with five patients with dyspnoea. RESULTS: A Swedish version of the Dyspnoea-12 was elaborated and evaluated carefully according to international guidelines. The Swedish version, 'Dyspne 12', has the same layout as the original version, including 12 items distributed on seven physical and five affective items. The Dyspnoea-12 is copyrighted by the developer but can be used free of charge after permission for not industry-funded research. CONCLUSION: A Swedish version of the Dyspnoea-12 is now available for clinical validation and multidimensional measurement across diseases and settings with the aim of improved evaluation and management of dyspnoea. PMID- 28592575 TI - A cross-sectional study measuring vanadium and chromium levels in paediatric patients with CKD. AB - OBJECTIVES: Although many secondary effects of high levels of vanadium (V) and chromium (Cr) overlap with symptoms seen in paediatric patients with chronic kidney disease (CKD), their plasma V and Cr levels are understudied. DESIGN: Ancillary cross-sectional study to a prospective, longitudinal, randomised controlled trial. SETTING: Children's Hospital of Western Ontario, London Health Sciences Centre, London, Ontario, Canada. PARTICIPANTS: 36 children and adolescents 4-18 years of age with CKD. INTERVENTIONS: 1-6 trace element measurements per patient. Cystatin C (CysC) estimated glomerular filtration rate (eGFR) was calculated using the Filler formula. Plasma V and Cr levels were measured using high-resolution sector field inductively coupled mass spectrometry. Anthropomorphic data and blood parameters were collected from our electronic chart programme. Water Cr and V data were obtained from the Ontario Water (Stream) Quality Monitoring Network. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes: plasma Cr and V. SECONDARY OUTCOMES: age, season, CysC, CysC eGFR, and Cr and V levels in environmental water. RESULTS: The median (IQR) eGFR was 51 mL/min/1.73 m2 (35, 75). The median V level was 0.12 ug/L (0.09, 0.18), which was significantly greater than the 97.5th percentile of the reference interval of 0.088 ug/L; 32 patients had at least one set of V levels above the published reference interval. The median Cr level was 0.43 ug/L (0.36, 0.54), which was also significantly greater than the established reference interval; 34 had at least one set of Cr levels above the published reference interval. V and Cr levels were moderately correlated. Only some patients had high environmental exposure. CONCLUSIONS: Our study suggests that paediatric patients with CKD have elevated plasma levels of V and Cr. This may be the result of both environmental exposure and a low eGFR. It may be necessary to monitor V and Cr levels in patients with an eGFR <30 mL/min/1.73 m2. TRIAL REGISTRATION NUMBER: NCT02126293; HC#172241. PMID- 28592576 TI - Patient-reported outcome measures (PROMs) for assessing perceived listening effort in hearing loss: protocol for a systematic review. AB - INTRODUCTION: In the UK, it is estimated that a disabling hearing loss (HL) affects 1 in 6 people. HL has functional, economic and social-emotional consequences for affected individuals. Intervention for HL focuses on improving access to the auditory signal using hearing aids or cochlear implants. However, even if sounds are audible and speech is understood, individuals with HL often report increased effort when listening.Listening effort (LE) may be measured using self-reported measures such as patient-reported outcome measures (PROMs). PROMs are validated questionnaires completed by patients to measure their perceptions of their own functional status and well-being. When selecting a PROM for use in research or clinical practice, it is necessary to appraise the evidence of a PROM's acceptability to patients, validity, responsiveness and reliability. METHODS AND ANALYSIS: A systematic review of studies evaluating the measurement properties of PROMs available to measure LE in HL will be undertaken. MEDLINE, EMBASE, CINAHL, PsychINFO and Web of Science will be searched electronically. Reference lists of included studies, key journals and the grey literature will be hand-searched to identify further studies for inclusion. Two reviewers will independently complete title, abstract and full-text screening to determine study eligibility. Data on the characteristics of each study and each PROM will be extracted. Methodological quality of the included studies will be appraised using the COnsensus-based Standards for the selection of health Measurement INstruments, the quality of included PROMs appraised and the credibility of the evidence assessed. A narrative synthesis will summarise extracted data. ETHICS AND DISSEMINATION: Ethical permission is not required, as this study uses data from published research. Dissemination will be through publication in peer-reviewed journals, conference presentations and the lead author's doctoral dissertation. Findings may inform the selection of PROMs used to measure LE in HL. PMID- 28592578 TI - Bacterial meningitis in Finland, 1995-2014: a population-based observational study. AB - OBJECTIVES: Bacterial meningitis remains an important cause of morbidity and mortality worldwide. Its epidemiological characteristics, however, are changing due to new vaccines and secular trends. Conjugate vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae (10-valent) were introduced in 1986 and 2010 in Finland. We assessed the disease burden and long-term trends of five common causes of bacterial meningitis in a population-based observational study. METHODS: A case was defined as isolation of S. pneumoniae, Neisseria meningitidis, Streptococcus agalactiae, Listeria monocytogenes or H. influenzae from cerebrospinal fluid and reported to national, population-based laboratory surveillance system during 1995-2014. We evaluated changes in incidence rates (Poisson or negative binomial regression), case fatality proportions (chi2) and age distribution of cases (Wilcoxon rank-sum). RESULTS: During 1995-2014, S. pneumoniae and N. meningitidis accounted for 78% of the total 1361 reported bacterial meningitis cases. H. influenzae accounted for 4% of cases (92% of isolates were non-type b). During the study period, the overall rate of bacterial meningitis per 1 00 000 person-years decreased from 1.88 cases in 1995 to 0.70 cases in 2014 (4% annual decline (95% CI 3% to 5%). This was primarily due to a 9% annual reduction in rates of N. meningitidis (95% CI 7% to 10%) and 2% decrease in S. pneumoniae (95% CI 1% to 4%). The median age of cases increased from 31 years in 1995-2004 to 43 years in 2005-2014 (p=0.0004). Overall case fatality proportion (10%) did not change from 2004 to 2009 to 2010-2014. CONCLUSIONS: Substantial decreases in bacterial meningitis were associated with infant conjugate vaccination against pneumococcal meningitis and secular trend in meningococcal meningitis in the absence of vaccination programme. Ongoing epidemiological surveillance is needed to identify trends, evaluate serotype distribution, assess vaccine impact and develop future vaccination strategies. PMID- 28592577 TI - The eSMART study protocol: a randomised controlled trial to evaluate electronic symptom management using the advanced symptom management system (ASyMS) remote technology for patients with cancer. AB - INTRODUCTION: While some evidence exists that real-time remote symptom monitoring devices can decrease morbidity and prevent unplanned admissions in oncology patients, overall, these studies have significant methodological weaknesses. The electronic Symptom Management using the Advanced Symptom Management System (ASyMS) Remote Technology (eSMART) study is designed to specifically address these weaknesses with an appropriately powered, repeated-measures, parallel-group stratified randomised controlled trial of oncology patients. METHODS AND ANALYSIS: A total of 1108 patients scheduled to commence first-line chemotherapy (CTX) for breast, colorectal or haematological cancer will be recruited from multiple sites across five European countries.Patients will be randomised (1:1) to the ASyMS intervention (intervention group) or to standard care currently available at each site (control group). Patients in the control and intervention groups will complete a demographic and clinical questionnaire, as well as a set of valid and reliable electronic patient-reported outcome measures at enrolment, after each of their CTX cycles (up to a maximum of six cycles) and at 3, 6, 9 and 12 months after completion of their sixth cycle of CTX. Outcomes that will be assessed include symptom burden (primary outcome), quality of life, supportive care needs, anxiety, self-care self-efficacy, work limitations and cost effectiveness and, from a health professional perspective, changes in clinical practice (secondary outcomes). ETHICS AND DISSEMINATION: Ethical approval will be obtained prior to the implementation of all major study amendments. Applications will be submitted to all of the ethics committees that granted initial approval.eSMART received approval from the relevant ethics committees at all of the clinical sites across the five participating countries. In collaboration with the European Cancer Patient Coalition (ECPC), the trial results will be disseminated through publications in scientific journals, presentations at international conferences, and postings on the eSMART website and other relevant clinician and consumer websites; establishment of an eSMART website (www.esmartproject.eu) with publicly accessible general information; creation of an eSMART Twitter Handle, and production of a toolkit for implementing/utilising the ASyMS technology in a variety of clinical practices and other transferable health care contexts. TRIAL REGISTRATION NUMBER: NCT02356081. PMID- 28592579 TI - Attitudes and behaviours of adolescents towards antibiotics and self-care for respiratory tract infections: a qualitative study. AB - BACKGROUND: To understand attitudes and behaviours of adolescents towards antibiotics, antimicrobial resistance and respiratory tract infections. DESIGN: Qualitative approach informed by the Theory of Planned Behaviour. Semi-structured interviews and focus groups were undertaken. We aimed to inform the development of an intervention in an international setting to improve antibiotic use among adolescents; therefore on completion of thematic analysis, findings were triangulated with qualitative data from similar studies in France, Saudi Arabia and Cyprus to elucidate differences in the behaviour change model and adaptation to diverse contexts. SETTING: 7 educational establishments from the south of England. PARTICIPANTS: 53 adolescents (16-18 years) participated in seven focus groups and 21 participated in interviews. RESULTS: Most participants had taken antibiotics and likened them to other common medications such as painkillers; they reported that their peers treat antibiotics like a 'cure-all' and that they themselves were not interested in antibiotics as a discussion topic. They demonstrated low knowledge of the difference between viral and bacterial infections.Participants self-cared for colds and flu but believed antibiotics are required to treat other RTIs such as tonsillitis, which they perceived as more 'serious'. Past history of taking antibiotics for RTIs instilled the belief that antibiotics were required for future RTIs. Those who characterised themselves as 'non-science students' were less informed about antibiotics and AMR. Most participants felt that AMR was irrelevant to them and their peers. Some 'non science' students thought resistance was a property of the body, rather than bacteria. CONCLUSION: Addressing adolescents' misperceptions about antibiotics and the treatment of RTIs using a behaviour change intervention should help improve antibiotic awareness and may break the cycle of patient demand for antibiotics to treat RTIs amongst this group. Schools should consider educating all students in further education about antibiotic usage and AMR, not only those taking science. PMID- 28592580 TI - The influence of multisite pain and psychological comorbidity on prognosis of chronic low back pain: longitudinal data from the Norwegian HUNT Study. AB - OBJECTIVES: This study aimed to investigate the prospective influence of multisite pain, depression, anxiety, self-rated health and pain-related disability on recovery from chronic low back pain (LBP). SETTING: The data is derived from the second (1995-1997) and third (2006-2008) wave of the Nord Trondelag Health Study (HUNT) in Norway. PARTICIPANTS: The study population comprises 4484 women and 3039 men in the Norwegian HUNT Study who reported chronic LBP at baseline in 1995-1997. PRIMARY OUTCOME MEASURES: The primary outcome was recovery from chronic LBP at the 11-year follow-up. Persons not reporting pain and/or stiffness for at least three consecutive months during the last year were defined as recovered. A Poisson regression model was used to estimate adjusted risk ratios (RRs) with 95% CIs. RESULTS: At follow-up, 1822 (40.6%) women and 1578 (51.9%) men reported recovery from chronic LBP. The probability of recovery was inversely associated with number of pain sites (P trend<0.001). Compared with reporting 2-3 pain sites, persons with only LBP had a slightly higher probability of recovery (RR 1.10, 95% CI 0.98 to 1.22 in women and RR 1.10, 95% CI 1.01 to 1.21 in men), whereas people reporting 6-9 pain sites had substantially lower probability of recovery (RR 0.58, 95% CI 0.52 to 0.63 in women and RR 0.70, 95% CI 0.63 to 0.79 in men). Poor/not so good self-rated general health, symptoms of anxiety and depression, and pain-related disability in work and leisure were all associated with reduced probability of recovery, but there was no statistical interaction between multisite pain and these comorbidities. CONCLUSIONS: Increasing number of pain sites was inversely associated with recovery from chronic LBP. In addition, factors such as poor self rated health, psychological symptoms and pain-related disability may further reduce the probability of recovery from chronic LBP. PMID- 28592581 TI - The STOP-AB trial protocol: efficacy and safety of discontinuing patient antibiotic treatment when physicians no longer consider it necessary. AB - INTRODUCTION: Since 2011, the Spanish Society of Family Medicine has recommended general practitioners (GPs) to ask their patients to stop taking antibiotics when they suspect a viral infection. However, this practice is seldom used because uncertainty about diagnosis, and fear of consequences of discontinuing antibiotic therapy, as well as perceived pressure to continue prescribing antibiotics and potential conflict with patients are more of a concern for GPs than antibiotic resistance. The main objective of this study is to determine whether discontinuation of antibiotic therapy when a GP no longer considers it necessary has any impact on the number of days with severe symptoms. METHODS AND ANALYSIS: This is a multicentre, open-label, randomised controlled clinical trial. The study was conducted in 10 primary care centres in Spain. We included patients from 18 to 75 years of age with uncomplicated acute respiratory tract infections acute rhinosinusitis, acute sore throat, influenza or acute bronchitis-who had previously taken any dose of antibiotic for <3 days, which physicians no longer considered necessary. The patients were randomly assigned to the usual strategy of continuing antibiotic treatment or to discontinuing antibiotic therapy. A sample size of 240 patients per group was calculated on the basis of a reduction of 1 day in the duration of severe symptoms being a clinically relevant outcome. The primary outcome was the duration of severe symptoms, that is, symptoms scored 5 or 6 by means of validated symptom diaries. Secondary outcomes included antibiotics taken, adverse events, patient satisfaction and complications within the first 3 months. ETHICS AND DISSEMINATION: The study was approved by the Ethical Board of Fundacio Jordi Gol i Gurina (reference number: 16/093). The findings of this trial will bedisseminated through research conferences and peer reviewed journals. TRIAL REGISTRATION NUMBER: NCT02900820; pre-results. PMID- 28592582 TI - Adverse childhood or adult experiences and risk of bilateral oophorectomy: a population-based case-control study. AB - OBJECTIVES: Bilateral oophorectomy has commonly been performed in conjunction with hysterectomy even in women without a clear ovarian indication; however, oophorectomy may have long-term deleterious consequences. To better understand this surgical practice from the woman's perspective, we studied the possible association of adverse childhood or adult experiences with the subsequent occurrence of bilateral oophorectomy. DESIGN: Population-based case-control study. SETTING: Olmsted County, Minnesota (USA). PARTICIPANTS: From an established population-based cohort study, we sampled 128 women who underwent bilateral oophorectomy before age 46 years for a non-cancerous condition in 1988 2007 (cases) and 128 age-matched controls (+/-1 year). METHODS: Information about adverse experiences was abstracted from the medical records dating back to age 15 years or earlier archived in the Rochester Epidemiology Project (REP) records linkage system. Adverse childhood experiences were summarised using the Adverse Childhood Experience (ACE) score. RESULTS: We observed an association of bilateral oophorectomy performed before age 46 years with verbal or emotional abuse, physical abuse, any abuse, substance abuse in the household, and with an ACE score >=1 experienced before age 19 years (OR=3.23; 95% CI 1.73 to 6.02; p<0.001). In women who underwent the oophorectomy before age 40 years, we also observed a strong association with physical abuse experienced during adulthood (OR=4.33; 95% CI 1.23 to 15.21; p=0.02). Several of the associations were higher in women who underwent oophorectomy at a younger age (<40 years) and in women without an ovarian indication for the surgery. None of the psychosocial or medical variables explored as potential confounders or intervening variables changed the results noticeably. CONCLUSIONS: Women who suffered adverse childhood experiences or adult abuse are at increased risk of undergoing bilateral oophorectomy before menopause. We suggest that the association may be explained by a series of biological, emotional, and psychodynamic mechanisms. PMID- 28592583 TI - Rehabilitation interventions to improve patient-reported outcomes and physical fitness in survivors of muscle invasive bladder cancer: a systematic review protocol. AB - INTRODUCTION: Survivors of muscle invasive bladder cancer (MIBC) experience physical and psychosocial side effects of cancer diagnosis and treatment. These negative side effects have a crucial impact on their health-related quality of life (HRQoL). To date, there is evidence that rehabilitation interventions such as physical activity and psychosocial support have a positive effect on the HRQoL of cancer survivors. Unfortunately, there are no specific guidelines for rehabilitation or survivorship programmes for MIBC survivors. Therefore, this systematic review aims to assess the effects of exercise-based and psychosocial rehabilitation interventions in MIBC survivors. METHODS AND ANALYSIS: The approach of this review is consistent with the Cochrane methodology. Randomized controlled trials and non-randomised studies will be included. The population of interest is patients (>=18 years of age) with diagnosis of MIBC or high-risk non MIBC for whom a radical cystectomy is indicated. There will be two eligible intervention types for inclusion: exercise-based and psychosocial rehabilitation interventions. The primary outcome measures are patient-reported outcomes (eg, HRQoL, fatigue and pain) and physical fitness. Studies will be identified independently by two review authors by searching the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science and the Physiotherapy Evidence Database. A third reviewer will be asked by disagreements. Risk of bias will be assessed using the Cochrane Collaboration tool and the Newcastle-Ottawa Scale. Data will be summarised descriptively. If homogeneity of the studies is sufficient, meta-analysis will be undertaken. The broad scope of this review (ie, different interventions and study designs) is needed to have a comprehensive view on effective rehabilitation interventions. ETHICS AND DISSEMINATION: Ethics approval is not required, as no primary data will be collected. Results will be disseminated through a peer-reviewed publication. PMID- 28592585 TI - A systematic review of alcohol screening and assessment measures for young people: a study protocol. AB - INTRODUCTION: Alcohol consumption creates a significant public health burden, and young people who drink alcohol place themselves at risk of harm. Expert guidance and reviews have highlighted the pressing need for reliable and valid, age appropriate alcohol screening and assessment measures for young people. The proposed systematic review will evaluate existing alcohol screening and assessment measures for young people aged 24 and under. METHODS AND ANALYSIS: Six electronic databases will be searched for published and grey literature. In addition, reverse and forward citation searching and consultation with experts will be performed. Three sets of search terms will be combined, including alcohol use/problems, young people and validation studies. The titles and abstracts of reports from the searches will be screened, and potentially relevant full-text reports will be retrieved and independently assessed for inclusion by two reviewers based on prespecified criteria. Discrete validation studies within included reports will then be assessed for eligibility. There will be an a priori basic quality threshold for predictive validity, internal and test-retest for studies to warrant full data extraction. Studies above the quality threshold will be assessed for quality using the modified consensus-based standards for the selection of health measurement instruments checklist and a quality assessment tool for diagnostic accuracy studies. DISSEMINATION: This review will highlight the best performing measures both for screening and assessment based on their psychometric properties and the quality of the validation studies supporting their use. Providing clear guidance on which existing measures perform best to screen and assess alcohol use and problems in young people will inform policy, practice and decision-making, and clarify the need for further research. TRIAL REGISTRATION NUMBER: International Prospective Register of Systematic Reviews, CRD42016053330. PMID- 28592586 TI - Correction. PMID- 28592584 TI - Utilising advance care planning videos to empower perioperative cancer patients and families: a study protocol of a randomised controlled trial. AB - INTRODUCTION: Despite positive health outcomes associated with advance care planning (ACP), little research has investigated the impact of ACP in surgical populations. Our goal is to evaluate how an ACP intervention video impacts the patient centredness and ACP of the patient-surgeon conversation during the presurgical consent visit. We hypothesise that patients who view the intervention will engage in a more patient-centred communication with their surgeons compared with patients who view a control video. METHODS AND ANALYSIS: Randomised controlled superiority trial of an ACP video with two study arms (intervention ACP video and control video) and four visits (baseline, presurgical consent, postoperative 1 week and postoperative 1 month). Surgeons, patients, principal investigator and analysts are blinded to the randomisation assignment. SETTING: Single, academic, inner city and tertiary care hospital. Data collection began July 16, 2015 and continues to March 2017. PARTICIPANTS: Patients recruited from nine surgical oncology clinics who are undergoing major cancer surgery. INTERVENTIONS: In the intervention arm, patients view a patient preparedness video developed through extensive engagement with patients, surgeons and other stakeholders. Patients randomised to the control arm viewed an informational video about the hospital surgical programme. MAIN OUTCOMES AND MEASURES: Primary Outcome: Patient centredness and ACP of patient-surgeon conversations during the presurgical consent visit as measured through the Roter Interaction Analysis System. SECONDARY OUTCOMES: patient Hospital Anxiety and Depression Scale score; patient goals of care; patient, companion and surgeon satisfaction; video helpfulness; medical decision maker designation; and the frequency patients watch the video. Intent-to-treat analysis will be used to assess the impact of video assignment on outcomes. Sensitivity analyses will assess whether there are differential effects contingent on patient or surgeon characteristics. ETHICS AND DISSEMINATION: This study has been approved by the Johns Hopkins School of Medicine institutional review board and is registered on clinicaltrials.gov (NCT02489799, First received: July 1, 2015). TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT02489799. PMID- 28592588 TI - Fake peer review - too good to be true. PMID- 28592590 TI - Respite for 2-Dimensional Right Ventricular Imaging? PMID- 28592589 TI - Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models. AB - BACKGROUND: Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension. METHODS AND RESULTS: From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49+/-14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class >=III, and mean pulmonary vascular resistance was 11.2+/-6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9+/-2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N Terminal Pro-B-Type Natriuretic Peptide) were retained (chi2, 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics. CONCLUSIONS: RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension. PMID- 28592587 TI - Linaclotide activates guanylate cyclase-C/cGMP/protein kinase-II-dependent trafficking of CFTR in the intestine. AB - The transmembrane receptor guanylyl cyclase-C (GC-C), expressed on enterocytes along the intestine, is the molecular target of the GC-C agonist peptide linaclotide, an FDA-approved drug for treatment of adult patients with Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation. Polarized human colonic intestinal cells (T84, CaCo-2BBe) rat and human intestinal tissues were employed to examine cellular signaling and cystic fibrosis transmembrane conductance regulator (CFTR)-trafficking pathways activated by linaclotide using confocal microscopy, in vivo surface biotinylation, and protein kinase-II (PKG II) activity assays. Expression and activity of GC-C/cGMP pathway components were determined by PCR, western blot, and cGMP assays. Fluid secretion as a marker of CFTR cell surface translocation was determined using in vivo rat intestinal loops. Linaclotide treatment (30 min) induced robust fluid secretion and translocation of CFTR from subapical compartments to the cell surface in rat intestinal loops. Similarly, linaclotide treatment (30 min) of T84 and CaCo-2BBe cells increased cell surface CFTR levels. Linaclotide-induced activation of the GC-C/cGMP/PKGII signaling pathway resulted in elevated intracellular cGMP and pVASPser239 phosphorylation. Inhibition or silencing of PKGII significantly attenuated linaclotide-induced CFTR trafficking to the apical membrane. Inhibition of protein kinase-A (PKA) also attenuated linaclotide-induced CFTR cell surface trafficking, implying cGMP-dependent cross-activation of PKA pathway. Together, these findings support linaclotide-induced activation of the GC-C/cGMP/PKG-II/CFTR pathway as the major pathway of linaclotide-mediated intestinal fluid secretion, and that linaclotide-dependent CFTR activation and recruitment/trafficking of CFTR from subapical vesicles to the cell surface is an important step in this process. PMID- 28592591 TI - Identification of High-Risk Patients After ST-Segment-Elevation Myocardial Infarction: Comparison Between Angiographic and Magnetic Resonance Parameters. AB - BACKGROUND: The incidence of angiographic no reflow (NR) and microvascular obstruction (MVO) at cardiac magnetic resonance is significantly different. The aim of this study was to investigate the occurrence of NR and MVO in a cohort of consecutive patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary interventions. METHODS AND RESULTS: In this prospective study, 88 consecutive ST-segment-elevation myocardial infarction patients were enrolled within 12 hours from symptoms onset. All patients underwent cardiac magnetic resonance between 2 and 5 days after primary percutaneous coronary interventions. NR was defined as thrombolysis in myocardial infarction flow grade <=2 and as myocardial blush grade <2. Presence of early or late MVO was assessed 4 and 10 to 15 minutes after gadolinium injection. Thirty one patients (36%) had evidence of NR, whereas 58 (67%) had MVO. One NR patient did not have MVO. In contrast, NR was present in 30 of 58 MVO patients. MVO patients had higher troponin T peak (P<0.0001), larger late gadolinium enhancement area (P<0.0001), and lower left ventricular ejection fraction (P<0.001) because of an increased end-systolic volume (P=0.015). In contrast, patients with NR had higher troponin T peak (P=0.006) but similar late gadolinium enhancement area (P=0.24) compared with those without NR. Major cardiovascular adverse events-free survival was worse in patients with MVO (P=0.014), although it was similar in patients with and without NR (P=0.33). The independent predictors of major cardiovascular adverse events were MVO (hazard ratio, 3.418; P=0.046) and ischemic time (hazard ratio, 1.016; P<0.001). MVO was a strong predictor of target lesion revascularization occurrence (P=0.017 for log-rank test). CONCLUSIONS: Compared with coronary angiography performed soon after recanalization of the culprit artery, cardiac magnetic resonance performed during index hospitalization provides better prognostic stratification of ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary interventions. Another novel finding of our study is a significantly increased rate of clinically driven target lesion revascularization in the index event culprit vessel in patients with MVO. PMID- 28592594 TI - Arterial Loading and the Prevention of Atrial Dysfunction. PMID- 28592595 TI - Coronary Microvascular Obstruction: Key Factor in the Prognosis of ST-Segment Elevation Myocardial Infarction. PMID- 28592593 TI - Aortic Cross-Sectional Area/Height Ratio and Outcomes in Patients With Bicuspid Aortic Valve and a Dilated Ascending Aorta. AB - BACKGROUND: In patients with bicuspid aortic valve and dilated proximal ascending aorta, we sought to assess (1) factors associated with increased longer-term cardiovascular mortality and (2) incremental prognostic use of indexing aortic root to patient height. METHODS AND RESULTS: We studied 969 consecutive bicuspid aortic valve patients (50+/-13 years; 87% men) with proximal aorta >=4 cm, who also had a gated contrast-enhanced thoracic computed tomography or magnetic resonance angiography. A ratio of ascending aortic area/height was calculated on tomography, and >=10 cm2/m was considered abnormal, as previously reported. Society of Thoracic Surgeons score and cardiovascular death were recorded. Greater than or equal to III+ aortic regurgitation and severe aortic stenosis were seen in 37% and 10%, respectively. Society of Thoracic Surgeons score and right ventricular systolic pressure were 2+/-3 and 15+/-16 mm Hg, respectively. Abnormal ascending aortic area/height ratio was noted in 33%; 44% underwent ascending aortic surgery at 34 days. At 10.8 years (interquartile range, 9.6 12.3), 82 (9%) died (0.4% in-hospital postoperative mortality). On multivariable Cox survival analysis, ascending aortic area/height ratio (hazard ratio, 2; 95% confidence interval, 1.20-3.35) was associated with cardiovascular death, whereas aortic surgery (hazard ratio, 0.46; confidence interval, 0.26-0.80) was associated with improved survival (both P<0.01). Of the 405 patients with ascending aortic diameter of 4.5 to 5.5 cm, 64% had an abnormal ascending aortic area/height ratio, and 70% deaths occurred in patients with an abnormal ratio. CONCLUSIONS: In bicuspid aortic valve patients with dilated proximal ascending aorta, ascending aortic area/height ratio was independently associated with cardiovascular death. PMID- 28592592 TI - Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in Hypertension. AB - BACKGROUND: Late systolic load has been shown to cause diastolic dysfunction in animal models. Although the systolic loading sequence of the ventricular myocardium likely affects its coupling with the left atrium (LA), this issue has not been investigated in humans. We aimed to assess the relationship between the myocardial loading sequence and LA function in human hypertension. METHODS AND RESULTS: We studied 260 subjects with hypertension and 19 normotensive age- and sex-matched controls. Time-resolved central pressure and left ventricular geometry were measured with carotid tonometry and cardiac magnetic resonance imaging, respectively, for computation of time-resolved ejection-phase myocardial wall stress (MWS). The ratio of late/early ejection-phase MWS time integrals was computed as an index of late systolic myocardial load. Atrial mechanics were measured with cine-steady-state free-precession magnetic resonance imaging using feature-tracking algorithms. Compared with normotensive controls, hypertensive participants demonstrated increased late/early ejection-phase MWS and reduced LA function. Greater levels of late/early ejection-phase MWS were associated with reduced LA conduit, reservoir, and booster pump LA function. In models that included early and late ejection-phase MWS as independent correlates of LA function, late systolic MWS was associated with lower, whereas early systolic MWS was associated with greater LA function, indicating an effect of the relative loading sequence (late versus early MWS) on LA function. These relationships persisted after adjustment for multiple potential confounders. CONCLUSIONS: A myocardial loading sequence characterized by prominent late systolic MWS was independently associated with atrial dysfunction. In the context of available experimental data, our findings support the deleterious effects of late systolic loading on ventricular-atrial coupling. PMID- 28592596 TI - Indexed Aortic Area in Bicuspid Valve Disease: An Important Step Toward a More Personalized Approach to Risk Prediction and Clinical Decision Making. PMID- 28592597 TI - Trends in added sugars from packaged beverages available and purchased by US households, 2007-2012. AB - Background: The US Food and Drug Administration's updated nutrition labeling requirements will include added sugars starting in July 2018, but no measure currently exists to identify the added sugar content of products and what it represents among purchases. Beverages are one of the first targets for reducing added sugar consumption, and hence are the focus here.Objective: Our goal was to estimate trends in added sugars in nonalcoholic packaged beverage products available in the United States and to estimate amounts of added sugars obtained from these beverages given the purchases of US households overall and by subpopulations.Design: On the basis of nutrition label data from multiple sources, we used a stepwise approach to derive the added sugar content of 160,713 beverage products recorded as purchased by US households in 2007-2012 (345,193 observations from 110,539 unique households). We estimated the amounts of added sugars obtained from packaged beverages US households reported buying in 2007 2008, 2009-2010, and 2011-2012, overall and by subpopulations based on household composition, race/ethnicity, and income. The key outcomes are added sugars in terms of per capita grams per day and the percentage of calories from packaged beverages.Results: Packaged beverages alone account for per capita consumption of 12 g/d of added sugars purchased by US households in 2007-2012, representing 32 48% of calories from packaged beverages. Whereas the absolute amount of added sugars from beverages has not changed meaningfully over time, the relative contribution of added sugars to calories from beverages has increased. Non Hispanic black households and low-income households obtain both higher absolute and relative amounts of added sugars from beverages than non-Hispanic white households and high-income households (all P < 0.01).Conclusions: These results provide measures of added sugars from packaged beverages at both the product level and the population level in the United States and can be used for comparisons after the revised nutrition labels are implemented and for future monitoring. PMID- 28592598 TI - Twenty-year trends in dietary patterns in French-speaking Switzerland: toward healthier eating. AB - Background: Dietary patterns provide a summary of dietary intake, but to our knowledge, few studies have assessed trends in dietary patterns in the population.Objective: The aim was to assess 20-y trends in dietary patterns in a representative sample of the Geneva, Switzerland, population with the consideration of age, sex, education, and generation.Design: Repeated, independent cross-sectional studies were conducted between 1993 and 2014. Dietary intake was assessed by using a validated food-frequency questionnaire. Dietary patterns were assessed by using principal components analyses.Results: Among 18,763 adults, 1 healthy ("fish and vegetables") and 2 unhealthy ("meat and chips" and "chocolate and sweets") patterns were identified. Scores for the "fish and vegetables" pattern increased, whereas the "meat and chips" and "chocolate and sweets" pattern scores decreased in both sexes and across all age groups. The stronger increase in the "fish and vegetables" pattern score among the less well educated participants led to a narrowing of educational differences (mean +/- SD scores in 1993: -0.56 +/- 1.39 compared with -0.05 +/- 1.58 in low- compared with highly educated groups, respectively; P < 0.001; scores in 2014: 0.28 +/- 1.64 compared with 0.24 +/- 1.83, respectively; P = 0.772). Generational analysis showed that older age groups tended to show smaller changes than younger age groups: the yearly score change in "chocolate and sweets" was -0.021 (95% CI: 0.027, -0.014; P < 0.001) for the 35- to 44-y cohort compared with -0.002 (95% CI: -0.009, 0.005; P = 0.546) for the 45- to 54-y cohort.Conclusions: Three dietary patterns were identified; scores for the "fish and vegetables" pattern increased, whereas the "meat and chips" and the "chocolate and sweets" pattern scores decreased. The stronger increases in the "fish and vegetables" pattern score among the less well-educated participants led to a smaller difference in dietary intake across the different educational levels. PMID- 28592599 TI - Modeled dietary impact of industry-wide food and beverage reformulations in the United States and France. AB - Background: Food reformulation has been identified as a strategy to improve nutritional intakes; however, little is known about the potential impact of industry-wide reformulations.Objective: The aim of the study was to model the dietary impact of food and beverage reformulation following the Nestle Nutritional Profiling System (NNPS) standards for children, adolescents, and adults in the United States and France.Design: Dietary intakes of individuals aged >=4 y were retrieved from nationally representative surveys: the US NHANES 2011-2012 (n = 7456) and the French Individual and National Survey on Food Consumption (n = 3330). The composition of all foods and beverages consumed were compared with the NNPS standards for energy, total and saturated fats, sodium, added sugars, protein, fiber, and calcium. Two scenarios were modeled. In the first, the nutrient content of foods and beverages was adjusted to the NNPS standards if they were not met. In the second, products not meeting the standards were replaced by the most nutritionally similar alternative meeting the standards from the same category. Dietary intakes were assessed against local nutrient recommendations, and analyses were stratified by body mass index and socioeconomic status.Results: Scenarios 1 and 2 showed reductions in US adults' mean daily energy (-88 and -225 kcal, respectively), saturated fats (-4.2, -6.9 g), sodium (-406, -324 mg), and added sugars (-29.4, -35.8 g). Similar trends were observed for US youth and in France. The effects on fiber and calcium were limited. In the United States, the social gradient of added sugars intake was attenuated in both scenarios compared with the baseline values.Conclusions: Potential industry-wide reformulation of the food supply could lead to higher compliance with recommendations in both the United States and France, and across all socioeconomic groups. NNPS standards seemed to be especially effective for nutrients consumed in excess. PMID- 28592601 TI - The Enhanced Recovery After Surgery (ERAS) program: benefit and concerns. PMID- 28592600 TI - Association between noncow milk beverage consumption and childhood height. AB - Background: Cow milk consumption in childhood has been associated with increased height, which is an important measure of children's growth and development. Many parents are choosing noncow milk beverages such as soy and almond milk because of perceived health benefits. However, noncow milk contains less protein and fat than cow milk and may not have the same effect on height.Objective: We sought to determine whether there is an association between noncow milk consumption and lower height in childhood and assess whether cow milk consumption mediates the relation between noncow milk consumption and height.Design: This was a cross sectional study of 5034 healthy Canadian children aged 24-72 mo enrolled in the Applied Research Group for Kids cohort. The primary exposure was the volume of noncow milk consumption (number of 250-mL cups per day). The primary outcome was height, which was measured as height-for-age z score. Multivariable linear regression was used to determine the association between noncow milk consumption and height. A mediation analysis was conducted to explore whether cow milk consumption mediated the association between noncow milk consumption and height.Results: There was a dose-dependent association between higher noncow milk consumption and lower height (P < 0.0001). For each daily cup of noncow milk consumed, children were 0.4 cm (95% CI: 0.2, 0.8 cm) shorter. In the mediation analysis, lower cow milk consumption only partially mediated the association between noncow milk consumption and lower height. The height difference for a child aged 3 y consuming 3 cups noncow milk/d relative to 3 cups cow milk/d was 1.5 cm (95% CI: 0.8, 2.0 cm).Conclusions: Noncow milk consumption was associated with lower childhood height. Future research is needed to understand the causal relations between noncow milk consumption and height. PMID- 28592602 TI - Cholecystokinin responsiveness varies across the population dependent on metabolic phenotype. AB - Background: Cholecystokinin (CCK) is an important satiety factor, acting at type 1 receptors (CCK1Rs) on vagal afferent neurons; however, CCK agonists have failed clinical trials for obesity. We postulated that CCK1R function might be defective in such patients due to abnormal membrane composition, such as that observed in cholesterol gallstone disease.Objective: Due to the challenges in directly studying CCK1Rs relevant to appetite control, our goal was to develop and apply a method to determine the impact of a patient's own cellular environment on CCK stimulus-activity coupling and to determine whether CCK sensitivity correlated with the metabolic phenotype of a high-risk population.Design: Wild-type CCK1Rs were expressed on leukocytes from 112 Hispanic patients by using adenoviral transduction and 24-h culture, with quantitation of cholesterol composition and intracellular calcium responses to CCK. Results were correlated with clinical, biochemical, and morphometric characteristics.Results: Broad ranges of cellular cholesterol and CCK responsiveness were observed, with elevated cholesterol correlated with reduced CCK sensitivity. This was prominent with increasing degrees of obesity and the presence of diabetes, particularly when poorly controlled. No single standard clinical metric correlated directly with CCK responsiveness. Reduced CCK sensitivity best correlated with elevated serum triglycerides in normal-weight participants and with low HDL concentrations and elevated glycated hemoglobin in obese and diabetic patients.Conclusions: CCK responsiveness varies widely across the population, with reduced signaling in patients with obesity and diabetes. This could explain the failure of CCK agonists in previous clinical trials and supports the rationale to develop corrective modulators to reverse this defective servomechanism for appetite control. This trial was registered at www.clinicaltrials.gov as NCT03121755. PMID- 28592603 TI - Chronic fructose substitution for glucose or sucrose in food or beverages has little effect on fasting blood glucose, insulin, or triglycerides: a systematic review and meta-analysis. AB - Background: Conflicting evidence exists on the role of long-term fructose consumption on health. No systematic review has addressed the effect of isoenergetic fructose replacement of other sugars and its effect on glycated hemoglobin (HbA1c), fasting blood glucose, insulin, and triglycerides.Objective: The objective of this study was to review the evidence for a reduction in fasting glycemic and insulinemic markers after chronic, isoenergetic replacement of glucose or sucrose in foods or beverages by fructose. The target populations were persons without diabetes, those with impaired glucose tolerance, and those with type 2 diabetes.Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials of isoenergetic replacement of glucose, sucrose, or both by fructose in adults or children with or without diabetes of >=2 wk duration that measured fasting blood glucose. The main outcomes analyzed were fasting blood glucose and insulin as well as fasting triglycerides, blood lipoproteins, HbA1c, and body weight.Results: We included 14 comparison arms from 11 trials, including 277 patients. The studies varied in length from 2 to 10 wk (mean: 28 d) and included doses of fructose between 40 and 150 g/d (mean: 68 g/d). Fructose substitution in some subgroups resulted in significantly but only slightly lowered fasting blood glucose (-0.14 mmol/L; 95% CI: -0.24, -0.036 mmol/L), HbA1c [-10 g/L (95% CI: -12.90, -7.10 g/L; impaired glucose tolerance) and -6 g/L (95% CI: -8.47, -3.53 g/L; normoglycemia)], triglycerides (-0.08 mmol/L; 95% CI: -0.14, -0.02 mmol/L), and body weight (-1.40 kg; 95% CI: -2.07, 0.74 kg). There was no effect on fasting blood insulin or blood lipids.Conclusions: The evidence suggests that the substitution of fructose for glucose or sucrose in food or beverages may be of benefit to individuals, particularly those with impaired glucose tolerance or type 2 diabetes. However, additional high-quality studies in these populations are required. PMID- 28592604 TI - A methodologic framework for modeling and assessing biomarkers of environmental enteropathy as predictors of growth in infants: an example from a Peruvian birth cohort. AB - Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune function and causes decelerations in statural growth that manifest gradually over time.Objective: To illustrate an approach for assessing emerging biomarkers of EE, we separately assessed the associations between 3 such markers and subsequent nutritional status.Design: Stool samples were routinely collected between January 2010 and November 2014 from a cohort of 303 Peruvian infants and analyzed for concentrations of the biomarkers alpha-1-antitrypsin (AAT), myeloperoxidase, and neopterin. For each marker, a mixed-effects linear regression model was fitted for length-for-age z scores (LAZs) obtained from anthropometric assessments that incorporated covariate predictors, polynomial terms for age, and product interaction terms to test associations over varying lag lengths. The biomarkers' contribution to the models was assessed with the use of the likelihood ratio test and partial R2 statistics.Results: Test statistics for the combined inclusion of the 4-model terms that involved the biomarker were highly statistically significant for AAT (28.71; P < 0.0001) and myeloperoxidase (62.79; P < 0.0001) over a 3-mo lag and moderately so for neopterin (13.97; P = 0.0074). AAT and myeloperoxidase seemed to interact strongly with age, with the magnitude and direction of the effect varying considerably over the first 3 y of life. The largest proportion of the variance explained by any biomarker (2.8%) and the largest difference in LAZ predicted between the 5th and 95th percentile (0.25) was by myeloperoxidase over a 2-mo lag.Conclusions: Of the 3 fecal biomarkers studied, 2 that related to intestinal function-AAT and myeloperoxidase were associated with small but highly statistically significant differences in future statural growth trajectories in infants in this cohort, lending further evidence to the EE hypothesis that increased gut permeability and inflammation adversely affects subsequent nutritional status. This association exhibited a complex interaction with age. This trial was registered at clinicaltrials.gov as NCT02441426. PMID- 28592606 TI - High dietary phosphorus density is a risk factor for incident chronic kidney disease development in diabetic subjects: a community-based prospective cohort study. AB - Background: High serum phosphorus concentrations are associated with an increased risk of cardiovascular disease and progression of chronic kidney disease (CKD). However, the relation between dietary phosphorus intake and CKD development has not been well evaluated.Objective: In this study, we investigated the impact of dietary phosphorus density on the development of incident CKD in a cohort of subjects with normal renal function.Design: Data were retrieved from the Korean Genome and Epidemiology Study, a prospective community-based cohort study. The study cohort consisted of subjects aged 40-69 y, who were followed up biennially from 2001 to 2014. A total of 873 subjects with diabetes mellitus (DM) and 5846 subjects without DM (non-DM) were included in the final analysis. The primary endpoint was incident CKD, defined as a composite of estimated glomerular filtration rate <60 mL . min-1 . 1.73 m-2 and/or the development of proteinuria.Results: In the DM and non-DM groups, the mean ages of the participants were 55.6 +/- 8.7 and 51.4 +/- 8.6 y, the numbers of male subjects were 454 (52.0%) and 2784 (47.6%), and the mean estimated glomerular filtration rates were 91.6 +/- 14.0 and 94.5 +/- 14.0 mL . min-1 . 1.73 m-2, respectively. The mean values of dietary phosphorus density, defined as the ratio of a single day dietary phosphorus amount to the total daily calorie intake, were 0.51 +/- 0.08 mg/kcal in the DM group and 0.51 +/- 0.07 mg/kcal in the non-DM group. During the follow-up, CKD newly developed in 283 (32.4%) and 792 subjects (13.5%) in the DM and non-DM groups, respectively. When the subjects were divided into quartiles according to the dietary phosphorus density in each group, the highest quartile was significantly associated with the development of incident CKD by multiple Cox proportional hazard analysis in the DM group (P = 0.02) but not in the non-DM group (P = 0.72).Conclusions: High dietary phosphorus density is associated with an increased risk of CKD development in DM patients with normal renal function. The causality in this association needs to be tested in a randomized controlled trial. PMID- 28592608 TI - Nutrition in the elderly: a recommendation for more (evenly distributed) protein? PMID- 28592605 TI - Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct. AB - Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date.Objective: We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study.Design: We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution.Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (omega-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates.Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions. PMID- 28592607 TI - Maternal dietary intakes of refined grains during pregnancy and growth through the first 7 y of life among children born to women with gestational diabetes. AB - Background: Refined grains, a major source of dietary carbohydrates, have been related to impaired glucose homeostasis and obesity. Emerging animal data suggest that in utero exposure to dietary refined carbohydrates may predispose offspring to an obese phenotype, indicating a potential role for nutritional programming in the early origins of obesity, but intergenerational human data are lacking.Objective: We prospectively investigated refined-grain intake during pregnancy in association with offspring growth through age 7 y among high-risk children born to women with gestational diabetes mellitus (GDM).Design: The analysis included 918 mother-singleton child dyads from the Danish National Birth Cohort. Offspring body mass index z scores (BMIZs) were calculated by using weight and length or height measured at birth, 5 and 12 mo, and 7 y. Overweight or obesity was defined by WHO cutoffs. Linear and Poisson regressions were used, with adjustment for maternal demographic, lifestyle, and dietary factors.Results: Refined-grain intake during pregnancy was positively associated with offspring BMIZ (adjusted beta per serving increase per day: 0.09; 95% CI: 0.02, 0.15) and risk of overweight or obesity at age 7 y [adjusted RR (aRR) comparing the highest with the lowest quartile: 1.80; 95% CI: 1.09, 2.98; P-trend = 0.032]. The association appeared to be more pronounced among children who were breastfed <6 mo. The substitution of 1 serving refined grains/d with an equal serving of whole grains during pregnancy was related to a 10% reduced risk of offspring overweight or obesity at 7 y of age (aRR: 0.90; 95% CI: 0.82, 0.98). No associations were observed between refined-grain intake and infant growth.Conclusions: Higher maternal refined-grain intake during pregnancy was significantly related to a greater BMIZ and a higher risk of overweight or obesity at age 7 y among children born after pregnancies complicated by GDM. The findings highlight pregnancy as a potential window of susceptibility associated with offspring growth and obesity risk among this high-risk population. Data with longer follow-up are warranted. PMID- 28592609 TI - Tracking of vitamin D status from childhood to early adulthood and its association with peak bone mass. AB - Background: To our knowledge, there are few longitudinal studies of vitamin D status from childhood to early adulthood, and it is uncertain whether vitamin D predicts peak bone mass in young adults.Objectives: The purpose of this longitudinal study was to evaluate the long-term stability of vitamin D status from ages 6 to 20 y in healthy individuals and to study associations between serum 25-hydroxyvitamin D [25(OH)D] at different developmental stages and bone mass measured at age 20 y.Design: Participants were offspring of the Western Australian Pregnancy Cohort (Raine) study. Serum 25(OH)D was assessed at ages 6, 14, 17, and 20 y, and whole-body bone mineral content (BMC) and bone mineral density (BMD) were measured at age 20 y through the use of dual-energy X-ray absorptiometry (DXA). Our analysis included 821 participants (385 females) who had >=3 serum 25(OH)D measures and DXA data. We used latent class growth analysis and identified 4 vitamin D status trajectories: consistently lower (n = 259), decreasing (n = 125), increasing (n = 138), and consistently higher (n = 299).Results: There were significant correlations between serum 25(OH)D concentrations at different time points in both sexes (r = 0.346-0.560, P < 0.001), with stronger correlations at adjacent time points. In males, but not in females, serum 25(OH)D at ages 6, 17, and 20 y was positively associated with total-body BMC and BMD at age 20 y [covariate-adjusted increments of 40.7-53.9 g and 14.7-18.6 mg/cm2, respectively, per 25 nmol/L 25(OH)D]; when 25(OH)D at all 4 ages was included in the same model, the concentration at age 6 y remained significant. Males in the "consistently higher" trajectory had 3.2-3.4% higher total body BMC and BMD than those who were in the "consistently lower" trajectory, accounting for age and anthropometric and lifestyle factors.Conclusions: Within both sexes, there are moderate associations between vitamin D status measured in prepuberty, adolescence, and early adulthood. Vitamin D status in childhood is a significant predictor of peak bone mass in male but not female subjects. PMID- 28592611 TI - Fructose replacement of glucose or sucrose in food or beverages lowers postprandial glucose and insulin without raising triglycerides: a systematic review and meta-analysis. AB - Background: Conflicting evidence exists on the effects of fructose consumption in people with type 1 and type 2 diabetes mellitus. No systematic review has addressed the effect of isoenergetic fructose replacement of glucose or sucrose on peak postprandial glucose, insulin, and triglyceride concentrations.Objective: The objective of this study was to review the evidence for postprandial glycemic and insulinemic responses after isoenergetic replacement of either glucose or sucrose in foods or beverages with fructose.Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials measuring peak postprandial glycemia after isoenergetic replacement of glucose, sucrose, or both with fructose in healthy adults or children with or without diabetes. The main outcomes analyzed were peak postprandial blood glucose, insulin, and triglyceride concentrations.Results: Replacement of either glucose or sucrose by fructose resulted in significantly lowered peak postprandial blood glucose, particularly in people with prediabetes and type 1 and type 2 diabetes. Similar results were obtained for insulin. Peak postprandial blood triglyceride concentrations did not significantly increase.Conclusions: Strong evidence exists that substituting fructose for glucose or sucrose in food or beverages lowers peak postprandial blood glucose and insulin concentrations. Isoenergetic replacement does not result in a substantial increase in blood triglyceride concentrations. PMID- 28592610 TI - Adult height, dietary patterns, and healthy aging. AB - Background: Adult height has shown directionally diverse associations with several age-related disorders, including cardiovascular disease, cancer, decline in cognitive function, and mortality.Objective: We investigated the associations of adult height with healthy aging measured by a full spectrum of health outcomes, including incidence of chronic diseases, memory, physical functioning, and mental health, among populations who have survived to older age, and whether lifestyle factors modified such relations.Design: We included 52,135 women (mean age: 44.2 y) from the Nurses' Health Study without chronic diseases in 1980 and whose health status was available in 2012. Healthy aging was defined as being free of 11 major chronic diseases and having no reported impairment of subjective memory, physical impairment, or mental health limitations.Results: Of all eligible study participants, 6877 (13.2%) were classified as healthy agers. After adjustment for demographic and lifestyle factors, we observed an 8% (95% CI: 6%, 11%) decrease in the odds of healthy aging per SD (0.062 m) increase in height. Compared with the lowest category of height (<=1.57 m), the OR of achieving healthy aging in the highest category (>=1.70 m) was 0.80 (95% CI: 0.73, 0.87; P trend < 0.001). In addition, we found a significant interaction of height with a prudent dietary pattern in relation to healthy aging (P-interaction = 0.005), and among the individual dietary factors characterizing the prudent dietary pattern, fruit and vegetable intake showed the strongest effect modification (P interaction = 0.01). The association of greater height with reduced odds of healthy aging appeared to be more evident among women with higher adherence to the prudent dietary pattern rich in vegetable and fruit intake.Conclusions: Greater height was associated with a modest decrease in the likelihood of healthy aging. A prudent diet rich in fruit and vegetables might modify the relation. PMID- 28592612 TI - Fried potato consumption is associated with elevated mortality: an 8-y longitudinal cohort study. AB - Background: Few studies have assessed the association between potato consumption and mortality.Objective: We investigated whether potato consumption (including fried and unfried potatoes) is associated with increased premature mortality risk in a North American cohort.Design: A longitudinal analysis included 4440 participants aged 45-79 y at baseline with an 8-y follow-up from the Osteoarthritis Initiative cohort study. Potato consumption (including fried and unfried potatoes) was analyzed by using a Block Brief 2000 food-frequency questionnaire and categorized as <=1 time/mo, 2-3 times/mo, 1 time/wk, 2 times/wk, or >=3 times/wk. Mortality was ascertained through validated cases of death. To investigate the association between potato consumption and mortality, Cox regression models were constructed to estimate HRs with 95% CIs, with adjustment for potential confounders.Results: Of the 4400 participants, 2551 (57.9%) were women with a mean +/- SD age of 61.3 +/- 9.2 y. During the 8-y follow-up, 236 participants died. After adjustment for 14 potential baseline confounders, and taking those with the lowest consumption of potatoes as the reference group, participants with the highest consumption of potatoes did not show an increased risk of overall mortality (HR: 1.11; 95% CI: 0.65, 1.91). However, subgroup analyses indicated that participants who consumed fried potatoes 2-3 times/wk (HR: 1.95; 95% CI: 1.11, 3.41) and >=3 times/wk (HR: 2.26; 95% CI: 1.15, 4.47) were at an increased risk of mortality. The consumption of unfried potatoes was not associated with an increased mortality risk.Conclusions: The frequent consumption of fried potatoes appears to be associated with an increased mortality risk. Additional studies in larger sample sizes should be performed to confirm if overall potato consumption is associated with higher mortality risk. This trial was registered at clinicaltrials.gov as NCT00080171. PMID- 28592613 TI - Diagnosis and assessment of dilated cardiomyopathy: a guideline protocol from the British Society of Echocardiography. AB - Heart failure (HF) is a debilitating and life-threatening condition, with 5-year survival rate lower than breast or prostate cancer. It is the leading cause of hospital admission in over 65s, and these admissions are projected to rise by more than 50% over the next 25 years. Transthoracic echocardiography (TTE) is the first-line step in diagnosis in acute and chronic HF and provides immediate information on chamber volumes, ventricular systolic and diastolic function, wall thickness, valve function and the presence of pericardial effusion, while contributing to information on aetiology. Dilated cardiomyopathy (DCM) is the third most common cause of HF and is the most common cardiomyopathy. It is defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of abnormal loading conditions (hypertension and valve disease) or coronary artery disease sufficient to cause global systolic impairment. This document provides a practical approach to diagnosis and assessment of dilated cardiomyopathy that is aimed at the practising sonographer. PMID- 28592614 TI - Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. AB - GW405833, widely accepted as a cannabinoid receptor 2 (CB2) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB1) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB1 antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB2 and CB1 knockout (KO) mice, their respective wild-type (WT) mice, and both CB2 and CB1 antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CB2KO mice and absent in CB1KO mice. Furthermore, the antiallodynic efficacy of GW405833 (30 mg/kg i.p.) was completely blocked by the CB1 antagonist rimonabant (10 mg/kg i.p.) but not by the CB2 antagonist SR144528 (10 mg/kg i.p.). Thus, the antinociceptive properties of GW405833 are dependent on CB1 receptors. GW405833 (30 mg/kg i.p.) was also inactive in a tetrad of tests measuring cardinal signs of CB1 activation. Additionally, unlike rimonabant (10 mg/kg i.p.), GW405833 (10 mg/kg, i.p.) did not act as a CB1 antagonist in vivo to precipitate withdrawal in mice treated chronically with Delta9-tetrahydrocannabinol. The present results suggest that the antiallodynic efficacy of GW405833 is CB1-dependent but does not seem to involve engagement of the CB1 receptor's orthosteric site. PMID- 28592617 TI - The Patients We Have to See. PMID- 28592615 TI - A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS. AB - LESSONS LEARNED: Cobimetinib and duligotuzumab were well tolerated as single agents and in combination with other agents.The cobimetinib and duligotuzumab combination was associated with increased toxicity, most notably gastrointestinal, and limited efficacy in the patient population tested. BACKGROUND: KRAS-mutant tumors possess abnormal mitogen-activated protein kinases (MAPK) pathway signaling, leading to dysregulated cell proliferation. Cobimetinib blocks MAPK signaling. The dual-action antibody duligotuzumab (MEHD7945A) inhibits ligand binding to both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). Blockade of EGFR/HER3 and inhibition of mitogen-activated protein kinase (MEK) in KRAS-mutant tumors may provide additive benefit. METHODS: Patients with KRAS-mutant solid tumors were eligible for this phase Ib dose-escalation study with a planned expansion phase. Duligotuzumab was given intravenously (IV) at 1,100 mg every 2 weeks (q2w), while cobimetinib was given orally in a standard 3 + 3 design to identify the recommended phase II dose (RP2D). The primary objective was to evaluate the safety and tolerability of this combination. RESULTS: Twenty-three patients were enrolled. Dose-limiting toxicities (DLTs) included grade 4 hypokalemia and grade 3 mucosal inflammation, asthenia, and dermatitis acneiform. Seventy percent of patients experienced grade 3 or worse adverse events (AEs). Five (22%) and 12 (52%) patients missed at least 1 dose of duligotuzumab and cobimetinib, respectively, and 9 (39%) patients required a cobimetinib dose reduction. Three (13%) patients discontinued due to an AE. Best response was limited to 9 patients with stable disease and 13 patients with progressive disease. CONCLUSION: Given the limited tolerability and efficacy of this combination, the study did not proceed to expansion stage and closed for enrollment. PMID- 28592616 TI - Multicenter Phase II Study of Panitumumab in Platinum Pretreated, Advanced Head and Neck Squamous Cell Cancer. AB - LESSONS LEARNED: Panitumumab shows activity in terms of disease control rate and preventing disease progression but not for tumor shrinkage in head and neck squamous cell cancer for second-line treatment. Epidermal growth factor receptor (EGFR) copy number gain, a property of tumor cells that theoretically could identify patients more likely to experience disease response, was common among patients having disease control.Our trial, given the lower toxicity with an every 2-week schedule, provides guidance for future trials, for example, in combinations of immune therapies and anti-EGFR-antibodies. BACKGROUND: The objective of this study was to investigate the efficacy and safety of panitumumab (anti-epidermal growth factor receptor [EGFR] antibody) given as a single agent in platinum-pretreated head and neck squamous cell cancer (HNSCC). METHODS: Patients with advanced HNSCC previously treated with platinum-containing therapy were included. Panitumumab was administered intravenously every 2 weeks at a dose of 6 mg/kg. Primary endpoint was overall response rate (ORR) according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1; secondary endpoints were progression-free survival (PFS) and safety. A Simon's two-step design was chosen; 4 partial remissions (PR) in the first 32 patients were required for continuing to step two. An exploratory biomarker analysis was performed. RESULTS: Thirty-three patients were enrolled. Two patients obtained a PR for an ORR of 6%, and 15 (45%) showed stable disease (SD) for at least 2 months, resulting in a 51% disease control rate. Median PFS was 2.6 months (95% confidence interval [CI]: 1.7-3.7), while median OS was 9.7 months (95% CI: 6.3 17.2). The most frequent adverse drug reactions were cutaneous rash (64%) and hypomagnesemia (55%). Overall, 30% of patients experienced grade 3/4 adverse events. No infusion-related reactions occurred. EGFR copy number gain (CNG) was more frequent in patients who benefitted from panitumumab. Two uncommon KRAS mutations (G48E, T50I) and 3 canonical PIK3CA mutations (all E545K) were detected. High-risk HPV16 was found in 10 patients and EGFR CNG in 13 treated patients. EGFR CNG seems to be more frequent in individuals with at least SD compared with patients with progressive disease (59% vs. 30%). PFS for patients with EGFR CNG was 4.6 months (95% CI: 1.0-9.2 months) and 1.9 months (95% CI: 1.0 3.2 months) for patients without CNG (p = .02). CONCLUSION: Panitumumab monotherapy in pretreated HNSCC patients was well tolerated but moderately active. We observed a considerable disease control rate. Future strategies with this agent comprise right patient selection through the identification of reliable biomarkers and gene signatures predicting response and, considering good tolerability and convenience, combination strategies with novel agents and immune therapeutic agents. PMID- 28592618 TI - Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results. AB - BACKGROUND: VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first-line treatment regimen for patients with HER2-positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co-infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co-infused, followed by vinorelbine. PATIENTS AND METHODS: During cycle 1, patients with HER2-positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co-infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30-35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression-free survival (PFS) and safety. RESULTS: Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0-73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3-15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade >=3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure. CONCLUSION: These results support the feasibility of pertuzumab and trastuzumab co-infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160-1168 IMPLICATIONS FOR PRACTICE: Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first-line HER2-positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately. PMID- 28592619 TI - Incorporating Tumor Characteristics to the American Joint Committee on Cancer Breast Cancer Staging System. AB - BACKGROUND: The American Joint Committee on Cancer (AJCC) breast cancer staging system provides important prognostic information. The recently published eighth edition incorporates biological markers and recommends the use of a complex "prognostic stage." In this study, we assessed the relationship between stage, breast cancer subtype, grade, and outcome in a large population-based cohort and evaluated a risk score system incorporating tumor characteristic to the AJCC anatomic staging system. MATERIALS AND METHODS: Patients diagnosed with primary breast cancer stage I-IV between 2005-2008 were identified in the California Cancer Registry. For patients with stage I-III disease, pathologic stage was recorded. For patients with stage IV disease, clinical stage was utilized. Five year breast cancer specific survival (BCSS) and overall survival (OS) rates were determined for each potential tumor size-node involvement-metastases (TNM) combination according to breast cancer subtype. A risk score point-based system using grade, estrogen receptor, and human epidermal growth factor receptor 2 (HER2) status was designed to complement the anatomic AJCC staging system. Survival probabilities between groups were compared using log-rank test. Cox proportional hazards models were used. RESULTS: Among 43,938 patients, we observed differences in 5-year BCSS and OS for each TNM combination according to breast cancer subtype. The most favorable outcomes were seen for hormone receptor positive tumors followed closely by HER2-positive tumors, with the worst outcomes observed for triple negative breast cancer. Our risk score system separated patients into four risk groups within each stage category (all p < .05). CONCLUSION: Our simple risk score system incorporates biological factors into the AJCC anatomic staging system, providing accurate prognostic information. IMPLICATIONS FOR PRACTICE: This study demonstrates that stage, but also breast cancer subtype and grade, define prognosis in a large population of breast cancer patients. It shows that a point-based risk score system that incorporates these biological factors provides refined stratification and information on prognosis, improving the anatomic American Joint Committee on Cancer (AJCC) staging system. In addition, the overall mortality and breast cancer specific mortality rates detailed here provide much-needed information about prognosis in the current era, refining the current AJCC staging. PMID- 28592621 TI - Bevacizumab for Metastatic Colorectal Cancer: A Global Cost-Effectiveness Analysis. AB - BACKGROUND: In the U.S., the addition of bevacizumab to first-line chemotherapy in metastatic colorectal cancer (mCRC) has been demonstrated to provide 0.10 quality-adjusted life years (QALYs) at an incremental cost-effectiveness ratio (ICER) of $571,000/QALY. Due to variability in pricing, value for money may be different in other countries. Our objective was to establish the cost effectiveness of bevacizumab in mCRC in the U.S., U.K., Canada, Australia, and Israel. METHODS: We performed the analysis using a previously established Markov model for mCRC. Input data for efficacy, adverse events, and quality of life were considered to be generalizable and therefore identical for all countries. We used country-specific prices for medications, administration, and other health service costs. All costs were converted from local currency to U.S. dollars at the exchange rates in March 2016. We conducted one-way and probabilistic sensitivity analyses (PSA) to assess the model robustness across parameter uncertainties. RESULTS: Base case results demonstrated that the highest ICER was in the U.S. ($571,000/QALY) and the lowest was in Australia ($277,000/QALY). In Canada, the U.K., and Israel, ICERs ranged between $351,000 and $358,000 per QALY. PSA demonstrated 0% likelihood of bevacizumab being cost-effective in any country at a willingness to pay threshold of $150,000 per QALY. CONCLUSION: The addition of bevacizumab to first-line chemotherapy for mCRC consistently fails to be cost effective in all five countries. There are large differences in cost effectiveness between countries. This study provides a framework for analyzing the value of a cancer drug from the perspectives of multiple international payers. IMPLICATIONS FOR PRACTICE: The cost-effectiveness of bevacizumab varies significantly between multiple countries. By conventional thresholds, bevacizumab is not cost-effective in metastatic colon cancer in the U.S., the U.K., Australia, Canada, and Israel. PMID- 28592622 TI - Li-Fraumeni versus Pseudo-Li-Fraumeni Syndrome: Key Insights for Interpreting Next-Generation Sequencing Reports in Patients with Suspected Cancer Predisposition Syndromes. PMID- 28592623 TI - Amani's Silence. PMID- 28592620 TI - Phase II Study of First-Line Trebananib Plus Sorafenib in Patients with Advanced Hepatocellular Carcinoma. AB - LESSONS LEARNED: Trebananib leveraging anti-angiogenic mechanism that is distinct from the classic sorafenib anti-vascular endothelial growth factor inhibition did not demonstrate improved progression-free survival at 4 months in patients with advanced hepatocellular carcinoma (HCC).In support of previously reported high Ang-2 levels' association with poor outcome in HCC for patients, trebananib treatment with lower baseline Ang-2 at study entry was associated with improved overall survival to 22 months and may suggest future studies to be performed within the context of low baseline Ang-2. BACKGROUND: Ang-1 and Ang-2 are angiopoietins thought to promote neovascularization via activation of the Tie-2 angiopoietin receptor. Trebananib sequesters Ang-1 and Ang-2, preventing interaction with the Tie-2 receptor. Trebananib plus sorafenib combination has acceptable toxicity. Elevated Ang-2 levels are associated with poor prognosis in hepatocellular carcinoma (HCC). METHODS: Patients with HCC, Eastern Cooperative Oncology Group <=2, and Childs-Pugh A received IV trebananib at 10 mg/kg or 15 mg/kg weekly plus sorafenib 400 mg orally twice daily. The study was planned for >=78% progression-free survival (PFS) rate at 4 months relative to 62% for sorafenib historical control (power = 80% alpha = 0.20). Secondary endpoints included safety, tolerability, overall survival (OS), and multiple biomarkers, including serum Ang-2. RESULTS: Thirty patients were enrolled sequentially in each of the two nonrandomized cohorts. Demographics were comparable between the two arms and the historical controls. PFS rates at 4 months were 57% and 54% on the 10 mg/kg and 15 mg/kg trebananib cohorts, respectively. Median OS was 17 and 11 months, respectively. Grade 3 and above events noted in >=10% of patients included fatigue, hypertension, diarrhea, liver failure, palmar-plantar erythrodysesthesia syndrome, dyspnea, and hypophosphatemia. One death was due to hepatic failure. Serum Ang-2 dichotomized at the median was associated with improved OS in both cohorts. CONCLUSION: There was no improvement in PFS rate at 4 months in either cohort, when compared with sorafenib historical control. PMID- 28592624 TI - Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results. AB - LESSONS LEARNED: Difficulties in translating in vitro results into clinical practice are inevitable.Further efforts to verify the efficacy of alternative schedules of pemetrexed in solid tumors are encouraged. BACKGROUND: We investigated the cytotoxic activity of pemetrexed in combination with several drugs (gemcitabine, carboplatin, vinorelbine, and mitomycin C) using different exposure schedules in three colon cancer cell lines. The best results were obtained with the following schedule: a prolonged pemetrexed exposure followed by a 48-hour wash-out and then gemcitabine. This combination was then advanced to a phase II clinical trial. METHODS: Patients with metastatic colorectal cancer in progression after standard treatment were included in the study. Adequate bone marrow reserve, normal hepatic and renal function, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were required. Treatment consisted of an 8-hour intravenous infusion of pemetrexed 150 mg/m2 on day 1 and a 30-minute intravenous infusion of gemcitabine 1,000 mg/m2 on day 3 of each cycle, repeated every 14 days. RESULTS: Fourteen patients were enrolled onto the study (first step). No objective responses were seen, and evidence of stable disease was observed in only one of the 12 evaluable patients. The most important grade 3-4 side effects were hematological toxicity (neutropenia 64.2%, thrombocytopenia 71.4%, anemia 28.7%), fatigue (50.0%), and stomatitis (21.5%). Median overall survival and time to progression were 5.8 months (95% confidence interval [CI]: 3.9-7.1) and 2.1 months (95% CI: 1.7-2.8), respectively. CONCLUSION: The experimental pemetrexed-gemcitabine combination proved to be inactive and moderately toxic. PMID- 28592626 TI - Longitudinal IP-10 Serum Levels Are Associated with the Course of Disease Activity and Remission in Patients with Rheumatoid Arthritis. AB - Although rheumatoid arthritis (RA) is a chronic, persistent autoimmune disease, 10 to 15% of RA patients achieve sustained disease-modifying antirheumatic drug (DMARD)-free remission over time. The biological mechanisms underlying the resolution of persistent inflammation in RA are still unidentified, and there is a lack of prognostic markers. It is well established that increased serum levels of gamma interferon-induced protein 10 (IP-10) are associated with (acute) increased inflammatory responses (e.g., in leprosy). In order to assess the potential of IP-10 as a diagnostic tool for inflammatory episodes of RA, we performed a retrospective study and assessed IP-10 levels in longitudinally banked serum samples obtained from patients upon first diagnosis of RA. The selection consisted of 15 persistent RA patients and 19 patients who achieved DMARD-free sustained remission. IP-10 levels, measured by use of a user-friendly quantitative lateral flow assay (LFA), showed up to 170-fold variation interindividually, and baseline IP-10 levels could not be differentiated between the two patient groups. However, a difference in the change in IP-10 levels between the first and last visits (DeltaIP-10) was observed (P = 0.003) between DMARD-free (median DeltaIP-10, -662 pg/ml [decrease]) and persistent (median DeltaIP-10, 468 pg/ml [increase]) RA patients. Moreover, intraindividual changes in IP-10 levels during the course of disease corresponded to the disease activity score (DAS) (P = 0.05). These data indicate that IP-10 is associated with disease activity and perseverance of RA. The association of IP-10 with DAS indicates that this tool may be a practical diagnostic aid to help in monitoring disease progression in RA patients and may also find applications in other chronic diseases with exacerbated inflammatory episodes. PMID- 28592625 TI - Current Clinical Practice Guidelines for the Treatment of Renal Cell Carcinoma: A Systematic Review and Critical Evaluation. AB - : The landscape of local and systemic therapy of renal cell carcinoma (RCC) is rapidly changing. The increase in the incidental finding of small renal tumors has increased the application of nephron-sparing procedures, while ten novel agents targeting the vascular endothelial growth factor (VEGF) or the mammalian target of rapamycin pathways, or inhibiting the interaction of the programmed death 1 receptor with its ligand, have been approved since 2006 and have dramatically improved the prognosis of metastatic RCC (mRCC). These rapid developments have resulted in continuous changes in the respective Clinical Practice Guidelines/Expert Recommendations. We conducted a systematic review of the existing guidelines in MEDLINE according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement, aiming to identify areas of agreement and discrepancy among them and to evaluate the underlying reasons for such discrepancies. Data synthesis identified selection criteria for nonsurgical approaches in renal masses; the role of modern laparoscopic techniques in the context of partial nephrectomy; selection criteria for cytoreductive nephrectomy and metastasectomy in mRCC; systemic therapy of metastatic non-clear-cell renal cancers; and optimal sequence of available agents in mRCC relapsed after anti VEGF therapy as the major areas of uncertainty. Agreement or uncertainty was not always correlated with the availability of data from phase III randomized controlled trials. Our review suggests that the combination of systematic review and critical evaluation can define practices of wide applicability and areas for future research by identifying areas of agreement and uncertainty among existing guidelines. IMPLICATIONS FOR PRACTICE: Currently, there is uncertainity on the role of surgery in MRCC and on the choice of available guidelines in relapsed RCC. The best practice is individualization of targeted therapies. Systematic review of guidelines can help to identify unmet medical needs and areas of future research. PMID- 28592630 TI - Management of superficial venous thrombosis of the leg. AB - Although for many people superficial venous thrombosis of the leg is a benign self-limiting condition, for others it is a potentially serious problem associated with an increased risk of deep vein thrombosis and pulmonary embolism.1-4 Here, we consider some of the challenges associated with managing superficial venous thrombosis and review the evidence for non-surgical treatment options. PMID- 28592627 TI - Cytokines Are Markers of the Clostridium difficile-Induced Inflammatory Response and Predict Disease Severity. AB - The host immune response affects pathogen virulence in Clostridium difficile infection (CDI). Thus, cytokine responses to CDI likely are associated with disease initiation and progression. Understanding the molecular drivers of inflammation and biochemical markers of disease severity is important for developing novel therapies and predicting disease prognosis. In this study, we investigated cytokine production in patients with CDI and evaluated the potential of cytokines to serve as biomarkers for CDI and predictors of disease severity. The systemic cytokine profiles of 36 CDI patients (20 with severe disease) and 8 healthy donors and the toxin-induced cytokine profiles of peripheral blood mononuclear cells (PBMC) were determined. Further, we evaluated glucosyltransferase (GT) activity in regulation of toxin-induced cytokine expression. We found upregulation of the majority of measured cytokines (11/20, 55%) in CDI patients. Interleukin-1beta (IL-1beta), IL-6, IL-8, IL-17A, and IL-16 were the most upregulated. High serum levels of IL-2 and IL-15 were associated with a poor prognosis in CDI patients, whereas high levels of IL-5 and gamma interferon (IFN-gamma) were associated with less severe disease. Both TcdA and TcdB were potent inducers of cytokine responses, as demonstrated by stimulation of a greater number and amount of cytokines. In addition to confirming prior reports on the role of IL-8, IL-1beta, and IL-6 in CDI, our data suggest that IL 16 and IL-17A, as well as the IL-1beta/Th17 axis, play a key role in driving inflammatory responses in CDI. A functional GT domain of C. difficile toxins was required for the induction of a majority of cytokines investigated. PMID- 28592628 TI - Chemiluminescence Immunoassay for the Detection of Antibodies against the 2C and 3ABC Nonstructural Proteins Induced by Infecting Pigs with Foot-and-Mouth Disease Virus. AB - The potential diagnostic value of chemiluminescence immunoassays (CLIAs) has been accepted in recent years, although their use for foot-and-mouth disease (FMD) diagnostics has not been reported. Full-length 3ABC and 2C proteins were expressed in bacteria and purified by affinity chromatography to develop a rapid and accurate approach to distinguish pigs infected with foot-and-mouth disease virus (FMDV) from vaccinated pigs. The recombinant proteins were then used as antigens to develop two CLIAs for the detection of antibodies against nonstructural viral proteins. The diagnostic performance of the two assays was compared by analyzing serum from pigs (naive pigs, n = 63; vaccinated, uninfected pigs, n = 532; naive, infected pigs, n = 117) with a known infection status. The 3ABC-2C CLIA had a higher accuracy rate, with a diagnostic sensitivity of 100% and a diagnostic specificity of 96.5%, than the 3ABC CLIA, which had a diagnostic sensitivity of 95.7% and a diagnostic specificity of 96.0%. The results of the 3ABC-2C CLIA also had a high rate of concordance with those of two commercial FMDV enzyme-linked immunosorbent assay (ELISA) kits used to assess serum collected from 962 pigs in the field (96.2% and 97.8%, respectively). The 3ABC-2C CLIA detected infection in serum samples from infected pigs earlier than the commercial ELISA kits. In addition, the 3ABC-2C CLIA produced results within 15 min. On the basis of these findings, the 3ABC-2C CLIA could serve as the foundation for the development of penside FMD diagnostics and offers an alternative method to detect FMDV infections. PMID- 28592629 TI - Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions. AB - Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor burden increase from baseline had longer OS than patients with >=20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with <20% tumor burden increase during therapy had significantly reduced hazards of death [HR = 0.19; 95% confidence interval (CI), 0.08-0.43; P < 0.0001 univariate; HR = 0.18; 95% CI, 0.08-0.41; P < 0.0001, multivariable]. Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.Conclusions: Tumor burden increase of <20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. Clin Cancer Res; 23(16); 4671-9. (c)2017 AACR. PMID- 28592631 TI - Why measure carbohydrate deficient transferrin? AB - The acute or chronic harmful use of alcohol is among the top five risk factors for disease, disability and death worldwide.1 Monitoring alcohol consumption is an important aspect of the management of alcohol-use disorders and may include subjective self-reported questionnaires or objective tests.1,2-6 Such tests include measuring alcohol or alcohol metabolite levels or biomarkers such as liver enzymes or red cell indices.2-6 Carbohydrate deficient transferrin (CDT) is a biomarker used for assessing chronic alcohol misuse.6 Here, we review CDT and its place in the assessment of chronic alcohol use. PMID- 28592632 TI - Rear-polarized Wnt5a-receptor-actin-myosin-polarity (WRAMP) structures promote the speed and persistence of directional cell migration. AB - In contrast to events at the cell leading edge, rear-polarized mechanisms that control directional cell migration are poorly defined. Previous work described a new intracellular complex, the Wnt5a-receptor-actomyosin polarity (WRAMP) structure, which coordinates the polarized localization of MCAM, actin, and myosin IIB in a Wnt5a-induced manner. However, the polarity and function for the WRAMP structure during cell movement were not determined. Here we characterize WRAMP structures during extended cell migration using live-cell imaging. The results demonstrate that cells undergoing prolonged migration show WRAMP structures stably polarized at the rear, where they are strongly associated with enhanced speed and persistence of directional movement. Strikingly, WRAMP structures form transiently, with cells displaying directional persistence during periods when they are present and cells changing directions randomly when they are absent. Cells appear to pause locomotion when WRAMP structures disassemble and then migrate in new directions after reassembly at a different location, which forms the new rear. We conclude that WRAMP structures represent a rear directed cellular mechanism to control directional migration and that their ability to form dynamically within cells may control changes in direction during extended migration. PMID- 28592634 TI - High-quality frozen extracts of Xenopus laevis eggs reveal size-dependent control of metaphase spindle micromechanics. AB - Cell-free extracts from unfertilized Xenopus laevis eggs offer the opportunity for a variety of biochemical and biophysical assays for analyzing essential cell cycle events such as metaphase spindle assembly. However, the extracts often exhibit substantial variation in quality and have low storage stability, factors that hamper their experimental utility. Here we report a simple two-step method for preparing frozen egg extracts that retain spindle assembly activity levels similar to those of freshly prepared extracts. Extract degradation associated with the freeze-thaw process can be substantially reduced by using centrifugal filter-based dehydration and slow sample cooling. Large amounts of frozen extract stocks from single-batch preparations allowed us to collect extensive data in micromanipulation experiments, which are often low-throughput, and thus enabled the clarification of correlations between metaphase spindle size and stiffness. Our method provides an assay platform with minimized biological variability and improves the accessibility of egg extracts for research. PMID- 28592633 TI - The phospho-caveolin-1 scaffolding domain dampens force fluctuations in focal adhesions and promotes cancer cell migration. AB - Caveolin-1 (Cav1), a major Src kinase substrate phosphorylated on tyrosine-14 (Y14), contains the highly conserved membrane-proximal caveolin scaffolding domain (CSD; amino acids 82-101). Here we show, using CSD mutants (F92A/V94A) and membrane-permeable CSD-competing peptides, that Src kinase-dependent pY14Cav1 regulation of focal adhesion protein stabilization, focal adhesion tension, and cancer cell migration is CSD dependent. Quantitative proteomic analysis of Cav1 GST (amino acids 1-101) pull downs showed sixfold-increased binding of vinculin and, to a lesser extent, alpha-actinin, talin, and filamin, to phosphomimetic Cav1Y14D relative to nonphosphorylatable Cav1Y14F. Consistently, pY14Cav1 enhanced CSD-dependent vinculin tension in focal adhesions, dampening force fluctuation and synchronously stabilizing cellular focal adhesions in a high tension mode, paralleling effects of actin stabilization. This identifies pY14Cav1 as a molecular regulator of focal adhesion tension and suggests that functional interaction between Cav1 Y14 phosphorylation and the CSD promotes focal adhesion traction and, thereby, cancer cell motility. PMID- 28592635 TI - A cytoskeletal clutch mediates cellular force transmission in a soft, three dimensional extracellular matrix. AB - The ability of cells to impart forces and deformations on their surroundings underlies cell migration and extracellular matrix (ECM) remodeling and is thus an essential aspect of complex, metazoan life. Previous work has resulted in a refined understanding, commonly termed the molecular clutch model, of how cells adhering to flat surfaces such as a microscope coverslip transmit cytoskeletally generated forces to their surroundings. Comparatively less is known about how cells adhere to and exert forces in soft, three-dimensional (3D), and structurally heterogeneous ECM environments such as occur in vivo. We used time lapse 3D imaging and quantitative image analysis to determine how the actin cytoskeleton is mechanically coupled to the surrounding matrix for primary dermal fibroblasts embedded in a 3D fibrin matrix. Under these circumstances, the cytoskeletal architecture is dominated by contractile actin bundles attached at their ends to large, stable, integrin-based adhesions. Time-lapse imaging reveals that alpha-actinin-1 puncta within actomyosin bundles move more quickly than the paxillin-rich adhesion plaques, which in turn move more quickly than the local matrix, an observation reminiscent of the molecular clutch model. However, closer examination did not reveal a continuous rearward flow of the actin cytoskeleton over slower moving adhesions. Instead, we found that a subset of stress fibers continuously elongated at their attachment points to integrin adhesions, providing stable, yet structurally dynamic coupling to the ECM. Analytical modeling and numerical simulation provide a plausible physical explanation for this result and support a picture in which cells respond to the effective stiffness of local matrix attachment points. The resulting dynamic equilibrium can explain how cells maintain stable, contractile connections to discrete points within ECM during cell migration, and provides a plausible means by which fibroblasts contract provisional matrices during wound healing. PMID- 28592636 TI - Interleukin 6 protects pancreatic beta cells from apoptosis by stimulation of autophagy. AB - IL-6 is a pleiotropic cytokine with complex roles in inflammation and metabolic disease. The role of IL-6 as a pro- or anti-inflammatory cytokine is still unclear. Within the pancreatic islet, IL-6 stimulates secretion of the prosurvival incretin hormone glucagon-like peptide 1 (GLP-1) by alpha cells and acts directly on beta cells to stimulate insulin secretion in vitro Uncovering physiologic mechanisms promoting beta-cell survival under conditions of inflammation and stress can identify important pathways for diabetes prevention and treatment. Given the established role of GLP-1 in promoting beta-cell survival, we hypothesized that IL-6 may also directly protect beta cells from apoptosis. Herein, we show that IL-6 robustly activates signal transducer and activator of transcription 3 (STAT3), a transcription factor that is involved in autophagy. IL-6 stimulates LC3 conversion and autophagosome formation in cultured beta cells. In vivo IL-6 infusion stimulates a robust increase in lysosomes in the pancreas that is restricted to the islet. Autophagy is critical for beta-cell homeostasis, particularly under conditions of stress and increased insulin demand. The stimulation of autophagy by IL-6 is regulated via multiple complementary mechanisms including inhibition of mammalian target of rapamycin complex 1 (mTORC1) and activation of Akt, ultimately leading to increases in autophagy enzyme production. Pretreatment with IL-6 renders beta cells resistant to apoptosis induced by proinflammatory cytokines, and inhibition of autophagy with chloroquine prevents the ability of IL-6 to protect from apoptosis. Importantly, we find that IL-6 can activate STAT3 and the autophagy enzyme GABARAPL1 in human islets. We also see evidence of decreased IL-6 pathway signaling in islets from donors with type 2 diabetes. On the basis of our results, we propose direct stimulation of autophagy as a novel mechanism for IL-6 mediated protection of beta cells from stress-induced apoptosis.-Linnemann, A. K., Blumer, J., Marasco, M. R., Battiola, T. J., Umhoefer, H. M., Han, J. Y., Lamming, D. W., Davis, D. B. Interleukin 6 protects pancreatic beta cells from apoptosis by stimulation of autophagy. PMID- 28592640 TI - Editorial: Looking Back on a Year as Editor-in-Chief. PMID- 28592637 TI - In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. AB - Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases. Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome. PMID- 28592639 TI - Physiological role of reactive oxygen species as promoters of natural defenses. AB - It has been 60 yr since the discovery of reactive oxygen species (ROS) in biology and the beginning of the scientific community's attempt to understand the impact of the unpaired electron of ROS molecules in biological pathways, which was eventually noted to be toxic. Several studies have shown that the presence of ROS is essential in triggering or acting as a secondary factor for numerous pathologies, including metabolic and genetic diseases; however, it was demonstrated that chronic treatment with antioxidants failed to show efficacy and positive effects in the prevention of diseases or health complications that result from oxidative stress. On the contrary, such treatment has been shown to sometimes even worsen the disease. Because of the permanent presence of ROS in organisms, elaborate mechanisms to adapt with these reactive molecules and to use them without necessarily blocking or preventing their actions have been studied. There is now a large body of evidence that shows that living organisms have conformed to the presence of ROS and, in retrospect, have adapted to the bioactive molecules that are generated by ROS on proteins, lipids, and DNA. In addition, ROS have undergone a shift from being molecules that invoked oxidative damage in regulating signaling pathways that impinged on normal physiological and redox responses. Working in this direction, this review unlocks a new conception about the involvement of cellular oxidants in the maintenance of redox homeostasis in redox regulation of normal physiological functions, and an explanation for its essential role in numerous pathophysiological states is noted.-Roy, J., Galano, J.-M., Durand, T., Le Guennec, J.-Y., Lee, J. C.-Y. Physiological role of reactive oxygen species as promoters of natural defenses. PMID- 28592641 TI - Distinct Neural Networks Support Autobiographical and Episodic Remembering. PMID- 28592643 TI - Back to the Future: Multiparent Populations Provide the Key to Unlocking the Genetic Basis of Complex Traits. PMID- 28592638 TI - Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. AB - A novel stress-inducible protein, Sestrin2 (Sesn2), declines in the heart with aging. AMPK has emerged as a pertinent stress-activated kinase that has been shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sesn2 and AMPK in the ischemic heart. To determine whether ischemic AMPK activation-modulated by the Sesn2-AMPK complex in the heart-is impaired in aging that sensitizes the heart to ischemic insults, young C57BL/6 mice (age 3-4 mo), middle-aged mice (age 10-12 mo), and aged mice (age 24-26 mo) were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia. The ex vivo working heart system was used for measuring substrate metabolism. The protein level of Sesn2 in hearts was gradually decreased with aging. Of interest, ischemic AMPK activation was blunted in aged hearts compared with young hearts (P < 0.05); the AMPK downstream glucose uptake and the rate of glucose oxidation were significantly impaired in aged hearts during ischemia and reperfusion (P < 0.05 vs. young hearts). Myocardial infarction size was larger in aged hearts (P < 0.05 vs. young hearts). Immunoprecipitation with Sesn2 Ab revealed that cardiac Sesn2 forms a complex with AMPK and upstream liver kinase B1 (LKB1) during ischemia. Of interest, the binding affinity between Sesn2 and AMPK upstream LKB1 is impaired in aged hearts during ischemia (P < 0.05 vs. young hearts). Furthermore, Sesn2-knockout hearts demonstrate a cardiac phenotype and response to ischemic stress that is similar to wild-type aged hearts (i.e., impaired ischemic AMPK activation and higher sensitivity to ischemia- and reperfusion- induced injury). Adeno-associated virus Sesn2 was delivered to aged hearts via a coronary delivery approach and significantly rescued the protein level of Sesn2 and the ischemic tolerance of aged hearts; therefore, Sesn2 is a scaffold protein that mediates AMPK activation in the ischemic myocardium via an interaction with AMPK upstream LKB1. Decreased Sesn2 levels in aging lead to a blunted ischemic AMPK activation, alterations in substrate metabolism, and an increased sensitivity to ischemic insults-Quan, N., Sun, W., Wang, L., Chen, X., Bogan, J. S., Zhou, X., Cates, C., Liu, Q., Zheng, Y., Li J. Sestrin2 prevents age-related intolerance to ischemia and reperfusion injury by modulating substrate metabolism. PMID- 28592644 TI - Epistasis: Searching for Interacting Genetic Variants Using Crosses. PMID- 28592645 TI - Inbred Strain Variant Database (ISVdb): A Repository for Probabilistically Informed Sequence Differences Among the Collaborative Cross Strains and Their Founders. AB - The Collaborative Cross (CC) is a panel of recently established multiparental recombinant inbred mouse strains. For the CC, as for any multiparental population (MPP), effective experimental design and analysis benefit from detailed knowledge of the genetic differences between strains. Such differences can be directly determined by sequencing, but until now whole-genome sequencing was not publicly available for individual CC strains. An alternative and complementary approach is to infer genetic differences by combining two pieces of information: probabilistic estimates of the CC haplotype mosaic from a custom genotyping array, and probabilistic variant calls from sequencing of the CC founders. The computation for this inference, especially when performed genome-wide, can be intricate and time-consuming, requiring the researcher to generate nontrivial and potentially error-prone scripts. To provide standardized, easy-to-access CC sequence information, we have developed the Inbred Strain Variant Database (ISVdb). The ISVdb provides, for all the exonic variants from the Sanger Institute mouse sequencing dataset, direct sequence information for CC founders and, critically, the imputed sequence information for CC strains. Notably, the ISVdb also: (1) provides predicted variant consequence metadata; (2) allows rapid simulation of F1 populations; and (3) preserves imputation uncertainty, which will allow imputed data to be refined in the future as additional sequencing and genotyping data are collected. The ISVdb information is housed in an SQL database and is easily accessible through a custom online interface (http://isvdb.unc.edu), reducing the analytic burden on any researcher using the CC. PMID- 28592647 TI - The Beavis Effect in Next-Generation Mapping Panels in Drosophila melanogaster. AB - A major goal in the analysis of complex traits is to partition the observed genetic variation in a trait into components due to individual loci and perhaps variants within those loci. However, in both QTL mapping and genetic association studies, the estimated percent variation attributable to a QTL is upwardly biased conditional on it being discovered. This bias was first described in two-way QTL mapping experiments by William Beavis, and has been referred to extensively as "the Beavis effect." The Beavis effect is likely to occur in multiparent population (MPP) panels as well as collections of sequenced lines used for genome wide association studies (GWAS). However, the strength of the Beavis effect is unknown-and often implicitly assumed to be negligible-when "hits" are obtained from an association panel consisting of hundreds of inbred lines tested across millions of SNPs, or in multiparent mapping populations where mapping involves fitting a complex statistical model with several d.f. at thousands of genetic intervals. To estimate the size of the effect in more complex panels, we performed simulations of both biallelic and multiallelic QTL in two major Drosophila melanogaster mapping panels, the GWAS-based Drosophila Genetic Reference Panel (DGRP), and the MPP the Drosophila Synthetic Population Resource (DSPR). Our results show that overestimation is determined most strongly by sample size and is only minimally impacted by the mapping design. When < 100, 200, 500, and 1000 lines are employed, the variance attributable to hits is inflated by factors of 6, 3, 1.5, and 1.1, respectively, for a QTL that truly contributes 5% to the variation in the trait. This overestimation indicates that QTL could be difficult to validate in follow-up replication experiments where additional individuals are examined. Further, QTL could be difficult to cross validate between the two Drosophila resources. We provide guidelines for: (1) the sample sizes necessary to accurately estimate the percent variance to an identified QTL, (2) the conditions under which one is likely to replicate a mapped QTL in a second study using the same mapping population, and (3) the conditions under which a QTL mapped in one mapping panel is likely to replicate in the other (DGRP and DSPR). PMID- 28592646 TI - Loci Contributing to Boric Acid Toxicity in Two Reference Populations of Drosophila melanogaster. AB - Populations maintain considerable segregating variation in the response to toxic, xenobiotic compounds. To identify variants associated with resistance to boric acid, a commonly-used household insecticide with a poorly understood mechanism of action, we assayed thousands of individuals from hundreds of strains. Using the Drosophila Synthetic Population Resource (DSPR), a multi-parental population (MPP) of inbred genotypes, we mapped six QTL to short genomic regions containing few protein-coding genes (3-188), allowing us to identify plausible candidate genes underlying resistance to boric acid toxicity. One interval contains multiple genes from the cytochrome P450 family, and we show that ubiquitous RNAi of one of these genes, Cyp9b2, markedly reduces resistance to the toxin. Resistance to boric acid is positively correlated with caffeine resistance. The two phenotypes additionally share a pair of QTL, potentially suggesting a degree of pleiotropy in the genetic control of resistance to these two distinct xenobiotics. Finally, we screened the Drosophila Genetic Reference Panel (DGRP) in an attempt to identify sequence variants within mapped QTL that are associated with boric acid resistance. The approach was largely unsuccessful, with only one QTL showing any associations at QTL-specific 20% False Discovery Rate (FDR) thresholds. Nonetheless, these associations point to a potential candidate gene that can be targeted in future validation efforts. Although the mapping data resulting from the two reference populations do not clearly overlap, our work provides a starting point for further genetic dissection of the processes underlying boric acid toxicity in insects. PMID- 28592648 TI - Allelic Variation in the Toll-Like Receptor Adaptor Protein Ticam2 Contributes to SARS-Coronavirus Pathogenesis in Mice. AB - Host genetic variation is known to contribute to differential pathogenesis following infection. Mouse models allow direct assessment of host genetic factors responsible for susceptibility to Severe Acute Respiratory Syndrome coronavirus (SARS-CoV). Based on an assessment of early stage lines from the Collaborative Cross mouse multi-parent population, we identified two lines showing highly divergent susceptibilities to SARS-CoV: the resistant CC003/Unc and the susceptible CC053/Unc. We generated 264 F2 mice between these strains, and infected them with SARS-CoV. Weight loss, pulmonary hemorrhage, and viral load were all highly correlated disease phenotypes. We identified a quantitative trait locus of major effect on chromosome 18 (27.1-58.6 Mb) which affected weight loss, viral titer and hemorrhage. Additionally, each of these three phenotypes had distinct quantitative trait loci [Chr 9 (weight loss), Chrs 7 and 12 (virus titer), and Chr 15 (hemorrhage)]. We identified Ticam2, an adaptor protein in the TLR signaling pathways, as a candidate driving differential disease at the Chr 18 locus. Ticam2-/- mice were highly susceptible to SARS-CoV infection, exhibiting increased weight loss and more pulmonary hemorrhage than control mice. These results indicate a critical role for Ticam2 in SARS-CoV disease, and highlight the importance of host genetic variation in disease responses. PMID- 28592649 TI - Oas1b-dependent Immune Transcriptional Profiles of West Nile Virus Infection in the Collaborative Cross. AB - The oligoadenylate-synthetase (Oas) gene locus provides innate immune resistance to virus infection. In mouse models, variation in the Oas1b gene influences host susceptibility to flavivirus infection. However, the impact of Oas variation on overall innate immune programming and global gene expression among tissues and in different genetic backgrounds has not been defined. We examined how Oas1b acts in spleen and brain tissue to limit West Nile virus (WNV) susceptibility and disease across a range of genetic backgrounds. The laboratory founder strains of the mouse Collaborative Cross (CC) (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, and NZO/HlLtJ) all encode a truncated, defective Oas1b, whereas the three wild derived inbred founder strains (CAST/EiJ, PWK/PhJ, and WSB/EiJ) encode a full length OAS1B protein. We assessed disease profiles and transcriptional signatures of F1 hybrids derived from these founder strains. F1 hybrids included wild-type Oas1b (F/F), homozygous null Oas1b (N/N), and heterozygous offspring of both parental combinations (F/N and N/F). These mice were challenged with WNV, and brain and spleen samples were harvested for global gene expression analysis. We found that the Oas1b haplotype played a role in WNV susceptibility and disease metrics, but the presence of a functional Oas1b allele in heterozygous offspring did not absolutely predict protection against disease. Our results indicate that Oas1b status as wild-type or truncated, and overall Oas1b gene dosage, link with novel innate immune gene signatures that impact specific biological pathways for the control of flavivirus infection and immunity through both Oas1b-dependent and independent processes. PMID- 28592650 TI - Identification of Ganoderma Disease Resistance Loci Using Natural Field Infection of an Oil Palm Multiparental Population. AB - Multi-parental populations are promising tools for identifying quantitative disease resistance loci. Stem rot caused by Ganoderma boninense is a major threat to palm oil production, with yield losses of up to 80% prompting premature replantation of palms. There is evidence of genetic resistance sources, but the genetic architecture of Ganoderma resistance has not yet been investigated. This study aimed to identify Ganoderma resistance loci using an oil palm multi parental population derived from nine major founders of ongoing breeding programs. A total of 1200 palm trees of the multi-parental population was planted in plots naturally infected by Ganoderma, and their health status was assessed biannually over 25 yr. The data were treated as survival data, and modeled using the Cox regression model, including a spatial effect to take the spatial component in the spread of Ganoderma into account. Based on the genotypes of 757 palm trees out of the 1200 planted, and on pedigree information, resistance loci were identified using a random effect with identity-by-descent kinship matrices as covariance matrices in the Cox model. Four Ganoderma resistance loci were identified, two controlling the occurrence of the first Ganoderma symptoms, and two the death of palm trees, while favorable haplotypes were identified among a major gene pool for ongoing breeding programs. This study implemented an efficient and flexible QTL mapping approach, and generated unique valuable information for the selection of oil palm varieties resistant to Ganoderma disease. PMID- 28592652 TI - Pedigree-Based Analysis in a Multiparental Population of Octoploid Strawberry Reveals QTL Alleles Conferring Resistance to Phytophthora cactorum. AB - Understanding the genetic architecture of traits in breeding programs can be critical for making genetic progress. Important factors include the number of loci controlling a trait, allele frequencies at those loci, and allele effects in breeding germplasm. To this end, multiparental populations offer many advantages for quantitative trait locus (QTL) analyses compared to biparental populations. These include increased power for QTL detection, the ability to sample a larger number of segregating loci and alleles, and estimation of allele effects across diverse genetic backgrounds. Here, we investigate the genetic architecture of resistance to crown rot disease caused by Phytophthora cactorum in strawberry (Fragaria * ananassa), using connected full-sib families from a breeding population. Clonal replicates of > 1100 seedlings from 139 full-sib families arising from 61 parents were control-inoculated during two consecutive seasons. Subgenome-specific single nucleotide polymorphism (SNP) loci were mapped in allo octoploid strawberry (2n = 8 * = 56), and FlexQTL software was utilized to perform a Bayesian, pedigree-based QTL analysis. A major locus on linkage group (LG) 7D, which we name FaRPc2, accounts for most of the genetic variation for resistance. Four predominant SNP haplotypes were detected in the FaRPc2 region, two of which are strongly associated with two different levels of resistance, suggesting the presence of multiple resistance alleles. The phenotypic effects of FaRPc2 alleles across trials and across numerous genetic backgrounds make this locus a highly desirable target for genetic improvement of resistance in cultivated strawberry. PMID- 28592651 TI - Identification of Nitrogen Consumption Genetic Variants in Yeast Through QTL Mapping and Bulk Segregant RNA-Seq Analyses. AB - Saccharomyces cerevisiae is responsible for wine must fermentation. In this process, nitrogen represents a limiting nutrient and its scarcity results in important economic losses for the wine industry. Yeast isolates use different strategies to grow in poor nitrogen environments and their genomic plasticity enables adaptation to multiple habitats through improvements in nitrogen consumption. Here, we used a highly recombinant S. cerevisiae multi-parent population (SGRP-4X) derived from the intercross of four parental strains of different origins to identify new genetic variants responsible for nitrogen consumption differences during wine fermentation. Analysis of 165 fully sequenced F12 segregants allowed us to map 26 QTL in narrow intervals for 14 amino acid sources and ammonium, the majority of which represent genomic regions previously unmapped for these traits. To complement this strategy, we performed Bulk segregant RNA-seq (BSR-seq) analysis in segregants exhibiting extremely high and low ammonium consumption levels. This identified several QTL overlapping differentially expressed genes and refined the gene candidate search. Based on these approaches, we were able to validate ARO1, PDC1, CPS1, ASI2, LYP1, and ALP1 allelic variants underlying nitrogen consumption differences between strains, providing evidence of many genes with small phenotypic effects. Altogether, these variants significantly shape yeast nitrogen consumption with important implications for evolution, ecological, and quantitative genomics. PMID- 28592653 TI - Approaches in Characterizing Genetic Structure and Mapping in a Rice Multiparental Population. AB - Multi-parent Advanced Generation Intercross (MAGIC) populations are fast becoming mainstream tools for research and breeding, along with the technology and tools for analysis. This paper demonstrates the analysis of a rice MAGIC population from data filtering to imputation and processing of genetic data to characterizing genomic structure, and finally quantitative trait loci (QTL) mapping. In this study, 1316 S6:8 indica MAGIC (MI) lines and the eight founders were sequenced using Genotyping by Sequencing (GBS). As the GBS approach often includes missing data, the first step was to impute the missing SNPs. The observable number of recombinations in the population was then explored. Based on this case study, a general outline of procedures for a MAGIC analysis workflow is provided, as well as for QTL mapping of agronomic traits and biotic and abiotic stress, using the results from both association and interval mapping approaches. QTL for agronomic traits (yield, flowering time, and plant height), physical (grain length and grain width) and cooking properties (amylose content) of the rice grain, abiotic stress (submergence tolerance), and biotic stress (brown spot disease) were mapped. Through presenting this extensive analysis in the MI population in rice, we highlight important considerations when choosing analytical approaches. The methods and results reported in this paper will provide a guide to future genetic analysis methods applied to multi-parent populations. PMID- 28592655 TI - Economic development, flow of funds, and the equilibrium interaction of financial frictions. AB - We use a variety of different datasets from Thailand to study not only the extremes of micro and macro variables but also within-country flow of funds and labor migration. We develop a general equilibrium model that encompasses regional variation in the type of financial friction and calibrate it to measured variation in regional aggregates. The model predicts substantial capital and labor flows from rural to urban areas even though these differ only in the underlying financial regime. Predictions for micro variables not used directly provide a model validation. Finally, we estimate the impact of a policy of counterfactual, regional isolationism. PMID- 28592654 TI - Water is an active matrix of life for cell and molecular biology. AB - Szent-Gyorgi called water the "matrix of life" and claimed that there was no life without it. This statement is true, as far as we know, on our planet, but it is not clear whether it must hold throughout the cosmos. To evaluate that question requires a close consideration of the many varied and subtle roles that water plays in living cells-a consideration that must be free of both an assumed essentialism that gives water an almost mystical life-giving agency and a traditional tendency to see it as a merely passive solvent. Water is a participant in the "life of the cell," and here I describe some of the features of that active agency. Water's value for molecular biology comes from both the structural and dynamic characteristics of its status as a complex, structured liquid as well as its nature as a polar, protic, and amphoteric reagent. Any discussion of water as life's matrix must, however, begin with an acknowledgment that our understanding of it as both a liquid and a solvent is still incomplete. PMID- 28592658 TI - The structural response of the cornea to changes in stromal hydration. AB - The primary aim of this study was to quantify the relationship between corneal structure and hydration in humans and pigs. X-ray scattering data were collected from human and porcine corneas equilibrated with polyethylene glycol (PEG) to varying levels of hydration, to obtain measurements of collagen fibril diameter, interfibrillar spacing (IFS) and intermolecular spacing. Both species showed a strong positive linear correlation between hydration and IFS2 and a nonlinear, bi phasic relationship between hydration and fibril diameter, whereby fibril diameter increased up to approximately physiological hydration, H = 3.0, with little change thereafter. Above H = 3.0, porcine corneas exhibited a larger fibril diameter than human corneas (p < 0.001). Intermolecular spacing also varied with hydration in a bi-phasic manner but reached a maximum value at a lower hydration (H = 1.5) than fibril diameter. Human corneas displayed a higher intermolecular spacing than porcine corneas at all hydrations (p < 0.0001). Human and porcine corneas required a similar PEG concentration to reach physiological hydration, suggesting that the total fixed charge that gives rise to the swelling pressure is the same. The difference in their structural responses to hydration can be explained by variations in molecular cross-linking and intra/interfibrillar water partitioning. PMID- 28592657 TI - Induced pluripotent stem cell models of lysosomal storage disorders. AB - Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Examples are provided to illustrate how iPSC-derived models can be employed to develop new therapeutic strategies for these disorders. We also discuss how models of these rare diseases could contribute to an enhanced understanding of more common neurodegenerative disorders such as Parkinson's disease, and discuss key challenges and opportunities in this area of research. PMID- 28592656 TI - Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity. AB - The 'obesity epidemic' represents a major global socioeconomic burden that urgently calls for a better understanding of the underlying causes of increased weight gain and its associated metabolic comorbidities, such as type 2 diabetes mellitus and cardiovascular diseases. Improving our understanding of the cellular basis of obesity could set the stage for the development of new therapeutic strategies. The CNS plays a pivotal role in the regulation of energy and glucose homeostasis. Distinct neuronal cell populations, particularly within the arcuate nucleus of the hypothalamus, sense the nutrient status of the organism and integrate signals from peripheral hormones including pancreas-derived insulin and adipocyte-derived leptin to regulate calorie intake, glucose metabolism and energy expenditure. The arcuate neurons are tightly connected to other specialized neuronal subpopulations within the hypothalamus, but also to various extrahypothalamic brain regions, allowing a coordinated behavioral response. This At a Glance article gives an overview of the recent knowledge, mainly derived from rodent models, regarding the CNS-dependent regulation of energy and glucose homeostasis, and illustrates how dysregulation of the neuronal networks involved can lead to overnutrition and obesity. The potential impact of recent research findings in the field on therapeutic treatment strategies for human obesity is also discussed. PMID- 28592659 TI - Mitochondrial DNA 3243A>G heteroplasmy is associated with changes in cytoskeletal protein expression and cell mechanics. AB - Mitochondrial and mechanical alterations in cells have both been shown to be hallmarks of human disease. However, little research has endeavoured to establish connections between these two essential features of cells in both functional and dysfunctional situations. In this work, we hypothesized that a specific genetic alteration in mitochondrial function known to cause human disease would trigger changes in cell mechanics. Using a previously characterized set of mitochondrial cybrid cell lines, we examined the relationship between heteroplasmy for the mitochondrial DNA (mtDNA) 3243A>G mutation, the cell cytoskeleton, and resulting cellular mechanical properties. We found that cells with increasing mitochondrial dysfunction markedly differed from one another in gene expression and protein production of various co-regulated cytoskeletal elements. The intracellular positioning and organization of actin also differed across cell lines. To explore the relationship between these changes and cell mechanics, we then measured cellular mechanical properties using atomic force microscopy and found that cell stiffness correlated with gene expression data for known determinants of cell mechanics, gamma-actin, alpha-actinin and filamin A. This work points towards a mechanism linking mitochondrial genetics to single-cell mechanical properties. The transcriptional and structural regulation of cytoskeletal components by mitochondrial function may explain why energetic and mechanical alterations often coexist in clinical conditions. PMID- 28592661 TI - Raman spectroscopy as a tool for ecology and evolution. AB - Scientists are always on the lookout for new modalities of information which could reveal new biological features that are useful for deciphering the complexity of biological systems. Here, we introduce Raman spectroscopy as a prime candidate for ecology and evolution. To encourage the integration of this microscopy technique in the field of ecology and evolution, it is crucial to discuss first how Raman spectroscopy fits within the conceptual, technical and pragmatic considerations of ecology and evolution. In this paper, we show that the spectral information holds reliable indicators of intra- and interspecies variations, which can be related to the environment, selective pressures and fitness. Moreover, we show how the technical and pragmatic aspects of this modality (non-destructive, non-labelling, speed, relative low cost, etc.) enable it to be combined with more conventional methodologies. With this paper, we hope to open new avenues of research and extend the scope of available methodologies used in ecology and evolution. PMID- 28592660 TI - Mechanical interactions in bacterial colonies and the surfing probability of beneficial mutations. AB - Bacterial conglomerates such as biofilms and microcolonies are ubiquitous in nature and play an important role in industry and medicine. In contrast to well mixed cultures routinely used in microbial research, bacteria in a microcolony interact mechanically with one another and with the substrate to which they are attached. Here, we use a computer model of a microbial colony of rod-shaped cells to investigate how physical interactions between cells determine their motion in the colony and how this affects biological evolution. We show that the probability that a faster-growing mutant 'surfs' at the colony's frontier and creates a macroscopic sector depends on physical properties of cells (shape, elasticity and friction). Although all these factors contribute to the surfing probability in seemingly different ways, their effects can be summarized by two summary statistics that characterize the front roughness and cell alignment. Our predictions are confirmed by experiments in which we measure the surfing probability for colonies of different front roughness. Our results show that physical interactions between bacterial cells play an important role in biological evolution of new traits, and suggest that these interactions may be relevant to processes such as de novo evolution of antibiotic resistance. PMID- 28592662 TI - A cohort of new adhesive proteins identified from transcriptomic analysis of mussel foot glands. AB - The adaptive attachment of marine mussels to a wide range of substrates in a high energy, saline environment has been explored for decades and is a significant driver of bioinspired wet adhesion research. Mussel attachment relies on a fibrous holdfast known as the byssus, which is made by a specialized appendage called the foot. Multiple adhesive and structural proteins are rapidly synthesized, secreted and moulded by the foot into holdfast threads. About 10 well-characterized proteins, namely the mussel foot proteins (Mfps), the preCols and the thread matrix proteins, are reported as representing the bulk of these structures. To explore how robust this proposition is, we sequenced the transcriptome of the glandular tissues that produce and secrete the various holdfast components using next-generation sequencing methods. Surprisingly, we found around 15 highly expressed genes that have not previously been characterized, but bear key similarities to the previously defined mussel foot proteins, suggesting additional contribution to byssal function. We verified the validity of these transcripts by polymerase chain reaction, cloning and Sanger sequencing as well as confirming their presence as proteins in the byssus. These newly identified proteins greatly expand the palette of mussel holdfast biochemistry and provide new targets for investigation into bioinspired wet adhesion. PMID- 28592665 TI - Signs of embryo-maternal communication: miRNAs in the maternal serum of pregnant pigs. AB - Circulating miRNAs were proposed to be indicators of normal or complicated pregnancies. Based on this knowledge and our recent transcriptomic approach showing expression of miRNAs in the porcine endometrium, conceptuses and uterine extracellular vesicles during pregnancy, we have hypothesized that signs of ongoing local embryo-maternal crosstalk involving miRNAs can be detected in the circulation of pregnant gilts as early as a few days after maternal recognition of pregnancy. By applying several molecular biology techniques that differ in dynamic range and precision in maternal serum of Day 16 pregnant pigs, we were able to show for the first time increased levels of several miRNAs, previously reported to be expressed in either conceptuses and extracellular vesicles (miR 26a and miR-125b) or pregnant endometrium (miR-23b). Our results clearly showed that real-time RT-PCR and digital PCR are the most reliable methods, being able to detect small-fold changes of low-abundant circulating miRNAs. Further validation in a separate group of gilts confirmed an increase in miR-23b and miR 125b levels. In silico analyses identified pregnancy-related biological processes and pathways affected by these miRNAs. Target prediction analysis revealed hundreds of porcine transcripts with conserved sites for these miRNAs, which were classified into signaling pathways relevant to pregnancy. We conclude that a unique set of miRNAs can already be observed in the circulation of pigs during the first weeks of pregnancy, as a result of the initiation of embryo-maternal communication. PMID- 28592664 TI - Altered retinoid signaling compromises decidualization in human endometriotic stromal cells. AB - Decidualization alters multiple molecular pathways in endometrium to permit successful embryo implantation. We have reported that paracrine factors, including retinoids, secreted from progesterone-treated endometrial stromal cells, act on nearby epithelial cells to induce the estradiol metabolizing enzyme HSD17B2. This same induction is not seen in endometriotic stromal cells. We have also shown significant differences in retinoid uptake, metabolism and action in endometriotic tissue and stromal cells compared to normal endometrium. Here, we characterize retinoid signaling during decidualization in these cells. Endometrial and endometriotic cells were isolated, cultured and incubated and decidualized. Genes involved in retinoid metabolism and trafficking were examined using RT-PCR and Western blotting. Prolactin, a decidualization marker, was also examined. We found that both endometrial and endometriotic stromal cells express all intracellular proteins involved in retinoid uptake and metabolism. Decidualization significantly reduced the expression of the genes responsible for retinoid uptake and shuttling to the nucleus. However, expression of CRBP1, an intracellular carrier protein for retinol, increased, as did RBP4, a carrier protein for retinol in the blood, which can function in a paracrine manner. Secreted RBP4 was detected in the media from decidualized endometrial cells but not from endometriotic cells. We believe that retinoid trafficking in endometrial stromal cells during decidualization may shift to favor paracrine rather than intracrine signaling, which may enhance signaling to the adjacent epithelium. There is blunting of this signaling in endometriotic cells. These alterations in retinoid signaling may help explain the decidualization defects and deficient estradiol inactivation (via HSD17B2) seen in endometriosis. PMID- 28592663 TI - Inspiration for wing design: how forelimb specialization enables active flight in modern vertebrates. AB - Harnessing flight strategies refined by millions of years of evolution can help expedite the design of more efficient, manoeuvrable and robust flying robots. This review synthesizes recent advances and highlights remaining gaps in our understanding of how bird and bat wing adaptations enable effective flight. Included in this discussion is an evaluation of how current robotic analogues measure up to their biological sources of inspiration. Studies of vertebrate wings have revealed skeletal systems well suited for enduring the loads required during flight, but the mechanisms that drive coordinated motions between bones and connected integuments remain ill-described. Similarly, vertebrate flight muscles have adapted to sustain increased wing loading, but a lack of in vivo studies limits our understanding of specific muscular functions. Forelimb adaptations diverge at the integument level, but both bird feathers and bat membranes yield aerodynamic surfaces with a level of robustness unparalleled by engineered wings. These morphological adaptations enable a diverse range of kinematics tuned for different flight speeds and manoeuvres. By integrating vertebrate flight specializations-particularly those that enable greater robustness and adaptability-into the design and control of robotic wings, engineers can begin narrowing the wide margin that currently exists between flying robots and vertebrates. In turn, these robotic wings can help biologists create experiments that would be impossible in vivo. PMID- 28592666 TI - ROOT DETERMINED NODULATION1 Is Required for M. truncatula CLE12, But Not CLE13, Peptide Signaling through the SUNN Receptor Kinase. AB - The combinatorial interaction of a receptor kinase and a modified CLE peptide is involved in several developmental processes in plants, including autoregulation of nodulation (AON), which allows legumes to limit the number of root nodules formed based on available nitrogen and previous rhizobial colonization. Evidence supports the modification of CLE peptides by enzymes of the hydroxyproline O arabinosyltransferase (HPAT/RDN) family. Here, we show by grafting and genetic analysis in Medicago truncatula that, in the AON pathway, RDN1, functioning in the root, acts upstream of the receptor kinase SUNN, functioning in the shoot. As expected for a glycosyltransferase, we found that RDN1 and RDN2 proteins are localized to the Golgi, as was shown previously for AtHPAT1. Using composite plants with transgenic hairy roots, we show that RDN1 and RDN2 orthologs from dicots as well as a related RDN gene from rice (Oryza sativa) can rescue the phenotype of rdn1-2 when expressed constitutively, but the less related MtRDN3 cannot. The timing of the induction of MtCLE12 and MtCLE13 peptide genes (negative regulators of AON) in nodulating roots is not altered by the mutation of RDN1 or SUNN, although expression levels are higher. Plants with transgenic roots constitutively expressing MtCLE12 require both RDN1 and SUNN to prevent nodule formation, while plants constitutively expressing MtCLE13 require only SUNN, suggesting that the two CLEs have different requirements for function. Combined with previous work, these data support a model in which RDN1 arabinosylates MtCLE12, and this modification is necessary for the transport and/or reception of the AON signal by the SUNN kinase. PMID- 28592667 TI - Motorboat noise impacts parental behaviour and offspring survival in a reef fish. AB - Anthropogenic noise is a pollutant of international concern, with mounting evidence of disturbance and impacts on animal behaviour and physiology. However, empirical studies measuring survival consequences are rare. We use a field experiment to investigate how repeated motorboat-noise playback affects parental behaviour and offspring survival in the spiny chromis (Acanthochromis polyacanthus), a brooding coral reef fish. Repeated observations were made for 12 days at 38 natural nests with broods of young. Exposure to motorboat-noise playback compared to ambient-sound playback increased defensive acts, and reduced both feeding and offspring interactions by brood-guarding males. Anthropogenic noise did not affect the growth of developing offspring, but reduced the likelihood of offspring survival; while offspring survived at all 19 nests exposed to ambient-sound playback, six of the 19 nests exposed to motorboat-noise playback suffered complete brood mortality. Our study, providing field-based experimental evidence of the consequences of anthropogenic noise, suggests potential fitness consequences of this global pollutant. PMID- 28592668 TI - Nineteenth-century collapse of a benthic marine ecosystem on the open continental shelf. AB - The soft-sediment seafloor of the open continental shelf is among the least-known biomes on Earth, despite its high diversity and importance to fisheries and biogeochemical cycling. Abundant dead shells of epifaunal suspension-feeding terebratulid brachiopods (Laqueus) and scallops on the now-muddy mainland continental shelf of southern California reveal the recent, previously unsuspected extirpation of an extensive offshore shell-gravel ecosystem, evidently driven by anthropogenic siltation. Living populations of attached epifauna, which formerly existed in a middle- and outer-shelf mosaic with patches of trophically diverse muds, are restricted today to rocky seafloor along the shelf edge and to the sandier shelves of offshore islands. Geological age-dating of 190 dead brachiopod shells shows that (i) no shells have been produced on the mainland shelf within the last 100 years, (ii) their shell production declined steeply during the nineteenth century, and (iii) they had formerly been present continuously for at least 4 kyr. This loss, sufficiently rapid (less than or equal to 100 years) and thorough to represent an ecosystem collapse, coincides with intensification of alluvial-plain land use in the nineteenth century, particularly livestock grazing. Extirpation was complete by the start of twentieth-century urbanization, warming, bottom fishing and scientific surveys. The loss of this filter-feeding fauna and the new spatial homogeneity and dominance of deposit- and detritus-feeders would have altered ecosystem functioning by reducing habitat heterogeneity and seawater filtering. This discovery, attesting to the power of this geological approach to recent ecological transitions, also strongly increases the spatial scope attributable to the negative effects of siltation, and suggests that it has been under-recognized on continental shelves elsewhere as a legacy of coastal land use. PMID- 28592669 TI - What shapes the continuum of reproductive isolation? Lessons from Heliconius butterflies. AB - The process by which species evolve can be illuminated by investigating barriers that limit gene flow between taxa. Recent radiations, such as Heliconius butterflies, offer the opportunity to compare isolation between pairs of taxa at different stages of ecological, geographical, and phylogenetic divergence. Here, we report a comparative analysis of existing and novel data in order to quantify the strength and direction of isolating barriers within a well-studied clade of Heliconius Our results highlight that increased divergence is associated with the accumulation of stronger and more numerous barriers to gene flow. Wing pattern is both under natural selection for Mullerian mimicry and involved in mate choice, and therefore underlies several isolating barriers. However, pairs which share a similar wing pattern also display strong reproductive isolation mediated by traits other than wing pattern. This suggests that, while wing pattern is a key factor for early stages of divergence, it may become facultative at later stages of divergence. Additional factors including habitat partitioning, hybrid sterility, and chemically mediated mate choice are associated with complete speciation. Therefore, although most previous work has emphasized the role of wing pattern, our comparative results highlight that speciation is a multi dimensional process, whose completion is stabilized by many factors. PMID- 28592671 TI - Biological interactions both facilitate and resist climate-related functional change in temperate reef communities. AB - Shifts in the abundance and location of species are restructuring life on the Earth, presenting the need to build resilience into our natural systems. Here, we tested if protection from fishing promotes community resilience in temperate reef communities undergoing rapid warming in Tasmania. Regardless of protection status, we detected a signature of warming in the brown macroalgae, invertebrates and fishes, through increases in the local richness and abundance of warm affinity species. Even so, responses in protected communities diverged from exploited communities. At the local scale, the number of cool-affinity fishes and canopy-forming algal species increased following protection, even though the observation window fell within a period of warming. At the same time, exploited communities gained turf algal and sessile invertebrate species. We further found that the recovery of predator populations following protection leads to marked declines in mobile invertebrates-this trend could be incorrectly attributed to warming without contextual data quantifying community change across trophic levels. By comparing long-term change in exploited and protected reefs, we empirically demonstrate the role of biological interactions in both facilitating and resisting climate-related biodiversity change. We further highlight the potential for trophic interactions to alter the progression of both range expansions and contractions. PMID- 28592670 TI - Tetranychus urticae mites do not mount an induced immune response against bacteria. AB - The genome of the spider mite Tetranychus urticae, a herbivore, is missing important elements of the canonical Drosophila immune pathways necessary to fight bacterial infections. However, it is not known whether spider mites can mount an immune response and survive bacterial infection. In other chelicerates, bacterial infection elicits a response mediated by immune effectors leading to the survival of infected organisms. In T. urticae, infection by either Escherichia coli or Bacillus megaterium did not elicit a response as assessed through genome-wide transcriptomic analysis. In line with this, spider mites died within days even upon injection with low doses of bacteria that are non-pathogenic to Drosophila Moreover, bacterial populations grew exponentially inside the infected spider mites. By contrast, Sancassania berlesei, a litter-dwelling mite, controlled bacterial proliferation and resisted infections with both Gram-negative and Gram positive bacteria lethal to T. urticae This differential mortality between mite species was absent when mites were infected with heat-killed bacteria. Also, we found that spider mites harbour in their gut 1000-fold less bacteria than S. berlesei We show that T. urticae has lost the capacity to mount an induced immune response against bacteria, in contrast to other mites and chelicerates but similarly to the phloem feeding aphid Acyrthosiphon pisum Hence, our results reinforce the putative evolutionary link between ecological conditions regarding exposure to bacteria and the architecture of the immune response. PMID- 28592672 TI - Primate energy input and the evolutionary transition to energy-dense diets in humans. AB - Humans and other large-brained hominins have been proposed to increase energy turnover during their evolutionary history. Such increased energy turnover is plausible, given the evolution of energy-rich diets, but requires empirical confirmation. Framing human energetics in a phylogenetic context, our meta analysis of 17 wild non-human primate species shows that daily metabolizable energy input follows an allometric relationship with body mass where the allometric exponent for mass is 0.75 +/- 0.04, close to that reported for daily energy expenditure measured with doubly labelled water in primates. Human populations at subsistence level (n = 6) largely fall within the variation of primate species in the scaling of energy intake and therefore do not consume significantly more energy than predicted for a non-human primate of equivalent mass. By contrast, humans ingest a conspicuously lower mass of food (-64 +/- 6%) compared with primates and maintain their energy intake relatively more constantly across the year. We conclude that our hominin hunter-gatherer ancestors did not increase their energy turnover beyond the allometric relationship characterizing all primate species. The reduction in digestive costs due to consumption of a lower mass of high-quality food, as well as stabilization of energy supply, may have been important evolutionary steps enabling encephalization in the absence of significantly raised energy intakes. PMID- 28592673 TI - Evidence for strategic cooperation in humans. AB - Humans may cooperate strategically, cooperating at higher levels than expected from their short-term interests, to try and stimulate others to cooperate. To test this hypothesis, we experimentally manipulated the extent an individual's behaviour is known to others, and hence whether or not strategic cooperation is possible. In contrast with many previous studies, we avoided confounding factors by preventing individuals from learning during the game about either pay-offs or about how other individuals behave. We found clear evidence for strategic cooperators-just telling some individuals that their groupmates would be informed about their behaviour led to them tripling their initial level of cooperation, from 17 to 50%. We also found that many individuals play as if they do not understand the game, and their presence obscures the detection of strategic cooperation. Identifying such players allowed us to detect and study strategic motives for cooperation in novel, more powerful, ways. PMID- 28592674 TI - Three-month-old human infants use vocal cues of body size. AB - Differences in vocal fundamental (F0) and average formant (Fn) frequencies covary with body size in most terrestrial mammals, such that larger organisms tend to produce lower frequency sounds than smaller organisms, both between species and also across different sex and life-stage morphs within species. Here we examined whether three-month-old human infants are sensitive to the relationship between body size and sound frequencies. Using a violation-of-expectation paradigm, we found that infants looked longer at stimuli inconsistent with the relationship that is, a smaller organism producing lower frequency sounds, and a larger organism producing higher frequency sounds-than at stimuli that were consistent with it. This effect was stronger for fundamental frequency than it was for average formant frequency. These results suggest that by three months of age, human infants are already sensitive to the biologically relevant covariation between vocalization frequencies and visual cues to body size. This ability may be a consequence of developmental adaptations for building a phenotype capable of identifying and representing an organism's size, sex and life-stage. PMID- 28592675 TI - Global biogeography since Pangaea. AB - The break-up of the supercontinent Pangaea around 180 Ma has left its imprint on the global distribution of species and resulted in vicariance-driven speciation. Here, we test the idea that the molecular clock dates, for the divergences of species whose geographical ranges were divided, should agree with the palaeomagnetic dates for the continental separations. Our analysis of recently available phylogenetic divergence dates of 42 pairs of vertebrate taxa, selected for their reduced ability to disperse, demonstrates that the divergence dates in phylogenetic trees of continent-bound terrestrial and freshwater vertebrates are consistent with the palaeomagnetic dates of continental separation. PMID- 28592676 TI - Life or death: disease-tolerant coral species activate autophagy following immune challenge. AB - Global climate change has increased the number and severity of stressors affecting species, yet not all species respond equally to these stressors. Organisms may employ cellular mechanisms such as apoptosis and autophagy in responding to stressful events. These two pathways are often mutually exclusive, dictating whether a cell adapts or dies. In order to examine differences in cellular response to stress, we compared the immune response of four coral species with a range of disease susceptibility. Using RNA-seq and novel pathway analysis, we were able to identify differences in response to immune stimulation between these species. Disease-susceptible species Orbicella faveolata activated pathways associated with apoptosis. By contrast, disease-tolerant species Porites porites and Porites astreoides activated autophagic pathways. Moderately susceptible species Pseudodiploria strigosa activated a mixture of these pathways. These findings were corroborated by apoptotic caspase protein assays, which indicated increased caspase activity following immune stimulation in susceptible species. Our results indicate that in response to immune stress, disease-tolerant species activate cellular adaptive mechanisms such as autophagy, while susceptible species turn on cell death pathways. Differences in these cellular maintenance pathways may therefore influence the organismal stress response. Further study of these pathways will increase understanding of differential stress response and species survival in the face of changing environments. PMID- 28592677 TI - Indirect effects of ocean acidification drive feeding and growth of juvenile crown-of-thorns starfish, Acanthaster planci. AB - The indirect effects of changing climate in modulating trophic interactions can be as important as the direct effects of climate stressors on consumers. The success of the herbivorous juvenile stage of the crown-of-thorns starfish (COTS), Acanthaster planci, may be affected by the impacts of ocean conditions on its crustose coralline algal (CCA) food. To partition the direct effects of near future ocean acidification on juvenile COTS and indirect effects through changes in their CCA food, COTS were grown in three pHT levels (7.9, 7.8, 7.6) and fed CCA grown at similar pH levels. Consumption of CCA by COTS was bolstered when the COTS were grown in low pH and when they were fed CCA grown in low pH regardless of the pH in which the COTS were reared. COTS fed CCA grown at pH 7.6 grew fastest, but the pH/pCO2 that the COTS were reared in had no direct effect on growth. Ocean acidification conditions decreased the C : N ratio and carbonate levels in the CCA. Bolstered growth in COTS may be driven by enhanced palatability, increased nutritive state and reduced defences of their CCA food. These results indicate that near future acidification will increase the success of early juvenile COTS and boost recruitment into the coral-eating life stage. PMID- 28592678 TI - The route of infection determines Wolbachia antibacterial protection in Drosophila. AB - Bacterial symbionts are widespread among metazoans and provide a range of beneficial functions. Wolbachia-mediated protection against viral infection has been extensively demonstrated in Drosophila. In mosquitoes that are artificially transinfected with Drosophila melanogaster Wolbachia (wMel), protection from both viral and bacterial infections has been demonstrated. However, no evidence for Wolbachia-mediated antibacterial protection has been demonstrated in Drosophila to date. Here, we show that the route of infection is key for Wolbachia-mediated antibacterial protection. Drosophila melanogaster carrying Wolbachia showed reduced mortality during enteric-but not systemic-infection with the opportunist pathogen Pseudomonas aeruginosaWolbachia-mediated protection was more pronounced in male flies and is associated with increased early expression of the antimicrobial peptide Attacin A, and also increased expression of a reactive oxygen species detoxification gene (Gst D8). These results highlight that the route of infection is important for symbiont-mediated protection from infection, that Wolbachia can protect hosts by eliciting a combination of resistance and disease tolerance mechanisms, and that these effects are sexually dimorphic. We discuss the importance of using ecologically relevant routes of infection to gain a better understanding of symbiont-mediated protection. PMID- 28592679 TI - Glacial survival of trophically linked boreal species in northern Europe. AB - Whether non-arctic species persisted in northern Europe during the Last Glacial Maximum (LGM) is highly debated. Until now, the debate has mostly focused on plants, with little consideration for other groups of organisms, e.g. the numerous plant-dependent insect species. Here, we study the late-Quaternary evolution of the European range of a boreo-montane leaf beetle, Gonioctena intermedia, which feeds exclusively on the boreal and temperate trees Prunus padus and Sorbus aucuparia Using species distribution models, we estimated the congruence between areas of past and present suitable climate for this beetle and its host plants. Then we derived historical hypotheses from the congruent range estimates, and evaluated their compatibility with observed DNA sequence variation at five independent loci. We investigated compatibility using computer simulations of population evolution under various coalescence models. We find strong evidence for range modifications in response to late-Quaternary climate changes, and support for the presence of populations of G. intermedia in northern Europe since the beginning of the last glaciation. The presence of a co-dependent insect in the region through the LGM provides new evidence supporting the glacial survival of cold-tolerant tree species in northern Europe. PMID- 28592680 TI - Chimpanzees, bonobos and children successfully coordinate in conflict situations. AB - Social animals need to coordinate with others to reap the benefits of group living even when individuals' interests are misaligned. We compare how chimpanzees, bonobos and children coordinate their actions with a conspecific in a Snowdrift game, which provides a model for understanding how organisms coordinate and make decisions under conflict. In study 1, we presented pairs of chimpanzees, bonobos and children with an unequal reward distribution. In the critical condition, the preferred reward could only be obtained by waiting for the partner to act, with the risk that if no one acted, both would lose the rewards. Apes and children successfully coordinated to obtain the rewards. Children used a 'both-partner-pull' strategy and communicated during the task, while some apes relied on an 'only-one-partner-pulls' strategy to solve the task, although there were also signs of strategic behaviour as they waited for their partner to pull when that strategy led to the preferred reward. In study 2, we presented pairs of chimpanzees and bonobos with the same set-up as in study 1 with the addition of a non-social option that provided them with a secure reward. In this situation, apes had to actively decide between the unequal distribution and the alternative. In this set-up, apes maximized their rewards by taking their partners' potential actions into account. In conclusion, children and apes showed clear instances of strategic decision-making to maximize their own rewards while maintaining successful coordination. PMID- 28592681 TI - Pay-off-biased social learning underlies the diffusion of novel extractive foraging traditions in a wild primate. AB - The type and variety of learning strategies used by individuals to acquire behaviours in the wild are poorly understood, despite the presence of behavioural traditions in diverse taxa. Social learning strategies such as conformity can be broadly adaptive, but may also retard the spread of adaptive innovations. Strategies like pay-off-biased learning, by contrast, are effective at diffusing new behaviour but may perform poorly when adaptive behaviour is common. We present a field experiment in a wild primate, Cebus capucinus, that introduced a novel food item and documented the innovation and diffusion of successful extraction techniques. We develop a multilevel, Bayesian statistical analysis that allows us to quantify individual-level evidence for different social and individual learning strategies. We find that pay-off-biased and age-biased social learning are primarily responsible for the diffusion of new techniques. We find no evidence of conformity; instead rare techniques receive slightly increased attention. We also find substantial and important variation in individual learning strategies that is patterned by age, with younger individuals being more influenced by both social information and their own individual experience. The aggregate cultural dynamics in turn depend upon the variation in learning strategies and the age structure of the wild population. PMID- 28592683 TI - Molecular basis of function and the unusual antioxidant activity of a cyanobacterial cysteine desulfurase. AB - Cysteine desulfurases, which supply sulfur for iron-sulfur cluster biogenesis, are broadly distributed in all phyla including cyanobacteria, the progenitors of plant chloroplasts. The SUF (sulfur utilization factor) system is responsible for Fe-S cluster biosynthesis under stress. The suf operon from cyanobacterium Anabaena PCC 7120 showed the presence of a cysteine desulfurase, sufS (alr2495), but not the accessory sulfur-accepting protein (SufE). However, an open reading frame (alr3513) encoding a SufE-like protein (termed AsaE, Anabaena sulfur acceptor E) was found at a location distinct from the suf operon. The purified SufS protein existed as a pyridoxal 5' phosphate (PLP)-containing dimer with a relatively low desulfurase activity. Interestingly, in the presence of the AsaE protein, the catalytic efficiency of this reaction increased 10-fold. In particular, for sulfur mobilization, the AsaE protein partnered only SufS and not other cysteine desulfurases from Anabaena. The SufS protein was found to physically interact with the AsaE protein, demonstrating that AsaE was indeed the missing partner of Anabaena SufS. The conserved cysteine of the SufS or the AsaE protein was essential for activity but not for their physical association. Curiously, overexpression of the SufS protein in Anabaena caused reduced formation of reactive oxygen species on exposure to hydrogen peroxide (H2O2), resulting in superior oxidative stress tolerance to the oxidizing agent when compared with the wild-type strain. Overall, the results highlight the functional interaction between the two proteins that mediate sulfur mobilization, in the cyanobacterial SUF pathway, and further reveal that overexpression of SufS can protect cyanobacteria from oxidative stress. PMID- 28592682 TI - Hotspots of age-related protein degradation: the importance of neighboring residues for the formation of non-disulfide crosslinks derived from cysteine. AB - Over time, the long-lived proteins that are present throughout the human body deteriorate. Typically, they become racemized, truncated, and covalently cross linked. One reaction responsible for age-related protein cross-linking in the lens was elucidated recently and shown to involve spontaneous formation of dehydroalanine (DHA) intermediates from phosphoserine. Cys residues are another potential source of DHA, and evidence for this was found in many lens crystallins. In the human lens, some sites were more prone to forming non disulfide covalent cross-links than others. Foremost among them was Cys5 in betaA4 crystallin. The reason for this enhanced reactivity was investigated using peptides. Oxidation of Cys to cystine was a prerequisite for DHA formation, and DHA production was accelerated markedly by the presence of a Lys, one residue separated from Cys5. Modeling and direct investigation of the N-terminal sequence of betaA4 crystallin, as well as a variety of homologous peptides, showed that the epsilon amino group of Lys can promote DHA production by nucleophilic attack on the alpha proton of cystine. Once a DHA residue was generated, it could form intermolecular cross-links with Lys and Cys. In the lens, the most abundant cross link involved Cys5 of betaA4 crystallin attached via a thioether bond to glutathione. These findings illustrate the potential of Cys and disulfide bonds to act as precursors for irreversible covalent cross-links and the role of nearby amino acids in creating 'hotpsots' for the spontaneous processes responsible for protein degradation in aged tissues. PMID- 28592684 TI - Trajectory curvature in saccade sequences: spatiotopic influences vs. residual motor activity. AB - When decisions drive saccadic eye movements, traces of the decision process can be inferred from the movement trajectories. For example, saccades can curve away from distractor stimuli, which was thought to reflect cortical inhibition biasing activity in the superior colliculus. Recent neurophysiological work does not support this theory, and two recent models have replaced top-down inhibition with lateral interactions in the superior colliculus or neural fatigue in the brainstem saccadic burst generator. All current models operate in retinotopic coordinates and are based on single saccade paradigms. To extend these models to sequences of saccades, we assessed whether and how saccade curvature depends on previously fixated locations and the direction of previous saccades. With a two saccade paradigm, we first demonstrated that second saccades curved away from the initial fixation stimulus. Furthermore, by varying the time from fixation offset and the intersaccadic duration, we distinguished the extent of curvature originating from the spatiotopic representation of the previous fixation location or residual motor activity of the previous saccade. Results suggest that both factors drive curvature, and we discuss how these effects could be implemented in current models. In particular, we propose that the collicular retinotopic maps receive an excitatory spatiotopic update from the lateral interparial region.NEW & NOTEWORTHY Saccades curve away from locations of previous fixation. Varying stimulus timing demonstrates the effects of both 1) spatiotopic representation and 2) motor residual activity from previous saccades. The spatiotopic effect can be explained if current models are augmented with an excitatory top-down spatiotopic signal. PMID- 28592685 TI - Robotic navigation to subcortical neural tissue for intracellular electrophysiology in vivo. AB - In vivo studies of neurophysiology using the whole cell patch-clamp technique enable exquisite access to both intracellular dynamics and cytosol of cells in the living brain but are underrepresented in deep subcortical nuclei because of fouling of the sensitive electrode tip. We have developed an autonomous method to navigate electrodes around obstacles such as blood vessels after identifying them as a source of contamination during regional pipette localization (RPL) in vivo. In mice, robotic navigation prevented fouling of the electrode tip, increasing RPL success probability 3 mm below the pial surface to 82% (n = 72/88) over traditional, linear localization (25%, n = 24/95), and resulted in high-quality thalamic whole cell recordings with average access resistance (32.0 MOmega) and resting membrane potential (-62.9 mV) similar to cortical recordings in isoflurane-anesthetized mice. Whole cell yield improved from 1% (n = 1/95) to 10% (n = 9/88) when robotic navigation was used during RPL. This method opens the door to whole cell studies in deep subcortical nuclei, including multimodal cell typing and studies of long-range circuits.NEW & NOTEWORTHY This work represents an automated method for accessing subcortical neural tissue for intracellular electrophysiology in vivo. We have implemented a novel algorithm to detect obstructions during regional pipette localization and move around them while minimizing lateral displacement within brain tissue. This approach leverages computer control of pressure, manipulator position, and impedance measurements to create a closed-loop platform for pipette navigation in vivo. This technique enables whole cell patching studies to be performed throughout the living brain. PMID- 28592687 TI - Efferent inhibition strength is a physiological correlate of hyperacusis in children with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a developmental disability that is poorly understood. ASD can influence communication, social interaction, and behavior. Children with ASD often have sensory hypersensitivities, including auditory hypersensitivity (hyperacusis). In adults with hyperacusis who are otherwise neurotypical, the medial olivocochlear (MOC) efferent reflex is stronger than usual. In children with ASD, the MOC reflex has been measured, but without also assessing hyperacusis. We assessed the MOC reflex in children with ASD by measuring the strength of MOC-induced inhibition of transient-evoked otoacoustic emissions (TEOAEs), a noninvasive physiological measure that reflects cochlear amplification. MOC activity was evoked by contralateral noise. Hyperacusis was assessed subjectively on the basis of the children's symptoms. We found a significant correlation between hyperacusis scores and MOC strength in children with ASD. When children were divided into ASD-with-severe-hyperacusis (ASDs), ASD with-not-severe-hyperacusis (ASDns), and neurotypical (NT) groups, the last two groups had similar hyperacusis and MOC reflexes, whereas the ASDs group, on average, had hyperacusis and MOC reflexes that were approximately twice as strong. The MOC inhibition of TEOAEs averaged larger at all frequencies in the ASDs compared with ASDns and NT groups. The results suggest that the MOC reflex can be used to estimate hyperacusis in children with ASD and might be used to validate future questionnaires to assess hyperacusis. Our results also provide evidence that strong MOC reflexes in children with ASD are associated with hyperacusis and that hyperacusis is a comorbid condition and is not a necessary, integral part of the abnormal neural processing associated with ASD.NEW & NOTEWORTHY Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms. PMID- 28592686 TI - Adaptation modulates correlated subthreshold response variability in visual cortex. AB - Cortical sensory responses are highly variable across stimulus presentations. This variability can be correlated across neurons (due to some combination of dense intracortical connectivity, cortical activity level, and cortical state), with fundamental implications for population coding. Yet the interpretation of correlated response variability (or "noise correlation") has remained fraught with difficulty, in part because of the restriction to extracellular neuronal spike recordings. Here, we measured response variability and its correlation at the most microscopic level of electrical neural activity, the membrane potential, by obtaining dual whole cell recordings from pairs of cortical pyramidal neurons during visual processing in the turtle whole brain ex vivo preparation. We found that during visual stimulation, correlated variability adapts toward an intermediate level and that this correlation dynamic is likely mediated by intracortical mechanisms. A model network with external inputs, synaptic depression, and structure reproduced the observed dynamics of correlated variability. These results suggest that intracortical adaptation self-organizes cortical circuits toward a balanced regime at which correlated variability is maintained at an intermediate level.NEW & NOTEWORTHY Correlated response variability has profound implications for stimulus encoding, yet our understanding of this phenomenon is based largely on spike data. Here, we investigate the dynamics and mechanisms of membrane potential-correlated variability (CC) in visual cortex with a combined experimental and computational approach. We observe a visually evoked increase in CC, followed by a fast return to baseline. Our results further suggest a link between this observation and the adaptation-mediated dynamics of emergent network phenomena. PMID- 28592688 TI - Validation of electrical stimulation models: intracellular calcium measurement in three-dimensional scaffolds. AB - Peripheral nerve injury can be disabling. Regeneration is limited by the rate of axonal extension, and proximal injury to peripheral nerves can take over a year to reach target organs. Electrical stimulation (ES) has been shown to increase the rate of neurite growth, though the mechanism is not yet well understood. In our prior manuscript, we developed a computational model that demonstrates how ES can functionally elevate intracellular calcium concentration ([Ca2+]i) based on ES intensity and duration. In this article, we validate the computation model for the [Ca2+]i changes in neuron soma. Embryonic chicken dorsal root ganglion cells were suspended in 3-dimensional collagen scaffolds. Fura-2 was used to measure [Ca2+]i in response to biphasic ES pulses ranging from 70 to 60,000 V/m in intensity and from 10 us to 100 ms in duration. The computational model most closely matched the experimental data of the neurons with the highest [Ca2+]i elevation for ES pulses 100 us or greater in duration. Nickel (200 uM) and cadmium (200 uM) blocked 98-99% of the [Ca2+]i rise, indicating that the rise in [Ca2+]i in response to ES is via voltage-dependent calcium channels. The average [Ca2+]i rise in response to ES was about one-tenth of the peak rise. Therefore, the computational model is validated for elevating [Ca2+]i of neurons and can be used as a tool for designing efficacious ES protocols for improving neuronal regeneration.NEW & NOTEWORTHY Electrical stimulation is used to enhance neuron growth, and the role of neuronal intracellular calcium concentration ([Ca2+]i) is an area of research interest. Widely varying stimulation parameters in the literature make it difficult to compare stimulation protocols. The results in this manuscript are the first to show neuronal [Ca2+]i in response to a broad and defined range of electrical pulse durations and intensities. These results validate our previously published novel computational model of [Ca2+]i. PMID- 28592689 TI - Control of the strength of visual-motor transmission as the mechanism of rapid adaptation of priors for Bayesian inference in smooth pursuit eye movements. AB - Bayesian inference provides a cogent account of how the brain combines sensory information with "priors" based on past experience to guide many behaviors, including smooth pursuit eye movements. We now demonstrate very rapid adaptation of the pursuit system's priors for target direction and speed. We go on to leverage that adaptation to outline possible neural mechanisms that could cause pursuit to show features consistent with Bayesian inference. Adaptation of the prior causes changes in the eye speed and direction at the initiation of pursuit. The adaptation appears after a single trial and accumulates over repeated exposure to a given history of target speeds and directions. The influence of the priors depends on the reliability of visual motion signals: priors are more effective against the visual motion signals provided by low-contrast vs. high contrast targets. Adaptation of the direction prior generalizes to eye speed and vice versa, suggesting that both priors could be controlled by a single neural mechanism. We conclude that the pursuit system can learn the statistics of visual motion rapidly and use those statistics to guide future behavior. Furthermore, a model that adjusts the gain of visual-motor transmission predicts the effects of recent experience on pursuit direction and speed, as well as the specifics of the generalization between the priors for speed and direction. We suggest that Bayesian inference in pursuit behavior is implemented by distinctly non-Bayesian internal mechanisms that use the smooth eye movement region of the frontal eye fields to control of the gain of visual-motor transmission.NEW & NOTEWORTHY Bayesian inference can account for the interaction between sensory data and past experience in many behaviors. Here, we show, using smooth pursuit eye movements, that the priors based on past experience can be adapted over a very short time frame. We also show that a single model based on direction-specific adaptation of the strength of visual-motor transmission can explain the implementation and adaptation of priors for both target direction and target speed. PMID- 28592690 TI - Dynamics of human subthalamic neuron phase-locking to motor and sensory cortical oscillations during movement. AB - Coupled oscillatory activity recorded between sensorimotor regions of the basal ganglia-thalamocortical loop is thought to reflect information transfer relevant to movement. A neuronal firing-rate model of basal ganglia-thalamocortical circuitry, however, has dominated thinking about basal ganglia function for the past three decades, without knowledge of the relationship between basal ganglia single neuron firing and cortical population activity during movement itself. We recorded activity from 34 subthalamic nucleus (STN) neurons, simultaneously with cortical local field potentials and motor output, in 11 subjects with Parkinson's disease (PD) undergoing awake deep brain stimulator lead placement. STN firing demonstrated phase synchronization to both low- and high-beta-frequency cortical oscillations, and to the amplitude envelope of gamma oscillations, in motor cortex. We found that during movement, the magnitude of this synchronization was dynamically modulated in a phase-frequency-specific manner. Importantly, we found that phase synchronization was not correlated with changes in neuronal firing rate. Furthermore, we found that these relationships were not exclusive to motor cortex, because STN firing also demonstrated phase synchronization to both premotor and sensory cortex. The data indicate that models of basal ganglia function ultimately will need to account for the activity of populations of STN neurons that are bound in distinct functional networks with both motor and sensory cortices and code for movement parameters independent of changes in firing rate.NEW & NOTEWORTHY Current models of basal ganglia-thalamocortical networks do not adequately explain simple motor functions, let alone dysfunction in movement disorders. Our findings provide data that inform models of human basal ganglia function by demonstrating how movement is encoded by networks of subthalamic nucleus (STN) neurons via dynamic phase synchronization with cortex. The data also demonstrate, for the first time in humans, a mechanism through which the premotor and sensory cortices are functionally connected to the STN. PMID- 28592691 TI - All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control. AB - Neocortical circuits use a family of homeostatic plasticity mechanisms to stabilize firing, including excitatory and inhibitory synaptic scaling and homeostatic intrinsic plasticity (Turrigiano and Nelson, 2004). All three mechanisms can be induced in tandem in cultured rat neocortical pyramidal neurons by chronic manipulations of firing, but it is unknown whether they are coinduced by the same activity-sensors and signaling pathways, or whether they are under independent control. Calcium/calmodulin-dependent protein kinase type IV (CaMKIV) is a key sensory/effector in excitatory synaptic scaling that senses perturbations in firing through changes in calcium influx, and translates this into compensatory changes in excitatory quantal amplitude (Ibata et al., 2008; Goold and Nicoll, 2010). Whether CaMKIV also controls inhibitory synaptic scaling and intrinsic homeostatic plasticity was unknown. To test this we manipulated CaMKIV signaling in individual neurons using dominant-negative (dn) or constitutively-active (ca) forms of nuclear-localized CaMKIV and measured the induction of all three forms of homeostatic plasticity. We found that excitatory synaptic scaling and intrinsic plasticity were bidirectionally coinduced by these manipulations. In contrast, these cell-autonomous manipulations had no impact on inhibitory quantal amplitude. Finally, we found that spontaneous firing rates were shifted up or down by dnCaMKIV or caCaMKIV, respectively, suggesting that uncoupling CaMKIV activation from activity generates an error signal in the negative feedback mechanism that controls firing rates. Together, our data show that excitatory synaptic scaling and intrinsic excitability are tightly coordinated through bidirectional changes in the same signaling pathway, whereas inhibitory synaptic scaling is sensed and regulated through an independent control mechanism.SIGNIFICANCE STATEMENT Maintaining stable function in highly interconnected neural circuits is essential for preventing circuit disorders, and is accomplished through a set of negative feedback mechanisms that sense and compensate for perturbations in activity. These "homeostatic" mechanisms can target synaptic excitation, synaptic inhibition, and intrinsic excitability, but whether they are independently controlled is not known. We find that synaptic excitation and intrinsic excitability are coregulated in individual neurons through CaMKIV signaling, which is tightly controlled by neuronal activity. In contrast, synaptic inhibition is unaffected by changes in firing or CaMKIV signaling in individual neurons. These results show that circuit stability is controlled both through cell-autonomous mechanisms that regulate some aspects of excitability, as well as circuit-level mechanisms that adjust inhibition. PMID- 28592692 TI - Genome-Wide Temporal Expression Profiling in Caenorhabditis elegans Identifies a Core Gene Set Related to Long-Term Memory. AB - The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets.SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes. PMID- 28592694 TI - Opening a New Time Window for Treatment of Stroke by Targeting HDAC2. AB - Narrow therapeutic window limits treatments with thrombolysis and neuroprotection for most stroke patients. Widening therapeutic window remains a critical challenge. Understanding the key mechanisms underlying the pathophysiological events in the peri-infarct area where secondary injury coexists with neuroplasticity over days to weeks may offer an opportunity for expanding the therapeutic window. Here we show that ischemia-induced histone deacetylase 2 (HDAC2) upregulation from 5 to 7 d after stroke plays a crucial role. In this window phase, suppressing HDAC2 in the peri-infarct cortex of rodents by HDAC inhibitors, knockdown or knock-out of Hdac2 promoted recovery of motor function from stroke via epigenetically enhancing cells survival and neuroplasticity of surviving neurons as well as reducing neuroinflammation, whereas overexpressing HDAC2 worsened stroke-induced functional impairment of both WT and Hdac2 conditional knock-out mice. More importantly, inhibiting other isoforms of HDACs had no effect. Thus, the intervention by precisely targeting HDAC2 in this window phase is a novel strategy for the functional recovery of stroke survivors.SIGNIFICANCE STATEMENT Narrow time window phase impedes current therapies for stroke patients. Understanding the key mechanisms underlying secondary injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study indicates that ischemia-induced histone deacetylase 2 upregulation from 5 to 7 d after stroke mediates the secondary functional loss by reducing survival and neuroplasticity of peri-infarct neurons as well as augmenting neuroinflammation. Thus, precisely targeting histone deacetylase 2 in the window phase provides a novel therapeutic strategy for stroke recovery. PMID- 28592695 TI - Unraveling the Role of the Hippocampus in Reversal Learning. AB - Research in reversal learning has mainly focused on the functional role of dopamine and striatal structures in driving behavior on the basis of classic reinforcement learning mechanisms. However, recent evidence indicates that, beyond classic reinforcement learning adaptations, individuals may also learn the inherent task structure and anticipate the occurrence of reversals. A candidate structure to support such task representation is the hippocampus, which might create a flexible representation of the environment that can be adaptively applied to goal-directed behavior. To investigate the functional role of the hippocampus in the implementation of anticipatory strategies in reversal learning, we first studied, in 20 healthy individuals (11 women), whether the gray matter anatomy and volume of the hippocampus were related to anticipatory strategies in a reversal learning task. Second, we tested 20 refractory temporal lobe epileptic patients (11 women) with unilateral hippocampal sclerosis, who served as a hippocampal lesion model. Our results indicate that healthy participants were able to learn the task structure and use it to guide their behavior and optimize their performance. Participants' ability to adopt anticipatory strategies correlated with the gray matter volume of the hippocampus. In contrast, hippocampal patients were unable to grasp the higher order structure of the task with the same success than controls. Present results indicate that the hippocampus is necessary to respond in an appropriately flexible manner to high-order environments, and disruptions in this structure can render behavior habitual and inflexible.SIGNIFICANCE STATEMENT Understanding the neural substrates involved in reversal learning has provoked a great deal of interest in the last years. Studies with nonhuman primates have shown that, through repetition, individuals are able to anticipate the occurrence of reversals and, thus, adjust their behavior accordingly. The present investigation is devoted to know the role of the hippocampus in such strategies. Importantly, our findings evidence that the hippocampus is necessary to anticipate the occurrence of reversals, and disruptions in this structure can render behavior habitual and inflexible. PMID- 28592693 TI - Nongenomic Actions of 17-beta Estradiol Restore Respiratory Neuroplasticity in Young Ovariectomized Female Rats. AB - Gonadal steroids modulate CNS plasticity, including phrenic long-term facilitation (pLTF), a form of spinal respiratory neuroplasticity resulting in increased phrenic nerve motor output following exposure to acute intermittent hypoxia (aIH; three 5 min episodes, 10.5% O2). Despite the importance of respiratory system neuroplasticity, and its dependence on estrogen in males, little is known about pLTF expression or mechanisms of estrogen signaling in females. Here, we tested the hypotheses that (1) pLTF expression in young, gonadally intact female rats would be expressed during estrous cycle stages in which 17beta-estradiol (E2) is naturally high (e.g., proestrus vs estrus), (2) pLTF would be absent in ovariectomized (OVX) rats and in physiological conditions in which serum progesterone, but not E2, is elevated (e.g., lactating rats, 3-10 d postpartum), and (3) acute E2 administration would be sufficient to restore pLTF in OVX rats. Recordings of phrenic nerve activity in female Sprague Dawley rats (3-4 months) revealed a direct correlation between serum E2 levels and pLTF expression in cycling female rats. pLTF was abolished with OVX, but was re established by acute E2 replacement (3 h, intraperitoneal). To identify underlying E2 signaling mechanisms, we intrathecally applied BSA-conjugated E2 over the spinal phrenic motor nucleus and found that pLTF expression was restored within 15 min, suggesting nongenomic E2 effects at membrane estrogen receptors. These data are the first to investigate the role of ovarian E2 in young cycling females, and to identify a role for nongenomic estrogen signaling in any form of respiratory system neuroplasticity.SIGNIFICANCE STATEMENT Exposure to acute intermittent hypoxia induces phrenic long-term facilitation (pLTF), a form of spinal respiratory motor plasticity that improves breathing in models of spinal cord injury. Although pathways leading to pLTF are well studied in males and estradiol (E2) is known to be required, it has seldom been investigated in females, and underlying mechanisms of E2 signaling are unknown in either sex. We found that while ovariectomy abolished pLTF, it could be restored by acute systemic E2, or by intraspinal application of the membrane-impermeable E2 (BSA conjugated E2; 15 min). The ability of nongenomic estrogen signaling within the cervical spinal cord to recover respiratory neuroplasticity in disorders of respiratory insufficiency suggests that membrane estrogen receptors may represent novel therapeutic targets to restore breathing in both sexes. PMID- 28592696 TI - Visual Working Memory Enhances the Neural Response to Matching Visual Input. AB - Visual working memory (VWM) is used to maintain visual information available for subsequent goal-directed behavior. The content of VWM has been shown to affect the behavioral response to concurrent visual input, suggesting that visual representations originating from VWM and from sensory input draw upon a shared neural substrate (i.e., a sensory recruitment stance on VWM storage). Here, we hypothesized that visual information maintained in VWM would enhance the neural response to concurrent visual input that matches the content of VWM. To test this hypothesis, we measured fMRI BOLD responses to task-irrelevant stimuli acquired from 15 human participants (three males) performing a concurrent delayed match-to sample task. In this task, observers were sequentially presented with two shape stimuli and a retro-cue indicating which of the two shapes should be memorized for subsequent recognition. During the retention interval, a task-irrelevant shape (the probe) was briefly presented in the peripheral visual field, which could either match or mismatch the shape category of the memorized stimulus. We show that this probe stimulus elicited a stronger BOLD response, and allowed for increased shape-classification performance, when it matched rather than mismatched the concurrently memorized content, despite identical visual stimulation. Our results demonstrate that VWM enhances the neural response to concurrent visual input in a content-specific way. This finding is consistent with the view that neural populations involved in sensory processing are recruited for VWM storage, and it provides a common explanation for a plethora of behavioral studies in which VWM-matching visual input elicits a stronger behavioral and perceptual response.SIGNIFICANCE STATEMENT Humans heavily rely on visual information to interact with their environment and frequently must memorize such information for later use. Visual working memory allows for maintaining such visual information in the mind's eye after termination of its retinal input. It is hypothesized that information maintained in visual working memory relies on the same neural populations that process visual input. Accordingly, the content of visual working memory is known to affect our conscious perception of concurrent visual input. Here, we demonstrate for the first time that visual input elicits an enhanced neural response when it matches the content of visual working memory, both in terms of signal strength and information content. PMID- 28592698 TI - A Screening of UNF Targets Identifies Rnb, a Novel Regulator of Drosophila Circadian Rhythms. AB - Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled (unf) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period (per) (Jaumouille et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837, which we termed R and B (Rnb), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit.SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics distinguishing the s-LNvs, the master pacemaker of the locomotor rhythms, from other clock neuron subtypes. We demonstrated that a newly identified gene Rnb is an s-LNv-specific regulator of the molecular clock and essential for the generation of circadian locomotor behavior. Our results provide additional evidence to the emerging view that the differential regulation of the molecular clocks underlies the functional differences among the pacemaker neuron subgroups. PMID- 28592697 TI - Top-Down Beta Enhances Bottom-Up Gamma. AB - Several recent studies have demonstrated that the bottom-up signaling of a visual stimulus is subserved by interareal gamma-band synchronization, whereas top-down influences are mediated by alpha-beta band synchronization. These processes may implement top-down control of stimulus processing if top-down and bottom-up mediating rhythms are coupled via cross-frequency interaction. To test this possibility, we investigated Granger-causal influences among awake macaque primary visual area V1, higher visual area V4, and parietal control area 7a during attentional task performance. Top-down 7a-to-V1 beta-band influences enhanced visually driven V1-to-V4 gamma-band influences. This enhancement was spatially specific and largest when beta-band activity preceded gamma-band activity by ~0.1 s, suggesting a causal effect of top-down processes on bottom-up processes. We propose that this cross-frequency interaction mechanistically subserves the attentional control of stimulus selection.SIGNIFICANCE STATEMENT Contemporary research indicates that the alpha-beta frequency band underlies top down control, whereas the gamma-band mediates bottom-up stimulus processing. This arrangement inspires an attractive hypothesis, which posits that top-down beta band influences directly modulate bottom-up gamma band influences via cross frequency interaction. We evaluate this hypothesis determining that beta-band top down influences from parietal area 7a to visual area V1 are correlated with bottom-up gamma frequency influences from V1 to area V4, in a spatially specific manner, and that this correlation is maximal when top-down activity precedes bottom-up activity. These results show that for top-down processes such as spatial attention, elevated top-down beta-band influences directly enhance feedforward stimulus-induced gamma-band processing, leading to enhancement of the selected stimulus. PMID- 28592699 TI - Lower Affinity of Isradipine for L-Type Ca2+ Channels during Substantia Nigra Dopamine Neuron-Like Activity: Implications for Neuroprotection in Parkinson's Disease. AB - Ca2+-influx through L-type Ca2+-channels (LTCCs) is associated with activity related stressful oscillations of Ca2+ levels within dopaminergic (DA) neurons in the substantia nigra (SN), which may contribute to their selective degeneration in Parkinson's disease (PD). LTCC blockers were neuroprotective in mouse neurotoxin models of PD, and isradipine is currently undergoing testing in a phase III clinical trial in early PD. We report no evidence for neuroprotection by in vivo pretreatment with therapeutically relevant isradipine plasma levels, or Cav1.3 LTCC deficiency in 6-OHDA-treated male mice. To explain this finding, we investigated the pharmacological properties of human LTCCs during SN DA-like and arterial smooth muscle (aSM)-like activity patterns using whole-cell patch clamp recordings in HEK293 cells (Cav1.2 alpha1-subunit, long and short Cav1.3 alpha1-subunit splice variants; beta3/alpha2delta1). During SN DA-like pacemaking, only Cav1.3 variants conducted Ca2+ current (ICa) at subthreshold potentials between action potentials. SN DA-like burst activity increased integrated ICa during (Cav1.2 plus Cav1.3) and after (Cav1.3) the burst. Isradipine inhibition was splice variant and isoform dependent, with a 5- to 11 fold lower sensitivity to Cav1.3 variants during SN DA-like pacemaking compared with Cav1.2 during aSM-like activity. Supratherapeutic isradipine concentrations reduced the pacemaker precision of adult mouse SN DA neurons but did not affect their somatic Ca2+ oscillations. Our data predict that Cav1.2 and Cav1.3 splice variants contribute differentially to Ca2+ load in SN DA neurons, with prominent Cav1.3-mediated ICa between action potentials and after bursts. The failure of therapeutically relevant isradipine levels to protect SN DA neurons can be explained by weaker state-dependent inhibition of SN DA LTCCs compared with aSM Cav1.2.SIGNIFICANCE STATEMENT The high vulnerability of dopamine (DA) neurons in the substantia nigra (SN) to neurodegenerative stressors causes Parkinson's disease (PD). Ca2+ influx through voltage-gated L-type Ca2+ channels (LTCCs), in particular Cav1.3, appears to contribute to this vulnerability, and the LTCC inhibitor isradipine is currently being tested as a neuroprotective agent for PD in a phase III clinical trial. However, in our study isradipine plasma concentrations approved for therapy were not neuroprotective in a PD mouse model. We provide an explanation for this observation by demonstrating that during SN DA like neuronal activity LTCCs are less sensitive to isradipine than Cav1.2 LTCCs in resistance blood vessels (mediating dose-limiting vasodilating effects) and even at supratherapeutic concentrations isradipine fails to reduce somatic Ca2+ oscillations of SN DA neurons. PMID- 28592700 TI - Thrombosis in diabetes: a shear flow effect? AB - Cardiovascular events are the major cause of morbidity and mortality in Type 2 diabetes (T2D). This condition is associated with heightened platelet reactivity, contributing to increased atherothrombotic risk. Indeed, individuals with diabetes respond inadequately to standard antiplatelet therapy. Furthermore, they often experience recurrent events as well as side effects that include excess bleeding. This highlights the need for identification of novel regulators of diabetes-associated thrombosis to target for therapeutic intervention. It is well established that platelet aggregation, a process essential for thrombus formation, is tightly regulated by shear stress; however, the mechanisms underlying shear activation of platelets, particularly in the setting of diabetes, are still poorly understood. This review will address the limitations of current diagnostic systems to assess the importance of shear stress in the regulation of thrombus formation in T2D, and the inability to recapitulate the pro-thrombotic phenotype seen clinically in the setting of T2D. Moreover, we will discuss recent findings utilizing new technologies to define the importance of shear stress in thrombus formation and their potential application to the setting of diabetes. Finally, we will discuss the potential of targeting shear-dependent mechanisms of thrombus formation as a novel therapeutic approach in the setting of T2D. PMID- 28592701 TI - Thrombospondin-1 contributes to slower aortic aneurysm growth by inhibiting maladaptive remodeling of extracellular matrix. AB - In this issue of Clinical Science, Krishna and colleagues describe recent work on thrombospondin-1 (TSP-1) maturation and its association with slower growth of aortic aneurysm in TSP-1 knockdown mouse models. The authors conclude that TSP-1 deficiency promotes maladaptive remodeling of the extracellular matrix (ECM) leading to accelerated aortic aneurysm progression. We comment on a causal relation between TSP-1 and the progression of aortic aneurysm. PMID- 28592702 TI - A past and present overview of macrophage metabolism and functional outcomes. AB - In 1986 and 1987, Philip Newsholme et al. reported macrophages utilize glutamine, as well as glucose, at high rates. These authors measured key enzyme activities and consumption and production levels of metabolites in incubated or cultured macrophages isolated from the mouse or rat intraperitoneal cavity. Metabolic pathways essential for macrophage function were then determined. Macrophages utilize glucose to generate (i) ATP in the pathways of glycolysis and mitochondrial oxidative phosphorylation, (ii) glycerol 3-phosphate for the synthesis of phospholipids and triacylglycerols, (iii) NADPH for the production of reactive oxygen species (ROS) and (iv) ribose for the synthesis of RNA and subsequently production and secretion of protein mediators (e.g. cytokines). Glutamine plays an essential role in macrophage metabolism and function, as it is required for energy production but also provides nitrogen for synthesis of purines, pyrimidines and thus RNA. Macrophages also utilize fatty acids for both energy production in the mitochondria and lipid synthesis essential to plasma membrane turnover and lipid meditator production. Recent studies utilizing metabolomic approaches, transcriptional and metabolite tracking technologies have detailed mitochondrial release of tricarboxylic acid (TCA) intermediates (e.g. citrate and succinate) to the cytosol, which then regulate pro-inflammatory responses. Macrophages can reprogramme their metabolism and function according to environmental conditions and stimuli in order to polarize phenotype so generating pro- or anti-inflammatory cells. Changes in macrophage metabolism result in modified function/phenotype and vice versa. The plasticity of macrophage metabolism allows the cell to quickly respond to changes in environmental conditions such as those induced by hormones and/or inflammation. A past and present overview of macrophage metabolism and impact of endocrine regulation and the relevance to human disease are described in this review. PMID- 28592704 TI - The added value of exhaled breath temperature in respiratory medicine. AB - Recognition of the huge economic burden chronic respiratory diseases pose for society motivated fundamental and clinical research leading to insight into the role of airway inflammation in various disease entities and their phenotypes. However, no easy, cheap and patient-friendly methods to assess it have found a place in routine clinical practice. Measurement of exhaled breath temperature (EBT) has been suggested as a non-invasive method to detect inflammatory processes in the airways as a result of increased blood flow within the airway walls. As EBT values are within a narrow range, the thermometers designed for the purpose of assessing it need to be precise and very sensitive. EBT increases linearly over the pediatric age range and seems to be influenced by gender, but not by height and body weight. In non-smoking individuals with no history of respiratory disease EBT has a natural circadian peak about noon and increases with food intake and physical exercise. When interpreting EBT in subjects with alleged airway pathology, the possibilities of tissue destruction (chronic obstructive pulmonary disease, cystic fibrosis) or excessive bronchial obstruction and air trapping (severe asthma) need to be considered, as these conditions drive (force) EBT down. A prominent advantage of the method is to assess EBT when patients are in a steady state of their disease and to use this 'personal best' to monitor them and guide their treatment. Individual devices outfitted with microprocessors and memory have been created, which can be used for personalized monitoring and disease management by telemedicine. PMID- 28592705 TI - Smoking Cessation without Educational Instruction could Promote the Development of Metabolic Syndrome. AB - AIM: Smoking cessation is particularly important for maintaining health; however, the subsequent risk of an increased body weight is of major concern. The present study investigated the influence of smoking cessation on the incidence of metabolic syndrome and its components in the Japanese general population. METHODS: This study enrolled individuals without metabolic syndrome or a history of smoking via our annual health checkup program (n=5,702, 55.2+/-11.5 years). Participants were divided into three groups mentioned below and followed up with the endpoint being the development of metabolic syndrome: (1) subjects who had never smoked and did not smoke during the observation period (non-smoker); (2) those who continued smoking during the observation period (continuous smoker); and (3) those who ceased smoking during the observation period (smoking cessation). RESULTS: During the observation period (median 1,089 days), 520 subjects developed metabolic syndrome, and Kaplan-Meier analysis showed a higher incidence of metabolic syndrome in the smoking cessation group than in the other groups. Smoking cessation was confirmed as an independent predictor of the new onset of metabolic syndrome by multivariate Cox proportional hazard analysis after adjustment. Subjects only from the smoking cessation group showed a significant deterioration in metabolic factors during the study in correlation with an increased waist circumference after smoking cessation. CONCLUSIONS: Smoking cessation without instruction could be followed by the development of metabolic syndrome, and the incidence of metabolic syndrome might reduce the benefit obtained from smoking cessation. Therefore, further educational outreach is needed to prevent the progression of metabolic syndrome during the course of smoking cessation. PMID- 28592706 TI - Efficacy and safety of long-acting pasireotide in Japanese patients with acromegaly or pituitary gigantism: results from a multicenter, open-label, randomized, phase 2 study. AB - A multicenter, open-label, phase 2 study was conducted to investigate the efficacy and safety of long-acting pasireotide formulation in Japanese patients with acromegaly or pituitary gigantism. Medically naive or inadequately controlled patients (on somatostatin analogues or dopamine agonists) were included. Primary end point was the proportion of all patients who achieved biochemical control (mean growth hormone [GH] levels<2.5MUg/L and normalized insulin-like growth factor-1 [IGF-1]) at month 3. Thirty-three patients (acromegaly, n=32; pituitary gigantism, n=1) were enrolled and randomized 1:1:1 to receive open-label pasireotide 20mg, 40mg, or 60mg. The median age was 52 years (range, 31-79) and 20 patients were males. At month 3, 18.2% of patients (6/33; 90% confidence interval: 8.2%, 32.8%) had biochemical control (21.2% [7/33] when including a patient with mean GH<2.5MUg/L and IGF-1< lower limit of normal). Reductions in the median GH and IGF-1 levels observed at month 3 were maintained up to month 12; the median percent change from baseline to month 12 in GH and IGF-1 levels were -74.71% and -59.33%, respectively. Twenty-nine patients completed the 12-month core phase, 1 withdrew consent, and 3 discontinued treatment due to adverse events (AEs; diabetes mellitus, hyperglycemia, liver function abnormality, n=1 each). Almost all patients (97%; 32/33) experienced AEs; the most common AEs were nasopharyngitis (48.5%), hyperglycemia (42.4%), diabetes mellitus (24.2%), constipation (18.2%), and hypoglycemia (15.2%). Serious AEs were reported in 7 patients with the most common being hyperglycemia (n=2). Long-acting pasireotide demonstrated clinically relevant efficacy and was well tolerated in Japanese patients with acromegaly or pituitary gigantism. PMID- 28592703 TI - Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer. AB - Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC.Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221-9. (c)2017 AACR. PMID- 28592708 TI - Low-signal Intensity Rims along the Cerebral Cortex and U-fibers on Susceptibility-weighted Imaging in Progressive Multifocal Leukoencephalopathy. PMID- 28592707 TI - Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice. AB - AIM: Statins have a protective impact against cardiovascular diseases through not only lipid-lowering effects but also pleiotropic effects, including activation of the endothelial nitric oxide synthase (eNOS) system. We aimed to clarify the protective effects of a statin against atherogenesis and ischemia in eNOS-/- mice. METHODS: Study 1. eNOS-/- Apolipoprotein E (ApoE)-/- mice were treated with a vehicle or pitavastatin (0.3 mg/kg/day) for 4 weeks. Study 2. eNOS-/- mice were also treated with a vehicle or the same dose of pitavastatin for 2 weeks prior to hind-limb ischemia. RESULTS: In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS-/- ApoE-/- mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin treated eNOS-/- mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models. CONCLUSION: Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules. PMID- 28592709 TI - Relationship between Contrast Enhancement of the Perivascular Space in the Basal Ganglia and Endolymphatic Volume Ratio. AB - PURPOSE: We routinely obtain the endolymphatic hydrops (EH) image using heavily T2-weighted three dimensional-fluid attenuated inversion recovery (hT2w-3D-FLAIR) imaging at 4 hours after intravenous administration of a single-dose of gadolinium-based contrast media (IV-SD-GBCM). While repeating the examination, we speculated that the contrast enhancement of the perivascular space (PVS) in the basal ganglia might be related to the degree of EH. Therefore, the purpose of this study was to investigate the relationship between the endolymphatic volume ratio (%ELvolume) and the signal intensity of the PVS (SI-PVS). MATERIALS AND METHODS: In 20 patients with a suspicion of EH, a heavily T2-weighted 3D-turbo spin echo sequence for MR cisternography (MRC) and an hT2w-3D-FLAIR as a positive perilymph image (PPI) were obtained at 4 hours after IV-SD-GBCM. The %ELvolume of the cochlea and the vestibule were measured on the previously reported HYDROPS2 Mi2 image. The PVS in the basal ganglia was segmented on MRC using a region growing method. The PVS regions were copied and pasted onto the PPI, and the SI PVS was measured. The larger value of the right and the left ears was employed as the %ELvolume, and the weighted average of both sides was employed as the SI-PVS. The correlation between the %ELvolume and the SI-PVS was evaluated. RESULT: There was a strong negative linear correlation between the %ELvolume of the cochlea and the SI-PVS (r = -0.743, P < 0.001); however, there was no significant correlation between the %ELvolume of the vestibule and the SI-PVS (r = -0.267, P = 0.256). CONCLUSION: There was a strong negative correlation between the cochlear %ELvolume and the SI-PVS. Contrast enhancement of PVS might be a biomarker of EH. PMID- 28592711 TI - Occupational violence in pregnant women in Brazil: a sample of cases in the Labor Court. AB - Brazilian women are still a recurring target of discrimination in the workplace, facing violence related to gender relations and moral harassment, especially when they are pregnant. When the worker perceives discriminatory acts and attitudes or any violation of the rights guaranteed by law, she may appeal to the Labor Court to initiate legal action. This in turn exposes the worker to a number of issues, such as workplace persecution and future dismissal. The rights of pregnant women to temporary stability, free time for medical examinations, change of duties and maternity leave contrast with the usurpation of the administration's workforce. The rights of pregnant women to temporary stability, free time for medical examinations, change of duties and maternity leave contrast with the growing power of labor administration. PMID- 28592710 TI - Possible changes of New-Generation inflammation markers with occupational lead exposure. AB - OBJECTIVES: Occupational lead (Pb) exposure is still an important health problem in the world. Long-term Pb exposure causes several adverse effects. The aim of this study was to investigate the changes of inflammation markers with chronic Pb exposure by analyzing neopterin levels and kynurenine (Kyn) to tryptophan (Trp) ratio that reflects indolamine 2,3-dioxygenase activity and to compare with healthy volunteers' parameters. METHODS: Blood lead levels (BLLs) were analyzed by atomic absorption spectrometry. Urinary neopterin and serum Kyn and Trp levels were analyzed by high-performance liquid chromatography. RESULTS: According to our results, mean BLL of the 29 workers was 20.4+/-9.6 MUg/dl. Urinary neopterin levels, serum Kyn levels, and Kyn/Trp of Pb workers (188+/-52 MUmol/mol creatinine, 2.70+/-0.66 MUM, and 43.19+/-10.38 MUmol/mmol, respectively) were significantly higher than controls (144+/-35 MUmol/mol creatinine, 2.08+/-0.34 MUM, and 32.24+/-7.69 MUmol/mmol, respectively). Pb-exposed workers were divided into further three groups according to their BLLs: as 10-19 MUg/dl (n=18), 20-29 MUg/dl (n=8), and 30-49 MUg/dl (n=3). Neopterin levels of the workers with BLL of 30-49 MUg/dl were significantly higher than those of BLL with 10-29 MUg/dl, while Trp levels decreased. Kyn/Trp of workers with BLL of 30-49 MUg/dl were elevated significantly compared with the workers with BLL<30 MUg/dl. In addition to neopterin, Kyn and Kyn/Trp levels were positively influenced by Pb exposure. CONCLUSIONS: Increased level of inflammation markers confirms the adverse effects of Pb even low BLLs, and we suggest that monitoring BLLs with inflammation markers could help to prevent serious occupational health problems. PMID- 28592712 TI - High Serum HDGF Levels Are Predictive of Bone Metastasis and Unfavorable Prognosis in Non-Small Cell Lung Cancer. AB - Hepatoma-derived growth factor (HDGF) is a heparin-binding protein possessing mitogenic activity and could be secreted from necrotic cells passively or actively, thereby functioning as a damage-associated molecular pattern (DAMP). The high expression of HDGF in non-small cell lung cancer (NSCLC) tissues is associated with unfavorable prognosis. However, the clinical significance of serum HDGF has not been elucidated in NSCLC yet. In the present study, we compared the serum levels of HDGF in 235 patients with NSCLC (141 adenocarcinoma and 94 squamous cell carcinoma cases) with those in 40 healthy subjects. Moreover, we explored the correlation between serum HDGF levels and clinicopathologic factors or the overall survival rates. We thus found that the serum HDGF levels were significantly higher in NSCLC patients than those in healthy subjects (P < 0.001). Moreover, there was no significant difference in the serum HDGF levels between adenocarcinoma and squamous cell carcinoma. Importantly, the higher serum levels of HDGF were significantly associated with bone metastasis and with lower overall survival rates. Thus, serum HDGF was identified as an independent prognostic factor indicating poor prognosis of NSCLC. Using A549 human lung adenocarcinoma cell line, we demonstrated that an autophagy inhibitor, chloroquine, could inhibit the HDGF secretion, while quercetin, an autophagy inducer derived from a traditional Chinese drug, could facilitate HDGF secretion. In conclusion, high serum levels of HDGF were significantly correlated to bone metastasis and poorer prognosis of NSCLC. We suggest that anti-HDGF therapy is potential to protect NSCLC patients with advanced stages from bone metastasis. PMID- 28592713 TI - Pulmonary-Limited Granulomatosis with Polyangiitis Coexisting with Mixed Connective Tissue Disease. AB - Granulomatosis with polyangiitis (GPA) is a systemic disease characterized by necrotizing, granulomatous vasculitis of the upper and lower respiratory tracts and glomerulonephritis, and is classified as a classical or limited form. The classical form of GPA demonstrates the involvement of the upper respiratory tract, sinuses, lungs and kidneys, whereas the limited form is characterized by the lack of the renal involvement with female predominance. On the other hand, mixed connective tissue disease (MCTD) shows the clinical and laboratorial features of systemic lupus erythematosus, systemic sclerosis and polymyositis, along with high titers of anti-ribonucleoprotein antibodies and is characterized by good response to corticosteroid therapy and favorable prognosis. We herein report a patient with a history of MCTD that developed into a limited form of GPA (pulmonary-limited GPA). A 39-year-old woman suffered from persistent cough, left back pain and appetite loss. At 21 years of age she was diagnosed with MCTD, but the persistent administration of prednisolone or immunosuppressants was not needed. On admission, high-resolution chest computed tomography showed bilateral, multiple, poorly circumscribed nodules and masses, some of which showed cavitation. A surgical lung biopsy demonstrated granulomas with vasculitis surrounding the necrotic lesions. She was diagnosed with pulmonary-limited GPA. In conclusion, we should recognize that GPA may develop during the disease course of MCTD even after prolonged disease remission. To prevent progression to an irreversible state, physicians should consider a surgical lung biopsy for the diagnosis in patients suspected of having pulmonary-limited GPA. PMID- 28592714 TI - The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision. AB - The updated 2016 edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) uses molecular parameters and the histology to define the main tumor categories for the first time. This represents a shift from the traditional principle of using neuropathological diagnoses, which are primarily based on the microscopic features, to using molecularly oriented diagnoses. Major restructuring was made with regard to diffuse gliomas, medulloblastomas and other embryonal tumors. New entities that are defined by both the histological and molecular features include glioblastoma, isocitrate dehydrogenase (IDH)-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, wingless (WNT)-activated and medulloblastoma, sonic hedgehog (SHH)-activated; and embryonal tumor with multilayered rosettes, C19MC-altered. In addition, some entities that are no longer diagnostically relevant-such as CNS-primitive neuroectodermal tumor-have been deleted from this updated edition. The WHO2016 certainly facilitates clinical and basic research to improve the diagnosis of brain tumors and patient care. PMID- 28592715 TI - Synthesis of Clovamide Analogues That Inhibit NO Production in Activated BV-2 Microglial Cells. AB - A series of methyl ester of clovamide analogues, where the hydroxyl group of catechol moiety in caffeic acid and L-3,4-dihydroxyphenylalanine (L-dopa) was replaced with various functional groups, were synthesized and their inhibitory effects on nitric oxide (NO) production and inducible NO synthase (iNOS) expression in lipopolysaccharide (LPS)-induced BV2 cells were tested. Among the synthesized compounds, 3,5-ditrifluoromethyl analogue 9l (IC50=2.8 uM) exhibited a potency about 26.3 times greater than that of the parent compound 9a (IC50=73.6 uM) and suppressed NO production dose-dependently without cytotoxicity. Compound 9l also inhibited iNOS expression in LPS-induced BV2 cells at 2.5, 5 and 10 uM concentrations. These results suggested that the dihydroxyl group of catechol moiety in caffeic acid unit is not essential for the suppression of NO production and that 9l has potential as a potent inhibitor of NO production. PMID- 28592716 TI - Animal ethics and welfare education in wet-lab training can foster residents' ethical values toward life. AB - Live animals are used in surgical skills training in wet lab, which has undeniable effectiveness for the development of future surgeons. However, where such training is provided, animal welfare is a major consideration. Increasingly, institutions that offer wet-lab training are incorporating animal ethics and welfare-related content into their training courses, but the effectiveness of such animal ethics education has yet to be evaluated quantitatively. We investigated whether the animal ethics content of a training course affected trainees by measuring increase in ethical awareness using visual analog scale questionnaires before and after training. Our results demonstrated a significant and positive increase in awareness of animal ethics (significance level of 5%; 0.0380<=P<=0.0016). PMID- 28592717 TI - Hypomethylated Ubiquitin-Conjugating Enzyme2 Q1 (UBE2Q1) Gene Promoter in the Serum Is a Promising Biomarker for Hepatitis B Virus-Associated Hepatocellular Carcinoma. AB - Aberrant DNA methylation, which can be detected in circulating cell-free DNA (cfDNA), is one of the major epigenetic alterations in hepatocellular carcinoma (HCC). UBE2Q1, a putative member of the ubiquitin-conjugating enzyme family, might play substantial roles in tumorigenesis. However, the methylation status of the UBE2Q1 gene in HCC remains unknown. We aimed to determine the methylation status of the UBE2Q1 gene promoter and to evaluate its potential clinical significance for HCC detection. The methylation-specific polymerase chain reaction (MSP) assay was used to detect the UBE2Q1 gene methylation status in serum samples from 80 patients with hepatitis B virus (HBV)-related HCC, 40 patients with liver cirrhosis (LC), 40 patients with chronic hepatitis B (CHB), and 20 healthy controls (HCs). Significantly lower methylation frequencies were detected in HCC patients (33.75%) compared with LC patients (55.00%, p = 0.026) and CHB patients (60.00%, p = 0.006) and HCs (65.00%, p = 0.011). Hypomethylation of the UBE2Q1 gene was negatively associated with the tumor node metastasis stage (rs = -0.30, p = 0.008). The UBE2Q1 gene methylation status combined with alpha fetoprotein using cut-off points of 20, 200 and 400 ng/ml showed sensitivity and specificity values of 58.8% and 75.0%, 53.8% and 87.5%, and 37.5% and 88.7%, respectively, and yielded a significantly increased area under the ROC curve (0.720, 0.760 and 0.694, respectively) for discriminating HCC from LC and CHB. Our study results suggest that hypomethylation of the UBE2Q1 gene promoter is a potential biomarker for detecting HBV-associated HCC. PMID- 28592718 TI - Long-Term Subclinical Hyperglycemia and Hypoglycemia as Independent Risk Factors for Mild Cognitive Impairment in Elderly People. AB - Dementia is one of the most common geriatric diseases, and mild cognitive impairment (MCI) is considered to be incipient dementia. MCI patients have elevated risk of progressing to dementia. Multiple metabolic abnormalities have an unconfirmed effect on MCI risk, and taking adequate measures against metabolic abnormalities might prevent the developing of MCI. Thus, the present study explored the association of MCI risk with common metabolic abnormalities, such as hyperglycemia, hypoglycemia, hyperlipidemia and hypouricemia, and to provide the basis for MCI prevention. A total of 1,262 elderly outpatients with normal cognitive function and without confirmed diabetes mellitus, hyperlipoidemia and gout were enrolled. During the five-year follow-up period, 142 subjects were diagnosed with MCI according to Mini Mental State Examination and Montreal Cognitive Assessment. Furthermore, annual blood glucose, glycated hemoglobin, lipids and uric acid values were obtained, and mean of each indicator was calculated. Only mean values were included in the study to reflect long-term effect of metabolic abnormalities on MCI risk. Thus, the increased risk of MCI was associated with the mean values of blood glucose < 4.7 mmol/L (RR: 1.57, 95% CI: 1.14-2.32), blood glucose >= 6.3 mmol/L (RR: 1.49, 95% CI: 1.03-2.39), glycated hemoglobin >= 5.9% (RR: 2.28, 95% CI: 1.59-3.91), triglycerides >= 2.0 mmol/L (RR: 2.79, 95% CI: 2.14-3.79), total cholesterol >= 5.5 mmol/L (RR: 2.37, 95% CI: 1.69-3.39) and uric acid <= 380 MUmol/L (RR: 1.62, 95% CI: 1.08-2.51). In conclusion, long-term subclinical hyperglycemia, hypoglycemia, hyperlipidemia, and hypouricemia are independent risk factors for MCI in elderly people. PMID- 28592720 TI - Effect of Flooding and the nosZ Gene in Bradyrhizobia on Bradyrhizobial Community Structure in the Soil. AB - We investigated the effects of the water status (flooded or non-flooded) and presence of the nosZ gene in bradyrhizobia on the bradyrhizobial community structure in a factorial experiment that examined three temperature levels (20 degrees C, 25 degrees C, and 30 degrees C) and two soil types (andosol and gray lowland soil) using microcosm incubations. All microcosms were inoculated with Bradyrhizobium japonicum USDA6T, B. japonicum USDA123, and B. elkanii USDA76T, which do not possess the nosZ gene, and then half received B. diazoefficiens USDA110Twt (wt for the wild-type) and the other half received B. diazoefficiens USDA110DeltanosZ. USDA110Twt possesses the nosZ gene, which encodes N2O reductase; 110DeltanosZ, a mutant variant, does not. Changes in the community structure after 30- and 60-d incubations were investigated by denaturing-gradient gel electrophoresis and an image analysis. USDA6T and 76T strains slightly increased in non-flooded soil regardless of which USDA110T strain was present. In flooded microcosms with the USDA110Twt strain, USDA110Twt became dominant, whereas in microcosms with the USDA110DeltanosZ, a similar change in the community structure occurred to that in non-flooded microcosms. These results suggest that possession of the nosZ gene confers a competitive advantage to B. diazoefficiens USDA110T in flooded soil. We herein demonstrated that the dominance of B. diazoefficiens USDA110Twt within the soil bradyrhizobial population may be enhanced by periods of flooding or waterlogging systems such as paddy-soybean rotations because it appears to have the ability to thrive in moderately anaerobic soil. PMID- 28592719 TI - Effects of toceranib phosphate (Palladia) monotherapy on multidrug resistant lymphoma in dogs. AB - We examined whether multidrug resistant (MDR) canine lymphoma increases gene expression for platelet-derived growth factor receptor alpha (PDGFRalpha), vascular endothelial growth factor receptor 2 (VEGFR2), and c-KIT, and whether toceranib phosphate (TOC) has potential as a treatment for MDR canine lymphoma. The clinical data showed that PDGFRalpha expression was higher in canine subjects with MDR T-cell lymphoma than in those with untreated T-cell lymphoma, and that c KIT expression was greater in subjects with T-cell lymphoma than in those with B cell lymphoma. TOC monotherapy was well tolerated without serious adverse effects, and two of the five subjects that received TOC exhibited partial responses. The data presented here could contribute to the assessment of TOC based therapy for dogs with MDR or T-cell lymphoma. PMID- 28592721 TI - Factors Determining the Biodiversity of Halophilic Microorganisms on Historic Masonry Buildings. AB - The aim of the present study was to obtain insights into the relationship between the chemical (salt content and pH) and physico-mechanical (humidity and compressive strength) properties of mineral-based materials from historic buildings with salt efflorescence and the growth and biodiversity of halophilic microorganisms. Samples were mainly characterized by pH 6.5-8.5 and a moisture content of between 0.12 and 3.3%. Significant variations were also found in the salt content (sulfates, chlorides, and nitrates) of the materials. An SEM/EDS analysis of material surfaces revealed the presence of halite, calcite, gypsum, sodium sulfate, and potassium-sodium sulfate. Culture-dependent and culture independent (clone library construction) approaches were both applied to detect halophilic microorganisms. Results derived from culturable methods and the materials analysis revealed a correlation between the total halophile count and pH value as well as sulfate content. A correlation was not observed between the concentration of chlorides or nitrates and the number of halophilic microorganisms. The materials studied were inhabited by the culturable halophilic bacteria Halobacillus sp., Virgibacillus sp., and Marinococcus sp. as well as the yeast Sterigmatomyces sp., which was isolated for the first time from mineral materials. Culture-independent techniques revealed the following bacterial species: Salinibacterium, Salinisphaera, Rubrobacter, Rubricoccus, Halomonas, Halorhodospira, Solirubrobacter, Salinicoccus, and Salinibacter. Biodiversity was the highest in materials with high or moderate salinity. PMID- 28592722 TI - Release and Constancy of an Antibiotic Resistance Gene in Seawater under Grazing Stress by Ciliates and Heterotrophic Nanoflagellates. AB - Extracellular DNA (exDNA) is released from bacterial cells through various processes. The antibiotic resistance genes (ARGs) coded on exDNA may be horizontally transferred among bacterial communities by natural transformation. We quantitated the released/leaked tetracycline resistance gene, tet(M) over time under grazing stress by ciliates and heterotrophic nanoflagellates (HNFs), and found that extracellular tet(M) (ex-tetM) increased with bacterial grazing. Separate microcosms containing tet(M)-possessing bacteria with ciliates or HNFs were prepared. The copy number of ex-tetM in seawater in the ciliate microcosm rapidly increased until 3 d after the incubation, whereas that in the HNF microcosm showed a slower increase until 20 d. The copy number of ex-tetM was stable in both cases throughout the incubation period, suggesting that extracellular ARGs are preserved in the environment, even in the presence of grazers. Additionally, ARGs in bacterial cells were constant in the presence of grazers. These results suggest that ARGs are not rapidly extinguished in a marine environment under grazing stress. PMID- 28592723 TI - Chondroma of the Sternum Growing in a Pregnant Patient: A Case Report. AB - PURPOSE: Benign tumors are known to grow or develop sometimes during pregnancy. We present a case report about a young woman with a growing sternal tumor. METHODS: After her second pregnancy, a 32-year-old female presented with a rapid growing sternal tumor. Computed tomography (CT) scan revealed a tumor measuring 10 * 8 * 7 cm with an intrathoracic bulk, compressing the heart and the upper margin of the liver. RESULTS: Resection of the tumor was performed uneventfully. Histologic examination of the resected mass revealed a chondroma. CONCLUSION: To the best of our knowledge, this is the first report of a huge sternal chondroma growing in a pregnant patient. There is not often a need to treat these patients before delivery, however, thereafter surgical treatment of growing tumors is recommended. PMID- 28592724 TI - Association of Airflow Limitation With Carotid Atherosclerosis in a Japanese Community - The Hisayama Study. AB - BACKGROUND: There has been no large-scale observational study examining the association between chronic obstructive pulmonary disease (COPD) or airflow limitation and carotid atherosclerosis in the general population across a wide range of generations in Asia. In the present study we assessed the association between airflow limitation and carotid intima-media thickness (IMT) in a general Japanese population, with consideration of a comprehensive array of cardiovascular risk factors.Methods and Results:In all, 2,099 community-dwelling Japanese subjects were included in the study. Airflow limitation was defined by spirometry. Maximum and mean IMT values were measured using carotid ultrasonography. Among the subjects, 352 (16.8%) had airflow limitation. The geometric mean values of maximum IMT and mean IMT were significantly higher in subjects with than without airflow limitation (1.27 vs. 1.18 mm, respectively, for maximum IMT; 0.73 mm vs. 0.72 mm, respectively, for mean IMT) and increased with the severity of airflow limitation after adjustment for conventional risk factors, including smoking habits and serum high-sensitivity C-reactive protein. It should be noted that the magnitude of these associations was greater in the middle-aged (40-64 years) than elderly (>=65 years) subgroup. CONCLUSIONS: The findings of the present study suggest that airflow limitation is a significant risk factor for carotid atherosclerosis, especially in midlife, in the general Japanese population. PMID- 28592725 TI - Useful Computed Tomography Score for Estimation of Early Neurologic Outcome in Post-Cardiac Arrest Patients With Therapeutic Hypothermia. AB - BACKGROUND: The Alberta Stroke Program Early CT Score (ASPECTS) is used to assess early ischemic stroke damage. This study compared bilateral ASPECTS (ASPECTS-b) with the gray:white matter ratio (GWR) and quantitative regional abnormality (QRA) to evaluate the prognostic utility of early computed tomography (CT) findings in post-cardiac arrest patients.Methods and Results:Out-of-hospital cardiac arrest patients with return of spontaneous circulation (ROSC) who underwent brain CT (<6 h after onset) and therapeutic hypothermia were recruited from a university hospital over a 2-year period. General demographics, ROSC characteristics, ASPECTS-b (total score=20 points), GWR, and QRA were assessed. Multivariate logistic regression analysis was used to predict neurologic outcome using cerebral performance category (CPC) at 1 month. The study population was divided into good (n=20; CPC 1-2) and poor (n=47; CPC 3-5) outcome groups. The good (vs. poor) outcome group was younger (mean [+/-SD] age 46.7+/-11.8 vs. 60.3+/-17.2 years; P=0.002) and had more initial shockable rhythms (40.0% vs. 8.5%; P=0.002). In addition, the good outcome group had a higher mean ASPECTS-b score (15.3+/-2.7 vs. 9.0+/-4.9; P<0.001), despite no differences in QRA and mean GWR. Age and ASPECTS-b were independent predictors of outcome after adjusting for potential confounders. CONCLUSIONS: These findings suggest that an initial CT score (ASPECTS-b) could help estimate early neurologic outcomes in post-cardiac arrest patients treated with therapeutic hypothermia. PMID- 28592726 TI - Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Outcome and Cardiac Function in Patients With Diabetes and Heart Failure - Insights From the Ibaraki Cardiac Assessment Study-Heart Failure (ICAS-HF) Registry. AB - BACKGROUND: Although experimental animal studies report many pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), their prognostic value has not been demonstrated in clinical trials.Methods and Results:Among 838 prospectively enrolled heart failure (HF) patients hospitalized for acute decompensated HF, 79 treated with DPP-4i were compared with 79 propensity score-matched non-DPP-4i diabetes mellitus (DM) patients. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of cardiovascular death and hospitalization. During follow-up (423+/-260 days), 8 patients (10.1%) in the DPP 4i group and 13 (16.5%) in the non-DPP-4i group died (log-rank, P=0.283). The DPP 4i group did not have a significantly higher rate of all-cause mortality (log rank, P=0.283), or cardiovascular death or hospitalization (log-rank, P=0.425). In a subgroup analysis of HF with preserved ejection fraction (HFpEF; n=75), the DPP-4i group had a significantly better prognosis than the non-DPP-4i group regarding the primary endpoint (log-rank, P=0.021) and a tendency to have better prognosis regarding the secondary endpoint (log-rank, P=0.119). In patients with HF with reduced EF (n=83), DPP-4i did not result in better prognosis. CONCLUSIONS: DPP-4i did not increase the risk of adverse clinical outcomes in patients with DM and HF. DPP-4i may be beneficial in HFpEF. PMID- 28592727 TI - Temporal Sequential Pattern of Right Ventricular Free Wall Contraction in Normal Children. AB - BACKGROUND: The temporal sequence of right ventricular (RV) deformation is related to RV dysfunction. The sequence of RV free wall contraction was investigated.Methods and Results:In this prospective study, strain profiles using speckle-tracking echocardiography and tissue Doppler-derived pulmonary and tricuspid annular motion were assessed in 60 normal children. Circumferential RV free wall strain of 3 individual segments (anterior, lateral, and inferior) was evaluated. Longitudinal strain was assessed in 3 individual segments (RV outflow tract [RVOT], apical, and RV inflow tract [RVIT]). The isovolumetric contraction time (ICT) and the time interval between the onset of the QRS wave to the peak s' wave were measured for pulmonary and tricuspid annular motion velocities. The time to peak circumferential strain was significantly lower in the anterior than in the lateral and inferior segments (339.1+/-19.5, 358.3+/-21.8, and 366.6+/ 22.4 ms, respectively; P<0.0001). Longitudinal deformation of the RVOT segment occurred before the apical and RVIT segments (351.8+/-23.1, 366.3+/-20.1, and 369.2+/-21.3 ms, respectively; P<0.0001). The ICT and the time to peak s' were significantly shorter in pulmonary than in tricuspid annular motion (49.4+/-10.1 vs 58.0+/-13.2 ms; and 104.7+/-12.2 vs. 160.5+/-27.1 ms; P<0.0001 for each). CONCLUSIONS: Longitudinal deformation of RVOT precedes RVIT. Circumferential deformation occurs in the anterior segment before the lateral and posterior segments. The presence of mechanical time heterogeneity appears important for RV performance. PMID- 28592728 TI - Inflammaging and age-associated diseases. PMID- 28592729 TI - Is dementia a treatable disease? PMID- 28592730 TI - Kumamoto Earthquake and health issues of the elderly. PMID- 28592731 TI - Health condition of elderlies and re-construction of the city after the Great East Earthquake and Tsunamis. -report from Rikuzentakata. PMID- 28592732 TI - The predicament of elderly disaster victims: 6 years after the Great East Japan Earthquake and Fukushima nuclear power plant accident. PMID- 28592733 TI - Disaster medicine for the elderlies -chronological aspects of the Great East Japan Earthquake and Tsunami and future issues. PMID- 28592734 TI - A cross-sectional study on the factors related to cognitive decline in community dwelling elderly. AB - AIM: The aim of this study was to examine the relationship between cognitive decline and physical activity, sitting time, and social participation among elderly people living independently in a local community. METHODS: In January 2015, 1,133 independently-living elderly individuals from a local Japanese community completed self-administrated questionnaires. A total of 929 participants completed the questionnaire (valid response rate: 82.0%). A multiple logistic regression analysis was conducted to examine the relationship between cognitive decline, physical activity, sitting time, and social participation. The factors related to cognitive decline were examined using three statistical models: (1) Model 1 was not adjusted for any factors; (2) Model 2 was adjusted for age, education level, smoking status, and drinking status; and (3) Model 3 was adjusted for the covariates in Model 2, plus depression. RESULTS: Cognitive decline was observed in 33% of men and 26% of women. The results indicated that decreased social participation was significantly related to cognitive decline in Models 1 and 2. For men, local community activity and political/economic activity were significantly associated with cognitive decline in Models 1 and 2. Among women, physical activity was significantly related to cognitive decline in Model 1. There was also a significant association between social participation and cognitive decline in Models 1 and 2; decreased volunteer activity was significantly related to cognitive decline in all three models. CONCLUSION: The results of the present study indicated that attending volunteer activities was significantly related to cognitive decline in women. PMID- 28592735 TI - The development of a scale for social participation among community-dwelling frail older adults: a preliminary survey. AB - AIM: The aim of our study was to draft a scale measuring the social participation of community-dwelling frail older adults. METHODS: A questionnaire consisting of 37 items was prepared based on the findings of previous studies. We recruited community-dwelling older adults >=65 years of age living in Mitaka City, Tokyo. The inclusion criteria were as follows: native speakers of Japanese; not being covered as support and care level; support level 1; support level 2; care level 1; and care level 2. In total, 328 individuals were investigated. The selected individuals were categorized into the following six groups, according to a Japanese frailty scale and the Japanese Long-term Care Insurance System: non frail, frail and at high-risk of requiring long-term care, support level 1, support level 2, care level 1, and care level 2. We then randomly selected individuals adjusted for age and gender in each group. The Rasch model was used to select items and to examine the validity. Cronbach's alpha was calculated to examine reliability. RESULTS: We analyzed 170 subjects. Of the 37 items, 22 were considered based on the Rasch model for inclusion in a draft scale of social participation. The Cronbach's alpha for these items ranged from 0.86-0.87. CONCLUSIONS: We conducted a preliminary survey to develop a scale describing social participation among community-dwelling frail older adults. The construct validity and reliability were adequate for this scale. Based on the findings of this preliminary survey, we will investigate a larger sample size to enhance the scale. PMID- 28592737 TI - Octreotide LAR was useful for avoiding hypoglycemia in an elderly patient with insulinoma. AB - An 80-year-old woman was admitted to our hospital with a hypoglycemia attack. She was diagnosed with insulinoma based on her high insulin level at the time of the hypoglycemia attack and the presence of a hypervascular tumor in her pancreas. The patient refused surgical treatment and octreotide was used to prevent hypoglycemia.It is known that octreotide suppresses the secretion of insulin from the pancreas; however, insulin secretion is not always suppressed in patients with insulinoma. Moreover, there is no particular protocol for the use of octreotide in the treatment of insulinoma.We examined the effect of octreotide in preventing hypoglycemia using CGM. The injection of octreotide (50 MUg) at 21: 00 prevented hypoglycemia during the night.However the patient could not perform self-injection due to the sequelae of a cerebral infarction. We therefore chose to have her eat an extra meal at 11 pm.After a while the patient became exhausted by eating meals at night. We examined the effects of octreotide LAR using CGM, and it was found to prevent hypoglycemia for 4 weeks. The patient's QOL was improved by being released from a restriction that affected her daily life. PMID- 28592736 TI - A cloud-based home health care information sharing system to connect patients with home healthcare staff -A case report of a study in a mountainous region. AB - We have developed a cloud system, the e-Renraku Notebook (e-RN) for sharing of home care information based on the concept of "patient-centricity". In order to assess the likelihood that our system will enhance the communication and sharing of information between home healthcare staff members and home-care patients, we selected patients who were residing in mountainous regions for inclusion in our study. We herein report the findings.Eighteen staff members from 7 medical facilities and 9 patients participated in the present study.The e-RN was developed for two reasons: to allow patients to independently report their health status and to have staff members view and respond to the information received. The patients and staff members were given iPads with the pre-installed applications and the information being exchanged was reviewed over a 54-day period.Information was mainly input by the patients (61.6%), followed by the nurses who performed home visits (19.9%). The amount of information input by patients requiring high-level nursing care and their corresponding staff member was significantly greater than that input by patients who required low-level of nursing care.This patient-centric system in which patients can independently report and share information with a member of the healthcare staff provides a sense of security. It also allows staff members to understand the patient's health status before making a home visit, thereby giving them a sense of security and confidence. It was also noteworthy that elderly patients requiring high-level nursing care and their staff counterpart input information in the system significantly more frequently than patients who required low-level care. PMID- 28592738 TI - A case of hereditary hemorrhagic telangiectasia with hepatic encephalopathy due to portal hepatic venous shunt. AB - An 86-year-old male who was able to perform all activities of daily living (ADL) was diagnosed with hereditary hemorrhagic telangiectasia (HHT) at 70 years of age. Following his diagnosis, he had been receiving treatment at our hospital. After the sudden onset of a consciousness disorder, he was admitted to our hospital's emergency department with asterixis, a high serum ammonia level, and hepatic encephalopathy. After angiography, he was diagnosed with hepatic encephalopathy due to portal hepatic venous shunts. HHT is characterized by abnormal blood vessel construction and the formation of peripheral vasodilatation and shunt blood vessels. Although rare, portal hepatic venous shunts may sometimes cause hepatic encephalopathy. The extent of this shunt increases with age. As Japan is an increasingly aging society, the number of HHT patients with hepatic encephalopathy is likely to increase markedly in the future. PMID- 28592739 TI - A case of idiopathic normal pressure hydrocephalus in an elder diabetic patient. AB - The clinical entity idiopathic normal pressure hydrocephalus (iNPH) is characterized by dementia, urinary incontinence, gait ataxia. An 80-year old man with a past history of Type 2 diabetes mellitus admitted to our hospital. Combination of twice Aspart and Aspart premixed30/70 insulin were used. Although, he was unable to inject insulin by himself recently. On physical examination, he walked in a mildly wide based manner. According to his family, urinary incontinence was existed. Laboratory data were as follows: Postrandial blood glucose 243 mg/dl and glycated hemoglobin 8.0% (NGSP). Brain magnetic resonance imaging (MRI) scans showed thinning of the corpus callosum with enlargement of the lateral ventricles on a colonal image. Evan's ratio was 0.29. The revised version of Hasegawa's Dementia scale (HDS-R) was 10. The patient showed no evidence a related antecedent event, such as head trauma, intracerebral hemorrhage and meningitis. Thus, he was diagnosed as having possible Idiopathic normal pressure hydrocephalus (iNPH). The following several psychological tests and walking test were applied. Before and after the tap, he was evaluated using the HDS-R, Mini mental state examination (MMSE), Timed Up and Go test (TUG). Insulin was replaced by glargine, and Sitagliptin was added. On the 31 day, the patient underwent Ventriculo-perioneal shunt. Laboratoly data and memory impairment were also improved. 8 month's later, HbA1c was 7.5%. iNPH occurs in the elderly and is characterized by a clinical triad of gait disturbance, urinary incontinence and dementia. In the present case, thinning of the corpus callosum with enlargement of the lateral ventricles was detected by MRI. 49% of iNPH patients had Diabetes mellitus. However, we were unable to detect a relationship iNPH and Diabetes mellitus. Cognitive impairment may interfere with the insulin therapy. In the present case, failure of insulin self-injection was the first clinical sign to appear. We were able to reduce dose of insulin. We conclude that iNPH is a treatable disorder, especially when treatment is started early in the course of the disease. PMID- 28592740 TI - Serum amyloid A protein in blistering skin disease and peripheral circulatory disturbance. PMID- 28592744 TI - Treatment advances and prognosis for patients with adult T-cell leukemia lymphoma. AB - A classification for adult T-cell leukemia-lymphoma (ATL) based on clinical features was proposed in 1991: acute, lymphoma, chronic, and smoldering types, and their median survival times (MSTs) were reported to be 6.2, 10.2, 24.3 months, and not reached, respectively. Several new therapies for ATL have since been developed, i.e. dose-intensity multi-agent chemotherapies, allogeneic hematopoietic stem cell transplantation (allo-HSCT), monoclonal antibodies, and anti-viral therapy. The monoclonal antibody to CCR4, mogamulizumab, clearly improved response rates in patients with treatment-naive and relapsed aggressive ATL, and has the potential to provide a survival advantage. The outcomes of allo HSCT have been reported since the early 2000s. High treatment-related mortality was initially the crucial issue associated with this treatment approach; however, reduced intensity conditioning regimens have decreased the risk of treatment related mortality. The introduction of allo- HSCT has had a positive impact on the prognosis of and potential curability with treatments for ATL. A meta analysis of a treatment with interferon-alpha and zidovudine (IFN/AZT) revealed a survival benefit in patients with the leukemic subtype. A phase 3 study comparing IFN/AZT with watchful waiting in patients with indolent ATL is ongoing in Japan. Several clinical trials on novel agents are currently being conducted, such as the histone deacetylase inhibitors, alemtuzumab, brentuximab vedotin, nivolumab, and an EZH1/2 dual inhibitor. PMID- 28592745 TI - Clinicopathological features of cryptococcal lymphadenitis and a review of literature. AB - Cryptococcosis is an invasive fungal infection in immunocompromised patients. The clinicopathological characteristics of cryptococcal lymphadenitis are not well known. We analyzed three cases of cryptococcal lymphadenitis and compared their characteristics with those in previous reports. Two patients were human immunodeficiency virus (HIV) carriers, and one patient was a human T-cell leukemia virus type-1 (HTLV-1) carrier. The age of the HTLV-1 carrier with cryptococcosis was much higher than that of the HIV-1 carriers. CD4-positive cell counts in peripheral blood were 5.8/MUL (Case 1) and 79.9/MUL (Case 2) in the HIV carriers and 3285/MUL in the HTLV-1 carrier (Case 3). According to flow cytometric analysis of the lymph nodes of Cases 1, 2, and 3, 50.0%, 87.1%, and 85.9%, respectively, of the T-cells were CD3; 9.8%, 16.3%, and 75.8%, respectively, were CD4; and 35.5%, 77.3%, and 10.2%, respectively, were CD8. Cryptococcus neoformans was detected in tissue culture in all patients. Although gelatinous lesions and numerous fungal cocci were observed in the two HIV patients, the granuloma formation was small. Gelatinous formation and granuloma formation were observed in the HTLV-1 carrier. Necrosis was observed in all cases. In previous reports, granuloma formation, epithelioid cells, and necrotic lesions were observed in most cases. Most of the patients were also immunosuppressed. However, no HTLV-1 carrier was detected. In conclusion, lymphadenopathy in a HTLV-1 carrier may suggest the presence of cryptococcal lymphadenitis. The frequency of cryptococcosis in HTVL-1 carriers may increase with increase in the long-term survival rate of HTLV-1 carriers. PMID- 28592746 TI - Examining Occupational Health Nurse Competencies when Collaborating with Public Health Services. AB - OBJECTIVES: The purpose of this study was to examine the competencies of occupational health nurses who collaborate with public health services. METHODS: Ten occupational health nurses who work for companies that collaborate with public health services were the subjects. They were the finalists selected from among those occupational health nurses who participated in a preparatory survey and phone interviews that inquired about their collaborative activity experiences with public health services; they were selected because of their greater experience with these collaborations. Semi-structured interviews using an interview guide were conducted, and a Qualitative Content Analysis approach developed by Mayring was used for data analysis. First, collected data were coded based on four aspects of collaborative activity: "Routine engagement"; "Execution of collaboration"; "Engagement for better understanding in the organization"; and "Perceptions, attitudes, and thoughts as foundations of collaboration." Then, categories and subcategories of responses were generated by similarity sorting. RESULTS: Our findings clarified the following specific competencies required of occupational health nurses when collaborating with public health services: "Collection of public health information," "Construction of good relationships with public health personnel," "Extraction of problems within the family among employees," "Connection of employees and their family members with public health personnel," "Utilization of public health resources," and "Demonstration of the importance of collaboration with public health services." Furthermore, the following attitudes and thoughts were clarified: "Retention of supportive attitude and viewpoint toward the entire life of employees and their family factors," "Retention of attitude of promoting collaboration with public health services by occupational health nurses," and "Being aware of the importance of occupational health nurses." CONCLUSIONS: These findings suggest that occupational health nurses need to engage in collaborative activities with more holistic attitudes and thoughts to consider the whole lives of employees and their families. Thus, it is important to provide occupational health nurses with more opportunities to acquire these competencies. Subjects in this study were making efforts to collaborate with public health personnel to enrich their support services by exhibiting "Construction of good relationships with public health personnel" and "Utilization of public health resources," even in understaffed environments with only one occupational health nurse. PMID- 28592747 TI - Roles of Hypoxia Response in Retinal Development and Pathophysiology. AB - The hypoxia response is a fundamental phenomenon mainly regulated by hypoxia inducible factors (HIFs). For more than a decade, we have investigated and revealed the roles of the hypoxia response in the development, physiology, and pathophysiology of the retina by generating and utilizing cell-type-specific conditional knockout mice. To investigate the functions of genes related to the hypoxia response in cells composing the retina, we generated various mouse lines that lack HIFs and/or related genes specifically in retinal neurons, astrocytes, myeloid cells, or retinal pigment epithelium cells. We found that these genes in the different types of retinal cells contribute in various ways to the homeostasis of ocular vascular and visual function. We hypothesized that the activation of HIFs is likely involved in the development and progress of retinal diseases, and we subsequently confirmed the pathological roles of HIFs in animal models of neovascular and atrophic ocular diseases. Currently, anti-vascular endothelial growth factor (anti-VEGF) therapy is a first-line treatment widely used for neovascular retinal diseases. However, alternative or additional targets are now required because several recent large-scale clinical trials and animal studies, including our own research, have indicated that VEGF antagonism may induce retinal vascular and neuronal degeneration. We have identified and confirmed a microRNA as a candidate for an alternative target against neovascular retinal diseases, and we are now working to establish a novel HIF inhibitor for clinical use based on the disease mechanism that we identified. PMID- 28592749 TI - Dynamics of Oxidative Stress Evoked by Myocardial Ischemia Reperfusion After Off Pump Coronary Artery Bypass Grafting Elucidated by Bilirubin Oxidation. AB - BACKGROUND: Revascularization therapy relieves myocardial ischemia, but can also result in ischemia-reperfusion injury caused by oxidative stress. However, the biokinetics of oxidative stress after myocardial ischemia-reperfusion are uncertain. This study aimed to evaluate the dynamics of oxidative stress after off-pump coronary artery bypass grafting (OPCAB) by measuring urinary biopyrrin levels. Biopyrrin is an oxidative metabolite of bilirubin thought to reflect oxidative stress, along with reactive nitrogen species (RNS).Methods and Results:The study included 18 patients who underwent OPCAB; patients were divided into effort angina pectoris (EAP; n=11) and unstable angina pectoris (UAP; n=7). Urinary biopyrrin and RNS levels were measured during the perioperative period (<=48 h after surgery). Biopyrrin levels transiently increased 4-12 h post surgery (early phase), followed by a prolonged increase approximately 24-32 h post-surgery (late phase). The delayed increase in biopyrrin tended to be higher in patients with UAP, with a simultaneous increase in RNS. The patients in the UAP group had generally high pulmonary capillary wedge pressure (PCWP), although the cardiac index was within a normal range during the delay phase. CONCLUSIONS: The dynamics of biopyrrin levels revealed a biphasic pattern of oxidative stress after OPCAB. Delayed production of oxidative stress may be influenced by preoperative severity of myocardial ischemia and delayed RNS production. PMID- 28592750 TI - Migration of Large Thrombus From the Left Atrial Appendage During Transesophageal Echocardiography in a Stroke Patient. PMID- 28592748 TI - Epigenetic Targeted Therapy for Diffuse Intrinsic Pontine Glioma. AB - Diffuse intrinsic pontine glioma (DIPG) is a rare but uniformly fatal cancer of the brain, with peak incidence in children of 5-7 years of age. In contrast to most types of human cancer, there has been no significant improvement in treatment outcomes for patients with DIPG. Since DIPG occurs in the brainstem, a vital region of the brain, there are no surgical options for providing relief to patients, and chemotherapy as well as radiation therapy provide palliative relief at best. To date, more than 250 clinical trials evaluating radiotherapy along with conventional cytotoxic chemotherapy, as well as newer biologic agents, have failed to improve the dismal outcome when compared with palliative radiation alone. The recent discovery of somatic oncogenic histone gene mutations affecting chromatin regulation in DIPG has dramatically improved our understanding of the disease pathogenesis in DIPG, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. This review will discuss about the role of histone modification in chromatin machinery and epigenetic therapeutic strategies for the treatment of DIPG. PMID- 28592752 TI - Successful Vascular Intervention Without Embolic Complications in Budd-Chiari Syndrome. PMID- 28592751 TI - Effect of Ezetimibe on Stabilization and Regression of Intracoronary Plaque - The ZIPANGU Study. AB - BACKGROUND: Diminishing yellow color is associated with plaque stabilization. We assessed the hypothesis that a combination of ezetimibe and statin provides more effective plaque stabilization and regression than statin alone as assessed by plaque color.Methods and Results:Stable coronary artery disease patients (n=131) who underwent elective percutaneous coronary intervention and had yellow plaques were randomized to combination therapy (atorvastatin 10-20 mg and ezetimibe 10 mg/day; Group C) or statin monotherapy (atorvastatin 10-20 mg; Group M). Changes in plaque color and plaque volume during 9 months were assessed by angioscopy and intravascular ultrasound. Low-density lipoprotein cholesterol (LDL-C) decreased from 103+/-28 to 63+/-18 mg/dL in Group C (P<0.001) and from 100+/-28 to 75+/-17 mg/dL in Group M (P<0.001). Yellow color grade decreased significantly in both Group M (2.1+/-1.1 vs. 1.7+/-1.0, P=0.005) and Group C (2.2+/-1.2 vs. 1.8+/-1.2, P=0.002), but did not differ between the groups. %plaque volume did not change in Group M (48.5+/-10.2% vs. 48.2+/-10.4%, P=0.4), but decreased significantly in Group C (50.0+/-9.8% vs. 49.3+/-9.8%, P=0.03). CONCLUSIONS: Compared with statin monotherapy, combination therapy with ezetimibe further reduced LDL-C levels. Significant plaque volume reduction was achieved by the combination therapy, but not statin monotherapy; however, plaque stabilization was similarly achieved by both therapies. Furthermore, reduction in plaque volume was dependent on reduction in LDL-C, regardless of whether it was achieved by statin alone or statin plus ezetimibe. PMID- 28592754 TI - Efficacy of chemotherapy in extremely elderly patients with diffuse large B-cell lymphoma. AB - The safety and effective dose of chemotherapy in treating non-Hodgkin lymphoma in elderly patients is yet to be established. In this study, we assessed the prognosis of diffuse large B-cell lymphoma (DLBCL) in elderly patients (>=75 years) treated with an optimal dose of R-CHOP. No significant differences were observed in progression-free survival between elderly patients and patients aged <74 years with DLBCL. Furthermore, no differences were observed between full-dose R-CHOP and 80% dose R-CHOP groups. Median relative dose intensity was 0.80 in elderly patients with DLBCL. Thus, our data suggested that 80% dose R-CHOP is tolerable and effective in these patients. PMID- 28592753 TI - Recent Surgical Results for Active Endocarditis Complicated With Perivalvular Abscess. AB - BACKGROUND: Surgical treatment for endocarditis patients with a perivalvular abscess is still challenging.Methods and Results:From 2009 to 2016, 470 patients underwent surgery for active endocarditis at 11 hospitals. Of these, 226 patients underwent aortic valve surgery. We compared the clinical results of 162 patients without a perivalvular abscess, 37 patients who required patch reconstruction of the aortic annulus (PR group) and 27 who underwent aortic root replacement (ARR group). Patients with a perivalvular abscess had a greater number ofStaphylococcusspecies and prosthetic valve endocarditis, a greater level of inflammation at diagnosis and symptomatic heart failure before surgery, especially in the ARR group. Nevertheless, the duration between diagnosis and surgery was similar, because of a high prevalence of intracranial hemorrhage in the ARR group. Hospital death occurred in 13 (9%) patients without a perivalvular abscess, in 4 (12%) in the PR and in 7 (32%) in the ARR group. Postoperative inflammation and end-organ function were similar between the groups. Overall survival of patients without a perivalvular abscess and that of the PR group was similar, but was significantly worse in the ARR group (P=0.050, 0.026). Freedom from endocarditis recurrence was similar among all patients. CONCLUSIONS: Patients treated with patch reconstruction showed favorable clinical results. Early surgical intervention is necessary when a refractory invasive infection is suspected. PMID- 28592755 TI - Acute myeloid leukemia developing secondary immune thrombocytopenia after umbilical cord blood transplantation. AB - A 64-year-old man was diagnosed with acute myeloid leukemia M2 (FLT3-ITD positive). After induction chemotherapy and four courses of consolidation therapy, he underwent umbilical cord blood transplantation (CBT) in his first remission. He developed acute graft-versus-host disease (skin stage 2) after successful engraftment. On post-transplantation day 147, he was admitted to the hospital suffering from pneumonia. During the treatment, drastic thrombocytopenia was observed on day 251. Both platelet-associated immunoglobulin G and platelet antibody producing B cells were detected, and he was diagnosed with immune thrombocytopenia (ITP). Treatment with prednisolone (1 mg/kg/day), eltrombopag (25 mg/day), and intravenous immunoglobulin (400 mg/kg) was commenced, but there was no improvement in his platelet count. After switching from eltrombopag to romiplostim (350 ug/week), and addition of cyclosporine, the platelet count rapidly elevated to 150,000/ul. ITP after allogenic stem cell transplantation is a rare complication, and it is often refractory to the 1st-line treatment such as steroids. Herein, we report successful treatment using a combination of romiplostim and an immunosuppressive agent in the case of treatment failure in ITP that developed after CBT. PMID- 28592756 TI - CEA-producing multiple myeloma with meningeal invasion during relapse. AB - Here we describe the case of a 62-year-old woman diagnosed with multiple myeloma (IgA-kappa type) who had a high serum CEA level of 27.7 ng/ml. Upper and lower gastrointestinal endoscopy and PET/CT scan showed no abnormality. After two courses of VAD therapy, the serum CEA level decreased to 5.7 ng/ml, with a decrease in the IgA level, suggesting the diagnosis of CEA-producing myeloma. After 4 years and 1 month, she had a relapse with an increase in the LDH level and myeloma cells in the blood, followed by cognitive loss and convulsion. She died 1 month after the onset of neurological symptoms. Several myeloma cells were detected in the cerebral spinal fluid, which suggested the diagnosis of myelomatous meningitis. Myelomatous meningitis is a rare disease and accounts for 1% of all myelomas. This is the fourth reported case of CEA-producing myeloma. PMID- 28592758 TI - Haploidentical transplantation using post-transplant high-dose cyclophosphamide for adult T-cell lymphoma after mogamulizumab treatment. AB - A 53-year-old man diagnosed with adult T-cell lymphoma (ATL) was treated with mLSG15 chemotherapy and achieved a first complete remission. Subsequently, a liver tumor emerged that was pathologically diagnosed as ATL (first relapse). A second remission was achieved after local irradiation and four cycles of mogamulizumab treatment. The patient received peripheral blood stem cell transplantation (HSCT) from a one haplotype HLA-mismatched daughter after total body irradiation and the administration of fludarabine as a myeloablative conditioning regimen, followed by post-transplant cyclophosphamide. While subsequent acute graft-versus-host disease (GVHD) was never more than Grade I, severe chronic GVHD (cGVHD) developed in the oral cavity and skin that was resistant to escalated doses of cyclosporine and prednisolone. The patient subsequently had a second relapse of ATL as a subcutaneous mass and eventually died of disease progression. Mogamulizumab is a humanized monoclonal IgG that targets CC chemokine receptor 4 (CCR4) and is a key treatment option for relapsed ATL. It reportedly increases the risk of acute GVHD after HSCT due to the depletion of CCR4-positive regulatory T-cells; however, information on its impact on cGVHD is unavailable. Here, we discuss the potential risks and benefits of mogamulizumab, particularly in a haploidentical donor setting during a HSCT for ATL. PMID- 28592757 TI - HIV-negative plasmablastic lymphoma attaining sustained remission with bortezomib combined dose-adjusted EPOCH therapy. AB - A 61-year-old, HIV-negative, immunocompetent woman was admitted to our hospital for significant weight loss, painful swelling of her right cheek, and rapid growth of a tumor in the right hard palate. A CT scan revealed a neoplastic lesion in the right maxillary sinus, extending to the surrounding soft bone tissue and oral cavity, as well as multiple osteolytic lesions in the skull. A pathologic examination revealed that the neoplastic cells in the oral cavity were plasmablasts tending to appear as differentiated plasma cells. The tumor cells strongly expressed CD138, Vs38c, EBER, and MYC, and were negative for CD20 and CD19. The MIB-1 index was 90%, and MYC/IgH fusion gene was detected by fluorescence in situ hybridization analysis. Based on these clinical and pathological findings, we confirmed the diagnosis of plasmablastic lymphoma. This disease has characteristics of aggressive lymphoma originating from differentiated plasma cells. Treatment was initiated with dose-adjusted EPOCH added to a concurrent bortezomib regimen. After completion of four cycles, the patient achieved and sustained complete remission. PMID- 28592760 TI - Overview. PMID- 28592759 TI - Primary breast diffuse large B-cell lymphoma in a male. AB - A 74-year-old male with a mass in the right breast visited the Department of Breast and Endocrine Surgery in November 20XX. Core needle biopsy was performed. Pathological diagnosis was diffuse large B-cell lymphoma. The Ann Arbor clinical stage was IIA, and international prognostic index was low-intermediate. Six courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone and four courses of intrathecal chemotherapy were administered, and the patient achieved complete remission. PMID- 28592761 TI - Acute lymphoblastic leukemia: pathophysiology and current therapy. AB - Acute lymphoblastic leukemia (ALL) is seen in both children and adults, but its incidence peaks between 2 and 5 years and also increases in the older population. Although most children can be cured, the prognosis of adults with ALL remains poor. Recent identification of novel genetic alterations and sequence mutations has contributed to the elucidation of the pathogenesis of ALL. The World Health Organization classification was revised in 2016. ALL was included within the subgroup of myeloid neoplasms and acute leukemia. New provisional entities with recurrent abnormalities have been recognized and incorporated into the classification. Treatment of ALL involves some of the most complex chemotherapy combinations and treatment schedules used in oncology. Two main chemotherapy regimens are being used. The Berlin-Frankfurt-Munster framework consists of an induction regimen, consolidation regimen, reintensification regimen, and maintenance therapy and is mostly used in Europe for adult ALL trials. Another approach is to alternatively repeat two different intensive chemotherapy cycles, such as the hyper-CVAD regimen designed by investigators at the MD Anderson Cancer Center. Furthermore, the treatment of older patients with ALL is an unmet medical need. Novel targeted therapies, immunotherapies, and reduced-intensity SCT are promising approaches. PMID- 28592762 TI - Chronic lymphocytic leukemia: pathophysiology and current therapy. AB - Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries, but it is rare in Japan. Several mutations have been identified in patients with CLL using next-generation sequencing, but disease-specific mutations were not found. Some mutations, such as those in TP53, NOTCH1, SF3B, and BIRC3 are useful for risk stratification and prognosis prediction in patients with CLL. Strategies for treating CLL are rapidly evolving, with targeted agents such as the B-cell receptor signaling pathway inhibitors (ibrutinib, idelalisib), novel anti-CD20 monoclonal antibody (obinutuzumab), and Bcl-2 inhibitor (venetoclax) being approved by the US Food and Drug Administration. Although key drugs such as chlorambucil and rituximab cannot be used in Japan, others such as ibrutinib and bendamustine were recently approved for CLL treatment in Japan. PMID- 28592764 TI - Multiple myeloma: pathophysiology and progress in management. AB - There have been dramatic recent advances in understanding the basic pathophysiology and treatment strategies for multiple myeloma (MM). Research has shown both a high inter-patient diversity and intra-clonal heterogeneity even in a single patient in terms of cytogenetic/molecular abnormalities, and has also identified marked diversity in the immunological factors involved in tumor surveillance among MM patients. In the presence of a variety of novel agents, including molecular-targeted agents, immunomodulatory agents, and monoclonal antibodies, the optimal translation of current knowledge on both molecular and immunologic findings into clinical use is crucial for managing MM. In addition, the application of the decision-making process for the selection of treatment strategies, the classification of disease risk, the prediction of outcome, and disease status monitoring have greatly influenced the clinical course of MM. In this review, we summarize recent advances in understanding the pathophysiology of MM, including molecular/cytogenetic/epigenetic abnormalities and immunologic dysregulation of both tumor and immune cells. In addition, we also briefly discuss the changes/innovations in both diagnostic approaches and treatment concepts. PMID- 28592763 TI - Malignant lymphoma: pathophysiology and current therapy. AB - Recent advances in the understanding of molecular pathogenesis of lymphoma have enabled us to clearly define disease entity by means of a disease-specific gene mutation and to select candidates for novel targeted therapy. In this review three different clinically relevant topics related to the molecular pathogenesis of lymphoma were covered. In the 2016 revision of the World Health Organization classification of lymphoid malignancies, firstly, disease-specific mutations such as MYD88 L265P in Waldenstrom macroglobulinemia and BRAF V600E in hairy cell leukemia were incorporated into diagnostic tests, and secondly, the determination of cell-of-origin in diffuse large B-cell lymphoma (DLBCL) was strongly recommended in diagnosis. Ibrutinib or lenalidomide was shown to be more effective in activated B-cell (ABC) -type-DLBCL than in germinal center B-cell type-DLBCL. Therefore, randomized trials to evaluate the efficacy of adding these agents to standard chemoimmunotherapy focused on the ABC type-DLBCL. Finally, the molecular mechanisms behind the efficacy of immune checkpoint inhibitors, such as anti-programmed cell death 1 antibody in Hodgkin lymphoma, and other lymphoma subtypes were discussed. PMID- 28592765 TI - Overview. PMID- 28592766 TI - Fecal microbiota transplantation for acute graft-versus-host disease of the gut. AB - Advances in microbial analysis have provided new insights into the complex interactions between the host and gut microbiota. An imbalance in the gut microbiota (dysbiosis) is associated with various disorders and their pathogenesis. Furthermore, in allogeneic stem cell transplantation, increasing evidence indicates that the gut microbiota is closely associated with acute graft versus-host disease (GVHD) and transplant outcomes, suggesting that its manipulation could be a new treatment strategy for this acute condition. We conducted a feasibility study of fecal microbiota transplantation (FMT) for acute GVHD of the gut in four human transplant recipients. No severe adverse events that were obviously attributable to FMT were observed. All patients responded to FMT: three patients showed a complete response and one a partial response. Our results indicate that FMT could be a new treatment option for acute GVHD of the gut. However, the use of FMT in treating acute GVHD is in the initial stages of clinical application. FMT has limitations that need to be addressed, such as safety and determination of the optimal donor screening or the treatment protocol. Further evaluation is thus warranted. PMID- 28592767 TI - Immune checkpoint inhibitors and allogeneic hematopoietic stem cell transplantation. AB - Immune checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1 antibodies, have revolutionized cancer therapy, particularly in the treatment of malignant melanoma and lung cancer. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is another form of immunotherapy and is being widely used to cure high risk hematological malignancies. However, more than one-third of patients suffer a relapse after allo-HCT and often have a poor prognosis. A phase I/Ib study to assess the safety and efficacy of ipilimumab (anti-CTLA-4 antibody) for the treatment of relapsed hematological malignancies after allo-HCT has shown that induction treatment with ipilimumab led to remissions in some patients, including those with myeloid malignancies, without eliciting severe graft versus host disease (GVHD). The efficacy of treatment with anti-PD-1 antibodies before or after allo-HCT has been reported in some case reports and in one retrospective study, but one case of fatal GVHD caused by anti-PD-1 antibody therapy after allo HCT raises a concern. Considering that remission status after transplantation is a strong prognostic factor in allo-HCT, immune checkpoint inhibitors might work better during post-remission consolidation than during induction. Further studies on immune checkpoint inhibitors in the treatment of hematological malignancies are warranted. PMID- 28592768 TI - Overview. PMID- 28592769 TI - Thrombotic complications after hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) involves some serious transplant associated complications (TACs) or vascular disorders, such as veno-occlusive disease (VOD), thrombotic microangiopathy (TMA), and graft-versus-host disease (GVHD). VOD is related to a clinical syndrome characterized by tender hepatomegaly, jaundice, fluid retention, and unexplained weight gain. When TMA is described in patients who have undergone HSCT, it is often implied that the clinical diagnosis of TMA is similar to that of thrombotic thrombocytopenic purpura. Therefore, levels of cytokines, chemokines, and soluble molecules are useful biomarkers for VOD and TMA after HSCT. Acute GVHD (aGVHD) occurs in the early period after transplantation and is initiated by alloreactive donor T cells. The mechanisms whereby immune responses trigger this post-transplantation condition remain unclear, but endothelial cell function might play a role in this. The authors investigated the expression of endothelial cell activation markers such as sE-selectin, sVCAM-1, PAI-1, and microparticle in patients undergoing allogeneic HSCT. Levels of endothelial cell activation markers were significantly higher in 143 patients who developed aGVHD than in those who did not develop aGVHD. Moreover, patients who received rTM exhibited a significantly lower frequency of aGVHD and reduced levels of endothelial cell activation markers. These findings suggest that endothelial cell activation might be linked to TAC and that rTM may, at least in part, act to prevent TAC through its effect on endothelial cells. PMID- 28592770 TI - DIC: an update on diagnosis and treatment. AB - Disseminated intravascular coagulation (DIC) was considered to be a fatal disease. However, it has recently been suggested that very early DIC protects the host against microthrombosis and infection localization. Therefore, early treatment of DIC may be contraindicated in patients with sepsis. These factors suggest that the diagnosis and treatment of DIC will gain further importance. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG2016), which include details regarding the management of DIC, have been recently published. Differences in recommendations for DIC treatment, such as antithrombin and recombinant human thrombomodulin, between J-SSCG2016 and other guidelines, including the Japanese Society on Thrombosis and Hemostasis (JSTH), British Committee for Standards in Haematology (BCST), Italian Society for Thrombosis and Haemostasis (SISET), and International Society on Thrombosis and Haemostasis (ISTH) have been discussed. Furthermore, differences in the diagnostic criteria for DIC between the Japanese Ministry of Health, Labor and Welfare, ISTH overt, ISTH non-overt, Japanese Association for Acute Medicine, and JSTH have been discussed. PMID- 28592771 TI - TTP and aHUS: new insights. AB - Both TTP and aHUS are officially designated as intractable diseases by a new Japanese law in 2015. New clinical practice guidelines for TTP and aHUS have been published. Both conditions share some common pathophysiology such as thrombotic microangiopathy. Unfortunately, most professionals in the fields of hematology/oncology are unaware of these diseases. Therefore, I will provide an updated overview of TTP and aHUS in this article. PMID- 28592772 TI - Current topics in primary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by early platelet destruction due to antiplatelet autoantibodies. Recently, significant progress has been made regarding the pathophysiology of ITP. Nonetheless, the diagnosis of ITP in daily clinical practice is still based on differential diagnosis because of the lack of laboratory tests that can diagnose autoimmunity in ITP. In this chapter, the recent topics regarding the diagnosis and management of ITP have been reviewed. PMID- 28592773 TI - Towards comprehensive health risk assessments of chemicals for occupational and environmental health. PMID- 28592774 TI - Erratum to: Transforming Growth Factor b1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression. AB - [This corrects the article on p. 211 in vol. 40.]. PMID- 28592776 TI - Audiovestibular Loss of a Vascular Cause: A Distinction Should Be Made between Cochlear and Vestibular Symptoms. PMID- 28592775 TI - Blood Pressure Management for Stroke Prevention and in Acute Stroke. AB - Elevated blood pressure (BP) is the leading modifiable risk factor for stroke and the benefit of BP lowering therapy on the stroke risk reduction is well established. The optimal BP target for preventing stroke and other vascular events have been controversial, but the evidences from epidemiological studies and randomized controlled trials (RCTs) support intensive BP lowering for greater vascular protection, particularly for stroke prevention. For secondary stroke prevention, the evidence of intensive BP lowering benefit is limited since only a single RCT for patients with lacunar infarctions was conducted and most data were driven by exploratory analyses. In acute intracerebral hemorrhage, immediate BP lowering targeting systolic BP<140 mm Hg is recommended by guidelines based on the results from RCTs. In contrast, in acute ischemic stroke, early BP lowering is not usually recommended because of no benefit on functional outcome and future vascular events and potential harm of stroke progression. This review aims to summarize the updated evidence for optimal BP management for primary and secondary stroke prevention and in patients with acute stroke. PMID- 28592777 TI - Causes and Solutions of Endovascular Treatment Failure. AB - In a meta-analysis of individual patient data from 5 randomized controlled trials, endovascular treatment (EVT) mainly using a stent retriever achieved successful recanalization in 71.1% of patients suffering from acute stroke due to anterior circulation large artery occlusion (LAO). However, EVT still failed in 28.9% of LAO cases in those 5 successful trials. Stent retriever failure may occur due to anatomical challenges (e.g., a tortuous arterial tree from the aortic arch to a target occlusion site), a large quantity of clots, tandem occlusion, clot characteristics (fresh versus organized clots), different pathomechanisms (embolic versus non-embolic occlusion), etc. Given that recanalization success is the most important factor in the neurological outcome of acute stroke patients, it is important to seek solutions for such difficult cases. In this review, the basic technique of EVT is briefly summarized and then various difficult cases with diverse conditions are discussed along with suggested solutions. PMID- 28592778 TI - Diagnostic and Therapeutic Strategies for Acute Intracranial Atherosclerosis related Occlusions. AB - Intracranial atherosclerosis-related occlusion (ICAS-O) is frequently encountered at the time of endovascular revascularization treatment (ERT), especially in Asian countries. However, because baseline angiographic findings are similar between ICAS-O and embolism-related occlusion (EMB-O), it is difficult to differentiate the etiologies before the ERT procedure. Moreover, despite successful randomized trials on ERT, results from studies examining the optimal treatment protocol in ICAS-O patients remain unclear. In this review, we describe the clinical and imaging factors that may possibly differentiate ICAS-O from EMB O. We will also discuss some current hurdles for treating ICAS-O in the hyperacute period and suggest the optimal ERT strategy for ICAS-O patients. PMID- 28592779 TI - Thrombectomy in Acute Ischemic Stroke: Challenges to Procedural Success. AB - The overwhelming clinical benefit of intra-arterial stroke therapy owes to the major advance in revascularization brought on by the current generation of thrombectomy devices. Nevertheless, there remains a sizeable proportion of patients for whom substantial reperfusion cannot be achieved or is achieved too late. This article addresses the persistent challenges that face neurointerventionists and reviews technical refinements that may help to mitigate these obstacles to procedural success. Insights from in vitro modeling and clinical research are organized around a conceptual framework that examines the interaction between the device, the thrombus and the vessel wall. PMID- 28592780 TI - Response to Letter by Dr. Cristina Brandolini. PMID- 28592781 TI - Endovascular Therapy: The Second Round Begins. PMID- 28592783 TI - Association of Optimal Combination Drug Treatment with Obesity Status among Recent Ischemic Stroke Patients: Results of the Vitamin Intervention for Stroke Prevention (VISP) Trial. AB - BACKGROUND AND PURPOSE: One explanation for the 'obesity paradox', where obese patients seem to have better cardiovascular outcomes than lean patients, is that obese patients display an identifiable high cardiovascular risk phenotype that may lead to receiving or seeking earlier/more aggressive treatment. METHODS: We analyzed a clinical trial dataset comprising 3643 recent (<120 days) ischemic stroke patients followed up for 2 years. Subjects were categorized as lean (body mass index [BMI], <25 kg/m2, n=1,006), overweight (25-29.9 kg/m2, n=1,493), or obese (>=30 kg/m2, n=1,144). Subjects were classified as level 0 to III depending on the number of secondary prevention prescriptions divided by the number of potentially indicated drugs (0=none of the indicated medications and III=all indicated medications as optimal combination drug treatment [OCT]). Independent associations between each BMI category and stroke/myocardial infarction/vascular death (major vascular events [MVEs]) and all-cause death were assessed. RESULTS: MVEs occurred in 17.4% of lean, 16.1% of overweight, and 17.1% of obese patients; death occurred in 7.3%, 5.5%, and 5.1%, respectively. Individuals with a higher BMI status received more OCT (45.8%, 51.7%, and 55.3%, respectively; P<0.001). In the lean patient group, multivariable adjusted Cox analyses, showed that compared with levels 0-I, level II and level III were linked to lower risk of MVEs (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.32-0.95 and HR 0.48; 95% CI: 0.28-0.83, respectively) and death (0.44; 0.21-0.96 and 0.23; 0.10-0.54, respectively). CONCLUSIONS: OCT for secondary prevention after an ischemic stroke is less frequent in lean (vs. obese) subjects, but when implemented is related to significantly better clinical outcomes. PMID- 28592784 TI - Nationwide "Hospital Emergent Capability Accreditation by Level-Stroke" Improves Stroke Treatment in Taiwan. AB - BACKGROUND AND PURPOSE: Recombinant tissue plasminogen activator (rtPA) is one of the proven therapies that improve the outcome of patients with acute ischemic stroke (AIS). In 2009, the Ministry of Health and Welfare, Executive Yuan, Republic of China, launched the project "Hospital Emergent Capability Accreditation by Level-Stroke (HECAL-Stroke)" to improve AIS treatment in Taiwan. The current study was performed to determine whether the project launched by the government was effective in promoting rtPA therapy among AIS patients. METHODS: All participating hospitals were verified and designated as "heavy duty (HD)," "moderate duty (MoD)," or "medium duty (MeD)" according to the stroke center criteria. Four annual indices (rates of treatment, protocol adherence, in-time treatment, and complications) were recorded from 2009 to 2014 as outcome measures. The data were analyzed using the chi2 test for significance. RESULTS: The number of certified hospitals progressively increased from 74 to 112 during the 6-year period and finally consisted of 33 HD, 9 MoD and 70 MeD hospitals in 2014. The annual intravenous rtPA treatment rate increased significantly from 3.0% in 2009 to 4.5% in 2014. The protocol adherence rates were 95.7% in the HD group, 92.4% in the MoD group and 72.8% in the MeD group. The annual in-time treatment rate significantly improved from 26.0% in 2009 to 60.1% in 2014. The overall symptomatic intracranial hemorrhagic rate after rtPA treatment was 8.6%. CONCLUSIONS: Initiation of the HECAL-Stroke project by the government significantly improved rtPA treatment in Taiwan. PMID- 28592782 TI - Family History and Stroke Risk in China: Evidence from a Large Cohort Study. AB - BACKGROUND AND PURPOSE: Large cohort studies on relationship between family history of stroke (FHS) and stroke risk are lacking in Asians. We aimed to systematically evaluate the association of FHS with stroke risk in a cohort study of 0.5 million Chinese adults. METHODS: Information about FHS was self-reported. The median follow-up time was 7.16 years and the end-point of follow-up was incident stroke, which was entered directly into the China Kadoorie Biobank system. Multivariate analyses were performed with Cox proportional hazards model, and interaction analyses were carried using likelihood-ratio tests. RESULTS: Compared with participants without FHS, the hazard ratio (HR) (95% confidence interval, CI) of stroke for participants with FHS was 1.50 (1.46-1.55). The HRs increased with the number of first degree relatives with stroke (HRs=1.41, 1.98 and 2.47 for 1, 2 and >=3 relatives, respectively, Ptrend <0.001). The HRs were 1.57 (95% CI: 1.50-1.66) and 1.49 (95% CI: 1.45-1.54) for sibling history and parental history, respectively. Similar associations with offspring stroke risk were observed between paternal history (HR=1.48, 95% CI: 1.43-1.54) and maternal history (HR=1.49, 95% CI: 1.43-1.55). Moreover, significant interactions were detected between FHS and health-risk behaviors (tobacco smoking and alcohol drinking). CONCLUSIONS: FHS is an independent risk factor for stroke in Chinese. The more first degree relatives are affected by stroke, the higher are individuals' risk of suffering from stroke. The management of the health-risk behaviors for reducing stroke should be highlighted, especially for the individuals with FHS. PMID- 28592785 TI - Multidisciplinary Approach to Decrease In-Hospital Delay for Stroke Thrombolysis. AB - BACKGROUND AND PURPOSE: Decreasing the time delay for thrombolysis, including intravenous thrombolysis (IVT) with tissue plasminogen activator and intra arterial thrombectomy (IAT), is critical for decreasing the morbidity and mortality of patients experiencing acute stroke. We aimed to decrease the in hospital delay for both IVT and IAT through a multidisciplinary approach that is feasible 24 h/day. METHODS: We implemented the Stroke Alert Team (SAT) on May 2, 2016, which introduced hospital-initiated ambulance prenotification and reorganized in-hospital processes. We compared the patient characteristics, time for each step of the evaluation and thrombolysis, thrombolysis rate, and post thrombolysis intracranial hemorrhage from January 2014 to August 2016. RESULTS: A total of 245 patients received thrombolysis (198 before SAT; 47 after SAT). The median door-to-CT, door-to-MRI, and door-to-laboratory times decreased to 13 min, 37.5 min, and 8 min, respectively, after SAT implementation (P<0.001). The median door-to-IVT time decreased from 46 min (interquartile range [IQR] 36-57 min) to 20.5 min (IQR 15.8-32.5 min; P<0.001). The median door-to-IAT time decreased from 156 min (IQR 124.5-212.5 min) to 86.5 min (IQR 67.5-102.3 min; P<0.001). The thrombolysis rate increased from 9.8% (198/2,012) to 15.8% (47/297; P=0.002), and the post-thrombolysis radiological intracranial hemorrhage rate decreased from 12.6% (25/198) to 2.1% (1/47; P=0.035). CONCLUSIONS: SAT significantly decreased the in-hospital delay for thrombolysis, increased thrombolysis rate, and decreased post-thrombolysis intracranial hemorrhage. Time benefits of SAT were observed for both IVT and IAT and during office hours and after-hours. PMID- 28592786 TI - Epstein-Barr Virus-Associated Lymphoproliferative Disorders: Review and Update on 2016 WHO Classification. AB - Epstein-Barr virus (human herpesvirus-4) is very common virus that can be detected in more than 95% of the human population. Most people are asymptomatic and live their entire lives in a chronically infected state (IgG positive). However, in some populations, the Epstein-Barr virus (EBV) has been involved in the occurrence of a wide range of B-cell lymphoproliferative disorders (LPDs), including Burkitt lymphoma, classic Hodgkin's lymphoma, and immune-deficiency associated LPDs (post-transplant and human immunodeficiency virus-associated LPDs). T-cell LPDs have been reported to be associated with EBV with a subset of peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphomas, extranodal nasal natural killer/T-cell lymphomas, and other rare histotypes. This article reviews the current evidence covering EBV-associated LPDs based on the 2016 classification of the World Health Organization. These LPD entities often pose diagnostic challenges, both clinically and pathologically, so it is important to understand their unique pathophysiology for correct diagnoses and optimal management. PMID- 28592788 TI - Levamisole-Induced Leukocytoclastic Vasculitis with Negative Serology in a Cocaine User. AB - BACKGROUND Levamisole is a common adulterant of cocaine. It can cause agranulocytosis and cutaneous vasculitis that can possibly lead to cutaneous necrosis. In all reported cases of levamisole-induced vasculitis, it has been described as a clinical syndrome characterized by a constellation of typical clinical features and a positive serum serology for ANCA levels, especially very high-titer p-ANCA levels, in the background of cocaine abuse. However, patients may have a negative serology and here, we present the first such case. CASE REPORT A 58-year-old African American man with a history of polysubstance abuse, 4 days after last cocaine use, presented with sudden onset of painful pruritic rash and polyarthralgias. He was found to have normal vital signs, with bilateral tender knees and erythematous-purplish maculopapular lesions involving the abdomen and the left thigh. Laboratory work-up was significant for elevated CRP, negative c-ANCA, p-ANCA ANA, and RA levels, and a positive urine toxicology for cocaine. Urine analysis by high-performance liquid chromatography was positive for levamisole. Ultimately, a final diagnosis was made by skin biopsy, which revealed findings suggestive of leukocytoclastic vasculitis. CONCLUSIONS Cutaneous leukocytoclastic vasculitis can be caused by levamisole, which is used as an adulterant in cocaine. Most cases are associated with positive ANCA levels; however, a negative serology is also a possibility. PMID- 28592789 TI - Are Sutureless Aortic Valves Suitable for Severe High-Risk Patients Suffering from Active Infective Aortic Valve Endocarditis? AB - BACKGROUND Sutureless aortic valves were introduced to facilitate minimally invasive aortic valve surgery. Since sutureless aortic valves are a feasible procedure, we evaluated if any benefits could be identified in severe high-risk patients with active infective endocarditis of the aortic valve. MATERIAL AND METHODS Between April 2014 and April 2015, a total of 42 patients received a sutureless Perceval(r) aortic valve (Sorin Biomedica Cardio Srl, Saluggia, Italy) for different indications. Nine of these patients (median age 71 years, range 47 83 years) suffered from active infective endocarditis, including four patients with prosthetic aortic valve endocarditis. Five patients underwent prior cardiac surgery, including transcatheter aortic valve implantation (TAVI). The median EuroSCORE II was 29.5% (range 16.8-87.7%). Post-operatively, data regarding mortality, operative results, and early operative morbidity were collected. RESULTS There were no cases of 30-day mortality. Four patients needed abscess closure with pericardium. Three patients underwent left atrial appendix closure: one left ventricular thrombectomy, one bypass grafting, and one arch replacement. Median aortic cross-clamp and cardiopulmonary bypass time was 35 minutes (range 26-88 minutes) and 52 minutes (range 40-133 minutes), respectively. The median intubation time was 14 hours (range 1-9 hours). In these high-risk patients, no postoperative morbidity was found except for one re-intubation due to extensive delirium and one re-exploration. No pacemaker implantation was needed. Echocardiographic evaluation showed no central or para-valvular regurgitation, and a median discharge mean gradient of 5.5 mm Hg (range 2.5-10.0 mm Hg). CONCLUSIONS Sutureless aortic valve replacement in very high-risk patients suffering from active infection endocarditis seems to be an option with limited morbidity and appropriate echocardiographic results, however, further studies are needed. PMID- 28592787 TI - Rare Gastric Lesions Associated with Helicobacter pylori Infection: A Histopathological Review. AB - Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. However, some rare gastric lesions exhibiting distinctive histological features may also be associated with H. pylori infection, including lymphocytic gastritis, granulomatous gastritis, Russell body gastritis, or crystal-storing histiocytosis. Although diverse factors can contribute to their development, there is convincing evidence that H. pylori infection may play a pathogenic role. These findings are mainly based on studies in patients with these lesions who exhibited clinical and histological improvements after H. pylori eradication therapy. Thus, H. pylori eradication therapy might be indicated in patients with no other underlying disease, particularly in countries with a high prevalence of H. pylori infection. This review describes the characteristic histological features of these rare lesions and evaluates the evidence regarding a causative role for H. pylori infection in their pathogenesis. PMID- 28592790 TI - miR-19a contributes to gefitinib resistance and epithelial mesenchymal transition in non-small cell lung cancer cells by targeting c-Met. AB - Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC). However, most NSCLC patients inevitably develop gefitinib resistance, and the mechanisms underlying this resistance are not fully understood. In this study, we show that miR-19a is significantly down-regulated in gefitinib resistant NSCLC cell lines compared with gefitinib-sensitive cell lines. In addition, the down-regulation of miR-19a suppressed the expression of epithelial markers but induced the expression levels of mesenchymal markers. A mechanistic analysis revealed that miR-19a regulated c-Met expression by directly targeting the c-Met 3'UTR. Overexpression of miR-19a decreased c-Met expression and re sensitized gefitinib-resistant NSCLC cells in vitro and in vivo. Consistent with the in vitro findings, the miR-19a serum level was significantly decreased in NSCLC patients with acquired gefitinib resistance compared with the level observed prior to the acquisition of resistance in each patient, indicating that miR-19a expression may be a valuable biomarker for the prediction of acquired gefitinib resistance in a clinical setting. Our data demonstrate that the miR 19a/c-Met pathway plays a critical role in acquired resistance to gefitinib and that the manipulation of miR-19a might provide a therapeutic strategy for overcoming acquired gefitinib resistance. PMID- 28592791 TI - Dimensionless number is central to stress relaxation and expansive growth of the cell wall. AB - Experiments demonstrate that both plastic and elastic deformation of the cell wall are necessary for wall stress relaxation and expansive growth of walled cells. A biophysical equation (Augmented Growth Equation) was previously shown to accurately model the experimentally observed wall stress relaxation and expansive growth rate. Here, dimensional analysis is used to obtain a dimensionless Augmented Growth Equation with dimensionless coefficients (groups of variables, or Pi parameters). It is shown that a single Pi parameter controls the wall stress relaxation rate. The Pi parameter represents the ratio of plastic and elastic deformation rates, and provides an explicit relationship between expansive growth rate and the wall's mechanical properties. Values for Pi are calculated for plant, algal, and fungal cells from previously reported experimental results. It is found that the Pi values for each cell species are large and very different from each other. Expansive growth rates are calculated using the calculated Pi values and are compared to those measured for plant and fungal cells during different growth conditions, after treatment with IAA, and in different developmental stages. The comparison shows good agreement and supports the claim that the Pi parameter is central to expansive growth rate of walled cells. PMID- 28592792 TI - Fabrication of Li4Ti5O12-TiO2 Nanosheets with Structural Defects as High-Rate and Long-Life Anodes for Lithium-Ion Batteries. AB - Development of high-power lithium-ion batteries with high safety and durability has become a key challenge for practical applications of large-scale energy storage devices. Accordingly, we report here on a promising strategy to synthesize a high-rate and long-life Li4Ti5O12-TiO2 anode material. The novel material exhibits remarkable rate capability and long-term cycle stability. The specific capacities at 20 and 30 C (1 C = 175 mA g-1) reach 170.3 and 168.2 mA h g-1, respectively. Moreover, a capacity of up to 161.3 mA h g-1 is retained after 1000 cycles at 20 C, and the capacity retention ratio reaches up to 94.2%. The extraordinary rate performance of the Li4Ti5O12-TiO2 composite is attributed to the existence of oxygen vacancies and grain boundaries, significantly enhancing electrical conductivity and lithium insertion/extraction kinetics. Meanwhile, the pseudocapacitive effect is induced owing to the presence of abundant interfaces in the composite, which is beneficial to enhancing specific capacity and rate capability. Additionally, the ultrahigh capacity at low rates, greater than the theoretical value of spinel Li4Ti5O12, may be correlated to the lithium vacancies in 8a sites, increasing the extra docking sites of lithium ions. PMID- 28592793 TI - Identification of a Simplest Hypervalent Hydrogen Fluoride Anion in Solid Argon. AB - Hypervalent molecules are one of the exceptions to the octet rule. Bonding in most hypervalent molecules is well rationalized by the Rundle-Pimentel model (three-center four-electron bond), and high ionic bonding between the ligands and the central atom is essential for stabilizing hypervalent molecules. Here, we produced one of the simplest hypervalent anions, HF-, which is known to deviate from the Rundle-Pimentel model, and identified its ro-vibrational features. High level ab inito calculations reveal that its bond dissociation energy is comparable to that of dihalides, as supported by secondary photolysis experiments with irradiation at various wavelengths. The charge distribution analysis suggested that the F atom of HF- is negative and hypervalent and the bonding is more covalent than ionic. PMID- 28592795 TI - Interferometric control of the absorption in optical patch antennas. AB - Optical patch nano-antennas possess unique absorption, field enhancement and concentration capabilities - but their crosssection, as well as their response outside of normal incidence are not well understood. Here we explain the large cross-section by considering that each patch nanoantenna is a cavity excited from both sides. Such a simple physical picture allows to fully understand the influence of the angle of incidence - that odd resonances have a very high absorption cross-section which decreases when the incidence angle increases, while even resonances cannot be excited in normal incidence. A direct application would be to use these structures as an optical nanometric set-square. PMID- 28592794 TI - The dynamic functional core network of the human brain at rest. AB - The human brain is an inherently complex and dynamic system. Even at rest, functional brain networks dynamically reconfigure in a well-organized way to warrant an efficient communication between brain regions. However, a precise characterization of this reconfiguration at very fast time-scale (hundreds of millisecond) during rest remains elusive. In this study, we used dense electroencephalography data recorded during task-free paradigm to track the fast temporal dynamics of spontaneous brain networks. Results obtained from network based analysis methods revealed the existence of a functional dynamic core network formed of a set of key brain regions that ensure segregation and integration functions. Brain regions within this functional core share high betweenness centrality, strength and vulnerability (high impact on the network global efficiency) and low clustering coefficient. These regions are mainly located in the cingulate and the medial frontal cortex. In particular, most of the identified hubs were found to belong to the Default Mode Network. Results also revealed that the same central regions may dynamically alternate and play the role of either provincial (local) or connector (global) hubs. PMID- 28592796 TI - Immunochemical Approach for Monitoring of Structural Transition of ApoA-I upon HDL Formation Using Novel Monoclonal Antibodies. AB - Apolipoprotein A-I (apoA-I) undergoes a large conformational reorganization during remodeling of high-density lipoprotein (HDL) particles. To detect structural transition of apoA-I upon HDL formation, we developed novel monoclonal antibodies (mAbs). Splenocytes from BALB/c mice immunized with a recombinant human apoA-I, with or without conjugation with keyhole limpet hemocyanin, were fused with P3/NS1/1-Ag4-1 myeloma cells. After the HAT-selection and cloning, we established nine hybridoma clones secreting anti-apoA-I mAbs in which four mAbs recognize epitopes on the N-terminal half of apoA-I while the other five mAbs recognize the central region. ELISA and bio-layer interferometry measurements demonstrated that mAbs whose epitopes are within residues 1-43 or 44-65 obviously discriminate discoidal and spherical reconstituted HDL particles despite their great reactivities to lipid-free apoA-I and plasma HDL, suggesting the possibility of these mAbs to detect structural transition of apoA-I on HDL. Importantly, a helix-disrupting mutation of W50R into residues 44-65 restored the immunoreactivity of mAbs whose epitope being within residues 44-65 against reconstituted HDL particles, indicating that these mAbs specifically recognize the epitope region in a random coil state. These results encourage us to develop mAbs targeting epitopes in the N-terminal residues of apoA-I as useful probes for monitoring formation and remodeling of HDL particles. PMID- 28592797 TI - Distinct Biological Potential of Streptococcus gordonii and Streptococcus sanguinis Revealed by Comparative Genome Analysis. AB - Streptococcus gordonii and Streptococcus sanguinis are pioneer colonizers of dental plaque and important agents of bacterial infective endocarditis (IE). To gain a greater understanding of these two closely related species, we performed comparative analyses on 14 new S. gordonii and 5 S. sanguinis strains using various bioinformatics approaches. We revealed S. gordonii and S. sanguinis harbor open pan-genomes and share generally high sequence homology and number of core genes including virulence genes. However, we observed subtle differences in genomic islands and prophages between the species. Comparative pathogenomics analysis identified S. sanguinis strains have genes encoding IgA proteases, mitogenic factor deoxyribonucleases, nickel/cobalt uptake and cobalamin biosynthesis. On the contrary, genomic islands of S. gordonii strains contain additional copies of comCDE quorum-sensing system components involved in genetic competence. Two distinct polysaccharide locus architectures were identified, one of which was exclusively present in S. gordonii strains. The first evidence of genes encoding the CylA and CylB system by the alpha-haemolytic S. gordonii is presented. This study provides new insights into the genetic distinctions between S. gordonii and S. sanguinis, which yields understanding of tooth surfaces colonization and contributions to dental plaque formation, as well as their potential roles in the pathogenesis of IE. PMID- 28592798 TI - Fate of neutral-charged gold nanoparticles in the roots of the Hordeum vulgare L. cultivar Karat. AB - Nanoparticles (NPs) have a significant impact on the environment and living organisms. The influence of NPs on plants is intensively studied and most of the data indicate that NPs can penetrate into plants. The studies presented here were performed on the roots of Hordeum vulgare L. seedlings using neutral-charge gold nanoparticles (AuNPs) of different sizes. In contrast to the majority of the published data, the results presented here showed that during the culture period, AuNPs: 1/did not enter the root regardless of their size and concentration, 2/that are applied directly into the cells of a root do not move into neighbouring cells. The results that were obtained indicate that in order to extend our knowledge about the mechanisms of the interactions between NPs and plants, further studies including, among others, on different species and a variety of growth conditions are needed. PMID- 28592800 TI - Paradoxical puborectalis syndrome on diffusion-weighted imaging: a retrospective study of 72 cases. AB - This study aimed to evaluate the application value of diffusion-weighted imaging (DWI) for assessing paradoxical puborectalis syndrome (PPS) in patients with obstructive defecation syndrome (ODS). The medical records of 72 ODS patients who underwent magnetic resonance (MR)-DWI and MR-defecography were retrospectively reviewed. The differences in the apparent diffusion coefficients (ADCs) and the thickness of the right and left branches of the puborectalis muscles between the PPS(+) and PPS(-) groups were compared. In addition, the absolute within-patient differences between the right and left branches (ADC, thickness) were compared between the two groups. The absolute difference in ADCs (right branch - left branch) was significantly different between the two groups. Regardless of whether the ADC was acquired through single-ROI (0.10 +/- 0.08 vs 0.23 +/- 0.18, P = 0.000) or multi-ROI (0.16 +/- 0.14 vs 0.27 +/- 0.17, P = 0.009) analysis, the PPS(+) patients displayed a lower absolute ADC difference than did the PPS(-) patients. However, there was no statistically significant difference in the ADC value, thickness or the absolute difference in thickness between the two groups. These findings suggest that DWI may have value in quantitatively assessing the puborectalis muscle in ODS patients, whereas the value of puborectalis thickness in such aspect needs further study. PMID- 28592799 TI - WhiB4 Regulates the PE/PPE Gene Family and is Essential for Virulence of Mycobacterium marinum. AB - During the course of infection, pathogenic mycobacteria including Mycobacterium tuberculosis (M. tb) encounter host environments of variable oxygen tension, ranging from the hypoxic center of granulomas to the most oxygenated region in the lung cavities. Mycobacterial responses to changes of oxygen tension are critically related to infection outcomes, such as latency and reactivation. WhiB4 is an iron-sulfur containing transcription factor that is highly sensitive to oxygen exposure. In this study, we found that WhiB4 of Mycobacterium marinum (M. marinum), a pathogenic mycobacterial species that is closely related to M. tb, is required for its virulence. M. marinum DeltawhiB4 exhibited defective intracellular replication in macrophages and diminished virulence in zebrafish. Histology analysis revealed that the host had successfully controlled DeltawhiB4 bacteria, forming well-organized granulomas. RNA-seq analysis identified a large number of pe/ppe genes that were regulated by WhiB4, which provides an explanation for the essential role of WhiB4 in M. marinum virulence. Several antioxidant enzymes were also upregulated in DeltawhiB4, supporting its role in modulation of oxidative stress response. Taken together, we have provided new insight into and proposed a model to explain the physiological role of WhiB4. PMID- 28592801 TI - Immune cell-derived cytokines contribute to obesity-related inflammation, fibrogenesis and metabolic deregulation in human adipose tissue. AB - Adipose tissue contains a variety of immune cells, which vary in abundance and phenotype with obesity. The contribution of immune cell-derived factors to inflammatory, fibrotic and metabolic alterations in adipose tissue is not well established in human obesity. Human primary adipose tissue cells, including pre adipocytes, endothelial cells and mature adipocytes, were used to investigate deregulation of cell- and pathway-specific gene profiles. Among factors known to alter adipose tissue biology, we focus on inflammatory (IL-1beta and IL-17) and pro-fibrotic (TGF-beta1) factors. rIL-1beta and rIL-17 induced concordant pro inflammatory transcriptional programs in pre-adipocytes and endothelial cells, with a markedly more potent effect of IL-1beta than IL-17. None of these cytokines had significant effect on fibrogenesis-related gene expression, contrasting with rTGF-beta1-induced up-regulation of extracellular matrix components and pro-fibrotic factors. In mature adipocytes, all three factors promoted down-regulation of genes functionally involved in lipid storage and release. IL-1beta and IL-17 impacted adipocyte metabolic genes in relation with their respective pro-inflammatory capacity, while the effect of TGF-beta1 occurred in face of an anti-inflammatory signature. These data revealed that IL 1beta and IL-17 had virtually no effect on pro-fibrotic alterations but promote inflammation and metabolic dysfunction in human adipose tissue, with a prominent role for IL-1beta. PMID- 28592802 TI - A kinetic Monte Carlo simulation method of van der Waals epitaxy for atomistic nucleation-growth processes of transition metal dichalcogenides. AB - Controlled growth of crystalline solids is critical for device applications, and atomistic modeling methods have been developed for bulk crystalline solids. Kinetic Monte Carlo (KMC) simulation method provides detailed atomic scale processes during a solid growth over realistic time scales, but its application to the growth modeling of van der Waals (vdW) heterostructures has not yet been developed. Specifically, the growth of single-layered transition metal dichalcogenides (TMDs) is currently facing tremendous challenges, and a detailed understanding based on KMC simulations would provide critical guidance to enable controlled growth of vdW heterostructures. In this work, a KMC simulation method is developed for the growth modeling on the vdW epitaxy of TMDs. The KMC method has introduced full material parameters for TMDs in bottom-up synthesis: metal and chalcogen adsorption/desorption/diffusion on substrate and grown TMD surface, TMD stacking sequence, chalcogen/metal ratio, flake edge diffusion and vacancy diffusion. The KMC processes result in multiple kinetic behaviors associated with various growth behaviors observed in experiments. Different phenomena observed during vdW epitaxy process are analysed in terms of complex competitions among multiple kinetic processes. The KMC method is used in the investigation and prediction of growth mechanisms, which provide qualitative suggestions to guide experimental study. PMID- 28592804 TI - Physiological mechanisms of drought-induced tree die-off in relation to carbon, hydraulic and respiratory stress in a drought-tolerant woody plant. AB - Drought-induced tree die-off related to climate change is occurring worldwide and affects the carbon stocks and biodiversity in forest ecosystems. Hydraulic failure and carbon starvation are two commonly proposed mechanisms for drought induced tree die-off. Here, we show that inhibited branchlet respiration and soil to-leaf hydraulic conductance, likely caused by cell damage, occur prior to hydraulic failure (xylem embolism) and carbon starvation (exhaustion of stored carbon in sapwood) in a drought-tolerant woody species, Rhaphiolepis wrightiana Maxim. The ratio of the total leaf area to the twig sap area was used as a health indicator after drought damage. Six adult trees with different levels of tree health and one dead adult tree were selected. Two individuals having the worst and second worst health among the six live trees died three months after our study was conducted. Soil-to-leaf hydraulic conductance and leaf gas exchange rates decreased linearly as tree health declined, whereas xylem cavitation and total non-structural carbon remained unchanged in the branchlets except in the dead and most unhealthy trees. Respiration rates and the number of living cells in the sapwood decreased linearly as tree health declined. This study is the first report on the importance of dehydration tolerance and respiration maintenance in living cells. PMID- 28592803 TI - First comprehensive proteome analysis of lysine crotonylation in seedling leaves of Nicotiana tabacum. AB - Histone crotonylation is a new lysine acylation type of post-translational modification (PTM) enriched at active gene promoters and potential enhancers in yeast and mammalian cells. However, lysine crotonylation in nonhistone proteins and plant cells has not yet been studied. In the present study, we performed a global crotonylation proteome analysis of Nicotiana tabacum (tobacco) using high resolution LC-MS/MS coupled with highly sensitive immune-affinity purification. A total of 2044 lysine modification sites distributed on 637 proteins were identified, representing the most abundant lysine acylation proteome reported in the plant kingdom. Similar to lysine acetylation and succinylation in plants, lysine crotonylation was related to multiple metabolism pathways, such as carbon metabolism, the citrate cycle, glycolysis, and the biosynthesis of amino acids. Importantly, 72 proteins participated in multiple processes of photosynthesis, and most of the enzymes involved in chlorophyll synthesis were modified through crotonylation. Numerous crotonylated proteins were implicated in the biosynthesis, folding, and degradation of proteins through the ubiquitin proteasome system. Several crotonylated proteins related to chromatin organization are also discussed here. These data represent the first report of a global crotonylation proteome and provide a promising starting point for further functional research of crotonylation in nonhistone proteins. PMID- 28592805 TI - Cdc6 contributes to abrogating the G1 checkpoint under hypoxic conditions in HPV E7 expressing cells. AB - The human papillomavirus (HPV) plays a central role in cervical carcinogenesis and its oncogene E7 is essential in this process. We showed here that E7 abrogated the G1 cell cycle checkpoint under hypoxia and analyzed key cell cycle related proteins for their potential role in this process. To further explore the mechanism by which E7 bypasses hypoxia-induced G1 arrest, we applied a proteomic approach and used mass spectrometry to search for proteins that are differentially expressed in E7 expressing cells under hypoxia. Among differentially expressed proteins identified, Cdc6 is a DNA replication initiation factor and exhibits oncogenic activities when overexpressed. We have recently demonstrated that Cdc6 was required for E7-induced re-replication. Significantly, here we showed that Cdc6 played a role in E7-mediated G1 checkpoint abrogation under hypoxic condition, and the function could possibly be independent from its role in DNA replication initiation. This study uncovered a new function of Cdc6 in regulating cell cycle progression and has important implications in HPV-associated cancers. PMID- 28592807 TI - Reconstruction of Complex Directional Networks with Group Lasso Nonlinear Conditional Granger Causality. AB - Reconstruction of networks underlying complex systems is one of the most crucial problems in many areas of engineering and science. In this paper, rather than identifying parameters of complex systems governed by pre-defined models or taking some polynomial and rational functions as a prior information for subsequent model selection, we put forward a general framework for nonlinear causal network reconstruction from time-series with limited observations. With obtaining multi-source datasets based on the data-fusion strategy, we propose a novel method to handle nonlinearity and directionality of complex networked systems, namely group lasso nonlinear conditional granger causality. Specially, our method can exploit different sets of radial basis functions to approximate the nonlinear interactions between each pair of nodes and integrate sparsity into grouped variables selection. The performance characteristic of our approach is firstly assessed with two types of simulated datasets from nonlinear vector autoregressive model and nonlinear dynamic models, and then verified based on the benchmark datasets from DREAM3 Challenge4. Effects of data size and noise intensity are also discussed. All of the results demonstrate that the proposed method performs better in terms of higher area under precision-recall curve. PMID- 28592806 TI - Platelet-rich plasma respectively reduces and promotes adipogenic and myofibroblastic differentiation of human adipose-derived stromal cells via the TGFbeta signalling pathway. AB - Autologous fat grafting is a gold standard therapy for soft tissue defects, but is hampered by unpredictable postoperative outcomes. Fat graft enrichment with adipose-derived stromal cell (ASCs) was recently reported to enhance graft survival. Platelet-rich plasma (PRP) has also emerged as a biologic scaffold that promotes fat graft viability. Combined ASC/PRP fat grafting enrichment is thus a promising new regenerative medicine approach. The effects of PRP on ASC proliferation are well documented, but the impact of PRP on ASC differentiation has yet to be investigated in depth to further elucidate the PRP clinical effects. Here we analyzed the human ASC fate upon PRP treatment. PRP was found to sharply reduce the potential of ASCs to undergo differentiation into adipocytes. Interestingly, the PRP anti-adipogenic effect was accompanied by the generation of myofibroblast-like cells. Among the various factors released from PRP, TGFbeta pathway activators played a critical role in both the anti-adipogenic and pro myofibroblastic PRP effects. Overall, these data suggest that PRP participates in maintaining a pool of ASCs and in the repair process by promoting ASC differentiation into myofibroblast-like cells. TGFbeta may provide an important target pathway to improve PRP clinical outcomes. PMID- 28592809 TI - Evidence for mutual assessment in a wild primate. AB - In aggressive interactions, game theory predicts that animals should assess an opponent's condition relative to their own prior to escalation or retreat. Despite the benefits of such mutual assessment, few studies have been able to reject simpler assessment strategies. Here we report evidence for mutual assessment in a wild primate. Gelada (Theropithecus gelada) males have conspicuous loud calls that may function as a signal of male quality. "Leader" males with harems putatively use loud calls to deter challenges from non reproductive "bachelor" males. By contrast, leader males pose no threat to each other and congregate in large groups for a dilution effect against bachelors. In playback experiments and natural observations, gelada males responded to loud calls according to both their own and their opponent's attributes. Although primates routinely classify others relative to themselves using individual attributes, this represents some of the first direct evidence for mutual assessment in primate signaling contests. PMID- 28592808 TI - SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts. AB - Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Vasterbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro. PMID- 28592810 TI - Historical and Projected Surface Temperature over India during the 20th and 21st century. AB - Surface Temperature (ST) over India has increased by ~0.055 K/decade during 1860 2005 and follows the global warming trend. Here, the natural and external forcings (e.g., natural and anthropogenic) responsible for ST variability are studied from Coupled Model Inter-comparison phase 5 (CMIP5) models during the 20th century and projections during the 21st century along with seasonal variability. Greenhouse Gases (GHG) and Land Use (LU) are the major factors that gave rise to warming during the 20th century. Anthropogenic Aerosols (AA) have slowed down the warming rate. The CMIP5 projection over India shows a sharp increase in ST under Representative Concentration Pathways (RCP) 8.5 where it reaches a maximum of 5 K by the end of the 21st century. Under RCP2.6 emission scenarios, ST increases up to the year 2050 and decreases afterwards. The seasonal variability of ST during the 21st century shows significant increase during summer. Analysis of rare heat and cold events for 2080-2099 relative to a base period of 1986-2006 under RCP8.5 scenarios reveals that both are likely to increase substantially. However, by controlling the regional AA and LU change in India, a reduction in further warming over India region might be achieved. PMID- 28592811 TI - Evaluating the impact of vitreomacular adhesion on anti-VEGF therapy for retinal vein occlusion using machine learning. AB - Vitreomacular adhesion (VMA) represents a prognostic biomarker in the management of exudative macular disease using anti-vascular endothelial growth factor (VEGF) agents. However, manual evaluation of VMA in 3D optical coherence tomography (OCT) is laborious and data on its impact on therapy of retinal vein occlusion (RVO) are limited. The aim of this study was to (1) develop a fully automated segmentation algorithm for the posterior vitreous boundary and (2) to study the effect of VMA on anti-VEGF therapy for RVO. A combined machine learning/graph cut segmentation algorithm for the posterior vitreous boundary was designed and evaluated. 391 patients with central/branch RVO under standardized ranibizumab treatment for 6/12 months were included in a systematic post-hoc analysis. VMA (70%) was automatically differentiated from non-VMA (30%) using the developed method combined with unsupervised clustering. In this proof-of-principle study, eyes with VMA showed larger BCVA gains than non-VMA eyes (BRVO: 15 +/- 12 vs. 11 +/- 11 letters, p = 0.02; CRVO: 18 +/- 14 vs. 9 +/- 13 letters, p < 0.01) and received a similar number of retreatments. However, this association diminished after adjustment for baseline BCVA, also when using more fine-grained VMA classes. Our study illustrates that machine learning represents a promising path to assess imaging biomarkers in OCT. PMID- 28592812 TI - Activity-independent targeting of mTOR to lysosomes in primary osteoclasts. AB - Mammalian target of rapamycin (mTOR) is activated by numerous stimuli, including amino acids and growth factors. This kinase is part of the mTOR complex 1 (mTORC1) which regulates cell proliferation, differentiation, and autophagy. Active mTORC1 is located on lysosomes and has been reported to disassociate from the lysosomal surface in the absence of amino acids. Furthermore, mTORC1 activity has been linked to the vacuolar H+-ATPases (V-ATPases), the proton pumps responsible for lysosomal acidification; however, the exact role of the V-ATPases in mTORC1 signaling is not known. To elucidate the mechanisms involved in mTORC1 regulation by the V-ATPases, we used primary osteoclasts derived from mice carrying a point (R740S) mutation in the a3 subunit of the V-ATPase. In these cells, the mutant protein is expressed but the pump is not functional, resulting in higher lysosomal pH. By analyzing mTOR activation, mTOR/lysosome co localization, and lysosomal positioning using confocal microscopy, fractionation, and ultrapure lysosomal purification methods, we demonstrate that in primary osteoclasts, mTOR is localized on the lysosomal surface even when mTOR activity is inhibited. Our findings reveal that mTOR targeting to the lysosome in osteoclasts is activity-independent, and that its disassociation from the lysosome during starvation is not universal. PMID- 28592813 TI - Simplifying the design of microstructured optical fibre pressure sensors. AB - In this paper, we propose a way to simplify the design of microstructured optical fibres with high sensitivity to applied pressure. The use of a capillary fibre with an embedded core allows the exploration of the pressure-induced material birefringence due to the capillary wall displacements and the photoelastic effect. An analytical description of pressure-induced material birefringence is provided, and fibre modal characteristics are explored through numerical simulations. Moreover, a capillary fibre with an embedded core is fabricated and used to probe pressure variations. Even though the embedded-core fibre has a non optimized structure, measurements showed a pressure sensitivity of (1.04 +/- 0.01) nm/bar, which compares well with more complex, specially designed fibre geometries reported in the literature. These results demonstrate that this geometry enables a novel route towards the simplification of microstructured fibre-based pressure sensors. PMID- 28592814 TI - Impairment of the activin A autocrine loop by lopinavir reduces self-renewal of distinct human adipose progenitors. AB - Maintenance of the adipose tissue requires a proper balance between self-renewal and differentiation of adipose progenitors (AP). Any deregulation leads either to fat overexpansion and obesity or fat loss and consequent lipodystrophies. Depending on the fat pad location, APs and adipocytes are heterogeneous. However, information on the pharmacological sensitivity of distinct APs to drugs known to alter the function of adipose tissue, especially HIV protease inhibitors (PIs) is scant. Here we show that PIs decreased proliferation and clonal expansion of APs, modifying their self-renewal potential. Lopinavir was the most potent PI tested. Decrease in self-renewal was accompanied by a reduced expression of the immediate early response gene IER3, a gene associated with tissue expansion. It was more pronounced in chin-derived APs than in knee-derived APs. Furthermore, lopinavir lowered the activin A-induced ERK1/2 phosphorylation. Expressions of the transcription factor EGR1 and its targets, including INHBA were subsequently altered. Therefore, activin A secretion was reduced leading to a dramatic impairment of APs self-renewal sustained by the activin A autocrine loop. All together, these observations highlight the activin A autocrine loop as a crucial effector to maintain APs self-renewal. Targeting this pathway by HIV-PIs may participate in the induction of unwanted side effects. PMID- 28592815 TI - Impact of genotype on endocrinal complications of Children with Alpha-thalassemia in China. AB - Alpha-thalassemia occurs with high frenquency in China. Four common alpha-globin gene deletion mutations (-SEA, -alpha3.7, and -alpha4.2, Haemoglobin Constant Spring (CS) mutation) were identified in Chinese patients. Individuals with alpha thalassemia syndrome are more often of children. However report on endocrinal complications in children with alpha thalassemia in China are still absent. The present study aimed to investigate the impact of genotype on endocrinal complications in Chinese children. Association analysis between genotype and endocrinal compliaction development was conducted on 200 patients with 200 healthy controls. Hypogonadism was found to be the most prominent endocrinal complications (84.0%) leading to the growth retardation, hypogonadism, diabetes mellitus, hypothyroidism and hypoparathyroidism whose incidence were significantly higher in pateints. (alphaCSalpha/-SEA) was the main genotype of Alpha thalassemia identified in the patients (37.5%), and patients with the ( alpha4.2/-SEA) genotype had a higher prevalence of hypogonadism, diabetes mellitus and hypoparathyroidism (P = 0.001, P = 0.001, P < 0.001, respectively). PMID- 28592816 TI - Comparing photoelectrochemical water oxidation, recombination kinetics and charge trapping in the three polymorphs of TiO2. AB - In this article we present the first comparative study of the transient decay dynamics of photo-generated charges for the three polymorphs of TiO2. To our knowledge, this is the first such study of the brookite phase of TiO2 over timescales relevant to the kinetics of water splitting. We find that the behavior of brookite, both in the dynamics of relaxation of photo-generated charges and in energetic distribution, is similar to the anatase phase of TiO2. Moreover, links between the rate of recombination of charge carriers, their energetic distribution and the mode of transport are made in light of our findings and used to account for the differences in water splitting efficiency observed across the three polymorphs. PMID- 28592817 TI - Imaging gold nanoparticles in mouse liver by laser ablation inductively coupled plasma mass spectrometry. AB - Imaging the size distribution of metal nanoparticles (NPs) in a tissue has important implications in terms of evaluating NP toxicity. Microscopy techniques used to image tissue NPs are limited by complicated sample preparation or poor resolution. In this study, we developed a laser ablation (LA) system coupled to single-particle inductively coupled plasma mass spectrometry (SP-ICP-MS) for quantitative imaging of gold (G)NPs in tissue samples. In this system, GNPs were ablated but did not disintegrate and integrate under optimised operation conditions, which were verified by characterising LA particles by scanning electron microscopy. The feasibility of imaging size distributions in tissue was validated using reference GNPs 60 and 80 nm in size on matrix-matched kidney. A transport efficiency of 6.07% was obtained by LA-SP-ICP-MS under optimal conditions. We used this system to image 80-nm GNPs in mouse liver and the size distribution thus obtained was in accordance with that determined by nebuliser SP ICP-MS. The images revealed that 80-nm GNPs mainly accumulate in the liver and did not obviously aggregate. Our results demonstrate that LA-SP-ICP-MS is an effective tool for evaluating the size distribution of metal NPs in tissue. PMID- 28592818 TI - Characteristics of Chinese Costal Cartilage and Costa Calcification Using Dual Energy Computed Tomography Imaging. AB - To assess characteristics of Chinese costal cartilage and costa calcification using Dual-Energy computed tomography(DECT). 154 patients who underwent chest DECT scanning were included in our study. They were divided into following groups: less than 30 years old, 31-40 years old, 41-50 years old, 51-60 years old and over 60 years old. The sixth, seventh and eighth costal cartilages and costas were evaluated. Calcification patterns of cartilage were classified as central(C), peripheral(P), mixed(M) and no calcification(N) types. Calcification degree of cartilage was distinguished as 1(0-25%), 2(26-50%) and 3(>50%). CT value, calcium and water concentrations were measured in costal cartilage, cortical or cancellous bone respectively. An increasing C pattern of cartilage was displayed in females, while P type preferred in males as age increased. Calcification degree generally changed from 1 to 2 or 3 in females. CT value and calcium concentration of cartilage went through a gradual rising course and peaked in their 40-50 years, while those two indices of cancellous bone decreased gradually since their 50 years in females. The findings suggest a gradual calcification of the costal cartilage took place before 40-50 years old and a sharp bone loss of the costa happened after 40-50 years old in females. PMID- 28592820 TI - One dimensional transport in silicon nanowire junction-less field effect transistors. AB - Junction-less nanowire transistors are being investigated to solve short channel effects in future CMOS technology. Here we demonstrate 8 nm diameter silicon nanowire junction-less transistors with metallic doping densities which demonstrate clear 1D electronic transport characteristics. The 1D regime allows excellent gate modulation with near ideal subthreshold slopes, on- to off-current ratios above 108 and high on-currents at room temperature. Universal conductance scaling as a function of voltage and temperature similar to previous reports of Luttinger liquids and Coulomb gap behaviour at low temperatures suggests that many body effects including electron-electron interactions are important in describing the electronic transport. This suggests that modelling of such nanowire devices will require 1D models which include many body interactions to accurately simulate the electronic transport to optimise the technology but also suggest that 1D effects could be used to enhance future transistor performance. PMID- 28592821 TI - Development of a 3D angiogenesis model to study tumour - endothelial cell interactions and the effects of anti-angiogenic drugs. AB - The tumour microenvironment and tumour angiogenesis play a critical role in the development and therapy of many cancers, but in vitro models reflecting these circumstances are rare. In this study, we describe the development of a novel tri culture model, using non-small cell lung cancer (NSCLC) cell lines (A549 and Colo699) in combination with a fibroblast cell line (SV 80) and two different endothelial cell lines in a hanging drop technology. Endothelial cells aggregated either in small colonies in Colo699 containing microtissues or in tube like structures mainly in the stromal compartment of microtissues containing A549. An up-regulation of hypoxia and vimentin, ASMA and a downregulation of E-cadherin were observed in co- and tri-cultures compared to monocultures. Furthermore, a morphological alteration of A549 tumour cells resembling "signet ring cells" was observed in tri-cultures. The secretion of proangiogenic growth factors like vascular endothelial growth factor (VEGF) was measured in supernatants. Inhibition of these proangiogenic factors by using antiangiogenic drugs (bevacizumab and nindetanib) led to a significant decrease in migration of endothelial cells into microtissues. We demonstrate that our method is a promising tool for the generation of multicellular tumour microtissues and reflects in vivo conditions closer than 2D cell culture. PMID- 28592824 TI - Structural Properties and Sensing Performance of CeYxOy Sensing Films for Electrolyte-Insulator-Semiconductor pH Sensors. AB - In this study we developed CeY x O y sensing membranes displaying super-Nernstian pH-sensitivity for use in electrolyte-insulator-semiconductor (EIS) pH sensors. We examined the effect of thermal annealing on the structural properties and sensing characteristics of the CeY x O y sensing membranes deposited through reactive co-sputtering onto Si substrates. X-ray diffraction, atomic force microscopy, and X-ray photoelectron spectroscopy revealed the structural, morphological, and chemical features, respectively, of the CeY x O y films after their annealing at 600-900 degrees C. Among the tested systems, the CeY x O y EIS device prepared with annealing at 800 degrees C exhibited the highest sensitivity (78.15 mV/pH), the lowest hysteresis voltage (1.4 mV), and the lowest drift rate (0.85 mV/h). Presumably, these annealing conditions optimized the stoichiometry of (CeY)O2 in the film and its surface roughness while suppressing silicate formation at the CeY x O y -Si interface. We attribute the super Nernstian pH-sensitivity to the incorporation of Y ions in the Ce framework, thereby decreasing the oxidation state Ce (Ce4+ -> Ce3+) and resulting in less than one electron transferred per proton in the redox reaction. PMID- 28592822 TI - Bacterial Sphingomyelinase is a State-Dependent Inhibitor of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). AB - Sphingomyelinase C (SMase) inhibits CFTR chloride channel activity in multiple cell systems, an effect that could exacerbate disease in CF and COPD patients. The mechanism by which sphingomyelin catalysis inhibits CFTR is not known but evidence suggests that it occurs independently of CFTR's regulatory "R" domain. In this study we utilized the Xenopus oocyte expression system to shed light on how CFTR channel activity is reduced by SMase. We found that the pathway leading to inhibition is not membrane delimited and that inhibited CFTR channels remain at the cell membrane, indicative of a novel silencing mechanism. Consistent with an effect on CFTR gating behavior, we found that altering gating kinetics influenced the sensitivity to inhibition by SMase. Specifically, increasing channel activity by introducing the mutation K1250A or pretreating with the CFTR potentiator VX-770 (Ivacaftor) imparted resistance to inhibition. In primary bronchial epithelial cells, we found that basolateral, but not apical, application of SMase leads to a redistribution of sphingomyelin and a reduction in forskolin- and VX-770-stimulated currents. Taken together, these data suggest that SMase inhibits CFTR channel function by locking channels into a closed state and that endogenous CFTR in HBEs is affected by SMase activity. PMID- 28592825 TI - Variation in growth rates of branching corals along Australia's Great Barrier Reef. AB - Coral growth is an important component of reef health and resilience. However, few studies have investigated temporal and/or spatial variation in growth of branching corals, which are important contributors to the structure and function of reef habitats. This study assessed growth (linear extension, density, and calcification) of three branching coral species (Acropora muricata, Pocillopora damicornis and Isopora palifera) at three distinct locations (Lizard Island, Davies/Trunk Reef, and Heron Island) along Australia's Great Barrier Reef (GBR). Annual growth rates of all species were highest at Lizard Island and declined with increasing latitude, corresponding with differences in temperature. Within locations, however, seasonal variation in growth did not directly correlate with temperature. Between October 2012 and October 2014, the highest growth of A. muricata was in the 2013-14 summer at Lizard Island, which was unusually cool and ~0.5 degrees C less than the long-term summer average temperature. At locations where temperatures reached or exceeded the long-term summer maxima, coral growth during summer periods was equal to, if not lower than, winter periods. This study shows that temperature has a significant influence on spatiotemporal patterns of branching coral growth, and high summer temperatures in the northern GBR may already be constraining coral growth and reef resilience. PMID- 28592823 TI - Comparison of the active and resident community of a coastal microbial mat. AB - Coastal microbial mats form a nearly closed micro-scale ecosystem harboring a complex microbial community. Previous DNA based analysis did not necessarily provide information about the active fraction of the microbial community because it includes dormant, inactive cells as well as a potential stable pool of extracellular DNA. Here we focused on the active microbial community by comparing 16S rRNA sequences obtained from the ribosomal RNA pool with gene sequences obtained from the DNA fraction. In addition, we aimed to establish an optimal and feasible sampling protocol that takes potential spatial and temporal heterogeneity into account. The coastal microbial mat investigated here was sampled randomly and at regular time points during one 24-h period. DNA and RNA was extracted and after conversion of the RNA fraction to cDNA, the V1-V3 and the V3-V4 regions of the 16S rRNA gene were targeted for high-throughput amplicon sequencing. We show that the community composition varies little in time and space whereas two amplified 16S regions gave significant different results. The largest differences were found when comparing the "resident community" (DNA) with the "active community" (cDNA/RNA); in the latter, Cyanobacteria dominated for almost 95% while they represented 60% of the resident fraction. PMID- 28592826 TI - PH-Dependent Enantioselectivity of D-amino Acid Oxidase in Aqueous Solution. AB - D-amino acid oxidases (DAAO) are stereospecific enzymes which are generally almost inactive towards L-enantiomer in neutral solution when L-, D-amino acids are supplied as substrates. In this paper, the D-amino acid oxidase can catalytic oxidize L-amino acids by modulating pH of aqueous solution. With L-Pro as substrate, the catalytic rate (k cat) and the affinity (K m) of DAAO were 6.71 s 1 and 33 mM at pH 8.0, respectively, suggesting that optimal pH condition enhanced the activity of DAAO towards L-Pro. Similar results were obtained when L Ala (pH 9.8), L-Arg (pH 6.5), L-Phe (pH 9.0), L-Thr (pH 9.4), and L-Val (pH 8.5) were catalyzed by DAAO at various pH values. The racemization of the L-amino acids was not found by capillary electrophoresis analysis during oxidation, and quantification analysis of L-amino acids before and after catalytic reaction was performed, which confirmed that the modulation of enantioselectivity of DAAO resulted from the oxidation of L-amino acids rather than D-amino acids by changing pH. A mechanistic model was proposed to explain enhanced activity of DAAO towards L-amino acids under optimal pH condition. PMID- 28592827 TI - A comprehensive characterisation of the metabolic profile of varicose veins; implications in elaborating plausible cellular pathways for disease pathogenesis. AB - Metabolic phenotypes reflect both the genetic and environmental factors which contribute to the development of varicose veins (VV). This study utilises analytical techniques to provide a comprehensive metabolic picture of VV disease, with the aim of identifying putative cellular pathways of disease pathogenesis. VV (n = 80) and non-VV (n = 35) aqueous and lipid metabolite extracts were analysed using 600 MHz 1H Nuclear Magnetic Resonance spectroscopy and Ultra Performance Liquid Chromatography Mass Spectrometry. A subset of tissue samples (8 subjects and 8 controls) were analysed for microRNA expression and the data analysed with mirBase (www.mirbase.org). Using Multivariate statistical analysis, Ingenuity pathway analysis software, DIANALAB database and published literature, the association of significant metabolites with relevant cellular pathways were understood. Higher concentrations of glutamate, taurine, myo-inositol, creatine and inosine were present in aqueous extracts and phosphatidylcholine, phosphatidylethanolamine and sphingomyelin in lipid extracts in the VV group compared with non-VV group. Out of 7 differentially expressed miRNAs, spearman correlation testing highlighted correlation of hsa-miR-642a-3p, hsa-miR-4459 and hsa-miR-135a-3p expression with inosine in the vein tissue, while miR-216a-5p, conversely, was correlated with phosphatidylcholine and phosphatidylethanolamine. Pathway analysis revealed an association of phosphatidylcholine and sphingomyelin with inflammation and myo-inositol with cellular proliferation. PMID- 28592828 TI - A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle. AB - The transporter associated with antigen processing (TAP) translocates antigenic peptides into the endoplasmic reticulum (ER) lumen for loading onto MHC class I molecules. This is a key step in the control of viral infections through CD8+ T cells. The herpes simplex virus type-1 encodes an 88 amino acid long species specific TAP inhibitor, ICP47, that functions as a high affinity competitor for the peptide binding site on TAP. It has previously been suggested that the inhibitory function of ICP47 resides within the N-terminal region (residues 1 35). Here we show that mutation of the highly conserved 50PLL52 motif within the central region of ICP47 attenuates its inhibitory capacity. Taking advantage of the human cytomegalovirus-encoded TAP inhibitor US6 as a luminal sensor for conformational changes of TAP, we demonstrated that the 50PLL52 motif is essential for freezing of the TAP conformation. Moreover, hierarchical functional interaction sites on TAP dependent on 50PLL52 could be defined using a comprehensive set of human-rat TAP chimeras. This data broadens our understanding of the molecular mechanism underpinning TAP inhibition by ICP47, to include the 50PLL52 sequence as a stabilizer that tethers the TAP-ICP47 complex in an inward facing conformation. PMID- 28592829 TI - Speckle Tracking Stress Echocardiography Uncovers Early Subclinical Cardiac Involvement in Pediatric Patients with Inflammatory Bowel Diseases. AB - Inflammatory bowel disease (IBD) is an established risk factor for cardiovascular disease (CVD). However, whether cardiac consequences present early in IBD is unknown. This is the first study in children aiming to unmask altered myocardial mechanics in IBD. We enrolled 50 consecutive normotensive children with Crohn's disease (CD) (n = 28) or ulcerative colitis (UC) (n = 22). The study groups consisted of 18 patients with active inflammatory disease (mean age 14.6 +/- 2.5 years) and 32 children with IBD in remission (14.3 +/- 2.3 years). 60 age- and gender-matched children served as healthy controls. Speckle tracking stress echocardiography (STE) was used to assess left ventricular (LV) myocardial strain and strain rate. Circumferential strain rate was significantly decreased in children with active IBD (-1.55 +/- 0.26 s-1) and IBD in remission (-1.49 +/- 0.26 s-1) versus healthy controls (1.8 +/- 0.4 s-1) both at rest (p < 0.001) and during exercise (p = 0.021). Moreover, longitudinal strain rate, circumferential strain and E/E' ratio were significantly impaired in IBD. Pediatric patients with IBD feature subclinical signs of LV systolic and diastolic myocardial impairment early in the course of CD and UC. This may not be reversible even when IBD is clinically controlled. Patients with IBD should be regularly screened for signs of CVD. PMID- 28592830 TI - Choice of analysis pathway dramatically affects statistical outcomes in breaking continuous flash suppression. AB - Breaking Continuous Flash Suppression (bCFS) has been adopted as an appealing means to study human visual awareness, but the literature is beclouded by inconsistent and contradictory results. Although previous reviews have focused chiefly on design pitfalls and instances of false reasoning, we show in this study that the choice of analysis pathway can have severe effects on the statistical output when applied to bCFS data. Using a representative dataset designed to address a specific controversy in the realm of language processing under bCFS, namely whether psycholinguistic variables affect access to awareness, we present a range of analysis methods based on real instances in the published literature, and indicate how each approach affects the perceived outcome. We provide a summary of published bCFS studies indicating the use of data transformation and trimming, and highlight that more compelling analysis methods are sparsely used in this field. We discuss potential interpretations based on both classical and more complex analyses, to highlight how these differ. We conclude that an adherence to openly available data and analysis pathways could provide a great benefit to this field, so that conclusions can be tested against multiple analyses as standard practices are updated. PMID- 28592831 TI - Genetic variation of dopamine and serotonin function modulates the feedback related negativity during altruistic punishment. AB - Why do humans cooperate and often punish norm violations of others? In the present study, we sought to investigate the genetic bases of altruistic punishment (AP), which refers to the costly punishment of norm violations with potential benefit for other individuals. Recent evidence suggests that norm violations and unfairness are indexed by the feedback-related negativity (FRN), an anterior cingulate cortex (ACC) generated neural response to expectancy violations. Given evidence on the role of serotonin and dopamine in AP as well as in FRN-generation, we explored the impact of genetic variation of serotonin and dopamine function on FRN and AP behavior in response to unfair vs. fair monetary offers in a Dictator Game (DG) with punishment option. In a sample of 45 healthy participants we observed larger FRN amplitudes to unfair DG assignments both for 7-repeat allele carriers of the dopamine D4 receptor (DRD4) exon III polymorphism and for l/l-genotype carriers of the serotonin transporter gene-linked polymorphic region (5-HTTLRP). Moreover, 5-HTTLPR l/l-genotype carriers punished unfair offers more strongly. These findings support the role of serotonin and dopamine in AP, potentially via their influence on neural mechanisms implicated in the monitoring of expectancy violations and their relation to impulsive and punishment behavior. PMID- 28592832 TI - High-precision spatial localization of mouse vocalizations during social interaction. AB - Mice display a wide repertoire of vocalizations that varies with age, sex, and context. Especially during courtship, mice emit ultrasonic vocalizations (USVs) of high complexity, whose detailed structure is poorly understood. As animals of both sexes vocalize, the study of social vocalizations requires attributing single USVs to individuals. The state-of-the-art in sound localization for USVs allows spatial localization at centimeter resolution, however, animals interact at closer ranges, involving tactile, snout-snout exploration. Hence, improved algorithms are required to reliably assign USVs. We develop multiple solutions to USV localization, and derive an analytical solution for arbitrary vertical microphone positions. The algorithms are compared on wideband acoustic noise and single mouse vocalizations, and applied to social interactions with optically tracked mouse positions. A novel, (frequency) envelope weighted generalised cross correlation outperforms classical cross-correlation techniques. It achieves a median error of ~1.4 mm for noise and ~4-8.5 mm for vocalizations. Using this algorithms in combination with a level criterion, we can improve the assignment for interacting mice. We report significant differences in mean USV properties between CBA mice of different sexes during social interaction. Hence, the improved USV attribution to individuals lays the basis for a deeper understanding of social vocalizations, in particular sequences of USVs. PMID- 28592834 TI - Impact of naturally leaking carbon dioxide on soil properties and ecosystems in the Qinghai-Tibet plateau. AB - One of the major concerns for CO2 capture and storage (CCS) is the potential risk of CO2 leakage from storage reservoirs on the shallow soil property and vegetation. This study utilizes a naturally occurring CO2 leaking site in the Qinghai-Tibet Plateau to analog a "leaking CCS site". Our observations from this site indicates that long-term CO2 invasion in the vadose zone results in variations of soil properties, such as pH fluctuation, slight drop of total organic carbon, reduction of nitrogen and phosphorus, and concentration changes of soluble ions. Simultaneously, XRD patterns of the soil suggest that crystallization of soil is enhanced and mineral contents of calcite and anorthite in soil are increased substantially. Parts of the whole ecosystem such as natural wild plants, soil dwelling animals and microorganisms in shallow soil are affected as well. Under a moderate CO2 concentration (less than 110000 ppm), wild plant growth and development are improved, while an intensive CO2 flux over 112000 ppm causes adverse effects on the plant growth, physiological and biochemical system of plants, and crop quality of wheat. Results of this study provide valuable insight for understanding the possible environmental impacts associated with potential CO2 leakage into shallow sediments at carbon sequestration sites. PMID- 28592833 TI - Demonstration of electron beam laser excitation in the UV range using a GaN/AlGaN multiquantum well active layer. AB - This study investigated electron beam laser excitation in the UV region using a GaN/AlGaN multiquantum well (MQW) active layer. Laser emission was observed when the GaN/AlGaN MQW was excited by an electron beam, with a wavelength of approximately 353 nm and a threshold power density of 230 kW/cm2. A comparison of optical pumping and electron beam pumping demonstrated that the rate of generation of electron-hole pairs when using electron beam excitation was approximately one quarter that of light excitation. PMID- 28592836 TI - Differential surface plasmon polaritons transmission line with controllable common mode rejection. AB - In this paper, a spoof surface plasmon polarions (SPPs) transmission line is designed by patterning thin metal film in open-cross shape arranged in array. Numerical simulations show the proposed open-cross array can support spoof SPPs with enlarged propagation constant and hence enhanced confinement at metal/dielectric interface as compared to the reported ultra-thin plasmonic waveguide with the rectangular groove or solid-cross. Furthermore, a differential transmission line pair is built with such two close plasmonic arrays. A narrow metal strip locates at the symmetrical plane of the two SPPs waveguides and acts as a resonator to realize common-mode rejection at specific frequency. The notch frequency for common mode can be adjusted by tuning the metal strip length of the resonator while differential mode propagation remains unaffected. Both simulated and experimental results with good agreement are given to verify the proposed idea. PMID- 28592835 TI - Increased platelet distribution width predicts poor prognosis in melanoma patients. AB - Activated platelets promote cancer progression and metastasis. Nevertheless, the prognostic value of platelet indices in melanoma had been rarely reported. The aim of this study was to investigate the predictive significance of platelet indices in melanoma. A total of 220 consecutive patients with melanoma were retrospectively enrolled between January 2009 and December 2009. The relationship between PDW and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW. Of the 220 patients, high platelet distribution width (PDW) levels were observed in 63 (28.6%) patients. Increased PDW was associated with tumor subtype (P < 0.001). Survival curves found that patients with increased PDW had significantly shorter survival time than those with normal PDW (P < 0.001). Cox regression analysis revealed that elevated PDW was an independent prognostic factor for overall survival (hazard ratio, 2.480; 95% confidence interval [CI], 1.386-4.436, P = 0.002). In conclusion, PDW is easily available in routine blood test. Our findings indicated that PDW is an independent predictor and that it may also be a potential parameter for targeted therapy in melanoma. PMID- 28592837 TI - Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver-Russell syndrome. AB - Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient's intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7 Mb duplication at 15q11.2-q13.1 encompassing the Prader-Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS. PMID- 28592838 TI - The first Neanderthal remains from an open-air Middle Palaeolithic site in the Levant. AB - The late Middle Palaeolithic (MP) settlement patterns in the Levant included the repeated use of caves and open landscape sites. The fossil record shows that two types of hominins occupied the region during this period-Neandertals and Homo sapiens. Until recently, diagnostic fossil remains were found only at cave sites. Because the two populations in this region left similar material cultural remains, it was impossible to attribute any open-air site to either species. In this study, we present newly discovered fossil remains from intact archaeological layers of the open-air site 'Ein Qashish, in northern Israel. The hominin remains represent three individuals: EQH1, a nondiagnostic skull fragment; EQH2, an upper right third molar (RM3); and EQH3, lower limb bones of a young Neandertal male. EQH2 and EQH3 constitute the first diagnostic anatomical remains of Neandertals at an open-air site in the Levant. The optically stimulated luminescence ages suggest that Neandertals repeatedly visited 'Ein Qashish between 70 and 60 ka. The discovery of Neandertals at open-air sites during the late MP reinforces the view that Neandertals were a resilient population in the Levant shortly before Upper Palaeolithic Homo sapiens populated the region. PMID- 28592839 TI - Inhibition of AURKA kinase activity suppresses collective invasion in a microfluidic cell culture platform. AB - Tumor local invasion is the first step of metastasis cascade which remains the key obstacle for cancer therapy. Collective cell migration plays a critical role in tumor invading into surrounding tissues. In vitro assays fail to assess collective invasion in a real time manner. Herein we aim to develop a three dimensional (3D) microfluidic cell invasion model to determine the dynamic process. In this model, collective invasion of breast cancer cells is induced by the concentration gradient of fetal bovine serum. We find that breast cancer cells adopt a collective movement rather than a random manner when the cells invade into extracellular matrix. The leading cells in the collective movement exhibit an increased expression of an Aurora kinase family protein - AURKA compared with the follower cells. Inhibition of AURKA kinase activity by VX680 or AKI603 significantly reduces the phosphorylation of ERK1/2 (Thr202/Tyr204) and collective cohort formation. Together, our study illustrates that AURKA acts as a potential therapeutic target for suppressing the process of tumor collective invasion. The 3D microfluidic cell invasion model is a reliable, measurable and dynamic platform for exploring potential drugs to inhibit tumor collective invasion. PMID- 28592840 TI - Overexpression of LINC00152 correlates with poor patient survival and knockdown impairs cell proliferation in lung cancer. AB - We employed RNA sequencing analysis to reveal dysregulated lncRNAs in lung cancer utilizing 461 lung adenocarcinomas and 156 normal lung tissues from 3 separate cohorts. We found that LINC00152 was highly overexpressed in lung tumors as compared to their adjacent normal tissues. Patients with high LINC00152 expression demonstrate a significantly poorer survival than those with low expression. We verified the diagnostic/prognostic potential of LINC00152 expression in an independent cohort of lung tumor tissues using quantitative RT PCR. After knockdown of LINC00152 using siRNAs in lung cancer cell lines, both cell proliferation and colony formation were decreased. Cell fractionation and qRT-PCR analysis indicated that LINC00152 is found mainly in the cytoplasm. Treatment with Trichostatin A in cell lines having low LINC00152 expression indicated that histone acetylation may be one mechanism underlying LINC00152 overexpression in NSCLC. Western blot analyses indicated that p38a, STAT1, STAT3, CREB1, CCNE1 and c-MYC proteins were decreased after LINC00152 siRNA treatment. Our study indicates LINC00152 plays an important role in lung tumor growth and is potentially a diagnostic/prognostic marker. Further characterization of LINC00152 in regulating its target proteins may provide a novel therapeutic target of lung cancer. PMID- 28592842 TI - The Effects of e-interventions on the Medical Outcomes of Hemodialysis Patients: A Retrospective Matched Patient Cohort Study. AB - Aggressively applying e-interventions in the health care industry has become a global trend to improve the quality of medical care. The present retrospective study evaluated the effect of electronic information systems on the quality of medical care provide to hemodialysis (HD) patients. In total, 600 patients (300 patients each in the e-intervention and non-e-intervention groups, were matched for sex, age, HD duration, diabetes, and hypertension) receiving HD at the study institute for four years were included in this study. The e-intervention group had significantly fewer hospitalization days than the non-e-intervention group. Cox regression analysis demonstrated that the non-e-intervention group had a significantly higher mortality rate than the e-intervention group. Stratified analysis revealed significant differences between the e-intervention and non-e intervention groups in their serum albumin levels, urea reduction ratios, and cardiothoracic ratios at 1-year follow-up. The patients in the e-intervention group had a significantly higher HD blood flow rate, fewer hospitalization days and a lower 4-year all-cause mortality rate than those in the non-e-intervention group. The implementation of the e-intervention improved patient outcomes, but additional studies are required to evaluate the cost effectiveness of such implementations. PMID- 28592841 TI - Lipopolysaccharides induced inflammatory responses and electrophysiological dysfunctions in human-induced pluripotent stem cell derived cardiomyocytes. AB - Severe infections like sepsis lead frequently to cardiomyopathy. The mechanisms are unclear and an optimal therapy for septic cardiomyopathy still lacks. The aim of this study is to establish an endotoxin-induced inflammatory model using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (hiPSC-CMs) for mechanistic and therapeutic studies. hiPSC-CMs were treated by lipopolysaccharide (LPS) in different concentrations for different times. ELISA, FACS, qPCR, and patch-clamp techniques were used for the study. TLR4 (Toll-like receptor 4) and its associated proteins, CD14, LBP (lipopolysaccharide binding protein), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), Ly96 (lymphocyte antigen 96) and nuclear factor kappa B as well as some pro-and anti-inflammatory factors are expressed in hiPSC-CMs. LPS-treatment for 6 hours increased the expression levels of pro-inflammatory and chemotactic cytokines (TNF-a, IL-1beta, IL-6, CCL2, CCL5, IL-8), whereas 48 hour-treatment elevated the expression of anti-inflammatory factors (IL-10 and IL-6). LPS led to cell injury resulting from exaggerated cell apoptosis and necrosis. Finally, LPS inhibited small conductance Ca2+-activated K+ channel currents, enhanced Na+/Ca2+-exchanger currents, prolonged action potential duration, suggesting cellular electrical dysfunctions. Our data demonstrate that hiPSC-CMs possess the functional reaction system involved in endotoxin-induced inflammation and can model some bacterium-induced inflammatory responses in cardiac myocytes. PMID- 28592843 TI - Pluronic F127 and D-alpha-Tocopheryl Polyethylene Glycol Succinate (TPGS) Mixed Micelles for Targeting Drug Delivery across The Blood Brain Barrier. AB - A novel polymeric mixed micelle composed of Pluronic F127 and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) was developed to improve the delivery of fluorescent dyes and protein across the blood brain barrier (BBB). Rhodamine 123 (Rho123) and DiR loaded mixed micelles, composed of Pluronic F127 and TPGS with proportion of 4:1 (FT), were prepared by thin-film hydration, and beta galactosidase (beta-Gal) loaded FT mixed micelles were prepared by self-assembly. The brain-targeted capability of FT mixed micelles were evaluated both in vitro and in vivo. The FT mixed micelles showed that a average particle size of 20.03 nm, and a low CMC of 0.0031% in water. The in vitro release of Rho123 from Rho123 loaded FT mixed micelles (FT/Rho123) presented a sustained-release property. FT/Rho123 also showed higher efficiency for the accumulation in brain capillary endothelial cells (BCECs) and brain tissues. beta-Gal, a model protein, was also delivered and accumulated efficiently in the brain by spontaneous loading in the FT mixed micelles. Therefore, the results indicated that F127/TPGS mixed micelles may be considered as an effective nanocarrier for the brain-targeted delivery of diagnostic and therapeutic drugs. PMID- 28592844 TI - The Complexity of Standing Postural Sway Associates with Future Falls in Community-Dwelling Older Adults: The MOBILIZE Boston Study. AB - Standing postural control is complex, meaning that it is dependent upon numerous inputs interacting across multiple temporal-spatial scales. Diminished physiologic complexity of postural sway has been linked to reduced ability to adapt to stressors. We hypothesized that older adults with lower postural sway complexity would experience more falls in the future. 738 adults aged >=70 years completed the Short Physical Performance Battery test (SPPB) test and assessments of single and dual-task standing postural control. Postural sway complexity was quantified using multiscale entropy. Falls were subsequently tracked for 48 months. Negative binomial regression demonstrated that older adults with lower postural sway complexity in both single and dual-task conditions had higher future fall rate (incident rate ratio (IRR) = 0.98, p = 0.02, 95% Confidence Limits (CL) = 0.96-0.99). Notably, participants in the lowest quintile of complexity during dual-task standing suffered 48% more falls during the four-year follow-up as compared to those in the highest quintile (IRR = 1.48, p = 0.01, 95% CL = 1.09-1.99). Conversely, traditional postural sway metrics or SPPB performance did not associate with future falls. As compared to traditional metrics, the degree of multi-scale complexity contained within standing postural sway-particularly during dual task conditions- appears to be a better predictor of future falls in older adults. PMID- 28592845 TI - Relaxing learned constraints through cathodal tDCS on the left dorsolateral prefrontal cortex. AB - We solve problems by applying previously learned rules. The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in automating this process of rule induction. Despite its usual efficiency, this process fails when we encounter new problems in which past experience leads to a mental rut. Learned rules could therefore act as constraints which need to be removed in order to change the problem representation for producing the solution. We investigated the possibility of suppressing the DLPFC by transcranial direct current stimulation (tDCS) to facilitate such representational change. Participants solved matchstick arithmetic problems before and after receiving cathodal, anodal or sham tDCS to the left DLPFC. Participants who received cathodal tDCS were more likely to solve the problems that require the maximal relaxation of previously learned constraints than the participants who received anodal or sham tDCS. We conclude that cathodal tDCS over the left DLPFC might facilitate the relaxation of learned constraints, leading to a successful representational change. PMID- 28592846 TI - Formation Mechanism for 2015/16 Super El Nino. AB - The extreme El Nino (EN) events in 1997/98 and 1982/83, referred to as super EN, exerted remarkable global influence. A super EN was anticipated on the way in early 2014 but failed to materialize toward the end of 2014. Whilst the scientific community was still puzzling about the cause of the aborted EN event in 2014, the remnants of the decaying warming in late 2014 unexpectedly reignited since February 2015 and grew into a super EN by the end of 2015. Understanding the onset mechanism of the 2015 EN event and its differences from past super EN events is crucial for improving EN prediction in a changing climate. Our observational analyses and modeling studies demonstrate that the principal difference between the 2015 EN and the past super ENs lies in exceptionally strong and consecutive occurrence of westerly wind burst events that turned around unfavorable ocean thermocline conditions in tropical western Pacific in early 2015, reigniting rapidly the surface warming in the eastern Pacific. By August the sea surface temperature anomalies reached a critical amplitude similar to that of the past super ENs; positive atmosphere-ocean feedbacks further amplify this warm episode into a super EN by the end of 2015. PMID- 28592847 TI - TGF-beta-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice. AB - Hepatocyte death, as well as the following inflammatory and fibrogenic signaling cascades, is the key trigger of liver fibrosis. Here, we isolated hepatocytes from CCl4-induced fibrotic liver and found that hepatocyte lincRNA-p21 significantly increased during liver fibrosis. The increase of hepatocyte lincRNA p21 was associated with the loss of miR-30, which can inhibit TGF-beta signaling by targeting KLF11. We revealed that lincRNA-p21 modulated miR-30 availability by acting as a competing endogenous RNA (ceRNA). The physiological significance of this interaction is highlighted by the feedback loop, in which lincRNA-p21 works as a downstream effector of the TGF-beta signaling to strengthen TGF-beta signaling and mediate its role in promoting liver fibrosis by interacting with miR-30. In vivo results showed that knockdown of hepatocyte lincRNA-p21 greatly reduced CCl4-induced liver fibrosis and inflammation, whereas ectopic expression of miR-30 in hepatocyte exhibited the similar results. Mechanistic studies further revealed that inhibition of miR-30 impaired the effects of lincRNA-p21 on liver fibrosis. Additionally, lincRNA-p21 promoted hepatocyte apoptosis in vitro and in vivo, whereas the proliferation rate of hepatocyte was suppressed by lincRNA-p21. The pleiotropic roles of hepatocyte lincRNA-p21 suggest that it may represent an unknown paradigm in liver fibrosis and serve as a potential target for therapy. PMID- 28592848 TI - Metal biogeochemistry in constructed wetlands based on fluviatile sand and zeolite- and clinopyroxene-dominated lava sand. AB - For the first time, speciation of Fe, Mn, Zn, Ni, Cu and Pb was determined along the profiles of 8 constructed wetlands (CWs) consisting of fluviatile sand (Fluv), clinopyroxene-dominated lava sand (Cl-LS) and zeolite-dominated lava sand (Ze-LS), aiming at quantifying metal behaviour in CWs and the impact caused by different filter materials. With the exception of Mn, which underwent reductive dissolution, CWs were sinks for the studied metals. Metal accumulation rates differed in the following order: Ze-LS >= Cl-LS > Fluv CWs, reflecting the highest metal adsorption capacity and the lowest hydraulic conductivity of Ze-LS. Sequential extraction data indicated the highest metal mobility (readily mobilised and adsorbed fractions summing up to ~60%) in Fluv CWs, implying a higher risk of metal release into adjacent environments if Fluv from CWs will be improperly disposed after usage. Zinc and Ni were transported into the deeper CW layers to a larger extent than Cu and Pb, reflecting adsorption affinity to all filter materials in the order of Pb > Cu > Zn > Ni. Therefore, understanding metal speciation and mobility in such materials is crucial when they are considered for application as filters in CWs. PMID- 28592849 TI - Imaging grading system for the diagnosis of dural ossification based on 102 segments of TOLF CT bone-window data. AB - Thoracic ossification of the ligamentum flavum (TOLF) complicated with dural ossification (DO) is a severe clinical disease. The diagnosis of DO preoperatively remains challenging. The current study retrospectively analyzed imaging features of 102 segments with TOLF from 39 patients and proposed a grading system for evaluating DO risk. Logistic regression results showed that unilateral spinal canal occupational rate (UCOR), tram track signs, and C-signs were all risk factors for DO (odds ratios of 5.393, 19.734 and 72.594, respectively). In validation analyses for the TOLF-DO grading system, sensitivity was 76.0% (19/25), specificity was 91.0% (70/77), and Youden's index was 0.66. Thus, implementation of the TOLF-DO grading system has the potential to improve the diagnosis of DO. PMID- 28592851 TI - Left ventricular hemodynamic forces as a marker of mechanical dyssynchrony in heart failure patients with left bundle branch block. AB - Left bundle branch block (LBBB) causes left ventricular (LV) dyssynchrony which is often associated with heart failure. A significant proportion of heart failure patients do not demonstrate clinical improvement despite cardiac resynchronization therapy (CRT). How LBBB-related effects on LV diastolic function may contribute to those therapeutic failures has not been clarified. We hypothesized that LV hemodynamic forces calculated from 4D flow MRI could serve as a marker of diastolic mechanical dyssynchrony in LBBB hearts. MRI data were acquired in heart failure patients with LBBB or matched patients without LBBB. LV pressure gradients were calculated from the Navier-Stokes equations. Integration of the pressure gradients over the LV volume rendered the hemodynamic forces. The findings demonstrate that the LV filling forces are more orthogonal to the main LV flow direction in heart failure patients with LBBB compared to those without LBBB during early but not late diastole. The greater the conduction abnormality the greater the discordance of LV filling force with the predominant LV flow direction (r2 = 0.49). Such unique flow-specific measures of mechanical dyssynchrony may serve as an additional tool for considering the risks imposed by conduction abnormalities in heart failure patients and prove to be useful in predicting response to CRT. PMID- 28592850 TI - NAD+ augmentation ameliorates acute pancreatitis through regulation of inflammasome signalling. AB - Acute pancreatitis (AP) is a complicated disease without specific drug therapy. The cofactor nicotinamide adenine dinucleotide (NAD+) is an important regulator of cellular metabolism and homeostasis. However, it remains unclear whether modulation of NAD+ levels has an impact on caerulein-induced AP. Therefore, in this study, we investigated the effect of increased cellular NAD+ levels on caerulein-induced AP. We demonstrated for the first time that the activities and expression of SIRT1 were suppressed by reduction of intracellular NAD+ levels and the p53-microRNA-34a pathway in caerulein-induced AP. Moreover, we confirmed that the increase of cellular NAD+ by NQO1 enzymatic action using the substrate beta Lapachone suppressed caerulein-induced AP with down-regulating TLR4-mediated inflammasome signalling, and thereby reducing the inflammatory responses and pancreatic cell death. These results suggest that pharmacological stimulation of NQO1 could be a promising therapeutic strategy to protect against pathological tissue damage in AP. PMID- 28592852 TI - Soil Respiration of the Dahurian Larch (Larix gmelinii) Forest and the Response to Fire Disturbance in Da Xing'an Mountains, China. AB - Despite the high frequency of wildfire disturbances in boreal forests in China, the effects of wildfires on soil respiration are not yet well understood. We examined the effects of fire severity on the soil respiration rate (Rs) and its component change in a Dahurian Larch (Larix gmelinii) in Northeast China. The results showed that Rs decreased with fire burning severity. Compared with the control plots, Rs in the low burning severity plots decreased by 19%, while it decreased by 28% in the high burning severity plots. The Rs decrease was mainly due to a decreased autotrophic respiration rate (Ra). The temperature sensitivity (Q 10) of Rs increased after the low severity fire disturbances, but it decreased after the high severity fire disturbance. The Rs were triggered by the soil temperature, which may explain most of the Rs variability in this area. Our study, for the first time, provides the data-based foundation to demonstrate the importance of assessing CO2 fluxes considering both fire severity and environmental factors post-fire in boreal forests of China. PMID- 28592853 TI - Framing susceptibility in a risky choice game is altered by galvanic vestibular stimulation. AB - Recent research provides evidence that galvanic vestibular stimulation (GVS) has a modulating effect on somatosensory perception and spatial cognition. However, other vestibular stimulation techniques have induced changes in affective control and decision making. The aim of this study was to investigate the effect of GVS on framing susceptibility in a risky-choice game. The participants were to decide between a safe and a risky option. The safe option was framed either positively or negatively. During the task, the participants were exposed to either left anodal/right cathodal GVS, right anodal/left cathodal GVS, or sham stimulation (control condition). While left anodal/right cathodal GVS activated more right hemispheric vestibular brain areas, right anodal/left cathodal GVS resulted in more bilateral activation. We observed increased framing susceptibility during left anodal/right cathodal GVS, but no change in framing susceptibility during right anodal/left cathodal GVS. We propose that GVS results in increased reliance on the affect heuristic by means of activation of cortical and subcortical vestibular-emotional brain structures and that this effect is modulated by the lateralization of the vestibular cortex. PMID- 28592854 TI - Transcriptomic analysis of short-fruit 1 (sf1) reveals new insights into the variation of fruit-related traits in Cucumis sativus. AB - Fruit size is an important quality trait in different market classes of Cucumis sativus L., an economically important vegetable cultivated worldwide, but the genetic and molecular mechanisms that control fruit size are largely unknown. In this study, we isolated a natural cucumber mutant, short fruit 1 (sf1), caused by a single recessive Mendelian factor, from the North China-type inbred line CNS2. In addition to significantly decreased fruit length, other fruit-related phenotypic variations were also observed in sf1 compared to the wild-type (WT) phenotype, indicating that sf1 might have pleiotropic effects. Microscopic imaging showed that fruit cell size in sf1 was much larger than that in WT, suggesting that the short fruit phenotype in sf1 is caused by decreased cell number. Fine mapping revealed that sf1 was localized to a 174.3 kb region on chromosome 6. Similarly, SNP association analysis of bulked segregant RNA-Seq data showed increased SNP frequency in the same region of chromosome 6. In addition, transcriptomic analysis revealed that sf1 might control fruit length through the fine-tuning of cytokinin and auxin signalling, gibberellin biosynthesis and signal transduction in cucumber fruits. Overall, our results provide important information for further study of fruit length and other fruit related features in cucumber. PMID- 28592855 TI - Statistical Analysis of Zebrafish Locomotor Behaviour by Generalized Linear Mixed Models. AB - Upon a drastic change in environmental illumination, zebrafish larvae display a rapid locomotor response. This response can be simultaneously tracked from larvae arranged in multi-well plates. The resulting data have provided new insights into neuro-behaviour. The features of these data, however, present a challenge to traditional statistical tests. For example, many larvae display little or no movement. Thus, the larval responses have many zero values and are imbalanced. These responses are also measured repeatedly from the same well, which results in correlated observations. These analytical issues were addressed in this study by the generalized linear mixed model (GLMM). This approach deals with binary responses and characterizes the correlation of observations in the same group. It was used to analyze a previously reported dataset. Before applying the GLMM, the activity values were transformed to binary responses (movement vs. no movement) to reduce data imbalance. Moreover, the GLMM estimated the variations among the effects of different well locations, which would eliminate the location effects when two biological groups or conditions were compared. By addressing the data imbalance and location-correlation issues, the GLMM effectively quantified true biological effects on zebrafish locomotor response. PMID- 28592856 TI - Quaternary history, population genetic structure and diversity of the cold adapted Alpine newt Ichthyosaura alpestris in peninsular Italy. AB - Mediterranean peninsulas are major biodiversity hotspots, and cold-adapted species are an important component of this biodiversity. However, cold-adapted species contributed surprisingly little to our knowledge of the intimate links between Quaternary environmental changes, species' responses to these changes, and current patterns of intraspecific biodiversity. Here, we investigated the genetic structure and evolutionary history of a cold-adapted amphibian, the Alpine newt Ichthyosaura alpestris, within the Italian peninsula. Nuclear and mitochondrial markers consistently identified three distinct genetic lineages, whose divergence dates to the Early Pleistocene (1.9 and 0.8 million years ago). Our results show that the Italian peninsula provided multiple Pleistocene refugia to this cold-adapted species, and suggest that allopatric fragmentation followed by secondary admixture have been key events in the formation of its current pattern of genetic diversity. Indeed, estimates of population genetic diversity clearly identified contact populations as those achieving the highest levels of diversity. Such concordance among cold-adapted and temperate species in terms of processes triggering the formation of regional patterns of genetic diversity provides strong support for the hypothesis that gene exchange between divergent lineages, rather than long-term stability of refugial populations, has been the main step toward the formation of hotspots of intraspecific biodiversity. PMID- 28592857 TI - Effects of transcranial direct current stimulation on temperature and pain perception. AB - Transcranial direct current stimulation modifies cortical excitability and in consequence some cerebral functions. In the present study we aimed to elucidate whether tDCS could affect temperature and pain perceptions in healthy subjects testing different stimulation parameters. A total of 20 healthy subjects were studied by means of quantitative sensory testing. Two different experiments were performed. First, we studied the effects of 15 minutes 2 mA anodal transcranial direct current stimulation applied over left M1 and parietal cortex in two separated sessions. Then, we tested the effects of 5 minutes tDCS over M1 by means of a sham controlled design to optimize the possibility to study minimal effects of tDCS using different polarities (cathodal and anodal) and intensities (1 and 2 mA). 2 mA anodal tDCS, when applied for both 15 and 5 minutes over the motor cortex, increased cold perception threshold. Conversely, motor cortex cathodal tDCS modulated cold perception threshold only when 1 mA intensity was used. M1-tDCS can modify the temperature perception; these effects are polarity and intensity dependent. As stimulation intensity seems critical to determine the effects, we suggest that for clinical application strong anodal tDCS (>1 mA) or weak cathodal tDCS (<2 mA) should be used for pain control. PMID- 28592858 TI - Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise. AB - This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain. PMID- 28592859 TI - Synthesis and characterization of ultralong SiC nanowires with unique optical properties, excellent thermal stability and flexible nanomechanical properties. AB - Several-millimeter long SiC nanowires (NWs) with unique optical properties, excellent thermal stability and flexible nanomechanical properties were synthesized using a simple method with silicon and phenolic resin as the raw materials. The SiC NWs displayed special optical properties that were attributed to their large size and Al-doping. They displayed broad green emission at 527.8 nm (2.35 eV) and purple emission concentrated at 438.9 nm (2.83 eV), in contrast to the other results, and the synthesized SiC NWs could also remain relatively stable in air up to 1000 degrees C indicating excellent thermal stability. The Young's moduli of the SiC NWs with a wide range of NW diameters (215-400 nm) were measured using an in situ nanoindentation method with a hybrid scanning electron microscopy/scanning probe microscopy (SEM/SPM) system for the first time. The results suggested that the values of the Young's modulus of the SiC NWs showed no clear size dependence, and the corresponding Young's moduli of the SiC NWs with diameters of 215 nm, 320 nm, and 400 nm were approximately 559.1 GPa, 540.0 GPa and 576.5 GPa, respectively. These findings provide value and guidance for studying and understanding the properties of SiC nanomaterials and for expanding their possible applications. PMID- 28592861 TI - Genomic admixture tracks pulses of economic activity over 2,000 years in the Indian Ocean trading network. AB - The Indian Ocean has long been a hub of interacting human populations. Following land- and sea-based routes, trade drove cultural contacts between far-distant ethnic groups in Asia, India, the Middle East and Africa, creating one of the world's first proto-globalized environments. However, the extent to which population mixing was mediated by trade is poorly understood. Reconstructing admixture times from genomic data in 3,006 individuals from 187 regional populations reveals a close association between bouts of human migration and trade volumes during the last 2,000 years across the Indian Ocean trading system. Temporal oscillations in trading activity match phases of contraction and expansion in migration, with high water marks following the expansion of the Silk Roads in the 5th century AD, the rise of maritime routes in the 11th century and a drastic restructuring of the trade network following the arrival of Europeans in the 16th century. The economic fluxes of the Indian Ocean trade network therefore directly shaped exchanges of genes, in addition to goods and concepts. PMID- 28592860 TI - Role of flagella and type four pili in the co-migration of Burkholderia terrae BS001 with fungal hyphae through soil. AB - Burkholderia terrae BS001 has previously been found to be able to disperse along with growing fungal hyphae in soil, with the type-3 secretion system having a supportive role in this movement. In this study, we focus on the role of two motility- and adherence-associated appendages, i.e. type-4 pili (T4P) and flagella. Electron microcopy and motility testing revealed that strain BS001 produces polar flagella and can swim on semi-solid R2A agar. Flagellum- and T4P negative mutants were then constructed to examine the ecological roles of the respective systems. Both in liquid media and on swimming agar, the mutant strains showed similar fitness to the wild-type strain in mixed culture. The flagellar mutant had completely lost its flagella, as well as its swimming capacity. It also lost its co-migration ability with two soil-exploring fungi, Lyophyllum sp. strain Karsten and Trichoderma asperellum 302, in soil microcosms. In contrast, the T4P mutant showed reduced surface twitching motility, whereas its co migration ability in competition with the wild-type strain was slightly reduced. We conclude that the co-migration of strain BS001 with fungal hyphae through soil is dependent on the presence of functional flagella conferring swimming motility, with the T4P system having a minor effect. PMID- 28592862 TI - Identification of unique cardiolipin and monolysocardiolipin species in Acinetobacter baumannii. AB - Acidic glycerophospholipids play an important role in determining the resistance of Gram-negative bacteria to stress conditions and antibiotics. Acinetobacter baumannii, an opportunistic human pathogen which is responsible for an increasing number of nosocomial infections, exhibits broad antibiotic resistances. Here lipids of A. baumannii have been analyzed by combined MALDI-TOF/MS and TLC analyses; in addition GC-MS analyses of fatty acid methyl esters released by methanolysis of membrane phospholipids have been performed. The main glycerophospholipids are phosphatidylethanolamine, phosphatidylglycerol, acyl phosphatidylglycerol and cardiolipin together with monolysocardiolipin, a lysophospholipid only rarely detected in bacterial membranes. The major acyl chains in the phospholipids are C16:0 and C18:1, plus minor amounts of short chain fatty acids. The structures of the cardiolipin and monolysocardiolipin have been elucidated by post source decay mass spectrometry analysis. A large variety of cardiolipin and monolysocardiolipin species were found in A. baumannii. Similar lysocardiolipin levels were found in the two clinical strains A. baumannii ATCC19606 T and AYE whereas in the nonpathogenic strain Acinetobacter baylyi ADP1 lysocardiolipin levels were highly reduced. PMID- 28592863 TI - Human cortical activity evoked by contextual processing in attentional orienting. AB - The ability to assess another person's direction of attention is paramount in social communication, many studies have reported a similar pattern between gaze and arrow cues in attention orienting. Neuroimaging research has also demonstrated no qualitative differences in attention to gaze and arrow cues. However, these studies were implemented under simple experiment conditions. Researchers have highlighted the importance of contextual processing (i.e., the semantic congruence between cue and target) in attentional orienting, showing that attentional orienting by social gaze or arrow cues could be modulated through contextual processing. Here, we examine the neural activity of attentional orienting by gaze and arrow cues in response to contextual processing using functional magnetic resonance imaging. The results demonstrated that the influence of neural activity through contextual processing to attentional orienting occurred under invalid conditions (when the cue and target were incongruent versus congruent) in the ventral frontoparietal network, although we did not identify any differences in the neural substrates of attentional orienting in contextual processing between gaze and arrow cues. These results support behavioural data of attentional orienting modulated by contextual processing based on the neurocognitive architecture. PMID- 28592865 TI - Comparison of Different Drying Methods for Recovery of Mushroom DNA. AB - Several methods have been reported for drying mushroom specimens for population genetic, taxonomic, and phylogenetic studies. However, most methods have not been directly compared for their effectiveness in preserving mushroom DNA. In this study, we compared silica gel drying at ambient temperature and oven drying at seven different temperatures. Two mushroom species representing two types of fruiting bodies were examined: the fleshy button mushroom Agaricus bisporus and the leathery shelf fungus Trametes versicolor. For each species dried with the eight methods, we assessed the mushroom water loss rate, the quality and quantity of extracted DNA, and the effectiveness of using the extracted DNA as a template for PCR amplification of two DNA fragments (ITS and a single copy gene). Dried specimens from all tested methods yielded sufficient DNA for PCR amplification of the two genes in both species. However, differences among the methods for the two species were found in: (i) the time required by different drying methods for the fresh mushroom tissue to reach a stable weight; and (ii) the relative quality and quantity of the extracted genomic DNA. Among these methods, oven drying at 70 degrees C for 3-4 h seemed the most efficient for preserving field mushroom samples for subsequent molecular work. PMID- 28592864 TI - Infectious DNAs derived from insect-specific flavivirus genomes enable identification of pre- and post-entry host restrictions in vertebrate cells. AB - Flaviviruses such as West Nile virus (WNV), dengue virus and Zika virus are mosquito-borne pathogens that cause significant human diseases. A novel group of insect-specific flaviviruses (ISFs), which only replicate in mosquitoes, have also been identified. However, little is known about the mechanisms of ISF host restriction. We report the generation of infectious cDNA from two Australian ISFs, Parramatta River virus (PaRV) and Palm Creek virus (PCV). Using circular polymerase extension cloning (CPEC) with a modified OpIE2 insect promoter, infectious cDNA was generated and transfected directly into mosquito cells to produce infectious virus indistinguishable from wild-type virus. When infectious PaRV cDNA under transcriptional control of a mammalian promoter was used to transfect mouse embryo fibroblasts, the virus failed to initiate replication even when cell entry steps were by-passed and the type I interferon response was lacking. We also used CPEC to generate viable chimeric viruses between PCV and WNV. Analysis of these hybrid viruses revealed that ISFs are also restricted from replication in vertebrate cells at the point of entry. The approaches described here to generate infectious ISF DNAs and chimeric viruses provide unique tools to further dissect the mechanisms of their host restriction. PMID- 28592866 TI - A protein-protein interaction dictates Borrelial infectivity. AB - Two Borrelia burgdorferi interacting proteins, BB0238 and BB0323, play distinct roles in pathogen biology and infectivity although a significance of their interaction remained enigmatic. Here we identified the polypeptide segment essential for BB0238-BB0323 interaction and examined how it supports spirochete infectivity. We show that the interaction region in BB0323 requires amino acid residues 22-200, suggesting that the binding encompasses discontinuous protein segments. In contrast, the interaction region in BB0238 spans only 11 amino acids, residues 120-130. A deletion of these 11 amino acids neither alters the overall secondary structure of the protein, nor affects its stability or oligomerization property, however, it reduces the post-translational stability of the binding partner, BB0323. Mutant B. burgdorferi isolates producing BB0238 lacking the 11-amino acid interaction region were able to persist in ticks but failed to transmit to mice or to establish infection. These results suggest that BB0238-BB0323 interaction is critical for post-translational stability of BB0323, and that this interaction is important for mammalian infectivity and transmission of B. burgdorferi. We show that saturation or inhibition of BB0238-BB0323 interaction could be studied in a luciferase assay, which could be amenable for future identification of small molecule inhibitors to combat B. burgdorferi infection. PMID- 28592867 TI - TiO(OH)2 - highly effective catalysts for optimizing CO2 desorption kinetics reducing CO2 capture cost: A new pathway. AB - The objective is to find a new pathway for significant reduction in CO2 capture energy consumption. Specifically, nanoporous TiO(OH)2 was used to realize the objective, which was desired as a catalyst to significantly accelerate the decomposition of aqueous NaHCO3, essentially CO2 desorption - the key step of Na2CO3/NaHCO3 based CO2 capture technologies from overall CO2 energy consumption perspective. Effects of several important factors on TiO(OH)2-catalyzed NaHCO3 decomposition were investigated. The quantity of CO2 generated from 0.238 mol/L NaHCO3 at 65 degrees C with catalyst is ~800% of that generated without the presence of catalyst. When a 12 W vacuum pump was used for carrying the generated CO2 out of reactor, the total amount of CO2 released was improved by ~2,500% under the given experimental conditions. No significant decrease in the catalytic effect of TiO(OH)2 was observed after five cyclic CO2 activated tests. In addition, characterizations with in-situ Fourier transform infrared spectroscopy, thermal gravity analysis and Brunauer-Emmett-Teller of TiO(OH)2 indicate that TiO(OH)2 is quite stable. The discovery in this research could inspire scientists' interests in starting to focus on a new pathway instead of making huge effort or investment in designing high-capacity but expensive CO2 sorbent for developing practical or cost-effective CO2 technologies. PMID- 28592869 TI - Experiment-based modelling of grain boundary beta-phase (Mg2Al3) evolution during sensitisation of aluminium alloy AA5083. AB - An empirical model for the evolution of beta-phase (Mg2Al3) along grain boundaries in aluminium alloy AA5083 (Al-Mg-Mn) during isothermal exposures is proposed herein. Developing a quantitative understanding of grain boundary precipitation is important to interpreting intergranular corrosion and stress corrosion cracking in this alloy system. To date, complete ab initio models for grain boundary precipitation based upon fundamental principles of thermodynamics and kinetics are not available, despite the critical role that such precipitates play in dictating intergranular corrosion phenomena. Empirical models can therefore serve an important role in advancing the understanding of grain boundary precipitation kinetics, which is an approach applicable beyond the present context. High resolution scanning electron microscopy was to quantify the size and distribution of beta-phase precipitates on Ga-embrittled intergranular fracture surfaces of AA5083. The results are compared with the degree of sensitisation (DoS) as judged by nitric acid mass loss testing (ASTM-G67-04), and discussed with models for sensitisation in 5xxx series Al-alloys. The work herein allows sensitisation to be quantified from an unambiguous microstructural perspective. PMID- 28592870 TI - Influence of a patient transfer network of US inpatient facilities on the incidence of nosocomial infections. AB - Antibiotic-resistant bacterial infections are a substantial source of morbidity and mortality and have a common reservoir in inpatient settings. Transferring patients between facilities could be a mechanism for the spread of these infections. We wanted to assess whether a network of hospitals, linked by inpatient transfers, contributes to the spread of nosocomial infections and investigate how network structure may be leveraged to design efficient surveillance systems. We construct a network defined by the transfer of Medicare patients across US inpatient facilities using a 100% sample of inpatient discharge claims from 2006-2007. We show the association between network structure and C. difficile incidence, with a 1% increase in a facility's C. difficile incidence being associated with a 0.53% increase in C. difficile incidence of neighboring facilities. Finally, we used network science methods to determine the facilities to monitor to maximize surveillance efficiency. An optimal surveillance strategy for selecting "sensor" hospitals, based on their network position, detects 80% of the C. difficile infections using only 2% of hospitals as sensors. Selecting a small fraction of facilities as "sensors" could be a cost-effective mechanism to monitor emerging nosocomial infections. PMID- 28592868 TI - The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation. AB - The extent of regeneration following biomaterial implantation is dependent on the microenvironment surrounding the implant. Since implant composition can have a profound effect on inflammation, it is essential to understand this process as a non-resolving inflammatory response can lead to fibrous encapsulation and insufficient integration. Incorporation of particulates into implants confers structural and functional benefits, thus optimizing particulate characteristics to enhance immune mediated efficacy is important. We investigated the relationship between the nature of hydroxyapatite (HA) particles and the innate immune response, focusing on how particle size (0.1 um, 5 um, 20 um, 100 um) and morphology (needle-shaped/spherical; smooth/rough surface) modulates inflammatory responses. We observed a shape and size-dependent activation of the NLRP3 inflammasome and IL-1beta secretion; while needle-shaped and smaller HA particles significantly enhanced cytokine secretion, larger particles did not. Moreover, HA particle characteristics profoundly influenced patterns of innate immune cell recruitment and cytokine production following injection. While small, needle shaped particles induced a strong inflammatory response, this was not observed with smooth, spherical particles of comparable size or with larger particles. These findings indicate that hydroxyapatite particle characteristics dictate immune cell recruitment and the ensuing inflammatory response, providing an opportunity to tailor HA particle characteristics to regulate immune responses induced after biomaterial implantation. PMID- 28592871 TI - Incorporation of Fluorescence Ceramide-Based HPLC Assay for Rapidly and Efficiently Assessing Glucosylceramide Synthase In Vivo. AB - Glucosylceramide synthase (GCS) is a rate-limiting enzyme catalyzing ceramide glycosylation, thereby regulating cellular ceramide levels and the synthesis of glycosphingolipids (GSLs) in cellular membranes. Alterations of GCS not only affect membrane integrity, but also closely correlate with stem cell pluripotency, cancer drug resistance, GSL storage disorders and other diseases. Enzyme activities measured conventionally with currently available ex-vivo methods do not enable reliable assessment of the roles played by GCS in vivo. We report herein a substrate-incorporation method enabling rapid and efficient assessment of GCS in-vivo activity. Upon nanoparticle-based delivery, fluorescent NBD C6-ceramide was efficiently converted to NBD C6-glucosylceramide in live cells or in mouse tissues, whereupon an HPLC assay enabled detection and quantification of NBD C6-glucosylceramide in the low-femtomolar range. The enzyme kinetics of GCS in live cells and mouse liver were well-described by the Michaelis-Menten model. GCS activities were significantly higher in drug resistant cancer cells and in tumors overexpressing GCS, but reduced after silencing GCS expression or inhibiting this enzyme. Our studies indicate that this rapid and efficient method provides a valuable means for accurately assessing the roles played by GCS in normal vs. pathological states, including ones involving cancer drug resistance. PMID- 28592873 TI - Synthesis method of asymmetric gold particles. AB - Asymmetric particles can exhibit unique properties. However, reported synthesis methods for asymmetric particles hinder their application because these methods have a limited scale and lack the ability to afford particles of varied shapes. Herein, we report a novel synthetic method which has the potential to produce large quantities of asymmetric particles. Asymmetric rose-shaped gold particles were fabricated as a proof of concept experiment. First, silica nanoparticles (NPs) were bound to a hydrophobic micro-sized polymer containing 2 chlorotritylchloride linkers (2-CTC resin). Then, half-planar gold particles with rose-shaped and polyhedral structures were prepared on the silica particles on the 2-CTC resin. Particle size was controlled by the concentration of the gold source. The asymmetric particles were easily cleaved from the resin without aggregation. We confirmed that gold was grown on the silica NPs. This facile method for synthesizing asymmetric particles has great potential for materials science. PMID- 28592872 TI - NOD1 deficiency impairs CD44a/Lck as well as PI3K/Akt pathway. AB - Pattern recognition receptors (PRRs) are crucial for host defense and tissue homeostasis against infecting pathogens. PRRs are highly conserved cross species, suggesting their key roles in fundamental biological processes. Though much have been learned for NOD1 receptor in the innate and adaptive immune responses, the roles of NOD1 during embryonic and larval stages remain poorly understood. Here, we report that NOD1 is necessary for the modulation of PI3K-Akt pathway and larval survival in zebrafish. Transcriptome analysis revealed that the significantly enriched pathways in NOD1 -/- zebrafish larvae were mainly involved in metabolism and immune system processes. Biochemical analysis demonstrated that NOD1 was required for the expression of CD44a that, in turn, activated the PI3K Akt pathway during larval development. Conversely, over-expression of CD44a in NOD1-deficient zebrafish restored the modulation of the PI3K-Akt pathway and improved larval survival. Collectively, our work indicates that NOD1 plays a previously undetected protective role in larval survival through CD44a-mediated activation of the PI3K-Akt signaling. PMID- 28592874 TI - CT-Based Local Distribution Metric Improves Characterization of COPD. AB - Parametric response mapping (PRM) of paired CT lung images has been shown to improve the phenotyping of COPD by allowing for the visualization and quantification of non-emphysematous air trapping component, referred to as functional small airways disease (fSAD). Although promising, large variability in the standard method for analyzing PRMfSAD has been observed. We postulate that representing the 3D PRMfSAD data as a single scalar quantity (relative volume of PRMfSAD) oversimplifies the original 3D data, limiting its potential to detect the subtle progression of COPD as well as varying subtypes. In this study, we propose a new approach to analyze PRM. Based on topological techniques, we generate 3D maps of local topological features from 3D PRMfSAD classification maps. We found that the surface area of fSAD (SfSAD) was the most robust and significant independent indicator of clinically meaningful measures of COPD. We also confirmed by micro-CT of human lung specimens that structural differences are associated with unique SfSAD patterns, and demonstrated longitudinal feature alterations occurred with worsening pulmonary function independent of an increase in disease extent. These findings suggest that our technique captures additional COPD characteristics, which may provide important opportunities for improved diagnosis of COPD patients. PMID- 28592875 TI - Splice variants as novel targets in pancreatic ductal adenocarcinoma. AB - Despite a wealth of genomic information, a comprehensive alternative splicing (AS) analysis of pancreatic ductal adenocarcinoma (PDAC) has not been performed yet. In the present study, we assessed whole exome-based transcriptome and AS profiles of 43 pancreas tissues using Affymetrix exon array. The AS analysis of PDAC indicated on average two AS probe-sets (ranging from 1-28) in 1,354 significantly identified protein-coding genes, with skipped exon and alternative first exon being the most frequently utilised. In addition to overrepresented extracellular matrix (ECM)-receptor interaction and focal adhesion that were also seen in transcriptome differential expression (DE) analysis, Fc gamma receptor mediated phagocytosis and axon guidance AS genes were also highly represented. Of note, the highest numbers of AS probe-sets were found in collagen genes, which encode the characteristically abundant stroma seen in PDAC. We also describe a set of 37 'hypersensitive' genes which were frequently targeted by somatic mutations, copy number alterations, DE and AS, indicating their propensity for multidimensional regulation. We provide the most comprehensive overview of the AS landscape in PDAC with underlying changes in the spliceosomal machinery. We also collate a set of AS and DE genes encoding cell surface proteins, which present promising diagnostic and therapeutic targets in PDAC. PMID- 28592876 TI - Elongation factor Tu on Escherichia coli isolated from urine of kidney stone patients promotes calcium oxalate crystal growth and aggregation. AB - Escherichia coli is the most common bacterium isolated from urine and stone matrix of calcium oxalate (CaOx) stone formers. Whether it has pathogenic role(s) in kidney stone formation or is only entrapped inside the stone remains unclear. We thus evaluated differences between E. coli isolated from urine of patients with kidney stone (EUK) and that from patients with urinary tract infection (UTI) without stone (EUU). From 100 stone formers and 200 UTI patients, only four pairs of EUK/EUU isolates had identical antimicrobial susceptibility patterns. Proteomic analysis revealed nine common differentially expressed proteins. Among these, the greater level of elongation factor Tu (EF-Tu) in EUK was validated by Western blotting. Outer membrane vesicles (OMVs) derived from EUK had greater promoting activities on CaOx crystallization, crystal growth and aggregation as compared to those derived from EUU. Neutralizing the OMVs of EUK with monoclonal anti-EF-Tu antibody, not with an isotype antibody, significantly reduced all these OMVs-induced promoting effects. Moreover, immunofluorescence staining of EF Tu on bacterial cell surface confirmed the greater expression of surface EF-Tu on EUK (vs. EUU). Our data indicate that surface EF-Tu and OMVs play significant roles in promoting activities of E. coli on CaOx crystallization, crystal growth and aggregation. PMID- 28592877 TI - omega-3 free fatty acids and all-trans retinoic acid synergistically induce growth inhibition of three subtypes of breast cancer cell lines. AB - All-trans retinoic acid (ATRA), one of vitamin A derivatives, shows greater growth inhibition of breast cancer cell for ER-positive than ER-negative cells, while triple negative breast cancer cell such as MDA-MB-231 cell is poorly responsive to ATRA treatment. In this study, we found that combination of omega-3 free fatty acids (omega-3 FFAs) and ATRA exhibited synergistic inhibition of cell growth in three subtypes (ER+ MCF7, HER2+ SK-BR-3, Triple negative HCC1806 and MDA-MB-231 cells) of human breast cancer cell lines. The combined treatment of omega-3 FFAs and ATRA resulted in cell cycle arrest. omega-3 FFAs combined with ATRA synergistically provoked cell apoptosis via the caspase signals but not p53. These findings suggest that combined chemotherapy of omega-3 FFAs with ATRA is beneficial for improvement of ATRA sensitivity in breast cancer cells. PMID- 28592878 TI - Imbalance-Aware Machine Learning for Predicting Rare and Common Disease Associated Non-Coding Variants. AB - Disease and trait-associated variants represent a tiny minority of all known genetic variation, and therefore there is necessarily an imbalance between the small set of available disease-associated and the much larger set of non deleterious genomic variation, especially in non-coding regulatory regions of human genome. Machine Learning (ML) methods for predicting disease-associated non coding variants are faced with a chicken and egg problem - such variants cannot be easily found without ML, but ML cannot begin to be effective until a sufficient number of instances have been found. Most of state-of-the-art ML-based methods do not adopt specific imbalance-aware learning techniques to deal with imbalanced data that naturally arise in several genome-wide variant scoring problems, thus resulting in a significant reduction of sensitivity and precision. We present a novel method that adopts imbalance-aware learning strategies based on resampling techniques and a hyper-ensemble approach that outperforms state-of the-art methods in two different contexts: the prediction of non-coding variants associated with Mendelian and with complex diseases. We show that imbalance-aware ML is a key issue for the design of robust and accurate prediction algorithms and we provide a method and an easy-to-use software tool that can be effectively applied to this challenging prediction task. PMID- 28592879 TI - Biogeography of Amazon birds: rivers limit species composition, but not areas of endemism. AB - Amazonian rivers are usually suggested as dispersal barriers, limiting biogeographic units. This is evident in a widely accepted Areas of Endemism (AoEs) hypothesis proposed for Amazonian birds. We empirically test this hypothesis based on quantitative analyses of species distribution. We compiled a database of bird species and subspecies distribution records, and used this dataset to identify AoEs through three different methods. Our results show that the currently accepted Amazonian AoEs are not consistent with areas identified, which were generally congruent among datasets and methods. Some Amazonian rivers represent limits of AoEs, but these areas are not congruent with those previously proposed. However, spatial variation in species composition is correlated with largest Amazonian rivers. Overall, the previously proposed Amazonian AoEs are not consistent with the evidence from bird distribution. However, the fact that major rivers coincide with breaks in species composition suggest they can act as dispersal barriers, though not necessarily for all bird taxa. This scenario indicates a more complex picture of the Amazonian bird distribution than previously imagined. PMID- 28592880 TI - Expression and Transcriptional Regulation of Human ATP6V1A Gene in Gastric Cancers. AB - Recent studies demonstrate that the invasion and metastasis of gastric cancer (GC) is closely associated with a multi-subunit vacuolar H+-ATPase (V-ATPase). Here we investigated the expression and role of the human ATP6V1A gene that encodes the catalytic subunit A of V-ATPase in GC. We found that ATP6V1A expression level is significantly elevated in GCs compared to normals, but GC patients with higher expression levels of ATP6V1A have a better prognosis. Genomic analysis revealed that APT6V1A copy number is gained in a small fraction of GC patients and lost in a minimum number. Moreover, the ATP6V1A copy number was positively correlated with its mRNA level. To explore additional mechanisms by which ATP6V1A overexpressed in GCs, we investigated the relationship between transcription factor YY1 and ATP6V1A, and found that mRNA expression of YY1 had significant correlation with that of ATP6V1A. To validate that YY1 transcriptionally regulates ATP6V1A, we discovered that the ATP6V1A core promoter region contains three YY1 binding sites. Moreover, RNAi-mediated knockdown of YY1 in GC cells significantly decreased ATP6V1A mRNA and protein expression, while YY1 overexpression increased ATP6V1A expression level. In conclusion, YY1 may play an important regulatory role in ATP6V1A expression with potential mechanistic and clinical implications in GC. PMID- 28592881 TI - Pretreatment C-reactive protein to albumin ratio for predicting overall survival in advanced pancreatic cancer patients. AB - Although previous studies demonstrated that elevated C-reactive protein to albumin ratio (CAR) predicted poor prognosis in various solid tumors, little was known about the prognostic value of CAR in patients with advanced pancreatic cancer (APC). The aim of the present study was to assess CAR as one independent prognostic factor in predicting overall survival (OS) in APC patients who had received palliative chemotherapy. Data of 142 APC patients who received palliative chemotherapy between 2009 and 2014 were retrospectively documented. We classified the patients into two groups based on the optimal cutoff value of CAR identified by generating receiver operating characteristics (ROC) curve. The clinicopathological parameters were compared between two CAR groups. Pearson correlation test showed that the level of C-reactive protein (CRP) was inversely correlated with albumin (r = -0.387; P < 0.001). Kaplan-Meier analysis demonstrated overall survival (OS) was significantly longer in CAR < 0.156 group than CAR >= 0.156 group (11.2 vs 5.9 months, P < 0.001). CAR was an independent prognostic factor for OS in the Cox regression model (HR, 1.623; 95% CI, 1.093 2.410; P = 0.016). Furthermore, the discrimination ability of CAR (AUC = 0.648, P = 0.025) was slightly higher than that of other inflammation-based factors. Therefore, pretreatment CAR could be an independent prognostic biomarker for APC patients. PMID- 28592882 TI - ML290 is a biased allosteric agonist at the relaxin receptor RXFP1. AB - Activation of the relaxin receptor RXFP1 has been associated with improved survival in acute heart failure. ML290 is a small molecule RXFP1 agonist with simple structure, long half-life and high stability. Here we demonstrate that ML290 is a biased agonist in human cells expressing RXFP1 with long-term beneficial actions on markers of fibrosis in human cardiac fibroblasts (HCFs). ML290 did not directly compete with orthosteric relaxin binding and did not affect binding kinetics, but did increase binding to RXFP1. In HEK-RXFP1 cells, ML290 stimulated cAMP accumulation and p38MAPK phosphorylation but not cGMP accumulation or ERK1/2 phosphorylation although prior addition of ML290 increased p-ERK1/2 responses to relaxin. In human primary vascular endothelial and smooth muscle cells that endogenously express RXFP1, ML290 increased both cAMP and cGMP accumulation but not p-ERK1/2. In HCFs, ML290 increased cGMP accumulation but did not affect p-ERK1/2 and given chronically activated MMP-2 expression and inhibited TGF-beta1-induced Smad2 and Smad3 phosphorylation. In vascular cells, ML290 was 10x more potent for cGMP accumulation and p-p38MAPK than for cAMP accumulation. ML290 caused strong coupling of RXFP1 to Galphas and GalphaoB but weak coupling to Galphai3. ML290 exhibited signalling bias at RXFP1 possessing a signalling profile indicative of vasodilator and anti-fibrotic properties. PMID- 28592883 TI - The lateral distance between a proton pump and ATP synthase determines the ATP synthesis rate. AB - We have investigated the effect of lipid composition on interactions between cytochrome bo 3 and ATP-synthase, and the ATP-synthesis activity driven by proton pumping. The two proteins were labeled by fluorescent probes and co-reconstituted in large (d ? 100 nm) or giant (d ? 10 um) unilamellar lipid vesicles. Interactions were investigated using fluorescence correlation/cross-correlation spectroscopy and the activity was determined by measuring ATP production, driven by electron-proton transfer, as a function of time. We found that conditions that promoted direct interactions between the two proteins in the membrane (higher fraction DOPC lipids or labeling by hydrophobic molecules) correlated with an increased activity. These data indicate that the ATP-synthesis rate increases with decreasing distance between cytochrome bo 3 and the ATP-synthase, and involves proton transfer along the membrane surface. The maximum distance for lateral proton transfer along the surface was found to be ~80 nm. PMID- 28592884 TI - Enhancement of Th1/Th17 inflammation by TRIM21 in Behcet's disease. AB - The etiology of Behcet's disease (BD), a chronic, multisystemic autoinflammatory and autoimmune disease, remains unknown; however, researchers have postulated that infectious agents, such as herpes simplex virus, are significant triggering factors of BD. Tripartite motif-containing (TRIM) proteins exhibit antiviral properties, mediating antiviral defense mechanisms. The purpose of this study was to investigate TRIM21 protein expression in the monocytes of BD patients and to identify the role of TRIM21 in immune dysregulation in BD. In this study, the expression of TRIM21 and related molecules, including interferon regulatory factor 8 (IRF8), was analyzed in monocytes from BD patients. Functional analyses using small interfering RNA and co-culture with responder T cells were performed to examine the pathological role of TRIM21 in BD. Peripheral blood monocytes from BD patients showed increased TRIM21 expression and decreased IRF8 expression compared with that in monocytes from healthy controls. TRIM21 was found to decrease IRF8 expression. BD monocytes facilitated Th1 and Th17 differentiation of co-cultured T cells, and knock-down of TRIM21 expression by small interfering RNA inhibited this differentiation. In conclusion, TRIM21 played a pivotal role in regulating the secretion of proinflammatory cytokines in monocytes of BD patients. PMID- 28592885 TI - Low genetic diversity and potential inbreeding in an isolated population of alder buckthorn (Frangula alnus) following a founder effect. AB - Alder buckthorn (Frangula alnus) is one of Ireland's rarest tree species, and in Northern Ireland the species is now restricted to a single population in Peatlands Park, Co. Armagh numbering ca. 140 mature trees. Genotyping of 95% of the trees at nine nuclear microsatellite loci revealed that levels of genetic diversity within this population were generally lower than those reported from larger populations in Spain. Analysis of six chloroplast microsatellite loci revealed no variation. The level of F IS was significantly higher than that in the Spanish populations, as well as in other populations across Europe, potentially indicating inbreeding. Spatial autocorrelation analysis indicated some evidence of fine-scale genetic structuring, most likely due to limited seed dispersal, but the overall level of differentiation between subpopulations was low, indicating high levels of gene flow, probably due to cross-pollination by bees. Our results are consistent with a gradual population expansion from a limited number of individuals. We suggest that more immediate conservation efforts might be best focused on ensuring suitable habitat for the continued recovery of this isolated population. PMID- 28592886 TI - MDS with deletions in the long arm of chromosome 11 are associated with a high frequency of SF3B1 mutations. PMID- 28592887 TI - CHIP, ICUS, CCUS and other four-letter words. AB - Clonal hematopoiesis can be identified by the presence of somatic mutations in blood or bone marrow even in individuals without a myeloid malignancy. Advances in DNA sequencing have led to the discovery that clonal hematopoiesis is remarkably common and occurs in a wide variety of settings, each often described by unique acronym. These distinctions can be useful as the implications of clonal hematopoiesis depend almost entirely on the clinical context in which it is identified. However, some generalizations can be made. The prevalence of clonal hematopoiesis increases with age, particularly after the fifth decade of life. Clonal hematopoiesis in normal individuals with very small clones is typically benign, while patients with clinically abnormal hematopoiesis, larger clones and more driver gene mutations appear to be at much greater risk. Understanding the significance of clonal hematopoiesis in the various contexts in which it occurs can influence how physicians assess risk, select therapies and counsel their patients. This concise review examines the implications of clonal hematopoiesis in several settings, including normal aging, aplastic anemia, unexplained cytopenias and patients receiving cytotoxic chemotherapy. PMID- 28592888 TI - TCRalpha rearrangements identify a subgroup of NKL-deregulated adult T-ALLs associated with favorable outcome. AB - T-cell acute lymphoblastic leukemia (T-ALL) results from leukemic transformation of T-cell precursors arrested at specific differentiation stages, including an 'early-cortical' thymic maturation arrest characterized by expression of cytoplasmic TCRbeta but no surface T-cell receptor (TCR) and frequent ectopic expression of the TLX1/3 NK-like homeotic proteins (NKL). We designed a TCRalpha VJC PCR to identify clonal TCRalpha rearrangements in 32% of 127 T-ALLs, including 0/52 immature/TCRgammadelta lineage cases and 41/75 (55%) TCRalphabeta lineage cases. Amongst the latter, TCRalpha rearrangements were not identified in 30/54 (56%) of IMbeta/pre-alphabeta early-cortical T-ALLs, of which the majority (21/30) expressed TLX1/3. We reasoned that the remaining T-ALLs might express other NKL proteins, so compared transcript levels of 46 NKL in T-ALL and normal thymic subpopulations. Ectopic overexpression of 10 NKL genes, of which six are unreported in T-ALL (NKX2-3, BARHL1, BARX2, EMX2, LBX2 and MSX2), was detectable in 17/104 (16%) T-ALLs. Virtually all NKL overexpressing T-ALLs were TCRalpha unrearranged and ectopic NKL transcript expression strongly repressed Ealpha activity, suggesting that ectopic NKL expression is the major determinant in early-cortical thymic T-ALL maturation arrest. This immunogenetic T-ALL subtype, defined by TCRbeta VDJ but no TCRalpha VJ rearrangement, is associated with a favorable outcome in GRAALL-treated adult T-ALLs. PMID- 28592889 TI - Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. AB - In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations. PMID- 28592890 TI - Polymorphism in the gene encoding toll-like receptor 10 may be associated with asthma after bronchiolitis. AB - Toll-like receptors (TLRs) recognise microbes that contribute to the severity of bronchiolitis and the subsequent risk of asthma. We evaluated whether post bronchiolitis asthma was associated with polymorphisms in the TLR3 rs3775291, TLR4 rs4986790, TLR7 rs179008, TLR8 rs2407992, TLR9 rs187084, and TLR10 rs4129009 genes. The gene polymorphisms were studied at the age of 6.4 years (mean) in 135 children hospitalised for bronchiolitis in infancy. The outcome measure was current or previous asthma. Current asthma was more common (30%) in children with the variant AG or GG genotype in the TLR10 rs4129009 gene versus those who were homozygous for the major allele A (11%) (p = 0.03). The adjusted odds ratio (aOR) was 4.30 (95% CI 1.30-14.29). Asthma ever was more common (34.6%) in girls with the TLR7 variant AT or TT genotype versus those who were homozygous for the major allele A (12.5%) (p = 0.03). The adjusted OR was 3.93 (95% CI 1.06-14.58). Corresponding associations were not seen in boys. There were no significant associations between TLR3, TLR4, TLR8, or TLR9 polymorphisms and post bronchiolitis asthma. Polymorphism in the TLR10 gene increases and in the TLR7 gene may increase the risk of asthma in preschool-aged children after infant bronchiolitis. PMID- 28592891 TI - Dynamic Triple-Mode Sorption and Outgassing in Materials. AB - Moisture uptake and outgassing can be detrimental to a system by altering the chemical and mechanical properties of materials within the system over time. In this work, we conducted isotherm experiments to investigate dynamic moisture sorption and desorption in markedly different materials, i.e., a polymeric material, Sylgard-184 and a ceramic aluminosilicate material, Zircar RS-1200, at different temperatures (30 degrees C-70 degrees C) by varying the water activity (0.0-0.90). Sylgard-184 showed a linear sorption and outgassing behavior with no-hysteresis over the entire temperature and water activity range considered here. Whereas, the sorption and outgassing of Zircar RS-1200 was highly non-linear with significant hysteresis, especially at higher water activities, at all temperatures considered here. The type of hysteresis suggested the presence of mesopores in Zircar RS-1200, whereas the lack of hysteresis in Sylgard-184 indicates that it has a nonporous structure. A diffusion model coupled with a dynamic, triple-mode sorption (Langmuir, Henry, and pooling modes) model employed in this study matched our experimental data very well and provides mechanistic insight into the processes. Our triple-mode sorption model was adaptive enough to (1) model these distinctly different materials and (2) predict sorption and outgassing under conditions that are distinctly different from the parameterization experiments. PMID- 28592892 TI - Noncanocial cell death program independent of caspase activation cascade and necroptotic modules is elicited by loss of TGFbeta-activated kinase 1. AB - Programmed cell death (PCD) occurs in several forms including apoptosis and necroptosis. Apoptosis is executed by the activation of caspases, while necroptosis is dependent on the receptor interacting protein kinase 3 (RIPK3). Precise control of cell death is crucial for tissue homeostasis. Indeed, necroptosis is triggered by caspase inhibition to ensure cell death. Here we identified a previously uncharacterized cell death pathway regulated by TAK1, which is unexpectedly provoked by inhibition of caspase activity and necroptosis cascades. Ablation of TAK1 triggers spontaneous death in macrophages. Simultaneous inhibition of caspases and RIPK3 did not completely restore cell viability. Previous studies demonstrated that loss of TAK1 in fibroblasts causes TNF-induced apoptosis and that additional inhibition of caspase leads to necroptotic cell death. However, we surprisingly found that caspase and RIPK3 inhibitions do not completely suppress cell death in Tak1-deficient cells. Mechanistically, the execution of the third cell death pathway in Tak1-deficient macrophages and fibroblasts were mediated by RIPK1-dependent rapid accumulation of reactive oxygen species (ROS). Conversely, activation of RIPK1 was sufficient to induce cell death. Therefore, loss of TAK1 elicits noncanonical cell death which is mediated by RIPK1-induced oxidative stress upon caspase and necroptosis inhibition to further ensure induction of cell death. PMID- 28592895 TI - Spondyloarthropathies: Targeting IL-17 in refractory PsA. PMID- 28592896 TI - Lupus nephritis: NLRP3 inflammasome ignites podocyte dysfunction. PMID- 28592897 TI - Stem cells: Synovial stem cells respond to a YAP. PMID- 28592893 TI - Regional brain functions in the resting state indicative of potential differences between depression and chronic pain. AB - Complex relationships between depression and chronic pain have been reported in previous studies. However, only a few neuroimaging studies have investigated similarities and differences in neural systems underlying them. We examined the brain functions in the resting state of 43 patients with depression, 41 patients with chronic pain (somatoform pain disorder) and 41 healthy controls, by using regional homogeneity (ReHo) and functional connectivity analysis. Depressive symptoms were assessed by using the Beck Depression Inventory-Second Edition (BDI II). ReHo values for the dorsolateral prefrontal cortex (DLPFC) significantly decreased for chronic pain patients, and functional connectivity between the DLPFC and thalamus decreased only for these patients. These findings are indicative of distinct brain functions related to depression and chronic pain. Understanding these differences would further elucidate the pathophysiology of these conditions. PMID- 28592894 TI - Rheumatoid arthritis: Forward and reverse inheritance - the yin and the yang. PMID- 28592898 TI - Historical grassland desertification changes in the Horqin Sandy Land, Northern China (1985-2013). AB - Since rural reforms in the 1980s, both the state and local governments of China have devoted great efforts to combating desertification through a number of eco environmental restoration campaigns, resulting in burgeoning contention at all levels of government and sparking public concern. Monitoring and accurately assessing the statuses and trends of grassland desertification are important for developing effective restoration strategies. The Horqin Sandy Land (HSL), a very typical desertified grassland (DG) with better hydrothermal conditions among sandy lands in north China, was recently selected (1985-2013) to assess the spatiotemporal dynamic performances of grassland desertification before and after implementing restoration projects. Landsat images (TM/ETM+/OLI), field investigations and expert review were integrated to form a classification scheme for the HSL. Then, spectral mixture analysis and the decision-tree method were used to extract bare-sand ratios and vegetation cover fraction dynamics. A favourable phenomenon of DG was seen to be reversed in an accelerated pace during 2001-2013, despite challenge from both climatic and anthropogenic factors. However, overexploitation of grassland (especially for farming) and ground water for irrigation has led to remarkable decreases in the ground water level in recent decades, which should be highly concerning regarding the formulation of restoration campaigns in the sandy land. PMID- 28592899 TI - Origin and evolutionary history of freshwater Rhodophyta: further insights based on phylogenomic evidence. AB - Freshwater representatives of Rhodophyta were sampled and the complete chloroplast and mitochondrial genomes were determined. Characteristics of the chloroplast and mitochondrial genomes were analyzed and phylogenetic relationship of marine and freshwater Rhodophyta were reconstructed based on the organelle genomes. The freshwater member Compsopogon caeruleus was determined for the largest chloroplast genome among multicellular Rhodophyta up to now. Expansion and subsequent reduction of both the genome size and GC content were observed in the Rhodophyta except for the freshwater Compsopogon caeruleus. It was inferred that the freshwater members of Rhodophyta occurred through diverse origins based on evidence of genome size, GC-content, phylogenomic analysis and divergence time estimation. The freshwater species Compsopogon caeruleus and Hildenbrandia rivularis originated and evolved independently at the inland water, whereas the Bangia atropurpurea, Batrachospermum arcuatum and Thorea hispida are derived from the marine relatives. The typical freshwater representatives Thoreales and Batrachospermales are probably derived from the marine relative Palmaria palmata at approximately 415-484 MYA. The origin and evolutionary history of freshwater Rhodophyta needs to be testified with more organelle genome sequences and wider global sampling. PMID- 28592901 TI - High-Resolution Magnetic Resonance Imaging of the Regenerating Adult Zebrafish Heart. AB - The adult zebrafish is a well-established model for studying heart regeneration, but due to its tissue opaqueness, repair has been primarily assessed using destructive histology, precluding repeated investigations of the same animal. We present a high-resolution, non-invasive in vivo magnetic resonance imaging (MRI) method incorporating a miniature respiratory and anaesthetic perfusion set-up for live adult zebrafish, allowing for visualization of scar formation and heart regeneration in the same animal over time at an isotropic 31 um voxel resolution. To test the method, we compared well and poorly healing cardiac ventricles using a transgenic fish model that exhibits heat-shock (HS) inducible impaired heart regeneration. HS-treated groups revealed persistent scar tissue for 10 weeks, while control groups were healed after 4 weeks. Application of the advanced MRI technique allowed clear discrimination of levels of repair following cryo- and resection injury for several months. It further provides a novel tool for in vivo time-lapse imaging of adult fish for non-cardiac studies, as the method can be readily applied to image wound healing in other injured or diseased tissues, or to monitor tissue changes over time, thus expanding the range of questions that can be addressed in adult zebrafish and other small aquatic species. PMID- 28592900 TI - White matter microstructural changes are related to cognitive dysfunction in essential tremor. AB - Diffusion tensor imaging (DTI) studies have detected white matter microstructural changes in essential tremor (ET). However, it is still unclear whether these changes are related to cognitive deficits, which have been described in ET patients. DTI-derived fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity measures were compared between 23 ET patients and 23 age-, gender-, and education-matched healthy individuals, using whole-brain tract-based spatial statistics. Correlations of white matter changes with scores obtained from a detailed neuropsychological assessment were subsequently examined. ET patients demonstrated increases in MD in the bilateral posterior corona radiata, bilateral superior longitudinal fasciculus, bilateral fornix (cres)/stria terminalis, genu and splenium of the corpus callosum, bilateral anterior and posterior limbs of internal capsule, bilateral retrolenticular region part of internal capsule, and left posterior thalamic radiation. Except for the genu of the corpus callosum, an increase in AD values was also found in these same tracts. Furthermore, increased MD and AD values in different white matter areas was negatively correlated with performance on language and verbal memory and positively with visuospatial ability. These correlations suggest that white matter changes might be involved in the pathogenesis of cognitive deficits in ET. PMID- 28592902 TI - GGNBP2 is necessary for testis morphology and sperm development. AB - Gametogenetin Binding Protein 2 (GGNBP2) was identified as a tumor suppressor and verified as such by several studies. GGNBP2 has also been reported to be essential for pregnancy maintenance via regulation of trophoblast stem cells. Gametogenetin (GGN) is a testicular germ cell-specific gene expressed in adult testes. As a potential GGN1-interacting protein, the role of GGNBP2 in spermatogenesis has not yet been clarified. We generated heterozygous GGNBP2 knockout mice and bred them by intercrossing. We found that among the offspring, homozygous GGNBP2 knockout (KO) mice were present in severely reduced numbers. The GGNBP2 KO pups developed normally, but the male siblings showed dramatically reduced fertility. In these male homozygous GGNBP2 KO mice, the only pathological finding was abnormal morphology of the testes and absence of spermatozoa. In addition, increased apoptosis was observed in the testes of GGNBP2 KO mice. SOX9 staining revealed that SOX9-positive Sertoli cells were absent in the seminiferous tubules. In homozygous mice, proliferating cell nuclear antigen (PCNA)-positive cells were localized in the lumen of the convoluted seminiferous tubules. These results suggest that GGNBP2 plays a key role in spermatogenesis by affecting the morphology and function of SOX9-positive Sertoli cells. PMID- 28592903 TI - Learning and memory: When novel becomes familiar. PMID- 28592906 TI - Erratum to Bortkiewicz et al. "Mobile phone use and risk for intracranial tumors and salivary gland tumors - A meta-analysis" (Int J Occup Med Environ Health 2017;30(1):27-43). PMID- 28592907 TI - [Epidemiology of asthma in adults living in the Silesian voivodeship according to secondary epidemiological data]. AB - BACKGROUND: Asthma is a serious public health challenge because of the increasing number of people with a new diagnosis and consequently the increasing costs of medical treatment (direct and indirect). The aim of this study is to analyze available epidemiological data with respect to their spatial and temporal variability in the Silesian voivodeship. In addition, the costs incurred by the National Health Fund (Narodowy Fundusz Zdrowia - NFZ) in treating asthmaic patients are analyzed. MATERIAL AND METHODS: The epidemiological descriptive study concerns adult inhabitants of the Silesian voivodeship with asthma diagnosed under the health service delivery system, financed by NFZ, as well as diagnossis and/or hospitalization registed in the routine register run by the NFZ in Katowice. Crude and standardized incidence and prevalence rates are calculated and their changes are evaluated. Spatial variability in districts is evaluated as well and costs incurred by NFZ are revealed. RESULTS: In the years 2006-2010 the standardized rate of asthma remained at a high level of 392.3-469.6/100 000 inhabitants. Greater values were related to women than to men, as well as to inhabitants of districts located in the central and southern parts of the Silesian voivodeship. A slight decrease in the values of crude prevalence rates, from 52/100 000 inhabitants to 42/100 000, is reported. The annual cost of new cases treatment is 17 million PLN while the annual cost of all hospitalizations is at the level of 10 million PLN. CONCLUSIONS: Variability of incidence and prevalence due to asthma in the Silesian voivodeship is observed. An attempt at explaining this diversity requires in-depth research. A slight decrease in the values of both rates over time indicates less significant reduction in expenditure devoted to hospital treatment of asthmatic patients. Med Pr 2017;68(4):479-489. PMID- 28592908 TI - [How do Polish workers respond to the information concerning health-oriented lifestyle?] AB - BACKGROUND: Information overload, including commercial ones, about healthy lifestyle, is a challenge for perception of health education. MATERIAL AND METHODS: The empirical data gathered from 100 employees in 2010 by means of free interviews with a standardized list of required information, aimed at analyzing a feeling of pressure to lead a healthy lifestyle, including reactions to meassages provided by the media. RESULTS: Respondents feel pressure associated with a healthy lifestyle from doctors, the state, relatives, friends and themselves. They accept pressure exerted by doctors and appreciate it from relatives and friends, however, the latter may stimulate adverse behavior. As a negative pressure they perceive that imposed by the media, government's shifting the responsibility for citizens' health, information overload contradictory to their own knowledge, unattainable recommendations and their volatility. Such pressure evokes conviction for their own resistance or rejection of the messages. They criticize the media for promoting unhealthy behavior, attending interests of advertisers, hiding information about harmful environmental influence. They appreciate the media for facilitating learning about health and preventive examinations. Health education messages are only occasionally identified by better educated people. CONCLUSIONS: "Dense" information environment is a hostile background for health education. An excess of critically evaluated information evokes pressure and lack of trust in information. Therefore, health education should facilitate the identification of its contents, avoid normative methods, limit the number of guidelines and better explain the faced changes, counteract tendencies to associate healthy lifestyle mainly with consumer behaviors, teach how to maintain self orientation in information overload conditions, and build up awareness of one's own brand. Med Pr 2017;68(4):525-543. PMID- 28592910 TI - Psychometric Properties of the Connor-Davidson Resilience Scale With Older American Indians: The Native Elder Care Study. AB - Resilience is a term that refers to a person's ability to successfully adapt to adversity. Resilience research has been relatively limited with older adults, particularly with older American Indians. Also, none of the resilience measures have been validated in older American Indians. This study's objective was to assess the psychometric properties of the full 25-item and abbreviated 10-item versions of Connor-Davidson Resilience Scale (CD-RISC) with a sample of older American Indians. Both CD-RISC versions performed similarly in the study sample compared with what has been reported in other populations. The full version demonstrated adequate internal consistency and convergent and divergent validity, but a meaningful factor structure was not confirmed. The abbreviated version showed good internal consistency and convergent and divergent validity and appeared to have a stable one-factor solution. These findings lend greater support to the use of the abbreviated version than the full version of the CD RISC with older American Indians. PMID- 28592909 TI - Does Partner Responsiveness Predict Hedonic and Eudaimonic Well-Being? A 10-Year Longitudinal Study. AB - Motivated by attachment theory and recent conceptualizations of perceived partner responsiveness as a core feature of close relationships, the present study examined change in hedonic and eudaimonic well-being over a decade in a sample of more than 2,000 married adults across the United States. Longitudinal analyses revealed that perceived partner responsiveness- the extent to which individuals believe that their partner cares for, appreciates, and understands them-predicted increases in eudaimonic well-being a decade later. These results remained after controlling for initial hedonic and eudaimonic well-being, age, gender, extraversion, neuroticism, and perceived responsiveness of family and friends. Affective reactivity, measured via an 8-day diary protocol in a subset of the sample, partially mediated this longitudinal association. After controlling for covariates, perceived partner responsiveness did not prospectively predict hedonic well-being. These findings are the first to document the long-term benefits of perceived partner responsiveness on eudaimonic well-being. PMID- 28592911 TI - Marginal Shape Deep Learning: Applications to Pediatric Lung Field Segmentation. AB - Representation learning through deep learning (DL) architecture has shown tremendous potential for identification, localization, and texture classification in various medical imaging modalities. However, DL applications to segmentation of objects especially to deformable objects are rather limited and mostly restricted to pixel classification. In this work, we propose marginal shape deep learning (MaShDL), a framework that extends the application of DL to deformable shape segmentation by using deep classifiers to estimate the shape parameters. MaShDL combines the strength of statistical shape models with the automated feature learning architecture of DL. Unlike the iterative shape parameters estimation approach of classical shape models that often leads to a local minima, the proposed framework is robust to local minima optimization and illumination changes. Furthermore, since the direct application of DL framework to a multi parameter estimation problem results in a very high complexity, our framework provides an excellent run-time performance solution by independently learning shape parameter classifiers in marginal eigenspaces in the decreasing order of variation. We evaluated MaShDL for segmenting the lung field from 314 normal and abnormal pediatric chest radiographs and obtained a mean Dice similarity coefficient of 0.927 using only the four highest modes of variation (compared to 0.888 with classical ASM1 (p-value=0.01) using same configuration). To the best of our knowledge this is the first demonstration of using DL framework for parametrized shape learning for the delineation of deformable objects. PMID- 28592904 TI - Non-motor features of Parkinson disease. AB - Many of the motor symptoms of Parkinson disease (PD) can be preceded, sometimes for several years, by non-motor symptoms that include hyposmia, sleep disorders, depression and constipation. These non-motor features appear across the spectrum of patients with PD, including individuals with genetic causes of PD. The neuroanatomical and neuropharmacological bases of non-motor abnormalities in PD remain largely undefined. Here, we discuss recent advances that have helped to establish the presence, severity and effect on the quality of life of non-motor symptoms in PD, and the neuroanatomical and neuropharmacological mechanisms involved. We also discuss the potential for the non-motor features to define a prodrome that may enable the early diagnosis of PD. PMID- 28592905 TI - Functional consequences of neuropeptide and small-molecule co-transmission. AB - Colocalization of small-molecule and neuropeptide transmitters is common throughout the nervous system of all animals. The resulting co-transmission, which provides conjoint ionotropic ('classical') and metabotropic ('modulatory') actions, includes neuropeptide- specific aspects that are qualitatively different from those that result from metabotropic actions of small-molecule transmitter release. Here, we focus on the flexibility afforded to microcircuits by such co transmission, using examples from various nervous systems. Insights from such studies indicate that co-transmission mediated even by a single neuron can configure microcircuit activity via an array of contributing mechanisms, operating on multiple timescales, to enhance both behavioural flexibility and robustness. PMID- 28592913 TI - ERRATUM. AB - [This corrects the article DOI: 10.1016/S0377-1237(08)80076-7.]. PMID- 28592912 TI - Prospective and Descriptive Study on Serum Androstenedione Concentration in Healthy Children from Birth until 18 Years of Age and Its Associated Factors. AB - INTRODUCTION: Androstenedione (A4) is an adrenal and gonadal steroid biomarker, useful in the assessment of children in whom steroidogenic disorders are suspected. The first key step in the evaluation of a diagnostic test resides on confident reference intervals (RI). The lack of updated A4-RI with current methods in pediatrics may mislead A4 results and limit its diagnosis accuracy. AIM: To provide A4 reference ranges in healthy children. METHODS: Prospective, descriptive study. 283 children aged 4 days to 18 years were included. In children < 1 yr, A4 was measured directly in serum (NE-A4) and postorganic solvent extraction (E-A4) for the assessment of interfering steroids. The influence of chronological age (CA), gender, and Tanner stage (T) were investigated. RESULTS: In the neonatal period, E-A4 was significantly lower than NE-A4; boys had higher NE-A4; sexual dimorphism disappeared after extraction procedure. In children older than 4 months, A4 concentration remained low until the age of 5 years. Thereafter, A4 increased significantly in association with CA and T (r2 = 0.65; p < 0.001), obtaining the highest concentrations in children within pubertal ages without sexual dimorphism. CONCLUSION: We recommend to perform solvent extraction in neonates and to take into account age and sexual development to properly interpret A4 results in childhood. PMID- 28592914 TI - Size-controlled gold nanoparticles on octahedral anatase particles as efficient plasmonic photocatalyst. AB - Octahedral anatase particles (OAPs), prepared by ultrasonication-hydrothermal reaction (US-HT), were modified with 2 wt% of gold by photodeposition. Conditions of US-HT process such as durations of US and durations of HT were varied to obtain OAPs products different by physicochemical and morphological properties. Au/OAPs samples were characterized by X-ray diffraction (XRD), scanning transmission electron microscopy (STEM), X-ray photoelectron spectroscopy (XPS) and diffuse reflectance spectroscopy (DRS). The photocatalytic activity was tested under UV irradiation for decomposition of acetic acid (CO2 system) and dehydrogenation of methanol (H2 system) under aerobic and anaerobic conditions, respectively, and for oxidation of 2-propanol under visible light irradiation. Photodeposition of gold was very fast for all OAPs samples (0.5-10 min) under Ar atmosphere, and the clear correlation between the content of electron traps (ETs) and the induction period, during which nanoparticles (NPs) of gold are formed, indicates that ETs in titania samples are a key-factor for rapidity of gold photodeposition on titania surface. It was found that better morphology of titania (larger content of faceted particles) resulted in formation of larger gold NPs, while small gold NPs were deposited on structural defects. Modification of OAPs with gold NPs resulted in significant enhancement of photocatalytic activity, being e.g., 1.5 (CO2 system), 7.7 (H2 system), and even more than 40 under vis irradiation. It was found that both the properties of titania and gold are crucial for resultant photocatalytic activity, but a direct correlation between one structural/physical property and photocatalytic activity could not be obtained since all structural properties changed simultaneously when conditions of photocatalyst preparation (US-HT) were changed. Therefore, gold NPs of controlled sizes were deposited on OAPs product with the best morphology by modified photodeposition method. Clear correlation between photocatalytic activity under visible light and the size of gold NPs indicates that gold properties are decisive for visible light activity rather than titania properties. 3D-FDTD simulations confirm that an increase in the size of gold NPs results in extended surface areas with field enhancement. PMID- 28592915 TI - Activated Platelets Induce an Anti-Inflammatory Response of Monocytes/Macrophages through Cross-Regulation of PGE2 and Cytokines. AB - Platelets are well known for their role in hemostasis and are also increasingly recognized for their roles in the innate immune system during inflammation and their regulation of macrophage activation. Here, we aimed to study the influence of platelets on the production of inflammatory mediators by monocytes and macrophages. Analyzing cocultures of platelets and murine bone marrow-derived macrophages or human monocytes, we found that collagen-activated platelets release high amounts of prostaglandin E2 (PGE2) that leads to an increased interleukin- (IL-) 10 release and a decreased tumor necrosis factor (TNF) alpha secretion out of the monocytes or macrophages. Platelet PGE2 mediated the upregulation of IL-10 in both cell types via the PGE2 receptor EP2. Notably, PGE2 mediated IL-10 synthesis was also mediated by EP4 in murine macrophages. Inhibition of TNFalpha synthesis via EP2 and EP4, but not EP1, was mediated by IL 10, since blockade of the IL-10 receptor abolished the inhibitory effect of both receptors on TNFalpha release. This platelet-mediated cross-regulation between PGE2 and cytokines reveals one mechanism how monocytes and macrophages can attenuate excessive inflammatory responses induced by activated platelets in order to limit inflammatory processes. PMID- 28592916 TI - A Reduction in Selenoprotein S Amplifies the Inflammatory Profile of Fast-Twitch Skeletal Muscle in the mdx Dystrophic Mouse. AB - Excessive inflammation is a hallmark of muscle myopathies, including Duchenne muscular dystrophy (DMD). There is interest in characterising novel genes that regulate inflammation due to their potential to modify disease progression. Gene polymorphisms in Selenoprotein S (Seps1) are associated with elevated proinflammatory cytokines, and in vitro SEPS1 is protective against inflammatory stress. Given that SEPS1 is highly expressed in skeletal muscle, we investigated whether the genetic reduction of Seps1 exacerbated inflammation in the mdx mouse. F1 male mdx mice with a heterozygous Seps1 deletion (mdx:Seps1-/+) were generated. The mdx:Seps1-/+ mice had a 50% reduction in SEPS1 protein expression in hindlimb muscles. In the extensor digitorum longus (EDL) muscles, mRNA expression of monocyte chemoattractant protein 1 (Mcp-1) (P = 0.034), macrophage marker F4/80 (P = 0.030), and transforming growth factor-beta1 (Tgf-beta1) (P = 0.056) were increased in mdx:Seps1-/+ mice. This was associated with a reduction in muscle fibre size; however, ex vivo EDL muscle strength and endurance were unaltered. In dystrophic slow twitch soleus muscles, SEPS1 reduction had no effect on the inflammatory profile nor function. In conclusion, the genetic reduction of Seps1 appears to specifically exacerbate the inflammatory profile of fast-twitch muscle fibres, which are typically more vulnerable to degeneration in dystrophy. PMID- 28592918 TI - Electrochemiluminescence Arrays for Studies of Metabolite-related Toxicity. AB - This article reviews recent progress from our laboratory in electrochemiluminescence (ECL) arrays designed for screening toxicity-related chemistry of chemical and drug candidates. Cytochrome P450s and metabolic bioconjugation enzymes convert lipophilic chemicals in our bodies by oxidation and bioconjugation that can lead to toxic metabolites. DNA can be used as an easily measurable toxicity-related endpoint, targeting DNA oxidation and addcut formation with metabolites. ECL using guanosines in the DNA strands as co reactants have been used in high throughput arrays utilizing DNA-enzyme films fabricated layer-by-layer. This review describes approaches developed to provide new high throughput ECL arrays to aid in toxicity assessment for drug and chemical product development. PMID- 28592917 TI - Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome. AB - Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha 1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model. PMID- 28592920 TI - Phase I dose-escalation trial of intravaginal curcumin in women for cervical dysplasia. AB - BACKGROUND: This is a Phase I trial demonstrating safety and tolerability of intravaginal curcumin for future use in women with cervical neoplasia. OBJECTIVE: The objective of this study was to assess the safety, tolerability, and pharmacokinetics of intravaginal curcumin in healthy women. STUDY DESIGN: We conducted a 3+3 dose-escalation Phase I trial in a group of women aged 18-45 years. Thirteen subjects were given one of four doses of curcumin powder (500 mg, 1,000 mg, 1,500 mg, and 2,000 mg) packed in gelatin capsules, which was administered intravaginally daily for 14 days. The primary end point for this study was safety based on severe adverse events regarding laboratory toxicity, clinical findings, and colposcopic abnormalities. We administered an acceptability questionnaire to assess product experience and attributes. RESULTS: No dose-limiting toxicities (0/13) were experienced (95% confidence interval: 0.0%-22.8%) in this study. The pharmacokinetics data demonstrated that curcumin and curcumin conjugates were not measurable in the serum and negligible in the urine of the study participants. Although 23 adverse events occurred during the course of the trial, all events were grade I based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and were resolved by the end of the study in an average of 9 days. Fifty-six percent of the adverse events were related to the study drug, which included genital pruritus (23% of subjects), vaginal discharge (100%), vaginal dryness (15%), abnormal prothrombin (23%), and hypokalemia (8%). CONCLUSION: Intravaginal curcumin was well tolerated by all subjects and safe. In this Phase I trial, there were no severe adverse events observed at any of the administered dose levels. All adverse events were grade I and did not result in early termination of the study. There was no evidence of systemic absorption or significant local absorption of intravaginally administered curcumin. PMID- 28592919 TI - Multiplex Immunosensor Arrays for Electrochemical Detection of Cancer Biomarker Proteins. AB - Measuring panels of protein biomarkers offer a new personalized approach to early cancer detection, disease monitoring and patients' response to therapy. Multiplex electrochemical methods are uniquely positioned to provide faster, more sensitive, point of care (POC) devices to detect protein biomarkers for clinical diagnosis. Nanomaterials-based electrochemical methods offer sensitivity needed for early cancer detection. This review discusses recent advances in multiplex electrochemical immunosensors for cancer diagnostics and disease monitoring. Different electrochemical strategies including enzyme-based immunoarrays, nanoparticle-based immunoarrays and electrochemiluminescence methods are discussed. Many of these methods have been integrated into microfluidic systems, but measurement of more than 2-4 protein markers in a small single serum sample is still a challenge. For POC applications, a simple, low cost method is required. Major challenges in multiplexed microfluidic immunoassays are reagent additions and washing steps that require creative engineering solutions. 3-D printed microfluidics and paper-based microfluidic devices are also explored. PMID- 28592921 TI - Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies. AB - Malignant peripheral nerve sheath tumor (MPNST) is the leading cause of mortality in patients with neurofibromatosis type 1. In 2002, an MPNST consensus statement reviewed the current knowledge and provided guidance for the diagnosis and management of MPNST. Although the improvement in clinical outcome has not changed, substantial progress has been made in understanding the natural history and biology of MPNST through imaging and genomic advances since 2002. Genetically engineered mouse models that develop MPNST spontaneously have greatly facilitated preclinical evaluation of novel drugs for translation into clinical trials led by consortia efforts. Continued work in identifying alterations that contribute to the transformation, progression, and metastasis of MPNST coupled with longitudinal follow-up, biobanking, and data sharing is needed to develop prognostic biomarkers and effective prevention and therapeutic strategies for MPNST. PMID- 28592922 TI - Development and evaluation of a modified brief assertiveness training for nurses in the workplace: a single-group feasibility study. AB - BACKGROUND: Effective communication has a great impact on nurses' job satisfaction, team relationships, as well as patient care/safety. Previous studies have highlighted the various beneficial effects of enhancing communication through assertiveness training programs for nurses. However, most programs take a long time to implement; thus, briefer programs are urgently required for universal on-the-job-training in the workplace. The purpose of this feasibility study was to develop and evaluate a modified brief assertiveness training program (with cognitive techniques) for nurses in the workplace. METHODS: This study was carried out as a single-group, open trial (pre-post comparison without a control group). Registered nurses and assistant nurses, working at two private psychiatric hospitals in Miyazaki Prefecture in Japan, were recruited. After enrolling in the study, participants received a program of two 90-min sessions with a 1-month interval between sessions. The primary outcome was the Rathus Assertiveness Schedule (RAS), with secondary measurements using the Brief Version of the Fear of Negative Evaluation Scale (BFNE) and the Brief Job Stress Questionnaire (BJSQ). Assessments were conducted at baseline and after a 1-month interval (pre- and post-intervention). RESULTS: A total of 22 participants enrolled in the study and completed the program. The mean total score on the primary outcome (RAS) significantly improved from -12.9 (SD = 17.2) to -8.6 (SD = 18.6) (p = 0.01). The within-group effect size at the post intervention was Cohen's d = 0.24; this corresponds to the small effect of the program. Regarding secondary outcomes, there were no statistically significant effects on the BFNE or any of the BJSQ subscales (job-stressors, psychological distress, physical distress, worksite support, and satisfaction). CONCLUSIONS: This single-group feasibility study demonstrated that our modified brief assertiveness training for nurses seems feasible and may achieve a favorable outcome in improving their assertiveness. Further controlled trials with longer follow-up periods are required in order to address the limitations of this study. PMID- 28592924 TI - Suppression of endothelial cell migration by tumor associated macrophage-derived exosomes is reversed by epithelial ovarian cancer exosomal lncRNA. AB - OBJECTIVE: To study the mechanism by which epithelial ovarian cancer (EOC) derived exosomes restore the migration of endothelial cells that is suppressed by TAM-derived exosomes. METHODS: Exosomes were isolated from TAMs in the ascites of patients with EOC. The effect of exosomes on the expression of endothelial cell miRNA was monitored by PCR. The miRNA mimics were transfected to explore their effects. Microarray data and literature searches were used to predict target genes and the impact of target gene pathways, and small interfering RNA was used to target these genes. We used migration assays to determine whether ovarian cancer cell-derived exosomes participate in the regulation of TAMs and endothelial cells. We used microarray data to identify the target lncRNA, and we constructed target lncRNA expression plasmids to validate targets by Western blotting. RESULTS: We separated TAMs from the ascites of patients with EOC and isolated exosomes from TAM supernatants. After co-culture with HUVECs, these exosomes were efficiently incorporated into HUVECs. The migration of HUVECs was suppressed significantly in the exosome group compared with blank controls (P < 0.05).The miRNA mimic transfection and target gene prediction found that TAM derived exosomes targeted the miR-146b-5p/TRAF6/NF-kappaB/MMP2 pathway to suppress endothelial cell migration; this result was supported by PCR and Western blotting analyses. The expression of exosomal miR-146b-5p isolated from serum in the EOC group was significantly increased compared to healthy individuals. Finally, TAM-derived exosomes and EOC SKOV3-derived exosomes in combination stimulated HUVEC cells and overcame the inhibition of endothelial cell migration caused by TAM-derived exosomes. Two lncRNAs that were carried by SKOV3-derived exosomes were identified as NF-kappaB pathway-associated genes by Western blotting. CONCLUSION: TAM-derived exosomes can inhibit the migration of endothelial cells by targeting the miR-146b-5p/TRAF6/NF-kB/MMP2 pathway. However, EOC-derived exosomes can transfer lncRNAs to remotely reverse this effect of TAMs on endothelial cells. PMID- 28592926 TI - The treatment of palmar contact burns in children: a five-year review. AB - Pediatric palmar contact burns are becoming a common trauma, especially in young children. Treatment of this kind of burn is challenging as well as controversial, regarding the choice between split-thickness or full-thickness skin graft to close the defect. The aim of this review was to evaluate the treatment algorithm at our clinic. We conducted a retrospective study including all patients 0 - 5 years of age admitted to our department from 2008 to 2012 with isolated superficial or deep partial-thickness palmar burns. The mean age was 16.1 months. In 27 cases (52.9%) we were able to close the wound conservatively. Average healing time in this group was 13.3 days. Two of these 27 patients developed flexion contractures, but none of them required additional operation. Twenty-four patients were treated using split-thickness skin graft. The average time period from the day of injury to the day of surgery was 14.2 days. Contractures occurred in 5 (20.8%) of the patients who underwent grafting, Secondary reconstruction using full-thickness skin graft was performed in all 5 of them, which represents 9.8% of all patients. We consider split-thickness grafting quick, easy and effective, with minimal to no donor site morbidity and insignificant inflammation complications. Due to reduced healing time after the actual grafting, rehabilitation can commence earlier. PMID- 28592925 TI - Second generation multiple reaction monitoring assays for enhanced detection of ultra-low abundance Mycobacterium tuberculosis peptides in human serum. AB - BACKGROUND: Mycobacterium tuberculosis (Mtb) is the causative agent of Tuberculosis (TB), the number one cause of death due to an infectious disease. TB diagnosis is performed by microscopy, culture or PCR amplification of bacterial DNA, all of which require patient sputum or the biopsy of infected tissue. Detection of mycobacterial products in serum, as biomarkers of diagnosis or disease status would provide an improvement over current methods. Due to the low abundance of mycobacterial products in serum, we have explored exosome enrichment to improve sensitivity. Mtb resides intracellularly where its secreted proteins have been shown to be packaged into host exosomes and released into the bloodstream. Exosomes can be readily purified assuring an enrichment of mycobacterial analytes from the complex mix of host serum proteins. METHODS: Multiple reaction monitoring assays were optimized for the enhanced detection of 41 Mtb peptides in exosomes purified from the serum of individuals with TB. Exosomes isolated from the serum of healthy individuals was used to create and validate a unique data analysis algorithm and identify filters to reduce the rate of false positives, attributed to host m/z interference. The final optimized method was tested in 40 exosome samples from TB positive patients. RESULTS: Our enhanced methods provide limit of detection and quantification averaging in the low femtomolar range for detection of mycobacterial products in serum. At least one mycobacterial peptide was identified in 92.5% of the TB positive patients. Four peptides from the Mtb proteins, Cfp2, Mpt32, Mpt64 and BfrB, show normalized total peak areas significantly higher in individuals with active TB as compared to healthy controls; three of the peptides from these proteins have not previously been associated with serum exosomes from individuals with active TB disease. Some of the detected peptides were significantly associated with specific geographical locations, highlighting potential markers that can be linked to the Mtb strains circulating within each given region. CONCLUSIONS: An enhanced MRM method to detect ultra-low abundance Mtb peptides in human serum exosomes is demonstrated, highlighting the potential of this methodology for TB diagnostic biomarker development. PMID- 28592927 TI - Cost-utility of burns management in Nigeria: a case study of the National Orthopaedic Hospital, Enugu. AB - A major problem of burns is the high cost of management, as well as the discrimination and disability they can cause to patients. Maximising resource utilisation is of key importance for lower-middle-income countries (LMICs) like Nigeria. There is a need to know if Nigerian patients who were victims of burns get the best value for money. This study aimed to evaluate the average cost of managing burns in Nigeria, and determine if the treatment approach is cost effective. The study was a cost-utility analysis from the perspective of health service providers in Nigeria, a case study of the National Orthopaedic Hospital Enugu (NOHE) using 2013 Microsoft excel. Data on the cost of burn management were obtained from a retrospective study conducted in NOHE in 2012 on 285 patients. Costs were adjusted to reflect the future (2015) value using a real interest rate of 3%. These costs were presented in 2015 US dollars, and a discount rate of 3% was used for both cost and outcome. Health outcome was presented in disability adjusted life years (DALYs). Based on a cost-effectiveness threshold of $2,758.4 (i.e. representing Nigerian GDP/capita), burn management is cost-effective in Nigeria ($526.68/DALY averted). The result also showed that the cost of managing burns in Nigeria is $7,123.28 per patient, which is more than the average income. Burn management in Nigeria is cost-effective but too expensive for most Nigerians to afford. PMID- 28592928 TI - Comparison of six outcome prediction models in an adult burn population in a developing country. AB - There are two types of prognostic model - burn-specific and general - to predict mortality risk in burn patients. Most prediction models were devised in developed countries. The aim of this study was to compare the performance of six outcome models in a developing country. In a retrospective cohort study, data of all thermal burned adult patients (age >= 18 years) admitted to the Burn Intensive Care Unit (BICU) were collected and then the following six prediction models were used to assess each patient: Acute Physiology and Chronic Health Evaluation (APACHE II), Abbreviated Burn Severity Index (ABSI), Belgian Outcome in Burn Injury (BOBI), the Ryan model, revised Baux and FLAMES model. Discriminative ability and goodness-of-fit of the prediction models were determined by receiver operating characteristic curve analysis and Hosmer-Lemeshow tests. We included 238 patients (mean age: 38.3 +/- 18.39 years, average TBSA: 58.27% +/- 24.55) in our study; 172 (72.3%) of them were diagnosed with inhalation injury and 178 (72.4%) were intubated. Mortality rate was 69.7%. Deceased patients had significantly higher mean age, %TBSA and number of inhalation injury. The area under the curve of the models was between 64.5 (APACHE II) and 85.9 (ABSI). The best estimation of predicted mortality was obtained with the ABSI model (67.2%). PMID- 28592923 TI - Omics-based molecular techniques in oral pathology centred cancer: prospect and challenges in Africa. AB - BACKGROUND: The completion of the human genome project and the accomplished milestones in the human proteome project; as well as the progress made so far in computational bioinformatics and "big data" processing have contributed immensely to individualized/personalized medicine in the developed world. MAIN BODY: At the dawn of precision medicine, various omics-based therapies and bioengineering can now be applied accurately for the diagnosis, prognosis, treatment, and risk stratification of cancer in a manner that was hitherto not thought possible. The widespread introduction of genomics and other omics-based approaches into the postgraduate training curriculum of diverse medical and dental specialties, including pathology has improved the proficiency of practitioners in the use of novel molecular signatures in patient management. In addition, intricate details about disease disparity among different human populations are beginning to emerge. This would facilitate the use of tailor-made novel theranostic methods based on emerging molecular evidences. CONCLUSION: In this review, we examined the challenges and prospects of using currently available omics-based technologies vis-a-vis oral pathology as well as prompt cancer diagnosis and treatment in a resource limited setting. PMID- 28592929 TI - ? AB - Cement burn is a common cause of chemical burns in France. They usually need surgical treatment. This retrospective study was performed among 49 patients, aged 21-71 years, admitted to the St Joseph-St Luc Hospital in Lyon, France. Patients were mainly male, fairly young (mean 44 years) and had a professional activity, although burns usually occurred at home. Burns were deep, on the lower limbs, and were not extensive (3% TBS). All but one patient needed grafting, performed on d13. LOS was eight days. Seven patients had to be admitted to a rehabilitation centre afterwards. This study confirms the local seriousness of cement burns. It emphasises their socio-economic impact since they occur in job active patients. Education on cement hazards should be developed, targeting this population, who are seldom building professionals. Current regulations, classifying cement as an 'irritant', do not address the causticity of wet cement and should be amended. PMID- 28592930 TI - The airway in inhalational injury: diagnosis and management. AB - It is estimated that 13.000 to 22.000 individuals suffer from inhalational burns each year in the United States alone. Despite these high numbers, inhalational burns remain a major challenge to otolaryngologists. In this paper, a review of literature is presented in order to provide otolaryngologists with a systematic approach to patients with inhalational burns to optimize treatment, cost, morbidity and, most importantly, mortality. For this purpose, a broad PubMed search was conducted. The available literature was found to highlight the importance of airway management in terms of the timing of intubation, method of intubation, trachea-esophageal (TE) fistula formation and TE rupture. It also emphasizes the importance of carbon monoxide intoxication and prompt correction. Drugs such as heparin sulfate, N-acetylcysteine and albuterol have been proven to help in the treatment of patients with inhalational burns, and more research is currently underway with the purpose of developing chelating drugs that scavenge the toxic substances in the smoke before they can damage the airway. PMID- 28592931 TI - Burn-related factors affecting anxiety, depression and self-esteem in burn patients: an exploratory study. AB - Burns are physically, psychologically and economically challenging injuries, and the factors leading to them are many and under-studied. The aim of the current study was to assess level of anxiety, depression and self-esteem in burn patients, and look at various burn-related variables that affect them. This cross sectional study included 100 patients with burn injuries admitted to a tertiary care private hospital in an urban metropolis in India. The patients were assessed for anxiety, depression and self-esteem using the Hamilton anxiety rating scale, Hamilton depression rating scale and Rosenberg self-esteem scale respectively. Assessment was carried out within 2-8 weeks of injury following medical stabilization. The data was tabulated and statistically analyzed. The study sample was predominantly male (54%), married (69%), with a mean age of 34.1 +/- 10.8 years. Accidental burns (94%) were the most common modality of injury. The majority (46%) suffered burns involving 20-59% total body surface area (TBSA), and facial burns were present (57%). No significant association was found between TBSA and anxiety, depression or self-esteem, and the same was true for facial burns. Deep burns, however, were significantly associated with anxiety (p=0.03) and depression (p=0.0002). High rates of anxiety and depression are associated with burn injuries and related to burn depth. Adjustment and recovery in these patients depends on various other factors like the patient's psychological status, nature/extent of the injury and ensuing medical care. Further research is warranted to reveal the magnitude and predictors of psychological problems in burn patients. PMID- 28592932 TI - Lactate: prognostic biomarker in severely burned patients. AB - Plasma lactate (PL) has been used as a marker of cellular hypoxia and shock. The correlation between PL and clinical outcome has been well accepted in hemorrhagic and septic shock. In contrast to the existing evidence, there are no or almost no data dealing with lactate and burn-related outcome. We attempted to assess whether early plasma lactate (PL) is a useful parameter to predict outcome in burned patients. A prospective study was conducted in a 20-bed adult burn ICU at a university-affiliated teaching hospital in Tunis. Patients admitted within the first 24h post burn with greater than 10% total body surface area (TBSA) burned were enrolled in the study. There were 60 males and 20 females. Mean age was 40.7 +/- 19.5 years old, and average TBSA was 32 +/- 21%. At admission, 86.7% patients had an initial lactate value of more than 2 mmol/L. In our study, an initial lactate value of 4 mmol/L provided the best sensitivity and specificity: 88% and 79% respectively for predicting sepsis, with an area under the ROC curve of 0,82. Furthermore, plasma lactate cut-off value for mortality prediction was 4.46 mmol/l with a good sensitivity (86%) and specificity (92%). Mortality rate was 36.25%. Plasma lactate appears to be a powerful predictor biomarker of sepsis and mortality in burn patients. PMID- 28592933 TI - Prevalence of biofilm producing aerobic bacterial isolates in burn wound infections at a tertiary care hospital in northern India. AB - Burn wounds frequently get infected due to a break in skin integrity and prolonged hospitalization. Microbial flora originating from the patient's own flora colonize and infect the burn wounds. Bacterial biofilms in particular are postulated as the culprit for the development of non-healing burn wounds by inducing chronic inflammation in these patients. In the present study, 190 wound isolates obtained from patients admitted to the burn ward at the Pt. B.D. Sharma PGIMS, Rohtak, were evaluated for biofilm formation along with Antimicrobial Susceptibility Testing (AST). Biofilm detection was done by modified Tissue Culture Plate method and AST was done by Kirby-Bauer disc diffusion method. A total of 190 isolates were studied, which included Staphylococcus aureus, Coagulase negative Staphylococcus, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp., Proteus spp., Citrobacter spp., Escherichia coli and Enterobacter spp. Of these, 68.9% isolates showed biofilm formation. Biofilm formation was more common in Pseudomonas aeruginosa followed by Klebsiella spp. and Staphylococcus aureus. Biofilm producing isolates showed greater multidrug resistance than non-biofilm producers. In our study, a high rate of biofilm formation and antimicrobial drug resistance was seen. PMID- 28592934 TI - New dressing combination for the treatment of partial thickness burn injuries in children. AB - Burns are among the most common causes of injury in children. Several wound dressings are available to conservatively treat second-degree burns. Seventy three children were treated with Aquacel Ag foam and Zn-hyaluronon gel to determine their effectiveness on partial thickness burns. We applied silver nitrate solution on 25% of patients for 24 hrs, then checked burn depth. If the burn was superficial second degree, we applied the dressing under study. All dressings were removed 6-7 days later. In the remaining children we used Aquacel Ag foam dressing with Zn-hyaluronon gel at first intervention. The dressing was checked on the second day, and removed on the sixth or seventh day (unless it had spontaneously separated). Hot water scalds were the main cause of injury. Other causes included hot oil, flame and contact, among others. Wound size was on average 5% total body surface area. Burns were seen on all body parts, and in 38 cases on more than one area. None of the 73 children treated with this dressing were diagnosed with wound infection. We observed the epithelialization of the burned areas on the 6th or 7th day after primary treatment. These dressings efficiently promote epithelialization, and a further advantage of Zn-hyaluronon gel is that it enhances cell regeneration and inhibits dressing fixation into the wound. Based on our experience, with this dressing combination we can achieve gentle, child-friendly and cost-effective treatment, excellent wound healing and favourable cosmetic results. PMID- 28592935 TI - Surgery on burns sequelae in developing countries. AB - The purpose of this study is to analyze the effectiveness of surgery and follow up of children operated on for burn sequelae. For many years, we have organized two missions per year to Benin and Togo, one for surgery and one for follow-up. We analyzed the files of children born in Africa and victims of burns from the years 2002 to 2011. Children were referred through a non-governmental organization (NGO) and assessed in Africa by local paediatricians before and after surgery. Treatment consisted in operating on burn sequelae such as contractures, hypertrophic scars and hard cords. Impaired mobility was our only indication for the operation. We kept a database on all patients. Sixty files were reviewed, of which fifty were deemed suitable for analysis. The most common methods of surgery were skin grafting and Z-plasty. There were no complications, such as infection or graft/flap necrosis after immediate surgery. Long-term follow-up revealed a recurrence of hypertrophic scarring (47%), retractions (24%) and hard cords (2%) due to a lack of occupational therapy and physiotherapy treatment. Partnership with an NGO and a local team allows us to treat children with burn injury sequelae in Western Africa. A continued and often long-lasting follow-up by occupational therapists and physiotherapists is highly mandatory in order to guarantee good long-term results. In 2010, we initiated local rehabilitation therapy. PMID- 28592936 TI - Grafting both acute wound site and adjacent donor site with the same graft: an easy and safe procedure to improve healing and minimize pain in elderly and bedridden patients. AB - In harvesting skin to cover the defect caused by a burn, a second wound is created, the donor site wound. We propose an alternative method to manage the donor site: taking a split-thickness skin graft (STSG) from a donor site adjacent to the burn wound to be treated, and meshing at a 3:1 ratio to cover both sites at once. The main objective of this study is to evaluate the effectiveness of covering both burn wound and adjacent donor site with the same STSG in elderly and bedridden patients. We retrospectively reviewed the medical records of 6 patients over 60 years old or/and bedridden presenting with a small burn wound who underwent STSG of both burn wound and adjacent donor site between April 2016 and November 2016 in the Department of Plastic Surgery and Burn Treatment at Percy Military Hospital (France). Their data were compared with data of five patients who had undergone the usual STSG procedure during the same period. There was a statistically significant difference between patients who underwent adjacent STSG procedure and those who underwent usual STSG procedure in healing time (days) mean (SD) (7,33 +/- 1,03 vs. 16,2 +/- 0,83; p = 0,007) and Numeric Rating Scale pain mean (SD) at day 2 (0,33 +/- 0,33 vs. 2,4 +/- 1,35; p = 0,04). Grafting both acute burn wound and adjacent donor site with the same graft seems to be an easy method to improve healing and minimize pain in the STSG donor site in elderly and bedridden patients. PMID- 28592937 TI - The pedicled groin flap in resurfacing hand burn scar release and other injuries: a five-case series report and review of the literature. AB - XX. PMID- 28592938 TI - Thermal burn in a 30-minute-old newborn: report on the youngest patient with iatrogenic burn injury. AB - Burns in infants are rare. The majority of neonatal burns occur in the hospital setting. The immaturity of their immune system, their fragile and thin skin, difficulties in resuscitation, engraftment paucity limited by donor sites, and long-term complications make taking care of burned newborns extremely difficult. We present the case of a newborn burned 30 minutes after his birth over a total body surface of 35%, when the hot water bottle used in the hospital accidentally burst. This is the earliest iatrogenic burn in a newborn reported to date. The newborn was discharged home after 30 days in hospital for resuscitation, dressings and skin grafting. He is now under regular observation. PMID- 28592939 TI - Ashura: a festival of charity associated with a serious and disabling eye injury (report of 12 cases). PMID- 28592940 TI - MBC News. PMID- 28592942 TI - Reaction of Global Collection of Rye (Secale cereale L.) to Tan Spot and Pyrenophora tritici-repentis Races in South Dakota. AB - Rye (Secale cereale L.) serves as an alternative host of Pyrenophora tritici repentis (PTR) the cause of tan spot on wheat. Rye is cultivated as a forage or cover crop and overlaps with a significant portion of wheat acreage in the U.S. northern Great Plains; however, it is not known whether the rye crop influences the evolution of PTR races. We evaluated a global collection of 211 rye accessions against tan spot and assessed the diversity in PTR population on rye in South Dakota. All the rye genotypes were inoculated with PTR races 1 and 5, and infiltrated with Ptr ToxA and Ptr ToxB, at seedling stage. We observed 21% of the genotypes exhibited susceptibility to race 1, whereas, 39% were susceptible to race 5. All 211 accessions were insensitive to both the Ptr toxins. It indicates that though rye exhibits diversity in reaction to tan spot, it lacks Ptr ToxA and ToxB sensitivity genes. This suggests that unknown toxins or other factors can lead to PTR establishment in rye. We characterized the race structure of 103 PTR isolates recovered from rye in South Dakota. Only 22% of the isolates amplified Ptr ToxA gene and were identified as race 1 based on their phenotypic reaction on the differential set. The remaining 80 isolates were noted to be race 4. Our results show that races 1 and 4 are prevalent on rye in South Dakota with a higher frequency of race 4, suggesting a minimal role of rye in the disease epidemiology. PMID- 28592943 TI - Identification and Characterization of Pathogenic and Endophytic Fungal Species Associated with Pokkah Boeng Disease of Sugarcane. AB - Pokkah Boeng is a serious disease of sugarcane, which can lead to devastating yield losses in crop-producing regions, including southern China. However, there is still uncertainty about the causal agent of the disease. Our aim was to isolate and characterize the pathogen through morphological, physiological, and molecular analyses. We isolated sugarcane-colonizing fungi in Fujian, China. Isolated fungi were first assessed for their cell wall degrading enzyme capabilities, and five isolates were identified for further analysis. Internal transcribed spacer sequencing revealed that these five strains are Fusarium, Alternaria, Phoma, Phomopsis, and Epicoccum. The Fusarium isolate was further identified as F. verticillioides after Calmodulin and EF-1alpha gene sequencing and microscopic morphology study. Pathogenicity assay confirmed that F. verticillioides was directly responsible for disease on sugarcane. Co-inoculation of F. verticillioides with other isolated fungi did not lead to a significant difference in disease severity, refuting the idea that other cellulolytic fungi can increase disease severity as an endophyte. This is the first report characterizing pathogenic F. verticillioides on sugarcane in southern China. PMID- 28592944 TI - Potential Reasons for Prevalence of Fusarium Wilt in Oriental Melon in Korea. AB - This study aims to examine the potential reasons for the current prevalence of the fusarium wilt in the oriental melon. Twenty-seven Fusarium isolates obtained from oriental melon greenhouses in 2010-2011 were identified morphologically and by analysis of elongation factor-1 alpha gene (EF-1alpha) and internal transcribed spacer (ITS) rDNA sequences as 6 Fusarium species (8 isolates of F. oxysporum, 8 F. commune, 5 F. proliferatum, 3 F. equiseti, 2 F. delphinoides, and 1 F. andiyazi), which were classified as same into 6 EF-1alpha sequence-based phylogenetic clades. Pathogenicity of the Fusarium isolates on the oriental melon was highest in F. proliferatum, next in F. oxysporum and F. andiyazi, and lowest in the other Fusarium species tested, suggesting F. proliferatum and F. oxysporum were major pathogens of the oriental melon, inducing stem rots and vascular wilts, respectively. Oriental melon and watermelon were more susceptible to F. oxysporum than shintosa and cucumber; and cucumber was most, oriental melon and watermelon, medially, and shintosa was least susceptible to F. proliferatum, whose virulence varied among and within their phylogenetic subclades. Severe root knot galls were formed on all the crops infected with Meloidogyne incognita; however, little indication of vascular wilts or stem and/or root rots was shown by the nematode infection. These results suggest the current fungal disease in the oriental melon may be rarely due to virulence changes of the fusarium wilt pathogen and the direct cause of the severe root-knot nematode infection, but may be potentially from other Fusarium pathogen infection that produces seemingly wilting caused by severe stem rotting. PMID- 28592941 TI - The Plant Cellular Systems for Plant Virus Movement. AB - Plasmodesmata (PDs) are specialized intercellular channels that facilitate the exchange of various molecules, including sugars, ribonucleoprotein complexes, transcription factors, and mRNA. Their diameters, estimated to be 2.5 nm in the neck region, are too small to transfer viruses or viral genomes. Tobacco mosaic virus and Potexviruses are the most extensively studied viruses. In viruses, the movement protein (MP) is responsible for the PD gating that allows the intercellular movement of viral genomes. Various host factors interact with MP to regulate complicated mechanisms related to PD gating. Virus replication and assembly occur in viral replication complex (VRC) with membrane association, especially in the endoplasmic reticulum. VRC have a highly organized structure and are highly regulated by interactions among the various host factors, proteins encoded by the viral genome, and the viral genome. Virus trafficking requires host machineries, such as the cytoskeleton and the secretory systems. MP facilitates the virus replication and movement process. Despite the current level of understanding of virus movement, there are still many unknown and complex interactions between virus replication and virus movement. While numerous studies have been conducted to understand plant viruses with regards to cell-to-cell movement and replication, there are still many knowledge gaps. To study these interactions, adequate research tools must be used such as molecular, and biochemical techniques. Without such tools, virologists will not be able to gain an accurate or detailed understanding of the virus infection process. PMID- 28592946 TI - Characterization of the rcsA Gene from Pantoea sp. Strain PPE7 and Its Influence on Extracellular Polysaccharide Production and Virulence on Pleurotus eryngii. AB - RcsA is a positive activator of extracellular polysaccharide (EPS) synthesis in the Enterobacteriaceae. The rcsA gene of the soft rot pathogen Pantoea sp. strain PPE7 in Pleurotus eryngii was cloned by PCR amplification, and its role in EPS synthesis and virulence was investigated. The RcsA protein contains 3 highly conserved domains, and the C-terminal end of the open reading frame shared significant amino acid homology to the helix-turn-helix DNA binding motif of bacterial activator proteins. The inactivation of rcsA by insertional mutagenesis created mutants that had decreased production of EPS compared to the wild-type strain and abolished the virulence of Pantoea sp. strain PPE7 in P. eryngii. The Pantoea sp. strain PPE7 rcsA gene was shown to strongly affect the formation of the disease symptoms of a mushroom pathogen and to act as the virulence factor to cause soft rot disease in P. eryngii. PMID- 28592947 TI - Efficacy of Tissue Culture in Virus Elimination from Caprifig and Female Fig Varieties (Ficus carica L.). AB - Fig mosaic disease (FMD) is a viral disease that spreads in all Tunisian fig (Ficus carica L.) orchards. RT-PCR technique was applied to leaf samples of 29 fig accessions of 15 fig varieties from the fig germplasm collection of High Agronomic Institute (I.S.A) of Chatt-Mariem, to detect viruses associated to FMD. Analysis results show that 65.5% of the accessions (19/29) and 80.0% (12/15) of the fig varieties are infected by FMD-associated viruses. From all fig accessions, 41.4% of them are with single infection (one virus) and 24.1% are with multi-infections (2 virus and more). Viruses infecting fig leaf samples are Fig mosaic virus (FMV) (20.7%), Fig milde-mottle-associated virus (FMMaV) (17.25%), Fig fleck associated virus (FFkaV) (3.45%), and Fig cryptic virus (FCV) (55.17%). A reliable protocol for FCV and FMMaV elimination from 4 local fig varieties Zidi (ZDI), Soltani (SNI), Bither Abiadh (BA), and Assafri (ASF) via in vitro culture of 3 meristem sizes was established and optimized. With this protocol, global sanitation rates of 79.46%, 65.55%, 68.75%, and 70.83% respectively for ZDI, SNI, BA, and ASF are achieved. For all sanitized varieties, the effectiveness of meristem culture for the elimination of FCV and FMMaV viruses was related to meristem size. Meristem size 0.5 mm provides the highest sanitation rates ranging from 70% to 90%. PMID- 28592945 TI - Defense Response and Suppression of Phytophthora Blight Disease of Pepper by Water Extract from Spent Mushroom Substrate of Lentinula edodes. AB - The spent mushroom substrate (SMS) of Lentinula edodes that was derived from sawdust bag cultivation was used as materials for controlling Phytophthora blight disease of pepper. Water extract from SMS (WESMS) of L. edodes inhibited mycelial growth of Phytophthora capsici, suppressed Phytophthora blight disease of pepper seedlings by 65% and promoted growth of the plant over 30%. In high performance liquid chromatography (HPLC) analysis, oxalic acid was detected as the main organic acid compound in WESMS and inhibited the fungal mycelium at a minimum concentration of 200 mg/l. In quantitative real-time PCR, the transcriptional expression of CaBPR1 (PR protein 1), CaBGLU (beta-1,3-glucanase), CaPR-4 (PR protein 4), and CaPR-10 (PR protein 10) were significantly enhanced on WESMS and DL-beta-aminobutyric acid (BABA) treated pepper leaves. In addition, the salicylic acid content was also increased 4 to 6 folds in the WESMS and BABA treated pepper leaves compared to water treated leaf sample. These findings suggest that WESMS of L. edodes suppress Phytophthora blight disease of pepper through multiple effects including antifungal activity, plant growth promotion, and defense gene induction. PMID- 28592948 TI - Occurrence and Evolutionary Analysis of Coat Protein Gene Sequences of Iranian Isolates of Sugarcane mosaic virus. AB - Sugarcane mosaic virus (SCMV) is one of the most damaging viruses infecting sugarcane, maize and some other graminaceous species around the world. To investigate the genetic diversity of SCMV in Iran, the coat protein (CP) gene sequences of 23 SCMV isolates from different hosts were determined. The nucleotide sequence identity among Iranian isolates was more than 96%. They shared nucleotide identities of 75.5-99.9% with those of other SCMV isolates available in GenBank, the highest with the Egyptian isolate EGY7-1 (97.5-99.9%). The results of phylogenetic analysis suggested five divergent evolutionary lineages that did not completely reflect the geographical origin or host plant of the isolates. Population genetic analysis revealed greater between-group than within-group evolutionary divergence values, further supporting the results of the phylogenetic analysis. Our results indicated that natural selection might have contributed to the evolution of isolates belonging to the five identified SCMV groups, with infrequent genetic exchanges occurring between them. Phylogenetic analyses and the estimation of genetic distance indicated that Iranian isolates have low genetic diversity. No recombination was found in the CP cistron of Iranian isolates and the CP gene was under negative selection. These findings provide a comprehensive analysis of the population structure and driving forces for the evolution of SCMV with implications for global exchange of sugarcane germplasm. Gene flow, selection and somehow homologous recombination were found to be the important evolutionary factors shaping the genetic structure of SCMV populations. PMID- 28592949 TI - Development of Multiplex PCR for Simultaneous Detection of Citrus Viruses and the Incidence of Citrus Viral Diseases in Late-Maturity Citrus Trees in Jeju Island. AB - Satsuma dwarf virus (SDV) or Citrus mosaic sadwavirus (CiMV) were not consistently detected in RT-PCR assay with the primer sets based on gene of Japan isolates. SDV and CiMV isolates were distinctively divided into two groups based on phylogenetic analysis of PP2 gene cloned from 22 Korean isolates, and the Korean CiMV and SDV isolates shared 95.5-96.2% and 97.1-97.7% sequence identity with Japanese isolate, respectively. We developed PP2-1 primer set based on the PP2 gene sequence of Korean isolates to simultaneously and effectively detect SDV and CiMV. And CTLV-2013 and CTV-po primer sets were newly designed for detection of Citrus tatter leaf virus (CTLV) and Citrus tristeza virus (CTV), respectively. Using these primer sets, a new multiplex PCR assay was developed as a means to simultaneously detect 4 citrus viruses, CTV, CTLV, SDV, and CiMV. The degree of detection by the multiplex PCR were consistent with those of uniplex RT-PCR for detection of each of the viruses. Therefore, the new multiplex PCR provides an efficient method for detecting 4 citrus viruses, which will help diagnose many citrus plants at the same time. We verified that 35.2% and 72.1% of 775 trees in 155 orchards were infected with SDV or CiMV (SDV/CiMV) and CTV by the multiplex PCR assay, respectively, and CTLV was not detected in any of the trees tested. PMID- 28592950 TI - Purification and Characterization of a Major Extracellular Chitinase from a Biocontrol Bacterium, Paenibacillus elgii HOA73. AB - Chitinase-producing Paenibacillus elgii strain HOA73 has been used to control plant diseases. However, the antimicrobial activity of its extracellular chitinase has not been fully elucidated. The major extracellular chitinase gene (PeChi68) from strain HOA73 was cloned and expressed in Escherichia coli in this study. This gene had an open reading frame of 2,028 bp, encoding a protein of 675 amino acid residues containing a secretion signal peptide, a chitin-binding domain, two fibronectin type III domains, and a catalytic hydrolase domain. The chitinase (PeChi68) purified from recombinant E. coli exhibited a molecular mass of approximately 68 kDa on SDS-PAGE. Biochemical analysis indicated that optimum temperature for the actitvity of purified chitinase was 50oC. However, it was inactivated with time when it was incubated at 40oC and 50oC. Its optimum activity was found at pH 7, although its activity was stable when incubated between pH 3 and pH 11. Heavy metals inhibited this chitinase. This purified chitinase completely inhibited spore germination of two Cladosporium isolates and partially inhibited germination of Botrytis cinerea spores. However, it had no effect on the spores of a Colletotricum isolate. These results indicate that the extracellular chitinase produced by P. elgii HOA73 might have function in limiting spore germination of certain fungal pathogens. PMID- 28592951 TI - Application of Arbuscular Mycorrhizal Fungi during the Acclimatization of Alpinia purpurata to Induce Tolerance to Meloidogyne arenaria. AB - An experiment was conducted to evaluate the tolerance of micropropagated and mycorrhized alpinia plants to the parasite Meloidogyne arenaria. The experimental design was completely randomized with a factorial arrangement of four inoculation treatments with arbuscular mycorrhizal fungi (AMF) (Gigaspora albida, Claroideoglomus etunicatum, Acaulospora longula, and a non-inoculated control) in the presence or absence of M. arenaria with five replicates. The following characteristics were evaluated after 270 days of mycorrhization and 170 days of M. arenaria inoculation: height, number of leaves and tillers, fresh mass of aerial and subterranean parts, dry mass of aerial parts, foliar area, nutritional content, mycorrhizal colonization, AMF sporulation, and the number of galls, egg masses, and eggs. The results indicated a significant interaction between the treatments for AMF spore density, total mycorrhizal colonization, and nutrient content (Zn, Na, and N), while the remaining parameters were influenced by either AMF or nematodes. Plants inoculated with A. longula or C. etunicatum exhibited greater growth than the control. Lower N content was observed in plants inoculated with AMF, while Zn and Na were found in larger quantities in plants inoculated with C. etunicatum. Fewer galls were observed on mycorrhized plants, and egg mass production and the number of eggs were lower in plants inoculated with G. albida. Plants inoculated with A. longula showed a higher percentage of total mycorrhizal colonization in the presence of the nematode. Therefore, the association of micropropagated alpinia plants and A. longula enhanced tolerance to parasitism by M. arenaria. PMID- 28592952 TI - Development of a Biofungicide Using a Mycoparasitic Fungus Simplicillium lamellicola BCP and Its Control Efficacy against Gray Mold Diseases of Tomato and Ginseng. AB - To develop a commercial product using the mycoparasitic fungus Simplicillium lamellicola BCP, the scaleup of conidia production from a 5-l jar to a 5,000-l pilot bioreactor, optimization of the freeze-drying of the fermentation broth, and preparation of a wettable powder-type formulation were performed. Then, its disease control efficacy was evaluated against gray mold diseases of tomato and ginseng plants in field conditions. The final conidial yields of S. lamellicola BCP were 3.3 * 109 conidia/ml for a 5-l jar, 3.5 * 109 conidia/ml for a 500-l pilot vessel, and 3.1 * 109 conidia/ml for a 5,000-l pilot bioreactor. The conidial yield in the 5,000-l pilot bioreactor was comparable to that in the 5-l jar and 500-l pilot vessel. On the other hand, the highest conidial viability of 86% was obtained by the freeze-drying method using an additive combination of lactose, trehalose, soybean meal, and glycerin. Using the freeze-dried sample, a wettable powder-type formulation (active ingredient 10%; BCP-WP10) was prepared. A conidial viability of more than 50% was maintained in BCP-WP10 until 22 weeks for storage at 40 degrees C. BCP-WP10 effectively suppressed the development of gray mold disease on tomato with control efficacies of 64.7% and 82.6% at 500- and 250-fold dilutions, respectively. It also reduced the incidence of gray mold on ginseng by 65.6% and 81.3% at 500- and 250-fold dilutions, respectively. The results indicated that the new microbial fungicide BCP-WP10 can be used widely to control gray mold diseases of various crops including tomato and ginseng. PMID- 28592953 TI - Efficient Transmission and Propagation of Tomato Chlorosis Virus by Simple Single Leaflet Grafting. AB - Tomato chlorosis virus (ToCV), a member of the genus Crinivirus, has caused an epidemic disease in tomato worldwide. ToCV is phloem-limited and transmitted by whiteflies in a semi-persistent manner, but not by mechanical inoculation. Experimental propagation of ToCV has been performed primarily by using whitefly mediated inoculation. To develop a simple and convenient method for transmission of ToCV, we investigated grafting single-leaflets from tomato plants infected with ToCV to recipient tomato seedlings. Forty-one of 46 tomato seedlings tested were grafted successfully with single-leaflets infected with ToCV. Among them, 36 seedlings (87.8%) were systemically infected with ToCV and developed typical symptoms. Our results demonstrated that single-leaflet grafting could provide a sufficient amount of inoculum for the transmission of ToCV to the grafted seedlings. PMID- 28592955 TI - Atrial fibrillation in the elderly. PMID- 28592956 TI - Prevalence and incidence of interatrial block in global population and in different clinical situations. PMID- 28592954 TI - Pharmaceuticals and personal care products in waters: occurrence, toxicity, and risk. AB - Pharmaceuticals and personal care products (PPCP) are compounds with special physical and chemical properties that address the care of animal and human health. PPCP have been detected in surface water and wastewater in the ng/L to ug/L concentration range worldwide. PPCP ecotoxicity has been studied in a variety of organisms, and multiple methods have been used to assess the risk of PPCP in the environment to ecological health. Here we review the occurrence, effects, and risk assessment of PPCP in aquatic systems, as well as the sustainability of current methods for managing PPCP contamination in aquatic systems. The major points are the following: (1) a number of PPCP present potential concerns at environmentally relevant concentrations. PPCP mixtures may produce synergistic toxicity. (2) Various methods have been used for the ecological risk assessment of PPCP in aquatic systems. There are similarities in these methods, but no consensus has emerged regarding best practices for the ecological risk assessment of these compounds. (3) Human health risk assessments of PPCP contamination in aquatic systems have generally indicated little cause for concern. However, there is a lack of information regarding whether antibiotic contamination in wastewater and aquatic systems could lead to an increase in clinically relevant antibiotic-resistant bacteria and antibiotic-resistant genes. (4) Over the next century, the combination of increasing global population size and potential droughts may result in reduced water availability, increased need for water reuse, and increasing concentrations of PPCP in wastewaters. The current wastewater treatment methods do not remove all PPCP effectively. This, coupled with the possibility that antibiotics may promote the development of antibiotic-resistant bacteria and antibiotic-resistant genes, leads to concerns about the sustainability of global water supplies. PMID- 28592957 TI - Diagnosis of interatrial block. PMID- 28592958 TI - Anticoagulation in elderly patients at high risk of atrial fibrillation without documented arrhythmias. PMID- 28592959 TI - Advanced interatrial block as a key marker for atrial fibrillation recurrence: Bayes' syndrome. PMID- 28592960 TI - Atrial fibrosis: an obligatory component of arrhythmia mechanisms in atrial fibrillation? PMID- 28592961 TI - Predisposing factors for atrial fibrillation in the elderly. AB - Atrial fibrillation (AF) in the elderly occurs as a consequence of cardiovascular aging and an age related increase of comorbidity. Several predisposing factors for AF have been identified for the overall AF population. Most of them, cardiovascular disease in particular, play a role in younger and older patients. The longer time period during which these risk factors can cause structural changes that ultimately lead to AF may, at least in part, explain the association between age and AF. In addition, less well defined age-related changes in cellular electrophysiologic properties and structure predispose to AF in the elderly. PMID- 28592962 TI - How to detect atrial fibrosis. AB - In the last twenty years, new imaging techniques to assess atrial function and to predict the risk of recurrence of atrial fibrillation after treatment have been developed. The present review deals with the role of these techniques in the detection of structural and functional changes of the atrium and diagnosis of atrial remodeling, particularly atrial fibrosis. Echocardiography allows the detection of anatomical, functional changes and deformation of the atrial wall during the phases of the cardiac cycle. For this, adequate acquisition of atrial images is necessary using speckle tracking imaging and interpretation of the resulting strain and strain rate curves. This allows to predict new-onset atrial fibrillation and recurrences. Its main limitations are inter-observer variability, the existence of different software manufacturers, and the fact that the software used were originally developed for the evaluation of the ventricular function and are now applied to the atria. Cardiac magnetic resonance, using contrast enhancement with gadolinium, plays a key role in the visualization and quantification of atrial fibrosis. This is the established method for in vivo visualization of myocardial fibrotic tissue. The non-invasive evaluation of atrial fibrosis is associated with the risk of recurrence of atrial fibrillation and with electro-anatomical endocardial mapping. We discuss the limitations of these techniques, derived from the difficulty of demonstrating the correlation between fibrosis imaging and histology, and poor intra- and inter-observer reproducibility. The sources of discordance are described, mainly due to image acquisition and processing, and the challenges ahead in an attempt to eliminate differences between operators. PMID- 28592964 TI - A rare case of single right coronary artery arising from the right sinus of Valsalva with severe three-vessel disease. PMID- 28592963 TI - Atrial fibrillation: the current epidemic. AB - Atrial fibrillation (AF) is the most common arrhythmia diagnosed in clinical practice. The consequences of AF have been clearly established in multiple large observational cohort studies and include increased stroke and systemic embolism rates if no oral anticoagulation is prescribed, with increased morbidity and mortality. With the worldwide aging of the population characterized by a large influx of "baby boomers" with or without risk factors for developing AF, an epidemic is forecasted within the next 10 to 20 years. Although not all studies support this evidence, it is clear that AF is on the rise and a significant amount of health resources are invested in detecting and managing AF. This review focuses on the worldwide burden of AF and reviews global health strategies focused on improving detection, prevention and risk stratification of AF, recently recommended by the World Heart Federation. PMID- 28592965 TI - Is there any link between homocysteine and atherosclerosis? PMID- 28592966 TI - Patient satisfaction with TB care clinical consultations in Kampala: a cross sectional study. AB - BACKGROUND: Patient satisfaction towards care during encounter with clinicians is key for better treatment outcomes. We assessed patient satisfaction with TB clinical care consultations in Kampala, Uganda. METHODS: This was a facility based cross sectional study done between September 2012 and February 2013 using qualitative method of data collection. Participants consecutively completed a pre tested structured satisfaction questionnaire. A criteria of the rating as good; >75% was considered acceptable, (50-75%) as more effort is needed and <50 as unacceptable and require immediate action was used to categorize data for analysis using Epi-info 7.1.4.0. RESULTS: Of the 260 registered TB patients, 178(68.5%) completed the questionnaire. Overall, 162 (91.0%) were satisfied with the clinical consultation. Factors that contributed to high patient satisfaction, were: time spent with clinician (85.4%), explanation of what was done (87.6%), technical skills (91.6%), personal manner of the clinician seen (91.6%). Factors for low satisfaction were; waiting time before getting an appointment (61.8%), convenience of location of consultation office (53.4%), getting through to the office by phone (21.3%) and length of time waiting at the office (61.2%). CONCLUSION: Tuberculosis patients in Kampala are satisfied with TB clinical care consultations. Addressing factors with low patient satisfaction may significantly impact on treatment outcome. PMID- 28592967 TI - Nomogram Prediction of Anastomotic Leakage and Determination of an Effective Surgical Strategy for Reducing Anastomotic Leakage after Laparoscopic Rectal Cancer Surgery. AB - BACKGROUND: Although many surgical strategies have been used to reduce the anastomotic leak (AL) rate after laparoscopic rectal cancer surgery, limited data are available on the risk factors for AL and the effective strategy to reduce AL. METHODS: The present study enrolled 736 consecutive patients who underwent laparoscopic resection without a diverting stoma for rectal adenocarcinoma. A nomogram was constructed to predict AL. Based on the nomogram, personalized risk was calculated and sequential surgical strategies were monitored using risk adjusted cumulative sum (RA-CUSUM) analysis. RESULTS: Among the 736 patients, clinical AL occurred in 65 patients (8.8%). Sex, an American Society of Anesthesiologists score, operation time, blood transfusion, and tumor location were identified as significant predictive factors for AL. Based on these factors, a nomogram was created to predict AL, with a concordance index (C-index) of 0.753 (95% confidence interval, 0.690-0.816). A calibration plot showed good statistical performance on internal validation (bias-corrected C-index of 0.742). The RA-CUSUM curve showed that extended splenic flexure mobilization (SFM) could be the most influential strategy to reduce AL. CONCLUSIONS: Our nomogram for predicting AL after laparoscopic rectal cancer surgery might be helpful to identify the individual risk of AL. Furthermore, extended SFM might be the most appropriate strategy for reducing AL. PMID- 28592968 TI - Endoscopic Submucosal Dissection of Gastric Epithelial Neoplasms after Partial Gastrectomy: A Single-Center Experience. AB - AIMS: To investigate the feasibility and safety of endoscopic submucosal dissection (ESD) of gastric epithelial neoplasms in the remnant stomach (GEN-RS) after various types of partial gastrectomy. METHODS: This study included 29 patients (31 lesions) who underwent ESD for GEN-RS between March 2006 and August 2016. Clinicopathologic data were retrieved retrospectively to assess the therapeutic ESD outcomes, including en bloc and complete resection rates and procedure-related adverse events. RESULTS: The en bloc, complete, and curative resection rates were 90%, 77%, and 71%, respectively. The types of previous gastrectomy, tumor size, macroscopic type, and tumor histology were not associated with incomplete resection. Only tumors involving the suture lines from the prior partial gastrectomy were significantly associated with incomplete resection. The procedure-related bleeding and perforation rates were 6% and 3%, respectively; none of the adverse events required surgical intervention. During a median follow-up period of 25 months (range, 6-58 months), there was no recurrence in any case. CONCLUSIONS: ESD is a safe and feasible treatment for GEN RS regardless of the previous gastrectomy type. However, the complete resection rate decreases for lesions involving the suture lines. PMID- 28592969 TI - Corrigendum to "Pharmacogenetics of Risperidone and Cardiovascular Risk in Children and Adolescents". AB - [This corrects the article DOI: 10.1155/2016/5872423.]. PMID- 28592971 TI - Formulation Development of High Strength Gel System and Evaluation on Profile Control Performance for High Salinity and Low Permeability Fractured Reservoir. AB - For the large pores and cracks of reservoirs with low temperatures, high salinity, and low permeability, a new type of high strength gel ABP system is developed in this paper. The defects of conventional gels such as weak gel strength, no gelling, and easy dehydration are overcome under the conditions of low temperature and high salinity. The temperature and salt resistance, plugging characteristics, and EOR of the gel system are studied. Under the condition of 32 degrees C and 29500 mg/L salinity, the ABP system formulation is for 0.3% crosslinking agent A + 0.09% coagulant B + 3500 mg/L polymer solution P. The results show that when the temperature was increased, the delayed crosslinking time of the system was shortened and the gel strength was increased. The good plugging characteristics of the ABP system were reached, and the plugging rate was greater than 99% in cores with different permeability. A good profile control performance was achieved, and the recovery rate was improved by 19.27% on the basis of water flooding. In the practical application of the gel system, the salinity of formation water and the permeability of fractures are necessary to determine the appropriate formulation. PMID- 28592970 TI - LPS from P. gingivalis Negatively Alters Gingival Cell Mitochondrial Bioenergetics. AB - OBJECTIVE: Oral inflammatory pathologies are linked to increased oxidative stress, thereby partly explaining their relevance in the etiology of systemic disorders. The purpose of this work was to determine the degree to which LPS from Porphyromonas gingivalis, the primary pathogen related to oral inflammation, altered gingival mitochondrial function and reactive oxygen species generation. METHODS: Human gingival fibroblast (HGF-1) cells were treated with lipopolysaccharide of P. gingivalis. Mitochondrial function was determined via high-resolution respirometry. P GINGIVALIS: Mitochondrial function was determined via high-resolution respirometry. RESULTS: LPS-treated HGF-1 cells had significantly higher mitochondrial complex IV and higher rates of mitochondrial respiration. However, this failed to translate into greater ATP production, as ATP production was paradoxically diminished with LPS treatment. Nevertheless, production of the reactive H2O2 was elevated with LPS treatment. CONCLUSIONS: LPS elicits an increase in gingival cell mitochondria content, with a subsequent increase in reactive oxygen species production (i.e., H2O2), despite a paradoxical reduction in ATP generation. These findings provide an insight into the nature of oxidative stress in oral inflammatory pathologies. PMID- 28592972 TI - Fabrication of Polycaprolactone/Polyurethane Loading Conjugated Linoleic Acid and Its Antiplatelet Adhesion. AB - Polycaprolactone/polyurethane (PCL/PU) fibrous scaffold was loaded with conjugated linoleic acid (CLA) by electrospinning method to improve the hemocompatibility of the polymeric surface. Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Scanning Electron Microscopy (SEM) observation were employed to characterize the chemical structure and the changing morphology of electrospun PCL/PU and PCL/PU loaded with CLA (PCL/PU-CLA) scaffolds. Platelet adhesion and whole blood clot formation tests were used to evaluate the effect of CLA on antithrombotic property of PCL/PU-CLA scaffold. Endothelial cells (EC) were also seeded on the scaffold to examine the difference in the morphology of EC layer and platelet attachment with and without the presence of CLA. SEM results showed that CLA supported the spreading and proliferation of EC and PCL/PU-CLA surface induced lower platelet adhesion as well as attachment of other blood cells compared to the PCL/PU one. These results suggest that electrospinning method can successfully combine the antiplatelet effects of CLA to improve hemocompatibility of PCL/PU scaffolds for applications in artificial blood vessels. PMID- 28592973 TI - Exploring the Concern about Food Allergies among Secondary School and University Students in Ontario, Canada: A Descriptive Analysis. AB - Our objective was to explore the perceived risk of food allergies among students in Ontario, Canada. We analyzed blinding questions ("I am concerned about food allergies"; "food allergies are currently a big threat to my health") from three existing food safety surveys, given to high school and university undergraduate students (n = 3,451) circa February 2015, using descriptive analysis, and explored how concern related to demographics and self-reported cooking ability using linear regression. Overall, high school students were neutral in their concern, although Food and Nutrition students specifically were significantly less concerned (p = 0.002) than high school students overall. University undergraduates were moderately unconcerned about food allergies. Concern was highest in younger students, decreasing between 13 and 18 years of age and plateauing between 19 and 23 years. Among students aged 13-18 years, concern was higher among those who worked or volunteered in a daycare and who had previously taken a food preparation course. Among students aged 19-23 years, concern was higher among females and those with less advanced cooking abilities. Concern was significantly correlated with perceiving food allergies as a personal threat. This study offers a first exploration of perceived risk of food allergies among this demographic and can guide future, more rigorous assessments. PMID- 28592974 TI - Clitoral size in term newborns in Kumasi, Ghana. AB - BACKGROUND: Data on normative clitoral sizes in newborns is relatively sparse and racial/ethnic differences have also been reported. This study was performed to establish norms for clitoral size in term Ghanaian female newborns. METHODS: This was a cross-sectional study of all apparently well full-term newborns of postnatal age < 48 h and birth weight between 2.5 and 4.0 kg delivered at Komfo Anokye Teaching Hospital between May and September, 2014. Anthropometric and genital parameters were documented for study subjects as well as parental socio demographic indices. RESULTS: In 612 newborn females studied, the mean (+/-SD) clitoral length (MCL) and the mean (+/-SD) clitoral width (MCW) were 4.13 +/- 1.6 mm and 4.21 +/- 1.1 mm, respectively. MCL was inversely related to birth weight (r = -0.62; p < 0.001 ) while MCW was inversely related to both gestational age (r = -0.1; p = 0.02 ) and birth weight (r = -0.54; p < 0.001 ). Babies with a clitoris that was completely covered by the labia majora had relatively lower clitoral sizes (p < 0.001) than those who had a partially covered or prominent clitoris. Neither MCL nor MCW differed significantly by birth length or maternal tribe. CONCLUSIONS: Clitoral size varies with birth weight and gestational age. Babies with a completely covered clitoris are unlikely to warrant detailed clitoral measurements for clitoromegaly. PMID- 28592975 TI - Prognostic factors and treatment of pediatric acute lymphoblastic leukemia. AB - The event-free survival (EFS) for pediatric acute lymphoblastic leukemia (ALL) has shown remarkable improvement in the past several decades. In Korea also, a recent study showed 10-year EFS of 78.5%. Much of the improved outcome for pediatric ALL stems from the accurate identification of prognostic factors, the designation of risk group based on these factors, and treatment of appropriate duration and intensity according to risk group, done within the setting of cooperative clinical trials. The schema of first-line therapy for ALL remains mostly unchanged, although many groups have now reported on the elimination of cranial irradiation in all patients with low rates of central nervous system relapse. Specific high risk subgroups, such as Philadelphia chromosome-positive (Ph+) ALL and infant ALL continue to have significantly lower survival than other ALL patients. The introduction of tyrosine kinase inhibitors into therapy has led to enhanced outcome for Ph+ ALL patients. Infant ALL patients, particularly those with MLL rearrangements, continue to have poor outcome, despite treatment intensification including allogeneic hematopoietic cell transplantation. Relapsed ALL is a leading cause of mortality in pediatric cancer. Recent advances in immunotherapy targeting the CD19 of the ALL blast have shown remarkable efficacy in some of these relapsed and refractory patients. With improved survival, much of the current focus is on decreasing the long-term toxicities of treatment. PMID- 28592976 TI - Healthcare access challenges facing six African refugee mothers in South Korea: a qualitative multiple-case study. AB - PURPOSE: Following legal reform in 2013, the annual number of asylum seekers entering South Korea has increased from 1,143 in 2012 to 5,711 in 2015. We interviewed six African refugee mothers of young children regarding their health needs and barriers to access maternal child health services. METHODS: We recruited mothers who had visited a clinic for immigrants between July 2013 and August 2015. Participants were African refugee women, aged over 18 years, who had given birth in Korea within the previous 5 years and had come to Korea over a year before recruitment. Interview questions examined participants' experiences in pregnancy and childbirth and concerns regarding their child's health status. Initial data analysis involved all researchers' immersion in the entire collection of transcripts. We then noted recurrent topics and themes and identified similar issues. RESULTS: At the time of giving birth, 5 participants were asylum seekers and one had undocumented status. The following barriers impeded their access to maternal child healthcare: socioeconomic factors (unstable social identity, low economic status, difficulty obtaining health insurance), language barriers (lack of linguistically appropriate health information, limited access to translation services), and cultural barriers (religious and cultural differences). Weak social support also hindered access to healthcare soon after migration; however, social links with the community emerged as a key coping strategy following settlement. CONCLUSION: We identified barriers to maternal and child healthcare and coping strategies among African refugee mothers in Korea. Future research should assess refugees' health status and improve health access and literacy among refugee mothers. PMID- 28592977 TI - Clostridium difficile colonization and/or infection during infancy and the risk of childhood allergic diseases. AB - PURPOSE: The gut microbiota can influence several diseases through immune modulation; however, the exact role of microbes such as Clostridium difficileand the relationship between microbiota colonization and allergic diseases are not well known. This study aimed to determine the relationship between C. difficilecolonization and/or infection (CDCI) during infancy and allergic diseases during early childhood. METHODS: Infants 1-12 months of age presenting changes in bowel habits for more than 2 weeks were enrolled in this study. After dividing them into 2 groups according to the presence and absence of C. difficile, the risk of allergic disease development during childhood was identified and compared. RESULTS: Sixty-five patients were included in this study; 22 (33.8%) were diagnosed with CDCI. No significant differences were observed in baseline characteristics between the C. difficile-positive and negative groups except for antibiotic exposure (22.7% vs. 60.5%, P=0.004). Compared to the C. difficile-negative group, the risk of developing at least one allergic disease was higher in the C. difficile-positive group after adjusting other variables (adjusted odds ratios, 5.61; 95% confidence interval, 1.52-20.74; P=0.007). Furthermore, food allergies were more prevalent in the C. difficile positive group (P=0.03). CONCLUSION: CDCI during infancy were associated with a higher risk of developing allergic diseases during early childhood. These results suggest that CDCI during infancy might reflect the reduced diversity of the intestinal microbiota, which is associated with an increased risk of allergic sensitization. To identify the underlying mechanism, further investigation and a larger cohort study will be needed. PMID- 28592978 TI - Prevalence and clinical manifestations of macrolide resistant Mycoplasma pneumoniae pneumonia in Korean children. AB - PURPOSE: Macrolide resistance rate of Mycoplasma pneumoniae has rapidly increased in children. Studies on the clinical features between macrolide susceptible-M. pneumoniae (MSMP) and macrolide resistant-M. pneumoniae (MRMP) are lacking. The aim of this study was to identify the macrolide resistance rate of M. pneumoniae in Korean children with M. pneumoniae penupmonia in 2015 and compare manifestations between MSMP and MRMP. METHODS: Among 122 children (0-18 years old) diagnosed with M. pneumoniae pneumonia, 95 children with the results of macrolide sensitivity test were included in this study. Clinical manifestations were acquired using retrospective medical records. RESULTS: The macrolide resistant rate of M. pneumoniae was 87.2% (82 of 94 patients) in children with M. pneumoniae pneumonia. One patient showed a mixed type of wild type and A2063G mutation in 23S rRNA of M. pneumoniae. There were no significant differences in clinical, laboratory, and radiologic findings between the MSMP and MRMP groups at the first visit to our hospital. The time interval between initiation of macrolide and defervescence was significantly longer in the MRMP group (4.9+/-3.3 vs. 2.8+/-3.1 days, P=0.039). CONCLUSION: The macrolide resistant rate of M. pneumoniae is very high in children with M. pneumoniae pneumonia in Korea. The clinical manifestations of MRMP are similar to MSMP except for the defervescence period after administration of macrolide. Continuous monitoring of the occurrence and antimicrobial susceptibility of MRMP is required to control its spread and establish strategies for treating second-line antibiotic resistant M. pneumoniae infection. PMID- 28592980 TI - Decreased Spontaneous Electrical Activity and Acetylcholine at Myofascial Trigger Spots after Dry Needling Treatment: A Pilot Study. AB - OBJECTIVE: The aims of this study are to investigate the changes in spontaneous electrical activities (SEAs) and in acetylcholine (ACh), acetylcholine receptor (AChR), and acetylcholine esterase (AChE) levels after dry needling at myofascial trigger spots in model rats. MATERIALS AND METHODS: Forty-eight male Sprague Dawley rats were divided into four groups. Thirty-six rats were assigned to three model groups, which underwent MTrSs modeling intervention. Twelve rats were assigned to the blank control (BC) group. After model construction, the 36 model rats were randomly subdivided into three groups according to treatment: MTrSs model control (MC) and two dry needling groups. One dry needling group received puncturing at MTrSs (DN-M), whereas the other underwent puncturing at non-MTrSs (DN-nM). Dry needling treatment will last for two weeks, once a week. SEAs and ACh, AChR, and AChE levels were measured after one-week rest of dry needling treatment. RESULTS: The amplitudes and frequencies of endplate noise (EPN) and endplate spike (EPS) significantly decreased after dry needling treatment in the DN-M group. Moreover, ACh and AChR levels significantly decreased, whereas AChE significantly increased after dry needling treatment in the DN-M group. CONCLUSION: Dry needling at the exact MTrSs is more effective than dry needling at non-MTrSs. PMID- 28592979 TI - Sleep problems in children and adolescents at pediatric clinics. AB - PURPOSE: To investigate the frequency of childhood sleep problems at pediatric clinics in Seoul and Gyeonggi provinces. METHODS: Children (n=936) and their parents who visited 5 primary and 1 secondary pediatric outpatient clinics were invited to complete a Pediatric Sleep Questionnaire. RESULTS: Among patients, 901 (96.3%) answered questionnaires in sufficient detail for evaluation. The participant's mean age was 4.35+/-3.02 years (range, 0-18 years). The male to female ratio was 1:0.93 (466 boys, 435 girls). Habitual snoring (>3 day/week) was reported in 16.9% of the participants. The prevalence of habitual snoring in children <2 years and those between 2-5 years was 9% and 18%, respectively. Sleep disordered breathing was found in 15.1% (106 of 700) of children >2 years. Insomnia was reported in 13.2% of children. The prevalence of sleepwalking, night terrors, and bruxism, is 1.6%, 19%, and 21.1%, respectively. Snoring was associated with increased incidence of sleepwalking, night terrors, and bruxism. Age was associated with insomnia and habitual snoring (P<0.05). Insomnia was more prevalent in younger (21%) than in older children (6%). Snoring was more frequent in both preschool (34%) and school-aged children (33%). The frequency of sleep disordered breathing and insomnia did not vary significantly with gender. However, snoring was more prevalent in boys. CONCLUSION: Sleep problems are frequent among children in Korea. Children with snoring have an increased risk of sleepwalking, night terror, and bruxism. Primary clinicians should consider children's sleep habits to improve their health. PMID- 28592981 TI - Acupuncture Stimulation at GB34 Restores MPTP-Induced Neurogenesis Impairment in the Subventricular Zone of Mice. AB - Adult neurogenesis has recently been considered a new therapeutic paradigm of Parkinson's disease. In this study, we investigated whether acupuncture restores 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced impaired neurogenesis in the subventricular zone (SVZ). Male C57BL/6 mice were given 30 mg/kg of MPTP intraperitoneally once a day for 5 days, after which they were intraperitoneally injected with 50 mg/kg of bromodeoxyuridine (BrdU) and given acupuncture stimulation at HT7 or GB34 for 12 consecutive days. Dopaminergic neuronal survival in the nigrostriatal pathway and cell proliferation in the SVZ was then evaluated by immunostaining. MPTP administration induced dopaminergic neuronal death in the nigrostriatal pathway, which was suppressed by acupuncture stimulation at GB34. MPTP administration also suppressed the number of BrdU positive cells and glial fibrillary acidic protein/BrdU-positive cells and increased the number of doublecortin/BrdU-positive cells in the SVZ, which were restored by acupuncture stimulation at GB34. These results indicate that acupuncture stimulation at GB34 restores MPTP-induced neurogenesis impairment. PMID- 28592982 TI - Herbal Medicine Treatment for Children with Autism Spectrum Disorder: A Systematic Review. AB - OBJECTIVE: To summarize and evaluate the efficacy and safety of herbal medicines used for the treatment of autism spectrum disorder (ASD) in children. METHODS: Thirteen electronic databases were searched from their inception to November 2016. Randomized controlled trials (RCTs) that assessed the efficacy of herbal medicines alone or in combination with other Traditional Chinese Medicine treatments for ASD in children were included. The Cochrane Risk of Bias Tool was used and other data analyses were performed using RevMan (Version 5.3). RESULTS: Ten RCTs involving 567 patients with ASD were included for qualitative synthesis. In conjunction with conventional therapy, herbal medicines significantly improved the Childhood Autism Rating Scale (CARS) score, but the results of effects on total effective rate (TER) were different between the included studies. The use of herbal medicines with integrative therapy improved the CARS score and TER. In the studies that documented adverse events, no serious events were associated with herbal medicines. CONCLUSIONS: The efficacy of herbal medicines for the treatment of ASD appears to be encouraging but was inconclusive owing to low methodological quality, herbal medicine diversity, and small sample size of the examined studies. PMID- 28592983 TI - Age dependent accumulation patterns of advanced glycation end product receptor (RAGE) ligands and binding intensities between RAGE and its ligands differ in the liver, kidney, and skeletal muscle. AB - BACKGROUND: Much evidence indicates receptor for advanced glycation end products (RAGE) related inflammation play essential roles during aging. However, the majority of studies have focused on advanced glycation end products (AGEs) and not on other RAGE ligands. In the present study, the authors evaluated whether the accumulation of RAGE ligands and binding intensities between RAGE and its ligands differ in kidney, liver, and skeletal muscle during aging. RESULTS: In C57BL/6 N mice aged 12 weeks, 12 months, and 22 months, ligands accumulation, binding intensities between RAGE and its ligands, activated macrophage infiltration, M1/M2 macrophage expression, glyoxalase-1expression, and signal pathways related to inflammation were evaluated. The RAGE ligands age-associated accumulation patterns were found to be organ dependent. Binding intensities between RAGE and its ligands in kidney and liver increased with age, but those in skeletal muscle were unchanged. Infiltration of activated macrophages in kidney and liver increased with age, but infiltration in the skeletal muscle was unchanged. M1 expression increased and M2 and glyoxalase-1 expression decreased with age in kidney and liver, but their expressions in skeletal muscle were not changed. CONCLUSION: These findings indicate patterns of RAGE ligands accumulation, RAGE/ligands binding intensities, or inflammation markers changes during aging are organs dependent. PMID- 28592984 TI - On hazard ratio estimators by proportional hazards models in matched-pair cohort studies. AB - BACKGROUND: In matched-pair cohort studies with censored events, the hazard ratio (HR) may be of main interest. However, it is lesser known in epidemiologic literature that the partial maximum likelihood estimator of a common HR conditional on matched pairs is written in a simple form, namely, the ratio of the numbers of two pair-types. Moreover, because HR is a noncollapsible measure and its constancy across matched pairs is a restrictive assumption, marginal HR as "average" HR may be targeted more than conditional HR in analysis. METHODS: Based on its simple expression, we provided an alternative interpretation of the common HR estimator as the odds of the matched-pair analog of C-statistic for censored time-to-event data. Through simulations assuming proportional hazards within matched pairs, the influence of various censoring patterns on the marginal and common HR estimators of unstratified and stratified proportional hazards models, respectively, was evaluated. The methods were applied to a real propensity-score matched dataset from the Rotterdam tumor bank of primary breast cancer. RESULTS: We showed that stratified models unbiasedly estimated a common HR under the proportional hazards within matched pairs. However, the marginal HR estimator with robust variance estimator lacks interpretation as an "average" marginal HR even if censoring is unconditionally independent to event, unless no censoring occurs or no exposure effect is present. Furthermore, the exposure dependent censoring biased the marginal HR estimator away from both conditional HR and an "average" marginal HR irrespective of whether exposure effect is present. From the matched Rotterdam dataset, we estimated HR for relapse-free survival of absence versus presence of chemotherapy; estimates (95% confidence interval) were 1.47 (1.18-1.83) for common HR and 1.33 (1.13-1.57) for marginal HR. CONCLUSION: The simple expression of the common HR estimator would be a useful summary of exposure effect, which is less sensitive to censoring patterns than the marginal HR estimator. The common and the marginal HR estimators, both relying on distinct assumptions and interpretations, are complementary alternatives for each other. PMID- 28592985 TI - Child feeding practices and diarrheal disease among children less than two years of age of the nomadic people in Hadaleala District, Afar Region, Northeast Ethiopia. AB - BACKGROUND: Diarrhea is a serious public health problem in Ethiopia. It is responsible for 24-30% of all infant deaths and there is a lack of evidence on the health burdens among the nomadic people. This study was therefore designed to assess the prevalence of diarrhea among children less thanvtwo year's of age and its association with feeding practices among the nomadic people in Hadaleala district, northeast Ethiopia. METHODS: A cross-sectional study was conducted in Hadaleala district. A total of 367 children less than two years of age were included using the multistage cluster sampling technique. Data were collected by a structured questionnaire. Multivariable binary logistic regression analysis was used to identify variables associated with diarrheal disease. RESULTS: The prevalence of diarrhea among children less than two year's of age during the two week period was 31.3% (95% CI, 25.9, 36.1%). Diarrhea occurrence was associated with; children aged between 6-11 months (AOR 6.28, 95% CI, 3.00, 13.12), aged between 12-24 months (AOR 6.21, 95% CI, 3.13, 12.30), illiterate mothers (AOR 6.61, 95% CI, 2.27, 19.21), delay to initiate early breastfeeding for children aged less than six months (AOR 9.13, 95% CI, 1.78, 46.72), children less than six months of age not currently exclusively breastfed (AOR 13.33, 95% CI, 1.59, 112.12), delay to initiate early breastfeeding for children aged 6-24 months (AOR 2.87, 95% CI, 1.49, 5.51), no breastfeeding at the time of the survey (AOR 3.51, 95% CI, 1.57, 7.82), children aged 6-24 months who didn't exclusively breastfeed in the first six months (AOR 19.24, 95% CI, 8.26, 44.82), consuming uncooked foods (AOR 6.99, 95% CI, 2.89, 16.92), not eating cooked foods immediately after cooking (AOR 3.74, 95% CI, 1.48, 9.45), hand washing with only water (AOR 24.94, 95% CI, 6.68, 93.12), and rotavirus vaccination (AOR 0.09, 95% CI, 0.03, 0.29). CONCLUSIONS: The prevalence of diarrhea among children less than two year's of age in Hadaleala district was high. To prevent diarrhea, the mothers should start breastfeeding early and practice exclusive breastfeeding. Moreover, mothers should improve the hygiene of supplementary foods. PMID- 28592987 TI - An efficient protocol for perennial ryegrass mesophyll protoplast isolation and transformation, and its application on interaction study between LpNOL and LpNYC1. AB - BACKGROUND: Perennial ryegrass (Lolium perenne L.) is an important temperate grass used for turf and forage purposes. With the increasing accumulation of genomic and transcriptomic data of perennial ryegrass, an efficient protoplast and transient gene expression protocol is highly desirable for in vivo gene functional studies in its homologous system. RESULTS: In this report, a highly efficient protoplast isolation (5.6 * 107 protoplasts per gram of leaf material) and transient expression (plasmid transformation efficiency at 55.2%) was developed and the detailed protocol presented. Using this protocol, the subcellular locations of two ryegrass proteins were visualized in chloroplasts and nuclei, respectively, and protein-protein interaction between two chlorophyll catabolic enzymes (LpNOL and LpNYC1) was recorded in its homologous system for the first time. CONCLUSION: This efficient protoplast isolation and transformation protocol is sufficient for studies on protein subcellular localization and protein-protein interaction, and shall be suitable for many other molecular biology applications where the mesophyll protoplast system is desirable in perennial ryegrass. PMID- 28592986 TI - Correlates of early neonatal feeding practice in Dabat HDSS site, northwest Ethiopia. AB - BACKGROUND: Delaying the start of breastfeeding and giving prelacteal feeding leads to a significant increase in neonatal and infant deaths, particularly in a resource limited countries, like Ethiopia. Therefore, this study aimed to assess early neonatal feeding practice and its determinants in Dabat HDSS site, northwest Ethiopia. METHODS: The census for the reconciliation of the surveillance of the Dabat Health and Demographic Surveillance System (HDSS) site was conducted from October to December 2014. Data were entered into the Household Registration System (HRS) version 2.1 and analyzed using Stata version 14. A total of 6,761 mother-child pairs were included in the study. Sociodemographic factors, maternal health care and early neonatal feeding practices (early initiation of breastfeeding and prelacteal feeding) were collected by interviewing the mothers. The prevalence of early/timely initiation of breastfeeding was computed as the ratio of children put to the breast within one hour of delivery to the total number of children. Prelacteal feeding was defined as giving anything to drink other than breast milk in the first three days following birth. Binary logistic regression models were used to identify variables which were associated with the dependent variable. A multivariable logistic regression analysis was carried out to identify factors associated with early initiation of breastfeeding. RESULTS: The prevalence of early initiation of breastfeeding was 43.9% (95% CI, 41.6, 46.2). More than half (56%) of the mothers gave prelacteal feeds. An urban residence (Adjusted Odds Ratio [AOR] 1.47, 95% Confidence Interval [CI] 1.25. 1.73) and antenatal care (AOR 1.41, 95% CI 1.24, 1.59) were correlated with early initiation of breastfeeding. Similarly, increased odds of timely initiation of breastfeeding were observed among mothers who didn't give prelacteal feeds (AOR 5.72; 95% CI, 5.12, 6.40). CONCLUSION: Delayed initiation of breastfeeding and prelacteal feeding still remain public health concerns in this community. The promotion of improved infant and young child feeding (IYCF) practices and the utilization of antenatal care services should be intensified. PMID- 28592988 TI - Algorithms for computing the double cut and join distance on both gene order and intergenic sizes. AB - BACKGROUND: Combinatorial works on genome rearrangements have so far ignored the influence of intergene sizes, i.e. the number of nucleotides between consecutive genes, although it was recently shown decisive for the accuracy of inference methods (Biller et al. in Genome Biol Evol 8:1427-39, 2016; Biller et al. in Beckmann A, Bienvenu L, Jonoska N, editors. Proceedings of Pursuit of the Universal-12th conference on computability in Europe, CiE 2016, Lecture notes in computer science, vol 9709, Paris, France, June 27-July 1, 2016. Berlin: Springer, p. 35-44, 2016). In this line, we define a new genome rearrangement model called wDCJ, a generalization of the well-known double cut and join (or DCJ) operation that modifies both the gene order and the intergene size distribution of a genome. RESULTS: We first provide a generic formula for the wDCJ distance between two genomes, and show that computing this distance is strongly NP-complete. We then propose an approximation algorithm of ratio 4/3, and two exact ones: a fixed-parameter tractable (FPT) algorithm and an integer linear programming (ILP) formulation. CONCLUSIONS: We provide theoretical and empirical bounds on the expected growth of the parameter at the center of our FPT and ILP algorithms, assuming a probabilistic model of evolution under wDCJ, which shows that both these algorithms should run reasonably fast in practice. PMID- 28592989 TI - Outcome of HIV-associated lymphoma in a resource-limited setting of Jos, Nigeria. AB - BACKGROUND: Lymphoma is a leading cause of cancer-related death among human immunodeficiency virus (HIV)-infected individuals in the current era of potent anti-retroviral therapy (ART). Globally, mortality after HIV-associated lymphoma has profound regional variation. Little is known about HIV-associated lymphoma mortality in Nigeria and other resource-limited setting in sub-Saharan Africa. Therefore, we evaluated the all-cause mortality after lymphoma and associated risk factors including HIV at the Jos University Teaching Hospital (JUTH) Nigeria. METHODS: We conducted a ten-year retrospective cohort study of lymphoma patients managed in JUTH. The main outcome measured was all-cause mortality and HIV infection was the main exposure variable. Overall death rate was estimated using the total number of death events and cumulative follow up time from lymphoma diagnosis to death. Cox proportional hazard regression was used to assess factors associated with mortality after lymphoma diagnosis. RESULTS: Out of 40 lymphoma patients evaluated, 8(20.0%) were HIV positive and 32(80.0%) were HIV negative. After 127.63 person- years of follow-up, there were 16 deaths leading to a crude mortality rate of 40.0 per 100 person-years. The 2-year probability of survival was 30% for HIV-infected patients and 74% for HIV uninfected. Median survival probability for HIV-infected patients was 2.1 years and 7.6 years for those without HIV. Unadjusted hazard of death was associated with late stage, HR 11.33(95% CI 2.55, 50.26,p = 0.001); low cumulative cycles of chemotherapy, HR 6.43(95% CI 1.80, 22.89,p = 0.004); greater age, HR 5.12(95% CI 1.45,18.08,p = 0.01); presence of comorbidity, HR 3.43(95% CI 1.10,10.78,p = 0.03); and HIV-infection, HR 3.32(95% CI 1.05, 10.51,p = 0.04). In an adjusted model only stage was significantly associated with death, AHR 5.45(1.14-26.06, p = 0.03). CONCLUSION: Our findings suggest that HIV- infection accounted for three times probability of death in lymphoma patients compared to their HIV-uninfected counterparts due to late stage of lymphoma presentation in this population. Also initiation of chemotherapy was associated with lower probability of death among lymphoma patients managed at JUTH, Nigeria. Earlier stage at lymphoma diagnosis and prompt therapeutic intervention is likely to improve survival in these patients. Future research should undertake collaborative studies to obtain comprehensive regional data and identify unique risk factors of poor outcomes among HIV-infected patients with lymphoma in Nigeria. PMID- 28592990 TI - Predictors of successful long-term weight loss maintenance: a two-year follow-up. AB - BACKGROUND: Weight regain is a common problem following weight loss intervention, with most people who seek treatment for obesity able to lose weight, but few able to sustain the changes in behavior required to prevent subsequent weight regain. The identification of factors that predict which patients will successfully maintain weight loss or who are at risk of weight regain after weight loss intervention is necessary to improve the current weight maintenance strategies. The aim of the present study is identify factors associated with successful weight loss maintenance by women with overweight or obesity who completed group cognitive behavioral treatment (CBT) for weight loss. METHODS: Ninety women with overweight or obesity completed a 7-month weight loss intervention. The data of 86 who completed follow-up surveys 12 and 24 months after the end of the treatment was analyzed. Depression, anxiety, binge eating, food addiction, and eating behaviors were assessed before and after the weight loss intervention. Participants who lost at least 10% of their initial weight during the weight loss intervention and had maintained the loss at the month 24 follow-up were defined as successful. RESULTS: The intervention was successful for 27 participants (31.3%) and unsuccessful for 59 (68.6%). Multiple logistic regression analysis extracted larger weight reduction during the weight loss intervention, a lower disinhibition score, and a low food addiction score at the end of the weight loss intervention as associated with successful weight loss maintenance. CONCLUSION: The results suggest that larger weight reduction during the weight loss intervention and lower levels of disinhibition and food addiction at the end of the weight loss intervention predicted successful weight loss maintenance. TRIAL REGISTRATION: Trial registry name: Development and validation of effective treatments of weight loss and weight-loss maintenance using cognitive behavioral therapy for obese patients. Registration ID: UMIN000006803 Registered 1 January 2012. URL: https://upload.umin.ac.jp/cgi-open bin/ctr/ctr_view.cgi?recptno=R000008052. PMID- 28592991 TI - AAV-based dual-reporter circuit for monitoring cell signaling in living human cells. AB - BACKGROUND: High-throughput methods based on molecular reporters have greatly advanced our knowledge of cell signaling in mammalian cells. However, their ability to monitor various types of cells is markedly limited by the inefficiency of reporter gene delivery. Recombinant adeno-associated virus (AAV) vectors are efficient tools widely used for delivering and expressing transgenes in diverse animal cells in vitro and in vivo. Here we present the design, construction and validation of a novel AAV-based dual-reporter circuit that can be used to monitor and quantify cell signaling in living human cells. RESULTS: We first design and construct the AAV-based reporter system. We then validate the versatility and specificity of this system in monitoring and quantifying two important cell signaling pathways, inflammation (NFkappaB) and cell growth and differentiation (AP-1), in cultured HEK293 and MCF-7 cells. Our results demonstrate that the AAV reporter system is both specific and versatile, and it can be used in two common experimental protocols including transfection with plasmid DNA and transduction with packaged viruses. Importantly, this system is efficient, with a high signal to-background noise ratio, and can be easily adapted to monitor other common signaling pathways. CONCLUSIONS: The AAV-based system extends the dual-reporter technology to more cell types, allowing for cost-effective and high throughput applications. PMID- 28592992 TI - Streamlining recombination-mediated genetic engineering by validating three neutral integration sites in Synechococcus sp. PCC 7002. AB - BACKGROUND: Synechococcus sp. PCC 7002 (henceforth Synechococcus) is developing into a powerful synthetic biology chassis. In order to streamline the integration of genes into the Synechococcus chromosome, validation of neutral integration sites with optimization of the DNA transformation protocol parameters is necessary. Availability of BioBrick-compatible integration modules is desirable to further simplifying chromosomal integrations. RESULTS: We designed three BioBrick-compatible genetic modules, each targeting a separate neutral integration site, A2842, A0935, and A0159, with varying length of homologous region, spanning from 100 to 800 nt. The performance of the different modules for achieving DNA integration were tested. Our results demonstrate that 100 nt homologous regions are sufficient for inserting a 1 kb DNA fragment into the Synechococcus chromosome. By adapting a transformation protocol from a related cyanobacterium, we shortened the transformation procedure for Synechococcus significantly. CONCLUSIONS: The optimized transformation protocol reported in this study provides an efficient way to perform genetic engineering in Synechococcus. We demonstrated that homologous regions of 100 nt are sufficient for inserting a 1 kb DNA fragment into the three tested neutral integration sites. Integration at A2842, A0935 and A0159 results in only a minimal fitness cost for the chassis. This study contributes to developing Synechococcus as the prominent chassis for future synthetic biology applications. PMID- 28592993 TI - Can we use short rotation coppice poplar for sugar based biorefinery feedstock? Bioconversion of 2-year-old poplar grown as short rotation coppice. AB - BACKGROUND: Feedstock cost is a substantial barrier to the commercialization of lignocellulosic biorefineries. Poplar grown using a short rotation coppice (SRC) system has the potential to provide a low-cost feedstock and economically viable sugar yields for fuels and chemicals production. In the coppice management regime, poplars are harvested after 2 years' growth to develop the root system and establish the trees. The biomass from these 2-year-old trees is very heterogeneous, and includes components of leaf, bark, branch, and wood chip. This material is quite different than the samples that have been used in most poplar bioconversion research, which come from mature trees of short rotation forestry (SRF) plantations. If the coppice management regime is to be used, it is important that feedstock growers maximize their revenue from this initial harvest, but the heterogeneous nature of the biomass may be challenging for bioconversion. This work evaluates bioconversion of 2-year-old poplar coppice and compares its performance to whitewood chips from 12-year-old poplar. RESULTS: The 2-year-old whole tree coppice (WTC) is comprised of 37% leaf, 9% bark, 12% branch, and 42% wood chip. As expected, the chemical compositions of each component were markedly different. The leaf has a low sugar content but is high in phenolics, ash, and extractives. By removing the leaves, the sugar content of the biomass increased significantly, while the phenolic, ash, and extractives contents decreased. Leaf removal improved monomeric sugar yield by 147 kg/tonne of biomass following steam pretreatment and enzymatic hydrolysis. Bioconversion of the no-leaf coppice (NLC) achieved a 67% overall sugar recovery, showing no significant difference to mature whitewood from forestry plantation (WWF, 71%). The overall sugar yield of NLC was 135 kg/tonne less than that of WWF, due to the low inherent sugar content in original biomass. An economic analysis shows the minimum ethanol selling price required to cover the operating cost of NLC bioconversion was $1.69/gallon. CONCLUSIONS: Leaf removal resulted in significant improvement in overall monomeric sugar production from SRC biomass. Leaf removal is essential to achieve good yields in bioconversion of poplar. Economic analysis suggests the NLC could be a reasonable feedstock provided it can be obtained at a discounted price. PMID- 28592994 TI - Effects of global transcription factor NtcA on photosynthetic production of ethylene in recombinant Synechocystis sp. PCC 6803. AB - BACKGROUND: Cyanobacteria are considered potential photosynthetic microbial cell factories for biofuel and biochemical production. Ethylene, one of the most important organic chemicals, has been successfully synthesized in cyanobacteria by introducing an exogenous ethylene-forming enzyme (Efe). However, it remains challenging to significantly improve the biosynthetic efficiency of cyanobacterial ethylene. Genetic modification of transcription factors is a powerful strategy for reprogramming cellular metabolism toward target products. In cyanobacteria, nitrogen control A (NtcA), an important global transcription regulator of primary carbon/nitrogen metabolism, is expected to play a crucial role in ethylene biosynthesis. RESULTS: The partial deletion of ntcA (MH021) enhanced ethylene production by 23%, while ntcA overexpression (MH023) in a single-copy efe recombinant Synechocystis (XX76) reduced ethylene production by 26%. Compared to XX76, the Efe protein content increased 1.5-fold in MH021. This result may be due to the release of the negative regulation of NtcA on promoter P cpcB , which controls efe expression. Glycogen content showed a 23% reduction in MH021, and the ratio of intracellular succinate to 2-oxoglutarate (2-OG) increased 4.8-fold. In a four-copy efe recombinant strain with partially deleted ntcA and a modified tricarboxylic acid (TCA) cycle (MH043), a peak specific ethylene production rate of 2463 +/- 219 MUL L-1 h-1 OD730-1 was achieved, which is higher than previously reported. CONCLUSIONS: The effects of global transcription factor NtcA on ethylene synthesis in genetically engineered Synechocystis sp. PCC 6803 were evaluated, and the partial deletion of ntcA enhanced ethylene production in both single-copy and multi-copy efe recombinant Synechocystis strains. Increased Efe expression, accelerated TCA cycling, and redirected carbon flux from glycogen probably account for this improvement. The results show great potential for improving ethylene synthetic efficiency in cyanobacteria by modulating global regulation factors. PMID- 28592996 TI - Immune responses upon Campylobacter jejuni infection of secondary abiotic mice lacking nucleotide-oligomerization-domain-2. AB - BACKGROUND: Campylobacter jejuni infections are of rising importance worldwide. Given that innate immune receptors including nucleotide-oligomerization-domain-2 (Nod2) are essentially involved in combating enteropathogenic infections, we here surveyed the impact of Nod2 in murine campylobacteriosis. METHODS AND RESULTS: In order to overcome physiological colonization resistance preventing from C. jejuni infection, we generated secondary abiotic Nod2-/- and wildtype (WT) mice by broad spectrum antibiotic treatment. Mice were then perorally infected with C. jejuni strain 81-176 on 2 consecutive days and could be stably colonized by the pathogen at high loads. Notably, Nod2 deficiency did not affect gastrointestinal colonization properties of C. jejuni. Despite high intestinal pathogenic burdens mice were virtually uncompromised and exhibited fecal blood in single cases only. At day 7 postinfection (p.i.) similar increases in numbers of colonic epithelial apoptotic cells could be observed in mice of either genotype, whereas C. jejuni infected Nod2-/- mice displayed more distinct regenerative properties in the colon than WT controls. C. jejuni infection was accompanied by increases in distinct immune cell populations such as T lymphocytes and regulatory T cells in mice of either genotype. Increases in T lymphocytes, however, were less pronounced in large intestines of Nod2-/- mice at day 7 p.i. when compared to WT mice, whereas colonic numbers of B lymphocytes were elevated in WT controls only upon C. jejuni infection. At day 7 p.i., colonic pro-inflammatory mediators including nitric oxide, TNF, IFN-gamma and IL-22 increased more distinctly in Nod2-/- as compared to WT mice, whereas C. jejuni induced IL-23p19 and IL-18 levels were lower in the large intestines of the former. Converse to the colon, however, ileal concentrations of nitric oxide, TNF, IFN-gamma, IL-6 and IL-10 were lower in Nod2-/- as compared to WT mice at day 7 p.i. Even though MUC2 was down-regulated in C. jejuni infected Nod2-/- mice, this did not result in increased pathogenic translocation from the intestinal tract to extra-intestinal compartments. CONCLUSION: In secondary abiotic mice, Nod2 signaling is involved in the orchestrated host immune responses upon C. jejuni infection, but does not control pathogen loads in the gastrointestinal tract. PMID- 28592995 TI - The quest for epigenetic regulation underlying unisexual flower development in Cucumis melo. AB - BACKGROUND: Melon (Cucumis melo) is an important vegetable crop from the Cucurbitaceae family and a reference model specie for sex determination, fruit ripening and vascular fluxes studies. Nevertheless, the nature and role of its epigenome in gene expression regulation and more specifically in sex determination remains largely unknown. RESULTS: We have investigated genome wide H3K27me3 and H3K9ac histone modifications and gene expression dynamics, in five melon organs. H3K9ac and H3K27me3 were mainly distributed along gene-rich regions and constrained to gene bodies. H3K9ac was preferentially located at the TSS, whereas H3K27me3 distributed uniformly from TSS to TES. As observed in other species, H3K9ac and H3K27me3 correlated with high and low gene expression levels, respectively. Comparative analyses of unisexual flowers pointed out sex-specific epigenetic states of TFs involved in ethylene response and flower development. Chip-qPCR analysis of laser dissected carpel and stamina primordia, revealed sex specific histone modification of MADS-box genes. Using sex transition mutants, we demonstrated that the female promoting gene, CmACS11, represses the expression of the male promoting gene CmWIP1 via deposition of H3K27me3. CONCLUSIONS: Our findings reveal the organ-specific landscapes of H3K9ac and H3K27me3 in melon. Our results also provide evidence that the sex determination genes recruit histone modifiers to orchestrate unisexual flower development in monoecious species. PMID- 28592998 TI - The use of lung ultrasound images for the differential diagnosis of pulmonary and cardiac interstitial pathology. AB - In recent years, great advances have been made in the use of lung ultrasound to detect pulmonary edema and interstitial changes in the lung. However, it is clear that B-lines oversimplify the description of the physical phenomena associated with their presence. The artifactual images that ultrasounds provide in interstitial pulmonary pathology are merely the ultimate outcome of the complex interaction of a specific acoustic wave with a specific three-dimensional biological structure. This interaction lacks a solid physical interpretation of the acoustic signs to support it. The aim of this paper was to describe the differences between the sonographic interstitial syndrome related to lung diseases and that related to cardiogenic edema in the light of current knowledge regarding the pleural plane's response to ultrasound waves. PMID- 28592997 TI - Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome. AB - BACKGROUND: A small percentage of people with autism spectrum disorders (ASD) have alterations in chromosome 15q11.2-q3, the critical region for Prader-Willi syndrome (PWS). Data are limited, however, on the rates and characteristics of ASD in PWS. Previous estimates of ASD in PWS (25 to 41%) are questionable as they are based solely on autism screeners given to parents. Inaccurate diagnoses of ASD in PWS can mislead intervention and future research. METHODS: One hundred forty-six children and youth with PWS aged 4 to 21 years (M = 11) were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). An expert clinical team-made best-estimate ASD diagnoses based on ADOS-2 videotapes, calibrated severity scores, and children's developmental histories and indices of current functioning. Children were also administered the Kaufman Brief Intelligence Test 2, and parents completed the Repetitive Behavior Scale-Revised and Vineland Adaptive Behavior Scales. Scores were compared across children with PWS + ASD versus PWS only. The performance of an ASD screener, the Social Communication Questionnaire (SCQ) and the ADOS-2 were evaluated in relation to best-estimate diagnoses. RESULTS: Best-estimate diagnoses of ASD were made in 18 children, or 12.3% of the sample, and the majority of them had the maternal uniparental disomy (mUPD) PWS genetic subtype. Compared to the PWS-only group, children with PWS + ASD had lower verbal and composite IQ's and adaptive daily living and socialization skills, as well as elevated stereotypies and restricted interests. Regardless of ASD status, compulsivity and insistence on sameness in routines or events were seen in 76-100% of children and were robustly correlated with lower adaptive functioning. The SCQ yielded a 29-49% chance that screen-positive cases will indeed have ASD. The ADOS-2 had higher sensitivity, specificity and predictive values. Communication problems were seen in children who were ADOS-2 positive but deemed not to have ASD by the clinical team. CONCLUSIONS: Autism screeners should not be the sole index of probable ASD in PWS; children need to be directly observed and evaluated. Compulsivity and insistence on sameness are salient in PWS and likely impede adaptive functioning. Most children with PWS only evidenced sub-threshold problems in social interactions that could signal risks for other psychopathologies. PMID- 28593000 TI - Ultrasound and EMG-NCV study (electromyography and nerve conduction velocity) correlation in diagnosis of nerve pathologies. AB - PURPOSE: Nerve disorders are commonly encountered in clinical practice. Ultrasonography (USG) is a useful modality in the evaluation of most of the peripheral and superficial pathologies amenable to penetration by ultrasound. The primary objective is to study the USG findings of various peripheral nerve pathologies and to correlate them with electrophysiological (EMG-NCV) findings. METHOD: 42 patients referred with suspicion of peripheral nervous system affection were evaluated with USG along with EMG-NCV. After reviewing detailed anatomy of the region, the affected nerve was visualized along the major neurovascular bundle or at a known anatomical landmark with a high-frequency (9 20 MHz) linear/hockey stick transducer. RESULTS: The USG parameters, namely loss of fibrillary pattern, hypoechogenicity and nerve thickening, showed significant p value (p < 0.05) on the tests of significance, suggesting these parameters are significant predictors of nerve affection/pathology on USG. Each ultrasound parameter was correlated individually with SNAP and CMAP. The results revealed positive correlation of echogenicity (r = 0.210, p = 0.05), fibrillary pattern (r = 0.209, p = 0.05) and thickening (r = 0.387, p < 0.05) with sensory nerve action potential (SNAP) and compound muscle action potential (CMAP). CONCLUSION: USG can be used as corroborative investigation to strengthen the findings of EMG-NCV. This combination represents a powerful tool in enabling appropriate planning for treatment, preventing unnecessary intervention and thus improving overall outcomes in patients with peripheral neuropathy. PMID- 28593001 TI - Teaching echoscopy for the early diagnosis of ascites in cirrhosis: assessment of an objective structured clinical examination (OSCE). AB - INTRODUCTION: We assessed the efficacy of a brief, 8-h teaching program, using an objective structured clinical examination (OSCE) for the use of a pocket ultrasound device (echoscope) focused on bed side diagnosis of subclinical ascites in chronic liver disease. PATIENTS AND METHODS: Ten cirrhotic patients, five with subclinical ascites and five without, were selected during ultrasound examination performed with a high performance equipment for screening of hepatocellular carcinoma. Five post graduate medical doctors residents in Gastroenterology or Internal Medicine underwent a brief, 8-h theoretical and hands-on examinations training. The methodology to assess the correct competence consisted in two phases defined by actions and answers to questions. RESULTS: The evaluation of the technical efficacy was positive in all five students. The diagnostic efficacy for the ten patients examined consisted in no false positive diagnosis of ascites and one false negative. CONCLUSIONS: In this preliminary experience, the use of a pocket ultrasound device (echoscope) for diagnosis of subclinical ascites in the context of a short structured teaching program and examination was efficient. PMID- 28592999 TI - Contrast-enhanced ultrasound of the carotid system: a review of the current literature. AB - Carotid disease is a major current health problem accounting for a significant part of stroke patients. Ultrasound with colour Doppler and spectral analysis is the primary imaging technique used for screening and diagnostic evaluation of the extracranial part of carotid arteries offering identification and grading of carotid disease. However, inherent limitations of this technique include flow related artefacts like Doppler angle dependence and aliasing artefact which may sometimes hinder complete assessment of a stenotic part of the vessel, potentially failing to address clinically significant differential diagnosis issues. The intravenous use of microbubbles as an US contrast agent has been introduced for the supplementation of conventional technique. The value of contrast-enhanced ultrasound (CEUS) has been investigated in the evaluation of carotid disease leading to promising results. CEUS provides improved flow visualization free of artefacts and detailed plaque surface delineation, thus being able to accurately grade stenosis, identify carotid plaque ulcerations, differentiate occlusion from highly stenotic plaques and identify carotid dissection. Furthermore, microbubbles can be used to identify and grade intraplaque neovascularization, carotid wall inflammation in patients with arteritis, follow-up patients after carotid intervention and assist interventional procedures reducing the need for nephrotoxic contrast agents. The purpose of this review is to present and discuss the current literature regarding the various uses of CEUS in carotid arteries. PMID- 28593002 TI - Management and outcomes of cystic hygromas: experience of a tertiary center. AB - PURPOSE: Cystic hygroma (CH) is a fetal sonographic finding with an incidence of 1%. Chromosomal abnormalities and structural malformations are commonly related with CH. We aimed to describe our experience and determine the association between diagnosis of CH and adverse pregnancy outcome. METHODS: We retrospectively reviewed data of prenatal CH diagnoses over a ten-year period. Cases were evaluated for maternal age, gestational week at CH diagnosis, invasive procedure, karyotype result, associated abnormality and perinatal outcome. We categorized cases into two groups to understand the impact of maternal age on perinatal outcomes, and the cut-off was 35 years old. RESULTS: Totally 28 individuals were enrolled in the study. The median maternal age at birth was 27.5 years old, and 7 patients were over 35 years old. Karyotype results were available for all individuals, and 15 had an abnormal chromosome (53.5%). Five fetuses had structural abnormalities, and they were all observed within patients under 35 years old. Healthy fetuses (without any problem at antenatal screening and birth) were found to be only 14.3% in advanced maternal age (AMA) group and 33.3% in young mothers. CONCLUSIONS: Women with AMA and CH had a higher risk of having a baby with a chromosomal abnormality, as compared with younger women. PMID- 28593003 TI - Focused cardiac ultrasound (FOCUS) by emergency medicine residents in patients with suspected cardiovascular diseases. AB - INTRODUCTION: Few studies have assessed the value and accuracy of focused cardiac ultrasound (FOCUS) performed by emergency physicians. The aim of the present study was to evaluate the diagnostic accuracy of FOCUS performed by emergency medicine residents compared to echocardiography performed by a cardiologist in emergency department (ED) patients suspected of cardiovascular disease. METHODS: The research involved a prospective observational cross-sectional study enrolling patients over 18-years old suspected of having cardiovascular disease who required an echocardiograph. For each patient, a FOCUS test was conducted by a trained emergency medicine resident. The diagnostic accuracy of ED performed FOCUS was compared to echocardiography performed by a cardiologist (gold standard) in the ED. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios were calculated for FOCUS. The agreement of EM residents and cardiologists on each finding was evaluated using Cohen's kappa coefficient with 95% CI. RESULTS: Two hundred and five patients, with a mean age of 61.0 +/- 17 years (50% male), were included in this study. Agreement between FOCUS performed by an emergency medicine resident and echocardiography performed by a cardiologist in measuring ejection fraction of the left ventricle was 91% (kappa = 0.85; 95% CI = 0.79-0.91). Reports of the two groups for identifying right ventricular enlargement showed 96% agreement (kappa = 0.86; 95% CI = 0.82 0.90). The agreements for right ventricular pressure overload, wall motion abnormality and pericardial effusion were 100% (kappa = 0.83; 95% CI = 0.77 0.89), 92% (kappa = 0.83; 95% CI = 0.76-0.90), and 96% (kappa = 0.83; 95% CI = 0.77-0.89), respectively. CONCLUSION: FOCUS performed by emergency medicine residents is comparable to echocardiography performed by cardiologists. Therefore, it could be a reliable tool and screening test for initial testing of patients suspected of cardiac abnormalities. PMID- 28593005 TI - Real-time elastography in Crohn's disease: feasibility in daily clinical practice. AB - Ultrasound (US) is the first-line investigation in patients with abdominal symptoms and it has a role in the diagnosis and monitoring of inflammatory bowel diseases. Strain elastography (SE) is a US method for estimating tissue elasticity. This method is still not routinely used in clinical practice, although it is suggested by the EFSUMB Guidelines for the characterization of intestinal stenosis in Crohn's disease. The purpose of this Pictorial Essay is to confirm the feasibility of elastography in Crohn's disease in clinical practice by comparing elastography images with corresponding endoscopic or radiological images. At present, diagnostic accuracy of SE is reported in the literature only in connection with detection of bowel wall fibrosis in advanced cases of Crohn's disease. However, in our opinion, SE can add useful diagnostic information to grayscale and color Doppler US by providing a more accurate characterization of the bowel wall in the various manifestations of Crohn's disease. PMID- 28593006 TI - Ultrasound detection of aortoenteric fistula in a patient with sepsis. AB - We report a case of an 81-year-old man, hospitalized for sepsis unresponsive to targeted antibiotic therapy, who underwent abdominal aortic aneurysmectomy with stent placement before 12 years. Point-of-care ultrasound examination showed the presence of a voluminous and inhomogeneous lesion adjacent to the anterior wall of aortic bifurcation with pulsatile flow from the aorta into the lesion, highlighted by Color-Doppler, and peripheral (closely with intestinal loops) floating hyperechoic spots marked by posterior comet tail artifact, suggestive for the presence of air bubbles. The presence of an aortoenteric fistula not excluding in differential diagnosis and the possibility of an abscess of aneurysmatic sac with colonization of gas-producing bacteria were suspected; an abdominal contrast-enhanced computed tomography was requested and it confirmed the suspicion of an aortoenteric fistula. The patient underwent emergency surgical intervention with good technical success (evidence of aorto-appendicular fistula), but he died the day after of cardiac arrest. PMID- 28593004 TI - Influence of subjects' characteristics and technical variables on muscle stiffness measured by shear wave elastosonography. AB - PURPOSE: The aim of this study is to quantitatively assess lower limbs muscle elasticity in a court of healthy subjects and to evaluate the influence of technical variables (e.g., diameter of the ROI-region of interest) and examined subjects' characteristics (e.g., sex, levels of physical activity, side evaluated) on muscle stiffness. MATERIALS AND METHODS: 54 healthy subjects (48 men, 6 women) were evaluated for a total of 108 lower limbs. Shear wave elastography was performed with a multifrequency linear probe (15-4 MHz). Two radiologists performed the evaluation of lower limbs from left to right side (first calf and then thigh). The measures were taken on gastrocnemius and on femoral biceps muscle belly. We chose to place for this study two ROIs of 4 and 2 mm of diameter. RESULTS: The mean muscle stiffness was 1.98 +/- 0.48 (range between 1.89 +/- 0.36 and 2.15 +/- 0.57 m/s). The difference in muscle stiffness between left and right side of the body and between different levels of physical activity never became statistically significant (p value between 0.314 and 0.915). Only in one test out of eight the difference of muscle stiffness between male and female resulted statistically significant (p value 0.020). When comparing the measurement obtained with a 2 and 4 mm diameter ROIs the values were statistically different only for the left thigh (p value 0.028). CONCLUSION: Our study, despite its limitations (low sample and low female population), seems to give some clear advice: physiological or technical factors do not determine statistically significant differences on passive muscle stiffness. PMID- 28593007 TI - Case report: acute portal vein thrombosis associated with acute cytomegalovirus infection in an immunocompetent adult. AB - Cytomegalovirus (CMV) infection is usually asymptomatic and self-limiting in healthy individuals, but significant complications can develop in immunosuppressed patients. Venous or arterial thromboembolic phenomena are uncommon yet very serious complications of CMV infection. Most published reports describe immunosuppressed patients, but thrombotic events in CMV-infected immunocompetent individuals may also occur. We describe the case of an immunocompetent young man with acute CMV hepatitis that was complicated with portal vein thrombosis (PVT). We also review the literature regarding the association between PVT and CMV in immunocompetent patients. Thromboembolism is an underestimated but significant complication of acute CMV infection. Several local and systemic factors are involved in the pathogenesis of acute PVT. This case emphasizes the central role of ultrasound in its diagnosis and the potentially serious complications that can occur in immunocompetent individuals with no other prothrombotic risk factors. PMID- 28593008 TI - Meckel-Gruber syndrome: ultrasonographic and fetal autopsy correlation. AB - Meckel-Gruber syndrome (MGS) is a rare autosomal recessive disorder which is characterized by a classic triad of occipital encephalocele, polycystic kidneys and postaxial polydactyly. We describe a case of classic MGS, diagnosed on ultrasonography and genetic analysis, with subsequent confirmation and correlation by fetal autopsy. PMID- 28593010 TI - Superb microvascular imaging: a potential tool in the detection of FNH. PMID- 28593011 TI - Pesticide exposure and subjective symptoms of cut-flower farmers. AB - Sales of cut-flowers depend much on the outer appearance of the flowers. They are not intended to be used as foodstuffs; thus, pesticides are used more liberally for cut flower growing than for other agricultural products. Flower production is often carried out in greenhouses; therefore, pesticide exposure seems to reach not only the person spraying the pesticides, but also the non-spraying workers as well. In 2009, a special research project on pesticide poisoning, affiliated with the Japanese Association of Rural Medicine, developed a study that focused on cut flower farmers' exposure to pesticide, subsequent adverse symptoms experienced, and treatment modalities to relieve pesticide-related symptoms. In this group of farmers, the pesticide sprayers were almost entirely male, while the females did not do any spraying. The organophosphate metabolite level in the urine of the males was higher than that of the females. However, in the female group, a positive relation was found between average working times in the greenhouse, and urine concentration of dialkylphosphates. In 2 males of this group, the level of dimethylphosphate was detected at 1,000 times the median level. Their butyrylcholinesterase activity levels on the day of testing had declined to 64%, 72% of their average level of the proximate 4 years, respectively. Communication with these subjects regarding pesticide exposure and methods of prevention appeared to be an effective approach for reducing symptom severity. Among soil fumigants, chloropicrin and 1,3-dichloropropene were most often used. Difficulty breathing was one of the subjective symptoms associated with chloropicrin, as well as watery eyes, coughing, and runny nose. These symptoms were effectively suppressed by the preventative practice of wearing gas masks and goggles while using soil fumigants. It would be beneficial to strongly encourage use of suitable protective gear among farmers exposed to soil fumigants. PMID- 28593009 TI - Ultrasound as point of care in management of polytrauma and its complication. AB - PURPOSE: Traumatic injuries constitute a major risk for patients in emergency units. Point-of-care ultrasound may be a determinant in reducing the deleterious impact of complications and in prognosis. METHODS: We describe the case of a 28 year-old female who reported cranial trauma, abdominal and thoracic trauma, and suspected bilateral fracture of the femur. RESULTS: Ultrasound was useful for evaluating and monitoring multiple organ failure. CONCLUSION: Combining cost effective advantages with bedside real-time imaging, ultrasound is a powerful adjunct to standard clinical assessment in the management of polytrauma when it is administered at the point of care. PMID- 28593013 TI - Emotional and instrumental support influencing male caregivers for people with dementia living at home. AB - Object: To clarify the emotional and instrumental support influencing male caregivers for people with dementia living at home. Patients/Materials and Methods: The subjects were 298 male caregivers. Nursing care burden was assessed using the Zarit Caregiver Burden Scale. Ability to cope with care problems was assessed using the Nursing Care Problems Coping Scale for Male Caregivers for People with Dementia Living at Home (NCSM). Emotional support was assessed using the Emotional Support Network Scale. Instrumental support was assessed using the question "Do you have someone to help when you have a problem with nursing care?". Results: There was a significant correlation (P < 0.04) between the point (index) of NCSM and Zarit Caregiver Burden Scale. A positive significant correlation was found in three coping styles. A negative significant correlation was found in one coping style, and no significant correlation in one coping style. The 'Solve the problem' coping style was linked to support from both within and beyond the family. Both 'Emotional avoidance' and 'Cognitive transformation' coping styles were linked to support from within the family, and "Request assistance" style only to external support. There were no correlations between the source of support and the "Careful supervision and waiting" coping style. Conclusion: Emotional and instrumental support for male caregivers was more than three times more likely to be obtained from within the family than outside it. With families becoming smaller, it is becoming more important for communities and society in general to provide emotional and instrumental support for male caregivers. Male caregivers need support from someone with whom they feel comfortable. It is particularly necessary to consider how to support male caregivers who use the "Emotional avoidance" coping style. PMID- 28593012 TI - Potential benefit of physician-staffed helicopter emergency medical service for regional trauma care system activation: An observational study in rural Japan. AB - Objective: Involvement of all regional medical facilities in a trauma system is challenging in rural regions. We hypothesized that the physician-staffed helicopter emergency medical service potentially encouraged local facilities to participate in trauma systems by providing the transport of patients with trauma to those facilities in a rural setting. Materials and Methods: We performed two retrospective observational studies. First, yearly changes in the numbers of patients with trauma and destination facilities were surveyed using records from the Miyazaki physician-staffed helicopter emergency medical service from April 2012 to March 2014. Second, we obtained data from medical records regarding the mechanism of injury, severity of injury, resuscitative interventions performed within 24 h after admission, secondary transports owing to undertriage by attending physicians, and deaths resulting from potentially preventable causes. Data from patients transported to the designated trauma center and those transported to non-designated trauma centers in Miyazaki were compared. Results: In total, 524 patients were included. The number of patients transported to non designated trauma centers and the number of non-designated trauma centers receiving patients increased after the second year. We surveyed 469 patient medical records (90%). There were 194 patients with major injuries (41%) and 104 patients with multiple injuries (22%), and 185 patients (39%) received resuscitative interventions. The designated trauma centers received many more patients with trauma (366 vs. 103), including many more patients with major injuries (47% vs. 21%, p < 0.01) and multiple injuries (25% vs. 13%, p < 0.01), than the non-designated trauma centers. The number of patients with major injuries and patients who received resuscitative interventions increased for non designated trauma centers after the second year. There were 9 secondary transports and 26 deaths. None of these secondary transports resulted from undertriage by staff physicians and none of these deaths resulted from potentially preventable causes. Conclusion: The rural physician-staffed helicopter emergency medical service potentially encouraged non-designated trauma centers to participate in trauma systems while maintaining patient safety. PMID- 28593015 TI - Target range of motion for rehabilitation after total knee arthroplasty. AB - Objective: Postoperative knee range of motion (ROM) is among the most important factors influencing patient satisfaction after total knee arthroplasty (TKA). The purpose of this study was to clarify the time course of improvement in knee ROM up to 12 months after TKA, including intraoperative knee ROM after implantation, and to clarify a target ROM for rehabilitation after TKA. Patients and Methods: In total, 39 knee joints in 26 patients with osteoarthritis who underwent TKA (retaining the posterior cruciate ligament) were evaluated. Goniometry was used to measure the knee range of extension and flexion preoperatively; intraoperatively; at 1 and 2 weeks after TKA; and then at 1, 3, 6, and 12 months after TKA. Results: The postoperative extension range gradually improved up to a maximum at 6 months after TKA; there were no significant differences in the extension range between intraoperative and 6 months after TKA, intraoperative and 12 months after TKA, or 6 and 12 months after TKA. The postoperative flexion range gradually improved, with the maximum improvement observed at 3 months after TKA; there were no significant differences in the flexion range before TKA and 3, 6, and 12 months after TKA. There were no significant differences between flexion ROM measured at 3, 6, and 12 months after TKA. Conclusions: The changes in the knee range of extension plateaued 6 months after TKA, and those in the knee range of flexion plateaued 3 months after TKA. The target range of extension for rehabilitation from 6 months to 12 months after TKA was the intraoperative range, and the target range of flexion for rehabilitation from 3 months to 12 months after TKA was the preoperative range. PMID- 28593014 TI - A qualitative study on barriers to achieving high-quality, community-based integrated dementia care. AB - Introduction: High-quality, community-based dementia care requires a comprehensive, holistic approach. This study aimed to identify the barriers to achieving efficient cooperation and coordination among medical professionals, care managers, and medical social workers, and to improve the management model of community-based, integrated dementia care. Methods: We collected qualitative data through three focus group discussions at JA Konan Kosei Hospital. Thirteen participants (four directors of nursing service departments, three chief nurses, four medical social workers, and two care managers) were recruited for the discussions. The data were analyzed using an inductive, multi-step approach referred to as the qualitative content analysis. Results: Nine themes arose as follows: little attention given to patient wishes, lack of time and space to provide high-quality care, disturbing hospital environment, poor compensation for staff members, refusing to visit outpatient clinics, declined admission, daily life support by family members and caregivers, dementia care team, and community bonding. Conclusion: The participants wanted to launch a dementia care team in their hospital to improve the care environment and the quality of dementia specific care. The study also suggested that advance care planning could be systematically implemented in clinical practice as a way to honor the decisions made by dementia patients. PMID- 28593016 TI - Associations among anthropometric measures, food consumption, and quality of life in school-age children in Tanzania. AB - Objectives: The factors associated with quality of life (QOL) and anthropometric measurements as outcomes of food consumption were examined among school-age children in Tanzania. Methods: A cross-sectional study was undertaken in September 2013 in Tanzania. Anonymous self-administered questionnaire surveys were conducted in the Kiswahili language among primary school children in the fifth and/or sixth grade aged 10-14 years. The survey probed sociodemographic characteristics such as age, gender, living with family members, number of meals/snacks per day, food consumption in the previous 24 hours, and QOL, as well as anthropometric measurements (height and weight). The Rohrer index was calculated based on height and weight. After presenting the mean and standard deviation (SD) of height, weight, and the Rohrer index score by age and gender, the Rohrer index score was categorized into three groups (low weight, normal weight, and overweight) and analyzed according to sociodemographic characteristics and food consumption using the chi-square test. Furthermore, the QOL score was analyzed using the t test. Multivariate linear regression analysis was used to analyze the associations between the QOL score and sociodemographic characteristics and food consumption. Results: A total of 694 children (male: 312; female: 382) participated in this study. According to the Rohrer index, 273 (39.3%) children were classified as low weight, 353 (50.9%) were normal weight, and 68 (9.8%) were overweight. A total of 459 (66.1%) children reported having had three or more meals and/or snacks on the day before the study. In addition, 127 (18.3%) children had not eaten any protein-rich food on the day before the study, although almost all had eaten at least one carbohydrate-rich food per day. Regardless of region, location, gender, and age, living without parents was associated with short stature (P = 0.010). A high QOL score was associated with having three or more meals and/or snacks per day (P < 0.001). Conclusions: The security of physiological needs such as a guarantee of three meals per day could contribute to higher QOL among underserved children. PMID- 28593017 TI - The rendezvous technique involving insertion of a guidewire in a percutaneous transhepatic gallbladder drainage tube for biliary access in a case of difficult biliary cannulation. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is a diagnostic method and treatment approach for biliary diseases. However, biliary cannulation can be difficult in some cases. We performed ERCP in a 97-year-old woman with abdominal pain resulting from acute cholangitis caused by choledocholithiasis and observed difficult biliary cannulation. Eventually, the patient was successfully treated with the rendezvous technique. We could not cannulate the biliary duct during ERCP twice. Therefore, we placed a percutaneous transhepatic gallbladder drainage (PTGBD) tube without intrahepatic dilation. The rendezvous technique was performed using the PTGBD tube. The patient did not experience pancreatitis or perforation. PMID- 28593018 TI - Rheumatoid arthritis following ciguatera poisoning: A case report. AB - Objective: To report the first case of ciguatera-associated rheumatoid arthritis in Japan. Patient: A 53-year-old man presented to our clinic with morning stiffness and pain in the fingers and wrists. Results: For six months, he had suffered from chronic pain in both hands and shoulders caused by ciguatera poisoning. He was referred to a local general hospital and diagnosed with RA. Conclusion: When synovitis becomes evident in chronic ciguatera poisoning, reevaluation is necessary, including investigation of chronic arthritis, which might be associated with the onset of RA. PMID- 28593019 TI - Rural physicians' scope of practice on remote islands: A case report of severe pneumonia that required overnight artificial airway management. AB - Objective: To clarify the scope of practice on rural islands of Okinawa. Patient: A 59-year-old man presented to our clinic with shortness of breath. He was intubated due to acute respiratory failure caused by severe pneumonia. We could not transfer him owing to bad weather, and had to continue patient care in the clinic for more than 24 hours. Discussion: In remote regions, rural physicians may require a broad scope of practice from primary to tertiary care, in addition to preventive and end-of-life care. Conclusion: This case illustrates the current state of emergency care and unique scope of practice on rural islands of Okinawa. PMID- 28593020 TI - Corrigendum to "Basic Fibroblast Growth Factor Inhibits Apoptosis and Promotes Proliferation of Adipose-Derived Mesenchymal Stromal Cells Isolated from Patients with Type 2 Diabetes by Reducing Cellular Oxidative Stress". AB - [This corrects the article DOI: 10.1155/2017/3027109.]. PMID- 28593022 TI - MicroRNA Regulation of Oxidative Stress-Induced Cellular Senescence. AB - Aging is a time-related process of functional deterioration at cellular, tissue, organelle, and organismal level that ultimately brings life to end. Cellular senescence, a state of permanent cell growth arrest in response to cellular stress, is believed to be the driver of the aging process and age-related disorders. The free radical theory of aging, referred to as oxidative stress (OS) theory below, is one of the most studied aging promoting mechanisms. In addition, genetics and epigenetics also play large roles in accelerating and/or delaying the onset of aging and aging-related diseases. Among various epigenetic events, microRNAs (miRNAs) turned out to be important players in controlling OS, aging, and cellular senescence. miRNAs can generate rapid and reversible responses and, therefore, are ideal players for mediating an adaptive response against stress through their capacity to fine-tune gene expression. However, the importance of miRNAs in regulating OS in the context of aging and cellular senescence is largely unknown. The purpose of our article is to highlight recent advancements in the regulatory role of miRNAs in OS-induced cellular senescence. PMID- 28593021 TI - Tissue- and Condition-Specific Isoforms of Mammalian Cytochrome c Oxidase Subunits: From Function to Human Disease. AB - Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain and catalyzes the transfer of electrons from cytochrome c to oxygen. COX consists of 14 subunits, three and eleven encoded, respectively, by the mitochondrial and nuclear DNA. Tissue- and condition-specific isoforms have only been reported for COX but not for the other oxidative phosphorylation complexes, suggesting a fundamental requirement to fine-tune and regulate the essentially irreversible reaction catalyzed by COX. This article briefly discusses the assembly of COX in mammals and then reviews the functions of the six nuclear-encoded COX subunits that are expressed as isoforms in specialized tissues including those of the liver, heart and skeletal muscle, lung, and testes: COX IV-1, COX IV-2, NDUFA4, NDUFA4L2, COX VIaL, COX VIaH, COX VIb-1, COX VIb-2, COX VIIaH, COX VIIaL, COX VIIaR, COX VIIIH/L, and COX VIII-3. We propose a model in which the isoforms mediate the interconnected regulation of COX by (1) adjusting basal enzyme activity to mitochondrial capacity of a given tissue; (2) allosteric regulation to adjust energy production to need; (3) altering proton pumping efficiency under certain conditions, contributing to thermogenesis; (4) providing a platform for tissue-specific signaling; (5) stabilizing the COX dimer; and (6) modulating supercomplex formation. PMID- 28593023 TI - Mechanisms Underlying the Essential Role of Mitochondrial Membrane Lipids in Yeast Chronological Aging. AB - The functional state of mitochondria is vital to cellular and organismal aging in eukaryotes across phyla. Studies in the yeast Saccharomyces cerevisiae have provided evidence that age-related changes in some aspects of mitochondrial functionality can create certain molecular signals. These signals can then define the rate of cellular aging by altering unidirectional and bidirectional communications between mitochondria and other organelles. Several aspects of mitochondrial functionality are known to impact the replicative and/or chronological modes of yeast aging. They include mitochondrial electron transport, membrane potential, reactive oxygen species, and protein synthesis and proteostasis, as well as mitochondrial synthesis of iron-sulfur clusters, amino acids, and NADPH. Our recent findings have revealed that the composition of mitochondrial membrane lipids is one of the key aspects of mitochondrial functionality affecting yeast chronological aging. We demonstrated that exogenously added lithocholic bile acid can delay chronological aging in yeast because it elicits specific changes in mitochondrial membrane lipids. These changes allow mitochondria to operate as signaling platforms that delay yeast chronological aging by orchestrating an institution and maintenance of a distinct cellular pattern. In this review, we discuss molecular and cellular mechanisms underlying the essential role of mitochondrial membrane lipids in yeast chronological aging. PMID- 28593025 TI - Ziziphus nummularia Inhibits Inflammation-Induced Atherogenic Phenotype of Human Aortic Smooth Muscle Cells. AB - Cardiovascular disease (CVD) continues to be the leading cause of death worldwide. Atherosclerosis is a CVD characterized by plaque formation resulting from inflammation-induced insults to endothelial cells, monocytes, and vascular smooth muscle cells (VSMCs). Despite significant advances, current treatments for atherosclerosis remain insufficient, prompting the search for alternative modalities, including herbal medicine. Ziziphus nummularia is an herb commonly used in the amelioration of symptoms associated with many health conditions such as cold, diarrhea, cancer, and diabetes. However, its effect on the inflammation induced behavior of VSMCs remains unknown. In this study, we sought to determine the effect of the ethanolic extract of Z. nummularia (ZNE) on TNF-alpha-induced phenotypic changes of human aortic smooth muscle cells (HASMCs). The treatment of HASMCs with ZNE decreased cell proliferation, adhesion to fibronectin, migration, and invasion. ZNE treatment also caused a concentration- and time-dependent reduction in the TNF-alpha-induced expression of matrix metalloproteases MMP-2 and MMP-9, NF-kappaB, and cell adhesion molecules ICAM-1 and VCAM-1. Furthermore, ZNE decreased the adhesion of THP-1 monocytes to HASMCs and endothelial cells in a concentration-dependent manner. These data provide evidence for the anti inflammatory effect of Ziziphus nummularia, along with potential implications for its use as an agent that could ameliorate inflammation-induced atherogenic phenotype of VSMCs in atherosclerosis. PMID- 28593026 TI - Corrigendum to "(-)-Epicatechin Prevents Blood Pressure Increase and Reduces Locomotor Hyperactivity in Young Spontaneously Hypertensive Rats". AB - [This corrects the article DOI: 10.1155/2016/6949020.]. PMID- 28593024 TI - Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress. AB - Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol) in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies. PMID- 28593027 TI - Draft genome sequence of Desulfoplanes formicivorans Pf12BT, a sulfate-reducing bacterium of the family Desulfomicrobiaceae. AB - Desulfoplanes formicivorans strain Pf12BT is the type strain of the type species in the genus Desulfoplanes, which is the one of the genera in the family Desulfomicrobiaceae within the order Desulfovibrionales. This deltaproteobacterium was isolated from a blackish meromictic lake sediment. D. formicivorans strain Pf12BT is a Gram-negative, motile and sulfate-reducing bacterium. Cells of strain Pf12BT are characterized by possession of vibroid morphology and red fluorescent pigment. Here we describe the features, draft genome sequence and annotation of this organism, the sole species of the genus Desulfoplanes. The genome comprised 3,000,979 bp, 2,657 protein-coding genes and 58 RNA genes. PMID- 28593029 TI - ANATOMICAL GUIDED SEGMENTATION WITH NON-STATIONARY TISSUE CLASS DISTRIBUTIONS IN AN EXPECTATION-MAXIMIZATION FRAMEWORK. AB - High quality segmentation of brain MR images is a challenging task. To deal with this problem many automatic segmentation methods rely on atlas information of anatomical structures. We further investigate this line of research by introducing hierarchical representations of anatomical structures in an Expectation-Maximization framework. This new approach enables us to divide a complex segmentation scenario into less difficult sub-problems reducing the scenario's statistical complexity. We demonstrate the method's strength by segmenting a set of brain MR images into 31 different anatomical structures as well as comparing it to other methods. PMID- 28593030 TI - MONITORING SLOWLY EVOLVING TUMORS. AB - Change detection is a critical task in the diagnosis of many slowly evolving pathologies. This paper describes an approach that semi-automatically performs this task using longitudinal medical images. We are specifically interested in meningiomas, which experts often find difficult to monitor as the tumor evolution can be obscured by image artifacts. We test the method on synthetic data with known tumor growth as well as ten clinical data sets. We show that the results of our approach highly correlate with expert findings but seem to be less impacted by inter- and intra-rater variability. PMID- 28593028 TI - Genomics insights into production of 2-methylisoborneol and a putative cyanobactin by Planktothricoides sp. SR001. AB - Planktothricoides is a free-living filamentous cyanobacterium belonging to the order Oscillatoriales and the family Phormidiaceae, capable of forming bloom in fresh and brackish waters. A unicyanobacterial non-axenic culture dominated by Planktothricoides sp. SR001 was obtained from a freshwater reservoir in Singapore. The draft genome presented here is the first tropical freshwater Planktothricoides sp. ever sequenced. The genome of 7.0Mbp contains 5,776 genes predicted using the JGI IMG pipeline. The whole genome sequence allows identification of genes encoding for nitrogen-fixation, accessory photosynthetic pigments and biosynthesis of an off-flavor compound, 2-methylisoborneol, which has been experimentally verified here based on metabolite detection. In addition, strain SR001 genome contains an operon putatively involved in the production of a linear tripeptide cyanobactin related to viridisamide A and aeruginosamide, with the later known to possess anti-microbial or cytotoxic effect. PMID- 28593031 TI - COMBINING REGIONAL METRICS FOR DISEASE-RELATED BRAIN POPULATION ANALYSIS. AB - In this paper, we present a new metric combining regional measurements to improve image based population studies that use manifold learning techniques. These studies currently rely on a single score over the whole brain image domain. Thus, they require large amount of training data to uncover spatially complex variation in the whole brain impacted by diseases. We reduce the impact of this issue by first computing pairwise measurements in local regions separately and then combining regional measurements into a single pairwise metric. We apply the new metric to learn the manifold of ADNI data and evaluate the resulting morphological representation by fitting multiple linear regression models to the mini-mental state examination (MMSE) score. The regression models show that the morphological representations from the proposed metric achieves higher estimation accuracy of MMSE score compared to those from the conventional global scores. PMID- 28593032 TI - AUTO-ENCODING OF DISCRIMINATING MORPHOMETRY FROM CARDIAC MRI. AB - We propose a fully-automatic morphometric encoding targeted towards differentiating diseased from healthy cardiac MRI. Existing encodings rely on accurate segmentations of each scan. Segmentation generally includes labour intensive editing and increases the risk associated with intra- and inter-rater variability. Our morphometric framework only requires the segmentation of a template scan. This template is non-rigidly registered to the other scans. We then confine the resulting deformation maps to the regions outlined by the segmentations. We learn a manifold for each region and identify the most informative coordinates with respect to distinguishing diseased from healthy scans. Compared with volumetric measurements and a deformation-based score, this encoding is much more accurate in capturing morphometric patterns distinguishing healthy subjects from those with Tetralogy of Fallot, diastolic dysfunction, and hypertrophic cardiomyopathy. PMID- 28593033 TI - Acoustic Radiation Force of a Quasi-Gaussian Beam on an Elastic Sphere in a Fluid. AB - Acoustic radiation force has many applications. One of the related technologies is the ability to noninvasively expel stones from the kidney. To optimize the procedure it is important to develop theoretical approaches that can provide rapid calculations of the radiation force depending in stone size and elastic properties, together with ultrasound beam diameter, intensity, and frequency. We hypothesize that the radiation force nonmonotonically depends on the ratio between the acoustic beam width and stone diameter because of coupling between the acoustic wave in the fluid and shear waves in the stone. Testing this hypothesis by considering a spherical stone and a quasi-Gaussian beam was performed in the current work. The calculation of the radiation force was conducted for elastic spheres of two types. Dependence of the magnitude of the radiation force on the beam diameter at various fixed values of stone diameters was modeled. In addition to using real material properties, speed of shear wave in the stone was varied to reveal the importance of shear waves in the stone. It was found that the radiation force reaches its maximum at the beamwidth comparable to the stone diameter; the gain in the force magnitude can reach 40% in comparison with the case of a narrow beam. PMID- 28593036 TI - Disseminated and late metastatic disease from nasal pit leiomyosarcoma after radical surgical resection. Case report of a singular presentation of a rare disease. AB - BACKGROUND: Leiomyosarcoma of the head and neck is a rare cancer with high local aggressiveness. Radical surgery and adjuvant treatment offer the best chance for cure, nonetheless 5-years recurrence rate remains high. Despite international guidelines are available for soft tissue sarcomas, no recommendations are specifically endorsed for leiomyosarcoma of the head and neck, due to the rarity of its presentation and consequently scarcity of data on long-term outcome. CASE PRESENTATION: A 50-year old woman, operated 10 years before for leiomyosarcoma of the nasal pit and with negative 5-years follow-up, was admitted to our ward for impairment of the hepatic function. Total-body CT scan detected multiple localizations at lungs, kidneys, pancreas, bones, muscles, lymph nodes and thyroid. The pathologic report after lung biopsy confirmed the diagnosis of metastasis from leiomyosarcoma and the patients was scheduled for first line chemo-radiotherapy. CONCLUSIONS: Despite adequate primary treatment, distant and disseminated metastatic disease may be not excluded in leiomyosarcoma of the head and neck. PMID- 28593037 TI - Targeted approaches to improve outcomes for highest-cost patients. AB - Bash and colleagues, using data from Maccabi Healthcare Services, have documented increased cost and utilization attributable to patients with congestive heart failure (CHF). The CHF patients were older than the general population and had high rates of important comorbid conditions. While it is somewhat predictable that such a population would have higher healthcare utilization and costs, the extent of the difference was still surprising. Most CHF patients (78%) were hospitalized at least once, compared to only 21% of patients without CHF. CHF patients used dramatically more of every kind of health care, including physician visits, emergency department visits, and specialty care visits. In this paper, Bash and colleagues have provided essential information about the "cost epidemiology" of CHF patients in the Israeli context. This commentary places these results in a broader context of how "cost epidemiology" information can be translated into targeted programs to improve outcomes and costs for vulnerable populations. The commentary makes three key points. First, beyond showing the increased utilization and cost attributable to CHF, there is also a need to examine which patients within this broad category contribute most to these increased costs, and might therefore be targeted for enhanced services. Second, it is helpful to make a business case for intervening to improve outcomes with a subpopulation, focusing in particular on the return on investment from the standpoint of the payer. Finally, while Israeli health collectives have already deployed programs to improve outcomes in older and sicker patients, there may be a need to more precisely define important subpopulations based on social risk factors or particularly severe disease manifestations, and then target those subpopulations with tailored programs focused on their particular needs. PMID- 28593039 TI - Is it time for comprehensive geriatric assessment to move beyond primary care? The case for targeting medical sub-specialty practice. AB - Comprehensive geriatric assessment (CGA) as a consultative service for older adults with complex medical and psychosocial challenges has existed for decades. However, studies have often showed inconsistent acceptance and implementation of geriatric recommendations by primary care providers (PCPs) raising doubts about the overall benefits of CGA in this setting. Press and colleagues investigated the patient- and provider-related factors that affect recommendation implementation, and like previous studies, they too found similarly low rates of implementation. In this commentary, we acknowledge the perennial challenges that exist to improving the acceptance of CGA in primary care practice, and we suggest an alternative target: medical sub-specialty practice. By highlighting three medical sub-specialty fields (oncology, nephrology, and cardiology), which have demonstrated that CGA can be incorporated into their respective clinical practices, we argue that CGA may prove to have greater impact in these settings than in primary care. We also propose initial research steps that could further delineate the trends, outcomes, and next steps for such consultations. PMID- 28593038 TI - Comprehensive healthcare resource use among newly diagnosed congestive heart failure. AB - BACKGROUND: Congestive heart failure (CHF) is among the most common causes of hospital admissions and readmissions in the Western world. However, the burden of ambulatory care has not been as well investigated. The objective of this study was to assess the relative burden and direct medical costs of CHF including inpatient and outpatient care. METHODS: We used longitudinal clinical data from a two-million member health organization in Israel (Maccabi Healthcare Services) to identify adults with newly diagnosed CHF between January 2006 and December 2012, either in the in- or outpatient setting. Adults without CHF were age- and sex matched to CHF patients and healthcare utilization and all modes of healthcare costs were compared among them, excluding those in their last year of life. RESULTS: The burden posed by 6592 CHF patients was significantly (p < 0.001) larger than that of 32,960 matched controls. CHF patients had significantly higher rates of baseline comorbidity and healthcare utilization compared to non CHF controls. This was evident in all categories of healthcare services and expenses, including in- and outpatient visits, laboratory expenses, medication costs, among younger and older, men and women. Among those who incurred any healthcare costs, younger (45-64y) and older (65 + y) subjects with CHF were observed to have about 3.25 (95% CI: 2.96-3.56) and 2.08 (95% CI: 1.99-2.17) times the healthcare costs, respectively, compared to subjects without CHF after adjusting for patient characteristics. CONCLUSION: CHF is associated with an overall two- to three-fold higher cost of healthcare services depending on patient age, accounting for over half of all healthcare costs incurred by elderly CHF patients, and more than two-thirds of all costs among younger CHF patients. Observations of the large burden posed on one of the youngest societies in the developed world are profound, implicative of great opportunities to control the costs of CHF. Further research to understand how resource use impacts health outcomes and quality of care is warranted. PMID- 28593040 TI - The impact of penicillin allergy labels on antibiotic and health care use in primary care: a retrospective cohort study. AB - BACKGROUND: Suspected penicillin allergy (Pen-A) is often not verified by diagnostic testing. In third line penicillin allergy labels were associated with prescription of broad spectrum antibiotics, hospital stay duration and readmission. OBJECTIVE: Assess the impact of Pen-A labels on antibiotic and health care use in primary care. METHODS: A retrospective cohort study was conducted in primary care in the Utrecht area, the Netherlands. All patients registered with a penicillin allergy on 31 December 2013 were selected from the General Practitioner Network database. Each patient with a Pen-A label was matched for age, gender, follow-up period with three patients without Pen-A label. Risk (OR) of receiving a reserve and second choice antibiotic, number and type of antibiotics prescribed during follow-up and number of GP contacts were compared between the two cohorts. RESULTS: Of 196,440 patients, 1254 patients (0.6%) with a Pen-A label were identified and matched with 3756 patients without Pen-A label. Pen-A labels resulted in higher risk of receiving >=1 antibiotic prescription per year (OR 2.56, 95% CI 2.05-3.20), >=1 s choice antibiotic prescription per year (OR 2.21 95% CI 1.11-4.40), and >=4 GP contacts per year (OR 1.71 95% CI 1.46-2.00). The chance of receiving tetracyclins (OR 2.24, 95% CI 1.29-3.89), macrolides/lincosamides/streptogamins (OR 8.69, 95% CI 4.26-17.73) and quinolones (OR 2.59, 95% CI 1.22-5.48) was higher in Pen-A patients. CONCLUSIONS: In primary health care Pen-A labels are associated with increased antibiotic use, including second choice antibiotics, and more health care use. PMID- 28593041 TI - The biopsychosocial model and chiropractic: a commentary with recommendations for the chiropractic profession. AB - There is an increasing awareness, interest and acceptance of the biopsychosocial (BPS) model by all health care professionals involved with patient care. The areas of spine care and pain medicine are no exception, and in fact, these areas of health care are a major centerpiece of the movement from the traditional biomedical model to a BPS model of patient assessment and delivery of care. The chiropractic approach to health care has a history that is grounded in key aspects of the BPS model. The profession has inherently implemented certain features of the BPS model throughout its history, perhaps without a full understanding or realization. The purpose of this paper is to present an overview of the BPS model, its relationship with spine care and pain management, and to discuss the BPS model, particularly psychosocial aspects, in the context of its historical relationship with chiropractic. We will also provide recommendations for the chiropractic profession as it relates to successful adoption of a full integration of the BPS model. PMID- 28593042 TI - Challenges facing the veterinary profession in Ireland: 1. clinical veterinary services. AB - BACKGROUND: The provision of veterinary clinical services is known to elicit a range of challenges which require an ethical appraisal. In a recent Policy Delphi study, referrals/second opinions and 24 h emergency care were identified as matters of key concern by veterinary professionals in Ireland. In this case study (the first in a series of three resulting from a research workshop exploring challenges facing the veterinary profession in Ireland; the other two case studies investigate the on-farm use of veterinary antimicrobials and emergency/casualty slaughter certification) we aim to provide a value-based reflection on the constraints and possible opportunities for two prominent veterinary clinical services in Ireland: referrals/second opinions and 24 h emergency care. RESULTS: Using a qualitative focus group approach, this study gathered evidence from relevant stakeholders, namely referral and referring veterinarians, clients, animal charities, and the regulatory body. Six overarching, interrelated constraints emerged from the thematic analysis: the need to improve current guidance, managing clients' expectations, concerns with veterinarian well-being, financial issues, timeliness of referral, and conflicts between veterinary practices. CONCLUSIONS: Possible solutions to improve veterinary referral and out-of-hours clinical services included clarifying the terms used in current norms and regulations (namely 'referral', 'second opinion', '24 h emergency care' and '24 h cover'), improved communication (making the client aware of the different levels of veterinary care that are being offered, and transparent and full disclosure of clinical records), and the promotion of Continuing Veterinary Education in communication, business management and ethical decision-making. These findings may help inform the Veterinary Council of Ireland about future recommendations and regulatory measures. PMID- 28593044 TI - Surveillance of surgical site infections by Pseudomonas aeruginosa and strain characterization in Tanzanian hospitals does not provide proof for a role of hospital water plumbing systems in transmission. AB - BACKGROUND: The role of hospital water systems in the development of Pseudomonas aeruginosa (P. aeruginosa) surgical site infections (SSIs) in low-income countries is barely studied. This study characterized P. aeruginosa isolates from patients and water in order to establish possible epidemiological links. METHODS: Between December 2014 and September 2015, rectal and wound swabs, and water samples were collected in the frame of active surveillance for SSIs in the two Tanzanian hospitals. Typing of P. aeruginosa was done by multi-locus sequence typing. RESULTS: Of 930 enrolled patients, 536 were followed up, of whom 78 (14.6%, 95% CI; 11.6-17.5) developed SSIs. P. aeruginosa was found in eight (14%) of 57 investigated wounds. Of the 43 water sampling points, 29 were positive for P. aeruginosa. However, epidemiological links to wound infections were not confirmed. The P. aeruginosa carriage rate on admission was 0.9% (8/930). Of the 363 patients re-screened upon discharge, four (1.1%) possibly acquired P. aeruginosa during hospitalization. Wound infections of the three of the eight P. aeruginosa SSIs were caused by a strain of the same sequence type (ST) as the one from intestinal carriage. Isolates from patients were more resistant to antibiotics than water isolates. CONCLUSIONS: The P. aeruginosa SSI rate was low. There was no evidence for transmission from tap water. Not all P. aeruginosa SSI were proven to be endogenous, pointing to other routes of transmission. PMID- 28593043 TI - Diffusion of clindamycin-resistant and erythromycin-resistant methicillin susceptible Staphylococcus aureus (MSSA), potential ST398, in United States Veterans Health Administration Hospitals, 2003-2014. AB - BACKGROUND: Changing phenotypic profiles of methicillin-susceptible Staphylococcus aureus (MSSA) isolates can indicate the emergence of novel sequence types (ST). The diffusion of MSSA ST can be tracked by combining established genotypic profiles with phenotypic surveillance data. ST398 emerged in New York City (NYC) and exhibits resistance to clindamycin and erythromycin but tetracycline susceptibility ("potential ST398"). Trends of potential ST398 were examined in a national cohort of all Veterans Health Administration patients with MSSA invasive infections during 2003-2014. METHODS: A retrospective cohort of all patients with MSSA invasive infections, defined as a positive clinical culture from a sterile site, during 2003-2014 was created. Only isolates tested against clindamycin, erythromycin and tetracycline were included. Annual hospital level proportions of potential ST398 were compared according to facility distance from NYC and region. RESULTS: A total of 34,025 patient isolates from 136 VA medical centers met the inclusion criteria. Of those, 4582 (13.5%) met the definition of potential ST398. Potential ST398 increased over the 12-year cohort and diffused outwards from NYC. Incidence Rate Ratios of >1.0 (p < 0.01) reflect increases in potential ST398 over time in hospitals nearer to NYC. CONCLUSIONS: We observe an increase in the phenotypic profile of potential ST398 MSSA isolates in invasive infections in a national cohort of patients in the US. The increase is not evenly distributed across the US but appears to diffuse outwards from NYC. Novel MSSA strain emergence may have important clinical implications, particularly for the use of clindamycin for suspected S. aureus infections. PMID- 28593046 TI - Erratum to: The evidence on tiotropium bromide in asthma: from the rationale to the bedside. AB - [This corrects the article DOI: 10.1186/s40248-017-0094-3.]. PMID- 28593045 TI - Virulence traits associated with Burkholderia cenocepacia ST856 epidemic strain isolated from cystic fibrosis patients. AB - BACKGROUND: Burkholderia cenocepacia is considered one of the most problematic cystic fibrosis (CF) pathogens. Colonization prevalence in the Serbian CF population is high and virtually exclusively limited to a single highly transmissible clone of B. cenocepacia ST856 which is positive for both the B. cepacia epidemic strain marker (BCESM) and cable pilin, and is closely related to the epidemic strain CZ1 (ST32). METHODS: Biofilm formation for 182 isolates, and adhesion to components of the host extracellular matrix, proteolytic activity, mucoidy and motility of selected ST856 representatives, as well as B. cenocepacia ST858 and ST859, and B. stabilis ST857, novel STs isolated from Serbian CF patients, were investigated in this study. The presence of the cepI, cepR, fliG, llpE, wbiI, and bcscV genes was analyzed. RESULTS: Biofilm-formation ability of analyzed strains was poor under standard laboratory conditions, but changed in stress conditions (cold stress) and conditions that mimic CF milieu (increased CO2). All strains expressed ability to bind to collagen and fibronectin albeit with different intensity. Representatives of ST856 exhibited gelatinase activity. ST858, ST859 and 9/11 of ST856 genotypes were positive for swimming and twitching motility whereas ST857 was non-motile. Mucoidy was demonstrated in all ST856 genotypes, ST857 was semi-mucoid, and ST858 and ST859 were non-mucoid. Molecular analysis for major virulence factors revealed that ST856 and ST857 carried the six analyzed genes, while ST858 and ST859 were negative for the llpE gene. CONCLUSION: Variations in virulence phenotypes in different genotypes of epidemic B. cenocepacia ST856 clone, in vitro, could be a consequence of diversification driven by pathoadaptation. Diversity of epidemic clone genotypes virulence, could be challenging for accurate diagnosis and treatment, as well as for infection control. PMID- 28593047 TI - Integration of a bacterial gene sequence into a chronic eosinophilic leukemia patient's genome as part of a fusion gene linker. AB - Analysis of databases from the human genome project (HGP), the 1000 Genomes Project (1KGP), and The Cancer Genome Atlas (TCGA) revealed bacterial DNA integration into the human somatic genome, particularly in tumor tissues. Fusion genes have also been associated with tumorigenesis and 34 PDGFR fusion genes are linked to hematological malignancies. Here, we determined that a 17-bp homologous sequence in Marinobacter sp. Hb8, Rhodococcus fascians D188, Rhodococcus sp. PBTS2, Micrococcus luteus strain trpE16 and M. luteus NCTC 2665 integrates into the genome of a chronic eosinophilic leukemia patient as part of the linker for the novel CDK5RAP2-PDGFRalpha fusion gene. The resulting fusion protein that has CDK5RAP2's self-activating domain and PDGFRa's tyrosine kinase domain but lacks PDGFRa's membrane-binding and ligand-dependent activation properties may act together with the integrated bacterial sequence to readily phosphorylate downstream targets, amplify proliferation signals and promote leukemic cancer progression. PMID- 28593048 TI - Neural correlates of ataxia severity in spinocerebellar ataxia type 3/Machado Joseph disease. AB - BACKGROUND: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is an autosomal dominant inherited neurodegenerative disorder. Several post-mortem and imaging studies have shown cerebellar and brainstem atrophy. A number of studies have used volumetric regional information to investigate the relationship between neurodegeneration and the ataxia severity. However, regional analysis can obscure the specific location in which the degenerative process is affecting the brain tissue, which can be crucial for the development of new target treatments for this disease. Here we explored the relationship between the gray matter degeneration and the ataxia severity on a cohort of SCA3 patients using a voxel wise approach. METHODS: Seventeen patients with molecular diagnose of SCA3 and 17 matched healthy controls participated in this study. Magnetic resonance imaging (MRI) brain images were acquired and voxel-based morphometry was used to obtain the grey matter volume of each participant. Ataxia severity in the patient group was evaluated using the scale for the assessment and rating of ataxia (SARA). RESULTS: Group comparison revealed significant atrophy in SCA3 including bilateral cerebellum, vermis, brainstem, and occipital cortex. Significant negative correlations between gray matter volume and SARA scores were found in the cerebellum and the cingulate gyrus. CONCLUSIONS: These findings highlight the specific contribution of the cerebellum and the cingulate cortex to the ataxia deficits among the other regions showing neurodegeneration in SCA3 patients. PMID- 28593049 TI - Development of a scoring system for non-specialist ratings of clinical competence in global mental health: a qualitative process evaluation of the Enhancing Assessment of Common Therapeutic Factors (ENACT) scale. AB - Task-sharing is the involvement of non-specialist providers to deliver mental health services. A challenge for task-sharing programs is to achieve and maintain clinical competence of non-specialists, including primary care workers, paraprofessionals, and lay providers. We developed a tool for non-specialist peer ratings of common factors clinical competency to evaluate and optimize competence during training and supervision in global mental health task-sharing initiatives. The 18-item ENhancing Assessment of Common Therapeutic factors (ENACT) tool was pilot-tested with non-specialists participating in mental health Gap Action Programme trainings in Nepal. Qualitative process evaluation was used to document development of the peer rating scoring system. Qualitative data included interviews with trainers and raters as well as transcripts of pre- and post training observed structured clinical evaluations. Five challenges for non specialist peer ratings were identified through the process evaluation: (1) balance of training and supervision objectives with research objectives; (2) burden for peer raters due to number of scale items, number of response options, and use of behavioral counts; (3) capturing hierarchy of clinical skills; (4) objective v. subjective aspects of rating; and (5) social desirability when rating peers. The process culminated in five recommendations based on the key findings for the development of scales to be used by non-specialists for peer ratings in low-resource settings. Further research is needed to determine the ability of ENACT to capture the relationship of clinical competence with client outcomes and to explore the relevance of these recommendations for non-specialist peer ratings in high-resource settings. PMID- 28593050 TI - RimabotulinumtoxinB in sialorrhea: systematic review of clinical trials. AB - OBJECTIVE: The aim of this study was to examine the efficacy, safety and dosing practices of rimabotulinumtoxinB (BoNT-B) for the treatment of patients with sialorrhea based on a systematic review of clinical trials. METHODS: A systematic literature review was performed to identify randomized controlled trials and other comparative clinical studies of BoNT-B for the treatment of sialorrhea published in English between January 1999 and December 2015. Medical literature databases (PubMed, Cochrane Library, and EMBASE) were searched and a total of 41 records were identified. Of these, six primary publications that evaluated BoNT-B for the treatment of sialorrhea met criteria and were included in the final data report. SYNTHESIS: Total BoNT-B doses ranged from 1500 to 4000 units for sialorrhea. Most of the studies in sialorrhea showed statistically significant benefits of BoNT-B versus placebo (range 4-19.2 weeks). BoNT-B was generally well tolerated across the individual studies; most adverse events reported were considered unrelated to treatment. Adverse events considered potentially associated with BoNT-B included: dry mouth, change in saliva thickness, mild transient dysphagia, mild weakness of chewing and diarrhea. CONCLUSIONS: BoNT-B significantly reduces sialorrhea at doses between 1500 and 4000 units. The relatively mild dose-dependent adverse events suggest both direct and remote toxin effects. PMID- 28593051 TI - The need for preventive and curative services for malaria when the military is deployed in endemic overseas territories: a case study and lessons learned. AB - BACKGROUND: Sri Lanka has been free from indigenous malaria since November 2012 and received the WHO certificate for malaria-free status in September 2016. Due to increased global travel, imported malaria cases continue to be reported in the country. Military personnel returning home from international peace-keeping missions in malaria endemic countries represent a key risk group in terms of imported malaria. The present study intended to characterize the potential causes of a malaria outbreak among the Sri Lankan security forces personnel deployed in the Central African Republic (CAR). METHODS: Data were collected from a cross sectional survey distributed among Sri Lankan Air Force personnel who had returned from United Nations peace-keeping missions in the CAR region. A pre tested questionnaire was used for the data collection, and focus group discussions were also conducted. RESULTS: One hundred twenty male Air Force personnel were interviewed (out of a group of 122 officers and airmen). All participants were deployed in the CAR for 14 months and were aware of the existence of chemoprophylaxis against malaria. The majority of the subjects (92.5%, 111/120) also knew that prophylaxis should be started prior to departure. However, the regular use of chemoprophylaxis was reported by only 61.7% (74/120) of the sample. Overall, 30.8% of the participants (37/120) had 44 symptomatic episodes of malaria during deployment, and one person succumbed to severe malaria. All cases were associated with noncompliance with chemoprophylaxis. CONCLUSION: Better coordination with overseas healthcare services and the establishment of directly observed chemoprophylaxis may help to avoid similar outbreaks in the future. PMID- 28593052 TI - Scaling up contraceptives use in the division with lowest contraceptives use in Bangladesh: sources, methods, and determinants. AB - BACKGROUND: Total fertility rate (TFR) is high and at a static level for the last two decades in Bangladesh. Reduction of fertility by increasing contraceptives use could reduce maternal and neonatal mortality. To achieve the targeted contraceptive prevalence rate (CPR) of Family Planning 2020 (FP2020) Initiative, it is important to increase CPR in all regions of the country. However, it is lower in Sylhet Division compared to other divisions in Bangladesh. This study looked into the methods, source and determinants of contraceptives use in this division. METHODS: Data from the Bangladesh Demographic and Health Survey 2014 (BDHS 2014) were analyzed. After reporting the sources of obtaining contraceptives and choice of methods, distributions of contraceptives use were reported by selected characteristics. Logistic regression was applied to calculate the odds ratios. RESULTS: A total of 599 women were analyzed. CPR was lower in rural areas compared to urban areas, 45.4% and 58.5%, respectively. The majority of the women received services from governmental sectors. The birth control pill was the most common contraceptive method. The proportion of women using long-acting permanent methods was low (<10%) in both urban and rural areas. In the multivariate analyses, number of alive children (adjusted odds ratio (AOR) of >=5 children: 1.6, 95% confidence interval (CI): 1.1-2.2), presence of a male child (AOR: 1.7; 95% CI: 1.1-2.6), higher education level of the husband (AOR: 1.7; 95% CI: 1.1-2.6), receiving a visit from a family planning worker (AOR: 2.4; 95% CI: 1.6-3.4) and membership in a non-governmental organization (AOR:1.4, 95% CI: 1.1-1.8) were positively associated with contraceptives use in Sylhet after controlling for age, education level and other contextual factors. Conversely, rural women had the lower likelihood of using contraceptives (AOR: 0.6; 95% CI: 0.4-0.8) than urban women. Women's education level and religion were not statistically significant. CONCLUSIONS: A comprehensive strategy is required for this division to address multiple factors which simultaneously influence contraceptives use. In addition to more awareness programs to increase contraceptives use, providing contraceptive distribution services through family planning workers, involving women with non-governmental organizations and prioritizing rural areas could increase contraceptives use in Sylhet Division. PMID- 28593054 TI - Meibomian Gland Dysfunction in Type 2 Diabetic Patients. AB - PURPOSE: To investigate meibomian gland and tear film function in patients with type 2 diabetes. METHODS: This prospective study compared changes in meibomian gland and tear film function in type 2 diabetic patients with nondiabetic patients. Meibomian gland function was evaluated by measuring lipid layer thickness (LLT), grading of meibomian gland loss, lid margin abnormalities, and expression of meibum. Tear film function was assessed by measuring tear breakup time (TBUT), the Schirmer I test, noninvasive breakup time (NIBUT), tear meniscus height (TMH), and corneal fluorescein staining. RESULTS: Meibography scores were significantly higher in the diabetic group compared with the nondiabetic group (p = 0.004). The number of expressible glands was significantly lower in the diabetic group in temporal, central, and nasal third of the lower eyelid (nasal: p = 0.002; central: p = 0.040; and temporal: p = 0.039). The lid margin abnormality score was significantly higher in the diabetic group than in the nondiabetic group (p = 0.04). There was no statistically significant difference in the tear film function parameters between the two groups. CONCLUSIONS: Meibomian gland dysfunction (MGD) in type 2 diabetic patients is more severe compared with nondiabetic patients. Overall, most of the diabetic patients manifest as having asymptomatic MGD. PMID- 28593055 TI - A Surgical Cryoprobe for Targeted Transcorneal Freezing and Endothelial Cell Removal. AB - PURPOSE: To examine the effects of transcorneal freezing using a new cryoprobe designed for corneal endothelial surgery. METHODS: A freezing console employing nitrous oxide as a cryogen was used to cool a series of different cryoprobe tip designs made of silver for high thermal conductivity. In vitro studies were conducted on 426 porcine corneas, followed by preliminary in vivo investigations on three rabbit corneas. RESULTS: The corneal epithelium was destroyed by transcorneal freezing, as expected; however, the epithelial basement membrane remained intact. Reproducible endothelial damage was optimally achieved using a 3.4 mm diameter cryoprobe with a concave tip profile. Stromal edema was seen in the pre-Descemet's area 24 hrs postfreeze injury, but this had been resolved by 10 days postfreeze. A normal collagen fibril structure was seen 1 month postfreeze, concurrent with endothelial cell repopulation. CONCLUSIONS: Transcorneal freezing induces transient posterior stromal edema and some residual deep stromal haze but leaves the epithelial basement membrane intact, which is likely to be important for corneal re-epithelialization. Localized destruction of the endothelial monolayer was achieved in a consistent manner with a 3.4 mm diameter/concave profile cryoprobe and represents a potentially useful approach to remove dysfunctional corneal endothelial cells from corneas with endothelial dysfunction. PMID- 28593057 TI - Clomiphene Associated Inferior STEMI in a Young Female due to Right Coronary Artery Dissection. AB - Nonatherosclerotic spontaneous coronary artery dissection (NA-SCAD) is an uncommon cause of myocardial infarction. It most commonly affects females in the perimenopausal age. NA-SCAD has been associated with many predisposing factors including pregnancy and hormonal therapy for both contraception and ovulation induction. The presented case is a previously healthy 41-year-old woman diagnosed with inferior ST-elevation myocardial infarction due to right descending coronary artery dissection associated with recent use of clomiphene monotherapy for ovulation induction (a previously fertile woman), which was not previously reported. Learning Objectives. Emergency physicians (EPs) should be aware about NA-SCAD as a cause of acute coronary syndrome (ACS) especially in perimenopausal women even with no risk factors. NA-SCAD occurs more commonly in the postpartum period and in females following hormonal therapy. Here, clomiphene monotherapy was reported as a possible contributing factor to NA-SCAD. Guidelines for NA-SCAD management are not up to date, and EPs should avoid some interference before the final diagnosis of the cause of myocardial infarction. PMID- 28593058 TI - Yokenella regensburgei Septicemia in a Chinese Farmer Immunosuppressed by HIV: A Case Report and Literature Review. AB - Yokenella regensburgei is a member in the family Enterobacteriaceae and a few cases have been reported in immunocompromised hosts. Herein, we described a case of septicemia in a human immunodeficiency virus (HIV) infected patient in South West China, which is the first reported case of Y. regensburgei infection in HIV infected populations. We then reviewed the literature on all the reported cases of Y. regensburgei infection worldwide and presented some common features of them. Our case report and literature review will help increase the knowledge of the bacterium Y. regensburgei and its clinical implications. PMID- 28593053 TI - Natural graft tissues and synthetic biomaterials for periodontal and alveolar bone reconstructive applications: a review. AB - Periodontal disease is categorized by the destruction of periodontal tissues. Over the years, there have been several clinical techniques and material options that been investigated for periodontal defect repair/regeneration. The development of improved biomaterials for periodontal tissue engineering has significantly improved the available treatment options and their clinical results. Bone replacement graft materials, barrier membranes, various growth factors and combination of these have been used. The available bone tissue replacement materials commonly used include autografts, allografts, xenografts and alloplasts. These graft materials mostly function as osteogenic, osteoinductive and/or osteoconductive scaffolds. Polymers (natural and synthetic) are more widely used as a barrier material in guided tissue regeneration (GTR) and guided bone regeneration (GBR) applications. They work on the principle of epithelial cell exclusion to allow periodontal ligament and alveolar bone cells to repopulate the defect before the normally faster epithelial cells. However, in an attempt to overcome complications related to the epithelial down-growth and/or collapse of the non-rigid barrier membrane and to maintain space, clinicians commonly use a combination of membranes with hard tissue grafts. This article aims to review various available natural tissues and biomaterial based bone replacement graft and membrane options used in periodontal regeneration applications. PMID- 28593059 TI - Fulminating Postcaesarean Necrotising Fasciitis: A Rare and Lethal Condition Successfully Managed in a Resource-Disadvantaged Setting in Sub-Saharan Africa. AB - Necrotising fasciitis is a rare but potentially lethal condition in obstetrics which usually presents with fulminant tissue destruction and a resultant high mortality. We report a 19-year-old Sub-Saharan female diagnosed with a rapidly erosive necrotising fasciitis on day 5 after caesarean section in a resource limited setting. Timely diagnosis, aggressive antibiotic therapy, and prompt surgical intervention via an extensive abdominal wall debridement were pivotal to her survival. PMID- 28593060 TI - Fracture of the Tibial Baseplate 16 Years after Miller-Galante II Total Knee Arthroplasty. AB - We report a rare case of tibial baseplate fracture of Miller-Galante II (MG II) prosthesis. We examine the factors that may cause such late fracture and review the literature on radiographic analysis and retrieval studies. A 76-year-old woman, who had undergone bilateral MG II total knee arthroplasty due to rheumatoid arthritis 16 years earlier, presented to our department with a 3-month history of left knee pain. Plain radiographs revealed severe distortion of the medial tibial component. During revision knee arthroplasty, we observed severe metallosis in the knee joint, polyethylene insert deformation, and posteromedial coronal baseplate fracture. After removal of the fractured tray, a bone deficit due to osteolysis was noted. The revision prosthesis (LCCK, Zimmer-Biomet) was implanted uneventfully. Four months after revision surgery, the patient was ambulating and had no complications. The implants on the right side had survived without complications for 17 years. We speculate that the primary causative factor of the fatigue fracture of the base plate due to loss of bony support most likely secondary to osteolysis was varus malalignment at primary implantation. This case highlights the importance of paying close attention to the correct alignment of each component at primary implantation. PMID- 28593062 TI - Elastic Intramedullary Nailing of a Medial Clavicle Fracture in a Pediatric Patient. AB - INTRODUCTION: Injuries to the medial clavicle in pediatric patients typically involve the physis and/or sternoclavicular joint. Clavicle fractures are one of the most common injuries in children, but ones at its medial end are rare. Most medial clavicle fractures are treated nonoperatively, but surgery is indicated in some cases. This original case report is unique in describing the use of an elastic intramedullary nail for fixation of a completely displaced medial clavicle fracture in a pediatric patient. CASE PRESENTATION: A pediatric patient sustained a completely displaced fracture of the medial clavicle. The fracture was lateral to the medial physis of the clavicle and did not involve the sternoclavicular joint. Internal fixation was achieved in an anatomic position with an elastic intramedullary nail. The postoperative course was unremarkable and resulted in complete healing of the fracture in an anatomic position. The patient returned to full activities without any pain or dysfunction. CONCLUSION: The use of elastic intramedullary nails is a viable option for internal fixation of displaced medial clavicle fractures. Knowledge of the surgical anatomy, potential implant complications, and rehabilitation principles is essential to a successful outcome. PMID- 28593061 TI - Fibroma of Tendon Sheath Presenting Limited Flexion of the Fingers. AB - A 35-year-old Japanese man presented with a 1-month history of limited flexion and radiating pain in the left middle and ring fingers. A physical examination revealed a hard nodular mass in his left palm. Magnetic resonance imaging showed a 2 * 1.5 * 1 cm mass of low intensity on T1-weighted images and high intensity on T2-weighted images and gadolinium enhancement. The tumor was marginally resected, adhering to the flexor digitorum profundus of both the third and fourth fingers. The histological diagnosis was fibroma of tendon sheath. After the surgery, the range of motion and hand function were improved. No recurrence has been observed. Fibroma of tendon sheath usually arises on the fingers and hands with strong attachment to the tendon or tendon sheath. The tumor in the present case probably limited the range of flexion of the fingers by obstruction of the transverse carpal ligament. PMID- 28593056 TI - Management Options for Advanced Low or Intermediate Grade Gastroenteropancreatic Neuroendocrine Tumors: Review of Recent Literature. AB - Our understanding of the biology, genetics, and natural history of neuroendocrine tumors (NETs) of the gastrointestinal tract and pancreas has improved considerably in the last several decades and the spectrum of available therapeutic options is rapidly expanding. The management of patients with metastatic low or intermediate grade NETs has been revolutionized by the development of new treatment strategies such as molecular targeting therapies with everolimus and sunitinib, somatostatin analogs, tryptophan hydroxylase inhibitors, and peptide receptor radionuclide therapy that can be used alone or as a multimodal approach with or without surgery. To further define and clarify the utility, appropriateness, and the sequence of the growing list of available therapies for this patient population will require more high level evidence; however, data from well-designed randomized phase III clinical trials is rapidly accumulating that will further stimulate development of new management strategies. It is therefore important to thoroughly review emerging evidence and report major findings in frequent updates, which will expand our knowledge and contribute to a better understanding, characterization, and management of advanced NETs. PMID- 28593063 TI - Parotitis as an Initial Symptom of Kawasaki Disease. AB - We report the case of a 13-month-old boy who developed right side parotitis as a first symptom of Kawasaki disease (KD). The data presented herein suggest that physicians should be aware that nonsuppurative parotitis is a possible manifestation of KD. PMID- 28593064 TI - Physiological Striae Atrophicae of Adolescence with Involvement of the Axillae and Proximal Arms. AB - We report a 16-year-old adolescent male with multiple violaceous, atrophic, vertical linear striae isolated to the axillae and proximal arms of approximately one-year duration. In the past two years, he indulged in heavy weight-lifting. He experienced a growth spurt over the past few years. The patient was otherwise in good health and was not on any medications. Physiological striae atrophicae of adolescence where the striae were restricted to the axillae and proximal arms have very rarely been reported. PMID- 28593065 TI - High Expression of Galectin-3 in Patients with IgG4-Related Disease: A Proteomic Approach. AB - OBJECTIVES: Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan condition manifesting itself in different forms. This study aimed to investigate protein expression profiles and to find the possible biomarker for IgG4-RD by liquid chromatography mass spectrometry (LC-MS) using tissue sections in IgG4-RD patients. METHODS: Protein expression profiles in five IgG4-related pancreatitis and three normal pancreatic samples were compared using LC-MS and were validated by quantitative real-time PCR (qRT-PCR), immunoblotting, and immunohistochemistry. ELISA was employed in the serum of 20 patients with systemic IgG4-RD before and during steroid treatment. RESULTS: LC-MS indicated that the levels of 17 proteins were significantly higher and 12 others were significantly lower in IgG4-related pancreatitis patients compared to controls. Among these proteins, galectin-3 levels were 13-fold higher in IgG4-related pancreatitis (P < 0.01). These results were confirmed by immunoblotting and qRT PCR. The average number of galectin-3 + cells in various organs of IgG4-RD patients, including salivary glands, lungs, and lymph nodes, was higher than in controls. Galectin-3 was detectable in macrophages, dendritic cells, and stromal myofibroblast-like cells, but not in lymphocytes by immunofluorescence staining. Serum galectin-3 levels were higher in patients with IgG4-RD compared with healthy donors and remained high during steroid therapy. CONCLUSION: Galectin-3 was overexpressed in IgG4-RD and the levels were indirectly related to clinical activity. PMID- 28593066 TI - Sequence Analysis of Long-Term Readmissions among High-Impact Users of Cerebrovascular Patients. AB - OBJECTIVE: Understanding the chronological order of the causes of readmissions may help us assess any repeated chain of events among high-impact users, those with high readmission rate. We aim to perform sequence analysis of administrative data to identify distinct sequences of emergency readmissions among the high impact users. METHODS: A retrospective cohort of all cerebrovascular patients identified through national administrative data and followed for 4 years. RESULTS: Common discriminating subsequences in chronic high-impact users (n = 2863) of ischaemic stroke (n = 34208) were "urological conditions-chest infection," "chest infection-urological conditions," "injury-urological conditions," "chest infection-ambulatory condition," and "ambulatory condition chest infection" (p < 0.01). Among TIA patients (n = 20549), common discriminating (p < 0.01) subsequences among chronic high-impact users were "injury-urological conditions," "urological conditions-chest infection," "urological conditions-injury," "ambulatory condition-urological conditions," and "ambulatory condition-chest infection." Among the chronic high-impact group of intracranial haemorrhage (n = 2605) common discriminating subsequences (p < 0.01) were "dementia-injury," "chest infection-dementia," "dementia-dementia-injury," "dementia-urine infection," and "injury-urine infection." Conclusion. Although common causes of readmission are the same in different subgroups, the high-impact users had a higher proportion of patients with distinct common sequences of multiple readmissions as identified by the sequence analysis. Most of these causes are potentially preventable and can be avoided in the community. CONCLUSION: Although common causes of readmission are the same in different subgroups, the high-impact users had a higher proportion of patients with distinct common sequences of multiple readmissions as identified by the sequence analysis. Most of these causes are potentially preventable and can be avoided in the community. PMID- 28593068 TI - Occupational Exposure to Knee Loading and the Risk of Osteoarthritis of the Knee: A Systematic Review and a Dose-Response Meta-Analysis. AB - BACKGROUND: Osteoarthritis of the knee is considered to be related to knee straining activities at work. The objective of this review is to assess the exposure dose-response relation between kneeling or squatting, lifting, and climbing stairs at work, and knee osteoarthritis. METHODS: We included cohort and case-control studies. For each study that reported enough data, we calculated the odds ratio (OR) per 5,000 hours of cumulative kneeling and per 100,000 kg of cumulative lifting. We pooled these incremental ORs in a random effects meta analysis. RESULTS: We included 15 studies (2 cohort and 13 case-control studies) of which nine assessed risks in more than two exposure categories. We considered all but one study at high risk of bias. The incremental OR per 5,000 hours of kneeling was 1.26 (95% confidence interval 1.17-1.35, 5 studies, moderate quality evidence) for a log-linear exposure dose-response model. For lifting, there was no exposure dose-response per 100,000 kg of lifetime lifting (OR 1.00, 95% confidence interval 1.00-1.01). For climbing, an exposure dose-response could not be calculated. CONCLUSION: There is moderate quality evidence that longer cumulative exposure to kneeling or squatting at work leads to a higher risk of osteoarthritis of the knee. For other exposure, there was no exposure dose response or there were insufficient data to establish this. More reliable exposure measurements would increase the quality of the evidence. PMID- 28593067 TI - Strategies for Worksite Health Interventions to Employees with Elevated Risk of Chronic Diseases. AB - Chronic disease rates have become more prevalent in the modern American workforce, which has negative implications for workplace productivity and healthcare costs. Offering workplace health interventions is recognized as an effective strategy to reduce chronic disease progression, absenteeism, and healthcare costs as well as improve population health. This review documents intervention and evaluation strategies used for health promotion programs delivered in workplaces. Using predetermined search terms in five online databases, we identified 1,131 published items from 1995 to 2014. Of these items, 27 peer-reviewed articles met the inclusion criteria; reporting data from completed United States-based workplace interventions that recruited at-risk employees based on their disease or disease-related risk factors. A content rubric was developed and used to catalogue these 27 published field studies. Selected workplace interventions targeted obesity (n = 13), cardiovascular diseases (n = 8), and diabetes (n = 6). Intervention strategies included instructional education/counseling (n = 20), workplace environmental change (n = 6), physical activity (n = 10), use of technology (n = 10), and incentives (n = 13). Self-reported data (n = 21), anthropometric measurements (n = 17), and laboratory tests (n = 14) were used most often in studies with outcome evaluation. This is the first literature review to focus on interventions for employees with elevated risk for chronic diseases. The review has the potential to inform future workplace health interventions by presenting strategies related to implementation and evaluation strategies in workplace settings. These strategies can help determine optimal worksite health programs based on the unique characteristics of work settings and the health risk factors of their employee populations. PMID- 28593069 TI - Reproductive Toxic Chemicals at Work and Efforts to Protect Workers' Health: A Literature Review. AB - A huge number of chemicals are produced and used in the world, and some of them can have negative effects on the reproductive health of workers. To date, most chemicals and work environments have not been studied for their potential to have damaging effects on the workers' reproductive system. Because of the lack of information, many workers may not be aware that such problems can be related to occupational exposures. Newly industrialized countries such as Republic of Korea have rapidly amassed chemicals and other toxicants that pose health hazards, especially to the reproductive systems of workers. This literature review provides an overview of peer-reviewed literature regarding the teratogenic impact and need for safe handling of chemicals. Literature searches were performed using PubMed, Google Scholar, and ScienceDirect. Search strategies were narrowed based on author expertise and 100 articles were chosen for detailed analysis. A total of 47 articles met prespecified inclusion criteria. The majority of papers contained studies that were descriptive in nature with respect to the Medical Subject Headings (MeSH) terms and keywords: "reproductive and heath or hazard and/or workplace or workers or occupations." In the absence of complete information about the safe occupational handling of chemicals in Republic of Korea (other than a material safety data sheet), this review serves as a valuable reference for identifying and remedying potential gaps in relevant regulations. The review also proposes other public health actions including hazard surveillance and primary prevention activities such as reduction, substitution, ventilation, as well as protective equipment. PMID- 28593070 TI - Safety Evaluation of the Lighting at the Entrance of a Very Long Road Tunnel: A Case Study in Ilam. AB - BACKGROUND: At the entrance of a tunnel, reflection of sunlight from the surrounding environment and a lack of adequate lighting usually cause some vision problems. The purpose of this study was to perform a safety evaluation of lighting on a very long road in Ilam, Iran. METHODS: The average luminance was measured using a luminance meter (model S3; Hagner, Solna, Sweden). A camera (model 108, 35-mm single-lens reflex; Yashica, Nagano, Japan) was used to take photographs of the safe stopping distance from the tunnel entrance. Equivalent luminance was determined according to the Holliday polar diagram. RESULTS: Considering the average luminance at the tunnel entrance (116.7 cd/m2) and using Adrian's equation, the safe level of lighting at the entrance of the tunnel was determined to be 0.7. CONCLUSION: A comparison between the results of the safe levels of lighting at the entrance of the tunnel and the De Boer scale showed that the phenomenon of black holes is created at the tunnel entrance. This may lead to a misadaptation of the drivers' eyes to the change in luminance level at the entrance of the tunnel, thereby increasing the risk of road accidents in this zone. PMID- 28593071 TI - Evaluation of the Quality of Occupational Health and Safety Management Systems Based on Key Performance Indicators in Certified Organizations. AB - BACKGROUND: Occupational Health and Safety Management Systems are becoming more widespread in organizations. Consequently, their effectiveness has become a core topic for researchers. This paper evaluates the performance of the Occupational Health and Safety Assessment Series 18001 specification in certified companies in Iran. METHODS: The evaluation is based on a comparison of specific criteria and indictors related to occupational health and safety management practices in three certified and three noncertified companies. RESULTS: Findings indicate that the performance of certified companies with respect to occupational health and safety management practices is significantly better than that of noncertified companies. CONCLUSION: Occupational Health and Safety Assessment Series 18001-certified companies have a better level of occupational health and safety; this supports the argument that Occupational Health and Safety Management Systems play an important strategic role in health and safety in the workplace. PMID- 28593072 TI - Recovery and Return to Work After a Pelvic Fracture. AB - BACKGROUND: Pelvic ring fractures (PRFs) may influence the daily activities and quality of life of the injured. The aim of this retrospective study was to explore the functional outcomes and factors related to return to work (RTW) after PRF. METHODS: During the years 2003-2012, 282 injured individuals aged 20-55 years on the date of the accident, were hospitalized and treated for PRFs in a large tertiary hospital in Athens, Greece. One hundred and three patients were traced and contacted; 77 who were on paid employment prior to the accident gave their informed consent to participate in the survey, which was conducted in early 2015 through telephone interviews. The questionnaire included variables related to injury, treatment and activities, and the Majeed pelvic score. Univariate and multiple regression analyses were used for statistical assessment. RESULTS: Almost half of the injured (46.7%) fully RTW, and earning losses were reported to be 35% after PRF. The univariate analysis confirmed that RTW was significantly related to accident site (labor or not), the magnitude of the accident's force, concomitant injuries, duration of hospitalization, time to RTW, engagement to the same sport, Majeed score, and complications such as limp and pain as well as urologic and sexual complaints (p < 0.05 for all). On multiple logistic regression analysis, the accident sustained out of work (odds ratio: 6.472, 95% confidence interval: 1.626-25.769) and Majeed score (odds ratio: 3.749, 95% confidence interval: 2.092-6.720) were identified as independent predictive factors of full RTW. CONCLUSION: PRFs have severe socioeconomic consequences. Possible predictors of RTW should be taken into account for health management and policies. PMID- 28593073 TI - Cancer Incidence in Asbestos-Exposed Workers: An Update on Four Finnish Cohorts. AB - BACKGROUND: We assessed the cancer risks of four different Finnish asbestos exposed cohorts. We also explored if the cohorts with varying profiles of asbestos exposure exhibited varying relative risks of cancer. METHODS: The incident cancer cases for the asbestos-exposed worker cohorts were updated to the end of 2012 using the files of the Finnish Cancer Registry. The previously formed cohorts consisted of asbestos mine workers, asbestosis patients, asbestos sprayers, and workers who had taken part in a screening study based on asbestos exposure at work. RESULTS: The standardized incidence ratio (SIR) for mesothelioma varied from about threefold to > 100-fold in the different cohorts. In the screening cohort the SIR for mesothelioma was highest in 2003-2007, In other cohorts it was more constant in 5-year period inspection. The SIR for lung cancer was about twofold to tenfold in all except the screening cohort. Asbestos sprayers were at the highest risk of mesothelioma and lung cancer. CONCLUSION: The SIR for mesothelioma is high in all of the cohorts that represent different kinds of asbestos exposure. The smaller SIR for mesothelioma in the screening cohort with lowest level of asbestos exposure might suggest dose-responsiveness between asbestos exposure and mesothelioma. It does seem that the highest risk of lung cancer in these cohorts except in the youngest of the cohorts, the screening cohort, is over. The highest SIR for lung cancer of the asbestosis patient and sprayers cohort is explained by their heavy asbestos exposure. PMID- 28593074 TI - Safety and Health Perceptions in Work-related Transport Activities in Ghanaian Industries. AB - BACKGROUND: With the recent rapid industrialization, occupational safety and health (OSH) has become an important issue in all industrial and human activities. However, incidents of injuries and fatality rates in the Ghanaian industry sector continue to increase. Despite this increase, there is no evidence regarding the element of OSH management in transport activities in Ghanaian industries. Thus, this study aims to examine the perceptions regarding the importance of safety and health in work-related transport activities in Ghanaian industries. METHODS: A survey data collection technique was used to gather information on best safety practices over a 5-month period. We randomly selected 298 respondents from industries to answer structured questionnaires. The respondents included drivers, transport managers, and safety engineers. Standard multiple regression model and Pearson product-movement correlation were used to performed the analysis. RESULTS: The result shows that for interventions to improve safety and health, concentration has been on drivers' safety practice with less attention to safe driving environments and vehicle usage. Additionally, the respondents are aware of the importance of OSH in transport activities, but the level of integration does not measure up to the standard to reduce operational accidents and injuries. Finally, strong commitment to changing unsafe practices at all levels of operations appears to be the effective way to improve safety situations. CONCLUSION: OSH culture is not fully complied in industries transport activities. This study, therefore, supports the use of safety seminars and training sessions for industry workers responsible for transport operations for better integration of safety standards. PMID- 28593075 TI - Cardiorespiratory Fitness Is Associated with Gait Changes among Firefighters after a Live Burn Training Evolution. AB - BACKGROUND: Recommendations have been proposed for minimum aerobic fitness among firefighters but it is unclear if those criteria relate to performance on the fireground. Less fit individuals fatigue more quickly than fit individuals when working at comparable intensity and may have gait changes, increasing risk of falls. We evaluated the effect of fatigue during a live burn evolution on gait parameters and functional balance comparing them to aerobic fitness levels. METHODS: A total of 24 firefighters had gait and balance tested before and after a live burn evolution. Data were stratified by aerobic fitness of greater/less than 14 metabolic equivalents (METs). RESULTS: Analysis of gait cycles measurements before and after the live burn evolution revealed that single leg stance, cycle, and swing time decreased (p < 0.05) but there were no differences in the other measures. There were no differences in time to complete the functional balance test, or errors committed before or after a live burn evolution. When firefighters were sorted by fitness level of 14 METs, there were no differences for errors or time before or after the live burn evolution. Balance data were analyzed using a linear regression. Individuals with lower fitness levels required more time to complete the test. CONCLUSION: A 14-MET criterion failed to distinguish gait or balance characteristics in this group. However, less fit firefighters did require more time to complete the balance test (p = 0.003). Aerobic fitness alone does not predict gait changes among firefighters following a live burn evolution but does appear to influence functional balance. PMID- 28593076 TI - Control of Industrial Safety Based on Dynamic Characteristics of a Safety Budget Industrial Accident Rate Model in Republic of Korea. AB - BACKGROUND: Despite the recent efforts to prevent industrial accidents in the Republic of Korea, the industrial accident rate has not improved much. Industrial safety policies and safety management are also known to be inefficient. This study focused on dynamic characteristics of industrial safety systems and their effects on safety performance in the Republic of Korea. Such dynamic characteristics are particularly important for restructuring of the industrial safety system. METHODS: The effects of damping and elastic characteristics of the industrial safety system model on safety performance were examined and feedback control performance was explained in view of cost and benefit. The implications on safety policies of restructuring the industrial safety system were also explored. RESULTS: A strong correlation between the safety budget and the industrial accident rate enabled modeling of an industrial safety system with these variables as the input and the output, respectively. A more effective and efficient industrial safety system could be realized by having weaker elastic characteristics and stronger damping characteristics in it. A substantial decrease in total social cost is expected as the industrial safety system is restructured accordingly. CONCLUSION: A simple feedback control with proportional integral action is effective in prevention of industrial accidents. Securing a lower level of elastic industrial accident-driving energy appears to have dominant effects on the control performance compared with the damping effort to dissipate such energy. More attention needs to be directed towards physical and social feedbacks that have prolonged cumulative effects. Suggestions for further improvement of the safety system including physical and social feedbacks are also made. PMID- 28593077 TI - Alteration in Leukocyte Subsets and Expressions of FcgammaR and Complement Receptors among Female Ragpickers in Eastern India. AB - BACKGROUND: There are a million ragpickers in India who gather and trade recyclable municipal solid wastes materials for a living. The objective of this study was to examine whether their occupation adversely affects their immunity. METHODS: Seventy-four women ragpickers (median age, 30 years) and 65 age-matched control housemaids were enrolled. Flow cytometry was used to measure leukocyte subsets, and leukocyte expressions of Fcgamma receptor I (CD64), FcgammaRIII (CD16), complement receptor 1 (CD35) and CR3 (CD11b/CD18), and CD14. Serum total immunoglobulin-E was estimated with enzyme-linked immunosorbent assay. RESULTS: Compared with the controls, ragpickers had significantly (p < 0.0001) higher levels of CD8+T-cytotoxic, CD16+CD56+natural killer, and CD4+CD45RO+memory T cells, but depleted levels of CD19+B-cells. The percentage of CD4+T-helper-cells was lower than the control group (p < 0.0001), but their absolute number was relatively unchanged (p = 0.42) due to 11% higher lymphocyte counts in ragpickers. In ragpickers, the percentages of CD14+CD16+intermediate and CD14dim CD16+nonclassical monocyte subsets were elevated with a decline in CD14+CD16 classical monocytes. The expressions of CD64, CD16, CD35, and CD11b/CD18 on both monocytes and neutrophils, and CD14 on monocytes were significantly higher in ragpickers. In addition, ragpickers had 2.7-times more serum immunoglobulin-E than the controls (p < 0.0001). After controlling potential confounders, the profession of ragpicking was positively associated with the changes. CONCLUSION: Ragpicking is associated with alterations in both innate (neutrophils, monocytes, and natural killer cell numbers and expression of complement and Fcgamma receptors) and adaptive immunity (numbers of circulating B cells, helper, cytotoxic, and memory T cells). PMID- 28593078 TI - Non-chemical Risk Assessment for Lifting and Low Back Pain Based on Bayesian Threshold Models. AB - BACKGROUND: Self-reported low back pain (LBP) has been evaluated in relation to material handling lifting tasks, but little research has focused on relating quantifiable stressors to LBP at the individual level. The National Institute for Occupational Safety and Health (NIOSH) Composite Lifting Index (CLI) has been used to quantify stressors for lifting tasks. A chemical exposure can be readily used as an exposure metric or stressor for chemical risk assessment (RA). Defining and quantifying lifting nonchemical stressors and related adverse responses is more difficult. Stressor-response models appropriate for CLI and LBP associations do not easily fit in common chemical RA modeling techniques (e.g., Benchmark Dose methods), so different approaches were tried. METHODS: This work used prospective data from 138 manufacturing workers to consider the linkage of the occupational stressor of material lifting to LBP. The final model used a Bayesian random threshold approach to estimate the probability of an increase in LBP as a threshold step function. RESULTS: Using maximal and mean CLI values, a significant increase in the probability of LBP for values above 1.5 was found. CONCLUSION: A risk of LBP associated with CLI values > 1.5 existed in this worker population. The relevance for other populations requires further study. PMID- 28593079 TI - Seat Pressure Distribution Characteristics During 1 Hour Sitting in Office Workers With and Without Chronic Low Back Pain. AB - BACKGROUND: Low back pain (LBP) is a major problem for office workers. Individuals adopting poor postures during prolonged sitting have a considerably increased risk of experiencing LBP. This study aimed to investigate seat pressure distribution characteristics, i.e., average pressure, peak pressure ratio, frequency of postural shift, and body perceived discomfort (BPD), during 1 hour of sitting among office workers with and without chronic LBP. METHODS: Forty-six participants (chronic LBP = 23, control = 23) typed a standardized text passage at a computer work station for an hour. A seat pressure mat device was used to collect the seat pressure distribution data. Body discomfort was assessed using the Body Perceived Discomfort scale. RESULTS: Office workers with chronic LBP sat significantly more asymmetrically than their healthy counterparts. During 1-hour sitting, all workers appeared to assume slumped sitting postures after 20 minutes of sitting. Healthy workers had significantly more frequent postural shifts than chronic LBP workers during prolonged sitting. CONCLUSION: Different sitting characteristics between healthy and chronic LBP participants during 1 hour of sitting were found, including symmetry of sitting posture and frequency of postural shift. Further research should examine the roles of these sitting characteristics on the development of LBP. PMID- 28593080 TI - Urinary Trans, Trans-Muconic Acid is Not a Reliable Biomarker for Low-level Environmental and Occupational Benzene Exposures. AB - BACKGROUND: Benzene is a known occupational and environmental pollutant. Its urinary metabolite trans, trans-muconic acid (tt-MA) has been introduced by some environmental and occupational health regulatory associations as a biological index for the assessment of benzene exposure; however, recently, doubts have been raised about the specificity of tt-MA for low-level benzene exposures. In the present study, we investigated the association between urinary levels of tt-MA and inhalational exposure to benzene in different exposure groups. METHODS: Benzene exposure was assessed by personal air sampling. Collected benzene on charcoal tube was extracted by carbon disulfide and determined by a gas chromatograph (gas chromatography with a flame ionization detector). Urinary tt MA was extracted by a strong anion-exchange column and determined with high performance liquid chromatography-UV. RESULTS: Urinary levels of tt-MA in intensive benzene exposure groups (chemical workers and police officers) were significantly higher than other groups (urban and rural residents), but its levels in the last two groups with significant different exposure levels (mean = 0.081 ppm and 0.019 ppm, respectively) showed no significant difference (mean = 388 MUg/g creatinine and 282 MUg/g, respectively; p < 0.05). Before work shift, urine samples of workers and police officers showed a high amount of tt-MA and its levels in rural residents' samples were not zero. CONCLUSION: Our results suggest that tt-MA may not be a reliable biomarker for monitoring low-level (below 0.5 ppm) benzene exposures. PMID- 28593081 TI - The Use of Noise Dampening Mats to Reduce Heavy-Equipment Noise Exposures in Construction. AB - The performance of sound barriers was evaluated to determine their technical effectiveness and practicality in reducing noise exposures to operating engineers in construction. Commercially purchased sound dampening mats (SDMats) were installed inside three heavy-equipment engine compartments. Sound pressure levels (SPLs) were measured before and after installing the SDMats while the equipment was on idle and full-throttle settings where it normally operates. SPLs inside the heavy-equipment operator cabs were significantly reduced by 5.6-7.6 dBA on the full-throttle setting following installation of the SDMats (p < 0.01). The evaluated engineering control intervention was simple to install, affordable, and substantially reduced the engine noise reaching the heavy-equipment operator, potentially reducing reliance on hearing-protection devices to protect construction workers from noise exposures. PMID- 28593082 TI - Control of Selectivity through Synergy between Catalysts, Silanes and Reaction Conditions in Cobalt-Catalyzed Hydrosilylation of Dienes and Terminal Alkenes. AB - Readily accessible ( i-PrPDI)CoCl2 [ i-Pr PDI = 2,6-bis(2,6 diisopropylphenyliminoethyl)pyridine] reacts with 2 equivalents of NaEt3BH at -78 degrees C in toluene to generate a catalyst that effects highly selective anti Markovnikov hydrosilylation of the terminal double bond in 1,3- and 1,4-dienes. Primary and secondary silanes such as PhSiH3, Ph2SiH2 and PhSi(Me)H2 react with a broad spectrum of terminal dienes without affecting the configuration of the other double bond. When dienes conjugated to an aromatic ring are involved, both Markovnikov and anti-Markovnikov products are formed. The reaction is tolerant of various functional groups such as an aryl bromide, aryl iodide, protected alcohol, and even a silyl enol ether. Reactions of 1-alkene under similar conditions cleanly lead to a mixture of Markovnikov and anti-Markovnikov hydrosilation products, where ratio of the products increasingly favors the latter, as the size of the 2,6-substituents in the iminoylaryl group becomes larger. The complex ( i-PrPDI)CoCl2 gives exclusively the linear silane for a wide variety of terminal alkenes. Mechanistic studies suggest a pathway that involves a key role for an in situ generated metal hydride, (L)Co(I)-H. Exclusive reduction of the terminal double bond (vis-a-vis hydrosilylation) when (EtO)2Si(Me)H is used in the place of PhSiH3 is explained on the basis of an alternate silane-mediated decomposition path for the linear Co(I)-alkyl intermediate. PMID- 28593083 TI - DYNAMIC OSCILLATORY STRETCHING EFFICACY ON HAMSTRING EXTENSIBILITY AND STRETCH TOLERANCE: A RANDOMIZED CONTROLLED TRIAL. AB - BACKGROUND: While static stretch (SS), proprioceptive neuromuscular facilitation (PNF) and oscillatory physiological mobilization techniques are documented to have positive effects on a range of motion (ROM), there are no reports on the effect of dynamic oscillatory stretching (DOS), a technique that combines these three techniques, on hamstring extensibility. PURPOSE: To determine whether DOS improves hamstring extensibility and stretch tolerance to a greater degree than SS in asymptomatic young participants. STUDY DESIGN: Randomized Controlled Trial. METHODS: Sixty participants (47 females, 13 males, mean age 22 +/- 1 years, height 166 +/- 6 centimeters, body mass 67.6 +/- 9.7 kg) completed a passive straight leg (SLR) to establish hamstring extensibility and stretch tolerance as perceived by participants, using a visual analogue scale (VAS). Participants were randomly assigned to one of two treatment groups (SS or DOS) or a placebo control (20 per group). Tests were repeated immediately following and one hour after each intervention. Data were assessed using a two-way repeated measure analysis of variance (ANOVA) and Tukey's post hoc test. RESULTS: Immediately post intervention, there was a significant improvement in the hamstring extensibility as measured by the SLR in both the SS and DOS groups, with the DOS group exhibiting a significantly greater increase than the SS group (Control 73 +/- 12 degrees , SS 86 +/- 8 degrees , DOS 94 +/- 11 degrees , p < 0.001). One hour post intervention, hamstring extensibility in the DOS group remained elevated, while the SS group no longer differed from the control group (Control 73 +/- 12 degrees , SS 80 +/- 8 degrees , DOS 89 +/- 12 degrees , p = 0.001). Furthermore, the stretch tolerance remained significantly elevated for the SS group, but there was no difference between the control and DOS groups, (Control 4.6 +/- 1.3, SS 5.9 +/ 0.8, DOS 4.3 +/- 1.0 AU, p < 0.001). CONCLUSION: DOS was more effective than SS at achieving an immediate increase in hamstring extensibility, and DOS demonstrated an increased stretch tolerance one-hour post-intervention. LEVEL OF EVIDENCE: 2C. PMID- 28593084 TI - STRENGTH PROFILES IN HEALTHY INDIVIDUALS WITH AND WITHOUT SCAPULAR DYSKINESIS. AB - BACKGROUND: Muscular weakness of the shoulder complex is commonly found in patients presenting with scapular dyskinesis; however, little is known regarding muscular performance in healthy individuals with scapular dyskinesis. PURPOSE: To compare isometric strength measures of the shoulder complex between healthy individuals with and without scapular dyskinesis. It was hypothesized that healthy individuals with scapular dyskinesis would demonstrate decreased isometric strength of the scapular stabilizers and rotator cuff when compared to healthy individuals without scapular dyskinesis. STUDY DESIGN: Cross-sectional study. METHODS: Forty healthy, college-aged participants were recruited. Sixty eight percent of subjects (27 of 40) presented with scapular dyskinesis. Thus, a matched-pairs analysis was conducted with 26 subjects (age: 22.00 +/- 2.06 y; height: 168.77 +/- 8.07 cm; mass: 70.98 +/- 13.14 kg; BMI: 24.75 +/- 3.04 kg/m2; 6 males; 20 females). The presence of scapular dyskinesis was determined visually using the scapular dyskinesis test with a dichotomous outcome (yes/no). Strength of the scapular stabilizers and rotator cuff was assessed via manual muscle testing using a handheld dynamometer. Force measures obtained with the handheld dynamometer were used to quantify strength. For each muscle tested, the mean peak force of three trials were normalized to body weight and used for data analysis. Additionally, strength ratios were calculated and analyzed. Differences in strength and strength ratios between those with and without scapular dyskinesis were compared using separate two-way mixed ANOVAs with repeated measures. RESULTS: No significant differences for either strength (F1.83,43.92 = 1.10, p = .34) or strength ratios (F1.83,44.02 = 1.93, p = .16) were observed between those with and without scapular dyskinesis. A significant main effect (F1.83,43.92 = 239.32, p < .01) for muscles tested was observed, and post-hoc analysis revealed significant trends resulting in a generalized order: the upper trapezius generated the greatest amount of force, followed by serratus anterior and middle trapezius, lower trapezius, supraspinatus, medial rotators, and lateral rotators. CONCLUSION: The results of this study indicate that differences in shoulder muscle strength do not exist between healthy subjects with and without scapular dyskinesis. Additionally, scapular dyskinesis appears to be prevalent in healthy populations. LEVEL OF EVIDENCE: Level 3. PMID- 28593085 TI - POSTURAL STABILITY AND KINETIC CHANGE IN SUBJECTS WITH PATELLOFEMORAL PAIN AFTER A NINE-WEEK HIP AND CORE STRENGTHENING INTERVENTION. AB - BACKGROUND: Idiopathic patellofemoral pain (PFP) has been linked to hip weakness and abnormal lower extremity mechanics. The effect of a strengthening intervention on balance has not been well studied among individuals with PFP. HYPOTHESIS/PURPOSE: The primary aim of this study was to evaluate changes in center of pressure displacement during the single limb squat following a nine week physical therapy intervention among adolescent females with PFP. STUDY DESIGN: Interventional and cross-sectional. METHODS: Seven adolescent females with PFP (10 extremities) were included in the study. Center of Pressure (CoP) excursions during a single limb squat task were measured before and after a nine week of physical therapy intervention focused on strengthening of the hip and core. Seven asymptomatic females were matched to the PFP group on the basis of age and activity level, and were tested as a reference group. CoP trajectories were reduced into four variables: mean distance (MDIST), root-mean-square distance (RDIST), range (RANGE), and 95% confidence interval circle area (AREA CC). Maximum knee flexion angle, peak knee power generation and absorption were also recorded. Linear mixed models were used to test for within and between group differences in CoP metrics. RESULTS: Pre-intervention, CoP range, knee power absorption and generation were significantly decreased in the PFP group relative to the reference group. Post-intervention, the PFP group reported a significant decrease in symptom severity. There was also a significant (p<0.05) increase in MDIST, RDIST, RANGE, AREA-CC, peak knee flexion angle, peak power absorption and power generation. There was no difference (p>0.05) in knee flexion, knee power or CoP displacement between the two groups after the physical therapy intervention. CONCLUSION: Hip and core-strengthening resulted in a significant decrease in symptom severity as well as significant reductions in CoP displacement. LEVEL OF EVIDENCE: 3. PMID- 28593086 TI - KINEMATIC AND KINETIC VARIABLES DIFFER BETWEEN KETTLEBELL SWING STYLES. AB - BACKGROUND: Kettlebell (KB) and indian club swings (ICS) are used diversely for developing strength and power. It has been proposed that multiple swing techniques can be used interchangeably to elicit similar adaptations within performance training. Hypothesis/Purpose: It was hypothesized that there will be not be a difference in peak joint angles between types of swings. Furthermore, given the nature of the overhead kettlebell swing (OKS), it was hypothesized that the OKS will be associated with a greater cycle time and a greater vertical impulse compared to shoulder height swing (SKS) and ICS. The purpose of this study was to analyze the kinematics and kinetics of the SKS, OKS, and ICS. STUDY DESIGN: Cross-sectional cohort. METHODS: Fifteen healthy subjects underwent 3D biomechanical analysis for assessment of kinematic and kinetic data. Subjects performed two trials of ten repetitions at full effort for each swing in a randomized order using either a standard set of 0.45 kg indian clubs or sex specific KB loads (Female = 12kg, Male = 20kg). Lower extremity sagittal plane kinematics and kinetics were analyzed for peak values during the down and up portions of the swing patterns. Statistical analyses were carried out utilizing one-way ANOVAs (p<.05) and effect size indices. RESULTS: Cycle time for the OKS was 34% longer than the SKS and ICS (p<.001; ESISKS = 2.09, ESIICS=1.92). In general, ankle (SKS: 0.82 +/- 0.16; OKS: 0.90 +/- 0.21; ICS: 0.60 +/- 0.15 BW*BH) and hip joint moments (SKS: 2.34 +/- 0.68; OKS: 2.32 +/- 0.53; ICS: 1.84 +/- 0.47 BW*BH) and joint powers, along with peak vertical ground reaction forces (vGRF) (SKS: 0.98 +/- 0.14; OKS: 0.96 +/- 0.10; ICS: 0.86 +/- 0.11 BW/s), were higher in the SKS and OKS than the ICS (p<.001; ankle: ESISKS/OKS=0.43, ESISKS/ICS=1.42; hip: ESISKS/OKS=0.03, ESISKS/ICS=0.87; vGRF: ESISKS/OKS=1.80, ESISKS/ICS=0.20). There were no observed differences found in peak joint angles between the movements. CONCLUSION: Although these swings are kinematically similar, the differing kinetic demands of these exercises may be important in selecting the right training modality for specific strength and power training. LEVEL OF EVIDENCE: 2. PMID- 28593087 TI - A DYNAMIC VALGUS INDEX THAT COMBINES HIP AND KNEE ANGLES: ASSESSMENT OF UTILITY IN FEMALES WITH PATELLOFEMORAL PAIN. AB - BACKGROUND: Two=dimensional motion analysis of lower=extremity movement typically focuses on the knee frontal plane projection angle, which considers the position of the femur and the tibia. A measure that includes the pelvis may provide a more comprehensive and accurate indicator of lower=extremity movement. Hypothesis/Purpose: The purpose of the study was to describe the utility of a two=dimensional dynamic valgus index (DVI) in females with patellofemoral pain. The hypothesis was that the DVI would be more reliable and valid than the knee frontal plane projection angle, be greater in females with patellofemoral pain during a single=limb squat than in females without patellofemoral pain, and decrease in females with patellofemoral pain following instruction. Study Design: Controlled Laboratory Study. METHODS: Data were captured while participants performed single limb squats under two conditions: usual and corrected. Two=dimensional hip and knee angles and a DVI that combined the hip and knee angles were calculated. Three=dimensional sagittal, frontal, and transverse plane angles of the hip and knee and a DVI combining the frontal and transverse plane angles were calculated. RESULTS: The two=dimensional DVI demonstrated moderate reliability (ICC=0.74). The correlation between the two=dimensional and three=dimensional DVI's was 0.635 (p<0001). Females with patellofemoral pain demonstrated a greater two=dimensional DVI (31.14 degrees +/-13.36 degrees ) than females without patellofemoral pain (18.30 degrees +/-14.97 degrees ; p=0.010). Females with patellofemoral pain demonstrated a decreased DVI in the corrected (19.04 degrees +/-13.70 degrees ) versus usual (31.14 degrees +/ 13.36 degrees ) condition (p=0.001). CONCLUSION: The DVI is a reliable and valid measure that may provide a more comprehensive assessment of lower=extremity movement patterns than the knee frontal plane projection angle in individuals with lower=extremity musculoskeletal pain problems. LEVEL OF EVIDENCE: 2b. PMID- 28593088 TI - THE ASSOCIATIONS BETWEEN HIP STRENGTH AND HIP KINEMATICS DURING A SINGLE LEG HOP IN RECREATIONAL ATHLETES POST ACL RECONSTRUCTION COMPARED TO HEALTHY CONTROLS. AB - BACKGROUND: Only a small amount of evidence exists linking hip abductor weakness to dynamic knee valgus during static and dynamic activities. The associations of hip extensor strength and hip kinematics during the landing of a single leg hop are not known. Purpose: To determine if relationships exist between hip extensor and abductor strength and hip kinematics in both involved and uninvolved limb during the landing phase of a single leg hop in recreational athletes post anterior cruciate ligament (ACL) reconstruction. The presence of similar associations was also evaluated in healthy recreational athletes. STUDY DESIGN: Controlled Laboratory Study; Cross-sectional. METHODS: Twenty-four recreational college-aged athletes participated in the study (12 post ACL reconstruction; 12 healthy controls). Sagittal and frontal plane hip kinematic data were collected for five trials during the landing of a single leg hop. Hip extensor and abductor isometric force production was measured using a hand-held dynamometer and normalized to participants' height and weight. Dependent and independent t-tests were used to analyze for any potential differences in hip strength or kinematics within and between groups, respectively. Pearson's r was used to demonstrate potential associations between hip strength and hip kinematics for both limbs in the ACL group and the right limb in the healthy control group. RESULTS: Independent t-tests revealed that participants post ACL reconstruction exhibited less hip extensor strength (0.18 N/Ht*BW vs. 0.25 N/Ht*BW, p=<.01) and landed with greater hip adduction (9.0 o vs. 0.8 o, p=<.01) compared with their healthy counterparts. In the ACL group, Pearson's r demonstrated a moderate and indirect relationship (r=-.62, p=.03) between hip extensor strength and maximum hip abduction/adduction angle in the involved limb. A moderate and direct relationship between hip abductor strength and maximum hip flexion angle was demonstrated in the both the involved (r=.62) and uninvolved limb (r=.65, p=.02). No significant associations were demonstrated between hip extensor or abductor strength and hip flexion and/or abduction/adduction angles in the healthy group. CONCLUSION: The results suggest that hip extensors may play a role in minimizing hip adduction in the involved limb while the hip abductors seem to play a role in facilitating hip flexion during the landing phase of a single leg hop for both limbs following ACL reconstruction. Researchers and clinicians alike should consider the importance of the hip extensors in playing a more prominent role in contributing to frontal plane motion. LEVELS OF EVIDENCE: Level 2a. PMID- 28593089 TI - INJURY INCIDENCE, DANCE EXPOSURE AND THE USE OF THE MOVEMENT COMPETENCY SCREEN (MCS) TO IDENTIFY VARIABLES ASSOCIATED WITH INJURY IN FULL-TIME PRE-PROFESSIONAL DANCERS. AB - BACKGROUND/PURPOSES: Prospective studies utilizing standardized injury and exposure measures are needed to consolidate our knowledge of injury incidence and associated risk factors for musculoskeletal injury amongst pre-professional dancers. The purpose of this study was to investigate the injury incidence amongst pre-professional dancers attending a fulltime training school in New Zealand. The secondary purposes of this study were to investigate the relationship between dance exposure and injury risk, and the relationship between risk factors (specifically the MCS outcome scores) and injury risk. METHODS: A prospective cohort study of 66 full-time pre-professional dancers was undertaken over one full academic year (38 weeks), included 40 females (mean age 17.78 yrs, SD 1.18) and 26 males (mean age 18.57yrs, SD 1.72). Injury surveillance included both reported and self reported injury data. Dancers were screened using the MCS in the first week of term one. RESULTS: Eighty-six per cent of dancers sustained one or more injuries. Fifty-nine per cent of all injuries were time-loss. The injury incidence rate was 2.27 per 1000 hours of dance exposure (DEhr) and 3.35 per 1000 dance exposures (DE). There was a significant association between the total number of injuries and total DE per month (B=0.003, 95% CI 0.001 - 0.006, p=0.016). Dancers who had a MCS score < 23 were more likely to be injured than those who scored >=23 (B = -0.702, 95% CI = -1.354 - -0.050, p=0.035). CONCLUSION: Injury prevalence and incidence was comparable with other international cohorts. The number of dance exposures was more highly associated with injury risk than the hours of dance exposure. The MCS may be a useful tool to help identify dancers at risk of injury. LEVEL OF EVIDENCE: Level 3b, Prospective Longitudinal Cohort Study. PMID- 28593090 TI - DYNAMIC HIP ADDUCTION, ABDUCTION AND ABDOMINAL EXERCISES FROM THE HOLMICH GROIN INJURY PREVENTION PROGRAM ARE INTENSE ENOUGH TO BE CONSIDERED STRENGTHENING EXERCISES - A CROSS-SECTIONAL STUDY. AB - BACKGROUND: Training intensity is an important variable in strength training and above 80% of one repetition maximum is recommended for promoting strength for athletes. Four dynamic and two isometric on-field exercises are included in the Holmich groin-injury prevention study that initially failed to show a reduction in groin injuries in soccer players. It has been speculated that exercise intensity in this groin-injury prevention program was too low to induce the strength gains necessary to protect against groin-related injuries. PURPOSE: To estimate the intensity of the six exercises from the Holmich program using electromyography (EMG) and possibly categorize them as strength-training exercises. STUDY DESIGN: Cross-sectional study. METHODS: 21 adult male soccer players training >5 hours weekly were included. Surface-EMG was recorded from adductor longus, gluteus medius, rectus abdominis and external obliques during isometric adduction against a football placed between the ankles (IBA), isometric adduction against a football placed between the knees (IBK), folding knife (FK), cross-country skiing on one leg (CCS), adduction partner (ADP) and abduction partner (ABP). The EMG-signals were normalized (nEMG) to an isometric maximal voluntary contraction for each tested muscle. RESULTS: Adductor longus activity during IBA was 84% nEMG (95% CI: 70-98) and during IBK it was 118% nEMG (95% CI 106-130). For the dynamic exercises, ADP evoked 87% nEMG (95% CI 69-105) in adductor longus, ABP evoked 88% nEMG (95% CI 76-100) in gluteus medius, FK evoked 82% nEMG (95% CI 68-96) rectus abdominis, and 101% nEMG (95% CI 85-118) in external obliques. During CSS < 37% nEMG was evoked from all muscles. CONCLUSION: These data suggest that exercise-intensity of all the six investigated exercises in the Holmich groin injury prevention program, except cross-county skiing, is sufficient to be considered strength-training for specific muscle groups in and around the groin region. LEVEL OF EVIDENCE: 3. PMID- 28593091 TI - A COMPREHENSIVE INSTRUMENT FOR EVALUATING MILD TRAUMATIC BRAIN INJURY (MTBI)/CONCUSSION IN INDEPENDENT ADULTS: A PILOT STUDY. AB - BACKGROUND: One common component of concussion rehabilitation is a computerized cognitive test free of concomitant physical demands. Healthcare professionals may be able to provide more patient-centered care after a diagnosed concussion if specific areas of impairment are identified and treated, such as the physical aspect of neurocognitive function. Hypothesis/Purpose: To evaluate the test retest reliability of a unique combination of neurocognitive assessment tools currently utilized in concussion assessments into one single, inclusive instrument that measures both neurocognitive function and physical capability. STUDY DESIGN: Original research - diagnostic tests. METHODS: Fourteen individuals (nine males, age: 29 + 17.9, five females, age: 46.0 +/- 21.5 years) either with normal cognitive function (NBI) without history of a health event (e.g. cerebral vascular accident/stroke, mTBI) that resulted in brain injury within one year of the study, or who had suffered a health event that has resulted in a medically documented brain injury (BI) participated in the study. Participants completed the full hybrid assessment instrument for a baseline test, then completed a follow-up test using the same instrument within 72-96 hours of baseline. Test retest reliability was measured using Pearson product-moment correlations of the first and second testing sessions, and a two-way ANOVA (group between factor: NBI and BI and time within factor: session 1 and session 2) was performed on the summative scores to determine differences between each group. RESULTS: Test retest reliability was strong and statistical significant for both the NBI (r = .858, p = .014) and the BI (r = .967, p = .033) groups. There was a significant difference between summative scores for the NBI and BI groups (F1,20 = 42.325, p < .0001). CONCLUSION: The newly created Comprehensive Instrument for Evaluating Mild Traumatic Brain Injury (CIEMTBI) demonstrates good test-retest reliability and was able to discriminate the results between individuals in the NBI and BI groups. Further research, specifically with different samples, is needed to better determine the reliability and diagnostic accuracy of the instrument. LEVEL OF EVIDENCE: 2c. PMID- 28593092 TI - AORTIC INJURY DUE TO PARAGLIDING: A CASE REPORT. AB - : A 64-year-old male fell from an altitude of 10 m while paragliding after stalling due to the wind. The purpose of this case report is to describe the outcomes after multiple injuries sustained during a paragliding accident, including a potentially life-threating injury to the thoracic aorta. The subject sustained a bite wound on his tongue, injuries to his chest (left side) and back, and a right forearm deformity. Enhanced whole body computed tomography (CT) revealed fractures of the bilateral laminae of the second and third cervical bones, right first rib, the tenth thoracic vertebral body (compression type), second lumbar vertebral body (burst type) and the right radius, Other injuries included an injury to the thoracic aortic arch and the presence of intraabdominal fluid collection without perforation of the digestive tract. Endovascular treatment was selected for the aortic injury because of multiple injuries. Immediate management included hypotensive rate control therapy using calcium and a beta blocker. On the fourth hospital day, the subject underwent deployment of a stent-graft to the aorta and subsequent surgical immobilization for the lumbar burst fracture. He also underwent surgical immobilization of the radial fracture and was discharged on the 28th hospital day. First responders or physicians should consider the possibility of aortic injury when treating patients who suffer falls while paragliding and provide appropriate management. Failure to provide appropriate management of an aortic injury could result in death. LEVEL OF EVIDENCE: 4. PMID- 28593093 TI - SUPERIOR CAPSULE RECONSTRUCTION FOR MASSIVE ROTATOR CUFF TEARS - KEY CONSIDERATIONS FOR REHABILITATION. AB - : Superior capsule reconstruction is a recently-developed surgical technique for the treatment of massive, irreparable rotator cuff tears. So far, biomechanical cadaveric studies and clinical outcomes results have been promising concerning integrity, stability, and ROM after superior capsule reconstruction. As this technique has only been recently developed, an evidence-based rehabilitation protocol has not been previously designed. Thus, the purpose of this clinical commentary is to provide an overview of superior capsule reconstruction and to propose a rehabilitation program based on the available scientific evidence. The existing evidence is supplemented by the experience of the senior author who has performed more than forty superior capsule reconstruction procedures to date. This proposed rehabilitation protocol consists of four distinct phases, focusing on maximal protection, range of motion and muscular endurance, muscular strength and return to activity. LEVEL OF EVIDENCE: 5. PMID- 28593094 TI - ANODAL TRANSCRANIAL DIRECT CURRENT STIMULATION (TDCS) INCREASES ISOMETRIC STRENGTH OF SHOULDER ROTATORS MUSCLES IN HANDBALL PLAYERS. AB - BACKGROUND: Weakness of the rotator cuff muscles can lead to imbalances in the strength of shoulder external and internal rotators, change the biomechanics of the glenohumeral joint and predispose an athlete to injury. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has demonstrated promising results in a variety of health conditions. However few studies addressed its potential approach in the realm of athletics. HYPOTHESIS/PURPOSE: The purpose of this study was to investigate if transcranial direct current stimulation (tDCS) technique increases the isometric muscle strength of shoulder external and internal rotators in handball athletes. STUDY DESIGN: Randomized, double-blind, placebo-controlled, crossover study. METHODS: Eight female handball players aged between 17 and 21 years (Mean=19.65; SD=2.55) with 7.1 +/- 4.8 years of experience in training, participating in regional and national competitions were recruited. Maximal voluntary isometric contraction (MVIC) of shoulder external and internal rotator muscles was evaluated during and after 30 and 60 minutes post one session of anodal and sham current (2mA; 0.057mA/cm2) with a one-week interval between stimulations. RESULTS: Compared to baseline, MVIC of shoulder external and internal rotators significantly increased after real but not sham tDCS. Between-group differences were observed for external and internal rotator muscles. Maximal voluntary isometric contraction of external rotation increased significantly during tDCS, and 30 and 60 minutes post tDCS for real tDCS compared to that for sham tDCS. For internal rotation MVIC increased significantly during and 60 minutes post-tDCS. CONCLUSIONS: The results indicate that transcranial direct current stimulation temporarily increases maximal isometric contractions of the internal and external rotators of the shoulder in handball players. LEVEL OF EVIDENCE: 2. PMID- 28593095 TI - LOAD-ENHANCED MOVEMENT QUALITY SCREENING AND TACTICAL ATHLETICISM: AN EXTENSION OF EVIDENCE. AB - BACKGROUND: Military organizations use movement quality screening for prediction of injury risk and performance potential. Currently, evidence of an association between movement quality and performance is limited. Recent work has demonstrated that external loading strengthens the relationship between movement screens and performance outcomes. Such loading may therefore steer us toward robust implementations of movement quality screens while maintaining their appeal as cost effective, field-expedient tools. PURPOSE: The purpose of the current study was to quantify the effect of external load-bearing on the relationship between clinically rated movement quality and tactical performance outcomes while addressing the noted limitations. STUDY DESIGN: Crossover Trial. METHODS: Fifty young adults (25 male, 25 female, 22.98 +/- 3.09 years, 171.95 +/- 11.46 cm, 71.77 +/- 14.03 kg) completed the Functional Movement ScreenTM with (FMSTMW) and without (FMSTMC) a weight vest in randomized order. Following FMSTM testing, criterion measures of tactical performance were administered, including agility T Tests, sprints, a 400-meter run, the Mobility for Battle (MOB) course, and a simulated casualty rescue. For each performance outcome, regression models were selected via group lasso with smoothed FMSTM item scores as candidate predictor variables. RESULTS: For all outcomes, proportion of variance accounted for was greater in FMSTMW (R2 = ;0.22 [T-Test], 0.29 [Sprint], 0.17 [400 meter], 0.29 [MOB], and 0.11 [casualty rescue]) than in FMSTMC (R2 = ;0.00 [T-Test], 0.11 [Sprint], 0.00 [400 meter], 0.19 [MOB], and 0.00 [casualty rescue]). From the FMSTMW condition, beneficial performance effects (p<0.05) were observed for Deep Squat (sprint, casualty rescue), Hurdle Step (T-Agility, 400 meter run), Inline Lunge (sprint, MOB), and Trunk Stability Push Up (all models). Similar effects for FMSTMC item scores were limited to Trunk Stability Push Up (p<0.05, all models). CONCLUSIONS: The present study extends evidence supporting the validity of load-enhanced movement quality screening as a predictor of tactical performance ability. Future designs should seek to identify mechanisms explaining this effect. LEVEL OF EVIDENCE: 3. PMID- 28593096 TI - EMG OF SHOULDER MUSCLES DURING REACTIVE ISOMETRIC ELASTIC RESISTANCE EXERCISES. AB - BACKGROUND: Traditionally, shoulder isometrics are introduced in the early stages of shoulder rehabilitation. A patient's isometric torque output is based on a subjective perception of force generation. By utilizing elastic resistance elongation (strain) to standardize force output, clinicians could prescribe shoulder therapeutic isometrics based on % maximum voluntary contraction (%MVC). PURPOSE/HYPOTHESIS: The purpose of this study was to measure electromyographic (EMG) activity and determine the %MVC during shoulder flexion, external rotation and abduction isometrics at varying lengths of TheraBand(r) elastic resistance. It was hypothesized that increased elongation of progressive resistance bands would proportionately increase the %MVC of the shoulder musculature. STUDY DESIGN: Laboratory design using healthy subjects. METHODS: Eight healthy subjects (16 shoulders) (5 females, 3 males; avg. age 29.2) were tested. Surface EMG electrodes were placed over the anterior deltoid, middle deltoid, and infraspinatus muscles. A force transducer was anchored to a stable surface with its corresponding end in series with an extremity strap securely holding the elastic band. Subjects were asked to maintain shoulder position for the proper isometric contraction (flexion, abduction and external rotation) while taking incremental steps away from the anchored elastic resistance, to the beat of a metronome to clearly marked distances on the floor (50, 100, 150, 200 and 250% of band elongation). This was repeated with yellow, red, green, and blue TheraBand(r) resistance levels. Maximum voluntary contractions for both force and EMG were collected for each subject in all three test positions. EMG data were normalized and expressed as a %MVC. RESULTS: For external rotation and flexion, the infraspinatus and anterior deltoid activity increased with band elongation (p<0.01) and progressive colors (p<0.01). The increases in EMG activity with elongation plateaued with the yellow and red bands but continued to increase with the green and blue bands (p<0.01). The increase in infraspinatus and anterior deltoid EMG activity with progressive band color was more apparent for green and blue bands compared with yellow and red band (p<0.01). For the abduction exercise, middle deltoid activity increased with band elongation (p<0.01) and progressive color (p<0.01). In all three exercises, there was an increase in force exerted by the band with increasing length and band color (p < 0.001). However, while there were clear increases in force from red to green to blue, there was no difference in force between yellow and red regardless of elongation (p<0.01). CONCLUSION: Isometric flexion, external rotation and abduction muscle activity can be accurately prescribed clinically by adjusting the elongation and resistance associated with progressive colors of resistance bands. LEVEL OF EVIDENCE: 3. PMID- 28593097 TI - THE EFFECT OF ELECTRICAL STIMULATION VERSUS SHAM CUEING ON SCAPULAR POSITION DURING EXERCISE IN PATIENTS WITH SCAPULAR DYSKINESIS. AB - BACKGROUND: Conventional therapeutic exercise programs are commonly used to treat patients with scapular dyskinesis. There are no studies that have examined traditional therapeutic exercise programs with the addition of remote triggered electrical stimulation (ES) to affect the position of the scapula (using spine to scapular border distance as a reference point) during the performance of exercises that have lower upper trapezius (UT) to lower trapezius (LT) ratio exercises. PURPOSE: The purpose of this pilot study was to compare scapular position after performance of three low UT/LT ratio therapeutic exercises in two conditions, electrical stimulation (ESTherex) and sham electrical stimulation (ShamTherex) in asymptomatic persons who were positive for scapular dyskinesis. STUDY DESIGN: Randomized trial, single-blinded. METHODS: Eleven asymptomatic university students representing 15 scapulae with a positive Scapular Dyskinesis Test were recruited as subjects. Participants were randomized into exercise and electrical stimulation (ESTherex) or exercise and sham electrical stimulation (ShamTherex). Subjects performed side-lying shoulder external rotation and flexion, and prone horizontal abduction with external rotation in both conditions. Scapular position was assessed during active abduction at four angles before and after performance of these exercises. RESULTS: There were no significant differences in scapula to spine distance between ESTherex and ShamTherex groups at 0, 45, 90 and 120 degrees of shoulder abduction. A between group difference (ESTherex and ShamTherex) approached significance at 45 degrees (p = 0.089, CI=-.152 to 1.88 cm) with the post mean measurement of the ShamTherex group (6.44 cm) greater than the post mean measurement of the ESTherex group (5.57 cm). The ESTherex showed a significant pre-to-post mean within group improvement in spine to scapula distance at 120 degrees (mean 2.76 cm, t=4.89, p=.003). CONCLUSIONS: Electrical stimulation with exercises for scapular dyskinesis showed improvements in spine to scapula distance at 120 degrees of shoulder abduction. LEVEL OF EVIDENCE: Therapy, level 1b. PMID- 28593098 TI - RELIABILITY AND VALIDITY OF A BIOMECHANICALLY BASED ANALYSIS METHOD FOR THE TENNIS SERVE. AB - BACKGROUND: An observational tennis serve analysis (OTSA) tool was developed using previously established body positions from three-dimensional kinematic motion analysis studies. These positions, defined as nodes, have been associated with efficient force production and minimal joint loading. However, the tool has yet to be examined scientifically. PURPOSE: The primary purpose of this investigation was to determine the inter-observer reliability for each node between two health care professionals (HCPs) that developed the OTSA, and secondarily to investigate the validity of the OTSA. METHODS: Two separate studies were performed to meet these objectives. An inter-observer reliability study preceded the validity study by examining 28 videos of players serving. Two HCPs graded each video and scored the presence or absence of obtaining each node. Discriminant validity was determined in 33 tennis players using video taped records of three first serves. Serve mechanics were graded using the OSTA and categorized players into those with good ( >= 5) and poor ( <= 4) mechanics. Participants performed a series of field tests to evaluate trunk flexibility, lower extremity and trunk power, and dynamic balance. RESULTS: The group with good mechanics demonstrated greater backward trunk flexibility (p=0.02), greater rotational power (p=0.02), and higher single leg countermovement jump (p=0.05). Reliability of the OTSA ranged from K = 0.36-1.0, with the majority of all the nodes displaying substantial reliability (K>0.61). CONCLUSION: This study provides HCPs with a valid and reliable field tool used to assess serve mechanics. Physical characteristics of trunk mobility and power appear to discriminate serve mechanics between players. Future intervention studies are needed to determine if improvement in physical function contribute to improved serve mechanics. LEVEL OF EVIDENCE: 3. PMID- 28593099 TI - DO GENERAL MEDICAL PRACTITIONERS EXAMINE INJURED RUNNERS? AB - BACKGROUND: General Medical Practitioners (GMP) in Denmark perform clinical examinations of patients with musculoskeletal pain. However, the prevalence proportion of examinations caused by running-related injuries remains unknown. PURPOSE: The primary purpose of the present study was to estimate the prevalence proportion of consultations in general medical practice caused by running-related injuries. The secondary purpose was to estimate the prevalence proportion of injured runners, who consult their GMP, that are referred to additional examinations or treatments. STUDY DESIGN: A survey-based study. METHODS: An online survey was distributed in October and November 2015 to more than 370 GMPs in Denmark and completed by 27. RESULTS: The median prevalence proportion of consultations caused by running-related injuries in the prior two weeks was 0.80% [25th percentile = 0.00%; 75th percentile = 1.43%]. Ten (37%) GMPs reported to refer between 0-24% of the injured runners to additional examination or treatment, whereas thirteen (48%) of GMPs referred between 25-49% and four (15%) referred 50-74% of injured runners. CONCLUSION: Although a very small part (<1%) of the GMPs consultations were related to running injuries, this result suggests that injured runners seek advice in the primary health-care system in Denmark. As a consequence, physiotherapists willing to treat runners with running-related injuries may inform the GMPs in their local community about the treatment possibilities they offer. The low response-proportion highlights the challenges recruiting GMPs willing to respond to questionnaires on running-related injuries. It is plausible to assume that the estimates reported in the present study are overestimated owing to selection bias. LEVEL OF EVIDENCE: 3. PMID- 28593100 TI - IMPAIRMENT BASED EXAMINATION AND TREATMENT OF COSTOCHONDRITIS: A CASE SERIES. AB - BACKGROUND: Costochondritis is commonly encountered in primary care, but is not routinely referred to PT. Costochondritis can last from several weeks to several months, limiting the patient's ability to perform tasks at work and home. PURPOSE: Identify common impairments and examine the effects of treatment in subjects with costochondritis. STUDY DESIGN: Retrospective case series. CASE DESCRIPTION: Eight subjects were referred to physical therapy for costochondritis (mean duration of condition 6.3 +/- 1.3 months) and reported that their condition restricted their ability to participate in occupational and fitness activities. The numerical pain rating scale (NPRS) and patient-specific functional scale (PSFS) were administered at the initial evaluation and at discharge. The Global Rating of Change (GROC) scale was only administered at discharge. All subjects received treatment directed at the cervicothoracic spine and ribcage and consisting of manual therapy and exercise. OUTCOMES: Subjects were seen 4.8 +/- 0.9 (mean+/-standard deviation) times. All subjects showed clinically meaningful changes at discharge. The mean NPRS decreased by 5.1 +/- 1.7 points; the mean PSFS increased by 5.3 +/- 1.4 points; and the mean GROC was 5.9 +/- 1.1 points. All subjects were able to return to participation in previous activities without restrictions at discharge. DISCUSSION - CONCLUSION: The results of this case series suggests that PT utilizing an impairment based examination and treatment approach including manual therapy and therapeutic exercise may facilitate the resolution of costochondritis. LEVEL OF EVIDENCE: Level IV. PMID- 28593101 TI - DRY NEEDLING INCREASES MUSCLE THICKNESS IN A SUBJECT WITH PERSISTENT MUSCLE DYSFUNCTION: A CASE REPORT. AB - BACKGROUND AND PURPOSE: Muscle dysfunction is very common following musculoskeletal injury. There is very little evidence to suggest that muscle function may be positively impacted by soft tissue interventions, such as dry needling. The purpose of this case report is to describe the immediate effect of dry needling on muscle thickness in a subject after shoulder surgery. CASE DESCRIPTION: A 22 year-old competitive gymnast presented seven months post shoulder surgery with significant impairments and functional limitations. Previous physical therapy focused on restoration of range of motion and strength using general exercise interventions, but the subject had persistent tightness and weakness of musculature of the shoulder complex. A subject-specific physical therapy program including manual physical therapy resulted in significant initial improvement, but lack of flexibility and weakness of the rotator cuff limited progress. Dry needling was used to address persistent myofascial trigger points. OUTCOMES: Immediately after dry needling the infraspinatus, the muscle's thickness was significantly improved as measured by rehabilitative ultrasound imaging. There was a corresponding increase in force production of external rotation at 90 degrees of abduction. DISCUSSION: Minimal research exists that validates the potential of dry needling on muscle function, as assessed by muscle thickness measured using rehabilitative ultrasound imaging. The results of this case report suggest that dry needling contributed to improvement in muscle thickness and strength in a subject with muscle dysfunction following an injury. LEVEL OF EVIDENCE: 4. PMID- 28593103 TI - Natural History of Rod-Mediated Dark Adaptation over 2 Years in Intermediate Age Related Macular Degeneration. AB - PURPOSE: To characterize the natural history of rod-mediated dark adaptation (RMDA) over 2 years in eyes with intermediate age-related macular degeneration (AMD). This information will be useful in understanding the potential of RMDA to serve as a functional endpoint in proof-of-concept studies and clinical trials on intermediate AMD. METHODS: RMDA was measured in eyes with intermediate AMD at baseline and follow-up visits over 2 years at 6, 12, 18, and 24 months. A computerized dark adaptometer measured sensitivity for targets centered at 11 degrees on the superior vertical meridian of the retina. Rod intercept time (RIT) characterized the speed of dark adaptation and was defined as the duration (in minutes) required for sensitivity to reach a criterion level of 3.0 log units of attenuation of the stimulus. RESULTS: Mean change in RIT over 24 months for 30 eyes was 10.5 minutes (standard deviation 19.4), p < 0.0001; 73.3% of eyes had a RIT increase >1 minute, 56.7% had an increase >3 minutes, and 36.7% had an increase >6 minutes; for 26.7% RIT was unchanged (0- to 1-minute increase) or decreased. Greater increase in RIT over 24 months was associated with smoking. CONCLUSIONS: RMDA slows in intermediate AMD over 2 years in most eyes. There was wide variability in RIT at both baseline and in the extent to which it increased over 24 months. A major risk factor for AMD, smoking, exacerbated RMDA slowing. TRANSLATIONAL RELEVANCE: RMDA as assessed by RIT may be useful as a functional endpoint in proof-of-concept studies and clinical trials on intermediate AMD with 2-year designs. PMID- 28593102 TI - REHABILITATION FOLLOWING MEDIAL PATELLOFEMORAL LIGAMENT RECONSTRUCTION FOR PATELLAR INSTABILITY. AB - : Patellar instability is a common problem seen by physical therapists, athletic trainers and orthopedic surgeons. Although following an acute dislocation, conservative rehabilitation is usually the first line of defense; refractory cases exist that may require surgical intervention. Substantial progress has been made in the understanding of the medial patellofemoral ligament (MPFL) and its role as the primary stabilizer to lateral patellar displacement. Medial patellofemoral ligament disruption is now considered to be the essential lesion following acute patellar dislocation due to significantly high numbers of ruptures following this injury. Evidence is now mounting that demonstrates the benefits of early reconstruction with a variety of techniques. Recently rehabilitation has become more robust and progressive due to our better understanding of soft tissue reconstruction and repair techniques. The purpose of this manuscript is to describe the etiology of patellar instability, the anatomy and biomechanics and examination of patellofemoral instability, and to describe surgical intervention and rehabilitation following MPFL rupture. LEVEL OF EVIDENCE: 5. PMID- 28593106 TI - A Post Hoc Summary of a Memorable Annual Meeting: The 27th Annual NASBS Meeting: March 1-5, 2017; The Roosevelt Hotel, New Orleans, Louisiana, United States. PMID- 28593105 TI - Photobiomodulation with Near Infrared Light Helmet in a Pilot, Placebo Controlled Clinical Trial in Dementia Patients Testing Memory and Cognition. AB - Alzheimer's disease (AD) is a common, chronic expensive debilitating neurodegenerative disease with no current treatments to prevent the physical deterioration of the brain and the consequent cognitive deficits. The current pathophysiology of Alzheimer's disease is the accumulation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau protein and amyloid-beta (Abeta) plaques. Antibody therapy of Tau and Amyloid beta, vaccines and other methods to decrease Tau and or Amyloid have not been successful after considerable pharmaceutical and biotech efforts. For example, Eli Lilly announced a major change to its closely watched clinical trial for the Alzheimer's drug solanezumab which failed to reach statistical significance. Recently, a report on animal models using photomodulation with near infrared light to treat AD pathology in K369I tau transgenic model (K3) l engineered to develop neurofibrillary tangles, and the APPs/PSEN1dE9 transgenic model (APP/PS1) to develop amyloid plaques. Mice were treated with NIR 20 times over a four-week period and NIR treatment (600 1000 nm) was associated with a reduction in the size and number of amyloid-beta plaques in the neocortex and hippocampus. We now report a small pilot double blind, placebo-controlled trial (n=11) 6 active, 3 controls and 2 dropouts assessing the effect of 28 consecutive, sixminute transcranial sessions of near infrared (NIR) stimulation using 1060-1080 nm light emitting diodes. Subjects were independently diagnosed with dementia conducted in an outpatient behavioral healthcare clinic. IRB approval was obtained through the Quietmind Foundation's institutional review Board (IRB). Results showed changes in executive functioning; clock drawing, immediate recall, praxis memory, visual attention and task switching (Trails A&B) as well as a trend of improved EEG amplitude and connectivity measures. Neuroplasticity has also been reported with NIR light stimulation and mitochondrial enhancement. PMID- 28593107 TI - Minimally Invasive Approach for Resection of Parameningeal Rhabdomyosarcoma. AB - Background About one-third of rhabdomyosarcomas arise in the head and neck, with parameningeal primaries accounting for half of these. Principles of management involve chemotherapy, radiation, or both, in addition to surgical biopsy, debulking, and complete or near-complete resection. In the head and neck, diagnostic biopsies have historically been performed without attempt at resection due to proximity to critical structures and cosmetic considerations. Methods Retrospective chart review of three cases of rhabdomyosarcoma at the cranial base managed through minimally invasive endoscopic surgical resection and adjuvant therapy. Results Three patients were identified as having undergone endoscopic surgical debulking or margin-negative resection of a rhabdomyosarcoma of the cranial base. Two of three patients had complete resection based on intraoperative margin control. All three patients underwent adjuvant therapy within 1 month of diagnosis. Follow-up time ranged from 5 months to 3 years with all patients disease-free at last follow-up. Conclusion Skull base surgeons should routinely be involved in multidisciplinary treatment planning for parameningeal rhabdomyosarcomas, as surgical options have evolved to allow for potential endoscopic resection with low morbidity and no or minimal delay in additional treatment options. PMID- 28593109 TI - Extent of Endoscopic Resection for Anterior Skull Base Tumors: An MRI-Based Volumetric Analysis. AB - Objective To determine the volume of ventral skull base tumor removed following endoscopic endonasal (EEA) resection using MRI-based volumetric analysis and to evaluate the inter-rater reliability of such analysis. Design Retrospective case series. Setting Academic tertiary care hospital. Participants EEA patients November 2012 to August 2015. Main Outcome Measures Volumetric analysis of pre- and immediately postoperative MR imaging was performed independently by two investigators. The percentage of total tumor resected was evaluated according to resection goal and tumor type. Results A total of 39 patients underwent resection. Intraclass correlation coefficients between the raters were 0.9988 for preoperative and 0.9819 for postoperative images. Tumors (and average percentage removed) included 17 nonsecreting pituitary adenomas (95.3%), 8 secreting pituitary adenomas (86.2%), 4 meningiomas (81.6%), 3 olfactory neuroblastomas (100%), 2 craniopharyngiomas (100%), 1 large B-cell lymphoma (90.5%), 1 germ cell neoplasm (48.3), 1 benign fibrous connective tissue mass (93.4%), 1 epidermoid cyst (68.4%), and 1 chordoma (100%). For tumors treated with intent for gross total resection, 96.9 +/- 4.8% was removed. Conclusion EEAs achieved tumor resection rates of ~97% when total resection was attempted. The radiographic finding of residual tumor is of uncertain clinical significance. The volumetric analysis employed in this study demonstrated high inter-rater reliability and could facilitate further study. PMID- 28593104 TI - Acidic Ca2+ stores in neurodegeneration. AB - Lysosomes have emerged in the last decade as an immensely important intracellular site of Ca2+ storage and signalling. More recently there has been an increase in the number of new ion channels found to be functional on lysosomes and the potential roles that these signalling pathways might play in fundamental cellular processes are being uncovered. Defects in lysosomal function have been shown to result in changes in lysosomal Ca2+ homeostasis and ultimately can result in cell death. Several neurodegenerative diseases, from rare lysosomal storage diseases through to more common diseases of ageing, have recently been identified as having alterations in lysosomal Ca2+ homeostasis that may play an important role in neuronal excitotoxicity and ultimately cell death. This review will critically summarise these recent findings. PMID- 28593108 TI - Nano-hemostats and a Pilot Study of Their Use in a Large Animal Model of Major Vessel Hemorrhage in Endoscopic Skull Base Surgery. AB - Nano-hemostats are synthetic amino acid chains that self-assemble into a scaffold under certain conditions. These have been shown to be effective in stopping bleeding in small animal models of hemorrhage. Proposed mechanisms for their effect are that they form a mesh analogous to the fibrin plug in native hemostasis and that they may potentiate both platelet activation and the coagulation cascade. These may potentially become valuable adjuncts to endoscopic skull base surgery where there is the potential for both major vessel injury and smaller perforator injury to eloquent areas where bipolar cautery may not be suitable. We present a summary of the clinical studies to date and a small pilot study of nano-hemostat in an endoscopic sheep model of major vessel hemorrhage to determine its efficacy in stopping bleeding in this potentially catastrophic complication. PMID- 28593110 TI - Endoscopic Endonasal Transclival Approach versus Dual Transorbital Port Technique for Clip Application to the Posterior Circulation: A Cadaveric Anatomical and Cerebral Circulation Simulation Study. AB - Purpose Simulation training offers a useful opportunity to appreciate vascular anatomy and develop the technical expertise required to clip intracranial aneurysms of the posterior circulation. Materials and Methods In cadavers, a comparison was made between the endoscopic transclival approach (ETA) alone and a combined multiportal approach using the ETA and a transorbital precaruncular approach (TOPA) to evaluate degrees of freedom, angles of visualization, and ergonomics of aneurysm clip application to the posterior circulation depending on basilar apex position relative to the posterior clinoids. Results ETA alone provided improved access to the posterior circulation when the basilar apex was high riding compared with the posterior clinoids. ETA + TOPA provided a significantly improved functional working area for instruments and visualization of the posterior circulation for a midlevel basilar apex. A single-shaft clip applier provided improved visualization and space for instruments. Proximal and distal vascular control and feasibility of aneurysmal clipping were demonstrated. Conclusions TOPA is a medial orbital approach to the central skull base; a transorbital neuroendoscopic surgery approach. This anatomical simulation provides surgical teams an alternative to the ETA approach alone to address posterior circulation aneurysms, and a means to preoperatively prepare for intraoperative anatomical and surgical instrumentation challenges. PMID- 28593111 TI - Phantosmia and Dysgeusia following Endoscopic Transcribriform Approaches to Olfactory Groove Meningiomas. AB - The endoscopic, endonasal transcribriform approach (EETA) is an important technique used to directly access the anterior skull base and is increasingly being used in the management of olfactory groove meningiomas (OGMs). As this approach requires removal of the cribriform plate and olfactory epithelium en route to the tumor, patients are anosmic postoperatively. Here, we report the development of phantosmia and dysgeusia in two patients who underwent EETAs for OGMs, which has not yet been reported in the literature. We hypothesize that phantosmia and dysgeusia may result from aberrant neuronal signals or misinterpretation centrally from the remaining distal portions of the olfactory and taste pathways. Since EETAs are newer than traditional open craniotomy-based techniques, reporting these outcomes will be important to appropriately counsel patients preoperatively. PMID- 28593112 TI - Comparative Neurologic Outcomes of Salvage and Definitive Gamma Knife Radiosurgery for Glomus Jugulare: A 20-Year Experience. AB - Objective This case series investigates management of glomus jugulare (GJ) tumors utilizing definitive and salvage Gamma Knife stereotactic radiosurgery (GKSRS). Methods A retrospective chart review was performed to collect data. Statistical analysis included patient, tumor, and treatment information. Results From 1996 to 2013, 17 patients with GJ received GKSRS. Median age was 64 years (range, 27-76). GKSRS was delivered for definitive treatment in eight (47%) and salvage in nine (53%) patients. Median tumor volume was 9.8 cm 3 (range, 2.8-42 cm 3 ). Median dose was 15 Gy (range, 13-18 Gy). Median follow-up was 123 months (range, 38-238 months). Tumor size decreased in 10 (59%), stabilized in 6 (35%), and increased in 1 patient (6%). Overall neurological deficit improved in 53%, stabilized in 41%, and worsened in 6% of patients. Overall cause-specific survival was 100%, and actuarial local control was 94%. Eighty-eight percent of patients without prior resection experienced neurologic deficit improvement, while 25% of patients with prior resection experienced neurologic improvement ( p = 0.02). Conclusion Gamma Knife radiosurgery provides effective long-term control of GJ and overall improvement or stabilization of neurological deficit in most patients. Patients with prior resection are less likely to experience improvement of neurologic deficit. PMID- 28593114 TI - Transient Exacerbation of Nasal Symptoms following Endoscopic Transsphenoidal Surgery for Pituitary Tumors: A Prospective Study. AB - Object Endoscopic transsphenoidal surgery is the commonest approach to pituitary tumors. One disadvantage of this approach is the development of early postoperative nasal symptoms. Our aim was to clarify the peak onset of these symptoms and their temporal evolution. Methods The General Nasal Patient Inventory (GNPI) was administered to 56 patients undergoing endoscopic transsphenoidal surgery for pituitary tumors preoperatively and at 1 day, 3 days, 2 weeks, 3 months, and 6 to 12 months postoperatively. Most patients underwent surgery for pituitary adenomas ( N = 49; 88%) and through a uninostril approach ( N = 55; 98%). Total GNPI (0-135) and scores for the 45 individual components were compared. Results GNPI scores peaked at 1 to 3 days postoperatively, with rapid reduction to baseline by 2 weeks and below baseline by 6 to 12 months postsurgery ( p < 0.01). Of the 45 individual symptoms on the GNPI scale, 19 (42%) worsened transiently after surgery ( p < 0.05). Functioning tumors had a higher GNPI scores at postoperative day 1 and 3 than nonfunctioning tumors, although their temporal evolution was the same ( p < 0.05). Conclusions Nasal morbidity following endoscopic transsphenoidal pituitary surgery is common, but transient, more so in the functioning subgroup. Nasal symptoms improve below baseline by 6 to 12 months, without the need for specific long-term postoperative interventions in the vast majority of patients. PMID- 28593115 TI - Clival Osteomyelitis Presenting as a Skull Base Mass. AB - Central skull base osteomyelitis is a rare, but potentially life-threatening disease entity often lacking otologic symptoms or external auditory canal pathology. We present a case of a man in his 70s who had developed cranial nerve deficits with radiographic evidence that was consistent with a tumor due to this uncommon entity. The radiologic findings and our experience are discussed to increase awareness in the otolaryngology community. PMID- 28593113 TI - The Added Value of Diffusion Magnetic Resonance Imaging in the Diagnosis and Posttreatment Evaluation of Skull Base Chordomas. AB - Objectives To determine the use of diffusion-weighted imaging (DWI) in the pre- and posttreatment evaluation of skull base chordomas. Design Retrospective study. Setting Tertiary care university hospital. Participants In total, 17 patients with histopathological diagnosis of chordoma who had magnetic resonance (MR) imaging and DWI were evaluated. Of them, 13 patients had posttreatment MR imaging including DWI. Main Outcome Measures Three apparent diffusion coefficient (ADC) values were obtained from tumor, and an ADC value was measured from pons for the purpose of normalization. ADC values of the subtypes of chordomas (typical and chondroid chordomas) were compared. Results Ten (59%) masses had increased signal on trace DWI at pretreatment evaluation. The mean ADC entire tumor /ADC pons was calculated as 1.55 +/- 0.44. The mean ADC entire tumor values of typical and chondroid chordomas were 1.26 +/- 0.29 * 10 -3 mm 2 /s and 0.99 +/- 0.46 * 10 -3 mm 2 /s, respectively. There was no statistically significant difference between ADC values of the subtypes ( p > 0.05). For posttreatment evaluation, DWI enabled detection of residual tumor in the majority (85%) of cases. Conclusions DWI is useful in diagnosis and posttreatment evaluation of skull base chordomas. However, ADC values in our series did not distinguish the subtypes of chordomas. PMID- 28593116 TI - Bridging the gap between clinical practice and public health: Using EHR data to assess trends in the seasonality of blood-pressure control. AB - Electronic health records (EHRs) provide timely access to millions of patient data records while limiting errors associated with manual data extraction. To demonstrate these advantages of EHRs to public health practice, we examine the ability of a EHR calculated blood-pressure (BP) measure to replicate seasonal variation as reported by prior studies that used manual data extraction. Our sample included 609 primary-care practices in New York City. BP control among hypertensives was defined as systolic blood pressure of 140 or less and diastolic blood pressure of 90 or less (BP < 140/90 mm Hg). An innovative query distribution system was used to extract monthly BP control values from the EHRs of adult patients diagnosed with hypertension over a 25-month period. Generalized estimating equations were used to compare the association between seasonal temperature variations and BP control rates at the practice level, while adjusting for known demographic factors (age, gender), comorbid diseases (diabetes) associated with blood pressure, and months since EHR implementation. BP control rates increased gradually from the spring months to peak summer months before declining in the fall months. In addition to seasonal variation, the adjusted model showed that a 1% increase in patients with a diabetic comorbidity is associated with an increase of 3% (OR 1.03; CI 1.028-1.032) on the BP measure. Our findings identified cyclic trends in BP control and highlighted greater association with increased proportion of diabetic patients, therefore confirming the ability of the EHR as a tool for measuring population health outcomes. PMID- 28593117 TI - Seasonality in swimming and cycling: Exploring a limitation of accelerometer based studies. AB - Accelerometer-based studies of children's physical activity have reported seasonal patterns in activity levels. However, the inability of many accelerometers to detect activity while the wearer is swimming or cycling may introduce a bias to the estimation of seasonality if participation in these activities are themselves seasonally patterned. We explore seasonal patterns in children's swimming and cycling among a sample of 7-8 year olds (N = 591) participating in the Millennium Cohort Study, UK. Participating children wore an accelerometer for one week on up to five occasions over the year and their parents completed a diary recording daily minutes spent swimming and cycling. Both swimming and cycling participation showed seasonal patterns, with 2.7 (SE 0.8) more minutes swimming and 5.7 (0.7) more minutes cycling performed in summer compared to winter. Adding swimming and cycling time to accelerometer-determined MVPA increased the summer-winter difference in MVPA from 16.6 (1.6) to 24.9 min. The seasonal trend in swimming and cycling appears to follow the same pattern as accelerometer-measured MVPA. Studies relying solely on accelerometers may therefore underestimate seasonal differences in children's activity. PMID- 28593118 TI - Ideal cardiovascular health and peripheral artery disease in African Americans: Results from the Jackson Heart Study. AB - We sought to determine the association of Life's Simple Seven (LSS) with peripheral artery disease (PAD) in African Americans. We performed a cross sectional analysis of baseline data (2000-2004) from subjects participating in the Jackson Heart Study. African American men and women (N = 4403) age 35-84 years participated in the study. PAD was defined by an ankle-brachial index (ABI) of < 0.9. We assessed frequency of LSS (body mass index [BMI], blood pressure, total cholesterol, glucose, dietary habits, physical activity, and smoking) among participants with and without PAD. LSS variables were categorized as ideal, intermediate, or poor to indicate a participant's health status. Data were analyzed using logistic regression to assess the association of PAD with LSS. PAD was diagnosed in 113 participants (2.6%). The percentage of the cohort meeting criteria for ideal health for each of the seven LSS factors was: 14.2% for BMI, 17.1% for blood pressure, 38.0% for total cholesterol, 72.9% for glucose, 1.0% for dietary habits, 19.2% for physical activity, and 84.6% for smoking. Having >= 3 LSS variables within the category of poor health was associated with elevated odds for PAD (odds ratio (OR) 1.34, 95% CI 1.11-1.63) after adjusting for age. Among African American adults, LSS variables are associated with PAD. Further studies are needed to determine the association of LSS with PAD among other racial/ethnic groups. PMID- 28593119 TI - Provider-patient communication about Zika during prenatal visits. AB - Zika virus transmission within and between the Americas is of global concern. This study assessed knowledge about the Zika virus among pregnant women in the United States, their travel plans to endemic areas, and whether their health care providers discussed Zika with them. This cross-sectional study used data from 492 pregnant women (18-50 years) from an online survey conducted from April 8 to July 27, 2016. Pregnant women were recruited online through Facebook, Twitter, Craigslist, and Reddit. Almost all (97.8%) participants had heard of the Zika virus, of which 71% first learned about it from the internet. Over one third of these pregnant women reported that their health providers discussed transmission of the Zika virus with them. Most respondents reported that their providers had discussed risks related to travelling to areas with Zika outbreaks. Half of the survey respondents reported that their providers gave them information about avoiding mosquito bites. Pregnant women were not concerned about Zika affecting their own health, but 34% were very or extremely concerned about it affecting their babies' health. Almost no pregnant women currently had travel plans to areas with ongoing Zika transmissions, and of the 14% who previously had plans, most (85%) cancelled their travel due to concerns about Zika. Overall, pregnant women in our sample were highly knowledgeable about Zika virus. Over one third of women received suggestions regarding prevention of Zika from their healthcare providers. PMID- 28593120 TI - Addition of estimated cardiorespiratory fitness to the clinical assessment of 10 year coronary heart disease risk in asymptomatic men. AB - The Framingham Risk Score (FRS) was developed to quantify a patient's coronary heart disease (CHD) risk. Non-exercise estimated CRF (e-CRF) may provide a clinically practical method for describing cardiorespiratory fitness. We computed e-CRF and tested its association with the FRS and CHD. Male participants (n = 29,854) in the Aerobics Center Longitudinal Study (ACLS) who completed a baseline examination between 1979-2002 were followed for 12 years to determine incident CHD defined by self-report of myocardial infarction, revascularization, or CHD mortality. e-CRF was defined from a 7-item scale and categorized using age specific tertiles. Multivariable survival analysis determined associations between FRS, e-CRF, and CHD. Interaction between e-CRF and FRS was tested by stratified analysis by 'low' and 'moderate or high' 10-year CHD risk. Men with high e-CRF were significantly (p-value < 0.0001) younger, and less likely to be smokers, compared to men with low e-CRF. Multivariable survival analysis reported men with high e-CRF were 29% (HR = 0.71; 95% 0.56, 0.88) less likely to experience a CHD event compared to men with low e-CRF. Stratified analyses showed men with 'low' 10-year FRS predicted CHD risk and high e-CRF had a 28% (HR = 0.72; 95% CI 0.57, 0.91) lower CHD-mortality risk compared to men with low e-CRF, no association was found in this group and men with moderate e-CRF. Men who were more fit had a decreased risk for CHD compared to men in the lowest third of fitness. Estimated CRF may add clinical value to the FRS and help clinicians better predict long-term CHD risk. PMID- 28593121 TI - Adherence support strategies for exercise interventions in people with mild cognitive impairment and dementia: A systematic review. AB - Exercise-based therapy may improve health status for people with Mild Cognitive Impairment (MCI) or dementia but cannot work without adherence, which has proven difficult. This review aimed to evaluate strategies to support adherence among people with MCI or Dementia and was completed in Nottingham/UK in 2017. A narrative synthesis was used to investigate the effectiveness or usefulness of adherence support strategies. Fifteen adherence support strategies were used including theoretical underpinning (programmes based on behavior change theories), individual tailoring, worksheets and exercise booklets, goal setting, phone calls or reminders, newsletters, support to overcome exercise barriers, information, adaptation periods, individual supervision, support for clinicians, group setting, music, accelerometers/pedometers and emphasis on enjoyable activities. Music was the only strategy that was investigated in a comparative design but was found to be effective only for those who were generally interested in participating in activities. A wide range of adherence support strategies are being included in exercise interventions for people with MCI or dementia, but the evidence regarding their effectiveness is limited. PMID- 28593122 TI - Trends over time in enrollment in non-group health insurance plans by tobacco use in the United States. AB - Healthcare.gov was created to facilitate the market for non-group insurance in states that did not establish their own marketplaces. In Healthcare.gov, families are asked to report their tobacco use status, and tobacco use surcharges of up to 50% may result. We tabulate enrollment information for 35 states offering insurance plans through Healthcare.gov in both 2014 and 2016. The Centers for Medicare and Medicaid Services provided counts of enrollees indicating tobacco use, by state, year, and risk level. The number of enrollees increased from 5.0 million in 2014 to 9.4 million in 2016. From 2014 to 2016, the number of enrollees rose 39% for tobacco users and 90% for non-tobacco users. Reported non tobacco user enrollment rose faster than reported tobacco user enrollment in 30 out of 35 states. Reported tobacco users are enrolling in marketplace plans at a lower rate and are more likely to enroll in less generous plans. The decline in smoking as reported when purchasing insurance on Healthcare.gov surpasses declines in smoking observed in other data sources, which suggests that tobacco users may be decreasingly likely to report their tobacco use status accurately to avoid surcharges. Finally, we find no evidence of the surcharges being associated with lower enrollment among self-reported tobacco users, or in rates of smoking. PMID- 28593123 TI - Socio-demographic predictors of residential fire and unwillingness to call the fire service in New South Wales. AB - In most industrialised countries, the majority of fire-related deaths and injuries occur in the home. Australia has implemented fire prevention programs and strategies, including the use of smoke alarms, to minimise this burden. The number of reported house fires has declined over the past decade. However, there is a growing recognition that unreported fires are important in the estimation of total fire hazards and their associated injuries. This current study used data from the 2014 New South Wales (NSW) Population Health Survey, a yearly telephone survey, consisting of 14,732 survey respondents. Univariate and multiple binary logistic regression models were conducted to examine predictors of residential fire and (un)willingness to call the fire service in the event of a residential fire. The proportion of respondents who experienced residential fires in NSW was 10% (95% confidence interval [CI]: 9.3, 10.8). The proportion of respondents who were willing to call the fire service was 3.1% (95% CI: 2.7%, 3.6%) and that of respondents unwilling to call was 6.9% (95% CI: 6.3%, 7.6%). Multivariate analyses revealed that respondents spoke another language in addition to English were significantly less likely to have experienced a home fire (odds ratio [OR] = 0.46; 95% CI: 0.32, 0.65, p < 0.001) and significantly less likely to call the fire service (OR = 0.34; 95% CI: 0.21, 0.54, p < 0.001), compared with those who only spoke English at home. The results in this study will inform Fire & Rescue NSW's ongoing development of appropriate interventions and awareness-raising programs about residential fire prevention. PMID- 28593124 TI - Pragmatic evaluation of the Go2Play Active Play intervention on physical activity and fundamental movement skills in children. AB - Active play is a novel approach to addressing low physical activity levels and fundamental movement skills (FMS) in children. This study aimed to determine if a new school-based, 'Go2Play Active Play' intervention improved school day physical activity and FMS. This was a pragmatic evaluation conducted in Scotland during 2015-16. Participants (n = 172; mean age = 7 years) were recruited from seven primary schools taking part in the 5-month intervention, plus 24 participants not receiving the intervention were recruited to act as a comparison group.189 participants had physical activity measured using an Actigraph GT3X accelerometer at baseline and again at follow-up 5 months later. A sub-sample of participants from the intervention (n = 102) and comparison (n = 21) groups had their FMS assessed using the Test of Gross Motor Development (TGMD-2) at baseline and follow-up. Changes in school day physical activity and FMS variables were examined using repeated measures ANOVA. The main effect was 'group' on 'time' from baseline to follow-up. Results indicated there was a significant interaction for mean counts per minute and percent time in sedentary behavior, light intensity physical activity and moderate to vigorous physical activity (MVPA) (all p < 0.01) for school day physical activity. There was a significant interaction for gross motor quotient (GMQ) score (p = 0.02) and percentile (p = 0.04), locomotor skills score and percentile (both p = 0.02), but no significant interaction for object control skills score (p = 0.1) and percentile (p = 0.3). The Go2Play Active Play intervention may be a promising way of improving physical activity and FMS but this needs to be confirmed in an RCT. PMID- 28593125 TI - Physiological health parameters among college students to promote chronic disease prevention and health promotion. AB - This study aimed to provide physiologic health risk parameters by gender and age among college students enrolled in a U.S. Midwestern University to promote chronic disease prevention and ameliorate health. A total of 2615 college students between 18 and 25 years old were recruited annually using a series of cross-sectional designs during the spring semester over an 8-year period. Physiologic parameters measured included body mass index (BMI), percentage body fat (%BF), blood serum cholesterol (BSC), and systolic (SBP) and diastolic (DBP) blood pressure. These measures were compared to data from NHANES to identify differences in physiologic parameters among 18-25 year olds in the general versus college-enrolled population. A quantitative instrument assessed health behaviors related to physical activity, diet, and licit drug use. Results suggest that average physiologic parameters from 18 to 25 year olds enrolled in college were significantly different from parameters of 18-25 year olds in the general population. Generally, men reported higher percentiles for BMI, SBP, and DBP than women, but lower %BF and BSC percentiles than women at each age. SBP and DBP significantly increased with age and alcohol use. Students in the lowest (5th) and highest percentiles (95th and 75th), for most age groups, demonstrated DBP, BMI, and %BF levels potentially problematic for health and future development of chronic disease based on percentiles generated for their peer group. Newly identified physiologic parameters may be useful to practitioners serving college students 18-25 years old from similar institutions in determining whether behavior change or treatment interventions are appropriate. PMID- 28593126 TI - Aerobic fitness and metabolic health in children: A clinical validation of directly measured maximal oxygen consumption versus performance measures as markers of health. AB - High aerobic fitness is consistently associated with a favorable metabolic health profile in children. However, measurement of oxygen uptake, regarded as the gold standard for evaluating aerobic fitness, is often not feasible. Thus, the aim of the present study was to perform a clinical validation of three measures of aerobic fitness (peak oxygen consumption [VO2peak] and time to exhaustion [TTE] determined from a graded treadmill protocol to exhaustion, and the Andersen intermittent running test) with clustered metabolic health in 10-year-old children. We included 93 children (55 boys and 38 girls) from Norway during 2012 2013 in the study. Associations between aerobic fitness and three different composite metabolic health scores (including lipoprotein subgroup particle concentrations, triglyceride, glucose, systolic blood pressure, and waist-to height ratio) were determined by regression analyses adjusting for sex. The relationships among the measures of aerobic fitness were r = 0.78 for VO2peak vs. TTE, r = 0.63 for VO2peak vs. the Andersen test, and r = 0.67 for TTE vs. the Andersen test. The Andersen test showed the strongest associations across all markers of metabolic health (r = - 0.45 to - 0.31, p < 0.002), followed by VO2peak (r = - 0.35 to - 0.12, p < 0.256), and TTE (r = - 0.28 to - 0.10, p < 0.334). Our findings indicate that indirect measures of aerobic fitness do not stand back as markers of metabolic health status in children, compared to VO2peak. This is of great importance as good field tests provide opportunities for measuring aerobic fitness in many settings where measuring VO2peak are impossible. PMID- 28593127 TI - Cessation-related weight concern among homeless male and female smokers. AB - Concern about post-cessation weight gain is a barrier to making attempts to quit smoking; however, its effect on smoking cessation is unclear. In this study we examine cessation-related weight concern among the homeless, which hasn't been studied. Homeless males (n = 320) and females (n = 110) participating in a smoking cessation RCT in the Twin Cities, Minnesota from 2009 to 2011 completed surveys on cessation-related weight concern, smoking status, and components from the Behavioral Model for Vulnerable Populations. Generalized estimating equations were used to examine baseline predictors of cessation-related weight concern at baseline, the end of treatment, and 26-weeks follow-up. Logistic regression models were used to examine the relationship between cessation-related weight concern and smoking status at the end of treatment and follow-up. Females had higher cessation-related weight concern than males. Among males, older age, Black race, higher BMI, depression, and having health insurance were associated with higher cessation-related weight concern. Among females, nicotine dependence, greater cigarette consumption, indicating quitting is more important, older age of smoking initiation, and less support to quit from family were associated with higher cessation-related weight concern. In multivariate analyses, cessation related weight concern decreased over time among females. Cessation-related weight concern wasn't associated with smoking cessation. Although several types of characteristics predicted cessation-related weight concern among males, only smoking characteristics predicted cessation-related weight concern among females. Given the small proportion of quitters in this study (8% of males and 5% of females), further research on the impact of cessation-related weight concern on smoking cessation among the homeless is warranted. PMID- 28593128 TI - Including mobile-only telephone users in a statewide preventive health survey Differences in the prevalence of health risk factors and impact on trends. AB - The Queensland preventive health survey is conducted annually to monitor the prevalence of behavioural risk factors in the north-east Australian state. Prompted by domestic and international trends in mobile telephone usage, the 2015 survey incorporated both mobile and landline telephone numbers from a list-based sampling frame. Estimates for landline-accessible and mobile-only respondents are compared to assess potential bias in landline-only surveys in the context of public health surveillance. Significant differences were found in subcategories of all health prevalence estimates considered (alcohol consumption, body mass index, smoking, and physical activity) from 2015 survey results. Results from Australian and international studies that have considered mobile telephone non coverage bias are also summarised and discussed. We find that adjusting for sampling biases of telephone surveys by weighting does not fully compensate for the differences in prevalence estimates. However, predicted trends from previous years' surveys only differ significantly for the 2015 prevalence estimates of alcohol consumption. We conclude that the inclusion of mobile telephones into standard telephones surveys is important for obtaining valid, reliable and representative data to reduce bias in health prevalence estimates. Importantly, unlike some international experiences, the addition of mobiles telephones into the Queensland preventive health survey occurred before population trends were significantly affected. PMID- 28593129 TI - Associations between green area in school neighbourhoods and overweight and obesity among Norwegian adolescents. AB - The aim of the present study was to investigate the relationship between green areas and adolescents' body mass index (BMI). This is based on the notion that nature environment is known to have beneficial effects on human health, and that some of the explanation for this is that green areas are especially motivating or suitable as arenas for physical activity. We included 10,527 participants from the Norwegian Youth Study, which was conducted between 2001 and 2004. The participants reported body weight, height, and important potential confounding variables about lifestyle, family situation, and neighbourhood characteristics. Green area was assessed from land cover maps and we calculated the percentage of green areas within 1 km and 5 km buffers around the adolescents' schools. We found that the percentage of overweight and obese adolescents increased significantly when the percentage of green areas in the participants' surrounding increased (p < 0.001 for both outcomes and buffer sizes). The same results were found in logistic regression models where we adjusted for a large set of variables. As an example, the odds for being overweight was 1.38 times higher (95% CI: 1.02-1.85) for participants living in the most green surroundings compared to participants living in the least green surroundings (1 km buffer). Norwegian green areas are typically farmland, woods, and mountains, and we speculate if these areas are less accessible and attractive for adolescents, who might need more facilitated green areas for sport and physical activity. PMID- 28593130 TI - The neuronal and astrocytic protein SLC38A10 transports glutamine, glutamate, and aspartate, suggesting a role in neurotransmission. AB - In brain cells, glutamine transporters are vital to monitor and control the levels of glutamate and GABA. There are 11 members of the SLC38 family of amino acid transporters of which eight have been functionally characterized. Here, we report the first histological and functional characterization of the previously orphan member, SLC38A10. We used pairwise global sequence alignments to determine the sequence identity between the SLC38 family members. SLC38A10 was found to share 20-25% transmembrane sequence identity with several family members, and was predicted to have 11 transmembrane helices. SLC38A10 immunostaining was abundant in mouse brain using a custom-made anti-SLC38A10 antibody and colocalization of SLC38A10 immunoreactivity with markers for neurons and astrocytes was detected. Using Xenopus laevis oocytes overexpressing SLC38A10, we show that SLC38A10 mediates bidirectional transport of l-glutamine, l-alanine, l-glutamate, and d aspartate, and efflux of l-serine. This profile mostly resembles system A members of the SLC38 family. In conclusion, the bidirectional transport of glutamine, glutamate, and aspartate by SLC38A10, and the immunostaining detected in neurons and astrocytes, suggest that SLC38A10 plays a role in pathways involved in neurotransmission. PMID- 28593131 TI - miR-127-5p negatively regulates enterovirus 71 replication by directly targeting SCARB2. AB - Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease in young children and can cause severe cerebral and pulmonary complications and even fatality. This study aimed at elucidating whether and how EV71 infection is regulated by a cellular microRNA, miR-127-5p. We found that miR-127-5p can downregulate the expression of SCARB2, a main receptor of EV71, by targeting two potential sites in its 3' UTR region and inhibit EV71 infection. Meanwhile, miR 127-5p expression was upregulated during EV71 infection. Notably, transfecting cells with miR-127-5p mimics led to a significant decrease in viral replication, while inhibition of endogenous miR-127-5p facilitated viral replication. Furthermore, our evidence showed that miR-127-5p did not affect postentry viral replication. Taken together, these results indicated that miR-127-5p inhibited EV71 replication by targeting the SCARB2 mRNA. PMID- 28593132 TI - Activation of Wnt/beta-catenin signaling by lithium chloride attenuates d galactose-induced neurodegeneration in the auditory cortex of a rat model of aging. AB - Degeneration of the central auditory system, which is characterized by reduced understanding of speech and source localization of sounds, is an important cause of age-related hearing loss (presbycusis). Accumulating evidence has demonstrated that Wnt/beta-catenin signaling plays an essential role in the development of the auditory system but its potential role in presbycusis remains unclear. In this study, we used a rat model of aging, created by chronic systemic exposure to d galactose (d-gal), and explored changes in Wnt/beta-catenin signaling in the auditory cortex. A decrease in Wnt/beta-catenin signaling in the auditory cortex was found in both naturally aging and d-gal-mimetic aging rats, as indicated by increased GSK3beta activity and decreased beta-catenin activity. Moreover, lithium chloride (Licl), an activator of Wnt signaling pathway, was administered long term to 15-month-old d-gal-treated rats. Activation of Wnt/beta-catenin signaling by Licl attenuated d-gal-induced auditory cortex apoptosis and neurodegeneration. Bmi1, a transcription factor implicated in antiaging and resistance to apoptosis, can be modulated by beta-catenin activity. Here, we showed that the expression of Bmi1 was reduced and the expression of its downstream genes, p16INK4a , p19Arf , and p53 were increased in the auditory cortex both of naturally aging and d-gal-mimetic aging rats. In addition, Licl significantly increased Bmi1 expression and reduced p16INK4a, p19Arf, and p53 expression. Our results indicated that decreased Wnt/beta-catenin signaling might participate in the pathogenesis of central presbycusis through modulating the expression of Bmi1. Wnt/beta-catenin signaling might be used as a potential therapeutic target against presbycusis. PMID- 28593134 TI - Quantum chemical modeling of the reaction path of chorismate mutase based on the experimental substrate/product complex. AB - Chorismate mutase is a well-known model enzyme, catalyzing the Claisen rearrangement of chorismate to prephenate. Recent high-resolution crystal structures along the reaction coordinate of this enzyme enabled computational analyses at unprecedented detail. Using quantum chemical simulations, we investigated how the catalytic reaction mechanism is affected by electrostatic and hydrogen-bond interactions. Our calculations showed that the transition state (TS) was mainly stabilized electrostatically, with Arg90 playing the leading role. The effect was augmented by selective hydrogen-bond formation to the TS in the wild-type enzyme, facilitated by a small-scale local induced fit. We further identified a previously underappreciated water molecule, which separates the negative charges during the reaction. The analysis includes the wild-type enzyme and a non-natural enzyme variant, where the catalytic arginine was replaced with an isosteric citrulline residue. PMID- 28593135 TI - Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells. AB - Effective drug combinations have the potential to strengthen therapeutic efficacy and combat drug resistance. Both melatonin and valproic acid (VPA) exhibit antitumor activities in various cancer cells. The aim of this study was to evaluate the cell death pathways initiated by anticancer combinatorial effects of melatonin and VPA in bladder cancer cells. The results demonstrated that the combination of melatonin and VPA leads to significant synergistic growth inhibition of UC3 bladder cancer cells. Gene expression studies revealed that cotreatment with melatonin and VPA triggered the up-regulation of certain genes related to apoptosis (TNFRSF10A and TNFRSF10B), autophagy (BECN, ATG3 and ATG5) and necrosis (MLKL, PARP-1 and RIPK1). The combinatorial treatment increased the expression of endoplasmic reticulum (ER)-stress-related genes ATF6, IRE1, EDEM1 and ERdj4. Cotreatment with melatonin and VPA enhanced the expression of E cadherin, and decreased the expression of N-cadherin, Fibronectin, Snail and Slug. Furthermore, the Wnt pathway and Raf/MEK/ERK pathway were activated by combinatorial treatment. However, the effects on the expression of certain genes were not further enhanced in cells following combinatorial treatment in comparison to individual treatment of melatonin or VPA. In summary, these findings provided evidence that cotreatment with melatonin and VPA exerted increased cytotoxicity by regulating cell death pathways in UC3 bladder cancer cells, but the clinical significance of combinatorial treatment still needs to be further exploited. PMID- 28593133 TI - The Hfq regulon of Neisseria meningitidis. AB - The conserved RNA-binding protein, Hfq, has multiple regulatory roles within the prokaryotic cell, including promoting stable duplex formation between small RNAs and mRNAs, and thus hfq deletion mutants have pleiotropic phenotypes. Previous proteome and transcriptome studies of Neisseria meningitidis have generated limited insight into differential gene expression due to Hfq loss. In this study, reversed-phase liquid chromatography combined with data-independent alternate scanning mass spectrometry (LC-MSE) was utilized for rapid high-resolution quantitative proteomic analysis to further elucidate the differentially expressed proteome of a meningococcal hfq deletion mutant. Whole-cell lysates of N. meningitidis serogroup B H44/76 wild-type (wt) and H44/76Deltahfq (Deltahfq) grown in liquid growth medium were subjected to tryptic digestion. The resulting peptide mixtures were separated by liquid chromatography (LC) prior to analysis by mass spectrometry (MSE). Differential expression was analyzed by Student's t test with control for false discovery rate (FDR). Reliable quantitation of relative expression comparing wt and Deltahfq was achieved with 506 proteins (20%). Upon FDR control at q <= 0.05, 48 up- and 59 downregulated proteins were identified. From these, 81 were identified as novel Hfq-regulated candidates, while 15 proteins were previously found by SDS/PAGE/MS and 24 with microarray analyses. Thus, using LC-MSE we have expanded the repertoire of Hfq-regulated proteins. In conjunction with previous studies, a comprehensive network of Hfq regulated proteins was constructed and differentially expressed proteins were found to be involved in a large variety of cellular processes. The results and comparisons with other gram-negative model systems, suggest still unidentified sRNA analogs in N. meningitidis. PMID- 28593136 TI - AMP-activated protein kinase regulates lipid metabolism and the fibrotic phenotype of hepatic stellate cells through inhibition of autophagy. AB - Hepatic stellate cells (HSCs) are the principal hepatic cell type responsible for liver fibrosis. Although AMP-activated protein kinase (AMPK) is known to regulate the activation of HSCs, little is known about its underlying molecular mechanisms. In the present study, we demonstrate that AMPK activation by 5 aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR) restricts the fibrotic potential elicited by transforming growth factor beta (TGF-beta) in LX-2 cells through modulation of autophagy. AICAR treatment activated the mechanistic target of rapamycin/Akt pathway and thus inhibited autophagy flux and lipid droplet degradation in lysosomes induced by TGF-beta. Pretreatment with the autophagy inducer rapamycin reversed the effects of AMPK, further confirming that AICAR inhibited TGF-beta-induced HSC activation via the regulation of autophagy flux. Our study indicates that AICAR exerts its anti-fibrotic and anti-lipid depletion effect, at least in part, by inhibiting TGF-beta-induced autophagy flux. PMID- 28593137 TI - MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins. AB - The immediate early gene activity-regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain-derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic-AMP response element-binding protein (CREB) on Ser133. However, this is not required for BDNF-induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF). PMID- 28593138 TI - Licochalcone A specifically induces cell death in glioma stem cells via mitochondrial dysfunction. AB - Glioblastoma multiforme is the most malignant primary intrinsic brain tumor. Glioma stem cells (GSCs) are associated with chemoradiotherapy resistance and the recurrence of glioblastomas after conventional therapy. The targeting of GSCs is potentially an effective treatment for the long-term survival of glioblastoma patients. Licochalcone A, a natural chalconoid from licorice root, exerts anticancer effects; however, its effect on GSCs remains unknown. We found that Licochalcone A induced massive caspase-dependent death in GSCs but not in differentiated GSCs nor normal somatic and neural stem cells. Prior to cell death, Licochalcone A caused mitochondrial fragmentation and reduced the membrane potential and ATP production in GSCs. Thus, Licochalcone A induces mitochondrial dysfunction and shows promise as an anticancer stem cell drug. PMID- 28593139 TI - Oxygen binding and nitric oxide dioxygenase activity of cytoglobin are altered to different extents by cysteine modification. AB - Cytoglobin (Cygb), like other members of the globin family, is a nitric oxide (NO) dioxygenase, metabolizing NO in an oxygen (O2)-dependent manner. We examined the effect of modification of cysteine sulfhydryl groups of Cygb on its O2 binding and NO dioxygenase activity. The two cysteine sulfhydryls of Cygb were modified to form either an intramolecular disulfide bond (Cygb_SS), thioether bonds to N-ethylmaleimide (NEM; Cygb_SC), or were maintained as free SH groups (Cygb_SH). It was observed that the NO dioxygenase activity of Cygb only slightly changed (~ 25%) while the P50 of O2 binding to Cygb changed over four-fold with these modifications. Our results suggest that it is possible to separately regulate one Cygb function (such as O2 binding) without largely affecting the other Cygb functions (such as its NO dioxygenase activity). PMID- 28593140 TI - DNA-induced unfolding of the thyroid hormone receptor alpha A/B domain through allostery. AB - The A/B domains of nuclear receptors such as thyroid receptor alpha (TRalpha) are considered to be conformationally flexible and can potentially adopt multiple structural conformations. We used intrinsic tryptophan fluorescence quenching and circular dichroism spectroscopy to characterize the unfolding of this A/B domain upon DNA binding to the contiguous DNA-binding domain (DBD). We propose that this allosteric change in A/B domain conformation can allow it to make the multiple interactions with distinct molecular factors of the transcriptional preinitiation complex. We further suggest that by influencing the affinity of the DBD for DNA, A/B domain can fine-tune the recognition of promotor DNA by TRalpha. PMID- 28593141 TI - Glycosyl chains and 25-hydroxycholesterol contribute to the intracellular transport of amyloid beta (Abeta-42) in Jurkat T cells. AB - Amyloid beta (Abeta) is a peptide responsible for the development of Alzheimer's disease (AD). Misfolding and accumulation of endogenous Abeta can lead to neural cell apoptosis through endoplasmic reticulum (ER) stress. Added exogenous Abeta can also result in ER stress, leading to neurotoxicity and apoptosis, which is identical to that caused by the endogenous peptide. We have speculated that the endocytic transport of Abeta causes ER stress and have previously shown that the oxysterol, in particular, 7-ketocholesterol (7-keto) induces more surface interaction between Abeta-42 and Jurkat cells than cholesterol. However, the interaction was not enough to induce intracellular transfer of the peptide. In this study, we investigated the effect of another oxysterol, 25 hydroxycholesterol (25-OH) on the membrane raft-dependent transport of Abeta-42 in Jurkat cells. Interestingly, intracellular transfer of Abeta-42 was observed in the presence of 25-OH only after the inclusion of cholera toxin B subunit (CT B), a marker used to detect the raft domain. We speculated that 25-OH can induce intracellular movement of Abeta peptides. Furthermore, CT-B together with GM1 provided negative curvature, which resulted in the intracellular transport of Abeta-42. Notably, we used a protofibrillar species of Abeta-42 in this study. We have shown that the transport was microtubule-dependent since it could not be observed in depolymerized microtubules. These results demonstrate that oxysterols and glycosyl chains are important factors affecting intracellular transport. These compounds are also associated with aging and advanced glycation are risk factors for AD. Thus, this study should further understanding of the pathology of AD. PMID- 28593142 TI - Spontaneous formation of neutrophil extracellular traps in serum-free culture conditions. AB - Neutrophils play a critical role in the innate immune response. Recently, a new neutrophilic biological defense mechanism, termed neutrophil extracellular traps (NETs), has been attracting attention. Neutrophils have been observed to release both lysosomal enzymes and their nuclear contents, including unfolded chromatin, which together trap and inactivate bacteria. The environment in tissues where neutrophils act is thought to be different from that of the blood serum. In this study, we assessed the effect of serum on NET formation. We found that neutrophils spontaneously form NETs in serum-free cultivation conditions at early times. These NETs functioned properly to trap bacteria. Furthermore, we demonstrated that reactive oxygen species play a critical role in the spontaneous formation of NETs. These results suggest that the serum condition must be considered in studies on neutrophils, including the formation and mechanism of action of NETs. PMID- 28593143 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/2211-5463.12205.]. PMID- 28593144 TI - Schwannoma of the femur: A rare case report. AB - Schwannoma is a benign tumor derived from Schwann cells that cover myelinated nerve fibers (1). Among primary bone tumors, intraosseous schwannoma accounts for less than 0.2% (2). We are reporting a rare case of an 18-year-old female presented with swelling in the posterior right thigh. The patient was asymptomatic and this was incidentally discovered by her massage therapist. However, the swelling was gradually growing since then. The plain radiograph findings were suggestive of a benign bone tumor. MRI with gadolinium was performed for further evaluation but it demonstrated suspicious features as evidenced by the extra osseous enhancing soft tissue component. Three phase bone scan was done thereafter and it showed hyperemia with mild increased uptake of the lesion on the delayed phase. Osteosarcoma was suspected and chest CT was performed for staging purposes which turned out to be negative for metastasis. The lesion was biopsied under ultrasound guidance. The histologic features and the immunohistochemically profile were consistent with a benign schwannoma. The posterior thigh soft tissue mass was surgically resected with femur bone grafting. Recurrence of schwannoma should be considered but its malignant transformation is exceedingly rare and this can be discounted (3). PMID- 28593145 TI - Secondary syphilis-related oral mucous patches. PMID- 28593146 TI - Cholesterol Granuloma of the Abdominal Wall: An Unusual Finding in the Setting of Renal Cell Carcinoma. AB - Cholesterol granulomas are composed of a distinct type of granulation tissue that contains lipids and cholesterol crystals. They are not believed to be a pathological entity, but rather an inflammatory tissue reaction to the presence of trapped blood secondary to localized hemorrhage.1 Cholesterol granulomas can be identified histologically by the presence of multi-nucleated giant cells, hemosiderin, and red blood cells along with their associated break-down products.1 Recognizing cholesterol granulomas can provide clinical utility as they demonstrate a tendency to mimic carcinoma both clinically and radiologically. PMID- 28593147 TI - Single Large Bladder Stone in a Young Male Adult with Primary Hyperparathyroidism. AB - Bladder stones are caused when minerals are built up in the bladder, especially if the bladder is incompletely emptied. These stones will pass while they are small. Otherwise, they get stuck to the bladder wall or ureter. If this happens, they gradually gather more mineral crystals, becoming larger over time. Primary hyperparathyroidism is usually caused by a tumor within the parathyroid gland, and elevated calcium levels can cause digestive symptoms, psychiatric abnormalities, bone disease and multiple kidney stones. PMID- 28593148 TI - Endovascular Repair in Acute Complicated Type B Aortic Dissection: 3-Year Results from the Valiant US Investigational Device Exemption Study. AB - Acute complicated type B aortic dissection (TBAD) is a potentially catastrophic, life-threatening condition. If left untreated, there is a high risk of aortic rupture, irreversible organ or limb damage, or death. Several risk factors have been associated with acute complicated TBAD, including age and refractory hypertension. In the acute phase, even uncomplicated patients are more prone to develop complications if hypertension and pain are left medically untreated. Innovations in stent graft technologies have incrementally improved outcomes since their first use for this condition in 1999, though improvement is needed in mitigating periprocedural complications, adverse events, and mortality. In the past decade, endovascular repair has become the preferred treatment because of its superior outcomes to open repair and medical therapy. The Valiant Captivia Thoracic Stent Graft System is a third-generation endovascular stent graft with advancements in minimally invasive delivery, conformability to the anatomy, and the minimization of adverse sequelae. Herein, this stent graft is briefly reviewed and its 3-year outcomes are presented. Freedom from all-cause and dissection-related mortality was 79.1% and 90.0%, respectively. The Valiant Captivia Stent Graft represents a safe, effective intervention for acute complicated TBAD. Continued surveillance is needed to verify its longer-term durability. PMID- 28593150 TI - The Antitumor Effect of C-terminus of Hsp70-Interacting Protein via Degradation of c-Met in Small Cell Lung Cancer. AB - BACKGROUND: The mesenchymal-epithelial transition factor (MET) receptor can be overexpressed in solid tumors, including small cell lung cancer (SCLC). However, the molecular mechanism regulating MET stability and turnover in SCLC remains undefined. One potential mechanism of MET regulation involves the C-terminus of Hsp70-interacting protein (CHIP), which targets heat shock protein 90-interacting proteins for ubiquitination and proteasomal degradation. In the present study, we investigated the functional effects of CHIP expression on MET regulation and the control of SCLC cell apoptosis and invasion. METHODS: To evaluate the expression of CHIP and c-Met, which is a protein that in humans is encoded by the MET gene (the MET proto-oncogene), we examined the expression pattern of c-Met and CHIP in SCLC cell lines by western blotting. To investigate whether CHIP overexpression reduced cell proliferation and invasive activity in SCLC cell lines, we transfected cells with CHIP and performed a cell viability assay and cellular apoptosis assays. RESULTS: We found an inverse relationship between the expression of CHIP and MET in SCLC cell lines (n=5). CHIP destabilized the endogenous MET receptor in SCLC cell lines, indicating an essential role for CHIP in the regulation of MET degradation. In addition, CHIP inhibited MET-dependent pathways, and invasion, cell growth, and apoptosis were reduced by CHIP overexpression in SCLC cell lines. CONCLUSION: CHIP is capable of regulating SCLC cell apoptosis and invasion by inhibiting MET-mediated cytoskeletal and cell survival pathways in NCI-H69 cells. CHIP suppresses MET-dependent signaling, and regulates MET-mediated SCLC motility. PMID- 28593149 TI - Effects of a Proteasome Inhibitor on Cardiomyocytes in a Pressure-Overload Hypertrophy Rat Model: An Animal Study. AB - BACKGROUND: The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of NF-kappaB and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. METHODS: We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG 132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and NF-kappaB was measured in the left ventricle. RESULTS: Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not NF-kappaB, was found in the TAC MG132 group than in the TAC-cont group (p<0.05). CONCLUSION: MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, NF-kappaB expression levels were not related to UPS function. PMID- 28593151 TI - The Absence of Atrial Contraction as a Predictor of Permanent Pacemaker Implantation after Maze Procedure with Cryoablation. AB - BACKGROUND: The absence of atrial contraction (AC) after the maze procedure has been reported to cause subsequent annular dilatation and to increase the risk of embolic stroke. We hypothesized that the lack of AC could increase the risk of permanent pacemaker (PPM) implantation in patients undergoing the maze procedure. METHODS: In 376 consecutive patients who had undergone a cryo-maze procedure and combined valve operation, recovery of AC was assessed at baseline and at immediate (<=2 weeks), early (<=1 year, 4.6+/-3.8 months), and late (>1 year, 3.5+/-1.1 years) postoperative stages. RESULTS: With a median follow-up of 53 months, 10 patients underwent PPM implantation. Seven PPM implants were for sinus node dysfunction (pauses of 9.6+/-2.4 seconds), one was for marked sinus bradycardia, and two were for advanced/complete atrioventricular block. The median (interquartile range) time to PPM implantation was 13.8 (0.5-68.2) months. Our time-varying covariate Cox models showed that the absence of AC was a risk factor for PPM implantation (hazard ratio, 11.92; 95% confidence interval, 2.52 to 56.45; p=0.002). CONCLUSION: The absence of AC may be associated with a subsequent risk of PPM implantation. PMID- 28593152 TI - Treatment of Atrial Fibrillation in Elderly Patients with the Cox Maze Procedure Concurrently with Other Cardiac Operations. AB - BACKGROUND: In elderly patients who have atrial fibrillation (AF), surgical ablation of the arrhythmia during cardiac surgery may be challenging. Despite the reported advantages of ablating AF with the Cox maze procedure (CMP), the addition of the CMP may complicate other cardiac operations. We evaluated the effect of the CMP in elderly patients concurrent with other cardiac operations. METHODS: From October 2007 to December 2015, we enrolled 27 patients aged >70 years who had AF and who underwent the CMP concurrently with other cardiac operations. The mean preoperative additive European System for Cardiac Operative Risk Evaluation score was 8+/-11 (high risk). RESULTS: Only 1 hospital death occurred (4%). The Kaplan-Meier method showed a high 5-year cumulative survival rate (92%). At mean follow-up of 51 months, 23 patients (89%) had sinus rhythm conversion. The postoperative left atrial dimensions did not significantly differ between the 8 patients who had reduction plasty for giant left atrium (53.4+/-7.5 cm) and the 19 patients who did not have reduction plasty (48.7+/-5.7 cm). CONCLUSION: In patients aged >70 years, concurrent CMP may be associated with a high rate of sinus rhythm conversion without increased surgical risk, despite the added complexity of the main cardiac procedure. PMID- 28593153 TI - Early Detection of the Acute Exacerbation of Interstitial Pneumonia after the Surgical Resection of Lung Cancer by Planned Chest Computed Tomography. AB - BACKGROUND: To improve postoperative outcomes associated with interstitial pneumonia (IP) in patients with lung cancer, the management of the postoperative a cute exacerbation of IP (PAEIP) was investigated. METHODS: Patients with primary lung cancer were considered to be at risk for PAEIP (possible PAEIP) based on a preoperative evaluation. The early phase of this study was from January 2001 to December 2008, and the late phase was from January 2009 to December 2014. In the early phase, chest computed tomography (CT) was performed for patients for whom PAEIP was suspected based on their symptoms, whereas in the late phase, chest CT was routinely performed within a few days postoperatively. The numbers of possible PAEIP cases, actual PAEIP cases, and deaths within 90 days due to PAEIP were compared between both phases. RESULTS: In the early and late phases, surgery was performed in 712 and 617 patients, 31 and 72 possible PAEIP cases were observed, nine and 12 actual PAEIP cases occurred, and the mean interval from the detection of PAEIP to starting treatment was 7.3+/-2.3 and 5.0+/-1.8 days, respectively. Five patients died in the early phase, and one patient died in the late phase. Significantly fewer PAEIP-related deaths were observed in the late phase (p<0.05). CONCLUSION: Identifying patients at risk for PAEIP by routine postoperative CT examinations led to the early diagnosis and treatment of PAEIP, resulting in the reduction of PAEIP-related mortality. PMID- 28593154 TI - Mid-Term Outcomes of Single-Port versus Conventional Three-Port Video-Assisted Thoracoscopic Surgery for Primary Spontaneous Pneumothorax. AB - BACKGROUND: The benefits of video-assisted thoracoscopic surgery (VATS) have been demonstrated over the past decades; as a result, VATS has become the gold standard treatment for primary spontaneous pneumothorax (PSP). Due to improvements in surgical technique and equipment, single-port VATS (s-VATS) is emerging as an alternative approach to conventional three-port VATS (t-VATS). The aim of this study was to evaluate s-VATS as a treatment for PSP by comparing operative outcomes and recurrence rates for s-VATS versus t-VATS. METHODS: Between March 2013 and December 2015, VATS for PSP was performed in 146 patients in Kyungpook National University Hospital. We retrospectively reviewed the medical records of these patients. RESULTS: The mean follow-up duration was 13.4+/-6.5 months in the s-VATS group and 28.7+/-3.9 months in the t-VATS group. Operative time (p<0.001), the number of staples used for the operation (p=0.001), duration of drainage (p=0.001), and duration of the postoperative stay (p<0.001) were significantly lower in the s-VATS group than in the t-VATS group. There was no difference in the overall recurrence-free survival rate between the s-VATS and t-VATS groups. CONCLUSION: No significant differences in operative outcomes and recurrence rates were found between s-VATS and t-VATS for PSP. Therefore, we cautiously suggest that s-VATS may be an appropriate alternative to t-VATS in the treatment of PSP. PMID- 28593155 TI - Feasibility and Safety of Single-Port Video-Assisted Thoracic Surgery for Primary Lung Cancer. AB - BACKGROUND: The feasibility of single-port video-assisted thoracic surgery (SPVATS) for primary lung cancer is not well understood. In this study, we compared SP and multi-port (MP) VATS for the surgical treatment of patients with primary lung cancer. METHODS: Surgical treatment was performed in 181 patients with primary lung cancer at Inje University Haeundae Paik Hospital between June 2012 and December 2015. A propensity-matched analysis was used to compare the postoperative outcomes and to evaluate the comparative feasibility and safety of SPVATS and MPVATS. RESULTS: There were 37 patients in the SPVATS group and 67 patients in the MPVATS group. Propensity matching produced 32 pairs. The operation time (210 minutes versus 200 minutes, p=0.11), volume of the estimated blood loss (170 mL versus 160 mL, p=0.19), duration of chest tube drainage (5 days versus 6 days, p=0.66), and length of hospital stay (9 days versus 10 days, p=0.89) were similar between the 2 groups. CONCLUSION: In our study, SPVATS for primary lung cancer was safe and feasible in well selected patients. A prospective, randomized study with a large group and long-term follow-up is necessary to evaluate the clinical feasibility and the advantages of SPVATS for primary lung cancer. PMID- 28593156 TI - Comparison of the Long-Term Results of R3 and R4 Sympathicotomy for Palmar Hyperhidrosis. AB - BACKGROUND: Video-assisted thoracoscopic sympathicotomy has been determined to be the best way to treat palmar hyperhidrosis. However, satisfaction with the surgical outcomes decreases with the onset of compensatory hyperhidrosis (CH) over time. The ideal level of sympathicotomy is controversial. Therefore, we compared the long-term results of R3 and R4 sympathicotomy. METHODS: We retrospectively reviewed 186 patients who underwent video-assisted thoracoscopic sympathicotomy between September 2001 and September 2015. We analyzed the long term results with respect to hand sweating and CH, and the overall satisfaction in 186 patients. RESULTS: With respect to hand sweating, significantly more patients complained of overly dry hands in the R3 group (25% versus 3.7%, p<0.001) and of mildly wet hands in the R4 group (2.9% versus 13.4%, p=0.007). There was a significantly increased occurrence rate of CH in the R3 group (97.1% versus 65.9%, p< 0.001). The most frequent site of CH was the trunk area. The overall satisfaction was higher in the R4 group, but without significance (75% versus 85.4%, p=0.082). Significantly more patients reported being very satisfied in the R4 group (5.8% versus 22.0%, p=0.001). CONCLUSION: The R4 group had a higher rate of satisfaction than the R3 group with respect to hand sweating. CH and hand dryness were significantly less common in the R4 group than in the R3 group. The lower occurrence of hand dryness and CH resulted in a higher satisfaction rate in the R4 group. PMID- 28593157 TI - Early Aggressive Surgical Treatment of Multiloculated Empyema. AB - BACKGROUND: Empyema is the collection of purulent exudate within the pleural space. Overall, 36%-65% of patients with empyema cannot be treated by medical therapy alone and require surgery. Multiloculated empyema is particularly difficult to treat with percutaneous drainage. Therefore, we describe our experiences with early aggressive surgical treatment for rapid progressive multiloculated empyema. METHODS: From January 2001 to October 2015, we retrospectively reviewed 149 patients diagnosed with empyema who received surgery. The patients were divided into 2 groups according to whether they underwent emergency surgery or not. We then compared surgical outcomes between these groups. RESULTS: The patients in group A (emergency surgery, n=102) showed a more severe infectious state, but a lower complication rate and shorter length of hospital stay. The incidence of lung abscess was higher in group A, and abscesses were associated with diabetes and severe alcoholism. CONCLUSION: Early aggressive surgical treatment resulted in good surgical outcomes for patients with rapid progressive multiloculated empyema. Furthermore, we suspect that the most likely causes of multiloculated empyema are lung abscesses found in patients with diabetes mellitus as well as severe alcoholism. PMID- 28593158 TI - Fontan Revision with Y-Graft in a Patient with Unilateral Pulmonary Arteriovenous Malformation. AB - The extracardiac conduit Fontan procedure is the last surgical step in the treatment of patients with a functional single ventricle. An acquired pulmonary arteriovenous malformation may appear perioperatively or postoperatively due to an uneven hepatic flow distribution. Here we report a case of a bifurcated Y graft Fontan operation in a 15-year-old male patient with a unilateral pulmonary arteriovenous malformation after an extracardiac conduit Fontan operation. PMID- 28593159 TI - Delayed Repair of Ventricular Septal Rupture Following Preoperative Awake Extracorporeal Membrane Oxygenation Support. AB - Outcomes of ventricular septal rupture (VSR) as a complication of acute myocardial infarction are extremely poor, with an in-hospital mortality rate of 45% in surgically treated patients and 90% in patients managed with medication. Delaying surgery for VSR is a strategy for reducing mortality. However, hemodynamic instability is the main problem with this strategy. In the present case, venoarterial extracorporeal membrane oxygenation (ECMO) was used to provide stable hemodynamic support before the delayed surgery. Awake ECMO was also used to avoiding the complications of sedatives and mechanical ventilation. Here, we describe a successful operation using awake ECMO as a bridge to surgery. PMID- 28593160 TI - Development of a Pulmonary Arteriovenous Fistula after a Modified Glenn Shunt in Tetralogy of Fallot and Its Resolution after Shunt Takedown in a 57-Year-Old Patient. AB - Pulmonary arteriovenous fistula (PAVF) is a complication of the Glenn shunt. A 57 year-old tetralogy of Fallot (TOF) patient, who had undergone a Glenn shunt and TOF total correction, complained of dyspnea and cyanosis. PAVFs were present in the right lung, and right lung perfusion was nearly absent. After coil embolization, takedown of the Glenn shunt, and reconstruction of the right pulmonary artery, the patient's symptoms were relieved. Extrapulmonary radioisotope uptake caused by the PAVFs shown in lung perfusion scans decreased, and right lung perfusion increased gradually. Although the development and resolution of PAVFs after a Glenn shunt have been reported in the pediatric population, this may be the first report on this change in old age. PMID- 28593161 TI - Surgical Management of a Coronary-Bronchial Artery Fistula Combined with Myocardial Ischemia Revealed by 13N-Ammonia Positron Emission Tomography. AB - A 71-year-old male with known bronchiectasis and atrial fibrillation was admitted to Seoul St. Mary's Hospital with recurrent transient ischemic attack. Radiofrequency ablation was performed to resolve the patient's atrial fibrillation, but failed. However, a fistula between the left circumflex artery and the bilateral bronchial arteries was found on computed tomography. Fistula ligation and a left-side maze operation were planned due to his recurrent symptom of dizziness, and these procedures were successfully performed. After the operation, the fistula was completely divided and no recurrence of atrial fibrillation took place. A coronary-bronchial artery fistula is a rare anomaly, and can be safely treated by surgical repair. PMID- 28593162 TI - Extravascular Migration of a Fractured Inferior Vena Cava Filter Strut. AB - A 20-year-old man presented with a femur fracture and epidural hemorrhage (EDH) following a fall. One month after fracture surgery, swelling developed in both legs, and he was diagnosed as having a deep-vein thrombosis and pulmonary embolism. A retrievable inferior vena cava filter (IVCF) was inserted, because EDH is a contraindication to anticoagulants. Four months later, he complained of abdominal pain, and a computed tomography scan showed a fractured IVCF strut. After percutaneous removal failed 3 times, the IVCF was surgically removed by orthopedists using a portable image intensifier without cardiopulmonary bypass. PMID- 28593163 TI - Corrigendum: Circulating Aneuploid Cells Detected in the Blood of Patients with Infectious Lung Diseases. AB - [This corrects the article on p. 126 in vol. 50, PMID: 28382274.]. PMID- 28593164 TI - Chemiluminescence systems; do all lead to same results in prolactin analysis? AB - BACKGROUND: Human prolactin (PRL) is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland and is involved in many biological processes including lactation and reproduction. Prolactin level may be determined quantitatively in serum by many different systems including chemiluminescence systems. However, comparison of the measured values between systems is difficult. METHODS: The prolactin values obtained and compared in two chemiluminescence systems; AUTOBIO DIAGNOSTICS MICROPLATE LUMOMETER and LIAISON XL Analyzer using BioRad tri level serum quality control materials and serum samples from n = 44 female patients; (Age mean & range) = (33: 21-65) years. RESULTS: Obtained PRL mean and range in Autobio and Liason systems were X = 414.8 +/- 230.0; Range: 25.7-980.9 MUlU/mL & X = 391.7 +/- 225.6; Range: 26.0-991.4 MUlU/mL respectively. Both system's results were correlated (Pearson product moment correlation r = 0.97 at p = 0.01 and Regression Analysis). CONCLUSION: Because of the differences between CLIA systems the authors conclude laboratories measuring range for PRL be accomplished on particular analyzer and verified against reference intervals stated by the manufacture. More importantly, consecutive PRL level determinations and patients follow up should be performed on only one analyzer rather than different analyzers. In this regard, mentioning the method and system type on the final laboratory reports become important and verify that a laboratory considers the clinical aspects of laboratory request as well as the quality assurance in performing the PRL determination. PMID- 28593165 TI - Minimally invasive surgical therapies for benign prostatic hypertrophy: The rise in minimally invasive surgical therapies. AB - The prevalence of benign prostatic hypertrophy (BPH) causing bothersome lower urinary tract symptoms increases with our ageing population. Treatment of BPH traditionally begins with medical therapy and surgical intervention is then considered for those whose symptoms progress despite treatment. Minimally invasive surgical therapies have been developed as an intermediary in the treatment of BPH with the aim of decreasing the invasiveness of interventions. These therapies also aim to reduce morbidity and dysfunction related to invasive surgical procedures. Multiple treatment options exist in this group including mechanical and thermo-ablative strategies. Emerging therapies utilizing differing technologies range from the established to the experimental. We review the current literature related to these minimally invasive therapies and the evidence of their effectiveness in treating BPH. The role of minimally invasive surgical therapies in the treatment of BPH is still yet to be strongly defined. Given the experimental nature of many of the modalities, further study is required prior to their recommendation as alternatives to invasive surgical therapy. More mature evidence is required for the analysis of durability of effect of these therapies to make robust conclusions of their effectiveness. PMID- 28593166 TI - Protective effect of Chuquiraga spinosa extract on N-methyl-nitrosourea (NMU) induced prostate cancer in rats. AB - BACKGROUND: The main objective was to evaluate the possible protective effect of Chuquiraga spinosa extract on N-methyl nitrosourea (NMU)-induced prostate cancer in rats and DU-145 cell line. MATERIALS AND METHODS: Prostate carcinogenesis was induced in 30 male Holtzman rats by providing cyproterone acetate, testosterone, and NMU. The tumors were monitored and hematological and biochemical parameters and frequency of micronucleated polychromatic erythrocytes were recorded. The cell line was assessed by a cytotoxicity assay. RESULTS: Oral administration of C. spinosa extract significantly lowered superoxide dismutase malondialdehyde, NO, C-reactive protein, and prostate-specific antigen levels (all P < 0.01 compared with Inductor Group). There was a significant decrease in the frequency of micronucleated polychromatic erythrocytes (P < 0.05). C. spinosa presented a selectivity index of 17.24 in the cytotoxicity assay. CONCLUSIONS: Considering its anti-inflammatory, antioxidant, and antigenotoxic effects, and important variations on biochemical and hematological parameters, including prostate specific antigen of C. spinosa extract, we conclude that it has a protective effect on NMU-induced prostate cancer in rats and cytotoxicity in the DU-145 cell line. PMID- 28593168 TI - Prostate-specific antigen reduction after empiric antibiotic treatment does not rule out biopsy in patients with lower urinary tract symptoms: prospective, controlled, single-center study. AB - BACKGROUND: To evaluate men, with lower urinary tract symptoms and newly elevated serum prostate specific antigen (PSA) to determine whether a three-week course of ciprofloxacin antibiotics lowers serum PSA levels and affects recommendations for prostate biopsy. METHODS: A prospective, controlled, single-center prospective trial of 177 men with a newly elevated PSA and lower urinary tract symptoms was conducted. Patients were randomized to three weeks of ciprofloxacin or observation. After three weeks, patients PSA levels and derivatives were repeated. At the end of 3 weeks, all patients underwent TRUS guided systematic 12 core prostate biopsies regardless of the final PSA value. RESULTS: Of 177 men who completed the study, 88 were in the treatment and 89 in the observation group. 46.5% of treatment and %18 of control groups patients PSA levels had decreased after 3 weeks and a significant PSA reduction was observed in the treatment group compare to control group (p: 0.035) but no significant prostate cancer detection rates were observed between the groups (p: 0.418). Also, in the treatment group prostate cancer detection rate was significantly higher in patients whom PSA levels were decreased (p: 0.011). CONCLUSION: This study has shown that, use empirical antibiotic treatment decreased the PSA levels but did not have any effect on prostate cancer detection. In addition, prostate cancer detection rates were found to be higher in patients with reduced PSA levels after treatment. Therefore, it may not be safe to rule out biopsies in patients who achieve a satisfactory PSA response to antibiotics. PMID- 28593167 TI - Correlation between postoperative prostate-specific antigen and biochemical recurrence in positive surgical margin patients: Single surgeon series. AB - BACKGROUND: To evaluate the relationship between postoperative prostate-specific antigen (PSA) levels and biochemical recurrence (BCR) after radical prostatectomy, especially in patients with positive surgical margins (PSMs). MATERIALS AND METHODS: A total of 144 patients who underwent radical prostatectomies performed by a single surgeon without any neoadjuvant or adjuvant treatment were analyzed. Differences in clinicopathological factors were compared by surgical margin status, and the relationship between postoperative PSA level and BCR in patients with PSMs was evaluated. RESULTS: Fifty of the 144 patients (34.7%) had PSMs. Of these, 74% experienced BCR. The negative surgical margins and PSMs groups differed significantly in terms of PSA level at diagnosis, clinical T stage, and risk group by the cancer of the prostate risk assessment score (P = 0.002, P = 0.002, and P = 0.004, respectively). Also, the nadir PSA level, tumor volume, and BCR rate differed between the two groups (P = 0.007, P = 0.015, and P = 0.005, respectively) On Kaplan-Meier analysis, BCR-free survival was better in the negative surgical margins than the PSMs group (64.1 vs. 55.4 months, log-rank test, P = 0.011). BCR-free survival did not differ significantly in PSMs patients according to whether PSA level was or was not detectable at 1 month postoperatively. However, BCR-free survival improved when the nadir PSA level was undetectable (compared to detectable) in PSMs patients (64.3 vs. 26.1 months, log-rank test, P < 0.001). In PSMs patients belonging to the high risk group by cancer of the prostate risk assessment score, BCR-free survival was significantly better when the PSA level attained the nadir within 3 months, compared to > 6 months, postoperatively (64.2 vs. 29.5 months, log-rank test, P = 0.022). CONCLUSION: If PSA is detectable in PSMs patients until 1 month after operation, cautious observation may be possible. If the nadir is attained within 3 months postoperatively in high-risk patients with PSMs, better BCR-free survival may be expected. PMID- 28593169 TI - Atherosclerosis is associated with erectile function and lower urinary tract symptoms, especially nocturia, in middle-aged men. AB - BACKGROUND: Atherosclerosis is a systematic disease in which plaque builds up inside the arteries that can lead to serious problems related to quality of life (QOL). Lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and late onset hypogonadism (LOH) are highly prevalent in aging men and are significantly associated with a reduced QOL. However, few questionnaire-based studies have fully examined the relation between atherosclerosis and several urological symptoms. MATERIALS AND METHODS: The study comprised 303 outpatients who visited our clinic with symptoms of LOH. Several factors influencing atherosclerosis, including serum concentrations of triglyceride, fasting blood sugar, and total testosterone measured by radioimmunoassay, were investigated. We also measured brachial-ankle pulse wave velocity (baPWV) and assessed symptoms by specific questionnaires, including the Sexual Health Inventory for Men (SHIM), Erection Hardness Score (EHS), International Prostate Symptom Score (IPSS), QOL index, and Aging Male Symptoms rating scale (AMS). Stepwise associations between the ratio of measured/age standard baPWV and clinical factors including laboratory data and the scores of the questionnaires were compared using the Jonckheere-Terpstra test for trend. The associations between the ratio of measured/age standard baPWV and each IPSS score were assessed in a multivariate linear regression model after adjustment for serum triglyceride, fasting blood sugar, and total testosterone. RESULTS: Regarding ED, a higher level of the ratio of measured/age standard baPWV was associated with a lower EHS, whereas no association was found with SHIM. Regarding LUTS, a higher ratio of measured/age standard baPWV was associated with a higher IPSS and QOL index. However, there was no statistically significant difference between the ratio of measured/age standard baPWV and AMS. A multivariate linear regression model showed only nocturia to be associated with the ratio of measured/age standard baPWV for each IPSS score. CONCLUSION: Atherosclerosis is associated with erectile function and LUTS, especially nocturia. PMID- 28593170 TI - Increased detrusor collagen is associated with detrusor overactivity and decreased bladder compliance in men with benign prostatic obstruction. AB - BACKGROUND: This study aimed to investigate the relationship between detrusor collagen content and urodynamic parameters in men with benign prostatic obstruction. MATERIAL AND METHODS: Nineteen consecutive patients undergoing open prostatectomy for bladder outlet obstruction (BOO) due to benign prostatic hyperplasia (BPH) were evaluated. Urodynamic tests were performed in all patients. BOO and detrusor contractility were assessed with the BOO index (BOOI) and the bladder contractility index (BCI), respectively. A bladder fragment was obtained during prostatectomy. Eight cadaveric organ donors composed the control group. Bladder sections were stained with picrosirius red and hematoxylin-eosin. The collagen to smooth muscle ratio (C/M) in the detrusor was measured and its relationship with urodynamic parameters was investigated. RESULTS: Seven (36.8%) patients were operated on due to lower urinary tract symptoms and 12 (63.2%) had urinary retention. The mean prostate volume was 128.6 cm3 +/- 32.3 cm3, the mean BOOI was 76.4 +/- 33.0, and the mean BCI was 116.1 +/- 33.7. The mean C/M in BPH patients and controls were 0.43 +/- 0.13 and 0.33 +/- 0.09, respectively (P = 0.042). A negative correlation was shown between C/M and bladder compliance (r = 0.488, P = 0.043). The C/M was increased in BPH patients with detrusor overactivity (DO) compared to those without DO (0.490 +/- 0.110 and 0.360 +/- 0.130, respectively; P = 0.030) and also in patients with urinary retention (P = 0.002). No correlation was shown between C/M and maximum cystometric capacity, BOOI, or BCI. CONCLUSION: Men with BOO/BPH have increased detrusor collagen content which is associated with decreased bladder compliance, detrusor overactivity, and urinary retention. PMID- 28593171 TI - Withania somnifera targets interleukin-8 and cyclooxygenase-2 in human prostate cancer progression. AB - BACKGROUND: Prostate cancer (PC) is a common noncutaneous malignancy in men. The incidence of PC is increasing at an alarming rate across the globe. Progression of PC is associated with elevated levels of interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) in malignant cells. Overexpression of these players is accompanied by chronic inflammation, increased angiogenesis, proliferation, migration, and inhibition of apoptosis. Moreover, their elevated circulating levels promote the disease progression from androgen-dependent to androgen independent state. Thus, inhibiting the expression of IL-8 and COX-2 would be a promising target in the development of PC therapeutics. In this study, we investigated the inhibitory effects of Withania somnifera extract on highly metastatic, androgen-independent prostate cancer cell line (PC3). Additionally, we compared the real-time expression of IL-8 and COX-2 in prostate tissue samples. MATERIALS AND METHODS: The cell viability and cytotoxicity of W. somnifera extract in PC3 cells was quantified colorimetrically by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase leakage assay, respectively. Hematoxylin and eosin staining for histological examination, trypan blue, and acridine orange dyes to enumerate apoptotic and live cells, quantitative real-time polymerase chain reaction to determine the expression and flow cytometry to study the cell cycle analysis were used. RESULTS: We observed a significant decrease in the cell viability with a half maximal inhibitory concentration (IC50) of 10 MUg/mL. The expression levels of IL 8 and COX-2 in prostate tissue samples and in PC3 cells were predominantly high; however, the lowest dose of W. somnifera significantly inhibited the enhanced expression of IL-8 and COX-2 in PC3 cells in 24 hours. Furthermore, W. somnifera extract (10 MUg/mL) irreversibly arrested the cell cycle in G2/M phase, which was evident from the rapid accumulation of PC3 cells significantly. CONCLUSION: Our results indicate that inherent metastatic and selective inhibitory potential of W. somnifera against PC. W. somnifera may be a good therapeutic agent in addition to the existing drugs for PC. Further studies with more prostate tissue samples are warranted. PMID- 28593172 TI - Allied Health Professional Support in Pediatric Inflammatory Bowel Disease: A Survey from the Canadian Children Inflammatory Bowel Disease Network-A Joint Partnership of CIHR and the CH.I.L.D. Foundation. AB - OBJECTIVES: The current number of healthcare providers (HCP) caring for children with inflammatory bowel disease (IBD) across Canadian tertiary-care centres is underinvestigated. The aim of this survey was to assess the number of healthcare providers (HCP) in ambulatory pediatric IBD care across Canadian tertiary-care centres. METHODS: Using a self-administered questionnaire, we examined available resources in academic pediatric centres within the Canadian Children IBD Network. The survey evaluated the number of HCP providing ambulatory care for children with IBD. RESULTS: All 12 tertiary pediatric gastroenterology centres participating in the network responded. Median full-time equivalent (FTE) of allied health professionals providing IBD care at each site was 1.0 (interquartile range (IQR) 0.6-1.0) nurse, 0.5 (IQR 0.2-0.8) dietitian, 0.3 (IQR 0.2-0.8) social worker, and 0.1 (IQR 0.02-0.3) clinical psychologists. The ratio of IBD patients to IBD physicians was 114 : 1 (range 31 : 1-537 : 1), patients to nurses/physician assistants 324 : 1 (range 150 : 1-900 : 1), dieticians 670 : 1 (range 250 : 1-4500 : 1), social workers 1558 : 1 (range 250 : 1-16000 : 1), and clinical psychologists 2910 : 1 (range 626 : 1-3200 : 1). CONCLUSIONS: There was a wide variation in HCP support among Canadian centres. Future work will examine variation in care including patients' outcomes and satisfaction across Canadian centres. PMID- 28593173 TI - A Type III Effector NleF from EHEC Inhibits Epithelial Inflammatory Cell Death by Targeting Caspase-4. AB - Enterohemorrhagic E. coli (EHEC) is a highly pathogenic bacterial strain capable of inducing severe gastrointestinal disease. Here, we show that EHEC uses the T3SS effector NleF to counteract the host inflammatory response by dampening caspase-4-mediated inflammatory epithelial cell death and by preventing the production of IL-1beta. The other two inflammatory caspases, caspase-1 and caspase-5, are not involved in EHEC DeltanleF-induced inflammatory cell death. We found that NleF not only interrupted the heterodimerization of caspase-4-p19 and caspase-4-p10, but also inhibited the interaction of caspase-1 and caspase-4. The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death. PMID- 28593175 TI - Polyketide-Terpene Hybrid Metabolites from an Endolichenic Fungus Pestalotiopsis sp. AB - Five new polyketide-terpene hybrid metabolites (1-5) with highly functionalized groups, together with six known derivatives (6-11), were isolated from the endolichenic fungus Pestalotiopsis sp. Their structures were elucidated by extensive NMR experiments including 1H, 13C, HMQC, COSY, and HMBC. The relative configurations of the new compounds were determined by analysis of coupling constants and ROESY correlations. The absolute configurations especially the secondary alcohol at C-15 in 1 and secondary alcohol at C-14 in 5 were established via the CD experiments of the in situ formed [Rh2(OCOCF3)4] complex with the acetonide derivatives. These compounds were tested for their inhibition activity against six plant pathogens. Compounds 1 and 5 exhibited pronounced efficiency against Fusarium oxysporum, and compounds 5 and 6 potently inhibited Fusarium gramineum with MIC value of 8 ug/mL, which revealed the plausible ecological role of endolichenic fungus in providing chemical protection for its host lichen in the fungus-plant relationship. The biosynthetic pathway of compounds 1-11 was postulated for the first time, which paved the way for its further biosynthesis research. PMID- 28593174 TI - Current Evidence for a Role of Neuropeptides in the Regulation of Autophagy. AB - Neuropeptides drive a wide diversity of biological actions and mediate multiple regulatory functions involving all organ systems. They modulate intercellular signalling in the central and peripheral nervous systems as well as the cross talk among nervous and endocrine systems. Indeed, neuropeptides can function as peptide hormones regulating physiological homeostasis (e.g., cognition, blood pressure, feeding behaviour, water balance, glucose metabolism, pain, and response to stress), neuroprotection, and immunomodulation. We aim here to describe the recent advances on the role exerted by neuropeptides in the control of autophagy and its molecular mechanisms since increasing evidence indicates that dysregulation of autophagic process is related to different pathological conditions, including neurodegeneration, metabolic disorders, and cancer. PMID- 28593177 TI - In-Hospital Outcomes and Long-Term Follow-Up after Percutaneous Transcatheter Closure of Postinfarction Ventricular Septal Defects. AB - Postinfarction ventricular septal defects (VSD) represent a devastating complication of acute myocardial infarction and are associated with high mortality. Percutaneous interventional closure of postinfarction VSD has been proposed as a potential alternative to surgery. The study aimed to evaluate the therapeutic safety and efficacy of percutaneous interventional closure of postinfarction ventricular septal defects (VSD). Each patient was assigned to one of two groups, based on whether they died during hospitalization (death group) or survived (survival group) in this retrospective study. In-hospital and follow-up data were analyzed. Placement of the VSD occluder was successful in 12 procedures (80%). The mean defect size was 14.20 +/- 4.89 mm. Compared to the patients who died, those who survived had higher systolic blood pressure, diastolic blood pressure, and left ventricular ejection fraction upon admission, as well as lower pulmonary/systemic flow ratio and shorter time from acute myocardial infarction to procedure. The incidence of cardiac shock and class IV heart failure was lower in the survival group than in the death group, and these factors correlated with in-hospital and 30-day mortality. Percutaneous closure of postinfarction VSD is an effective technique, which can be performed with a high procedural success rate. PMID- 28593176 TI - Radix Bupleuri: A Review of Traditional Uses, Botany, Phytochemistry, Pharmacology, and Toxicology. AB - Radix Bupleuri (Chaihu) has been used as a traditional medicine for more than 2000 years in China, Japan, Korea, and other Asian countries. Phytochemical studies demonstrated that this plant contains essential oils, triterpenoid saponins, polyacetylenes, flavonoids, lignans, fatty acids, and sterols. Crude extracts and pure compounds isolated from Radix Bupleuri exhibited various biological activities, such as anti-inflammatory, anticancer, antipyretic, antimicrobial, antiviral, hepatoprotective, neuroprotective, and immunomodulatory effects. However, Radix Bupleuri could also lead to hepatotoxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that the major bioactive compounds (saikosaponins a, b2, c, and d) were absorbed rapidly in rats after oral administration of the extract of Radix Bupleuri. This review aims to comprehensively summarize the traditional uses, botany, phytochemistry, pharmacology, toxicology, and pharmacokinetics of Radix Bupleuri reported to date with an emphasis on its biological properties and mechanisms of action. PMID- 28593178 TI - Association of Toll-Like Cell Receptors TLR2 (p.Arg753GLN) and TLR4 (p.Asp299GLY) Polymorphisms with Indicators of General and Local Immunity in Patients with Atopic Dermatitis. AB - A whole group of polymorphisms of genes involved in the formation of the epidermal barrier, immune responses, and their regulation is important in the formation of atopic phenotype. The purpose of the study is to determine the relationship of polymorphisms of genes of Toll-like receptors TLR2 and TLR4 with clinical and immunological parameters in atopic dermatitis patients in a "case control" study. Polymorphisms of genes TLR2 (p.Arg753Gln) and TLR4 (Asp299Gly) were detected by PCR. Parameters of the state of innate and adaptive immunity were assessed by the level of local production of sIgA, cytokine profile of blood serum for IL-4, IL-10, and IFN-gamma. Biological samples from 50 people with allergic pathology, aged 4.5 to 35 years, and 100 healthy individuals (controls) were analyzed. Observed dysregulation of cytokine production (IL-4, IL-10) in patients with heterozygous polymorphic genotypes probably reflects an imbalance of Th1/Th2/Th17 regulation of immune system response in these individuals. PMID- 28593179 TI - Rapamycin reduces Drosophila longevity under low nutrition. AB - Rapamycin treatment is considered a pharmacological intervention with the potential to mimic the longevity benefits of dietary manipulations. However, how rapamycin interacts with nutrition is not fully understood. Here we studied the effect of rapamycin on the longevity of Drosophila under a range of dietary conditions. In diets low in nutrients, rapamycin reduced longevity in a dosage dependent manner. This dosage effect requires some nutrients as rapamycin has no impact on survival under starvation conditions. Under a balanced diet of yeast and sugar, rapamycin had no repeatable beneficial effect on organismal longevity. These results show that the effect of rapamycin on longevity is sensitive to the nutritional environment and it can reduce lifespan when nutrients are limited. PMID- 28593180 TI - Surgical management of spontaneous, late-onset Descemet membrane detachment after penetrating keratoplasty for keratoconus: a case report. AB - BACKGROUND: To report a surgical method for treating corneal oedema in a case of late-onset Descemet membrane detachment after penetrating keratoplasty. CASE PRESENTATION: A 55-year old patient presented with sudden visual loss in his left eye 28 years after penetrating keratoplasty for keratoconus. Slit-lamp biomicroscopy revealed a distortion of the corneal graft anatomy with protrusion of the graft and peripheral thinning and steepening in the residual host tissue, accompanied by corneal graft oedema. Anterior segment optical coherence tomography revealed detachment of Descemet membrane localized to the area of the graft oedema. We proceeded with a full-thickness, partially circumferential incision in the graft-host junction, followed by repositioning and re-suturing of the graft in place, and intracameral air injection in order to achieve reattachment of Descemet membrane. CONCLUSIONS: Corneal graft repositioning in combination with re-bubbling may represent an effective therapeutic option in keratoconic patients with peripheral thinning in the residual host corneal tissue and subsequent Descemet membrane detachment. PMID- 28593181 TI - Representing and Learning Complex Object Interactions. AB - We present a framework for representing scenarios with complex object interactions, in which a robot cannot directly interact with the object it wishes to control, but must instead do so via intermediate objects. For example, a robot learning to drive a car can only indirectly change its pose, by rotating the steering wheel. We formalize such complex interactions as chains of Markov decision processes and show how they can be learned and used for control. We describe two systems in which a robot uses learning from demonstration to achieve indirect control: playing a computer game, and using a hot water dispenser to heat a cup of water. PMID- 28593182 TI - The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration. AB - BACKGROUND & AIMS: The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied. METHODS: We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture. RESULTS: The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway. CONCLUSIONS: Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology. PMID- 28593183 TI - Columnar Metaplasia in Three Types of Surgical Mouse Models of Esophageal Reflux. AB - BACKGROUND AND AIMS: Esophageal adenocarcinoma develops in the setting of gastroesophageal reflux and columnar metaplasia in distal esophagus. Columnar metaplasia arising in gastroesophageal reflux models has developed in rat; however, gastroesophageal reflux models in mice have not been well-characterized. METHODS: One hundred thirty-five C57Bl/6J mice aged 8 weeks old were divided into the following operations: esophagogastrojejunostomy (side-to-side) (EGJ), esophageal separation and esophagojejunostomy (end-to-side) (EJ), and EJ and gastrectomy (end-to-side) (EJ/TG). The animals were euthanized after 40 weeks and the histology of the junction was examined. Immunohistochemistry for p53, PDX-1, and CDX-2 was performed. RESULTS: Metaplasia developed in 15/33 (45.5%) of EGJ, 0/38 (0%) of EJ, and 6/39 (15.4%) of EJ/TG (P < .05) and dysplasia developed 7/33 (21.2%) of EGJ, 0% of EJ, and 1/39 (2.6%) of EJ/TG. p53 was positive in all of the dysplastic regions, 12/15 (80%) metaplasias in the EGJ model, and 1/6 (16.7%) metaplasia in the EJ/TG model. CDX-2 was positive in all cases of metaplasias, but decreased in some cases of dysplasia. PDX-1 was positive in 7/8 (88%) cases of dysplasia and in 15/21 (71%) cases of metaplasia (P < .05). CONCLUSIONS: The EGJ model, which causes reflux of gastric acid and duodenal content, developed metaplasia and dysplasia most frequently. No metaplasia developed in the EJ model in which gastric juice and duodenal content mixed before reflux. Thus, duodenal contents alone can induce columnar metaplasia and dysplasia; however, the combination of gastric acid with duodenal content reflux can cause metaplasia and dysplasia more efficiently. PMID- 28593186 TI - Origin of Barrett's Epithelium: Esophageal Submucosal Glands. AB - The origin of the progenitor cell for Barrett's esophagus remains a major unsolved mystery. Understanding the source of this progenitor may improve strategies to prevent the development of esophageal adenocarcinoma. Esophageal submucosal glands (ESMGs) and ducts may serve as a potential source of progenitor cells that respond to esophageal injury. Through the use of human histologic and molecular analysis, ESMGs and ducts have been described in physical continuity with areas of columnar esophagus, and shared mutations have been described between ESMG ducts and Barrett's esophagus. Acinar ductal metaplasia, associated with carcinogenesis in other organs, occurs within ESMGs with human esophageal injury and esophageal adenocarcinoma. By using atypical animal models, a squamous epithelial defect well above the gastroesophageal junction healed to columnar epithelium and continuity of ESMG ducts was noted in the new epithelium. Increased proliferation in ESMGs and ducts in response to injury also has been noted in human beings and animals. PMID- 28593184 TI - Epigenetics and Liver Fibrosis. AB - Liver fibrosis arises because prolonged injury combined with excessive scar deposition within hepatic parenchyma arising from overactive wound healing response mediated by activated myofibroblasts. Fibrosis is the common end point for any type of chronic liver injury including alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, and cholestatic liver diseases. Although genetic influences are important, it is epigenetic mechanisms that have been shown to orchestrate many aspects of fibrogenesis in the liver. New discoveries in the field are leading toward the development of epigenetic biomarkers and targeted therapies. This review considers epigenetic mechanisms as well as recent advances in epigenetic programming in the context of hepatic fibrosis. PMID- 28593185 TI - Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor. AB - BACKGROUND & AIMS: Mesalamine is a first-line drug for treatment of inflammatory bowel diseases (IBD). However, its mechanisms are not fully understood. CD4+ Foxp3+ regulatory T cells (Tregs) play a potential role in suppressing IBD. This study determined whether the anti-inflammatory activity of mesalamine is related to Treg induction in the colon. METHODS: We examined the frequencies of Tregs in the colons of wild-type mice, mice deficient for aryl hydrocarbon receptor (AhR-/ mice), and bone marrow-chimeric mice lacking AhR in hematopoietic cells (BM-AhR /- mice), following oral treatment with mesalamine. We also examined the effects of mesalamine on transforming growth factor (TGF)-beta expression in the colon. RESULTS: Treatment of wild-type mice with mesalamine increased the accumulation of Tregs in the colon and up-regulated the AhR target gene Cyp1A1, but this effect was not observed in AhR-/- or BM-AhR-/- mice. In addition, mesalamine promoted in vitro differentiation of naive T cells to Tregs, concomitant with AhR activation. Mice treated with mesalamine exhibited increased levels of the active form of TGF-beta in the colon in an AhR-dependent manner and blockade of TGF-beta signaling suppressed induction of Tregs by mesalamine in the colon. Furthermore, mice pretreated with mesalamine acquired resistance to dextran sodium sulfate induced colitis. CONCLUSIONS: We propose a novel anti-inflammatory mechanism of mesalamine for colitis: induction of Tregs in the colon via the AhR pathway, followed by TGF-beta activation. PMID- 28593187 TI - The Esophageal Squamous Epithelial Cell-Still a Reasonable Candidate for the Barrett's Esophagus Cell of Origin? AB - Barrett's esophagus is the metaplastic change of the squamous epithelium lining the distal esophagus into an intestinalized columnar epithelium that predisposes to esophageal adenocarcinoma development. The cell that gives rise to Barrett's esophagus has not been identified definitively, although several sources for the Barrett's esophagus cell of origin have been postulated. One possible source is a fully differentiated squamous epithelial cell or a squamous epithelial progenitor or stem cell native to the esophagus that, through molecular reprogramming, either transdifferentiation or transcommitment, could give rise to an intestinalized columnar cell. Multilayered epithelium found in human patients and rodents with Barrett's esophagus and direct phenotypic conversion of mouse embryonic esophageal epithelium provide support for this. Limitations in current experimental approaches may explain why it has been difficult to fully change an esophageal squamous epithelial cell into an intestinalized columnar cell in vitro. PMID- 28593188 TI - Barrett's Stem Cells as a Unique and Targetable Entity. AB - Although metaplasias have always attracted because of their strangeness, it is now clear they represent precursors for some of the most intractable human cancers. Despite this notoriety, they remain curiously understudied, and even their origins have been the subject of acrimonious debate stretching back to Virchow in the 19th century. Barrett's esophagus, with its high incidence, easy endoscopic access, and strong link to esophageal adenocarcinoma, would seem an ideal opportunity to address the origin problem. However, the field has settled into an uneasy status quo marked by no fewer than 4 parallel hypotheses, each of which is said to suffer fatal flaws. We favor one of these deficient hypotheses, that Barrett's arises from a distinct lineage of junctional cells present in all normal individuals, and discuss efforts to shore it up. It will be important to resolve this dialectic so that preemptive strategies for the eradication of Barrett's can reach patient care. PMID- 28593189 TI - Formulation and Development of a Validated UV-Spectrophotometric Analytical Method of Rutin Tablet. AB - Rutin is available in some foods, fruits, and vegetables. It has various beneficial medical effects making it useful in the treatment of various diseases. Rutin is available in different oral dosage forms such as tablets or capsules, widely available in the market. Rutin and many herbal medicines lack quality control due to unavailability of analytical methods. In this study, we formulated rutin tablet and studied its stability using a simple developed analytical method. The dissolution profile of our formulated tablet was also inspected. The results showed that our developed method was linear (R2 = 0.999), precise (% RSD = 0.026), and accurate (% recovery = 98.55-103.34). The formulated rutin tablet was stable under accelerated conditions as well as room temperature for 150 days (% assay > 91.69). The dissolution profile over 45 minutes of our formulated tablet showed a better dissolution (26.5%) compared with the internationally marketed Rutin(r) tablet (18.5%). This study can serve as a guideline to companies that manufacture herbal products to improve their formulated herbs and apply validated analytical methods to check the quality of their product. PMID- 28593191 TI - At What Latency Does the Phase of Brain Oscillations Influence Perception? AB - Recent evidence has shown a rhythmic modulation of perception: prestimulus ongoing electroencephalography (EEG) phase in the theta (4-8 Hz) and alpha (8-13 Hz) bands has been directly linked with fluctuations in target detection. In fact, the ongoing EEG phase directly reflects cortical excitability: it acts as a gating mechanism for information flow at the neuronal level. Consequently, the key phase modulating perception should be the one present in the brain when the stimulus is actually being processed. Most previous studies, however, reported phase modulation peaking 100 ms or more before target onset. To explain this discrepancy, we first use simulations showing that contamination of spontaneous oscillatory signals by target-evoked ERP and signal filtering (e.g., wavelet) can result in an apparent shift of the peak phase modulation towards earlier latencies, potentially reaching the prestimulus period. We then present a paradigm based on linear systems analysis which can uncover the true latency at which ongoing EEG phase influences perception. After measuring the impulse response function, we use it to reconstruct (rather than record) the brain activity of human observers during white noise sequences. We can then present targets in those sequences, and reliably estimate EEG phase around these targets without any influence of the target-evoked response. We find that in these reconstructed signals, the important phase for perception is that of fronto occipital ~6 Hz background oscillations at about 75 ms after target onset. These results confirm the causal influence of phase on perception at the time the stimulus is effectively processed in the brain. PMID- 28593190 TI - Nucleus Accumbens Shell Dopamine Preferentially Tracks Information Related to Outcome Value of Reward. AB - Effective decision-making requires organisms to predict reward values and bias behavior toward the best available option. The mesolimbic dopamine system, including the nucleus accumbens (NAc) shell and core, is involved in this process. Although studies support a role of the shell and core in specific aspects of decision-making (e.g., risk, effort, delay), no studies have directly compared dopamine release dynamics in these subregions to cues exclusively signaling the availability of different reward magnitudes. Here, fast-scan cyclic voltammetry was used to compare rapid dopamine release dynamics in the NAc subregions during a magnitude-based decision-making task. Rats learned that distinct cues signaled the availability of either a small or large reward (one or two sugar pellets), and then were given an opportunity to choose their preferred option. We found that peak dopamine release tracked the more preferred (higher magnitude) option in both core and shell subregions. Critically, however, overall (i.e., global) dopamine release was significantly higher and longer lasting in the shell and tracked the preferred magnitude during the entire cue period. Further, in the shell (not core), dopamine signaling significantly declined immediately at the lever press for reward but increased during the period of reward consumption. Collectively, the results indicate that although dopamine release in both the core and shell are activated by cues signaling the opportunity to respond for rewards of different magnitudes, dopamine release in the shell plays a differential and unique role in tracking information related to the outcome value of reward. PMID- 28593192 TI - Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response. AB - Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 MUg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO2 levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity. PMID- 28593193 TI - Differential Expression and Cell-Type Specificity of Perineuronal Nets in Hippocampus, Medial Entorhinal Cortex, and Visual Cortex Examined in the Rat and Mouse. AB - Perineuronal nets (PNNs) are specialized extracellular matrix (ECM) structures that condense around the soma and proximal dendrites of subpopulations of neurons. Emerging evidence suggests that they are involved in regulating brain plasticity. However, the expression of PNNs varies between and within brain areas. A lack of quantitative studies describing the distribution and cell specificity of PNNs makes it difficult to reveal the functional roles of PNNs. In the current study, we examine the distribution of PNNs and the identity of PNN enwrapped neurons in three brain areas with different cognitive functions: the dorsal hippocampus, medial entorhinal cortex (mEC) and primary visual cortex (V1). We compared rats and mice as knowledge from these species are often intermingled. The most abundant expression of PNNs was found in the mEC and V1, while dorsal hippocampus showed strikingly low levels of PNNs, apart from dense expression in the CA2 region. In hippocampus we also found apparent species differences in expression of PNNs. While we confirm that the PNNs enwrap parvalbumin-expressing (PV+) neurons in V1, we found that they mainly colocalize with excitatory CamKII-expressing neurons in CA2. In mEC, we demonstrate that in addition to PV+ cells, the PNNs colocalize with reelin-expressing stellate cells. We also show that the maturation of PNNs in mEC coincides with the formation of grid cell pattern, while PV+ cells, unlike in other cortical areas, are present from early postnatal development. Finally, we demonstrate considerable effects on the number of PSD-95-gephyrin puncta after enzymatic removal of PNNs. PMID- 28593194 TI - Fine-Scale Structure Analysis Shows Epidemic Patterns of Clonal Complex 95, a Cosmopolitan Escherichia coli Lineage Responsible for Extraintestinal Infection. AB - The Escherichia coli lineage known as clonal complex 95 (CC95) is a cosmopolitan human-associated lineage responsible for a significant fraction of extraintestinal infections of humans. Whole-genome sequence data of 200 CC95 strains from various origins enabled determination of the CC95 pangenome. The pangenome analysis revealed that strains of the complex could be assigned to one of five subgroups that vary in their serotype, extraintestinal virulence, virulence gene content, and antibiotic resistance gene profile. A total of 511 CC95 strains isolated from humans living in France, Australia, and the United States were screened for their subgroup membership using a PCR-based method. The CC95 subgroups are nonrandomly distributed with respect to their geographic origin. The relative frequency of the subgroups was shown to change through time, although the nature of the changes varies with continent. Strains of the subgroups are also nonrandomly distributed with respect to source of isolation (blood, urine, or feces) and host sex. Collectively, the evidence indicates that although strains belonging to CC95 may be cosmopolitan, human movement patterns have been insufficient to homogenize the distribution of the CC95 subgroups. Rather, the manner in which CC95 strains evolve appears to vary both spatially and temporally. Although CC95 strains appeared globally as pandemic, fine-scale structure analysis shows epidemic patterns of the CC95 subgroups. Furthermore, the observation that the relative frequency of CC95 subgroups at a single locality has changed over time indicates that the relative fitness of the subgroups has changed. IMPORTANCEEscherichia coli clonal complex 95 represents a cosmopolitan, genetically diverse lineage, and the extensive substructure observed in this lineage is epidemiologically and clinically relevant. The frequency with which CC95 strains are responsible for extraintestinal infection appears to have been stable over the past 15 years. However, the different subgroups identified within this lineage have an epidemic structure depending on the host, sample, continent, and time. Thus, the evolution and spread of strains belonging to CC95 are very different from those of another cosmopolitan human associated clonal complex, CC131, which has increased significantly in frequency as a cause of extraintestinal infection over the past 15 years due to the evolution and spread of two very closely related, nearly monomorphic lineages. PMID- 28593195 TI - Lake Bacterial Assemblage Composition Is Sensitive to Biological Disturbance Caused by an Invasive Filter Feeder. AB - One approach to improve forecasts of how global change will affect ecosystem processes is to better understand how anthropogenic disturbances alter bacterial assemblages that drive biogeochemical cycles. Species invasions are important contributors to global change, but their impacts on bacterial community ecology are rarely investigated. Here, we studied direct impacts of invasive dreissenid mussels (IDMs), one of many invasive filter feeders, on freshwater lake bacterioplankton. We demonstrated that direct effects of IDMs reduced bacterial abundance and altered assemblage composition by preferentially removing larger and particle-associated bacteria. While this increased the relative abundances of many free-living bacterial taxa, some were susceptible to filter feeding, in line with efficient removal of phytoplankton cells of <2 MUm. This selective removal of particle-associated and larger bacteria by IDMs altered inferred bacterial functional group representation, defined by carbon and energy source utilization. Specifically, we inferred an increased relative abundance of chemoorganoheterotrophs predicted to be capable of rhodopsin-dependent energy generation. In contrast to the few previous studies that have focused on the longer-term combined direct and indirect effects of IDMs on bacterioplankton, our study showed that IDMs act directly as a biological disturbance to which freshwater bacterial assemblages are sensitive. The negative impacts on particle associated bacteria, which have been shown to be more active than free-living bacteria, and the inferred shifts in functional group representation raise the possibility that IDMs may directly alter bacterially mediated ecosystem functions. IMPORTANCE Freshwater bacteria play fundamental roles in global elemental cycling and are an intrinsic part of local food webs. Human activities are altering freshwater environments, and much has been learned regarding the sensitivity of bacterial assemblages to a variety of these disturbances. Yet, relatively few studies have focused on how species invasion, which is one of the most important aspects of anthropogenic global change, affects freshwater bacterial assemblages. This study focuses on the impact of invasive dreissenid mussels (IDMs), a globally distributed group of invasive species with large impacts on freshwater phyto- and zooplankton assemblages. We show that IDMs have direct effects on lake bacterioplankton abundance, taxonomic composition, and inferred bacterial functional group representation. PMID- 28593197 TI - Significant Impacts of Increasing Aridity on the Arid Soil Microbiome. AB - Global deserts occupy one-third of the Earth's surface and contribute significantly to organic carbon storage, a process at risk in dryland ecosystems that are highly vulnerable to climate-driven ecosystem degradation. The forces controlling desert ecosystem degradation rates are poorly understood, particularly with respect to the relevance of the arid-soil microbiome. Here we document correlations between increasing aridity and soil bacterial and archaeal microbiome composition along arid to hyperarid transects traversing the Atacama Desert, Chile. A meta-analysis reveals that Atacama soil microbiomes exhibit a gradient in composition, are distinct from a broad cross-section of nondesert soils, and yet are similar to three deserts from different continents. Community richness and diversity were significantly positively correlated with soil relative humidity (SoilRH). Phylogenetic composition was strongly correlated with SoilRH, temperature, and electrical conductivity. The strongest and most significant correlations between SoilRH and phylum relative abundance were observed for Acidobacteria, Proteobacteria, Planctomycetes, Verrucomicrobia, and Euryarchaeota (Spearman's rank correlation [rs] = >0.81; false-discovery rate [q] = <=0.005), characterized by 10- to 300-fold decreases in the relative abundance of each taxon. In addition, network analysis revealed a deterioration in the density of significant associations between taxa along the arid to hyperarid gradient, a pattern that may compromise the resilience of hyperarid communities because they lack properties associated with communities that are more integrated. In summary, results suggest that arid-soil microbiome stability is sensitive to aridity as demonstrated by decreased community connectivity associated with the transition from the arid class to the hyperarid class and the significant correlations observed between soilRH and both diversity and the relative abundances of key microbial phyla typically dominant in global soils. IMPORTANCE We identify key environmental and geochemical factors that shape the arid soil microbiome along aridity and vegetation gradients spanning over 300 km of the Atacama Desert, Chile. Decreasing average soil relative humidity and increasing temperature explain significant reductions in the diversity and connectivity of these desert soil microbial communities and lead to significant reductions in the abundance of key taxa typically associated with fertile soils. This finding is important because it suggests that predicted climate change driven increases in aridity may compromise the capacity of the arid-soil microbiome to sustain necessary nutrient cycling and carbon sequestration functions as well as vegetative cover in desert ecosystems, which comprise one third of the terrestrial biomes on Earth. PMID- 28593196 TI - Quantitative Proteomics Shows Extensive Remodeling Induced by Nitrogen Limitation in Prochlorococcusmarinus SS120. AB - Prochlorococcus requires the capability to accommodate to environmental changes in order to proliferate in oligotrophic oceans, in particular regarding nitrogen availability. A precise knowledge of the composition and changes in the proteome can yield fundamental insights into such a response. Here we report a detailed proteome analysis of the important model cyanobacterium Prochlorococcus marinus SS120 after treatment with azaserine, an inhibitor of ferredoxin-dependent glutamate synthase (GOGAT), to simulate extreme nitrogen starvation. In total, 1,072 proteins, corresponding to 57% of the theoretical proteome, were identified the maximum proteome coverage obtained for any Prochlorococcus strain thus far. Spectral intensity, calibrated quantification by the Hi3 method, was obtained for 1,007 proteins. Statistically significant changes (P value of <0.05) were observed for 408 proteins, with the majority of proteins (92.4%) downregulated after 8 h of treatment. There was a strong decrease in ribosomal proteins upon azaserine addition, while many transporters were increased. The regulatory proteins PII and PipX were decreased, and the global nitrogen regulator NtcA was upregulated. Furthermore, our data for Prochlorococcus indicate that NtcA also participates in the regulation of photosynthesis. Prochlorococcus responds to the lack of nitrogen by slowing down translation, while inducing photosynthetic cyclic electron flow and biosynthesis of proteins involved in nitrogen uptake and assimilation. IMPORTANCEProchlorococcus is the most abundant photosynthetic organism on Earth, contributing significantly to global primary production and playing a prominent role in biogeochemical cycles. Here we study the effects of extreme nitrogen limitation, a feature of the oligotrophic oceans inhabited by this organism. Quantitative proteomics allowed an accurate quantification of the Prochlorococcus proteome, finding three main responses to nitrogen limitation: upregulation of nitrogen assimilation-related proteins, including transporters; downregulation of ribosome proteins; and induction of the photosystem II cyclic electron flow. This suggests that nitrogen limitation affects a range of metabolic processes far wider than initially believed, with the ultimate goal of saving nitrogen and maximizing the nitrogen uptake and assimilation capabilities of the cell. PMID- 28593199 TI - Analysis of instrumentation failures after three column osteotomies of the spine. AB - BACKGROUND: Correction of fixed spinal imbalance in a sagittal and/or coronal plane frequently needs a tricolumnar wedge resection when the deformity is rigid. Complications associated with deformity correction surgery are pseudoarthrosis and implant failure located along the construct. The purposes of this study were to assess comparative rates of pseudoarthrosis (implant failure) at weaker points along lumbosacral junction and level of osteotomy, estimate overall incidence of implant failure, and comparatively analyze failures at different points along the construct. METHODS: This was an IRB approved, single center study retrospective analysis. Twenty-six patients who underwent three column osteotomies were grouped according to procedure: pedicle subtraction osteotomy (PSO, (n = 18)); vertebral column resection (VCR, (n = 4)); hemivertebra excision (HE, (n = 2)); and extracavitary corpectomy (EC, (n = 2)). Follow-up data is presented on all of the study patients. Number of levels of fusion, anchors, percent saturation of fixation levels, type of bone graft and graft substitutes, and rod material and diameter were recorded. Radiographical data was reviewed preoperatively and postoperatively at 2 weeks and 3, 6, and 12 months and annually to determine sagittal and coronal balance, lumbopelvic parameters, presence or absence of interbody structural support, laterality or rod failure, and time to implant failure. RESULTS: Twenty-seven percent (7/26) patients demonstrated rod breakage either unilaterally (N = 2) or bilaterally (N = 5) during follow-up. Seventy-one percent had increasing back pain or worsening sagittal balance, while remaining failures found incidentally. No failures in children were seen. CONCLUSION: Tricolumnar osteotomy by posterior approach is a valuable tool. Rod failures found approximately 1 year from surgery, with 86% located at level of osteotomy and 14% at lumbosacral junction. Possible reasons are increased stress in the rod at this point and relatively deficient bone stock secondary to wide laminectomy. The low rate of rod breakage at lumbosacral junction may be related to adoption of structural interbody graft and stronger iliac screws. Additional biomechanical studies needed to assess the importance of these factors. This was a level IV study. PMID- 28593200 TI - SKELETAL MUSCLE MITOCHONDRIAL ALTERATIONS IN CARBOXYL TERMINUS OF HSC70 INTERACTING PROTEIN (CHIP) -/- MICE. AB - AIM: Hereditary ataxias are characterized by a slowly progressive loss of gait, hand, speech, and eye coordination and cerebellar atrophy. A subset of these, including hypogonadism, are inherited as autosomal recessive traits involving coding mutations of genes involved in ubiquitination including RNF216, OTUD4, and STUB1. Cerebellar CHIPopathy (MIM 615768) is a form of autosomal recessive spinocerebellar ataxia (SCAR16) and when accompanied with hypogonadism, clinically resembles the Gordon Holmes Syndrome (GHS). A causal missense mutation in the gene that encodes the carboxy terminus of HSP-70 interacting protein (CHIP) protein was reported for the first time in 2014. CHIP-/- mice were found to phenocopy the motor deficiencies and some aspects of the hypogonadism observed in patients with STUB1 mutations. However, mechanisms responsible for these deficits are not known. METHODS: In a survey of skeletal muscle by transmission electron microscopy. RESULTS: CHIP-/- mice at 6 months of age were found to have morphological changes consistent with increased sarcoplasmic reticulum compartments in quadriceps muscle and gastrocnemius (toxic oligomers and tubular aggregates), but not in soleus. CONCLUSION: Since CHIP has been implicated in ER stress in non-muscle cells, these findings illustrate potential parallel roles of CHIP in the muscle sarcoplasmic reticulum, a hypothesis that may be clinically relevant in a variety of common muscular and cardiac diseases. PMID- 28593198 TI - Biphasic Metabolism and Host Interaction of a Chlamydial Symbiont. AB - Chlamydiae are obligate intracellular bacteria comprising well-known human pathogens and ubiquitous symbionts of protists, which are characterized by a unique developmental cycle. Here we comprehensively analyzed gene expression dynamics of Protochlamydia amoebophila during infection of its Acanthamoeba host by RNA sequencing. This revealed a highly dynamic transcriptional landscape, where major transcriptional shifts are conserved among chlamydial symbionts and pathogens. Our data served to propose a time-resolved model for type III protein secretion during the developmental cycle, and we provide evidence for a biphasic metabolism of P. amoebophila during infection, which involves energy parasitism and amino acids as the carbon source during initial stages and a postreplicative switch to endogenous glucose-based ATP production. This fits well with major transcriptional changes in the amoeba host, where upregulation of complex sugar breakdown precedes the P. amoebophila metabolic switch. The biphasic chlamydial metabolism represents a unique adaptation to exploit eukaryotic host cells, which likely contributed to the evolutionary success of this group of microbes. IMPORTANCE Chlamydiae are known as major bacterial pathogens of humans, causing the ancient disease trachoma, but they are also frequently found in the environment where they infect ubiquitous protists such as amoebae. All known chlamydiae require a eukaryotic host cell to thrive. Using the environmental chlamydia Protochlamydia amoebophila within its natural host, Acanthamoeba castellanii, we investigated gene expression dynamics in vivo and throughout the complete chlamydial developmental cycle for the first time. This allowed us to infer how a major virulence mechanism, the type III secretion system, is regulated and employed, and we show that the physiology of chlamydiae undergoes a complete shift regarding carbon metabolism and energy generation. This study provides comprehensive insights into the infection strategy of chlamydiae and reveals a unique adaptation to life within a eukaryotic host cell. PMID- 28593201 TI - Risk Factors for Visual Impairment in an Uninsured Population and the Impact of the Affordable Care Act. AB - PURPOSE: To assess risk factors for visual impairment in a high-risk population of people: those without medical insurance. Secondarily, we assessed risk factors for remaining uninsured after implementation of the Affordable Care Act (ACA) and evaluated whether the ACA changed demand for local safety net ophthalmology clinic services one year after its implementation. METHODS: In a retrospective cohort study of patients who attended a community-academic partnership free ophthalmology clinic in Southeastern, Michigan between September 2012 - March 2015, we assessed the prevalence of presenting with visual impairment, the most common causes of presenting with visual impairment and used logistic regression to assess socio-demographic risk factors for visual impairment. We assessed the initial impact of the ACA on clinic utilization. We also analyzed risk factors for remaining uninsured one year after implementation of the ACA private insurance marketplace and Medicaid expansion in the state of Michigan. RESULTS: Among 335 patients, one-fifth (22%) presented with visual impairment; refractive error was the leading cause for presenting with visual impairment. Unemployment was the single significant risk factor for presenting with visual impairment after adjusting for multiple confounding factors (OR = 3.05, 95% CI 1.19-7.87, p=0.01). There was no difference in proportion of visual impairment or type of vision-threatening disease between the insured and uninsured (p=0.26). Seventy six percent of patients remained uninsured one year after ACA implementation. Patients who were white, spoke English as a first language and were US Citizens were more likely to gain insurance coverage through the ACA in our population (p<= 0.01). There was a non-significant decline in the mean number of patient treated per clinic (52 to 43) before and after ACA implementation (p=0.69). CONCLUSION: Refractive error was a leading cause for presenting with visual impairment in this vulnerable population, and being unemployed significantly increased the risk for presenting with visual impairment. The ACA did not significantly reduce the need for our free ophthalmology services. It is critically important to continue to support safety net specialty care initiatives and policy change to provide care for those in need. PMID- 28593203 TI - Two-dimensional salt and temperature DNA denaturation analysis using a magnetoresistive sensor. AB - We present a microfluidic system and its use to measure DNA denaturation curves by varying the temperature or salt (Na+) concentration. The readout is based on real-time measurements of DNA hybridization using magnetoresistive sensors and magnetic nanoparticles (MNPs) as labels. We report the first melting curves of DNA hybrids measured as a function of continuously decreasing salt concentration at fixed temperature and compare them to the corresponding curves obtained vs. temperature at fixed salt concentration. The magnetoresistive sensor platform provided reliable results under varying temperature as well as salt concentration. The salt concentration melting curves were found to be more reliable than temperature melting curves. We performed a two-dimensional mapping of the melting profiles of a target to probes targeting its wild type (WT) and mutant type (MT) variants in the temperature-salt concentration plane. This map clearly showed a region of optimum ability to differentiate between the two variants. We finally demonstrated single nucleotide polymorphysm (SNP) genotyping using both denaturation methods on both separate sensors but also using a differential measurement on a single sensor. The results demonstrate that concentration melting provides an attractive alternative to temperature melting in on-chip DNA denaturation experiments and further show that the magnetoresistive platform is attractive due to its low cross-sensitivity to temperature and liquid composition. PMID- 28593202 TI - Feature Selection Based on Iterative Canonical Correlation Analysis for Automatic Diagnosis of Parkinson's Disease. AB - Parkinson's disease (PD) is a major progressive neurodegenerative disorder. Accurate diagnosis of PD is crucial to control the symptoms appropriately. However, its clinical diagnosis mostly relies on the subjective judgment of physicians and the clinical symptoms that often appear late. Recent neuroimaging techniques, along with machine learning methods, provide alternative solutions for PD screening. In this paper, we propose a novel feature selection technique, based on iterative canonical correlation analysis (ICCA), to investigate the roles of different brain regions in PD through T1-weighted MR images. First of all, gray matter and white matter tissue volumes in brain regions of interest are extracted as two feature vectors. Then, a small group of significant features were selected using the iterative structure of our proposed ICCA framework from both feature vectors. Finally, the selected features are used to build a robust classifier for automatic diagnosis of PD. Experimental results show that the proposed feature selection method results in better diagnosis accuracy, compared to the baseline and state-of-the-art methods. PMID- 28593204 TI - Steering patchy particles using multivalent electrolytes. AB - Proteins and many recently designed colloids can be regarded as patchy particles where directional interactions strongly influence and govern assembly behavior. Using explicit ion implicit solvent Metropolis Monte Carlo simulations, we investigate spherical model particles, carrying both charge and electric patches, in dilute aqueous 1 : 1, 1 : 3, and 3 : 1 electrolyte solutions. Striking differences in pair interaction free energies and orientational correlations are induced by three different salts which are discussed and rationalized in terms of ion-binding to surface groups, ion-ion correlations, and double layer forces. These findings suggest a general strategy where directional, intermolecular interactions can be invoked and tuned via small amounts of a carefully chosen electrolyte. PMID- 28593205 TI - Elastic properties and short-range structural order in mixed network former glasses. AB - Elastic properties of alkali containing glasses are of great interest not only because they provide information about overall structural integrity but also they are related to other properties such as thermal conductivity and ion mobility. In this study, we investigate two mixed-network former glass systems, sodium borosilicate 0.2Na2O + 0.8[xBO1.5 + (1 - x)SiO2] and sodium borogermanate 0.2Na2O + 0.8[xBO1.5 + (1 - x)GeO2] glasses. By mixing network formers, the network topology can be changed while keeping the network modifier concentration constant, which allows for the effect of network structure on elastic properties to be analyzed over a wide parametric range. In addition to non-linear, non additive mixed-glass former effects, maxima are observed in longitudinal, shear and Young's moduli with increasing atomic number density. By combining results from NMR spectroscopy and Brillouin light scattering with a newly developed statistical thermodynamic reaction equilibrium model, it is possible to determine the relative proportions of all network structural units. This new analysis reveals that the structural characteristic predominantly responsible for effective mechanical load transmission in these glasses is a high density of network cations coordinated by four or more bridging oxygens, as it provides for establishing a network of covalent bonds among these cations with connectivity in three dimensions. PMID- 28593211 TI - Architecture of CoNx single clusters on nanocarbon as excellent oxygen reduction catalysts with high-efficient atomic utilization. AB - A new strategy to fabricate CoNx single cluster supported nanocarbon catalysts (C/P/2Co600) with enhanced atomic utilization towards the oxygen reduction reaction (ORR) is reported. N-Coordination protection and low-temperature pyrolysis are the two key factors for the formation of CoNx single clusters on nanocarbon supports. Morphological and structural identification confirmed the simultaneous anchoring of homo-dispersed CoNx single clusters and N-doping on the nanocarbon under relatively mild thermal treatment conditions. Expectedly, the obtained single cluster catalyst with a trace amount of metal atoms exhibited excellent ORR performance including a positive half-wave potential (0.846 V), a high mass activity (0.98 A mgCo-1, ampere per milligram of cobalt) and outstanding chemical durability after 8000 potential cycles. We believe that our findings provide a new route for the rational design of low-cost and highly active ORR catalytic materials. PMID- 28593213 TI - Obituary for Professor Dr. rer. nat. Karl Sommer, Berlin. PMID- 28593212 TI - [Myokard-Perfusions-SPECT. Myocardial perfusion SPECT - Update S1 guideline]. AB - The S1 guideline for myocardial perfusion SPECT has been published by the Association of the Scientific Medical Societies in Germany (AWMF) and is valid until 2/2022. This paper is a short summary with comments on all chapters and subchapters wich were modified and amended. PMID- 28593214 TI - Association Between Gender and Drug Cost for Over-the-Counter Minoxidil. PMID- 28593215 TI - Cutting-edge Efforts in Surgical Patient Safety. PMID- 28593219 TI - Massive Intra-abdominal Mass. PMID- 28593216 TI - Real-World Effectiveness of Antipsychotic Treatments in a Nationwide Cohort of 29 823 Patients With Schizophrenia. AB - Importance: It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to the impossibility of including large unselected patient populations in randomized clinical trials, as well as residual confounding from selection biases in observational studies. Objective: To study the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia. Design, Setting, and Participants: Prospectively gathered nationwide databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (29 823 patients in the total prevalent cohort; 4603 in the incident cohort of newly diagnosed patients). Within-individual analyses were used for primary analyses, in which each individual was used as his or her own control to eliminate selection bias. Traditional Cox proportional hazards multivariate regression was used for secondary analyses. Main Outcomes and Measures: Risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death). Results: There were 29 823 patients (12 822 women and 17 001 men; mean [SD] age, 44.9 [12.0] years). During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly long-acting injectable paliperidone (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64), long-acting injectable zuclopenthixol (HR, 0.53; 95% CI, 0.48-0.57), clozapine (HR, 0.53; 95% CI, 0.48 0.58), long-acting injectable perphenazine (HR, 0.58; 95% CI, 0.52-0.65), and long-acting injectable olanzapine (HR, 0.58; 95% CI, 0.44-0.77) compared with no use of antipsychotic medication. Oral flupentixol (HR, 0.92; 95% CI, 0.74-1.14), quetiapine (HR, 0.91; 95% CI, 0.83-1.00), and oral perphenazine (HR, 0.86; 95% CI, 0.77-0.97) were associated with the highest risk of rehospitalization. Long acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort). Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine. The results of several sensitivity analyses were consistent with those of the primary analyses. Conclusions and Relevance: Clozapine and long acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with equivalent oral formulations. PMID- 28593242 TI - Primary Care-Based Skin Cancer Screening in a Veterans Affairs Health Care System. AB - Importance: Skin cancer screening may improve melanoma outcomes and keratinocyte carcinoma morbidity, but little is known about the feasibility of skin cancer training and clinical skin examination (CSE) by primary care practitioners (PCPs) in large health care systems. Objective: To assess the association of skin cancer training and screening by PCPs with dermatology referral patterns and rates of skin biopsies. Design, Setting, and Participants: In this pilot interventional study performed at the Veterans Affairs Palo Alto Health Care System, patients 35 years or older scheduled for an annual health habits screen in the PCP general medicine clinics were studied. Interventions: Six PCPs underwent Internet Curriculum for Melanoma Early Detection (INFORMED) training in May 2015, and 5 screened patients during the following 14 months. Main Outcomes and Measures: Proportion of dermatology referrals, subsequent skin biopsies, and PCP diagnostic accuracy for skin cancer or precancer compared with dermatologist diagnosis were assessed in screened patients 14 months before the intervention (February 18, 2014, through April 30, 2015) and after the intervention (June 18, 2015, through August 30, 2016). Results: Among 258 patients offered screening (median age, 70 years; age range, 35-94 years; 255 [98.8%] male), 189 (73.3%) received CSE and 69 (26.7%) declined. A total of 62 of 189 patients (32.8%) were referred to a dermatologist after intervention: 33 (53.2%) for presumptive skin cancers and 15 (24.2%) for precancers. Nine of 50 patients (18.0%) evaluated in dermatology clinic underwent biopsy to exclude skin cancer. Correct diagnoses were made by PCPs in 13 of 38 patients (34.2%; 4 of 27 patients [14.8%] diagnosed with skin cancers and 5 of 11 patients [45.5%] diagnosed with actinic keratoses). Comparison of all outpatient visits for the 5 main participating PCPs before vs after intervention revealed no significant differences in dermatology referrals overall and those for presumptive skin cancer or actinic keratoses, skin biopsies, or PCP diagnostic accuracy with the exception of significantly fewer postintervention dermatology referrals that lacked specific diagnoses (25 [1.0%] vs 10 [0.4%], P = .01). Conclusions and Relevance: This pilot study suggests that PCP-based skin cancer training and screening are feasible and have the potential to improve PCP diagnostic accuracy without increasing specialty referrals or skin biopsies. Additional studies comparing screening rates, specialty referrals, and patient outcomes in trained vs untrained PCPs are needed before screening is widely implemented in large health care systems in the United States. PMID- 28593243 TI - The Increasing Call for Protective Ventilation During Anesthesia. PMID- 28593244 TI - Effect of Mandarin Orange Yogurt on Allergic Conjunctivitis Induced by Conjunctival Allergen Challenge. AB - Purpose: To evaluate the effects of mandarin orange yogurt containing nobiletin and beta-lactoglobulin on the allergic conjunctivitis induced by a conjunctival allergen challenge (CAC). Methods: Experiment 1 was performed on 26 asymptomatic patients (age, 25.3 +/- 5.3 years) with proven seasonal allergic conjunctivitis due to cedar pollen. We compared the degree of conjunctivitis induced by CAC before and after ingesting mandarin orange yogurt for 2 weeks. Experiment 2 was a double-blind, placebo-controlled trial performed on 31 patients (age, 32.5 +/- 12.2 years). A diet containing mandarin orange yogurt was compared to a diet containing yogurt lacking the mandarin orange on the conjunctivitis induced by CAC. The temperature of the inferior bulbar conjunctiva was measured before and 20 minutes after the CAC with an ocular surface thermographer (OST). The degree of conjunctival injection and chemosis was graded by slit-lamp biomicroscopy. The changes in the symptoms were evaluated by a questionnaire. Results: In experiment 1, the scores of redness (3.07 +/- 3.03 vs. 1.05 +/- 1.70), chemosis (2.84 +/- 2.27 vs. 0.81 +/- 1.11), itching (4.34 +/- 3.05 vs. 1.39 +/- 2.12), and temperature (0.73 +/- 0.42 degrees C vs. 0.45 +/- 0.43 degrees C) were significantly lower (P < 0.001) after a diet of mandarin orange yogurt for 2 weeks. In experiment 2, the scores of redness (1.03 +/- 0.18 vs. 1.28 +/- 0.52; P = 0.0156), itching (1.93 +/- 1.92 vs. 2.82 +/- 2.21; P = 0.0133), and surface temperature (0.54 +/- 0.21 degrees C vs. 0.31 +/- 0.25 degrees C; P < 0.001) were significantly lower in the mandarin orange yogurt group than in the control yogurt group. Conclusions: Mandarin orange yogurt can be an effective nutritional intervention for allergic conjunctivitis. PMID- 28593246 TI - Socially Assistive Robots Help Patients Make Behavioral Changes. PMID- 28593247 TI - Demodex-Positive Acneiform Eruption Responsive to Ivermectin in a Patient Taking an Epidermal Growth Factor Inhibitor. PMID- 28593248 TI - Human efficiency in detecting and discriminating biological motion. AB - Using an "information meter" provided by ideal observer analysis, we measured the efficiency with which human observers processed different walking stimuli against luminance noise and spatial uncertainty to either detect the presence of a walker or to discriminate the walking direction. Human efficiency was examined across four renderings of a human walker: contour, point lights, silhouette, and skeleton. We replicated the previous finding of low discrimination efficiency in biological motion (Gold, Tadin, Cook, & Blake, 2008) and also found low detection efficiency for biological motion. Interestingly, in both detection and discrimination tasks, the skeleton display was among those yielding the highest level of efficiency in processing visual information. This finding suggests that structural information about the relative position of joints, highlighted in the skeleton display, provides a critical component of the internal representation for biological motion. PMID- 28593245 TI - A GPR119 Signaling System in the Murine Eye Regulates Intraocular Pressure in a Sex-Dependent Manner. AB - Purpose: GPR119 is a G protein-coupled receptor that may be the endogenous target for 2-oleoylglycerol (2-OG), a lipid related to the endocannabinoid family of neuromodulators. Interest in GPR119 has centered on its role in regulating insulin secretion; however, the role of GPR119 has not been examined in the eye. The purpose of this study was to explore a potential GPR119-based signaling system in the murine eye. Methods: We used a combination of RT-PCR, immunohistochemistry, lipid measurement, and IOP measurement in a normotensive mouse model, with GPR119 knockout mice as controls. Results: We detected GPR119 mRNA and protein in the anterior eye of the mouse and cow, with GPR119 mRNA levels elevated in female relative to male mice. GPR119 protein expression is most prominent in structures near the angle, including trabecular meshwork, as well as iris and corneal epithelium. We detected 2-OG in the anterior eye and detected alterations in lipid levels in GPR119 knockout versus wild type and also by sex. Last, we found that 2-OG preferentially reduces IOP in female mice in a normotensive model. Conclusions: In summary, we offer evidence for a GPR119-based signaling system in the mammalian eye, with receptors, ligands, and function in the form of a reduction in IOP. Notably this reduction in pressure is restricted to female mice. PMID- 28593250 TI - Asymptomatic Pigmented Lesions of the Gingiva. PMID- 28593249 TI - Personal familiarity enhances sensitivity to horizontal structure during processing of face identity. AB - What makes identification of familiar faces seemingly effortless? Recent studies using unfamiliar face stimuli suggest that selective processing of information conveyed by horizontally oriented spatial frequency components supports accurate performance in a variety of tasks involving matching of facial identity. Here, we studied upright and inverted face discrimination using stimuli with which observers were either unfamiliar or personally familiar (i.e., friends and colleagues). Our results reveal increased sensitivity to horizontal spatial frequency structure in personally familiar faces, further implicating the selective processing of this information in the face processing expertise exhibited by human observers throughout their daily lives. PMID- 28593251 TI - Are There Differences in Disruptions of Reward Processing Between Substance Use Disorder and Gambling Disorder?-Reply. PMID- 28593252 TI - Standard vs Expanded Indications for Esophageal Magnetic Sphincter Augmentation for Reflux Disease. PMID- 28593268 TI - Incorrect SD Values in Table 1. PMID- 28593266 TI - Wireless Monitoring Program of Patient-Centered Outcomes and Recovery Before and After Major Abdominal Cancer Surgery. AB - Importance: A combined subjective and objective wireless monitoring program of patient-centered outcomes can be carried out in patients before and after major abdominal cancer surgery. Objective: To conduct a proof-of-concept pilot study of a wireless, patient-centered outcomes monitoring program before and after major abdominal cancer surgery. Design, Setting, and Participants: In this proof-of concept pilot study, patients wore wristband pedometers and completed online patient-reported outcome surveys (symptoms and quality of life) 3 to 7 days before surgery, during hospitalization, and up to 2 weeks after discharge. Reminders via email were generated for all moderate to severe scores for symptoms and quality of life. Surgery-related data were collected via electronic medical records, and complications were calculated using the Clavien-Dindo classification. The study was carried out in the inpatient and outpatient surgical oncology unit of one National Cancer Institute-designated comprehensive cancer center. Eligible patients were scheduled to undergo curative resection for hepatobiliary and gastrointestinal cancers, were English speaking, and were 18 years or older. Twenty participants were enrolled over 4 months. The study dates were April 1, 2015, to July 31, 2016. Main Outcomes and Measures: Outcomes included adherence to wearing the pedometer, adherence to completing the surveys (MD Anderson Symptom Inventory and EuroQol 5-dimensional descriptive system), and satisfaction with the monitoring program. Results: This study included a final sample of 20 patients (median age, 55.5 years [range, 22-74 years]; 15 [75%] female) with evaluable data. Pedometer adherence (88% [17 of 20] before surgery vs 83% [16 of 20] after discharge) was higher than survey adherence (65% to 75% [13 of 20 and 15 of 20] completed). The median number of daily steps at day 7 was 1689 (19% of daily steps at baseline), which correlated with the Comprehensive Complication Index, for which the median was 15 of 100 (r = -0.64, P < .05). Postdischarge overall symptom severity (2.3 of 10) and symptom interference with activities (3.5 of 10) were mild. Pain (4.4 of 10), fatigue (4.7 of 10), and appetite loss (4.0 of 10) were moderate after surgery. Quality-of-life scores were lowest at discharge (66.6 of 100) but improved at week 2 (73.9 of 100). While patient-reported outcomes returned to baseline at 2 weeks, the number of daily steps was only one-third of preoperative baseline. Conclusions and Relevance: Wireless monitoring of combined subjective and objective patient centered outcomes can be carried out in the surgical oncology setting. Preoperative and postoperative patient-centered outcomes have the potential of identifying high-risk populations who may need additional interventions to support postoperative functional and symptom recovery. PMID- 28593269 TI - Confusion Regarding Surgical Delirium-Is Dexmedetomidine the Answer? PMID- 28593267 TI - National Trends in Use and Outcomes of Pulmonary Artery Catheters Among Medicare Beneficiaries, 1999-2013. AB - Importance: Recent studies have observed an increase in the rate of pulmonary artery catheter (PAC) use in heart failure admissions. Little is known about the national trends in other previously common indications for PAC placement, PAC use overall, or outcomes associated with PAC placement. Objective: To determine national trends in PAC use overall as well as across sociodemographic groups and key clinical conditions, including acute myocardial infarction, heart failure, and respiratory failure. Design, Setting, and Participants: Centers for Medicare and Medicaid Services inpatient claims data and International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to conduct a serial cross-sectional cohort study between January 1, 1999, and December 31, 2013, identifying hospitalizations during which a PAC was placed. Data analysis was conducted from September 25, 2015, to April 10, 2017. Main Outcomes and Measures: Rate of use of a PAC per 1000 admissions, 30-day mortality, and length of stay. Results: Among the 68 374 904 unique Medicare beneficiaries in the study, there were 469 582 hospitalizations among 457 193 patients (204 232 women and 252 961 men; mean [SD] age, 76.3 [6.9] years) during which a PAC was placed. There was a 67.8% relative decrease in PAC use (6.28 per 1000 admissions in 1999 to 2.02 per 1000 admissions in 2013; P < .001), with 2 distinct trends: significant year-on-year decreases from 1999 to 2011, followed by stable use through 2013. There was variation in rates of PAC use across race/ethnicity, age, and sex, but use decreased across all subgroups. Although there were sustained decreases in PAC use for acute myocardial infarction (20.0 PACs placed per 1000 admissions in 1999 to 5.2 in 2013 [74.0% reduction]; P < .001 for trend) and respiratory failure (29.9 PACs placed per 1000 admission in 1999 to 2.3 in 2013 [92.3% reduction]; P < .001 for trend) during the study period, there was an initial decrease in PAC use in heart failure, with a nadir in 2009 followed by a subsequent increase (9.1 PACs placed per 1000 admissions in 1999 to 4.0 in 2009 to 5.8 in 2013). In-hospital mortality, 30-day mortality, and length of stay decreased during the study period. Conclusions and Relevance: In the wake of mounting evidence suggesting a lack of benefit to the routine use of PACs, there has been a de-adoption of PAC use overall and across sociodemographic groups but heterogeneity in patterns of use across clinical conditions. The clinical outcomes of patients with PACs have significantly improved. These findings raise important questions about the optimal use of PACs and the drivers of the observed trends. PMID- 28593270 TI - Are There Differences in Disruptions of Reward Processing Between Substance Use Disorder and Gambling Disorder? PMID- 28593271 TI - Increased Cardiovascular Risk Associated With E-Cigarette Use-Reply. PMID- 28593298 TI - Increased Cardiovascular Risk Associated With E-Cigarette Use. PMID- 28593281 TI - Simultaneous Antidepressant and Benzodiazepine New Use and Subsequent Long-term Benzodiazepine Use in Adults With Depression, United States, 2001-2014. AB - Importance: Benzodiazepines have been prescribed for short periods to patients with depression who are beginning antidepressant therapy to improve depressive symptoms more quickly, mitigate concomitant anxiety, and improve antidepressant treatment continuation. However, benzodiazepine therapy is associated with risks, including dependency, which may take only a few weeks to develop. Objectives: To examine trends in simultaneous benzodiazepine and antidepressant new use among adults with depression initiating an antidepressant, assess antidepressant treatment length by simultaneous new use status, estimate subsequent long-term benzodiazepine use in those with simultaneous antidepressant and benzodiazepine new use, and identify determinants of simultaneous new use and long-term benzodiazepine use. Design, Setting, and Participants: This cohort study using a US commercial claims database included commercially insured adults (aged 18-64 years) from January 1, 2001, through December 31, 2014, with a recent depression diagnosis who began antidepressant therapy but had not used antidepressants or benzodiazepines in the prior year. Exposures: Simultaneous new use, defined as a new benzodiazepine prescription dispensed on the same day as a new antidepressant prescription. Main Outcomes and Measures: The proportion of antidepressant initiators with simultaneous new use and continuing antidepressant treatment for 6 months and the proportion of simultaneous new users receiving long-term (6 months) benzodiazepine therapy. Results: Of the 765 130 adults (median age, 39 years; interquartile range, 29-49 years; 507 451 women [66.3%]) who initiated antidepressant treatment, 81 020 (10.6%) also initiated benzodiazepine treatment. The mean annual increase in the proportion simultaneously starting use of both agents from 2001 to 2014 was 0.49% (95% CI, 0.47%-0.51%), increasing from 6.1% (95% CI, 5.5%-6.6%) in 2001 to 12.5% (95% CI, 12.3%-12.7%) in 2012 and stabilizing through 2014 (11.3%; 95% CI, 11.1%-11.5%). Similar findings were apparent by age group and physician type. Antidepressant treatment length was similar in simultaneous new users and non-simultaneous new users. Among simultaneous new users, 12.3% (95% CI, 12.0%-12.5%) exhibited long-term benzodiazepine use (64.0% discontinued taking benzodiazepines after the initial fill). Determinants of long-term benzodiazepine use after simultaneous new use were longer initial benzodiazepine days' supply, first prescription for a long acting benzodiazepine, and recent prescription opioid fills. Conclusions and Relevance: One-tenth of antidepressant initiators with depression simultaneously initiated benzodiazepine therapy. No meaningful difference in antidepressant treatment at 6 months was observed by simultaneous new use status. Because of the risks associated with benzodiazepines, simultaneous new use at antidepressant initiation and the benzodiazepine regimen itself require careful consideration. PMID- 28593300 TI - Trends in Cardiovascular Health of US Adults by Income, 2005-2014. PMID- 28593301 TI - Income Disparities in Absolute Cardiovascular Risk and Cardiovascular Risk Factors in the United States, 1999-2014. AB - Importance: Large improvements in the control of risk factors for cardiovascular disease have been achieved in the United States, but it remains unclear whether adults in all socioeconomic strata have benefited equally. Objective: To assess temporal trends in 10-year predicted absolute cardiovascular risk and cardiovascular risk factors among US adults in different socioeconomic strata. Design, Setting, and Participants: A cross-sectional analysis was conducted using data on adults 40 to 79 years of age without established cardiovascular disease from the 1999 to 2014 National Health and Nutrition Examination Survey. Exposures: Socioeconomic status was based on the family income to poverty ratio and participants were divided into the following 3 groups: high income (family income to poverty ratio, >=4), middle income (>1 and <4), or at or below the federal poverty level (<=1). Main Outcomes and Measures: We assessed predicted absolute cardiovascular risk using the pooled cohort equation. We assessed the following 4 risk factors: systolic blood pressure, smoking status, diabetes, and total cholesterol. Results: Of the 17 199 adults whose data were included in the study (8828 women and 8371 men; mean age, 54.4 years), from 1999-2014, trends in the percentage of adults with predicted absolute cardiovascular risk of 20% or more, mean systolic blood pressure, and the percentage of current smokers varied by income strata (P <= .02 for interaction). For adults with incomes at or below the federal poverty level, there was little evidence of a change in any of these outcomes across survey years (cardiovascular risk >=20%, 14.9% [95% CI, 12.9% 16.8%] in 1999-2004; 16.5% [95% CI, 13.7%-19.2%] in 2011-2014; P = .41; mean systolic blood pressure, 127.6 [95% CI, 126.1-129.0] mm Hg in 1999-2004; 126.8 [95% CI, 125.2-128.5] mm Hg in 2011-2014; P = .44; and smoking, 36.5% [95% CI, 32.1%-41.0%] in 1999-2004; 36.0% [95% CI, 31.1%-40.8%] in 2011-2014; P = .87). For adults in the high-income stratum, these variables decreased across survey years (cardiovascular risk >=20%, 12.0% [95% CI, 10.7%-13.3%] in 1999-2004; 9.5% [95% CI, 8.2%-10.7%] in 2011-2014; P = .003; systolic blood pressure, 126.0 [95% CI, 125.0-126.9] mm Hg in 1999-2004; 122.3 [95% CI, 121.3-123.3] mm Hg in 2011 2014; P < .001; and smoking, 14.1% [95% CI, 12.0%-16.2%] in 1999-2004; 8.8% [95% CI, 6.6%-11.0%] in 2011-2014; P = .001). Trends in the percentage of adults with diabetes and the mean total cholesterol level did not vary by income. Conclusions and Relevance: Adults in each socioeconomic stratum have not benefited equally from efforts to control cardiovascular risk factors. PMID- 28593302 TI - The Increasing Call for Protective Ventilation During Anesthesia-Reply. PMID- 28593304 TI - Incorrect Correspondence Address. PMID- 28593303 TI - Factors in Early Adolescence Associated With a Mole-Prone Phenotype in Late Adolescence. AB - Importance: Nevi are important phenotypic risk factors for melanoma in adults. Few studies have examined the constitutional and behavioral factors associated with a mole-prone phenotype in adolescents. Objective: To identify host, behavioral, and dermoscopic factors in early adolescence (age, 14 years) that are associated with a mole-prone phenotype in late adolescence (age, 17 years). Design, Setting, and Participants: A prospective observational cohort study from the Study of Nevi in Children was conducted from January 1, 2009, to December 31, 2014, with a 2- to 3-year follow-up. A total of 569 students from the school system in Framingham, Massachusetts, were enrolled in the 8th or 9th grade (baseline; mean [SD] age, 14.4 [0.7] years). The overall retention rate was 73.3%, and 417 students were reassessed in the 11th grade. Main Outcome and Measures: Mole-prone phenotype in the 11th grade, defined as total nevus count of the back and 1 randomly selected leg in the top decile of the cohort or having any nevi greater than 5 mm in diameter. Results: Of the 417 students assessed at follow-up in the 11th grade (166 females and 251 males; mean [SD] age, 17.0 [0.4] years), 111 participants (26.6%) demonstrated a mole-prone phenotype: 69 students (62.2%) with 1 nevus greater than 5 mm in diameter, 23 students (20.7%) with total nevus count in the top decile, and 19 students (17.1%) with both characteristics. On multivariate analysis, baseline total nevus count (adjusted odds ratio, 9.08; 95% CI, 4.0-23.7; P < .001) and increased variability of nevus dermoscopic pattern (adjusted odds ratio, 4.24; 95% CI, 1.36-13.25; P = .01) were associated with a mole-prone phenotype. Conclusions and Relevance: This study found clinically recognizable factors associated with a mole-prone phenotype that may facilitate the identification of individuals at risk for melanoma. These findings could have implications for primary prevention strategies and help target at-risk adolescents for higher-intensity counseling about sun protection and skin self-examination. PMID- 28593305 TI - Study of drug diffusion rate by laser beam deflection technique. AB - Drug administration is an unavoidable part of treatment. When a drug is administered orally or intravenously, it gets absorbed into the blood stream. The rate and efficiency of absorption depend on the route of administration. When a drug is administered through the oral route, it penetrates the epithelial cells of the intestinal mucosa. The diffusion of the drug into the blood stream depends on various parameters, such as concentration, temperature, and the nature of the mucous membrane. The passive diffusion of drugs is found to obey Fick's law. Water soluble drugs penetrate the cell membrane through aqueous channel or pores. Hence, the study of diffusion of drugs into the water and finally into the blood stream is important. An attempt has been made to study the diffusion of the drug in water as 60% to 80% of human body is water. For the study of drug diffusion in water, a commonly used cough syrup of specific gravity 1.263 is used. It is found that the diffusion rate increases with the concentration of the drug. PMID- 28593325 TI - The Big Bang. PMID- 28593306 TI - Comparative Analysis of Tumor Cell Dissemination to the Sentinel Lymph Nodes and to the Bone Marrow in Patients With Nonmetastasized Colon Cancer: A Prospective Multicenter Study. AB - Importance: Small nodal tumor infiltrates (SNTI; isolated tumor cells and micrometastases) in sentinel lymph nodes and bone marrow micrometastases (BMM) were independently described as prognostic factors in patients with colon cancer. Objective: To examine the association between the occurrence of SNTI and BMM as well as their prognostic relevance. Design, Setting, and Participants: This prospective study was conducted at 3 university-affiliated institutions in Switzerland between May 2000 and December 2006. Statistical analyses were performed in October 2016. A total of 122 patients with stage I to III colon cancer were included. Follow-up time exceeded 6 years, with no patients lost to follow-up. Interventions: Bone marrow aspiration from the iliac crests and in vivo sentinel lymph node mapping were performed during open standard oncological resection. Bone marrow aspirates were stained with the pancytokeratin marker A45 B/B3. All sentinel lymph nodes underwent multilevel sectioning and were stained with hematoxylin-eosin and the pancytokeratin marker AE1/AE3. Main Outcomes and Measures: Association of SNTI in sentinel lymph nodes and BMM in patients with stage I to III colon cancer and the prognostic effect on disease-free survival (DFS) and overall survival (OS). Results: Of the 122 patients, 63 (51.6%) were female, with a mean (SD) age of 71.2 (11.7) years. Small nodal tumor infiltrates and BMM were found in a total of 21 patients (17.2%) and 46 patients (37.7%), respectively. The occurrence of BMM was not associated with the presence of SNTI by standard correlation (kappa, -0.07; 95% CI, -0.29 to 0.14; P = .49) nor by univariate logistic regression analysis (odds ratio, 0.64; 95% CI, 0.22-1.67; P = .37) or multivariate logistic regression analysis (odds ratio, 1.09; 95% CI, 0.34 3.28; P = .88). The presence of SNTI was an independent negative prognostic factor for DFS (hazard ratio [HR], 2.93; 95% CI, 1.24-6.93; P = .02) and OS (HR, 4.04; 95% CI, 1.56-10.45; P = .005), as was BMM (HR, 2.07; 95% CI, 1.06-4.06; P = .04; and HR, 2.68; 95% CI, 1.26-5.70; P = .01; respectively). The combined detection of BMM and SNTI demonstrated the poorest DFS (HR, 6.73; 95% CI, 2.29 19.76; P = .006) and OS (HR, 5.96; 95% CI, 1.66-21.49; P = .03). Conclusions and Relevance: This study demonstrates no association between the occurrence of SNTI and BMM in patients with stage I to III colon cancer. However, both SNTI and BMM are independent negative prognostic factors regarding DFS and OS, and the occurrence of both is associated with significantly worse prognosis compared with either one of them. Trial Registration: clinicaltrials.gov Identifier: NCT00826579. PMID- 28593327 TI - QTL mapping of root traits in phosphorus-deficient soils reveals important genomic regions for improving NDVI and grain yield in barley. AB - KEY MESSAGE: Major QTLs for root rhizosheath size are not correlated with grain yield or yield response to phosphorus. Important QTLs were found to improve phosphorus efficiency. Root traits are important for phosphorus (P) acquisition, but they are often difficult to characterize and their breeding values are seldom assessed under field conditions. This has shed doubts on using seedling-based criteria of root traits to select and breed for P efficiency. Eight root traits were assessed under controlled conditions in a barley doubled-haploid population in soils differing in P levels. The population was also phenotyped for grain yield, normalized difference vegetation index (NDVI), grain P uptake and P utilization efficiency at maturity (PutEGY) under field conditions. Several quantitative traits loci (QTLs) from the root screening and the field trials were co-incident. QTLs for root rhizosheath size and root diameter explained the highest phenotypic variation in comparison to QTLs for other root traits. Shared QTLs were found between root diameter and grain yield, and total root length and PutEGY. A common major QTL for rhizosheath size and NDVI was mapped to the HvMATE gene marker on chromosome 4H. Collocations between major QTLs for NDVI and grain yield were detected on chromosomes 6H and 7H. When results from BIP and MET were combined, QTLs detected for grain yield were also those QTLs found for NDVI. QTLs qGY5H, qGY6H and qGY7Hb on 7H were robust QTLs in improving P efficiency. A selection of multiple loci may be needed to optimize the breeding outcomes due to the QTL x Environment interaction. We suggest that rhizosheath size alone is not a reliable trait to predict P efficiency or grain yield. PMID- 28593328 TI - Abnormalities in the brain-immune system in psychotic disorders: from pathogenesis to prevention. PMID- 28593326 TI - Intraoperative Infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery: A Randomized Clinical Trial. AB - Importance: Postoperative delirium occurs in 10% to 60% of elderly patients having major surgery and is associated with longer hospital stays, increased hospital costs, and 1-year mortality. Emerging literature suggests that dexmedetomidine sedation in critical care units is associated with reduced incidence of delirium. However, intraoperative use of dexmedetomidine for prevention of delirium has not been well studied. Objective: To evaluate whether an intraoperative infusion of dexmedetomidine reduces postoperative delirium. Design, Setting, and Participants: This study was a multicenter, double-blind, randomized, placebo-controlled trial that randomly assigned patients to dexmedetomidine or saline placebo infused during surgery and for 2 hours in the recovery room. Patients were assessed daily for postoperative delirium (primary outcome) and secondarily for postoperative cognitive decline. Participants were elderly (>68 years) patients undergoing major elective noncardiac surgery. The study dates were February 2008 to May 2014. Interventions: Dexmedetomidine infusion (0.5 ug/kg/h) during surgery and up to 2 hours in the recovery room. Main Outcomes and Measures: The primary hypothesis tested was that intraoperative dexmedetomidine administration would reduce postoperative delirium. Secondarily, the study examined the correlation between dexmedetomidine use and postoperative cognitive change. Results: In total, 404 patients were randomized; 390 completed in-hospital delirium assessments (median [interquartile range] age, 74.0 [71.0 78.0] years; 51.3% [200 of 390] female). There was no difference in postoperative delirium between the dexmedetomidine and placebo groups (12.2% [23 of 189] vs 11.4% [23 of 201], P = .94). After adjustment for age and educational level, there was no difference in the postoperative cognitive performance between treatment groups at 3 months and 6 months. Adverse events were comparably distributed in the treatment groups. Conclusions and Relevance: Intraoperative dexmedetomidine does not prevent postoperative delirium. The reduction in delirium previously demonstrated in numerous surgical intensive care unit studies was not observed, which underscores the importance of timing when administering the drug to prevent delirium. Trial Registration: clinicaltrials.gov Identifier NCT00561678. PMID- 28593329 TI - Core curriculum illustration: pediatric buckle fracture of the distal radius. AB - This is the 38th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at: http://www.erad.org/page/CCIP_TOC. PMID- 28593330 TI - Core curriculum illustration: pediatric viral parotitis. AB - This is the 36th installment of a series that will highlight one case per publication issue from the bank of cases available online as part of the American Society of Emergency Radiology (ASER) educational resources. Our goal is to generate more interest in and use of our online materials. To view more cases online, please visit the ASER Core Curriculum and Recommendations for Study online at http://www.aseronline.org/curriculum/toc.htm . PMID- 28593332 TI - Population health intervention research: myths and misconceptions. PMID- 28593333 TI - Survival and Adaptation of the Thermophilic Species Geobacillus thermantarcticus in Simulated Spatial Conditions. AB - Astrobiology studies the origin and evolution of life on Earth and in the universe. According to the panspermia theory, life on Earth could have emerged from bacterial species transported by meteorites, that were able to adapt and proliferate on our planet. Therefore, the study of extremophiles, i.e. bacterial species able to live in extreme terrestrial environments, can be relevant to Astrobiology studies. In this work we described the ability of the thermophilic species Geobacillus thermantarcticus to survive after exposition to simulated spatial conditions including temperature's variation, desiccation, X-rays and UVC irradiation. The response to the exposition to the space conditions was assessed at a molecular level by studying the changes in the morphology, the lipid and protein patterns, the nucleic acids. G. thermantarcticus survived to the exposition to all the stressing conditions examined, since it was able to restart cellular growth in comparable levels to control experiments carried out in the optimal growth conditions. Survival was elicited by changing proteins and lipids distribution, and by protecting the DNA's integrity. PMID- 28593331 TI - Clustering of energy balance-related behaviours, sleep, and overweight among Finnish adolescents. AB - OBJECTIVES: To examine how clusters of energy balance-related behaviours (EBRBs), including sleep related factors, were associated with overweight among adolescents. METHODS: In Finland, 4262 adolescents, aged 13-15, participated in the cross-national Health Behaviour in School-aged Children study. The adolescents completed questionnaires assessing EBRBs [sleep duration, discrepancy and quality, physical activity (PA), screen time, junk food, fruit, and vegetable intake] and height and weight. Clusters were identified with kappa-means cluster analysis and their associations with overweight with logistic regression analyses. RESULTS: Common clusters for boys and girls were labelled "Healthy lifestyle" and "High screen time, unhealthy lifestyle". In addition, the cluster "Low/moderate screen time, unhealthy lifestyle" was identified among boys, and the cluster "Poor sleep, unhealthy lifestyle" among girls. Only girls in the cluster "High screen time, unhealthy lifestyle" were at increased risk for overweight. CONCLUSIONS: Girls, whose EBRB was characterized by high screen time and low PA, but not with poor sleep, were at increased risk for overweight. Future studies should examine ways to promote PA among adolescent girls with high interest in screen-based activities. PMID- 28593334 TI - Seasonal variation in patient characteristics and in-hospital outcomes of Takotsubo syndrome: a nationwide retrospective cohort study in Japan. AB - Although there is reportedly seasonal variation in the occurrence of Takotsubo syndrome (TTS), it is unknown whether there is a relationship between season and patient characteristics, or whether season influences outcomes. Using the Diagnosis Procedure Combination database in Japan, we retrospectively identified 4306 patients (mean age 73.6 years) hospitalized with TTS between January 2011 and December 2013. We divided patients into four groups according to season of admission [n = 914, Spring (March-May); n = 1243, Summer (June-August); n = 1245, Autumn (September-November); n = 904, Winter (December-February)]. The outcomes were in-hospital mortality and cardiovascular complications. We compared patient backgrounds and outcomes across seasons and estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for outcomes in logistic regression analyses adjusted for multiple propensity scores. Although there was no significant difference in age across seasons, the proportion of males differed significantly (from 18.5% in autumn to 23.9% in winter; p = 0.016). The incidence of psychiatric disease (from 4.9% in spring to 7.9% in summer; p = 0.025) and sepsis (from 0.8% in winter to 2.6% in summer; p = 0.019) also differed significantly with season. In-hospital mortality was not significantly influenced by season (p = 0.377): spring, 5.1%; summer, 6.0%; autumn, 4.6%; winter, 6.0%. However, in-hospital mortality ranged widely across months from 3.0% in September to 7.5% in April. The incidence of ventricular tachycardia/fibrillation was significantly different (p = 0.038): spring, 2.2% (reference); summer, 3.3% (aOR 1.46, 95% CI 0.84-2.51); autumn, 2.7% (aOR 1.27, 95% CI 0.72-2.22); winter, 4.4% (aOR 1.92, 95% CI 1.11-3.33). Although season did not appear to influence the in hospital mortality of TTS, monthly variation may exist in the risk of death in patients with TTS. There were significant seasonal variations in the proportions of males, patients with psychiatric disease or sepsis, and the incidence of ventricular arrhythmias among patients with TTS. PMID- 28593335 TI - Key points to optimizing management and research on cancer-associated thrombosis. AB - Despite the fact that thromboembolism is relatively common in oncology patients and that the interrelationship between thrombotic risk and specific mechanisms of tumorigenesis has long been known, many cardinal elements of prevention and treatment remain unresolved. Among the existing knowledge gaps, the need to validate the Ay scale and compare it to the Khorana index, develop, and standardize the use of predictive biomarkers for thrombotic risk, conduct clinical trials in thromboprophylaxis adapted to thrombotic risk, evaluate the efficacy and safety of direct anticoagulants, select patients who can benefit from anticoagulants for antitumor treatment, validate the EPIPHANY study decision tree to choose patients with low-risk pulmonary embolism, and accumulate more practical experience in special situations (rethrombosis, prolonged therapy beyond 6 months, etc.) are especially remarkable. These gray areas surrounding cancer-related thromboembolism explain why it continues to be a relatively common cause of serious events, at times interfering significantly with the development of new tumor-fighting strategies. PMID- 28593336 TI - Effect of urea-supplemented diets on the ruminal bacterial and archaeal community composition of finishing bulls. AB - In this study, we evaluated the effects of urea-supplemented diets on the ruminal bacterial and archaeal communities of finishing bulls using sequencing technology. Eighteen bulls were fed a total mixed ration based on maize silage and concentrate (40:60) and randomly allocated to one of three experimental diets: a basal diet with no urea (UC, 0%), a basal diet supplemented with low urea levels (UL, 0.8% dry matter (DM) basis), and a basal diet supplemented with high urea levels (UH, 2% DM basis). All treatments were iso-nitrogenous (14% crude protein, DM basis) and iso-metabolic energetic (ME = 11.3 MJ/kg, DM basis). After a 12-week feeding trial, DNA was isolated from ruminal samples and used for 16S rRNA gene amplicon sequencing. For bacteria, the most abundant phyla were Firmicutes (44.47%) and Bacteroidetes (41.83%), and the dominant genera were Prevotella (13.17%), Succiniclasticum (4.24%), Butyrivibrio (2.36%), and Ruminococcus (1.93%). Urea supplementation had no effect on most phyla (P > 0.05), while there was a decreasing tendency in phylum TM7 with increasing urea levels (P = 0.0914). Compared to UC, UH had lower abundance of genera Butyrivibrio and Coprococcus (P = 0.0092 and P = 0.0222, respectively). For archaea, the most abundant phylum was Euryarchaeota (99.81% of the sequence reads), and the most abundant genus was Methanobrevibacter (90.87% of the sequence reads). UH increased the abundance of genus Methanobrevibacter and Methanobacterium (P = 0.0299 and P = 0.0007, respectively) and decreased the abundance of vadinCA11 (P = 0.0151). These findings suggest that urea supplemented diets were associated with a shift in archaeal biodiversity and changes in the bacterial community in the rumen. PMID- 28593337 TI - Functionalization of natural compounds by enzymatic fructosylation. AB - Enzymatic fructosylation of organic acceptors other than sugar opens access to the production of new molecules that do not exist in nature. These new glycoconjugates may have improved physical-chemical and bioactive properties like solubility, stability, bioavailability, and bioactivity. This review focuses on different classes of acceptors including alkyl alcohols, aromatic alcohols, alkaloids, flavonoids, and xanthonoids, which were tested for the production of fructoderivatives using enzymes from the glycoside hydrolase (GH) families 32 and 68 that use sucrose as donor substrate. The enzymatic strategies and the reaction conditions required for the achievement of these complex reactions are discussed, in particular with regard to the type of acceptors. The solubility and pharmacokinetic and antioxidant activity of some of these new beta-D fructofuranosides in comparison is reviewed and compared with their glucoside analogs to highlight the differences between these molecules for technological applications. PMID- 28593338 TI - [Diagnostic workup and therapy of acute venous diseases]. AB - Acute venous diseases, especially deep leg and pelvic vein thrombosis, present an angiological emergency and can lead to acute life-threatening events such as pulmonary embolism. Long-term consequences may be postthrombotic syndromes. In addition to stroke and myocardial infarction, deep leg and pelvic vein thrombosis are one of the most common cardiovascular diseases. Early diagnosis and rapid initiation of therapy are important. PMID- 28593339 TI - [Facial manifestations of granulomatous diseases]. AB - Clinical manifestations of granulomatous diseases are a recurring challenge in everyday dermatological practice. Clinical presentation and histological patterns are variable, depending on the particular disease. Knowledge about the differential diagnosis of granulomatous changes in the face is of decisive importance for making a rational diagnosis and therapy considering the patient's well-being. Therefore, histological and clinical characteristics of important granulomatous diseases that typically manifest on the face are presented here. PMID- 28593340 TI - A previously unclassified variant of sternalis muscle. AB - PURPOSE: We propose an addition to the Snosek et al. classification to include a subtype variant of sternalis muscle: mixed type and triple subtype. METHODS: Dissection of the anterior thorax of a 96-year-old female cadaver revealed bilateral sternalis muscles with an undocumented variant of the right sternalis muscle. RESULTS: The left sternalis muscle presented as a simple type-left single using the Snosek et al. classification scheme. The right sternalis muscle revealed a previously undocumented classification type. It consisted of three bellies and two heads, with the lateral head formed by two converging bellies and the medial head formed from the superficial medial belly. CONCLUSIONS: The unique presentation of right sternalis muscle can be classified by expanding the Snosek et al. classification scheme to include triple-bellied subtypes. This presentation is classified as a mixed type-right triple, with single bicipital converging and single bicipital diverging. Documentation of sternalis muscle variations can prevent misdiagnoses within the anterior thorax. PMID- 28593342 TI - The role of dual leucine zipper kinase (DLK) in beta-cell apoptosis: a potential target for the prevention and treatment of type 2 diabetes? : Commentary to: Borchers et al., TNF-alpha induced DLK activation contributes to apoptosis in the beta-cell line HIT. PMID- 28593343 TI - Configurations and characteristics of boron and B36 clusters. AB - Characteristics of the ring and linear structures of the boron cluster B36 and its doped clusters were investigated with DFT/B3LYP/6-31G. The results illustrate that the ring B3 structure is the most stable configuration compared with other rings. Odd and even linear structures have different bonding; there is one different bond in the center of even linear structures, while the remaining bonds have left and right symmetry. The B36 cluster upholds the configuration rule of pure ring and linear molecules. However, the N-doped B36N cluster exhibits obvious distortion compared with the B36 molecule. The impurity N changes the structure of the energy band of the B36 cluster. The wavelength of absorption spectra and electronic circular dichroism of the N-doped B36N cluster shifts to a longer wavelength compared with that of the B36 cluster. PMID- 28593341 TI - Activation of remote monitoring for cardiac implantable electronic devices: small dog for tall weeds. AB - BACKGROUND: Remote monitoring (RM) of cardiac implantable electronic devices (CIEDs) has been popularized as a precious patients' management tool. We have investigated RM within the premises of a multicenter, prospective, real-world registry, i.e., the German Device II. METHODS: We have focused on: (1) CIEDs with RM capabilities implantation rate and (2) actual rate of RM features activation. RESULTS: A cohort of 1223 CIEDs patients were treated from 04/11 to 02/14. Of these, 720 (58.8%) were implanted with RM-capable devices and were presenting significantly more often a clinical diagnosis of dilatative cardiomyopathy and an indication for cardiac resynchronization. At discharge, the RM feature was activated in only 12.6% (91/720) of the total number of patients implanted with RM-capable CIEDs. After adjusting for implanting center, there was no significant correlation between any of the patient clinical characteristics and RM activation. One-year estimated mortality was 9.0% in patients with activated RM, 5.6% in those with not activated RM, and 7.7% in those without RM capability (p = 0.3). The RM feature was still activated in 13.8% of the patients surviving at follow-up. Patients undergoing RM had a trend for higher re-hospitalization rate and less visits in the device outpatient clinic. CONCLUSIONS: Although RM in CIEDs may be a clinically valuable technological armamentarium, its activation does not reflect patients' clinical profile. In fact, RM is often not activated, most probably because it is still recognized as a source of increased workload in a reality where reimbursement plans for dedicated human resources are not yet optimized. PMID- 28593344 TI - The addition reactions of germylenoid H2GeAlCl3 with ethylene: a theoretical investigation. AB - Theoretical calculations using the M062X and QCISD methods were performed on the addition reactions of the aluminum germylenoid H2GeAlCl3 with ethylene. The most two stable structures of germylenoid H2GeAlCl3, i.e., the p-complex and three membered ring structures, respectively, were employed as reactants. The calculated results indicate that, for the p-complex, H2GeAlCl3 there are two pathways, I and II, of which path I involves just one transition state, while path II involves two transition states between reactants and products. Comparing the reaction barrier heights of path I (44.6 kJ mol-1) and II (37.6 kJ mol-1), the two pathways are competitive, with similar barriers under the same conditions, while for the three-membered ring structure, another two pathways, III and IV, also exist. Path III has one transition state; however, in path IV, two transition states exist. By comparing their barrier heights, path III (barrier height 39.2 kJ mol-1) could occur more easily than path IV (barrier height 92.8 kJ mol-1). Considering solvent effects on these addition reactions, the PCM model and CH2Cl2 solvent were used in calculations, and the calculated results demonstrate that CH2Cl2 solvent is unfavorable for the reactions, except for path II. In CH2Cl2 solvent, paths II and III are more favorable than paths I and IV. PMID- 28593345 TI - Exocrine Gland Morphogenesis: Insights into the Role of Amphiregulin from Development to Disease. AB - Amphiregulin (AREG) is a well-characterized member of the epidermal growth factor (EGF) family and is one of the ligands of the EGF receptor (EGFR). AREG plays a key role in mammalian development and in the control of branching morphogenesis in various organs. Furthermore, AREG participates in a wide range of physiological and pathological processes activating the major intracellular signalling cascades governing cell survival, proliferation and motility. In this article, we review current advances in exocrine glands morphogenesis, focusing on the salivary gland, and discuss the essential aspects of AREG structure, function and regulation, and its differential role within the EGFR family of ligands. Finally, we identify emerging aspects in AREG research applied to mammary gland development and the salivary gland autoimmune disease, Sjogren's syndrome. PMID- 28593346 TI - The first identified cathelicidin from tree frogs possesses anti-inflammatory and partial LPS neutralization activities. AB - As of February 2017, approximately 7639 amphibian species have been described in the AmphibiaWeb database. However, only 20 cathelicidin-like antimicrobial peptides have been identified to date from 10 amphibian species. Half of these peptides were identified from genome sequences and have not yet been functionally characterized. In this study, a novel cathelicidin-like peptide designated cathelicidin-PP was purified from the skin of tree frog Polypedates puerensis. Cathelicidin-PP is a 32 residue peptide of sequence ASENGKCNLLCLVKKKLRAVGNVIKTVVGKIA. Circular dichroism spectroscopy indicated that cathelicidin-PP mainly adopts a beta-sheet structure in membrane-mimetic solutions. Cathelicidin-PP exhibits potent antimicrobial activity against bacteria and fungi, especially Gram-negative bacteria. Meanwhile, it shows low cytotoxicity toward mammalian cells. Scanning electron microscopy analysis indicated that cathelicidin-PP kills bacteria through the disruption of the bacterial cell membrane integrity. Furthermore, cathelicidin-PP exerts significant anti-inflammatory functions by inhibiting the lipopolysaccharide (LPS)-mediated generation of nitric oxide and pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6. The MAPKs (ERK, JNK, and p38) and NF-kappaB signaling pathways are involved in the anti-inflammatory effect. Cathelicidin-PP caused partial neutralization of LPS in a dose-dependent manner. Quantitative PCR indicated that infection of tree frogs with bacteria causes increased expression of cathelicidin-PP in immune-related tissues. Taken together, cathelicidin-PP is the first identified cathelicidin-like peptide from tree frogs. Our findings demonstrate that in addition to direct bactericidal capacity, cathelicidin-PP also possesses immunomodulatory properties, including partial neutralization of LPS, and inhibiting the production of inflammatory cytokines. PMID- 28593347 TI - [Pathology of the R1 classification in visceral cancer surgery]. AB - The completeness of tumor removal is described in the residual tumor classification (R classification). The R category of a surgical specimen reflects the effects of treatment, influences further treatment decisions and is associated with patient survival. Thorough pathological examination of all resection planes, including the circumferential margin, is necessary for accurate classification. PMID- 28593348 TI - Acute effects of binary mixtures of Type II pyrethroids and organophosphate insecticides on Oreochromis niloticus. AB - Pyrethroid and organophosphate insecticides have been used for more than 20 years worldwide to control a variety of insect pest in different settings. These pesticides have been detected in a variety of environmental samples, including surface waters and sediments and therefore there is significant concern about their potential toxic effects on non-target organisms. Mixtures of compounds from these groups of pesticides have been found to frequently show enhanced toxicity but it has been a challenge to predict whether or not enhanced toxicity will occur for a given combination of compounds. This study therefore studied the effects of binary pyrethroid-organophosphate mixtures using cypermethrin, deltamethrin and dimethoate in an acute toxicity test system with Oreochromis niloticus. The 96 h LC50s for individual insecticides were 9.13 ug/l, 9.42 ug/l and 45.52 mg/l for cypermethrin, deltamethrin and dimethoate respectively. These showed that the pyrethroid insecticides were highly toxic to Oreochromis niloticus and were far more toxic than dimethoate. All mixtures were also more toxic than single insecticides throughout the concentration-response curve with mixtures resulting in mortality at concentrations which the individual pesticides in the mixture were below their respective NOECs. In addition, observed mixture toxicities deviated from the predicted mixture effects based either on the Concentration Addition (CA) or Independent Action (IA) models independent of mixture ratio. However, the extent of observed mixture mortality deviation was dependent on the effect level. Significant deviations (MDR > 2.0) were observed at lower concentrations indicating synergistic effects at lower and possibly environmentally relevant concentrations. This is not unexpected since organophosphate insecticides are known to inhibit acetylcholinesterase as well as inactivate esterase, resulting in reduced detoxification of pyrethroid insecticides and consequently greater toxicity than would be expected. This has important implications for risk assessment of mixtures since the risk of pyrethroid-organophosphate mixtures may be underestimated if either the CA or IA model is employed. PMID- 28593349 TI - Transcriptomic Analysis of the Swarm Motility Phenotype of Salmonella enterica Serovar Typhimurium Mutant Defective in Periplasmic Glucan Synthesis. AB - Movement of food-borne pathogens on moist surfaces enables them to migrate towards more favorable niches and facilitate their survival for extended periods of time. Salmonella enterica serovar Typhimurium mutants defective in Osmoregulated periplasmic glucans (OPG) synthesis are unable to exhibit motility on moist surfaces (swarming); however, their mobility in liquid (swim motility) remains unaffected. In order to understand the role of OPG in swarm motility, transcriptomic analysis was performed using cells growing on a moist agar surface. In opgGH deletion mutant, lack of OPG significantly altered transcription of 1039 genes out of total 4712 genes (22%). Introduction of a plasmid-borne copy of opgGH into opgGH deletion mutant restored normal expression of all but 30 genes, indicating a wide-range influence of OPG on gene expression under swarm motility condition. Major pathways that were differentially expressed in opgGH mutants were motility, virulence and invasion, and genes related to the secondary messenger molecule, cyclic di-GMP. These observations provide insights and help explain the pleiotropic nature of OPG mutants such as sub-optimal virulence and competitive organ colonization in mice, biofilm formation, and sensitivity towards detergent stress. PMID- 28593352 TI - Bone and joint infection, from prevention to complications. PMID- 28593351 TI - [What is the perception of the 10-point plan of the German Federal Ministry of Health against multidrug-resistant pathogens and measures of antibiotic stewardship? : An interdisciplinary analysis among German clinicians and development of a decision tool for urologists]. AB - BACKGROUND: Due to increasing antibiotic resistances, relevant treatment problems are currently emerging in clinical practice. In March 2015, the German Federal Ministry of Health (BMG) published a 10-point plan designed to combat this development. Furthermore, the first German guideline on antibiotic stewardship (ABS) was implemented in 2013 and instructs physicians of different specialties about several treatment considerations. Evidence is scarce on how such concepts (10-point plan/BMG, ABS) are perceived among clinicians. MATERIALS AND METHODS: Within the MR2 study (Multiinstitutional Reconnaissance of practice with MultiResistant bacteria - a survey focusing on German hospitals), a questionnaire including 4 + 35 items was sent to 18 German hospitals between August and October 2015, surveying internists, gynecologists, general surgeons, and urologists. Using multivariate logistic regression models (MLRM), the impact of medical specialty and further criteria on the endpoints (1) awareness of the 10-point plan/BMG and (2) knowledge of ABS measures were assessed. Fulfillment of endpoints was predefined when average or full knowledge was reported (reference: poor to no knowledge). RESULTS: Overall response rate was 43% (456/1061) for fully evaluable questionnaires. Only 63.0 and 53.6% of urologists and nonurologists (internists, gynecologists, and general surgeons), respectively, attended training courses regarding multidrug-resistance or antibiotic prescribing in the 12 months prior to the study (P = 0.045). The endpoints average and full knowledge regarding 10-point plan/BMG and ABS measures were fulfilled in only 31.4 and 32.8%, respectively. In MLRM, clinicians with at least one previous training course (reference: no training course) were 2.5- and 3.8 fold more likely to meet respective endpoint criteria (all P < 0.001). Medical specialty (urologists vs. nonurologists) did not significantly impact the endpoints in both MLRM. CONCLUSIONS: The 10-point plan/BMG and ABS programs should be implemented into clinical practice, but awareness and knowledge of both is insufficient. Thus, it stands to reason that the actual realization of such measures is inadequate and continuous training towards rational prescription of antibiotics is necessary, regardless of medical specialty. PMID- 28593350 TI - Age-Related Changes in the Composition of Gut Bifidobacterium Species. AB - Bifidobacteria are one of the major components in human microbiota that are suggested to function in maintaining human health. The colonization and cell number of Bifidobacterium species in human intestine vary with ageing. However, sequential changes of Bifidobacterium species ranging from newborns to centenarians remain unresolved. Here, we investigated the gut compositional changes of Bifidobacterium species over a wide range of ages. Faecal samples of 441 healthy Japanese subjects between the ages of 0 and 104 years were analysed using real-time PCR with species-specific primers. B. longum group was widely detected from newborns to centenarians, with the highest detection rate. B. breve was detected in approximately 70% of children under 3 years old. B. adolescentis and B. catenulatum groups were predominant after weaning. B. bifidum was detected at almost all ages. The detection rate of B. dentium was higher in the elderly than in other ages. B. animalis ssp. lactis was detected in 11.4% of the subjects and their ages were restricted. B. gallinarum goup was detected in only nine subjects, while B. minimum and B. mongoliense were undetected at any age. The presence of certain Bifidobacterium groups was associated with significantly higher numbers of other Bifidobacterium species/subspecies. Inter-species correlations were found among each species, exception for B. animalis ssp. lactis. These results revealed the patterns and transition points with respect to compositional changes of Bifidobacterium species that occur with ageing, and the findings indicate that there may be symbiotic associations between some of these species in the gut microbiota. PMID- 28593353 TI - Diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes-naive population with schizophrenia: a nationwide nested case control study. AB - AIMS/HYPOTHESIS: Diabetic ketoacidosis (DKA) is a potentially fatal metabolic emergency of both type 1 and type 2 diabetes. Although there is a reduced risk of type 1 diabetes in schizophrenia, the incidence of DKA is tenfold higher than that of the general population. Thus, we aimed to investigate associations between exposure to antipsychotic medication (within 3 months prior to event) and DKA, type 1 diabetes and type 2 diabetes. We also reported related, clinically relevant outcomes. METHODS: Using a nested case-control study design, we identified cases of DKA, type 1 diabetes and type 2 diabetes in a previously diabetes-naive population with schizophrenia in Denmark from 1995 to 2014. Cases were matched (by age, sex and year of schizophrenia onset) 1:5 to schizophrenic control individuals who were alive and had not emigrated prior to event. Conditional logistic regression was used to compute ORs with 95% CIs. Other outcomes included diabetes aetiology of DKA, in-hospital mortality, DKA readmissions and temporal trends of use of insulin and oral glucose-lowering agents. RESULTS: Of 29,955 individuals with schizophrenia, we identified 28 individuals with DKA, 90 with type 1 diabetes and 2140 with type 2 diabetes. These were matched to 137, 410 and 9861 individuals in the control group, respectively. Antipsychotic exposure was associated with DKA (OR 2.60; 95% CI 1.06, 6.38) and type 2 diabetes (OR 1.64; 95% CI 1.48, 1.83). A trend towards increased risk of type 1 diabetes was found but remained insignificant (OR 1.38; 95% CI 0.84, 2.29). Diabetes aetiology of DKA was type 1 in eight cases and type 2 in 14 cases. Of the remaining six cases of DKA, aetiology could not be determined, as four were fatal within 8 days and for two, no prescriptions for insulin and oral glucose-lowering agents were redeemed. Of all DKA cases, six had more than one episode of DKA, and of all type 1 diabetes and type 2 diabetes cases, four and 11, respectively, had at least one episode. Use of insulin and oral glucose-lowering agents was higher among individuals with DKA relative to those with type 1 diabetes and type 2 diabetes. CONCLUSIONS/INTERPRETATION: Antipsychotic exposure was associated with DKA and type 2 diabetes in a previously diabetes-naive schizophrenia population. Antipsychotic-associated DKA is relevant not only for psychiatrists but also for other physicians who may manage and admit such patients. PMID- 28593354 TI - [Educational gerontology and social work]. AB - Educational gerontology has become established over the past 40 years in a multifaceted, differentiated practice which, against the background of social change processes, combined with the phenomena of demographic change, takes up and creates room for accompanying irritations, learning requirements and opportunities. A corresponding theoretical foundation exists in the scientific discipline of geragogy, which is located at the interfaces between gerontology, educational science and social work. The close proximity between education of and social work with the elderly is meanwhile also evident in many recent research and development projects, in which theory formation for geragogy and social work as scientific disciplines take place at the same time. Against this background, the core developmental lines of geragogy are briefly sketched in this article and linked with the exemplary scientific discourse within gerontology and social work sciences. The result is a form of synthesis of central theoretical premises of social gerontology in the field of educational gerontology. This claim becomes more concrete by a recourse to the results of relevant research and development projects, which refer to different facets of educational work in different gerontological fields or as a conscious approach to methodological integration, also in the sense of participatory procedures. Theoretical and didactic approaches to educational gerontology are of increasing importance in terms of enabling integration and participation and also in the context of research and development projects. This also involves participation of the elderly as experts in their own field as well as participatory procedures and approaches. Willingness to learn and openness to educational approaches will also be the basic prerequisites for older people in the future, creating orientation in a rapidly changing world and social participation. One important task for educational gerontology in this context is to reach and to involve older people who are not very well educated and to open them up to the necessary room for social integration and participation. Methods of social work can therefore be very helpful. PMID- 28593356 TI - [Gerontological research in social and behavioral sciences in Germany since 1968 : Review, critical assessment and perspectives]. AB - This article addresses the development of German social and behavioral aging research during the last 50 years based on four propositions: (a) the development and unfolding of social and behavioral aging research in the 1960s and 1970s was tedious. (b) During the 1980s and 1990s the significance of social and behavioral aging research grew considerably. (c) The last 20 years brought increasing and strong recognition of social and behavioral aging research. (d) Currently, social and behavioral aging research in Germany follows high and internationally established standards, and findings are published in internationally recognized journals. In a resume and outlook the structural aspects, future research topics, funding dynamics, and issues of the application of social and behavioral aging science are discussed. PMID- 28593355 TI - [Municipalities as places for social work for the elderly]. AB - Against the background of social and demographic changes, this article addresses the design and organization of processes of aging within municipal contexts. It is assumed that the renaissance of the local communal situation corresponds to processes of individualization and subjectivation, which are characteristic for (post)industrial western societies, and that this development is one of the reasons that community-based social work is regaining importance. A case study of social work for the elderly in a municipality of the Ruhr area, which is imbedded in a municipal senior citizens policy concept, illustrates this assumption. The conclusion identifies the scope of actions for social work for the elderly as well as their limitations. PMID- 28593357 TI - HIV infection or HAART therapy: what is the cause of adverse obstetric outcomes. PMID- 28593358 TI - Accuracy in identifying the elbow rotation axis on simulated fluoroscopic images using a new anatomical landmark. AB - External fixation of the elbow requires identification of the elbow rotation axis, but the accuracy of traditional landmarks (capitellum and trochlea) on fluoroscopy is limited. The relative distance (RD) of the humerus may be helpful as additional landmark. The first aim of this study was to determine the optimal RD that corresponds to an on-axis lateral image of the elbow. The second aim was to assess whether the use of the optimal RD improves the surgical accuracy to identify the elbow rotation axis on fluoroscopy. CT scans of elbows from five volunteers were used to simulate fluoroscopy; the actual rotation axis was calculated with CT-based flexion-extension analysis. First, three observers measured the optimal RD on simulated fluoroscopy. The RD is defined as the distance between the dorsal part of the humerus and the projection of the posteromedial cortex of the distal humerus, divided by the anteroposterior diameter of the humerus. Second, eight trauma surgeons assessed the elbow rotation axis on simulated fluoroscopy. In a preteaching session, surgeons used traditional landmarks. The surgeons were then instructed how to use the optimal RD as additional landmark in a postteaching session. The deviation from the actual rotation axis was expressed as rotational and translational error (+/-SD). Measurement of the RD was robust and easily reproducible; the optimal RD was 45%. The surgeons identified the elbow rotation axis with a mean rotational error decreasing from 7.6 degrees +/- 3.4 degrees to 6.7 degrees +/- 3.3 degrees after teaching how to use the RD. The mean translational error decreased from 4.2 +/- 2.0 to 3.7 +/- 2.0 mm after teaching. The humeral RD as additional landmark yielded small but relevant improvements. Although fluoroscopy-based external fixator alignment to the elbow remains prone to error, it is recommended to use the RD as additional landmark. PMID- 28593359 TI - Guided growth for valgus deformity correction of knees in a girl with osteopetrosis: a case report. AB - : Autosomal dominant osteopetrosis (Albers-Schonberg disease) classically displays the radiographic signs of osteosclerosis. The main ADO complications involve the skeleton: low-impact bone fractures, scoliosis and hip osteoarthritis. Management of osteopetrosis-related orthopedic problems is a surgical challenge due to increased bone density. The healing process is very slow in these patients because of bone remodeling defects related to osteoblast function failure. In case of bone deformities, a realignment method should be appropriated to osteopetrosis conditions. This article presents a case report of operative treatment of an 11-year-old girl affected with ADO, who underwent a simultaneous valgus knee deformity correction of both limbs with medial eight plate epiphysiodesis. Simultaneous correction of valgus deformity on both limbs using an extraperiosteal tension plate technique for medial tibial hemiepiphysiodesis was performed in a girl of 11.5 years old with autosomal dominant osteopetrosis. The treatment duration from surgery to complete deformity correction and removal of plates was 18 months. The final aMPTA was 86 degrees on the right side and 85 degrees on the left side. The correction rate was 0.61 degrees /month (right tibia) and 0.67 degrees /month (left tibia). The MAD correction rate was evaluated as 1.5 mm/month for the right limb and 1.6 mm/month for the left limb. At the moment of plate removal, one screw was broken because of tight fixation in osteopetrotic bone. But it did not compromise the final result. The latest follow-up visit at the age of 14 years 6 months revealed excellent realignment without any deformity relapse. There was no any functional impairment. We consider the guided growth by tension band technique as very interesting and promising solution for treatment of pediatric angular deformity in patients with OP. This method allows to avoid osteotomy and related important risk of delayed union or nonunion frequently observed in osteopetrosis. LEVEL OF EVIDENCE: Level IV. PMID- 28593362 TI - Hepatocyte nuclear factor 1beta maturity-onset diabetes of the young in a Chinese child presenting with hyperglycemic hyperosmolar state. PMID- 28593360 TI - Strongest FamiliesTM Managing Our Mood (MOM): a randomized controlled trial of a distance intervention for women with postpartum depression. AB - The present study investigated whether a distance-delivered intervention could significantly decrease mild to moderate postpartum depression (PPD) in mothers as compared to usual care. Mothers with PPD (n = 62) were randomly assigned to the intervention or standard community care. Participants receiving the intervention followed a 12-session cognitive behavioural informed handbook supplemented with telephone-based coaching support. Diagnostic status and depressive symptoms were assessed at baseline and 3, 6 and 12 months postrandomization. Odds ratios indicated that intervention group participants were 1.5 times as likely to experience diagnostic remission at 3 months (mid-intervention) (p = 0.742), 1.54 times as likely at 6 months (p = 0.696) and 12.5 times as likely at 12 months (p = 0.009). Intervention 'dosage' significantly moderated this effect; for every additional coaching session completed, individuals had a 1.4 times greater chance of showing improvement at 3 and 6 months. Mothers reported high satisfaction with the intervention. Findings suggest positive outcomes at each time point and superior outcomes to the control condition at the long-term follow-up. Caution in interpreting these results is warranted due to small sample size and incomplete data; however, they support further investigation into the use of distance interventions as an accessible and effective solution for women with PPD. PMID- 28593361 TI - Different patterns of depressive symptoms during pregnancy. AB - Recently, the US Preventive Services Task Force has advocated to screen pregnant and postpartum women for depression. However, we questioned the meaning of a single elevated depression score: does it represent just one episode of depression or do these symptoms persist throughout the entire pregnancy? This study assessed depressive symptoms at each trimester in a cohort of 1813 pregnant women and evaluated whether women with different patterns of depressive symptoms showed other characteristics. Depending on the trimester, elevated depression scores were prevalent in 10-15% of the pregnant women. Up to 4% reported persistent symptoms of depression throughout pregnancy. Different patterns of depressive symptoms were observed, for which persistent symptoms were related to other characteristics than incidentally elevated symptoms. Besides a previous history of mental health problems as best overall predictor, incidentally elevated depression scores were related to major life events. Furthermore, persistently depressive symptoms were related to unplanned pregnancy and multiparity. An EDS assessment at 12 weeks of gestation including three additional items (history of mental health problems, unplanned pregnancy and multiparity) enabled us to identify 83% of the women with persistent depressive symptoms. A depression screening strategy in pregnant women should take into account the potential chronicity of depressive symptoms by repeated assessments in order to offer an intervention to the most vulnerable women. PMID- 28593364 TI - Transvaginal approach to distal ureterectomy in an obstructed remnant. PMID- 28593363 TI - The glenoid track: a review of the clinical relevance, method of calculation and current evidence behind this method. AB - In the setting of bipolar bone injury, orthopedic surgeons are currently making use of the glenoid track method to guide surgical management. Using preoperative CT or MR imaging, this method allows the identification of patients who are more likely to fail a primary capsuloligamentous Bankart repair. As the glenoid track method becomes increasingly used in preoperative planning, it is important for the radiologist to become familiar with its concept and method of calculation. This review article aims to concisely summarize the current literature and the clinical implications of the glenoid track method. PMID- 28593366 TI - Vaginal evisceration following colpocleisis. PMID- 28593365 TI - Urinary symptoms after bladder flap at the time of primary cesarean delivery: a randomized controlled trial (RTC). AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate urinary symptoms in the postpartum period after omission of the bladder flap at the time of primary cesarean delivery. METHODS: This was a single-blind parallel-group randomized comparison (bladder flap, no bladder flap) in women scheduled for a primary cesarean delivery at 37 weeks gestation or later. The primary outcome was urinary symptom scores at 6-8 weeks postpartum. Secondary outcomes included comparisons of preoperative and postoperative pelvic floor symptom scores and the proportions of symptom bother responses between the study groups. RESULTS: A total 43 women were available for analysis. Randomization was as follows: omission of the bladder flap (n = 22) and bladder flap (n = 21). Demographic characteristics and baseline pelvic floor symptom scores were similar between the groups. The primary outcome, urinary symptom scores at 6-8 weeks postpartum, did not differ significantly between the groups, but urinary symptom bother was significantly higher in women who received a bladder flap. Pelvic floor symptom scores improved significantly following delivery. CONCLUSIONS: Urinary symptom scores as measured by the UDI-6 did not differ between women randomized to bladder flap or omission of the bladder flap, but the proportion of women with urinary symptom bother was significantly higher among those who received a bladder flap. PMID- 28593367 TI - Vulvar lichen sclerosus in women is associated with lower urinary tract symptoms. AB - INTRODUCTION AND HYPOTHESIS: Lichen sclerosus (LS) is thought to be primarily a disease of postmenopausal women. Little is reported about lower urinary tract symptoms (LUTS) in association with LS. The aims of this study were to evaluate the odds of having LS-associated LUTS and to identify the predominant type of LS associated bladder dysfunction. METHODS: This was a cross-sectional study with two cohorts investigating the association between LS and LUTS and the predominant type of LS-associated bladder dysfunction. RESULTS: The odds of LUTS in women with LS were more than four times higher than in women without LS (OR 4.5, 95% CI 2.6-8.0; p < 0.0001). There was no significant difference in the occurrence of LUTS between women who experienced the first LS symptoms before and after the age of 50 years (36% and 53%, respectively, p = 0.14), or in the occurrence of the different types of LUTS between women with and without LS (p = 0.3). The most common type of LUTS was overactive bladder (OAB) in both women with LS (67.3%) and without LS (60%). The most prevalent type of LS-associated LUTS was OAB. CONCLUSIONS: The odds of developing LUTS (self-reported) are four times higher in women with LS than in those without. The predominant type of LUTS in women with and without LS is OAB. PMID- 28593368 TI - Intrauterine device visualized as extrinsic bladder mass on cystoscopy. PMID- 28593369 TI - Miniaturised sample preparation method for the multiresidual determination of regulated organohalogenated pollutants and related compounds in wild bird eggs. AB - A simplified, miniaturised matrix solid-phase dispersion (MSPD)-based method allowing the simultaneous extraction and purification of contaminants belonging to selected families of regulated persistent organic pollutants (POPs), i.e. polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and penta- to octa-polybrominated diphenyl ethers (PBDEs), and related contaminants of emerging concern, such as deca-BDE and Dechlorane Plus (DP), has been proposed. Wild bird eggs were used as biotic fat-containing model matrices. Once optimised, the procedure allowed sample preparation to be accomplished within 30 min, in a single step, and with minimal sample and reagent consumption and waste generation. These features contributed to speeding up and greening the analytical process as compared to the large-scale multistep procedures for these types of analyses. The method was combined with gas chromatography-quadrupole mass spectrometry (GC-qMS) for PCB and OCP analysis and with GC-negative ion chemical ionisation-quadrupole mass spectrometry (NCI-qMS) for PBDE and DP determination. The complete analytical method provided satisfactory recoveries of the target compounds (above 83% for all analytes, except for PBDE 209, 63%), although as small an amount of sample as 0.300 g was used. The repeatability of the complete procedure was less than 16% (with the only exception for PCB 153, which looked to be affected by an interference). The limits of detection were in all cases lower than 34 pg g-1 dry weight (as calculated for real samples), demonstrating the feasibility of the proposed procedure for accurate determination of the target compounds in biological samples. The proposed procedure was applied to the analysis of the target POPs in unhatched eggs of wild bird species. Graphical abstract Scheme of the miniaturised methodology proposed for environmental monitoring of POPs and related compounds in wild bird eggs. PMID- 28593370 TI - Identification of optimum fatty acid extraction methods for two different microalgae Phaeodactylum tricornutum and Haematococcus pluvialis for food and biodiesel applications. AB - Microalgae have the potential to synthesize and accumulate lipids which contain high value fatty acids intended for nutrition and biodiesel applications. Nevertheless, lipid extraction methods for microalgae cells are not well established and there is not a standard analytical methodology to extract fatty acids from lipid-producing microalgae. In this paper, current lipid extraction procedures employing organic solvents (chloroform/methanol, 2:1 and 1:2, v/v), sodium hypochlorite solution (NaClO), acid-catalysed hot-water extraction and the saponification process [2.5 M KOH/methanol (1:4, v/v)] have been evaluated with two species of microalgae with different types of cell walls. One is a marine diatom, Phaeodactylum tricornutum, and the other a freshwater green microalga, Haematococcus pluvialis. Lipids from all types of extracts were estimated gravimetrically and their fatty acids were quantified by a HPLC equipped with Q TOF mass spectrometer. Results indicated significant differences both in lipids yield and fatty acids composition. The chloroform and methanol mixture was the most effective extraction solvent for the unsaturated fatty acids such as DPA (C22:05), DHA, (C22:06), EPA (C20:05) and ARA (C20:04). While acid treatments improved the saturated fatty acids (SFAs) yield, especially the short chain SFA, lauric acid (C12:0), whose amount was 64% higher in P. tricornutum and 156% higher in H. pluvialis compared to organic solvent extractions. Graphical abstract ?. PMID- 28593371 TI - Design of a novel electrochemical biosensor based on intramolecular G-quadruplex DNA for selective determination of lead(II) ions. AB - An electrochemical DNA biosensor based on a G-quadruplex (G4) for the sensitive determination of Pb2+ was reported using a carbon paste electrode (CPE) or a multi-walled carbon nanotube paste electrode (MWCNTPE) as working electrodes, ethyl green (EG) as a new G4 intercalator, and a single-stranded nucleic acid sequence rich in guanine (G) as DNA probe. Electrochemical determination of Pb2+ relied on probe structural changes from single - stranded to the stabilized intramolecular G4 in the presence of Pb2+, which caused a change in the current of the EG reduction peak due to the intercalation of EG into the G4 structure. The change in the reduction peak of EG before and after its intercalation into the stabilized G4 (?I) had a linear correlation to the concentration of Pb2+ ions. The linear ranges of 4.0 * 10-10-5.0 * 10-9 M and 2 * 10-7-1 * 1-5 M with a detection limit (LOD) of 1.04 * 10-10 M were obtained using CPE, while improved linear ranges of 4.0 * 10-11-1.0 * 10-9 M and 2 * 10-7-1 * 10-5 M with a lower LOD of 2.64 * 10-11 M were achieved using the MWCNTPE biosensor. The biosensors exhibited satisfactory results in terms of selectivity and practical applicability in the analysis of real samples. Graphical abstract The principle of the electrochemical sensing of Pb2+ based on intramolecular G-quadruplex using EG. PMID- 28593372 TI - Simultaneous determination of dechloranes, polybrominated diphenyl ethers and novel brominated flame retardants in food and serum. AB - A sensitive method for the simultaneous quantification of dechloranes, polybrominated diphenyl ethers (PBDEs) and novel brominated flame retardants (NBFRs) has been developed for gas chromatography (GC) coupled to tandem mass spectrometry operating in electron capture negative ionization (ECNI) mode. The major advance has been achieved by combining selected ion monitoring (SIM) and multiple reaction monitoring (MRM) modes in well-defined time windows, to determine dechloranes, PBDEs and NBFRs at picogram per gram level in one single analysis in complex matrix biological samples. From the chromatographic point of view, efforts were devoted to study several injection modes using multimode inlet (MMI) in order to obtain low instrumental detection limits, necessary for trace compounds such as Dechlorane Plus (DP) isomers. Method performance was also evaluated: calibration curves were linear from 20 fg MUL-1 to 100 pg MUL-1 for the studied compounds, with method detection limits at levels of 50 fg g-1 for DPs. Repeatability and reproducibility, expressed as relative standard deviation, were better than 5% even in solvent vent mode for the injection of standards. The application to a wide range of complex samples (including food, human and animal serum samples) indicated a sensitive and reliable way to quantify at the picogram per gram level 4 halogenated norbornenes (HNs), Dechlorane Plus (anti-DP and syn DP) and 2 of their homologues (Dechlorane-602 and Dechlorane-603), 11 PBDE congeners (no. 28, 47, 49, 66, 85, 99, 100, 153, 154, 183 and 209) and 5 novel BFRs, i.e. decabromodiphenyl ethane (DBDPE), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), hexabromobenzene (HBB), 2,3,4,5-tetrabromo-ethylhexyl-benzoate (TBB) and tetrabromophthalate (TBPH). Graphical Abstract GC-ECNI-MS/MS chromatograms showing the most sensitive transition for DPs when injecting 2 MUL of a 16 fg/MUL standard solution of s-DP and a-DP at three different source temperatures. PMID- 28593373 TI - Preparation of a self-cleanable molecularly imprinted sensor based on surface enhanced Raman spectroscopy for selective detection of R6G. AB - Novel molecularly imprinted polymers (MIPs) based on the technique of surface enhanced Raman scattering (SERS) were successfully prepared. Firstly, ZnO nanorods were fabricated with Ag by reduction of Ag+ on the surface of the ZnO nanorods. Then, ZnO/Ag heterostructures were used as the substrate, rhodamine 6G was used as the template molecule, acrylamide was used as the functional monomer, ethylene glycol dimethacrylate was used as the cross-linker, and 2,2'-azobis(2 methylpropionitrile) was used as the initiator to prepare the ZnO/Ag MIPs (ZOA MIPs). Through characterization analysis, it was proved that the novel ZOA-MIPs exhibited excellent SERS properties and selectivity. Under the optimal conditions, there was a good linear relationship (R 2 = 0.996) between the Raman signal (at 1654 cm-1) and the concentration of the templates, and the detection limit was 10-13 mol L-1. It was also proved that the ZOA-MIPs had the property of self-cleaning, resulting in good reusability. It is envisaged that the sensitivity of SERS coupled with the selectivity of MIPs could result in a promising chemosensor for practical applications. PMID- 28593376 TI - Insight into Signal Response of Protein Ions in Native ESI-MS from the Analysis of Model Mixtures of Covalently Linked Protein Oligomers. AB - Native ESI-MS is increasingly used for quantitative analysis of biomolecular interactions. In such analyses, peak intensity ratios measured in mass spectra are treated as abundance ratios of the respective molecules in solution. While signal intensities of similar-size analytes, such as a protein and its complex with a small molecule, can be directly compared, significant distortions of the peak ratio due to unequal signal response of analytes impede the application of this approach for large oligomeric biomolecular complexes. We use a model system based on concatenated maltose binding protein units (MBPn, n = 1, 2, 3) to systematically study the behavior of protein mixtures in ESI-MS. The MBP concatamers differ from each other only by their mass while the chemical composition and other properties remain identical. We used native ESI-MS to analyze model mixtures of MBP oligomers, including equimolar mixtures of two proteins, as well as binary mixtures containing different fractions of the individual components. Pronounced deviation from a linear dependence of the signal intensity with concentration was observed for all binary mixtures investigated. While equimolar mixtures showed linear signal dependence at low concentrations, distinct ion suppression was observed above 20 MUM. We systematically studied factors that are most often used in the literature to explain the origin of suppression effects. Implications of this effect for quantifying protein-protein binding affinity by native ESI-MS are discussed in general and demonstrated for an example of an anti-MBP antibody with its ligand, MBP. Graphical Abstract ?. PMID- 28593375 TI - Clinical implication of novel drug resistance-conferring mutations in resistant tuberculosis. AB - Evolving novel and/or unfamiliar mutations are revolutionizing the pathways of antibiotic resistance of clinical tuberculosis. The accumulation and interaction of these poorly characterized mutations augment the complexity of resistant pathogenic strains and raise public health concerns. This article reviews our current understanding of the genetic changes that characterize drug resistance in tuberculosis and highlights the imperative for further investigations focusing on the effects of an individual mutation and interacting mutations with detailed strain epidemiology, particularly as these pertain to technology-limited countries with high tuberculosis incidence rates. Concomitantly, there is a need for the development, testing, and uptake of new tools for studying the effects of these mutations in drug resistance and fitness cost of the pathogen. Such genetic data are critical for effective localized and global tuberculosis control interventions and for accurate epidemiological predictions. PMID- 28593378 TI - Letter to the Editor concerning "New classification for the treatment of pyogenic spondylodiscitis: validation study on a population of 250 patients with a follow up of 2 years" by Enrico Pola et al. Eur Spine J (2017) doi:10.1007/s00586-017 5043-5. PMID- 28593377 TI - microMS: A Python Platform for Image-Guided Mass Spectrometry Profiling. AB - Image-guided mass spectrometry (MS) profiling provides a facile framework for analyzing samples ranging from single cells to tissue sections. The fundamental workflow utilizes a whole-slide microscopy image to select targets of interest, determine their spatial locations, and subsequently perform MS analysis at those locations. Improving upon prior reported methodology, a software package was developed for working with microscopy images. microMS, for microscopy-guided mass spectrometry, allows the user to select and profile diverse samples using a variety of target patterns and mass analyzers. Written in Python, the program provides an intuitive graphical user interface to simplify image-guided MS for novice users. The class hierarchy of instrument interactions permits integration of new MS systems while retaining the feature-rich image analysis framework. microMS is a versatile platform for performing targeted profiling experiments using a series of mass spectrometers. The flexibility in mass analyzers greatly simplifies serial analyses of the same targets by different instruments. The current capabilities of microMS are presented, and its application for off-line analysis of single cells on three distinct instruments is demonstrated. The software has been made freely available for research purposes. Graphical Abstract ?. PMID- 28593379 TI - Erratum to: Stereoradiography imaging motion artifact: does it affect radiographic measures after spinal instrumentation? PMID- 28593374 TI - Chromatin loops and causality loops: the influence of RNA upon spatial nuclear architecture. AB - An intrinsic and essential trait exhibited by cells is the properly coordinated and integrated regulation of an astoundingly large number of simultaneous molecular decisions and reactions to maintain biochemical homeostasis. This is especially true inside the cell nucleus, where the recognition of DNA and RNA by a vast range of nucleic acid-interacting proteins organizes gene expression patterns. However, this dynamic system is not regulated by simple "on" or "off" signals. Instead, transcription factor and RNA polymerase recruitment to DNA are influenced by the local chromatin and epigenetic environment, a gene's relative position within the nucleus and the action of noncoding RNAs. In addition, major phase-separated structural features of the nucleus, such as nucleoli and paraspeckles, assemble in direct response to specific transcriptional activities and, in turn, influence global genomic function. Currently, the interpretation of these data is trapped in a causality dilemma reminiscent of the "chicken and the egg" paradox as it is unclear whether changes in nuclear architecture promote RNA function or vice versa. Here, we review recent advances that suggest a complex and interdependent interaction network between gene expression, chromatin topology, and noncoding RNA function. We also discuss the functional links between these essential nuclear processes from the nanoscale (gene looping) to the macroscale (sub-nuclear gene positioning and nuclear body function) and briefly highlight some of the challenges that researchers may encounter when studying these phenomena. PMID- 28593380 TI - Expert's comment concerning Grand Rounds case entitled "Paraspinal hibernoma: Grand Round presentation of a rare benign adipocytic tumor" by S. Ghailane et al. (Eur Spine J; 2017: DOI 10.1007/s00586-017-5124-5). PMID- 28593381 TI - Paraspinal hibernoma: Grand Round presentation of a rare benign adipocytic tumor. AB - INTRODUCTION: We report an uncommon case of paraspinal hibernoma with a T12-L1 foraminal extension and discuss the potential differential diagnoses of paraspinal adipocytic tumors. MATERIALS AND METHODS: A 32-year-old woman consulted our department with a right subscapular and paraspinal mass. There was no associated neurological deficit. The MRI revealed a paraspinal adipocytic tumor with a T12-L1 right foraminal extension. Percutaneous biopsy suggested a diagnosis of hibernoma. RESULTS: Hibernoma is a rare and benign adipocytic tumor arising from embryologic remnants of brown fat. Specific MRI findings are discussed to differentiate hibernoma from other soft-tissue tumors. A planned marginal resection was undertaken with the final histopathology confirming the diagnosis of hibernoma. CONCLUSION: Based on the Grand Round case and relevant literature, we discuss a rare case of paraspinal hibernoma with a foraminal component and no recurrence at 3-year follow-up. PMID- 28593382 TI - Idiopathic spinal cord herniation: consideration of its pathogenesis based on the histopathology of the dura mater. AB - INTRODUCTION: We present a patient with idiopathic spinal cord herniation (ISCH) whose dura mater was histopathologically examined to elucidate its pathogenesis. CASE REPORT: A 33-year-old previously healthy man presented with progressive walking difficulty, spasticity of the right lower leg, and hyperesthesia below the right chest. Neuroimaging revealed right ventral displacement of the spinal cord at T5-6. The diagnosis was ISCH and he underwent release of the herniation from the ventral dural opening. Dural biopsy at the edge of the ventral opening and in the dorsal durotomy was performed. Postoperatively, his gait was improved. Histopathological examination of the ventral dural specimen showed non-specific degeneration, i.e., loose arrangements of collagen fibers, edematous changes, minor inflammatory cell infiltration, and angiogenesis. The specimen from the dorsal durotomy was normal. CONCLUSION: It is unclear whether the observed degeneration besides the ventral opening was the primary cause of ISCH or reflected secondary changes resulting from cumulative damage due to pulsation of the herniated spinal cord. However, the degeneration limited to the ventral opening suggests that ISCH was a local event in an individual with a normal dural theca. PMID- 28593383 TI - Tubercular spondylodiscitis in elderly is a more severe disease: a report of 66 consecutive patients. AB - PURPOSE: (1) To analyze peculiarities of presentation and prognosis of tubercular spondylodiscitis (TBS) in elderly. (2) To assess if associated co-morbidities and risks lead to poorer outcome (3) To observe if different management strategy needs to be implemented in them. METHODS: Retrospective analysis of 66 consecutive elderly TBS patients (>60 years) treated conservatively or surgically between January 2010 and July 2013 was performed. Details regarding clinical presentation (general health, ambulatory status, co-morbidities), neurological status, medical or surgical complications and outcome measurements [visual analog score, clinico-radiological evidence of healing and lumbar lordosis in lumbar (L) or lumbo-sacral (LS) or focal kyphosis in thoracic (T) or thoraco-lumbar (TL) disease] were analysed. RESULTS: Of 66 patients (mean age 67.9 years), 85% had at least one medical co-morbidity and only 45% were community ambulators. Mean delay in presentation was 132 days and lumbar disease was commonest. 35% had neuro deficit. Most patients had stage 2 (38%) or 3 (42.4%) disease. 19 patients were conservatively managed, while others underwent surgery. Significant complications occurred in 23 patients, most common being liver dysfunction (9 patients). Five patients (8%) expired during treatment: three succumbed to multi-focal tubercular disease, while two expired secondary to medical illnesses. Mean loss of lordosis in conservatively treated (CG) L/LS disease was 8 degrees , while lordosis was restored by 11.6 degrees in operative group (OG). In T/TL disease, sagittal alignment correction by 12.6 degrees was observed in OG as against 5.7 degrees kyphotic collapse in CG patients. 92% patients were cured with no recurrences. The final VAS scores in operative and conservative groups were not significantly different (OG 1.4 +/- 0.6, CG 1.9 +/- 0.7). CONCLUSION: TBS in elderly differed from that in younger by having a higher co-morbidities, later presentation, higher neuro-deficit, greater mortality and increased complications. Nevertheless, in those who survived, clinico-radiological outcomes of both conservative and surgical treatments were good. PMID- 28593384 TI - Anterior cervical osteotomy: operative technique. AB - PURPOSE: Correction of rigid cervical deformities often requires osteotomies to realign the spine. Cervical pedicle subtraction osteotomy can be technically challenging due to the presence of cervical nerve roots and usually can only be performed at C7 or T1 due to the presence of vertebral arteries. In contrast, anterior cervical osteotomy can be performed throughout the cervical spine and is a safe and effective method for correction of both sagittal and coronal cervical deformities. We describe the anterior cervical osteotomy technique with a review of the pertinent literature. METHODS: A step-by-step technical guide for anterior cervical osteotomy is provided with a focus on surgical nuances and complication avoidance. Two illustrative cases of fixed sagittal and coronal deformities are included to demonstrate the substantial amount of deformity correction achievable using the anterior cervical osteotomy technique. RESULTS: Both patients in the illustrative cases had successful clinical and radiographic outcome following deformity correction utilizing the anterior cervical osteotomy technique. CONCLUSION: Anterior cervical osteotomy is a safe and effective technique for correction of rigid cervical deformities. Spine surgeons should be familiar with this technique to optimize clinical outcome in patients undergoing cervical deformity correction. PMID- 28593385 TI - Tailor-made management of thoracic scoliosis with cervical hyperextension in muscular dystrophy. AB - PURPOSE: We report the case of a 13-year-old boy managed for fixed cervical hyperextension due to congenital muscular dystrophy with partial merosin deficiency. He presented a right decompensated thoracic scoliosis (T6-L1 Cobb angle 72 degrees ) associated with cervical and lumbar lordosis. The spinal extension was accompanied by major flexion of the hip resulting in the trunk being bent forward. This posture caused daily severe back pain responsible for significant loss of quality of life. This led to the decision to perform surgery. METHODS: Initially, the surgery was limited to the thoraco-lumbo-sacral area. An anterior release was done, followed by posterior T1-pelvis vertebral fusion using a modified Luque-Galveston technique. The correction achieved was satisfactory in the coronal plane, but the correction of the thoracic kyphosis was insufficient to compensate for the cervical hyperextension. Cervical spine was fixed at 52 degrees of lordosis, and associated with a left 50 degrees rotation and a right 45 degrees inclination of the head. We performed a posterior and lateral release of the cervical muscles followed by positioning of the halo, itself connected to a made-for-measure thoracic corset. A daily adjustment of the threaded rods was done daily for 3 months to correct the cervical position. Then, we performed a spinal fusion without instrumentation, by posterior articular abrasion and grafting from the occiput to T1. Following that, the halo-corset was kept in place for 4 months. RESULTS: At the end of 8 month treatment, the clinical result was satisfactory with a balanced spine both face on, and sideways, allowing for comfortable painless positioning. At 5 year follow-up, he showed stable spinal fusion without any loss of correction. CONCLUSION: There is no gold standard treatment for cervical hyperextension, but approaches have to be tailor-made to the patient's needs and the team's experience. PMID- 28593386 TI - Prostate-specific membrane antigen PET imaging and immunohistochemistry in adenoid cystic carcinoma- a preliminary analysis. AB - BACKGROUND: Adenoid cystic carcinoma (AdCC) of the head and neck is an uncommon malignant epithelial tumour of the secretory glands. Many patients develop slowly growing local recurrence and/or distant metastasis, for which treatment options are limited. A retrospective analysis of 9 AdCC patients was conducted to analyse the visualization of AdCC on PSMA PET/CT and to investigate the expression of PSMA on primary, recurrent and metastatic AdCC tumour tissue using immunohistochemistry. RESULTS: Local recurrence occurred in six patients and eight developed distant metastasis. All PET/CTs depicted PSMA-ligand uptake. Four PSMA PET/CTs showed suspected residual disease, eight scans depicted uptake in areas suspected of distant metastasis. Median Maximum Standardized Uptake Value (SUVmax) in local recurrent and distant metastatic AdCC was 2.52 (IQR 2.41-5.95) and 4.01 (IQR 2.66-8.71), respectively. All primary tumours showed PSMA expression on immunohistochemistry (5-90% expression), as well as all available specimens of local recurrence and distant metastases. CONCLUSION: PSMA PET/CT is able to detect and visualize local recurrent and distant metastatic AdCC. PSMA specific targeting is supported by PSMA expression on immunohistochemistry. PMID- 28593387 TI - Increased odds of patient-reported success at 2 years after anterior cruciate ligament reconstruction in patients without cartilage lesions: a cohort study from the Swedish National Knee Ligament Register. AB - PURPOSE: To investigate whether the surgical technique of single-bundle anterior cruciate ligament (ACL) reconstruction, the visualization of anatomic surgical factors and the presence or absence of concomitant injuries at primary ACL reconstruction are able to predict patient-reported success and failure. The hypothesis of this study was that anatomic single-bundle surgical procedures would be predictive of patient-reported success. METHODS: This cohort study was based on data from the Swedish National Knee Ligament Register during the period of 1 January 2005 through 31 December 2014. Patients who underwent primary single bundle ACL reconstruction with hamstring tendons were included. Details on surgical technique were collected using an online questionnaire comprising essential anatomic anterior cruciate ligament reconstruction scoring checklist items, defined as the utilization of accessory medial portal drilling, anatomic tunnel placement, the visualization of insertion sites and pertinent landmarks. A univariate logistic regression model adjusted for age and gender was used to determine predictors of patient-reported success and failure, i.e. 20th and 80th percentile, respectively, in the Knee injury and Osteoarthritis Outcome Score (KOOS), 2 years after ACL reconstruction. RESULTS: In the 6889 included patients, the surgical technique used for single-bundle ACL reconstruction did not predict the predefined patient-reported success or patient-reported failure in the KOOS4. Patient-reported success was predicted by the absence of concomitant injury to the meniscus (OR = 0.81 [95% CI, 0.72-0.92], p = 0.001) and articular cartilage (OR = 0.70 [95% CI, 0.61-0.81], p < 0.001). Patient-reported failure was predicted by the presence of a concomitant injury to the articular cartilage (OR = 1.27 [95% CI, 1.11-1.44], p < 0.001). CONCLUSION: Surgical techniques used in primary single-bundle ACL reconstruction did not predict the KOOS 2 years after the reconstruction. However, the absence of concomitant injuries at index surgery predicted patient-reported success in the KOOS. The results provide further evidence that concomitant injuries at ACL reconstruction affect subjective knee function and a detailed knowledge of the treatment of these concomitant injuries is needed. LEVEL OF EVIDENCE: Retrospective cohort study, Level III. PMID- 28593389 TI - Erratum to: Delayed spontaneous closure of postsurgical cyclodialysis cleft. PMID- 28593388 TI - Different clinical effect of several types of airborne allergens on the severity of bronchial hyperreactivity. AB - BACKGROUND: Atopic sensitization belongs to the most common risk factors for bronchial asthma. However, in clinical practice, it is not clear whether sensitization against pollen and perennial allergens is differently associated with the severity of bronchial hyperresponsiveness (BHR). AIM: To find out whether patients sensitized to perennial allergens differ in severity of bronchial hyperresponsiveness from patients sensitized to pollen allergens. METHODS: The study includes 109 patients. Based on the results of skin prick tests, patients were divided into three groups: sensitivity to pollen allergens - group A; sensitivity to perennial allergens - group B; sensitivity to both pollen and perennial allergens - group C. Based on the histamine bronchoprovocation test, we compared the values of histamine provocative concentration causing a 20% drop in FEV1 (PC20) among particular groups of patients. Mild bronchial hyperresponsiveness was determined if the value of PC20 was >4 mg/ml, while if the value of PC20 was <4 mg/ml, the bronchial hyperresponsiveness was considered as moderate/severe. RESULTS: A statistically significant difference was found in the degrees of bronchial hyperresponsiveness between the three groups of patients, namely, group A with the patients sensitized only to the pollen allergens, group B comprising patients sensitized to the perennial allergens only, and group C, involving patients sensitized to the combination of both pollen and perennial allergens. The PC20 values were higher among the patients from the group A (7.46 mg/ml) compared to group B (4.25 mg/ml) and C (4.52 mg/ml). The odds ratio for moderate/severe BHR was 5.21 and 5.04 in group B and group C, respectively. CONCLUSION: Severity of bronchial hyperresponsiveness shows differences according to sensitization to particular allergens. Perennial allergens are more often associated with serious forms of bronchial hyperresponsiveness which also have an impact on the severity and prognosis of bronchial asthma. PMID- 28593390 TI - Origin, differentiation and functional ultrastructure of egg envelopes in the cestode Echinococcus multilocularis Leuckart, 1863 (Cyclophyllidea: Taeniidae). AB - The origin, differentiation and functional ultrastructure of oncospheral or egg envelopes in Echinococcus multilocularis Leuckart, 1863 were studied by transmission electron microscopy (TEM) and cytochemistry. The purpose of our study is to describe the formation of the four primary embryonic envelopes, namely vitelline capsule, outer envelope, inner envelope and oncospheral membrane, and their transformation into the oncospheral or egg envelopes surrounding the mature hexacanth. This transformation takes place in the preoncospheral phase of embryonic development. The vitelline capsule and oncospheral membrane are thin membranes, while the outer and inner envelopes are thick cytoplasmic layers formed by two specific types of blastomeres: the outer envelope by cytoplasmic fusion of two macromeres and the inner envelope by cytoplasmic fusion of three mesomeres. Both outer and inner envelopes are therefore cellular in origin and syncytial in nature. During the advanced phase of embryonic development, the outer and inner envelopes undergo great modifications. The outer envelope remains as a metabolically active layer involved in the storage of glycogen and lipids for the final stages of egg development and survival. The inner envelope is the most important protective layer because of its thick layer of embryophoric blocks that assures oncospheral protection and survival. This embryophore is the principal layer of mature eggs, affording physical and physiological protection for the differentiated embryo or oncosphere, since the outer envelope is stripped from the egg before it is liberated. The embryophore is very thick and impermeable, consisting of polygonal blocks of an inert keratin-like protein held together by a cementing substance. The embryophore therefore assures extreme resistance of eggs, enabling them to withstand a wide range of environmental temperatures and physicochemical conditions. PMID- 28593391 TI - Wavelet decomposition analysis in the two-flash multifocal ERG in early glaucoma: a comparison to ganglion cell analysis and visual field. AB - PURPOSE: To further improve analysis of the two-flash multifocal electroretinogram (2F-mfERG) in glaucoma in regard to structure-function analysis, using discrete wavelet transform (DWT) analysis. METHODS: Sixty subjects [35 controls and 25 primary open-angle glaucoma (POAG)] underwent 2F mfERG. Responses were analyzed with the DWT. The DWT level that could best separate POAG from controls was compared to the root-mean-square (RMS) calculations previously used in the analysis of the 2F-mfERG. In a subgroup analysis, structure-function correlation was assessed between DWT, optical coherence tomography and automated perimetry (mf103 customized pattern) for the central 15 degrees . RESULTS: Frequency level 4 of the wavelet variance analysis (144 Hz, WVA-144) was most sensitive (p < 0.003). It correlated positively with RMS but had a better AUC. Positive relations were found between visual field, WVA 144 and GCIPL thickness. The highest predictive factor for glaucoma diagnostic was seen in the GCIPL, but this improved further by adding the mean sensitivity and WVA-144. CONCLUSIONS: mfERG using WVA analysis improves glaucoma diagnosis, especially when combined with GCIPL and MS. PMID- 28593392 TI - Multimodal imaging and functional correlations identify unusual cases of macular retinal pigment epithelium hypopigmentation occurring without functional loss. AB - PURPOSE: Patients with unusual macular retinal pigment epithelium (RPE) hypopigmentation are described and analyzed using retinal multimodal imaging. METHODS: We report three cases of patients with unilateral (2) or bilateral (1) macular lesions discovered incidentally on fundoscopy. A comprehensive ophthalmic examination including visual acuity, fundoscopy, spectral-domain optical coherence tomography (SD-OCT), short-wavelength light and near-infrared autofluorescence, fluorescein angiography, microperimetry, multifocal electroretinogram, adaptive optics (AO), and OCT-angiography (OCT-A) has been performed. RESULTS: Visual acuity was 20/20 in both eyes of all patients. The lesion appeared hyperautofluorescent on short-wavelength light and hypoautofluorescent on near-infrared light. Fluorescein angiography revealed a sharply demarcated macular hyperfluorescence without any leakage, suggesting a window defect. Interestingly, SD-OCT revealed only a choroidal hyperreflectivity in relation to the lesions without any abnormality of the outer retinal layers. Microperimetry was normal except for 1 patient with bilateral lesion and subtle decrease in macular sensitivity. Mf ERG was normal in all three patients. AO showed a well-preserved cone mosaic, suggesting that the abnormality was localized under the photoreceptor layers. OCT-A revealed hyperreflectivity just below the RPE layer, corresponding to the macular lesion observed on fundoscopy and the choroidal hyperreflectivity seen on SD-OCT. CONCLUSIONS: Macular RPE hypopigmentation should be considered in case of an isolated macular lesion without functional visual impairment or anatomical defect on SD-OCT. PMID- 28593394 TI - Double Balloon-Assisted Coil Embolization (BACE) Combined with Proximal and Distal Balloon Inflation for Short Abdominal Arterial Segments: Comparison with Single BACE. AB - PURPOSE: To evaluate the differences of technique between coil embolization for short abdominal arterial segments with only proximal balloon inflation and combined proximal and distal balloon inflation, as well as the volume embolization ratio (VER) and the ratio of the first coil diameter to the target vessel diameter (first coil diameter ratio). MATERIALS AND METHODS: From January 2014 to August 2016, we performed coil embolization of the short segment in seven patients. The target vessels were the common hepatic arteries before distal pancreatectomy with en bloc celiac axis resection in five patients, the superior mesenteric artery for isolation of pseudoaneurysm in one patient and the celiac trunk for preventing Type II endoleak before endovascular aortic repair in one patient. We evaluate VER and first coil diameter ratio in single balloon-assisted coil embolization (BACE) with only proximal balloon inflation and double BACE with combined proximal and distal balloon inflation. RESULTS: The BACE (single BACE; n = 4, double BACE; n = 3) was safely finished. The VER was median 12.1% (single BACE; mean 11.7%, double BACE; mean 12.4%). The first coil diameter ratio was median 1.82 in both groups. CONCLUSION: The coil embolization was safely performed by BACE. Double BACE allowed planning of the distal end of the coil embolization site and the embolization segment prior to coil placement. We achieved sufficient friction to prevent coil migration by choosing detachable microcoils with a median diameter 1.82 times larger than that of the target vessel and a VER >=12%, allowing us to embolize short vascular segments. PMID- 28593393 TI - Endovascular Management of Severe Arterial Haemorrhage After Radical Prostatectomy: A Case Series. AB - PURPOSE: The aim of this study is to assess the safety, effectiveness and long term outcome of endovascular management of arterial haemorrhage after radical prostatectomy (RP). MATERIALS AND METHODS: Ten patients who received endovascular treatment for refractory bleeding after RP between January 2008 and December 2016 were retrospectively identified. Contrast-enhanced computed tomography (CT) was performed and followed by catheter-directed treatment by means of transarterial embolization (TAE) or stent graft placement. Follow-up included analysis of bleeding recurrence, embolization-related adverse events and tumour recurrence. RESULTS: Contrast-enhanced CT and catheter-directed angiography showed pelvic contrast extravasation in nine patients. Nine patients were successfully treated with TAE of the internal pudendal, superior and/or inferior vesical or (the anterior division or main branch of) the internal iliac arteries using microparticles in two patients, coils in two patients, a combination of microparticles and coils in three patients, glue in one patient and Gelfoam in one patient. The remaining patient was treated with stent graft placement in the external iliac artery, which was most likely injured during robot-assisted lymphadenectomy. One patient developed a puncture site pseudoaneurysm. No other complications related to the endovascular procedures occurred, in particular no pelvic ischaemic complications were identified. Mean follow-up period was 45 months (range 22-80). CONCLUSIONS: The endovascular management of arterial haemorrhage after RP is safe and effective, without post-embolization ischaemic events. PMID- 28593395 TI - Anti-tumor Effects of Sorafenib Administered at Different Time Points in Combination with Transarterial Embolization in a Rabbit VX2 Liver Tumor Model. AB - OBJECTIVE: To investigate the most suitable timing parameters when using sorafenib to enhance the anti-tumor effects of transarterial embolization (TAE) in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: Twenty-five Japanese white rabbits were randomly assigned to five equal groups two weeks after VX2 tumor transplantation to the liver. We then performed the combination treatment with sorafenib and TAE in the according ways; Group 1 (TAE just before consecutive 7-day administration of sorafenib), Group 2 (TAE on second day of the administration period), Group 3 (TAE on fourth day of the administration period), and Group 4 (TAE after the administration period). Group 5 underwent TAE only. The anti-tumor effects were assessed by the tumor growth rates and by the immunohistochemical analysis of the density of intratumoral vessels. RESULTS: The tumor size increased by 103 +/- 23% in Group 1, 126 +/- 50% in Group 2, 177 +/- 44% in Group 3 196 +/- 78% in Group 4, and 211 +/- 20% in Group 5. The difference between Group 1 and Group 5 and Group 2 and Group 5 was significant. The ratio of areas positive for CD31 in specimens was 2.06 +/- 0.90% in Group 1, 1.86 +/- 0.59% in Group 2, 3.51 +/- 2.10% in Group 3, 3.67 +/- 0.79% in Group 4, and 4.84 +/- 0.81% in Group 5. The difference between Group 1 and Group 5, Group 2 and Group 5, and Group 2 and Group 4 was significant. CONCLUSION: We suggest that the ideal time of TAE is prior to or early after commencement of sorafenib administration. PMID- 28593396 TI - Balloon-Occluded Microwave Ablation: A Potential Therapeutic Option in Liver Lesions Bearing Close Proximity to Major Hepatic and/or Portal Veins. PMID- 28593397 TI - 5-ALA fluorescence behavior of cerebral infectious and inflammatory disease. PMID- 28593398 TI - Localization of angiosarcoma by peri-operative transesophageal echocardiography. AB - Transthoracic echocardiography (TTE), computed tomography (CT) and magnetic resonance (MR) cannot always clearly identify angiosarcoma. A 22 year old woman presented with dyspnea. Preoperative TTE showed no tumor, and CT and MR both gave the impression that an extra-cardiac, mediastinal tumor was present. Transesophageal echocardiography (TEE), performed during surgery showed an intra cardiac tumor, which was a well-delineated mass at the intra-ventricular groove of the right heart and surrounding the superior vena cava. The tumor was excised and found to be a malignant angiosarcoma. TEE provides diagnostic advantages over other cardiac imaging techniques and can serve as a useful adjunct during and before intrathoracic surgery. PMID- 28593399 TI - MRI use for atrial tissue characterization in arrhythmias and for EP procedure guidance. AB - We review the utilization of magnetic resonance imaging methods for classifying atrial tissue properties that act as a substrate for common cardiac arrhythmias, such as atrial fibrillation. We then review state-of-the-art methods for mapping this substrate as a predicate for treatment, as well as methods used to ablate the electrical pathways that cause arrhythmia and restore patients to sinus rhythm. PMID- 28593400 TI - A collaborative intervention to improve surgical antibiotic prophylaxis in children: results from a prospective multicenter study. AB - PURPOSE: The use of surgical antibiotic prophylaxis (SAP) in children is poorly characterized. Our aim was to evaluate the effectiveness of a quality improvement (QI) intervention targeting SAP in children, by means of a multicenter prospective intervention study, with a before and after design. METHODS: We prospectively investigated elective surgical procedures performed in children <18 years, prior to the QI intervention, after the intervention and at 9-month follow up. The primary outcomes were adherence to SAP indications and SAP appropriateness, defined considering antibiotic choice, timing of first dose and duration of administration. We compared SAP adherence and appropriateness prior the QI intervention, to the post-intervention and the follow-up. We considered patient and procedure characteristics as covariates in two logistic regression models to assess the effect of the QI intervention on SAP adherence and appropriateness. RESULTS: We collected information on 2383 procedures (pre intervention: 784; post-intervention: 790; follow-up: 809). The QI intervention had a significant impact on the adherence to SAP indications (86.6% in the post intervention, compared to 82.0% prior to the intervention; p < 0.05), and on its appropriateness (35.7% compared to 19.9%; p < 0.01). The impact of the intervention on SAP appropriateness was maintained at follow-up (38.3%; p < 0.01 compared to pre-intervention). All components of SAP appropriateness significantly improved after the intervention and at follow-up. The logistic regression analyses confirmed the effect of intervention in improving adherence to SAP indications and appropriateness. CONCLUSIONS: Following the QI intervention, there was a significant improvement in quality of SAP in pediatric surgery, though more efforts are needed to increase SAP appropriateness. PMID- 28593401 TI - External validation of a biomarker and clinical prediction model for hospital mortality in acute respiratory distress syndrome. AB - PURPOSE: Mortality prediction in ARDS is important for prognostication and risk stratification. However, no prediction models have been independently validated. A combination of two biomarkers with age and APACHE III was superior in predicting mortality in the NHLBI ARDSNet ALVEOLI trial. We validated this prediction tool in two clinical trials and an observational cohort. METHODS: The validation cohorts included 849 patients from the NHLBI ARDSNet Fluid and Catheter Treatment Trial (FACTT), 144 patients from a clinical trial of sivelestat for ARDS (STRIVE), and 545 ARDS patients from the VALID observational cohort study. To evaluate the performance of the prediction model, the area under the receiver operating characteristic curve (AUC), model discrimination, and calibration were assessed, and recalibration methods were applied. RESULTS: The biomarker/clinical prediction model performed well in all cohorts. Performance was better in the clinical trials with an AUC of 0.74 (95% CI 0.70-0.79) in FACTT, compared to 0.72 (95% CI 0.67-0.77) in VALID, a more heterogeneous observational cohort. The AUC was 0.73 (95% CI 0.70-0.76) when FACTT and VALID were combined. CONCLUSION: We validated a mortality prediction model for ARDS that includes age, APACHE III, surfactant protein D, and interleukin-8 in a variety of clinical settings. Although the model performance as measured by AUC was lower than in the original model derivation cohort, the biomarker/clinical model still performed well and may be useful for risk assessment for clinical trial enrollment, an issue of increasing importance as ARDS mortality declines, and better methods are needed for selection of the most severely ill patients for inclusion. PMID- 28593402 TI - Clinical presentation and prognostic indicators in 100 adults and children with neurofibromatosis 1 associated non-optic pathway brain gliomas. AB - Type 1 Neurofibromatosis (NF1) is a common autosomal dominant condition, with a major impact on the nervous system, eye, bone, and skin, and a predisposition to malignancy. At present it is not possible to predict clinically or on imaging, whether a brain tumour will remain indolent or undergo high-grade change. There are no consensus guidelines on the follow-up of non-optic pathway glioma (non OPG) tumours in NF1. One hundred patients from the National NF1 Service with generalised NF1 and a diagnosis of non-OPG glioma were followed up for a median time of 63 months after glioma detection. Forty-two patients underwent surgical intervention. Ninety-one percent (38) of those requiring surgery did so within 5 years of diagnosis of glioma. Serial neuroimaging was undertaken in 88 patients. In 66 (75%), the lesion on the scan was stable or had improved at follow-up. High grade lesions were present in five patients and were strongly associated with tumours in the thalamus (p = 0.001). Five patients died during follow-up. The diagnosis of high-grade glioma had a HR of 99.7 (95% CI 11.1-898.9, p < 000.1) on multivariate Cox regression to evaluate predictive factors related to death. In our cohort of 100 patients with NF1, we have shown that tumours in the thalamus are more likely to be associated with radiological progression, high-grade tumours, and surgical intervention. As a result of this finding, heightened surveillance with more frequent imaging should be considered in thalamic involvement. We have also demonstrated that over 40% of patients underwent surgery, and did so within 5 years of tumour diagnosis. Serial imaging should be undertaken for at the very least, 5 years from tumour detection. PMID- 28593403 TI - Submuscular double bridge plating for complex distal fractures of the humerus: an alternative, safe, and efficient treatment method. AB - PURPOSE: The aim of our study is to show the functional outcomes and complication rates of humeral complex fractures in adults, using osteosynthesis with two bridging orthogonal submuscular plates. METHODS: The study consists of a prospective case series of 13 patients with isolated humeral complex fractures treated with two bridging orthogonal submuscular plates. Functional assessment was performed using disabilities of the arm, shoulder, and hand (DASH) score with 30 items. The age ranged from 22 to 68 years, with a mean age of 39 years. Functional assessment with DASH score was performed at the twelfth postoperative week. RESULTS: All patients presented fracture healing in the fourth postoperative month. Of the 13 patients, five (38%) had a DASH score of zero (best function possible). One patient developed neuropraxis and presented with a score of 100 (worst possible). One case developed superficial infection, which was treated with oral antibiotics and local debridement. CONCLUSIONS: This study demonstrated satisfactory functional outcome in patients with distal-third diaphyseal humeral complex fractures treated with two locked submuscular plates. The authors consider it as a safe method and an efficient alternative, especially in younger patients who require early functional recovery. PMID- 28593404 TI - Association Between Depressive Symptom Patterns and Clinical Profiles Among Persons Living with HIV. AB - To describe patterns of depressive symptoms across 10-years by HIV status and to determine the associations between depressive symptom patterns, HIV status, and clinical profiles of persons living with HIV from the Multicenter AIDS Cohort Study (N = 980) and Women's Interagency HIV Study (N = 1744). Group-based trajectory models were used to identify depressive symptoms patterns between 2004 and 2013. Multinomial logistic regressions were conducted to determine associations of depression risk patterns. A 3-group model emerged among HIV negative women (low: 58%; moderate: 31%; severe: 11%); 5-groups emerged among HIV positive women (low: 28%; moderate: 31%; high: 25%; decreased: 7%; severe: 9%). A 4-group model emerged among HIV-negative (low: 52%; moderate: 15%; high: 23%; severe: 10%) and HIV-positive men (low: 34%; moderate: 34%; high: 22%; severe: 10%). HIV+ women had higher odds for moderate (adjusted odds ratio [AOR] 2.10, 95% CI 1.63-2.70) and severe (AOR 1.96, 95% CI 1.33-2.91) depression risk groups, compared to low depression risk. HIV+ men had higher odds for moderate depression risk (AOR 3.23, 95% CI 2.22-4.69), compared to low risk. The Framingham Risk Score, ART use, and unsuppressed viral load were associated with depressive symptom patterns. Clinicians should consider the impact that depressive symptoms may have on HIV prognosis and clinical indicators of comorbid illnesses. PMID- 28593405 TI - Inducible nitric oxide synthase gene polymorphisms are associated with a risk of nephritis in Henoch-Schonlein purpura children. AB - : Henoch-Schonlein purpura (HSP) is the most common form of systemic small-vessel vasculitis in children, and HSP nephritis (HSPN) is a major complication of HSP and is the primary cause of morbidity and mortality. Previous studies have suggested that inducible nitric oxide synthase (iNOS) may play an important role in the pathogenesis of HSP. In this study, we performed a detailed analysis to investigate the potential association between iNOS polymorphisms and the risk of HSP and the tendency for children with HSP to develop HSPN in a Chinese Han population. A promoter pentanucleotide repeat (CCTTT)n and 10 functional single nucleotide polymorphisms (SNPs) from 532 healthy controls and 513 children with HSP were genotyped using the MassARRAY system and GeneScan. The results suggested that the allelic and genotypic frequencies of the rs3729508 polymorphism were nominally associated with susceptibility to HSP. In addition, there was a significant difference in the allelic distribution of the (CCTTT)12 repeats and rs2297518 between the HSP children with and without nephritis; the HSP children with nephritis exhibited a significantly higher frequency of the (CCTTT)12 repeats and A allele of rs2297518 than the HSP children without nephritis (P FDR = 0.033, OR = 1.624, 95% CI = 1.177-2.241 and P FDR = 0.030, OR = 1.660, 95% CI = 1.187-2.321, respectively). CONCLUSION: Our results support that iNOS polymorphisms are associated with the risk of HSP and may strongly contribute to the genetic basis of individual differences in the progression to nephritis among children with HSP in the Chinese Han population. What is Known: * The etiology of HSP is unknown, but the genetic factors may play an important role in the pathogenesis of HSP. * iNOS could contribute to the development and clinical manifestations of HSP, and this has not been studied extensively so far. What is New: * Our results support that iNOS polymorphisms not only are associated with HSP risk but also strongly contribute to the genetic basis of individual differences in the progression of HSP to nephritis among Chinese Han children. PMID- 28593407 TI - Feasibility of real-time location systems in monitoring recovery after major abdominal surgery. AB - BACKGROUND: Early mobilization after major abdominal surgery decreases postoperative complications and length of stay, and has become a key component of enhanced recovery pathways. However, objective measures of patient movement after surgery are limited. Real-time location systems (RTLS), typically used for asset tracking, provide a novel approach to monitoring in-hospital patient activity. The current study investigates the feasibility of using RTLS to objectively track postoperative patient mobilization. METHODS: The real-time location system employs a meshed network of infrared and RFID sensors and detectors that sample device locations every 3 s resulting in over 1 million data points per day. RTLS tracking was evaluated systematically in three phases: (1) sensitivity and specificity of the tracking device using simulated patient scenarios, (2) retrospective passive movement analysis of patient-linked equipment, and (3) prospective observational analysis of a patient-attached tracking device. RESULTS: RTLS tracking detected a simulated movement out of a room with sensitivity of 91% and specificity 100%. Specificity decreased to 75% if time out of room was less than 3 min. All RTLS-tagged patient-linked equipment was identified for 18 patients, but measurable patient movement associated with equipment was detected for only 2 patients (11%) with 1-8 out-of-room walks per day. Ten patients were prospectively monitored using RTLS badges following major abdominal surgery. Patient movement was recorded using patient diaries, direct observation, and an accelerometer. Sensitivity and specificity of RTLS patient tracking were both 100% in detecting out-of-room ambulation and correlated well with direct observation and patient-reported ambulation. CONCLUSION: Real-time location systems are a novel technology capable of objectively and accurately monitoring patient movement and provide an innovative approach to promoting early mobilization after surgery. PMID- 28593406 TI - Laparoscopic liver surgery: towards a day-case management. AB - BACKGROUND: Ambulatory surgery (AS) is a contemporary subject of interest. The feasibility and safety of AS for solid abdominal organs are still dubious. In the present study, we aimed at defining potential surgical criteria for AS by analyzing a large database of patients who underwent laparoscopic liver surgery (LLS) in two French expert centers. METHODS: This study was performed using prospectively filled databases including patients that underwent pure LLS between 1998 and 2015. Patients whose perioperative medical characteristics (ASA score <3, no associated extra-hepatic procedure, surgical duration <=180 min, blood loss <=300 mL, no intraoperative anesthesiological or surgical complication, no postoperative drainage) were potentially adapted for ambulatory LLS were included in the analysis. In order to determine the risk factors for postoperative complications, multivariate analysis was carried out. RESULTS: During the study period, pure LLS was performed in 994 patients. After preoperative and intraoperative characteristics screening, 174 (17.5%) patients were considered for the final analysis. Lesions (benign (46%) and liver metastases (43%)) were predominantly single with a mean size of 37 +/- 32 mm in an underlying normal or steatotic liver parenchyma (94.8%). The vast majority of LLS performed were single procedures including wedge resections and liver cyst unroofing or left lateral sectionectomies (74%). The global morbidity rate was 14% and six patients presented a major complication (Dindo-Clavien >=III). The mean length of stay was 5 +/- 4 days. Multivariate analysis showed that major hepatectomy [OR 29.04 (2.26 37.19); P = 0.01] and resection of tumors localized in central segments [OR 41.24 (1.08-156.47); P = 0.04] were independent predictors of postoperative morbidity. CONCLUSIONS: In experienced teams, approximately 7% of highly selected patients requiring laparoscopic hepatic surgery (wedge resection, liver cyst unroofing, or left lateral sectionectomy) could benefit from ambulatory surgery management. PMID- 28593408 TI - A novel model for prediction of pure laparoscopic liver resection surgical difficulty. AB - BACKGROUND: Extending the clinical indications for laparoscopic liver resection (LLR) should be carefully considered based on a surgeon's experience and skill. However, objective indexes to help surgeons assess the estimated difficulty of LLR are scarce. The aim of our study was to develop the first objective numerical rating scale to predict the surgical difficulty of various LLR procedures. METHODS: We performed a retrospective review of the operative outcomes of 187 patients who underwent a pure LLR. First, the value of preoperative factors for predicting surgical time was evaluated by multivariate linear regression analyses, and a scoring system was constructed. Next, the integrity of our predictive linear model was evaluated against the documented operative outcomes for patients forming our study group. RESULTS: Four predictive factors were identified and scored based on the weighted contribution of each factor predicting surgical time: extent of resection (scored 0, 2, or 3); location of tumor (scored 0, 1, or 2); obesity (scored 0 or 1); and platelet count (scored 0 or 1). The scores were summed to classify surgical difficulty into three levels: low (total score <=1); medium (total score 2-3); and high (total score >=4). Operative outcomes, including surgical time, volume of blood loss, length of hospital stay, and rate of morbidity, were significantly different between the three surgical difficulty levels. CONCLUSION: Our novel model will be useful for surgeons to predict the difficulty of an LLR procedure relative to their own experience and skill. PMID- 28593409 TI - Validation of newly developed physical laparoscopy simulator in transabdominal preperitoneal (TAPP) inguinal hernia repair. AB - BACKGROUND: A realistic simulator for transabdominal preperitoneal (TAPP) inguinal hernia repair would enhance surgeons' training experience before they enter the operating theater. The purpose of this study was to create a novel physical simulator for TAPP inguinal hernia repair and obtain surgeons' opinions regarding its efficacy. METHODS: Our novel TAPP inguinal hernia repair simulator consists of a physical laparoscopy simulator and a handmade organ replica model. The physical laparoscopy simulator was created by three-dimensional (3D) printing technology, and it represents the trunk of the human body and the bendability of the abdominal wall under pneumoperitoneal pressure. The organ replica model was manually created by assembling materials. The TAPP inguinal hernia repair simulator allows for the performance of all procedures required in TAPP inguinal hernia repair. Fifteen general surgeons performed TAPP inguinal hernia repair using our simulator. Their opinions were scored on a 5-point Likert scale. RESULTS: All participants strongly agreed that the 3D-printed physical simulator and organ replica model were highly useful for TAPP inguinal hernia repair training (median, 5 points) and TAPP inguinal hernia repair education (median, 5 points). They felt that the simulator would be effective for TAPP inguinal hernia repair training before entering the operating theater. All surgeons considered that this simulator should be introduced in the residency curriculum. CONCLUSIONS: We successfully created a physical simulator for TAPP inguinal hernia repair training using 3D printing technology and a handmade organ replica model created with inexpensive, readily accessible materials. Preoperative TAPP inguinal hernia repair training using this simulator and organ replica model may be of benefit in the training of all surgeons. All general surgeons involved in the present study felt that this simulator and organ replica model should be used in their residency curriculum. PMID- 28593410 TI - Xanthogranulomatous cholecystitis: Is an initial laparoscopic approach feasible? AB - BACKGROUND: Xanthogranulomatous cholecystitis is an inflammatory disease with pathologically distinct characteristics such as accumulation of lipid-laden macrophages, fibrous tissue, and acute and chronic inflammatory cells. It often involves adjacent organs and mimics gallbladder cancer. The purpose of this study was to review the clinical findings of xanthogranulomatous cholecystitis and to determine the appropriate treatment plan. METHODS: We retrospectively analyzed clinical demographics, operation records, and postoperative results of 31 patients with a pathological diagnosis of xanthogranulomatous cholecystitis who underwent surgery between January 2010 and 2015 at two university hospitals. RESULTS: Xanthogranulomatous cholecystitis was found in 0.81% (31/3820) of cholecystectomy patients in our hospital over 5 years. The most frequently observed clinical symptom was abdominal pain (21 patients, 67.7%). Preoperative radiological studies showed cholelithiasis in 23 patients (74.2%), thickening of the gallbladder wall in 23 patients (74.2%), and suspicious cancer in 2 patients (6.5%), but there were no cases of gallbladder cancer accompanying xanthogranulomatous cholecystitis. Laparoscopic cholecystectomy was planned in all patients and was converted to open cholecystectomy in five patients. T-tube choledocholithotomy was needed in one patient due to common bile duct injury. Mean operation time was 149.2 min, and estimated blood loss was 270.1 mL. There were two patients with complications greater than Clavien-Dindo Classification grade III (CBD injury, pleural effusion). CONCLUSION: An initial laparoscopic approach is possible for xanthogranulomatous cholecystitis. However, it is troublesome and challenging, with significantly higher conversion and complication rates compared to standard laparoscopic cholecystectomy. PMID- 28593411 TI - C-reactive protein, fibrinogen, and procalcitonin levels as early markers of staple line leak after laparoscopic sleeve gastrectomy in morbidly obese patients within an Enhanced Recovery After Surgery (ERAS) program. AB - INTRODUCTION: The performance of most bariatric procedures within an Enhanced Recovery After Surgery program has resulted in significant advantages, including a reduction in the length of hospital stay to 2-3 days. However, some postoperative complications may appear after the patient has been discharged. The aim of this study was to investigate the efficacy of various acute-phase parameters determined 24 h after a laparoscopic sleeve gastrectomy for predicting staple line leak in the postoperative course. PATIENTS AND METHODS: A prospective study of 208 morbidly obese patients undergoing laparoscopic sleeve gastrectomy as bariatric procedure between 2012 and 2015 was performed. Blood analysis was performed 24 h after surgery. Acute-phase parameters (C-reactive protein, procalcitonin, fibrinogen, and White Blood Cell count) were investigated. RESULTS: Staple line leak appeared in eight patients (3.8%). Using receiver operating characteristic analysis at 24 h postoperatively, a cutoff level of CRP at 9 mg/dL achieved 85% sensitivity and 90% specificity for predicting staple line leak, a cutoff level of procalcitonin at 0.85 ng/mL achieved 70% sensitivity and 90% specificity, and a cutoff level of fibrinogen at 600 mg/dL achieved 80% sensitivity and 87.5% specificity. CONCLUSION: An elevation of CRP > 9 mg/dL, procalcitonin > 0.85 ng/mL and fibrinogen > 600 mg/dL should alert the surgeon the possibility of occurrence of postoperative staple line leak. PMID- 28593412 TI - Does laparoscopic adhesiolysis decrease the risk of recurrent symptoms in small bowel obstruction? A propensity score-matched analysis. AB - BACKGROUND: The outcomes of laparoscopic adhesiolysis for small bowel obstruction have generally been satisfactory over the short term. However, the long-term outcomes, including recurrence of symptoms and management of recurrence, remain controversial. This study compares the long-term outcomes of a series of laparoscopic and open surgery procedures for the treatment of small bowel obstruction. METHODS: Patients who underwent adhesiolysis for small bowel obstruction at our institution between 2008 and 2015 were retrospectively reviewed. In total, 156 patients were enrolled, 78 with laparoscopic and 78 with open surgery. Propensity score matching was used to minimize the bias in patient selection. Long-term outcomes included incidence of recurrent symptoms and reoperation. In addition to the comparison of outcomes, risk factor assessment for recurrent symptoms and analysis of detailed information in patients with reoperation were performed. Statistical methods included chi 2 test, Mann-Whitney U test, Cox proportional hazards model, and Kaplan-Meier plots with log-rank comparison. RESULTS: Laparoscopy was performed in a younger population with milder bowel dilation and less complicated etiologies. These factors were used to construct the propensity score model, which yielded a matched cohort of 52 legs in each group. Laparoscopy achieved good short-term outcomes including early recovery of gastrointestinal function, reduced incidence of complications, and shorter hospital stay. For long-term outcomes, while the overall recurrence rate did not differ between the groups (11.5 vs 7.7%), the incidence of reoperation for recurrence was significantly higher in the laparoscopically treated group (7.7 vs 0%, p = .017). The Cox proportional hazards model showed that multiple prior surgeries (>=3 times) were a risk factor for overall recurrence (hazard ratio 7.39, p = .041). CONCLUSION: Laparoscopic adhesiolysis did not decrease the incidence of recurrent symptoms; rather, it was related to higher incidence of recurrent small bowel obstruction requiring surgical treatment. PMID- 28593413 TI - Effect of ulinastatin on postoperative renal function in patients undergoing robot-assisted laparoscopic partial nephrectomy: a randomized trial. AB - BACKGROUND: Robot-assisted laparoscopic partial nephrectomy (RLPN) is an emerging technique for treating small renal masses. Although RLPN has many advantages, ischemic kidney injury is inevitable during renal artery clamping. The overall incidence of acute kidney injury (AKI) after partial nephrectomy has been reported to be up to 39%. Moreover, effective pharmacological protection against AKI after partial nephrectomy has not yet been demonstrated. Ulinastatin has been shown to protect the kidney from ischemia/reperfusion injury via its anti inflammatory and anti-oxidant activities. Therefore, this study aimed to evaluate the effect of ulinastatin on postoperative kidney function in patients undergoing RLPN. METHODS: In this randomized, double-blinded, placebo-controlled study, patients undergoing RLPN received either intravenous ulinastatin (100,000 units/10 kg; ulinastatin group, n = 35) or the same volume of normal saline (control group, n = 35) for 1 h starting 10 min before renal artery clamping. The primary outcome was incidence of postoperative AKI. Secondary outcomes were levels of serum creatinine, estimated glomerular filtration rate (eGFR), cystatin C, and inflammatory markers and were measured before operation and at 1, 24, 48, and 72 h postoperatively. RESULTS: The incidence of postoperative AKI was 18% in the ulinastatin group, whereas it was 30% in the control group (p = 0.251). No significant differences in postoperative changes of serum creatinine, eGFR, or cystatin C were observed between the two groups. Postoperative inflammatory markers including C-reactive protein, white blood cell count, and neutrophil percentage were significantly increased until 72 h after operation compared to the preoperative values in both groups, with no significant differences between the groups. CONCLUSIONS: Administration of ulinastatin (100,000 units/10 kg) during the warm ischemia and reperfusion periods did not show any beneficial effects on postoperative kidney function or inflammatory responses in patients undergoing RLPN. PMID- 28593414 TI - Safety and effectiveness of day-surgery laparoscopic cholecystectomy is still uncertain: meta-analysis of eight randomized controlled trials based on GRADE approach. AB - BACKGROUND: Currently, there is no consensus on whether laparoscopic cholecystectomy (LC) performed as day-surgery is safe and effective and can be considered as the standard for the management of symptomatic gallbladder disease. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the safety and effectiveness of this intervention based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. METHODS: We conducted a systematic search of several databases from their inception to November 10, 2016 for entries on the mortality, morbidity after discharge, readmission, postoperative morbidity, and patient satisfaction at 1 week of day surgery LC. Pooled risk ratio (RR) with 95% confidence intervals (CI) was calculated using the fixed-effects model. Rare outcomes were presented as the Peto odds ratio (Peto OR). Meta-analysis was performed by using the RevMan 5.1 software, and the level of evidence was assessed by using the GRADE guideline and GRADEpro GDT software. RESULTS: Eight RCTs totaling 624 participants were included. The result showed no intergroup difference in short-term mortality. Compared to overnight-stay surgery, day-surgery did not show any clear evidence of reduced morbidity after discharge (Peto OR 0.89; 95% CI 0.39-2.02), lower readmission rate (Peto OR 0.68; 95% CI 0.23-2.05), or higher postoperative morbidity rates (RR 1.28; 95% CI 0.81-2.02). However, the results suggested that day-surgery may improve patient satisfaction at 1 week (RR 1.17; 95% CI 1.03 1.33). Evaluation by the GRADE approach revealed that the quality of evidence for each outcome was of low to very low quality due to the risk of bias, imprecision, and inconsistency. CONCLUSION: Our meta-analysis shows that the safety and effectiveness of day-surgery LC is still uncertain. Additional well-designed and adequately powered RCTs are required before the procedure can be recommended as the standard for clinical practice. PMID- 28593415 TI - The effects of laparoscopic graspers with enhanced haptic feedback on applied forces: a randomized comparison with conventional graspers. AB - BACKGROUND: Haptic feedback, which enables surgeons to perceive information on interaction forces between instrument and tissue, is deficient in laparoscopic surgery. This information, however, is essential for accurate tissue manipulation and recognition of tissue consistencies. To this end, a laparoscopic grasper with enhanced haptic feedback has been developed: the force reflecting operation instrument (FROI). This study tested the effects of enhanced haptic feedback on force control, tissue consistency interpretation, and the associated surgeons' level of confidence through a randomized controlled crossover experiment. METHODS: A randomized three-period crossover trial was conducted, in which seven surgical residents and 13 medical students participated. The setup involved a box trainer in which slices of porcine organs (lung, small intestine, or liver) were presented. Participants performed three series of blinded palpation tasks involving three different graspers: the conventional grasper, the FROI with enhanced haptic feedback activated, and the FROI with enhanced haptic feedback deactivated. In each series, nine pairs of organ tissues were palpated to compare consistencies. The orders of presenting both instruments and tissues were randomized. RESULTS: The force applied during tissue palpation significantly decreased, by a mean factor of 3.1 with enhanced haptic feedback. Tissue consistency interpretation was significantly improved with more correct assessments and participants answered with significantly more confidence when enhanced haptic feedback was available. CONCLUSION: The availability of enhanced haptic feedback enabled participants to operate with significantly reduced interaction force between instrument and tissues. This observation is expected to have multiple important clinical implications, such as less tissue damage, fewer complications, shorter operation times, and improved ergonomics. PMID- 28593416 TI - Laparoscopic left liver resections: how far can we go? AB - INTRODUCTION: The aim of this study was to analyse the outcomes of laparoscopic anatomic hepatectomies of the left liver segments. METHODS: This is a retrospective multicentre study including all patients operated on laparoscopically divided into unisegmentectomy of 2, 3 or 4 (Group 1), left lobectomy (or left lateral sectionectomy LLS) (Group 2), left hepatectomy (Group 3) and extended left hepatectomy (Group 4) between 2000 and 2016. These four groups were compared in terms of demographics, intraoperative data and postoperative outcomes. RESULTS: Among the 190 selected patients, the groups 1, 2, 3, 4 included 25 (13.2%), 116 (61.0%), 27 (14.2%) and 22 (11.6%) patients, respectively. The cohorts were comparable except for the number of lesions (p = 0.001) and tumour diameter (p = 0.004). The operative time, blood loss and the use of vascular clamping were more frequent in the Groups 3 and 4 (p = 0.0001), as is the rate of conversion to laparotomy (p = 0.001). Total morbidity was 23.3%, and major complications were more frequent in Group 4 (p = 0.0001). The prevalence of hepatic complications (11.6%), intra-abdominal collections (7.4%) and respiratory complications (3.7%) was proportionally correlated to the hepatectomy extension (p = 0.0001). CONCLUSION: All laparoscopic left liver resections seem safe and feasible even though extended hepatectomy is associated with a significant morbidity. PMID- 28593417 TI - Laparoscopic approach for the treatment of chronic groin pain after inguinal hernia repair : Laparoscopic approach for inguinodynia. AB - BACKGROUND: Traditional methods of clinical research may not be adequate to improve the value of care for patients with complex medical problems such as chronic pain after inguinal hernia repair. This problem is very complex with many potential factors contributing to the development of this complication. METHODS: We have implemented a clinical quality improvement (CQI) effort in an attempt to better measure and improve outcomes for patients suffering with chronic groin pain (inguinodynia) after inguinal hernia repair. Between April 2011 and June 2016, there were 93 patients who underwent 94 operations in an attempt to relieve pain (1 patient had two separate unilateral procedures). Patients who had prior laparoscopic inguinal hernia repair (26) had their procedure completed laparoscopically. Patients who had open inguinal hernia repair (68) had a combination of a laparoscopic and open procedure in an attempt to relieve pain. Initiatives to attempt to improve measurement and outcomes during this period included the administration of pre-operative bilateral transversus abdominis plane and intra-operative inguinal nerve blocks using long-acting local anesthetic as a part of a multimodal regimen, the introduction of a low pressure pneumoperitoneum system, and the expansion of a pre-operative questionnaire to assess emotional health pre-operatively. RESULTS: The results included the assessment of how much improvement was achieved after recovery from the operation. Forty-five patients (48%) reported significant improvement, 39 patients (41%) reported moderate improvement, and 10 patients (11%) reported little or no improvement. There were 3 (3%) complications, 13 (11%) hernia recurrences, and 15 patients (13%) developed a new pain in the inguinal region after the initial pain had resolved. CONCLUSIONS: The principles of CQI can be applied to a group of patients suffering from chronic pain after inguinal hernia repair. Based on these results additional process improvement ideas will be implemented in an attempt to improve outcomes. PMID- 28593419 TI - Multiple detection of zoonotic variegated squirrel bornavirus 1 RNA in different squirrel species suggests a possible unknown origin for the virus. AB - The recently discovered variegated squirrel bornavirus 1 (VSBV-1) caused the death of three squirrel breeders in Germany. Subsequent first screening of squirrels with in vivo collected swab samples and a VSBV-1-specific RT-qPCR revealed not only variegated squirrel infections (Sciurus variegatoides), but also Prevost's squirrels (Callosciurus prevostii) as positive for VSBV-1 genome. In this study, 328 squirrels were tested using the established RT-qPCR assays. In 16 individual animals VSBV-1 RNA could be detected; 15 individuals were from small breedings and zoological gardens in Germany, with the remaining individual being from a zoological garden in Croatia. Positive animals belonged to the species C. prevostii, C. finlaysonii, and Tamiops swinhoei within the subfamily Callosciurinae and Sciurus granatensis within the subfamily Sciurinae. Repeated non-invasive oral swab sampling in one holding indicated positive animals months after a first negative result. Besides the oral swabs, VSBV-1 was also detected in fecal (pool) samples allowing the future monitoring of squirrel holdings based on RT-qPCR investigation of such samples. The detection in zoological gardens emphasizes the need for further investigations into the transmission route to humans in order to develop rational public health measures for prevention of transmission. Finally, the detection of several closely related VSBV-1 sequences in squirrels from different subfamilies raises questions as to the origin of the virus. PMID- 28593418 TI - A novel training device for tip control in colonoscopy: preliminary validation and efficacy as a training tool. AB - BACKGROUND: Effective control of the colonoscope tip is one of the most fundamental components of colonoscopy skill. Mastering fine tip control can be problematic for novice trainees, yet no validated training regimes exist for developing this specific skill component in isolation. We aimed to conduct a preliminary validation of a novel training device for colonoscopic tip control, and to assess its efficacy as a training tool. METHODS: In study 1 (validation), 13 experienced colonoscopists and 16 novices used a colonoscope to accurately track 28 targets on each of four concave "training surfaces" as quickly as possible, and we compared their performance. In study 2 (pre-post-training study), another 16 novices were tested before and after a six-session training program. In both studies, the main outcome measurements were completion time (measured automatically by the device) and variability of individual performance (the SD of each individual's completion times across trials). RESULTS: Compared with novices, experienced colonoscopists were faster (P < 0.0001) and their performances less variable (P < 0.0001). With training, novices became faster (P < 0.0001) and more consistent (P = 0.003), and these improvements also generalized to novel training surfaces (P's < 0.01). After training, the novices' tip control performance was indistinguishable from that of the experienced colonoscopists (P's > 0.05). The composite measures of completion time used in both studies all had acceptable to excellent internal consistency reliability (alpha's ranged from 0.72 to 0.93). CONCLUSIONS: We found that performance measures derived from using the device to assess skill can discriminate between experienced colonoscopists and novices in terms of their ability to control and guide the colonoscope tip precisely, providing preliminary evidence to support the construct validity of the metrics. The device is also an effective training tool for this fundamental component of colonoscopy skill. PMID- 28593421 TI - Interventional treatment of the aortic valve : Current evidence. AB - Transcatheter aortic valve replacement (TAVR) has become a standard treatment for patients with severe, symptomatic aortic stenosis. Whereas its use was first limited to inoperable high-risk patients, recent studies demonstrated that TAVR was not inferior to standard surgical aortic valve replacement (SAVR) for intermediate-risk patients. Besides equivalent outcomes, the type and rates of complications differ between the two procedures. Here, we provide an overview of the latest randomized study results comparing TAVR with SAVR and describe possible future directions in transcatheter aortic valve treatment. PMID- 28593420 TI - Does the histologic predominance of pathological stage IA lung adenocarcinoma influence the extent of resection? AB - OBJECTIVES: We studied whether histologic subtype according to the new IASLC/ATS/ERS adenocarcinoma classification influences the extent of resection in patients with pathological stage IA lung adenocarcinoma. METHODS: Data on 288 patients with pathological stage IA lung adenocarcinoma were analyzed retrospectively. Recurrence-free survival (RFS) rates were compared according to clinicopathological characteristics, including predominant histologic subtype and extent of resection. RESULTS: Median follow-up was 38.9 months. Lobectomy was performed in 146 patients, and sublobar resection in 142 patients. When recurrence was compared among the low-grade group (adenocarcinoma in situ, AIS; minimally invasive adenocarcinoma, MIA), intermediate-grade group (lepidic, acinar, and papillary) and high-grade group (solid and micropapillary), the RFS rate decreased as the grade increased (p = 0.037). There was no recurrence in the low-grade or lepidic predominant groups. The recurrence pattern did not differ according to the type of resection or histological subtype. Even in the intermediate- and high-grade groups, the extent of resection was not significantly related to the RFS rate (p = 0.622, p = 0.516). The results were unchanged after adjusting for independent risk factors. The concordance rate between clinical and pathological stage IA was good in low (98.6%) and intermediate grade (84.6%) and poor in high grade (41.2%). CONCLUSIONS: AIS, MIA, and lepidic predominant may be curable by any type of complete resection. Even in invasive subtypes, lobectomy does not offer a recurrence-free advantage over sublobar resection. However, in the high-grade group, less than half of clinical stage IA was actually pathological stage IA. Physicians should exercise caution whenever sublobar resection is planned. PMID- 28593422 TI - Treatment of asymptomatic aortic valve stenosis : Watchful waiting or early intervention? AB - There is ongoing debate about the optimal management of severe asymptomatic aortic stenosis (AS). Thus far, current guidelines recommend a watchful waiting strategy for the majority of asymptomatic patients. However, data on the prognosis of asymptomatic AS are inconsistent. Some reports claim an increased risk of complications and even mortality in this subset of patients when treated conservatively. Several factors are considered to contribute to the impaired outcome of asymptomatic patients, such as progressive myocardial damage or sudden cardiac death, during the watchful waiting period. Indeed, a few nonrandomized studies are available in the literature showing improved survival with early aortic valve replacement during the asymptomatic phase compared with watchful waiting. However, these studies have several limitations particularly with regard to methodology, and thus making a clear recommendation on treatment options impossible. Therefore, randomized controlled trials are urgently needed in order to treat these patients on the basis of adequate evidence. PMID- 28593424 TI - Hepatopancreatic cells of a stone crab Menippe frontalis from Peru: separation, viability study, and evaluation of lipoperoxidation against cadmium contamination. AB - Crustaceans are frequently used as bioindicators, and changes in their metabolism at the hepatopancreas (HP) level are often followed in these studies. The HP is the site of digestion, absorption, nutrient storage, and toxic metal detoxification, enabling crabs to survive in metal contaminated regions. Cellular damage and high lipid peroxidation (LPO) levels have been found in crab populations under high cadmium (Cd) concentrations. The aim of this work was to separate and characterize the HP cells of the stone crab Menippe frontalis from the Pacific Ocean, Peru (5 degrees 5' 21" S-81 degrees 6' 51" W) and to measure the cellular viability and LPO after exposure to the non-essential metal Cd. The HP cells were dissociated by magnetic stirring, with posterior separation by sucrose gradient at concentrations of 10, 20, 30, and 40%. We found the same cell types that were described for other species (e.g., Ucides cordatus, Atlantic Ocean, Brazil). High cellular viability against 1 mmol L-1 of Cd was observed for resorptive (R) cells in 20% sucrose layer (88 +/- 8%, *P < 0.05, ANOVA), and blister (B) cells in the 40% sucrose layers (92 +/- 7%, *P < 0.05, ANOVA). Cd (1 mmol L-1) caused an increase in LPO levels, suggesting that crabs from polluted areas can be affected by toxic metals, generating a physiological stress. The gradient sucrose methodology can be used for different species and results in a similar separation, viability, and cellular identification. The results are a starting point for toxic metal studies for species distributed across different geographic coordinates. PMID- 28593423 TI - [Telemonitoring in heart failure : Update on health-related and economic implications]. AB - BACKGROUND: Heart failure is one of the most common and cost-intensive chronic diseases worldwide. Telemonitoring offers the potential to improve care of heart failure treatment and reduce cost. Empirical findings of its efficacy are inconsistent up to now. This systematic review examines the current state of research regarding health-related and economic endpoints. METHODS: A systematic review was conducted in July 2016 using the PubMed database and randomised controlled trials for the years 2011-2016. Only clinical research trials with heart failure patients were considered where the intervention was performed using external monitoring devices which transmitted data via information and communication technology. In all, 10 clinical trials were included. RESULTS: There is no definite evidence regarding improvement in care based solely on the most recent literature. Hospitalisation for heart failure and health-related quality of life were most positively influenced. There was no correlation between mortality and hospitalisations for all causes regarding telemonitoring. The overall costs tended to be higher for telemonitoring. CONCLUSION: Further research is needed to examine the health-related and economic benefits of telemonitoring for heart failure. A particular challenge is the evidence of cause effect relationships within complex technology-supported health-care settings. The latest studies support the previous state of research. PMID- 28593425 TI - Challenges with cataract surgery in pars planitis patients. PMID- 28593426 TI - [Spondyloarthritides]. AB - Spondyloarthritides (SpA) are inflammatory rheumatic diseases affecting the axial skeleton, peripheral joints and entheses, and also manifest at extraskeletal sites. According to the more recently introduced nomenclature, predominant axial SpA is distinguished from predominant peripheral SpA. Axial SpA is further divided into radiographic and nonradiographic axial SpA. Genetic factors are relevant, with HLA-B27 being most important. The interleukin 23/17 pathway seems to be relevant and points towards new therapeutic targets. Inflammatory back pain is the leading symptom in axial SpA and has certain characteristics. In addition, HLA-B27 and sacroiliitis on imaging are important for diagnosis. Therapy consists of physiotherapy, nonsteroidal anti-inflammatory drugs (first line) and biologicals (second line). Conventional disease-modifying antirheumatic drugs are effective only in peripheral arthritis. PMID- 28593429 TI - Ultrasound imaging of the thenar motor branch of the median nerve: a cadaveric study. AB - INTRODUCTION: Anatomic variations of the median nerve (MN) increase the risk of iatrogenic injury during carpal tunnel release surgery. We investigated whether high-frequency ultrasonography could identify anatomic variations of the MN and its thenar motor branch (MBMN) in the carpal tunnel. METHODS: For each volar wrist of healthy non-embalmed cadavers, the type of MN variant (Lanz classification), course and orientation of the MBMN, and presence of hypertrophic muscles were scored by 18-MHz ultrasound and then by dissection. RESULT: MBMN was identified by ultrasound in all 30 wrists (15 subjects). By dissection, type 1, 2 and 3 variants were found in 84%, 3%, and 13% of wrists, respectively. Ultrasound had good agreement with dissection in identifying the variant type (kappa =0.9). With both techniques, extra-, sub-, and transligamentous courses were recorded in 65%, 31%, and 4% of cases, respectively. With both techniques, the bifid nerve, hypertrophic muscles, and bilateral symmetry for variant type were identified in 13.3%, 13.3%, and 86.7% of wrists, respectively. Agreement between ultrasound and dissection was excellent for the MBMN course and orientation (kappa =1). CONCLUSION: Ultrasound can be used reliably to identify anatomic variations of the MN and MBMN. It could be a useful tool before carpal tunnel release surgery. KEY POINTS: * Ultrasound can identify variations of the motor branch of the median nerve. * Ultrasound mapping should be used prior to carpal tunnel release surgery. * All sub-, extra-, and transligamentous courses were accurately identified. * Type 3 variants (bifid nerve), hypertrophic muscles, and bilateral symmetry were accurately identified. PMID- 28593427 TI - Drinking and exercise behaviors among college students: between and within-person associations. AB - Prior work has suggested a paradoxical positive relationship between the risk behavior alcohol use and the health behavior exercise, particularly in young adults. Though seldom tested, different theoretical perspectives exist on the mechanisms that may explain the positive relationship. The aims of this study were to test theorized mechanisms of association, including common causes shared by both behaviors (e.g., personality, motives, affective), compensatory processes such as exercising to compensate for calories from alcohol consumption, and methodological confounds (e.g., between vs. within subject effects) in a college sample (N = 132; 56.3% male; 76% Caucasian; M age = 19.15, SD = 0.99) using a cross-sectional design and time line follow back methods. A positive, between subjects association between alcohol and exercise was found and explained by exercising to compensate for calories of alcohol consumption, enhancement motives, and physical activity enjoyment. However, we also observed a significant and negative within-subjects association between the two constructs, suggesting that, on a given day, individuals who exercise more tended to drink less. Furthermore, individuals who exercised more during the week tended to have declines in weekend drinking over time. Results suggest a complex relationship between exercise and alcohol use among young adults, and highlight the importance of distinguishing between and within subject processes, as well as the temporal ordering of the two behaviors. Implications are discussed in regard to theory, prevention, and intervention. PMID- 28593428 TI - Size matters: The width and location of a ureteral stone accurately predict the chance of spontaneous passage. AB - OBJECTIVES: To determine how to most accurately predict the chance of spontaneous passage of a ureteral stone using information in the diagnostic non-enhanced computed tomography (NECT) and to create predictive models with smaller stone size intervals than previously possible. METHODS: Retrospectively 392 consecutive patients with ureteric stone on NECT were included. Three radiologists independently measured the stone size. Stone location, side, hydronephrosis, CRP, medical expulsion therapy (MET) and all follow-up radiology until stone expulsion or 26 weeks were recorded. Logistic regressions were performed with spontaneous stone passage in 4 weeks and 20 weeks as the dependent variable. RESULTS: The spontaneous passage rate in 20 weeks was 312 out of 392 stones, 98% in 0-2 mm, 98% in 3 mm, 81% in 4 mm, 65% in 5 mm, 33% in 6 mm and 9% in >=6.5 mm wide stones. The stone size and location predicted spontaneous ureteric stone passage. The side and the grade of hydronephrosis only predicted stone passage in specific subgroups. CONCLUSION: Spontaneous passage of a ureteral stone can be predicted with high accuracy with the information available in the NECT. We present a prediction method based on stone size and location. KEY POINTS: * Non-enhanced computed tomography can predict the outcome of ureteral stones. * Stone size and location are the most important predictors of spontaneous passage. * Prediction models based on stone width or length and stone location are introduced. * The observed passage rates for stone size in mm-intervals are reported. * Clinicians can make better decisions about treatment. PMID- 28593430 TI - The prevalence and significance of renal perfusion defects in early kidney transplants quantified using 3D contrast enhanced ultrasound (CEUS). AB - OBJECTIVES: Vascular complications are one of the most common causes of early kidney transplant dysfunction. Contrast enhanced ultrasound increases sensitivity to vascular changes. The aim of this study was to assess the prevalence and size of vascular abnormalities in early renal transplants using 3D CEUS and the significance of perfusion defects on renal function. METHODS: Ninety-nine renal transplant patients underwent 3D CEUS after surgery to quantify perfusion defects as percentage total renal volume (TRV). Serum creatinine and estimated glomerular filtration rate (eGFR) were recorded up to 3 months post-surgery. RESULTS: Twenty participants had focal perfusion defects (0.2-43%TRV). There was a meaningful difference in patients with perfusion defects in eGFR at 1 month (90% CI 2.7-19.2 mL/min/1.73 m2) and 3 months (90% CI 1.9-19.6 mL/min/1.73 m2) and creatinine at 3 months (90% CI -56 - -8 MUmol/L) using a predetermined clinical threshold. Perfusion defect size correlated well with both serum creatinine and eGFR at 3 months (R = 0.80, p <= 0.000 and 0.58, p = 0.038). No correlation was seen prior to 3 months. CONCLUSIONS: Perfusion defects in kidney transplants were more common than expected and were highly likely to reduce renal function at 1-3 months, and the size of the defect affected the degree of functional change at 3 months. KEY POINTS: * Perfusion defects were more common than previously thought. * Perfusion defects could be quantified using 3D CEUS. * The presence of even small perfusion defects may affect kidney function. * Size of perfusion defects correlated with subsequent kidney function at 3 months. * Potentially useful in informing clinician expectations of kidney function post-surgery. PMID- 28593431 TI - Prognostic implication of the metastatic lesion-to-ovarian cancer standardised uptake value ratio in advanced serous epithelial ovarian cancer. AB - OBJECTIVES: To evaluate the prognostic value of metabolic activity of metastatic lesions measured by 18F-flurodeoxyglucose (18F-FDG) uptake on preoperative positron emission tomography/computed tomography (PET/CT) in patients with advanced serous epithelial ovarian cancer (EOC). METHODS: Clinico-pathological variables and PET/CT parameters such as the maximum standardised uptake value of the ovarian cancer (SUVovary), metastatic lesions (SUVmeta), and the metastatic lesion-to-ovarian cancer standardised uptake value ratio (SUVmeta/SUVovary) were assessed in International Federation of Gynaecology and Obstetrics (FIGO) stage III, IV patients. RESULTS: Clinico-pathological data were retrospectively reviewed for 94 eligible patients. The median progression-free survival (PFS) was 18.5 months (range, 6-90 months), and 57 (60.6%) patients experienced recurrence. Older age [P = 0.017, hazard ratio (HR) 1.036, 95% CI 1.006-1.066], residual disease after surgery (P = 0.024, HR 1.907, 95% CI 1.087-3.346), and high SUVmeta/SUVovary (P = 0.019, HR 2.321, 95% CI 1.148-4.692) were independent risk factors of recurrence. Patients with high SUVmeta/SUVovary showed a significantly worse PFS than those with low SUVmeta/SUVovary (P = 0.007, log-rank test). CONCLUSIONS: Preoperative SUVmeta/SUVovary was significantly associated with recurrence and has an incremental prognostic value for PFS in patients with advanced serous EOC. KEY POINTS: * The prognostic value of the metabolic activity of metastatic lesions was investigated. * SUVmeta/SUVovary was significantly associated with recurrence of serous EOC. * Preoperative SUVmeta/SUVovary can be a predicator of serous EOC recurrence. PMID- 28593432 TI - Risk of acute kidney injury after transarterial chemoembolisation in hepatocellular carcinoma patients: A nationwide population-based cohort study. AB - OBJECTIVE: This nationwide population-based cohort study evaluated the association between acute kidney injury (AKI) and transarterial chemoembolisation (TACE) in patients with hepatocellular carcinoma (HCC). METHODS: The case cohort included patients with HCC who had undergone TACE treatment between 1 January 1998 and 31 March 2010. Patients with baseline chronic kidney disease, with baseline end-stage renal disease, and aged younger than 20 years were excluded. HCC patients with TACE and HCC patients without TACE were matched 1:1 in terms of propensity scores. RESULTS: A total of 1132 HCC patients with TACE and 1132 HCC patients without TACE (controls) were enrolled, of which 72 and 66 patients developed AKI, respectively. After adjustment for age, sex, comorbidity, and other medications, the risk of AKI was higher in HCC patients with TACE [hazard ratio (HR) = 1.66, 95% CI = 1.17-2.34]. The HRs of post-TACE AKI were 1.56 (95% CI = 1.02-2.37) and 1.74 (95% CI = 1.23-2.48) for patients having at least one comorbidity and less frequent sessions of TACE (<=3 times), respectively. CONCLUSIONS: Our study demonstrates that TACE increases the risk of AKI in patients with HCC without chronic kidney disease or end-stage renal disease. KEY POINTS: * Seventy-two of1132 patients with TACE and 62/1132 patients without TACE developed AKI. * AKI risk was higher in HCC patients with TACE. * HRs were 1.56 and 1.74 for those with comorbidities and less frequent TACE. PMID- 28593433 TI - Additional value of diffusion-weighted imaging to evaluate multifocal and multicentric breast cancer detected using pre-operative breast MRI. AB - OBJECTIVES: To investigate whether diffusion-weighted imaging (DWI) aids pre operative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to evaluate additional lesions in breast cancer patients. METHODS: DCE-MRI and DWI were performed on 131 lesions, with available histopathological results. The apparent diffusion coefficient (ADC) of each lesion was measured, and the cut-off value for differentiation between malignant and benign lesions was calculated. A protocol combining the ADC cut-off value with DCE-MRI was validated in a cohort of 107 lesions in 77 patients. RESULTS: When an ADC cut-off value of 1.11 * 10-3 mm2/s from the development cohort was applied to the additional lesions in the validation cohort, the specificity increased from 18.9% to 67.6% (P < 0.001), and the diagnostic accuracy increased from 61.7% to 82.2% (P = 0.05), without significant loss of sensitivity (98.6% vs. 90.0%, P = 0.07). The negative predictive values of lesions in the same quadrant had decreased, as had those of lesions >=1 cm in diameter. The ADC cut-off value in the validation cohort was 1.05 * 10-3 mm2/s. CONCLUSIONS: Additional implementation of DWI for breast lesions in pre-operative MRI can help to obviate unnecessary biopsies by increasing specificity. However, to avoid missing cancers, clinicians should closely monitor lesions located in the same quadrant or lesions >=1 cm. KEY POINTS: * DWI can be used to further differentiate lesions during pre-operative cancer staging. * ADC cut-off values were similar in the development and validation cohorts. * DWI improves both PPV and NPV in cases of multicentric lesions. * DWI improves both PPV and NPV in lesions <1 in diameter. * NPVs are decreased in multifocal lesions and lesions >=1 cm in diameter. PMID- 28593434 TI - Pam2CSK4 and Pam3CSK4 induce iNOS expression via TBK1 and MyD88 molecules in mouse macrophage cell line RAW264.7. AB - OBJECTIVE: The aim of this study was to investigate the involvement of TLR adaptor molecules, such as TRIF, MyD88, and TBK1 in the induction of iNOS and nitric oxide (NO) production in Pam2CSK4 and Pam3CSK4-treated mouse macrophages. METHOD: Mouse macrophage cell line (RAW264.7) was transfected with trif, myd88, and tbk1 siRNAs before stimulated with Pam2CSK4 and Pam3CSK4. The iNOS gene and protein expression were determined by RT-PCR and immunoblotting, respectively. The NO production was determined by Griess reaction assay. RESULTS: The results showed that the induction of iNOS expression and NO production by Pam2CSK4 and Pam3CSK4 were diminished in tbk1 and myd88-depleted mouse macrophages but not trif-depleted cells. CONCLUSION: These results suggested that the TBK1 and MyD88 molecules were essential for the induction of iNOS expression and NO production by both Pam2CSK4 and Pam3CSK4 via TLR2 signaling. PMID- 28593435 TI - Hypoxanthine Induces Neuroenergetic Impairment and Cell Death in Striatum of Young Adult Wistar Rats. AB - Hypoxanthine is the major purine involved in the salvage pathway of purines in the brain. High levels of hypoxanthine are characteristic of Lesch-Nyhan Disease. Since hypoxanthine is a purine closely related to ATP formation, the aim of this study was to investigate the effect of intrastriatal hypoxanthine administration on neuroenergetic parameters (pyruvate kinase, succinate dehydrogenase, complex II, cytochrome c oxidase, and ATP levels) and mitochondrial function (mitochondrial mass and membrane potential) in striatum of rats. We also evaluated the effect of cell death parameters (necrosis and apoptosis). Wistar rats of 60 days of life underwent stereotactic surgery and were divided into two groups: control (infusion of saline 0.9%) and hypoxanthine (10 MUM). Intrastriatal hypoxanthine administration did not alter pyruvate kinase activity, but increased succinate dehydrogenase and complex II activities and diminished cytochrome c oxidase activity and immunocontent. Hypoxanthine injection decreased the percentage of cells with mitochondrial membrane label and increased mitochondrial membrane potential labeling. There was a decrease in the number of live cells and an increase in the number of apoptotic cells by caused hypoxanthine. Our findings show that intrastriatal hypoxanthine administration altered neuroenergetic parameters, and caused mitochondrial dysfunction and cell death by apoptosis, suggesting that these processes may be associated, at least in part, with neurological symptoms found in patients with Lesch-Nyhan Disease. PMID- 28593436 TI - Long-Term Plasticity in Amygdala Circuits: Implication of CB1-Dependent LTD in Stress. AB - The amygdala mediates many forms of emotional learning, during which the central nucleus of amygdala (CeA) functions as a major output of the amygdala by converging inputs from the basolateral nucleus (BLA) and other amygdalar subregions. However, the contribution of BLA-CeA synaptic transmission and plasticity of this transmission after exposure to emotional stimuli remains to be completely understood. Using paired recording, we simultaneously recorded BLA and CeA neurons, and observed that BLA-CeA transmission was glutamatergic. In this transmission, high-frequency stimulation induced NMDA receptor (NMDAR)-dependent LTP, low-frequency stimulation induced NMDAR-dependent LTD, whereas modest frequency stimulation induced cannabinoid receptor1 (CB1)-dependent LTD. After acute stress, CB1-dependent LTD of this transmission was selectively abolished. This effect of stress was mimicked by intra-CeA administration of CB1-selective agonists and prevented by CB1-selective antagonists. Furthermore, intra-CeA administration of CB1 antagonists prevented stress-induced reduction of explorative behaviors. These results indicate that CB1 signaling-mediated plasticity in local circuits of the amygdala plays a critical role in emotional responses. PMID- 28593437 TI - Incidence and Clinical Outcomes of Inflammatory Bowel Disease in South Korea, 2011-2014: A Nationwide Population-Based Study. AB - BACKGROUND: The incidence of inflammatory bowel disease (IBD) is increasing in East Asia; however, population-based data from this region are lacking. AIM: We conducted a nationwide, population-based study to examine the incidence and disease course of IBD in South Korea. METHODS: Using the National Health Insurance claims data, we collected data on patients diagnosed with IBD [10,049 with ulcerative colitis (UC) and 5595 with Crohn's disease (CD)] from 2011 to 2014. RESULTS: During the study period, the average annual incidence of UC was 5.0 per 105, while that of CD was 2.8 per 105. Among patients with UC, the cumulative rates of surgery 1 and 4 years after diagnosis were 1.0 and 2.0%; those among patients with CD were 9.0 and 13.9%, respectively. The 1- and 4-year cumulative rates of moderate- to high-dose corticosteroid use were, respectively, 26.6 and 45.2% among patients with UC, and 29.9 and 50.8% among those with CD. Similarly, the 1- and 4-year cumulative rates of immunomodulator use were 14.1 and 26.4% among patients with UC, and 58.3 and 76.1% among those with CD, respectively. With regard to biologic use, the 1- and 4-year cumulative rates were 3.0 and 9.0% among patients with UC, and 11.1 and 31.7% among those with CD, respectively. CONCLUSIONS: The recent incidence of IBD in South Korea has been the highest in East Asia. Patients who had been diagnosed recently with IBD showed lower rates of surgery and higher rates of immunomodulator and biologic use compared to those reported ever in South Korea. PMID- 28593438 TI - Eye Movements Are Correctly Timed During Walking Despite Bilateral Vestibular Hypofunction. AB - Individuals with bilateral vestibular hypofunction (BVH) often report symptoms of oscillopsia (the perception that the world is bouncing or unstable) during walking. Efference copy/proprioception contributes to locomotion gaze stability in animals, sometimes inhibiting the vestibulo-ocular reflex (VOR). Gaze stability requires both adequate eye velocity and appropriate timing of eye movements. It is unknown whether eye velocity (VOR gain), timing (phase), or both are impaired for individuals with BVH during walking. Identifying the specific mechanism of impaired gaze stability can better inform rehabilitation options. Gaze stability was measured for eight individuals with severe BVH and eight healthy age- and gender-matched controls while performing a gaze fixation task during treadmill walking. Frequency response functions (FRF) were calculated from pitch eye and head velocity. A one-way ANOVA was conducted to determine group differences for each frequency bin of the FRF. Pearson correlation coefficients were calculated to determine the relationship between the real and imaginary parts of the FRF and the Oscillopsia Visual Analog Scale (oVAS) scores. Individuals with BVH demonstrated significantly lower gains than healthy controls above 0.5 Hz, but their phase was ideally compensatory for frequencies below 3 Hz. Higher oVAS scores were correlated with lower gain. Individuals with BVH demonstrated ideal timing for vertical eye movements while walking despite slower than ideal eye velocity when compared to healthy controls. Rehabilitation interventions focusing on enhancing VOR gain during walking should be developed to take advantage of the intact timing reported here. Specifically, training VOR gain while walking may reduce oscillopsia severity and improve quality of life. PMID- 28593440 TI - Multi-level mental representations of written, auditory, and audiovisual text in children and adults. AB - We examined whether the comprehension of narrative texts differed between auditory, audiovisual, and written text presentations in a sample of 8- and 10 year-olds and adults. Based on multi-level theories of text comprehension that assume text comprehension to involve at least three levels of mental representation, we applied a sentence recognition task that enabled the separate assessment of the memory of the text surface, text base, and the situation model. Results indicate that 8-year-olds benefit from audiovisual and auditory text presentations in comparison with written text presentations in terms of their memory of situation model information. For 10-year-olds and adults, their text comprehension did not differ between audiovisual, auditory, and written text presentations. Additionally, the mode of text presentation had no effect on the memory of text surface and text base information. PMID- 28593439 TI - Clinical and Histopathological Amelioration of Experimental Autoimmune Encephalomyelitis by AAV Vectors Expressing a Soluble Interleukin-23 Receptor. AB - The role of the T helper (Th)17 pathway has been clearly demonstrated in the onset and progression of autoimmune diseases, where interleukin (IL)-23 is a key molecule in maintaining the response mediated by Th17 cells. As a consequence, recent strategies based on blocking the interaction between IL-23 and its receptor (IL-23R), for example the anti-p19 antibody tildrakizumab, have been developed to regulate the Th17 pathway from the initial stages of the disease. Here, a soluble (s)IL-23R cDNA was cloned in expression plasmids and viral vectors. The clinical efficacy of sIL-23R was evaluated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis mice intravenously injected with a single dose of adeno-associated virus AAV8-sIL-23R vectors. Cytokine secretion was determined by multiplex assay, while histopathological analysis of the central nervous system was performed to study demyelination, inflammatory infiltration, and microglia and astroglia activation. We observed that administration of adeno-associated vector 8 encoding sIL-23R was associated with a significant disease improvement, including delay in the onset of the clinical signs; slower progress of the disease; interference with IL-23-mediated signal transducer and activator of transcription response by inhibiting of signal transducer and activator of transcription 3 phosphorylation; reduced demyelination and infiltration in the central nervous system; and lower astrocyte and microglia activation. Our results suggest that the use of vectors carrying sIL-23R to block the IL-23/IL-23R interaction may be a new therapeutic strategy for the treatment of multiple sclerosis. PMID- 28593443 TI - Impact of Diclofenac Sodium on Tilmicosin-Induced Acute Cardiotoxicity in Rats (Tilmicosin and Diclofenac Cardiotoxicity). AB - To assess the influence of diclofenac sodium (DIC) treatment on tilmicosin (TIL) prompted cardiotoxicity, forty albino rats were randomly divided into four equal groups: control, TIL group (single subcutaneous injection of 75 mg/kg BW tilmicosin phosphate 30%), TIL + DIC group (single subcutaneous injection of tilmicosin phosphate 30% and then injection intramuscularly of 13.5 mg/kg BW/day for 6 days diclofenac sodium) and DIC group (intramuscular injection of 13.5 mg/kg BW/day diclofenac sodium for 6 days). Creatine kinase-MB, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, urea and creatinine significantly elevated in all treated groups, but markedly in TIL + DIC group serum. Lipid peroxidation significantly increased, and reduced glutathione significantly decreased in tissues of all groups. Several histopathological alterations were noticed in heart, liver, kidneys and lungs of all treated groups, particularly TIL + DIC group. Ultrastructurally, myocardium of TIL and TIL + DIC groups showed characteristic changes for myocardial apoptosis and degeneration. Significant differences were detected in area percentage of caspase-3 protein expression and bcl-2 immunoreactivity in cardiomyocytes, particularly in TIL + DIC group. This study is the first to indicate that one of the possible mechanisms of TIL cardiotoxicity is myocardial apoptosis. DIC amplifies TIL-induced cardiotoxicity besides its hepato nephrotoxicity. PMID- 28593442 TI - Remodeling of heterochromatin structure slows neuropathological progression and prolongs survival in an animal model of Huntington's disease. AB - Huntington's disease (HD) is an autosomal-dominant inherited neurological disorder caused by expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. Altered histone modifications and epigenetic mechanisms are closely associated with HD suggesting that transcriptional repression may play a pathogenic role. Epigenetic compounds have significant therapeutic effects in cellular and animal models of HD, but they have not been successful in clinical trials. Herein, we report that dSETDB1/ESET, a histone methyltransferase (HMT), is a mediator of mutant HTT-induced degeneration in a fly HD model. We found that nogalamycin, an anthracycline antibiotic and a chromatin remodeling drug, reduces trimethylated histone H3K9 (H3K9me3) levels and pericentromeric heterochromatin condensation by reducing the expression of Setdb1/Eset. H3K9me3-specific ChIP-on-ChIP analysis identified that the H3K9me3-enriched epigenome signatures of multiple neuronal pathways including Egr1, Fos, Ezh1, and Arc are deregulated in HD transgenic (R6/2) mice. Nogalamycin modulated the expression of the H3K9me3-landscaped epigenome in medium spiny neurons and reduced mutant HTT nuclear inclusion formation. Moreover, nogalamycin slowed neuropathological progression, preserved motor function, and extended the life span of R6/2 mice. Together, our results indicate that modulation of SETDB1/ESET and H3K9me3-dependent heterochromatin plasticity is responsible for the neuroprotective effects of nogalamycin in HD and that small compounds targeting dysfunctional histone modification and epigenetic modification by SETDB1/ESET may be a rational therapeutic strategy in HD. PMID- 28593441 TI - Context and craving during stressful events in the daily lives of drug-dependent patients. AB - RATIONALE: Knowing how stress manifests in the lives of people with substance-use disorders could help inform mobile "just in time" treatment. OBJECTIVES: The purpose of this paper is to examine discrete episodes of stress, as distinct from the fluctuations in background stress assessed in most EMA studies. METHODS: For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated an entry whenever they experienced a stressful event (SE) and when randomly prompted (RP) three times daily. Participants reported the severity of stress and craving and the context of the report (location, activities, companions). Decomposition of covariance was used to separate within person from between-person effects; r effect sizes below are within-person. RESULTS: Participants (158 of 182; 87%) made 1787 stress-event entries. Craving for opioids increased with stress severity (r effect = 0.50). Stress events tended to occur in social company (with acquaintances, 0.63, friends, 0.17, or on the phone, 0.41) rather than with family (spouse, -0.14; child, -0.18), and in places with more overall activity (bars, 0.32; outside, 0.28; walking, 0.28) and more likelihood of unexpected experiences (with strangers, 0.17). Being on the internet was slightly protective (-0.22). Our prior finding that being at the workplace protects against background stress in our participants was partly supported in these stressful-event data. CONCLUSIONS: The contexts of specific stressful events differ from those we have seen in prior studies of ongoing background stress. However, both are associated with drug craving. PMID- 28593445 TI - Erratum to: Compartmental tongue resection with submental island flap reconstruction for large carcinoma of the oral tongue. PMID- 28593444 TI - Efficacy of dietary supplementation of fatty acid compound on performance and production in finishing pigs. AB - The present study was conducted to evaluate the efficacy of dietary supplementation of 0.5 and 1% of fatty acid (FA) compound containing conjugated linoleic acid as active component on growth performance, apparent nutrient digestibility, serum lipid profile, meat quality, and fatty acid profiles in muscle and adipose tissue in finishing pigs. A total of 90 finishing pigs ([Yorkshire * Landrace] * Duroc) were used in 5-week trial. The growth performance and nutrient digestibility were unaffected with FA supplementation. The lean percentage was greater (P = 0.05) in pigs fed FA-supplemented diet whereas the 2-thiobarbituric acid reactive substances value was reduced (P < 0.05) during the storage. The FA supplementation tended (P = 0.06) to reduce serum total cholesterol. However, it improved (P < 0.05) C14:0, C16:0, C18:0, saturated fatty acid, conjugated linoleic acid, and omega 3 levels and reduced (P < 0.05) C18:1, C18:2, unsaturated fatty acid, and omega 6 levels in muscle and subcutaneous adipose tissue. In conclusion, FA supplementation tended to reduce total serum cholesterol and improved lean percentage as well as meat value through enrichment of conjugated linoleic acid and omega 3 fatty acid in the muscle and adipose tissue. PMID- 28593446 TI - C3 glomerulonephritis with a severe crescentic phenotype. AB - BACKGROUND: C3 glomerulopathy (C3G) is rare type of glomerulonephritis resulting from the glomerular deposition of C3 due to dysregulation of the alternative pathway of complement. It is further subdivided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), depending on the ultrastructural features. C3GN usually presents with a membranoproliferative pattern of injury. Crescents may or may not be present. However, we have noted a severe necrotizing and crescentic glomerulonephritis in a small subset of C3GN patients. CASE DIAGNOSIS/TREATMENT: We present the clinical features, kidney biopsy findings, complement evaluation, treatment, and follow-up of four C3GN patients. We also compare the findings with four DDD patients with a severe necrotizing and crescentic glomerulonephritis. The patients were young and presented with hematuria and proteinuria. The biopsy was remarkable for the large number of crescents, in association with bright glomerular staining for C3. The patients were treated with steroids/immunosuppressive drugs. Three of the 4 C3GN patients and 2 of the 4 DDD patients showed stable renal function at follow-up. We find remarkable similarities between our C3GN patients with crescents and the previously described entity of juvenile acute nonproliferative glomerulonephritis. CONCLUSIONS: To summarize, C3G with a severe crescentic phenotype is rare, affects children and young adults, and has a variable response to steroid and immunosuppressive treatment. It is important to recognize this rare cause of crescentic glomerulonephritis so that appropriate evaluation and treatment can be carried out. PMID- 28593448 TI - Erratum to: Assessing the feasibility of the Effectiveness of Discontinuing Bisphosphonates trial: a pilot study. PMID- 28593447 TI - Predictors of near-term fracture in osteoporotic women aged >=65 years, based on data from the study of osteoporotic fractures. AB - : Using data from the Study of Osteoporotic Fractures (SOF), several clinical characteristics predictive of near-term (1-year) risk of hip and non-vertebral fracture among elderly osteoporotic women were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Additional research is needed to validate study findings. INTRODUCTION: While several risk factors are known to contribute to long-term fracture risk in women with osteoporosis, factors predicting fracture risk over a shorter time horizon, such as over a 1-year period, are less well-established. METHODS: We utilized a repeated-observations design and data from the Study of Osteoporotic Fractures to identify factors contributing to near-term risk of hip fracture and any non vertebral fracture, respectively, among osteoporotic women aged >=65 years. Potential predictors of hip fracture and any non-vertebral fracture over the 1 year period subsequent to each qualifying SOF exam were examined using multivariable frailty models. Because the discriminative ability of the hip fracture model was acceptable, a corresponding risk-prediction tool was also developed. RESULTS: Study population included 2499 women with osteoporosis, who contributed 6811 observations. Incidence of fracture in the 1-year period subsequent to each exam was 2.2% for hip fracture and 6.6% for any non-vertebral fracture. Independent predictors of hip fracture included low total hip T-score, prior fracture, and risk factors for falls (multivariable model c-statistic = 0.71 (95% CI 0.67-0.76)). Independent predictors of any non-vertebral fracture included age, total hip T-score, prior falls, prior fracture, walking speed, Parkinson's disease or stroke, and smoking (multivariable model c-statistic = 0.62 (0.59-0.65)). CONCLUSIONS: Several clinical characteristics predictive of hip and non-vertebral fracture within a 1-year follow-up period among elderly women with osteoporosis were identified, and a subset of those for hip fracture was incorporated into a risk assessment tool. Assessment of these risk factors may help guide osteoporosis treatment choices by identifying patients in whom there is urgency to treat. Additional research is needed to validate the findings of this study and the accuracy of the risk assessment tool. PMID- 28593449 TI - FRAX for fracture prediction shorter and longer than 10 years: the Manitoba BMD registry. AB - : In a large clinical registry for the province of Manitoba, Canada, FRAX predicted incident MOF and hip fracture from 1 to 15 years following baseline assessment. A simple linear rescaling of FRAX outputs seems useful for predicting both short- and long-term fracture risk in this population. INTRODUCTION: FRAX(r) estimates 10-year probability of major osteoporotic fracture (MOF) and hip fracture. We examined FRAX predictions over intervals shorter and longer than 10 years. METHODS: Using a population-based clinical registry for Manitoba, Canada, we identified 62,275 women and 6455 men 40 years and older with baseline dual energy X-ray absorptiometry scans and FRAX scores. Incident MOF and hip fracture were assessed up to 15 years from population-based data. We assessed agreement between estimated fracture probability from 1 to 15 years using linearly rescaled FRAX scores and observed cumulative fracture probability. The gradient of risk for FRAX probability and incident fracture was examined overall and for 5-year intervals. RESULTS: FRAX predicted incident MOF and hip fracture for all time intervals. There was no attenuation in the gradient of risk for MOF even for years >10. Gradient of risk was slightly lower for hip fracture prediction in years >10 vs years <5, though HRs remained high. Linear agreement was seen in the relationships between observed vs predicted (rescaled) FRAX probabilities (R 2 0.95-1.00). Among women, there was near-perfect linearity in MOF predictions. Deviations from linearity, with a slightly higher observed than predicted MOF probability, were most evident in the first years following a fracture event and after 10 years for hip fracture prediction in women using FRAX with BMD. Simulations showed that results were robust to large differences in fracture rates and moderate differences in mortality rates. CONCLUSIONS: FRAX predicts incident MOF and hip fracture up to 15 years and could be adapted to predict fracture over time periods shorter and longer term than 10 years in populations with fracture and mortality epidemiology similar to Canada. PMID- 28593450 TI - Clinical assessment of endothelial function in patients with chronic obstructive pulmonary disease: a systematic review with meta-analysis. AB - Patients with chronic obstructive pulmonary disease (COPD) have an increased cardiovascular morbidity and mortality. Flow-mediated (FMD) and nitrate-mediated dilatation (NMD) are considered non-invasive methods to assess endothelial function and surrogate markers of subclinical atherosclerosis. We performed a systematic review with meta-analysis and meta-regression to evaluate the impact of COPD on FMD and NMD. Studies were systematically searched in the PubMed, Web of Science, Scopus and EMBASE databases. The random-effect method was used to take into account the variability among included studies. A total of eight studies were included in the final analysis, eight with data on FMD (334 COPD patients) and two on NMD (104 COPD patients). Compared to controls, COPD patients show a significantly lower FMD (MD -3.15%; 95% CI -4.89, -1.40; P < 0.001) and NMD (MD -3.53%; 95% CI -7.04, -0.02; P = 0.049). Sensitivity analyses substantially confirms the results. Meta-regression models show that a more severe degree of airway obstruction is associated with a more severe FMD impairment in COPD patients than in controls. Regression analyses confirm that the association between COPD and endothelial dysfunction is independent of baseline smoking status and most traditional cardiovascular risk factors. In conclusion, COPD is significantly and independently associated with endothelial dysfunction. These findings may be useful to plan adequate cardiovascular prevention strategies in this clinical setting, with particular regard to patients with a more severe disease. PMID- 28593451 TI - Clinical, diagnostic, and therapeutic features of patients admitted to acute care hospitals with trunk compared to lower limb cellulitis. AB - The objective of this study is to report the clinical course and risk factors of trunk cellulitis, to identify diagnostic and therapeutic approaches, and compare them to patients with lower limb cellulitis. Medical records of adult patients with trunk cellulitis were reviewed and compared to an equal number of randomly selected patients with lower limb cellulitis. Demographic, clinical, and laboratory data were collected and analyzed using binary univariate and multivariate logistic regression analyses. Primary outcome was surgical drainage. Secondary outcomes were use of imaging studies, length of stay, readmission within 30 days, and 30-day mortality. During the study period, 74 patients were diagnosed with trunk cellulitis. Compared to patients with lower limb cellulitis, there are more women (57 vs. 39%, p = 0.032) and they are younger (mean age 59.7 vs. 68.4 years, p = 0.005). The only co-morbidity found as a significant risk factor for trunk cellulitis is malignancy (p = 0.017). These variables remain independent risk factors for trunk cellulitis after multivariate regression analysis. There is a trend toward more surgical interventions in the study group [6 (8%) patients vs. 1 (1%) with leg cellulitis, p = 0.116], and a longer hospital stay (5.8 days in the study group vs. 4.3 days in the control group, p = 0.025). Laboratory data are similar in both groups. There are risk factors for trunk cellulitis compared to lower limb cellulitis. However, diagnostic and therapeutic approaches are similar, except for a trend for more surgical interventions. PMID- 28593452 TI - Physical therapy in the management of stone fragments: progress, status, and needs. AB - With an increased risk of symptomatic events, the complications related to residual fragments are complex and intractable. The management of stone fragments is a challenge to urologists. This review focused on the progress, status, and needs of the newly developed physical therapies to remove fragments and improve the stone-free rate. Physical therapies, including mechanical percussion, diuresis, and inversion therapy, ultrasonic propulsion technology, glue-clot technology, and magnetization technology, will facilitate progress in endoscopic stone fragment retrieval. PMID- 28593453 TI - Targeting Small Bowel Receptors to Treat Constipation and Diarrhea. AB - BACKGROUND: The options for the treatment of diarrhea and constipation are evolving as emerging therapies target small bowel receptors. The goal of this review is to discuss small bowel receptors involved in intestinal absorption, secretion, and motility. The review highlights therapies already approved or currently being studied for the modulation of these receptors. METHODS: The articles cited in this review focus on the molecular level of pathways involved in diarrhea and constipation, and highlight the respective pharmacotherapies. RESULTS: The majority of the studies in the current literature investigate the effects of both the small and large intestine receptors on diarrhea and constipation. There are fewer studies that isolate the effects of these receptors solely on the small bowel, and focusing more on the receptors found distinctly in the small intestine may be an area of interest for future studies as this can inspire more targeted therapies. PMID- 28593455 TI - Monitoring tissue oxygen heterogeneities and their influence on optical glucose measurements in an animal model. AB - The purpose of this study was to characterize the heterogeneity of oxygen partial pressure in different adipose tissue zones and to assess the possibility of compensating these heterogeneities during optical glucose measurements. In this proof of concept study, the heterogeneity of oxygen partial pressure was determined in the adipose tissue of a pig by using 48 oxygen sensors in 3 zones of the abdominal region at two different blood oxygen levels. Sensor oxygen values correlated well with reference blood oxygen values and we identified heterogeneities in oxygen partial pressure among the defined zones of the abdominal region. Significant differences in the mean oxygen partial pressure were found when comparing the three abdominal zones but no significant differences were found when comparing two sensors located in close proximity (on one cannula). The low heterogeneity on one cannula allows the compensation of physiological oxygen variations for optical glucose measurements by using an additional oxygen sensor in close proximity to the glucose sensor. In addition, this setup can be used to continuously monitor tissue oxygenation e.g. in patients with adipose tissue dysfunction or serve limb ischemia. PMID- 28593454 TI - Permanent Cerebellar Degeneration After Acute Hyperthermia with Non-toxic Lithium Levels: a Case Report and Review of Literature. AB - This was a study of a 33-year-old man with bipolar disorder treated with lithium who developed cerebellar atrophy after an event of extreme hyperthermia. Unlike previously reported cases of acute cerebellar atrophy after heat stroke, neuroleptic syndrome or lithium toxicity, this case was characterized by a chronic cerebellar atrophy that developed after sepsis-induced hyperthermia in the setting of non-toxic lithium levels. Unique to this case also was the early finding of cerebellar atrophy on MRI 2 weeks after the episode of hyperthermia, long-term neurotoxicity after the novo lithium therapy, and longest follow-up case of chronic cerebellar syndrome after hyperthermia with non-toxic lithium levels. PMID- 28593457 TI - Use of solvent mixtures for total lipid extraction of Chlorella vulgaris and gas chromatography FAME analysis. AB - Lipid extraction is the bottleneck step for algae-based biodiesel production. Herein, 12 solvent mixture systems (mixtures of three non-polar and two polar organic solvents) were examined to evaluate their effects on the total lipid yield from Chlorella vulgaris (C. vulgaris). Moreover, the extraction yields of three solvent systems with maximum extraction efficiency of esterifiable lipids were determined by acidic transesterification and GC-FID analysis. Three solvent systems, which resulted in a higher extraction yield, were further subjected to fatty acid methyl ester (FAME) analysis. The total lipid extraction yields (based on dry biomass) were (38.57 +/- 1.51), (25.33 +/- 0.58), and (25.17 +/- 1.14) %, for chloroform-methanol (1:2) (C1M2), hexane-methanol (1:2) (H1M2), and chloroform-methanol (2:1) (C2M1), respectively. The extraction efficiency of C1M2 was approximately 1.5 times higher than H1M2 and C2M1, whereas the FAME profile of extracted lipids by H1M2 and C1M2 were almost identical. Moreover, the esterifiable lipid extraction yields of (18.14 +/- 2.60), (16.66 +/- 0.35), and (13.22 +/- 0.31) % (based on dry biomass) were obtained for C1M2, H1M2, and C2M1 solvent mixture systems, respectively. The biodiesel fuel properties produced from C. vulgaris were empirically predicted and compared to that of the EN 14214 and ASTM 6751 standard specifications. PMID- 28593456 TI - Impact of hemodynamic goal-directed resuscitation on mortality in adult critically ill patients: a systematic review and meta-analysis. AB - The effect of hemodynamic optimization in critically ill patients has been challenged in recent years. The aim of the meta-analysis was to evaluate if a protocolized intervention based on the result of hemodynamic monitoring reduces mortality in critically ill patients. We performed a systematic review and meta analysis according to the Cochrane Handbook for Systematic Reviews of Interventions. The study was registered in the PROSPERO database (CRD42015019539). Randomized controlled trials published in English, reporting studies on adult patients treated in an intensive care unit, emergency department or equivalent level of care were included. Interventions had to be protocolized and based on results from hemodynamic measurements, defined as cardiac output, stroke volume, stroke volume variation, oxygen delivery, and central venous-or mixed venous oxygenation. The control group had to be treated without any structured intervention based on the parameters mentioned above, however, monitoring by central venous pressure measurements was allowed. Out of 998 screened papers, thirteen met the inclusion criteria. A total of 3323 patients were enrolled in the six trials with low risk of bias (ROB). The mortality was 22.4% (374/1671 patients) in the intervention group and 22.9% (378/1652 patients) in the control group, OR 0.94 with a 95% CI of 0.73-1.22. We found no statistically significant reduction in mortality from hemodynamic optimization using hemodynamic monitoring in combination with a structured algorithm. The number of high quality trials evaluating the effect of protocolized hemodynamic management directed towards a meaningful treatment goal in critically ill patients in comparison to standard of care treatment is too low to prove or exclude a reduction in mortality. PMID- 28593458 TI - Sensitivity-based adaptive mesh refinement collocation method for dynamic optimization of chemical and biochemical processes. AB - Collocation on finite element (CFE) is an effective simultaneous method of dynamic optimization to increase the profitability or productivity of industrial process. The approach needs to select an optimal mesh of time interval to balance the computational cost with desired solution. A new CFE approach with non-uniform refinement procedure based on the sensitivity analysis for dynamic optimization problems is, therefore, proposed, where a subinterval is further refined if the obtained control parameters have significant effect on the performance index. To improve the efficiency, the sensitivities of state parameters with respect to control parameters are derived from the solution of the discretized dynamic system. The proposed method is illustrated by testing two classic dynamic optimization problems from chemical and biochemical engineering. The detailed comparisons among the proposed method, the CFE with uniform mesh, and other reported methods are also carried out. The research results reveal the effectiveness of the proposed approach. PMID- 28593459 TI - Impact of surgery and surveillance in the management of branch duct intraductal papillary mucinous neoplasms of the pancreas according to Fukuoka guidelines: the Bologna experience. AB - The objective of the study was to evaluate the Fukuoka guidelines in indicating the proper management for recognising the risk factors of malignancy. Data of patients with branch duct intraductal papillary mucinous neoplasms who underwent pancreatic resection or surveillance according to the Fukuoka risk parameters were collected in a prospective database. The clinical outcome (development of pancreatic cancer, overall and disease-specific survival) and pathological results were evaluated in all patients and in resected cases, respectively. The data of 197 patients were collected: 23 primarily resected and 174 primarily followed. Of the latter, 16 were secondarily resected. Among the patients resected, 21 (53.9%) showed diagnosis of in situ or invasive carcinoma and only contrast-enhancing mural nodules were significantly related to malignancy (P = 0.002), with a DOR of 3.3 and an LH+ of 2.2. Development of pancreatic cancer was shown in ten (5.7%) of the patients primarily followed. The overall survival and disease-specific survival were similar between patients primarily followed and primarily resected. It seems reasonable to suggest that a branch duct intraductal papillary mucinous neoplasm should be treated as a benign and indolent disease that is rarely malignant. Enhancing mural nodules represent the best indicator for surgery. PMID- 28593460 TI - Telegraphing your telomere length to the next generation. PMID- 28593461 TI - Self-prioritization and perceptual matching: The effects of temporal construal. AB - Recent research has revealed that self-referential processing enhances perceptual judgments - the so-called self-prioritization effect. The extent and origin of this effect remains unknown, however. Noting the multifaceted nature of the self, here we hypothesized that temporal influences on self-construal (i.e., past/future-self continuity) may serve as an important determinant of stimulus prioritization. Specifically, as representations of the self increase in abstraction as a function of temporal distance (i.e., distance from now), self prioritization may only emerge when stimuli are associated with the current self. The results of three experiments supported this prediction. Self-relevance only enhanced performance in a standard perceptual-matching task when stimuli (i.e., geometric shapes) were connected with the current self; representations of the self in the future (Expts. 1 & 2) and past (Expt. 3) failed to facilitate decision making. To identify the processes underlying task performance, data were interrogated using a hierarchical drift diffusion model (HDDM) approach. Results of these analyses revealed that self-prioritization was underpinned by a stimulus bias (i.e., rate of information uptake). Collectively, these findings elucidate when and how self-relevance influences decisional processing. PMID- 28593462 TI - Moderators of the effects of meaning-centered group psychotherapy in cancer survivors on personal meaning, psychological well-being, and distress. AB - PURPOSE: There is evidence to support that meaning-centered group psychotherapy for cancer survivors (MCGP-CS) is an effective intervention for improving personal meaning and psychological well-being, as well as reducing psychological distress. In order to investigate which subpopulations MCGP-CS specifically benefits, this explorative study aims to analyze potential sociodemographic, clinical, and psychosocial factors that may moderate the effects. METHODS: Cancer survivors (N = 114) were randomly assigned to MCGP-CS, or care as usual (CAU). Potential moderators included age, sex, relationship, education, employment, religion, cancer type, tumor stage, cancer treatment, time since treatment, anxiety, depression, other negative life events, and previous psychological treatment. Outcome measures were the Personal Meaning Profile (PMP), Scales of Psychological Well-Being (SPWB), and the Hospital Anxiety and Depression Scale (HADS). Assessment took place at baseline, post-intervention (short-term), and 3- and 6-month follow-ups (long-term). For each moderator, separate short-term and long-term linear mixed models were built. RESULTS: Short-term effect of MCGP-CS was moderated by (male) sex (on HADS-D; F(1,98) = 6.1, p = .015) and (a high level of) depressive symptoms at baseline (on SPWB; F(1,93) = 5.7, p = .019). Long-term effect of MCGP-CS was moderated by (not having received) previous psychological treatment (on HADS-total; F(3253) = 3.4, p = .017). CONCLUSIONS: Most sociodemographic and clinical characteristics do not appear to moderate the positive effect of MCGP-CS on personal meaning. However, MCGP-CS appears to reduce depressive symptoms, particularly in males, and to improve purpose in life of survivors with depressive symptoms. In the long-term, MCGP-CS appears to reduce psychological distress in survivors who had not received psychological treatment in the past year. TRIAL REGISTRATION: NTR3571. PMID- 28593463 TI - Factors which modulate the rates of skeletal muscle mass loss in non-small cell lung cancer patients: a pilot study. AB - PURPOSE: Advanced non-small cell lung cancer (NSCLC) is associated with weight loss which may reflect skeletal muscle mass (SMM) and/or total adipose tissue (TAT) depletion. This study aimed to describe changes in body composition (BC) parameters and to identify the factors unrelated to the tumor which modulate them. METHODS: SMM, TAT, and the proportion of SMM to SMM + TAT were assessed with computed tomography. Estimates of each BC parameter at follow-up initiation and across time were derived from a mixed linear model of repeated measurements with a random intercept and a random slope. The same models were used to assess the independent effect of gender, age, body mass index (BMI), and initial values on changes in each BC parameter. RESULTS: Sixty-four patients with stage III or IV NSCLC were reviewed. The mean +/- SD decreases in body weight and SMM were respectively 59 +/- 3 g/week (P < 0.03) and 7 mm2/m2/week (P = 0.0003). During follow-up, no changes were identified in TAT nor in muscle density or in the proportion of SMM to SMM + TAT, estimated at 37 +/- 2% at baseline. SMM loss was influenced by initial BMI (P < 0.0001) and SMM values (P = 0.0002): the higher the initial BMI or SMM values, the greater the loss observed. Weight loss was greater when the initial weight was heavier (P < 0.0001). CONCLUSION: Our results demonstrate that SMM wasting in NSCLC is lower when initial SMM and BMI values are low. These exploratory findings after our attempt to better understand the intrinsic factors associated with muscle mass depletion need to be confirmed in larger studies. PMID- 28593464 TI - Fine root endophytes under scrutiny: a review of the literature on arbuscule producing fungi recently suggested to belong to the Mucoromycotina. AB - Fine root endophytes (FRE) are arbuscule-forming fungi presently considered as a single species-Glomus tenue in the Glomeromycota (Glomeromycotina)-but probably belong within the Mucoromycotina. Thus, FRE are the only known arbuscule-forming fungi not within the arbuscular mycorrhizal fungi (AMF; Glomeromycotina) as currently understood. Phylogenetic differences between FRE and AMF could reflect ecological differences. To synthesize current ecological knowledge, we reviewed the literature on FRE and identified 108 papers that noted the presence of FRE and, in some, the colonization levels for FRE or AMF (or both). We categorized these records by geographic region, host-plant family and environment (agriculture, moderate-natural, low-temperature, high-altitude and other) and determined their influence on the percentage of root length colonized by FRE in a meta-analysis. We found that FRE are globally distributed, with many observations from Poaceae, perhaps due to grasses being widely distributed. In agricultural environments, colonization by FRE often equalled or exceeded that of AMF, particularly in Australasia. In moderate-natural and high-altitude environments, average colonization by FRE (~10%) was lower than that of AMF (~35%), whereas in low-temperature environments, colonization was similar (~20%). Several studies suggested that FRE can enhance host-plant phosphorus uptake and growth, and may be more resilient than AMF to environmental stress in some host plants. Further research is required on the functioning of FRE in relation to the environment, host plant and co-occurring AMF and, in particular, to examine whether FRE are important for plant growth in stressful environments. Targeted molecular primers are urgently needed for further research on FRE. PMID- 28593466 TI - High-content drug screening for rare diseases. AB - Per definition, rare diseases affect only a small number of subjects within a given population. Taken together however, they represent a considerable medical burden, which remains poorly addressed in terms of treatment. Compared to other diseases, obstacles to the development of therapies for rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Recently, advances in high-throughput and high-content screening (HTS and HCS) have been fostered by the development of specific routines that use robot- and computer-assisted technologies to automatize tasks, allowing screening of a large number of compounds in a short period of time, using experimental model of diseases. These approaches are particularly relevant for drug repositioning in rare disease, which restricts the search to compounds that have already been tested in humans, thereby reducing the need for extensive preclinical tests. In the future, these same tools, combined with computational modeling and artificial neural network analyses, may also be used to predict individual clinical responses to drugs in a personalized medicine approach. PMID- 28593465 TI - High effectiveness of Rhizophagus irregularis is linked to superior modulation of antioxidant defence mechanisms in Cajanus cajan (L.) Millsp. genotypes grown under salinity stress. AB - Salinity stress leads to the production of reactive oxygen species (ROS) which can cause oxidative damage in plants. A correlation between antioxidant capacity and salt tolerance has been demonstrated in several plant species, which may be enhanced by inoculation with arbuscular mycorrhizal fungi (AMF). However, plant responses to mycorrhization may differ depending on the host plant as well as AMF isolate. It has been proposed that AMF sourced from stressed environments may be better suited as stress ameliorators than non-native/exotic ones. The present study compared the effectiveness of a native inoculum from saline soil and two exotic single isolates, Funneliformis mossseae and Rhizophagus irregularis (single or dual mix), and associated their effectiveness with modulation of antioxidant defence, in two Cajanus cajan (pigeonpea) genotypes (salt sensitive Paras, salt tolerant-Pusa 2002) under NaCl stress. Plants subjected to NaCl (0 100 mM) recorded a substantial build-up of ROS, more in Paras than Pusa 2002. Although mycorrhization with all AMF improved plant biomass and reduced oxidative burst by strengthening antioxidant enzymatic activities, inoculation with R. irregularis (alone or in combination with F. mosseae) resulted in higher biomass accumulation which correlated with its higher root colonization and improved redox stability through rapid recycling of reduced ascorbate and glutathione. The study thus suggested that mitigation of salt-induced oxidative burden by increased activation of scavenging antioxidants is an important mechanism that determined the higher effectiveness of R. irregularis over the native saline mix in pigeonpea plants. PMID- 28593468 TI - Association of the IL6 rs1800796, but not of the IL6 rs1800795, IL6R rs4845617 and rs2228145 polymorphisms with hip fracture in elderly Mexican women. AB - BACKGROUND AND AIMS: Polymorphisms in Interleukin-6 (IL6) and its receptor (IL6R) have been associated with bone mineral density. In this work, the G-174C and G 572C polymorphisms in IL6, G-208A, and Asp358Ala in IL6R were analyzed in Mexican women with hip fracture. METHODS: Postmenopausal Mexican women (60 years or over) with hip fragility fracture (77.97 +/- 8 years) and without hip fracture (70.5 +/ 7.02 years) were genotyped by real-time PCR. RESULTS: The rs1800796 GG genotype was associated with low risk of fracture (p = 0.05), while GC genotype was associated with high risk of fracture [p = 0.047, OR 2.3 (95% CI 1.013-5.2)]. The AA genotype of the rs2228145 SNP (IL6R) was significantly different [p = 0.033, OR 1.94 (95% CI 1.01-3.75)], but when data were adjusted by age and body mass index, there were no differences (p = 0.9). CONCLUSION: Our results suggest that the IL6 rs1800796 SNP is a good marker for hip fracture risk in Mexican women. PMID- 28593469 TI - A patient-specific aortic valve model based on moving resistive immersed implicit surfaces. AB - In this paper, we propose a full computational framework to simulate the hemodynamics in the aorta including the valve. Closed and open valve surfaces, as well as the lumen aorta, are reconstructed directly from medical images using new ad hoc algorithms, allowing a patient-specific simulation. The fluid dynamics problem that accounts from the movement of the valve is solved by a new 3D-0D fluid-structure interaction model in which the valve surface is implicitly represented through level set functions, yielding, in the Navier-Stokes equations, a resistive penalization term enforcing the blood to adhere to the valve leaflets. The dynamics of the valve between its closed and open position is modeled using a reduced geometric 0D model. At the discrete level, a finite element formulation is used and the SUPG stabilization is extended to include the resistive term in the Navier-Stokes equations. Then, after time discretization, the 3D fluid and 0D valve models are coupled through a staggered approach. This computational framework, applied to a patient-specific geometry and data, allows to simulate the movement of the valve, the sharp pressure jump occurring across the leaflets, and the blood flow pattern inside the aorta. PMID- 28593470 TI - Effect of Selenium from Selenium-Enriched Kale Sprout Versus Other Selenium Sources on Productivity and Selenium Concentrations in Egg and Tissue of Laying Hens. AB - A 6-week trial was conducted to compare the effect of selenium (Se) from hydroponically produced Se-enriched kale sprout (HPSeKS), sodium selenite (SS), and Se-enriched yeast (SeY) in laying hens. A total of 144 40-week-old hens were randomly divided into four groups, according to a completely randomized design. Each group consisted of four replicates with nine hens per replicate. The dietary treatments were T1 (basal diet) and T2, T3, and T4 (basal diets supplemented with 0.30 mg Se/kg from SS, SeY, and HPSeKS, respectively). Results showed that Se supplement did not affect (p > 0.05) productivity and egg quality. Hens fed Se from HPSeKS and SeY exhibited higher (p < 0.05) Se bioavailability than hens fed Se from SS. Whole egg Se concentration of hens fed Se from HPSeKS was similar (p > 0.05) to that of hens fed Se from SeY, but higher (p < 0.05) than that of hens fed Se from SS. However, the breast muscle and heart tissue Se concentrations of hens fed Se from SS, SeY, and HPSeKS were not different (p > 0.05). The results of this trial demonstrated that Se from HPSeKS and SeY was more efficient than Se from SS on Se bioavailability and whole egg Se concentration in laying hens. PMID- 28593471 TI - Effects of Combined Exposure to Chronic High-Fat Diet and Arsenic on Thyroid Function and Lipid Profile in Male Mouse. AB - The thyroid is one of the major endocrine glands that contribute to body and fat metabolism. The present study evaluated the effects of combined exposure to chronic high-fat diet (HFD) and arsenic on thyroid function and lipid profile. In this experimental study, 72 male Naval Medical Research Institute mice were divided into six groups and fed HFD or low-fat diet (LFD) while being exposed to 25 or 50 ppm of arsenic in drinking water for 20 weeks. After 24 h of the last experimental day, blood samples were collected for hormonal and biochemical measurements. The data indicated that exposure to HFD alone increased the levels of triiodothyronine (T3), thyroid-stimulating hormone (TSH), leptin, lipid profile, reactive oxygen species (ROS), and malondialdehyde (MDA) and decreased the levels of high-density lipoprotein, albumin, adiponectin, and glutathione sulfhydryl reductase (GSH), whereas exposure to arsenic alone decreased the levels of T3 and GSH and increased the levels of TSH, leptin, ROS, MDA, and T4/T3 ratio compared to those in the control LFD group. Furthermore, concomitant administration of HFD and arsenic decreased the lipid profile and levels of T4, albumin, total protein, T3, and GSH and increased the levels of TSH, adiponectin, leptin, ROS, MDA, and T4/T3 ratio compared to those in the control LFD or HFD group. In conclusion, combined exposure to HFD and arsenic induced hypothyroidism via reduction of thyroid hormones and enhancement of plasma TSH and T3 uptake levels concomitant with hypolipidemia, hyperleptinemia, hyperadiponectinemia, induction of oxidative stress, and reduction of GSH levels. PMID- 28593472 TI - L-Glutamine in vitro Modulates some Immunomodulatory Properties of Bone Marrow Mesenchymal Stem Cells. AB - Glutamine (GLUT) is a nonessential amino acid that can become conditionally essential under stress conditions, being able to act in the modulation of the immune responses. Mesenchymal stem cells (MSCs) are known to their capability in the modulation of immune responses through cell-cell contact and by the secretion of soluble factors. Considering that GLUT is an immunonutrient and little is known about the influence of GLUT on the capability of MSCs to modulate immune cells, this work aims to investigate how variations in GLUT concentrations in vitro could affect some immunomodulatory properties of MSCs. In order to evaluate the effects of GLUT on MSCs immunomodulatory properties, cell proliferation rates, the expression of NFkappaB and STAT-3, and the production of IL-1beta, IL 6, IL-10, TGF-beta and TNF-alpha by MSCs were assessed. Based on our findings, GLUT at high doses (10 mM) augmented the proliferation of MSCs and modulated immune responses by decreasing levels of pro-inflammatory cytokines, such as IL 1beta and IL-6, and by increasing levels of anti-inflammatory cytokines IL-10 and TGF-beta. In addition, MSCs cultured in higher GLUT concentrations (10 mM) expressed lower levels of NF-kappaB and higher levels of STAT-3. Furthermore, conditioned media from MSCs cultured at higher GLUT concentrations (10 mM) reduced lymphocyte and macrophage proliferation, increased IL-10 production by both cells types, and decreased IFN-gamma production by lymphocytes. Overall, this study showed that 10 mM of GLUT is able to modify immunomodulatory properties of MSCs. PMID- 28593473 TI - Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin Induced Dermal Blood Flow in Healthy and Migraine Subjects. AB - PURPOSE: Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects. METHODS: Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated. RESULTS: Two compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87-91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF. CONCLUSIONS: Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF. PMID- 28593474 TI - High Throughput Prediction Approach for Monoclonal Antibody Aggregation at High Concentration. AB - PURPOSE: Characterization of the monoclonal antibody aggregation process and identification of stability factors that could be used as indicators of aggregation propensity with an emphasis on a large number of samples and low protein material consumption. METHODS: Differential scanning calorimetry, dynamic light scattering and size exclusion chromatography were used as the main methodological approaches. Conformational stability, colloidal stability and aggregation kinetics were assessed for two different IgG monoclonal antibody (mAbs) subclasses. Aggregation was induced by exposing the mAbs to 55 degrees C for 3 weeks. mAb samples were prepared in different formulations and concentrations from 1 mg/mL to 50 mg/mL. RESULTS: High temperature stress of mAb samples revealed that monoclonal antibodies followed first order aggregation kinetics, which suggests that the rate-limiting step of monomer loss was unimolecular. Conformational stability of mAbs was estimated with denaturation temperature measurements. Colloidal stability was assessed with dynamic interaction parameter k D . The correlation between aggregation kinetics and colloidal and conformational stability factors was evaluated and the dynamic interaction parameter was found to be a promising predictor of aggregation propensity of monoclonal antibodies. The meaning of using an intermolecular interaction parameter for prediction of what is essentially a unimolecular process is also discussed. CONCLUSIONS: This work estimates the significance of different predictors of aggregation propensity at high concentrations as a part of a high throughput, low resource screening method and is a contribution towards determining protein aggregation phenomena in actual systems used for the development and production of biopharmaceuticals. PMID- 28593476 TI - Synergy between azoles and 1,4-dihydropyridine derivative as an option to control fungal infections. AB - With emerging fungal infections and developing resistance, there is a need for understanding the mechanisms of resistance as well as its clinical impact while planning the treatment strategies. Several approaches could be taken to overcome the problems arising from the management of fungal diseases. Besides the discovery of novel effective agents, one realistic alternative is to enhance the activity of existing agents. This strategy could be achieved by combining existing antifungal agents with other bioactive substances with known activity profiles (combination therapy). Azole antifungals are the most frequently used class of substances used to treat fungal infections. Fluconazole is often the first choice for antifungal treatment. The aim of this work was to study potential synergy between azoles and 1,4-dihydropyridine-2,3,5-tricarboxylate (termed derivative H) in order to control fungal infections. This article points out the synergy between azoles and newly synthesized derivative H in order to fight fungal infections. Experiments confirmed the role of derivative H as substrate/inhibitor of fungal transporter Cdr1p relating to increased sensitivity to fluconazole. These findings, plus decreased expression of ERG11, are responsible for the synergistic effect. PMID- 28593475 TI - Functional metagenomics of oil-impacted mangrove sediments reveals high abundance of hydrolases of biotechnological interest. AB - Mangroves are located in coastal wetlands and are susceptible to the consequences of oil spills, what may threaten the diversity of microorganisms responsible for the nutrient cycling and the consequent ecosystem functioning. Previous reports show that high concentration of oil favors the incidence of epoxide hydrolases and haloalkane dehalogenases in mangroves. This finding has guided the goals of this study in an attempt to broaden the analysis to other hydrolases and thereby verify whether oil contamination interferes with the prevalence of particular hydrolases and their assigned microorganisms. For this, an in-depth survey of the taxonomic and functional microbial diversity recovered in a fosmid library (Library_Oil Mgv) constructed from oil-impacted Brazilian mangrove sediment was carried out. Fosmid DNA of the whole library was extracted and submitted to Illumina HiSeq sequencing. The resulting Library Oil_Mgv dataset was further compared with those obtained by direct sequencing of environmental DNA from Brazilian mangroves (from distinct regions and affected by distinct sources of contamination), focusing on hydrolases with potential use in biotechnological processes. The most abundant hydrolases found were proteases, esterases and amylases, with similar occurrence profile in all datasets. The main microbial groups harboring such hydrolase-encoding genes were distinct in each mangrove, and in the fosmid library these enzymes were mainly assigned to Chloroflexaceae (for amylases), Planctomycetaceae (for esterases) and Bradyrhizobiaceae (for proteases). Assembly and analysis of Library_Oil Mgv reads revealed three potentially novel enzymes, one epoxide hydrolase, one xylanase and one amylase, to be further investigated via heterologous expression assays. PMID- 28593477 TI - Trends of 'urolithiasis: interventions, simulation, and laser technology' over the last 16 years (2000-2015) as published in the literature (PubMed): a systematic review from European section of Uro-technology (ESUT). AB - PURPOSE: To look at the bibliometric publication trends on 'Urolithiasis' and aspects of treatment and training associated with it over a period of 16 years from 2000 to 2015. To this end, we conducted this study to look at the publication trends associated with urolithiasis, including the use of simulation, laser technology, and all types of interventions for it. MATERIALS AND METHODS: We performed a systematic review of the literature using PubMed over the last 16 years, from January 2000 to December 2015 for all published papers on 'Urolithiasis'. While there were no language restrictions, English language articles and all non-English language papers with published English abstracts were also included. Case reports, animal and laboratory studies, and those studies that did not have a published abstract were excluded from our analysis. We also analyzed the data in two time periods, period-1 (2000-2007) and period-2 (2008-2015). RESULTS: During the last 16 years, a total of 5343 papers were published on 'Urolithiasis', including 4787 in English language and 556 in non English language. This included papers on URS (n = 1200), PCNL (n = 1715), SWL (n = 887), open stone surgery (n = 87), laparoscopic stone surgery (n = 209), pyelolithotomy (n = 35), simulation in Endourology (n = 82), and use of laser for stone surgery (n = 406). When comparing the two time periods, during period 2, the change was +171% (p = 0.007), +279% (p < 0.001), and -17% (p = 0.2) for URS, PCNL, and SWL, respectively. While there was a rise in laparoscopic surgery (+116%), it decreased for open stone surgery (-11%) and pyelolithotomy (-47%). A total of 82 papers have been published on simulation for stone surgery including 48 papers for URS (67% rise in period-2, p = 0.007), and 34 papers for PCNL (480% rise in period-2, p < 0.001). A rising trend for the use of laser was also seen in period 2 (increase of 126%, p < 0.02, from 124 papers to 281 papers). CONCLUSIONS: Published papers on intervention for Urolithiasis have risen over the last 16 years. While there has been a steep rise of URS and minimally invasive PCNL techniques, SWL and open surgery have shown a slight decline over this period. A similar increase has also been seen for the use of simulation and lasers in Endourology. PMID- 28593478 TI - Which MR sequences should we use for the reliable detection and localization of bone marrow edema in spondyloarthritis? AB - OBJECTIVES: To assess the diagnostic confidence in detecting and localizing areas of bone marrow edema in the sacroiliac joint of patients with suspected spondyloarthritis using a single-plane method and comparing it with multiplanar unenhanced and enhanced methods. MATERIALS AND METHODS: Patients with clinical suspicion of spondyloarthritis undergoing an MRI of the sacroiliac joint were included in this retrospective study. To assess sacroiliitis, three methods were applied: single-plane (i.e., para-coronal STIR alone), multiplanar unenhanced (i.e., para-coronal STIR and para-axial PD-fs), and multiplanar enhanced method (i.e., para-coronal and para-axial post-contrast T1-fs). Two 4-point scales were used to evaluate, respectively, the diagnostic confidence in detection and localization of bone marrow edema. The distribution of certain and uncertain rating according to signal intensity and size of the lesions was also calculated. RESULTS: Seventy-four patients met the inclusion criteria. Both multiplanar methods increased the diagnostic confidence in detection (p < 0.001) and localization (p < 0.001) of sacroiliitis; no significant difference occurred between the multiplanar unenhanced and enhanced methods (p = 0.405 and p = 1.00, respectively, for detection and localization). A statistically significant difference between the distributions of certain and uncertain rating for detection based on the size and signal intensity of each lesion emerged (p = 0.006 and p < 0.001, respectively), whereas no statistically significant difference occurred for the confidence of localization (p = 0.452 and p = 0.694, respectively). CONCLUSIONS: The multiplanar methods increased the diagnostic confidence in detection and localization of sacroiliitis. The absence of a significant difference between the proposed unenhanced and enhanced methods suggests that contrast medium is not mandatory for the detection of sacroiliitis. PMID- 28593479 TI - RNA-binding protein Dnd1 inhibits epithelial-mesenchymal transition and cancer stem cell-related traits on hepatocellular carcinoma cells. AB - OBJECTIVES: To investigate the roles of Dead end 1 (Dnd1) in modulating cancer stem cell-related traits of hepatocellular carcinoma (HCC). RESULTS: Dead end (Dnd1) inhibited spheroid formation, suppressed the expression of stemness related genes, and increased sensitivity to sorafenib in HCC cells. Mechanistically, Dnd1 could bind to 3'-UTR of LATS2, the key kinase of Hippo pathway, thus elevating LATS2 mRNA stability and its expression, subsequently leading to phosphorylation of YAP and its cytoplasmic retention. As a result, epithelial-mesenchymal transition (EMT) was weakened and therefore the generation of HCC stem cell properties was suppressed. CONCLUSIONS: Dnd1 functions as a tumor suppressor by prohibiting CSC-like characteristics via activating Hippo pathway in HCC cells. Dnd1 could thus be a novel therapeutic target for HCC patients. PMID- 28593480 TI - Difference in susceptibility of small rodent host species to infestation by Ixodes ricinus larvae. AB - In a laboratory experiment (repeated eight times) individuals of six small rodent species were mixed with 500 Ixodes ricinus larvae for 24 h, than over a 3-day long observation period engorged ticks fallen from individually kept rodents were counted. Forty engorged larvae fell from the hosts, 25% from striped field mice, 32.5% from house mice, 22.5% from common voles, 10% from bank voles, while wood mouse and steppe mouse proved to be almost free of successfully infesting ticks (both 5%). Statistical analysis indicated, that tick burden differed significantly among host species. Similarly significant differences were shown between sensitivity of two related species, house mouse and steppe mouse, and more ticks were collected on the second observation day compared to the first day. The difference in susceptibility of hosts to Ixodes infestation could be due to various anti-tick behavior habits of hosts, or difference in preference of the ticks between host species. PMID- 28593481 TI - Molecular survey of Coxiella burnetii in wildlife and ticks at wildlife-livestock interfaces in Kenya. AB - Coxiella burnetii is the causative agent of Q fever, a zoonotic disease of public health importance. The role of wildlife and their ticks in the epidemiology of C. burnetii in Kenya is unknown. This study analysed the occurrence and prevalence of the pathogen in wildlife and their ticks at two unique wildlife-livestock interfaces of Laikipia and Maasai Mara National Reserve (MMNR) with the aim to determine the potential risk of transmission to livestock and humans. Blood from 79 and 73 animals in Laikipia and MMNR, respectively, and 756 and 95 ixodid ticks in each of the areas, respectively, was analysed. Ticks were pooled before analyses into 137 and 29 samples in Laikipia and MMNR, respectively, of one to eight non-engorged ticks according to species and animal host. Real-time PCR amplifying the repetitive insertion element IS1111a of the transposase gene was used to detect C. burnetii DNA. Although none of the animals and ticks from MMNR tested positive, ticks from Laikipia had an overall pooled prevalence of 2.92% resulting in a maximum-likelihood estimate of prevalence of 0.54%, 95% CI 0.17 1.24. Ticks positive for C. burnetii DNA belonged to the genus Rhipicephalus at a pooled prevalence of 2.96% (maximum-likelihood estimate of prevalence of 0.54%, 95% CI 0.17-1.26). These ticks were Rhipicephalus appendiculatus, R. pulchellus and R. evertsi at pooled prevalence of 3.77, 3.03 and 2.04%, respectively. The presence of C. burnetii in ticks suggests circulation of the pathogen in Laikipia and demonstrates they may play a potential role in the epidemiology of Q fever in this ecosystem. The findings warrant further studies to understand the presence of C. burnetii in domestic animals and their ticks within both study areas. PMID- 28593482 TI - Diagnostic Performance of C-Reactive Protein in Detecting Post-Operative Infectious Complications After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Gastric leak is the most common and dreaded post-operative infectious complication (PIC) after laparoscopic sleeve gastrectomy (LSG). Accurate identification of patients at risk postoperatively is of cardinal importance. OBJECTIVE: The aim of this study is to assess the diagnostic performance of C reactive protein (CRP) in predicting PICs and the most optimal time to measure it. METHODS: CRP results were collected in patients undergoing LSG between 2011 and 2015. CRP was systematically measured on post-operative days (POD) 1, 3, and 5. RESULTS: Of 1326 patients, 42 (3.2%) developed a PIC at a median of 5 days after surgery. The incidence of leakage was 1.9%. The best area under the curve was observed on POD5 (0.87; 95% CI 0.77-0.96). At this time point, a cut-off of 115 mg/L yielded a sensitivity of 66.7% (95% CI 46.5-86.8%), a specificity of 95.1% (95% CI 93.9-96.3%), a positive and negative predictive values of 19.4% (95% CI 10.3-28.6%) and 99.4% (95% CI 99.0-100%), respectively, and a positive and negative likelihood ratios (LRs) of 13.62 and 0.35, respectively. The combination of sequential assessments of CRP on POD3 and 5 provided a sensitivity of 84.4% (95% CI 71.8-97.0%), a specificity of 91.1% (95% CI 89.5-92.8%), a positive and negative predictive values of 20.9% (95% CI 14.0-27.9%) and 99.5% (95% CI 99.1-99.9%), respectively, and a positive and a negative LRs of 9.58 and 0.17, respectively. CONCLUSIONS: CRP may be useful to identify patients at risk of PICs after LSG and, therefore, to prompt early investigation. However, CRP does not help rule out PICs. PMID- 28593483 TI - Adverse Childhood Experiences in a Post-bariatric Surgery Psychiatric Inpatient Sample. AB - BACKGROUND: Sixty-three inpatients in a psychiatric hospital who had previously undergone bariatric surgery were interviewed by the hospital dietitian. The purpose of the study was to determine the frequency of adverse childhood experiences in this population. METHODS: Participants completed the Adverse Childhood Experiences (ACE) Scale. RESULTS: The average score on the ACE was 5.4 (3.3); 76% of participants reported childhood emotional neglect, 70% childhood verbal abuse, and 64% childhood sexual abuse; only two participants reported no adverse childhood experiences. CONCLUSIONS: The participants in the study reported high levels of adverse childhood experiences compared to the general population, which is consistent with prior literature on rates of childhood trauma in post-bariatric surgery patients. The role of adverse childhood experiences in post-bariatric surgery adaptation should be investigated in future research, including in prospective studies. PMID- 28593485 TI - Diffuse large B-cell lymphoma presenting as bilateral renal infiltration leading to acute kidney injury. AB - Acute kidney injury (AKI) because of bilateral renal infiltration is an uncommon presentation of diffuse large B-cell lymphoma (DLBCL). A 52-year-old man presented to our institution with AKI and complaints of fatigue. Ultrasonography revealed a large, 15 cm granulomatous mass arising from the bilateral kidneys. The mass was biopsied laparoscopically, and histopathological analysis revealed evidence of DLBCL. The patient subsequently underwent R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Chemotherapy resulted in a rapid decrease in mass size and improvement in kidney function. However, after five courses of R-CHOP, relapse was observed in the central nervous system, and the patient died 220 days after the initial onset of AKI. Post-mortem analysis of renal tissue confirmed the initial diagnosis of DLBCL associated renal infiltration. To our knowledge, this is the first report of DLBCL presenting as bilateral renal infiltration and AKI. PMID- 28593484 TI - Reflux, Sleeve Dilation, and Barrett's Esophagus after Laparoscopic Sleeve Gastrectomy: Long-Term Follow-Up. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (SG) has become the most frequently performed bariatric procedure worldwide. De novo reflux might impact patients' quality of life, requiring lifelong proton pump inhibitor medication. It also increases the risk of esophagitis and formation of Barrett's metaplasia. Besides weight regain, gastroesophageal reflux disease (GERD) is the most common reason for conversion to Roux-en-Y gastric bypass. METHODS: We performed 24-h pH metries, manometries, gastroscopies, and questionnaires focusing on reflux (GIQLI, RSI) in SG patients with a follow-up of more than 10 years who did not suffer from symptomatic reflux or hiatal hernia preoperatively. RESULTS: From a total of 53 patients, ten patients after adjustable gastric banding were excluded. From the remaining 43, six patients (14.0%) were converted to RYGB due to intractable reflux over a period of 130 months. Ten out of the remaining non converted patients (n = 26) also suffered from symptomatic reflux. Gastroscopies revealed de novo hiatal hernias in 45% of the patients and Barrett's metaplasia in 15%. SG patients suffering from symptomatic reflux scored significantly higher in the RSI (p = 0.04) and significantly lower in the GIQLI (p = 0.02) questionnaire. CONCLUSIONS: This study shows a high incidence of Barrett's esophagus and hiatal hernias at more than 10 years after SG. Its results therefore suggest maintaining pre-existing large hiatal hernia, GERD, and Barrett's esophagus as relative contraindications to SG. The limitations of this study-its small sample size as well as the fact that it was based on early experience with SG-make drawing any general conclusions about this procedure difficult. PMID- 28593486 TI - Urinary mulberry cells and mulberry bodies are useful tool to detect late-onset Fabry disease. AB - Fabry disease is an X-linked lysosomal storage disorder caused by a lack of alpha galactosidase A activity, which leads to the accumulation of globotriaosylceramide in various organs. A complete lack of alpha-galactosidase A activity in a hemizygous male is the classical phenotype, and some hemizygous males show primarily cardiac and/or renal symptoms that appear in adulthood; this is called the variant type or the late-onset type. The kidney and heart are the major target organs, with damage to these organs related to mortality. Thus, in Fabry patients, early detection and early treatment are critical to longevity. Here, we present a 55-year-old Japanese male patient who was diagnosed with late onset Fabry nephropathy with cardiomyopathy but with no abnormal urinary findings except for urinary mulberry cells and mulberry bodies. In spite of the absence of abnormal urinary findings, the light microscopic and electron microscopic pathological findings showed extensive deposition of globotriaosylceramide to podocytes. In this paper, we propose that the presence of mulberry cells and mulberry bodies can be used for the earlier detection of Fabry nephropathy, especially the late-onset type. PMID- 28593487 TI - Commentary: Micro-Autologous Fat Transplantation (MAFT) for Forehead Volumizing and Contouring. PMID- 28593488 TI - Optimizing Patient Selection for Direct-to-Implant Immediate Breast Reconstruction Using Wise-Pattern Skin-Reducing Mastectomy in Large and Ptotic Breasts. AB - BACKGROUND: Immediate breast reconstruction in large and ptotic breasts is challenging, often requiring skin-reducing procedures. The Wise-pattern skin reducing mastectomy (WPSRM) technique provides reliable one-stage implant coverage using the pectoralis muscle and a de-epithelialized inferiorly based dermal flap. However, de-vascularization may result in mastectomy skin flap necrosis. We aimed to critically evaluate and isolate patients at high risk of complications using this procedure. METHODS: We retrospectively reviewed consecutive patients undergoing WPSRM by the senior author from January 2008 to December 2011. Data collected included patient demographics, breast cancer staging, smoking, preoperative radiation, chemotherapy, BMI, mastectomy weight, implant size and type. We analyzed their effect on complications, revisions and failure rate. RESULTS: Fifty-nine WPSRMs were performed in 39 patients with a minimum of 12-month follow-up. Complications occurred in 43.75% patients and 34.88% breasts. Multivariate statistical analysis revealed that age (p = 0.093) and BMI (p = 0.631) were not significant risk factors as opposed to previously published data. Mastectomy weight was significantly associated with major complications requiring secondary surgery (odds ratio per 100 g of breast tissue was 1.18; 95% CI 1.01-1.39; p = 0.036) as 90.5% of our complications occurred in those patients with mastectomy weight exceeding 700 g. Complications were reduced twofold when selecting a Becker adjustable implant over a silicone one for these higher mastectomy weights. CONCLUSION: WPSRM was found to be associated with an increased complication rate in patients with high mastectomy weights and immediate reconstruction with silicone implants. We propose an algorithm offering better patient selection for this technique in immediate breast reconstruction. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28593489 TI - Comment to: "The Characteristics and Short-Term Surgical Outcomes of Adolescent Gynecomastia". PMID- 28593490 TI - Stenotic Breast Malformation and Its Reconstructive Surgical Correction: A New Concept From Minor Deformity to Tuberous Breast. AB - BACKGROUND: Several classification systems have been reported to define the spectrum of tuberous breast deformity, and a range of surgical techniques has been described. In this paper, we proposed a new classification including tuberous breast and minor deformity based on stenosis type, glandular trophism and ptosis adapting surgical planning to different breast types. METHODS: A total of 246 patients meeting our definition for stenotic breasts asking for surgery were analyzed in this study. We considered eight different types of stenotic breasts analyzing anatomical presentations, and we then proposed eight key-point maneuvers, finalized to the correction of different breast deformities and their possible association according to the stenotic breast type. Results have been evaluated by a group of three surgeons and by patients. In addition, we evaluated the complication incidence in terms of re-intervention rate. RESULTS: Following our classification eight different groups were distinguished. For each one we reported the prevalence and the surgical procedure adopted. Results evaluated by the surgeon group reported a mean aesthetic outcome of 8.2 (range 5-10), whereas patients reported a mean value of 7.9 (range 6-10). During a follow-up period with a mean of 16 months we observed a 4.9% re-intervention rate. CONCLUSIONS: We believe this new classification to be very complete in evaluating breast shape, including most of the breast evaluable features. Our results confirmed the suitability of the approach for appropriate preoperative planning, thus improving the global surgical outcome. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28593491 TI - Prune Belly Syndrome with Sacrococcygeal Teratoma. PMID- 28593492 TI - Classical determinants of coronary artery disease as predictors of complexity of coronary lesions, assessed with the SYNTAX score. AB - BACKGROUND: We need new biomarkers that can predict cardiovascular disease to improve both diagnosis and therapeutic strategies. The CIRCULATING CELLS study was designed to study the role of several cellular mediators of atherosclerosis as biomarkers of coronary artery disease (CAD). An objective and reproducible method for the quantification of CAD extension is required to establish relationships with these potential biomarkers. We sought to analyse the correlation of the SYNTAX score with known CAD risk factors to test it as a valid marker of CAD extension. METHODS AND RESULTS: A subgroup of 279 patients (67.4% males) were included in our analysis. Main exclusion criteria were a history of previous percutaneous coronary intervention or surgical revascularisation that prevent an accurate assessment of the SS. Diabetes mellitus, smoking, renal insufficiency, body mass index and a history of CAD and myocardial infarction were all positively and strongly associated with a higher SYNTAX score after adjustment for the non-modifiable biological factors (age and sex). In the multivariate model, age and male sex, along with smoking and renal insufficiency, remain statistical significantly associated with the SYNTAX score. CONCLUSION: In a selected cohort of revascularisation-naive patients with CAD undergoing coronary angiography, non-modifiable cardiovascular risk factors such as advanced age, male sex, as well as smoking and renal failure were independently associated with CAD complexity assessed by the SYNTAX score. The SYNTAX score may be a valid marker of CAD extension to establish relationships with potential novel biomarkers of coronary atherosclerosis. PMID- 28593494 TI - ? PMID- 28593493 TI - ? PMID- 28593496 TI - Compliance with indoor tanning bans for minors among businesses in the USA. AB - Indoor tanning is a known risk factor for skin cancer and is especially dangerous for adolescents. Some states have passed indoor tanning bans for minors, but business compliance with the bans is not well understood. Thus far, studies have assessed ban compliance in one or two states at a time. This study aimed to assess compliance with indoor tanning bans for minors and knowledge of dangers and benefits of tanning among indoor tanning businesses. Female research assistants posing as minors telephoned a convenience sample of 412 businesses in 14 states with tanning bans for minors under age 17 or 18. We evaluated differences in compliance by census region and years since ban was implemented and differences in reported dangers and benefits by compliance. Most (80.1%) businesses told the "minor" caller she could not use the tanning facilities. Businesses in the south and in states with more recent bans were less compliant. Among those (n = 368) that completed the full interview, 52.2% identified burning and 20.1% mentioned skin cancer as potential dangers. However, 21.7% said dangers were no worse than the sun and 10.3% denied any dangers. Stated benefits included vitamin D (27.7%), social/cosmetic (27.2%), and treats skin diseases (26.4%), with only 4.9% reporting no benefits. While most businesses followed the indoor tanning ban when a minor called, one-fifth did not. Many stated inaccurate health claims. Additional enforcement or education might increase compliance with indoor tanning bans and action is needed to prevent businesses from stating false health information. PMID- 28593495 TI - Association of Ferredoxin:NADP+ oxidoreductase with the photosynthetic apparatus modulates electron transfer in Chlamydomonas reinhardtii. AB - Ferredoxins (FDX) and the FDX:NADP+ oxidoreductase (FNR) represent a key junction of electron transport downstream of photosystem I (PSI). Dynamic recruitment of FNR to the thylakoid membrane has been considered as a potential mechanism to define the fate of photosynthetically derived electrons. In this study, we investigated the functional importance of the association of FNR with the photosynthetic apparatus in Chlamydomonas reinhardtii. In vitro assays based on NADP+ photoreduction measurements as well as NMR chemical shift perturbation analyses showed that FNR preferentially interacts with FDX1 compared to FDX2. Notably, binding of FNR to a PSI supercomplex further enhanced this preference for FDX1 over FDX2, suggesting that FNR is potentially capable of channelling electrons towards distinct routes. NADP+ photoreduction assays and immunoblotting revealed that the association of FNR with the thylakoid membrane including the PSI supercomplex is impaired in the absence of Proton Gradient Regulation 5 (PGR5) and/or Proton Gradient Regulation 5-Like photosynthetic phenotype 1 (PGRL1), implying that both proteins, directly or indirectly, contribute to the recruitment of FNR to the thylakoid membrane. As assessed via in vivo absorption spectroscopy and immunoblotting, PSI was the primary target of photodamage in response to high-light stress in the absence of PGR5 and/or PGRL1. Anoxia preserved the activity of PSI, pointing to enhanced electron donation to O2 as the source of the observed PSI inactivation and degradation. These findings establish another perspective on PGR5/PGRL1 knockout-related phenotypes and potentially interconnect FNR with the regulation of photosynthetic electron transport and PSI photoprotection in C. reinhardtii. PMID- 28593498 TI - BPDE-induced genotoxicity: relationship between DNA adducts, mutagenicity in the in vitro PIG-A assay, and the transcriptional response to DNA damage in TK6 cells. AB - Benzo[a]pyrene is a known human carcinogen. As underlying mechanism, the induction of stable DNA adducts and mutations have been repeatedly demonstrated. Also, the activation of cellular stress response on the transcriptional level has been described. Nevertheless, the interrelationship between these different events is less well understood, especially at low, for human exposure relevant concentrations. Within the present study, we applied the reactive metabolite benzo[a]pyrene diolepoxide (BPDE) in the nanomolar, non-cytotoxic concentration range in human TK6 cells and quantified the induction and repair of stable DNA adducts at the N 2-position of guanine by HPLC with fluorescence detection. Significant levels of DNA lesions were detected even at the lowest concentration of 10 nM BPDE, with a linear increase up to 50 nM. Relative repair was similar at all damage levels, reaching about 30% after 8 h and 60% after 24 h. Mutation frequencies were quantified as GPI-deficient cells by the recently established in vitro PIG-A mutagenicity assay. Again, a linear dose-response-relationship in the before-mentioned concentration range was observed, also when plotting the number of GPI-deficient cells against the number of DNA adducts. Furthermore, we explored the time- and concentration-dependent DNA damage response on the transcriptional level via a high-throughput RT-qPCR technique by quantifying the impact of BPDE on the transcription of 95 genes comprising DNA damage response, DNA repair factors, oxidative stress response, cell cycle arrest, cell proliferation, and apoptosis. As expected, BPDE activated DNA damage signaling, p53 and AP-1 dependent signaling, oxidative stress response, and apoptosis. However, in contrast to DNA adducts and mutations, the onset of the transcriptional DNA damage response was restricted to higher concentrations, indicating that its respective activations require a certain level of DNA lesions. Altogether, the results indicate that in case of BPDE, DNA lesions and mutations were correlated at all concentrations, suggesting that repair is not complete even at low levels of DNA damage. Considering the ongoing discussion on potential thresholds also for genotoxic carcinogens, the results are of major relevance, both with respect to basic research as well as to risk assessment of chemical carcinogens. PMID- 28593499 TI - In-utero exposure to nicotine alters the development of the rabbit cardiac conduction system and provides a potential mechanism for sudden infant death syndrome. AB - In-utero exposure to tobacco smoke remains the highest risk factor for sudden infant death syndrome (SIDS). To alleviate the risks, nicotine replacement therapies are often prescribed to women who wish to quit smoking during their pregnancy. Cardiac arrhythmias is considered the final outcome leading to sudden death. Our goal in this study was to determine if exposing rabbit fetus to nicotine altered the cardiac conduction system of newborn kittens in a manner susceptible to cause SIDS. Using neuronal markers and a series of immunohistological and electrophysiological techniques we found that nicotine delayed the development of the cardiac pacemaker center (sinoatrial node) and decreased its innervation. At the molecular level, nicotine favored the expression of cardiac sodium channels with biophysical properties that will tend to slow heart rate and diminish electrical conduction. Our results show that alterations of the cardiac sodium current may contribute to the bradycardia, conduction disturbances and other cardiac arrhythmias often associated to SIDS and raise awareness on the use of replacement therapy during pregnancy. PMID- 28593497 TI - Mathematical and Computational Modeling for Tumor Virotherapy with Mediated Immunity. AB - We propose a new mathematical modeling framework based on partial differential equations to study tumor virotherapy with mediated immunity. The model incorporates both innate and adaptive immune responses and represents the complex interaction among tumor cells, oncolytic viruses, and immune systems on a domain with a moving boundary. Using carefully designed computational methods, we conduct extensive numerical simulation to the model. The results allow us to examine tumor development under a wide range of settings and provide insight into several important aspects of the virotherapy, including the dependence of the efficacy on a few key parameters and the delay in the adaptive immunity. Our findings also suggest possible ways to improve the virotherapy for tumor treatment. PMID- 28593500 TI - Bilateral thalamic deep brain stimulation for essential tremor in elderly patients. AB - The purpose of this study was to assess the influence of age on thalamic deep brain stimulation (DBS) in essential tremor (ET). Tremor, cognition, mood and adverse events in patients with thalamic DBS for ET were evaluated in 26 consecutive patients with established standardized methods for tremor and cognition. Twelve patients <70 and 14 patients >=70 years were included and followed for 2 years. Clinical outcomes did not differ significantly. DBS seems to be safe and effective for ET independent of age. PMID- 28593501 TI - Drying or anaerobic digestion of fish sludge: Nitrogen fertilisation effects and logistics. AB - Application of fish sludge as fertiliser to agricultural land can contribute to closing nutrient cycles in fish farming. The effect of different treatment technologies on the nitrogen fertilisation effects of fish sludge was studied by a bioassay with barley (Hordeum vulgare), an incubation and a field experiment. Dried fish sludge resulted in relative agronomic efficiency of 50-80% compared with mineral fertiliser. The anaerobic digestate based on fish sludge (20 vol%) and dairy manure did not increase nitrogen uptake in barley. Increasing the ratio of fish sludge in the digestate increased the fertilisation effect, but requires optimisation of the biogas process. A simple logistics analysis conducted for a case hatchery showed that on-site drying and co-digestion of fish sludge in a central biogas plant can be regarded as equal in terms of costs. Norway can become an exporter of fish sludge-based recycling fertilisers if current regulations are modified to facilitate nutrient recycling. PMID- 28593502 TI - Prognostic Factors in Surgical Patients with Chordomas of the Cervical Spine: A Study of 52 Cases from a Single Institution. AB - BACKGROUND: The recurrence rate of cervical chordomas is high, and hence it is important to discern the prognostic factors for local relapse and overall survival (OS). METHODS: A retrospective review of 52 patients with cervical chordoma operated in our institution from January 1999 to March 2015 was performed. The association of clinicopathologic characteristics with local relapse-free survival (LRFS) and OS was analyzed. Univariate analysis was performed to determine whether tumor characteristics and types of therapy affected prognosis, and a multivariate Cox proportional hazard model was developed to further investigate local recurrence and mortality. RESULTS: Mean follow-up time was 50 months. The cumulative 5- and 10-year LRFS was 35 and 0%, respectively, while the cumulative 5- and 10-year OS was 69 and 53%, respectively. The univariate analysis identified contiguous segments involved, intralesional surgical margin at primary surgery, primary surgery in local hospital, incisional biopsy, and without adjuvant radiotherapy as negative prognostic factors for LRFS, whereas for OS, only tumor location in the upper cervical spine was statistically significant. In the multivariate analysis, contiguous vertebral segments involved, intralesional surgical margins, and incisional biopsy were identified as negative prognostic factors for LRFS, whereas for OS, again only tumor location in the upper cervical spine was statistically significant. CONCLUSIONS: Contiguous vertebral segments involved, intralesional surgical margin, without adjuvant radiotherapy, and incisional biopsy significantly increase local recurrence, while tumor location in the upper cervical spine significantly increases tumor-related mortality. Thus, computed tomography-guided fine-needle aspiration biopsy and total spondylectomy with marginal excision may improve survival of patients with cervical chordoma. PMID- 28593504 TI - An Algorithm to Identify Generic Drugs in the FDA Adverse Event Reporting System. AB - INTRODUCTION: Although generic drugs constitute approximately 88% of drugs prescribed in the US, there are no reliable methods to identify generic drugs in the US FDA Adverse Event Reporting System (FAERS). OBJECTIVE: The aim of this study was to develop an algorithm for identifying generic drugs in the FAERS. DATA SOURCE: We used 1237 adverse event reports for tamsulosin, levothyroxine, and amphetamine/dextroamphetamine from the publicly available FAERS from 2011 2013, and 277 source case narratives obtained from the FDA. METHODS: Two reviewers independently and in duplicate used a three-item algorithm including the following criteria: manufacturer name, New Drug Application (NDA) number/abbreviated NDA (ANDA), and specific use of the term 'generic' or 'brand' to classify the focal drug of each case report as definitely generic (two of three criteria), probably generic (one of three criteria), brand, and cannot be assessed. Inter-rater reliability was estimated using kappa coefficients, and internal consistency was estimated using Cronbach's alpha. We compared the classification of the drugs as generic versus non-generic in publicly available FAERS compared with the original case reports (reference). RESULTS: The focal drug was classified as generic (definite or probable) in 15.8% (39/234), 9% (67/742), and 16.7% (42/261) of tamsulosin, levothyroxine and amphetamine/dextroamphetamine cases, respectively (overall kappa 0.89, 95% confidence interval 0.85-0.93), while 37% of reports could not be classified due to incomplete information. Among the drugs classified as generics using the publicly available FAERS, we categorized 95.3% as generic drugs using the original case reports. Among those drugs that did not meet the algorithm-based definition of generic in the publicly available data, 20.9% were reclassified as generics using the original case reports. CONCLUSIONS: The algorithm demonstrated high inter-rater reliability with moderate internal consistency for identifying generic drugs in the FAERS, in our sample. Future efforts should focus on improving the reliability and validity of identifying generics through improving the completeness of reporting in the FAERS. PMID- 28593505 TI - Correlates of Social Support Among Latino Immigrants. AB - Latino immigrants encounter considerable stressors that pose risks to health and well-being during settlement in the USA. Social support serves as a protective factor that can help to buffer the negative effects of stress. Despite the importance of social support, we know little about how Latino immigrants differentially experience this protective factor. The current study analyzed data from 100 Latino immigrants residing in Tennessee. Hierarchical multiple regression analysis was employed to examine variation in self-reported social support by immigrant characteristics and immigration-related factors. Females, immigrants who are not married/cohabitating, and those who reported experiencing a greater number of discrete stressors in the USA each reported lower levels of social support. Implications for practice include an increased emphasis on assessing levels of social support and designing services to strengthen support for the most vulnerable immigrants. Future research should consider a longitudinal analysis and specific types of social support. PMID- 28593503 TI - Global Level of Plasma DNA Methylation is Associated with Overall Survival in Patients with Hepatocellular Carcinoma. AB - BACKGROUND: The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. METHODS: We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. RESULTS: Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with >=70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12 2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. >=27.7 nmol/L; HR = 1.96; 95% CI, 1.24-3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance (P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival. CONCLUSIONS: These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients. PMID- 28593506 TI - Conformal mapping of carotid vessel wall and plaque thickness measured from 3D ultrasound images. AB - Measurements of vessel-wall-plus-plaque thickness (VWT) from 3D carotid ultrasound have been shown to be sensitive to the effect of pharmaceutical interventions. Since the geometry of carotid arteries is highly subject-specific, quantitative comparison of the distributions of point-wise VWT measured for different patients or for the same patients at different ultrasound scanning sessions requires the development of a mapping strategy to adjust for the geometric variability of different carotid surface models. In this paper, we present an algorithm mapping each 3D carotid surface to a 2D carotid template with an emphasis on preserving the local geometry of the carotid surface by minimizing local angular distortion. The previously described arc-length scaling (AL) approach was applied to generate an initial 2D VWT map. Using results established in the quasi-conformal theory, a new map was computed to compensate for the angular distortion incurred in AL mapping. As the 2D carotid template lies on an L-shaped non-convex domain, one-to-one correspondence of the mapping operation was not guaranteed. To address this issue, an iterative Beltrami differential chopping and smoothing procedure was developed to enforce bijectivity. Evaluations performed in the 20 carotid surface models showed that the reduction in average angular distortion made by the proposed algorithm was highly significant (P = 2.06 * 10-5). This study is the first study showing that a bijective conformal map to a non-convex domain can be obtained using the iterative Beltrami differential chopping and smoothing procedure. The improved consistency exhibited in the 2D VWT map generated by the proposed algorithm will allow for unbiased quantitative comparisons of VWT as well as local geometric and hemodynamic quantities in population studies. PMID- 28593507 TI - A stochastic algorithm for automatic hand pose and motion estimation. AB - In this paper, a novel, robust, and simple method for automatically estimating the hand pose is proposed and validated. The method uses a multi-camera optoelectronic system and a model-based stochastic algorithm. The approach is marker-based and relies on an Unscented Kalman Filter. A hand kinematic model is introduced for constraining relative marker's positions and improving the algorithm robustness with respect to outliers and possible occlusions. The algorithm outputs are 3D coordinate measures of markers and hand joint angle values. To validate the proposed algorithm, a comparison with ground truths for angular and 3D coordinate measures is carried out. The comparative analysis shows the advantages of using the model-based stochastic algorithm with respect to standard processing software of optoelectronic cameras in terms of implementation simplicity, time consumption, and user effort. The accuracy is remarkable, with a difference of maximum 0.035r a d and 4m m with respect to angular and 3D Cartesian coordinates ground truths, respectively. PMID- 28593509 TI - Health expenditure and economic growth - a review of the literature and an analysis between the economic community for central African states (CEMAC) and selected African countries. AB - African leaders accepted in the year 2001 through the Abuja Declaration to allocate 15% of their government expenditure on health but by 2013 only five (5) African countries achieved this target. In this paper, a comparative analysis on the impact of health expenditure between countries in the CEMAC sub-region and five other African countries that achieved the Abuja declaration is provided. Data for this study was extracted from the World Development Indicators (2016) database, panel ordinary least square (OLS), fully modified ordinary least square (FMOLS) and dynamic ordinary least square (DOLS) were used as econometric technic of analysis. Results showed that health expenditure has a positive and significant effect on economic growth in both samples. A unit change in health expenditure can potentially increase GDP per capita by 0.38 and 0.3 units for the five other African countries that achieve the Abuja target and for CEMAC countries respectively, a significant difference of 0.08 units among the two samples. In addition, a long-run relationship also exist between health expenditure and economic growth for both groups of countries. Thus African Economies are strongly advised to achieve the Abuja target especially when other socio-economic and political factors are efficient. PMID- 28593508 TI - BET bromodomain inhibitor JQ1 decreases CD30 and CCR4 expression and proliferation of cutaneous T-cell lymphoma cell lines. AB - Bromodomain and external domain (BET) proteins regulate cell growth, proliferation, cell cycle, and differentiation in various cancers. Therefore, they have emerged as interesting targets. The effect of BET inhibitor on cutaneous T-cell lymphoma (CTCL), however, is yet to be known. Here, we examined the effect of BET inhibitor JQ1 on four cell lines (MyLa, SeAx, Hut78 and HH cells). CTCL cell lines were treated with JQ1 and cell number, cell cycle, frequency of apoptosis, and expressions of CD25, CD30 and CCR4 on the cell surface were evaluated by flow cytometry. Cell surface molecules were also analyzed by quantitative RT-PCR. JQ1 dose-dependently decreased the cell number of CTCL cells through G1 arrest concomitantly with downregulation of c-Myc expression. JQ1 induced senescence in MyLa cells and apoptosis in Hut78 and HH cells. We also showed that JQ1 inhibited tumor growth of HH cells in vivo. Moreover, JQ1 downregulated CD30 and CCR4 expression both on the cell surface and at mRNA levels. Thus, BET bromodomain inhibitor JQ1 may be useful for treatment of CTCL. PMID- 28593510 TI - Within-Bolus Variability of the Penetration-Aspiration Scale Across Two Subsequent Swallows in Patients with Head and Neck Cancer. AB - To compare two consecutive swallowing attempts to study if there is a difference in Rosenbek's penetration-aspiration scale (PAS) scores between the first and second swallowing attempt of the same bolus type in videofluoroscopic examination of swallowing (VFS). Additional aims include reflecting on which bolus sizes and consistencies are the most relevant to include in further studies for head and neck cancer (HNC) patients. The VFS for 38 patients curatively treated for HNC was studied. All included patients showed swallowing difficulties (PAS >= 2). The examination protocol included two swallows each of six different boluses: 3, 5, 10, 20 ml thin, 5 ml mildly thick, and 3 ml of extremely thick liquid. All boluses were compared between the first and second swallowing attempt with regard to PAS scores. No statistically significant differences in PAS were found between the first and second swallow for any of the boluses in this study on group level. For 20 ml thin and 3 ml extremely thick liquid, there were low Intra-Class Correlations, indicating a low within-bolus agreement. The greatest within-bolus differences were found for 20 ml thin, 5 ml mildly thick and 3 ml extremely thick liquid, which demonstrated high intra-individual coefficient of variation (0.458 0.759). The data of this study show a high within-bolus variability of the PAS score between two subsequent swallows for all different consistencies. In order to assess swallowing safety, the highest PAS score for each bolus type is suggested for use in studies of HNC patients. PMID- 28593512 TI - PIPAC puts pressure on peritoneal metastases from pancreatic cancer. PMID- 28593511 TI - De novo exonic duplication of ATP1A2 in Italian patient with hemiplegic migraine: a case report. AB - BACKGROUND: Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine. CASE PRESENTATION: We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine. CONCLUSIONS: Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission. PMID- 28593513 TI - Gene therapy with helper-dependent adenoviral vectors: lessons from studies in large animal models. AB - Helper-dependent adenoviral vectors (HDAd) are deleted of all viral genes and they can efficiently transduce a wide variety of dividing and non-dividing cells to mediate high transgene expression levels. Unlike early generation adenoviral vectors, the absence of viral genes in HDAd results in long-term transgene expression without chronic toxicity and permits a large cloning capacity of 36 kb. Moreover, HDAd genomes exist extra-chromosomally thus minimizing the risks of germline transmission and insertional mutagenesis. For these reasons, HDAd offers tremendous potential for in vivo gene therapy. This chapter reviews preclinical studies using HDAd in large animal models to assess safety and efficacy in a wide variety of gene therapy applications. PMID- 28593515 TI - Cu-resistant Kocuria sp. CRB15: a potential PGPR isolated from the dry tailing of Rakha copper mine. AB - Rhizobacteria may enhance biomass production and heavy metal tolerance of plants under stress conditions. The present study was carried out for isolation of metal resistant bacteria that can be further utilized for phytoremediation process. A potential metal-resistant strain CRB15 was isolated from rhizospheric region of Saccharum spontaneum that was found to be resistant against Cu (6.29 mM), Zn (3.25 mM), Pb (1.5 mM), Ni (1.25 mM), and Cd (0.25 mM). SEM analysis was performed for evaluation of morphological changes on bacterial isolate. FTIR analysis observed the change in wavenumbers after the addition of Cu. 16S rDNA sequence analysis showed that CRB15 isolate matched best with genus of Kocuria and was named as Kocuria sp. CRB15. The isolate Kocuria sp. CRB15 was a potential plant growth-promoting rhizobacterium as it had a high IAA (46 ug ml-1), P solubilisation (39.37 ug ml-1), ammonia production (30.46 umol ml-1), and hydrogen cyanide production capacity. Root-shoot elongation assay conducted on Brassica nigra under lab conditions with strain CRB15 demonstrated positive effects of strain CRB15 in root and shoot elongation of Cu-treated seedlings. This study proved the Kocuria sp. CRB15 a potential PGPR for bacterial-assisted phytoremediation. PMID- 28593514 TI - Influence of Formulation Factors on the Aerosol Performance of Suspension and Solution Metered Dose Inhalers: A Systematic Approach. AB - Metered dose inhalers (MDIs) are complex drug-device combination products widely used to treat pulmonary disorders. The efficacy, driven by aerosol performance of the products, depends on a multitude of factors including, but not limited to, the physicochemical properties of drug and nature and amount of excipient(s). Under the quality by design (QbD) paradigm, systematic investigations are necessary to understand how changes in critical quality attributes (CQAs) of formulation, device, and manufacturing process influence key product performance parameters, such as delivered dose (DD) and fine particle dose (FPD). The purpose of this work is to provide a better understanding of the effects of different levels of excipients and drug particle size distribution on the aerosol performance of MDI products, while using two fundamentally different MDI products as relevant model systems, Proventil(r) HFA (albuterol sulfate suspension) and Qvar(r) (beclomethasone dipropionate solution). These MDI products, as model systems, provided mid-points around which a design of experiments (DOE), consisting of 22 suspension and 9 solution MDI formulations, were defined and manufactured. The DOE included formulations factors with varying ethanol (2 to 20% w/w and 7 to 9% w/w for the suspension and solution, respectively) and oleic acid concentrations (0.005 to 0.25% w/w and 0 to 2% w/w for the suspension and solution, respectively) and drug volumetric median particle size distribution (PSD D50, 1.4 to 2.5 MUm for the suspension). The MDI formulations were analyzed using compendial methods to elucidate the effect of these formulation variables (ethanol, oleic acid, and PSD D50) on DD and FPD. The outcomes of this study allowed defining design spaces for the formulation factors, such that DD and FPD would remain within specific pre-defined requirements. The systematic approach utilized in this work can contribute as a QbD tool to evaluate the extent to which the formulation factors govern the aerosol performance of MDI drug products, helping to design MDI formulations with desired product performance parameters. PMID- 28593517 TI - Ginger extract as green biocide to control microbial corrosion of mild steel. AB - In latest years, various techniques and chemicals have been used for the control of microbial influenced corrosion (MIC) of metals. The application of botanical based biocides is one of the effective and practical techniques in the fight against MIC. In the present study, the role of aqueous extract of ginger (Zingiber officinale) (GIE) as green biocide to control MIC of mild steel 1010 (MS) in a cooling water system was investigated. Biocorrosion behavior of Bacillus thuringiensis EN2 on MS and its control by GIE was analyzed by electrochemical measurements. Polarization, electrochemical studies (ES), weight loss measurements (WL), and surface analysis (XRD, X-ray diffraction spectroscopy, and FTIR, Fourier transform infra-red spectroscopy) were performed under various incubation periods up to 4 weeks. We observed that EN2 forms a thick biofilm on the MS metal surface at the end of the incubation period and the WL significantly increased to 993 mg at fourth week when compared to the initial immersion period (194 +/- 2 mg). In contrast, with addition of GIE, WL was reduced about 41 +/- 2 mg over biotic system (993 +/- 2 mg). GC-MS analysis confirmed the adsorption of active component of GIE (beta-turmerone) on the metal surface as a protective layer to prevent the biofilm formation and thus leads to reduction of corrosion. The optimum 20 ppm of GIE was found to be effective corrosion inhibition efficiency which was about 80%. From the results of WL, ES, XRD, FTIR, and GC-MS, GIE was identified as biocide and thus inhibits the bacterial growth on MS metal surface and it leads to control MIC. XRD showed that the GIE with EN2 resulted in less formation of corrosion products over biotic and abiotic systems. Overall, this research first shed light on the antibacterial activity of GIE inhibiting biofilm formation, thus reducing the corrosion of MS in cooling water systems. PMID- 28593516 TI - Antidepressant and anxiolytic effects of Garcinia indica fruit rind via monoaminergic pathway. AB - Depression and anxiety are the most crippling neuropsychiatric disorders of this modern era. These mostly occur as anxiety followed by depression or in mixed state. Therefore, there is an urgent need of a safe and effective treatment, which proves its worth in this ailment. What else than a conventional food would be a better choice for a convenient therapy. Therefore, Garcinia indica, commonly known as Kokam, fruit rind has been used in the present study to investigate its antidepressant and anti-anxiety potential using forced swim test, tail suspension test, and reserpine-induced hypothermia; and elevated plus maze, hole-board test, and light dark model, respectively. Garcinia indica fruit rind given to mice with food for consecutive 14 days at 0.5, 1, and 2% w/w significantly (p < 0.05) reduced despair behavior in forced swim test, immobility duration in tail suspension test, and also switched the hypothermia (reserpine induced) to normal temperature significantly (p < 0.05). Garcinia indica significantly (p < 0.05) raised the time elapsed and count of entries in open arms of elevated plus maze, enhanced incidence of head dipping in holes of hole board along with duration of expending time in lit compartment of light dark model, exhibiting its anti anxiety effect. Garcinia indica significantly reduced monoamine oxidase and malondialdehyde levels providing support to neuroprotective potential of fruit rind. The mechanistic study showed the participation of G. indica at alpha1 adrenoceptor and D2-dopamine receptor, by attenuating prazosin and sulpiride induced increase in immobility duration. Garcinia indica fruit rind showed a significant antidepressant and anxiolytic effect while no effect on locomotor activity, i.e., no psycho-stimulation. PMID- 28593519 TI - Solid-state fermentation for production of a bioherbicide from Diaporthe sp. and its formulation to enhance the efficacy. AB - In this study, a bioherbicide was produced by solid-state fermentation (SSF) using Diaporthe sp. Adjuvants were employed in a formulation to enhance the herbicidal activity towards the target (Cucumis sativus). The study was divided into two steps: (1) the fermentation condition for bioherbicide production was assessed; (2) evaluation of different formulations containing palm oil, Tween(r) 80 and Span(r) 80, in order to increase phytotoxicity. In step 1, the maximum herbicidal activity (1.23% of the leaves had lesions) was obtained at 25 degrees C, moisture content of 50 wt%, supplemented with 10 wt% of corn steep liquor and soybean bran and inoculum density of 15 wt%. In step 2, the formulation containing 8.2 wt% of palm oil, 8.2 wt% of Tween(r) 80 and Span(r) 80, resulting in an HLB of 12.8 showed the highest phytotoxicity on the leaves. At this condition, dry matter and height of target were reduced about 36% in comparison with control. Diaporthe sp. has the potential to produce molecules with herbicidal activity and the use of adjuvants enhanced three times its efficiency. PMID- 28593518 TI - Purification, characterization and retting of Crotolaria juncea fibres by an alkaline pectin lyase from Fusarium oxysporum MTCC 1755. AB - Using solid-state fermentation, production of an industrially important pectin lyase from a fungal strain Fusarium oxysporum MTCC 1755 was attempted, which was further subjected to purification and characterization. The enzyme was purified by three steps, namely ammonium sulfate fractionation, cation-exchange chromatography on CM cellulose followed by gel filtration chromatography using Sephadex G-100 column. A 16-fold purification with 31.2% yield and 3.2 U/mg specific activity was achieved. The optimum pH of the purified enzyme was 9.0 and stability ranged from pH 5.0-7.0 for 24 h. Optimum temperature of purified enzyme was found to be 40 degrees C while temperature stability ranged from 10 to 50 degrees C for 30 min. The K m and k cat of the enzyme was 1.75 mg/ml and 83.3 s 1, respectively. The purified enzyme was found to be highly stimulated by Ca2+ ions while sugars like mannitol and sorbitol, and salts like NaCl and CaCl2 enhanced the thermostability. The purified pectin lyase was found suitable for retting of Crotolaria juncea fiber. PMID- 28593520 TI - Antioxidant properties and polyphenolic content in terrestrial cyanobacteria. AB - Cell-free extracts of twenty terrestrial cyanobacteria were evaluated for their antioxidant properties in terms of free-radical scavenging (DPPH and ABTS) and metal chelating activity and deoxyribose protection. Extract of Anabaena constricta was the most prominent antioxidant agent (IC50 for DPPH activity 0.91 mg ml-1, ABTS 0.23 mg ml-1, deoxyribose protection 0.63 mg ml-1 and Fe+2-ion chelating 0.9 mg ml-1). The extracts of cyanobacterial species contained high quantity of total phenol and total flavonoid that were supposed to impart prominent antioxidant properties. Cyanobacterial species also showed fairly high PAL activity. We reported varied quantities of polyphenolics gallic, chlorogenic, caffeic, vanillic and ferulic acids and flavonoids rutin, quercetin and kaempferol in cyanobacterial extracts. The presence of these polyphenolics was linked with the free radical scavenging, metal chelating and antioxidative damage protecting properties of the organisms. Cyanobacteria are the most feasible, promising and alternative candidates for searching out new chemical leads for industrial applications in pharmaceuticals, neutraceuticals and biomolecules of importance. Presence of biomolecules such as polyphenolics and their connection with the prominent biological functions (e.g., antioxidant properties) make these organisms a potential source of secondary metabolites with predominant biological activities. Additionally, dominant presence of polyphenols as antioxidant agents in cyanobacterial species may reflect their adaptation strategies against abiotic stresses for their ecological success in different habitats. PMID- 28593521 TI - Identification of siderophore producing and cynogenic fluorescent Pseudomonas and a simple confrontation assay to identify potential bio-control agent for collar rot of chickpea. AB - In soil, plant roots coexist with bacteria and fungi that produce siderophores capable of sequestering the available iron. Microbial cyanogenesis has been demonstrated in many species of fungi and in a few species of bacteria (e.g., Chromobacterium and Pseudomonas). Fluorescent Pseudomonas isolates P29, P59, P144, P166, P174, P187, P191 and P192 were cyanogenic and produced siderophores in the presence of a strong chelater 8-Hydroxyquinoline (50 mg/l). A simple confrontation assay for identifying potential antagonists was developed. Fluorescent Pseudomonas isolates P66, P141, P144, P166 and P174 were antagonistic against both Rhizoctonia solani and Sclerotium rolfsii. Vigorous plant growth was observed following seed bacterization with P141, P200 and P240. In field experiments, seed bacterization with selected bacterial isolates resulted in reduced collar rot (S. rolfsii) incidence. PMID- 28593522 TI - Using an artificial neural network to predict the optimal conditions for enzymatic hydrolysis of apple pomace. AB - The enzymatic degradation of lignocellulosic biomass such as apple pomace is a complex process influenced by a number of hydrolysis conditions. Predicting optimal conditions, including enzyme and substrate concentration, temperature and pH can improve conversion efficiency. In this study, the production of sugar monomers from apple pomace using commercial enzyme preparations, Celluclast 1.5L, Viscozyme L and Novozyme 188 was investigated. A limited number of experiments were carried out and then analysed using an artificial neural network (ANN) to model the enzymatic hydrolysis process. The ANN was used to simulate the enzymatic hydrolysis process for a range of input variables and the optimal conditions were successfully selected as was indicated by the R 2 value of 0.99 and a small MSE value. The inputs for the ANN were substrate loading, enzyme loading, temperature, initial pH and a combination of these parameters, while release profiles of glucose and reducing sugars were the outputs. Enzyme loadings of 0.5 and 0.2 mg/g substrate and a substrate loading of 30% were optimal for glucose and reducing sugar release from apple pomace, respectively, resulting in concentrations of 6.5 g/L glucose and 28.9 g/L reducing sugars. Apple pomace hydrolysis can be successfully carried out based on the predicted optimal conditions from the ANN. PMID- 28593523 TI - Dilute acid pretreatment of sorghum biomass to maximize the hemicellulose hydrolysis with minimized levels of fermentative inhibitors for bioethanol production. AB - Conversion of lignocellulosic biomass into monomeric carbohydrates is economically beneficial and suitable for sustainable production of biofuels. Hydrolysis of lignocellulosic biomass using high acid concentration results in decomposition of sugars into fermentative inhibitors. Thus, the main aim of this work was to investigate the optimum hydrolysis conditions for sorghum brown midrib IS11861 biomass to maximize the pentose sugars yield with minimized levels of fermentative inhibitors at low acid concentrations. Process parameters investigated include sulfuric acid concentration (0.2-1 M), reaction time (30-120 min) and temperature (80-121 degrees C). At the optimum condition (0.2 M sulfuric acid, 121 degrees C and 120 min), 97.6% of hemicellulose was converted into xylobiose (18.02 mg/g), xylose (225.2 mg/g), arabinose (20.2 mg/g) with low concentration of furfural (4.6 mg/g). Furthermore, the process parameters were statistically optimized using response surface methodology based on central composite design. Due to the presence of low concentration of fermentative inhibitors, 78.6 and 82.8% of theoretical ethanol yield were attained during the fermentation of non-detoxified and detoxified hydrolyzates, respectively, using Pichia stipitis 3498 wild strain, in a techno-economical way. PMID- 28593524 TI - Virulence factors associated with Coagulase Negative Staphylococci isolated from human infections. AB - Infections caused by commensal organisms by changing to infectious life style generate much challenge to the current treatment strategies. Coagulase Negative Staphylococci (CoNS) are one of them, with their coexisting biofilm forming and multiple antibiotic resistance properties form important agents of nosocomial infection. To evaluate species distribution, biofilm formation, and antibiogram, CoNS isolates from various clinical samples were isolated. The presence of biofilm and associated genes icaAB, aap, atlE, embp, bhp, and fbe in CoNS was screened by PCR. The biofilm chemical composition and its correlation with the genotypes were also analysed. Staphylococcus epidermidis (59%) was found to be the most prevalent CoNS species. Most of the CoNS isolates harboring biofilm gene showed carbohydrate-protein-eDNA biofilm, whereas carbohydrate-protein biofilms were also observed. High percentage of multiple drug resistance, and biofilm gene frequency among these CoNS isolates point towards the need of periodic surveillance as CoNS are recently identified to cause difficult to treat infections. PMID- 28593525 TI - Lithium Chloride Facilitates Autophagy Following Spinal Cord Injury via ERK dependent Pathway. AB - Spinal cord injury (SCI) is one major cause of death and results in long-term disability even in the most productive periods of human lives with few efficacious drugs. Autophagy is a potential therapeutic target for SCI. In the present study, we examined the role of lithium in functional recovery in the rat model of SCI and explored the related mechanism. Locomotion tests were employed to assess the functional recovery after SCI, Western blotting and RT-PCT to determine the level of p-ERK and LC3-II as well as p62, immunofluorescence imaging to localize LC3 and p62. Here, we found that both the expression of LC3 II and p62 were increased after SCI. However, lithium chloride enhanced the level of LC3-II while abrogated the abundance of p62. Furthermore, lithium treatment facilitated ERK activation in vivo, and inhibition of MEK/ERK signaling pathway suppressed lithium-evoked autophagy flux. Taken together, our results illustrated that lithium facilitated functional recovery by enhancing autophagy flux. PMID- 28593527 TI - Role of CACNA1C gene polymorphisms and protein expressions in the pathogenesis of schizophrenia: a case-control study in a Chinese population. AB - The study aimed to investigate the correlations of CACNA1C genetic polymorphisms and protein expression with the pathogenesis of schizophrenia in a Chinese population. This research included 139 patients diagnosed with schizophrenia (case group) and 141 healthy volunteers (control group). Case and control samples were genotyped using denaturing high-performance liquid chromatography (DHPLC). Haplotypes of rs10848683, rs2238032, and rs2299661 were analyzed using the Shesis software. A mouse model of schizophrenia was established and assigned to test and blank groups. Western blotting was used to detect CACNA1C protein expression. The genotype and allele distribution of rs2238032 and rs2299661 differed between the case and control groups. TT genotype of rs2238032 and G allele of rs2299661 could potentially reduce the risk of schizophrenia. The distribution of rs2238032 genotype has a close connection with cognitive disturbance and the results of the general psychopathology classification exam. The distribution of rs2299661 genotypes was closely related to sensory and perceptual disorders, negative symptom subscales, and the results of the general psychopathology classification exam. CTC haplotype increased and CTG decreased the risk of schizophrenia in healthy people. In the brain tissues of mice with schizophrenia, the CACNA1C protein expression was higher in the test group than in the blank group. Our study demonstrated that CACNA1C gene polymorphisms and CACNA1C protein expression were associated with schizophrenia and its clinical phenotypes. PMID- 28593529 TI - Bisexual-Specific Minority Stressors, Psychological Distress, and Suicidality in Bisexual Individuals: the Mediating Role of Loneliness. AB - Bisexual individuals are at higher risk for poor mental health outcomes compared to heterosexual as well as lesbian and gay individuals and experience minority stressors, such as discrimination, from both heterosexual and sexual minority communities. However, there is little research examining the negative effects of bisexual-specific minority stressors on bisexual individuals' mental health as well as psychological factors that might help explain minority stressors' deleterious effects. This research examined the effects of distal minority stressors (i.e., anti-bisexual experiences from both heterosexual as well as lesbian and gay people) and proximal stressors (i.e., internalized heterosexism and sexual orientation concealment) on psychological distress and suicidality among bisexual adults (N = 503). Building on the relational framing of the minority stress model, we also tested one relational factor (i.e., loneliness) as a mediator of the associations between distal and proximal minority stressors and poor mental health (i.e., psychological distress and suicidality). Structural equation modeling analyses were used to test the mediating effects of loneliness on the associations between minority stressors and psychological distress and suicidality. Although distal and proximal minority stressors were not associated with each other, loneliness mediated the effects of distal and proximal minority stressors on psychological distress and suicidality. The results of this study underscore the importance of targeting bisexual-specific minority stressors as well as loneliness in preventive interventions to improve the mental health of bisexual individuals. PMID- 28593530 TI - Erratum to: Two early eudicot fossil flowers from the Kamikitaba assemblage (Coniacian, Late Cretaceous) in northeastern Japan. PMID- 28593528 TI - The neuropathological basis to the functional role of microglia/macrophages in gliomas. AB - The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade. PMID- 28593531 TI - Distinguishing appraisal and personality influences on quality of life in chronic illness: introducing the quality-of-life Appraisal Profile version 2. AB - BACKGROUND: Cognitive appraisal of quality of life (QOL) differs across individuals in ways that explain otherwise paradoxical findings, such as similar QOL ratings among individuals in highly divergent health states. Although warranted by a growing body of evidence, routine assessment of appraisal in QOL research has been impeded by measurement challenges. This study describes the QOL Appraisal Profile-version 2 (QOLAPv2), a new measure that addresses these challenges. METHODS: A heterogeneous, on-line cohort of chronic disease patients and caregivers completed the QOLAPv2, along with demographics, PROMIS10 and Brief NEO Personality Inventory (NEO-PI). Analyses address the psychometric properties and construct validity of this new measure using principal components, bivariate, canonical correlation, and linear regression analyses. RESULTS: Analysis including 4173 respondents yielded 12 second-order QOLAPv2 principal components. Appraisal components varied with age and disease duration. Appraisals involving "Wellness," "Health," and "Recent Challenges" were correlated with QOL and with NEO-PI scales of "Agreeableness" and "Conscientiousness." Canonical correlation analysis revealed that QOL scales were associated with appraisals involving "Spirituality," "Anticipating Decline," and "Lightness of Being." Appraisal dimensions of "Relationships," "Maintaining Roles," "Independence," "Pursuing Dreams," and "Lightness of Being" were also associated with personality scales. Appraisal measures accounted for significantly more variance in QOL than personality and demographics alone. CONCLUSIONS: Findings corroborate the Rapkin and Schwartz QOL appraisal theory. QOL appraisal measures correlate as expected with personality scales, and explain more variance in QOL than does personality. The QOLAPv2 can be used across populations to provide insight into patients' concerns, salient experiences, and comparators. PMID- 28593533 TI - Heart combined with adrenal multiple pheochromocytomas. AB - Pheochromocytoma is a kind of rare tumor, occurring at any site in the sympathoadrenal system. Main lesions occur within the adrenal gland; only 1%-2% occur within the chest, and most of these are located in the posterior mediastinum. Intrapericardial pheochromocytoma is extremely rare in clinic, only about 100 cases have been reported in total in both the domestic and foreignliterature since Besterman et al. first reported in 1974. It is often difficult to diagnose and locate these tumors. Hence, we present here a case of adrenal combined with heart multiple pheochromocytomas and discuss about techniques contributed to diagnosis and localization. PMID- 28593532 TI - Establishing benchmark EQ-5D-3L population health state utilities and identifying their correlates in Gansu Province, China. AB - PURPOSES: Despite a flurry of cost utility analyses conducted in the Chinese population in recent years, a standard set of health state utilities (HSUs) for the Chinese population is lacking. The aims of this study were to (1) determine benchmark age- and sex-specific HSUs for a Chinese population, and (2) assess key correlates of HSUs in this population. METHODS: Quality-of-life was evaluated using the validated EQ-5D-3L questionnaire. HSUs were calculated using data collected from Gansu Province (n = 9833). Overall differences in HSUs were analysed using linear regression and a two-tailed p value <0.05 was determined to be statistically significant. The minimal difference in weighted index was set at 0.074. RESULTS: HSUs decreased with age in both males and females. Living in the non-capital areas, being separated/divorced/widowed or never married, being never educated, diagnosed with chronic disease, and no regular physical activity were associated with lower HSUs. HSUs for women were lower than for men in univariate regression analysis; however, no differences were found after adjusting for other covariates. In addition, the difference in HSU reached the level of minimal difference in weighted index for participants with chronic disease. HSUs for those who were diagnosed with chronic disease were 0.098 (0.092-0.104) lower than those without chronic disease. CONCLUSIONS: This study reports HSUs for a Chinese population in Gansu and investigates the key correlates of HSUs in this population. In addition, the use of EQ-5D-3L in assessing population health is limited given the high ceiling effect and skewed HSUs. PMID- 28593534 TI - Neurocardiac imaging has a proven value in patient management. PMID- 28593535 TI - Neuro-cardiac imaging has a proven value in patient management: Con. PMID- 28593536 TI - Molecular typing of non-polio enteroviruses isolated from acute flaccid paralysis cases in Iran from 2010 to 2015. PMID- 28593537 TI - Building Provincial Mental Health Capacity in Primary Care: An Evaluation of a Project ECHO Mental Health Program. AB - OBJECTIVE: Project Extension for Community Healthcare Outcomes (Project ECHO(c)) addresses urban-rural disparities in access to specialist care by building primary care provider (PCP) capacity through tele-education. Evidence supporting the use of this model for mental health care is limited. Therefore, this study evaluated a mental health and addictions-focused ECHO program. Primary outcome measures were PCP knowledge and perceived self-efficacy. Secondary objectives included: satisfaction, engagement, and sense of professional isolation. PCP knowledge and self-efficacy were hypothesized to improve with participation. METHODS: Using Moore's evaluation framework, we evaluated the ECHO program on participant engagement, satisfaction, learning, and competence. A pre-post design and weekly questionnaires measured primary and secondary outcomes, respectively. RESULTS: Knowledge test performance and self-efficacy ratings improved post-ECHO (knowledge change was significant, p < 0.001, d = 1.13; self-efficacy approached significance; p = 0.056, d = 0.57). Attrition rate was low (7.7%) and satisfaction ratings were high across all domains, with spokes reporting reduced feelings of isolation. DISCUSSION: This is the first study to report objective mental health outcomes related to Project ECHO. The results indicate high participant retention is achievable, and provide preliminary evidence for increased knowledge and self-efficacy. These findings suggest this intervention may improve mental health management in primary care. PMID- 28593538 TI - Physiological and biochemical responses of Machilus ichangensis Rehd. et Wils and Taxus chinensis (Pilger) Rehd. to elevated O3 in subtropical China. AB - Considerable researches have documented the negative effects of ozone on woody species in North America and Europe; however, little is known about how woody tree species respond to elevated O3 in subtropical China, and most of the previous studies were conducted using pot experiment. In the present study, Machilus ichangensis Rehd. et Wils (M. ichangensis) and Taxus chinensis (Pilger) Rehd. (T. chinensis), evergreen tree species in subtropical China, were exposed to non-filtered air (NF), 100 nmol mol-1 O3 (E1) and 150 nmol mol-1 O3 (E2), in open-top chambers under field conditions from 21st March to 2nd November 2015. In this study, O3 fumigation significantly reduced net photosynthesis rate (Pn) in M. ichangensis in the three measurements and in T. chinensis in the last measurement. Also, non-stomatal factors should be primarily responsible for the decreased Pn. O3 fumigation-induced increase in malondialdehyde, superoxide dismutase, and reduced ascorbic acid levels indicated that antioxidant defense mechanism had been stimulated to prevent O3 stress and repair the oxidative damage. Yet, the increase of antioxidant ability was not enough to counteract the harm of O3 fumigation. Because of the decrease in CO2 assimilation, the growth of the two tree species was restrained ultimately. The sensitivity of the two tree species to O3 can be determined: M. ichangensis > T. chinensis. It suggests a close link between the rising O3 concentrations and the health risk of some tree species in subtropics in the near future. PMID- 28593539 TI - The AhRR-c.565C>G transversion may increase total antioxidant capacity levels of the seminal plasma in infertile men. AB - The Aryl hydrocarbon receptor (AhR)-repressor (AhRR) is a regulator of the AhR pathway, which plays an important role in xenobiotic and reactive oxygen species (ROS) metabolism. Total antioxidant capacity (TAC) is a major factor in semen quality that protects sperm against ROS stress. Malondialdehyde (MDA) is the indicator of lipid peroxidation damage that is occurred due to ROSs. In this study, we determined and compared the MDA and TAC levels of infertile men's semen and blood plasma regarding genotype groups of AhRR-c.565C>G transversion. Semen and blood samples of 123 infertile males were collected from the Fatemeh Zahra IVF Centre, Babol, Iran. TAC and MDA levels of seminal and blood plasma were measured by TBARS and FRAP methods, respectively. Cases were genotyped by the PCR RFLP method. The frequency of c.565C>G genotypes was determined as CC (34.14%), CG (55.28%) and GG (10.58%). Mean levels of TAC MUm/L and MDA nmol/mL in semen plasma of CC, CG and GG groups were (1365.7, 1.28), (1542.8, 1.51) and (1860.2, 0.82), respectively. Also, mean levels of TAC MUm/L and MDA nmol/mL in blood plasma samples in CC, CG and GG genotypes were (806.14, 1.168), (727.1, 1.006) and (635.7, 0.83), respectively. Comparison of marker levels between genotypes revealed that the TAC level of semen plasma in the GG genotype was significantly higher than its level in the CC group (p < 0.05). Our findings showed that in seminal plasma of infertile men with the GG genotype of AhRR-c.565C>G transversion, the level of total antioxidant capacity is significantly higher in comparison with the CC genotype. Then, the G allele of AhRR-c.565C>G transversion may have a role in the increase in antioxidant capacity of seminal plasma. PMID- 28593540 TI - Mesorhizobium bacterial strains isolated from the legume Lotus corniculatus are an alternative source for the production of polyhydroxyalkanoates (PHAs) to obtain bioplastics. AB - Polyhydroxyalkanoic acids (PHAs) are natural polyesters that can be used to produce bioplastics which are biodegradable. Numerous microorganisms accumulate PHAs as energy reserves. Combinations of different PHAs monomers lead to the production of bioplastics with very different properties. In the present work, we show the capability of strains belonging to various phylogenetic lineages within the genus Mesorhizobium, isolated from Lotus corniculatus nodules, to produce different PHA monomers. Among our strains, we found the production of 3 hydroxybutyrate, 3-hydroxyvalerate, 3-hydroxydodecanoate, and 3 hydroxyhexadecanoate. Most of the PHA-positive strains were phylogenetically related to the species M. jarvisii. However, our findings suggest that the ability to produce different monomers forming PHAs is strain-dependent. PMID- 28593541 TI - Assessment and potential sources of metals in the surface sediments of the Yellow River Delta, Eastern China. AB - The Yellow River Delta is the most intact estuary wetland in China and suffers from great pressure of metals. Seventy-seven surface sediment samples were collected in the delta, and contents of Cu, Pb, Cd, Cr, Zn, Ni, and Mn were analyzed by inductively coupled plasma spectrometry and those of Hg and As by atomic fluorescence spectrometry. The results showed that means of metal contents (ppm, dry weight) were as follows: Hg, 0.04; Cr, 61.72; Cu, 20.97; Zn, 60.73; As, 9.47; Pb, 21.91; Cd, 0.12; Ni, 27.24; and Mn, 540.48. 43.8% of Hg and 14.3% of Cd were from the allogenic source while others from the authigenic source. The results of the geoaccumulation indexes appeared that 6.5% of sites from the estuarine and the Gudao areas were moderately polluted by Hg. All ecological risk index values of Hg and 37.7% of Cd were more than 40, which were the main factors of strongly and moderately potential ecological risks of 37.7% of sites in the delta. High Cd contents may be due to the alkaline conditions of the delta and the unreasonable management of the farmland, while the abnormal distribution of Hg to the wet or dry deposition and the erosion of the seawater. It was suggested to monitor Hg content in the atmosphere of the Yellow River Delta. The results were expected to update the pollution status of metals in the delta and created awareness of preserving the sound condition of the Yellow River Delta. PMID- 28593542 TI - Quality of institution and the FEG (forest, energy intensity, and globalization) environment relationships in sub-Saharan Africa. AB - The current share of sub-Saharan Africa in global carbon dioxide emissions is negligible compared to major contributors like Asia, Americas, and Europe. This trend is, however, likely to change given that both economic growth and rate of urbanization in the region are projected to be robust in the future. The current study contributes to the literature by examining both the direct and the indirect impacts of quality of institution on the environment. Specifically, we investigate whether the institutional setting in the region provides some sort of a complementary role in the environment-FEG relationships. We use the panel two step system generalized method of moments (GMM) technique to deal with the simultaneity problem. Data consists of 43 sub-Saharan African countries. The result shows that energy inefficiency compromises environmental standards. However, the quality of the institutional setting helps moderate this negative consequences; countries with good institutions show greater prospects than countries with poor institutions. On the other hand, globalization of the region and increased forest size generate positive environmental outcomes in the region. Their impacts are, however, independent of the quality of institution. Afforestation programs, promotion of other clean energy types, and investment in energy efficiency, basic city infrastructure, and regulatory and institutional structures, are desirable policies to pursue to safeguard the environment. PMID- 28593545 TI - Improved strength and durability of concrete through metabolic activity of ureolytic bacteria. AB - In recent years, biomineralization process is being employed in development of bioconcrete, which is emerging as a sustainable method to enhance the durability of concrete by way of increasing compressive strength and reducing the chloride permeability. In this study, different bacterial strains isolated from the soils of the Laguna Region of Mexico were selected for further study. ACRN5 strain demonstrated higher urease activity than other strains, and the optimum substrate concentration, pH, and temperature were 120 mM, pH 8, and 25 degrees C, respectively. Further, Km and Vmax of urease activity of ACRN5 were 21.38 mM and 0.212 mM min-1, respectively. It was observed that addition of ACRN5 at 105 cells ml-1 to cement-water mixture significantly increased (14.94%) in compressive strength after 36 days of curing and reduced chloride penetration. Deposition of calcite in bio-mortars was observed in scanning electron microscopy and energy dispersive X-ray diffraction spectrometry analyses. Results of this study demonstrated the role of microbially induced calcium carbonate precipitation in improving the physico-mechanical properties of bio-mortars. PMID- 28593543 TI - The effect of Mg2+ on digestion performance and microbial community structures in sludge digestion systems. AB - The important criteria in anaerobic digestion is the rate-limiting step which decides the fate of value-added products especially from waste-activated sludge (WAS). Hence, the present study investigated the effect of magnesium (Mg2+) addition on anaerobic digestion of WAS. The lab-scale experiments were conducted at 25 degrees C with Mg2+ doses ranging from 0.01 to 0.2 mol/L. Maximum total volatile fatty acids (VFAs) production (372.78 mg COD/L) occurred at a Mg2+ dose of 0.2 mol/L, which was about eight times higher than the control tests. Further, Mg2+ addition facilitated sludge dewaterability and phosphorus removal. The mechanism of improved VFAs generation was analyzed from the view of both chemical and biological effects. Chemical effect significantly enhanced the release of calcium and iron in WAS, resulting in the disintegration of WAS, which benefited hydrolysis and acidification processes. Illumina MiSeq sequencing analysis revealed that enrichment of functional bacteria and the increase of bacterial diversity were obtained in the 0.2 mol Mg2+/L experiment, while the influence was negative on the reactor with 0.025 mol/L Mg2+. Meanwhile, methanogens were accordantly inhibited in the experiments with Mg2+ addition. PMID- 28593546 TI - Differential toxicity of arsenic on renal oxidative damage and urinary metabolic profiles in normal and diabetic mice. AB - Diabetes is a common metabolic disease, which might influence susceptibility of the kidney to arsenic toxicity. However, relative report is limited. In this study, we compared the influence of inorganic arsenic (iAs) on renal oxidative damage and urinary metabolic profiles of normal and diabetic mice. Results showed that iAs exposure increased renal lipid peroxidation in diabetic mice and oxidative DNA damage in normal mice, meaning different effects of iAs exposure on normal and diabetic individuals. Nuclear magnetic resonance (NMR)-based metabolome analyses found that diabetes significantly changed urinary metabolic profiles of mice. Oxidative stress-related metabolites, such as arginine, glutamine, methionine, and beta-hydroxybutyrate, were found to be changed in diabetic mice. The iAs exposure altered amino acid metabolism, lipid metabolism, carbohydrate metabolism, and energy metabolism in normal and diabetic mice, but had higher influence on metabolic profiles of diabetic mice than normal mice, especially for oxidative stress-related metabolites and metabolisms. Above results indicate that diabetes increased susceptibility to iAs exposure. This study provides basic information on differential toxicity of iAs on renal toxicity and urinary metabolic profiles in normal and diabetic mice and suggests that diabetic individuals should be considered as susceptible population in toxicity assessment of arsenic. PMID- 28593544 TI - The environmental risks of neonicotinoid pesticides: a review of the evidence post 2013. AB - Neonicotinoid pesticides were first introduced in the mid-1990s, and since then, their use has grown rapidly. They are now the most widely used class of insecticides in the world, with the majority of applications coming from seed dressings. Neonicotinoids are water-soluble, and so can be taken up by a developing plant and can be found inside vascular tissues and foliage, providing protection against herbivorous insects. However, only approximately 5% of the neonicotinoid active ingredient is taken up by crop plants and most instead disperses into the wider environment. Since the mid-2000s, several studies raised concerns that neonicotinoids may be having a negative effect on non-target organisms, in particular on honeybees and bumblebees. In response to these studies, the European Food Safety Authority (EFSA) was commissioned to produce risk assessments for the use of clothianidin, imidacloprid and thiamethoxam and their impact on bees. These risk assessments concluded that the use of these compounds on certain flowering crops poses a high risk to bees. On the basis of these findings, the European Union adopted a partial ban on these substances in May 2013. The purpose of the present paper is to collate and summarise scientific evidence published since 2013 that investigates the impact of neonicotinoids on non-target organisms. Whilst much of the recent work has focused on the impact of neonicotinoids on bees, a growing body of evidence demonstrates that persistent, low levels of neonicotinoids can have negative impacts on a wide range of free living organisms. PMID- 28593547 TI - Occurrence and human dietary assessment of sulfonamide antibiotics in cultured fish around Tai Lake, China. AB - As the most important fishery medicines, sulfonamides are widely used to prevent diseases caused by pathogens in aquaculture. However, relatively little is known about the residues and dietary risks associated with cultured fish around Tai Lake. In the present study, a sampling strategy for a complete aquaculture period was conducted. Specifically, 12 selected sulfonamide antibiotics were measured among 116 fish samples recruited from four sampling periods, four species, four areas, and 18 fish ponds. All 12 antibiotics were detected at detection frequencies of 4.31-28.45%. Total sulfonamides were detected in 77.59% of the fish samples, with 57.76% of fish samples containing from 0.1 to 10 MUg kg-1. Sulfadiazine (SDZ), sulfamethoxazole (SMZ), sulfamethazine (SDD), and sulfamonomethoxine (SMM) were the main types of antibiotics used, and these were present at high concentrations (>100 MUg kg-1) with high occurrences, especially in the middle of the aquaculture season. Dietary assessment showed that residual antibiotics in all fish that were being sent to market were far below the maximum residue limit (MRL) of total sulfonamides and that there was almost no risk associated with fish consumption. The results of the present study will facilitate development of effective measures to produce safe aquatic products and meaningful suggestions for consuming aquatic products. PMID- 28593548 TI - Cancer risk from gaseous carbonyl compounds in indoor environment generated from household coal combustion in Xuanwei, China. AB - Airborne carbonyls were characterized from emitted indoor coal combustion. Samples were collected in Xuanwei (Yunnan Province), a region in China with a high rate of lung cancer. Eleven of 19 types of samples (58%) demonstrated formaldehyde concentrations higher than the World Health Organization exposure limit (a 30-min average of 100 MUg m-3). Different positive significant correlations between glyoxal/methylglyoxal and formaldehyde/acetaldehyde concentrations were observed, suggesting possible different characteristics in emissions between two pairs of carbonyl compounds. A sample in the highest inhalation risk shows 29.2 times higher risk than the lowest sample, suggesting different coal sampling locations could contribute to the variation of inhalation risk. Inhabitants in Xuanwei also tend to spend more time cooking and more days per year indoors than the national average. The calculated cancer risk ranged from 2.2-63 * 10-5, which shows 13 types of samples at high-risk level. Cumulative effect in combination with different carbonyls could have contributed to the additive actual inhalation cancer risk. There is a need to explicitly address the health effects of environmentally relevant doses, considering life long exposure in indoor dwellings. PMID- 28593550 TI - YH18421, a novel GPR119 agonist exerts sustained glucose lowering and weight loss in diabetic mouse model. AB - G-protein-coupled receptor 119 (GPR119) represents a promising target for the treatment of type 2 diabetes as it can increase both GLP-1 secretion from intestinal L cells and glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells. Due to this dual mechanism of action, the development of small molecule GPR119 agonists has received much interest for the treatment of type 2 diabetes. Here, we identified a novel small-molecule GPR119 agonist, YH18421 and evaluated its therapeutic potential. YH18421 specifically activated human GPR119 with high potency and potentiated GLP-1 secretion and GSIS in vitro cell based systems. In normal mice, single oral administration of YH18421 improved glucose tolerance. Combined treatment of YH18421 and the DPP-4 inhibitor augmented both plasma active GLP-1 levels and glycemic control. In diet induced obese (DIO) mice model, glucose lowering effect of YH18421 was maintained after 4 weeks of repeat dosing and YH18421 acted additively with DPP-IV inhibitor. We also observed that YH18421 inhibited weight gain during 4 weeks of administration in DIO mice. These data demonstrate that YH18421 is capable of delivering sustained glucose control and preventing weight gain and combination with the DPP IV inhibitor maybe an effective strategy for the treatment of type 2 diabetes. PMID- 28593549 TI - Nitrogen and plant population change radiation capture and utilization capacity of sunflower in semi-arid environment. AB - The combination of nitrogen and plant population expresses the spatial distribution of crop plants. The spatial distribution influences canopy structure and development, radiation capture, accumulated intercepted radiation (Sa), radiation use efficiency (RUE), and subsequently dry matter production. We hypothesized that the sunflower crop at higher plant populations and nitrogen (N) rates would achieve early canopy cover, capture more radiant energy, utilize radiation energy more efficiently, and ultimately increase economic yield. To investigate the above hypothesis, we examined the influences of leaf area index (LAI) at different plant populations (83,333, 66,666, and 55,555 plants ha-1) and N rates (90, 120, and 150 kg ha-1) on radiation interception (Fi), photosynthetically active radiation (PAR) accumulation (Sa), total dry matter (TDM), achene yield (AY), and RUE of sunflower. The experimental work was conducted during 2012 and 2013 on sandy loam soil in Punjab, Pakistan. The sunflower crop captured more than 96% of incident radiant energy (mean of all treatments), 98% with a higher plant population (83,333 plants ha-1), and 97% with higher N application (150 kg ha-1) at the fifth harvest (60 days after sowing) during both study years. The plant population of 83,333 plants ha-1 with 150 kg N ha-1 ominously promoted crop, RUE, and finally productivity of sunflower (AY and TDM). Sunflower canopy (LAI) showed a very close and strong association with Fi (R 2 = 0.99 in both years), PAR (R 2 = 0.74 and 0.79 in 2012 and 2013, respectively), TDM (R 2 = 0.97 in 2012 and 0.91 in 2013), AY (R 2 = 0.95 in both years), RUE for TDM (RUETDM) (R 2 = 0.63 and 0.71 in 2012 and 2013, respectively), and RUE for AY (RUEAY) (R 2 = 0.88 and 0.87 in 2012 and 2013, respectively). Similarly, AY (R 2 = 0.73 in 2012 and 0.79 in 2013) and TDM (R 2 = 0.75 in 2012 and 0.84 in 2013) indicated significant dependence on PAR accumulation of sunflower. High temperature during the flowering stage in 2013 shortened the crop maturity duration, which reduced the LAI, leaf area duration (LAD), crop growth rate (CGR), TDM, AY, Fi, Sa, and RUE of sunflower. Our results clearly revealed that RUE was enhanced as plant population and N application rates were increased and biomass assimilation in semi-arid environments varied with radiation capture capacity of sunflower. PMID- 28593551 TI - Esophageal motility disorders-Symptomatic and manometric spectrum in Punjab, northern India. AB - BACKGROUND: Data on the spectrum of esophageal motility disorders in Indian population are scarce. We aimed to study the symptomatic and manometric profile of patients with suspected esophageal motility disorders. METHODS: Consecutive patients with esophageal symptoms who underwent esophageal high-resolution manometry (HRM) from January 2010 to December 2014 were included in this retrospective analysis of prospectively acquired data. HRM was performed with 22 channel water-perfusion system and patients classified using Chicago classification v3.0. RESULTS: Of the 401 patients studied [median age 43 (18-85) years; 61% males], 217 presented with dysphagia, 157 with predominant retrosternal discomfort and 27 with predominant regurgitation. Among patients with dysphagia, 43.8% had ineffective esophageal motility [IEM], 26.3% had achalasia cardia [AC], 6.9% had distal esophageal spasm [DES] and 19.4% had normal manometry [NM]. Among patients with retrosternal discomfort, 42.7% had IEM, 5.7% had AC, 4.5% had DES and 42% had NM. AC was significantly more common among patients presenting with dysphagia compared to those with retrosternal discomfort [p< 0.001] or regurgitation [p< 0.001]. NM was significantly more common among patients presenting with retrosternal symptoms compared to those with dysphagia [p< 0.001]. AC patients had longer duration of dysphagia, more frequent bolus obstruction and more weight loss compared to those with IEM or NM [p< 0.05]. CONCLUSION: Dysphagia was the commonest presenting symptom followed by retrosternal discomfort. Ineffective esophageal motility (not achalasia cardia) was the commonest manometric finding both among patients with dysphagia and retrosternal discomfort. This study highlights the high prevalence of IEM among patients with esophageal symptoms, which can present with dysphagia or retrosternal discomfort due to poor bolus transit. PMID- 28593552 TI - A reformed surgical treatment modality for children with giant cystic craniopharyngioma. AB - OBJECTIVE: Surgical removal plays an important role in treating children's craniopharyngioma. For a safe and minimally invasive craniotomy, a reformed surgical modality was proposed in this paper by combining the insertion of an Ommaya reservoir system (ORS) by stereotactic puncture, aspiration of cystic fluid in 2-day interval for consecutive 7-10 days, and the delayed tumor resection. PATIENTS AND METHODS: Eleven patients (aged from 5 to 9 years old) with giant cystic craniopharyngiomas who had undergone the reformed surgical modality during November 2014 and December 2015 were collected as group A. In contrast, seven patients (aged from 5 to 11 years old) who had undergone the traditional directed operation without any prior management from January 2014 to October 2014 were collected into group B. A retrospective analysis was performed for both groups at one institution. The preoperative and postoperative clinical presentations, neuroimaging, early postoperative outcome, and the surgery-related complications of both groups were reviewed. RESULTS: For group A, the mean value of the maximum tumor diameters shank from 52.36 to 23.82 mm after implementing aspiration of the cystic fluid in 1-day interval for consecutive 8.23 days. Eight patients (72.73%) in group A underwent a gross total resection (GTR), while two (28.57%) patients underwent GTR in group B. The postoperative electrolyte disturbance rate and endocrine disorder rate of group B were significantly higher than those of group A (42.86 vs 36.36%; 71.43 vs 45.45%). Postoperative long-term diabetes insipidus only occurred in one patient of group B, and postoperative visual deterioration occurred in two patients of group B. Besides, one patient of group B died of severe postoperative hypothalamus dysfunction. Patients with residual tumors were applied with additional adjuvant radiotherapy, and no recurrence was observed in follow-up examinations. CONCLUSION: A favorable outcome can be achieved by combining the insertion of an ORS by stereotactic puncture, aspiration of cystic fluid in 2-day interval for continuously 7-10 days, and the delayed tumor resection. This combined treatment modality maybe an effective method to treat children with giant cystic craniopharyngiomas. PMID- 28593554 TI - Hydrocephalus and mucopolysaccharidoses: what do we know and what do we not know? AB - INTRODUCTION: The precise incidence of hydrocephalus in patients with mucopolysaccharidoses (MPS) is hard to determine, because the condition lacks a formal, consensus-based definition. The diagnosis of hydrocephalus depends on symptom profile, presence of neuroimaging features, and the outcome of diagnostic tests. Although numerous techniques are used to identify MPS patients who are most likely to have hydrocephalus and respond to treatment, no definitive method exists to prove diagnosis. PURPOSE: The authors propose an algorithm to aid in the diagnosis and management of hydrocephalus in MPS patients. CONCLUSIONS: The theory of venous hypertension associated with the morphological changes in the skull base and craniocervical junction indicate the need for future neuroimaging studies including cerebrospinal fluid (CSF) and venous flow measurements to monitor hydrocephalus progression and select therapeutic interventions in MPS patients. Preoperative planning should also be based on the increased risk of intraoperative and postoperative hemorrhagic complications. PMID- 28593556 TI - Airway management changes in patients with mucopolysaccharidoses: the role of video laryngoscopy. PMID- 28593553 TI - Prenatal diagnosis of spina bifida: from intracranial translucency to intrauterine surgery. AB - Accurate and timely prenatal diagnosis of spina bifida (SB) is a major goal of modern antenatal care. Prenatal screening for open SB should be first performed at the time of routine first-trimester ultrasound by examining the posterior fossa for obliteration or non-visualization of the fourth ventricle ("intracranial translucency") and cisterna magna. The second step of screening is the second-trimester anatomy scan, at which time the features of the Chiari type II malformation should be looked for, including ventriculomegaly, scalloping of the frontal bones ("lemon" sign), and backward and caudal displacement of the cerebellar vermis with obliteration of the cisterna magna ("banana" sign). In cases with positive findings, evaluation must include a focused examination of the spine for defects. In cases of closed SB and SB occulta, the cranial and posterior fossa features will not be present as they are not associated with leaking of spinal fluid and resultant hindbrain herniation, highlighting the fact that the spine should be examined thoroughly whenever possible during the second trimester scan. In tertiary fetal medicine centers, two-dimensional and three dimensional ultrasound allows an accurate determination of the location, type, extent, and upper level of the spinal defect as well as the presence of associated anomalies. Fetal magnetic resonance imaging should be restricted to candidates for intrauterine surgery as part of the preoperative protocol. PMID- 28593555 TI - Genetic analysis of IRF6, a gene involved in craniofacial midline formation, in relation to pituitary and facial morphology of patients with idiopathic growth hormone deficiency. AB - INTRODUCTION: Growth hormone is secreted by the pituitary gland, which forms part of the craniofacial midline. IRF6 encodes a transcription factor involved in the development of the craniofacial midline and mutations in IRF6 are known to disturb craniofacial development. Craniofacial and pituitary development are closely related. After whole exome sequencing revealed a new mutation in IRF6 in a family with Idiopathic Growth Hormone Deficiency (IGHD), we screened the remainder of our IGHD cohort for mutations in this gene and related their genotypes to pituitary and craniofacial morphology. MATERIALS AND METHODS: We sequenced all coding exons and exon-intron boundaries of IRF6 in 81 patients with IGHD. We performed a multiplex ligation-dependent probe amplification (MLPA) in order to exclude copy number variations in IRF6. We analyzed facial measurements taken from standardized digital pictures of 48 patients. RESULTS: We found two new variants and eleven polymorphisms. Apart from the new mutation found in the index family (p.Arg233Cys), we found one other new heterozygous missense mutation in IRF6 (Pro456Ser). p.Arg233Cys was reported as extremely rare in exome databases (1 allele out of 120.852 alleles sequenced), strictly conserved among species and was predicted deleterious by all variant predictor programs. Pro456Ser was predicted to be benign. MLPA did not reveal any exon deletions or duplications in any of the patients. CONCLUSION: This is the first report of IRF6 analysis in an IGHD cohort. We found one new mutation which, based on in silico analysis, could be of functional relevance. However, we did not find any mutations in the other patients. Therefore, we conclude that IRF6 defects are rare in IGHD patients and further research should focus on new candidate genes. PMID- 28593558 TI - Combined effect of pulse density and grid cell size on predicting and mapping aboveground carbon in fast-growing Eucalyptus forest plantation using airborne LiDAR data. AB - BACKGROUND: LiDAR remote sensing is a rapidly evolving technology for quantifying a variety of forest attributes, including aboveground carbon (AGC). Pulse density influences the acquisition cost of LiDAR, and grid cell size influences AGC prediction using plot-based methods; however, little work has evaluated the effects of LiDAR pulse density and cell size for predicting and mapping AGC in fast-growing Eucalyptus forest plantations. The aim of this study was to evaluate the effect of LiDAR pulse density and grid cell size on AGC prediction accuracy at plot and stand-levels using airborne LiDAR and field data. We used the Random Forest (RF) machine learning algorithm to model AGC using LiDAR-derived metrics from LiDAR collections of 5 and 10 pulses m-2 (RF5 and RF10) and grid cell sizes of 5, 10, 15 and 20 m. RESULTS: The results show that LiDAR pulse density of 5 pulses m-2 provides metrics with similar prediction accuracy for AGC as when using a dataset with 10 pulses m-2 in these fast-growing plantations. Relative root mean square errors (RMSEs) for the RF5 and RF10 were 6.14 and 6.01%, respectively. Equivalence tests showed that the predicted AGC from the training and validation models were equivalent to the observed AGC measurements. The grid cell sizes for mapping ranging from 5 to 20 also did not significantly affect the prediction accuracy of AGC at stand level in this system. CONCLUSION: LiDAR measurements can be used to predict and map AGC across variable-age Eucalyptus plantations with adequate levels of precision and accuracy using 5 pulses m-2 and a grid cell size of 5 m. The promising results for AGC modeling in this study will allow for greater confidence in comparing AGC estimates with varying LiDAR sampling densities for Eucalyptus plantations and assist in decision making towards more cost effective and efficient forest inventory. PMID- 28593557 TI - Assessment of myocardial blood flow and coronary flow reserve with positron emission tomography in ischemic heart disease: current state and future directions. AB - Positron emission tomography (PET) is a versatile imaging technology that allows assessment of myocardial perfusion, both at a spatially relative scale and also in absolute terms, thereby enabling noninvasive evaluation of myocardial blood flow (MBF) and coronary flow reserve (CFR). Assessment of MBF using FDA-approved PET isotopes, such as 82Rb and 13N-ammonia, has been well validated, and several software packages are currently available, thereby allowing for MBF evaluation to be incorporated into routine workflow in contemporary nuclear laboratories. Incremental diagnostic and prognostic information provided with the knowledge of MBF has the potential for widespread applications. Improving the ability to identify the true burden of obstructive epicardial coronary stenoses and allowing for noninvasive assessment of coronary micro circulatory function can be achieved with MBF assessment. On the other hand, attenuated CFR has been shown to predict adverse cardiovascular prognosis in a variety of clinical settings and patient subgroups. With expanding applications of MBF, this tool promises to provide unique insight into the integrity of the entire coronary vascular bed beyond what is currently available with relative perfusion assessment. This review intends to provide an in-depth discussion of technical and clinical aspects of MBF assessment with PET as it relates to patients with ischemic heart disease. PMID- 28593559 TI - 1H, 13C and 15N NMR assignments of a bacterial immunoglobulin-like domain (group 2) of a protein of a bacterium Paenarthrobacter aurescens TC1. AB - The bacterial immunoglobulin-like (Big) domain is one of the prevalent domain types, which facilitates cell-cell adhesion by assembling into multi-domain architectures. We selected a four Big_2 domain protein (named 'Arig') from a Gram positive, Paenarthrobacter aurescens TC1 (known earlier as Arthrobacter aurescens TC1). In an attempt to characterize structural and ligand-binding features of individual Big_2 domains, we have cloned, overexpressed, isolated and purified the second Big_2 domain of Arig along with a few of its adjacent Big_2 domain residues (residue 143 to 269) referred to as 'Arig2'. The 13C/15N-doubly-labeled His-tagged Arig2 (133 residues long) showed an ordered conformation as revealed by the well dispersed 2D [15N-1H]-HSQC spectrum. Subsequently, a suite of heteronuclear 3D NMR experiments has enabled almost complete 1H, 13C and 15N NMR resonance assignments of Arig2. PMID- 28593560 TI - 1H, 13C and 15N NMR chemical shift assignments of A. thaliana RCD1 RST. AB - The A. thaliana RCD1 (radical-induced cell death1) protein is a cellular signaling hub protein which interacts with numerous plant transcription factors from different families. It consists of three conserved domains and intervening unstructured regions, the C-terminal RST domain being responsible for the interactions with the transcription factors. It has been shown that many partner proteins interact with RCD1 RST via their intrinsically disordered regions, and that the domain is able to house partners with divergent folds. We aim to structurally characterize the RCD1 RST domain and its complexes [complex with DREB2A]. Here we report the 1H, 15N and 13C chemical shift assignments of the backbone and sidechain atoms for RCD1 (468-589) containing the RST (510-567) domain. PMID- 28593561 TI - Application of a GIS-/remote sensing-based approach for predicting groundwater potential zones using a multi-criteria data mining methodology. AB - This study integrates the application of Dempster-Shafer-driven evidential belief function (DS-EBF) methodology with remote sensing and geographic information system techniques to analyze surface and subsurface data sets for the spatial prediction of groundwater potential in Perak Province, Malaysia. The study used additional data obtained from the records of the groundwater yield rate of approximately 28 bore well locations. The processed surface and subsurface data produced sets of groundwater potential conditioning factors (GPCFs) from which multiple surface hydrologic and subsurface hydrogeologic parameter thematic maps were generated. The bore well location inventories were partitioned randomly into a ratio of 70% (19 wells) for model training to 30% (9 wells) for model testing. Application results of the DS-EBF relationship model algorithms of the surface- and subsurface-based GPCF thematic maps and the bore well locations produced two groundwater potential prediction (GPP) maps based on surface hydrologic and subsurface hydrogeologic characteristics which established that more than 60% of the study area falling within the moderate-high groundwater potential zones and less than 35% falling within the low potential zones. The estimated uncertainty values within the range of 0 to 17% for the predicted potential zones were quantified using the uncertainty algorithm of the model. The validation results of the GPP maps using relative operating characteristic curve method yielded 80 and 68% success rates and 89 and 53% prediction rates for the subsurface hydrogeologic factor (SUHF)- and surface hydrologic factor (SHF)-based GPP maps, respectively. The study results revealed that the SUHF-based GPP map accurately delineated groundwater potential zones better than the SHF-based GPP map. However, significant information on the low degree of uncertainty of the predicted potential zones established the suitability of the two GPP maps for future development of groundwater resources in the area. The overall results proved the efficacy of the data mining model and the geospatial technology in groundwater potential mapping. PMID- 28593562 TI - Assessing the impacts of the changes in farming systems on food security and environmental sustainability of a Chinese rural region under different policy scenarios: an agent-based model. AB - Since China has undergone a series of economic reforms and implemented opening up policies, its farming systems have significantly changed and have dramatically influenced the society, economy, and environment of China. To assess the comprehensive impacts of these changes on food security and environmental sustainability, and establish effective and environment-friendly subsidy policies, this research constructed an agent-based model (ABM). Daligang Town, which is located in the two-season rice region of Southern China, was selected as the case study site. Four different policy scenarios, i.e., "sharply increasing" (SI), "no-increase" (NI), "adjusted-method" (AM), and "trend" (TD) scenarios were investigated from 2015 to 2029. The validation result shows that the relative prediction errors between the simulated and actual values annually ranged from 20 to 20%, indicating the reliability of the proposed model. The scenario analysis revealed that the four scenarios generated different variations in cropping systems, rice yield, and fertilizer and pesticide inputs when the purchase price of rice and the non-agricultural income were assumed to increase annually by 0.1 RMB per kg and 10% per person, respectively. Among the four different policy scenarios in Daligang, the TD scenario was considered the best, because it had a relatively high rice yield, fairly minimal use of fertilizers and pesticides, and a lower level of subsidy. Despite its limitations, ABM could be considered a useful tool in analyzing, exploring, and discussing the comprehensive effects of the changes in farming system on food security and environmental sustainability. PMID- 28593563 TI - Spatio-temporal monitoring of cotton cultivation using ground-based and airborne multispectral sensors in GIS environment. AB - Multispectral sensor capability of capturing reflectance data at several spectral channels, together with the inherent reflectance responses of various soils and especially plant surfaces, has gained major interest in crop production. In present study, two multispectral sensing systems, a ground-based and an aerial based, were applied for the multispatial and temporal monitoring of two cotton fields in central Greece. The ground-based system was Crop Circle ACS-430, while the aerial consisted of a consumer-level quadcopter (Phantom 2) and a modified Hero3+ Black digital camera. The purpose of the research was to monitor crop growth with the two systems and investigate possible interrelations between the derived well-known normalized difference vegetation index (NDVI). Five data collection campaigns were conducted during the cultivation period and concerned scanning soil and plants with the ground-based sensor and taking aerial photographs of the fields with the unmanned aerial system. According to the results, both systems successfully monitored cotton growth stages in terms of space and time. The mean values of NDVI changes through time as retrieved by the ground-based system were satisfactorily modelled by a second-order polynomial equation (R 2 0.96 in Field 1 and 0.99 in Field 2). Further, they were highly correlated (r 0.90 in Field 1 and 0.74 in Field 2) with the according values calculated via the aerial-based system. The unmanned aerial system (UAS) can potentially substitute crop scouting as it concerns a time-effective, non destructive and reliable way of soil and plant monitoring. PMID- 28593564 TI - Activation of adrenergic receptor in H9c2 cardiac myoblasts co-stimulates Nox2 and the derived ROS mediate the downstream responses. AB - In recent years, NADPH oxidases (Noxes) have emerged as an important player in cardiovascular pathophysiology. Despite the growing evidences on the role of specific Nox isoforms, mechanisms of their activation, targets of reactive oxygen species (ROS) generated, and their downstream effects are poorly understood as yet. In this study, we treated H9c2 cardiac myoblasts with norepinephrine (NE, 2 uM), inducing ROS generation that was inhibited by Nox2-specific peptide inhibitor gp91ds-tat. Organelle-specific hydrogen peroxide-sensitive probe HyPer showed that the site of ROS generation is primarily in the cytosol, to some extent in the endoplasmic reticulum (ER) but not the mitochondria. Modulation of mRNAs of marker genes of cardiac hypertrophy i.e. induction in ANP and beta-MHC, and reduction in alpha-MHC by NE treatment was prevented by specific inhibition of Nox2 by gp91ds-tat. Induction of ANP and beta-MHC at the protein level were also attenuated by the inhibition of Nox2. Induction of c-Jun and FosB, the two members of the transcription factor family AP-1, were also blocked by the inhibition of Nox2 by gp91ds-tat. Induction of promoter-reporter constructs harboring multiple AP-1 elements and the upstream of FosB and ANP genes by NE were also blocked by the inhibition of Nox2 by gp91ds-tat and a dominant negative mutant of p22phox, a constituent of Nox2 that prevents its activation. This study for the first time establishes the significant role of Nox2 in mediating the NE induced pathological adrenergic signaling in cardiac myoblasts. PMID- 28593565 TI - Aggregatibacter actinomycetemcomitans regulates the expression of integrins and reduces cell adhesion via integrin alpha5 in human gingival epithelial cells. AB - Gingival epithelial cells form a physiological barrier against bacterial invasion. Excessive bacterial invasion destroys the attachment between the tooth surface and the epithelium, resulting in periodontitis. Integrins play a significant role in cell attachment; therefore, we hypothesized that bacterial infection might decrease the expressions of these integrins in gingival epithelial cells, resulting in reduced cell adhesion. Immortalized human gingival epithelial cells were co-cultured with Aggregatibacter actinomycetemcomitans Y4 (Aa Y4), and the gene expression levels of IL-8, proliferating cell nuclear antigen (PCNA), and integrins (alpha2, alpha3, alpha5, beta4, and beta6) were measured using quantitative reverse transcription polymerase chain reaction. Expression of PCNA and integrins, except integrin alpha5, was significantly downregulated, while expression of IL-8 and integrin alpha5 was significantly upregulated in the cells co-cultured with Aa Y4. The number of adherent cells significantly decreased when co-cultured with Aa Y4, as determined using cell adhesion assays. In the cells co-cultured with Aa Y4 and an integrin alpha5 neutralizing antibody, there was no effect on the expression of IL-8 and PCNA, while the expressions of integrins alpha2, alpha3, beta4, and beta6, and the number of adherent cells did not decrease. The number of invading bacteria in the cells was reduced in the presence of the antibody and increased in the presence of TLR2/4 inhibitor. Therefore, integrin alpha5 might be involved in Aa Y4 invasion into gingival epithelial cells, and the resulting signal transduction cascade reduces cell adhesion by decreasing the expression of integrins, while the TLR2/4 signaling cascade regulates IL-8 expression. PMID- 28593568 TI - Erdosteine : A Viewpoint by Margaret Wilsher. PMID- 28593569 TI - Erdosteine : A Viewpoint by Carlo Felice Marchioni and Maurizio Moretti. PMID- 28593574 TI - Challenges of Realising Patient-Centred Outcomes for Deaf Patients. AB - In general populations, it has been recognised that patients play a key role in the quality of their own healthcare. However, the idea of realising patient centred outcomes for the signing Deaf community, who experience the world in a visual way, raises some challenging issues that are rarely acknowledged. Using published research and translational health projects involving Deaf people both in the UK and internationally, this article discusses the challenges of realising patient-centred outcomes for Deaf people who are sign language users. The discussion includes an examination of: barriers to accessing healthcare for Deaf people; the impact of an insufficient acquisition of knowledge about health related issues; Deaf people's limited fund of information; not recognising Deaf people's values and citizenship rights; and challenges in gathering Deaf people's reported outcomes. We contend that without including Deaf people in shaping the healthcare experience for them, whether at an interpersonal level of patient engagement or at a structural level, the concept of fulfilling patient-centred outcomes for Deaf people is not achievable. PMID- 28593573 TI - Asthma exacerbations: risk factors for hospital readmissions. AB - OBJECTIVE: The aim of our study is to analyse hospital readmissions due to asthma, as well as the factors associated with their increase. STUDY DESIGN: We carried out a retrospective study including all admissions of patients over 18 years old due to exacerbation of asthma occurring in our hospital between the years 2000 and 2010. METHODS: The data were gathered by two members of the research team, by reviewing the clinical records. The first hospital admission of each patient was included for this study. An early readmission (ER) was defined as that which occurred in the following 15 days after hospital discharge and late readmission (LR) to that occurring from 16 days after discharge. RESULTS: This study included 2166 hospital admissions and 1316 patients, with a mean age of 62.6 years. Of the 1316 patients analysed, 36 (2.7%) had one ER and 313 (23.8%) one LR. The only factor independently associated with a higher probability of an ER was poor lung function. A higher probability of LR was associated with a greater severity of the asthma (OR: 17.8, for severe asthma versus intermittent asthma), to have had any hospital admission in the previous year (OR: 3.5) and the use of a combination of ICS-LABA as maintenance treatment. CONCLUSIONS: About 25% of the patients in our area admitted to hospital due to asthma exacerbation had repeat episodes of hospitalisation. PMID- 28593575 TI - The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells. AB - PURPOSE: The transition of cells from the epithelial to the mesenchymal state (EMT) plays an important role in tumor progression. EMT allows cells to acquire mobility, stem-like behavior and resistance to apoptosis and drug treatment. These features turn EMT into a central process in tumor biology. Ion channels are attractive targets for the treatment of cancer since they play critical roles in controlling a wide range of physiological processes that are frequently deregulated in cancer. Here, we investigated the role of ether-a-go-go-related 1 (hERG1) ion channels in the EMT of colorectal cancer cells. METHODS: We studied the epithelial-mesenchymal profile of different colorectal cancer-derived cell lines and the expression of hERG1 potassium channels in these cell lines using real-time PCR. Next, we knocked down hERG1 expression in HCT116 cells using lentivirus mediated RNA interference and characterized the hERG1 silenced cells in vitro and in vivo. Finally, we investigated the capacity of riluzole, an ion channel-modulating drug used in humans to treat amyotrophic lateral sclerosis, to reduce the resistance of the respective colorectal cancer cells to the chemotherapeutic drug cisplatin. RESULTS: We found that of the colorectal cancer derived cell lines tested, HCT116 showed the highest mesenchymal profile and a high hERG1 expression. Subsequent hERG1 expression knockdown induced a change in cell morphology, which was accompanied by a reduction in the proliferative and tumorigenic capacities of the cells. Notably, we found that hERG1expression knockdown elicited a reversion of the EMT profile in HCT116 cells with a reacquisition of the epithelial-like profile. We also found that riluzole increased the sensitivity of HCT116 cisplatin-resistant cells to cisplatin. CONCLUSIONS: Our data indicate that hERG1 plays a role in the EMT of colorectal cancer cells and that its knockdown reduces the proliferative and tumorigenic capacities of these cells. In addition, we conclude that riluzole may be used in combination with cisplatin to reduce chemo-resistance in colorectal cancer cells. PMID- 28593566 TI - Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. AB - Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC. PMID- 28593576 TI - Treatment of Osgood-Schlatter disease: review of the literature. AB - BACKGROUND: Osgood-Schlatter disease (OSD) is a self-limiting condition which occurs commonly in adolescence. PURPOSE: The objective of this article is to review published literature regarding pathophysiology, diagnosis and treatment of OSD. METHODS: A search of the literature was performed on the electronic databases PubMed, Cochrane and SCOPUS databases between 1962 and 2016 for pathophysiology, diagnosis and treatment of Osgood-Schlatter disease. RESULTS: OSD, also known as apophysitis of the tibial tubercle, is a common disease with most cases resolving spontaneously with skeletal maturity. In pathophysiology, the most accepted theory is repetitive knee extensor mechanism contraction. The pain is localized to the anterior aspect of the proximal tibia over the tibial tuberosity. They may describe a dull ache exacerbated by jumping or stair climbing. Radiological evaluation may indicate superficial ossicle in the patellar tendon. Osgood-Schlatter is a self-limited disease and generally ceases with skeletal maturity. Treatment is usually symptomatic. Adults with continued symptoms may need surgical treatment if they fail to respond to conservative treatment. Surgical procedures include open, bursoscopic and arthroscopic technique. Arthroscopic surgery is beneficial over an open procedure due to early postoperative recovery, no incisional scar in front of the tuberosity that usually causes discomfort in kneeling with a better cosmetic result and the ability to address concomitant intra-articular pathology. CONCLUSION: Osgood Schlatter syndrome runs a self-limiting course, and usually complete recovery is expected with closure of the tibial growth plate. Overall prognosis for Osgood Schlatter syndrome is good, except for some discomfort in kneeling and activity restriction in a few cases. Arthroscopic techniques seem to be the best choice of treatment of unresolved Osgood-Schlatter lesions. PMID- 28593577 TI - MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling. AB - : Abnormal pulmonary arterial smooth muscle cells (PASMCs) proliferation is an important pathological process in hypoxic pulmonary arterial hypertension. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation-apoptosis balance. However, the molecular mechanism is still unknown. We used hypoxic animal models, cell biology, and molecular biology to determine the effect of mitofusin 1 (Mfn1) on hypoxia-mediated PASMCs mitochondrial homeostasis. We found that Mfn1 expression was increased in hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and smooth muscle cell proliferation as well as hypoxia-stimulated cell-cycle transition from the G0/G1 phase to S phase. Subsequently, we studied the role of microRNAs in mitochondrial function associated with PASMC proliferation under hypoxic conditions. The promotive effect of Mfn1 on pulmonary vascular remodeling was alleviated in the presence of miR-125a agomir, and miR-125a antagomir mimicked the hypoxic damage effects to mitochondrial homeostasis. Moreover, in vivo and in vitro treatment with miR-125a agomir protected the pulmonary vessels from mitochondrial dysfunction and abnormal remodeling. In the present study, we determined that mitochondrial homeostasis, particularly Mfn1, played an important role in PASMCs proliferation. MiR-125a, an important underlying factor, which inhibited Mfn1 expression and decreased PASMCs disordered growth during hypoxia. These results provide a theoretical basis for the prevention and treatment of pulmonary vascular remodeling. KEY MESSAGES: Hypoxia leads to upregulation of mitofusin 1 (Mfn1) both in vivo and in vitro. Mfn1 is involved in hypoxia-induced PASMCs proliferation. Mfn1-mediated mitochondrial homeostasis is regulated by miR 125a. MiR-125a plays a role in PASMCs oxidative phosphorylation and glycolysis. PMID- 28593579 TI - The reciprocal lagged effects of substance use and recidivism in a prisoner reentry context. AB - BACKGROUND: Much work has investigated the association between substance use, crime, and recidivism, yet little scholarship has examined these associations longitudinally among samples of recently released prisoners. We examine the lagged reciprocal effects of hard substance use and crime, among other covariates, in the context of the prisoner reentry process. METHODS: We rely on data from the Serious and Violent Offender Reentry Initiative (SVORI) evaluation and employ cross-lagged panel models to examine short-term changes in substance use and crime over time among a large sample of high-risk, former prisoners (N = 1697). RESULTS: Substance use marginally predicted increased odds of rearrest at one wave, and rearrest significantly (p < .05) predicted increased odds of substance use at another. As such, the results provide limited evidence for a degree of lagged mutual causation; associations vary over the reentry process and are complicated by other realities of life after prison. A key finding is that both behaviors are more consistently influenced by other factors, such as service needs and instrumental and emotional supports. CONCLUSIONS: Although there are relationships between drug use and criminal behavior, these behaviors alone are insufficient explanations for one another in an adult reentry population. Alternatively, the compounding social and personal needs of the reentry population, and the extent to which they received support or services to address these needs, appear to have the strongest influence on both behaviors in the reentry context. PMID- 28593580 TI - Erratum to: Interventions for the endodontic management of non-vital traumatised immature permanent anterior teeth in children and adolescents: a systematic review of the evidence and guidelines of the European Academy of Paediatric Dentistry. PMID- 28593578 TI - Induced pluripotent stem cell-based modeling of neurodegenerative diseases: a focus on autophagy. AB - The advent of cell reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts or blood cells and their subsequent differentiation into tissue-specific cells, including neurons and glia. This approach can be used to recapitulate disease-specific phenotypes in classical cell culture paradigms and thus represents an invaluable asset for disease modeling and drug validation in the framework of personalized medicine. The autophagy pathway is a ubiquitous eukaryotic degradation and recycling system, which relies on lysosomal degradation of unwanted and potentially cytotoxic components. The relevance of autophagy in the pathogenesis of neurodegenerative diseases is underlined by the observation that disease-linked genetic variants of susceptibility factors frequently result in dysregulation of autophagic-lysosomal pathways. In particular, disrupted autophagy is implied in the accumulation of potentially neurotoxic products such as protein aggregates and their precursors and defective turnover of dysfunctional mitochondria. Here, we review the current state of iPSC-based assessment of autophagic dysfunction in the context of neurodegenerative disease modeling. The collected data show that iPSC technology is capable to reveal even subtle alterations in subcellular homeostatic processes, which form the molecular basis for disease manifestation. PMID- 28593581 TI - Intraoperative adjustment of alignment under valgus stress reduces outliers in patients undergoing medial opening-wedge high tibial osteotomy. AB - INTRODUCTION: A considerable percentage of outliers with under- or over correction continue to be reported despite precise preoperative planning and cautious intraoperative correction of lower limb alignment in medial opening wedge high tibial osteotomy (MOWHTO). The purpose of this study was to determine whether our novel technique for the intraoperative adjustment of alignment under valgus stress reduces the number of outliers in patients undergoing MOWHTO compared to the conventional technique, which corrects alignment according to the cable method only. MATERIALS AND METHODS: One hundred seventeen consecutive knees were enrolled in this case-control study. The first 52 knees (51 patients) were corrected in accordance with preoperative plans using the Dugdale method with modification with an intraoperative cable (group 1). In the other 65 knees (60 patients), the angle was corrected using the Dugdale method and limb alignment was adjusted using the intraoperative cable technique by applying valgus stress to the knee joint (group 2). The postoperative weight bearing line ratios and mechanical axis of the lower limb were compared at postoperative one year. Each knee was evaluated according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score preoperatively and at postoperative one year. RESULTS: A significant reduction in the number of outliers was seen in group 2 compared to group 1 (group 1 = 48.1%, group 2 = 9.2%, p < 0.001). Nineteen of 52 knees (36.5%) were under-corrected in group 1, whereas 6 of 65 knees (9.2%) were under-corrected in group 2 (p < 0.001). Six of 52 knees (11.6%) were over corrected in group 1, whereas 0 of 65 knees (0.0%) were over-corrected in group 2 (p = 0.005). At one -year after operation, group 2 showed significantly lower WOMAC score than group 1 (p = 0.014). CONCLUSIONS: Intraoperative adjustment of alignment under valgus stress significantly reduced the number of outliers compared to a technique that corrected alignment using the cable method in patients undergoing MOWHTO. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 28593582 TI - Morphological size evaluation of the mid-substance insertion areas and the fan like extension fibers in the femoral ACL footprint. AB - PURPOSE: The purpose of this study was to evaluate the detailed anatomy of the femoral anterior cruciate ligament (ACL) insertion site, with special attention given to the morphology of the mid-substance insertion areas and the fan-like extension fibers. METHODS: Twenty-three non-paired human cadaver knees were used (7 Males, 16 Females, median age 83, range 69-96). All soft tissues around the knee were resected except the ligaments. The ACL was divided into antero-medial (AM) and postero-lateral (PL) bundles according to the difference in macroscopic tension patterns. The ACL was carefully dissected and two outlines were made of the periphery of each bundle insertion site: those which included and those which excluded the fan-like extension fibers. An accurate lateral view of the femoral condyle was photographed with a digital camera, and the images were downloaded to a personal computer. The area of each bundle, including and excluding the fan like extension fibers, was measured with Image J software (National Institution of Health). The width and length of the mid-substance insertion sites were also evaluated using same image. RESULTS: The femoral ACL footprint was divided into four regions (mid-substance insertion sites of the AM and PL bundles, and fan like extensions of the AM and PL bundles). The measured areas of the mid substance insertion sites of the AM and PL bundles were 35.5 +/- 12.5, and 32.4 +/- 13.8 mm2, respectively. Whole width and length of the mid-substance insertion sites were 5.3 +/- 1.4, and 15.5 +/- 2.9 mm, respectively. The measured areas of the fan-like extensions of the AM and PL bundles were 27 +/- 11.5, and 29.5 +/- 12.4 mm2, respectively. CONCLUSION: The femoral ACL footprint was divided into quarters of approximately equal size (mid-substance insertion sites of the AM and PL bundles, and fan-like extensions of the AM and PL bundles). For clinical relevance, to perform highly reproducible anatomical ACL reconstruction, the presence of the fan-like extension fibers should be taken into consideration. PMID- 28593589 TI - Quinupristin-Dalfopristin A Viewpoint : A Viewpoint by Roland Leclercq. PMID- 28593584 TI - The action effect: Support for the biased competition hypothesis. AB - The action effect refers to the finding that faster response times are found when a previously responded to stimulus contains a target item than when it serves as a distracting item in a visual search. The action effect has proven robust to a number of perceptual and attentional manipulations, but the mechanisms underlying it remain unclear. In the current study, we present two experiments investigating a possible underlying mechanism of the action effect; that responding to a stimulus increases its attentional weight causing the system to prioritize it in the visual search. In Experiment 1, we presented the search stimulus in isolation and found no evidence of an action effect. Thus, when there was no requirement for prioritization, there was no action effect. In Experiment 2, we tested whether stimulus-based priming (rather than the action) can account for the observed validity effects. We found no evidence of a priming effect when there were never any actions. These findings are consistent with the biased competition hypothesis and provide a framework for explaining the action effect while also ruling out other potential explanations such as event file updating. PMID- 28593590 TI - Quinupristin-Dalfopristin A Viewpoint : A Viewpoint by Caroline C. Johnson. PMID- 28593583 TI - Regulating Autophagy as a Therapeutic Target for Diabetic Nephropathy. AB - PURPOSE OF REVIEW: Autophagy promotes cellular health in response to various cellular stresses and to changes in nutrient conditions. In this review, we focus on the role of autophagy in the pathogenesis of diabetic nephropathy and discuss the regulation of autophagy as a new therapeutic target for the suppression of diabetic nephropathy. RECENT FINDINGS: Previous studies have indicated that autophagy deficiency or insufficiency in renal cells, including podocytes, mesangial cells, endothelial cells and tubular cells, contributes to the pathogenesis of diabetic nephropathy. Alterations in the nutrient-sensing pathways, including mammalian target of rapamycin complex1 (mTORC1), AMP activated kinase (AMPK) and Sirt1, due to excess nutrition in diabetes are implicated in the impairment of autophagy. Maintaining both basal and adaptive autophagy against cellular stress may protect the kidney from diabetes-induced cellular stresses. Therefore, the activation of autophagy through the modulation of nutrient-sensing pathways may be a new therapeutic option for the suppression of diabetic nephropathy. PMID- 28593591 TI - Remifentanil : A Viewpoint by Peter S.A. Glass. PMID- 28593592 TI - Remifentanil : A Viewpoint by R.M. Jones. PMID- 28593595 TI - Psychometric Properties of the Adapted Skillstreaming Checklist for High functioning Children with ASD. AB - This study examined the reliability and criterion-related validity of parent ratings on the Adapted Skillstreaming Checklist (ASC) for a sample of 275 high functioning children, ages 6-12 years, with ASD. Internal consistency for the total sample was 0.92. For two subsamples, test-retest reliability was very good at the 6-week and good at the 9-month intervals. Child age, IQ, and language abilities were unrelated to the ASC score. The ASC total score was inversely and strongly related to parent ratings of ASD symptom severity. Significant positive correlations (moderate-to-high) were found between the ASC and prosocial skills scales and significant negative correlations (low-to-moderate) with problem behavior scales on a broad measure of child functioning. Implications and suggestions for future study are discussed. PMID- 28593596 TI - Physiological Arousal and Emotion Regulation Strategies in Young Children with Autism Spectrum Disorders. AB - This study aimed to assess physiological arousal and behavioral regulation of emotion in the context of frustration in 29 children with Autism Spectrum Disorders (ASD) and 45 typically developing children (41-81 months). Heart rate was continuously measured and emotion strategies were coded, during a locked-box task. Results revealed increases in arousal followed by a decline during recovery, significant for both groups indicating that heart rate patterns between groups were identical. The ASD group deployed less constructive and more venting and avoidance strategies, which was related to language impairments. We conclude that rather than abnormal levels of emotional arousal, a key impairment in young children with ASD may be difficulties in behaviorally regulating and expressing experienced emotions to others. PMID- 28593597 TI - The Stability of Self-Reported Anxiety in Youth with Autism Versus ADHD or Typical Development. AB - Children with autism spectrum disorder (ASD) are at risk for anxiety symptoms. Few anxiety measures are validated for individuals with ASD, and the nature of ASD raises questions about reliability of self-reported anxiety. This study examined longitudinal stability and change of self-reported anxiety in higher functioning youth with ASD (HFASD) compared to youth with symptoms of attention deficit hyperactivity disorder and typical development (TD) using the Multidimensional Anxiety Scale for Children (March, 2012; March et al. J Am Acad Child Adolesc Psychiatry 36(4):554-565, 1997). Diagnostic groups demonstrated comparable evidence of stability for most dimensions of anxiety. The HFASD group displayed higher anxiety than both comparison groups, especially physical symptoms. These findings have implications for identification and measurement of anxiety in ASD. PMID- 28593598 TI - Brief Report: Macrocephaly Phenotype and Psychiatric Comorbidity in a Clinical Sample of Mexican Children and Adolescents with Autism Spectrum Disorders. AB - Autism spectrum disorders (ASD) may present with macrocephaly. Few studies have analyzed the association with psychiatric comorbidity. Participants were 94 children with any ASD with an age range from 2 to 16 years (Mdn 6 years), 82% were boys. It was found that 20% of the sample had macrocephaly and 1% microcephaly. There was no association between the presence of macrocephaly and subtype of ASD. The most associated comorbidity was attention deficit/hyperactivity disorder (ADHD) 54.2%, followed by specific phobia 34%, dysthimia 29.7%, oppositional defiant disorder 13.83% motor tics 11.7%, separation anxiety 9.5% and Gilles de la Tourette 8.5%. In conclusion, macrocephaly and psychiatric comorbidity in this clinical sample of children with ASD is similar to the international literature results. PMID- 28593599 TI - Behavioral Symptoms of Reported Abuse in Children and Adolescents with Autism Spectrum Disorder in Inpatient Settings. AB - The objective of this study was to examine how behavioral manifestations of trauma due to abuse are expressed in youth with autism spectrum disorder (ASD). Analysis of covariance (ANCOVA) compared outcomes between patients with a caregiver reported history of abuse and those without. Findings indicate that patients with ASD and reported abuse (i.e. physical, sexual, and/or emotional) have more intrusive thoughts, distressing memories, loss of interest, irritability, and lethargy than those without reported maltreatment. Those with clinical diagnoses of posttraumatic stress disorder (PTSD) had more severe and externalized symptoms than those with reported abuse not diagnosed with PTSD. Results emphasize the need for trauma screening measures to guide evidence-based treatments for children with ASD. PMID- 28593600 TI - Developmental Changes in Empathic Concern and Self-Understanding in Toddlers at Genetic Risk for Autism Spectrum Disorder. AB - Toddlers with an older sibling with autism spectrum disorder (ASD) and low risk (LR) toddlers were observed at 22, 28, and 34 months during two empathy probes: a crying baby and an adult who pretended to hurt her finger. Toddlers with a later ASD diagnosis showed less empathic concern and self-distress at each age on both empathy probes than LR toddlers. HR toddlers with no diagnosis showed growth in empathic concern between 22 and 34 months in response to the adult's pain, differing from the children with ASD, but not the LR children, by 34 months. Developmental changes in parent-rated self-understanding showed a similar pattern. Results highlight individual differences in the social development of HR toddlers. PMID- 28593602 TI - Efficient Biotransformation of Astragaloside IV to Cycloastragenol by Bacillus sp. LG-502. AB - Cycloastragenol (CA), an exclusive telomerase activator, was derived from the Astragali Radix which is widely distributed in Turkey. Until now, there is no report to produce CA with effective and environment-friendly methods. Biotransformation is considered to be a promising technology. Thus, the present study was aimed to establish a biotransformation technology that could efficiently produce CA. In this paper, a microorganism, LG-502, was used to successfully transform astragaloside IV (ASI) to CA by analysis of thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC). The phylogenetic analysis of the 16S rRNA indicated that this strain belongs to Bacillus sp. Three metabolites were separated during the fermentation and characterized to be cyclogaleginoside B, CA, and 20R, 24S-epoxy-6alpha, 16beta, 25-trihydroxy-9, 19-cycloartan-3-one based on NMR and MS spectroscopic analyses. The conversion rate of ASI and yield rate of CA were achieved as high as 89 and 84%, respectively, under optimized conditions. Enzymatic analysis showed that the glycosidases were mainly located inside the bacterial body, and the activities of glucosidases were much higher than the xylosidases under the experimental conditions. This study provides a feasible, effective, and eco-friendly way to prepare CA from ASI, which might greatly contribute to the applications of ASI. PMID- 28593601 TI - How Competent are Adolescent Bullying Perpetrators and Victims in Mastering Normative Developmental Tasks in Early Adulthood? AB - A substantive body of literature suggests that those involved in bullying as perpetrators but particularly victims are at greater risk for psychological maladjustment. In comparison, relatively little is known about associations between bullying-victimization and perpetration and mastery of early adult tasks in domains including romantic relationships, education, work, financial competence, and conduct. These links were tested using data from two Dutch cohorts (RADAR-young, n = 497, 43% girls; TRAILS, n = 2230, 51% girls) who reported on victimization and perpetration at age 11 (TRAILS) and 13 (RADAR young) and mastery of developmental tasks in early adulthood. Unadjusted regression analyses suggested for both cohorts that perpetrators were less likely to abide the law and more likely to smoke. Victims in TRAILS were less competent in the domains of education, work, and finances, and more likely to smoke in RADAR-young. Adjusting for childhood demographics and child intelligence and including psychopathology in the prediction models substantially reduced the strength of associations between bullying involvement and later outcomes in both cohorts; although association were retained between victimization and welfare dependence and perpetration and crime involvement in TRAILS. Parental support did not buffer associations in either sample and neither were gender differences detected. Overall, findings underline that negative outcomes of bullying are not only a concern for victims but also for their perpetrators although involvement in bullying is not a stable predictor of mastery of developmental tasks when childhood demographics, child intelligence, and psychopathology are taken into account. PMID- 28593603 TI - Optimization of Inexpensive Agricultural By-Products as Raw Materials for Bacitracin Production in Bacillus licheniformis DW2. AB - Bacitracin is a broad-spectrum antibiotic used extensively as a feed additive. In this study, inexpensive agricultural by-products were used as nitrogen sources for bacitracin production. Based on both the orthogonal tests, a combination of 7% soybean meal (SBM) +2% low protein rapeseed cake (LPRC) was optimal for bacitracin production. Compared to the original formula, the titer of bacitracin increased by 20.5% reaching 910.4 U/ml in flasks. The titer of bacitracin and the ratio of bacitracin A increased by 12.4 and 6.8% in a 50-l fermentor. Furthermore, this study also explored the effects of exogenously adding different amino acids on the yield of bacitracin. The addition of Cys and Glu enhanced bacitracin production by 5.7 and 5.0%, respectively. This study provided the inexpensive nutrient inputs into efficient bacitracin production and also the insight to further research enabling better utilization of oil cakes for economic viability of the bioprocess industry. PMID- 28593605 TI - Online webcam-based eye tracking in cognitive science: A first look. AB - Online experimentation is emerging in many areas of cognitive psychology as a viable alternative or supplement to classical in-lab experimentation. While performance- and reaction-time-based paradigms are covered in recent studies, one instrument of cognitive psychology has not received much attention up to now: eye tracking. In this study, we used JavaScript-based eye tracking algorithms recently made available by Papoutsaki et al. (International Joint Conference on Artificial Intelligence, 2016) together with consumer-grade webcams to investigate the potential of online eye tracking to benefit from the common advantages of online data conduction. We compared three in-lab conducted tasks (fixation, pursuit, and free viewing) with online-acquired data to analyze the spatial precision in the first two, and replicability of well-known gazing patterns in the third task. Our results indicate that in-lab data exhibit an offset of about 172 px (15% of screen size, 3.94 degrees visual angle) in the fixation task, while online data is slightly less accurate (18% of screen size, 207 px), and shows higher variance. The same results were found for the pursuit task with a constant offset during the stimulus movement (211 px in-lab, 216 px online). In the free-viewing task, we were able to replicate the high attention attribution to eyes (28.25%) compared to other key regions like the nose (9.71%) and mouth (4.00%). Overall, we found web technology-based eye tracking to be suitable for all three tasks and are confident that the required hard- and software will be improved continuously for even more sophisticated experimental paradigms in all of cognitive psychology. PMID- 28593604 TI - Neutralization of matrix metalloproteinase-9 potentially enhances oncolytic efficacy of tanapox virus for melanoma therapy. AB - Matrix metalloproteinases (MMPs), which are involved in degradation of extracellular matrix, are critical regulators in tumor progression, metastasis and angiogenesis. Although induction of MMPs is frequently observed during the viral infection, the effect of MMPs on viral replication varies between viruses. MMP-9, for instance, is upregulated and promotes the replication of some viruses, such as herpes simplex virus, but inhibits the replication of others. Here, we report that infection with tanapox virus (TPV) promotes the expression of MMP-9 in the melanoma cells. In addition, we show that MMP-9 exerts an anti-viral effect on TPV replication and plays a protective role in TPV-infected melanoma cells in vitro. Moreover, the neutralization of MMP-9 in melanoma cells remarkably enhances the TPV infection and leads to a significant reduction in cell survival. In summary, this study contributes to understanding of the role played by MMP-9 in TPV infectivity and provides more insights for using TPV as cancer virotherapy in future studies. Since TPV has shown substantial oncolytic efficacy in promoting melanoma tumor regression in animal models, identifying mechanisms that suppress MMP-9 expression upon TPV infection can potentially improve its use as a melanoma virotherapy. PMID- 28593606 TI - Gazepath: An eye-tracking analysis tool that accounts for individual differences and data quality. AB - Eye-trackers are a popular tool for studying cognitive, emotional, and attentional processes in different populations (e.g., clinical and typically developing) and participants of all ages, ranging from infants to the elderly. This broad range of processes and populations implies that there are many inter- and intra-individual differences that need to be taken into account when analyzing eye-tracking data. Standard parsing algorithms supplied by the eye tracker manufacturers are typically optimized for adults and do not account for these individual differences. This paper presents gazepath, an easy-to-use R package that comes with a graphical user interface (GUI) implemented in Shiny (RStudio Inc 2015). The gazepath R-package combines solutions from the adult and infant literature to provide an eye-tracking parsing method that accounts for individual differences and differences in data quality. We illustrate the usefulness of gazepath with three examples of different data sets. The first example shows how gazepath performs on free-viewing data of infants and adults, compared to standard EyeLink parsing. We show that gazepath controls for spurious correlations between fixation durations and data quality in infant data. The second example shows that gazepath performs well in high-quality reading data of adults. The third and last example shows that gazepath can also be used on noisy infant data collected with a Tobii eye-tracker and low (60 Hz) sampling rate. PMID- 28593607 TI - Focus on what works and why it works: bridging the gap between research knowledge and practical knowledge. PMID- 28593608 TI - Tumor necrosis factor-alpha -308 A/G gene polymorphism in children with juvenile idiopathic arthritis: relation to disease activity, damage, and functional status. AB - The study aims to evaluate the clinical significance of serum levels of tumor necrosis factor alpha (TNF-alpha) and -308 A/G promoter polymorphism in juvenile idiopathic arthritis (JIA) patients and find any association to the subsets, clinical and laboratory features, disease activity, and damage as well as functional disability. Forty-eight JIA children and 30 controls were included in the present study. Juvenile arthritis disease activity score in 27 joints (JADAS 27) was calculated, juvenile arthritis damage index (JADI) was assessed, and Childhood Health Assessment Questionnaire (CHAQ) measured the functional status. Serum TNF-alpha was assayed by ELISA and gene (-308) promoter polymorphism was determined by polymerase chain reaction. The 48 JIA children (mean age 11.5 +/- 2.8 years) were 13 systemic, 17 oligoarticular, and 18 polyarticular onset. The serum TNF-alpha was significantly higher in patients (90.4 +/- 6.3 ng/ml) compared to control (3.5 +/- 2.6 ng/ml) (p < 0.0001) with a tendency to be higher in the polyarticular subtype. All controls had TNF-alpha -308 GG alleles. The frequency of GG genotype tended to be higher in systemic onset compared to oligoarticular and polyarticular subtypes. The serum TNF-alpha significantly correlated with JADAS-27 (r = 0.32, p = 0.03) and CHAQ (r = 0.37, p = 0.01) and negatively with the presence of GG alleles (r = -0.48, p = 0.001). The GG alleles were significantly negatively associated with C-reactive protein (r = -0.32, p = 0.03) with a tendency to negatively correlate with JADAS-27, CHAQ, and JADI extrarticular (r = -0.28, p = 0.06; r = -0.25, p = 0.09 and r = -0.25, p = 0.09, respectively). There is evidence of a possible influence of the -308 SNP promoter position on the production of TNF-alpha, the severity of JIA which may consequently influence the response to anti-TNF-alpha treatment. PMID- 28593609 TI - Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: results of a 12-month observational prospective cohort study. AB - The objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice. All rheumatic patients on INX treatment (Remicade(r)) and >=18 years were switched to INB (Inflectra(r)) as part of routine care, but in a controlled setting. Patients were monitored by taking blood samples just before the first infusion of INB (T1), and after the second (T2), fourth (T3), and seventh (T4) infusion of INB. T4 reflects the patients' status after ~12 months. Infliximab trough levels, antibodies-to-infliximab (ATI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and validated disease activity scores (if possible) were measured. Our population consisted of 27 patients with seven different rheumatic diseases who had received INX for 143 (58-161) months (median (IQR)). Half of the patients (52%) received concomitant immunosuppressives. We found widely varying infliximab levels, with only 56% within the proposed therapeutic range of 1-5 MUg/mL. One patient had very high ATI levels (>880 au/mL), and two had low ATI levels (<=30 au/mL). After switching to INB, seven patients (26%) discontinued the therapy, partially due to subjective reasons. No difference in infliximab levels, CRP levels, and disease activity scores was found between the four time points (p >= 0.2460). In conclusion, no pharmacokinetic or clinical differences were found between INX and INB in our diverse rheumatic cohort. TDM is a helpful tool to monitor patients switching from INX to INB. PMID- 28593610 TI - Brief report: Decreased expression of CD244 (SLAMF4) on monocytes and platelets in patients with systemic lupus erythematosus. AB - The signalling lymphocyte activation molecule (SLAM) family receptors play important roles in modulating immune responses. Previous studies in murine models and patients have suggested an association of the SLAM family (SLAMF) members with the development of autoimmunity, particularly systemic lupus erythematosus (SLE). Since previous investigations on CD244 expression have focussed on NK and T cells, the aim of this study was to evaluate the surface expression of major SLAMF members across monocytes and polymorphonuclear cells in an Asian SLE cohort and explore their potential associations with SLE-related disease activity and autoantibodies. Thirty-nine SLE patients and twenty-nine healthy controls (HC) were evaluated for the expression of CD150, CD84, CD229, CD48, CD244, CD352 and CD319. We determined a significantly lower expression of CD244 on monocytes in SLE patients compared to HC. Furthermore, monocyte CD244 expression was negatively associated with several serum autoantibody titres. Our findings suggest that this molecule plays an important role in immune tolerance mechanisms and should be investigated further. PMID- 28593611 TI - A case of ruptured infective coronary artery aneurysm. AB - Infective coronary artery aneurysm is extremely rare and ruptured aneurysm is life-threatening. We report a case of ruptured coronary artery aneurysm, which was successfully treated by the patch closure technique and coronary artery bypass grafting. Pathological examination revealed purulent inflammation in the aneurysmal wall. Prompt diagnosis and appropriate treatment were essential. PMID- 28593613 TI - Effects of distributional information on categorization of prosodic contours. AB - Although prosody clearly affects the interpretation of utterances, the mapping between prosodic representations and acoustic features is highly variable. Listeners may in part cope with this variability by adapting to distributions of acoustic features in the input. We examined whether listeners adapt to distributional changes using the construction It looks like an X. When pronounced with an H* pitch accent on the final noun and a low boundary tone, the construction supports an affirmative interpretation (e.g., It looks like a ZEBRA [and I think it is one]). Conversely, when pronounced with a L+H* pitch accent and a rising boundary tone, it suggests a negative interpretation (e.g., It LOOKS like a zebra.... [but it is not]). Experiment 1 elicited pragmatic interpretations of resynthesized 12-step continua with these two contours as the end points. In Experiment 2, one group of listeners heard items sampled from the most ambiguous region along the continua followed by affirmative continuations (e.g., It looks like a zebra because it has stripes all over its body) and items near the contrastive endpoint followed by negative continuations (e.g., It looks like a zebra but it is actually something else). Another group heard the reverse (i.e., ambiguous items with negative continuations and non-contrastive items with affirmative continuations). The two groups of participants subsequently derived diverging interpretations for novel ambiguous items, suggesting that prosodic processing involves flexible mappings between acoustic features and prosodic representations that are meaningful in interpretation of speech. PMID- 28593612 TI - An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis. AB - Brodsky et al. (Cardiovasc Pathol 25(6), 515-520, 2016) recently have reported that there was an unexpected and highly significant inverse correlation between body mass index (BMI) and atherosclerosis of the aortas of morbidly obese decedents (BMI >40 kg/m2). In a series of 304 decedents, 65 of whom were morbidly obese, minimal or no atherosclerosis was seen in 46 of them (70%) versus 20 (30%) who had severe atherosclerosis (P = 0.008). This obesity paradox was unexpected and raises important questions about the etiology and pathogenesis of atherosclerosis, which will be the subject of this commentary. The concept of healthy versus unhealthy adiposity may in part provide an explanation for the "obesity paradox." Another factor that will be considered is the possible role of adipokines and their genetic determinants that may significantly reduce the risk of developing aortic atherosclerosis in morbidly obese individuals. Considering the marked variability in the pattern and extent of atherosclerosis of the aorta, hemodynamic factors and endothelial cell shear stress may be the most important determinants that might explain the obesity paradox that we have observed. Finally, the possible role of gut microbiota and inflammation as factors in the etiopathogenesis of atherosclerosis will be considered, but their importance is less clear than that of hemodynamic factors. We conclude with the remarkable finding that a 5300-year-old, well-preserved mummy of the "Iceman," Otzi had atherosclerotic disease of a number of major arteries and the interesting questions that this raises. PMID- 28593614 TI - Circulating anti-Mullerian hormone (AMH) associates with the maturity of boys' drawings: Does AMH slow cognitive development in males? AB - PURPOSE: High levels of circulating anti-Mullerian hormone are unique to developing males, but the function of anti-Mullerian hormone in boys is unknown. In mice, anti-Mullerian hormone contributes to the male biases in the brain, but its receptors are present throughout non-sexually dimorphic portions of the brain. In humans, the speed of maturation is the most overt difference between girls and boys. We postulate that this is because anti-Mullerian hormone slows the maturation of the male human brain. METHODS: One hundred and fourty three 5 year or 6-year-old boys and 38 age-matched girls drew a person and donated a blood sample. The children's drawings were blind-scored to generate a maturity index. The level of anti-Mullerian hormone and the other Sertoli cell hormone, inhibin B, were measured by ELISA. The relationship between the children's age, hormones and maturity index were examined by linear regression analysis. RESULTS: The girls drew more complex and realistic person than the boys (32%, p = 0.001), with their drawings also being larger (39%, p = 0.037) and more coloured-in (235%, p = 0.0005). The maturity index in boys correlated with age (+r = 0.43, p < 0.0005) and anti-Mullerian hormone level (-r = -0.29, p < 0.0005). The association between maturity index and anti-Mullerian hormone level persisted when corrected for age and for inhibin B (r = -0.24, p = 0.0005). The calculated effect of the median level of anti-Mullerian hormone (1 nM) was equal to 0.81 months of development. The size and colouring of the drawings did not correlate with the boys' age, anti-Mullerian hormone or inhibin B. CONCLUSIONS: This exploratory study provides the first indicative evidence that circulating anti Mullerian hormone may influence the development of the human brain. PMID- 28593615 TI - A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in type 2 diabetes mellitus. AB - AIMS: SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes. METHODS: We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level. RESULTS: There were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 +/- 12.08, 23.19 +/- 8.10, and 9.84 +/- 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was -6.57 +/- 7.34 mg/ml (p = 0.04). CONCLUSIONS: A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies. PMID- 28593616 TI - New insights on diabetes in Turner syndrome: results from an observational study in adulthood. AB - OBJECTIVE: To explore the characteristics of diabetes mellitus in adults with Turner syndrome. DESIGN: Observational study consisting of a prospective phase after the access of adults with Turner syndrome to the Endocrinology Unit (median period of follow-up 15.6, interquartile range: 12.0-24.5 months) and a retrospective collection of data from the diagnosis of Turner syndrome until the time of access to the Endocrinology Unit. A total of 113 Italian Turner syndrome patients were included in the study. During the prospective phase of the study, each patient underwent physical examination, fasting blood sampling, and an oral glucose tolerance test on a yearly basis. Oral glucose tolerance test was used to perform the diagnosis of diabetes mellitus. RESULTS: Before access to the Endocrinology Unit, diabetes mellitus was diagnosed in two Turner syndrome patients. Another five cases of diabetes mellitus were diagnosed at the first access to the Endocrinology Unit, whereas seven new cases of diabetes mellitus were diagnosed during the prospective phase of the study. At the diagnosis of diabetes mellitus, only one patient had fasting glucose above 126 mg/dL, and only two had an HbA1c value >6.5% (48 mmol/mol). When compared to normo-glucose tolerant patients, the diabetic patients had a significantly lower insulin-to glucose ratio at 30 and 60 min of the oral glucose tolerance test. In the regression analyses, only age was associated with the development of diabetes mellitus. CONCLUSIONS: This study confirms that diabetes mellitus is frequent in Turner syndrome and suggests that it is specific to the syndrome. In addition, this study demonstrates that oral glucose tolerance test is a more sensitive test than HbA1c for the diagnosis of diabetes mellitus in Turner syndrome. PMID- 28593617 TI - The dangers of extreme body mass index values in patients with Clostridium difficile. AB - PURPOSE: To examine the association between body mass index (BMI) and in-hospital mortality in patients presenting with Clostridium difficile infections in emergency department visits (ED) in the USA. Infected patients with extreme BMIs may have an elevated mortality risk, but prior studies examining this question have been too small to reach definitive conclusions. METHODS: Data were from the Nationwide Emergency Department Sample (NEDS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality during 2012. NEDS records emergency department (ED) visits across the USA and provides statistical sampling weights to approximate a nationally representative sample of US hospital based EDs. Inclusion criteria were adults age 18 or older with an ICD-9 code for C. difficile infection (008.45) and a documented body mass index ICD-9 V code (V85.x). Logistic regression was used to predict mortality after adjusting for demographic variables and chronic comorbidities defined by Elixhauser. RESULTS: A weighted sample of 22,937 ED visits met all inclusion criteria. The cohort's mean age was 66. 64.6% were female. The unadjusted mortality rate was 6.5%. Patients with a BMI < 19 kg/m2 had an adjusted odds ratio of 2.73; 95% CI (1.80, 4.16), p < 0.001 compared to patients with a BMI of 19.0-4.9 kg/m2 (the referent category). In obese patients, only BMI values >40 kg/m2 were associated with significantly greater mortality risk. CONCLUSION: Being underweight (BMI < 19) or morbidly obese (BMI > 40) was associated with increased risk of in-hospital mortality in patients presenting with C. difficile infections. PMID- 28593619 TI - [Do the advantages of modern mental health care have drawbacks?] PMID- 28593618 TI - RIG-I: a multifunctional protein beyond a pattern recognition receptor. AB - It was widely known that retinoic acid inducible gene I (RIG-I) functions as a cytosolic pattern recognition receptor that initiates innate antiviral immunity by detecting exogenous viral RNAs. However, recent studies showed that RIG-I participates in other various cellular activities by sensing endogenous RNAs under different circumstances. For example, RIG-I facilitates the therapy resistance and expansion of breast cancer cells and promotes T cell-independent B cell activation through interferon signaling activation by recognizing non-coding RNAs and endogenous retroviruses in certain situations. While in hepatocellular carcinoma and acute myeloid leukemia, RIG-I acts as a tumor suppressor through either augmenting STAT1 activation by competitively binding STAT1 against its negative regulator SHP1 or inhibiting AKT-mTOR signaling pathway by directly interacting with Src respectively. These new findings suggest that RIG-I plays more diverse roles in various cellular life activities, such as cell proliferation and differentiation, than previously known. Taken together, the function of RIG-I exceeds far beyond that of a pattern recognition receptor. PMID- 28593620 TI - [A comparative study of the structural stigmatisation of ADHD and autism spectrum disorder in Flemish newspapers]. AB - BACKGROUND: Children and adults with adhd and autism spectrum disorder (asd) often find themselves being stigmatised. There is ample evidence of public stigma, but much less is known about negative coverage in the media, a phenomenon that can be regarded as a form of structural stigma.
AIM: To explore the different types of structural stigma that characterise the coverage of adhd and asd in Flemish newspapers.
METHOD: We used the online databases of seven Flemish newspapers in order to select articles on adhd (n=772) and asd (n=1940) published between 2010 and 2014. We divided these articles into separate categories relating to the domain of coverage (e.g. symptomatology, epidemiology, medical treatment) and valence (i.e. positive, neutral and negative).
RESULTS: We found significantly more negative than neutral/positive coverage of adhd than of asd (or 2.1). This finding was most striking in the domains of symptomatology (or 8.42), diagnostics (or 2.28) and medical treatment (or 9.40). Furthermore, with respect to articles specifically on adhd, the title of the article was significantly more negative than the actual message in the main article itself (chi2(2)=22.454, p < 0.001).
CONCLUSION: These findings show that Flemish newspapers need to adjust and correct their negative and inaccurate portrayal of symptomatology, diagnostics and treatment of adhd and, to a lesser extent, of asd. Readers of these newspapers also need to be given a less negative impression of adhd and asd. PMID- 28593622 TI - [Emotional scars: impact of childhood trauma on the development of depressive and anxiety disorders later in life]. AB - BACKGROUND: Childhood trauma and negative life events in childhood are risk factors for the development of anxiety and depressive disorders in adulthood.
AIM: To increase our understanding of the specific associations between trauma and negative life events in childhood and the development and course of anxiety and depressive disorders in adulthood.
METHOD: Our research findings are based on data from the Netherlands Study of Depression and Anxiety (NESDA). In our article we report on two cross-sectional and three prospective studies.
RESULTS: All domains of childhood trauma are risk factors for the development of anxiety and/or depressive disorders in adulthood. Emotional neglect is the main independent predictor of the occurrence and the course of anxiety and depressive disorders. Certain personality characteristics and more unfavorable clinical factors play an important role in mediating the relationship between childhood trauma and the course of anxiety and depressive disorders later in life.
CONCLUSION: Not only does childhood trauma increase an individual's vulnerability to the development of anxiety and depressive disorders, it is also associated with a more serious and more chronic course of these disorders. Our studies have provided new insights into the underlying mechanism that links childhood trauma and anxiety and later anxiety depressive disorders. Consequently, we feel justified in making some recommendations with regards to clinical practice and public health interventions. PMID- 28593621 TI - [Measuring changes during the treatment of eating disorders: a comparison of two types of questionnaires]. AB - BACKGROUND: In mental health care routine outcome monitoring (ROM) has become an important part of everyday clinical practice in the Netherlands. It is important that the questionnaires involved are sensitive to therapeutic change. The Brief Symptom Inventory (BSI) is a generic instrument that is widely used and that seems to be responsive to therapeutic change. However, in relation to patients with an eating disorder, more valuable information might be obtained from a questionnaire that is better geared to the primary symptoms of the eating disorder.
AIM: To find out whether the BSI and the Eating Disorder Examination Questionnaire (EDE-Q), which is a questionnaire designed to measure eating disorder psychopathology, reveal different degrees of therapeutic change in patients with an eating disorder.
METHOD: The sample consisted of 1062 patients seeking treatment for an eating disorder (DSM-IV). We performed an analysis of variance (2 x 2 design) in order to detect any difference between the two instruments regarding their sensitivity to change at the two time points. Patients were divided into four categories: recovered, improved, unchanged or deteriorated. We used a chi-squares test to determine whether the two questionnaires differed with regard to the proportions they gave for improved and recovered patients.
RESULTS: The analyses revealed that in this patient group the EDE-Q was more sensitive to change than the BSI. The percentage of patients in the categories 'recovered' and 'improved' was higher in the EDE-Q than in the BSI. The same practice emerged with regards to the various subtypes of eating disorders.
CONCLUSION: It does seem to matter what type of questionnaire is used to measure the course and outcome of treatment. When responsiveness to change is being measured, it is important to use an instrument that assesses the symptoms that are the primary focus of treatment. If the primary aim is to reduce eating disorder symptoms, then the best type of questionnaire to use is one that assesses eating disorder psychopathology. PMID- 28593623 TI - [Smoking cessation and schizophrenia]. AB - BACKGROUND: People with schizophrenia smoke about 5.6 times as much as people without the disease. This factor is a major but treatable cause of morbidity and mortality in this patient population. Nevertheless, health professionals make relatively little effort to discourage people from smoking or to give it up altogether.
AIM: To increase health professionals' knowledge about possible therapeutic interventions that can help people with schizophrenia to stop smoking.
METHOD: We studied the relevant literature.
RESULTS: Many people with schizophrenia do in fact want to give up smoking. However, many health professionals are reluctant to intervene because, as a result, people with schizophrenia might experience a deterioration in their mental state. We believe that people with schizophrenia who are determined to give up smoking need to receive a combination of pharmacotherapy and psychological support. This patient population requires a longer than normal period of treatment.
CONCLUSION: So far, a combination of bupropion, nicotine patches and psychological support has proved the most effective form of support for this target group consisting of people with schizophrenia. PMID- 28593625 TI - [Reaction on 'Towards a positive psychiatry?'] PMID- 28593624 TI - [The Othello syndrome in Parkinson's disease: an example of a lesser-known delusion]. AB - Delusions are fairly common features of Parkinson's disease. Some delusions are easily recognised, but others are less well-known and can be missed by health professionals. We describe the case of a female patient with Parkinson's disease who believed, erroneously, that her partner was being unfaithful; this type of delusion is also called the Othello syndrome. After psychoeducation and the start of clozapine, the delusion faded and the relationship became more peaceful. PMID- 28593626 TI - Safety of Lateral Interbody Fusion Surgery without Intraoperative Monitoring. AB - AIM: Oblique lateral interbody fusion (OLIF) is a minimally invasive surgical method that can provide an access to the lumbar spine without direct dissection of psoas muscle and the need for intraoperative neuromonitoring (IOM) is questionable. The aim of this study was to examine and document the transient and persistent perioperative complications in patients who underwent OLIF for degenerative lumbar disease without IOM. MATERIAL AND METHODS: A total of 129 consecutive patients who were diagnosed as degenerative spinal disease from L1 to S1 and underwent mini-open OLIF were identified and retrospectively reviewed. All patients were classified as two groups; non-IOM group and IOM group. According to the relation to surgical procedure, the complications were divided into two groups; "procedurerelated" and "procedure-unrelated". Based on the effect of duration, the complications were defined as "transient" where the symptom is relieved within 30 days postoperatively, and "persistent" where the symptom remains for more than 30 days postoperatively. RESULTS: The study groups comprised 57 cases in the IOM group and 72 in the non-IOM group. The complication rate was 24.6% (transient; 17.6%, persistent; 7.0%) in the IOM group and 29.2% (transient; 25.0%, persistent; 4.2%) in the non-IOM group. The incidence of postoperative leg symptoms related to lumbar plexus and/or psoas muscle injury was 6 transient and 3 persistent in the IOM group (overall 15.3%), and 12 transient and 3 persistent in the non-IOM group (overall 20.9%). CONCLUSION: Mini open OLIF can be safely carried out without the aid of IOM. PMID- 28593627 TI - Efficacy and Safety of Using N-Butyl Cyanoacrylate in Cranial Fixation Following Trauma and Other Pathologies. AB - AIM: Skull bone fixation following different cranial surgeries is essential and should be rigid, simple and cheap. We describe our technique of cranial fixation using the adhesive cyanoacrylates. MATERIAL AND METHODS: At the end of cranial and intracranial surgeries the craniotomy flap and bone pieces are returned, realigned and fixed using HistoacrylZ (N-Butyl Cyanoacrylate) glue. The glue is applied all around the flap in 360-degree fashion. RESULTS: The adhesive material was used in 24 cases after different surgeries involving the calvaria of the skull. Patient age ranged from 1 month to 55 years. Seven cases presented with depressed fractures, 5 traumatic hematomas, and 2 cases after decompressive craniotomies for malignant middle cerebral artery (MCA) infarctions, and 10 cases operated for brain tumors. No skin or bone flap infections were encountered during the follow up period and fusion of the edges of bone flap was observed on follow-up imaging in most of the cases. CONCLUSION: Skull bone realignment and fixation using glue is a simple, safe, and inexpensive method. The operative procedure was not prolonged. Good cosmetic appearance and realignment and fusion of the bone flap were achieved. Further neuroimaging methods are not prohibited. Glue is suitable for the growing skull of children. Glue is also suitable in compound depressed fractures of the skull with possibility of infection. PMID- 28593628 TI - Outcome of Microsurgical Revascularization in Patients with Moyamoya Disease: First Report from the Iranian Population. AB - AIM: To report the outcome of microsurgical revascularization in patients with Moyamoya Disease (MMD) in Southern Iran. MATERIAL AND METHODS: This cross sectional study was conducted in Southern Iran during a 7-year period from 2009 to 2016. All the patients with Moyamoya Disease (confirmed with digital substraction angiography) who underwent microsurgical revascularization (extracranial-intracranial bypass or synangiosis) were included. All the patients were followed for at least 1 year and the outcome was measured using the Glasgow outcome scale (GOS) and modified Rankin scale (MRS). RESULTS: Overall we included 13 patients with 14 involved hemispheres undergoing direct and indirect revascularization. The mean age of the patients was 20.6+/-17.5 (ranging from 0.5 to 55) years and there were 5 (38.4%) males and 8 (61.6%) females. We did not have any unfavorable outcome defined as mortality and persistent vegetative state. We performed 12 (85.7%) superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and 2 (14.3%) encephalo-myo-synangiosis (EMS) procedures. The symptoms improved in 7 (53.8%) patients and remained as the preoperative course in 5 (38.5%) patients. Only 1 (7.7%) patient developed immediate postoperative vasospasm and brain swelling, and was managed successfully with decompressive craniectomy and subsequent cranioplasty (GOS=5, MRS=0). CONCLUSION: This is the first study to report the safety, efficacy and outcome of the direct (STA-MCA bypass) and indirect (EMS) revascularization in patients with MMD in the Iranian population. As the prevalence of MMD is low in Iranian population, the experience and technique remains in its infancy and further advancements in the field is required. PMID- 28593629 TI - Type 2 diabetes, adiposity and cancer morbidity and mortality risk taking into account competing risk of noncancer deaths in a prospective cohort setting. AB - Type 2 diabetes (T2D) and adiposity associate with increased risk of several cancers, but the impact of competing risk of noncancer deaths on these associations is not known. We prospectively examined participants in the Malmo Diet and Cancer Study aged 44-73 years with no history of cancer at baseline (n = 26,953, 43% men). T2D was ascertained at baseline and during follow-up, and body mass index (BMI) and waist circumference (WC) at baseline. Multivariable cause specific hazard ratios (HR) and subdistribution hazard ratios (sHR), taking into account noncancer deaths, were estimated using Cox- and competing risk regression. During follow-up (mean 17 years), 7,061 incident cancers (3,220 obesity-related cancer types) and 2,848 cancer deaths occurred. BMI and WC were associated with increased risk of obesity-related cancer incidence and cancer mortality. In T2D subjects, risk of obesity-related cancer was elevated among men (HR = 1.31, 95% CI: 1.12-1.54; sHR = 1.29, 95% CI: 1.10-1.52), and cancer mortality among both men and women (HR = 1.34, 95% CI: 1.20-1.49; sHR = 1.30, 95% CI: 1.16-1.45). There was no elevated actual risk of cancer death in T2D patients with long disease duration (sHR = 1.00, 95% CI: 0.83-1.20). There was a significant additive effect of T2D and adiposity on risk of obesity-related cancer and cancer mortality. In conclusion, detection bias may partially explain the increased risk of cancer morbidity among T2D patients. Both excess risk of competing events among patients with T2D and depletion of susceptibles due to earlier cancer detection will lower the actual risk of cancer, particularly with longer diabetes duration and at older ages. PMID- 28593630 TI - Investigating the DSM-5 severity specifiers based on thinness for adults with anorexia nervosa. AB - OBJECTIVE: The DSM-5 severity classification scheme for adults with anorexia nervosa (AN) is based upon current body mass index (BMI; kg/m2 ). This study examined the utility of the DSM-5 severity specifiers for adults with AN in relation to core cognitive and behavioral features of eating pathology and associated psychosocial impairment. METHODS: A clinical sample of 146 adult AN patients (140 women, 6 men) were categorized using DSM-5 current BMI severity specifiers and assessed with the Eating Disorder Examination-Questionnaire (EDE Q) and Clinical Impairment Assessment (CIA). RESULTS: A total of 34 (23.3%) patients were categorized as mild (>=17.0 BMI), 35 (24.0%) as moderate (16-16.99 BMI), 32 (21.9%) as severe (15-15.99 BMI), and 45 (30.8%) as extreme (<15 BMI). No significant group differences were found for age, CIA and EDE-Q global or subscale scores, frequency of laxative use, self-induced vomiting, binge eating, or excessive exercise. DISCUSSION: This study found little empirical evidence to support the utility of DSM-5 severity rating scheme to differentiate adults with AN in terms of core eating disorder pathology or associated psychosocial impairment. PMID- 28593632 TI - Rutherglen bug: An agricultural pest and an under-recognised biting culprit. PMID- 28593631 TI - Bivalirudin versus heparin and provisional GP IIb/IIIa inhibitors in patients treated for ST-segment elevation myocardial infarctions: Comparison of outcomes in a "real-world" setting. AB - INTRODUCTION: The beneficial effects of bivalirudin during primary PCIs are controversially discussed, data on unselected patients are rare. It was the aim of the study to compare bivalirudin versus heparin and provisional glycoprotein IIb/IIIa inhibitors (GPIs) in a "real-world" study. METHODS: From 05/2013 until 11/2014, the STEMI-patients in the Bremen STEMI registry were treated with periinterventional bivalirudin; before and after this period the standard anticoagulative treatment was heparin and provisional GPIs. RESULTS: In 714 patients bivalirudin was used for PCI, this cohort was compared to 683 patients with heparin and provisional GPIs. In patients with bivalirudin a significantly lower rate of hospital bleedings was observed compared to patients with heparin (4.6% vs 8.1%, P < 0.01, multivariate HR 0.57, 95%CI 0.35-0.93), in an exclusive analysis of severe bleedings a trend toward less bleedings was found in patients with bivalirudin (2.0% vs 3.5%, P = 0.07, multivariate HR 0.66, 95%CI 0.30-1.42). The rate of stent thromboses reinfarctions and mortality was not different between the bivalirudin and the heparin group. During 1-year follow-up bivalirudin was associated with a lower rate of bleedings and no significant differences in stent thromboses, reinfarctions, and mortality. Bivalirudin was not associated with an excess of bleedings or stent thromboses in subgroups that are regularly underrepresented in randomized trials (older patients, women, cardiogenic shock). CONCLUSIONS: In this "real-world" cohort of patients with STEMI bivalirudin compared to heparin and GPIs was associated with less bleedings and no significant differences in stent thromboses, reinfarctions, and mortality during hospital and long-term course. PMID- 28593633 TI - A sequence analysis of patterns in self-harm in young people with and without experience of being looked after in care. AB - OBJECTIVES: Young people in the public care system ('looked-after' young people) have high levels of self-harm. DESIGN: This paper reports the first detailed study of factors leading to self-harm over time in looked-after young people in England, using sequence analyses of the Card Sort Task for Self-harm (CaTS). METHODS: Young people in care (looked-after group: n = 24; 14-21 years) and young people who had never been in care (contrast group: n = 21; 13-21 years) completed the CaTS, describing sequences of factors leading to their first and most recent episodes of self-harm. Lag sequential analysis determined patterns of significant transitions between factors (thoughts, feelings, behaviours, events) leading to self-harm across 6 months. RESULTS: Young people in care reported feeling better immediately following their first episode of self-harm. However, fearlessness of death, impulsivity, and access to means were reported most proximal to recent self-harm. Although difficult negative emotions were salient to self-harm sequences in both groups, young people with no experience of being in care reported a greater range of negative emotions and transitions between them. For the contrast group, feelings of depression and sadness were a significant starting point of the self-harm sequence 6 months prior to most recent self-harm. CONCLUSIONS: Sequences of factors leading to self-harm can change and evolve over time, so regular monitoring and assessment of each self-harm episode are needed. Support around easing and dealing with emotional distress is required. Restricting access to means to carry out potentially fatal self-harm attempts, particularly for the young persons with experience of being in care, is recommended. PRACTITIONER POINTS: Self-harm (and factors associated with self harm) can change and evolve over time; assessments need to reflect this. Looked after young people reported feeling better after first self-harm; fearlessness of death, access to means, and impulsivity were reported as key in recent self-harm. Underlying emotional distress, particularly depression and self-hatred were important in both first and most recent self-harm. Looked-after young people should undergo regular monitoring and assessment of each self-harm episode and access to potentially fatal means should be restricted. The CaTS would have clinical utility as an assessment tool Recruiting participants can be a significant challenge in studies with looked-after children and young people. Future research with larger clinical samples would be valuable. PMID- 28593634 TI - First isolation of Rickettsia monacensis from a patient in South Korea. AB - A Rickettsia sp. was isolated from the blood of a patient with an acute febrile illness using the shell vial technique; the isolate was named CN45Kr and was identified by molecular assay as Rickettsia monacensis, which was first recognized as a pathogen in Spain. Sequencing analysis showed that the gltA sequence of the isolate was identical to that of Rickettsia sp. IRS3. The ompA 5mp fragment sequence showed 100% identity to those of R. monacensis and Rickettsia sp. In56 and ompA-3pA In56 and 100% identity to that of Rickettsia sp. IRS3. The ompB sequence was found to have 99.9% similarity to that of R. monacensis IrR/Munich. This study confirms the pathogenicity of this agent and provides additional information about its geographic distribution. PMID- 28593635 TI - Multichannel compressed sensing MR image reconstruction using statistically optimized nonlinear diffusion. AB - PURPOSE: Eliminate the need for parametric tuning in total variation (TV) based multichannel compressed-sensing image reconstruction using statistically optimized nonlinear diffusion without compromising image quality. THEORY AND METHODS: Nonlinear diffusion controls the denoising process using a contrast parameter that separates the gradients corresponding to noise and true edges in the image. This parameter is statistically estimated from the variance of combined image gradient to yield minimum steady-state reconstruction error. In addition, it uses acquired k-space data to bias the diffusion process toward an optimal solution. RESULTS: The proposed method is compared with TV using a set of noisy spine and brain data sets for three, four, and five-fold undersampling. It is observed that the choice of regularization parameter (step size) of TV-based methods requires prior tuning based on an extensive search procedure. In contrast, statistical estimation of contrast parameter removes this need for tuning by adapting to the changes in data sets and undersampling levels. CONCLUSIONS: Although an a-priori tuned TV-based reconstruction can provide a comparable image quality to that of controlled nonlinear diffusion, there are practical limitations with regard to its time complexity for ad-hoc applications to multicoil compressed-sensing reconstruction. Magn Reson Med 78:754-762, 2017. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28593636 TI - Biosynthesis of 1alpha-hydroxycorticosterone in the winter skate Leucoraja ocellata: evidence to suggest a novel steroidogenic route. AB - The present study explores the ability of intracellular bacteria within the renal inter-renal tissue of the winter skate Leucoraja ocellata to metabolize steroids and contribute to the synthesis of the novel elasmobranch corticosteroid, 1alpha hydroxycorticosterone (1alpha-OH-B). Despite the rarity of C1 hydroxylation noted in the original identification of 1alpha-OH-B, literature provides evidence for steroid C1 hydroxylation by micro-organisms. Eight ureolytic bacterial isolates were identified in the renal-inter-renal tissue of L. ocellata, the latter being the site of 1alpha-OH-B synthesis. From incubations of bacterial isolates with known amounts of potential 1alpha-OH-B precursors, one isolate UM008 of the genus Rhodococcus was seen to metabolize corticosteroids and produce novel products via HPLC analysis. Cations Zn2+ and Fe3+ altered metabolism of certain steroid precursors, suggesting inhibition of Rhodococcus steroid catabolism. Genome sequencing of UM008 identified strong sequence and structural homology to that of Rhodococcus erythropolis PR4. A complete enzymatic pathway for steroid-ring oxidation as documented within other Actinobacteria was identified within the UM008 genome. This study highlights the potential role of Rhodococcus bacteria in steroid metabolism and proposes a novel alternative pathway for 1alpha-OH-B synthesis, suggesting a unique form of mutualism between intracellular bacteria and their elasmobranch host. PMID- 28593637 TI - Sleep hygiene behaviours in Iranian adolescents: an application of the Theory of Planned Behavior. AB - Poor sleep quality and inadequate sleep in adolescents are a rising trend globally. The Theory of Planned Behaviour (TPB)-which centres on an individual's attitude toward performing the behaviour, subjective norms and perceived behavioural control-has been applied to examine sleep hygiene behaviours in young adults. We expanded on prior works by using a longitudinal design to examine the effects of TPB factors, together with sleep hygiene knowledge and planning constructs, on sleep hygiene behaviours and on sleep quality and health in a group of Iranian adolescents. A total of 1822 healthy adolescents (mean age = 13.97) from 25 high schools in Qazvin, Iran, completed a self-reported survey at baseline and 6 months later. Structural equation modelling (SEM) was used to delineate the pathway from adolescents' sleep hygiene knowledge, TPB constructs of their behavioural intentions and sleep hygiene behaviours and their sleep quality and self-reported health. The SEM model demonstrated that although behavioural intention, coping planning and action planning predicted the sleep hygiene behaviours positively 6 months later with acceptable model fit [comparative fit index (CFI) = 0.936; Tucker-Lewis index (TLI) = 0.902; root mean square error of approximation (RMSEA) = 0.080; standardized root mean square residual (SRMR) = 0.044], sleep hygiene knowledge did not predict behavioural intentions significantly. Sleep hygiene behaviours were associated with sleep quality and psychiatric wellbeing. Thus, the TPB, combined with coping and action planning, is useful in understanding the sleep hygiene behaviours of adolescents. Health-care providers may want to emphasize TPB constructs and coping and action planning to improve adolescents' sleep hygiene behaviours, rather than rely solely upon increasing adolescents' sleep hygiene knowledge. PMID- 28593638 TI - Thrombotic and Nonthrombotic Types of Intratesticular Varicoceles: Value of Sonography for the Diagnosis. AB - An intratesticular varicocele is an uncommon entity, and its clinical importance remains unclear. The diagnosis can be made in the case of an intratesticular tortuous vein that shows retrograde flow on color Doppler sonography. The anatomic location and course of the intratesticular varicocele within the testicular parenchyma and its association with the existence of an ipsilateral extratesticular varicocele may vary among patients. The pathophysiologic mechanisms remain unclear; however, it may be questioned whether there is an association between testicular atrophy and intratesticular varicocele development. Although the diagnosis is usually made incidentally, patients may rarely present with acute scrotal pain due to acute thrombosis of an intratesticular varicocele. PMID- 28593640 TI - Truth in Advertising in Neuromodulation in the Era of "Alternative Facts". PMID- 28593639 TI - The Neurostimulation Appropriateness Consensus Committee (NACC): Recommendations on Bleeding and Coagulation Management in Neurostimulation Devices. PMID- 28593641 TI - The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines. PMID- 28593642 TI - Assembly and performance of a 6.4 T cryogen-free dynamic nuclear polarization system. AB - We report on the assembly and performance evaluation of a 180-GHz/6.4 T dynamic nuclear polarization (DNP) system based on a cryogen-free superconducting magnet. The DNP system utilizes a variable-field superconducting magnet that can be ramped up to 9 T and equipped with cryocoolers that can cool the sample space with the DNP assembly down to 1.8 K via the Joule-Thomson effect. A homebuilt DNP probe insert with top-tuned nuclear magnetic resonance coil and microwave port was incorporated into the sample space in which the effective sample temperature is approximately 1.9 K when a 180-GHz microwave source is on during DNP operation. 13 C DNP of [1-13 C] acetate samples doped with trityl OX063 and 4-oxo TEMPO in this system have resulted in solid-state 13 C polarization levels of 58 +/- 3% and 18 +/- 2%, respectively. The relatively high 13 C polarization levels achieved in this work have demonstrated that the use of a cryogen-free superconducting magnet for 13 C DNP is feasible and in fact, relatively efficient a major leap to offset the high cost of liquid helium consumption in DNP experiments. PMID- 28593643 TI - Did the Affordable Care Act's Dependent Coverage Expansion Affect Race/Ethnic Disparities in Health Insurance Coverage? AB - OBJECTIVE: To test the impact of the dependent coverage expansion (DCE) on insurance disparities across race/ethnic groups. DATA SOURCES/STUDY SETTING: Survey data from the National Survey of Drug Use and Health (NSDUH). STUDY DESIGN: Triple-difference (DDD) models were applied to repeated cross-sectional surveys of the U.S. adult population. DATA COLLECTION/EXTRACTION METHODS: Data from 6 years (2008-2013) of the NSDUH were combined. PRINCIPAL FINDINGS: Following the DCE, the relative odds of insurance increased 1.5 times (95 percent CI 1.1, 1.9) among whites compared to blacks and 1.4 times (95 percent CI 1.1, 1.8) among whites compared to Hispanics. CONCLUSIONS: Health reform efforts, such as the DCE, can have negative effects on race/ethnic disparities, despite positive impacts in the general population. PMID- 28593644 TI - Efficient tRNA degradation and quantification in Escherichia coli cell extract using RNase-coated magnetic beads: A key step toward codon emancipation. AB - Emancipating sense codons toward a minimized genetic code is of significant interest to science and engineering. A key approach toward sense codon emancipation is the targeted in vitro removal of native tRNA. However, challenges remain such as the insufficient depletion of tRNA in lysate-based in vitro systems and the high cost of the purified components system (PURE). Here we used RNase-coated superparamagnetic beads to efficiently degrade E. coli endogenous tRNA. The presented method removes >99% of tRNA in cell lysates, while partially preserving cell-free protein synthesis activity. The resulting tRNA-depleted lysate is compatible with in vitro-transcribed synthetic tRNA for the production of peptides and proteins. Additionally, we directly measured residual tRNA using quantitative real-time PCR. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1401-1407, 2017. PMID- 28593645 TI - Ultraviolet A photosensitivity profile of dexchlorpheniramine maleate and promethazine-based creams: Anti-inflammatory, antihistaminic, and skin barrier protection properties. AB - BACKGROUND: Unwanted side effects such as dryness, hypersensitivity, and cutaneous photosensitivity are challenge for adherence and therapeutical success for patients using treatments for inflammatory and allergic skin response. AIMS: In this study, we compared the effects of two dermatological formulations, which are used in inflammatory and/or allergic skin conditions: dexchlorpheniramine maleate (DCP; 10 mg/g) and promethazine (PTZ; 20 mg/g). METHODS: We evaluated both formulations for phototoxicity potential, skin irritation, anti-inflammatory and antihistaminic abilities, and skin barrier repair in vitro and ex vivo using the standard OECD test guideline n degrees 432, the ECVAM protocol n degrees 78, and cultured skin explants from a healthy patient. Ultraviolet A was chosen as exogenous agent to induce allergic and inflammatory response. RESULTS: Both PTZ and DCP promoted increases in interleukin-1 (IL-1) synthesis in response to ultraviolet A (UVA) radiation compared to control. However, the increase observed with PTZ was significantly greater than the DCP, indicating that the latter has a lower irritant potential. DCP also demonstrated a protective effect on UVA induced leukotriene B4 and nuclear factor kappa B (NF-kappaB) synthesis. Conversely, PTZ demonstrates more robust UVA antihistaminic activity. Likewise, PTZ promoted a significantly greater increase in the production of involucrin and keratin 14, both associated with protective skin barrier property. CONCLUSION: In conclusion, these data suggest possible diverging UVA response mechanisms of DCP and PTZ, which gives greater insight into the contrasting photosensitizing potential between DCP and PTZ observed in the patients. PMID- 28593646 TI - Cancer incidence and mortality: A cohort study in China, 2008-2013. AB - The National Central Cancer Registry of China (NCCR) was the only available source of cancer monitoring in China, even though only about 70% of cancer registration sites were qualified by now. In this study, based on a national large prospective cohort-the China Kadoorie Biobank (CKB), we aimed to provide additional cancer statistics and compare the difference of cancer burden between urban and rural areas of China. A total of 497,693 cancer-free participants aged 35-74 years were recruited and successfully followed up from 2004 to 2013 in 5 urban and 5 rural areas across China. Except for traditional registration systems, the national health insurance system and active follow-up were used to determine new cancer incidents and related deaths. The mortality-to-incidence ratio (MIR) was used to compare the differences of cancer burden between urban and rural areas of China. We found that cancer mortality coincided well between our cohort and NCCR, while the incidence was much higher in our cohort. Based on CKB, we found the MIR of all cancers was 0.54 in rural areas, which was approximately one-third higher than that in urban areas with 0.39. Cancer profiles in urban areas were transiting to Western distributions, which were characterized with high incidences of breast cancer and colorectal cancer; while cancers of the esophagus, liver and cervix uteri were still common in rural areas of China. Our results provide additional cancer statistics of China and demonstrate the differences of cancer burden between urban and rural areas of China. PMID- 28593647 TI - Diets and trophic guilds of small fishes from coastal marine habitats in western Taiwan. AB - The diets and trophic guilds of small fishes were examined along marine sandy beaches and in estuaries at depths <1.5 m in western Taiwan, Republic of China. Copepods were the most frequently identified item in fish guts, indicating they are key prey for the fish assemblages studied. Piscivore, crustacivore, detritivore, omnivore, zooplanktivore and terrestrial invertivore trophic guilds were identified. The zooplanktivore guild contained the most fish species. Maximum prey size consumption was positively correlated with standard length (LS ) in seven species and at the assemblage level and negatively correlated with LS in a single detritivorous species. The diet data and trophic guild scheme produced by this study contribute to an understanding of coastal marine food webs and can inform ecosystem-based fisheries management. PMID- 28593648 TI - Evaluation of First-Line Sorafenib Treatment for Metastatic Renal Cell Carcinoma in Kidney Transplant Patients: A Single-Center Experience With Four Cases. PMID- 28593649 TI - The Effect of Gabapentin and Tramadol in Cancer Pain Induced by Glioma Cell in Rat Femur. AB - Preclinical Research The presence of pain as part of the cancer process is variable. Glioblastoma multiform (GBM) can produce bone metastasis, a condition that involves other pathological phenotypes including neuropathic and inflammatory pain. Tramadol and gabapentin are drugs used in the treatment of neuropathic pain. However, there are no studies evaluating their analgesic effects in bone metastasis. We produced a pain model induced by the inoculation of glioma cells (105 ) into the rat femur, by perforating the intercodiloid fossa. Painful behavior was evaluated by measuring mechanical allodynia using the Von Frey test while thermal hyperalgesia was assessed in the plantar test. Histopathological features were evaluated and antinociceptive responses were compared using tramadol and gabapentin. The inoculation of cells inside the right femur produced nociceptive behaviors. Tramadol and gabapentin produced an anti allodynic effect in this condition, but tramadol did not produce an anti hyperalgesic response. The development of this model will allow us to perform tests to elucidate the pathology of bone metastasis, cancer pain, and in particular the pain produced by glioma. Drug Dev Res 78 : 173-183, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28593650 TI - Delocalized Spin States in 2D Atomic Layers Realizing Enhanced Electrocatalytic Oxygen Evolution. AB - The electrocatalytic activity of transition-metal-based compounds is strongly related to the spin states of metal atoms. However, the ways for regulation of spin states of catalysts are still limited, and the underlying relationship between the spin states and catalytic activities remains unclear. Herein, for the first time, by taking NiII -based compounds without high or low spin states for example, it is shown that their spin states can be delocalized after introducing structural distortion to the atomic layers. The delocalized spin states for Ni atoms can provide not only high electrical conductivity but also low adsorption energy between the active sites and reaction intermediates for the system. As expected, the ultrathin nanosheets of nickel-chalcogenides with structural distortions show dramatically enhanced activity in electrocatalytic oxygen evolution compared to their corresponding bulk samples. This work establishes new way for the design of advanced electrocatalysts in transition-metal-based compounds via regulation of spin states. PMID- 28593651 TI - Outcomes for patients with synchronous and metachronous primary lung cancer after diagnosis of head and neck cancer. AB - BACKGROUND: Not-infrequently patients with head and neck cancer are also diagnosed with synchronous lung cancer or metachronous primary lung cancer, which complicates the treatment decisions and prognosis. METHODS: Patients were identified from a database of patients with head and neck cancer with second primary non-small cell lung cancer (NSCLC). RESULTS: Thirty-four eligible patients (15 with synchronous lung cancer and 19 with metachronous lung cancer) were identified. Thirteen of 15 patients with synchronous lung cancer received curative intent treatment for head and neck cancer first. Six of 15 patients were in complete remission, 5 of 15 patients had died, and 4 were alive with progressive disease. Median time between 2 diagnoses was 47 months in the metachronous lung cancer group. Twelve patients had died, 3 were alive with disease, and 4 were lost to follow-up. Median survival from the time of lung cancer diagnosis was 13 months with a trend to better survival with synchronous lung cancer (15 vs 11 months; p = .11). CONCLUSION: Aggressive multidisciplinary management of second primary lung malignancies in patients with head and neck cancer can result in respectable long-term disease control particularly in patients with synchronous lung cancer. (c) 2017 Wiley Periodicals, Inc. Head Neck 39: 1544-1549, 2017. PMID- 28593652 TI - Pupil size as a measure of within-task learning. AB - Pupillometry is commonly used in research to determine how much mental effort an individual is exerting while completing tasks. Traditionally, larger pupils are associated with increased mental effort when completing more difficult tasks. However, little research has investigated how pupils change as individuals learn a new task. In theory, as one repeatedly completes a task, the task demands should reduce, reliance on working memory should decrease, and the task should become more automatic. This should translate to faster completion times and smaller peak pupil dilations. We tested this hypothesis by having participants complete multiple trials of a cognitive task that requires individuals to orient themselves in space relative to a target. We found that trial completion times and maximum pupil size significantly reduced across trials. These data suggest that measuring changes in pupil dilation may help researchers determine whether individuals have shifted from a learned procedure to an automatic processing of information when learning a new task. PMID- 28593653 TI - Cellular Potts modeling of complex multicellular behaviors in tissue morphogenesis. AB - Mathematical modeling is an essential approach for the understanding of complex multicellular behaviors in tissue morphogenesis. Here, we review the cellular Potts model (CPM; also known as the Glazier-Graner-Hogeweg model), an effective computational modeling framework. We discuss its usability for modeling complex developmental phenomena by examining four fundamental examples of tissue morphogenesis: (i) cell sorting, (ii) cyst formation, (iii) tube morphogenesis in kidney development, and (iv) blood vessel formation. The review provides an introduction for biologists for starting simulation analysis using the CPM framework. PMID- 28593654 TI - Linkage of microbial kinetics and bacterial community structure of MBR and hybrid MBBR-MBR systems to treat salinity-amended urban wastewater. AB - Three pilot-scale bioreactors were started up and operated under salinity-amended urban wastewater feeding. The bioreactors were configured as membrane bioreactor and two different hybrid, moving bed biofilm reactor-membrane bioreactor and operated with a hydraulic retention time of 9.5 h, a solid residence time of 11.75 days and a total solids concentration of 2500 mg L-1 . The three systems showed excellent performance in suspended solids, BOD5 , and COD removal (values of 96-100%, 97-99%, and 88-90%, respectively), but poor nitrogen removal (values of 20-30%). The bacterial community structure during the start-up phase and the stabilization phase were different, as showed by beta-diversity analyses. The differences between aerobic and anoxic biomass-and between suspended and attached biomass-were higher at the start-up phase than at the stabilization phase. The start-up phase showed high abundances of Chiayiivirga (mean values around 3-12% relative abundance) and Luteimonas (5-8%), but in the stabilization phase, the domination belonged to Thermomonas (3-14%), Nitrobacter (3-7%), Ottowia (3 11.5%), and Comamonas (2-6%), among others. Multivariate redundancy analyses showed that Thermomonas and Nitrosomonas were positively correlated with fast autotrophic kinetics, while Caulobacter and Ottowia were positively correlated with fast heterotrophic kinetics. Nitrobacter, Rhodanobacter, and Comamonas were positively correlated with fast autotrophic and heterotrophic kinetics. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1483-1495, 2017. PMID- 28593655 TI - Vitamin D levels strongly influence bone mineral density and bone turnover markers during weight gain in female patients with anorexia nervosa. AB - OBJECTIVE: The aim of the study was to investigate a potential role for vitamin D status on bone mineral density (BMD) during weight gain in patients with anorexia nervosa (AN). METHOD: Spine and hip BMD assessed by dual-energy X-ray absorptiometry (DXA), serum vitamin D (25-OH-D), N-propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (CTX), and intact parathyroid hormone (PTH) were measured before and after a 20-week intensive weight restoration program in ninety-one female patients with AN and secondary amenorrhoea. RESULTS: Ninety-one consecutive female patients (age 13-45 years; weight 39.4 +/- 5.6 kg, body mass index [BMI] 15.1 +/- 1.6 kg m-2 ) were included in the study. Although weight and BMI significantly increased in all patients during treatment, mean BMD only significantly increased at the spine (1.0% +/- 3.6%, p = .009). The increase in spine BMD was significantly higher only above post-treatment 25-OH-D levels of 30 ng mL-1 (2.5% vs. 0.5%, respectively, for 25 OH-D >= and < 30 ng mL-1 , p = .026). There was a significant decrease in bone resorption (CTX; p = .043) and increased bone formation (P1NP; p < .001) after weight restoration. Nevertheless, a significant increase in PTH was also found, which was inversely correlated with decreased post-treatment 25-OH-D levels (R2 = .153, p < .001). DISCUSSION: Hypovitaminosis D may counteract the efficacy of refeeding in AN through increased bone resorption mediated by secondary hyperparathyroidism, which strongly supports the use of vitamin D supplements for bone health in AN. PMID- 28593657 TI - The silencing effects of the childhood innocence ideal: the perceptions and practices of fathers in educating their children about sexuality. AB - This study employed Interpretative Phenomenological Analysis to explore eight fathers' perceptions and practices in talking to their ten year old children about puberty, relationships and reproduction. The fathers participated in face to face interviews which were analysed idiographically initially, followed by analysis at the group level. Interpretations were then developed through critical application of a Foucauldian lens of governmentality and biopower. The results revealed a tension between the fathers' cognitions, accounts and behaviours. Their practices were largely characterised by silence yet they reported positive attitudes towards children's sexuality education and perceived themselves as equipped and willing to take on the role of sexuality educator. They also reported enjoying open relationships with their children. Interpretations centred on contradictions and conflict between the majority of the fathers' aspirations and the compelling nature of the childhood innocence discourse as a technology of governmentality. Whilst all of the fathers felt that it was in their children's interests to learn about sexuality, all but one adhered to hegemonic protective discourses and unquestioningly integrated their normalising effects into their fathering practices which, it is argued, may paradoxically render their children more vulnerable both now and in the future. PMID- 28593656 TI - Clinical outcome and its predictors in hemodialysis patients with critical limb ischemia undergoing endovascular therapy. AB - OBJECTIVES: This study aimed to examine prognosis and causes of death in hemodialysis (HD) patients with critical limb ischemia (CLI) after endovascular therapy (EVT). BACKGROUND: EVT is becoming a first-line treatment in patients with CLI. Nonetheless, only a few studies have examined prognosis and its predictors in HD patients with CLI undergoing EVT, who are known to be at high risk. Moreover, causes of death in this population are not clarified to date. METHODS: We examined 175 consecutive patients who underwent EVT for CLI between March 2009 and March 2014. RESULTS: Among these, 126 patients were dependent on HD and their 2-year all-cause death and 2-year major amputation rates were 28% and 14%, respectively. Cox proportional hazards analyses revealed that lower body mass index (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.82-0.98, P = 0.03) and prior stroke (HR = 2.34, 95%CI = 1.10-4.85, P = 0.03) were independent predictors of all-cause death, and lower serum albumin (HR = 0.44, 95%CI = 0.22-0.92, P = 0.03) along with currently smoking (HR = 4.73, 95%CI = 1.43-14.1, P = 0.01) were independent predictors of major amputation in HD patients. The leading cause of death in this population was infections, most of which were lower extremity infections. CONCLUSIONS: The incidences of all-cause death and major amputation seemed acceptable in HD patients undergoing EVT for CLI. In this high-risk subset, management of infection might be a potential therapeutic target. PMID- 28593658 TI - Dermoscopic features of mucoepidermoid carcinoma of the lip. PMID- 28593659 TI - Interleukin-17-induced expression of monocyte chemoattractant protein-1 in cardiac myocytes requires nuclear factor kappaB through the phosphorylation of p65. AB - IL-17 plays a key role in a variety of autoimmune diseases. MCP-1 is involved in the infiltration of mononuclear cells of myocardium in VMC. However, the relationship between IL-17 and MCP-1 in myocardial injury remains unclear. In this study, expression of MCP-1 mRNA and protein in cardiac myocytes was detected with qRT-PCR and ELISA, respectively. It was found that IL-17A induced MCP-1 expression in a dose- and time-dependent manner in cardiac myocytes, which could be blocked by IL-17A and IL-17RA neutralizing antibodies. NF-kappaB p65 and p-p65 protein expression in cardiac myocytes was studied with western blotting. Rates of p-p65 in whole lysates and in nuclear lysates all increased in the first 15 min. Meanwhile, the amount of NF-kappaB p65 in whole lysates did not change, but the amount of NF-kappaB p65 in nuclear lysates increased in the first 15 min. Then the optimal sequence and concentration of NF-kappaB p65 siRNAs was selected. After transfection of 10 nM siRNA-2 of NF-kappaB p65 into cardiac myocytes before stimulation by IL-17A, expression of MCP-1 mRNA and protein obviously decreased. In conclusion, expression of MCP-1 induced by IL-17 requires NF-kappaB through the phosphorylation of p65 in cardiac myocytes, which is meaningful to study the onset of chronic viral myocarditis and will provide a new target for the treatment of viral myocarditis. PMID- 28593661 TI - LONG-TERM EXPERIMENTAL EVOLUTION IN ESCHERICHIA COLI. III. VARIATION AMONG REPLICATE POPULATIONS IN CORRELATED RESPONSES TO NOVEL ENVIRONMENTS. AB - Twelve populations of Escherichia coli were founded from a single clone and propagated for 2000 generations in identical glucose-limited environments. During this time, the mean fitnesses of the evolving populations relative to their common ancestor improved greatly, but their fitnesses relative to one another diverged only slightly. Although the populations showed similar fitness increases, they may have done so by different underlying adaptations, or they may have diverged in other respects by random genetic drift. Therefore, we examined the relative fitnesses of independently derived genotypes in two other sugars, maltose and lactose, to determine whether they were homogeneous or heterogeneous in these environments. The genetic variation among the derived lines in fitness on maltose and lactose was more than 100-times greater than their variation in fitness on glucose. Moreover, the glucose-adapted genotypes, on average, showed significant adaptation to lactose, but not to maltose. That pathways for use of maltose and glucose are virtually identical in E. coli, except for their distinct mechanisms of uptake, suggests that the derived genotypes have adapted primarily by improved glucose transport. From consideration of the number of generations of divergence, the mutation rate in E. coli, and the proportion of its genome required for growth on maltose (but not glucose), we hypothesize that pleiotropy involving the selected alleles, rather than random genetic drift of alleles at other loci, was the major cause of the variation among the derived genotypes in fitness on these other sugars. PMID- 28593660 TI - Inhibition of left ventricular stimulation due to left ventricular lead failure and the left ventricular T-wave protection algorithm in patient with cardiac resynchronization therapy and pacemaker dependency. AB - The electrocardiogram (ECG) interpretation in patients with cardiac resynchronization therapy (CRT) is often a perplexing problem. The difficulty in the device evaluation increases in the presence of unfamiliar timing cycles and a lead dysfunction. Authors describe a special function of a Biotronik CRT devices called the left ventricle T-wave protection (LVTP), and demonstrate its behavior in a patient with left ventricular (LV) lead failure. This report shows that sometimes it might be difficult to understand the loss of resynchronization in 12 lead ECG when LVTP feature is on, and a malfunction of left ventricular lead sensing occurs. PMID- 28593662 TI - FINE-SCALE GENETIC STRUCTURE OF A TURKEY OAK FOREST. AB - Theoretical models and computer simulations of the genetic structure of a continuous population predict the existence of patches of highly inbred individuals when gene flow within the population is limited. A map of the three genotypes of a two-allele locus is expected to exhibit patches of homozygotes embedded in a matrix of heterozygotes, when gene flow is limited. A search for such patch structure was made on a 160 * 160 m plot within a continuous 60+ ha old-growth stand of Quercus laevis (turkey oak). Approximately 3400 trees were genotyped for 9 polymorphic loci using starch-gel electrophoresis, and the genetic structure was analyzed with spatial autocorrelation (both nominal and interval), hierarchical F statistics, and number-of-alleles-in-common. Adults (diameter at breast height > 0) and juveniles were analyzed separately but showed similar structure. While no distinct patch structure was found, a greater degree of relatedness was observed on a scale of 5 m-10 m than at greater distances, probably because of the limited acorn dispersal from maternal trees and a small amount of cloning by root sprouts. A computer simulation of a 10,000 tree forest breeding for 10,000 yr indicates that the effective neighborhood sizes (of randomly drawn seed- and pollen-donors) are both in excess of 440 individuals. The model thus cannot distinguish the observed data from panmictic mating. PMID- 28593663 TI - CYTOGENETIC ANALYSIS OF CHROMOSOMAL INTERMEDIATES FROM A HYBRID ZONE BETWEEN TWO CHROMOSOME RACES OF THE SCELOPORUS GRAMMICUS COMPLEX (SAURIA, PHRYNOSOMATIDAE). AB - Underdominance for chromosomal rearrangements is the central assumption of several models of chromosomally based speciation including the cascade model, proposed for the Sceloporus grammicus complex. Several cytotypes of the S. grammicus complex hybridize at localities in central Mexico. A hybrid zone between two of the most chromosomally divergent races (= cytotypes) of S. grammicus (F5, 2n = 34 and FM2, 2n = 44-46) was examined to assess the meiotic effects of heterozygosity at multiple chromosomes. Meiosis was examined in males heterozygous for "simple" Robertsonian fissions at chromosomes 1, 3, 4, and 6 and/or a pericentric inversion at chromosome 4. Analysis of synaptonemal complexes and chromosomal configurations at diakinesis showed trivalent formation in fission heterozygotes and heterosynapsis (lack of reverse-loop formation) in an inversion heterozygote. Analysis of metaphase II configurations revealed primarily balanced segregation and low levels of nondisjunction regardless of chromosomal background. The lack of underdominance associated with "simple" fission heterozygosity in this narrow hybrid zone contradicts the key premise of most chromosomally based models of speciation. PMID- 28593665 TI - OVULE PACKAGING IN STOCHASTIC POLLINATION AND FERTILIZATION ENVIRONMENTS. AB - The modular morphology of plants has important consequences for reproductive strategies. Ovules are packaged in discrete structures (flowers) that usually vary stochastically in pollen capture and ovule fertilization, because of the vagaries of pollen transfer by external agents. Different ovule packaging schemes may use limited reproductive resources more or less effectively, so that some number of ovules per flower may be optimal, given the prevailing probabilities of ovule fertilization. I derive a phenotypic model for ovule number per flower that maximizes the expected total ovule fertilizations on a plant when pollination and fertilization vary randomly among individual flowers. This model predicts that, except for small or inexpensive flowers, ovules should be "oversupplied" relative to the mean receipt of pollen tubes, so that pollen limitation of seed set should be common. Published data are congruent with this prediction. Additional hypotheses on the relation of ovule packaging to floral cost, plant size, and variance in pollen receipt are suggested by the model, but few data exist to evaluate these hypotheses. PMID- 28593664 TI - EVOLUTION AND EXTINCTION IN A CHANGING ENVIRONMENT: A QUANTITATIVE-GENETIC ANALYSIS. AB - Because of the ubiquity of genetic variation for quantitative traits, virtually all populations have some capacity to respond evolutionarily to selective challenges. However, natural selection imposes demographic costs on a population, and if these costs are sufficiently large, the likelihood of extinction will be high. We consider how the mean time to extinction depends on selective pressures (rate and stochasticity of environmental change, and strength of selection), population parameters (carrying capacity, and reproductive capacity), and genetics (rate of polygenic mutation). We assume that in a randomly mating, finite population subject to density-dependent population growth, individual fitness is determined by a single quantitative-genetic character under Gaussian stabilizing selection with the optimum phenotype exhibiting directional change, or random fluctuations, or both. The quantitative trait is determined by a finite number of freely recombining, mutationally equivalent, additive loci. The dynamics of evolution and extinction are investigated, assuming that the population is initially under mutation-selection-drift balance. Under this model, in a directionally changing environment, the mean phenotype lags behind the optimum, but on the average evolves parallel to it. The magnitude of the lag determines the vulnerability to extinction. In finite populations, stochastic variation in the genetic variance can be quite pronounced, and bottlenecks in the genetic variance temporarily can impair the population's adaptive capacity enough to cause extinction when it would otherwise be unlikely in an effectively infinite population. We find that maximum sustainable rates of evolution or, equivalently, critical rates of environmental change, may be considerably less than 10% of a phenotypic standard deviation per generation. PMID- 28593666 TI - POSITIVE CORRELATIONS BETWEEN SELFING RATE AND POLLEN-OVULE RATIO WITHIN PLANT POPULATIONS. PMID- 28593667 TI - THE GENETIC STRUCTURE OF A HYBRID ZONE BETWEEN TWO CHROMOSOME RACES OF THE SCELOPORUS GRAMMICUS COMPLEX (SAURIA, PHRYNOSOMATIDAE) IN CENTRAL MEXICO. AB - The F5 (2n = 34) and FM2 (2n = 44-46) chromosome races of the Sceloporus grammicus complex form a parapatric hybrid zone in the Mexican state of Hidalgo, characterized by steep concordant clines among three diagnostic chromosome markers across a straight-line distance of about 2 km. Here, we show that this zone is actually structured into local patches in which hybridization extends over an extremely irregular front. The distribution of hybrid-index (HI) scores across the transect reveals some hybridization at almost all localities mapped in a central 7 km * 3 km area. Pooling the central samples produces both a strong heterozygote deficit for all diagnostic markers and strong linkage disequilibria between all pairwise combinations of these (unlinked) markers. Moreover, a highly significant association exists between the habitat on which each individual was caught and its karyotype (F5 chromosomes are more likely to be found on oak). Analysis of genotype frequencies over a range of spatial scales shows that there is no significant heterozygote deficit or habitat association within local areas of less than about 200 m; however, there is significant linkage disequilibrium over the smallest scales (R = D (pquv)1/2 = 0.29, support limits, 0.18-0.36) over 100 m. These patterns suggest that lizards mate and choose habitats randomly within local patches. This conclusion is supported by mark-recapture estimates of dispersal (~ 80 m in a generation) and by inference of matings from embryo and maternal karyotypes. Closer examination of the two-dimensional pattern reveals a convoluted cline for all three markers, with a width of 830 m (support limits 770 m-930 m). This cline width, combined with the strength of local linkage disequilibrium, implies a dispersal rate of sigma = 160 m in a generation and an effective selection pressure of 30% on each chromosome marker. The proportion of inviable embryos is greater in females from the center of the hybrid zone; this is caused by effects associated with both karyotype and location. The hybrid zone is likely to be maintained by selection against chromosomal heterozygotes, by other kinds of selection against hybrids, and by selection adapting the chromosome races to different habitats. The structure of the contact may be caused by both random drift and by selection in relation to habitat. PMID- 28593668 TI - EVOLUTION OF ASEXUALITY IN THE COSMOPOLITAN MARINE CLAM LASAEA. AB - The marine clam genus Lasaea is unique among marine bivalves in that it contains both sexual and asexual lineages. We employed molecular tools to infer intrageneric relationships of geographically restricted sexual versus cosmopolitan asexual forms. Polymerase chain reaction primers were used to amplify and sequence homologous 624 nucleotide fragments of COIII from polyploid, asexual, direct-developing individuals representing northeastern Pacific, northeastern Atlantic, Mediterranean, southern Indian Ocean, and Australian populations. DNA sequences also were obtained from the two known diploid congeners, the Australian sexual, indirect developer, Lasaea australis, and an undescribed meiotic Australian direct developer. Estimated tree topologies did not support monophyly for polyploid asexual Lasaea lineages. A robust dichotomy was evident in all phylogenetic trees and each of the two main branches included one of the diploid meitoic Australian congeners. Lasaea australis clustered with two of the direct-developing, polyploid asexual haplotypes, one from Australia, the other from the northeastern Atlantic. Monophyly is supported for the diploid Australian direct-developing lineage together with the remaining polyploid asexual lineages from the northeastern Pacific, northeastern Atlantic, Mediterranean, and southern Indian Ocean. These results indicate that asexual Lasaea lineages are polyphyletic and may have resulted from multiple hybridization events. The high degree of genetic divergence of asexual lineages from co-clustering meiotic congeners (16%-22%) and among geographically restricted monophyletic clones (9%-11%) suggests that asexual Lasaea lineages may be exceptionally long lived. PMID- 28593669 TI - FLORAL SEX ALLOCATION IN SEQUENTIALLY BLOOMING PLANTS. AB - In plants whose flowers develop in a sequence, different flowers may exhibit temporal variation in pollen donation and receipt such that the fitness contributions through male and female functions can vary among flowers. Dichogamy, or directional pollinator movements within inflorescences, can create situations where flowers in different stages in the sequence may differ in the numbers of flowers in the female stage available as potential mates. We present an evolutionarily stable strategy (ESS) analysis of the resource allocations expected in different flowers in hermaphroditic plants when the mating environments vary among flowers. This introduces a modular element into sex allocation models. Our analysis shows that such variation in the mating environments of flowers can select for differences in sex allocation between flowers. When male and female fertilities are nonlinear functions of the allocations, variation in resource availability can also select for variation in sex allocation among flowers. The influence of dichogamy and pollinator directionality on floral sex allocation is discussed, and the empirical evidence supporting the predictions derived from the model is briefly reviewed. The implications of our results for the evolution of andromonoecy and monoecy are discussed. PMID- 28593670 TI - A REEXAMINATION OF THE POLLEN-DONATION HYPOTHESIS IN AN EXPERIMENTAL POPULATION OF ASCLEPIAS EXALTATA. AB - The evolution of large floral displays in hermaphroditic flowering plants has been attributed to natural selection acting to enhance male, rather than female, reproductive success. Proponents of the "pollen-donation hypothesis" have assumed that maternal resources, rather than levels of effective pollination, limit fruit set. We investigated the pollen-donation hypothesis in an experimental population of poke milkweed, Asclepias exaltata, where effective pollination did not limit fruit set. Specifically, we examined the effects of flower number per plant, and flower number per umbel on male reproductive success (number of fruits sired) and female reproductive success (number of fruits matured). In 1990, a paternity analysis was performed on fruits collected from 53 plants whose inflorescences were not manipulated. Flower number per plant was significantly correlated with male success, but not with plant gender. Flower number per plant was also significantly correlated with female success, but umbel number and stem number per plant together explained more than half (58%) the variation in female success. The percentage of fruit set was not significantly correlated with flower number per plant. Plants with large floral displays did not disproportionately increase in male reproductive success, relative to female success, as predicted by the pollen-donation hypothesis. In 1991, the effect of flower number per umbel on male and female reproductive success was investigated. Flower number per umbel was manipulated on four umbels per plant by removing flowers to leave 6, 12, or 18 flowers in each umbel. Plants with the largest umbels effectively pollinated twice as many flowers on other plants, but produced only 1.35 times as many fruits as plants with 6 and 12 flowers per umbel. Relative maleness of plants with large umbels was nearly twice that of small and medium umbels. Although these observations are consistent with the pollen-donation hypothesis at the level of umbels, they are problematic, because much of the variation in flower number per umbel exists within, rather than among, plants in natural populations. Thus, plants consist of both reproductively male (large) and female (small) inflorescences, which act to increase total reproductive success. It is therefore inappropriate to explain the evolution of large floral displays in milkweeds solely in terms of potential male reproductive success. PMID- 28593671 TI - DECEIT POLLINATION AND SELECTION ON FEMALE FLOWER SIZE IN BEGONIA INVOLUCRATA: AN EXPERIMENTAL APPROACH. PMID- 28593672 TI - THE EVOLUTION OF FITNESS. AB - In every generation, the mean fitness of populations increases because of natural selection and decreases because of mutations and changes in the environment. The magnitudes of these effects can be measured in two ways: either directly, by comparing the fitnesses of selected and unselected populations, or indirectly, by measuring the additive variance of fitness and making use of the fundamental theorem of natural selection. The available data suggest that the amount by which natural selection increases mean fitness each generation (or degradation decreases mean fitness) will usually be between 0.1% and 30%; more tentatively, it is suggested that values will typically fall between 1% and 10%. These values can be used to set an upper limit of 5%-10% on the genetic advantage of mate choice. PMID- 28593673 TI - THE EVOLUTION OF FLORAL LONGEVITY: RESOURCE ALLOCATION TO MAINTENANCE VERSUS CONSTRUCTION OF REPEATED PARTS IN MODULAR ORGANISMS. AB - The component parts of modular organisms often show interspecific variation in their longevity. In plants, the flower is an example of such a structure. Models are developed in this paper to predict optimal floral longevity (the optimal length of time that flowers should remain open and functional) under a variety of conditions. A tradeoff involving allocation of resources to floral construction versus floral maintenance is assumed. The main model variables are the rate at which pollen and seed fitness accrue over time (fitness-accrual rates) and the daily cost of maintaining an existing flower relative to the cost of constructing a new one (floral maintenance cost). Long-lived flowers are selected when fitness accrual rates and floral maintenance costs are low, whereas short-lived flowers are selected when fitness-accrual rates and floral maintenance costs are high. Dichogamy favors longer-lived flowers relative to homogamy, whereas nonindependence among flowers in their attractiveness to pollinators (attraction to flower clusters) selects for shorter-lived flowers. Reduction in floral maintenance costs later on in the flower's life favors longer-lived flowers. Observations on the dissemination and receipt of pollen in individual flowers over time, together with measurements of corolla respiration and nectar sugar production rate are required to test the model quantitatively. The parameters important to the evolution of optimal floral longevity (i.e., maintenance and construction costs, and fitness-accrual rates) may be general features of evolution of optimal longevities of other repeated structures. PMID- 28593674 TI - FEMALE FECUNDITY IN A HYBRID ZONE BETWEEN TWO CHROMOSOME RACES OF THE SCELOPORUS GRAMMICUS COMPLEX (SAURIA, PHRYNOSOMATIDAE). AB - Individuals of the F5 and FM2 cytotypes of the Sceloporus grammicus complex form a narrow zone of parapatric hybridization near Tulancingo, Hidalgo, Mexico. Reproductive parameters were examined among chromosomally parental and hybrid females to assess the degree to which reduced clutch size is correlated with the level of chromosomal heterozygosity. Although clutch size in the two parental groups was highly correlated with female body size, this was not the case for females with intermediate karyotypes. These females displayed increased levels of infertility manifested as smaller clutches and as inviable embryos. F1 females produced the smallest average clutches and suffered the most precipitous fecundity loss (up to 75%). The number of heterozygous marker chromosomes and heterozygosity at chromosome 2 had significant effects on the number of viable embryos. Analysis of embryo karyotypes revealed the production of triploid offspring and an excess number of embryos heterozygous at chromosome 1. Differences in viability, among females heterozygous for the same number of chromosomes, suggest that genetic background of the female and/or sire may be an important factor in determining reproductive success. PMID- 28593675 TI - GENETIC VARIATION IN INBREEDING DEPRESSION IN THE RED FLOUR BEETLE TRIBOLIUM CASTANEUM. AB - Inbreeding depression varies among species and among populations within a species. Few studies, however, have considered the extent to which inbreeding depression varies within a single population. We report on two experiments to provide evidence that inbreeding depression is genetically variable, such that within a single population some lineages suffer severe inbreeding depression, others suffer only mild inbreeding depression, and some lineages actually increase in phenotypic value at higher levels of inbreeding. We examine the effects of population structure on inbreeding depression for two traits in the first experiment (adult dry weight and female relative fitness), and for seven traits in the second experiment (female and male adult dry weight, female and male relative fitness, female and male developmental time, and egg-to-adult viability). In the first experiment, we collected data from 4 families within each of 38 lineages derived from a single ancestral stock population and maintained for four generations of full-sib mating. Both traits demonstrate significant inbreeding depression and provide evidence that even within a single lineage there is significant genetic variability in inbreeding depression. In the second experiment, we collected data from 5 replicates for each of 15 lineages derived from the same ancestral population used in the first experiment; these lineages were maintained for four generations of full-sib mating. We also collected data on outbred control beetles in each generation and incorporated these data into the analyses to account for environmental effects in an unbiased manner. All traits except female and male developmental time show significant inbreeding depression. All traits showing inbreeding depression are genetically variable in inbreeding depression, as is evident from a significant linear lineage-*-f component. For both experiments, the effect of population structure on inbreeding depression is further evident from the increasing amount of variation that can be explained by the models used to measure inbreeding depression when additional levels of population structure are included. Genetic variation in inbreeding depression has important implications for conservation biology and may be an important factor in mating-system evolution. PMID- 28593676 TI - SEED SET AND SEED MASS IN IPOMOPSIS AGGREGATA: VARIANCE PARTITIONING AND INFERENCES ABOUT POSTPOLLINATION SELECTION. AB - Events that follow pollination, such as pollen-tube growth and seed maturation, comprise an important phase of angiosperm reproduction. Differential success during this "postpollination" phase may represent phenotypic selection, including sexual selection, or interaction between parents caused, for example, by their genetic similarity. By providing a detailed partitioning of variance in success, diallel crossing designs offer great potential to determine which processes are occurring and their relative magnitudes. We performed three partial diallels with the montane herb Ipomopsis aggregata, using a large sample of parental plants (69 total). Embedded in the designs were crossing-distance treatments of 1 m, 10 m, and 100 m, reflecting a range of parental genetic similarity. We partitioned phenotypic variance in seed set per fruit into six components using restricted maximum-likelihood (REML) analysis. For one diallel, we also partitioned variance in seed mass into five components, and estimated two components of covariance between seed set and mass. Variance caused by maternal effects (Vmat ) comprised 12%-35% of total variance in seed set and 62% of variance in seed mass, and there was a significant negative environmental covariance between seed set and seed mass. Parental interaction made no detectable contribution to phenotypic variance in either of our measures of postpollination success, although crossing distance did contribute slightly but significantly to fit of the model in some cases. Finally, there was no detectable paternal variance (Vpat ) in seed set or seed mass. These results are in keeping with reports from other studies of natural plant populations. The finding of little or no paternal variance in particular suggests little scope for postpollination sexual selection through the male function of cosexual plants such as I. aggregata. PMID- 28593677 TI - WHEN DOES EVOLUTION BY NATURAL SELECTION PREVENT EXTINCTION? PMID- 28593678 TI - SEX ALLOCATION IN THE MONOECIOUS HERB BEGONIA SEMIOVATA. AB - Sex-allocation models predict that the evolution of self-fertilization should result in a reduced allocation to male function and pollinator attraction in plants. The evolution of sex allocation may be constrained by both functional and genetic factors, however. We studied sex allocation and genetic variation for floral sex ratio and other reproductive traits in a Costa Rica population of the monoecious, highly selfing annual Begonia semiovata. Data on biomass of floral structures, flower sex ratios, and fruit set in the source population were used to calculate the average proportion of reproductive allocation invested in male function. Genetic variation and genetic correlations for floral sex ratio and for floral traits related to male and female function were estimated from the greenhouse-grown progeny of field-collected maternal families. The proportion of reproductive biomass invested in male function was low (0.34 at flowering, and 0.07 for total reproductive allocation). Significant among-family variation was detected in the size (mass) of individual male and female flowers, in the proportion of male flowers produced, and in the proportion of total flower mass invested in male flowers. Significant among-family variation was also found in flower number per inflorescence, petal length of male and female flowers, and petal number of female flowers. Except for female petal length, we found no difference in the mean value of these characters between selfed and outcrossed progeny, indicating that, with the possible exception of female petal length, the among-family variation detected was not the result of variation among families in the level of inbreeding. Significant positive phenotypic and broad-sense genetic correlations were detected between the mass of individual male and female flowers, between male and female petal length, and between number of male and number of female flowers per inflorescence. The ratio of stamen-to-pistil mass (0.33) was low compared to published data for autogamous species with hermaphroditic flowers, suggesting that highly efficient selfing mechanisms may evolve in monoecious species. Our results indicate that the study population harbors substantial genetic variation for reproductive characters. The positive genetic correlation between investment in male and female flowers may reflect selection for maximum pollination efficiency, because in this self-pollinating species, each female flower requires a neighboring male flower to provide pollen. PMID- 28593679 TI - DYNAMICS OF A NOVEL CHROMOSOMAL POLYMORPHISM WITHIN A HYBRID ZONE BETWEEN TWO CHROMOSOME RACES OF THE SCELOPORUS GRAMMICUS COMPLEX (SAURIA, PHRYNOSOMATIDAE). AB - Several chromosome races of the mesquite lizard, Sceloporus grammicus complex, hybridize at localities in central Mexico. In most cases, the hybridizing populations are delineated by centric fissions at one or more of the macrochromosomes. One notable exception is the Tulancingo hybrid zone between the F5 and FM2 cytotypes. In addition to fission and/or inversion differences at chromosomes 1, 3, 4, and 6, these races differ by a complex rearrangement of chromosome 2, which carries the nucleolus-organizer region in this species. The meiotic consequences of heterozygosity at this chromosome were examined in males to assess the potential for this chromosome to contribute to the dynamics of the hybrid zone. Chromosomal analysis revealed several putative F1 hybrids and confirmed the production of nonparental chromosomal morphologies through recombination. Pachytene analysis revealed meiotic pairing difficulties associated with chromosome 2 in males heterozygous for the parental chromosomal morphologies. Significant aneuploidy is expected because of random disjunction of the chromosome-2 elements. As a result, these males likely suffer reduced fertiliity and fitness. In contrast, males heterozygous for recombinant chromosomal morphologies displayed low levels of meiotic irregularities and presumably exhibit higher fertility than individuals heterozygous for parental morphologies. It is hypothesized that the recombinant phenotypes facilitate gene flow between the F5 and FM2 cytotypes. PMID- 28593680 TI - DOES RECOMBINATION CONSTRAIN NEUTRAL DIVERGENCE AMONG BACTERIAL TAXA? AB - A coalescence model for predicting the fate of neutral divergence among closely related taxa distinguishable as separate DNA sequence clusters is presented here. The model simulates iteratively the positive feedback between sequence divergence and sexual isolation among taxa, where increases in sequence divergence result in reduced recombination, and reduced recombination results in increased sequence divergence. Iteration of this feedback is continued until sequence divergence either converges on a steady state or reaches a runaway process. The eventual outcome of sequence divergence was shown to depend on four estimable population genetic parameters: the expected intrataxon sequence diversity, the baseline rate of intertaxon recombination, the sensitivity of the recombination rate to sequence divergence, and the neutral mutation rate. The model can be used to determine whether neutral divergence among actual taxa is destined to stop at an equilibrium level, or whether neutral divergence will reach a runaway process. Application of the model to the group of taxa containing Bacillus subtilis and its closest relatives showed these taxa to be on a trajectory of unbounded neutral divergence from one another. PMID- 28593682 TI - Interactive pediatric emergency checklists to the palm of your hand - How the Pedi Crisis App traveled around the world. AB - BACKGROUND: Cognitive aids help clinicians manage critical events and have been shown to improve outcomes by providing critical information at the point of care. Critical event guidelines, such as the Society of Pediatric Anesthesia's Critical Events Checklists described in this article, can be distributed globally via interactive smartphone apps. From October 1, 2013 to January 1, 2014, we performed an observational study to determine the global distribution and utilization patterns of the Pedi Crisis cognitive aid app that the Society for Pediatric Anesthesia developed. We analyzed distribution and utilization metrics of individuals using Pedi Crisis on iOS (Apple Inc., Cupertino, CA) devices worldwide. We used Google Analytics software (Google Inc., Mountain View, CA) to monitor users' app activity (eg, screen views, user sessions). METHODS: The primary outcome measurement was the number of user-sessions and geographic locations of Pedi Crisis user sessions. Each user was defined by the use of a unique Apple ID on an iOS device. RESULTS: Google Analytics correlates session activity with geographic location based on local Internet service provider logs. Pedi Crisis had 1 252 active users (both new and returning) and 4 140 sessions across 108 countries during the 3-month study period. Returning users used the app longer and viewed significantly more screens that new users (mean screen views: new users 1.3 [standard deviation +/-1.09, 95% confidence interval 1.22 1.55]; returning users 7.6 [standard deviation +/-4.19, 95% confidence interval 6.73-8.39]P<.01) CONCLUSIONS: Pedi Crisis was used worldwide within days of its release and sustained utilization beyond initial publication. The proliferation of handheld electronic devices provides a unique opportunity for professional societies to improve the worldwide dissemination of guidelines and evidence-based cognitive aids. PMID- 28593683 TI - Aging in hair follicle stem cells and niche microenvironment. AB - Hair graying and hair loss are prominent and common characteristics of the elderly population. In some individuals these processes can significantly impact their quality of life, leading to depression, anxiety and other serious mental health problems. Accordingly, there has been much interest in understanding the complex physiological changes within the hair follicle in the aging individual. It is now known that hair follicles represent a prototypical stem cell niche, where both micro- and macroenvironmental influences are integrated alongside stem cell-stem cell and stem cell-stem niche interactions to determine hair growth or hair follicle senescence. Recent studies have identified imbalanced stem cell differentiation and altered stem cell activity as important factors during hair loss, indicating new avenues for the development of therapeutic agents to stimulate hair growth. Here, we pull together the latest findings on the hair follicle stem cell niche and the multifactorial interactions underlying the various forms of hair loss. PMID- 28593681 TI - Initial anticoagulation in patients with pulmonary embolism: thrombolysis, unfractionated heparin, LMWH, fondaparinux, or DOACs? AB - The initial treatment of haemodynamically stable patients with pulmonary embolism (PE) has dramatically changed since the introduction of low molecular weight heparins (LMWHs). With the recent discovery of the direct oral anticoagulant drugs (DOACs), initial treatment of PE will be simplified even further. In several large clinical trials it has been demonstrated that DOACs are not inferior to standard therapy for the initial treatment of PE, and because of their practicability they are becoming the agents of first choice. However, many relative contraindications to DOACs were exclusion criteria in the clinical trials. Therefore, LMWHs will continue to play an important role in initial PE treatment and in some cases there still is a role for unfractionated heparin (UFH). In this review we will give an overview of the biophysical, pharmacokinetic and pharmacodynamic properties of anticoagulants currently available for the initial management of PE. In addition, we will provide a comprehensive overview of the indications for the use of UFH, LMWHs and DOACs in the initial management of PE from a pharmacokinetic/-dynamic point of view. PMID- 28593686 TI - Hypostomus sertanejo (Siluriformes: Loricariidae), new armoured catfish species from north-eastern Brazil. AB - A re-evaluation of the armoured catfish species of Hypostomus in the Rio Jaguaribe, north-eastern Brazil, was prompted by the discovery of specimens with pale spots on a dark background collected from that basin c. 1936 and deposited at the Academy of Natural Sciences of Philadelphia. Recent field collections in the Rio Jarguaribe basin confirmed the presence of the pale-spotted specimens and its distinctiveness as a new species. Hypostomus sertanejo n. sp. is diagnosed from other species of Hypostomus by having fins and dermal-plated regions of head and body with pale spots or vermiculations on darker background, teeth slender, asymmetrically bicuspid and numerous (34-75) on dentary and premaxilla, depressed dorsal-fin spine not reaching adipose spine, unbranched pectoral-fin spine longer than unbranched pelvic-fin ray, seven branched dorsal-fin rays and one (rarely two) predorsal plate(s) bordering supraoccipital. Ancistrus salgadae Fowler 1941 is hypothesized to be a junior synonym of Hypostomus carvalhoi (Miranda-Ribeiro, 1937), a dark-spotted Hypostomus described from the Rio Granjeiro, a tributary to the upper Rio Salgado. PMID- 28593684 TI - Thyroglobulin level at week 16 of pregnancy is superior to urinary iodine concentration in revealing preconceptual and first trimester iodine supply. AB - Pregnant women are prone to iodine deficiency due to the increased need for iodine during gestation. Progress has recently occurred in establishing serum thyroglobulin (Tg) as an iodine status biomarker, but there is no accepted reference range for iodine sufficiency during pregnancy. An observational study was conducted in 164 pregnant women. At week 16 of gestation urinary iodine concentration (UIC), serum Tg, and thyroid functions were measured, and information on the type of iodine supplementation and smoking were recorded. The parameters of those who started iodine supplementation (>=150 MUg/day) at least 4 weeks before pregnancy (n = 27), who started at the detection of pregnancy (n = 51), and who had no iodine supplementation (n = 74) were compared. Sufficient iodine supply was found in the studied population based on median UIC (162 MUg/L). Iodine supplementation >=150 MUg/day resulted in higher median UIC regardless of its duration (nonusers: 130 MUg/L vs. prepregnancy iodine starters: 240 MUg/L, and pregnancy iodine starters: 205 MUg/L, p < .001, and p = .023, respectively). Median Tg value of pregnancy starters was identical to that of nonusers (14.5 vs. 14.6 MUg/L), whereas prepregnancy starters had lower median Tg (9.1 MUg/L, p = .018). Serum Tg concentration at week 16 of pregnancy showed negative relationship (p = .010) with duration of iodine supplementation and positive relationship (p = .008) with smoking, a known interfering factor of iodine metabolism, by multiple regression analysis. Serum Tg at week 16 of pregnancy may be a promising biomarker of preconceptual and first trimester maternal iodine status, the critical early phase of foetal brain development. PMID- 28593688 TI - Similarity between non-neural granular cell tumors and granular cell fibrous papules. PMID- 28593687 TI - Self-Assembly of Cyclohelicate [M3 L3 ] Triangles Over [M4 L4 ] Squares, Despite Near-Linear Bis-terdentate L and Octahedral M. AB - Self-assembly of 1:1:2 MII (BF4 )2 (M=Zn or Fe), pyrazine-2,5-dicarbaldehyde (1) and 2-(2-aminoethyl)pyridine gave trimetallic triangle architectures rather than the anticipated tetrametallic [2*2] squares. Options for the nontrivial synthesis of 1 are considered, and synthetic details provided for both preferred routes. Rare cyclohelicate triangle architectures are observed for the pair of structurally characterized yellow-brown [Zn3 L3 ](BF4 )6 and dark green [Fe3 L3 ](BF4 )6 complexes of the neutral bis-terdentate Schiff base L. In order to form these pyrazine-edged triangles, the octahedral metal ions-with all 6 N-donors provided by the terdentate binding pockets of two L-are located 0.4-0.5 A out of the plane of the bridging pyrazines, towards the center of the triangle. Density functional theory calculations confirm that simple particle counting entropic arguments, which predict triangles over squares, are correct here, with the triangles shown to be energetically favored over the corresponding squares. However, importantly, DFT analysis of these and related triangle versus square systems also show that vibrational contributions to entropy dominate and may significantly influence the preferred architecture, such that simple particle counting cannot in general be reliably employed to predict the observed architecture. PMID- 28593685 TI - One-year effectiveness and safety of vedolizumab therapy for inflammatory bowel disease: a prospective multicentre cohort study. AB - BACKGROUND: We recently showed that vedolizumab is effective in patients with Crohn's disease (CD) and ulcerative colitis (UC) with prior anti-TNF failure in a multicentre compassionate early-access programme before marketing authorisation was granted to vedolizumab. AIMS: To assess effectiveness and safety of vedolizumab at week 54 in patients UC and CD. METHODS: Between June and December 2014, 173 patients with Crohn's disease (CD) and 121 with ulcerative colitis (UC) were treated with vedolizumab induction therapy. Among those 294 patients, 272 completed the induction period and were evaluated at the week 14 visit (161 patients with CD and 111 with UC). Disease activity was assessed using the Harvey Bradshaw Index for CD and the partial Mayo Clinic score for UC. The primary outcome was steroid-free clinical remission at week 54. RESULTS: At week 54, steroid-free clinical remission rates at week 54 were 27.2% and 40.5% in patients with CD and UC respectively. In addition, the sustained steroid-free clinical remission (from week 14 to week 54) rates were 8.1% and 19.0% respectively. No deaths were observed. Severe adverse events occurred in 17 (7.2%) patients, including six (2.5%) leading to vedolizumab discontinuation. CONCLUSION: Vedolizumab is able to maintain steroid-free clinical remission in up to one third of patients with UC and CD at week 54 with a reasonable safety profile. A significant number of patients experienced loss of response during the first year of treatment, particularly in patients with CD. PMID- 28593689 TI - Measuring the speed of newborn object recognition in controlled visual worlds. AB - How long does it take for a newborn to recognize an object? Adults can recognize objects rapidly, but measuring object recognition speed in newborns has not previously been possible. Here we introduce an automated controlled-rearing method for measuring the speed of newborn object recognition in controlled visual worlds. We raised newborn chicks (Gallus gallus) in strictly controlled environments that contained no objects other than a single virtual object, and then measured the speed at which the chicks could recognize that object from familiar and novel viewpoints. The chicks were able to recognize the object rapidly, at presentation rates of 125 ms per image. Further, recognition speed was equally fast whether the object was presented from familiar viewpoints or novel viewpoints (30 degrees and 60 degrees azimuth rotations). Thus, newborn chicks can recognize objects across novel viewpoints within a fraction of a second. These results demonstrate that newborns are capable of both rapid and invariant object recognition at the onset of vision. PMID- 28593690 TI - Stigma experience of families supporting an adult member with substance misuse. AB - Stigmatization of families supporting an adult member with substance misuse is common and undermines their capacity to support the person and maintain their own well-being. The aims of the present study were to understand affected family members (AFMs)' experience of stigma within the context of substance misuse, and to explicate what steps, if any, they took to try to counteract stigma and social isolation. Semistructured, audio-recorded qualitative interviews were conducted with 31 AFMs from Victoria in Australia. Interpretative phenomenological analysis was used to guide data collection and analysis. Two main themes and related subthemes abstracted from the data illustrated how participants perceived and responded to stigma associated with a family member's substance misuse: 'engaging in secrecy, and minimizing contact with others' and 'lack of knowledge and empathy, and judgmental attitudes reinforcing isolation'. A third theme, 'adopting measures to moderate the effect of stigma', highlights how some attempted to respond to stigma by challenging informal supports' misconceptions about substance misuse, and being open selectively with others about their situation. Stigma against AFMs should be identified and challenged. Mental health nurses and other clinicians in the alcohol and other drugs field are in a strong position to support AFMs, with a particular focus on reducing courtesy stigma, challenging some clinicians' judgmental attitudes, and improving ways of communicating with families. PMID- 28593691 TI - Psychopharmacological treatment of psychotic mania and psychotic bipolar depression compared to non-psychotic mania and non-psychotic bipolar depression. AB - OBJECTIVES: An evidence base for the treatment of mania and bipolar depression with psychotic symptoms is lacking. Nevertheless, clinicians may have a preference for treating episodes of bipolar disorder with or without psychotic symptoms in different ways, which is likely to reflect notions of differential efficacy of treatments between these subtypes. This study aimed to investigate whether the psychopharmacological treatment of psychotic and non-psychotic episodes of mania and bipolar depression, respectively, differs in clinical practice. METHODS: We conducted a register-based study assessing the psychopharmacological treatment of all individuals receiving their first diagnosis of mania or bipolar depression between 2010 and 2012. The psychopharmacological treatment within 3 months following the time of diagnosis was considered. Potential differences in psychopharmacological treatment between the psychotic and non-psychotic subtypes of mania and bipolar depression, respectively, were investigated by means of Pearson's chi2 test and logistic regression adjusted for sex and age at diagnosis of bipolar disorder. RESULTS: A total of 827 patients were included in the analyses. The adjusted odds ratio (aOR) for treatment with an antipsychotic was 1.71 (95% confidence interval [CI]: 1.18-2.48, P<.01) for psychotic mania and 3.89 (95% CI: 1.95-7.76, P<.001) for psychotic bipolar depression. The aOR for treatment with the combination of an antipsychotic and an anticonvulsant was 1.60 (95% CI: 1.06-2.43, P<.05) for psychotic mania. The aOR for treatment with the combination of an antipsychotic and an antidepressant was 2.50 (95% CI: 1.43-4.37, P<.01) for bipolar psychotic depression. CONCLUSIONS: It would be of interest to conduct studies evaluating whether antipsychotics represent the superior pharmacological treatment for psychotic mania and psychotic bipolar depression. PMID- 28593692 TI - It's worth the wait: optimizing questioning methods for effective intraoperative teaching. AB - BACKGROUND: The use of questioning to engage learners is critical to furthering resident education intraoperatively. Previous studies have demonstrated that higher level questioning and optimal wait times (>3 s) result in learner responses reflective of higher cognition and retention. Given the importance of intraoperative learning, we investigated question delivery in the operating room. METHODS: A total of 12 laparoscopic cholecystectomies were observed and recorded. All questions were transcribed and classified using Bloom's Taxonomy, a framework associated with hierarchical levels of learning outcomes. Wait time between question end and response was recorded. RESULTS: Six faculty attendings and seven house officers at our institution were observed. A total of 133 questions were recorded with an average number of questions per case of 11.2. The majority of questions 112 out of 133 (84%) were classified as Bloom's levels 1-3, with only 6% of questions of the highest level. The wait time before the resident answered the question averaged 1.75 s, with attendings interceding after 2.50 s. Question complexity and wait time did not vary based on resident postgraduate year level suggesting limited tailoring of question to learner. CONCLUSIONS: Intraoperative questioning is not aligned with higher level thinking. The majority of questions were Bloom's level 3 or below, limiting the complexity of answer formulation. Most responses were given within 2 s, hindering opportunity to pursue higher order thinking. This suggests including higher level questions and tailoring questions to learner level may improve retention and maximize gains. In addition, with attendings answering 20% of their own questions, increasing their wait time offers another area for teaching development. PMID- 28593693 TI - Double Gold Activation of 1-Ethynyl-2-(Phenylethynyl)Benzene Toward 5-exo-dig and 6-endo-dig Cyclization Reactions. AB - In this work, a detailed characterization was carried out of the ring-closure mechanism of EPB (1-ethynyl-2-(phenylethynyl)benzene) toward the 5-exo-dig and 6 endo-dig cyclization reactions, catalyzed by two Au-N-heterocyclic carbene (NHC) moieties. It was found that the 5-exo-dig cyclization takes place with a slightly lower activation barrier and larger exothermicity compared to that of the 6-endo dig cyclization, in agreement with the available experimental data. A phenomenological partition (structural and electronic) for rate constants computed using transition-state theory and the reaction force analysis was used to shed light into the nature of the activation rate constant. It was found that rate constants are influenced by a strong structural component, which is larger for the 5-exo-dig cyclization due to the strain to form the five-membered ring. On the other hand, the gold activation mechanism is evidenced by a sigma- and pi coordination of the Au-NHC moieties to the EPB substrate. It was found that differences in the sigma-coordination arise on the reaction path for the 5-exo dig and 6-endo-dig cyclizations. Thus, in the 6-endo-dig cyclization the sigma gold-EPB interaction is weakened as a consequence of the formation of the cationic aryl intermediate, while for the 5-exo-dig cyclization this interaction was found to be favored. Furthermore, although minor changes in the Au-EPB coordination occur on the reaction path, these bonds are formally established in the TS vicinity. Results support the concerted nature of the dual gold activation mechanism. PMID- 28593694 TI - Investigation of superficial mycosis in cutaneous allergy patients using topical or systemic corticosteroids. PMID- 28593695 TI - Protozoa inhibition by different salts: Osmotic stress or ionic stress? AB - Cell density and morphology changes were tested to examine the effects of salts including NaHCO3 , NaCl, KHCO3 , and KCl at 160 mM on protozoa. It was demonstrated that ionic stress rather than osmotic stress led to protozoa cell death and NaHCO3 was shown to be the most effective inhibitor. Deformation of cells and cell shrinkage were observed when protozoan cells were exposed to polyethylene glycol (PEG) or any of the salts. However, while PEG treated cells could fully recover in both number and size, only a small portion of the salt treated cells survive and cell size was 36-58% smaller than the regular. The disappearance of salt-treated protozoa cells was hypothetically attributed to disruption of the cytoplasmic membrane of these cells. It is further hypothesized that the PEG-treated protozoan cells carried out regulatory volume increase (RVI) after the osmotic shock but the RVI of salt-treated protozoa was hurdled to varied extents. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1418-1424, 2017. PMID- 28593696 TI - Synergistic analgesic, anti-pyretic and anti-inflammatory effects of extra virgin olive oil and ibuprofen in different experimental models of albino mice. AB - AIM: Olive oil was used in the past as a remedy for many diseases due to its unlimited benefits in health. This study was carried out to assess the analgesic, anti-pyretic and anti-inflammatory activities of extra virgin olive oil (EVOO) at a dose of 8 mL/kg body weight and to compare it with ibuprofen (IBU) as an individual drug therapy and in combination with two different doses of IBU (therapeutic dose 100 mg/kg and low dose 40 mg/kg), on different animal models in albino mice. METHOD: A total of 132 adult healthy male Swiss albino mice were used in this study. The analgesic effect was assessed using acetic acid-induced writhing test. The antipyretic effect was evaluated by brewer's yeast-induced pyrexia, while the anti-inflammatory activity was assessed by two different models; the carrageenan-induced paw edema and the carrageenan-induced peritonitis in which the levels of total leukocyte count (TLC), neutrophil count, prostaglandin E2 (PGE2) and interferon gamma (INF-gamma) were measured in the peritoneal exudates. RESULTS: The results revealed significant protection in all the treated groups; however, the combination of EVOO with IBU at its therapeutic dose showed superiority over the two compounds when used separately. CONCLUSION: Using EVOO with the therapeutic dose of IBU showed synergistic effect in controlling the cardinal signs of acute inflammation rather than using non steroidal anti-inflammatory drugs alone. PMID- 28593697 TI - On the Accessible Reaction Channels of Vinyl Gold(I) Species: pi- and sigma Pathways. AB - The potential of vinyl Au species to react either through a controlled pi- or sigma-pathway is demonstrated. This nomenclature is directly derived from the orbitals of the vinyl Au species leading to the newly formed bonds. When the pi bond of the vinyl Au intermediate is transformed into a sigma-bond, we name it pi pathway, and a sigma- to sigma- transformation is named sigma-pathway. Examples of reactions following these pathways are a Au-catalysed [3,3]-sigmatropic rearrangement and a protodeauration reaction. These reactions have been studied using intrinsic bond orbitals (IBOs) and allow for the clear identification of these pathways. Energies for the reaction path of the Au-catalysed [3,3] sigmatropic rearrangement were in addition computed using CCSD(T)-F12. Analysis of the intrinsic reaction coordinate (IRC) of the [3,3]-sigmatropic rearrangement using IBOs further allows us to refine the previous mechanistic proposal and identifies a hidden intermediate along the reaction path. PMID- 28593698 TI - Associations between expressive and receptive language and internalizing and externalizing behaviours in a community-based prospective study of slow-to-talk toddlers. AB - BACKGROUND: Evidence suggests that language and social, emotional and behavioural (SEB) difficulties are associated in children and adolescents. When these associations emerge and whether they differ by language or SEB difficulty profile is unclear. This knowledge is crucial to guide prevention and intervention programmes for children with language and SEB difficulties. AIMS: To determine whether receptive and expressive language skills are associated with internalizing and externalizing behaviours in slow-to-talk toddlers. METHODS & PROCEDURES: In a community-based prospective study of 200 slow-to-talk children, language was measured at 24 and 36 months using Preschool Language Scale 4th Edition and at 48 months using Clinical Evaluation of Language Fundamentals Preschool 2nd Edition. Internalizing and externalizing behaviours were measured by parent report at each age. Longitudinal data were analysed using repeated measures regression, with up to three observations per child. Robust standard errors were used to account for non-independence of measures within participants. The shape of the associations were examined by fitting quadratic and cubic terms. The effects of confounders on the associations were examined. OUTCOMES & RESULTS: Receptive language had a negative linear association with internalizing behaviours after adjusting for confounders (beta = -0.16, 95% [CI = -0.26, 0.07], p = .001); and a negative curved association with externalizing behaviours after adjusting for biological confounders (betaquadratic = 0.08 [0.01, 0.15], p = .03, betacubic = -0.04 [-0.07, -0.02], p = .001), attenuating after adjusting for environmental confounders (betaquadratic = 0.06 [-0.01, 0.13], p = .09, betacubic = -0.03 [-0.06, -0.003], p = .03). The curvature suggests that the negative association with externalizing behaviours only existed for children with either very low or very high receptive language scores. After controlling for confounders, there was no evidence that expressive language scores were associated with internalizing (beta = -0.08, 95% [CI = -0.17, 0.01], p = .10) or externalizing behaviours (beta = 0.03, 95% [CI = -0.09, 0.18], p = .61). Tests of interaction revealed no evidence of a differential association by age. CONCLUSIONS & IMPLICATIONS: In 24-48-month-old slow-to-talk children, lower receptive language scores were associated with higher internalizing behaviours. The magnitude of the association was small. For children with very poor receptive language scores, lower receptive language skills were associated with higher externalizing behaviours. Young children with low receptive language abilities may be at risk of internalizing difficulties; those with very low receptive language skills may be at particular risk of externalizing difficulties. This has clinical implications for interventions for young children with receptive language difficulties. PMID- 28593699 TI - Angiogenic potential of human mesenchymal stromal cell and circulating mononuclear cell cocultures is reflected in the expression profiles of proangiogenic factors leading to endothelial cell and pericyte differentiation. AB - Endothelial progenitors found among the peripheral blood (PB) mononuclear cells (MNCs) are interesting cells for their angiogenic properties. Mesenchymal stromal cells (MSCs) in turn can produce proangiogenic factors as well as differentiate into mural pericytes, making MSCs and MNCs an attractive coculture setup for regenerative medicine. In this study, human bone marrow-derived MSCs and PB derived MNCs were cocultured in basal or osteoblastic medium without exogenously supplied growth factors to demonstrate endothelial cell, pericyte and osteoblastic differentiation. The expression levels of various proangiogenic factors, as well as endothelial cell, pericyte and osteoblast markers in cocultures were determined by quantitative polymerase chain reaction. Immunocytochemistry for vascular endothelial growth factor receptor-1 and alpha smooth muscle actin as well as staining for alkaline phosphatase were performed after 10 and 14 days. Messenger ribonucleic acid expression of endothelial cell markers was highly upregulated in both basal and osteoblastic conditions after 5 days of coculture, indicating an endothelial cell differentiation, which was supported by immunocytochemistry for vascular endothelial growth factor receptor 1. Stromal derived factor-1 and vascular endothelial growth factor were highly expressed in MSC-MNC coculture in basal medium but not in osteoblastic medium. On the contrary, the expression levels of bone morphogenetic protein-2 and angiopoietin-1 were significantly higher in osteoblastic medium. Pericyte markers were highly expressed in both cocultures after 5 days. In conclusion, it was demonstrated endothelial cell and pericyte differentiation in MSC-MNC cocultures both in basal and osteoblastic medium indicating a potential for neovascularization for tissue engineering applications. PMID- 28593700 TI - The One Past Health workshop: connecting ancient DNA and zoonosis research. PMID- 28593702 TI - The Editor recommends this issue's article to the reader. PMID- 28593701 TI - Comparison of efficacy of low-carbohydrate and low-fat diet education programs in non-alcoholic fatty liver disease: A randomized controlled study. AB - AIM: Composition of macronutrients is important in non-alcoholic fatty liver disease (NAFLD). Diet education programs that mainly emphasize reducing fat consumption have been used for NAFLD patients. We compared the efficacy of conventional low-fat diet education with low-carbohydrate diet education in Korean NAFLD patients. METHODS: One hundred and six NAFLD patients were randomly allocated to low-fat diet education or low-carbohydrate education groups for 8 weeks. Liver chemistry, liver / spleen ratio, and visceral fat using abdominal tomography were measured. RESULTS: Intrahepatic fat accumulation decreased significantly in the low-carbohydrate group compared to low-fat group (liver/spleen 0.85 vs. 0.92, P < 0.05). Normalization of ALT activity at week 8 was 38.5% for the low-carbohydrate and 16.7% for the low-fat group (P = 0.016). Not only liver enzyme, but also low density lipoprotein cholesterol and blood pressure levels significantly decreased in the low-carbohydrate group. Total energy intake was also further decreased in the low-carbohydrate group compared to the low-fat group. Although body weight changes were not different between the two groups, the carbohydrate group had a lower total abdominal fat amount. CONCLUSIONS: A low-carbohydrate diet program is more realistic and effective in reducing total energy intake and hepatic fat content in Korean NAFLD patients. This trial is registered with the National Research Institute of Health: KCT0000970 (https://cris.nih.go.kr/cris/index.jsp). PMID- 28593703 TI - Effect of ethnicity on clinical presentation and risk of antiphospholipid syndrome in Roma and Caucasian patients with systemic lupus erythematosus: a multicenter cross-sectional study. AB - AIM: To determine if there are ethnic differences in the prevalence of antiphospholipid syndrome (APS), clinical presentation and autoantibody profile between Roma and Caucasian patients with systemic lupus erythematosus (SLE). METHOD: A cross-sectional study was conducted including data from Roma and Caucasian SLE patients consecutively attending six hospitals in Spain. Socio demographic characteristics, prevalence of APS, clinical and analytical features of SLE and APS were compared between ethnic groups. RESULTS: Data from 52 Roma and 98 Caucasian SLE patients were included. Roma SLE patients had a higher risk (odds ratio 2.56, 95% CI 1.02-6.39) and prevalence of APS (28.8% vs. 13.3%, P = 0.027). Furthermore, Roma SLE patients had a statistically significant higher prevalence of abortions (23.5% vs. 10.2%, P = 0.049). In relation to other APS diagnostic criteria, Roma SLE patients had a non-statistically significant higher prevalence of fetal deaths (14.3% vs. 5.1%, P = 0.106) and thrombotic events (21.1% vs. 12.2%, P = 0.160). In relation to SLE clinical features, Roma patients had a significantly higher prevalence of arthritis (75% vs. 57.1%, P = 0.034) and non-significant higher prevalence of serositis (44.2% vs. 29.6%, P = 0.104), discoid lesions (11.5% vs. 5.1%, P = 0.191), oral ulcers (46.1% vs. 34.7%, P = 0.218) and livedo reticularis (21.1% vs. 15.3%, P = 0.374). No statistically significant differences were found in the Systemic Lupus International Collaborating Clinics Damage Index or the autoimmune serological profile. CONCLUSION: Prevalence and risk of APS were significantly higher in Roma SLE patients. Furthermore, Roma patients had a significantly higher prevalence of abortions and a non-significant higher prevalence of fetal deaths and thrombotic events. PMID- 28593704 TI - Fragmentation increases wind disturbance impacts on forest structure and carbon stocks in a western Amazonian landscape. AB - Tropical second-growth forests could help mitigate climate change, but the degree to which their carbon potential is achieved will depend on exposure to disturbance. Wind disturbance is common in tropical forests, shaping structure, composition, and function, and influencing successional trajectories. However, little is known about the impacts of extreme winds on second-growth forests in fragmented landscapes, though these ecosystems are often located in mosaics of forest, pasture, cropland, and other land cover types. Indirect evidence suggests that fragmentation increases risk of wind damage in tropical forests, but no studies have found such impacts following severe storms. In this study, we ask whether fragmentation and forest type (old vs. second growth) were associated with variation in wind damage after a severe convective storm in a fragmented production landscape in western Amazonia. We applied linear spectral unmixing to Landsat 8 imagery from before and after the storm, and combined it with field observations of damage to map wind effects on forest structure and biomass. We also used Landsat 8 imagery to map land cover with the goals of identifying old- and second-growth forest and characterizing fragmentation. We used these data to assess variation in wind disturbance across 95,596 ha of forest, distributed over 6,110 patches. We find that fragmentation is significantly associated with wind damage, with damage severity higher at forest edges and in edgier, more isolated patches. Damage was also more severe in old-growth than in second-growth forests, but this effect was weaker than that of fragmentation. These results illustrate the importance of considering landscape context in planning tropical forest restoration and natural regeneration projects. Assessments of long-term carbon sequestration potential need to consider spatial variation in disturbance exposure. Where risk of extreme winds is high, minimizing fragmentation and isolation could increase carbon sequestration potential. PMID- 28593705 TI - Frequency Domain Analysis of Multiwavelength Photoacoustic Signals for Differentiating Among Malignant, Benign, and Normal Thyroids in an Ex Vivo Study With Human Thyroids. AB - OBJECTIVES: This study investigated the capability of spectral parameters, extracted by frequency domain analysis of photoacoustic signals, to differentiate among malignant, benign, and normal thyroid tissue. METHODS: We acquired multiwavelength photoacoustic images of freshly excised thyroid specimens collected from 50 patients who underwent thyroidectomy after having a diagnosis of suspected thyroid lesions. A thyroid cytopathologist marked histologic slides of each tissue specimen. These marked slides were used as ground truth to identify the regions of interest (ROIs) corresponding to malignant, benign, and normal thyroid tissue. Three spectral parameters: namely, slope, midband fit, and intercept, were extracted from photoacoustic signals corresponding to different ROIs. RESULTS: Spectral parameters were extracted from a total of total of 65 ROIs. According to the ground truth, 12 of 65 ROIs belonged to malignant thyroids; 28 of 65 ROIs belonged to benign thyroids; and 25 of 65 ROIs belonged to normal thyroids. Besides slope, the other 2 spectral parameters and grayscale photoacoustic image pixel values were found to be significantly different (P < .05) between malignant and normal thyroids. Between benign and normal thyroids, all 3 spectral parameters and photoacoustic pixel values were significantly different (P < .05). CONCLUSIONS: Preliminary results of our ex vivo human thyroid study show that the spectral parameters extracted from radiofrequency photoacoustic signals as well as the pixel values of 2-dimensional photoacoustic images can be used for differentiating among malignant, benign, and normal thyroid tissue. PMID- 28593706 TI - Does the ileal brake mechanism contribute to sustained weight loss after bariatric surgery? AB - Bariatric surgery is currently the most effective strategy for treating morbid obesity. Weight regain following significant weight loss, however, remains a problem, with the outcome proportional to the period of follow-up. This review revisits a well-established physiological neurohormonally-mediated feedback loop, the so called ileal brake mechanism, with a special emphasis on the gut hormone peptide tyrosine tyrosine. The manuscript not only highlights the potential role of the ileal brake mechanism in weight loss and weight maintenance thereafter following obesity surgery, it also provides a compelling argument for using this appetite suppressing feedback loop to enable sustained long-term weight loss in patients undergoing surgery for morbid obesity. PMID- 28593707 TI - Soluble CEACAM1 and CEACAM6 are differently expressed in blood serum of pregnant women during normal pregnancy. AB - PROBLEM: CEACAM1 and CEACAM6 belong to the carcinoembryonic antigen (CEA) family and may play an immune-modulatory role during pregnancy. The aim of the study was to determine the blood serum levels of soluble CEACAM1 and CEACAM6 over the course of pregnancy and postpartum. METHOD OF STUDY: CEACAM1 and CEACAM6 levels were determined with customized in-house Sandwich-enzyme-linked immunosorbent assay (ELISA) systems. The study population (n=125) was divided into four groups according to the pregnancy trimester and postpartum. Additionally, samples of non pregnant women (n=14) were analyzed. RESULTS: Serum levels of CEACAM1 in healthy pregnant women were much lower than in non-pregnant women, a difference not seen for CEACAM6. Comparison between the trimesters and postpartum revealed a significant difference in CEACAM1 serum levels. The highest CEACAM1 levels were detected in third trimester. These levels were statistically significantly different from the CEACAM1 levels in first trimester and second trimester. The lowest levels were observed in the second trimester. Postpartum CEACAM1 serum concentrations were slightly lower than in the third trimester, but higher than in the first trimester and significantly higher compared to levels in the second trimester. CONCLUSION: Decreased concentration of CEACAM1 during the pregnancy suggests its regulatory role in the immune tolerance during the course of pregnancy. PMID- 28593708 TI - Age 80 years and over is not associated with increased morbidity and mortality following pancreaticoduodenectomy. AB - BACKGROUND: Pancreaticoduodenectomy (PD) is associated with high morbidity, which is perceived to be increased in the elderly. To our knowledge there have been no Australian series that have compared outcomes of patients over the age of 80 undergoing PD to those who are younger. METHODS: Patients who underwent PD between January 2008 and November 2015 were identified from a prospectively maintained database. RESULTS: A total of 165 patients underwent PD of whom 17 (10.3%) were aged 80 or over. The pre-operative health status, according to American Society of Anesthesiologists class was similar between the groups (P = 0.420). The 90-day mortality rates (5.9% in the elderly and 2% in the younger group; P = 0.355) and the post-operative complication rates (64.7% in the elderly versus 62.8% in the younger group; P = 0.88) were similar. Overall median length of hospital stay was also similar between the groups, but older patients were far more likely to be discharged to a rehabilitation facility than younger patients (47.1 versus 12.8%; P < 0.0001). Older patients with pancreatic adenocarcinoma (n = 10) had significantly lower median survival than the younger group (n = 69) (16.6 versus 22.5 months; P = 0.048). CONCLUSION: No significant differences were seen in the rate of complications following PD in patients aged 80 or over compared to younger patients, although there appears to be a shorter survival in the elderly patients treated for pancreatic cancer. Careful selection of elderly patients and optimal peri-operative care, rather than age should be used to determine whether surgical intervention is indicated in this patient group. PMID- 28593709 TI - Respiratory motion model based on the noise covariance matrix of a receive array. AB - PURPOSE: Tracking of the internal anatomy by means of a motion model that uses the MR-derived motion fields and noise covariance matrix (NCM) dynamic as a surrogate signal. METHODS: A 2D respiratory motion model was developed based on the MR-derived motion fields and the NCM of a receive array used in MRI. Temporal dynamics of the NCM were used as a motion surrogate for a linear correspondence motion model. The model performance was tested on five healthy volunteers with a liver as the target. The motion fields were calculated from the cineMR frames with an optical flow registration tool. RESULTS: The model estimated the liver motion with an average residual error of 2.3 mm (13% of the motion amplitude). The model formation takes 3 min and the model latency was 0.5 s in the current implementation. The limiting factor for the latency is the current update time of the NCM (0.48 s), which in principle can be reduced to 0.004 s with an alternative way to determine the NCM. CONCLUSIONS: The 2D respiratory motion of the liver can be effectively estimated with the linear motion model that uses the temporal behavior of the NCM as motion surrogate. Magn Reson Med 79:1730-1735, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 28593711 TI - Iniencephaly Apertus: Prenatal Autopsy by Sonography and Embryoscopy. PMID- 28593710 TI - Ultrasound-Guided Subgluteal Sciatic Nerve Perineural Injection: Report on Safety and Efficacy at a Single Institution. AB - OBJECTIVES: To determine the safety and efficacy of ultrasound (US)-guided subgluteal sciatic nerve injections. METHODS: A retrospective chart review of US guided subgluteal sciatic nerve injections at our institution was performed. RESULTS: Of 221 US-guided subgluteal sciatic nerve injections, 100% achieved technical success, with no postprocedure complications. Sixty-eight percent of patients with follow-up reported symptom relief. Most patients with no relief had suboptimal preprocedure screening. CONCLUSIONS: With appropriate screening, our technique of US-guided subgluteal sciatic nerve injection is safe and effective. PMID- 28593712 TI - Human adipose tissue-derived tenomodulin positive subpopulation of stem cells: A promising source of tendon progenitor cells. AB - Cell-based therapies are of particular interest for tendon and ligament regeneration given the low regenerative potential of these tissues. Adipose tissue is an abundant source of stem cells, which may be employed for the healing of tendon lesions. However, human adult multipotent adipose-derived stem cells (hASCs) isolated from the stromal vascular fraction of adipose tissue originate highly heterogeneous cell populations that hinder their use in specific tissue oriented applications. In this study, distinct subpopulations of hASCs were immunomagnetic separated and their tenogenic differentiation capacity evaluated in the presence of several growth factors (GFs), namely endothelial GF, basic fibroblast GF, transforming GF-beta1 and platelet-derived GF-BB, which are well known regulators of tendon development, growth and healing. Among the screened hASCs subpopulations, tenomodulin-positive cells were shown to be more promising for tenogenic applications and therefore this subpopulation was further studied, assessing tendon-related markers (scleraxis, tenomodulin, tenascin C and decorin) both at gene and protein level. Additionally, the ability for depositing collagen type I and III forming extracellular matrix structures were weekly assessed up to 28 days. The results obtained indicated that tenomodulin-positive cells exhibit phenotypical features of tendon progenitor cells and can be biochemically induced towards tenogenic lineage, demonstrating that this subset of hASCs can provide a reliable source of progenitor cells for therapies targeting tendon regeneration. PMID- 28593713 TI - Effectiveness of sleep self-management group intervention in Chinese patients with insomnia disorder. AB - PURPOSE: The purpose of this study was to explore the effectiveness of sleep self management group intervention for insomnia disorder. DESIGN AND METHODS: One hundred four patients with insomnia disorder were recruited from The Seventh Hospital of Hangzhou, from February to November 2015. After completing the Pittsburgh Sleep Quality Index (PSQI) and Sleep Diary and Beliefs and Attitudes about Sleep Scale (DBAS), they were randomly assigned into the intervention group (n = 52) and the control group (n = 52). The intervention group received the "sleep self-management group intervention," while the control group was trained with routine intervention in the same form combined with 5 to 10 mg Zolpidem nightly. Patients from both groups completed the PSQI, DBAS, and Sleep Diary after 8 weeks of treatment. FINDINGS: The intervention group scored significantly lower on the PSQI total score, Objective Sleep Efficacy, and Sleep Disturbance but higher on the DBAS total score, misconceptions about the causes of insomnia, misattribution or amplification of the consequences of insomnia, faulty beliefs about sleep-promoting practices than the control group after intervention. PRACTICE IMPLICATIONS: The sleep self-management group intervention could enhance sleep efficacy, improve sleep disturbance, and sleep misbeliefs. PMID- 28593714 TI - Autism awareness in children and young people: surveys of two populations. AB - BACKGROUND: Increasingly, pupils on the autism spectrum are educated in inclusive mainstream classrooms. However, they often experience social isolation and bullying, and raising the awareness of autism in peers has been suggested as a remedy. METHODS: In order to assess autism awareness in peers, autism-related questions were included in two large-scale surveys: the Kids Life and Times survey for 11-year olds and the Young Life and Times survey for 16-year olds; a total of n = 3353 children and young people completed the surveys. RESULTS: Autism awareness was higher for the teenagers (80%) than for the younger children (50%). Many of the children knew someone with autism (50%) and generally reported positive and supportive attitudes. Self-reported prevalence of autism was 3.1% for teenagers and 2.7% for the younger children. Peers recognised bullying as a problem and were willing to help. CONCLUSIONS: Children and young people have good levels of awareness and knowledge about autism and reported positive attitudes towards peers with autism and are willing to help those who are bullied. A higher than expected number of children and young people self-reported being on the autism spectrum. These findings bode well for peer-mediated support strategies for inclusive education. PMID- 28593715 TI - Can animal habitat use patterns influence their vulnerability to extreme climate events? An estuarine sportfish case study. AB - Global climate forecasts predict changes in the frequency and intensity of extreme climate events (ECEs). The capacity for specific habitat patches within a landscape to modulate stressors from extreme climate events, and animal distribution throughout habitat matrices during events, could influence the degree of population level effects following the passage of ECEs. Here, we ask (i) does the intensity of stressors of an ECE vary across a landscape? And (ii) Do habitat use patterns of a mobile species influence their vulnerability to ECEs? Specifically, we measured how extreme cold spells might interact with temporal variability in habitat use to affect populations of a tropical, estuarine-dependent large-bodied fish Common Snook, within Everglades National Park estuaries (FL US). We examined temperature variation across the estuary during cold disturbances with different degrees of severity, including an extreme cold spell. Second, we quantified Snook distribution patterns when the passage of ECEs is most likely to occur from 2012 to 2016 using passive acoustic tracking. Our results revealed spatial heterogeneity in the intensity of temperature declines during cold disturbances, with some habitats being consistently 3-5 degrees C colder than others. Surprisingly, Snook distributions during periods of greatest risk to experience an extreme cold event varied among years. During the winters of 2013-2014 and 2014-2015 a greater proportion of Snook occurred in the colder habitats, while the winters of 2012-2013 and 2015-2016 featured more Snook observed in the warmest habitats. This study shows that Snook habitat use patterns could influence vulnerability to extreme cold events, however, whether Snook habitat use increases or decreases their vulnerability to disturbance depends on the year, creating temporally dynamic vulnerability. Faunal global change research should address the spatially explicit nature of extreme climate events and animal habitat use patterns to identify potential mechanisms that may influence population effects following these disturbances. PMID- 28593717 TI - Genetic architecture of acne vulgaris. AB - Acne vulgaris is a ubiquitary skin disease characterized by chronic inflammation of the pilosebaceous unit resulting from bacterial colonization of hair follicles by Propionibacterium acnes, androgen-induced increased sebum production, altered keratinization and inflammation. Here, we review our current understanding of the genetic architecture of this intriguing disease. We analysed genomewide association studies (GWAS) and candidate genes studies for acne vulgaris. Moreover, we included GWAS studies for the associated disease polycystic ovary syndrome (PCOS). Overall, the available data revealed sixteen genetic loci flagged by single nucleotide polymorphisms (SNPs), none of which has been confirmed yet by independent studies. Moreover, a GWAS for PCOS identified 21 susceptible loci. The genetic architecture is complex which has been revealed by GWAS. Further and larger studies in different populations are required to confirm or disprove results from candidate gene studies as well to identify signals that may overlap between different populations. Finally, studies on rare genetic variants in acne and associated diseases like PCOS may deepen our understanding of its pathogenesis. PMID- 28593716 TI - Does an epidemiological comparison support a common cellular lineage for similar subtypes of postmenopausal uterine and ovarian carcinoma? The Norwegian Women and Cancer Study. AB - Uterine and ovarian carcinomas have the same major histological subtypes, but whether they originate from the same cell types is a matter of ongoing debate. Uterine and ovarian endometrioid and clear cell carcinoma (ECC) and uterine and ovarian serous carcinoma (SC) may originate in the same location, or share a common lineage of differentiation. Epidemiologically, a common cellular lineage should be reflected in similar risk associations, and we explored the similarity of uterine and ovarian ECC and uterine and ovarian SC. We included 146,316 postmenopausal participants from the Norwegian Women and Cancer Study. Exposure information was taken from self-administered questionnaires, and cancer cases were identified through linkage to the Cancer Registry of Norway. Hazard ratios with 95% confidence intervals for uterine and ovarian carcinoma and their subtypes were calculated using multivariable Cox regression models, and a Wald test was used to check for heterogeneity. During 1.6 million person-years, 1,006 uterine and 601 ovarian carcinomas were identified. Parity, total menstrual lifespan, body mass index and smoking were differentially associated with total uterine and total ovarian carcinoma (pheterogeneity = 0.041, 0.027, <0.001 and 0.001, respectively). The corresponding associations for uterine and ovarian ECC did not differ significantly (pheterogeneity > 0.05). Smoking was differentially associated with uterine and ovarian SC (pheterogeneity = 0.021). Our epidemiological analyses do not contradict a common differentiation lineage for uterine and ovarian ECC. Uterine and ovarian SC are less likely to be of a common lineage of differentiation, based on their difference in risk associated with smoking. PMID- 28593718 TI - Metal Immiscibility Route to Synthesis of Ultrathin Carbides, Borides, and Nitrides. AB - Ultrathin ceramic coatings are of high interest as protective coatings from aviation to biomedical applications. Here, a generic approach of making scalable ultrathin transition metal-carbide/boride/nitride using immiscibility of two metals is demonstrated. Ultrathin tantalum carbide, nitride, and boride are grown using chemical vapor deposition by heating a tantalum-copper bilayer with corresponding precursor (C2 H2 , B powder, and NH3 ). The ultrathin crystals are found on the copper surface (opposite of the metal-metal junction). A detailed microscopy analysis followed by density functional theory based calculation demonstrates the migration mechanism, where Ta atoms prefer to stay in clusters in the Cu matrix. These ultrathin materials have good interface attachment with Cu, improving the scratch resistance and oxidation resistance of Cu. This metal metal immiscibility system can be extended to other metals to synthesize metal carbide, boride, and nitride coatings. PMID- 28593719 TI - Penalized estimation in latent Markov models, with application to monitoring serum calcium levels in end-stage kidney insufficiency. AB - We introduce a penalized likelihood form for latent Markov models. We motivate its use for biomedical applications where the sample size is in the order of the tens, or at most hundreds, and there are only few repeated measures. The resulting estimates never break down, while spurious solutions are often obtained by maximizing the likelihood itself. We discuss model choice based on the Takeuchi Information Criterion. Simulations and a real-data application to monitoring serum Calcium levels in end-stage kidney disease are used for illustration. PMID- 28593720 TI - Phytoestrogen-Rich Natural Preparation for Treatment of Climacteric Syndrome and Atherosclerosis Prevention in Perimenopausal Women. AB - The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds, green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder. The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale. Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of climacteric syndrome's severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after 24 months of follow up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life Scale was also observed in Karinat group. However, difference in carotid intima media thickness between the two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric syndrome and cardiovascular disease prevention in perimenopausal women. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28593721 TI - Nurse-patient communication within the context of non-sedated mechanical ventilation: A hermeneutic-phenomenological study. AB - AIMS AND OBJECTIVES: To explore non-sedated mechanically ventilated patients' communication with nurses in the intensive care unit. BACKGROUND: Mechanically ventilated patients are temporarily voiceless, making interpersonal communication complex. Both nurses and patients find communication challenging and may experience negative emotions when communication fails. In Nordic countries, sedation protocols have changed to light/non-sedation, resulting in more patients being conscious and more clinical practitioners experiencing communication difficulties. DESIGN: The study was qualitative with a phenomenological hermeneutic approach. Data were collected at two intensive care units in Denmark from January to April 2015. METHODS: Data collection consisted of interviews with patients, focus group interviews with nurses and field observations concerning nurse-patient communication. Data were analysed as one collective body of data using Ricoeur's theory of interpretation. FINDINGS: The main theme showed that communication is a movement between the two opposite feelings of comprehension and frustration. Sub-themes showed (1) the dynamics of power change when the patient is voiceless; (2) consciousness and voicelessness make caring difficult; and (3) the process of interpreting and structuring communication is situational. CONCLUSION: These findings are important in nursing care and provide perspectives on the shift from communication towards comprehension and, thus, away from frustration. A non-sedation protocol is a major change in clinical practice in relation to communication. It requires a new way of thinking where communication becomes an integrated part of care, and the nurse has to be constantly alert and adjust his or her communication strategies to the patient's changing needs and communication ability. RELEVANCE TO CLINICAL PRACTICE: Some nursing interventions may optimize communication: (1) systematic assessment of patients' communication; (2) education of nurses in Augmentative and Alternative Communication; (3) using communication tools when possible; and (4) securing time, continuity, empathy and patience in nursing care. PMID- 28593722 TI - Macronutrient intake associated with weight gain in adolescent girls with anorexia nervosa. AB - OBJECTIVE: Adolescents and women with anorexia nervosa (AN) are known to severely restrict total calorie and fat intake. However, data are limited regarding specific macronutrient intake associated with weight gain in AN. OBJECTIVE: To prospectively investigate dietary macronutrient composition associated with weight gain in adolescent girls with AN. METHOD: A prospective naturalistic study of 90 girls 12-18 years old; 45 with AN and 45 healthy normal-weight-controls over a 6-12-month period. Participants completed four-day food diaries and underwent body composition assessment using dual energy X-ray absorptiometry. Weight gain was defined as a >=10% increase in body mass index (BMI) from baseline. RESULTS: Baseline clinical characteristics did not differ between girls with AN who did not gain weight (AN-0) versus those who did (AN-1) over the following 6-12 month period except for percentage of calories from proteins (p = 0.046). At 6-12 month follow-up, AN-1 consumed a lower percentage of total calories from protein (p = .001), and a higher percentage of total calories from fat (p = .02) compared to AN-0. AN-1 had a significant increase in the percentage of total calories obtained from and poly-unsaturated-fatty acids (PUFA) (p = 0.006) compared to AN-0, between baseline and follow-up. Within the AN group, BMI at follow-up was associated positively with percentage of total calories obtained from fat, MUFA, and PUFA (p < .05) at 6/12 months, and inversely with the percentage of total calories obtained from carbohydrates and proteins (p = .03). DISCUSSION: Consuming a greater proportion of total calories from fat is associated with weight gain in adolescent girls with AN. PMID- 28593723 TI - Imbalanced nutrient recycling in a warmer ocean driven by differential response of extracellular enzymatic activities. AB - Ocean oligotrophication concurrent with warming weakens the capacity of marine primary producers to support marine food webs and act as a CO2 sink, and is believed to result from reduced nutrient inputs associated to the stabilization of the thermocline. However, nutrient supply in the oligotrophic ocean is largely dependent on the recycling of organic matter. This involves hydrolytic processes catalyzed by extracellular enzymes released by bacteria, which temperature dependence has not yet been evaluated. Here, we report a global assessment of the temperature-sensitivity, as represented by the activation energies (Ea ), of extracellular beta-glucosidase (betaG), leucine aminopeptidase (LAP) and alkaline phosphatase (AP) enzymatic activities, which enable the uptake by bacteria of substrates rich in carbon, nitrogen, and phosphorus, respectively. These Ea were calculated from two different approaches, temperature experimental manipulations and a space-for-time substitution approach, which generated congruent results. The three activities showed contrasting Ea in the subtropical and tropical ocean, with betaG increasing the fastest with warming, followed by LAP, while AP showed the smallest increase. The estimated activation energies predict that the hydrolysis products under projected warming scenarios will have higher C:N, C:P and N:P molar ratios than those currently generated, and suggest that the warming of oceanic surface waters leads to a decline in the nutrient supply to the microbial heterotrophic community relative to that of carbon, particularly so for phosphorus, slowing down nutrient recycling and contributing to further ocean oligotrophication. PMID- 28593724 TI - A Strategy for Creating Organisms Dependent on Noncanonical Amino Acids. AB - The use of noncanonical amino acids (ncAAs) to control the viability of an organism provides a strategy for the development of conditional "kill switches" for live vaccines or engineered human cells. We report an approach inspired by the posttranslational acetylation/deacetylation of lysine residues, in which a protein encoded by a gene with an in-frame nonsense codon at an essential lysine can be expressed in its native state only upon genetic incorporation of N-epsilon acetyl-l-Lys (AcK), and subsequent enzymatic deacetylation in the host cell. We applied this strategy to two essential E. coli enzymes: the branched-chain aminotransferase BCAT and the DNA replication initiator protein DnaA. We also devised a barnase-based conditional suicide switch to further lower the escape frequency of the host cells. This strategy offers a number of attractive features for controlling host viability, including a single small-molecule-based kill switch, low escape frequency, and unaffected protein function. PMID- 28593725 TI - Xenotransplantation literature update, March/April 2017. PMID- 28593726 TI - The evolution of basal septal hypertrophy: From benign and age-related normal variant to potentially obstructive and symptomatic cardiomyopathy. AB - Localized thickening of the basal portion of the ventricular septum or basal septal hypertrophy (BSH) has been identified both at autopsy and by imaging studies for decades; despite numerous investigations, there is no consensus on the significance of this finding and a remarkable lack of consistency in terminology. This paper summarizes the scientific literature on the topic, focusing on recent echocardiographic findings. A case description illustrating some of the complex issues involved in measurement and diagnosis and differentiation from sigmoidal hypertrophic cardiomyopathy (HCM) is presented. Criteria are proposed for diagnosing pathologic BSH which include the following: (1) Exertional symptoms compatible with left ventricular outflow tract obstruction (LVOTO) such as dyspnea, near-syncope, and chest discomfort; (2) Documented LVOTO gradient demonstrated at peak bicycle or post-treadmill exercise >30 mm Hg; and (3) Symptomatic improvement with beta-blocker (or other negative inotropic) therapy (preferably accompanied by documentation of reduction of exercise-induced LVOT). PMID- 28593727 TI - Influence of a collagen membrane positioned subjacent the sinus mucosa following the elevation of the maxillary sinus. A histomorphometric study in rabbits. AB - OBJECTIVE: To evaluate the healing after elevation of the sinus mucosa when a collagen membrane was placed between the sinus mucosa and a xenograft used as filler. MATERIALS AND METHODS: Eighteen rabbits were used. Sinus mucosa elevation was performed bilaterally, and a collagen membrane was applied subjacent to the sinus mucosa only at a randomly selected test site. At both sites, a collagenated corticocancellous porcine bone was placed within the elevated space and the access window was covered with a collagen membrane. The animals were sacrificed after 2, 4, and 8 weeks of healing, six animals for group. Ground sections were prepared. RESULTS: At the histomorphometric evaluation, the elevated area after 2 and 8 weeks was 11.8 and 8.8 mm2 at the test, and 10.0 and 5.3 mm2 at the control sites, respectively. The available area was obtained subtracting the remaining area occupied by the membrane from the elevated area and, after 8 weeks, was 6.7 +/- 0.9 mm2 . After 8 weeks of healing, the mineralized new bone within the elevated space was 18.2 +/- 5.5% at the test and 26.7 +/- 7.7% at the control sites. Within the available space at the test site, the percentage was 27.3 +/- 7.0% after 8 weeks of healing. At 2 and 8 weeks of healing, within the elevated space, the xenograft proportion was 30.9 +/- 4.4% and 6.9 +/- 2.8% at the test, and 35.2 +/- 7.3% and 9.6 +/- 4.9% at the control sites, respectively. CONCLUSIONS: The placement of a collagen membrane subjacent the sinus mucosa did not reveal any major morphometric difference. The collagen membrane was not completely resorbed after 8 weeks. PMID- 28593728 TI - Association of risk genotypes of ARMS2/LOC387715 A69S and CFH Y402H with age related macular degeneration with and without reticular pseudodrusen: a meta analysis. AB - To pool the results of published data regarding association of ARMS2/LOC387715 A69S, CFH Y402H and CFH I62V genotypes with age-related macular degeneration (AMD) with and without reticular pseudodrusen (RPD). The results of this pooled data used to estimate the contribution of each of these genes in the pathogenesis of RPD. Heterogeneity of studies was evaluated using Cochran Q-test and I2 index. To modify the heterogeneity in the variables, we used the random effects model. Meta-analysis was performed using STATA. Odds ratio (OR) of genotypes in each study was calculated. Six studies of AMD with RPD and AMD without RPD cases included in this analysis. Analysis of pooled data showed that risk genotypes frequency of ARMS2 A69S was significantly different between AMD with RPD and AMD without RPD [OR = 1.82, 95% confidence interval (CI): 1.26-2.63 for GT versus GG ARMS2 A69S; OR = 2.40, 95% CI: 1.50-3.84 for TT versus GG ARMS2 A69S]. Further analysis also showed that the risk genotype frequency of CFH Y402H was not significantly different between these two groups (OR = 1.02, 95% CI: 0.69-1.50 for CT versus TT CFH Y402H; OR = 1.09, 95% CI: 0.74-1.60 for CC versus TT CFH Y402H). Comparison of above-mentioned ORs revealed statistically higher values for GT and TT genotypes of ARMS2 A69S compared with CFH Y402H genotypes (p = 0.011, p = 0.014, respectively).Our analysis showed stronger contribution of ARMS2 in AMD with RPD group versus AMD without RPD group, in comparison with CFH genotypes. PMID- 28593729 TI - Synthesis and Structural Characterization of Butadienylcalcium-based Heavy Grignard Reagents and a Ca4 [O] Inverse Crown Ether Complex. AB - The structure elucidation of heavy Grignard reagents (RAeX, Ae=Ca, Sr, and Ba, X=halides) has been greatly strived after, mainly because of their inaccessibility and remarkable instability. The synthesis of a series of butadienylcalcium compounds is presented, including 1-calcio-4-lithio-1,3 butadiene, 1,4-dicalcio-1,3-butadiene, and a Ca4 [O] inverse crown ether complex, via the reaction between 1,4-dilithio-1,3-butadienes and calcium iodide in THF. Single-crystal X-ray analysis of these unprecedented heavy Grignard reagents revealed unique structural characteristics and bonding modes. Preliminary reaction chemistry was investigated. This study provides a novel class of alkenyl heavy Grignard reagents and a useful synthetic strategy for otherwise unavailable reactive organometallic compounds. PMID- 28593730 TI - Dynamics of cytokine gene expression in peripheral blood mononuclear cells of indigenous and exotic breeds of pigs in India. AB - To incorporate immune competence traits in swine breeding programs, association between immune responsiveness and susceptibility to specific infectious diseases must be established. In order to understand the differences in immune competence between indigenous (Zovawk) and exotic (Large White Yorkshire: LWY) pigs reared in India, we carried out a time course expression analysis of immune-regulating key cytokine genes (interleukin (IL)-2, interferon (IFN)-gamma, IL-4 and IL-10) in the phytohemagglutinin-P stimulated peripheral blood mononuclear cells (PBMCs). The IL-2 transcript levels in PBMCs increased several thousand-fold when compared to unstimulated cells in both the breeds, albeit the response in that of Zovawk was remarkably higher. Higher and earlier IFN-gamma and IL-4 expression levels in Zovawk pigs suggest that both TH 1 and TH 2 immune responsiveness of this indigenous breed affords better preparedness for danger signals. Moreover, the low expression levels of IL-10 depict a regulated adaptive immune responsiveness. Remarkable difference between the two breeds of the pigs is evident showing a clear advantage of the Zovawk over LWY in terms of a shorter lag period of adaptive immune response. These findings provide a lead for understanding the genetic differences with respect to immune competence levels of indigenous pigs compared to exotic counterparts. PMID- 28593731 TI - Multimodal-3D imaging based on MUMRI and MUCT techniques bridges the gap with histology in visualization of the bone regeneration process. AB - Bone repair/regeneration is usually investigated through X-ray computed microtomography (MUCT) supported by histology of extracted samples, to analyse biomaterial structure and new bone formation processes. Magnetic resonance imaging (MUMRI) shows a richer tissue contrast than MUCT, despite at lower resolution, and could be combined with MUCT in the perspective of conducting non destructive 3D investigations of bone. A pipeline designed to combine MUMRI and MUCT images of bone samples is here described and applied on samples of extracted human jawbone core following bone graft. We optimized the coregistration procedure between MUCT and MUMRI images to avoid bias due to the different resolutions and contrasts. Furthermore, we used an Adaptive Multivariate Clustering, grouping homologous voxels in the coregistered images, to visualize different tissue types within a fused 3D metastructure. The tissue grouping matched the 2D histology applied only on 1 slice, thus extending the histology labelling in 3D. Specifically, in all samples, we could separate and map 2 types of regenerated bone, calcified tissue, soft tissues, and/or fat and marrow space. Remarkably, MUMRI and MUCT alone were not able to separate the 2 types of regenerated bone. Finally, we computed volumes of each tissue in the 3D metastructures, which might be exploited by quantitative simulation. The 3D metastructure obtained through our pipeline represents a first step to bridge the gap between the quality of information obtained from 2D optical microscopy and the 3D mapping of the bone tissue heterogeneity and could allow researchers and clinicians to non-destructively characterize and follow-up bone regeneration. PMID- 28593732 TI - Severe metabolic impairment with increasing age for CYP3A and CYP2D substrates in rats: Possible consequences for drug development. PMID- 28593733 TI - Two new species in the Chaetoceros socialis complex (Bacillariophyta): C. sporotruncatus and C. dichatoensis, and characterization of its relatives, C. radicans and C. cinctus. AB - The diatom genus Chaetoceros is one of the most abundant and diverse phytoplankton in marine and brackish waters worldwide. Within this genus, Chaetoceros socialis has been cited as one of the most common species. However, recent studies from different geographic areas have shown the presence of pseudo cryptic diversity within the C. socialis complex. Members of this complex are characterized by curved chains (primary colonies) aggregating into globular clusters, where one of the four setae of each cell curves toward the center of the cluster and the other three orient outwards. New light and electron microscopy observations as well as molecular data on marine planktonic diatoms from the coastal waters off Chile revealed the presence of two new species, Chaetoceros sporotruncatus sp. nov. and C. dichatoensis. sp. nov. belonging to the C. socialis complex. The two new species are similar to other members of the complex (i.e., C. socialis and C. gelidus) in the primary and secondary structure of the colony, the orientation pattern of the setae, and the valve ultrastructure. The only morphological characters that can be used to differentiate the species of this complex are aspects related to resting spore morphology. The two newly described species are closely related to each other and form a sister clade to C. gelidus in molecular phylogenies. We also provide a phylogenetic status along with the morphological characterization of C. radicans and C. cintus, which are genetically related to the C. socialis complex. PMID- 28593735 TI - New insights into the clinical signs of supraventricular tachycardia: The "sign of lace-tying". AB - BACKGROUND: Supraventricular tachycardias (SVT) are a common arrhythmia therefore an accurate diagnosis is of clinical importance. Although an ECG performed during tachycardia greatly aids diagnosis, patient history and predisposing factors also improve diagnostic accuracy. METHODS: This prospective study included 100 consecutive patients undergoing electrophysiological study for SVT with the aim to reassess their clinical characteristics and describe frequent predisposing factors, such as the "sign of lace-tying" that to our knowledge has not previously been reported. Each patient completed an extensive questionnaire (70 questions) during their hospital stay. RESULTS: Our series comprised: 67% of patients with atrioventricular nodal reentrant tachycardia (AVNRT); 24% with an accessory pathway; and 9% presented atrial tachycardia. Half of the population were male and 29% of the cohort presented hypertension. Syncope during tachycardia appeared in 15% of patients, dizziness in 52% and thoracic pain in 59%. We encountered a predisposing risk factor for SVT in 53% of cases; with 32% exhibiting an anteflexion of the trunk termed the "sign of lace-tying." Data also showed that younger patients tended to present AVRT and regular pounding in the neck appeared only in patients with AVNRT. CONCLUSIONS: Overall, our study has highlighted the importance of considering clinical signs and patient characteristics both before and during SVT for the precise diagnosis of paroxysmal SVT. Furthermore, 32% of patients presented the "sign of lace-tying" or body position change before SVT, implying a diagnosis of SVT. PMID- 28593736 TI - Usefulness of the sigma-Aromaticity and sigma-Antiaromaticity Concepts for Clusters and Solid-State Compounds. AB - In this Review we present examples of clusters, molecules, and solid-state compounds, for which the use of sigma-aromaticity and sigma-antiaromaticity concepts is essential for understanding of chemical bonding. We show that the bonding patterns in these sigma-aromatic and sigma-antiaromatic compounds are similar to those of the corresponding pi-aromatic and pi-antiaromatic chemical systems, respectively. Undoubtedly, sigma-aromaticity helps us understand why the high symmetry isomers are the most stable among myriads of other potential structures. We also show that besides systems exhibiting either sigma- or pi aromatic features, there are species, which can possess multiple aromaticity/antiaromaticity, or conflicting aromaticity patterns. We believe that the sigma-aromaticity and sigma-antiaromaticity concepts will be helpful in rationalizing chemical bonding, structure, stability, and molecular properties of chemical species in both organic and inorganic chemistry. We hope that they will also be useful for other areas of science such as material science, catalysis, nanotechnology, and biochemistry. PMID- 28593734 TI - Can an NTI-tss device be effective as a first-line therapy in patients with TMD myofascial pain? AB - This study was conducted to evaluate whether integrating a nociceptive trigeminal inhibition-tension suppression system (NTI-tss) device with first-line therapy of myofascial pain, which includes guidance, assurance, counselling and behavioural changes, would be more effective in alleviating symptoms. This randomised controlled clinical trial included 40 patients who were clinically diagnosed with myofascial pain according to Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Patients were randomly divided into two groups: the first group comprised patients who received guidance, assurance, counselling and behavioural changes; an NTI-tss device was integrated to this protocol in the second group. Both groups exhibited reduction in pain levels and improvement of jaw function compared with baseline values, but the difference was not significant. Both groups demonstrated improvements in 6 weeks; however, the integration of NTI-tss device into the therapy protocol did not provide any additional benefit in relieving symptoms of myofascial pain. PMID- 28593738 TI - Sex differences in the regulation of porcine coronary artery tone by perivascular adipose tissue: a role of adiponectin? AB - BACKGROUND AND PURPOSE: As there is sexual dimorphism in the regulation of vascular tone, the aim of this present study was to determine whether there are sex differences in perivascular adipose tissue (PVAT)-mediated regulation of the porcine coronary artery (PCA) tone. EXPERIMENTAL APPROACH: Isometric tension recording system was used to record changes in tone in PCAs. Western blot analysis was performed to examine the expression of adiponectin in PVAT and adiponectin receptors and adiponectin binding protein (APPL1) in PCA. The level of adiponectin released from PVAT was measured using elisa. KEY RESULTS: In the presence of adherent PVAT, contractions to the thromboxane mimetic U46619 and endothelin-1 were significantly reduced in PCAs from females, but not males. In PCAs pre-contracted with U46619, re-addition of PVAT caused relaxation in PCAs from females, but not males. This relaxant response in females was attenuated by combined inhibition of NOS (with L-NAME) and COX (with indomethacin). Pre incubation with an anti-adiponectin antibody abolished the relaxant effects of PVAT. The adiponectin receptor agonist (adipoRon) produced a greater relaxation in PCAs from females compared with males. However, there was no difference in either the expression or release of adiponectin from PVAT between sexes. Similarly, there was no difference in the expression of adiponectin receptors or the adiponectin receptor adaptor protein APPL1 in PCAs. CONCLUSION AND IMPLICATIONS: These findings demonstrate a clear sex difference in the regulation of coronary arterial tone in response to adiponectin receptor stimulation, which may underlie the anticontractile effects of PVAT in females. PMID- 28593739 TI - Systematic review and meta-analysis to determine the impact of iron depletion in dysmetabolic iron overload syndrome and non-alcoholic fatty liver disease. AB - AIMS: Iron reduction has been proposed as treatment for dysmetabolic iron overload syndrome (DIOS) and non-alcoholic fatty liver disease (NAFLD), but results of published trials are conflicting. We undertook a systematic review and meta-analysis to determine the impact of phlebotomy in DIOS and NAFLD. METHODS: We searched multiple databases systematically for studies evaluating the impact of phlebotomy in DIOS and NAFLD. We calculated weighted summary estimates using the inverse variance method. Study quality was assessed using the Cochrane collaboration tool. RESULTS: We identified nine studies with 820 patients (427 had phlebotomy, 393 lifestyle changes alone). Iron depletion did not improve the Homeostasis Model Assessment (HOMA) index (mean difference [MD] -0.6; confidence interval (CI), -1.7, 0.5; P = 0.3), insulin level (MD -0.8 mU/L; CI, -5.3, 3.7; P = 0.73), or aspartate aminotransferase (AST) (MD -0.7 IU/L; CI, -3.2, 1.8; P = 0.6) in DIOS and/or NAFLD patients as compared to lifestyle changes alone (five studies, 626 patients). There was mild improvement in alanine aminotransferase (ALT) (MD -6.6 IU/L; CI, -11, -2.1); P < 0.01), but the effect size was very small (Cohen's d, 0.15; r statistic, 0.07). Even in the subgroup of patients with NAFLD and hyperferritinemia, phlebotomy did not improve the HOMA index, insulin level, ALT, or AST. Additionally, no study showed significant improvement in liver inflammation or fibrosis with iron reduction. CONCLUSIONS: Phlebotomy does not bring about significant improvement in indices of insulin resistance, liver enzymes, or liver histology in patients with DIOS and/or NAFLD compared to lifestyle changes alone. Current evidence does not support the use of phlebotomy in patients with DIOS or NAFLD. PMID- 28593740 TI - Combination of Mass Signal Amplification and Isotope-Labeled Alkanethiols for the Multiplexed Detection of miRNAs. AB - We report a fast and sensitive method for the multiplexed detection of miRNAs by combining mass signal amplification and isotope-labeled signal reporter molecules. In our strategy, target miRNAs are captured specifically by immobilized DNAs on gold nanoparticles (AuNPs), which carry a large number of small molecules, called amplification tags (Am-tags), as the reporter for the detection of target miRNAs. For multiplexed detection, we designed and synthesized four Am-tags containing 0, 4, 8, 12 isotopes so that they had same molecular properties but different molecular weights. By observing the mass signals of the Am-tags on AuNPs decorated along with different probe DNAs, four types of miRNAs in a sample could be easily discriminated, and the relative amounts of these miRNAs could be quantified. The practicability of our strategy was further verified by measuring the expression levels of two miRNAs in HUVECs in response to different CuSO4 concentrations. PMID- 28593737 TI - Influence of opioids on immune function in patients with cancer pain: from bench to bedside. AB - : In patients with cancer, opioids are principally used for the management of acute surgical and chronic cancer-related pain. However, opioids have many non analgesic effects, including direct and indirect effects on cancer cells and on anti-tumour immunity (NK cells, macrophages and T-cells). Direct effects on immune cells are manifested via opioid and non-opioid toll-like receptors, whereas indirect effects are manifested via the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Opioids can also decrease/alter immune cell infiltration into the tumour micro-environment. Animal models have shown that this is not a class effect, in that morphine and fentanyl suppress NK cell cytotoxicity; buprenorphine does not affect NK cell cytotoxicity, whereas tramadol increases NK cell cytotoxicity, reducing metastasis. In healthy individuals, morphine suppresses and fentanyl enhances NK cell cytotoxicity. In patients undergoing surgery, fentanyl decreased and tramadol increased NK cell cytotoxicity; clinical outcomes were not determined. Meta-analyses of opioid sparing surgical studies report an association between improved recurrence-free and/or overall survival with regional/neuraxial anaesthesia compared with systemic opioids. In patients receiving opioids for non-surgical cancer-related pain, morphine has variable effects on immunity; clinical outcomes were not assessed. Although there is a potential association between systemic opioid administration and shorter survival in cancer patients with a prognosis of months to years, studies have not been designed to primarily assess survival, as a consequence of which causality cannot be apportioned. Pain is immunosuppressive, so analgesia is important. Opioids for cancer-related pain will continue to be recommended until definitive data on the effects of opioids on clinical outcomes in specific patient groups becomes available. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc. PMID- 28593741 TI - Comparison of different methods for telomere length measurement in whole blood and blood cell subsets: Recommendations for telomere length measurement in hematological diseases. AB - Different methods of telomere length measurement are used to identify patients with telomeropathies. In our lab, we established four different methods for telomere length measurement, terminal restriction fragment (TRF) analysis by Southern blot analysis, quantitative PCR (qPCR), quantitative telomere/centromere fluorescence in situ hybridization (T/C-FISH) and fluorescence in situ hybridization combined with flow cytometry (FlowFISH). The methods each have distinct properties and apart from this-according to our experience and data-may have an impact on the individual result. In this study, we therefore compared and validated these methods measuring 154 healthy individuals of different age groups (newborn-81 years). A linear decline was found for every method (Southern blotting 64 bp per year; qPCR 31 bp per year; T/C-FISH 36 bp per year; FlowFISH 50 bp per year). With the equation of the regression line the values of each method (T/S ratio, T/C value, RTL value) can be expressed in absolute kb. All methods showed acceptable accuracy. The analysis indicated good agreement between all methods, with the best agreement between T/C-FISH and FlowFISH. Here, FlowFISH was the most precise, accurate, and reproducible method compared to the other methods. Based on our data, we emphasize the influence of expertise and experience that is required to produce robust and reliable telomere length analyses. Furthermore, we want to provide the scientific community working in diagnostics and research with data-funded advice on how to choose the appropriate method to safely discriminate between natural variability and pathological telomere shortening in individual cases. PMID- 28593742 TI - Overview of surgery for laryngeal and hypopharyngeal cancer in Ontario, 2003 2010. AB - BACKGROUND: The primary purpose of this study was to describe variations in incidence rates, resections rates, and types of surgical resection for patients diagnosed with laryngeal and hypopharyngeal cancers in Ontario. METHODS: All laryngeal and hypopharyngeal cancer cases in Ontario (2003-2010) were identified from the Ontario Cancer Registry (n = 3034). Variations in incidence rates, resection rates, and type of surgical resection were compared by sex, age group, neighborhood income, community population, health region, and physician specialty. RESULTS: Incidence rates per 100 000 vary significantly by sex, age, neighborhood income, and community size. Women, the elderly (75+ years), those in the higher income quintiles, and those living in larger communities were significantly less likely to receive a laryngectomy procedure. CONCLUSIONS: Laryngeal and hypopharyngeal cancer incidence rates vary by sex, age, neighborhood income, community size, and health region. Resection rates vary by age, sex, and health region. These disparities warrant further evaluation to improve the quality of delivered care in Ontario. PMID- 28593743 TI - Sensitive and Reversible Detection of Methanol and Water Vapor by In Situ Electrochemically Grown CuBTC MOFs on Interdigitated Electrodes. AB - The in situ electrochemical growth of Cu benzene-1,3,5-tricarboxylate (CuBTC) metal-organic frameworks, as an affinity layer, directly on custom-fabricated Cu interdigitated electrodes (IDEs) is described, acting as a transducer. Crystalline 5-7 um thick CuBTC layers are grown on IDEs consisting of 100 electrodes with a width and a gap of both 50 um and a height of 6-8 um. These capacitive sensors are exposed to methanol and water vapor at 30 degrees C. The affinities show to be completely reversible with higher affinity toward water compared to methanol. For exposure to 1000 ppm methanol, a fast response is observed with a capacitance change of 5.57 pF at equilibrium. The capacitance increases in time followed diffusion-controlled kinetics (k = 2.9 mmol s-0.5 g 1CuBTC ). The observed capacitance change with methanol concentration follows a Langmuir adsorption isotherm, with a value for the equilibrium affinity Ke = 174.8 bar-1 . A volume fraction fMeOH = 0.038 is occupied upon exposure to 1000 ppm of methanol. The thin CuBTC affinity layer on the Cu-IDEs shows fast, reversible, and sensitive responses to methanol and water vapor, enabling quantitative detection in the range of 100-8000 ppm. PMID- 28593744 TI - Thermosensitive heparin-poloxamer hydrogels enhance the effects of GDNF on neuronal circuit remodeling and neuroprotection after spinal cord injury. AB - Traumatic spinal cord injury (SCI) results in paraplegia or quadriplegia, and currently, therapeutic interventions for axonal regeneration after SCI are not clinically available. Animal studies have revealed that glial cell-derived neurotrophic factor (GDNF) plays multiple beneficial roles in neuroprotection, glial scarring remodeling, axon regeneration and remyelination in SCI. However, the poor physicochemical stability of GDNF, as well as its limited ability to cross the blood-spinal cord barrier, hampers the development of GDNF as an effective therapeutic intervention in clinical practice. In this study, a novel temperature-sensitive heparin-poloxamer (HP) hydrogel with high GDNF-binding affinity was developed. HP hydrogels showed a supporting scaffold for GDNF when it was injected into the lesion epicenter after SCI. GDNF-HP by orthotopic injection on lesioned spinal cord promoted the beneficial effects of GDNF on neural stem cell proliferation, reactive astrogliosis inhibition, axonal regeneration or plasticity, neuroprotection against cell apoptosis, and body functional recovery. Most interestingly, GDNF demonstrated a bidirectional regulation of autophagy, which inhibited cell apoptosis at different stages of SCI. Furthermore, the HP hydrogel promoted the inhibition of autophagy-induced apoptosis by GDNF in SCI. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2816-2829, 2017. PMID- 28593745 TI - ox-LDL increases microRNA-29a transcription through upregulating YY1 and STAT1 in macrophages. AB - Macrophages and oxidized low-density lipoprotein (ox-LDL) have been verified playing vital roles in the pathogenesis of atherosclerosis (AS). Previous studies demonstrated that microRNA-29a (miR-29a) was upregulated in many atherogenic process and cells, thus acting as an important participant in AS. But the detailed regulation mechanism of miR-29a in AS has not been fully understood. In our study, we demonstrated a positive feedback loop of ox-LDL-SRA-miR-29a. Furthermore, we found that YY1 and STAT1 were upregulated in ox-LDL-stimulating macrophages followed by translocation in the nucleus and binding to the transcriptional promoter region of miR-29a, thus leading to the increase of miR 29a expression. In addition, we demonstrated that JAK1/2 signaling was involved in miR-29a upregulation. Finally, we found that miR-29a played important roles in the secretion of proinflammation factors and lipid uptake in macrophages. We uncovered the molecular mechanism and provide novel insights into the function and regulatory network of miR-29a expression regulated by ox-LDL in macrophages. PMID- 28593747 TI - Novel serum metabolomics-based approach by gas chromatography/triple quadrupole mass spectrometry for detection of human skin cancers: Candidate biomarkers. AB - Skin cancer incidence rates are continuing to rise; however, if detected at an early stage, they can be cured with minimally invasive treatment. Therefore, the identification of novel and robust biomarkers for the early detection of skin cancer is required to improve the quality of life of the patient after treatment. In the present study, we aimed to identify novel biomarkers of skin cancers. We carried out serum metabolomics using gas chromatography/triple quadrupole mass spectrometry for two types of skin cancer: squamous cell carcinoma and melanoma. The changes in the expression of metabolites compared with healthy volunteers were analyzed by principal component analysis. Among all 118 metabolites, 27 in patients with squamous cell carcinoma and 33 in patients with melanoma showed significant changes in comparison with healthy volunteers. Principal component analysis showed that both skin cancer groups could be distinguished from the healthy volunteers group. We further investigated the specific metabolites most useful for these distinctions. In the squamous cell carcinoma group, these metabolites were glycerol, 4-hydroxybenzoic acid, sebacic acid, fucose and suberic acid. In the melanoma group, these metabolites were glutamic acid, sebacic acid, suberic acid, 4-hydroxybenzoic acid and phenylalanine. The present study identified several metabolites that were distinct for certain skin cancer types, which could potentially be used as diagnostic biomarkers leading to novel clinical management strategies. PMID- 28593746 TI - Long-term measurements of chlorophyll a fluorescence using the JIP-test show that combined abiotic stresses influence the photosynthetic performance of the perennial ryegrass (Lolium perenne) in a managed temperate grassland. AB - Several experiments have highlighted the complexity of stress interactions involved in plant response. The impact in field conditions of combined environmental constraints on the mechanisms involved in plant photosynthetic response, however, remains understudied. In a long-term field study performed in a managed grassland, we investigated the photosynthetic apparatus response of the perennial ryegrass (Lolium perenne L.) to environmental constraints and its ability to recover and acclimatize. Frequent field measurements of chlorophyll a fluorescence (ChlF) were made in order to determine the photosynthetic performance response of a population of L. perenne. Strong midday declines in the maximum quantum yield of primary photochemistry (FV FM ) were observed in summer, when a combination of heat and high light intensity increased photosynthetic inhibition. During this period, increase in photosystem I (PSI) activity efficiency was also recorded, suggesting an increase in the photochemical pathway for de-excitation in summer. Strong climatic events (e.g. heat waves) were shown to reduce electron transport between photosystem II (PSII) and PSI. This reduction might have preserved the PSI from photo-oxidation. Periods of low soil moisture and high levels of sun irradiance increased PSII sensitivity to heat stress, suggesting increased susceptibility to combined environmental constraints. Despite the multiple inhibitions of photosynthetic functionality in summer, the L. perenne population showed increased PSII tolerance to environmental stresses in August. This might have been a response to earlier environmental constraints. It could also be linked to the selection and/or emergence of well-adapted individuals. PMID- 28593748 TI - Characteristics and response to treatment among Indigenous people receiving injectable diacetylmorphine or hydromorphone in a randomised controlled trial for the treatment of long-term opioid dependence. AB - INTRODUCTION AND AIMS: To determine the effectiveness of injectable hydromorphone and dicaetylmorphine for Indigenous participants in the Study to Assess Longer term Opioid Medication Effectiveness (SALOME) clinical trial. The study additionally aims to explore the prevalence and frequency of crack cocaine use among subgroups of participants (by gender and ethnicity). This secondary analysis is particularly relevant given the current need for expanded medication assisted treatments for opioid dependence across North America. DESIGN AND METHODS: Participants self-identifying as First Nations, Metis or Inuit were included in the analysis of Indigenous participants. Six-month treatment outcomes are reported as the difference between diacetylmorphine and hydromorphone treatment arms among Indigenous participants and change from baseline to 6 months in each treatment arm. Differences in outcomes are tested between Indigenous and non-Indigenous participants. Crack cocaine use was explored to determine differences between and within subgroups. RESULTS: Approximately one-third of SALOME participants self-identified as Indigenous. Indigenous participants presented to treatment with more structural vulnerabilities (e.g. lower education, higher rates of foster care and separation from biological parents) compared to non-Indigenous participants. After 6 months, Indigenous participants in both treatment arms had a significant reduction in days of street heroin use, opioid use, crack cocaine use and illegal activity. Treatment retention did not differ by treatment arm. DISCUSSION AND CONCLUSIONS: Indigenous people that are not engaged by first-line treatments for opioid dependence are in need of effective alternative treatments. Given the political and logistical barriers facing diacetylmorphine, hydromorphone could serve as a more accessible medication to reach and treat this population. [Oviedo-Joekes E, Palis H, Guh D, Marchand K, Brissette S, Lock K, MacDonald S, Harrison S, Anis AH, Krausz M, March DC, Schechter MT. Characteristics and response to treatment among Indigenous people receiving injectable diacetylmorphine or hydromorphone in a randomised controlled trial for the treatment of long-termopioid dependence. Drug Alcohol Rev 2018;37:137-146]. PMID- 28593751 TI - Depth of anesthesia monitors in sedation: running together or learning from their distances? PMID- 28593749 TI - Impact of atrial fibrillation on long-term survival following oesophagectomy: a 21-year observational study. AB - BACKGROUND: Post-operative atrial fibrillation (AF) is a common complication of oesophagectomy and thought to signal a complicated post-operative course. AF is associated with prolonged admissions, increased healthcare costs and inpatient mortality. However, the impact of post-operative AF on long-term outcomes remains uncertain. METHODS: Patients undergoing open Ivor-Lewis oesophagectomy from 1994 to 2014 at Palmerston North Hospital, New Zealand, were retrospectively evaluated. Demographic, perioperative and tumour variables were collected. Regression models were used to identify independent predictors of AF and assess post-discharge survival following oesophagectomy. RESULTS: In total, 89 patients were included. New-onset AF developed post-operatively in 27 patients (30%). Median follow-up was 6.3 years. Logistic regression identified volume of intravenous fluid in the first 24 h post-operatively as a predictor of AF. Post discharge survival was predicted by AF occurrence (hazard ratio (HR): 2.99, 95% confidence interval (CI): 1.37-6.53, P = 0.006), preoperative chemoradiotherapy (HR: 0.43, 95% CI: 0.20-0.91, P = 0.03), 1-4 positive lymph nodes (HR: 2.29, 95% CI: 1.06-4.96, P = 0.04), >=5 positive nodes (HR: 2.95, 95% CI: 1.25-6.94, P = 0.01) and year of operation from 2008 to 2014 (HR: 0.30, 95% CI: 0.12-0.75, P = 0.01). CONCLUSION: Post-operative AF was associated with poorer long-term survival following oesophagectomy in this cohort. Further research should evaluate the influence of AF on cardiovascular and oncological outcomes following oesophagectomy. PMID- 28593750 TI - Impact of obesity on mortality in patients with diabetes: Meta-analysis of 20 studies including 250,016 patients. AB - AIMS/INTRODUCTION: The impact of body mass index on mortality among patients with diabetes remains controversial. Therefore, we carried out a meta-analysis of pertinent studies. MATERIALS AND METHODS: We searched OVID/MEDLINE, EMBASE and Cochrane databases for all reported studies, which investigated the relationship between body mass index and mortality in patients with diabetes. Summary estimates of hazard ratios (HRs) were obtained with a random effects model. Univariate meta-regressions were carried out. RESULTS: A total of 20 studies including 250,016 patients with diabetes were identified. The results of the present study showed a significantly reduced risk of all-cause mortality in overweight patients (HR 0.82, 95% CI: 0.74-0.91, P < 0.0001, and I2 = 91.6%) as compared with normal weight patients. The survival benefits of obesity were only observed in the elderly patients (HR 0.69, 95% CI: 0.63-0.75, P < 0.0001, and I2 = 50.4%), but not in the younger patients (HR 1.01, 95% CI: 0.84-1.20, P = 0.96, I2 = 80.1%). Furthermore, the beneficial prognostic impacts on overweight (coefficient = 0.030, P = 0.041) and obesity (coefficient = 0.032, P = 0.010) were attenuated with clinical follow-up duration. CONCLUSIONS: The present meta analysis showed a significantly lower risk of all-cause mortality in overweight patients with diabetes compared with normal weight patients. However, the survival benefits of obesity were only observed among the elderly patients. PMID- 28593752 TI - Transparent Flash Memory Using Single Ta2O5 Layer for Both Charge-Trapping and Tunneling Dielectrics. AB - We report reproducible multibit transparent flash memory in which a single solution-derived Ta2O5 layer is used simultaneously as a charge-trapping layer and a tunneling layer. This is different from conventional flash memory cells where two different dielectric layers are typically used. Under optimized programming/erasing operations, the memory device shows excellent programmable memory characteristics with a maximum memory window of ~10.7 V. Moreover, the flash memory device shows a stable 2-bit memory performance and good reliability, including data retention for more than 104 s and endurance performance for more than 100 cycles. The use of a common charge-trapping and tunneling layer can simplify the fabrication of advanced flash memories. PMID- 28593753 TI - Identification of an Imine Reductase for Asymmetric Reduction of Bulky Dihydroisoquinolines. AB - A new imine reductase from Stackebrandtia nassauensis (SnIR) was identified, which displayed over 25- to 1400-fold greater catalytic efficiency for 1-methyl 3,4-dihydroisoquinoline (1-Me DHIQ) compared to other imine reductases reported. Subsequently, an efficient SnIR-catalyzed process was developed by simply optimizing the amount of cosolvent, and up to 15 g L-1 1-Me DHIQ was converted completely without a feeding strategy. Furthermore, the reaction proceeded well for a panel of dihydroisoquinolines, affording the corresponding tetrahydroisoquinolines (mostly in S-configuration) in good yields (up to 81%) and with moderate to excellent enantioselectivities (up to 99% ee). PMID- 28593754 TI - Simulation Protocol for Prediction of a Solid-Electrolyte Interphase on the Silicon-based Anodes of a Lithium-Ion Battery: ReaxFF Reactive Force Field. AB - We propose the ReaxFF reactive force field as a simulation protocol for predicting the evolution of solid-electrolyte interphase (SEI) components such as gases (C2H4, CO, CO2, CH4, and C2H6), and inorganic (Li2CO3, Li2O, and LiF) and organic (ROLi and ROCO2Li: R = -CH3 or -C2H5) products that are generated by the chemical reactions between the anodes and liquid electrolytes. ReaxFF was developed from ab initio results, and a molecular dynamics simulation with ReaxFF realized the prediction of SEI formation under real experimental conditions and with a reasonable computational cost. We report the effects on SEI formation of different kinds of Si anodes (pristine Si and SiOx), of the different types and compositions of various carbonate electrolytes, and of the additives. From the results, we expect that ReaxFF will be very useful for the development of novel electrolytes or additives and for further advances in Li-ion battery technology. PMID- 28593755 TI - Exothermicity Is Not a Necessary Condition for Enhanced Diffusion of Enzymes. AB - Recent experiments have revealed that the diffusivity of exothermic and fast enzymes is enhanced when they are catalytically active, and different physical mechanisms have been explored and quantified to account for this observation. We perform measurements on the endothermic and relatively slow enzyme aldolase, which also shows substrate-induced enhanced diffusion. We propose a new physical paradigm, which reveals that the diffusion coefficient of a model enzyme hydrodynamically coupled to its environment increases significantly when undergoing changes in conformational fluctuations in a substrate concentration dependent manner, and is independent of the overall turnover rate of the underlying enzymatic reaction. Our results show that substrate-induced enhanced diffusion of enzyme molecules can be explained within an equilibrium picture and that the exothermicity of the catalyzed reaction is not a necessary condition for the observation of this phenomenon. PMID- 28593756 TI - Specific Affinity Enrichment of Electrochemically Cleaved Peptides Based on Cu(II)-Mediated Spirolactone Tagging. AB - Specific digestion of proteins is an essential step for mass spectrometry-based proteomics, and the chemical labeling of the resulting peptides is often used for peptide enrichment or the introduction of desirable tags. Electrochemical oxidation yielding specific cleavage C-terminal to tyrosine (Tyr) and tryptophan (Trp) residues provides a potential alternative to enzymatic digestion and a possibility for further chemical labeling by introducing reactive spirolactone moieties. However, spirolactone-containing peptides suffer from low stability due to hydrolysis and intramolecular side reactions. We found that Cu(II) ions stabilize the spirolactone and prevent intramolecular side reactions during chemical labeling, allowing efficient chemical tagging with a reduced excess of labeling reagent without intramolecular side reactions. On the basis of this reaction, we developed an analytical procedure combining electrochemical digestion, Cu(II)-mediated spirolactone biotinylation, and enrichment by avidin affinity chromatography with mass spectrometry. The method was optimized with the tripeptide LWL and subsequently applied to chicken egg white lysozyme, in which one biotinylated electrochemistry (EC)-cleaved peptide was identified after affinity enrichment. This proof-of-principle shows that specific enrichment of electrochemically cleaved spirolactone-containing peptides can be used for protein identification and notably that inclusion of Cu(II) ions is essential for stabilizing spirolactones for subsequent biotinylation. PMID- 28593757 TI - Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, epi-Costaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G, and Dihydrosetoclavine. AB - A new approach for the divergent total synthesis of eight ergot alkaloids is reported. The approach allows the first total syntheses of pyroclavine, pibocin A, 9-deacetoxyfumigaclavine C, and fumigaclavine G and also enables the efficient synthesis of festuclavine, costaclavine, epi-costaclavine, and dihydrosetoclavine. The main feature of the synthesis is the use of an unprecedented Pd-catalyzed intramolecular Larock indole annulation/Tsuji-Trost allylation cascade to assemble the tetracyclic core in one step. PMID- 28593758 TI - Fabrication of Crack-Free Photonic Crystal Films on Superhydrophobic Nanopin Surface. AB - On the basis of their superior optical performance, photonic crystals (PCs) have been investigated as excellent candidates for widespread applications including sensors, displays, separation processes, and catalysis. However, fabrication of structurally controllable large-area PC assemblies with no defects is still a tough task. Herein, we develop an effective strategy for preparing centimeter scale crack-free photonic crystal films by the combined effects of soft assembly and superhydrophobic nanopin surfaces. Owing to its large contact angle and low adhesive force on the superhydrophobic substrate, the colloidal suspension exhibits a continuous retraction of the three-phase (gas-liquid-solid) contact line (TCL) in the process of solvent (water molecules) evaporation. The constantly receding TCL can bring the colloidal spheres closer to each other, which could timely close the gaps due to the loss of water molecules. As a result, close-packed and well-ordered assembly structures can be easily obtained. We expect that this work may pave the way to utilize novel superhydrophobic materials for designing and developing high-quality PCs and to apply PCs in different fields. PMID- 28593759 TI - Enzymatic Synthesis and Purification of Galactosylated Chitosan Oligosaccharides Reducing Adhesion of Enterotoxigenic Escherichia coli K88. AB - Enterotoxigenic Escherichia coli (ETEC) K88 causes diarrhea in weaned piglets and represent a suitable model system for ETEC causing childhood diarrhea. This study aimed to evaluate the effects of oligosaccharides against ETEC K88 adhesion to porcine erythrocytes with two bioassays. Galactosylated chitosan-oligosaccharides (Gal-COS) were synthesized through transgalactosylation by beta-galactosidase. Fractions 2-5 of Gal-COS were obtained through cation exchange and size exclusion chromatography. Fractions 2-5 of acetylated Gal-COS were obtained through chemical acetylation followed by size exclusion chromatography. Gal-COS F2 containing the largest oligosaccharides had the highest antiadhesion activity with the minimum inhibitory concentration of 0.22 g/L, followed by F3 and F4. Acetylation of Gal-COS decreased their ability to reduce ETEC K88 adhesion. The composition of active oligosaccharides was determined with LC-MS. Galactosylation of COS produces oligosaccharides which reduce ETEC K88 adhesion; moreover, resulting oligosaccharides match the composition of human milk oligosaccharides, which prevent adhesion of multiple pathogens. PMID- 28593760 TI - Highly Efficient All-Solution-Processed Fluorescent Organic Light-Emitting Diodes Based on a Novel Self-Host Thermally Activated Delayed Fluorescence Emitter. AB - Here, we conveniently designed and synthesized a self-host thermally activated delayed fluorescence (TADF) emitter, which can not only form a uniform thin film through wet-process, but also allow the subsequently deposition of electron transporting layer (ETL) by orthogonal solvent. By using this self-host material as emitter, the all-solution-processed multilayer TADF organic light emitting diodes (OLEDs) was successfully fabricated. The maximum current, power and external quantum efficiencies of this nondoped device are 46.3 cd A-1, 39.3 lm W1 and 15.5%, respectively, which are much higher than the values of all-solution processed OLEDs based on tranditional fluorescence and even comparable to the TADF devices with vacuum-deposited ETL. Moreover, the device maintains the high efficiency of 42.9 cd A-1 and 39.0 cd A-1 at the luminance of 100 cd m-2 for display and 1000 cd m-2 for practical lighting. The high efficiency and small efficiency roll-off of the all-solution-processed fluorescent OLEDs can be attributed to the superiority of the newly designed self-host TADF emitter, which possesses the perfect electroluminescent property and sufficient solvent resistance at the same time. PMID- 28593761 TI - Enediol-Ligands-Encapsulated Liposomes Enables Sensitive Immunoassay: A Proof-of Concept for General Liposomes-Based Photoelectrochemical Bioanalysis. AB - Sensitive photoelectrochemical (PEC) bioanalysis usually relies on enzyme assisted signal amplification. This work describes the first proof-of-concept study for liposome-based PEC bioanalysis. Specifically, unilamellar liposomes were prepared and then utilized to carry the enediol-ligands and antibodies within their internal cavities and upon their external surfaces, respectively. On the other hand, the 96-well plate was used for accommodating the sandwich immunocomplexing, and then the confined liposomes were directed to release the encapsulated enediol-ligands into an individual well. The subsequent in situ sensitization of the TiO2 nanoparticles (NPs) electrode was then used to transduce the recognition events. This facile strategy allows for sensitive immunoassay without the involvement of laborious electrode fabrication and enzymatic amplification. Importantly, the protocol can be extended as a general PEC method for numerous other targets of interest. We believe this work could offer a new perspective for the rational implementation of various liposome complexes for novel PEC bioanalysis. PMID- 28593762 TI - Chiral-at-Metal Rh(III) Complex Catalyzed Asymmetric Conjugate Addition of Unactivated Alkenes with alpha,beta-Unsaturated 2-Acyl Imidazoles. AB - A newly prepared chiral-at-metal Rh(III) complex catalyzed highly efficient asymmetric conjugate addition of para-vinylanilines with alpha,beta-unsaturated 2 acyl imidazoles is developed, affording the corresponding adducts in 67-95% yields with 86-95% ee. Remarkably, employing as low as 0.05 mol % of Rh(III) complex as catalyst, a gram-scale reaction still affords the desired product in 81% yield with 92% ee. PMID- 28593763 TI - High-Performance Electroactive Polymer Actuators Based on Ultrathick Ionic Polymer-Metal Composites with Nanodispersed Metal Electrodes. AB - Ionic polymer-metal composites (IPMCs) have been proposed as biomimetic actuators that are operable at low applied voltages. However, the bending strain and generating force of the IPMC actuators have generally exhibited a trade-off relationship, whereas simultaneous enhancement of both the qualities is required for their practical applications. Herein, a significant improvement in both the strain and force of the IPMC actuators is achieved by a facile approach, exploiting thickness-controlled ion-exchange membranes and nanodispersed metal electrodes. To guarantee a large generating force of the IPMC actuators, ultrathick ion-exchange membranes are prepared by stacking pre-extruded Nafion films. Metal electrodes with a nanodispersed structure are formed on the membranes via alcohol-assisted electroless plating, which allows increased capacitance and facilitated ion transport. The resulting actuators exhibit greatly enhanced electromechanical properties, including an approximately four times larger strain and two times larger force compared to those of actuators having the conventional structure. Moreover, the ability to lift 16 coins (a weight of 124 g) has been successfully demonstrated using ultrathick IPMC actuators, which shows great promise in realizing artificial muscles. PMID- 28593764 TI - Selective Ring-Opening of N-Alkyl Pyrrolidines with Chloroformates to 4 Chlorobutyl Carbamates. AB - Our study shows that among aza-heterocycles of various ring sizes, including aziridines, azetidines, pyrrolidines, and piperidines, only N-alkyl pyrrolidines undergo competitive reaction pathways with chloroformates to yield N-dealkylated pyrrolidines and 4-chlorobutyl carbamates. The pathway taken depends on the substituent on the nitrogen, i.e., ring-opening with methyl and ethyl substituents and dealkylation with a benzyl substituent. Computational calculations support the substituent-dependent product formation by showing the energy difference between the transition states of both reaction pathways. Selective ring-opening reactions of N-methyl and N-ethyl pyrrolidine derivatives with chloroformates were utilized to prepare various 4-chlorobutyl carbamate derivatives as valuable 1,4-bifunctional compounds. PMID- 28593766 TI - Phase-Defined van der Waals Schottky Junctions with Significantly Enhanced Thermoelectric Properties. AB - We demonstrate a van der Waals Schottky junction defined by crystalline phases of multilayer In2Se3. Besides ideal diode behaviors and the gate-tunable current rectification, the thermoelectric power is significantly enhanced in these junctions by more than three orders of magnitude compared with single-phase multilayer In2Se3, with the thermoelectric figure-of-merit approaching ~1 at room temperature. Our results suggest that these significantly improved thermoelectric properties are not due to the 2D quantum confinement effects but instead are a consequence of the Schottky barrier at the junction interface, which leads to hot carrier transport and shifts the balance between thermally and field-driven currents. This "bulk" effect extends the advantages of van der Waals materials beyond the few-layer limit. Adopting such an approach of using energy barriers between van der Waals materials, where the interface states are minimal, is expected to enhance the thermoelectric performance in other 2D materials as well. PMID- 28593765 TI - Formation of Annular Protofibrillar Assembly by Cysteine Tripeptide: Unraveling the Interactions with NMR, FTIR, and Molecular Dynamics. AB - Both hydrogen-bonding and hydrophobic interactions play a significant role in molecular assembly, including self-assembly of proteins and peptides. In this study, we report the formation of annular protofibrillar structure (diameter ~500 nm) made of a newly synthesized s-benzyl-protected cysteine tripeptide, which was primarily stabilized by hydrogen-bonding and hydrophobic interactions. Atomic force microscopy and field emission scanning electron microscopy analyses found small oligomers (diameter ~60 nm) to bigger annular (outer diameter ~300 nm; inner diameter, 100 nm) and protofibrillar structures after 1-2 days of incubation. Rotating-frame Overhauser spectroscopic (ROESY) analysis revealed the presence of several nonbonded proton-proton interactions among the residues, such as amide protons with methylene group, aromatic protons with tertiary butyl group, and methylene protons with tertiary butyl group. These added significant stability to bring the peptides closer to form a well-ordered assembled structure. Hydrogen-deuterium exchange NMR measurement further suggested that two individual amide protons among the three amide groups were strongly engaged with the adjacent tripeptide via H-bond interaction. However, the remaining amide proton was found to be exposed to solvent and remained noninteracting with other tripeptide molecules. In addition to chemical shift values, a significant change in amide bond vibrations of the tripeptide was found due to the formation of the self-assembled structure. The amide I mode of vibrations involving two amide linkages appeared at 1641 and 1695 cm-1 in the solid state. However, in the assembled state, the stretching band at 1695 cm-1 became broad and slightly shifted to ~1689 cm-1. On the contrary, the band at 1641 cm-1 shifted to 1659 cm 1 and indicated that the -C?O bond associated with this vibration became stronger in the assembled state. These changes in Fourier transform infrared spectroscopy frequency clearly indicated changes in the amide backbone conformation and the associated hydrogen-bonding pattern due to the formation of the assembled structure. In addition to hydrogen bonding, molecular dynamics simulation indicated that the number of pi-pi interactions also increased with increasing number of tripeptides participated in the self-assembly process. Combined results envisaged a cross beta-sheet assembly unit consisting of four intermolecular hydrogen bonds. Such noncovalent peptide assemblies glued by hydrogen-bonding and other weak forces may be useful in developing nanocapsule and related materials. PMID- 28593767 TI - Pd(II)-Catalyzed Arylation and Intramolecular Amidation of gamma-C(sp3)-H Bonds: En Route to Arylheteroarylmethane and Pyrrolidone Ring Annulated Furan/Thiophene Scaffolds. AB - We report the Pd(II)-catalyzed, bidentate directing group (BDG)-assisted arylation and successive arylation/intramolecular amidation of gamma-C(sp3)-H bonds. The Pd(II)-catalyzed BDG-assisted C-H activation and functionalization of the beta-C(sp3)-H bonds of carboxylic acids are well documented, but only a few reports are available that deal with the BDG-directed functionalization of the gamma-C(sp3)-H bonds. Various 3-methylthiophene/furan-2-carboxamides (1a-e) were derived from their corresponding carboxylic acids and bidentate directing groups. These compounds were then used as substrates to investigate the arylation and successive arylation/intramolecular amidation of the gamma-C(sp3)-H bonds. The gamma-C(sp3)-H arylation arose from the Pd(II)-catalyzed reactions of these compounds with aryl iodides with reaction periods of 4-24 h (except a few reactions which required 36 or 48 h). Notably, these reactions led to the construction of various unsymmetrical diarylmethane scaffolds, such as thiophene/furan-based arylheteroarylmethanes (3-6). Prolonging the reaction period to 48-70 h led to successive gamma-C(sp3)-H arylation/intramolecular amidation and the construction of both C-C and C-N bonds. Accordingly, these reactions led to the construction of new classes of pyrrolidone-ring annulated thiophene/furan-based heterocyclic scaffolds (e.g., 4,5-dihydro-6H-thieno[2,3 c]pyrrol-6-ones (8), 4,5-dihydro-6H-furo[2,3-c]pyrrol-6-ones (10), and 1-phenyl 1,2-dihydro-3H-benzo[4,5]thieno[2,3-c]pyrrol-3-ones (12)), and notably, compounds 8, 10, and 12 resemble the skeletons of 3-phenylisoindolin-1-ones. PMID- 28593768 TI - SEM as a Facile Tool for Real-Time Monitoring of Microcrystal Growth during Electrodeposition: The Merit of Ionic Liquids. AB - Due to the extremely low vapor pressure of ionic liquids (ILs), electrochemical deposition/dissolution of hexagonal hollow CuSn alloy tubes in IL can be real time observed with a scanning electron microscope (SEM). Two specially made electrochemical cells are used for the top-view and side-view observations. A series of clear SEM images reveals the hexagonal cones are formed prior to further developing hexagonal tubes. At the beginning, many small nuclei are formed on the electrode surface. Due to the electrodeposition rate being slow enough for the nuclei to crystallize into hexagonal structures, the electrodeposition rate is faster on the periphery than the inside of the structures. As the electrodeposition progresses, the tube wall will grow thicker, and a secondary tube emerges inside the primary tube. Finally, shell-by-shell hexagonal tubes are formed. Furthermore, the in situ SEM observation also reveals that the dissolution of tube starts from its inner wall followed by a sudden collapse of its wall. In this paper, we establish a simple and convenient method, which can be broadly applied to the study of metal, alloy, and semiconductor growth in real time. PMID- 28593769 TI - Structure and Dynamics of a N-Methylfulleropyrrolidine-Mediated Gold Nanocomposite: A Spectroscopic Ruler. AB - A mechanistic understanding of the structure and dynamics of a chemically tunable N-methylfulleropyrrolidine (8-NMFP)-assisted gold nanocomposite and its aggregation via a controllable interparticle interaction is reported as a function of the molar ratio and pH of the medium. Electronic structure calculations adopting density functional theory methods implied electrostatic interactions to play a dominant role between 8-NMFP and citrate-capped gold nanoparticles. MM+ molecular mechanics force field computations revealed intermolecular gold-gold interactions, contributing toward the formation of spherical composite aggregates. Corroborating these, optical absorption spectra showed the usual surface plasmon band along with a higher-wavelength feature at ~600-650 nm, indicative of the aggregated nanocomposite. pH-controlled reversible tuning of the plasmonic features in the composite was evident in a pH interval ~5 6.8, revealing prevalent interparticle electrostatic interactions. In addition, photoluminescence (PL) and time-correlated single-photon counting studies revealed a strong nanocomposite interaction with a pure fluorescent dye, Rhodamine B, indicating excitation energy transfer from the dye to the composite. The dye upon interaction with the nanocomposite showed a significant quenching of its PL intensity and shortening of lifetime. Energy coupling between the metal nanoparticle composite and the emitting molecular dipole resulted in a long-range surface energy transfer (SET) from the donor dye to the surface plasmon modes of the nanoparticle following a donor-acceptor distance dependence of 1/r4. This molecular beacon with correlation between the nanoscale structure and the nonradiative nanometal SET can be used as a spectroscopic/molecular ruler in probing advanced functional materials. PMID- 28593770 TI - [Retrospective analysis of monochorionic twin pregnancies born in the Institute for the Care of Mother and Child between 2012-2015]. AB - OBJECTIVE: The purpose of this study was to describe monochorionic twin pregnancies and their complications, born between 24th and 37th week of gestation in the Institute for the Care of Mother and Child in years 2012-2015. DESIGN: Retrospective cohort. SETTING: The Institute for the Care of Mother and Child, Praha. METHODS: From 2012 to 2015 we observed 177 monochorionic twin pregnancies from which two or one viable fetuses were born, or both fetuses died in utero. RESULTS: From a total of 177 women, 12 (6.8%) gave birth before 26th week of gestation, between 26+0 - 27+6 four women (2.3%) gave birth, 37 women (20.9%) between 28+0 - 31+6, 84 women (47.8%) between 32+0 - 35+6 and after 36th week of gestation 40 women (22.6%) gave birth. Mean week of delivery was 33.8. Indications for termination of pregnancies were premature rupture of membranes (PPROM) in 11.9%, onset of spontaneus uterine contractions in 12.4% and in 53.3% other iatrogenic indication. 23.3% of pregnancies in our cohort were uncomplicated and terminated after 36th week of gestation. We performed caesarean section in 94.3%, in 5.7% patients gave birth vaginally. In vitro fertilization had 19.9% women, 80.1% conceived spontaneously. The age range of pregnant women in our cohort was 20-43, with median 32.3. Mean weight of bigger fetus was 2047.6 g (min. 520 g, max. 3530 g), mean weight of smaller fetus was 1799.5 g (min. 350 g, max. 2790 g). In 30 cases (16. 9%) we performed intrauterine intervetion. In 21/30 cases (11.9%) for TTTS diagnose, in 5/30 cases (2.8%) for congenital abnormalities or TRAP sequence and in 4/30 cases (2.2%) for sIUGR type III. The most frequent complication in our cohort was sIUGR (36 patients - 20.3%), TTTS (21 patients - 11.9%) and on the third place congenital abnormality or TRAP sequence (five patients - 2.8%) Nineteen patients gave birth to one viable fetus, in two cases both fetuses died in utero. In one case, in twin pair, one new-born died shortly after the birth - it had several congenital abnormalities and due to anhydramnion it was impossible to perform amnioinfusion and umbilical cord occlusion. After the birth it was given palliative care. CONCLUSION: The study brought data about specific risks in monochorionic twin pregnancies and suggests careful observation of women in fixed intervals and necessity of immediate referral to perinatal centre in case of any suspicious or pathological finding. PMID- 28593771 TI - [Rare forms of feto-fetal transfusion in a clinical practice]. AB - OBJECTIVE: To analyze monochorionic twin pregnancies with twin anemia polycythemia sequence (TAPS) and acute peripartal twin to twin syndrome (aTTTS), to compare their prenatal management and perinatal outcome. METHODS: Retrospective analysis of monochorionic biamniotic twin pregnancies without signs of chronic TTTS within a period 10/2010 to 10/2013. Further selection of cases with haemoglobin difference in neonates greater than 50 g/l was made, type of feto-fetal haemorrhage was determined and their prenatal and postnatal characteristics were described. RESULTS: Based on the criteria described above we selected four cases out of 55 monochorionic pregnancies. One case of prenatally diagnosed spontaneous TAPS which fulfilled all the diagnostic criteria with typical angioarchitecture inclusive, one case of spontaneous TAPS diagnosed postnatally, a case of postlaser TAPS with a spontaneous resolution and one unusual case of feto-fetal haemorrhage which does not fully meet criteria of TAPS or aTTTS. All the pregnancies were delivered by caesarean section. All the anaemic neonates required blood transfusion postpartum and two of the polycythemic neonates needed partial exsanguination. CONCLUSION: Rare forms of feto-fetal transfusion syndrome form a heterogenous group and it may be difficult to distinguish between TAPS and aTTTS in certain cases. A recommendation for a management of TAPS cases was published in recent literature. However, correct interpretation of dopplerometric measurments belongs to the hands of experienced ultrasonographers in perinatal centers. PMID- 28593772 TI - [Complications arising out of insufficient reporting of clinical data to the pathologist investigating placentas]. AB - OBJECTIVE: To inform gynecologists-obstetricians about the problems associated with pathological examination of placentas, with special regard to the possibility of crucial role of complete and relevant clinical data in establishing the correct pathological diagnosis. DESIGN: Case report and overview of the problems associated with examination of placentas by pathologist. SETTING: Sikl's Institute of Pathology, Faculty Hospital and Medical Faculty Pilzen of the Charles University in Prague; Biopticka laborator, s.r.o., Pilzen. METHODS: Own observation in the setting of routine pathological examination. RESULTS: Case report representing a typical complication resulting from insufficient interdisciplinary communication describes a case of unsatisfactory result of pathological investigation of placenta due to the missing clinical information about complications of the late phase of pregnancy which eventually led to intrauterine death of the fetus. Due to the absence of the clinical information of paramount importance, the initial investigation of placenta was untargeted and thus imperfect. Therefore, the primary investigation of the placenta did not reveal pathological changes responsible for the complications of pregnancy. It was only the revision of material necessitated by the information additionally conveyed by gynecologist-obstetrician leading to the final correct pathological diagnosis, which even averted the possibility of serious forensic consequences. CONCLUSION: The basic prerequisite for proper pathological examination of placenta is sharing the available clinical data with the pathologist performing the morphological investigation, mainly focusing on complications of pregnancy. Lack of such information causes examination of placenta more difficult and sometimes even unable to interpret, as the interpretation of morphological changes of placenta have to interpreted in the context of clinical data on the course of pregnancy. Regarding the extreme emotional and possibly even legal consequences of lethal complications of pregnancy or delivery, the correct pathological diagnosis may be of crucial importance. PMID- 28593773 TI - [HELLP syndrome requiring therapeutic plasma exchange due to progression to multiple organ dysfunction syndrome with predominant encephalopathy, respiratory and renal insufficiency]. AB - OBJECTIVE: Case report of woman with twin pregnancy complicated by HELLP syndrome which progressed to multiple organ dysfunction syndrome with predominant encephalopathy, renal and respiratory insufficiency with the need to perform repeated therapeutic plasma exchange. DESIGN: Case report. SETTING: Department of gynecology and obstetrics, University Hospital in Ostrava; Departmet of hematooncology, University Hospital in Ostrava; Department of gynecology and obstetrics, Vsetin hospital; Department of hematology and transfusion, Vsetin Hospital. RESULTS: Case of 35-year-old III gravida/II para with previously normal ongoing twin bichorionic biamniotic pregnancy in week 35+0, which was admitted to secondary care delivery room for three days lasting "flu like" symptoms and the right upper quadrant pain. She was icteric, exhausted, but normotensive (120/75 mm Hg). Acute caesarean section was performed for suspected fetal hypoxia and HELLP syndrome. The laboratory exams confirmed coagulopathy and HELLP syndrome second class during the operation. Blood loss was 800 ml. Despite standard treatment of HELLP syndrome, the condition had developed to renal insufficiency, bilateral fluidothorax, alveolar pulmonary edema, encephalopathy and hypertension. In laboratory results dominates markers of coagulopathy, thrombocytopenia and microangiopathic hemolytic anemia with presence of schistocytes. Due to multiple organ dysfunction syndrome with hemolysis of unclear origin, patient was transferred to referral hospital on sixth postoperative day. Therapeutic plasma exchange (TPEX) was promptly begun. Improvement of laboratory parameters occurred already after the first TPEX and after two days there was a significant improvement of neurological status. Nine TPEX procedures were performed. The treatment was terminated after platelet count reached 100*109/l. She was discharged from hospital 21 days after delivery. After exclusion of other clinical entities, the case was closed as postpartum thrombotic microangiopathic syndrome. CONCLUSION: Postpartum thrombotic microangiopathic syndrome includes states, which resemble HELLP syndrome with their laboratory result and clinical expression, but their behavior is different progressively worsening with signs of disseminated intravascular coagulation and complex microangiopathy with multiple organ dysfunction. It is not responding to classic treatment of HELLP syndrome. In this cases usually improvement of patients condition follow initiation of therapeutic plasma exchange. PMID- 28593774 TI - [Two years of pharmacological termination of pregnancy in the Silesian hospital Opava, success and lessons]. AB - OBJECTIVE: The purpose of this study was to summarize our departments experience with pharmacological termination of pregnancy up to 49 days of amenorrhea, to assess the success, and especially, to offer a closer analysis of the complications of this method. DESIGN: Retrospective analysis. SETTING: Department of Gynaecology and Obstetrics at the Silesian Hospital. METHODS: The monitored sample consisted of 161 female patients who underwent pharmacological termination of pregnancy at our department from 1. 7. 2014 to 30. 6. 2016 being administered 600 mg of mifepristone (Mifegyne) and 400 ug of misoprostol (Mispregnol). Within the sample of patients we observed the objective process of pharmacological termination of pregnancy with special attention being payed to an analysis of complications. We compared the number of complications occurred under classic surgical intervention and those occurred under pharmacological termination of pregnancy. RESULTS: A complete abortion without the necessity of surgical intervention occurred with 151 patients (93.79%) of whom 15 patients with administering uterotonic medicaments. Ten patients (6.21%) required a consequent instrumental revision of the uterine cavity, seven of them (70%) had a history of surgical intervention in the uterine cavity. In case of one patient persisted vital pregnancy. Two patients underwent medical termination of pregnancy twice. In one case there were twins. CONCLUSION: The method of pharmacological pregnancy termination has a good efficiency, it is safe with minimal side effects. PMID- 28593775 TI - [The importance of maternal microbiome in pregnancy]. AB - OBJECTIVE: To bring the most actual published findings of the influence of maternal microbiome on the development of pregnancy and possibilities of its adjusting. DESIGN: Review. SETTING: 2nd Department of Gyneacology and Obstetrics of the Faculty of Medicine and the University Hospital, Bratislava. METHODS: Review of the literature. CONCLUSIONS: The appearance of microbes on various body surface areas determines the overall health status of the individual in significant manner. The change in composition of microbioma in pregnant woman is well known. It was believed that the placenta and the body of the newborn is sterile environment. Modern diagnostic methods proved the presence of microorganisms inside the fetoplacentar unit without the signs of inflammation. Mutual interaction between the immune system of the mother, microbioma and immune system of the newborn can decrease the risk of serious obstetrical syndromes as well as define the lifelong health status of the newborn. The risk can be decreased by the administration of probiotics during the pregnancy. PMID- 28593776 TI - [Ultrasound staging of stage I-II endometrial cancer, analysis of own file in the years 2012-2016]. AB - OBJECTIVE: The aim of the presented study was to evaluate the accuracy of ultrasound staging of early stage endometrial cancer depending on grading, evaluation of ultrasound examination accuracy growing overtime with gained experience of examiners and comparison of subjective versus objective modalities of deep myometrial invasion assessment in the file of patients who were referred in The Oncogyneacologic Center, Department of Gyneacology and Obstetrics in Ceske Budejovice. DESIGN: Retrospective study. SETTINGS: Department of Gyneacology and Obstetrics, Hospital Ceske Budejovice a.s.Methods and the file: In this arcticle we retrospectively evaluate the file of 136 patients with early stage endometrial cancer. The patients underwent diagnostic and therapeutic procedures during the years 2012-2016 in our department. All these patients were able to be compared in different aproaches to deep myometrial invasion assessment using ultrasound examination. RESULTS: Comparing the used methods of deep myometrial invasion assessment with ultrasound examination of early stage endometrial cancer patients the examiner's subjective evaluation seems to be the best approach. After the first year of doing these assessments sensitivity performed 80%, specificity 79% and infiltration of cervix sensitivity 70% and specificity 99%. In case the patients were divided into groups according to the grading, low grade assessed worst sensitivity 64% (high grade l00%), but the best specificity 75% (high grade 56%). The evaluation of objective approaches of ultrasound assement with used cut offs performed the best sensitivity 81% tumour free minimal margin (specificity 67%). On the contrary the best specificity 90% performed the ratio AP (anteroposterior) diameter tumour/AP diameter uterine (senzitivity 54%). CONCLUSION: Generally in oncological therapy the most important things to put stress on the very accurate staging of oncological disease. In oncogyneacology ultrasound becomes more and more required examination. In our file we proved the significance of ultrasound examination in diagnostics and staging of endometrial cancer and we also proved that the accuracy level in early stage depends on the examiner's experience. After one year practice our results reach the level of the results presented globally, no matter which of the methods - ultrasound MRI or frozen section - was used. PMID- 28593777 TI - [Aggressive angiomyxoma - case report]. AB - OBJECTIVE: We present a case report of 47-years old woman with a rare mesenchymal tumor misdiagnosed as a cyst Bartholins gland. DESIGN: Case report. SETTING: Department of Gynecology, Hospital Atlas, EUC, in ZlinConclusion: Aggressive angiomyxoma is a rare mesenchymal tumor, which is occuring more in women, affects the vulva, perineum and pelvis. Typical is slowly and infiltrative growth with high-risk of local recurence. PMID- 28593778 TI - [Current FIGO staging classification for cancer of ovary, fallopian tube and peritoneum]. AB - INTRODUCTION: Pelvic high-grade serous carcinomas (HGSCs) include carcinoma of ovary, fallopian tube, and peritoneum. Five-year survival, irrespective of the stage, is between 35-40%. Most patients are diagnosed in advanced stages of the disease. The new revised and expanded dualistic model of ovarian carcinogenesis shows that type II tumors are composed for the most part of high-grade serous ovarian carcinoma, carcinosarcoma, undifferentiated carcinoma and can be further subdivided into morphologic and molecular subtypes. Many type II carcinomas develop from STIC predominantly in the distal portion of the fallopian tube and it is very likely the point of the origin of a significant subset of the pelvic high-grade serous carcinomas. OBJECTIVE: To provide an overview of major changes in our understanding of the origin of ovarian cancer, that led to the revision of FIGO (International Federation of Gynecology and Obstetrics) classification and its unification for the ovary, fallopian tube and peritoneum. We summarize the new classification, main changes compared to the former one and their clinical impact. METHODS: For this review, we have used the results of studies and review articles on the subject published in English up to October 2016. They were identified through a search of literature using PubMed, MEDLINE-Ovid, Scopus and Cochrane Library with the keywords ("serous tubal intraepithelial carcinoma" or "high-grade serous ovarian carcinoma" or "FIGO ovarian cancer staging 2014"). We retrieved and assessed potentially relevant studies, and checked the reference lists of all papers of interest to identify additional relevant publications. CONCLUSION: The origin of most cases of pelvic HGSC (carcinoma of ovary, the fallopian tube, and peritoneum) is expected in the fallopian tube epithelium. The main changes in the revised FIGO classification for extrauterine pelvic serous carcinomas were subdivision of stages IC, III and IV and elimination of the stage IIC, based on new knowledge and prognostic data. A prerequisite for the proper treatment of patients is to perform adequate surgical and pathological staging, including determining the grade of carcinoma. These factors, coupled with appropriately performed operation with zero postoperative residuum (R0), are the most important prognostic factors for patients with carcinoma of the ovary, fallopian tube, and peritoneum. PMID- 28593779 TI - [Hirsutism]. AB - OBJECTIVE: Overview of excessive hair growth in women, hirsutism. Although women with hirsutism typically present because of cosmetic concerns, the majority also have an underlying endocrine disorder. DESIGN: Review article. SETTING: Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Faculty of Medicine of Charles Universtity, Prague. MATERIAL AND METHODS: Hirsutism is a clinical diagnosis defined by the presence of excess terminal hair growth (dark, coarse hairs) in androgen-sensitive areas. It affects between five and ten percent of women of reproductive age. It may be the initial, and possibly only, sign of an underlying androgen disorder. CONCLUSIONS: The most common cause of hirsutism is polycystic ovary syndrome (PCOS). In some cases, hirsutism is mild and requires only reassurance and local (nonsystemic) therapy, while in others it causes significant psychological distress and requires more extensive therapy. In case of rapid progressive hair growth should be first exclude androgen-secerning tumour (ovarian, adrenal) as the most serious condition. PMID- 28593780 TI - [Complications tension-free vaginal tape surgery]. AB - OBJECTIVE: A comprehensive overview of the potential complications associated with vaginal tape operations, which are commonly used in the treatment of stress urinary incontinence in women. DESIGN: Review article. SETTING: Department of Obstetrics and Gynecology, Oblastni nemocnice Kolin, a.s. METHODS: Using medical databases were searched articles dealing with complications tension-free vaginal tape procedures. In individual cases, complications were observed their causes and solutions. RESULTS: Complications were divided into three groups according to the time of their formation due to the operation performed. Intra-operative complications are further divided into a group of severe, when they were wound blood vessels, nerves and bowel. For less serious complications result in injuries to the bladder, vagina injuries. Among peri-operative complications include retropubic hematoma, blood loss > 200 mL and urinary tract infections. The last group are the post-operative complications and transient urinary retention, persistent urinary retention, vaginal erosion, urethral erosion, abscess, actinomycosis, de novo urgency, erosion, bladder, urethral obstruction. Further complications were compared by the method of keeping tapes - retropubic and transobturator procedure. CONCLUSION: Minimally invasive treatment of stress urinary incontinence is not without serious long-term complications and their successful resolution can be a problem. Knowledge of the specifics of individual surgical procedures and their limitations. Given the statements FDA-party use of foreign material in reconstructive procedures for stress incontinence is required safest choice material tapes. Furthermore, the operation was carried out by a surgeon familiar with the method and at the same time able to solve any problems. PMID- 28593781 TI - Influence of type 2 diabetes mellitus on Khorana venous thromboembolism risk in colorectal cancer patients. AB - BACKGROUND: Many studies have documented the association between venous thromboembolism (VTE) and colorectal cancer (CRC). The Khorana model is a VTE risk assessment model for predicting cancer-associated thrombosis. Type 2 diabetes (T2DM) has also been reported to increase the risk of VTE. PURPOSE: The aim of this study was to investigate the influence of T2DM on Khorana VTE risk in CRC patients and to explore the relationship between Khorana VTE category and CRC clinicopathological factors. METHODS: This analysis included 615 CRC patients (205 with T2DM). Fibrinogen and D-dimer levels were compared within each group. A comparison was made of the proportion of patients in different Khorana VTE risk categories in CRC patients with and without T2DM. The association between Khorana VTE risk category and clinicopathological factors among all the CRC patients was evaluated. RESULTS: Fibrinogen levels of CRC patients with T2DM were significantly higher than those of non-diabetes patients (4.13 +/- 1.06 vs 3.94 +/- 0.98, p < 0.001). A higher proportion of CRC patients with T2DM were in the Khorana intermediate-to-high risk category (H = 4.749, p = 0.029). Female sex, diabetes, colon location (compared with rectum), larger tumor size, advanced pT stage and pN stage were correlated with the intermediate-to-high Khorana VTE risk category, with odd ratios (95% confidence intervals [CI]) of 1.537 (1.064-2.220), 1.499 (1.027-2.186), 2.313 (1.588-3.370), 2.284 (1.542-3.383), 4.429 (2.088 9.396) and 1.822 (1.230-2.698), respectively. CONCLUSION: T2DM increases Khorana VTE risk in CRC patients. Female sex, diabetes, colon location, large tumor size and poor stage are associated with the intermediate-to-high Khorana VTE risk category. PMID- 28593782 TI - The impact of screening on short-term outcome after surgery for colorectal cancer. AB - AIM: To investigate the influence of a screening program on the short-term outcome of patients undergoing surgery for colorectal cancer. METHODS: Between April 2010 and December 2012 patients diagnosed with colorectal cancer via the screening program (n = 80) were compared with patients diagnosed elsewhere (n = 106). Only patients of >= 50 and <= 69 years of age diagnosed outside the program were selected as controls. The clinical variables included age, sex, American Society of Anesthesiologists (ASA) status, Charlson index, preoperative hemoglobin and serum albumin levels, surgical approach, tumor location and stage, perioperative transfusion and postoperative morbidity. A multivariate analysis was used to identify variables independently associated with outcome. RESULTS: There were no significant differences with regard to age, sex and ASA status. Preoperative hemoglobin (14.1 +/- 1.6 g/dl vs 12.3 +/- 2.3 g/dl; p < 0.001) and serum albumin (4.45 +/- 0.26 g/dl vs 4.0 +/- 0.6 g/dl; p < 0.001) levels were significantly higher in the screening group. The overall morbidity was significantly lower in the screening group (38.8% vs 63.2; p < 0.001) and mainly related to a higher rate of Clavien-Dindo grade II complications in controls. There were no differences with regard to wound infection, postoperative ileus, anastomotic leakage or reoperations. The median length of hospital stay was shorter in the screening group (6 vs 9 days; p = 0.003). Multivariate analysis showed that diagnosis outside the screening program, type of surgical procedure, open surgery and Charlson index were independent risk factors for postoperative complications. CONCLUSIONS: The diagnosis of colorectal cancer via the screening program is associated with a lower rate of postoperative minor complications and a shorter hospital stay. PMID- 28593783 TI - Colonic lesions in patients undergoing small bowel capsule endoscopy: incidence, diagnostic and therapeutic impact. AB - BACKGROUND: Nowadays, capsule endoscopy is the first-line procedure to assess the small bowel. During small bowel procedures, other segments of the gastrointestinal tract may be visualized. The aim of the current study was to evaluate the incidence of colonic abnormalities in patients undergoing small bowel capsule and its impact on patient management. PATIENTS AND METHODS: This study is a retrospective analysis of data from 526 consecutive capsule endoscopy procedures performed at a single tertiary-care centre between 2008 and 2011. Patients with incomplete procedures were excluded from the analysis. Patient baseline characteristics, colonic lesions, diagnosis and management before and after capsule endoscopy were recorded and a descriptive analysis was performed. RESULTS: Four hundred and sixty four patients were finally included in the analysis. Two hundred and ninety three patients were male (57.3%) and the mean age was 61.3 +/- 20.03 years (18-86). Obscure gastrointestinal bleeding (59%) and inflammatory bowel disease (19%) were the main indications for the procedure. Colonic abnormalities were detected by capsule endoscopy in 47 (9%) of 464 patients. The most common types of missed lesions were vascular lesions (34%) and colonic ulcers (32%). This information had a clinical or diagnostic impact of 7.55% and a therapeutic impact of 6.03%. CONCLUSION: All images of the colon should be evaluated during small bowel capsule endoscopy as they may provide relevant information that may result in changes in patient management. PMID- 28593784 TI - Abdominal compartment syndrome secondary to acute necrotizing pancreatitis. AB - Severe acute pancreatitis occurs in around 20% of patients and is associated with mortality rates between 8-40%. Abdominal compartment syndrome is a fatal complication that is associated with new organ failure or acute worsening of existing organ failure and has an associated mortality of around 60%. Intra abdominal pressure measurements are recommended in patients with risk factors for intra-abdominal hypertension or abdominal compartment syndrome. Management should be based on a step-up method and surgical intervention may be indicated when conservative treatment fails. PMID- 28593785 TI - Endoscopically placed stents: a useful alternative for the management of refractory benign cervical esophageal stenosis. AB - INTRODUCTION: Benign esophageal strictures are relatively frequent and can severely affect the quality of life of a patient. Stenting has been proposed for the treatment of refractory cases. Lesions affecting the cervical esophagus are more difficult to treat, and the placement of stents in this location has traditionally been restricted due to potential adverse events. The aim of this study was to describe the efficacy and safety of endoscopic stenting in the management of refractory benign cervical esophageal strictures (RBCES) in a single-center cohort study. METHODS: We analyzed 12 patients with RBCES (Kochman's criteria) and severe dysphagia. We recorded previous endoscopic treatments, stricture characteristics and demographic data. The two types of stents used were fully covered self-expandable metallic stents (FCSEMS) and uncovered biodegradable stents (BDS). FCSEMS were removed eight weeks after placement, and BDS were followed-up until degradation. We assessed technical and clinical success, rate of stricture recurrence and adverse events. RESULTS: The mean age of participants was 64 years (range 30-85). A total of 23 stents (13 FCSEMS and 10 BDS) were placed in 12 patients (median 1.92, range 1-4). The technical success rate was 96% (22/23 stents). Eight patients (66.6%) maintained adequate oral intake at the end of follow-up (median 33.3 months, range 3-84 months). Migration was recorded in 7/23 stents (30.4%) and epithelial hyperplasia in 4/23 stents (17.4%). No severe adverse events were noted. All patients complained of minor cervical pain after placement that was well controlled with mild analgesia. CONCLUSIONS: Endoscopic stent therapy seems to be effective and safe in the management of RBCES. PMID- 28593786 TI - Characterization of liver changes in ZSF1 rats, an animal model of metabolic syndrome. AB - BACKGROUND: The non-alcoholic fatty liver disease is the hepatic counterpart of the metabolic syndrome. ZSF1 rats are a metabolic syndrome animal model in which liver changes have not been described yet. AIM: The characterization of liver histological and innate immunity changes in ZSF1 rats. METHODS: Five groups of rats were included (n = 7 each group): healthy Wistar-Kyoto control rats (Ctrl), hypertensive ZSF1 lean (Ln), ZSF1 obese rats with a normal diet (Ob), ZSF1 obese rates with a high-fat diet (Ob-HFD), and ZSF1 obese rats with low-intensity exercise training (Ob-Ex). The animals were sacrificed at 20 weeks of age, their livers were collected for: a) measurements of the area of steatosis, fibrosis and inflammation (histomorphological analysis); and b) innate immunity (toll-like receptor [TLR] 2, TLR4, peroxisome proliferator-activated receptor gamma [PPARgamma], toll interacting protein [TOLLIP]) and inflammatory marker (tumor necrosis factor-alpha [TNFalpha], interleukin 1 [IL-1]) expression analysis by real-time PCR. RESULTS: Ob, Ob-HFD and Ob-Ex were significantly heavier than Ln and Ctrl animals. Ob, Ob-HFD and Ob-Ex animals had impaired glucose tolerance and insulin resistance. ZSF1 Ob, Ob-HFD and Ob-Ex presented a higher degree of steatosis (3,5x; p < 0.05) than Ctrl or ZSF1 Ln rats. Steatohepatitis and fibrosis were not observed in any of the groups. No differences in expression were observed between Ctrl, Ln and Ob animals (except for the significantly higher expression of TOLLIP observed in the Ob vs Ln comparison). Ob-HFD and Ob Ex rats showed increased expression of PPARgamma and TOLLIP as compared to other groups. However, both groups also showed increased expression of TLR2 and TLR4. Nevertheless, this did not translate into a differential expression of TNFalpha or IL-1 in any of the groups. CONCLUSION: The ZSF1 model is associated with liver steatosis but not with steatohepatitis or a significantly increased expression of innate immunity or inflammation markers. PMID- 28593787 TI - Cholangitis after endoscopic retrograde cholangiopancreatography: a rare complication? AB - In our experience, post-ERCP acute cholangitis developed in approximately 5% of cases with a not negligible mortality of nearly 30% in spite of antibiotic therapy. Analytical factors can help to identify the most serious cases that could benefit from a more aggressive approach. PMID- 28593788 TI - A complication following a biopsy sample in eosinophilic esophagitis. AB - We present a case of a young 16 year old patient that had an esophageal perforation in the context of eosinophilic esophagitis. The esophagus showed vertical lacerations and mucosal thickness on endoscopy, thus a biopsy was performed in the proximal section which resulted in profuse bleeding due to a deep mucosal tear. A subsequent computed tomography scan revealed a perforation. Due to the absence of symptoms the patient was managed conservatively. The patient was discharged within 48 hours after admission. The histopathology analysis showed a massive eosinophilic infiltration of the mucosa that verified the clinical suspicion. PMID- 28593790 TI - Molecular diagnostics for hereditary hearing loss in children. AB - INTRODUCTION: Hearing loss (HL) is the most common birth defect in industrialized countries with far-reaching social, psychological and cognitive implications. It is an extremely heterogeneous disease, complicating molecular testing. The introduction of next-generation sequencing (NGS) has resulted in great progress in diagnostics allowing to study all known HL genes in a single assay. The diagnostic yield is currently still limited, but has the potential to increase substantially. Areas covered: In this review the utility of NGS and the problems for comprehensive molecular testing for HL are evaluated and discussed. Expert commentary: Different publications have proven the appropriateness of NGS for molecular testing of heterogeneous diseases such as HL. However, several problems still exist, such as pseudogenic background of some genes and problematic copy number variant analysis on targeted NGS data. Another main challenge for the future will be the establishment of population specific mutation-spectra to achieve accurate personalized comprehensive molecular testing for HL. PMID- 28593792 TI - A Sensitive Photometric Procedure for Cobalt Determination in Water Employing a Compact Multicommuted Flow Analysis System. AB - In this work, a multicommuted flow analysis procedure is proposed for the spectrophotometric determination of cobalt in fresh water, employing an instrument setup of downsized dimension and improved cost-effectiveness. The method is based on the catalytic effect of Co(II) on the Tiron oxidation by hydrogen peroxide in alkaline medium, forming a complex that absorbs radiation at 425 nm. The photometric detection was accomplished using a homemade light emitting-diode (LED)-based photometer designed to use a flow cell with an optical path-length of 100 mm to improve sensitivity. After selecting adequate values for the flow system variables, adherence to the Beer-Lambert-Bouguer law was observed for standard solution concentrations in the range of 0.13-1.5 ug L-1 Co(II). Other useful features including a relative standard deviation of 2.0% (n = 11) for a sample with 0.49 ug L-1 Co(II), a detection limit of 0.06 ug L-1 Co(II) (n = 20), an analytical frequency of 42 sample determinations per hour, and waste generation of 1.5 mL per determination were achieved. PMID- 28593789 TI - Prevalence and outcome of patients with cancer and acute coronary syndrome undergoing percutaneous coronary intervention: a BleeMACS substudy. AB - BACKGROUND: The prevalence and outcome of patients with cancer that experience acute coronary syndrome (ACS) have to be determined. METHODS AND RESULTS: The BleeMACS project is a multicentre observational registry enrolling patients with acute coronary syndrome undergoing percutaneous coronary intervention worldwide in 15 hospitals. The primary endpoint was a composite event of death and re infarction after one year of follow-up. Bleedings were the secondary endpoint. 15,401 patients were enrolled, 926 (6.4%) in the cancer group and 14,475 (93.6%) in the group of patients without cancer. Patients with cancer were older (70.8+/ 10.3 vs. 62.8+/-12.1 years, P<0.001) with more severe comorbidities and presented more frequently with non-ST-segment elevation myocardial infarction compared with patients without cancer. After one year, patients with cancer more often experienced the composite endpoint (15.2% vs. 5.3%, P<0.001) and bleedings (6.5% vs. 3%, P<0.001). At multiple regression analysis the presence of cancer was the strongest independent predictor for the primary endpoint (hazard ratio (HR) 2.1, 1.8-2.5, P<0.001) and bleedings (HR 1.5, 1.1-2.1, P=0.015). Despite patients with cancer generally being undertreated, beta-blockers (relative risk (RR) 0.6, 0.4 0.9, P=0.05), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (RR 0.5, 0.3-0.8, P=0.02), statins (RR 0.3, 0.2-0.5, P<0.001) and dual antiplatelet therapy (RR 0.5, 0.3-0.9, P=0.05) were shown to be protective factors, while proton pump inhibitors (RR 1, 0.6-1.5, P=0.9) were neutral. CONCLUSION: Cancer has a non-negligible prevalence in patients with acute coronary syndrome undergoing percutaneous coronary intervention, with a major risk of cardiovascular events and bleedings. Moreover, these patients are often undertreated from clinical despite medical therapy seems to be protective. Registration:The BleeMACS project (NCT02466854). PMID- 28593791 TI - Eosinophil-rich tissue infiltrates in chronic myelomonocytic leukemia patients. AB - Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder that associates dysplastic and proliferative features. Tissue inflammatory disorders occur in a fraction of CMML patients during the course of their disease. Here, we describe the occurrence of eosinophil-rich tissue inflammation, including eosinophilic pneumonia, chondritis, and cystitis, in CMML patients. Whole exome sequencing of leukemic cells did not identify a recurrent genetic abnormality among these three patients who were clinically improved by local or oral corticosteroids. Hypomethylating drugs were subsequently added in two of them, allowing decreasing corticosteroid doses and further treating their hematopoietic malignancy. PMID- 28593793 TI - Erratum. AB - Yuka A, Tan J, Baibergenova A, Barankin B, Cochrane CL, Humphrey S, Lynde CW, Marcoux D, Poulin Y, Rivers JK, Sapijaszko M, Sibbald RG, Toole J, Ulmer M, Zip C. Canadian Clinical Practice Guidelines for Rosacea. J Cutan Med Surg. 2016;20(5):432-445. Original DOI: 10.1177/1203475416650427 In the above article, the author affiliation for Ulmer M should have been listed as Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada and Carruthers & Humphrey, Vancouver, BC, Canada. The affiliation for Rivers JK should have been listed as Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada and Pacific DermAesthetics, Vancouver, BC, Canada. PMID- 28593795 TI - Reply to the letter by Siamak Sabour. PMID- 28593794 TI - CtHtrA: the lynchpin of the chlamydial surface and a promising therapeutic target. AB - Chlamydia trachomatis is the most prevalent sexually transmitted bacterial infection worldwide and the leading cause of preventable blindness. Reports have emerged of treatment failure, suggesting a need to develop new antibiotics to battle Chlamydia infection. One possible candidate for a new treatment is the protease inhibitor JO146, which is an effective anti-Chlamydia agent that targets the CtHtrA protein. CtHtrA is a lynchpin on the chlamydial cell surface due to its essential and multifunctional roles in the bacteria's stress response, replicative phase of development, virulence and outer-membrane protein assembly. This review summarizes the current understanding of CtHtrA function and presents a mechanistic model that highlights CtHtrA as an effective target for anti Chlamydia drug development. PMID- 28593796 TI - The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis. AB - Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low , low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk. PMID- 28593797 TI - Suicidal behaviors among newly diagnosed people living with HIV in Changsha, China. AB - Newly-diagnosed people living with HIV (NPLWH) are at high risk of suicide. We aimed to evaluate the prevalence of suicidal behaviors among NPLWH, and explore the relationships between HIV-related stress, depression, anxiety, and social support and suicidal ideation after diagnosed with HIV infection. A cross sectional study was conducted using a standard set of questionnaires during 1 March 2013 and 30 September 2014 in the HIV/AIDS Voluntary Counseling and Testing Clinic of the Changsha Center for Disease Control and Prevention. Among 557 NPLWH, 27.5% (n = 153) had lifetime suicidal ideation, and 25.0% (n = 139) had suicidal ideation after HIV diagnosis. The results of multiple regression analyses indicated that suicidal ideation after HIV diagnosis was associated with HIV-related clinical symptoms (OR = 2.50), HIV-related stress (OR = 3.64), the co morbidity of positive depressive and anxiety symptoms (OR = 3.30), and social support (OR = 0.52). Overall, the prevalence of suicidal behaviors is high among NPLWH in Changsha emphasizing the need of suicidality monitoring and tracking, depression and anxiety screening, with an additional focus on stress management and social support enhancement in this vulnerable group. PMID- 28593798 TI - Nocebo in motor neuron disease: systematic review and meta-analysis of placebo controlled clinical trials. AB - INTRODUCTION: Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in placebo-controlled randomised clinical trials (RCTs) for motor neuron disease (MND). METHODS: After a systematic literature search for RCTs for MND pharmacotherapy treatments, we assessed the number of discontinuations because of placebo intolerance. RESULTS: Data were extracted from 12 RCTs fulfilling our search criteria. Approximately eight in 10 placebo treated patients (78.3%, 95% CI 74.3-82.0%) reported at least one AE and approximately one in 12 placebo-treated patients discontinued placebo treatment because of AEs (8.4%, 95% CI 6.7-10.4%). All patients participating in the MND trials reported similar AEs independently of the study arm to which they belonged. CONCLUSION: Our study indicates significant nocebo in trials for MND treatment, adversely affecting adherence and efficacy of current treatments in clinical practice, with additional implications for trial design. PMID- 28593799 TI - What can evolutionary rescue tell us about the emergence of new resistant bacteria? PMID- 28593800 TI - Use of copeptin for rapid rule-out of acute myocardial infarction. AB - Copeptin is currently understood as a quantitative marker of endogenous stress. It rises rapidly in multiple acute disorders including acute myocardial infarction. As a single variable, it has only modest diagnostic accuracy for acute myocardial infarction. However, the use of copeptin within a dual-marker strategy together with conventional cardiac troponin increases the diagnostic accuracy and particularly the negative predictive value of cardiac troponin alone for acute myocardial infarction. The rapid rule-out of acute myocardial infarction is the only application in acute cardiac care mature enough to merit consideration for routine clinical care. However, the dual-marker approach seems to provide only very small incremental value when used in combination with sensitive or high-sensitivity cardiac troponin assays. This review aims to update and educate regarding the potential and the procedural details, as well as the caveats and challenges of using copeptin in clinical practice. PMID- 28593801 TI - Renal dysfunction indicative of outcomes in hospitalized patients with takotsubo syndrome. AB - BACKGROUND:: Left ventricular dysfunction as part of takotsubo syndrome is reversible, and the long-term prognosis appears favorable. However, life threatening complications are not uncommon during the acute phase, and it remains unclear whether renal dysfunction is a factor in complications suffered by hospitalized patients with takotsubo syndrome. The present study was conducted to investigate the implications of renal dysfunction in this setting. METHODS:: Data from 61 consecutive patients (male, 21; female, 40) diagnosed with takotsubo syndrome at our hospital between years 2010 and 2016 were evaluated retrospectively. In-hospital complications by definition were all-cause deaths and severe pump failure (Killip class >=III). RESULTS:: Overall, 30 patients (49%) developed renal dysfunction. In the 32 patients (52%) who suffered in hospital complications (mortality, 10; severe pump failure, 22), estimated glomerular filtration rate (eGFR) was significantly lower by comparison (51.3+/ 29.8 vs. 69.5+/-29.0; p=0.019). Low eGFR (<30 ml/min per 1.73m2) proved independently predictive of in-hospital complications (hazard ratio =2.84, 95% confidence interval: 1.20-6.69) in multivariate Cox hazard analysis, also showing a significant association with peak event rate of Kaplan-Meier curve (log-rank test, p=0.0073). Similarly, patients with chronic kidney disease were at significantly greater risk of in-hospital complications (hazard ratio=2.49, 95% confidence interval: 1.01-5.98), relative to non-compromised counterparts (eGFR >60 ml/min per 1.73m2). CONCLUSION:: Renal dysfunction is a simple but useful means of predicting complications in hospitalized patients with takotsubo syndrome, especially those with chronic kidney disease. PMID- 28593803 TI - Impact of tumor size on the outcome of patients with small renal cell carcinoma. AB - BACKGROUND: This study aims to establish potential correlation between tumor size and outcomes in patients with T1a kidney cancer registered within the surveillance, epidemiology and end results (SEER) database. METHODS: SEER database (2004-2013) has been accessed through SEER*Stat program to determine the correlation between tumor size and cancer-specific survival in patients with T1a kidney cancer. Survival analysis was conducted through Kaplan-Meier analysis and log-rank testing. RESULTS: Five year kidney cancer-specific survival rates show progressive decline with increasing tumor size. Moreover, kidney cancer-specific survival has been compared according to the initial local treatment modality (observation, ablation, partial or radical nephrectomy) across different size categories (<1 cm, 1-2 cm, 2-3 cm and 3-4 cm). Survival curves of different treatment modalities were almost overlapping for patients with renal mass < 1cm. For patients with tumor size 1-2 cm, treatment modalities were overlapping at the first 60 months then the curve of observation diverged (P <0.0001). For patients with tumor size 2-3 cm and 3-4 cm, the curve of observation diverged early in the time course (P <0.0001). CONCLUSION: Primary tumor size is an important factor that should be taken into consideration when evaluating the different treatment options for patients with small kidney cancers.. PMID- 28593802 TI - The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study. AB - OBJECTIVE: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor's list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors' services in collaborative parts of the health care system. DESIGN: An observational study. SETTING: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before-after setting in a Finnish city. SUBJECTS: Patients who consulted different doctors in a local health care unit. MAIN OUTCOME MEASURES: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage. RESULTS: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased. CONCLUSIONS: The data suggested that the reverse triage causes redistribution of the use of doctors' services rather than a true decrease in the use of these services. PMID- 28593805 TI - Ectopic Liver Within the Placental Parenchyma of a Stillborn Fetus. AB - Rarely, liver tissue can be seen in the umbilical cord, where it is thought to result from ectopic localization during embryogenesis. The placental parenchyma is also a rare site for this occurrence. The exact pathophysiology of ectopic liver in the placenta is unknown. It has been considered that aberrant migration or displacement of cells from the developing hepatic buds leads to ectopic liver formation, including groups of liver cells that become entrapped in the foregut as the diaphragm closes. Additional hypotheses put forward have included monodermal teratoma and hepatocellular adenoma. While the lesions may not actually be adenomas, this term has been most utilized in the literature. Hepatocellular adenomas of the placenta are extremely rare; only 9 cases have been reported thus far. We report an additional occurrence of ectopic liver in the placenta, which is the only one reported in a stillborn, and review the literature. PMID- 28593804 TI - The search for new sporicidal agents for medical use: where are we? PMID- 28593806 TI - A nitrogen removal system to limit water exchange for recirculating freshwater aquarium using DHS-USB reactor. AB - This study proposes a biological nitrogen removal system for freshwater aquaria consisting of a down-flow hanging sponge (DHS) and an up-flow sludge blanket (USB). DHS-USB systems can perform nitrification and denitrification simultaneously, reducing ammonia (NH3) and nitrate (NO3-) toxicity in the water. The performance of the system was evaluated using on-site fresh water aquaria at ambient temperature (23-34 degrees C) over 192 days. NH3 and nitrite (NO2-) were maintained at a detection limit of 0.01 mg N L-1 and NO3- was maintained below 10 mg N L-1, despite limited water exchange. The 16S rRNA gene of microorganisms from the sludge retained in the bioreactors was sequenced to identify the microbial communities present. Microbial community analysis revealed that ammonia oxidizing archaea (AOA), Ca. Nitrososphaera and Nitrosopumilus, played an important role in nitrification in the DHS reactor, while denitrifying bacteria Thauera played an important role in denitrification in the USB reactor. The proposed DHS-USB system is a promising technological advancement in the development of lower maintenance aquaria. PMID- 28593807 TI - Cyclic filtration behavior of structured cattail fiber assembly for oils removal from wastewater. AB - Structured cattail fiber assembly was reported as the filter for removing oils from runoff. The oil-wetted filter was recovered by rotational centrifugation and reused in the next filtration. The cyclic filtration behavior of the assembly was characterized by oil removal efficiency, oil sorption capacity, influence of packing density and number of filtration cycles. The efficiency of liquid removal and oil recovery from the centrifuged filter were also investigated. Cattail filters showed an excellent oil cyclic filtration performance which was found to have a close relationship with the inner structural characteristic of the fibers. The filters removed vegetable oil and diesel completely from runoff in the initial 40-90 min and 30-60 min in the first cycle, respectively, after which the oils broke through the filter's body and 29.4-71.4 L and 21.0-46.2 L of clean water were collected. The time of breakthrough was decreased with decreasing cattail's packing density. The wetted filters which absorbed up to 693.11 g (14.81 g/g) of vegetable oil and 497.02 g (10.62 g/g) of diesel took separately 7 min and 30 s to be recovered. Seventy-five to ninety percent of liquids were removed and 70-93% of oils were re-collected. PMID- 28593809 TI - Nitrate analogs as attractants for soybean cyst nematode. AB - Soybean cyst nematode (SCN) Heterodera glycines Ichinohe, a plant parasite, is one of the most serious pests of soybean. In this paper, we report that SCN is attracted to nitrate and its analogs. We performed attraction assays to screen for novel attractants for SCN and found that nitrates were attractants for SCN and SCN recognized nitrate gradients. However, attraction of SCN to nitrates was not observed on agar containing nitrate. To further elucidate the attraction mechanism in SCN, we performed attraction assays using nitrate analogs ([Formula: see text], [Formula: see text], [Formula: see text]). SCN was attracted to all nitrate analogs; however, attraction of SCN to nitrate analogs was not observed on agar containing nitrate. In contrast, SCN was attracted to azuki root, irrespective of presence or absence of nitrate in agar media. Our results suggest that the attraction mechanisms differ between plant-derived attractant and nitrate. PMID- 28593808 TI - Polymorphism rs2073618 of the osteoprotegerin gene as a potential marker of subclinical carotid atherosclerosis in Caucasians with type 2 diabetes mellitus. AB - BACKGROUND: The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor kappaB ligand/receptor-activator of nuclear factor kappaB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM). PATIENTS AND METHODS: 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA. RESULTS: Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques. CONCLUSIONS: Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects. PMID- 28593810 TI - Saccharomyces cerevisiae immobilized onto cross-linked chitosan beads: application of a novel material for the removal of dye toxicity. AB - Waste from textile industries can severely harm the environment. Dyes are the main residues of these effluents. Saccharomyces cerevisiae is already known to be an efficient adsorbent for the removal of dyes. However, the lack of applicability and limitation of the use of cell biomass in an industrial treatment makes it impossible to apply them. Thus the aim of this work was to immobilize S. cerevisiae in cross-linked chitosan beads by two different techniques (contact immobilization and encapsulation in the polymer matrix), proposing two new materials for adsorption. Adsorption experiments were carried out to analyse the kinetics, isotherm and thermodynamics adsorptive of the synthesized materials. The adsorption data obtained were compared with the S. cerevisiae biomass and with the cell-free cross-linked chitosan beads to evaluate the efficiency of the two synthesized materials. The Fourier transform infrared spectrophotometer was used to characterize and analyse the main adsorption sites of the tested materials. Bioassays using the microcrustacean Daphnia similis verified if the materials could reduce the toxicity of the medium after its application in the treatment. Both materials synthesized in this work can potentially remove dyes from effluents, in addition to being able to significantly decrease dye toxicity from an aqueous medium. PMID- 28593811 TI - Leptin induction following irradiation is a conserved feature in mammalian epithelial cells and tissues. AB - PURPOSE: Leptin (LEP) is a peptide hormone with multiple physiological functions. Besides its systemic actions, it has important peripheral roles such as a mitogen action on keratinocytes following skin lesions. We previously showed that LEP mRNA is significantly induced in response to neutron irradiation in mouse skin and that the protein increases in the irradiated epidermis and in the related subcutaneous adipose tissue. In this work, we investigated the post transcriptional regulation of LEP by miRNAs and the conservation of LEP's role in radiation response in human cells. METHODS: We used microarray analysis and real time polymerase chain reaction (RT-PCR) to analyze modulation of miRNAs potentially targeting LEP in mouse skin following irradiation and bioinformatic analysis of transcriptome of irradiated human cell lines and cancer tissues from radiotherapy-treated patients to evaluate LEP expression. RESULTS AND CONCLUSIONS: We show that a network of miRNAs potentially targeting LEP mRNA is modulated in irradiated mouse skin and that LEP itself is significantly modulated by irradiation in human epithelial cell lines and in breast cancer tissues from radiotherapy-treated patients. These results confirm and extend the previous evidence that LEP has a general and important role in the response of mammalian cells to irradiation. PMID- 28593812 TI - A retrospective study comparing the loss of anchorage following the extraction of maxillary first or second premolars during orthodontic treatment with fixed appliances in adolescent patients. AB - INTRODUCTION: This retrospective study assessed the difference in anchorage loss using 3D superimposition of study models between cases treated with extraction of maxillary first premolars and maxillary second premolars carried out in orthodontic specialist practice. METHOD: Sixty subjects who have undergone extractions of either maxillary first or second premolars as part of their orthodontic treatment were selected. Eligibility criteria included patients with a Class I, mild Class II or III malocclusions, mild-to-moderate crowding with no anchorage reinforcement. Pre- and post-treatment maxillary dental study cases were scanned using a surface laser scanner to produced 3D digital images which were superimposed using areas of stability on the anterior hard palate. Anchorage loss was measured by the mesial movement of the maxillary first permanent molar. RESULTS: The mean mesial movement for the maxillary first molars, when adjusted for confounding factors was 4.7 mm (SD 1.6) in the maxillary first premolar extraction group and 4.6 mm (SD 1.6) in the maxillary second premolar extraction group. CONCLUSIONS: There is no difference in anchorage loss when comparing the extraction of the maxillary first premolars to the extraction maxillary second premolars. PMID- 28593813 TI - Association of Vascular Endothelial Growth Factor Gene Polymorphism With Renal Cell Carcinoma Risk. AB - The conclusion of the relationship between vascular endothelial growth factor gene polymorphism and renal cell carcinoma risk was inconsistent. This study was performed to assess the relationship between vascular endothelial growth factor gene polymorphism and renal cell carcinoma risk using meta-analysis. The association studies were identified from PubMed, Embase, and Web of Science, and eligible studies were included and calculated. Ten studies were included for this meta-analysis. vascular endothelial growth factor (VEGF) +405G > CC allele and GG genotype were associated with renal cell carcinoma risk for overall populations in this meta-analysis (C allele: odds ratio = 1.18, 95% confidence interval: 1.05 1.33, P = .004; CC genotype: odds ratio = 1.20, 95% confidence interval: 0.96 1.50, P = .12; GG genotype: odds ratio = 0.79, 95% confidence interval: 0.67 0.93, P = .004). Furthermore, VEGF +936C>T gene polymorphism and VEGF -2578 C>A gene polymorphism were associated with renal cell carcinoma risk for overall populations (+936C>T: T allele: odds ratio = 1.16, 95% confidence interval: 1.05 1.29, P = .004; TT genotype: odds ratio = 1.25, 95% confidence interval: 1.02 1.52, P = .03; CC genotype: odds ratio = 0.86, 95% confidence interval: 0.75 0.98, P = .03; -2578 C>A: A allele: odds ratio = 1.26, 95% confidence interval: 1.15-1.38, P < .00001; AA genotype: odds ratio = 1.39, 95% confidence interval: 1.16-1.67, P = .0004; CC genotype: odds ratio = 0.75, 95% confidence interval: 0.61-0.92, P = .006). However, VEGF -634G>C, VEGF -460T>C, VEGF -1154 G>A, and VEGF +1612 G>A gene polymorphisms were not associated with renal cell carcinoma risk. In conclusion, VEGF +405G>CC allele and GG genotype, VEGF +936C>T gene polymorphism, and VEGF -2578 C>A gene polymorphism were associated with renal cell carcinoma risk for overall populations. However, more studies should be performed to assess this relationship in the future. PMID- 28593815 TI - Homogenous UV/periodate process in treatment of p-nitrophenol aqueous solutions under mild operating conditions. AB - Aqueous solutions of p-nitrophenol (PNP) were treated with UV-activated potassium periodate (UV/KPI) in an efficient photo-reactor. Either periodate or UV alone had little effect; however, their combination led to a significant degradation and mineralization. The response surface methodology was employed for design of experiments and optimization. The optimum conditions for treatment of 30 mg/L of the substrate were determined as [KPI] = 386.3 mg/L, pH = 6.2 and T = 34.6 degrees C, under which 79.5% degradation was achieved after 60 min. Use of 25 and 40 kHz ultrasound waves caused the degradation to enhance to 88.3% and 92.3%, respectively. The intermediates were identified by gas chromatography-mass spectroscopy analysis, leading to propose the reaction pathway. The presence of water conventional bicarbonate, chloride, sulfate and nitrate anions caused unfavorable effects in efficiency. Meanwhile, the kinetic study showed that PNP degradation follows a pseudo-first-order reaction and the activation energy was determined. The irradiation energy consumption required for one order of magnitude degradation was estimated as 11.18 kWh/m3. Accordingly, comparison with the previously reported processes showed the superiority of PNP treatment with the employed process. PMID- 28593816 TI - The experience of physicians in pharmacogenomic clinical decision support within eight German university hospitals. AB - AIM: The aim of this study was to assess the physicians' attitude, their knowledge and their experience in pharmacogenomic clinical decision support in German hospitals. MATERIALS & METHODS: We conducted an online survey to address physicians of 13 different medical specialties across eight German university hospitals. In total, 564 returned questionnaires were analyzed. RESULTS: The remaining knowledge gap, the uncertainty of test reimbursement and the physicians' lack of awareness of existing pharmacogenomic clinical decision support systems (CDSS) are the major barriers for implementing pharmacogenomic CDSS into German hospitals. Furthermore, pharmacogenomic CDSS are most effective in the form of real-time decision support for internists. CONCLUSION: Physicians in German hospitals require additional education of both genetics and pharmacogenomics. They need to be provided with access to relevant pharmacogenomic CDSS. PMID- 28593817 TI - The Meanings of Helping: An Analysis of Cystic Fibrosis Patients' Reasons for Participating in Biomedical Research. AB - Research participants often report wanting to help as a reason for participation, but who they want to help and why is rarely explored. We examined meanings associated with helping among 21 adults with cystic fibrosis (CF)-a group with high participation in research. Meanings included helping to advance research, helping others with CF, helping as their job, helping themselves, helping because they are special, and helping to give back. While some meanings were primarily oriented toward helping others, some also involved hoping for benefits for oneself, and some included feelings of responsibility. Despite indicating that they understood that research is not designed to help them directly, participants nevertheless hoped that it might. We discuss implications for research ethics oversight. PMID- 28593818 TI - Sensitivity and specificity should never be interpreted in isolation without consideration of other clinical utility metrics. AB - OBJECTIVE: The purpose of this paper is to highlight the risks and pitfalls of interpreting sensitivity and specificity in isolation when evaluating the clinical utility of a new test/measure to predict a target behavior, disease, or condition. METHOD: This paper (a) provides a primer for a set of metrics that can be used to appropriately examine the clinical utility of a test/measure (i.e. test operating characteristics - TOC), and (b) provides a discussion regarding various interpretative considerations when using TOCs that supports the tenet of this paper. CONCLUSIONS: There are two primary conclusions. First, sensitivity and specificity should never be interpreted in isolation as a means for evaluating the clinical utility of a test/measure. When sensitivity and specificity are used in this manner, more often than not, this will result in erroneous and/or incomplete conclusions regarding the clinical utility of a new test/measure. Second, sensitivity and specificity values are important, but they must be interpreted in conjunction with other more relevant clinical utility metrics (e.g. positive predictive power and negative predictive power). PMID- 28593819 TI - Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders. AB - OBJECTIVES: Physical exercise has gained increasing interest as a treatment modality that improves prognosis in psychiatric patients. The disrupted in schizophrenia 1 (DISC1) gene is a candidate gene for major mental illness. In this study, we aimed to determine whether voluntary wheel running can improve cognitive deficits of dominant-negative DISC1 transgenic mice (DN-DISC1). METHODS: DN-DISC1 and control mice (10-week-old male and female) were placed for 14 days in a cage with or without access to a running wheel. Two weeks later, mice underwent behavioural tests evaluating cognition and social approach and recognition. RESULTS: Voluntary exercise improved performance in the novel object recognition test, restored the impairment in spatial memory in the Y maze, and reversed the deficit in social recognition memory in DN-DISC1 females. DN-DISC1 males did not exhibit behavioural deficits at baseline. Tissue analysis revealed that exercise induced a significant increase in hippocampal expression of doublecortin (DCX), brain-derived neurotrophic factor (BDNF) and cannabinoid receptor type 1 (CB1R) only in DN-DISC1 females. CONCLUSIONS: Voluntary exercise is beneficial in attenuating cognitive deficits observed in a rodent model relevant for neuropsychiatric disorders. The data add a preclinical aspect to the accumulating clinical data supporting the incorporation of physical exercise to patients' care. PMID- 28593814 TI - Expanding Axonal Transcriptome Brings New Functions for Axonally Synthesized Proteins in Health and Disease. AB - Intra-axonal protein synthesis has been shown to play critical roles in both development and repair of axons. Axons provide long-range connectivity in the nervous system, and disruption of their function and/or structure is seen in several neurological diseases and disorders. Axonally synthesized proteins or losses in axonally synthesized proteins contribute to neurodegenerative diseases, neuropathic pain, viral transport, and survival of axons. Increasing sensitivity of RNA detection and quantitation coupled with methods to isolate axons to purity has shown that a surprisingly complex transcriptome exists in axons. This extends across different species, neuronal populations, and physiological conditions. These studies have helped define the repertoire of neuronal mRNAs that can localize into axons and imply previously unrecognized functions for local translation in neurons. Here, we review the current state of transcriptomics studies of isolated axons, contrast axonal mRNA profiles between different neuronal types and growth states, and discuss how mRNA transport into and translation within axons contribute to neurological disorders. PMID- 28593820 TI - Spirulina platensis biomass composition is influenced by the light availability and harvest phase in raceway ponds. AB - The behavior of cyanobacteria and its potential use for biofuel production in scale-up conditions is a topic of growing importance. The aim of our work is to study the effects of illumination, stirring, and different growth phases on the cultivation of the cyanobacteria Spirulina platensis in 10 L raceways. The cultivations were carried out in a greenhouse under measured, but not controlled, illumination and in agitated raceways with stirring speeds varying from 0.1 to 0.4 m s-1, using culture media with nutrient depletion. At the end of the stationary phase (SP) and decline of culture, the biomass was harvested and used to determine the chemical composition. The stirring rate and the growing phase influenced the carbohydrate concentration. In both phases of cultivation, compared to high-speed stirring, stirring at lower speeds produced fewer carbohydrates in the culture. Biomass grown until the end of the SP with a stirring speed of 0.35 m s-1 had a carbohydrate content of 72%, which is very high compared to that reported in the literature. PMID- 28593821 TI - The effects of cleaning/disinfecting agents on biogas production in the anaerobic digestion of cow dung slurry. AB - Cleaning/disinfecting agents (CDA) are compounds known to affect the growth of microbes and could have impacts on biogas production in a digester. In this study, three commonly used CDAs (harpic, hypo and izal) in livestock pens and slaughter houses were applied at different digestion stages and concentrations to cow dung (CD) slurry, with the aim of determining their effects on biogas production. Three application stages (early addition, late addition and graduated addition) were carried out for each CDA, and a CD treatment with no CDA applied was set up as the control. The results showed that application stage had different effects on the parameters of CD monitored during the digestion. Significant (p <= .05) effect was recorded on: temperature of izal + CD treatment, pH of harpic + CD and hypo + CD treatments, total bacterial count of hypo + CD and izal + CD treatments and biogas of harpic + CD, hypo + CD and izal + CD treatments. Early addition and increased concentration of hypo appeared toxic to anaerobic bacteria, whereas early addition of izal seemed not to affect their development. While early addition and increased concentration of harpic and hypo inhibited biogas production, the contrary was observed with izal. At the end of digestion, biogas yield (% of control) in the CDA + CD treatments ranged between 8% and 69.4% (harpic + CD), 5.4-23.5% (hypo + CD) and 16.1-52.5% (izal + CD). Among the CDAs used, hypo had the highest inhibitory effect on biogas production from CD slurry. The introduction of harpic at fourth week of digestion showed the least inhibitory effect. PMID- 28593822 TI - Measurement and Structural Invariance of Posttraumatic Stress Disorder Symptoms in Hispanic and Caucasian Firefighters. AB - This study compared across Hispanic and Caucasian firefighters the relative fit of the four-factor Emotional Numbing and Dysphoria posttraumatic stress disorder models to the more recently proposed Dysphoric Arousal five-factor model. As hypothesized, the Dysphoric Arousal five-factor model emerged as the best fitting model within each ethnic group and it also showed measurement invariance between groups (configural invariance). Results of multigroup confirmatory factor analyses and a bias-corrected bootstrap confidence intervals analytic approach indicated that the five factor model also demonstrated invariance in factor loadings (metric invariance) and item-level intercepts (scalar invariance) across the two ethnic groups. Results indicate that the Dysphoric Arousal five factor model captures similar psychological constructs across Caucasian and English speaking Hispanic firefighters. Therefore, observed factor scores are comparable across ethnic groups and can be combined when examining predictors of posttraumatic stress disorder severity. PMID- 28593823 TI - Adult Burkitt's lymphoma presenting as intussusception: first UK case report. AB - Colonic intussusception is rare in adults and can present with non-specific symptoms that can make diagnosis difficult and delayed. Unlike in children, it is commonly due to a pathological lead point that is often malignant. This case is the first reported case of adult intussusception due to Burkitt's lymphoma in the UK. We describe the case of a 22-year-old woman who presented with 4-week history of intermittent epigastric pain. On the third hospital admission, the diagnosis was made by abdominal computed tomography, which showed the 'target' sign, suggestive of intussusception. A right hemicolectomy was performed and histology later confirmed Burkitt's lymphoma. This case demonstrates the difficulty in diagnosing intussusception in adults, which must be considered in recurrent abdominal pain when more common causes have been ruled out. The rare diagnosis of Burkitt's lymphoma made early diagnosis and treatment important. PMID- 28593824 TI - Should CYP2D6 be genotyped when treating with tamoxifen? AB - Letter in regards to: Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics 17(18), 1967 1969 (2016). In response to: Damkier P. Don't think twice it's all right: tamoxifen and CYP2D6 genotyping in the treatment of breast cancer patients. Pharmacogenomics 18(8), XXX (2017). PMID- 28593825 TI - Point-of-care ultrasonography in Norwegian out-of-hours primary health care. AB - OBJECTIVE: The objective of this study is to determine the extent of ultrasound availability in Norwegian casualty clinics and estimate the prevalence of its use. DESIGN: A retrospective study based on a national casualty clinic registry and data from reimbursement claims. SETTING: Out-of-hours primary health care in Norway. SUBJECTS: All Norwegian casualty clinics in 2016 and reimbursement claims from 2008 to 2015. MAIN OUTCOME MEASURES: Percent of casualty clinics with ultrasound, types of ultrasound devices and probes, reasons for/against ultrasound access, characteristics of clinics with/without ultrasound, frequency of five ultrasound indications and characteristics of the physicians using/not using ultrasound. RESULTS: Out of 182 casualty clinics, 41 (23%) reported access to ultrasound. Mobile (49%) and stationary (44%) devices were most frequent. Physician request was the most common cited reason for ultrasound access (66%). Neither population served by the casualty clinic nor distance to hospital showed any clear association with ultrasound access. All of the five ultrasound reimbursement codes showed a substantial increase from 2008 to 2015 with 14.1 ultrasound examinations being performed per 10,000 consultations in 2015. Only 6.5% of physicians performed ultrasound in 2015 and males were significantly more likely to use ultrasound than females (OR 1.85, 95% CI: 1.38-2.47, p < .001), even when adjusted for age, speciality status and geography. CONCLUSIONS: Although the use of ultrasound is increasing in out-of-hours Norwegian primary health care, most casualty clinics do not have access and only a minority of physicians use ultrasound. PMID- 28593826 TI - Exposure to static magnetic fields increases insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins. AB - PURPOSE: To evaluate the effect of static magnetic fields (SMFs) on insulin secretion and explore the mechanisms underlying exposure to SMF-induced insulin secretion in rat insulinoma INS-1 cells. MATERIALS AND METHODS: INS-1 cells were exposed to a 400 mT SMF for 72 h, and the proliferation of INS-1 cells was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The secretion of insulin was measured with an enzyme linked immunosorbent assays (ELISA), the expression of genes was detected by real-time PCR, and the expression of proteins was measured by Western blotting. RESULTS: Exposure to an SMF increased the expression and secretion of insulin by INS-1 cells but did not affect cell proliferation. Moreover, SMF exposure up-regulated the expression of several pancreas-specific transcriptional factors. Specifically, the activity of the rat insulin promoter was enhanced in INS-1 cells exposed to an SMF, and the expression levels of synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A were up-regulated after exposure to an SMF. CONCLUSIONS: SMF exposure can promote insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins. PMID- 28593827 TI - Liposome-based immunotherapy against autoimmune diseases: therapeutic effect on multiple sclerosis. AB - AIM: Based on the ability of apoptosis to induce immunological tolerance, liposomes were generated mimicking apoptotic cells, and they arrest autoimmunity in Type 1 diabetes. Our aim was to validate the immunotherapy in other autoimmune disease: multiple sclerosis. MATERIALS & METHODS: Phosphatidylserine-rich liposomes were loaded with disease-specific autoantigen. Therapeutic capability of liposomes was assessed in vitro and in vivo. RESULTS: Liposomes induced a tolerogenic phenotype in dendritic cells, and arrested autoimmunity, thus decreasing the incidence, delaying the onset and reducing the severity of experimental disease, correlating with an increase in a probably regulatory CD25+ FoxP3- CD4+ T-cell subset. CONCLUSION: This is the first work that confirms phosphatidylserine-liposomes as a powerful tool to arrest multiple sclerosis, demonstrating its relevance for clinical application. PMID- 28593828 TI - Oral naringenin nanocarriers: Fabrication, optimization, pharmacokinetic and chemotherapeutic efficacy assessments. AB - AIM: To enhance oral bioavailability and chemotherapeutic efficacy of naringenin (NG) by fabricating the NG-encapsulated Soluthin-maltodextrin-based nanocarrier (NC) system. MATERIALS & METHODS: NG-encapsulated nanocarriers (NG/NCs) were developed, and in vitro physicochemically characterized. Furthermore, Wistar rats were used to evaluate the pharmacokinetic profile. Furthermore, in vitro and in vivo colorectal cancer efficacy was evaluated in BALB/c mice-bearing colon-26 cells. RESULTS: The NG/NCs demonstrated favorable mean particle size (176 +/- 2.35 nm) and percent entrapment efficiency (70.83 +/- 4.55%), respectively. The oral bioavailability was found to be approximately 116-fold higher and in vitro cytotoxicity exhibited approximately 21-fold reduction as compared with pure NG. Moreover, optimized NG/NCs demonstrated significant tumor suppression compared with pure NG in vivo. CONCLUSION: The NG/NCs would be an efficient formulation for enhancing oral bioavailability and chemotherapeutic efficacy of NG. PMID- 28593829 TI - Communication behaviors associated with successful conversation in semantic variant primary progressive aphasia. AB - BACKGROUND: Primary progressive aphasia (PPA) affects a range of language and cognitive domains that impact on conversation. Little is known about conversation breakdown in the semantic variant of PPA (svPPA, also known as semantic dementia). This study investigates conversation of people with svPPA. METHODS: Dyadic conversations about everyday activities between seven individuals with svPPA and their partners, and seven control pairs were video recorded and transcribed. Number of words, turns, and length of turns were measured. Trouble indicating behaviors (TIBs) and repair behaviors were categorized and identified as successful or not for each participant in each dyad. RESULTS: In general, individuals with svPPA were active participants in conversation, taking an equal proportion of turns, but indicating a great deal of more trouble in conversation, shown by the significantly higher number of TIBs than evidenced by partners or control participants. TIBs were interactive (asking for confirmation with a shorter repetition of the original utterance or a repetition which included a request for specific information) and non-interactive (such as failing to take up or continue the topic or a minimal response) and unlike those previously reported for people with other PPA variants and dementia of the Alzheimer type. Communication behaviors of the partner were critical to conversational success. CONCLUSIONS: Examination of trouble and repair in 10-min conversations of individuals with svPPA and their important communication partners has potential to inform speech pathology interventions to enhance successful conversation, in svPPA and should be an integral part of the comprehensive care plan. PMID- 28593830 TI - The Development and Evaluation of the Psychometric Properties of the Negative Beliefs about Post-Event Processing Scale. AB - BACKGROUND: Although negative beliefs have been found to be associated with worry symptoms and depressive rumination, negative beliefs have yet to be examined in relation to post-event processing and social anxiety symptoms. AIMS: The purpose of the current study was to examine the psychometric properties of the Negative Beliefs about Post-Event Processing Questionnaire (NB-PEPQ). METHOD: A large, non referred undergraduate sample completed the NB-PEPQ along with validation measures, including a measure of post-event processing and social anxiety symptoms. RESULTS: Based on factor analysis, a single-factor model was obtained, and the NB-PEPQ was found to exhibit good validity, including positive associations with measures of post-event processing and social anxiety symptoms. CONCLUSIONS: These findings add to the literature on the metacognitive variables that may lead to the development and maintenance of post-event processing and social anxiety symptoms, and have relevant clinical applications. PMID- 28593831 TI - Osmoregulated Periplasmic Glucans. AB - Among all the systems developed by enterobacteria to face osmotic stress, only osmoregulated periplasmic glucans (OPGs) were found to be modulated during osmotic fluxes. First detected in 1973 by E.P. Kennedy's group in a study of phospholipid turnover in Escherichia coli, OPGs have been shown across alpha, beta, and gamma subdivisions of the proteobacteria. Discovery of OPG-like compounds in the epsilon subdivision strongly suggested that the presence of periplasmic glucans is essential for almost all proteobacteria. This article offers an overview of the different classes of OPGs. Then, the biosynthesis of OPGs and their regulation in E. coli and other species are discussed. Finally, the biological role of OPGs is developed. Beyond structural function, OPGs are involved in pathogenicity, in particular, by playing a role in signal transduction pathways. Recently, OPG synthesis proteins have been suggested to control cell division and growth rate. PMID- 28593832 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 67, part 3, of the IJSEM. PMID- 28593833 TI - Proposed revisions of the Statutes of the International Committee of Systematics of Prokaryotes. AB - The following revisions of the Statutes (Labeda D, Whitman WB. Int J Syst Evol Microbiol 2015;65:1093-1100) are proposed by the Executive Board of the International Committee of Systematics of Prokaryotes (ICSP) to eliminate some internal inconsistencies and address other issues as discussed below. Comments may be sent to the Secretary of the ICSP, Lenie Dijkshoom at L.Dijkshoom@lumc.nl for distribution to the delegates at the Plenary Meeting in Valencia, Spain, on July 7-9, 2017. PMID- 28593834 TI - Salibacter halophilus gen. nov., sp. nov., isolated from a saltern. AB - A Gram-stain-negative and facultatively anaerobic bacterium, JZ3C34T, was isolated from a saltern in Feicheng, China (36 degrees 8' 24.45" E 116 degrees 49' 22.46" N). Cells of strain JZ3C34T were 0.3-0.4 um wide and 1.5-2.0 um long, catalase-positive and oxidase-negative. Colonies on modified marine agar 2216 were orange, circular, convex, translucent and approximately 1 mm in diameter after incubation for 96 h at 33 degrees C. Growth occurred at 20-50 degrees C (optimally at 33 degrees C), at pH 6.5-8.5 (optimally at 7.0-8.0) and in the presence of 2-18 % (w/v) NaCl (optimally in 6 % NaCl). Phylogenetic analysis of the 16S rRNA gene indicated that strain JZ3C34T was a member of the family Cryomorphaceae within the order Flavobacteriales and the most closely related species was Owenweeksia hongkongensis DSM 17368T (89.2 % 16S rRNA gene sequence similarity). The major respiratory quinone of strain JZ3C34T was menaquinone MK 7, and the dominant fatty acids were iso-C15 : 0 and iso-C15 : 1 G. The major polar lipids were two unidentified lipids and phosphatidylethanolamine, and the genomic DNA G+C content was 39.6 mol%. Polyphasic taxonomy clearly places the new strain as a novel species within a new genus of the family Cryomorphaceae, for which the name Salibacter halophilus gen. nov., sp. nov. The type strain of Salibacter halophilus is JZ3C34T (=KCTC 52047T=MCCC 1K02288T). PMID- 28593836 TI - Predictors and generation of risk equations for albuminuria progression in type 2 diabetes. AB - BACKGROUND: Diabetes is the most common cause of end-stage renal disease and is associated with increased mortality. Although only a proportion of type 2 diabetic subjects develop albuminuria or progress, it is not currently possible to identify those patients who will develop this complication or who will progress. AIM: The aim of the study was to identify baseline risk factors for the development and progression of albuminuria in a cohort with type 2 diabetes and use this data to generate risk equations. PATIENTS AND METHODS: Type 2 diabetic subjects who had albumin-creatinine ratio (ACR) measurement in 2007 - 2008 were recruited and followed-up for 8 years. RESULTS: 260 patients were included in the study. Of all the normoalbuminuric and microalbuminuric patients, 24.3% progressed. Baseline HbA1c, white cell count (WCC), smoking, and duration of diabetes were associated with progression of albuminuria stage in univariate analysis. Duration of diabetes (p = 0.034) was independently associated with progression in binary logistic regression. Baseline HbA1c (p = 0.002), age (p = 0.01), serum creatinine (p = 0.02), serum potassium (p = 0.04), serum urea (p = 0.0004), WCC (p = 0.02), serum triglycerides (p = 0.02), systolic blood pressure (p = 0.02), and duration of diabetes (p = 0.003) were positively correlated with percentage change (% change) in ACR, whilst baseline estimated glomerular filtration rate (eGFR) (p = 0.03), serum sodium (p = 0.04), hemoglobin (p = 0.0006), and hematocrit (p = 0.0002) were negatively correlated in Spearman correlation. Duration of diabetes (p = 0.025) and baseline HbA1c (p = 0.02) were independently associated with % change in ACR in multivariate analysis. Based on these results, novel risk equations were generated. CONCLUSIONS: We have identified baseline characteristics associated with progression of renal disease in type 2 diabetic subjects and generated equations to estimate the risk of progression. If validated in other populations, these equations might be useful in predicting risk of progression in clinical practice. PMID- 28593837 TI - Rhadinorhynchus oligospinosus n. sp. (Acanthocephala, Rhadinorhynchidae) from mackerels in the Pacific Ocean off Peru and related rhadinorhynchids in the Pacific, with notes on metal analysis. AB - Specimens of a new species of Rhadinorhynchus Luhe, 1911 are described from the chub mackerel Scomber japonicus (Scombridae) and the Chilean Jack mackerel Trachurus murphyi (Carangidae) (possibly a subspecies of Trachurus symmetricus) from the Pacific Ocean off the Peruvian coast at the Port of Chicama, La Libertad. Specimens of Rhadinorhynchus oligospinosus n. sp. are somewhat small having 11-14 rows of alternating proboscis hooks with 20-22 hooks each with posteriormost hooks in a continuous ring. Ventral hooks are robust with prominent roots but dorsal hooks are slender and shorter with discoid roots. Trunk spines are in two zones separated by a non-spiny region. Anterior trunk spines are in 2 3 complete circles but posterior spines are only ventral and lateral, and do not extend posterior to the level of the posterior end of the proboscis receptacle in both sexes. The new species is closest to Rhadinorhynchus seriolae (Yamaguti, 1963) Golvan, 1969 found in Japanese and Australian waters, but not as close to 19 other species found in the same Pacific waters off Australia, Japan, and Vietnam. In R. seriolae, posterior trunk spines extend well past the receptacle in females, among other diagnostic differences. Proboscis hooks of the new species were analyzed for chemical elements using X-ray in conjunction with EDAX (energy-dispersive analysis for X-ray) software; sulfur had a higher concentration at the edge than the middle of cut hooks. PMID- 28593839 TI - Zika in Africa-the invisible epidemic? PMID- 28593838 TI - Attractiveness of black and white modified Shannon traps to phlebotomine sandflies (Diptera, Psychodidae) in the Brazilian Amazon Basin, an area of intense transmission of American cutaneous leishmaniasis. AB - In the Amazon region the phlebotomine fauna is considered one of the most diverse in the world. The use of Shannon traps may provide information on the anthropophily of the species and improve the traps' performance in terms of diversity and quantity of insects collected when white and black colored traps are used together. This study sought to verify the attractiveness of the traps to the phlebotomine species of the Brazilian Amazon basin using Shannon traps under these conditions. The insects were collected using two Shannon traps installed side by side, one white and the other black, in a primary forest area of the municipality of Xapuri, Acre, Brazil. Samples were collected once a month during the period August 2013 to July 2015. A sample of females was dissected to test for natural infection by flagellates. A total of 6,309 (864 males and 5,445 females) specimens (36 species) were collected. Psychodopygus carrerai carrerai (42%), Nyssomyia shawi (36%), and Psychodopygus davisi (13%), together represented 90% of the insects collected. Nyssomyia shawi and Psychodopygus davisi were more attracted by the white color. Specimens of Nyssomyia shawi, Nyssomyia whitmani, and Psychodopygus hirsutus hirsutus were found naturally infected by flagellates in the mid and hindgut. This is the first study in Acre state using and comparing both black and white Shannon traps, demonstrating the richness, diversity, and anthropophilic behavior of the phlebotomine species and identifying proven and putative vectors of the etiological agents of leishmaniasis. PMID- 28593840 TI - Preventing prevention: Indian politics and public health clash. PMID- 28593841 TI - Neoadjuvant chemotherapy in localised soft-tissue sarcomas: where do we go from here? PMID- 28593844 TI - Cracking the cancer code: a personalised genomic approach. PMID- 28593843 TI - Under-representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer. PMID- 28593842 TI - Improving childhood cancer care in Latin America and the Caribbean: a PAHO Childhood Cancer Working Group position statement. PMID- 28593845 TI - Chernobyl's tomb. PMID- 28593846 TI - Do cytogenetics of acute lymphoblastic leukaemia blasts affect required duration and intensity of maintenance therapy? PMID- 28593847 TI - Do cytogenetics of acute lymphoblastic leukaemia blasts affect required duration and intensity of maintenance therapy? - Authors' reply. PMID- 28593848 TI - Short-course radiotherapy with delayed surgery for rectal cancer. PMID- 28593849 TI - Short-course radiotherapy with delayed surgery for rectal cancer. PMID- 28593850 TI - Short-course radiotherapy with delayed surgery for rectal cancer - Authors' reply. PMID- 28593851 TI - Genetics of gallbladder cancer. PMID- 28593852 TI - Genetics of gallbladder cancer - Authors' reply. PMID- 28593853 TI - "Finding NEMO" in NRAS-mutant melanoma: a step towards a sequential strategy? PMID- 28593854 TI - Incidence and prognosis of carcinoid syndrome: hormones or tumour burden? PMID- 28593855 TI - Incidence and prognosis of carcinoid syndrome: hormones or tumour burden? - Authors' reply. PMID- 28593856 TI - Correction to Lancet Oncol 2017; 18: 719-31. PMID- 28593857 TI - Correction to Lancet Oncol 2017; 18: 63-74. PMID- 28593858 TI - Correction to Lancet Oncol 2017; 18: 812. PMID- 28593859 TI - European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma. AB - Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning. PMID- 28593860 TI - Evolving adoptive cellular therapies in urological malignancies. AB - Immunotherapies have long been used to treat urological cancers but rarely lead to cure. In the past 5 years, success of immune checkpoint inhibition has led to a resurgence of enthusiasm for immunotherapy in the treatment of solid tumours. Increased understanding of tumour immune biology, technological advancements of gene transfer and cell culture, and improved clinical infrastructures for routine delivery of cell products, has made cell-based immunotherapeutics a real prospect for cancer therapy. These scientific and clinical activities, attempting to exploit the innate and adaptive immune systems for therapeutic gain, are well exemplified by the urological malignancies of renal, bladder, prostate, and penile cancer, a group of anatomically localised diseases, each with a distinct biology and different immunotherapeutic challenges. In this Review, we present the results of clinical studies investigating autologous cellular therapies in urological malignancies. Specifically, we discuss the rationale for upcoming studies, and how novel therapies and adoptive cell combinations can be used for personalised cancer therapy. PMID- 28593861 TI - Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. AB - For patients with high-risk stage II or stage III colon cancer, adjuvant chemotherapy with fluoropyrimidine monotherapy reduces the risk of recurrence and death by approximately 20-30%. Additional improvements have been reported in three phase 3 colon cancer trials when oxaliplatin was added to the chemoradiation regimen, although the effect was mainly on disease-free survival. However, patients with rectal cancer were specifically excluded from these landmark studies because of potential toxicity and the confounding impact of radiotherapy and chemoradiation. Hence, despite evidence from smaller individual postoperative adjuvant phase 3 trials, meta-analyses, retrospective analyses, reviews, and population studies, the precise benefit of adjuvant chemotherapy for patients with rectal cancer following radiotherapy or chemoradiation remains unclear. Consequently, clinical guidelines offer inconsistent recommendations for the management of this patient population. In this Review, we suggest that the available data do not robustly support the routine use of postoperative adjuvant chemotherapy for patients with rectal cancer treated with preoperative chemoradiation. We discuss sources of bias and offer potential reasons to explain this observation, as well as propose a recommended schema for a randomised phase 3 trial that might potentially answer this question definitively. PMID- 28593862 TI - Malignancy in a child or something else? PMID- 28593864 TI - Oral Immunotherapy for Food Allergy: A Spanish Guideline. Egg and Milk Immunotherapy Spanish Guide (ITEMS GUIDE). Part II: Maintenance Phase of Cow Milk (CM) and Egg Oral Immunotherapy (OIT), Special Treatment Dosing Schedules. Models of Dosing Schedules of OIT With CM and Egg. AB - BACKGROUND AND OBJECTIVE: Cow milk and egg are the most frequent causes of food allergy in the first years of life. Oral immunotherapy (OIT) has been investigated as an alternative to avoidance diets. No clinical practice guidelines on the management of OIT with milk and egg are currently available. Objectives: To develop clinical guidelines for OIT based on available scientific evidence and the opinions of experts. METHODS: A review was made of studies published between 1984 and June 2016, doctoral theses published in Spain, summaries of communications at scientific meetings (SEAIC, SEICAP, EAACI, and AAAAI), and the consensus of opinion established by a group of experts from the scientific societies SEICAP and SEAIC. RESULTS: Recommendations were established regarding the indications, requirements and practical aspects of the different phases of OIT, as well as special protocols for patients at high risk of adverse reactions. CONCLUSIONS: Clinical practice guidelines based on the consensus reached between Spanish experts are presented for the management of OIT with milk and egg. PMID- 28593865 TI - The semiology of benign focal epilepsy with affective symptoms. AB - Benign focal epilepsy with affective symptoms (BFEAS) is a rare childhood epilepsy syndrome essentially characterized by "epileptic attacks with affective symptoms of a terrifying type". Since the original description, approximately 50 cases have been reported. To our knowledge, however, none of the studies included video-EEG data. Herein, we detail the electroclinical features of a neurodevelopmentally normal 9-year-old boy with epilepsy since the age of 2 years. His seizure semiology essentially consisted of nocturnal focal seizures featuring abrupt fear and autonomic phenomena (such as excessive sweating, repeated swallowing, and coughing), associated with impaired consciousness. These seizures were often secondary generalized, and he had multiple episodes of convulsive status epilepticus. He has been seizure-free for the past year and a half on dual antiepileptic therapy with sulthiamine and valproate. His intellectual and social abilities are excellent (IQ of 116), although he does have difficulties particularly in language learning, and was recently diagnosed with phonological dyslexia with dysorthography. By presenting our patient's history and video-EEG, we intend to further detail the semiology of seizures with affective symptomatology. [Published with video sequence on www.epilepticdisorders.com]. PMID- 28593866 TI - [Open digit amputation in cattle: Surgery, wound healing and follow-up]. AB - INTRODUCTION: The aim of this retrospective study was to document secondary wound healing and outcome in 20 cattle that had undergone digit amputation at the level of the distal metaphysis of the first phalanx between April 2009 and June 2015. The surgical technique for amputation was simple and fast, and granulation tissue covered the stump of the first phalanx 9 to 30 days postoperatively. Complications associated with wound healing were seen in 7 animals and in 3, a second surgery was required; all 20 cattle were discharged from the clinic. Epithelial closure was complete after a mean of 3 months (range, 2 to 7 months). The mean postoperative survival time was 15 months (range, 1 to 34 months), and 6 animals were still alive at the time of follow-up inquiry. Wound healing and long term outcome did not differ between cattle that had undergone a more intensive aftercare regime than those with a less intensive postoperative treatment. PMID- 28593867 TI - [Diagnosis, therapy and prophylactic measures of parturient paresis in dairy cattle: results of an online survey for Swiss veterinarians]. AB - INTRODUCTION: The aim of this study was to obtain the diagnostic, therapeutic and prophylactic approach among Swiss veterinary practitioners in cows with parturient hypocalcemia. All members of the Association for Ruminant Health were contacted per e-mail. The survey was completed by 108 (28%) of 393 that were contacted. According to the questionnaire responses, the typical presentation of a parturient paresis cow is a pluriparous middle-yielding dairy cow one day post partum in sternal recumbency with normal consciousness. The diagnosis is usually based upon the medical history. Therapy of parturient paresis consists of mixed infusions (with calcium, phosphorus, magnesium or glucose) as well as oral preparations with calcium. The veterinarians estimate that 25-50% of the cows treated for parturient paresis need more than one treatment and that one case of parturient paresis costs CHF 200-300. Prophylactic treatments are usually used for cows, which have suffered from parturient paresis in the previous lactation, elder cows (>= 3 lactations) as well as cows with a high body condition score (> 3.25). Prophylactic measures used by the veterinarians are vitamin D3 injections and oral preparations with calcium. They recommended a special diet, for example a low calcium diet ante-partum. PMID- 28593870 TI - High-sensitivity cardiac troponin: do think twice, it's not all right. AB - A questionable scientific approach to measuring at low concentrations and inappropriate censoring of results below certain cut-offs have resulted in the dichotomous classification of troponin assays based on their so-called analytical sensitivity. The definition of "high-sensitivity" cardiac troponin is flawed. Evidence suggests that its apparent diagnostic superiority may be explained by the censoring of data. In the evaluation of the detection and quantification capabilities of analytical methods we recommend alignment with International Union of Pure and Applied Chemistry (IUPAC) guidelines, including reporting of all results. This will allow the objective evaluation of the diagnostic performance of troponin assays and will render the current troponin assay classification and nomenclature obsolete. PMID- 28593871 TI - Traceability in laboratory medicine: a global driver for accurate results for patient care. AB - Laboratory medicine results influence a high percentage of all clinical decisions. Globalization requires that laboratory medicine results should be transferable between methods in the interests of patient safety. International collaboration is necessary to deliver this requirement. That collaboration should be based on traceability in laboratory medicine and the adoption of higher order international commutable reference materials and measurement procedures. Application of the metrological traceability chain facilitates a universal approach. The measurement of serum cholesterol and blood HbA1c serve as examples of the process of method standardization where an impact on clinical outcomes is demonstrable. The measurement of plasma parathyroid hormone and blood HbA2 serve as examples where the current between-method variability is compromising patient management and method standardization and/or harmonization is required. Challenges to the widespread adoption of traceability in laboratory medicine include the availability of reference materials and methods, geographical differences, the use of variable units, complex analytes and limited global coordination. The global collaboration requires the involvement of several different stakeholder groups ranging from international experts to laboratory medicine specialists in routine clinical laboratories. A coordinated action plan is presented with actions attributable to each of these stakeholder groups. PMID- 28593872 TI - Establishing consensus-based, assay-specific 99th percentile upper reference limits to facilitate proper utilization of cardiac troponin measurements. AB - Implementation of the 99th percentile as the upper reference limit for cardiac troponin (cTn) assays is a seemingly lucid recommendation, but, in reality, is incredibly complex. Lack of harmonization between cTn assays diminishes the ability to have a single medical decision point across manufacturer assay/instruments. Moreover, even within a single cTn assay there are several published values corresponding to the "99th percentile". Variability in the determined value is primarily a function of population selection including: sample size, age, sex, exclusion criteria, and statistical methods. Given the complexities associated with this value, some countries have taken an expert consensus approach to endorsing harmonized, assay-specific, cTn 99th percentile values. The purpose of this manuscript is to highlight the intricacies associated with selecting a cTn 99th percentile and to review the approach that Australia used to endorse a nationwide upper reference limit for the Architect STAT hs-cTnI assay. PMID- 28593873 TI - Can we still trust hemoglobin A1c in all situations? PMID- 28593874 TI - Parameter Estimation of a Two-Colored Urn Model Class. AB - Though widely used in applications, reinforced random walk on graphs have never been the subject of a valid statistical inference. We develop in this paper a statistical framework for a general two-colored urn model. The probability to draw a ball at each step depends on the number of balls of each color and on a multidimensional parameter through a function, called choice function. We introduce two estimators of the parameter: the maximum likelihood estimator and a weighted least squares estimator which is less efficient, but is closer to the calibration techniques used in the applied literature. In general, the model is an inhomogeneous Markov chain and this property makes the estimation of the parameter impossible on a single path, even if it were infinite. Therefore we assume that we observe i.i.d. experiments, each of a predetermined finite length. This is coherent with the usual experimental set-ups. We apply the statistical framework to a real life experiment: the selection of a path among pre-existing channels by an ant colony. We performed experiments, which consisted of letting ants pass through the branches of a fork. We consider the particular urn model proposed by J.-L. Deneubourg et al. in 1990 to describe this phenomenon. We simulate this model for several parameter values in order to assess the accuracy of the MLE and the WLSE. Then we estimate the parameter from the experimental data and evaluate confident regions with Bootstrap algorithms. The findings of this paper do not contradict the biological literature, but give statistical significance to the values of the parameter found therein. PMID- 28593875 TI - Intrauterine growth restriction and placental gene expression in severe preeclampsia, comparing early-onset and late-onset forms. AB - OBJECTIVE: To evaluate placental gene expression in severe early- or late-onset preeclampsia with intrauterine growth restriction compared to controls. STUDY DESIGN: Chorionic villus sampling was conducted after cesarean section from the placentas of five women with early- or late-onset severe preeclampsia and five controls for each preeclampsia group. Microarray analysis was performed to identify gene expression differences between the groups. RESULTS: Pathway analysis showed over-representation of gene ontology (GO) biological process terms related to inflammatory and immune response pathways, platelet development, vascular development, female pregnancy and reproduction in early-onset preeclampsia. Pathways related to immunity, complement and coagulation cascade were overrepresented in the hypergeometric test for the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Ten genes (ABI3BP, C7, HLA-G, IL2RB, KRBOX1, LRRC15, METTL7B, MPP5, RFLNB and SLC20A) had a >=+/-1 fold expression difference in severe early-onset preeclampsia group compared to early controls. There were 362 genes that had a >=+/-1 fold expression difference in severe early-onset preeclampsia group compared to late-onset preeclampsia group including ABI3BP, C7, HLA-G and IL2RB. CONCLUSION: There are significant differences in placental gene expression between severe early- and late-onset preeclampsia when both are associated with intrauterine growth restriction. ABI3BP, C7, HLA-G and IL2RB might contribute to the development of early form of severe preeclampsia. PMID- 28593876 TI - Missing value imputation for gene expression data by tailored nearest neighbors. AB - High dimensional data like gene expression and RNA-sequences often contain missing values. The subsequent analysis and results based on these incomplete data can suffer strongly from the presence of these missing values. Several approaches to imputation of missing values in gene expression data have been developed but the task is difficult due to the high dimensionality (number of genes) of the data. Here an imputation procedure is proposed that uses weighted nearest neighbors. Instead of using nearest neighbors defined by a distance that includes all genes the distance is computed for genes that are apt to contribute to the accuracy of imputed values. The method aims at avoiding the curse of dimensionality, which typically occurs if local methods as nearest neighbors are applied in high dimensional settings. The proposed weighted nearest neighbors algorithm is compared to existing missing value imputation techniques like mean imputation, KNNimpute and the recently proposed imputation by random forests. We use RNA-sequence and microarray data from studies on human cancer to compare the performance of the methods. The results from simulations as well as real studies show that the weighted distance procedure can successfully handle missing values for high dimensional data structures where the number of predictors is larger than the number of samples. The method typically outperforms the considered competitors. PMID- 28593877 TI - Advanced lipoprotein testing for cardiovascular diseases risk assessment: a review of the novel approaches in lipoprotein profiling. AB - With the increasing prevalence of cardiovascular diseases (CVD) worldwide, finding reliable and clinically relevant biomarkers to predict acute cardiovascular events has been a major aim of the scientific and medical community. Improvements of the understanding of the pathophysiological pathways of the disease highlighted the major role of lipoprotein particles, and these past decades have seen the emergence of a number of new methodologies to separate, measure and quantitate lipoproteins. Those methods, also known as advanced lipoprotein testing methods (ALT), have gained acceptance in the field of CVD risk assessment and have proven their clinical relevance. In the context of worldwide standardization and harmonization of biological assays, efforts have been initiated toward standardization of ALT methods. However, the complexity of lipoprotein particles and the multiple approaches and methodologies reported to quantify them have rendered these initiatives a critical issue. In this context and to better understand these challenges, this review presents a summary of the major methods available for ALT with the aim to point out the major differences in terms of procedures and quantities actually measured and to discuss the resulting comparability issues. PMID- 28593878 TI - Microbiota abnormalities and the therapeutic potential of probiotics in the treatment of mood disorders. AB - Major depressive disorder (MDD) and bipolar disorder (BD) are among the leading causes of burden and disability worldwide. Despite intensified research efforts to improve the treatment options and remission rates in mood disorders, no disease modifying treatment exists for these disorders. Accumulating evidence implicates the involvement of the gut microbiota in processes relevant to etiopathology of central nervous system-based disorders. The objective of this article was to critically evaluate the evidence supporting the link between gastrointestinal microbiota and mood disorders and to discuss the potential benefits of using probiotics in the treatment of MDD and BD. The concept of psychobiotics, which is bacterial-based interventions with mental health benefit, is emerging in the field. On the other hand, while probiotics might potentially represent a significant advance, specific roles of microbiota in the pathophysiology of mood disorders still need further investigation along with intervention studies. PMID- 28593879 TI - Deciphering the route to cyclic monoterpenes in Chrysomelina leaf beetles: source of new biocatalysts for industrial application? AB - The drastic growth of the population on our planet requires the efficient and sustainable use of our natural resources. Enzymes are indispensable tools for a wide range of industries producing food, pharmaceuticals, pesticides, or biofuels. Because insects constitute one of the most species-rich classes of organisms colonizing almost every ecological niche on earth, they have developed extraordinary metabolic abilities to survive in various and sometimes extreme habitats. Despite this metabolic diversity, insect enzymes have only recently generated interest in industrial applications because only a few metabolic pathways have been sufficiently characterized. Here, we address the biosynthetic route to iridoids (cyclic monoterpenes), a group of secondary metabolites used by some members of the leaf beetle subtribe Chrysomelina as defensive compounds against their enemies. The ability to produce iridoids de novo has also convergently evolved in plants. From plant sources, numerous pharmacologically relevant structures have already been described. In addition, in plants, iridoids serve as building blocks for monoterpenoid indole alkaloids with broad therapeutic applications. As the commercial synthesis of iridoid-based drugs often relies on a semisynthetic approach involving biocatalysts, the discovery of enzymes from the insect iridoid route can account for a valuable resource and economic alternative to the previously used enzymes from the metabolism of plants. Hence, this review illustrates the recent discoveries made on the steps of the iridoid pathway in Chrysomelina leaf beetles. The findings are also placed in the context of the studied counterparts in plants and are further discussed regarding their use in technological approaches. PMID- 28593880 TI - How I first met Dr. Morton K. Schwartz. PMID- 28593883 TI - Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). AB - Congenital anomalies of the kidneys and urinary tract (CAKUT) are found in 3-6 out of 1.000 of the newborns, or according to some statistics they are represented in 0.5% of all pregnancies. Congenital abnormalities of the kidneys and urinary tract present a family of diseases of various anatomic spectrum, including renal anomalies, and anomalies of the bladder and urethra. The study was retrospective-prospective which means that it included newly diagnosed patients suffering from CAKUT, as well as those patients with already diagnosed and well defined CAKUT on the basis of imaging studies which have been processed according to the protocol for this study. PMID- 28593884 TI - Transposition of Subclavian Artery - Is It the Appropriate Choice? AB - INTRODUCTION: To present patients with symptomatic subclavian artery disease and treatment possibility. CASE REPORT: A 53-year-old female was admitted with vertigo and left arm claudication. Duplex-scan and MSCT arteriography verified subclavian artery occlusion. After the endovascular treatment failure, the patient was switched to surgical treatment - subclavian artery transposition. After the successful surgical treatment, the patient was discharged on the second postoperative day. If the patient is a candidate for surgery, the literature review shows good initial and long-term results after the subclavian artery transposition, and emphasizes this technique as superior. CONCLUSION: Subclavian carotid transposition is a safe and effective method of treatment in patients after endovascular treatment failure or other indication. Also, the surgical treatment is technically demanding because of the difficult access to the vessel origin, and it requires experienced surgeons. PMID- 28593885 TI - Prognostic Factors on the Positivity for Metastases of the Axillary Lymph Nodes from Primary Breast Cancer. AB - AIM: The aim of the study was to identify the impact of T stage, the presence of estrogen, progesterone, HER2neu receptors and the values of the Ki67 on the positivity for metastases of the axillary lymph nodes, from primary breast cancer. MATERIAL AND METHODS: 290 surgically treated patients for breast cancer were included in the study. All cases have been analyzed by standard histological analysis including microscopic analysis on standard H&E staining. For determining the molecular receptors - HER2neu, ER, PR, p53 and Ki67, immunostaining by PT LINK immunoperoxidase has been done. RESULTS: Patients age was ranged between 18 90 years, average of 57.6+11.9. The mean size of the primary tumor in the surgically treated patient was 30.27 + 18.3 mm. On dissection from the axillary pits 8 to 39 lymph nodes were taken out, an average of 13.81+5.56. Metastases have been found in 1 to 23 lymph nodes, an average 3.14+4.71. In 59% of the patients there have been found metastases in the axillary lymph nodes. The univariate regression analysis showed that the location, size of tumor, differentiation of the tumor, stage, the value of the Ki67 and presence of lymphovascular invasion influence on the positivity of the axillary lymph nodes. The presence of the estrogen receptors, progesterone receptors and HER2neu receptors showed that they do not have influence on the positivity for metastatic deposits in axillary lymph nodes. The multivariate model and the logistic regression analysis as independent significant factors or predictors of positivity of the axillary lymph nodes are influenced by the tumor size and the positive lymphovascular invasion. CONCLUSION: Our study showed that the involving of the axillary lymph nodes is mainly influenced by the size of the tumor and the presence of lymphovascular invasion in the tumor. Ki67 determined proliferative index in the univariate analysis points the important influence of positivity in the axillary lymph nodes, but not in the multivariate regressive analysis. PMID- 28593886 TI - Correlation Between Microvessel Density and Morphological Features in Skin Squamous Cell Carcinoma. AB - INTRODUCTION: Abnormal angiogenesis is described in tumor growth and it facilitates its metastatic spread. Tumors with high angiogenic activity belong to the category of aggressive tumors with poor prognosis for patients. The aim of this study was to determine the blood vessels density (BVD), i.e. neovascularization at the tumor invasive front in skin squamous cell carcinoma (SCC) in order to determine its possible role in the tumor progression, and to correlate it to the blood vessels density of healthy skin and with the prognostic parameters of the TNM classification: T status, depth of tumor invasion (DI) and tumor histological grade (G), which were also correlated between each other. MATERIAL AND METHODS: The material consisted of surgical specimens obtained from 30 patients with skin SCC, who underwent surgery. Tissue samples were routinely processed by standard paraffin technique stained by Hematoxilin-Eosin and immunohistochemically with antibodies against smooth muscle actin (SMA) and CD34. The BVD in the invasive front of the neoplasms was correlated to the healthy skin, tumor status (pT), depth of invasion and grade of histological differentiation (pG). RESULTS: The histological analysis has shown a high statistical difference in the density of blood vessels in SCC compared to the healthy skin and statistical difference in BVD in neoplasms with different depth of invasion and different grade of differentiation. The density of neovascularzation increased with the deeper invasion and the worse differentiation. CONCLUSION: The increased vascularization at the invasive front of SCC with deeper invasion and worse differentiation has pointed out to its possible role in neoplasm progression. PMID- 28593887 TI - Type 2 Diabetes in People from Culturally and Linguistically Diverse Backgrounds: Perspectives for Training and Practice from Nutritional Therapy and Dietician Professions. AB - OBJECTIVE: To explore the perspectives of nutritional therapy and dietician practitioners, undergraduate students and academics working with people with type 2 diabetes and who are from culturally and linguistically diverse (CALD) backgrounds. METHODS: A qualitative study design of in-depth semi-structured one on-one interviews with a total of 24 participants (8 practitioners, 8 students and 8 academics) in the fields of nutritional therapy and dietetics. Open-ended questions focused on the perspectives and experiences (learning, practice and teaching) of working with people of CALD backgrounds who have type 2 diabetes. All interviews were recorded for thematic and textual analysis. RESULTS: Inter related themes which were confirmed with investigator triangulation were the understanding of (i) the concepts of culture and diversity, (ii) the concepts and influences of health, diabetes and food across cultures, (iii) influences within and across cultures and (iv) systems and resourcing. Overarching perspectives across these themes suggested frustration in having sufficient capacity to assess comprehensively, to deliver effective, comprehensive and high quality management plans, and to achieve required health behavioural changes with people from different CALD backgrounds. CONCLUSIONS: There's a need for improvements in the undergraduate education and training and in professional development programs; training and resourcing of interpreters in delivery of health-related information and working with health professionals; for focus on culturally appropriate management plans that involve consultation with key decision makers in families and communities; and, reviews of the systems for supporting and resourcing nutritional therapists and dieticians in professional development from undergraduate to practice levels. PMID- 28593888 TI - BDI in the Assessment of Depression in Different Medical Conditions. AB - As a common disorder, depression must be diagnosed not only in psychiatric but also in different medical settings, especially in patients with chronic diseases. Beck Depression Inventory is valuable and sensitive self-report inventory used worldwide for assessment depressive symptoms. In this research we present obtained scores of BDI in different group of disorders and we showed that BDI scores are related to the clinical condition, as well as with the age. PMID- 28593889 TI - Circonscript Subcutaneous Arteriovenous Malformation of the Head. AB - : The aim of this study is to show the various possibilities to treat this rare malformation, accentuating the results of the early surgical treatment before complications. MATERIAL: The authors present 8 cases of patients with subcutaneous arteriovenous malformations, 5 females and 3 males (age of 7, 13, 19, 23, 27, 52 and 58 years) treated in the period of 1999 until 2015 at the Clinic for Neurosurgery and the Clinic for Plastic, Aesthetic and Reconstructive Surgery in Skopje, Republic of Macedonia. This malformation has been observed by the parents in the childhood, around the age of 3 years in all cases. Local red circonscripted nodule, soft, with manually discharging tendency and varicose dilated veins have been observed in all cases, deaf on both sides in one case, while in the older case, a cavernous sinus thrombosis caused unilateral exophthalmia, hyaline indurated ophthalmic vein, vertigo, arrhythmia, heart failure and bradypsychia have been observed. The size of the malformation has been from 2.5 to 7 cm. The diagnostics was done using CT, CT-angiography and digital angiography including external carotid angiography. Endocranial arterials peduncle was present in all cases. RESULTS: Six cases underwent surgery, while two cases were treated with several treatments of endovascular embolization. The follow up has been ranged from 2 to 15 years. All surgically treated patients improved without recurrence, the exophthalmia, bradypsychia and the heart problems regressed, while in patients treated with endovascular non-complete occlusion the AVM decreased, but still remained. IN CONCLUSION: The Surgical treatment remains a first option if it is possible, and as earlier as possible, while embolization is a useful tool in cases where a complete excision is not possible. PMID- 28593890 TI - Extremely Locally Advanced Ovarian Malignant Mixed Mullerian Tumor in 37-Years Old Female. AB - Ovarian carcinosarcomas, rare variant of ovarian carcinoma, composed of both carcinomatous and mesenchymal components, solid and/or cystic, fleshy and hemorrhagic, frequently spreading beyond the ovary, are treated with surgery and adjuvant chemotherapy according to the treatment principles of ovarian carcinomas due to the small number of reported cases and lack of randomized studies. We report a case of a 37-year-old woman with clinical signs of extremely locally advanced tumor of ovarian origin, infiltrating the lower left quadrant of the abdominal wall with necrosis of the covering skin. Prior biopsy of the left ovary and omentum confirmed poorly differentiated serous adenocarcinoma. Bulky tumor the size of a child's head, originating from the left ovary and infiltrating into the lower left quadrant abdominal wall was debulked with wide excision of the abdominal wall and creation of wide defect of the lower left part of abdominal wall covered with Dexon mesh. After the recovery, the medial part of the defect with exposed mesh was closed with pedicled tensor fasciae latae fasciomyocutaneous flap, while the lateral part of the defect was covered with split thickness skin graft. Optimal surgical cytoreduction and adjuvant chemotherapy in case of extremely locally advanced ovarian malignant Mullerian tumor provide satisfactory recurrence-free survival period. PMID- 28593891 TI - On Our Science and Scientific Workers. PMID- 28593892 TI - Neonatal Hypoglycemia: Risk Factors and Outcomes. AB - BACKGROUND AND AIMS: Severe neonatal hypoglycemia (HG) leads to neurologic damage, mental retardation, epilepsy, personality disorders, impaired cardiac performance and muscle weakness. We aimed to assess the clinical characteristics of children with hypoglycemia in a random population of newborns. PATIENTS, METHODS AND RESULTS: We investigated 84 patients (M:F=35:48) born at the University Clinic for Gynecology and Obstetrics in Skopje (hospitalized in the NICU) who were found to have hypoglycemia. In total 89.25% of the babies were premature. The mean birth weight was 1795.95 +/596.08 grams, the mean birth length was 41.92+/- 4.62 cm, while the mean gestational age was 33.05+/-3.19 weeks. 32 children (38.08%) were very low birth weight (<1500g), 38 (45.22%) were low birth weight (1500-2500g), while there were 8 children (9.52%) appropriate for age BW and no high BW for age patients (>4000 g). HG duration was 2.42+/-2.41 hours. In the group as a whole, hypoxic-ischemic encephalopathy (HIE) was found in 3 children (3.57%), infections in 22 (26.18%), respiratory distress syndrome (RDS) in 9 patients (10.62%), intracranial haemorrhage in 2 patients (2.38%). There were no inborn errors of metabolism. There were two deaths (2.38%). CONCLUSION: Neonatal HG is a significant factor in the overall neonatal mortality. HG can also cause severe invalidity. We found that infections, LBW and low gestational age were most commonly associated with neonatal HG. However the Spearman test showed weak direct correlation, without statistical significance. Neonatal HG requires complex and team interaction of prenatal and postnatal approaches to reduce the incidence of seizures, their consequences and the overall mortality. Special consideration is to be taken in measures that avoid neonatal infections, HIE, LBW and low gestational age. Further studies on a larger population are needed to fully understand and prevent the phenomenon of HG in newborns. PMID- 28593893 TI - Trigonocephaly - Our Experience and Treatment in the Republic of Macedonia. AB - INTRODUCTION: Prematurely fused metopic suture results in developmental anomaly named trigonocephaly. The treatment of trigonocephaly is a surgical reconstruction, starting from the simple suturectomy toward the complicated cranial vault reconstructions with aim to obtain enough endocranial space for normal development of the brain and aesthetic correction as well. THE AIM: The aim of our paper is to present our experience on this pathology in the Republic of Macedonia, stressing the trigonocephaly as one of the rare forms of craniosynostosis. Our material: During a period of 20 years (from 1996 to 2015) at the Pediatric department of the Clinic for Neurosurgery in Skopje, we observed 18 babies with trigonocephaly, including one with Carpenter syndrome and trigonocephaly, 14 males and 4 females. All children had simple trigonocephaly, one had syndromic trigonocephaly (Carpenter's syndrome). According to Oi and Matsumoto classification done in 19865 severe trigonocephaly is observed in 11 cases and, moderate trigonocephaly in 7 cases. Our method: Our treatment consisted of slightly modified Di Rocco's3 surgical procedure named "shell" operation, adding transposition of the "bone flap". RESULTS: The postoperative period was uneventful except for the expected forehead swelling. The babies were discharged from the hospital on average at the 8th postoperative day. At the three months control after the surgery, the head had excellent aesthetic appearance, with regular psychomotor development according to the age of the patient (Fig 3a and 3b). We had no serious complications except the expected postoperative swelling of the forehead. All operated children had excellent "long term" aesthetic effect and normal psychomotor development. CONCLUSION: The early recognition of these anomalies including all craniosynostoses, the deformities of the newborn and infant's head and the preventive operative reconstruction would prevent abnormal disturbance of the psychomotor development during the child's growth. The multidisciplinary approach can prevent new disabled individuals in the society. Our technique allows shortening the entire surgical procedure, especially in the departments where blood saving devices are not available. PMID- 28593894 TI - 5th Rare Disease South Eastern Europe (SEE) Meeting, Skopje, Macedonia (November 15th, 2016). AB - The fifth SEE meeting on rare diseases (RDs) was held in Macedonian Academy of Sciences and Arts (MASA) the November 11th, 2016. Several lectures dealt with mucopolysaccharidosis, glycogen storage diseases and the possibilities for their diagnosis and treatment. Enzyme replacement treatment (ERT), its availability, effects (or the lack of it) on the brain, and further prospects of eventual gene treatment were comprehensively exposed and discussed. Special accent was on Gaucher, Morquio IVA, Hunter and the audience was given new knowledge on the complexities of diagnosis and treatment. A block of lectures on rare renal diseases was also impressive. From renal stones, their molecular and genetic mechanisms to different forms of CAKUT the use of NGS and other molecular methods in diagnosis of RDs. Mitochondrial diseases, the novelties and importance of early discovery were comprehensively exposed. Special lecture was given on the complement system. Endocrine disruptors, microprolactinomas were also the topic of the meeting. A rather reach session of posters was also presented. PMID- 28593895 TI - Congenital Anomalies of the Kidney and Urinary Tract in Children Born Small for Gestational Age. AB - INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) represent several types of malformations with occurrence of 1 in about 500 live births. OBJECTIVE: Small for gestation age (SGA) may influence in prevalence of CAKUT and progression of chronic kidney disease (CKD) in children. The aim of this study was to elaborate our experiences with detected CAKUT in a cohort of SGA born children in Macedonia. METHODS: Our cohort consisted of 100 SGA born children investigated for associated congenital anomalies of urinary tract. We analyzed anthropometric and clinical birth data in children with diagnosed CAKUT and estimated the stage and time of onset of CKD by biochemical and imaging technics. RESULTS: We revealed 7 (7.0%) SGA born children with congenital anomalies of the urinary tract. Their mean birth weight was very low 1855 gr ( 3.93 SDS) and the birth length 45.57cm (-2.17 SDS), as well. A significant growth failure with reduced weight and BMI were noticed at the time of diagnosis. A diagnosis of CAKUT in 4/7 was established in the first few months of life, but in others 3 later in early childhood. Three children revealed with unilateral kidney agenesis, 2 had hypo-dysplastic kidneys and in 2 children was found vesicoureteral reflux. Normal glomerular filtration rate was estimated in 2 children with CAKUT. Stage 2 CKD with GFR 60-90 ml/minx1.73m2 had 3 children, 1 patient was graded in stage 3 and one child needed kidney transplantation, stage 5 CKD. CONCLUSIONS: We presented 7 SGA born children with CAKUT. An early recognition, assessment and treatment of these anomalies might improve their quality of life. PMID- 28593896 TI - Synergistic Effect of Hyperoxia and Biotrauma On Ventilator-Induced Lung Injury. AB - Patients undergoing mechanical ventilation in intensive care units (ICUs) may develop ventilator-induced lung injury (VILI). Beside the high tidal volume (Vt) and plateau pressure (Pplat), hyperoxia is supposed to precipitate lung injury. Oxygen toxicity is presumed to occur at levels of fraction of inspired oxygen (FiO2) exceeding 0.40. The exposure time to hyperoxia is certainly very important and patients who spend extended time on mechanical ventilation (MV) are probably more exposed to severe hyperoxic acute lung injury (HALI). Together, hyperoxia and biotrauma (release of cytokines) have a synergistic effect and can induce VILI. In the clinical practice, the reduction of FiO2 to safe levels through the appropriate use of the positive end expiratory pressure (PEEP) and the alignment of mean airway pressure is an appropriate goal. The strategy for lung protective ventilation must include setting up FiO2 to a safe level that is accomplished by using PaO2/FiO2 ratio with a lower limit of FiO2 to achieve acceptable levels of PaO2, which will be safe for the patient without local (lungs) or systemic inflammatory response. The protocol from the ARDS-net study is used for ventilator setup and adjustment. Cytokines (IL-1, IL-6, TNFalpha and MIP-2) that are involved in the inflammatory response are determined in order to help the therapeutic approach in counteracting HALI. Computed tomography findings reflect the pathological phases of the diffuse alveolar damage. At least preferably the lowest level of FiO2 should be used in order to provide full lung protection against the damage induced by MV. PMID- 28593898 TI - Clinical Evaluation of Root End Resection Bevel in Periapical Surgery. AB - Root end resections play an important role in the success of periapical surgery. Beveling of the root end resections can vary significantly depending on the surgical technique, the root and canal morphology. The intention of this article was to clinically assess the root resections bevels and to estimate their relation to applied periapical surgeries. A prospective clinical study consisted of sixty periapical surgeries performed on teeth with chronic periapical lesions. Thirty periapical surgeries were performed in a conventional manner, while thirty were contemporary ultrasonic surgeries. Following the completion of strictly planned and performed intraoperative procedures, the resection bevels were assessed. To obtain the real bevel angles a compass was used. Root resections were significantly less beveled in all teeth operated with contemporary ultrasonic surgery, with mean values between 2.1 degrees to 7.8 degrees . The number of roots and their dilacerations didn't influence the root resection bevel. For comparison, root resections were significantly beveled in all conventionally operated teeth, with mean values of 46 degrees . Due to the technical limitations of the conventional periapical surgery, mandibular premolars were exclusively operated with ultrasonic periapical surgery, with mean values of resection bevel not exceeding 20.7 degrees . Significantly lesser resection bevel associated with ultrasonic periapical surgery contributes to root preservation and favorable surgical outcome. PMID- 28593897 TI - Factors That Influence the Virological Response in Patients with Chronic Hepatitis C Treated with Pegylated Interferon and Ribavirin. AB - INTRODUCTION: The success of the antiviral treatment in patients with chronic hepatitis C depends on the factors related to the virus and the host. The aim of the study is the analysis of the antiviral therapy which is a combination of pegylated interferon and ribavirin, considering various factors that will identify the predictors of the sustained virological response. MATERIAL AND METHODS: This retrospective study included 226 patients, divided in two groups. Patients with sustained virological response and patients without sustained virological response were compared in terms of the following factors: genotype, viral load, gender, age, inflammatory and fibrotic changes in the liver, metabolic abnormalities, obesity and fatty liver. RESULTS: The rate of the sustained virological response is 83.6%, more frequently in patients with genotype 3, with evidenced statistical significance (90.54%). The factors that significantly contribute to sustained virological response are related to the age (p = 0.0001), genotype (p = 0.002), mode of transmission (p = 0.005), inflammatory changes in the liver (p = 0.028), body mass index (p = 0.022) and insulin resistance (p = 0.039). The high rate of sustained virological response is related to the younger age of the patients which indirectly means short Hepatitis C Virus infection duration, absence of advanced liver disease and lack of significant co-morbid conditions. Single confirmed independent predictors of sustained virological response are the age (OR 0.928, p = 0.0001) and genotype (OR 3.134, p = 0.005). CONCLUSIONS: Factors that are related to the virological response are the age, genotype, mode of transmission, inflammatory changes in the liver, body mass index and insulin resistance, but still, independent predictors of sustained virologic response are the age and the genotype. PMID- 28593899 TI - A time warping approach to multiple sequence alignment. AB - We propose an approach for multiple sequence alignment (MSA) derived from the dynamic time warping viewpoint and recent techniques of curve synchronization developed in the context of functional data analysis. Starting from pairwise alignments of all the sequences (viewed as paths in a certain space), we construct a median path that represents the MSA we are looking for. We establish a proof of concept that our method could be an interesting ingredient to include into refined MSA techniques. We present a simple synthetic experiment as well as the study of a benchmark dataset, together with comparisons with 2 widely used MSA softwares. PMID- 28593900 TI - Phellinus rimosus improves mitochondrial energy status and attenuates nephrotoxicity in diabetic rats. AB - BACKGROUND: Mitochondrial dysfunction and increase in reactive oxygen species during diabetes can lead to pathological consequences in kidneys. The present study was aimed to investigate the effect of Phellinus rimosus in the streptozotocin (STZ)-induced diabetic rat renal mitochondria and the possible mechanism of protection. METHODS: Phellinus rimosus (50 and 250 mg/kg, p.o) was treated after inducing diabetes by STZ (45 mg/kg, i.p) in rats. The serum samples were subjected to creatinine and urea estimation. Mitochondrial antioxidant status such as mitochondrial superoxide dismutase, glutathione peroxidase, and reduced glutathione; adenosine triphosphate level; and lipid peroxidation were measured. The activities of Krebs cycle enzymes such as isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, III, and IV in kidney mitochondria were also determined. RESULTS: Administration of P. rimosus (250 mg/kg b.wt) once daily for 30 days, significantly (p<0.05) enhanced the activities of Krebs cycle dehydrogenases, mitochondrial electron transport chain complexes, and ATP level. Further, P. rimosus had significantly protected the renal mitochondrial antioxidant status and lipid peroxidation. CONCLUSIONS: The results of the study concluded that by limiting the extent of renal mitochondrial damage in the hyperglycemic state, P. rimosus alleviated nephrotoxicity. PMID- 28593901 TI - Pseudohypoaldosteronism types I and II: little more than a name in common. AB - Pseudohypoaldosteronism (PHA) comprises a diverse group of rare diseases characterized by sodium and potassium imbalances incorrectly attributed to a defect in aldosterone production. Two different forms of PHA have been described, type I (PHAI) and type II (PHAII). PHAI has been subclassified into renal and systemic. Given the rarity and heterogeneity of this group of disorders we report three patients who carry PHA and a brief revision of current literature focused on the comparative analysis of PHAI and PHAII. Cases 1 and 2 presented with hyponatremia, hyperkalemia, metabolic acidosis and elevated plasma aldosterone and plasma renin activity in the neonatal period. Sequence analysis of the NRC2 gene demonstrated a novel heterozygous c.403C>T mutation in case 1 and a complete deletion in case 2, confirming the diagnosis of renal PHAI. Case 3 was a 4-year old with hypertension, hyperkalemia, metabolic acidosis, normal plasma aldosterone and decreased plasma renin activity. Sequence analysis of the CUL3 gene demonstrated a previously unreported heterozygous c.1377+2T>3 mutation, confirming the diagnosis of PHAII-E. We highlight the importance of the determination of plasma aldosterone and plasma renin activity in the context of persistent sodium and potassium imbalances in children. PMID- 28593902 TI - Inverted pyramid of prenatal care - is it enough? Should it be - extended inverted pyramid of prenatal care? PMID- 28593904 TI - On the 'data stirring' role of the dentate gyrus of the hippocampus. AB - Understanding hippocampal (HC) function, as it is presently known, includes exploring the HC role in episodic memory storage. As pointed out by Teyler and DiScenna in the 1980s, the apparatus needed for recalling a stored episode, and awakening all its components in a coordinated manner, by necessity includes a triggering device able to reach each of the mental entities that must be awakened. In the context of neuronal networks, the triggering device in question takes the form of a large cell assembly, a separate one made for every new episode stored. The present paper deals with the creation and the properties of these cell assemblies ('pointer groups'). To perform the function of episodic memory retrieval, each of these must possess the information capacity (entropy) enabling it to single out an episode and the network connections enabling it to reach all components of it; further, to deal with the unpredictability of the memory items it has to address, it must have its member neurons well distributed through the length of the network (the HC). The requirements imply that the creation of a pointer group must include a randomizing step analogous to 'stirring'. It is argued that many of the known peculiarities of granule cells in the dentate gyrus arise as solutions to the practical problems presented by the creation of the pointer groups and the details of 'stirring', and so do a series of other features of the HC network, some of them only discovered in the last few years. PMID- 28593903 TI - Hippocampal BDNF in physiological conditions and social isolation. AB - Exposure of an organism to chronic psychosocial stress may affect brain-derived neurotrophic factor (BDNF) expression that has been implicated in the etiology of psychiatric disorders, such as depression. Given that depression in humans has been linked with social stress, the chronic social stress paradigms for modeling psychiatric disorders in animals have thus been developed. Chronic social isolation in animal models generally causes changes in hypothalamic-pituitary adrenal axis functioning, associated with anxiety- and depressive-like behaviors. Also, this chronic stress causes downregulation of BDNF protein and mRNA in the hippocampus, a stress-sensitive brain region closely related to the pathophysiology of depression. In this review, we discuss the current knowledge regarding the structure, function, intracellular signaling, inter-individual differences and epigenetic regulation of BDNF in both physiological conditions and depression and changes in corticosterone levels, as a marker of stress response. Since BDNF levels are age dependent in humans and rodents, this review will also highlight the effects of adolescent and adult chronic social isolation models of both genders on the BDNF expression. PMID- 28593906 TI - Biomarkers of acute kidney injury: a step forward. PMID- 28593907 TI - Opioid-induced hyponatremia in a patient with central diabetes insipidus: independence from ADH. AB - Hyponatremia can be a complication of opioid therapy, which has been postulated to occur secondary to inappropriate antidiuretic hormone secretion (syndrome of inappropriate antidiuretic hormone secretion [SIADH]). We report severe hyponatremia following wisdom teeth extraction with opioid analgesia in a 19-year old female with diabetes insipidus (DI) and acquired panhypopituitarism that challenges this theory. As this patient has DI, we believe opioid treatment caused severe hyponatremia by the following mechanisms: (1) Opioids have a direct antidiuretic effect independent of changes in ADH, as demonstrated in Brattleboro rats with central DI. (2) Hydrocodone may have stimulated this patient's thirst center contributing to hyponatremia, as demonstrated in animal studies. Opioid use can cause hyponatremia in patients independent of ADH. It is important for clinicians to be aware of this so that patients can be appropriately counseled. PMID- 28593909 TI - Distinction between urine crystals by automated urine analyzer SediMAX conTRUST is specific but lacks sensitivity. PMID- 28593910 TI - The EFLM strategy for harmonization of the preanalytical phase. PMID- 28593911 TI - The challenges of genetic risk scores for the prediction of coronary heart disease. PMID- 28593905 TI - Targeting and inactivation of bacterial toxins by human defensins. AB - Defensins, as a prominent family of antimicrobial peptides (AMP), are major effectors of the innate immunity with a broad range of immune modulatory and antimicrobial activities. In particular, defensins are the only recognized fast response molecules that can neutralize a broad range of bacterial toxins, many of which are among the deadliest compounds on the planet. For a decade, the mystery of how a small and structurally conserved group of peptides can neutralize a heterogeneous group of toxins with little to no sequential and structural similarity remained unresolved. Recently, it was found that defensins recognize and target structural plasticity/thermodynamic instability, fundamental physicochemical properties that unite many bacterial toxins and distinguish them from the majority of host proteins. Binding of human defensins promotes local unfolding of the affected toxins, destabilizes their secondary and tertiary structures, increases susceptibility to proteolysis, and leads to their precipitation. While the details of toxin destabilization by defensins remain obscure, here we briefly review properties and activities of bacterial toxins known to be affected by or resilient to defensins, and discuss how recognized features of defensins correlate with the observed inactivation. PMID- 28593912 TI - Impact of FGF21 on glycemic control. AB - Fibroblast growth factor 21 (FGF21) plays a role in regulating adaptation to various metabolic abnormalities. In addition, FGF21 is involved in controlling glucose and lipid homeostasis. The regulation of FGF21 is a complex process and depends upon multiple metabolic factors and hormones. Humans and animals with obesity or type 2 diabetes have abnormal expression and changes of FGF21 in the circulation. Interventional studies in rodents and monkeys with obesity, insulin resistance or type 2 diabetes revealed a potential therapeutic relevance of FGF21 in correcting these abnormalities. This review summarizes the current knowledge about the regulation of FGF21 by distinct metabolic and endogenous factors, considering the most relevant studies. In this context, the results of interventional studies in humans and various animal models of diseases, such as diabetes and obesity, are discussed. In addition, potential mechanisms of the molecular regulation of FGF21 expression and secretion are reviewed. PMID- 28593913 TI - Excessive weight gain in exclusively breast-fed infants. AB - BACKGROUND: Breastfeeding is recommended as the best source of nutrition in the first months of life and observational studies have associated exclusive breastfeeding with decreased weight gain and a protective effect against obesity in childhood. The objective of this study was to describe the characteristics of a cohort of exclusively breastfed obese infants to determine factors that may lead to this unusual weight gain. METHODS: Infants seen between 2003 and 2015 who were exclusively breastfed and showed excessive weight gain in the first year of life were followed with a focus on features of the mother, the child, feeding patterns and the presence of concomitant factors that influence nutritional status. Additionally, in a subset of the sample, macronutrients of the maternal breast milk were analyzed. A descriptive, prospective cross-sectional study was conducted. RESULTS: Of 73 patients, 63% were girls. At 3 months of life, 64% had a weight-for-height standard deviation score (SDS) >2. At 6 and at 12 months, 100% of the patients had a weight-for-height >2 SDS. The mean age at semisolid food introduction was 7 months. The mean age at weaning was 15.8 months. The babies were fed on demand and no hunger-satiety pattern was observed. In the breast milk samples analyzed, a significantly lower fat content was found. CONCLUSIONS: The results of our study lead to the assumption that inter individual variations in mother's milk composition may affect the growth patterns of children. PMID- 28593914 TI - Improved metabolic control in tetrahydrobiopterin (BH4), responsive phenylketonuria with sapropterin administered in two divided doses vs. a single daily dose. AB - BACKGROUND: Phenylketonuria (PKU) often requires a lifelong phenylalanine (Phe) restricted diet. Introduction of 6R-tetrahydrobiopterin (BH4) has made a huge difference in the diets of patients with PKU. BH4 is the co-factor of the enzyme phenylalanine hydroxylase (PAH) and improves PAH activity and, thus, Phe tolerance in the diet. A limited number of published studies suggest a pharmacodynamic profile of BH4 more suitable to be administered in divided daily doses. METHODS: After a 72-h BH4 loading test, sapropterin was initiated in 50 responsive patients. This case-control study was conducted by administering the same daily dose of sapropterin in group 1 (n=24) as a customary single dose or in two divided doses in group 2 (n=26) over 1 year. RESULTS: Mean daily consumption of Phe increased significantly after the first year of BH4 treatment in group 2 compared to group 1 (p<0.05). At the end of the first year of treatment with BH4, another dramatic difference observed between the two groups was the ability to transition to a Phe-free diet. Eight patients from group 2 and two from group 1 could quit dietary restriction. CONCLUSIONS: When given in two divided daily doses, BH4 was more efficacious than a single daily dose in increasing daily Phe consumption, Phe tolerance and the ability to transition to a Phe-unrestricted diet at the end of the first year of treatment. PMID- 28593915 TI - Analytical performance specifications for external quality assessment - definitions and descriptions. AB - External Quality Assurance (EQA) is vital to ensure acceptable analytical quality in medical laboratories. A key component of an EQA scheme is an analytical performance specification (APS) for each measurand that a laboratory can use to assess the extent of deviation of the obtained results from the target value. A consensus conference held in Milan in 2014 has proposed three models to set APS and these can be applied to setting APS for EQA. A goal arising from this conference is the harmonisation of EQA APS between different schemes to deliver consistent quality messages to laboratories irrespective of location and the choice of EQA provider. At this time there are wide differences in the APS used in different EQA schemes for the same measurands. Contributing factors to this variation are that the APS in different schemes are established using different criteria, applied to different types of data (e.g. single data points, multiple data points), used for different goals (e.g. improvement of analytical quality; licensing), and with the aim of eliciting different responses from participants. This paper provides recommendations from the European Federation of Laboratory Medicine (EFLM) Task and Finish Group on Performance Specifications for External Quality Assurance Schemes (TFG-APSEQA) and on clear terminology for EQA APS. The recommended terminology covers six elements required to understand APS: 1) a statement on the EQA material matrix and its commutability; 2) the method used to assign the target value; 3) the data set to which APS are applied; 4) the applicable analytical property being assessed (i.e. total error, bias, imprecision, uncertainty); 5) the rationale for the selection of the APS; and 6) the type of the Milan model(s) used to set the APS. The terminology is required for EQA participants and other interested parties to understand the meaning of meeting or not meeting APS. PMID- 28593916 TI - Preparation, calibration and evaluation of the First International Standard for human C-peptide. AB - BACKGROUND: Measurement of C-peptide by immunoassay contributes to the diagnosis of a number of disorders related to beta cell function. Stocks of the current international reference reagent (IRR) for C-peptide, used to calibrate these immunoassays, are exhausted, and this report summarises the international study to establish a replacement World Health Organization (WHO) international standard (IS) to maintain the availability of a globally available reference material and support efforts to standardise C-peptide assays. METHODS: The study was conducted in three phases; phase I involved the assignment of a value to a primary calibrant in mass units by amino acid analysis and phase II applied this value to the calibration of a candidate standard, 13/146, by reversed phase high performance liquid chromatography (RP-HPLC) assay. In phase III, the candidate standard was compared to the first IRR by current immunoassays to assess its suitability to serve as an IS. RESULTS: Calibration of the candidate standard by RP-HPLC gave a final estimated content of 8.64 MUg/ampoule with expanded uncertainty of 8.21-9.07 MUg/ampoule (95% confidence; k=2.45). The candidate standard also appears sufficiently stable to serve as an IS, based on HPLC analysis of accelerated thermal degradation samples of 13/146, and was also shown to have appropriate immunological activity. A difference in bias approach was used to assess the commutability of 13/146 with human serum and urine samples. With the exception of two laboratories, the candidate standard demonstrated commutability with respect to the serum and urine samples included in this study. CONCLUSIONS: The candidate standard, 13/146, is suitable to serve as the First International Standard for human C-peptide, and it has been formally adopted by the Expert Committee on Biological Standardisation of the WHO. PMID- 28593917 TI - Vitamin D deficiency in pregnancy at term: risk factors and pregnancy outcomes. AB - Background Vitamin D deficiency during pregnancy is a worldwide epidemic. The aim of this study was to determine the prevalence of vitamin D deficiency, its predictive factors and the association with pregnancy outcomes. Materials and methods This was a prospective observational study in a tertiary teaching hospital over 2-years' duration from August 2013 to August 2015. A total of 680 women who completed 37 weeks of pregnancy were recruited. Results Five hundred and seventy-five patients were enrolled in the final analysis for pregnancy outcomes (response rate of 84.6%). There were 71.7% patients who exhibited vitamin D deficiency, 21.0% vitamin D insufficiency and only 7.3% who had adequate levels of 25-hydroxyvitamin D (25-OH-vit D) of more than 30 ng/mL. There was no statistically significant association between vitamin D status with maternal (parity, gestational diabetes mellitus, hypertension, preeclampsia, intrauterine growth restriction, preterm labor, antenatal infection, bacterial vaginosis and anemia) and neonatal outcomes (low birth weight baby and neonatal intensive care unit admission) among the three groups. Conclusion A high prevalence of low vitamin D level among pregnant women at term was seen in this study, however, there was no significant finding observed between vitamin D status and both maternal and neonatal outcomes. PMID- 28593918 TI - Beyond obesity - thermogenic adipocytes and cardiometabolic health. AB - The global prevalence of obesity and related cardiometabolic disease continues to increase through the 21st century. Whilst multi-factorial, obesity is ultimately caused by chronic caloric excess. However, despite numerous interventions focussing on reducing caloric intake these either fail or only elicit short-term changes in body mass. There is now a focus on increasing energy expenditure instead which has stemmed from the recent 're-discovery' of cold-activated brown adipose tissue (BAT) in adult humans and inducible 'beige' adipocytes. Through the unique mitochondrial uncoupling protein 1 (UCP1), these thermogenic adipocytes are capable of combusting large amounts of chemical energy as heat and in animal models can prevent obesity and cardiometabolic disease. At present, human data does not point to a role for thermogenic adipocytes in regulating body weight or fat mass but points to a pivotal role in regulating metabolic health by improving insulin resistance as well as glucose and lipid homeostasis. This review will therefore focus on the metabolic benefits of BAT activation and the mechanisms and signalling pathways by which these could occur including improvements in insulin signalling in peripheral tissues, systemic lipid and cholesterol metabolism and cardiac and vascular function. PMID- 28593919 TI - Effects of interleukin-1 receptor antagonist (IL-1Ra) gene 86 bp VNTR polymorphism on recurrent pregnancy loss: a case-control study. AB - Objective Recurrent pregnancy loss (RPL) is a heterogeneous disease which is defined as two or more consecutive fetal losses during early pregnancy. Interleukin-1 receptor antagonist (IL-1Ra) is a anti-inflammatory cytokine, which inhibits IL-1 activity by binding to its receptors. The aim of this study was to investigate the association between RPL and IL-1Ra intron 2 polymorphism (86 bp VNTR) in Iranian women. Materials and methods In this case control study, genetic polymorphism was studied in 140 RPL patients and 140 healthy women as controls. Genomic DNA was extracted from the blood samples and polymorphism analysis was performed using the polymerase chain reaction (PCR) method. Finally, the data obtained were analyzed by statistical software. Results We found an increased frequency of the IL-1Ra 1/1 genotype in the case group compared to the control group. Whereas, the frequency of IL-1Ra genotype 1/2 was higher in control group than in the case group. However, we did not observe an association between IL-1Ra 86 bp VNTR polymorphism in intron 2 and RPL patients (p > 0.05). Conclusion IL 1Ra VNTR polymorphism may not be a genetic factor for RPL. However, investigation of IL-1Ra polymorphism was recommended in other populations and patients with recurrent pregnancy loss. PMID- 28593920 TI - Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients. AB - BACKGROUND: Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose adjusted concentrations (C0/D) in stable kidney transplant recipients. METHODS: This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T), CYP2C8 rs10509681 (c.1196A>G) and ABCB1 rs1045642 (c.3435C>T), rs1128503 (c.1236C>T), and rs2032582 (c.2677G>T/A) polymorphisms. RESULTS: In the TAC group, CYP3A4 rs2242480 A allele carriers were associated with lower TAC C0/D. For CYP3A5 rs15524 SNP, C0/D was higher among patients carrying TT genotype when compared with CT and CC genotype carriers in the SRL and, more consistently, in the TAC groups. For ABCB1 rs1045642 SNP, TT genotype was associated with reduced SRL C0/D, but only at month 15. CONCLUSIONS: CYP3A4 rs2242480 and CYP3A5 rs15524 SNPs resulted in significant changes in SRL and TAC C0/D at different times after transplantation. PMID- 28593921 TI - Hyperandrogenism in adolescent girls: relationship with the somatotrophic axis. AB - BACKGROUND: During puberty there is a physiologic increase in adrenal and ovarian androgens. It has been suggested that the somatotrophic axis may be related to the development of hyperandrogenism and anovulation in non-obese adult women with polycystic ovarian syndrome (PCOS). The objective of the study was to investigate whether ovarian androgen secretion in young postmenarchal girls is related to the function of their somatotropic axis. METHODS: This was a cross-sectional study of adolescent girls. We studied non-obese adolescent girls with hyperandrogenism (HA; n = 21) matched with control girls (C; n = 25) for chronological age, age at menarche and body mass index. We obtained a fasting blood sample for measurement of serum glucose, insulin, 17-hydroxyprogesterone (17OH-Prog), dehydroepiandrosterone-sulfate (DHEA-S), androstenedione, sex hormone-binding globulin (SHBG), total testosterone, IGF-I, IGF-II, IGFBP-1, IGFBP-3, ghrelin, leptin, AMH (antiMullerian hormone), luteinizing hormone (LH) and follicle stimulating hormone (FSH) during the follicular phase of the menstrual period. We performed an oral glucose tolerance test to determine blood glucose, insulin and ghrelin levels and urine samples to measure urinary GH (growth hormone) levels. RESULTS: As expected, the hyperandrogenic girls had significantly higher Ferriman scores, basal total testosterone, free androgen index (FAI), androstenedione, AMH, and basal LH levels compared with the girls in controls. Serum IGF-I, IGF II, IGFBP-3 and urinary GH did not differ between HA and C. There was a correlation between urinary GH and FAI in all girls (r 0.29, p < 0.05). In addition, in HA girls FAI correlated with insulin, homeostasis model assessment (HOMA) and ghrelin. CONCLUSIONS: We observed a correlation between urinary GH and FAI in the hyperandrogenic and control girls, suggesting that the function of the somatotrophic axis may influence the secretion of androgens in adolescent girls. PMID- 28593922 TI - Copy number variations in "classical" obesity candidate genes are not frequently associated with severe early-onset obesity in children. AB - BACKGROUND: Obesity is genetically heterogeneous and highly heritable, although polymorphisms explain the phenotype in only a small proportion of obese children. We investigated the presence of copy number variations (CNVs) in "classical" genes known to be associated with (monogenic) early-onset obesity in children. METHODS: In 194 obese Caucasian children selected for early-onset and severe obesity from our obesity cohort we screened for deletions and/or duplications by multiplex ligation-dependent probe amplification reaction (MLPA). As we found one MLPA probe to interfere with a polymorphism in SIM1 we investigated its association with obesity and other phenotypic traits in our extended cohort of 2305 children. RESULTS: In the selected subset of most severely obese children, we did not find CNV with MLPA in POMC, LEP, LEPR, MC4R, MC3R or MC2R genes. However, one SIM1 probe located at exon 9 gave signals suggestive for SIM1 insufficiency in 52 patients. Polymerase chain reaction (PCR) analysis identified this as a false positive result due to interference with single nucleotide polymorphism (SNP) rs3734354/rs3734355. We, therefore, investigated for associations of this polymorphism with obesity and metabolic traits in our extended cohort. We found rs3734354/rs3734355 to be associated with body mass index-standard deviation score (BMI-SDS) (p = 0.003), but not with parameters of insulin metabolism, blood pressure or food intake. CONCLUSIONS: In our modest sample of severely obese children, we were unable to find CNVs in well established monogenic obesity genes. Nevertheless, we found an association of rs3734354 in SIM1 with obesity of early-onset type in children, although not with obesity-related traits. PMID- 28593923 TI - The effects of transport by car on coagulation tests. AB - BACKGROUND: This research investigated the effects of the transport of blood samples between centers/laboratories by car on coagulation tests. METHODS: Five tubes of blood samples were taken from 20 healthy volunteers. The samples consisted of a baseline (control) group, centrifuged and noncentrifuged transported samples; centrifuged and noncentrifuged untransported samples. The groups of centrifuged and noncentrifuged samples were transported by car for 2 h. The centrifuged and noncentrifuged untransported samples were incubated in the laboratory until the transported samples arrived. Prothrombin time (PT) and activated partial thromboplastin time (APTT) tests were conducted for all samples. RESULTS: Significant differences between the baseline group and the centrifuged and noncentrifuged transported samples and the noncentrifuged untransported samples were found for APTT levels (p<0.05, for all). In addition, significant mean percentage differences in PT values were found between the baseline group and the noncentrifuged transported samples (p<0.001) and the noncentrifuged untransported samples (p=0.005). The mean level of PT in the noncentrifuged transported samples was outside the upper limit of the clinical decision level. CONCLUSIONS: Noncentrifuged transported samples showed clinically significant differences in PT test results that may have stemmed from mechanical agitation during transportation. Therefore, we recommend not transporting noncentrifuged specimens for PT testing by car. PMID- 28593925 TI - Intensive educational efforts combined with external quality assessment improve the preanalytical phase in general practitioner offices and nursing homes. AB - BACKGROUND: Errors in the preanalytical phase in clinical laboratories affect patient safety. The aim of this study was to evaluate the effect of intensive educational efforts together with external quality assessment (EQA) of the preanalytical phase from 2013 to 2015 to improve patient identification in primary health care in Norway. In addition, routines for venous and capillary blood sampling were investigated. METHODS: A preanalytical EQA was circulated in 2013 by the Norwegian Quality Improvement of Laboratory Examinations (Noklus) to general practitioner offices and nursing homes (n=2000) to obtain information about important issues to focus on before launching an intensive educational program with courses, posters and visits in 2013-2015. Preanalytical EQA surveys were further circulated in 2014 and 2015. RESULTS: The response rate varied between 42% and 55%. The percentages of participants asking for the patients' name and the Norwegian identification number increased from about 8% in 2013 to about 35% in 2015. The increase was similar for those participating in only one EQA survey and for those who participated in EQA surveys both in 2013 and 2015. Guidelines for venous and capillary blood sampling were not always followed. CONCLUSIONS: Educational efforts more than the preanalytical EQA influenced the actions and resulted in an increase in the percentages of participants that followed the guidelines for patient identification. Some aspects of blood sampling routines need improvement. PMID- 28593924 TI - Influence of age, gender and body mass index on late-night salivary cortisol in healthy adults. AB - BACKGROUND: Late-night salivary cortisol (LNSC) is one of the most reliable tests to screen for endogenous Cushing syndrome. This test is simple, inexpensive and noninvasive and has high sensitivity and specificity. The aim of our study was to analyze the putative influence of age, gender and body mass index (BMI) on LNSC levels in a healthy population. METHODS: Cross-sectional study conducted in healthy adults. Midnight saliva samples were collected at home. Participants refrained from teeth brushing, eating or drinking for 2 h prior to collection. Salivary cortisol measured by electrochemiluminescence immunoassay (ECLIA). The study was approved by the Ethics Committee of the hospital (number 140073). RESULTS: We evaluated 122 nonsmoking healthy volunteers. Mean age was 35+/-14 years (range, 18-74 years); 63% were women. Mean BMI was 24+/-3 kg/m2, blood pressure 115/74 mmHg and fasting plasma glucose 4.8+/-0.5 mmol/L. LNSC presented a non-Gaussian distribution; the median was 3.58 (range, 0.55-8.55) nmol/L (0.13 [range, 0.02-0.31] MUg/dL), and the 97.5th percentile (P97.5) was 8.3 nmol/L (0.3 MUg/dL). Multiple linear regression disclosed a significant positive association between salivary cortisol levels and age (r2=0.21, p<0.001), but no association with gender (p=0.105) or BMI (p=0.119). Accordingly, participants aged >50 years had significantly higher salivary cortisol as compared to those aged <50 years (5.24 nmol/L [0.19 MUg/dL] vs. 3.31 nmol/L [0.12 MUg/dL], respectively, p<0.001). CONCLUSIONS: The maximum reference value (P97.5) of LNSC was set at 8.3 nmol/L (0.3 MUg/dL) using ECLIA. Advanced age was associated with higher LNSC levels, with no evident influence of gender or BMI. PMID- 28593926 TI - The impact of pneumatic tube system on routine laboratory parameters: a systematic review and meta-analysis. AB - BACKGROUND: Pneumatic tube system (PTS) is a widely used method of transporting blood samples in hospitals. The aim of this study was to evaluate the effects of the PTS transport in certain routine laboratory parameters as it has been implicated with hemolysis. METHODS: A systematic review and a meta-analysis were conducted. PubMed and Scopus databases were searched (up until November 2016) to identify prospective studies evaluating the impact of PTS transport in hematological, biochemical and coagulation measurements. The random-effects model was used in the meta-analysis utilizing the mean difference (MD). Heterogeneity was quantitatively assessed using the Cohran's Q and the I2 index. Subgroup analysis, meta-regression analysis, sensitivity analysis, cumulative meta analysis and assessment of publication bias were performed for all outcomes. RESULTS: From a total of 282 studies identified by the searching procedure, 24 were finally included in the meta-analysis. The meta-analysis yielded statistically significant results for potassium (K) [MD=0.04 mmol/L; 95% confidence interval (CI)=0.015-0.065; p=0.002], lactate dehydrogenase (LDH) (MD=10.343 U/L; 95% CI=6.132-14.554; p<10-4) and aspartate aminotransferase (AST) (MD=1.023 IU/L; 95% CI=0.344-1.702; p=0.003). Subgroup analysis and random effects meta-regression analysis according to the speed and distance of the samples traveled via the PTS revealed that there is relation between the rate and the distance of PTS with the measurements of K, LDH, white blood cells and red blood cells. CONCLUSIONS: This meta-analysis suggests that PTS may be associated with alterations in K, LDH and AST measurements. Although these findings may not have any significant clinical effect on laboratory results, it is wise that each hospital validates their PTS. PMID- 28593927 TI - Laboratory characterization of leukemic cell procoagulants. AB - BACKGROUND: In acute myeloid leukemias, there is an increased chance to develop thrombotic disorders. We hypothesized that in addition to leukemic promyelocytes, monocytic leukemia cells may also have a higher procoagulant activity. METHODS: Fibrin formation was assessed by a one-stage clotting assay using a magnetic coagulometer. The thrombin generation test (TGT) of magnetically isolated normal human monocytes, intact leukemic cells and their isolated microparticles was performed by a fluorimetric assay. Phosphatidylserine (PS) expression of leukemic cells and microparticle number determinations were carried out by flow cytometry. RESULTS: All cell lines displayed a significant procoagulant potential compared to isolated normal human monocytes. In the TGT test, the mean of lagtime and the time to peak parameters were significantly shorter in leukemic cells (3.9-4.7 and 9.9-10.3 min) compared to monocytes (14.9 and 26.5 min). The mean of peak thrombin in various monocytic leukemia cell lines was 112.1-132.9 nM vs. 75.1 nM in monocytes; however, no significant difference was observed in the ETP parameter. Factor VII-deficient plasma abolished all procoagulant activity, whereas factor XII-deficient plasma did not affect the speed of fibrin formation and thrombin generation but modulated the amount of thrombin. Factor XI-deficient plasma affected the time to peak values in one leukemic cell line and also attenuated peak thrombin. Leukemia cell-derived microparticles from all three cell lines exerted a procoagulant effect by significantly shortening the lagtime in TGT; there was a nonsignificant difference in case of ETP parameter. CONCLUSIONS: All investigated monocytic leukemia cell lines exhibited significant thrombin generation. This phenomenon was achieved by the procoagulants on the surface of leukemic cells as well as by their microparticles. PMID- 28593928 TI - A survey of patients' views from eight European countries of interpretive support from Specialists in Laboratory Medicine. AB - BACKGROUND: There is increasing interest in direct patient engagement including receiving their laboratory medicine results. We previously established an appetite for Specialists in Laboratory Medicine to support patients in understanding results. The aim of this study was to establish whether patients agreed with such an approach, determined through surveying views in eight European countries. METHODS: A standardized five-question survey was administered across eight European countries to a total of 1084 individuals attending medical outpatient clinics, with 100 patients each in Poland, Serbia, Netherlands, Turkey and Czech Republic, 101 in Estonia, 116 in Denmark and 367 in Norway. The responses across countries were compared using the chi-square test (p<0.05). RESULTS: Patients wanting their results ranged from 50% to 94% (mean 65%) of those responding positively, a mean of 72% wanted additional information with their results; direct receipt was preferred over referral to a website. Specialists in Laboratory Medicine providing such information were acceptable to a mean of 62% of those respondents wishing their results; in countries where payment was possible, there was little interest in making additional payment for such a service. CONCLUSIONS: A clear proportion of patients are interested in receiving their laboratory medicine results, the majority with explanatory notes; a role for Specialists in Laboratory Medicine is acceptable and raises the potential for direct engagement by such specialists with patients offering a new paradigm for the provision of laboratory medicine activities. PMID- 28593929 TI - High titers of anti-infliximab antibody do not interfere with Abbott immunoassays. PMID- 28593930 TI - Intra-articular injections of ketamine and 25% dextrose improve clinical and pathological outcomes in the monosodium iodoacetate model of osteoarthritis. AB - BACKGROUND: The study evaluated the effect of intra-articular injections of ketamine and 25% dextrose with triamcinolone acetate (TA) and hyaluronic acid (HA) on joint pathology and pain behavior in monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in experimental mice. METHODS: In phase I, the MIA-induced OA model was standardized. In phase II, mice were divided into three groups: disease controls (DC), ketamine 12 mg/kg (K12) and ketamine 24 mg/kg (K24) to select an effective dose of ketamine for phase III. In phase III, the groups were: DC, normal controls (NC), K24, 25% dextrose (D25) - 10 MUL, TA 6 mg/kg, and HA - 3.5 mg/kg. The effect of ketamine was compared with the standard drugs - TA and HA. In phases II and III, after 7 days following the induction of OA, animals were subjected to weekly behavioral tests and biweekly drug administration from week 2 to week 4. Subsequently, after 4 weeks knee joint samples were collected and sent for histopathological evaluation to a veterinary pathologist. RESULTS: In phase I, the DC group showed significant OA changes as compared to NC on knee joint histopathology scoring. In phase II, all the behavioral tests and knee joint histopathology results demonstrated a significant improvement with K24 as compared to DC. In phase III, significant differences were found between DC vs. HA, DC vs. D25, DC vs. K24, K24 vs. TA, HA vs. TA for open field test and hot plate test (p<0.001), whereas HA and ketamine showed comparable results for these tests. There was a significant improvement in D25, TA and K24, HA groups as compared to DC in histopathology scores, (p<0.05). CONCLUSIONS: The NMDA antagonist effect of ketamine and the proliferative effect of 25% dextrose showed a reduction in pain and disease activity in the OA model. PMID- 28593931 TI - Performance characterization of a 3D liquid scintillation detector for discrete spot scanning proton beam systems. AB - Existing systems for proton beam dosimetry are limited in their ability to provide a complete, accurate, and detailed account of volumetric dose distribution. In this work, we describe the design and development of a portable, fast, and reusable liquid scintillator-based three-dimensional (3D) optical detection system for use in proton therapy. Our long-term goal is to use this system clinically for beam characterization, dosimetry, and quality assurance studies of discrete spot scanning proton beam systems. The system used a 20 * 20 * 20 cm3 liquid scintillator volume. Three mutually orthogonal cameras surrounding this volume captured scintillation photons emitted in response to the proton beams. The cameras exhibited a mean spatial resolution of 0.21 mm over the complete detection volume and a temporal resolution of 11 ms. The system is shown to be capable of capturing all 94 beam energies delivered by a synchrotron and performing rapid beam range measurements with a mean accuracy of 0.073 +/- 0.030 mm over all energies. The range measurement uncertainty for doses less than 1 cGy was found to be +/-0.355 mm, indicating high precision for low dose detection. Finally, we demonstrated that using multiple cameras allowed for the precise locations of the delivered beams to be tracked in 3D. We conclude that this detector is capable of real-time and accurate tracking of dynamic spot beam deliveries in 3D. The high-resolution light profiles it generates will be useful for future 3D construction of dose maps. PMID- 28593932 TI - Study of structural properties and defects of Ni-doped SnO2 nanorods as ethanol gas sensors. AB - An ethanol gas sensor with enhanced sensor response was fabricated using Ni-doped SnO2 nanorods, synthesized via a simple hydrothermal method. It was found that the response (R = R 0/R g) of a 5.0 mol% Ni-doped SnO2 (5.0Ni:SnO2) nanorod sensor was 1.4 * 104 for 1000 ppm C2H5OH gas, which is about 13 times higher than that of pure SnO2 nanorods, (1.1 * 103) at the operating temperature of 450 degrees C. Moreover, for 50 ppm C2H5OH gas, the 5.0Ni:SnO2 nanorod sensor still recorded a significant response reading, namely 2.0 * 103 with a response time of 30 s and recovery time of 10 min. To investigate the effect of Ni dopant (0.5-5.0 mol%) on SnO2 nanorods, structural characterizations were demonstrated using field emission scanning electron microscopy, high-resolution transmission electron microscopy, Fourier transform infrared spectroscopy, x-ray diffraction (XRD) analysis, x-ray photoelectron spectroscopy and an ultraviolet-visible spectrometer. XRD results confirmed that all the samples consisted of tetragonal shaped rutile SnO2 nanorods. It was found that the average diameter and length of the nanorods formed in 5.0Ni:SnO2 were four times smaller (~6 and ~35 nm, respectively) than those of the nanorods formed in pure SnO2 (~25 and 150 nm). Interestingly, both samples had the same aspect ratio, ~6. It is proposed that the high response of the 5.0Ni:SnO2 nanorod sensor can be attributed to the particle size, which causes an increase in the thickness of the charge depletion layer, and the presence of oxygen vacancies within the matrix of SnO2 nanorods. PMID- 28593933 TI - On the persistence of polar domains in ultrathin ferroelectric capacitors. AB - The instability of ferroelectric ordering in ultra-thin films is one of the most important fundamental issues pertaining realization of a number of electronic devices with enhanced functionality, such as ferroelectric and multiferroic tunnel junctions or ferroelectric field effect transistors. In this paper, we investigate the polarization state of archetypal ultrathin (several nanometres) ferroelectric heterostructures: epitaxial single-crystalline BaTiO3 films sandwiched between the most habitual perovskite electrodes, SrRuO3, on top of the most used perovskite substrate, SrTiO3. We use a combination of piezoresponse force microscopy, dielectric measurements and structural characterization to provide conclusive evidence for the ferroelectric nature of the relaxed polarization state in ultrathin BaTiO3 capacitors. We show that even the high screening efficiency of SrRuO3 electrodes is still insufficient to stabilize polarization in SrRuO3/BaTiO3/SrRuO3 heterostructures at room temperature. We identify the key role of domain wall motion in determining the macroscopic electrical properties of ultrathin capacitors and discuss their dielectric response in the light of the recent interest in negative capacitance behaviour. PMID- 28593934 TI - Origins of life: a problem for physics, a key issues review. AB - The origins of life stands among the great open scientific questions of our time. While a number of proposals exist for possible starting points in the pathway from non-living to living matter, these have so far not achieved states of complexity that are anywhere near that of even the simplest living systems. A key challenge is identifying the properties of living matter that might distinguish living and non-living physical systems such that we might build new life in the lab. This review is geared towards covering major viewpoints on the origin of life for those new to the origin of life field, with a forward look towards considering what it might take for a physical theory that universally explains the phenomenon of life to arise from the seemingly disconnected array of ideas proposed thus far. The hope is that a theory akin to our other theories in fundamental physics might one day emerge to explain the phenomenon of life, and in turn finally permit solving its origins. PMID- 28593935 TI - Justifying quasiparticle self-consistent schemes via gradient optimization in Baym-Kadanoff theory. AB - The question of which non-interacting Green's function 'best' describes an interacting many-body electronic system is both of fundamental interest as well as of practical importance in describing electronic properties of materials in a realistic manner. Here, we study this question within the framework of Baym Kadanoff theory, an approach where one locates the stationary point of a total energy functional of the one-particle Green's function in order to find the total ground-state energy as well as all one-particle properties such as the density matrix, chemical potential, or the quasiparticle energy spectrum and quasiparticle wave functions. For the case of the Klein functional, our basic finding is that minimizing the length of the gradient of the total energy functional over non-interacting Green's functions yields a set of self-consistent equations for quasiparticles that is identical to those of the quasiparticle self consistent GW (QSGW) (van Schilfgaarde et al 2006 Phys. Rev. Lett. 96 226402-4) approach, thereby providing an a priori justification for such an approach to electronic structure calculations. In fact, this result is general, applies to any self-energy operator, and is not restricted to any particular approximation, e.g., the GW approximation for the self-energy. The approach also shows that, when working in the basis of quasiparticle states, solving the diagonal part of the self-consistent Dyson equation is of primary importance while the off diagonals are of secondary importance, a common observation in the electronic structure literature of self-energy calculations. Finally, numerical tests and analytical arguments show that when the Dyson equation produces multiple quasiparticle solutions corresponding to a single non-interacting state, minimizing the length of the gradient translates into choosing the solution with largest quasiparticle weight. PMID- 28593936 TI - Yolk-shell type nanoprobe with excellent fluorescence 'blinking' behavior for optical super resolution imaging. AB - A new yolk-shell type nanoprobe for super-resolution imaging is demonstrated. Using the proposed nanoprobe and single molecule localization based super resolution imaging strategy, intracellular nanoparticle tracking and super resolution imaging are realized. The localization precision is about 50 nm and single-molecule localization microscopy using the proposed nanoprobe requires only one single excitation laser and no specific imaging buffer. PMID- 28593937 TI - Basaloid Squamous Cell Carcinoma of the Head and Neck: Subclassification into Basal, Ductal, and Mixed Subtypes Based on Comparison of Clinico-pathologic Features and Expression of p53, Cyclin D1, Epidermal Growth Factor Receptor, p16, and Human Papillomavirus. AB - BACKGROUND: Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma with distinct pathologic characteristics. The histogenesis of BSCC is not fully understood, and the cancer has been suggested to originate from a totipotent primitive cell in the basal cell layer of the surface epithelium or in the proximal duct of secretory glands. METHODS: Twenty-six cases of head and neck BSCC from Asan Medical Center, Seoul, Korea, reported during a 14-year-period were subclassified into basal, ductal, and mixed subtypes according to the expression of basal (cytokeratin [CK] 5/6, p63) or ductal markers (CK7, CK8/18). The cases were also subject to immunohistochemical study for CK19, p53, cyclin D1, epidermal growth factor receptor (EGFR), and p16 and to in situ hybridization for human papillomavirus (HPV), and the results were clinico-pathologically compared. RESULTS: Mixed subtype (12 cases) was the most common, and these cases showed hypopharyngeal predilection, older age, and higher expression of CK19, p53, and EGFR than other subtypes. The basal subtype (nine cases) showed frequent comedo-necrosis and high expression of cyclin D1. The ductal subtype (five cases) showed the lowest expression of p53, cyclin D1, and EGFR. A small number of p16- and/or HPV-positive cases were not restricted to one subtype. BSCC was the cause of death in 19 patients, and the average follow-up period for all patients was 79.5 months. Overall survival among the three subtypes was not significantly different. CONCLUSIONS: The results of this study suggest a heterogeneous pathogenesis of head and neck BSCC. Each subtype showed variable histology and immunoprofiles, although the clinical implication of heterogeneity was not determined in this study. PMID- 28593938 TI - Myosin-dependent cell-cell communication controls synchronicity of division in acute and chronic stages of Toxoplasma gondii. AB - The obligate intracellular parasite Toxoplasma gondii possesses a repertoire of 11 myosins. Three class XIV motors participate in motility, invasion and egress, whereas the class XXII myosin F is implicated in organelle positioning and inheritance of the apicoplast. Here we provide evidence that TgUNC acts as a chaperone dedicated to the folding, assembly and function of all Toxoplasma myosins. The conditional ablation of TgUNC recapitulates the phenome of the known myosins and uncovers two functions in parasite basal complex constriction and synchronized division within the parasitophorous vacuole. We identify myosin J and centrin 2 as essential for the constriction. We demonstrate the existence of an intravacuolar cell-cell communication ensuring synchronized division, a process dependent on myosin I. This connectivity contributes to the delayed death phenotype resulting from loss of the apicoplast. Cell-cell communication is lost in activated macrophages and during bradyzoite differentiation resulting in asynchronized, slow division in the cysts. PMID- 28593939 TI - Magnetic forces enable controlled drug delivery by disrupting endothelial cell cell junctions. AB - The vascular endothelium presents a major transport barrier to drug delivery by only allowing selective extravasation of solutes and small molecules. Therefore, enhancing drug transport across the endothelial barrier has to rely on leaky vessels arising from disease states such as pathological angiogenesis and inflammatory response. Here we show that the permeability of vascular endothelium can be increased using an external magnetic field to temporarily disrupt endothelial adherens junctions through internalized iron oxide nanoparticles, activating the paracellular transport pathway and facilitating the local extravasation of circulating substances. This approach provides a physically controlled drug delivery method harnessing the biology of endothelial adherens junction and opens a new avenue for drug delivery in a broad range of biomedical research and therapeutic applications. PMID- 28593940 TI - Time-programmable drug dosing allows the manipulation, suppression and reversal of antibiotic drug resistance in vitro. AB - Multi-drug strategies have been attempted to prolong the efficacy of existing antibiotics, but with limited success. Here we show that the evolution of multi drug-resistant Escherichia coli can be manipulated in vitro by administering pairs of antibiotics and switching between them in ON/OFF manner. Using a multiplexed cell culture system, we find that switching between certain combinations of antibiotics completely suppresses the development of resistance to one of the antibiotics. Using this data, we develop a simple deterministic model, which allows us to predict the fate of multi-drug evolution in this system. Furthermore, we are able to reverse established drug resistance based on the model prediction by modulating antibiotic selection stresses. Our results support the idea that the development of antibiotic resistance may be potentially controlled via continuous switching of drugs. PMID- 28593942 TI - Dynamic contrast-enhanced photoacoustic imaging using photothermal stimuli responsive composite nanomodulators. AB - Molecular photoacoustic imaging has shown great potential in medical applications; its sensitivity is normally in pico-to-micro-molar range, dependent on exogenous imaging agents. However, tissue can produce strong background signals, which mask the signals from the imaging agents, resulting in orders of magnitude sensitivity reduction. As such, an elaborate spectral scan is often required to spectrally un-mix the unwanted background signals. Here we show a new single-wavelength photoacoustic dynamic contrast-enhanced imaging technique by employing a stimuli-responsive contrast agent. Our technique can eliminate intrinsic background noises without significant hardware or computational resources. We show that this new contrast agent can generate up to 30 times stronger photoacoustic signals than the concentration-matched inorganic nanoparticle counterparts. By dynamically modulating signals from the contrast agents with an external near-infrared optical stimulus, we can further suppress the background signals leading to an additional increase of more than five-fold in imaging contrast in vivo. PMID- 28593941 TI - Cross-orientation suppression in visual area V2. AB - Object recognition relies on a series of transformations among which only the first cortical stage is relatively well understood. Already at the second stage, the visual area V2, the complexity of the transformation precludes a clear understanding of what specifically this area computes. Previous work has found multiple types of V2 neurons, with neurons of each type selective for multi-edge features. Here we analyse responses of V2 neurons to natural stimuli and find three organizing principles. First, the relevant edges for V2 neurons can be grouped into quadrature pairs, indicating invariance to local translation. Second, the excitatory edges have nearby suppressive edges with orthogonal orientations. Third, the resulting multi-edge patterns are repeated in space to form textures or texture boundaries. The cross-orientation suppression increases the sparseness of responses to natural images based on these complex forms of feature selectivity while allowing for multiple scales of position invariance. PMID- 28593944 TI - Non-Ising and chiral ferroelectric domain walls revealed by nonlinear optical microscopy. AB - The properties of ferroelectric domain walls can significantly differ from those of their parent material. Elucidating their internal structure is essential for the design of advanced devices exploiting nanoscale ferroicity and such localized functional properties. Here, we probe the internal structure of 180 degrees ferroelectric domain walls in lead zirconate titanate (PZT) thin films and lithium tantalate bulk crystals by means of second-harmonic generation microscopy. In both systems, we detect a pronounced second-harmonic signal at the walls. Local polarimetry analysis of this signal combined with numerical modelling reveals the existence of a planar polarization within the walls, with Neel and Bloch-like configurations in PZT and lithium tantalate, respectively. Moreover, we find domain wall chirality reversal at line defects crossing lithium tantalate crystals. Our results demonstrate a clear deviation from the ideal Ising configuration that is traditionally expected in uniaxial ferroelectrics, corroborating recent theoretical predictions of a more complex, often chiral structure. PMID- 28593946 TI - Carbon nanotube-based three-dimensional monolithic optoelectronic integrated system. AB - Single material-based monolithic optoelectronic integration with complementary metal oxide semiconductor-compatible signal processing circuits is one of the most pursued approaches in the post-Moore era to realize rapid data communication and functional diversification in a limited three-dimensional space. Here, we report an electrically driven carbon nanotube-based on-chip three-dimensional optoelectronic integrated circuit. We demonstrate that photovoltaic receivers, electrically driven transmitters and on-chip electronic circuits can all be fabricated using carbon nanotubes via a complementary metal oxide semiconductor compatible low-temperature process, providing a seamless integration platform for realizing monolithic three-dimensional optoelectronic integrated circuits with diversified functionality such as the heterogeneous AND gates. These circuits can be vertically scaled down to sub-30 nm and operates in photovoltaic mode at room temperature. Parallel optical communication between functional layers, for example, bottom-layer digital circuits and top-layer memory, has been demonstrated by mapping data using a 2 * 2 transmitter/receiver array, which could be extended as the next generation energy-efficient signal processing paradigm. PMID- 28593947 TI - Water pumping in mantle shear zones. AB - Water plays an important role in geological processes. Providing constraints on what may influence the distribution of aqueous fluids is thus crucial to understanding how water impacts Earth's geodynamics. Here we demonstrate that ductile flow exerts a dynamic control on water-rich fluid circulation in mantle shear zones. Based on amphibole distribution and using dislocation slip-systems as a proxy for syn-tectonic water content in olivine, we highlight fluid accumulation around fine-grained layers dominated by grain-size-sensitive creep. This fluid aggregation correlates with dislocation creep-accommodated strain that localizes in water-rich layers. We also give evidence of cracking induced by fluid pressure where the highest amount of water is expected. These results emphasize long-term fluid pumping attributed to creep cavitation and associated phase nucleation during grain size reduction. Considering the ubiquitous process of grain size reduction during strain localization, our findings shed light on multiple fluid reservoirs in the crust and mantle. PMID- 28593945 TI - Human LACC1 increases innate receptor-induced responses and a LACC1 disease-risk variant modulates these outcomes. AB - Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the LACC1 (C13orf31) region. Here we show that human peripheral and intestinal myeloid-derived cells express laccase domain containing 1 (LACC1); LACC1 is expressed in both the cytoplasm and mitochondria. Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2 signalling complex, and is critical for optimal NOD2-induced signalling, mitochondrial ROS (mtROS) production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A, and amplifies pattern recognition receptor (PRR)-induced SDH activity, an important contributor to mtROS production. Relative to LACC1 Ile254, cells transfected with Crohn's disease-risk LACC1 Val254 or LACC1 with mutations of the nearby histidines (249,250) have reduced PRR-induced outcomes. Relative to LACC1 Ile254 carriers, Val254 disease-risk carrier macrophages demonstrate decreased PRR induced mtROS, signalling, cytokine secretion and bacterial clearance. Therefore, LACC1 is critical for amplifying PRR-induced outcomes, an effect that is attenuated by the LACC1 disease-risk variant. PMID- 28593949 TI - Current-induced skyrmion generation and dynamics in symmetric bilayers. AB - Magnetic skyrmions are quasiparticle-like textures which are topologically different from other states. Their discovery in systems with broken inversion symmetry sparked the search for materials containing such magnetic phase at room temperature. Their topological properties combined with the chirality-related spin-orbit torques make them interesting objects to control the magnetization at nanoscale. Here we show that a pair of coupled skyrmions of opposite chiralities can be stabilized in a symmetric magnetic bilayer system by combining Dzyaloshinskii-Moriya interaction (DMI) and dipolar coupling effects. This opens a path for skyrmion stabilization with lower DMI. We demonstrate in a device with asymmetric electrodes that such skyrmions can be independently written and shifted by electric current at large velocities. The skyrmionic nature of the observed quasiparticles is confirmed by the gyrotropic force. These results set the ground for emerging spintronic technologies where issues concerning skyrmion stability, nucleation and propagation are paramount. PMID- 28593950 TI - Origin of the crossover from polarons to Fermi liquids in transition metal oxides. AB - Transition metal oxides host a wealth of exotic phenomena ranging from charge, orbital and magnetic order to nontrivial topological phases and superconductivity. In order to translate these unique materials properties into device functionalities these materials must be doped; however, the nature of carriers and their conduction mechanism at the atomic scale remain unclear. Recent angle-resolved photoelectron spectroscopy investigations provided insight into these questions, revealing that the carriers of prototypical metal oxides undergo a transition from a polaronic liquid to a Fermi liquid regime with increasing doping. Here, by performing ab initio many-body calculations of angle resolved photoemission spectra of titanium dioxide, we show that this transition originates from non-adiabatic polar electron-phonon coupling, and occurs when the frequency of plasma oscillations exceeds that of longitudinal-optical phonons. This finding suggests that a universal mechanism may underlie polaron formation in transition metal oxides, and provides a pathway for engineering emergent properties in quantum matter. PMID- 28593948 TI - Conditional internalization of PEGylated nanomedicines by PEG engagers for triple negative breast cancer therapy. AB - Triple-negative breast cancer (TNBC) lacks effective treatment options due to the absence of traditional therapeutic targets. The epidermal growth factor receptor (EGFR) has emerged as a promising target for TNBC therapy because it is overexpressed in about 50% of TNBC patients. Here we describe a PEG engager that simultaneously binds polyethylene glycol and EGFR to deliver PEGylated nanomedicines to EGFR+ TNBC. The PEG engager displays conditional internalization by remaining on the surface of TNBC cells until contact with PEGylated nanocarriers triggers rapid engulfment of nanocargos. PEG engager enhances the anti-proliferative activity of PEG-liposomal doxorubicin to EGFR+ TNBC cells by up to 100-fold with potency dependent on EGFR expression levels. The PEG engager significantly increases retention of fluorescent PEG probes and enhances the antitumour activity of PEGylated liposomal doxorubicin in human TNBC xenografts. PEG engagers with specificity for EGFR are promising for improved treatment of EGFR+ TNBC patients. PMID- 28593952 TI - Quantum annealing with all-to-all connected nonlinear oscillators. AB - Quantum annealing aims at solving combinatorial optimization problems mapped to Ising interactions between quantum spins. Here, with the objective of developing a noise-resilient annealer, we propose a paradigm for quantum annealing with a scalable network of two-photon-driven Kerr-nonlinear resonators. Each resonator encodes an Ising spin in a robust degenerate subspace formed by two coherent states of opposite phases. A fully connected optimization problem is mapped to local fields driving the resonators, which are connected with only local four body interactions. We describe an adiabatic annealing protocol in this system and analyse its performance in the presence of photon loss. Numerical simulations indicate substantial resilience to this noise channel, leading to a high success probability for quantum annealing. Finally, we propose a realistic circuit QED implementation of this promising platform for implementing a large-scale quantum Ising machine. PMID- 28593951 TI - Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information. AB - Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin beta1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the beta1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor beta1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets. PMID- 28593955 TI - Palaeoanthropology: On the origin of our species. PMID- 28593953 TI - New fossils from Jebel Irhoud, Morocco and the pan-African origin of Homo sapiens. AB - Fossil evidence points to an African origin of Homo sapiens from a group called either H. heidelbergensis or H. rhodesiensis. However, the exact place and time of emergence of H. sapiens remain obscure because the fossil record is scarce and the chronological age of many key specimens remains uncertain. In particular, it is unclear whether the present day 'modern' morphology rapidly emerged approximately 200 thousand years ago (ka) among earlier representatives of H. sapiens or evolved gradually over the last 400 thousand years. Here we report newly discovered human fossils from Jebel Irhoud, Morocco, and interpret the affinities of the hominins from this site with other archaic and recent human groups. We identified a mosaic of features including facial, mandibular and dental morphology that aligns the Jebel Irhoud material with early or recent anatomically modern humans and more primitive neurocranial and endocranial morphology. In combination with an age of 315 +/- 34 thousand years (as determined by thermoluminescence dating), this evidence makes Jebel Irhoud the oldest and richest African Middle Stone Age hominin site that documents early stages of the H. sapiens clade in which key features of modern morphology were established. Furthermore, it shows that the evolutionary processes behind the emergence of H. sapiens involved the whole African continent. PMID- 28593957 TI - Nomenclature: Rules for new species from live specimens. PMID- 28593956 TI - Corrigendum: Black hole growth in the early Universe is self-regulated and largely hidden from view. AB - This corrects the article DOI: 10.1038/nature10103. PMID- 28593959 TI - Condensed-matter physics: Magnetism in flatland. PMID- 28593962 TI - Minerals: A rescue package for imperilled collection. PMID- 28593963 TI - Accelerated discovery of two crystal structure types in a complex inorganic phase field. AB - The discovery of new materials is hampered by the lack of efficient approaches to the exploration of both the large number of possible elemental compositions for such materials, and of the candidate structures at each composition. For example, the discovery of inorganic extended solid structures has relied on knowledge of crystal chemistry coupled with time-consuming materials synthesis with systematically varied elemental ratios. Computational methods have been developed to guide synthesis by predicting structures at specific compositions and predicting compositions for known crystal structures, with notable successes. However, the challenge of finding qualitatively new, experimentally realizable compounds, with crystal structures where the unit cell and the atom positions within it differ from known structures, remains for compositionally complex systems. Many valuable properties arise from substitution into known crystal structures, but materials discovery using this approach alone risks both missing best-in-class performance and attempting design with incomplete knowledge. Here we report the experimental discovery of two structure types by computational identification of the region of a complex inorganic phase field that contains them. This is achieved by computing probe structures that capture the chemical and structural diversity of the system and whose energies can be ranked against combinations of currently known materials. Subsequent experimental exploration of the lowest-energy regions of the computed phase diagram affords two materials with previously unreported crystal structures featuring unusual structural motifs. This approach will accelerate the systematic discovery of new materials in complex compositional spaces by efficiently guiding synthesis and enhancing the predictive power of the computational tools through expansion of the knowledge base underpinning them. PMID- 28593964 TI - Flavour-changing neutral currents making and breaking the standard model. AB - The standard model of particle physics is our best description yet of fundamental particles and their interactions, but it is known to be incomplete. As yet undiscovered particles and interactions might exist. One of the most powerful ways to search for new particles is by studying processes known as flavour changing neutral current decays, whereby a quark changes its flavour without altering its electric charge. One example of such a transition is the decay of a beauty quark into a strange quark. Here we review some intriguing anomalies in these decays, which have revealed potential cracks in the standard model-hinting at the existence of new phenomena. PMID- 28593965 TI - Population growth: Help to make food go further in Egypt. PMID- 28593966 TI - Mining: Heritage status could safeguard fossil beds. PMID- 28593967 TI - The age of the hominin fossils from Jebel Irhoud, Morocco, and the origins of the Middle Stone Age. AB - The timing and location of the emergence of our species and of associated behavioural changes are crucial for our understanding of human evolution. The earliest fossil attributed to a modern form of Homo sapiens comes from eastern Africa and is approximately 195 thousand years old, therefore the emergence of modern human biology is commonly placed at around 200 thousand years ago. The earliest Middle Stone Age assemblages come from eastern and southern Africa but date much earlier. Here we report the ages, determined by thermoluminescence dating, of fire-heated flint artefacts obtained from new excavations at the Middle Stone Age site of Jebel Irhoud, Morocco, which are directly associated with newly discovered remains of H. sapiens. A weighted average age places these Middle Stone Age artefacts and fossils at 315 +/- 34 thousand years ago. Support is obtained through the recalculated uranium series with electron spin resonance date of 286 +/- 32 thousand years ago for a tooth from the Irhoud 3 hominin mandible. These ages are also consistent with the faunal and microfaunal assemblages and almost double the previous age estimates for the lower part of the deposits. The north African site of Jebel Irhoud contains one of the earliest directly dated Middle Stone Age assemblages, and its associated human remains are the oldest reported for H. sapiens. The emergence of our species and of the Middle Stone Age appear to be close in time, and these data suggest a larger scale, potentially pan-African, origin for both. PMID- 28593968 TI - Microresonator-based solitons for massively parallel coherent optical communications. AB - Solitons are waveforms that preserve their shape while propagating, as a result of a balance of dispersion and nonlinearity. Soliton-based data transmission schemes were investigated in the 1980s and showed promise as a way of overcoming the limitations imposed by dispersion of optical fibres. However, these approaches were later abandoned in favour of wavelength-division multiplexing schemes, which are easier to implement and offer improved scalability to higher data rates. Here we show that solitons could make a comeback in optical communications, not as a competitor but as a key element of massively parallel wavelength-division multiplexing. Instead of encoding data on the soliton pulse train itself, we use continuous-wave tones of the associated frequency comb as carriers for communication. Dissipative Kerr solitons (DKSs) (solitons that rely on a double balance of parametric gain and cavity loss, as well as dispersion and nonlinearity) are generated as continuously circulating pulses in an integrated silicon nitride microresonator via four-photon interactions mediated by the Kerr nonlinearity, leading to low-noise, spectrally smooth, broadband optical frequency combs. We use two interleaved DKS frequency combs to transmit a data stream of more than 50 terabits per second on 179 individual optical carriers that span the entire telecommunication C and L bands (centred around infrared telecommunication wavelengths of 1.55 micrometres). We also demonstrate coherent detection of a wavelength-division multiplexing data stream by using a pair of DKS frequency combs-one as a multi-wavelength light source at the transmitter and the other as the corresponding local oscillator at the receiver. This approach exploits the scalability of microresonator-based DKS frequency comb sources for massively parallel optical communications at both the transmitter and the receiver. Our results demonstrate the potential of these sources to replace the arrays of continuous-wave lasers that are currently used in high-speed communications. In combination with advanced spatial multiplexing schemes and highly integrated silicon photonic circuits, DKS frequency combs could bring chip scale petabit-per-second transceivers into reach. PMID- 28593969 TI - Optical physics: One ring to multiplex them all. PMID- 28593970 TI - Layer-dependent ferromagnetism in a van der Waals crystal down to the monolayer limit. AB - Since the discovery of graphene, the family of two-dimensional materials has grown, displaying a broad range of electronic properties. Recent additions include semiconductors with spin-valley coupling, Ising superconductors that can be tuned into a quantum metal, possible Mott insulators with tunable charge density waves, and topological semimetals with edge transport. However, no two dimensional crystal with intrinsic magnetism has yet been discovered; such a crystal would be useful in many technologies from sensing to data storage. Theoretically, magnetic order is prohibited in the two-dimensional isotropic Heisenberg model at finite temperatures by the Mermin-Wagner theorem. Magnetic anisotropy removes this restriction, however, and enables, for instance, the occurrence of two-dimensional Ising ferromagnetism. Here we use magneto-optical Kerr effect microscopy to demonstrate that monolayer chromium triiodide (CrI3) is an Ising ferromagnet with out-of-plane spin orientation. Its Curie temperature of 45 kelvin is only slightly lower than that of the bulk crystal, 61 kelvin, which is consistent with a weak interlayer coupling. Moreover, our studies suggest a layer-dependent magnetic phase, highlighting thickness-dependent physical properties typical of van der Waals crystals. Remarkably, bilayer CrI3 displays suppressed magnetization with a metamagnetic effect, whereas in trilayer CrI3 the interlayer ferromagnetism observed in the bulk crystal is restored. This work creates opportunities for studying magnetism by harnessing the unusual features of atomically thin materials, such as electrical control for realizing magnetoelectronics, and van der Waals engineering to produce interface phenomena. PMID- 28593972 TI - Publishing: Springer Nature's reply on fake review. PMID- 28593973 TI - A challenge to lepton universality in B-meson decays. AB - One of the key assumptions of the standard model of particle physics is that the interactions of the charged leptons, namely electrons, muons and taus, differ only because of their different masses. Whereas precision tests comparing processes involving electrons and muons have not revealed any definite violation of this assumption, recent studies of B-meson decays involving the higher-mass tau lepton have resulted in observations that challenge lepton universality at the level of four standard deviations. A confirmation of these results would point to new particles or interactions, and could have profound implications for our understanding of particle physics. PMID- 28593971 TI - Nutrient acquisition strategies of mammalian cells. AB - Mammalian cells are surrounded by diverse nutrients, such as glucose, amino acids, various macromolecules and micronutrients, which they can import through transmembrane transporters and endolysosomal pathways. By using different nutrient sources, cells gain metabolic flexibility to survive periods of starvation. Quiescent cells take up sufficient nutrients to sustain homeostasis. However, proliferating cells depend on growth-factor-induced increases in nutrient uptake to support biomass formation. Here, we review cellular nutrient acquisition strategies and their regulation by growth factors and cell-intrinsic nutrient sensors. We also discuss how oncogenes and tumour suppressors promote nutrient uptake and thereby support the survival and growth of cancer cells. PMID- 28593976 TI - Rare particle decays offer hope of new physics. PMID- 28593975 TI - We need a science of philanthropy. PMID- 28593977 TI - AI summit aims to help world's poorest. PMID- 28593978 TI - Romania's science reforms prompt boycott. PMID- 28593979 TI - The mathematicians who want to save democracy. PMID- 28593980 TI - Italy rebuked for failure to prevent olive-tree tragedy. PMID- 28593981 TI - Trump pulls United States out of Paris climate agreement. PMID- 28593982 TI - A sugar high in structural biology. PMID- 28593983 TI - The G20 must govern the shift to low-carbon energy. PMID- 28593984 TI - NASA's dark-energy probe faces cost crisis. PMID- 28593985 TI - Six decades of struggle over the pill. PMID- 28593986 TI - US exits Paris, Jupiter's new moons and the biggest prize in science. PMID- 28593987 TI - Spaser as a biological probe. AB - Understanding cell biology greatly benefits from the development of advanced diagnostic probes. Here we introduce a 22-nm spaser (plasmonic nanolaser) with the ability to serve as a super-bright, water-soluble, biocompatible probe capable of generating stimulated emission directly inside living cells and animal tissues. We have demonstrated a lasing regime associated with the formation of a dynamic vapour nanobubble around the spaser that leads to giant spasing with emission intensity and spectral width >100 times brighter and 30-fold narrower, respectively, than for quantum dots. The absorption losses in the spaser enhance its multifunctionality, allowing for nanobubble-amplified photothermal and photoacoustic imaging and therapy. Furthermore, the silica spaser surface has been covalently functionalized with folic acid for molecular targeting of cancer cells. All these properties make a nanobubble spaser a promising multimodal, super-contrast, ultrafast cellular probe with a single-pulse nanosecond excitation for a variety of in vitro and in vivo biomedical applications. PMID- 28593988 TI - Ebola virus VP30 and nucleoprotein interactions modulate viral RNA synthesis. AB - Ebola virus (EBOV) is an enveloped negative-sense RNA virus that causes sporadic outbreaks with high case fatality rates. Ebola viral protein 30 (eVP30) plays a critical role in EBOV transcription initiation at the nucleoprotein (eNP) gene, with additional roles in the replication cycle such as viral assembly. However, the mechanistic basis for how eVP30 functions during the virus replication cycle is currently unclear. Here we define a key interaction between eVP30 and a peptide derived from eNP that is important to facilitate interactions leading to the recognition of the RNA template. We present crystal structures of the eVP30 C terminus in complex with this eNP peptide. Functional analyses of the eVP30-eNP interface identify residues that are critical for viral RNA synthesis. Altogether, these results support a model where the eVP30-eNP interaction plays a critical role in transcription initiation and provides a novel target for the development of antiviral therapy. PMID- 28593991 TI - Parity-time-symmetric quantum critical phenomena. AB - Synthetic non-conservative systems with parity-time (PT) symmetric gain-loss structures can exhibit unusual spontaneous symmetry breaking that accompanies spectral singularity. Recent studies on PT symmetry in optics and weakly interacting open quantum systems have revealed intriguing physical properties, yet many-body correlations still play no role. Here by extending the idea of PT symmetry to strongly correlated many-body systems, we report that a combination of spectral singularity and quantum criticality yields an exotic universality class which has no counterpart in known critical phenomena. Moreover, we find unconventional low-dimensional quantum criticality, where superfluid correlation is anomalously enhanced owing to non-monotonic renormalization group flows in a PT-symmetry-broken quantum critical phase, in stark contrast to the Berezinskii Kosterlitz-Thouless paradigm. Our findings can be experimentally tested in ultracold atoms and predict critical phenomena beyond the Hermitian paradigm of quantum many-body physics. PMID- 28593989 TI - Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge. AB - The RV144 Thai trial HIV-1 vaccine of recombinant poxvirus (ALVAC) and recombinant HIV-1 gp120 subtype B/subtype E (B/E) proteins demonstrated 31% vaccine efficacy. Here we design an ALVAC/Pentavalent B/E/E/E/E vaccine to increase the diversity of gp120 motifs in the immunogen to elicit a broader antibody response and enhance protection. We find that immunization of rhesus macaques with the pentavalent vaccine results in protection of 55% of pentavalent vaccine-immunized macaques from simian-human immunodeficiency virus (SHIV) challenge. Systems serology of the antibody responses identifies plasma antibody binding to HIV-infected cells, peak ADCC antibody titres, NK cell-mediated ADCC and antibody-mediated activation of MIP-1beta in NK cells as the four immunological parameters that best predict decreased infection risk that are improved by the pentavalent vaccine. Thus inclusion of additional gp120 immunogens to a pox-prime/protein boost regimen can augment antibody responses and enhance protection from a SHIV challenge in rhesus macaques. PMID- 28593990 TI - Loss of Asxl2 leads to myeloid malignancies in mice. AB - ASXL2 is frequently mutated in acute myeloid leukaemia patients with t(8;21). However, the roles of ASXL2 in normal haematopoiesis and the pathogenesis of myeloid malignancies remain unknown. Here we show that deletion of Asxl2 in mice leads to the development of myelodysplastic syndrome (MDS)-like disease. Asxl2-/- mice have an increased bone marrow (BM) long-term haematopoietic stem cells (HSCs) and granulocyte-macrophage progenitors compared with wild-type controls. Recipients transplanted with Asxl2-/- and Asxl2+/- BM cells have shortened lifespan due to the development of MDS-like disease or myeloid leukaemia. Paired daughter cell assays demonstrate that Asxl2 loss enhances the self-renewal of HSCs. Deletion of Asxl2 alters the expression of genes critical for HSC self renewal, differentiation and apoptosis in Lin-cKit+ cells. The altered gene expression is associated with dysregulated H3K27ac and H3K4me1/2. Our study demonstrates that ASXL2 functions as a tumour suppressor to maintain normal HSC function. PMID- 28593992 TI - Insights into Hunter syndrome from the structure of iduronate-2-sulfatase. AB - Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, a crucial enzyme in the lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles in cell adhesion, growth, proliferation and repair, and their degradation and recycling in the lysosome is essential for cellular maintenance. A variety of disease-causing mutations have been identified throughout the IDS gene. However, understanding the molecular basis of the disease has been impaired by the lack of structural data. Here, we present the crystal structure of human IDS with a covalently bound sulfate ion in the active site. This structure provides essential insight into multiple mechanisms by which pathogenic mutations interfere with enzyme function, and a compelling explanation for severe Hunter syndrome phenotypes. Understanding the structural consequences of disease-associated mutations will facilitate the identification of patients that may benefit from specific tailored therapies. PMID- 28593993 TI - MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma. AB - Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research. PMID- 28593994 TI - Protein-directed ribosomal frameshifting temporally regulates gene expression. AB - Programmed -1 ribosomal frameshifting is a mechanism of gene expression, whereby specific signals within messenger RNAs direct a proportion of translating ribosomes to shift -1 nt and continue translating in the new reading frame. Such frameshifting normally occurs at a set ratio and is utilized in the expression of many viral genes and a number of cellular genes. An open question is whether proteins might function as trans-acting switches to turn frameshifting on or off in response to cellular conditions. Here we show that frameshifting in a model RNA virus, encephalomyocarditis virus, is trans-activated by viral protein 2A. As a result, the frameshifting efficiency increases from 0 to 70% (one of the highest known in a mammalian system) over the course of infection, temporally regulating the expression levels of the viral structural and enzymatic proteins. PMID- 28593995 TI - Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance. AB - KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS, which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS. This difference is ascribed to common codon bias in HRAS, which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRASQ61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRASG12-driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS-driven resistance and provide a rationale for targeting translation to overcome resistance. PMID- 28593996 TI - Epidemiology and treatment of pulmonary arterial hypertension. AB - In the past 2 decades, major changes have occurred in the epidemiological and treatment landscape of pulmonary arterial hypertension (PAH). Previously regarded as a disease of the young and middle-aged, contemporary registries from the Western world have demonstrated an increase in the age of patients with PAH, many of whom are elderly with multiple comorbidities. Another important observation is the improvement in survival of patients with PAH in the modern treatment era compared with historical cohorts, before the availability of advanced therapy. The management of PAH has also become more complex, and numerous drugs are now approved that target the endothelin 1, nitric oxide, and prostacyclin pathways. Combining drugs from different classes is now considered the standard of care and has been demonstrated to improve outcomes. Furthermore, the current treatment paradigm is the early use of combination therapy, often at the time of diagnosis, particularly in patients with severe disease. This Review provides a comprehensive update on the epidemiology and pharmacotherapy of PAH. PMID- 28593999 TI - A Novel PKC Inhibitor Shows Promise for Amphetamine Use Disorders. PMID- 28593998 TI - The ubiquitin ligase ZNRF1 promotes caveolin-1 ubiquitination and degradation to modulate inflammation. AB - Caveolin-1 (CAV1), the major constituent of caveolae, plays a pivotal role in various cellular biological functions, including cancer and inflammation. The ubiquitin/proteasomal pathway is known to contribute to the regulation of CAV1 expression, but the ubiquitin ligase responsible for CAV1 protein stability remains unidentified. Here we reveal that E3 ubiquitin ligase ZNRF1 modulates CAV1 protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. We demonstrate that ZNRF1 physically interacts with CAV1 in response to lipopolysaccharide and mediates ubiquitination and degradation of CAV1. The ZNRF1-CAV1 axis regulates Akt-GSK3beta activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti inflammatory cytokine IL-10. Mice with deletion of ZNRF1 in their hematopoietic cells display increased resistance to endotoxic and polymicrobial septic shock due to attenuated inflammation. Our study defines ZNRF1 as a regulator of TLR4 induced inflammatory responses and reveals another mechanism for the regulation of TLR4 signalling through CAV1. PMID- 28593997 TI - Severe congenital neutropenias. AB - Severe congenital neutropenias are a heterogeneous group of rare haematological diseases characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life threatening infections beginning in their first months of life. The most frequent pathogenic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte colony-stimulating factor (G CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophil count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (for example, monosomy 7 and trisomy 21) as well as somatic pre-leukaemic mutations are recommended. PMID- 28594001 TI - A BaSiC tool for background and shading correction of optical microscopy images. AB - Quantitative analysis of bioimaging data is often skewed by both shading in space and background variation in time. We introduce BaSiC, an image correction method based on low-rank and sparse decomposition which solves both issues. In comparison to existing shading correction tools, BaSiC achieves high-accuracy with significantly fewer input images, works for diverse imaging conditions and is robust against artefacts. Moreover, it can correct temporal drift in time lapse microscopy data and thus improve continuous single-cell quantification. BaSiC requires no manual parameter setting and is available as a Fiji/ImageJ plugin. PMID- 28594000 TI - Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib. AB - Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C labelling process and an iodonium ylide-based radiofluorination. Carbon-11 labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability. PMID- 28594003 TI - Microwave-assisted deposition of a highly active cobalt catalyst on mesoporous silica for photochemical CO2 reduction. AB - Coupling with robust surfaces is a promising approach to improve the stability and recyclability of highly active molecular catalysts. This study builds on our prior success to deposit a Co(iii) cyclam complex, where cyclam is 1,4,8,11 tetraazacyclotetradecane, on mesoporous silica via a microwave-assisted process. The Co(iii) complex was successfully deposited on the silica surface through reacting with silanol groups in the silica mesopores. The resulting surface Co(iii) catalyst was characterized by different techniques and tested in photochemical CO2 reduction in the presence of p-terphenyl as a photosensitizer. The synthesized Co(iii) catalyst showed significantly higher activity and selectivity than the unbound Co(iii) cyclam complex and a surface Co(iii) catalyst prepared by other methods. Microwave-assisted heating was found to be essential for the deposition of uniform Co(iii) sites in the silica mesopores, which likely accounts for the superior activity and selectivity of the synthesized surface Co(iii) catalyst. PMID- 28594002 TI - Vector assembly of colloids on monolayer substrates. AB - The key to spontaneous and directed assembly is to encode the desired assembly information to building blocks in a programmable and efficient way. In computer graphics, raster graphics encodes images on a single-pixel level, conferring fine details at the expense of large file sizes, whereas vector graphics encrypts shape information into vectors that allow small file sizes and operational transformations. Here, we adapt this raster/vector concept to a 2D colloidal system and realize 'vector assembly' by manipulating particles on a colloidal monolayer substrate with optical tweezers. In contrast to raster assembly that assigns optical tweezers to each particle, vector assembly requires a minimal number of optical tweezers that allow operations like chain elongation and shortening. This vector approach enables simple uniform particles to form a vast collection of colloidal arenes and colloidenes, the spontaneous dissociation of which is achieved with precision and stage-by-stage complexity by simply removing the optical tweezers. PMID- 28594004 TI - Influence of the alkyl side-chain length on the ultrafast vibrational dynamics of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (CnmimNTf2) ionic liquids. AB - Probing the vibrational dynamics of 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide (CnmimNTf2) ionic liquids (ILs) using femtosecond time-resolved coherent anti-Stokes Raman scattering (fs-CARS) has indicated the ultrafast vibrational energy transfer between counter ions which is governed by interionic interactions and facilitated by hydrogen bonds. In this study, fs-CARS is used to investigate the ultrafast dynamics of the vibrational modes of the CnmimNTf2 ILs with n = 6, 8, 10, and 12 in a spectral region, which involves the imidazolium ring and the alkyl side-chain vibrations. The vibrational Raman modes with wavenumbers around 1418 cm-1 are excited through the CARS process and the ultrafast time evolution of the consequently excited vibrational modes is monitored. The investigation of the life times of the fs CARS transient signals indicates that the time scale of the dynamics becomes much faster when the alkyl side-chain length of the CnmimNTf2 is longer than n = 8. This observation suggests an increase in the hydrogen bonding interactions due to the nano-structuring of the ionic liquids, which became evident with an increasing length of the alkyl side-chain. This behavior is also found in molecular dynamics simulations. There, an increase of the oxygen density around the C(2)-H moiety of the imidazolium ring, which is the predominant site for hydrogen bond formation, is observed. In other words, the longer the alkyl side chain, the more reorganization of the ionic liquid into polar and non-polar domains occurs and the higher the probability of finding interionic hydrogen bonds at the C(2)-H position becomes. PMID- 28594005 TI - The effect of STW defects on the mechanical properties and fracture toughness of pristine and hydrogenated graphene. AB - Graphene is emerging as a versatile material with a diverse field of applications. Synthesis techniques for graphene introduce several topological defects such as vacancies, dislocations and Stone-Thrower-Wales (STW) defects. Among them STW defects are generated without deleting any atom from the lattice position, but are introduced by rotating single C-C bonds. In this article, molecular dynamics based simulations have been performed to study the effect of STW defects on the fracture toughness of pristine graphene as well as graphene with crack edges passivated with hydrogen atoms. STW defects help in generating out of plane displacement in conjunction with redistribution of stress around the crack edges that can be used to improve the fracture toughness of brittle graphene. An overall improvement in the fracture toughness of pristine graphene as well as graphene containing hydrogen at the crack edges was predicted in this work. PMID- 28594006 TI - A semi-combinatorial approach for investigating polycatenar ligand-controlled synthesis of rare-earth fluoride nanocrystals. AB - Rare-earth nanocrystals (RE NCs) are a valuable class of nanomaterials due to their ability to bring the attractive properties of rare earth bulk crystals to biomedical applications and solution-processable engineering. Of the bottom-up synthesis approaches, solvothermal methods yield highly crystalline and monodisperse RE NCs. Herein, we report a polycatenar ligand controlled synthesis of RE NCs using a semi-combinatorial approach with a microreactor setup that enables the investigation of the influences of several reaction parameters on the growth of the RE NCs. This approach enabled the discovery of conditions that yield highly monodisperse elongated plates with neutral, positive, and negative curvatures, as well as provide evidence of the formation of chiral morphologies. PMID- 28594007 TI - Gold(i)-BODIPY-imidazole bimetallic complexes as new potential anti-inflammatory and anticancer trackable agents. AB - Two new gold(i)-BODIPY-imidazole based trackable therapeutic bimetallic complexes have been synthesized and fully characterized. They display strong antiproliferative properties on several types of cancers including colon, breast, and prostate and one of them presents a significant anti-inflammatory effect. Additionally, the two compounds could be visualised in vitro by confocal microscopy in the submicromolar range. PMID- 28594009 TI - Two-dimensional transition metal dichalcogenide/conducting polymer composites: synthesis and applications. AB - The exploration of hybridizing transition metal dichalcogenide (TMD) nanosheets with other materials as a unique approach for engineering their properties has attracted considerable attention from the scientific community for both basic studies and numerous potential applications. Among the various kinds of functional materials in hand, the utilization of intrinsically conducting polymers (CPs) in the construction of advanced hybrid composites with TMD nanosheets is considered as a fascinating approach. In this review, we aim at providing a survey of the literature on recent progress in composites based on 2D TMD and CPs. In this regard, we first discuss the different synthetic strategies used for the fabrication of two-dimensional transition metal dichalcogenide/conducting polymer (2D TMD/CP) composites in detail. Subsequently, we demonstrate the state-of-the-art advances in the utilization of these novel composites in promising applications such as energy storage, sensing devices, hydrogen production and so on. Finally, we also highlight some perspectives on the major challenges and future directions in this field of research. PMID- 28594010 TI - trans-Chalcone, a flavonoid precursor, inhibits UV-induced skin inflammation and oxidative stress in mice by targeting NADPH oxidase and cytokine production. AB - trans-Chalcone is a plant flavonoid precursor, which lacks broad investigation on its biological activity in inflammatory processes. In the present study, anti inflammatory and antioxidant mechanisms of systemic administration with trans chalcone, a flavonoid precursor, on ultraviolet (UV) irradiation-induced skin inflammation and oxidative stress in hairless mice were investigated by the following parameters: skin edema, myeloperoxidase activity (neutrophil marker), matrix metalloproteinase-9 activity, reduced glutathione levels, catalase activity, lipid peroxidation products, superoxide anion production, gp91phox (NADPH oxidase subunit) mRNA expression by quantitative PCR and cytokine production by ELISA. Systemic treatment with trans-chalcone inhibited skin inflammation by reducing skin edema and neutrophil recruitment, and also inhibited matrix metalloproteinase-9 activity. trans-Chalcone also inhibited oxidative stress, gp91phox mRNA expression, and the production of a wide range of pro-inflammatory cytokines, while it did not affect anti-inflammatory cytokines induced by UV irradiation. However, trans-chalcone did not prevent oxidative stress in vitro, suggesting that its in vivo effect is more related to anti inflammatory properties rather than a direct antioxidant effect. In conclusion, treatment with trans-chalcone inhibited UV-induced skin inflammation resulting in oxidative stress inhibition in vivo. Therefore, systemic supplementation with this compound may represent an important therapeutic approach in inflammatory skin diseases induced by UV irradiation. PMID- 28594011 TI - A chiral salen-based MOF catalytic material with high thermal, aqueous and chemical stabilities. AB - A highly stable chiral salen-based metal-organic framework [(Cu4I4)2L4].20DMF.3CH3CN (1) [L = (R,R)-N,N'-bis(3-tert-butyl-5-(4 pyridyl)salicylidene)-1,2-diphenylethylenediamine nickel(ii)] has been synthesized and characterized by single crystal X-ray diffraction and other physicochemical methods. 1 exhibits a rare 8-fold interpenetrated 3D framework constructed by a 4-connecting Cu4I4 cluster and a 2-coordinating L ligand. Remarkably, in spite of 8-fold interpenetration, 1 still possesses two types of 1D chiral hydrophobic channels with pore window sizes of 6.77 * 8.64 A2 and 6.09 * 10.96 A2 along the crystallographic a axis. All Ni(salen) moieties of L lie inside the 1D channels and the empty coordination sites of Ni2+ are oriented to the cavities. PXRD and N2 adsorption measurements confirmed that 1 is extremely stable under high temperature (>400 degrees C), in water vapor (90% relative humidity), in acid/base aqueous solution (pH 0-14), and in saturated NaOH solution at 100 degrees C, as well as in 30 wt% H2O2 and 70 wt% tert-butyl hydroperoxide solution. 1 was proved to be an excellent recycled heterogeneous catalyst for the conversion of simulated industrial CO2 (that is, involving tiny amounts of water vapor and other acidic gases) with epoxides into cyclic carbonates under mild conditions for the first time. The synthesis of beta hydroxy-1,2,3-triazoles from the same epoxides, alkyne and sodium azide was also catalyzed by 1 in aqueous solution with high yield. Interestingly, the cycloaddition reaction of CO2 to bulky epoxides shows a decrease in the activity with an increase in the alkyl chain length of the substrate because of confinement of the channel size of 1, showing size-dependent selectivity. The plausible catalytic mechanisms for these two reactions have also been proposed. PMID- 28594012 TI - Biosynthetic considerations of triscatechol siderophores framed on serine and threonine macrolactone scaffolds. AB - Bacteria often produce siderophores to facilitate iron uptake. One of the most studied siderophores is enterobactin, the macrolactone trimer of 2,3 dihydroxybenzoyl-l-serine, produced by E. coli and many other enteric bacteria. Other siderophores are variants of enterobactin, with structural modifications including expansion of the tri-serine core to a tetra-serine macrolactone, substitution of l-serine with l-threonine, insertion of amino acids (i.e., Gly, l Ala, d-Lys, d- and l-Arg, l-Orn), catechol glucosylation, and linearization of the tri-serine macrolactone core. In this review we summarize the current understanding of the biosyntheses of these enterobactin variants, placing them in contrast with the well-established biosynthesis of enterobactin. PMID- 28594013 TI - How predictive could alchemical derivatives be? AB - The chemical space contains all possible compounds that can be imagined. Its size easily equals the number of fundamental particles in the observable universe. Rational design of compounds aims to find those sectors of the chemical space where compounds optimize a set of desired properties. Then, rational design demands tools to efficiently navigate the chemical space. Ab initio alchemical derivatives offer the possibility to navigate, without empiricism, the energy landscape through alchemical transformations. An alchemical transformation is any process, physical or fictitious, that connects to points in the chemical space. In this work, those transformations are constructed as a perturbative expansion of the energy with respect to perturbations in the stoichiometry. The response functions of that expansion are what is called alchemical derivatives. In this work we assess how effective alchemical derivatives are in predicting energy changes associated to changes in the composition. We do this by including in the expansion, for the first time, electrostatic, polarization and electron-transfer effects. The system we chose is one that challenges alchemical derivatives because none of these effects dominates its behavior. The transmutations studied here correspond to substitutional doping of Al13 with up to four atoms of Si, Al13-nSin. Two types of transformations are considered, those in which the number of electrons remains constant and those in which the number of electrons also changes. It is found that contrary to what has been reported before, polarization cannot be neglected. If polarization is not included, alchemical derivatives fail to predict the change of energy and the relative energy between isomers. For isoelectronic substitution of four or more atoms, the perturbative approach collapses because the strength of the perturbation becomes too strong to guarantee convergence of the series. It is shown, however, that if only one atom is mutated at a time, alchemical derivatives rank pretty well the isomers of Al13 nSin according to their energy. In the case of non-isoelectronic transformations, it is observed that the series rapidly diverges with increasing number of electrons. In this situation, it becomes more important to keep the degree of transmutation of the parent system small. PMID- 28594015 TI - New amidinate complexes of indium(iii): promising CVD precursors for transparent and conductive In2O3 thin films. AB - For the first time, synthesis of two new amidinate-ligand comprising heteroleptic indium complexes, namely [InCl(amd)2] (1) and [InMe(amd)2] (2), via salt metathesis and their detailed characterization is reported. For comparison, the earlier reported homoleptic tris-amidinate [In(amd)3] (3) was also synthesized and analyzed in detail especially with respect to the thermal properties and molecular crystal structure analysis which are reported here for the first time. From nuclear magnetic resonance spectroscopy (NMR) and single-crystal X-ray diffraction (XRD), all three compounds were found to be monomeric with C2 (compound 1 and 2) and C3 symmetry (compound 3). Both halide-free compounds 2 and 3 were evaluated regarding their thermal properties using temperature-dependent 1H-NMR, thermogravimetric analysis (TGA) and iso-TGA, revealing suitable volatility and thermal stability for their application as potential precursors for chemical vapor phase thin film deposition methods. Indeed, metalorganic chemical vapor deposition (MOCVD) experiments over a broad temperature range (400 degrees C-700 degrees C) revealed the suitability of these two compounds to fabricate In2O3 thin films in the presence of oxygen on Si, thermally grown SiO2 and fused silica substrates. The as-deposited thin films were characterized in terms of their crystallinity via X-ray diffraction (XRD), morphology by scanning electron microscopy (SEM) and composition through complementary techniques such as Rutherford-backscattering spectrometry (RBS) in combination with nuclear reaction analysis (NRA) and X-ray photoelectron spectroscopy (XPS). From UV/Vis spectroscopy, the deposited In2O3 thin films on fused silica substrates were found to be highly transparent (T > 95% at 560 nm, compound 3). In addition, Hall measurements revealed high charge carrier densities of 1.8 * 1020 cm-3 (2) and 6.5 * 1019 cm-3 (3) with a Hall-mobility of 48 cm2 V-1 s-1 (2) and 74 cm2 V-1 s-1 (3) for the respective thin films, rendering the obtained thin films applicable as a transparent conducting oxide that could be suitable for optoelectronic applications. PMID- 28594016 TI - Optimization of hydrophilic/hydrophobic phase separation in sPEEK membranes by hydrothermal treatments. AB - Via SAXS, herein, we studied how a sPEEK microstructure evolves when it is immersed in water at a wide range of temperatures (20-100 degrees C) and time scales (from a few hours to dozens of days). In particular, we scrutinized the behavior of sPEEK at the temperature and time associated with the appearance of a well-defined nanosegregated morphology. At 80 degrees C, we observed nanoscale swelling along with smoothing of the water/polymer interface over a long period of time (several days). Herein, two of the main membrane properties, i.e., water uptake and proton conductivity, were studied for different immersion times and temperatures. It was found that the abovementioned properties were remarkably correlated with the evolution of the membrane microstructure, which was partly conserved after drying. The present findings helped us to understand that the thermally activated evolutions observed at both the nanoscale and macroscale were associated with the sPEEK beta-relaxation crossover. Therefore, the very different swelling behaviors of sPEEK and Nafion are correlated to the much higher beta-relaxation of sPEEK vs. Nafion (75 degrees C vs. -20 degrees C - dry state). From a practical viewpoint, this study emphasizes, for membranes alternative to Nafion, the importance and impact of the membrane pretreatment on their functional properties. PMID- 28594017 TI - Thermo-enhanced ring-opening polymerization of epsilon-caprolactone: the synthesis, characterization, and catalytic behavior of aluminum hydroquinolin-8 olates. AB - A series of highly sensitive aluminum hydroquinolin-8-olates (C1-C8) was synthesized and characterized by 1H/13C NMR spectroscopy. The molecular structures of compounds C1, C3, C4, and C5 were confirmed by single crystal X-ray crystallography and demonstrated the binuclear form. In the presence of BnOH, all the aluminum complexes exhibited moderate to high activities towards the ring opening polymerization of epsilon-CL at high temperatures, but quite low activities at ambient temperature. Microstructure analysis of the resultant polycaprolactones showed that the polymers were linear in nature with a BnO- end group. In addition, the mechanism was investigated by monitoring the 1H NMR and 27Al NMR of C1 and these results suggested that the complexes existed as dimeric species at low temperature and partly converted into active mononuclear species at higher temperatures, which was easily coordinated by BnOH to afford the active species for the ring-opening polymerization of epsilon-caprolactone. PMID- 28594018 TI - Biodegradable injectable polymer systems exhibiting a longer and controllable duration time of the gel state. AB - Here, we report biodegradable temperature-triggered covalent gelation systems exhibiting a longer and controllable duration time of the gel state by a "mixing strategy" utilizing a thiol-ene reaction. We synthesized a tri-block copolymer of poly(caprolactone-co-glycolic acid) and PEG (tri-PCG) as a temperature-responsive injectable polymer (IP) and attached acryloyl groups on both termini (tri-PCG Acryl). A tri-PCG micelle solution containing hydrophobic hexa-functional polythiol (Solution-A) and a tri-PCG-Acryl micelle solution (Solution-B) were mixed together. After mixing, the solution was still in the sol state at r.t., but exhibited an irreversible sol-to-gel transition in response to temperature. The duration time of the gel state while soaking in PBS could be altered from 1 day to 93 days by changing the mixing ratio of Solution-A/B. The physical strengths of the hydrogels were also controllable by changing the mixing ratio. The IP system showed good biocompatibility and a long duration time of the gel state after subcutaneous implantation. PMID- 28594019 TI - Recent progress in the biomedical applications of polydopamine nanostructures. AB - Polydopamine is a dark brown-black insoluble biopolymer produced by autoxidation of dopamine. Although its structure and polymerization mechanism have not been fully understood, there has been a rapid growth in the synthesis and applications of polydopamine nanostructures in biomedical fields such as drug delivery, photothermal therapy, bone and tissue engineering, and cell adhesion and patterning, as well as antimicrobial applications. This article is dedicated to reviewing some of the recent polydopamine developments in these biomedical fields. Firstly, the polymerization mechanism is introduced with a discussion of the factors that influence the polymerization process. The discussion is followed by the introduction of various forms of polydopamine nanostructures and their recent applications in biomedical fields, especially in drug delivery. Finally, the review is summarized followed by brief comments on the future prospects of polydopamine. PMID- 28594020 TI - Aerosol-assisted chemical vapor deposition of WS2 from the single source precursor WS(S2)(S2CNEt2)2. AB - WS(S2)(S2CNEt2)2 has been successfully employed in the aerosol-assisted chemical vapor deposition of WS2 at temperatures above 350 degrees C. This precursor was found to decompose primarily through the loss of H2S, CS2, and SCNEt. The WS2 deposits were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and X-ray diffraction. The deposits exhibited plate-like structures growing vertically from the substrate. PMID- 28594021 TI - Phase diagram of water-methane by first-principles thermodynamics: discovery of MH-IV and MH-V hydrates. AB - Searching novel gas hydrates is an enduring topic of scientific investigations, owing to its outstanding implications on planetology, the origin of life and the exploitation of energy resources. Taking the methane-water system as a representative, we disclose two new dense methane hydrate phases (MH-IV and MH-V) using the Monte-Carlo packing algorithm and density-functional theory (DFT) optimization. Both of these methane clathrates with (CH4)(H2O)4 stoichiometry can be regarded as filled ices, since their hydrogen bond networks are closely related to that of ice i and ice XI, respectively. In particular, the former ice i network is observed for the first time in all gas hydrates. A new chemical composition phase diagram of methane hydrate is constructed. Our newly identified methane hydrate IV emerges in the transition zone for a water-methane ratio between 2 : 1 and 5.75 : 1. It suggests that our MH-IV phase can be stabilized without external pressure, which is superior to previous reported filled ices to apply to energy storage. These findings attest to the importance of composition effects on the packing mechanism of gas hydrate, and provide new perspectives for understanding the physicochemical and geophysical processes in the giant planets of the solar system. PMID- 28594022 TI - A remote controllable fiber-type near-infrared light-responsive actuator. AB - A novel near-infrared (NIR) light-responsive sodium polyacrylate (PAAS)/graphene oxide (GO) fiber with a torsional pre-deformation structure is reported to realize remote control actuation. The torsional pre-deformed PAAS/GO fiber exhibited various actuation phenomena, under the control of a low powered near infrared light (50 mW cm-2), such as rotating in a low-temperature range (<25 degrees C), rolling a distance of 10 times of its diameter within 10 s, and even driving the shape change of a fabric (the weight is as high as 20 times of the fiber itself). PMID- 28594023 TI - Ultrafast permeation of seawater pervaporation using single-layered C2N via strain engineering. AB - Emerging two-dimensional (2D) ultra-thin nanomaterials are ideal candidates for next-generation high-throughput membranes. 2D carbon nitride C2N possesses intrinsic regular and uniformly distributed sub-nanometer pores which probably allow a high permeation flux. This work reports on the investigation of seawater pervaporation through a single-layered C2N membrane via a combined approach of first-principles calculations and molecular dynamics simulations. The C2N layer remains stable when the strain is less than a threshold point of 12% at which the pore size is enlarged by 50%. The strained C2N membrane only allows water molecules from seawater to permeate, and the water flux in C2N is enhanced by one to four orders of magnitude compared to that in other membranes. The water flux exhibits an Arrhenius-type relation with temperature. The hydrogen-bonding interaction among water molecules in C2N is weaker and decays faster than that in bulk water, which is because it is energetically unfavorable for water molecules to enter C2N. This proof-of-concept study suggests that C2N might be an appealing membrane material for seawater pervaporation. PMID- 28594024 TI - Low loss optical waveguiding in large single crystals of a thiophene-based oligomer. AB - Active optical waveguides based on functional small organic molecules in micro/nano regime have attracted great interest for their potential applications in high speed miniaturized photonic integrations. Here, we report on the active waveguiding properties of millimeter sized single crystals of a newly synthesized thiophene-based oligomer. These large crystals exhibit low optical loss compared to other organic nanostructures, and optical losses depend on the emission energy. Moreover, we find that the coupling of photoluminescence to waveguide modes is very efficient, typically greater than 40%. These features indicate that such perfect single crystals with a low density of defects and extremely smooth surfaces exhibit low propagation loss, which makes them good candidates for the design and the fabrication of novel organic optical fibers and lasers. PMID- 28594025 TI - Stable AuIII complexes with four N-heterocyclic carbene groups can be prepared in high yield directly from KAuCl4. AB - Gold(iii) N-heterocyclic carbene (NHC) complexes of form [Au(NHC)4Cl2]Cl were synthesized by reaction of KAuCl4 with bis- and tetrakis(imidazolium) salts in the presence of a mild base. Treatment of these complexes with KPF6 afforded four coordinate AuIII complexes of form [Au(NHC)4](PF6)3. X-Ray crystallography showed the [AuIII(NHC)4]3+ cations in the hexafluorophosphate salts to have a square planar Au(NHC)4 moiety [AuCNHC 2.024(4)-2.082(7) A]. In the [AuIII(NHC)4Cl2]+ cations in the chloride salts, coordination about Au was tetragonally-distorted octahedral, the axial Au-Cl bonds being substantially longer [AuCl 3.148(2) 3.693(1) A] than the equatorial Au-CNHC bonds [AuC 2.024(4)-2.082(7) A]. NMR and conductance studies suggested that the structures of the complexes seen in the solid state persisted in DMSO solution, except in one case where a chlorido ligand dissociated from [AuIII(NHC)4Cl2]+ to form [AuIII(NHC)4Cl]2+. The AuIII(NHC)4 unit was surprisingly robust. An AuIII complex was found to undergo H/D exchange reactions in D2O solution at 100 degrees C with no signs of decomposition detectable by 1H NMR spectroscopy. 1H NMR studies showed that various complexes containing AuIII(NHC)4 moieties underwent little or no decomposition when heated at 120 degrees C in DMSO-d6 for extended periods. PMID- 28594026 TI - Photoactivatable europium luminescence turn-on by photo-oxygenation of beta diketone having pyrrole rings. AB - This work demonstrates a novel photoactivatable turn-on-type lanthanide(iii) luminescence. A beta-diketone substrate having redox-active pyrrole moieties (LH2) undergoes efficient photo-oxygenation to afford the corresponding alpha alkoxy diketone (LHOH) in the presence of lanthanide(iii) ions, which trigger bright europium(iii) red luminescence (PA-EuIII) turn-on, as well as activating the near-infrared luminescence (lambdaem = 976 nm) of ytterbium(iii). A photo patterning process for security imaging is successfully demonstrated. PMID- 28594028 TI - The role of liquid-liquid transition in glass formation of CuZr alloys. AB - Some glass-forming liquids have different liquid phases that have the same composition but different structure, density and entropy. Based on experimental and molecular dynamics simulation, we here report thermodynamic, dynamic, and structural evidence of the liquid-liquid transition (LLT) in ten Cu-Zr glass forming liquids well above the liquidus temperature. We find that for Cu-Zr alloys, the LLT is beneficial to glass formation, and there is a close relationship between the relative transition strength (RTS) of the LLT and the critical thickness representing the glass forming ability (GFA): the bigger the value of the RTS parameters, the stronger the GFA of Cu-Zr alloys. This work not only uncovers the role of the LLT of melts in the glass formation of solids, but also sheds light on the inheritance of properties of glassy solids from the aspect of the detectable dynamics of high-temperature melts. PMID- 28594029 TI - Positron annihilation characteristics, water uptake and proton conductivity of composite Nafion membranes. AB - The free volumes and proton conductivities of Nafion membranes were investigated at different humidities by positron annihilation lifetime spectroscopy (PALS) and using an electrochemical workstation, respectively. The results showed that the variation in o-Ps lifetime tauo-Ps was closely associated with the microstructure evolution and the development of hydrophilic ion clusters in Nafion membranes as a function of water uptake, regardless of metal oxide additives. In particular, with increasing relative humidity, the maximum value of tauo-Ps in the Nafion membranes corresponded to the formation of numerous water channels for proton transportation. Numerous well-connected water channels in Nafion-TiO2 hybrid membranes could be formed at a much lower relative humidity (~40% RH) than in the pristine one (~75% RH), due to the better water retention ability of the Nafion TiO2 membranes. Further, a percolation behavior of proton conductivity at high water uptake in Nafion membranes was observed, which showed that the percolation of ionic-water clusters occurred at the water uptake of ~4.5 wt%, and ~6 wt% was basically enough for the formation of a well-connected water channel network. PMID- 28594033 TI - Electrochemical synthesis to convert a Ag film into Ag nanoflowers with high electrocatalytic activity. AB - The cyclic scanning electrodeposition method was proposed to convert a thin Ag film into nanocrystals (NCs) with various shapes including nanoflowers, nanorods, dendrites, decahedrons, and icosahedrons. The flower-like Ag NCs exhibit a remarkably enhanced catalytic activity for electro-oxidation of glucose. PMID- 28594034 TI - Tryptophan/copper-catalyzed aromatization reaction of chiral cyclohexanones to phenols. AB - By merging organocatalysis with copper catalysis, a highly efficient stereospecific approach for the synthesis of chiral phenols from cyclohexanones has been developed for the first time. The aromatization reaction proceeds through the in situ formation of enone intermediates and further subsequent bromination/dehydrobromination reactions. And a series of functionalized phenol derivatives are obtained in good yields (up to 89%) and good to excellent enantioselectivities (up to 99% ee). PMID- 28594040 TI - A porous metal-organic framework based on an asymmetric angular diisophthalate for selective adsorption of C2H2 and CO2 over CH4. AB - A new copper-based metal-organic framework [Cu2L(H2O)2].5DMF.2H2O (ZJNU-56) has been solvothermally synthesized using a custom-designed asymmetric rigid bent diisophthalate ligand, 5,5'-(1-amine-naphthyl-2,4-diyl) diisophthalic acid (H4L), and structurally determined by single-crystal X-ray diffraction. ZJNU-56 features a three-dimensional (3D) open framework incorporating three different types of metal-organic cages and two distinct types of one-dimensional channels. With a moderate BET surface area of 1655 m2 g-1, optimized pore structure, and functional sites (open copper sites and Lewis basic amine groups) on the cage surface, ZJNU-56 after desolvation exhibits highly selectively adsorptive separation of C2H2 and CO2 over CH4 under ambient conditions. At 298 K, the predicted IAST selectivities are 35.7-72.9 for an equimolar C2H2/CH4 gas mixture and 6.8-7.0 for an equimolar CO2/CH4 gas mixture at pressures varying from 1 to 109 kPa, respectively, which are among the highest reported to date for copper based MOFs. PMID- 28594044 TI - Quantum tunneling injection of hot electrons in Au/TiO2 plasmonic photocatalysts. AB - Visible light absorption of plasmonic Au nanoparticles supported on semiconductor TiO2 leads to injection of their photoactivated "hot electrons (ehot-)" into the TiO2 conduction band. This charge separation facilitates several oxidation and reduction reactions. These plasmonic systems, however, suffer from low quantum yields because the Schottky barrier created at the Au-TiO2 interface suppresses ehot- injection. Here we report that Au nanoparticles supported on the anatase particles isolated from Degussa (Evonik) P25 TiO2 promote ehot- injection with much higher efficiency than those supported on other commercially-available TiO2 and catalyze aerobic oxidation with very high quantum yield (7.7% at 550 nm). Photoelectrochemical and spectroscopic analysis revealed that the number of Ti4+ atoms located at the Au-TiO2 interface is the crucial factor. These Ti4+ atoms neutralize the negative charge of the Au particles and create a Schottky barrier with narrower depletion layer. This facilitates efficient ehot- injection by "quantum tunneling" through the Schottky barrier without overbarrier energy. The ehot- injection depends on several factors, and loading of 2 wt% Au particles with 3.5-4 nm diameters at around room temperature exhibits the highest activity of plasmonic photocatalysis. PMID- 28594045 TI - Chromophorylation (in Escherichia coli) of allophycocyanin B subunits from far red light acclimated Chroococcidiopsis thermalis sp. PCC7203. AB - Cyanobacterial phycobilisomes funnel the harvested light energy to the reaction centers via two terminal emitters, allophycocyanin B and the core-membrane linker. ApcD is the alpha-subunit of allophycocyanin B responsible for its red shifted absorbance (lambdamax 665 nm). Far-red photo-acclimated cyanobacteria contain certain allophycocyanins that show even further red-shifted absorbances (lambdamax > 700 nm). We studied the chromophorylation of the three far-red induced ApcD subunits ApcD2, ApcD3 and ApcD4 from Chroococcidiopsis thermalis sp. PCC7203 during the expression in E. coli. The complex behavior emphasizes that a variety of factors contribute to the spectral red-shift. Only ApcD2 bound phycocyanobilin covalently at the canonical position C81, while ApcD3 and ApcD4 gave only traces of stable products. The product of ApcD2 was, however, heterogeneous. The major fraction had a broad absorption around 560 nm and double peaked fluorescence at 615 and 670 nm. A minor fraction was similar to the product of conventional ApcD, with maximal absorbance around 610 nm and fluorescence around 640 nm. The heterogeneity was lost in C65 and C132 variants; in these variants only the conventional product was formed. With ApcD4, a red shifted product carrying non-covalently bound phycocyanobilin could be detected in the supernatant after cell lysis. While this chromophore was lost during purification, it could be stabilized by co-assembly with a far-red light-induced beta-subunit, ApcB3. PMID- 28594046 TI - Balancing the intermolecular forces in peptide amphiphiles for controlling self assembly transitions. AB - While the influence of alkyl chain length and headgroup size on self-assembly behaviour has been well-established for simple surfactants, the rational control over the pH- and concentration-dependent self-assembly behaviour in stimuli responsive peptides remains an elusive goal. Here, we show that different amphiphilic peptides can have similar self-assembly phase diagrams, providing the relative strengths of the attractive and repulsive forces are balanced. Using palmitoyl-YYAAEEEEK(DO3A:Gd)-NH2 and palmitoyl-YAAEEEEK(DO3A:Gd)-NH2 as controls, we show that reducing hydrophobic attractive forces through fewer methylene groups in the alkyl chain will lead to a similar self-assembly phase diagram as increasing the electrostatic repulsive forces via the addition of a glutamic acid residue. These changes allow creation of self-assembled MRI vehicles with slightly different micelle and nanofiber diameters but with minimal changes in the spin-lattice T1 relaxivity. These findings reveal a powerful strategy to design self-assembled vehicles with different sizes but with similar self assembly profiles. PMID- 28594047 TI - Base-catalyzed diastereoselective trimerization of trifluoroacetone. AB - Amphiphilic fluorocarbons have unique properties that facilitate their self assembly and adhesion to both inorganic and biological substrates. Incorporation of these moieties into valuable constructs typically require complex synthetic routes that have limited their use. Here, the base-catalyzed diastereoselective synthesis of 6-methyl-2,4,6-tris(trifluoromethyl)tetrahydro-2H-pyran-2,4-diol is reported. Trimerization of trifluoroacetone in the presence of 5 mol% KHMDS delivers one of four diastereomers selectively in 81% yield with no column chromatography. Temperature screening revealed the reversibility of this trimerization and the funneling of material into the most thermodynamically stable oxane. Subsequent functionalization with boronic acids is reported. PMID- 28594048 TI - [In vivo-efficacy of an ear medication using gelatin powder as a vehicle for the therapy of canine otitis externa]. AB - OBJECTIVE: Otitis externa is normally treated with daily topical medication. Longer application intervals may be useful to facilitate therapy. In this study, the in vivo efficacy of a gel preparation containing marbofloxacin, dexamethasone and enilconazole was compared to that of a commercial otologic agent containing marbofloxacin, dexamethasone and clotrimazole based on clinical signs, ear cytology and bacterial/fungal cultures. MATERIAL AND METHODS: A gel preparation (group A) or a registered otologic agent (group B), respectively, was applied to 41 dogs. A total of 50 ears (25 per group) were analysed. The gel preparation was administered on days 0 and 5; the combination preparation was administered daily according to the manufacturer's recommendations. Dogs were reevaluated clinically and cytologically after 5 and 10 days. Initially and after 10 days, ear swabs were taken for bacterial and fungal cultures. RESULTS: No significant clinical or cytological differences were found between the groups. Significantly more isolates resistant to marbofloxacin were identified in group A after 10 days, although >98% of marbofloxacin was still detectable in vitro after 15 days. CONCLUSION: The clinical and cytological efficacy of a gel containing defined active agents applied twice 5 days apart was comparable to that of an authorised otologic agent applied once daily. There appears to be an increased risk with the gel in that a resistance to fluoroquinolones develops. Local adverse effects are also possible. CLINICAL RELEVANCE: A gelatine preparation containing active agents may be an alternative to daily topical therapy of canine otitis externa. The development of resistances is possible. PMID- 28594049 TI - Venous thromboembolism: Past, present and future. AB - Venous thromboembolism (VTE), the third most frequent acute cardiovascular syndrome, is associated with a considerable disease burden which continues to grow along with the longer life expectancy of the population worldwide. In the past century, parenteral heparin prophylaxis was established for hospitalised patients at elevated risk of VTE. More recently, non-vitamin K antagonist oral anticoagulants (NOACs) with a direct inhibiting effect on factor Xa or thrombin, underwent extensive testing in clinical trials and have been approved for patients undergoing hip or knee replacement. Clinical investigation is ongoing in further areas of thromboprophylaxis, including medical prophylaxis in patients and high-risk situations in the outpatient setting. The diagnostic approach to suspected VTE is now based on advanced imaging techniques and robust diagnostic algorithms which ensure high sensitivity and specificity. Nevertheless, the role of clinical, or pre-test, probability assessment remains crucial to avoid overdiagnosis and treatment errors. Advances in reperfusion strategies, along progressive establishment of the NOACs as the new standard of anticoagulation treatment, have simplified the management of VTE, improving outcomes and particularly safety. While new molecular targets for anticoagulation are being investigated in the quest to further reduce bleeding risk, adjusting the initial regimen to the patient's risk and finding the optimal duration of anticoagulation after an index VTE event will be some of the top priorities in the years to come. Importantly, and in parallel to new drugs and technical advances in imaging, incentives such as hospital accreditation and funding based on evidence-based practice need to be implemented to increase guideline adherence. PMID- 28594050 TI - Extracellular nucleic acids in immunity and cardiovascular responses: between alert and disease. AB - Severe inflammatory complications are a potential consequence in patients with predetermined conditions of infections, pulmonary diseases, or cardiovascular disorders. Notably, the amplitude of the inflammatory response towards these complications can dictate the disease progression and outcome. During the recent years, evidence from basic research as well as from clinical studies has identified self-extracellular nucleic acids as important players in the crosstalk between immunity and cardiovascular diseases. These stress- or injury-induced endogenous polymeric macromolecules not only serve as "alarmins" or "Danger associated molecular patterns" (DAMPs), but their functional repertoire goes far beyond such activities in innate immunity. In fact, (patho-) physiological functions of self-extracellular DNA and RNA are associated and in many cases causally related to arterial and venous thrombosis, atherosclerosis, ischemia reperfusion injury or tumour progression. Yet, the underlying molecular mechanisms are far from being completely understood. Interestingly enough, however, novel antagonistic approaches in vitro and in vivo, particularly using natural endonucleases or synthetic nucleic acid binding polymers, appear to be promising and safe therapeutic options for future studies. The aim of this review article is to provide an overview of the current state of (patho-) physiological functions of self-extracellular nucleic acids with special emphasis on their role as beneficial / alerting or adverse / damaging factors in connection with immune responses, inflammation, thrombosis, and cardiovascular diseases. PMID- 28594051 TI - Antithrombotic therapy for acute coronary syndrome: Past, present and future. AB - Plaque erosions and ruptures are the histopathological hallmarks of arterial thrombus formation in the coronary arteries. The clinical condition associated with this process is usually referred to as acute coronary syndrome (ACS). Importantly, both blood platelets and the coagulation cascade are key players for initiation, amplification and perpetuation of ACS. There has been great progress in ACS treatment in recent decades, both at the technical level of (percutaneous) revascularisation and at the level of antithrombotic treatment. Numerous trials have led to significant advancements in the development of effective anticoagulant and antiplatelet drugs. The large number of randomised controlled clinical trials (RCTs) and the huge number of patients enrolled in these RCTs, with mega trials including >10,000 patients, is unique in the history of medical research and also reflects the exceptional efforts associated with these huge research activities. The crucial issue, however, with respect to optimising treatment, relates to finding the delicate balance between the reduction of thrombotic events by effective drug treatment and the induction of bleeding that is linked to the use of potent or multiple antithrombotic agents. Interestingly, there is a gap in modern days between current guideline recommendations favouring potent platelet inhibition in ACS and the utilization of the respective drugs in clinical practice. In this review, we will summarise and discuss the past, present and future antithrombotic treatment for ACS patients with a focus on the development of optimised antiplatelet treatment strategies and their utilisation in the real world. PMID- 28594052 TI - Coagulation factor and protease pathways in thrombosis and cardiovascular disease. AB - The biochemical characterisation of the proteolytic pathways that constitute blood coagulation was one of the most relevant achievements in biomedical research during the second half of the 20th century. Understanding these pathways was of crucial importance for improving global health through application in haemostasis and thrombosis pathologies. Immediately after the cloning of the genes corresponding to these proteins, mutations were discovered in them that were associated with imbalances in haemostasis. Later, the importance of coagulation pathways in other pathological processes was demonstrated, such as in atherosclerosis and inflammation, both essential processes involved in vascular disease. In the present review we evaluate the concepts that have allowed us to reach the integrated vision on coagulation that we have today. The thrombo inflammation model encompassing these aspects includes a pivotal role for the proteases of the coagulation pathway as well as the regulatory proteins thereof. These concepts illustrate the importance of the coagulation cascade in cardiovascular pathology, not only in thrombotic processes, but also in atherosclerotic processes and in the response to ischaemia-reperfusion injury, making it a central mechanism in cardiovascular disease. PMID- 28594053 TI - Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future. AB - Even two centuries after they were first described, atherosclerosis and atherothrombosis remain among the leading causes of death worldwide. Over the last decades it has become clear that atherosclerosis is not only a lipid-driven disease but also a multifactorial process largely driven by inflammatory mediators, an insight that has instigated additional research and drug development focussing on anti-inflammatory therapies. In this review, we will provide a brief historical overview, followed by a more general synopsis of the range of currently available state-of-the-art therapies for atherosclerosis and atherothrombosis. Finally, we will highlight some of the promising therapeutic strategies that are currently under intense investigation. We believe that the next years will witness highly interesting developments and clinical trials investigating yet more novel therapies, and at the same time looking into potential combinations of all available therapies. This prospect closes in on the ultimate goal, which is to reduce the residual risk that still persists despite present therapeutic options. PMID- 28594054 TI - Personality patterns predict the risk of antisocial behavior in Spanish-speaking adolescents. AB - INTRODUCTION: There is a renewed interest in incorporating personality variables in criminology theories in order to build models able to integrate personality variables and biological factors with psychosocial and sociocultural factors. The aim of this article is the assessment of personality dimensions that contribute to the prediction of antisocial behavior in adolescents. METHODS: For this purpose, a sample of adolescents from El Salvador, Mexico, and Spain was obtained. The sample consisted of 1035 participants with a mean age of 16.2. There were 450 adolescents from a forensic population (those who committed a crime) and 585 adolescents from the normal population (no crime committed). All of participants answered personality tests about neuroticism, extraversion, psychoticism, sensation seeking, impulsivity, and violence risk. RESULTS: Principal component analysis of the data identified two independent factors: (i) the disinhibited behavior pattern (PDC), formed by the dimensions of neuroticism, psychoticism, impulsivity and risk of violence; and (ii) the extrovert behavior pattern (PEC), formed by the dimensions of sensation risk and extraversion. Both patterns significantly contributed to the prediction of adolescent antisocial behavior in a logistic regression model which properly classifies a global percentage of 81.9%, 86.8% for non-offense and 72.5% for offense behavior. CONCLUSIONS: The classification power of regression equations allows making very satisfactory predictions about adolescent offense commission. Educational level has been classified as a protective factor, while age and gender (male) have been classified as risk factors. PMID- 28594055 TI - Influence of attention deficit hyperactivity disorder symptoms on quality of life and functionality in adults with eating disorders. AB - INTRODUCTION: Eating disorders (ED) have been linked to attention deficit hyperactivity disorder (ADHD) because they present some symptoms in common. The aim of this study was to explore the influence on ED of symptoms suggestive of adult ADHD and how these symptoms affect the clinical presentation of adult patients. A further aim was to assess the impact of ADHD symptoms on quality of life and feelings of disability. METHOD: Participants comprised 89 patients diagnosed with ED according to DSM-5 criteria. The ASRS v.1.1 was used to divide them into two groups depending on whether they presented symptoms suggestive of adult ADHD or not, using a cut-off point of 4. Subsequently, we administered the EAT-40, BITE, BIS-11, SDI and Q-LES-Q scales. RESULTS: Patients diagnosed with ED who also had symptoms suggestive of ADHD presented a higher number and severity of eating disorder symptoms, greater motor and cognitive impulsivity, increased dysfunction and a poorer quality of life. CONCLUSIONS: The results indicate that on average, patients with eating disorders and ADHD symptoms presented more and worse eating disorder symptoms, greater impulsivity, increased dysfunction and a poorer quality of life. It is therefore important to assess the presence of ADHD symptoms in patients with ED due to the implications for prognosis and progression. PMID- 28594056 TI - The effect of add-on memantine on positive, negative and depressive symptoms of schizophrenia: a doubleblind, randomized, controlled trial. AB - : treatment of schizophrenia, they don’t adequately address residual positive, negative and depressive symptoms. The aim of the present study is to assess the effect of adjunctive memantine treatment on positive, negative and depressive symptoms of schizophrenia. METHODS: This randomized, placebo controlled study was conducted in Noor Hospital, Isfahan, Iran, 2013-2014; 32 patients in maintenance treatment were included in each group, using block sampling; inclusion criteria were age 18- 65 years, normal intellectual ability, being diagnosed with schizophrenia for the past two years, being treated with fixed doses of atypical antipsychotic for at least three months before randomization. Exclusion criteria were pregnancy, breast feeding, having received electro-convulsive therapy in the past two weeks, drug or substance abuse and dependence, psychiatric/ neurological comorbidities, and sensitivity to memantine. Patients in the intervention group were treated with memantine plus atypical antipsychotic; while in the control group, patients received placebo and atypical antipsychotic. Patients were assessed by Positive and Negative Symptom Scale (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) initially and every four weeks to the end of the 12th week. Data were analyzed in SPSS 17.0 using t-test, chi square, analysis of variance (ANOVA), and analysis of covariance (ANCOVA). RESULTS: Positive symptoms (p=0.028), negative symptoms (0.004), general psychopathology (p<0.001), depressive symptoms (p<0.001) and total symptom severity (p<0.001) decreased significantly in patients receiving add-on memantine. CONCLUSION: This study shows that, add-on memantine would be helpful, in the adjunctive treatment of depressive, positive, negative and general symptoms in patients with schizophrenia. PMID- 28594057 TI - Online interventions for caregivers of people with dementia: a systematic review. AB - INTRODUCTION: The elderly population is growing driven by the increase in life expectancy, which in turn entails an increase in the number of people with chronic diseases such as dementia. The vast majority of people suffering from this illness is assisted by informal caregivers, who play a key role in fulfilling the patients’ needs, promoting the possibility for people with dementia to live in their home environment. The Internet as a support tool in psychoeducational programs can significantly improve accessibility of them, becoming a currently consolidated interactive resource for the training of patients with acute and chronic diseases, and their caregivers. POPULATION AND METHOD: A literature search of the Pubmed, PsyINFO, Scopus, SciELO and Psicodoc databases was performed to systematically review those studies related to web based interventions for informal caregivers of people with dementia or cognitive impairment. RESULTS: On balance, the studies show a significant improvement after the psychoeducational intervention. Specifically, the improvement in caregivers’ wellbeing can be observed in the measures for self-efficacy, anxiety and depression. CONCLUSIONS: Online interventions are a promising strategy for the care of people with dementia. It would be advisable to perform further randomized trials to assess the reasons for lack of adherence to intervention, as well as usability studies to test the different software programs used. PMID- 28594058 TI - Mental disorder and mitochondrial dysfunction. Review on a case report. PMID- 28594059 TI - Cost-effectiveness analyses in neuropsychiatry and mental health. PMID- 28594062 TI - VSGBI abstracts from The Vascular Societies' Annual Scientific Meeting, 30 November - 2 December 2016. PMID- 28594060 TI - Lamotrigine induced dress syndrome in bipolar disorder. PMID- 28594061 TI - Successful implantation of a leadless pacemaker in a patient with an IVC filter. PMID- 28594063 TI - On the reciprocal effects between multiple group identifications and mental health: A longitudinal study of Scottish adolescents. AB - OBJECTIVES: The aim of the study was to investigate the link between social group identification and mental health outcomes in a sample of secondary school pupils. Based on previous work, it was predicted that multiple high group identifications would protect against psychological ill health. Furthermore, it was predicted that better mental health would also predict greater number of group identifications, thus creating a 'virtuous circle'. DESIGN: A longitudinal questionnaire design was used. METHODS: A total of 409 Scottish secondary school pupils aged 13-17 completed a questionnaire twice over a year. Pupils' responses regarding their mental health and the extent of their identification with three groups (the family, school, and friends) were measured. RESULTS: A path analysis of the data showed that greater number of high group identifications predicted better mental health outcomes amongst participants. However, better mental health also predicted greater number of high group identifications, suggesting that there is a cyclical relationship between both variables. CONCLUSIONS: The findings have both theoretical and practical implications. They highlight the importance of conceptualizing the link between group identification and mental health as cyclical, rather than unidirectional. This reconceptualization has implications for mental health promotion strategies, as it highlights the importance of attempting to turn a potentially 'vicious cycle' of social disidentification and mental ill health into a 'virtuous cycle' of social identification and mental health. PRACTITIONER POINTS: Results showed that in a population of 409 high school pupils, the more high group identifications pupils had, the better their mental health outcomes. Better mental health also predicted a greater number of high group identifications over time. The findings suggest that we would benefit from conceptualizing the relationship between group identification and mental outcomes as being cyclical rather than unidirectional. Viewing the relationship between group identification and mental health in this way enables us to consider interventions which help turn a 'vicious cycle' into a 'virtuous cycle'. Limitations A potential limitation of the work relates to the use of self-report questionnaires which may elicit socially desirable responses. The sample only consists of high school pupils from mainstream public schools within Scotland. PMID- 28594064 TI - Cobalt-Catalyzed Esterification of Amides. AB - The first cobalt-catalyzed amide activation of N-Boc-amides, and their conversion into esters, is reported here. This new methodology presents a very practical process that does not require an inert atmosphere, uses an inexpensive cobalt catalyst, and proceeds under mild reaction conditions. This catalytic system has a broad substrate scope and has been shown to be highly efficient, with catalyst loadings as low as 1 mol %. PMID- 28594065 TI - alpha,beta-Unsaturated Amides as Dipolarophiles: Catalytic Asymmetric exo Selective 1,3-Dipolar Cycloaddition with Nitrones. AB - 1,3-Dipolar cycloaddition is a commonly exploited method to access 5-membered chemical entities with a variety of peripheral functionalities and their stereochemical arrangements. Nitrones are isolable 1,3-dipoles that exhibit sufficient reactivity toward electron-deficient olefins in the presence of Lewis acids to deliver highly substituted isoxazolidines. Herein we document that alpha,beta-unsaturated amides, generally regarded as barely reactive in a 1,3 dipolar reaction manifold, were effectively activated using the designed 7 azaindoline auxiliary in an In(OTf)3 /bishydroxamic acid catalytic system. The broad substrate scope and clean removal of the 7-azaindoline auxiliary from the product highlight the synthetic utility of the present catalysis. PMID- 28594066 TI - Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination. AB - Recent studies suggest that impaired transcription or mitochondrial translation of small RNAs can cause abnormal myelination. A polynucleotide phosphorylase (PNPase) encoded by PNPT1 facilitates the import of small RNAs into mitochondria. PNPT1 mutations have been reported in patients with neurodevelopmental diseases with mitochondrial dysfunction. We report here 2 siblings with PNPT1 mutations who presented delayed myelination as well as mitochondrial dysfunction. We identified compound heterozygous mutations (c.227G>A; p.Gly76Asp and c.574C>T; p.Arg192*) in PNPT1 by quartet whole-exome sequencing. Analyses of skin fibroblasts from the patient showed that PNPase expression was markedly decreased and that import of the small RNA RNaseP into mitochondria was impaired. Exogenous expression of wild-type PNPT1, but not mutants, rescued ATP production in patient skin fibroblasts, suggesting the pathogenicity of the identified mutations. Our cases expand the phenotypic spectrum of PNPT1 mutations that can cause delayed myelination. PMID- 28594067 TI - Feeling the Pulse of Chemistry-Already in Practical Laboratory Courses. AB - "... The lessons that students can draw from a lab course are unique throughout the entire study of chemistry. Equally important and valuable is the authentic lab experience and the constant repetition of the link between acquiring knowledge, thorough observations, logical thinking, self-critical tenacity, and capacity for success throughout the experiments. The ultimate gain is satisfaction ..." Read more in the Editorial by Roland A. Fischer. PMID- 28594068 TI - Chimpanzee ankle and foot joint kinematics: Arboreal versus terrestrial locomotion. AB - OBJECTIVES: Many aspects of chimpanzee ankle and midfoot joint morphology are believed to reflect adaptations for arboreal locomotion. However, terrestrial travel also constitutes a significant component of chimpanzee locomotion, complicating functional interpretations of chimpanzee and fossil hominin foot morphology. Here we tested hypotheses of foot motion and, in keeping with general assumptions, we predicted that chimpanzees would use greater ankle and midfoot joint ranges of motion during travel on arboreal supports than on the ground. METHODS: We used a high-speed motion capture system to measure three-dimensional kinematics of the ankle and midfoot joints in two male chimpanzees during three locomotor modes: terrestrial quadrupedalism on a flat runway, arboreal quadrupedalism on a horizontally oriented tree trunk, and climbing on a vertically oriented tree trunk. RESULTS: Chimpanzees used relatively high ankle joint dorsiflexion angles during all three locomotor modes, although dorsiflexion was greatest in arboreal modes. They used higher subtalar joint coronal plane ranges of motion during terrestrial and arboreal quadrupedalism than during climbing, due in part to their use of high eversion angles in the former. Finally, they used high midfoot inversion angles during arboreal locomotor modes, but used similar midfoot sagittal plane kinematics across all locomotor modes. DISCUSSION: The results indicate that chimpanzees use large ranges of motion at their various ankle and midfoot joints during both terrestrial and arboreal locomotion. Therefore, we argue that chimpanzee foot anatomy enables a versatile locomotor repertoire, and urge caution when using foot joint morphology to reconstruct arboreal behavior in fossil hominins. PMID- 28594069 TI - Glucose targets for preventing diabetic kidney disease and its progression. AB - BACKGROUND: Diabetes is the leading cause of end-stage kidney disease (ESKD) around the world. Blood pressure lowering and glucose control are used to reduce diabetes-associated disability including kidney failure. However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure. OBJECTIVES: To evaluate the benefits and harms of intensive (HbA1c < 7% or fasting glucose levels < 120 mg/dL versus standard glycaemic control (HbA1c >= 7% or fasting glucose levels >= 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 31 March 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials evaluating glucose-lowering interventions in which people (aged 14 year or older) with type 1 or 2 diabetes with and without kidney disease were randomly allocated to tight glucose control or less stringent blood glucose targets. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and risks of bias, extracted data and checked the processes for accuracy. Outcomes were mortality, cardiovascular complications, doubling of serum creatinine (SCr), ESKD and proteinuria. Confidence in the evidence was assessing using GRADE. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: Fourteen studies involving 29,319 people with diabetes were included and 11 studies involving 29,141 people were included in our meta analyses. Treatment duration was 56.7 months on average (range 6 months to 10 years). Studies included people with a range of kidney function. Incomplete reporting of key methodological details resulted in uncertain risks of bias in many studies. Using GRADE assessment, we had moderate confidence in the effects of glucose lowering strategies on ESKD, all-cause mortality, myocardial infarction, and progressive protein leakage by kidney disease and low or very low confidence in effects of treatment on death related to cardiovascular complications and doubling of serum creatinine (SCr).For the primary outcomes, tight glycaemic control may make little or no difference to doubling of SCr compared with standard control (4 studies, 26,874 participants: RR 0.84, 95% CI 0.64 to 1.11; I2= 73%, low certainty evidence), development of ESKD (4 studies, 23,332 participants: RR 0.62, 95% CI 0.34 to 1.12; I2= 52%; low certainty evidence), all-cause mortality (9 studies, 29,094 participants: RR 0.99, 95% CI 0.86 to 1.13; I2= 50%; moderate certainty evidence), cardiovascular mortality (6 studies, 23,673 participants: RR 1.19, 95% CI 0.73 to 1.92; I2= 85%; low certainty evidence), or sudden death (4 studies, 5913 participants: RR 0.82, 95% CI 0.26 to 2.57; I2= 85%; very low certainty evidence). People who received treatment to achieve tighter glycaemic control probably experienced lower risks of non-fatal myocardial infarction (5 studies, 25,596 participants: RR 0.82, 95% CI 0.67 to 0.99; I2= 46%, moderate certainty evidence), onset of microalbuminuria (4 studies, 19,846 participants: RR 0.82, 95% CI 0.71 to 0.93; I2= 61%, moderate certainty evidence), and progression of microalbuminuria (5 studies, 13,266 participants: RR 0.59, 95% CI 0.38 to 0.93; I2= 75%, moderate certainty evidence). In absolute terms, tight versus standard glucose control treatment in 1,000 adults would lead to between zero and two people avoiding non-fatal myocardial infarction, while seven adults would avoid experiencing new-onset albuminuria and two would avoid worsening albuminuria. AUTHORS' CONCLUSIONS: This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure, death and major cardiovascular events as people who received less stringent blood glucose control, while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infarction. The adverse effects of glycaemic management are uncertain. Based on absolute treatment effects, the clinical impact of targeting an HbA1c < 7% or blood glucose < 6.6 mmol/L is unclear and the potential harms of this treatment approach are largely unmeasured. PMID- 28594070 TI - Labor, delivery, and anesthesia experiences of women with physical disability. AB - BACKGROUND: Although many women with physical disabilities report poor quality reproductive health care, little research has addressed labor, delivery, and anesthesia experiences of these women. This study was conducted to explore these experiences in women with significant mobility disabilities. METHODS: A qualitative descriptive study was conducted with 22 women from the United States who had delivered newborns within the prior 10 years. All had significant mobility disabilities. Two-hour, in-depth telephone interviews were conducted using a semistructured, open-ended interview protocol, which addressed many topics, including labor, delivery, and anesthesia experiences. We recruited most participants through social networks, interviewing women from 17 states. Conventional content analysis, facilitated by NVivo software, was used to identify major themes. RESULTS: The mean age of women was 34.8 +/- 5.3 years. Most women were white, college educated, and used wheeled mobility aids. Four key themes emerged from participants' narratives of laboring and giving birth with a disability. These included women's preferences for type of delivery, clinicians and some women expected no labor pain, fears prompting active advocacy, and positive experiences. As participants discussed their experiences with anesthesia, four additional themes were identified: importance of consultation with the anesthesia team, decisions about epidural/spinal vs general anesthesia, failed epidural with repeated efforts, and fear of injury related to anesthesia. CONCLUSIONS: The responses of women in this study suggest that there is need to make intrapartum care better for women with physical disabilities and to improve their experiences with labor, birth, and obstetric anesthesia care. PMID- 28594071 TI - Inhibition strategies of Listeria monocytogenes biofilms-current knowledge and future outlooks. AB - There is an increasing trend in the food industry on the Listeria monocytogenes biofilm formation and inhibition. This is attributed to its easy survival on contact surfaces, resistance to disinfectants or antibiotics and growth under the stringent condition used for food processing and preservation thereby leading to food contamination products by direct or indirect exposure. Though, there is a lack of conclusive evidences about the mechanism of biofilm formation, in this review, the concept of biofilm formation and various chemical, physical, and green technology approaches to prevent or control the biofilm formed is discussed. State-of-the-art approaches ranging from the application of natural to synthetic molecules with high effectiveness and non-toxicity targeted at the different steps of biofilm formation could positively influence the biofilm inhibition in the future. PMID- 28594072 TI - Empowering Marginalized Youth: A Self-Transformative Intervention for Promoting Positive Youth Development. AB - This article reports the results of a positive youth development (PYD) intervention for adolescents in alternative high schools (209 African American and Hispanic American adolescents, aged 14-18; 118 females and 91 males). The intervention was guided by a self-transformative model of PYD (Eichas, Meca, Montgomery, & Kurtines, 2014). This model proposes that the actions youth take to define themselves function as active ingredients in positive development over the life course. Consistent with the self-transformative model, results provided support for direct or mediated intervention effects on the self-transformative processes of self-construction and self-discovery, life goal development, identity synthesis, and internalizing problems. The findings illustrate the utility of using a self-transformative approach to PYD in work with marginalized youth populations. PMID- 28594073 TI - Work-related injury factors and safety climate perception in truck drivers. AB - INTRODUCTION: The trucking industry has a high burden of work-related injuries. This study examined factors, such as safety climate perceptions, that may impact injury risk. METHOD: A random sample of 9800 commercial driver's license holders (CDL) were sent surveys, only 4360 were eligible truck drivers. Descriptive statistics and logistic regression models were developed to describe the population and identify variables associated with work-related injury. RESULTS: 2189 drivers completed the pertinent interview questions. Driving less-than truckload, daytime sleepiness, pressure to work faster, and having a poor composite score for safety perceptions were all associated with increased likelihood of work-related injury. Positive safety perception score was protective for odds of work-related injury, and increased claim filing when injured. CONCLUSIONS: Positive psychological safety climate is associated with decreased likelihood of work-related injury and increased likelihood that a driver injured on the job files a workers' compensation claim. PMID- 28594075 TI - Influence of dietary fat source on sow and litter performance, colostrum and milk fatty acid profile in late gestation and lactation. AB - The objective of this study was to investigate the effects of dietary supplementation with various fat sources (3.8-3.9% of diet) during late pregnancy and lactation on the reproductive performance, fatty acids profile in colostrum, milk and serum of sow progeny. A total of 80 multiparous sows were randomly fed a control (adding no oil), palm oil (PO), fish oil (FO) or soybean oil (SO) supplemented diet from 90 days of pregnancy to weaning. Supplementation of FO increased litter size of weak piglets, compared with the control-fed sows (P < 0.05). Dietary FO and SO supplementation, enhanced the weaning survival rate, litter weaning weight, litter weight gain and fat content in milk (P < 0.05). The highest immunoglobulin (Ig)G and IgM levels in colostrum and milk were observed in the FO group (P < 0.05). Meanwhile, the highest concentration of C22:5 (n-3) and C22:6 (n-3) in colostrum, milk and piglet serum was observed in the FO group (P < 0.05). Taken together, dietary inclusion of FO or SO improved growth performance of nursing piglets by increasing milk fat output, and FO consumption by sows might benefit the piglets via increasing n-3 polyunsaturated fatty acid availability and immunoglobulins (IgG and IgM) secretion. PMID- 28594074 TI - Testosterone and dihydrotestosterone levels in the transition zone correlate with prostate volume. AB - BACKGROUND: There is still no consensus regarding intraprostatic androgen levels and the accumulation of androgens in the hyperplastic prostatic tissue. The current opinion is that intraprostatic dihydrotestosterone (DHT) concentrations are maintained but not elevated in benign prostatic hyperplasia (BPH), while there is no similar data concerning intraprostatic testosterone (T). METHODS: Tissue T (tT) and tissue DHT (tDHT) concentration were determined in 93 patients scheduled for initial prostate biopsy. The criteria for biopsy were abnormal DRE and/or PSA > 4 ng/mL. Total prostate volume (TPV) was determined by transrectal ultrasound (TRUS). During TRUS- guided prostate biopsy, 10-12 samples were collected from the peripheral zone (PZ) and two additional samples were collected from the transition zone (TZ). The samples from the TZ were immediately frozen in liquid nitrogen at -70 degrees C, and transported for tissue androgen determination, using liquid chromatography mass spectrometry (LC-MS). RESULTS: Pathological analysis revealed that prostate cancer (PCa) was present in 45 and absent in 48 patients. In the whole group, there were 42 men with small prostate (TPV < 30 mL) and 51 with enlarged prostate (TPV >= 31 mL). The overall average tT level was 0.79 +/- 0.66 ng/g, while the average tDHT level was 10.27 +/- 7.15 ng/g. There were no differences in tT and tDHT level in prostates with and without PCa. However, tT and tDHT levels were significantly higher in larger, than in smaller prostates (tT: 1.05 +/- 0.75 and 0.46 +/- 0.29 ng/g, and tDHT: 15.0 +/- 6.09 and 4.51 +/- 2.75 ng/g, respectively). There were strong correlations between tT and TPV (r = 0.71), and tDHT and TPV (r = 0.74). CONCLUSIONS: The present study confirmed that both T and DHT accumulated in the stroma of enlarged prostates; the degree of accumulation correlated with prostate volume. PMID- 28594076 TI - The future of safety science is happening now: The modernization of the benefit risk paradigm. AB - The future of safety science is happening now and has the potential to improve patient outcomes through an evolving approach to benefit-risk assessment. Three building blocks for the future of safety science, cognitive and behavioral systems, medical assessment, and data science, individually and collaboratively advance and modernize the benefit-risk paradigm. Incorporating the patient perspective and patient experiences will help identify tools that are useful in real-world practice. Medical assessment teams will bring together the study of toxicity and toxicogenomics, biomarkers, and special populations to personalize the benefit-risk profile. Personalized benefit-risk profiles for patients will help improve outcomes. Data science and related quantitative sciences such as safety statistics, database integration, technology, and epidemiology will provide new approaches and tools for analysis of safety data as well as more rapid access to insights that benefit patients. PMID- 28594077 TI - Trends in antidepressant prescribing to children and adolescents in Canadian primary care: A time-series analysis. AB - PURPOSE: The purpose of this study was to describe the trends and patterns of antidepressant (AD) prescribing to children and adolescents in Canadian primary care before and after the black-box warning in 2004. METHODS: Prescription data from the Canadian Primary Care Sentinel Surveillance Network, a repository of primary care data on over 1 million patients, was used to analyze AD prescribing to children (8-11 y) and adolescents (12-18 y) between 2000 and 2014. Interrupted time series analyses were used to assess the impact of the 2004 black-box warning on the prescribing levels of ADs. RESULTS: The 2004 black-box warning had a significant and immediate effect on the prescribing of AD. However, this drop was not sustained, and 5 years after the advisory AD prescribing rates reversed direction and started to rise. Selective serotonin reuptake inhibitors dominated as the most common AD prescribed throughout the study period, increasing from 66% prior to the black-box warning to 83.12% after 2009. CONCLUSIONS: The black-box warning effectively reduced AD prescribing in primary care for approximately 5 years before a reversal back to a positive rate of prescribing. This rebounding could reflect an emerging consensus about the trade-off in risks and benefits. PMID- 28594078 TI - Eruptive xanthoma with isomorphic response of Koebner in a construction worker with severe hyperlipidemia. PMID- 28594079 TI - Development of the breast immobilization system in prone setup: The effect of bra in prone position to improve the breast setup error. AB - PURPOSE/OBJECTIVE(S): Accurate and reproducible positioning of the breast is difficult due to its deformability and softness; thus, targeting a breast tumor or tumor bed with fractionated radiotherapy using external beam radiation is difficult. The aim of this study was to develop a novel bra to aid in breast immobilization in the prone position. MATERIALS & METHODS: To assess the accuracy of prone position fixation of breast tumors, 33 breast cancer patients with 34 lesions were recruited. The bra used in this verification was customized from a commercially available bra. Duplicate MRI were acquired in the prone position, alternating with and without the bra, and for each series, patients were asked to step off the MRI table and re-set up in the prone position. Patients were also asked to remove and re-fit the bra for the second MRI. Each pair of images were superimposed to match the shape of the skin surface, and the maximum difference in tumor geometric center in three axes was measured. The required set up margin was calculated as: required margin = mean difference in geometric center + 2.5 standard deviation. The volumetric overlap of the tumor, as well as contouring uncertainties, was evaluated using contour analysis software. RESULTS: The median breast size was 498 cc. The required margins for the lateral, vertical, and longitudinal directions were estimated to be 4.1, 4.1, and 5.0 mm, respectively, with the bra, and 5.1, 6.9, and 6.7 mm, respectively, without the bra. These margins covered the dislocation of more than 33 lesions in total. With the bra, 33 lesions had achieved an objective overlap of 95% and 99% with 2 and 4 mm margins, respectively, whereas 4 and 8 mm, respectively, were needed without the bra. CONCLUSION: The use of an immobilizing bra reduced the setup margin for prone position fixation of breast tumors. PMID- 28594080 TI - Structural Basis for Expansion of the Genetic Alphabet with an Artificial Nucleobase Pair. AB - Hydrophobic artificial nucleobase pairs without the ability to pair through hydrogen bonds are promising candidates to expand the genetic alphabet. The most successful nucleobase surrogates show little similarity to each other and their natural counterparts. It is thus puzzling how these unnatural molecules are processed by DNA polymerases that have evolved to efficiently work with the natural building blocks. Here, we report structural insight into the insertion of one of the most promising hydrophobic unnatural base pairs, the dDs-dPx pair, into a DNA strand by a DNA polymerase. We solved a crystal structure of KlenTaq DNA polymerase with a modified template/primer duplex bound to the unnatural triphosphate. The ternary complex shows that the artificial pair adopts a planar structure just like a natural nucleobase pair, and identifies features that might hint at the mechanisms accounting for the lower incorporation efficiency observed when processing the unnatural substrates. PMID- 28594081 TI - New evidence suggesting a dissociated etiology for cribra orbitalia and porotic hyperostosis. AB - OBJECTIVES: Porotic hyperostosis (PH), characterized by porotic lesions on the cranial vault, and cribra orbitalia (CO), a localized appearance of porotic lesions on the roof of the orbits, are relatively common osteological conditions. Their etiology has been the focus of several studies, and an association with anemia has long been suggested. Anemia often causes bone marrow hypertrophy or hyperplasia, leading to the expansion in trabecular or cranial diploic bone as a result of increased hematopoiesis. Hypertrophy and/or hyperplasia is often coupled with a disruption of the remodeling process of outer cortical bone, cranially and/or postcranially, leading to the externally visible porotic lesions reported in osteological remains. In this article, we investigate whether individuals with CO have increased thickness of the diploe, the common morphological direct effect of increased hematopoiesis, and thus test the relationship between the two conditions, as well as explore the type of anemia that underlie it. METHODS: An analysis of medical CT scans of a worldwide sample of 98 complete, young to middle-aged adult dry skulls from the Duckworth Collection was conducted on male and female cribrotic individuals (n = 23) and noncribrotic individuals (n = 75), all of whom lacked any evidence of porotic lesions on the vault. Measurements of total and partial cranial thickness were obtained by virtual landmark placement, using the Amira 5.4 software; all analyses were conducted in IBM SPSS 21. RESULTS: Cribriotic individuals have significantly thinner diploic bone and thicker outer and inner tables than noncribriotic individuals, contrary to the expected diploic expansion that would result from anemic conditions associated to bone marrow hypertrophy or hyperplasia. Additionally, individuals without CO and those with the condition have distinctive cranial thickness at particular locations across the skull and the severity to which CO is expressed also differentiates between those with mild and those with a moderate to severe form of the condition. CONCLUSIONS: Our results suggest a complex pattern of causality in relation to the pathologies that may lead to the formation of porotic lesions on the vault and the roof of the orbits. A form of anemia may be behind the osteological changes observed in PH and CO, but it is unlikely to be the same type of anemic condition that underlies both types of osteological lesions. We suggest that CO may be associated to anemias that lead to diploic bone hypocellularity and hypoplasia, such as those caused by anemia of chronic disease and, to a lesser extent, of renal failure, aplastic anemia, protein deficiency, and anemia of endocrine disorders, and not those that lead to bone marrow hypercellularity and hyperplasia and potential PH. This leads us to the conclusion that the terms PH and CO should be used to reflect different underlying conditions. PMID- 28594082 TI - Acneiform eruptions caused by vitamin B12: A report of five cases and review of the literature. AB - We describe five cases of acneiform eruption caused by vitamin B12 in five females aged 37, 32, 62, 29, and 21 years, respectively. The eruption appeared from 1 week to 5 months after the beginning of the therapy with i.m. or oral vitamin B12. Clinical picture was characterized by papules and pustules located on the face. In three patients, similar lesions were also present on the neck, shoulders, chest, and upper portion of the back. Comedones and cysts were absent. In two patients, serum vitamin B12 levels were very high. Histopathologic examination in one patient revealed an eosinophilic folliculitis. Spontaneous and complete remission was observed in all patients 3-6 weeks after vitamin B12 discontinuation. PMID- 28594083 TI - Fetal echocardiographic evaluation in cases of heterotaxy syndrome. PMID- 28594084 TI - Erratum. PMID- 28594085 TI - Preliminary study of clinical application on IMRT three-dimensional dose verification-based EPID system. AB - The three-dimensional dose (3D) distribution of intensity-modulated radiation therapy (IMRT) was verified based on electronic portal imaging devices (EPIDs), and the results were analyzed. Thirty IMRT plans of different lesions were selected for 3D EPID-based dose verification. The gamma passing rates of the 3D dose verification-based EPID system (Edose, Version 3.01, Raydose, Guangdong, China) and Delta4 measurements were then compared with treatment planning system (TPS) calculations using global gamma criteria of 5%/3 mm, 3%/3 mm, and 2%/2 mm. Furthermore, the dose-volume histograms (DVHs) for planning target volumes (PTVs) as well as organs at risk (OARs) were analyzed using Edose. For dose verification of the 30 treatment plans, the average gamma passing rates of Edose reconstructions under the gamma criteria of 5%/3 mm, 3%/3 mm, and 2%/2 mm were (98.58 +/- 0.93)%, (95.67 +/- 1.97)%, and (83.13 +/- 4.53)%, respectively, whereas the Delta4 measurement results were (99.14% +/- 1.16)%, (95.81% +/- 2.88)%, and (84.74% +/- 7.00)%, respectively. The dose differences between Edose reconstructions and TPS calculations were within 3% for D95% , D98% , and Dmean in each PTV, with the exception that the D98% of the PTV-clinical target volume (CTV) in esophageal carcinoma cases was (3.21 +/- 2.33)%. However, the larger dose deviations in OARs (such as lens, parotid gland, optic nerve, and spinal cord) can be determined based on DVHs. The difference was particularly obvious for OARs with small volumes; for example, the maximum dose deviation for the lens reached (-6.12 +/- 5.28)%. A comparison of the results obtained with Edose and Delta4 indicated that the Edose system could be applied for 3D pretreatment dose verification of IMRT. This system could also be utilized to evaluate the gamma passing rate of each treatment plan. Furthermore, the detailed dose distributions of PTVs and OARs could be indicated based on DVHs, providing additional reliable data for quality assurance in a clinic setting. PMID- 28594086 TI - Proteomic Characterization of Primary Mouse Hepatocytes in Collagen Monolayer and Sandwich Culture. AB - Dedifferentiation of primary hepatocytes in vitro makes their application in long term studies difficult. Embedding hepatocytes in a sandwich of extracellular matrix is reported to delay the dedifferentiation process to some extent. In this study, we compared the intracellular proteome of primary mouse hepatocytes (PMH) in conventional monolayer cultures (ML) to collagen sandwich culture (SW) after 1 day and 5 days of cultivation. Quantitative proteome analysis of PMH showed no differences between collagen SW and ML cultures after 1 day. Glycolysis and gluconeogenesis were strongly affected by long-term cultivation in both ML and SW cultures. Interestingly, culture conditions had no effect on cellular lipid metabolism. After 5 days, PMH in collagen SW and ML cultures exhibit characteristic indications of oxidative stress. However, in the SW culture the defense system against oxidative stress is significantly up-regulated to deal with this, whereas in the ML culture a down-regulation of these important enzymes takes place. Regarding the multiple effects of ROS and oxidative stress in cells, we conclude that the down-regulation of these enzymes seem to play a role in the loss of hepatic function observed in the ML cultivation. In addition, enzymes of the urea cycle were clearly down-regulated in ML culture. Proteomics confirms lack in oxidative stress defense mechanisms as the major characteristic of hepatocytes in monolayer cultures compared to sandwich cultures. J. Cell. Biochem. 119: 447-454, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28594088 TI - Isomerism: When right and left are similar, and why it matters. PMID- 28594087 TI - Adult prostatic sarcoma: A contemporary multicenter Rare Cancer Network study. AB - INTRODUCTION: Adult prostatic sarcoma (PS) is a rare disease. While surgery is considered the standard approach, the role of other therapies is not completely established. We report results of the largest multicentric contemporary cohort of PS patients. MATERIALS AND METHODS: This study included 61 adult PS patients treated in 16 American and European Institutions. Median age was 64.4 years (range: 22-87). Curative surgery was delivered in 48 patients (prostatectomy = 26, cystoprostatectomy = 22), usually with lymphadenectomy (n = 40). Curative radiotherapy (RT) was delivered in 32 patients, as radical (n = 5), neoadjuvant (n = 10), or postoperative treatment (n = 17). Eighteen patients received chemotherapy. None of the patients received hormonal therapy. RESULTS: Median follow-up was 72 months (95%CI: 55-not reached). Five-year local control (LC), overall survival (OS), cancer-specific survival, disease-free survival, and metastases-free rates were 47%, 53%, 56%, 35%, and 35%, respectively. Notably, curative RT (neoadjuvant, adjuvant, or definitive) was associated with improved 5 year LC (55% vs. 31%, P = 0.02) and OS (59% vs. 46%, P = 0.1). Surgically treated patients presenting with a cT3-4 tumor (n = 31), who received RT (n = 24), had a significantly improved 5-year LC (68% vs, 33%, P = 0.004) and OS (65% vs. 21%, P < 0.001) rates compared to patients not receiving RT. cT4 patients demonstrated a significantly lower 5-year OS (43% vs. 61%, P = 0.006) and LC (29% vs. 69%, P < 0.001) rates. Histologic subtype was not associated with LC and OS, but patients with prostatic stromal sarcoma, rhabdomyosarcoma, or sarcomatoid carcinoma had worse 5-year LC compared to other types (47% vs. 55%) and OS (49% vs. 58%). CONCLUSION: Adult PS has a poor prognosis. Locally advanced tumors have poor LC and OS rates. Curative RT should be considered part of the multidisciplinary approach to PS. PMID- 28594089 TI - Validity of spectral analysis based on heart rate variability from 1-minute or less ECG recordings. AB - BACKGROUND: To broaden the utility of heart rate variability (HRV) in clinical medicine and mass screening, results based on shorter electrocardiogram (ECG) recordings require validation with those based on standard 5-minute recordings. We investigated the association between HRV variables obtained from 5-minute ECGs with those obtained from ECGs shorter than 5 minutes. METHODS: Twenty-two participants aged 20-69 years underwent 5-minute resting ECG recordings in the supine position with natural breathing. Spectral analysis using MemCalc method was performed to calculate high-frequency (HF, which required at least 10 seconds) and low-frequency (LF, which required at least 30 seconds) components. Participants were not strictly preconditioned as in previous experimental studies in order to simulate a setting similar to that of a general health checkup. Associations of each variable between the 5-minute ECG recordings and those for shorter recordings were examined by Pearson's correlation coefficients and Bland Altman plots. RESULTS: HF and LF components were log-transformed based on their distributions. Correlation coefficients between 5-minute data and shorter recordings in the supine position with natural breathing ranged from 0.80 to 0.91 (HF by 10-second recording, 0.80; LF by 30-second recording, 0.83, respectively). Bland-Altman plots showed that gaps between the values from both methods slightly increased as the HF and LF component values increased. CONCLUSIONS: Although slight proportional errors were possible, values from standard 5-minute and shorter recordings in the supine position were strongly correlated. Our findings suggest that shorter ECG data without strict preconditioning can be reliably used for spectral analysis. PMID- 28594090 TI - Design and Synthesis of 1,2,4-Triazolo[3,2-b]-1,3,5-thiadiazine Derivatives as a Novel Template for Analgesic/Anti-Inflammatory Activity. AB - Previously, we demonstrated that certain heterocyclic compounds derived from 3 substituted-1,2,4-triazole-5-thiones had promising analgesic/anti-inflammatory activities together with low ulcerogenic properties. Therefore, we sought to design and synthesize new derivatives of triazol-5-thiones-fused heterocycles. In the present study, a series of novel bis-Mannich bases, namely 2,6-disubstituted 6,7-dihydro-5H-1,2,4-triazolo[3,2-b]-1,3,5-thiadiazines (1a-d, 2a-c, and 3a-d), were synthesized and characterized to assess their possible anti inflammatory/analgesic properties. Additionally, their ability to induce gastric toxicity was also evaluated. Several of the condensed compounds produced a degree of analgesic activity comparable to reference drugs in both the hot plate and tail-flick tests. A strong anti-inflammatory effect was observed for the derivatives carrying a benzyl group at the second position (2a-c). The majority of the prepared compounds caused comparatively less gastrointestinal (GI) side effects than the reference drugs naproxen and indomethacin did. These results showed that 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine derivatives might afford a safer alternative to currently available analgesic/anti-inflammatory agents for the treatment and management of inflammatory disease and pain. PMID- 28594091 TI - Contingent maternities? Maternal claims-making in third party reproduction. AB - The new reproductive technologies have significantly impacted definitions of motherhood. Historically, mothers were defined through the act of giving birth, but egg donation, embryo donation, and surrogacy disrupt this. Now multiple women can potentially claim maternity through gestational, genetic, legal, and social ties. Although there is some legal precedent for designating parentage, there is no simple solution to identify the 'true' mother. I address maternal claims making in third party reproduction via a content analysis of US patient literature for infertile women. Major tensions arise over which link to privilege, especially regarding genetic versus gestational ties in egg donation versus surrogacy; however, adding embryo donation to the analysis illuminates another crucial dimension previously overlooked - that heterosexual women's maternal claims are supported by their partner's paternity claims. Ultimately, I argue that although reproductive organisational discourse carefully constructs credible options for maternal claims-making, contemporary reproductive medicine does not define maternity through assisted reproduction as a truly autonomous connection. Rather, maternity is highly contingent and thus potentially discreditable. PMID- 28594093 TI - Size- and shape-dependent effects of microplastic particles on adult daggerblade grass shrimp (Palaemonetes pugio). AB - The incidence of microplastics in marine environments has been increasing over the past several decades. The objective of the present study was to characterize the size- and shape-dependent effects of microplastic particles (spheres, fibers, and fragments) on the adult daggerblade grass shrimp (Palaemonetes pugio). Grass shrimp were exposed to 11 sizes of plastic: spheres (30, 35, 59, 75, 83, 116, and 165 MUm), fragments (34 and 93 MUm), and fibers (34 and 93 MUm) at a concentration of 2000 particles/400 mL (= 50 000 particles/L) for 3 h. Following exposure, grass shrimp were monitored for survival, ingested and ventilated microplastics, and residence time. Mortality ranged from 0% to 55%. Spheres and fragments <50 MUm were not acutely toxic. Mortality rates in experiments with spheres and fragments >50 MUm ranged from 5% to 40%. Mortality was significantly higher in the exposure to 93-MUm fibers than other sizes tested (p < 0.001). The shape of the particle had a significant influence on the number of particles ingested by the shrimp (p < 0.001). The residence time of particles in the gut ranged from 27 to 75 h, with an average of 43.0 +/- 13.8 h. Within the gills, the residence time ranged from 27 to 45 h, with an average of 36.9 +/- 5.4 h. The results suggest that microplastic particles of various sizes and shapes can be ingested and ventilated by adult daggerblade grass shrimp, resulting in acute toxicity. Environ Toxicol Chem 2017;36:3074-3080. (c) 2017 SETAC. PMID- 28594094 TI - The Application of CRISPR/Cas Technology to Efficiently Model Complex Cancer Genomes in Stem Cells. AB - CRISPR/Cas gene editing technologies have emerged as powerful tools in the study of oncogenic transformation. The system's specificity, versatility, and ease of implementation allow researchers to identify important molecular markers and pathways which grant cancers stem cell like properties. This technology has already been applied to researching specific cancers, but has seen restricted therapeutic applications due to inherent ethical and technical limitations. Active development and adaptation of the CRISPR/Cas system has produced new methods to take advantage of both non-homologous end joining and homologous recombination repair mechanisms in attempts to remedy these limitations and improve the versatility of gene edits that can be created. Nonetheless, until issues with specificity and in vivo efficiency are resolved, utilization of CRISPR/Cas systems would be best employed in the modeling and study of various cancer genes. While it may have potential therapeutic applications to targeted cancer therapies in the future, presently CRISPR/Cas is a remarkable technique that can be utilized for easy and efficient gene editing when it comes to cancer research. J. Cell. Biochem. 119: 134-140, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28594092 TI - Understanding the relationship between cesarean birth and stress, anxiety, and depression after childbirth: A nationwide cohort study. AB - BACKGROUND: Women who undergo cesarean birth might have an increased risk for poor mental health after childbirth, possibly because of maternal and neonatal physical problems, low parental confidence, and decreased levels of oxytocin. However, this relationship remains controversial and requires further examination. The study aimed to examine the effect of cesarean birth on postpartum stress, anxiety, and depression. METHODS: This nationwide population based cohort study was conducted using the Taiwan National Health Insurance Database. A total of 12 619 women who underwent cesarean birth and 12 619 control women who underwent vaginal birth were matched by propensity score based on age, socioeconomic status, residential urbanicity, antepartum comorbidity, and index year of delivery. We compared the incidence of stress, anxiety, and depression during the first postpartum year between cesarean and comparison groups by calculating incidence rate ratios (IRRs). RESULTS: The cesarean group showed a significantly higher risk for stress symptoms (IRR 1.4 [95% confidence interval {CI} 1.02-1.92]), but not anxiety (IRR 1.14 [95% CI 0.95-1.38]) or depression (IRR 1.32 [95% CI 0.94-1.87]), although the IRRs were also greater than one. The cesarean group had a significantly higher risk of any of the above-listed three disorders than the comparison group (incidence 27.6 vs 23.4 per 1000 person years; IRR 1.18 [95% CI 1.01-1.38]). CONCLUSIONS: Cesarean birth was associated with an increased risk of postpartum stress symptoms. Health professionals should avoid unnecessary cesarean birth, pay attention to women who deliver by cesarean, and intervene appropriately in an attempt to improve mental health among postpartum women. PMID- 28594095 TI - Electronic remote blood issue: near patient blood allocation using an automated blood storage system. PMID- 28594096 TI - Tetrathiafulvalene-Polychlorotriphenylmethyl Dyads: Influence of Bridge and Open Shell Characteristics on Linear and Nonlinear Optical Properties. AB - Three conjugated donor-pi-acceptor radical systems (1 a-1 c) were prepared by bridging a tetrathiafulvalene (TTF) electron-donor unit to a polychlorotriphenylmethyl (PTM) electron-acceptor radical through vinylene units of different lengths. The dependence of the intramolecular charge transfer on the length of the conjugated bridge has been analyzed by different electrochemical and spectroscopic techniques. Linear optical properties and the second-order nonlinear optical (NLO) response of these derivatives have been computed by comparing systems 1 a-1 c with the non-radical analogues (2 a-2 c). Interestingly, an enhanced NLO response is predicted for dyads 1 a-1 c with PTM in the radical form and for compounds with longer vinylene bridges. Calculations confirm the active role the bridge plays for electronic communication between the donor TTF and the acceptor PTM units. PMID- 28594098 TI - Target Identification of Kinase Inhibitor Alisertib (MLN8237) by Using DNA Programmed Affinity Labeling. AB - Accurate identification of the molecular targets of bioactive small molecules is a highly important yet challenging task in biomedical research. Previously, a method named DPAL (DNA-programmed affinity labeling) for labeling and identifying the cellular targets of small molecules and nucleic acids was developed. Herein, DPAL is applied for the target identification of Alisertib (MLN8237), which is a highly specific aurora kinase A (AKA) inhibitor and a drug candidate being tested in clinical trials for cancer treatment. Apart from the well-established target of AKA, several potential new targets of MLN8237 were identified. Among them, p38 mitogen-activated protein kinase (p38) and laminin receptor (LAMR) were validated to be implicated in the anticancer activities of MLN8237. Interestingly, these new targets were not identified with non-DNA-based affinity probes. This work may facilitate an understanding of the molecular basis of the efficacy and side effects of MLN8237 as a clinical drug candidate. On the other hand, this work has also demonstrated that the method of DPAL could be a useful tool for target identification of bioactive small molecules. PMID- 28594099 TI - Cerebroplacental ratio thresholds measured within 2 weeks before birth and risk of Cesarean section for intrapartum fetal compromise and adverse neonatal outcome. AB - OBJECTIVES: Prediction of intrapartum fetal compromise in uncomplicated, term pregnancies is a global obstetric challenge. Currently, no widely accepted screening test for this condition exists, although the cerebroplacental ratio (CPR) shows promise. We aimed to evaluate prospectively the screening performance of the CPR 10th centile threshold for prediction of Cesarean section for intrapartum fetal compromise (IFC) and composite adverse neonatal outcome (ANO) after 36 weeks' gestation in low-risk women, and to compare this with CPR <= 1 and < 5th centile thresholds described previously in the literature. METHODS: This was a blinded, prospective, observational, cohort study of 483 women with uncomplicated singleton pregnancy who underwent fortnightly CPR measurements from 36 weeks to delivery, and their intrapartum and neonatal outcomes were recorded. The CPR 10th centile threshold screening performance was calculated for emergency Cesarean section for IFC and composite ANO (defined as acidosis at birth, 5-min Apgar score < 7 and/or admission to the neonatal intensive care unit). Comparison of screening performance of CPR <= 1 and < 5th and < 10th centile thresholds was also undertaken for these specified outcomes. RESULTS: In total, 437 women were included in the analysis, of whom 4.1% had an emergency Cesarean section for IFC and 17.8% had a composite ANO. Sensitivity and specificity for CPR < 10th centile were, respectively, 55.6% and 87.9% for prediction of Cesarean section for IFC, and 28.2% and 88.0% for composite ANO. Compared with CPR <= 1 and < 5th centile, CPR < 10th centile yielded the best overall test performance for detection of Cesarean section for IFC and composite ANO, although its predictive value was only fair for Cesarean section for IFC (area under the receiver-operating characteristics curve (AUC) = 0.72) and poor for composite ANO (AUC = 0.58). CONCLUSION: The CPR 10th centile threshold may be useful as a component of a risk assessment tool for Cesarean section for IFC in low-risk pregnancies at term. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28594100 TI - More Effective Consolidation of Episodic Long-Term Memory in Children Than Adults Unrelated to Sleep. AB - Abilities to encode and remember events in their spatiotemporal context (episodic memory) rely on brain regions that mature late during childhood and are supported by sleep. We compared the temporal dynamics of episodic memory formation and the role of sleep in this process between 62 children (8-12 years) and 57 adults (18 37 years). Subjects recalled "what-where-when" memories after a short 1-hr retention interval or after a long 10.5-hr interval containing either nocturnal sleep or daytime wakefulness. Although children showed diminished recall of episodes after 1 hr, possibly resulting from inferior encoding, unlike adults, they showed no further decrease in recall after 10.5 hr. In both age groups, episodic memory benefitted from sleep. However, children's more effective offline retention was unrelated to sleep. PMID- 28594097 TI - Functional activity of the sensorimotor cortex and cerebellum relates to cervical dystonia symptoms. AB - Cervical dystonia (CD) is the most common type of focal dystonia, causing abnormal movements of the neck and head. In this study, we used noninvasive imaging to investigate the motor system of patients with CD and uncover the neural correlates of dystonic symptoms. Furthermore, we examined whether a commonly prescribed anticholinergic medication in CD has an effect on the dystonia-related brain abnormalities. Participants included 16 patients with CD and 16 healthy age-matched controls. We collected functional MRI scans during a force task previously shown to extensively engage the motor system, and diffusion and T1-weighted MRI scans from which we calculated free-water and brain tissue densities. The dystonia group was also scanned ca. 2 h after a 2-mg dose of trihexyphenidyl. Severity of dystonia was assessed pre- and post-drug using the Burke-Fahn-Marsden Dystonia Rating Scale. Motor-related activity in CD was altered relative to controls in the primary somatosensory cortex, cerebellum, dorsal premotor and posterior parietal cortices, and occipital cortex. Most importantly, a regression model showed that increased severity of symptoms was associated with decreased functional activity of the somatosensory cortex and increased activity of the cerebellum. Structural imaging measures did not differ between CD and controls. The single dose of trihexyphenidyl altered the fMRI signal in the somatosensory cortex but not in the cerebellum. Symptom severity was not significantly reduced post-treatment. Findings show widespread changes in functional brain activity in CD and most importantly that dystonic symptoms relate to disrupted activity in the somatosensory cortex and cerebellum. Hum Brain Mapp 38:4563-4573, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28594101 TI - Effects of different n-6 to n-3 polyunsaturated fatty acids ratio on reproductive performance, fecal microbiota and nutrient digestibility of gestation-lactating sows and suckling piglets. AB - This study was conducted to evaluate the effects of dietary ratios of n-6:n-3 polyunsaturated fatty acids (PUFA) on reproductive performance, fecal microbiota and nutrient digestibility of gestation-lactating sows and suckling piglets. Fifteen primiparous sows (Landrace * Yorkshire) were randomly allotted into three treatments. Fed diets contained different ratios of n-6:n-3 PUFA, including 20:1, 15:1 and 10:1. No differences were detected among the treatments for average daily feed intake (ADFI) of sows and the back fat levels during lactation (P > 0.05). Body weight (BW) loss of sows after farrowing to weanling was greater in the 10:1 treatment compared with 15:1 or 20:1 (P < 0.05). In piglets, a great significant difference for BW was observed at 4 weeks (P < 0.01). Furthermore, average daily gain (ADG) of piglets in the 10:1 treatment was higher (P < 0.05). No difference was observed among treatments in nutrient digestibility of sows (P > 0.05). A great significant difference for fecal microbiota was in the 10:1 treatment compared with 20:1 and 15:1 treatments (P < 0.01). In conclusion, altering the ratio of n-6:n-3 PUFA in gestation-lactating sow diet had no difference on nutrient digestibility in gestation-lactating sows, but it can partially improve reproductive performance. PMID- 28594102 TI - The inhibition effects of some natural products on lactoperoxidase purified from bovine milk. AB - In this study, inhibition profiles of some natural products, which are digoxin, L Dopa, dopamine, isoliquiritigenin, and 1,1,2,2-tetrakis(p-hydroxyphenyl)ethane (Tetrakis), were investigated against bovine lactoperoxidase (LPO) enzyme. Digoxin, L-Dopa, and dopamine are active ingredients of some drugs, which have important functions in our body, especially in cases of heart failure. Isoliquiritigenin and tetrakis are types of natural phenolic compounds, which play an important role in cancer prevention and treatment. LPO enzyme was purified from bovine milk using sepharose-4B-l-tyrosine sulfonamide affinity column chromatography. LPO is responsible for the nonimmune biological defense system and has antibacterial activity so selection of these active substances is important. The inhibition studies are performed with the ABTS substrate. Bovine LPO enzyme was effectively inhibited by phenolic molecules. Ki values of these natural products were found as 0.20 +/- 0.09, 0.22 +/- 0.17, 0.49 +/- 0.11, 0.49 +/- 0.27, and 1.20 +/- 0.25 MUM, respectively. Tetrakis and digoxin exhibited noncompetitive inhibition, and other molecules showed competitive inhibition. PMID- 28594104 TI - The risk factor of false-negative and false-positive for T-SPOT.TB in active tuberculosis. AB - OBJECTIVES: T-SPOT.TB is a promising diagnosis tool to identify both pulmonary tuberculosis and extrapulmonary tuberculosis, as well as latent tuberculosis; however, the factors that affect the results of T-SPOT.TB remains unclear. In this study, we aim to figure out the risk factor of T-SPOT.TB for active TB. METHODS: A total of 349 patients were recruited between January 1st, 2016 and January 22st, 2017 at Renmin Hospital of Wuhan University, including 98 subjects with TB and 251 subjects with non-TB disease, and received T-SPOT.TB (Oxford Immunotec Ltd). Statistics were analyzed by SPSS 19.0 using logistic regression. RESULTS: The overall specificity and sensitivity of the T-SPOT.TB was 92.83% (233/251; 95%CI 0.8872-0.9557) and 83.67% (82/98; 95%CI 0.7454-0.9010), respectively. Patients with tuberculous meningitis were more likely to have false negative results (OR 17.4, 95%CI 3.068-98.671; P<.001) while patients with cured TB tended to induce false-positive results (OR 30.297; 95%CI 7.069-129.849; P<.001). The results were not affected by sex, age, onset time, smoke, alcohol, treatment, allergic history, co-morbidity, TB (exclude tuberculous meningitis) (P>.05). CONCLUSION: Tuberculous meningitis was a risk factor of false-negative for T-SPOT.TB, while cured TB was a risk factor of false-positive. PMID- 28594105 TI - Effects of cucumber mosaic virus-infected chilli plants on non-vector Bemisia tabaci (Hemiptera: Aleyrodidae). AB - Plant virus infections are known to alter host plant attractiveness and suitability for insect herbivores. This study was conducted to determine how cucumber mosaic virus (CMV)-infected chilli plants affect the fitness and settling preferences of nonvector whitefly, Bemisia tabaci adults under dual choice conditions with volatile organic compounds analyzed using solid phase microextraction coupled with gas chromatography-mass spectrometry (GC-MS). Results showed that the presence of CMV in chilli plants substantially affects the settling preferences of the B. tabaci, which preferred to settle on noninfected plants. Duration of the egg stage and the longevity and fecundity of adult B. tabaci on CMV-infected chilli plants were not markedly different from those on noninfected chilli plants. In contrast, the developmental time from egg to adult was significantly reduced in CMV-infected chilli plants compared to the noninfected plants. The results also showed that CMV-infected chilli plants released significantly more linalool and phenylacetaldehyde than noninfected plants. Overall, it was suggested that the behavioral response of B. tabaci might be modified by CMV-infected plants, which alter the release of specific headspace volatiles. Based on these results, the modification of plant volatile profiles may help in enhancing the effectiveness of biological control and the protection of crop plants against B. tabaci. PMID- 28594106 TI - Inaugural Ryoji Noyori ACES Award: C.-M. Che / Honorary Membership of the Chemical Society of Japan: G. Erker. PMID- 28594103 TI - Dietary alpha-ketoglutarate supplementation improves hepatic and intestinal energy status and anti-oxidative capacity of Cherry Valley ducks. AB - alpha-Ketoglutarate (AKG) is an extensively used dietary supplement in human and animal nutrition. The aim of the present study was to investigate effects of dietary AKG supplementation on the energy status and anti-oxidative capacity in liver and intestinal mucosa of Cherry Valley ducks. A total of 80 1-day-old ducks were randomly assigned into four groups, in which ducks were fed basal diets supplemented with 0% (control), 0.5%, 1.0% and 1.5% AKG, respectively. Graded doses of AKG supplementation linearly decreased the ratio of adenosine monophosphate (AMP) to adenosine triphosphate (ATP) in the liver, but increased ATP content and adenylate energy charge (AEC) in a quadratic and linear manner, respectively (P < 0.05). Increasing dietary AKG supplemental levels produced linear positive responses in ATP content and AEC, and negative responses in AMP concentration, the ratio of AMP to ATP and total adenine nucleotide in the ileal mucosa (P < 0.05). All levels of dietary AKG reduced the production of jejunal hydrogen peroxide and hepatic malondialdehyde (P < 0.05). Hepatic and ileal messenger RNA expression of AMP kinase alpha-1 and hypoxia-inducible factor 1alpha were linearly up-regulated as dietary AKG supplemental levels increased (P < 0.05). In conclusion, dietary AKG supplementation linearly or quadratically enhanced hepatic and intestinal energy storage and anti-oxidative capacity of Cherry Valley ducks. PMID- 28594107 TI - miRNAs in nutrition, obesity, and cancer: The biology of miRNAs in metabolic disorders and its relationship with cancer development. AB - SCOPE: The scope of this review is to explain how metabolic disorders originated by a deficient nutrition can develop into a neoplastic process by the alteration of epigenetic mechanisms like miRNAs. Obesity is a proinflammatory state with a wide impact on health around the world that is associated with neoplastic diseases. Epigenetic mechanisms have a central role in the obesogenic environment, which participates on the development of comorbidities such as cancer. METHODS AND RESULTS: We made an exhaustive review of the most recent reports about metabolic disorders with nutrition and their relationship with miRNAs, and their risk of developing into oncogenic processes. MicroRNAs (miRNAs) act as one of the major epigenetic mechanisms that can affect the metabolic reprogramming of cellular metabolism that plays an important role in the oncogenic process. There is evidence that some foods may contribute to diminishing the risk of cancer as well as epidemiological studies that support the notion that diets high in animal protein and fat promote cancer risk. Therefore, diets high in fruit and vegetables reduce the risk of cancer. One of the principal explanations is that these foods contain bioactive compounds that increase the efficacy of epigenetic mechanisms, which in turn decrease the risk of obesity and its comorbidities. CONCLUSION: In this review, we show how miRNAs are implicated in several signaling pathways as well as illustrating some bioactive compounds that impact inflammation and cancer development. PMID- 28594108 TI - Punch up your podium presentations. AB - The goal of most presentations is to engage audience participants. Effective presenters go beyond content expertise to connect with audiences through various techniques, formats, and presentation styles. Mayer's theory of multimedia learning, neurocognitive factors, and the assertion-evidence approach are essential elements that presenters can use if they have not had formal training in creating presentations. Tips are offered on how to connect with the audience and how to avoid known pitfalls. PMID- 28594109 TI - A cell-free testing platform to screen chemicals of potential neurotoxic concern across twenty vertebrate species. AB - There is global demand for new in vitro testing tools for ecological risk assessment. The objective of the present study was to apply a set of cell-free neurochemical assays to screen many chemicals across many species in a relatively high-throughput manner. The platform assessed 7 receptors and enzymes that mediate neurotransmission of gamma-aminobutyric acid, dopamine, glutamate, and acetylcholine. Each assay was optimized to work across 20 vertebrate species (5 fish, 5 birds, 7 mammalian wildlife, 3 biomedical species including humans). We tested the screening assay platform against 80 chemicals (23 pharmaceuticals and personal care products, 20 metal[loid]s, 22 polycyclic aromatic hydrocarbons and halogenated organic compounds, 15 pesticides). In total, 10 800 species-chemical assay combinations were tested, and significant differences were found in 4041 cases. All 7 assays were significantly affected by at least one chemical in each species tested. Among the 80 chemicals tested, nearly all resulted in a significant impact on at least one species and one assay. The 5 most active chemicals were prochloraz, HgCl2 , Sn, benzo[a]pyrene, and vinclozolin. Clustering analyses revealed groupings according to chemicals, species, and chemical-assay combinations. The results show that cell-free assays can screen a large number of samples in a short period of time in a cost-effective manner in a range of animals not easily studied using traditional approaches. Strengths and limitations of this approach are discussed, as well as next steps. Environ Toxicol Chem 2017;36:3081-3090. (c) 2017 SETAC. PMID- 28594110 TI - Novel application of fluorescence coupled capillary electrophoresis to resolve the interaction between the G-quadruplex aptamer and thrombin. AB - The dynamic binding status between the thrombin and its G-quadruplex aptamers and the stability of its interaction partners were probed using our previously established fluorescence-coupled capillary electrophoresis method. A 29-nucleic acid thrombin binding aptamer was chosen as a model to study its binding affinity with the thrombin ligand. First, the effects of the cations on the formation of G quadruplex from unstructured 29-nucleic acid thrombin binding aptamer were examined. Second, the rapid binding kinetics between the thrombin and 6 carboxyfluorescein labeled G-quadruplex aptamer was measured. Third, the stability of G-quadruplex aptamer-thrombin complex was also examined in the presence of the interfering species. Remarkably, it was found that the complementary strand of 29-nucleic acid thrombin binding aptamer could compete with G-quadruplex aptamer and thus disassociated the G-quadruplex structure into an unstructured aptamer. These data suggest that our in-house established fluorescence-coupled capillary electrophoresis assay could be applied to binding studies of the G-quadruplex aptamers, thrombin, and their ligands, while overcoming the complicated and costly approaches currently available. PMID- 28594112 TI - Cytologic perspectives on neoteric B-cell lymphoproliferative disorders. AB - The 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tissues has been recently revised, and publication of the updated 2016 version is expected soon. Given that cytopathologists are often involved in the diagnosis of primary, recurrent, and transformed lymphoproliferative disorders, knowledge of updates to the WHO lymphoma classification, including terminology, pathogenesis, ancillary techniques, and targeted therapies is necessary. Herein, we reference the last decade of cytology specific literature for seven newer B cell disorders and provide illustrative examples of each entity from our files. PMID- 28594111 TI - Bone Histomorphometry in an Osteoporotic Hemodialysis Patient Treated With Denosumab. PMID- 28594113 TI - Self-gated 4D-MRI of the liver: Initial clinical results of continuous multiphase imaging of hepatic enhancement. AB - PURPOSE: To evaluate the feasibility of a self-gated free-breathing volume interpolated breath-hold examination (VIBE) sequence using compressed sensing (CS) for contrast-enhanced multiphase liver MRI. MATERIALS AND METHODS: We identified 23 patients who underwent multiphase gadobutrol-enhanced liver magnetic resonance imaging (MRI) using 1) a prototype free-breathing VIBE sequence with respiratory self-gating and CS (VIBECS ), and 2) a standard breath hold VIBE (VIBESTD ) on the same 1.5T scanner at two timepoints. VIBECS was continuously acquired for 128 seconds and a time-series of 16 timepoints was jointly reconstructed from the dataset. The unenhanced, arterial, portal-venous, and venous timepoints with the best image quality were selected and compared to the corresponding VIBESTD series serving as reference. Image quality was assessed qualitatively (image quality, sharpness, lesion conspicuity, vessel contrast, noise, motion/other artifacts; two readers independently; 5-point Likert scale; 5 = excellent) and quantitatively (vessel contrast [VC], coefficient-of-variation [CV]) Statistics were performed using Wilcoxon-sign-rank (ordinal) and paired t test (continuous variables). RESULTS: Image quality and lesion conspicuity revealed no significant differences between the sequences (P >= 0.3). VIBESTD showed a tendency to higher motion artifacts (P >= 0.07). Image sharpness significantly increased in VIBECS as compared to VIBESTD (P <= 0.03). Arterial phase vessel contrast appeared significantly lower in VIBECS than in VIBESTD (P = 0.04). VIBECS showed reconstruction artifacts not present in VIBESTD (P = 0.001). Image noise was significantly lower in VIBECS than in VIBESTD (P <= 0.004). Arterial phase VC was significantly lower in VIBECS than in VIBESTD (P = 0.01). CV revealed no differences between sequences (P = 0.7). CONCLUSION: VIBECS is feasible for continuous free-breathing contrast-enhanced multiphase liver MRI, providing similar image quality and lesion conspicuity as VIBESTD . LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:459-467. PMID- 28594115 TI - Therapeutic relevance of ozone therapy in degenerative diseases: Focus on diabetes and spinal pain. AB - Ozone, one of the most important air pollutants, is a triatomic molecule containing three atoms of oxygen that results in an unstable form due to its mesomeric structure. It has been well-known that ozone has potent ability to oxidize organic compounds and can induce respiratory irritation. Although ozone has deleterious effects, many therapeutic effects have also been suggested. Since last few decades, the therapeutic potential of ozone has gained much attention through its strong capacity to induce controlled and moderated oxidative stress when administered in precise therapeutic doses. A plethora of scientific evidence showed that the activation of hypoxia inducible factor-1alpha (HIF-1a), nuclear factor of activated T-cells (NFAT), nuclear factor-erythroid 2-related factor 2 antioxidant response element (Nrf2-ARE), and activated protein-1 (AP-1) pathways are the main molecular mechanisms underlying the therapeutic effects of ozone therapy. Activation of these molecular pathways leads to up-regulation of endogenous antioxidant systems, activation of immune functions as well as suppression of inflammatory processes, which is important for correcting oxidative stress in diabetes and spinal pain. The present study intended to review critically the available scientific evidence concerning the beneficial properties of ozone therapy for treatment of diabetic complications and spinal pain. It finds benefit for integrating the therapy with ozone into pharmacological procedures, instead of a substitutive or additional option to therapy. PMID- 28594114 TI - Defect Chemistry, Electrical Properties, and Evaluation of New Oxides Sr2 CoNb1-x Tix O6-delta (0<=x<=1) as Cathode Materials for Solid Oxide Fuel Cells. AB - The perovskite series Sr2 CoNb1-x Tix O6-delta (0<=x<=1) was investigated in the full compositional range to assess its potential as cathode material for solid oxide fuel cell (SOFC). The variation of transport properties and thus, the area specific resistances (ASR) are explained by a detailed investigation of the defect chemistry. Increasing the titanium content from x=0-1 produces both oxidation of Co3+ to Co4+ (from 0 up to 40 %) and oxygen vacancies (from 6.0 to 5.7 oxygen atom/formula unit), although each charge compensation mechanism predominates in different compositional ranges. Neutron diffraction reveals that samples with high Ti-contents lose a significant amount of oxygen upon heating above 600 K. Oxygen is partially recovered upon cooling as the oxygen release and uptake show noticeably different kinetics. The complex defect chemistry of these compounds, together with the compositional changes upon heating/cooling cycles and atmospheres, produce a complicated behavior of electrical conductivity. Cathodes containing Sr2 CoTiO6-delta display low ASR values, 0,13 Omega cm2 at 973 K, comparable to those of the best compounds reported so far, being a very promising cathode material for SOFC. PMID- 28594116 TI - Minimum clinically important difference analysis confirms the efficacy of IgPro10 in CIDP: the PRIMA trial. PMID- 28594117 TI - Serum anti-phenolic glycolipid-1 IgA correlates to IgM isotype in leprosy patients: a possible candidate for seroepidemiological surveys? AB - OBJECTIVE: The aim of this study was to compare serum anti-phenolic glycolipid-1 IgA, IgG, and IgM levels in leprosy patients and controls. METHOD: Analysis of anti-PGL-1 IgA, IgG, or IgM in serum samples from multibacillary (MB, n=32) and paucibacillary (PB, n=22) leprosy patients, and in non-endemic controls (n=17), using an indirect enzyme-linked immunosorbent assay. RESULTS: A strong correlation between serum IgM and IgA isotypes was found (r=.745, P<.0001) in MB patients. A moderate correlation was found in all analyses in PB patients. A moderate agreement was found between anti-PGL1 IgA and IgM tests. Based on the ROC curves, the cut-off values were selected and the parameters of validation were calculated. Considering the clinical forms altogether, the diagnostic sensitivities were 50.0% for IgA, 22.2% for IgG, and 74.1% for IgM. The positive (VPP) and negative (VPN) predictive values were estimated for each isotype. For IgA, the VPP and VPN were, respectively, 100.0% (87.0%-100.0%; 95% confidence interval) and 38.7% (24.4%-54.5%); for IgG, 100% (87.0%-100.0%) and 28.8% (17.8% 42.1%), respectively; and for IgM, 95.2% (83.8%-99.4%) and 51.7% (32.5%-70.6%), respectively. CONCLUSION: Despite the limiting factors, anti-PGL1 IgA correlates to IgM levels and it could be considered as a possible laboratorial tool to be also used, for instance, in serological follow-up studies. PMID- 28594119 TI - Does Ocular Neuropathic Pain Deserve an Autonomous Position in the IHS Classification? Clinical and Diagnostic Evidences. PMID- 28594118 TI - Switching Between Giant Positive and Negative Thermal Expansions of a YFe(CN)6 based Prussian Blue Analogue Induced by Guest Species. AB - The control of thermal expansion of solid compounds is intriguing but remains challenging. The effect of guests on the thermal expansion of open-framework structures was investigated. Notably, the presence of guest ions (K+ ) and molecules (H2 O) can substantially switch thermal expansion of YFe(CN)6 from negative (alphav =-33.67*10-6 K-1 ) to positive (alphav =+42.72*10-6 K-1 )-a range that covers the thermal expansion of most inorganic compounds. The mechanism of such substantial thermal expansion switching is revealed by joint studies with synchrotron X-ray diffraction, X-ray absorption fine structure, neutron powder diffraction, and density functional theory calculations. The presence of guest ions or molecules plays a critical damping effect on transverse vibrations, thus inhibiting negative thermal expansion. An effective method is demonstrated to control the thermal expansion in open-framework materials by adjusting the presence of guests. PMID- 28594120 TI - Migraine in Children. PMID- 28594121 TI - A Review of Vomiting and Migraine-Related Clinical Parameters in Pediatric Migraine. PMID- 28594122 TI - AHS Members' Choice Award. PMID- 28594124 TI - Melatonin in the Treatment of Primary Headache Disorders. PMID- 28594125 TI - The SUN Also Rises. PMID- 28594126 TI - Pearls and Pitfalls in Migraine Neuroimaging. PMID- 28594128 TI - Predatory journals: will they survive or thrive? PMID- 28594127 TI - No clear support for a role for vitamin D in Parkinson's disease: A Mendelian randomization study. AB - BACKGROUND: Observational studies have found that relative to healthy controls, patients with Parkinson's disease have lower circulating concentrations of 25 hydroxyvitamin D, a clinical biomarker of vitamin D status. However, the causality of this association is uncertain. We undertook a Mendelian randomization study to investigate whether genetically decreased 25 hydroxyvitamin D concentrations are associated with PD to minimize confounding and prevent bias because of reverse causation. METHODS: As instrumental variables for the Mendelian randomization analysis, we used 4 single-nucleotide polymorphisms that affect 25-hydroxyvitamin D concentrations (rs2282679 in GC, rs12785878 near DHCR7, rs10741657 near CYP2R1, and rs6013897 near CYP24A1). Summary effect size estimates of the 4 single-nucleotide polymorphisms on PD were obtained from the International Parkinson's Disease Genomics Consortium (including 5333 PD cases and 12,019 controls). The estimates of the 4 single nucleotide polymorphisms were combined using an inverse-variance weighted meta analysis. RESULTS: Of the 4 single-nucleotide polymorphisms associated with 25 hydroxyvitamin D concentrations, one (rs6013897 in CYP24A1) was associated with PD (odds ratio per 25-hydroxyvitamin D-decreasing allele, 1.09; 95% confidence interval, 1.02-1.16; P = 0.008), whereas no association was observed with the other 3 single-nucleotide polymorphisms (P > 0.23). The odds ratio of PD per genetically predicted 10% lower 25-hydroxyvitamin D concentration, based on the 4 single-nucleotide polymorphisms, was 0.98 (95% confidence interval, 0.93-1.04; P = 0.56). CONCLUSIONS: This Mendelian randomization study provides no clear support that lowered 25-hydroxyvitamin D concentration is causally associated with risk of PD. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28594129 TI - Ranking predatory journals in dermatology: distinguishing the bad from the ugly. AB - BACKGROUND: The scientific community depends on high-quality peer-reviewed research, which is being polluted with pseudoscience published in fake journals that have exploited the open-access model. This "predatory publishing" has made its way into the field of dermatology. In a recent study, we identified and listed these journals. METHODS: The "predatory rate" was calculated for 76 journals in order to rank the journals based on specific criteria associated with unethical publishing. RESULTS: Of the 76 journals, 89.5% were classified as predatory journals and the remaining as journals involved in predatory practices. CONCLUSION: The field of dermatology is not immune to predatory publishers. This study validates Beall's list as well as other previous studies. Strategies to a solution include spreading awareness throughout academic institutions and dermatology departments as well as avoiding publishers that are involved in predatory practices. However, some journals may be able to make necessary adjustments and become legitimate contributors to the field. PMID- 28594130 TI - Maintaining good miRNAs in the body keeps the doctor away?: Perspectives on the relationship between food-derived natural products and microRNAs in relation to exosomes/extracellular vesicles. AB - During the last decade, it has been uncovered that microRNAs (miRNAs), a class of small non-coding RNAs, are related to many diseases including cancers. With an increase in reports describing the dysregulation of miRNAs in various tumor types, it has become abundantly clear that miRNAs play significant roles in the formation and progression of cancers. Intriguingly, miRNAs are present in body fluids because they are packed in exosomes/extracellular vesicles and released from all types of cells. The miRNAs in the fluids are measured in a relatively simple way and the profile of miRNAs is likely to be an indicator of health condition. In recent years, various studies have demonstrated that some naturally occurring compounds can control tumor-suppressive and oncogenic miRNAs in a positive manner, suggesting that food-derived compounds could maintain the expression levels of miRNAs and help maintain good health. Therefore, our daily food and compounds in food are of great interest. In addition, exogenous diet derived miRNAs have been indicated to function in the regulation of target mammalian transcripts in the body. These findings highlight the possibility of diet for good health through the regulation of miRNAs, and we also discuss the perspective of food application and health promotion. PMID- 28594131 TI - Optimization of puncture injury to rat caudal disc for mimicking early degeneration of intervertebral disc. AB - The caudal discs of rats have been proposed as a puncture model in which intervertebral disc (IVD) degeneration can be induced and novel therapies can be tested. For biological repair, treatments for ongoing IVD degeneration are ideally administered during the earlier stages. The purpose of this study was to elucidate the optimal puncture needle size for creating a model that mimicked the earlier stages of IVD degeneration. According to the disc height index, histologic score, and MRI grading, a puncture needle sized 21G or larger induced rapid degenerative processes in rat caudal discs during the initial 2-4 weeks. The degenerative changes were severe and continued deteriorating after 4 weeks. Conversely, puncture injury induced by needles sized 25G or smaller also produced degenerative changes in rat caudal discs during initial 2-4 weeks; however, the changes were less severe. Furthermore, the degenerative process became stabilized and showed no further deterioration or spontaneous recovery after 4 weeks. In the discs punctured by 25G needles, the expression of collagen I was increased at 2-4 weeks with a gradually fibrotic transformation thereafter. The expressions of collagen II and SOX9 were enhanced initially but returned to pre-injury levels at 4-8 weeks. The above-mentioned findings were more compatible with earlier degeneration in discs punctured by needles sized 25G or smaller than by needles sized 21G or larger, and the appropriate timing for intradiscal administration of proposed therapeutic agents would be 4 weeks or longer after puncture. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:202-211, 2018. PMID- 28594132 TI - Are neonicotinoids killing bees? PMID- 28594134 TI - Many genes involved in Tourette syndrome pathogenesis. PMID- 28594133 TI - Diagnostic value of STMN1, LMO2, HGAL, AID expression and 1p36 chromosomal abnormalities in primary cutaneous B cell lymphomas. AB - AIMS: Distinction between primary cutaneous follicular lymphoma (PCFL) and primary cutaneous marginal zone lymphoma (PCMZL) is challenging, as clear-cut immunophenotypical and cytogenetic criteria to segregate both entities are lacking. METHODS AND RESULTS: To characterize PCFL and PCMZL more clearly and to define criteria helpful for the differential diagnosis, we compared expression of immunohistochemical markers [LIM-only transcription factor 2 (LMO2), human germinal centre-associated lymphoma (HGAL), stathmin 1 (STMN1), activation induced cytidine deaminase (AID), myeloid cell nuclear differentiation antigen (MNDA)] and the presence of cytogenetic abnormalities described previously in nodal follicular lymphoma [B cell lymphoma 2 (BCL2) and BCL6 breaks, 1p36 chromosomal region deletion (del 1p36)] in a series of 48 cutaneous follicular and marginal zone lymphomas [cutaneous follicular lymphoma (CFL) and cutaneous marginal zone lymphoma (CMZL)]. Immunostaining for STMN1, LMO2, HGAL and AID allowed the distinction between CFL and CMZL, and STMN1 was the most sensitive marker (100% CFL, 0% CMZL). LMO2, HGAL and AID were positive in 93.2%, 82.1% and 86.2% CFL (all CMZL-negative). MNDA was expressed in both entities without significant difference (10.3% CFL, 30.8% CMZL, P = 0.18). BCL2, BCL6 breaks and the del 1p36 were present in 16.7%, 10.7% and 18.5% CFL and no CMZL. Finally, three and 29 CFL were reclassified as secondary cutaneous follicular lymphomas (SCFL) and PCFL without significant differences concerning phenotypical and cytogenetic features. BCL2, BCL6 breaks and the del 1p36 were present in 11.1%, 8% and 16.7% PCFL and did not impact the prognosis. CONCLUSION: LMO2, HGAL, STMN1 and AID, but not MNDA, are discriminant for the recognition between CFL and CMZL. BCL2, BCL6 rearrangements and the del 1p36 have a role in the pathogenesis of PCFL, the latest being the most common alteration. PMID- 28594135 TI - The IGF-1/Akt/S6 pathway and expressions of glycolytic myosin heavy chain isoforms are upregulated in chicken skeletal muscle during the first week after hatching. AB - Skeletal muscle mass is an important trait in the animal industry. We previously reported an age-dependent downregulation of the insulin-like growth factor 1 (IGF 1)/Akt/S6 pathway, major protein synthesis pathway, in chicken breast muscle after 1 week of age, despite a continuous increase of breast muscle weight. Myosin heavy chain (HC), a major protein in muscle fiber, has several isoforms depending on chicken skeletal muscle types. HC I (fast-twitch glycolytic type) is known to be expressed in adult chicken breast muscle. However, little is known about the changes in the expression levels of protein synthesis-related factors and HC isoforms in perihatching chicken muscle. In the present study, protein synthesis-related factors, such as IGF-1 messenger RNA (mRNA) levels, phosphorylation of Akt, and phosphorylated S6 content, increased in an age dependent manner after post-hatch day (D) 0. The mRNA levels of HC I, III and V (fast-twitch glycolytic type) dramatically increased after D0. The increase ratio of breast muscle weight was approximately 1100% from D0 to D7. To our knowledge, these findings provide the first evidence that upregulation of protein synthesis pathway and transcription of fast twitch glycolytic HC isoforms play critical roles in the increase of chicken breast muscle weight during the first week after hatching. PMID- 28594136 TI - Extension of the culture period for the in vitro growth of bovine oocytes in the presence of bone morphogenetic protein-4 increases oocyte diameter, but impairs subsequent developmental competence. AB - Bone morphogenetic protein-4 (BMP-4) inhibits luteinization of granulosa cells during in vitro growth (IVG) culture of bovine oocytes; however, oocytes derived from a 12 day IVG were less competent for development than in vivo-grown oocytes. We herein investigated whether an extended IVG culture with BMP-4 improves oocyte growth and development to blastocysts after in vitro fertilization. Oocyte granulosa cell complexes (OGCs) were cultured for 14 or 16 days with BMP-4 (10 ng/mL), while a 12 day culture with BMP-4 served as the in vitro control. OGC viability was maintained for the 16 day culture with BMP-4 (83.2%), but was significantly lower without BMP-4 (58.9%) than the control (83.0%). Prolong cultured oocytes at 16 days had statistically greater diameter (114.6 MUm) than the control (111.7 MUm). IVG oocytes with BMP-4 for the 16 day culture had a similar nuclear maturation rate to the control (approximately 67%); however, blastocyst rates in BMP-4 treated oocytes of 14 (1.8%) and 16 day (0%) IVG were statistically lower than that of 12 day IVG (9.0%). In conclusion, BMP-4 maintained OGC viability and promoted oocyte growth in a prolonged culture, but impaired the developmental competence of oocytes. Prolonged culture may not be an appropriate strategy for enhancing the developmental competence of IVG oocytes. PMID- 28594137 TI - Increased Adipocyte Size, Macrophage Infiltration, and Adverse Local Adipokine Profile in Perirenal Fat in Cushing's Syndrome. AB - OBJECTIVE: To analyze changes in fat cell size, macrophage infiltration, and local adipose tissue adipokine profiles in different fat depots in patients with active Cushing's syndrome. METHODS: Subcutaneous (SC) and perirenal (PR) adipose tissue of 10 patients with Cushing's syndrome was compared to adipose tissue of 10 gender-, age-, and BMI-matched controls with regard to adipocyte size determined by digital image analysis on hematoxylin and eosin stainings, macrophage infiltration determined by digital image analysis on CD68 stainings, and adipose tissue leptin and adiponectin levels using fluorescent bead immunoassays and ELISA techniques. RESULTS: Compared to the controls, mean adipocyte size was larger in PR adipose tissue in patients. The percentage of macrophage infiltration of the PR adipose tissue and PR adipose tissue lysate leptin levels were higher and adiponectin levels were lower in SC and PR adipose tissue lysates in patients. The adiponectin levels were also lower in the SC adipose tissue supernatants of patients. Associations were found between the severity of hypercortisolism and PR adipocyte size. CONCLUSIONS: Cushing's syndrome is associated with hypertrophy of PR adipocytes and a higher percentage of macrophage infiltration in PR adipose tissue. These changes are associated with an adverse local adipokine profile. PMID- 28594138 TI - Therapeutic plasma exchange in refractory warm autoimmune hemolytic anemia. PMID- 28594139 TI - The questions surrounding stored blood do not get old. PMID- 28594142 TI - Corrigendum. PMID- 28594141 TI - Patient Blood Management: the new standard. PMID- 28594143 TI - Kids, colds, and complement: paroxysmal cold hemoglobinuria. PMID- 28594144 TI - Cytomegalovirus-safe blood: the unclear effect of sickle hemoglobin. PMID- 28594145 TI - Use of antidepressant medication in pregnancy and adverse neonatal outcomes: A population-based investigation. AB - BACKGROUND: Untreated depression and antidepressant use during pregnancy may have negative consequences for births. There are still conflicting data on the potential harmful effects of prenatal antidepressant treatment on child health. OBJECTIVE: To investigate the relationship between the use of antidepressant medication during pregnancy and selected neonatal outcomes. METHODS: A population based cohort study including 9825 deliveries exposed to an antidepressant between 9 months before last menstrual date through to delivery, from January 2005 to December 2010 in the Lombardy region of Italy, was conducted. We evaluated the prevalence ratio (PR) of low Apgar score, small for gestational age, intrauterine hypoxia and birth asphyxia, neonatal convulsion, and other respiratory conditions, among infants born to mothers exposed to an antidepressant during pregnancy using log-binomial regression analysis. Fine stratification was applied to the propensity score to account for all potential confounders. Sensitivity and subgroup analyses restricted to specific types of antidepressant, time of exposure, and women with vaginal deliveries and full-term births were also performed. RESULTS: A total of 33.4% of women filled at least one prescription during pregnancy. Compared to infants born to mothers with exposure to antidepressants only before pregnancy, those with exposure to antidepressants during pregnancy had an increased prevalence ratio of a low Apgar score (PR, 1.63, 95% CI, 1.01-2.61), intrauterine hypoxia and birth asphyxia (aPR, 1.37, 1.08-1.73), neonatal convulsion (aPR, 2.81, 1.07-7.36), and other respiratory condition (aPR, 1.24, 1.00-1.52). Results were similar in the sensitivity and subgroup analyses. CONCLUSIONS: Use of antidepressants during pregnancy may have an increased risk for several neonatal outcomes. PMID- 28594146 TI - beta-Co(OH)2 Nanosheets: A Superior Pseudocapacitive Electrode for High-Energy Supercapacitors. AB - In this work, beta-Co(OH)2 nanosheets are explored as efficient pseudocapacitive materials for the fabrication of 1.6 V class high-energy supercapacitors in asymmetric fashion. The as-synthesized beta-Co(OH)2 nanosheets displayed an excellent electrochemical performance owing to their unique structure, morphology, and reversible reaction kinetics (fast faradic reaction) in both the three-electrode and asymmetric configuration (with activated carbon, AC). For example, in the three-electrode set-up, beta-Co(OH)2 exhibits a high specific capacitance of ~675 F g-1 at a scan rate of 1 mV s-1 . In the asymmetric supercapacitor, the beta-Co(OH)2 ?AC cell delivers a maximum energy density of 37.3 Wh kg-1 at a power density of 800 W kg-1 . Even at harsh conditions (8 kW kg 1 ), an energy density of 15.64 Wh kg-1 is registered for the beta-Co(OH)2 ?AC assembly. Such an impressive performance of beta-Co(OH)2 nanosheets in the asymmetric configuration reveals the emergence of pseudocapacitive electrodes towards the fabrication of high-energy electrochemical charge storage systems. PMID- 28594148 TI - Analysis of selected genes associated with cardiomyopathy by next-generation sequencing. AB - BACKGROUND: As the leading cause of congestive heart failure, cardiomyopathy represents a heterogenous group of heart muscle disorders. Despite considerable progress being made in the genetic diagnosis of cardiomyopathy by detection of the mutations in the most prevalent cardiomyopathy genes, the cause remains unsolved in many patients. High-throughput mutation screening in the disease genes for cardiomyopathy is now possible because of using target enrichment followed by next-generation sequencing. The aim of the study was to analyze a panel of genes associated with dilated or hypertrophic cardiomyopathy based on previously published results in order to identify the subjects at risk. METHODS: The method of next-generation sequencing by IlluminaHiSeq 2500 platform was used to detect sequence variants in 16 individuals diagnosed with dilated or hypertrophic cardiomyopathy. Detected variants were filtered and the functional impact of amino acid changes was predicted by computational programs. RESULTS: DNA samples of the 16 patients were analyzed by whole exome sequencing. We identified six nonsynonymous variants that were shown to be pathogenic in all used prediction softwares: rs3744998 (EPG5), rs11551768 (MGME1), rs148374985 (MURC), rs78461695 (PLEC), rs17158558 (RET) and rs2295190 (SYNE1). Two of the analyzed sequence variants had minor allele frequency (MAF)<0.01: rs148374985 (MURC), rs34580776 (MYBPC3). CONCLUSION: Our data support the potential role of the detected variants in pathogenesis of dilated or hypertrophic cardiomyopathy; however, the possibility that these variants might not be true disease-causing variants but are susceptibility alleles that require additional mutations or injury to cause the clinical phenotype of disease must be considered. PMID- 28594147 TI - Casein kinase 1-epsilon deletion increases mu opioid receptor-dependent behaviors and binge eating1. AB - Genetic and pharmacological studies indicate that casein kinase 1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0.2 mg/kg i.p.) as well as enhanced sensitivity to low-dose fentanyl reward (0.05 mg/kg). Interestingly, female knockout mice also showed a markedly greater escalation in consumption of sweetened palatable food - a behavioral pattern consistent with binge eating that also depends on mu opioid receptor activation. No difference was observed in fentanyl analgesia in the 52.5 degrees C hot plate assay (0-0.4 mg/kg), naloxone conditioned place aversion (4 mg/kg), or methamphetamine conditioned place preference (0-4 mg/kg). To identify molecular adaptations associated with increased drug and food behaviors in knockout mice, we completed transcriptome analysis via mRNA sequencing of the striatum. Enrichment analysis identified terms associated with myelination and axon guidance and pathway analysis identified a differentially expressed gene set predicted to be regulated by the Wnt signaling transcription factor, Tcf7l2. To summarize, Csnk1e deletion increased mu opioid receptor-dependent behaviors, supporting previous studies indicating an endogenous negative regulatory role of Csnk1e in opioid behavior. PMID- 28594151 TI - Pembrolizumab for Advanced Urothelial Carcinoma. PMID- 28594149 TI - MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma. AB - AIMS: Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and the long-term prognosis is poor. In this study, we examined alterations of AdCC-associated genes, MYB, MYBL1, MYBL2 and NFIB, and their target molecules, including MYC. The results were correlated to clinicopathological profile of the patients. METHODS AND RESULTS: Using paraffin tumour sections from 33 cases of salivary gland AdCC, we performed a detailed fluorescence in-situ hybridization (FISH) analysis for gene splits and fusions of MYB, MYBL1, MYBL2 and NFIB. We found that 29 of 33 (88%) AdCC cases showed gene splits in either MYB, MYBL1 or NFIB. None of the cases showed an MYBL2 gene alteration. AdCCs were divided genetically into six gene groups, MYB-NFIB (n = 16), MYB-X (n = 4), MYBL1-NFIB (n = 2), MYBL1-X (n = 1), NFIB-X (n = 6) and gene split-negative (n = 4). AdCC patients showing the MYB or MYBL1 gene splits were associated with microscopically positive surgical margins (P = 0.0148) and overexpression of MYC (P = 0.0164). MYC expression was detected in both ductal and myoepithelial tumour cells, and MYC overexpression was associated with shorter disease-free survival of the patients (P = 0.0268). CONCLUSIONS: The present study suggests that (1) nearly 90% of AdCCs may have gene alterations of either MYB, MYBL1 or NFIB, suggesting the diagnostic utility of the FISH assay, (2) MYB or MYBL1 gene splits may be associated with local aggressiveness of the tumours and overexpression of MYC, which is one of the oncogenic MYB/MYBL1 targets and (3) MYC overexpression may be a risk factor for disease-free survival in AdCC. PMID- 28594152 TI - Data-Sharing Models PMID- 28594150 TI - Cortical thickness is not associated with current depression in a clinical treatment study. AB - BACKGROUND: Reduced cortical thickness is a candidate biological marker of depression, although findings are inconsistent. This could reflect analytic heterogeneity, such as use of region-wise cortical thickness based on the Freesurfer Desikan-Killiany (DK) atlas or surface-based morphometry (SBM). The Freesurfer Destrieux (DS) atlas (more, smaller regions) has not been utilized in depression studies. This could also reflect differential gender and age effects. METHODS: Cortical thickness was collected from 170 currently depressed adults and 52 never-depressed adults. Visually inspected and approved Freesurfer-generated surfaces were used to extract cortical thickness estimates according to the DK atlas (68 regions) and DS atlas (148 regions) for region-wise analysis (216 total regions) and for SBM. RESULTS: Overall, except for small effects in a few regions, the two region-wise approaches generally failed to discriminate depressed adults from nondepressed adults or current episode severity. Differential effects by age and gender were also rare and small in magnitude. Using SBM, depressed adults showed a significantly thicker cluster in the left supramarginal gyrus than nondepressed adults (P = 0.047) but there were no associations with current episode severity. CONCLUSIONS: Three analytic approaches (i.e., DK atlas, DS atlas, and SBM) converge on the notion that cortical thickness is a relatively weak discriminator of current depression status. Differential age and gender effects do not appear to represent key moderators. Robust associations with demographic factors will likely hinder translation of cortical thickness into a clinically useful biomarker. Hum Brain Mapp, 2017. (c) 2017 Wiley Periodicals, Inc. Hum Brain Mapp 38:4370-4385, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28594153 TI - Data-Sharing Models PMID- 28594154 TI - Tight Glycemic Control in Critically Ill Children. PMID- 28594155 TI - Blinatumomab for Acute Lymphoblastic Leukemia. PMID- 28594156 TI - Acute Lower Gastrointestinal Bleeding. PMID- 28594157 TI - Validity of transcutaneous oxygen measurement in peripheral arterial disease. PMID- 28594158 TI - High-kappa Samarium-Based Metal-Organic Framework for Gate Dielectric Applications. AB - The self-assembly of a samarium-based metal-organic framework [Sm2(bhc)(H2O)6]n (1) in good yield was achieved by reacting Sm(NO3)3.6H2O with benzenehexacarboxylic acid (bhc) in a mixture of H2O-EtOH under hydrothermal conditions. A structural analysis showed that compound 1 crystallized in a space group of Pnmn and adopted a 3D structure with (4,8) connected nets. Temperature dependent dielectric measurements showed that compound 1 behaves as a high dielectric material with a high dielectric constant (kappa = 45.1) at 5 kHz and 310 K, which is comparable to the values for some of the most commonly available dielectric inorganic metal oxides such as Sm2O3, Ta2O5, HfO2, and ZrO2. In addition, electrical measurements of 1 revealed an electrical conductivity of about 2.15 * 10-7 S/cm at a frequency of 5 kHz with a low leakage current (Ileakage = 8.13 * 10-12 Amm-2). Dielectric investigations of the Sm-based MOF provide an effective path for the development of high dielectric materials in the future. PMID- 28594159 TI - Honeycomb-Like Interconnected Network of Nickel Phosphide Heteronanoparticles with Superior Electrochemical Performance for Supercapacitors. AB - Transition-metal-based heteronanoparticles are attracting extensive attention in electrode material design for supercapacitors owing to their large surface-to volume ratios and inherent synergies of individual components; however, they still suffer from limited interior capacity and cycling stability due to simple geometric configurations, low electrochemical activity of the surface, and poor structural integrity. Developing an elaborate architecture that endows a larger surface area, high conductivity, and mechanically robust structure is a pressing need to tackle the existing challenges of electrode materials. This work presents a supercapacitor electrode consisting of honeycomb-like biphasic Ni5P4-Ni2P (NixPy) nanosheets, which are interleaved by large quantities of nanoparticles. The optimized NixPy delivers an ultrahigh specific capacity of 1272 C g-1 at a current density of 2 A g-1, high rate capability, and stability. An asymmetric supercapacitor employing as-synthesized NixPy as the positive electrode and activated carbon as the negative electrode exhibits significantly high power and energy densities (67.2 W h kg-1 at 0.75 kW kg-1; 20.4 W h kg-1 at 15 kW kg-1). These results demonstrate that the novel nanostructured NixPy can be potentially applied in high-performance supercapacitors. PMID- 28594160 TI - Spontaneous Pt Deposition on Defective Surfaces of In2O3 Nanocrystals Confined within Cavities of Hollow Silica Nanoshells: Pt Catalyst-Modified ITO Electrode with Enhanced ECL Performance. AB - Although the deposition of metallic domains on a preformed semiconductor nanocrystal provides an effective pathway to access diverse hybrid nanocrystals with synergistic metal/semiconductor heterojunction interface, those reactions that take place on the surface of semiconductor nanoscrystals have not been investigated thoroughly, because of the impediments caused by the surface-capping organic surfactants. By exploiting the interfacial reactions occurring between the solution and nanoparticles confined with the cavities of hollow nanoparticles, we propose a novel nanospace-confined strategy for assessing the innate reactivity of surfaces of inorganic semiconductor nanoparticles. This strategy was adopted to investigate the newly discovered process of spontaneous Pt deposition on In2O3 nanocrystals. Through an in-depth examination involving varying key reaction parameters, the Pt deposition process was identified to be templated by the defective In2O3 surface via a unique redox process involving the oxygen vacancies in the In2O3 lattice, whose density can be controlled by high temperature annealing. The product of the Pt-deposition reaction inside the hollow silica nanoparticle, bearing In2O3-supported Pt catalysts inside the cavity protected by a porous silica shell, was proved to be an effective nanoreactor system which selectively and sustainably catalyzed the reduction reaction of small-sized aromatic nitro-compounds. Moreover, the surfactant-free and electroless Pt deposition protocol, which was devised based on the surface chemistry of the In2O3 nanoparticles, was successfully employed to fabricate Pt catalyst-modified ITO electrodes with enhanced electrogenerated chemiluminescece (ECL) performance. PMID- 28594161 TI - Layered/Spinel Heterostructured and Hierarchical Micro/Nanostructured Li-Rich Cathode Materials with Enhanced Electrochemical Properties for Li-Ion Batteries. AB - Although holding a high capacity, Li-rich materials are far from the demand of practical market because of their inherent drawbacks, such as poor initial efficiency and rate capability. Herein, Li-rich materials of Li1.16Mn0.6Ni0.12Co0.12O2 have been prepared via a one-step solvothermal strategy. The detail characterizations demonstrate that the as-prepared materials present morphology of nanoparticle-aggregated hierarchical microspheres and a heterostructure of layered and Li4Mn5O12-type spinel components. Compared to materials of pure-layered structure, layered/spinel heterostructured materials exhibit simultaneously great reversible capacity (302 mAh g-1 at 0.2 C), high initial Coulombic efficiency (94% at 0.2 C) and remarkable rate capability (193 mAh g-1 at 10 C). PMID- 28594162 TI - Mn-Based Cathode with Synergetic Layered-Tunnel Hybrid Structures and Their Enhanced Electrochemical Performance in Sodium Ion Batteries. AB - A synergistic approach for advanced cathode materials is proposed. Sodium manganese oxide with a layered-tunnel hybrid structure was designed, synthesized, and subsequently investigated. The layered-tunnel hybrid structure provides fast Na ion diffusivity and high structural stability thanks to the tunnel phase, enabling high rate capability and greatly improved cycling stability compared to that of the pure P2 layered phase while retaining the high specific capacity of the P2 layered phase. The hybrid structure provided a decent discharge capacity of 133.4 mAh g-1 even at 8 C, which exceeds the reported best rate capability for Mn-based cathodes. It also displayed an impressive cycling stability, maintaining 83.3 mAh g-1 after 700 cycles at 10 C. Theoretical calculation and the potentiostatic intermittent titration technique (PITT) demonstrated that this hybrid structure helps enhance Na ion diffusivity during charge and discharge, attaining, as a result, an unprecendented electrochemical performance. PMID- 28594163 TI - Superior Impact Toughness and Excellent Storage Modulus of Poly(lactic acid) Foams Reinforced by Shish-Kebab Nanoporous Structure. AB - Poly(lactic acid) (PLA) foams, with the combination of shish-kebab and spherulite nanoporous structure in skin and core layer respectively, was prepared using a novel technique comprising loop oscillating push-pull molding (LOPPM) and supercritical carbon dioxide low-temperature foaming process (SC-CO2LTFP). The foams present superior impact toughness which is 6-fold higher than that of neat PLA, and no significant decrease was observed for the storage modulus. Moreover, SC-CO2LTFP at soaking temperature ranging from 110 to 150 degrees C were performed to determine the evolution of pore morphology. The ultratough and supermoduli are unprecedented for PLA, and are in great need for broader applications. PMID- 28594164 TI - Augmenting Glioblastoma Chemotherapy with Polymers. AB - Chemotherapeutics are vital for treating brain tumors such as glioblastoma, an aggressive and prolific cancer predominantly treated with DNA alkylating agents. The efficacy of antiglioblastoma drugs, such as temozolomide, is limited by their rapid clearance and instability under normal physiological conditions. Both local and systemic polymer-based therapeutics have shown promise for treating many cancers, and as such there is a growing interest in applying polymer techniques to augment the efficacy and stability of glioblastoma chemotherapeutics. Notably, brain tumor chemotherapy presents unique challenges and will require tailored delivery systems to develop markedly improved treatments. PMID- 28594165 TI - Conjugated Polyelectrolyte-Based New Strategy for in Situ Detection of Carbon Dioxide. AB - A conjugated polymer centered on fluorene and 2,1,3-benzothia-diazole (PFBT) is prepared for sensing CO2 in situ with high sensitivity and low background. Upon introducing CO2, the weaker electrostatic repulsion and stronger hydrophobic interactions between neighboring PFBT molecules enhance the interchain contacts compared to that without CO2, leading to the energy transfer from fluorene to 2,1,3-benzothia-diazole sites and the emission color shift from blue to green, which is sensitive to sensing CO2 in atmospheric air with a content of ~400 ppm. Importantly, PFBT is employed to monitor photosynthesis and respiration upon cycling day and night in situ. PMID- 28594166 TI - Correction to Epitaxial Halide Perovskite Lateral Double Heterostructure. PMID- 28594168 TI - Large Scale Risks from Agricultural Pesticides in Small Streams. AB - Small streams are important refuges for biodiversity. In agricultural areas, they may be at risk from pesticide pollution. However, most related studies have been limited to a few streams on the regional level, hampering extrapolation to larger scales. We quantified risks as exceedances of regulatory acceptable concentrations (RACs) and used German monitoring data to quantify the drivers thereof and to assess current risks in small streams on a large scale. The data set was comprised of 1 766 104 measurements of 478 pesticides (including metabolites) related to 24 743 samples from 2301 sampling sites. We investigated the influence of agricultural land use, catchment size, as well as precipitation and seasonal dynamics on pesticide risk taking also concentrations below the limit of quantification into account. The exceedances of risk thresholds dropped 3.7-fold at sites with no agriculture. Precipitation increased detection probability by 43%, and concentrations were the highest from April to June. Overall, this indicates that agricultural land use is a major contributor of pesticides in streams. RACs were exceeded in 26% of streams, with the highest exceedances found for neonicotinoid insecticides. We conclude that pesticides from agricultural land use are a major threat to small streams and their biodiversity. To reflect peak concentrations, current pesticide monitoring needs refinement. PMID- 28594167 TI - Toward an Expanded Genome: Structural and Computational Characterization of an Artificially Expanded Genetic Information System. AB - Although the fundamental properties of DNA as first proposed by Watson and Crick in 1953 provided a basic understanding of how duplex DNA was organized and might be replicated, it was not until the first crystal structures of DNA (Z-DNA in 1979, B-DNA in 1980, and A-DNA in 1982) that the true complexity of the molecule began to be appreciated. Many crystal structures of oligonucleotides have since shed light on the helical forms that "Watson-Crick" DNA can adopt, their associated groove widths, and the properties of the nucleobase pairs and their interactions in all three helical forms. Additional understanding of the properties of Watson-Crick DNA has been provided by computational studies employing a variety of theoretical methods. Together with these studies devoted to understanding Watson-Crick DNA, recent efforts to expand the genetic alphabet have founded a new field in synthetic biology. One of these efforts, the artificially expanded genetic information system (AEGIS) developed by Steven Benner and co-workers, takes advantage of orthogonal hydrogen bonding to produce DNA comprised of six nucleobase pairs, of which the most extensively studied is referred to as P:Z with P being 2-amino-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one) and Z being 6-amino-5-nitro-2(1H)-pyridone. P:Z forms three edge-on hydrogen bonds that differ from standard Watson-Crick pairs in the arrangement of acceptors and donor groups; P presents acceptor, acceptor, donor, and Z presents donor, donor, acceptor. Z is unique among the AEGIS nucleobases in having a nitro group present in the major groove. PZ-containing DNA has been exploited in a number of clinical applications and is being used to develop receptors and catalysts. Ultimately, the grand challenge will be to create a semisynthetic organism with an expanded genome. Furthermore, just as our understanding of the properties of natural DNA have benefited from structural and computational characterization, so too will our understanding of artificial DNA. This Account focuses on the structural and biophysical properties of AEGIS DNA containing P:Z pairs. We begin with the fundamental properties of P:Z nucleobase pairs, including their electrostatic potential and hydrogen-bonding energies, as elucidated by quantum mechanical calculations. We then examine the impact of including multiple consecutive P:Z pairs into duplex DNA providing an opportunity to investigate stacking interactions between P:Z pairs. The self-complementary 5' CTTATPPTAZZATAAG was crystallized in B-form using the host-guest system along with analogous natural sequences including Gs or As. Use of the host-guest system to characterize B-DNA obviates a number of limitations on the structural characterization of sequences of interest; these include the ability to crystallize the desired sequences and to distinguish structural effects imparted by the lattice constraints from those inherent in the sequence itself. On the other hand, 3/6ZP, 5'-CTTATPPPZZZATAAG, was crystallized in A-form in a DNA-only lattice allowing a comparative analysis of P:Z pairs in two of the biologically relevant helical forms: A- and B-DNA. Computational studies on the 3/6ZP sequence starting in A-form provide additional evidence for a more energetically favorable stacking interaction, which we term the "slide" conformer, observed in the A-form crystal structure; this unusual stacking interaction plays a major role in altering the conformational dynamics observed for the PZ-containing duplex as compared to a GC-containing "control" duplex in long time scale molecular dynamics simulations. This combined use of structural and computational strategies paves the way for obtaining a detailed description of artificial DNA, both in how it differs from Watson-Crick DNA and in the rational discovery of proteins, such as endonucleases, transcription factors, and polymerases, which can specifically manipulate DNA containing AEGIS nucleobase pairs. PMID- 28594170 TI - Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms. AB - There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the beta-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections. PMID- 28594171 TI - Introducing Cobalt(II) Porphyrin/Cobalt(III) Corrole Containing Transducers for Improved Potential Reproducibility and Performance of All-Solid-State Ion Selective Electrodes. AB - A novel solid contact type for all-solid-state ion-selective electrodes is introduced, yielding high stability and reproducibility of potential readings between sensors as well as improved analytical performance. The transducer phase herein proposed takes advantage of the presence of porphyrinoids containing the same metal ion at different oxidation states. In contrast to the traditional approach, the compounds of choice are not a redox pair; although they have different oxidation states, they cannot be electrochemically driven one to another. The compounds of choice were cobalt(II) porphyrin and cobalt(III) corrole-both characterized by a high stability of the coordinated metal ions in their respective redox states and electrical neutrality, as well as relatively high lipophilicity. The porphyrinoids were used together with carbon nanotubes to yield transducer layers for ion-selective electrodes. As a result, we obtained a high stability of potential readings of the resulting ion-selective electrodes together with good reproducibility between different sensor batches. Moreover, advantageously the presence of porphyrinoids in the transducer phase results in improvement of the analytical performance of the sensors: linear response range and selectivity due to interactions with membrane components, resulting in tailoring of ion fluxes through the membrane phase. Thus, carbon nanotubes with the cobalt(II) porphyrin/cobalt(III) corrole system are promising alternatives for existing transducer systems for potentiometric sensors. PMID- 28594169 TI - Biosynthesis of Fluorinated Peptaibols Using a Site-Directed Building Block Incorporation Approach. AB - Synthetic biological approaches, such as site-directed biosynthesis, have contributed to the expansion of the chemical space of natural products, making possible the biosynthesis of unnatural metabolites that otherwise would be difficult to access. Such methods may allow the incorporation of fluorine, an atom rarely found in nature, into complex secondary metabolites. Organofluorine compounds and secondary metabolites have both played pivotal roles in the development of drugs; however, their discovery and development are often via nonintersecting tracks. In this context, we used the biosynthetic machinery of Trichoderma arundinaceum (strain MSX70741) to incorporate a fluorine atom into peptaibol-type molecules in a site-selective manner. Thus, fermentation of strain MSX70741 in media containing ortho- and meta-F-phenylalanine resulted in the biosynthesis of two new fluorine-containing alamethicin F50 derivatives. The fluorinated products were characterized using spectroscopic (1D and 2D NMR, including 19F) and spectrometric (HRESIMS/MSn) methods, and their absolute configurations were established by Marfey's analysis. Fluorine-containing alamethicin F50 derivatives exhibited potency analogous to the nonfluorinated parent when evaluated against a panel of human cancer cell lines. Importantly, the biosynthesis of fluorinated alamethicin F50 derivatives by strain MSX70741 was monitored in situ using a droplet-liquid microjunction-surface sampling probe coupled to a hyphenated system. PMID- 28594173 TI - Excited-State Proton Transfer of Cyanonaphthols in Protic Ionic Liquids: Appearance of a New Fluorescent Species. AB - Excited-state proton transfer (ESPT) of 5-cyano-2-naphthol (5CN2) and 5,8-dicyano 2-naphthol (DCN2) in three different protic ionic liquids (PILs), triethylammonium trifluoromethanesulfonate ([N222H][CF3SO3]), triethylammonium methanesulfonate ([N222H][CH3SO3]), and triethylammonium trifluoroacetate ([N222H][CF3COO]), was studied by time-resolved fluorescence. In [N222H][CF3SO3], both 5CN2 and DCN2 showed fluorescence only from ROH* (normal form of substituted naphthol in the excited states), indicating that no ESPT occurred in [N222H][CF3SO3]. For 5CN2 in [N222H][CH3SO3], fluorescence bands from ROH* and RO * (anionic form of substituted naphthol in the excited states) were observed, indicating that 5CN2 could dissociate proton to surrounding solvents and form RO *. More interestingly, 5CN2 in [N222H][CF3COO] and DCN2 in [N222H][CH3SO3] and [N222H][CF3COO] showed an anomalous fluorescence band around 470 nm (5CN2) or around 520 nm (DCN2) which has not been reported previously. The kinetics of each fluorescent component of 5CN2 and DCN2 was analyzed on the basis of the time profile of fluorescence intensity. Plausible ESPT schemes of 5CN2 and DCN2 were discussed on the basis of the kinetics and the basicity of anion in PILs. PMID- 28594174 TI - Improving Robustness: In Situ Generation of a Pd(0) Catalyst for the Cyanation of Aryl Bromides. AB - Conditions have been developed for the palladium-catalyzed cyanation of aryl bromides utilizing the air-stable XantPhos-PdCl2 precatalyst. By employing a trialkylamine as a reducing agent, the active Pd(0) species is generated in situ, alleviating the need to employ the air-sensitive Pd2(dba)3. Twenty-two substituted benzonitriles have been synthesized using this method. PMID- 28594172 TI - Structure-Based Optimization of Pyridoxal 5'-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis. AB - The pyridoxal 5'-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N'-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 MUM (0.6 MUg/mL) against Mtb in biotin-free medium. PMID- 28594176 TI - Radical Deaminative ipso-Cyclization of 4-Methoxyanilines with 1,7-Enynes for Accessing Spirocyclohexadienone-Containing Cyclopenta[c]quinolin-4-ones. AB - A new C-center radical-triggered bicyclization cascade of N-tethered 1,7-enynes for forming 28 examples of biologically interesting spirocyclohexadienone containing cyclopenta[c]quinolin-4-ones with two all-carbon quaternary stereocenters has been established under mild conditions. The in situ generated diazonium salts from 4-methoxyanilines and t-BuONO are served as 4-methoxyphenyl precursors without additional oxidant, enabling 6-exo-dig cyclization/5-exo-trig ipso-cyclization to construct three new C-C bonds through metal-free dearomatization. The reaction also features broad substrate scope, annulation efficiency, and high functional group tolerance. PMID- 28594175 TI - Hepatitis C Virus NS3/4A Protease Inhibitors Incorporating Flexible P2 Quinoxalines Target Drug Resistant Viral Variants. AB - A substrate envelope-guided design strategy is reported for improving the resistance profile of HCV NS3/4A protease inhibitors. Analogues of 5172-mcP1P3 were designed by incorporating diverse quinoxalines at the P2 position that predominantly interact with the invariant catalytic triad of the protease. Exploration of structure-activity relationships showed that inhibitors with small hydrophobic substituents at the 3-position of P2 quinoxaline maintain better potency against drug resistant variants, likely due to reduced interactions with residues in the S2 subsite. In contrast, inhibitors with larger groups at this position were highly susceptible to mutations at Arg155, Ala156, and Asp168. Excitingly, several inhibitors exhibited exceptional potency profiles with EC50 values <=5 nM against major drug resistant HCV variants. These findings support that inhibitors designed to interact with evolutionarily constrained regions of the protease, while avoiding interactions with residues not essential for substrate recognition, are less likely to be susceptible to drug resistance. PMID- 28594177 TI - A Versatile Toolbox for the Control of Protein Levels Using Nepsilon-Acetyl-l lysine Dependent Amber Suppression. AB - The analysis of the function of essential genes in vivo depends on the ability to experimentally modulate levels of their protein products. Current methods to address this are based on transcriptional or post-transcriptional regulation of mRNAs, but approaches based on the exploitation of translation regulation have so far been neglected. Here we describe a toolbox, based on amber suppression in the presence of Nepsilon-acetyl-l-lysine (AcK), for translational tuning of protein output. We chose the highly sensitive luminescence system LuxCDABE as a reporter and incorporated a UAG stop codon into the gene for the reductase subunit LuxC. The system was used to measure and compare the effects of AcK- and Nepsilon-(tert butoxycarbonyl)-l-lysine (BocK) dependent amber suppression in Escherichia coli. We also demonstrate here that, in combination with transcriptional regulation, the system allows protein production to be either totally repressed or gradually adjusted. To identify sequence motifs that provide improved translational regulation, we varied the sequence context of the amber codon and found that insertion of two preceding prolines drastically decreases luminescence. In addition, using LacZ as a reporter, we demonstrated that a strain encoding a variant with a Pro-Pro amber motif can only grow on lactose when AcK is supplied, thus confirming the tight translational regulation of protein output. In parallel, we constructed an E. coli strain that carries an isopropyl beta-d-1 thiogalactopyranoside (IPTG)-inducible version of the AcK-tRNA synthetase (AcKRS) gene on the chromosome, thus preventing mischarging of noncognate substrates. Subsequently, a diaminopimelic acid auxotrophic mutant (DeltadapA) was generated demonstrating the potential of this strain in regulating essential gene products. Furthermore, we assembled a set of vectors based on the broad-host-range pBBR ori that enable the AcK-dependent amber suppression system to control protein output not only in E. coli, but also in Salmonella enterica and Vibrio cholerae. PMID- 28594178 TI - Catalytic Dehydrogenative C-C Coupling by a Pincer-Ligated Iridium Complex. AB - The pincer-iridium fragment (iPrPCP)Ir (RPCP = kappa3-2,6-C6H3(CH2PR2)2) has been found to catalyze the dehydrogenative coupling of vinyl arenes to afford predominantly (E,E)-1,4-diaryl-1,3-butadienes. The eliminated hydrogen can undergo addition to another molecule of vinyl arene, resulting in an overall disproportionation reaction with 1 equiv of ethyl arene formed for each equivalent of diarylbutadiene produced. Alternatively, sacrificial hydrogen acceptors (e.g., tert-butylethylene) can be added to the solution for this purpose. Diarylbutadienes are isolated in moderate to good yields, up to ca. 90% based on the disproportionation reaction. The results of DFT calculations and experiments with substituted styrenes indicate that the coupling proceeds via double C-H addition of a styrene molecule, at beta-vinyl and ortho-aryl positions, to give an iridium(III) metalloindene intermediate; this intermediate then adds a beta-vinyl C-H bond of a second styrene molecule before reductively eliminating product. Several metalloindene complexes have been isolated and crystallographically characterized. In accord with the proposed mechanism, substitution at the ortho-aryl positions of the styrene precludes dehydrogenative homocoupling. In the case of 2,4,6-trimethylstyrene, dehydrogenative coupling of beta-vinyl and ortho-methyl C-H bonds affords dimethylindene, demonstrating that the dehydrogenative coupling is not limited to C(sp2)-H bonds. PMID- 28594179 TI - Organocatalytic Direct N-Acylation of Amides with Aldehydes under Oxidative Conditions. AB - The direct oxidative N-acylation reaction of primary amides with aryl/alpha,beta unsaturated aldehydes was achieved in the presence of azolium salt C3 and an inorganic base using 3,3',5,5'-tetra-tert-butyldiphenoquinone as the oxidant, thus providing an efficient approach for the synthesis of three types of imide compounds including N-sulfonylcarboxamides, N-sulfinylcarboxamides, and dicarboxyimides in good yield. PMID- 28594180 TI - Accurate Determination of Ion Polarizabilities in Aqueous Solutions. AB - We present a novel method for obtaining salt polarizabilities in aqueous solutions based on our recent theory for the refractive index of salt solutions, which predicts a linear relationship between the refractive index and the salt concentration at low concentrations, with a slope determined by the intrinsic values of the salt polarizability and the density of the solution. Here we apply this theory to determine the polarizabilities of 32 strong electrolyte salts in aqueous solutions from refractive index and density measurements. Setting Li+ as the standard ion, we then determine the polarizabilities of seven cations (Na+, K+, Rb+, Cs+, Ca2+, Ba2+, and Sr2+) and seven anions (F-, Cl-, Br-, I-, ClO4-, NO3-, and SO42-), which can be used as important reference data. We investigate the effect of temperature on salt polarizabilities, which decreases slightly with increasing temperature. The ion polarizability is found to be proportional to the cube of bare ionic radius (rbare3) for univalent ions, but the relationship does not hold for multivalent ions. Contrary to findings of Krishnamurti, we find no significant linear relationship between ion polarizability and the square of the atomic number (N2) for smaller ions. PMID- 28594181 TI - d0a3 Synthon Equivalents for the Stereocontrolled Synthesis of Functionalized 1,4 Amino Alcohol Precursors. AB - This study demonstrates the design, synthesis, and first application of novel aminooxylating reagents that serve as a useful d0a3 synthon equivalents for organic synthesis. It has been demonstrated that their reaction with alpha,beta unsaturated aldehydes performed under aminocatalytic conditions provides a straightforward access to polysubstituted tetrahydro-1,2-oxazine derivatives, direct precursors of functionalized 1,4-amino alcohols. Target tetrahydro-1,2 oxazine derivatives have been obtained with high yields (up to 89%) and with excellent stereocontrol (up to >20:1 dr, > 99.5:0.5 er). Furthermore, the synthetic usefulness of tetrahydro-1,2-oxazines obtained has been demonstrated in various selective transformations. PMID- 28594182 TI - Novel Composite Gel Electrolytes with Enhanced Electrical Conductivity and Thermal Stability Prepared Using Self-Assembled Nanofibrillar Networks. AB - Novel composite gel electrolytes were prepared using self-assembled organogels as scaffolds. Mixing silica with the low-molecular-weight poly(ethylene glycol) (PEG)-based electrolytes resulted in precipitation due to significant aggregation of silica. However, clear and transparent PEG-silica composite gel electrolytes were obtained with 1,3:2,4-dibenzylidene-d-sorbitol (DBS) organogels. The organogels resulted from the formation of DBS nanofibrillar networks in which the diameter sizes of the nanofibrils ranged from 10 to 100 nm, as observed by transmission electron microscopy. These three-dimensional nanofibrillar networks entrapped the silica and prevented its aggregation. The thermal properties, such as gel dissolution and thermal degradation temperatures, of the composite gels significantly increased with increasing silica content, as determined by polarizing optical microscopy and thermogravimetric analysis. The conductivity of the prepared composite gel electrolytes was clearly enhanced by increasing the silica content. The silica was well dispersed along the DBS nanofibrillar networks, establishing homogeneous microstructures and effective contact with other components of the electrolytes, leading to an increase in the conductivity. PMID- 28594183 TI - The Opposite Effect of Water and N-Methyl-2-Pyrrolidone Cosolvents on the Nanostructural Organization of Ethylammonium Butanoate Ionic Liquid: A Small- and Wide-Angle X-Ray Scattering and Molecular Dynamics Simulations Study. AB - Two series of mixtures of ethylammoniumbutanoate (EAB, [N0 0 0 2][C3CO2]) in water and N-methyl-2-pyrrolidone (NMP) have been prepared at different molar fractions to assess the effect of these two polar solvents on the nanostructural order present in [N0 0 0 2][C3CO2]. The small- and wide-angle X-ray scattering (SWAXS) pattern of the liquid in neat state shows a prepeak at Q = 0.513 A-1, which is associated with the aggregation of nonpolar alkyl chains of both cations and anions. Interestingly, the two solvents affect the nanostructure of [N0 0 0 2][C3CO2] differently, though both are polar. In the case of water addition to the mixture, the prepeak shifts to lower Q values, while in NMP, it moves toward higher values. Also, the principal peaks move in opposite direction in both solvents. The underlying expansion (water) or contraction (NMP) of the solutions observed by the scattering experiments is discussed in terms of molecular dynamics (MD) simulations, which are in very good agreement with the observed patterns. PMID- 28594184 TI - Lattice-Gas Modeling of Adsorbate Diffusion in Mixed-Linker Zeolitic Imidazolate Frameworks: Effect of Local Imidazolate Ordering. AB - The rates of adsorbate diffusion in zeolitic imidazolate frameworks (ZIFs) can be varied by several orders of magnitude by incorporating two different imidazolate linkers in the ZIF crystals. Although some prior measurements of short-range order in these mixed-linker materials have been reported, it is unclear how this short-range order impacts the net diffusion of adsorbates. We introduce a lattice diffusion model that treats diffusion in ZIF-8x-90100-x crystals as a series of activated hops between cages, allowing us to assess the effects of short-range imidazolate order on molecular diffusion. PMID- 28594186 TI - Methods for Generating Highly Magnetically Responsive Lanthanide-Chelating Phospholipid Polymolecular Assemblies. AB - Mixtures of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and its lanthanide ion (Ln3+) chelating phospholipid conjugate, 1,2-dimyristoyl-sn-glycero-3-phospho ethanolamine-diethylene triaminepentaacetate (DMPE-DTPA), assemble into highly magnetically responsive polymolecular assemblies such as DMPC/DMPE-DTPA/Ln3+ (molar ratio 4:1:1) bicelles. Their geometry and magnetic alignability is enhanced by introducing cholesterol into the bilayer in DMPC/Cholesterol/DMPE DTPA/Ln3+ (molar ratio 16:4:5:5). However, the reported fabrication procedures remain tedious and limit the generation of highly magnetically alignable species. Herein, a simplified procedure where freeze thawing cycles and extrusion are replaced by gentle heating and cooling cycles for the hydration of the dry lipid film was developed. Heating above the phase transition temperature Tm of the lipids composing the bilayer before cooling back below the Tm was essential to guarantee successful formation of the polymolecular assemblies composed of DMPC/DMPE-DTPA/Ln3+ (molar ratio 4:1:1). Planar polymolecular assemblies in the size range of hundreds of nanometers are achieved and deliver unprecedented gains in magnetic response. The proposed heating and cooling procedure further allowed to regenerate the highly magnetically alignable DMPC/Cholesterol/DMPE-DTPA/Ln3+ (molar ratio 16:4:5:5) species after storage for one month frozen at -18 degrees C. The simplicity and viability of the proposed fabrication procedure offers a new set of highly magnetically responsive lanthanide ion chelating phospholipid polymolecular assemblies as building blocks for the smart soft materials of tomorrow. PMID- 28594185 TI - Double Magnetic Relaxation and Magnetocaloric Effect in the {Mn9[W(CN)8]6(4,4' dpds)4} Cluster-Based Network. AB - Cyanide-bridged {MnII9[WV(CN)8]6} clusters with the ground state spin SSG = 39/2 were connected by a 4,4'-dipyridyl disulfide (4,4'-dpds) linker into 2-D double connected coordination layers of the I0O2 type, {MnII9(4,4' dpds)4(MeOH)16[WV(CN)8]6}.12MeOH (1). The intercluster contacts are controlled by the bridging MnII-(4,4'-dpds)-MnII coordination modes and direct hydrogen bonds W CN...HOMeOH-Mn in three crystallographic directions, with the vertex-to-vertex contact unprecedented in {Mn9W6}-based networks dominating over the typical edge to-edge contacts. The resulting 3D supramolecular network of high-spin clusters was subjected to a thorough magnetic characterization in context of two critical issues. First, the intracluster WV-CN-MnII exchange coupling and intercluster interaction were successfully modeled through the combination of dc measurements, Quantum Monte Carlo simulations, and mean-field calculations, yielding a reasonable Jap = -8.0 cm-1, Jeq = -19.2 cm-1 (related to apical and equatorial CN bridges, depending on the angle they form with the S4 axis of dodecahedral [W(CN)8]3- units, respectively), and zJ' = 0.014 cm-1 with the average gW = gMn = 2.0 parameter set. Continuing this approach, we simulated the magnetocaloric effect (MCE) and compared it to the experimental result of DeltaSmax = 7.31 J kg 1 K-1 for fields >5.0 T. Second, two relaxation processes were induced by a relatively weak magnetic field, Hdc = 500 Oe, at an Hac field frequency range of up to 10 kHz, which are related to dipole-dipole interactions between high-spin (39/2) moieties. The observed relaxation times significantly differ from each other, the slow process with tauslow at tenths of a second being temperature independent and the faster process being 3-5 orders of magnitude faster with the effective energy barrier Deltaeff = 17.6 K. These dynamic properties are surprising, since the compound is made up of isotropic high-spin molecules. PMID- 28594188 TI - Caregiving experience and its relation to perceptual narrowing of face gender. AB - This research examined whether infants tested longitudinally at 10, 14, and 16 months of age (N = 58) showed evidence of perceptual narrowing based on face gender (better discrimination of female than male faces) and whether changes in caregiving experience longitudinally predicted changes in infants' discrimination of male faces. To test face discrimination, infants participated in familiarization/novelty preference tasks and visual search tasks including female and male faces. At each age of participation, they were coded as having a female primary caregiver only or distributed caregiving experience (alternating experience with a female and male primary caregiver). Perceptual narrowing was evident for infants with a female primary caregiver, but only within the visual search task, which required location of a familiarized face among 3 novel distractor faces (exemplar-based discrimination); it was not evident within the familiarity/novelty preference task, which required discrimination between a familiarized and novel face (individual-based discrimination). Caregiving experience significantly explained individual changes in infants' ability to locate male faces during the visual search task after 10 months. These data are the first to demonstrate flexibility of the face processing system in relation to gender discrimination when there is a change in caregiver within the infants' natural environment after perceptual narrowing normally manifests. (PsycINFO Database Record PMID- 28594189 TI - Shifting between mental sets: An individual differences approach to commonalities and differences of task switching components. AB - Switching between mental sets has been extensively investigated in both experimental and individual differences research using a wide range of task switch paradigms. However, it is yet unclear whether these different tasks measure a unitary shifting ability or reflect different facets thereof. In this study, 20 task pairs were administered to 119 young adults to assess 5 proposed components of mental set shifting: switching between judgments, stimulus dimensions, stimulus-response mappings, response sets, and stimulus sets. Modeling latent factors for each of the components revealed that a model with 5 separate yet mostly correlated factors fit the data best. In this model, the components most strongly related to the other latent factors were stimulus response mapping shifting and, to a lesser degree, response set shifting. In addition, both factors were statistically indistinguishable from a second-order general shifting factor. In contrast, shifting between judgments as well as stimulus dimensions consistently required separate factors and could, hence, not fully be accounted for by the general shifting factor. Finally, shifting between stimulus sets was unrelated to any other shifting component but mapping shifting. We conclude that tasks assessing shifting between mappings are most adequate to assess general shifting ability. In contrast, shifting between stimulus sets (e.g., as in the Trail Making Test) probably reflects shifts in visual attention rather than executive shifting ability. (PsycINFO Database Record PMID- 28594187 TI - Genetic and environmental sources of covariation between early drinking and adult functioning. AB - The vast majority of individuals initiate alcohol consumption for the first time in adolescence. Given the widespread nature of its use and evidence that adolescents may be especially vulnerable to its effects, there is concern about the long-term detrimental impact of adolescent drinking on adult functioning. While some researchers have suggested that genetic processes may confound the relationship, the mechanisms linking drinking and later adjustment remain unclear. The current study utilized a genetically informed sample and biometric modeling to examine the nature of the familial influences on this association and identify the potential for genetic confounding. The sample was drawn from the Minnesota Twin Family Study (MTFS), a longitudinal study consisting of 2,764 twins assessed in 2 cohorts at regular follow-ups from age 17 to age 29 (older cohort) or age 11 to age 29 (younger cohort). A broad range of adult measures was included assessing substance use, antisocial behavior, personality, socioeconomic status, and social functioning. A bivariate Cholesky decomposition was used to examine the common genetic and environmental influences on adolescent drinking and each of the measures of adult adjustment. The results revealed that genetic factors and nonshared environmental influences were generally most important in explaining the relationship between adolescent drinking and later functioning. While the presence of nonshared environmental influences on the association are not inconsistent with a causal impact of adolescent drinking, the findings suggest that many of the adjustment issues associated with adolescent alcohol consumption are best understood as genetically influenced vulnerabilities. (PsycINFO Database Record PMID- 28594190 TI - Mnemonic transmission, social contagion, and emergence of collective memory: Influence of emotional valence, group structure, and information distribution. AB - Social transmission of memory and its consequence on collective memory have generated enduring interdisciplinary interest because of their widespread significance in interpersonal, sociocultural, and political arenas. We tested the influence of 3 key factors-emotional salience of information, group structure, and information distribution-on mnemonic transmission, social contagion, and collective memory. Participants individually studied emotionally salient (negative or positive) and nonemotional (neutral) picture-word pairs that were completely shared, partially shared, or unshared within participant triads, and then completed 3 consecutive recalls in 1 of 3 conditions: individual-individual individual (control), collaborative-collaborative (identical group; insular structure)-individual, and collaborative-collaborative (reconfigured group; diverse structure)-individual. Collaboration enhanced negative memories especially in insular group structure and especially for shared information, and promoted collective forgetting of positive memories. Diverse group structure reduced this negativity effect. Unequally distributed information led to social contagion that creates false memories; diverse structure propagated a greater variety of false memories whereas insular structure promoted confidence in false recognition and false collective memory. A simultaneous assessment of network structure, information distribution, and emotional valence breaks new ground to specify how network structure shapes the spread of negative memories and false memories, and the emergence of collective memory. (PsycINFO Database Record PMID- 28594191 TI - Overgeneral autobiographical memory in healthy young and older adults: Differential age effects on components of the capture and rumination, functional avoidance, and impaired executive control (CaRFAX) model. AB - The CaRFAX model (Williams et al., 2007) has been used to explain the causes of overgeneral autobiographical memory (OGM; the difficulty to retrieve specific autobiographical memories), a cognitive phenomenon generally related with different psychopathologies. This model proposes 3 different mechanisms to explain OGM: capture and rumination (CaR), functional avoidance (FA) and impaired executive functions (X). However, the complete CaRFAX model has not been tested in nonclinical populations. This study aims to assess the usefulness of the CaRFAX model to explain OGM in 2 healthy samples: a young sample and an older sample, to test for possible age-related differences in the underlying causes of OGM. A total of 175 young (age range: 19-36 years) and 175 older (age range: 53 88 years) participants completed measures of brooding rumination (CaR), functional avoidance (FA), and executive tasks (X). Using structural equation modeling, we found that memory specificity is mainly associated with lower functional avoidance and higher executive functions in the older group, but only with executive functions in young participants. We discuss the different roles of emotional regulation strategies used by young and older people and their relation to the CaRFAX model to explain OGM in healthy people. (PsycINFO Database Record PMID- 28594192 TI - Networks of loss: Relationships among symptoms of prolonged grief following spousal and parental loss. AB - The death of a loved one can trigger a range of emotional, behavioral, motivational and cognitive reactions collectively labeled as "grief." There has been a recent resurgence of empirical interest in grief reactions, and there is now a general consensus that 7%-10% of bereaved individuals experience intense and chronic reactions termed Prolonged Grief (PG). However, there is ongoing debate about how best to conceptualize the construct. Recent studies have advanced this debate by applying a network, or causal systems approach. Whereas traditional views of psychopathology posit symptoms of disorders reflect the independent actions of latent entities, the network approach argues that the symptoms themselves interact to give rise to the disorder. A network conceptualization offers novel approaches to studying the mechanisms that contribute to PG. To date, however, research has focused only on spousal loss and only used a single archival data set. Therefore, in this paper we apply network analysis to examine relationships among PG symptoms in samples of individuals bereaved by loss of a spouse (Study 1, N = 193) and a parent (Study 2, N = 180). Participants completed the PG-13 and a measure of depression. A comparison test suggested the networks produced from each sample were not reliably different. The strongest link in both networks was between yearning and emotional pain. Meaninglessness was relatively central, whereas avoidance was peripheral in both networks. Findings are discussed with reference to theoretical models and the potential benefits a network approach may hold for understanding relationships between symptoms of PG. (PsycINFO Database Record PMID- 28594193 TI - Examination of traumatic brain injury exposure among veterans with spinal cord injury. AB - OBJECTIVE: The authors investigated lifetime exposure to traumatic brain injury (TBI) among veterans with spinal cord injury (SCI) in order to describe outcome differences as a function of self-reported TBI history. DESIGN: Cross sectional study, veterans with SCI (N = 857) completed the Ohio State University TBI Identification interview method (OSU-TBI); Veterans RAND 36-Item Health Survey (VR-36); Quick Inventory for Depressive Symptomatology, Self-Report (QIDS-SR); Patient Health Questionnaire-9; Satisfaction with Life Scale; Craig Handicap Assessment and Reporting Technique (CHART; along with clinician-rated Functional Independence Measure (FIM) Total, Motor, and Cognitive scores. RESULTS: Probable TBI exposure was described by 77.6% of participants, with 38% reporting sustaining more than one injury. Self-reported TBIs classified as moderate/severe comprised 49.5% of injuries. Participants with self-reported TBI obtained significantly lower scores on the FIM-Cognitive and CHART Cognitive Independence scales and reported more alcohol use. A history of multiple TBIs was additionally associated with lower mental well-being on the VR-36. CONCLUSIONS: These findings highlight the need to consider more than co-occurring injuries and the potential utility of the OSU-TBI for this purpose. Recognizing lifetime exposure to TBI among veterans with SCI may help identify those with broader impairments and enhance the rehabilitation process. (PsycINFO Database Record PMID- 28594194 TI - Conducting preference assessments for youth with disorders of consciousness during rehabilitation. AB - PURPOSE: Care and rehabilitation for individuals with disorders of consciousness (DOC) can be challenging; the use of observational data collection, individualized treatment programs, and incorporation of preferred, personally meaningful and salient items may be helpful in addressing such challenges during assessment and intervention. In this article, we extend the predominantly adult literature on use of salient items to promote differential responding by describing our methodology to identify preferred items across sensory domains for application during inpatient rehabilitation with children with DOC. METHOD: Details on the indirect and direct preference assessment procedures rooted in applied behavior analysis that we have tailored for this population are provided. We describe steps of the procedures, including structured caregiver interview, staff survey, item inclusion, in vivo single-item stimulus preference assessment, and treatment. Clinical case examples further illustrate implementation of our methodology, observed response topographies, individually identified preferred items, and their application for 3 children in a minimally conscious state. In addition, we introduce a new structured caregiver interview, the Preference Assessment for Youth with Disorders of Consciousness (PAYDOC), modeled on the Reinforcer Assessment for Individuals with Severe Disabilities (RAISD; Fisher, Piazza, Bowman, & Amari, 1996) and modified to be appropriate for future use as a clinical tool to enhance assessment of preferences with this pediatric brain injury population. IMPLICATIONS: This methodology can be used to identify highly idiosyncratic stimuli that can be incorporated in multiple ways throughout rehabilitation to optimize care for youth with DOC. (PsycINFO Database Record PMID- 28594196 TI - Online and mobile technologies for self-management in bipolar disorder: A systematic review. AB - OBJECTIVE: Internet (eHealth) and smartphone-based (mHealth) approaches to self management for bipolar disorder are increasingly common. Evidence-based self management strategies are available for bipolar disorder and provide a useful framework for reviewing existing eHealth/mHealth programs to determine whether these strategies are supported by current technologies. This review assesses which self-management strategies are most supported by technology. METHOD: Based on 3 previous studies, 7 categories of self-management strategies related to bipolar disorder were identified, followed by a systematic literature review to identify existing eHealth and mHealth programs for this disorder. Searches were conducted by using PubMed, CINAHL, PsycINFO, EMBASE, and the Cochrane Database of Systematic Reviews for relevant peer-reviewed articles published January 2005 to May 2015. eHealth and mHealth programs were summarized and reviewed to identify which of the 7 self-management strategy categories were supported by eHealth or mHealth programs. RESULTS: From 1,654 publications, 15 papers were identified for inclusion. From these, 9 eHealth programs and 2 mHealth programs were identified. The most commonly supported self-management strategy categories were "ongoing monitoring," "maintaining hope," "education," and "planning for and taking action"; the least commonly supported categories were "relaxation" and "maintaining a healthy lifestyle." eHealth programs appear to provide more comprehensive coverage of self-management strategies compared with mHealth programs. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Both eHealth and mHealth programs present a wide range of self-management strategies for bipolar disorder, although individuals seeking comprehensive interventions might be best served by eHealth programs, while those seeking more condensed and direct interventions might prefer mHealth programs. (PsycINFO Database Record PMID- 28594195 TI - Pain-related anxiety as a predictor of early lapse and relapse to cigarette smoking. AB - Although emerging research suggests that pain-related anxiety may play a role in the maintenance of tobacco dependence, no previous work has examined pain-related anxiety as a predictor of smoking cessation outcomes. The current study aimed to test the hypothesis that pain-related anxiety would predict early lapse and relapse to cigarette smoking. These data were collected in the context of a primary study examining the role of emotional vulnerabilities in smoking cessation. The current analyses were conducted among 55 daily cigarette smokers who attempted to quit without psychosocial or pharmacological cessation aids. Pain-related anxiety was assessed at baseline using the Pain Anxiety Symptom Scale-20 (PASS-20). Early lapse and relapse were assessed using timeline follow back procedures. Cox regression analyses indicated that pain-related anxiety was a significant predictor of both early smoking lapse and relapse such that for every 1-point increase on the PASS-20, the risk of early lapse increased by 3.7% and the risk of early relapse increased by 3.6%. These effects were evident above and beyond the variance accounted for by tobacco dependence, past 4-week pain severity, anxiety sensitivity, and the presence of current Axis I psychopathology. Kaplan-Meier survival analyses further revealed that among early lapsers, greater pain-related anxiety predicted a more rapid trajectory to lapse. Pain-related anxiety was also a significant predictor of early lapse when the sample was limited to smokers with past 4-week pain. These findings lend empirical support to the notion that pain-related anxiety may contribute to the maintenance of tobacco dependence among smokers who experience varying levels of pain intensity. (PsycINFO Database Record PMID- 28594197 TI - The mediating role of mattering to others in recovery and stigma. AB - OBJECTIVE: This study examines the role of mattering to others as an intrapersonal construct that may mediate the relationship between social support and 2 separate criterion variables: recovery and internalized stigma associated with living with a serious mental health condition. Adults living with serious mental health disorders, such as schizophrenia, face numerous social challenges that may leave them feeling isolated, stigmatized, and that they do not matter to others, thus thwarting the potential for recovery. Theorists and researchers conceptualize the sense of mattering to others as the perception that 1 is valued, recognized by others along with the feelings that others are concerned about our well-being. METHOD: Clubhouse members (N = 119) completed 1-hr, in depth personal interviews assessing perceived social support, experiences of mental health recovery, and stigma associated with living with a mental health condition as well as a sense of mattering to others. RESULTS: Mediation analyses revealed the significant effects of mattering to others as explaining the relationship between social support and recovery as well as the relationship between social support and internalized stigma. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The findings illuminate our understanding as to how social support interventions can enhance recovery and reduce stigma associated with living with a psychiatric condition by attention to perceptions of whether one is valued and recognized by others. Mattering to others among consumers of social and health care interventions can serve to engage individuals who may withdraw from supports or internalize negative self-stereotypes based on internalized stigma. (PsycINFO Database Record PMID- 28594198 TI - The reliability paradox of the Parent-Child Conflict Tactics Corporal Punishment Subscale. AB - In the present investigation we consider and explain an apparent paradox in the measurement of corporal punishment with the Parent-Child Conflict Tactics Scale (CTS-PC): How can it have poor internal consistency and still be reliable? The CTS-PC was administered to a community sample of 453 opposite sex couples who were parents of 3- to 7-year-old children. Internal consistency was marginal, yet item response theory analyses revealed that reliability rose sharply with increasing corporal punishment, exceeding .80 in the upper ranges of the construct. The results suggest that the CTS-PC Corporal Punishment subscale reliably discriminates among parents who report average to high corporal punishment (64% of mothers and 56% of fathers in the present sample), despite low overall internal consistency. These results have straightforward implications for the use and reporting of the scale. (PsycINFO Database Record PMID- 28594200 TI - A mixed-methods study of personality conceptions in the Levant: Jordan, Lebanon, Syria, and the West Bank. AB - Personality taxonomies are investigated using either etic-style studies that test whether Western-developed models fit in a new culture, or emic-style studies that derive personality dimensions from a local culture, using a psycholexical approach. Recent studies have incorporated strengths from both approaches. We combine the 2 approaches in the first study of personality descriptors in spoken Arabic. In Study 1, we collected 17,283 responses from a sample of adults in Lebanon, Syria, Jordan, and the West Bank (N = 545). Qualitative analysis revealed 9 personality dimensions: Soft-Heartedness, Positive Social Relatedness, Integrity, Humility versus Dominance, Conscientiousness, Extraversion, Emotional Stability, Intellect, and Openness. In Study 2, we converted the qualitative model into an indigenous personality inventory and obtained self-ratings of a sample of adults in the same region (N = 395). We also simultaneously obtained self-ratings on an adapted etic inventory that measures the lexical Big Five (N = 325). Psychometric and conceptual considerations yielded a robust 7-factor indigenous model: Agreeableness/Soft Heartedness, Honesty/Integrity, Unconventionality, Emotional Stability, Conscientiousness, Extraversion/Positive Social Relatedness, and Intellect. Initial validation evidence shows that 5 of the 7 factors overlapped with the Big Five, whereas Honesty/Integrity and Unconventionality did not overlap. Also, scores on the indigenous tools were better predicted by relevant demographic variables than scores on the etic tool. Our study demonstrated the viability of combining etic and emic approaches as key to the understanding of personality in its cultural context. (PsycINFO Database Record PMID- 28594199 TI - Spillover between interparental conflict and parent-child conflict within and across days. AB - The present study used a daily reporting design to examine the bidirectional spillover in conflict and conflict strategies between the interparental relationship and the parent-child relationship. Participants were 60 parents with a preadolescent child at risk for aggressive behavior. Parents reported on their experience of interparental and parent-child conflict and their use of constructive and destructive conflict strategies through daily telephone interviews over 7 days. Each day was divided into 3 equal time periods roughly corresponding to early morning, daytime, and evening. Time-lagged analyses investigated the spillover in conflict within and across days. Results revealed that the presence of interparental conflict significantly predicted the presence of parent-child conflict 1 time period later and 1 full day later. Likewise, the presence of parent-child conflict significantly predicted the presence of interparental conflict 1 full day later. In terms of conflict strategy use, results revealed that parents who engaged in constructive patterns of interparental conflict were more likely to engage in constructive patterns of parent-child conflict 1 time period later and 1 full day later. Reciprocal effects for constructive parent-child conflict predicting subsequent interparental conflict were significant across all 3 time lags assessed. There were no significant, bidirectional effects for the spillover in destructive conflict. Findings have important clinical implications. (PsycINFO Database Record PMID- 28594201 TI - Hypocritical flip-flop, or courageous evolution? When leaders change their moral minds. AB - How do audiences react to leaders who change their opinion after taking moral stances? We propose that people believe moral stances are stronger commitments, compared with pragmatic stances; we therefore explore whether and when audiences believe those commitments can be broken. We find that audiences believe moral commitments should not be broken, and thus that they deride as hypocritical leaders who claim a moral commitment and later change their views. Moreover, they view them as less effective and less worthy of support. Although participants found a moral mind changer especially hypocritical when they disagreed with the new view, the effect persisted even among participants who fully endorsed the new view. We draw these conclusions from analyses and meta-analyses of 15 studies (total N = 5,552), using recent statistical advances to verify the robustness of our findings. In several of our studies, we also test for various possible moderators of these effects; overall we find only 1 promising finding: some evidence that 2 specific justifications for moral mind changes-citing a personally transformative experience, or blaming external circumstances rather than acknowledging opinion change-help moral leaders appear more courageous, but no less hypocritical. Together, our findings demonstrate a lay belief that moral views should be stable over time; they also suggest a downside for leaders in using moral framings. (PsycINFO Database Record PMID- 28594202 TI - The four faces of rumination to stressful events: A psychometric analysis. AB - OBJECTIVE: To increase the knowledge of rumination and its associations with stressful events, we explored the relationships between 4 types of rumination (brooding, reflection, intrusive, and deliberate rumination) in a sample of 750 adult participants who experienced a highly stressful event. We also explored the predictive value of the different types of rumination on posttraumatic stress symptoms and posttraumatic growth 6 months after the highly stressful event occurred. METHOD: Participants completed the Ruminative Response Scale and the Event-Related Rumination Inventory. Brooding and reflection rumination were obtained from the Ruminative Response Scale, whereas deliberate and intrusive rumination were obtained from the Event-Related Rumination Inventory. Confirmatory factorial analyses were conducted using the 4 types of rumination to test 3 different models: (a) 4-factor model (brooding, reflection, intrusive, and deliberate rumination), (b) 2-factor model: adaptive rumination (reflection and deliberate) and maladaptive rumination (brooding and intrusive), and (c) 2-factor model: depressive rumination (brooding and reflection) and posttraumatic rumination (intrusive and deliberate). RESULTS: It was observed that the 4-factor model showed the best fit to the data. Moreover, 6 months later it was observed that the most significant predictor of posttraumatic symptoms was intrusive rumination, whereas deliberate rumination was the most significant predictor of posttraumatic growth. CONCLUSIONS: Results indicate that the 4 types of rumination are differentiated constructs. Ruminative thoughts experienced after a stressful event predicted posttraumatic consequences 6 months later. Implications of these findings are discussed. (PsycINFO Database Record PMID- 28594203 TI - Predictors of posttraumatic growth 10-11 months after a fatal earthquake. AB - OBJECTIVE: Posttraumatic growth (PTG) is a commonly observed phenomenon in the wake of a distressing event, capturing potentially beneficial effects for posttraumatic adaptation. However, it is not entirely clear what factors are essential for the development of PTG, especially after natural disasters. Most importantly, it is uncertain what type of relationship exists between posttraumatic stress symptoms (PTSS) and PTG. As yet, there is also no consensus on whether PTG can best be seen as a process outcome or as a coping mechanism. The current study aimed to elucidate these uncertainties. METHOD: The study explored PTG in a community sample (N = 412) 10-11 months after a major earthquake in Christchurch, New Zealand. Nonsymptomatic predictors of PTG were assessed 4-7 months after the earthquake, and symptomatic predictors were assessed both 4-7 and 10-11 months after the earthquake, with PTG measured in the second assessment. RESULTS: Results showed that the unique relationship between PTSS and PTG was modeled best both linearly and curvilinearly, suggesting that PTSS over a certain level shift from a positive association with PTG to a negative one. PTG was predicted by being female, having less household income, PTSS symptoms modeled linearly and curvilinearly at Time 1, and PTSS modeled linearly at Time 2. CONCLUSION: Support was found for the coping model of PTG, suggesting the importance of fostering growth to manage posttraumatic distress. (PsycINFO Database Record PMID- 28594204 TI - Taking forensic mental health assessment "out of the lab" and into "the real world": Introduction to the special issue on the field utility of forensic assessment instruments and procedures. AB - The last several decades have seen a major upswing in the development and use of psychological assessment instruments in forensic and correctional settings. At the same time, admissibility standards increasingly have stressed the importance of the reliability and validity of evidence in legal proceedings. Recent research has, however, raised serious concerns about (a) the reliability of forensic science evidence in general, (b) the replicability of psychological research findings in general and in field settings especially, and (c) the interrater reliability and predictive validity of forensic psychological assessment evidence in particular. In this introduction to the special issue of Psychological Assessment on the field utility of forensic assessment instruments and procedures, we provide an overview of key issues bearing on field studies, focusing on why such research is critically important to improving the quality of the practice of forensic mental health assessments. We also identify various methodological issues and constraints relevant to conducting research outside of controlled settings. We conclude with recommendations for how future field research can improve upon the current state of the discipline in forensic mental health assessment. (PsycINFO Database Record PMID- 28594206 TI - Actuarial risk assessment of sexual offenders: The psychometric properties of the Sex Offender Risk Appraisal Guide (SORAG). AB - The Sex Offender Risk Appraisal Guide (SORAG) is one of the most commonly used actuarial risk assessment instruments for sexual offenders. The aims of the present field study were to examine the predictive validity of the German version of the SORAG and its individual items for different offender subgroups and recidivism criteria in sexual offenders released from the Austrian Prison System (N = 1,104; average follow-up period M = 6.48 years) within a prospective longitudinal research design. For the prediction of violent recidivism the German version of the SORAG yielded an effect size of AUC = .74 (p < .001, 95% CI = .70 .78). The predictive accuracy for general and violent recidivism was slightly higher than for general sexual and sexual hands-on recidivism. The effect sizes were found to be higher for the child molester sample than for rapists. However, the differences were significant only for general recidivism (z = 2.48, p = .001). Further analyses exhibited the SORAG to have incremental predictive validity beyond the VRAG and the PCL-R, and to remain the only significant predictor for violent recidivism once all 3 instruments were forced into a combined regression model. Twelve out of the 14 SORAG items were found to have a significant positive relationship with violent recidivism. The comparison of the relative and absolute risk indices between the Austrian and the Canadian samples showed that the normative data distribution yielded more (absolute risk indices) or less (relative risk indices) meaningful differences between the 2 countries. (PsycINFO Database Record PMID- 28594207 TI - "Psychometric properties of the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5) in veterans": Correction to Bovin et al. (2016). AB - Reports an error in "Psychometric properties of the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5) in veterans" by Michelle J. Bovin, Brian P. Marx, Frank W. Weathers, Matthew W. Gallagher, Paola Rodriguez, Paula P. Schnurr and Terence M. Keane (Psychological Assessment, 2016[Nov], Vol 28[11], 1379-1391). In the article, the departments and affiliations were incorrectly listed for authors Michelle J. Bovin, Brian P. Marx, Matthew W. Gallagher, Paola Rodriguez, Paula P. Schnurr, and Terence M. Keane. The first department and affiliation for authors Michelle J. Bovin, Brian P. Marx, Matthew W. Gallagher, Paola Rodriguez, and Terence M. Keane and should have read "National Center for PTSD at VA Boston Healthcare System, Boston, Massachusetts". The first department and affiliation for author Paula P. Schnurr should have read "National Center for PTSD, White River Junction, Vermont." The online version of this article has been corrected. (The following abstract of the original article appeared in record 2015-55809-001.) This study examined the psychometric properties of the posttraumatic stress disorder (PTSD) Checklist for Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (PCL-5; Weathers, Litz, et al., 2013b) in 2 independent samples of veterans receiving care at a Veterans Affairs Medical Center (N = 468). A subsample of these participants (n = 140) was used to define a valid diagnostic cutoff score for the instrument using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers, Blake, et al., 2013) as the reference standard. The PCL-5 test scores demonstrated good internal consistency (alpha = .96), test-retest reliability (r = .84), and convergent and discriminant validity. Consistent with previous studies (Armour et al., 2015; Liu et al., 2014), confirmatory factor analysis revealed that the data were best explained by a 6-factor anhedonia model and a 7 factor hybrid model. Signal detection analyses using the CAPS-5 revealed that PCL 5 scores of 31 to 33 were optimally efficient for diagnosing PTSD (kappa(.5) = .58). Overall, the findings suggest that the PCL-5 is a psychometrically sound instrument that can be used effectively with veterans. Further, by determining a valid cutoff score using the CAPS-5, the PCL-5 can now be used to identify veterans with probable PTSD. However, findings also suggest the need for research to evaluate cluster structure of DSM-5. (PsycINFO Database Record PMID- 28594205 TI - Field validity of Static-99/R scores in a statewide sample of 34,687 convicted sexual offenders. AB - The Static-99 (and revision, the Static-99R) reflect the most researched and widely used approach to sex offender risk assessment. Because the measure is so widely applied in jurisdictions beyond those on which it was developed, it becomes crucial to examine its field validity and the degree to which published norms and recidivism rates apply to other jurisdictions. We present a new and greatly expanded field study of the predictive validity (M = 5.23 years follow up) of the Static-99 as applied system-wide in Texas (N = 34,687). Results revealed stronger predictive validity than a prior Texas field study, especially among offenders scored after the release of an updated scoring manual in 2003 (AUC = .66 to .67, d = .65 to .69), when field reliability was also stronger. But calibration analyses revealed that the Static-99R routine sample norms led to a significant overestimation of risk in Texas, especially for offenders with scores ranging from 1 to 5. We used logistic regression to develop local Texas recidivism norms (with confidence intervals) for Static-99R scores. Overall, findings highlight the importance of revisiting and updating field study findings, and the potential benefits of using statewide data to develop local norms. (PsycINFO Database Record PMID- 28594208 TI - Field measures of psychopathy and sexual deviance as predictors of recidivism among sexual offenders. AB - Offenders with high levels of both psychopathy and deviant sexual interests are often described as being more prone to recidivate than other sexual offenders, and many forensic evaluators report considering this psychopathy and sexual deviance interaction when coming to conclusions about sex offender risk. However, empirical support for the interaction comes from studies using sexual deviance measures that are rarely used in the field. We examined the ability of Psychopathy Checklist-Revised (PCL-R) field scores and possible field measures of sexual deviance (e.g., paraphilia diagnosis, offense characteristics) to predict sexual recidivism among 687 offenders released after being evaluated for postrelease civil commitment (M follow-up = 10.5 years). PCL-R total scores and antisocial personality diagnoses were predictive of a combined category of violent or sexual recidivism, but not sexual recidivism. Paraphilia diagnoses and offense characteristics were not associated with an increased likelihood of reoffending. There was no evidence that those with high levels of both psychopathy and sexual deviance were more likely than others to reoffend. Although the psychopathy and sexual deviance interaction findings from prior studies are large and compelling, our findings highlight the need for research examining the best ways to translate those findings into routine practice. (PsycINFO Database Record PMID- 28594209 TI - Use of structured professional judgment by probation officers to assess risk for recidivism in adolescent offenders. AB - The current study tested a method of risk assessment for adolescent offenders that relies on structured professional judgment: the Structured Assessment of Violence Risk for Youth (SAVRY; Borum, Bartel, & Forth, 2006). Trained probation officers in 3 jurisdictions administered the SAVRY to 505 adjudicated adolescents (M age = 15.43 years, SD = 1.62). The results supported the validity of the SAVRY administered in this juvenile justice context. Specifically, scores from the SAVRY differentiated violent from nonviolent offenders and predicted both violent and nonviolent recidivism over a 12-month follow-up period. Violent offenders showed more historical and individual risk factors than nonviolent offenders, and violent sex offenders were rated as more deficient in empathy and remorse. The anger control item was a particularly important indicator of risk for reoffending in the violent offender group. The implications of these findings for weighting risk factors in individual cases when using structured professional judgment are discussed. (PsycINFO Database Record PMID- 28594210 TI - Are risk assessments racially biased?: Field study of the SAVRY and YLS/CMI in probation. AB - Risk assessment instruments are widely used by juvenile probation officers (JPOs) to make case management decisions; however, few studies have investigated whether these instruments maintain their predictive validity when completed by JPOs in the field. Moreover, the validity of these instruments for use with minority groups has been called into question. This field study examined the predictive validity of both the Structured Assessment of Violence Risk in Youth (SAVRY; n = 383) and the Youth Level of Service/Case Management Inventory (YLS/CMI; n = 359) for reoffending when completed by JPOs. The study also compared Black and White youth to examine the presence of test bias. The SAVRY and YLS/CMI significantly predicted reoffending at the test level, with most of the variance in reoffending accounted for by dynamic risk scales not static scales. The instruments did not differentially predict reoffending as a function of race but Black youth scored higher than White youth on the YLS/CMI scale related to official juvenile history. The implications for use of risk assessments in the field are discussed. (PsycINFO Database Record PMID- 28594211 TI - How well do juvenile risk assessments measure factors to target in treatment? Examining construct validity. AB - There has been a surge of interest in using 1 type of risk assessment instrument to tailor treatment to juveniles to reduce recidivism. Unlike prediction-oriented instruments, these reduction-oriented instruments explicitly measure variable risk factors as "needs" to be addressed in treatment. There is little evidence, however, that the instruments accurately measure specific risk factors. Based on a sample of 237 serious juvenile offenders (Mage = 18, SD = 1.6), we tested whether California Youth Assessment Inventory (CA-YASI) scores validly assess the risk factors they purport to assess. Youth were assessed by practitioners with good interrater reliability on the CA-YASI, and by research staff on a battery of validated, multimethod criterion measures of target constructs. We meta analytically tested whether each CA-YASI risk domain score (e.g., Attitudes) related more strongly to scores on convergent measures of theoretically similar constructs (e.g., criminal thinking styles) than to scores on discriminant measures of theoretically distinct constructs (e.g., intelligence, somatization, and pubertal status). CA-YASI risk domain scores with the strongest validity support were those that assess criminal history. The only variable CA-YASI risk domain score that correlated more strongly with convergent (Zr = .35) than discriminant (Zr = .07) measures was Substance Use. There was little support for the construct validity of the remaining 6 variable CA-YASI risk domains-including those that ostensibly assess strong risk factors (e.g., "Attitudes," "Social Influence"). Our findings emphasize the need to test the construct validity of reduction-oriented instruments-and refine instruments to precisely measure their targets so they can truly inform risk reduction. (PsycINFO Database Record PMID- 28594212 TI - Diagnostic field reliability in forensic mental health evaluations. AB - How likely are multiple forensic evaluators to agree on defendants' diagnoses in routine forensic mental health evaluations? A total of 720 evaluation reports were examined from 240 cases in which 3 evaluators, working independently, provided diagnoses for the same defendant. Results revealed perfect agreement across 6 independent diagnostic categories in 18.3% of cases. Agreement for individual diagnostic categories was higher, with all 3 evaluators agreeing on the separate presence of psychotic, mood, or substance disorders in more than 64.7% of cases and agreeing on the presence of cognitive or developmental disorders in more than 89.7% of cases. However, evaluators agreed about the combination of psychotic and substance-related diagnoses in only 46.5% of cases. Agreement was enhanced by diagnoses with low base rates, and it was suppressed in evaluations conducted in jails. Psychiatrists and contracted evaluators were more likely to provide dissenting diagnostic categories than psychologists and state employed evaluators. These results are among the first to document diagnostic agreement among nonpartisan practitioners in forensic evaluations conducted in the field, and they allow for practice and policy recommendations for evaluators in routine forensic practice to be made. (PsycINFO Database Record PMID- 28594213 TI - Assessing "credible fear": A psychometric examination of the Trauma Symptom Inventory-2 in the context of immigration court evaluations. AB - Recent immigration trends indicate that the United States is home to a remarkably diverse and rapidly growing population of displaced persons. Many of these individuals have survived exceptional trauma and are thus particularly vulnerable to trauma-related behavioral health disorders. Mental health professionals are commonly asked to assess immigrants within this population in the service of immigration court decision making. These assessments present a variety of challenges for clinicians, including the assessment and documentation of trauma related symptoms across cultural bounds. The Trauma Symptom Inventory-2 (TSI-2) may be uniquely suited to the demands of immigration court assessments, but it has not been previously examined in a culturally diverse sample. The current study provided an examination of the TSI-2 within a sample of immigrants with histories of trauma. De-identified TSI-2 data were drawn from several clinicians' existing immigration assessment files. Reliability and standardization sample comparison results indicated that the TSI-2 exhibits sufficient internal consistency within this population, and that immigrants with histories of trauma generally respond similarly to individuals in trauma-specific clinical samples (with several notable exceptions). Specific clinical implications are discussed. (PsycINFO Database Record PMID- 28594214 TI - The influence of veteran race and psychometric testing on veterans affairs posttraumatic stress disorder (PTSD) disability exam outcomes. AB - This study examined the influence of veterans' race and examiners' use of psychometric testing during a Department of Veterans Affairs posttraumatic stress disorder (PTSD) disability examination on diagnostic and service connection status outcomes. Participants were 764 veterans enrolled in a national longitudinal registry. Current and lifetime PTSD diagnostic status was determined with the Structured Clinical Interview for DSM-IV (SCID) and was compared with PTSD diagnosis conferred upon veterans by their compensation and pension (C&P) examiners as well as with ultimate Veterans Affairs (VA) PTSD service connected status. The concordance rate between independent SCID current PTSD diagnosis and PTSD disability examination diagnosis was 70.4%, and between SCID lifetime PTSD diagnosis and PTSD disability examination diagnosis was 77.7%. Among veterans with current SCID diagnosed PTSD, Black veterans were significantly less likely than White veterans to receive a PTSD diagnosis from their C&P examiner (odds ratio [OR] = .39, p = .003, confidence interval [CI] = .20-.73). Among veterans without current SCID diagnosed PTSD, White veterans were significantly more likely than Black veterans to receive a PTSD diagnosis from their C&P examiner (OR = 4.07, p = .005, CI = 1.51-10.92). Splitting the sample by use of psychometric testing revealed that examinations that did not include psychometric testing demonstrated the same relation between veteran race and diagnostic concordance. However, for examinations in which psychometric testing was used, the racial disparity between SCID PTSD status and disability exam PTSD status was no longer significant. Results suggest that psychometric testing may reduce disparities in VA PTSD disability exam outcomes. (PsycINFO Database Record PMID- 28594215 TI - Identifying mental health issues in detained youth: Testing the structure and invariance of the Massachusetts Youth Screening Inventory-Version 2 (MAYSI-2). AB - This study examined the factor structure of the Massachusetts Youth Screening Instrument-Version 2 (MAYSI-2), a brief self-report measure designed to flag clinically significant mental health needs among youth entering the juvenile justice system. Participants were 981 detained youth in the southeastern United States (mean age = 14.58 years; SD = 1.28 years; 67.5% male; 71.5% African American). Confirmatory factor analyses showed that a seven-factor model represented a satisfactory solution for the data, similar to previous research. The factor structure fit well across gender, age group, race (Black/White), and offense type (violent/nonviolent). Given the widespread use of the MAYSI-2 in juvenile justice settings, examining its psychometric properties is of key importance. Implications and limitations of the study are discussed. (PsycINFO Database Record PMID- 28594217 TI - Psychometric properties and prognostic usefulness of the Youth Psychopathic Traits Inventory (YPI) as a component of a clinical protocol for detained youth: A multiethnic examination. AB - Prior studies have shown that the Youth Psychopathic Traits Inventory (YPI) holds promise as a self-report tool for assessing psychopathic traits in detained adolescents. However, these studies have been conducted in a research context where anonymity and confidentiality are provided. Few studies have examined the usefulness of the YPI in clinical settings. To address this research gap, the present study examined data from 1,559 detained boys who completed the YPI as part of a clinical protocol. Official criminal records were available for a subsample (n = 848), allowing us to test the prognostic usefulness of the YPI. Results of confirmatory factor analyses, overall, support the proposed 3-factor structure, though model fit indices were not as good in Dutch boys compared to boys from other ethnic groups. Measurement invariance tests showed that the YPI scores are manifested in the same way across all 4 ethnic groups and suggest that means scores between the 4 ethnic groups are comparable. The YPI scores were internally consistent, and correlations with external variables, including aggression and conduct problems, support the convergent validity of the interpretation of YPI scores. Finally, results demonstrated that YPI scores were not significantly positively related to future criminality. In conclusion, this study suggests that the YPI may hold promise as a self-report tool for assessing psychopathic traits in detained male adolescents during a clinical protocol. However, the finding that the YPI did not predict future offending suggests that this tool should not yet be used for risk assessment purposes in forensic settings. (PsycINFO Database Record PMID- 28594216 TI - Using the MAYSI-2 to identify mental disorder among Latino juvenile offenders. AB - Many juvenile justice agencies have adopted the Massachusetts Youth Screening Inventory-Version 2 (MAYSI-2; Grisso & Barnum, 2006) to facilitate appropriate programming for young offenders with mental illness. Although Latinos are the fastest-growing ethnic group in the criminal justice system, there is scant research on the utility of the MAYSI-2 among Latino adolescents. The present study examined the utility of the MAYSI-2 in detecting diagnosable mental illness among 398 Latino and 60 European American adolescents in a juvenile justice agency. In addition to testing the scoring configuration used by the agency to identify adolescents in need of further attention, we tested 2 additional scoring configurations of the MAYSI-2. We found that the MAYSI-2 had similar utility at identifying serious mood and anxiety disorders for both ethnic groups, but was less sensitive to behavioral and substance use disorders among Latinos than it was among European Americans. In addition, the MAYSI-2 overall was less sensitive to mental illness among Latino boys compared with Latina girls. We discuss these findings within the context of best practices for identifying adolescents with mental illness in juvenile justice agencies. (PsycINFO Database Record PMID- 28594218 TI - Examining the interrater reliability of the Hare Psychopathy Checklist-Revised across a large sample of trained raters. AB - The goal of the current study was to assess the interrater reliability of the Psychopathy Checklist-Revised (PCL-R) among a large sample of trained raters (N = 280). All raters completed PCL-R training at some point between 1989 and 2012 and subsequently provided complete coding for the same 6 practice cases. Overall, 3 major conclusions can be drawn from the results: (a) reliability of individual PCL-R items largely fell below any appropriate standards while the estimates for Total PCL-R scores and factor scores were good (but not excellent); (b) the cases representing individuals with high psychopathy scores showed better reliability than did the cases of individuals in the moderate to low PCL-R score range; and (c) there was a high degree of variability among raters; however, rater specific differences had no consistent effect on scoring the PCL-R. Therefore, despite low reliability estimates for individual items, Total scores and factor scores can be reliably scored among trained raters. We temper these conclusions by noting that scoring standardized videotaped case studies does not allow the rater to interact directly with the offender. Real-world PCL-R assessments typically involve a face to-face interview and much more extensive collateral information. We offer recommendations for new web-based training procedures. (PsycINFO Database Record PMID- 28594219 TI - The MacArthur Competence Assessment Tool-Criminal Adjudication: Factor structure, interrater reliability, and association with clinician opinion of competence in a forensic inpatient sample. AB - Adjudicative competence is the most frequently referred evaluation in the forensic context, and it is because of this that periodic evaluation of competence assessment instruments is imperative. Among those instruments, the MacArthur Competence Assessment Tool-Criminal Adjudication (MacCAT-CA) has demonstrated adequate psychometric properties suggesting its utility in informing the forensic inquiry. The purpose of the current study was to further investigate the psychometric properties and ultimate utility of subscale scores using archival data from a sample of 103 male and female forensic patients who were hospitalized for competence restoration treatment. Results of the present study suggested adequate internal consistency and good model fit for the factor structure. Interrater reliability was evaluated by comparing the absolute agreement of scores derived from 2 independent research assistants for each of the subscales; 2 of the 3 subscales fell within the acceptable range given established interpretative benchmarks for forensic assessment. Of particular interest was that the Appreciation subscale, while heralding the lowest intraclass correlation coefficient, explained the largest proportion of variance in clinician opinion relative to the other 2 subscales. In other words, the most subjective subscale (as evidenced by the lowest intraclass correlation), explained the largest proportion of variance in ultimate opinion. The authors argue that, although these results are an important consideration in these assessments, they are neither surprising nor entirely problematic when considering the case-specific nature of the inquiries on the subscale, as well as the subjectivity of scoring criteria for each of the Appreciation items. (PsycINFO Database Record PMID- 28594220 TI - Field reliability influences field validity: Risk assessments of individuals found not guilty by reason of insanity. AB - Individuals acquitted as not guilty by reason of insanity (NGRI) are usually committed to psychiatric hospitals for treatment until they are considered suitable for conditional release back to the community. The clinical evaluations that inform conditional release decisions have rarely been studied but provide an ideal opportunity to examine the reliability and validity of complex evaluations in the field. For example, to what extent do forensic evaluators agree about an acquittee's readiness for conditional release? And how accurate are their opinions? We reviewed 175 evaluation reports across 62 cases from Hawaii, which requires 3 separate evaluations from independent clinicians for each felony NGRI acquittee referred for conditional release evaluation. Evaluators agreed about an NGRI acquittee's readiness for conditional release in only 53.2% of evaluations (kappa = .35). Courts followed the majority evaluator opinion in 79.3% of all cases but ruled in an opposite direction from the majority evaluator opinion in more than a third of cases in which evaluators disagreed. Evaluators accurately differentiated those conditionally released acquittees who remained in the community from those who were rehospitalized in 62.4% of cases. Among the 43 insanity acquittees who were ultimately released, evaluator agreement was significantly associated with rehospitalization within 3 years. When the evaluators unanimously agreed that conditional release was appropriate, only 34.5% were rehospitalized. When the evaluators disagreed, 71.4% were rehospitalized. Overall, results reveal poor agreement among independent evaluators in routine practice but suggest that opinions may be more accurate when evaluators agree than when they disagree. (PsycINFO Database Record PMID- 28594221 TI - Field reliability of competency and sanity opinions: A systematic review and meta analysis. AB - We know surprisingly little about the interrater reliability of forensic psychological opinions, even though courts and other authorities have long called for known error rates for scientific procedures admitted as courtroom testimony. This is particularly true for opinions produced during routine practice in the field, even for some of the most common types of forensic evaluations-evaluations of adjudicative competency and legal sanity. To address this gap, we used meta analytic procedures and study space methodology to systematically review studies that examined the interrater reliability-particularly the field reliability-of competency and sanity opinions. Of 59 identified studies, 9 addressed the field reliability of competency opinions and 8 addressed the field reliability of sanity opinions. These studies presented a wide range of reliability estimates; pairwise percentage agreements ranged from 57% to 100% and kappas ranged from .28 to 1.0. Meta-analytic combinations of reliability estimates obtained by independent evaluators returned estimates of kappa = .49 (95% CI: .40-.58) for competency opinions and kappa = .41 (95% CI: .29-.53) for sanity opinions. This wide range of reliability estimates underscores the extent to which different evaluation contexts tend to produce different reliability rates. Unfortunately, our study space analysis illustrates that available field reliability studies typically provide little information about contextual variables crucial to understanding their findings. Given these concerns, we offer suggestions for improving research on the field reliability of competency and sanity opinions, as well as suggestions for improving reliability rates themselves. (PsycINFO Database Record PMID- 28594222 TI - Can credibility criteria be assessed reliably? A meta-analysis of criteria-based content analysis. AB - This meta-analysis synthesizes research on interrater reliability of Criteria Based Content Analysis (CBCA). CBCA is an important component of Statement Validity Assessment (SVA), a forensic procedure used in many countries to evaluate whether statements (e.g., of sexual abuse) are based on experienced or fabricated events. CBCA contains 19 verbal content criteria, which are frequently adapted for research on detecting deception. A total of k = 82 hypothesis tests revealed acceptable interrater reliabilities for most CBCA criteria, as measured with various indices (except Cohen's kappa). However, results were largely heterogeneous, necessitating moderator analyses. Blocking analyses and meta regression analyses on Pearson's r resulted in significant moderators for research paradigm, intensity of rater training, type of rating scale used, and the frequency of occurrence (base rates) for some CBCA criteria. The use of CBCA summary scores is discouraged. Implications for research vs. field settings, for future research and for forensic practice in the United States and Europe are discussed. (PsycINFO Database Record PMID- 28594223 TI - Bayesian hypothesis testing: Editorial to the Special Issue on Bayesian data analysis. AB - In the past 20 years, there has been a steadily increasing attention and demand for Bayesian data analysis across multiple scientific disciplines, including psychology. Bayesian methods and the related Markov chain Monte Carlo sampling techniques offered renewed ways of handling old and challenging new problems that may be difficult or impossible to handle using classical approaches. Yet, such opportunities and potential improvements have not been sufficiently explored and investigated. This is 1 of 2 special issues in Psychological Methods dedicated to the topic of Bayesian data analysis, with an emphasis on Bayesian hypothesis testing, model comparison, and general guidelines for applications in psychology. In this editorial, we provide an overview of the use of Bayesian methods in psychological research and a brief history of the Bayes factor and the posterior predictive p value. Translational abstracts that summarize the articles in this issue in very clear and understandable terms are included in the Appendix. (PsycINFO Database Record PMID- 28594224 TI - A systematic review of Bayesian articles in psychology: The last 25 years. AB - Although the statistical tools most often used by researchers in the field of psychology over the last 25 years are based on frequentist statistics, it is often claimed that the alternative Bayesian approach to statistics is gaining in popularity. In the current article, we investigated this claim by performing the very first systematic review of Bayesian psychological articles published between 1990 and 2015 (n = 1,579). We aim to provide a thorough presentation of the role Bayesian statistics plays in psychology. This historical assessment allows us to identify trends and see how Bayesian methods have been integrated into psychological research in the context of different statistical frameworks (e.g., hypothesis testing, cognitive models, IRT, SEM, etc.). We also describe take-home messages and provide "big-picture" recommendations to the field as Bayesian statistics becomes more popular. Our review indicated that Bayesian statistics is used in a variety of contexts across subfields of psychology and related disciplines. There are many different reasons why one might choose to use Bayes (e.g., the use of priors, estimating otherwise intractable models, modeling uncertainty, etc.). We found in this review that the use of Bayes has increased and broadened in the sense that this methodology can be used in a flexible manner to tackle many different forms of questions. We hope this presentation opens the door for a larger discussion regarding the current state of Bayesian statistics, as well as future trends. (PsycINFO Database Record PMID- 28594225 TI - Bayesian evaluation of constrained hypotheses on variances of multiple independent groups. AB - Research has shown that independent groups often differ not only in their means, but also in their variances. Comparing and testing variances is therefore of crucial importance to understand the effect of a grouping variable on an outcome variable. Researchers may have specific expectations concerning the relations between the variances of multiple groups. Such expectations can be translated into hypotheses with inequality and/or equality constraints on the group variances. Currently, however, no methods are available for testing (in)equality constrained hypotheses on variances. This article proposes a novel Bayesian approach to this challenging testing problem. Our approach has the following useful properties: First, it can be used to simultaneously test multiple (non)nested hypotheses with equality as well as inequality constraints on the variances. Second, our approach is fully automatic in the sense that no subjective prior specification is needed. Only the hypotheses need to be provided. Third, a user-friendly software application is included that can be used to perform this Bayesian test in an easy manner. (PsycINFO Database Record PMID- 28594226 TI - Bayesian analyses of cognitive architecture. AB - The question of cognitive architecture-how cognitive processes are temporally organized-has arisen in many areas of psychology. This question has proved difficult to answer, with many proposed solutions turning out to be spurious. Systems factorial technology (Townsend & Nozawa, 1995) provided the first rigorous empirical and analytical method of identifying cognitive architecture, using the survivor interaction contrast (SIC) to determine when people are using multiple sources of information in parallel or in series. Although the SIC is based on rigorous nonparametric mathematical modeling of response time distributions, for many years inference about cognitive architecture has relied solely on visual assessment. Houpt and Townsend (2012) recently introduced null hypothesis significance tests, and here we develop both parametric and nonparametric (encompassing prior) Bayesian inference. We show that the Bayesian approaches can have considerable advantages. (PsycINFO Database Record PMID- 28594227 TI - Decision qualities of Bayes factor and p value-based hypothesis testing. AB - The purpose of this article is to investigate the decision qualities of the Bayes factor (BF) method compared with the p value-based null hypothesis significance testing (NHST). The performance of the 2 methods is assessed in terms of the false- and true-positive rates, as well as the false-discovery rates and the posterior probabilities of the null hypothesis for 2 different models: an independent-samples t test and an analysis of variance (ANOVA) model with 2 random factors. Our simulation study results showed the following: (a) The common BF > 3 criterion is more conservative than the NHST alpha = .05 criterion, and it corresponds better with the alpha = .01 criterion. (b) An increasing sample size has a different effect on the false-positive rate and the false-discovery rate, depending on whether the BF or NHST approach is used. (c) When effect sizes are randomly sampled from the prior, power curves tend to be flat compared with when effect sizes are prespecified. (d) The larger the scale factor (or the wider the prior), the more conservative the inferential decision is. (e) The false-positive and true-positive rates of the BF method are very sensitive to the scale factor when the effect size is small. (f) While the posterior probabilities of the null hypothesis ideally follow from the BF value, they can be surprisingly high using NHST. In general, these findings were consistent independent of which of the 2 different models was used. (PsycINFO Database Record PMID- 28594229 TI - Posterior calibration of posterior predictive p values. AB - In order to accurately control the Type I error rate (typically .05), a p value should be uniformly distributed under the null model. The posterior predictive p value (ppp), which is commonly used in Bayesian data analysis, generally does not satisfy this property. For example there have been reports where the sampling distribution of the ppp under the null model was highly concentrated around .50. In this case, a ppp of .20 would indicate model misfit, but when comparing it with a significance level of .05, which is standard statistical practice, the null model would not be rejected. Therefore, the ppp has very little power to detect model misfit. A solution has been proposed in the literature, which involves calibrating the ppp using the prior distribution of the parameters under the null model. A disadvantage of this "prior-cppp" is that it is very sensitive to the prior of the model parameters. In this article, an alternative solution is proposed where the ppp is calibrated using the posterior under the null model. This "posterior-cppp" (a) can be used when prior information is absent, (b) allows one to test any type of misfit by choosing an appropriate discrepancy measure, and (c) has a uniform distribution under the null model. The methodology is applied in various testing problems: testing independence of dichotomous variables, checking misfit of linear regression models in the presence of outliers, and assessing misfit in latent class analysis. (PsycINFO Database Record PMID- 28594228 TI - A comparison of Bayesian and frequentist model selection methods for factor analysis models. AB - We compare the performances of well-known frequentist model fit indices (MFIs) and several Bayesian model selection criteria (MCC) as tools for cross-loading selection in factor analysis under low to moderate sample sizes, cross-loading sizes, and possible violations of distributional assumptions. The Bayesian criteria considered include the Bayes factor (BF), Bayesian Information Criterion (BIC), Deviance Information Criterion (DIC), a Bayesian leave-one-out with Pareto smoothed importance sampling (LOO-PSIS), and a Bayesian variable selection method using the spike-and-slab prior (SSP; Lu, Chow, & Loken, 2016). Simulation results indicate that of the Bayesian measures considered, the BF and the BIC showed the best balance between true positive rates and false positive rates, followed closely by the SSP. The LOO-PSIS and the DIC showed the highest true positive rates among all the measures considered, but with elevated false positive rates. In comparison, likelihood ratio tests (LRTs) are still the preferred frequentist model comparison tool, except for their higher false positive detection rates compared to the BF, BIC and SSP under violations of distributional assumptions. The root mean squared error of approximation (RMSEA) and the Tucker-Lewis index (TLI) at the conventional cut-off of approximate fit impose much more stringent "penalties" on model complexity under conditions with low cross-loading size, low sample size, and high model complexity compared with the LRTs and all other Bayesian MCC. Nevertheless, they provided a reasonable alternative to the LRTs in cases where the models cannot be readily constructed as nested within each other. (PsycINFO Database Record PMID- 28594230 TI - Conserved HIV-1 Gag p24 Epitopes Elicit Cellular Immune Responses That Impact Disease Outcome. AB - Although the breadth of the human immunodeficiency virus type 1 (HIV-1)-specific cellular immune response and its impact on the control of viral replication have already been addressed, reported data have proven controversial. We hypothesize that the nature of targeted epitopes, rather than the simple breadth or magnitude of responses, correlates with disease outcome. In this study, we explore the occurrence of patterns of Gag p24 recognition among untreated HIV-1-infected patients by identifying the epitopes that compose such patterns and how they distinctly associate with disease progression. Utilizing enzyme-linked immunospot (ELISPOT) interferon gamma (IFN-gamma), we screened cellular responses of 27 HIV 1-infected subjects against 15-mer peptides encompassing the whole Gag p24 protein. Obtained data were used to develop a clustering analysis that allowed definition of two groups of individuals with totally distinct patterns of recognition. Although targeted Gag p24 peptides were completely different between the two groups, the breadth and magnitude of the responses were not. Interestingly, viral control and preservation of CD4+ T cells were increased in one group. In addition, we compared genetic conservation of amino acid sequences of the recognized peptides, as well as of the human leucocyte antigen class I (HLA-I)-restricted epitopes within them. Subjects presenting higher control of HIV-1 replication targeted more conserved epitopes, and higher genetic variation was present mainly in anchor residues for HLA-I molecules. We strengthen the existing evidence from cases of HIV-1 infection in humans that, cellular immune responses targeting conserved epitopes, rather than the magnitude and breadth of responses, associate with a better control of viral replication and maintenance of peripheral CD4+ T cell counts. PMID- 28594231 TI - Comparison of the effects of three surgical techniques on the rate of orthodontic tooth movement in a rat model. AB - OBJECTIVE: To evaluate the effect of corticotomy and corticision, with and without a full mucoperiosteal flap, on the rate of tooth movement and alveolar response in a rat model. MATERIALS AND METHODS: Sixty male, 6-week-old Wistar rats were divided into five groups based on surgical procedure, as follows: control (no tooth movement), orthodontic tooth movement (OTM) only, corticotomy, corticision, and corticision with full mucoperiosteal flap (corticision + flap). A force of 10-15g was applied from the maxillary left first molar to the maxillary incisors using nickel-titanium springs. Surgery was performed at the time of appliance placement (day 0), and tooth movement occurred for 21 days. Micro-computed tomography was performed on day 21 to evaluate the amount of tooth movement and alveolar bone parameters. Histomorphometry, including tartrate resistant acid phosphatase staining, was performed to quantify the osteoclast parameters at day 21. RESULTS: No statistical differences in the amount of OTM, bone volume fraction, and tissue density and the osteoclast parameters were found among all experimental groups. CONCLUSIONS: Corticotomy and corticision, with or without a full mucoperiosteal flap, did not show a significant effect on either the OTM magnitude or alveolar bone response. PMID- 28594232 TI - Revisiting the AIDS Epidemic in Pakistan: Where We Stand and What We Must Aim For. AB - Human immunodeficiency virus type 1 (HIV-1) is the major cause of acquired immunodeficiency syndrome (AIDS) in humans, where the immune system totally succumbs to the virus. A large proportion of the AIDS infected belong to developing countries and AIDS prevalence is intensified by severe poverty, malnutrition, and famine; fatal illnesses with a scorn shortage of medical amenities complemented with the lack of education and development. Current Pakistani health system setting is in a dire need of improvement. Low literacy rates, high birth rates, and associated maternal mortality plus a lack of clean drinking water and appropriate sanitation system have a serious impact on general living conditions contributing to a relatively short lifespan. HIV is, therefore, becoming a growing health concern in Pakistan with a rapid rise in the reported cases. AIDS is most prevalent among injection drug users (IDUs), male/female sex workers, and unchecked deported migrant workforce. To combat this virus, the Pakistan Government has been working hard over the past few years with local bodies and international organizations in an effort to combat this menace. This review aims to discuss the risk factors for the rise of this epidemic in the country and the recommendations, efforts to be done to address this alarming issue. PMID- 28594233 TI - Own and partners' dyadic coping and depressive symptoms in individuals with early stage dementia and their caregiving partners. AB - OBJECTIVES: In patients with early-stage dementia and their caregiving partners, reciprocal dyadic coping (DC) is crucial for preventing or reducing depressive symptoms in both partners. This study examines the relationships between 'own DC' and 'perceived partner DC' with depressive symptoms in couples coping with dementia on individual (actor effects) and cross-person (partner effects) levels. METHOD: 164 individuals (82 patients with early-stage dementia and their 82 caregiving partners; ND = 82 dyads) participated in this prospective study with measures (DC, depressive symptoms, and dementia severity) taken at baseline and at six months. Each partner evaluated their own and the perceived partner DC. Actor-partner interdependence models were applied to the resulting four independent evaluations. RESULTS: Results differed substantially between patients and caregivers. DC was significantly related to patients' but not to caregivers' depressive symptoms, when adjustments were made for individual coping. Perceived partner DC showed a negative association with depressive symptoms in patients, whereas own DC was adversely related for actor as well as for partner effects across individuals. CONCLUSION: The adverse association between the own DC of the caregiver and the patient on depressive symptoms of the patient might be due to inappropriate efforts or to the loss of autonomy as a care-receiver. DC is important in both patients and caregivers, as shown by the negative association between perceived partner DC and depressive symptoms in the patients, which might inform interventions that target the couple as a whole. PMID- 28594236 TI - The blood of my veins - mercury, Minamata and the soul of Japan. AB - The methylmercury contamination of Minamata Bay during the WWII postwar period resulted in thousands of Japanese citizens suffering horrific neurological injury. Fear and miscommunication destroyed and changed family and social structure. In addition, the Minamata poisoning caused momentous changes in the civic discourse in Japan and was an instrumental event in the democratization of the country. This manuscript describes the effects that the environmental contamination and human poising had in the transition of Japan from a feudal society to a democratic one. PMID- 28594235 TI - Live-attenuated auxotrophic mutant of Salmonella Typhimurium expressing immunogenic HA1 protein enhances immunity and protective efficacy against H1N1 influenza virus infection. AB - AIM: To evaluate the efficacy of attenuated Salmonella Typhimurium (JOL912) as a live bacterial vaccine vector. MATERIALS & METHODS: The JOL912 engineered to deliver HA1 protein from influenza A/Puerto Rico/8/1934 (H1N1; PR8) virus was coined as JOL1635 and further evaluated for immunogenicity and protective efficacy. RESULTS: The JOL1635 stably harbored the HA1 gene within pMMP65 plasmid with periplasmic expression and effective delivery of HA1 protein to RAW264.7 cells. The JOL1635 immunized chickens showed the significant increase in HA1 specific IgG, sIgA antibody, IFN-gamma, IL-6 cytokine and cellular immune responses. The postoral challenge, the JOL1635-immunized chickens showed a faster clearance of PR8 virus cloacal shedding than the control group. CONCLUSION: Generated JOL1635 can establish specific immunogenicity and protection against the PR8 virus in chickens. PMID- 28594237 TI - Description of general practitioners' practices when suspecting cognitive impairment. Recourse to care in dementia (Recaredem) study. AB - OBJECTIVE: General practitioners (GPs) play a major role in the assessment of dementia but it is still unrecognized in primary care and its management is heterogeneous. Our objective is to describe the usual practices, and their determinants, of French GPs in this field. METHODS: GPs' characteristics and practices when facing cognitive decline were collected through a telephone interview and a postal questionnaire. A descriptive analysis of all study variables was conducted. The study of quantitative explanatory variables was done by testing the equality of means and the choice of qualitative variables was based on the chi-square independence test or Fischer test. RESULTS: Hundred two GPs completed the study. GPs were in majority men, working in urban areas. Mean age was 54.4 years old. GPs' feeling of confidence and self-perception of follow up of national recommendations is linked with their practices. Performing a clinical interview to assess cognitive impairment is linked with good communication skills. GPs feel less confident to give information about resources for dementia. The main reason alleged for underdiagnosis is the limited effectiveness of drug therapy. CONCLUSIONS: This study underlines the importance of GPs' feeling of confidence when managing cognitively impaired patients with dementia, and the need of increasing training in the field of dementia, which could improve the awareness of GPs about diagnosis and available resources. PMID- 28594234 TI - Peroxiredoxins and Redox Signaling in Plants. AB - SIGNIFICANCE: Peroxiredoxins (Prxs) are thiol peroxidases with multiple functions in the antioxidant defense and redox signaling network of the cell. Our progressing understanding assigns both local and global significance to plant Prxs, which are grouped in four Prx types. In plants they are localized to the cytosol, mitochondrion, plastid, and nucleus. Antioxidant defense is fundamentally connected to redox signaling, cellular communication, and acclimation. The thiol-disulfide network is central part of the stress sensing and processing response and integrates information input with redox regulation. Recent Advances: Prxs function both as redox sensory system within the network and redox-dependent interactors. The processes directly or indirectly targeted by Prxs include gene expression, post-transcriptional reactions, including translation, post-translational regulation, and switching or tuning of metabolic pathways, and other cell activities. The most advanced knowledge is available for the chloroplast 2-CysPrx wherein recently a solid interactome has been defined. An in silico analysis of protein structure and coexpression reinforces new insights into the 2-CysPrx functionality. CRITICAL ISSUES: Up to now, Prxs often have been investigated for local properties of enzyme activity. In vitro and ex vivo work with mutants will reveal the ability of Prxs to interfere with multiple cellular components, including crosstalk with Ca2+-linked signaling pathways, hormone signaling, and protein homeostasis. FUTURE DIRECTIONS: Complementation of the Prxs knockout lines with variants that mimic specific states, namely devoid of peroxidase activity, lacking the oligomerization ability, resembling the hyperoxidized decamer, or with truncated C-terminus, should allow dissecting the roles as thiol peroxidase, oxidant, interaction partner, and chaperone. Antioxid. Redox Signal. 28, 609-624. PMID- 28594238 TI - On the selection of stimulus for the auditory variant of the detection response task method for driving experiments. AB - OBJECTIVES: The detection response task (DRT) is a method for measuring attentional effects of secondary tasks on a driver's cognitive load by measuring response times and hit rates to different types of stimuli as indirect indicators of increased cognitive load. ISO 17488 (International Organization for Standardization 2016) only provides guidelines for the technical implementation and measurement methods for the visual and tactile versions (use of visual and tactile stimuli) of the DRT method. This article presents a study with the goal of finding the most appropriate auditory stimulus for the implementation of an auditory version of the DRT method. METHODS: This article presents the results of an experiment in which responses to 7 different auditory DRT stimuli-varying in frequency-were compared while inducing users' cognitive load with a modified n back task. The experiment was conducted in a surrogate driving environment and in a within-subject design. Response times, hit rates, and secondary task performances were observed as indicators of increased cognitive load. RESULTS: Significantly shorter response times were found for the white noise signal compared to single-frequency signals. However, the largest differences in response times, for trials without and with a cognitive task, were found for 4- and 8-kHz single-frequency signals. No significant differences were found for hit rates and secondary task performances between the different stimuli. CONCLUSIONS: Consistent significant differences in response times for all tested stimuli prove that the auditory DRT variant is also sensitive to changes in cognitive load. The mean increase in response times of more than 25% for 4- and 8-kHz signals for trials with a cognitive task compared to trials without one indicates that one of these signals could be used as a potential auditory stimulus for the auditory DRT variant. PMID- 28594239 TI - Accidental copper sulfate toxicity after flame colorant ingestion. PMID- 28594240 TI - Dimethylarginine Dimethylaminohydrolase 1 Deficiency Induces the Epithelial to Mesenchymal Transition in Renal Proximal Tubular Epithelial Cells and Exacerbates Kidney Damage in Aged and Diabetic Mice. AB - AIMS: Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Emerging evidence suggests that plasma ADMA accumulation and DDAH1 activity/expression reduction are linked to chronic kidney disease (CKD) pathology, but the mechanisms remain largely unknown. Here, we examined the role of ADMA/DDAH1 in the epithelial-mesenchymal transition (EMT) of tubular epithelial cells (TECs), an important mechanism for the pathogenesis of renal fibrosis. RESULTS: In HK-2 cells, DDAH1 expression was reduced by aldosterone treatment, and overexpression of DDAH1 significantly attenuated aldosterone induced EMT. More interestingly, DDAH1 deficiency resulted in EMT-related changes in primary TECs via increasing oxidative stress, impairing adenosine monophosphate-activated kinase (AMPK) signaling, and downregulating of peroxiredoxin 5 (Prdx5). However, those effects could not be mimicked by increasing the ADMA concentration. After regular feeding for 24 months or inducing type 2 diabetes, Ddah1-/- mice had higher serum creatinine levels than wild-type (WT) mice. In the kidneys of the aged or diabetic mice, loss of DDAH1 resulted in more interstitial fibrosis, more collagen deposition, and greater induction of EMT-related changes and oxidative stress than in the WT kidneys. Innovation and Conclusion: Our results provide the first direct evidence that the DDAH1 has a marked effect on kidney fibrosis and oxidative stress induced by aging or diabetes. Our findings suggest that strategies to increase DDAH1 activity in TECs may provide a novel approach to attenuate CKD development. Antioxid. Redox Signal. 27, 1347-1360. PMID- 28594241 TI - Hepatotoxicity evaluation of traditional Chinese medicines using a computational molecular model. AB - BACKGROUND: Liver injury caused by traditional Chinese medicines (TCMs) is reported from many countries around the world. TCM hepatotoxicity has attracted worldwide concerns. OBJECTIVE: This study aims to develop a more applicable and optimal tool to evaluate TCM hepatotoxicity. METHODS: A quantitative structure activity relationship (QSAR) analysis was performed based on published data and U.S. Food and Drug Administration's Liver Toxicity Knowledge Base (LTKB). RESULTS: Eleven herbal ingredients with proven liver toxicity in the literature were added into the dataset besides chemicals from LTKB. The finally generated QSAR model yielded a sensitivity of 83.8%, a specificity of 70.1%, and an accuracy of 80.2%. Among the externally tested 20 ingredients from TCMs, 14 hepatotoxic ingredients were all accurately identified by the QSAR model derived from the dataset containing natural hepatotoxins. CONCLUSIONS: Adding natural hepatotoxins into the dataset makes the QSAR model more applicable for TCM hepatotoxicity assessment, which provides a right direction in the methodology study for TCM safety evaluation. The generated QSAR model has the practical value to prioritize the hepatotoxicity risk of TCM compounds. Furthermore, an open access international specialized database on TCM hepatotoxicity should be quickly established. PMID- 28594242 TI - Attitudes and Perceptions of Cancer Patients Toward Biospecimen Donation for Cancer Research: A Cross-Sectional Survey Among Chinese Cancer Patients. AB - BACKGROUND: High-quality biospecimen collection from consented patients is crucial for cancer research activities. Patients' attitudes and willingness toward specimen donation influence high-quality biospecimen collection for cancer research activities. METHODS: We carried out a cross-sectional study among randomly selected patients from 11 cancer departments of Tianjin Medical University Cancer Institute and Hospital between August 2014 and August 2015. A total of 784 patients were included to complete a 30-item self-administered survey. We evaluated the patients' willingness to consider providing leftover samples and additional samples for cancer research purposes. RESULTS: Among 784 patients, 683 (87.1%) and 653 (83.3%) were willing to donate leftover tissue and surplus blood after diagnosis, respectively. Six hundred thirty-one (80.5%) were favorably disposed to consider donating both tissue and blood samples for future cancer research. Female patients showed less willingness to donate biospecimens or related clinical data for research. First-hospitalized or older patients were less willing to provide leftover biospecimens or additional blood samples or even clinical data for research. By contrast, patients with a higher education level were more likely to donate leftover tissues after biopsy or surgery for research activities. CONCLUSIONS: Most Chinese cancer patients were willing to consider donating blood and tissue samples for cancer research. Several factors, including age, gender, first hospitalization, and education level, can influence their willingness to donate biospecimens. We need to provide proper education to increase understanding of patients in biobanking activities. IMPACT: This study provides novel empirical data on the likelihood of donating surplus and additional biospecimens and clinical health information among Chinese cancer patients. PMID- 28594243 TI - Supplement. PMID- 28594244 TI - Acute cholinergic syndrome in a patient with mild Alzheimer's type dementia who had applied a large number of rivastigmine transdermal patches on her body. AB - CASE PRESENTATION: A 91-year-old woman was transferred to our Emergency Medical Center and Poison Center with somnolence, hypertension (186/61 mm Hg), and repeated vomiting. Three hours later, 10 transdermal patches, each containing 18 mg of rivastigmine (9.5 mg/24 h), were found on her lower back and both thighs, when miosis, facial and trunk sweating, enhanced bowel sound, hypertension, and sinus tachycardia were noted. She was diagnosed with acute cholinergic syndrome due to rivastigmine poisoning. Her hypertension and sinus tachycardia peaked 8 and 5 h after all the patches were removed, respectively. Her symptoms subsided spontaneously after 17 h. DISCUSSION: In the present case, our patient was presented with acute cholinergic syndrome due to carbamate intoxication after massive transdermal exposure to rivastigmine. Toxicological analysis revealed a remarkably high estimated serum rivastigmine concentration (150.6 ng/ml) and notably low serum butyrylcholinesterase activity (35 IU/l) on admission, with a markedly prolonged calculated elimination half-life of 6.5 h. CONCLUSIONS: Emergency physicians should consider acetylcholinesterase inhibitor exposure (e.g., rivastigmine) when patients are present with acute cholinergic syndrome. PMID- 28594245 TI - Chronotype correlates with developmental index, intelligence and academic achievement: A study based on nationwide indicators. AB - Chronotype or morningness-eveningness (M/E) is an individual trait with a biological basis. In this study, I analysed the relationship between M/E and nationwide available data, such as economic variables, school achievement, intelligence and conscientiousness, which is a personality trait. These variables have been chosen because, first, they are linked on the individual level with circadian preference, and, second these associations have been found based on meta-analyses, which gives these findings a high plausibility. In addition, economic status has also been proposed to be related to M/E. Higher developed countries showed a lower morningness, based on both, the ranking of countries as well as on the HDI value. Similarly, GNI was related to morningness, while higher intelligence and performance in PISA were related to eveningness. Conscientiousness was related to morningness, although the results failed the significance level marginally. When using IQ as a control variable in partial correlations, the relationship between GNI and morningness disappeared, as did the correlation between eveningness and PISA results. PMID- 28594246 TI - A review of vilazodone exposures with focus on serotonin syndrome effects. AB - BACKGROUND: Vilazodone is an antidepressant with selective serotonin reuptake inhibition and partial 5HT1A agonism. Serotonin syndrome is believed to be due to excessive stimulation of 5-HT2A and 5-HT1A receptors, resulting in the clinical triad of altered mentation, autonomic instability and neuromuscular abnormalities. The goal of this study is to define serotonergic effects after vilazodone exposure. METHODS: A retrospective review of two databases: the American Association of Poison Controls Centers' National Poison Data System (NPDS) and the American College of Medical Toxicology's Toxicology Investigators Consortium (ToxIC Registry). A case series of four patients from one medical toxicology service is also presented. RESULTS: During the 52-month study period, a total of 3192 vilazodone human exposures were reported to NPDS. Of these, 1734 (54%) were isolated vilazodone cases. The clinical effects of vilazodone toxicity included drowsiness (20%), vomiting (14%), tachycardia (11%) and agitation (10%). Most patients (71%) had symptoms for between 2 and 24 h, though some (14%) remained symptomatic for more than 24 h. The most common treatment was intravenous fluids (15%) and the most serious intubation (2%). From the ToxIC Registry, a total of 23 cases of vilazodone exposures were identified. Of these, 17 (74%) had vilazodone listed as the first (primary) agent and 10 (43%) involved vilazodone-only ingestions. Nine (39%) cases documented serotonin syndrome; and most (8/9; 89%) listed vilazodone as the primary agent. All (n = 4) subjects in the case series with acute vilazodone toxicity had serotonin syndrome. CONCLUSIONS: Vilazodone overdose, including vilazodone-only ingestions, are associated with serotonin syndrome. Serotonergic toxicity and appropriate treatments should be considered when caring for patients with vilazodone ingestions. PMID- 28594247 TI - Differences in the kinematics of booster-seated pediatric occupants using two different car seats. AB - OBJECTIVE: The objective of this article is to compare the performance of forward facing child restraint systems (CRS) mounted on 2 different seats. METHODS: Two different anthropomorphic test device (ATD) sizes (P3 and P6), using the same child restraint system (a non-ISOFIX high-back booster seat), were exposed to the ECE R44 regulatory deceleration pulse in a deceleration sled. Two different seats (seat A, seat B) were used. Three repetitions per ATD and mounting seat were done, resulting in a total of 12 sled crashes. Dummy sensors measured the head tri-axial acceleration and angular rate and the thorax tri-axial acceleration, all acquired at 10,000 Hz. A high-speed video camera recorded the impact at 1,000 frames per second. The 3D kinematics of the head and torso of the ATDs were captured using a high-speed motion capture system (1,000 Hz). A pair-matched statistical analysis compared the outcomes of the tests using the 2 different seats. RESULTS: Statistically significant differences in the kinematic response of the ATDs associated with the type of seat were observed. The maximum 3 ms peak of the resultant head acceleration was higher on seat A for the P3 dummy (54.5 +/ 1.9 g vs. 44.2 +/- 0.5 g; P =.012) and for the P6 dummy (56.0 +/- 0.8 g vs. 51.7 +/- 1.2 g; P =.015). The peak belt force was higher on seat A than on seat B for the P3 dummy (5,488.0 +/- 198.0 N vs. 4,160.6 +/- 63.6 N; P =.008) and for the P6 dummy (7,014.0 +/- 271.0 N vs. 5,719.3 +/- 37.4 N; P =.015). The trajectory of the ATD head was different between the 2 seats in the sagittal, transverse, and frontal planes. CONCLUSION: The results suggest that the overall response of the booster-seated occupant exposed to the same impact conditions was different depending on the seat used regardless of the size of the ATD. The differences observed in the response of the occupants between the 2 seats can be attributed to the differences in cushion stiffness, seat pan geometry, and belt geometry. However, these results were obtained for 2 particular seat models and a specific CRS and therefore cannot be directly extrapolated to the generality of vehicle seats and CRS. PMID- 28594248 TI - Advanced phases and reduced amplitudes are suggested to characterize the daily rest-activity cycles in depressed adolescent boys. AB - Self-reported eveningness has been previously associated with depressed mood among adults and adolescents. Here, we study how circadian indicators based on actigraphic data differ between depressed and healthy adolescent boys. Our sample consisted of 17 medication-free adolescent boys, aged 14.5 to 17.5 years, of which eight had depressive disorder and were currently depressed and nine were healthy comparison participants. Psychiatric assessment was conducted by diagnostic interviews and complemented with observer-rating and self-rating scales. Actigraphic data were collected with wrist actigraphs for a minimum period of 25 consecutive days (range of 25 to 44 days). The behavioral trait of morningness-eveningness was measured with the 19-item Horne-Ostberg Morningness Eveningness Questionnaire. Based on the self-report, the depressed boys were more prone to eveningness than healthy controls, but based on the actigraphic data, they had earlier phases especially on school days and lower activity levels especially on weekends. On weekends, the depressed boys showed a greater shift toward later-timed phases than healthy controls. Our results confirm a mismatch of the subjective morningness-eveningness preference (late-preference) and the objective rest-activity rhythm (early-prone) during school days in depressed adolescent boys. PMID- 28594249 TI - A pilot randomized trial of school-based administration of inhaled corticosteroids for at-risk children with asthma. AB - OBJECTIVE: To investigate whether high adherence to inhaled corticosteroids (ICS) among disadvantaged urban public school children on public insurance with persistent asthma is achievable by having school nurses administer morning doses on each day that school is in session. DESIGN/METHODS: This was a pilot prospective randomized clinical trial of home versus school nurse-administered ICS among children on Medicaid enrolled in grades K-8. The primary outcome was the proportion of expected morning doses of ICS given to the intervention group in school over the 60-day treatment period. Secondary outcomes included the relative proportions of expected doses (morning, evening, and total), asthma related morbidity, quality of life, and health-care utilization. RESULTS: A total of 46 patients were enrolled (mean age 8.21 +/- 2.45; 56.5% male; 91.3% non Hispanic, African-Americans), and follow-up data were available for 44/46 (95.7%) patients. The groups did not differ in age, gender, race/ethnicity, or asthma severity. The intervention group received 91.7% of expected morning doses of ICS at school over the 60-day treatment period (95% CI [87.7, 95.5]). Intervention patients reported significantly less functional limitation (42.9% vs. 73.9%, p = 0.04), adjustment to family life (23.8% vs. 56.5%, p = 0.03), and sleep loss (1.7 vs. 4.1 nights in last 2 weeks, p = 0.035) than control patients at the end of the 60-days study period. There were no differences in unscheduled health-care utilization by group. CONCLUSIONS: These pilot data suggest that school-based administration of ICS has the potential to achieve high adherence to morning doses of ICS on school days among urban, disadvantaged, and largely minority children with asthma. PMID- 28594251 TI - Timely-regulated intron retention as device to fine-tune protein expression. PMID- 28594250 TI - Relationship between blood toxin level and clinical features in patients with grayanotoxin poisoning - six clinical cases. AB - BACKGROUND: The purpose of this study was to investigate grayanotoxin (GTX) levels in the blood of patients with GTX intoxication and in the consumed Rhododendron liqueur, and to determine whether there was an association between blood GTX level and the patient's clinical status. METHODS: In September 2015, six patients were concurrently presented to the emergency department with various toxicity symptoms, which occurred after the consumption of Rhododendron liqueur at the same toxin concentration. Liquid chromatography-tandem mass spectrometry analysis was conducted on blood samples obtained from six cases of GTX intoxication treated in our emergency department. RESULTS: At the initial evaluation in the emergency department, the mean arterial pressure of the patients ranged from 36.7 to 76.7 mm Hg. The concentrations of GTX-I and GTX-III in Rhododendron liqueur were 1.436 and 16.907 ng/mL, respectively. The initial blood GTX-III and GTX-I levels ranged from 2.9 to 58.0 ng/mL and the lower limit of quantification (LLOQ) to 8.33 ng/mL, respectively. After 20 h, the mean arterial pressure ranged from 76.7 to 93.3 mm Hg, while the blood GTX-III and GTX I levels ranged from the LLOQ to 17.8 and 2.52 ng/mL, respectively. DISCUSSION: We estimated that the minimum blood GTX-III and GTX-I levels that caused hypotension were between 17.83 and 27.3 ng/mL, and 2.52 and 4.55 ng/mL, respectively. PMID- 28594252 TI - Not all TNF inhibitors in rheumatoid arthritis are created equal: important clinical differences. AB - INTRODUCTION: Anti-TNF therapy has dramatically changed how we manage rheumatoid arthritis. There are many similarities among the five approved agents but also some important differences. Rheumatologists have 5 different options to choose from when they are ready to commence anti-TNF therapy. Although all block the TNF cytokine, there are important critical differences among them that affect their safety profile and clinical utility in certain scenarios. Unfortunately, there are no head to head trials to compare the different anti-TNF agents and none appear to be in the horizon. Areas covered: This article reviews the various clinical situations where it may be important to use a particular anti-TNF agent. The authors also give their expert opinion and future perspectives on the area. Expert opinion: Although there are many similarities among the five different TNFi that are clinically available, there are important clinical niches, where the limited data that are available, that clearly support the preferential use of a particular agent or class of agents. Assays or tests that allow us to find the 'sweet spot' of TNF inhibition at the level of each patient are long overdue. PMID- 28594253 TI - Neuropsychological functioning following cardiac transplant in Danon disease. AB - PURPOSE: To present a unique case involving a 31-year-old male with Danon disease (diagnosed at 14) who received cardiac transplant and subsequent cardiac re transplant. RESEARCH DESIGN: Brief report/case study. METHODS: Serial neuropsychological assessment across a 23-year span along with a review of school records and prior psychoeducational assessment. RESULTS: A consistent pattern of higher level cognitive impairment from childhood through adulthood was found. This pattern is interpreted in light of the sparse literature regarding cognitive and adaptive functioning related to Danon disease. CONCLUSIONS: The noteworthy aspects of this case include the preservation of some academic abilities and an unexpected level of functional independence given cognitive concerns. This case study further explores the nature of the deficits related to Danon disease and highlights the benefits of neuropsychological evaluation to guide functional interventions and maximize level of independence across the life span. PMID- 28594254 TI - Predictive factors of success in neurofeedback training for children with ADHD. AB - INTRODUCTION: Neurofeedback (NF) training aims the enhancement of self-regulation over brain activities. While it is largely recognized as an effective treatment for attention deficit hyperactivity disorder (ADHD), the existence of non learners has also been reported. The present study explored pre-training assessment indices that could predict learners prior to NF training. METHODS: Twenty-two children with ADHD participated in slow cortical potential (SCP) NF training and completed pre- and post-training assessments. Participants were classified into learners or non-learners based on their progress in the SCP regulation, and pre-training indices that differentiate the two groups were examined by decision tree analysis. RESULTS AND DISCUSSION: The learner rate in NF training was 45.5%. Learners were predicted by pre-training cognitive and neurophysiological measures regarding Stroop tasks, which suggested relatively intact executive function as their characteristics. Given that NF training is not universally effective for children with ADHD, further studies are necessary to establish application criteria. PMID- 28594255 TI - The human mitochondrial Hsp60 in the APO conformation forms a stable tetradecameric complex. AB - The human mitochondrial chaperonin is a macromolecular machine that catalyzes the proper folding of mitochondrial proteins and is of vital importance to all cells. This chaperonin is composed of 2 distinct proteins, Hsp60 and Hsp10, that assemble into large oligomeric complexes that mediate the folding of non-native polypeptides in an ATP dependent manner. Here, we report the bacterial expression and purification of fully assembled human Hsp60 and Hsp10 recombinant proteins and that Hsp60 forms a stable tetradecameric double-ring conformation in the absence of co-chaperonin and nucleotide. Evidence of the stable double-ring conformation is illustrated by the 15 A resolution electron microscopy reconstruction presented here. Furthermore, our biochemical analyses reveal that the presence of a non-native substrate initiates ATP-hydrolysis within the Hsp60/10 chaperonin to commence protein folding. Collectively, these data provide insight into the architecture of the intermediates used by the human mitochondrial chaperonin along its protein folding pathway and lay a foundation for subsequent high resolution structural investigations into the conformational changes of the mitochondrial chaperonin. PMID- 28594256 TI - Nitidine chloride inhibited the expression of S phase kinase-associated protein 2 in ovarian cancer cells. AB - Nitidine chloride (NC) has been reported to exert its anti-tumor activity in various types of human cancers. However, the molecular mechanism of NC-mediated tumor suppressive function is largely unclear. In the current study, we used several approaches such as MTT, FACS, RT-PCR, Western blotting analysis, invasion assay, transfection, to explore the molecular basis of NC-triggered anti-cancer activity. We found that NC inhibited cell growth, induced cell apoptosis, caused cell cycle arrest in ovarian cancer cells. Emerging evidence has demonstrated that Skp2 plays an important oncogenic role in ovarian cancer. Therefore, we also explored whether NC exerts its biologic function via downregulation of Skp2 in ovarian cancer cells. We observed that NC significantly inhibited the expression of Skp2 in ovarian cancer cells. Notably, overexpression of Skp2 abrogated the anti-cancer activity induced by NC in ovarian cancer cells. Consistently, downregulation of Skp2 expression enhanced the sensitivity of ovarian cancer cells to NC treatment. Thus, inactivation of Skp2 by NC could be a novel strategy for the treatment of human ovarian cancer. PMID- 28594257 TI - MRI Evaluation of an Elastic TPU Mesh under Pneumoperitoneum in IPOM Position in a Porcine Model. AB - BACKGROUND: The frequency of laparoscopic approaches increased in hernia surgery over the past years. After mesh placement in IPOM position, the real extent of the meshes configurational changes after termination of pneumoperitoneum is still largely unknown. To prevent a later mesh folding it might be useful to place the mesh while it is kept under tension. Conventionally used meshes may lose their Effective Porosity under these conditions due to poor elastic properties. The aim of this study was to evaluate a newly developed elastic thermoplastic polyurethane (TPU) containing mesh that retains its Effective Porosity under mechanical strain in IPOM position in a porcine model. It was visualized under pneumoperitoneum using MRI in comparison to polyvinylidenefluoride (PVDF) meshes with similar structure. METHODS: In each of ten minipigs, a mesh (TPU containing or native PVDF, 10 * 20 cm) was randomly placed in IPOM position at the center of the abdominal wall. After 8 weeks, six pigs underwent MRI evaluation with and without pneumoperitoneum to assess the visibility and elasticity of the mesh. Finally, pigs were euthanized and abdominal walls were explanted for histological and immunohistochemical assessment. The degree of adhesion formation was documented. RESULTS: Laparoscopic implantation of elastic TPU meshes in IPOM position was feasible and safe in a minipig model. Mesh position could be precisely visualized and assessed with and without pneumoperitoneum using MRI after 8 weeks. Elastic TPU meshes showed a significantly higher surface increase under pneumoperitoneum in comparison to PVDF. Immunohistochemically, the amount of CD45-positive cells was significantly lower and the Collagen I/III ratio was significantly higher in TPU meshes after 8 weeks. There were no differences regarding adhesion formation between study groups. CONCLUSIONS: The TPU mesh preserves its elastic properties in IPOM position in a porcine model after 8 weeks. Immunohistochemistry indicates superior biocompatibility regarding CD45 positive cells and Collagen I/III ratio in comparison to PVDF meshes with a similar structure. PMID- 28594258 TI - First-line chemotherapy with pemetrexed plus cisplatin for malignant peritoneal mesothelioma. AB - BACKGROUND: Mesothelioma of peritoneal origin has wider variation in treatment outcomes than mesothelioma of pleural origin, likely because peritoneal mesothelioma comprises borderline malignant variants and aggressive malignant peritoneal mesothelioma (MPeM). This study retrospectively evaluates the efficacy of first-line systemic pemetrexed and cisplatin chemotherapy in MPeM. RESEARCH DESIGN AND METHODS: Twenty-four patients with histologically proven MPeM were treated with pemetrexed plus cisplatin as a first-line systemic chemotherapy. The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Twenty-two patients underwent 18F fluorodeoxyglucose positron emission tomography/(FDG-PET)/computed tomography(CT) at baseline, and 13 were eligible for metabolic assessment. RESULTS: Two complete responses and 9 partial responses were achieved. Overall response rate and disease control rate were 45.8% and 91.7%, respectively. Median progression-free survival and median overall survival were 11.0 months and 15.8 months, respectively. Wet- type MPeM had significantly longer survival (40.9 months median) than other clinical types (15.5 months) (P = 0.045). The baseline maximum standardized uptake value in 22 patients was 8.93 (range, 2.5-16.77). CONCLUSIONS: Systemic pemetrexed plus cisplatin is active for MPeM. Disparity with the outcome of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50%. PMID- 28594259 TI - Targeting CDK4/6 to oppose hypoxia-mediated therapeutic resistance. PMID- 28594260 TI - Thermoresponsive nanocomposite gel for local drug delivery to suppress the growth of glioma by inducing autophagy. AB - Although the treatments of malignant glioma include surgery, radiotherapy and chemotherapy by oral drug administration, the prognosis of patients with glioma remains very poor. We developed a polyethylene glycol-dipalmitoylphosphatidyle- thanoiamine (mPEG-DPPE) calcium phosphate nanoparticles (NPs) injectable thermoresponsive hydrogel (nanocomposite gel) that could provide a sustained and local delivery of paclitaxel (PTX) and temozolomide (TMZ). In addition, the proportion of PTX and TMZ for the optimal synergistic antiglioma effect on C6 cells was determined to be 1:100 (w/w) by the Chou and Talalay method. Our results clearly indicated that the autophagy induced by PTX:TMZ NPs plays an important role in regulating tumor cell death, while autophagy inhibition dramatically reverses the antitumor effect of PTX:TMZ NPs, suggesting that antiproliferative autophagy occurs in response to PTX:TMZ NPs treatment. The antitumor efficacy of the PTX:TMZ NP-loaded gel was evaluated in situ using C6 tumor-bearing rats, and the PTX:TMZ NP-loaded gel exhibited superior antitumor performance. The antitumor effects of the nanocomposite gel in vivo were shown to correlate with autophagic cell death in this study. The in vivo results further confirmed the advantages of such a strategy. The present study may provide evidence supporting the development of nanomedicine for potential clinical application. PMID- 28594261 TI - Hemodynamic studies of platelet thrombosis using microfluidics. AB - Platelets contribute to thrombus formation in a variety of ways. Platelet adhesion, activation, and thrombus growth depend greatly on the type of hemodynamic environment surrounding an inciting event. Microfluidic systems may be used to explore these relationships. In this review, we describe some important considerations required in the design of a microfluidic system and identify some limitations that may require use of a macroscale system. PMID- 28594262 TI - An analysis of gene expression data involving examination of signaling pathways activation reveals new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia. AB - Androgenetic alopecia is the most common form of hair loss. Minoxidil has been approved for the treatment of hair loss, however its mechanism of action is still not fully clarified. In this study, we aimed to elucidate the effects of 5% minoxidil topical foam on gene expression and activation of signaling pathways in vertex and frontal scalp of men with androgenetic alopecia. We identified regional variations in gene expression and perturbed signaling pathways using in silico Pathway Activation Network Decomposition Analysis (iPANDA) before and after treatment with minoxidil. Vertex and frontal scalp of patients showed a generally similar response to minoxidil. Both scalp regions showed upregulation of genes that encode keratin associated proteins and downregulation of ILK, Akt, and MAPK signaling pathways after minoxidil treatment. Our results provide new insights into the mechanism of action of minoxidil topical foam in men with androgenetic alopecia. PMID- 28594264 TI - Treatment response and tolerability with once-monthly paliperidone palmitate initiated shortly after hospital admission in patients with schizophrenia. AB - OBJECTIVES: Partial or non-adherence in patients with schizophrenia is common and increases the risk of relapse. This study explored safety, tolerability and treatment outcomes in patients hospitalised for an exacerbation of schizophrenia initiated on maintenance treatment of once-monthly paliperidone palmitate (PP1M). METHODS: A 6-week, observational cohort study of patients initiated on PP1M within 3 weeks after hospital admission. RESULTS: Overall, 367 patients were documented, 85.8% with paranoid schizophrenia subtype. Mean time from hospital admission to PP1M initiation was 9.4 +/- 7.7 days. Treatment-emergent adverse events were reported by 22.9% of patients. From baseline to endpoint, significant improvements were observed in psychotic symptoms (Brief Psychiatric Rating Scale total score mean change -19.3 +/- 12.6, P < .0001) and functioning (Personal and Social Performance scale total score mean change 14.3 +/- 12.4, P < .0001). Overall, 6.0% of patients were very or extremely satisfied with their prior antipsychotic medication at baseline compared with 47.2% very or extremely satisfied with PP1M treatment at endpoint. CONCLUSIONS: Initiating PP1M in patients with exacerbated schizophrenia shortly after hospital admission was well tolerated and resulted in statistically significant and clinically relevant improvements in symptoms and patient functioning, suggesting that patients may benefit from early initiation of PP1M during their hospital stay. PMID- 28594265 TI - beta cell self-renewal: Cyclin D2 to the rescue. PMID- 28594263 TI - Phototrophy and starvation-based induction of autophagy upon removal of Gcn5 catalyzed acetylation of Atg7 in Magnaporthe oryzae. AB - Magnaporthe oryzae, the ascomycete fungus that causes rice blast disease, initiates conidiation in response to light when grown on Prune-Agar medium containing both carbon and nitrogen sources. Macroautophagy/autophagy was shown to be essential for M. oryzae conidiation and induced specifically upon exposure to light but is undetectable in the dark. Therefore, it is inferred that autophagy is naturally induced by light, rather than by starvation during M. oryzae conidiation. However, the signaling pathway(s) involved in such phototropic induction of autophagy remains unknown. We identified an M. oryzae ortholog of GCN5 (MGG_03677), encoding a histone acetyltransferase (HAT) that negatively regulates light- and nitrogen-starvation-induced autophagy, by acetylating the autophagy protein Atg7. Furthermore, we unveiled novel regulatory mechanisms on Gcn5 at both transcriptional and post-translational levels, governing its function associated with the unique phototropic response of autophagy in this pathogenic fungus. Thus, our study depicts a signaling network and regulatory mechanism underlying the autophagy induction by important environmental clues such as light and nutrients. PMID- 28594266 TI - Simple fluorescence-based detection of protein kinase A activity using a molecular beacon probe. AB - Protein kinase A was detected by quantifying the amount of ATP used after a protein kinase reaction. The ATP assay was performed using the T4 DNA ligase and a molecular beacon (MB). In the presence of ATP, DNA ligase catalyzed the ligation of short DNA. The ligation product then hybridized to MB, resulting in a fluorescence enhancement of the MB. This assay was capable of determining protein kinase A in the range of 12.5~150 nM, with a detection limit of 1.25 nM. Furthermore, this assay could also be used to investigate the effect of genistein on protein kinase A. It was a universal, non-radioisotopic, and homogeneous method for assaying protein kinase A. PMID- 28594267 TI - A plant pathogenic bacterium exploits the tricarboxylic acid cycle metabolic pathway of its insect vector. AB - Huanglongbing in citrus is caused by a phloem-limited, uncultivable, gram negative alpha-proteobacterium, Candidatus Liberibacter asiaticus (CLas). CLas is transmitted by the phloem-sucking insect, Diaphorina citri (Hemiptera: Liviidae), in a persistent, circulative, and propagative manner. In this study, we investigated the metabolomic and respiration rates changes in D. citri upon infection with CLas using gas chromatography-mass spectrometry (GC-MS) and gas exchange analysis. The level of glycine, L-serine, L-threonine, and gamma-amino butyric acid were higher in CLas-infected D. citri, while L-proline, L-aspartic acid, and L-pyroglutamic acid were lower in CLas-infected D. citri compared with the control. Citric acid was increased in CLas-infected D. citri, whereas malic and succinic acids were reduced. Interestingly, most of the reduced metabolites such as malate, succinate, aspartate, and L-proline are required for the growth of CLas. The increase in citric acid, serine, and glycine indicated that CLas induced glycolysis and the tricarboxylic acid cycle (TCA) in its vector. In agreement with the GC-MS results, the gene expression results also indicated that glycolysis and TCA were induced in CLas-infected D. citri and this was accompanied with an increases in respiration rate. Phosphoric acid and most of the sugar alcohols were higher in CLas-infected D. citri, indicating a response to the biotic stress or cell damage. Only slight increases in the levels of few sugars were observed in CLas-infected D. citri, which indicated that sugars are tightly regulated by D. citri. Our results indicated that CLas induces nutrient and energetic stress in its host insect. This study may provide some insights into the mechanism of colonization of CLas in its vector. PMID- 28594268 TI - Simultaneous but spatially different regulation of non-photosynthetic callus formation and photosynthetic root development after shoot removal. AB - Plants coordinate plastid differentiation and cellular differentiation during tissue development. Recently, we reported a mechanism of chloroplast development and photosynthetic improvement in Arabidopsis roots after shoot removal. Shoot removal induces the expression of WOUND INDUCED DEDIFFERENTIATION (WIND) transcription factors at the wound site, which activates type-B ARABIDOPSIS RESPONSE REGULATOR (ARR)-mediated cytokinin signaling in roots. The type-B ARR signaling upregulates chloroplast-related transcription factors along with photosynthesis-associated genes, thereby inducing chloroplast development in detached roots. However, at the wound site, WINDs promote the development of non green callus cells in a type-B ARR-dependent manner. Thus, in shoot-removed roots, WIND-mediated cytokinin signaling has spatially distinct roles: it represses chloroplast development at the wound site while activating the development in adjacent regions. Because WINDs are strong inducers of cell dedifferentiation, spatial differences in their expression levels between the wound site and other areas may determine the fate of chloroplast development. PMID- 28594270 TI - Detection of text-based social cues in adults with traumatic brain injury. AB - OBJECTIVES: Written text contains verbal immediacy cues-word form or grammatical cues that indicate positive attitude or liking towards an object, action, or person. We asked if adults with moderate-severe traumatic brain injury (TBI) would respond to these cues, given evidence of TBI-related social communication impairments. METHODS: Sixty-nine adults with TBI and 74 healthy comparison (HC) peers read pairs of sentences containing different types of immediacy cues (e.g., speaker A said "these Canadians" vs. B said "those Canadians.") and identified which speaker (A or B) had a more positive attitude towards the underlined entity (Task 1); and pairs of sentences comprised of a context sentence (e.g., Fred is asked, "Did you visit Joan and Sue?") and a statement sentence (Fred says, "I visited Sue and Joan.") and were asked to indicate how much Fred liked or disliked the underlined words (Task 2). RESULTS: HC group scores were significantly higher on Task 1, indicating more sensitivity to cues. On Task 2, TBI and HC group ratings differed across cue types and immediacy types, and the TBI group appeared to have less sensitivity to these cues. CONCLUSIONS: Findings suggest that TBI-related impairments may reduce sensitivity to subtle social cues in text. PMID- 28594271 TI - Treatment of Cyclosporin A retains host defense against invasive pulmonary aspergillosis in a non-immunosuppressive murine model by preserving the myeloid cell population. AB - Cyclosporin A (CsA) is widely used as an immunosuppressive agent for organ transplant recipients. CsA inhibits calcineurin, which is highly conserved in mammals and fungi, and thus affects both types of organism. In mammals, the immunosuppressive effect of CsA is via hampering T cell activation. In fungi, the growth inhibitory effect of CsA is via interference with hyphal growth. The aim of this study was to determine whether CsA renders mice susceptible to invasive pulmonary aspergillosis (IPA) and whether it can protect immunosuppressed mice from infection. We therefore examined both the antifungal and the immunosuppressive activity of CsA in immunosuppressed and in immunocompetent mice infected with Aspergillus fumigatus to model IPA. We found that daily injections of CsA could not produce an antifungal effect sufficient to rescue immunosuppressed mice from lethal IPA. However, a 100% survival rate was obtained in non-immunosuppressed mice receiving daily CsA, indicating that CsA did not render the mice vulnerable to IPA. The lymphocyte subset was significantly suppressed by CsA, while the myeloid subset was not. Therefore, we speculate that CsA does not impair the host defense against IPA since the myeloid cells are preserved. PMID- 28594272 TI - The future is now: the impact of present fluency in judgments about the future. AB - Recent research has emphasised the role of episodic memory in both remembering past events and in envisaging future events. On the other hand, it has been repeatedly shown that judgments about past events are affected by the fluency with which retrieval cues are processed. In this paper we investigate whether perceptual fluency also plays a role in judgments about future events. For this purpose we conducted four experiments. The first experiment replicated recent findings showing that stimuli that are processed fluently tend to be wrongly recognised as having been encountered in the past outside the laboratory walls [Brown, A. S., & Marsh, E. J. (2009). Creating illusions of past encounter through brief exposure. Psychological Science, 20, 534-538. doi: 10.1111/j.1467 9280.2009.02337.x ]. Two follow-up experiments using Brown and Marsh's [(2009). Creating illusions of past encounter through brief exposure. Psychological Science, 20, 534-538. doi: 10.1111/j.1467-9280.2009.02337 ] task tested the influence of perceptual fluency on future judgments. The fourth and last experiment was designed to rule out a potential confounding factor in the two previous experiments. Across experiments, we found that people rely on fluency when making judgments about events that are yet to come. These results suggest that fluency is an equally valid cue for past and future judgments. PMID- 28594273 TI - Effect of TPA and HTLV-1 Tax on BRCA1 and ERE controlled genes expression. AB - Interference with the expression and/or functions of the multifunctional tumor suppressor BRCA1 leads to a high risk of breast and ovarian cancers. BRCA1 expression is usually activated by the estrogen (E2) liganded ERalpha receptor. Activated ERalpha is considered as a potent transcription factor which activates various genes expression by 2 pathways. A classical pathway, ERalpha binds directly to E2-responsive elements (EREs) in the promoters of the responsive genes and a non-classical pathway where ERalpha indirectly binds with the appropriate gene promoter. In our previous study, HTLV-1Tax was found to strongly inhibit ERalpha induced BRCA1 expression while stimulating ERalpha induced ERE dependent genes. TPA is a strong PKC activator which found to induce the expression of HTLV-1. Here we examined the effect of TPA on the expression of BRCA1 and genes controlled by ERE region in MCF-7 cells and on Tax activity on these genes. Our results showed strong stimulatory effect of TPA on both BRCA1 and ERE expression without treatment with E2. Tax did not show any significant effect on these TPA activities. It seems that TPA activation of BRCA1 and ERE expression is dependent on PKC activity but not through the NFkappaB pathway. However, 53BP1 may be involved in this TPA activity because its overexpression significantly reduced the TPA stimulatory effect on BRCA1 and ERE expression. Additionally, our Chip assay results probably exclude possible involvement of ERalpha pathway in this TPA activity because TPA did not interfere with the binding of ERalpha to both BRCA1 promoter and ERE region. PMID- 28594274 TI - Wall ingrowth deposition in phloem parenchyma transfer cells in Arabidopsis: Heteroblastic variations and a potential role in pathogen defence. AB - Transfer cell (TCs) develop unique wall ingrowth networks which amplify plasma membrane surface area and thus maximize nutrient transporter density at key anatomic sites for nutrient exchange within plants and their external environment. These sites fall into 4 main groups corresponding to 4 categories of trans-membrane flux: absorption/secretion of solutes from or to the external environment, and absorption/secretion of solutes from or to internal, extra cytoplasmic compartments. Research on TC biology over recent decades has demonstrated correlations between wall ingrowth deposition in TCs and enhanced transport capacity in many major agricultural species such as pea, fava bean, cotton and maize. Consequently, there is general consensus that the existence of wall ingrowth morphology implies an augmentation in membrane transport capacity. However, this may not be entirely applicable for phloem parenchyma (PP) TCs in Arabidopsis. Our recent survey of PP TC abundance and distribution in Arabidopsis veins indicated that PP TC development reflects heteroblastic status. A consequence of this observation is the suggestion that PP TCs, or at least wall ingrowth deposition in these cells, potentially act as a physical barrier to defend access of invading pathogens to sugar-rich sieve elements rather than solely in facilitating the export of photoassimilate from collection phloem in leaves. PMID- 28594276 TI - Pharmacological factors affecting accumulation of gemcitabine's active metabolite, gemcitabine triphosphate. AB - Gemcitabine is an anticancer agent acting against several solid tumors. It requires nucleoside transporters for cellular uptake and deoxycytidine kinase for activation into active gemcitabine-triphosphate, which is incorporated into the DNA and RNA. However, it can also be deaminated in the plasma. The intracellular level of gemcitabine-triphosphate is affected by scheduling or by combination with other chemotherapeutic regimens. Moreover, higher concentrations of gemcitabine-triphosphate may affect the toxicity, and possibly the clinical efficacy. As a consequence, different nucleoside analogs have been synthetized with the aim to increase the concentration of gemcitabine-triphosphate into cells. In this review, we summarize currently published evidence on pharmacological factors affecting the intracellular level of gemcitabine triphosphate to guide future trials on the use of new nucleoside analogs. PMID- 28594275 TI - Roles of superoxide anion and hydrogen peroxide during replication of two unrelated plant RNA viruses in Nicotiana benthamiana. AB - Reactive oxygen species (ROS), including superoxide anion (O2-), hydrogen peroxide (H2O2), and hydroxyl radical, act as signaling molecules to transduce biotic and abiotic stimuli into stress adaptations in plants. A respiratory burst oxidase homolog B of Nicotiana benthamiana (NbRBOHB) is responsible for O2- production to inhibit pathogen infection during plant innate immunity. RBOH derived O2- can be immediately converted into H2O2 by the action of superoxide dismutase. Interestingly, we recently showed that red clover necrotic mosaic virus (RCNMV), a plant positive-strand RNA [(+)RNA] virus, hijacks the host's ROS generating machinery during infection. An RCNMV replication protein associates with NbRBOHB and triggers intracellular ROS bursts. These bursts are required for robust viral RNA replication. However, what types of ROS are required for viral replication is currently unknown. Here, we found that RCNMV replication was sensitive to an O2- scavenger but insensitive to an H2O2 scavenger. Interestingly, replication of another plant (+)RNA virus, brome mosaic virus, was sensitive to both types of scavengers. These results indicate a virus-specific pattern requirement of O2- and H2O2 for (+)RNA virus replication and suggest a conserved nature of the roles of ROS in (+)RNA virus replication. PMID- 28594277 TI - Metabolomics analysis of rice responses to salinity stress revealed elevation of serotonin, and gentisic acid levels in leaves of tolerant varieties. AB - A GC-MS based analytical approach was undertaken to understand the metabolomic responses of seedlings of 2 salt sensitive (Sujala and MTU 7029) and 2 tolerant varieties (Bhutnath, and Nonabokra) of indica rice (Oryza sativa L.) to NaCl induced stress. The 4 varieties responded differently to NaCl treatment with respect to the conserved primary metabolites (sugars, polyols, amino acids, organic acids and certain purine derivatives) of the leaf of rice seedlings. However, there were significant differences in salt induced production of chorismic acid derivatives. Serotonin level was increased in both the salt tolerant varieties in response to NaCl induced stress. In both the salt tolerant varieties, increased production of the signaling molecule gentisic acid in response to NaCl treatment was noticed. Salt tolerant varieties also produced increased level of ferulic acid and vanillic acid. In the salt sensitive varieties, cinnamic acid derivatives, 4-hydroxycinnamic acid (in Sujala) and 4 hydroxybenzoic acid (in MTU 7029), were elevated in the leaves. So increased production of the 2 signaling molecules serotonin and gentisic acid may be considered as 2 important biomarker compounds produced in tolerant varieties contributing toward NaCl tolerance. PMID- 28594278 TI - Clinical and educational impact of pharmacogenomics testing: a case series from the INGENIOUS trial. AB - Pharmacogenomic testing has become increasingly widespread. However, there remains a need to bridge the gap between test results and providers lacking the expertise required to interpret these results. The Indiana Genomics Implementation trial is underway at our institution to examine total healthcare cost and patient outcomes after genotyping in a safety-net healthcare system. As part of the study, trial investigators and clinical pharmacology fellows interpret genotype results, review patient histories and medication lists and evaluate potential drug-drug interactions. We present a case series of patients in whom pharmacogenomic consultations aided providers in appropriately applying pharmacogenomic results within the clinical context. Formal consultations not only provide valuable patient care information but educational opportunities for the fellows to cement pharmacogenomic concepts. PMID- 28594279 TI - Single Nucleotide Polymorphisms in 5' Upstream Region of Bovine TLR4 Gene Affecting Expression Profile and Transcription Factor Binding Sites. AB - The present study in the 5' upstream region of TLR4 gene revealed four Single Nucleotide Polymorphisms (SNPs) in Vrindavani and Tharparkar cattle. The polymorphic information content (PIC), heterozygosity and allelic diversity values were low to moderate for these SNPs. In Vrindavani cattle, one SNP was found to be in Hardy-Weinberg Equilibrium (HWE) and the remaining three were found to be in linkage disequilibrium (LD) as indicated statistically (P > 0.05). In Tharparkar cattle, two SNPs were found to be in HWE and were not in LD as indicated statistically (P > 0.05). These SNPs were used for construction of haplotypes. In-silico analysis of these SNPs predicted abolition of eight transcription factor binding sites and creation of eight new sites. The quantitative real time PCR analysis did not show any significant variation of gene expression among haplotypes. However, gene expression between breed was found to be significant (P < 0.05) which suggested that upstream region of bovine TLR4 gene has a crucial role in its expression. These findings in TLR4 gene offer essential evidence that can be useful in future research exploring its role in immunity. TLR4 can be used as a marker for selection for disease resistance in bovines. PMID- 28594280 TI - Rapid and reliable screening of HLA-B*15:02 in four Chinese populations using single-tube multiplex real-time PCR assay. AB - AIM: HLA-B*15:02 screening should be performed to prevent antiepileptic drug induced severe cutaneous adverse reactions in populations of Asian origin. This study aimed to develop fast and reliable HLA-B*15:02 genotyping method and to investigate the distribution of HLA-B*15:02 in different Chinese ethnicities. MATERIALS & METHODS: A single-tube multiplex real-time PCR assay for HLA-B*15:02 genotyping was established by combining allele-specific primers with TaqMan probes. RESULTS: The HLA-B*15:02 genotyping results in Bouyei (n = 100) by the established assay were completely consistent with the corresponding PCR sequence based typing findings. The percentage of HLA-B*15:02 carrier in Bouyei (19%; n = 100) was significantly higher than those of Han (1%; n = 100), Tibetan (0%; n = 100) and Uyghur (0%; n = 50) populations (p < 0.001). CONCLUSION: The novel method provides rapid, reliable and cost-effective detection of HLA-B*15:02 allele in clinical applications. PMID- 28594281 TI - Are You Smiling, or Have I Seen You Before? Familiarity Makes Faces Look Happier. AB - It is clear that unreinforced repetition (familiarization) influences affective responses to social stimuli, but its effects on the perception of facial emotion are unknown. Reporting the results of two experiments, we show for the first time that repeated exposure enhances the perceived happiness of facial expressions. In Experiment 1, using a paradigm in which subjects' responses were orthogonal to happiness in order to avoid response biases, we found that faces of individuals who had previously been shown were deemed happier than novel faces. In Experiment 2, we replicated this effect with a rapid "happy or angry" categorization task. Using psychometric function fitting, we found that for subjects to classify a face as happy, they needed less actual happiness to be present in the face if the target was familiar than if it was novel. Critically, our results suggest that familiar faces appear happier than novel faces because familiarity selectively enhances the impact of positive stimulus features. PMID- 28594282 TI - Availability of CYP2D6 genotyping results in general practitioner and community pharmacy medical records. AB - AIM: To investigate the availability of CYP450-2D6 (CYP2D6) genotyping results in general practitioner (GP) and/or community pharmacy records, and the influence thereof on psychotropic CYP2D6 substrate dosing. MATERIALS & METHODS: Primary outcome was the percentage of patients genotyped for CYP2D6 with their genotype/phenotype registered in GP and/or pharmacy records. Secondary outcome was the number of defined daily doses of psychotropic CYP2D6 substrates prescribed after genotyping. RESULTS: For 216 out of 1307 eligible patients, medication overviews could be obtained. Genotyping results were available at GPs for 3.1% and at pharmacies for 5.9%. The average psychotropic CYP2D6 substrate dose was not different between any non-extensive metabolizer group and extensive metabolizer group (all p >= 0.486). CONCLUSION: Valuable information for individualizing psychiatric pharmacotherapy is lost on a large scale. PMID- 28594283 TI - A Common Eurasian Fish Tapeworm, Caryophyllaeides fennica (Cestoda), in Western North America: Further Evidence of 'Amphi-Pacific' Vicariance in Freshwater Fish Parasites. AB - The freshwater fish faunas of the Palaearctic and Nearctic regions show similarities but also notable differences, resulting in diverse distributions of their parasites. Relatively few parasite species occur in both regions and fewer still have been examined using molecular data. We report a rare example of 'amphi Pacific' distribution, involving the common Palaearctic parasite, the caryophyllidean cestode Caryophyllaeides fennica (Schneider, 1902), in the chiselmouth Acrocheilus alutaceus Agassiz and Pickering, 1855, an endemic cyprinid in northwestern Nearctic, Oregon. Available information on nonnative fish species in Oregon suggests that the parasite is native to the area and not introduced. Molecular data (18S ribosomal [r]DNA, 28S rDNA, internal transcribed spacer 2, and cytochrome c oxidase subunit 1 gene) indicate very little genetic divergence between representatives from the Palaearctic and Nearctic, and possibly a relatively more recent colonization of the Nearctic region by this cestode via the Beringian land bridge. This is remarkable considering that Acrocheilus has reportedly been in Oregon since the Miocene. PMID- 28594284 TI - Evidence-based medicine and contemporary certification: Analysis of the American Board of Vascular Medicine endovascular board examination. AB - Since 2005, the American Board of Vascular Medicine (ABVM) endovascular examination has been used to certify vascular practitioners. Annual rigorous review has confirmed it is psychometrically valid and reliable. However, the evidence basis underlying the examination items has not been studied systematically. The aim of this study was to adjudicate class of recommendation (COR) and level of evidence (LOE) for the 2015 ABVM endovascular examination and establish an additional feedback mechanism for examination improvement based on contemporary evidence-based guidelines. We performed a pooled consensus process to classify each of the 110 items in the 2015 ABVM endovascular examination by COR and LOE as detailed in the current guideline statements. We added additional categories for items that were not eligible for assignment using traditional current evidence-based metrics: 'COR X', cannot be determined, not applicable, or simple recognition; and 'LOE X', cannot be determined or not applicable. COR classifications were assigned in the following proportion: Class I=15%, Class II=40%, Class III=3%, COR X=42%. LOE classifications were assigned in the following proportion: Level A=12%, Level B=34%, Level C=32%, LOE X=22%. Our analysis showed that nearly half of the 2015 ABVM endovascular examination items were supported by strong scientific evidence or fact-based knowledge. COR and LOE analysis yielded notably different results. Use of alternate classification schema may be powerful tools for improving certification exams in healthcare. PMID- 28594285 TI - Cognitive Event-Related Potentials during the Sub-Acute Phase of Severe Traumatic Brain Injury and Their Relationship to Outcome. AB - Predicting outcome in the early phase after severe traumatic brain injury (sTBI) is a major clinical challenge, particularly identifying patients with potential for good cognitive outcome. The current single-center prospective study aimed to explore presence and normalization of electroencephalography (EEG)-based event related potentials (ERPs) in the early phase followings TBI, and their relationship to functional and cognitive outcome 6 months post-injury. Fourteen adult patients (eight males) with sTBI were recruited from the neurointensive care unit (mean age = 38.2 years [standard deviation (SD) = 14.7]; mean lowest Glasgow Coma Scale (GCS) score within first 24 h = 5.4, SD = 1.87). EEG recordings were conducted biweekly at three time-points applying an ERP paradigm encompassing a passive condition involving hearing their own name randomly interspersed between an unfamiliar name (UN), and an active condition with instruction to count their own name. Functional and cognitive outcome 6 months post-injury was measured with Glasgow Outcome Scale-Extended (GOSE) and neuropsychological tests of attention and memory. Ten patients demonstrated a significantly enhanced cognitive P3 in the active counting task compared with passive listening across recordings, and six presented with normalization of P3 in the counting task. Moreover, P3 amplitude to the counting task at the third time-point was positively correlated with both functional outcome (GOSE) and cognition (verbal learning, attentional set-shifting, and switching) 6 months post-injury. ERP can index cognitive capacities in the early phase following sTBI, and the cognitive P3 component in an active design is associated with functional and cognitive outcome, demonstrating that the cognitive P3 may yield valuable information of residual cognition and provide supplementary prognostic information. PMID- 28594286 TI - Peroxisomes as Modulators of Cellular Protein Thiol Oxidation: A New Model System. AB - AIMS: Peroxisomes are ubiquitous, single-membrane-bounded organelles that contain considerable amounts of enzymes involved in the production or breakdown of hydrogen peroxide (H2O2), a key signaling molecule in multiple biological processes and disease states. Despite this, the role of this organelle in cross compartmental H2O2 signaling remains largely unclear, mainly because of the difficulty to modulate peroxisomal H2O2 production in a selective manner. This study aimed at establishing and validating a cellular model suitable to decipher the complex signaling processes associated with peroxisomal H2O2 release. RESULTS: Here, we report the development of a human cell line that can be used to selectively generate H2O2 inside peroxisomes in a time- and dose-controlled manner. In addition, we provide evidence that peroxisome-derived H2O2 can oxidize redox-sensitive cysteine residues in multiple proteins within (e.g., peroxiredoxin-5 [PRDX5]) and outside (e.g., nuclear factor kappa B subunit 1 [NFKB1] and subunit RELA proto-oncogene [RELA], phosphatase and tensin homolog [PTEN], forkhead box O3 [FOXO3], and peroxin 5 [PEX5]) the peroxisomal compartment. Furthermore, we show that the extent of protein oxidation depends on the subcellular location of the target protein and is inversely correlated to catalase activity and cellular glutathione content. Finally, we demonstrate that excessive H2O2 production inside peroxisomes does not induce their selective degradation, at least not under the conditions examined. INNOVATION: This study describes for the first time a powerful model system that can be used to examine the role of peroxisome-derived H2O2 in redox-regulated (patho)physiological processes, a research area in need of further investigation and innovative approaches. CONCLUSION: Our results provide unambiguous evidence that peroxisomes can serve as regulatory hubs in thiol-based signaling networks. PMID- 28594287 TI - Electromyographic analyses of the erector spinae muscles during golf swings using four different clubs. AB - The purpose of this study was to compare the electromyography (EMG) patterns of the thoracic and lumbar regions of the erector spinae (ES) muscle during the golf swing whilst using four different golf clubs. Fifteen right-handed male golfers performed a total of twenty swings in random order using the driver, 4-iron, 7 iron and pitching-wedge. Surface EMG was recorded from the lead and trail sides of the thoracic and lumbar regions of the ES muscle (T8, L1 and L5 lateral to the spinous-process). Three-dimensional high-speed video analysis was used to identify the backswing, forward swing, acceleration, early and late follow through phases of the golf swing. No significant differences in muscle-activation levels from the lead and trail sides of the thoracic and lumbar regions of the ES muscle were displayed between the driver, 4-iron, 7-iron and pitching-wedge (P > 0.05). The highest mean thoracic and lumbar ES muscle-activation levels were displayed in the forward swing (67-99% MVC) and acceleration (83-106% MVC) phases of the swing for all clubs tested. The findings from this study show that there were no significant statistical differences between the driver, 4-iron, 7-iron and pitching-wedge when examining muscle activity from the thoracic and lumbar regions of the ES muscle. PMID- 28594288 TI - In Vitro Maturation of Human iPSC-Derived Neuroepithelial Cells Influences Transplant Survival in the Stroke-Injured Rat Brain. AB - Stem cell transplantation is a promising strategy for brain tissue regeneration; yet, despite some success, cell survival following transplantation remains low. In this study, we demonstrate that cell viability is enhanced by control over maturation of neuronal precursor cells, which are delivered in an injectable blend of hyaluronan and methylcellulose. We selected three subpopulations of human neuronal precursor cells derived from a cortically specified neuroepithelial stem cell (cNESC) population based on differences in expression of multipotent and neuron-specific proteins: early-, mid-, and late differentiated neurons. These cells were transplanted into an endothelin-1 stroke injured rat brain and their survival and fate were investigated 1 week later. Significantly, more cells were found in the brain after transplanting early- or mid- differentiated cNESCs compared to the late-differentiated population. The mid-differentiated population also had significantly more beta-III tubulin positive cells than either the early- or late-differentiated populations. These results suggest that maturity has a significant impact on cell survival following transplantation and cells with an intermediate maturity differentiate to neurons. PMID- 28594289 TI - Hypoxic Three-Dimensional Cellular Network Construction Replicates Ex Vivo the Phenotype of Primary Human Osteocytes. AB - Osteocytes are deeply embedded in the mineralized matrix of bone and are nonproliferative, making them a challenge to isolate and maintain using traditional in vitro culture methods without sacrificing their inimitable phenotype. We studied the synergistic effects of two microenvironmental factors that are vital in retaining, ex vivo, the phenotype of primary human osteocytes: hypoxia and three-dimensional (3D) cellular network. To recapitulate the lacunocanalicular structure of bone tissue, we assembled and cultured primary human osteocytic cells with biphasic calcium phosphate microbeads in a microfluidic perfusion culture device. The 3D cellular network was constructed by the following: (1) the inhibited proliferation of cells entrapped by microbeads, biomimetically resembling lacunae, and (2) the connection of neighboring cells by dendrites through the mineralized, canaliculi-like interstitial spaces between the microbeads. We found that hypoxia synergistically and remarkably upregulated the mature osteocytic gene expressions of the 3D-networked cells, SOST (encoding sclerostin) and FGF23 (encoding fibroblast growth factor 23), by several orders of magnitude in comparison to those observed from two-dimensional and normoxic culture controls. Intriguingly, hypoxia facilitated the self-assembly of a nonproliferating, osteoblastic monolayer on the surface of the 3D-networked cells, replicating the osteoblastic endosteal cell layer found at the interface between native bone and bone marrow tissues. Our ability to replicate, with hypoxia, the strong expressions of these mature osteocytic markers, SOST and FGF23, is important since these (1) could not be significantly produced in vitro and (2) are new important targets for treating bone diseases. Our findings are therefore expected to facilitate ex vivo studies of human bone diseases using primary human bone cells and enable high-throughput evaluation of potential bone targeting therapies with clinical relevance. PMID- 28594290 TI - Do rapid comprehensive urine drug screens change clinical management in children? AB - CONTEXT: Multiple studies have concluded that urine drug screens rarely change clinical management. The rapid comprehensive urine drug screen (RCUDS) at our institution detects over 300 substances using a combination of EIA and GC/MS and typically takes 2-5 h for completion. OBJECTIVE: We sought to determine whether this RCUDS altered management in the pediatric population. METHODS: All patients >1 month and <18 years of age in which a RCUDS was completed from 1 January 2012 to 31 December 2012 were eligible for the study. Assuming that clinical management would not be altered in at least 90% of cases with a confidence interval of 95%, an alpha error of 5%, we calculated a sample size of 122 cases to ensure adequate study power. Four board-certified medical toxicologists reviewed 160 cases. Cases were assigned to the toxicologists based on a random number generator. In addition, each toxicologist reviewed 12 random cases from the other three toxicologist's cases to determine inter-rater reliability. All four toxicologists reviewed any case in which a RCUDS was believed to have changed management. RESULTS: A total of 908 RCUDS were performed during the study period, and 160 were selected for study. Mean age was 10.5 years; male = 83, female = 77. Most were ordered from the ED (101/160 = 63%), followed by the inpatient unit (36/160 = 23%), outpatient (14/160 = 9%), and ICU (9/160 = 6%). 111/160 (69%) had a history of ingestion. Of the 160 randomly chosen cases, only three cases were found in which overall clinical management was altered based on the results of the RCUDS. All three cases were children <3 years old with a RCUDS positive for amfetamines. In all the three cases, police, Division of Family Services (DFS), and social work were involved. In no case did the acute clinical management change occurred due to the results of the RCUDS. CONCLUSIONS: The RCUDS rarely changed management in patients at our institution. Further study is warranted. PMID- 28594291 TI - Rickets in a 6-year-old girl resulting in extreme deformities. AB - Rickets remains endemic in low- and middle-income countries (LMIC) and has re emerged in high-income countries. Poverty, ignorance and poor healthcare in LMIC still contribute to development of the disease and, if untreated, its progression to severe forms. A 6-year-old girl from a poor background presented with malnutrition, anaemia, rachitic rosary and severe deformities of the upper and lower limbs owing to vitamin D deficiency. Although she responded well to treatment initially, some of the deformities required surgical intervention. Unfortunately, she was lost to follow-up. PMID- 28594292 TI - Men's perspectives on women's empowerment and intimate partner violence in rural Bangladesh. AB - Intimate partner violence (IPV) may increase as women in patriarchal societies become empowered, implicitly or explicitly challenging prevailing gender norms. Prior evidence suggests an inverse U-shaped relationship between women's empowerment and IPV, in which violence against women first increases and then decreases as more egalitarian gender norms gradually gain acceptance. By means of focus-group discussions and in-depth interviews with men in 10 Bangladeshi villages, this study explored men's evolving views of women, gender norms and the legitimacy of men's perpetration of IPV in the context of a gender transition. It examines men's often-contradictory narratives about women's empowerment and concomitant changes in norms of masculinity, and identifies aspects of women's empowerment that are most likely to provoke a male backlash. Findings suggest that men's growing acceptance of egalitarian gender norms and their self-reported decreased engagement in IPV are driven largely by pragmatic self-interest: their desire to improve their economic status and fear of negative consequences of IPV. PMID- 28594293 TI - The SHIVA01 trial: what have we learned? PMID- 28594294 TI - CeO2 nanoparticles alter the outcome of species interactions. AB - Despite considerable research on the environmental impacts of nanomaterials, we know little about how they influence interactions between species. Here, we investigated the acute (12 d) and chronic (64 d) toxicities of cerium oxide nanoparticles (CeO2 NPs) and bulk particles (0-200 mg/L) to three ciliated protist species (Loxocephalus sp., Paramecium aurelia, and Tetrahymena pyriformis) in single-, bi-, and multispecies microcosms. The results show that CeO2 NPs strongly affected the interactions between ciliated protozoan species. When exposed to the highest CeO2 NPs (200 mg/L), the intrinsic growth rates of Loxocephalus and Paramecium were significantly decreased by 18.87% and 88.27%, respectively, while their carrying capacities declined by more than 90%. However, CeO2 NP exposure made it difficult to predict outcomes of interspecific competition between species. At higher NP exposure (100 and 200 mg/L), competition led to the extinction of both species in the Loxocephalus and Paramecium microcosms that survived in the absence of competitors or CeO2 NPs. Further, the presence of potential competitors improved the survival of Loxocephalus to hundreds of individuals per milliliter in microcosms with Tetrahymena where Loxocephalus would otherwise not be able to tolerate high levels of NP exposure. This result could be attributed to weakened NP adsorption on the cell surface due to competitor-caused reduction of NP surface charge (from -18.52 to -25.17 mV) and intensified NP aggregation via phagocytosis of NPs by ciliate cells. Our results emphasize the need to explicitly consider species interactions for a more comprehensive understanding of the ecological consequences of NP exposure. PMID- 28594295 TI - Long-term outcomes of second-line antiretroviral treatment in an adult and adolescent cohort in Myanmar. AB - BACKGROUND: Myanmar has a high burden of Human Immunodeficiency Virus (HIV) and second-line antiretroviral treatment (ART) has been available since 2008 in the public health sector. However, there have been no published data about the outcomes of such patients until now. OBJECTIVE: To assess the treatment and programmatic outcomes and factors associated with unfavorable outcomes (treatment failure, death and loss to follow-up from care) among people living with HIV (aged >= 10 years) receiving protease inhibitor-based second-line ART under the Integrated HIV Care Program in Myanmar between October 2008 and June 2015. DESIGN: Retrospective cohort study using routinely collected program data. RESULTS: Of 824 adults and adolescents on second-line ART, 52 patients received viral load testing and 19 patients were diagnosed with virological failure. However, their treatment was not modified. At the end of a total follow-up duration of 7 years, 88 (11%) patients died, 35 (4%) were lost to follow-up, 21 (2%) were transferred out to other health facilities and 680 (83%) were still under care. The incidence rate of unfavorable outcomes was 7.9 patients per 100 person years follow-up. Patients with a history of injecting drug use, with a history of lost to follow-up, with a higher baseline viral load and who had received didanosine and abacavir had a higher risk of unfavorable outcomes. Patients with higher baseline C4 counts, those having taken first-line ART at a private clinic, receiving ART at decentralized sites and taking zidovudine and lamivudine had a lower risk of unfavorable outcomes. CONCLUSIONS: Long-term outcomes of patients on second-line ART were relatively good in this cohort. Virological failure was relatively low, possibly because of lack of viral load testing. No patient who failed on second-line ART was switched to third-line treatment. The National HIV/AIDS Program should consider making routine viral load monitoring and third-line ART drugs available after a careful cost-benefit analysis. PMID- 28594297 TI - Assessment of sleep in subjects with visual impairment: Comparison using subjective and objective methods. AB - The objective of the present study was to verify the agreement between objective and subjective measures of sleep in people with and without visual impairment. Thirty-seven subjects with visual impairment participated in the study (19 blind without light perception and 18 low-vision), as well as 34 subjects with normal vision, with paired age and gender characteristics. For the subjective sleep evaluation, we used the Sleep Quality Index-PSQI and for the objective evaluation we used the ActiGraph GT3X+. Among the three analyzed groups, the blind was the only ones who presented differences between subjective and objective sleep duration (p = 0.021). Furthermore, the concordance between subjective and objective sleep duration (ICC = 0.388; p = 0.108) was not observed in blind subjects, and a greater variability of differences in sleep duration between the two methods was observed by the Bland Altman scatter plot. We concluded that the sleep duration obtained by PSQI did not show agreement for the objective sleep duration in blind subjects without light perception. PMID- 28594296 TI - The p53 R72P polymorphism does not affect the physiological response to ionizing radiation in a mouse model. AB - Tissue culture and mouse model studies show that the presence of the arginine (R) or proline (P) coding single nucleotide polymorphism (SNP) of the tumor suppressor gene p53 at codon 72 (p53 R72P) differentially affects the responses to genotoxic insult. Compared to the P variant, the R variant shows increased apoptosis in most cell cultures and mouse model tissues in response to genotoxins, and epidemiological studies suggest that the R variant may enhance cancer survival and reduce the risks of adverse reactions to genotoxic cancer treatment. As ionizing radiation (IR) treatment is often used in cancer therapy, we sought to test the physiological effects of IR in mouse models of the p53 R72P polymorphism. By performing blood counts, immunohistochemical (IHC) staining and survival studies in mouse populations rigorously controlled for strain background, sex and age, we discovered that p53 R72P polymorphism did not differentially affect the physiological response to IR. Our findings suggest that genotyping for this polymorphism to personalize IR therapy may have little clinical utility. PMID- 28594298 TI - To stop or not to stop disease modifying therapies in secondary progressive multiple sclerosis, that is the question. PMID- 28594299 TI - Dimerization of GTR1 regulates their plasma membrane localization. AB - Members of the nitrate transporter 1/peptide transporter family (NPF) are multifunctional transporters of various compounds including plant hormones and play important roles in plant growth and responses to environmental stress. Recently, we found that Arabidopsis GTR1 (also known as NPF2.10) takes up gibberellic acid and jasmonoyl-L-isoleucine in addition to glucosinolates. For normal plant growth, GTR1 is regulated at the gene expression level; however, it is unclear whether post-translational regulation also occurs. Here, we found that dimerization of GTR1, possibly induced by dephosphorylation of the Thr residue located between the possible transmembrane regions, regulates its plasma membrane localization, leading to transport of glucosinolates and gibberellic acid in Xenopus oocytes. These findings suggest that dimerization of multifunctional transporters contributes to their activities at the plasma membrane. PMID- 28594300 TI - Pre-operative experiences and post-operative benefits of ptosis surgery: A qualitative study. AB - This qualitative study sought to explore the experiences of patients who had undergone successful ptosis correction surgery. Participants were recruited from Bristol Eye Hospital. Nine participants were interviewed using a semi-structured interview schedule and open ended questions. Data were analysed using inductive thematic analysis. Four major themes were identified from patient accounts. Patients described the psychosocial and functional difficulties they experienced living with ptosis, and the subsequent benefits of surgery. Patients reported experiencing appearance related anxiety pre-operatively due to their condition and engaging in behaviours to avoid social encounters. Gender differences were noted in the internalization of perceived negative reactions from others, with men describing fewer adverse impacts. Patients described perceived barriers to seeking surgery including a lack of awareness of ptosis as a treatable condition, the perception that being concerned with their appearance could be seen as vain and the view that ptosis surgery is synonymous with cosmetic surgery. Following successful surgery patients outlined positive impacts on their vision, appearance and psychosocial well-being after successful surgery. This qualitative study highlights the complexities of the factors and processes contributing to the psychosocial impacts of ptosis and the potential benefits of surgery and/or psychosocial support. An increased awareness amongst people with ptosis of the potential positive impacts of surgery and an enhanced understanding of the reasons why patients may not seek treatment amongst health care professionals are likely to benefit this often overlooked patient group. PMID- 28594302 TI - Ectopic orbital meningioma: Fact or fiction? AB - Primary intraorbital ectopic meningiomas are rare and their existence remains controversial. We present a 30-year-old female with painless, non-axial proptosis and a palpable superomedial mass. The MRI demonstrated that the mass had no optic nerve sheath or sphenoid wing involvement and was initially reported to have no intracranial extension. The patient was initially thought to have an ectopic orbital meningioma. Subsequent multidisciplinary team (MDT) consultation and further specialist review of the MRI revealed a subtle dural tail connecting to an enhancing mass in the olfactory groove. Biopsy revealed a WHO Grade 1 transitional meningioma with an infiltrative pattern. We argue that some previously reported cases of ectopic meningioma may lack the requisite imaging to discover the primary disease. Our report highlights the importance of MRI in this group of patients and the role of a skull-base MDT with specialist neuroradiology input to determine the true origin and extent of these extradural orbital meningiomas. PMID- 28594301 TI - Orbital abscess following posterior subtenon injection of triamcinolone acetonide. AB - Orbital cellulitis is a serious sight threatening and potentially life threatening condition which can be complicated by orbital abscess formation. Posterior subtenon (PST) injection of corticosteroid is commonly used in the treatment of posterior segment inflammation including post-operative macular oedema. We report a case of orbital abscess formation as a late complication of PST triamcinolone acetonide and discuss the presentation, diagnosis and management. PMID- 28594303 TI - Self-inflicted enucleations: Clinical features of seven cases. AB - We report the clinical presentation, radiography, and management outcomes of autoenucleations (AE). Charts of 7 patients evaluated at 4 institutions with AE were reviewed. Four males and three females had a mean age of 50 years (range 26 72 years). The etiologies were psychosis secondary to underlying mental illness (6, 88%) and substance use (1, 12%), and the mechanism was largely blunt digital injury (6, 88%). Three (43%) AE patients suffered bilateral enucleations. Common concomitant injuries included eyelid lacerations (5, 71%) and optic nerve avulsion (3, 43%). Radiography was utilized for all of the study patients with computed tomography as the most common (5, 71%), followed by ultrasound (1, 14%), and magnetic resonance imaging with CT angiography (1, 14). Orbital exploration was performed in the management of all patients. Orbital implants were placed in 4 (57%) patients. Patients were followed for a mean of 1.9 months (range 1-4 months). Autoenucleation affects both genders and is commonly associated with eyelid lacerations, optic nerve avulsion, and intracranial hemorrhage. The association with intracranial hemorrhage is consistent with prior reports of internal carotid artery injury following shearing of the optic nerve. Autoenucleation cases were seen secondary to mental or substance induced psychosis, and these patients may be at risk for future injuries such as AE of the contralateral globe. The common causes for psychosis reported our patient group include schizophrenia, depression, schizoaffective disorder, and methamphetamine-induced psychosis, which corroborates with similar cases in the literature. Two of three cases of bilateral AE suffered sequential AE where the contralateral globe was enucleated days apart. All patients suffering AE should have full medical, psychiatric, neurologic, and radiologic evaluation and monitoring while under care. When evaluating patients with obvious ocular injury, accompanying intracranial injuries should be ruled out in a timely fashion before pursuing surgical intervention. PMID- 28594304 TI - Role of vitamin D pathway gene polymorphisms on rifampicin plasma and intracellular pharmacokinetics. AB - AIM: We retrospectively evaluate the pharmacogenetic role of single nucleotide polymorphisms involved in rifampicin transport (SLCO1B1, MDR1 and PXR genes) and vitamin D (VDR, CYP24A1 and CYP27B1 genes) metabolism and activity on drug plasma and intracellular concentrations. PATIENTS & METHODS: Rifampicin Cmax and Ctrough were measured at weeks 2 and 4 using Ultra-Performance Liquid Chromatography tandem mass spectroscopy methods. Allelic discrimination was performed by real time polymerase chain reaction. RESULTS: Twenty-four patients were enrolled. At week 2, OATP1B1 521TT and CYP27B1 +2838CC/CT considering plasma and BsmIAA for intraperipheral blood mononuclear cells Cmax, remained in regression analysis. Concerning week 4, TaqITC/CC and CYP24A1 22776CT/TT were retained in plasma Cmax regression model. CONCLUSION: This study confirms the role of SLCO1B1 and it suggests the involvement of vitamin D pathway gene polymorphisms in rifampicin pharmacokinetics. PMID- 28594307 TI - 5th Congress of WUWHS Abstract book Florence, Italy September 25-29 2016. AB - The abstract book contains the abstracts of keynote lectures, focus sessions, symposia, workshops, AIUC annual meeting, AISLEC annual meeting, EPUAP annual meeting, ETRS special session, sponsor symposia, oral presentations, poster presentations and the subject index. PMID- 28594305 TI - Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily. AB - While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%-23.8% for LSIL, and 19.0%-32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases. PMID- 28594306 TI - A pilot study investigating the association between chronic bilateral vestibulopathy and components of a clinical functional assessment tool. AB - BACKGROUND: This study aimed to analyze the association between prospectively assessed falls and functional abilities in patients with bilateral vestibulopathy (BVP). METHODS: Nineteen BVP patients had functional abilities assessed at baseline with the expanded timed get-up-and-go (ETGUG) test. Falls were prospectively recorded with a monthly "fall calendar" over a one-year period. Association between baseline functional abilities and falls was evaluated by Mann Whitney U testing. Logistic regression was applied to describe the relationship between falls and functional abilities. Area under the receiver-operating characteristic curve (AUC) was used predicting falls based on gait speed. RESULTS: Eight (45%) of 18 patients (61.11 +/- 15.19 years, 12 male) reported 19 falls. Fallers had a significantly faster preferred gait speed (p = 0.03) in the fifth component of the ETGUG. Preferred gait speed was a significant factor in the prediction of falls model (odds ratio = 2.00, p = 0.05, CI = 1.00/4.00 per 10 cm/s). ACU was 0.80 and the cutoff score of 1.35m/s (sensitivity = 75%, specificity = 70%) in predicting falls. DISCUSSION: BVP patients classified as fallers demonstrated significant faster gait speed after a turning maneuver. Future studies in larger BVP patient samples are needed to refute or confirm our findings. PMID- 28594308 TI - Atrazine, chlorpyrifos, and iprodione effect on the biodiversity of bacteria, actinomycetes, and fungi in a pilot biopurification system with a green cover. AB - The use of biopurification systems can mitigate the effects of pesticide contamination on farms. The primary aim of this study was to evaluate the effect of pesticide dissipation on microbial communities in a pilot biopurification system. The pesticide dissipation of atrazine, chlorpyrifos and iprodione (35 mg kg-1 active ingredient [a.i.]) and biological activity were determined for 40 days. The microbial communities (bacteria, actinomycetes and fungi) were analyzed using denaturing gradient gel electrophoresis (DGGE). In general, pesticide dissipation was the highest by day 5 and reached 95%. The pesticides did not affect biological activity during the experiment. The structure of the actinomycete and bacterial communities in the rhizosphere was more stable during the evaluation than that in the communities in the control without pesticides. The rhizosphere fungal communities, detected using DGGE, showed small and transitory shifts with time. To conclude, rhizosphere microbial communities were not affected during pesticide dissipation in a pilot biopurification system. PMID- 28594309 TI - Understanding media publics and the antimicrobial resistance crisis. AB - Antimicrobial resistance (AMR) imperils health for people across the world. This enormous challenge is being met with the rationalisation of prescription, dispensing and consumption of antimicrobials in clinical settings and in the everyday lives of members of the general population. Individuals need to be reached outside clinical settings to prepare them for the necessary changes to the pharmaceutical management of infections; efforts that depend on media and communications and, therefore, how the AMR message is mediated, received and applied. In 2016, the UK Review on Antimicrobial Resistance called on governments to support intense, worldwide media activity to promote public awareness and to further efforts to rationalise the use of antimicrobial pharmaceuticals. In this article, we consider this communications challenge in light of contemporary currents of thought on media publics, including: the tendency of health communications to cast experts and lay individuals in opposition; the blaming of individuals who appear to 'resist' expert advice; the challenges presented by negative stories of AMR and their circulation in public life, and; the problems of public trust tied to the construction and mediation of expert knowledge on the effective management of AMR. PMID- 28594310 TI - Local narratives of sexual and other violence against children and young people in Zanzibar. AB - Understandings of violence, and especially sexual violence against children, must be situated within the local context. The 2009 Violence against Children Survey in Zanzibar indicated that 6% of girls and 9% of boys reported having experienced sexual violence before the age of 18 years. This paper reports on an in-depth qualitative study conducted in Zanzibar to provide further insights to these findings by examining the circumstances for sexual and other violence against children in Zanzibar. Twenty-four in-depth interviews with young people and 18 focus-group discussions with young people and adults were conducted in rural and urban Zanzibar. A further 8 interviews were conducted with parents and key stakeholders in government and NGO offices that provide services for children. The findings revealed that religious and cultural practices, which form the foundation of Swahili culture in Zanzibar, provide a moral frame for childhood development, but structural factors make children vulnerable to sexual violence. Both boys and girls are vulnerable to sexual violence in the home, neighbourhood, at school and, in particular, at madrasa or Qur'anic schools. As religion and culture are strong influences on childhood, preventing sexual violence at madrasa schools would strengthen the positive aspects of religious teachings for ensuring a safe childhood. PMID- 28594312 TI - Warning About the Use of Critical-Size Defects for the Translational Study of Bone Repair: Analysis of a Sheep Tibial Model. AB - The repair of large long bone defects requires complex surgical procedures as the bone loss cannot simply be replaced by autologous grafts due to an insufficient bone stock of the human body. Tissue engineering strategies and the use of Advanced Therapy Medicinal Products (ATMPs) for these reconstructions remain a considerable challenge, in particular since robust outcomes in well-defined large animal models are lacking. To be suitable as a model for treatment of human sized bone defects, we developed a large animal model in both skeletally immature and mature sheep and made close observations on the spontaneous healing of defects. We warn for the spontaneous repair of large defects in immature animals, which can mask the (in)effectiveness of ATMP therapies, and propose the use of large 4.5 cm defects that are pretreated with a polymethylmethacrylate (PMMA) spacer in skeletally mature animals. PMID- 28594311 TI - A lentiviral vector bearing a reverse intron demonstrates superior expression of both proteins and microRNAs. AB - While lentiviral expression vectors are widely used in many facets of molecular biology, due to their ability to stably express heterologous genes in both dividing and non-dividing cells, they suffer from the disadvantage that introns inserted into the vector genome are generally rapidly lost by splicing in packaging cell lines. The presence of an intron, if achievable, has the potential to facilitate the expression of transgene cDNAs, as splicing has been extensively shown to facilitate mRNA biogenesis and function. Moreover, if a stable intron could be introduced into a lentiviral vector, this could greatly facilitate the expression of microRNAs (miRNAs), and especially miRNA clusters, as the introduction of pri-miRNA stems into the exonic region of a lentiviral vector can strongly reduce both vector titer and the expression of any miRNA-linked indicator gene due to cleavage of the vector RNA genome by cellular Drosha. Here, we describe a novel lentiviral vector design in which transgenes and/or miRNAs are expressed using an antisense-orientated, inducible promoter driving an expression cassette bearing a functional intron. We demonstrate that this lentiviral vector, called pTREX, is able to express higher levels of both transgenes and pri-miRNA clusters when compared with a closely similar conventional lentiviral vector. PMID- 28594313 TI - Protection against TBI-Induced Neuronal Death with Post-Treatment with a Selective Calpain-2 Inhibitor in Mice. AB - Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide. The calcium-dependent protease, calpain, has been shown to be involved in TBI induced neuronal death. However, whereas various calpain inhibitors have been tested in several animal models of TBI, there has not been any clinical trial testing the efficacy of calpain inhibitors in human TBI. One important reason for this could be the lack of knowledge regarding the differential functions of the two major calpain isoforms in the brain, calpain-1 and calpain-2. In this study, we used the controlled cortical impact (CCI) model in mice to test the roles of calpain-1 and calpain-2 in TBI-induced neuronal death. Immunohistochemistry (IHC) with calpain activity markers performed at different time-points after CCI in wild-type and calpain-1 knock-out (KO) mice showed that calpain-1 was activated early in cortical areas surrounding the impact, within 0-8 h after CCI, whereas calpain-2 activation was delayed and was predominant during 8-72 h after CCI. Calpain-1 KO enhanced cell death, whereas calpain-2 activity correlated with the extent of cell death, suggesting that calpain-1 activation suppresses and calpain 2 activation promotes cell death following TBI. Systemic injection(s) of a calpain-2 selective inhibitor, NA101, at 1 h or 4 h after CCI significantly reduced calpain-2 activity and cell death around the impact site, reduced the lesion volume, and promoted motor and learning function recovery after TBI. Our data indicate that calpain-1 activity is neuroprotective and calpain-2 activity is neurodegenerative after TBI, and that a selective calpain-2 inhibitor can reduce TBI-induced cell death. PMID- 28594314 TI - Tailoring of recommendations to reduce serious cutaneous adverse drug reactions: a pharmacogenomics approach. AB - The Health Sciences Authority launched a pharmacogenetics initiative in 2008 to facilitate evaluation of pharmacogenetics associations pertinent for Chinese, Malays and Indians in Singapore. The aim was to reduce the incidence and unpredictability of serious adverse drug reactions, with a focus on serious skin adverse drug reactions. This paper describes the gathering of evidence and weighing of factors that led to different genotyping recommendations for HLA B*15:02 with carbamazepine and HLA-B*58:01 with allopurinol, despite both having strong genetic associations. Translation of pharmacogenomics at a national level requires careful deliberation of the prevalence of at-risk allele, strength of genetic associations, positive predictive value, cost-effectiveness and availability of alternative therapies. Our experience provides a perspective on translating genomic discoveries in advancing drug safety. PMID- 28594317 TI - Understanding vantage points to stimulate dialogue. PMID- 28594315 TI - Forecasting Financial Resources for Future Traumatic Spinal Cord Injury Care Using Simulation Modeling. AB - Survivors of traumatic spinal cord injury (tSCI) have intense healthcare needs during acute and rehabilitation care and often through the rest of life. To prepare for a growing and aging population, simulation modeling was used to forecast the change in healthcare financial resources and long-term patient outcomes between 2012 and 2032. The model was developed with data from acute and rehabilitation care facilities across Canada participating in the Access to Care and Timing project. Future population and tSCI incidence for 2012 and 2032 were predicted with data from Statistics Canada and the Canadian Institute for Health Information. The projected tSCI incidence for 2012 was validated with actual data from the Rick Hansen SCI Registry of the participating facilities. Using a medium growth scenario, in 2032, the projected median age of persons with tSCI is 57 and persons 61 and older will account for 46% of injuries. Admissions to acute and rehabilitation facilities in 2032 were projected to increase by 31% and 25%, respectively. Because of the demographic shift to an older population, an increase in total population life expectancy with tSCI of 13% was observed despite a 22% increase in total life years lost to tSCI between 2012 and 2032. Care cost increased 54%, and rest of life cost increased 37% in 2032, translating to an additional CAD $16.4 million. With the demographics and management of tSCI changing with an aging population, accurate projections for the increased demand on resources will be critical for decision makers when planning the delivery of healthcare after tSCI. PMID- 28594318 TI - Editorial. PMID- 28594319 TI - Up Front. PMID- 28594316 TI - Effects of Irisin and Exercise on Metabolic Parameters and Reproductive Hormone Levels in High-Fat Diet-Induced Obese Female Mice. AB - It has been documented that exogenously administered irisin (1010 fibronectin type III domain-containing 5 [FNDC5]), which is a new polypeptide hormone, induces the browning of subcutaneous fat and thermogenesis. In this study, effects of physical activity and exogenous administration of irisin were investigated on parameters related with reproduction and metabolism in the high fat diet-induced obesity model of the female C57BL/6J mice. Sixty mice were gathered at age approximately 5 to 6weeks and were divided into 3 groups. Control group remained sedentary. Irisin group remained also sedentary but intravenously received 1010 FNDC5-expressing adenovirus after 20 weeks. Exercise group performed treadmill after 6 weeks. All mice were sacrificed 22 to 23 weeks after the start of the study. There was a significantly greater Delta weight in the controls compared with the irisin and exercise groups ( P < .05). Glucose and insulin levels were significantly higher in the controls ( P < .05). The serum irisin level was significantly higher in the exercise group ( P < .05). Serum luteinizing hormone levels were significantly increased in the irisin group ( P < .05). Serum anti-Mullerian hormone levels were significantly higher in irisin and exercise groups ( P < .05). There were significant negative correlations between serum irisin levels and Delta weight and homeostatic model assessment of insulin resistance ( r = -0.327, r = -0.297, respectively; P < .05 for both). The numbers of primordial follicles per ovary were similar ( P > .05), whereas primary and secondary follicles per ovary were higher in the irisin and exercise groups compared with controls ( P < .05). Pharmacologic introduction of irisin may improve metabolic factors such as insulin sensitivity and obesity by promoting weight loss and consequently improving the reproductive potential. PMID- 28594320 TI - Silver-containing foam dressings with Safetac: a review of the scientific and clinical data. AB - Background Topical antimicrobials, such as silver dressings, are progressively being used alongside systemic antibiotics to provide adjunctive, antimicrobial therapy to wounds that are clinically infected or at risk of infection. To help improve wound management, dressings that use Safetac soft silicone technology in combination with a silver-impregnated foam dressing material were developed by Molnlycke Health Care (Gothenburg, Sweden). The range comprises Mepilex Ag, Mepilex Border Ag and Mepilex Transfer Ag. Aims A literature review was undertaken to identify and summarise clinical data from the entire evidence hierarchy, as well as data from in vitro tests, which support the use of silver containing foam dressings with Safetac. Method The MEDLINE (National Library of Medicine, Bethesda, US) and EMBASE (Elsevier BV, Amsterdam, Netherlands) bibliographic databases were searched. In addition, abstract books and proceedings documents relating to national and international conferences were scanned in order to identify presentations (oral, e-poster and poster) of relevance to the review. Results In vitro test results showed that the silver containing foam dressings with Safetac have both rapid and sustained activity against a range of wound pathogens, reducing planktonic and established biofilm cultures, and preventing biofilm formation. In numerous clinical studies, silvercontaining foam dressings with Safetac were used to manage wound bioburden effectively and resolve signs of localised infection in both acute wounds (such as surgical, traumatic and burn injuries) and chronic wounds (such as leg ulcers, pressure ulcers (PUs), diabetic foot ulcers (DFUs), and cancerous wounds). Studies reported that silver-containing foam dressings with Safetac are easy to use, provide an optimal environment for wound healing, and are associated with atraumatic and virtually painfree removal. As well as being clinically effective, they are reported to be cost-effective when used on wounds that require topical antimicrobial therapy. Conclusion The findings of both scientific and clinical studies clearly indicate that clinical, patient-related and economic benefits are associated with the use of Mepilex Ag, Mepilex Border Ag and Mepilex Transfer Ag with Safetac in the treatment of wounds where antimicrobial activity is needed to help manage bioburden. PMID- 28594321 TI - Pharmacogenomics in Asia: a systematic review on current trends and novel discoveries. AB - While early pharmacogenomic studies have primarily been carried out in Western populations, there has been a notable increase in the number of Asian studies over the past decade. We systematically reviewed all pharmacogenomic studies conducted in Asia published before 2016 to highlight trends and identify research gaps in Asia. We observed that pharmacogenomic research in Asia was dominated by larger developed countries, notably Japan and Korea, and mainly driven by local researchers. Studies were focused on drugs acting on the CNS, chemotherapeutics and anticoagulants. Significantly, several novel pharmacogenomic associations have emerged from Asian studies. These developments are highly encouraging for the strength of regional scientific and clinical community and propound the importance of discovery studies in different populations. PMID- 28594322 TI - Caspase-8 contributes to angiogenesis and chemotherapy resistance in glioblastoma. AB - Caspase-8 is a key player in extrinsic apoptosis and its activity is often downregulated in cancer. However, human Caspase-8 expression is retained in some tumors, including glioblastoma (GBM), suggesting that it may support cancer growth in these contexts. GBM, the most aggressive of the gliomas, is characterized by extensive angiogenesis and by an inflammatory microenvironment that support its development and resistance to therapies. We have recently shown that Caspase-8 sustains neoplastic transformation in vitro in human GBM cell lines. Here, we demonstrate that Caspase-8, through activation of NF-kB, enhances the expression and secretion of VEGF, IL-6, IL-8, IL-1beta and MCP-1, leading to neovascularization and increased resistance to Temozolomide. Importantly, the bioinformatics analysis of microarray gene expression data derived from a set of high-grade human gliomas, shows that high Caspase-8 expression levels correlate with a worse prognosis. PMID- 28594323 TI - Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1. AB - Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors. PMID- 28594324 TI - MeCP2 regulates Tet1-catalyzed demethylation, CTCF binding, and learning dependent alternative splicing of the BDNF gene in Turtle. AB - MECP2 mutations underlying Rett syndrome cause widespread misregulation of gene expression. Functions for MeCP2 other than transcriptional are not well understood. In an ex vivo brain preparation from the pond turtle Trachemys scripta elegans, an intraexonic splicing event in the brain-derived neurotrophic factor (BDNF) gene generates a truncated mRNA transcript in naive brain that is suppressed upon classical conditioning. MeCP2 and its partners, splicing factor Y box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naive but dissociate during conditioning; the dissociation correlating with decreased DNA methylation. Surprisingly, conditioning results in new occupancy of BDNF chromatin by DNA insulator protein CCCTC-binding factor (CTCF), which is associated with suppression of splicing in conditioning. Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing. PMID- 28594325 TI - Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses. AB - RIG-I is a key cytosolic pattern recognition receptor that interacts with MAVS to induce type I interferons (IFNs) against RNA virus infection. In this study, we found that cyclophilin A (CypA), a peptidyl-prolyl cis/trans isomerase, functioned as a critical positive regulator of RIG-I-mediated antiviral immune responses. Deficiency of CypA impaired RIG-I-mediated type I IFN production and promoted viral replication in human cells and mice. Upon Sendai virus infection, CypA increased the interaction between RIG-I and its E3 ubiquitin ligase TRIM25, leading to enhanced TRIM25-mediated K63-linked ubiquitination of RIG-I that facilitated recruitment of RIG-I to MAVS. In addition, CypA and TRIM25 competitively interacted with MAVS, thereby inhibiting TRIM25-induced K48-linked ubiquitination of MAVS. Taken together, our findings reveal an essential role of CypA in boosting RIG-I-mediated antiviral immune responses by controlling the ubiquitination of RIG-I and MAVS. PMID- 28594326 TI - ER retention is imposed by COPII protein sorting and attenuated by 4 phenylbutyrate. AB - Native cargo proteins exit the endoplasmic reticulum (ER) in COPII-coated vesicles, whereas resident and misfolded proteins are substantially excluded from vesicles by a retention mechanism that remains unresolved. We probed the ER retention process using the proteostasis regulator 4-phenylbutyrate (4-PBA), which we show targets COPII protein to reduce the stringency of retention. 4-PBA competes with p24 proteins to bind COPII. When p24 protein uptake is blocked, COPII vesicles package resident proteins and an ER-trapped mutant LDL receptor. We further show that 4-PBA triggers the secretion of a KDEL-tagged luminal resident, implying that a compromised retention mechanism causes saturation of the KDEL retrieval system. The results indicate that stringent ER retention requires the COPII coat machinery to actively sort biosynthetic cargo from diffusible misfolded and resident ER proteins. PMID- 28594328 TI - Does steatosis affect the performance of diffusion-weighted MRI values for fibrosis evaluation in patients with chronic hepatitis C genotype 4? AB - BACKGROUND/AIMS: To evaluate the effect of hepatic steatosis on the apparent diffusion coefficient (ADC) of hepatic fibrosis in patients with HCV genotype 4 related chronic hepatitis. MATERIALS AND METHODS: Overall, 268 chronic hepatitis C patients (164 males and 104 females) underwent liver biopsy for fibrosis assessment by the METAVIR score and grading for hepatic steatosis. They were classified into early fibrosis stage (F1, F2) and advanced fibrosis stage (F3, F4). Diffusion-weighted MRI (DWI) of the liver was performed using 1.5-Tesla scanners, and the ADC value of the patients with and without steatosis in different stages of fibrosis was estimated and compared. RESULTS: In patients with early fibrosis, the ADC value significantly decreased in patients with steatosis (1.52+/-0.17*10-3 mm2/s) compared to that in patients without steatosis (1.65+/-0.11*10-3 mm2/s) (p<0.001). In those with an advanced stage of fibrosis, the ADC value was also significantly decreased in patients with steatosis (1.07+/ 0.16*10-3 mm2/s) compared with that in patients without steatosis (1.35+/-0.11*10 3 mm2/s) (p<=0.001). The cutoff value for ADC for steatosis prediction in the early fibrosis group was 1.585 according to the AUROC curve, with a sensitivity of 76.8% and a specificity of 73.5%. The cutoff value for ADC for steatosis prediction in patients with an advanced stage of fibrosis was 1.17*10-3 mm2/s, with a sensitivity of 97% and a specificity of 88.5%. CONCLUSION: Histologically detected hepatic steatosis should always be considered when assessing hepatic fibrosis using diffusion-weighted MRI to avoid the underestimation of the ADC value in patients with chronic hepatitis C genotype 4. PMID- 28594329 TI - Updating predictors of endoscopic recurrence after ileocolic resection for Crohn disease. AB - BACKGROUND/AIMS: Identifying predictors of endoscopic recurrence (ER) has become very important to guide the decision of postoperative strategy. This study aimed to determine the rate of endoscopic recurrence until 12 months after ileocolic resection for Crohn disease (CD) in a cohort and identify its possible predictors. MATERIALS AND METHODS: We conducted a retrospective single-center study that included patients with CD who underwent ileocolic resection between 2003 and 2014. ER was defined according to the Rutgeerts' score, defined as i2, i3, or i4 at ileocolonoscopy that was performed 6-12 months after surgery. The patients were classified into two groups according to the Rutgeerts' score: non ER (Rutgeerts i0/i1) and ER (Rutgeerts >=i2). Multivariate logistic regression analysis was performed, including significant variables on univariable analysis, to identify ER predictors. RESULTS: Forty-two patients were included. The mean period of the first postoperative colonoscopy was 9 months, and ER was observed in 25 patients (59.5%). The perianal disease and shorter duration of CD were the only ER predictors (p=0.024; OR, 8.36; 95% CI, 1.329-52.642 and p=0.039; OR, 0.965; 95% CI, 0.933-0.998, respectively). CONCLUSION: Endoscopic recurrence affects almost two-thirds of patients with CD after ileocolic resection, with perianal involvement and a shorter duration of disease being significant risk factors. These factors may indicate a more aggressive disease associated with rapid progression and support the need of intensive early treatment to improve patients' outcomes. PMID- 28594330 TI - Risk factors of the rebleeding according to the patterns of nonvariceal upper gastrointestinal bleeding. AB - BACKGROUND/AIMS: Despite of successful endoscopic hemostasis of nonvariceal upper gastrointestinal bleeding (NGIB), rebleeding rate has not decreased. The aim of this study was to identify risk factors for rebleeding after endoscopic hemostasis in patients with NGIB according to bleeding patterns. MATERIALS AND METHODS: A retrospective analysis was performed on the consecutive patients with NGIB in whom successful primary endoscopic hemostasis had been achieved at three university hospitals in Korea. All patients underwent endoscopic treatment with hemoclips, epinephrine injection, argon-plasma coagulation, or its combinations within 12 h. RESULTS: A total of 198 patients were studied. The male-to-female ratio was 3:1. Mean age was 60.7+/-14.9 years. Rebleeding occurred in 41 cases (20.7%). Median day of rebleeding after endoscopic therapy was 2.0 days. Overall mortality rate was 5.1%. Risk factors for rebleeding were inpatients [odds ratio (OR) 2.61, 95% confidence interval (CI): 1.05-6.46, p=0.038) and Forrest Ib (OR=2.73, 95% CI: 1.15-6.47, p=0.023) by multivariate regression analysis. CONCLUSION: Despite of successful emergent endoscopic therapy for NGIB, rebleeding occurred in 17.7% within a week. Endoscopic treatments should be more carefully performed for patients in hospitalization or patients with active oozing. PMID- 28594327 TI - Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity. AB - T cells are mechanosensitive but the effect of stiffness on their functions is still debated. We characterize herein how human primary CD4+ T cell functions are affected by stiffness within the physiological Young's modulus range of 0.5 kPa to 100 kPa. Stiffness modulates T lymphocyte migration and morphological changes induced by TCR/CD3 triggering. Stiffness also increases TCR-induced immune system, metabolism and cell-cycle-related genes. Yet, upon TCR/CD3 stimulation, while cytokine production increases within a wide range of stiffness, from hundreds of Pa to hundreds of kPa, T cell metabolic properties and cell cycle progression are only increased by the highest stiffness tested (100 kPa). Finally, mechanical properties of adherent antigen-presenting cells modulate cytokine production by T cells. Together, these results reveal that T cells discriminate between the wide range of stiffness values found in the body and adapt their responses accordingly. PMID- 28594331 TI - A 52-year-old man with abdominal pain and distension. PMID- 28594332 TI - Pooled analysis of HCV genotype 1 resistance-associated substitutions in NS5A, NS3 and NS5B pre-and post-treatment with 12 weeks of daclatasvir, asunaprevir and beclabuvir. AB - BACKGROUND: Daclatasvir (DCV; non-structural [NS]5A inhibitor) plus asunaprevir (ASV; NS3 inhibitor) plus beclabuvir (BCV; non-nucleoside NS5B inhibitor) is an approved regimen for hepatitis C virus (HCV) genotype (GT)-1 treatment in Japan. A comprehensive analysis of pre-treatment and treatment-emergent HCV resistance to this regimen +/- ribavirin (RBV) was performed. METHODS: Data were pooled from five Phase 2/3 studies of DCV+ASV+BCV+/-RBV given for 12 weeks to GT-1a- or GT-1b infected patients. The prevalence and impact of pre-treatment resistance associated substitutions (RAS) in NS5A, NS3, and NS5B on sustained virological response (SVR) was assessed, as were emergent RAS and their post-treatment persistence. RESULTS: Baseline NS5A RAS (GT-1a: M28T, Q30H/L/R/S, L31M, Y93C/H; GT-1b: L31I/M, Y93C/H) were present in 5% (26/561) of GT-1a and 16% (85/537) of GT-1b sequences. SVR12 for GT-1b without RBV was 100% (82/82) with RAS and >99% (427/428) without RAS. For GT-1a, SVR12 without RAS was 97% (85/88) with RBV and 92% (410/447) without RBV; SVR12 with RAS was 100% (2/2) with RBV and 54% (13/24) without RBV. Baseline NS3 (at R155 or D168) and NS5B (at P495) RAS were rare (<=1%). Treatment-emergent NS5A RAS (mostly Q30E/H/K/R+/-Y93H/N) in GT-1a persisted 60 weeks post-treatment, while NS3 RAS (mostly R155K) and NS5B-P495L/S were no longer detected after 48 or 24 weeks, respectively. CONCLUSIONS: DCV+ASV+BCV+/-RBV was highly efficacious in HCV GT-1 infection, including HCV GT 1b with NS5A RAS. The fitness of treatment-emergent RAS post-treatment was NS5A > NS3 > NS5B; NS3 and NS5B RAS were generally replaced by wild-type sequence within 48 weeks. PMID- 28594334 TI - Self-consistent hybrid functionals for solids: a fully-automated implementation. AB - A fully-automated algorithm for the determination of the system-specific optimal fraction of exact exchange in self-consistent hybrid functionals of the density functional-theory is illustrated, as implemented into the public Crystal program. The exchange fraction of this new class of functionals is self-consistently updated proportionally to the inverse of the dielectric response of the system within an iterative procedure (Skone et al 2014 Phys. Rev. B 89, 195112). Each iteration of the present scheme, in turn, implies convergence of a self consistent-field (SCF) and a coupled-perturbed-Hartree-Fock/Kohn-Sham (CPHF/KS) procedure. The present implementation, beside improving the user-friendliness of self-consistent hybrids, exploits the unperturbed and electric-field perturbed density matrices from previous iterations as guesses for subsequent SCF and CPHF/KS iterations, which is documented to reduce the overall computational cost of the whole process by a factor of 2. PMID- 28594335 TI - Enhanced second and third harmonic generations of vertical and planar spiral MoS2 nanosheets. AB - Molybdenum disulfide (MoS2), as one of the atomically thin two-dimensional transition metal dichalcogenides has novel layer-dependent optical and electronic properties, which make it competitive for potential applications in optoelectronics. Here, we report chemical vapor deposition growth of vertically standing and planar spiral MoS2 nanosheets. These vertical spiral MoS2 nanosheets are formed by the compression between planar spiral MoS2 in a close proximity. Both structures have a polytype 3R stacking with broken inversion symmetry, exhibiting strong second and third harmonic generations. PMID- 28594333 TI - Quantification of carotid artery plaque stability with multiple region of interest based ultrasound strain indices and relationship with cognition. AB - Vulnerability and instability in carotid artery plaque has been assessed based on strain variations using noninvasive ultrasound imaging. We previously demonstrated that carotid plaques with higher strain indices in a region of interest (ROI) correlated to patients with lower cognition, probably due to cerebrovascular emboli arising from these unstable plaques. This work attempts to characterize the strain distribution throughout the entire plaque region instead of being restricted to a single localized ROI. Multiple ROIs are selected within the entire plaque region, based on thresholds determined by the maximum and average strains in the entire plaque, enabling generation of additional relevant strain indices. Ultrasound strain imaging of carotid plaques, was performed on 60 human patients using an 18L6 transducer coupled to a Siemens Acuson S2000 system to acquire radiofrequency data over several cardiac cycles. Patients also underwent a battery of neuropsychological tests under a protocol based on National Institute of Neurological Disorders and Stroke and Canadian Stroke Network guidelines. Correlation of strain indices with composite cognitive index of executive function revealed a negative association relating high strain to poor cognition. Patients grouped into high and low cognition groups were then classified using these additional strain indices. One of our newer indices, namely the average L - 1 norm with plaque (AL1NWP) presented with significantly improved correlation with executive function when compared to our previously reported maximum accumulated strain indices. An optimal combination of three of the new indices generated classifiers of patient cognition with an area under the curve (AUC) of 0.880, 0.921 and 0.905 for all (n = 60), symptomatic (n = 33) and asymptomatic patients (n = 27) whereas classifiers using maximum accumulated strain indices alone provided AUC values of 0.817, 0.815 and 0.813 respectively. PMID- 28594338 TI - Association of alcohol consumption with the risk of stomach cancer in a Japanese population: a prospective cohort study. AB - Biological studies have provided confirmation of alcohol-related carcinogenesis in the stomach, but the association between alcohol consumption and the risk of stomach cancer remains controversial. We aimed to investigate whether quantitative alcohol intake is associated with the risk of stomach cancer in a large prospective cohort study among a Japanese population. Study participants included 30 714 participants (14 171 men and 16 543 women) aged 35 years or older, who were enrolled in the Takayama study launched on 1 September 1992. Alcohol consumption was assessed quantitatively using a validated food frequency questionnaire. According to alcohol intake (g/day), male participants were classified into quartile groups: Q1, Q2, Q3, or Q4. Female participants were classified into three groups: nondrinkers, and drinkers below or above the median alcohol level. We estimated the hazard ratios and 95% confidence intervals (CIs) for stomach cancer adjusted for age, smoking, BMI, education, total energy intake, salt intake, physical activity, and medical history of diabetes mellitus for each alcohol intake group using the Cox proportional hazards regression model. By the end of March 2008, a total of 678 participants had been diagnosed with stomach cancer. For men, the multivariate-adjusted HRs of stomach cancer for Q2, Q3, and Q4 relative to Q1 were 1.39 (95% CI: 1.07-1.81), 1.35 (95% CI: 1.02 1.79), and 1.38 (95% CI: 1.02-1.87), respectively. In women, no associations were observed. These data suggest that alcohol consumption could be associated with an increased risk of stomach cancer among Japanese men. PMID- 28594336 TI - Flagged uniform particle splitting for variance reduction in proton and carbon ion track-structure simulations. AB - Flagged uniform particle splitting was implemented with two methods to improve the computational efficiency of Monte Carlo track structure simulations with TOPAS-nBio by enhancing the production of secondary electrons in ionization events. In method 1 the Geant4 kernel was modified. In method 2 Geant4 was not modified. In both methods a unique flag number assigned to each new split electron was inherited by its progeny, permitting reclassification of the split events as if produced by independent histories. Computational efficiency and accuracy were evaluated for simulations of 0.5-20 MeV protons and 1-20 MeV u-1 carbon ions for three endpoints: (1) mean of the ionization cluster size distribution, (2) mean number of DNA single-strand breaks (SSBs) and double strand breaks (DSBs) classified with DBSCAN, and (3) mean number of SSBs and DSBs classified with a geometry-based algorithm. For endpoint (1), simulation efficiency was 3 times lower when splitting electrons generated by direct ionization events of primary particles than when splitting electrons generated by the first ionization events of secondary electrons. The latter technique was selected for further investigation. The following results are for method 2, with relative efficiencies about 4.5 times lower for method 1. For endpoint (1), relative efficiency at 128 split electrons approached maximum, increasing with energy from 47.2 +/- 0.2 to 66.9 +/- 0.2 for protons, decreasing with energy from 51.3 +/- 0.4 to 41.7 +/- 0.2 for carbon. For endpoint (2), relative efficiency increased with energy, from 20.7 +/- 0.1 to 50.2 +/- 0.3 for protons, 15.6 +/- 0.1 to 20.2 +/- 0.1 for carbon. For endpoint (3) relative efficiency increased with energy, from 31.0 +/- 0.2 to 58.2 +/- 0.4 for protons, 23.9 +/- 0.1 to 26.2 +/- 0.2 for carbon. Simulation results with and without splitting agreed within 1% (2 standard deviations) for endpoints (1) and (2), within 2% (1 standard deviation) for endpoint (3). In conclusion, standard particle splitting variance reduction techniques can be successfully implemented in Monte Carlo track structure codes. PMID- 28594339 TI - Cardiac Dysrhythmias Associated With Substitutive Use of Loperamide: A Systematic Review. AB - BACKGROUND: Recently, several deaths secondary to cardiac arrhythmias have been reported in association with substitutive use of loperamide. Therefore, we conducted a systematic review of all reported cases to overview the epidemiologic patterns and clinical outcomes to better elucidate loperamide-induced cardiac complications. AREAS OF UNCERTAINTY: Association between substitutive use of loperamide and cardiac arrhythmias. DATA SOURCES: A comprehensive literature search was conducted across 6 databases using variety of keywords to identify all reports of cardiac side effects associated with loperamide abuse. Only original case reports of cardiac toxicity or cardiac arrhythmias after loperamide abuse or overuse were included. Data were extracted by 2 authors independently using a structured template from the selected reports. Quality assessment of the reports was performed by using a high-quality evaluation tool. RESULTS: Thirteen reports describing 19 cases were included in our review. Except for coronary artery spasm in one case, cardiac arrhythmias were the major reported cardiac adverse event. The average age of patients was 31 years with majority being men (79%). The most common presentation was syncope (63%). All cases were reported in US except for 1 case. Three patients were concomitantly taking cimetidine, which is known to cause inhibition of CYP3A4 and CYP2C8 leading to increased levels of loperamide. Thirteen of 19 patients were successfully treated and discharged in a stable condition. CONCLUSIONS: Our results indicate that measures such as restricting over-the-counter availability of loperamide and increasing awareness regarding loperamide's toxicity are imperative to prevent deaths associated with loperamide abuse. PMID- 28594340 TI - A New Scoring System to Predict Recurrent Disease in Grade 1 and 2 Nonfunctional Pancreatic Neuroendocrine Tumors. AB - OBJECTIVE: The aim of this study was to predict recurrence in patients with grade 1 or 2 nonfunctioning pancreatic neuroendocrine tumors (NF-pNET) after curative resection. BACKGROUND: Surgical resection is the preferred treatment for NF-pNET; however, recurrence occurs frequently after curative surgery, worsening prognosis of patients. METHODS: Retrospectively, patients with NF-pNET of 3 institutions were included. Patients with distant metastases, hereditary syndromes, or grade 3 tumors were excluded. Local or distant tumor recurrence was scored. Independent predictors for survival and recurrence were identified using Cox-regression analysis. The recurrence score was developed to predict recurrence within 5 years after curative resection of grade 1 to 2 NF-pNET. RESULTS: With a median follow up of 51 months, 211 patients with grade 1 to 2 NF-pNET were included. Thirty five patients (17%) developed recurrence. The 5- and 10-year disease specific/overall survival was 98%/91% and 84%/68%, respectively. Predictors for recurrence were tumor grade 2, lymph node metastasis, and perineural invasion. On the basis of these predictors, the recurrence score was made. Discrimination [c statistic 0.81, 95% confidence interval (95% CI) 0.75-0.87] and calibration (Hosmer Lemeshow Chi-square 11.25, P = 0.258) indicated that the ability of the recurrence score to identify patients at risk for recurrence is good. CONCLUSIONS: This new scoring system could predict recurrence after curative resection of grade 1 and 2 NF-pNET. With the use of the recurrence score, less extensive follow-up could be proposed for patients with low recurrence risk. For high-risk patients, clinical trials should be initiated to investigate whether adjuvant therapy might be beneficial. External validation is ongoing due to limited availability of adequate cohorts. PMID- 28594341 TI - Study on Impact Acoustic-Visual Sensor-Based Sorting of ELV Plastic Materials. AB - This paper concentrates on a study of a novel multi-sensor aided method by using acoustic and visual sensors for detection, recognition and separation of End-of Life vehicles' (ELVs) plastic materials, in order to optimize the recycling rate of automotive shredder residues (ASRs). Sensor-based sorting technologies have been utilized for material recycling for the last two decades. One of the problems still remaining results from black and dark dyed plastics which are very difficult to recognize using visual sensors. In this paper a new multi-sensor technology for black plastic recognition and sorting by using impact resonant acoustic emissions (AEs) and laser triangulation scanning was introduced. A pilot sorting system which consists of a 3-dimensional visual sensor and an acoustic sensor was also established; two kinds commonly used vehicle plastics, polypropylene (PP) and acrylonitrile-butadiene-styrene (ABS) and two kinds of modified vehicle plastics, polypropylene/ethylene-propylene-diene-monomer (PP EPDM) and acrylonitrile-butadiene-styrene/polycarbonate (ABS-PC) were tested. In this study the geometrical features of tested plastic scraps were measured by the visual sensor, and their corresponding impact acoustic emission (AE) signals were acquired by the acoustic sensor. The signal processing and feature extraction of visual data as well as acoustic signals were realized by virtual instruments. Impact acoustic features were recognized by using FFT based power spectral density analysis. The results shows that the characteristics of the tested PP and ABS plastics were totally different, but similar to their respective modified materials. The probability of scrap material recognition rate, i.e., the theoretical sorting efficiency between PP and PP-EPDM, could reach about 50%, and between ABS and ABS-PC it could reach about 75% with diameters ranging from 14 mm to 23 mm, and with exclusion of abnormal impacts, the actual separation rates were 39.2% for PP, 41.4% for PP/EPDM scraps as well as 62.4% for ABS, and 70.8% for ABS/PC scraps. Within the diameter range of 8-13 mm, only 25% of PP and 27% of PP/EPDM scraps, as well as 43% of ABS, and 47% of ABS/PC scraps were finally separated. This research proposes a new approach for sensor-aided automatic recognition and sorting of black plastic materials, it is an effective method for ASR reduction and recycling. PMID- 28594342 TI - Development and Testing of a Dual Accelerometer Vector Sensor for AUV Acoustic Surveys. AB - This paper presents the design, manufacturing and testing of a Dual Accelerometer Vector Sensor (DAVS). The device was built within the activities of the WiMUST project, supported under the Horizon 2020 Framework Programme, which aims to improve the efficiency of the methodologies used to perform geophysical acoustic surveys at sea by the use of Autonomous Underwater Vehicles (AUVs). The DAVS has the potential to contribute to this aim in various ways, for example, owing to its spatial filtering capability, it may reduce the amount of post processing by discriminating the bottom from the surface reflections. Additionally, its compact size allows easier integration with AUVs and hence facilitates the vehicle manoeuvrability compared to the classical towed arrays. The present paper is focused on results related to acoustic wave azimuth estimation as an example of its spatial filtering capabilities. The DAVS device consists of two tri-axial accelerometers and one hydrophone moulded in one unit. Sensitivity and directionality of these three sensors were measured in a tank, whilst the direction estimation capabilities of the accelerometers paired with the hydrophone, forming a vector sensor, were evaluated on a Medusa Class AUV, which was sailing around a deployed sound source. Results of these measurements are presented in this paper. PMID- 28594343 TI - Modeling HSV-1 Latency in Human Embryonic Stem Cell-Derived Neurons. AB - Herpes simplex virus 1 (HSV-1) uses latency in peripheral ganglia to persist in its human host, however, recurrent reactivation from this reservoir can cause debilitating and potentially life-threatening disease. Most studies of latency use live-animal infection models, but these are complex, multilayered systems and can be difficult to manipulate. Infection of cultured primary neurons provides a powerful alternative, yielding important insights into host signaling pathways controlling latency. However, small animal models do not recapitulate all aspects of HSV-1 infection in humans and are limited in terms of the available molecular tools. To address this, we have developed a latency model based on human neurons differentiated in culture from an NIH-approved embryonic stem cell line. The resulting neurons are highly permissive for replication of wild-type HSV-1, but establish a non-productive infection state resembling latency when infected at low viral doses in the presence of the antivirals acyclovir and interferon-alpha. In this state, viral replication and expression of a late viral gene marker are not detected but there is an accumulation of the viral latency-associated transcript (LAT) RNA. After a six-day establishment period, antivirals can be removed and the infected cultures maintained for several weeks. Subsequent treatment with sodium butyrate induces reactivation and production of new infectious virus. Human neurons derived from stem cells provide the appropriate species context to study this exclusively human virus with the potential for more extensive manipulation of the progenitors and access to a wide range of preexisting molecular tools. PMID- 28594344 TI - Design and Synthesis of Non-Peptide Mimetics Mapping the Immunodominant Myelin Basic Protein (MBP83-96) Epitope to Function as T-Cell Receptor Antagonists. AB - Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83-96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83-96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83-99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS. PMID- 28594345 TI - Synthesis and Evaluation of Antimicrobial Activity of [R4W4K]-Levofloxacin and [R4W4K]-Levofloxacin-Q Conjugates. AB - The development of a new class of antibiotics to fight bacterial resistance is a time-consuming effort associated with high-cost and commercial risks. Thus, modification, conjugation or combination of existing antibiotics to enhance their efficacy is a suitable strategy. We have previously reported that the amphiphilic cyclic peptide [R4W4] had antibacterial activity with a minimum inhibitory concentration (MIC) of 2.97 ug/mL against Methicillin-resistant Staphylococcus aureus (MRSA). Herein, we hypothesized that conjugation or combination of the amphiphilic cyclic peptide [R4W4] with levofloxacin or levofloxacin-Q could improve the antibacterial activity of levofloxacin and levofloxacin-Q. Fmoc/tBu solid-phase chemistry was employed to synthesize conjugates of [R4W4K] levofloxacin-Q and [R4W4K]-levofloxacin. The carboxylic acid group of levofloxacin or levofloxacin-Q was conjugated with the amino group of beta alanine attached to lysine in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3 tetramethyluronium hexafluorophosphate (HBTU) and N,N-diisopropylethylamine (DIPEA) for 3 h to afford the products. Antibacterial assays were conducted to determine the potency of conjugates [R4W4K]-levofloxacin-Q and [R4W4K] levofloxacin against MRSA and Klebsiella pneumoniae. Although levofloxacin-Q was inactive even at a concentration of 128 ug/mL, [R4W4K]-levofloxacin-Q conjugate and the corresponding physical mixture showed MIC values of 8 ug/mL and 32 ug/mL against MRSA and Klebsiella pneumonia, respectively, possibly due to the activity of the peptide. On the other hand, [R4W4K]-levofloxacin conjugate (MIC = 32 ug/mL and MIC = 128 ug/mL) and the physical mixture (MIC = 8 ug/mL and 32 ug/mL) was less active than levofloxacin (MIC = 2 ug/mL and 4 = ug/mL) against MRSA and Klebsiella pneumoniae, respectively. The data showed that the conjugation of levofloxacin with [R4W4K] significantly reduced the antibacterial activity compared to the parent analogs, while [R4W4K]-levofloxacin-Q conjugate was more significantly potent than levofloxacin-Q alone. PMID- 28594348 TI - Correction: Vialard, L., et al. Toward a Socio-Territorial Approach to Health: Health Equity in West Africa. Int. J. Environ. Res. Public Health 2017, 14, 106. AB - n/a. PMID- 28594347 TI - 'Hidden Habitus': A Qualitative Study of Socio-Ecological Influences on Drinking Practices and Social Identity in Mid-Adolescence. AB - This study explored mid-adolescents' views and experiences of socio-ecological influences on their drinking practices in order to help inform the development of interventions to reduce alcohol-related risk. We conducted 31 in-depth interviews with young people aged 13-17 in North East England. Verbatim interview transcripts and field notes were coded systematically and analysed thematically, following the principles of constant comparison. We adopted Bourdieu's idea of social game-playing and elements of his conceptual toolkit (particularly habitus, capital and field) during analysis. Analysis yielded three intersecting themes: (1) 'drinking etiquette': conveying taste and disgust; (2) 'playing the drinking game': demonstrating cultural competency; (3) 'hidden habitus'-the role of alcohol marketing. Our work demonstrates that there is a nexus of influential factors which come together to help shape and reinforce mid-adolescents' behaviour, norms and values in relation to alcohol consumption. Drinking practices are not just formed by friendships and family traditions, these are also subject to wider cultural shaping including by the alcohol industry which can encourage brand identification, and gear specific products to add 'distinction'. However young people are not inactive players and they use aspects of capital and social games to help cement their identity and present themselves in particular ways which in turn are influenced by age, gender and social status. Guided by promising work in the tobacco field, interventions which focus on critical awareness of the framing of alcohol products by key stakeholders, such as policymakers, commercial industry and public health professionals, and by wider society may facilitate behaviour change among young people. PMID- 28594349 TI - An Effective, Versatile, and Inexpensive Device for Oxygen Uptake Measurement. AB - In the last ten years, the use of fluorescent probes developed to measure oxygen has resulted in several marketed devices, some unreasonably expensive and with little flexibility. We have explored the use of the effective, versatile, and inexpensive Redflash technology to determine oxygen uptake by a number of different biological samples using various layouts. This technology relies on the use of an optic fiber equipped at its tip with a membrane coated with a fluorescent dye (www.pyro-science.com). This oxygen-sensitive dye uses red light excitation and lifetime detection in the near infrared. So far, the use of this technology has mostly been used to determine oxygen concentration in open spaces for environmental studies, especially in aquatic media. The oxygen uptake determined by the device can be easily assessed in small volumes of respiration medium and combined with the measurement of additional parameters, such as lactate excretion by intact cells or the membrane potential of purified mitochondria. We conclude that the performance of by this technology should make it a first choice in the context of both fundamental studies and investigations for respiratory chain deficiencies in human samples. PMID- 28594346 TI - Interactive Roles of DNA Helicases and Translocases with the Single-Stranded DNA Binding Protein RPA in Nucleic Acid Metabolism. AB - Helicases and translocases use the energy of nucleoside triphosphate binding and hydrolysis to unwind/resolve structured nucleic acids or move along a single stranded or double-stranded polynucleotide chain, respectively. These molecular motors facilitate a variety of transactions including replication, DNA repair, recombination, and transcription. A key partner of eukaryotic DNA helicases/translocases is the single-stranded DNA binding protein Replication Protein A (RPA). Biochemical, genetic, and cell biological assays have demonstrated that RPA interacts with these human molecular motors physically and functionally, and their association is enriched in cells undergoing replication stress. The roles of DNA helicases/translocases are orchestrated with RPA in pathways of nucleic acid metabolism. RPA stimulates helicase-catalyzed DNA unwinding, enlists translocases to sites of action, and modulates their activities in DNA repair, fork remodeling, checkpoint activation, and telomere maintenance. The dynamic interplay between DNA helicases/translocases and RPA is just beginning to be understood at the molecular and cellular levels, and there is still much to be learned, which may inform potential therapeutic strategies. PMID- 28594350 TI - Micro-Electromechanical Affinity Sensor for the Monitoring of Glucose in Bioprocess Media. AB - An affinity-viscometry-based micro-sensor probe for continuous glucose monitoring was investigated with respect to its suitability for bioprocesses. The sensor operates with glucose and dextran competing as binding partner for concanavalin A, while the viscosity of the assay scales with glucose concentration. Changes in viscosity are determined with a micro-electromechanical system (MEMS) in the measurement cavity of the sensor probe. The study aimed to elucidate the interactions between the assay and a typical phosphate buffered bacterial cultivation medium. It turned out that contact with the medium resulted in a significant long-lasting drift of the assay's viscosity at zero glucose concentration. Adding glucose to the medium lowers the drift by a factor of eight. The cglc values measured off-line with the glucose sensor for monitoring of a bacterial cultivation were similar to the measurements with an enzymatic assay with a difference of less than +/-0.15 g.L-1. We propose that lectin agglomeration, the electro-viscous effect, and constitutional changes of concanavalin A due to exchanges of the incorporated metal ions may account for the observed viscosity increase. The study has demonstrated the potential of the MEMS sensor to determine sensitive viscosity changes within very small sample volumes, which could be of interest for various biotechnological applications. PMID- 28594351 TI - Exploring Diet Quality between Urban and Rural Dwelling Women of Reproductive Age. AB - Health disparities, including weight gain and obesity exist between urban and rural dwelling women. The primary aim was to compare diet quality in urban and rural women of reproductive age, and secondary analyses of the difference in macronutrient and micronutrient intake in urban and rural women, and the predictors of diet quality. Diet quality was assessed in urban (n = 149) and rural (n = 394) women by a modified version of the Dietary Guideline Index (DGI) energy, macronutrient and micronutrient intake from a food frequency questionnaire (FFQ) and predictors of diet quality. Diet quality did not significantly differ between urban and rural women (mean +/- standard deviation (SD), 84.8 +/- 15.9 vs. 83.9 +/- 16.5, p = 0.264). Rural women reported a significantly higher intake of protein, fat, saturated fat, monounsaturated fat, cholesterol and iron and a higher score in the meat and meat alternatives component of the diet quality tool in comparison to urban women. In all women, a higher diet quality was associated with higher annual household income (>$Australian dollar (AUD) 80,000 vs. <$AUD80,000 p = 0.013) and working status (working fulltime/part-time vs. unemployed p = 0.043). Total diet quality did not differ in urban and rural women; however, a higher macronutrient consumption pattern was potentially related to a higher lean meat intake in rural women. Women who are unemployed and on a lower income are an important target group for future dietary interventions aiming to improve diet quality. PMID- 28594353 TI - The Development of an Open Hardware and Software System Onboard Unmanned Aerial Vehicles to Monitor Concentrated Solar Power Plants. AB - Concentrated solar power (CSP) plants are increasingly gaining interest as a source of renewable energy. These plants face several technical problems and the inspection of components such as absorber tubes in parabolic trough concentrators (PTC), which are widely deployed, is necessary to guarantee plant efficiency. This article presents a system for real-time industrial inspection of CSP plants using low-cost, open-source components in conjunction with a thermographic sensor and an unmanned aerial vehicle (UAV). The system, available in open-source hardware and software, is designed to be employed independently of the type of device used for inspection (laptop, smartphone, tablet or smartglasses) and its operating system. Several UAV flight missions were programmed as follows: flight altitudes at 20, 40, 60, 80, 100 and 120 m above ground level; and three cruising speeds: 5, 7 and 10 m/s. These settings were chosen and analyzed in order to optimize inspection time. The results indicate that it is possible to perform inspections by an UAV in real time at CSP plants as a means of detecting anomalous absorber tubes and improving the effectiveness of methodologies currently being utilized. Moreover, aside from thermographic sensors, this contribution can be applied to other sensors and can be used in a broad range of applications where real-time georeferenced data visualization is necessary. PMID- 28594352 TI - Automatic Artifact Removal in EEG of Normal and Demented Individuals Using ICA-WT during Working Memory Tasks. AB - Characterizing dementia is a global challenge in supporting personalized health care. The electroencephalogram (EEG) is a promising tool to support the diagnosis and evaluation of abnormalities in the human brain. The EEG sensors record the brain activity directly with excellent time resolution. In this study, EEG sensor with 19 electrodes were used to test the background activities of the brains of five vascular dementia (VaD), 15 stroke-related patients with mild cognitive impairment (MCI), and 15 healthy subjects during a working memory (WM) task. The objective of this study is twofold. First, it aims to enhance the recorded EEG signals using a novel technique that combines automatic independent component analysis (AICA) and wavelet transform (WT), that is, the AICA-WT technique; second, it aims to extract and investigate the spectral features that characterize the post-stroke dementia patients compared to the control subjects. The proposed AICA-WT technique is a four-stage approach. In the first stage, the independent components (ICs) were estimated. In the second stage, three-step artifact identification metrics were applied to detect the artifactual components. The components identified as artifacts were marked as critical and denoised through DWT in the third stage. In the fourth stage, the corrected ICs were reconstructed to obtain artifact-free EEG signals. The performance of the proposed AICA-WT technique was compared with those of two other techniques based on AICA and WT denoising methods using cross-correlation X C o r r and peak signal to noise ratio ( P S N R ) (ANOVA, p ? 0.05). The AICA-WT technique exhibited the best artifact removal performance. The assumption that there would be a deceleration of EEG dominant frequencies in VaD and MCI patients compared with control subjects was assessed with AICA-WT (ANOVA, p ? 0.05). Therefore, this study may provide information on post-stroke dementia particularly VaD and stroke-related MCI patients through spectral analysis of EEG background activities that can help to provide useful diagnostic indexes by using EEG signal processing. PMID- 28594354 TI - Letter to the Editor Re: McClure et al. Nutrients 2017, 9, 95. AB - n/a. PMID- 28594355 TI - Comparing Proteolytic Fingerprints of Antigen-Presenting Cells during Allergen Processing. AB - Endolysosomal processing has a critical influence on immunogenicity as well as immune polarization of protein antigens. In industrialized countries, allergies affect around 25% of the population. For the rational design of protein-based allergy therapeutics for immunotherapy, a good knowledge of T cell-reactive regions on allergens is required. Thus, we sought to analyze endolysosomal degradation patterns of inhalant allergens. Four major allergens from ragweed, birch, as well as house dust mites were produced as recombinant proteins. Endolysosomal proteases were purified by differential centrifugation from dendritic cells, macrophages, and B cells, and combined with allergens for proteolytic processing. Thereafter, endolysosomal proteolysis was monitored by protein gel electrophoresis and mass spectrometry. We found that the overall proteolytic activity of specific endolysosomal fractions differed substantially, whereas the degradation patterns of the four model allergens obtained with the different proteases were extremely similar. Moreover, previously identified T cell epitopes were assigned to endolysosomal peptides and indeed showed a good overlap with known T cell epitopes for all four candidate allergens. Thus, we propose that the degradome assay can be used as a predictor to determine antigenic peptides as potential T cell epitopes, which will help in the rational design of protein-based allergy vaccine candidates. PMID- 28594356 TI - Synergistic Antibacterial Effects of Chitosan-Caffeic Acid Conjugate against Antibiotic-Resistant Acne-Related Bacteria. AB - The object of this study was to discover an alternative therapeutic agent with fewer side effects against acne vulgaris, one of the most common skin diseases. Acne vulgaris is often associated with acne-related bacteria such as Propionibacteriumacnes, Staphylococcusepidermidis, Staphylococcusaureus, and Pseudomonasaeruginosa. Some of these bacteria exhibit a resistance against commercial antibiotics that have been used in the treatment of acne vulgaris (tetracycline, erythromycin, and lincomycin). In the current study, we tested in vitro antibacterial effect of chitosan-phytochemical conjugates on acne-related bacteria. Three chitosan-phytochemical conjugates used in this study exhibited stronger antibacterial activity than that of chitosan (unmodified control). Chitosan-caffeic acid conjugate (CCA) showed the highest antibacterial effect on acne-related bacteria along with minimum inhibitory concentration (MIC; 8 to 256 MUg/mL). Additionally, the MIC values of antibiotics against antibiotic-resistant P. acnes and P.aeruginosa strains were dramatically reduced in combination with CCA, suggesting that CCA would restore the antibacterial activity of the antibiotics. The analysis of fractional inhibitory concentration (FIC) indices clearly revealed a synergistic antibacterial effect of CCA with antibiotics. Thus, the median sum of FIC (?FIC) values against the antibiotic-resistant bacterial strains ranged from 0.375 to 0.533 in the combination mode of CCA and antibiotics. The results of the present study suggested a potential possibility of chitosan-phytochemical conjugates in the control of infections related to acne vulgaris. PMID- 28594358 TI - Activation of Magnesium Lignosulfonate and Kraft Lignin: Influence on the Properties of Phenolic Resin-Based Composites for Potential Applications in Abrasive Materials. AB - Magnesium lignosulfonate and kraft lignin were activated by different oxidizing agents for use in phenolic resin composites used for the production of abrasive components. The physicochemical properties of the oxidized materials were analyzed by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), dynamic mechanical-thermal analysis (DMTA) and inverse gas chromatography (IGC). The homogeneity of the model abrasive composites containing the studied products was assessed based on observations obtained using a scanning electron microscope (SEM). FTIR and XPS analysis of the oxidized products indicated that the activation process leads mainly to the formation of carbonyl groups. The IGC technique was used to assess changes in the surface energy and the acid-base properties of the studied biopolymers. The changes in the acid-base properties suggest that more groups acting as electron donors appear on the oxidized surface of the materials. DMTA studies showed that the model composites with 5% magnesium lignosulfonate oxidized by H2O2 had the best thermomechanical properties. Based on the results it was possible to propose a hypothetical mechanism of the oxidation of the natural polymers. The use of such oxidized products may improve the thermomechanical properties of abrasive articles. PMID- 28594359 TI - Data Acquisition Based on Stable Matching of Bipartite Graph in Cooperative Vehicle-Infrastructure Systems. AB - Existing studies on data acquisition in vehicular networks often take the mobile vehicular nodes as data carriers. However, their autonomous movements, limited resources and security risks impact the quality of services. In this article, we propose a data acquisition model using stable matching of bipartite graph in cooperative vehicle-infrastructure systems, namely, DAS. Contents are distributed to roadside units, while vehicular nodes support supplementary storage. The original distribution problem is formulated as a stable matching problem of bipartite graph, where the data and the storage cells compose two sides of vertices. Regarding the factors relevant with the access ratio and delay, the preference rankings for contents and roadside units are calculated, respectively. With a multi-replica preprocessing algorithm to handle the potential one-to-many mapping, the matching problem is addressed in polynomial time. In addition, vehicular nodes carry and forward assistant contents to deliver the failed packets because of bandwidth competition. Furthermore, an incentive strategy is put forward to boost the vehicle cooperation and to achieve a fair bandwidth allocation at roadside units. Experiments show that DAS achieves a high access ratio and a small storage cost with an acceptable delay. PMID- 28594357 TI - Identification of Novel Placentally Expressed Aspartic Proteinase in Humans. AB - This study presents pioneering data concerning the human pregnancy-associated glycoprotein-Like family, identified in the genome, of the term placental transcriptome and proteome. RNA-seq allowed the identification of 1364 bp hPAG L/pep cDNA with at least 56.5% homology with other aspartic proteinases (APs). In silico analyses revealed 388 amino acids (aa) of full-length hPAG-L polypeptide precursor, with 15 aa-signal peptide, 47 aa-blocking peptide and 326 aa-mature protein, and two Asp residues (D), specific for a catalytic cleft of the APs (VVFDTGSSNLWV91-102 and AIVDTGTSLLTG274-285). Capillary sequencing identified 9330 bp of the hPAG-L gene (Gen Bank Acc. No. KX533473), composed of nine exons and eight introns. Heterologous Western blotting revealed the presence of one dominant 60 kDa isoform of the hPAG-L amongst cellular placental proteins. Detection with anti-pPAG-P and anti-Rec pPAG2 polyclonals allowed identification of the hPAG-L proteins located within regions of chorionic villi, especially within the syncytiotrophoblast of term singleton placentas. Our novel data extend the present knowledge about the human genome, as well as placental transcriptome and proteome during term pregnancy. Presumably, this may contribute to establishing a new diagnostic tool for examination of some disturbances during human pregnancy, as well as growing interest from both scientific and clinical perspectives. PMID- 28594360 TI - Rapid Complexation of Aptamers by Their Specific Antidotes. AB - Nucleic acid ligands, aptamers, harbor the unique characteristics of small molecules and antibodies. The specificity and high affinity of aptamers enable their binding to different targets, such as small molecules, proteins, or cells. Chemical modifications of aptamers allow increased bioavailability. A further great benefit of aptamers is the antidote (AD)-mediated controllability of their effect. In this study, the AD-mediated complexation and neutralization of the thrombin binding aptamer NU172 and Toll-like receptor 9 (TLR9) binding R10-60 aptamer were determined. Thereby, the required time for the generation of aptamer/AD-complexes was analyzed at 37 degrees C in human serum using gel electrophoresis. Afterwards, the blocking of aptamers' effects was analyzed by determining the activated clotting time (ACT) in the case of the NU172 aptamer, or the expression of immune activation related genes IFN-1beta, IL-6, CXCL-10, and IL-1beta in the case of the R10-60 aptamer. Gel electrophoresis analyses demonstrated the rapid complexation of the NU172 and R10-60 aptamers by complementary AD binding after just 2 min of incubation in human serum. A rapid neutralization of anticoagulant activity of NU172 was also demonstrated in fresh human whole blood 5 min after addition of AD. Furthermore, the TLR9-mediated activation of PMDC05 cells was interrupted after the addition of the R10-60 AD. Using these two different aptamers, the rapid antagonizability of the aptamers was demonstrated in different environments; whole blood containing numerous proteins, cells, and different small molecules, serum, or cell culture media. Thus, nucleic acid ADs are promising molecules, which offer several possibilities for different in vivo applications, such as antagonizing aptamer-based drugs, immobilization, or delivery of oligonucleotides to defined locations. PMID- 28594361 TI - Atom Efficient Preparation of Zinc Selenates for the Synthesis of Selenol Esters under "On Water" Conditions. AB - We describe here an atom efficient procedure to prepare selenol esters in good to excellent yields by reacting [(PhSe)2Zn] or [(PhSe)2Zn]TMEDA with acyl chlorides under "on water" conditions. The method is applicable to a series of aromatic and aliphatic acyl chlorides and tolerates the presence of other functionalities in the starting material. PMID- 28594362 TI - Green Synthesis of Zinc Oxide Nanoparticles for Enhanced Adsorption of Lead Ions from Aqueous Solutions: Equilibrium, Kinetic and Thermodynamic Studies. AB - In the present study, ZnO nanoparticles (NPs) were synthesized in zerumbone solution by a green approach and appraised for their ability to absorb Pb(II) ions from aqueous solution. The formation of as-synthesized NPs was established by X-ray diffraction (XRD), Transmission Electron Microscopy (TEM), and UV visible studies. The XRD and TEM analyses revealed high purity and wurtzite hexagonal structure of ZnO NPs with a mean size of 10.01 +/- 2.6 nm. Batch experiments were performed to investigate the impact of process parameters viz. Pb(II) concentration, pH of solution, adsorbent mass, solution temperature, and contact time variations on the removal efficiency of Pb(II). The adsorption isotherm data provided that the adsorption process was mainly monolayer on ZnO NPs. The adsorption process follows pseudo-second-order reaction kinetic. The maximum removal efficiencies were 93% at pH 5. Thermodynamic parameters such as enthalpy change (DeltaH0), free energy change (DeltaG0), and entropy change (DeltaS0) were calculated; the adsorption process was spontaneous and endothermic. The good efficiency of the as-synthesized NPs makes them attractive for applications in water treatment, for removal of heavy metals from aqueous system. PMID- 28594364 TI - Undernutrition and Overnutrition Burden for Diseases in Developing Countries: The Role of Oxidative Stress Biomarkers to Assess Disease Risk and Interventional Strategies. AB - The increased life expectancy, urbanization, and unhealthy lifestyle characterized by a shift towards a sedentary lifestyle and decreased energy expenditure are considered the main drivers of epidemiological transition. In particular, developing countries are facing a double burden caused by coexisting under- and over-nutrition, which causes a change in the disease profile from infectious diseases to a chronic degenerative pattern. This review discusses the under- and over-nutrition context in Mauritania and India, two countries that are experiencing a nutritional transition, and where we began a collaboration with local medical staff to integrate interventional and diagnostic guidelines. If many studies about diet and its relationship to non-communicable diseases are available for India, very few nutrition and cardiovascular risk studies have been conducted in Mauritania. Presently, with the exponential increase of nutrition related diseases, targeted approaches are needed to provide balanced diets in parallel with the development of national preventive health systems and screening programs adapted to local needs. In this context, the measurement of oxidative stress biomarkers could be promising as an additive tool to assess cardiovascular (CV) risk in general population, and ameliorating prevention in patients at CV risk or with overt CV disease. Moreover, the possibility of improving the outcome by the direct employment of antioxidant remains plausible. Moreover, studies on the content of antioxidant in different foods may be helpful to develop a balanced diet, and achieve the maximal nutritional and functional properties of cultivars with benefits for human health. PMID- 28594363 TI - Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy. AB - The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP 1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p STAT3 signaling and combined strategies that were/are discovered in our and our colleagues' laboratories. PMID- 28594366 TI - RF EMF Risk Perception Revisited: Is the Focus on Concern Sufficient for Risk Perception Studies? AB - An implicit assumption of risk perception studies is that concerns expressed in questionnaires reflect concerns in everyday life. The aim of the present study is to check this assumption, i.e., the extrapolability of risk perceptions expressed in a survey, to risk perceptions in everyday life. To that end, risk perceptions were measured by a multidimensional approach. In addition to the traditional focus on measuring the magnitude of risk perceptions, the thematic relevance (how often people think about a risk issue) and the discursive relevance (how often people think about or discuss a risk issue) of risk perceptions were also collected. Taking into account this extended view of risk perception, an online survey was conducted in six European countries with 2454 respondents, referring to radio frequency electromagnetic field (RF EMF) risk potentials from base stations, and access points, such as WiFi routers and cell phones. The findings reveal that the present study's multidimensional approach to measuring risk perception provides a more differentiated understanding of RF EMF risk perception. High levels of concerns expressed in questionnaires do not automatically imply that these concerns are thematically relevant in everyday life. We use thematic relevance to distinguish between enduringly concerned (high concern according to both questionnaire and thematic relevance) and not enduringly concerned participants (high concern according to questionnaire but no thematic relevance). Furthermore, we provide data for the empirical value of this distinction: Compared to other participants, enduringly concerned subjects consider radio frequency electromagnetic field exposure to a greater extent as a moral and affective issue. They also see themselves as highly exposed to radio frequency electromagnetic fields. However, despite these differences, subjects with high levels of thematic relevance are nevertheless sensitive to exposure reduction as a means for improving the acceptance of base stations in their neighborhood. This underlines the value of exposure reduction for the acceptance of radio frequency electromagnetic field communication technologies. PMID- 28594367 TI - From Intermolecular Interactions to Texture in Polycrystalline Surfaces of 1,omega-alkanediols (omega = 10-13). AB - Differences on herringbone molecular arrangement in two forms of long-chain 1,omega-alkanediols (CnH2n+2O2 with n = 10, 11, 12, 13) are explained from the analysis of O-H...O hydrogen-bond sequences in infinite chains and the role of a C-H...O intramolecular hydrogen-bond in stabilization of a gauche defect, as well as the inter-grooving effectiveness on molecular packing. GIXD (Glancing Incidence X-ray Diffraction) experiments were conducted on polycrystalline monophasic samples. Diffracted intensities were treated with the multi-axial March-Dollase method to correlate energetic and geometrical features of molecular interactions with the crystalline morphology and textural pattern of samples. The monoclinic (P21/c, Z = 2) crystals of the even-numbered members (n = 10, 12; DEDOL and DODOL, respectively) are diametrical prisms with combined form {104}/{ 104}/{001} and present a two-fold platelet-like preferred orientation, whereas orthorhombic (P212121, Z = 4) odd-numbered members (n = 11, 13; UNDOL and TRDOL, respectively) present a dominant needle-like orientation on direction [101] (fiber texture). We show that crystalline structures of medium complexity and their microstructures can be determined from rapid GIXD experiments from standard radiation, combined with molecular replacement procedure using crystal structures of compounds with higher chain lengths as reference data. PMID- 28594365 TI - BrWRKY65, a WRKY Transcription Factor, Is Involved in Regulating Three Leaf Senescence-Associated Genes in Chinese Flowering Cabbage. AB - Plant-specific WRKY transcription factors (TFs) have been implicated to function as regulators of leaf senescence, but their association with postharvest leaf senescence of economically important leafy vegetables, is poorly understood. In this work, the characterization of a Group IIe WRKY TF, BrWRKY65, from Chinese flowering cabbage (Brassica rapa var. parachinensis) is reported. The expression of BrWRKY65 was up-regulated following leaf chlorophyll degradation and yellowing during postharvest senescence. Subcellular localization and transcriptional activation assays showed that BrWRKY65 was localized in the nucleus and exhibited trans-activation ability. Further electrophoretic mobility shift assay (EMSA) and transient expression analysis clearly revealed that BrWRKY65 directly bound to the W-box motifs in the promoters of three senescence-associated genes (SAGs) such as BrNYC1 and BrSGR1 associated with chlorophyll degradation, and BrDIN1, and subsequently activated their expressions. These findings demonstrate that BrWRKY65 may be positively associated with postharvest leaf senescence, at least partially, by the direct activation of SAGs. Taken together, these findings provide new insights into the transcriptional regulatory mechanism of postharvest leaf senescence in Chinese flowering cabbage. PMID- 28594369 TI - Calibration of Magnetometers with GNSS Receivers and Magnetometer-Aided GNSS Ambiguity Fixing. AB - Magnetometers provide compass information, and are widely used for navigation, orientation and alignment of objects. As magnetometers are affected by sensor biases and eventually by systematic distortions of the Earth magnetic field, a calibration is needed. In this paper, a method for calibration of magnetometers with three Global Navigation Satellite System (GNSS) receivers is presented. We perform a least-squares estimation of the magnetic flux and sensor biases using GNSS-based attitude information. The attitude is obtained from the relative positions between the GNSS receivers in the North-East-Down coordinate frame and prior knowledge of these relative positions in the platform's coordinate frame. The relative positions and integer ambiguities of the periodic carrier phase measurements are determined with an integer least-squares estimation using an integer decorrelation and sequential tree search. Prior knowledge on the relative positions is used to increase the success rate of ambiguity fixing. We have validated the proposed method with low-cost magnetometers and GNSS receivers on a vehicle in a test drive. The calibration enabled a consistent heading determination with an accuracy of five degrees. This precise magnetometer-based attitude information allows an instantaneous GNSS integer ambiguity fixing. PMID- 28594368 TI - Methods for Measuring Autophagy in Mice. AB - Autophagy is a dynamic intracellular process that mediates the degradation of damaged cytoplasmic components by the lysosome. This process plays important roles in maintaining normal cellular homeostasis and energy balance. Measuring autophagy activity is critical and although the determination of autophagic flux in isolated cells is well documented, there is a need to have reliable and quantitative assays to evaluate autophagy in whole organisms. Because mouse models have been precious in establishing the functional significance of autophagy under physiological or pathological conditions, we present in this chapter a compendium of the current available methods to measure autophagy in mice, and discuss their advantages and limitations. PMID- 28594370 TI - Security-Enhanced Push Button Configuration for Home Smart Control. AB - With the emergence of smart and converged home services, the need for the secure and easy interplay of various devices has been increased. Push Button Configuration (PBC) is one of the technologies proposed for easy set-up of a secure session between IT and consumer devices. Although the Wi-Fi Direct specification explicitly states that all devices must support the PBC method, its applicability is very limited. This is because the security vulnerability of PBC can be maliciously exploited so that attackers can make illegitimate sessions with consumer devices. To address this problem, this paper proposes a novel Security-enhanced PBC (SePBC) scheme with which we can uncover suspicious or malicious devices. The proposed mechanism has several unique features. First, we develop a secure handshake distance measurement protocol by preventing an adversary sitting outside the region from maliciously manipulating its distance to be fake. Second, it is compatible with the original Wi-Fi PBC without introducing a brand-new methodology. Finally, SePBC uses lightweight operations without CPU-intensive cryptography computation and employs inexpensive H/W. Moreover, it needs to incur little overhead when there is no attack. This paper also designs and implements the proposed SePBC in the real world. Our experimental results and analysis show that the proposed SePBC scheme effectively defeats attacks on PBC while minimizing the modification of the original PBC equipment. PMID- 28594371 TI - On Line Service Composition in the Integrated Clinical Environment for eHealth and Medical Systems. AB - Medical and eHealth systems are progressively realized in the context of standardized architectures that support safety and ease the integration of the heterogeneous (and often proprietary) medical devices and sensors. The Integrated Clinical Environment (ICE) architecture appeared recently with the goal of becoming a common framework for defining the structure of the medical applications as concerns the safe integration of medical devices and sensors. ICE is simply a high level architecture that defines the functional blocks that should be part of a medical system to support interoperability. As a result, the underlying communication backbone is broadly undefined as concerns the enabling software technology (including the middleware) and associated algorithms that meet the ICE requirements of the flexible integration of medical devices and services. Supporting the on line composition of services in a medical system is also not part of ICE; however, supporting this behavior would enable flexible orchestration of functions (e.g., addition and/or removal of services and medical equipment) on the fly. iLandis one of the few software technologies that supports on line service composition and reconfiguration, ensuring time-bounded transitions across different service orchestrations; it supports the design, deployment and on line reconfiguration of applications, which this paper applies to service-based eHealth domains. This paper designs the integration between ICE architecture and iLand middleware to enhance the capabilities of ICE with on line service composition and the time-bounded reconfiguration of medical systems based on distributed services. A prototype implementation of a service-based eHealth system for the remote monitoring of patients is described; it validates the enhanced capacity of ICE to support dynamic reconfiguration of the application services. Results show that the temporal cost of the on line reconfiguration of the eHealth application is bounded, achieving a low overhead resulting from the addition of ICE compliance. PMID- 28594373 TI - An FPGA-Based WASN for Remote Real-Time Monitoring of Endangered Species: A Case Study on the Birdsong Recognition of Botaurus stellaris. AB - Fast environmental variations due to climate change can cause mass decline or even extinctions of species, having a dramatic impact on the future of biodiversity. During the last decade, different approaches have been proposed to track and monitor endangered species, generally based on costly semi-automatic systems that require human supervision adding limitations in coverage and time. However, the recent emergence of Wireless Acoustic Sensor Networks (WASN) has allowed non-intrusive remote monitoring of endangered species in real time through the automatic identification of the sound they emit. In this work, an FPGA-based WASN centralized architecture is proposed and validated on a simulated operation environment. The feasibility of the architecture is evaluated in a case study designed to detect the threatened Botaurus stellaris among other 19 cohabiting birds species in The Parc Natural dels Aiguamolls de l'Empord. PMID- 28594372 TI - Purine Acquisition and Synthesis by Human Fungal Pathogens. AB - While members of the Kingdom Fungi are found across many of the world's most hostile environments, only a limited number of species can thrive within the human host. The causative agents of the most common invasive fungal infections are Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. During the infection process, these fungi must not only combat the host immune system while adapting to dramatic changes in temperature and pH, but also acquire sufficient nutrients to enable growth and dissemination in the host. One class of nutrients required by fungi, which is found in varying concentrations in their environmental niches and the human host, is the purines. These nitrogen containing heterocycles are one of the most abundant organic molecules in nature and are required for roles as diverse as signal transduction, energy metabolism and DNA synthesis. The most common life-threatening fungal pathogens can degrade, salvage and synthesize de novo purines through a number of enzymatic steps that are conserved. While these enable them to adapt to the changing purine availability in the environment, only de novo purine biosynthesis is essential during infection and therefore an attractive antimycotic target. PMID- 28594374 TI - Higher Anti-Liver Fibrosis Effect of Cordyceps militaris-Fermented Product Cultured with Deep Ocean Water via Inhibiting Proinflammatory Factors and Fibrosis-Related Factors Expressions. AB - Deep ocean water (DOW) has been shown to enhance the functional components of fungi, resulting in increased health benefits. Therefore, using DOW for culturing fungi can enhance the cordycepin and adenosine of Cordyceps militaris (CM) and its protective effects on the liver. In this study, the antiliver fibrosis effects and mechanisms of ultrapure water-cultured CM (UCM), DOW-cultured CM (DCM), synthetic water-cultured CM, DOW, cordycepin, and adenosine were compared in the liver fibrosis mice induced by intraperitoneal injections of thioacetamide (TAA). The results indicated that DCM exhibited superior performance in reducing liver collagen accumulation, mitigating liver injuries, inhibiting proinflammatory factors and fibrosis-related factor (TGF-beta1, Smad2/3, alpha SMA, COL1A1) expression compared with UCM. DOW, cordycepin, and adenosine also performed antiliver fibrosis effect. Therefore, because DCM is rich in DOW and functional components, it can achieve anti-liver fibrosis effects through multiple pathways. These ameliorative effects are considerably superior to those of UCM. PMID- 28594375 TI - A High-Protein Diet Reduces Weight Gain, Decreases Food Intake, Decreases Liver Fat Deposition, and Improves Markers of Muscle Metabolism in Obese Zucker Rats. AB - A primary factor in controlling and preventing obesity is through dietary manipulation. Diets higher in protein have been shown to improve body composition and metabolic health during weight loss. The objective of this study was to examine the effects of a high-protein diet versus a moderate-protein diet on muscle, liver and fat metabolism and glucose regulation using the obese Zucker rat. Twelve-week old, male, Zucker (fa/fa) and lean control (Fa/fa) rats were randomly assigned to either a high-protein (40% energy) or moderate-protein (20% energy) diet for 12 weeks, with a total of four groups: lean 20% protein (L20; n = 8), lean 40% protein (L40; n = 10), obese 20% protein (O20; n = 8), and obese 40% protein (O40; n = 10). At the end of 12 weeks, animals were fasted and euthanized. There was no difference in food intake between L20 and L40. O40 rats gained less weight and had lower food intake (p < 0.05) compared to O20. O40 rats had lower liver weight (p < 0.05) compared to O20. However, O40 rats had higher orexin (p < 0.05) levels compared to L20, L40 and O20. Rats in the L40 and O40 groups had less liver and muscle lipid deposition compared to L20 and L40 diet rats, respectively. O40 had decreased skeletal muscle mechanistic target of rapamycin complex 1 (mTORC1) phosphorylation and peroxisome proliferator activated receptor gamma (PPARgamma) mRNA expression compared to O20 (p < 0.05), with no difference in 5' AMP-activated protein kinase (AMPK), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), protein kinase B (Akt) or p70 ribosomal S6 kinase (p70S6K) phosphorylation. The data suggest that high-protein diets have the potential to reduce weight gain and alter metabolism, possibly through regulation of an mTORC1-dependent pathway in skeletal muscle. PMID- 28594376 TI - The Roles of Reactive Oxygen Species and Nitric Oxide in Perfluorooctanoic Acid Induced Developmental Cardiotoxicity and l-Carnitine Mediated Protection. AB - Perfluorooctanoic acid (PFOA) is an environmental contaminant that could induce developmental cardiotoxicity in a chicken embryo, which may be alleviated by l carnitine. To explore the roles of reactive oxygen species (ROS) and nitric oxide (NO) in such changes and the potential effects of l-carnitine, fertile chicken eggs were exposed to PFOA via an air cell injection, with or without l-carnitine co-treatment. The ROS and NO levels in chicken embryo hearts were determined with electron spin resonance (ESR), and the protein levels of the nuclear factor kappa light chain-enhancer of activated B cells (NF-kappaB) p65 and inducible nitric oxide synthase (iNOS) in chicken embryo hearts were assessed with western blotting. The results of ESR indicated that PFOA exposure induced an elevation in the ROS levels in ED19 chicken embryo hearts and hatchling chicken hearts, while l-carnitine could alleviate such changes. Meanwhile, increased NO levels were observed in ED19 embryo hearts and hatchling hearts following PFOA exposure, while l-carnitine co-treatment exerted modulatory effects. Western blotting revealed that p65 translocation in ED19 embryo hearts and hatchling hearts was enhanced by PFOA, while l-carnitine co-treatment alleviated such changes. iNOS expression levels in ED19 embryo hearts followed the same pattern as NO levels, while a suppression of expression was observed in hatchling hearts exposed to PFOA. ROS/NF-kappaB p65 and iNOS/NO seem to be involved in the late stage (ED19 and post hatch) of PFOA-induced developmental cardiotoxicity in a chicken embryo. l-carnitine could exert anti-oxidant and NO modulatory effects in the developing chicken embryo hearts, which likely contribute to its cardioprotective effects. PMID- 28594377 TI - Ovicidal and Insecticidal Activities of Pyriproxyfen Derivatives with an Oxime Ester Group. AB - Based on the structural framework of a pyriproxyfen metabolite, nineteen oxime ester derivatives were synthesized via reaction of the carboxylic acids with 4-(2 (2-pyridinyloxy)ethoxy)benzaldehyde oxime. The corresponding structures were comprehensively characterized by 1H-nuclear magnetic resonance (NMR), 13C-NMR, and electrospray ionization high-resolution mass spectrometry (ESI-HRMS). All of the compounds were screened for their insecticidal activities against Plutella xylostella and Myzus persicae, and for their ovicidal activities against Helicoverpa armigera eggs. The results obtained show that most of the oxime ester derivatives displayed moderate to high insecticidal activities and ovicidal activities at a concentration of 600 ug/mL. In particular, the ovicidal activity of compounds 5j, 5o, 5p, 5q, and 5s was determined to be 100%. Importantly, some of the compounds presented even higher biological activities than the reference compound pyriproxyfen. For example, compound 5j displayed an insecticidal activity value of 87.5% against Myzus persicae, whereas the activity value of pyriproxyfen was 68.3% at a concentration of 600 ug/mL. Among the synthesized compounds 5j and 5s exhibited broad biological activity spectra. PMID- 28594378 TI - Structural Inheritance and Redox Performance of Nanoporous Electrodes from Nanocrystalline Fe85.2B10-14P0-4Cu0.8 Alloys. AB - Nanoporous electrodes have been fabricated by selectively dissolving the less noble alpha-Fe crystalline phase from nanocrystalline Fe85.2B14-xPxCu0.8 alloys (x= 0, 2, 4 at.%). The preferential dissolution is triggered by the weaker electrochemical stability of alpha-Fe nanocrystals than amorphous phase. The final nanoporous structure is mainly composed of amorphous residual phase and minor undissolved alpha-Fe crystals and can be predicted from initial microstructure of nanocrystalline precursor alloys. The structural inheritance is proved by the similarity of the size and outlines between nanopores formed after dealloying in 0.1 M H2SO4 and alpha-Fe nanocrystals precipitated after annealing of amorphous Fe85.2B14-xPxCu0.8 (x = 0, 2, 4 at.%) alloys. The Redox peak current density of the nanoporous electrodes obtained from nanocrystalline Fe85.2B10P4Cu0.8 alloys is more than one order higher than those of Fe plate electrode and its counterpart nanocrystalline alloys due to the large surface area and nearly-amorphous nature of ligaments. PMID- 28594379 TI - Anti-Inflammatory Activities and Liver Protection of Alisol F and 25 Anhydroalisol F through the Inhibition of MAPK, STAT3, and NF-kappaB Activation In Vitro and In Vivo. AB - Alisol F and 25-anhydroalisol F isolated from Alisma orientale, were proved to exhibit anti-inflammatory potential in our previous work. In the current study, the anti-inflammatory effects and action mechanisms of alisol F and 25 anhydroalisol F were investigated in vitro. Moreover, the pharmacological effects of alisol F in lipopolysaccharide (LPS)/d-galactosamine (d-gal)-induced acute liver-injured mice were evaluated. The results demonstrated that alisol F and 25 anhydroalisol F could suppress LPS-induced production of nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta), as well as inhibit the mRNA and protein levels of inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX-2). In addition, we investigated the role of alisol F and 25-anhydroalisol F in mediating mitogen-activated protein kinases (MAPKs), signal transducers, and activators of transcription 3 (STAT3) and nuclear factor kappaB (NF-kappaB) pathways involved in the inflammation process of LPS-stimulated RAW 264.7 cells. The phosphorylation of ERK, JNK, p38, and STAT3, and the NF-kappaB signaling pathway, were obviously suppressed in alisol F and 25-anhydroalisol F treated cells. Results obtained from in vitro experiments suggested alisol F obviously improved liver pathological injury by inhibiting the production of TNF-alpha, IL-1beta, and IL 6, and significantly decreasing the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in LPS/d-gal-induced mice. Furthermore, the reduction of phosphorylation of ERK and JNK, as well as suppression of the NF kappaB signaling pathway, were also observed in liver tissues of the alisol F treated mice model. Alisol F and 25-anhydroalisol F may serve as potential leads for development of anti-inflammatory agents for acute liver failure treatment. PMID- 28594380 TI - Effects of Obesity on Pro-Oxidative Conditions and DNA Damage in Liver of DMBA Induced Mammary Carcinogenesis Models. AB - The prevalence of the overweight and obesity is on the rise worldwide. Obesity can increase the risk of certain cancers and liver steatosis development. Previously, we reported that obesity increased liver steatosis in a mammary tumor model, but little is known about the effects of obesity in the liver in regard to global DNA methylation, DNA damage, and oxidative/nitrosative stress. Using a mammary tumor model, we investigated the effects of obesity on oxidative stress and DNA reaction. Five-week-old lean and obese female rats were used. At 50 days of age, all rats received 7,12-dimethylbenz(alpha)anthracene (DMBA) and were sacrificed 155 days later. HPLC with electrochemical and ultraviolet detection and LC-MS were used. Obesity caused higher (p < 0.0004) methionine levels, had no effect (p < 0.055) on SAM levels, caused lower (p < 0.0005) SAH levels, caused higher (p < 0.0005) SAM/SAH ratios, and increased (p < 0.02) global DNA methylation. Levels of free reduced GSH were not significantly lower (p < 0.08), but free oxidized GSSG was higher (p < 0.002) in obese rats. The GSH/GSSG ratio was lower (p < 0.0001), and oxidized guanosine was higher (p < 0.002) in DNA of obese rats compared to lean rats. Obesity caused significant oxidative/nitrosative stress, oxidative DNA damage, and change of DNA methylation pattern in the liver, and these changes may contribute to the development of liver steatosis in breast cancer models. PMID- 28594381 TI - Lipophilicity Studies on Thiosemicarbazide Derivatives. AB - The lipophilicity of two series of thiosemicarbazide derivatives was assessed by the RP-HPLC method with the RP-18 chromatographic column and the methanol-water mixture as the mobile phase. Distribution coefficients logPHPLC were compared to calculated values generated by commonly used AClogP software and quantum chemical calculations. The reliability of the predictions was evaluated using the correlation matrix and PCA. For 4-benzoylthiosemicarbazides, a high correlation between theoretical and experimental logP parameters was obtained using the XlogP3 algorithm, while for 4-aryl/(cyclohexyl)thiosemicarbazides, the XlogP2 parameter was strongly correlated with the experimentally obtained logP. PMID- 28594383 TI - Image Processing of Porous Silicon Microarray in Refractive Index Change Detection. AB - A new method for extracting the dots is proposed by the reflected light image of porous silicon (PSi) microarray utilization in this paper. The method consists of three parts: pretreatment, tilt correction and spot segmentation. First, based on the characteristics of different components in HSV (Hue, Saturation, Value) space, a special pretreatment is proposed for the reflected light image to obtain the contour edges of the array cells in the image. Second, through the geometric relationship of the target object between the initial external rectangle and the minimum bounding rectangle (MBR), a new tilt correction algorithm based on the MBR is proposed to adjust the image. Third, based on the specific requirements of the reflected light image segmentation, the array cells are segmented into dots as large as possible and the distance between the dots is equal in the corrected image. Experimental results show that the pretreatment part of this method can effectively avoid the influence of complex background and complete the binarization processing of the image. The tilt correction algorithm has a shorter computation time, which makes it highly suitable for tilt correction of reflected light images. The segmentation algorithm makes the dots in a regular arrangement, excludes the edges and the bright spots. This method could be utilized in the fast, accurate and automatic dots extraction of the PSi microarray reflected light image. PMID- 28594384 TI - The Development of the Differential MEMS Vector Hydrophone. AB - To solve the problem that MEMS vector hydrophones are greatly interfered with by the vibration of the platform and flow noise in applications, this paper describes a differential MEMS vector hydrophone that could simultaneously receive acoustic signals and reject acceleration signals. Theoretical and simulation analyses have been carried out. Lastly, a prototype of the differential MEMS vector hydrophone has been created and tested using a standing wave tube and a vibration platform. The results of the test show that this hydrophone has a high sensitivity, Mv = -185 dB (@ 500 Hz, 0 dB reference 1 V/MUPa), which is almost the same as the previous MEMS vector hydrophones, and has a low acceleration sensitivity, Mv = -58 dB (0 dB reference 1 V/g), which has decreased by 17 dB compared with the previous MEMS vector hydrophone. The differential MEMS vector hydrophone basically meets the requirements of acoustic vector detection when it is rigidly fixed to a working platform, which lays the foundation for engineering applications of MEMS vector hydrophones. PMID- 28594386 TI - The Technology Acceptance of a TV Platform for the Elderly Living Alone or in Public Nursing Homes. AB - In Mexico, many seniors are alone for most of the day or live in public nursing homes. Simple interaction with computer systems is required for older people. This is why we propose the exploration of a medium well known by seniors, such as the television (TV). The primary objective of this study is to improve the quality of life of seniors through an easier reminder system, using the television set. A technological platform was designed based on interactive television, through which seniors and their caregivers can have a better way to track their daily activities. Finally, an evaluation of the technology adoption was performed with 50 seniors living in two public nursing homes. The evaluation found that the elderly perceived the system as useful, easy to use, and they had a positive attitude and good intention to use it. This helped to generate initial evidence that the system supported them in achieving a better quality of life, by reminding them to take their medications and increasing their rate of attendance to their medical appointments. PMID- 28594385 TI - Review of SERS Substrates for Chemical Sensing. AB - The SERS effect was initially discovered in the 1970s. Early research focused on understanding the phenomenon and increasing enhancement to achieve single molecule detection. From the mid-1980s to early 1990s, research started to move away from obtaining a fundamental understanding of the phenomenon to the exploration of analytical applications. At the same time, significant developments occurred in the field of photonics that led to the advent of inexpensive, robust, compact, field-deployable Raman systems. The 1990s also saw rapid development in nanoscience. This convergence of technologies (photonics and nanoscience) has led to accelerated development of SERS substrates to detect a wide range of chemical and biological analytes. It would be a monumental task to discuss all the different kinds of SERS substrates that have been explored. Likewise, it would be impossible to discuss the use of SERS for both chemical and biological detection. Instead, a review of the most common metallic (Ag, Cu, and Au) SERS substrates for chemical detection only is discussed, as well as SERS substrates that are commercially available. Other issues with SERS for chemical detection have been selectivity, reversibility, and reusability of the substrates. How these issues have been addressed is also discussed in this review. PMID- 28594387 TI - 3D Printing-Based Integrated Water Quality Sensing System. AB - The online and accurate monitoring of drinking water supply networks is critically in demand to rapidly detect the accidental or deliberate contamination of drinking water. At present, miniaturized water quality monitoring sensors developed in the laboratories are usually tested under ambient pressure and steady-state flow conditions; however, in Water Distribution Systems (WDS), both the pressure and the flowrate fluctuate. In this paper, an interface is designed and fabricated using additive manufacturing or 3D printing technology-material extrusion (Trade Name: fused deposition modeling, FDM) and material jetting-to provide a conduit for miniaturized sensors for continuous online water quality monitoring. The interface is designed to meet two main criteria: low pressure at the inlet of the sensors and a low flowrate to minimize the water bled (i.e., leakage), despite varying pressure from WDS. To meet the above criteria, a two dimensional computational fluid dynamics model was used to optimize the geometry of the channel. The 3D printed interface, with the embedded miniaturized pH and conductivity sensors, was then tested at different temperatures and flowrates. The results show that the response of the pH sensor is independent of the flowrate and temperature. As for the conductivity sensor, the flowrate and temperature affect only the readings at a very low conductivity (4 uS/cm) and high flowrates (30 mL/min), and a very high conductivity (460 uS/cm), respectively. PMID- 28594382 TI - Coralsnake Venomics: Analyses of Venom Gland Transcriptomes and Proteomes of Six Brazilian Taxa. AB - Venom gland transcriptomes and proteomes of six Micrurus taxa (M. corallinus, M. lemniscatus carvalhoi, M. lemniscatus lemniscatus, M. paraensis, M. spixii spixii, and M. surinamensis) were investigated, providing the most comprehensive, quantitative data on Micrurus venom composition to date, and more than tripling the number of Micrurus venom protein sequences previously available. The six venomes differ dramatically. All are dominated by 2-6 toxin classes that account for 91-99% of the toxin transcripts. The M. s. spixii venome is compositionally the simplest. In it, three-finger toxins (3FTxs) and phospholipases A2 (PLA2s) comprise >99% of the toxin transcripts, which include only four additional toxin families at levels >=0.1%. Micrurus l. lemniscatus venom is the most complex, with at least 17 toxin families. However, in each venome, multiple structural subclasses of 3FTXs and PLA2s are present. These almost certainly differ in pharmacology as well. All venoms also contain phospholipase B and vascular endothelial growth factors. Minor components (0.1-2.0%) are found in all venoms except that of M. s. spixii. Other toxin families are present in all six venoms at trace levels (<0.005%). Minor and trace venom components differ in each venom. Numerous novel toxin chemistries include 3FTxs with previously unknown 8- and 10 cysteine arrangements, resulting in new 3D structures and target specificities. 9 cysteine toxins raise the possibility of covalent, homodimeric 3FTxs or heterodimeric toxins with unknown pharmacologies. Probable muscarinic sequences may be reptile-specific homologs that promote hypotension via vascular mAChRs. The first complete sequences are presented for 3FTxs putatively responsible for liberating glutamate from rat brain synaptosomes. Micrurus C-type lectin-like proteins may have 6-9 cysteine residues and may be monomers, or homo- or heterodimers of unknown pharmacology. Novel KSPIs, 3* longer than any seen previously, appear to have arisen in three species by gene duplication and fusion. Four species have transcripts homologous to the nociceptive toxin, (MitTx) alpha-subunit, but all six species had homologs to the beta-subunit. The first non-neurotoxic, non-catalytic elapid phospholipase A2s are reported. All are probably myonecrotic. Phylogenetic analysis indicates that the six taxa diverged 15-35 million years ago and that they split from their last common ancestor with Old World elapines nearly 55 million years ago. Given their early diversification, many cryptic micrurine taxa are anticipated. PMID- 28594390 TI - Does the Health Impact of Exposure to Neighbourhood Green Space Differ between Population Groups? An Explorative Study in Four European Cities. AB - It has been suggested that certain residents, such as those with a low socioeconomic status, the elderly, and women, may benefit more from the presence of neighbourhood green space than others. We tested this hypothesis for age, gender, educational level, and employment status in four European cities. Data were collected in Barcelona (Spain; n = 1002), Kaunas (Lithuania; n = 989), Doetinchem (The Netherlands; n = 847), and Stoke-on-Trent (UK; n = 933) as part of the EU-funded PHENOTYPE project. Surveys were used to measure mental and general health, individual characteristics, and perceived neighbourhood green space. Additionally, we used audit data about neighbourhood green space. In Barcelona, there were positive associations between neighbourhood green space and general health among low-educated residents. In the other cities and for the other population groups, there was little evidence that the association between health and neighbourhood green space differed between population groups. Overall, our study does not support the assumption that the elderly, women, and residents who are not employed full-time benefit more from neighbourhood green space than others. Only in the highly urbanised city of Barcelona did the low-educated group benefit from neighbourhood green spaces. Perhaps neighbourhood green spaces are more important for the health of low-educated residents in particularly highly urbanised areas. PMID- 28594388 TI - Gene Therapy for Pancreatic Cancer: Specificity, Issues and Hopes. AB - A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells strategy). Nowadays, there is a specific development of oncolytic virus therapies including oncolytic adenoviruses, herpes virus, parvovirus or reovirus. A summary of all published and on-going phase-1 trials is given. Most of them associate gene therapy and chemotherapy or radiochemotherapy. The first results are encouraging for most of the trials but remain to be confirmed in phase 2 trials. PMID- 28594389 TI - The Role of NOX4 and TRX2 in Angiogenesis and Their Potential Cross-Talk. AB - The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) family is the major source of reactive oxygen species (ROS) in the vascular system. In this family, NOX4, a constitutive active form of NOXs, plays an important role in angiogenesis. Thioredoxin 2 (TRX2) is a key mitochondrial redox protein that maintains normal protein function and also provides electrons to peroxiredoxin 3 (PRX3) to scavenge H2O2 in mitochondria. Angiogenesis, a process of new blood vessel formation, is involved in a variety of physiological processes and pathological conditions. It seems to be paradoxical for ROS-producing NOX4 and ROS-scavenging TRX2 to have a similar role in promoting angiogenesis. In this review, we will focus on data supporting the role of NOX4 and TRX2 in angiogenesis and their cross-talks and discuss how ROS can positively or negatively regulate angiogenesis, depending on their species, levels and locations. NOX4 and TRX2-mediated ROS signaling could be promising targets for the treatment of angiogenesis-related diseases. PMID- 28594391 TI - Galectins-1, -3, and -7 Are Prognostic Markers for Survival of Ovarian Cancer Patients. AB - There is a tremendous need for developing new useful prognostic factors in ovarian cancer. Galectins are a family of carbohydrate binding proteins which have been suggested to serve as prognostic factors for various cancer types. In this study, the presence of Galectin-1, -3, and -7 was investigated in 156 ovarian cancer specimens by immunochemical staining. Staining was evaluated in the cytoplasm and nucleus of cancer cells as well as the peritumoral stroma using a semi quantitative score (Remmele (IR) score). Patients' overall survival was compared between different groups of Galectin expression. Galectin (Gal)-1 and -3 staining was observed in the peritumoral stroma as well as the nucleus and cytoplasm of tumor cells, while Gal-7 was only present in the cytoplasm of tumor cells. Patients with Gal-1 expression in the cytoplasm or high Gal-1 expression in the peritumoral stroma showed reduced overall survival. Nuclear Gal-3 staining correlated with a better outcome. We observed a significantly reduced overall survival for cases with high Gal-7 expression and a better survival for Gal-7 negative cases, when compared to cases with low expression of Gal-7. We were able to show that both tumor and stroma staining of Gal-1 could serve as negative prognostic factors for ovarian cancer. We were able to confirm cytoplasmic Gal-7 as a negative prognostic factor. Gal-3 staining in the nucleus could be a new positive prognosticator for ovarian cancer. PMID- 28594393 TI - Maritime Data Transfer Protocol (MDTP): A Proposal for a Data Transmission Protocol in Resource-Constrained Underwater Environments Involving Cyber-Physical Systems. AB - The utilization of autonomous maritime vehicles is becoming widespread in operations that are deemed too hazardous for humans to be directly involved in them. One of the ways to increase the productivity of the tools used during missions is the deployment of several vehicles with the same objective regarding data collection and transfer, both for the benefit of human staff and policy makers. However, the interchange of data in such an environment poses major challenges, such as a low bandwidth and the unreliability of the environment where transmissions take place. Furthermore, the relevant information that must be sent, as well as the exact size that will allow understanding it, is usually not clearly established, as standardization works are scarce in this domain. Under these conditions, establishing a way to interchange information at the data level among autonomous maritime vehicles becomes of critical importance since the needed information, along with the size of the transferred data, will have to be defined. This manuscript puts forward the Maritime Data Transfer Protocol, (MDTP) a way to interchange standardized pieces of information at the data level for maritime autonomous maritime vehicles, as well as the procedures that are required for information interchange. PMID- 28594392 TI - The Human Gut Phage Community and Its Implications for Health and Disease. AB - In this review, we assess our current understanding of the role of bacteriophages infecting the human gut bacterial community in health and disease. In general, bacteriophages contribute to the structure of their microbial communities by driving host and viral diversification, bacterial evolution, and by expanding the functional diversity of ecosystems. Gut bacteriophages are an ensemble of unique and shared phages in individuals, which encompass temperate phages found predominately as prophage in gut bacteria (prophage reservoir) and lytic phages. In healthy individuals, only a small fraction of the prophage reservoir is activated and found as extracellular phages. Phage community dysbiosis is characterized by a shift in the activated prophage community or an increase of lytic phages, and has been correlated with disease, suggesting that a proper balance between lysis and lysogeny is needed to maintain health. Consequently, the concept of microbial dysbiosis might be extended to the phage component of the microbiome as well. Understanding the dynamics and mechanisms to restore balance after dysbiosis is an active area of research. The use of phage transplants to re-establish health suggests that phages can be used as disease treatment. Such advances represent milestones in our understanding of gut phages in human health and should fuel research on their role in health and disease. PMID- 28594394 TI - Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin. AB - OBJECTIVE: To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin. STUDY DESIGN: Multicenter retrospective observational study of patients ?44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria. RESULTS: The rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0). CONCLUSION: Among neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%. PMID- 28594395 TI - Neurodevelopmental outcomes of preterm infants resuscitated with different oxygen concentration at birth. AB - OBJECTIVE: To compare the neurodevelopmental outcomes at 18 to 21 months corrected age (CA) of infants born at <29 weeks that received room air, an intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation. STUDY DESIGN: In this retrospective cohort study, we compared neonatal and neurodevelopmental outcomes at 18 to 21 months CA among inborn infants born before 29 weeks' gestation that received room air, intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation. RESULTS: Of 1509 infants, 445 received room air, 483 received intermediate oxygen concentrations and 581 received 100% oxygen. Compared to infants that received room air, the primary outcome of death or neurodevelopmental impairment (NDI) was not different in intermediate oxygen (adjusted odds ratio (aOR) 1.01; 95% confidence interval (CI) 0.77, 1.34) or 100% oxygen (aOR 1.03; 95% CI 0.78, 1.35). Compared to room air, there was no difference in odds of death or severe NDI in intermediate oxygen (aOR 1.14; 95% CI 0.82, 1.58) or 100% oxygen group (aOR 1.22; 95% CI 0.90, 1.67). The odds of severe NDI among survivors were significantly higher in infants that received 100% oxygen as compared to room air (aOR 1.57, 95% CI 1.05, 2.35). CONCLUSIONS: We observed no significant difference in the primary composite outcomes of death or NDI and death or severe NDI at 18 to 21 months CA between infants that received room air, intermediate oxygen concentration or 100% oxygen at the initiation of resuscitation. However, use of 100% oxygen was associated with increased odds of severe NDI among survivors as compared to room air. PMID- 28594397 TI - Establishment of a Quick and Highly Accurate Breath Test for ALDH2 Genotyping. AB - OBJECTIVES: Acetaldehyde, the first metabolite of ethanol, is a definite carcinogen for the esophagus, head, and neck; and aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that catalyzes the metabolism of acetaldehyde. The ALDH2 genotype exists as ALDH2*1/*1 (active ALDH2), ALDH2*1/*2 (heterozygous inactive ALDH2), and ALDH2*2/*2 (homozygous inactive ALDH2). Many epidemiological studies have reported that ALDH2*2 carriers are at high risk for esophageal or head and neck squamous cell carcinomas by habitual drinking. Therefore, identification of ALDH2*2 carriers would be helpful for the prevention of those cancers, but there have been no methods suitable for mass screening to identify these individuals. METHODS: One hundred and eleven healthy volunteers (ALDH2*1/*1 carriers: 53; ALDH2*1/*2 carriers: 48; and ALDH2*2/*2 carriers: 10) were recruited. Breath samples were collected after drinking 100 ml of 0.5% ethanol using specially designed gas bags, and breath ethanol and acetaldehyde levels were measured by semiconductor gas chromatography. RESULTS: The median (range) breath acetaldehyde levels at 1 min after alcohol ingestion were 96.1 (18.1 399.0) parts per billion (p.p.b.) for the ALDH2*1/*1 genotype, 333.5 (78.4 1218.4) p.p.b. for the ALDH2*1/*2 genotype, and 537.1 (213.2-1353.8) p.p.b. for the ALDH2*2/*2 genotype. The breath acetaldehyde levels in ALDH2*2 carriers were significantly higher than for the ALDH2*1/*1 genotype. Notably, the ratio of breath acetaldehyde level-to-breath ethanol level could identify carriers of the ALDH2*2 allele very accurately (whole accuracy; 96.4%). CONCLUSIONS: Our novel breath test is a useful tool for identifying ALDH2*2 carriers, who are at high risk for esophageal and head and neck cancers. PMID- 28594398 TI - Loss of the novel mitochondrial protein FAM210B promotes metastasis via PDK4 dependent metabolic reprogramming. AB - Recent advances in tumor metabolism have revealed that metabolic reprogramming could dramatically promote caner metastasis. However, the relation and mechanism between metastasis and metabolic reprogramming are not thoroughly explored. Cell proliferation, colony formation, and invasion analysis were performed to evaluate the role of FAM210B in human cancer cells. Human ovarian cancer xenograft model was used to determine the effects of inhibiting FAM210B by shRNA on tumor metastasis. Microarray analysis was used to determine the target genes of FAM210B. FAM210B cellular localization was performed by mitochondria isolation and mitochondria protein extraction. To detect FAM210B-mediated metabolic reprogramming, oxygen consumption rate and extracellular acidification rate were measured. Our previous study screened a novel cancer progression-suppressor gene, FAM210B, which encodes an outer mitochondrial membrane protein, by the suppression of mortality by antisense rescue technique (SMART). Here we demonstrated that FAM210B loss was significantly associated with cancer metastasis and decreased survival in a clinical setting. Additionally, it was found that low expression of FAM210B was significantly correlated with decreased survival and enhanced metastasis in vivo and in vitro, and the loss of FAM210B led to an increased mitochondrial respiratory capacity and reduced glycolysis through the downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which activated the EMT program and enhanced migratory and invasive properties. Collectively, our data unveil a potential metabolic target and mechanism of cancer metastasis. PMID- 28594399 TI - Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart. AB - Congenital heart defects contribute to embryonic or neonatal lethality but due to the complexity of cardiac development, the molecular changes associated with such defects are not fully understood. Here, we report that transcription factors (TFs) Brn-3a (POU4F1) and Brn-3b (POU4F2) are important for normal cardiac development. Brn-3a directly represses Brn-3b promoter in cardiomyocytes and consequently Brn-3a knockout (KO) mutant hearts express increased Brn-3b mRNA during mid-gestation, which is linked to hyperplastic growth associated with elevated cyclin D1, a known Brn-3b target gene. However, during late gestation, Brn-3b can cooperate with p53 to enhance transcription of pro-apoptotic genes e.g. Bax, thereby increasing apoptosis and contribute to morphological defects such as non-compaction, ventricular wall/septal thinning and increased crypts/fissures, which may cause lethality of Brn-3a KO mutants soon after birth. Despite this, early embryonic lethality in e9.5 double KO (Brn-3a-/- : Brn-3b-/-) mutants indicate essential functions with partial redundancy during early embryogenesis. High conservation between mammals and zebrafish (ZF) Brn-3b (87%) or Brn-3a (76%) facilitated use of ZF embryos to study potential roles in developing heart. Double morphant embryos targeted with morpholino oligonucleotides to both TFs develop significant cardiac defects (looping abnormalities and valve defects) suggesting essential roles for Brn-3a and Brn-3b in developing hearts. PMID- 28594400 TI - The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke. AB - Following stroke-induced neuronal damage, quiescent oligodendrocyte precursors (OPCs) are activated to proliferate and later to differentiate to myelin producing cells. GPR17, a receptor transiently expressed on early OPCs, has emerged as a target to implement stroke repair through stimulation of OPC maturation. However, being GPR17 completely downregulated in myelin-producing oligodendrocytes, its actual role in determining the final fate of OPCs after cerebral ischemia is still uncertain. Here, to univocally define the spatiotemporal changes and final fate of GPR17-expressing OPCs, we induced ischemia by middle cerebral artery occlusion (MCAo) in reporter GPR17iCreERT2:CAG eGreen florescent protein (GFP) mice, in which, upon tamoxifen treatment, cells expressing GPR17 become green and traceable for their entire life. Starting from 3 days and up to 2 weeks after MCAo, GFP+ cells markedly accumulated in regions surrounding the ischemic lesion; several of them proliferated, as shown by co labeling of the DNA synthesis marker 5-Bromo-2'-deoxyuridine (BrdU). Almost all GFP+/BrdU+ cells expressed the OPC early marker neural/glial antigen 2 (NG2), indicating that they were still precursors. Accumulation of GFP+ cells was also because of OPC recruitment from surrounding areas, as suggested in vivo by acquisition of typical features of migrating OPCs, shown in vitro in presence of the chemoattractant PDGF-AA and confirmed by transplantation of GFP+-OPCs in wild type MCAo mice. Eight weeks after MCAo, only some of these precociously recruited cells had undergone maturation as shown by NG2 loss and acquisition of mature myelinating markers like GSTpi. A pool of recruited GFP+-OPCs was kept at a precursor stage to likely make it available for further insults. Thus, very early after ischemia, GFP+-OPCs proliferate and migrate toward the lesion; however, most of these cells remain undifferentiated, suggesting functional roles other than myelination. PMID- 28594401 TI - Upconversion nanoparticle-mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage-derived foam cells via ROS generation. AB - Macrophage-derived foam cells are a major component of atherosclerotic plaques and have an important role in the progression of atherosclerotic plaques, thus posing a great threat to human health. Photodynamic therapy (PDT) has emerged as a therapeutic strategy for atherosclerosis. Here, we investigated the effect of PDT mediated by upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) on the cholesterol efflux of THP-1 macrophage-derived foam cells and explored the possible mechanism of this effect. First, we found that PDT notably enhanced the cholesterol efflux and the induction of autophagy in both THP-1 and peritoneal macrophage-derived foam cells. The autophagy inhibitor 3-methyladenine and an ATG5 siRNA significantly attenuated PDT-induced autophagy, which subsequently suppressed the ABCA1-mediated cholesterol efflux. Furthermore, the reactive oxygen species (ROS) produced by PDT were responsible for the induction of autophagy, which could be blocked by the ROS inhibitor N-acetyl cysteine (NAC). NAC also reversed the PDT-induced suppression of p-mTOR and p-Akt. Therefore, our findings demonstrate that PDT promotes cholesterol efflux by inducing autophagy, and the autophagy was mediated in part through the ROS/PI3K/Akt/mTOR signaling pathway in THP-1 and peritoneal macrophage-derived foam cells. PMID- 28594402 TI - ARRDC4 regulates enterovirus 71-induced innate immune response by promoting K63 polyubiquitination of MDA5 through TRIM65. AB - Enterovirus 71 (EV71) is the main causative agent of hand, foot and mouth disease (HFMD), which induces significantly elevated levels of cytokines and chemokines, leading to local or system inflammation and severe complications, whereas the underlying regulatory mechanisms and the inflammatory pathogenesis remain elusive. ARRDC4 is one member of arrestins family, having important roles in glucose metabolism and G-protein-coupled receptors (GPCRs) related physiological and pathological processes, however, the function of ARRDC4 in innate immune system is largely unknown. Here we identified that ARRDC4 expression was increased after EV71 infection in THP-1-derived macrophages and verified in EV71 infected HFMD patients and the healthy candidates. The expression level of ARRDC4 was positively correlated with the serum concentration of IL-6, TNF-alpha and CCL3 in clinical specimens. ARRDC4 interacted with MDA5 via the arrestin-like N domain, and further recruited TRIM65 to enhance the K63 ubiquitination of MDA5, resulting in activation of the downstream innate signaling pathway and transcription of proinflammatory cytokines during EV71 infection. Our data highlight new function of ARRDC4 in innate immunity, contributing to the better understanding about regulation of MDA5 activation after EV71 infection, and also suggest ARRDC4 may serve as a potential target for intervention of EV71-induced inflammatory response. PMID- 28594403 TI - Long noncoding RNA CRNDE stabilized by hnRNPUL2 accelerates cell proliferation and migration in colorectal carcinoma via activating Ras/MAPK signaling pathways. AB - Recent studies have furthered our understanding of the function of long noncoding RNAs (lncRNAs) in numerous biological processes, including cancer. This study investigated the expression of a novel lncRNA, colorectal neoplasia differentially expressed (CRNDE), in colorectal carcinoma (CRC) tissues and cells by real-time RT-PCR and in situ hybridization, and its biological function using a series of in vitro and in vivo experiments to determine its potential as a prognostic marker and therapeutic target. CRNDE was found to be upregulated in primary CRC tissues and cells (P<0.05), and the upregulation of CRNDE expression is a powerful predictor of advanced TNM stage (P<0.05) and poor prognosis for CRC patients (P=0.002). The promoting effects of CRNDE on the cell proliferation, cell cycling and metastasis of CRC cells were confirmed both in vitro and in vivo by gain-of-function and loss-of-function experiments. Mechanistically, it was demonstrated that CRNDE could form a functional complex with heterogeneous nuclear ribonucleoprotein U-like 2 protein (hnRNPUL2) and direct the transport of hnRNPUL2 between the nucleus and cytoplasm. hnRNPUL2 that was accumulated in the cytoplasm could interact with CRNDE both physically and functionally, increasing the stability of CRNDE RNA. Moreover, gene expression profile data showed that CRNDE depletion in cells downregulated a series of genes involved in the Ras/mitogen-activated protein kinase signaling pathways. Collectively, these findings provide novel insights into the function and mechanism of lncRNA CRNDE in the pathogenesis of CRC and highlight its potential as a therapeutic target for CRC intervention. PMID- 28594404 TI - Precision medicine for hepatocelluar carcinoma using molecular pattern diagnostics: results from a preclinical pilot study. AB - The aim of this study was to design a road map for personalizing cancer therapy in hepatocellular carcinoma (HCC) by using molecular pattern diagnostics. As an exploratory study, we investigated molecular patterns of tissues of two tumors from individual HCC patients, which in previous experiments had shown contrasting reactions to the phase 2 transforming growth factor beta receptor 1 inhibitor galunisertib. Cancer-driving molecular patterns encompass - inter alias - altered transcription profiles and somatic mutations in coding regions differentiating tumors from their respective peritumoral tissues and from each other. Massive analysis of cDNA ends and all-exome sequencing demonstrate a highly divergent transcriptional and mutational landscape, respectively, for the two tumors, that offers potential explanations for the tumors contrasting responses to galunisertib. Molecular pattern diagnostics (MPDs) suggest alternative, individual-tumor-specific therapies, which in both cases deviate from the standard sorafenib treatment and from each other. Suggested personalized therapies use kinase inhibitors and immune-focused drugs as well as low-toxicity natural compounds identified using an advanced bioinformatics routine included in the MPD protocol. The MPD pipeline we describe here for the prediction of suitable drugs for treatment of two contrasting HCCs may serve as a blueprint for the design of therapies for various types of cancer. PMID- 28594405 TI - Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1alpha-modulated fatty acid metabolism. AB - The occurrence and progress of colon cancer are closely associated with obesity. Therefore, the lipid metabolism, especially fatty acid metabolism, is a significant section of energy homeostasis in colon cancer cells, and it affects many important cellular processes. Oroxylin A is one of the main bioactive flavonoids of Scutellariae radix, which has a strong anticancer effect but low toxicity to normal tissue. In previous studies, we have proved that oroxylin A reprogrammes metabolism of cancer cells by inhibiting glycolysis. Here, we further investigated the metabolism-modulating effects of oroxylin A on the fatty acid metabolism in colon cancer cells under hypoxia. We found that HIF1alpha upregulated adipophilin, fatty acid synthase and sterol regulatory element binding protein 1, and downregulated carnitine palmitoyltransferase 1 (CPT1), resulting in the promoted lipid uptake and transport, increased de novo fatty acid synthesis and suppressed fatty acid oxidation. Oroxylin A inactivated HIF1alpha and reprogrammed fatty acid metabolism of HCT116 cells, decreasing intracellular fatty acid level and enhancing fatty acid oxidation. Furthermore, the rapid decrease of fatty acid level caused by oroxylin A inhibited the nuclear translocation of beta-cantenin and inactivated the Wnt pathway, arousing cell cycle arrest in G2/M phase. In vivo studies demonstrated that high-fat diet increased the incidence of colon cancer and accelerated tumor development. Importantly, besides the growth inhibitory effects on colon cancer xenograft, oroxylin A prevented carcinogenesis and delayed progress of primary colon cancer as well. Our studies enriched the metabolic regulatory mechanism of oroxylin A, and suggested that oroxylin A was a potent candidate for the treatment and prevention of colorectal cancer. PMID- 28594406 TI - Simvastatin treatment boosts benefits of apoptotic cell infusion in murine lung fibrosis. AB - A single early-phase infusion of apoptotic cells can inhibit bleomycin-induced lung inflammation and fibrosis; however, it is unknown whether these effects can be enhanced with additional infusions and/or statin treatment. Here, we investigated whether an increased frequency of apoptotic cell injection, with or without efferocytosis enhancer simvastatin, facilitates therapeutic efficacy. An additional injection of apoptotic cells during the intermediate phase (7 days post-bleomycin treatment) or simvastatin administration alone on days 7-13 post treatment did not promote anti-fibrotic responses beyond those induced by a single early apoptotic cell infusion alone. Additional administration of apoptotic cells with simvastatin further enhanced the efferocytic ability of alveolar macrophages and PPARgamma activity, and induced hepatocyte growth factor and interleukin-10 expression, in alveolar macrophages and lung tissue. Additional administration of apoptotic cells with simvastatin also reduced mRNA expression of bleomycin-induced epithelial-mesenchymal transition (EMT) markers in isolated alveolar type II epithelial cells, fibrotic markers in fibroblasts, and hydroxyproline in lung tissue. Enhanced anti-EMT and anti-fibrotic efficacy was confirmed by immunofluorescence and trichrome staining of lung tissue. This suggests that additional administration of apoptotic cells with simvastatin during the intermediate phase of bleomycin-induced lung fibrosis may boost the anti-fibrotic properties of early apoptotic cell infusion. PMID- 28594407 TI - EGR-1/ASPP1 inter-regulatory loop promotes apoptosis by inhibiting cyto protective autophagy. AB - The decrease of ASPP1 (Apoptosis-Stimulating Protein of p53 1), a known p53 activator, has been linked to carcinogenesis and the cytotoxic resistance in various cancers, yet the underlying mechanisms of ASPP1 expression and its complex functions are not yet clear. Here, we report that ASPP1 forms an inter regulatory loop with Early Growth Response 1 (EGR-1), and promotes apoptosis via inhibiting cyto-protective autophagy, independent of the well-documented p53 dependent mechanisms. We show that ASPP1 mRNA and protein were remarkably elevated by ectopic EGR-1 expression or endogenous EGR-1 activation, in cells with different tissue origins and p53 status. Conversely, RNAi-mediated EGR-1 knockdown suppressed ASPP1. The further mechanism studies revealed that ASPP1 promoter, mapped to -283/+88, which contained three conserved EGR-1 binding sites, was required for both binding and transactivity of EGR-1. In addition, we demonstrate that ASPP1 promoted EGR-1 in a positive feedback loop by preventing proteasome-mediated EGR-1 degradation or promoting EGR-1 nuclear import in response to anticancer natural compound Quercetin. Furthermore, albeit activating p53 in the nucleus is the well-studied function of ASPP1, we found that ASPP1 was predominately localized in the cytoplasm. Interestingly, the cytoplasmic ASPP1 retained its pro-apoptosis capability. Mechanistically, ASPP1 suppressed Atg5 Atg12 and also bound with Atg5-Atg12 to prevent its further complex formation with Atg16, resulting in the inhibition of cyto-protective autophagy. In conclusion, our results provide new insights into EGR-1/ASPP1 regulatory loop in sensitizing Quercetin-induced apoptosis. EGR-1/ASPP1, therefore, may be potentially used as therapeutic targets to improve cancer's response to pro apoptosis treatments. PMID- 28594408 TI - Autophagy blockade and lysosomal membrane permeabilization contribute to lead induced nephrotoxicity in primary rat proximal tubular cells. AB - Lead (Pb) is a known nephrotoxicant that causes damage to proximal tubular cells. Autophagy has an important protective role in various renal injuries, but the role of autophagy in Pb-elicited nephrotoxicity remains largely unknown. In this study, Pb promoted the accumulation of autophagosomes in primary rat proximal tubular (rPT) cells, and subsequent findings revealed that this autophagosome accumulation was caused by the inhibition of autophagic flux. Moreover, Pb exposure did not affect the autophagosome-lysosome fusion in rPT cells. Next, we found that Pb caused lysosomal alkalinization, may be through suppression of two V-ATPase subunits. Simultaneously, Pb inhibited lysosomal degradation capacity by affecting the maturation of cathepsin B (CTSB) and cathepsin D (CTSD). Furthermore, translocation of CTSB and CTSD from lysosome to cytoplasm was observed in this study, suggesting that lysosomal membrane permeabilization (LMP) occurred in Pb-exposed rPT cells. Meanwhile, Pb-induced caspase-3 activation and apoptosis were significantly but not completely inhibited by CTSB inhibitor (CA 074) and CTSD inhibitor (pepstatin A), respectively, demonstrating that LMP induced lysosomal enzyme release was involved in Pb-induced apoptosis in rPT cells. In conclusion, Pb-mediated autophagy blockade in rPT cells is attributed to the impairment of lysosomal function. Both inhibition of autophagic flux and LMP-mediated apoptosis contribute to Pb-induced nephrotoxicity in rPT cells. PMID- 28594409 TI - EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway. AB - Recent evidence suggests that dysregulated eIF3d expression may be critical in various genetic disorders as well as cancer. In this study, we observed that EIF3d levels increased in gallbladder cancer (GBC) samples compared with non tumor tissue. High eIF3d levels were associated with advanced tumor stage and metastasis and were correlated with poor prognosis in 92 patients with GBC. Depletion of EIF3d in GBC cell lines inhibited cell proliferation, colony formation and metastasis and induced apoptosis and cell cycle arrest in vitro and in vivo. In contrast, ectopic expression of eIF3d had the opposite effects. Moreover, in this study, we revealed that a novel non-translational factor function of eIF3d mediated its protumoral effects. In details, eIF3d stabilizes GRK2 protein by blocking ubiquitin-mediated degradation, consequently activates PI3K/Akt signaling, and promotes GBC cell proliferation and migration. In conclusion, eIF3d promotes GBC progression mainly via eIF3d-GRK2-AKT axis and it may be used as a prognostic factor. The therapeutic targeting of eIF3d-GRK2 axis may be a potential treatment approach for GBC. PMID- 28594412 TI - Attitudes, knowledge and consequences of uncertain genetic findings in hypertrophic cardiomyopathy. AB - With the surge of next-generation sequencing (NGS) technologies making almost all genetic tests more affordable and available, cardiac genetic testing now routinely encompasses a large number of genes within a panel setting. The additional sensitivity of this practice is limited and has the potential to inflict a spectrum of uncertainty. We sought to explore attitudes, preferences, recall and psychological consequences of informative and uninformative genetic results amongst probands diagnosed with hypertrophic cardiomyopathy (HCM). We conducted semi-structured interviews and analysed the qualitative data using a framework analysis process. In general, we found probands were more concerned with their clinical diagnosis than gene result and in some, recall and understanding of genetic diagnosis was poor. Several participants expected genetic testing would alleviate uncertainty, often holding an altruistic view of participation in testing, removing their sense of self and failing to appreciate fully the familial implications. With the key utility of HCM genetic testing and counselling being for greater risk prediction for at-risk relatives, effective communication within the family is critical. While communication appeared adequate, further questioning found it was often vague, failing to translate into meaningful action by relatives. Based on these findings, a framework of key outcomes to assist multidisciplinary teams in genetic counselling of probands receiving an HCM gene result was developed. PMID- 28594415 TI - Expanded carrier screening: what determines intended participation and can this be influenced by message framing and narrative information? AB - Next-generation sequencing enabled us to create a population-based expanded carrier screening (ECS) test that simultaneously tests for 50 serious autosomal recessive diseases. Before offering this test universally, we wanted to know what factors are related to intended participation and how the general public can be informed about the test without being influenced in their intention to participate. We studied this by measuring to what extent 'message framing' and 'narrative information' can influence people's intended participation. Data were collected by means of an online survey of 504 potential users, and the factors examined were based on the Theory of Planned Behaviour and on previous research on intended participation in preconception carrier screening. Message framing was manipulated by explaining the risk of couple carriership in different ways, while narrative information was provided to only half of the respondents. The factors most positively related to intended participation were perceiving benefits of the screening, having a positive attitude towards the screening, having no religion, having an actual child wish and experiencing the choice to participate as easy. Perceived benefits and a positive attitude were most influential factors by far. Message framing and narrative information had no significant effect on intended participation, reinforcing that message framing and narrative information can help to inform the general public about ECS without influencing their intended participation. Future research should study if the importance of perceived benefits and a positive attitude can be replicated when other factors are included and when actual participation is measured instead of intended participation. PMID- 28594418 TI - Microemulsion-made gadolinium carbonate hollow nanospheres showing magnetothermal heating and drug release. AB - Gadolinium carbonate (Gd2(CO3)3) hollow nanospheres and their suitability for drug transport and magnetothermally-induced drug release are presented. The hollow nanospheres are prepared via a microemulsion-based synthesis using tris(tetramethylcyclopentadienyl)gadolinium(iii) and CO2 as the starting materials. Size, structure and composition of the as-prepared Gd2(CO3)3 hollow nanospheres are comprehensively validated by several independent analytical methods (HRTEM, HAADF-STEM, DLS, EDXS, XRD, FT-IR, DTA-TG). Accordingly, they exhibit an outer diameter of 26 +/- 4 nm, an inner cavity of 7 +/- 2 nm, and a wall thickness of 9 +/- 3 nm. As a conceptual study, the nanocontainer functionality of the Gd2(CO3)3 hollow nanospheres is validated upon filling with the anti-cancerogenic agent doxorubicin (DOX), which is straightforward via the microemulsion (ME) strategy. The resulting DOX@Gd2(CO3)3 nanocontainers provide the option of multimodal imaging including optical and magnetic resonance imaging (OI, MRI) as well as magnetothermal heating and drug release. As a proof-of concept, we could already prove the intrinsic DOX-based fluorescence, a low systemic toxicity according to in vitro studies as well as the magnetothermal effect and a magnetothermally-induced DOX release. In particular, the latter is new for Gd-containing nanoparticles and highly promising in view of theranostic nanocontainers and synergistic physical and chemical tumor treatment. PMID- 28594419 TI - Carbon nitrides: synthesis and characterization of a new class of functional materials. AB - Carbon nitride compounds with high N : C ratios and graphitic to polymeric structures are being investigated as potential next-generation materials for incorporation in devices for energy conversion and storage as well as for optoelectronic and catalysis applications. The materials are built from C- and N containing heterocycles with heptazine or triazine rings linked via sp2-bonded N atoms (N(C)3 units) or -NH- groups. The electronic, chemical and optical functionalities are determined by the nature of the local to extended structures as well as the chemical composition of the materials. Because of their typically amorphous to nanocrystalline nature and variable composition, significant challenges remain to fully assess and calibrate the structure-functionality relationships among carbon nitride materials. It is also important to devise a useful and consistent approach to naming the different classes of carbon nitride compounds that accurately describes their chemical and structural characteristics related to their functional performance. Here we evaluate the current state of understanding to highlight key issues in these areas and point out new directions in their development as advanced technological materials. PMID- 28594421 TI - Reversible light-dependent molecular switches on Ag/AgCl nanostructures. AB - Nanostructured Ag/AgCl substrates were used to generate reversible and highly efficient light-dependent chemical switches based on adsorbed 4,4' dimercaptoazobenzene (DMAB). DMAB was formed in situ via laser-induced dimerization either from 4-nitrothiophenol (4-NTP) or 4-aminothiophenol (4-ATP). The subsequent reaction pathways of DMAB, however, were quite different as monitored by surface enhanced Raman spectroscopy. In the 4-NTP/DMAB system, AgCl catalyses the reversal of the dimerization. Conversely, irradiation of adsorbed 4 ATP first generated cis-DMAB attached to the surface via two Ag-S bonds, followed by AgCl-catalysed cleavage of one Ag-S bond and cis -> trans photoisomerisation of DMAB. In the dark, the trans-isomer thermally reverts to cis-DMAB. The here presented light-dark chemical switches, which work without changing other parameters (e.g., pH, anaerobic vs. aerobic), are based on the (photo)catalytic properties of the Ag/AgCl substrate and do not function on pure metal surfaces. PMID- 28594416 TI - A comparison of Cox and logistic regression for use in genome-wide association studies of cohort and case-cohort design. AB - Logistic regression is often used instead of Cox regression to analyse genome wide association studies (GWAS) of single-nucleotide polymorphisms (SNPs) and disease outcomes with cohort and case-cohort designs, as it is less computationally expensive. Although Cox and logistic regression models have been compared previously in cohort studies, this work does not completely cover the GWAS setting nor extend to the case-cohort study design. Here, we evaluated Cox and logistic regression applied to cohort and case-cohort genetic association studies using simulated data and genetic data from the EPIC-CVD study. In the cohort setting, there was a modest improvement in power to detect SNP-disease associations using Cox regression compared with logistic regression, which increased as the disease incidence increased. In contrast, logistic regression had more power than (Prentice weighted) Cox regression in the case-cohort setting. Logistic regression yielded inflated effect estimates (assuming the hazard ratio is the underlying measure of association) for both study designs, especially for SNPs with greater effect on disease. Given logistic regression is substantially more computationally efficient than Cox regression in both settings, we propose a two-step approach to GWAS in cohort and case-cohort studies. First to analyse all SNPs with logistic regression to identify associated variants below a pre-defined P-value threshold, and second to fit Cox regression (appropriately weighted in case-cohort studies) to those identified SNPs to ensure accurate estimation of association with disease. PMID- 28594414 TI - Genotype and phenotype spectrum of NRAS germline variants. AB - RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots. PMID- 28594423 TI - High performance bi-layer atomic switching devices. AB - Atomic switches, also known as conductive bridging random access memory devices, are resistive-switching devices that utilize the electrochemical reactions within a solid electrolyte between metal electrodes, and are considered essential components of future information storage and logic building blocks. In spite of their advantages as next generation switching components such as high density, large scalability, and low power consumption, the large deviations in their electrical properties and the instability of their switching behaviors hinder their application in information processing systems. Here, we report the fabrication of a uniform, low-power atomic switch with a bi-layer structure consisting of Ta2O5-x as the main switching layer (SL) and a relatively oxygen deficient TaOx as an oxygen vacancy control layer (VCL). The depth profiles of the filaments in the bi-layer device were obtained by performing conductive atomic force microscopy to assess the improvements in uniformity, reliability, and electrical performance that result from the insertion of the VCL. The coefficient of variation of the high resistance state of the bi-layer device was found to be drastically reduced from 60.92% to 2.77% in the cycle-to-cycle measurements and from 82.73% to 4.85% in the device-to-device measurements when compared with the values obtained for a single-layer device. The bi-layer device also exhibits a forming-free low operation voltage of ~0.4 V, a high on/off ratio of ~106, and high reliability with 10 years data retention at 85 degrees C. PMID- 28594424 TI - Protective effect of Lycium barbarum polysaccharides against cadmium-induced testicular toxicity in male mice. AB - The present study was performed to determine whether Lycium barbarum polysaccharides (LBPs) would protect mice against cadmium (Cd)-induced testicular toxicity. Seventy-two male mice were randomly divided into six groups with twelve mice per group. Four groups were administered orally with cadmium chloride (5.0 mg per kg body weight) for 35 days and treated in combination with LBPs (0, 10.0, 33.3 or 100 mg kg-1) from one week before exposure to Cd until the end of the experiment. The other two groups were administered orally with vehicle or LBP (100 mg kg-1) only. Pretreatment with LBP ameliorated the Cd-induced reduction in the body weights, sperm motility as well as the level of testosterone in serum. Moreover, Cd-induced increase in the abnormal sperms was reduced and effects of Cd on the levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) were reversed. Histopathological examination further confirmed that the LBPs effectively attenuated Cd-induced degeneration of seminiferous tubules. Thus, LBPs attenuated Cd-induced testicular injury by improving the activity of antioxidant enzymatic activity and lowering the oxidative stress, so it could be a potential auxiliary therapeutic agent for Cd-induced testicular toxicity. PMID- 28594426 TI - New developments in anticoagulants: Past, present and future. AB - Thrombosis is a leading cause of death and disability worldwide, and anticoagulants are the mainstay of its prevention and treatment. Starting with unfractionated heparin (UFH) and vitamin K antagonists (VKAs) such as warfarin, the choices of anticoagulants have exploded in the past 20 years. With over 90 % subcutaneous bioavailability, no need for coagulation monitoring and dose adjustment, and a lower risk of heparin-induced thrombocytopenia, low-molecular weight heparin and fondaparinux have replaced UFH for prevention and initial treatment of venous thromboembolism and for secondary prevention in cancer patients. In patients undergoing percutaneous interventions, bivalirudin is often used instead of UFH. Oral anticoagulation therapy has advanced with the introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban and edoxaban. With efficacy at least equal to that of VKAs but with greater safety and convenience, the NOACs are now replacing VKAs for many indications. This paper a) highlights these advances, b) outlines how specific reversal agents for the NOACs will enhance their safety, c) reviews some of the ongoing trials with the NOACs, and d) describes the inhibitors of factor XII and XI that are under investigation as anticoagulants. PMID- 28594427 TI - Angiogenesis in metabolic-vascular disease. AB - Angiogenesis, literally formation of new blood vessels, is the main process through which the vascular system expands during embryonic and postnatal development. Endothelial cells, which constitute the inner lining of all blood vessels, are typically in a quiescent state in the healthy adult organism. However, in vascular and metabolic diseases, the endothelium becomes unstable and dysfunctional. The resulting tissue hypoxia may thereby induce pathological angiogenesis, which is a hallmark of disease conditions like cancer or diabetic retinopathy. However, recent evidence suggests that angiogenesis is also a major player in the context of further metabolic diseases, especially in obesity. In particular, deregulated angiogenesis is linked with adipose tissue dysfunction and insulin resistance. On the other hand, signalling pathways, such as the PI3K pathway, may regulate metabolic activities in the endothelium. Endothelial cell metabolism emerges as an important regulator of angiogenesis. This review summarises the role of angiogenesis in metabolic-vascular disease, with specific focus on the role of angiogenesis in obesity-related metabolic dysfunction and on signaling pathways, especially PI3K, linking cell metabolism to endothelial function. PMID- 28594428 TI - Compromised Integrity of Central Visual Pathways in Patients With Macular Degeneration. AB - Purpose: Macular degeneration (MD) affects the central retina and leads to gradual loss of foveal vision. Although, photoreceptors are primarily affected in MD, the retinal nerve fiber layer (RNFL) and central visual pathways may also be altered subsequent to photoreceptor degeneration. Here we investigate whether retinal damage caused by MD alters microstructural properties of visual pathways using diffusion-weighted magnetic resonance imaging. Methods: Six MD patients and six healthy control subjects participated in the study. Retinal images were obtained by spectral-domain optical coherence tomography (SD-OCT). Diffusion tensor images (DTI) and high-resolution T1-weighted structural images were collected for each subject. We used diffusion-based tensor modeling and probabilistic fiber tractography to identify the optic tract (OT) and optic radiations (OR), as well as nonvisual pathways (corticospinal tract and anterior fibers of corpus callosum). Fractional anisotropy (FA) and axial and radial diffusivity values (AD, RD) were calculated along the nonvisual and visual pathways. Results: Measurement of RNFL thickness reveals that the temporal circumpapillary retinal nerve fiber layer was significantly thinner in eyes with macular degeneration than normal. While we did not find significant differences in diffusion properties in nonvisual pathways, patients showed significant changes in diffusion scalars (FA, RD, and AD) both in OT and OR. Conclusions: The results indicate that the RNFL and the white matter of the visual pathways are significantly altered in MD patients. Damage to the photoreceptors in MD leads to atrophy of the ganglion cell axons and to corresponding changes in microstructural properties of central visual pathways. PMID- 28594429 TI - Effects of serial and concurrent training on receptive identification tasks: A Systematic replication. AB - The current study compared the use of serial and concurrent methods to train multiple exemplars when teaching receptive language skills, providing a systematic replication of Wunderlich, Vollmer, Donaldson, and Phillips (2014). Five preschoolers diagnosed with developmental delays or autism spectrum disorders were taught to receptively identify letters or letter sounds. Subjects learned the target stimuli slightly faster in concurrent training and a high degree of generalization was obtained following both methods of training, indicating that both the serial and concurrent methods of training are efficient and effective instructional procedures. PMID- 28594430 TI - Substrate characteristics and ablation outcome of left atrial tachycardia in rheumatic mitral valve disease. AB - BACKGROUND: Right atrial tachycardia (AT) is a common arrhythmia postsurgical valve replacement in patients with rheumatic heart disease (RHD). However, the substrate and the mechanism of left AT in such patients and the ablation efficacy is less known. METHODS AND RESULTS: Twenty-seven RHD patients with AT were enrolled in this study; nine of them (33%) had left AT. Five and four patients had left AT during the first and second procedure, respectively. A spontaneous scar in the left posterior wall was identified in all patients, and obvious anterior scar in three patients. Dual-roof-dependent AT was found in three patients and macroreentry AT surrounding right pulmonary vein was identified in one patient, two of whom had left anterior scar. Three patients had AT circuit going around the mitral annulus, one of whom had left anterior scar. Entrainment pacing at different sites confirmed the mechanism of these macroreentries. Two patients had a focal origin, one was localized in posterior wall at the edge of the scar and the other one was originated from the left septum with normal voltage. After a mean follow-up of 27.4 +/- 7.9 months, the left AT group had a similar recurrence rate compared with the right AT group alone (67% vs 56%, P = 0.58). In the left AT group, 11% of patients had AT recurrence and 56% of patients developed atrial fibrillation. CONCLUSION: Left atrial AT can occur in RHD patients postmitral valve replacement. Catheter ablation is feasible with high acute success rate. The incidence of late development atrial fibrillation is considerable after successful ablation. PMID- 28594431 TI - Distinguishing Two Ammonium and Triazolium Sites of Interaction in a Three Station [2]Rotaxane Molecular Shuttle. AB - This paper reports on the synthesis of a tri-stable [2]rotaxane molecular shuttle, in which the motion of the macrocycle is triggered by either selective protonation/deprotonation or specific carbamoylation/decarbamoylation of an alkylbenzylamine. The threaded axle is surrounded by a dibenzo[24]crown[8] (DB24C8) macrocycle and contains three sites of different binding affinities towards the macrocycle. An N-methyltriazolium moiety acts as a molecular station that has weak affinity for the DB24C8 macrocycle and is located in the centre of the molecular axle. Two other molecular stations, arylammonium and alkylbenzylammonium moieties, sit on either side of the triazolium moiety along the molecular axle and have stronger affinities for the DB24C8 macrocycle. These two ammonium moieties are covalently linked to two different stopper groups at each extremity of the thread: a tert-butylphenyl group and a substituted DB24C8 unit. Owing to steric hindrance, the former does not allow any pi-pi stacking interactions with the encircling DB24C8 macrocycle, whereas the latter residue does; therefore, this allows the discrimination of the two ammonium stations by the surrounding DB24C8 macrocycle in the fully protonated state. In the deprotonated state, the contrasting reactivity of the amine functional groups, as either a base or a nucleophile, allows for selective reactions that trigger the controlled shuttling of the macrocycle around the three molecular stations. PMID- 28594432 TI - Involvement of the IgE-basophil system and mild complement activation in haemophilia B with anti-factor IX neutralizing antibodies and anaphylaxis. AB - INTRODUCTION: Patients with haemophilia B who develop factor IX (FIX) neutralizing antibodies (inhibitors) after FIX infusion are at high risk of hypersensitivity reactions upon FIX re-exposure, but the underlying mechanisms are incompletely understood. AIM: To investigate biomechanisms of FIX hypersensitivity. METHODS: A cellular antigen stimulation test (CAST) was employed to evaluate leukotriene C4 (LTC4) release from basophils stimulated by FIX in three treated children with haemophilia B, one of whom developed FIX inhibitor and experienced anaphylaxis following FIX re-exposure. Anti-FIX IgE and IgG antibodies and markers of complement activation (C5b9, C3d and iC3b) were measured in plasma, the last also after FIX infusion. Ten healthy children served as controls. RESULTS: The patient who developed anti-FIX inhibitors and anaphylaxis had a nonsense mutation in FIX gene (p.Arg298Stop) and, compared to controls, had higher plasma levels of specific anti-FIX IgE (2.285 vs 0.084 OD492 nm ), with marked LTC4 release from his FIX-stimulated basophils (519.8 vs 39.9 pg/mL). Further, he had higher plasma levels of anti-FIX IgG of all the four subclasses (total IgG 1.180 vs 0.120 OD492 nm ) with FIX neutralizing activity (1.5 BU); mild complement activation occurred during FIX-induced anaphylaxis (C5b9 increased from 258.5 to 351.1 ng/mL). The same parameters were normal in the two patients who tolerated FIX infusion. CONCLUSION: In the patient with haemophilia B who experienced anaphylaxis after FIX, but not in the patients with haemophilia B who tolerated FIX, the CAST assay showed FIX-induced LTC4 release, which was associated with high plasma levels of specific anti-FIX IgE and IgG antibodies. PMID- 28594433 TI - Cactus-Like Hollow Cu2-x S@Ru Nanoplates as Excellent and Robust Electrocatalysts for the Alkaline Hydrogen Evolution Reaction. AB - The development of Pt-free electrocatalysts for the hydrogen evolution reaction (HER) recently is a focus of great interest. While several strategies are developed to control the structural properties of non-Pt catalysts and boost their electrocatalytic activities for the HER, the generation of highly reactive defects or interfaces by combining a metal with other metals, or with metal oxides/sulfides, can lead to notably enhanced catalytic performance. Herein, the preparation of cactus-like hollow Cu2-x S@Ru nanoplates (NPs) that contain metal/metal sulfide heterojunctions and show excellent catalytic activity and durability for the HER in alkaline media is reported. The initial formation of Ru islands on presynthesized Cu1.94 S NPs, via cation exchange between three Cu+ ions and one Ru3+ , induces the growth of the Ru phase, which is concomitant with the dissolution of the Cu1.94 S nanotemplate, culminating in the formation of a hollow nanostructure with numerous thin Ru pillars. Hollow Cu2-x S@Ru NPs exhibit a small overpotential of 82 mV at a current density of -10 mA cm-2 and a low Tafel slope of 48 mV dec-1 under alkaline conditions; this catalyst is among state-of-the-art HER electrocatalysts in alkaline media. The excellent performance of hollow Cu2-x S@Ru NPs originates from the facile dissociation of water in the Volmer step. PMID- 28594434 TI - A Facile Method and Novel Mechanism Using Microneedle-Structured PDMS for Triboelectric Generator Applications. AB - The triboelectric generator (TEG) is a cost-effective, multi-fabricated, friendly mechanical-energy-harvesting device. The traditional TEG, generally formed by two triboelectric materials in multilayers or a simple pattern, generated triboelectricity as it worked in the cycling contact-separation operation. This paper demonstrates a novel, high-aspect-ratio, microneedle (MN)-structured polydimethylsiloxane (PDMS)-based triboelectric generator (MN-TEG) by means of a low-cost, simple fabrication using CO2 laser ablation on the polymethyl methacrylate substrate and a molding process. The MN-TEG, consisting of an aluminum foil and a microneedle-structured PDMS (MN-PDMS) film, generates an output performance with an open-circuit voltage up to 102.8 V, and a short circuit current of 43.1 uA, corresponding to the current density of 1.5 uA cm-2 . With introducing MN-PDMS into the MN-TEG, a great increase of randomly closed bending-friction-deformation (BFD) behavior of MNs leads to highly enhanced triboelectric performance of the MN-TEG. The BFD keeps increasingly on in-contact between MN with Al that results in enhancement of electrical capacitance of PDMS. The effect of aspect ratio and density of MN morphology on the output performance of MN-PDMS TEG is studied further. The MN-TEG can rapidly charge electric energy on a 0.1 uF capacitor up to 2.1 V in about 0.56 s. The MN-TEG source under tapping can light up 53 light-emitting diodes with different colors, connected in series. PMID- 28594435 TI - Texture and lubrication properties of functional cream cheese: Effect of beta glucan and phytosterol. AB - : The effect of beta-glucan (BG) and phytosterols (PS) as fat replacers on textural, microstructural, and lubrication properties of reduced-fat cream cheese was investigated. Five formulations (BG-PS ester, PS ester, BG-PS emulsions, PS emulsions, and BG) of cream cheese with added beta-glucan and phytosterols (in emulsified and esterified form) were investigated and compared with commercial cheese. Among the five formulations used in this experiment, the effect of beta glucan appeared to be more pronounced imparting increased viscosity and firmness to reduced-fat cream cheese, similar to commercial high-fat cream cheese sample. Conversely, in lubrication study both the phytosterols (esterified and emulsified) were effective in reducing the coefficient of friction resulting in a more spreadable cream cheese. The microstructure of cream cheese with added beta glucan and phytosterols, used solo or in combination, exhibited more open structure of casein matrix, although differences in fat globule size were observed. Cream cheese made from PS emulsion (emulsified from phytosterols powder) resulted in a larger fat globule size than PS ester and beta-glucan as shown by confocal laser scanning microscopy. In addition, the particle size distribution of cream cheese formulation containing beta-glucan only showed a monomodal curves with small globule size, while a bimodal distribution with larger particle size was observed from cream cheese with phytosterols alone. PRACTICAL APPLICATIONS: Reducing the fat content, impacts the quality characteristics of low-fat cream cheese. This research showed a novel way to incorporate beta-glucan and phytosterols as fat replacers and functional ingredients in cream cheese formulation that improves its textural and lubrication properties. In addition, this article discusses the effect of beta glucan and phytosterols used both individually and in combination on the particle size, microstructural and rheological characteristics of functional cream cheese and compares them against commercial product. The potential use of beta-glucan and phytosterols as fat replacers in low-fat cream cheese will be useful for the industries to develop functional cream cheese that meets consumers demand. PMID- 28594436 TI - The First Step of the Oxidation of Elemental Sulfur: Crystal Structure of the Homopolyatomic Sulfur Radical Cation [S8 ]. AB - The oxidation of elemental sulfur in superacidic solutions and melts is one of the oldest topics in inorganic main group chemistry. Thus far, only three homopolyatomic sulfur cations ([S4 ]2+ , [S8 ]2+ , and [S19 ]2+ ) have been characterized crystallographically although ESR investigations have given evidence for the presence of at least two additional homopolyatomic sulfur radical cations in solution. Herein, the crystal structure of the hitherto unknown homopolyatomic sulfur radical cation [S8 ].+ is presented. The radical cation [S8 ].+ represents the first step of the oxidation of the S8 molecule present in elemental sulfur. It has a structure similar to the known structure of [S8 ]2+ , but the transannular sulfur???sulfur contact is significantly elongated. Quantum-chemical calculations help in understanding its structure and support its presence in solution as a stable compound. The existence of [S8 ].+ is also in accord with previous ESR investigations. PMID- 28594437 TI - Crosslinked Carbon Nanotube Aerogel Films Decorated with Cobalt Oxides for Flexible Rechargeable Zn-Air Batteries. AB - Air electrodes with high catalytic activity are of great importance for rechargeable zinc-air batteries. Herein, a flexible, binder-free composite air electrode for zinc-air batteries is reported, which utilizes a lightweight, conductive, and crosslinked aerogel film of carbon nanotubes (CNTs) functioned as a 3D catalyst-supporting scaffold for bifunctional cobalt (II/III) oxides and as a current collector. The composite electrode shows high catalytic activities for both oxygen reduction reaction and oxygen evolution reaction, resulting from the synergistic effect of nitrogen-doped CNTs and spinel Co3 O4 nanoparticles. Solid state Zn-air batteries assembled using such free-standing air electrodes (without the need of additional current collectors) are bendable and show low resistances, low charge/discharge overpotentials, and a high cyclic stability. PMID- 28594438 TI - Quest for the ultimate cardiac CT scanner. AB - PURPOSE: To quantitatively evaluate and compare six proposed system architectures for cardiac CT scanning. METHODS: Starting from the clinical requirements for cardiac CT, we defined six dedicated cardiac CT architectures. We selected these architectures based on a previous screening study and defined them in sufficient detail to comprehensively analyze their cost and performance. We developed rigorous comparative evaluation methods for the most important aspects of performance and cost, and we applied these evaluation criteria to the defined cardiac CT architectures. RESULTS: We found that CT system architectures based on the third-generation geometry provide nearly linear performance improvement versus the increased cost of additional beam lines (i.e., source-detector pairs), although similar performance improvement could be achieved with advanced motion correction algorithms. The third-generation architectures outperform even the most promising of the proposed architectures that deviate substantially from the traditional CT system architectures. CONCLUSION: This work confirms the validity of the current trend in commercial CT scanner design. However, we anticipate that over time, CT hardware and software technologies will evolve, the relative importance of the performance criteria will change, the relative costs of components will vary, some of the remaining challenges will be addressed, and perhaps new candidate architectures will be identified; therefore, the conclusion of a comparative analysis like this may change. The evaluation methods that we used can provide a framework for other researchers to analyze their own proposed CT architectures. PMID- 28594439 TI - Genetic and psychosocial predictors of alcohol use trajectories among disaster exposed adolescents. AB - BACKGROUND AND OBJECTIVES: Adolescent alcohol misuse is associated with numerous long-term adverse outcomes, so we examined predictors of alcohol use among disaster-exposed adolescents, a group at-risk for alcohol misuse. METHODS: The current study (n = 332) examined severity of tornado-related exposure, posttraumatic stress disorder (PTSD) symptoms, emotional support, and a genetic risk sum score (GRSS) as predictors of alcohol use trajectories. RESULTS: Severity of exposure interacted with the GRSS to predict both intercept (12-month follow up quantity of alcohol use) and growth rate. Emotional support also interacted with adolescent PTSD symptoms to predict intercept and growth rate. DISCUSSION AND CONCLUSIONS: Adolescents with greater severity of disaster exposure and high genetic risk comprise a high risk group, on which efforts to prevent alcohol use should be focused. Additionally, emotional support is essential in buffering the effects of PTSD symptoms on alcohol use outcomes among adolescents. SCIENTIFIC SIGNIFICANCE: Toward the aim of reducing adolescent alcohol misuse following disaster exposure, there is utility in inserting immediate supports (e.g., basic resources) into communities/families that have experienced significant disaster-related severity, particularly among adolescents at high levels of genetic risk for alcohol use/misuse. Additionally, prevention efforts aimed at improving emotional supports for adolescents with more PTSD symptoms may reduce propensity for alcohol misuse following disaster. This information can be easily incorporated into existing web-based interventions. (Am J Addict 2017;26:623-631). PMID- 28594440 TI - Calcium signalling in medial intercalated cell dendrites and spines. AB - KEY POINTS: Dendritic and spine calcium imaging in combination with electrophysiology in acute slices revealed that in medial intercalated cells of the amygdala: Action potentials back-propagate into the dendritic tree, but due to the presence of voltage-dependent potassium channels, probably Kv4.2 channels, attenuate over distance. A mixed population of AMPA receptors with rectifying and linear I-V relations are present at individual spines of a single neuron. Decay kinetics and pharmacology suggest tri-heteromeric NMDA receptors at basolateral intercalated cell synapses. NMDA receptors are the main contributors to spine calcium entry in response to synaptic stimulation. Calcium signals in response to low- and high-frequency stimulation, and in combination with spontaneous action potentials are locally restricted to the vicinity of active spines. Together, these data show that calcium signalling in these GABAergic neurons is tightly controlled and acts as a local signal. ABSTRACT: The amygdala plays a central role in fear conditioning and extinction. The medial intercalated (mITC) neurons are GABAergic cell clusters interspaced between the basolateral (BLA) and central amygdala (CeA). These neurons are thought to play a key role in fear and extinction, controlling the output of the CeA by feed-forward inhibition. BLA to mITC cell inputs are thought to undergo synaptic plasticity, a mechanism underlying learning, which is mediated by NMDA receptor-dependent mechanisms that require changes in cytosolic calcium. Here, we studied the electrical and calcium signalling properties of mITC neurons in GAD67-eGFP mice using whole-cell patch clamp recordings and two-photon calcium imaging. We show that action potentials back-propagate (bAP) into dendrites, and evoke calcium transients in both the shaft and the dendritic spine. However, bAP-mediated calcium rises in the dendrites attenuate with distance due to shunting by voltage-gated potassium channels. Glutamatergic inputs make dual component synapses on spines. At these synapses, postsynaptic AMPA receptors can have linear or rectifying I-V relationships, indicating that some synapses express GluA2-lacking AMPA receptors. Synaptic NMDA receptors had intermediate decay kinetics, and were only partly blocked by GuN2B selective blockers, indicating these receptors are GluN1/GluN2A/GluN2B trimers. Low- or high-frequency synaptic stimulation raised spine calcium, mediated by calcium influx via NMDA receptors, was locally restricted and did not invade neighbouring spines. Our results show that in mITC neurons, postsynaptic calcium is tightly controlled, and acts as a local signal. PMID- 28594441 TI - Rapid computation of single PET scan rest-stress myocardial blood flow parametric images by table look up. AB - PURPOSE: We have recently reported a method for measuring rest-stress myocardial blood flow (MBF) using a single, relatively short, PET scan session. The method requires two IV tracer injections, one to initiate rest imaging and one at peak stress. We previously validated absolute flow quantitation in ml/min/cc for standard bull's eye, segmental analysis. In this work, we extend the method for fast computation of rest-stress MBF parametric images. METHODS: We provide an analytic solution to the single-scan rest-stress flow model which is then solved using a two-dimensional table lookup method (LM). Simulations were performed to compare the accuracy and precision of the lookup method with the original nonlinear method (NLM). Then the method was applied to 16 single scan rest/stress measurements made in 12 pigs: seven studied after infarction of the left anterior descending artery (LAD) territory, and nine imaged in the native state. Parametric maps of rest and stress MBF as well as maps of left (fLV ) and right (fRV ) ventricular spill-over fractions were generated. Regions of interest (ROIs) for 17 myocardial segments were defined in bull's eye fashion on the parametric maps. The mean of each ROI was then compared to the rest (K1r ) and stress (K1s ) MBF estimates obtained from fitting the 17 regional TACs with the NLM. RESULTS: In simulation, the LM performed as well as the NLM in terms of precision and accuracy. The simulation did not show that bias was introduced by the use of a predefined two-dimensional lookup table. In experimental data, parametric maps demonstrated good statistical quality and the LM was computationally much more efficient than the original NLM. Very good agreement was obtained between the mean MBF calculated on the parametric maps for each of the 17 ROIs and the regional MBF values estimated by the NLM (K1mapLM = 1.019 * K1ROINLM + 0.019, R2 = 0.986; mean difference = 0.034 +/- 0.036 mL/min/cc). CONCLUSIONS: We developed a table lookup method for fast computation of parametric imaging of rest and stress MBF. Our results show the feasibility of obtaining good quality MBF maps using modest computational resources, thus demonstrating that the method can be applied in a clinical environment to obtain full quantitative MBF information. PMID- 28594443 TI - Growth factors for angiogenesis in peripheral arterial disease. AB - BACKGROUND: Peripheral artery disease (PAD) is associated with a high clinical and socioeconomic burden. Treatments to alleviate the symptoms of PAD and decrease the risks of amputation and death are a high societal priority. A number of growth factors have shown a potential to stimulate angiogenesis. Growth factors delivered directly (as recombinant proteins), or indirectly (e.g. by viral vectors or DNA plasmids encoding these factors), have emerged as a promising strategy to treat patients with PAD. OBJECTIVES: To assess the effects of growth factors that promote angiogenesis for treating people with PAD of the lower extremities. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Specialised Register (June 2016) and CENTRAL (2016, Issue 5). We searched trial registries for details of ongoing or unpublished studies. We also checked the reference lists of relevant publications and, if necessary, tried to contact the trialists for details of the studies. SELECTION CRITERIA: We included randomised controlled trials comparing growth factors (delivered directly or indirectly) with no intervention, placebo or any other intervention not based on the growth factor's action in patients with PAD of the lower extremities. The primary outcomes were limb amputation, death and adverse events. The secondary outcomes comprised walking ability, haemodynamic measures, ulceration and rest pain. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and assessed the risk of bias. We used outcomes of the studies at low risk of bias for the main analysis and of all studies in the sensitivity analyses. We calculated odds ratios (OR) for dichotomous outcomes and mean differences for continuous outcomes with 95% confidence intervals (CI). We evaluated statistical heterogeneity using the I2 statistic and Cochrane's Q test. We conducted meta analysis for the overall effect and for each growth factor as a subgroup analysis using OR in a fixed-effect model. We evaluated the robustness of the results in a sensitivity analysis using risk ratio (RR) and/or a random-effects model. We also assessed the quality of the evidence for each outcome. MAIN RESULTS: We included 20 trials in the review and used 14 studies (on approximately 1400 participants) with published results in the analyses. Six published studies compared fibroblast growth factors (FGF), four studies hepatocyte growth factors (HGF) and another four studies vascular endothelial growth factors (VEGF), versus placebo or no therapy. Six of these studies exclusively or mainly investigated participants with intermittent claudication and eight studies exclusively participants with critical limb ischaemia. Follow-up generally ranged from three months to one year. Two small studies provided some data at 2 years and one of them also at 10 years.The direction and size of effects for growth factors on major limb amputations (OR 0.99, 95% CI 0.71 to 1.38; 10 studies, N = 1075) and death (OR 0.99, 95% CI 0.69 to 1.41; 12 studies, N = 1371) at up to two years are uncertain. The quality of the evidence is low due to risk of bias and imprecision (at one year, moderate-quality evidence due to imprecision). However, growth factors may decrease the rate of any limb amputations (OR 0.56, 95% CI 0.31 to 0.99; 6 studies, N = 415). The quality of the evidence is low due to risk of bias and selective reporting.The direction and size of effects for growth factors on serious adverse events (OR 1.09, 95% CI 0.79 to 1.50; 13 studies, N = 1411) and on any adverse events (OR 1.10, 95% CI 0.73 to 1.64; 4 studies, N = 709) at up to two years are also uncertain. The quality of the evidence is low due to risk of bias and imprecision (for serious adverse events at one year, moderate-quality evidence due to imprecision).Growth factors may improve haemodynamic measures (low-quality evidence), ulceration (very low-quality evidence) and rest pain (very low-quality evidence) up to one year, but they have little or no effect on walking ability (low-quality evidence). We did not identify any relevant differences in effects between growth factors (FGF, HGF and VEGF). AUTHORS' CONCLUSIONS: The results of this review do not support the use of therapy with the growth factors FGF, HGF or VEGF in people with PAD of the lower extremities to prevent death or major limb amputation or to improve walking ability. However, the use of these growth factors may improve haemodynamic measures and decrease the rate of any limb amputations (probably due to preventing minor amputations) with an uncertain effect on adverse events; an improvement of ulceration and rest pain is very uncertain. New trials at low risk of bias are needed to generate evidence with more certainty. PMID- 28594444 TI - 2D Black Phosphorus for Energy Storage and Thermoelectric Applications. AB - Recent progress in the currently available methods of producing black phosphorus bulk and phosphorene are presented. The effective passivation approaches toward improving the air stability of phosphorene are also discussed. Furthermore, the research efforts on the phosphorene and phosphorene-based materials for potential applications in lithium ion batteries, sodium ion batteries, and thermoelectric devices are summarized and highlighted. Finally, the outlook including challenges and opportunities in these research fields are discussed. PMID- 28594442 TI - Body mass index and risk of gastric cancer: A 30-year follow-up study in the Linxian general population trial cohort. AB - Although a number of previous studies have noted either positive or no association for body mass index (BMI) and gastric cancer risk, little evidence exists in the Chinese population. We prospectively examined the associations of BMI with risk of gastric cancer in the Linxian General Population Trial cohort, with 29 584 healthy adults enrolled in 1985 and followed through to the end of 2014. Body weight and height were measured during physical examination at baseline and BMI was calculated as weight in kilograms divided by height in meters squared. Body mass index from 138 subjects was missing, and a total of 29 446 participants were included in the final analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. During 30 years of follow-up, we confirmed 1716 newly diagnosed gastric cardia adenocarcinoma (GCA) cases and 626 new gastric non-cardia adenocarcinoma (GNCA) cases. Overall, compared to the lowest quartile (BMI <20.32 kg/m2 ), subjects in the fourth quartile (BMI >=23.31 kg/m2 ) subjects had lower risk of developing GNCA (hazard ratio, 0.65; 95% confidence interval, 0.51-0.83). Age- and sex specific analyses showed that this protective effect was only observed in men and older (52 + years) persons. No associations were observed for BMI with GCA incidence. Higher BMI was associated with decreased risk of GNCA in this population, particularly in men and older persons. Future studies are needed to confirm these findings. The trial is registered with ClinicalTrials.gov: NCT00342654. PMID- 28594445 TI - Mitochondrial heterogeneity, metabolic scaling and cell death. AB - Heterogeneity in mitochondrial content has been previously suggested as a major contributor to cellular noise, with multiple studies indicating its direct involvement in biomedically important cellular phenomena. A recently published dataset explored the connection between mitochondrial functionality and cell physiology, where a non-linearity between mitochondrial functionality and cell size was found. Using mathematical models, we suggest that a combination of metabolic scaling and a simple model of cell death may account for these observations. However, our findings also suggest the existence of alternative competing hypotheses, such as a non-linearity between cell death and cell size. While we find that the proposed non-linear coupling between mitochondrial functionality and cell size provides a compelling alternative to previous attempts to link mitochondrial heterogeneity and cell physiology, we emphasise the need to account for alternative causal variables, including cell cycle, size, mitochondrial density and death, in future studies of mitochondrial physiology. PMID- 28594446 TI - Sow housing associated with reproductive performance in breeding herds. AB - Female pigs in breeding herds can be managed through four phases-gilt development, breeding, gestation, and lactation-during which they may be housed in group or individual pens, stalls, or on pasture. In this review, we focus on housing environments that optimize outcomes during gestation and lactation. Appropriate housing is important during early gestation, to protect embryos and to confirm pregnancy, and from mid-to-late gestation, to ensure sufficient nutrition to increase placental and fetal growth. No difference in the number of pigs born alive were reported between group housing and individual stall housing, although more risk factors for reproductive performance are associated with group housing than stall housing including genetics, bedding, floor space allowance, group size, social ranking, and parity. Furthermore, lameness in pregnant pigs is more frequent in group housing than in stall housing. Housing during lactation helps protect piglets from being crushed or from contracting disease, and can foster the transfer of enough colostrum from mother to piglets. Indeed, lactating sows in pen housing tend to have higher pre-weaning mortality and lighter litter weights than those in crated housing. PMID- 28594447 TI - Potential overtreatment among men aged 80 years and older with localized prostate cancer in Japan. AB - Despite treatment guidelines recommending observation for men with low-risk prostate cancer with life expectancy <10 years, a majority of elderly patients choose active treatment, which may result in overtreatment. Given the growing burden of prostate cancer among men aged >=80 years (super-elderly men), accumulation of survival data for evaluation of overtreatment among super-elderly patients is imperative. Here, we report results of a population-based cohort study to clarify potential overtreatment of super-elderly men with localized prostate cancer. We used cancer registry data from the Monitoring of Cancer Incidence in Japan project, which covers 47% of the Japanese population. The subjects were men diagnosed with prostate cancer between 2006 and 2008. Follow-up period was 5 years. We calculated 5-year relative survival rates among the active treatment and observation groups after imputation for missing values. Of the 48 782 patients with prostate cancer included in the analysis, 15.1% were super elderly men. The 5-year relative survival rates of super-elderly men with localized cancer were 105.9% and 104.1% among the active treatment and observation groups, respectively. This excellent relative survival rate in the observation group remained consistent even after stratification by tumor grade. Of the 2963 super-elderly men with localized cancer, 252 (8.5%) with curative treatment and 1476 (49.8%) with hormone therapy were assumed to have been overtreated. The proportion of overtreatment was estimated to reach 80% after imputation. These specific survival data in super-elderly men in the observation group can be useful in shared decision-making for these patients and may lead to a reduction in overtreatment. PMID- 28594448 TI - Emotion dysregulation as a mechanism linking anxiety and hazardous drinking among Latinos in primary care. AB - BACKGROUND AND OBJECTIVES: Research suggests that Latinos experience significantly more mental health and alcohol use problems than non-Latino whites. However, relatively little is known about the mechanisms underlying alcohol use in this population. One factor associated with excessive alcohol use in Latinos is anxiety. A potential explanatory mechanism for this relationship is emotion dysregulation, as emotion dysregulation in the context of anxiety may lead to alcohol use problems/disorders. The aim of the current study was to examine the indirect effect of anxiety, through emotion dysregulation, on drinking severity and probable hazardous drinking in Latinos. METHODS: Latino adults (N = 264) were recruited from a primary care health clinic as part of a larger ongoing study examining mental health among Latinos in primary care. Participants were interviewed using the MINI and then completed various self-report assessments (in Spanish). Structural equation modeling was used to evaluate model fit. RESULTS: Structural models fit the data well. Additionally, there were statistically significant indirect effects of anxiety via emotion dysregulation on drinking severity and probable screen for hazardous drinking. DISCUSSION AND CONCLUSIONS: Anxiety may contribute to alcohol use problems due to an overall tendency to engage in maladaptive attempts to regulate emotions. SCIENTIFIC SIGNIFICANCE: Targeting emotion dysregulation in the context of anxiety and hazardous alcohol use among Latinos may be one therapeutic strategy to reduce severity of alcohol use (and hazardous drinking). (Am J Addict 2017;26:615-622). PMID- 28594449 TI - Predictive therapeutic planning for irreversible electroporation treatment of spontaneous malignant glioma. AB - PURPOSE: Irreversible electroporation (IRE) has been developed as a promising minimally invasive treatment to ablate spontaneous brain tumors with pulsed electric fields in canine patients. The purpose of the study is to determine the Peleg-Fermi parameters needed to incorporate pulse number and pulse duration into the therapeutic planning of IRE. METHODS: Seven canine patients were treated with IRE for spontaneous malignant glioma with MRI-based treatment planning. The treatment planning method consists of building patient-specific finite element models and using them to compute electric fields used in the IRE treatment. We evaluate the predictive power of tumor coverage with electric field alone vs. cell kill probability using radiographically confirmed clinical outcomes. RESULTS: Results of post-treatment diagnostic imaging, tumor biopsies, and neurological examinations indicated successful tumor ablation without significant direct neurotoxicity in six of the seven dogs. Objective tumor responses were seen in four (80%) of five dogs with quantifiable target lesions according to RANO criteria. Two dogs experienced survivals in excess of 1 yr, including one dog that resulted in complete response to IRE treatment for 5+ years to date. Tumor fraction exposed to electric field over 600 V/cm was between 0.08 and 0.73, while tumor fraction exposed to electric field over 300 V/cm was between 0.17 and 0.95. Probability of cell kill of >= 90% was found in tumor volume fractions between 0.21 and 0.99. CONCLUSIONS: We conclude that IRE is a safe and effective minimally invasive treatment for malignant glioma and can be predicted with the Peleg-Fermi cell kill probability function. A tumor coverage of >= 0.9 at a cell kill probability >= 90% can be used to guide IRE treatments of spontaneous malignant glioma based on the radiographically confirmed clinical outcomes achieved. PMID- 28594450 TI - Evaluation of the Effectiveness of Two Morphine Protocols to Treat Neonatal Abstinence Syndrome in a Level II Nursery in a Community Hospital. AB - The authors sought to evaluate the impact on length of hospital stay and treatment duration of morphine after implementation of a change in the institutional protocol for managing neonatal abstinence syndrome (NAS) in an effort to improve patient outcomes. A single-center, retrospective chart review was conducted at a Level II nursery in a community hospital in Kentucky. Fifty nine neonates born between January 1, 2014, and December 31, 2015, who were diagnosed with NAS and received morphine for treatment were included. The protocol 1 group consisted of 33 neonates who received an initial dose of morphine 0.04 mg/kg/dose administered orally every 4 hours (January 1-December 31, 2014), and the protocol 2 group consisted of 26 neonates who received an initial dose of morphine 0.06 mg/kg/dose administered orally every 3 hours (January 1-November 30, 2015), after a change in the protocol for managing NAS was implemented on January 1, 2015. Data were reviewed and compared between the two protocol groups to determine the impact that the dosage change had on length of hospital stay and morphine treatment duration. The average length of stay decreased by 7 days in the protocol 2 group compared with the protocol 1 group (21 vs 28.65 days). The average duration of treatment decreased by 7 days in the protocol 2 group compared with the protocol 1 group (18.3 vs 25.4 days). These differences between groups were not statistically significant, however, because the population size was not large enough to achieve adequate power. These results indicate that protocol 2 displayed the potential to decrease length of stay and duration of treatment compared with protocol 1 at this facility; however, balancing higher starting doses with the risk of oversedation will continue to challenge the health care team. Concern for oversedation when using the higher starting dose in protocol 2 has prompted further research (e.g., protocol 3, initial morphine 0.05 mg/kg/dose every 3 hrs). Continued research is also necessary with larger patient populations to enable generalizability to other institutions. PMID- 28594451 TI - Two-Step Spin-Crossover with Three Inequivalent FeII Sites in a Two-Dimensional Hofmann-Type Coordination Polymer. AB - An unprecedented two-step spin-crossover behavior with the sequence of gammaHS =1<->gammaHS =3/4<->gammaHS =1/4 was observed in two-dimensional Hofmann type coordination polymer [Fe(isoq)2 {Ag(CN)2 }2 ] (isoq=isoquinoline), which resulted from three crystallographically inequivalent FeII sites with distinct transition temperatures. PMID- 28594452 TI - Progress on Electronic and Optoelectronic Devices of 2D Layered Semiconducting Materials. AB - 2D layered semiconducting materials (2DLSMs) represent the thinnest semiconductors, holding many novel properties, such as the absence of surface dangling bonds, sizable band gaps, high flexibility, and ability of artificial assembly. With the prospect of bringing revolutionary opportunities for electronic and optoelectronic applications, 2DLSMs have prospered over the past twelve years. From materials preparation and property exploration to device applications, 2DLSMs have been extensively investigated and have achieved great progress. However, there are still great challenges for high-performance devices. In this review, we provide a brief overview on the recent breakthroughs in device optimization based on 2DLSMs, particularly focussing on three aspects: device configurations, basic properties of channel materials, and heterostructures. The effects from device configurations, i.e., electrical contacts, dielectric layers, channel length, and substrates, are discussed. After that, the affect of the basic properties of 2DLSMs on device performance is summarized, including crystal defects, crystal symmetry, doping, and thickness. Finally, we focus on heterostructures based on 2DLSMs. Through this review, we try to provide a guide to improve electronic and optoelectronic devices of 2DLSMs for achieving practical device applications in the future. PMID- 28594453 TI - Risk Factors associated with defaulting from visceral leishmaniasis treatment: analysis under routine programme conditions in Bihar, India. AB - OBJECTIVE: To assess the rate of default from treatment in the visceral leishmaniasis (VL) elimination programme and to identify risk factors and its underlying causes. METHODS: Case-control study conducted between December 2009 and June 2012 in three primary health centres (PHCs) of Muzaffarpur district, India. Patients who defaulted from treatment from the PHCs were considered as 'cases' and those who completed their treatment as 'controls'. Two controls were included in the study for each case. Respondents' opinion and satisfaction with the services provided at the PHCs were also elicited. Logistic regression was performed to assess the contribution of sociodemographic variables on patient status, and a discriminant analysis was used (after decomposing the original data) to identify factors that can predict the patient status as defaulter or not, based on factor scores of the components as predictor variables. RESULTS: During the study period, 16.3% (89/544) of patients defaulted; 87 cases and 188 controls were interviewed through a semistructured questionnaire. Women tended to be more at risk for default (OR, 1.6, 95% CI (0.9 -2.9). Treatment received was miltefosine in 55.6% and sodium stibogluconate (SSG) in 44.4%. Most (86%) defaulters completed their treatment at other healthcare facilities; 70% of them preferred non-governmental institutions. Most cited reasons for default were seeking a second opinion for VL treatment and preferring to be treated in specialised VL centres. Discriminant analysis showed only one significant predictor: dissatisfaction with the medical care received in PHCs. CONCLUSION: Efforts are needed to enhance the quality of VL care at PHC level, which will be beneficial in increasing treatment completion rates. PMID- 28594454 TI - Precise Control of the Lateral and Vertical Growth of Two-Dimensional Ag Nanoplates. AB - Tuning localized surface plasmon resonance (LSPR) is crucial for practical applications of two-dimensional Ag nanoplates (AgNPs) and relies on the precise control of their lateral length or/and thickness. In the present seed-mediated synthetic method, by taking advantage of underpotential deposition (UPD) of Cu on the (111) surfaces of AgNPs, a solely lateral growth of AgNPs was achieved when Cu(NO3 )2 was employed, while a vertical growth of AgNPs could be attained by introducing CuCl2 into our growth solutions. The lateral length and the vertical thickness of the AgNPs could be tuned in the ranges of 115 to nearly 300 nm and 13.4 to around 200 nm, respectively. Along with control of the dimensional size of AgNPs, LSPR could also be tuned in the visible to near infrared range. Plausible growth mechanisms for the precise control of the lateral and vertical growth of AgNPs were proposed. PMID- 28594455 TI - Broadband Light Absorption and Efficient Charge Separation Using a Light Scattering Layer with Mixed Cavities for High-Performance Perovskite Photovoltaic Cells with Stability. AB - CH3 NH3 PbI3 is one of the promising light sensitizers for perovskite photovoltaic cells, but a thick layer is required to enhance light absorption in the long-wavelength regime ranging from PbI2 absorption edge (500 nm) to its optical band-gap edge (780 nm) in visible light. Meanwhile, the thick perovskite layer suppresses visible-light absorption in the short wavelengths below 500 nm and charge extraction capability of electron-hole pairs produced upon light absorption. Herein, we find that a new light scattering layer with the mixed cavities of sizes in 100 and 200 nm between transparent fluorine-doped tin oxide and mesoporous titanium dioxide electron transport layer enables full absorption of short-wavelength photons (lambda < 500 nm) to the perovskite along with enhanced absorption of long-wavelength photons (500 nm < lambda < 780 nm). Moreover, the light-driven electric field is proven to allow efficient charge extraction upon light absorption, thereby leading to the increased photocurrent density as well as the fill factor prompted by the slow recombination rate. Additionally, the photocurrent density of the cell with a light scattering layer of mixed cavities is stabilized due to suppressed charge accumulation. Consequently, this work provides a new route to realize broadband light harvesting of visible light for high-performance perovskite photovoltaic cells. PMID- 28594456 TI - Total Synthesis of 7-epi-Pukalide and 7-Acetylsinumaximol B. AB - Convergent total syntheses of the furanocembranoids 7-epi-pukalide and 7 acetylsinumaximol B have been achieved using a one-pot Knoevenagel condensation and thioether-mediated furan-forming reaction. Furan formation proceeds via a sulfur ylide and results in rapid introduction of structural complexity during the coupling of two highly functionalised fragments. The targets have been prepared in 16 steps from (R)-perillyl alcohol. PMID- 28594457 TI - Highly Doped Carbon Nanobelts with Ultrahigh Nitrogen Content as High-Performance Supercapacitor Materials. AB - Nitrogen-doped and nitrogen and oxygen codoped carbon nanobelts (CNBs) (denoted as N-CNBs and N-O-CNBs, respectively) are respectively obtained by pyrolyzing the self-aligned polypyrrole (PPy) NBs and Se@poly(2-methoxy-5-nitroaniline) core@shell nanowires. Particularly, the uniform size, unique nanostructure, and well-defined edges of the PPy NBs result in the uniform size of the doped CNBs with an extraordinarily high N doping level (~16 at%), especially the very large concentrations of the redox active pyridinic (9 at%) and pyrrolic N (3.5 at%) species. Furthermore, the precursors in highly self-aligned, dense arrays give rise to a very high packing density for the N-CNBs and N-O-CNBs. These incomparable features provide not only appropriate pathways for the introduction of pseudocapacitance via rapid Faradaic reactions and enhancement of volumetric capacitance but also structural design and synthesis approach to new types of nanostructured carbon. Notably, the N-CNBs obtained at the pyrolysis temperature of 800 degrees C (N-CNB8) in symmetric electrochemical cells deliver a specific capacitance of 458 F g-1 and ultrahigh volumetric capacitance of 645 F cm-3 in aqueous solution, which are among the best performance ever reported for carbon based supercapacitive materials. PMID- 28594458 TI - Concizumab, an anti-tissue factor pathway inhibitor antibody, induces increased thrombin generation in plasma from haemophilia patients and healthy subjects measured by the thrombin generation assay. AB - AIMS: Concizumab, a humanized monoclonal antibody against tissue factor pathway inhibitor (TFPI), is being developed as a subcutaneously (s.c.) administered treatment for haemophilia. It demonstrated a concentration-dependent procoagulant effect in functional TFPI assays; however, global haemostatic assays, such as the thrombin generation assay (TGA), offer a more complete picture of coagulation. We investigated how concizumab affects thrombin generation following ex vivo spiking in plasma from haemophilia patients using the TGA, and if the assay can detect the effect of multiple s.c. concizumab doses in healthy subjects. METHODS: For the ex vivo spiking study, platelet-poor plasma (PPP) from 18 patients with severe haemophilia was spiked with 0.001-500 nm concizumab. For the multiple dosing study, four healthy males received concizumab 250 MUg kg-1 s.c. every other day for eight doses; blood was collected before and after dosing and processed into PPP. In both studies, thrombin generation was measured using a Calibrated Automated Thrombogram(r) system with 1 pm tissue factor. RESULTS: In spiked samples from haemophilia patients, peak thrombin and endogenous thrombin potential (ETP) increased concentration dependently, reaching near-normal levels at concizumab concentrations >10 nm. Repeated s.c. doses of concizumab in healthy subjects increased both peak thrombin and ETP; these effects were sustained throughout the dosing interval. CONCLUSIONS: Thrombin generation assay demonstrated increased thrombin generation with concizumab after ex vivo spiking of haemophilia plasma and multiple s.c. doses in healthy subjects, supporting both the utility of the TGA in evaluating concizumab treatment and the potential of s.c. concizumab as a novel haemophilia therapy. PMID- 28594459 TI - Computer vision syndrome-A common cause of unexplained visual symptoms in the modern era. AB - OBJECTIVES: The aim of this study was to assess the evidence and available literature on the clinical, pathogenetic, prognostic and therapeutic aspects of Computer vision syndrome. METHODS: Information was collected from Medline, Embase & National Library of Medicine over the last 30 years up to March 2016. The bibliographies of relevant articles were searched for additional references. FINDINGS: Patients with Computer vision syndrome present to a variety of different specialists, including General Practitioners, Neurologists, Stroke physicians and Ophthalmologists. While the condition is common, there is a poor awareness in the public and among health professionals. INTERPRETATIONS AND IMPLICATIONS: Recognising this condition in the clinic or in emergency situations like the TIA clinic is crucial. The implications are potentially huge in view of the extensive and widespread use of computers and visual display units. Greater public awareness of Computer vision syndrome and education of health professionals is vital. Preventive strategies should form part of work place ergonomics routinely. Prompt and correct recognition is important to allow management and avoid unnecessary treatments. PMID- 28594460 TI - Detection and diagnosis of colitis on computed tomography using deep convolutional neural networks. AB - PURPOSE: Colitis refers to inflammation of the inner lining of the colon that is frequently associated with infection and allergic reactions. In this paper, we propose deep convolutional neural networks methods for lesion-level colitis detection and a support vector machine (SVM) classifier for patient-level colitis diagnosis on routine abdominal CT scans. METHODS: The recently developed Faster Region-based Convolutional Neural Network (Faster RCNN) is utilized for lesion level colitis detection. For each 2D slice, rectangular region proposals are generated by region proposal networks (RPN). Then, each region proposal is jointly classified and refined by a softmax classifier and bounding-box regressor. Two convolutional neural networks, eight layers of ZF net and 16 layers of VGG net are compared for colitis detection. Finally, for each patient, the detections on all 2D slices are collected and a SVM classifier is applied to develop a patient-level diagnosis. We trained and evaluated our method with 80 colitis patients and 80 normal cases using 4 * 4-fold cross validation. RESULTS: For lesion-level colitis detection, with ZF net, the mean of average precisions (mAP) were 48.7% and 50.9% for RCNN and Faster RCNN, respectively. The detection system achieved sensitivities of 51.4% and 54.0% at two false positives per patient for RCNN and Faster RCNN, respectively. With VGG net, Faster RCNN increased the mAP to 56.9% and increased the sensitivity to 58.4% at two false positive per patient. For patient-level colitis diagnosis, with ZF net, the average areas under the ROC curve (AUC) were 0.978 +/- 0.009 and 0.984 +/- 0.008 for RCNN and Faster RCNN method, respectively. The difference was not statistically significant with P = 0.18. At the optimal operating point, the RCNN method correctly identified 90.4% (72.3/80) of the colitis patients and 94.0% (75.2/80) of normal cases. The sensitivity improved to 91.6% (73.3/80) and the specificity improved to 95.0% (76.0/80) for the Faster RCNN method. With VGG net, Faster RCNN increased the AUC to 0.986 +/- 0.007 and increased the diagnosis sensitivity to 93.7% (75.0/80) and specificity was unchanged at 95.0% (76.0/80). CONCLUSION: Colitis detection and diagnosis by deep convolutional neural networks is accurate and promising for future clinical application. PMID- 28594461 TI - Evaluation of a composite Gel-Alanine phantom on an end-to-end test to treat multiple brain metastases by a single isocenter VMAT technique. AB - PURPOSE: This work aims to evaluate the application of a cylindrical phantom made of dosimetric gel containing alanine pellets distributed inside the gel volume during an end-to-end test of a single isocenter VMAT for simultaneous treatment of multiple brain metastases. The evaluation is based on the comparison of the results obtained with the composite phantom with the treatment planning system (TPS) dose distribution validated by using the clinical conventional quality control with point and planar dose measurements. METHODS: A cylindrical MAGIC-f gel phantom containing alanine dosimeters (composite phantom) was used to design the VMAT plan in the treatment planning system (TPS). The alanine dosimeters were pellets with radius of 2.5 mm and height of 3 mm, and played the role of brain metastasis inside the gel cylinder, which simulated the cerebral tissue. Five of the alanine dosimeters were selected to simulate five lesions; five planning target volumes (PTVs) were created including the dosimeters and irradiated with different doses. Conventional quality assurance (QA) was performed on the TPS plan and on the composite phantom; a phantom containing only gel (Gel 1 phantom) was also irradiated. One day after irradiation, magnetic resonance images were acquired for both phantoms on a 3T scanner. An electron spin resonance spectrometer was used to evaluate alanine doses. Calibration curves were constructed for the alanine and the gel dosimeters. All the gel only measurement was repeated (Gel 2 phantom) in order to confirm the previous gel measurement. RESULTS: The VMAT treatment plan was approved by the conventional QA. The doses measured by alanine dosimeters on the composite gel phantom agreed to the TPS on average within 3.3%. The alanine dose for each lesion was used to calibrate the gel dosimeter measurements of the concerned PTV. Both gel dose volume histograms (DVH) achieved for each PTV were in agreement with the expected TPS DVH, except for a small discrepancy observed for the Gel 2 curve of PTV1 and the Gel 1 curve of PTV5. In a 3D gamma analyses performed for each PTV volume independently, comparing both the gels' measurements to the TPS and using 3%/3 mm, 5%/2 mm, and 7%/2 mm, more than 90% of the points were approved for all the PTVs, except for the PTV5 comparison in the Gel 1 measurement and for the PTV2 comparison in the Gel 2 measurement. A 3D gamma analysis was also applied for each PTV independently, to compare both gel measurements in order to evaluate the consistence of repeated gel measurements of the same plan, and more than 94.5% of the points were approved. CONCLUSIONS: The composite Gel-Alanine phantom can be used for the end-to-end test of a single isocenter VMAT for simultaneous treatment of multiple brain metastases. The use of the alanine as the lesion cores for the treatment planning provided the precise dose measurements inside each lesion and allowed the conversion of the gel R2 values based on an accurate dose measurement inside the target. PMID- 28594462 TI - Determinants of sexual function and dysfunction in men and women with stroke: A systematic review. AB - AIM: The aim of this systematic review was to examine determinants of sexual function and dysfunction in men and women poststroke, and to evaluate effectiveness of interventions. METHODS: A systematic review was conducted using the databases of PubMed, Medline, CINAHL, Cochrane, and Psychinfo, for studies published between January, 2000 and October, 2016. Included were original research, adult >=18 years, English language, and experimental and non experimental designs. Excluded were studies of stroke caused by sexual activity, stroke triggered unusual behaviours, and changes in sexual orientation. Studies were evaluated for quality using The Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Of 19 studies reviewed, 13 were descriptive, three case-controlled and three intervention/randomised controlled trials (RCTs) designs. RESULTS: Participants across studies were predominantly men (90%), with moderate erectile dysfunction (ED), and mild depression. Changes in sexual activity, sexual dissatisfaction and sexual dysfunction were common, including decreased libido, orgasmic problems and ED, significantly worse from pre to poststroke. Results for side of hemiparesis and sexual dysfunction were inconclusive. Sexual rehabilitation interventions differed, but resulted in improved sexual satisfaction, sexual activity frequency and erectile function in two studies. CONCLUSIONS: Sexual dysfunction commonly occurred poststroke, continuing for months or as long as 2 years. Intervention studies were limited, with only two RCTs, thus, firm conclusions cannot be made. Few studies included women or younger stroke patients, indicating the need for further RCTs with larger and more diverse samples. PMID- 28594463 TI - Ultralarge Bending Strain and Fracture-Resistance Investigation of Tungsten Carbide Nanowires. AB - Hard tungsten carbide (WC) with brittle behavior is frequently applied for mechanical purposes. Here, ultralarge elastic bending deformation is reported in defect-rare WC [0001] nanowires; the tested bending strain reaches a maximum of 20% +/- 3.33%, which challenges the traditional understanding of this material. The lattice analysis indicates that the dislocations are confined to the inner part of the WC nanowires. First, the high Peierls-Nabarro barrier hinders the movement of the locally formed dislocations, which causes rapid dislocation aggregation and hinders long-range glide, resulting in a dense distribution of the dislocation network. In this case, the loading is dispersed along multiple points, which is then balanced by the complex internal mechanical field. In the compressive part, the possible dislocations predominantly emerge in the (0001) plane and mainly slip along the axial direction. The disordered shell first forms at the tensile side and prevents the generation of nanocracks at the surface. The novel lattice kinetics make WC nanowires capable of substantial bending strain resistance. Analytical results of the force-displacement (F-d) curves based on the double-clamped beam model exhibit an obvious nonlinear elastic characteristic, which originates fundamentally from the lattice anharmonicity under moderate stress. PMID- 28594464 TI - Do changes in neuromuscular activation contribute to the knee extensor angle torque relationship? AB - NEW FINDINGS: What is the central question of the study? Do changes in neuromuscular activation contribute to the knee extensor angle-torque relationship? What is the main finding and its importance? Both agonist (quadriceps) and antagonist coactivation (hamstrings) differed with knee joint angle during maximal isometric knee extensions and thus both are likely to contribute to the angle-torque relationship. Specifically, two independent measurement techniques showed quadriceps activation to be lower at more extended positions. These effects might influence the capacity for neural changes in response to training and rehabilitation at different knee joint angles. The influence of joint angle on knee extensor neuromuscular activation is unclear, owing in part to the diversity of surface electromyography (sEMG) and/or interpolated twitch technique (ITT) methods used. The aim of the study was to compare neuromuscular activation, using rigorous contemporary sEMG and ITT procedures, during isometric maximal voluntary contractions (iMVCs) of the quadriceps femoris at different knee joint angles and examine whether activation contributes to the angle-torque relationship. Sixteen healthy active men completed two familiarization sessions and two experimental sessions of isometric knee extension and knee flexion contractions. The experimental sessions included the following at each of four joint angles (25, 50, 80 and 106 deg): iMVCs (with and without superimposed evoked doublets); submaximal contractions with superimposed doublets; and evoked twitch and doublet contractions whilst voluntarily passive, and knee flexion iMVC at the same knee joint positions. The absolute quadriceps femoris EMG was normalized to the peak-to-peak amplitude of an evoked maximal M-wave, and the doublet-voluntary torque relationship was used to calculate activation with the ITT. Agonist activation, assessed with both normalized EMG and the ITT, was reduced at the more extended compared with the more flexed positions (25 and 50 versus 80 and 106 deg; P <= 0.016), whereas antagonist coactivation was greatest in the most flexed compared with the extended positions (106 versus 25 and 50 deg; P <= 0.02). In conclusion, both agonist and antagonist activation differed with knee joint angle during knee extension iMVCs, and thus both are likely to contribute to the knee extensor angle-torque relationship. PMID- 28594465 TI - Reporting of inequalities in blindness in low income and middle income countries: a review of cross sectional surveys. PMID- 28594466 TI - Bleeding is not the main clinical issue in many patients with inherited thrombocytopaenias. AB - Bleeding diathesis has been considered for a long time the main clinical issue impacting the lives of patients affected by inherited thrombocytopaenias. However, the number of known inherited thrombocytopaenias greatly increased in recent years, and careful evaluation of hundreds of patients affected by these 'new' disorders revealed that most of them are at risk of developing additional life-threatening disorders during childhood or adult life. These additional disorders are usually more serious and dangerous than low platelet count. For instance, it is known that mutations in RUNX1, ANKRD26 and ETV6 cause congenital thrombocytopaenia, but we now know that they also predispose to haematological malignancies. Similarly, MYH9 mutations result in congenital thrombocytopaenia and increase the risk of developing kidney failure, cataracts and hearing loss at a later stage, while MPL mutations cause a congenital thrombocytopaenia that almost always evolves into deadly bone marrow failure. Thus, identification of patients with these disorders is essential for evaluation of their prognosis, enabling effective genetic counselling, personalizing follow-up and giving appropriate treatments in case of development of additional diseases. Careful clinical evaluation and peripheral blood film examination are extremely useful tools in guiding the diagnostic process and identifying the candidate genes to be sequenced. PMID- 28594467 TI - Biochemical characterization of LR769, a new recombinant factor VIIa bypassing agent produced in the milk of transgenic rabbits. AB - BACKGROUND: The bypassing agent factor VII (FVIIa) is a first-line therapy for the treatment of acute bleeding episodes in patients with haemophilia and high titre inhibitors. FVIIa is a highly post-translationally modified protein that requires eukaryotic expression systems to produce a fully active molecule. A recombinant FVIIa was produced in the milk of transgenic rabbits to increase expression and provide an efficient, safe and affordable product after purification to homogeneity (LR769). AIM: To present the biochemical and functional in vitro characteristics of LR769. RESULTS: Mass spectrometric analyses of the intact protein and of heavy and light chains revealed a fully activated, mature and properly post-translationally modified protein notably regarding N/O-glycosylations and gamma-carboxylation. Primary structure analysis, performed by peptide mapping, confirmed 100% of the sequence and the low level or absence of product-derived impurities such as oxidized, deamidated and glycated forms. Low levels of aggregates and fragments were observed by different chromatographic methods. Higher order structure investigated by circular dichroism showed appropriate secondary/tertiary structures and conformational change in the presence of Ca2+ ions. Finally, activated partial thromboplastin time and thrombin generation assays showed the ability of LR769 to decrease coagulation time and to generate thrombin in haemophiliac-A-plasmas, even in the presence of inhibitors. CONCLUSION: The innovative expression system used to produce LR769 yields a new safe and effective rhFVIIa for the treatment of haemophilia A or B patients with inhibitors. PMID- 28594468 TI - Application of an advanced maximum likelihood estimation restoration method for enhanced-resolution and contrast in second-harmonic generation microscopy. AB - Second-harmonic generation (SHG) microscopy has gained popularity because of its ability to perform submicron, label-free imaging of noncentrosymmetric biological structures, such as fibrillar collagen in the extracellular matrix environment of various organs with high contrast and specificity. Because SHG is a two-photon coherent scattering process, it is difficult to define a point spread function (PSF) for this modality. Hence, compared to incoherent two-photon processes like two-photon fluorescence, it is challenging to apply the various PSF-engineering methods to improve the spatial resolution to be close to the diffraction limit. Using a synthetic PSF and application of an advanced maximum likelihood estimation (AdvMLE) deconvolution algorithm, we demonstrate restoration of the spatial resolution in SHG images to that closer to the theoretical diffraction limit. The AdvMLE algorithm adaptively and iteratively develops a PSF for the supplied image and succeeds in improving the signal to noise ratio (SNR) for images where the SHG signals are derived from various sources such as collagen in tendon and myosin in heart sarcomere. Approximately 3.5 times improvement in SNR is observed for tissue images at depths of up to ~480 nm, which helps in revealing the underlying helical structures in collagen fibres with an ~26% improvement in the amplitude contrast in a fibre pitch. Our approach could be adapted to noisy and low resolution modalities such as micro-nano CT and MRI, impacting precision of diagnosis and treatment of human diseases. PMID- 28594469 TI - Modular Assembly of Reversible Multivalent Cancer-Cell-Targeting Drug Conjugates. AB - Herein is described a new modular platform for the construction of cancer-cell targeting drug conjugates. Tripodal boronate complexes featuring reversible covalent bonds were designed to accommodate a cytotoxic drug (bortezomib), poly(ethylene glycol) (Peg) chains, and folate targeting units. The B-complex core was assembled in one step, proved stable under biocompatible conditions, namely, in human plasma (half-life up to 60 h), and underwent disassembly in the presence of glutathione (GSH). Stimulus-responsive intracellular cargo delivery was confirmed by confocal fluorescence microscopy, and a mechanism for GSH induced B-complex hydrolysis was proposed on the basis of mass spectrometry and DFT calculations. This platform enabled the modular construction of multivalent conjugates with high selectivity for folate-positive MDA-MB-231 cancer cells and IC50 values in the nanomolar range. PMID- 28594470 TI - Effective size of density-dependent two-sex populations: the effect of mating systems. AB - Density dependence in vital rates is a key feature affecting temporal fluctuations of natural populations. This has important implications for the rate of random genetic drift. Mating systems also greatly affect effective population sizes, but knowledge of how mating system and density regulation interact to affect random genetic drift is poor. Using theoretical models and simulations, we compare Ne in short-lived, density-dependent animal populations with different mating systems. We study the impact of a fluctuating, density-dependent sex ratio and consider both a stable and a fluctuating environment. We find a negative relationship between annual Ne /N and adult population size N due to density dependence, suggesting that loss of genetic variation is reduced at small densities. The magnitude of this decrease was affected by mating system and life history. A male-biased, density-dependent sex ratio reduces the rate of genetic drift compared to an equal, density-independent sex ratio, but a stochastic change towards male bias reduces the Ne /N ratio. Environmental stochasticity amplifies temporal fluctuations in population size and is thus vital to consider in estimation of effective population sizes over longer time periods. Our results on the reduced loss of genetic variation at small densities, particularly in polygamous populations, indicate that density regulation may facilitate adaptive evolution at small population sizes. PMID- 28594471 TI - Centralisation of radical cystectomies for bladder cancer in England, a decade on from the 'Improving Outcomes Guidance': the case for super centralisation. AB - OBJECTIVE: To analyse the impact of centralisation of radical cystectomy (RC) provision for bladder cancer in England, on postoperative mortality, length of stay (LoS), complications and re-intervention rates, from implementation of centralisation from 2003 until 2014. In 2002, UK policymakers introduced the 'Improving Outcomes Guidance' (IOG) for urological cancers after a global cancer surgery commission identified substantial shortcomings in provision of care of RCs. One key recommendation was centralisation of RCs to high-output centres. No study has yet robustly analysed the changes since the introduction of the IOG, to assess a national healthcare system that has mature data on such institutional transformation. PATIENTS AND METHODS: RCs performed for bladder cancer in England between 2003/2004 and 2013/2014 were analysed from Hospital Episode Statistics (HES) data. Outcomes including 30-day, 90-day, and 1-year all-cause postoperative mortality; median LoS; complication and re-intervention rates, were calculated. Multivariable statistical analysis was undertaken to describe the relationship between each surgeon and the providers' annual case volume and mortality. RESULTS: In all, 15 292 RCs were identified. The percentage of RCs performed in discordance with the IOG guidelines reduced from 65% to 12.4%, corresponding with an improvement in 30-day mortality from 2.7% to 1.5% (P = 0.024). Procedures adhering to the IOG guidelines had better 30-day mortality (2.1% vs 2.9%; P = 0.003) than those that did not, and better 1-year mortality (21.5% vs 25.6%; P < 0.001), LoS (14 vs 16 days; P < 0.001), and re- intervention rates (30.0% vs 33.6%; P < 0.001). Each single extra surgery per centre reduced the odds of death at 30 days by 1.5% (odds ratio [OR] 0.985, 95% confidence interval [CI] 0.977 0.992) and 1% at 1 year (OR 0.990, 95% CI 0.988-0.993), and significantly reduced rates of re-intervention. CONCLUSION: Centralisation has been implemented across England since the publication of the IOG guidelines in 2002. The improved outcomes shown, including that a single extra procedure per year per centre can significantly reduce mortality and re-intervention, may serve to offer healthcare planners an evidence base to propose new guidance for further optimisation of surgical provision, and hope for other healthcare systems that such widespread institutional change is achievable and positive. PMID- 28594472 TI - Gel network shampoo formulation and hair health benefits. AB - OBJECTIVE: The objective of this work was to create a shampoo formula that contains a stable ordered gel network structure that delivers fatty alcohols inside hair. METHODS: X-ray diffraction (SAXS and WAXS), SEM and DSC have been used to confirm formation of the ordered Lbeta gel network with fatty alcohol (cetyl and stearyl alcohols) and an anionic surfactant (SLE1S). Micro autoradiography and extraction methods using GC-MS were used to confirm penetration of fatty alcohols into hair, and cyclic fatigue testing was used to measure hair strength. RESULTS: In this work, evidence of a stable Lbeta ordered gel network structure created from cetyl and stearyl alcohols and anionic surfactant (SLE1S) is presented, and this is confirmed via scanning electron microscopy images showing lamella layers and differential scanning calorimetry (DSC) showing new melting peaks vs the starting fatty alcohols. Hair washed for 16 repeat cycles with this shampoo showed penetration of fatty alcohols from the gel network into hair as confirmed by a differential extraction method with GC-MS and by radiolabelling of stearyl alcohol and showing its presence inside hair cross-sections. The gel network role in delivering fatty alcohol inside hair is demonstrated by comparing with a shampoo with added fatty alcohol not in an ordered gel network structure. The hair containing fatty alcohol was measured via the Dia-stron cyclic fatigue instrument and showed a significantly higher number of cycles to break vs control. CONCLUSIONS: The formation of a stable gel network was confirmed in the formulated shampoo, and it was demonstrated that this gel network is important to deliver cetyl and stearyl alcohols into hair. The presence of fatty alcohol inside hair was shown to deliver a hair strength benefit via cyclic fatigue testing. PMID- 28594473 TI - TPGS-Functionalized Polydopamine-Modified Mesoporous Silica as Drug Nanocarriers for Enhanced Lung Cancer Chemotherapy against Multidrug Resistance. AB - A nanocarrier system of d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) functionalized polydopamine-coated mesoporous silica nanoparticles (NPs) is developed for sustainable and pH-responsive delivery of doxorubicin (DOX) as a model drug for the treatment of drug-resistant nonsmall cell lung cancer. Such nanoparticles are of desired particle size, drug loading, and drug release profile. The surface morphology, surface charge, and surface chemical properties are also successfully characterized by a series of techniques such as transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller (BET) method, thermal gravimetric analysis (TGA), dynamic light scattering (DLS), and Fourier transform infrared spectroscopy (FTIR). The normal A549 cells and drug-resistant A549 cells are employed to access the cytotoxicity and cellular uptake of the NPs. The therapeutic effects of TPGS conjugated nanoparticles are evaluated in vitro and in vivo. Compared with free DOX and DOX-loaded NPs without TPGS ligand modification, MSNs-DOX@PDA-TPGS exhibits outstanding capacity to overcome multidrug resistance and shows better in vivo therapeutic efficacy. This splendid drug delivery platform can also be sued to deliver other hydrophilic and hydrophobic drugs. PMID- 28594474 TI - Cyclopenta Ring Fused Bisanthene and Its Charged Species with Open-Shell Singlet Diradical Character and Global Aromaticity/ Anti-Aromaticity. AB - Cyclopenta ring fused bisanthene and its charged species were synthesized. The neutral compound has an open-shell singlet ground state and displays global anti aromaticity. The dication also exhibits singlet diradical character but has a unique [10]annulene-within-[18]annulene global aromatic structure. The dianion is closed-shell singlet in the ground state and shows global aromaticity with 22 pi electrons delocalized on the periphery. These findings prrovide new insight into the design and properties of global aromatic/anti-aromatic systems based on pi conjugated polycyclic hydrocarbons. PMID- 28594475 TI - What is safety?: Miracles, benefit-risk assessments, and the "right to try". AB - Public discourse is full of quick solutions to health care problems like cancer and rare diseases. Among these is Right to Try legislation for experimental therapies. Right to Try legislation is based on the premise that all experimental agents in clinical trials are safe and guaranteed to produce miracles. Unfortunately, this notion is at odds with expert understanding, which indicates that the benefits and risks of drug products can only be understood together and evaluated incrementally and over time. The current manuscript examines why benefit to risk considerations, a lynchpin of the ethical conduct of clinical research since the Nuremberg Code, might be easily elided from public discourse. This paper considers guidelines for regulatory writing, which routinely separate discussions of effectiveness and safety, as a possible source for some confusion. The internationally-accepted ICH M4E (Common Technical Document) guideline published in 2016 now provides additional guidance for composing Benefits and Risks Conclusions, which weigh and consider effectiveness and safety together. Yet fundamental differences in understanding the "safety" of medicinal products continue to exist between experts in biomedicine, politicians, and healthcare activists. Examining differences in the understanding of "safety" between experts and non-experts also may help explain the source for flawed logic about the safety of investigational products in Right To Try narratives. No drug product is 100% safe. Continuing to weigh benefits and risks together is an important intellectual practice necessary to safeguard human health worldwide, and testing clinical safety is the only way to provide meaningful protections to patients. Science, not miracles, can ensure the protection of patients in clinical research as well as clinical practice. Weighing benefits and risks is an essential intellectual act that informs public health. Science, not miracles, can guide this work. PMID- 28594476 TI - Fibrinogen Mahdia: A congenitally abnormal fibrinogen characterized by defective fibrin polymerization. AB - INTRODUCTION: Congenital dysfibrinogenemia is a rare qualitative fibrinogen deficiency. Molecular defects that result in dysfibrinogenemia are usually caused by mutations which affect fibrinopeptide release, fibrin polymerization, fibrin cross-linking or fibrinolysis. AIM: Here, we investigated the genetic basis of hypodysfibrinogenemia in two Tunisian siblings with major bleeding. METHODS: Coagulation-related tests were performed on the patients and their family members. Functional analysis was performed in plasma fibrinogen to characterize fibrin polymerization. The sequences of fibrinogen genes were amplified and analysed by sequencing. RESULTS: Coagulation studies revealed a reduced functional and a borderline low antigenic fibrinogen plasma levels with prolonged thrombin and activated partial thromboplastin times. The fibrinogen is also characterized by a markedly impaired polymerization and could incorporate into fibrin fibres to a smaller extent (22%). Mutational screening disclosed a heterozygous single nucleotide deletion (G) at c.1025, resulting in a frameshift mutation (AalphaGly323GlufsX79) that is predicted to delete a part of the alphaC domain containing some of the FXIII cross-linking sites. Both the normal and the aberrant Aalpha-chain (approximately 43 kDa) were detected by electrophoretic analysis in the patients. CONCLUSION: The new dysfunctional fibrinogen, Mahdia variant, describes its impact on fibrin assembly after the loss of the alphaC domains which are involved in the lateral aggregation of protofibrils. The study confirms that the truncated Aalpha-chain could be incorporated into mature fibrinogen molecules. PMID- 28594477 TI - Azo-Based Fluorogenic Probes for Biosensing and Bioimaging: Recent Advances and Upcoming Challenges. AB - The use of nonfluorescent azo dyes as dark quenchers in activatable optical bioprobes based on the Forster resonance energy transfer (FRET) mechanism and designed to target a wide range of enzymes has been established for over two decades. The key value of the azo moiety (-N=N-) to act as an efficient "ON-OFF" switch of fluorescence once introduced within the core structure of conventional organic-based fluorophores (mainly fluorescent aniline derivatives) has recently been exploited in the development of alternative reaction-based small-molecule probes based on the "profluorescence" concept. These unprecedented "azobenzene caged" fluorophores are valuable tools for the detection of a wide range of reactive (bio)analytes. This review highlights the most recent and relevant advances made in the design and biosensing/bioimaging applications of azo-based fluorogenic probes. Emphasis is also placed on relevant achievements in the synthesis of bioconjugatable/biocompatible azo dyes used as starting building blocks in the rational and rapid construction of these fluorescent chemodosimeters. Finally, a brief glimpse of possible future biomedical applications (theranostics) of these "smart" azobenzene-based molecular systems is presented. PMID- 28594478 TI - What Influences the Cost Effectiveness of Dabigatran versus Warfarin for Stroke Prevention in Atrial Fibrillation: A Systematic Review. AB - OBJECTIVES: The introduction of new oral anticoagulants for the prevention of stroke in atrial fibrillation (AF) has changed the clinical management of AF. To inform decision making around dabigatran by identifying factors influencing cost effectiveness results, we undertook a systematic review of economic evaluations of dabigatran versus warfarin for the prevention of stroke in AF patients. METHODS: A systematic literature search of Ovid Medline and Embase, Wiley's Cochrane Library, HEED, PubMed databases and grey literature was carried out for primary economic evaluations comparing dabigatran versus warfarin in patients with AF. Data on study characteristics, model inputs and results, and sensitivity analyses were abstracted and synthesized qualitatively. RESULTS: Twenty-three economic evaluations were identified and RE-LY was cited in 52% of studies as the source of the efficacy data. Twenty evaluations used Markov modelling, 2 performed discrete event simulation, and 1 was a trial-based evaluation. Eighty two percent reported base case incremental cost-effectiveness ratios (ICERs) of less than $50,000 USD/QALY. Key variables, including international normalized ratio (INR) control, the cost of monitoring, risk of stroke and bleeding, and age were found to alter the conclusions in only a few studies. Less commonly explored factors included time horizon and cost of long-term care follow-up. CONCLUSIONS: Several factors should be considered when interpreting the results of economic analyses which are based on randomized clinical trial evidence. Real-world data are needed to further assess the clinical and economic consequences of dabigatran relative to warfarin for the prevention of stroke in AF. PMID- 28594479 TI - Does the Number of Pharmacies a Patient Frequents Affect Adherence to Statins? AB - BACKGROUND: We hypothesized that medication adherence is affected by the number of pharmacies a patient frequents. OBJECTIVES: The objective was to estimate the strength of association between the number of pharmacies a patient frequents and adherence to statins. METHODS: Using administrative data from the Nova Scotia Seniors' Pharmacare program, a retrospective cohort study was conducted among subjects aged 65 years and older first dispensed statin between 1998 and 2008. The Usual Provider of Care (UPC), was defined as the number of dispensation days from the most frequented pharmacy divided by the total number of dispensation days. Estimated adherence of over 80% of the Medication Possession Ratio was defined as adherent. Data were analyzed using hierarchical linear regression. RESULTS: The cohort of 25,641 subjects was 59% female with a mean age of 74 years. During follow-up, subjects filled prescriptions in a median of 2 (mean = 2; standard deviation = 0.88) pharmacies and visited pharmacies a median of 28 (mean = 30) times. During that time, 61% of patients used one pharmacy exclusively. Among subjects using 1 pharmacy, 59% were adherent while 58% using more than one pharmacy were adherent. However, upon adjustment for differences in distributions of age, sex, and other confounders, subjects who used more than one pharmacy had 10% decreased odds of statin adherence (odds ratio: 0.90, 95% confidence interval: 0.86-0.96). These results were robust in sensitivity analyses. CONCLUSIONS: Among seniors newly starting statin therapy, using a single community pharmacy was modestly associated with adherence. PMID- 28594480 TI - Comparison of Drug Benefits Provided by Veterans Affairs Canada and the Canadian Forces Health Services Group. AB - BACKGROUND: Drug benefits are provided at public expense to all actively serving Canadian Armed Forces (CAF) personnel, with ongoing drug coverage offered by Veterans Affairs Canada (VAC) for selected conditions following termination of employment. Differences in drug coverage between these programs could introduce risks for treatment disruption. OBJECTIVES: Work was undertaken to establish a process that would allow systematic comparison of the entire VAC and CAF formularies, and to identify and explain discordant listings in 14 therapeutic categories that pose risk of adverse outcomes with sudden treatment interruption. METHODS: Lists of medications were created for each program, including regular benefit and restricted use drugs, using files obtained from the claims processor in January 2015. Products were coded using the Anatomic-Therapeutic-Chemical (ATC) system. Degree of alignment within therapeutic categories was assessed based on the percentage of fifth-level ATCs that were covered in common. Discordantly listed drugs in 14 categories of concern were reviewed to identify similarities in product characteristics. RESULTS: A total of 1124 medications were identified in 80 therapeutic categories. Coverage of medications was identical in 11 categories, and overall, almost three-quarters of identified drugs (73.4%, n = 825) were covered in common by both plans. Many discordant listings reflected known differences in the programs' operating procedures. A number of discrepancies were also identified in newer therapeutic categories. CONCLUSIONS: There is significant overlap in the medications covered by the CAF and VAC drug benefit programs. Application of the ATC coding system allowed for discrepancies to be readily identified across the entire formulary, and in specific therapeutic categories of concern. PMID- 28594481 TI - Emotional Understanding in School-Aged Children with Fetal Alcohol Spectrum Disorders: A Promising Target for Intervention. AB - BACKGROUND: Children with fetal alcohol spectrum disorders (FASD) are at high risk for secondary conditions, including mental health difficulties. Data on both children with typical development and other clinical conditions suggest that limited emotional understanding (EU) raises risk for psychopathology, but little is known about EU in FASD. OBJECTIVES: To determine if EU is a reasonable treatment target for children with FASD. METHODS: 56 children (6-13 years) with FASD completed the Kusche Affective Interview-Revised, a verbal interview measure of EU. RESULTS: Children showed striking delays in EU (2-5 years delay) relative to published normative data, despite mean IQ (IQ=94.56) within normal limits. Individual variability was considerable even after accounting for age and verbal IQ. CONCLUSIONS: Despite variability in individual differences, treatments targeting EU may benefit children with FASD as components within a comprehensive, tailored intervention focused on child self-regulation and caregiver behavior management. PMID- 28594482 TI - Non-severe Hypoglycemia Risk Difference between Sulfonylurea and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT2-I) as an Add-On to Metformin in Randomized Controlled Trials. AB - BACKGROUND: Non-severe hypoglycemia reduces well-being, lowers quality of life, reduces productivity and increases treatment costs. The non-severe hypoglycemia rate, attributable to sulfonylurea (SU) utilization compared with newer classes such as SGLT2-I, could be of clinical significance. OBJECTIVES: To explore the non-severe hypoglycemia risk difference (RD) for SU use compared with SGLT2-I in randomized controlled trials (RCTs) as an add on to metformin. METHODS: A search was conducted for RCTs of SGLT2-I. PubMed database were utilized for this search. The search was limited to RCTs reported in English language for canagliflozin, dapagliflozin, and empagliflozin. SU dose comparison was utilized to convert the dose of SUs to glimepiride equivalent doses. RESULTS: Totally, 118 RCTs were reviewed; 6 articles had an arm for a SU as add on to metformin. Six articles belong to 3 RCTs, which reported results for 52 weeks and 104 weeks. Average non severe hypoglycemia rate for SU arm was 30% (5.5%) [Mean (SD)] for 52 weeks and 35.6% (6.1%) for 104 weeks. RD for non-severe hypoglycemia events for SU compared to SGLT2-I was 26.7% (4.9%) for 52 weeks (p-value less than 0.001) and 30.6% (5.5%) for 104 weeks (p-value less than 0.001). There was a significant correlation between dose of SU and hypoglycemia rate (Pearson correlation 0.995; R-square 99%). CONCLUSIONS: This study illustrated that a large proportion of patients who had exposure to SU in RCTs of SGLT2-I experienced non-severe hypoglycemia compared to SGLT2-I. There was a close relation between SU dose and increased probability of non-severe hypoglycemia events. PMID- 28594485 TI - Acetabular Fractures: A Problem-Oriented Approach. AB - The main goals of acetabular fracture management are to restore the congruity and stability of the hip joint. These goals are the same for all patients who have an acetabular fracture, regardless of the morphology or etiology of the fracture. Nevertheless, certain acetabular fracture types and several patient factors pose management challenges for surgeons. Therefore, surgeons who manage acetabular fractures must understand the distinctive features of acetabular fractures as well as the soft-tissue and patient-related factors that play a critical role in patient outcomes. Particular challenges in the management of acetabular fractures include acetabular fracture types that involve the posterior wall, acetabular fractures with soft-tissue concerns, acetabular fractures in patients with multiple injuries, and acetabular fractures in the geriatric population. Although the well-known protocols that were established by Judet and Letournel continue to be important guidelines for the management of acetabular fractures, the injury characteristics of acetabular fractures, the demographics of the patients in whom acetabular fractures occur, and the treatment options for acetabular fractures have evolved. Therefore, surgeons must be aware of new and more recently published information on acetabular fractures. PMID- 28594486 TI - Challenges and Controversies of Foot and Ankle Trauma. AB - Traumatic injury to the foot and ankle can result in long-term disability, which may have substantial negative implications on a patient's functional outcomes and quality of life. The diagnosis and appropriate management of these challenging injuries are not always agreed on or straightforward. In particular, the appropriate diagnosis and management of distal tibiofibular syndesmotic injuries as well as the surgical approach and role of primary subtalar arthrodesis for intra-articular calcaneal fractures are controversial. PMID- 28594483 TI - Effect of an Institutional Medication Adherence Program for Long-Acting Injectable Risperidone on Adherence and Psychiatric Hospitalizations: Evidence from a Prospective Cohort Study. AB - BACKGROUND: Long-acting injectable (LAI) atypical antipsychotics are associated with improved adherence and reduced relapse rates in schizophrenia but reminder based interventions may further improve outcomes. OBJECTIVES: To assess an institutional medication adherence program's (IMAP) effectiveness on adherence and psychiatric hospitalizations among schizophrenia patients taking risperidone LAI (RLAI). METHODS: Between 2009 and 2010, we recruited patients meeting DSM-IV criteria for schizophrenia treated with RLAI receiving outpatient care from psychiatric centres in France. The IMAP consisted of calling patients 48 hours prior to their scheduled RLAI injections and within 3 days of a missed appointment. Centres applying the IMAP to >=50% of scheduled patient injections were deemed compliant. Patients were followed up to one year for adherence (>=80% of scheduled RLAI injections received within 5 days of the scheduled date) and psychiatric hospitalizations. RESULTS: Among 506 patients recruited from 36 centres, the hospitalization rate was 32.5 per 100 person-years. 15 centres treating 243 patients were IMAP compliant and 21 centres treating 263 patients were not. IMAP compliance was associated with lower psychiatric hospitalization rates (crude RR: 0.64 [95% CI: 0.44-0.93]; adjusted RR: 0.78 [95% CI: 0.47 1.27]). Nearly 75% of patients were adherent to RLAI. While patient adherence had little impact on hospitalization rates (adjusted RR: 0.92 [95% CI: 0.59-1.44]), IMAP compliance was more effective among non-adherent (adjusted RR: 0.45 [95% CI: 0.16-1.28]) than adherent (adjusted RR: 0.88 [95% CI: 0.51-1.53]) patients. CONCLUSIONS: IMAPs may improve patient adherence and reduce psychiatric hospitalizations, particularly among patients with difficulties adhering to LAI antipsychotics. PMID- 28594487 TI - Current Management of Talar Fractures. AB - Talar fractures are some of the most challenging injuries that orthopaedic traumatologists manage. The current knowledge of functional alterations with regard to malreduction of talar fractures is well established. Decision making with regard to timing, approach, and implant selection as well as strategies to help achieve accurate restoration of talar anatomy substantially affect outcomes and must be carefully considered. Perfect anatomic talar reconstruction should always be attempted, and orthopaedic surgeons should have a strong working knowledge of the vascular, three-dimensional, and radiographic anatomy of the talus before performing talar surgery. Almost the entire talus is surgically accessible via several approaches, all of which surgeons should be clinically familiar with to optimize reduction and fixation and safely preserve the soft tissue envelope. Furthermore, surgeons must appreciate the plantarmedial vascular area of the talus, which must be avoided during dissection. The complication rates in patients who have talar fractures are high, particularly in those who have talar neck and talar body fractures; therefore, patients should be counseled on their expected outcome, with a specific discussion on the risk of osteonecrosis and subtalar arthritis. PMID- 28594489 TI - Diagnosis and Management of the Biceps-Labral Complex. AB - The long head of the biceps tendon (LHBT) is a common source of pathology. The biceps-labral complex (BLC) is the collective anatomic and clinical features shared by the biceps tendon and the superior labrum. LHBT pathology can be caused by inflammation, instability, or trauma. Numerous tests can be performed to determine the existence of biceps tendon and superior labrum anterior to posterior (SLAP) lesions; however, many of these tests do not have high sensitivity and specificity, which limit their clinical utility. Because it is difficult to diagnose both LHBT and SLAP pathology, management strategies are best guided by a strong clinical suspicion and imaging findings on either MRI or ultrasonography. Initial nonsurgical management of LHBT and SLAP pathology includes focused physical therapy, anti-inflammatory medications, and corticosteroid injections. If nonsurgical management fails, surgical techniques for the management of LHBT pathology include biceps anchor reattachment (SLAP repair), biceps tenotomy, and biceps tenodesis. Techniques for biceps tenodesis, which can be performed in either an arthroscopic or open manner, include soft tissue tenodesis, suprapectoral tenodesis, and subpectoral tenodesis. If appropriately managed, patients with LHBT pathology often have excellent clinical outcomes. PMID- 28594488 TI - Fractures of the Calcaneus. AB - Calcaneal fractures are potentially devastating injuries. To effectively manage calcaneal fractures, surgeons must understand the anatomy of the calcaneus as well as the surgical techniques necessary to restore normal biomechanics of the foot. Surgeons also must understand calcaneal fracture patterns and classifications; initial management techniques, surgical indications and rationale, temporizing management techniques, surgical approaches, definitive management techniques, and postoperative management for calcaneal fractures; as well as outcomes and common complications of calcaneal fractures. PMID- 28594490 TI - Patients in Whom Arthroscopic Bankart Repair is Not Enough: Evaluation and Management of Complex Anterior Glenohumeral Instability. AB - Arthroscopic Bankart repair has become the most common treatment option for patients who have anterior shoulder instability. Although arthroscopic Bankart repair is generally an effective treatment method, it may be insufficient for the treatment of many patients who have anterior shoulder instability. Risk factors for failure of arthroscopic Bankart repair include younger age, level and type of sport, and shoulder specific risks, such as ligamentous laxity and the presence of bone loss. Recently, researchers have defined the limits of arthroscopic Bankart repair and more clearly defined treatment options for patients who have a high risk for failure after arthroscopic Bankart repair. Surgeons must recognize patients with anterior shoulder instability in whom a more aggressive surgical approach should be considered as well as patients who have a high risk for failure after arthroscopic Bankart repair to optimize outcomes in this patient population. PMID- 28594491 TI - Cubital Tunnel Syndrome. AB - Cubital tunnel syndrome is the most common cause of symptomatic ulnar neuropathy. The unique anatomic course of the ulnar nerve around the elbow makes it particularly vulnerable at a location far from its terminal destination. The natural progression of cubital tunnel syndrome allows patients who have mild symptoms to be adequately treated nonsurgically. Minor changes in activity combined with appropriate splinting may acceptably alleviate symptoms. Surgical intervention is recommended for patients who have more severe symptoms. Current data confirm that in situ ulnar nerve decompression, partial medial epicondylectomy, and anterior transposition result in equal success rates; however, more invasive techniques may increase the risk for complications. If primary surgical intervention fails, revision surgery can provide good results. Modern techniques for revision surgery incorporate the placement of a protective circumferential barrier around the pathologic nerve to mitigate cicatrix formation. Although several attractive options are currently available for the management of cubital tunnel syndrome, further research is necessary to guide treatment. PMID- 28594492 TI - Thoracic Outlet Syndrome: Getting It Right So You Don't Have to Do It Again. AB - Thoracic outlet syndrome is a disorder caused by thoracic outlet compression of the brachial plexus and/or the subclavian vessels. The characteristics of thoracic outlet syndrome are highly variable. Objective tests, such as electrodiagnostic studies, are often unreliable in characterizing thoracic outlet syndrome. The existence of thoracic outlet syndrome as a discrete entity is controversial. Surgeons who accept the existence of thoracic outlet syndrome acknowledge that diagnosis is clinical. The variability and complexity of thoracic outlet syndrome lends itself to mistakes in both diagnosis and surgical treatment. PMID- 28594493 TI - Management of Hand Fractures: Simple to Complex. AB - Hand fractures are among the most common skeletal injuries. Approximately 150,000 hand fractures occur in the United States each year. The management of hand fractures consists of reduction, immobilization, and rehabilitation to return patients to their preinjury status. Hand fractures are managed by restoring articular congruity, reducing malrotation and angulation of the fracture, and maintaining the reduction, all of which should be accomplished with minimal surgical intervention. Surgeons must assess concomitant soft-tissue injuries and respect the soft tissues during the surgical management of hand fractures. Fractures through the metaphyseal bone at the base and neck will heal more quickly than fractures through the diaphyseal bone of the shaft, which makes provisional fixation of metaphyseal fractures more practical compared with provisional fixation of diaphyseal fractures. The fracture pattern determines the most practical type of fixation. Patterns of angulation should be anticipated and corrected during reduction. More rigid fixation is required if substantial comminution and bone loss are present. Bone loss also indicates a high-energy injury, which likely indicates more substantial soft-tissue injury. As the number of injured structures increases, the likelihood of full function after rehabilitation decreases. PMID- 28594494 TI - Carpal Tunnel Syndrome: Initial Management and the Treatment of Recalcitrant Patients. AB - Carpal tunnel syndrome (CTS) is a focal compressive neuropathy of the median nerve at the level of the wrist. CTS is the most common type of compressive neuropathy that occurs in the upper extremity. Typically, patients with CTS have paresthesia, pain, and numbness in the radial three and one-half digits. Nighttime symptoms are more common earlier in the disease process, with daytime symptoms becoming more frequent as CTS progresses. Electrodiagnostic studies may be performed to confirm a diagnosis of CTS or to obtain a baseline before surgical treatment; however, electrodiagnostic studies may be normal in a subset of patients who have CTS. Patients who have mild CTS should undergo an initial trial of nonsurgical treatment that includes lifestyle modifications, nighttime splinting, and corticosteroid injections. Carpal tunnel release should be performed in patients in whom nonsurgical treatment fails and patients who have acute CTS secondary to infection or trauma or have advanced symptoms. Recalcitrant CTS, which may occur in as many as 25% of patients who undergo carpal tunnel release, most commonly results from an incomplete transverse carpal ligament release or an incorrect initial diagnosis. Patients with recurrent symptoms often have perineural fibrosis that tethers the median nerve. PMID- 28594495 TI - Ulnar Tunnel Syndrome, Radial Tunnel Syndrome, Anterior Interosseous Nerve Syndrome, and Pronator Syndrome. AB - In addition to the more common carpal tunnel and cubital tunnel syndromes, orthopaedic surgeons must recognize and manage other potential sites of peripheral nerve compression. The distal ulnar nerve may become compressed as it travels through the wrist, which is known as ulnar tunnel or Guyon canal syndrome. The posterior interosseous nerve may become entrapped in the proximal forearm as it travels through the radial tunnel, which results in a pain syndrome without motor weakness. The median nerve may become entrapped in the proximal forearm, which can result in a variety of symptoms. Spontaneous neuropathy of the anterior interosseous nerve branch of the median nerve can be observed without external compression. Electrodiagnostic and imaging studies may aid surgeons in the diagnosis of these syndromes; however, a thorough physical examination is paramount to localize compressed segments of these nerves. An understanding of the anatomy of each of these nerve areas allows surgeons to appreciate a patient's clinical findings and helps guide surgical decompression. PMID- 28594496 TI - Primary Total Hip Arthroplasty: Everything You Need to Know. AB - Total hip arthroplasty is an extremely successful procedure that relieves pain and improves function. Orthopaedic surgeons should understand how to improve outcomes of patients who undergo primary total hip arthroplasty. Orthopaedic surgeons can enhance the outcomes of total hip arthroplasty by optimizing preoperative and perioperative management, improving surgical techniques, and selecting an appropriate femoral component and bearing surface. PMID- 28594497 TI - Arthroplasty for Unreconstructable Acute Fractures and Failed Fracture Fixation About the Hip and Knee in the Active Elderly: A New Paradigm. AB - The techniques, materials, and designs for total joint arthroplasty underwent major improvements in the past 30 years. During this time, trauma surgeons classified the severity of fractures as well as identified certain articular fractures that do not have good outcomes and have a high rate of failure after internal fixation. Advanced improvements in arthroplasty have increased its reliability and longevity. Total joint arthroplasty is becoming a standard of care for some acute articular fractures, particularly displaced femoral neck fractures in the active elderly. Total joint arthroplasty also has become the standard of care after failed internal fixation in patients who have very complicated fractures about the knee, hip, and shoulder. As the population ages, fractures worldwide continue to rapidly increase. Elderly patients have a high risk for fractures that result from falls because of their poor bone quality. The current active elderly population participates in higher risk activities than previous elderly populations, which places them at risk for more injuries. This has become both a worldwide healthcare problem and an economic problem. Surgeons need to manage fractures in the active elderly with the latest advancements in technology and patient selection to ensure rapid recovery and the reduction of complications. PMID- 28594498 TI - Bicompartmental Knee Arthroplasty. AB - Knee arthritis is one of the leading causes of disability and functional limitations in the United States and worldwide. Total knee arthroplasty results in good functional outcomes and high survival rates in patients who have tricompartmental arthritis. Bicompartmental knee arthroplasty is being used more often in patients who have arthritis that is isolated to two compartments: the patellofemoral compartment and either the medial or the lateral compartment. Bicompartmental knee arthroplasty preserves the kinematics, ligaments, and bone stock of the knee and is a good option for younger, active, high-demand patients who wish to return to their previous level of activity. PMID- 28594499 TI - Medial Unicompartmental Knee Arthroplasty. AB - Unicompartmental knee arthroplasty (UKA) has substantial benefits, including lower perioperative morbidity and earlier recovery, compared with total knee arthroplasty. The traditionally strict indications for UKA have been challenged by studies that expanded the indications based on a diagnosis of anteromedial osteoarthritis of the knee and demonstrated successful outcomes. The Nuffield criteria no longer prohibit patients from UKA based on age, obesity, anterior knee pain, or involvement of the patellofemoral joint. UKA implant designs have evolved substantially in the past three decades, and both fixed- and mobile bearing UKA implants are currently available. Both fixed- and mobile-bearing UKA implants demonstrate excellent clinical outcomes at more than 10 years postoperatively but continue to have different modes of long-term implant failure. Proper patient selection and execution of surgical technique are critical to optimize patient outcomes. PMID- 28594500 TI - Patellofemoral Arthroplasty: An Evolving Science. AB - Patellofemoral arthroplasty (PFA) has long been a clinical option for patients with isolated patellofemoral arthritis. However, a high rate of failure as a result of patellar instability related to component malposition, soft-tissue imbalance, errant surgical techniques, and poor trochlear implant designs contributed to the underutilization of PFA. The evolution of surgical indications, trochlear implant design, component positioning, and soft-tissue balance has led to improved patellar tracking, fewer failures related to patellar instability, and improved functional outcomes. The development and broad adoption of onlay-style trochlear components, which can be positioned perpendicular to the AP axis of the femur, has substantially improved patellar tracking and, thus, improved the durability of PFA. In addition, favorable data showing success after secondary surgery or revision to total knee arthroplasty after PFA have emerged, which has led to increased use of PFA in appropriately selected patients. PMID- 28594501 TI - Prevention and Diagnosis of Periprosthetic Knee Infection. AB - Total knee arthroplasty (TKA) has become an increasingly common treatment option for patients who have debilitating knee arthritis. TKA is a relatively safe and efficient procedure that results in promising outcomes and has a positive effect on a patient's quality of life. More TKAs are being performed annually because the procedure substantially reduces pain and improves functionality; however, as the number of TKAs continues to rise, there is concern for potential complications that may result in prosthetic joint failure. Primary TKA failure may result in revision procedures that have high costs and an increased risk for additional complications. Infection is the second most common cause of primary TKA failure and the single most common cause of revision TKA failure. Surgeons who have a better understanding of the epidemiology, risk factors, and diagnostic modalities associated with periprosthetic knee infection will be able to implement preventive measures and treat patients in whom such a complication occurs. PMID- 28594502 TI - Single-Stage Revision Total Knee Arthroplasty in the Setting of Periprosthetic Knee Infection: Indications, Contraindications, and Postoperative Outcomes. AB - Single-stage revision total knee arthroplasty has become an increasingly common treatment option for patients with failed knee prostheses. Periprosthetic knee infection is the leading and most devastating cause of revision total knee arthroplasty. Although periprosthetic knee infection has been extensively studied in the orthopaedic literature, the role of single-stage revision total knee arthroplasty for the treatment of periprosthetic knee infection warrants further research. As healthcare reform shifts from a volume-based to a value-based system, it is imperative that orthopaedic surgeons understand the procedural indications, risks, and benefits of single-stage revision total knee arthroplasty. PMID- 28594503 TI - Two-Stage Revision Total Knee Arthroplasty in the Setting of Periprosthetic Knee Infection. AB - Two-stage revision total knee arthroplasty (TKA) is the standard of care for patients who require a revision procedure for the mangement of a late or chronic periprosthetic knee infection. A careful examination of two-stage revision TKA is warranted as the number of patients who require revision TKA in the United States continues to rise. Surgeons should understand the intricacies involved in two stage revision TKA, including the indications, procedural variations, and current deliberations on two-stage revision TKA in the literature. Surgeons also should understand the alternative treatments for periprosthetic knee infections. PMID- 28594504 TI - Achilles Tendon Rupture in Elite Athletes. AB - The management of acute Achilles tendon rupture in elite athletes is a current area of clinical controversy. Recent studies have reported near-equivocal outcomes in patients who undergo either nonsurgical or surgical treatment of Achilles tendon rupture; however, similar functional outcomes may not be observed in elite athletes who are at the highest levels of athletic performance and undergo nonsurgical or surgical treatment of Achilles tendon rupture. Surgeons should understand the risks and benefits of nonsurgical and surgical management of acute Achilles tendon rupture. Surgeons also should understand the accelerated rehabilitation protocols; functional nonsurgical and postoperative rehabilitation protocols; as well as the standard open, percutaneous, and minimally invasive surgical techniques for the management of Achilles tendon rupture from the perspective of a sports medicine foot and ankle specialist. PMID- 28594505 TI - Lisfranc Injuries in the Elite Athlete. AB - The management of sports-related Lisfranc injuries is optimized by a detailed understanding of the relevant anatomy, mechanisms of injury, clinical diagnostic maneuvers, imaging, and treatment options for patients with this disabling injury. A lower energy ligamentous variant Lisfranc injury, which was first observed in professional football players, has recently been described. The treatment options for patients with a Lisfranc injury include nonsurgical management, open reduction and internal fixation, suture-button fixation techniques, and arthrodesis. PMID- 28594506 TI - High-Risk Stress Fractures in Elite Athletes. AB - Surgeons should understand common factors that predispose high-level athletes to stress injuries as well as the importance of vitamin D and specifics related to vascular supply, location of injury, biomechanics, and susceptibility factors in high-level athletes who have stress injuries. Surgeons should be aware of diagnostic- and management-based recommendations for and the outcomes of anterior tibia, medial malleolus, tarsal navicular, and proximal fifth metatarsal stress fractures in professional athletes. PMID- 28594507 TI - Management of Osteochondral Lesions of the Talus. AB - Management strategies for symptomatic osteochondral lesions of the talus are primarily surgical. Treatment options for symptomatic osteochondral lesions of the talus most commonly include bone marrow stimulation techniques, osteochondral autograft transplantation, osteochondral allograft transplantation, autologous chondrocyte implantation, matrix-induced autologous chondrocyte implantation, and particulated juvenile articular cartilage. The selection of the most appropriate treatment option should be based on the specifics of a talar lesion, in particular, lesion size. PMID- 28594508 TI - Lateral Ankle Instability and Peroneal Tendon Pathology. AB - Surgeons should understand the anatomic, vascular, biomechanical, and predisposing factors related to lateral ankle instability and peroneal tendon injuries, including peroneal tendinitis and tenosynovitis, peroneal tendon tears and ruptures, as well as peroneal tendon subluxation and dislocation. Surgeons should understand the treatment options and recommendations for patients who have lateral ankle instability and peroneal tendon injuries from the perspective of a sports medicine foot and ankle specialist. In addition, surgeons should be aware of arthroscopic approaches and an algorithm for the treatment of patients who have lateral ankle instability and peroneal tendon injuries. PMID- 28594509 TI - Differentiating Hip Pathology From Lumbar Spine Pathology: Key Points of Evaluation and Management. AB - The diagnosis and treatment of patients who have both hip and lumbar spine pathologies may be a challenge because overlapping symptoms may delay a correct diagnosis and appropriate treatment. Common complaints of patients who have both hip and lumbar spine pathologies include low back pain with associated buttock, groin, thigh, and, possibly, knee pain. A thorough patient history should be obtained and a complete physical examination should be performed to identify the primary source of pain. Plain and advanced imaging studies and diagnostic injections can be used to further delineate the primary pathology and guide the appropriate sequence of treatment. Both the surgeon and the patient should understand that although one pathology is managed, management of the other pathology may be necessary because of persistent pain. The recognition of both entities may help reduce the likelihood of misdiagnosis, and the management of both entities in the appropriate sequence may help reduce the likelihood of persistent symptoms. PMID- 28594510 TI - Surgical Management of Cervical Spondylotic Myelopathy. AB - Cervical spondylotic myelopathy (CSM) is a common cause of neurologic impairment in adults worldwide. Numerous studies have investigated the pathophysiology of CSM, which has provided surgeons with insight on the important factors that lead to the symptoms and deficits observed in patients who have CSM. However, further analysis of many unknown aspects of CSM is required to fully understand the disease and potential alternative treatment modalities. The diagnosis of CSM is based on a patient's history and physical examination and then confirmed with imaging studies. Progression, symptomatology, and imaging findings may vary by patient. Because of the variability of CSM, the disease course and a patient's response to treatment are difficult to predict. CSM can be managed either nonsurgically or it can be managed surgically via posterior or anterior cervical approaches, each of which has its own indications and possible complications. PMID- 28594511 TI - Adult Lumbar Scoliosis: Nonsurgical Versus Surgical Management. AB - Adult spinal deformity has become an increasingly recognized condition, with a 32% incidence in the adult population and a 68% incidence in the elderly population. Often, patients with adult spinal deformity are initially offered nonsurgical treatment for their symptoms despite the lack of data to support its efficacy because of the high complication rate associated with surgical treatment in this age group. Determining which patients would benefit the most from nonsurgical versus surgical treatment remains a challenge. Limited evidence exists to support guidelines on the most effective way to treat patients with adult spinal deformity. Treatment decisions for patients with adult spinal deformity often rely on individual surgeon experience and patient preferences. PMID- 28594512 TI - Realignment Planning in Adult Spinal Deformity: Formulas and Planning Tools. AB - Adult spinal deformity is a complex pathologic process that has many etiologies and several mechanisms of compensation. A complete understanding of spinopelvic alignment is required to differentiate the origin of spinal deformity from its compensation and, ultimately, optimize surgical correction. Surgeons should understand the spinopelvic parameters involved in the evaluation of a patient who has an adult spinal deformity and their implications for treatment. PMID- 28594513 TI - Minimally Invasive Lateral Approach for the Management of Adult Degenerative Scoliosis. AB - Minimally invasive lateral releases for the correction of lumbar scoliosis are becoming an increasingly common treatment alternative to posterior osteotomies or surgery via an open anterior approach. Minimally invasive approaches minimize blood loss and morbidity, which may be important in older patients who often have substantial comorbidities. Anterior column realignment allows lumbar lordosis to be restored via a minimally invasive lateral approach, which restores sagittal balance and is correlated with improvements in health-related quality of life. Surgeons should understand the development of, the indications for, the surgical technique for, and the complications and early clinical outcomes of the minimally invasive lateral approach to the spine. PMID- 28594514 TI - How to Decrease Complications in the Management of Adult Lumbar Scoliosis. PMID- 28594515 TI - Cervical Spine Injuries in the Athlete. AB - Cervical spine injuries are common and range from relatively minor injuries, such as cervical muscle strains, to severe, life-threatening cervical fractures with spinal cord injuries. Although cervical spine injuries are most common in athletes who participate in contact and collision sports, such as rugby and American football, they also have been reported in athletes who participate in noncontact sports, such as baseball, gymnastics, and diving. Cervical spine injuries in athletes are not necessarily the result of substantial spine trauma; some athletes have chronic conditions, such as congenital stenosis, that increase their risk for a serious cervical spine injury after even minor trauma. Therefore, physicians who cover athletic events must have a thorough knowledge of cervical spine injures and the most appropriate methods for managing them. Although cervical spine injuries can be career-ending injuries, athletes often are able to return to play after appropriate treatment if the potential for substantial reinjury is minimized. PMID- 28594516 TI - Lumbar Spine Injuries in the Athlete. AB - Low back pain is the most common complaint expressed by adult patients in the primary care setting, and the incidence of low back pain in adolescents is rising. Adolescents who are involved in athletics most commonly suffer from spondylolysis, spondylolisthesis, mechanical low back pain, and herniated disks, whereas adult athletes most commonly suffer from lumbosacral strain and herniated or degenerative disks. Initial nonsurgical management aims to reduce inflammation and noninvasively strengthen damaged tissues. Although most patients who have low back pain will return to sports after nonsurgical treatment, surgery may be required in patients who have persistent or progressive neurologic symptoms. PMID- 28594517 TI - Adolescent Spondylolysis: Management and Return to Play. AB - The most common causes of low back pain in adolescents are spondylolysis and spondylolisthesis. Mechanical factors combined with rapid growth during adolescence place stress on the spine and can result in a stress fracture. Sports that require athletes to repeatedly place the spine in hyperextension may exacerbate both spondylolysis and spondylolisthesis. Many adolescent athletes with spondylolysis or low-grade spondylolisthesis have minimal symptoms and require no treatment or alteration in activity, including sports activity. For adolescents with spondylolysis or low-grade spondylolisthesis who have symptoms, nonsurgical treatment with activity restrictions and a structured rehabilitation program can help in return to most sports. Surgical treatment may be required for patients who have symptoms that are unresponsive to nonsurgical treatment and patients who have grade III or grade IV spondylolisthesis. Treatment and return to competitive sports must be individualized based on the severity and symptoms of the disease in each patient. PMID- 28594518 TI - Pediatric Phalanx Fractures. AB - Phalangeal fractures are the most common type of hand fracture that occurs in the pediatric population and account for the second highest number of emergency department visits in the United States for fractures. The incidence of phalangeal fractures is the highest in children aged 10 to 14 years, which coincides with the time that most children begin playing contact sports. Younger children are more likely to sustain a phalangeal fracture in the home setting as a result of crush and laceration injuries. Salter-Harris type II fractures of the proximal phalanx are the most common type of finger fracture. An unmineralized physis is biomechanically weaker compared with the surrounding ligamentous structures and mature bone, which make fractures about the physis likely. A thorough physical examination is necessary to assess the digital cascade for signs of rotational deformity and/or coronal malalignment. Plain radiographs of the hand and digits are sufficient to confirm a diagnosis of a phalangeal fracture. The management of phalangeal fractures is based on the initial severity of the injury and depends on the success of closed reduction techniques. Nondisplaced phalanx fractures are managed with splint immobilization. Stable, reduced phalanx fractures are immobilized but require close monitoring to ensure maintenance of fracture reduction. Unstable, displaced phalanx fractures require surgical management, preferably via closed reduction and percutaneous pinning. PMID- 28594519 TI - Pediatric Scaphoid Fractures. AB - Scaphoid fractures are the most common type of carpal injuries that occur in children and adolescents. The injury pattern seen in children and adolescents who have scaphoid fractures has recently shifted to resemble that of adults who have scaphoid fractures, with scaphoid waist fractures being the most common injury pattern. This shift has been attributed to increased body mass index in children and adolescents as well as more intense participation in extreme sports by both children and adolescents. The diagnosis of scaphoid fractures is based on both a clinical examination and radiographic fi ndings. If a scaphoid fracture is clinically suspected but initial radiographs are negative, cast immobilization followed by repeat imaging can lead to accurate diagnosis of the injury. MRI can aid in the diagnosis of a scaphoid injury in pediatric patients with incomplete ossifi cation of the scaphoid. Acute nondisplaced scaphoid fractures have a high rate of healing with cast immobilization; however, surgery should be considered in patients who have displaced scaphoid fractures with delayed presentation. In general, patients with scaphoid fractures who undergo appropriate treatment and achieve successful union have excellent long-term functional outcomes. PMID- 28594520 TI - Pediatric Metacarpal Fractures. AB - Metacarpal fractures account for 10% to 35% of all pediatric hand fractures. Pediatric metacarpal fractures commonly occur in patients aged 13 to 16 years, with most injuries sustained during sports activities. Pseudoepiphyses can be confused with metacarpal fractures; however, a careful physical examination can help physicians distinguish the two. Thumb metacarpal base fractures that involve the physis warrant special attention. Thumb metacarpal base fractures with lateral metaphyseal fragments and pediatric Bennett fracture variants (Salter Harris type III and type IV fractures) are unstable and require surgical management. Finger metacarpal base fractures, especially those in young children, are often the result of high-energ y injuries and should increase a physician's concern for compartment syndrome. Metacarpal shaft fractures can result from a simple bending moment; however, they also can result from a rotational force, which may cause finger crossover that will not remodel and requires reduction. Metacarpal neck fractures account for three-fourths of all finger metacarpal fractures, and increasing acceptable alignment of the index finger through the little finger metacarpal necks (10 degrees , 20 degrees , 30 degrees , and 40 degrees across the digits, respectively) is commonly recommended. Metacarpal head fractures are rare intra-articular injuries that require anatomic fixation and may be underappreciated in children because of the complex geometry and largely cartilaginous nature of the metacarpal head. PMID- 28594521 TI - Pediatric Distal Radius Fractures. AB - Distal radius fractures are the most common orthopaedic injury that occur in the pediatric population. The annual incidence of distal radius fractures has increased as a result of earlier participation in sporting activities, increased body mass index, and decreased bone mineral density. Most distal radius fractures are sustained after a fall onto an outstretched arm that results in axial compression on the extremity or from direct trauma to the extremity. Physeal fractures of the distal radius are described based on the Salter-Harris classification system. Extraphyseal fractures of the distal radius are described as incomplete or complete based on the amount of cortical involvement. A thorough physical examination of the upper extremity is necessary to rule out any associated injuries. PA and lateral radiographs of the wrist usually are sufficient to diagnose a distal radius fracture. The management of distal radius fractures is based on several factors, including patient age, fracture pattern, and the amount of growth remaining. Nonsurgical management is the most common treatment option for patients who have distal radius fractures because marked potential for remodeling exists. If substantial angulation or displacement is present, closed reduction maneuvers with or without percutaneous pinning should be performed. Patients with physeal fractures of the distal radius that may result in malunion who present more than 10 days postinjury should not undergo manipulation of any kind because of the increased risk for physeal arrest. PMID- 28594522 TI - Skeletally Immature Anterior Cruciate Ligament Injuries: Controversies and Management. AB - At one time, anterior cruciate ligament (ACL) tears in skeletally immature patients were considered rare. The recommended treatment option for skeletally immature patients with ACL tears was to modify activities until skeletal maturity, at which point definitive ACL reconstruction could be safely performed. The management of ACL tears in skeletally immature patients has evolved as a result of the increased frequency of ACL tears in younger patients and an increased awareness for the potential development or worsening of meniscal tears, chondral lesions, and degenerative changes that occur with the "wait-and-fix later" approach. The surgical options for ACL reconstruction in skeletally immature patients include physeal-sparing, partial transphyseal, and complete transphyseal techniques. The timing and ideal technique for ACL reconstruction in skeletally immature patients are controversial. Accurate assessment of skeletal growth remaining and concerns for iatrogenic growth disturbances continually challenge treating physicians. Similar controversies with regard to the treatment of skeletally immature patients who have partial ACL tears or congenital absence of the ACL also exist. PMID- 28594523 TI - Congenital Scoliosis: A Case-Based Approach. AB - Congenital scoliosis is lateral curvature of the spine caused by vertebral anomalies. Congenital scoliosis is associated with congenital anomalies of other organ systems. Traditionally, treatment options for patients with congenital scoliosis focused on posterior spinal fusion. Current surgical treatment options for young children include growing rods, vertical expandable prosthetic titanium ribs, and, most recently, magnetic rods. Hemivertebrae resection is an important early treatment option for patients who have a hemivertebra. Intraoperative navigation may be an important tool that can be used to improve the accuracy of pedicle screw placement in patients who have abnormal pedicles. PMID- 28594524 TI - Adolescent Idiopathic Scoliosis: Update on Bracing, Surgical Techniques, and Patient Safety. AB - The primary goal in the management of adolescent idiopathic scoliosis is to prevent the progression of spinal deformity either with the use of a brace or with surgery. The goals of surgery, if indicated, are to correct the spinal deformity safely and to preserve overall spinal balance and as many motion segments as possible, which maximizes the long-term health of a patient's spine. Recently, tremendous advances have been made in the surgical techniques that are used to correct adolescent idiopathic scoliosis, and improved tools have allowed surgeons to perform spinal deformity surgery as safely and with as few complications as possible. Surgeons should be aware of recent evidence that demonstrates the efficacy of bracing in patients who have adolescent idiopathic scoliosis. In addition, surgeons should understand recent advances in spinal deformity surgery with regard to fusion level selection, implant placement, three dimensional deformity correction, and techniques that are used to minimize perioperative complications. PMID- 28594525 TI - Update in Pediatric Musculoskeletal Infections: When It Is, When It Isn't, and What to Do. AB - Musculoskeletal infections, including osteomyelitis, septic arthritis, and pyomyositis, are a substantial cause of morbidity in children and adolescents. The increased virulence of infectious agents and the increased prevalence of antimicrobial-resistant pathogens, particularly methicillin-resistant Staphylococcus aureus, have resulted in a more complicated clinical course for diagnosis and management, which is evidenced by an increased length of hospital stays, incidence of complications, and number of surgical interventions. Musculoskeletal infections are a challenge for surgeons because they vary substantially in their presentation and in their required treatment, which is based on the causative organism, the location of the infection, and the age of the patient. The necessity for a prompt diagnosis is complicated by several diseases that may mimic musculoskeletal infection, including transient synovitis, autoimmune arthritis, and tumors. Recent innovations in diagnosis and management have provided surgeons with new options to differentiate musculoskeletal infections from these rapidly evolving disease pathologies. As diagnostic and treatment modalities improve, collaboration among surgeons from multiple disciplines is required to develop evidence-based clinical practice guidelines that minimize the effect of musculoskeletal infection and optimize clinical outcomes for patients. PMID- 28594526 TI - The Four Most Common Types of Knee Cartilage Damage Encountered in Practice: How and Why Orthopaedic Surgeons Manage Them. AB - Cartilage damage of the knee is common and may present in patients as a variety of symptoms. These conditions can be classified based on location, etiology, and/or pathophysiology. A systematic approach to the evaluation and classification of chondral injuries helps improve definitive management. The four most common types of knee cartilage damage are osteochondritis dissecans, incidental chondral defects, patellofemoral defects, and defects encountered after meniscectomy. PMID- 28594527 TI - Management of Patellofemoral Arthritis: From Cartilage Restoration to Arthroplasty. AB - The management of patellofemoral cartilage lesions is controversial and should begin with a comprehensive nonsurgical treatment plan. Patients with patellofemoral cartilage lesions in whom nonsurgical treatment fails may be candidates for surgical treatment. Surgical treatment strategies for the management of patellofemoral cartilage lesions are guided by the size, quality, and location of the defect. Recent advancements in cartilage restoration and arthroplasty techniques as well as appropriate patient selection and meticulous surgical technique have resulted in promising outcomes for patients with patellofemoral cartilage lesions who undergo surgical treatment. PMID- 28594528 TI - International Perspective on Revision Anterior Cruciate Ligament Reconstruction: What Have We Been Missing? AB - Primary anterior cruciate ligament (ACL) reconstruction is a common orthopaedic procedure. A graft failure rate of 5% to 10% after primary ACL reconstruction has resulted in an increased need for revision ACL reconstruction. ACL reconstruction failure etiologies include trauma, technical errors, and biologic factors. Based on the current literature, the outcomes of revision ACL reconstruction are clearly inferior compared with those of primary reconstruction. A thorough patient evaluation, including surgical history, a physical examination, and imaging studies, is crucial in the assessment of a failed ACL reconstruction. Tunnel malposition, which is a technical error, is the most common reason for ACL reconstruction failure. Tunnel positioning and widening are important factors to consider in the decision to perform either one-stage or two-stage revision ACL reconstruction. Other concomitant factors such as malalignment, pathologic posterior tibial slope, and meniscal or ligamentous deficiency (in particular, deficiency of the anterolateral ligament) must be considered and addressed to achieve an optimal outcome. Patients who have a positive pivot shift test and rotational instability may require extra-articular anterolateral ligament reconstruction. In addition, patients who have severe pathologic tibial slope and anterior tibial translation may require a tibial deflexion osteotomy. PMID- 28594529 TI - Concussion in Sports: What Do Orthopaedic Surgeons Need to Know? AB - A concussion is a relatively common sports-related injury that affects athletes of all ages. Although not expected to replace sports medicine physicians and neurologists with regard to the management of concussions, orthopaedic surgeons, particularly those who are fellowship-trained in sports medicine, must have a current knowledge base of what a concussion is, how a concussion is diagnosed, and how a concussion should be managed. Orthopaedic surgeons should understand the pathophysiology, assessment, and management of concussion so that they have a basic comprehension of this injury that is at the forefront of the academic literature and North American media. This understanding will prepare orthopaedic surgeons to work in concert with and assist sports medicine physicians, athletic trainers, and physical therapists in providing comprehensive care for athletes with a concussion. PMID- 28594530 TI - Key Concepts of Musculoskeletal Infection. AB - Over the past few decades, musculoskeletal infections have increased in both incidence and severity. The clinical manifestations of musculoskeletal infections range from isolated osteomyelitis to multisite infections with systemic complications. Although this increased incidence of musculoskeletal infections correlates with the increased incidence of methicillin-resistant Staphylococcus aureus infections, other nonresistant infectious organisms have been associated with severe musculoskeletal infections; this finding supports the likelihood that an antibiotic resistance profile is not a major factor in bacterial virulence. Instead, a multitude of virulence factors allow infectious organisms to manipulate and evade the immune response of the host. Organisms such as S aureus and Streptococcus pyogenes are able to hijack the acute phase response of the host, which allows for protected proliferation and dissemination. The serum factors produced by the acute phase response, including interleukin-6, C-reactive protein, erythrocytes/fibrinogen, and platelets, can be used to assess musculoskeletal infection severity and monitor treatment. Bacterial genome sequencing has identified virulence factors in a wide variety of clinical manifestations of musculoskeletal infections and may help identify targets for clinical therapy. Currently, however, the management of musculoskeletal infections relies on accurate organism identification and a thorough recognition of the sites of infection and the tissues that are involved. MRI aids in the localization of musculoskeletal infection and identification of sites that require surgical debridement. PMID- 28594531 TI - Soft-Tissue Tumors: A Pictorial- and Case-Based Guide to Diagnosis and Management. AB - General orthopaedic surgeons must learn how to appropriately evaluate patients with soft-tissue masses who present at their office. Although the incidence of benign soft-tissue sarcomas substantially outnumbers that of malignant soft tissue sarcomas, the mismanagement of soft-tissue tumors markedly increases a patient's morbidity. The appropriate use of imaging modalities helps general orthopaedic surgeons accurately diagnose a soft-tissue mass, initiate appropriate management of a soft-tissue mass, and gain a better understanding of which patients with soft-tissue lesions should be referred to an orthopaedic oncologist. PMID- 28594532 TI - What's Wrong With the Bone? An Overview of Metabolic and Neoplastic Bone Conditions. AB - The evaluation of any orthopaedic condition often begins with obtaining plain radiographs. Fortuitously, plain radiographs provide surgeons with direct information on the biologic activity and, therefore, the aggressiveness of any bone lesion. More advanced imaging modalities may fail to elucidate the problem and may even obscure the diagnosis. The accurate interpretation of the aggressiveness of a bone lesion on plain radiographs is the first step in establishing a differential diagnosis for any bone lesion and, often, may result in a correct diagnosis without the need for additional imaging studies. A thorough understanding of the radiographic classification of bone lesions will allow surgeons to accurately diagnose and manage metabolic bone disease, benign bone lesions, and malignant bone lesions. PMID- 28594533 TI - Implementation of TeamSTEPPS in Orthopaedic Surgery. AB - An Institute of Medicine report published in 2000 brought attention to the devastating consequences of medical errors. The report estimated that 98,000 deaths occurred in US hospitals each year as a result of medical errors and spawned investigations into factors that are associated with medical errors as well as strategies to avoid them. Taking cues from high-reliability organizations, such as the airline industry, evidence-based tools were developed to minimize human risk factors and foster teamwork, communication, and other skills that are essential to patient safety and quality. Orthopaedic surgeons are in a unique position to advocate for patients and to lead healthcare teams through the cultural changes that are necessary to avoid harm and improve outcomes. The American Academy of Orthopaedic Surgeons has made a commitment to educate interdisciplinary healthcare teams and uses TeamSTEPPS to educate orthopaedic surgeons on the knowledge, skills, and attitudes that are necessary to develop teamwork and improve patient safety and the quality of care. Orthopaedic surgeons should understand the need for improved teamwork and the resources that are available to shape the cultural changes that are necessary to avoid harm and improve outcomes. PMID- 28594534 TI - Patient-Reported Outcome Metrics in Total Joint Arthroplasty. AB - The Patient Protection and Affordable Care Act includes several provisions that focus on improving the delivery of health care in the United States. Reducing overall healthcare costs and improving the quality of care delivered are two overarching themes of the Patient Protection and Affordable Care Act. An evaluation of quality in total joint arthroplasty focuses on three main areas: complications, readmissions, and, more recently, patient-reported outcomes. Patient-reported outcomes allow surgeons and patients to objectively document pain relief and functional gain after total joint arthroplasty. Surgeons, groups, or hospitals that commit to the collection of patient-reported outcomes must consider which patient-reported outcomes to capture, the workflow and timing of postoperative patient-reported outcome collection, and how to minimize the burden of patient-reported outcome collection on both patients and surgeons. PMID- 28594535 TI - Collaborative Orthopaedic Research Between and Within Institutions. AB - Collaborative research is common in many medical disciplines; however, the field of orthopaedics has been relatively slow to adopt this type of research approach. Collaborative research efforts can occur between multiple institutions and, in some instances, may benefit from subspecialty society sponsorship. Collaborative research efforts between several research spheres within a single institution also can be advantageous. Collaborative research has many benefits, including a larger number of patients in studies, more power in the research, and better generalizability. In addition, collaborative research efforts allow resources to be pooled within and between institutions. The challenges of collaborative research include data management, funding, and the publication of manuscripts that have many authors. PMID- 28594536 TI - Surgeon-Patient Communication: The Key to Patient Satisfaction, Patient-Centered Care, and Shared Decision Making. AB - The surgeon-patient relationship is rapidly evolving from surgeon-centric to patient-centric. External forces, such as the Affordable Care Act and the unsustainable growth of healthcare costs in the United States, have disrupted the old model of medical care. Effective communication between surgeons and patients as well as patient satisfaction, treatment adherence, and shared decision making are essential components of the patient-centered care paradigm. Effective communication carries high stakes for surgeons, including increased surgeon satisfaction and a reduced risk of surgeon burnout and malpractice litigation. Communication skills are one of the six Accreditation Council for Graduate Medical Education core competencies, and an assessment of communication skills is now included in a surgeon's summative evaluations for employment, compensation, licensing, and maintenance of certification. PMID- 28594537 TI - Surgeon-Patient Communication: Disclosing Unanticipated Medical Outcomes and Errors. AB - The disclosure of unanticipated medical outcomes and errors is essential as physicians strive to create a safer, higher quality healthcare delivery system. Physicians and other healthcare providers should use an organized approach to guide the disclosure of unanticipated medical outcomes and errors. An expression of sympathy or an apology on behalf of a physician depends on whether the medical outcome or error occurred after appropriate care (maloccurrence) or there was a deviation from the standard of care (malpractice). PMID- 28594538 TI - Getting Research Published and Achieving the Highest Impact Factor. AB - High-quality surgical clinical trials are fundamental to the delivery of evidence based orthopaedics; however, fewer than 1% of patients who undergo surgery worldwide are enrolled in surgical clinical trials. Advances in orthopaedic surgery depend on the creativity and innovation of researchers who investigate, develop, and execute local, national, and international surgical clinical trials, all of which will ultimately affect surgical practice and patient care. Surgeons should understand the challenges of surgical clinical trials, including identifying important research questions; getting support for ideas; establishing clinical research networks; collecting, collating, and analyzing data; as well as getting research published and achieving the highest impact factor. Surgeons also should understand how research material should be formatted and presented in a manuscript that is submitted for publication as well as the elements an editor seeks in a research manuscript. PMID- 28594539 TI - SERS Assay for Copper(II) Ions Based on Dual Hot-Spot Model Coupling with MarR Protein: New Cu2+-Specific Biorecognition Element. AB - We have developed a rapid and ultrasensitive surface-enhanced Raman scattering (SERS) assay for Cu2+ detection using the multiple antibiotic resistance regulator (MarR) as specific bridging molecules in a SERS hot-spot model. In the assay, Cu2+ induces formation of MarR tetramers, which provide Au nanoparticle (NP)-AuNP bridges, resulting in the formation of SERS hot spots. 4 Mercaptobenzoic acid (4-MBA) was used as a Raman reporter. The addition of Cu2+ increased the Raman intensity of 4-MBA. Use of a dual hot-spot signal amplification strategy based on AuNP-AgNP heterodimers combined through antigen antibody reactions increased the sensitivity of the sensing platform by 50-fold. The proposed method gave a linear response for Cu2+ detection in the range of 0.5 1000 nM, with a detection limit of 0.18 nM, which is 5 orders of magnitude lower than the U.S. Environmental Protection Agency limit for Cu2+ in drinking water (20 MUM). In addition, all analyses can be completed in less than 15 min. The high sensitivity, high specificity, and rapid detection capacity of the SERS assay therefore provide a combined advantage over current assays. PMID- 28594540 TI - Noradrenergic Modulation of Dopamine Transmission Evoked by Electrical Stimulation of the Locus Coeruleus in the Rat Brain. AB - Central norepinephrine (NE) and dopamine (DA) are involved in a variety of physiological functions and behaviors. Accumulating evidence suggests that NE neurons originating from the locus coeruleus (LC) innervate DA neurons of the ventral tegmental area (VTA) and influence VTA-DA neural activity. However, the underlying mechanisms of how LC-NE regulates DA transmission via VTA-DA neurons remain largely unexplored. Herein, we investigated how electrical stimulation of the LC modulates VTA-DA neurotransmission in the nucleus accumbens (NAc). For this study, catecholamine release in the NAc and VTA evoked by electrical stimulation of the LC in urethane-anesthetized rats was simultaneously monitored with carbon-fiber microelectrodes using in vivo multichannel fast-scan cyclic voltammetry for comparison of its extracellular regulation. Pharmacological, anatomical, and electrochemical evidence suggest that electrical stimulation of the LC evokes NE release in the VTA and activates VTA-DA neurons, resulting in DA release in the NAc. The electrically evoked DA in the NAc was regulated by D2 receptors and DA transporters (DAT) as well as alpha1-adrenergic receptors in the VTA, whereas NE release in the VTA was regulated by alpha2-adrenergic receptors and NE transporters (NET) not by D2 receptors or DAT. These results suggest that electrical stimulation of LC modulates VTA-DA neurons and DA transmission in the NAc via NE receptors. PMID- 28594541 TI - Direct Visualization of Nucleation and Growth Processes of Solid Electrolyte Interphase Film Using in Situ Atomic Force Microscopy. AB - An understanding of the formation mechanism of solid electrolyte interphase (SEI) film at the nanoscale is paramount because it is one of the key issues at interfaces in lithium-ion batteries (LIBs). Herein, we explored the nucleation, growth, and formation of SEI film on highly oriented pyrolytic graphite (HOPG) substrate in ionic liquid-based electrolytes 1-butyl-1-methyl-pyrrolidinium bis(fluorosulfonyl)imide ([BMP]+[FSI]-) and 1-butyl-1-methylpyrrolidinium bis(trifluoromethanesulfonyl)imide ([BMP]+[TFSI]-) by in situ atomic force microscopy (AFM) and found that the types of anions have significant influence on the structure of the formed SEI. In [BMP]+[FSI]- containing LiFSI, a compact and thin SEI film prefers to grow in the plane of HOPG substrate, while a rough and loose film tends to form in [BMP]+[TFSI]- containing LiTFSI. On the basis of in situ AFM observations, the relationship between the SEI structure and the electrochemical performance was clarified. PMID- 28594542 TI - Development of Hybrid Ultrafiltration Membranes with Improved Water Separation Properties Using Modified Superhydrophilic Metal-Organic Framework Nanoparticles. AB - Metal-organic frameworks (MOFs) are being intensively explored as filler materials for polymeric membranes primarily due to their high polymer affinity, large pore volumes, and alterable pore functionalities, but the development of MOF-based ultrafiltration (UF) membranes for water treatment lags behind. Herein, poly(sulfobetaine methacrylate) (PSBMA)-functionalized MOF UiO-66-PSBMA was developed, and incorporated into polysulfone (PSf) casting solution to fabricate novel hybrid UF membranes via phase-inversion method. The resultant UiO-66 PSBMA/PSf membrane exhibited significantly improved water flux (up to 602 L m-2 h 1), which was 2.5 times that of the pristine PSf membrane (240 L m-2 h-1) and 2 times that of UiO-66-NH2/PSf membrane (294 L m-2 h-1), whereas the rejection of UiO-66-PSBMA/PSf membrane was still maintained at a high level. Moreover, UiO-66 PSBMA/PSf membrane exhibited improved antifouling performance. The improvement of membrane performances could be attributed to the well-tailored properties of UiO 66-PSBMA. On one hand, the excellent dispersion and compatibility of UiO-66-PSBMA ensured the formation of a uniform structure with few defects. On the other hand, the superhydrophilicity of UiO-66-PSBMA could accelerate the exchange rate between solvent and nonsolvent, resulting in a more hydrophilic surface and a more porous structure. Besides, UiO-66-PSBMA nanoparticles in the thin layer provided additional flow paths for water permeation through their hydrophilic porous structure as well as the tiny interspace between PSf matrix. This study indicates the great application potential of UiO-66-PSBMA in fabricating hybrid UF membranes and provides a useful guideline to integrate other modified hydrophilic MOFs to design UF membranes for water treatment. PMID- 28594544 TI - CuV2S4: A High Rate Capacity and Stable Anode Material for Sodium Ion Batteries. AB - The ternary compound CuV2S4 exhibits an excellent performance as anode material for sodium ion batteries with a high reversible capacity of 580 mAh g-1 at 0.7 A g-1 after 300 cycles. A Coulombic efficiency of ~99% is achieved after the third cycle. Increase of the C-rate leads to a drop of the capacity, but a full recovery is observed after switching back to the initial C-rate. In the early stages of Na uptake first Cu+ is reduced and expelled from the electrode as nanocrystalline metallic Cu. An increase of the Na content leads to a full conversion of the material with nanocrystalline Cu particles and elemental V embedded in a Na2S matrix. The formation of Na2S is evidenced by 23Na MAS NMR spectra and X-ray powder diffraction. During the charge process the nanocrystalline Cu particles are retained, but no crystalline materials are formed. At later stages of cycling the reaction mechanism changes which is accompanied by the formation of copper(I) sulfide. The presence of nanocrystalline metallic Cu and/or Cu2S improves the electrical conductivity, leading to superior cycling and rate capability. PMID- 28594543 TI - Nickel-Catalyzed C-Alkylation of Nitroalkanes with Unactivated Alkyl Iodides. AB - Enabled by nickel catalysis, a mild and general catalytic method for C-alkylation of nitroalkanes with unactivated alkyl iodides is described. Compatible with primary, secondary, and tertiary alkyl iodides; and tolerant of a wide range of functional groups, this method allows rapid access to diverse nitroalkanes. PMID- 28594545 TI - Dye Wastewater Cleanup by Graphene Composite Paper for Tailorable Supercapacitors. AB - Currently, the energy crisis and environmental pollution are two critical challenges confronted by humans. The development of smart strategies to address the above-mentioned issues simultaneously is significant. As the main accomplices for water pollution, several kinds of organic dyes with intrinsic redox functional groups such as phenothiazines derivatives, anthraquinone, and indigoid dyes are potential candidates for the replacement of the conventional pseudocapacitive materials. In this work, three typical organic dyes can be efficiently removed by a facile adsorption procedure using reduced graphene oxide coated cellulose fiber (rGO@CF) paper. Flexible supercapacitors based on dye/rGO@CF electrodes exhibit excellent electrochemical performances that are superior to or comparable with those of conventional pseudocapacitive materials based devices, presenting a new type of promising electrode materials. Moreover, benefiting from the high flexibility and considerable mechanical strength of the graphene composite paper, the operating potential and capacitance of the devices can be easily adjusted by tailoring the hybrid electrodes into different specific shapes followed by rational integrating. The smart design of these dye/rGO@CF paper based electrodes shows that energy storage and environmental remediation can be achieved simultaneously. PMID- 28594546 TI - Neuropeptide VGF C-Terminal Peptide TLQP-62 Alleviates Lipopolysaccharide-Induced Memory Deficits and Anxiety-like and Depression-like Behaviors in Mice: The Role of BDNF/TrkB Signaling. AB - Peripheral inflammatory responses affect central nervous system (CNS) function, manifesting in symptoms of memory deficits, depression, and anxiety. Previous studies have revealed that neuropeptide VGF (nonacronymic) C-terminal peptide TLQP-62 rapidly reinforces brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, regulating memory consolidation and antidepressant-like action. However, whether it is beneficial for lipopolysaccharide (LPS)-induced neuropsychiatric dysfunction in mice is unknown. Herein, we explored the involvement of BDNF/TrkB signaling and biochemical alterations in inflammatory or oxidative stress markers in the alleviating effects of TLQP-62 on LPS-induced neuropsychiatric dysfunction. The mice were treated with TLQP-62 (2 MUg/side) via intracerebroventricular (i.c.v.) injection 1 h before LPS (0.5 mg/kg, i.p.) administration. Our results showed that a single treatment with LPS (0.5 mg/kg, i.p) is sufficient to produce recognition memory deficits (in the novel object recognition test), depression-like behavior (in the forced swim test and sucrose preference test), and anxiety-like behavior (in the elevated zero maze). However, pretreatment with TLQP-62 prevented LPS-induced behavioral dysfunction, neuroinflammatory, and oxidative responses. In addition, our results further demonstrated that a reduction in BDNF expression mediated by BDNF-shRNA lentivirus significantly blocked the effects of TLQP-62, suggesting the critical role of BDNF/TrkB signaling in the neuroprotective effects of TLQP 62 in the mice. In conclusion, TLQP-62 could be a therapeutic approach for neuropsychiatric disorders, which are closely associated with neuroinflammation and oxidative stress. PMID- 28594547 TI - Influence of the Surface Roughness of Platinum Electrodes on the Calibration of the Electrochemical Quartz-Crystal Nanobalance. AB - The electrochemical quartz-crystal nanobalance (EQCN) is an in situ technique that measures mass changes (Deltam) associated with interfacial phenomena. Analysis of Deltam sheds light on the mass balance (in addition to the charge and energy balances) and provides new insight into the nature of electrochemical processes. The EQCN measures changes in frequency (Deltaf) of a quartz-crystal resonator, which are converted into Deltam using the Sauerbrey equation containing the characteristic constant (Cf). The value of Cf is determined by physical parameters of the crystal and refers to an atomically smooth surface. However, real resonators are not smooth and electrodes have their intrinsic roughness. Thus, the conversion of Deltaf to Deltam should be done using an experimentally determined characteristic constant (Cf,exp) for a given value of the surface roughness factor (R). Here, we calibrate the system using Ag electrodeposition on Pt electrodes of gradually increasing R; the latter is adjusted through Pt electrodeposition. The surface morphology of the Pt substrates prior to and after Ag electrodeposition is examined using atomic force microscopy. The values of Cf,exp are determined by analyzing the slopes of charge density versus Deltaf plots for the Ag electrodeposition. They are different than Cf and increase logarithmically with R. The Cf and Cf,exp values are used in a comparative analysis of the mass changes (deltaDeltam) for complete cyclic voltammetry profiles covering the 0.05-1.40 V range. This reveals that the employment of Cf instead of Cf,exp provides inaccurate values of deltaDeltam, and the magnitude of the discrepancy increases with R. PMID- 28594549 TI - PlayMolecule ProteinPrepare: A Web Application for Protein Preparation for Molecular Dynamics Simulations. AB - Protein preparation is a critical step in molecular simulations that consists of refining a Protein Data Bank (PDB) structure by assigning titration states and optimizing the hydrogen-bonding network. In this application note, we describe ProteinPrepare, a web application designed to interactively support the preparation of protein structures. Users can upload a PDB file, choose the solvent pH value, and inspect the resulting protonated residues and hydrogen bonding network within a 3D web interface. Protonation states are suggested automatically but can be manually changed using the visual aid of the hydrogen bonding network. Tables and diagrams provide estimated pKa values and charge states, with visual indication for cases where review is required. We expect the graphical interface to be a useful instrument to assess the validity of the preparation, but nevertheless, a script to execute the preparation offline with the High-Throughput Molecular Dynamics (HTMD) environment is also provided for noninteractive operations. PMID- 28594548 TI - CuH-Catalyzed Regioselective Intramolecular Hydroamination for the Synthesis of Alkyl-Substituted Chiral Aziridines. AB - This report details a general and enantioselective means for the synthesis of alkyl-substituted aziridines. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. Readily accessed allylic hydroxylamine esters undergo copper hydride-catalyzed intramolecular hydroamination with a high degree of regio- and enantiocontrol to afford the aziridine products in good to excellent yields in highly enantioenriched form. The utility of the products derived from this method is further demonstrated through derivatization of the chiral aziridine products to obtain a diverse array of functionalized enantioenriched amines. PMID- 28594551 TI - Pressure-Enabled Synthesis of Hetero-Dimers and Hetero-Rods through Intraparticle Coalescence and Interparticle Fusion of Quantum-Dot-Au Satellite Nanocrystals. AB - This report presents the fabrication and pressure-driven processing of heterostructural nanocrystal superlattices (HNC-SLs) self-assembled from quantum dot-Au (QD-Au) satellite-type HNCs. In situ small/wide-angle X-ray scattering and electron microscopic measurements showed that the HNC-SLs underwent structural transformation at both atomic- and mesoscales during the pressure processing. Upon deviatoric stress-driven orientational migration, the intraparticle coalescence of Au satellites at QD surfaces transforms individual HNCs into heterodimers, whereas the interparticle fusion drives assembled HNCs into ordered heterorod arrays. These results demonstrate high-pressure-processing as a clean and fast means for conversion of HNCs into novel heteromaterials that are difficult to achieve through conventional synthetic routes. PMID- 28594550 TI - Methylseleninic Acid Prevents Patulin-Induced Hepatotoxicity and Nephrotoxicity via the Inhibition of Oxidative Stress and Inactivation of p53 and MAPKs. AB - Patulin is one of the common food-borne mycotoxins. Previous studies have demonstrated that patulin can cause diverse toxic effects in animals including hepatotoxicity and nephrotoxicity. In the present study, we have addressed the protective effect of two forms of selenium compounds methylseleninic acid (MSeA) and sodium selenite on patulin-induced nephrotoxicity and hepatotoxicity using both in vitro and in vivo models. Results showed that MSeA at concentrations of 3 5 MUM, not sodium selenite at the same concentrations, is capable of protecting against patulin-induced cytotoxicity in the cell culture model. Moreover, the hepatoprotective and nephroprotective effects of MSeA (2 mg/kg body weight, oral administration) on patulin-induced toxicity (10 mg/kg body weight, intraperitoneal injection) were also achieved in the animal model. A further mechanistic study revealed that the protective effect of MSeA on patulin-mediated toxicity is attributed to its ability to inhibit patulin-mediated ROS generation and inactivate p53 and mitogen-activated protein kinase (MAPK) signaling pathways. Our findings support a possible usefulness of MSeA as a novel detoxicant to mitigate the toxicities of patulin. PMID- 28594552 TI - 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. AB - Herein we describe the identification of 4-{[1,2,4]triazolo[1,5-a]pyridin-5 yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties. PMID- 28594554 TI - Correction to Efficient Calculation of Electronic Absorption Spectra by Means of Intensity-Selected Time-Dependent Density Functional Tight Binding. PMID- 28594553 TI - Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands. AB - Targeted protein degradation using small molecules is a novel strategy for drug development. We have developed hybrid molecules named specific and nongenetic inhibitor of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) that recruit IAP ubiquitin ligases to degrade target proteins. Here, we show novel SNIPERs capable of inducing proteasomal degradation of the androgen receptor (AR). Through derivatization of the SNIPER(AR) molecule at the AR ligand and IAP ligand and linker, we developed 42a (SNIPER(AR)-51), which shows effective protein knockdown activity against AR. Consistent with the degradation of the AR protein, 42a inhibits AR-mediated gene expression and proliferation of androgen dependent prostate cancer cells. In addition, 42a efficiently induces caspase activation and apoptosis in prostate cancer cells, which was not observed in the cells treated with AR antagonists. These results suggest that SNIPER(AR)s could be leads for an anticancer drug against prostate cancers that exhibit AR dependent proliferation. PMID- 28594555 TI - Effect of Aging on the Absorption of Small Peptides in Spontaneously Hypertensive Rats. AB - In the present study, we aimed to evaluate the effect of aging on the absorption of small peptides in spontaneously hypertensive rats (SHRs). Three kinds of dipeptides, glycyl-sarcosine (Gly-Sar), Trp-His, and captopril (a dipeptidomimetic drug), a Gly-Sar-Sar tripeptide, a Gly-Sar-Sar-Sar tetrapeptide, and a Gly-Sar-Sar-Sar-Sar pentapeptide were administered at doses of 10 mg/kg each to 8- and 40-week-old SHRs. The peptides were all detected in their intact forms in the blood. There was a significantly promoted absorption of di/tripeptides in aged SHRs compared with young SHRs. In contrast, the absorption of tetra/pentapeptides was not affected by aging. PepT1 expression in the mid jejunum was significantly increased in 40-week-old SHRs compared with 8-week-old SHRs, whereas aging did not alter the expression of claudin-1, a tight junction related protein. Thus, the present results suggest that SHR aging may enhance the absorption of di/tripeptides through the enhanced PepT1 transport route, although oligopeptides may be absorbed in an age-independent manner. PMID- 28594556 TI - Theoretical Investigation of Metallic Heterofullerenes of Silicon and Germanium Mixed with Phosphorus and Arsenic Atoms M-A8E6, A = Si, Ge; E = P, As; and M = Cr, Mo, W. AB - Recently, metallic heterofullerenes were experimentally prepared from mixed Ge-As clusters and heavier elements of groups 14 and 15. We found that the shape of these heterofullerenes doped by transition metals appears to be a general structural motif for both silicon and germanium clusters when mixing with phosphorus and arsenic atoms. Structural identifications for MSi8P6, MSi8As6, MGe8P6, and MGe8As6 clusters, with M being a transition metal of group 6 (Cr, Mo and W), showed that most MA8E6 clusters, except for Cr-doped derivatives CrSi8As6, CrGe8P6, and CrGe8As6, exhibit a high-symmetry fullerene shape in which metal dopant is centered in a D3h A8E6 heterocage consisting of six A3E2 pentagonal faces and three A2E2 rhombus faces. The stability of the MA8E6 metallic heterofullerene is significantly enhanced by formation an electron configuration of [1S2 1P6 1D10 1F14 1G18 2S2 2P6 2D10] enclosing 68 electrons. The A8E6 heterocages give a great charge transfer (~4 electrons) to centered dopant, establishing subsequently a d10 configuration for metal, and as a consequence, it induces an additional stabilization of the resulting ME8P6 fullerene in a high-symmetry D3h shape and completely quenches the high spin of the metal atom, finally yielding a singlet spin ground state. PMID- 28594558 TI - Dynamics of Dissolutive Wetting: A Molecular Dynamics Study. AB - Dissolutive wetting, i.e., dynamic wetting of a liquid droplet on dissolvable substrates, has been studied by molecular dynamics simulations. In dissolutive wetting, the geometry and properties of the solid-liquid interface evolve with the solid dissolving into the droplet; meanwhile, the droplet spreads on the receding solid surfaces. The droplets advance on the dissolvable substrate following different dynamic laws, compared with spreading on nondissolutive substrate. On the basis of molecular kinetic theory, we develop a theoretical model to reveal physical mechanisms behind the dissolutive wetting phenomena. We also find that solid particles are pulled by their hydration shells to dissolve into liquid, changing the flow field, the atomic structure, and the hydrogen bond network in the droplet. Our findings may help to comprehend the dynamics of dissolutive wetting and assist future design in practical applications. PMID- 28594557 TI - Long-Lived 13C2 Nuclear Spin States Hyperpolarized by Parahydrogen in Reversible Exchange at Microtesla Fields. AB - Parahydrogen is an inexpensive and readily available source of hyperpolarization used to enhance magnetic resonance signals by up to four orders of magnitude above thermal signals obtained at ~10 T. A significant challenge for applications is fast signal decay after hyperpolarization. Here we use parahydrogen-based polarization transfer catalysis at microtesla fields (first introduced as SABRE SHEATH) to hyperpolarize 13C2 spin pairs and find decay time constants of 12 s for magnetization at 0.3 mT, which are extended to 2 min at that same field, when long-lived singlet states are hyperpolarized instead. Enhancements over thermal at 8.5 T are between 30 and 170 fold (0.02 to 0.12% polarization). We control the spin dynamics of polarization transfer by choice of microtesla field, allowing for deliberate hyperpolarization of either magnetization or long-lived singlet states. Density functional theory calculations and experimental evidence identify two energetically close mechanisms for polarization transfer: First, a model that involves direct binding of the 13C2 pair to the polarization transfer catalyst and, second, a model transferring polarization through auxiliary protons in substrates. PMID- 28594559 TI - Anion Exchange on Cationic Surfactant Micelles, and a Speciation Model for Estimating Anion Removal on Micelles during Ultrafiltration of Water. AB - Surfactant micelles combined with ultrafiltration can partially, or sometimes nearly completely, separate various ionic and nonionic pollutants from water. To this end, the selectivity of aqueous micelles composed of either cetyltrimethylammonium (CTA+) bromide or cetylpyridinium (CP+) chloride toward many environmentally relevant anions (IO3-, F-, Cl-, HCO3-, NO2-, Br-, NO3-, H2PO4-, HPO42-, SO42-, and CrO42-) was investigated. Selectivity coefficients of CTA+ micelles (with respect to Br-) and CP+ micelle (with respect to Cl-) for these anions were evaluated using a simple thermodynamic ion exchange model. The sequence of anion affinity for the CTA+ micelles and for the CP+ micelles were the same, with decreasing affinity occurring in the order of: CrO42- > SO42- > HPO42- > NO3- > Br- > NO2- > Cl- > HCO3- > H2PO4- ~ F-. From the associated component mass balance and ion exchange (i.e., mass action) equations, an overall speciation model was developed to predict the distribution of all anions between the aqueous and micellar pseudophase for complex ionic mixtures. Experimental results of both artificial and real surface waters were in good agreement to model predictions. Further, the results indicated that micelles combined with ultrafiltration may be a potential technology for nutrient and other pollutant removal from natural or effluent waters. PMID- 28594560 TI - Reflective Metasurfaces for Incoherent Light To Bring Computer Graphics Tricks to Optical Systems. AB - The normal mapping technique is widely used in computer graphics to visualize three-dimensional (3D) objects displayed on a flat screen. Taking advantage of optical properties of metasurfaces, which provide a highly efficient approach for manipulation of incident light wavefront, we have designed a metasurface to implement diffuse reflection and used the concept of normal mapping to control its scattering properties. As a proof of principle, we have fabricated and characterized a flat diffuse metasurface imitating lighting and shading effects of a 3D cube. The 3D image is displayed directly on the illuminated metasurface and it is brighter than a standard white paper by up to 2.4 times. The designed structure performs equally well under coherent and incoherent illumination. The normal mapping approach based on metasurfaces can complement traditional optical engineering methods of surface profiling and gradient refractive index engineering in the design of 3D security features, high-performance planar optical diffusers, novel optical elements, and displays. PMID- 28594562 TI - Correction to "Ionomers of Intrinsic Microporosity: In Silico Development of Ionic-Functionalized Gas-Separation Membranes". PMID- 28594561 TI - Steering Self-Assembly of Amphiphilic Molecular Nanostructures via Halogen Exchange. AB - In the field of self-assembly, the quest for gaining control over the supramolecular architecture without affecting the functionality of the individual molecular building blocks is intrinsically challenging. By using a combination of synthetic chemistry, cryogenic transmission electron microscopy, optical absorption measurements, and exciton theory, we demonstrate that halogen exchange in carbocyanine dye molecules allows for fine-tuning the diameter of the self assembled nanotubes formed by these molecules, while hardly affecting the molecular packing determined by hydrophobic/hydrophilic interactions. Our findings open a unique way to study size effects on the optical properties and exciton dynamics of self-assembled systems under well-controlled conditions. PMID- 28594563 TI - Foaming Behavior of Polymer-Coated Colloids: The Need for Thick Liquid Films. AB - The current study examined the foaming behavior of poly(vinylpyrrolidone) (PVP) silica composite nanoparticles. Individually, the two components, PVP and silica nanoparticles, exhibited very little potential to partition at the air-water interface, and as such, stable foams could not be generated. In contrast, combining the two components to form silica-PVP core-shell nanocomposites led to good "foamability" and long-term foam stability. Addition of an electrolyte (Na2SO4) was shown to have a marked effect on the foam stability. By varying the concentration of electrolyte between 0 and 0.55 M, three regions of foam stability were observed: rapid foam collapse at low electrolyte concentrations, delayed foam collapse at intermediate concentrations, and long-term stability (~10 days) at the highest electrolyte concentration. The observed transitions in foam stability were better understood by studying the microstructure and physical and mechanical properties of the particle-laden interface. For rapidly collapsing foams the nanocomposite particles were weakly retained at the air-water interface. The interfaces in this case were characterized as being "liquid-like" and the foams collapsed within 100 min. At an intermediate electrolyte concentration (0.1 M), delayed foam collapse over ~16 h was observed. The particle-laden interface was shown to be pseudo-solid-like as measured under shear and compression. The increased interfacial rigidity was attributed to adhesion between interpenetrating polymer layers. For the most stable foam (prepared in 0.55 M Na2SO4), the ratio of the viscoelastic moduli, G'/G", was found to be equal to ~3, confirming a strongly elastic interfacial layer. Using optical microscopy, enhanced foam stability was assessed and attributed to a change in the mechanism of foam collapse. Bubble-bubble coalescence was found to be significantly retarded by the aggregation of nanocomposite particles, with the long-term destabilization being recognized to result from bubble coarsening. For rapidly destabilizing foams, the contribution from bubble-bubble coalescence was shown to be more significant. PMID- 28594564 TI - Dynamic Modulation of Radiative Heat Transfer beyond the Blackbody Limit. AB - Dynamic control of electromagnetic heat transfer without changing mechanical configuration opens possibilities in intelligent thermal management in nanoscale systems. We confirmed by experiment that the radiative heat transfer is dynamically modulated beyond the blackbody limit. The near-field electromagnetic heat exchange mediated by phonon-polariton is controlled by the metal-insulator transition of tungsten-doped vanadium dioxide. The functionalized heat flux is transferred over an area of 1.6 cm2 across a 370 nm gap, which is maintained by the microfabricated spacers and applied pressure. The uniformity of the gap is validated by optical interferometry, and the measured heat transfer is well modeled as the sum of the radiative and the parasitic conductive components. The presented methodology to form a nanometric gap with functional heat flux paves the way to the smart thermal management in various scenes ranging from highly integrated systems to macroscopic apparatus. PMID- 28594565 TI - Structure Formation in Langmuir Peptide Films As Revealed from Coarse-Grained Molecular Dynamics Simulations. AB - Molecular dynamics simulations in conjunction with the Martini coarse-grained model have been used to investigate the (nonequilibrium) behavior of helical 22 residue poly(gamma-benzyl-l-glutamate) (PBLG) peptides at the water/vapor interface. Preformed PBLG mono- or bilayers homogeneously covering the water surface laterally collapse in tens of nanoseconds, exposing significant proportions of empty water surface. This behavior was also observed in recent AFM experiments at similar areas per monomer, where a complete coverage had been assumed in earlier work. In the simulations, depending on the area per monomer, either elongated clusters or fibrils form, whose heights (together with the portion of empty water surface) increase over time. Peptides tend to align with respect to the fiber axis or with the major principal axis of the cluster, respectively. The aspect ratio of the cluster observed is 1.7 and, hence, comparable to though somewhat smaller than the aspect ratio of the peptides in alpha-helical conformation, which is 2.2. The heights of the fibrils is 3 nm after 20 ns and increases to 4.5 nm if the relaxation time is increased by 2 orders of magnitude, in agreement with the experiment. Aggregates with heights of about 3 or 4.5 nm are found to correspond to local bi- or trilayer structures, respectively. PMID- 28594566 TI - Severe Hypoglycemia Before Landing in a Patient with Type 1 Diabetes Using Sensor Augmented Pump Therapy. PMID- 28594567 TI - Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease, a Precursor for Epithelial Cancers: Understanding and Translation to Early Therapy. PMID- 28594568 TI - Repellents and New "Spaces of Concern" in Global Health. AB - Today, malaria prevention hinges upon two domestic interventions: insecticide treated bed nets and indoor residual spraying. As mosquitoes grow resistant to these tools, however, novel approaches to vector control have become a priority area of malaria research and development. Spatial repellency, a volumetric mode of action that seeks to reduce disease transmission by creating an atmosphere inimical to mosquitoes, represents one way forward. Drawing from research that sought to develop new repellent chemicals in conversation with users from sub Saharan Africa and the United States, we consider the implications of a non insecticidal paradigm of vector control for how we understand the political ecology of malaria. PMID- 28594569 TI - Presence of Human Pathogens in Produce from Retail Markets in Northern Germany. AB - Two hundred fresh produce samples (cucumber, carrots, herbs, leaf lettuce, and ready-to-eat mixed salad leaves) were obtained from retail in northern Germany in 2015. These were investigated for microbial contamination and the presence of foodborne pathogens, including Listeria monocytogenes, Salmonella serovars, presumptive Bacillus (B.) cereus, and Shiga toxin-producing Escherichia coli using culture-dependent (enrichment, plating on selective media) and -independent (real-time polymerase chain reaction [PCR]) techniques. Overall, our results showed that the fresh produce samples generally showed high mean aerobic mesophilic bacterial counts of between 7 and 8 log10 cfu/g. However, there was also a considerable variation in total aerobic bacterial counts between different product samples. Although real-time PCR signals for pathogenic E. coli were detected in 14.0% of total samples analyzed, only one (0.5%) Shiga toxin producing E. coli isolate of serotype O26:H11 was recovered from mixed salad leaves and contained stx1, stx2, and eae genes. Two L. monocytogenes isolates (1% of total samples) were recovered from packaged mixed salad leaves and belonged to PCR serogroups IIb and IVb, respectively. One Salmonella isolate (0.5%) was recovered after selective enrichment also from mixed salad leaves and it was identified as Salmonella Szentes serotype 16:k:1,2. Overall the incidence of foodborne pathogens on the northern German retail market in 2015 was very low. PMID- 28594570 TI - Obstructive Sleep Apnea and Retinopathy in Patients with Type 2 Diabetes. A Longitudinal Study. AB - RATIONALE: Obstructive sleep apnea (OSA) is associated with several pathophysiological deficits found in diabetic retinopathy (DR). Hence, it's plausible that OSA could play a role in the pathogenesis of sight-threatening DR (STDR). OBJECTIVES: To assess the relationship between OSA and DR in patients with type 2 diabetes and to assess whether OSA is associated with its progression. METHODS: A longitudinal study was conducted in diabetes clinics within two U.K. hospitals. Patients known to have any respiratory disorder (including OSA) were excluded. DR was assessed using two-field 45-degree retinal images for each eye. OSA was assessed using a home-based multichannel cardiorespiratory device. MEASUREMENTS AND MAIN RESULTS: A total of 230 patients were included. STDR and OSA prevalence rates were 36.1% and 63.9%, respectively. STDR prevalence was higher in patients with OSA than in those without OSA (42.9% vs. 24.1%; P = 0.004). After adjustment for confounders, OSA remained independently associated with STDR (odds ratio, 2.3; 95% confidence interval, 1.1 4.9; P = 0.04). After a median (interquartile range) follow-up of 43.0 (37.0 51.0) months, patients with OSA were more likely than patients without OSA to develop preproliferative/proliferative DR (18.4% vs. 6.1%; P = 0.02). After adjustment for confounders, OSA remained an independent predictor of progression to preproliferative/proliferative DR (odds ratio, 5.2; 95% CI confidence interval, 1.2-23.0; P = 0.03). Patients who received continuous positive airway pressure treatment were significantly less likely to develop preproliferative/proliferative DR. CONCLUSIONS: OSA is associated with STDR in patients with type 2 diabetes. OSA is an independent predictor for the progression to preproliferative/proliferative DR. Continuous positive airway pressure treatment was associated with reduction in preproliferative/proliferative DR. Interventional studies are needed to assess the impact of OSA treatment on STDR. PMID- 28594571 TI - ZMPSTE24 Is Downstream Effector of Interferon-Induced Transmembrane Antiviral Activity. AB - The zinc metalloprotease ZMPSTE24 is a constitutively and ubiquitously expressed host restriction factor that is responsible for limiting infection by a broad spectrum of enveloped viruses, including influenza A, vesicular stomatitis, zika, ebola, Sindbis, cowpox, and vaccinia viruses, but not murine leukemia or adenovirus. Antiviral function is independent of ZMPSTE24 enzymatic activity. Protein interaction and genetic complementation studies indicate that ZMPSTE24 is a component of a common antiviral pathway that is associated with interferon induced transmembrane proteins. In vivo studies with zmpste24-deficient mice demonstrate the importance of ZMPSTE24 for antiviral defense. PMID- 28594572 TI - Effect of High-Pressure Processing on Human Noroviruses in Laboratory Contaminated Oysters by Bio-Accumulation. AB - The contamination of oysters with human noroviruses poses a human health risk, since oysters are often consumed raw. In this study, human norovirus genogroup II was allowed to bio-accumulate in oysters, and then the effect of high-pressure processing (HPP) on human noroviruses in oysters was determined through a polymerase chain reaction (PCR)-based method with enzymatic pretreatment to distinguish infectious noroviruses. As a result, oysters could be artificially contaminated to a detectable level of norovirus genome by the reverse transcription-PCR. Concentrations of norovirus genome in laboratory-contaminated oysters were log normally distributed, as determined by the real-time PCR, suggesting that artificial contamination by bio-accumulation was successful. In two independent HPP trials, a 1.87 log10 and 1.99 log10 reduction of norovirus GII.17 genome concentration was observed after HPP at 400 MPa for 5 min at 25 degrees C. These data suggest that HPP is a promising process of inactivation of infectious human noroviruses in oysters. To our knowledge, this is the first report to investigate the effect of HPP on laboratory-contaminated noroviruses in oysters. PMID- 28594573 TI - Activation of the Integrated Stress Response and Metabolic Dysfunction in a Murine Model of Sleep Apnea. AB - Intermittent hypoxia (IH) induces activation of the integrated stress response (ISR), but its role in IH-induced visceral white adipose tissue (vWAT) insulin resistance is unknown. CHOP is activated by chronic ISR, whereas GADD34 dephosphorylates the subunit of translation initiation factor 2 (eIF2alpha), leading to termination of the ISR. We hypothesized that CHOP/Gadd34 null mice would not manifest evidence of insulin resistance after IH exposures. Eight-week old CHOP/GADD34-/- (double mutant [DM]) and wild-type (WT) littermates were randomly assigned to IH or room air (RA) exposures for 6 weeks. Glucose and insulin tolerance tests were performed, and regulatory T cells (Tregs) and macrophages in vWAT were assessed. Phosphorylated eIF2alpha:total eIF2alpha, ATF4, XBP1 expression, and insulin-induced pAKT/AKT expression changes were examined in vWATs. Single GADD34-/- and PERK+/- mice were also evaluated. Body weight and vWAT mass were reduced in DM and WT mice after IH. M1/M2 macrophages and inflammatory macrophages (Ly-6chigh) were significantly increased in WT vWAT but remained unchanged in DM mice. Tregs were significantly decreased in WT vWAT but not in DM mice. Systemic insulin and glucose tolerance tests revealed insulin resistance in IH-WT but not in IH-DM mice. Similarly, decreased pAKT/AKT responses to exogenous insulin emerged in IH-WT compared with RA-WT mice, whereas no significant differences emerged in IH-DM compared with DM-RA. Chronic ISR activation appears to contribute to the insulin resistance and vWAT inflammation that characteristically emerge after long-term IH exposures in a murine model of obstructive sleep apnea. PMID- 28594574 TI - A Geospatial Epidemiologic Analysis of Nontuberculous Mycobacterial Infection: An Ecological Study in Colorado. AB - RATIONALE: Nontuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms. Infection is thought to result primarily from exposure to soil and/or water sources. NTM disease prevalence varies greatly by geographic region, but the geospatial factors influencing this variation remain unclear. OBJECTIVES: To identify sociodemographic and environmental ecological risk factors associated with NTM infection and disease in Colorado. METHODS: We conducted an ecological study, combining data from patients with a diagnosis of NTM disease from National Jewish Health's electronic medical record database and ZIP code-level sociodemographic and environmental exposure data obtained from the U.S. Geological Survey, the U.S. Department of Agriculture, and the U.S. Census Bureau. We used spatial scan methods to identify high-risk clusters of NTM disease in Colorado. Ecological risk factors for disease were assessed using Bayesian generalized linear models assuming Poisson-distributed discrete responses (case counts by ZIP code) with the log link function. RESULTS: We identified two statistically significant high-risk clusters of disease. The primary cluster included ZIP codes in urban regions of Denver and Aurora, as well as regions south of Denver, on the east side of the Continental Divide. The secondary cluster was located on the west side of the Continental Divide in rural and mountainous regions. After adjustment for sociodemographic, drive time, and soil variables, we identified three watershed areas with relative risks of 12.2, 4.6, and 4.2 for slowly growing NTM infections compared with the mean disease risk for all watersheds in Colorado. This study population carries with it inherent limitations that may introduce bias. The lack of complete capture of NTM cases in Colorado may be related to factors such as disease severity, education and income levels, and insurance status. CONCLUSIONS: Our findings provide evidence that water derived from particular watersheds may be an important source of NTM exposure in Colorado. The watershed with the greatest risk of NTM disease contains the Dillon Reservoir. This reservoir is also the main water supply for major cities located in the two watersheds with the second and third highest disease risk in the state, suggesting an important possible source of infection. PMID- 28594576 TI - Provision of Nutrients to the Acutely Ill. Introducing the "Baby Stomach" Concept. PMID- 28594575 TI - Bolus Calculator Reduces Hypoglycemia in the Short Term and Fear of Hypoglycemia in the Long Term in Subjects with Type 1 Diabetes (CBMDI Study). AB - BACKGROUND: In a previous study we demonstrated improvement in metabolic control and reduction in hypoglycemia in people with type 1 diabetes on multiple daily injections, after having used a bolus calculator for 4 months. OBJECTIVE: To demonstrate whether (1) extending its use (2) or introducing it in the control group, previously subjected to treatment intensification, could further improve metabolic control and related psychological issues. METHODS: After the previous clinical trial, in which the subjects were randomized either to treatment with the calculator or to control group for 4 months, both groups used the calculator during an additional 4-month period. RESULTS: In the previous control group, after using the device, HbA1c did not improve (7.86% +/- 0.87% vs. 8.01% +/- 0.93%, P 0.215), although a significant decrease in postprandial hypoglycemia was observed (2.3 +/- 2 vs. 1.1 +/- 1.2/2 weeks, P 0.002). In the group in which the treatment was extended from 4 to 8 months, HbA1c did not improve either (7.61 +/- 0.58 vs. 7.73 +/- 0.65, P 0.209); however this group had a greater perceived treatment satisfaction (12.03 +/- 4.26 vs. 13.71 +/- 3.75, P 0.007) and a significant decrease in fear of hypoglycemia (28.24 +/- 8.18 basal vs. 25.66 +/- 8.02 at 8 months, P 0.026). CONCLUSIONS: The extension in the use of the calculator or its introduction in a previously intensified control group did not improve metabolic control, although it did confirm a decrease in hypoglycemic episodes in the short term, while the extension of its use to 8 months was associated with a reduction in fear of hypoglycemia and greater treatment satisfaction. PMID- 28594577 TI - Test-retest reliability and convergent validity of attention measures. AB - Recently, numerous pretest-posttest study designs have evaluated attention impairments and effectiveness of attention training. However, some of the attention tasks used in these studies show a lack of temporal stability analysis that reduces confidence in attention training outcomes. We aim to analyze the temporal stability within three attention tasks using different measures of attention (speed measures, accuracy measures, and global attention indexes) and the convergent validity between the measures. A total of 178 university students completed three attention tasks with a time interval of one week. Speed measures of attention showed higher test-retest reliability and higher convergence than accuracy measures. Accuracy measures showed nonnormal distributions and small range of variability to provide sufficient discrimination. Speed measures showed high practice effects. These results are consistent with previous studies of temporal stability and convergent validity of attention tasks. However, further studies of commonly used attention tasks are necessary in healthy and clinical samples. Additionally, attention training studies should include a control group to subtract the practice effect of speed measures. PMID- 28594578 TI - Cognitive reserve is not associated with improved performance in all cognitive domains. AB - Cognitive reserve beneficially affects cognitive performance, even into advanced age. However, the benefits afforded by high cognitive reserve may not extend to all cognitive domains. This study investigated whether cognitive reserve differentially affects performance on cognitive tasks, in 521 cognitively healthy individuals aged 60 to 98 years (Mage = 68, SD = 6.22, 287 female); years of education was used to index cognitive reserve. Cognitive performance variables assessed attention, executive functions, verbal memory, motor performance, orientation, perception of emotion, processing speed, and working memory. Bootstrapped regression analyses revealed that cognitive reserve was associated with attention, executive functions, verbal and working memory, and orientation; and not significantly related to emotion perception, processing speed, or motor performance. Cognitive reserve appears to differentially affect individual cognitive domains, which extends current theory that purports benefits for all domains. This finding highlights the possibility of using tests not (or minimally) associated with cognitive reserve, to screen for cognitive impairment and dementia in late life; these tests will likely best track brain health, free of compensatory neural mechanisms. PMID- 28594580 TI - The management of 'hard-to-prepare' colonoscopy patients. AB - INTRODUCTION: Effective bowel cleansing is crucial for high quality colonoscopy. A notable portion of patients still present with low quality bowel preparation prior to their colonoscopy, compromising the overall quality of their colonoscopy. Areas covered: This review focuses on the main strategies that can improve the cleansing quality with a special interest on those clinical conditions that have been associated with a poor bowel preparation quality, such as patients with chronic constipation, history of bowel resection, liver cirrhosis, diabetes mellitus and chronic kidney disease. The review provides a practical and evidence-based approach to help clinicians in the management of 'hard-to-prepare' patients. Expert commentary: In the past few years, the quality of colonoscopy has become a hot topic and bowel cleansing is a crucial part of it; however, the approach to patients with an increased risk of poor bowel preparation quality is still not always supported by high-quality evidence, since most of these patients are routinely excluded from the clinical studies. Trials focused on this subgroup of patients are recommended to provide tailored bowel preparation regimens and guarantee high-quality procedures. PMID- 28594579 TI - "From Snail Mode to Rocket Ship Mode": Adolescents and Young Adults' Experiences of Returning to Work and School After Hematopoietic Cell Transplantation. AB - PURPOSE: Resuming normal activities, such as work and school, is an important dimension of psychosocial recovery in cancer survivorship. Minimal data exist regarding adolescents or young adults' experiences of returning to school or work after cancer. The purpose of this study was to explore the processes of resuming work and school among adolescents and young adults after hematopoietic cell transplantation (HCT). METHODS: In-depth interviews were conducted with 18 adolescents and young adults, who were 15-29 years when they underwent HCT and 6 60 months post-transplant at study enrollment. Interview transcripts were systematically analyzed using Grounded Theory methodology. RESULTS: Participants described the context in which they attempted to return to work or school, specific challenges they faced, and strategies they developed in these environments. Feeling left behind from their peers and their pre-diagnosis selves, participants described "rushing" back to school and work impulsively, taking on too much too quickly while facing overwhelming physical and cognitive demands. Factors motivating this sense of urgency as well as barriers to successful and sustainable reentry in these settings are also addressed. CONCLUSION: Findings are discussed in the context of important opportunities for clinical management, age-appropriate interventions, and implications for future research. A better understanding of psychosocial late effects, specifically related to school and work trajectories after cancer, is critical to survivorship care for adolescent and young adult cancer survivors. PMID- 28594581 TI - Learning Curve Analysis of Laparoscopic Kasai Portoenterostomy. AB - OBJECTIVE: To compare the surgical outcomes of Kasai Portoenterostomy (PE) and investigate the learning curve of laparoscopic Kasai Portoenterostomy (Lap-PE). MATERIALS AND METHODS: Retrospective chart review of 80 cases of biliary atresia (type III) undergoing Lap-PE at Shenzhen Children's Hospital from January 2011 to June 2015, all of which were performed by the same surgical team. According to the operative sequences, the cases were equally divided into four phases (Phase I, II, III, and IV), which contain 20 cases in each. The age, weight, and gender, the volume of intraoperative blood loss, the postoperative clearance rate of bilirubin, the incidence of postoperative cholangitis, and the first and second year native liver survival rate were all reviewed. RESULTS: There was no significant difference among the four phases regarding age, weight at operation, and gender (P > .05). Statistical difference was observed with respect to operative time, the volume of intraoperative blood loss, the postoperative jaundice clearance, and the first and second year native liver survival rate among Phase III and IV compared to Phase I and II (P < .05), but showed no significant difference in neither the first two phases nor the latter two phases (P > .05). The incidence of postoperative cholangitis showed no significant variation among the four phases. CONCLUSION: A surgeon is able to become more experienced after performing approximately 40 laparoscopic Kasai Portoenterostomys. PMID- 28594582 TI - Profile-likelihood Confidence Intervals in Item Response Theory Models. AB - Confidence intervals (CIs) are fundamental inferential devices which quantify the sampling variability of parameter estimates. In item response theory, CIs have been primarily obtained from large-sample Wald-type approaches based on standard error estimates, derived from the observed or expected information matrix, after parameters have been estimated via maximum likelihood. An alternative approach to constructing CIs is to quantify sampling variability directly from the likelihood function with a technique known as profile-likelihood confidence intervals (PL CIs). In this article, we introduce PL CIs for item response theory models, compare PL CIs to classical large-sample Wald-type CIs, and demonstrate important distinctions among these CIs. CIs are then constructed for parameters directly estimated in the specified model and for transformed parameters which are often obtained post-estimation. Monte Carlo simulation results suggest that PL CIs perform consistently better than Wald-type CIs for both non-transformed and transformed parameters. PMID- 28594584 TI - Attribution Through the Layperson's Lens: Development and Preliminary Validation of an Inclusive, International Measure of Beliefs About the Causes of Mental Illness. AB - Attributions, or beliefs about the causes of mental illness, have traditionally been dichotomized based on their locus, controllability, specificity, and stability. However, scholars have introduced an alternative lay beliefs model identifying attributions related to specific biological, social, and spiritual attributions. This research describes the potential benefits of this alternative model and outlines the validation of a comprehensive, international measure of lay beliefs, the Mental Illness Attribution Questionnaire (MIAQ). Validation included piloting, qualitative rating, confirmatory factor analysis, and evaluation of internal consistency, convergent validity, and test-retest reliability with a sample of 680 U.S.-based international students representing 94 nations. Scales measured attributions related to supernatural forces, social stress, lifestyle, health, substance use, heredity, and personal weakness. This structure was tested across 3 conditions-schizophrenia, depression, and alcoholism-demonstrating strong psychometric properties. The lay beliefs model appears to closely reflect the manner in which laypersons attribute cause for mental health problems, making it a natural fit for community-based research. Further, its validation with 2 international samples supports its utility in diverse populations. Together, the results support the MIAQ as a valid and reliable measure of mental illness attribution with potential for examining help seeking and stigmatizing behavior across cultures. PMID- 28594586 TI - Differences in Function and Fracture Risk in Postmenopausal Women With and Without a Recent Distal Radius Fracture. AB - A distal radius fracture (DRF) is commonly the first fracture to occur in early postmenopausal women. The reasons for sustaining a DRF may be related to fall risk, bone fragility, or both. The objective of this study was to compare functional and fracture risk status in postmenopausal women with and without a recent DRF and explore the relationships between function, grip strength, and fracture risk status. Seventy-seven women a ges 50-78 with (n = 32) and without (n = 45) a history of DRF in the past 2 years participated. Balance, timed up and go (TUG), gait velocity, balance confidence, sit to stand, grip strength, and fracture risk were assessed. There was a significant group difference after controlling for physical activity level (Pillai's Trace, p < .05) where women with DRF had poorer outcomes on sit to stand, gait velocity, TUG, and fracture risk status. Grip strength was associated with functional tests, particularly in women with DRF. Women with a recent DRF demonstrated lower functional status and higher fracture risk compared to women without. Grip strength was associated with measures of function and fracture risk, and may complement screening tools for this population. PMID- 28594583 TI - Impact of Surgeon Specialty on Perioperative Outcomes of Surgery for Benign Esophageal Diseases: A NSQIP Analysis. AB - BACKGROUND: Surgery for benign esophageal disease is mostly performed either by general surgeons (GS) or cardiothoracic surgeons (CTS) in the United States. The purpose of this study was to evaluate the effect of surgeon specialty on perioperative outcomes of surgery for benign esophageal diseases. MATERIALS AND METHODS: We have conducted a retrospective analysis using the ACS-NSQIP during the period of 2006-2013. Patients who underwent paraesophageal hernia (PEH) repair, gastric fundoplication, or Heller esophagomyotomy were divided into two groups according to the specialty of the surgeon (GS or CTS). Outcomes compared between the two groups using multivariable logistic regression included 30-day mortality, overall morbidity, discharge destination, hospital length of stay (LOS), and readmission rates. RESULTS: Most of the surgeries were performed by general surgeons (PEH: 97.1%; fundoplication: 97.6%; Heller: 91.6%). Patients had lower comorbidities, better physical condition, and underwent a laparoscopic approach more frequently in the GS group. Regression analysis showed that GS group had a lower mortality rate (operating room, 0.44; 95% confidence interval [CI]: 0.23-0.86; P = .017), shorter LOS, and more home discharge for patients undergoing PEH repair. Mortality, morbidity, readmission, LOS, and home discharge were comparable between GS and CTS in fundoplication and Heller esophagomyotomy. CONCLUSION: GS perform most of esophageal surgeries for benign diseases. GS group has better outcomes in PEH repair compared with CTS, whereas there is no difference in the overall outcomes between GS and CTS in fundoplication and Heller esophagomyotomy. These results show that specialization is not always the answer to better outcomes. Difference in outcomes, however, might be related to disease severity, approach needed, or case volume. PMID- 28594585 TI - Impact of Palliative Medicine Involvement on End-of-Life Services for Patients With Cancer With In-Hospital Deaths. AB - PURPOSE: Palliative care (PC) has been shown to improve the quality of care and resource utilization for inpatients. We examined the relationship between PC consultation before and during final admission and patterns of care for dying patients at our tertiary cancer center. METHODS: We retrospectively reviewed adult patients with solid tumor cancer with a length of stay >= 3 days who died in hospital between December 2012 and November 2014. We recorded services, including laboratory testing, imaging, blood products, medications, diet orders, do not resuscitate orders, and consultations, delivered within 3 days of death. We assessed the differences among services delivered to patients with outpatient PC, inpatient PC only, and no PC involvement. RESULTS: Of 695 patients, 21% received outpatient PC, 46% received inpatient PC only, and 33% received no PC. During their final admission, 11.2% of patients received radiation therapy, and 12.5% received tumor-directed therapy, with no differences on the basis PC involvement ( P = .09 to .17). In the last 3 days of life, imaging tests occurred in 50.1%; patients with outpatient or inpatient-only PC underwent fewer studies (43.5% and 47.3%) than did those with no PC involvement (58.1%; P = .048). Do not resuscitate orders were in place within the 6 months before final admission at a greater rate for patients with outpatient PC (22%) than for patients with inpatient-only PC (8%) or those with no PC involvement (12%; P = .002). CONCLUSION: In this retrospective cohort of patients with solid tumor dying in hospital, few patients received cancer-directed therapies at the end of life. Involvement of PC was associated with a decrease in diagnostic testing and other services not clearly promoting comfort as patients approached death. PMID- 28594587 TI - Response to Indacaterol/Glycopyrronium (IND/GLY) by Sex in Patients with COPD: A Pooled Analysis from the IGNITE Program. AB - In this pooled analysis, we compared the effect of indacaterol/glycopyrronium (IND/GLY) by sex versus other commonly used chronic obstructive pulmonary disease (COPD) treatments and placebo. Male and female patients with moderate-to-very severe COPD who had participated in six randomized controlled trials were included in the analysis. Baseline demographics and disease characteristics were analyzed by sex, and any differences noted. The effects of IND/GLY versus salmeterol/fluticasone (SFC), glycopyrronium, tiotropium and placebo, on lung function and the patient-reported outcomes (health status, dyspnea, rescue medication use and symptoms) were assessed by sex after 26 weeks treatment. The analysis population comprised 4719 men and 1389 women. Most baseline parameters differed significantly between men and women. Nonetheless, despite these differences in baseline characteristics, IND/GLY significantly improved lung function versus placebo (p < 0.0001) and all active comparators (p < 0.01) in men and women. Overall, IND/GLY showed better improvement in dyspnea and health status compared with all other treatments in both sex. Greater reduction of rescue medication use was observed with IND/GLY versus placebo and other treatments (all p < 0.01 expect IND/GLY versus SFC). Although some variability was observed, improvements in health status, dyspnea, rescue medication use and symptoms were generally larger in women than in men. Irrespective of sex, IND/GLY provided superior efficacy to monotherapy or SFC in both men and women. Small differences in efficacy response by sex were observed, which should be evaluated further in prospective clinical studies. Nevertheless, the benefits observed with IND/GLY confirm dual bronchodilator as the preferred therapy in patients with moderate-to-very-severe COPD regardless of sex. PMID- 28594588 TI - Impact of Bedside Tracheostomy on Procalcitonin Kinetics in Critically Ill Patients. AB - BACKGROUND: Critically ill patients are particularly vulnerable to invasive procedures and complications; however, tracheostomy is frequently performed in the intensive care unit (ICU). We analyzed the effects of tracheostomy on procalcitonin (PCT) kinetics and investigated whether PCT could reliably predict septic complications after tracheostomy. METHODS: We retrospectively identified 134 patients who underwent bedside tracheostomy during their ICU stay at a Japanese university hospital from October 2010 to December 2015. We extracted PCT data from the day of the procedure (day 0) to postoperative day 2 and defined alert PCT as a PCT level >=0.5 ng/mL, which had not decreased from the previous day. We divided patients into the following groups: nonevent, aseptic complication, and septic complication. RESULTS: Twelve (9.2%) patients developed acute aseptic complications, and 12 (9.2%) patients developed septic complications. In the nonevent group, the PCT value decreased continuously in the initial PCT >= 0.5 ng/mL subgroup ( P < .001, P <.001 for trend). In contrast, significant changes were not observed in the initial PCT < 0.5 ng/mL subgroup. Significant differences and an upward trend in alert PCT incidence rate existed between the groups ( P < .001, P < .001 for trend): nonevent group, 5.5%; aseptic complication group, 41.7%; and septic complication group, 66.7%. In a multivariate linear regression model, septic complications were independently associated with PCT change at postoperative days 1 and 2 (adjusted beta = 3.58, P < .001; adjusted beta = 9.84, P < .001, respectively). Procalcitonin predicted septic complications more accurately than C-reactive protein, with the area under the receiver operating characteristic curves of 0.8 versus 0.63 ( P = .058) and 0.91 versus 0.69 ( P = .036) at postoperative days 1 and 2, respectively. CONCLUSION: Our results demonstrated that PCT was not elevated after uncomplicated surgical tracheostomy in critically ill patients. PMID- 28594589 TI - MEK inhibitors in oncology: a patent review (2015-Present). AB - INTRODUCTION: The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways have been identified as promising therapeutic targets for cancer therapy. Over-activation of these pathways and their components including gene mutations has been considered as one of the major causes of melanoma. Mitogen-activated protein kinase (MEK) is a downstream kinase of RAS pathway found in two different forms MEK1/2. The MEK inhibitors in combination with other kinase/mutant gene inhibitors have shown promising results in patients with metastatic melanoma. Areas covered: A comprehensive review of the patent literature (2015 - Present) on MEK inhibitors, their combinations with other kinase inhibitors and structural insights has been highlighted. Expert opinion: Recently mitogen-activated protein kinase (MEK) inhibitors have attracted considerable interest in oncology especially in melanoma. The MEK inhibitors showed promising results in patients with metastatic melanoma harboring mutant genes such as BRAF, KRAS. The MEK1/2 inhibitors in combination with BRAF, KRAS and/or PI3K inhibitors showed promising results in mutated colorectal, pancreatic adenocarcinoma, solid tumor, and relapsed/refractory melanoma. The combination delays the onset of acquired resistance, resulting in increased progression-free and overall survival. The combination and/or multi-targeted kinase/mutant gene inhibitors may be a therapeutic option for the personalized cancer treatment of patients with relapsed or refractory multiple myeloma. PMID- 28594590 TI - The Past, Present, and Future of Nutrition and Cancer: Part 1-Was A Nutritional Association Acknowledged a Century Ago? AB - Professional interest in the association of diet and nutrition with cancer first appeared in the early 1800s, if not before. Yet, progress in understanding this association over the past two centuries has been exceedingly slow and confusing. Without addressing this confusion, progress in using diet and nutrition information to prevent and even to treat cancer, will remain uncertain. To better understand this issue, the present paper is the first of two to explore the history of the diet and cancer relationship prior to a 1982 National Academy of Sciences (NAS) report on Diet, Nutrition and Cancer. This report was a milestone in the nutrition and cancer history because it was the first science-based, institutional report on this topic. But, based on the evidence cited in that report, it could be inferred that this topic was relatively new, perhaps beginning around 1940. While it attracted great public interest, it also generated great controversy, some of which was a natural response from affected industries. Exploring the history prior to 1940, therefore, might provide clues on the present-day confusion concerning the relationship between diet and cancer. This investigation asks three questions. First (the subject of this paper), was the relationship of nutrition to cancer even considered prior to 1940 and, if so, what was said? Second (the subject of the upcoming paper), assuming that nutrition was seriously considered, why then was it ignored or forgotten? Third, has the forgotten information contributed to the contemporary confusion surrounding the relationship to cancer? The answer to the first question, considered here, is that, yes, nutrition as a possible cause of cancer was not only hypothesized, it was a major topic for discussion in some quarters. But it also was a topic struggling to be heard among the authorities who had most of the power and influence in the professional cancer community. This paper documents that history and the corresponding struggle for this message to be heard. One figure, Frederick Hoffman, founder of the American Cancer Society and prodigious researcher, led much of that effort during the period of 1913-1943, but his contributions have remained almost totally unknown. PMID- 28594591 TI - Thirty Years of Translational Research in Zirconia Dental Implants: A Systematic Review of the Literature. AB - Thirty years of transitional research in zirconia (Zr) ceramics has led to significant improvements in the biomedical field, especially in dental implantology. Oral implants made of yttria-tetragonal zirconia polycrystals (Y TZP) because of their excellent mechanical properties, good biocompatibility, and esthetically acceptable color have emerged as an attractive metal-free alternative to titanium (Ti) implants. The aim of the review was to highlight the translation research in Zr dental implants that has been conducted over the past 3 decades using preclinical animal models. A computer search of electronic databases, primarily PubMed, was performed with the following key words: "zirconia ceramics AND animal trials," "ceramic implants AND animal trials," "zirconia AND animal trials," "zirconia AND in vivo animal trials," without any language restriction. However, the search was limited to animal trials discussing percentage bone-implant contact (%BIC) around zirconia implants/discs. This search resulted in 132 articles (reviews, in vivo studies, and animal studies) of potential interest. We restricted our search terms to "zirconia/ceramic," "bone implant-contact," and "animal trials" and found 29 relevant publications, which were then selected for full-text reading. Reasons for exclusion included the article's not being an animal study, being a review article, and not discussing %BIC around Zr implants/discs. Most of the studies investigated BIC around Zr in rabbits (30%), pigs (approximately 20%), dogs, sheep, and rats. This review of the literature shows that preclinical animal models can be successfully used to investigate osseointegration around Zr ceramics. Results of the reviewed studies demonstrated excellent %BIC around Zr implants. It should be noted that most of the studies investigated %BIC/removal torque under nonloading conditions, and results would have been somewhat different in functional loading situations because of inherent limitations of Zr ceramics. Further trials are needed to evaluate the performance of Zr ceramics in clinical conditions using implants designed and manufactured via novel techniques that enhance their biomechanical properties. PMID- 28594592 TI - Alveolar Ridge Preservation Using Allografts and Dense Polytetrafluoroethylene Membranes With Open Membrane Technique in Unhealthy Extraction Socket. AB - We evaluated the effectiveness of the open membrane technique using a high density polytetrafluoroethylene (dPTFE) membrane with freeze-dried bone allografts in damaged sockets for alveolar ridge preservation (ARP). This retrospective study included 26 sites from 20 patients who had received ARP for the placement of dental implants. ARP was conducted using dPTFE membrane with allografts on the day of extraction without primary closure. When the membrane was removed after 4 weeks, the newly formed reddish tissue at the grafted site was checked (first outcome, clinical evaluation). Four months after membrane removal, a core biopsy was performed from the center of the grafted site before implant placement (second outcome, histomorphometric evaluation). Radiographic measurements of alveolar bone changes between implant prosthesis delivery and the 1-year follow-up were obtained (third outcome, radiographic evaluation). A total of 23 sites from 18 patients had no complications during the follow-up period. Three sites from two patients were excluded because of early membrane removal. Newly formed reddish tissue was found at 15 sites, and partially formed tissue was found at 8 sites. Although we were unable to harvest bone core from all sites, histomorphometric analysis in 11 patients indicated that the mean area of new bone was 28.48% +/- 6.60%, that of the remaining graft particle was 27.68% +/ 9.18%, and that of fibrous tissue was 43.84% +/- 6.98%. The mean loss of marginal bone was 0.13 +/- 0.06 mm at the mesial area and 0.15 +/- 0.06 mm at the distal area, as assessed using radiographic evaluations. The results of this nonrandomized study suggest that this technique may be an appropriate procedure for ARP. Further studies with a control group and more subjectives can be designed based on this study. PMID- 28594593 TI - Critical issues in ALS case-control studies: the case of the Euro-MOTOR study. AB - : Backround: Political and sociocultural differences between countries can affect the outcome of clinical and epidemiological studies in ALS. Cross-national studies represent the ideal process by which risk factors can be assessed using the same methodology in different geographical areas. METHODS: A survey of three European countries (The Netherlands, Ireland and Italy) has been conducted in which incident ALS patients and matched controls were recruited in a population based study based on age, gender and area of residency, under the Euro-MOTOR systems biology programme of research. FINDINGS: We have identified strengths and limitations during the trajectory of the Euro-MOTOR study, from the research design to data analysis. We have analysed the implications of factors including cross-national differences in healthcare systems, sample size, types of matching, the definition of exposures and statistical analysis. CONCLUSIONS: Addressing critical methodological aspects of the design of the Euro-MOTOR project minimises bias and will facilitate scientific assessment of the independent role of well defined exposures. PMID- 28594594 TI - Laparoscopic-Assisted Extravesical Ureteral Reimplantation and Extracorporeal Ureteral Tapering Repair for Primary Obstructive Megaureter in Children. AB - BACKGROUND: Open surgery is a preferred treatment for primary obstructive megaureter (POM) in cases where the conservative treatment fails, with reported success rates of 90%-96%. OBJECTIVE: To describe our initial experience in the treatment of POM by laparoscopic-assisted extracorporeal ureteral tapering repair (EUTR) and laparoscopic ureteral extravesical reimplantation (LUER) by following Lich Gregoir technique as an alternative to open surgery. DESIGN, SETTING, AND PARTICIPANTS: A total of 7 patients with POM underwent laparoscopic-assisted extracorporeal ureteral tapering repair and ureteral extravesical reimplantation by following Lich Gregoir technique between 2011 and 2014. Postoperative follow up included the following: Renal and bladder ultrasound, voiding cystourethrogram (VCUG), and mercaptoacetyltriglycine (MAG3) renogram were done at 6 months. Outcome Measurements and Statistical Analysis: Statistical analysis was performed by using the SPSS software package (version 15.0; SPSS, Chicago, IL), and P < .05 was considered statistically significant. Paired tests and Wilcoxon test were performed to compare pre- and post-measures. RESULTS: LUER and EUTR were completed successfully in all patients without conversion. A postoperative MAG3 renogram showed nonobstructive pattern in all patients. Statistical analysis revealed significant differences before and after surgery in the average time of elimination on the MAG3 renogram (T1/2 59.10 minutes versus 13.57 minutes, P < .0001). After medium-term follow-up, the overall POM resolution was 100%. One case of vesicoureteral reflux (VUR) was found during VCUG control. A total of 7 patients were asymptomatic without recurrence of POM. CONCLUSION: Laparoscopic assisted extracorporeal ureteral tapering repair and ureteral extravesical reimplantation by following Lich Gregoir technique for POM constitutes a safe and good option when the first line of treatment fails, with a success rate similar to the open procedure. Nevertheless, larger randomized prospective trials and long-term follow-up are required to validate this technique. PMID- 28594595 TI - Validation of the Sexual Sensation Seeking Scale in Spanish Samples. AB - The aim of this study was to validate the Sexual Sensation Seeking Scale (SSSS; Kalichman, 2011) in Spanish samples. Two independent studies were conducted. In Study 1, we examined the factor structure of the SSSS in a sample of 1,272 heterosexual undergraduate students (40.0% men, 60.0% women). Results revealed a 2-factor structure. Factor 1 was related to physical sexual sensations and risky sexual behaviors and Factor 2 was related to exploratory or novel sex. A confirmatory factor analysis confirmed this factor structure in a sample of 373 community adults (33.8% men, 66.2% women). Two items were deleted, resulting in a final version composed of 8 items. This version showed good test-retest reliability and evidence of its concurrent validity. In Study 2, the factor structure was further confirmed in a sample of 1,596 university students (28.8% men, 71.2% women). More evidence of construct validity was provided, which revealed that higher levels of sexual sensation seeking were associated with more frequent sexual risk behaviors and poorer sexual health. Internal consistency reliability did not reach acceptable levels on all of the subscales. Results suggest that, although it has been used before, this scale needs a revision before its use in Spanish-speaking contexts. PMID- 28594596 TI - Mortality in Patients Admitted for Concurrent COPD Exacerbation and Pneumonia. PMID- 28594598 TI - Journal Honors Burles Johnson III, MD, PhD, As Recipient of the 2017 Journal of Clinical Oncology Young Investigator Award. PMID- 28594597 TI - A Cautionary Tale: Risks of Radiation Therapy De-Escalation in Pediatric Malignancies. PMID- 28594599 TI - Genetic Variants in the IL-4/IL-13 Pathway Influence Measles Vaccine Responses and Vaccine Failure in Children from Mozambique. AB - Despite effective measles vaccines, measles still causes severe morbidity and mortality worldwide, particularly in developing countries. The Th2 pathway involving interleukin (IL)-4 and IL-13 cytokines, and their receptor IL-4Ralpha, play important roles in the Th1/Th2 balance and antibody production. A Th2 skewing of the cytokine milieu may affect vaccine responses. We investigated IL 4, IL-13, and IL-4Ralpha polymorphisms and their impact on measles IgG responses and measles vaccine failure, in two separate cohorts: 12-month-old Australian children immunized with measles-mumps-rubella vaccine (n = 137) and a case/control cohort of children aged 6 months-14 years from Mozambique, Africa (n = 89), some of whom were vaccinated, but still contracted measles (vaccine failure). We found that IL-4Ralpha haplotypes for Val75Ile, Ser503Pro, and Arg576Gln were associated with measles IgG in Mozambican children (p = 0.016 and p = 0.032 for Val.Pro.Arg and Val.Ser.Arg, respectively), but not Australian children. IL-4Ralpha 503Pro was more prevalent in Mozambique vaccine failure cases compared with controls (p = 0.008). We showed that the impact of Th2 genes on measles vaccine responses differs between ethnicities and IL-4Ralpha polymorphisms may work in combination to affect measles antibody responses and vaccine failure in Mozambican children. Studies in this area are particularly important in developing countries like Mozambique where measles is still a major health issue. PMID- 28594600 TI - Psychosocial and environmental factors in the prognosis of individuals with chronic pain and comorbid mental health. AB - Chronic pain has considerable medical, social, and economic implications as its high prevalence rate and negative societal burden provides justification that it is a major health issue. The value of understanding psychological, social, and environmental factors in chronic pain has become widely recognized and accepted as a biopsychosocial phenomenon in which the social work perspective offers a valuable lens. Through the critical application of systems theory and ecological perspective, accompanied with the diathesis stress model, this article examines psychosocial and environmental influences as being contributory factors in the prognosis of individuals with chronic pain and comorbid mental health disorders. The social work profession will also be explored as playing a definite role in addressing elements pertaining to pain management depicted from these theories. Lastly, implications for research, policy, and practice will be reviewed to better understand the association between psychosocial and environmental influences of individuals with chronic pain and comorbid mental health issues. PMID- 28594601 TI - A parenting education program for women in treatment for opioid-use disorder at an outpatient medical practice. AB - Opioid use during pregnancy poses serious risks for the mother and the unborn child. Opioid-use disorder may be managed with medication-assisted treatment (MAT) in an outpatient setting, but few MAT practices specifically address the challenges faced by pregnant women. This article describes a medical office-based educational support group for women in MAT for opioid-use disorder who were pregnant and/or parenting young children. Focus groups were conducted to elicit patient feedback. Women indicated that they found the educational support groups beneficial and offered suggestions. In-office educational support groups for pregnant women in treatment for opioid-use disorder are feasible and well received. PMID- 28594602 TI - Randomized Pilot of an Anxiety Sensitivity-Based Intervention for Individuals in a Substance Use Day Program. AB - Anxiety sensitivity (AS), or the tendency to appraise physical symptoms as intolerable or dangerous, may maintain the cycle between co-occurring anxiety and substance use disorders. This study examined preliminary efficacy of a brief intervention targeting AS for individuals with heterogeneous substance use disorders. Forty-one patients with high AS entering an addictions day program were randomized to treatment as usual (TAU) or to TAU plus a nine-hour AS-focused intervention that consisted of interoceptive exposures, psychoeducation about the cycle of problematic substance use and anxiety, and a single session of cognitive challenging (e.g., reviewing common cognitive distortions and decatastrophizing anxiety symptoms). Mixed-effects intent-to-treat models suggested that participants in the AS condition showed greater decreases in AS at post treatment, but this effect was lost at follow-up three months later. Intervention conditions did not differ in change in percent days abstinent or self-reported anxiety, with both conditions showing significant improvement at post-treatment. Results suggest that the nine-hour AS-focused intervention led to a short-term benefit over TAU alone, but this benefit was not sustained at three months' follow-up. Future AS interventions may need to target specific subconstructs of AS for selected populations, or target emotional distress tolerance more broadly. PMID- 28594605 TI - MOONLIGHT, Directed by Barry Jenkins. PMID- 28594603 TI - Behavior Problems and Psychiatric Diagnoses in Girls with Gender Identity Disorder: A Follow-Up Study. AB - This study evaluated the presence of clinical range behavior problems and psychiatric diagnoses in 25 girls referred for gender identity disorder (GID) in childhood (mean age: 8.88 years) at the time of follow-up in adolescence or adulthood (mean age: 23.2 years). At follow-up, three (12%) of the girls were judged to have persistent GID based on DSM-IV criteria. With regard to behavior problems at follow-up, 39.1% of the girls had a clinical range score on either the Child Behavior Checklist or Adult Behavior Checklist as rated by their mothers, and 33.3% had a clinical range score on either the Youth Self-Report or the Adult Self-Report. On either the Diagnostic Interview for Children and Adolescents or the Diagnostic Interview Schedule, the girls had, on average, 2.67 diagnoses (range: 0-10); 46% met criteria for three or more diagnoses. From the childhood assessment, five variables were significantly associated with a composite Psychopathology Index (PI) at follow-up: a lower IQ, living in a non two-parent or reconstituted family, a composite behavior problem index, and poor peer relations. At follow-up, degree of concurrent homoeroticism and a composite index of gender dysphoria were both associated with the composite PI. Girls with GID show a psychiatric vulnerability at the time of follow-up in late adolescence or adulthood, although there was considerable variation in their general well being. PMID- 28594607 TI - The role of mindfulness skills in terms of anxiety-related cognitive risk factors among college students with problematic alcohol use. AB - BACKGROUND: The aim of the current study was to examine the associations between the specific mindfulness skills of observing, describing, awareness, nonjudgment, and nonreactivity in terms of anxiety sensitivity (AS), distress tolerance (DT), and intolerance of uncertainty (IU) among college students with problematic alcohol use. METHODS: Participants were 202 (69.3% male; Mage = 18.96, SD = 2.24, range = 18-45 years) undergraduate college students with problematic alcohol use who completed self-report measures for course credit. RESULTS: Results indicated that after controlling for the effects of gender, smoking status, marijuana use status, and negative affectivity, greater use of the mindfulness skill of observing was associated with higher AS, greater describing was associated with lower AS and higher DT, greater nonjudgment was associated with lower AS and IU and higher DT, and greater nonreactivity was associated with increased DT. Awareness did not significantly predict any of the examined risk factors. CONCLUSIONS: These results suggest that specific mindfulness skills are associated with a greater tolerance of physiological, emotional, and uncertain states. An important next step will be to examine whether mindfulness skills are associated with decreased problematic alcohol use due to improvements in these anxiety-related risk factors. PMID- 28594608 TI - Etiology of Onychomycosis in Patients in Turkey. AB - BACKGROUND: Onychomycosis is a chronic nail infection caused by dermatophytes, Candida, nondermatophyte molds, and Trichosporon. The purpose of this study was to identify the underlying pathogen in patients with onychomycosis in our region. METHODS: A retrospective analysis of 225 cases with onychomycosis, diagnosed over a 27-month period at the Department of Dermatoveneorology, Bezmialem Vakif University, Istanbul, Turkey, and confirmed with culture, was performed. RESULTS: Patient age ranged from 2 to 87 years (mean +/- SD, 41.59 +/- 17.61), and female patients were more commonly affected (120 cases, 53.3%) than male patients. Lateral and distal subungual onychomycosis was detected in 180 cases (80%). Etiologic agents were as follows: Trichophyton rubrum, 77 cases (34.2%); Trichophyton mentagrophytes, 30 cases (13.3%), Candida albicans, 28 cases (12.4%); Candida parapsilosis, 25 cases (11.1%); Acremonium species, one case (0.4%); Aspergillus species, two cases (0.9%); Fusarium species, four cases (1.3%); and Trichosporon species, three cases (1.3%). CONCLUSIONS: The most frequent isolated etiologic agents were T rubrum for toenails and C albicans for fingernails. PMID- 28594609 TI - Next-Generation Sequencing Analysis of the Diversity of Human Noroviruses in Japanese Oysters. AB - To obtain detailed information on the diversity of infectious norovirus in oysters (Crossostrea gigas), oysters obtained from fish producers at six different sites (sites A, B, C, D, E, and F) in Japan were analyzed once a month during the period spanning October 2015-February 2016. To avoid false-positive polymerase chain reaction (PCR) results derived from noninfectious virus particles, samples were pretreated with RNase before reverse transcription-PCR (RT-PCR). RT-PCR products were subjected to next-generation sequencing to identify norovirus genotypes in oysters. As a result, all GI genotypes were detected in the investigational period. The detection rate and proportion of norovirus GI genotypes differed depending on the sampling site and month. GII.3, GII.4, GII.13, GII.16, and GII.17 were detected in this study. Both the detection rate and proportion of norovirus GII genotypes differed depending on the sampling site and month. In total, the detection rate and proportion of GII.3 were highest from October to December among all detected genotypes. In January, the detection rates of GII.4 and GII.17 reached the same level as that of GII.3. The proportion of GII.17 was relatively lower from October to December, whereas it was the highest in January. To our knowledge, this is the first investigation on noroviruses in oysters in Japan, based on a method that can distinguish their infectivity. PMID- 28594612 TI - What compassion means to me. AB - In the first instalment in a series of blogs, Clare Price-Dowd, Senior Programme Lead, NHS Leadership Academy, Leeds, talks about her personal experience of compassionate nursing and discusses why it is so important in the NHS. PMID- 28594611 TI - Healthcare students' experiences when integrating e-learning and flipped classroom instructional approaches. AB - This article describes the experiences of undergraduate healthcare students taking a module adopting a 'flipped classroom' approach. Evidence suggests that flipped classroom as a pedagogical tool has the potential to enhance student learning and to improve healthcare practice. This innovative approach was implemented within a healthcare curriculum and in a module looking at public health delivered at the beginning of year two of a 3-year programme. The focus of the evaluation study was on the e-learning resources used in the module and the student experiences of these; with a specific aim to evaluate this element of the flipped classroom approach. A mixed-methods approach was adopted and data collected using questionnaires, which were distributed across a whole cohort, and a focus group involving ten participants. Statistical analysis of the data showed the positive student experience of engaging with e-learning. The thematic analysis identified two key themes; factors influencing a positive learning experience and the challenges when developing e-learning within a flipped classroom approach. The study provides guidance for further developments and improvements when developing e-learning as part of the flipped classroom approach. PMID- 28594613 TI - Long-term sustainability. PMID- 28594614 TI - Establishing a nurse-led pelvic floor and functional bowel service. AB - Jane Turner, Colorectal Nurse Specialist, Cardiff and Vale University Health Board, was awarded a travel scholarship by the Florence Nightingale Foundation. She used it to find out about the running of nurse-led pelvic floor and functional bowel services around the UK. PMID- 28594616 TI - Psychological effects of skin disease: the psoriasis exemplar. PMID- 28594615 TI - Oral decontamination techniques and ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) is one of the major nosocomial infections in the intensive care unit (ICU), contributing to increased mortality and morbidity. Studies have shown that oral decontamination through the use of mechanical and pharmacological agents significantly reduces the incidence of VAP, but oral care practices in ICUs are not consistent. A double-blind randomised controlled trial was undertaken in the medical ICU of a tertiary care centre in India, to assess the efficacy of a toothbrush-based oral care technique in reducing incidence of VAP. Tooth-brushing with concurrent suctioning technique was not proved to be superior to mouth-swabbing. The greatest risk factor for developing VAP was the number of ventilator days (length of time on a ventilator). There was a statistical association between gender and presence of antibiotics with VAP. PMID- 28594617 TI - A disclosure scheme for protecting the victims of domestic violence. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, explains how the Domestic Violence Disclosure Scheme aims to protect potential victims by allowing disclosure of a partner's previous crimes. PMID- 28594618 TI - Complaints processes: moving forwards. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, discusses the issue of complaints handling, and shares a new approach aimed at making training on the process more memorable. PMID- 28594619 TI - Managing acute respiratory tract infections in children. AB - Respiratory tract infections (RTIs), including community-acquired pneumonia (CAP), bronchiolitis, viral-induced wheeze and croup, account for more primary care consultations than any other illness group and are the most likely reason for a parent or carer to contact a health professional. The majority of RTIs in fully immunised children are usually self-limiting. However, in a small percentage of children RTIs may become life threatening and it is crucial that all front-line health professionals are able to recognise and identify these children who are at risk of deterioration. To ensure this, fast recognition of symptoms is important, with care taken to exclude any 'red flag' features that may prompt a referral to secondary care. Nurses are well placed to reassure and support families, and to provide education regarding the facts about fever, the appropriate use of a single antipyretic medication, how to avoid dehydration in children with RTIs, and the beneficial role of immunisation in preventing infection. It is also important to explain in cases of CAP where antibiotics are necessary about how soon to expect a response, any side effects from antibiotics, and to provide 'safety net advice' on when to consider reassessment for the child. An illustrative case study is included to highlight some of the challenges that are likely to be encountered in clinical practice. PMID- 28594620 TI - Abdominal pain-related functional gastrointestinal disorders in children. AB - Recurrent abdominal pain is a common presentation in children and mostly non organic in origin. Nearly one-fifth of the childhood population are known to suffer from it worldwide, although only 50% of these may seek consultation with a health professional. Non-organic recurrent abdominal pain encompasses four main conditions broadly labelled as abdominal pain-related functional gastrointestinal disorders (FGIDs). These are diagnosed following exclusion of organic pathologies and by symptom concordance with defined parameters, published as the Rome IV criteria for FGIDs. Appropriate evaluation includes assessment for 'red flag' manifestations to rule out organic causes. Appropriate review of social and family circumstances is vital to identify triggers and protective factors. Management is based on explanation, reassurance and therapeutic interventions that need to be decided on an individual basis. Treatment focuses primarily on dietary and biopsychosocial interventions, with a minimal role for pharmacological agents. A case study is included to highlight some of the challenges that may arise while managing abdominal pain-related FGIDs. Nurses play a vital role in early identification, providing support and education to children and their families. There is increasing evidence for the effectiveness of nurse-led services in managing these disorders, as well as providing continuity of care. PMID- 28594621 TI - An undergraduate placemement at the St John Eye Hospital, Jerusalem. AB - The elective placement is an opportunity for nursing undergraduates to independently decide where to go and what to do to widen their clinical experience. Being able to decide on and participate in an elective placement provides student nurses with a chance to work in a different area and explore personal ambitions. This reflective account examines a student nurse's experiences while on an elective placement at an eye hospital in East Jerusalem and the West Bank. PMID- 28594622 TI - Making the NHS Litigation Authority more effective as NHS Resolution. AB - John Tingle, Reader in Health Law at Nottingham Trent University, discusses a recent publication of the NHS Litigation Authority, now renamed NHS Resolution, which points to realignment of activity and focus in core areas. PMID- 28594624 TI - Recognising outstanding care. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses a report from the Care Quality Commission that sets out some examples of good and outstanding care. PMID- 28594623 TI - How work environments affect nurse burnout and patient outcomes. PMID- 28594625 TI - Music in the dermatology theatre: what do patients want to listen to? PMID- 28594626 TI - Proposed changes to nurse education: get ready to have your say. AB - Elizabeth Rosser, Deputy Dean (Education and Professional Practice) and Professor of Nursing at Bournemouth University, examines the radical changes to undergraduate nurse education currently proposed. PMID- 28594627 TI - Blood donation: I'm there. PMID- 28594628 TI - Three-Dimensional Versus Two-Dimensional Laparoscopic Cholecystectomy: A Systematic Review. AB - BACKGROUND AND AIMS: In the last decades, the three-dimensional (3D) imaging systems have been introduced in an attempt to improve depth perception and image quality during laparoscopic cholecystectomy interventions. The goal of our systematic review was to provide enough convincing evidences on superiority and benefits of 3D over two-dimensional (2D) imaging systems, from both surgeon's and patient's point of view, justifying the cost-effectiveness of newly developed 3D systems. METHODS: Two authors separately performed a full literature search aiming to find randomized controlled trials evaluating the advantages and disadvantages of 3D versus 2D laparoscopic cholecystectomy procedures. The patients who underwent elective laparoscopic cholecystectomy were included in this study irrespective of their age and sex. Differing opinions between the two authors were reviewed by the third author. RESULTS: A total of 912 articles were initially reviewed by their titles and abstracts for eligibility. After being filtered through predetermined inclusion and exclusion criteria, and excluding the duplicates, only 10 studies underwent the final evaluation by the full text assessment. Eventually, only five randomized controlled studies were included in this study. Operative time and depth perception/image quality were set as the primary and secondary outcomes, respectively. The operative time was significantly shorter in 60% of the studies. Of five studies that evaluated the depth perception and image quality, all five (100%) reported a better depth perception and image quality. CONCLUSIONS: 3D imaging systems tend to shorten the operative time compared to 2D systems and result in a better depth perception. More studies and investigations with bigger cohort sizes and using unique 3D visual systems are necessary to justify the cost-effectiveness of the new, more expensive 3D systems. PMID- 28594629 TI - Adverse Effects of Outcome Monitoring Feedback in Patients With Personality Disorders: A Randomized Controlled Trial in Day Treatment and Inpatient Settings. AB - This study aimed to evaluate the differential effect of outcome monitoring feedback to therapists and to patients on outcomes in cluster B, cluster C, and personality disorder not otherwise specified (PD-NOS) patients. Day treatment patients (n = 112) and inpatients (n = 94) were randomly assigned to a feedback to therapist (FbT), feedback to therapist and patient (FbTP), or no feedback (NFb) condition. Feedback was based on weekly administrations of the Outcome Questionnaire-45 (OQ-45). In cluster B and PD-NOS patients FbTP resulted in increased OQ-45 scores during the first 6 months of therapy for not on track (NOT) patients. In cluster C patients, no adverse effects of feedback were found. These results suggest that for certain personality disorder patient groups, providing feedback during treatment may not always be beneficial, although more research is needed to further assess these effects. PMID- 28594630 TI - Psychopathy and Deviant Workplace Behavior: A Comparison of Two Psychopathy Models. AB - Although psychopathy is an interpersonally harmful construct, few studies have compared different psycho athy models in predicting different types of workplace deviance. We examined how the Triarchic Psychopathy Model (TRI-PM) and the Self Report Psychopathy-Short Form (SRP-SF) predicted deviant workplace behaviors in two forms: sexual harassment and deviant work behaviors. Using structural equations modeling, the latent factor of psychopathy was predictive for both types of deviant workplace behavior. Specifically, the SRP-SF signif cantly predicted both measures of deviant workplace behavior. With respect to the TRI PM, meanness and disinhibition significantly predicted higher scores of workplace deviance and workplace sexual harassment measures. Future research needs to investigate the influence of psychopathy on deviant workplace behaviors, and consider the measures they use when they investigate these constructs. PMID- 28594631 TI - The Role of Dimensional Personality Psychopathology in a Forensic Inpatient Psychiatric Setting. AB - The Minnesota Multiphasic Personality Inventory-2 Restructured Form is a widely used measure of psychopathology and includes the Personality Psychopathology Five (PSY-5) scales, which measure dimensional maladaptive personality traits similar to those in the DSM-5 alternative model for personality disorder (PD) diagnosis. The current study evaluated the role of these dimensional personality psychopathology characteristics in a sample of 1,110 inpatients in a forensic psychiatric setting, where personality psychopathology plays a significant but understudied role. The authors examined the extent to which dimensional personality psychopathology characteristics (as measured by the PSY-5) were associated with borderline and antisocial PD diagnoses and institutional aggression. Results support the usefulness of measuring dimensional personality traits for understanding PD diagnoses, as well as incidents of institutional aggression. More specifically, the PSY-5 scales appear to measure the core features of borderline and antisocial PDs. This study supports the inclusion of dimensional personality assessment in understanding aggressive behavior in inpatient settings. PMID- 28594632 TI - High Prevalence of Physical Pain Among Treatment-Seeking Individuals With Borderline Personality Disorder. AB - Research has demonstrated that about 30% of chronic pain patients suffer from borderline personality disorder (BPD), yet pain is not often discussed in research on the treatment of BPD. Sixty-five patients entering outpatient treatment for BPD were assessed at baseline for the prevalence of DSM-IV lifetime pain disorder, current medical problems, and the experience of current pain as measured by the McGill Pain Questionnaire. DSM-IV lifetime pain disorder diagnosis was present in 65% of patients. Current pain was experienced by 89% of participants, with intensity ranging from mild (19%) to excruciating (2%). Some individuals (21.5%) also reported experiencing daily medical problems in the past month prior to entering treatment. Physical pain is highly prevalent among treatment-seeking individuals with BPD. This pain phenomenon should be considered during treatment to help prevent a lifetime of functional impairment, including the possibility of abusing substances as a maladaptive coping mechanism. PMID- 28594633 TI - The Influence of Emotional State on Learning From Reward and Punishment in Borderline Personality Disorder. AB - Despite preliminary evidence that individuals with borderline personality disorder (BPD) demonstrate deficits in learning from corrective feedback, no studies have examined the influence of emotional state on these learning deficits in BPD. This laboratory study examined the influence of negative emotions on learning among participants with BPD (n = 17), compared with clinical (past-year mood/anxiety disorder; n = 20) and healthy (n = 23) controls. Participants completed a reinforcement learning task before and after a negative emotion induction. The learning task involved presenting pairs of stimuli with probabilistic feedback in the training phase, and subsequently assessing accuracy for choosing previously rewarded stimuli or avoiding previously punished stimuli. ANOVAs and ANCOVAs revealed no significant between-group differences in overall learning accuracy. However, there was an effect of group in the ANCOVA for postemotion induction high-conflict punishment learning accuracy, with the BPD group showing greater decrements in learning accuracy than controls following the negative emotion induction. PMID- 28594634 TI - Dissemination of blaOXA-23, blaOXA-24, blaOXA-58, and blaNDM-1 Genes of Acinetobacter baumannii Isolates from Four Tertiary Hospitals in Thailand. AB - Acinetobacter baumannii is a major threat to public health due to the emergence and dissemination of antibiotic-resistant strains. The purpose of this study was to determine the molecular epidemiology of antibiotic-resistant A. baumannii isolates collected from four tertiary hospitals in Thailand during the period November 2013-February 2015. We screened 339 A. baumannii, nonrepetitive clinical isolates to determine drug susceptibility. Among all isolates, we found that 7.9% was nondrug-resistant A. baumannii (NR-AB). Carbapenem-resistant A. baumannii (CR AB) strains accounted for 84.9% of the total isolates, with extensively drug resistant A. baumannii (XDR-AB) accounting for 7.9% of the total isolates. We further investigated class D carbapenemase genes using multiplex-PCR amplification and class B metallo-beta-lactamase genes, including blaIMP, blaVIM, and blaNDM-1 genes, using PCR and sequencing methods. We found that 300 (88.5%) isolates carried acquired class D carbapenemase genes, including blaOXA-23 (82.6%), blaOXA-24 (0.3%), and blaOXA-58 (6.5%). The genes blaIMP and blaVIM were not detected in any isolates. The blaNDM-1 was detected in 31 isolates from two hospitals (9.1%). All of the blaNDM-1-positive A. baumannii (NDM-AB) had ISAba125 sequences upstream of the blaNDM-1 gene. A coexistence of three resistance genes blaOXA-23-blaOXA-58-blaNDM-1-was found in one isolate. A repetitive element palindromic-PCR (REP-PCR) revealed that all A. baumannii isolates were genetically diverse and could be divided into 33 genotypes. Only three genotypes were found to be predominant in all hospitals. Data from our study indicate the widespread emergence of multiple resistance determinants in A. baumannii isolates in Thailand, suggesting the need for more stringent infection control measures. PMID- 28594635 TI - Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections in a Chinese Children's Hospital: Predominance of New Delhi Metallo-beta Lactamase-1. AB - The spread of carbapenem-resistant Klebsiella pneumoniae (CRKp) has become a significant problem worldwide; however, relevant data in children are limited. We performed a retrospective study to better understand the epidemiology of CRKp bloodstream infections at Beijing Children's Hospital. A total of 164 K. pneumoniae strains were collected from blood cultures between January 2011 and September 2014, of which 52 (31.7%) were CRKp strains. All 52 CRKp strains were multidrug resistant; 46 (88.5%) and 49 (94.2%) isolates were resistant to meropenem and imipenem, respectively. Low rates of resistance to amikacin (5.8%), levofloxacin (7.7%), and ciprofloxacin (15.4%) were observed. All isolates were susceptible to colistin. Among the tested carbapenem resistance genes, the predominant gene was blaNDM-1, detected in 28 (53.8%) isolates, followed by blaIMP-4 (19, 36.5%) and blaKPC-2 (4, 7.7%). Multilocus sequence typing identified 31 sequence types (STs), the most predominant of which was ST782 (9, 29.0%). All ST782 strains were New Delhi metallo-beta-lactamase-1 (NDM-1) producing. Four novel STs (ST2010, ST2011, ST2012, and ST2013) and two novel alleles (phoE243 and tonB324) were also detected. Hematologic disease was the most common underlying disease (73.1%). All children received initial empirical therapy. A total of 59.6% (31/52) patients received inappropriate empirical therapy, and 45.2% (14/31) changed antimicrobial therapy after blood culture results were obtained. The overall mortality rate was 11.5%. In conclusion, we observed a high rate of CRKp isolates collected from blood cultures and the predominance of NDM-1-producing K. pneumoniae among children from 2011 to 2014. PMID- 28594637 TI - Applying a potential difference to minimise damage to carbon fibres during carbon nanotube grafting by chemical vapour deposition. AB - The application of an in situ potential difference between carbon fibres and a graphite foil counter electrode (300 V, generating an electric field ca 0.3-0.7 V MUm-1), during the chemical vapour deposition synthesis of carbon nanotube (CNT) grafted carbon fibres, significantly improves the uniformity of growth without reducing the tensile properties of the underlying carbon fibres. Grafted CNTs with diameters 55 nm +/- 36 nm and lengths around 10 MUm were well attached to the carbon fibre surface, and were grown without the requirement for protective barrier coatings. The grafted CNTs increased the surface area to 185 m2 g-1 compared to the as-received sized carbon fibre 0.24 m2 g-1. The approach is not restricted to batch systems and has the potential to improve CNT grafted carbon fibre production for continuous processing. PMID- 28594636 TI - Contemporary alcohol use patterns among a national sample of U.S. adult drinkers. AB - The aim of the current article is to identify subgroups of adult drinkers characterized by typical drinking patterns. Data from the National Epidemiologic Survey on Alcohol and Related Conditions-III were used to classify drinkers based on several indicators of drinking. Past-year drinkers aged 18-64 were included (n = 22,776). Latent class analysis revealed a 5-class model: Occasional, Light Drinkers (28%), Frequent Drinkers (25%), Infrequent Drinkers with Occasional Binging (5%), Frequent Drinkers with Occasional Binging (22%), and High-Intensity Drinkers (20%). Although most were Light Drinkers, many engaged in excessive drinking. Given the potential risk for harm, prevention efforts are warranted particularly for High-Intensity Drinkers. PMID- 28594639 TI - Spin-valley dynamics of electrically driven ambipolar carbon-nanotube quantum dots. AB - An ambipolar n-p double quantum dot defined by potential variation along a semiconducting carbon-nanotube is considered. We focus on the (1e,1h) charge configuration with a single excess electron of the conduction band confined in the n-type dot and a single missing electron in the valence band state of the p type dot for which lifting of the Pauli blockade of the current was observed in the electric-dipole spin resonance (Laird et al 2013 Nat. Nanotechnol. 8 565). The dynamics of the system driven by periodic electric field is studied with the Floquet theory and the time-dependent configuration interaction method with the single-electron spin-valley-orbitals determined for atomistic tight-binding Hamiltonian. We find that the transitions lifting the Pauli blockade are strongly influenced by coupling to a vacuum state with an empty n dot and a fully filled p dot. The coupling shifts the transition energies and strongly modifies the effective g factors for axial magnetic field. The coupling is modulated by the bias between the dots but it appears effective for surprisingly large energy splitting between the (1e,1h) ground state and the vacuum (0e, 0h) state. Multiphoton transitions and high harmonic generation effects are also discussed. PMID- 28594638 TI - Recognition of normal-abnormal phonocardiographic signals using deep convolutional neural networks and mel-frequency spectral coefficients. AB - : Intensive care unit patients are heavily monitored, and several clinically relevant parameters are routinely extracted from high resolution signals. OBJECTIVE: The goal of the 2016 PhysioNet/CinC Challenge was to encourage the creation of an intelligent system that fused information from different phonocardiographic signals to create a robust set of normal/abnormal signal detections. APPROACH: Deep convolutional neural networks and mel-frequency spectral coefficients were used for recognition of normal-abnormal phonocardiographic signals of the human heart. This technique was developed using the PhysioNet.org Heart Sound database and was submitted for scoring on the challenge test set. MAIN RESULTS: The current entry for the proposed approach obtained an overall score of 84.15% in the last phase of the challenge, which provided the sixth official score and differs from the best score of 86.02% by just 1.87%. PMID- 28594640 TI - Ultra-broad polypyrrole (PPy) nano-ribbons seeded by racemic surfactants aggregates and their high-performance electromagnetic radiation elimination. AB - Ribbon-like nano-structures possess high aspect ratios, and thus have great potential in the development of high-performance microwave absorption (MA) materials that can effectively eliminate adverse electromagnetic radiation. However, these nano-structures have been scarcely constructed in the field of MA, because of the lack of efficient synthetic routes. Herein, we developed an efficient method to successfully construct polypyrrole (PPy) nano-ribbons using the self-assembly aggregates of a racemic surfactant as the seeds. The frequency range with a reflection loss value of lower than -10 dB reached 7.68 GHz in the frequency range of 10.32-18.00 GHz, and surpassed all the currently reported PPy nano-structures, as well as most other MA nano-materials. Through changing the amount of surfactant, both the nano-structures and MA performance can be effectively regulated. Furthermore, the reason behind the high-performance MA of PPy nano-ribbons has been deeply explored. It opens up the opportunity for the application of conducting polymer nano-ribbons as a lightweight and tunable high performance MA material, especially in applications of special aircraft and flexible electronics. PMID- 28594641 TI - Detection of pathological heart sounds. AB - : Heart sound analysis has been a major topic of research over the past few decades. However, the necessity for a large and reliable database has been a major concern in these studies. OBJECTIVE: Noting that the current heart sound classification methods do not work properly for noisy signals, the PhysioNet/CinC Challenge 2016 aims to develop the heart sound classification algorithms by providing a global open database for challengers. This paper addresses the problem of heart sound classification methods within noisy real-world phonocardiogram recordings by implementing an innovative approach. SIGNIFICANCE: After locating the fundamental heart sounds and the systolic and diastolic components, a novel method named cycle quality assessment is applied to each recording. The presented method detects those cycles which are less affected by noise and better segmented by the use of two criteria here proposed in this paper. The selected cycles are the inputs of a further feature extraction process. APPROACH: Due to the variability of the heart sound signal induced by various cardiac arrhythmias, four sets of features from the time, time-frequency and perceptual domains are extracted. Before starting the main classification process, the obtained 90-dimensional feature vector is mapped to a new feature space to pre-detect normal recordings by applying a Fisher's discriminant analysis. The main classification procedure is then done based on three feed forward neural networks and a voting system among classifiers. MAIN RESULTS: The presented method is evaluated using the training and hidden test sets of the PhysioNet/CinC Challenge 2016. Also, the results are compared with the top five ranked submissions. The results indicate that the proposed method is effective in classifying heart sounds as normal versus abnormal recordings. PMID- 28594642 TI - CE: Health and the Human Microbiome: A Primer for Nurses. AB - : The profound impact of the human microbiome on health makes it imperative that nurses understand the basic structures and functions of the various microbial communities. In studying the human microbiome, advances in DNA and RNA sequencing technology offer benefits over traditional culture-based methods. Such technology has permitted more thorough investigations of microbial communities, particularly those of the gastrointestinal (GI) and female reproductive tracts. Although individual variations exist, each site exhibits distinct compositions. The diverse GI microbiota aid in digestion, mood regulation, and vitamin synthesis. While many factors affect the composition and functions of the GI microbiota, diet likely exerts the strongest influence. Vaginal microbiota tend to be less diverse, and mainly serve to protect women from infection. The composition of the vaginal microbiota is influenced by sexual activity, hygienic practices, medications, smoking, and other factors. Our increasing knowledge about the structures and functions of the GI and vaginal microbiota allows nurses to provide targeted, evidence-based education and care for various populations. PMID- 28594643 TI - CE: Early Intervention in Patients with Poststroke Depression. AB - : Nearly one-third of stroke survivors experience depression. Poststroke depression is associated with longer hospital stays, poor physical and cognitive recovery, poor quality of life, high caregiver distress, increased risk of recurrent stroke, and higher rates of morbidity and mortality. Poststroke depression, however, often goes unrecognized and untreated because the physical and cognitive repercussions of stroke make it difficult to identify. Nurses are well positioned to recognize poststroke depression, educate patient caregivers, and aid patients who have poststroke depression in their efforts to achieve physical, cognitive, and emotional recovery. This article explains how poststroke depression often manifests, describes associated risk factors, and discusses the screening tools and therapeutic interventions nurses can use to identify and help manage depression in patients following stroke. PMID- 28594645 TI - Novel imaging techniques in gynaecological cancer. AB - PURPOSE OF REVIEW: To describe the added value of novel functional MRI techniques towards detection, staging, characterization, response monitoring and prognostication in gynaecological cancer. RECENT FINDINGS: Functional MRI including diffusion-weighted imaging (DWI)-MRI and dynamic contrast-enhanced (DCE)-MRI adds structural, hemodynamic and physiological information to anatomical MRI. In endometrial and cervical cancer, the addition of DWI-MRI and DCE-MRI improves tumour detection as well as staging of uterine and extra-uterine pelvic spread. Quantitative assessment of DWI and DCE-MRI reflecting tissue properties of biological aggressiveness or treatment resistance may enable the prediction of risk of extra-uterine or extra-ovarian disease spread, predict risk of recurrence and assess treatment response. DWI shows high accuracy for detecting peritoneal metastases and allows for comprehensive staging of (recurrent) ovarian cancer following the clinical development of whole body DWI MRI. SUMMARY: The added value of DWI/DCE-MRI for characterization and staging of gynaecological malignancy is becoming increasingly established and may improve treatment stratification. Ongoing multicentre studies are expected to further consolidate its use in clinical routine. Quantitative evaluation of functional MRI may help in prognostication and risk stratification. PMID- 28594646 TI - Minimally invasive surgery in pelvic floor repair. AB - PURPOSE OF REVIEW: To review the use and efficacy of minimally invasive surgery in pelvic organ prolapse (POP) repair. This review summarizes surgical options for management of POP with special emphasis on minimally invasive surgical approach and discusses the recent experience and feasibility of integrating robot assisted technology. RECENT FINDINGS: Minimally invasive approaches have equal efficacy and less morbidity than laparotomy for POP repair, particularly apical prolapse. Robotics may facilitate the rate of minimally invasive surgery for POP repair with greater cost and as yet no proven superiority for conventional laparoscopy. SUMMARY: Minimally invasive surgery is the preferred approach to POP repair. Conventional laparoscopic or robotic sacral colpopexy is recommended for apical defect and procidentia. PMID- 28594647 TI - Tricuspid Valve Endocarditis Partly Due to a Penicillin Susceptible, Ceftriaxone Resistant Streptococcus anginosus Isolate. PMID- 28594648 TI - Risk profiles of ectasia after keratorefractive surgery. AB - PURPOSE OF REVIEW: To identify and evaluate the risk factors of iatrogenic ectasia after refractive surgery. RECENT FINDINGS: We reviewed recently published papers that identified various risk factors associated with ectasia after LASIK, photorefractive keratectomy, small incision lenticule extraction, and other refractive surgical procedures. We also attempted to evaluate the relative contributions of these factors to the development of ectasia following refractive surgery. Forme fruste keratoconus, genetic predisposition to keratoconus, low residual stromal bed thickness (through high myopia, thin preoperative cornea, or thick LASIK flap), and irregular corneal topography have been identified as risk factors for keratectasia development after refractive surgical procedures. A newly proposed metric, percentage tissue altered, has been reported to be a robust indicator for post LASIK ectasia risk calculation. Several cases of keratectasia have also been reported 6 to 12 months following minimally invasive small incision lenticule extraction procedure. Other risk factors associated with iatrogenic ectasia include eye rubbing, young age, and pregnancy. SUMMARY: Ectasia after refractive surgery is a relatively rare complication which can lead to sight-threatening complications if not detected and treated in time. It is important to continue our quest to improve our methods of identifying absolute and relative risk factors of ectasia and their cut-off values following various keratorefractive surgical procedures. PMID- 28594650 TI - Impact of an Obstetrical Hospitalist Program on the Safety Events in a Mid-Sized Obstetrical Unit. AB - OBJECTIVE: Because internal medicine hospitalist programs were developed to address issues in medicine such as a need to improve quality, improve efficiency, and decrease healthcare cost, obstetrical (OB) hospitalist models were developed to address needs specific to the obstetrics and gynecology field. Our objective was to compare outcomes measured by occurrence of safety events before and after implementation of an OB hospitalist program in a mid-sized OB unit. METHODS: From July 2012 to September 2014, 11 safety events occurred on the labor and delivery floor. A full-time OB hospitalist program was implemented in October 2014. RESULTS: From October 2014 to December 2016, there was 1 safety event associated with labor and delivery. CONCLUSION: It has been speculated that implementation of an OB hospitalist model would be associated with improved maternal and neonatal outcomes; our regional OB referral hospital demonstrated a statistically significant decrease in OB safety events after the OB hospitalist program implementation. PMID- 28594649 TI - Accelerated versus conventional corneal crosslinking for refractive instability: an update. AB - PURPOSE OF REVIEW: Corneal crosslinking (CXL) is a relatively new treatment modality offering refractive stability in patients with ectatic disorders. The procedure as initially described (Dresden protocol) is time consuming; accelerated protocols have been lately developed. The purpose of this review is to present the recent findings regarding the comparison of accelerated CXL with the conventional Dresden protocol. RECENT FINDINGS: A variety of accelerated protocols are described in the literature. Safety and efficacy of the procedures with regard to stability seem to be equivalent in initial studies but indirect measures of efficacy, such as demarcation line depth and laboratory measurements, do not always confirm equivalence of accelerated protocols in comparison to conventional one. Modified accelerated protocols must be developed in order to overcome this. SUMMARY: Accelerated CXL protocols seem to be a valid alternative to the conventional protocol; however, more comparative long term studies are needed to confirm the validity and to elucidate which accelerated protocol is ideal in each case. PMID- 28594652 TI - Providing Culturally Sensitive Care for Islamic Patients and Families. AB - Nurses can expect to care for patients from different cultures and faith traditions and need to develop cultural competence. This article describes what is important in providing culturally and religiously sensitive care to Muslim and Middle Eastern patients. The Crescent of Care Model by Lovering is offered to aid understanding of five key areas of culturally competent care. Jesus' story of the Good Samaritan (Luke 10:25-37) offers guidance for Christian nurses caring for those in need. PMID- 28594653 TI - A Nursing Practice Model Based on Christ: The Agape Model. AB - Nine out of 10 American adults believe Jesus was a real person, and almost two thirds have made a commitment to Jesus Christ. Research further supports that spiritual beliefs and religious practices influence overall health and well being. Christian nurses need a practice model that helps them serve as kingdom nurses. This article introduces the Agape Model, based on the agape love and characteristics of Christ, upon which Christian nurses may align their practice to provide Christ-centered care. PMID- 28594651 TI - miR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling. AB - BACKGROUND: As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population. METHODS: MicroRNA (miRNA) and mRNA expression was examined in nondysplastic rectosigmoid mucosa from UC patients with (n = 19) or without remote colon neoplasia (n = 23). We developed a method to identify miRNA regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling was further evaluated in vitro and through examination of expression in UC-cancers. RESULTS: There were 101 significantly up-regulated and 98 down-regulated miRNAs (adjusted P < 0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down regulation of miR-4728-3p in nondysplastic tissue remote from UC-neoplasia and in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3' untranslated region compared with a mutant 3' untranslated region for all 3 genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes. CONCLUSIONS: Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in nondysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor suppressor in UC-associated colon carcinogenesis. PMID- 28594654 TI - Rationale, study design, and pilot phase of tHE Management of AntiThrOMbotic therApy (HEMATOMA) in patients undergoing electrophysiological device surgery: Italian National Multicenter Observational REgistry. AB - AIMS: To investigate the different strategies adopted for the management of antithrombotic therapy and the related hemorrhagic and infective complication rates in patients undergoing cardiac implantable electronic devices (CIEDs) surgery in a real-world setting. METHODS: THE Management of AntiThrOMbotic therApy in patients undergoing electrophysiological device surgery: Italian NatiOnal Multicenter Observational REgistry (HEMATOMA NO MORE) is an observational, prospective, multicenter, national cohort study (with a retrospective, multicenter, regional pilot phase) designed to enroll patients with standard indications to CIED implantations/replacements receiving concomitant antithrombotic therapy. The primary outcome is clinically significant pocket hematoma defined as a postprocedural hematoma, resulting in prolonged hospitalization and/or requiring interruption of antithrombotic therapy and/or requiring further surgery and/or requiring transfusion. RESULTS: The pilot phase included 569 patients from 11 centers in Tuscany enrolled between September 2014 and May 2015 and followed up for 1 month. Patients were categorized according to the strategy of management of antithrombotic therapy, with heparin bridging being associated with the highest incidence of clinically significant pocket hematoma (12.3%). Overall nonpocket hemorrhagic events rate was quite low (0.52%) and thromboembolic complications were negligible (0.17%). CONCLUSION: Occurrence of pocket hematoma in patients undergoing CIED surgery is largely influenced by the strategy of management of antithrombotic therapy. The HEMATOMA NO MORE will assess the impact of different strategies on the risk of developing pocket hematoma and of subsequent CIED-related infections. PMID- 28594655 TI - Life Balance in Nurse Educators: A Mixed-Methods Study. AB - AIM: The aim of the study was to explore relationships among nurse educator life balance, quality of life, and lived experience of life balance that may be used to develop strategies to prevent or minimize challenging aspects of the profession that lead to dissatisfaction and/or burnout. BACKGROUND: Nurse educator balance is significant to the national nurse faculty shortage crisis. The inability to achieve life balance contributes to job dissatisfaction and burnout, which contribute to the educator shortage. METHOD: Convergent parallel mixed-methods design. RESULTS: Participants were found to have moderate life balance correlating with greater perceived satisfaction. Four themes emerged from the qualitative data: Support, Demands, Workload, and Personal/Time Attributes. CONCLUSION: Findings from this study can be utilized to develop strategies to minimize the nurse educator shortage. PMID- 28594656 TI - Mentoring and Development Resources Available to New Doctorally Prepared Faculty in Nursing. AB - AIM: This study examined faculty mentoring practices and strategies currently in place in nursing programs. BACKGROUND: Mentoring is a critical component of organizations and can be especially important in times of organizational change. Schools of nursing are experiencing rapid organizational shifts with increases in retirement and the proliferation of Doctor of Nursing Practice-prepared faculty. METHOD: Deans and department chairs of baccalaureate and higher degree programs across the United States participated in a web-based survey. RESULTS: Results from the survey suggested that the vast majority of nursing programs had practices and strategies aimed at mentoring faculty that were based on the traditional mentor-protege approach. Few programs differentiated their mentoring practices depending on the type of doctoral education or anticipated roles of the faculty member. CONCLUSION: Our research highlights the fact that nursing programs still employ traditional methods of faculty mentoring. Recommendations for nursing programs are discussed. PMID- 28594657 TI - Fitness Moderates Glycemic Responses to Sitting and Light Activity Breaks. AB - PURPOSE: This study aimed to experimentally determine whether cardiorespiratory fitness (CRF) modifies postprandial glycemia during prolonged sitting and investigated the potentially blunting influence this may have on the benefits of interrupting postprandial sitting time with light activity breaks. METHODS: Thirty-four adults (18 women; 16 men; mean +/- SD age, 40 +/- 9 yr, body mass index, 24.5 +/- 3 kg.m) undertook two 7.5-h experimental conditions in a randomized order: 1) Prolonged sitting; 2) Sitting interspersed with 5 min light walking bouts every 30 min. Blood samples were obtained while fasting and postprandially after ingestion of two identical meals. Incremental area under the curve (iAUC) was calculated for glucose and insulin throughout experimental conditions. Maximal exercise testing quantified peak oxygen consumption (VO2 peak) as a measure of CRF. A repeated-measures ANOVA investigated whether VO2 peak modified glucose and insulin iAUC between conditions. RESULTS: Breaking sedentary time with light walking breaks reduced blood glucose iAUC from 3.89 +/- 0.7 to 2.51 +/- 0.7 mmol.L.h (P = 0.015) and insulin iAUC from 241 +/- 46 to 156 +/- 24 mU.L.h (P = 0.013) after adjustment for VO2 peak and sex. A significant interaction between treatment response and VO2 peak was observed for glucose (P = 0.035), but not insulin (P = 0.062), whereby the treatment effect reduced with higher CRF. Average blood glucose iAUC responses for a man at the 25th centile of CRF within our cohort (42.5 mL.kg.min) went from 5.80 to 2.98 mmol.L.h during the prolonged sitting and light walking break conditions respectively, whereas average responses for a man at the 75th centile of CRF (60.5 mL.kg.min) went from 1.99 to 1.78 mmol.L.h. Similar trends were observed for women. CONCLUSIONS: Individuals with low CRF gained the most metabolic benefit from breaking prolonged sitting with regular bouts of light walking. PMID- 28594658 TI - Total Percutaneous Cardiopulmonary Bypass for Robotic and Endoscopic Atrioventricular Valve Surgery. AB - Continuous technological advances in endoscopic-, robotic- and catheter-based cardiac interventions are paralleled by rapid evolution in cannulation strategies for circulatory support. The recent introduction of suture-based percutaneous vascular closure devices resulted in innovative strategies to deliver peripheral endovascular therapeutic devices through the iliac and femoral arteries. Percutaneous access allows rapid postoperative mobilization and potentially avoids the devastating neuro-lympho-vascular- and wound infection morbidities associated with conventional open surgical exposure. We routinely perform endoscopic port access surgery for all isolated atrioventricular valve pathology and extended the application of suture-based percutaneous vascular closure device to establish total percutaneous peripheral cardiopulmonary bypass in disabled, immune-suppressed, and morbidly obese patients at risk neuro-lympho-vascular- and wound infection. In this report, we provide a stepwise description of our total percutaneous peripheral cardiopulmonary bypass technique. PMID- 28594659 TI - Repeat Revascularization After Minimally Invasive Coronary Artery Bypass Grafting: Is It a Problem? AB - OBJECTIVE: Minimally invasive coronary artery bypass grafting (MICS CABG) via a small left thoracotomy is a novel technique for coronary revascularization that is increasingly used around the world. However, multivessel MICS CABG is difficult, and concerns about repeat revascularization (RR) have been raised. This longitudinal study describes the rates of RR among patients who have undergone MICS CABG and identifies targets for improvement. METHODS: A prospective observational study was performed on the 306 MICS CABG patients operated on by a single surgeon from 2005 to 2015. Minimally invasive coronary artery bypass grafting was performed through a small left thoracotomy, using the in situ left internal mammary artery, +/- a radial artery, and 1 to 3 saphenous veins anastomosed proximally to the aorta. Patients were followed annually. We examined the difference between the first half and second half of the series to ascertain the effects of a learning curve. RESULTS: Eighty percent of the procedures were performed off-pump. The median number of grafts performed were 2, and the left anterior descending, diagonals, obtuse marginals, and posterior interventricular artery were the distal targets in 94%, 12%, 44%, and 26%, respectively. The graftability index (#grafts/#diseased vessels) was 0.93. Revascularization of targets smaller than 1.5 mm decreased from 69% to 50% (P = 0.002) between the series' first and second halves. Overall, RR was needed in 21 patients (6.9%) and was performed at a mean +/- SD of 1.7 +/- 1.6 years postoperatively. The culprit lesion was attributed to the index surgical procedure ("graft-associated") in 52%, to a stent stenosis or progression of native disease in 43%, and was unidentified in 5%. Patients with graft-associated RR had a lower graftability index at operation (0.73 vs 0.94) and more frequent involvement of the circumflex system (0.8 vs 0.3). The overall rate of RR at 3 years decreased from 11% in the first half to 2.6% in the second half (P = 0.001). CONCLUSIONS: The need for RR is part of the learning curve with MICS CABG, involves a graft in half of the cases, is more common in patients who had a lower graftability index at operation, and markedly improves with experience. PMID- 28594661 TI - Paracrine regulation of normal and malignant hematopoiesis. AB - PURPOSE OF REVIEW: The paradigm of niche-regulation of hematopoiesis has rapidly and substantially evolved within the last 12 months. Here, we will review the most critical advances in understanding of paracrine regulation of normal and malignant hematopoietic stem cell fate during the past year. RECENT FINDINGS: Several novel paracrine mechanisms have been recently identified, highlighting the function of mesenchymal progenitor cells, osteoprogenitor cells and endothelial cells in regulating hematopoietic stem cell maintenance and regeneration. Similarly, niche-driven inflammatory states, paracrine mechanisms, exosomes, and endocytosis have each been shown to powerfully regulate the maintenance and propagation of leukemic cells. SUMMARY: The elucidation of paracrine mechanisms that regulate normal and malignant hematopoiesis is critical for both fundamental understanding of hematology and for the identification of novel molecular targets for therapeutic translation. PMID- 28594662 TI - Patient-derived tumor xenografts of lymphoproliferative disorders: are they surrogates for the human disease? AB - PURPOSE OF REVIEW: Patient-derived tumor xenografts (PDTXs) have emerged as powerful platforms in medical oncology. A plethora of PDTXs were generated to study solid cancers, but limited data are as yet available on hematological diseases. The aim of this review is to describe the state of art of lymphoma PDTXs, discussing future directions for the development of integrated/personalized cancer programs. RECENT FINDINGS: In the last decades, several PDTXs of lymphoproliferative disorders have been produced. Most studies focused on acute lymphoblastic leukemias, but consistent results have recently been obtained also for indolent and aggressive B-/T-cell lymphomas. These models have contributed to characterize lymphoma biology and therapy, despite technical and scientific issues have partially limited their application (e.g. high costs, relatively low engraftment rates, lack of human-derived tumor microenvironment, clonal selection of engrafted cells, limited characterization of tumor grafts). In the next future, such limitations should be overcome by new technical approaches and dedicated multiinstitutional programs. SUMMARY: PDTXs represent an unprecedented opportunity to study the biology and clinical management of lymphoproliferative disorders. Many of the current models display limitations, which will be resolved by rigorous approaches and comprehensive libraries, recapitulating the extreme heterogeneity of such neoplasms. PMID- 28594664 TI - NACNS Newsletter: President's Message. PMID- 28594660 TI - Regulation of the hematopoietic stem cell lifecycle by the endothelial niche. AB - PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) predominantly reside either in direct contact or in close proximity to the vascular endothelium throughout their lifespan. From the moment of HSC embryonic specification from hemogenic endothelium, endothelial cells (ECs) act as a critical cellular-hub that regulates a vast repertoire of biological processes crucial for HSC maintenance throughout its lifespan. In this review, we will discuss recent findings in endothelial niche-mediated regulation of HSC function during development, aging and regenerative conditions. RECENT FINDINGS: Studies employing genetic vascular models have unequivocally confirmed that ECs provide the essential instructive cues for HSC emergence during embryonic development as well as adult HSC maintenance during homeostasis and regeneration. Aging of ECs may impair their ability to maintain HSC function contributing to the development of aging associated hematopoietic deficiencies. These findings have opened up new avenues to explore the therapeutic application of ECs. ECs can be adapted to serve as an instructive platform to expand bona fide HSCs and also utilized as a cellular therapy to promote regeneration of the hematopoietic system following myelosuppressive and myeloablative injuries. SUMMARY: ECs provide a fertile niche for maintenance of functional HSCs throughout their lifecycle. An improved understanding of the EC-HSC cross-talk will pave the way for development of EC directed strategies for improving HSC function during aging. PMID- 28594665 TI - Expanding the Practice Model for Greater Influence. PMID- 28594666 TI - Negligence and the Nurse: The Value of the Code of Ethics for Nurses. PMID- 28594667 TI - The Ethics, Cost, and Evidence Surrounding Current Pharmacological Treatment of Hepatitis C Virus Infection. PMID- 28594668 TI - Hysterectomy With Radiotherapy or Chemotherapy or Both for Women With Locally Advanced Cervical Cancer. PMID- 28594669 TI - Collaborative Research: An Advanced Practice Nurse's Experience in Genome Research and Treatment. PMID- 28594670 TI - Stories and Music for Adolescent/Young Adult Resilience During Transplant Partnerships: Strategies to Support Academic-Clinical Nurse Collaborations in Behavioral Intervention Studies. AB - Evidence-based nursing is in the forefront of healthcare delivery systems. Federal and state agencies, academic institutions, and healthcare delivery systems recognize the importance of nursing research. This article describes the mechanisms that facilitate nursing partnerships yielding high-level research outcomes in a clinical setting. A phase-II multicenter behavioral intervention study with pediatric stem cell transplant patients was the context of this academic/clinical research partnership. Strategies to develop and maintain this partnership involved a thorough understanding of each nurse's focus and barriers. A variety of communication plans and training events maximized preexisting professional networks. Academic/clinical nurses' discussions identified barriers to the research process, the most significant being role conflict. Communication and validation of benefits to each individual and institution facilitated the research process during challenging times. Establishing strong academic/clinical partnerships should lead to evidence-based research outcomes for the nursing profession, healthcare delivery systems, and patients and families. PMID- 28594671 TI - Incorporating Relationship-Based Care Into a Nurse Education Program for Managing Disruptive Patient Behaviors. AB - PURPOSE: In the hospitalized patient, stressors can be manifested as disruptive behaviors. Nursing staff confronted with disruptive behaviors from their patients or families may have difficulty delivering care and developing therapeutic relationships. The purpose of this project was to evaluate the effects of an education program using the concepts of relationship-based care with role-play and reflective practice on the knowledge, attitudes, and confidence of the nursing staff in managing disruptive patient behaviors. DESCRIPTION: Nursing staff (N = 68) from an adult medical unit participated in an interactive education program. We compared participants' self-responses about knowledge, attitudes, and confidence before intervention and at 3-month and 1-year postintervention. The number of disruptive incidents requiring hospital security was also measured. OUTCOME: At 3-month and 1-year postintervention, staff reported higher levels of knowledge, attitudes, and confidence in managing disruptive behaviors. The number of disruptive incidents per 1000 patient days decreased from 0.78 to 0.39. CONCLUSION: Effectively managing disruptive behaviors creates a safe, healthy environment for patients and nurses. Role-play and reflective practice are useful educational methods to teach skills to manage these encounters. Clinical nurse specialists can play a key role in developing innovative education programs through interprofessional collaboration. PMID- 28594672 TI - The Experiences of Specialist Nurses Working Within the Uro-oncology Multidisciplinary Team in the United Kingdom. AB - PURPOSE: United Kingdom prostate cancer nursing care is provided by a variety of urology and uro-oncology nurses. The experience of working in multidisciplinary teams (MDT) was investigated in a national study. DESIGN: The study consisted of a national survey with descriptive statistics and thematic analysis. METHODS: A secondary analysis of a data subset from a UK whole population survey was undertaken (n = 285) of the specialist nursing workforce and the services they provide. Data were collected on the experience of working in the MDT. RESULTS: Forty-five percent of the respondents felt that they worked in a functional MDT, 12% felt that they worked in a dysfunctional MDT, and 3.5% found the MDT meeting intimidating. Furthermore, 34% of the nurses felt that they could constructively challenge all members of the MDT in meetings. Themes emerging from open-ended questions were lack of interest in nonmedical concerns by other team members, ability to constructively challenge decisions or views within the meeting, and little opportunity for patients' wishes to be expressed. CONCLUSIONS: Despite expertise and experience, nurses had a variable, often negative, experience of the MDT. It is necessary to ensure that all participants can contribute and are heard and valued. More emphasis should be given to patients' nonmedical needs. PMID- 28594673 TI - Facilitators and Barriers for Interprofessional Rounding: A Qualitative Study. AB - PURPOSE: The purpose of this qualitative study was to describe the barriers and facilitators for interprofessional patient-centered rounding across 4 acute care units in a large urban hospital. DESIGN: A qualitative descriptive method that included data gathered over an 18-month period was used. METHODS: Three data sources were included: participant observation of rounding activities, focused meetings related to interprofessional practice, and exit interviews with key informants representing multiple professions and roles. The data were analyzed, and the findings were developed through an extensive transcription, coding, and discussion process. RESULTS: The facilitators and barriers related to the team included high versus low turnover of team membership, structured versus unstructured rounding, valuing versus skepticism about interprofessional practice, and confidence versus hesitancy about skills. Facilitator/barrier pairs related to the environment included rounding aligned versus mismatched with hospital's mission, time for rounding versus competing demands, geographically cohorted versus distributed teams, and readiness for change and innovation versus saturation. CONCLUSION: Factors associated with the members of the interprofessional team were important in successful implementation of interprofessional rounding. The organizational context and structure were also important. Leaders who anticipate implementing interprofessional rounding may incorporate knowledge of these facilitators and barriers into their planning process. PMID- 28594674 TI - The Tragic Consequences of Indifference. PMID- 28594675 TI - Feasibility and Acceptability of the Use of Patient-Reported Outcome Measures in the Delivery of Nurse-Led, Supportive Care to Women With Cervical Cancer. AB - PURPOSE/AIMS: Patient-reported outcome measures (PROMs) can be effectively used to uncover the unmet needs of women with cervical cancer for supportive care. Our aim was to explore the feasibility and acceptability of PROM-driven, nurse-led consultations to enhance delivery of supportive care to women with cervical cancer during active anticancer treatment. DESIGN: A 2-phased, mixed-method prospective study was conducted. Main research variables included feasibility and acceptability parameters of the trialed intervention. METHODS: Preconsultation PROM data were collected during 3 consecutive monthly consultations and used by the gynecology cancers nurse specialist (CNS) to deliver personalized supportive care. The problem checklist and Cervical Cancer Concerns Questionnaire were used to aid data collection. FINDINGS: Because of considerable recruitment challenges, a recruitment rate of 27% (3/11 patients) was achieved. Two patients completed all 3 study assessments. Seven in-clinic patient assessments were performed over 6 months. The study participants praised the opportunity for dedicated time for patients to raise concerns and for the CNS to provide sensitive and personalized support. CONCLUSION: Women with cervical cancer perceive important benefits from participating in PROM-driven, time-protected sessions with their CNS. Our findings provide tentative evidence to support the feasibility and acceptability of this intervention model and warrant future confirmation. IMPLICATIONS FOR PRACTICE: . PMID- 28594676 TI - Retrospective Analysis of Catheter-Acquired Urinary Tract Infection: Relationship to Stroke Diagnosis. AB - AIMS: The objective of this study was to determine if a diagnosis of stroke was associated with a higher incidence of catheter-associated urinary tract infections (CAUTIs). Secondary aims included examining the effect of healthcare related variables including antibiotic and steroid use, length of stay before catheter insertion, and duration of catheter use on the incidence of CAUTI in stroke patients. DESIGN: This was a retrospective chart review analysis set in a large teaching hospital in the Southeastern United States. METHODS: A total of 300 patients with indwelling urinary catheter use who also had a stroke diagnosis were randomly selected and matched (on age, gender, race, and admission date) to 300 randomly selected patients with indwelling urinary catheter use and without stroke. Bivariate statistical tests included Wilcoxon signed-rank test and McNemar's test, whereas the multivariate test consisted of generalized estimating equations. RESULTS: The incidence of CAUTIs in stroke patients was significantly higher than that in nonstroke patients (6.0% vs 1.7%, P = .005). In the multivariable generalized estimating equations analysis, stroke patients were found to be approximately 3.5 times more likely to experience CAUTI compared with nonstroke patients (odds ratio = 3.53; 95% confidence interval, 1.24-10.03; P = .018). The proportion of patients who used steroids was greater among stroke patients who experienced CAUTI compared with those who did not experience CAUTI (55.6% vs 24.5%, P = .004). CONCLUSION: Stroke patients were more likely to develop CAUTI compared with nonstroke patients. These patients should be considered as key targets when implementing interventions aimed at reducing CAUTIs. Use of steroids may be associated with a higher likelihood of CAUTI in stroke patients. IMPLICATIONS: Clinical nurse specialists are directly influential in preventing CAUTIs. This study provides evidence regarding the association between stroke and CAUTI to clinical nurse specialists to help them plan CAUTI prevention initiatives. PMID- 28594678 TI - Transplantation of Bioprinted Tissues and Organs: Technical and Clinical Challenges and Future Perspectives. AB - : Three-dimensional (3D) bioprinting is a revolutionary technology in building living tissues and organs with precise anatomic control and cellular composition. Despite the great progress in bioprinting research, there has yet to be any clinical translation due to current limitations in building human-scale constructs, which are vascularized and readily implantable. In this article, we review the current limitations and challenges in 3D bioprinting, including in situ techniques, which are one of several clinical translational models to facilitate the application of this technology from bench to bedside. A detailed discussion is made on the technical barriers in the fabrication of scalable constructs that are vascularized, autologous, functional, implantable, cost effective, and ethically feasible. Clinical considerations for implantable bioprinted tissues are further expounded toward the correction of end-stage organ dysfunction and composite tissue deficits. PMID- 28594679 TI - Initial Experience With Biologic Polymer Scaffold (Poly-4-hydroxybuturate) in Complex Abdominal Wall Reconstruction. AB - OBJECTIVE: To evaluate the use of the new absorbable polymer scaffold poly-4 hydroxybutyrate (P4HB) in complex abdominal wall reconstruction. BACKGROUND: Complex abdominal wall reconstruction has witnessed tremendous success in the last decade after the introduction of cadaveric biologic scaffolds. However, the use of cadaveric biologic mesh has been expensive and plagued by complications such as seroma, infection, and recurrent hernia. Despite widespread application of cadaveric biologic mesh, little data exist on the superiority of these materials in the setting of high-risk wounds in patients. P4HB, an absorbable polymer scaffold, may present a new alternative to these cadaveric biologic grafts. METHODS: A retrospective analysis of our initial experience with the absorbable polymer scaffold P4HB compared with a consecutive contiguous group treated with porcine cadaveric mesh for complex abdominal wall reconstructions. Our analysis was performed using SAS 9.3 and Stata 12. RESULTS: The P4HB group (n = 31) experienced shorter drain time (10.0 vs 14.3 d; P < 0.002), fewer complications (22.6% vs 40.5%; P < 0.046), and reherniation (6.5% vs 23.8%; P < 0.049) than the porcine cadaveric mesh group (n = 42). Multivariate analysis for infection identified: porcine cadaveric mesh odds ratio 2.82, length of stay odds ratio 1.11; complications: drinker odds ratio 6.52, porcine cadaveric mesh odds ratio 4.03, African American odds ratio 3.08, length of stay odds ratio 1.11; and hernia recurrence: porcine cadaveric mesh odds ratio 5.18, drinker odds ratio 3.62, African American odds ratio 0.24. Cost analysis identified that P4HB had a $7328.91 financial advantage in initial hospitalization and $2241.17 in the 90 day postdischarge global period resulting in $9570.07 per case advantage over porcine cadaveric mesh. CONCLUSIONS: In our early clinical experience with the absorbable polymer matrix scaffold P4HB, it seemed to provide superior clinical performance and value-based benefit compared with porcine cadaveric biologic mesh. PMID- 28594680 TI - Antibiotic Therapy in Comatose Mechanically Ventilated Patients Following Aspiration: Differentiating Pneumonia From Pneumonitis. AB - OBJECTIVES: To determine the proportion of patients with documented bacterial aspiration pneumonia among comatose ICU patients with symptoms suggesting either bacterial aspiration pneumonia or non-bacterial aspiration pneumonitis. DESIGN: Prospective observational study. SETTING: University-affiliated 30-bed ICU. PATIENTS: Prospective cohort of 250 patients admitted to the ICU with coma (Glasgow Coma Scale score <= 8) and treated with invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients with microbiologically documented bacterial aspiration pneumonia. Patients meeting predefined criteria for aspiration syndrome routinely underwent telescopic plugged catheter sampling during bronchoscopy before starting probabilistic antibiotic treatment. When cultures were negative, the antibiotic treatment was stopped. Of 250 included patients, 98 (39.2%) had aspiration syndrome, including 92 before mechanical ventilation discontinuation. Telescopic plugged catheter in these 92 patients showed bacterial aspiration pneumonia in 43 patients (46.7%). Among the remaining 49 patients, 16 continued to receive antibiotics, usually for infections other than pneumonia; of the 33 patients whose antibiotics were discontinued, only two subsequently showed signs of lung infection. In the six patients with aspiration syndrome after mechanical ventilation, and therefore without telescopic plugged catheter, antibiotic treatment was continued for 7 days. Mechanical ventilation duration, ICU length of stay, and mortality did not differ between the 43 patients with bacterial aspiration pneumonia and the 49 patients with non-bacterial aspiration pneumonitis. The 152 patients without aspiration syndrome did not receive antibiotics. CONCLUSIONS: Among comatose patients receiving mechanical ventilation, those without clinical, laboratory, or radiologic evidence of bacterial aspiration pneumonia did not require antibiotics. In those with suspected bacterial aspiration pneumonia, stopping empirical antibiotic therapy when routine telescopic plugged catheter sampling recovered no microorganisms was nearly always effective. This strategy may be a valid alternative to routine full course antibiotic therapy. Only half the patients with suspected bacterial aspiration pneumonia had this diagnosis confirmed by telescopic plugged catheter sampling. PMID- 28594681 TI - Delirium and Benzodiazepines Associated With Prolonged ICU Stay in Critically Ill Infants and Young Children. AB - OBJECTIVES: Delirium is prevalent among critically ill children, yet associated outcomes and modifiable risk factors are not well defined. The objective of this study was to determine associations between pediatric delirium and modifiable risk factors such as benzodiazepine exposure and short-term outcomes. DESIGN: Secondary analysis of collected data from the prospective validation study of the Preschool Confusion Assessment Method for the ICU. SETTING: Tertiary-level PICU. PATIENTS: Critically ill patients 6 months to 5 years old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Daily delirium assessments were completed using the Preschool Confusion Assessment Method for the ICU. Associations between baseline and in-hospital risk factors were analyzed for likelihood of ICU discharge using Cox proportional hazards regression and delirium duration using negative binomial regression. Multinomial logistic regression was used to determine associations between daily risk factors and delirium presence the following day. Our 300-patient cohort had a median (interquartile range) age of 20 months (11-37 mo), and 44% had delirium for at least 1 day (1-2 d). Delirium was significantly associated with a decreased likelihood of ICU discharge in preschool-aged children (age-specific hazard ratios at 60, 36, and 12 mo old were 0.17 [95% CI, 0.05-0.61], 0.50 [0.32-0.80], and 0.98 [0.68-1.41], respectively). Greater benzodiazepine exposure (75-25th percentile) was significantly associated with a lower likelihood of ICU discharge (hazard ratio, 0.65 [0.42-1.00]; p = 0.01), longer delirium duration (incidence rate ratio, 2.47 [1.36-4.49]; p = 0.005), and increased risk for delirium the following day (odds ratio, 2.83 [1.27 6.59]; p = 0.02). CONCLUSIONS: Delirium is associated with a lower likelihood of ICU discharge in preschool-aged children. Benzodiazepine exposure is associated with the development and longer duration of delirium, and lower likelihood of ICU discharge. These findings advocate for future studies targeting modifiable risk factors, such as reduction in benzodiazepine exposure, to mitigate iatrogenic harm in pediatric patients. PMID- 28594682 TI - Preface and Introduction. PMID- 28594684 TI - Arthrogryposis Introduction. PMID- 28594685 TI - Background to the 2nd International Symposium on Arthrogryposis. AB - Arthrogryposis multiplex congenital is a relatively uncommon condition, with little consensus on treatment. In 2007, the 1st International Symposium on Arthrogryposis was held in Birmingham, United Kingdom, to bring together patients, their families, and a multinational group of health care experts in the field of arthrogryposis, to discuss various aspects of the care of patients with arthrogryposis multiplex congenital. From that meeting, there was a coalescence of thought on diagnosis and classification, a sharing of practices on treatments and their outcomes, and an agreement on future directions. At the beginning of the 2nd International Symposium on Arthrogryposis held in Saint Petersburg in September 2014, Russia, these "lessons learnt" were synopsized to set the tone for the new meeting. PMID- 28594686 TI - Genetics and Classifications. AB - Arthrogryposis multiplex congenital (AMC) is a descriptive term for a group of conditions that all share the characteristic of congenital contractures. There are an estimated 400 discrete diagnoses that can lead to a child being born with arthrogryposis. The 2 biggest categories of conditions are amyoplasia and distal arthrogryposis, which combined make up ~50% to 65% of all diagnoses within the AMC subset. Amyoplasia, the most common AMC condition, seems to be a nongenetic syndrome, leading to very characteristic upper and lower limb contractures. The distal arthrogryposes, in contrast, have an underlying genetic abnormality, which in many cases seems to target the fast twitch muscles of the developing fetus. Classifying AMC is a difficult task, given the broad range of conditions represented. Four different classification schemes are presented. PMID- 28594687 TI - Treatment of the Upper Extremity Contracture/Deformities. AB - Patients with arthrogryposis multiplex congenita have a characteristic upper extremity resting posture consisting of internal rotation of the shoulders, elbow extension, flexed wrists, thumb-in palm deformities, and variable degrees of finger contractures. Treatment of these patients is aimed at improving independence and performance of activities of daily living. Although each area needs to be assessed independently for the most appropriate surgical procedure, often multiple areas can be addressed at the same operative setting. This limits the number of anesthetic exposures and cast immobilization time. The following is a synopsis of treatment strategies presented at the second international symposium on Arthrogryposis which took place in St Petersburg in September 2014. PMID- 28594688 TI - Treatment of the Lower Extremity Contracture/Deformities. AB - Lower extremity deformities of patients with arthrogryposis multiplex congenita present a wide spectrum of severity and deformity combinations. Treatment goals range from merely ensuring comfortable seating and shoe wear, to fully independent and active ambulation, but the overarching intention is to help realize the patient's greatest potential for independence and function. Treatment of hip and knee contractures and dislocations has become more interventional, whereas treatment of foot deformities has paradoxically become much less surgical. This article synopsizes the treatment strategies presented in September 2014 in Saint Petersburg, Russia at the second international symposium on arthrogryposis. PMID- 28594689 TI - Treatment of Scoliosis Associated With Arthrogryposis Multiplex Congenita. AB - Scoliosis in children with arthrogryposis occurs in the minority of patients, but appears early, often present at birth. Curves can progress quickly. Treatment options include spine casting, bracing, expandable implant surgery, and spinal fusion. The goal is to allow as much chest growth and development as possible, along with a resulting well-balanced spine. PMID- 28594690 TI - Anaesthesiology for Children With Arthrogryposis. AB - Patients with arthrogryposis often require anesthesia for surgical procedures. Intubation can be challenging due to lack of visualization. Anesthetic maintenance is fairly routine. Pheripheral blocks are an important adjunct to postoperative pain management. PMID- 28594691 TI - Multidisciplinary Clinics. AB - More than 400 acquired and genetic diseases are labeled as arthrogryposis. Because of their rarity and complexity coordinated patient management is often lacking. Multidisciplinary clinics are the ideal setting to provide coordinated and comprehensive care to patients with special needs. Two similar experiences of multidisciplinary clinics for the care of patients with arthrogryposis were reported at the Symposium on Arthrogryposis held in Saint Petersburg in September 2014. These clinics are organized to bring together professionals from several disciplines, with the aim to provide patient-centered, comprehensive clinical care, and reduce the burden of multiple medical appointments for the families. PMID- 28594692 TI - Adults Living With Amyoplasia: Function, Psychosocial Aspects, and the Benefit of AMC Support Groups. AB - Little is known about how adults manage living with amyoplasia. Two studies concerning adults with amyoplasia were conducted; a cross-sectional study and a qualitative study. The aims were to describe body functions, activity and participation, and to explore psychosocial dimensions. This article also emphasizes the importance of Patient Support Groups as arenas for sharing experience and gaining knowledge. PMID- 28594693 TI - Navigating the challenges of Meniere disease. PMID- 28594694 TI - Supracondylar Fracture Practice Improvement Module. PMID- 28594695 TI - Wrist Arthroscopy in Children and Adolescent With Chronic Wrist Pain: Arthroscopic Findings Compared With MRI. AB - BACKGROUND: Wrist arthroscopy is a dynamic diagnostic procedure and its indications are growing as a treatment modality in the adult population. The aim of the study was to retrospectively report our series of pediatric and adolescence with chronic wrist pain, with or without wrist instability who underwent wrist arthroscopy after failing at least 4 months of conservative management. Our secondary aim was to report the sensitivity and specificity of clinical examination and magnetic resonance imaging evaluation for various injury subgroups against the gold standard of the arthroscopic findings. Technical challenges, complications, and outcomes are also discussed. METHODS: A retrospective review of the medical records of 32 pediatric and adolescent patients who underwent wrist arthroscopy was conducted. Preoperative clinical diagnosis, radiographic, and intraoperative findings including classifications of triangular fibrocartilage complex (TFCC) and interosseous ligaments were obtained. Patients were followed up to 1 year postoperatively and were discharged if symptom free. RESULTS: Thirty-three wrist arthroscopies in 32 patients were performed from 1996 to 2004. There were 2 male and 30 female patients. At arthroscopy 16 wrists were found to have TFCC injuries, 11 wrists had scapholunate injuries, and 8 had lunotriquetral (LT) injuries. Clinical examination for diagnosis of TFCC injury was too sensitive and nonspecific; however, clinical diagnosis of scapholunate injury was sensitive and specific. LT injury was under diagnosed clinically. Magnetic resonance imaging was found to have a low sensitivity for diagnosis of LT injury but diagnosis of TFCC was sensitive and specific. CONCLUSIONS: The sex ratio of 2 males:30 females was startling. Nevertheless, this therapeutic level 3 study supports a thorough search for pathology in any patient with persistent wrist symptoms because pathology was identified in 32 of the 33 wrists at arthroscopy. LEVEL OF EVIDENCE: Level III-Therapeutic. PMID- 28594696 TI - Quality measures in gastrointestinal endoscopy: the current state. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the current state of endoscopic quality measurement and use of measures in enhancing the value of endoscopic services. RECENT FINDINGS: Initially, quality measurement of endoscopic procedures was claims based or included small unit or practice specific efforts. Now we have a mature national registry and large electronic medical or procedural records that are designed to yield valuable data relevant to quality measurement. SUMMARY: With the advent of better measures, we are beginning to understand that initial process and surrogate outcome measures (adenoma detection rate) can be improved to provide a better reflection of endoscopic quality. Importantly, however, even measures currently in use relate to important patient outcomes such as missed colon cancers. At a federal level, older cumbersome pay-for-performance initiatives have been combined into a new overarching program named the quality payment program within the centers for medicare and medicaid services. This program is an additional step toward furthering the progress from volume-to-value-based reimbursement. The legislation mandating the movement toward outcomes-linked (value) reimbursement is the medicare access and children's health insurance program reauthorization act, which was passed with overwhelming bipartisan support and will not be walked back by alterations of the affordable care act. Increasing portions of medicare reimbursement (and likely commercial to follow) will be linked to quality metrics, so familiarity with the underlying process and rationale will be important for all proceduralists. PMID- 28594697 TI - Comparison of Femtosecond Laser-Enabled Descemetorhexis and Manual Descemetorhexis in Descemet Membrane Endothelial Keratoplasty. AB - PURPOSE: To introduce a novel method to perform descemetorhexis in Descemet membrane endothelial keratoplasty (DMEK) using the femtosecond laser and to compare it with Descemet membrane endothelial keratoplasty performed with manual descemetorhexis (M-DMEK). METHODS: A retrospective medical chart review of 2 groups of patients who underwent DMEK surgery combined with cataract surgery secondary to Fuchs corneal endothelial dystrophy and cataract: 17 patients underwent femtosecond laser-enabled descemetorhexis Descemet membrane endothelial keratoplasty (FE-DMEK) and 89 patients underwent DMEK surgery with M-DMEK. Best spectacle-corrected visual acuity, endothelial cell density (ECD), graft detachment rate, and complications were compared. RESULTS: Average age of the 106 patients (64 women and 42 men) was 68 +/- 11 years. Postoperative best spectacle corrected visual acuity was 0.19 +/- 0.13 logarithm of the minimum angle of resolution in the FE-DMEK group and 0.35 +/- 0.48 logarithm of the minimum angle of resolution in the M-DMEK group (P = 0.218). One day after surgery, there were no significant graft detachments in the FE-DMEK group, compared with 20% graft detachment rate in the M-DMEK group (P = 0.041). Rebubbling was performed in 17% of eyes in the M-DMEK group compared with none in the FE-DMEK group (P = 0.066). The mean endothelial cell count in the FE-DMEK and M-DMEK groups at 6 months after surgery were 2105 +/- 285 cells per square millimeter (24% cells loss) and 1990 +/- 600 cells per square millimeter (29% cells loss), respectively (P = 0.579). CONCLUSIONS: FE-DMEK shows efficacy similar to that of M-DMEK with apparently less graft detachment and reduced need for rebubbling. PMID- 28594698 TI - Short-Term Effects of Y-27632, a Rho-Associated Protein Kinase Inhibitor, on Chromatin Supraorganization and DNA Amount in Epithelial Cells of the Rat Cornea and Limbus. AB - PURPOSE: To assess the short-term effects of instilling Y-27632, an inhibitor of Rho/Rho-associated protein kinases, on the chromatin supraorganization and DNA amount of corneal and limbal epithelial cells of healthy rats. METHODS: Longitudinal sections (7 MUm) of enucleated eyes of healthy rats that received, by instillation, balanced salt solution with or without 10 mM of Y-27632 daily for 7 or 15 days, were subjected to the Feulgen reaction. Feulgen-stained nuclei of corneal and limbal epithelial cells were studied by microscopy and video image analysis to establish the nuclear size (area and perimeter), supraorganization of chromatin (texture and degrees of condensation), and the Feulgen-DNA amount. RESULTS: Instillation of Y-27632 for up to 15 days did not change the size of the nucleus or the chromatin texture of corneal and limbal epithelial cells. Samples treated with Y-27632 for 7 days showed condensed chromatin and a high Feulgen-DNA amount. Both corneal and limbal epithelium showed the presence of near-tetraploid nuclei corresponding to cells in the S and G2 phases of the cell cycle. The degrees of condensation and Feulgen-DNA amount of the nuclei of epithelial cells of the cornea and limbus of eyes from rats receiving Y-27632 for 15 days did not differ from control (no drug). CONCLUSIONS: Changes in chromatin supraorganization and DNA amount, such as seen in this study, are indicative of cell proliferation and do not seem to be associated with disturbances in gene activity and transcription of DNA. PMID- 28594699 TI - Solitary Iris Plasmacytoma With Anterior Chamber Crystalline Deposits. AB - PURPOSE: To report a case of solitary iris plasmacytoma successfully treated with ruthenium plaque radiotherapy. METHODS: A 44-year-old white woman presented with pain in the right eye and raised intraocular pressure. Her medical history included breast cancer treated 11 years earlier with lumpectomy, lymph node clearance, chemotherapy, and radiotherapy. On examination, the right iris had a tan-colored mass with crystalline deposits visible on the mass surface and on the corneal endothelium. The fundus and left eye were normal. An anterior segment ultrasound scan showed a mass with mixed internal echogenicity and internal blood flow. RESULTS: An iris biopsy showed an infiltrate of plasma cells. Immunohistochemistry for kappa and lambda light chains demonstrated lambda light chain restriction. Systemic hematologic investigations including complete blood count, serum paraproteins, bone marrow biopsy, and full-body magnetic resonance image were normal. The monoclonal plasma cell infiltrate was consistent with a solitary iris plasmacytoma. The mass was treated with ruthenium plaque radiotherapy. After 4 years of follow-up, the mass remained regressed, and no systemic myeloma has developed. CONCLUSIONS: Iris plasmacytoma is rare and should prompt systemic evaluation to rule out multiple myeloma. Solitary iris plasmacytoma can be successfully treated with plaque radiotherapy. PMID- 28594701 TI - 20 Things You Didn't Know About Type 2 Diabetes in Emerging Adults. PMID- 28594702 TI - Ozone-Related Respiratory Morbidity in a Low-Pollution Region. AB - OBJECTIVE: We evaluated the effects of ozone on respiratory-related hospital admissions in three counties in Washington State from 1990 to 2006. We further examined vulnerability to ozone by key demographic factors. METHOD: Using linked hospital admission and ambient monitoring data, we estimated the age-, sex-, and health insurance-stratified associations between ozone (0 to 3 days' lag) and respiratory-related hospital admissions in King, Spokane, and Clark County, Washington. RESULTS: The adjusted relative risk (RR) for a 10 ppb increase in ozone at 3 days' lag was 1.04 (95% confidence interval [CI]: 1.02, 1.07) for Clark County, 1.03 (95% CI: 1.01, 1.05) for Spokane County, and 1.02 (95% CI: 1.01, 1.03) for King County. There was consistent evidence of effect modification by age. CONCLUSION: Ozone at levels below federal standards contributes to respiratory morbidity among high-risk groups in Washington. PMID- 28594703 TI - The Centers for Disease Control and Prevention: Findings From The National Healthy Worksite Program. AB - OBJECTIVE: To evaluate employers' implementation of evidence-based interventions, and changes in employees' behaviors associated with participating in the national healthy worksite program (NHWP). METHODS: NHWP recruited 100 small and mid-sized employers and provided training and support for 18 months. Outcome measures were collected with an employer questionnaire, an employee survey, and biometric data at baseline and 18 months later. RESULTS: The 41 employers who completed the NHWP implemented significantly more evidence-based interventions and had more comprehensive worksite health promotion programs after participating. Employees made significant improvements in physical activity and nutritional behaviors, but did not significantly improve employee weight. CONCLUSIONS: Training and technical support can help small and mid-sized employers implement evidence-based health interventions to promote positive employee behavior changes. A longer follow up period may be needed to assess whether NHWP led to improvements in clinical outcomes. PMID- 28594704 TI - Impact on Employee Productivity From Presenteeism and Absenteeism: Evidence From a Multinational Firm in Sri Lanka. AB - OBJECTIVE: This study examines the effects of 13 psychological and physical health conditions on work productivity. METHODS: One hundred fifty-two staff at the headquarters of a Sri Lankan multinational firm completed a questionnaire asking whether they experienced 13 health conditions common in workplaces, and about their related absenteeism and presenteeism. RESULTS: Most respondents (85.5%) reported absenteeism, presenteeism, or both. Among those reporting a health condition, 57.6% reported losing days due to absenteeism, and 69.5% reported losing additional days to presenteeism. Among those caring for a sick adult or child, 57.3% reported losing days due to absenteeism, and 36.5% reported losing additional days due to presenteeism. Overall productivity loss was 10.43 days each year, 3.95% of employee capacity, equating to about Sri Lanka Rupees 8 million (US$54,421) for all headquarters employees. CONCLUSIONS: The health conditions' effects on productivity significantly increased employee costs. PMID- 28594705 TI - Chronic Obstructive Pulmonary Disease in Farmers: A Systematic Review. AB - OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a significant public health problem but it is unclear whether agricultural work causes an increased risk of disease. The aim of this review was to study COPD risk among farmers and analyze occupational exposures in agricultural workplaces. METHODS: A systematic literature search was conducted to identify epidemiological studies investigating COPD prevalence in farmers. RESULTS: In the 14 studies reviewed, COPD prevalence ranged from 3% to 68% due to different characteristics of study population, working activities, case definition/diagnosis. Livestock farmers were at higher risk and significant associations were observed for exposure to organic dusts, endotoxins, mites, ammonia, and hydrogen sulfide. CONCLUSIONS: Farming work was associated with greater risk of developing COPD. However, considering the several variables that may influence the disease prevalence in farmers, we suggest the adoption of a standardized research strategy. PMID- 28594706 TI - Diagnosis of tuberous sclerosis complex in a patient referred for uncontrolled hypertension and renal dysfunction: a case highlighting the importance of proper diagnostic work-up of hypertensive patients. AB - : We report a case of a 39-year-old woman with resistant hypertension and renal dysfunction. The patient was hospitalized 3 months earlier for dyspnea at the Department of Cardiology, where she was diagnosed with heart failure (left ventricle injection fraction: 25-30%), pulmonary hypertension, chronic kidney disease (serum creatinine: 1.58 mg/dl), and resistant hypertension and discharged with optimal heart failure treatment. At presentation to our clinic, apart from uncontrolled hypertension for more than 10 years and history of pre-eclampsia and fetal loss, the patient had obesity (BMI: 38 kg/m) and facial fibromas. The first diagnostic steps proposed by the European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines to identify other target-organ damage and causes of secondary hypertension revealed typical proteinuric hypertensive nephropathy, hypertensive retinopathy, and sleep-apnea syndrome. Furthermore, a renal ultrasound showed multiple bilateral renal angiomyolipomas, confirmed by an MRI scan. Following consultation with the Neurology and Dermatology Departments, the diagnosis of tuberous sclerosis complex, based on presence of six major criteria, was confirmed. During the following 10 months, careful adjustments in the patient's antihypertensive treatment, reinforcement of lifestyle interventions, and improved compliance enabled her to reduce her body weight, control blood pressure, improve her heart (left ventricle injection fraction: >40%), and renal injury (creatinine urine clearance: 125 ml/min, urine protein: 178 mg/24 day) and serum triglycerides (153 mg/dl). These improvements enabled the start of everolimus, required for a slight increase in angiomyolipomas' size (3.46 cm) in the repeated examinations. PMID- 28594707 TI - A comparison of blood pressure in community pharmacies with ambulatory, home and general practitioner office readings: systematic review and meta-analysis. AB - BACKGROUND: Blood pressure (BP) readings are traditionally taken in a clinic setting, with treatment recommendations based on these measurements. The clinical interpretation of BP readings taken in community pharmacies is currently unclear. This study aimed to systematically review all literature comparing community pharmacy BP (CPBP) readings with ambulatory BP monitoring (ABPM), home BP monitoring and general practitioner clinic readings. METHOD: Studies were included if they compared CPBP with at least one other measurement modality used for the diagnosis or management of hypertension. Mean CPBP readings were compared with other measurement modalities and summarized using random-effects meta analyses. The primary outcome was to compare CPBP with gold standard ABPM readings. RESULTS: Searches generated 3815 studies of which eight were included in the meta-analyses. The mean systolic CPBP-daytime ABPM difference was small [+1.6 mmHg (95% confidence interval -1.2 to 4.3) three studies, n = 319]. CPBP was significantly higher than 24-h ABPM [+7.8 mmHg (95% confidence interval 1.5 14.1) three studies n = 429]. Comparisons with general practitioner clinic readings (six studies, n = 2100) were inconclusive with significant heterogeneity between studies. CPBP and home BP monitoring readings (five studies, n = 1848) were nonsignificantly different. Diastolic comparisons mirrored systolic comparisons in all but the CPBP-daytime ABPM comparison, where CPBP was significantly higher. CONCLUSION: Current evidence around the clinical interpretation of CPBP is inconclusive. Although this review suggests that adopting the 135/85 mmHg threshold for hypertension might be reasonable and potentially result in a higher sensitivity for detecting patients with truly raised BP in pharmacies, the impact of this lower threshold on increased referrals to general practice clinics must be considered. PMID- 28594708 TI - Reference values of cardio-ankle vascular index in a random sample of a white population. AB - OBJECTIVES: Cardio-ankle vascular index (CAVI), a parameter of arterial stiffness, has been increasingly used for cardiovascular risk estimation. Currently used CAVI reference values are derived from the Japanese population. It is not clear whether the same reference values can be used in the white population. The aim of the present study was to describe cardiovascular risk factors influencing CAVI and to establish CAVI reference values. METHODS: A total of 2160 individuals randomly selected from the Brno city population aged 25-65 years were examined. Of these, 1347 patients were free from cardiovascular disease, nondiabetic and untreated by antihypertensive or lipid-lowering drugs, forming the reference value population. CAVI was measured using the VaSera VS 1000 device (Fukuda Denshi, Tokyo, Japan). RESULTS: At each blood pressure (BP) level, there was a quadratic association between CAVI and age, except for a linear association in the optimal BP group. Although there was no association between BP and CAVI in younger patients, there was a linear association between CAVI and BP after 40 years of age. Reference values by age and sex were established. In each age group, except for the male 60-65-year group, reference values in our population were lower than in the Japanese one with the difference ranging from -0.29 to 0.21 for men, and from -0.38 to -0.03 for women. CONCLUSION: This is the first study providing CAVI reference values in a random sample of the white population. Our results suggest that the currently used values slightly overestimate CAVI in younger white, possibly underestimating cardiovascular risk. PMID- 28594709 TI - Effect of oxidative stress on racial differences in vascular function at rest and during hand grip exercise. AB - OBJECTIVES: African-Americans have a higher prevalence of hypertension compared with whites, possibly due to elevated oxidative stress and subsequent vascular dysfunction. It is unclear the contribution of aging on oxidative stress and vascular function in a racially diverse cohort. METHODS: Ninety-three young and older African-American and white participants received antioxidant (AOX) or placebo supplementation in a double-blind, randomized, cross-over design. Measures of endothelial function (reactive hyperemia, flow-mediated dilation), exercise blood flow, and biomarkers of oxidative stress and AOX activity were measured following supplementation. RESULTS: In young adults, there were racial differences in resistance vessel response to reactive hyperemia and no effects of race on macrovascular function following AOX supplementation. Following AOX supplementation, older white adults improved while African-Americans reduced resistance vessel function responses to reactive hyperemia, whereas macrovascular function improved in both races, with a greater increase in African-Americans. There were racial differences in blood flow normalized to lean mass during handgrip exercise at 20% maximal voluntary contraction in the young group and AOX supplementation led to increased forearm vascular conductance in older whites with a decrease in older African-Americans. There was a supplement effect in superoxide dismutase activity in younger adults only. CONCLUSION: The results of the current study show that there are differential effects of AOX supplementation on macrovascular and resistance vessel function, and this is impacted by both age and race. PMID- 28594710 TI - Twenty-four-hour central blood pressure is not better associated with hypertensive target organ damage than 24-h peripheral blood pressure. AB - BACKGROUND AND AIM: Central blood pressure (BP) is increasingly considered as a better estimator of hypertension associated risks. We aimed to evaluate the association of 24-h central BP, in comparison with 24-h peripheral BP, with the presence of target organ damage (TOD). METHODS: Cross-sectional study of 208 hypertensive patients, aged 57 +/- 12 years, 34% women. Office (mean of 4 measurements) and 24-h central and peripheral BP were measured by the oscillometric Mobil-O-Graph device. TOD was assessed at cardiac (left ventricular hypertrophy by echocardiography), renal (reduction of glomerular filtration rate and/or microalbuminuria), and arterial (increased aortic pulse wave velocity) levels. RESULTS: A total of 107 patients (51.4%) had TOD (77, 35% patients left ventricular hypertrophy; 54, 25.9% renal abnormalities; and 40, 19.2% arterial stiffness). All SBP and pulse BP estimates (office, 24-h, daytime, and night time) were associated with the presence of TOD, after adjustment for age, sex, and antihypertensive treatment, with higher odds ratios for ambulatory-derived values. Odds ratios for central and peripheral BP were similar for all office, 24 h, daytime, and night-time BP. After simultaneous adjustment, peripheral, but not central, 24-h and night-time SBP and pulse pressures were associated with the presence of TOD. CONCLUSION: TOD in hypertension is associated with BP elevation, independently of the type of measurement (office or ambulatory, central or peripheral). Central BP, even monitored during 24 h, is not better associated with TOD than peripheral BP. These results do not support a routine measurement of 24-h central BP. PMID- 28594711 TI - Effects of repeated yearly exposure to exercise-training on blood pressure and metabolic syndrome evolution. AB - OBJECTIVE: To study if repeated yearly training programs consolidate the transient blood pressure (BP) improvements of one exercise program into durable adaptations. METHODS: Obese middle-age individuals with metabolic syndrome (MetS) underwent high-intensity aerobic interval training during 16 weeks (November to mid-March) in 3 consecutive years [training group (TRAIN); N = 23]. Evolution of MetS components was compared with a matched-group that remained sedentary [control group (CONT); N = 26]. RESULTS: At the end of the first training program (0-4 months), TRAIN lowered systolic arterial pressure, blood glucose, waist circumference and MetS Z-score below CONT (-8.5 +/- 2.5 mmHg; -19.9 +/- 2.6 mg/dl; -3.8 +/- 0.1 cm and -0.3 +/- 0.1, respectively, all P < 0.05). With detraining (month 4-12) TRAIN adaptations relapsed to the levels of baseline (month 0) except for BP. A second exercise program (month 12-16) lowered blood glucose and waist circumference below CONT (-19.0 +/- 2.0 mg/dl; -4.1 +/- 0.1 cm). After detraining (month 16-24) BP, blood glucose and Z-score started below CONT values (-6.8 +/- 0.9 mmHg; -24.6 +/- 2.5 mg/dl and -0.4 +/- 0.05, respectively, all P < 0.05) and those differences enlarged with the last training program (month 24-28). Ten-year atherosclerotic cardiovascular disease risk estimation increased only in CONT (8.6 +/- 1.1-10.1 +/- 1.3%; year 2-3; P < 0.05). CONCLUSION: At least two consecutive years of 4-month aerobic interval training are required to chronically improve MetS (Z-score). The chronic effect is mediated by BP that does not fully return to pretraining values allowing a cumulative improvement. On the other hand, sedentarism in MetS patients during 3 years increases their predicted atherosclerotic diseases risk. CLINICALTRIALS. GOV IDENTIFIER: NCT03019796. PMID- 28594712 TI - Treatment of Locally Advanced Rectal Cancer: Turning Good Rationale Into Good Evidence? PMID- 28594713 TI - Postoperative Venous Thromboembolism in IBD: It's All About the Disease. PMID- 28594714 TI - Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial. AB - BACKGROUND: Preoperative radiochemotherapy and total mesorectal excision are the standard-of-care for locally advanced rectal carcinoma, but some patients could be over- or undertreated. OBJECTIVE: This study aimed to assess the feasibility of radiochemotherapy tailored based on the tumor response to induction chemotherapy (FOLFIRINOX) to obtain a minimum R0 resection rate of 90% in the 4 arms of the study. DESIGN: This study is a multicenter randomized trial (NCT01333709). SETTING: This study was conducted at 16 French cancer specialty centers. PATIENTS: Two hundred six patients with locally advanced rectal carcinoma were enrolled between 2011 and 2014. INTERVENTIONS: Good responders (>=75% tumor volume reduction) were randomly assigned to immediate surgery (arm A) or standard radiochemotherapy (Cap 50: 50 Gy irradiation and 1600 mg/m oral capecitabine daily) plus surgery (arm B). Poor responders were randomly assigned to Cap 50 (arm C) or intensive radiochemotherapy (Cap 60, 60 Gy irradiation, arm D) before surgery. OUTCOME MEASURES: The primary end point was a R0 resection rate (circumferential resection margin >1 mm). STATISTICAL CONSIDERATIONS: The experimental strategies were to be considered effective if at least 28 successes (R0 resection) among 31 patients in each arm of stratum I and 34 successes among 40 patients in each arm of stratum II were reported (Simon 2-stage design). RESULTS: After induction treatment (good compliance), 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders who were included in arms A and B (16 and 14 patients) and arms C and D (113 and 51 patients). The trial was prematurely stopped because of low accrual in arms A and B and recruitment completion in arms C and D. Data from 133 randomly assigned patients were analyzed: 11, 19, 52, and 51 patients in arms A, B, C, and D. Good responders had smaller tumors than poor responders (23 cm vs 45 cm; p < 0.001). The surgical procedure was similar among groups. The R0 resection rates [90% CI] were 100% [70-100], 100% [85-100], 83% [72-91], and 88% [77-95]. Among the first 40 patients, 34 successes were reported in arms C and D (85% R0 resection rate). The circumferential resection margin <=1 rates were 0%, 0%, 12%, and 5% in arms A, B, C, and D. The rate of transformation from positive to negative circumferential resection margin was 93%. LIMITATIONS: There was low accrual in arms A and B. CONCLUSION: Tailoring preoperative radiochemotherapy based on the induction treatment response appears safe for poor responders and promising for good responders. Long-term clinical results are needed to confirm its efficacy. See Video Abstract at http://links.lww.com/DCR/A359. PMID- 28594715 TI - Long-term Outcomes of Single-Site Laparoscopic Colectomy With Complete Mesocolic Excision for Colon Cancer: Comparison With Conventional Multiport Laparoscopic Colectomy Using Propensity Score Matching. AB - BACKGROUND: Complete mesocolic excision has been suggested to improve oncological outcomes for patients with colon cancer. However, the long-term outcomes of single-site laparoscopic colectomy with complete mesocolic excision remain unclear. OBJECTIVE: We evaluated the long-term outcomes of single-site laparoscopic colectomy with complete mesocolic excision compared with conventional multiport laparoscopic colectomy for colon cancer, as well as the short-term outcomes. DESIGN: This is a single-center, retrospective study. SETTINGS: The study was conducted at Osaka University Hospital in Japan. PATIENTS: A total of 971 consecutive patients who underwent laparoscopic surgery for colon cancer between 2008 and 2014 were included. Of these patients, 517 were analyzed using propensity score matching (231 with single-site laparoscopic colectomy and 286 with conventional multiport laparoscopic colectomy). MAIN OUTCOME MEASURES: Recurrence, survival, intraoperative morbidity, and postoperative complications were analyzed. RESULTS: Before propensity score matching, the single-site laparoscopic colectomy group had greater proportions of women and of patients with right-sided and early stage tumors compared with the conventional multiport laparoscopic colectomy group. After matching, the 2 groups each included 200 patients and did not significantly differ in any patient characteristics. The median follow-up period was 41.4 months. The 2 groups showed similar rates of intraoperative morbidity (p = 0.22) and postoperative complications (p = 0.87). Rates of 3-year disease-free and overall survival in single-site laparoscopic colectomy and conventional, multiport, laparoscopic colectomy groups were 95.5% and 91.3% (p = 0.44) and 100.0% and 98.7% (p = 0.24). The 3-year disease-free and overall survival rates in each stage did not significantly differ between the 2 groups. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Single-site laparoscopic colectomy with complete mesocolic excision for colon cancer provided acceptable perioperative outcomes and oncological outcomes, similar to those achieved with conventional multiport laparoscopic colectomy. Evidence accumulation from randomized controlled trials will be necessary to promote the wide acceptance of single-site laparoscopic colectomy. See Video Abstract at http://links.lww.com/DCR/A326. PMID- 28594716 TI - Mesenteric Lymphadenectomy in Well-Differentiated Appendiceal Neuroendocrine Tumors. AB - BACKGROUND: Surgical resection is the primary therapy for local and locally advanced appendiceal neuroendocrine tumors. The role of mesenteric lymphadenectomy in these patients is undefined. OBJECTIVE: The purpose of this study was to define the role and prognostic significance of mesenteric lymphadenectomy. DESIGN: This was a retrospective, observational study. SETTINGS: A population-based cohort from the National Cancer Institute Surveillance, Epidemiology, and End Results registry (January 1988 to November 2013) was used. PATIENTS: Patients with well-differentiated neuroendocrine tumors and nonmixed histologies undergoing surgical resection were included. MAIN OUTCOME MEASURES: The risk of lymph node metastases as a function of tumor size and overall survival with respect to lymph node count and tumor size was measured. Lymph node cut-point was determined using the Contal and O'Quigely method. RESULTS: Of the 573 patients who met the inclusion criteria, 64% were women, 79% were white, and 76% were <60 years of age. Seventy percent of the tumors were <=2 cm, and 77% were lymph node negative. Median lymph nodes retrieved were 0 (interquartile range, 0-14). The probability of nodal metastases was 2.7% in tumors <=1.0 cm, 31.0% in tumors 1.1 to 2.0 cm, and 64.0% in tumors >2.0 cm. The probability of a positive lymph node increased with increasing lymph node count up to 26 lymph nodes. An ideal cut-point of 12 lymph nodes was identified by statistical modeling. After adjustment in the multivariable model, the group with 12 or fewer lymph nodes examined had significantly worse overall survival (HR = 4.33 (95% CI, 1.54-12.15); p = 0.005; 5-year survival, 88% versus 96%) than the group with more than 12 lymph nodes examined. LIMITATIONS: Analysis was limited by the variables available in the database. CONCLUSIONS: This is the largest study to date that looks at prognostic significance of lymph node count for well-differentiated appendiceal neuroendocrine tumors. Overall survival was worse where 12 or fewer lymph nodes were identified for tumors >1 cm. See Video Abstract at http://links.lww.com/DCR/A352. PMID- 28594717 TI - Long-term Risk of Urinary Adverse Events in Curatively Treated Patients With Rectal Cancer: A Population-Based Analysis. AB - BACKGROUND: Treatment modalities for rectal cancer, including radiation, are associated with urinary adverse effects. OBJECTIVE: The purpose of this study was to determine the influence of surgery and radiation therapy for rectal cancer on long-term urinary complications. DESIGN: Using the Surveillance Epidemiology and End Results-Medicare data set from the United States, patients with rectal cancer older than 66 years of age who underwent rectal resection between 1992 and 2007 were stratified into treatment groups that accounted for surgical resection and the timing of radiation therapy, if used. A control group of patients who did not have rectal cancer were matched by age, sex, demographics, and comorbidities. The primary outcome was a urinary adverse event defined as a relevant urinary diagnosis with an associated procedure. Patients with rectal cancer in different treatment groups were compared with control patients using a propensity-adjusted, multivariable Cox regression analysis. SETTINGS: The study was conducted with the Surveillance Epidemiology and End Results-Medicare data set from the United States at our institution. RESULTS: Of the 11,068 patients with rectal cancer, 56.2% had surgical resection alone, 21.7% received preoperative radiation, and 22.1% received postoperative radiation. The median follow-up for all of the groups of patients was >2 years. All of the groups of patients with rectal cancer were more likely to develop a urinary adverse event compared with control subjects. Adjusted HRs were 2.28 (95% CI, 2.02-2.57) for abdominoperineal resection alone, 2.24 (95% CI, 1.79-2.80) for preoperative radiation and surgical resection, 2.04 (95% CI, 1.70-2.44) for surgical resection and postoperative radiation, and 1.69 (95% CI, 1.52-1.89) for low anterior resection alone. LIMITATIONS: Treatment patterns are somewhat outdated, with a large proportion of patients receiving postoperative radiation. The data did not allow for accurate assessment of urinary tract infections or mild urinary retention that is not managed with a procedure. CONCLUSIONS: Rectal cancer surgery with or without radiation is associated with a higher risk of urinary complications requiring procedures. Patients who undergo low anterior resection without radiation tend toward the lowest risk for a urinary adverse event. PMID- 28594718 TI - Risk of Ovarian Involvement in Advanced Colorectal or Appendiceal Tumors Involving the Peritoneum. AB - BACKGROUND: Ovarian metastases of GI tumors grow rapidly and are relatively resistant to systemic chemotherapy. They may be unilateral or bilateral and macroscopic or occult. The risk of macroscopic ovarian involvement or occult involvement of macroscopically normal ovaries is unquantified. OBJECTIVE: This study aims to quantify the risks of ovarian involvement in patients with peritoneal malignancy undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. DESIGN: This was a retrospective analysis of a dedicated prospective malignancy database. SETTINGS: This study was conducted at a high-volume tertiary referral center for peritoneal malignancy. PATIENTS: Female patients with at least 1 remaining ovary, undergoing complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal tumors or colorectal peritoneal metastases between January 2010 and March 2015 were included. OUTCOME MEASURES: Data regarding ovarian involvement was extracted from surgical and histological records. RESULTS: Two hundred fifty eight female patients with at least 1 ovary underwent complete cytoreduction and hyperthermic intraperitoneal chemotherapy during the study period. In total, 141 of 258 (54.7%) patients had ovarian tumor involvement, and 80% with at least 1 macroscopically abnormal ovary had bilateral involvement. Of 40 patients with 1 macroscopic ovarian metastasis, microscopic involvement of the contralateral ovary was found in 18 of 40 (45.0%). Of 141 patients in whom both ovaries were macroscopically normal, 24 of 141 (17.0%) patients had microscopic ovarian involvement. LIMITATIONS: The retrospective nature limits the interpretation of these results. CONCLUSIONS: Occult malignancy was present in 17% when both ovaries looked macroscopically normal and in 45% of contralateral normal-looking ovaries if the other ovary was macroscopically involved. These results help to inform preoperative consent and intraoperative decision making in patients with advanced appendiceal and colorectal malignancy, and are of benefit in managing advanced lower GI tract malignancy. PMID- 28594719 TI - Bowel Dysfunction After Low Anterior Resection With Neoadjuvant Chemoradiotherapy or Chemotherapy Alone for Rectal Cancer: A Cross-Sectional Study from China. AB - BACKGROUND: Neoadjuvant therapy plays a vital role in the treatment of locally advanced rectal cancer but impairs bowel function after restorative surgery. Optimal decision making requires adequate information of functional outcomes. OBJECTIVE: This study aimed to assess postoperative bowel function and to identify predictors for severe dysfunction. DESIGN: The study included a cross sectional cohort and retrospective assessments of pelvic anatomic features. SETTINGS: The study was conducted at a tertiary GI hospital in China. PATIENTS: Included patients underwent neoadjuvant chemoradiotherapy or chemotherapy without radiation and curative low anterior resection for rectal cancer between 2012 and 2014. MAIN OUTCOME MEASURES: Bowel function was assessed using the validated low anterior resection syndrome score. The thicknesses of the rectal wall, obturator internus, and levator ani were measured by preoperative MRI. RESULTS: A total of 151 eligible patients were identified, and 142 patients (94.0%) participated after a median of 19 months from surgery. Bowel dysfunction was observed in 71.1% (101/142) of patients, with 44.4% (63/142) reporting severe dysfunction. Symptoms of urgency and clustering were found to be major disturbances. Regression analysis identified preoperative long-course radiotherapy (p < 0.001) and a lower third tumor (p = 0.002) independently associated with severe bowel dysfunction. Irradiated patients with a lower-third tumor (OR = 14.06; p < 0.001) or thickening of the rectal wall (OR = 11.09; p < 0.001) had a markedly increased risk of developing severe dysfunction. LIMITATIONS: The study was based on a limited cohort of patients and moderate follow-up after the primary surgery. CONCLUSIONS: Bowel function deteriorates frequently after low anterior resection for rectal cancer. Severe bowel dysfunction is significantly associated with preoperative long-course radiotherapy and a lower-third tumor, and the thickening of rectal wall after radiation is a strong predictor. Treatment decisions and patient consent should be implemented with raising awareness of bowel symptom burdens. See Video Abstract at http://links.lww.com/DCR/A317. PMID- 28594720 TI - Clinical Relevance of a Grading System for Anastomotic Leakage After Low Anterior Resection: Analysis From a National Cohort Database. AB - BACKGROUND: Anastomotic leakage is a severe complication after low anterior resection for rectal cancer. With a global increase in registration initiatives, adapting uniform definitions and grading systems is highly relevant. OBJECTIVE: This study aimed to provide clinical parameters to categorize anastomotic leakage into subcategories according to the International Study Group of Rectal Cancer. DESIGN: All of the patients who underwent a low anterior resection in the Netherlands with primary anastomosis were included using the population-based Dutch Surgical Colorectal Audit. SETTINGS: Data were derived from the Dutch Surgical Colorectal Audit. MAIN OUTCOME MEASURES: The development of grade B anastomotic leakage (requiring invasive treatment but no surgery) versus grade C anastomotic leakage (requiring reoperation) was measured. RESULTS: Overall, 4287 patients underwent low anterior resection with primary anastomosis. A total of 159 patients (4%) were diagnosed with grade B anastomotic leakage versus 259 (6%) with grade C. Hospital stay and intensive care unit visits were significantly higher in patients with grade C anastomotic leakage compared with patients with grade B leakage. Mortality in patients with grade C leakage was higher compared with grade B leakage, although nonsignificant (5.8% vs 2.5%; p = 0.12). Multivariate analysis showed that patients with diverting stomas (n = 2866) had a decreased risk of developing grade C leakage compared with grade B (OR = 0.17 (95% CI, 0.10-0.29)). Male patients had an increased risk of developing grade C anastomotic leakage, and patients receiving neoadjuvant treatment before surgery had an increased risk of developing grade B anastomotic leakage. LIMITATIONS: Some possibly relevant variables, such as smoking and nutritional status, were not recorded in the database. CONCLUSIONS: Anastomotic leakage after low anterior resection for rectal cancer was a frequent observed complication in this cohort. Differences in clinical outcome suggest that grade B and C leakage should be considered separate entities in future registrations. In patients with a diverting stoma, the chances of experiencing grade C anastomotic leakage were reduced. See Video Abstract at http://links.lww.com/DCR/A315. PMID- 28594721 TI - Analysis of Postoperative Venous Thromboembolism in Patients With Chronic Ulcerative Colitis: Is It the Disease or the Operation? AB - BACKGROUND: Patients with IBD have a higher baseline risk of venous thromboembolism, which further increases with surgery. Therefore, extended venous thromboembolism chemoprophylaxis has been suggested in certain high-risk cohorts. OBJECTIVE: The purpose of this study was to determine whether the underlying diagnosis, operative procedure, or both influence the incidence of postoperative venous thromboembolism. DESIGN: This was a retrospective review. SETTINGS: The American College of Surgeons-National Surgical Quality Improvement Project database was analyzed. PATIENTS: The NSQIP database was queried for patients with chronic ulcerative colitis and non-IBD undergoing colorectal resections using surgical Current Procedural Terminology codes modeled after the 3 stages used for the surgical management of chronic ulcerative colitis from 2005 to 2013. MAIN OUTCOME MEASURES: We measured 30-day postoperative venous thromboembolism risk in patients with chronic ulcerative colitis based on operative stage and risk factors for development of venous thromboembolism. RESULTS: A total of 18,833 patients met inclusion criteria, with an overall rate of venous thromboembolism of 3.8. Among procedure risk groups, venous thromboembolism rates were high risk, 4.4%; intermediate risk, 1.6%; and low risk, 0.7% (across risk groups, p < 0.01). Emergent case subjects exhibited a higher rate of venous thromboembolism than their elective counterparts (6.9% vs 3.1%). Factors significantly associated with venous thromboembolism on adjusted analysis included emergent risk case (adjusted OR = 7.85), high-risk elective case (adjusted OR = 5.07), intermediate-risk elective case (adjusted OR = 2.69), steroid use (adjusted OR = 1.54), and preoperative albumin <3.5 g/dL (adjusted OR = 1.45). LIMITATIONS: Because of its retrospective nature, correlation between procedures and venous thromboembolism risk can be demonstrated, but causation cannot be proven. In addition, data on inpatient and extended venous thromboembolism prophylaxis use are not available. CONCLUSIONS: Emergent status and operative procedure are the 2 highest risk factors for postoperative venous thromboembolism. Extended venous thromboembolism prophylaxis might be appropriate for patients undergoing these high-risk procedures or any emergent colorectal procedures. See Video Abstract at http://links.lww.com/DCR/A339. PMID- 28594722 TI - Treatment of Complex Fistula-in-Ano With a Nitinol Proctology Clip. AB - BACKGROUND: The treatment of complex anocutaneous fistulas remains a major therapeutic challenge balancing the risk of incontinence against the chance of permanent closure. OBJECTIVE: The purpose of this study was to investigate the efficacy of a nitinol proctology clip for closure of complex anocutaneous fistulas. DESIGN: This is a single-center cohort study with retrospective analysis of all of the treated patients. SETTINGS: Data were obtained from patient records and MRI reports, as well as follow-up telephone calls and clinical follow-up with endoanal ultrasonography. PATIENTS: All of the patients were treated for high transsphincteric and suprasphincteric anocutaneous fistulas at the Digestive Disease Center, Bispebjerg Hospital, between May 2013 and February 2015. INTERVENTIONS: All of the patients were treated with the nitinol proctology clip. MAIN OUTCOME MEASURES: Primary outcome was fistula healing after proctology clip placement, as evaluated through clinical examination, endoanal ultrasonography, and MRI. RESULTS: The fistula healing rate 1 year after the clip procedure was 54.3% (19 of 35 included patients). At the end of follow-up, 17 (49%) of 35 patients had persistent closure of the fistula tracks. No impairment of continence function was observed. Treatment outcome was not found to be statistically associated with any clinicopathological characteristics. LIMITATIONS: The study is limited by its retrospective and nonrandomized design. Selection bias may have occurred, because treatment options other than the clip were available during the study period. The small number of patients means that there is a nonnegligible risk of type II error in the conclusion, and the follow up may be too short to have detected all of the failures. CONCLUSIONS: Healing rates were comparable with those of other noninvasive, sphincter-sparing techniques for high-complex anocutaneous fistulas, with no risk of incontinence. Predictive parameters for fistula healing using this technique remain uncertain. See Video Abstract at http://links.lww.com/DCR/A347. PMID- 28594723 TI - Is There a Role for Oral Antibiotic Preparation Alone Before Colorectal Surgery? ACS-NSQIP Analysis by Coarsened Exact Matching. AB - BACKGROUND: Recent studies demonstrated reduced postoperative complications using combined mechanical bowel and oral antibiotic preparation before elective colorectal surgery. OBJECTIVE: The aim of this study was to assess the impact of these 2 interventions on surgical site infections, anastomotic leak, ileus, major morbidity, and 30-day mortality in a large cohort of elective colectomies. DESIGN: This is a retrospective comparison of 30-day outcomes using the American College of Surgeons National Surgical Quality Improvement Program colectomy targeted database with coarsened exact matching. SETTINGS: Interventions were performed in hospitals participating in the national surgical database. PATIENTS: Adult patients who underwent elective colectomy from 2012 to 2014 were included. INTERVENTIONS: Preoperative bowel preparations were evaluated. MAIN OUTCOME MEASURES: The primary outcomes measured were surgical site infections, anastomotic leak, postoperative ileus, major morbidity, and 30-day mortality. RESULTS: A total of 40,446 patients were analyzed: 13,219 (32.7%), 13,935 (34.5%), and 1572 (3.9%) in the no-preparation, mechanical bowel preparation alone, and oral antibiotic preparation alone groups, and 11,720 (29.0%) in the combined preparation group. After matching, 9800, 1461, and 8819 patients remained in the mechanical preparation, oral antibiotic preparation, and combined preparation groups for comparison with patients without preparation. On conditional logistic regression of matched patients, oral antibiotic preparation alone was protective of surgical site infection (OR, 0.63; 95% CI, 0.45-0.87), anastomotic leak (OR, 0.60; 95% CI, 0.34-0.97), ileus (OR, 0.79; 95% CI, 0.59 0.98), and major morbidity (OR, 0.73; 95% CI, 0.55-0.96), but not mortality (OR, 0.32; 95% CI, 0.08-1.18), whereas a regimen of combined oral antibiotics and mechanical bowel preparation was protective for all 5 major outcomes. When directly compared with oral antibiotic preparation alone, the combined regimen was not associated with any difference in any of the 5 postoperative outcomes. LIMITATIONS: This study was limited by its retrospective design with heterogeneous data. CONCLUSIONS: Oral antibiotic preparation alone significantly reduced surgical site infection, anastomotic leak, postoperative ileus, and major morbidity after elective colorectal surgery. A combined regimen of oral antibiotics and mechanical bowel preparation offered no superiority when compared with oral antibiotics alone for these outcomes. See Video Abstract at http://links.lww.com/DCR/A358. PMID- 28594724 TI - The American Society of Colon and Rectal Surgeons Assessment Tool for Performance of Laparoscopic Colectomy. AB - BACKGROUND: The lack of consensus for performance assessment of laparoscopic colorectal resection is a major impediment to quality improvement. OBJECTIVE: The purpose of this study was to develop and assess the validity of an evaluation tool for laparoscopic colectomy that is feasible for wide implementation. DESIGN: During the pilot phase, a small group of experts modified previous assessment tools by watching videos for laparoscopic right colectomy with the following categories of experience: novice (less than 20 cases), intermediate (50-100 cases), and expert (more than 500 cases). After achieving sufficient reliability (kappa > 0.8), a user-friendly tool was validated among a large group of blinded, trained experts. SETTING: The study was conducted through the American Society of Colon and Rectal Surgeons Operative Competency Evaluation Committee. PATIENTS: Raters were from the Operative Competency Evaluation Committee of the American Society of Colon and Rectal Surgeons. MAIN OUTCOME MEASURES: Assessment tool reliability and internal consistency were measured. RESULTS: From October 2014 through February 2015, 4 groups of 5 raters blinded to surgeon skill level evaluated 6 different laparoscopic right colectomy videos (novice = 2, intermediate = 2, expert = 2). The overall Cronbach alpha was 0.98 (>0.9 = excellent internal consistency). The intraclass correlation for the overall assessment was 0.93 (range, 0.77-0.93) and was >0.74 (excellent) for each step. The average scores (scale, 1-5) for experts were significantly better than those in the intermediate category, with a mean (SD) of 4.51 (0.56) versus 2.94 (0.56; p = 0.003). Videos in the intermediate group scored more favorably than beginner videos for each individual step and overall performance (mean (SD) = 3.00 (0.32) vs 1.78 (0.42); p = 0.006). LIMITATIONS: The study was limited by rater bias to technique and style. CONCLUSIONS: The unique and robust methodology in this trial produced an assessment tool that was feasible for raters to use when assessing videotaped laparoscopic right hemicolectomies. The potential applications for this new tool are widespread, including both training and evaluation of competence at the attending level. See Video Abstract at http://links.lww.com/DCR/A369, http://links.lww.com/DCR/A370, http://links.lww.com/DCR/A371. PMID- 28594725 TI - Pelvic Exenteration Surgery: The Evolution of Radical Surgical Techniques for Advanced and Recurrent Pelvic Malignancy. AB - Pelvic exenteration was first described by Alexander Brunschwig in 1948 in New York as a palliative procedure for recurrent carcinoma of the cervix. Because of initially high rates of morbidity and mortality, the practice of this ultraradical operation was largely confined to a small number of American centers for most of the 20 century. The post-World War II era saw advances in anaesthesia, blood transfusion, and intensive care medicine that would facilitate the evolution of more radical and heroic abdominal and pelvic surgery. In the last 3 decades, pelvic exenteration has continued to evolve into one of the most important treatments for locally advanced and recurrent rectal cancer. This review aimed to explore the evolution of pelvic exenteration surgery and to identify the pioneering surgeons, seminal articles, and novel techniques that have led to its current status as the procedure of choice for locally advanced and recurrent rectal cancer. PMID- 28594726 TI - Treatment of Anastomotic Stricture of a Handsewn Coloanal Anastomosis With Transanal Approach. PMID- 28594727 TI - Omission of Adjuvant Chemotherapy or Inadequate Surgery? PMID- 28594728 TI - The Authors Reply. PMID- 28594729 TI - Regarding the Clinical Practice Guidelines for the Surgical Treatment of Patients With Lynch Syndrome. PMID- 28594730 TI - The Authors Reply. PMID- 28594731 TI - Fecal Incontinence Reduces Quality of Life More Than You May Think. PMID- 28594734 TI - General Versus Local Anesthesia for Deep Brain Stimulator Insertion. PMID- 28594735 TI - PRO: General Anesthesia for Deep Brain Stimulator Insertion in Patients With Parkinson Disease. PMID- 28594736 TI - CON: Deep Brain Stimulator Insertion for Functional Neurosurgery Under General Anesthesia. PMID- 28594737 TI - Safe Treatment of a Patient With an Ommaya Reservoir With Electroconvulsive Therapy. PMID- 28594738 TI - HEMORRHAGIC VASCULITIS AND RETINOPATHY HERALDING AS AN EARLY SIGN OF BACTERIAL ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION. AB - PURPOSE: To describe a case series of postintravitreal injection, bacterial endophthalmitis heralded by hemorrhagic retinal vasculitis. METHODS: Observational case series of three patients with a history of intravitreal injections for age-related macular degeneration at a tertiary referral center who presented with vision changes and eye pain that were eventually found to have bacterial endophthalmitis. Clinical course was then followed. RESULTS: All patients developed bacterial endophthalmitis and hemorrhagic retinal vasculitis. CONCLUSION: These three cases highlight the importance of hemorrhagic retinal vasculitis as the presenting fundus finding of bacterial endophthalmitis and that this finding in a postinjection patient should be treated as endophthalmitis until proven otherwise. PMID- 28594739 TI - POSTERIOR VITRECTORHEXIS: A SURGICAL MODIFICATION FOR INTRAOCULAR FOREIGN BODY REMOVAL THROUGH LIMBAL ROUTE. AB - PURPOSE: To describe a modified surgical technique of creating a posterior capsule opening for removal of retained intraocular foreign body, what we call as retroillumination-assisted posterior vitrectorhexis. METHODS: Vitrectomy probe through pars plana route is used to create a well-controlled circular posterior vitrectorhexis. RESULTS: A uniformly circular posterior capsule opening is created after standard pars plana vitrectomy for the removal of foreign body. CONCLUSION: Posterior vitrectorhexis is a well-controlled technique in the setting of a penetrating injury that can facilitate safe removal of different sizes of intraocular foreign body simultaneously preserving capsular support. PMID- 28594740 TI - The Importance of Registries in the Postmarketing Surveillance of Surgical Meshes. AB - OBJECTIVE: To assess the role of registries in the postmarketing surveillance of surgical meshes. BACKGROUND: To date, surgical meshes are classified as group II medical devices. Class II devices do not require premarket clearance by clinical studies. Ethicon initiated a voluntary market withdrawal of Physiomesh for laparoscopic use after an analysis of unpublished data from the 2 large independent hernia registries-Herniamed German Registry and Danish Hernia Database. This paper now presents the relevant data from the Herniamed Registry. METHODS: The present analysis compares the prospective perioperative and 1-year follow-up data collected for all patients with incisional hernia who had undergone elective laparoscopic intraperitoneal onlay mesh repair either with Physiomesh (n = 1380) or with other meshes recommended in the guidelines (n = 3834). RESULTS: Patients with Physiomesh repair had a markedly higher recurrence rate compared with the other recommended meshes (12.0% vs 5.0%; P < 0.001). In the multivariable analysis, the recurrence rate was highly significantly influenced by the mesh type used (P < 0.001). If Physiomesh was used, that led to a highly significant increase in the recurrence rate on 1-year follow-up (odds ratio 2.570, 95% CI 2.057, 3.210). The mesh type used also had a significant influence on chronic pain rates. CONCLUSIONS: The importance of real-world data for postmarketing surveillance of surgical meshes has been demonstrated in this registry-based study. Randomized controlled trials are needed for premarket approval of new devices. The role of sponsorship of device studies by the manufacturing company must be taken into account. PMID- 28594742 TI - Outcomes of Lymphedema Microsurgery for Breast Cancer-related Lymphedema With or Without Microvascular Breast Reconstruction. AB - OBJECTIVE: This study investigated the outcome of lymphedema microsurgery with or without microsurgical breast reconstruction for breast cancer-related lymphedema (BCRL). BACKGROUND: Complete decongestive therapy, lymphovenous anastomosis, and vascularized lymph node flap transfer are the 3 major treatment modalities for BCRL. Releasing axillary contracture and transferring a free flap may potentially improve the BCRL. METHODS: Between 2004 and 2015, 124 patients with BCRL who underwent 3 treatment modalities without or with microsurgical breast reconstruction were included in this study as groups I and II, respectively. Patients were offered the lymphedema microsurgery depending on the availability of patent lymphatic ducts on indocyanine green lymphography if they failed to complete decongestive therapy. The circumferential difference, reduction rate, and episodes of cellulitis were used to evaluate the outcome of treatments. RESULTS: Improvements in the circumferential difference (12.8 +/- 4.2% vs 11.5 +/ 5.3%), the reduction rate (20.4 +/- 5.1% vs 14.7 +/- 6%), and episodes of cellulitis (1.7 +/- 1.1 vs 2.1 +/- 2.4 times/yr) did not significantly differ between groups I and II (P = 0.06, 0.07, and 0.06, respectively). In both groups, vascularized lymph node flap transfer was significantly superior to lymphovenous anastomosis or complete decongestive therapy in terms of improvements in the circumferential difference, reduction rate and episodes of cellulitis (P = 0.04, 0.04, and 0.06, respectively). CONCLUSIONS: Microsurgical breast reconstruction did not improve the outcome of BCRL. Improvements in BCRL were better for lymphatic microsurgery than complete decongestive therapy. Moreover, vascularized lymph node flap transfer provided greater improvements in the BCRL than lymphovenous anastomosis. PMID- 28594741 TI - Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy. AB - OBJECTIVE: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. BACKGROUND: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. METHODS: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. RESULTS: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25-0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30-0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an "optimal" mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001). CONCLUSIONS: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes. PMID- 28594743 TI - Increased Severe Trauma Patient Volume is Associated With Survival Benefit and Reduced Total Health Care Costs: A Retrospective Observational Study Using a Japanese Nationwide Administrative Database. AB - OBJECTIVE: The aim of this study was to evaluate the associations of severe trauma patient volume with survival benefit and health care costs. BACKGROUND: The effect of trauma patient volume on survival benefit is inconclusive, and reports on its effects on health care costs are scarce. METHODS: We conducted a retrospective observational study, including trauma patients who were transferred to government-approved tertiary emergency hospitals, or hospitals with an intensive care unit that provided an equivalent quality of care, using a Japanese nationwide administrative database. We categorized hospitals according to their annual severe trauma patient volumes [1 to 50 (reference), 51 to 100, 101 to 150, 151 to 200, and >=201]. We evaluated the associations of volume categories with in-hospital survival and total cost per admission using a mixed-effects model adjusting for patient severity and hospital characteristics. RESULTS: A total of 116,329 patients from 559 hospitals were analyzed. Significantly increased in hospital survival rates were observed in the second, third, fourth, and highest volume categories compared with the reference category [94.2% in the highest volume category vs 88.8% in the reference category, adjusted odds ratio (95% confidence interval, 95% CI) = 1.75 (1.49-2.07)]. Furthermore, significantly lower costs (in US dollars) were observed in the second and fourth categories [mean (standard deviation) for fourth vs reference = $17,800 ($17,378) vs $20,540 ($32,412), adjusted difference (95% CI) = -$2559 (-$3896 to -$1221)]. CONCLUSIONS: Hospitals with high volumes of severe trauma patients were significantly associated with a survival benefit and lower total cost per admission. PMID- 28594744 TI - Probability of Opioid Prescription Refilling After Surgery: Does Initial Prescription Dose Matter? AB - OBJECTIVE: We sought to determine the correlation between the probability of postoperative opioid prescription refills and the amount of opioid prescribed, hypothesizing that a greater initial prescription yields a lower probability of refill. BACKGROUND: Although current guidelines regarding opioid prescribing largely address chronic opioid use, little is known regarding best practices and postoperative care. METHODS: We analyzed Optum Insight claims data from 2013 to 2014 for opioid-naive patients aged 18 to 64 years who underwent major or minor surgical procedures (N = 26,520). Our primary outcome was the occurrence of an opioid refill within 30 postoperative days. Our primary explanatory variable was the total oral morphine equivalents provided in the initial postoperative prescription. We used logistic regression to examine the probability of an additional refill by initial prescription strength, adjusting for patient factors. RESULTS: We observed that 8.67% of opioid-naive patients refilled their prescriptions. Across procedures, the probability of a single postoperative refill did not change with an increase with initial oral morphine equivalents prescribed. Instead, patient factors were correlated with the probability of refill, including tobacco use [odds ratio (OR) 1.42, 95% confidence interval (CI) 1.23-1.57], anxiety (OR 1.30, 95% CI 1.15-1.47), mood disorders (OR 1.28. 95% CI 1.13-1.44), alcohol or substance abuse disorders (OR 1.43, 95% CI 1.12-1.84), and arthritis (OR 1.21, 95% CI 1.10-1.34). CONCLUSIONS: The probability of refilling prescription opioids after surgery was not correlated with initial prescription strength, suggesting surgeons could prescribe smaller prescriptions without influencing refill requests. Future research that examines the interplay between pain, substance abuse, and mental health could inform strategies to tailor opioid prescribing for patients. PMID- 28594745 TI - Indications for Contralateral Prophylactic Mastectomy: A Consensus Statement Using Modified Delphi Methodology. AB - OBJECTIVE: To reach a consensus about contralateral prophylactic mastectomy in unilateral breast cancer. SUMMARY BACKGROUND DATA: There has been a substantial increase in the number of North American women with unilateral breast cancer undergoing a therapeutic mastectomy and a contralateral prophylactic mastectomy (CPM) either simultaneously or sequentially. The purpose of this project was to create a nationally endorsed consensus statement for CPM in women with unilateral breast cancer using modified Delphi consensus methodology. METHODS: A nationally representative expert panel of 19 general surgeons, 2 plastic surgeons, 2 medical oncologists, 2 radiation oncologists, and 1 psychologist was invited to participate in the generation of a consensus statement. Thirty-nine statements were created in 5 topic domains: predisposing risk factors for breast cancer, tumor factors, reconstruction/symmetry issues, patient factors, and miscellaneous factors. Panelists were asked to rate statements on a 7-point Likert scale. Two electronic rounds of iterative rating and feedback were anonymously completed, followed by an in-person meeting. Consensus was reached when there was at least 80% agreement. RESULTS: Our panelists did not recommend for average risk women with unilateral breast cancer. The panel recommended CPM for women with a unilateral breast cancer and previous Mantle field radiation or a BrCa1/2 gene mutation. The panel agreed that CPM could be considered by the surgeon on an individual basis for: women with unilateral breast cancer and a genetic mutation in the CHEK2/PTEN/p53/PALB2/CDH1 gene, and in women who may have significant difficulty achieving symmetry after unilateral mastectomy. CONCLUSION: Contralateral prophylactic mastectomy is rarely recommended for women with unilateral breast cancer. PMID- 28594746 TI - Enhanced Recovery After Surgery (ERAS) Eliminates Racial Disparities in Postoperative Length of Stay After Colorectal Surgery. AB - OBJECTIVE: To investigate the effects of enhanced recovery after surgery (ERAS) on racial disparities in postoperative length of stay (pLOS) after colorectal surgery. BACKGROUND: Racial disparities in surgical outcomes exist. We hypothesized that ERAS would reduce disparities in pLOS between black and white patients. METHODS: Patients undergoing ERAS in 2015 were 1:1 matched by race/ethnicity, age, sex, and procedure to a pre-ERAS group from 2010 to 2014. After stratification by race/ethnicity, expected pLOS was calculated using the American College of Surgeons National Surgical Quality Improvement Project Risk Calculator. Primary outcome was the observed pLOS and observed-to-expected difference in pLOS. Secondary outcomes were National Surgical Quality Improvement Project postoperative complications including 30-day readmissions and mortality. Adjusted sensitivity analyses on pLOS were also performed. RESULTS: Of 420 patients (210 ERAS and 210 pre-ERAS) examined, 28.3% were black. Black and white patients were similar in age, body mass index, sex, American Anesthesia Association class, and minimally invasive approaches. Within the pre-ERAS group, black patients stayed a mean of 2.7 days longer than expected compared with white patients (P < 0.05). Overall, ERAS patients had a significantly shorter pLOS (5.7 vs 8 days) and observed-to-expected difference (-0.7 vs 1.4 days) compared with pre-ERAS patients (P < 0.01). In the ERAS group, disparities in pLOS were reduced with no differences in readmissions or mortality between black and white patients. On sensitivity analyses, race/ethnicity remained a significant predictor of pLOS among pre-ERAS patients, but not for ERAS patients. CONCLUSIONS: ERAS eliminated racial differences in pLOS between black and white patients undergoing colorectal surgery. Reduced pLOS occurred without increases in mortality, readmissions, and most postoperative complications. ERAS may provide a practical approach to reducing disparities in surgical outcomes. PMID- 28594747 TI - Groin Pain Characteristics and Recurrence Rates: Three-year Results of a Randomized Controlled Trial Comparing Self-gripping Progrip Mesh and Sutured Polypropylene Mesh for Open Inguinal Hernia Repair. AB - OBJECTIVE: The aim of this study was to investigate long-term groin pain and inguinal hernia recurrence rates of 2 types of mesh and to describe the evolution of postoperative groin sensory disturbances. SUMMARY OF BACKGROUND DATA: Some patients with an inguinal hernia develop chronic pain following open mesh insertion. Previous trials comparing a semi-resorbable, self-gripping Progrip mesh with a standard sutured polypropylene mesh found conflicting results regarding recurrence rates and residual groin pain. METHODS: Patients aged >18 years scheduled for open primary hernia repair were randomized to a self-gripping mesh (Progrip) or a polypropylene mesh (standard). Removal of the inguinal nerves was left to the discretion of the surgeon. Pain was measured using Visual Analogue Scale (VAS) over a 3-year period. Pain characteristics and hernia recurrences were determined using physical examination. RESULTS: Data of 274 patients were complete (75% three-year follow-up rate). Pain steadily decreased over time in both groups in a similar fashion (moderate pain 3.7% in each group). Hyperesthesia was experienced by 2.2% and 3.7% and hypoesthesia in 12% and 19% in Progrip and standard group, respectively. One of seven Progrip patients reported a foreign body feeling versus 1 of 5 standard patients (P = 0.06). Altered skin sensations were not related to a neurectomy. Hernia recurrence rate was 11.5% in the Progrip and 5% in the standard group (P = 0.05). CONCLUSIONS: Three years after insertion of a self-gripping Progrip mesh or a sutured polypropylene mesh for an open primary inguinal hernia repair, groin pain is minimal, although altered groin skin sensations and foreign body feeling are quite common. A Progrip hernia repair is associated with a high recurrence rate. PMID- 28594748 TI - Inhibition of Spleen Tyrosine Kinase Reduces Renal Allograft Injury in a Rat Model of Acute Antibody-Mediated Rejection in Sensitized Recipients. AB - BACKGROUND: Organ transplantation into sensitized patients with preexisting donor specific antibodies (DSA) is very challenging. Spleen tyrosine kinase (Syk) promotes leukocyte recruitment and activation via signaling through various cell surface receptors. We investigated whether a selective Syk inhibitor (GS-492429) could suppress antibody-mediated rejection (AMR) in a rat model of AMR in sensitized recipients. METHODS: Recipient Lewis rats (RT1) were immunized with donor (Dark Agouti, RT1) spleen cells (day -5). Recipients underwent bilateral nephrectomy and orthotopic renal transplantation (day 0). Cellular rejection was minimized by tacrolimus treatment from day -1. Groups received GS-492429 (30 mg/kg, twice a day) (n = 11) or vehicle (n = 12) from 1 hour before transplantation until being killed on day 3. RESULTS: Vehicle-treated recipients developed graft dysfunction on day 1 which rapidly worsened by day 3. Histology showed severe damage (thrombosis, acute tubular injury, capillaritis) and infiltration of many Syk leukocytes. GS-492429 did not affect graft dysfunction on day 1, but treatment reduced allograft damage and prevented the rapid deterioration of graft function on day 3. GS-492429 reduced the prominent macrophage infiltrate and reduced the M1 proinflammatory response. Neutrophil and NK cell infiltration and capillary thrombosis were also significantly reduced by GS-492429 treatment. Serum DSA levels and the deposition of IgG and C4d in the allograft were equivalent in the 2 groups. CONCLUSIONS: Treatment with a Syk inhibitor significantly reduced renal allograft injury in a model of severe antibody-mediated damage in highly sensitized recipients. Further studies are warranted to determine whether Syk inhibition is a potential adjunctive treatment in clinical AMR. PMID- 28594749 TI - CMV-Specific T Cell Monitoring Offers Superior Risk Stratification of CMV Seronegative Kidney Transplant Recipients of a CMV-Seropositive Donor. AB - BACKGROUND: Detectable cytomegalovirus (CMV)-specific T cells in CMV-seronegative kidney transplant recipients (KTRs) have been attributed to an absence of circulating antibodies despite CMV sensitization. The diagnostic value of CMV specific T cells, however, needs to be implemented in risk stratification for CMV replication. METHODS: Three hundred twenty-six KTRs were studied and classified with respect to CMV serostatus and presence of CMV-specific T cells. Samples were collected pretransplantation, at +1, +2, and +3 months posttransplantation. CMV specific T cells directed to CMV-IE1 and CMV-pp65 were measured by interferon gamma Elispot assay. RESULTS: Nineteen (28%) of 67 D+R- KTRs showed pretransplant CMV-specific T cells. Although no differences were observed for CMV replication, KTRs with CMV-specific T cells presented with lower initial and peak CMV loads (P < 0.05). KTRs with decreasing/undetectable CMV-IE1-specific T cells pretransplantation and posttransplantation were at greatest risk of CMV replication. KTRs with stable/increasing CMV-IE1-specific T cells from pretransplantation to posttransplantation, however, showed low risk of CMV replication (P < 0.001). One hundred sixty-two (80%) of 203 R+ KTRs showed pretransplant CMV-specific T cells. Decreasing/undetectable CMV-IE1-specific T cells from pretransplantation and posttransplantation identified those R+ KTRs at increased risk of CMV replication (65/80 KTRs; 81%; P < 0.001). CONCLUSIONS: Despite CMV prophylaxis, D+R- KTRs are at greatest risk of CMV disease. Our data suggest that monitoring CMV-specific T cell kinetics from pretransplantation to posttransplantation, particularly directed to CMV-IE1, offers superior risk stratification compared with CMV serostatus alone. PMID- 28594751 TI - DHRS9 Is a Stable Marker of Human Regulatory Macrophages. AB - BACKGROUND: The human regulatory macrophage (Mreg) has emerged as a promising cell type for use as a cell-based adjunct immunosuppressive therapy in solid organ transplant recipients. In this brief report, dehydrogenase/reductase 9 (DHRS9) is identified as a robust marker of human Mregs. METHODS: The cognate antigen of a mouse monoclonal antibody raised against human Mregs was identified as DHRS9 by immunoprecipitation and MALDI-MS sequencing. Expression of DHRS9 within a panel of monocyte-derived macrophages was investigated by quantitative PCR, immunoblotting and flow cytometry. RESULTS: DHRS9 expression discriminated human Mregs from a panel of in vitro derived macrophages in other polarisation states. Likewise, DHRS9 expression distinguished Mregs from a variety of human monocyte-derived tolerogenic antigen-presenting cells in current development as cell-based immunotherapies, including Tol-DC, Rapa-DC, DC-10, and PGE2-induced myeloid-derived suppressor cells. A subpopulation of DHRS9-expressing human splenic macrophages was identified by immunohistochemistry. Expression of DHRS9 was acquired gradually during in vitro development of human Mregs from CD14 monocytes and was further enhanced by IFN-gamma treatment on day 6 of culture. Stimulating Mregs with 100 ng/mL lipopolysaccharide for 24 hours did not extinguish DHRS9 expression. Dhrs9 was not an informative marker of mouse Mregs. CONCLUSION: DHRS9 is a specific and stable marker of human Mregs. PMID- 28594752 TI - RESIDUAL VITREOUS CORTEX AT THE FOVEA DURING VITRECTOMY FOR PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT REPAIR. AB - PURPOSE: To investigate the frequency of residual cortex and the effectiveness of removal of residual cortex in the fovea during vitrectomy for primary rhegmatogenous retinal detachment repair. METHODS: We retrospectively reviewed the charts and the operative videos of the 80 patients (80 eyes) who underwent vitrectomy for repair and who were observed for more than 6 months. After triamcinolone acetonide injection, we observed residual cortex on the surface of the retina. Residual cortex was removed with a diamond-dusted scraper. After surgery, we watched for the occurrence of epiretinal membrane (ERM) for at least 6 months. We graded ERM according to the postoperative visual acuity (thin membranes that did not affect vision vs. thick membranes that reduced vision). RESULTS: Of the 80 eyes, 60 eyes (75%) showed macular residual cortex, which we removed with a scraper, and 20 eyes (25%) did not have visible cortical remnants. Postoperative ERM occurred in 30% of eyes (24/80). The rate of postoperative ERM was 35% (21/60) in eyes with residual cortex and 15% (3/20) in eyes without residual cortex (P = 0.091). In the 60 eyes with residual cortex during vitrectomy, a thin membrane occurred in 18 eyes (30%) and a thick membrane occurred in 3 eyes (5%). In the 20 eyes without residual cortex, however, a thin membrane occurred in 3 eyes (15%) and no thick membrane was found. CONCLUSION: Eyes with residual cortex have a higher rate of ERM than eyes with no residual cortex after vitrectomy for primary repair. It is uncertain whether removing the cortex reduces the rate of postoperative ERM. The residual cortex may have already started the pathogenesis of ERM, or surgical trauma may have played a role. PMID- 28594754 TI - False Labor at Term in Singleton Pregnancies: Discharge After a Standardized Assessment and Perinatal Outcomes. AB - OBJECTIVE: To evaluate perinatal outcomes in women sent home with a diagnosis of false labor at term and assess the time interval to return for delivery. METHODS: This was a prospective observational cohort study of women at 37 0/7 to 41 6/7 weeks of gestation without pre-existing medical complications who presented to our hospital-based triage unit with symptoms of labor and underwent a standardized evaluation. Women diagnosed as having false labor with a live singleton fetus in cephalic presentation without a prior cesarean delivery and sent home were compared with a group of similar women diagnosed to be in spontaneous labor. Women with hypertension, diabetes, and known fetal malformations were excluded. Using a perinatal composite outcome of respiratory insufficiency, intraventricular hemorrhage, culture-proven sepsis, Apgar score 3 or less at 5 minutes, phototherapy, and perinatal death, we tested the noninferiority of being sent home compared with being admitted for labor. The relationship of cervical dilatation to the time interval from discharge home to delivery was also analyzed. RESULTS: Between October 2012 and March 2016, a total of 3,949 women met inclusion criteria and were diagnosed with false labor, discharged, and returned to deliver, whereas 2,592 similar women were admitted in early labor. The mean interval from discharge to return was 4.9 days. Cesarean delivery rates were not different between the study groups-11% for both (P=.69), and the perinatal composite outcome rates were not significantly different between those sent home and those admitted-3.2% compared with 3.1% (P=.79). Women with more advanced cervical dilatation at discharge returned and delivered significantly earlier than those with less dilatation regardless of parity. CONCLUSION: Discharge with false labor at term after a standardized assessment in a triage unit was not associated with increased rates of adverse perinatal composite outcomes or cesarean delivery. The time interval to return for delivery was significantly associated with the cervical dilatation at discharge. PMID- 28594755 TI - Contraception Insurance Coverage and Receipt of Long-Acting Reversible Contraception or Depot Medroxyprogesterone Acetate on the Day of Abortion. AB - OBJECTIVE: To evaluate whether contraceptive insurance coverage for women who present for an abortion is associated with obtaining long-acting reversible contraception or depot medroxyprogesterone acetate (DMPA) on the day the abortion is completed. METHODS: We conducted a prospective cohort study of women presenting for medical or surgical abortion at a single health center in North Carolina. Eligible women were 18 years or older and fluent in English or Spanish. Data were from participant questionnaires, medical charts, and financial records. Our main exposure was whether the woman had insurance coverage for contraception at clinic intake. Our primary outcome was receiving DMPA, an intrauterine device, or a contraceptive subdermal implant on the same day of their surgical abortion or at the visit that determined their medication abortion was complete. We used univariable, bivariable, and multivariable analysis to report our findings. RESULTS: Five hundred seventy-five women enrolled in our cohort between September 2015 and April 2016. One hundred twenty-eight (22%) had insurance coverage and 447 (78%) did not. In the group with insurance coverage for contraception, 38% (49/128) received a long-acting reversible contraception method or DMPA compared with 7% (33/447) in the group without insurance coverage for contraception. After adjusting for confounding, women with contraceptive coverage were more than five times as likely to receive immediate postabortion contraception with one of these methods compared with women without coverage (relative risk 5.6, 95% confidence interval 3.8-8.3). CONCLUSION: Women with contraceptive insurance coverage on the day of their abortion were more likely to leave the abortion clinic with an intrauterine device or implant in place or receive DMPA injection compared with women without coverage. PMID- 28594753 TI - Opioid Use in Pregnancy, Neonatal Abstinence Syndrome, and Childhood Outcomes: Executive Summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, Society for Maternal-Fetal Medicine, Centers for Disease Control and Prevention, and the March of Dimes Foundation. AB - In April 2016, the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited experts to a workshop to address numerous knowledge gaps and to review the evidence for the screening and management of opioid use in pregnancy and neonatal abstinence syndrome. The rising prevalence of opioid use in pregnancy has led to a concomitant dramatic fivefold increase in neonatal abstinence syndrome over the past decade. Experts from diverse disciplines addressed research gaps in the following areas: 1) optimal screening for opioid use in pregnancy; 2) complications of pregnancy associated with opioid use; 3) appropriate treatments for pregnant women with opioid use disorders; 4) the best approaches for detecting, treating, and managing newborns with neonatal abstinence syndrome; and 5) the long-term effects of prenatal opioid exposure on children. Workshop participants identified key scientific opportunities to advance the understanding of opioid use disorders in pregnancy and to improve outcomes for affected women, their children, and their families. This article provides a summary of the workshop presentations and discussions. PMID- 28594756 TI - Short Cervix in a Patient With Twin Gestation. AB - A 28-year-old woman, gravida 1 para 0, with twin gestation presents for routine anatomic survey at 20 weeks of gestation without any complaints. On transabdominal ultrasonography, the ultrasonographer notes concern for cervical funneling and proceeds to perform a transvaginal ultrasonogram, which reveals a short cervix of 18 mm. PMID- 28594757 TI - Anesthetic Cream Use During Office Pessary Removal and Replacement: A Randomized Controlled Trial. AB - OBJECTIVE: To estimate the effect of lidocaine-prilocaine cream on patient pain at the time of office pessary removal and reinsertion. METHODS: In this double blind, randomized placebo-controlled trial, participants undergoing routine pessary care in a urogynecology office at a tertiary referral center were randomized to application of 4 g of either lidocaine-prilocaine or placebo cream 5 minutes before pessary change. Visual analog scale pain scores were collected from the patient at baseline, after pessary removal, and after pessary reinsertion. Physicians also recorded their estimate of patient pain at pessary removal and reinsertion. The primary outcome was the participant-reported visual analog scale pain score at the time of pessary removal and reinsertion. A sample size of 26 per group (n=52) was planned to estimate an absolute mean difference in visual analog scale pain of 2.1 cm at the time of pessary removal. An analysis of covariance was used to evaluate pain at removal and reinsertion as a function of treatment assignment controlling for baseline pain. RESULTS: From July 2015 through February 2016, 116 women were screened and 54 were recruited: 28 in the lidocaine-prilocaine cream group and 26 in the placebo group. One patient in the lidocaine-prilocaine cream group was later withdrawn owing to vaginal erosion. The participants were all postmenopausal women, with an average age of 77.8 years. Most characteristics were similar between groups. After adjusting for baseline pain, participants randomized to the lidocaine-prilocaine group had lower pain at pessary removal when compared with those assigned to placebo (mean difference=-2.05, 95% confidence interval -3.69 to -0.41; P=.015). CONCLUSION: Lidocaine-prilocaine cream use at the time of office pessary removal reduces patient-reported pain. Clinicians may wish to include this simple intervention to optimize patient comfort and compliance. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02380742. PMID- 28594758 TI - Timing of Etonogestrel-Releasing Implants and Growth of Breastfed Infants: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the growth of breastfed infants whose mothers had inserted an etonogestrel-releasing implant in the immediate postpartum period. METHODS: An open, randomized controlled, and parallel trial of postpartum women who were block-randomized to early (up to 48 hours postpartum before discharge) or conventional (at 6 weeks postpartum) insertion of an etonogestrel implant. The primary outcome was average infant weight at 12 months (360 days) and a difference of equal to or greater than 10% between groups was considered clinically significant. The secondary outcomes were infant's height and head and arm circumferences. These variables were measured at baseline and at 14, 40, 90, 180, 270, and 360 days postpartum. The mixed-effects linear regression model was used to evaluate the outcomes with a power of 80% and a significance level of 1% for the primary outcome and 0.3% for secondary outcomes as a result of correction for multiple hypothesis testing. RESULTS: From June to August 2015, a total of 100 women were randomized: 50 to early and 50 to conventional postpartum etonogestrel insertion. Sociodemographic characteristics were similar between the groups, except for educational attainment. The conventional insertion group included a higher proportion of women with 8 or more years of formal education than the early insertion group (88% [44/50] compared with 70% [35/50], P=.02). There was no difference in infant weight at 360 days between the groups (early [mean+/-standard deviation] 10.1+/-1.2 kg compared with conventional 9.8+/-1.3 kg, mean difference estimate 0.3 kg, 95% confidence interval 0-0.7 kg). Growth curves, height, and head and arm circumferences did not differ between the groups. CONCLUSION: There is no difference in growth at 12 months among breastfed infants whose mothers underwent early compared with conventional postpartum insertion of the etonogestrel implant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02469454. PMID- 28594759 TI - Associations of Parity, Breastfeeding, and Fractures in the Women's Health Observational Study. AB - OBJECTIVE: To examine associations of several aspects of parity and history of lactation with incident hip fractures and clinical fractures and, in a subset of women, with bone mineral density. METHODS: In this observational study, we analyzed data from 93,676 postmenopausal women participating in the Women's Health Initiative Observational Study and all bone density data from the subset of participants who underwent bone density testing at three clinical centers. At baseline, participants were aged 50-79 years. Using Cox proportional hazards regression analysis, we examined associations of fracture incidence and bone density with several aspects of parity (number of pregnancies, age at first pregnancy lasting 6 months or greater, and number of pregnancies lasting 6 months or greater) and breastfeeding (number of episodes of breastfeeding for at least 1 month, number of children breastfed, age when first breastfed, age when last breastfed, total number of months breastfed). RESULTS: The mean baseline age (standard deviation) of participants was 64 (+/-7.4) years (mean follow-up 7.9 years). During follow-up, the incident rate of hip fracture was 1.27%. Ten percent of participants were nulligravid. In fully adjusted models, number of pregnancies, parity, age at first birth, number of children breastfed, age at first breastfeeding, age at last breastfeeding, and total duration of breastfeeding were not statistically significantly associated with hip fracture incidence. There were no consistent associations of parity or lactation characteristics with overall clinical fracture risk or bone density. However, compared with never breastfeeding, a history of breastfeeding for at least 1 month was associated with a decreased risk of hip fracture (yes compared with no, hazard ratio 0.84, 95% confidence interval 0.73-0.98). CONCLUSION: Patterns of parity and history of lactation were largely unrelated to fracture risk or bone density. PMID- 28594760 TI - An Initiative to Reduce the Episiotomy Rate: Association of Feedback and the Hawthorne Effect With Leapfrog Goals. AB - OBJECTIVE: To assess the association of education, performance feedback, and the Hawthorne effect with a reduction in the episiotomy rate in a large academic institution. METHODS: We describe a prospective observational study of a project conducted between March 2012 and February 2017 to assist clinicians in meeting the Leapfrog Group (www.leapfroggroup.org) target rates for episiotomy. Phases of this project included preintervention (phase 1, March 2012 to April 2014), education and provision of collective department episiotomy rates (phase 2, May 2014 to December 2014), ongoing education with emphasis on a revised Leapfrog target rate (phase 3, January 2015 to February 2016), and provision of individual episiotomy rates to practitioners on a monthly basis (phase 4, March 2016 to February 2017). We analyzed the department episiotomy rates before, during, and after these efforts. Cases of shoulder dystocia were excluded from this analysis. Statistical analysis was performed using a two-tailed Student t test and chi test with P<.05 considered significant. RESULTS: During the study period 1,176 episiotomies were performed in 16,441 vaginal deliveries (7.2%). In phase 2 (2,352 vaginal deliveries), there was a nonsignificant drop in the episiotomy rate with education alone (9.0-8.2%, P=.21). In phase 3 (4,379 vaginal deliveries), the episiotomy rate demonstrated an additional, significant drop to 5.9% (P<.001), but this reduction did not reach the new Leapfrog goal of 5%. In phase 4 (3,160 vaginal deliveries), the hospital episiotomy rate again dropped significantly from 5.9% to 4.37% (P=.007) and met the target rate of 5%. This reduction was sustained over a 12-month time period. During this same time period, the rate of operative vaginal delivery among vaginal births increased (4.5-5.4%, P=.003) and there was no significant change in the rates of third- and fourth-degree perineal laceration (3.8-3.3%, P=.19). CONCLUSION: Education, performance feedback, and the Hawthorne effect were associated with a reduction in the episiotomy rate in a large academic institution without a reduction in the rate of operative vaginal delivery or an increase in the rate of third- and fourth-degree lacerations. PMID- 28594761 TI - Wound Complication Rates After Staples or Suture for Midline Vertical Skin Closure in Obese Women: A Randomized Controlled Trial. AB - OBJECTIVE: To compare wound complication rates after skin closure with staples and subcuticular suture in obese gynecology patients undergoing laparotomy through a midline vertical incision. METHODS: In this randomized controlled trial, women with body mass indexes (BMIs) of 30 or greater undergoing surgery by a gynecologic oncologist through a midline vertical incision were randomized to skin closure with staples or subcuticular 4-0 monofilament suture. The primary outcome was the rate of wound complication, defined as the presence of a wound breakdown, or infection, within 8 weeks postoperatively. Secondary outcomes included operative time, Stony Brook scar cosmetic score, and patient satisfaction. A sample size of 162 was planned to detect a 50% reduction in wound complications. At planned interim review (n=82), there was no significant difference in primary outcome. RESULTS: Between 2013 and 2016, 163 women were analyzed, including 84 who received staples and 79 suture. Women who received staples were older (mean age 59 compared with 57 years), had lower mean BMI (37.3 compared with 38.9), and fewer benign indications for surgery (22 compared with 27). There were no differences in wound complication rates between staple compared with suture skin closure (28 [33%] compared with 25 [32%], relative risk 1.05, 95% confidence interval [CI] 0.68-1.64). Women with staples reported worse median cosmetic scores (four of five compared with five of five, P<.001), darker scar color (37 [49%] compared with 13 [18%], relative risk 2.69, 95% CI 1.57 4.63), and more skin marks (30 [40%] compared with three [4%], relative risk 9.47, 95% CI 3.02-29.65) compared with women with suture closure. There was no group difference regarding satisfaction with their scar. Stepwise multivariate analysis revealed BMI (odds ratio [OR] 1.13, 95% CI 1.07-1.20), maximum postoperative glucose (OR 1.01, 95% CI 1.00-1.01), and cigarette smoking (OR 4.96, 95% CI 1.32-18.71) were correlates of wound complication. CONCLUSION: Closure of midline vertical skin incisions with subcuticular suture does not reduce surgical site wound complications compared with staples in obese gynecology patients. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01977612. PMID- 28594762 TI - A Shared Decision-Making Intervention to Guide Opioid Prescribing After Cesarean Delivery. AB - OBJECTIVE: To assess whether a shared decision-making intervention decreases the quantity of oxycodone tablets prescribed after cesarean delivery. TECHNIQUE: A tablet computer-based decision aid formed the basis of a shared decision-making session to guide opioid prescribing after cesarean delivery. Women first received information on typical trajectories of pain resolution and expected opioid use after cesarean delivery and then chose the number of tablets of 5 mg oxycodone they would be prescribed up to the institutional standard prescription of 40 tablets. EXPERIENCE: From April 11, 2016, to June 10, 2016, 105 women were screened, 75 were eligible, and 51 consented to participate; one patient was excluded after enrollment as a result of prolonged hospitalization. The median number of tablets (5 mg oxycodone) women chose for their prescription was 20.0 (interquartile range 15.0-25.0), which was less than the standard 40-tablet prescription (P<.001). CONCLUSION: A shared decision-making approach to opioid prescribing after cesarean delivery was associated with approximately a 50% decrease in the number of opioids prescribed postoperatively in this cohort compared with our institutional standard prescription. This approach is a promising strategy to reduce the amount of leftover opioid medication after treatment of acute postcesarean pain. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02770612. PMID- 28594764 TI - Outpatient Hysterectomy Volume in the United States. AB - OBJECTIVE: To estimate the number of outpatient hysterectomies being performed annually in the United States in an effort to offer more correct estimates of hysterectomy use in light of reported decreasing inpatient case volume. METHODS: This is a cross-sectional analysis of State Ambulatory Surgery and Services Databases from 16 states with complete information for year 2011. Adult women undergoing hysterectomy were included. Procedure volume, route, and associated patient and surgical characteristics were calculated. RESULTS: There were 64,612 ambulatory hysterectomies reported; 81.5% of surgeries were performed laparoscopically and 16% vaginally. If these numbers are extrapolated to national estimates, this represents 100,000-200,000 outpatient hysterectomies per year. The strongest driver of the laparoscopic, compared with vaginal, route of hysterectomy in this data set was presence of cancer (odds ratio 4.01 [3.19 5.05], P<.001). In addition to indication for surgery, patient characteristics such as age, race, income, location, and primary payer were associated with mode of hysterectomy. The laparoscopic surgeries were associated with shorter length of stay (mean stay 0.65 days, [99% confidence interval 0.65-0.66] compared with 0.79 days [0.78-0.81], adjusted incidence rate ratio 0.89 [0.86-0.92], P<.001) and higher mean charges ($24,227 [$24,053-24,402] versus $14,068 [$13,811 14,330], P<.001) compared with vaginal surgeries. CONCLUSION: The perceived decline that has been reported in national hysterectomy volume may represent lack of reporting of surgeries performed in ambulatory settings. This information has considerable implications for business, public health interventions, and insurance carriers among other key stakeholders in women's health care delivery. PMID- 28594763 TI - Patterns of Opioid Prescription and Use After Cesarean Delivery. AB - OBJECTIVE: To define the amount of opioid analgesics prescribed and consumed after discharge after cesarean delivery. METHODS: We conducted a survey at six academic medical centers in the United States from September 2014 to March 2016. Women who had undergone a cesarean delivery were contacted by phone 2 weeks after discharge and participated in a structured interview about the opioid prescription they received on discharge and their oral opioid intake while at home. RESULTS: A total of 720 women were enrolled; of these, 615 (85.4%) filled an opioid prescription. The median number of dispensed opioid tablets was 40 (interquartile range 30-40), the median number consumed was 20 (interquartile range 8-30), and leftover was 15 (interquartile range 3-26). Of those with leftover opioids, 95.3% had not disposed of the excess medication at the time of the interview. There was an association between a larger number of tablets dispensed and the number consumed independent of patient characteristics. The amount of opioids dispensed did not correlate with patient satisfaction, pain control, or the need to refill the opioid prescription. CONCLUSION: The amount of opioid prescribed after cesarean delivery generally exceeds the amount consumed by a significant margin, leading to substantial amounts of leftover opioid medication. Lower opioid prescription correlates with lower consumption without a concomitant increase in pain scores or satisfaction. PMID- 28594766 TI - Postdischarge Opioid Use After Cesarean Delivery. AB - OBJECTIVE: To characterize postdischarge opioid use and examine factors associated with variation in opioid prescribing and consumption. METHODS: We conducted a prospective observational cohort study by recruiting all women undergoing cesarean delivery during an 8-week period, excluding those with major postoperative morbidities or chronic opioid use. Starting on postoperative day 14, women were queried weekly regarding number of opioid pills used, amount remaining, and their pain experience until they had stopped opioid medication. Demographic and delivery information and in-hospital opioid use were recorded. The state Substance Monitoring Program was accessed to ascertain prescription filling details. Morphine milligram equivalents were calculated to perform opioid use comparisons. Women in the highest quartile of opioid use (top opioid quartile use) were compared with those in the lowest three quartiles (average opioid use). RESULTS: Of 251 eligible patients, 246 (98%) agreed to participate. Complete follow-up data were available for 179 (71% of eligible). Most women (83%) used opioids after discharge for a median of 8 days (interquartile range 6-13 days). Of women who filled their prescriptions (165 [92%]), 75% had unused tablets (median per person 75 morphine milligram equivalents, interquartile range 0-187, maximum 630) and the majority (63%) stored tablets in an unlocked location. This amounts to an equivalent of 2,540 unused 5-mg oxycodone tablets over our study period. Women who used all prescribed opioids (n=40 [22%]) were more likely to report that they received too few tablets than women who used some (n=109 [61%]) or none (n=30 [17%]) of the prescribed opioids (33% compared with 4% compared with 5%, P<.001). The top quartile was more likely to be smokers than average users and consumed more opioid morphine milligram equivalents per hour of inpatient stay than average opioid users (1.6, interquartile range 1.1-2.3 compared with 1.0, interquartile range 0.5-1.4, P<.001). CONCLUSION: Most women especially those with normal in-hospital opioid use-are prescribed opioids in excess of the amount needed. PMID- 28594767 TI - The Case for a National Maternal Mortality Review Committee. AB - The United States has the highest maternal mortality ratio of any high-resource country; the 2014 ratio of 22 per 100,000 live births is in fact four to five times higher than that of the best-performing nations, and recent data suggest that this ratio may be increasing. The causes of this disparity are unknown and may be related to social, economic, cultural, or medical issues or a combination of factors. Repeated counts of categories of maternal death are of little assistance in determining the actual cause of death or in identifying preventive measures. Furthermore, when based on administrative data, such tallies may themselves be inaccurate. We propose the creation of a national maternal mortality review committee, modeled after those in other high-resource nations, to assist in addressing the problem of maternal mortality in the United States. PMID- 28594765 TI - Patterns of Specialty-Based Referral and Perioperative Outcomes for Women With Endometrial Cancer Undergoing Hysterectomy. AB - OBJECTIVE: To examine patterns of referral to gynecologic oncologists and perioperative outcomes based on surgeon specialty for women with endometrial cancer and hyperplasia. METHODS: The National Surgical Quality Improvement Program database was used to perform a retrospective cohort study of women with endometrial cancer and hyperplasia who underwent hysterectomy from 2014 to 2015. Patients were stratified based on treatment by a gynecologic oncologist or other health care provider. Patterns of referral to a gynecologic oncologist was the primary outcome, and mode of hysterectomy and complications were secondary outcomes. RESULTS: A total of 6,510 women were identified. Gynecologic oncologists performed 90.9% (95% confidence interval [CI] 90.1-91.7) of the hysterectomies for endometrial cancer, 66.8% (95% CI 63.1-70.4) for complex atypical endometrial hyperplasia, and 49.3% (95% CI 44.7-53.8) for endometrial hyperplasia without atypia. Older women and those with a higher American Society of Anesthesiology score were more likely to be treated by an oncologist. Minimally invasive hysterectomy was performed in 73.6% (95% CI 72.1-75.1) of women with endometrial cancer operated on by gynecologic oncologists compared with 73.8% (95% CI 68.8-78.2) of those treated by other physicians (odds ratio [OR] 0.99, 95% CI 0.80-1.23); lymphadenectomy was performed in 56.3% of women treated by gynecologic oncologists compared with 34.8% of those treated by other specialists (OR 2.42, 95% CI 1.99-2.94). Severe complications were uncommon and there was no difference in complication rates based on specialty, 2.6% (95% CI 2.2-3.1) compared with 2.0% (95% CI 0.8-3.3). CONCLUSION: Gynecologic oncologists provide care for the majority of women with endometrial cancer who undergo hysterectomy in the United States and are also involved in the care of a large percentage of women with endometrial hyperplasia. PMID- 28594768 TI - Detection of an Inherited Deletion in Products of Conception in a Patient With Recurrent Losses and Normal Karyotype. AB - BACKGROUND: Microarray analysis testing on products of conception can provide valuable information in the evaluation of recurrent pregnancy loss beyond ploidy status. CASE: A maternally inherited deletion on the X chromosome was detected by microarray analysis performed on products of conception in a couple with recurrent pregnancy loss. The mother had a previously demonstrated normal karyotype with standard cytogenetic analysis but was subsequently determined to have the same X chromosome deletion by oligonucleotide single-nucleotide polymorphism (SNP) microarray analysis. CONCLUSION: Direct testing of products of conception using oligonucleotide SNP microarray identified a maternally inherited microdeletion on the X chromosome in a patient with recurrent losses and normal karyotype. Going forward, the couple may use preimplantation genetic diagnosis testing to identify embryos free of this deletion for transfer. PMID- 28594769 TI - Four Cases of Parkinson Disease Diagnosed During the Postpartum Period. AB - BACKGROUND: There is little experience with the effect of pregnancy on Parkinson disease because the number of women with Parkinson disease who are of childbearing age is small. We report four cases beginning during the postpartum period and discuss the potential contribution of different factors that may influence the occurrence of Parkinson disease in this time period. CASES: Four women aged 29-35 years developed arm tremor, shoulder pain, dizziness, or decreased dexterity of the hand in the first few days or months after childbirth. They were initially diagnosed with postpartum depression or psychogenic parkinsonism. Finally, dopamine transporter imaging confirmed the diagnosis of young-onset Parkinson disease. CONCLUSION: Early-onset Parkinson disease may present in postpartum women. In women with atypical motor symptoms in addition to depression, this diagnosis should be considered. PMID- 28594770 TI - Placental Abruption With Delayed Fetal Compromise in Maternal Acetaminophen Toxicity. AB - BACKGROUND: After maternal acetaminophen overdose, fetal fulminant liver failure, stillbirth, neonatal death, or preterm delivery may occur. CASE: A 27-year-old woman, gravida 2 para 1, presented at 28 weeks of gestation after unintentional acetaminophen overdose. Four days after ingestion, her laboratory values worsened, including serum aspartate aminotransferase of 5,460 units/L, alanine aminotransferase of 4,936 units/L, and international normalized ratio of 2.9. On day 6 after ingestion, fetal monitoring showed minimal variability with repetitive variable and late decelerations, which prompted cesarean delivery when a hematoma was noted on the maternal placental surface, consistent with placental abruption. The neonate showed no evidence of hepatic dysfunction. Review of the literature suggests that maternal acetaminophen overdose in the second and third trimester is associated with a 5% incidence of fetal compromise (mostly the result of nonreassuring fetal status leading to delivery or stillbirth) occurring within 6 days of ingestion. CONCLUSION: Maternal acetaminophen overdose can be associated with delayed fetal compromise, suggesting the importance of continued fetal surveillance several days after ingestion. PMID- 28594771 TI - Serial Head and Brain Imaging of 17 Fetuses With Confirmed Zika Virus Infection in Colombia, South America. AB - OBJECTIVE: To evaluate fetal ultrasound and magnetic resonance imaging findings among a series of pregnant women with confirmed Zika virus infection to evaluate the signs of congenital Zika syndrome with respect to timing of infection. METHODS: We conducted a retrospective case series of pregnant women referred to two perinatal clinics in Barranquilla and Ibague, Colombia, who had findings consistent with congenital Zika syndrome and Zika virus infection confirmed in maternal, fetal, or neonatal samples. Serial ultrasound measurements, fetal magnetic resonance imaging results, laboratory results, and perinatal outcomes were evaluated. RESULTS: We describe 17 cases of confirmed prenatal maternal Zika virus infection with adverse fetal outcomes. Among the 14 symptomatic women, the median gestational age for maternal Zika virus symptoms was 10 weeks (range 7-14 weeks of gestation). The median time between Zika virus symptom onset and microcephaly (head circumference less than 3 standard deviations below the mean) was 18 weeks (range 15-24 weeks). The earliest fetal head circumference measurement consistent with microcephaly diagnosis was at 24 weeks of gestation. The earliest sign of congenital Zika syndrome was talipes equinovarus, which in two patients was noted first at 19 weeks of gestation. Common findings on fetal magnetic resonance imaging were microcephaly, ventriculomegaly, polymicrogyria, and calcifications. CONCLUSION: Our analysis suggests a period of at least 15 weeks between maternal Zika virus infection in pregnancy and development of microcephaly and highlights the importance of serial and detailed neuroimaging. PMID- 28594772 TI - Gestational Diabetes Mellitus and Frequency of Blood Glucose Monitoring: A Randomized Controlled Trial. AB - OBJECTIVE: To assess whether testing blood glucose four times daily compared with four times every other day would lead to similar birth weights among patients with gestational diabetes mellitus (GDM). METHODS: This noninferiority randomized controlled trial was conducted at five centers. After receiving a diagnosis of GDM, women tested their blood glucose every day for 7 days. After that period, compliant women without hyperglycemia requiring treatment were randomized to either blood glucose testing four times a day or every other day. Noninferiority would be declared if the mean birth weight in the every-other-day group was no higher than 165 g (5% difference assuming an average birth weight of 3,296 g) compared with the four times a day group. A total sample size of 286 women allowed noninferiority to be tested (one-sided .05 level of significance). RESULTS: From May 2013 to May 2016, of the 293 women with GDM who were randomized, 149 (51%) were tested four times a day and 144 (49%) were tested every other day. Between the two groups, there were no significant differences with regard to need for medical treatment, induction, gestational age at delivery, mode of delivery, rate of preeclampsia, or shoulder dystocia. Birth weight was similar between both groups and the upper bound of the 90% confidence interval (CI) was less than 165 g, establishing noninferiority with a mean difference of -41 g (90% CI -137 to 54 g). Rate of compliance with blood glucose testing was higher in the every-other-day group (89% compared with 92%, P<.01). The differences in rates of macrosomia and birth weight greater than the 95th percentile were not clinically significant. Neonatal outcomes including neonatal hypoglycemia were similar. CONCLUSION: Among patients with well-controlled GDM, testing blood glucose values every other day did not increase birth weight, although it did increase compliance with testing when compared with women who tested every day. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01818557. PMID- 28594773 TI - All-Cause Mortality After Fertility-Sparing Surgery for Stage I Epithelial Ovarian Cancer. AB - OBJECTIVE: To compare all-cause mortality between women who underwent fertility sparing surgery with those who underwent conventional surgery for stage I ovarian cancer. METHODS: In a cohort study using the National Cancer Database, we identified women younger than 40 years diagnosed with stage IA and unilateral IC epithelial ovarian cancer between 2004 and 2012. Fertility-sparing surgery was defined as conservation of one ovary and the uterus. The primary outcome was time from diagnosis to death. We used propensity score methods to assemble a cohort of women who underwent fertility-sparing or conventional surgery but were otherwise similar on observed covariates and conducted survival analyses using the Kaplan Meier method and Cox proportional hazard models. RESULTS: We identified 1,726 women with stage IA and unilateral IC epithelial ovarian cancer of whom 825 (47.8%) underwent fertility-sparing surgery. Fertility-sparing surgery was associated with younger age, residence in the northeastern and western United States, and serous or mucinous histology (P<.05 for all). Propensity score matching yielded a cohort of 904 women who were balanced on observed covariates. We observed 30 deaths among women who underwent fertility-sparing surgery and 37 deaths among propensity-matched women who underwent conventional surgery after a median follow-up of 63 months. Fertility-sparing surgery was not associated with hazard of death (hazard ratio 0.80, 95% confidence interval [CI] 0.49-1.29, P=.36). The probability of survival 10 years after diagnosis was 88.5% (95% CI 82.4-92.6) in the fertility-sparing group and 88.9% (95% CI 84.9-92.0) in the conventional surgery group. In patients with high-risk features such as clear cell histology, grade 3, or stage IC, 10-year survival was 80.5% (95% CI 68.5 88.3) among women who underwent fertility-sparing surgery and 83.4% (95% 76.0 88.7) among those who had conventional surgery (hazard ratio 0.86, 95% CI 0.49 1.53, P=.61). CONCLUSION: Compared with conventional surgery, fertility-sparing surgery was not associated with increased risk of death in young women with stage I epithelial ovarian cancer. PMID- 28594775 TI - Perinatal and Maternal Outcomes After Training Residents in Forceps Before Vacuum Instrumental Birth. AB - OBJECTIVE: To compare the rates of attempted and successful instrumental births, intrapartum cesarean delivery, and subsequent perinatal and maternal morbidity before and after implementing a training intervention to arrest the decline in forceps competency among resident obstetricians. METHODS: This retrospective cohort study examined all attempted instrumental births at Monash Health from 2005 to 2014. We performed an interrupted time-series analysis to compare outcomes of attempted instrumental births in 2005-2009 with those in 2010-2014. RESULTS: There were 72,490 births from 2005 to 2014 at Monash Health, of which 8,789 (12%) were attempted instrumental vaginal births. After the intervention, rates of forceps births increased [autoregressive integrated moving average coefficient (beta) 1.5, 95% confidence interval (CI) 1.03-1.96; P<.001], and vacuum births decreased (beta -1.43, 95% CI -2.5 to -0.37; P<.01). Rates of postpartum hemorrhage decreased (beta -1.3, 95% CI -2.07 to -0.49; P=.002) and epidural use increased (beta 0.03, 95% CI 0.02-0.05; P<.001). There was no change in rates of unsuccessful instrumental births (beta -0.39, 95% CI -3.03 to 2.43; P=.83), intrapartum cesarean delivery (beta -0.29, 95% CI -0.55 to 0.14; P=.24), third- and fourth-degree tears (beta -1.04, 95% CI -3.1 to 1.00; P=.32), or composite neonatal morbidity (beta -0.18, 95% CI -0.38 to 0.02, P=.08). Unsuccessful instrumental births were more likely to be in nulliparous women (P<.001), less likely to have a senior obstetrician present (P<.001), be at later gestation (P<.001), and involved larger birth weight neonates (P<.001). CONCLUSION: A policy of ensuring obstetric forceps competency before beginning vacuum training results in more forceps births, fewer postpartum hemorrhages, and no increase in third- and fourth-degree perineal injuries or episiotomies. PMID- 28594774 TI - Cervical Evaluation: From Ancient Medicine to Precision Medicine. AB - Since ancient times, cervical assessment for predicting timing of delivery has relied primarily on digital (subjective) assessment of dilatation, softening, and length. To date, transvaginal ultrasound cervical length is the only one of these parameters that meets criteria for a biomarker; no objective, quantitative measure of cervical dilatation or softening has gained clinical acceptance. This review discusses how the cervix has been assessed from ancient times to the present day and how a precision medicine approach could improve understanding of not only the cervix, but also parturition in general. PMID- 28594776 TI - Surgical Pain After Transobturator and Retropubic Midurethral Sling Placement. AB - OBJECTIVE: To compare prevalence and severity of any surgical pain between transobturator and retropubic slings; secondary aims were to compare pain at anatomic locations, pain medication use, and pain resolution between transobturator and retropubic slings and to compare pain between types of transobturator slings. METHODS: This is a secondary analysis of the Trial of Mid Urethral Slings, which compared retropubic and transobturator sling outcomes and included 597 participants from 2006 to 2008. Postoperative assessments included body maps, visual analog scales, Surgical Pain Scales, and medication inventories for 30 days, at 6 weeks, and 6, 12, and 24 months. Postoperative pain prevalence and severity were compared. Mixed models compared pain resolution and severity over time. Regression models compared pain prevalence and severity between types of transobturator slings. Eighty percent power was provided for the primary outcome pain prevalence and 95% power was provided for the primary outcome pain severity. RESULTS: Postoperative prevalence of any surgical pain, pain severity, and pain medication was not different between retropubic and transobturator slings. Retropubic sling was associated with greater prevalence of suprapubic pain at 2 weeks (proportion difference 10.6%; 95% confidence interval [CI] 4.6 16.4%; P<.001). Transobturator sling was associated with greater prevalence of groin pain at 2 weeks (proportion difference 12.0%; 95% CI 7.1-16.8%; P<.001). There was no difference in pain resolution (odds ratio [OR] 1.11, 95% CI 0.88 1.40; P=.38). Between types of transobturator slings, the odds of surgical pain were similar at 2 (OR 2.39, 95% CI 0.51-11.31; P=.27) and 6 weeks (OR 0.46, 95% CI 0.02-9.20; P=.61). CONCLUSION: Transobturator and retropubic slings are associated with low prevalence of any surgical pain. Transobturator sling was associated with greater prevalence of groin pain at 2 weeks, and retropubic sling was associated with greater prevalence of suprapubic pain at 2 weeks. Surgical pain resolved quickly in both groups. PMID- 28594777 TI - Medical and Surgical Innovations in Health Care. PMID- 28594778 TI - What Is New in Zika Virus in Pregnancy?: Best Articles From the Past Year. AB - This month we focus on current research in Zika virus in pregnancy. Dr. Ramsey discusses four recent publications that are concluded with a "bottom line" that is a take-home message. A complete reference for each can be found in on this page along with direct links to abstracts. PMID- 28594780 TI - Clinical Conundrums: Is One Clinician's Quandary the Next Clinical Trial? PMID- 28594782 TI - Connect the Dots-July 2017. PMID- 28594781 TI - A Comprehensive Approach to the Opioid Epidemic. PMID- 28594779 TI - Clinical Validation of a Test for the Diagnosis of Vaginitis. AB - OBJECTIVE: Vaginitis may be diagnosed as bacterial vaginosis, vulvovaginal candidiasis, trichomoniasis, or coinfection. A new molecular test assays the vaginal microbiome and organisms that cause three common infections. The objective of the trial was to evaluate the clinical accuracy of the investigational test for vaginal swabs collected by patients (self) or clinicians. The primary and secondary outcomes were to compare the investigational test with reference methods for the three most common causes of vaginitis and compare clinician-collected with self-collected swabs. METHODS: We conducted a cross-sectional study in which women with symptoms of vaginitis were recruited at ten clinical centers and consented to the investigation between May and September 2015. The woman collected a vaginal swab, sheathed, and then handed it to the clinician. These swabs were to evaluate how self-collected swabs compared with clinician-collected swabs. The clinician collected an investigational test swab and reference test swabs. From 1,740 symptomatic patients, clinician-collected and self-collected vaginal swabs were evaluated by the molecular test and six tests. The reference methods for bacterial vaginosis were Nugent's score and Amsel's criteria for intermediate Nugent results. The reference methods for Candida infection were isolation of any potential Candida microorganisms from inoculation of two culture media: chromogenic and Sabouraud agar and sequencing. The reference methods for trichomoniasis were wet mount and culture. RESULTS: For clinician-collected swabs, by reference methods, bacterial vaginosis was diagnosed in 56.5%, vaginal candidiasis in 32.8%, trichomoniasis in 8%, and none of the three infections in 24% with a coinfection rate of 20%. The investigational test sensitivity was 90.5% (95% confidence interval [CI] 88.3 92.2%) and specificity was 85.8% (95% CI 83.0-88.3%) for bacterial vaginosis. The investigational test sensitivity was 90.9% (95% CI 88.1-93.1%) and specificity was 94.1% (95% CI 92.6-95.4%) for the Candida group. Sensitivity for Candida glabrata was 75.9% (95% CI 57.9-87.8%) and specificity was 99.7% (95% CI 99.3 99.9%). Investigational test sensitivity was 93.1% (95% CI 87.4-96.3%) and specificity was 99.3% (95% CI 98.7-99.6%) for trichomoniasis. Results from self collected swabs were similar to clinician-collected swabs. CONCLUSION: A molecular-based test using vaginal swabs collected by clinicians or patients can accurately diagnose most common bacterial, fungal, and protozoan causes of vaginitis. Women and their clinicians seeking accurate diagnosis and appropriate selection of efficacious treatment for symptoms of vaginitis might benefit from this molecular test. PMID- 28594785 TI - Notes from the Field: Two Cases of Legionnaires' Disease in Newborns After Water Births - Arizona, 2016. PMID- 28594783 TI - Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial. AB - OBJECTIVE: To assess the efficacy of progestogens for maintenance tocolysis in women undelivered after their first preterm labor episode. METHODS: Women with singleton pregnancies between 22 0/7 and 31 6/7 weeks of gestation with arrested preterm labor and a cervical length 25 mm or less at hospital discharge were eligible. Patients with a previous preterm birth were excluded. In a randomized controlled trial conducted in five university hospitals, women were randomized to receive vaginal progesterone (200 mg per day) or intramuscular 17alpha hydroxyprogesterone caproate (341 mg per week) or to an observation groups (control group). The primary outcome was the proportion of women with preterm birth at less than 37 weeks of gestation. A sample size of 160 per group (n=480) was planned to compare vaginal progesterone and 17alpha-hydroxyprogesterone caproate groups with those in the control group. The sample size estimation was based on the hypothesis that the risk of experiencing preterm birth in the control group would be 30% and that 17alpha-hydroxyprogesterone caproate or progesterone would decrease this risk to 15%. A P value of <.025 was defined as statistically significant. At planned interim analysis (n=254), the trial was stopped for futility. RESULTS: Between July 2010 and June 2015, 257 women were eligible and 254 were subsequently randomly assigned to vaginal progesterone (n=86), 17alpha-hydroxyprogesterone caproate (n=87), or observation (n=81). Nineteen (8%) were excluded from the analysis because they either dropped out or information was missing, leaving 235 women available for analysis. Demographic characteristics were similar across groups. The preterm birth rate did not differ significantly between groups: 23% in the 17alpha-hydroxyprogesterone caproate group, 39% in the vaginal progesterone group, and 22% in the women in the control group (P=.949 for 17alpha-hydroxyprogesterone caproate compared with the women in the control group and P=.027 for vaginal progesterone compared with women in the control group). CONCLUSION: The use of progestogens for maintenance tocolysis in women with a short cervix did not reduce the rate of preterm birth. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01178788. PMID- 28594784 TI - Retrospective Study to Compare Selective Decongestive Devascularization and Gastrosplenic Shunt versus Splenectomy with Pericardial Devascularization for the Treatment of Patients with Esophagogastric Varices Due to Cirrhotic Portal Hypertension. AB - BACKGROUND For patients with esophagogastric varices secondary to portal hypertension due to liver cirrhosis, portosystemic shunts and devascularization have become the most commonly used treatment methods. We have developed a novel surgical approach for the treatment of patients with cirrhotic portal hypertension, selective decongestive devascularization, and shunt of the gastrosplenic region (SDDS-GSR). This aim of this study was to compare the efficacy and safety of SDDS-GSR with splenectomy with pericardial devascularization (SPD). MATERIAL AND METHODS A retrospective study was undertaken between 2006 and 2013 and included 110 patients with cirrhotic portal hypertension, 34 of whom underwent SDDS-GSR; 76 patients underwent SPD. Kaplan Meier analysis was used to evaluate clinical outcomes, mortality, the incidence of re-bleeding, encephalopathy, and portal venous system thrombosis (PVST). RESULTS Postoperatively portal venous pressure decreased by 20% in both groups. The long-term incidence of re-bleeding and PVST was significantly lower in the SDDS-GSR group compared with the SPD group (P=0.018 and P=0.039, respectively). CONCLUSIONS This preliminary retrospective study has shown that SDDS-GSR was an effective treatment for patients with esophagogastric varices secondary to portal hypertension that may be used as a first-line treatment to prevent variceal bleeding and lower the incidence of PVST. PMID- 28594786 TI - Hospitalizations for Endocarditis and Associated Health Care Costs Among Persons with Diagnosed Drug Dependence - North Carolina, 2010-2015. AB - Opioid dependence and overdose have increased to epidemic levels in the United States. The 2014 National Survey on Drug Use and Health estimated that 4.3 million persons were nonmedical users of prescription pain relievers (1). These users are 40 times more likely than the general population to use heroin or other injection drugs (2). Furthermore, CDC estimated a near quadrupling of heroin related overdose deaths during 2002-2014 (3). Although overdose contributes most to drug-associated mortality, infectious complications of intravenous drug use constitute a major cause of morbidity leading to hospitalization (4). In addition to infections from hepatitis C virus (HCV) and human immunodeficiency virus (HIV), injecting drug users are at increased risk for acquiring invasive bacterial infections, including endocarditis (5,6). Evidence that hospitalizations for endocarditis are increasing in association with the current opioid epidemic exists (7-9). To examine trends in hospitalizations for endocarditis among persons in North Carolina with drug dependence during 2010 2015, data from the North Carolina Hospital Discharge database were analyzed. The incidence of hospital discharge diagnoses for drug dependence combined with endocarditis increased more than twelvefold from 0.2 to 2.7 per 100,000 persons per year over this 6-year period. Correspondingly, hospital costs for these patients increased eighteenfold, from $1.1 million in 2010 to $22.2 million in 2015. To reduce the risk for morbidity and mortality related to opioid-associated endocarditis, public health programs and health care systems should consider collaborating to implement syringe service programs, harm reduction strategies, and opioid treatment programs. PMID- 28594787 TI - Measures Taken to Prevent Zika Virus Infection During Pregnancy - Puerto Rico, 2016. AB - Zika virus infection during pregnancy remains a serious health threat in Puerto Rico. Infection during pregnancy can cause microcephaly, brain abnormalities, and other severe birth defects (1). From January 1, 2016 through March 29, 2017, Puerto Rico reported approximately 3,300 pregnant women with laboratory evidence of possible Zika virus infection (2). There is currently no vaccine or intervention to prevent the adverse effects of Zika virus infection during pregnancy; therefore, prevention has been the focus of public health activities, especially for pregnant women (3). CDC and the Puerto Rico Department of Health analyzed data from the Pregnancy Risk Assessment Monitoring System Zika Postpartum Emergency Response (PRAMS-ZPER) survey conducted from August through December 2016 among Puerto Rico residents with a live birth. Most women (98.1%) reported using at least one measure to avoid mosquitos in their home environment. However, only 45.8% of women reported wearing mosquito repellent daily, and 11.5% reported wearing pants and shirts with long sleeves daily. Approximately one third (38.5%) reported abstaining from sex or using condoms consistently throughout pregnancy. Overall, 76.9% of women reported having been tested for Zika virus by their health care provider during the first or second trimester of pregnancy. These results can be used to assess and refine Zika virus infection prevention messaging and interventions for pregnant women and to reinforce measures to promote prenatal testing for Zika. PMID- 28594789 TI - QuickStats: Average Number of Deaths from Motor Vehicle Injuries, Suicide, and Homicide,* by Day of the Week - National Vital Statistics System, United States, 2015. AB - In 2015, an average of 103 motor vehicle injury deaths, 121 suicides, and 49 homicides occurred each day. Motor vehicle injury deaths were more likely to occur on Saturdays and Sundays and least likely to occur on Tuesdays. The highest number of suicides occurred on Mondays and Tuesdays and the lowest on Saturdays. Homicides peaked on Sundays, followed by Saturdays; homicides were less likely to occur on weekdays. PMID- 28594788 TI - Vital Signs: Health Care-Associated Legionnaires' Disease Surveillance Data from 20 States and a Large Metropolitan Area - United States, 2015. AB - BACKGROUND: Legionnaires' disease, a severe pneumonia, is typically acquired through inhalation of aerosolized water containing Legionella bacteria. Legionella can grow in the complex water systems of buildings, including health care facilities. Effective water management programs could prevent the growth of Legionella in building water systems. METHODS: Using national surveillance data, Legionnaires' disease cases were characterized from the 21 jurisdictions (20 U.S. states and one large metropolitan area) that reported exposure information for >=90% of 2015 Legionella infections. An assessment of whether cases were health care-associated was completed; definite health care association was defined as hospitalization or long-term care facility residence for the entire 10 days preceding symptom onset, and possible association was defined as any exposure to a health care facility for a portion of the 10 days preceding symptom onset. All other Legionnaires' disease cases were considered unrelated to health care. RESULTS: A total of 2,809 confirmed Legionnaires' disease cases were reported from the 21 jurisdictions, including 85 (3%) definite and 468 (17%) possible health care-associated cases. Among the 21 jurisdictions, 16 (76%) reported 1-21 definite health care-associated cases per jurisdiction. Among definite health care-associated cases, the majority (75, 88%) occurred in persons aged >=60 years, and exposures occurred at 72 facilities (15 hospitals and 57 long-term care facilities). The case fatality rate was 25% for definite and 10% for possible health care-associated Legionnaires' disease. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Exposure to Legionella from health care facility water systems can result in Legionnaires' disease. The high case fatality rate of health care-associated Legionnaires' disease highlights the importance of case prevention and response activities, including implementation of effective water management programs and timely case identification. PMID- 28594790 TI - Japanese Encephalitis Surveillance and Immunization - Asia and Western Pacific Regions, 2016. AB - Japanese encephalitis (JE) virus is the most important vaccine-preventable cause of encephalitis in the Asia-Pacific region. The World Health Organization (WHO) recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority (1). This report updates a previous summary of JE surveillance and immunization programs in Asia and the Western Pacific in 2012 (2). Since 2012, funding for JE immunization has become available through the GAVI Alliance, three JE vaccines have been WHO prequalified,* and an updated WHO JE vaccine position paper providing guidance on JE vaccines and vaccination strategies has been published (1). Data for this report were obtained from a survey of JE surveillance and immunization practices administered to health officials in countries with JE virus transmission risk, the 2015 WHO/United Nations Children's Fund Joint Reporting Form on Immunization, notes and reports from JE meetings held during 2014-2016, published literature, and websites. In 2016, 22 (92%) of 24 countries with JE virus transmission risk conducted JE surveillance, an increase from 18 (75%) countries in 2012, and 12 (50%) countries had a JE immunization program, compared with 11 (46%) countries in 2012. Strengthened JE surveillance, continued commitment, and adequate resources for JE vaccination should help maintain progress toward prevention and control of JE. PMID- 28594791 TI - [Prospects of clinical application of pharmacological imitation of the phenomenon of ischaemic postconditioning of the heart]. AB - Pharmacological imitation of the phenomenon of ischaemic postconditioning of the heart appears to exert a cardioprotective effect in the reperfusion period. It was determined that the protective effect may be carried out resulting from activation of the adenosine, opioid and bradykinin receptors. However, there is yet no common point of view concerning the question as to the activation of what subtypes of the receptors the cardioprotective effect of adenosine, opioids and bradykinin is associated with. The clinical findings strongly suggest that further studies are required, since the data obtained in the hitherto carried out trials are ambiguous, scarce, and sometimes yield contradicting results. Several clinical trials of adenosine have been conducted and in the majority of cases positive results were obtained. Adenosine administered in a dropwise manner was found to exert a cardioprotective effect. However, not all researchers succeeded in demonstrating this protective effect. Only one clinical trial was carried out with the opioid receptor agonist - morphine, yielding positive results, with morphine exerting a cardioprotective effect. Feasibility of the clinical application of bradykinin as a cardioprotector is not of current relevance because of its numerous side effects. PMID- 28594793 TI - [Efficacy of walking training in patients with obliterating atherosclerosis of lower limb arteries]. AB - The authors assessed efficacy of treating patients with atherosclerosis obliterans of lower-limb arteries using the method of walking training. Our prospective study included a total of 84 patients suffering from intermittent claudication. They were divided in two groups. The Study Group (Group I) comprised 64 patients undergoing comprehensive treatment including walking training (WT) and the Control Group (Group II) consisted of 20 patients treated without a physical training programme. The patients were followed up monthly during three months, with registration of the pain-free walking distance (PFWD), maximum walking distance (MWD), and the ankle-brachial index (ABI). There were no baseline statistically significant differences between Group I and Group II patients in the parameters examined. The Study Group patients were found to have a considerable increase in the PFWD and MWD values, with the statistical significance of differences from the Control Group patients observed as early as at one month of treatment. The baseline PFWD value in the Study Group amounted to 132.4+/-14.7 m, being at 3 months 259.7+/-29.6 m (p<0.05); the MWD value in the Study Group initially equalled 170.2+/-12.3 m, amounting at 3 months to 364.6+/ 39.2 m (p<0.05). The Study Group patients by the end of follow up were also found to have an increase in the ankle-brachial index by nearly 25% from the baseline level. The carried out treatment resulted in an increase in the number of patients with less severe stages of arterial insufficiency: initially stage IIa was diagnosed in 18 (28.2%) patients and at 3 months in 47 (73.4%) patients, with stage IIb being diagnosed in 46 (71.8 %) and 17 (26.6%) subjects, respectively. A conclusion was drawn that training walking considerably improved clinical manifestations of the disease. Taking into consideration availability of this therapeutic method, it should be recommended for patients suffering from intermittent claudication in long-term courses and in all cases where there are no contraindications thereto. PMID- 28594792 TI - [Assessment of functional state of microcirculatory bed of the foot in patients with lower limb critical ischaemia]. AB - The authors assessed perfusion of the foot in patients presenting with lower limb critical ischaemia before and after endovascular revascularization, as well as analysed the interrelationship between the change of perfusion and the clinical result of treatment. The study includes a total of 15 patients presenting with ulcerative-necrotic defects of the foot. All patients underwent study of 2D perfusion of the foot before and after the endovascular intervention. The '2D perfusion' package was used within the framework of an angiographic examination, and required neither increase in the volume of the contrast medium nor radiation load. Four parameters of perfusion were evaluated: the time of ingress, the time of reaching the peak value, the peak value and the area under the curve. After the intervention, as compared with the baseline values there were statistically significant differences by the time of ingress (a 2.4-fold decrease; p<0.0001), the peak value (a 1.8-fold increase; p<0.0001) and the area under the curve (a 2.4-fold increase; p<0.0001). No statistically significant differences were revealed while comparing the time of reaching the peak value before and after the intervention (p=0.767). Trophic defects healed in 11 (73.3%) patients, and in 4 (26.7%) patients the process of healing continued with positive dynamics at the check-up examination. Hence, our first experience of using the assessment of 2D perfusion demonstrates simplicity of the method with no increase of the radiation load and the dose of the contrast medium. The method makes it possible to obtain important data about the state of microcirculation of the foot in patients with lower limb critical ischaemia, to evaluate alterations after the endovascular intervention. Improvement of the parameters of perfusion is associated with a good clinical outcome. PMID- 28594794 TI - [Use of a thrombin inhibitor for treatment of deep vein thrombosis and pulmonary thromboembolism in patients with thrombophilia]. AB - Presented herein are the results of oral administration of dabigatran etexilate for treatment and secondary prevention of lower-limb deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE) in patients with established thrombophilia, studying its efficacy and safety in prolonged administration during a year as compared with warfarin. The study group included a total of fifty-seven 18-to-79 year-old patients (33 men and 24 women) with DVT and PTE, taking dabigatran etexilate. The comparison group was composed of a total of 126 patients (65 men and 61 women) with DVT and PTE, taking warfarin. Efficacy of the drugs was analysed in relation to the development of relapses thromboembolic complications, with the drugs' safety profile being evaluated in relation to the development of major and clinically significant haemorrhage. It was determined that prolonged administration of dabigatran etexilate taken at a fixed dose (150 mg twice daily) for 6-12 months in patients with DVT and PTE and with confirmed thrombophilia turned out to be effective for secondary prevention of relapsing venous thromboembolic complications and lethal outcomes, indirectly contributing to recanalization of the lower-limb venous bed, with the drug possessing a favourable profile of safety concerning the development of haemorrhagic complications as compared with warfarin and requiring no routine laboratory monitoring. PMID- 28594795 TI - [Assessing efficacy of carotid endarterectomy by means of intraoperative flowmetry]. AB - AIM: The study was aimed at determining volumetric blood flow velocity (VBFV) through the internal carotid artery (ICA) and assessing functional outcomes of treatment of patients, taking into consideration the dynamics of VBFV before and after the operation. PATIENTS AND METHODS: The study comprised a total of 53 patients subjected to examination of VBFV through the ICA before and after carotid endarterectomy (CEA) assessed by means of flowmetry. Neurological deficit was evaluated by means of the NIHS Scale (the M NIHSS prior to operation equalling 2.49), the degree of disability and functional independence of the patient after endured stroke was assessed by the modified Rankin Scale (the M mRS before operation amounting to 1.23) and the Rivermead Mobility Index, the severity of cognitive dysfunctions was determined by the Mini-Mental State Examination (the M MMSE before surgery equalling 24.85) and the Montreal Cognitive Assessment scale (the M MoCA before surgery scoring 23.3). RESULTS: At the first stage of examination we determined that the VBFV after the operation increased in all patients, but the highest values of the increment were observed in groups of patients with ICA stenoses of 80-89% and 90-99%. During the second stage, it was determined that with a higher value of the VBFV after carotid endarterectomy regression of neurological deficit occurred faster (the postoperative M NIHSS scoring 2.09, with the M mRS of 1.00), the patients demonstrated higher results while undergoing the tests for intellectual ability (the postoperative MMSE and MoCA equalling 25.4 and 23.91, respectively) compared with the patients showing low values of the increment of the VBFV after the operation. CONCLUSION: Intraoperative flowmetry is a simple and efficient method of evaluating the VBFV through the ICA, an increase in volumetric blood flow (VBF) contributes to restoration of normal perfusion of the brain and creates prerequisites for more complete and faster restoration of the lost functions after ischaemic stroke (IS) and chronic cerebral ischaemia. PMID- 28594796 TI - Hybrid surgery in chronic thoracoabdominal aortic dissection. AB - The authors describe and analyse their experience gained in performing prosthetic repair of the thoracoabdominal portion of the aorta, combined with open aortic stenting using the Djumbodis uncovered metal stent. Over the period from 2013 to 2015 we performed a total of 16 hybrid interventions. All patients were found to have type B aortic dissection, with their false and true lumens patent. All patients underwent reconstruction of the thoracoabdominal aorta combined with open implantation of the Djumbodis uncovered metal stent into the area of lower thoracic and visceral arteries. The patients underwent either isolated prosthetic repair of the thoracic aortic portion - type A correction, or prosthetic repair of the thoracic and infrarenal portions - type B correction. In the postoperative period we performed MSCT angiography of the thoracic and abdominal aortic portions in order to control patency of the true and false lumens, patency of visceral arteries, to assess the diameter of the aorta, presence or absence of thrombosis. All five patients subjected to type B correction (100% of the total number of this type operation) were found to develop thrombosis of the false lumen, and eight patients undergoing type A correction (72.7% of the total number of operations of this type) were diagnosed with false channel thrombosis. There was 1 (6.3%) lethal case registered at the hospital stage in the group of patients with type A correction. There were no cases of neurological deficit, malperfusion of visceral organs or lower-limb ischaemia. Our experience shows that using hybrid technologies in surgery of the thoracoabdominal portion of the aorta is (appears to be) optimal from the point of view of decreasing intraoperative trauma, reducing the complications rate and without detriment to the radicality. PMID- 28594797 TI - [Single-centre experience with implantation of the 'E-vita open plus' hybrid stent graft]. AB - Hybrid technologies appear to have been gaining ground in surgery of the thoracic aorta. The present study was aimed at assessing the immediate clinical outcomes of surgical treatment of diseases of the thoracic aorta by means of the 'E-vita open plus' hybrid stent graft. The 'E-vita open plus' hybrid stent graft was implanted to 18 patients. All operations were carried out in the conditions of moderate hypothermia. The brain was protected by unilateral cerebral perfusion through the brachiocephalic trunk. The duration of artificial circulation averagely amounted to 265.1 [214; 281] min., with the mean aortic cross-clamping time equalling 150.8 [121; 177] min., and circulatory arrest lasting 55 [47.5; 62.5] min. In one (5.5%) case resternotomy was performed for haemorrhage. Five (27.8%) patients required haemodialysis to perform for postoperative renal insufficiency. A further five (27.8%) patients were found to have transient impairment of cerebral circulation. One (5.5%) patient was diagnosed as having haemorrhage into the area of the 'old ischaemic focus', one (5.5%) patient developed transient spinal ischaemia spontaneously disappearing within the first 24 hours. There were no cases of cardiac complications. A conclusion was drawn that hybrid operations according to the 'frozen elephant trunk' technique yield satisfactory immediate clinical results of treatment in patients with thoracic aortic aneurysms and dissection. PMID- 28594798 TI - [Anatomical aspects of formation of corona phlebectatica]. AB - The data concerning the anatomy of perforant veins of the foot can by no means be referred to as insufficiently known. At the same time, these descriptions are encountered rather rarely in the educational-and-methodical literature. To a certain degree, this may be explained by low pathogenetic significance of perforant veins of the foot; however, these data are required for the surgeon in carrying out both standard phlebectomy and sclerotherapy of subcutaneous varicose veins, especially if the zone of surgical intervention is situated immediately on the foot. Also, these data may be important for explaining clinical manifestations of chronic venous insufficiency. The present study was aimed at specifying the anatomical ground of formation of the corona phlebecatica and topography of perforant veins of the foot. The material for the study consisted of 15 lower extremities (cadaveric material) with no evidence of chronic venous diseases. The method of the study - anatomical dissection. From 4 to 6 perforant veins were found on the medial surface of the foot. They directly connected the medial marginal vein and vv. plantaris medialis. From 2 to 3 perforant veins were found on the lateral surface of the foot. They connected directly the lateral marginal vein and vv. plantaris lateralis. Topographically perforant veins pass behind the muscles of the lateral group of the foot, along the lateral intermuscular septum. Perforant veins of each group were found to have lateral affluents part of which independently drained the integumentary tissues of the lateral surfaces of the foot, and part formed anastomoses with the superficial venous plantar net. This makes it possible to characterize perforant veins not only as anastomoses connecting subcutaneous rear venous net with deep veins of the foot and with the superficial plantar net, but also as independently draining vessels. Besides, in the majority of cases, nearby a perforant vein we managed to isolate an artery and a nerve branchlet, originating from a. plantaris and n. plantaris. Hence, perforant veins of the medial and lateral surfaces of the foot constitute the anatomical ground for formation of the corona phlebectatica and are component parts of the neurovascular bundle (vein-artery-nerve). PMID- 28594799 TI - [Pleiotropic effects of phlebotropic drugs: from pharmacological advantages to adverse drug interaction]. AB - A distinctive property of phlebotropic drugs consists in their intrinsic capability of exerting pronounced pleiotropic (multiple) effects. The authors discuss the fundamental mechanisms of pleiotropy, advantages and disadvantages of various types of targeted therapy (mono- and polytargeted therapy) in treatment of chronic venous diseases. Special attention is paid to analysing the nature of adverse drug interactions, methods of reducing the risk of their development. An electronic service known as the Drug Interactions Checker is proposed as a tool for assessing drug interactions in everyday practice of the angiologist/phlebologist. PMID- 28594800 TI - [Results of administering oral anticoagulants for treatment of patients with venous thromboembolic complications]. AB - The objective of the study was to compare safety and efficacy of rivaroxaban and dabigatran with warfarin in treatment of patients with acute venous thromboembolic complications (VTEC). The authors analysed the results of examining and treating a total of 95 patients presenting with VTEC and randomly divided into three groups. In all groups the initial anticoagulant therapy consisted in unfractionated heparin administered for 5 days, after which the patients followed by switching were switched to a 6-month course of treatment with oral anticoagulants. Patients from Group One received warfarin, Group Two patients were treated with dabigatran etexilate, and Group Three patients were treated with rivaroxaban. Relapses of the disease were diagnosed in 2 (5.7%) patients from Group One. Haemorrhagic complications were noted in 8 (22.9%) Group One patients, in 3 (10%) Group Two patients and in 2 (6.7%) Group Three patients. After the end of treatment, complete recanalization of the thrombosed veins was revealed 13 (37.1%) patients from Group One, in 15 (50%) patients from Group Two and in 14 (46.7%) patients from Group Three. One year after the end of treatment, freedom from chronic venous insufficiency was observed in 8 (23.3%) patients of Group One, in 12 (40%) patients of Group Two and in 11 (36.6%) patients of Group Three. The composite quality of life indices after the treatment course were (appeared to be) higher in Group Two and Three patients compared with those of Group One. Hence, a conclusion was drawn that dabigatran and rivaroxaban turned out to be superior by efficacy and safety to warfarin in treatment of this patient cohort. No statistically significant differences were observed while comparing dabigatran and rivaroxaban. PMID- 28594801 TI - [Correction of blood microcirculation parameters and endothelial function in chronic venous insufficiency of lower limbs]. AB - The authors assessed efficacy of the phlebotonic agent Venarus in treatment of patients presenting with chronic venous insufficiency of the lower extremities. The study included a total of 34 patients with various degree of chronic venous insufficiency according to the CEAP classification. Before the beginning of the study and on the background of treatment with Venarus we assessed the parameters of blood microcirculation by means of digital capillaroscopy of the nail bed of the fingers and toes, as well as determined the indices of arterial stiffness and endothelial function. All patients on the background of treatment demonstrated a decrease in the degree of symptoms of chronic venous insufficiency. A group of patients was revealed in whom treatment with Venarus turned out to be most effective: patients with initial perivascular oedema (an increase in the linear size of the perivascular zones) and a decrease in the mean velocity of capillary blood flow. On the background of treatment with Venarus they were found to have a decrease in perivascular oedema, an increase in the mean velocity of capillary blood flow, and improvement of endothelial function. PMID- 28594802 TI - [Remote results of carotid endarterectomy in patients with type 2 diabetes mellitus]. AB - The authors comparatively analysed the remote results of carotid endarterectomy and risk factors for unfavourable outcomes in patients with and without type 2 diabetes mellitus (DM). The outcomes of carotid endarterectomy were studied in a total of 168 patients, with the follow-up terms up to 8 years. Depending on the presence or absence of DM, the patients were divided into two groups. Group One comprised 79 patients with an atherosclerotic lesion of the internal carotid artery and accompanying DM, with Group Two consisting of 89 non-diabetic patients. There were no lethal outcomes in the early postoperative period. The composite measure 'lethality + stroke' in Group One amounted to 2.5% and in Group Two to 2.2%. In the remote period the survival rate was as follows: 65 (82.3%) people for Group One and 83 (93.3%) for Group Two, with the 5-year cumulative survival rate amounting to 75.1+/-6.4% and 92.5+/-3.0%, respectively. The index of freedom from acute vascular complications (myocardial infarction, ischaemic stroke) at 5 years in Group One was 54.2+/-7.2% and in Group Two 86.1+/-4.3%. Acute vascular complications were causes of lethal outcomes in 13 cases in the group with DM and in 3 cases in the group without DM. Death was most often caused by acute coronary complications. The index of freedom from restenosis at 5 years in Group One amounted to 74.5+/-8.0% and at 7 years of follow-up in Group Two to 92.3+/-7.3%. The risk factors for the development of acute vascular complications in diabetic patients according to the findings of the Cox regression analysis were as follows: age above 65 years, DM duration of more than 5 years; the level of glycated haemoglobin above 7.5%; a history of myocardial infarction; presence of degree III arterial hypertension. The risk factors for restenosis included: DM duration of more than 5 years, the level of glycated haemoglobin above 7.5% and presence of degree III arterial hypertension. The results of the study make it possible to regard carotid endarterectomy efficient and safe for both cohorts of patients (with and without DM). In the remote postoperative period, such parameters as survival rate, indices of freedom from acute vascular complications and restenosis turned out to be statistically significantly lower in diabetic patients than in non-diabetic, with the predominating coronary complications induced by insufficient assessment of the coronary reserve and the presence of occult forms of ischaemic heart disease. Long-term results may be improved by means of widening the indications for performing coronarography in patients with DM. PMID- 28594803 TI - Treatment of vertebrobasilar insufficiency due to stenosis and aneurysm of the vertebral artery. AB - A dissecting aneurysm of the vertebral artery in the extracranial portion is a rare pathology. It may either have a symptom-free course or induce a clinical picture of vertebrobasilar insufficiency. To the main methods of surgical treatment belong endovascular techniques and resection of an aneurysm with shunting of the V3 segment of the vertebral artery. Presented in the article is a clinical case report regarding successful surgical management of a dissecting aneurysm of the extracranial portion in a young woman presenting with a clinical course of vertebrobasilar insufficiency and treated by means of ligation of the vertebral artery in the V1 segment and autovenous shunting from the external carotid artery to the V3 segment of the vertebral artery. PMID- 28594804 TI - [Use of an ex vivo technique in a patient with renal arteriovenous malformation in complication endovascular treatment]. AB - Renal arteriovenous malformation is a rarely encountered disease characterized by the presence of a direct arteriovenous shunt between the renal artery and vein. This nosology was first described by Varela in 1928, and by 1997 the number of such cases amounted to slightly more than 200. Endovascular closure of a fistula seems to be an attractive method of treatment in view of low traumaticity and a short period of rehabilitation. However, as shown by our case report, this type of intervention in large-diameter fistulas may be associated with the development of life-threatening complications. In case of rupture of the renal capsule and/or arteriovenous aneurysm, radical nephrectomy, unfortunately, remains to be a method of choice. Described below is a case concerning treatment of a female patient presenting with bilateral arteriovenous malformations and the world's first emergency operation for a ruptured intraparenchymatous arteriovenous aneurysm using an extracorporeal technique. PMID- 28594805 TI - [Survival of patients with primary and secondary amputations for critical lower limb ischaemia]. AB - The authors analysed therapeutic outcomes in a total of 171 patients presenting with critical lower limb ischaemia and subjected to amputation at various levels. In so doing, eighty-eight (Group One) patients sustained primary amputation and the remaining eighty-three (Group Two) patients endured secondary amputation after an initially undertaken attempt at revascularization. It was determined that performing primary amputation statistically significantly shortened the lifespan in the postoperative period as compared with secondary amputation performed. There was no clear-cut interrelationship between the presence of accompanying pathology and the lifespan in the post-amputation period. 18 months after discharge from hospital the mortality rate in Group One patients amounted to 52% and in Group Two patients to 29% (p<0.05). PMID- 28594806 TI - [A new method of endoscopic harvesting of the great saphenous vein in an open system]. AB - We examined a total of 246 patients subjected to coronary artery bypass grafting with the use of the great saphenous vein (GSV). The patients were subdivided into two groups. Group One (n=121) patients endured procurement of the great saphenous vein by a new endoscopic technique in an open system with the help of the equipment Karl Storz and electric dissector Ligasure. In Group Two (n=125) patients the vein was harvested by means of the traditional open method. In all patients we evaluated complications in the early postoperative period 13+/-2.5 days after the operation. The rate of relapsing angina pectoris in both Groups turned out to be low and did not differ (1.65% in Group One and 1.6% in Group Two). Patients of the both groups differed significantly by the incidence of postoperative complications on the lower limbs in the zone of procurement of the GSV (9.09% in Group One and 26.4% in Group Two, p=0.131). Group Two patients (open method of procurement of the GSV) were considerably more often found to have developed cases of lymphorrhoea, haematomas, disjunction of the sutures (21.6%) compared with Group One (endoscopic method) patients (3.3%) (p=0.167), which in 10.4% of cases required secondary surgical debridement of wounds in patients after the open harvest of the GSV. Eventually, the length of hospital stay for Group Two patients increased significantly (15 +/- 4.5 days) compared with Group One patients (8+/-1.1 days) (p=0.361). Hence, the endoscopic method of harvesting the GSV in the open CO2 system makes it possible to obtain a good cosmetic effect on the lower limbs after the operation, to considerably decrease the complications rate, thus reducing the length of hospital stay. PMID- 28594807 TI - [Development of surgery of combined gun-shot osteo-vascular injuries of extremities (middle XIX century - middle XX century)]. AB - The presented review by the example of a long historical period traces the development of surgery of combined gun-shot osteo-vascular injuries of extremities, also describing both objective and subjective causes of unsatisfactory outcomes of treatment and presenting ways of solving the problem of treatment of these injuries during the period after World War II. PMID- 28594808 TI - [Risk factors for progression of atherosclerosis of the shunted coronary artery in the remote postoperative period]. AB - The study was aimed at revealing risk factors for progression of atherosclerosis in the shunted coronary artery in the remote period following coronary artery bypass grafting. Our prospective study included a total of 292 patients having endured coronary artery bypass grafting. All patients were divided in two groups depending on the type of the bypass grafts used: either autoarterial shunts (Group 1) or autovenous grafts (Group 2). We thus assessed a total of 516 autoarterial grafts and 257 autovenous grafts, as well as the coronary arteries shunted thereby. The long-term results were evaluated by means of coronaroshuntography performed not earlier than 12 months after surgery. The average duration of follow up amounted to 53.4+/-26.5 months. Analysing the cumulative risk for progression of atherosclerosis in the arteries shunted demonstrated that for autoarterial grafts the rate of the development of proximal stenosis of the coronary artery (CA) shunted was lower compared with autovenous grafts (p<=0.001). The Cox regression model showed that an autovein used as a graft increased the risk for the development of occlusion of the shunted CA by 43% from the baseline each postoperative month. The presence of proximal stenosis of the shunted coronary artery amounting to or exceeding 90% increases the risk of occlusion by 68% per month. Also, for the patients with the SYNTAX scoring >= 32 points the risk of coronary artery occlusion increases 2.2-fold each month after the operation. Such factors as the patient's gender, the diameter of the shunted artery, diabetes mellitus, tobacco smoking, multifocal atherosclerosis by the findings of the study exerted no influence on the progression of proximal stenosis of the shunted coronary artery. PMID- 28594809 TI - [Prevention of cerebrovascular complications in coronary artery bypass grafting]. AB - The authors carried out a comparative analysis of the incidence rate of cerebrovascular complications following coronary artery bypass grafting performed using either a differentiated approach to surgical policy depending on the findings of epiaortic ultrasonographic scanning or the standard conventional approach. A total of 3,454 operations of coronary artery bypass grafting were performed. All patients were divided into two groups. Patients of the Study Group (n=765) were subjected to obligatory intraoperative epiaortic scanning, with the variant of further surgical intervention depending on the obtained findings of the examination. The Control Group patients (n=2,689) underwent standard coronary artery bypass grafting in the conditions of artificial circulation (AC). In the Study Group patients, depending on the degree and localization of the atherosclerotic lesion of the aorta, determined by the findings of epiaortic scanning, one of the following techniques of coronary artery bypass grafting (CABG) was chosen: cases with no lesion were managed by CABG with AC (585 patients); a local solitary lesion was managed by altering the site of cannulation and application of the clamp (92 patients) or by the operation according to the 'single clamp' technique (43 patients); cases of manifested atherosclerosis of the ascending aorta were treated by the 'on-pump beating heart' technique in the conditions of AC without placing clamps (27 patients); cases of massive involvement of the ascending aorta and aortic arch were managed by CABG performed according to the 'no-touch aorta' technique (18 patients). The total mortality rate amounted to 1.1%. Thirty-three (0.96%) patients in the postoperative period were found to have ischaemic stroke. The mortality rate in the Control Group amounted to 1.4% and that in the Study Group equalled 0.3%, with the number of cases of ischaemic strokes amounting to 33 (1.4%) and 0, respectively. Perioperative infarction was diagnosed in 16 (0.6%) cases in the Control Group and in 5 (0.7%) patients in the group treated using the differentiated approach. A conclusion was drawn that the differentiated approach to choosing the technique of CABG based on the findings obtained by means of epiaortic scanning was associated with a statistically significant decrease in both the number of ischaemic strokes and the mortality rate after CABG operations. PMID- 28594810 TI - Kidney injury secondary to endovascular treatment of renal artery stenosis. AB - In this paper, we present a case of kidney injury as a complication of renal artery angioplasty in a 54-year-old female patient that suffered from resistant renovascular hypertension. This case emphasises the unpredictable nature of endovascular procedures, the need for careful post-procedure evaluation and the role of 'old fashioned' surgical techniques in resolving complications of endovascular procedures. PMID- 28594811 TI - [Successful two-stage surgical treatment of a thoracoabdominal aortic aneurysm: a case report]. AB - Presented herein is a clinical case report regarding hybrid or two-stage surgical treatment of a Crawford type II thoracoabdominal aortic aneurysm in an 87-year old woman. For the first stage operation we performed open resection of the abdominal aortic aneurysm with aortofemoral bifurcation prosthetic repair and debranching of visceral and renal arteries. Several months thereafter, the second stage operation was performed, consisting in transcatheter exclusion of the thoracoabdominal aortic aneurysm with the help of two stent grafts. The postoperative period turned out uneventful, with no complications. The check-up contrast-enhanced multislice computed tomography (MSCT) carried out 8 months later showed neither endoleaks nor migration of the stent grafts, with the bypass shunts' patency preserved. PMID- 28594812 TI - [Staged implantation of an abdominal stent graft]. AB - The article deals with a case report regarding successful surgical management of a patient presenting with an anatomically complicated aneurysm of the aortic infrarenal portion and iliac arteries. The first stage consisted in performing implantation of the Ovation Prime stent graft into the abdominal aorta. One month later, the second stage carried out for residual type IB endoleak consisted in implantation of the iliac components of the stent graft into the external iliac arteries on the right and the left. The postoperative period turned out uneventful. The findings of the check ultrasonographic examination showed no evidence of endoleak, with the stent graft's patency preserved. The patient was discharged in a satisfactory condition. The check multispiral computed tomography performed 30 days after the operation also demonstrated complete isolation of the aneurysm of the aorta and iliac arteries from blood flow, with the graft's being patent. The presented herein clinical case report is of sporadic occurrence and is of practical importance for extending the indications for aortic endoprosthetic repair. PMID- 28594814 TI - [Deliberations on lumbar sympathectomy: years and practice on the occasion of the 90th anniversary of using the method in Russia]. AB - The article deals with the literature data on history of and modern attitude to lumbar sympathectomy in treatment for occlusive lesions of lower-limb peripheral arteries. This is followed by analysing the experience of 1,764 operations both independent and those combined with vascular reconstructions over more than a 45 year period. A conclusion is drawn that lumbar sympathectomy remains an operation associated with minimal traumaticity and a low complication rate, thus for long years improving the quality of life and destiny of patients. PMID- 28594813 TI - [Open thrombectomy in acute iliofemoral venous thrombosis]. AB - AIM: The study was aimed at assessing efficacy of open thrombectomy in acute iliofemoral venous thrombosis. PATIENTS AND METHODS: From January 2012 to December 2016, a total of 37 patients underwent transfemoral thrombectomy for acute iliofemoral venous thrombosis. The Control Group consisted of 24 patients receiving standard anticoagulant therapy. Six patients were subjected to a hybrid operation consisting in thrombectomy supplemented with stenting of the residual compression stenosis of the left common iliac vein (CIV). The outcomes of the operations were controlled by means of duplex scanning. Clinical efficacy of the operations was evaluated with the help of the Venous Clinical Severity Score (VCSS) and CEAP classification. RESULTS: Patency of the iliofemoral segment at 6 months of follow up after thrombectomy was observed in 92% of patients. At the same time, in patients receiving anticoagulant therapy recanalization of the iliofemoral segment was observed in only 21% (5/24; chi2=31, p<0.01) of cases. Recanalization of the femoropopliteal segment 6 months after thrombectomy was noted to occur in 70% (23/33) of patients. The median of the composite index by the VCSS after 6 months decreased from 7 to 2 (p=0.002). The cumulative patency of the iliofemoral segment 36 months after surgery amounted to 86%. Clinical assessment of the remote results of thrombectomy according to the CEAP classification demonstrated that 90% (19/21) of patients were either free from or had weakly pronounced symptoms of post-thrombotic syndrome. CONCLUSION: Performing thrombectomy for iliofemoral thrombosis by selective indications using modern methods of restoring patency of deep veins significantly increases efficacy of treating patients presenting with this severe pathology and prevents the development of pronounced manifestations of post-thrombotic syndrome. PMID- 28594815 TI - Preparation of biomimetic hierarchically helical fiber actuators from carbon nanotubes. AB - Mechanically responsive materials that are able to sense and respond to external stimuli have important applications in soft robotics and the formation of artificial muscles, such as intelligent electronics, prosthetic limbs, comfort adjusting textiles and miniature actuators for microfluidics. However, previous artificial muscles based on polymer materials are insufficient in generating large actuations, fast responses, diverse deformation modes and high cycle performances. To this end, carbon nanotubes (CNTs) are proposed as promising candidates to be assembled into artificial muscles, as they are lightweight, robust and have high surface-to-volume ratios. This protocol describes a reproducible biomimetic method for preparing a family of hierarchically arranged helical fiber (HHF) actuators that are responsive to solvents and vapors. These HHFs are produced through helical assembly of CNTs into primary fibers and further twisting of the multi-ply primary fibers into a helical structure. A large number of nanoscale gaps between the CNTs and micron-scale gaps between the primary fibers ensure large volume changes and fast responses upon the infiltration of solvents and vapors (e.g., water, ethanol, acetone and dichloromethane) by capillarity. The modes of shape transformations can be modulated precisely by controlling how the CNTs are assembled into primary fibers, multi-ply primary fibers, HHFs and hierarchical springs. This protocol provides a prototype for preparing actuators with different fiber components. The overall time required for the preparation of HHF actuators is 17 h. PMID- 28594816 TI - mRNA quantification using single-molecule FISH in Drosophila embryos. AB - Spatial information is critical to the interrogation of developmental and tissue level regulation of gene expression. However, this information is usually lost when global mRNA levels from tissues are measured using reverse transcriptase PCR, microarray analysis or high-throughput sequencing. By contrast, single molecule fluorescence in situ hybridization (smFISH) preserves the spatial information of the cellular mRNA content with subcellular resolution within tissues. Here we describe an smFISH protocol that allows for the quantification of single mRNAs in Drosophila embryos, using commercially available smFISH probes (e.g., short fluorescently labeled DNA oligonucleotides) in combination with wide field epifluorescence, confocal or instant structured illumination microscopy (iSIM, a super-resolution imaging approach) and a spot-detection algorithm. Fixed Drosophila embryos are hybridized in solution with a mixture of smFISH probes, mounted onto coverslips and imaged in 3D. Individual fluorescently labeled mRNAs are then localized within tissues and counted using spot-detection software to generate quantitative, spatially resolved gene expression data sets. With minimum guidance, a graduate student can successfully implement this protocol. The smFISH procedure described here can be completed in 4-5 d. PMID- 28594817 TI - A shifting mutational landscape in 6 nutritional states: Stress-induced mutagenesis as a series of distinct stress input-mutation output relationships. AB - Environmental stresses increase genetic variation in bacteria, plants, and human cancer cells. The linkage between various environments and mutational outcomes has not been systematically investigated, however. Here, we established the influence of nutritional stresses commonly found in the biosphere (carbon, phosphate, nitrogen, oxygen, or iron limitation) on both the rate and spectrum of mutations in Escherichia coli. We found that each limitation was associated with a remarkably distinct mutational profile. Overall mutation rates were not always elevated, and nitrogen, iron, and oxygen limitation resulted in major spectral changes but no net increase in rate. Our results thus suggest that stress-induced mutagenesis is a diverse series of stress input-mutation output linkages that is distinct in every condition. Environment-specific spectra resulted in the differential emergence of traits needing particular mutations in these settings. Mutations requiring transpositions were highest under iron and oxygen limitation, whereas base-pair substitutions and indels were highest under phosphate limitation. The unexpected diversity of input-output effects explains some important phenomena in the mutational biases of evolving genomes. The prevalence of bacterial insertion sequence transpositions in the mammalian gut or in anaerobically stored cultures is due to environmentally determined mutation availability. Likewise, the much-discussed genomic bias towards transition base substitutions in evolving genomes can now be explained as an environment-specific output. Altogether, our conclusion is that environments influence genetic variation as well as selection. PMID- 28594819 TI - Wide-Open: Accelerating public data release by automating detection of overdue datasets. AB - Open data is a vital pillar of open science and a key enabler for reproducibility, data reuse, and novel discoveries. Enforcement of open-data policies, however, largely relies on manual efforts, which invariably lag behind the increasingly automated generation of biological data. To address this problem, we developed a general approach to automatically identify datasets overdue for public release by applying text mining to identify dataset references in published articles and parse query results from repositories to determine if the datasets remain private. We demonstrate the effectiveness of this approach on 2 popular National Center for Biotechnology Information (NCBI) repositories: Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA). Our Wide-Open system identified a large number of overdue datasets, which spurred administrators to respond directly by releasing 400 datasets in one week. PMID- 28594818 TI - Leveraging functional annotations in genetic risk prediction for human complex diseases. AB - Genetic risk prediction is an important goal in human genetics research and precision medicine. Accurate prediction models will have great impacts on both disease prevention and early treatment strategies. Despite the identification of thousands of disease-associated genetic variants through genome wide association studies (GWAS), genetic risk prediction accuracy remains moderate for most diseases, which is largely due to the challenges in both identifying all the functionally relevant variants and accurately estimating their effect sizes in the presence of linkage disequilibrium. In this paper, we introduce AnnoPred, a principled framework that leverages diverse types of genomic and epigenomic functional annotations in genetic risk prediction for complex diseases. AnnoPred is trained using GWAS summary statistics in a Bayesian framework in which we explicitly model various functional annotations and allow for linkage disequilibrium estimated from reference genotype data. Compared with state-of-the art risk prediction methods, AnnoPred achieves consistently improved prediction accuracy in both extensive simulations and real data. PMID- 28594820 TI - Serum proteins mediate depression's association with dementia. AB - The latent variable "delta" (for "dementia") uniquely explains dementia severity. Depressive symptoms are independent predictors of delta. We explored 115 serum proteins as potential causal mediators of the effect of depressive symptoms on delta in a large, ethnically diverse, longitudinal cohort. All models were adjusted for age, apolipoprotein E, education, ethnicity, gender, hemoglobin A1c, and homocysteine, and replicated in randomly selected 50% subsets. Alpha1 antitrypsin (A1AT), FAS, Heparin-binding EGF-like Growth Factor (HB-EGF), Insulin like Growth Factor-1 (IGF-1), Luteinizing Hormone (LH), Macrophage Inflammatory Protein type 1 alpha (MIP-1alpha), Resitin, S100b, Tissue Inhibitor of Metalloproteinase type 1 (TIMP-1), and Vascular Cell Adhesion Molecule type 1 (VCAM-1) each were partial mediators of depression's association with delta. These proteins may offer targets for the treatment of depression's specific effect on dementia severity and Alzheimer's Disease (AD) conversion risk. PMID- 28594823 TI - Video based object representation and classification using multiple covariance matrices. AB - Video based object recognition and classification has been widely studied in computer vision and image processing area. One main issue of this task is to develop an effective representation for video. This problem can generally be formulated as image set representation. In this paper, we present a new method called Multiple Covariance Discriminative Learning (MCDL) for image set representation and classification problem. The core idea of MCDL is to represent an image set using multiple covariance matrices with each covariance matrix representing one cluster of images. Firstly, we use the Nonnegative Matrix Factorization (NMF) method to do image clustering within each image set, and then adopt Covariance Discriminative Learning on each cluster (subset) of images. At last, we adopt KLDA and nearest neighborhood classification method for image set classification. Promising experimental results on several datasets show the effectiveness of our MCDL method. PMID- 28594821 TI - Dynamics of DNA methylomes underlie oyster development. AB - DNA methylation is a critical epigenetic regulator of development in mammals and social insects, but its significance in development outside these groups is not understood. Here we investigated the genome-wide dynamics of DNA methylation in a mollusc model, the oyster Crassostrea gigas, from the egg to the completion of organogenesis. Large-scale methylation maps reveal that the oyster genome displays a succession of methylated and non methylated regions, which persist throughout development. Differentially methylated regions (DMRs) are strongly regulated during cleavage and metamorphosis. The distribution and levels of methylated DNA within genomic features (exons, introns, promoters, repeats and transposons) show different developmental lansdscapes marked by a strong increase in the methylation of exons against introns after metamorphosis. Kinetics of methylation in gene-bodies correlate to their transcription regulation and to distinct functional gene clusters, and DMRs at cleavage and metamorphosis bear the genes functionally related to these steps, respectively. This study shows that DNA methylome dynamics underlie development through transcription regulation in the oyster, a lophotrochozoan species. To our knowledge, this is the first demonstration of such epigenetic regulation outside vertebrates and ecdysozoan models, bringing new insights into the evolution and the epigenetic regulation of developmental processes. PMID- 28594824 TI - Comparing yield and relative costs of WHO TB screening algorithms in selected risk groups among people aged 65 years and over in China, 2013. AB - OBJECTIVE: To calculate the yield and cost per diagnosed tuberculosis (TB) case for three World Health Organization screening algorithms and one using the Chinese National TB program (NTP) TB suspect definitions, using data from a TB prevalence survey of people aged 65 years and over in China, 2013. METHODS: This was an analytic study using data from the above survey. Risk groups were defined and the prevalence of new TB cases in each group calculated. Costs of each screening component were used to give indicative costs per case detected. Yield, number needed to screen (NNS) and cost per case were used to assess the algorithms. FINDINGS: The prevalence survey identified 172 new TB cases in 34,250 participants. Prevalence varied greatly in different groups, from 131/100,000 to 4651/ 100,000. Two groups were chosen to compare the algorithms. The medium-risk group (living in a rural area: men, or previous TB case, or close contact or a BMI <18.5, or tobacco user) had appreciably higher cost per case (USD 221, 298 and 963) in the three algorithms than the high-risk group (all previous TB cases, all close contacts). (USD 72, 108 and 309) but detected two to four times more TB cases in the population. Using a Chest x-ray as the initial screening tool in the medium risk group cost the most (USD 963), and detected 67% of all the new cases. Using the NTP definition of TB suspects made little difference. CONCLUSIONS: To "End TB", many more TB cases have to be identified. Screening only the highest risk groups identified under 14% of the undetected cases,. To "End TB", medium risk groups will need to be screened. Using a CXR for initial screening results in a much higher yield, at what should be an acceptable cost. PMID- 28594822 TI - Hybridization and polyploidy enable genomic plasticity without sex in the most devastating plant-parasitic nematodes. AB - Root-knot nematodes (genus Meloidogyne) exhibit a diversity of reproductive modes ranging from obligatory sexual to fully asexual reproduction. Intriguingly, the most widespread and devastating species to global agriculture are those that reproduce asexually, without meiosis. To disentangle this surprising parasitic success despite the absence of sex and genetic exchanges, we have sequenced and assembled the genomes of three obligatory ameiotic and asexual Meloidogyne. We have compared them to those of relatives able to perform meiosis and sexual reproduction. We show that the genomes of ameiotic asexual Meloidogyne are large, polyploid and made of duplicated regions with a high within-species average nucleotide divergence of ~8%. Phylogenomic analysis of the genes present in these duplicated regions suggests that they originated from multiple hybridization events and are thus homoeologs. We found that up to 22% of homoeologous gene pairs were under positive selection and these genes covered a wide spectrum of predicted functional categories. To biologically assess functional divergence, we compared expression patterns of homoeologous gene pairs across developmental life stages using an RNAseq approach in the most economically important asexually reproducing nematode. We showed that >60% of homoeologous gene pairs display diverged expression patterns. These results suggest a substantial functional impact of the genome structure. Contrasting with high within-species nuclear genome divergence, mitochondrial genome divergence between the three ameiotic asexuals was very low, signifying that these putative hybrids share a recent common maternal ancestor. Transposable elements (TE) cover a ~1.7 times higher proportion of the genomes of the ameiotic asexual Meloidogyne compared to the sexual relative and might also participate in their plasticity. The intriguing parasitic success of asexually-reproducing Meloidogyne species could be partly explained by their TE-rich composite genomes, resulting from allopolyploidization events, and promoting plasticity and functional divergence between gene copies in the absence of sex and meiosis. PMID- 28594825 TI - Intraoperative hypothermia and its clinical outcomes in patients undergoing general anesthesia: National study in China. AB - BACKGROUND/OBJECTIVE: Inadvertent intraoperative hypothermia (core temperature <36 degrees C) is a frequently preventable complication with several adverse consequences. Our study aimed to determine the overall incidence of inadvertent intraoperative hypothermia and its risk factors associated with clinical outcomes in this national survey in China. METHODS: We conducted a national cross sectional study with 30 days postoperative follow-up from November 2014 through August 2015. A total of 3132 eligible patients underwent general anesthesia were randomly selected from 28 hospitals in the nationwide of China. RESULTS: The overall incidence of intraoperative hypothermia was as high as 44.3%, in which cumulative incidence rates of hypothermia being 17.8%, 36.2%, 42.5% and 44.1% within 1 h, 2 h, 3 h and 4 h respectively following induction of anesthesia. All patients were warmed passively by covering of surgical draping, sheets or cotton blankets, whereas only 14.2% of patients received active warming with space heaters or electric heater or electronic blankets. Compared to normothermic patients, patients with hypothermia is associated with more postoperative ICU admit, longer PACU and more postoperative hospital days, but no difference in surgical site infection (SSI) rates or 30-day mortality. Several factors were shown to be associated with decreased risk of hypothermia. They are active warming (OR = 0.46, 95% CI 0.26-0.81), BMI >= 25 (OR = 0.54, 95% CI 0.45-0.65), higher baseline core temperature (OR = 0.04, 95% CI 0.03-0.06), and higher ambient temperature (OR = 0.83, 95% CI 0.78-0.88). Risk factors associated with an increased risk of hypothermia included major-plus surgery (OR = 1.49, 95% CI 1.23-1.79), and long anesthesia (>2 h) (OR = 2.60, 95% CI 2.09-3.24). CONCLUSIONS: The incidence of intraoperative hypothermia in China is high, and the rate of active warming of patients during operation is low. Hypothermia is associated with more postoperative shivering, increased ICU admissions, and longer postoperative hospital days. PMID- 28594826 TI - A highly specific phage defense system is a conserved feature of the Vibrio cholerae mobilome. AB - Vibrio cholerae-specific bacteriophages are common features of the microbial community during cholera infection in humans. Phages impose strong selective pressure that favors the expansion of phage-resistant strains over their vulnerable counterparts. The mechanisms allowing virulent V. cholerae strains to defend against the ubiquitous threat of predatory phages have not been established. Here, we show that V. cholerae PLEs (phage-inducible chromosomal island-like elements) are widespread genomic islands dedicated to phage defense. Analysis of V. cholerae isolates spanning a 60-year collection period identified five unique PLEs. Remarkably, we found that all PLEs (regardless of geographic or temporal origin) respond to infection by a myovirus called ICP1, the most prominent V. cholerae phage found in cholera patient stool samples from Bangladesh. We found that PLE activity reduces phage genome replication and accelerates cell lysis following ICP1 infection, killing infected host cells and preventing the production of progeny phage. PLEs are mobilized by ICP1 infection and can spread to neighboring cells such that protection from phage predation can be horizontally acquired. Our results reveal that PLEs are a persistent feature of the V. cholerae mobilome that are adapted to providing protection from a single predatory phage and advance our understanding of how phages influence pathogen evolution. PMID- 28594828 TI - An individual-level meta-analysis assessing the impact of community-level sanitation access on child stunting, anemia, and diarrhea: Evidence from DHS and MICS surveys. AB - BACKGROUND: A lack of access to sanitation is an important risk factor child health, facilitating fecal-oral transmission of pathogens including soil transmitted helminthes and various causes of diarrheal disease. We conducted a meta-analysis of cross-sectional surveys to determine the impact that community level sanitation access has on child health for children with and without household sanitation access. METHODOLOGY/PRINCIPAL FINDINGS: Using 301 two-stage demographic health surveys and multiple indicator cluster surveys conducted between 1990 and 2015 we calculated the sanitation access in the community as the proportion of households in the sampled cluster that had household access to any type of sanitation facility. We then conducted exact matching of children based on various predictors of living in a community with high access to sanitation. Using logistic regression with the matched group as a random intercept we examined the association between the child health outcomes of stunted growth, any anemia, moderate or severe anemia, and diarrhea in the previous two weeks and the exposure of living in a community with varying degrees of community-level sanitation access. For children with household-level sanitation access, living in a community with 100% sanitation access was associated with lowered odds of stunting (adjusted odds ratio [AOR] = 0.97, 95%; confidence interval (CI) = 0.94 1.00; n = 14,153 matched groups, 1,175,167 children), any anemia (AOR = 0.73; 95% CI = 0.67-0.78; n = 5,319 matched groups, 299,033 children), moderate or severe anemia (AOR = 0.72, 95% CI = 0.68-0.77; n = 5,319 matched groups, 299,033 children) and diarrhea (AOR = 0.94; 95% CI = 0.91-0.97); n = 16,379 matched groups, 1,603,731 children) compared to living in a community with < 30% sanitation access. For children without household-level sanitation access, living in communities with 0% sanitation access was associated with higher odds of stunting (AOR = 1.04, 95% CI = 1.02-1.06; n = 14,153 matched groups, 1,175,167 children), any anemia (AOR = 1.05, 95% CI = 1.00-1.09; n = 5,319 matched groups, 299,033 children), moderate or severe anemia (AOR = 1.04, 95% CI = 1.00-1.09; n = 5,319 matched groups, 299,033 children) but not diarrhea (AOR = 1.00, 95% CI = 0.98-1.02; n = 16,379 matched groups, 1,603,731 children) compared to children without household-level sanitation access living in communities with 1-30% sanitation access. CONCLUSIONS/SIGNIFICANCE: Community-level sanitation access is associated with improved child health outcomes independent of household-level sanitation access. The proportion of children living in communities with 100% sanitation access throughout the world is appallingly low. Ensuring sanitation access to all by 2030 will greatly improve child health. PMID- 28594827 TI - Unicycler: Resolving bacterial genome assemblies from short and long sequencing reads. AB - The Illumina DNA sequencing platform generates accurate but short reads, which can be used to produce accurate but fragmented genome assemblies. Pacific Biosciences and Oxford Nanopore Technologies DNA sequencing platforms generate long reads that can produce complete genome assemblies, but the sequencing is more expensive and error-prone. There is significant interest in combining data from these complementary sequencing technologies to generate more accurate "hybrid" assemblies. However, few tools exist that truly leverage the benefits of both types of data, namely the accuracy of short reads and the structural resolving power of long reads. Here we present Unicycler, a new tool for assembling bacterial genomes from a combination of short and long reads, which produces assemblies that are accurate, complete and cost-effective. Unicycler builds an initial assembly graph from short reads using the de novo assembler SPAdes and then simplifies the graph using information from short and long reads. Unicycler uses a novel semi-global aligner to align long reads to the assembly graph. Tests on both synthetic and real reads show Unicycler can assemble larger contigs with fewer misassemblies than other hybrid assemblers, even when long read depth and accuracy are low. Unicycler is open source (GPLv3) and available at github.com/rrwick/Unicycler. PMID- 28594829 TI - Mendel,MD: A user-friendly open-source web tool for analyzing WES and WGS in the diagnosis of patients with Mendelian disorders. AB - Whole exome and whole genome sequencing have both become widely adopted methods for investigating and diagnosing human Mendelian disorders. As pangenomic agnostic tests, they are capable of more accurate and agile diagnosis compared to traditional sequencing methods. This article describes new software called Mendel,MD, which combines multiple types of filter options and makes use of regularly updated databases to facilitate exome and genome annotation, the filtering process and the selection of candidate genes and variants for experimental validation and possible diagnosis. This tool offers a user-friendly interface, and leads clinicians through simple steps by limiting the number of candidates to achieve a final diagnosis of a medical genetics case. A useful innovation is the "1-click" method, which enables listing all the relevant variants in genes present at OMIM for perusal by clinicians. Mendel,MD was experimentally validated using clinical cases from the literature and was tested by students at the Universidade Federal de Minas Gerais, at GENE-Nucleo de Genetica Medica in Brazil and at the Children's University Hospital in Dublin, Ireland. We show in this article how it can simplify and increase the speed of identifying the culprit mutation in each of the clinical cases that were received for further investigation. Mendel,MD proved to be a reliable web-based tool, being open-source and time efficient for identifying the culprit mutation in different clinical cases of patients with Mendelian Disorders. It is also freely accessible for academic users on the following URL: https://mendelmd.org. PMID- 28594831 TI - A morphometric system to distinguish sheep and goat postcranial bones. AB - Distinguishing between the bones of sheep and goat is a notorious challenge in zooarchaeology. Several methodological contributions have been published at different times and by various people to facilitate this task, largely relying on a macro-morphological approach. This is now routinely adopted by zooarchaeologists but, although it certainly has its value, has also been shown to have limitations. Morphological discriminant criteria can vary in different populations and correct identification is highly dependent upon a researcher's experience, availability of appropriate reference collections, and many other factors that are difficult to quantify. There is therefore a need to establish a more objective system, susceptible to scrutiny. In order to fulfil such a requirement, this paper offers a comprehensive morphometric method for the identification of sheep and goat postcranial bones, using a sample of more than 150 modern skeletons as a basis, and building on previous pioneering work. The proposed method is based on measurements-some newly created, others previously published-and its use is recommended in combination with the more traditional morphological approach. Measurement ratios, used to translate morphological traits into biometrical attributes, are demonstrated to have substantial diagnostic potential, with the vast majority of specimens correctly assigned to species. The efficacy of the new method is also tested with Discriminant Analysis, which provides a successful verification of the biometrical indices, a statistical means to select the most promising measurements, and an additional line of analysis to be used in conjunction with the others. PMID- 28594830 TI - Effect of irrigation and nitrogen application on grain amino acid composition and protein quality in winter wheat. AB - Water management and nitrogen application are critical factors in wheat grain yield and protein quality. This study aimed to evaluate the effect of irrigation and nitrogen application on the grain yield, protein content and amino acid composition of winter wheat. Field experiments were conducted in a split-plot design with three replications in high-yielding land on the North China Plain in 2012/2013, 2013/2014 and 2014/2015. Three irrigation treatments were examined in main plots: no irrigation, irrigation at jointing, and irrigation at jointing plus anthesis, while subplots were assigned to nitrogen treatment at four different rates: 0, 180, 240, 300 kg N ha-1, respectively. The results indicated that irrigation at jointing and at jointing plus anthesis improved grain yield by an average of 12.79 and 18.65% across three cropping seasons, respectively, compared with no irrigation. However, different irrigation treatments had no significant effect on grain protein content in any cropping season. Compared with no N treatment, 180, 240, and 300 kg N ha-1 N application significantly increased grain yield, by 58.66, 61.26 and 63.42% respectively, averaged over three cropping seasons. Grain protein and the total, essential and non-essential amino acid content significantly increased with increasing nitrogen application. Irrigation significantly improved the essential amino acid index (EAAI) and protein-digestibility-corrected amino acid score (PDCAAS) compared with no irrigation; however, N application decreased them by an average of 7.68 and 11.18% across three cropping seasons, respectively. EAAI and PDCAAS were positively correlated, however, they were highly negatively correlated with yield and grain protein content. PMID- 28594832 TI - The road not taken: Could stress-specific mutations lead to different evolutionary paths? AB - Organisms often encounter stressful conditions, some of which damage their DNA. In response, some organisms show a high expression of error-prone DNA repair machinery, causing a temporary increase in the genome-wide mutation rate. Although we now have a detailed map of the molecular mechanisms underlying such stress-induced mutagenesis (SIM), it has been hotly debated whether SIM alters evolutionary dynamics. Key to this controversy is our poor understanding about which stresses increase mutagenesis and their long-term consequences for adaptation. In a new study with Escherichia coli, Maharjan and Ferenci show that while only some nutritional stresses (phosphorous and carbon limitation) increase total mutation rates, each stress generates a unique spectrum of mutations. Their results suggest the potential for specific stresses to shape evolutionary dynamics and highlight the necessity for explicit tests of the long-term evolutionary impacts of SIM. PMID- 28594833 TI - Diet and trophic ecology of the tiger shark (Galeocerdo cuvier) from South African waters. AB - Knowledge of the diet and trophic ecology of apex predators is key for the implementation of effective ecosystem as well as species-based management initiatives. Using a combination of stomach content data and stable isotope analysis (delta15N and delta13C) the current study provides information on size based and sex-specific variations in diet, trophic position (TP) and foraging habitat of tiger sharks (Galeocerdo cuvier) caught in the KwaZulu-Natal Sharks Board bather protection program. This study presents the longest time-series and most detailed analysis of stomach content data for G. cuvier worldwide. Prey identified from 628 non-empty stomachs revealed a size-based shift in diet. Reptiles, birds, mysticetes, and large shark species increased in dietary importance with G. cuvier size, concomitant with a decrease in smaller prey such as batoids and teleosts. Seasonal and decadal shifts in diet driven primarily by changes in the importance of elasmobranchs and mammal (cetacean) prey were recorded for medium sized (150-220 cm) G. cuvier. Both stomach content and stable isotope analysis indicated that G. cuvier is a generalist feeder at the population level. Size-based delta13C profiles indicated a movement to offshore foraging habitats by larger G. cuvier. Calculated TP varied by method ranging from 4.0 to 5.0 (TPSCA for stomach contents) and from 3.6 to 4.5 (TPscaled and TPadditive for delta15N). Large (> 220 cm) G. cuvier did not feed at discrete trophic levels, but rather throughout the food web. These data provide key information on the ecological role of G. cuvier to improve the accuracy of regional food web modelling. This will enable a better understanding of the ecological impacts related to changes in the abundance of this predator. PMID- 28594834 TI - Toll-like receptor mediated activation is possibly involved in immunoregulating properties of cow's milk hydrolysates. AB - Immunomodulating proteins and peptides are formed during the hydrolysis of cow's milk proteins. These proteins are potential ingredients in functional foods used for the management of a range of immune related problems, both in infants and adults. However, the mechanism behind these effects is unknown. We hypothesize that the interaction of peptides with Toll-like receptors (TLRs) can induce immune effects, since these receptors are known to sample many dietary molecules in the intestine in order to regulate immune effects. To investigate this, we compared the immune effects and TLR activation and inhibition by whey and casein hydrolysates with different hydrolysis levels. We first measured cytokine production in primary peripheral blood mononuclear cells stimulated with either whey, casein, or their hydrolysates. IL-10 and TNFalpha were induced by whey hydrolysates (decreasing with increasing hydrolysis level), but not by casein hydrolysates. Next, the activation of TLR 2, 3, 5 and 9 receptors were observed by intact and mildly hydrolysed whey proteins only and not by casein hydrolysates in TLR reporter cell lines. Many casein hydrolysates inhibited TLR signaling (mainly TLR 5 and 9). These results demonstrate that the effects of cow's milk proteins on the immune system are protein type and hydrolysis dependent. TLR signaling is suggested as a possible mechanism for differences in effect. This knowledge contributes to a better understanding of the immune effects of hydrolysates and the design of infant formula, and nutrition in general, with specific immunoregulatory effects. PMID- 28594836 TI - Enhancing fish Underwater Visual Census to move forward assessment of fish assemblages: An application in three Mediterranean Marine Protected Areas. AB - Monitoring fish assemblages is needed to assess whether Marine Protected Areas (MPAs) are meeting their conservation and fisheries management goals, as it allows one to track the progress of recovery of exploited species and associated communities. Underwater Visual Census techniques (UVC) are used to monitor fish assemblages in MPAs. UVCs should be adapted to fish abundance, body-size and behaviour, which can strongly affect fish detectability. In Mediterranean subtidal habitats, however, UVC strip transects of one surface area (25x5 m2) are commonly used to survey the whole fish assemblage, from large shy fish to small crypto-benthic fish. Most high trophic level predators (HTLPs) are large shy fish which rarely swim close to divers and, consequently, their abundance may be under estimated with commonly used transects. Here, we propose an improvement to traditional transect surveys to better account for differences in behaviour among and within species. First, we compared the effectiveness of combining two transect surface areas (large: 35x20 m2; medium: 25x5 m2) in quantifying large, shy fish within and outside Mediterranean MPAs. We identified species-specific body-size thresholds defining a smaller and a larger size class better sampled by medium and large transects respectively. Combining large and medium transects provided more accurate biomass and species richness estimates for large, shy species than using medium transects alone. We thus combined the new approach with two other transect surface areas commonly used to survey crypto-benthic (10x1 m2) and necto-benthic (25x5 m2) species in order to assess how effectively MPAs protection the whole fish assemblage. We verified that MPAs offer significant protection for HTLPs, their response in terms of biomass and density increase in MPAs was always higher in magnitude than other functional groups. Inside MPAs, the contribution of HTLP reached >25% of total fish biomass, against < 2% outside MPAs. Surveys with multiple transect surface areas allow for a more realistic assessment of the structure of the whole fish assemblage and better assessment of potential recovery of HTLPs within reserves of HTLP. PMID- 28594835 TI - Rapid immunoassays for diagnosis of heparin-induced thrombocytopenia: Comparison of diagnostic accuracy, reproducibility, and costs in clinical practice. AB - BACKGROUND: Immunoassays are crucial in the work-up of patients with suspected heparin-induced thrombocytopenia (HIT) and rapid tests have been recently developed. However, comparative data on diagnostic accuracy, reproducibility, and analytical costs of different immunoassays in clinical practice are limited. METHODS: Samples of 179 consecutive patients evaluated for suspected HIT in clinical practice using a polyspecific enzyme-linked immunoabsorbent assay (GTI diagnostics; ELISA) and a rapid particle gel immunoassay (PaGIA), were additionally analysed with a IgG-specific chemiluminescent immunoassay (AcuStar HIT-IgG). Presence of HIT was defined as a positive functional heparin-induced platelet aggregation test. Diagnostic accuracy was determined for low, intermediate and high thresholds as previously established (ELISA: optical density 0.4, 1.3, and 2.0 respectively; PaGIA: positive/negative, titre of 4, titre of 32; AcuStar HIT-IgG: 1.0 U/ml, 2.8, 9.4) and reproducibility was assessed by repeated measurements. Costs of test determination were calculated taking reagents, controls, and working time of technicians according to Swiss health care system into account. RESULTS: Data on PaGIA results were available for 171 patients (95.5%), ELISA for 144 patients (80.4%), and AcuStar HIT-IgG for 179 patients (100%). Sensitivity was above 95% for all assays at low and intermediate thresholds. Specificity increased with higher thresholds and was above 90% for all assays with intermediate and high thresholds. Specificity of AcuStar HIT-IgG (92.8%; 95% CI 87.7, 96.2) was significantly higher than PaGIA (83.0%; 95% CI 76.3, 88.5) and higher than ELISA (81.8%, 95% CI 74.2, 88.0) at low threshold (p<0.05). Reproducibility was adequate for all assays. Total costs per test were CHF 51.02 for ELISA, 117.70 for AcuStar HIT-IgG, and 83.13 for PaGIA. CONCLUSIONS: We observed favourable diagnostic accuracy measures and a high reproducibility for PaGIA and AcuStar HIT-IgG. Implementation into 24-hours service might improve patient care but the results must be confirmed in other settings and larger populations as well. PMID- 28594837 TI - Genetic variants in ALDH1B1 and alcohol dependence risk in a British and Irish population: A bioinformatic and genetic study. AB - Alcohol is metabolized in the liver via the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Polymorphisms in the genes encoding these enzymes, which are common in East Asian populations, can alter enzyme kinetics and hence the risk of alcohol dependence and its sequelae. One of the most important genetic variants, in this regards, is the single nucleotide polymorphism (SNP) rs671 in ALDH2, the gene encoding the primary acetaldehyde metabolizing enzyme ALDH2. However, the protective allele of rs671 is absent in most Europeans although ALDH1B1, which shares significant sequence homology with ALDH2, contains several, potentially functional, missense SNPs that do occur in European populations. The aims of this study were: (i) to use bioinformatic techniques to characterize the possible effects of selected variants in ALDH1B1 on protein structure and function; and, (ii) to genotype three missense and one stop-gain, protein-altering, non-synonymous SNPs in 1478 alcohol dependent cases and 1254 controls of matched British and Irish ancestry. No significant allelic associations were observed between the three missense SNPs and alcohol dependence risk. The minor allele frequency of rs142427338 (Gln378Ter) was higher in alcohol dependent cases than in controls (allelic P = 0.19, OR = 2.98, [0.62-14.37]) but as this SNP is very rare the study was likely underpowered to detect an association with alcohol dependence risk. This potential association will needs to be further evaluated in other large, independent European populations. PMID- 28594838 TI - A comprehensive overview and evaluation of circular RNA detection tools. AB - Circular RNA (circRNA) is mainly generated by the splice donor of a downstream exon joining to an upstream splice acceptor, a phenomenon known as backsplicing. It has been reported that circRNA can function as microRNA (miRNA) sponges, transcriptional regulators, or potential biomarkers. The availability of massive non-polyadenylated transcriptomes data has facilitated the genome-wide identification of thousands of circRNAs. Several circRNA detection tools or pipelines have recently been developed, and it is essential to provide useful guidelines on these pipelines for users, including a comprehensive and unbiased comparison. Here, we provide an improved and easy-to-use circRNA read simulator that can produce mimicking backsplicing reads supporting circRNAs deposited in CircBase. Moreover, we compared the performance of 11 circRNA detection tools on both simulated and real datasets. We assessed their performance regarding metrics such as precision, sensitivity, F1 score, and Area under Curve. It is concluded that no single method dominated on all of these metrics. Among all of the state of-the-art tools, CIRI, CIRCexplorer, and KNIFE, which achieved better balanced performance between their precision and sensitivity, compared favorably to the other methods. PMID- 28594839 TI - Exploratory graph analysis: A new approach for estimating the number of dimensions in psychological research. AB - The estimation of the correct number of dimensions is a long-standing problem in psychometrics. Several methods have been proposed, such as parallel analysis (PA), Kaiser-Guttman's eigenvalue-greater-than-one rule, multiple average partial procedure (MAP), the maximum-likelihood approaches that use fit indexes as BIC and EBIC and the less used and studied approach called very simple structure (VSS). In the present paper a new approach to estimate the number of dimensions will be introduced and compared via simulation to the traditional techniques pointed above. The approach proposed in the current paper is called exploratory graph analysis (EGA), since it is based on the graphical lasso with the regularization parameter specified using EBIC. The number of dimensions is verified using the walktrap, a random walk algorithm used to identify communities in networks. In total, 32,000 data sets were simulated to fit known factor structures, with the data sets varying across different criteria: number of factors (2 and 4), number of items (5 and 10), sample size (100, 500, 1000 and 5000) and correlation between factors (orthogonal, .20, .50 and .70), resulting in 64 different conditions. For each condition, 500 data sets were simulated using lavaan. The result shows that the EGA performs comparable to parallel analysis, EBIC, eBIC and to Kaiser-Guttman rule in a number of situations, especially when the number of factors was two. However, EGA was the only technique able to correctly estimate the number of dimensions in the four-factor structure when the correlation between factors were .7, showing an accuracy of 100% for a sample size of 5,000 observations. Finally, the EGA was used to estimate the number of factors in a real dataset, in order to compare its performance with the other six techniques tested in the simulation study. PMID- 28594840 TI - Phylogeography on the rocks: The contribution of current and historical factors in shaping the genetic structure of Chthamalus montagui (Crustacea, Cirripedia). AB - The model marine broadcast-spawner barnacle Chthamalus montagui was investigated to understand its genetic structure and quantify levels of population divergence, and to make inference on historical demography in terms of time of divergence and changes in population size. We collected specimens from rocky shores of the north east Atlantic Ocean (4 locations), Mediterranean Sea (8) and Black Sea (1). The 312 sequences 537 bp) of the mitochondrial cytochrome c oxidase I allowed to detect 130 haplotypes. High within-location genetic variability was recorded, with haplotype diversity ranging between h = 0.750 and 0.967. Parameters of genetic divergence, haplotype network and Bayesian assignment analysis were consistent in rejecting the hypothesis of panmixia. C. montagui is genetically structured in three geographically discrete populations, which corresponded to north-eastern Atlantic Ocean, western-central Mediterranean Sea, and Aegean Sea Black Sea. These populations are separated by two main effective barriers to gene flow located at the Almeria-Oran Front and in correspondence of the Cyclades Islands. According to the 'isolation with migration' model, adjacent population pairs diverged during the early to middle Pleistocene transition, a period in which geological events provoked significant changes in the structure and composition of palaeocommunities. Mismatch distributions, neutrality tests and Bayesian skyline plots showed past population expansions, which started approximately in the Mindel-Riss interglacial, in which ecological conditions were favourable for temperate species and calcium-uptaking marine organisms. PMID- 28594841 TI - Probabilistic Entity-Relationship Diagram: A correlation between functional connectivity and spontaneous brain activity during resting state in major depressive disorder. AB - BACKGROUND: Alterations of functional connectivity (FC) and spontaneous brain activity (SBA) during the resting state has been observed in subjects with major depressive disorder (MDD). Although there are many studies separately describing on the alterations of FC and SBA in major depressive disorder, their correlation are still have not been performed. METHODS: A literature search based on Pubmed and Embase was conducted until 20 April 2016 to identify studies evaluating the correlation for the alterations between functional connectivity and spontaneous brain activity during resting-state in MDD. Meta-analyses were performed using the Probabilistic Entity-Relationship Diagram (PERD) approach to summarize the relationships among multiple factors in an intuitive manner. RESULTS: A total of 30 studies (747 individuals with MDD and 757 healthy controls) met the inclusion criteria. In this study, we demonstrated that the functional connectivity and spontaneous brain activity, which was quantitatively measured by the primary analysis methods, was decreased in the parahippocampal gyrus, orbitofrontal cortex (OFC) and postcentral gyrus (PCG), and increased in insula and left dorsal medial prefrontal cortex (DMPFC) in MDD patients. Furthermore, we found that MDD patients presented negative correlation alterations both FC and SBA in the default mode network and the dorsal attention network, but positive correlation alterations both FC and SBA in the insular network, executive control network, the salience network and the other network. CONCLUSIONS: Our results first suggested that there were correlation alterations between functional connectivity and spontaneous brain activity during resting-state in patients with MDD. Besides, we applied a recent meta-analysis approach (PERD) to summarize and integrate the inconsistence of the existing findings regarding the network dysfunction of MDD. PMID- 28594842 TI - "If my husband leaves me, I will go home and suffer, so better cling to him and hide this thing": The influence of gender on Option B+ prevention of mother-to child transmission participation in Malawi and Uganda. AB - The role of gender in prevention of mother-to-child transmission (PMTCT) participation under Option B+ has not been adequately studied, but it is critical for reducing losses to follow-up. This study used qualitative methods to examine the interplay of gender and individual, interpersonal, health system, and community factors that contribute to PMTCT participation in Malawi and Uganda. We conducted in-depth interviews with women in PMTCT, women lost to follow-up, government health workers, and stakeholders at organizations supporting PMTCT as well as focus group discussions with men. We analyzed the data using thematic content analysis. We found many similarities in key themes across respondent groups and between the two countries. The main facilitators of PMTCT participation were knowledge of the health benefits of ART, social support, and self-efficacy. The main barriers were fear of HIV disclosure and stigma and lack of social support, male involvement, self-efficacy, and agency. Under Option B+, women learn about their HIV status and start lifelong ART on the same day, before they have a chance to talk to their husbands or families. Respondents explained that very few husbands accompanied their wives to the clinic, because they felt it was a female space and were worried that others would think their wives were controlling them. Many respondents said women fear disclosing, because they fear HIV stigma as well as the risk of divorce and loss of economic support. If women do not disclose, it is difficult for them to participate in PMTCT in secret. If they do disclose, they must abide by their husbands' decisions about their PMTCT participation, and some husbands are unsupportive or actively discouraging. To improve PMTCT participation, Ministries of Health should use evidence-based strategies to address HIV stigma, challenges related to disclosure, insufficient social support and male involvement, and underlying gender inequality. PMID- 28594843 TI - Microbes and masculinity: Does exposure to pathogenic cues alter women's preferences for male facial masculinity and beardedness? AB - Women's preferences for men's androgen dependent secondary sexual traits are proposed to be phenotypically plastic in response to exposure to pathogens and pathogen disgust. While previous studies report that masculinity in facial shape is more attractive to women who have recently been exposed to pathogenic cues and who are high in self-reported pathogen disgust, facial hair may reduce male attractiveness under conditions of high pathogens as beards are a possible breeding ground for disease carrying ectoparasites. In the present study, we test whether women's preferences for beardedness and facial masculinity vary due to exposure to different pathogenic cues. Participants (N = 688, mean age + 1SD = 31.94 years, SD = 6.69, range = 18-67) rated the attractiveness of facial composite stimuli of men when they were clean-shaven or fully bearded. These stimuli were also manipulated in order to vary sexual dimorphism by +/-50%. Ratings were conducted before and after exposure to one of four experimental treatments in which participants were primed to either high pathogens (e.g. infected cuts), ectoparasites (e.g. body lice), a mixture of pathogens and ectoparasites, or a control condition (e.g. innocuous liquids). Participants then completed the three-domain disgust scale measuring attitudes to moral, sexual and pathogen disgust. We predicted that women would prefer facial masculinity following exposure to pathogenic cues, but would show reduced preferences for facial hair following exposure to ectoparasites. Women preferred full beards over clean-shaven faces and masculinised over feminised faces. However, none of the experimental treatments influenced the direction of preferences for facial masculinity or beardedness. We also found no association between women's self reported pathogen disgust and their preferences for facial masculinity. However, there was a weak positive association between moral disgust scores and preferences for facial masculinity, which might reflect conservatism and preferences for gender typicality in faces. Women's preferences for beards were positively associated with their pathogen disgust, which runs contrary to our predictions and may reflect preferences for high quality individuals who can withstand any costs of beardedness, although further replications are necessary before firm conclusions can be made. We conclude that there is little support for pathogenic exposure being a mechanism that underpins women's directional preferences for masculine traits. PMID- 28594844 TI - Prediction of adjuvant chemotherapy response in triple negative breast cancer with discovery and targeted proteomics. AB - BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and usually requires the administration of adjuvant chemotherapy after surgery but even with this treatment many patients still suffer from a relapse. The main objective of this study was to identify proteomics-based biomarkers that predict the response to standard adjuvant chemotherapy, so that patients at are not going to benefit from it can be offered therapeutic alternatives. METHODS: We analyzed the proteome of a retrospective series of formalin-fixed, paraffin-embedded TNBC tissue applying high-throughput label-free quantitative proteomics. We identified several protein signatures with predictive value, which were validated with quantitative targeted proteomics in an independent cohort of patients and further evaluated in publicly available transcriptomics data. RESULTS: Using univariate Cox analysis, a panel of 18 proteins was significantly associated with distant metastasis-free survival of patients (p<0.01). A reduced 5-protein profile with prognostic value was identified and its prediction performance was assessed in an independent targeted proteomics experiment and a publicly available transcriptomics dataset. Predictor P5 including peptides from proteins RAC2, RAB6A, BIEA and IPYR was the best performance protein combination in predicting relapse after adjuvant chemotherapy in TNBC patients. CONCLUSIONS: This study identified a protein combination signature that complements histopathological prognostic factors in TNBC treated with adjuvant chemotherapy. The protein signature can be used in paraffin embedded samples, and after a prospective validation in independent series, it could be used as predictive clinical test in order to recommend participation in clinical trials or a more exhaustive follow-up. PMID- 28594845 TI - Temperature-amplitude coupling for stable biological rhythms at different temperatures. AB - Most biological processes accelerate with temperature, for example cell division. In contrast, the circadian rhythm period is robust to temperature fluctuation, termed temperature compensation. Temperature compensation is peculiar because a system-level property (i.e., the circadian period) is stable under varying temperature while individual components of the system (i.e., biochemical reactions) are usually temperature-sensitive. To understand the mechanism for period stability, we measured the time series of circadian clock transcripts in cultured C6 glioma cells. The amplitudes of Cry1 and Dbp circadian expression increased significantly with temperature. In contrast, other clock transcripts demonstrated no significant change in amplitude. To understand these experimental results, we analyzed mathematical models with different network topologies. It was found that the geometric mean amplitude of gene expression must increase to maintain a stable period with increasing temperatures and reaction speeds for all models studied. To investigate the generality of this temperature-amplitude coupling mechanism for period stability, we revisited data on the yeast metabolic cycle (YMC) period, which is also stable under temperature variation. We confirmed that the YMC amplitude increased at higher temperatures, suggesting temperature-amplitude coupling as a common mechanism shared by circadian and 4 h metabolic rhythms. PMID- 28594847 TI - Kidney volume to GFR ratio predicts functional improvement after revascularization in atheromatous renal artery stenosis. AB - BACKGROUND: Randomized controlled trials (RCT) have shown no overall benefit of renal revascularization in atherosclerotic renovascular disease (ARVD). However, 25% of patients demonstrate improvement in renal function. We used the ratio of magnetic resonance parenchymal volume (PV) to isotopic single kidney glomerular filtration rate (isoSKGFR) ratio as our method to prospectively identify "improvers" before revascularization. METHODS: Patients with renal artery stenosis who were due revascularization were recruited alongside non-ARVD hypertensive CKD controls. Using the controls, 95% CI were calculated for expected PV:isoSK-GFR at given renal volumes. For ARVD patients, "improvers" were defined as having both >15% and >1ml/min increase in isoSK-GFR at 4 months after revascularization. Sensitivity and specificity of PV:isoSK-GFR for predicting improvers was calculated. RESULTS: 30 patients (mean age 68 +/-8 years), underwent revascularization, of whom 10 patients had intervention for bilateral RAS. Stented kidneys which manifested >15% improvement in function had larger PV:isoSK-GFR compared to controls (19+/-16 vs. 6+/-4ml/ml/min, p = 0.002). The sensitivity and specificity of this equation in predicting a positive renal functional outcome were 64% and 88% respectively. Use of PV:isoSK-GFR increased prediction of functional improvement (area under curve 0.93). Of note, non-RAS contralateral kidneys which improved (n = 5) also demonstrated larger PV:isoSK GFR (15.2+/-16.2 ml/ml/min, p = 0.006). CONCLUSION: This study offers early indicators that the ratio of PV:isoSK-GFR may help identify patients with kidneys suitable for renal revascularization which could improve patient selection for a procedure associated with risks. Calculation of the PV:isoSK-GFR ratio is easy, does not require MRI contrast agent. PMID- 28594846 TI - SbCOMT (Bmr12) is involved in the biosynthesis of tricin-lignin in sorghum. AB - Lignin in plant biomass represents a target for engineering strategies towards the development of a sustainable bioeconomy. In addition to the conventional lignin monomers, namely p-coumaryl, coniferyl and sinapyl alcohols, tricin has been shown to be part of the native lignin polymer in certain monocot species. Because tricin is considered to initiate the polymerization of lignin chains, elucidating its biosynthesis and mechanism of export to the cell wall constitute novel challenges for the engineering of bioenergy crops. Late steps of tricin biosynthesis require two methylation reactions involving the pathway intermediate selgin. It has recently been demonstrated in rice and maize that caffeate O methyltransferase (COMT) involved in the synthesis syringyl (S) lignin units derived from sinapyl alcohol also participates in the synthesis of tricin in planta. In this work, we validate in sorghum (Sorghum bicolor L.) that the O methyltransferase responsible for the production of S lignin units (SbCOMT / Bmr12) is also involved in the synthesis of lignin-linked tricin. In particular, we show that biomass from the sorghum bmr12 mutant contains lower level of tricin incorporated into lignin, and that SbCOMT can methylate the tricin precursors luteolin and selgin. Our genetic and biochemical data point toward a general mechanism whereby COMT is involved in the synthesis of both tricin and S lignin units. PMID- 28594848 TI - Examining the correlation between diabetes and odontogenic infection: A nationwide, retrospective, matched-cohort study in Taiwan. AB - More than 90% of head and neck infections are caused by pathological changes originating in the teeth. When odontogenic infections are not properly treated, infections may spread to distant spaces and cause more serious infections in fascial spaces, ultimately leading to deep neck infections. Clinical experience has indicated that patients with diabetes mellitus (DM) may be more susceptible to facial cellulitis and deep neck infections caused by odontogenic infections. This study used the Taiwan National Health Insurance Database (NHIRD) to analyze and examine the correlation between DM and odontogenic infections in patients. To this end, this study analyzed 1 million NHIRD individual datasets from 2005, of which 964,182 individuals had medical treatment records. The insurance database also recorded related factors such as age, sex, duration of hospital stays, season, and whether patients were low income. We also analyzed the correlation between urbanization and the studied diseases. The results indicated that the correlation between facial cellulitis and DM patients was confirmed; facial cellulitis was most likely to occur 2 years after the initial DM diagnosis, with a risk occurrence 1.409 times greater than that of the control group. Facial cellulitis is more likely to occur in patients originating from poorer socioeconomic backgrounds, and female DM patients are more likely to experience this condition. These conclusions may facilitate the establishment of clinical guidelines for preventative education and treatment. Oral prevention and health education for high-risk patients, as well as early-stage surgical intervention and antibiotic usage in early-stage odontogenic infections, can prevent disease progression, improve patient recovery rates, and reduce the use and waste of medical resources. PMID- 28594849 TI - High sodium diet converts renal proteoglycans into pro-inflammatory mediators in rats. AB - BACKGROUND: High dietary sodium aggravates renal disease by affecting blood pressure and by its recently shown pro-inflammatory and pro-fibrotic effects. Moreover, pro-inflammatory modification of renal heparan sulfate (HS) can induce tissue remodeling. We aim to investigate if high sodium intake in normotensive rats converts renal HS into a pro-inflammatory phenotype, able to bind more sodium and orchestrate inflammation, fibrosis and lymphangiogenesis. METHODS: Wistar rats received a normal diet for 4 weeks, or 8% NaCl diet for 2 or 4 weeks. Blood pressure was monitored, and plasma, urine and tissue collected. Tissue sodium was measured by flame spectroscopy. Renal HS and tubulo-interstitial remodeling were studied by biochemical, immunohistochemical and qRT-PCR approaches. RESULTS: High sodium rats showed a transient increase in blood pressure (week 1; p<0.01) and increased sodium excretion (p<0.05) at 2 and 4 weeks compared to controls. Tubulo-interstitial T-cells, myofibroblasts and mRNA levels of VCAM1, TGF-beta1 and collagen type III significantly increased after 4 weeks (all p<0.05). There was a trend for increased macrophage infiltration and lymphangiogenesis (both p = 0.07). Despite increased dermal sodium over time (p<0.05), renal concentrations remained stable. Renal HS of high sodium rats showed increased sulfation (p = 0.05), increased L-selectin binding to HS (p<0,05), and a reduction of sulfation-sensitive anti-HS mAbs JM403 (p<0.001) and 10E4 (p<0.01). Hyaluronan expression increased under high salt conditions (p<0.01) without significant changes in the chondroitin sulfate proteoglycan versican. Statistical analyses showed that sodium-induced tissue remodeling responses partly correlated with observed HS changes. CONCLUSION: We show that high salt intake by healthy normotensive rats convert renal HS into high sulfated pro-inflammatory glycans involved in tissue remodeling events, but not in increased sodium storage. PMID- 28594850 TI - No changes in functional connectivity during motor recovery beyond 5 weeks after stroke; A longitudinal resting-state fMRI study. AB - Spontaneous motor recovery after stroke appears to be associated with structural and functional changes in the motor network. The aim of the current study was to explore time-dependent changes in resting-state (rs) functional connectivity in motor-impaired stroke patients, using rs-functional MRI at 5 weeks and 26 weeks post-stroke onset. For this aim, 13 stroke patients from the EXPLICIT-stroke Trial and age and gender-matched healthy control subjects were included. Patients' synergistic motor control of the paretic upper-limb was assessed with the upper extremity section of the Fugl-Meyer Assessment (FMA-UE) within 2 weeks, and at 5 and 26 weeks post-stroke onset. Results showed that the ipsilesional rs functional connectivity between motor areas was lower compared to the contralesional rs-functional connectivity, but this difference did not change significantly over time. No relations were observed between changes in rs functional connectivity and upper-limb motor recovery, despite changes in upper limb function as measured with the FMA-UE. Last, overall rs-functional connectivity was comparable for patients and healthy control subjects. To conclude, the current findings did not provide evidence that in moderately impaired stroke patients the lower rs-functional connectivity of the ipsilesional hemisphere changed over time. PMID- 28594851 TI - Serum N-glycome characterization and anti-carbohydrate antibody profiling in oral squamous cell carcinoma patients. AB - Glycosylation is a protein post translational modification which plays important role in protein function, stabilization, trafficking, and turnover. Alteration of protein glycosylation is a common phenomenon during tumor progression, migration, invasion, angiogenesis, as well as metastasis. Hence, aberrant glycan structures and the induced corresponding anti-carbohydrate antibodies are potential biomarkers for cancer diagnosis. In this study, serum N-glycomes and anti carbohydrate antibodies from normal populations and oral squamous cell carcinoma (OSCC) patients were investigated. Total serum proteins were lyophilized and subjected to chemical reduction, alkylation and trypsin digestion. The N-glycans were released, purified, permethylated, and analyzed using MALDI-TOF-Mass spectrometry. In addition, the serum anti-carbohydrate antibody profiles were also investigated by carbohydrate microarray. We found that the relative abundances of seven N-glycans were decreased or increased in serum of OSCC with diagnostic accuracy greater than 75%. The relative abundances of total tri antennary and tetra-antennary glycans with varying degrees of fucosylation and sialylation were also increased in serum N-glycomes of OSCC. In an independent validation group of forty-eight OCCC patients, most of the high-molecular weight serum N-glycans showed significantly high sensitivity and specificity according to the identified cutoff values. Furthermore, the serum levels of two IgM antibodies were elevated accompanied with the decreased levels of nine IgG antibodies in patient serum. Taken together, these serum N-glycans and antibodies identified in this study should be considered as the candidates of potential biomarkers for OSCC diagnosis. PMID- 28594852 TI - Three-dimensional characterization of root morphology for maxillary incisors. AB - The aim of this study was to test the reproducibility of three-dimensional (3D) surface models of maxillary incisors and to propose a characterization of root morphology. The sample was comprised of pre-treatment cone-beam computed tomography (CBCT) images of fifty-five patients. The CBCTs were used to construct 3D surface models of the maxillary incisors. The reproducibility of surface models was tested by repeated construction of them by two observers. A 3D surface model that corresponded to the average of all lateral and all central incisors was generated. 3D surface distances and vector differences were calculated for each individual tooth and the average of the teeth considered. The corresponding points on the 3D surface mesh for each subgroup were compared statistically to those of the neutral subgroup using shape analysis MANCOVA and Hotelling's t statistic (p < 0.05). Repeated construction of surface models demonstrated adequate inter-rater reproducibility. The distribution of 3D models into root morphology subgroups was: blunt (11% and 26% of the central and lateral incisors, respectively), conical (15% of the central incisors), long (27% and 20% of the central and lateral incisors, respectively), and short (15% and 4% of the central and lateral incisors, respectively). Compared to the neutral average, statistically significant differences in root morphology were found for blunt, long, conical, and short central incisors and for blunt, long, and short lateral incisors. We can conclude that 3D surface models construction for upper incisors is reproducible. 3D shape analysis using CBCT images allows a phenotypic characterization of incisor root morphology. PMID- 28594853 TI - The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics. AB - BACKGROUND: The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. METHODS AND FINDINGS: We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked beta-amyloid pathology and two cases had Alzheimer's pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). CONCLUSIONS: In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question. PMID- 28594855 TI - The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice. AB - Artificial sweeteners have been widely used in the modern diet, and their observed effects on human health have been inconsistent, with both beneficial and adverse outcomes reported. Obesity and type 2 diabetes have dramatically increased in the U.S. and other countries over the last two decades. Numerous studies have indicated an important role of the gut microbiome in body weight control and glucose metabolism and regulation. Interestingly, the artificial sweetener saccharin could alter gut microbiota and induce glucose intolerance, raising questions about the contribution of artificial sweeteners to the global epidemic of obesity and diabetes. Acesulfame-potassium (Ace-K), a FDA-approved artificial sweetener, is commonly used, but its toxicity data reported to date are considered inadequate. In particular, the functional impact of Ace-K on the gut microbiome is largely unknown. In this study, we explored the effects of Ace K on the gut microbiome and the changes in fecal metabolic profiles using 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) metabolomics. We found that Ace-K consumption perturbed the gut microbiome of CD-1 mice after a 4 week treatment. The observed body weight gain, shifts in the gut bacterial community composition, enrichment of functional bacterial genes related to energy metabolism, and fecal metabolomic changes were highly gender-specific, with differential effects observed for males and females. In particular, ace-K increased body weight gain of male but not female mice. Collectively, our results may provide a novel understanding of the interaction between artificial sweeteners and the gut microbiome, as well as the potential role of this interaction in the development of obesity and the associated chronic inflammation. PMID- 28594854 TI - Identification of key microRNAs and genes in preeclampsia by bioinformatics analysis. AB - Preeclampsia is a leading cause of perinatal maternal-foetal mortality and morbidity. The aim of this study is to identify the key microRNAs and genes in preeclampsia and uncover their potential functions. We downloaded the miRNA expression profile of GSE84260 and the gene expression profile of GSE73374 from the Gene Expression Omnibus database. Differentially expressed miRNAs and genes were identified and compared to miRNA-target information from MiRWalk 2.0, and a total of 65 differentially expressed miRNAs (DEMIs), including 32 up-regulated miRNAs and 33 down-regulated miRNAs, and 91 differentially expressed genes (DEGs), including 83 up-regulated genes and 8 down-regulated genes, were identified. The pathway enrichment analyses of the DEMIs showed that the up regulated DEMIs were enriched in the Hippo signalling pathway and MAPK signalling pathway, and the down-regulated DEMIs were enriched in HTLV-I infection and miRNAs in cancers. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses of the DEGs were performed using Multifaceted Analysis Tool for Human Transcriptome. The up-regulated DEGs were enriched in biological processes (BPs), including the response to cAMP, response to hydrogen peroxide and cell-cell adhesion mediated by integrin; no enrichment of down-regulated DEGs was identified. KEGG analysis showed that the up-regulated DEGs were enriched in the Hippo signalling pathway and pathways in cancer. A PPI network of the DEGs was constructed by using Cytoscape software, and FOS, STAT1, MMP14, ITGB1, VCAN, DUSP1, LDHA, MCL1, MET, and ZFP36 were identified as the hub genes. The current study illustrates a characteristic microRNA profile and gene profile in preeclampsia, which may contribute to the interpretation of the progression of preeclampsia and provide novel biomarkers and therapeutic targets for preeclampsia. PMID- 28594856 TI - Municipal wastewater treatment by the bioaugmentation of Bacillus sp. K5 within a sequencing batch reactor. AB - Artificial municipal wastewater was treated successfully by the bioaugmentation of Bacillus sp. K5 capable of simultaneous nitrification and denitrification (SND) within a sequencing batch reactor (SBR). During the long-term operation, the bioaugmentation system exhibited an excellent and steady COD and NH4+-N removal without nitrite and nitrate accumulation. The average removal efficiency for COD and NH4+-N achieved to 98% and 95%, respectively. PCR-DGGE, SEM and FISH revealed that the introduced Bacillus sp. K5 should be an important functional strain and exerted a critical influence on the structure of microbial community. qPCR analysis indicated that the strain K5 facilitated aerobic nutrients removal capabilities and SND might be the primary pathway for the nitrogen removal in the SBR. Overall, the SBR system used in our study should be very promising for the future wastewater treatment. PMID- 28594858 TI - Factors associated with delayed defibrillation in cardiopulmonary resuscitation: A prospective simulation study. AB - INTRODUCTION: Early defibrillation is an important factor of survival in cardiac arrest. However, novice resuscitators often struggle with cardiac arrest patients. We investigated factors leading to delayed defibrillation performed by final-year medical students within a simulated bystander cardiac arrest situation. METHODS: Final-year medical students received a refresher lecture and basic life support training before being confronted with a simulated cardiac arrest situation in a simulation ambulance. The scenario was analyzed for factors leading to delayed defibrillation. We compared the time intervals the participants needed for various measures with a benchmark set by experienced resuscitators. After training, the participants were interviewed regarding challenges and thoughts during the scenario. RESULTS: The median time needed for defibrillation was 158 s (n = 49, interquartile range: 107-270 s), more than six fold of the benchmark time. The major part of total defibrillation time (49%; median, n = 49) was between onset of ventricular fibrillation and beginning to prepare the defibrillator, more specifically the time between end of preparation of the defibrillator and actual delivery of the shock, with a mean proportion of 26% (n = 49, SD = 17%) of the overall time needed for defibrillation (maximum 67%). Self-reported reasons for this delay included uncertainty about the next step to take, as reported by 73% of the participants. A total of 35% were unsure about which algorithm to follow. Diagnosing the patient was subjectively difficult for 35% of the participants. Overall, 53% of the participants felt generally confused. CONCLUSIONS: Our study shows that novice resuscitators rarely achieve guideline-recommended defibrillation times. The most relative delays were observed when participants had to choose what to do next or which algorithm to follow, and thus i.e. performed extensive airway management before a life-saving defibrillation. Our data provides a first insight in the process of defibrillation delay and can be used to generate new hypotheses on how to provide a timely defibrillation. PMID- 28594857 TI - Noninvasive assessment of respiratory muscle strength and activity in Myotonic dystrophy. AB - OBJECTIVE: To evaluate sensitivity/specificity of the maximum relaxation rate (MRR) of inspiratory muscles, amplitude of electromyographic activity of the sternocleidomastoid (SCM), scalene (SCA), parasternal (2ndIS) and rectus abdominis (RA) muscles; lung function and respiratory muscle strength in subjects with Myotonic dystrophy type 1 (DM1) compared with healthy subjects. DESIGN AND METHODS: Quasi-experimental observational study with control group. MRR of inspiratory muscles, lung function and amplitude of the electromyographic activity of SCM, SCA, 2ndIS and RA muscles during maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) and sniff nasal inspiratory pressure (SNIP) tests were assessed in eighteen DM1 subjects and eleven healthy. RESULTS: MRR was lower in DM1 group compared to healthy (P = 0.001) and was considered sensitive and specific to identify disease in DM1 and discard it in controls, as well as SNIP% (P = 0.0026), PImax% (P = 0.0077) and PEmax% (P = 0.0002). Contraction time of SCM and SCA was higher in DM1 compared to controls, respectively, during PImax (P = 0.023 and P = 0.017) and SNIP (P = 0.015 and P = .0004). The DM1 group showed lower PImax (P = .0006), PEmax (P = 0.0002), SNIP (P = 0.0014), and higher electromyographic activity of the SCM (P = 0.002) and SCA (P = 0.004) at rest; of 2ndIS (P = 0.003) during PEmax and of SCM (P = 0.02) and SCA (P = 0.03) during SNIP test. CONCLUSIONS: MD1 subjects presented restrictive pattern, reduced respiratory muscle strength, muscular electrical activity and MRR when compared to higher compared to controls. In addition, the lower MRR found in MD1 subjects showed to be reliable to sensitivity and specificity in identifying the delayed relaxation of respiratory muscles. PMID- 28594859 TI - The coordinating evaluation and spatial correlation analysis of CSGC: A case study of Henan province, China. AB - This study investigates the basic characteristics and proposes a concept for the complex system of geographical conditions (CSGC). By analyzing the DPSIR model and its correlation with the index system, we selected indexes for geographical conditions according to the resources, ecology, environment, economy and society parameters to build a system. This system consists of four hierarchies: index, classification, element and target levels. We evaluated the elements or indexes of the complex system using the TOPSIS method and a general model coordinating multiple complex systems. On this basis, the coordination analysis experiment of geographical conditions is applied to cities in the Henan province in China. The following conclusions were reached: 1According to the pressure, state and impact of geographical conditions, relatively consistent measures are taken around the city, but with conflicting results. 2The coordination degree of geographical conditions is small among regions showing large differences in classification index value. The degree of coordination of such regions is prone to extreme values; however, the smaller the difference the larger the coordination degree. 3The coordinated development of geographical conditions in the Henan province is at the stage of the point axis. PMID- 28594861 TI - Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder. Reactive oxygen species (ROS) and pro-inflammatory cytokines have been believed to be involved in the etiopathogenesis of the disease. The aim of the study was to determine the correlation of inflammatory cytokines with 25-hydroxy vitamin D and ROS. METHODS: 100 RA patients and 50 healthy age and sex matched individuals were included in the study. Patients were further divided on the basis of presence or absence of rheumatoid factor and disease severity. Serum 25-hydroxy vitamin D levels were monitored by chemiluminescent immunoassay. 10% hematocrit was used to detect the level of ROS by spectro fluorometer. The levels of inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-10 and IL-17) were determined in plasma by ELISA. RESULTS: The level of 25-hydroxy vitamin D was found to be decreased in RA patients in comparison to the control group. However the level of ROS and inflammatory cytokines were found to be elevated in RA patients in comparison with the healthy controls, with the increase being more pronounced in seropositive and RA patients having high disease severity. Inflammatory cytokines showed negative correlation with 25-hydroxy vitamin D and positive correlation with ROS. CONCLUSION: This study for the first time shows the association of inflammatory cytokines with 25-hydroxy vitamin D and ROS in RA patients. The results suggest that 25-hydroxy vitamin D being an immune modulator is decreased in the serum of RA patients. Further ROS and cytokines play an important role in the pathogenesis of RA and are responsible for increasing the severity of disease. PMID- 28594860 TI - Effect of probiotic Lactobacillus on lipid profile: A systematic review and meta analysis of randomized, controlled trials. AB - OBJECTIVE: To assess the efficacy of probiotic Lactobacillus on serum lipids using a meta-analysis of randomized, controlled trials. METHODS: Fifteen studies containing 15 trials, with 976 subjects were included. The pooled WMD was calculated by random effects model. RESULTS: Probiotic Lactobacillus consumption significantly reduced TC by 0.26mmol/l (95% CI, -0.40 to -0.12) and LDL-C by 0.23mmol/l (95% CI, -0.36 to -0.10). Subgroup analysis of trials found significantly reduction of TC using L. plantarum and reduction of LDL-C using L. plantarum or L. reuteri. No significant effects were found on TG and HDL-C levels after supplementation with probiotic Lactobacillus. While, subgroup analysis found significantly beneficial effects on TG and HDL-C by consuming synbiotic food, containing L. sporogenes and inulin. CONCLUSION: Consuming probiotic Lactobacillus, especially L. reuteri and L. plantarm, could reduce TC and LDL-C significantly. The study also suggested significantly beneficial effects on TG and HDL-C by consuming synbiotic food, containing L. sporogenes and inulin. PMID- 28594862 TI - Application of acoustic agglomeration to enhance air filtration efficiency in air conditioning and mechanical ventilation (ACMV) systems. AB - The recent episodes of haze in Southeast Asia have caused some of the worst regional atmospheric pollution ever recorded in history. In order to control the levels of airborne fine particulate matters (PM) indoors, filtration systems providing high PM capturing efficiency are often sought, which inadvertently also results in high airflow resistance (or pressure drop) that increases the energy consumption for air distribution. A pre-conditioning mechanism promoting the formation of particle clusters to enhance PM capturing efficiency without adding flow resistance in the air distribution ductwork could provide an energy efficient solution. This pre-conditioning mechanism can be fulfilled by acoustic agglomeration, which is a phenomenon that promotes the coagulation of suspended particles by acoustic waves propagating in the fluid medium. This paper discusses the basic mechanisms of acoustic agglomeration along with influencing factors that could affect the agglomeration efficiency. The feasibility to apply acoustic agglomeration to improve filtration in air-conditioning and mechanical ventilation (ACMV) systems is investigated experimentally in a small-scale wind tunnel. Experimental results indicate that this novel application of acoustic pre conditioning improves the PM2.5 filtration efficiency of the test filters by up to 10% without introducing additional pressure drop. The fan energy savings from not having to switch to a high capturing efficiency filter largely outstrip the additional energy consumed by the acoustics system. This, as a whole, demonstrates potential energy savings from the combined acoustic-enhanced filtration system without compromising on PM capturing efficiency. PMID- 28594863 TI - High viral abundance as a consequence of low viral decay in the Baltic Sea redoxcline. AB - Throughout the Baltic Sea redoxcline, virus production and the frequency of lytically-infected prokaryotic cells were estimated from parallel incubations of undiluted seawater and seawater that contained prokaryotes with substantially reduced numbers of viruses (virus dilution approach), effectively preventing viral reinfection during the incubation period. Undiluted seawater incubations resulted in much higher estimates of virus production (6-35*104 mL-1 h-1) and the frequency of infected cells (5-84%) than the virus dilution approach (virus production: 1-3*104 mL-1 h-1; frequency of infected cells: 1-11%). Viral production and the frequency of infected cells from both approaches, however, cannot be directly compared, as data obtained from undiluted incubations were biased by viral reinfection and other uncontrollable processes during the incubation period. High in situ viral abundance (1-2*107 mL-1) together with low virus production rates based on the virus dilution approach resulted in some of the longest viral turnover times (24-84 d) ever reported for the epipelagial. Throughout a wide range of environmental conditions, viral turnover time and burst size were negatively correlated. Given that viral decay estimated in ultra filtered water was below the detection limit and the burst size was low (1-17), we conclude that prokaryotic viruses in the Baltic Sea redoxcline are investing most of their resources into stress defense (strong capsids) rather than proliferation (high burst size). In summary, the Baltic Sea redoxcline constitutes an environment where low virus production is found in combination with low viral decay, resulting in high viral abundance. PMID- 28594864 TI - Consistency in the supply of larval fishes among coral reefs in French Polynesia. AB - For marine fishes with a bipartite life cycle, pelagic larval dispersal can shape the distribution, connectivity, composition and resilience of adult populations. Numerous studies of larval dispersal, and associated settlement and recruitment processes, have examined the relationship between population connectivity and oceanographic features. However, relatively little is known about spatial and temporal variation in the abundance of larvae settling among different reefs and the extent to which the species assemblage of larvae settling at one location is reflective of the assemblage in neighbouring areas. Here, using crest nets, which provide a non-selective measure of the total abundance and assemblage of larvae settling to a reef (i.e. larval supply), we collected larval coral reef fishes at five locations surrounding two spatially disparate French Polynesian islands: Moorea and Nengo-Nengo. Overall, larval settlement patterns were correlated with the lunar cycle, with larval abundance peaking during the new moon. Although there were some spatial differences in larval supply among the five monitored sites, settlement patterns were largely consistent, even at the species level, irrespective of factors such as coastline orientation or distance between sites. This study provides further insights into the mechanisms driving patterns of dispersal and settlement of larval fishes over large spatial scales. PMID- 28594865 TI - Gender-linked impact of epicardial adipose tissue volume in patients who underwent coronary artery bypass graft surgery or non-coronary valve surgery. AB - BACKGROUND: Traditional and non-traditional risk factors for atherosclerotic cardiovascular disease (ASCVD) are different between men and women. Gender-linked impact of epicardial adipose tissue volume (EATV) in patients undergoing coronary artery bypass grafting (CABG) remains unknown. METHODS: Gender-linked impact of EATV, abdominal fat distribution and other traditional ASCVD risk factors were compared in 172 patients (men: 115; women: 57) who underwent CABG or non-coronary valvular surgery (non-CABG). RESULTS: In men, EATV, EATV index (EATV/body surface area) and the markers of adiposity such as body mass index, waist circumference and visceral fat area were higher in the CABG group than in the non-CABG group. Traditional ASCVD risk factors were also prevalent in the CABG group. In women, EATV and EATV index were higher in the CABG group, but other adiposity markers were comparable between CABG and non-CABG groups. Multivariate logistic regression analysis showed that in men, CABG was determined by EATV Index and other ASCVD risk factors including hypertension, dyslipidemia, adiponectin, high sensitive C-reactive protein (hsCRP) and type 2 diabetes mellitus (Corrected R2 = 0.262, p < 0.0001), while in women, type 2 diabetes mellitus is a single strong predictor for CABG, excluding EATV Index (Corrected R2 = 0.266, p = 0.005). CONCLUSIONS: Our study found that multiple risk factors, including epicardial adipose tissue volume and traditional ASCVD factors are determinants for CABG in men, but type 2 diabetes mellitus was the sole determinant in women. Gender specific disparities in risk factors of CABG prompt us to evaluate new diagnostic and treatment strategies and to seek underlying mechanisms. PMID- 28594866 TI - Revisiting the co-existence of Attention-Deficit/Hyperactivity Disorder and Chronic Tic Disorder in childhood-The case of colour discrimination, sustained attention and interference control. AB - OBJECTIVE: Attention Deficit / Hyperactivity Disorder (ADHD) and Chronic Tic Disorder (CTD) are two common and frequently co-existing disorders, probably following an additive model. But this is not yet clear for the basic sensory function of colour processing sensitive to dopaminergic functioning in the retina and higher cognitive functions like attention and interference control. The latter two reflect important aspects for psychoeducation and behavioural treatment approaches. METHODS: Colour discrimination using the Farnsworth-Munsell 100-hue Test, sustained attention during the Frankfurt Attention Inventory (FAIR), and interference liability during Colour- and Counting-Stroop-Tests were assessed to further clarify the cognitive profile of the co-existence of ADHD and CTD. Altogether 69 children were classified into four groups: ADHD (N = 14), CTD (N = 20), ADHD+CTD (N = 20) and healthy Controls (N = 15) and compared in cognitive functioning in a 2*2-factorial statistical model. RESULTS: Difficulties with colour discrimination were associated with both ADHD and CTD factors following an additive model, but in ADHD these difficulties tended to be more pronounced on the blue-yellow axis. Attention problems were characteristic for ADHD but not CTD. Interference load was significant in both Colour- and Counting Stroop-Tests and unrelated to colour discrimination. Compared to Controls, interference load in the Colour-Stroop was higher in pure ADHD and in pure CTD, but not in ADHD+CTD, following a sub-additive model. In contrast, interference load in the Counting-Stroop did not reveal ADHD or CTD effects. CONCLUSION: The co-existence of ADHD and CTD is characterized by additive as well as sub-additive performance impairments, suggesting that their co-existence may show simple additive characteristics of both disorders or a more complex interaction, depending on demand. The equivocal findings on interference control may indicate limited validity of the Stroop-Paradigm for clinical assessments. PMID- 28594867 TI - Gene essentiality, conservation index and co-evolution of genes in cyanobacteria. AB - Cyanobacteria, a group of photosynthetic prokaryotes, dominate the earth with ~ 1015 g wet biomass. Despite diversity in habitats and an ancient origin, cyanobacterial phylum has retained a significant core genome. Cyanobacteria are being explored for direct conversion of solar energy and carbon dioxide into biofuels. For this, efficient cyanobacterial strains will need to be designed via metabolic engineering. This will require identification of target knockouts to channelize the flow of carbon toward the product of interest while minimizing deletions of essential genes. We propose "Gene Conservation Index" (GCI) as a quick measure to predict gene essentiality in cyanobacteria. GCI is based on phylogenetic profile of a gene constructed with a reduced dataset of cyanobacterial genomes. GCI is the percentage of organism clusters in which the query gene is present in the reduced dataset. Of the 750 genes deemed to be essential in the experimental study on S. elongatus PCC 7942, we found 494 to be conserved across the phylum which largely comprise of the essential metabolic pathways. On the contrary, the conserved but non-essential genes broadly comprise of genes required under stress conditions. Exceptions to this rule include genes such as the glycogen synthesis and degradation enzymes, deoxyribose-phosphate aldolase (DERA), glucose-6-phosphate 1-dehydrogenase (zwf) and fructose-1,6 bisphosphatase class1, which are conserved but non-essential. While the essential genes are to be avoided during gene knockout studies as potentially lethal deletions, the non-essential but conserved set of genes could be interesting targets for metabolic engineering. Further, we identify clusters of co-evolving genes (CCG), which provide insights that may be useful in annotation. Principal component analysis (PCA) plots of the CCGs are demonstrated as data visualization tools that are complementary to the conventional heatmaps. Our dataset consists of phylogenetic profiles for 23,643 non-redundant cyanobacterial genes. We believe that the data and the analysis presented here will be a great resource to the scientific community interested in cyanobacteria. PMID- 28594868 TI - Design of short peptides to block BTLA/HVEM interactions for promoting anticancer T-cell responses. AB - Antibody based immune-checkpoint blockade therapy is a major breakthrough in oncology, leading to clinical benefit for cancer patients. Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), which interacts with herpes virus entry mediator (HVEM), is a promising target for immunotherapy. Indeed, BTLA inhibits T-cell proliferation and cytokine production. The crystal structure of the BTLA/HVEM complex has shown that the HVEM(26-38) fragment is directly involved in protein binding. We designed and analyzed the capacity of several analogs of this fragment to block the ligation between BTLA and HVEM, using competitive ELISA and cellular assay. We found that the HVEM(23-39) peptide can block BTLA/HVEM ligation. However, the blocking ability was due to the Cys encompassed in this peptide and that even free cysteine targeted the BTLA protein and blocked its interaction with HVEM. These data highlight a Cys-related artefact in vitro, which should be taken in consideration for future development of BTLA/HVEM blocking compounds. PMID- 28594870 TI - Spatial planning for a green economy: National-level hydrologic ecosystem services priority areas for Gabon. AB - Rapidly developing countries contain both the bulk of intact natural areas and biodiversity, and the greatest untapped natural resource stocks, placing them at the forefront of "green" economic development opportunities. However, most lack scientific tools to create development plans that account for biodiversity and ecosystem services, diminishing the real potential to be sustainable. Existing methods focus on biodiversity and carbon priority areas across large geographies (e.g., countries, states/provinces), leaving out essential services associated with water supplies, among others. These hydrologic ecosystem services (HES) are especially absent from methods applied at large geographies and in data-limited contexts. Here, we present a novel, spatially explicit, and relatively simple methodology to identify countrywide HES priority areas. We applied our methodology to the Gabonese Republic, a country undergoing a major economic transformation under a governmental commitment to balance conservation and development goals. We present the first national-scale maps of HES priority areas across Gabon for erosion control, nutrient retention, and groundwater recharge. Priority sub-watersheds covered 44% of the country's extent. Only 3% of the country was identified as a priority area for all HES simultaneously, highlighting the need to conserve different areas for each different hydrologic service. While spatial tradeoffs occur amongst HES, we identified synergies with two other conservation values, given that 66% of HES priority areas intersect regions of above average area-weighted (by sub-watersheds) total forest carbon stocks and 38% intersect with terrestrial national parks. Considering implications for development, we identified HES priority areas overlapping current or proposed major roads, forestry concessions, and active mining concessions, highlighting the need for proactive planning for avoidance areas and compensatory offsets to mitigate potential conflicts. Collectively, our results provide insight into strategies to protect HES as part of Gabon's development strategy, while providing a replicable methodology for application to new scales, geographies, and policy contexts. PMID- 28594869 TI - Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction. AB - Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis. Using whole exome sequencing we identified compound heterozygous novel variants, c.803C>T; p.(Thr268Ile) and c.1234C>T; p.(Arg412Cys), in GARS in the proband. Spectrophotometric evaluation of the MRC complexes showed reduced activity of Complex I, III and IV in patient skeletal muscle and reduced Complex I and IV activity in the patient liver, with Complex IV being the most severely affected in both tissues. Immunoblot analysis of GARS protein and subunits of the MRC enzyme complexes in patient fibroblast extracts showed significant reduction in GARS protein levels and Complex IV. Together these studies provide evidence that the identified compound heterozygous GARS variants may be the cause of the mitochondrial dysfunction in our patient. PMID- 28594871 TI - Association among presence of cancer pain, inadequate pain control, and psychotropic drug use. AB - INTRODUCTION: Pain is a common symptom in cancer patients, and its control and management are complex. Despite the high concomitant use of psychotropic drugs among such patients, the association among pain, inadequate pain control, and psychotropic drug use has not been fully determined. This study examined the prevalence of cancer pain and inadequate pain control and the association with psychotropic drug use. MATERIALS AND METHODS: In this cross-sectional study, we investigated 402 medical records obtained by simple random sampling of oncology patients at a hospital in northern Spain from July 2012 to July 2014. Adjusted odds ratios (ORs) were estimated together with their 95% confidence intervals (95% CIs) by unconditional logistic regression for each type of psychotropic drug (anxiolytics, hypnotics, and antidepressants). RESULTS: The mean patient age was 61.17 (standard deviation +/- 13.14) years; 57.5% were women, 42.5% men. Pain was present in 18.4% of patients and inadequate pain control in 54.2%. We found a statistically significant association between the presence of cancer pain and anxiolytic use (adjusted OR, 3.15; 95% CI, 1.49-6.68) and hypnotic use (adjusted OR, 5.19; 95% CI, 1.77-15.25). Inadequate pain control was associated to a greater extent with the use of those drugs: adjusted OR for anxiolytic use, 4.74 (95% CI, 1.91-11.80); adjusted OR for hypnotic use, 6.09 (95% CI, 1.74-21.32). By contrast, no association was found between pain and antidepressant use (adjusted OR, 0.99). CONCLUSION: The presence of pain and (to a greater extent) poor pain control were associated with increased use of certain psychotropic drugs, such as anxiolytics and hypnotics. There appeared to be no association between pain and antidepressant use. PMID- 28594872 TI - Unraveling the environmental and anthropogenic drivers of bacterial community changes in the Estuary of Bilbao and its tributaries. AB - In this study, 16S rRNA gene sequencing was used to characterize the changes in taxonomic composition and environmental factors significantly influencing bacterial community structure across an annual cycle in the Estuary of Bilbao as well as its tributaries. In spite of this estuary being small and characterized by a short residence time, the environmental factors most highly correlated with the bacterial community mirrored those reported to govern larger estuaries, specifically salinity and temperature. Additionally, bacterial community changes in the estuary appeared to vary with precipitation. For example, an increase in freshwater bacteria (Comamonadaceae and Sphingobacteriaceae) was observed in high precipitation periods compared to the predominately marine-like bacteria (Rhodobacterales and Oceanospirillales) that were found in low precipitation periods. Notably, we observed a significantly higher relative abundance of Comamonadaceae than previously described in other estuaries. Furthermore, anthropic factors could have an impact on this particular estuary's bacterial community structure. For example, ecosystem changes related to the channelization of the estuary likely induced a low dissolved oxygen (DO) concentration, high temperature, and high chlorophyll concentration period in the inner euhaline water in summer (samples with salinity >30 ppt). Those samples were characterized by a high abundance of facultative anaerobes. For instance, OTUs classified as Cryomorphaceae and Candidatus Aquiluna rubra were negatively associated with DO concentration, while Oleiphilaceae was positively associated with DO concentration. Additionally, microorganisms related to biological treatment of wastewater (e.g Bdellovibrio and Zoogloea) were detected in the samples immediately downstream of the Bilbao Wastewater Treatment Plant (WWTP). There are several human activities planned in the region surrounding the Estuary of Bilbao (e.g. sediment draining, architectural changes, etc.) which will likely affect this ecosystem. Therefore, the addition of bacterial community profiling and diversity analysis into the estuary's ongoing monitoring program would provide a more comprehensive view of the ecological status of the Estuary of Bilbao. PMID- 28594873 TI - Oral uricase eliminates blood uric acid in the hyperuricemic pig model. AB - An elevated level of serum uric acid-hyperuricemia, is strongly associated with the development of gout and chronic kidney disease (CKD) which is often accompanied by a significantly reduced glomerular filtration rate (GFR). In the present study, we investigated the extra-renal elimination of uric acid via the intestine in a healthy pig model and the effect of oral uricase therapy on plasma uric acid concentrations in pigs with induced hyperuricemia and CKD. The experiment was conducted on eleven, ten-week-old pigs (n = 11). The porcine model of CKD was developed by performing 9/10 nephrectomy surgery on eight pigs. A stable model of hyperuricemia was established in only five of the eight nephrectomized pigs by frequent injections of uric acid (UA) into the jugular vein. All pigs (three healthy pigs and five CKD pigs) were operated for implantation of jugular vein catheters and the three healthy pigs also had portal vein catheters inserted. Blood uric acid concentrations were measured spectrophotometrically, using the Uric Acid Assay Kit (BioAssay Systems, Hayward, USA). The piglets with CKD received orally administered uricase (treatment) and served as their own controls (without uricase supplementation). Oral uricase therapy significantly decreased plasma uric acid concentrations in pigs with CKD, whereas hyperuricemia was observed in the pigs whilst not being treated with uricase. Urinary uric acid excretion was similar during both the treatment and control periods during the first 8 h and 24 h after UA infusions in the CKD pigs. To demonstrate the elimination of UA via the intestine, the healthy pigs were infused with UA into the jugular vein. The blood collected from the jugular vein represents circulating UA concentrations and the blood collected from the portal vein represents the concentration of UA leaving the intestine. The final (after 2 h) concentration of UA was significantly lower in blood collected from the portal vein compared to that collected from the jugular vein (3.34 vs. 2.43 mg/dL, respectively, p = 0.024). The latter allows us to suggest that UA is eliminated from the blood via the gut tissue. PMID- 28594874 TI - A comparative analysis of suicide attempts in left-behind children and non-left behind children in rural China. AB - To estimate the prevalence of suicide attempts and explore the shared and unique factors influencing suicide risk in left-behind children (LBC) and non-left behind children (NLBC) in rural China, this study collected data using a multi stage cluster random sampling method from 13,952 children including 6,034 LBC and 7,918 NLBC. Sociodemographic characteristics, suicide attempts, neglect and physical abuse, negative life events, and loneliness were measured by self reported questionnaires. Data were analyzed using logistic regression models. Gender and mother's education level were unique influential factors for NLBC while family structure type was a unique influential factor for LBC. The study provides two novel findings regarding NLBC specifically: 1. Children with optimal family socioeconomic status are more likely to report suicide attempts (odds ratio OR = 1)than are those in the general children population, OR 0.52 (95% CI: 0.39-0.70), and 2. Children with higher mother's education level are subject to higher suicide rates in high school, OR 1.67 (95% CI: 1.13-2.46), and post secondary education, OR 2.14 (95% CI: 1.37-3.37). The unique characteristics of LBC and NLBC in China suggest that investigating risk factors and determining the factors that might be targeted in intervention programs are urgently needed currently. PMID- 28594875 TI - Analytical evaluation of three enzymatic assays for measuring total bile acids in plasma using a fully-automated clinical chemistry platform. AB - BACKGROUND: Although the clinical significance of measuring bile acids concentration in plasma or serum has been recognized for long in patients with hepatobiliary disease and/or bile acid malabsorption, the reference separation techniques are expensive and mostly unsuitable for early diagnosis and for measuring large volumes of samples. Therefore, this study was aimed to evaluate the analytical performance of three commercial enzymatic techniques for measuring total bile acids in plasma using a fully-automated clinical chemistry platform. METHODS: Three commercial enzymatic assays (from Diazyme, Randox and Sentinel) were adapted for use on a Cobas Roche c501. We performed imprecision and linearity studies, and we compared results with those obtained using a reference liquid chromatography-mass spectrometry (LC-MS) technique on an identical set of lithium-heparin plasma samples. RESULTS: Total imprecision was optimal, always equal or lower than 3%. All assays had optimal linearity between 3-138 MUmol/L. The comparison studies showed good correlation with LC-MS data (Spearman's correlation coefficients always >0.92), but all plasma samples values were significantly underestimated using the commercial enzymatic assays (-44% for Diazyme, -16% for Randox and -12% for Sentinel). The agreement at the 10 and 40 MUmol/L diagnostic thresholds of total bile acids in plasma ranged between 86 92%. This discrepancy was found to be mainly attributable to a heterogeneous composition in terms of bile acids content of the three assay calibrators. CONCLUSIONS: This study suggests that the analytical performance of the three commercial enzymatic assays is excellent, thus confirming that automation of this important test by means of enzymatic assessment may be feasible, practical, reliable and supposedly cheap. Nevertheless, the underestimation of values compared to the reference LC-MS also suggests that the local definition and validation of reference ranges according to the combination between the specific enzymatic assay and the different clinical chemistry platforms may be advisable. PMID- 28594876 TI - Discretionary decisions and disparities in receiving drug-eluting stents under a universal healthcare system: A population-based study. AB - OBJECTIVES: One of the main objectives behind the expansion of insurance coverage is to eliminate disparities in health and healthcare. However, researchers have not yet fully elucidated the reasons for disparities in the use of high-cost treatments among patients of different occupations. Furthermore, it remains unknown whether discretionary decisions made at the hospital level have an impact on the administration of high-cost interventions in a universal healthcare system. This study investigated the adoption of drug-eluting stents (DES) versus bare metal-stents (BMS) among patients in different occupations and income levels, with the aim of gauging the degree to which the inclination of health providers toward treatment options could affect treatment choices at the patient level within a universal healthcare system. DESIGN AND PARTICIPANTS: We adopted a cross-sectional observational study design using hierarchical modeling in conjunction with the population-based National Health Insurance database of Taiwan. Patients who received either a BMS or a DES between 2007 and 2010 were included in the study. RESULTS: During the period of study, 42,124 patients received a BMS (65.3%) and 22,376 received DES (34.7%). Patients who were physicians or the family members of physicians were far more likely to receive DES (OR: 3.18, CI: 2.38-4.23) than were patients who were neither physicians nor in other high-status jobs (employers, other medical professions, or public service). Similarly, patients in the top 5% income bracket had a higher probability of receiving a DES (OR: 2.23, CI: 2.06-2.47, p < .001), than were patients in the lowest income bracket. After controlling for patient-level factors, the inclination of hospitals (proportion of DES>50% or between 25% and 50%) was shown to be strongly associated with the selection of DESs (OR: 3.64 CI: 3.24-4.09 and OR: 2.16, CI: 2.01-2.33, respectively). CONCLUSIONS: Even under the universal healthcare system in Taiwan, socioeconomic disparities in the use of high-cost services remain widespread. Differences in the care received by patients of lower socioeconomic status may be due to the discretionary decisions of healthcare providers. PMID- 28594878 TI - Development and evaluation of a culturally appropriate hypertension education (CAHE) training program for health care providers. AB - BACKGROUND: In Western countries, hypertension and hypertension-related complication are more common in ethnic minority groups of African descent than in indigenous populations. Addressing ethnic minority patients' perceptions of hypertension and its treatment through the use of cultural appropriate hypertension education (CAHE) increases adherence to medication and lifestyle recommendations. Given these effects, it seems warranted to develop a training program on how to deliver this type of patient education for Primary Care Nurse Practitioners (PCNPs). OBJECTIVE: Development and evaluation of a training program for PCNPs aimed at providing culturally appropriate hypertension patient education. DESIGN: Prospective cohort study evaluating attitude and intended behavioral changes. PARTICIPANTS: Both experienced PCNPs and PCNPs in training participated in this study. MAIN MEASURES: The effects of the CAHE-training were measured by 3 different questionnaires on 1) the satisfaction with the training program, 2) the attitude towards culturally appropriate care, and 3) the commitment to change. RESULTS: The CAHE-training program consists of 10 different components divided over two 4-hour sessions and was taught to 87 participating PCNPs. The program utilizes constructivist-learning principles and educational evidence on adult learning. The content of the program is based on the knowledge obtained from our previous studies on culturally appropriate care. The mean satisfaction-score was 7.5 (1-10 scale), with the role-play exercise with patient actors scoring highest (8.2). We observed non-significant but positive changes in attitude. PCNPs who reported on the implementation of their intended behavior change showed significant attitude changes after three months. CONCLUSION: We demonstrated that our evidence based training program for PCNPs resulted in a positive learning experience with adequate intended behavioral changes in practice. Unfortunately, response rates were too low to demonstrate persistent changes in attitude. PMID- 28594877 TI - An indicator cell assay for blood-based diagnostics. AB - We have established proof of principle for the Indicator Cell Assay PlatformTM (iCAPTM), a broadly applicable tool for blood-based diagnostics that uses specifically-selected, standardized cells as biosensors, relying on their innate ability to integrate and respond to diverse signals present in patients' blood. To develop an assay, indicator cells are exposed in vitro to serum from case or control subjects and their global differential response patterns are used to train reliable, disease classifiers based on a small number of features. In a feasibility study, the iCAP detected pre-symptomatic disease in a murine model of amyotrophic lateral sclerosis (ALS) with 94% accuracy (p-Value = 3.81E-6) and correctly identified samples from a murine Huntington's disease model as non carriers of ALS. Beyond the mouse model, in a preliminary human disease study, the iCAP detected early stage Alzheimer's disease with 72% cross-validated accuracy (p-Value = 3.10E-3). For both assays, iCAP features were enriched for disease-related genes, supporting the assay's relevance for disease research. PMID- 28594880 TI - Application of the 3D slicer chest imaging platform segmentation algorithm for large lung nodule delineation. AB - PURPOSE: Accurate segmentation of lung nodules is crucial in the development of imaging biomarkers for predicting malignancy of the nodules. Manual segmentation is time consuming and affected by inter-observer variability. We evaluated the robustness and accuracy of a publically available semiautomatic segmentation algorithm that is implemented in the 3D Slicer Chest Imaging Platform (CIP) and compared it with the performance of manual segmentation. METHODS: CT images of 354 manually segmented nodules were downloaded from the LIDC database. Four radiologists performed the manual segmentation and assessed various nodule characteristics. The semiautomatic CIP segmentation was initialized using the centroid of the manual segmentations, thereby generating four contours for each nodule. The robustness of both segmentation methods was assessed using the region of uncertainty (delta) and Dice similarity index (DSI). The robustness of the segmentation methods was compared using the Wilcoxon-signed rank test (pWilcoxon<0.05). The Dice similarity index (DSIAgree) between the manual and CIP segmentations was computed to estimate the accuracy of the semiautomatic contours. RESULTS: The median computational time of the CIP segmentation was 10 s. The median CIP and manually segmented volumes were 477 ml and 309 ml, respectively. CIP segmentations were significantly more robust than manual segmentations (median deltaCIP = 14ml, median dsiCIP = 99% vs. median deltamanual = 222ml, median dsimanual = 82%) with pWilcoxon~10-16. The agreement between CIP and manual segmentations had a median DSIAgree of 60%. While 13% (47/354) of the nodules did not require any manual adjustment, minor to substantial manual adjustments were needed for 87% (305/354) of the nodules. CIP segmentations were observed to perform poorly (median DSIAgree~50%) for non-/sub-solid nodules with subtle appearances and poorly defined boundaries. CONCLUSION: Semi-automatic CIP segmentation can potentially reduce the physician workload for 13% of nodules owing to its computational efficiency and superior stability compared to manual segmentation. Although manual adjustment is needed for many cases, CIP segmentation provides a preliminary contour for physicians as a starting point. PMID- 28594881 TI - Importance of demographic surveys and public lands for the conservation of eastern hellbenders Cryptobranchus alleganiensis alleganiensis in southeast USA. AB - Comparisons of recent and historic population demographic studies of eastern hellbenders Cryptobranchus alleganiensis alleganiensis have identified significant population declines and extirpations associated with habitat degradation, poor water quality and disease, leading to nomination as a candidate for listing under the Endangered Species Act. However, populations in the southern Appalachian region of the range have received less attention despite relatively high levels of watershed protection due to the establishment of federally protected National Forest and National Park public lands. These watersheds likely represent some of the best remaining available habitat, yet the lack of published studies make assessment of population stability and viability very difficult. Our objectives were to (1) conduct a capture-mark-recapture (CMR) demographic study and a point transect survey on the Hiwassee River in Tennessee which is designated a National Scenic River, and is largely contained within the Cherokee National Forest, (2) quantify the size structure of the population, (3) compare abundance, survival and recruitment with historic and contemporary hellbender populations across the range, (4) assess the importance of this population and the significance of National Forest and National Park lands in the context of hellbender population conservation in the southeastern United States. We detected all age classes present, with larval hellbenders comprising 21.5% of captures. Using a combination of static life table and CMR methods, we determined that survival rates during the first year were low (~10%), but were high (68-94%) for taggable sized hellbenders. Density of hellbenders at the study site was very high (84 taggable sized hellbenders per 100m of river) compared to recent demographic studies conducted in other regions of the range. We detected hellbenders over ~28 km of river, with a mean density of 23 taggable sized hellbenders per 100m of river, and a total population estimate of 6440 taggable hellbenders. National Forest and National Park lands are likely to continue to play a particularly important role in providing suitable habitat for hellbenders in the southern Appalachians. In fact, only six of 21 known hellbender locations in Tennessee appear to show consistent larval recruitment, all of which are located within or adjacent to National Forest or National Park land. PMID- 28594879 TI - Molecular surveillance of Plasmodium falciparum resistance to artemisinin-based combination therapies in the Democratic Republic of Congo. AB - Malaria is a major public health problem in the Democratic Republic of Congo. Despite progress achieved over the past decade in the fight against malaria, further efforts have to be done such as in the surveillance and the containment of Plasmodium falciparum resistant strains. We investigated resistance to artemisinin-based combination therapies currently in use in Democratic Republic of Congo by surveying molecular polymorphisms in three genes: pfcrt, pfmdr1 and pfk13 to explore possible emergence of amodiaquine, lumefantrine or artemisinin resistance in Democratic Republic of Congo. This study essentially revealed that resistance to chloroquine is still decreasing while polymorphism related to amodiaquine resistance seems to be not present in Democratic Republic of Congo, that three samples, located in the east of the country, harbor Pfmdr1 amplification and that none of the mutations found in South-East Asia correlated with artemisinine resistance have been found in Democratic Republic of Congo. But new mutations have been identified, especially the M476K, occurred in the same position that the M476I previously identified in the F32-ART strain, strongly resistant to artemisinine. Antimalarial first-line treatments currently in use in Democratic Republic of Congo are not associated with emergence of molecular markers of resistance. PMID- 28594882 TI - Rickettsia amblyommatis infecting ticks and exposure of domestic dogs to Rickettsia spp. in an Amazon-Cerrado transition region of northeastern Brazil. AB - This study was performed in Maranhao state, a transition area two Brazilian biomes, Amazon and Cerrado. During 2011-2013, 1,560 domestic dogs were sampled for collection of serum blood samples and ticks in eight counties (3 within the Amazon and 5 within the Cerrado). A total of 959 ticks were collected on 150 dogs (9.6%). Rhipicephalus sanguineus sensu lato (s.l.) was the most abundant tick (68% of all collected specimens), followed by Amblyomma cajennense sensu lato (s.l.) (12.9%), Amblyomma parvum (9.2%), and Amblyomma ovale (5.2%). Other less abundant species (<1%) were Amblyomma oblongoguttatum, Rhipicephalus microplus, Haemaphysalis juxtakochi, and Amblyomma rotundatum. Females of A. cajennense s.l. ticks were morphologically identified as A. cajennense sensu stricto (s.s.) or A. sculptum. Molecular analyses of 779 canine ticks revealed three Rickettsia species: Rickettsia amblyommatis in 1% (1/100) A. cajennense s.l., 'Candidatus Rickettsia andeanae' in 20.7% (12/58) A. parvum, Rickettsia bellii in 6.8% (3/44) A. ovale and 100% (1/1) A. rotundatum ticks. An additional collection of A. sculptum from horses in a Cerrado area, and A. cajennense s.s. from pigs in an Amazon area revealed R. amblyommatis infecting only the A. cajennense s.s. ticks. Serological analysis of the 1,560 canine blood samples revealed 12.6% canine seroreactivity to Rickettsia spp., with the highest specific seroreactivity rate (10.2%) for R. amblyommatis. Endpoint titers to R. amblyommatis were significantly higher than those for the other Rickettsia antigens, suggesting that most of the seroreactive dogs were exposed to R. amblyommatis-infected ticks. Highest canine seroreactivity rates per locality (13.1-30.8%) were found in Amazon biome, where A. cajennense s.s. predominated. Lowest seroreactivity rates (1.9-6.5%) were found in Cerrado localities that were further from the Amazon, where A. sculptum predominated. Multivariate analyses revealed that canine seroreactivity to Rickettsia spp. or R. amblyommatis was statistically associated with rural dogs, exposed to Amblyomma ticks. PMID- 28594883 TI - Qat use and esophageal cancer in Ethiopia: A pilot case-control study. AB - BACKGROUND: Qat (Catha edulis) chewing is reported to induce lesions in the buccal mucosa, irritation of the esophagus, and esophageal reflux. Case series suggest a possible etiological role in oral and esophageal cancers. This pilot study aimed to generate preliminary estimates of the magnitude and direction of the association between qat use and esophageal cancer (EC) risk and to inform the logistics required to conduct a multi-center case-control study. METHODS: Between May 2012 and May 2013, 73 EC cases (including 12 gastro-esophageal junction cases) and 133 controls matched individually on sex, age, and residence were enrolled at two endoscopy clinics and a cancer treatment hospital in Addis Ababa. A face-to-face structured questionnaire was administered. Qat use was defined as ever having chewed qat once a week or more frequently for at least one year. Odds ratios were calculated using conditional logistic regression. RESULTS: Only 8% of cases resided in Addis Ababa. Qat use was more frequent in cases (36%) than in controls (26%). A 2-fold elevation in EC risk was observed in ever qat chewers compared with never users in unadjusted conditional logistic regression (OR = 2.12; 95% CI = 0.94, 4.74), an association that disappeared after adjusting for differences in tobacco use, consumption of alcohol and green vegetables, education level, and religion (OR = 0.95; 0.22, 4.22). Among never tobacco users, however, a non-significant increase in EC risk was suggested in ever qat users also after adjustment. Increases in EC risk were observed with ever tobacco use, alcohol consumption, low consumption of green vegetables, a salty diet, illiteracy, and among Muslims; the four latter associations were significant. CONCLUSIONS: This pilot study generated EC risk estimates in association with a habit practiced by millions of people and never before studied in a case-control design. Results must be interpreted cautiously in light of possible selection bias, with some demographics such as education level and religion differing between cases and controls. A large case-control study with enrolment of EC cases and carefully matched controls at health facilities from high-risk areas in the countryside, where the majority of cases occur, is needed to further investigate the association between qat use and EC. PMID- 28594886 TI - Impacts of El Nino-Southern Oscillation on the wheat market: A global dynamic analysis. AB - Although the widespread influence of the El Nino-Southern Oscillation (ENSO) occurrences on crop yields of the main agricultural commodities is well known, the global socio-economic consequences of ENSO still remain uncertain. Given the global importance of wheat for global consumption by providing 20% of global calories and nourishment, the monitoring and prediction of ENSO-induced variations in the worldwide wheat market are essential for allowing national governments to manage the associated risks and to ensure the supplies of wheat for consumers, including the underprivileged. To this end, we propose a global dynamic model for the analysis of ENSO impacts on wheat yield anomalies, export prices, exports and stock-to-use ratios. Our framework focuses on seven countries/regions: the six main wheat-exporting countries-the United States, Argentina, Australia, Canada, the EU, and the group of the main Black Sea export countries, i.e. Russia, Ukraine, and Kazakhstan-plus the rest of the world. The study shows that La Nina exerts, on average, a stronger and negative impact on wheat yield anomalies, exports and stock-to-use ratios than El Nino. In contrast, wheat export prices are positively related to La Nina occurrences evidencing, once again, its steady impact in both the short and long run. Our findings emphasize the importance of the two ENSO extreme phases for the worldwide wheat market. PMID- 28594884 TI - Correlation between white matter microstructure and executive functions suggests early developmental influence on long fibre tracts in preterm born adolescents. AB - MAIN OBJECTIVES: Executive functions are frequently a weakness in children born preterm. We examined associations of executive functions and general cognitive abilities with brain structure in preterm born adolescents who were born with appropriate weight for gestational age and who have no radiological signs of preterm brain injury on neuroimaging. METHODS: The Stockholm Neonatal Project (SNP) is a longitudinal, population-based study of children born preterm (<36 weeks of gestation) with very low birth weight (<1501g) between 1988-1993. At age 18 years (mean 18 years, SD 2 weeks) 134 preterm born and 94 full term participants underwent psychological assessment (general intelligence, executive function measures). Of these, 71 preterm and 63 full term participants underwent Magnetic Resonance Imaging (MRI) at mean 15.2 years (range 12-18 years), including 3D T1-weighted images for volumetric analyses and Diffusion Tensor Imaging (DTI) for assessment of white matter microstructure. Group comparisons of regional grey and white matter volumes and fractional anisotropy (FA, as a measure of white matter microstructure) and, within each group, correlation analyses of cognitive measures with MRI metrics were carried out. RESULTS: Significant differences in grey and white matter regional volumes and widespread differences in FA were seen between the two groups. No significant correlations were found between cognitive measures and brain volumes in any group after correction for multiple comparisons. However, there were significant correlations between FA in projection fibres and long association fibres, linking frontal, temporal, parietal, and occipital lobes, and measures of executive function and general cognitive abilities in the preterm born adolescents, but not in the term born adolescents. OVERALL SIGNIFICANCE OF THE STUDY: In persons born preterm, in the absence of perinatal brain injury on visual inspection of MRI, widespread alterations in regional brain tissue volumes and microstructure are present in adolescence/young adulthood. Importantly, these alterations in WM tracts are correlated with measures of executive function and general cognitive abilities. Our findings suggest that disturbance of neural pathways, rather than changes in regional brain volumes, are involved in the impaired cognitive functions. PMID- 28594885 TI - Effect of a new formulation of micronized and ultramicronized N palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome. AB - Complex regional pain syndrome type 1 (CRPS-I) is a disabling and frequently chronic condition. It involves the extremities and is a frequent consequence of distal tibia and radius fractures. The inflamed appearance of the affected CRPS-I limb suggests that local production of inflammatory mediators may be implicated in the ensuing etiology. A rodent tibia fracture model, characterized by inflammation, chronic unilateral hindlimb warmth, edema, protein extravasation, allodynia and hyperalgesia resembles the clinical features of patients with acute CRPS-I. N-palmitoylethanolamine (PEA), a member of the family of naturally occurring N-acylethanolamines, is well-known for its ability to modulate inflammatory processes and regulate pain sensitivity. However, the large particle size and lipidic nature of PEA may limit its bioavailability and solubility when given orally. Micronized formulations are frequently used to enhance the dissolution rate of drug and reduce its variability of absorption when orally administered. The aim of this study was to assess the effects of a formulation of micronized and ultramicronized PEA (PEA-MPS), given orally in a mouse model of CRPS-I. CD-1 male mice were subjected to distal tibia fracture and divided into two groups: control and treated with PEA-MPS (PEA micronized 300 mg/kg and ultramicronized 600 mg/kg). Sensibility to pain was monitored in all mice throughout the course of the experiment. Twenty-eight days after tibia fracture induction animals were sacrificed and biochemical parameters evaluated. The PEA MPS-treated group showed an improved healing process, fracture recovery and fibrosis score. PEA-MPS administration decreased mast cell density, nerve growth factor, matrix metalloproteinase 9 and cytokine expression. This treatment also reduced (poly-ADP)ribose polymerase activation, peroxynitrite formation and apoptosis. Our results suggest that PEA-MPS may be a new therapeutic strategy in the treatment of CRPS-I. PMID- 28594887 TI - Study of structural stability and damaging effect on membrane for four Abeta42 dimers. AB - Increasing evidence shows that Abeta oligomers are key pathogenic molecules in Alzheimer's disease. Among Abeta oligomers, dimer is the smallest aggregate and toxic unit. Therefore, understanding its structural and dynamic properties is quite useful to prevent the formation and toxicity of the Abeta oligomers. In this study, we performed molecular dynamic simulations on four Abeta42 dimers, 2NCb, CNNC, NCNC and NCCN, within the hydrated DPPC membrane. Four Abeta42 dimers differ in the arrangements of two Abeta42 peptides. This study aims to investigate the impact of aggregation pattern of two Abeta peptides on the structural stability of the Abeta42 dimer and its disruption to the biological membrane. The MD results demonstrate that the NCCN, CNNC and NCNC have the larger structural fluctuation at the N-terminus of Abeta42 peptide, where the beta strand structure converts into the coil structure. The loss of the N-terminal beta-strand further impairs the aggregate ability of Abeta42 dimer. In addition, inserting Abeta42 dimer into the membrane can considerably decrease the average APL of DPPC membrane. Moreover this decrease effect is largely dependent on the distance to the location of Abeta42 dimer and its secondary structure forms. Based on the results, the 2NCb is considered as a stable dimeric unit for aggregating the larger Abeta42 oligomer, and has a potent ability to disrupt the membrane. PMID- 28594888 TI - Semiochemicals released from five bacteria identified from animal wounds infested by primary screwworms and their effects on fly behavioral activity. AB - BACKGROUND: The Primary screwworm, Cochliomyia hominivorax (Coquerel), is a serious pest feeding on living flesh of any warm-blooded animal, including humans. It was eradicated from the United States in the early 1980s using the sterile male technique. However, it was recently detected in populations of wild deer and pets in the Florida Keys of the US. For monitoring purposes, screwworm flies are normally trapped using attractant bait with liver. However, there has been little effort to develop an efficient monitoring system for detection of screwworm flies using a specific synthetic attractant blend. Several studies have shown that odors from animal wound fluids attract screwworm adults, particularly gravid females. Bacteria associated with animal wounds have been identified that act as a major source for this attraction. To understand what volatiles attract screwworms we inoculated bovine blood with previously identified bacteria. We identified volatile chemicals released from the inoculated blood and other selected media over time and assessed the effect of those chemicals on behavioral activity of adult screwworm flies. METHODOLOGY/PRINCIPAL FINDINGS: A total of 7 volatile compounds were collected from bacteria incubated in either broth or blood using solid-phase microextraction, and their chemical structures were identified by their characteristic mass spectrum fragments and confirmed by retention times in comparison to those of synthetic standards via gas chromatograph combined mass spectrometry analyses. Five major volatiles including dimethyl disulfide, dimethyl trisulfide, phenol, p-cresol and indole were detected from a mixture of 5 bacteria incubated in blood. The ratios of volatiles released differed among different incubation media, time and individual bacteria. A synthetic mixture containing the five compounds was demonstrated to be attractive to adult screwworm flies both in laboratory assays and field trapping trials. CONCLUSIONS/SIGNIFICANCE: The results obtained from this study may assist in developing an efficient trapping system using the identified attractant blend to detect the infestation of primary screwworms. This is also the first study to explore the complex systems in volatile release profiles from 5 bacteria isolated from screwworm-infested animal wounds that are incubated with different media and incubation time, as well as individual and multi-species bacterial communities. PMID- 28594889 TI - Use of the FDA nozzle model to illustrate validation techniques in computational fluid dynamics (CFD) simulations. AB - A "credible" computational fluid dynamics (CFD) model has the potential to provide a meaningful evaluation of safety in medical devices. One major challenge in establishing "model credibility" is to determine the required degree of similarity between the model and experimental results for the model to be considered sufficiently validated. This study proposes a "threshold-based" validation approach that provides a well-defined acceptance criteria, which is a function of how close the simulation and experimental results are to the safety threshold, for establishing the model validity. The validation criteria developed following the threshold approach is not only a function of Comparison Error, E (which is the difference between experiments and simulations) but also takes in to account the risk to patient safety because of E. The method is applicable for scenarios in which a safety threshold can be clearly defined (e.g., the viscous shear-stress threshold for hemolysis in blood contacting devices). The applicability of the new validation approach was tested on the FDA nozzle geometry. The context of use (COU) was to evaluate if the instantaneous viscous shear stress in the nozzle geometry at Reynolds numbers (Re) of 3500 and 6500 was below the commonly accepted threshold for hemolysis. The CFD results ("S") of velocity and viscous shear stress were compared with inter-laboratory experimental measurements ("D"). The uncertainties in the CFD and experimental results due to input parameter uncertainties were quantified following the ASME V&V 20 standard. The CFD models for both Re = 3500 and 6500 could not be sufficiently validated by performing a direct comparison between CFD and experimental results using the Student's t-test. However, following the threshold based approach, a Student's t-test comparing |S-D| and |Threshold-S| showed that relative to the threshold, the CFD and experimental datasets for Re = 3500 were statistically similar and the model could be considered sufficiently validated for the COU. However, for Re = 6500, at certain locations where the shear stress is close the hemolysis threshold, the CFD model could not be considered sufficiently validated for the COU. Our analysis showed that the model could be sufficiently validated either by reducing the uncertainties in experiments, simulations, and the threshold or by increasing the sample size for the experiments and simulations. The threshold approach can be applied to all types of computational models and provides an objective way of determining model credibility and for evaluating medical devices. PMID- 28594890 TI - Ellenberg's indicator values support prediction of suitable habitat for pre diapause larvae of endangered butterfly Euphydryas aurinia. AB - In spite of the great popularity of Ellenberg's Indicator Values (EIVs) in plant ecology, animal ecologists seldom use EIVs to address ecological questions. In this study we used EIVs to test their potential usefulness for the prediction of suitable habitat for pre-diapause larvae of the endangered butterfly species Euphydryas aurinia. Nine transects crossing grasslands in SW Poland with abundant populations of E. aurinia were designed. We sampled 76 vegetation plots along the transects. In addition, the presence of the larval webs of E. aurinia in sampled plots was also recorded. We then calculated the mean community EIVs of light, nitrogen, soil reaction, moisture and temperature for each sample plots. Generalized linear mixed-effects models (GLMMs) were used to assess which factors determine the local occurrence of larval webs of E. aurinia. We found the larval webs only in 12 plots, while the host plant was present in 39 of the examined plots. The presence of the host plant was the most important predictor in both models including all plots or including only plots with host plants. The other significant predictor was the mean EIV of light, and its importance increased in models considering all plots. We attributed the importance of the EIV of light to the site openness and density of the vegetation layer. A positive relationship between this predictor and the presence of larval webs indicates that sites with looser vegetation, a lower contribution of shrubs and tall herbs and better penetration of photosynthetically active radiation to lower vegetation layers are preferred by E. aurinia for oviposition. Moreover, the significance of EIV of light may be linked with management practices. Many light-demanding species decline after cessation of mowing as a result of litter accumulation and the dominance of tall herbs. An absence of light-demanding species decreases the community's mean EIV of light and thus indicates the influence of meadow abandonment. PMID- 28594891 TI - Neighborhood-targeted and case-triggered use of a single dose of oral cholera vaccine in an urban setting: Feasibility and vaccine coverage. AB - INTRODUCTION: In June 2015, a cholera outbreak was declared in Juba, South Sudan. In addition to standard outbreak control measures, oral cholera vaccine (OCV) was proposed. As sufficient doses to cover the at-risk population were unavailable, a campaign using half the standard dosing regimen (one-dose) targeted high-risk neighborhoods and groups including neighbors of suspected cases. Here we report the operational details of this first public health use of a single-dose regimen of OCV and illustrate the feasibility of conducting highly targeted vaccination campaigns in an urban area. METHODOLOGY/PRINCIPAL FINDINGS: Neighborhoods of the city were prioritized for vaccination based on cumulative attack rates, active transmission and local knowledge of known cholera risk factors. OCV was offered to all persons older than 12 months at 20 fixed sites and to select groups, including neighbors of cholera cases after the main campaign ('case-triggered' interventions), through mobile teams. Vaccination coverage was estimated by multi stage surveys using spatial sampling techniques. 162,377 individuals received a single-dose of OCV in the targeted neighborhoods. In these neighborhoods vaccine coverage was 68.8% (95% Confidence Interval (CI), 64.0-73.7) and was highest among children ages 5-14 years (90.0%, 95% CI 85.7-94.3), with adult men being less likely to be vaccinated than adult women (Relative Risk 0.81, 95% CI: 0.68 0.96). In the case-triggered interventions, each lasting 1-2 days, coverage varied (range: 30-87%) with an average of 51.0% (95% CI 41.7-60.3). CONCLUSIONS/SIGNIFICANCE: Vaccine supply constraints and the complex realities where cholera outbreaks occur may warrant the use of flexible alternative vaccination strategies, including highly-targeted vaccination campaigns and single-dose regimens. We showed that such campaigns are feasible. Additional work is needed to understand how and when to use different strategies to best protect populations against epidemic cholera. PMID- 28594892 TI - A behavioral typology of opioid overdose risk behaviors among recent veterans in New York City. AB - OBJECTIVE: To identify meaningful classes of opioid-using military veterans in terms of self-reported opioid overdose risk behaviors. METHOD: The study recruited a sample of 218 military veterans in the NYC area who were discharged from active duty service after September 11, 2001 and reported past-month opioid use. Survey data including measures of mental health, social stressors, substance use, and opioid-related overdose risk behaviors were analyzed using Latent Class Analysis (LCA). RESULTS: A five group solution had excellent fit scores and interpretability. Factor analysis confirmed the existence of two major dimensions of variation: non-adherence and heroin use. The five groups included lower-risk prescription opioid users, non-adherent prescription opioid users and heroin users. The non-adherent prescription opioid users and heroin user classes were both further subdivided into "occasional" and "regular" use categories. In addition to endorsing a greater number of overdose risk behaviors, users in the regular use classes were more likely to screen positive for alcohol and substance use disorders, reported greater self-medicating opioid use to relieve anxiety, reported greater problems with physical pain, were more likely to have had mental health, alcohol and drug treatment, and were less likely to be employed or in school. Heroin users also were less likely to report stable housing. CONCLUSIONS: Findings indicate that opioid overdose risk classes are grounded in contextual factors related to experiences of psychological, physiological, and social adjustment pain and distress which should be addressed in tailored interventions targeting opioid users' unique constellations of risk behaviors and comorbid conditions. PMID- 28594893 TI - Pandemic extra-intestinal pathogenic Escherichia coli (ExPEC) clonal group O6-B2 ST73 as a cause of avian colibacillosis in Brazil. AB - Extra-intestinal pathogenic Escherichia coli (ExPEC) represent an emerging pathogen, with pandemic strains increasingly involved in cases of urinary tract infections (UTIs), bacteremia, and meningitis. In addition to affecting humans, the avian pathotype of ExPEC, avian pathogenic E. coli (APEC), causes severe economic losses to the poultry industry. Several studies have revealed overlapping characteristics between APEC and human ExPEC, leading to the hypothesis of a zoonotic potential of poultry strains. However, the description of certain important pandemic clones, such as Sequence Type 73 (ST73), has not been reported in food sources. We characterized 27 temporally matched APEC strains from diverse poultry farms in Brazil belonging to the O6 serogroup because this serogroup is frequently described as a causal factor in UTI and septicemia in humans in Brazil and worldwide. The isolates were genotypically characterized by identifying ExPEC virulence factors, phylogenetically tested by phylogrouping and multilocus sequence type (MLST) analysis, and compared to determine their similarity employing the pulsed field gel electrophoresis (PFGE) technique. The strains harbored a large number of virulence determinants that are commonly described in uropathogenic E. coli (UPEC) and sepsis associated E. coli (SEPEC) strains and, to a lesser extent in neonatal meningitis associated E. coli (NMEC), such as pap (85%), sfa (100%), usp (100%), cnf1 (22%), kpsMTII (66%), hlyA (52%), and ibeA (4%). These isolates also yielded a low prevalence of some genes that are frequently described in APEC, such as iss (37%), tsh, ompT, and hlyF (8% each), and cvi/cva (0%). All strains were classified as part of the B2 phylogroup and sequence type 73 (ST73), with a cluster of 25 strains showing a clonal profile by PFGE. These results further suggest the zoonotic potential of some APEC clonal lineages and their possible role in the epidemiology of human ExPEC, in addition to providing the first description of the O6-B2-ST73 clonal group in poultry. PMID- 28594894 TI - MicroRNAs upregulated during HIV infection target peroxisome biogenesis factors: Implications for virus biology, disease mechanisms and neuropathology. AB - HIV-associated neurocognitive disorders (HAND) represent a spectrum neurological syndrome that affects up to 25% of patients with HIV/AIDS. Multiple pathogenic mechanisms contribute to the development of HAND symptoms including chronic neuroinflammation and neurodegeneration. Among the factors linked to development of HAND is altered expression of host cell microRNAs (miRNAs) in brain. Here, we examined brain miRNA profiles among HIV/AIDS patients with and without HAND. Our analyses revealed differential expression of 17 miRNAs in brain tissue from HAND patients. A subset of the upregulated miRNAs (miR-500a-5p, miR-34c-3p, miR-93-3p and miR-381-3p), are predicted to target peroxisome biogenesis factors (PEX2, PEX7, PEX11B and PEX13). Expression of these miRNAs in transfected cells significantly decreased levels of peroxisomal proteins and concomitantly decreased peroxisome numbers or affected their morphology. The levels of miR-500a 5p, miR-34c-3p, miR-93-3p and miR-381-3p were not only elevated in the brains of HAND patients, but were also upregulated during HIV infection of primary macrophages. Moreover, concomitant loss of peroxisomal proteins was observed in HIV-infected macrophages as well as in brain tissue from HIV-infected patients. HIV-induced loss of peroxisomes was abrogated by blocking the functions of the upregulated miRNAs. Overall, these findings point to previously unrecognized miRNA expression patterns in the brains of HIV patients. Targeting peroxisomes by up-regulating miRNAs that repress peroxisome biogenesis factors may represent a novel mechanism by which HIV-1 subverts innate immune responses and/or causes neurocognitive dysfunction. PMID- 28594895 TI - ATP-sensitive potassium (KATP) channel openers diazoxide and nicorandil lower intraocular pressure by activating the Erk1/2 signaling pathway. AB - Elevated intraocular pressure is the most prevalent and only treatable risk factor for glaucoma, a degenerative disease of the optic nerve. While treatment options to slow disease progression are available, all current therapeutic and surgical treatments have unwanted side effects or limited efficacy, resulting in the need to identify new options. Previous reports from our laboratory have established a novel ocular hypotensive effect of ATP-sensitive potassium channel (KATP) openers including diazoxide (DZ) and nicorandil (NCD). In the current study, we evaluated the role of Erk1/2 signaling pathway in KATP channel opener mediated reduction of intraocular pressure (IOP). Western blot analysis of DZ and NCD treated primary normal trabecular meshwork (NTM) cells, human TM (isolated from perfusion cultures of human anterior segments) and mouse eyes showed increased phosphorylation of Erk1/2 when compared to vehicle treated controls. DZ and NCD mediated pressure reduction (p<0.02) in human anterior segments (n = 7 for DZ, n = 4 for NCD) was abrogated by U0126 (DZ + U0126: -9.7 +/- 11.5%, p = 0.11; NCD + U0126: -0.1 +/- 11.5%, p = 1.0). In contrast, U0126 had no effect on latanoprostfree acid-induced pressure reduction (-52.5 +/- 6.8%, n = 4, p = 0.001). In mice, DZ and NCD reduced IOP (DZ, 14.9 +/- 3.8%, NCD, 16.9 +/- 2.5%, n = 10, p<0.001), but the pressure reduction was inhibited by U0126 (DZ + U0126, 0.7 +/- 3.0%; NCD + U0126, 0.9 +/- 2.2%, n = 10, p>0.1). Histologic evaluation of transmission electron micrographs from DZ + U0126 and NCD + U0126 treated eyes revealed no observable morphological changes in the ultrastructure of the conventional outflow pathway. Taken together, the results indicate that the Erk1/2 pathway is necessary for IOP reduction by KATP channel openers DZ and NCD. PMID- 28594896 TI - Zoledronate suppressed angiogenesis and osteogenesis by inhibiting osteoclasts formation and secretion of PDGF-BB. AB - PURPOSE: Bisphosphonates related osteonecrosis of jaw (BRONJ) is a severe complication of systemic BPs administration, the mechanism of which is still unclarified. Recently, platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts was reported to promote angiogenesis and osteogenesis. This study aimed to clarify whether bisphosphonates suppressed preosteoclasts releasing PDGF BB, and whether the suppression harmed coupling of angiogenesis and osteogenesis, which could contribute to BRONJ manifestation. METHODS AND RESULTS: Zoledronate significantly inhibited osteoclast formation by tartrate-resistant acid phosphatase (TRAP) staining and PDGF-BB secretion tested by ELISA. In line with decreasing secretion of PDGF-BB by preosteoclasts exposed to zoledronate, conditioned medium (CM) from the cells significantly induced less migration of endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) compared to CM from unexposed preosteoclasts. Meanwhile, angiogenic function of EPCs and osteoblastic differentiation of MSCs also declined when culturing with CM from preosteoclasts treated by zoledronate (PZ-CM), evidenced by tube formation assay of EPCs and alkaline phosphatase activity of MSCs. Western blot assay showed that the expression of VEGF in EPCs and OCN, RUNX2 in MSCs declined when culturing with PZ-CM compared to CM from preostoeclasts without exposure of zoledronate. CONCLUSION: Our study found that zoledronate was able to suppress preosteoclasts releasing PDGF-BB, resulting in suppression of angiogenesis and osteogenesis. Our study may partly contributed to the mechanism of BRONJ. PMID- 28594898 TI - Clinical and genetic analysis of recurrent adult-type granulosa cell tumor of the ovary: Persistent preservation of heterozygous c.402C>G FOXL2 mutation. AB - BACKGROUND: Adult-type granulosa cell tumors of the ovary (aGCTs) are rare tumors that represent 2-5% of ovarian malignancies. The prognosis of this tumor is favorable, and it is characterized by slow progression. 10-30% of these tumors recur after 4-7 years of the primary surgery and the 5-year survival rate from the first recurrence is 55%, for the incompletely resected patients. At this time, complete resection is the only prognostic factor for better outcome, and establishing a novel strategy for identification and/or treatment of recurrent tumors is crucial. After the discovery of heterozygous c.402C>G FOXL2 mutations in 97% of cases of aGCT, much effort has been made to find the role of the mutation on the pathogenesis of aGCT, however, little is known about the role of the mutation in disease progression. METHODS: We analyzed the clinical data of 56 aGCT patients to find a marker of recurrence. In particular, we compared the FOXL2 status in 5 matched primary and recurrent samples by immunohistochemistry, and TaqMan allelic discrimination assay to address the role of FOXL2 in potential mechanisms of recurrence. RESULTS: The clinical data analysis was consistent with complete resection as an indicator of disease eradication, though the sample size was limited. The genetic analysis showed all the samples, including recurrent tumor samples up to 14 years after the primary surgery, expressed heterozygous c.402C>G FOXL2 mutation and the FOXL2 protein expression. CONCLUSION: This report describes the preservation of heterozygous c.402C>G FOXL2 mutation in recurrent aGCTs. This finding adds further credence to the concept that the c.402C>G FOXL2 mutation is oncogenic and integral to this disease. PMID- 28594899 TI - Validation of energy intake from a web-based food recall for children and adolescents. AB - The purpose of this study was to validate estimated energy intake from a web based food recall, designed for children and adolescents. We directly compared energy intake to estimates of total energy expenditure, calculated from accelerometer outputs, combined with data on weight and sex or resting energy expenditure prediction equations. Children (8-9 years) and adolescents (12-14 years) were recruited through schools in Norway in 2013 (N = 253). Results showed that more than one third (36-37%) were identified as under-reporters of energy. In contrast, only 2-4% were defined as over-reporters of energy. The mean energy intake was under-reported with -1.83 MJ/day for the entire study sample. Increased underestimation was observed for overweight and obese participants, the oldest age group (12-14 years), boys, those with parents/legal guardians with low educational level and those living in non-traditional families. In conclusion, energy intake from the web-based food recall is significantly underestimated compared with total energy expenditure, and should be used with caution in young people. PMID- 28594897 TI - Prognostic value of long non-coding RNA CCAT1 expression in patients with cancer: A meta-analysis. AB - BACKGROUND: LncRNA CCAT1 is significantly overexpressed in various types of cancers, suggesting that it might be associated with prognosis and clinicopathological features in patients with cancer. METHODS: A comprehensive search was performed in Pubmed, Web of Science, OVID and CNKI databases. We also retrieved articles from other sources, such as retrieving from the reference lists of relevant articles. Eligible studies were included based on defined exclusion and inclusion criteria to perform a meta-analysis. STATA 14.0 was used to estimate pooled hazard ratios (HRs) with 95% confidence interval (95% CI), the heterogeneity among studies and publication bias to judge the prognostic value. RESULTS: A total of 1587 patients from 11 eligible studies were included in the meta-analysis. The results showed that high expression level of CCAT1 was significantly associated with shorter overall survival in cancer patients (HR 2.335, 95% CI:1.551-3.517); in the subgroup analysis, region (China or UK), sample size (more or less than 100), type of cancer (digestive or non-digestive disease) and paper quality (score more or less than 7) did not alter the association between CCAT1 expression and cancer prognosis but preoperative treatment did. And CCAT1 expression was an independent prognostic marker for overall survival in patients with cancer (pooled HR 2.195, 95%CI:1.316-3.664) using Cox multivariate analyses. The clinicopathological parameters analysis further showed that increased expression level of CCAT1 was correlated with tumor size, lymph node metastasis, TNM stage, distant metastasis, microvascular invasion and capsular formation in relevant cancers. CONCLUSIONS: The meta analysis results from present study suggested that increased expression level of CCAT1 was associated with poor prognosis and can serve as an independent biomarker. And the expression level of CCAT1 was associated with clinicopathological features in relevant cancers. PMID- 28594901 TI - Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects. AB - The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1.7%) cases showed consistent positivity on repeat PCR testing. HCMV UL144, ISH and IHC assays were all negative. The HCMV UL73 positive cases did not show significant difference in the clinicopathological characters including age, gender, Karnofsky performance status, extent of resection, bevacizumab treatment, isocitrate dehydrogenase 1 mutation, O6-methylguanine-DNA methyltranferase status and Ki67 labeling index, and did not reveal prognostic significance. As only one HCMV gene was detected at low concentration in 7.8% of GBMs and there was no evidence of transcription, protein expression or prognostic impact, we cannot conclude a relationship between HCMV and GBM in Taiwanese patients. PMID- 28594900 TI - Systematic genomic and translational efficiency studies of uveal melanoma. AB - To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation. PMID- 28594902 TI - The stable isotope composition of nitrogen and carbon and elemental contents in modern and fossil seabird guano from Northern Chile - Marine sources and diagenetic effects. AB - Seabird excrements (guano) have been preserved in the arid climate of Northern Chile since at least the Pliocene. The deposits of marine organic material in coastal areas potentially open a window into the present and past composition of the coastal ocean and its food web. We use the stable isotope composition of nitrogen and carbon as well as element contents to compare the principal prey of the birds, the Peruvian anchovy, with the composition of modern guano. We also investigate the impact of diagenetic changes on the isotopic composition and elemental contents of the pure ornithogenic sediments, starting with modern stratified deposits and extending to fossil guano. Where possible, 14C systematics is used for age information. The nitrogen and carbon isotopic composition of the marine prey (Peruvian anchovy) of the birds is complex as it shows strong systematic variations with latitude. The detailed study of a modern profile that represents a few years of guano deposition up to present reveals systematic changes in nitrogen and carbon isotopic composition towards heavier values that increase with age, i.e. depth. Only the uppermost, youngest layers of modern guano show compositional affinity to the prey of the birds. In the profile, the simultaneous loss of nitrogen and carbon occurs by degassing, and non-volatile elements like phosphorous and calcium are passively enriched in the residual guano. Fossil guano deposits are very low in nitrogen and low in carbon contents, and show very heavy nitrogen isotopic compositions. One result of the study is that the use of guano for tracing nitrogen and carbon isotopic and elemental composition in the marine food web of the birds is restricted to fresh material. Despite systematic changes during diagenesis, there is little promise to retrieve reliable values of marine nitrogen and carbon signatures from older guano. However, the changes in isotopic composition from primary marine nitrogen isotopic signatures towards very heavy values generate a compositionally unique material. These compositions trace the presence of guano in natural ecosystems and its use as fertilizer in present and past agriculture. PMID- 28594904 TI - Gridding discretization-based multiple stability switching delay search algorithm: The movement of a human being on a controlled swaying bow. AB - Delay represents a significant phenomenon in the dynamics of many human-related systems-including biological ones. It has i.a. a decisive impact on system stability, and the study of this influence is often mathematically demanding. This paper presents a computationally simple numerical gridding algorithm for the determination of stability margin delay values in multiple-delay linear systems. The characteristic quasi-polynomial-the roots of which decide about stability-is subjected to iterative discretization by means of pre-warped bilinear transformation. Then, a linear and a quadratic interpolation are applied to obtain the associated characteristic polynomial with integer powers. The roots of the associated characteristic polynomial are closely related to the estimation of roots of the original characteristic quasi-polynomial which agrees with the system's eigenvalues. Since the stability border is crossed by the leading one, the switching root locus is enhanced using the Regula Falsi interpolation method. Our methodology is implemented on-and verified by-a numerical bio-cybernetic example of the stabilization of a human-being's movement on a controlled swaying bow. The advantage of the proposed novel algorithm lies in the possibility of the rapid computation of polynomial zeros by means of standard programs for technical computing; in the low level of mathematical knowledge required; and, in the sufficiently high precision of the roots loci estimation. The relationship to the direct search QuasiPolynomial (mapping) Rootfinder algorithm and computational complexity are discussed as well. This algorithm is also applicable for systems with non-commensurate delays. PMID- 28594903 TI - The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice. AB - Mesenchymal stromal cells (MSCs) have shown to be a promising tool in cell therapies to treat different conditions. Several pre-clinical and clinical studies have proved that the transplantation of MSCs improves wound healing. Here, we compare the beneficial effects of mouse bone marrow-derived allogeneic MSCs (allo-mBM-MSCs) and their acelullar derivatives (allo-acd-mMSCs) on skin wound healing in Non-Obese Diabetic (NOD) mice. One dose of allo-mBM-MSCs (1*106 cells) or one dose of allo-acd-mMSCs (1X) were intradermally injected around wounds in 8-10 week old female NOD mice. Wound healing was evaluated macroscopically (wound closure) every two days, and microscopically (reepithelialization, dermoepidermal junction, skin appendage regeneration, leukocyte infiltration, vascularization, granulation tissue formation, and density of collagen fibers in the dermis) after 16 days of MSC injection. In addition, we measured growth factors and specific proteins that were present in the allo-acd-mMSCs. Results showed significant differences in the wound healing kinetics of lesions that received allo-acd-mMSCs compared to lesions that received vehicle or allo-mBM-MSCs. In particular, mice treated with allo-acd mMSCs reached significantly higher percentages of wound closure at day 4, 6 and 8, relative to the allo-mBM-MSCs and vehicle groups (p < 0.05), while wound closure percentages could not be statistically distinguished between the allo-mBM MSCs and vehicle groups. Also, allo-acd-mMSCs had a greater influence in the skin would healing process. Specifically, they caused a less pronounced inflammatory severe response (p < 0.0001), more granulation tissue formation at an advanced stage (p < 0.0001), and higher density of collagen fibers (p < 0.05) compared to the other groups. Nevertheless, at day 16, both allo-mBM-MSCs and allo-acd-mMSCs revealed a higher effect on the recovery of the quality skin (continuous epidermis; regular dermoepidermal junction and skin appendages) relative to untreated lesions (p < 0.0001), but not between them. On the other hand, ELISA analyses indicated that the allo-acd-mMSCs contained growth factors and proteins relevant to wound healing such as IGF-1, KGF, HGF, VEGF, ANG-2, MMP-1, CoL-1 and PGE2. Compared to allo-acd-mMSCs, the administration of allo-mBM-MSCs is insufficient for wound healing in diabetic mice and delays the therapeutic effect, which maybe explained by the fact that trophic factors secreted by MSCs are critical for skin regeneration, and not the cells per se, suggesting that MSCs may require some time to secrete these factors after their administration. PMID- 28594905 TI - Comparative risk of hospitalized infection between biological agents in rheumatoid arthritis patients: A multicenter retrospective cohort study in Japan. AB - OBJECTIVE: Knowing the risk of hospitalized infection associated with individual biological agents is an important factor in selecting the best treatment option for patients with rheumatoid arthritis (RA). This study examined the comparative risk of hospitalized infection between biological agents in a routine care setting. METHODS: We used data for all RA patients who had first begun biological therapy at rheumatology divisions of participating community hospitals in Japan between January 2009 and December 2014. New treatment episodes with etanercept, infliximab, adalimumab, abatacept, or tocilizumab were included. Patients were allowed to contribute multiple treatment episodes with different biological agents. Incidence rates (IRs) of hospitalized infection during the first year of follow-up were examined. Cox regression analysis was used to calculate hazard ratios (HRs) for overall hospitalized infection and for pulmonary hospitalized infection, adjusting for possible confounders. RESULTS: A total of 1596 new treatment episodes were identified. The incidence of overall hospitalized infection during the first year was 86 with 1239 person-years (PYs), yielding a crude IR of 6.9 per 100 PYs (95% confidence interval [CI], 5.6-8.6). After correction for confounders, no significant difference in risk of hospitalized infection was observed between treatment groups: adjusted HRs (95% CI) were 1.54 (0.78-3.04) for infliximab, 1.72 (0.88-3.34) for adalimumab, 1.11 (0.55-2.21) for abatacept, and 1.02 (0.55-1.87) for tocilizumab compared with etanercept. Patient specific factors such as age, RA functional class, body mass index (BMI), prednisolone use, and chronic lung disease contributed more to the risk of hospitalized infection than specific biological agents. The incidence of pulmonary hospitalized infection was 50 and a crude IR of 4.0 per 100 PYs (95% CI, 3.1-5.3). After adjustment for confounders, adalimumab had a significantly higher HR for pulmonary hospitalized infection compared with tocilizumab: an adjusted HR (95% CI) was 4.43 (1.72-11.37) for adalimumab. BMI, prednisolone use, diabetes mellitus, and chronic lung disease were also significant factors associated with the risk of pulmonary hospitalized infection. CONCLUSIONS: The magnitude of the risk of overall hospitalized infection was not determined by the type of biological agents, and patient-specific risk factors had more impact on the risk of hospitalized infection. For pulmonary hospitalized infections, the use of adalimumab was significantly associated with a greater risk of this complication than tocilizumab use. PMID- 28594908 TI - Distribution and drivers of global mangrove forest change, 1996-2010. AB - For the period 1996-2010, we provide the first indication of the drivers behind mangrove land cover and land use change across the (pan-)tropics using time series Japanese Earth Resources Satellite (JERS-1) Synthetic Aperture Radar (SAR) and Advanced Land Observing Satellite (ALOS) Phased Array-type L-band SAR (PALSAR) data. Multi-temporal radar mosaics were manually interpreted for evidence of loss and gain in forest extent and its associated driver. Mangrove loss as a consequence of human activities was observed across their entire range. Between 1996-2010 12% of the 1168 1 degrees x1 degrees radar mosaic tiles examined contained evidence of mangrove loss, as a consequence of anthropogenic degradation, with this increasing to 38% when combined with evidence of anthropogenic activity prior to 1996. The greatest proportion of loss was observed in Southeast Asia, whereby approximately 50% of the tiles in the region contained evidence of mangrove loss, corresponding to 18.4% of the global mangrove forest tiles. Southeast Asia contained the greatest proportion (33.8%) of global mangrove forest. The primary driver of anthropogenic mangrove loss was found to be the conversion of mangrove to aquaculture/agriculture, although substantial advance of mangroves was also evident in many regions. PMID- 28594907 TI - Gastrointestinal cancer cells treatment with bevacizumab activates a VEGF autoregulatory mechanism involving telomerase catalytic subunit hTERT via PI3K AKT, HIF-1alpha and VEGF receptors. AB - BACKGROUND: Targeting angiogenesis has been considered a promising treatment of choice for a large number of malignancies, including gastrointestinal cancers. Bevacizumab is an anti-vascular endothelial growth factor (anti-VEGF) being used for this purpose. However, treatment efficacy is largely questioned. Telomerase activity, responsible for cancer cell immortality, is detected in 85-95% of human cancers and is considered a potential regulator of VEGF. The aim of our study was to investigate the interrelationship between VEGF and hTERT in gastrointestinal cancers and to explore cell response to a combined inhibition of telomerase and VEGF. METHODS: AGS (gastric cancer), Caco-2 (colorectal cancer) and HepG2/C3A (hepatocellular carcinoma), were treated with telomerase inhibitors BIBR-1232 (10MUM) and costunolide (10MUM), with bevacizumab (Avastin(r) at 5 ng/ml or 100MUg/ml) or with a combination of both types of inhibitors. VEGF and hTERT mRNA levels, and telomerase activity were detected by RT-PCR. VEGF levels were quantified by ELISA. Telomerase was knocked down using hTERT siRNA and hTERT was overexpressed in the telomerase negative cell line, Saos-2 (osteosarcoma), using constructs expressing either wild type hTERT (hTERT-WT) or dominant negative hTERT (hTERT-DN). Tube formation by HUVECs was assessed using ECMatrixTM (EMD Millipore). RESULTS: Our results showed that telomerase regulates VEGF expression and secretion through its catalytic subunit hTERT in AGS, Caco2, and HepG2/C3A, independent of its catalytic activity. Interestingly, VEGF inhibition with bevacizumab (100MUg/ml) increased hTERT expression 42.3% in AGS, 94.1% in Caco2, and 52.5% in HepG2/C3A, and increased telomerase activity 30-fold in AGS, 10.3 fold in Caco2 and 8-fold in HepG2/C3A. A further investigation showed that VEGF upregulates hTERT expression in a mechanism that implicates the PI3K/AKT/mTOR pathway and HIF-1alpha. Moreover, bevacizumab treatment increased VEGFR1 and VEGFR2 expression in cancer cells and human umbilical vein endothelial cells (HUVECs) through hTERT. Thus, the combination of bevacizumab with telomerase inhibitors decreased VEGF expression and secretion by cancer cells, inhibited VEGFR1 and VEGFR2 upregulation, and reduced tube formation by HUVECs. CONCLUSIONS: Taken together, our results suggest that bevacizumab treatment activates a VEGF autoregulatory mechanism involving hTERT and VEGF receptors and that an inhibition of this pathway could improve tumor cell response to anti-VEGF treatment. PMID- 28594906 TI - The anti-inflammatory and immunomodulatory potential of braylin: Pharmacological properties and mechanisms by in silico, in vitro and in vivo approaches. AB - Braylin belongs to the group of natural coumarins, a group of compounds with a wide range of pharmacological properties. Here we characterized the pharmacological properties of braylin in vitro, in silico and in vivo in models of inflammatory/immune responses. In in vitro assays, braylin exhibited concentration-dependent suppressive activity on activated macrophages. Braylin (10-40 MUM) reduced the production of nitrite, IL-1beta, TNF-alpha and IL-6 by J774 cells or peritoneal exudate macrophages stimulated with LPS and IFN-gamma. Molecular docking calculations suggested that braylin present an interaction pose to act as a glucocorticoid receptor ligand. Corroborating this idea, the inhibitory effect of braylin on macrophages was prevented by RU486, a glucocorticoid receptor antagonist. Furthermore, treatment with braylin strongly reduced the NF-kappaB-dependent transcriptional activity on RAW 264.7 cells. Using the complete Freund's adjuvant (CFA)-induced paw inflammation model in mice, the pharmacological properties of braylin were demonstrated in vivo. Braylin (12.5-100 mg/kg) produced dose-related antinociceptive and antiedematogenic effects on CFA model. Braylin did not produce antinociception on the tail flick and hot plate tests in mice, suggesting that braylin-induced antinociception is not a centrally-mediated action. Braylin exhibited immunomodulatory properties on the CFA model, inhibiting the production of pro inflammatory cytokines IL-1beta, TNF-alpha and IL-6, while increased the anti inflammatory cytokine TGF-beta. Our results show, for the first time, anti inflammatory, antinociceptive and immunomodulatory effects of braylin, which possibly act through the glucocorticoid receptor activation and by inhibition of the transcriptional activity of NF-kappaB. Because braylin is a phosphodiesterase 4 inhibitor, this coumarin could represent an ideal prototype of glucocorticoid receptor ligand, able to induce synergic immunomodulatory effects. PMID- 28594909 TI - Waves of novelties in the expansion into the adjacent possible. AB - The emergence of novelties and their rise and fall in popularity is an ubiquitous phenomenon in human activities. The coexistence of popular evergreens with novel and sometimes ephemeral trends pervades technological, scientific and artistic production. Though this phenomenon is very intuitively captured by our common sense, a comprehensive explanation of how waves of novelties are not hampered by well established old-comers is still lacking. Here we first quantify this phenomenology by empirically looking at different systems that display innovation at very different levels: the creation of hashtags in Twitter, the evolution of online code repositories, the creation of texts and the listening of songs on online platforms. In all these systems surprisingly similar patterns emerge as the non-trivial outcome of two contrasting forces: the tendency of retracing already explored avenues (exploit) and the inclination to explore new possibilities. These findings are naturally explained in the framework of the expansion of the adjacent possible, a recently introduced theoretical framework that postulates the restructuring of the space of possibilities conditional to the occurrence of innovations. The predictions of our theoretical framework are borne out in all the phenomenologies investigated, paving the way to a better understanding and control of innovation processes. PMID- 28594910 TI - Testosterone improves the differentiation efficiency of insulin-producing cells from human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) may provide potential resource for regenerative medicine research, including generation of insulin-producing cells for diabetes research and insulin production. Testosterone (T) is an androgen hormone which promotes protein synthesis and improves the management of type 2 diabetes in clinical studies. Concurrently, co-existed hyperandrogenism and hyperinsulinism is frequently observed in polycystic ovary syndrome, congenital adrenal hyperplasia and some of Wermer's syndrome. However, the relationship among androgens, insulin and the differentiation of pancreatic beta cells is still not fully clear. Here we find that T improves the differentiation efficiency of insulin-producing cells from hiPSCs. The addition of T into routine differentiation formula for pancreatic beta cells increases the differentiation efficiency from 12% to 35%. The administration of T promotes the expression of key genes associated with beta cells differentiation including NGN3, NEUROD1 and INS. This finding benefits the ongoing process to optimize the differentiation protocol of pancreatic beta cells from hiPSCs, and provides some degree of understanding the clinical management of T for type 2 diabetes. PMID- 28594912 TI - Cancer cell redirection biomarker discovery using a mutual information approach. AB - Introducing tumor-derived cells into normal mammary stem cell niches at a sufficiently high ratio of normal to tumorous cells causes those tumor cells to undergo a change to normal mammary phenotype and yield normal mammary progeny. This phenomenon has been termed cancer cell redirection. We have developed an in vitro model that mimics in vivo redirection of cancer cells by the normal mammary microenvironment. Using the RNA profiling data from this cellular model, we examined high-level characteristics of the normal, redirected, and tumor transcriptomes and found the global expression profiles clearly distinguish the three expression states. To identify potential redirection biomarkers that cause the redirected state to shift toward the normal expression pattern, we used mutual information relationships between normal, redirected, and tumor cell groups. Mutual information relationship analysis reduced a dataset of over 35,000 gene expression measurements spread over 13,000 curated gene sets to a set of 20 significant molecular signatures totaling 906 unique loci. Several of these molecular signatures are hallmark drivers of the tumor state. Using differential expression as a guide, we further refined the gene set to 120 core redirection biomarker genes. The expression levels of these core biomarkers are sufficient to make the normal and redirected gene expression states indistinguishable from each other but radically different from the tumor state. PMID- 28594911 TI - Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans. AB - We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] * C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin alpha5beta1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin alpha5beta1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain specific differences could contribute to susceptibility to S. aureus. Down regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naive and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus. PMID- 28594913 TI - Reduction in all-cause otitis media-related outpatient visits in children after PCV10 introduction in Brazil. AB - Few studies have reported the effect of 10-valent pneumococcal conjugate vaccine (PCV10) on otitis media (OM) in infants. In particular, no population-based study in upper-middle income countries is available. In 2010, Brazil introduced PCV10 into its routine National Immunization Program using a 3+1 schedule. We measured the impact of PCV10 on all-cause OM in children. An interrupted time-series analysis was conducted in Goiania/Brazil considering monthly rates (per 100,000) of all-cause OM outpatient visits in children aged 2-23 months. We used case based data from the Outpatient Visits Information System of the Unified Health System coded for ICD-10 diagnosis for the period of August/2008 to July/2015. As a comparator, we used rates of outpatient visits due to all-other causes. The relative reduction of all-cause OM and all-other causes of outpatient visits were calculated as the difference between the predicted and observed cumulative rates of the PCV10 post-vaccination period. We then subtracted the relative reduction of all-other causes of outpatient visits from all-cause OM to obtain the impact of PCV10 on OM. In total, 6,401 OM outpatient visits were recorded in 4,793 children aged 2-23 months. Of these, 922 (19.2%) children had more than one OM episode. A significant reduction in all-cause OM visits was observed (50.7%; 95%CI: 42.2-59.2%; p = 0.013), while the reduction in visits due to all-other causes was 7.7% (95% CI 0.8-14.7%; p<0.001). The impact of PCV10 on all-cause OM was thus estimated at 43.0% (95%CI 41.4-44.5). This is the first study to show significant PCV10 impact on OM outpatient visits in infants in a developing country. Our findings corroborate the available evidence from developed countries. PMID- 28594914 TI - Associations between dental knowledge, source of dental knowledge and oral health behavior in Japanese university students: A cross-sectional study. AB - The aim of this study was to investigate the associations between dental knowledge, the source of dental knowledge and oral health behavior in a group of students at a university in Japan. A total of 2,220 university students (1,276 males, 944 females) volunteered to undergo an oral examination and answer a questionnaire. The questionnaire assessed dental knowledge, the source of dental knowledge and oral health behavior (e.g., daily frequency of tooth brushing, use of dental floss and regular dental checkups). The odds ratio and 95% confidence interval for oral health behavior based on dental knowledge and source of dental knowledge were calculated using logistic regression models. Of the participants, 1,266 (57.0%) students obtained dental knowledge from dental clinics, followed by school (39.2%) and television (29.1%). Logistic regression analyses indicated that use of dental floss was significantly associated with source of dental knowledge from dental clinics (P = 0.006). Receiving regular dental checkups was significantly associated with source of dental knowledge; the positive source was dental clinic (P < 0.001) and the negative sources were school (P = 0.004) and television (P = 0.018). Dental clinic was the most common source of dental knowledge and associated with better oral health behavior among the Japanese university students in this study. PMID- 28594915 TI - Conophylline inhibits non-alcoholic steatohepatitis in mice. AB - Conophylline (CnP), a vinca alkaloid extracted from the leaves of the tropical plant Ervatamia microphylla, attenuates hepatic fibrosis in mice. However, little is known about whether CnP inhibits steatosis, inflammation, and fibrosis in non alcoholic steatohepatitis (NASH) in mice. A methionine-choline-deficient (MCD) diet was administered to male db/db mice as a NASH model, and CnP (1 MUg/kg/d) was co-administered. Eight weeks after the commencement of the MCD diet, hepatic steatosis, inflammation, and fibrosis, and hepatic fat metabolism-, inflammation , and fibrosis-related markers were examined. Feeding on an MCD for 8 weeks induced hepatic steatosis, inflammation, and fibrosis. CnP significantly attenuated the MCD-induced increases in hepatic steatosis, as well as hepatic inflammation and fibrosis. The MCD diet increased hepatic transforming growth factor-beta (TGF-beta) mRNA levels, which are correlated with hepatic steatosis, inflammation, and fibrosis. The diet also attenuated acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1 (CPT1) mRNA levels, which are involved in beta-oxidation. The putative mechanism of the CnP effect involves reduced hepatic TGF-beta mRNA levels, and increased mRNA levels of hepatic peroxisome proliferator-activated receptor (PPAR) alpha and its target genes ACOX1 and CPT1. The results of this study indicate that CnP inhibits steatohepatitis, possibly through the inhibition of hepatic TGF-beta mRNA levels, and induces an increase in PPARalpha mRNA levels, resulting in the attenuation of hepatic steatosis, inflammation, and fibrosis in mice. CnP might accordingly be a suitable therapeutic option for NASH. PMID- 28594917 TI - Taxicab tipping and sunlight. AB - Does the level of sunlight affect the tipping percentage in taxicab rides in New York City? We examined this question using data on 13.82 million cab rides from January to October in 2009 in New York City combined with data on hourly levels of solar radiation. We found a small but statistically significant positive relationship between sunlight and tipping, with an estimated tipping increase of 0.5 to 0.7 percentage points when transitioning from a dark sky to full sunshine. The findings are robust to two-way clustering of standard errors based on hour-of the-day and day-of-the-year and controlling for day-of-the-year, month-of-the year, cab driver fixed effects, weather conditions, and ride characteristics. The NYC cab ride context is suitable for testing the association between sunlight and tipping due to the largely random assignment of riders to drivers, direct exposure to sunlight, and low confounding from variation in service experiences. PMID- 28594916 TI - Identification of key amino acid residues in the hTGR5-nomilin interaction and construction of its binding model. AB - TGR5, a member of the G protein-coupled receptor (GPCR) family, is activated by bile acids. Because TGR5 promotes energy expenditure and improves glucose homeostasis, it is recognized as a key target in treating metabolic diseases. We previously showed that nomilin, a citrus limonoid, activates TGR5 and confers anti-obesity and anti-hyperglycemic effects in mice. Information on the TGR5 nomilin interaction regarding molecular structure, however, has not been reported. In the present study, we found that human TGR5 (hTGR5) shows higher nomilin responsiveness than does mouse TGR5 (mTGR5). Using mouse-human chimeric TGR5, we also found that three amino acid residues (Q77ECL1, R80ECL1, and Y893.29) are important in the hTGR5-nomilin interaction. Based on these results, an hTGR5-nomilin binding model was constructed using in silico docking simulation, demonstrating that four hydrophilic hydrogen-bonding interactions occur between nomilin and hTGR5. The binding mode of hTGR5-nomilin is vastly different from those of other TGR5 agonists previously reported, suggesting that TGR5 forms various binding patterns depending on the type of agonist. Our study promotes a better understanding of the structure of TGR5, and it may be useful in developing and screening new TGR5 agonists. PMID- 28594919 TI - Weaned beef calves fed selenium-biofortified alfalfa hay have an enriched nasal microbiota compared with healthy controls. AB - Selenium (Se) is an essential trace mineral important for immune function and overall health of cattle. The nasopharyngeal microbiota in cattle plays an important role in overall respiratory health, especially when stresses associated with weaning, transport, and adaptation to a feedlot affect the normal respiratory defenses. Recent evidence suggests that cattle diagnosed with bovine respiratory disease complex have significantly less bacterial diversity. The objective of this study was to determine whether feeding weaned beef calves Se enriched alfalfa (Medicago sativa) hay for 9 weeks in a preconditioning program prior to entering the feedlot alters nasal microbiota. Recently weaned beef calves (n = 45) were blocked by sex and body weight, randomly assigned to 3 treatment groups with 3 pens of 5 calves per treatment group, and fed an alfalfa hay based diet for 9 weeks. Alfalfa hay was harvested from fields fertilized with sodium selenate at a rate of 0, 45.0 or 89.9 g Se/ha. Blood samples were collected biweekly and analyzed for whole-blood Se concentrations. Nasal swabs were collected during week 9 from one or two calves from each pen (total n = 16). Calculated Se intake from dietary sources was 3.0, 15.6, and 32.2 mg Se/head/day for calves consuming alfalfa hay with Se concentrations of 0.34 to 2.42 and 5.17 mg Se/kg dry matter, respectively. Whole-blood Se concentrations after 8 weeks of feeding Se-fertilized alfalfa hay were dependent upon Se-application rates (0, 45.0, or 89.9 g Se/ha) and were 155, 345, and 504 ng/mL (PLinear < 0.0001). Microbial DNA was extracted from nasal swabs and amplified and sequenced. Alpha rarefaction curves comparing the species richness (observed OTUs) and overall diversity (Chao1, Observed OTU, and Shannon index) between calves fed selenium biofortified alfalfa hay compared with control calves showed that Se supplementation tended to be associated with an enriched nasal microbiota. ANOSIM of unweighted UniFrac distances showed that calves fed high Se-biofortified alfalfa hay clustered separately when compared with control calves in the PCoA plot (R = 0.216, P = 0.04). The bacterial orders Lactobacillales and Flavobacteriales were increased in healthy control calves compared with Clostridiales and Bacteroidales being increased in calves fed Se-biofortified alfalfa hay. Although there were strong trends, no significant differences were noted for any of the bacterial taxa. Based upon these findings, we suggest that weaned beef calves fed Se-biofortified hay tend to have an enriched nasal microbiota. Feeding Se-biofortified alfalfa hay to weaned beef calves prior to entering the feedlot is a strategy for increasing nasopharyngeal microbial diversity. PMID- 28594918 TI - Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study. AB - BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior. PMID- 28594921 TI - T6SS: The bacterial "fight club" in the host gut. PMID- 28594920 TI - Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART). AB - Hepatic steatosis can occur with any antiretroviral therapy (cART). Although single nucleotide polymorphisms (SNPs) have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409), CSPG3/NCAN (rs2228603), GCKR (rs780094), PPP1R3B (rs4240624), TM6SF (rs8542926), LYPLAL1 (rs12137855) and MBOAT7 (rs626283) by RT PCR in 117 HIV-positive patients on cART and stratified participants based on their "controlled attenuation parameter" (CAP) into probable (CAP: 215-300 dB/m) and definite (CAP >300 dB/m) hepatic steatosis. We analyzed CAP values and routine metabolic parameters according to the allele frequencies. Sixty-five (55.6%) and 13 (11.1%) patients were allocated to probable and definite steatosis. CAP values (p = 0.012) and serum triglycerides (p = 0.043) were increased in carriers of the GCKR (rs780094) A allele. Cox logistic regression identified triglycerides (p = 0.006), bilirubin (p = 0.021) and BMI (p = 0.068), but not the genetic parameters as risk factors for the occurrence of hepatic steatosis. Taken together, according to the limited sample size, this exploratory study generates the hypothesis that genetic polymorphisms seem to exert minor effects on the risk for fatty liver disease in HIV-positive patients on cART. Nevertheless, SNPs may modify metabolic complications once metabolic abnormalities have developed. Hence, subsequent analysis of a larger cohort is needed. PMID- 28594922 TI - The learning curve of endoscopic total mastectomy in Taiwan: A multi-center study. AB - INTRODUCTION: Laparoscopic techniques are commonly used in abdominal and gynecologic surgery, while breast cancer surgery has remained largely unchanged. In Asia, especially in Japan, many surgeons have started to use endoscopic surgery for breast cancer. In Taiwan, endoscopy-assisted breast surgery started in 2010. The benefits of this surgical method include smaller incisions, an axillary anatomic approach, clear vision, no oncologic compromise, and good cosmetic outcomes. This is the first report to discuss the learning curve of endoscopy-assisted breast surgery, including the difficulties experienced. MATERIALS AND METHODS: From June 2011 to December 2013, data were collected from 134 patients who received an endoscopic total mastectomy at the Taipei Medical University Hospital (TMUH) or Changhua Christian Hospital (CCH). We divided these patients into a learning group (TMUH, n = 15; CCH, n = 15) and a mature group (TMUH, n = 50; CCH, n = 54). Patient data and perioperative variables were recorded by retrospective chart review. Variables were compared using the chi2 test and Student's t-test. RESULTS: There was a significant difference in operation time (275.3 vs. 228.9 minutes, p < 0.01) between the learning and mature groups. Perioperative variables (lymph node dissection method, nipple preservation, and reconstruction method) were also analyzed, but there were no demographic differences between the groups. The complication rate was higher in the learning group, although this difference was also not statistically significant. CONCLUSION: Our study is the first to discuss the learning curve of endoscopic total mastectomy. The operation time decreased significantly after 15 cases at each hospital. Although the operation is still more time-consuming than traditional methods, it has the benefit of smaller wounds and improved cosmetic outcomes if combined with immediate reconstruction. PMID- 28594923 TI - Computer-aided detection of brain metastasis on 3D MR imaging: Observer performance study. AB - PURPOSE: To assess the effect of computer-aided detection (CAD) of brain metastasis (BM) on radiologists' diagnostic performance in interpreting three dimensional brain magnetic resonance (MR) imaging using follow-up imaging and consensus as the reference standard. MATERIALS AND METHODS: The institutional review board approved this retrospective study. The study cohort consisted of 110 consecutive patients with BM and 30 patients without BM. The training data set included MR images of 80 patients with 450 BM nodules. The test set included MR images of 30 patients with 134 BM nodules and 30 patients without BM. We developed a CAD system for BM detection using template-matching and K-means clustering algorithms for candidate detection and an artificial neural network for false-positive reduction. Four reviewers (two neuroradiologists and two radiology residents) interpreted the test set images before and after the use of CAD in a sequential manner. The sensitivity, false positive (FP) per case, and reading time were analyzed. A jackknife free-response receiver operating characteristic (JAFROC) method was used to determine the improvement in the diagnostic accuracy. RESULTS: The sensitivity of CAD was 87.3% with an FP per case of 302.4. CAD significantly improved the diagnostic performance of the four reviewers with a figure-of-merit (FOM) of 0.874 (without CAD) vs. 0.898 (with CAD) according to JAFROC analysis (p < 0.01). Statistically significant improvement was noted only for less-experienced reviewers (FOM without vs. with CAD, 0.834 vs. 0.877, p < 0.01). The additional time required to review the CAD results was approximately 72 sec (40% of the total review time). CONCLUSION: CAD as a second reader helps radiologists improve their diagnostic performance in the detection of BM on MR imaging, particularly for less-experienced reviewers. PMID- 28594924 TI - Multiple extracellular vesicle types in peritoneal dialysis effluent are prominent and contain known biomarkers. AB - Peritoneal dialysis inevitability results in activation of inflammatory processes and its efficiency is highly variable between patients. An improved method to isolate biomarkers and study pathophysiological mechanisms in peritoneal dialysis effluent (PDE) is expected to be of much benefit for the development of this treatment approach and help with patient management. Extracellular vesicles (EVs) are released as part of normal cellular processes. Their proteome is expected to reflect both type and health of their cell of origin. Although there is a significant interest in using EVs for "liquid biopsies", little is reported of their presence or composition in plentiful dialysis waste fluids, including peritoneal dialysis effluent (PDE). Here we determined the presence of EVs in PDE and subsequently characterized their proteome. EVs were first isolated from PDE using differential centrifugation, then a further enrichment using size exclusion chromatography (SEC) was performed. The presence of EVs was demonstrated using transmission electron microscopy, and their particle counts were investigated using nanoparticle tracking analysis and dynamic light scattering. Using tandem mass spectrometry, marker proteins from three types of EVs i.e. apoptotic bodies, ectosomes, and exosomes were identified. The proteomic results demonstrated that the isolation of EVs by differential centrifugation helped enrich for over 2,000 proteins normally masked by abundant proteins in PDE such as albumin and SEC markedly further improved the isolation of low abundant proteins. Gene ontology analysis of all identified proteins showed the marked enrichment of exosome and membrane-associated proteins. Over 3,700 proteins were identified in total, including many proteins with known roles in peritoneal pathophysiology. This study demonstrated the prominence of EVs in PDE and their potential value as a source of biomarkers for peritoneal dialysis patients. PMID- 28594925 TI - A comparative study of the effect of the dose and exposure duration of anabolic androgenic steroids on behavior, cholinergic regulation, and oxidative stress in rats. AB - The aim of this study was to assess if the dose and exposure duration of the anabolic androgenic steroids (AAS) boldenone (BOL) and stanazolol (ST) affected memory, anxiety, and social interaction, as well as acetylcholinesterase (AChE) activity and oxidative stress in the cerebral cortex (CC) and hippocampus (HC). Male Wistar rats (90 animals) were randomly assigned to three treatment protocols: (I) 5 mg/kg BOL or ST, once a week for 4 weeks; (II) 2.5 mg/kg BOL or ST, once a week for 8 weeks; and (III) 1.25 mg/kg BOL or ST, once a week for 12 weeks. Each treatment protocol included a control group that received an olive oil injection (vehicle control) and AAS were administered intramuscularly (a total volume of 0.2 ml) once a week in all three treatment protocols. In the BOL and ST groups, a higher anxiety level was observed only for Protocol I. BOL and ST significantly affected social interaction in all protocols. Memory deficits and increased AChE activity in the CC and HC were found in the BOL groups treated according to Protocol III only. In addition, BOL and ST significantly increased oxidative stress in both the CC and HC in the groups treated according to Protocol I and III. In conclusion, our findings show that the impact of BOL and ST on memory, anxiety, and social interaction depends on the dose and exposure duration of these AAS. PMID- 28594927 TI - Estimating an area-level socioeconomic status index and its association with colonoscopy screening adherence. AB - Socioeconomic status (SES) is often considered a risk factor for health outcomes. SES is typically measured using individual variables of educational attainment, income, housing, and employment variables or a composite of these variables. Approaches to building the composite variable include using equal weights for each variable or estimating the weights with principal components analysis or factor analysis. However, these methods do not consider the relationship between the outcome and the SES variables when constructing the index. In this project, we used weighted quantile sum (WQS) regression to estimate an area-level SES index and its effect in a model of colonoscopy screening adherence in the Minnesota-Wisconsin Metropolitan Statistical Area. We considered several specifications of the SES index including using different spatial scales (e.g., census block group-level, tract-level) for the SES variables. We found a significant positive association (odds ratio = 1.17, 95% CI: 1.15-1.19) between the SES index and colonoscopy adherence in the best fitting model. The model with the best goodness-of-fit included a multi-scale SES index with 10 variables at the block group-level and one at the tract-level, with home ownership, race, and income among the most important variables. Contrary to previous index construction, our results were not consistent with an assumption of equal importance of variables in the SES index when explaining colonoscopy screening adherence. Our approach is applicable in any study where an SES index is considered as a variable in a regression model and the weights for the SES variables are not known in advance. PMID- 28594926 TI - Rotating night work, lifestyle factors, obesity and promoter methylation in BRCA1 and BRCA2 genes among nurses and midwives. AB - Some recent evidence suggests that environmental and lifestyle factors may modify DNA methylation. We hypothesized that rotating night work and several modifiable factors may be associated with the methylation of the promoter regions within two tumor suppressor and DNA repair genes: BRCA1 and BRCA2. The methylation status of BRCA1 and BRCA2 was determined via qMSP reactions using DNA samples derived from blood leucocytes of 347 nurses and midwives working rotating nights and 363 working during the days. The subjects were classified into unmethylated vs methylated BRCA1 and BRCA2 when the methylation index was 0% or >0%, respectively. The adjusted odds ratios with 95% confidence intervals were calculated for night work status, smoking, obesity, physical activity and alcohol drinking. Current night shift work or night work history was not associated with methylation status of the promoter sites within BRCA1 and BRCA2 genes. We observed weak associations between smoking and the methylation status of BRCA1 with OR = 1.50 (95%CI: 0.98-2.29) for current smoking, OR = 1.83, 95CI: 1.08-3.13 for smoking longer than 31 years, and 0.1>p>0.05 for trends for the number of cigarettes per day, smoking duration and packyears. In conclusion, no links between night shift work and methylation of the promoter region within the BRCA1, and BRCA2 genes were observed in this exploratory analysis. The findings of our study weakly support the hypothesis that smoking may contribute to epigenetic events. PMID- 28594928 TI - Should the WHO withdraw support for mass deworming? PMID- 28594929 TI - Intermittent hypoxia increases kidney tumor vascularization in a murine model of sleep apnea. AB - We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages. PMID- 28594930 TI - Evaluation of an enhanced cleaning and disinfection protocol in Salmonella contaminated pig holdings in the United Kingdom. AB - Salmonella is the second most commonly reported zoonotic gastrointestinal pathogen in the European Union, and a significant proportion of the cases are linked to the consumption of contaminated pork. Reduction of Salmonella at the farm level helps to mininimise the contamination pressure at the slaughterhouse, and therefore the number of Salmonella bacteria entering the food chain. Cleaning and disinfection (C&D) between batches of pigs is an intervention measure that has potential to reduce the transmission of Salmonella contamination within farms. In this study, two pig finisher buildings in each of 10 Salmonella positive farms were sampled pre-C&D, post-C&D, post-restocking with the following batch of pigs, and shortly before these pigs were sent to slaughter. The incoming batch of pigs was also sampled before it reached the study building (pre restocking). At each visit, pooled and individual faecal samples were collected and Salmonella isolation was carried out according to an ISO 6579:2002 Annex D based method. One building on each farm (intervention) was cleaned and disinfected according to a rigorous protocol consisting of several steps and a Defra-approved disinfectant used at the General Orders concentration, whilst the other building (control) was cleaned and disinfected as per normal farm routine. At the post-C&D visit, Enterobacteriaceae and total bacterial counts were determined to evaluate residual faecal contamination and general hygiene levels. Rodent specialists visited the farms before and after C&D and rodent carcasses were collected for Salmonella testing. The intervention buildings were significantly less likely (p = 0.004) to be positive for Salmonella after C&D. The pre-restocking pigs had the highest likelihood (p<0.001) of being Salmonella positive (often with multiple serovars) and there was no significant difference between intervention and control buildings in Salmonella prevalence at the post restocking visit (p = 0.199). However, the pigs housed in the intervention buildings were significantly less likely (p = 0.004) to be positive for Salmonella at slaughter age. Multivariable analysis suggested that cleaning all fixtures of buildings, leaving the pens empty for 2-3 days and using an effective disinfectant are factors significantly improving the likelihood of removing Salmonella contamination during C&D. Signs of rodents were recorded in all farms, but rodent activity and harbourage availability decreased between visits. All the rats tested were Salmonella negative. S. Typhimurium or its monophasic variants were isolated from 6 mouse carcasses in 3 farms where the same serovars were isolated from pigs. This study demonstrates that an appropriate C&D programme significantly reduces the likelihood of residual contamination in Salmonella positive pig buildings, and suggests a significant reduction in the prevalence of Salmonella in the pigs in appropriately cleaned and disinfected buildings when sampled before slaughter. Due to a high prevalence of infection in replacement pigs, control of Salmonella in pig farms is challenging. Rodents may also contribute to the carry-over of infection between batches. C&D is a useful measure to help reduce the number of infected pigs going to the slaughterhouse, but should be supplemented by other control measures along the pig breeding and production chain. PMID- 28594931 TI - De novo transcriptome assembly and quantification reveal differentially expressed genes between soft-seed and hard-seed pomegranate (Punica granatum L.). AB - Pomegranate (Punica granatum L.) belongs to Punicaceae, and is valued for its social, ecological, economic, and aesthetic values, as well as more recently for its health benefits. The 'Tunisia' variety has softer seeds and big arils that are easily swallowed. It is a widely popular fruit; however, the molecular mechanisms of the formation of hard and soft seeds is not yet clear. We conducted a de novo assembly of the seed transcriptome in P. granatum L. and revealed differential gene expression between the soft-seed and hard-seed pomegranate varieties. A total of 35.1 Gb of data were acquired in this study, including 280,881,106 raw reads. Additionally, de novo transcriptome assembly generated 132,287 transcripts and 105,743 representative unigenes; approximately 13,805 unigenes (37.7%) were longer than 1,000 bp. Using bioinformatics annotation libraries, a total of 76,806 unigenes were annotated and, among the high-quality reads, 72.63% had at least one significant match to an existing gene model. Gene expression and differentially expressed genes were analyzed. The seed formation of the two pomegranate cultivars involves lignin biosynthesis and metabolism, including some genes encoding laccase and peroxidase, WRKY, MYB, and NAC transcription factors. In the hard-seed pomegranate, lignin-related genes and cellulose synthesis-related genes were highly expressed; in soft-seed pomegranates, expression of genes related to flavonoids and programmed cell death was slightly higher. We validated selection of the identified genes using qRT PCR. This is the first transcriptome analysis of P. granatum L. This transcription sequencing greatly enriched the pomegranate molecular database, and the high-quality SSRs generated in this study will aid the gene cloning from pomegranate in the future. It provides important insights into the molecular mechanisms underlying the formation of soft seeds in pomegranate. PMID- 28594932 TI - NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains. AB - Hepatitis C virus (HCV) RNA is synthesized by the replicase complex (RC), a macromolecular assembly composed of viral non-structural proteins and cellular co factors. Inhibitors of the HCV NS5A protein block formation of new RCs but do not affect RNA synthesis by pre-formed RCs. Without new RC formation, existing RCs turn over and are eventually lost from the cell. We aimed to use NS5A inhibitors to estimate the half-life of the functional RC of HCV. We compared different cell culture-infectious strains of HCV that may be grouped based on their sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistant (LPOR) viruses (e.g. JFH-1 or H77D) and more slowly replicating, lipid peroxidation sensitive (LPOS) viruses (e.g. H77S.3 and N.2). In luciferase assays, LPOS HCV strains declined under NS5A inhibitor therapy with much slower kinetics compared to LPOR HCV strains. This difference in rate of decline was not observed for inhibitors of the NS5B RNA-dependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability. In further analyses, we compared two isoclonal HCV variants: the LPOS H77S.3 and the LPOR H77D that differ only by 12 amino acids. Differences in rate of decline between H77S.3 and H77D following NS5A inhibitor addition were not due to amino acid sequences in NS5A but rather due to a combination of amino acid differences in the non-structural proteins that make up the HCV RC. Mathematical modeling of intracellular HCV RNA dynamics suggested that differences in RC stability (half lives of 3.5 and 9.9 hours, for H77D and H77S.3, respectively) are responsible for the different kinetics of antiviral suppression between LPOS and LPOR viruses. In nascent RNA capture assays, the rate of RNA synthesis decline following NS5A inhibitor addition was significantly faster for H77D compared to H77S.3 indicating different half-lives of functional RCs. PMID- 28594933 TI - How reliable are the effects of self-control training?: A re-examination using self-report and physical measures. AB - In light of recent challenges to the strength model of self-control, our study re examines the effects of self-control training on established physical and self report measures of self-control. We also examined whether beliefs about the malleability of self-control qualify any training effects. Participants in the training condition were assigned to increase use of their non-dominant hand for two weeks, and did comply mainly if they held high-malleability beliefs; yet, compared to a control condition, the physical measure of self-control did not improve. This was also evident in a secondary objective measure of self-control, a Stroop task, as well as in self-reported self-control. The discussion focuses on the lack of replication of training effects on self-control. PMID- 28594934 TI - Effects of PPARalpha inhibition in head and neck paraganglioma cells. AB - Head and neck paragangliomas (HNPGLs) are rare tumors that may cause important morbidity, because of their tendency to infiltrate the skull base. At present, surgery is the only therapeutic option, but radical removal may be difficult or impossible. Thus, effective targets and molecules for HNPGL treatment need to be identified. However, the lack of cellular models for this rare tumor hampers this task. PPARalpha receptor activation was reported in several tumors and this receptor appears to be a promising therapeutic target in different malignancies. Considering that the role of PPARalpha in HNPGLs was never studied before, we analyzed the potential of modulating PPARalpha in a unique model of HNPGL cells. We observed an intense immunoreactivity for PPARalpha in HNPGL tumors, suggesting that this receptor has an important role in HNPGL. A pronounced nuclear expression of PPARalpha was also confirmed in HNPGL-derived cells. The specific PPARalpha agonist WY14643 had no effect on HNPGL cell viability, whereas the specific PPARalpha antagonist GW6471 reduced HNPGL cell viability and growth by inducing cell cycle arrest and caspase-dependent apoptosis. GW6471 treatment was associated with a marked decrease of CDK4, cyclin D3 and cyclin B1 protein expression, along with an increased expression of p21 in HNPGL cells. Moreover, GW6471 drastically impaired clonogenic activity of HNPGL cells, with a less marked effect on cell migration. Notably, the effects of GW6471 on HNPGL cells were associated with the inhibition of the PI3K/GSK3beta/beta-catenin signaling pathway. In conclusion, the PPARalpha antagonist GW6471 reduces HNPGL cell viability, interfering with cell cycle and inducing apoptosis. The mechanisms affecting HNPGL cell viability involve repression of the PI3K/GSK3beta/beta catenin pathway. Therefore, PPARalpha could represent a novel therapeutic target for HNPGL. PMID- 28594936 TI - Climatic and drought characteristics in the loess hilly-gully region of China from 1957 to 2014. AB - The loess hilly-gully region is a focus region of the "Grain for Green" program in China. Drought is the main problem in the study region. Precipitation and temperature are two indicators that directly characterize climatic drought. A thorough analysis of the precipitation, temperature and drought characteristics of the loess hilly-gully region can clarify the current water and heat conditions in the region to improve regional water resource management and provide a reliable reference for effectively improving water use efficiency. In this study, we fully analyzed the precipitation and temperature characteristics at 11 representative synoptic stations in the loess hilly-gully region over the period from 1957 to 2014 using a combination of trend-free pre-whitening, linear trend estimation, Spearman's rho test, the Mann-Kendall (M-K) trend and abrupt change tests and wavelet analysis. The standardized precipitation evapotranspiration index was calculated and analyzed on different time scales. The following conclusions were drawn: (1) There were significant spatial differences and inter annual variations in precipitation at the 11 synoptic stations in the study area between 1957 and 2014; the precipitation consistently decreased with fluctuations, and the extent of the decrease varied from a maximum of 17.74 mm/decade to a minimum of 2.92 mm/decade. Except for the downward trends of the autumn and winter mean temperatures at Hequ, the seasonal and annual mean temperatures at the stations showed upward trends, including highly significant upward trends. (2) Alternating drought and wetness occurred in the study area; the wet period mainly appeared in the 1960s, and the main dry period lasted from the late 20th century to 2012. There were fewer dry and wet years than normal years; however, the study area still showed a drying trend, and the severity of the drought was increasing. (3) The annual precipitation and annual mean temperature showed marked cyclical fluctuations at each synoptic station, and the first primary cycle was approximately 28 years. The seasonal precipitation and seasonal temperature showed different cycle lengths; the seasonal cycles of precipitation for spring, summer, autumn and winter were 10, 28, 10 and 26 years long, respectively, and the cycles of the temperature fluctuations for all four seasons were approximately 28 years long. PMID- 28594935 TI - A nested case-control study of 277 prediagnostic serum cytokines and glioma. AB - Recent research shows bidirectional communication between the normal brain and the peripheral immune system. Glioma is a primary brain tumor characterized by systemic immunosuppression. To better understand gliomagenesis, we evaluated associations between 277 prediagnostic serum cytokines and glioma. We used glioma (n = 487) and matched control (n = 487) specimens from the Janus Serum Bank Cohort in Oslo, Norway. Conditional logistic regression allowed us to identify those cytokines that were individually associated with glioma. Next, we used heat maps to compare case to control Pearson correlation matrices of 12 cytokines modeled in an in silico study of the interaction between the microenvironment and the tumor. We did the same for case-control correlation matrices of lasso selected cytokines and all 277 cytokines in the data set. Cytokines related to glioma risk (P <= .05) more than 10 years before diagnosis are sIL10RB, VEGF, beta-Catenin and CCL22. LIF was associated with decreased glioma risk within five years before glioma diagnosis (odds ratio (OR) = 0.47, 95% confidence interval (CI) = 0.23, 0.94). After adjustment for cytokines above, the previously observed interaction between IL4 and sIL4RA persisted (> 20 years before diagnosis, OR = 1.72, 95% CI = 1.20, 2.47). In addition, during this period, case correlations among 12 cytokines were weaker than were those among controls. This pattern was also observed among 30 lasso- selected cytokines and all 277 cytokines. We identified four cytokines and one interaction term that were independently related to glioma risk. We have documented prediagnostic changes in serum cytokine levels that may reflect the presence of a preclinical tumor. PMID- 28594937 TI - Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending. PMID- 28594939 TI - Ambiguity in the processing of Mandarin Chinese relative clauses: One factor cannot explain it all. AB - This study addresses the question of whether native Mandarin Chinese speakers process and comprehend subject-extracted relative clauses (SRC) more readily than object-extracted relative clauses (ORC) in Mandarin Chinese. Presently, this has been a hotly debated issue, with various studies producing contrasting results. Using two eye-tracking experiments with ambiguous and unambiguous RCs, this study shows that both ORCs and SRCs have different processing requirements depending on the locus and time course during reading. The results reveal that ORC reading was possibly facilitated by linear/temporal integration and canonicity. On the other hand, similarity-based interference made ORCs more difficult, and expectation based processing was more prominent for unambiguous ORCs. Overall, RC processing in Mandarin should not be broken down to a single ORC (dis)advantage, but understood as multiple interdependent factors influencing whether ORCs are either more difficult or easier to parse depending on the task and context at hand. PMID- 28594938 TI - The enemy within: Targeting host-parasite interaction for antileishmanial drug discovery. AB - The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites' intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival. PMID- 28594941 TI - Low level laser (LLL) attenuate LPS-induced inflammatory responses in mesenchymal stem cells via the suppression of NF-kappaB signaling pathway in vitro. AB - BACKGROUND: Considering promising results in animal models and patients, therapeutic use of MSCs for immune disease is likely to undergo continued evaluation. Low-lever laser (LLL) has been widely applied to retard the inflammatory reaction. LLL treatment can potentially be applied in anti inflammatory therapy followed by stem cell therapy. AIM OF THE STUDY: The purpose of this study was to investigate the effect of LLL (660 nm) on the inflammatory reaction induced by LPS in human adipose derived mesenchymal stem cells (hADSCs) and pertinent mechanism. MATERIALS AND METHODS: Anti-inflammatory activity of LLL was investigated by LPS-induced mesenchymal stem cells. The production and expression of pro-inflammatory cytokines were evaluated by ELISA kits and RT qPCR. Nuclear translocation of NF-kappaB was indicated by immunofluorescent staining. Phosphorylation status of NF-kappaB p65 and IkappaBalpha were illustrated by western blot assay. ROS generation was measured with CM-H2DCFDA, and NO secretion was determined by DAF-FM. We studied surface expression of lymphocyte activation markers when Purified peripheral blood mononuclear cell (PBMC) were activated by phytohaemagglutinin (PHA) in the presence of 3 types of treated MSCs. RESULTS: LLL reduced the secretion of IL-1beta, IL-6, IL8, ROS and NO in LPS treated MSCs. Immunofluorescent assay demonstrated the nuclear translocation decrease of NF-kappaB in LLL treated LPS induced MSCs. Western blot analysis also suggested that LLL suppressed NF-kappaB activation via regulating the phosphorylation of p65 and IkappaBalpha. MSC significantly reduced the expression of activation markers CD25 and CD69 on PHA-stimulated lymphocytes. CONCLUSION: The results indicate that LLL suppressed the activation of NF-kappaB signaling pathway in LPS treated MSCs through inhibiting phosphorylation of p65 and IkappaBalpha, which results in good anti-inflammatory effect. In addition, LLL attenuated activation-associated markers CD25 and CD69 in co-cultures of PBMC and 3 types of treated MSCs. PMID- 28594942 TI - Potential distribution of mosquito vector species in a primary malaria endemic region of Colombia. AB - Rapid transformation of natural ecosystems changes ecological conditions for important human disease vector species; therefore, an essential task is to identify and understand the variables that shape distributions of these species to optimize efforts toward control and mitigation. Ecological niche modeling was used to estimate the potential distribution and to assess hypotheses of niche similarity among the three main malaria vector species in northern Colombia: Anopheles nuneztovari, An. albimanus, and An. darlingi. Georeferenced point collection data and remotely sensed, fine-resolution satellite imagery were integrated across the Uraba -Bajo Cauca-Alto Sinu malaria endemic area using a maximum entropy algorithm. Results showed that An. nuneztovari has the widest geographic distribution, occupying almost the entire study region; this niche breadth is probably related to the ability of this species to colonize both, natural and disturbed environments. The model for An. darlingi showed that most suitable localities for this species in Bajo Cauca were along the Cauca and Nechi river. The riparian ecosystems in this region and the potential for rapid adaptation by this species to novel environments, may favor the establishment of populations of this species. Apparently, the three main Colombian Anopheles vector species in this endemic area do not occupy environments either with high seasonality, or with low seasonality and high NDVI values. Estimated overlap in geographic space between An. nuneztovari and An. albimanus indicated broad spatial and environmental similarity between these species. An. nuneztovari has a broader niche and potential distribution. Dispersal ability of these species and their ability to occupy diverse environmental situations may facilitate sympatry across many environmental and geographic contexts. These model results may be useful for the design and implementation of malaria species-specific vector control interventions optimized for this important malaria region. PMID- 28594940 TI - The introduction of mesenchymal stromal cells induces different immunological responses in the lungs of healthy and M. tuberculosis infected mice. AB - Mesenchymal stromal cells (MSC) have strong immunomodulatory properties and therefore can be used to control inflammation and tissue damage. It was suggested recently that MSC injections can be used to treat multi-drug resistant tuberculosis (TB). However, MSC trafficking and immunomodulatory effects of MSC injections during Mycobacterium tuberculosis (Mtb) infection have not been studied. To address this issue we have analyzed MSC distribution in tissues and local immunological effects of MSC injections in Mtb infected and uninfected mice. After intravenous injection, MSC accumulated preferentially in the lungs where they were located as cell aggregates in the alveolar walls. Immunological analysis of MSC effects included detection of activated, IFN-gamma and IL-4 producing CD4+ lymphocytes, the frequency analysis of dendritic cells (CD11c+F4/80) and macrophages (CD11c-F4/80+) located in the lungs, the expression of IA/IE and CD11b molecules by these cells, and evaluation of 23 cytokines/chemokines in lung lysates. In the lungs of uninfected mice, MSC transfer markedly increased the percentage of IFN-gamma+ CD4+ lymphocytes and dendritic cells, elevated levels of IA/IE expression by dendritic cells and macrophages, augmented local production of type 2 cytokines (IL-4, IL-5, IL-10) and chemokines (CCL2, CCL3, CCL4, CCL5, CXCL1), and downregulated type 1 and hematopoietic cytokines (IL-12p70, IFN-gamma, IL-3, IL-6, GM-CSF). Compared to uninfected mice, Mtb infected mice had statistically higher "background" frequency of activated CD69+ and IFN-gamma+ CD4+ lymphocytes and dendritic cells, and higher levels of cytokines in the lungs. The injections of MSC to Mtb infected mice did not show statistically significant effects on CD4+ lymphocytes, dendritic cells and macrophages, only slightly shifted cytokine profile, and did not change pathogen load or slow down TB progression. Lung section analysis showed that in Mtb infected mice, MSC could not be found in the proximity of the inflammatory foci. Thus, in healthy recipients, MSC administration dramatically changed T-cell function and cytokine/chemokine milieu in the lungs, most likely, due to capillary blockade. But, during Mtb infection, i.e., in the highly inflammatory conditions, MSC did not affect T-cell function and the level of inflammation. The findings emphasize the importance of the evaluation of MSC effects locally at the site of their predominant post-injection localization and question MSC usefulness as anti-TB treatment. PMID- 28594943 TI - Childhood cancer risk in those with chromosomal and non-chromosomal congenital anomalies in Washington State: 1984-2013. AB - BACKGROUND: The presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies. METHODS: Records of children diagnosed with cancer at <20 years of age during 1984-2013 in Washington State cancer registries were linked to their birth certificates (N = 4,105). A comparison group of children born in the same years was identified. Congenital anomalies were assessed from birth records and diagnosis codes in linked hospital discharge data. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for cancer, and for specific cancer types in relation to the presence of any anomaly and specific anomalies. RESULTS: Having any congenital anomaly was associated with an increased risk of childhood cancer (OR: 1.46, 95% CI 1.28-1.65). Non-chromosomal anomalies were also associated with increased childhood cancer risk overall (OR: 1.35; 95% CI: 1.18-1.54), and with increased risk of several cancer types, including neuroblastoma, renal, hepatoblastoma, soft-tissue sarcoma, and germ cell tumors. Increasing number of non-chromosomal anomalies was associated with a stronger risk of childhood cancer (OR for 3+ anomalies: 3.11, 95% CI: 1.54-6.11). Although central nervous system (CNS) anomalies were associated with CNS tumors (OR: 6.05, 95% CI 2.75-13.27), there was no strong evidence of other non-chromosomal anomalies being specifically associated with cancer occurring in the same organ system or anatomic location. CONCLUSIONS: Non-chromosomal anomalies increased risk of several cancer types. Additionally, we found that increasing number of non chromosomal anomalies was associated with a stronger risk of cancer. Pooling similar data from many regions would increase power to identify specific associations in order to inform molecular studies examining possible common developmental pathways in the etiologies of birth defects and cancer. PMID- 28594944 TI - Development and evaluation of a core genome multilocus typing scheme for whole genome sequence-based typing of Acinetobacter baumannii. AB - We have employed whole genome sequencing to define and evaluate a core genome multilocus sequence typing (cgMLST) scheme for Acinetobacter baumannii. To define a core genome we downloaded a total of 1,573 putative A. baumannii genomes from NCBI as well as representative isolates belonging to the eight previously described international A. baumannii clonal lineages. The core genome was then employed against a total of fifty-three carbapenem-resistant A. baumannii isolates that were previously typed by PFGE and linked to hospital outbreaks in eight German cities. We defined a core genome of 2,390 genes of which an average 98.4% were called successfully from 1,339 A. baumannii genomes, while Acinetobacter nosocomialis, Acinetobacter pittii, and Acinetobacter calcoaceticus resulted in 71.2%, 33.3%, and 23.2% good targets, respectively. When tested against the previously identified outbreak strains, we found good correlation between PFGE and cgMLST clustering, with 0-8 allelic differences within a pulsotype, and 40-2,166 differences between pulsotypes. The highest number of allelic differences was between the isolates representing the international clones. This typing scheme was highly discriminatory and identified separate A. baumannii outbreaks. Moreover, because a standardised cgMLST nomenclature is used, the system will allow inter-laboratory exchange of data. PMID- 28594945 TI - Participatory evaluation of delivery of animal health care services by community animal health workers in Karamoja region of Uganda. AB - AIM: An evaluation exercise was carried out to assess the performance of Community Animal Health Workers (CAHWs) in the delivery of animal health care services in Karamoja region, identify capacity gaps and recommend remedial measures. MATERIALS & METHODS: Participatory methods were used to design data collection tools. Questionnaires were administered to 204 CAHWs, 215 farmers and 7 District Veterinary Officers (DVOs) to collect quantitative data. Seven DVOs and 1 Non Government Organization (NGO) representative were interviewed as key informants and one focus group discussion was conducted with a farmer group in Nakapiripirit to collect qualitative data. Questionnaire data was analyzed using SPSS version 19. Key messages from interviews and the focus group discussion were recorded in a notebook and reported verbatim. RESULTS: 70% of the farmers revealed that CAHWs are the most readily available animal health care service providers in their respective villages. CAHWs were instrumental in treatment of sick animals, disease surveillance, control of external parasites, animal production, vaccination, reporting, animal identification, and performing minor surgeries. Regarding their overall performance 88.8%(191/215) of the farmers said they were impressed. The main challenges faced by the CAHWs were inadequate facilitation, lack of tools and equipments, unwillingness of government to integrate them into the formal extension system, poor information flow, limited technical capacity to diagnose diseases, unwillingness of farmers to pay for services and sustainability issues. CONCLUSIONS AND RECOMMENDATIONS: CAHWs remain the main source of animal health care services in Karamoja region and their services are largely satisfactory. The technical deficits identified require continuous capacity building programs, close supervision and technical backstopping. For sustainability of animal health care services in the region continuous training and strategic deployment of paraprofessionals that are formally recognised by the traditional civil service to gradually replace CAHWs is recommended. PMID- 28594946 TI - Association of vaginal dysbiosis and biofilm with contraceptive vaginal ring biomass in African women. AB - We investigated the presence, density and bacterial composition of contraceptive vaginal ring biomass and its association with the vaginal microbiome. Of 415 rings worn by 120 Rwandese women for three weeks, the biomass density was assessed with crystal violet and the bacterial composition of biomass eluates was assessed with quantitative polymerase chain reaction (qPCR). The biomass was visualised after fluorescence in situ hybridisation (FISH) and with scanning electron microscopy (SEM). The vaginal microbiome was assessed with Nugent scoring and vaginal biofilm was visualised after FISH. All vaginal rings were covered with biomass (mean optical density (OD) of 3.36; standard deviation (SD) 0.64). Lactobacilli were present on 93% of the rings, Gardnerella vaginalis on 57%, and Atopobium vaginae on 37%. The ring biomass density was associated with the concentration of A. vaginae (OD +0.03; 95% confidence interval (CI) 0.01-0.05 for one log increase; p = 0.002) and of G. vaginalis (OD +0.03; (95% CI 0.01 0.05; p = 0.013). The density also correlated with Nugent score: rings worn by women with a BV Nugent score (mean OD +0.26), and intermediate score (mean OD +0.09) had a denser biomass compared to rings worn by participants with a normal score (p = 0.002). Furthermore, presence of vaginal biofilm containing G. vaginalis (p = 0.001) and A. vaginae (p = 0.005) correlated with a denser ring biomass (mean OD +0.24 and +0.22 respectively). With SEM we observed either a loose network of elongated bacteria or a dense biofilm. We found a correlation between vaginal dysbiosis and the density and composition of the ring biomass, and further research is needed to determine if these relationships are causal. As multipurpose vaginal rings to prevent pregnancy, HIV, and other sexually transmitted diseases are being developed, the potential impact of ring biomass on the vaginal microbiota and the release of active pharmaceutical ingredients should be researched in depth. PMID- 28594947 TI - Mass spectrometry-based serum peptidome profiling accurately and reliably predicts outcomes of pemetrexed plus platinum chemotherapy in patients with advanced lung adenocarcinoma. AB - BACKGROUND: Although pemetrexed plus cis/carboplatin has become the most effective chemotherapy regimen for patients with advanced lung adenocarcinoma, predictive biomarkers are not yet available, and new tools to identify chemosensitive patients who would likely benefit from this treatment are desperately needed. In this study, we constructed and validated predictive peptide models using the serum peptidome profiles of two datasets. METHODS: One hundred eighty-three patients treated with first-line platinum-based pemetrexed treatment for advanced lung adenocarcinoma were retrospectively enrolled and randomized into the training (n = 92) or validation (n = 91) set, and pre treatment serum samples were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Serum peptidome profiles from the training set were used to identify potential predictive peptide biomarkers and construct a predictive peptide model for accurate group discrimination; which was then used to classify validation samples into "good" and "poor" outcome groups. The clinical outcomes of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed based on the classification result. RESULTS: Eight potential peptide biomarkers were identified. A predictive peptide model based on four distinct m/z features (2,142.12, 3,316.19, 4,281.94, and 6,624.02 Da) was developed based on the clinical outcomes of training set patients after first-line pemetrexed plus platinum treatment. In the validation set, the good group had significantly higher ORR (49.1% vs. 8.3%, P <0.001) and DCR (96.4% vs. 47.2%, P <0.001), and longer PFS (7.3 months vs. 2.7 months, P <0.001) vs. the poor group. However, the model did not predict OS (13.6 months vs. 12.7 months, P = 0.0675). CONCLUSION: Our predictive peptide model could predict pemetrexed plus platinum treatment outcomes in patients with advanced lung adenocarcinoma and might thus facilitate appropriate patient selection. Further studies are needed to confirm these findings. PMID- 28594949 TI - The nutrition and health risks faced by pregnant adolescents: Insights from a cross-sectional study in Bangladesh. AB - Little is known about nutrition and well-being indicators of pregnant adolescents and the availability and use of nutrition interventions delivered through maternal, newborn, and child health (MNCH) programs. This study compared the differences between pregnant adolescents and adult pregnant women in services received, and in maternal and child nutrition and health conditions. A survey of 2,000 recently delivered women with infants <6 months of age was carried out in 20 sub-districts in Bangladesh where MNCH program is being implemented. Differences in service use and outcomes between pregnant adolescents and adult women were tested using multivariate regression models. The coverage of antenatal care and nutrition services was similar for adolescent and adult mothers. Compared to adult mothers, adolescent mothers had significantly fewer ownership of assets and lower decision making power. Adolescent mothers weighed significantly less than adult women (45.8 vs 47.1 kg, p = 0.001), and their body mass index was significantly lower (19.7 vs 21.3, p = 0.001). Adolescents recovered later and with greater difficulty after childbirth. Infants of adolescent mothers had significant lower height-for-age z-score (-0.89 vs -0.74, p = 0.04), lower weight-for age z-score (-1.21 vs -1.08, p = 0.02) and higher underweight prevalence (22.4% vs 17.9%, p = 0.04) compared to infants of adult women. In conclusion, this study confirms that adolescent pregnancy poses substantial risks for maternal and infant outcomes, and emphasizes that these risks are significant even where services during pregnancy are available and accessed. A focus on preventing adolescent pregnancy is imperative, while also strengthening health and nutrition services for all pregnant women, whether adult or adolescent. PMID- 28594948 TI - Easy and non-invasive disease detection in pigs by adenosine deaminase activity determinations in saliva. AB - The quantification of adenosine deaminase (ADA) in porcine saliva samples has been analyzed for its use as a marker of disease. First, an analytical validation of the enzymatic assay used for ADA measurements was performed. Afterwards, saliva samples were collected from 50 healthy animals and 64 animals with different symptoms of disease, which were divided into local inflammation, gastrointestinal disorder, respiratory disorder and growth retardation. To optimize ADA measurements, total ADA (tADA), specific ADA (sADA) and ADA isoforms 1 and 2 activities were calculated. Moreover, to preliminarily estimate the diagnostic value of tADA activity measurements for disease detection, receiver operating characteristic (ROC) analyses was performed and compared to the results obtained for salivary acute phase proteins, haptoglobin (Hp) and C-reactive protein (CRP). The salivary levels of tADA activity were significantly elevated in animals with local inflammation, gastrointestinal disorder and respiratory disorder. The calculation of the different ADA activities did not provide additional information to tADA activity quantification for disease detection. The diagnostic value of tADA activity was superior to those observed for Hp and CRP measurements in the present study. It might be concluded that ADA analysis in saliva could be used as a simple, rapid, economic and non-invasive diagnostic tool in porcine production in field conditions. PMID- 28594950 TI - Association between computed tomography obstruction index and mortality in elderly patients with acute pulmonary embolism: A prospective validation study. AB - INTRODUCTION: Computed tomography pulmonary angiography (CTPA) has not only become the method of choice for diagnosing acute pulmonary embolism (PE), it also allows for risk stratification of patients with PE. To date, no study has specifically examined the predictive value of CTPA findings to assess short-term prognosis in elderly patients with acute PE who are particularly vulnerable to adverse outcomes. METHODS: We studied 291 patients aged >=65 years with acute symptomatic PE in a prospective multicenter cohort. Outcomes were 90-day overall and PE-related mortality, recurrent venous thromboembolism (VTE), and length of hospital stay (LOS). We examined associations of the computed tomography obstruction index (CTOI) and the right ventricular (RV) to left ventricular (LV) diameter ratio with mortality and VTE recurrence using survival analysis, adjusting for provoked VTE, Pulmonary Embolism Severity Index (PESI), and anticoagulation as a time-varying covariate. RESULTS: Overall, 15 patients died within 90 days. There was no association between the CTOI and 90-day overall mortality (adjusted hazard ratio per 10% CTOI increase 0.92; 95% confidence interval [CI] 0.70-1.21; P = 0.54), but between the CTOI and PE-related 90-day mortality (adjusted sub-hazard ratio per 10% CTOI increase 1.36; 95% CI 1.03 1.81; P = 0.03). The RV/LV diameter ratio was neither associated with overall nor PE-related 90-day mortality. The CTOI and the RV/LV diameter ratio were significantly associated with VTE recurrence and LOS. CONCLUSIONS: In elderly patients with acute PE, the CTOI was associated with PE-related 90-day mortality but not with overall 90-day mortality. The RV/LV diameter ratio did not predict mortality. Both measures predicted VTE recurrence and LOS. The evaluated CTPA findings do not appear to offer any advantage over the PESI in terms of mortality prediction. PMID- 28594951 TI - Transcriptome profiling analysis reveals the role of silique in controlling seed oil content in Brassica napus. AB - Seed oil content is an important agronomic trait in oilseed rape. However, the molecular mechanism of oil accumulation in rapeseeds is unclear so far. In this report, RNA sequencing technique (RNA-Seq) was performed to explore differentially expressed genes in siliques of two Brassica napus lines (HFA and LFA which contain high and low oil contents in seeds, respectively) at 15 and 25 days after pollination (DAP). The RNA-Seq results showed that 65746 and 66033 genes were detected in siliques of low oil content line at 15 and 25 DAP, and 65236 and 65211 genes were detected in siliques of high oil content line at 15 and 25 DAP, respectively. By comparative analysis, the differentially expressed genes (DEGs) were identified in siliques of these lines. The DEGs were involved in multiple pathways, including metabolic pathways, biosynthesis of secondary metabolic, photosynthesis, pyruvate metabolism, fatty metabolism, glycophospholipid metabolism, and DNA binding. Also, DEGs were related to photosynthesis, starch and sugar metabolism, pyruvate metabolism, and lipid metabolism at different developmental stage, resulting in the differential oil accumulation in seeds. Furthermore, RNA-Seq and qRT-PCR data revealed that some transcription factors positively regulate seed oil content. Thus, our data provide the valuable information for further exploring the molecular mechanism of lipid biosynthesis and oil accumulation in B. nupus. PMID- 28594952 TI - Age and axial length on peripapillary retinal nerve fiber layer thickness measured by optical coherence tomography in nonglaucomatous Taiwanese participants. AB - PURPOSE: This study investigates the influence of age and axial length (AL) on the peripapillary retinal nerve fiber layer (RNFL) thickness, as measured by optical coherence tomography (OCT). METHODS: Healthy patients visiting an eye clinic at a county hospital were recruited. All participants underwent comprehensive ophthalmologic examinations, and their retinas were scanned using 3D OCT-1000. In total, 223 patients with 446 eyes were included. The mean age and AL were 42.07 +/- 13.16 (21-76) years and 25.38 +/- 1.73 (21.19-30.37) mm, respectively. RESULTS: The average RNFL thickness decreased by 2.71 MUm for every 10-year increase in age (P < 0.001). Age-related RNFL thinning was more significant in participants older than 41 years (-0.24MUm/year; P = 0.015). The earliest sector showing a significant decline in RNFL thickness was after 35 years of age (-0.70MUm/year; P = 0.011) at the superior quadrant and at the 1-2 o'clock hour (-1.42MUm/year; P = 0.009). Meanwhile, the maximal rate of age associated RNFL decay was observed in these two regions as well. The reduction of RNFL with age progression did not differ in eyes with long AL (> 27 mm; 0.16MUm/year) or those with short AL (< 25 mm; -0.22MUm/year). For every 1-mm greater AL, RNFL was thinner by 1.78 MUm (P < 0.001). The inferior quadrant showed the greatest tendency of RNFL decline with longer AL (4.46 MUm/mm; P < 0.001). CONCLUSIONS: The factors of age and AL should be considered when interpreting the results. Significantly age-associated RNFL thinning was found in participants older than 41 years. Reduction of RNFL thickness with increasing age was not affected by AL. Topographic variations in RNFL thinning were observed in that the maximal decline of RNFL thickness with advancing age at the superior quadrant whereas with elongation of AL at the inferior quadrant. PMID- 28594953 TI - Non-invasive genetics outperforms morphological methods in faecal dietary analysis, revealing wild boar as a considerable conservation concern for ground nesting birds. AB - Capercaillie (Tetrao urogallus) and other grouse species represent conservation concerns across Europe due to their negative abundance trends. In addition to habitat deterioration, predation is considered a major factor contributing to population declines. While the role of generalist predators on grouse predation is relatively well known, the impact of the omnivorous wild boar has remained elusive. We hypothesize that wild boar is an important predator of ground-nesting birds, but has been neglected as a bird predator because traditional morphological methods underestimate the proportion of birds in wild boar diet. To distinguish between different mammalian predator species, as well as different grouse prey species, we developed a molecular method based on the analysis of mitochondrial DNA that allows accurate species identification. We collected 109 wild boar faeces at protected capercaillie leks and surrounding areas and analysed bird consumption using genetic methods and classical morphological examination. Genetic analysis revealed that the proportion of birds in wild boar faeces was significantly higher (17.3%; 4.5*) than indicated by morphological examination (3.8%). Moreover, the genetic method allowed considerably more precise taxonomic identification of consumed birds compared to morphological analysis. Our results demonstrate: (i) the value of using genetic approaches in faecal dietary analysis due to their higher sensitivity, and (ii) that wild boar is an important predator of ground-nesting birds, deserving serious consideration in conservation planning for capercaillie and other grouse. PMID- 28594954 TI - The monoclonal S9.6 antibody exhibits highly variable binding affinities towards different R-loop sequences. AB - The monoclonal antibody S9.6 is a widely-used tool to purify, analyse and quantify R-loop structures in cells. A previous study using the surface plasmon resonance technology and a single-chain variable fragment (scFv) of S9.6 showed high affinity (0.6 nM) for DNA-RNA and also a high affinity (2.7 nM) for RNA-RNA hybrids. We used the microscale thermophoresis method allowing surface independent interaction studies and electromobility shift assays to evaluate additional RNA-DNA hybrid sequences and to quantify the binding affinities of the S9.6 antibody with respect to distinct sequences and their GC-content. Our results confirm high affinity binding to previously analysed sequences, but reveals that binding affinities are highly sequence specific. Our study presents R-loop sequences that independent of GC-content and in different sequence variations exhibit either no binding, binding affinities in the micromolar range and as well high affinity binding in the nanomolar range. Our study questions the usefulness of the S9.6 antibody in the quantitative analysis of R-loop sequences in vivo. PMID- 28594955 TI - Inorganic salts and intracellular polyphosphate inclusions play a role in the thermotolerance of the immunobiotic Lactobacillus rhamnosus CRL 1505. AB - In this work, the thermotolerance of Lactobacillus rhamnosus CRL1505, an immunobiotic strain, was studied as a way to improve the tolerance of the strain to industrial processes involving heat stress. The strain displayed a high intrinsic thermotolerance (55 degrees C, 20 min); however, after 5 min at 60 degrees C in phosphate buffer a two log units decrease in cell viability was observed. Different heat shock media were tested to improve the cell survival. Best results were obtained in the mediumcontaining inorganic salts (KH2PO4, Na2HPO4, MnSO4, and MgSO4) likely as using 10% skim milk. Flow cytometry analysis evinced 25.0% live cells and a large number of injured cells (59.7%) in the inorganic salts medium after heat stress. The morphological changes caused by temperature were visualized by transmission electronic microscopy (TEM). In addition, TEM observations revealed the presence of polyphosphate (polyP) granules in the cells under no-stress conditions. A DAPI-based fluorescence technique, adjusted to Gram-positive bacteria for the first time, was used to determine intracellular polyP levels. Results obtained suggest that the high initial polyP content in L. rhamnosus CRL 1505 together with the presence of inorganic salts in the heat shock medium improve the tolerance of the cells to heat shock. To our knowledge, this is the first report giving evidence of the relationship between polyP and inorganic salts in thermotolerance of lactic acid bacteria. PMID- 28594956 TI - Candidate odorant binding proteins and chemosensory proteins in the larval chemosensory tissues of two closely related noctuidae moths, Helicoverpa armigera and H. assulta. AB - In order to acquire enough nutrients and energy for further development, larvae need to invest a large portion of their sensory equipments to identify food sources. Yet, the molecular basis of odor-driven behavior in larvae has been poorly investigated. Information on olfactory genes, particularly odorant binding proteins (OBPs) and chemosensory proteins (CSPs) which are involved in the initial steps of olfaction is very scarce. In this study, we have identified 26 OBP and 21 CSP genes from the transcriptomes of Helicoverpa armigera larval antennae and mouthparts. A comparison with the 34 OBP and 18 CSP genes of the adult antenna, revealed four novel OBPs and seven novel CSPs. Similarly, 27 OBPs (six novel OBPs) and 20 CSPs (6 novel CSPs) were identified in the transcriptomes of Helicoverpa assulta larval antennae and mouthparts. Tissue-specific profiles of these soluble proteins in H. armigera showed that 6 OBP and 4 CSP genes are larval tissue-specific, 15 OBPs and 13 CSPs are expressed in both larvae and adult, while the rest are adult- specific. Our data provide useful information for functional studies of genes involved in larval foraging. PMID- 28594958 TI - The effects of different frequency treadmill exercise on lipoxin A4 and articular cartilage degeneration in an experimental model of monosodium iodoacetate-induced osteoarthritis in rats. AB - The aim was to investigate the effects of different frequencies treadmill exercise with total exercise time being constancy on articular cartilage, lipoxin A4 (LXA4) and the NF-kappaB pathway in rat model of monosodium iodoacetate induced osteoarthritis (OA). Fifty male Sprague-Dawley rats were randomly divided into five groups (n = 10): controls (CG), knee OA model (OAG), OA + treadmill exercise once daily (OAE1), OA + treadmill exercise twice daily, rest interval between exercise>4h (OAE2) and OA + treadmill exercise three times daily, rest interval between exercise>4h (OAE3). Rats were evaluated after completing the treadmill exercise program (speed, 18 m/min; total exercise time 60 min/day; 5 days/week for 8 weeks). Interleukin (IL)-1beta, tumor necrosis factor (TNF) alpha, and LXA4 in serum and intra-articular lavage fluid were measured by ELISA. Changes in articular cartilage were evaluated by histology, immunohistochemistry, western blotting and quantitative real-time-PCR. LXA4 in the serum and intra articular lavage fluid increased in all OAE groups, and histological evaluation indicated that the OAE3 group had the best treatment response. The expression of COL2A1 and IkappaB-beta in articular cartilage increased in all OAE groups vs the OAG group, whereas expression of IL-1beta, TNF-alpha, matrix metalloproteinase (MMP)-13, and NF-kappaB p65 was reduced in all OAE groups compared with the OAG. Under the condition of 60 min treadmill exercise with moderate-intensity, to fulfill in three times would have better chondroprotective effects than to fulfill in two or one time on monosodium iodoacetate-induced OA in rats. And it may be worked through the anti-inflammatory activity of LXA4 and the NF-kappaB pathway. PMID- 28594957 TI - Distinctive features and differential regulation of the DRTS genes of Arabidopsis thaliana. AB - In plants and protists, dihydrofolate reductase (DHFR) and thymidylate synthase (TS) are part of a bifunctional enzyme (DRTS) that allows efficient recycling of the dihydrofolate resulting from TS activity. Arabidopsis thaliana possesses three DRTS genes, called AtDRTS1, AtDRTS2 and AtDRTS3, that are located downstream of three members of the sec14-like SFH gene family. In this study, a characterization of the AtDRTS genes identified alternatively spliced transcripts coding for AtDRTS isoforms which may account for monofunctional DHFR enzymes supporting pathways unrelated to DNA synthesis. Moreover, we discovered a complex differential regulation of the AtDRTS genes that confirms the expected involvement of the AtDRTS genes in cell proliferation and endoreduplication, but indicates also functions related to other cellular activities. AtDRTS1 is widely expressed in both meristematic and differentiated tissues, whereas AtDRTS2 expression is almost exclusively limited to the apical meristems and AtDRTS3 is preferentially expressed in the shoot apex, in stipules and in root cap cells. The differential regulation of the AtDRTS genes is associated to distinctive promoter architectures and the expression of AtDRTS1 in the apical meristems is strictly dependent on the presence of an intragenic region that includes the second intron of the gene. Upon activation of cell proliferation in germinating seeds, the activity of the AtDRTS1 and AtDRTS2 promoters in meristematic cells appears to be maximal at the G1/S phase of the cell cycle. In addition, the promoters of AtDRTS2 and AtDRTS3 are negatively regulated through E2F cis-acting elements and both genes, but not AtDRTS1, are downregulated in plants overexpressing the AtE2Fa factor. Our study provides new information concerning the function and the regulation of plant DRTS genes and opens the way to further investigations addressing the importance of folate synthesis with respect to specific cellular activities. PMID- 28594959 TI - Reduced total serum bilirubin levels are associated with ulcerative colitis. AB - Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. Low levels of serum bilirubin, an endogenous antioxidant, have been associated with increased risk for Crohn's disease (CD). Therefore, the aim of this study was to examine whether total serum bilirubin levels are associated with ulcerative colitis (UC). We identified a retrospective case-control population (n = 6,649) from a single tertiary care center, Penn State Hershey Medical Center (PSU) and a validation cohort (n = 1,996) from Virginia Commonwealth University Medical Center (VCU). Cases were age- and sex-matched to controls (PSU: CD n = 254, UC n = 187; VCU: CD n = 233, UC n = 124). Total serum bilirubin levels were obtained from de-identified medical records and segregated into quartiles. Logistic regression analysis was performed on each quartile of total serum bilirubin compared to the last quartile (highest bilirubin levels) to determine the association of total serum bilirubin with UC. Similar to CD patients, UC patients demonstrated reduced levels of total serum bilirubin compared to controls at PSU and VCU. The lowest quartile of total serum bilirubin was independently associated with UC for the PSU (OR: 1.98 [95% CI: 1.09-3.63]) and VCU cohorts (OR: 6.07 [95% CI: 3.01-12.75]). Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. Therapeutics that reduce oxidative stress may be beneficial for these patients. PMID- 28594960 TI - A portable image-based cytometer for rapid malaria detection and quantification. AB - Increasing resistance by malaria parasites to currently used antimalarials across the developing world warrants timely detection and classification so that appropriate drug combinations can be administered before clinical complications arise. However, this is often challenged by low levels of infection (referred to as parasitemia) and presence of predominantly young parasitic forms in the patients' peripheral blood. Herein, we developed a simple, inexpensive and portable image-based cytometer that detects and numerically counts Plasmodium falciparum infected red blood cells (iRBCs) from Giemsa-stained smears derived from infected blood. Our cytometer is able to classify all parasitic subpopulations by quantifying the area occupied by the parasites within iRBCs, with high specificity, sensitivity and negligible false positives (~ 0.0025%). Moreover, we demonstrate the application of our image-based cytometer in testing anti-malarial efficacy against a commercial flow cytometer and demonstrate comparable results between the two methods. Collectively, these results highlight the possibility to use our image-based cytometer as a cheap, rapid and accurate alternative for antimalarial testing without compromising on efficiency and minimal processing time. With appropriate filters applied into the algorithm, to rule out leukocytes and reticulocytes, our cytometer may also be used for field diagnosis of malaria. PMID- 28594963 TI - Biosimilars-Curb Your Enthusiasm. PMID- 28594962 TI - Effects of bilateral anterior agranular insula lesions on food anticipatory activity in rats. AB - Food anticipatory activity (FAA) refers to a daily rhythm of locomotor activity that emerges under conditions of food restriction, whereby animals develop an intense, predictable period of activity in the few hours leading up to a predictable, daily delivery of food. The neural mechanisms by which FAA is regulated are not yet fully understood. Although a number of brain regions appear to be involved in regulating the development and expression of FAA, there is little evidence to date concerning the role of the anterior agranular insular cortex (AICa). The AICa plays a critical role in integrating the perception of visceral states with motivational behaviour such as feeding. We assessed the effect of bilateral electrolytic or ibotenic acid lesions of the AICa on FAA in male Wistar rats receiving food for varying lengths of time (2 h, 3 h, or 5 h) during the middle of the light phase (starting at either ZT4 or ZT6). Contrary to our initial expectations, we found that both electrolytic and ibotenic acid lesions significantly increased, rather than decreased, the amount of FAA expressed in lesioned rats. Despite increased FAA, lesioned rats did not eat significantly more during restricted feeding (RF) periods than control rats. Similar to controls, AlCa-lesioned rats showed negligible anticipatory activity to a restricted treat suggesting that the increased anticipatory activity in lesioned rats is associated with food restriction, rather than the appetitive value of the meal. Monitoring behaviour in an open field indicated that increased FAA in AlCa-lesioned rats was not explained by a general increase in locomotor activity. Together, these findings suggest that the AICa contributes to the network of brain regions involved in FAA. PMID- 28594964 TI - Vitamin D and Breast Cancer Survival-In Reply. PMID- 28594961 TI - PirB regulates asymmetries in hippocampal circuitry. AB - Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRepsilon2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of epsilon2 subunits, we previously found that beta2-microglobulin deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB), an MHCI receptor. As in beta2 microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry. PMID- 28594965 TI - Vitamin D and Breast Cancer Survival: The Good and the Bad. PMID- 28594967 TI - Response: Lack of osteopathic component in Anxiety supplement. PMID- 28594968 TI - Response 2: Lack of osteopathic component in Anxiety supplement. PMID- 28594970 TI - CME Quiz Answers. PMID- 28594972 TI - AACOM update: Graduate medical education concerns in light of OPTI. PMID- 28594971 TI - CME Quiz. PMID- 28594973 TI - Patient Coauthored History Could Improve Health Record Accuracy. PMID- 28594975 TI - Missing Source Credit for Figure and Table. PMID- 28594974 TI - Association Between Prognosis and Tumor Laterality in Early-Stage Colon Cancer. AB - Importance: Recent data have suggested that disease biology and outcome of colon cancer may differ between right-sided and left-sided tumors. However, the literature on the prognostic value of tumor laterality is conflicting. Objective: To explore differences in laterality based on disease characteristics and outcomes in a population-based cohort of early-stage colon cancer. Design, Setting, and Participants: This investigation was a population-based retrospective cohort study of patients with early-stage colon cancer from the province of Ontario, Canada. Electronic records of treatment were linked to the Ontario Cancer Registry to identify all patients with colon cancer who underwent resection between January 1, 2002, and December 31, 2008. The date of the final analysis was October 20, 2016. The study population included a 25% random sample of all patients with resected stage I to III disease. Right-sided colon cancer was defined as any tumor arising in the cecum, ascending colon, hepatic flexure, or transverse colon. Left-sided colon cancer was defined as any tumor arising in the splenic flexure, descending colon, sigmoid colon, or rectosigmoid colon. Main Outcomes and Measures: Overall survival (OS) and cancer-specific survival (CSS) measured from the time of resection. Results: This study identified 6365 patients with early-stage colon cancer (48.7% [3098 of 6365] female). Their median age was 72 years, and 51.7% (3291 of 6365) had right-sided disease. Stage distribution was 18.3% (1163 of 6365) stage I, 38.4% (2446 of 6365) stage II, and 43.3% (2756 of 6365) stage III. Patients with right-sided colon cancer were more likely to be older (median age, 73 vs 70 years; P < .001) and female (54.4% [1790 of 3291] vs 42.6% [1308 of 3074], P < .001) and have greater comorbidity. Right-sided cancers were more likely to be T4 (19.2% [631 of 3291] vs 15.9% [490 of 3074], P < .001) and poorly differentiated (21.1% [695 of 3291] vs 9.6% [295 of 3074], P < .001) but less likely to be node positive (42.0% [1383 of 3291] vs 44.7% [1373 of 3074], P = .03) compared with left-sided disease. In adjusted analyses, there was no difference in long-term survival for right-sided compared with left-sided colon cancer: the hazard ratios were 1.00 (95% CI, 0.92-1.08) for OS and 1.00 (95% CI, 0.91-1.10) for CSS. These results were consistent when the survival analyses were restricted to stage III disease: the hazard ratios were 1.03 (95% CI, 0.93-1.14) for OS and 1.10 (95% CI, 0.97-1.24) for CSS. Conclusions and Relevance: In this population-based cohort of early-stage resected colon cancer, disease laterality was not associated with long-term OS or CSS. PMID- 28594976 TI - Patient-Reported Outcome Measures in Upper Airway-Related Dyspnea: A Systematic Review. AB - Importance: Patient-reported outcome (PRO) measures address the need for patient centered data and are now used in diverse clinical, research, and policy pursuits. They are important in conditions causing upper airway-related dyspnea in which the patient's reported experience and physiological data can be discrepant. Objectives: To perform a systematic review of the literature on upper airway dyspnea-related PRO measures and to rigorously evaluate each measure's developmental properties, validation, and applicability. Evidence Review: This study strictly adhered to Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. MEDLINE via the PubMed interface, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), and the Health and Psychosocial Instruments (HaPI) database were searched using relevant vocabulary terms and key terms related to PRO measures and upper airway-related dyspnea. Three investigators performed abstract review, and 2 investigators independently performed full-text review by applying an established checklist to evaluate the conceptual model, content validity, reliability, construct validity, scoring and interpretability, and respondent burden and presentation of each identified instrument. The initial literature search was conducted in November 2014 and was updated in April 2016. Findings: Of 1269 studies reviewed, 3 upper airway-related dyspnea PRO measures met criteria for inclusion. One PRO measure was designed de novo to assess upper airway-related dyspnea symptoms and monitor treatment outcomes, while 2 were adapted from established instruments designed for lower airway disease. Measurement properties and psychometric characteristics differed, and none met all checklist criteria. Two met a criterion in each of 7 domains evaluated. Two demonstrated test-retest and internal consistency reliability, and 2 showed that their scores were responsive to change. Thematic deficiencies in current upper airway-related dyspnea PRO measures are lack of patient involvement in item development (content validity), plan for interpretation, and literacy level assessments. Conclusions and Relevance: PRO measures are critical in the assessment of patients with upper airway-related dyspnea. Three instruments with disparate developmental rigor have been designed or adapted to assess this construct. Care must be taken to understand the measurement characteristics and contextual relevance before applying these PRO measures for clinical, research, or quality initiatives. PMID- 28594977 TI - Association of Glaucoma-Related, Optical Coherence Tomography-Measured Macular Damage With Vision-Related Quality of Life. AB - Importance: Little is known about the association between structural macular damage and self-reported visual function of people with glaucoma. Objective: To determine the association between vision-related quality of life among patients with primary open-angle glaucoma with structural macular retinal ganglion cell plus inner plexiform layer (RGC+IPL) loss identified by spectral-domain optical coherence tomography (SD-OCT) machine-generated deviation maps and thickness measurements. Design, Setting, and Participants: This cross-sectional prospective study was conducted from March 1, 2014, to March 30, 2015, at the Department of Ophthalmology at Columbia University Medical Center. The participants were 107 patients who were enrolled in the study and represented the entire range of glaucomatous damage. All 214 eyes of the 107 participants underwent 10-2 visual field tests and SD-OCT scans, and all participants completed the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). They also received ophthalmologic examination, including medical history review, best-corrected visual acuity, slitlamp biomicroscopy, intraocular pressure measurement, gonioscopy, dilated ophthalmoscopy, and standard automated perimetry. Macular RGC+IPL loss was determined by diffuse or focal patterns on SD-OCT-generated deviation maps (probability map that compared patients with aged-matched normative database) and thickness measurements. Main Outcomes and Measures: Regression analyses to assess the association of NEI VFQ-25 scores (score range: 41.9-99.5; higher scores indicate better functioning) with patterns of RGC+IPL loss and with RGC+IPL thickness measurements. Results: Of the 107 patients, 48 (45%) were men and the mean (SD) age was 65 (11) years. The self-reported race/ethnicity of participants consisted of 45 (46%) black, 47 (48%) white, and 6 (6%) "other" individuals. In the univariable analyses, patients with diffuse macular RGC+IPL loss had mean composite Rasch-calibrated NEI VFQ-25 scores that were 6.15 points lower than the scores of patients with focal damage (beta = 6.15; 95% CI, -11.7 to -0.59; P = .03). The effect remained significant even after controlling for mean RGC+IPL thickness (beta = -7.64; 95% CI, -14.2 to 1.03; P = .02). Conclusions and Relevance: Characteristic patterns of glaucoma related macular RGC+IPL loss appeared to be more important predictors of vision related quality of life than thickness measures, with diffuse RGC+IPL loss as an indicator for diminished vision-related quality of life. PMID- 28594980 TI - Training Current and Future Residents in Facial Plastic Surgery. PMID- 28594981 TI - Cognitive Training Program to Treat Tinnitus-Reply. PMID- 28594978 TI - Association of Gel-Forming Mucins and Aquaporin Gene Expression With Hearing Loss, Effusion Viscosity, and Inflammation in Otitis Media With Effusion. AB - Importance: Persistent, viscous middle ear effusion in pediatric otitis media (OM) contributes to increased likelihood of anesthesia and surgery, conductive hearing loss, and subsequent developmental delays. Biomarkers of effusion viscosity and hearing loss have not yet been identified despite the potential that such markers hold for targeted therapy and screening. Objective: To investigate the association of gel-forming mucins and aquaporin 5 (AQP5) gene expression with inflammation, effusion viscosity, and hearing loss in pediatric OM with effusion (OME). Design, Setting, and Participants: Case-control study of 31 pediatric patients (aged 6 months to 12 years) with OME undergoing tympanostomy tube placement and control individuals (aged 1 to 10 years) undergoing surgery for cochlear implantation from February 1, 2013, through November 30, 2014. Those with 1 or more episodes of OM in the previous 12 months, immunologic abnormality, anatomical or physiologic ear defect, OM-associated syndrome (ie, Down syndrome, cleft palate), chronic mastoiditis, or history of cholesteatoma were excluded from the study. All patients with OME and 1 control were recruited from Children's Hospital of Wisconsin, Milwaukee. The remainder of the controls were recruited from Sick Kids Hospital in Toronto, Ontario, Canada. Main Outcomes and Measures: Two to 3 middle ear biopsy specimens, effusions, and preoperative audiometric data (obtained <3 weeks before surgery) were collected from patients; only biopsy specimens were collected from controls. Expression of the mucin 2 (MUC2), mucin 5AC (MUC5AC), mucin 5B (MUC5B), and AQP5 genes were assayed in middle ear biopsy specimens by quantitative polymerase chain reaction. One middle ear biopsy specimen was sectioned for histopathologic analysis. Reduced specific viscosity of effusions was assayed using rheometry. Results: Of the 31 study participants, 24 patients had OME (mean [SD] age, 50.4 [31.9] months; 15 [62.5%] male; 16 [66.7%] white) and 7 acted as controls (mean [SD] age, 32.6 [24.4] months; 2 [26.6%] male; 6 [85.7%] white). Mucins and AQP5 gene expression were significantly higher in patients with OME relative to controls (MUC2: ratio, 127.6 [95% CI, 33.7-482.7]; MUC5AC: ratio, 3748.8 [95% CI, 558.1-25 178.4]; MUC5B: ratio, 471.1 [95% CI, 130.7-1697.4]; AQP5: ratio, 2.4 [95% CI, 1.1 5.6]). A 2-fold increase in MUC5B correlated with increased hearing loss (air bone gap: 7.45 dB [95% CI, 2.65-12.24 dB]; sound field: 6.66 dB [95% CI, 6.63 6.69 dB]), effusion viscosity (2.75 mL/mg; 95% CI, 0.89-4.62 mL/mg), middle ear epithelial thickness (3.5 MUm; 95% CI, 1.96-5.13 MUm), and neutrophil infiltration (odds ratio, 1.7; 95% CI, 1.07-2.72). A 2-fold increase in AQP5 correlated with increased effusion viscosity (1.94 mL/mg; 95% CI, 0.08-3.80 mL/mg). Conclusions and Relevance: Further exploration of the role of MUC5B in the pathophysiology of OME holds promise for development of novel, targeted therapies to reduce effusion viscosity, facilitation of effusion clearance, and prevention of disease chronicity and hearing loss in patients with OME. PMID- 28594979 TI - Use of Corneal Confocal Microscopy to Evaluate Small Nerve Fibers in Patients With Human Immunodeficiency Virus. AB - Importance: Objective quantification of small fiber neuropathy in patients with human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is difficult but needed for diagnosis and monitoring. In vivo corneal confocal microscopy (IVCCM) can quantify small fiber damage. Objective: To establish whether IVCCM can identify an abnormality in corneal nerve fibers and Langerhans cells in patients with and without HIV-SN. Design, Setting, and Participants: This prospective, cross-sectional cohort study was conducted between July 24, 2015, and September 17, 2015. Twenty patients who were HIV positive were recruited from adult outpatient clinics at Chelsea and Westminster Hospital NHS Foundation Trust in England. These patients underwent IVCCM at Moorfields Eye Hospital NHS Foundation Trust in London, England, and the IVCCM images were analyzed at Weill Cornell Medicine-Qatar in Ar-Rayyan, Qatar. Patients were given a structured clinical examination and completed validated symptom questionnaires and the Clinical HIV-Associated Neuropathy Tool. Results from patients with HIV were compared with the results of the age- and sex-matched healthy control participants (n = 20). All participants were classified into 3 groups: controls, patients with HIV but without SN, and patients with HIV-SN. Main Outcomes and Measures: Comparison of corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber tortuosity, and corneal Langerhans cell density between healthy controls and patients with HIV with and without SN. Results: All 40 participants were male, and most (>=70%) self identified as white. Of the 20 patients with HIV, 14 (70%) had HIV-SN. This group was older (mean [SD] age, 57.7 [7.75] years) than the group without HIV-SN (mean [SD] age, 42.3 [7.26] years) and the controls (mean [SD] age, 53.8 [10.5] years). Corneal nerve fiber density was reduced in patients with HIV compared with the controls (26.7/mm2 vs 38.6/mm2; median difference, -10.37; 95.09% CI, -14.27 to 6.25; P < .001) and in patients with HIV-SN compared with those without (25.8/mm2 vs 30.7/mm2; median difference, -4.53; 95.92% CI, -8.85 to -0.26; P = .03). Corneal nerve branch density and corneal nerve fiber length were reduced in patients with HIV, but no differences were identified between those with neuropathy and without neuropathy (corneal nerve branch density: 95.83/mm2 for the controls vs 72.37/mm2 for patients with HIV; median difference, -24.53; 95.32% CI, -50.62 to -3.13; P = .01; and corneal nerve fiber length: 28.4 mm/mm2 for the controls vs 21.9 mm/mm2 for patients with HIV; median difference, -5.24; 95.09% CI, -8.83 to -1.38; P = .001). Tortuosity coefficient was increased in patients with HIV compared with controls (16.44 vs 13.95; median difference, 2.34; 95.09% CI, 0.31 to 4.65; P = .03) and in those with HIV-SN compared with those without (17.84 vs 14.18; median difference, 4.32; 95.92% CI, 0.68-9.23; P = .01). No differences were identified in corneal Langerhans cell density (19.84 cells/mm2 for the controls vs 41.43 cells/mm2 for patients with HIV; median difference, 9.38; 95% CI, -12.51 to 26.34; P = .53). Conclusions and Relevance: In vivo corneal confocal microscopy could be used in the assessment of HIV-SN, but larger studies are required to confirm this finding. PMID- 28594982 TI - Bilateral Retinal Problem in a Patient With Alport Syndrome. PMID- 28594984 TI - Prognostic and Predictive Ability of Tumor Sidedness: Another Vexing Difference Between Localized and Advanced Colon Cancer. PMID- 28594985 TI - Use of Structural End Points in Glaucoma: Beyond Visual Field Loss. PMID- 28594983 TI - A Facial Trauma Simulation Course for Evaluation and Treatment of Facial Fractures. AB - Importance: Traditional facial trauma laboratories are used for teaching basic concepts of fracture reduction and hardware manipulation. Facial trauma simulation laboratories allow training physicians the opportunity to develop unique treatment plans as they would in real patient encounters. Objective: To assess the value of a novel facial trauma simulation course requiring residents to practice advanced decision making. Design, Setting, and Participants: Data were prospectively collected July 23 and August 23 and 24, 2016, in a survey study during a resident physician trauma simulation course. Fresh frozen cadaver heads were fractured using an impactor that applied a measurable amount of force. Each head was scanned with high-resolution computed tomography. Residents were paired and tasked with evaluating their specimen's imaging findings and developing a treatment plan. Main Outcomes and Measures: Before the course, residents were asked their postgraduate year level, number of facial fractures treated as a resident surgeon, and their comfort level based on the Otolaryngology Milestone for Facial Trauma (OMFT; ratings range from 0-5, with 5 indicating equivalent to fellow-level experience). After the course, residents were asked to assess the course's value relative to a theoretical number of actual operative cases, and a posttraining OMFT assessment was obtained. Results: Thirty resident physicians completed the course at 2 institutions. Residents represented an equivalent distribution of postgraduate year levels. The residents stated that the course was worth a mean (SD) of 6.4 (2.8) operative cases of facial trauma in terms of surgical learning. The mean change in self-reported OMFT rating after the course was 0.87 (95% CI, 0.67-1.07; P < .001, paired t test). On the basis of this change in self-perceived OMFT rating, the course was deemed to be worth 1.5 years of residency training in the management of facial fractures. Conclusion and Relevance: Conducting a facial trauma simulation course increases resident experience with advanced surgical decision making. Level of Evidence: NA. PMID- 28594986 TI - Error in Text. PMID- 28594987 TI - Vitamin D and Breast Cancer Survival: The Good and the Bad. PMID- 28594988 TI - Cognitive Training Program to Treat Tinnitus. PMID- 28594991 TI - Can Personalized Care Planning Improve Primary Care? PMID- 28594992 TI - Association of Modified Frailty Index Score With Perioperative Risk for Patients Undergoing Total Laryngectomy. AB - Importance: Objective preoperative risk assessment tools, such as the Modified Frailty Index (mFI), may inform patient and physician decision making when considering total laryngectomy. Estimation of outcomes may help to set realistic expectations about recovery and outcomes and facilitate optimal resource management. Objective: To evaluate the association between the mFI score as a measure of frailty and outcomes following total laryngectomy. Design, Setting, and Participants: Retrospective evaluation using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), a risk- and case-mix adjusted national quality assessment program. The ACS NSQIP database identified 595 patients who underwent total laryngectomy between 2006 and 2012. Patients were assessed for demographics and comorbidity and were stratified on the basis of calculated mFI score. Outcomes, including postoperative complications, length of hospitalization, and discharge destination, were evaluated as a function of increasing frailty using multivariable logistic regression and Cox proportional hazards regression models. Main Outcomes and Measures: Risk of postoperative complications, length of hospitalization, and discharge disposition. Results: After exclusion of patients who experienced significant deviation from standard care protocols and those with missing or incomplete data, 343 individuals were included in the analysis. Of these, 278 (81.0%) were men, and the mean age was 63 years (95% CI, 61.9-64.4 years). Increasing frailty resulted in a nonlinear but progressive rise in incidence of postoperative adverse events. Overall, 96 (28.0%) patients experienced a postoperative complication, and patients with an mFI score of 3 or higher were more likely to develop postoperative complications than were patients with an mFI score of 0 (50.0% vs 16.7%; OR, 3.83; 95% CI, 1.72 8.51). Patients in the highest frailty group experienced a longer mean duration of hospitalization (14.2 vs 9.5 days; difference, 4.7; 95% CI, 1.3-8.1 days) and were more likely to require skilled care after discharge (33.3% vs 3.2%; difference, 30.1%; 95% CI, 7.4%-52.9%). Conclusions and Relevance: An mFI score of 3 or higher is associated with increased risk for postoperative complications, longer hospitalization, and need for postdischarge skilled care following total laryngectomy. The mFI provides a personalized risk assessment to better inform patients, physicians, and payers when planning a total laryngectomy. PMID- 28594993 TI - Descemet Membrane Splitting Following Deep Anterior Lamellar Keratoplasty. PMID- 28594994 TI - Peripheral Hypertrophic Subepithelial Corneal Degeneration. PMID- 28594995 TI - Folds in Descemet Membrane Associated With Forceps-Induced Injury. PMID- 28594996 TI - Echographic Assessment of Optic Nerve Pit. PMID- 28594999 TI - Regenerating Bone via Multifunctional Coatings: The Blending of Cell Integration and Bacterial Inhibition Properties on the Surface of Biomaterials. AB - In dentistry and orthopedics, it is well accepted that implant fixation is a major goal. However, an emerging concern is bacterial infection. Infection of metallic implants can be catastrophic and significantly reduce patient quality of life. Accordingly, in this work, we focus on multifunctional coatings to simultaneously address and mitigate both these problems. We have developed a tailor-made peptide-based chemical platform that integrates the well-known RGD cell adhesive sequence and the lactoferrin-derived LF1-11 antimicrobial peptide. The platform was covalently grafted on titanium via silanization and the functionalization process characterized by contact angle, XPS, and QCM-D. The presence of the platform statistically improved the adhesion, proliferation and mineralization of osteoblast-like cells compared to control surfaces. At the same time, colonization by representative bacterial strains was significantly reduced on the surfaces. Furthermore, the biological potency of the multifunctional platform was verified in a co-culture in vitro model. Our findings demonstrate that this multifunctional approach can be useful to functionalize biomaterials to both improve cell integration and reduce the risk of bacterial infection. PMID- 28595000 TI - Antimicrobial Gold Nanoclusters. AB - Bulk gold (Au) is known to be chemically inactive. However, when the size of Au nanoparticles (Au NPs) decreases to close to 1 nm or sub-nanometer dimensions, these ultrasmall Au nanoclusters (Au NCs) begin to possess interesting physical and chemical properties and likewise spawn different applications when working with bulk Au or even Au NPs. In this study, we found that it is possible to confer antimicrobial activity to Au NPs through precise control of their size down to NC dimension (typically less than 2 nm). Au NCs could kill both Gram positive and Gram-negative bacteria. This wide-spectrum antimicrobial activity is attributed to the ultrasmall size of Au NCs, which would allow them to better interact with bacteria. The interaction between ultrasmall Au NCs and bacteria could induce a metabolic imbalance in bacterial cells after the internalization of Au NCs, leading to an increase of intracellular reactive oxygen species production that kills bacteria consequently. PMID- 28595001 TI - Tailoring the Adsorption and Reaction Chemistry of the Metal-Organic Frameworks UiO-66, UiO-66-NH2, and HKUST-1 via the Incorporation of Molecular Guests. AB - Metal-organic frameworks (MOFs) are versatile materials highly regarded for their porous nature. Depending on the synthetic method, various guest molecules may remain in the pores or can be systematically loaded for various reasons. Herein, we present a study that explores the effect of guest molecules on the adsorption and reactivity of the MOF in both the gas phase and solution. The differences between guest molecule interactions and the subsequent effects on their activity are described for each system. Interestingly, different effects are observed and described in detail for each class of guest molecules studied. We determine that there is a strong effect of alcohols with the secondary building unit of UiO MOFs, while Lewis bases have an effect on the reactivity of the -NH2 group in UiO 66-NH2 and adsorption by the coordinatively unsaturated copper sites in HKUST-1. These effects must be considered when determining synthesis and activation methods of MOFs toward various applications. PMID- 28595003 TI - The In Vivo Potential-Regulated Protective Protein of Nitrogenase in Azotobacter vinelandii Supports Aerobic Bioelectrochemical Dinitrogen Reduction In Vitro. AB - Nitrogenase, the only enzyme known to be able to reduce dinitrogen (N2) to ammonia (NH3), is irreversibly damaged upon exposure to molecular oxygen (O2). Several microbes, however, are able to grow aerobically and diazotrophically (fixing N2 to grow) while containing functional nitrogenase. The obligate aerobic diazotroph, Azotobacter vinelandii, employs a multitude of protective mechanisms to preserve nitrogenase activity, including a "conformational switch" protein (FeSII, or "Shethna") that reversibly locks nitrogenase into a multicomponent protective complex upon exposure to low concentrations of O2. We demonstrate in vitro that nitrogenase can be oxidatively damaged under anoxic conditions and that the aforementioned conformational switch can protect nitrogenase from such damage, confirming that the conformational change in the protecting protein can be achieved solely by regulating the potential of its [2Fe-2S] cluster. We further demonstrate that this protective complex preserves nitrogenase activity upon exposure to air. Finally, this protective FeSII protein was incorporated into an O2-tolerant bioelectrosynthetic cell whereby NH3 was produced using air as a substrate, marking a significant step forward in overcoming the crippling limitation of nitrogenase's sensitivity toward O2. PMID- 28595005 TI - 3D Porphyrin-Based Covalent Organic Frameworks. AB - The design and synthesis of three-dimensional covalent organic frameworks (3D COFs) bearing photoelectric units have been considered as a big challenge. Herein, for the first time, we reported the targeted synthesis of two 3D porphyrin-based COFs (3D-Por-COF and 3D-CuPor-COF), starting from tetrahedral (3D Td) and square (2D-C4) building blocks connected through [4 + 4] imine condensation reactions. On the basis of structural characterizations, 3D-Por-COF and 3D-CuPor-COF are microporous materials with high surface areas, and are proposed to adopt a 2-fold interpenetrated pts topology with Pmc21 space group. Interestingly, both 3D COFs are photosensitive and can be used as heterogeneous catalyst for generating singlet oxygen under photoirradiation. However, 3D-Por COF shows enhanced photocatalytic activity compared with 3D-CuPor-COF, indicating the properties of 3D porphyrin-based COFs can be tuned by metalation of porphyrin rings. The results reported here will greatly inspire us to design and synthesize 3D COFs bearing other metalloporphyrins for interesting applications (e.g., catalysis) in the future. PMID- 28595004 TI - Origin of the Intrinsic Fluorescence of the Green Fluorescent Protein. AB - Green fluorescent protein, GFP, has revolutionized biology, due to its use in bioimaging. It is widely accepted that the protein environment makes its chromophore fluoresce, whereas the fluorescence is completely lost when the native chromophore is taken out of GFP. By the use of a new femtosecond pump probe scheme, based on time-resolved action spectroscopy, we demonstrate that the isolated deprotonated GFP chromophore can be trapped in the first excited state when cooled to 100 K. The trapping is shown to last for 1.2 ns, which is long enough to establish conditions for fluorescence and consistent with calculated trapping barriers in the electronically excited state. Thus, GFP fluorescence is traced back to an intrinsic chromophore property, and by improving excited-state trapping, protein interactions enhance the molecular fluorescence. PMID- 28595002 TI - Diacetyl/l-Xylulose Reductase Mediates Chemical Redox Cycling in Lung Epithelial Cells. AB - Reactive carbonyls such as diacetyl (2,3-butanedione) and 2,3-pentanedione in tobacco and many food and consumer products are known to cause severe respiratory diseases. Many of these chemicals are detoxified by carbonyl reductases in the lung, in particular, dicarbonyl/l-xylulose reductase (DCXR), a multifunctional enzyme important in glucose metabolism. DCXR is a member of the short-chain dehydrogenase/reductase (SDR) superfamily. Using recombinant human enzyme, we discovered that DCXR mediates redox cycling of a variety of quinones generating superoxide anion, hydrogen peroxide, and, in the presence of transition metals, hydroxyl radicals. Redox cycling activity preferentially utilized NADH as a cosubstrate and was greatest for 9,10-phenanthrenequinone and 1,2-naphthoquinone, followed by 1,4-naphthoquinone and 2-methyl-1,4-naphthoquinone (menadione). Using 9,10-phenanthrenequinone as the substrate, quinone redox cycling was found to inhibit DCXR reduction of l-xylulose and diacetyl. Competitive inhibition of enzyme activity by the quinone was observed with respect to diacetyl (Ki = 190 MUM) and l-xylulose (Ki = 940 MUM). Abundant DCXR activity was identified in A549 lung epithelial cells when diacetyl was used as a substrate. Quinones inhibited reduction of this dicarbonyl, causing an accumulation of diacetyl in the cells and culture medium and a decrease in acetoin, the reduced product of diacetyl. The identification of DCXR as an enzyme activity mediating chemical redox cycling suggests that it may be important in generating cytotoxic reactive oxygen species in the lung. These activities, together with the inhibition of dicarbonyl/l xylulose metabolism by redox-active chemicals, as well as consequent deficiencies in pentose metabolism, are likely to contribute to lung injury following exposure to dicarbonyls and quinones. PMID- 28595006 TI - Selective Targeting of Neurons with Inorganic Nanoparticles: Revealing the Crucial Role of Nanoparticle Surface Charge. AB - Nanoparticles (NPs) are increasingly used in biomedical applications, but the factors that influence their interactions with living cells need to be elucidated. Here, we reveal the role of NP surface charge in determining their neuronal interactions and electrical responses. We discovered that negatively charged NPs administered at low concentration (10 nM) interact with the neuronal membrane and at the synaptic cleft, whereas positively and neutrally charged NPs never localize on neurons. This effect is shape and material independent. The presence of negatively charged NPs on neuronal cell membranes influences the excitability of neurons by causing an increase in the amplitude and frequency of spontaneous postsynaptic currents at the single cell level and an increase of both the spiking activity and synchronous firing at neural network level. The negatively charged NPs exclusively bind to excitable neuronal cells, and never to nonexcitable glial cells. This specific interaction was also confirmed by manipulating the electrophysiological activity of neuronal cells. Indeed, the interaction of negatively charged NPs with neurons is either promoted or hindered by pharmacological suppression or enhancement of the neuronal activity with tetrodotoxin or bicuculline, respectively. We further support our main experimental conclusions by using numerical simulations. This study demonstrates that negatively charged NPs modulate the excitability of neurons, revealing the potential use of NPs for controlling neuron activity. PMID- 28595007 TI - Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds. AB - The design of proteolysis-targeting chimeras (PROTACs) is a powerful small molecule approach for inducing protein degradation. PROTACs conjugate a target warhead to an E3 ubiquitin ligase ligand via a linker. Here we examined the impact of derivatizing two different BET bromodomain inhibitors, triazolodiazepine JQ1 and the more potent tetrahydroquinoline I-BET726, via distinct exit vectors, using different polyethylene glycol linkers to VHL ligand VH032. Triazolodiazepine PROTACs exhibited positive cooperativities of ternary complex formation and were more potent degraders than tetrahydroquinoline compounds, which showed negative cooperativities instead. Marked dependency on linker length was observed for BET-degrading and cMyc-driven antiproliferative activities in acute myeloid leukemia cell lines. This work exemplifies as a cautionary tale how a more potent inhibitor does not necessarily generate more potent PROTACs and underscores the key roles played by the conjugation. The provided insights and framework for structure-activity relationships of bivalent degraders are anticipated to have wide future applicability. PMID- 28595008 TI - Rapid and Convenient Oxidative Release of Thiol-Conjugated Forms of Microcystins for Chemical Analysis. AB - Microcystins are potent cyclic heptapeptide toxins found in some cyanobacteria, and usually contain an alpha,beta-unsaturated carbonyl group that is readily conjugated to thiol-containing amino acids, peptides, and proteins in vivo and in vitro. Methods for deconjugating these types of adducts have recently been reported, but the reactions are slow or result in derivatized microcystins. Mercaptoethanol derivatives of a range of microcystins were therefore used as model compounds to develop deconjugation procedures in which the dialkyl sulfide linkage was oxidized to a sulfoxide or sulfone that, when treated with base, rapidly eliminated the adducted thiol as its sulfenate or sulfinate via beta elimination to afford free microcystins with the alpha,beta-unsaturated carbonyl group intact. These free microcystins can be analyzed by LC/MS to determine the toxin profile of bound microcystins. The method was tested on Cys- and GSH derivatives of [Dha7]MC-LR. In solution, the deconjugation reactions were complete within minutes at pH 10.7 and within a few hours at pH 9.2. Oxidation of sulfides to sulfoxides is easier and more rapid than oxidation to sulfones, allowing the use of milder oxidants and shorter reaction times. Oxidation of any methionine residues present in the microcystins occurs inevitably during these procedures, and interpretation of the microcystin profile obtained by LC/MS analysis needs to take this into account. Oxidation of tryptophan residues and degradation of microcystins by excess oxidant were circumvented by the addition of Me2SO as a sacrificial reducing agent. These methods may be useful for other compounds that undergo conjugation via thia-Michael addition, such as acrylamide and deoxynivalenol. Oxidation of sulfides to sulfoxides can occur in vivo and could affect the bioavailability of toxins and drugs conjugated via thia-Michael addition, potentially exacerbating oxidative stress by catalytically converting GSH to its sulfenate via conjugation, oxidation, and elimination to regenerate the free toxin. PMID- 28595009 TI - Controlled Dopant Migration in CdS/ZnS Core/Shell Quantum Dots. AB - The physical properties of a doped quantum dot (QD) are strongly influenced by the dopant site inside the host lattice, which determines the host-dopant coupling from the overlap between the dopant and exciton wave functions of the host lattice. Although several synthetic methodologies have been developed for introducing dopants inside the size-confined semiconductor nanocrystals, the controlled dopant-host lattice coupling by dopant migration is still unexplored. In this work, the effect of lattice mismatch of CdS/ZnS core/shell QDs on Mn(II) dopant behavior was studied. It was found that the dopant migration toward the alloyed interface of core/shell QDs is a thermodynamically driven process to minimize the lattice strain within the nanocrystals. The dopant migration rate could be represented by the Arrhenius equation and therefore can be controlled by the temperature and lattice mismatch. Furthermore, the energy transfer between host CdS QDs and dopants can be finely turned in a wide range by dopant migration toward the alloyed interface during ZnS shell passivation, which provides an efficient method to control both the number of the emission band and the ratio of the emission from the host lattice and dopant ions. PMID- 28595011 TI - Acidities under the Perspective of Energy Decomposition Analysis. AB - The rationalization of acid/base behavior is a central concern for chemistry and related fields. In this work, we describe an alternative approach toward the understanding of gas phase acidities based on the localized molecular orbital energy decomposition analysis (LMOEDA) method. Upon partitioning the molecules (and the corresponding anions) over the X-OH (or X-O-) bond, we have observed a perfect correlation between the interaction energy of the two fragments and the acidity, as given by the energy difference between the anion and the neutral molecule. On the basis of this correlation, acidities could be interpreted according to the energy components provided by LMOEDA, namely, electrostatic, exchange repulsion, polarization, and dispersion. For example, alkyl groups increase the gas phase acidities of alcohols mainly due to electrostatic and polarization interactions. Carboxylic acids are stronger acids than alcohols through the ability of oxygen to stabilize the extra charge formed in the anion (electrostatic interactions) and also through a decrease of exchange repulsions between the two fragments. Polarization interaction (orbital relaxation) also plays an important role. Electrostatic and polarization interactions dominate the enhanced acidity of sulfuric acid over ethanol. Electrostatic and polarization interactions are also responsible for the higher acidity of sulfuric over boric acid. The anomalous behavior of formic acid compared to acetic, propionic, and butyric acids is also explained. The examples worked in this report evince the still unexplored potential of energy decomposition to the comprehension of acid/base phenomena. PMID- 28595010 TI - Electrolyte-Induced Surface Transformation and Transition-Metal Dissolution of Fully Delithiated LiNi0.8Co0.15Al0.05O2. AB - Enabling practical utilization of layered R3m positive electrodes near full delithiation requires an enhanced understanding of the complex electrode electrolyte interactions that often induce failure. Using Li[Ni0.8Co0.15Al0.05]O2 (NCA) as a model layered compound, the chemical and structural stability in a strenuous thermal and electrochemical environment was explored. Operando microcalorimetry and electrochemical impedance spectroscopy identified a fingerprint for a structural decomposition and transition-metal dissolution reaction that occurs on the positive electrode at full delithiation. Surface sensitive characterization techniques, including X-ray absorption spectroscopy and high-resolution transmission electron microscopy, measured a structural and morphological transformation of the surface and subsurface regions of NCA. Despite the bulk structural integrity being maintained, NCA surface degradation at a high state of charge induces excessive transition-metal dissolution and significant positive electrode impedance development, resulting in a rapid decrease in electrochemical performance. Additionally, the impact of electrolyte salt, positive electrode surface area, and surface Li2CO3 content on the magnitude and character of the dissolution reaction was studied. PMID- 28595012 TI - Ionic Exchange of Metal-Organic Frameworks to Access Single Nickel Sites for Efficient Electroreduction of CO2. AB - Single-atom catalysts often exhibit unexpected catalytic activity for many important chemical reactions because of their unique electronic and geometric structures with respect to their bulk counterparts. Herein we adopt metal-organic frameworks (MOFs) to assist the preparation of a catalyst containing single Ni sites for efficient electroreduction of CO2. The synthesis is based on ionic exchange between Zn nodes and adsorbed Ni ions within the cavities of the MOF. This single-atom catalyst exhibited an excellent turnover frequency for electroreduction of CO2 (5273 h-1), with a Faradaic efficiency for CO production of over 71.9% and a current density of 10.48 mA cm-2 at an overpotential of 0.89 V. Our findings present some guidelines for the rational design and accurate modulation of nanostructured catalysts at the atomic scale. PMID- 28595013 TI - Fibroblast Activation Protein alpha Activated Tripeptide Bufadienolide Antitumor Prodrug with Reduced Cardiotoxicity. AB - Bufadienolides are the major pharmacologic constituents of traditional Chinese medicine Chan'su, which is frequently used clinically for cancer treatment in China. Motivated by reducing or avoiding the cardiac toxicity of bufadienolides, we have designed, synthesized, and evaluated the fibroblast activation protein alpha (FAPalpha) activated tripeptide arenobufagin prodrugs with the purpose of improving the safety of arenobufagin (a representative bufadienolide). Among these FAPalpha-activated prodrugs, 3f exhibited the best hydrolytic efficiency by recombinant human FAPalpha (rhFAPalpha) and was activated in tumors. The LD50 of 3f was 6.5-fold higher than that of arenobufagin. We also observed that there are nonapparent changes in echocardiography, pathological section of cardiac muscle, and the lactate dehydrogenase activities (LDH) in 3f-treatment tumor-bearing mice, even when the dose reached 3 times the amount of parent drug arenobufagin that was used. Compound 3f also exhibits significant antitumor activity in vitro and in vivo. The improved safety profile and favorable anticancer properties of 3f warrant further studies of the potential clinical implications. Our study suggests that FAPalpha prodrug strategy is an effective approach for successful increasing the therapeutic window of bufadienolides. PMID- 28595014 TI - Chelator-Free and Biocompatible Melanin Nanoplatform with Facile-Loading Gadolinium and Copper-64 for Bioimaging. AB - Development of a chelator-free and biocompatible platform for the facile construction of gadolinium3+ (Gd3+)-loaded nanoparticle based probes for in vivo magentic resonance imaging (MRI) is still challenging. Herein, biocompatible Gd3+ loading melanin dots (Gd-M-dots) have been easily prepared and have exhibited good loading efficiency for Gd3+, high stability, and higher T1 relaxivity compared to the commercial Gd-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) agent. Furthermore, Gd-M-dots showed unique photoacoustic (PA) properties, and a high PA imaging signal could be observed in vivo 1 h after injection. Compared to the traditional Gd3+-loaded nanoparticles for single-modal MRI, Gd-M-dots can also be radiolabeled with 64Cu2+ for positron emission tomography. Overall, these attractive properties of Gd-M-dots render them a promising imaging agent for various biomedical applications. PMID- 28595015 TI - 2'-Chloro,2'-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture. AB - Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a beta-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent. PMID- 28595016 TI - Stabilization of the Metastable Lead Iodide Perovskite Phase via Surface Functionalization. AB - Metastable structural polymorphs can have superior properties and applications to their thermodynamically stable phases, but the rational synthesis of metastable phases is a challenge. Here, a new strategy for stabilizing metastable phases using surface functionalization is demonstrated using the example of formamidinium lead iodide (FAPbI3) perovskite, which is metastable at room temperature (RT) but holds great promises in solar and light-emitting applications. We show that, through surface ligand functionalization during direct solution growth at RT, pure FAPbI3 in the cubic perovskite phase can be stabilized in nanostructures and thin films at RT without cation or anion alloying. Surface characterizations reveal that long-chain alkyl or aromatic ammonium (LA) cations bind to the surface of perovskite structure. Calculations show that such functionalization reduces the surface energy and plays a dominant role in stabilizing the metastable perovskite phase. Excellent photophysics and optically pumped lasing from the stabilized single-crystal FAPbI3 nanoplates with low thresholds were demonstrated. High-performance solar cells can be fabricated with such directly synthesized stabilized phase-pure FAPbI3 with a lower bandgap. Our results offer new insights on the surface chemistry of perovskite materials and provide a new strategy for stabilizing metastable perovskites and metastable polymorphs of solid materials in general. PMID- 28595017 TI - Unprecedented Ferroelectric-Antiferroelectric-Paraelectric Phase Transitions Discovered in an Organic-Inorganic Hybrid Perovskite. AB - As a promising candidate for energy storage capacitors, antiferroelectric (AFE) materials have attracted great concern due to their congenital advantages of large energy storage ability from double polarization versus electric field (P-E) hysteresis characteristics in contrast to ferroelectrics and linear dielectrics. However, antiferroelectricity has only been discovered in inorganic oxides and some hydrogen-bonded molecular systems. In view of the structural diversity and unique physical properties of organic-inorganic hybrid system, it remains a great opportunity to introduce antiferroelectricity into organic-inorganic hybrid perovskites. Here, we report that polarizable antiparallel dipole arrays can be realized in an organic-inorganic hybrid perovskite, (3-pyrrolinium)CdBr3, which not only exhibits an excellent ferroelectric property (with a high spontaneous polarization of 7.0 MUC/cm2), but also presents a striking AFE characteristic revealed by clear double P-E hysteresis loops. To the best of our knowledge, it is the first time that such successive ferroelectric-antiferroelectric paraelectric phase transitions have been discovered in organic-inorganic perovskites. Besides, a giant dielectric constant of 1600 even at high frequency of 1000 kHz and a bulk electrocaloric effect with entropy change of 1.18 J K-1 kg 1 under 7.41 kV/cm are also observed during the phase transition. Apparently, the combined striking AFE characteristic and giant dielectric constant make (3 pyrrolinium)CdBr3 a promising candidate for next generation high-energy-storage capacitors. PMID- 28595018 TI - Predictors of Physical Activity Levels in Community-Dwelling Older Adults: A Multivariate Approach Based on a Socio-Ecological Framework. AB - The purpose of this study was to explore cross-sectional relationships between self-reported physical activity (PA) and personal, social, and environmental factors in community-dwelling adults aged 50 years and older. Accounting for clustering by neighborhood, generalized estimating equations were used to examine associations between selected correlates and the Physical Activity Scale for the Elderly (PASE) score while adjusting for confounders. Data for 601 participants were analyzed: 79% female, 37% married, mean age 76.8 (+/- 8.7) years, mean PASE score 112.6 (+/- 64.8). Age, living in seniors' housing, using nursing/home care services, receiving encouragement to be active, and having benches available in the neighborhood were inversely associated with PASE. Self-efficacy, SF-12 score, PA barriers, social support, and the presence of trails showed positive associations. Several personal, social, and environmental factors associated with PA were identified. The inverse association between PA and living in seniors' housing units should be considered when developing PA programs for older adults. PMID- 28595019 TI - The Validity of Consumer-Level Activity Monitors in Healthy Older Adults in Free Living Conditions. AB - Consumer-level activity monitors, such as Fitbit and Misfit devices, are a popular and low-cost means of measuring physical activity. This study aims to compare the accuracy of step counts from two consumer-level activity monitors against two reference devices in healthy, community-dwelling older adults in free living conditions. Twenty-five older adults (aged 65-84) simultaneously wore 5 devices (e.g., Misfit Shine and Fitbit Charge HR) over 7 consecutive days. All consumer-level activity monitors positively correlated with reference devices (p < .001). There was also substantial to near perfect agreement between all consumer-level activity monitors and reference devices. Compared to the ActiGraph GT3X+, the waist-worn Misfit Shine displayed the highest agreement amongst the devices worn (ICC = 0.96, 95% 0.91 to 0.99). The wrist-worn devices showed poorer agreement to reference devices. Future research needs to consider that not all consumer-level activity monitors are equal in terms of accuracy, design, and function. PMID- 28595021 TI - Facilitators of Attendance and Adherence to Group-Based Physical Activity for Older Adults: A Literature Synthesis. AB - This review examines program features that influence attendance and adherence to group-based physical activity (PA) by older adults. Medline, PubMed, CINAHL plus, PsycINFO, and the Cochrane Library were searched for studies published from 1995 2016. Quantitative and qualitative studies investigating factors related to PA group attendance or adherence by persons aged 55 years and over were included. Searching yielded eight quantitative and 13 qualitative studies, from 2,044 titles. Quantitative findings identified social factors, instructor characteristics, PA types, class duration and frequency, and perceived PA outcomes as important for attendance and adherence, whilst qualitative studies identified settings, leadership, PA types, observable benefits, and social support factors. Studies were predominantly low- to moderate-quality. This review identified design and delivery considerations for group-based PA programs to inform best-practice frameworks and industry capacity building. Future research should use longitudinal and mixed-methods designs to strengthen evidence about facilitators of program reach and engagement. PMID- 28595020 TI - Tamoxifen inhibits mitochondrial membrane damage caused by disulfiram. AB - In this work, we studied the protective effects of tamoxifen (TAM) on disulfiram (Dis)-induced mitochondrial membrane insult. The results indicate that TAM circumvents the inner membrane leakiness manifested as Ca2+ release, mitochondrial swelling, and collapse of the transmembrane electric gradient. Furthermore, it was found that TAM prevents inactivation of the mitochondrial enzyme aconitase and detachment of cytochrome c from the inner membrane. Interestingly, TAM also inhibited Dis-promoted generation of hydrogen peroxide. Given that TAM is an antioxidant molecule, it is plausible that its protection may be due to the inhibition of Dis-induced oxidative stress. PMID- 28595022 TI - Combined Protein-Rich Diet With Resistance Exercise Intervention to Counteract Sarcopenia: A Qualitative Study on Drivers and Barriers of Compliance. AB - Interventions combining protein-rich diets with resistance exercises seem a promising avenue in helping to prevent sarcopenia. However, compliance to health interventions is generally low. The aim of the present study was to provide qualitative insights into the drivers and barriers that older adults experience when trying to comply with a combined dietary and physical exercise intervention. Semi-structured interviews with 18 older adults participating in such an intervention were conducted and analyzed using thematic content analysis. Most frequently reported drivers to comply with the diet were a fit with existing habits, knowledge on the health benefits, and product properties (taste, convenience, package). Drivers for physical exercises were existing habits, social contacts, customized support, and experienced physical improvement. It is suggested that customized support is important to successfully implement exercise protein interventions amongst older adults, especially regarding participants' habits, product preferences, and social environment. PMID- 28595023 TI - Human Papillomavirus Vaccine Is Crucial for Adolescent and Young Adult Cancer Survivors. PMID- 28595024 TI - Sedentary Time in Male and Female Masters and Recreational Athletes Aged 55 and Older. AB - The purpose of this study was to quantify sedentary time among recreational and Masters (competitive) athletes aged 55 and older. A cross-sectional survey including questions on demographics, sport participation, as well as a short form of the International Physical Activity Questionnaire, and the Measure of Older Adult's Sedentary Time questionnaire was administered (n = 203). Male Masters athletes reported more time spent in vigorous intensity physical activity and less time watching TV than recreational athletes. Among females, being a Masters athlete was associated with being more sedentary than being a recreational athlete, while among males, being a recreational athlete was associated with being more sedentary. The intensity and duration that older Masters and recreational athletes spent in their sport was inversely associated with the amount of sedentary time accumulated. Future research using inclinometers is needed to further elucidate sedentary time in older male and female athletes. PMID- 28595026 TI - Lack of Palliative Mortality Prediction Tools for People with a Hematological Malignancy: Call for Action. PMID- 28595025 TI - The Validity of Using Health Administrative Data To Identify the Involvement of Specialized Pediatric Palliative Care Teams in Children with Cancer in Ontario, Canada. AB - BACKGROUND: Population-based research to identify underserviced populations and the impact of palliative care (PC) is limited as the validity of such data to identify PC services is largely unknown. OBJECTIVE: To determine the validity of using such data to identify the involvement of specialized pediatric PC teams among children with cancer. DESIGN: Retrospective cohort. SUBJECTS: Ontario children with cancer who died between 2000 and 2012, received care through a pediatric institution with a specialized PC team and a clinical PC database. MEASUREMENTS: All patients in the clinical databases were linked to population based health services administrative databases. Six algorithms were created to indicate the use of formal pediatric PC teams based on the record type (physician billings vs. inpatient records vs. both) and number of eligible codes required (>=1 vs. >=2). Each was validated against the pediatric PC clinical databases. RESULTS: The cohort comprised 572 children; 243 were in the clinical databases. Algorithms using only inpatient records had high specificity (80%-95%) but poor sensitivity (21%-56%). Including physician billings increased sensitivity but lowered specificity. The algorithm with overall best performance required >=2 physician billing or inpatient diagnosis codes indicating PC [sensitivity 0.79 (95% CI 0.73-0.84), specificity 0.58 (95% CI 0.53-0.64)]. CONCLUSIONS: Health administrative data identifies involvement of specialized pediatric PC teams with good sensitivity but low specificity. Studies using such data alone to compare patients receiving and not receiving specialized pediatric PC are at significant risk of misclassification and potential bias. Population-based PC databases should be established to conduct rigorous population-based PC research. PMID- 28595027 TI - Clinical Outcomes of Start-Low, Go-Slow Methadone Initiation for Cancer-Related Pain: What's the Hurry? AB - BACKGROUND: Methadone has been shown to be effective for cancer pain. Most published switching methods are complete in less than three days, requiring very close supervision, usually in an inpatient setting. This need for hospitalization is a barrier to access. We present a large retrospective study of slow outpatient methadone starts and describe our starting method. METHODS: Charts were reviewed of patients referred to the Pain and Symptom Management/Palliative Care clinics at the six BC Cancer Agency's regional centers that underwent initiation of methadone for analgesia over a 14-year period. Patient characteristics, method of start, and outcomes of methadone treatment were recorded. RESULTS: Of the 652 identified patients, we were able to determine outcomes of methadone initiation in 564 (86.5%). Among these, 422 (74.8%) were deemed successful initiations, as determined by whether or not the patient remained on methadone at follow-up with subjective improvement in pain control, on a stable dose of methadone. Of the unsuccessful trials, 97/142 were primarily due to adverse events, 16 of which were considered serious enough to require hospitalization, including two due to sudden cessation of opioid therapy leading to withdrawal. Some of the included adverse events were not necessarily causal from the initiation of methadone, for example, development of bowel obstruction or delirium. Only one death occurred from a deliberate overdose of multiple medications, including methadone. CONCLUSIONS: Initiation of methadone for analgesia in ambulatory cancer patients can be done safely in an outpatient setting using a start-low go-slow method, and can be expected to be helpful in ~75% of patients. Discontinuation is more likely to be for side effects than for inadequate analgesia. Access to methadone therapy can safely be widened by slow initiation, avoiding more dangerous rapid switching protocols and reducing the need for hospitalization. PMID- 28595028 TI - The Role of Clinical Pharmacists on the Interdisciplinary Team #334. PMID- 28595030 TI - Preventing Chronic Disease: Recognizing Accomplishments in 2016 and Tracking Progress of Priorities in 2017. PMID- 28595029 TI - Advancing the Public's Health by Scaling Innovations in Clinical Quality. PMID- 28595031 TI - Factors Associated With Parents' Intent to Vaccinate Adolescents for Human Papillomavirus: Findings From the 2014 National Immunization Survey-Teen. AB - INTRODUCTION: While factors associated with receipt of human papillomavirus (HPV) vaccination have been well characterized, less is known about the characteristics associated with parents' intent to have their adolescent children vaccinated. This study aimed to examine factors associated with parental intention toward HPV vaccination. METHODS: We analyzed data on 10,354 adolescents aged 13 to 17 years from the 2014 National Immunization Survey-Teen. Weighted multivariable logistic regression was used to examine associations between sociodemographic characteristics of mothers and adolescents, as well as a health care provider recommendation with parents' intention to have their children receive HPV vaccine. RESULTS: Among unvaccinated adolescents, Hispanic ethnicity (boys adjusted odds ratio [AOR], 1.87, 95% confidence interval [CI], 1.34-2.61; and girls AOR, 1.57; 95% CI, 1.05-2.35), mothers with less than a high school diploma (boys AOR, 2.41; 95% CI, 1.58-3.67; and girls AOR, 1.86; 95% CI, 1.02-3.38), and having a health care provider recommend the vaccine (boys AOR, 1.87; 95% CI, 1.52 2.31; and girls AOR, 1.38; 95% CI, 1.05-1.82) were significantly associated with parents' intention to have their adolescent child vaccinated within the next 12 months. In addition, non-Hispanic black race was a significant predictor of parents' intent to vaccinate for boys (AOR, 1.89; 95% CI, 1.35-2.65). CONCLUSION: Maternal education and Hispanic ethnicity were the strongest predictors of parental intent to vaccinate against HPV, followed by provider recommendation. As HPV vaccination rates in the United States remain below the Healthy People 2020 goal, messages may need to be targeted based on maternal education, race/ethnicity, and provider recommendation. PMID- 28595032 TI - Comparing Prevalence Estimates From Population-Based Surveys to Inform Surveillance Using Electronic Health Records. AB - INTRODUCTION: Electronic health record (EHR) systems provide an opportunity to use a novel data source for population health surveillance. Validation studies that compare prevalence estimates from EHRs and surveys most often use difference testing, which can, because of large sample sizes, lead to detection of significant differences that are not meaningful. We explored a novel application of the two one-sided t test (TOST) to assess the equivalence of prevalence estimates in 2 population-based surveys to inform margin selection for validating EHR-based surveillance prevalence estimates derived from large samples. METHODS: We compared prevalence estimates of health indicators in the 2013 Community Health Survey (CHS) and the 2013-2014 New York City Health and Nutrition Examination Survey (NYC HANES) by using TOST, a 2-tailed t test, and other goodness-of-fit measures. RESULTS: A +/-5 percentage-point equivalence margin for a TOST performed well for most health indicators. For health indicators with a prevalence estimate of less than 10% (extreme obesity [CHS, 3.5%; NYC HANES, 5.1%] and serious psychological distress [CHS, 5.2%; NYC HANES, 4.8%]), a +/-2.5 percentage-point margin was more consistent with other goodness-of-fit measures than the larger percentage-point margins. CONCLUSION: A TOST with a +/-5 percentage-point margin was useful in establishing equivalence, but a +/-2.5 percentage-point margin may be appropriate for health indicators with a prevalence estimate of less than 10%. Equivalence testing can guide future efforts to validate EHR data. PMID- 28595033 TI - Temperature gradients in vivo influence maturing male and female gametes in mammals: evidence from the cow. AB - Since 1980 several reports have indicated that temperatures vary between preovulatory follicles and other ovarian tissues in rabbit, cow, pig and human. However, these observations did not achieve prominence; they were regarded as artefacts due to the use of anaesthetics and open surgery (laparotomy). Recently, without resorting to anaesthesia or surgery, direct measurements of temperature in preovulatory follicles have been performed in the cow by means of a thermistor probe introduced into the antrum under ultrasonic guidance. Such follicles revealed a mean antral (follicular fluid) temperature 0.74 degrees C and 1.54 degrees C cooler than uterine surface and rectal temperatures respectively in ovulating cows, whereas no such temperature differences were detected in non ovulating cows. Cows are predominantly monovular and preovulatory follicles attain a diameter of 15-22mm or more. These features and the timescale of response to the preovulatory gonadotrophin surge make them a valuable model for the human preovulatory follicle. Temperature gradients are interpreted primarily in a context of final maturation of gametes immediately before the onset of fertilisation. Preovulatory follicular temperature in women could be assessed by a comparable approach and might become a valuable selection guide for oocyte viability. PMID- 28595034 TI - Preclinical and clinical studies of Coriolus versicolor polysaccharopeptide as an immunotherapeutic in China. AB - Conventional cancer treatments include surgery, chemotherapy, and radiation therapy. In recent years, immunotherapy in cancer care has been gaining momentum. Interestingly, an immunotherapeutic regime that employs polysaccharopeptide (PSP), a unique peptide-containing polysaccharide isolated from Coriolus versicolor, has already become a routine clinical practice in Japan since 1977 and in China since 1987. Coriolus versicolor is one of the most well-known traditional food and medicinal mushrooms in China for thousands of years. Medically used PSP is mostly obtained from the extraction of cultured Coriolus versicolor mycelia where beta-glucan is the major component. PSP has proven beneficial to survival and quality of life not only for cancer patients but also for patients with hepatitis, hyperlipidemia, and other chronic diseases. In this article, the results of PSP-related preclinical and clinical studies conducted in China from over 40 independent studies during the past 40 years based on searching the Chinese VIP, CNKI, and Wanfang databases are presented. Its immunomodulatory and anti-tumor molecular mechanisms are also summarized. PSP activates immune cells, increases the expressions of cytokines and chemokines such as tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-1beta and IL 6), histamine, and prostaglandin E, enhances dendritic and T-cell infiltration into tumors, and ameliorates the adverse events associated with chemotherapy. The clinical studies support PSP being a potential immunotherapeutic. However, the complicated chemical and multiple pharmacological properties of PSP need to be investigated further. PMID- 28595035 TI - N-methyl-D-aspartate receptors mediate epilepsy-induced axonal impairment and tau phosphorylation via activating glycogen synthase kinase-3beta and cyclin dependent kinase 5. AB - The mechanism of epilepsy-induced axonal impairment is poorly understood. N methyl-D-aspartate receptors (NMDARs) play important roles in epilepsy and mediate structural and functional axonal impairment. GSK-3beta and Cdk5 affect axons and are regulated by NMDARs, while their roles in epilepsy-induced axonal impairment are unclear. We demonstrated that axonal impairment is characterized by neurofilament heavy (NFH) reduction, amyloid precursor protein (APP) accumulation, and increased tau phosphorylation accompanied by a decrease of total tau in temporal lobe epilepsy (TLE) patients and pentylenetetrazol (PTZ) kindled rats. Inhibiting NMDARs using memantine and ifenprodil alleviated NFH reduction and APP accumulation, decreased Cdk5 expression, and inhibited the activity of GSK-3beta in the white matter of PTZ-kindled rats. Inhibiting GSK 3beta and Cdk5 using lithium chloride and roscovitine also alleviated axonal impairment induced by PTZ. Therefore, axonal impairment in TLE may be mediated by NMDAR via GSK-3beta and Cdk5. In addition, inhibiting either NMDARs or GSK-3beta lowered the relative tau phosphorylation level by reversing the decrease of total tau without affecting phosphorylated tau S396 and T231. Meanwhile inhibiting Cdk5 lowered the tau phosphorylation level by reducing phosphorylated tau without affecting total tau, indicating a possible role of GSK-3beta in NMDAR-mediated tau phosphorylation in epilepsy. PMID- 28595037 TI - Plasma apolipoprotein A1 levels at diagnosis are independent prognostic factors in invasive ductal breast cancer. AB - Strong evidence exists indicating that the risk of breast cancer (BC) occurrence is influenced by complex internal environmental factors, including blood lipid and lipoprotein components. However, the roles of these components in BC development and progression remain controversial. This study examined whether serial serum lipid and lipoprotein measurements were associated with breast cancer risk and whether lipoproteins had BC prognostic properties. We compared the plasma-related parameter levels, including lipid and lipoprotein levels between 299 patients with invasive ductal breast cancer, also known as invasive ductal carcinoma (IDC), and 200 healthy donors. We performed univariate and multivariate logistic regression analyses to assess overall survival (OS) and disease-free survival (DFS). We found that the serum glucose, triacylglycerol, and low-density lipoprotein levels were significantly higher in patients with IDC than in healthy donors. However, high-density lipoprotein and apolipoprotein A1 (apoA1) levels were lower in patients with IDC than in healthy donors. Multivariate regression analysis demonstrated that elevated apoA1 levels were associated with a reduced risk of IDC, and univariate analysis showed that patients with IDC with lower apoA1 levels at diagnosis had larger tumors than patients with high apoA1 levels. Moreover, patients with IDC with lower apoA1 levels were more likely to have positive axillary lymph nodes, and were diagnosed at more advanced disease stages than patients with high apoA1 levels. We used a Cox regression model to assess the relationships between the above parameters and DFS and OS, after adjusting for tumor T and N stages, which were determined using the TNM classification system, and immunohistochemical subtypes. We found that lower apoA1 levels at diagnosis were associated with poor DFS and OS. At 60 months of follow-up, the DFS rate is 74.5% in the apoA1 L1 group, 89.9% in apoA1 L2 group, and 93.1% in apoA1 L3 group (p=0.0002). Similarly, the OS rate is 78.2% in apoA1 L1 group, 91.3% in apoA1 L2 group, and 93.7% in apoA1 L3 group (p=0.0012). In conclusion, our data indicate that low apoA1 levels are an independent predictor of the poor clinical outcomes in IDC patients. PMID- 28595036 TI - S100A1 promotes cell proliferation and migration and is associated with lymph node metastasis in ovarian cancer. AB - S100A1 is a calcium-binding protein belonging to the family of S100 proteins, and is highly expressed in ovarian cancer. However, its role in ovarian cancer has not yet been fully elucidated. In this study, we examined S100A1 expression in ovarian cancer tissues and normal tissue controls and analyzed the correlation between S100A1 expression and clinicopathological parameters. We found that S100A1 expression was significantly upregulated in ovarian cancer tissues compared with fallopian and normal ovarian epithelium tissues and was significantly associated with lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stages and tumor grades. We then investigated the biological functions of S100A1 in ovarian cancer by cell proliferation, fluorescence-activated cell sorting (FACS), and migration and invasion assays. The results indicated that S100A1 enhanced the ovarian cancer cell proliferation and migration. Together, our findings demonstrated that S100A1 plays an important role in the malignancy of ovarian cancer, and serves as a useful marker for the detection of ovarian malignancy. PMID- 28595038 TI - Bio-electric field enhancement: the influence on hyaluronan mediated motility receptors in human breast carcinoma. AB - Mechanisms that regulate cancer cell metastasis are often intricately linked to mechanisms that control cell migration in wound repair. Hyaluronan Mediated Motility Receptor (HMMR) encodes a receptor for hyaluronan-mediated motility (RHAMM), a non-integral cell surface hyaluronan receptor and intracellular protein that promotes mitotic spindle formation and cell motility. RHAMM has been found to have increased expression in both cancers and wounds, and when cancers show increased RHAMM expression poor outcomes have occurred. Therefore, RHAMM has been shown to contribute to both natural healing mechanisms and cancer cell pathology. RHAMM is expressed in breast tissue and forms a polarity normalizing complex with BRCA1. Mutations of BRCA1 have been associated with a loss of apicobasal cell polarity along with a subsequent increased expression of RHAMM. Here we show how a human breast carcinoma cell line was maintained in media prepared with a dilute saline solution that had been exposed to a dielectrophoretic (DEP) electromagnetic field (EMF) generated by 3 amperes of direct current (dc) to a device housing an array of conductive rings. This Bio electric Field Enhancement (BEFE) device has been available commercially for use in baths/footbaths since 1996 and consumers claim that it provides health benefits ranging from lowering blood pressure to faster wound healing. Our studies showed a significant inhibition of growth of human breast carcinoma MDA MB-231 cells when they were maintained in media prepared with dc-DEP EMF force treated dilute saline while no growth inhibition occurred when the same cells were maintained in identically prepared but untreated media. Importantly, no growth inhibition was observed in human epithelial MCF-10A cells when grown in either treated or untreated media. Also, mitotic spindle formation was inhibited in the human breast carcinoma when they were grown in dc-DEP EMF force treated media. To determine if any gene expression changes contributed to the selective growth inhibition and absent mitotic spindle formation in the human breast carcinoma grown in the treated media, we employed microarray analysis and found that there was large-scale transcriptional reprogramming of the tumor cells grown in the treated media with over 1,000 genes up- or down-regulated over 2-fold, whereas the non-cancerous MCF-10A cells showed relatively modest changes in gene expression. Of the genes affected in the MDA-MB-231 cells, the significance of down-regulation of HMMR is discussed. The ability to enhance cell polarity through the application of this dc-DEP EMF force may offer another way to stabilize HMMR and differentially modulate its expression in cancerous and noncancerous cells. PMID- 28595039 TI - Metabolic processing of the amyloid precursor protein -- new pieces of the Alzheimer's puzzle. AB - Alzheimer's disease (AD) continues to be a daunting and costly challenge for research, medicine, and society. AD pathologies point toward the involvement of metabolic fragments of the amyloid precursor protein (APP) in the pathogenesis of the disease. Through sequential enzymatic processing, APP is metabolized into several potential polypeptides, including the toxic amyloid-beta (Abeta) peptide. Though great progress has been made in understanding the mechanism of conventional metabolic processing of APP to yield products such as Abeta, AD remains unpreventable and irreversible at any stage. Recent new reports provide data that add both complexity to the issue and new hope for potential avenues of therapeutic intervention. Novel metabolic processing events such as delta secretase and eta-secretase have been revealed that generate previously uncharacterized APP metabolic fragments with the potential to participate in AD pathogenesis. Additionally, enzymes known to act in other metabolic pathways, such as meprin beta, have been found to cleave APP to yield products known to participate in AD pathologies. This review provides an overview of current knowledge of conventional and novel APP processing. PMID- 28595040 TI - The "Kantian Principle" for natural history and its historical significance. PMID- 28595041 TI - Mercury concentrations in lean fish from the Western Mediterranean Sea: Dietary exposure and risk assessment in the population of the Balearic Islands. AB - The present study reports total mercury (THg) and methylmercury (MeHg) concentrations in 32 different lean fish species from the Western Mediterranean Sea, with a special focus on the Balearic Islands. The concentrations of THg ranged between 0.05mg/kg ww and 3.1mg/kg ww (mean 0.41mg/kg ww). A considerable number of the most frequently fish species consumed by the Spanish population exceed the maximum levels proposed by the European legislation when they originate from the Mediterranean Sea, such as dusky grouper (100% of the examined specimens), common dentex (65%), conger (45%), common sole (38%), hake (26%) and angler (15%), among others. The estimated weekly intakes (EWI) in children (7-12 years of age) and adults from the Spanish population (2.7ug/kg bw and 2.1ug/kg bw, respectively) for population only consuming Mediterranean fish were below the provisional tolerable weekly intake (PTWI) of THg established by EFSA in 2012, 4ug/kg bw. However, the equivalent estimations for methylmercury, involving PTWI of 1.3ug/kg bw, were two times higher in children and above 50% in adults. For hake, sole, angler and dusky grouper, the most frequently consumed fish, the estimated weekly intakes in both children and adults were below the maximum levels accepted. These intakes correspond to maximum potential estimations because fish from non-Mediterranean origin is often consumed by the Spanish population including the one from the Balearic Islands. PMID- 28595042 TI - Hydro-dam - A nature-based solution or an ecological problem: The fate of the Tonle Sap Lake. AB - Recent proliferation of hydro-dams was one of the nature-based solutions to meet the increasing demand for energy and food in the Lower Mekong River Basin (LMRB). While construction of these hydro-dams generated some hydropower and facilitated expansion of irrigated lands, it also significantly altered the basin-wide hydrology and subsequently impacted wetland ecosystems. Unintended adverse consequences of ecosystem services from lakes and wetlands offset the intended gains in hydroelectricity and irrigated agriculture. The trade-offs between gains in energy and food production and losses in aquatic ecosystem services were perceived to be significant but knowledge of the magnitude, spatial extent, and type of ecosystem services change is lacking and, therefore, the question whether the hydro-dam is an optimized solution or a potential ecological problem remains unanswered. In this study, as the first step to answer this question and using the Tonle Sap Lake as an example, we quantified one of the impacts of hydro-dams on lake ecosystem's phenology in terms of open water area, a critical ecological characteristic that affects lake systems' fish production, biodiversity, and livelihoods of the local communities. We used the MODIS-NDVI time series, forecast function and the Mann-Kendall trend test method to first quantify the open water area, analyzed its changes over time, and then performed correlation analysis with climate variables to disentangle dam impacts. The results showed reduced hydro-periods, diminishing lake seasonality and a declining trend in Tonle Sap Lake open water area over the past 15 years. These changes were insignificantly related to climatic influence during the same period. It is concluded that basin-wide hydro-dam construction and associated agricultural irrigation were deemed to be the primary cause of these ecological changes. Further analyses of changes in the lake's ecosystem services, including provision and cultural services, need to be carried out in order to have a holistic understanding of the trade-offs brought by the hydro-dam proliferation as a solution to the emerging energy and food demand in the LMRB. PMID- 28595044 TI - Enhanced Responsiveness and Low-Level Awareness in Stochastic Network States. AB - Desynchronized brain states are known to be associated with arousal and increased awareness, but the exact mechanisms are unknown. Here, we show that neuronal networks displaying asynchronous irregular (AI) activity can implement a low level form of awareness, due to their specific responsiveness properties. We emphasize the importance of the conductance state and stochasticity to explain these properties. We suggest that the purpose of cortical structures is to generate AI states with optimal responsiveness, to be globally aware of external stimuli. PMID- 28595043 TI - The association between the incidence of postmenopausal breast cancer and concentrations at street-level of nitrogen dioxide and ultrafine particles. AB - BACKGROUND: There is scant information as to whether traffic-related air pollution is associated with the incidence of breast cancer. Nitrogen dioxide (NO2) and ultrafine particles (UFPs, <0.1um), are two pollutants that capture intra-urban variations in traffic-related air pollution and may also be associated with incidence. METHODS: We conducted a population-based, case-control study of street-level concentrations of NO2 and UFPs and incident postmenopausal breast cancer in Montreal, Canada. Incident cases were identified between 2008 and 2011 from all but one hospital that treated breast cancer in the Montreal area. Population controls were identified from provincial electoral lists of Montreal residents and frequency-matched to cases using 5-year age groups. Concentrations of NO2 and UFPs were estimated using two separate land-use regression models. Exposures were assigned to residential locations at the time of recruitment, and we identified residential histories of women who had lived in these residences for 10 years or more. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models adjusting for individual-level and ecological covariates. We assessed the functional form of NO2 and UFP exposures using natural cubic splines. RESULTS: We found that the functional form of the response functions between incident postmenopausal breast cancer and concentrations of NO2 and UFPs were consistent with linearity. For NO2, we found increasing risks of breast cancer for all subjects combined and stronger associations when analyses were restricted to those women who had lived at their current address for 10 years or more. Specifically, the OR, adjusted for personal covariates, per increase in the interquartile range (IQR=3.75 ppb) of NO2 was 1.08 (95%CI: 0.92-1.27). For women living in their homes for 10 years or more, the adjusted OR was 1.17 (95%CI: 0.93-1.46; IQR=3.84 ppb); for those not living at that home 10 years before the study, it was 0.93 (95%CI: 0.64, 1.36; IQR=3.65 ppb). For UFPs, the ORs were lower than for NO2, with little evidence of association in any of the models or sub-analyses and little variability in the ORs (about 1.02 for an IQR of ~3500cm-3). On the other hand, we found higher ORs amongst cases with positive oestrogen and progesterone receptor status; namely for NO2, the OR was 1.13 (95%CI: 0.94-1.35) and for UFPs it was 1.05 (95%CI: 0.96 1.14). CONCLUSIONS: Our findings suggest that exposure to ambient NO2 and UFPs may increase the risk of incident postmenopausal breast cancer especially amongst cases with positive oestrogen and progesterone receptor status. PMID- 28595045 TI - Symmetry Breaking in Space-Time Hierarchies Shapes Brain Dynamics and Behavior. AB - In order to maintain brain function, neural activity needs to be tightly coordinated within the brain network. How this coordination is achieved and related to behavior is largely unknown. It has been previously argued that the study of the link between brain and behavior is impossible without a guiding vision. Here we propose behavioral-level concepts and mechanisms embodied as structured flows on manifold (SFM) that provide a formal description of behavior as a low-dimensional process emerging from a network's dynamics dependent on the symmetry and invariance properties of the network connectivity. Specifically, we demonstrate that the symmetry breaking of network connectivity constitutes a timescale hierarchy resulting in the emergence of an attractive functional subspace. We show that behavior emerges when appropriate conditions imposed upon the couplings are satisfied, justifying the conductance-based nature of synaptic couplings. Our concepts propose design principles for networks predicting how behavior and task rules are represented in real neural circuits and open new avenues for the analyses of neural data. PMID- 28595046 TI - Memory Retrieval from First Principles. AB - The dilemma that neurotheorists face is that (1) detailed biophysical models that can be constrained by direct measurements, while being of great importance, offer no immediate insights into cognitive processes in the brain, and (2) high-level abstract cognitive models, on the other hand, while relevant for understanding behavior, are largely detached from neuronal processes and typically have many free, experimentally unconstrained parameters that have to be tuned to a particular data set and, hence, cannot be readily generalized to other experimental paradigms. In this contribution, we propose a set of "first principles" for neurally inspired cognitive modeling of memory retrieval that has no biologically unconstrained parameters and can be analyzed mathematically both at neuronal and cognitive levels. We apply this framework to the classical cognitive paradigm of free recall. We show that the resulting model accounts well for puzzling behavioral data on human participants and makes predictions that could potentially be tested with neurophysiological recording techniques. PMID- 28595048 TI - How Does the Brain Work? PMID- 28595047 TI - From Brain-Environment Connections to Temporal Dynamics and Social Interaction: Principles of Human Brain Function. AB - Experimental data about brain function accumulate faster than does our understanding of how the brain works. To tackle some general principles at the grain level of behavior, I start from the omnipresent brain-environment connection that forces regularities of the physical world to shape the brain. Based on top-down processing, added by sparse sensory information, people are able to form individual "caricature worlds," which are similar enough to be shared among other people and which allow quick and purposeful reactions to abrupt changes. Temporal dynamics and social interaction in natural environments serve as further essential organizing principles of human brain function. PMID- 28595049 TI - Space-Time Dynamics of Membrane Currents Evolve to Shape Excitation, Spiking, and Inhibition in the Cortex at Small and Large Scales. AB - In the cerebral cortex, membrane currents, i.e., action potentials and other membrane currents, express many forms of space-time dynamics. In the spontaneous asynchronous irregular state, their space-time dynamics are local non-propagating fluctuations and sparse spiking appearing at unpredictable positions. After transition to active spiking states, larger structured zones with active spiking neurons appear, propagating through the cortical network, driving it into various forms of widespread excitation, and engaging the network from microscopic scales to whole cortical areas. At each engaged cortical site, the amount of excitation in the network, after a delay, becomes matched by an equal amount of space-time fine-tuned inhibition that might be instrumental in driving the dynamics toward perception and action. PMID- 28595050 TI - Inference in the Brain: Statistics Flowing in Redundant Population Codes. AB - It is widely believed that the brain performs approximate probabilistic inference to estimate causal variables in the world from ambiguous sensory data. To understand these computations, we need to analyze how information is represented and transformed by the actions of nonlinear recurrent neural networks. We propose that these probabilistic computations function by a message-passing algorithm operating at the level of redundant neural populations. To explain this framework, we review its underlying concepts, including graphical models, sufficient statistics, and message-passing, and then describe how these concepts could be implemented by recurrently connected probabilistic population codes. The relevant information flow in these networks will be most interpretable at the population level, particularly for redundant neural codes. We therefore outline a general approach to identify the essential features of a neural message-passing algorithm. Finally, we argue that to reveal the most important aspects of these neural computations, we must study large-scale activity patterns during moderately complex, naturalistic behaviors. PMID- 28595052 TI - Hierarchy of Information Processing in the Brain: A Novel 'Intrinsic Ignition' Framework. AB - A general theory of brain function has to be able to explain local and non-local network computations over space and time. We propose a new framework to capture the key principles of how local activity influences global computation, i.e., describing the propagation of information and thus the broadness of communication driven by local activity. More specifically, we consider the diversity in space (nodes or brain regions) over time using the concept of intrinsic ignition, which are naturally occurring intrinsic perturbations reflecting the capability of a given brain area to propagate neuronal activity to other regions in a given brain state. Characterizing the profile of intrinsic ignition for a given brain state provides insight into the precise nature of hierarchical information processing. Combining this data-driven method with a causal whole-brain computational model can provide novel insights into the imbalance of brain states found in neuropsychiatric disorders. PMID- 28595051 TI - Optimizing Neural Information Capacity through Discretization. AB - Discretization in neural circuits occurs on many levels, from the generation of action potentials and dendritic integration, to neuropeptide signaling and processing of signals from multiple neurons, to behavioral decisions. It is clear that discretization, when implemented properly, can convey many benefits. However, the optimal solutions depend on both the level of noise and how it impacts a particular computation. This Perspective discusses how current physiological data could potentially be integrated into one theoretical framework based on maximizing information. Key experiments for testing that framework are discussed. PMID- 28595053 TI - The Brain as an Efficient and Robust Adaptive Learner. AB - Understanding how the brain learns to compute functions reliably, efficiently, and robustly with noisy spiking activity is a fundamental challenge in neuroscience. Most sensory and motor tasks can be described as dynamical systems and could presumably be learned by adjusting connection weights in a recurrent biological neural network. However, this is greatly complicated by the credit assignment problem for learning in recurrent networks, e.g., the contribution of each connection to the global output error cannot be determined based only on locally accessible quantities to the synapse. Combining tools from adaptive control theory and efficient coding theories, we propose that neural circuits can indeed learn complex dynamic tasks with local synaptic plasticity rules as long as they associate two experimentally established neural mechanisms. First, they should receive top-down feedbacks driving both their activity and their synaptic plasticity. Second, inhibitory interneurons should maintain a tight balance between excitation and inhibition in the circuit. The resulting networks could learn arbitrary dynamical systems and produce irregular spike trains as variable as those observed experimentally. Yet, this variability in single neurons may hide an extremely efficient and robust computation at the population level. PMID- 28595055 TI - The Body Model Theory of Somatosensory Cortex. AB - I outline a microcircuit theory of somatosensory cortex as a body model serving both for body representation and "body simulation." A modular model of innervated and non-innervated body parts resides in somatosensory cortical layer 4. This body model is continuously updated and compares to an avatar (an animatable puppet) rather than a mere sensory map. Superficial layers provide context and store sensory memories, whereas layer 5 provides motor output and stores motor memories. I predict that layer-6-to-layer-4 inputs initiate body simulations allowing rehearsal and risk assessment of difficult actions, such as jumps. PMID- 28595054 TI - Neural Manifolds for the Control of Movement. AB - The analysis of neural dynamics in several brain cortices has consistently uncovered low-dimensional manifolds that capture a significant fraction of neural variability. These neural manifolds are spanned by specific patterns of correlated neural activity, the "neural modes." We discuss a model for neural control of movement in which the time-dependent activation of these neural modes is the generator of motor behavior. This manifold-based view of motor cortex may lead to a better understanding of how the brain controls movement. PMID- 28595056 TI - Shaping the Default Activity Pattern of the Cortical Network. AB - Slow oscillations have been suggested as the default emergent activity of the cortical network. This is a low complexity state that integrates neuronal, synaptic, and connectivity properties of the cortex. Shaped by variations of physiological parameters, slow oscillations provide information about the underlying healthy or pathological network. We review how this default activity is shaped, how it acts as a powerful attractor, and how getting out of it is necessary for the brain to recover the levels of complexity associated with conscious states. We propose that slow oscillations provide a robust unifying paradigm for the study of cortical function. PMID- 28595057 TI - Hospitalization cost at childbirth: Health parameters and colonization with antimicrobial resistant bacteria and methicillin susceptible Staphylococcus aureus. AB - OBJECTIVE: Antimicrobial resistant bacteria (AMR) are of public health and economic relevance. However, there is a lack of data regarding AMR colonization in pregnant women and in newborns. Furthermore, there are few studies analyzing hospital's net income (revenues and costs). STUDY DESIGN: The cross-sectional study took place in two Bavarian clinics. Available data regarding women and newborns were collected using a standardized questionnaire, personal IDs and medical records in addition to AMR/MSSA screening. Economic data consisted of estimated hospitalization costs, calculated using a billing system called G-DRG (German-Diagnosis Related Groups) as well as real hospitalization costs (e.g. staff, medical and non-medical infrastructure costs). RESULTS: Data from 635 pregnant women and 566 newborns were included. While AMR colonization has shown no significant association with clinical complications, or net hospital income; primipara status and medical condition during pregnancy did. AMR colonization did not have a significant influence on the health status of pregnant women or of the newborns. Net hospital income for pregnant women was mostly negative in 2014. In 2014 and 2015 the majority of the cases had a net income between +/-? 1000. Newborns with clinical complications differed significantly in Apgar score at 1min, weight, body length and AMR colonization of the pregnant woman and/or the newborn (p<=0.05). CONCLUSION: Results indicate that colonization does not lead to increased costs during hospitalization considering real hospitalization costs as well as G-DRG estimated costs. Both DRG groups had similar MSSA and AMR prevalence and health status. In future studies, a Centralized Cost Accounting as billing method and an improved possibility of AMR coding in G-DRG catalog would be desirable. PMID- 28595058 TI - Comparison of FSE T2 W PROPELLER and 3D-FIESTA of 3 T MR for the internal auditory canal. AB - OBJECTIVE: The study compared the use of periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) technique fast spin echo (FSE) T2 W and the sequence of three-dimensional fast imaging employing steady state acquisition (3D-FIESTA) technique in the MRI of the internal auditory canal for overall image quality improvement. MATERIALS AND METHODS: One hundred thirty two patients undergoing FSE T2 W PROPELLER and 3D-FIESTA examinations of the internal auditory canal were included. All examinations were performed at 3.0 T with comparison of a sagittal oblique FSE T2 W sequence with the PROPELLER technique to 3D-FIESTA in the same reconstructed orientation with PROPELLER. Image quality was evaluated by two radiologists using a 4-point scale. The Wilcoxon signed rank test was used to compare the data of the two techniques. RESULTS: The image quality of FSE T2 W PROPELLER was significantly improved compared to the reconstructed images of 3D-FIESTA. Observer 1: median FSE T2 W with PROPELLER, 4 [mean, 3.455] versus median reconstructed 3D-FIESTA, 3 [mean, 3.15], (P<.001); Observer 2: median FSE T2 W with PROPELLER, 4 [mean, 3.47] versus median reconstructed 3D-FIESTA, 3 [mean, 3.25], (P<.001). Interobserver agreement was good (k value, 0.73) for the rating of the overall image quality. CONCLUSION: The FSE T2 W PROPELLER technique for MRI of internal auditory canal reduced uncertainty caused by motion artifact and improved the quality of the image compared to the reconstructed 3D-FIESTA. It was affected by different parameters including the blade width, echo train length (ETL). This is explained by data oversampling at the center region of k-space, which requires additional imaging time over conventional MRI techniques. Increasing blade was expected to improve motion correction effects but also the signal-to-noise ratio. ETL increases the image sharpness and the overall image quality. PMID- 28595059 TI - Coming to the new D.A.R.E.: A preliminary test of the officer-taught elementary keepin' it REAL curriculum. AB - The present study reports a preliminary evaluation of D.A.R.E.'s new elementary school keepin' it REAL substance abuse prevention program. Given the widespread dissemination of D.A.R.E., this evaluation, even though of short term effects, has important implications for national prevention efforts. The new prevention curriculum teaches social and emotional competencies such as decision making and resistance skills. Social and emotional competencies and other risk factors were examined among students (N=943) in 26 classrooms, 13 classrooms in the treatment condition (n=359) and 13 classrooms in the control condition (n=584) using a quasi-experimental matched group design. Pretest comparisons of treatment and control groups were completed, along with attrition analyses, and hierarchical logistic and linear regressions were computed to assess the intervention. The results revealed that the intervention produced significant effects on preventative factors such as the likelihood of resisting peer pressure, increased responsible decision making knowledge and decision-making skills, and confidence in being able to explain why they would refuse offers of cigarettes. The results of this study suggest that D.A.R.E.'s elementary keepin' it REAL program has promise as a social and emotional learning (SEL) based prevention program. PMID- 28595061 TI - Synthesis of a glucosylated alpha-S-galactosylceramide as potential immunostimulant. AB - Synthesis of a glucosylated alpha-S-galactosylceramide (1), a potential immunostimulant, was achieved starting from D-galactose. Both O- and S-glycosidic linkages were constructed in highly stereoselective way, and the synthetic strategy could be extended to the synthesis of other alpha-S-GalCer analogues. PMID- 28595060 TI - Parent-adolescent relationships in Hispanic versus Caucasian families: Associations with alcohol and marijuana use onset. AB - Parent-adolescent relationship (PAR) factors such as social support and negative interactions are associated with initiation of alcohol and marijuana use during adolescence. However, few studies have examined whether the relationship between PAR, especially the paternal role, and substance use onset varies by ethnicity. This is important given that ethnic group differences have been related to alcohol and marijuana use, cultural values and parenting. This study examines whether ethnicity moderates the prospective prediction of substance use onset by PAR factors. The sample comprised 124 adolescents who self-identified as Hispanic and 795 adolescents who self-identified as non-Hispanic Whites, and was drawn from an ongoing longitudinal survey on adolescent substance use. Discrete-time survival modeling was used to prospectively predict age at onset of substance use among participants who were substance-naive at baseline. Interactions between ethnicity and PAR factors indicated that PAR factors had a larger influence on age of alcohol and marijuana onset for Hispanics than for Caucasians. Among Hispanics, greater social support from and greater negative interactions with the father-figure were more predictive of earlier onset of alcohol, and greater social support from the mother-figure was more predictive of later alcohol onset, compared to Caucasians. Similarly, greater negative interactions with the father figure were more predictive of earlier onset of marijuana use among Hispanics than among Caucasians. These findings suggest the influence of PAR on alcohol and marijuana use onset may be larger for Hispanics than for Caucasians. Incorporating these parenting factors in substance use prevention programs advances public health in a culturally sensitive manner that is relevant to at risk Hispanic adolescents. PMID- 28595062 TI - Self-esteem in children in joint physical custody and other living arrangements. AB - OBJECTIVES: Parental support has been shown to be important for children's self esteem, which in turn is related to later important life outcomes. Today, an increasing number of children in the Western world spend time in both the parents' respective households after a separation. Children who live with both parents report more parental support than children who live only with one parent after a divorce. We took the opportunity of the commonness of children sharing their time between their parents' homes in Sweden to investigate children's self esteem in relation to family type. STUDY DESIGN AND METHODS: With nationally representative survey data (ULF) collected from both parents and children, we analyze differences in children's self-esteem among 4823 10-18 year olds in nuclear families, joint physical custody and those living mostly or only with one parent after a separation using ordinary least squares regression, adjusting for demographic and socioeconomic characteristics. RESULTS: We found no significant difference in self-esteem between children who lived equally much with both parents, mostly with one parent and those in nuclear families, whereas children in single care showed lower self-esteem compared with children in the other living arrangements. The difference was not explained by socioeconomic factors. CONCLUSION: The self-esteem of children who share their time between their parent's respective homes after a separation does not deviate from that in their peers in nuclear families. Instead, those in single care reported lower self esteem than those in the other living arrangements. These differences were not explained by socioeconomic factors. Longitudinal studies are needed to establish pre- and post-separation family characteristics that influence self-esteem and well-being in young people. PMID- 28595063 TI - Motivations for volunteers in food rescue nutrition. AB - OBJECTIVE: A variety of organizations redistribute surplus food to low-income populations through food rescue nutrition. Why volunteers participate in these charitable organizations is unclear. The aim of this study is to document the participation and motivations of volunteers who are involved specifically in food rescue nutrition. STUDY DESIGN: A cross-sectional study was conducted in two phases. METHODS: In phase 1, a new instrument, Motivations to Volunteer Scale, was developed and validated in 40 participants (aged >=18 years). In phase 2, the new scale and a demographics questionnaire were administered to 300 participants who were volunteering in food pantries and churches. RESULTS: The pilot study showed that Motivations to Volunteer Scale exhibited an internal consistency of Cronbach's alpha of 0.73 (P < 0.01), and a reliability from a test-retest of times 1 and 2 was r = 0.9 (P < 0.05); paired t-test was insignificant (P > 0.05). The scale was validated also by comparison to the Volunteer Function Inventory (r = 0.86, P < 0.05). The constructs of the newly developed Motivations to Volunteer Scale were requirement, career improvement, social life, and altruism. The mean motivation score of the 300 volunteers was 9.15 +/- 0.17. Greater motivations were observed among participants who were aged >45 years, women, Hispanics, college/university graduates, physically inactive, non-smokers, and had an income >= $48,000. CONCLUSIONS: The Motivations to Volunteer Scale is a valid tool to assess why individuals volunteer in food rescue nutrition. The extent of motivations of participants was relatively high, and the primary reason for volunteering was altruism. Health professionals should be encouraged to participate in food redistribution. PMID- 28595064 TI - A means of improving public health in low- and middle-income countries? Benefits and challenges of international public-private partnerships. AB - OBJECTIVE: In the last two decades international public-private partnerships have become increasingly important to improving public health in low- and middle income countries. Governments realize that involving the private sector in projects for financing, innovation, development, and distribution can make a valuable contribution to overcoming major health challenges. Private-public partnerships for health can generate numerous benefits but may also raise some concerns. To guide best practice for public-private partnerships for health to maximize benefits and minimize risks, the first step is to identify potential benefits, challenges, and motives. We define motives as the reasons why private partners enter partnerships with a public partner. STUDY DESIGN: We conducted a systematic review of the literature using the PRISMA guidelines. METHOD: We reviewed the literature on the benefits and challenges of public-private partnerships for health in low- and middle-income countries provided by international pharmaceutical companies and other health-related companies. We provide a description of these benefits, challenges, as well as of motives of private partners to join partnerships. An approach of systematic categorization was used to conduct this research. RESULT: We identified six potential benefits, seven challenges, and three motives. Our main finding was a significant gap in the available academic literature on this subject. Further empirical research using both qualitative and quantitative approaches is required. From the limited information that is readily available, we conclude that public-private partnerships for health imply several benefits but with some noticeable and crucial limitations. CONCLUSION: In this article, we provide a description of these benefits and challenges, discuss key themes, and conclude that empirical research is required to determine the full extent of the challenges addressed in the literature. PMID- 28595065 TI - New quinoline-arylamidine hybrids: Synthesis, DNA/RNA binding and antitumor activity. AB - Four series of new hybrid molecules with 7-chloroquinoline and arylamidine moieties joined through the rigid -O- (groups I (2a-g) and II (5a-g)) or flexible -NH-CH2-CH2-O- (groups III (8a-g) and IV (10a-g)) linker were synthesized, and their DNA/RNA binding properties and cytotoxic activity were tested, against several human cancer lines. The compounds and their interaction with DNA and RNA were studied by UV-Vis and CD spectroscopy. The obtained results showed that the binding affinity of the investigated compounds increases proportionally with the increase of the length and number of groups able to form hydrogen bonds with ds polynucleotides. Improvement of binding was additionally achieved by reduction of the structural rigidity of the investigated compounds, new hybrid compounds preferentially bind to ctDNA. For most of them the DNA/RNA grooves are dominant binding sites, except for the compounds from group II for which intercalation in polyA-polyU was the dominant binding mode. The antiproliferative effects were tested by the MTT test on normal (MDCK1), carcinoma (HeLa and CaCo2) and leukemia cell lines (Raji and K462). The GI50 values for all investigated compounds ranged from 5 to more than 100 * 10-6 mol dm-3. Carcinoma cells were more resistant to the investigated compounds than leukemia cells. The most effective compounds against leukemia cell lines were from group IV (10a-g), with GI50 values ranging from of 5 and 35 * 10-6 mol dm-3. The cell cycle arrest was investigated by flow cytometry and the obtained results indicate that the selected compounds, 2d, 2e, 8a, 10d, 10e, and 10f, induce changes in the cell cycle of treated cells, but the cycle phase distribution varies between them. A significant decrease in the number of cells in S phase (p < 0.001) was observed in all treated cells, but only 10d and 10f induce cell cycle arrest at G0/G1 phase, dominantly. PMID- 28595066 TI - Synthesis, antiprotozoal activity, and chemoinformatic analysis of 2-(methylthio) 1H-benzimidazole-5-carboxamide derivatives: Identification of new selective giardicidal and trichomonicidal compounds. AB - A series of twelve new 2-(methylthio)-1H-benzimidazole-5-carboxamide derivatives (1-12) were synthesized and their antiparasitic activity was tested in vitro against Giardia intestinalis, Trichomonas vaginalis and Entamoeba histolytica. Experimental evaluations showed IC50 values within the nanomolar range for all tested compounds, some showing higher activity than metronidazole and albendazole. A chemoinformatic study was used to compare the structure-activity relationship of the synthesized carboxamides with those of 91 previously studied benzimidazoles, and with some Nitazoxanide-N-methylbenzimidazole hybrids recently synthetized by our group. Compounds 1 and 3 were identified as prominent selective compounds against T. vaginalis and G. intestinalis, respectively, while compound 4 was found to be of broad spectrum against the three protozoans. PMID- 28595068 TI - Molecular topology: A new strategy for antimicrobial resistance control. AB - The control of antimicrobial resistance (AMR) seems to have come to an impasse. The use and abuse of antibacterial drugs has had major consequences on the genetic mutability of both pathogenic and nonpathogenic microorganisms, leading to the development of new highly resistant strains. Because of the complexity of this situation, an in silico strategy based on QSAR molecular topology was devised to identify synthetic molecules as antimicrobial agents not susceptible to one or several mechanisms of resistance such as: biofilms formation (BF), ionophore (IA) activity, epimerase (EI) activity or SOS system (RecA inhibition). After selecting a group of 19 compounds, five of them showed significant antimicrobial activity against several strains of Staphylococcus (2 S. aureus, including 1 methicillin resistant, and 1 S. epidermidis), with MIC values between 16 and 32 mg/L. Among the compounds active on RecA, one showed a marked activity in decreasing RecA gene expression in Escherichia coli. PMID- 28595067 TI - Pentapeptides for the treatment of small cell lung cancer: Optimisation by Nind alkyl modification of the tryptophan side chain. AB - The pentapeptide, tert-Prenyl4th-NH2 (DMePhe-DTrp-Phe-DTrp(N-tert-prenyl)-Leu NH2), has recently been reported by our group to exhibit properties of substance P (SP) antagonist G against small cell lung cancer (SCLC). In this study, we undertook a systematic structure activity investigation to optimise this lead compound to improve its in vitro anti-tumour activity and biocompatibility. A series of d-tryptophan (D-Trp) derivatives were synthesised, with a range of aliphatic N-alkyl chains (methyl to pentyl) on the indole nitrogen (Nind). These were incorporated into the pentapeptide sequence by substitution of the Nind-tert prenylated D-Trp 4th residue with the Nind-alkylated D-Trp derivatives. These pentapeptides were significantly more potent than tert-Prenyl4th-NH2, with the Nind-butyl modification generating the most cytotoxic peptides. Compared to tert Prenyl4th-NH2, a single butyl modification on the 4th D-Trp residue (Butyl4th NH2) showed a ~3 fold enhancement in cytotoxicity in either the chemo-naive H69 or the DMS79 (originating from a patient treated with chemotherapeutics and radiation therapy) SCLC cell lines. In addition, the di-butylated sequence on the 2nd and 4th D-Trp residues (Butyl2nd,4th-NH2) gave ~4.5 times higher cytotoxicity against the H69 cell line and a ~2 fold increase against the DMS79 cell line, compared to tert-Prenyl4th-NH2. The favoured position for butyl modification was the 4th D-Trp residue, as the Butyl2nd-NH2 peptide gave lower cytotoxicity on both cell lines. Butylated peptide sequences, when exposed to neat mouse plasma for 24 h at 37 degrees C, were found to resist degradation with >80% remaining intact compared to ~58% for tert-Prenyl4th-NH2. The degradation pathway in plasma occurs via de-amidation of the C-terminus, confirmed by mass spectrometry and RP HPLC analysis. The butyl modification also conferred resistance to metabolism when tested using S9 liver fraction from mouse. The optimum analogue responsive against the DMS79 cell line was the Butyl4th-NH2 pentapeptide, which revealed a concentration dependent increase in apoptosis: the level of late apoptotic cells rose from ~36% at 2 MUM to ~96% at 6 MUM, as determined by flow cytometry, compared to the unmodified peptide that showed no such effect. Concluding, the butyl substitutions offered the best perspective for high cytotoxicity, induction of apoptosis and metabolic compatibility thereby comprising an improved broad spectrum SP antagonist candidate for treatment of SCLC. PMID- 28595069 TI - Kinetic analysis of aerobic biotransformation pathways of a perfluorooctane sulfonate (PFOS) precursor in distinctly different soils. AB - With the phaseout of perfluorooctane sulfonate (PFOS) production in most countries and its well known recalcitrance, there is a need to quantify the potential release of PFOS from precursors previously or currently being emitted into the environment. Aerobic biodegradation of N-ethyl perfluorooctane sulfonamidoethanol (EtFOSE) was monitored in two soils from Indiana, USA: an acidic forest silt loam (FRST-48, pH = 5.5) and a high pH agricultural loam (PSF 49, pH = 7.8) with similar organic carbon contents (2.4 and 2.6%) for 210 d and 180 d, respectively. At designated times, triplicate samples were sacrificed for which headspace samples were taken followed by three sequential extractions. Extracts were analyzed using HPLC-tandem mass spectrometry. Measured profiles of EtFOSE degradation and generation/degradation of subsequent metabolites were fitted to the Indiana soils data as well as to a previously published data set for a Canadian soil using an R-based model (KinGUII) to explore pathways and estimate half-lives (t1/2) for EtFOSE and metabolites. EtFOSE degradation ranged from a few days to up to a month. PFOS yields ranged form 1.06-5.49 mol% with the alkaline soils being four to five times higher than the acidic soil. In addition, a direct pathway to PFOS had to be invoked to describe the early generation of PFOS in the Canadian soil. Of all metabolites, the sulfonamidoacetic acids were the most persistent (t1/2 >= 3 months) in all soils. We hypothesized that while pH-pKa dependent speciation may have impacted rates, differences in microbial communities between the 3 soils arising from varied soil properties including pH, nutrient levels, soil management, and climatic regions are likely the major factors affecting pathways, rates, and PFOS yields. PMID- 28595070 TI - Effects of limited midwifery clinical education and practice standardisation of student preparedness. AB - AIM: To explore the perceptions of midwifery educators regarding effects of limited standardisation of midwifery clinical education and practice on clinical preparedness of midwifery students. BACKGROUND: Investigation of levels of clinical competency of students is a critical need in the current era. Such competency levels are especially important in midwifery practice in South Africa as there is a significant increase of maternal deaths and litigations in the country. Most of the deaths are in the primary healthcare level maternity units where the newly qualified midwives practise. These areas are mainly run by midwives only. The current article seeks to report the findings of the study that was conducted to investigate how midwifery educators prepare students adequately for clinical readiness. SETTINGS: The study was conducted amongst midwifery nurse educators on three campuses of the Nursing College in the Eastern Cape. DESIGN: A qualitative, explorative, descriptive and contextual research design was used for the study. DATA SOURCES AND METHODS: Seventeen purposively selected midwifery educators, with the researcher using set criteria, from a Nursing college in the Eastern Cape, were the participants in the study. Data was collected using focus group interviews that were captured by means of an audio-voice recorder. Tesch's data-analysis method was used to develop themes and sub-themes. Trustworthiness of the study was ensured using the criteria of credibility, transferability, dependability and confirmability. RESULTS: Inconsistent clinical practice amongst midwifery educators in their clinical teaching and assessment were found to be the major factors resulting from limited standardisation. The inconsistent clinical practice and assessments of midwifery educators was found to lead to loss of the necessary skills required by the students which led them to perform poorly in their final clinical assessments. CONCLUSION: There are some barriers in the current clinical teaching and education strategy used in this college that prohibit the production of confident, independent, and safe practitioners as planned. Midwifery educators need to be assisted in reviewing the current teaching strategy. Furthermore management should be involved if not the initiators of that reviewing and should put in-place new measures to support the teaching of the clinical module. PMID- 28595071 TI - Wastewater remediation by TiO2-impregnated chitosan nano-grafts exhibited dual functionality: High adsorptivity and solar-assisted self-cleaning. AB - This work provides a very infrequent and unique avenue of a novel bio-based nanografted polymeric composites achieving encouraging results in green management of dye contaminants in wastewater. A chitosan-grafted-polyN Methylaniline (Ch-g-PNMANI) and chitosan-grafted-polyN-Methylaniline imprinted TiO2 nanocomposites (Ch-g-PNMANI/TiO2) were prepared and efficiently applied in wastewater remediation. The nanocomposites were characterized by FT-IR spectroscopy, X-ray diffraction, transmission electron microscopy, UV-Vis diffuse reflectance spectroscopy and Brunauer-Emmett-Teller surface area (BET) measurements. The prepared composites exhibit higher adsorptivity in removing remazol red RB-133 (RR RB-133) dye compared to other adsorbents reported in literature. The effects of TiO2 loadings, initial dye concentration, contact time, and pH on dye adsorption were investigated. The maximum adsorption of dye was found at low pH values. Furthermore, Ch-g-PNMANI/TiO2 of the optimum TiO2 loading has higher adsorption capacity (116.3mg/g) than the pristine Ch-g-PNMANI (108.7mg/g). Moreover, the prepared adsorbents are photoactive under sunlight irradiation. The study addresses a nanocomposite of considerable adsorption and in the same time has the fastest self-cleaning photoactivity (t1/2=31.5min.) under sunlight irradiation where a plausible photodegradation mechanism was proposed. Interestingly, the presented photoactive adsorbents are still effective in removing dye after five adsorption/sunlight-assisted self-cleaning photoregeneration cycles and therefore, they can be potentially applied to the rapid, "green" and low-cost remediation of RR RB-133 enriched industrial printing and dyeing wastewater. PMID- 28595073 TI - Probing the binding reaction of cytarabine to human serum albumin using multispectroscopic techniques with the aid of molecular docking. AB - Cytarabine is a kind of chemotherapy medication. In the present study, the molecular interaction between cytarabine and human serum albumin (HSA) was investigated via fluorescence, UV-vis absorption, circular dichroism (CD) spectroscopy and molecular docking method under simulative physiological conditions. It was found that cytarabine could effectively quench the intrinsic fluorescence of HSA through a static quenching process. The apparent binding constants between drug and HSA at 288, 293 and 298K were estimated to be in the order of 103L.mol-1. The thermodynamic parameters DeltaH degrees , DeltaG degrees and DeltaS degrees were calculated, in which the negative DeltaG degrees suggested that the binding of cytarabine to HSA was spontaneous, moreover the negative DeltaS degrees and negative DeltaH degrees revealed that van der Waals force and hydrogen bonds were the major forces to stabilize the protein cytarabine (1:1) complex. The competitive binding experiments showed that the primary binding site of cytarabine was located in the site I (subdomain IIA) of HSA. In addition, the binding distance was calculated to be 3.4nm according to the Forster no-radiation energy transfer theory. The analysis of CD and three dimensional (3D) fluorescence spectra demonstrated that the binding of drug to HSA induced some conformational changes in HSA. The molecular docking study also led to the same conclusion obtained from the spectral results. PMID- 28595072 TI - Zinc phthalocyanines attached to gold nanorods for simultaneous hyperthermic and photodynamic therapies against melanoma in vitro. AB - Studies indicate that hyperthermic therapy using gold nanorods and photodynamic activity with many photosensitizers can present a synergistic effect, and offer a great therapeutic potential, although more investigation needs to be performed before such approach could be implemented. We proposed to investigate the effect of the attachment of phthalocyanines on the surface of gold nanorods (well characterized devices for hyperthermia generation) for the elimination of melanoma, one of the most important skin cancers due to its high lethality. Following the synthesis of nanorods through a seed-mediated method, the efficacy of photodynamic therapy (PDT) and hyperthermia was assessed separately. We chose to coat the nanorods with two tetracarboxylated zinc phthalocyanines - with or without methyl-glucamine groups. After the coating process, the phthalocyanines formed ionic complexes with the cetyltrimethylammonium bromide (CTAB) that was previously covering the nanoparticles. The nanorod-phthalocyanines complexes were analyzed by transmission electron microscopy (TEM), and their singlet oxygen and hydroxyl radical generation yields were assessed. Furthermore, they were tested in vitro with melanotic B16F10 and amelanotic B16G4F melanoma cells. The cells with nanoparticles were irradiated with laser (at 635nm), and the cell viability was assessed. The results indicate that the photodynamic properties of the phthalocyanines tested are enhanced when they are attached on the nanorods surface, and the combination of PDT and hyperthermia was able to eliminate over 90% of melanoma cells. This is a novel study because two tetracarboxylated phthalocyanines were used and because the same wavelength was irradiated to activate both the nanorods and the photosensitizers. PMID- 28595074 TI - Protective effect of Arthrospira platensis extracts against ultraviolet B-induced cellular senescence through inhibition of DNA damage and matrix metalloproteinase 1 expression in human dermal fibroblasts. AB - Ultraviolet (UV) light exposure causes skin photoaging, which is known to be preventable and controllable by application of UV-protective agents. In this study, we demonstrated, for the first time, that the extract of microalgae Arthrospira platensis has a reverse effect on UV-induced photodamage such as loss of cell viability, cellular senescence, DNA damage, and collagen destruction in dermal fibroblasts. Forty-eight extracts were prepared from the cell biomass by controlling culture light conditions, extract solvents, and disruption methods. Then, we analyzed their cytotoxicities using WST-1 assay and separated low and high cytotoxic extracts with normal human dermal fibroblasts (nHDFs). Using the low cytotoxic extracts, we performed UVB protection assay and selected the most effective extract demonstrating protective effect against UVB-induced nHDF damage. Flow cytometric analysis and senescence-associated (SA) beta galactosidase assay showed that pretreatment with the extract reversed UVB induced G2/M phase cell cycle arrest and senescence in nHDFs. Furthermore, UVB induced DNA damage in nHDFs, such as cyclobutane pyrimidine dimer formation, was significantly suppressed by the extract. Further, quantitative real-time PCR experiments revealed that the extract significantly inhibited UVB-induced upregulation of matrix metalloproteinase 1 (MMP1) and MMP3 expression in nHDFs. Therefore, we concluded that the microalgae extract can be a potential anti photoaging agent. PMID- 28595075 TI - Adsorption and photocatalysis efficiency of magnetite quantum dots anchored tin dioxide nanofibers for removal of mutagenic compound: Toxicity evaluation and antibacterial activity. AB - The Magnetite Fe3O4 quantum dots anchored SnO2 nanofibers (Fe3O4 QDs/SnO2 NFs) have been synthesized using the facile one step hydrothermal method. The characteristic structure of synthesized Fe3O4 QDs/SnO2 NFs was analyzed using X ray diffraction, Transmission electron Microscopy, Scanning electron microscopy, UV-vis diffuse reflectance, photoluminescence spectroscopy, and N2 adsorption desorption instrumental techniques. The crystallites size of Fe3O4QDs/SnO2 NFs was 7.0nm. The average diameters of Fe3O4QDs/SnO2 NFs were 7.25nm. BET surface area of Fe3O4QDs/SnO2 NFs has been found 53.064m2/g. The activity of Fe3O4 QDs/SnO2 NFs samples were compared towards adsorption and degradation of mutagenic compound such as Ethyl methanesulfonate (EMS). The Fe3O4 QDs/SnO2 NFs demonstrates 93.85% and 56.85% photo degradation and adsorption activity towards 10ppm EMS solution in 30 and 40min, respectively. Fe3O4 QDs/SnO2 NFs shows maximum removal of EMS at pH5. Additionally, cytotoxicity test showed that the newly developed catalyst has low cytotoxic effects on three kinds of human cells. The antibacterial activity evaluation against two bacterials, including Staphylococcus aureus (ATCC 43300), and Pseudomonas aeruginosa (ATCC 27853) was considered. It was found that the MIC values for the antibacterial assay in the presence of Fe3O4 QDs/SnO2 NFs were around 0.38mM with 83.4, and 85.5% inhibition for the S. aureus, and P. aeruginosa bacterial strains, respectively. PMID- 28595076 TI - Highly fluorescent carbon dots as selective and visual probes for sensing copper ions in living cells via an electron transfer process. AB - As an integral part of many important enzymes, Cu2+ is involved in a number of vital biological processes, which is linked to the oxidative damage and environmental contamination when Cu2+ is excessive. In this work, Cu2+ can be captured by the amino groups of carbon dots (CDs) to form complexes, resulting in a strong fluorescence quenching of CDs via a nonradiative electron transfer process, which offered a rapid, visual, and selective methodology for Cu2+ detection. The probe exhibited a wide response concentration range (0.01-2MUM) to Cu2+ with a detection limit of 6.7nM. Significantly, the CDs presented excellent biocompatibility and high photostability, which were applicable for the visualization of Cu2+ dynamic invasion into living cells and Tilapia mossambica. Furthermore, the toxicity of Cu2+ ions to living cells could be inhibited with CDs by the formation of complexes. PMID- 28595077 TI - A smartphone-based chloridometer for point-of-care diagnostics of cystic fibrosis. AB - Chloride in sweat is an important diagnostic marker for cystic fibrosis (CF), but the implementation of point-of-care systems for diagnosis is hindered by the prohibitive costs of existing chloride sensors. To enable low cost diagnostic solutions, we recently established a citrate-derived synthesis platform for the development of new fluorescence sensors with high selectivity for chloride. As a next step, we herein designed a smartphone operated chloridometer that optimizes the analytical performance of the citrate-derived sensor materials for the detection of chloride in sweat. The sensor material demonstrated a wide linear range of 0.8-200mM chloride and a diffusion-limited response time; sweat chloride levels corresponded to measurable changes in fluorescence emission that was captured by a smartphone. Clinical validation was performed with sweat from individuals with and without CF, demonstrating convenient sweat diagnostics with reliable detection of cystic fibrosis. To our knowledge, this is the first clinical study of a smartphone-based chloride sensor, paving the way for point-of care diagnostic systems for CF. PMID- 28595078 TI - Amyloidogenic proteins associated with neurodegenerative diseases activate the NLRP3 inflammasome. AB - Neuroinflammation has been shown as an essential factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, and Multiple Sclerosis. Furthermore, activated microglia and increased pro-inflammatory cytokines are the major hallmarks in neurodegenerative diseases. A multimolecular complex named as inflammasome is involved in the process of inflammatory response, which can activate inflammatory caspases, leading to the cleavage and secretion of inflammatory cytokines, and finally generates a potent inflammatory response. In neurodegenerative diseases, it has been widely assumed that some types of amyloid proteins might be the triggers to activate the NLRP3 inflammasome. In this review, we summarize the current researches about the role of NLRP3 inflammasome, by reviewing the main studies in vitro and in vivo experiments and discuss the potential for new therapeutic interventions in neurodegenerative diseases. PMID- 28595079 TI - Curcumin reduces the risk of chronic kidney damage in mice with nonalcoholic steatohepatitis by modulating endoplasmic reticulum stress and MAPK signaling. AB - Developing confirmation recommends that in patients with dynamic type of NAFLD, particularly nonalcoholic steatohepatitis (NASH) may have the pathogenic parts in the advancement of kidney damage. In this study we have examined the impact of curcumin on NASH instigated chronic kidney damage (CKD) and the putative mechanisms. To prepare this NASH model, neonatal C57BL/6J male mice were exposed to low-dose streptozotocin (STZ) and were fed high-fat diet (HFD) at the age of 4weeks and continued up to 14weeks, curcumin was given at 100mg/kg dose by oral gavage daily after 10weeks of STZ injection and continued for 4weeks along with HFD feeding. NASH incited mice demonstrated nephrotoxicity as proved by declining renal capacity, which was evaluated by measuring blood urea nitrogen and creatinine in serum and histopathological variations from the norm. These progressions were switched by curcumin treatment, which brought about huge change in renal capacity. Furthermore, curcumin markedly decreased NAD(P)H oxidase subunits (p67phox, p47phox, p22phox), nitrotyrosine and CYP2E1 renal protein expression as well as reduced pro-inflammatory cytokine expression (TNFalpha, IL 1beta, IFNgamma). Renal protein expression of mitogen activated protein kinases (MAPKs) (p-JNK, p-ERK1/2) and glucose regulated protein 78, CHOP were increased in NASH induced mice and curcumin treatment attenuated these increased expressions. In addition, curcumin treatment also decreased the apoptosis signaling proteins (cleaved caspase-3, cleaved caspase-12) in the NASH kidney. Taken together, our results suggest that curcumin preserves the renal function, probably by attenuating the ER stress mediated MAPK signaling. PMID- 28595080 TI - Administration of geniposide ameliorates dextran sulfate sodium-induced colitis in mice via inhibition of inflammation and mucosal damage. AB - Ulcerative colitis (UC), an idiopathic inflammatory bowel disease, not only affects millions of patients worldwide, but also increases the risk of colon cancer. Geniposide is an iridoid glycoside and has many biological activities such as anti-inflammatory and antioxidant. However, its protective efficacy and mechanism of action against UC are still unclear. In this study, we aimed to investigate the protective effects and mechanisms of geniposide on dextran sulfate sodium (DSS)-induced experimental colitis in mice. The results revealed that geniposide alleviated body weight loss, disease activity index, colon length shortening and colonic pathological damage induced by DSS. Geniposide significantly suppressed pro-inflammatory cytokines by regulating NF-kappaB and PPARgamma pathways in vivo and in vitro. Furthermore, geniposide also significantly regulated the expressions of ZO-1 and occludin in DSS-induced experimental colitis in mice and lipopolysaccharide (LPS)-triggered inflammation in Caco-2 cells. These findings indicated that geniposide may be a new natural chemopreventive agent to combat UC. PMID- 28595082 TI - A retrospective analysis of the effectiveness of antipsychotics in the treatment of ICU delirium. AB - PURPOSE: Conflicting data exists on the efficacy of antipsychotics for treatment of intensive care unit (ICU) delirium. The purpose of this study was to compare time to delirium resolution for ICU patients who were managed with and without antipsychotics. MATERIALS AND METHODS: This retrospective cohort evaluation included patients admitted to 12 ICUs at 5 sites over 5 weeks diagnosed with delirium. The primary outcome was time to delirium resolution. Secondary outcomes included ICU length of stay (LOS), mortality, discharge disposition and delirium redevelopment. A Cox proportional hazards model explored the relationship between covariates including antipsychotics and time to delirium resolution. RESULTS: A total of 255 patients met inclusion criteria; 69 (27%) received antipsychotics. In the antipsychotic group, time to resolution of delirium was longer (Median: 36hours vs. 13hours, p<0.001) and ICU LOS was longer (Median: 5.9days vs. 3.8days, p=0.005), but there were no differences in mortality or discharge disposition. Patients who used antipsychotics (HR=0.512; 95% CI: 0.276-0.952) and received mechanical ventilation (HR=0.381; 95% CI: 0.217-0.669) had slower rate for time to delirium resolution. CONCLUSIONS: While the treatment of delirium with antipsychotics remains common, antipsychotics were not associated with a shorter time to resolution of delirium. PMID- 28595081 TI - Pioglitazone attenuates lipopolysaccharide-induced depression-like behaviors, modulates NF-kappaB/IL-6/STAT3, CREB/BDNF pathways and central serotonergic neurotransmission in mice. AB - Immune activation and inflammation are closely associated with the development of depression. Pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, has exhibited antidepressant-like effects in a couple of studies. However, the underlying mechanisms are far from being fully elucidated. The study aimed to investigate the effects of PIO on depression-like behaviors induced by lipopolysaccharide (LPS) and to explore the possible underlying mechanisms. The results showed that PIO pretreatment attenuated the depression-like behaviors in mice challenged with intracerebroventricular (i.c.v.) LPS administration. Moreover, Western blot analysis revealed the effects of PIO on inhibiting activation of the nuclear factor kappa B/interleukin 6/signal transducer and activator of transcription 3 (NF-kappaB/IL-6/STAT3) pathway, improving down-regulation of the cAMP response-element-binding protein/brain derived neurotrophic factor (CREB/BDNF) pathway, as well as regulating disturbed expression of proteins involved in central serotonergic neurotransmission following LPS administration. The beneficial effects of PIO, at both the behavioral and molecular level, were significantly inhibited by the PPAR gamma specific antagonist GW9662. In summary, our data reveals for the first time that the modulation of the NF-kappaB/IL-6/STAT3 and CREB/BDNF pathways, as well as the potential impact on central serotonergic neurotransmission, may be involved in the PPAR-gamma-dependent effects of PIO on depression-like behaviors induced by LPS. Additionally, our findings may provide a novel therapeutic target for the treatment of depression-like behaviors in patients with inflammatory status. PMID- 28595083 TI - Therapeutic effect of beta-blocker in patients with traumatic brain injury: A systematic review and meta-analysis. AB - OBJECTIVE: beta-Blocker exposure has been shown to reduce mortality in traumatic brain injury (TBI); however, the efficacy of beta-blockers remains inconclusive. Therefore, a meta-analysis was conducted in this paper to evaluate the safety and efficacy of beta-blocker therapy on patients with TBI. METHODS: The electronic databases were systemically retrieved from construction to February 2017. The odds ratio (OR), mean difference (MD) and 95% confidence intervals (CI) were determined. RESULTS: A total of 13 observational cohort studies involving 15,734 cases were enrolled. The results indicated that beta-blocker therapy had remarkably reduced the in-hospital mortality (OR 0.33; 95% CI 0.27-0.40; p<0.001). However, beta-blocker therapy was also associated with increased infection rate (OR 2.01; 95% CI 1.50-2.69; p<0.001), longer length of stay (MD=7.40; 95% CI=4.39, 10.41; p<0.001) and ICU stay (MD=3.52; 95% CI=1.56, 5.47; p<0.001). In addition, beta-blocker therapy also led to longer period of ventilator support (MD=2.70; 95% CI=1.81, 3.59; p<0.001). CONCLUSION: The meta analysis demonstrates that beta-blockers are effective in lowering mortality in patients with TBI. However, beta-blocker therapy has markedly increased the infection rate and requires a longer period of ventilator support, intensive care management as well as length of stay. PMID- 28595084 TI - Identification of peripheral blood involvement in dogs with large B-cell lymphoma: Comparison of different methods. AB - Stage V lymphoma is defined as the presence of neoplastic cells in peripheral blood (PB), bone marrow, or any other non-lymphoid tissue. Still, official guidelines do not specify which technique should be used to assess infiltration. We assessed the agreement among flow cytometry (FC), blood smear evaluation, and ADVIA120 (LUC and BASO) to quantify PB infiltration in 100 dogs with large B-cell lymphoma (LBCL). Significant errors were found for all methods compared to FC. A moderate agreement was present between FC and blood smear evaluation, whereas LUC and BASO had excellent specificity but unsatisfactory sensitivity in detecting FC infiltrated PB samples. The different techniques should not be used alternatively. We support the use of LUC/BASO as a speedy preliminary test to detect infiltrated samples, and the joined use of blood smear evaluation and FC to quantify definitively the infiltration. Our results are valid only within canine LBCL staging workup, once the diagnosis has been confirmed. PMID- 28595085 TI - miR-152 regulated glioma cell proliferation and apoptosis via Runx2 mediated by DNMT1. AB - BACKGROUND: Aberrant DNA methylation is associated with tumor onset and progression. Study has verified that the DNA methylation of miR-152 was mediated in many tumors, but whether it involved in glioblastomas was still unclear. METHODS: This study enrolled 20 patients with glioma to analyze the expression pattern of miR-152. Real-time PCR and western blot were used to detect the mRNA or protein expression level, respectively. The relationship between miR-152 and runx2 was detected by Luciferase reporter assay. The methylation level of miR-152 was determined by methylation-specific PCR. Cell proliferation and apoptosis were detected by MTT and Annexin-FITC/PI assay. RESULTS: The expression of miR-152 was down-regulated while the expression of DNMT1 was up-regulated in both glioma tissue and cell lines. MiR-152 was hypermethylated and its expression was negatively correlated with DNMT in glioma cell lines. DNMT1 knockdown promoted the expression of miR-152, however, DNMT1 overexpression suppressed the expression of miR-152. MiR-152 overexpression promoted glioma cell apoptosis while miR-152 knockdown promoted cell proliferation. MiR-152 targets Runx2 to regulate its expression, Runx2 overexpression abolished the effects of miR-152 overexpression. CONCLUSION: MiR-152 regulated cell proliferation and apoptosis of glioma mediated by Runx2, while the mechanism of down regulated miR-152 in glioma tissues and cells was its hypermethylation. PMID- 28595086 TI - Evaluation of different PCR primers for denaturing gradient gel electrophoresis (DGGE) analysis of fungal community structure in traditional fermentation starters used for Hong Qu glutinous rice wine. AB - Denaturing gradient gel electrophoresis (DGGE) has become a widely used tool to examine microbial community structure. However, when DGGE is applied to evaluate the fungal community of traditional fermentation starters, the choice of hypervariable ribosomal RNA gene regions is still controversial. In the current study, several previously published fungal PCR primer sets were compared and evaluated using PCR-DGGE, with the purpose of screening a suitable primer set to study the fungal community of traditional fermentation starters for Hong Qu glutinous rice wine. Firstly, different primer sets were used to amplify different hypervariable regions from pure fungal cultures. Except NS1/FR1+ and ITS1fGC/ITS4, other primer sets (NL1+/LS2R, NL3A/NL4GC, FF390/FR1+, NS1/GCFung, NS3+/YM951r and ITS1fGC/ITS2r) amplified the target DNA sequences successfully. Secondly, the selected primer sets were further evaluated based on their resolution to distinguish different fungal cultures through DGGE fingerprints. Three primer sets (NL1+/LS2R, NS1/GCFung and ITS1fGC/ITS2r) were finally selected for investigating the fungal community structure of different traditional fermentation starters for Hong Qu glutinous rice wine. The internal transcribed spacer (ITS) region amplified by ITS1fGC/ITS2r, which is more hypervariable than the 18S rRNA gene and 26S rRNA gene, provides an excellent tool to separate amplification products of different fungal species. Results indicated that PCR DGGE profile using ITS1fGC/ITS2r showed more abundant fungal species than that using NL1+/LS2R and NS1/GCFung. Therefore, ITS1fGC/ITS2r is the most suitable primer set for PCR-DGGE analysis of fungal community structure in traditional fermentation starters for Hong Qu glutinous rice wine. DGGE profiles based on ITS1fGC/ITS2r revealed the presence of twenty-four fungal species in traditional fermentation starter. A significant difference of fungal community can be observed directly from DGGE fingerprints and principal component analysis. The statistical analysis results based on the band intensities of fungal DGGE profile showed that Saccharomyces cerevisiae, Saccharomycopsis fibuligera, Rhizopus oryzae, Monascus purpureus and Aspergillus niger were the dominant fungal species. In conclusion, the comparison of several primer sets for fungal PCR-DGGE would be useful to enrich our knowledge of the fungal community structures associated with traditional fermentation starters, which may facilitate the development of better starter cultures for manufacturing Chinese Hong Qu glutinous rice wine. PMID- 28595087 TI - Maternal high-fat diet leads to hippocampal and amygdala dendritic remodeling in adult male offspring. AB - Early-life exposure to calorie-dense food, rich in fat and sugar, contributes to the increasing prevalence of obesity and its associated adverse cognitive and emotional outcomes at adulthood. It is thus critical to determine the impact of such nutritional environment on neurobehavioral development. In animals, maternal high-fat diet (HFD) consumption impairs hippocampal function in adult offspring, but its impact on hippocampal neuronal morphology is unknown. Moreover, the consequences of perinatal HFD exposure on the amygdala, another important structure for emotional and cognitive processes, remain to be established. In rats, we show that adult offspring from dams fed with HFD (45% from fat, throughout gestation and lactation) exhibit atrophy of pyramidal neuron dendrites in both the CA1 of the hippocampus and the basolateral amygdala (BLA). Perinatal HFD exposure also impairs conditioned odor aversion, a task highly dependent on BLA function, without affecting olfactory or malaise processing. Neuronal morphology and behavioral alterations elicited by perinatal HFD are not associated with body weight changes but with higher plasma leptin levels at postnatal day 15 and at adulthood. Taken together, our results suggest that perinatal HFD exposure alters hippocampal and amygdala neuronal morphology which could participate to memory alterations at adulthood. PMID- 28595088 TI - The relationship between cannabis use and cortisol levels in youth at ultra high risk for psychosis. AB - Recent studies have posited a relationship between cannabis use and the biological stress system, but this critical relationship has not been evaluated during the ultra high-risk (UHR) period immediately preceding the onset of psychotic disorders. Salivary cortisol samples were collected on 46 UHR and 29 control adolescents; these individuals were assessed for current cannabis use with a urine panel and self-report. UHR participants where separated into two groups: Current Cannabis Use (UHR-CU) and No Current Cannabis Use (UHR-NC). Healthy Control participants (HC) were free of cannabis use. Consistent with the literature, results indicate UHR individuals showed elevated cortisol levels when compared to HC participants. Further, we also observed that UHR-CU participants exhibited elevated levels when compared to both the non-using UHR and HC groups. Findings suggest that cannabis use may interact with underlying biological vulnerability associated with the hypothalamic-pituitary-adrenal (HPA) axis system. PMID- 28595090 TI - Associations between motor proficiency in children with history of maltreatment and living in social economically vulnerability. AB - Maltreatment and living in poor socioeconomic conditions during childhood may implicate in deficits on motor proficiency, nevertheless, the literature on this issue is still scarce. The goal of the study was to investigate the possible associations among manual dexterity, aiming and catching tasks, and balance tasks for children who suffers maltreatment and lived in social vulnerability. Eighty two (82) children (08-09 years old) participated in the study. Forty-one (41) belong to the (SEV-M Group) children living in social economic vulnerability and were previously maltreated (lived in foster homes as results of parental neglect and domestic violence), and 41 belong to the (SEV Group) children living in social economical vulnerability with no history of childhood maltreatment. Children were assessed using the Movement Assessment Battery for Children -2nd Edition. Structural Equation Modeling was used to analyze the data. The results suggest the existence of a variety of motor difficulties in the group of children who suffered from neglect and domestic violence. The statistics model showed a negative effect for children in at-risk environments (regression coefficient= 0.30) and only showed a significant effect (p=0.04) for balance abilities. Traumatic experiences may have a negative effect on children' balance proficiency. PMID- 28595091 TI - Detection and characterisation of bone destruction in murine rheumatoid arthritis using statistical shape models. AB - Rheumatoid arthritis (RA) is an autoimmune disease in which chronic inflammation of the synovial joints can lead to destruction of cartilage and bone. Pre clinical studies attempt to uncover the underlying causes by emulating the disease in genetically different mouse strains and characterising the nature and severity of bone shape changes as indicators of pathology. This paper presents a fully automated method for obtaining quantitative measurements of bone destruction from volumetric micro-CT images of a mouse hind paw. A statistical model of normal bone morphology derived from a training set of healthy examples serves as a template against which a given pathological sample is compared. Abnormalities in bone shapes are identified as deviations from the model statistics, characterised in terms of type (erosion / formation) and quantified in terms of severity (percentage affected bone area). The colour-coded magnitudes of the deviations superimposed on a three-dimensional rendering of the paw show at a glance the severity of malformations for the individual bones and joints. With quantitative data it is possible to derive population statistics characterising differences in bone malformations for different mouse strains and in different anatomical regions. The method was applied to data acquired from three different mouse strains. The derived quantitative indicators of bone destruction have shown agreement both with the subjective visual scores and with the previous biological findings. This suggests that pathological bone shape changes can be usefully and objectively identified as deviations from the model statistics. PMID- 28595089 TI - Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study. AB - Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's<=0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD. PMID- 28595092 TI - Ebolavirus protein VP24 interferes with innate immune responses by inhibiting interferon-lambda1 gene expression. AB - Ebolaviruses (EBOV) cause severe disease with a recent outbreak in West Africa in 2014-2015 leading to more than 28 000 cases and 11 300 fatalities. This emphasizes the urgent need for better knowledge on these highly pathogenic RNA viruses. Host innate immune responses play a key role in restricting the spread of a viral disease. In this study we systematically analyzed the effects of cloned EBOV genes on the main host immune response to RNA viruses: the activation of RIG-I pathway and type I and III interferon (IFN) gene expression. EBOV VP24, in addition of inhibiting IFN-induced antiviral responses, was found to efficiently inhibit type III IFN-lambda1 gene expression. This inhibition was found to occur downstream of IRF3 activation and to be dependent on VP24 importin binding residues. These results emphasize the importance of VP24 in EBOV infection cycle, making VP24 as an excellent target for drug development. PMID- 28595093 TI - Association of polymorphisms in key Th-17 immune response genes with HBeAg positive chronic hepatitis B susceptibility and response to PEG-IFNa-2alpha. AB - This study aims to investigate effects of polymorphisms in key Th-17 immune response genes on the susceptibility to HBeAg-positive (HBeAg+) chronic hepatitis B (CHB) and response to PEG-IFNa-2alpha. A total of 139 patients with HBeAg+ CHB treated with PEG-IFNa-2alpha and 145 healthy controls were enrolled to explore the association between IL-17A, IL-17F, IL-21 and IL-23R polymorphisms and HBeAg+ CHB susceptibility, as well as treatment efficacies. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing. IL-17A rs4711998 and IL-17F rs763780 may affect susceptibility to HBeAg+ CHB and response to PEG-IFNa-2alpha treatment. The T allele of IL-21 rs12508721 may lower HBeAg+ CHB susceptibility but enhance PEG-IFNa-2alpha response, and the GA genotype and the A allele of IL-23R rs11209026 may reduce the susceptibility to HBeAg+ CHB. Th17-related gene polymorphisms were linked to HBeAg+ CHB susceptibility, and rs4711998, rs763780 and rs12508721 were associated with sustained responses to PEG-IFNa-2alpha. PMID- 28595094 TI - Two-plasmid system to increase the rescue efficiency of paramyxoviruses by reverse genetics: The example of rescuing Newcastle Disease Virus. AB - Within paramyxoviruses, conventional reverse genetics require the transfection of a minimum of four plasmids: three to reconstruct the viral polymerase complex that replicates and expresses the virus genome delivered by a fourth plasmid. The successful transfection of four or more plasmids of different sizes into one cell and the subsequent generation of at least one viable and replicable viral particle is a rare event, which explains the low rescue efficiency, especially of low virulent viruses with reduced replication efficiency in cell lines. In this study, we report on an improved reverse genetics system developed for an avian paramyxovirus, Newcastle Disease Virus (NDV), in which the number of plasmids was reduced from four to two. Compared to the conventional method, the 2-plasmid system enables earlier and increased production of rescued viruses and, in addition, makes it possible to rescue viruses that it was not possible to rescue using the 4-plasmid system. PMID- 28595095 TI - Differential expression between "DSP-only" and DSP-PP523 transcripts in rat molar teeth. AB - OBJECTIVE: To compare the expression patterns of two multiple transcripts derived from DSP-PP gene during tooth development. One is DSP-only transcript (i.e. does not encode PP) and the other is DSP-PP523 transcript, a main DSP-PP transcript. DESIGN: Unique antisense and sense riboprobes were generated from DSP-only and DSPPP523 cDNAs for in situ studies to examine DSP-only and DSP-PP523 transcript expression in developing molars. Paraffin-embedded sections (5-7MU m) from embryonic 20day, postnatal 2, 3 and 6days were deparaffined and hydrated. Tissues were prehybridized, then hybridized with DSP-only and DSP-PP523 anti-sense (AS) or sense (S) Digoxigenin labeled-riboprobes overnight, and washed. Anti Digoxigenin antibodies conjugated to alkaline phosphatase were used to detect the presence of bound riboprobes by color reaction with NBT/BCIP. Stro-1 antibody was used for immunohistochemical analysis of Stro-1 protein expression in rat molars. RESULTS: We found that unlike the DSP-PP523 transcript, the DSP-only transcript does not express in the entire polarized mature odontoblasts but is expressed in the areas subjacent to the mature odontoblast layer. In addition, DSP-only transcript is expressed in the dental pulp. Interestingly, Stro-1 protein, a stem cell marker, was also identified in the areas subjacentto odontoblasts and in dental pulp. CONCLUSION: Differential expression of DSP-only and DSP-PP523 transcripts suggest that these two kinds of transcripts may play different roles during dentinogenesis. DSP-PP523 transcript is expressed in mature odontoblasts, which actively participates in dentin formation. DSP-only transcript might have a different function. PMID- 28595096 TI - Occurrence and mobility of toxic elements in coals from endemic fluorosis areas in the Three Gorges Region, SW China. AB - Fluorine (F) is a topic of great interest in coal-combustion related endemic fluorosis areas. However, little extent research exists regarding the environmental geochemistry of toxic elements that are enriched in coals and coal wastes in traditional endemic fluorosis areas, particularly focusing on their occurrences and mobilities during the weathering-leaching processes of coals and coal wastes in the surface environment. This paper addressed the issue of toxic elements in coals and coal wastes in the Three Gorges Region, Southwest (SW) China, where endemic fluorosis has historically prevailed, and investigated the distribution, occurrence, mobility features, and associated potential health risks. For this purpose, a modified experiment combined with long-term humidity cell test and column leaching trial was applied to elucidate the mobility of toxic elements in coals and coal wastes. In addition, sequential chemical extraction (SCE) was used to ascertain the modes of occurrence of toxic elements. The results demonstrated that the contents of toxic elements in the study area followed the order: stone coals > gangues > coal balls > coals. Furthermore, modes of occurrence of toxic elements were obviously different in coals and coal wastes. For example, cadmium (Cd) was mainly associated with monosulfide fraction in coals, molybdenum (Mo) and arsenic (As) were mainly associated with carbonate and silicate in coal gangues and stone coals, chromium (Cr) mainly existed in silicate and insoluble matter in coal gangues and coal balls, thallium (Tl) mainly occurred in organic matter in stone coals and sulfide in coals, and the occurrence of antimony (Sb) varied with different kinds of samples. Moreover, a large amount of toxic elements released to the leachates during the weathering and leaching process, which might pollute the environment and threaten human health. Based on the geo-accumulation index (Igeo), single factor index (Pi) and Nemerow index (PN), soils in the study area were mainly polluted by Cd, which constituted a potential risk to locally planted crops. PMID- 28595097 TI - Neuropredictors of oromotor feeding impairment in 12month-old children. AB - BACKGROUND: Feeding impairment is prevalent in children with neurodevelopmental issues. Neuroimaging and neurobehavioural outcomes at term are predictive of later neuromotor impairment, but it is unknown whether they predict feeding impairment. AIMS: To determine whether neurobehavior and brain magnetic resonance imaging (MRI) at term predict oromotor feeding at 12months in preterm and term born children. STUDY DESIGN: Prospective cohort study. PMID- 28595098 TI - The continuity and duration of depression and its relationship to non-suicidal self-harm and suicidal ideation and behavior in adolescents 12-17. AB - BACKGROUND: There is a significant overlap between non-suicidal self-harm and suicidal ideation and behavior in young people with both symptom continuity and symptom duration implicated in this association. METHODS: A population sample of Australian 12-17 year olds. Interviewers collected measures for DSM disorders, symptom duration and continuity, and background information from their parents, while young people self-reported symptoms of depression, non-suicidal self-harm and suicidal ideation and behaviors. This report focusses on the 265 young people who met the DSM criteria for Major Depressive Disorder based on their own self reports. RESULTS: Relative to young people who had at least one period 2 months or longer without symptoms since first onset, young people who had the continuous presence of depressive symptoms since their first onset had significantly higher odds for life-time self-harm, 12-month self-harm, multiple self-harm, suicidal ideation and suicide attempt within the past 12 months. The duration of depressive symptoms and the continuity of these symptoms each independently contribute to elevating the risks of non-suicidal self-harming and suicidal ideation and behaviors. LIMITATIONS: Reliance on self-report from the young people and time constraints prohibiting administering diagnostic modules other than the Major Depressive Disorder and estimating self-reported co-morbidity. CONCLUSIONS: Among young people with a Major Depressive Disorder, self-reports about duration of depressive symptoms as well as the continuity of symptoms, each independently contributes to elevated risks of non-suicidal self-harming and suicidal ideation and behaviors. As well, un-remitting as opposed to episodic symptoms in this group of young people are common and are a powerful indicator of suffering associated with both self-harm and suicidal behavior. PMID- 28595099 TI - Circadian rhythm sleep-wake disorders as predictors for bipolar disorder in patients with remitted mood disorders. AB - BACKGROUND: Circadian rhythm dysfunction is thought to play a key role in the pathogenesis of bipolar disorder (BD). We focused on circadian rhythm sleep-wake disorders (CRSWD) as possible predictors for bipolar disorder in patients with remitted mood disorders. METHOD: One hundred four BD (41 type I and 63 type II) outpatients and 73 age- and sex-matched major depressive disorder (MDD) outpatients participated in this study. The subjects were asked to answer questionnaires including demographic variables, clinical course of the disorder, and family history of psychiatric disorders. Severity of mood status was evaluated by the Montgomery-Asberg Depression Rating Scale and Young Mania Rating Scale. CRSWD was diagnosed by clinical interview and sleep logs based on the International Classification of Sleep Disorders, third edition. RESULTS: The rate of CRSWD in BD subjects was significantly higher than that in MDD subjects (33.7% vs 9.6%; P < 0.001). A multiple logistic regression analysis revealed that comorbid CRSWD (OR = 3.35, 95% CI = 1.24 - 9.07; P = 0.018), two or more previous mood episodes within the past year (OR = 3.57, 95% CI = 1.10 - 11.63; P = 0.035), and antidepressant-related switch to mania/hypomania (OR = 10.01, 95% CI = 1.20 - 83.52; P = 0.033) were significantly associated with BD in patients with remitted mood disorders. CONCLUSION: CRSWD, as well as other factors, could be diagnostic predictors for BD in patients with remitted mood disorders. Combinations of these factors might be useful for predicting a BD diagnosis among the mood disorders in a clinical setting. PMID- 28595100 TI - Protective effects of Momordica grosvenori extract against lipid and protein oxidation-induced damage in dried minced pork slices. AB - The experiment was conducted to assess the protective effects of Momordica grosvenori extract (MGE) against lipid and protein oxidation-induced damage in vacuum-packed dried minced pork slices stored at room temperature for 21days. Antioxidant activity of MGE was evaluated by measuring its radical scavenging activities and reducing power with progressive concentrations from 40 to 200g/L. MGE was added to the dried minced pork slices at 7, 10 or 15g/100g. Results showed that inclusion of MGE in dried minced pork slice significantly delayed the formation of hexanal, thiobarbituric acid-reactive substances and carbonyls and reduced the sulfhydryl loss in a dose-dependent manner (P<0.05), indicating that MGE exerted a protective effect against lipids and protein oxidation. Concomitantly, an intense increase of redness and loss of lightness and yellowness was found to take place (P<0.05), though it exhibited little negative effects on the sensory properties of slices. Mogrosides, the main bioactive components in M. grosvenori, decreased primarily during processing while they were relatively stable during storage under vacuum condition, room temperature. All these results demonstrated MGE had great potential as a natural antioxidant used in meat products. PMID- 28595101 TI - Assessment of trabecular bone tissue elasticity with resonant ultrasound spectroscopy. AB - The material properties of the trabeculae (tissue-level properties), together with the trabecular architecture and the bone volume fraction determine the apparent millimetre-scale bone mechanical properties. We present a novel method to measure trabecular tissue elastic modulus Et using resonant ultrasound spectroscopy (RUS). The first mechanical resonance frequency fe of a freestanding cuboid specimen is measured and used to back-calculate Et. The steps of the back calculation are (1) the apparent stiffness tensors C(Et~) is computed using micro finite elements for a set of trial values of tissue Young's modulus Et~ based on the computed tomography image of the specimen; (2) the modeled free-vibration resonance frequencies fm(Et~) of the specimen is calculated with the Rayleigh Ritz method using C(Et~); (3) finally, Et is obtained by interpolation using fe and fm(Et~). Four bovine bone specimens were tested (nominal size 5*6 *6mm3). Average (standard deviation) of Et was 13.12 (1.06)GPa. The measurement of a single resonance frequency enabled an estimation of tissue elasticity in line with available data. RUS is a non destructive technique relatively easy to implement compared to traditional mechanical testing. The novel method could contribute to a better documentation of bone tissue elasticity which is an important parameter of micro-finite element analyses for the clinical assessment of bone strength. PMID- 28595102 TI - A comparative study of progressive wear of four dental monolithic, veneered glass ceramics. AB - OBJECTIVES: This study evaluated the wear performance and wear mechanisms of four dental glass-ceramics, based on the microstructure and mechanical properties in the progressive wear process. METHODS: Bar (N = 40, n = 10) and disk (N = 32, n = 8) specimens were prepared from (A) lithium disilicate glass-ceramic (LD), (B) leucite reinforced glass-ceramic (LEU), (C) feldspathic glass-ceramic (FEL), and (D) fluorapatite glass-ceramic (FLU). The bar specimens were tested for three point flexural strength, hardness, fracture toughness and elastic modulus. The disk specimens paired with steatite antagonists were tested in a pin-on-disk tribometer with 10N up to 1000,000 wear cycles. The wear analysis of glass ceramics was performed using a 3D profilometer after every 200,000 wear cycles. Wear loss of steatite antagonists was calculated by measuring the weight and density using sensitive balance and Archimedes' method. Wear morphologies and microstructures were analyzed by scanning electron microscopy (SEM). The crystalline phase compositions were determined using X-ray diffraction (XRD). One way analysis of variance (ANOVA) was used to analyze the data. Multiple pair-wise comparison of means was performed by Tukey's post-hoc test. RESULTS: LD showed the highest fracture toughness, flexural strength, elastic modulus and crystallinity, followed by LEU and FEL, and FLU showed the lowest. However, the hardness of LD was lower than all the other three types of ceramics. For steatite antagonists, LD produced the least wear loss of antagonist, followed by LEU and FEL, and FLU had the most wear loss. For glass-ceramic materials, LD exhibited similar wear loss as LEU, but more than FLU and FEL did. Moreover, fracture occurred on the wear surface of FLU. CONCLUSIONS: In the progressive wear process, veneering porcelains showed better wear resistance but fluorapatite veneering porcelains appeared fracture surface. Monolithic lithium disilicate glass-ceramics with higher mechanical properties showed more wear loss, however, they did not fracture and produced less wear loss of antagonists. PMID- 28595104 TI - Pre-beta1 HDL in type 2 diabetes mellitus. AB - BACKGROUND AND AIMS: Pre-beta1 HDL, being a major acceptor of free cholesterol from cells, plays an important role in reverse cholesterol transport. This study was performed to determine whether abnormalities in pre-beta1 HDL concentration were present in type 2 diabetes irrespective of their HDL-cholesterol levels, and the impact on cholesterol efflux. METHODS: 640 type 2 diabetic patients with or without cardiovascular disease (CVD) and 360 non-diabetic controls matched for serum HDL-cholesterol levels were recruited. Plasma pre-beta1 HDL was measured by ELISA, and cholesterol efflux to serum, mediated by ATP-binding cassette transporter A1 (ABCA1), was determined by measuring the transfer of [3H]cholesterol from cultured cells expressing ABCA1 to the medium containing the tested serum. RESULTS: Despite the diabetic subjects having matched HDL cholesterol and total apoA1 as controls, plasma pre-beta1 HDL was significantly reduced in both male (p < 0.01) and female diabetic patients (p < 0.05), and patients with CVD had the lowest pre-beta1 HDL level. Serum capacity to induce ABCA1-mediated cholesterol efflux was impaired in the diabetic group (p < 0.01) and cholesterol efflux correlated with pre-beta1 HDL (Pearson's r = 0.38, p < 0.01), and this association remained significantly even after controlling for age, gender, body mass index, diabetes status, smoking, apoA1, triglyceride and LDL. CONCLUSIONS: Plasma pre-beta1 HDL level was significantly decreased in type 2 diabetes and was associated with a reduction in cholesterol efflux mediated by ABCA1. Our data would suggest that low pre-beta1 HDL might cause impairment in reverse cholesterol transport in type 2 diabetes. PMID- 28595103 TI - Measured pulmonary arterial tissue stiffness is highly sensitive to AFM indenter dimensions. AB - The mechanical properties of pulmonary tissues are important in normal function and the development of diseases such as pulmonary arterial hypertension. Hence it is critical to measure lung tissue micromechanical properties as accurately as possible in order to gain insight into the normal and pathological range of tissue stiffness associated with development, aging and disease processes. In this study, we used atomic force microscopy (AFM) micro-indentation to characterize the Young's modulus of small human pulmonary arteries (vessel diameter less than 100um), and examined the influence of AFM tip geometry and diameter, lung tissue section thickness and the range of working force applied to the sample on the measured modulus. We observed a significant increase of the measured Young's modulus of pulmonary vessels (one order of magnitude) associated with the use of a pyramidal sharp AFM tips (20nm radius), compared to two larger spherical tips (1 and 2.5um radius) which generated statistically indistinguishable results. The effect of tissue section thickness (ranging from 10 to 50 MUm) on the measured elastic modulus was relatively smaller (<1-fold), but resulted in a significant increase in measured elastic modulus for the thinnest sections (10 MUm) relative to the thicker (20 and 50 MUm) sections. We also found that the measured elastic modulus depends modestly (again <1-fold), but significantly, on the magnitude of force applied, but only on thick (50 MUm) and not thin (10 MUm) tissue sections. Taken together these results demonstrate a dominant effect of indenter shape/radius on the measured elastic modulus of pulmonary arterial tissues, with lesser effects of tissue thickness and applied force. The results of this study highlight the importance of AFM parameter selection for accurate characterization of pulmonary arterial tissue mechanical properties, and allow for comparison of literature values for lung vessel tissue mechanical properties measured by AFM across a range of indenter and indentation parameters. PMID- 28595105 TI - Docosahexaenoic acid prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice. AB - At a population level, dietary consumption of fish rich in docosahexaenoic acid (DHA) is associated with prevention of cognitive decline but this association is not clear in carriers of the apolipoprotein E epsilon 4 allele (E4). Plasma and liver DHA concentrations show significant alterations in E4 carriers, in part corrected by DHA supplementation. However, whether DHA sufficiency in E4 carriers has consequences on cognition is unknown. Mice expressing human E4 or apolipoprotein E epsilon 3 allele (E3) were fed either a control diet or a diet containing DHA for 8 months and cognitive performance was tested using the object recognition test and the Barnes maze test. In E4 mice fed the control diet, impaired memory was detected and arachidonic acid concentrations were elevated in the hippocampus compared to E3 mice fed the control diet. DHA consumption prevented memory decline and restored arachidonic acid concentrations in the hippocampus of E4 mice. Our results suggest that long-term high-dose DHA intake may prevent cognitive decline in E4 carriers. PMID- 28595106 TI - Development and validation of a bioanalytical method based on LC-MS/MS analysis for the quantitation of CIGB-814 peptide in plasma from Rheumatoid Arthritis patients. AB - CIGB-814, originally named as E18-3 APL1 or APL1 in preclinical experiments, is a novel therapeutic peptide candidate for Rheumatoid Arthritis (RA). It is an altered peptide ligand containing a novel CD4+ T-cell epitope of human heat shock protein 60 (83-109, MW 2988.38g/mol) with a mutation (D100->L) that increases its affinity for HLA-II type molecules associated to RA. A bioanalytical method, based on LC-MS/MS analysis, in the SRM mode was developed and fully validated to quantify this peptide in human plasma. An internal standard with the same amino acid sequence but labeled with three (13C615N2)-Lys residues was used for quantitation. The method provides a linear range from 1.5 to 48ng/mL (without matrix effect and carry over) and an accuracy and precision good enough for monitoring more than 80% of the AUC of the PK profile in a phase I clinical trial. The peptide was administered subcutaneously in three dose levels (1, 2.5 and 5mg) not normalized to the body weight of patients with RA. The low doses imposed an analytical challenge; however, a LLOQ of 1.5ng/mL enabled the PK analysis. The Cmax, reached at 0.5h, showed a great variability, that was most likely due to the non-normalized doses; the proposed mechanism for this peptide; and the variability between patients. A rapid clearance of this peptide (4-6h) is advantageous for an immunomodulatory drug, because the therapeutic schedule requires repeated dosages to restore peripheral tolerance. PMID- 28595107 TI - Application of 1H NMR spectroscopy to the metabolic phenotyping of rodent brain extracts: A metabonomic study of gut microbial influence on host brain metabolism. AB - 1H NMR Spectroscopy has been applied to determine the neurochemical profiles of brain extracts from the frontal cortex and hippocampal regions of germ free and normal mice and rats. The results revealed a number of differences between germ free (GF) and conventional (CV) rats or specific pathogen-free (SPF) mice with microbiome-associated metabolic variation found to be both species- and region dependent. In the mouse, the GF frontal cortex contained lower amounts of creatine, N-acetyl-aspartate (NAA), glycerophosphocholine and lactate, but greater amounts of choline compared to that of specific pathogen free (SPF) mice. In the hippocampus, the GF mice had greater creatine, NAA, lactate and taurine content compared to those of the SPF animals, but lower relative quantities of succinate and an unidentified lipid-related component. The GF rat frontal cortex contained higher relative quantities of lactate, creatine and NAA compared to the CV animals whilst the GF hippocampus was characterized by higher taurine and phosphocholine concentrations and lower quantities of NAA, N acetylaspartylglutamate and choline compared to the CV animals. Of note is that, in both rat and mouse brain extracts, concentrations of hippocampal taurine were found to be greater in the absence of an established microbiome. The results provide further evidence that brain biochemistry can be influenced by gut microbial status, specifically metabolites involved in energy metabolism demonstrating biochemical dialogue between the microbiome and brain. PMID- 28595108 TI - Insulin signaling in various equine tissues under basal conditions and acute stimulation by intravenously injected insulin. AB - The aim of the study was to analyze key proteins of the equine insulin signaling cascade and their extent of phosphorylation in biopsies from muscle tissue (MT), liver tissue (LT), and nuchal AT, subcutaneous AT, and retroperitoneal adipose tissues. This was investigated under unstimulated (B1) and intravenously insulin stimulated (B2) conditions, which were achieved by injection of insulin (0.1 IU/kg bodyweight) and glucose (150 mg/kg bodyweight). Twelve warmblood horses aged 15 +/- 6.8 yr (yr), weighing 559 +/- 79 kg, and with a mean body condition score of 4.7 +/- 1.5 were included in the study. Key proteins of the insulin signaling cascade were semiquantitatively determined using Western blotting. Furthermore, modulation of the cascade was assessed. The basal expression of the proteins was only slightly influenced during the experimental period. Insulin induced a high extent of phosphorylation of insulin receptor in LT (P < 0.01) but not in MT. Protein kinase B and mechanistic target of rapamycin expressed a higher extent of phosphorylation in all tissues in B2 biopsies. Adenosine monophosphate protein kinase, as a component related to insulin signaling, expressed enhanced phosphorylation in MT (P < 0.05) and adipose tissues (nuchal AT P < 0.05; SCAT P < 0.01; retroperitoneal adipose tissue P < 0.05), but not in LT at B2. Tissue-specific variations in the acute response of insulin signaling to intravenously injected insulin were observed. In conclusion, insulin sensitivity in healthy horses is based on a complex concerted action of different tissues by their variations in the molecular response to insulin. PMID- 28595109 TI - Effects of nonglycosylated and glycosylated prolactin on basal and gonadotropin stimulated steroidogenesis in chicken ovarian follicles. AB - In galliformes, the circulating isoform of prolactin (PRL) significantly changes during different reproductive states. However, the role of the major isoform (glycosylated PRL [G-PRL]) in ovarian steroidogenesis is unknown. The present study aimed to compare the effects of nonglycosylated (NG-) and G-PRL on basal and gonadotropin-stimulated estradiol (E2) and progesterone (P4) production in granulosa cells or follicular walls of chicken of different size class follicles. In the initial experiment, granulosa cells of preovulatory F3-F1 and prehierarchical 6- to 8-mm follicles were incubated for 24 h with different concentrations of NG- or G-PRL (0, 1, 10, 100, or 1,000 ng/mL). In the subsequent experiments, these categorized granulosa cells and follicular walls of prehierarchical 4-6, 2-4, and <2-mm follicles were incubated for 24 h in the absence and presence of 10-ng/mL FSH or LH, or in combination with different concentrations of NG- or G-PRL (10, 100, or 1,000 ng/mL). We observed that lower levels of NG-PRL induced (P < 0.05) E2 and P4 secretion in granulosa cells of either preovulatory or prehierarchical follicles, but at higher levels, this effect was reduced. In contrast, G-PRL promoted (P < 0.05) basal E2 and P4 secretion in preovulatory granulosa cells but was inhibitory (P < 0.05) in prehierarchical granulosa cells. Results obtained by real-time quantitative PCR (qPCR) demonstrated that these effects were mediated through modulation of the expression of StAR, CYP11A1, CYP19A1, and 3beta-HSD. Furthermore, G-PRL was less potent than NG-PRL in inhibiting FSH- or LH-stimulated E2 and P4 production in granulosa cells of preovulatory follicles, whereas NG-PRL enhanced (P < 0.05) but G-PRL reduced (P < 0.05) FSH-induced P4 production in those of prehierarchical follicles. In follicular walls from each group of prehierarchical 4-6, 2-4, and <2-mm follicles, NG- and G-PRL had both stimulatory and inhibitory influences on the actions of FSH on E2 and P4 secretion, but both suppressed (P < 0.05) LH induced E2 and P4 secretion except for the synergistic effects of LH and G-PRL on P4 secretion by follicular walls of the follicles of 4-6 mm. Taken together, these results suggest that both NG- and G-PRL are biologically active in regulating basal and gonadotropin-stimulated E2 and P4 production in chicken ovarian follicles. However, their effects are different depending on the concentration, the type of gonadotropin (FSH or LH), and the stage of follicle development. PMID- 28595111 TI - Similarity and accuracy of mental models formed during nursing handovers: A concept mapping approach. AB - BACKGROUND: Shared mental models are crucial for constructing mutual understanding of the patient's condition during a clinical handover. Yet, scant research, if any, has empirically explored mental models of the parties involved in a clinical handover. OBJECTIVES: This study aimed to examine the similarities among mental models of incoming and outgoing nurses, and to test their accuracy by comparing them with mental models of expert nurses. DESIGN: A cross-sectional study, exploring nurses' mental models via the concept mapping technique. PARTICIPANTS: 40 clinical handovers. DATA COLLECTION: Data were collected via concept mapping of the incoming, outgoing, and expert nurses' mental models (total of 120 concept maps). Similarity and accuracy for concepts and associations indexes were calculated to compare the different maps. RESULTS: About one fifth of the concepts emerged in both outgoing and incoming nurses' concept maps (concept similarity=23%+/-10.6). Concept accuracy indexes were 35%+/ 18.8 for incoming and 62%+/-19.6 for outgoing nurses' maps. Although incoming nurses absorbed fewer number of concepts and associations (23% and 12%, respectively), they partially closed the gap (35% and 22%, respectively) relative to expert nurses' maps. The correlations between concept similarities, and incoming as well as outgoing nurses' concept accuracy, were significant (r=0.43, p<0.01; r=0.68 p<0.01, respectively). Finally, in 90% of the maps, outgoing nurses added information concerning the processes enacted during the shift, beyond the expert nurses' gold standard. DISCUSSION AND CONCLUSIONS: Two seemingly contradicting processes in the handover were identified. "Information loss", captured by the low similarity indexes among the mental models of incoming and outgoing nurses; and "information restoration", based on accuracy measures indexes among the mental models of the incoming nurses. Based on mental model theory, we propose possible explanations for these processes and derive implications for how to improve a clinical handover. PMID- 28595110 TI - Utilization of registered nurses in primary care teams: A systematic review. AB - BACKGROUND: Registered nurses are increasingly becoming embedded in primary care teams yet there is a wide variability in nursing roles and responsibilities across organizations. Policy makers are calling for a closer look at how to best utilize registered nurses in primary care teams. Lack of knowledge about effective primary care nursing roles and responsibilities challenges policy makers' abilities to develop recommendations to effectively deploy registered nurses in primary care needed to assure efficient, evidence-based, and quality health care. OBJECTIVE: To synthesize international evidence about primary care RN roles and responsibilities to make recommendations for maximizing the contributions of RNs in team-based primary care models. DESIGN: Systematic review. DATA SOURCES: The Meta-Analysis and Systematic Reviews of Observational Studies framework guided the conduct of this review. Five electronic databases (OVID Medline, CINAHL, EMBASE, PubMed and Cochrane Library) were searched using MeSH terms: primary care, roles, and responsibilities. The term "nurs*" was truncated to identify all literature relevant to nursing. REVIEW METHODS: The initial search yielded 2243. Abstracts and titles were screened for relevance and seventy-one full text reviews were completed by two researchers. Inclusion criteria included: (1) registered nurses practicing in interprofessional teams; (2) description of registered nursing roles and responsibilities; (3) primary care setting. All eligible studies underwent quality appraisal using the Integrative Quality Criteria for Review of Multiple Study Designs tool. RESULTS: Eighteen studies met eligibility across six countries: Australia, United States, Spain, Canada, New Zealand, and South Africa. Registered nurses play a large role in chronic disease management, patient education, medication management, and often can shift between clinical and administrative responsibilities. There are a limited number of registered nurses that participate in primary care policy making and research. CONCLUSION: Integrating registered nurses into primary care has the potential to increase patient access to a primary care provider because registered nurses can supplement some of the provider workload: they renew prescriptions, address patient questions, and provide patient education. Clear practice protocols and nursing policy should be written by registered nurses to ensure safe, and effective nursing care. The use of a medical assistant or nurse's aide to perform non-nursing tasks allows registered nurses to take on more complex patient care. Future research should expand on emerging payment models for nurse-specific tasks. PMID- 28595112 TI - Oxygen therapy for acute myocardial infarction: A systematic review and meta analysis. AB - BACKGROUND: Potential benefits or risks of oxygen inhalation for patients with acute myocardial infarction are not fully understood. OBJECTIVE: We performed this study to systematically assess the effectiveness and safety of oxygen therapy for patients with acute myocardial infarction. DESIGN: A systematic review and meta-analysis. DATA SOURCES: We searched randomized controlled trials systematically in PubMed, EMBASE, Web of Science and Cochrane Library up to June 2016. REVIEW METHODS: Randomized controlled trials that estimated the effectiveness and safety of oxygen therapy for patients with acute myocardial infarction were identified by two independent reviewers. The primary outcomes were short-term mortality and recurrent rate of myocardial infarction, and the secondary outcomes were arrhythmia incidence and pain incidence. Relative risks (RRs) and 95% confidence intervals (CIs) were used to measure the pooled data. RESULTS: A total of five randomized controlled trials were in accordance with inclusion criteria and were included in this meta-analysis. Compared with no oxygen group, the oxygen group did not significantly reduce short-term death (RR: 1.08, 95%CI: 0.31-3.74), and there was moderate heterogeneity (I2=50.8%, P<0.107) among studies. We found a significant increase in the rate of recurrent myocardial infarction (RR: 6.73, 95%CI: 1.80-25.17, I2=0.0%, P=0.598) in the oxygen group. The oxygen group did not have a significant reduction in arrhythmia (RR: 1.12, 95%CI: 0.91-1.36; I2=46.2%, P<0.156) or pain (RR: 0.97, 95%CI: 0.91 1.04; I2=7.2%, P=0.340). CONCLUSIONS: Oxygen inhalation did not benefit patients with acute myocardial infarction with normal oxygen saturation. It may increase the rate of recurrent myocardial infarction. High quality trials with larger sample sizes are required. PMID- 28595113 TI - The impact of semantically congruent and incongruent visual information on auditory object recognition across development. AB - The ability to use different sensory signals in conjunction confers numerous advantages on perception. Multisensory perception in adults is influenced by factors beyond low-level stimulus properties such as semantic congruency. Sensitivity to semantic relations has been shown to emerge early in development; however, less is known about whether implementation of these associations changes with development or whether development in the representations themselves might modulate their influence. Here, we used a Stroop-like paradigm that requires participants to identify an auditory stimulus while ignoring a visual stimulus. Prior research shows that in adults visual distractors have more impact on processing of auditory objects than vice versa; however, this pattern appears to be inverted early in development. We found that children from 8years of age (and adults) gain a speed advantage from semantically congruent visual information and are disadvantaged by semantically incongruent visual information. At 6years of age, children gain a speed advantage for semantically congruent visual information but are not disadvantaged by semantically incongruent visual information (as compared with semantically unrelated visual information). Both children and adults were influenced by associations between auditory and visual stimuli, which they had been exposed to on only 12 occasions during the learning phase of the study. Adults showed a significant speed advantage over children for well-established associations but showed no such advantage for newly acquired pairings. This suggests that the influence of semantic associations on multisensory processing does not change with age but rather these associations become more robust and, in turn, more influential. PMID- 28595114 TI - The tendency of unconscious thought toward global processing style. AB - This study explored whether unconscious thought has a tendency to process information globally. In three experiments, a Navon task was used to activate global or local processing styles. Findings showed that in the unconscious thought groups, those performing the local Navon task presented a poorer decision making performance when compared to those performing the global Navon task (Experiment 1); participants reported that their judgments were made based on partial attributes (Experiment 2), and evaluated a target individual mainly based on information consistent with stereotypes (Experiment 3). These results showed that when presented with distracter tasks, conscious thought activates local processing, which impairs its ability to process information globally. However, this impairment would not happen if global processing were activated instead. This study provides support to the idea that unconscious thought has a tendency to process information globally. PMID- 28595115 TI - The "weakest link" as an indicator of cognitive vulnerability differentially predicts symptom dimensions of anxiety in adolescents in China. AB - This multiwave longitudinal study examined the cognitive vulnerability-stress component of hopelessness theory to differentially predict symptom dimensions of anxiety using a "weakest link" approach in a sample of adolescents from Hunan Province, China. Baseline and 6-month follow-up data were obtained from 553 middle-school students. During an initial assessment, participants completed measures of assessing their weakest links, anxious symptoms, and the occurrence of stress. Participants subsequently completed measures assessing stress, and anxious symptoms one a month for six months. Higher weakest link scores were associated with greater increases in the harm avoidance and separation anxiety/panic dimensions, but not the physical or social anxiety dimension, of anxious symptoms following stress in Chinese adolescents. These results support the applicability of the "weakest link" approach, derived from hopelessness theory, in Chinese adolescents. Weakest link scores as cognitive vulnerability factors may play a role in the development of anxious symptoms, especially in the cognitive dimensions (e.g., harm avoidance and separation anxiety/panic). Our findings also have potential value in explaining the effectiveness of cognitive relevant therapy in treating the cognitive dimensions of anxious symptoms. PMID- 28595116 TI - The unique spliceosome signature of human pluripotent stem cells is mediated by SNRPA1, SNRPD1, and PNN. AB - Spliceosomes are the core host of pre-mRNA splicing, allowing multiple protein isoforms to be produced from a single gene. Herein, we reveal that spliceosomes are more abundant in human pluripotent stem cells (hPSs), including human embryonic stem cells (hESs) and human induced pluripotent stem cells (hiPSs), than non-hPSs, and their presence is associated with high transcriptional activity. Supportively, spliceosomal components involved in the catalytically active pre-mRNA splicing step were mainly co-localized with hPS spliceosomes. By profiling the gene expression of 342 selected splicing factors, we found that 71 genes were significantly altered during the reprogramming of human somatic cells into hiPSs. Among them, SNRPA1, SNRPD1, and PNN were significantly up-regulated during the early stage of reprogramming, identified as hub genes by interaction network and cluster analysis. SNRPA1, SNRPD1, or PNN depletion led to a pronounced loss of pluripotency and significantly blocked hiPS generation. SNRPA1, SNRPD1, and PNN co-localized with the hPS spliceosomes, physically interacted with each other, and positively influenced the appearance of hPS spliceosomes. Our data suggest that SNRPA1, SNRPD1, and PNN are key players in the regulation of pluripotency-specific spliceosome assembly and the acquisition and maintenance of pluripotency. PMID- 28595118 TI - Application of phenyl-based stationary phases for the study of retention and separation of oligonucleotides. AB - The main goal of our work was to apply three different phenyl-bonded stationary phases in ion pair chromatography for the analysis of synthetic oligonucleotides of various sequences. The influence of the stationary phase structure and the impact of ion-pairing reagent concentration on the retention of oligonucleotides were tested. Moreover the influence of oligonucleotide sequence on their interactions with phenyl-based stationary phases was also investigated. Such complex studies for analysis of oligonucleotides with these adsorbents were done for the first time. Investigations were implemented in the Quantitative Structure Retention Relationships analysis in order to improve the discussion on the retention mechanism of analyzed compounds. The retention of oligonucleotides was the lowest for polar embedded phenyl stationary phase, however its selectivity was high and allowed for complete separation of studied compounds in the shortest time. It was shown that the low retention factor value was observed for oligonucleotides forming secondary structures, such as hairpin loops. Moreover obtained data showed that except for electrostatic and hydrophobic interactions, pi-pi also influences on the retention mechanism. These interactions cause higher retention factor values for phenyl-based stationary phases compared to octadecyl ones. PMID- 28595117 TI - Effect of the anticoagulant, storage time and temperature of blood samples on the concentrations of 27 multiplex assayed cytokines - Consequences for defining reference values in healthy humans. AB - Cytokines are potentially useful biomarkers of sepsis and other inflammatory conditions. Many cytokines can be released by leukocytes and platelets after sampling. The sampling and processing techniques are consequently critically important to measure the in vivo levels. We therefore examined the effects of four different anticoagulants, EDTA, citrate, lepirudin, heparin compared to serum, on the levels of 27 different cytokines. The effects of storage temperature, freezing and thawing on the plasma cytokines were examined. Cytokines were analysed using a multiplex immunoassay. The cytokine levels in serum were significantly higher compared with plasma, consistent with release of cytokines in vitro during coagulation. In general, the lowest values for all cytokines were found in EDTA samples, stored on crushed ice, centrifuged within 4h and thereafter stored at -80 degrees C. MCP-1 and MIP-1beta levels were highest in heparin plasma and storage of blood for up to 4h at room temperature significantly increased the interleukin (IL)-2, IL-6, IL-8, IFN-gamma and GM-CSF levels in EDTA plasma, indicating post-sampling release. In contrast, the IP-10 levels were unaffected by sample storage at both temperatures. Our results indicate that the cytokines were more stable in plasma than in whole blood after sampling. Thus, cytokines should be analysed in EDTA plasma samples stored on ice and centrifuged within 4h. Based on these data, the reference ranges of 27 cytokines in EDTA plasma in 162 healthy human donors were calculated. PMID- 28595119 TI - Optimized fast mixing device for real-time NMR applications. AB - We present an improved fast mixing device based on the rapid mixing of two solutions inside the NMR probe, as originally proposed by Hore and coworkers (J. Am. Chem. Soc. 125 (2003) 12484-12492). Such a device is important for off equilibrium studies of molecular kinetics by multidimensional real-time NMR spectrsocopy. The novelty of this device is that it allows removing the injector from the NMR detection volume after mixing, and thus provides good magnetic field homogeneity independently of the initial sample volume placed in the NMR probe. The apparatus is simple to build, inexpensive, and can be used without any hardware modification on any type of liquid-state NMR spectrometer. We demonstrate the performance of our fast mixing device in terms of improved magnetic field homogeneity, and show an application to the study of protein folding and the structural characterization of transiently populated folding intermediates. PMID- 28595120 TI - Background field removal using a region adaptive kernel for quantitative susceptibility mapping of human brain. AB - Background field removal is an important MR phase preprocessing step for quantitative susceptibility mapping (QSM). It separates the local field induced by tissue magnetic susceptibility sources from the background field generated by sources outside a region of interest, e.g. brain, such as air-tissue interface. In the vicinity of air-tissue boundary, e.g. skull and paranasal sinuses, where large susceptibility variations exist, present background field removal methods are usually insufficient and these regions often need to be excluded by brain mask erosion at the expense of losing information of local field and thus susceptibility measures in these regions. In this paper, we propose an extension to the variable-kernel sophisticated harmonic artifact reduction for phase data (V-SHARP) background field removal method using a region adaptive kernel (R SHARP), in which a scalable spherical Gaussian kernel (SGK) is employed with its kernel radius and weights adjustable according to an energy "functional" reflecting the magnitude of field variation. Such an energy functional is defined in terms of a contour and two fitting functions incorporating regularization terms, from which a curve evolution model in level set formation is derived for energy minimization. We utilize it to detect regions of with a large field gradient caused by strong susceptibility variation. In such regions, the SGK will have a small radius and high weight at the sphere center in a manner adaptive to the voxel energy of the field perturbation. Using the proposed method, the background field generated from external sources can be effectively removed to get a more accurate estimation of the local field and thus of the QSM dipole inversion to map local tissue susceptibility sources. Numerical simulation, phantom and in vivo human brain data demonstrate improved performance of R-SHARP compared to V-SHARP and RESHARP (regularization enabled SHARP) methods, even when the whole paranasal sinus regions are preserved in the brain mask. Shadow artifacts due to strong susceptibility variations in the derived QSM maps could also be largely eliminated using the R-SHARP method, leading to more accurate QSM reconstruction. PMID- 28595121 TI - Magnetization transfer in a partly deuterated lyotropic liquid crystal by single- and dual-frequency RF irradiations. AB - The mechanism of magnetization transfer (MT) in a lyotropic liquid crystal made of sodium dodecyl sulfate, decanol, and water molecules is investigated by using deuterated molecules and single- and dual-frequency RF irradiations. The resulting Z-spectra suggest that the decanol molecules are mainly responsible for the MT effects in this system, through proton exchange to water. This is further confirmed by monitoring the relaxation of dipolar order, which allows one to estimate the transfer rate of magnetization from decanol to water. The potential benefits of using dual-frequency RF irradiation for inducing MT effects are explored through numerical solutions to a MT model based on Provotorov's partial saturation theory. PMID- 28595122 TI - Winds and the distribution of nearshore phytoplankton in a stratified lake. AB - The distribution of phytoplankton in lakes is notoriously patchy and dynamic, but wind-driven currents and algal buoyancy/motility are thought to determine where algae accumulate. In this study, nearshore phytoplankton were sampled from different parts of a lake basin twice a day for 4-5 consecutive days, in the spring and in late summer, to test whether short-term changes in phytoplankton biomass and community composition can be predicted from wind-driven currents. On windy days, phytoplankton biomass was higher at downwind than at upwind nearshore sites, and the magnitude of this difference increased linearly with increasing wind speed. However, contrary to the generally assumed downwind phytoplankton aggregations, these differences were mostly due to upwelling activity and the dilution of phytoplankton at upwind nearshore sites. The distribution of individual taxa was also related to wind speed, but only during late stratification (except for cryptophytes), and these relationships were consistent with the buoyancy and motility of each group. On windy days, large diatoms and cyanobacteria concentrated upwind, neutrally buoyant taxa (green algae, small diatoms) were homogeneously distributed, and motile taxa (cryptophytes, chrysophytes, dinoflagellates) concentrated downwind. Predictable differences in the biomass and composition of phytoplankton communities could affect the efficiency of trophic transfers in nearshore areas. PMID- 28595123 TI - Effects of humic acids with different polarities on the photocatalytic activity of nano-TiO2 at environment relevant concentration. AB - Large volume production and application of nano-TiO2 make it inevitably release to natural waters and its environmental behaviors would be affected by natural organic matters. In this study, the mechanisms of humic acid (HA) affecting the photocatalytic performance of nano-TiO2 were elucidated by using three HA fractions from the same source but with different polarities. Bulk HA was fractionated on a silica gel column to get three fractions with polarity increasing in the order of FA, FB and FC. FA was fulvic acid-like while FB and FC were humic acid-like. All the three fractions (at 0.1 mg/L) promoted the generation of hydroxyl radicals (OHs) by nano-TiO2, and thus in turn facilitated the photocatalytic degradation of bispheol A (BPA). FA and FC displayed a stronger promotion effect than FB and the bulk HA. Online in situ flow cell ATR FTIR and XPS analyses indicated that HA fractions could form charge-transfer complex with nano-TiO2 surface through the phenolic hydroxyl and carboxylic groups, which favored the separation of photogenerated electron-hole pairs. Through step methylation experiments, it was verified that the phenolic hydroxyl and carboxylic groups of HA fractions played important roles in promoting the photocatalytic performance of nano-TiO2, and the effect of carboxylic group was more significant than the phenolic hydroxyl group. PMID- 28595124 TI - Probing the interphase "HO zone" originated by carbon nanotube during catalytic ozonation. AB - Carbon nanotube (CNT) is an attractive metal-free catalyst that can be explored in combination with ozone treatment. Using fluorescence microscopy image analysis, we investigated the production of hydroxyl radicals (HO) within the solid-liquid interphase for CNT-mediated catalytic ozonation. The visualized results suggest that HO was vastly generated via catalysis and accumulated within a surface region of the CNT (we defined this region as the interphase "HO zone"). In this region, using 7-hydroxycoumarin as a HO marker, the radical abundance was at least 1000 times higher than that in the aqueous bulk phase. Owing to the observed inhomogeneity of HO, the CNT/ozone system effectively decomposed perfluorooctane sulfonate that was fairly resistant to non-catalytic ozonation, and the decomposition kinetics was not much inhibited by tert-butanol as bulk phase HO scavenger due to the remaining "HO zone" at surface region available for reaction. A longevity trial revealed the sustained formation of the interphase "HO zone" and strongly indicated that the graphitic structure may optimize the density of surface active sites responsible for the proliferation and local concentration of HO. CNT, with good catalytic efficiency, longevity and stability, is anticipated as the basis of future nanomaterials able to promote HO exposure in ozone treatment for advanced oxidation process. PMID- 28595125 TI - Quantifying nitrous oxide production pathways in wastewater treatment systems using isotope technology - A critical review. AB - Nitrous oxide (N2O) is an important greenhouse gas and an ozone-depleting substance which can be emitted from wastewater treatment systems (WWTS) causing significant environmental impacts. Understanding the N2O production pathways and their contribution to total emissions is the key to effective mitigation. Isotope technology is a promising method that has been applied to WWTS for quantifying the N2O production pathways. Within the scope of WWTS, this article reviews the current status of different isotope approaches, including both natural abundance and labelled isotope approaches, to N2O production pathways quantification. It identifies the limitations and potential problems with these approaches, as well as improvement opportunities. We conclude that, while the capabilities of isotope technology have been largely recognized, the quantification of N2O production pathways with isotope technology in WWTS require further improvement, particularly in relation to its accuracy and reliability. PMID- 28595126 TI - Effect of chelating agents on Reactive Green 19 decolorization through Fe0 activated persulfate oxidation process. AB - The effect of chelating agents on the decolorization of Reactive Green 19 (RG19) through Fe0 activated persulfate (PS/Fe0) process was investigated. Though other previous studies reported that chelating agent can enhance the degradation of organic contaminant in Fenton-like system, our finding showed that the presence of chelating agents would chelate free Fe2+ and minimize free Fe2+ concentration, which resulted in the retardation of RG19 decolorization. RG19 decolorization decreased to 7%, 21%, and 15% in the presence of sodium citrate, sodium EDTA, and sodium oxalate, compared with control test (without chelating agent, 99%) within 10 min. The degradation efficiencies decreased with increasing chelating agent concentrations because of complex formation with Fe2+. Higher PS concentration, Fe0 dosage, and temperature had an obvious enhancement for RG19 decolorization efficiency. Elucidation of RG19 containing sodium EDTA degradation pathways indicated that PS/Fe0 process could degrade RG19 to carboxylic acids and inorganic salts efficiently. The presence of sodium EDTA had no influence on by products, and EDTA just played a chelating agent function for chelating Fe ions. PMID- 28595127 TI - Key blackening and stinking pollutants in Dongsha River of Beijing: Spatial distribution and source identification. AB - Elimination of black-stinking water contamination has been listed as an urgent task in the Water pollution prevention action plan promulgated by State Council of China. However, the key blackening and stinking pollutants and their sources are still unclear. In this study, water quality of a black-stinking urban river in Beijing, Dongsha River, was evaluated firstly; then the distribution of the blackening and stinking pollutants was investigated, and the key pollutants and their potential sources were identified; and finally, the health risk of those pollutants was assessed. The results showed that NH3N, total phosphorus, dissolved oxygen and chemical oxygen demand ranged from 1.3 to 5.3 mg/L, 0.7-3.0 mg/L, 1.0-3.2 mg/L and 29-104 mg/L, respectively. The value of TP-based trophic level index indicated that Dongsha River reached severe eutrophication level; the maximum value of chroma and odor level reached 32 and 4, respectively. The main dissolved organic compounds included aromatic protein II, soluble microbiological metabolites, fulvic acids and humic acids. The blackening pollutants Fe, Mn, Cu and S2- were extensively detected, with significantly spatial differences along the river. Dimethyl sulfide, beta-ionone, 2-methylisoborneol and geosmin were identified to be the stinking pollutants. Their concentrations covered wide ranges, and even the lowest concentration value was thousands of times higher than its olfactory threshold. Correlation analysis indicated that in the overlaying water S2- was the key blackening pollutant, while beta-ionone and geosmin were the key stinking pollutants. Principal components analysis combining with the site survey revealed their potential sources. S2- was mainly associated with the decomposition of endogenous sulfur-containing organics; beta-ionone might be generated by the endogenous beta-carotene bio-conversion and the exogenous discharges, while geosmin might originate from the endogenous humus bio conversion and anthropic wastes. Furthermore, multi-metals in the sediment posed health risks to children, while dimethyl sulfide had non-cancer health risk for adults and children. PMID- 28595128 TI - Antenatal psychological and socioeconomic predictors of breastfeeding in a large community sample. AB - BACKGROUND: Despite much work to publicise the benefits of breastfeeding most women do not persist for the first 6months, as recommended by the WHO. Successful breastfeeding for 6months may depend on several factors, including perinatal mental health. We aimed to investigate the impact of antenatal depressive symptoms, attitudes towards breastfeeding and socio-demographic factors in predicting breastfeeding for 6months in a large community sample. METHODS: The sample was based on the Avon Longitudinal Study of Parents and Children (n=9479), a large-scale birth cohort. Breastfeeding was assessed at multiple time-points, from postnatal day 1 until 6months postnatal. Self-reported symptoms of maternal depression were assessed at 18 and 32weeks gestation and at 8weeks postnatal. Antenatal attitudes towards breastfeeding were assessed at 32weeks gestation. Antenatal, obstetric, psychosocial and socio-demographic variables were also assessed. RESULTS: Antenatal depressive symptoms at both 18 and 32weeks gestation were associated with decreased breastfeeding initiation and duration. However, the prediction of breastfeeding by these symptoms was confounded by socio demographic and psychosocial covariates. A positive antenatal attitude towards breastfeeding was the strongest predictor and was associated with a 20-30% increase in breastfeeding initiation and maintenance at all time points. CONCLUSION: This study highlights the wide range of factors that independently predict breastfeeding, and suggests that an intervention program to improve antenatal attitudes especially warrants investigation. PMID- 28595129 TI - Noisy EEG signals classification based on entropy metrics. Performance assessment using first and second generation statistics. AB - This paper evaluates the performance of first generation entropy metrics, featured by the well known and widely used Approximate Entropy (ApEn) and Sample Entropy (SampEn) metrics, and what can be considered an evolution from these, Fuzzy Entropy (FuzzyEn), in the Electroencephalogram (EEG) signal classification context. The study uses the commonest artifacts found in real EEGs, such as white noise, and muscular, cardiac, and ocular artifacts. Using two different sets of publicly available EEG records, and a realistic range of amplitudes for interfering artifacts, this work optimises and assesses the robustness of these metrics against artifacts in class segmentation terms probability. The results show that the qualitative behaviour of the two datasets is similar, with SampEn and FuzzyEn performing the best, and the noise and muscular artifacts are the most confounding factors. On the contrary, there is a wide variability as regards initialization parameters. The poor performance achieved by ApEn suggests that this metric should not be used in these contexts. PMID- 28595130 TI - Cyclotorsion measurement using scleral blood vessels. AB - BACKGROUND AND OBJECTIVES: Measurements of the cyclotorsional movement of the eye are crucial in refractive surgery procedures. The planned surgery pattern may vary substantially during an operation because of the position and eye movements of the patient. Since these factors affect the outcome of an operation, eye registration methods are applied in order to compensate for errors. While the majority of applications are based on features of the iris, we propose a registration method which uses scleral blood vessels. Unlike previous offline techniques, the proposed method is applicable during surgery. METHODS: The sensitivity of the proposed registration method is tested on an artificial benchmark dataset involving five eye models and 46,305 instances of eye images. The cyclotorsion angles of the dataset vary between -10 degrees and +10 degrees at 1 degrees intervals. Repeated measurements and ANOVA and Cochran's Q tests are applied in order to determine the significance of the proposed method. Additionally, a pilot study is carried out using data obtained from a commercially available device. The real data are validated using manual marking by an expert. RESULTS AND CONCLUSIONS: The results confirm that the proposed method produces a smaller error rate (mean = 0.44 +/- 0.41) compared to the existing method in [1] (mean = 0.64 +/- 0.58). A further conclusion is that feature extraction algorithms affect the results of the proposed method. The SIFT (mean = 0.74 +/- 0.78), SURF64 (mean = 0.56 +/- 0.46), SURF128 (mean = 0.57 +/- 0.48) and ASIFT (mean = 0.29 +/- 0.25) feature extraction algorithms were examined; the ASIFT method was the most successful of these algorithms. Scleral blood vessels are observed to be useful as a feature extraction region due to their textural properties. PMID- 28595131 TI - A precision-guided MWNT mediated reawakening the sunk synergy in RAS for anti angiogenesis lung cancer therapy. AB - Multi-walled carbon nanotube (MWNT) with its versatility has exhibited tremendous superiority in drug delivery. Despite plenty of researches on MWNT based delivery systems, precision-guided assistances to maximize their profitable properties are still lacking in substantive progress. We developed here a dual-targeting and co delivery system based on MWNT for antiangiogenesis therapy in lung cancer which aimed at renin-angiotensin system (RAS) dysregulation by synergistically conducting angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R) pathway. In this work, iRGD peptide connected to polyethyleneimine (PEI) was linked to MWNT skeleton, accompanying with candesartan (CD) conjugated to MWNT mediated by cystamine (SS). The functionalized MWNT is assembled with plasmid AT2 (pAT2) to form iRGD-PEI-MWNT-SS-CD/pAT2 complexes. iRGD and CD act as pilots for complexes to dually target symbolic alphanubeta3-integrin and AT1R both overexpressed on tumor angiogenic endothelium and lung cancer cell. CD as chemotherapy showed synergistic downregulation of VEGF when combining of pAT2 and efficiently inhibited angiogenesis. iRGD-PEI-MWNT-SS-CD/pAT2 complexes greatly appreciated drug activities by changing drug distribution and exhibited remarkable tumor growth suppression in A549 xenograft nude mice. Our work presents that such dual-targeting strategy highly improves the delivery performance of MWNT and open a new avenue for RAS related lung cancer therapy. PMID- 28595132 TI - Functionality based method for simultaneous isolation of rodent hepatic sinusoidal cells. AB - Chronic liver disease is the result of long term exposure to viruses or toxins such as alcohol, fat and drugs, and forms the basis for the development of liver fibrosis and primary liver cancer. In vitro and in vivo models are key to study the pathways involved in chronic liver disease and for the development of therapeutics. 3D co-culture systems are becoming the in vitro standard, which requires freshly isolated primary hepatic cells. We developed a novel isolation method to simultaneously isolate liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) and hepatic stellate cells (HSCs). The method exploits the scavenging activity of LSECs, the phagocytic capacity of KCs and the retinoid content of HSCs in vivo to enable direct processing by fluorescence-activated cell sorting without additional antibody binding and washing steps. UFACS3, for UV-FACS-based isolation of 3 non-parenchymal liver cell types, yields functional and pure LSECs (98 +/- 1%), KCs (98 +/- 1%) and HSCs (97 +/- 3%), with less hands on time from healthy and diseased rodent livers. This novel approach allows a fast and effective combined isolation of sinusoidal cells for further analysis. PMID- 28595133 TI - Nonclinical pharmacokinetic and pharmacodynamic characterisation of somapacitan: A reversible non-covalent albumin-binding growth hormone. AB - OBJECTIVE: Somapacitan is an albumin-binding growth hormone derivative intended for once weekly administration, currently in clinical development for treatment of adult as well as juvenile GH deficiency. Nonclinical in vivo pharmacological characterisation of somapacitan was performed to support the clinical trials. Here we present the pharmacokinetic and pharmacodynamic effects of somapacitan in rats, minipigs, and cynomolgus monkeys. METHODS: Pharmacokinetic studies investigating exposure, absorption, clearance, and bioavailability after single intravenous (i.v.) and subcutaneous (s.c.) administration were performed in all species. A dose-response study with five dose levels and a multiple dose pharmacodynamic study with four once weekly doses was performed in hypophysectomised rats to evaluate the effect of somapacitan on growth and IGF-I production. RESULTS: Pharmacokinetic profiles indicated first order absorption from the subcutaneous tissue after s.c. injections for somapacitan in all three species. Apparent terminal half-lives were 5-6h in rats, 10-12h in minipigs, and 17-20h in monkeys. Somapacitan induced a dose-dependent growth in hypophysectomised rats (p<0.001) and an increase in plasma IGF-I levels in rats (p<0.01), minipigs (p<0.01), and cynomolgus monkeys (p<0.05) after single dose administration. Multiple once weekly dosing of somapacitan in hypophysectomised rats induced a step-wise increase in body weight with an initial linear phase the first 3-4days in each dosing interval (p<0.001). CONCLUSION: The nonclinical pharmacokinetic and pharmacodynamic studies of somapacitan showed similar pharmacokinetic properties, with no absorption-limited elimination, increased clearance and increased and sustained levels of IGF-I in plasma for up to 10days after a single dose administration in all three species. Somapacitan induced a dose-dependent increase in body weight and IGF-I levels in hypophysectomised rats. Multiple dosing of somapacitan in hypophysectomised rats suggested a linear growth for the first 3-4days in each weekly dosing interval, whereas daily hGH dosing showed linear growth for approximately two weeks before reaching a plateau level. PMID- 28595134 TI - Fatigue-induced dissociation between rate of force development and maximal force across repeated rapid contractions. AB - We examined whether the presence of fatigue induced by prolonged running influenced the time courses of force generating capacities throughout a series of intermittent rapid contractions. Thirteen male amateur runners performed a set of 15 intermittent isometric rapid contractions of the knee extensor muscles, (3s/5s on/off) the day before (PRE) and immediately after (POST) a half marathon. The maximal voluntary contraction force, rate of force development (RFDpeak), and their ratio (relative RFDpeak) were calculated. At POST, considering the first (out of 15) repetition, the maximal force and RFDpeak decreased (p<0.0001) at the same extent (by 22+/-6% and 24+/-22%, respectively), resulting in unchanged relative RFDpeak (p=0.6). Conversely, the decline of RFDpeak throughout the repetitions was more pronounced at POST (p=0.02), thus the decline of relative RFDpeak was more pronounced (p=0.007) at POST (-25+/-13%) than at PRE (-3+/-13%). The main finding of this study was that the fatigue induced by a half-marathon caused a more pronounced impairment of rapid compared to maximal force in the subsequent intermittent protocol. Thus, the fatigue-induced impairment in rapid muscle contractions may have a greater effect on repeated, rather than on single, attempts of maximal force production. PMID- 28595135 TI - Soft nanocomposites of gelatin and poly(3-hydroxybutyrate) nanoparticles for dual drug release. AB - We developed a nanocomposite gel composed of gelatin and poly(3-hydroxybutyrate) polymeric nanoparticles (PNP) to be used as an injectable gel for the contemporaneous, dual sustained release of bioactive molecules. The hydrogel matrix was formed by a very simple process, using either the physical gelation of gelatin or the natural enzyme transglutaminase to covalently cross-link the gelatin chains in the presence of embedded PNP. Oscillatory rheological measurements showed that the addition of the PNP induced an increase in the storage modulus compared to pure gelatin gels, for both physical and chemical gels. Micrographs from scanning electron microscopy revealed that the presence of PNP disrupted the native structure of the gelatin chains in the hydrogel matrix. Dual drug encapsulation was achieved with curcumin (CM) in the PNP and naproxen sodium(NS) in the gelatin matrix. In vitro release studies showed that the hydrogel matrix acts both as a physical and chemical barrier, delaying the diffusion of the drugs. An initial burst release was observed in the first hours of the measurement, and around 90% was released on the third day for naproxen sodium. In free PNP, 82% of curcumin was relased after four days, while when PNP were embedded in the gelatin matrix only 40% was released over the same time period. Overall, these simple, sustainable soft nanocomposites show potential as an injectable co-sustained drug release system. PMID- 28595136 TI - Janus silver mesoporous silica nanobullets with synergistic antibacterial functions. AB - In this study, we exploited a one-pot method to fabricate cetyltrimethylammonium bromide (CTAB)-loaded Janus silver mesoporous silica nanoparticles (Janus Ag MSNs@CTAB). These bullet-like nanoparticles had a silver head (80nm in diameter) attached to a mesoporous silica stick (200-300nm in length). The CTAB-loaded nanobullets exhibited a marked affinity for the bacterial cell surface and the simultaneously sustained release behavior of CTAB and silver ions. The minimum inhibitory concentrations (MIC) of Janus Ag-MSNs@CTAB were determined to be 10MUg/mL and 20MUg/mL for E. coli and S. Aureus, respectively. Importantly, Janus Ag-MSNs@CTAB provided a single-particle nanoplatform with a synergistic effect against both Gram-positive and Gram-negative bacteria. A thorough investigation indicated that CTAB induces a dramatic loss of bacterial membrane integrity, which facilitated the internalization of silver. This report described an efficient and convenient method of synthesizing Janus silver mesoporous silica nanoparticles, and these nanobullets show promising potential in biomedical applications. PMID- 28595137 TI - Health-related quality of life in patients with metastatic colorectal cancer, association with systemic inflammatory response and RAS and BRAF mutation status. AB - BACKGROUND: The aim of this study was to evaluate the effect of cetuximab on health-related quality of life (HRQoL) in the NORDIC-VII trial on metastatic colorectal cancer (mCRC), and to assess HRQoL in relation to RAS and BRAF mutation status and inflammatory biomarkers. PATIENT AND METHODS: HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, after every fourth cycle of chemotherapy, and at the end of treatment. HRQoL during 12 cycles of chemotherapy was evaluated over time, compared between treatment arms, and assessed for association with tumour mutation status and inflammatory markers. RESULTS: QLQ-C30 was completed by 512 patients (90%) before start of treatment. HRQoL variables were well balanced across treatment arms at baseline, and no statistically significant differences during treatment were seen. Patients with BRAF-mutated tumours reported poorer HRQoL at baseline and subsequent time points than patients with RAS-mutated or RAS/BRAF wild-type tumours. Patients with high serum interleukin-6 (IL-6) or C-reactive protein (CRP) had markedly impaired HRQoL compared to patients with normal levels. There was a statistically significant association between reduction in IL-6 and CRP levels and improvement in HRQoL during treatment from baseline to cycle 4. CONCLUSION: The addition of cetuximab to chemotherapy did not affect HRQoL in mCRC patients. Patients with BRAF-mutated tumours have both a worse prognosis and a poor HRQoL. The associations between levels of systemic inflammatory markers and reduced HRQoL suggest that the patients might benefit from anti-inflammatory treatment. PMID- 28595138 TI - Association between distance to nearest supermarket and provision of fruits and vegetables in English nurseries. AB - With 796,500 places available for children in England, pre-school nurseries could serve as an important setting for population-wide dietary intervention. It is critical to understand the determinants of healthy food provision in this setting, which may include access to food stores. This study examined the association between objective, GIS-derived supermarket proximity and fruit and vegetable serving frequency, using data from 623 English nurseries. Overall, 116 (18%) nurseries served fruits and vegetables infrequently (<2-3 times/week), but provision differed by supermarket proximity. In adjusted multivariable regression models, nurseries farthest from their nearest supermarket (Q5, 1.7-19.8km) had 2.38 (95% CI 1.01-5.63) greater odds of infrequent provision. Our results suggest that supermarket access may be important for nurseries in meeting fruit and vegetable provision guidelines. We advance a growing body of international literature, for the first time linking the food practices of institutions to their neighbourhood food retail context. PMID- 28595140 TI - Conditioning task switching behavior. AB - Most reward studies focus on the reinforcement of simple tasks or stimulus response rules. However, recent theories (re)emphasized that cognitive control representations should adhere to the same reinforcement learning principles as do more basic stimulus and response representations. This study focused on the act of switching between different tasks, and investigated the effects of disproportionally rewarding task alternations or repetitions in a cued task switching paradigm on subsequent voluntary task switching behavior (i.e., when participants could choose which task to perform). The results show that subjects who were more rewarded for task alternations (relative to those more rewarded for repetitions) showed more task switching behavior. Moreover, this increased task switching behavior also came with a cost, with participants more rewarded for task repetitions showing a better task focus (i.e., smaller task-rule congruency effects). These results demonstrate that reward can reinforce more abstract control representations, beyond low-level stimulus or response representations. PMID- 28595139 TI - Time-dependent negative bias in plasma ammonia samples in a clinical setting. PMID- 28595141 TI - The interplay of language and visual perception in working memory. AB - How do perception and language interact to form the representations that guide our thoughts and actions over the short-term? Here, we provide a first examination of this question by investigating the role of verbal labels in a continuous visual working memory (WM) task. Across four experiments, participants retained in memory the continuous color of a set of dots which were presented sequentially (Experiments 1-3) or simultaneously (Experiment 4). At test, they reproduced the colors of all dots using a color wheel. During stimulus presentation participants were required to either label the colors (color labeling) or to repeat "bababa" aloud (articulatory suppression), hence prompting or preventing verbal labeling, respectively. We tested four competing hypotheses of the labeling effect: (1) labeling generates a verbal representation that overshadows the visual representation; (2) labeling yields a verbal representation in addition to the visual one; (3) the labels function as a retrieval cue, adding distinctiveness to items in memory; and (4) labels activate visual categorical representations in long-term memory. Collectively, our experiments show that labeling does not overshadow the visual input; it augments it. Mixture modeling showed that labeling increased the quantity and quality of information in WM. Our findings are consistent with the hypothesis that labeling activates visual long-term categorical representations which help in reducing the noise in the internal representations of the visual stimuli in WM. PMID- 28595142 TI - Changing word usage predicts changing word durations in New Zealand English. AB - This paper investigates the emergence of lexicalized effects of word usage on word duration by looking at parallel changes in usage and duration over 130years in New Zealand English. Previous research has found that frequent words are shorter, informative words are longer, and words in utterance-final position are also longer. It has also been argued that some of these patterns are not simply online adjustments, but are incorporated into lexical representations. While these studies tend to focus on the synchronic aspects of such patterns, our corpus shows that word-usage patterns and word durations are not static over time. Many words change in duration and also change with respect to frequency, informativity and likelihood of occurring utterance-finally. Analysis of changing word durations over this time period shows substantial patterns of co-adaptation between word usage and word durations. Words that are increasing in frequency are becoming shorter. Words that are increasing/decreasing in informativity show a change in the same direction in duration (e.g. increasing informativity is associated with increasing duration). And words that are increasingly appearing utterance-finally are lengthening. These effects exist independently of the local effects of the predictors. For example, words that are increasing utterance finally lengthen in all positions, including utterance-medially. We show that these results are compatible with a number of different views about lexical representations, but they cannot be explained without reference to a production perception loop that allows speakers to update their representations dynamically on the basis of their experience. PMID- 28595143 TI - Brominated and phosphate flame retardants (FRs) in indoor dust from different microenvironments: Implications for human exposure via dust ingestion and dermal contact. AB - Indoor dust has been widely used to monitor flame retardants (FRs) in indoor environment, but most studies only focused on floor dust. In the present study, FRs were examined in indoor dust from different locations. Dust from air conditioner (AC) filters, beddings, floor, and windows in bedrooms, and dust from AC filters, printer table surface, computer table surface, floor, and windows in offices were collected, respectively. Polybrominated diphenyl ether congener 209 (BDE 209) and decabromodiphenyl ethane (DBDPE) were the most abundant brominated flame retardants (BFRs), and tris(chloroisopropyl) phosphate (TCIPP), tris(1,3 dichloroisopropyl) phosphate (TDCIPP), and triphenyl phosphate (TPHP) were the most abundant phosphate flame retardants (PFRs). In bedrooms, the AC filter dust had the highest median levels of BDE 209 (536 ng/g) and DBDPE (2720 ng/g), while bed dust had the highest median levels of SigmaPFRs (2750 ng/g) among dust samples. In offices, printer table dust had higher median levels of BDE 209 (1330 ng/g), DBDPE (8470 ng/g), and SigmaPFRs (11,000 ng/g) than those in other dust samples. The high dust ingestion values of BDE 209, DBDPE, and individual PFR were 0.28, 1.20, and <0.01-0.32 ng/kg bw/day and 7.37, 31.2, and <0.01-4.54 ng/kg bw/day for BDE 209, DBDPE, and individual PFR for adults and toddlers, respectively. The high dermal exposure values of individual PFR during sleeping were <0.01-0.23 and <0.01-0.36 ng/kg bw/day for adults and toddlers, respectively. More human exposure pathways other than dust ingestion should be considered, such as the dermal contact with beddings and furniture. PMID- 28595144 TI - 37Cl/35Cl isotope ratio analysis in perchlorate by ion chromatography/multi collector -ICPMS: Analytical performance and implication for biodegradation studies. AB - In the present study we propose a new analytical method for 37Cl/35Cl analysis in perchlorate by Ion Chromatography(IC) coupled to Multicollector Inductively Coupled Plasma Mass Spectrometry (MC-ICPMS). The accuracy of the analytical method was validated by analysis of international perchlorate standard materials USGS-37 and USGS -38; analytical precision better than +/-0.40/00 was achieved. 37Cl/35Cl isotope ratio analysis in perchlorate during laboratory biodegradation experiment with microbial cultures enriched from the contaminated soil in Israel resulted in isotope enrichment factor epsilon37Cl = -13.3 +/- 10/00, which falls in the range reported previously for perchlorate biodegradation by pure microbial cultures. The proposed analytical method may significantly simplify the procedure for isotope analysis of perchlorate which is currently applied in environmental studies. PMID- 28595145 TI - Potential value of phosphate compounds in enhancing immobilization and reducing bioavailability of mixed heavy metal contaminants in shooting range soil. AB - Shooting range soils contain mixed heavy metal contaminants including lead (Pb), cadmium (Cd), and zinc (Zn). Phosphate (P) compounds have been used to immobilize these metals, particularly Pb, thereby reducing their bioavailability. However, research on immobilization of Pb's co-contaminants showed the relative importance of soluble and insoluble P compounds, which is critical in evaluating the overall success of in situ stabilization practice in the sustainable remediation of mixed heavy metal contaminated soils. Soluble synthetic P fertilizer (diammonium phosphate; DAP) and reactive (Sechura; SPR) and unreactive (Christmas Island; CPR) natural phosphate rocks (PR) were tested for Cd, Pb and Zn immobilization and later their mobility and bioavailability in a shooting range soil. The addition of P compounds resulted in the immobilization of Cd, Pb and Zn by 1.56 76.2%, 3.21-83.56%, and 2.31-74.6%, respectively. The reactive SPR significantly reduced Cd, Pb and Zn leaching while soluble DAP increased their leachate concentrations. The SPR reduced the bioaccumulation of Cd, Pb and Zn in earthworms by 7.13-23.4% and 14.3-54.6% in comparison with earthworms in the DAP and control treatment, respectively. Bioaccessible Cd, Pb and Zn concentrations as determined using a simplified bioaccessibility extraction test showed higher long-term stability of P-immobilized Pb and Zn than Cd. The differential effect of P-induced immobilization between P compounds and metals is due to the variation in the solubility characteristics of P compounds and nature of metal phosphate compounds formed. Therefore, Pb and Zn immobilization by P compounds is an effective long-term remediation strategy for mixed heavy metal contaminated soils. PMID- 28595146 TI - Removal of 2,4-dichlorophenoxyacetic acid in aqueous solution by pulsed corona discharge treatment: Effect of different water constituents, degradation pathway and toxicity assay. AB - A multiple pin-plane corona discharge reactor was used to generate plasma for the degradation of 2,4 dichlorophenoxyacetic acid (2,4-D) from the aqueous solution. The 2,4-D of concentration 1 mg/L was completely removed within 6 min of plasma treatment. Almost complete mineralization was achieved after the treatment time of 14 min for a 2,4-D concentration of 10 mg/L. Effects of different water constituents such as carbonates, nitrate, sulphate, chloride ions, natural organic matter (humic acids) and pH on 2,4-D degradation was studied. A significant antagonistic effect of carbonate and humic acid was observed, whereas, the effects of other ions were insignificant. A higher first order rate constant of 1.73 min-1 was observed, which was significantly decreased in the presence of carbonate ions and humic acids. Also, a higher degradation of 2,4-D was observed in acidic pH conditions. Different 2,4-D intermediates were detected and the degradation pathway of 2,4-D in plasma treatment process was suggested. The toxicity of 10 mg/L 2,4-D was completely eradicated after 10 min of plasma treatment. PMID- 28595147 TI - Predictors of treatment response and drop out in the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) study. AB - The Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) compared the efficacy of risperidone, olanzapine, and molindone over 8 weeks in 119 youths age 8-19 years with early-onset schizophrenia or schizoaffective disorder. From this large dataset, we examined predictors of treatment response and drop out using stepwise regression and receiver operating characteristics curve (ROC) analysis. Treatment response was defined as having both a >= 20% improvement in Positive and Negative Syndrome Scale (PANSS) score and a Clinical Global Impression-Improvement (CGI-I) score < 3. More severe baseline symptoms, having a history of being in an early education program, and previous prescription of a mood stabilizer increased the likelihood of responding to treatment. Anhedonia and poor community functioning predicted a reduction in symptom severity on the PANSS. Random assignment to different antipsychotic treatment was not predictive of outcome. Parental report of aggressive behaviors at baseline and being African American were associated with a greater likelihood of drop out. Our results suggest youth with more severe psychotic symptoms are most likely to benefit from treatment with antipsychotics and that aggressive youth may require additional support to improve treatment adherence. Further investigation is needed to understand potentially modifiable predictors of response like early education programs. PMID- 28595148 TI - Psychological strain and suicidal ideation: A comparison between Chinese and US college students. AB - OBJECTIVE: This study was to explore the relation between psychological strains and suicidal ideation among Chinese and American college students. Another secondary purpose of the study was to examine the reliability of the psychological strains scales (PPS: Ref) one more time in China and the United States in college populations. METHOD: Samples of college students were randomly recruited from China and United States. All of 529 college students (aged 17-27, 68.9% female) completed self-report assessments of psychological strains (Psychological Strain Scale), suicidal ideation (Beck Scale for Suicide Ideation), and indicators of psychological well-being (e.g., depression, anxiety, and stress). RESULTS: Empirical results show that Psychological Strain Scales (PSS) has a good reliability. Chinese college students reported higher suicide ideation scores than American students whereas there was no statistical difference in psychological strains. Psychological strains and, depression, anxiety, and stress, were positively related to suicidal ideation in both countries. Stepwise multiple regression analysis indicated that psychological strain can significantly predict suicidal ideation. CONCLUSIONS: These findings provide support for the Strain Theory of Suicide for both Chinese and American college students and some measures can be taken to reduce psychological strains in students. However, future work could extend these findings by utilizing a longitudinal design to determine whether psychological strains are in fact antecedents, and not simply correlates, of suicide ideation. PMID- 28595149 TI - Evidence of the paradoxical effect of social network support: A study among Filipino domestic workers in China. AB - Labor migrants are at an increased risk for poor mental health. Post-migration stressors contribute significantly to this risk. Social network supports are vitally important to protect health but little is known about the role of social network supports among labor migrants. The current study evaluated the role of migration stressors on poor mental health among Filipino female domestic workers (FDW) and whether family and friend social network support (SNS) modified this relationship. Data were collected from 261 FDWs in Macau, China from May to September 2013. Hierarchical multiple regression was conducted to test for direct and moderating effects of social networks on psychological distress. Post migration stress was associated with increased anxiety, depression, somatization, and post-traumatic stress disorder symptoms. SNS from family was not associated with the four psychological symptoms nor did it modify the association between stress and these symptoms. SNS from friends was positively associated with these symptoms, and significantly moderated the relationship between stress and these symptoms. Counterintuitive to the known buffering effects of SNS, greater SNS was associated with greater psychological symptoms among FDWs exposed to post migration stressors. The present findings suggest that reliance on SNS to cope with post-migration stressors may worsen psychological distress. PMID- 28595151 TI - Ionic liquids for low-tension oil recovery processes: Phase behavior tests. AB - Chemical flooding with surfactants for reducing oil-brine interfacial tensions (IFTs) to mobilize residual oil trapped by capillary forces has a great potential for Enhanced Oil Recovery (EOR). Surface-active ionic liquids (SAILs) constitute a class of surfactants that has recently been proposed for this application. For the first time, SAILs or their blends with an anionic surfactant are studied by determining equilibrium phase behavior for systems of about unit water-oil ratio at various temperatures. The test fluids were model alkane and aromatic oils, NaCl brine, and synthetic hard seawater (SW). Patterns of microemulsions observed are those of classical phase behavior (Winsor I-III-II transition) known to correlate with low IFTs. The two anionic room-temperature SAILs tested were made from common anionic surfactants by substituting imidazolium or phosphonium cations for sodium. These two anionic and two cationic SAILs were found to have little potential for EOR when tested individually. Thus, also tested were blends of an anionic internal olefin sulfonate (IOS) surfactant with one of the anionic SAILs and both cationic SAILs. Most promising for EOR was the anionic/cationic surfactant blend of IOS with [C12mim]Br in SW. A low equilibrium IFT of ~2.10 3mN/m was measured between n-octane and an aqueous solution having the optimal blend ratio for this system at 25 degrees C. PMID- 28595152 TI - An unexplored remarkable PNIPAM-osmolyte interaction study: An integrated experimental and simulation approach. AB - We investigate the aggregation and collapse of water soluble amphiphilic polymer, poly(N-isopropylacrylamide) (PNIPAM), in aqueous solution containing variable amount of trehalose, sucrose and sorbitol. The effect of these osmolytes on the coil to globular transition of the PNIPAM is studied by the use of comprehensive biophysical techniques like UV-visible spectroscopy, fluorescence spectroscopy, dynamic light scattering and Fourier transform infrared spectroscopy (FTIR). The polarization induced by these additives promotes the collapsed state of PNIPAM at much lower temperature as compared to the pure PNIPAM in aqueous solution. The decrease in the lower critical solution temperature (LCST) of the polymer with increase in the concentration of osmolyte is due to the significant changes in the interactions among polymer, osmolyte and water. The high affinity of these additives toward water destabilize the hydrated macromolecular structure via preferential interactions. To investigate the molecular mechanism behind the decrease in the LCST of the polymer in presence of the osmolytes, a molecular dynamics (MD) study was performed. The MD simulation has clearly shown the reduction in hydration shell of the polymer after interacting with the osmolyte. MD study revealed significant changes in polymer conformation because of osmolyte interaction and strongly supports the experimental observation of polymer phase transition at temperature lower than typical LCST. The driving force for concomitant sharp configurational transition has been attributed to the rupture of hydrogen bonds between water and polymer and to the hydrophobic association of the polymer. The results of the present study can be used in the bioresponsive smart PNIPAM-based devices as its LCST is close to body temperature. This study provides an alternative method to tune the LCST of the widely accepted model PNIPAM polymer. PMID- 28595150 TI - Psychotic-like experiences and correlation with childhood trauma and other socio demographic factors: A cross-sectional survey in adolescence and early adulthood in China. AB - Psychotic-like experiences (PLEs) in adolescence are found to be risk factors for later mental disorders. Previous research has also found that childhood trauma has a positive correlation with mental health problems. However, few studies have focused on the relationship between them, especially in adolescence and early adulthood. A total of 9122 students (age between 10 and 23.3) were surveyed and assessed with the positive and depressive subscales of the Community Assessment of Psychic Experiences and the Trauma History Questionnaire. A total of 20.7% students experienced frequent PLEs, 17.5% had frequent delusional experiences, and 7.6% had frequent hallucinatory experiences. Only a small portion of this sample experienced frequent PLEs, associated with more types of PLEs, more distress, and more depressive experiences. Several socio-demographic factors were associated with frequent PLEs in this sample, which could be further examined in future prevention studies. Students with frequent PLEs experienced significantly higher impact from trauma events, both at the time of the events and in the present, indicating a possible reciprocal effect between childhood trauma and PLEs. The impact of childhood trauma played an important role in the relationship between childhood trauma and PLEs. PMID- 28595153 TI - Preparation and characteristics of graphene oxide-blending PVDF nanohybrid membranes and their applications for hazardous dye adsorption and rejection. AB - Graphene oxide (GO) and lithium chloride (LiCl) were introduced into poly (vinylidene fluoride) (PVDF) membranes prepared using the immersion precipitation technique. The hydrophilicity, water flux, X-ray diffraction (XRD), zeta potential, SEM and AFM images of membranes were investigated. By adjusting the content of GO from 0wt% to 0.9 wt%, the water flux of PVDF/GO/LiCl nanohybrid membranes varied from 48.4L/m2h to 61.90L/m2h at 100kPa. Because of the synergistic effects of GO and LiCl particles, the surface free energy (|DeltaGs|) of M3 (0.5wt% GO) membrane was highest (103.50mJ/m2), indicating that the hydrophilicity of M3 membrane was highest. Rhodamine B aqueous solution was firstly used to determine the adsorption and desorption ability of membranes. After 20 cycles, the decolorization rates and flux recovery ratios of nanohybrid membranes exceeded 80% and 78.2% respectively, and the Rhodamine B rejection of M3 membrane was maximum (67.8%) at 100kPa, which illustrated that nanohybrid membranes can be reused as a better ultrafiltration and dye recovery material, and the characteristic of M3 membrane was best. PMID- 28595154 TI - A detailed exploration of intermolecular interactions in 4-(4 dimethylaminobenzylideneamino)-N-(5-methyl-3-isoxazolyl)benzenesulfonamide and related Schiff bases: Crystal structure, spectral studies, DFT methods, Pixel energies and Hirshfeld surface analysis. AB - The Schiff base of the title has been synthesized and its crystal structure determined by single-crystal X-ray diffraction. The compound was characterized by IR, Raman, 1H NMR, 13C NMR and electronic absorption spectra. DFT calculations provide the quantum chemical basis for the observed molecular conformation. A study of intermolecular interactions of the title compound is compared with seven other closely related structures and reveals that molecules in most of the compounds are linked by a cooperative effect of strong and weak hydrogen bonds, CH...pi, and pi...pi stacking interactions, and also lp...pi contacts. Lattice energy calculations indicate that the dispersion component is the major contribution, with the coulombic term playing a significant role in the total energy. Interaction energies for molecular pairs involving NH...N bonds indicate a dominant contribution to packing stabilization coming from coulomb component. Hirshfeld surfaces and 2D-fingerprint plots allowed us to visualize different intermolecular contacts and its relative contributions to total surface in each compound. The analysis of electrostatic potential (ESP) maps correlates well with the computed energies providing evidences on the dominant electrostatic nature of NH...N and NH...O interactions. PMID- 28595155 TI - Multielectron dissociative ionization of methane and formaldehyde molecules with optimally tailored intense femtosecond laser pulses. AB - The multielectron dissociative ionization of CH4 and CH2O molecules has been investigated using optimum convolution of different dual tailored short laser pulses. Based on three dimensional molecular dynamics simulations and TDDFT approach, the dissociation probability is enhanced by designing the dual chirped chirped laser pulses and chirped-ordinary laser pulses for formaldehyde molecule. However, it is interesting to notice that the sensitivity of enhanced dissociation probability into different tailored laser pulses is not significant for methane molecule. In this presented modifications, time variation of bond length, velocity, time dependent electron localization function and evolution of the efficient occupation states are presented to analyze the time evolution of molecular dynamics. This work is proved to be a potential way to reduce the controlling costs with a currently available pulse shaping technology. PMID- 28595156 TI - Self-assembly of exfoliated molybdenum disulfide (MoS2) nanosheets and layered double hydroxide (LDH): Towards reducing fire hazards of epoxy. AB - In present study, LDH/MoS2 hybrids were facilely prepared by self-assembly of exfoliated MoS2 nanosheets and LDH via electrostatic force. The structure and morphology of the LDH/MoS2 hybrids were characterized and then introduced into epoxy for reducing its fire hazards. Compared with single MoS2, LDH/MoS2 hybrids showed a more homogeneous dispersion in the epoxy matrix and no obvious agglomerates were observed. Compared with MoS2, the addition of LDH/MoS2 hybrids endowed more excellent fire resistance to epoxy matrix, which was reflected by the significantly reduced peak heat release rate, total heat release and total smoke production. A rational flame retardant mode of action for LDH/MoS2 hybrids was proposed based on the analysis of pyrolysis fragments and char residues. PMID- 28595157 TI - Fabrication of Fe-doped birnessite with tunable electron spin magnetic moments for the degradation of tetracycline under microwave irradiation. AB - Manganese oxides exhibit an excellent microwave absorption performance that could increase the degradation efficiency of organic pollutants in contaminated water. Incorporation of various transition metals into manganese oxides could bring about changes in their crystal structure and improve their physicochemical performance. In this work, a better microwave absorption material was obtained by adjusting and controlling the electron spin magnetic moments of Fe-doped birnessite. The powder X-ray diffraction, inductive coupled plasma emission spectrometer, X-ray photoelectron spectroscopy, and network analyses were performed to characterize the crystal structure, chemical composition, valence and content of the elements, and the microwave absorption performance of the obtained samples. Doping Fe into birnessite resulted in little changes to their crystal structure. The narrow energy spectrum of Fe (2p) revealed that the doped Fe was in the form of Fe (III) in birnessite structure. As the content of Fe (III) increased, the content of Mn (III) decreased accordingly. Substitution of Mn (III) by Fe (III) in the birnessite crystal lattice, confirmed by combining the characterization analyses with structure refinements for each doped sample, increased the overall numbers of unpaired electrons in birnessite structure, resulting in a higher electron spin magnetic moment and better microwave response. Compared with the non-doped sample, Fe-doped birnessite improved the efficiency of tetracycline degradation, which proved that Fe-doped birnessite indeed had better response towards the microwave, and thus, could be utilized for better removal of organic pollutants under microwave irradiation. PMID- 28595158 TI - Synthesis and characterization of a composite polymeric material including chelating agent for adsorption of uranyl ions. AB - In this study, a versatile polymeric material was synthesized by grafting Calcon Carboxylic Acid (CCA), which is known as a chelating agent for some metal ions, to polyacrylamide (PAA) structure. Thus, the adsorptive properties of inert PAA polymer were significantly improved owing to this procedure. The obtained new material, CCA-g-PAA, was characterized by point zero charge (PZC), FTIR, SEM, and UV-VIS-NIR analysis. The adsorption properties of new material were investigated comprehensively and experimental variables were optimized such as pH, temperature, time, and concentration. Experimental data were evaluated by using theoretical adsorption models. The maximum adsorption capacity of material was calculated as 0.079molkg-1 by considering Langmuir equation. The constants calculated from Freundlich and DR model were found as 6.98 and 0.441, respectively. Adsorption kinetic was also explained with pseudo second order and intra particular diffusion models. Experimental studies were showed that adsorption was endothermic and occurred spontaneously. The developed material has important advantages such as reusability, cost-effective synthesis procedure, high adsorption capacity, and selectivity. PMID- 28595159 TI - Magnetically separable sulfur-doped SnFe2O4/graphene nanohybrids for effective photocatalytic purification of wastewater under visible light. AB - In this report, magnetically recoverable sulfur-doped SnFe2O4/graphene (S-SFO/GR) nanohybrids have been successfully developed via a facile solvothermal method. The characterizations on the structural, morphology, and optical properties of the nanohybrids indicate that S-SFO particles are successfully embedded on the GR nanosheets. The photocatalytic activity has been evaluated by photocatalytic degradation of chlorotetracycline under visible light irradiation. Among the composites with various mass ratios, the quasi-first-order rate constant of the nanohybrids formed with 9wt% S in SFO and 15wt% GR (9S-SFO/GR-15) can reach as high as 1.83min-1, which is much higher than that of SFO (0.68min-1) and SFO/GR (0.91min-1), confirming the important role of S and GR for the photocatalytic process. The combination of the three components of S, SFO, and GR has enhanced the visible light absorption capability and inhibited the recombination of photogenerated electron-hole. The 9S-SFO/GR-15 nanohybrids can be recovered easily by a magnet and reused for five times with remained photocatalytic efficiency about 70%. A possible catalytic mechanism explaining the efficient photocatalytic performances of the prepared nanohybrids has been proposed. PMID- 28595160 TI - Redox signaling during hypoxia in mammalian cells. AB - Hypoxia triggers a wide range of protective responses in mammalian cells, which are mediated through transcriptional and post-translational mechanisms. Redox signaling in cells by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) occurs through the reversible oxidation of cysteine thiol groups, resulting in structural modifications that can change protein function profoundly. Mitochondria are an important source of ROS generation, and studies reveal that superoxide generation by the electron transport chain increases during hypoxia. Other sources of ROS, such as the NAD(P)H oxidases, may also generate oxidant signals in hypoxia. This review considers the growing body of work indicating that increased ROS signals during hypoxia are responsible for regulating the activation of protective mechanisms in diverse cell types. PMID- 28595162 TI - Rotator cuff tendinopathy alters the muscle activity onset and kinematics of scapula. AB - Athletes with rotator cuff (RC) tendinopathy demonstrate an aberrant pattern of scapular motion which might relate to deficits in the scapular muscles. This study aimed to determine whether alteration in scapular kinematics is associated with deficits in the activity onset of scapular muscles. Forty-three male volleyball players (17 asymptomatic and 26 with RC tendinopathy) joined the study. Three-dimensional scapular kinematics was quantified using an acromial marker cluster method. The activity onset of the upper (UT), middle (MT), and lower trapezius (LT), and serratus anterior (SA) during arm abduction was assessed with electromyography. Athletes with RC tendinopathy demonstrated less scapular upward rotation (6.6+/-2.3 vs. 8.2+/-1.1 degrees , p=0.021) in the early phase of shoulder abduction from 0 degrees to 30 degrees when compared to asymptomatic athletes. The tendinopathy group had delayed activity onset of LT (14.1+/-31.4ms vs. 74.4+/-45.1ms, p<0.001) and SA (-44.9+/-26.0ms vs. 23.0+/ 25.2ms, p<0.001) relative to UT when compared to the asymptomatic group. In asymptomatic athletes, earlier activity onset of MT and LT relative to UT was associated with more scapular upward rotation during 0-30 degrees of abduction (r=0.665, p=0.021) and 30-60 degrees of abduction (r=0.680, p=0.015), respectively. Our findings showed the control of the scapular upward rotation is related to the activity onset of the scapular muscles in athletes. PMID- 28595163 TI - A new method for the localization of the innervation zone based on monopolar surface-detected potentials. AB - In monopolar electrode configuration, the shape of the motor unit potential (MUP) undergoes essential morphologic changes with increasing distance from the innervation zone. In particular, the rising phase of the MUP slows down and becomes longer as the electrode is moved further from the innervation zone. Based on this, it is hypothesized that the maximum slope of the rising phase of a monopolar MUP (SlopeMAX) would reach its highest value at the innervation zone. Herein, we sought to determine whether the location of the innervation zone coincides with the position in the muscle of the monopolar MUP with highest SlopeMAX and whether new criteria for the localization of the innervation region can be proposed based on the SlopeMAX of monopolar potentials. Multichannel surface (13*5 electrode array) and intramuscular (wire electrodes inserted with needles of lengths 15 and 25mm) EMG signals were concurrently recorded in monopolar configuration from the biceps brachii muscle of 10 healthy subjects. The spatial distribution of monopolar and bipolar MUPs along the fibers' direction were obtained by spike-triggered averaging of the surface EMG. We found that the monopolar MUP with steepest rising phase (i.e., highest SlopeMAX) was located either just above or at half of the inter-electrode distance from the innervation zone. High levels of agreement (94-98%) were found between the position of the innervation zone assessed with the SlopeMAX criteria of monopolar potentials and the position identified using the phase reversal criteria of bipolar potentials. The present results legitimize the use of compound muscle action potentials (M waves) to localize the innervation zone: this location would correspond to the electrode position which yielded the monopolar M wave with highest SlopeMAX. PMID- 28595164 TI - Imaging and analysis of individual cavitation microbubbles around dental ultrasonic scalers. AB - Cavitation is a potentially effective and less damaging method of removing biofilm from biomaterial surfaces. The aim of this study is to characterise individual microbubbles around ultrasonic scaler tips using high speed imaging and image processing. This information will provide improved understanding on the disruption of dental biofilm and give insights into how the instruments can be optimised for ultrasonic cleaning. Individual cavitation microbubbles around ultrasonic scalers were analysed using high speed recordings up to a million frames per second with image processing of the bubble movement. The radius and rate of bubble growth together with the collapse was calculated by tracking multiple points on bubbles over time. The tracking method to determine bubble speed demonstrated good inter-rater reliability (intra class correlation coefficient: 0.993) and can therefore be a useful method to apply in future studies. The bubble speed increased over its oscillation cycle and a maximum of 27ms-1 was recorded during the collapse phase. The maximum bubble radii ranged from 40 to 80MUm. Bubble growth was observed when the ultrasonic scaler tip receded from an area and similarly bubble collapse was observed when the tip moved towards an area, corresponding to locations of low pressure around the scaler tip. Previous work shows that this cavitation is involved in biofilm removal. Future experimental work can be based on these findings by using the protocols developed to experimentally analyse cavitation around various clinical instruments and comparing with theoretical calculations. This will help to determine the main cleaning mechanisms of cavitation and how clinical instruments such as ultrasonic scalers can be optimised. PMID- 28595165 TI - Propagation characteristics of interface waves between a porous medium and a sediment-containing two-phase fluid. AB - Based on the modified Biot theory of Johnson, the propagation characteristics of the various interface waves at an interface between a semi-infinite fluid and a porous medium were studied. First, based on the characteristic equations of open pore and sealed-pore, which were derived from the wave equations, time-domain waveforms at the interface were obtained by inverse Fourier transform. The effects of the longitudinal frame modulus on the interface waves were investigated. For open-pore and sealed-pore, the effect of porosity on the propagation of the interface waves was studied; the porosity was found to strongly influence the true surface wave. Based on four ultrasonic suspension models-Utrick, Utrick-Ament (UA), Harker-Temple (HT) and McClement, the pseudo Stoneley wave propagation characteristics were analyzed at the interface between the sediment-containing two-phase fluid and the porous medium solid. The effects of volume fraction and particle diameter on the phase velocity, attenuation coefficient and dispersion for the pseudo-Stoneley and true surface wave were discussed, and the results demonstrated that the properties of the fluid strongly impacted the pseudo-Stoneley wave but exerted very little effect on the true surface wave. The conclusions drawn in this paper could contribute to elucidate the parameters of sediment and porous media. PMID- 28595161 TI - Non-linear actions of physiological agents: Finite disarrangements elicit fitness benefits. AB - Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term "mirror J-shaped curves" for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non linear responses to physiological agents. PMID- 28595166 TI - Comparison of four types of energy grasses as lignocellulosic feedstock for the production of bio-ethanol. AB - In order to utilize energy grasses as substrates for production of biofuels and expand the diversity of lignocellulosic feedstocks, this work developed an evaluation system considering 16 kinds of parameters related to the contents of three main compositions (cellulose, hemicellulose and lignin), inhibitors generated from the pretreatment, the extent of enzymatic hydrolysis and microbial fermentation. Giant reed, corn stalks, switch grass, pennisetum and silvergrass were investigated. Comprehensive utilization indexes of giant reed (55.0) and corn stalks (40.6) revealed that giant reed had the potential for producing biofuels but corn stalks, widely used in bio-ethanol and xylitol production, possessed high contents of inhibitors which were harmful to microbial fermentation. PMID- 28595167 TI - Modulating of the pnicogen-bonding by a H?pi interaction: An ab initio study. AB - An ab initio study of the cooperativity in XH2P?NCH?Z and XH2P?CNH?Z complexes (X=F, Cl, Br, CN, NC; Z=C2H2,C6H6) connected by pnicogen-bonding and H?pi interactions is carried out by means of MP2 computational method. A detailed analysis of the structures, interaction energies and bonding properties is performed on these systems. For each set of the complexes considered, a favorable cooperativity is observed, especially in X=F and CN complexes. However, for a given X or Z, the amount of cooperativity effects in XH2P?CNH?Z complexes are more important than XH2P?NCH?Z counterparts. Besides, the influence of a H?pi interaction on a P?N (C) bond is more pronounced than that of a P?N (C) bond on a H?pi bond. The quantum theory of atoms in molecules shows that ternary complexes have increased electron densities at their bond critical points relative to the corresponding binary systems. The results also indicate that the strength of the P?N(C) and H?pi interactions increases in the presence of the solvent. PMID- 28595168 TI - Reactivation of Multiple Infectious Pathogens after Hematopoietic Stem Cell Transplantation. PMID- 28595169 TI - The Addition of Target Therapy to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer: A Review. AB - Currently, neoadjuvant fluoropyrimidine-based chemoradiotherapy (CRT) is standard practice in the management of locally advanced rectal cancer (LARC). In the last decade there has been a lively interest in the improvement of clinical outcomes by modifying this standard regimen by the addition of further agents. We review combinations of targeted therapies and conventional CRT currently under investigation in LARC patients. PMID- 28595170 TI - Clustered Cardiovascular Risk Factors Are Associated with Inflammatory Markers in Adolescents. AB - BACKGROUND: Clusters of cardiovascular risk (CVR) factors are associated with an increased risk of developing cardiovascular diseases (CVDs). This cross-sectional study assessed the associations between classic CVR factor clusters and inflammatory markers in Brazilian adolescents. METHODS: Measurements included anthropometric, clinical and biochemical parameters and selected inflammatory markers in 487 adolescents (236 boys/251 girls; 12.06 +/- 1.41 years). RESULTS: After stratifying the population by gender and adjusting for potential confounding variables, principal component analysis was performed and it produced 5 independent components in both genders: adiposity, glucose metabolism, blood pressure, high-density lipoprotein (HDL)/triacylglycerols (TG), and cholesterol/low-density lipoprotein. Glucose metabolism was inversely associated with interleukin-1beta (IL-1beta) in both genders (r = -0.026; r = -0.021); blood pressure was inversely associated with tumor necrosis factor alpha (TNF-alpha) in girls (r = -0.046); HDL/TG was positively associated with interleukin-6 in girls (r = 0.012), with IL-1beta (r = 0.010) TNF-alpha (r = 0.045) in boys, and inversely associated with adiponectin in both genders (r = -0.015; r = -0.013). CONCLUSION: The results suggest that lipid metabolism alterations, as potential early events in the development of CVDs, have a strong link to the inflammatory process, in contrast to other clusters of risk factors. PMID- 28595172 TI - Routine Pouchoscopy Prior to Ileostomy Takedown May Not Be Necessary in Patients with Chronic Ulcerative Colitis. AB - BACKGROUND: Creation of a J pouch is the gold standard surgical intervention in the treatment of chronic ulcerative colitis (UC). Pouchoscopy prior to ileostomy takedown is commonly performed. We describe the frequency, indication, and findings on pouchoscopy, and determine if pouchoscopy affects rates of complications after takedown. METHODS: All UC or indeterminate inflammatory bowel disease patients with a J pouch were retrospectively evaluated from January 1994 to December 2014. Cases were defined as having routine (asymptomatic) pouchoscopy after pouch creation but before ileostomy takedown. Controls were defined as having no pouchoscopy or pouchoscopy on the same day as that of takedown. RESULTS: The study included 178 patients (81.5% cases, 18.5% controls). Fifty two percent of pouchoscopies were reported as normal. Common abnormal endoscopy findings included stricture (35%), pouchitis (7%), and cuffitis (0.7%). Length of stay during takedown hospitalization was shorter for cases than controls (3 vs. 5 days; p = 0.001), but neither short- nor long-term complications were statistically different between cases and controls. Abnormalities on pouchoscopy were not predictive for short-term complications (p = 0.73) or long-term complications (p = 0.55). Routine pouchoscopy did not delay takedown surgery in any of the included patients. CONCLUSIONS: Routine pouchoscopy may not be necessary prior to ileostomy takedown; its greatest utility is in patients with suspected pouch complications. PMID- 28595171 TI - Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients. AB - BACKGROUND/AIMS: Irisin is a peptide hormone cleaved from a plasma membrane protein fibronectin type III domain containing protein 5 (FNDC5). Emerging studies have indicated association between serum irisin and many major chronic diseases including cardiovascular diseases. However, the role of serum irisin as a predictor for mortality risk in acute heart failure (AHF) patients is not clear. METHODS: AHF patients were enrolled and serum was collected at the admission and all patients were followed up for 1 year. Enzyme-linked immunosorbent assay was used to measure serum irisin levels. To explore predictors for AHF mortality, the univariate and multivariate logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis were used. To determine the role of serum irisin levels in predicting survival, Kaplan-Meier survival analysis was used. RESULTS: In this study, 161 AHF patients were enrolled and serum irisin level was found to be significantly higher in patients deceased in 1-year follow-up. The univariate logistic regression analysis identified 18 variables associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 2 variables namely blood urea nitrogen and serum irisin. ROC curve analysis indicated that blood urea nitrogen and the most commonly used biomarker, NT-pro-BNP, displayed poor prognostic value for AHF (AUCs <= 0.700) compared to serum irisin (AUC = 0.753). Kaplan-Meier survival analysis demonstrated that AHF patients with higher serum irisin had significantly higher mortality (P<0.001). CONCLUSION: Collectively, our study identified serum irisin as a predictive biomarker for 1-year all-cause mortality in AHF patients though large multicenter studies are highly needed. PMID- 28595174 TI - Interactive Prosodic Marking of Focus, Boundary and Newness in Mandarin. AB - The current study investigates whether and how focus, phrase boundary and newness can be simultaneously marked in speech prosody in Mandarin Chinese. Homophones were used to construct three syntactic structures that differed only in boundary condition, focus was elicited by preceding questions, while newness of postboundary words was manipulated as whether they had occurred in the previous text. Systematic analysis of F0 and duration showed that (1) duration was a reliable correlate of boundary strength regardless of focus location, while involvement of F0 was only in terms of lowering of phrase-final F0 minima and raising of phrase-initial F0 minima at a relatively strong boundary, (2) postfocus compression (PFC) of F0 was applied across all boundaries, including those with long silent pauses (over 200 ms), and postfocus F0 was lowered to almost the same degree in all boundary conditions, and (3) newness of postfocus words had no systematic effect on F0 or duration. These results indicate that not only functionally focus is independent of prosodic structure and newness, but also phonetically its realization is separate from boundary marking. Focus is signaled mainly through pitch range adjustments, which can occur even across phrase breaks, whereas boundaries are mostly signaled by duration adjustments. PMID- 28595173 TI - Effects of Weight Loss with and without Exercise on Regional Body Fat Distribution in Postmenopausal Women. AB - BACKGROUND/AIMS: The purpose was to determine whether lifestyle interventions have different effects on regional fat in women with normal glucose tolerance vs. impaired glucose tolerance (NGT vs. IGT). METHODS: Changes in glucose metabolism (2-h oral glucose-tolerance tests), android to gynoid fat mass ratio (dual energy X-ray absorptiometry [DXA]), visceral to subcutaneous abdominal fat area ratio (CT), and abdominal to gluteal subcutaneous fat cell weight (FCW; adipose tissue biopsies) were determined in 60 overweight postmenopausal women (45-80 years) following 6 months of weight loss alone (WL; n = 28) or with aerobic exercise (AEX + WL; n = 32). RESULTS: The interventions led to ~8% decrease in weight, but only the AEX + WL group improved fitness (?11% in VO2max) and reduced the android to-gynoid fat mass ratio (?5%; p < 0.05). Both NGT and IGT groups reduced visceral and subcutaneous abdominal fat areas and abdominal and gluteal FCWs, which related to improvements in homeostatic model assessment (r = 0.34-0.42) and 2-h glucose (r = 0.34-0.35), respectively (p < 0.05). The decline in FCW was 2* greater in women with IGT following WL (p < 0.05). The ratios of abdominal-to gluteal FCW did not change following either intervention. CONCLUSIONS: The mechanisms by which WL with and without exercise impact regional fat loss should be explored as reductions in abdominal fat area and subcutaneous FCW appear to influence glucose metabolism. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel. PMID- 28595175 TI - Untreated Psoriasis Impairs Male Fertility: A Case-Control Study. AB - BACKGROUND: Recent evidence indicates that a systemic state of inflammation may impair fertility, but data about psoriatic males are scarce. OBJECTIVES: The aim of this study was to assess gonadal function in psoriatic males implementing our knowledge about fertility in these subjects. METHODS: Male psoriatic patients, aged between 18 and 55 years, and a group of healthy subjects matched for age, BMI and geographic origin were enrolled. All subjects underwent a complete physical and andrological examination, standard semen analysis, complete microbiological analysis and ultrasound evaluation of sexual glands. Seminal levels of soluble urokinase-type plasminogen activator receptor (suPAR) and serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone and follicle-stimulating hormone were also assessed. RESULTS: Fifty patients and 50 controls fulfilled the inclusion criteria and were enrolled in our study. Testosterone and SHBG were found to be significantly decreased in patients with psoriasis compared with the control group. Higher levels of E2 were also reported in psoriatic patients. Total sperm count, sperm motility and percent of spermatozoa with normal morphology were significantly reduced in patients compared to controls. suPAR levels were significantly increased in patients compared to controls and found to be above the reference limits. Ultrasound signs of inflammation of the accessory glands were observed in 35/50 patients with psoriasis and in none of the controls. CONCLUSION: Our study suggests that untreated psoriasis may impair male fertility. We also found that this might be due to an impact of systemic inflammation on the hormonal profile and on sexual accessory gland inflammation. PMID- 28595176 TI - Individual Talker and Token Covariation in the Production of Multiple Cues to Stop Voicing. AB - BACKGROUND/AIMS: Previous research found that individual talkers have consistent differences in the production of segments impacting the perception of their speech by others. Speakers also produce multiple acoustic-phonetic cues to phonological contrasts. Less is known about how multiple cues covary within a phonetic category and across talkers. We examined differences in individual talkers across cues and whether token-by-token variability is a result of intrinsic factors or speaking style by examining within-category correlations. METHODS: We examined correlations for 3 cues (voice onset time, VOT, talker relative onset fundamental frequency, f0, and talker-relative following vowel duration) to word-initial labial stop voicing in English. RESULTS: VOT for /b/ and /p/ productions and onset f0 for /b/ productions varied significantly by talker. Token-by-token within-category variation was largely limited to speaking rate effects. VOT and f0 were negatively correlated within category for /b/ productions after controlling for speaking rate and talker mean f0, but in the opposite direction expected for an intrinsic effect. Within-category talker means were correlated across VOT and vowel duration for /p/ productions. Some talkers produced more prototypical values than others, indicating systematic talker differences. CONCLUSION: Relationships between cues are mediated more by categories and talkers than by intrinsic physiological relationships.Talker differences reflect systematic speaking style differences. PMID- 28595177 TI - Genomics Perspectives on Metabolism, Survival Strategies, and Biotechnological Applications of Brettanomyces bruxellensis LAMAP2480. AB - Wine production is an important commercial issue for the liquor industry. The global production was estimated at 275.7 million hectoliters in 2015. The loss of wine production due to Brettanomyces bruxellensis contamination is currently a problem. This yeast causes a "horse sweat" flavor in wine, which is an undesired organoleptic attribute. To date, 6 B. bruxellensis annotated genome sequences are available (LAMAP2480, AWRI1499, AWRI1608, AWRI1613, ST05.12/22, and CBS2499), and whole genome comparisons between strains are limited. In this article, we reassembled and reannotated the genome of B. bruxellensis LAMAP2480, obtaining a 27-Mb assembly with 5.5 kb of N50. In addition, the genome of B. bruxellensis LAMAP2480 was analyzed in the context of spoilage yeast and potential as a biotechnological tool. In addition, we carried out an exploratory transcriptomic analysis of this strain grown in synthetic wine. Several genes related to stress tolerance, micronutrient acquisition, ethanol production, and lignocellulose assimilation were found. In conclusion, the analysis of the genome of B. bruxellensis LAMAP2480 reaffirms the biotechnological potential of this strain. This research represents an interesting platform for the study of the spoilage yeast B. bruxellensis. PMID- 28595179 TI - Epigenetic Changes in the Acute Kidney Injury-to-Chronic Kidney Disease Transition. AB - Previously acute kidney injury (AKI) had been believed to be a transient event, and recovery from AKI had been thought to lead to no consequences. However, recent epidemiological studies have shown that even if there is complete recovery of the kidney function, AKI can eventually result in chronic kidney disease (CKD) and eventually in end-stage kidney disease in the long term. Transition of AKI to CKD is mediated by multiple mechanisms, including aberrant cell cycle arrest and hypoxia. Hypoxia of the kidney is induced by rarefaction of the peritubular capillaries after AKI episodes, and induces inflammation and fibrosis. It should also be noted that epigenetic changes are closely related to hypoxia, and epigenetic changes induced by hypoxia, called "hypoxic memory" can explain the AKI-to-CKD transition in the long term after complete recovery from the initial AKI episode. Targeting hypoxia and subsequent epigenetic changes are promising strategies to block the transition from AKI to CKD. PMID- 28595178 TI - Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice. AB - AIMS: To determine whether irisin could improve endothelial dysfunction by regulating heme oxygenase-1(HO-1)/adiponectin axis in perivascular adipose tissue (PVAT) in obesity. METHODS: Male C57BL/6 mice were fed with a high-fat diet (HFD) with or without irisin treatment. Endothelium-dependent vasorelaxation of the thoracic aorta with or without PVAT (PVAT+ or PVAT-) was determined. Western blot was employed to determine the levels of HO-1 and adiponectin in PVAT. UCP-1, Cidea, and TNF-alpha gene expression in PVAT were tested by real-time PCR. RESULTS: The presence of PVAT significantly impaired endothelial function in the HFD mice. Treatment of HFD mice with irisin significantly restored this impairment and improved endothelial function in vivo or ex vivo. Incubated aortic rings (PVAT-) with PVAT-derived conditioned medium (CM) from HFD mice impaired endothelial function in control mice. This impairment was prevented by incubating the aortic rings (PVAT-) from HFD mice with PVAT-derived CM from irisin. However, the beneficial effects were partly attenuated in the presence of HO-1 inhibitor and adiponectin receptor blocking peptide. Treatment of HFD mice with irisin significantly increased NO production, protein levels of HO-1 and adiponectin, mRNA expressions of UCP-1 and Cidea, and decreased superoxide production and TNF alpha expression in PVAT. CONCLUSION: Irisin improved endothelial function by modulating HO-1/ adiponectin axis in PVAT in HFD-induced obese mice. These findings suggest that regulating PVAT function may be a potential mechanism by which irisin improves endothelial function in obesity. PMID- 28595180 TI - Fibrotic Changes Mediating Acute Kidney Injury to Chronic Kidney Disease Transition. AB - End-stage renal disease (ESRD) is common, costly, and it results from progressive chronic kidney disease (CKD). ESRD claims many lives every year. It is increasingly recognized that episodes of acute kidney injury (AKI) predispose to the future development of CKD and ESRD. While our understanding of the pathophysiology of the AKI to CKD transition is improving, there are no validated therapeutic strategies to prevent this transition. In this review, we summarize the recent progress made in defining the cellular and molecular events underlying the AKI to CKD transition and highlight potential therapeutic targets and strategies to reduce the incidence of CKD following AKI. PMID- 28595181 TI - Informant-Reported Cognitive Decline and Activity Engagement across Four Years in a Community Sample. AB - BACKGROUND: Subtle age-related cognitive decline may be associated with the capacity to remain engaged in mental, physical, and social activities. Informant reports of cognitive decline potentially provide additional information to psychometric tests on change in everyday cognitive function relevant to activity engagement. OBJECTIVE: To investigate relations between decline in everyday cognitive function as assessed by informant report and activity engagement in community-dwelling older adults. METHODS: A sample of cognitively normal older adults was drawn from the 2 latest waves of the PATH Through Life Study (n = 1,391; mean age 74.5 +/- 1.5, 48.4% female). PATH is a 16-year longitudinal cohort study set in the Canberra/Queanbeyan district, Australia. Assessments were carried out at baseline, and at 3 subsequent time-points 4 years apart. At wave 4, the IQCODE, an informant measure of 4-year cognitive decline was provided by a spouse, family member, or friend of each participant. Activity engagement was assessed by the abbreviated RIASEC Mental Activity List, self-reported frequency and duration of physical activity (Whitehall Questionnaire) and the Lubben Social Network Scale that assessed interaction with family/friends. Participants provided demographic information, self-reported health status (SF-12), and responses to the Goldberg Depression Scale. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test (CVLT) were used to measure objective 4-year cognitive change. Those with MMSE score of <=27 were excluded. RESULTS: IQCODE score predicted disengagement from mental activities over 4 years in cognitively healthy adults (beta = -0.056, standard error [SE] = 0.019, p = 0.004). This association was robust to covariate control and change on the SDMT which was also significantly related to mental activity disengagement. In models adjusted for change scores on the SDMT and the CVLT, the IQCODE was associated with less physical (beta = -0.692, SE = 0.24, p = 0.004) and social engagement (beta -0.046, SE = 0.021, p = 0.032), but relationships were attenuated with the inclusion of covariates. CONCLUSION: Informant-reported cognitive decline in a non-clinical sample was linked to activities that support cognitive health. Associations were robust to adjustment for cognitive change scores. Utilising informant reports prior to the manifestation of clinically relevant decline may identify those who would benefit most from personalised activity interventions. PMID- 28595182 TI - The Effect of Dietary Supplements Containing Green Tea, Capsaicin and Ginger Extracts on Weight Loss and Metabolic Profiles in Overweight Women: A Randomized Double-Blind Placebo-Controlled Clinical Trial. AB - BACKGROUND: This study was conducted to determine the effects of dietary supplements containing green tea, capsaicin and ginger extracts on weight loss and metabolic profiles among overweight women. METHODS: This randomized double blind placebo-controlled clinical trial was implemented among 50 overweight women. Participants were randomly divided into 2 groups. Group A received dietary supplements containing 125 mg green tea, 25 mg capsaicin and 50 mg ginger extracts (n = 25) group B received placebos (n = 25) twice with lunch and twice with dinner daily for 8 weeks. RESULTS: Compared with placebo, taking dietary supplements containing green tea, capsaicin and ginger resulted in a significant decrease in weight (-1.8 +/- 1.5 vs. +0.4 +/- 1.2 kg, respectively, p < 0.001) and body mass index (BMI; -0.7 +/- 0.5 vs. +0.1 +/- 0.5 kg/m2, respectively, p < 0.001). In addition, subjects who received green tea, capsaicin and ginger co supplements had significantly decreased serum insulin concentrations (-2.6 +/- 3.9 vs. -0.6 +/- 2.0 uIU/mL, p = 0.02), homeostatic model of assessment for insulin resistance (-0.5 +/- 0.8 vs. -0.05 +/- 0.6, p = 0.01), and increased quantitative insulin sensitivity check index (+0.01 +/- 0.01 vs. +0.001 +/- 0.01, p = 0.008) and plasma glutathione (GSH) levels (+73.8 +/- 120.6 vs. -28.3 +/- 193.4 umol/L, p = 0.03) compared with the placebo. CONCLUSIONS: Our study indicated that taking green tea, capsaicin and ginger co-supplements for 8 weeks among overweight women had beneficial effects on weight, BMI, markers of insulin metabolism and plasma GSH levels. PMID- 28595183 TI - Association between Leptin, Adiponectin, and Leptin/Adiponectin Ratio with Clustered Metabolic Risk Factors in Portuguese Adolescents: The LabMed Physical Activity Study. AB - INTRODUCTION: Circulating leptin and adiponectin levels have been associated with impaired vascular function, insulin resistance, and acute cardiovascular evens. This study aimed to evaluate the associations of leptin, adiponectin, and the leptin/adiponectin (L/A) ratio with a clustering of metabolic risk factors (MRF) in adolescents aged 12-18 years. METHODS: This is a cross-sectional analysis with 529 Portuguese adolescents aged 12-18 years. Blood samples were taken to analyze total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol (HDL-c), triglycerides glucose, insulin, leptin, and adiponectin levels. A continuous variable of clustered MRF score (sum of Z-scores of body fat percentage, systolic blood pressure, ratio TC/HDL, triglycerides, homeostatic model assessment insulin resistance, and cardiorespiratory fitness*[-1]) was computed. RESULTS: Regression analyses showed that adiponectin was a significant and negative predictor of MRF score (boys: beta = -0.199; p < 0.001; girls: beta = -0.200; p < 0.001); whereas leptin was a significant positive predictor of MRF score (boys: beta = 0.553; p < 0.001; girls: beta = 0.399; p < 0.001). The L/A ratio was also a significant positive predictor of MRF score in both sexes (boys: beta = 0.593; p < 0.001; girls: beta = 0.461; p < 0.001), after adjustments for age, pubertal stage, adherence to the Mediterranean diet, and socioeconomic status. In addition, adiponectin, leptin, and L/A ratio were accurate to predict MRF among adolescents, but L/A ratio showed the highest area under receiver operating characteristic curve. CONCLUSION: Leptin, adiponectin, and L/A ratio are associated with the clustering of MRF in adolescents after adjustments for age, sex, pubertal stage, adherence to the Mediterranean diet, and socioeconomic status. L/A ratio was more strongly associated with MRF score than adiponectin or leptin. PMID- 28595184 TI - Neuropsychological Profiles Differentiate Alzheimer Disease from Subcortical Ischemic Vascular Dementia in an Autopsy-Defined Cohort. AB - BACKGROUND/AIMS: The aim of this study was to assess the ability of neuropsychological tests to differentiate autopsy-defined Alzheimer disease (AD) from subcortical ischemic vascular dementia (SIVD). METHODS: From a sample of 175 cases followed longitudinally that underwent autopsy, we selected 23 normal controls (NC), 20 SIVD, 69 AD, and 10 mixed cases of dementia. Baseline neuropsychological tests, including Memory Assessment Scale word list learning test, control oral word association test, and animal fluency, were compared between the three autopsy-defined groups. RESULTS: The NC, SIVD, and AD groups did not differ by age or education. The SIVD and AD groups did not differ by the Global Clinical Dementia Rating Scale. Subjects with AD performed worse on delayed recall (p < 0.01). A receiver operating characteristics analysis comparing the SIVD and AD groups including age, education, difference between categorical (animals) versus phonemic fluency (letter F), and the first recall from the word learning test distinguished the two groups with a sensitivity of 85%, specificity of 67%, and positive likelihood ratio of 2.57 (AUC = 0.789, 95% CI 0.69-0.88, p < 0.0001). CONCLUSION: In neuropathologically defined subgroups, neuropsychological profiles have modest ability to distinguish patients with AD from those with SIVD. PMID- 28595185 TI - Association of Blood Fatty Acid Composition and Dietary Pattern with the Risk of Non-Alcoholic Fatty Liver Disease in Patients Who Underwent Cholecystectomy. AB - BACKGROUND/AIMS: The relationship between diet and non-alcoholic fatty liver disease (NAFLD) in patients with gallstone disease and in those who have a high risk for NAFLD has not been investigated. This study was conducted to investigate the association between the risk of NAFLD and dietary pattern in patients who underwent cholecystectomy. Additionally, we assessed the association between erythrocyte fatty acid composition, a marker for diet, and the risk of NAFLD. METHODS: Patients (n = 139) underwent liver ultrasonography to determine the presence of NAFLD before laparoscopic cholecystectomy, reported dietary intake using food frequency questionnaire, and were assessed for blood fatty acid composition. RESULTS: Fifty-eight patients were diagnosed with NAFLD. The risk of NAFLD was negatively associated with 2 dietary patterns: consuming whole grain and legumes and consuming fish, vegetables, and fruit. NAFLD was positively associated with the consumption of refined grain, meat, processed meat, and fried foods. Additionally, the risk of NAFLD was positively associated with erythrocyte levels of 16:0 and 18:2t, while it was negatively associated with 20:5n3, 22:5n3, and Omega-3 Index. CONCLUSION: The risk of NAFLD was negatively associated with a healthy dietary pattern of consuming whole grains, legumes, vegetables, fish, and fruit and with an erythrocyte level of n-3 polyunsaturated fatty acids rich in fish. PMID- 28595186 TI - Age-Related Insulin-Like Growth Factor Binding Protein-4 Overexpression Inhibits Osteogenic Differentiation of Rat Mesenchymal Stem Cells. AB - BACKGROUND/AIMS: Insulin-like growth factor binding proteins (IGFBP) play important roles in bone metabolism. IGFBP4 is involved in senescent-associated phenomena in mesenchymal stem cells (MSCs). The goal of the present study was to determine whether age-related IGFBP4 overexpression is associated with the impaired osteogenic differentiation potential of aged bone marrow derived MSCs. METHODS: MSCs were isolated from Sprague-Dawley rats aged 3-26 months. The bone morphogenetic protein (BMP)-2-induced osteogenic differentiation of rat MSCs was assessed by analyzing the expression levels of osteoblast marker genes [runt related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteocalcin (OC)], ALP activity and calcification. RESULTS: Our study showed that IGFBP4 mRNA and protein expression increased with age in parallel with impaired osteogenic differentiation of MSCs cultured in BMP2-containing osteogenic medium, as evidenced by the downregulation of osteoblast marker genes, and decreased ALP activity and calcium deposits. IGFBP4 overexpression impaired BMP2-induced osteogenic differentiation potential of young MSCs, whereas IGFBP4 knockdown restored the osteogenic potency of aged MSCs. Moreover, IGFBP4 knockdown stimulated the activation of Erk and Smad by increasing phosphorylation. CONCLUSION: Collectively, our results demonstrate that IGFBP4 overexpression plays a role in the impairment of MSC differentiation potential via the Erk and Smad pathways, suggesting potential targets to improve MSC function for cell therapy applications. PMID- 28595187 TI - rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor Is Associated with Diabetes Mellitus Type 2 in Caucasian Females with Obesity. AB - BACKGROUND: The role of brain-derived neurotrophic factor (BDNF) variants on diabetes prevalence, basal adipokine levels, body weight, and cardiovascular risk factors remains unclear in obese patients. OBJECTIVE: This study is aimed at analyzing the effects of rs10767664 BDNF gene polymorphism on diabetes mellitus prevalence, body weight, cardiovascular risk factors, and serum adipokine levels in obese female patients. DESIGN: A total of 507 obese women were enrolled in a prospective way. Biochemical evaluation and anthropometric measures were recorded. RESULTS: The frequency of diabetes mellitus in the group of patients with non-T allele was 20.1 and 28.3% in T-allele carriers. Logistic regression showed a risk of diabetes mellitus of 1.33 (95% CI 1.17-2.08) in subjects with T allele adjusted by age and body mass index (BMI). T-allele carriers with diabetes mellitus have a higher weight, BMI, waist circumference, blood pressure, glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and C reactive protein (CRP) levels than non-T-allele carriers. CONCLUSION: rs10767664 polymorphism of BDNF gene is associated with prevalence of diabetes mellitus in obese female patients. T-allele carriers with diabetes mellitus have a higher weight, fat mass, blood pressure, level of insulin, glucose, HOMA-IR, and CRP than non-T-allele carriers. PMID- 28595188 TI - Physical Growth and Biological Maturation of Children and Adolescents: Proposed Reference Curves. AB - BACKGROUND/AIM: The study of physical growth variables in terms of chronological age and biological maturation may provide a common reference point to reflect on the occurrence of body dimensions in and between individuals. The objectives of this study were as follows: (a) verify if the observed gender differences in the variables of physical growth by chronological age are confounded by physical maturation, (b) compare physical growth patterns with the reference of the Centers for Disease Control and Prevention (CDC)-2012, and (c) develop regional curves to assess physical growth in terms of biological maturation. METHODS: Researchers studied 3,674 children and adolescents. Weight, standing height, and sitting height were measured. Biological maturation was determined by using the age of peak velocity growth. Body mass index (BMI) was calculated. Growth variables were compared with the CDC-2012 reference. Percentiles were calculated by the LMS method. The students differed in weight and BMI when compared to the reference individuals. The differences in weight, standing height, and BMI between both genders are more pronounced when they are aligned with biological age rather than chronological age. CONCLUSION: Weight and BMI differ from the reference. Furthermore, the assessment of the physical growth trajectory should be analyzed in terms of biological maturation. The proposed regional curves may be used in and applied to clinical and epidemiological contexts. PMID- 28595189 TI - Increased Incretin But Not Insulin Response after Oral versus Intravenous Branched Chain Amino Acids. AB - BACKGROUND/AIMS: Branched chain amino acids (BCAAs) are known to exert an insulinotropic effect. Whether this effect is mediated by incretins (glucagon like peptide 1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) is not known. The aim of this study was to show whether an equivalent dose of BCAA elicits a greater insulin and incretin response when administered orally than intravenously (IV). METHODS: Eighteen healthy, male subjects participated in 3 tests: IV application of BCAA solution, oral ingestion of BCAA and placebo in an equivalent dose (30.7 +/- 1.1 g). Glucose, insulin, C-peptide, glucagon, GLP-1, GIP, valine, leucine and isoleucine concentrations were measured. RESULTS: Rise in serum BCAA was achieved in both BCAA tests, with incremental areas under the curve (iAUC) being 2.1 times greater for IV BCAA compared with those of the oral BCAA test (p < 0.0001). Oral and IV BCAA induced comparable insulin response greater than placebo (240 min insulin iAUC: oral 3,411 +/- 577 vs. IV 2,361 +/- 384 vs. placebo 961.2 +/- 175 pmol/L, p = 0.0006). Oral BCAA induced higher GLP-1 (p < 0.0001) and GIP response (p < 0.0001) compared with the IV or placebo. Glucose levels declined significantly (p < 0.001) in the same pattern during both BCAA tests with no change in the placebo group. CONCLUSIONS: An equivalent dose of BCAA elicited a comparable insulin and greater incretin response when administered orally and not when administered through IV. We conclude that insulinotropic effects of BCAA are partially incretin dependent. PMID- 28595190 TI - Nonpharmacological, Biomechanical Approaches to Control Inflammation in Acute Kidney Injury. AB - Inflammation is broadly recognized as an important factor in the pathogenesis of acute kidney injury (AKI), but pharmacological approaches to alleviate inflammation in AKI have been without success in clinical trials. Neuromodulation by nonpharmacological methods is emerging as a novel therapeutic strategy to treat inflammatory diseases. Recently, our group and others have demonstrated that vagus nerve stimulation and pulsed ultrasound ameliorated inflammation via the cholinergic anti-inflammatory pathway (CAP) in various animal models, including renal ischemia-reperfusion injury. Delineating the precise mechanisms by which these methods activate the CAP and ameliorate inflammation is mandatory for the broad clinical application in the future. Novel techniques, such as optogenetics, are expected to elucidate these complex mechanisms. PMID- 28595191 TI - Comparing Medical and Recreational Cannabis Users on Socio-Demographic, Substance and Medication Use, and Health and Disability Characteristics. AB - BACKGROUND: While recreational cannabis use is common, medical cannabis programs have proliferated across North America, including a federal program in Canada. Few comparisons of medical and recreational cannabis users (RCUs) exist; this study compared these groups on key characteristics. METHODS: Data came from a community-recruited sample of formally approved medical cannabis users (MCUs; n = 53), and a sub-sample of recreational cannabis users (RCUs; n = 169) from a representative adult survey in Ontario (Canada). Samples were telephone-surveyed on identical measures, including select socio-demographic, substance and medication use, and health and disability measures. Based on initial bivariate comparisons, multivariate logistical regression with a progressive adjustment approach was performed to assess independent predictors of group status. RESULTS: In bivariate analyses, older age, lower household income, lower alcohol use, higher cocaine, prescription opioid, depression and anxiety medication use, and lower health and disability status were significantly associated with medical cannabis use. In the multivariate analysis, final model, household income, alcohol use, and disability levels were associated with medical cannabis use. Conclusions/Scientific Significance: Compared to RCUs, medical users appear to be mainly characterized by factors negatively influencing their overall health status. Future studies should investigate the actual impact and net benefits of medical cannabis use on these health problems. PMID- 28595192 TI - Cancer Precision Medicine: Why More Is More and DNA Is Not Enough. AB - Every tumour is different. They arise in patients with different genomes, from cells with different epigenetic modifications, and by random processes affecting the genome and/or epigenome of a somatic cell, allowing it to escape the usual controls on its growth. Tumours and patients therefore often respond very differently to the drugs they receive. Cancer precision medicine aims to characterise the tumour (and often also the patient) to be able to predict, with high accuracy, its response to different treatments, with options ranging from the selective characterisation of a few genomic variants considered particularly important to predict the response of the tumour to specific drugs, to deep genome analysis of both tumour and patient, combined with deep transcriptome analysis of the tumour. Here, we compare the expected results of carrying out such analyses at different levels, from different size panels to a comprehensive analysis incorporating both patient and tumour at the DNA and RNA levels. In doing so, we illustrate the additional power gained by this unusually deep analysis strategy, a potential basis for a future precision medicine first strategy in cancer drug therapy. However, this is only a step along the way of increasingly detailed molecular characterisation, which in our view will, in the future, introduce additional molecular characterisation techniques, including systematic analysis of proteins and protein modification states and different types of metabolites in the tumour, systematic analysis of circulating tumour cells and nucleic acids, the use of spatially resolved analysis techniques to address the problem of tumour heterogeneity as well as the deep analyses of the immune system of the patient to, e.g., predict the response of the patient to different types of immunotherapy. Such analyses will generate data sets of even greater complexity, requiring mechanistic modelling approaches to capture enough of the complex situation in the real patient to be able to accurately predict his/her responses to all available therapies. PMID- 28595193 TI - The Economic Consequences of Acute Kidney Injury. AB - Acute kidney injury (AKI) is an increasingly common condition associated with poor health outcomes. Combined with its rising incidence, AKI has emerged as a major public health concern with high human and financial costs. In England, the estimated inpatient costs related to AKI consume 1% of the National Health Service budget. In the United States, AKI is associated with an increase in hospitalization costs that range from $5.4 to $24.0 billion. The most expensive patients are those with AKI of sufficient severity to require dialysis, where cost increases relative to patients without AKI range from $11,016 to $42,077 per hospitalization. Even with these high costs, significant hospital-level variation still exists in the cost of AKI care. In this article, we review the economic consequences of AKI for both the general and critically ill AKI population. Our primary objective is to shed light on an opportunity for hospitals and policymakers to develop new care processes for patients with AKI that have the potential to yield substantial cost savings. By exposing the high rates of death and disability experienced by affected patients and the immense financial burden attributable to AKI, we also hope to motivate scientists and entrepreneurs to pursue a variety of innovative therapeutic strategies to combat AKI in the near term. PMID- 28595194 TI - Long-Term Efficacy and Safety of Certolizumab Pegol in an Unselected Crohn's Disease Population: The FACTS III Survey. AB - BACKGROUND: Long-term data of certolizumab pegol (CZP) in Crohn's disease (CD) from pivotal registry trials are limited. We therefore aimed to evaluate the long term efficacy of CZP in clinical practice in Switzerland. METHODS: In the First Approved Certolizumab Therapeutic Experience in Switzerland-III phase IV multicenter cohort, patients receiving CZP were prospectively included all over Switzerland in (non-) academic hospitals and private practice. RESULTS: We included 104 CD patients (52 male; only 22.1% anti-tumor necrosis factor (TNF) naive, CZP as third anti-TNF agent in 46.2%) with follow-up time between 6 weeks up to 5 years. During treatment with CZP, we observed a significant decrease of the Harvey Bradshaw Index from a median of 7 at baseline (interquartile range 4 11) to 4, 5, 4, 3, 3, and 2 at weeks 6, 26, 52, 78, 104, and 156, respectively. While anti-TNF naive patients showed a significantly better response at the end of induction, during CZP maintenance therapy response was similar as compared to anti-TNF experienced patients as well as between patients with a short (0-5 years) vs. long duration of disease (>5 years). CONCLUSIONS: CZP is an effective long-term treatment option, including CD patients with long disease duration and prior treatment with 1 or 2 anti-TNF agents. PMID- 28595195 TI - GAS6 Oncogene and Reverse MLLT3-KMT2A Duplications in an Infant with Acute Myeloid Leukemia and a Novel Complex Hyperdiploid Karyotype: Detailed High Resolution Molecular Cytogenetic Studies. AB - Pediatric acute myeloid leukemia (AML) is a highly heterogeneous disease, presenting cytogenetic and molecular abnormalities which turned out to be critical prognostic factors. Ploidy changes as gain or loss of individual chromosomes are rare in AML, occurring only in about 1-2% of the affected children. Hyperdiploid karyotypes are exceedingly rare in infants less than 12 months of age. In this age group, structural rearrangements involving the KMT2A gene occur in about 58% of the cases. Among them, the translocation t(9;11)(p22;q23), KMT2A-MLLT3, is the most common abnormality accounting for approximately 22% of KMT2A rearrangements in infant AML cases. Here, we describe a 7- month-old girl with a history of fever and severe diarrhea, and a physical examination remarkable for pallor and hepatosplenomegaly. A novel complex hyperdiploid karyotype 53,XX,+X,+6,t(9;11)(p21.3;q23.3),+der(9)t(9;11)(p21.3;q23.3),dup(13)(q31q34),+14, 19,+21,+22 was characterized by high-resolution molecular cytogenetic approaches. Fluorescence in situ hybridization, multiplex-FISH, and multicolor chromosome banding were applied, revealing 2 reverse MLLT3-KMT2A fusions and a duplication of the GAS6 oncogene. Our work suggests that molecular cytogenetic studies are crucial for the planning of a proper strategy for risk therapy in AML infants with hyperdiploid karyotypes. PMID- 28595196 TI - Two-Year Effects of a Classroom-Based Smoking Prevention and Cessation Intervention Program. AB - BACKGROUND: Project EX is a classroom-based smoking prevention and cessation intervention program that has been well evaluated and designed for assessing the prevention and cessation effects among adolescents in Spain. However, its long term efficacy is still unknown. This study deals with the outcomes of a 2-year follow-up evaluation of Project EX. METHODS: The intervention was tested using a clustered randomized controlled trial involving 1,546 Spanish students from 3 program schools and 3 control schools. At the end of the 2-year follow-up period, 722 subjects had completed the questionnaires (266 in the control condition and 456 in the program condition) administered to them. RESULTS: Compared to the control condition, the program condition revealed a greater reduction in nicotine dependence (p = 0.04), smoking intention (p = 0.02), and in the number of cigarettes smoked during the previous month (p = 0.03). The CO monitor repeated assessments revealed a significant decrease of ppm levels in the program group (p < 0.001). Intent-to-treat quit rates were 14.28 and 0%, respectively, for the program and control conditions. CONCLUSIONS: This study provides evidence about the long-term effectiveness of the Project EX classroom-based program for smoking prevention and cessation among adolescents in Spain. PMID- 28595197 TI - High Serum Pepsinogen I and beta Helicobacter pylori Infection Are Risk Factors for Aspirin-Induced Gastroduodenal Injury. AB - BACKGROUND: Whether gastric hyperchlorhydria and Helicobacter pylori infection contribute to aspirin-induced gastroduodenal injury still lacks evidence. Because serum pepsinogens (PGs) and gastrin-17 (G17) can reflect gastric acid secretion, this study intended to elucidate whether serum PGs, serum G17, and H. pylori infection are associated with aspirin-induced gastrointestinal injury. SUMMARY: A total of 60 patients taking low-dose aspirin for more than 1 month were enrolled in this study. Serum PG I, PG II, and G17 were determined using ELISA. A 14C-urea breath test was used for the detection of an H. pylori infection. The modified Lanza score was used to evaluate the degree of gastroduodenal injury under endoscopy. The median serum PG I level was significantly higher in the intensive gastroduodenal injury (IGI) group compared to that in the mild gastroduodenal injury group (155.0 vs. 116.6 ng/mL, p = 0.006). The H. pylori infection rate was significantly higher in the IGI group (73 vs. 40%, p = 0.037). Receiver operator characteristic curves analysis revealed that the cutoff value of PG I was 123 ng/mL, with 80% sensitivity and 61.4% specificity. H. pylori infection combined with PG I at >123 ng/mL had an OR (95% CI) of 15.8 (2.4 +/- 104.5) for the prediction of aspirin-induced gastroduodenal injury. Key Messages: Serum PG I and H. pylori infection could be used to identify potential high-risk aspirin-induced gastroduodenal injury patients. PMID- 28595198 TI - [Daptomycin for the treatment of infective endocarditis: When do we use it?] PMID- 28595199 TI - [Coronary collateral circulation and ghrelin peptide]. PMID- 28595200 TI - [Daptomycin in left-sided endocarditis: A single center experience]. AB - OBJECTIVE: Infective endocarditis (IE) carries a high risk of cardiac morbidity and mortality, despite advances in the contemporary armamentarium. Along with the development of antibiotic resistant strains, research focusing on the efficacy of novel agents other than standard antibiotic regimens continues. Daptomycin, one of these antibiotics, is approved for the treatment of Staphylococcus bacteremia and right-sided endocarditis. This retrospective study was an investigation of the effectiveness of daptomycin in patients with left-sided IE. METHODS: Fourteen patients (mean age 50.9+/-16.5; range 24 to 70 years) with the diagnosis of left sided IE based on modified Duke criteria received daptomycin as monotherapy. Outcome was evaluated according to clinical improvement, microbiological eradication, and in-hospital mortality. RESULTS: Blood culture was positive in 13 patients (92.8%) and staphylococci were isolated in all but 1 patient (92.3%). Daptomycin was administered as monotherapy at a dose of 6 or 8 mg/kg/day for mean of 40.6+/-4.4 days. Clinical recovery rate was 71.4% and microbiological eradication rate was 85.7%. Mean duration of clinical recovery was 8.7+/-3.2 days and duration of microbiological eradication was 11.1+/-3.6 days. Side effects developed in 6 patients, but drug discontinuation was not required in any patient. Ten patients improved without complications. Two patients were lost due to heart failure and multiple-organ failure while treatment was continuing, and 2 patients died in early cardiac postoperative period. CONCLUSION: Daptomycin is an effective and safe alternative to standard antibiotic therapy for the treatment of left-sided IE. PMID- 28595201 TI - [As cardioprotective and angiogenic biomarker, can ghrelin predict coronary collateral development and severity of coronary atherosclerosis?] AB - OBJECTIVE: Ghrelin exerts protective effects on cardiovascular system by inhibiting progression of atherosclerosis, supression of vascular inflammation, and stimulating angiogenesis. Thus, the aim of this study was to investigate the effect of serum ghrelin on coronary collateral development and SYNTAX score in patients with severe coronary artery disease. METHODS: Total of 91 patients who had >=90% stenosis in at least one major coronary artery were prospectively included in this cross-sectional, observational study. Collateral degree was graded according to Rentrop-Cohen classification. Patients with grade 2 or 3 collateral degree were allocated to Good Collateral Group and patients with grade 0 or 1 collateral degree were included in Poor Collateral Group. Ghrelin and vascular endothelial growth factor A (VEGF-A) levels were measured using radioimmunoassay and ELISA kits. RESULTS: Serum ghrelin and VEGF-A levels were significantly higher in Good Collateral Group. Furthermore, ghrelin level showed significant inverse correlation with SYNTAX score (r=0.348; p=0.001). In multivariable regression analysis, ghrelin (Odds ratio, 1.013; 95% confidence interval, 1.011-1.017; p=0.013), VEGF-A, fasting plasma glucose and presence of chronic total occlusion were independent predictors of good collateral development. In receiver operating characteristic curve analysis, ghrelin value cut-off point of >=781 pg/mL predicted good collateral development with sensitivity of 73.1% and specificity of 67.7%. CONCLUSION: Findings suggested that ghrelin has antioxidant and antiinflammatory properties that protect endothelial functions and also stimulate angiogenesis, which results in development of good coronary collateral and inhibition of progression of coronary atherosclerosis. PMID- 28595202 TI - Vitamin D is a predictor of ST segment resolution and infarct size following thrombolysis in patients with acute ST elevation myocardial infarction. AB - OBJECTIVE: Vitamin D (VitD) insufficiency is linked to various chronic conditions, including cardiovascular disease. Aim of the present study was to examine role of serum VitD in resolution of ST segment elevation (STR) in response to thrombolytic therapy following acute ST elevation myocardial infarction (STEMI). METHODS: VitD was measured prospectively in all consecutive patients who were admitted with STEMI and received thrombolysis during the calendar year of 2014. STR was defined as >=50% decrease in initial magnitude of STR 90 minutes after treatment. Multivariate binary logistic regression analysis was performed to identify effect of confounding variables on STR. RESULTS: Average age was 58+/-14 years in 227 patients (41 female and 186 male). Total of 24.7% of patients had sufficient VitD (>30 ng/mL), whereas 46.2% had VitD insufficiency (10-30 ng/mL), and remaining 29.1% had VitD deficiency (<10 ng/mL). Significant STR occurred in 57.3% of the patients. In a nonlinear pattern, serum VitD concentration directly correlated with likelihood of STR (p=0.012). VitD deficient patients had larger enzymatic infarct size compared with those with sufficient VitD (p=0.026). In multivariate logistic regression analysis, while diabetes doubled (p=0.033) and involvement of anterior wall created 2.7-fold increase in probability of nonresolution (p=0.001), for every unit increase in serum VitD, likelihood of STR increased by 2.1% (p=0.023). CONCLUSION: VitD deficiency in patients with STEMI was associated with lower occurrence of STR and larger enzymatic infarct size in response to thrombolytic therapy. PMID- 28595203 TI - Parameters of ventricular repolarization in patients with autoimmune hepatitis. AB - OBJECTIVE: Autoimmune hepatitis (AIH) is a liver disorder that affects both children and adults. It is characterized by inflammatory liver histology, elevated transaminase level, circulating nonorgan-specific autoantibodies, and increased level of immunoglobulin G in the absence of known etiology. Ventricular repolarization has been evaluated using T wave and QT interval measurements in patients with hepatic cirrhosis. Ventricular repolarization may be defined using QT interval, QT dispersion, and T wave measurements. Recently, it has been demonstrated that peak and end of the T wave (Tp-e) interval, Tp-e/QT, and Tp e/corrected QT interval (QTc) ratios can be novel indicators for prediction of ventricular arrhythmias and mortality. In this study, an investigation of ventricular repolarization using Tp-e interval and Tp-e/QT ratio in patients with AIH was performed. METHODS: Total of 31 patients with AIH and 31 controls were enrolled in the present study. Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were measured on 12-lead electrocardiogram. RESULTS: QT interval (378.9+/-41.4 vs. 350.0+/-22.7; p=0.001), QTc interval (396.8+/-46.7 vs. 367.3+/-34.9; p=0.039), Tp e interval (68.2+/-12.3 vs. 42.5+/-6.8; p<0.001), Tp-e/QT ratio (0.18+/-0.02 vs. 0.12+/-0.01; p<0.001) and Tp-e/QTc ratio (0.17+/-0.02 vs. 0.11+/-0.01; p<0.001) were significantly higher in patients with AIH than control patients. CONCLUSION: The results of the present study indicated that Tp-e interval, Tp-e/QT, and Tp e/QTc ratios were greater in patients with AIH. PMID- 28595204 TI - Association of neutrophil/lymphocyte ratio and CHA2DS2-VASc score with left atrial thrombus in patients who are candidates for percutaneous mitral balloon valvuloplasty. AB - OBJECTIVE: Association between inflammation and pro-thrombotic state has been described previously. Aim of the present study was to investigate if presence of left atrial (LA) thrombus or spontaneous echocardiographic contrast (SEC) in rheumatic mitral stenosis (MS) was related to neutrophil/lymphocyte ratio (NLR), and to determine predictive utility of the CHA2DS2-VASc risk stratification score in patients with mitral stenosis complicated by LA thrombus. METHODS: NLR and CHA2DS2-VASc score of 188 patients with MS and 35 healthy controls were evaluated. All analyses were also conducted according to rhythm status, excluding control group. RESULTS: Among patients with MS, there were 31 patients in thrombus-positive group, 142 patients in SEC-positive group, and 15 patients in thrombus/SEC-negative group. Among patients with MS and sinus rhythm (SR) (n=105; 55.8%); 9.5% of them had LA thrombus, and 78% of them had SEC. In the SR group, median NLR was significantly higher in thrombus-positive group compared with thrombus/SEC-negative and control groups (p<0.001). Among patients with MS and atrial fibrillation (AF); there was no significant difference regarding NLR according to thrombus and SEC presence (p=0.214). In both SR and AF groups, there was no significant difference according to SEC/thrombus presence regarding median CHA2DS2-VASc score (p>0.05). CONCLUSION: Elevated NLR is related to presence of LA thrombus in patients with MS and SR. The utility of CHA2DS2-VASc score in patients with MS and SR complicated by LA thrombus is debatable, according to our results. PMID- 28595205 TI - The relationship between serum lipid parameters and renal frame count in hypertensive patients with normal renal functions. AB - OBJECTIVE: Atherosclerosis can contribute to renovascular disease, and high cholesterol level is an independent risk factor for disease progression. Renal frame count (RFC) is an objective angiographic method of measuring macrovascular blood flow in the main renal artery and its segmental branches. The aim of the present study was to demonstrate relationship between serum lipid parameters and RFC. METHODS: In this cross-sectional study, 116 hypertensive patients were allocated into 2 groups according to serum low-density lipoprotein (LDL) levels. Group 1 comprised 60 patients with LDL <130 mg/dL and Group 2 consisted of 56 individuals with LDL >=130 mg/dL. The patients were also divided into 2 groups according to total cholesterol (TC) levels (52 patients in group with TC <200 mg/dL and 64 patients in group with TC >=200 mg/dL). RESULTS: Group 2 had higher mean RFC than Group 1 (p<0.001). RFC of both kidneys in Group 2 was significantly higher than results in Group 1 (p<0.001 and p=0.023, respectively). We found similar significant results in comparison of TC-based patient groups. RFC had positive correlation with smoking, TC, and LDL (r=0.326, p=0.035; r=0.393, p=0.010; and r=0.386, p=0.012, respectively). In multivariate linear regression analysis, LDL, TC, smoking, and creatinine clearance were independent predictors of RFC. CONCLUSION: In conclusion, in hypertensive patients with normal renal function, LDL, TC, and smoking may be predictors of RFC and aggressive risk factor modification may help to reduce the risk of renal failure. PMID- 28595206 TI - Transcatheter closure of atrial septal defect with atrial septal occluder in a patient with nickel allergy. AB - Presently described is transcatheter closure of atrial septal defect with atrial septal occluder (ASO) device in a patient with nickel allergy. Patients with metal allergy who will undergo nitinol device implantation should be tested for possible nickel hypersensitivity. ASO device and treatment strategy (percutaneous or surgical) should be selected according to allergy test result. PMID- 28595207 TI - Eosinophilic myocarditis presenting as acute coronary syndrome. AB - Eosinophilic myocarditis (EM) is a rare condition that may result from several heterogeneous eosinophilic diseases, including parasite infection, hypersensitivity reaction, vasculitis, and hypereosinophilic syndrome. Regardless of etiology, the disease may present with various cardiac conditions, such as acute coronary syndrome, heart failure, or arrhythmia. Irreversible endomyocardial fibrosis, which causes restrictive cardiomyopathy, occurs in the late phase of the disease. Early diagnosis and treatment is crucial to prevent disease progression. Presently described is a case of EM presenting as acute coronary syndrome that was treated with steroids. PMID- 28595208 TI - Atrial fibrillation following synthetic cannabinoid abuse. AB - Marijuana and its synthetic forms, called synthetic cannabinoids (SCs), are used as recreational drugs. Bonzai is a kind of SC. Adverse cardiovascular events have been reported with abuse of marijuana and SCs, including arrhythmia, myocardial infarction, and sudden cardiac death. Presently described is a case of a 23-year old, previously healthy man, who was admitted to the emergency department with atrial fibrillation after Bonzai abuse. Sinus rhythm was restored during observation. PMID- 28595209 TI - Longest surviving case of unoperated Stanford type A aortic dissection. AB - Stanford type A aortic dissection requires urgent intervention and immediate surgical approach in the emergency department. Survival rate is low, even in patients who undergo immediate surgery. Presently described is a case of unoperated Stanford type A aortic dissection that has been in follow-up under beta-blocker treatment for 7 years. To the best of our knowledge, our case is the longest surviving patient with unoperated type A aortic dissection reported in the literature. PMID- 28595210 TI - Perioperative management of combined coronary bypass surgery and thyroidectomy. AB - Significant swelling of the thyroid compromising the airway can be a challenging situation when combined thyroidectomy and cardiac surgery is planned. Induction, intubation, intraoperative management, and extubation require special attention in such cases. PMID- 28595211 TI - [Closure of wide patent ductus arteriosus using a fenestrated muscular VSD occluder device in a pediatric patient with Down syndrome and pulmonary hypertension]. AB - Patients with wide patent ductus arteriosus and significant pulmonary hypertension not treated in time constitute a significant problem for cardiologists. For these patients, tests that could aid in decision-making for further planning include reversibility and balloon occlusion tests performed in the catheterization laboratory. Devices developed for the closure of ductus as well as different devices with off-label use may be employed in patients scheduled for transcatheter occlusion. When result of reversibility test is borderline positive, the use of fenestrated device may be applicable for selected patients. Presently described is case of a 10-year-old patient with Down syndrome who had a wide ductus and systemic pulmonary hypertension. Transcatheter closure procedure was performed with off-label use of a fenestrated muscular ventricular septal defect occluder device. PMID- 28595213 TI - Case Image: Long and single-piece thrombus aspirated from right coronary artery in inferior ST-elevation myocardial infarction. PMID- 28595212 TI - Data Sharing: A New Editorial Initiative of the International Committee of Medical Journal Editors. Implications for the Editors' Network. AB - The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship -emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology. PMID- 28595214 TI - Case Image: Extreme left diaphragm displacement in the context of tension pneumothorax after cardiac surgery. PMID- 28595215 TI - Case Image: The moment of return from the edge of death: Holter ECG recording in a patient with syncope. PMID- 28595217 TI - [Pulmonary Valve Plasty after Postoperative Pulmonary Insufficiency]. AB - A 6-year-old boy (weight 15.5 kg) underwent pulmonary valve plasty using autologous pericardium. He received a diagnosis of aortic coarctation and ventricular septal defect. Total correction was performed at the age of 18 days ( weight 2.2 kg). Intraoperatively, to confirm the position of the ventricular septum defect, we needed to incise from the main pulmonary artery to right ventricle through a commissure part of pulmonary valve. Although he exhibited stable hemodynamics, pulmonary valve regurgitation progressed. Six years after initial operation, we performed pulmonary valve plasty. A main pulmonary arteriotomy revealed that the right and anterior cusp were damaged in the initial operation. The right cusp had 2 defects near the commissure part, and the anterior cusp had a complete defect at the commissure part. The defects were filled with sufficient size of an autologous pericardial patch to preserve adequate coaptation zone. Echocardiography 1 year later revealed satisfactory result. PMID- 28595216 TI - Case Image: Unusual protruding intracardiac mass: Lipoma of left ventricular apex. PMID- 28595218 TI - [Disruption of Matsui-Kitamura Stent-graft Six Years after Treatment for Rupture of Thoracic Aortic Aneurysm]. AB - Matsui-Kitamura stent-graft (MKSG) is a home-made device for thoracic endovascular aortic repair (TEVAR) developed in Japan. A 76-year-old man who had been treated by TEVAR (zone 3) with a MKSG for ruptured thoracic aortic aneurysm was diagnosed as having type Ia endoleak caused by suture disruption and aneurysmal sac expansion 6 years later. He underwent TEVAR (zone 1) with debranching and type Ia endoleak disappeared. MKSG had been the effective device especially for acute aortic emergencies in the descending thoracic aorta until the stent-grafts became commercially available, but careful observation and appropriate re-intervention is mandatory for the continued life-saving contribution. PMID- 28595219 TI - [Hybrid Coronary Revascularization of Minimally Invasive Coronary Artery Bypass Grafting and Percutaneous Coronary Intervention in a Patient with Left Main Coronary Stenosis]. AB - We report a successful case of hybrid coronary revascularization of minimally invasive coronary artery bypass grafting( MICS-CABG) and percutaneous coronary intervention(PCI). The patient was a 78-year-old man with angina pectoris due to left main trunk (LMT) lesion, and had a history of repeated PCI to the left anterior descending artery (LAD) and the left circumflex artery (LCX) for angina pectoris. He presented with a chest pain on effort in June, 2015. A coronary angiogram showed a severe stenosis in the LMT extending to LAD and LCX. We performed hybrid therapy of CABG to LAD, and PCI to LMT and the proximal portion of LCX because the lesion was technically and suitable for PCI. CABG to LAD was performed via left mini thoracotomy using the left inter mammary artery (LIMA). LIMA was harvested under 3-dimentional endoscope. On the 5th post-operative day, PCI was performed to LMT and LCX. The postoperative course was uneventful and he was discharged on the 11th post-operative day. This case suggests that hybrid coronary revascularization is less invasive and feasible for selected patients with multi-vessel disease. PMID- 28595220 TI - [Metachronous Bilateral Hemothorax Due to Reverse Chance Type Thoracic Fracture]. AB - Metachronous bilateral hemothorax due to reverse Chance type thoracic fracture is very rare. In this case, we experienced a case of metachronous bilateral hemothorax, triggered by a thoracic fracture in which the anterior component of the spine collapsed, so-called reverse Chance type thoracic fracture. An 83-year old woman with spinal kyphosis traumatically injured thoracic spine burst fracture, and bone fragments appeared on both sides of the destroyed vertebra. After injury, the left hemothorax also appeared, followed by the right hemothorax causing hemorrhagic shock. In thoracic destructive anterior fracture, we should consider the possibility of metachronous bilateral hemothorax. PMID- 28595221 TI - [Resection of a Tuberculous Abscess of the Thoracic Wall]. AB - The patient was a 76-year-old man. Chest computed tomography revealed an abscess of the chest wall incidentally. Mycobacterium tuberculosis was detected by the aspiration of the abscess. Since the abscess cavity exhibited a larger trend in spite of 3 months of antituberculosis chemotherapy, surgical resection was performed. During the operation, indigo stain was injected thorough an aspiration tube to visualize the spread of the abscess. The abscess was completely resected with combined partial resection of the 7th, 8th, and 9th ribs, and the diaphragm. The patient has been well without recurrence of the lesion for 8 months after surgery with 3 months of adjuvant antituberculosis chemotherapy. PMID- 28595222 TI - [Mediastinal Pancreatic Pseudocyst with Pancreatic Pleural Effusion]. AB - A 72-year-old man with chronic alcohol related pancreatitis was admitted for dyspnea and pain at the upper body. Chest X-ray showed right massive pleural effusion. Chest and abdominal contrast enhanced thin slice computed tomography revealed the route from the pancreatic head reaching the right thoracic cavity via the esophagus hiatus and the communication between the cystic lesion and main pancreatic duct. We drained the pleural effusion that showed abnormally high amylase activity. We diagnosed his illness as mediastinal pancreatic pseudocyst with pancreatic pleural effusion. Endoscopic Nasopancreatic Drainage catheter was placed in the main pancreatic duct, and the pleural effusion disappeared. PMID- 28595223 TI - [Successful Combined Modality Therapy for an Advanced Malignant Mediastinal Non seminomatous Germ Cell Tumor in an Elderly Female]. AB - A 69-year-old woman was diagnosed with a germ cell tumor in the anterior mediastinum. Following 3 years follow-up, she experienced chest pain and an enlarging of the anterior mediastinal tumor and bilateral lung metastases were detected by chest X-ray. The tumor was diagnosed as a primary malignant mediastinal non-seminomatous germ cell tumor by needle biopsy. After initial radiotherapy (12 Gy/4 Fr), she was subsequently treated with EP chemotherapy which achieved a partial response. Complete resection of the residual tumors in the mediastinum and right lung was performed. No recurrence has been noted for 5 years post-operatively. PMID- 28595224 TI - [Gastrointestinal Stromal Tumor with Metastasis of Chest Wall and Both Lungs]. AB - A 60-years-old male, who had undergone surgery for gastrointestinal stromal tumor of small intestine 8 years before, was admitted to our hospital for surgical treatment of left 10th rib metastasis. Three months after the 1st operation new metastatic lesions appeared at hypodermic tissue at right anterior chest wall and left upper lobe of the lung and we performed 2nd operation to resect these lesions. Five months after 2nd operation, we performed 3rd operation to resect another metastatic pulmonary lesion at right upper lobe. PMID- 28595225 TI - [Mitral Valve Repair in a Patient with Two Aneurysms of the Mitral Valve Due to Infective Endocarditis;Report of a Case]. AB - Echocardiography revealed 2 aneurysms in the mitral valve with mitral regurgitation and aortic regurgitation,in a 42-years-old man. He had had infective endocarditis due to Streptococcus 9 months before. A prolapse in the right coronary cusp without vegetation and 2 aneurysms in the anterior mitral leaflet were found intraoperatively. Aortic valve was replaced, and then mitral aneurysms were resected and repaired using his own pericardium. There has been almost no regurgitation or recurrence of infection over 3 years. PMID- 28595226 TI - [Surgical Repair for the Ventricular Septal Perforation Following Blunt Chest Trauma;Report of a Case]. AB - Ventricular septal perforation(VSP) after blunt chest trauma is rare. As the clinical symptoms and timing of presentation are varied, appropriate diagnosis can be difficult or delayed. An 86-year-old man presented with a traumatic VSP following a forestry injury. He showed a normal cardiac structure at the time of injury, but echocardiography after 9 days revealed VSP. He was treated successfully with surgical closure of the VSP. PMID- 28595227 TI - [Aortic Valve Replacement and Mitral Valve Plasty in a Patient with Left Ventricular Noncompaction Associated with Aortic Regurgitation and Mitral Regurgitation;Report of a Case]. AB - Left ventricular noncompaction (LVNC) is believed to represent an arrest in the normal process of myocardial compaction, resulting in persistence of both hyper trabeculation and intra-trabecular recess within the left ventricle. The clinical features of this disease are left ventricular dilatation and systolic dysfunction, which carry a high mortality. Most patients die in infancy, but some cases of LVNC in adults have been reported. To the best of our knowledge, only 4 cases of LVNC with valvular heart disease in adults have recently been operated. We describe a 51-year-old man with LVNC and severe aortic regurgitation and mild mitral regurgitation, who was successfully operated upon with aortic valve replacement using a tissue valve, and mitral valve plasty with bilateral papillary muscle relocation. PMID- 28595228 TI - [Delayed Hemolytic Anemia Associated with Anti-Jk3 Antibody Following Cardiovascular Surgery;Report of a Case]. AB - We report a 73-year-old man who underwent total aortic arch replacement with an open stent graft for aortic arch aneurysm. The patient received blood transfusion intraoperatively without any signs of hemolysis. However, on post-operative day 16, he developed hemoglobinuria, and was found to have anemia, elevated serum lactate dehydrogenase, elevated total bilirubin, and decreased serum haptoglobin. Initially, the cause for these findings was unknown. Upon further testing, however, antibodies against the high frequency antigen, anti-Jk3 was identified. The patient was conservatively treated and was discharged in stable condition on post-operative day 24. Jka and/or Jkb are red blood cell antigens observed in over 99.9% of the population worldwide. Jk (a-b-) represents the null phenotype and is very rare. This specific phenotype can be extremely dangerous, as homologous transfusion might cause severe delayed hemolysis. The actual patient carried Jk (a-b-) phenotype and, due to intraoperative transfusion of red blood cells, anti-Jk3 antibody was produced. Although very rare, patients who carry the red blood cell phenotype Jk( a-b-) may experience dangerous, or even fatal outcome due to such a common medical treatment as blood transfusion, if this condition is not recognized beforehand. PMID- 28595229 TI - [Relapse of Mitral Regurgitation Due to Tethering after Valve Plasty with Edge-to edge Repair;Report of a Case]. AB - A 75-year-old woman with severe mitral regurgitation (MR) successfully underwent mitral valve plasty with edge-to-edge plasty and commissural annuloplasty. Three days after the operation, she was found to have moderate MR caused by tethering of the valve. Functional MR occurring as a complication of mitral edge-to-edge plasty could be treated conservatively. PMID- 28595230 TI - [Pulmonary Metastasis of Sacral Chordoma Fifteen Years after Resection of Primary Site;Report of a Case]. AB - A 71-years-old man, who had undergone resection for sacral chordoma 15 years before, was admitted to our hospital to treat a nodule in the right middle lobe detected by computed tomography. The nodule was resected and was histologically diagnosed as lung-metastasis of chordoma. PMID- 28595231 TI - [Pulmonary Alveolar Proteinosis Observed in the Subpleural Area;Report of a Case]. AB - A 39-year-old man consulted our hospital because of an abnormal shadow on a chest X-ray without any symptoms. A chest computed tomography revealed patchy peripheral ground-glass attenuation, in the subpleural area. Bronchoalveolar lavage fluid was clear and transbronchial lung biopsy findings were inconclutive. A video-assisted thoracic surgery-biopsy was performed. The specimens demonstrated accumulation of proteinaceous materials within alveolar spaces. The patient was given a diagnosis of pulmonary alveolar proteinosis. PMID- 28595232 TI - [Endobronchial Lipoma Treated Left Lower Lobectomy;Report of a Case]. AB - Endobronchial lipoma is a rare benign tumor. Bronchoscopic intervention or surgical resection is reported for its treatment. A 63-year-old woman underwent chest X-ray and computed tomography (CT) scan for observation of her continuous wheezing. CT scan showed atelectasis in the left lower lobe and a tumor in the left lower lobe bronchus. Bronchoscopic examinations could not confirm the diagnosis. Although laser therapy was conducted, the tumor could not be resected due to the bleeding and the patient underwent left lower lobectomy. The pathological diagnosis was endobronchial lipoma. After the operation, her symptoms improved. PMID- 28595233 TI - [Solitary Fibrous Tumor Originating from the Visceral Pleura Presenting an Extrapleural Sign;Report of a Case]. AB - We report a case of solitary fibrous tumor (SFT) originating from the visceral pleura, which presented an extrapleural sign on chest computed tomography (CT) and magnetic resonance imaging (MRI). A 44-year-old woman presented at our hospital for a growing mass visible in chest X-rays. Chest CT and MRI detected a 27*12 mm lesion on the intrathoracic side of the right 3rd intercostal space. The extrapleural signs strongly suggested the tumor to be chest wall origin. However, the tumor was found to be pedunculate with an umbrella-like appearance locating on the visceral pleura of the lung. Histopathological examination demonstrated SFT originating from the visceral pleura. PMID- 28595234 TI - [Lung Cancer with Multiple Cavitation and Ground Glass Opacity;Report of a Case]. AB - A 81-year-old man was referred to our hospital because of cough and fever. Chest computed tomography(CT) showed multiple cavitation and ground glass opacity in the right lower lobe. Antibiotic treatment was effective in the improvement of the infiltrative shadow and the inflammatory reaction. After 1 year, bronchoscopy was performed because the shadow remained on the following chest CT, and the adenocarcinoma of the lung was found. A lower lobectomy of the right lung was performed. PMID- 28595235 TI - A warm-up routine that incorporates a plyometric protocol potentiates the force generating capacity of the quadriceps muscles. AB - This study was designed to investigate whether a warm-up routine that incorporates drop jumps, induces post-activation potentiation (PAP), and if so, assess the magnitude and time course of the induced PAP. Participants performed a standard warm-up that incorporated either drop jumps (plyometric protocol) or a low-paced walk (control protocol). PAP was assessed by changes in electrically evoked isometric muscle twitches recorded throughout both protocols. The plyometric protocol increased peak twitch torque (PTT), rate of force development (RTD) and impulse significantly (by 23%, 39% and 46%, respectively) with no change in the amplitude of simultaneously-evoked M-waves, indicating that the augmented torque was due to PAP. These increases returned to baseline within 6 minutes, and PTT and RTD fell below baseline values at 11 - 16 minutes after the drop jumps. PTT, RTD and impulse decreased significantly following the standard warm-up. These results provide evidence that drop jumps induce PAP, markedly enhancing the force generating capacity of the muscle. In contrast, the standard warm-up did not potentiate, but rather reduced, the force generating capacity of the muscle. We suggest that drop jumps be incorporated into warm-up routines directly prior to athletic performance to maximize the force generating capacity of muscle. PMID- 28595237 TI - A comparison of muscle activation between back squats and belt squats. AB - A machine belt squat is a piece of equipment designed to allow the performance of squats while loading weight on the lifter's hips using a belt. The purpose of this investigation was to determine if belt squats differ from back squats in activation of the primary movers, and to determine the predictive capabilities of back squat load, training status, and anthropometric data on belt squat load. Thirty-one participants (16 males and 15 females) completed anthropometric measurements, a demographic questionnaire, a familiarization visit, and two testing visits, completing a 5 repetition maximum test for back squat and belt squat. Surface electromyography was used to measure muscle activation for the left and right vastus medialis (VMO), vastus lateralis (VLO), rectus femoris (RF), and gluteus maximus (GM). Comparison of muscle activation between the two exercises showed significant differences in the left GM (back squat: 0.84 +/- 0.45, belt squat: 0.69 +/- 0.22, p=0.015) and right GM (back squat: 0.86 +/- 0.45, belt squat: 0.71 +/- 0.29, p=0.004). Regression analysis computed significant prediction equations for belt squat load for general population, males, females, and advanced lifters. Overall, results indicate that belt squats may significantly differ in GM activation from back squats. Back squat load, as well as other variables, may be effective in accurately estimating appropriate belt squat load. These findings may help to more appropriately program for training with machine belt squats as a back squat alternative. PMID- 28595236 TI - Comparison of Serum Cytokine Levels in Men Who are Obese or Men Who are Lean: Effects of Nonlinear Periodized Resistance Training and Obesity. AB - Nikseresht, M. Comparison of serum cytokine levels in men who are obese or men who are lean: effects of nonlinear periodized resistance training and obesity. J Strength Cond Res 32(6): 1787-1795, 2018-This study examined the capacity of nonlinear resistance training (NRT) to alter some cytokines and markers of insulin resistance in men who are obese. An additional aim was to compare these variables between men who are obese and men who are lean. Age- and fitness matched men who are obese were randomly allocated to NRT (n = 12) and control (CON, n = 10) groups. An age- and fitness-matched control group of lean men (n = 11) were also recruited for baseline comparison. The NRT (12 weeks, 3 d.wk, 5-11 exercises) performed at different intensities (40-95% of 1 repetition maximum) with flexible periodization. Serum insulin, glucose, interleukin (IL)-6, IL-10, IL-17A, and IL-20 levels were measured at baseline and after training. Men who were obese had significantly lower IL-20 and higher glucose, insulin, insulin resistance (homeostasis model assessment, HOMA-IR), IL-10, and IL-6 than lean participants at baseline (all, p <= 0.05). There were significant negative correlations between IL-10 with anthropometric markers and HOMA-IR at baseline, whereas these variables were inversely correlated with IL-20. After training, V[Combining Dot Above]O2peak and 1 repetition maximum for bench press and knee extension of the NRT increased significantly compared with CON, which was accompanied by significant reductions in anthropometric markers, insulin and HOMA IR. IL-6 and IL-17A did not change significantly in response to training, but IL 10 and IL-20 increased significantly compared with baseline. An inverse relationship between the percent IL-20 increase and the percent waist circumference decrease suggests that adipocytes, or other metabolic factors such as glucose, may exert a lowering-effect on IL-20. PMID- 28595238 TI - Distinguishing Playing Status Through a Functionally Relevant Performance Measure in Female Division I Collegiate Soccer Athletes. AB - Although soccer is predominately an endurance sport, high velocity movements may be an important indicator of athletic success. The purpose of this investigation was to establish whether squat jumps (SJ) can differentiate starters from non starters with a female collegiate division I soccer team. Eighteen female division I soccer athletes were separated into two groups: 9 starters (age: 19.5 +/- 1.0; mass = 64.8 +/- 11.5 kg; height = 167.5 +/- 7.7 cm; games started = 18.2 +/- 4.7; minutes played = 1633.8 +/- 478.2 min) and 9 non-starters (age: 19.4 +/- 1.4 years; mass = 63.3 +/- 4.2 kg; height = 164.7 +/- 6.8 cm; games started 0.7 +/- 1.3; minutes played 158.2 +/- 269.3). Each athlete performed 3 maximal SJs at a starting knee angle of 110 degrees without arm swing. Each participant's SJ height, mean power (MP), peak power (PP), mean velocity (MV), and peak velocity (PV) were measured during each attempt by a linear position transducer (LPT). No statistically significant differences (p >= 0.05) in MP and PP between the starters and non-starters were observed. However, starters performed significantly better than non-starters in SJ height (p = 0.002), MV (p = 0.025), and PV (p = 0.015). Additionally, SJ height was strongly correlated with MV (r = 0.628) and PV (r = 0.647). These findings suggest that SJ height, MV and PV, may be important variables for discriminating differences between starters and non starters in division I female soccer athletes and a strong indicator of explosive performance. PMID- 28595239 TI - Changes in sprint-related outcomes during a period of systematic training in a girls' soccer academy. AB - Longitudinal data tracking performance indicators collected during structured training are lacking in young female soccer players. Therefore, changes in 5-m acceleration, 20-m speed, change-of-direction speed and repeated-sprint ability were quantified during a three-year period in an FA Centre of Excellence. Fourteen players (mean age = 12.1 years, SD = +/-0.9) were recruited and their best performance scores from pre-season and in-season testing were averaged. Players were typically exposed to soccer (2 x 90 min per week) and strength and conditioning training (1 x 70 min per week) and played 20 soccer matches (50-80 min) during 35-week seasons. Mean (+/-90%CL) overall improvements over the three years were 5.9% (1.3) (most likely large) for speed, 4.0% (1.0) (most likely large) for repeated-sprint ability, 8.8% (1.1) for acceleration and 8.3% (1.4) for change-of-direction speed (both most likely very large). Improvements between years one and two ranged from most likely moderate to very large. Further small improvements in change-of-direction speed and 20-m speed (both likely) were observed between years two and three. Individual differences in response were apparent only for change-of-direction speed, which were moderate and small between years two and three. Most likely very large to near perfect within-player correlations were observed between maturation and sprint measures. These data from a single-arm longitudinal study indicate that systematic exposure to training, which includes one dedicated strength and conditioning session each week, is associated with improvements in sprint related physical qualities in girls. PMID- 28595240 TI - Toll-like receptor 7 is overexpressed in the bladder of Hunner-type interstitial cystitis, and its activation in the mouse bladder can induce cystitis and bladder pain. AB - Toll-like receptor 7 (TLR7) is associated with the pathophysiology of systemic lupus erythematosus and Sjogren syndrome, well-known diseases accompanying interstitial cystitis (IC). We studied TLR7 expression in the bladder of patients with Hunner-type IC (HIC) and its functional roles in bladder inflammation and nociception using mice. Bladder biopsy specimens were obtained from patients with HIC. Specimens from the noncancerous portion of the bladder of patients with bladder cancer served as controls. The specimens were examined by immunohistochemistry and real-time polymerase chain reaction of TLR7. Loxoribine (LX), a TLR7 agonist, was instilled in the bladder of C57BL/6N female mice, and TLR7-mRNA expression and histological changes of the bladder, bladder pain-like licking behavior, voiding behavior, cystometry, and bladder afferent nerve activities were investigated. The effects of hydroxychloroquine, a TLR7 antagonist, on the LX-induced changes on cystometry and voiding behavior were studied. The number of TLR7 immuno-reactive cells and the mRNA expression of TLR7 were significantly increased in HIC specimens. Intravesical instillation of LX induced edema, congestion, inflammation, and significantly increased TLR7-mRNA expression in the mouse bladder. Loxoribine-instillation also significantly increased licking behavior, voiding frequency, and afferent nerve activities associated with decreased single-voided volume and intercontraction interval of micturitions. Hydroxychloroquine reversed the LX-induced cystometric and voiding behavioral changes. Toll-like receptor 7 was up-regulated in the bladder mucosa of patients with HIC, and activation of TLR7 in the mouse bladder induced cystitis with sensory hyperactivity of the bladder. Blocking the TLR7 pathway may be an innovative treatment target of HIC. PMID- 28595242 TI - Three-Dimensional Imaging as a Novel Method of Evaluating the Longevity of Hyaluronic Acid Fillers in a Mouse Model. PMID- 28595244 TI - Dermoscopy in Facilitating the Recognition of Poikiloderma of Civatte. PMID- 28595243 TI - Determinants and Timeline of Perioperative Anxiety in Mohs Surgery. AB - BACKGROUND: Patients undergoing Mohs micrographic surgery (MMS) exhibit anxiety relating to cancer cure or the expected cosmetic outcome. OBJECTIVE: To obtain quantitative measurements of perioperative cancer and cosmetic anxiety levels in first-time MMS patients. Parameters influencing anxiety and its natural course were assessed. METHODS: Prospective, single-blinded, questionnaire study of 173 patients undergoing MMS of the face. Anxiety levels were assessed using a visual analog scale preoperatively and postoperatively over 6 months. RESULTS: Mohs patients demonstrate a trend to greater or equal anxiety about cancer over cosmesis at all measured time points, but differences only reached statistical significance beginning 1 week postoperatively. Clinically relevant lowering of cancer anxiety levels is delayed until 3 months postoperatively. Cosmetic anxiety reaches a clinically relevant improvement by 1 week. The intuitive predictors of cosmetic anxiety, namely female gender and younger age, were quantitatively reinforced in this study. The predictor of cancer anxiety was the use of preoperative lorazepam. CONCLUSION: To maximize patient care, Mohs surgeons must be aware of covert patient anxieties and the parameters, which influence these anxieties. Identifying and anticipating the course of cancer- and cosmetic related anxieties will reduce patient fears, improving their satisfaction with the MMS experience. PMID- 28595241 TI - Stratifying patients with peripheral neuropathic pain based on sensory profiles: algorithm and sample size recommendations. AB - In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5. PMID- 28595245 TI - Massively Metastatic Dermatofibrosarcoma Protuberans With Fibrosarcomatous Transformation Years After Surgical Resection. PMID- 28595246 TI - Cryolipolysis for Reduction of Arm Fat: Safety and Efficacy of a Prototype CoolCup Applicator With Flat Contour. AB - BACKGROUND: Cryolipolysis of the arms has been shown to be an effective but somewhat time-consuming process. OBJECTIVE: The study evaluated safety and efficacy of a contoured cup cryolipolysis applicator for reduction of arm fat. The prototype was designed to maximize tissue contact with the cooling surface to improve comfort, while reducing treatment time by 25 minutes. MATERIALS AND METHODS: Both arms were treated using a prototype device that delivered treatment in 35 minutes at -11 degrees C. Photographic and ultrasound documentation was captured at baseline and 12 weeks post-treatment. Efficacy was assessed by photo review and measurement of fat reduction in ultrasound images. Immediately after 1, 4, and 12 weeks post-treatment, clinical assessments were performed to evaluate treatment areas and sensory alterations. RESULTS: Thirty women were enrolled and completed treatments to both arms. Ultrasound measurements found mean fat layer reduction of 3.2 mm with an SD of 2.7 mm. Blinded independent photo review found 85.2% correct identification of baseline photographs by at least 2/3 of reviewers. There were no unanticipated adverse device effects. Four study subjects experienced numbness in the treatment area beyond the 12-week visit that subsequently resolved without intervention. CONCLUSION: These data suggest that the CoolCup prototype applicator provides rapid, safe, and effective arm treatment. PMID- 28595247 TI - Mohs Melanoma Chemosurgery Simplified to a Single Brief Caustic Application: Possible Vaccine Effect. PMID- 28595248 TI - Novel Camera Mounting Technique for Dermatologic Surgeries. PMID- 28595249 TI - A Prospective, Randomized, Single-Blind Study Comparing Cyanoacrylate Adhesives to Sutures for Wound Closure in Skin Cancer Patients. AB - BACKGROUND: Cyanoacrylate tissue adhesives are not more likely to result in wound dehiscence or infection than sutured closures. However, suturing is the gold standard for optimal cosmetic appearance of scars. OBJECTIVE: To determine whether cyanoacrylate tissue adhesives produce a cosmetic outcome equivalent to sutures at 3 months. Secondary outcomes include time for wound closure, time spent on wound care, and surgeon and patient satisfaction. MATERIALS AND METHODS: Seventy-one patients scheduled for skin cancer excision at Beverly Hospital were included in this prospective, randomized, single-blind study. Cosmetic appearance was assessed by a masked panel of dermatologists and plastic surgeons who evaluated digital photographs. Secondary outcomes were assessed by nursing recordings and patient and surgeon evaluations. RESULTS: There was no significant difference in wound appearance (Visual Analog Scale: p = .4693, modified Hollander Wound Evaluation Score: p = .6413) between adhesives and sutures. It was faster and easier for a surgeon to use adhesives, and subjects spent less time caring for and were more satisfied by wounds sealed with adhesives than sutures. CONCLUSION: Cyanoacrylate tissue adhesives produce cosmetic outcomes that are not statistically significantly different than sutures; furthermore, they are associated with fast application, easy wound care, and patient satisfaction. PMID- 28595250 TI - Prospective, Split-Face, Randomized, Long-Term Blinded Objective Comparison of the Performance and Tolerability of Two New Hyaluronic Acid Fillers. AB - BACKGROUND: There are requirements for long-term, objective comparisons of hyaluronic acid (HA) dermal fillers. OBJECTIVE: To compare efficacy and tolerability of ART FILLER Universal (AFU) and ART FILLER Fine lines (AFFL) with the existing HA fillers for the treatment of nasolabial folds and crow's feet. MATERIALS AND METHODS: Prospective, randomized, rater- and patient-blind, split face comparison of AFU with JUVEDERM Ultra 3 (JUV) and AFFL with FIRST LINES PureSense (FLPS). The severity of nasolabial folds and crow's feet was assessed by independent blinded evaluators using the Lemperle scale at baseline, day (D) 30/D45, D90, and D180. Tolerability, Global Aesthetic Improvement Scale (GAIS), wrinkle volumes, and skin thickness and density were also measured at D30/D45, D90, and D180. RESULTS: At D30 and D180 respectively, 61 and 57 patients were assessed. Scores for nasolabial folds and crow's feet showed statistically significant improvements at D30, D90, and D180. AFU and AFFL were noninferior to JUV and FLPS, respectively. Most patients showed GAIS improvements, maintained until at least D180 and significant increases of collagen synthesis in crow's feet and nasolabial folds. Treatments were well tolerated. CONCLUSION: AFU and AFFL are noninferior to comparators. The methodology used represents a novel approach to augment existing clinical assessment of HA fillers. PMID- 28595251 TI - Use of Turn-in Skin Flaps for Nasal Lining Reconstruction. AB - BACKGROUND: Reconstruction of the nasal lining is the most difficult part of complex nasal reconstruction because the mucosa has a unique texture and fineness. Many techniques, ranging from skin grafts to local flaps, have been applied for the reconstruction of the mucosa. In some cases, even free flaps have been used. OBJECTIVE: The aim of this study was to discuss the feasibility of using turn-in flaps in nasal reconstruction. MATERIALS AND METHODS: Seventeen patients with full-thickness nasal defects underwent reconstruction with turn-in flaps. In all the patients, the bone structure was formed using cartilage grafts, and the skin defects were reconstructed using paramedian forehead flaps. A rhinoplasty procedure was added in 10 of the patients. RESULTS: Necrosis was not observed in any of the flaps, and the results were satisfactory for all the patients. CONCLUSION: This technique provided enough support for the onlay cartilage grafts, and the flap was thin enough to avoid any nasal airway obstruction. In selected patients, this technique can also be used in conjunction with a rhinoplasty procedure. PMID- 28595252 TI - Recurrent Tumors Referred for Mohs Micrographic Surgery: A 12-Year Experience at a Single Academic Center. AB - BACKGROUND: Mohs micrographic surgery (MMS) is used for treatment of primary and recurrent tumors. Compared with primary tumors, recurrent tumors are often more aggressive. OBJECTIVE: To understand differing characteristics between primary versus recurrent tumors treated by MMS. MATERIALS AND METHODS: The authors conducted a retrospective review of a 12-year period at 1 academic center. Recurrent tumors were defined as recurrent if previously treated with cryotherapy, topical chemotherapeutics, electrodesiccation and curettage, or excision. Statistical analysis was conducted with p <= .05 considered significant. RESULTS: A total of 17,971 cases were reviewed, of which 10.5% represented recurrent tumors. Recurrent tumors occurred more commonly in men (ratio 2.2:1). They presented in older individuals (p < .01) and occurred more commonly on the scalp (p < .0001), neck (p < .0001), and trunk (p < .0001). Primary tumors were more commonly located on the periocular (p < .0001), nose (p < .0001), and perioral areas (p < .0001). Squamous cell carcinoma more commonly presented as primary tumors (p = .02) while squamous cell carcinoma in situ more commonly presented as recurrent tumors (p < .001). CONCLUSION: Distinct characteristics separate primary and recurrent tumors treated by MMS. Primary tumors were more commonly located in Area H, compared with recurrent tumors, which were more commonly located in Area M. This suggests appropriate usage of MMS based on appropriate use criteria. PMID- 28595253 TI - Glomangiomyoma of the Vagina: A Report of 2 Cases and Literature Review. AB - We report 2 cases of vaginal glomangiomyoma in a 53-year-old who presented with a painful vaginal mass, and a 56-year-old who had postmenopausal bleeding and in whom an incidental vaginal mass was identified and resected at the time of hysterectomy. Histologic examination of the resected masses showed solid, circumscribed, benign, smooth muscle-predominant tumors with interspersed small islands of epithelioid glomus cells. The glomus cells were intimately related to small-caliber blood vessels and showed no cytologic atypia or mitotic activity. The tumor cells showed diffuse expression of smooth muscle actin, CD34, and focal expression of h-caldesmon, vimentin, and estrogen receptor. No immunolabeling for calponin B or desmin was found. To our knowledge, there are only isolated reports of vaginal glomus tumors, and these are the first reported case of vaginal glomangiomyoma in the literature. PMID- 28595254 TI - On Uterine Angiosarcomas: 2 Additional Cases. PMID- 28595255 TI - Pilot Electroacoustic Analyses of a Sample of Direct-to-Consumer Amplification Products. AB - OBJECTIVE: Recent national initiatives from the White House and Institute of Medicine have focused on strategies to increase the accessibility and affordability of hearing loss treatment given the average cost of $4700 for bilateral hearing aids. More affordable direct-to-consumer hearing technologies are increasingly gaining recognition, but the performance of these devices has been poorly studied. We investigated the technical and electroacoustic capabilities of several direct-to-consumer hearing devices to inform otolaryngologists who may be asked by patients to comment on these devices. PATIENTS/INTERVENTION: Nine direct-to-consumer hearing devices ranging in retail cost from $144.99 to $395.00 and one direct-to-consumer hearing device with a retail cost of $30.00. MAIN OUTCOME MEASURE: Electroacoustic results and simulated real-ear measurements. Main electroacoustic measures are frequency response, equivalent input noise, total harmonic distortion, and maximum output sound pressure level at 90 dB. RESULTS: Five devices met all four electroacoustic tolerances presented in this study, two devices met three tolerances, one device met two tolerances, one device met one tolerance, and one device did not meet any tolerances. Nine devices were able to approximate five of nine National Acoustics Laboratories (NAL) targets within 10 dB while only three devices were able to approximate five of nine NAL targets within a more stringent 5 dB. CONCLUSION: While there is substantial heterogeneity among the selection of devices, certain direct-to-consumer hearing devices may be able to provide appropriate amplification to persons with mild-to-moderate hearing loss and serve as alternatives for hearing aids in specific cases. PMID- 28595256 TI - Evaluation of Cochlear Duct Length Computations Using Synchrotron Radiation Phase Contrast Imaging. AB - HYPOTHESIS: Evaluation of cochlear duct length (CDL) using novel imaging techniques will help improve the accuracy of existing CDL equations. BACKGROUND: Various relationships relating A value measured from a patient's computed tomography scan and CDL have been proposed to aid in preoperative electrode selection and frequency mapping. METHODS: Ten cadaveric temporal bones were scanned using synchrotron radiation phase-contrast imaging. Reference CDL values were calculated by placing points representing the organ of Corti (OC), lateral wall (LW), and electrode location (I) on the synchrotron radiation phase-contrast imaging slices along the length of the cochlea. The CDL estimates from the existing three equations (OC, LW, I) in addition to two newly proposed equations (OC and LW) were compared with reference CDL values at each respective location. RESULTS: When compared with reference CDL values, the new OC equation improved the CDL estimates from a 6.2% error to a 5.1% error while the new LW equation improved the CDL estimate error from 3.9 to 3.6%. Bland-Altman plots revealed both new equations increased similarity to reference values and brought more samples to within clinically significant ranges. Validation of the original electrode location equation to the reference values showed a 4.6% difference. CONCLUSION: The newly proposed equations for LW and OC provided an improvement over past equations for determining CDL from the A value by showing improved agreement with reference values. Therefore, these equations can provide quick and accurate preoperative estimates of CDL for improving customized frequency mapping. PMID- 28595257 TI - Are Cervical Collars a Necessary Postprocedure Restriction in Patients With Benign Paroxysmal Positional Vertigo Treated With Particle Repositioning Maneuvers? AB - INTRODUCTION: Benign paroxysmal positional vertigo (BPPV) is managed with particle repositioning maneuvers (PRM), following which patients are advised of activity restrictions to prevent recurrence. This can include wearing a cervical collar. OBJECTIVE: Does the use of BPPV postprocedure restriction with a cervical collar impact on the number of PRMs required to resolve a patient's symptoms? METHOD: Combination of retrospective and prospective review of 624 patients treated in a tertiary UK hospital. All were diagnosed with posterior canal BPPV and received a modified Epley maneuver (PRM). The "with cervical collar" (WC) retrospective group 2002 to 2009 (n = 263) were advised to wear a cervical collar for 48 hours postprocedure, and the "no cervical collar" (NC) prospective group 2010 to 2014 (n = 361) were not. The main outcome measure was the resolution of patient symptoms following a PRM for BPPV. Quantitative and statistical analysis using chi test was undertaken. RESULTS: In the WC group, 84% (n = 221) had resolution of symptoms after the first PRM, versus 82.8% (n = 299) in the NC group. After the second PRM 11% (n = 29) resolved, versus 13.6% (n = 49) in the NC group. After the third PRM 4.9% (n = 13) resolved, versus 3.6% (n = 13) in the NC group. Both clinically and statistically there was no significant difference in outcome between groups. CONCLUSIONS: Our review of 624 patients is the largest study in this subject and the results demonstrate that wearing a cervical collar following PRM for BPPV concedes no significant benefit. Excluding this from postprocedure guidance allows patients to manage without the inconvenience of wearing a cervical collar, and allows departments to update clinical guidance. PMID- 28595258 TI - Microsurgery for Recurrent Vestibular Schwannoma After Previous Gross Total Resection. AB - OBJECTIVE: To present a single-institution experience and supportive systematic literature review examining outcomes after repeat microsurgery for recurrent vestibular schwannoma (VS) following previous gross total resection (GTR). STUDY DESIGN: Retrospective review of prospectively maintained VS database. Systematic literature review. SETTING: Tertiary referral center. PATIENTS: Six proven VS recurrences after primary GTR, treated via repeat microsurgery. INTERVENTION: Repeat microsurgery. MAIN OUTCOME MEASURES: Facial nerve function, extent-of resection, time-to-repeat surgery, same versus alternate approach at repeat surgery (relative to primary operation). RESULTS: GTR was achieved in four (67%). House-Brackmann (HB) grade I-II facial nerve function was achieved in five (87%), including one that improved from preoperative HB grade V. An alternate surgical approach was chosen in four (67%). Systematic review identified four studies documenting 50 cases with patient-specific outcomes after repeat microsurgery for recurrent VS. Our cohort had significantly longer mean time-to-repeat surgery (117 vs. 64 months, p = 0.03), was significantly less likely to have HB III-VI function postrepeat (17% vs. 68%, p = 0.04), and was significantly less likely to undergo same approach surgery (33% vs. 90%, p = 0.0002); rates of GTR were nonsignificant (67% vs. 94%, p = 0.1). CONCLUSION: We report a six-patient series of microsurgery for recurrent VS after GTR, and the first systematic review of this rare and challenging entity. Anecdotally, our findings suggest that an alternate surgical approach may facilitate easier access to the tumor, with less scar encountered during the approach. Our results confirm that repeat microsurgery for recurrent VS is safe and effective, even for larger tumors not typically amenable to stereotactic radiosurgery. PMID- 28595259 TI - Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies. AB - BACKGROUND: Signet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease. METHODS: Using test (n=26) and validation (n=18) cohorts, analysis of mutations, DNA methylation and transcriptome was carried out. Microsatellite instability (MSI) status was established and immunohistochemistry (IHC) was used to test for adaptive immunity (CD3) and the immune checkpoint PDL1. RESULTS: DNA methylation data split the cohorts into hypermethylated (n=18, 41%) and hypomethylated groups (n=26, 59%). The hypermethylated group predominant in the proximal colon was enriched for CpG island methylator phenotype (CIMP), BRAF V600E mutation and MSI (P<0.001). These cases also had a high CD3+ immune infiltrate (P<0.001) and expressed PDL1 (P=0.03 in intra-tumoural lymphoid cells). The hypomethylated group predominant in the distal colon did not show any characteristic molecular features. We also detected a common targetable KIT mutation (c.1621A>C) across both groups. No statistically significant difference in outcome was observed between the two groups. CONCLUSIONS: Our data show that SRCCa phenotype comprises two distinct genotypes. The MSI+/CIMP+/BRAF V600E+/CD3+/PDL1+ hypermethylated genotype is an ideal candidate for immune checkpoint inhibitor therapy. In addition, one fourth of SRCCa cases can potentially be targeted by KIT inhibitors. PMID- 28595262 TI - Dopaminergic Imaging and Prodromal Parkinson Disease: A Key Biomarker Arrives. PMID- 28595260 TI - KIF15 promotes pancreatic cancer proliferation via the MEK-ERK signalling pathway. AB - BACKGROUND: Pancreatic cancer is highly malignant and characterised by rapid and uncontrolled growth. While some of the important regulatory networks involved in pancreatic cancer have been determined, the cancer relevant genes have not been fully identified. METHODS: We screened genes that may control proliferation in pancreatic cancer in seven pairs of matched pancreatic cancer and normal pancreatic tissue samples. We examined KIF15 expression in pancreatic cancer tissues and the effect of KIF15 on cell proliferation in vitro and in vivo. The mechanisms underlying KIF15 promotion of cell proliferation were investigated. RESULTS: mRNA microarray and functional analysis identified 22 genes that potentially play an important role in the proliferation of pancreatic cancer. High-content siRNA screening evaluated whether silencing these 22 genes affected proliferation of pancreatic cancer. Notably, silencing KIF15 exhibited the most potent inhibition of proliferation compared with the rest of the 22 genes. KIF15 was upregulated in human pancreatic cancer tissues, and higher KIF15 expression levels correlated with shorter patient survival times. Upregulation KIF15 promoted pancreatic cancer growth. KIF15 upregulated cyclin D1, CDK2, and phospho RB and also promoted G1/S transition in pancreatic cancer cells. KIF15 upregulation activated MEK-ERK signalling by increasing p-MEK and p-ERK levels. MEK-ERK inhibitors successfully inhibited cell cycle progression, and PD98059 blocked KIF15-mediated pancreatic cancer proliferation in vivo and in vitro. CONCLUSIONS: This study identified KIF15 as a critical regulator that promotes pancreatic cancer proliferation, broadening our understanding of KIF15 function in tumorigenesis. PMID- 28595261 TI - Speech-Processing Fatigue in Children: Auditory Event-Related Potential and Behavioral Measures. AB - Purpose: Fatigue related to speech processing is an understudied area that may have significant negative effects, especially in children who spend the majority of their school days listening to classroom instruction. Method: This study examined the feasibility of using auditory P300 responses and behavioral indices (lapses of attention and self-report) to measure fatigue resulting from sustained listening demands in 27 children (M = 9.28 years). Results: Consistent with predictions, increased lapses of attention, longer reaction times, reduced P300 amplitudes to infrequent target stimuli, and self-report of greater fatigue were observed after the completion of a series of demanding listening tasks compared with the baseline values. The event-related potential responses correlated with the behavioral measures of performance. Conclusion: These findings suggest that neural and behavioral responses indexing attention and processing resources show promise as effective markers of fatigue in children. PMID- 28595263 TI - Assessing the Believability of Standardized Patients Trained to Portray Communication Disorders. AB - Purpose: The purpose of this study was to evaluate the believability of standardized patients portraying individuals with communication disorders as part of a larger study in which standardized patients help train medical and allied health students about communication disorders. Method: Two women portrayed persons with aphasia, and 2 men depicted persons with dysarthria associated with Parkinson's disease. Two stakeholder groups rated believability. Speech-language pathologists rated believability of videos online. Persons with aphasia rated aphasia videos during in-person sessions with the researchers. Results: Targeted believability was 80 or higher (0-100 scale; 0 = not at all believable, 100 = very believable). For speech-language pathologist raters, average ratings met the target for the portrayals of the aphasia characteristics of word-finding problems, agrammaticism, nonverbal communication, and overall portrayal but not for auditory comprehension problems. Targets for the portrayals were met for the dysarthria characteristics of reduced speech movements, reduced loudness, reduced intonation, flat affect, and overall portrayal but not for speech rate. Ratings for different standardized patients portraying the same case were not significantly different from each other on most characteristics. Ratings from persons with aphasia were highly variable. Conclusion: Standardized patients who do not have communication disorders can portray disorder characteristics in a believable manner. PMID- 28595264 TI - piRNA-independent PIWI function in spermatogenesis and male fertility. PMID- 28595265 TI - Oil Spill Field Trial at Sea: Measurements of Benzene Exposure. AB - Objectives: Characterize personal exposure to airborne hydrocarbons, particularly carcinogenic benzene, during spill of two different fresh crude oils at sea. Methods: The study included 22 participants taking part in an "oil on water" field trial in the North Sea. Two types of fresh crude oils (light and heavy) were released six times over two consecutive days followed by different oil spill response methods. The participants were distributed on five boats; three open sampling boats (A, B, and C), one release ship (RS), and one oil recovery (OR) vessel. Assumed personal exposure was assessed a priori, assuming high exposure downwind and close to the oil slick (sampling boats), low exposure further downwind (100-200 m) and upwind from the oil slick (main deck of RS and OR vessel), and background exposure indoors (bridge of RS/OR vessel). Continuous measurements of total volatile organic compounds in isobutylene equivalents were performed with photoionization detectors placed in all five boats. Full-shift personal exposure to benzene, toluene, ethylbenzene, xylenes, naphthalene, and n hexane was measured with passive thermal desorption tubes. Results: Personal measurements of benzene, averaged over the respective sample duration, on Day 1 showed that participants in the sampling boats (A, B, and C) located downwind and close to the oil slick were highest exposed (0.14-0.59 ppm), followed by participants on the RS main deck (0.02-0.10 ppm) and on the bridge (0.004-0.03 ppm). On Day 2, participants in sampling boat A had high benzene exposure (0.87 1.52 ppm) compared to participants in sampling boat B (0.01-0.02 ppm), on the ships (0.06-0.10 ppm), and on the bridge (0.004-0.01 ppm). Overall, the participants in the sampling boats had the highest exposure to all of the compounds measured. The light crude oil yielded a five times higher concentration of total volatile organic compounds in air in the sampling boats (max 510 ppm) than the heavy crude oil (max 100 ppm) but rapidly declined to <20 ppm within 24 min after release of oil, indicating short periods of exposure. Conclusions: The personal exposure to benzene downwind and close to the oil slick during spills of light crude oil was relatively high, with concentration levels approaching the occupational exposure limits for several participants. For bulk spill scenarios like in this study, cleanup should not be initiated the first 30-60 min to allow for evaporation, while appropriate personal protective equipment should be used in continuous spills when working downwind and close to the oil slick. PMID- 28595266 TI - Melatonin protects against cisplatin-induced ovarian damage in mice via the MT1 receptor and antioxidant activity. AB - This study evaluated the receptor- and/or antioxidant stress-mediated mechanisms by which melatonin prevents the ovarian toxicity of cisplatin treatment. The expression of the MT1 receptor in mouse ovaries was investigated by immunohistochemistry. Pretreatment with melatonin (5, 10, or 20 mg/kg body weight, i.p.) before cisplatin (5 mg/kg body weight, i.p.) was administered to mice once daily for 3 days (phase I). The pharmacological modulation via melatonin type 1 and/or 2 receptors was analyzed by administration of receptor antagonists (luzindole: nonselective MT1/MT2 antagonist; 5 mg/kg body weight or 4 phenyl-2-propionamidotetralin: selective MT2 antagonist; 4 mg/kg body weight) once daily for 3 days, 15 min before the treatment with melatonin and cisplatin (phase II). Thereafter, the ovaries were harvested and used for histological (morphology and activation), immunohistochemical (PCNA, activated caspase-3 and bcl-2 expression), terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, and fluorescence (reactive oxygen species [ROS], glutathione [GSH], and active mitochondria levels) analyses. The expression of the MT1 protein in mouse ovaries was documented. Pretreatment with 20 mg/kg melatonin before cisplatin administration preserved the normal follicular morphology and cell proliferation rate, reduced apoptosis, ROS production, mitochondrial damage and increased GSH expression, as compared to the cisplatin treatment alone. Additionally, administration of the nonselective MT1/MT2 receptor antagonist inhibited the melatonin ovarian protection from the cytotoxic effects of cisplatin. However, administration of a selective MT2 antagonist did not modify the protective effects observed at 20 mg/kg melatonin. In conclusion, pretreatment with 20 mg/kg melatonin effectively protected the ovaries against cisplatin-induced damage. Moreover, the MT1 receptor and melatonin antioxidant effects mediated this cytoprotective activity. PMID- 28595268 TI - Review: placental biomarkers for assessing fetal health. AB - The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways. The application of serum proteins and circulating placental derived DNA has been well demonstrated for the diagnosis of aneuploidy, and there is great interest in exploring the use of placental biomarkers for the prediction of a range of fetal health parameters. In this review, we discuss how placental biomarkers might be used for the diagnosis and early detection of preeclampsia, fetal growth restriction and inflammation associated with preterm birth. We emphasize how increased understanding of the underlying placental biology can aid in the interpretation of such approaches and development of new biomarkers that can help predict the onset of pregnancy and neonatal health concerns before they manifest. PMID- 28595267 TI - Cholesterol uptake and regulation in high-grade and lethal prostate cancers. AB - Lethal prostate cancers have higher expression of squalene monooxygenase (SQLE), the second rate-limiting enzyme of cholesterol synthesis. Preclinical studies suggested that aberrant cholesterol regulators, receptors and transporters contribute to cholesterol accumulation uniformly. We assessed their association with features of aggressive cancers. In the prospective prostate cancer cohorts within the Health Professional Follow-up Study, the Physicians' Health Study and the Swedish Watchful Waiting Study, tumor mRNA expression profiling was performed. Lethal disease was defined as mortality or metastases from prostate cancer (n = 266) in contrast to non-lethal disease without metastases after >8 years of follow-up (n = 476). Associations with Gleason grade were additionally assessed using The Cancer Genome Atlas primary prostate cancer dataset (n = 333). Higher Gleason grade was associated with lower LDLR expression, lower SOAT1 and higher SQLE expression. Besides high SQLE expression, cancers that became lethal despite primary treatment were characterized by low LDLR expression (odds ratio for highest versus lowest quintile, 0.37; 95% CI 0.18-0.76) and by low SOAT1 expression (odds ratio, 0.41; 95% CI 0.21-0.83). The association of LDLR expression and lethality was not present in tumors with high IDOL expression. ABCA1, PCSK9 or SCARB1 expressions were not associated with Gleason grade or lethal cancer. In summary, prostate cancers that progress to lethal disease rely on de novo cholesterol synthesis (via SQLE), rather than transcellular uptake (via LDLR) or cholesterol esterification (via SOAT1). These results may help design pharmacotherapy for high-risk patients. PMID- 28595270 TI - SPP1 genotype and glucocorticoid treatment modify osteopontin expression in Duchenne muscular dystrophy cells. AB - Glucocorticoids are beneficial in Duchenne muscular dystrophy (DMD). Osteopontin (OPN), the protein product of SPP1, plays a role in DMD pathology modulating muscle inflammation and regeneration. A polymorphism in the SPP1 promoter (rs28357094) has been recognized as a genetic modifier of DMD, and there is evidence suggesting that it modifies response to glucocorticoid treatment. The effect of the glucocorticoid deflazacort on SPP1 mRNA and protein expression was investigated in DMD primary human myoblasts and differentiated myotubes with defined rs28357094 genotype (TT versus TG). Both healthy and DMD myoblasts/myotubes abundantly express OPN. In immunoblot, OPN was detected as a doublet of 55 and 50 kDa bands, with a shift towards the lighter isoform in the transition from myoblasts to myotubes and to mature muscle. A significant increase in OPN expression was observed in DMD myotubes carrying the TG compared to the TT genotype at rs28357094. Deflazacort treatment led to a significant increase of OPN only in myotubes carrying the TG genotype, leading to OPN overexpression. Our study shows a strong effect of the rs28357094 G allele in increasing OPN expression in the presence of deflazacort, and adds to the evidence that rs28357094 polymorphism may predict response to glucocorticoids in DMD. PMID- 28595271 TI - Oviposition Preference and Survival of the Mexican Rice Borer (Lepidoptera: Crambidae) in Bioenergy and Conventional Sugarcane and Sorghum. AB - Oviposition preference and host suitability of the Mexican rice borer, Eoreuma loftini (Dyar) (Lepidoptera: Crambidae), on bioenergy and conventional cultivars of sugarcane, Saccharum spp., and sorghum, Sorghum spp., were examined in a series of greenhouse experiments. Two energycane cultivars, two sugarcane cultivars, two high-biomass sorghum cultivars, and one sweet sorghum cultivar were assessed at two phenological stages (immature and mature). Mature plants possessed greater availability of dry leaf material compared with immature plants, and all E. loftini eggs were observed exclusively on dry leaves. Oviposition did not vary among host combinations (cultivar by phenological stage); however, eggs per plant and eggs per oviposition event were numerically greater on mature plants than immature plants. In a no-choice experiment, survival from egg to adult did not vary among host combinations, with <2.0% of E. loftini larvae surviving to adulthood. Failed establishment by neonates on plants was 13.4- to 53.9-fold greater than successful establishment across all host combinations. Results from this study suggest that plant physical characteristics continue to play an important role in host selection, but further evaluations will be needed to quantify other characteristics which influence host suitability. PMID- 28595269 TI - Identification of a rare LAMB4 variant associated with familial diverticulitis through exome sequencing. AB - Diverticulitis is a chronic disease of the colon in which diverticuli, or outpouching through the colonic wall, become inflamed. Although recent observations suggest that genetic factors may play a significant role in diverticulitis, few genes have yet been implicated in disease pathogenesis and familial cases are uncommon. Here, we report results of whole exome sequencing performed on members from a single multi-generational family with early onset diverticulitis in order to identify a genetic component of the disease. We identified a rare single nucleotide variant in the laminin beta 4 gene (LAMB4) that segregated with disease in a dominant pattern and causes a damaging missense substitution (D435N). Targeted sequencing of LAMB4 in 148 non-familial and unrelated sporadic diverticulitis patients identified two additional rare variants in the gene. Immunohistochemistry indicated that LAMB4 localizes to the myenteric plexus of colonic tissue and patients harboring LAMB4 variants exhibited reduced LAMB4 protein levels relative to controls. Laminins are constituents of the extracellular matrix and play a major role in regulating the development and function of the enteric nervous system. Reduced LAMB4 levels may therefore alter innervation and morphology of the enteric nervous system, which may contribute to colonic dysmotility associated with diverticulitis. PMID- 28595272 TI - Superficial and deep changes of histology, texture and particle size distribution in broiler wooden breast muscle during refrigerated storage. AB - Recently the poultry industry faced an emerging muscle abnormality termed wooden breast (WB), the prevalence of which has dramatically increased in the past few years. Considering the incomplete knowledge concerning this condition and the lack of information on possible variations due to the intra-fillet sampling locations (superficial vs. deep position) and aging of the samples, this study aimed at investigating the effect of 7-d storage of broiler breast muscles on histology, texture, and particle size distribution, evaluating whether the sampling position exerts a relevant role in determining the main features of WB. With regard to the histological observations, severe myodegeneration accompanied by accumulation of connective tissue was observed within the WB cases, irrespective of the intra-fillet sampling position. No changes in the histological traits took place during the aging in either the normal or the WB samples. As to textural traits, although a progressive tenderization process took place during storage (P <= 0.001), the differences among the groups were mainly detected when raw meat rather than cooked was analyzed, with the WB samples exhibiting the highest (P <= 0.001) 80% compression values. In spite of the increased amount of connective tissue components in the WB cases, their thermally labile cross-links will account for the similar compression and shear-force values as normal breast cases when measured on cooked samples. Similarly, the enlargement of extracellular matrix and fibrosis might contribute in explaining the different fragmentation patterns observed between the superficial and the deep layer in the WB samples, with the superficial part exhibiting a higher amount of larger particles and an increase in particles with larger size during storage, compared to normal breasts. PMID- 28595273 TI - Acupuncture Therapy in a Group Setting for Chronic Pain. AB - Objective: This project was designed to test the feasibility and effectiveness of acupuncture therapy given in a group setting for chronic pain. Design: Nonrandomized, repeated measures quasi-experimental trial. Setting: Care was delivered in a primary care clinic waiting area after clinic hours. Subjects: Included were primary care patients (>=18 years old) with chronic pain of the neck, back, shoulder, or osteoarthritis of any site of at least three months' duration. Methods: Subjects received eight weekly acupuncture therapy sessions in a group setting. Acupuncture therapy included a combination of palpation, acupuncture needling, Tui na, Gua sha, and auricular treatment. Baseline pain levels were established in a two- to four-week run-in; assessment of the intervention impact on pain intensity, mood, and functional status were made at the end of the treatment period (eight weeks) and 16 weeks after completion of intervention (24 weeks). Results: Of the total 113 participants recruited for the trial, 96 completed the 24-week protocol. We found a statistically and clinically significant decrease in pain severity, pain interference, and depression in our study population. There were no serious adverse events. Conclusions: Acupuncture therapy offered in the group setting was effective in reducing pain severity, pain interference, and depression in patients with chronic neck, back, or shoulder pain or osteoarthritis. Benefit persisted through the 24-week measure despite no additional treatment. This finding has potentially important implications for improving access to effective acupuncture treatment for patients with limited financial resources. PMID- 28595274 TI - Antibiotics in 16-day-old broilers temporarily affect microbial and immune parameters in the gut. AB - Animal health benefits from a stable intestinal homeostasis, for which proper development and functioning of the intestinal microbiota and immune system are essential. It has been established that changes in microbial colonization in early life (the first 2 wk post hatch) impacts the functioning of the adult gut and the associated crosstalk between microbiota and intestinal mucosal cells. The aim of the present study was to study the effect of the administration of antibiotics later in life (d 15 to 20 post hatch) on microbiota and immune parameters. For this purpose, chickens received from 15 d post hatch during 5 d amoxicillin or enrofloxacin through their drinking water. Before and at 6, 16, and 27 d after start of the administration of antibiotics, the composition of the microbiota in the jejunum was determined using a 16S ribosomal RNA gene-targeted DNA microarray, the CHICKChip. At 6 d after the start of the administration of the antibiotics, the composition and diversity of the microbiota were affected significantly (P < 0.05), but this change was small and observed only temporarily since differences disappeared at 16 d after initiating treatment with amoxillin and at 27 d after starting treatment with enrofloxacin. Intestinal morphology and development were not visibly affected since there were no differences between villus/crypt ratios and numbers of PAS+ and PCNA+ cells in the duodenum and jejunum at any time point. At 16 d after the start of antibiotic administration, the number of CD4+ T-cells and CD8+ T-cells in the duodenum was lower compared to the control animals; however, this difference was not significant. At some time points, significant differences (P < 0.05) were observed among the groups to locally expressed IL-8, IL-1beta, IFN-gamma, IL-2, and IL-4 mRNA. However, this effect was not long lasting, as differences that were observed at 16 d after starting the treatment had disappeared at 27 d after treatment was started. The results of this study indicate that later in the broiler's life, antibiotics only temporarily affect intestinal microbial and immune parameters. PMID- 28595275 TI - Antifungal susceptibility of Sporothrix schenckii complex biofilms. AB - Sporotrichosis, caused by species of Sporothrix schenckii complex, is the most prevalent subcutaneous mycosis in many areas of Latin America. The aim of this study was to evaluate the ability of Sporothrix spp. to form biofilms in vitro and to characterize the growth kinetics, morphology, and antifungal susceptibility of biofilms against classical antifungals. We investigated the ability of strains to produce biofilms in vitro and determined the effects of exposure to amphotericin B, itraconazole, caspofungin, ketoconazole, voriconazole, and fluconazole at minimum inhibitory concentration (MIC) against planktonic form and at 10* MIC and 50* MIC on the biomass and metabolic activity of these biofilms. Biofilm structure was analyzed by optical microscopy using Congo-red staining, confocal and scanning electron microscopy. Strains were classified for biofilm-forming ability, through the analysis of absorbance of crystal violet retained by biomass of mature biofilms. We found that all S. brasiliensis (n = 10), S. schenckii sensu stricto (n = 2), S. globosa (n = 2), and S. mexicana (n = 4) strains were strong biofilm-producers. The analyzed biofilms had dense network of hyphae and conidia immersed in extracellular matrix, with presence of water channels. Antifungal drugs at the three tested concentrations showed different effects on biomass and metabolic activity of biofilms. However, the best inhibitory response was observed with 50* MIC of amphotericin B and caspofungin, which reduced these parameters. Furthermore, high drug concentrations, especially amphotericin B and caspofungin, showed antifungal activity against these biofilms, probably because they damaged the architecture and extracellular matrix, allowing diffusion of the drugs. PMID- 28595276 TI - Premorbid IQ Predicts Postconcussive Symptoms in OEF/OIF/OND Veterans with mTBI. AB - Objective: Extant literature has demonstrated that symptoms of postconcussive syndrome (PCS) persist well beyond the expected 3-month post-injury recovery period in a minority of individuals with mild traumatic brain injury (mTBI). Suboptimal performance on validity measures and pre- and post-injury psychosocial stressors - rather than actual mTBI or current cognitive functioning - have been identified as predictors of chronic PCS. Whether premorbid IQ has any influence on chronic PCS has been understudied, in the context of established psychogenic etiologies. Method: The sample included 31 veterans, who underwent mTBI neuropsychological evaluations six or more months post-injury in a VA outpatient neuropsychology clinic. A two-step multiple linear regression was conducted to examine the effects on the outcome variable, PCS (Neurobehavioral Symptom Inventory), of the following predictors: cognitive functioning (Repeatable Battery for the Assessment of Neuropsychological Status; Attention, Immediate Memory, and Delayed Memory Indices), performance validity, depression (Beck Depression Inventory-Second Edition), posttraumatic stress disorder (PTSD Checklist, Civilian Version), quality of sleep (Pittsburgh Sleep Quality Index), pain (Brief Pain Inventory), education, and Premorbid IQ (Wechsler Test of Adult Reading). Results: The overall regression model containing all nine predictor variables was statistically significant. Depression (p < .05) and premorbid IQ (p < .05) were the most salient predictors of chronic PCS; in that lower premorbid IQ and greater endorsed symptoms of depression were associated with higher PCS scores. In Step 2 of the multiple linear regression, the WTAR explained an additional 6.7% of the variance in PCS after controlling for psychosocial stressors and current cognitive ability. Conclusion: The findings support premorbid IQ as a unique and relevant predictor of chronic PCS, with significance variance accounted for beyond education, cognitive functioning, and psychosocial variables. Given the predictive relationship between premorbid IQ and PCS, adapting postconcussive interventions to meet the specific needs of individuals with varying levels of intellect may be important in minimizing ongoing symptomatology. PMID- 28595277 TI - Genetic alterations responsible for reduced susceptibility to vancomycin in community-associated MRSA strains of ST72. AB - Objectives: We previously reported the first case of vancomycin treatment failure due to development of vancomycin-intermediate resistance in a patient with an MRSA of ST72, a community genotype in Korea. We investigated two isogenic MRSA strains from this patient, who experienced treatment failure with vancomycin and rifampicin. Methods: We tracked the genetic alterations that confer reduced susceptibility to vancomycin on those two isogenic MRSA strains by WGS. Results: Five non-synonymous mutations were identified, including rpoB (H481Y), dprA (G196C), femA (F92C), vraR (E127K) and agrC (E391stop). We further studied the role of a mutation of vraR in reduced susceptibility to vancomycin. Introduction of the mutated vraR (E127K) into a vancomycin-susceptible Staphylococcus aureus strain resulted in an increase in vraSR mRNA expression and vancomycin MIC and development of the hetero-VISA phenotype, which was confirmed by the population analysis profile (PAP)/AUC. Electron microscopy showed increased cell wall thickness in the strains with mutated vraR. Conclusions: Based on the genomic data, molecular experiments and PAP and cell wall analyses, we propose that a single mutation of vraR is associated with the reduced susceptibility to vancomycin in MRSA and further treatment failure. PMID- 28595278 TI - Takayasu arteritis: active or not, that's the question. PMID- 28595279 TI - The Association of Progressive Tension Sutures and Drains Seems to Decrease the Drainage Output and Seroma Formation in Abdominoplasty. PMID- 28595280 TI - Estimating National-Level Exposure to Antineoplastic Agents in the Workplace: CAREX Canada Findings and Future Research Needs. AB - Objectives: Occupational exposure to antineoplastic agents occurs in various environments and is associated with increased cancer risk and adverse reproductive outcomes. National-level information describing the location and extent of occupational exposure to antineoplastic agents is unavailable in Canada and most other countries. CAREX Canada aimed to estimate the prevalence and relative levels of occupational exposures to antineoplastic agents across work setting, occupation, and sex. Methods: 'Exposure' was defined as any potential for worker contact with antineoplastic agents. Baseline numbers of licensed workers were obtained from their respective professional bodies. For unlicensed workers, Census data or data extrapolated from human resources reports (e.g., staffing ratios) were used. Prevalence was estimated by combining population estimates with exposure proportions from peer-reviewed and grey literature. Exposure levels (classified as low, moderate, and high) by occupation and work setting were estimated qualitatively by combining estimates of contact frequency and exposure control practices. Results: Approximately 75000 Canadians (0.42% of the total workforce) are estimated as occupationally exposed to antineoplastic agents; over 75% are female. The largest occupational group exposed to antineoplastic agents is community pharmacy workers, with 30200 exposed. By work setting, 39000 workers (52% of all exposed) are located in non-hospital settings; the remaining 48% are exposed in hospitals. The majority (75%) of workers are in the moderate exposure category. Conclusions: These estimates of the prevalence and location of occupational exposures to antineoplastic agents could be used to identify high-risk groups, estimate disease burden, and target new research and prevention activities. The limited secondary data available for developing these estimates highlights the need for increased quantitative measurement and documentation of antineoplastic agent contamination and exposure, particularly in work environments where use is emerging. PMID- 28595281 TI - Unraveling the Population History of Indian Siddis. AB - The Siddis are a unique Indian tribe of African, South Asian, and European ancestry. While previous investigations have traced their ancestral origins to the Bantu populations from subSaharan Africa, the geographic localization of their ancestry has remained elusive. Here, we performed biogeographical analysis to delineate the ancestral origin of the Siddis employing an admixture based algorithm, Geographical Population Structure (GPS). We evaluated the Siddi genomes in reference to five African populations from the 1000 Genomes project, two Bantu groups from the Human Genome Diversity Panel (HGDP) and five South Indian populations. The Geographic Population Structure analysis localized the ancestral Siddis to Botsawana and its present-day northeastern border with Zimbabwe, overlapping with one of the principal areas of secondary Bantu settlement in southeast Africa. Our results further indicated that while the Siddi genomes are significantly diverged from that of the Bantus, they manifested the highest genomic proximity to the North-East Bantus and the Luhyas from Kenya. Our findings resonate with evidences supporting secondary Bantu dispersal routes that progressed southward from the east African Bantu center, in the interlacustrine region and likely brought the ancestral Siddis to settlement sites in south and southeastern Africa from where they were disseminated to India, by the Portuguese. We evaluated our results in the light of existing historical, linguistic and genetic evidences, to glean an improved resolution into the reconstruction of the distinctive population history of the Siddis, and advance our knowledge of the demographic factors that likely contributed to the contemporary Siddi genomes. PMID- 28595282 TI - A giant septal diverticulum in a patient with medullary sponge kidney. PMID- 28595283 TI - Trends Over Time in Tobacco-Specific Nitrosamines (TSNAs) in Whole Tobacco and Smoke Emissions From Cigarettes Sold in Canada. AB - Introduction: Tobacco-specific nitrosamines (TSNAs) are potent carcinogens. Levels of TSNAs can be modified through manufacturing practices. In the 2000s, TSNA levels in cigarettes sold in Canada were reduced by changes in tobacco curing processes. The current study examined TSNA levels over the following decade to examine trends over time. Methods: Data submitted to Health Canada under the Tobacco Reporting Regulations were used to examine whole tobacco constituents for 1809 brands and mainstream smoke emissions for 191 brands manufactured by Canada's three leading cigarette companies from 2005 through 2011/12 using one-way analysis of variances (ANOVAs) and linear regression models. Results: Levels of N-nitrosoanatabine (NAT) (p < .001) and 4 (methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) (p < .001) in whole tobacco showed significant differences over time, decreasing between 2005 and 2007, and generally increasing from 2007 through 2012. Levels of all TSNAs in mainstream smoke emissions reflected a similar pattern: N-nitrosoanabasine (NAB) (p < .001), NAT (p < .001), NNK (p < .001), and N'-nitrosonornicotine (NNN) (p = .021). Linear regression analyses showed that TSNA levels varied by manufacturer over time in whole tobacco for NAT, NNK, and NNN (p < .001 for all), and in smoke emissions for NAB, NAT, NNK, and NNN (p < .001 for all). Conclusions: The findings indicate that levels of TSNAs in whole tobacco and smoke emissions of cigarettes sold in Canada increased from 2007 through 2011/12, following initial reductions over the previous 2 years. Differences in TSNA levels between companies raise questions about manufacturing practices that may be responsible for these changes. Although increased levels of carcinogenic TSNAs may be alarming, it remains unclear whether these differences translate into differences in health risk. Implications: The wide variation of TSNAs within the Canadian market across time and across cigarette companies demonstrates the feasibility of reducing the levels of these potent carcinogens. Although it is unclear whether changes made to levels of TSNAs will result in less tobacco-related disease, the tobacco industry bears a responsibility to minimize the harm from smoking to the fullest extent possible. PMID- 28595284 TI - Infertility diagnosis has a significant impact on the transcriptome of developing blastocysts. AB - STUDY QUESTION: Is the human blastocyst transcriptome associated with infertility diagnosis, specifically: polycystic ovaries (PCO), male factor (MF) and unexplained (UE)? SUMMARY ANSWER: The global blastocyst transcriptome was significantly altered in association with a PCO, MF and UE infertility diagnosis. WHAT IS KNOWN ALREADY: Infertility diagnosis has an impact on the probability for a successful outcome following an IVF cycle. Limited information is known regarding the relationship between a specific infertility diagnosis and blastocyst transcription during preimplantation development. STUDY DESIGN, SIZE, DURATION: Blastocysts created during infertility treatment from patients with specific infertility diagnoses (PCO, MF and UE) were analyzed for global transcriptome compared to fertile donor oocyte blastocysts (control). PARTICIPANTS/MATERIALS, SETTING, METHODS: Surplus cryopreserved blastocysts were donated with patient consent and institutional review board approval. Female patients were <38 years old with male patients <40 years old. Blastocysts were grouped according to infertility diagnosis: PCO (n = 50), MF (n = 50), UE (n = 50) and fertile donor oocyte controls (n = 50). Pooled blastocysts were lysed for RNA isolation followed by microarray analysis using the SurePrint G3 Human Gene Expression Microarray. Validation was performed on significant genes of interest using real-time quantitative PCR (RT-qPCR). MAIN RESULTS AND THE ROLE OF CHANCE: Transcription alterations were observed for all infertility etiologies compared to controls, resulting in differentially expressed genes: PCO = 869, MF = 348 and UE = 473 (P < 0.05; >2-fold). Functional annotation of biological and molecular processes revealed both similarities, as well as differences, across the infertility groups. All infertility etiologies displayed transcriptome alterations in signal transducer activity, receptor binding, reproduction, cell adhesion and response to stimulus. Blastocysts from PCO patients were also enriched for apoptotic genes while MF blastocysts displayed enrichment for genes involved in cancer processes. Blastocysts from couples with unexplained infertility displayed transcription alterations related to various disease states, which included mechanistic target of rapamycin (mTOR) and adipocytokine signaling. RT-qPCR validation confirmed differential gene expression for the following genes: BCL2 like 10 (BCL2L10), heat shock protein family A member 1A (HSPA1A), heat shock protein family A member 1B (HSPA1B), activating transcription factor 3 (ATF3), fibroblast growth factor 9 (FGF9), left-right determination factor 1 (LEFTY1), left-right determination factor 2 (LEFTY2), growth differentiation factor 15 (GDF15), inhibin beta A subunit (INHBA), adherins junctions associated protein 1 (AJAP1), cadherin 9 (CDH9) and laminin subunit alpha 4 (LAMA4) (P < 0.05; >2-fold). LARGE SCALE DATA: Not available due to participant privacy. LIMITATIONS, REASONS FOR CAUTION: Blastocyst samples for microarray analysis required pooling. While this allows for an overall average in each infertility etiology group and can reduce noise from sample-to-sample variation, it cannot give a detailed analysis of each blastocyst within the group. WIDER IMPLICATIONS OF THE FINDINGS: Underlying patient infertility diagnosis has an impact on the blastocyst transcriptome, modifying gene expression associated with developmental competence and implantation potential. STUDY FUNDING AND COMPETING INTEREST(S): No conflict of interest or outside funding provided. PMID- 28595286 TI - A Multinomial Regression Approach to Model Outcome Heterogeneity. AB - When a risk factor affects certain categories of a multinomial outcome but not others, outcome heterogeneity is said to be present. A standard epidemiologic approach for modeling risk factors of a categorical outcome typically entails fitting a polytomous logistic regression via maximum likelihood estimation. In this paper, we show that standard polytomous regression is ill equipped to detect outcome heterogeneity and will generally understate the degree to which such heterogeneity may be present. Specifically, nonsaturated polytomous regression will often a priori rule out the possibility of outcome heterogeneity from its parameter space. As a remedy, we propose to model each category of the outcome as a separate binary regression. For full efficiency, we propose to estimate the collection of regression parameters jointly using a constrained Bayesian approach that ensures that one remains within the multinomial model. The approach is straightforward to implement in standard software for Bayesian estimation. PMID- 28595285 TI - Quality of life predicts overall survival in women with platinum-resistant ovarian cancer: an AURELIA substudy. AB - Background: Women with platinum-resistant ovarian cancer are a heterogeneous group whose median overall survival is 12 months. We hypothesized that their quality of life (QoL) scores would be prognostic. Patients and methods: Data from AURELIA (n = 326), a randomized trial of chemotherapy with or without bevacizumab, were used to identify baseline QoL domains [EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and OV28] that were significantly associated with overall survival in multivariable Cox regression analyses. Patients were classified as having good, medium, or poor risk. Cutpoints were validated in an independent dataset, CARTAXHY (n = 136). Multivariable analyses of significant QoL domains on survival were adjusted for clinicopathological prognostic factors. The additional QoL information was assessed using C statistic. Results: In AURELIA, all domains, except cognitive function, predicted overall survival in univariable analyses. Physical function (P < 0.001) and abdominal/gastrointestinal symptom (P < 0.001) scores remained significant in multivariable models. In high (score <67), medium (67-93), and low (>93) risk categories for physical function, median overall survival was 11.0, 14.7, and 19.3 months, respectively (P < 0.001). In CARTAXHY, median overall survival was 7.9, 16.2, and 23.9 months (P < 0.001), respectively. For high- (>44), medium- (13-44), and low- (<13) risk categories for abdominal/gastrointestinal symptoms, median overall survival was 11.9, 14.3, and 19.7 months in AURELIA (P < 0.001) and 10.5, 19.6, and 24.1 months in CARTAXHY (P = 0.02). Physical function (P = 0.02) and abdominal/gastrointestinal symptoms (P = 0.03) remained independent prognostic factors after adjustment for clinicopathological factors. The C statistic of the full model was 0.71. For QoL factors alone, patient factors alone and disease factors alone, the C statistics were 0.61, 0.61, and 0.67 respectively. Conclusions: Physical function and abdominal/gastrointestinal symptom scores improved predictions of overall survival over clinicopathological factors alone in platinum-resistant ovarian cancer. This additional prognostic information could improve trial stratification, patient-doctor communication about prognosis, and clinical decision-making. Clinical trial registration: NCT00976911. PMID- 28595287 TI - Conversion to Parkinson Disease in the PARS Hyposmic and Dopamine Transporter Deficit Prodromal Cohort. AB - Importance: Detecting individuals at risk for Parkinson disease (PD) during the prodromal phase could clarify disease mechanisms and allow for treatment earlier in the disease process to possibly slow or prevent the onset of motor PD. Objective: To determine if the combination of smell identification testing followed by dopamine transporter (DAT) imaging can accurately and efficiently identify individuals from the general population at risk for conversion to a clinical diagnosis of PD. Design, Setting, and Participants: Participants were identified from the community by olfactory testing assessed longitudinally with DAT imaging 2 and 4 years after baseline and by annual clinical follow-up to determine whether they had clinical evidence to establish a PD diagnosis. Participants were contacted by mail and completed olfactory testing at home. Longitudinal follow-up of clinical measures and DAT imaging occurred at specialty centers. There were 203 hyposmic and 100 normosmic participants. A total of 185 hyposmic and 95 normosmic individuals had at least 1 follow-up visit, and 152 hyposmic participants (82.2%) were either observed for 4 years or converted to PD during follow-up. Main Outcomes and Measures: Percentage of individuals with hyposmia and a DAT deficit that converted to PD and the change in PD clinical scale scores (Unified Parkinson's Disease Rating Scale) and DAT imaging during 4 year follow-up. Results: Of 280 total participants, 140 (50.0%) were male, and the mean (SD) age of the cohort was 63 (8.7) years. Among 21 participants with hyposmia and a DAT deficit (65% or less of age-expected lowest putamen binding ratio) at baseline, 14 (67%) converted to PD at 4 years compared with 2 of 22 participants (9%) with a DAT in an indeterminate range (greater than 65%-80%) and 3 of 109 participants (2.8%) with no DAT deficit (greater than 80%) at baseline. Individuals with a baseline DAT deficit experienced a 4-year decline in DAT binding of 20.23% (SD, 15.04%) compared with 3.68% (SD, 18.36%) and 5.45% (SD, 13.58%) for participants with an indeterminate and no DAT deficit, respectively (P = .002). The relative risk of conversion to a diagnosis of PD in hyposmic individuals with a DAT deficit was 17.47 (95% CI, 7.02-43.45) compared with individuals with either indeterminate or no DAT deficit. Conclusions and Relevance: The combination of hyposmia and DAT deficit was highly predictive of conversion to PD within 4 years of clinical follow-up. Individuals with hyposmia and a DAT deficit had a 5% reduction in DAT binding annually, similar to early PD. These results provide a framework for planning disease prevention studies in PD. PMID- 28595288 TI - Does Resistance to Buprofezin Improve Heat and Cold Tolerance of Laodelphax striatellus (Hemiptera: Delphacidae)? AB - There is ample evidence that insecticide resistance causes fitness costs and benefits in pests, while the impact of insecticide resistance on thermotolerance of pests is mostly unclear. The Laodelphax striatellus (Fallen), is an important rice insect pest, which has developed resistance to buprofezin in China. Here, we investigated differences in heat tolerance and cold tolerance among L. striatellus lines with variable buprofezin resistance. The lethal time for 50% of the individuals to die (LT50) at 40 degrees C increased with an increase in buprofezin resistance level, whereas both the survival rate under -22 degrees C and the supercooling point of planthoppers did not differ significantly between resistant and susceptible strains. The metabolic enzyme carboxylesterase was found to have an association with buprofezin resistance. Our research showed that buprofezin resistance was positively related with heat tolerance in L. striatellus, but it had no effect on cold tolerance. Insecticide resistance in L. striatellus may therefore have broader implications for the ecology of L. striatellus, and the management of buprofezin resistance in this pest may be challenging. PMID- 28595289 TI - The Drivers of Acute and Long-term Care Clostridium difficile Infection Rates: A Retrospective Multilevel Cohort Study of 251 Facilities. AB - Background: Drivers of differences in Clostridium difficile incidence across acute and long-term care facilities are poorly understood. We sought to obtain a comprehensive picture of C. difficile incidence and risk factors in acute and long-term care. Methods: We conducted a case-cohort study of persons spending at least 3 days in one of 131 acute care or 120 long-term care facilities managed by the United States Veterans Health Administration between 2006 and 2012. Patient (n = 8) and facility factors (n = 5) were included in analyses. The outcome was the incidence of facility-onset laboratory-identified C. difficile infection (CDI), defined as a person with a positive C. difficile test without a positive test in the prior 8 weeks. Results: CDI incidence in acute care was 5 times that observed in long-term care (median, 15.6 vs 3.2 per 10000 person-days). History of antibiotic use was greater in acute care compared to long-term care (median, 739 vs 513 per 1000 person-days) and explained 72% of the variation in C. difficile rates. Importation of C. difficile cases (acute care: patients with recent long-term care attributable infection; long-term care: residents with recent acute care attributable infection) was 3 times higher in long-term care as compared to acute care (median, 52.3 vs 16.2 per 10000 person-days). Conclusions: Facility-level antibiotic use was the main factor driving differences in CDI incidence between acute and long-term care. Importation of acute care C. difficile cases was a greater concern for long-term care as compared to importation of long-term care cases for acute care. PMID- 28595291 TI - The expression of CXCR4 is induced by the luteinizing hormone surge and mediated by progesterone receptors in human preovulatory granulosa cells. AB - The chemokine CXC motif ligand 12 (CXCL12) and its cognate receptor, CXCR4, have been implicated in the ovulatory process in various animal models. However, little is known about the expression and regulation of CXCL12 and CXCR4 and their functions during the ovulatory period in the human ovary. In this study, we characterized the expression patterns of CXCL12 and CXCR4 in preovulatory follicles collected before the luteinizing hormone (LH) surge and at defined hours after hCG administration in women with the regular menstrual cycle. The levels of mRNA and protein for CXCR4 were increased in granulosa cells of late ovulatory follicles, whereas CXCL12 expression was constant in follicles throughout the ovulatory period. Both CXCR4 and CXCL12 were localized to a subset of leukocytes around and inside the vasculature of human preovulatory follicles. Using a human granulosa cell culture model, the regulatory mechanisms and functions of CXCL12 and CXCR4 expression were investigated. Human chorionic gonadotropin (hCG) stimulated CXCR4 expression, whereas CXCL12 expression was not affected, mimicking in vivo expression patterns. Both RU486 (progesterone receptor antagonist) and CoCl2 (HIFs activator) blocked the hCG-induced increase in CXCR4 expression, whereas AG1478 (EGFR inhibitor) had no effect. The treatment with CXCL12 had no effect on granulosa cell viability but decreased hCG stimulated CXCR4 expression. PMID- 28595290 TI - Dietary Fat Intake and Fecundability in 2 Preconception Cohort Studies. AB - The association between dietary fat and fertility is not well studied. We evaluated intakes of total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, trans fatty acids (TFA), omega-3 fatty acids, and omega-6 fatty acids in relation to fecundability in Danish and North American preconception cohort studies. Women who were attempting to become pregnant completed a validated food frequency questionnaire at baseline. Pregnancy status was updated bimonthly for 12 months or until pregnancy. Fecundability ratios (FR) and 95% confidence intervals were estimated using multivariable proportional probabilities regression. Intakes of total fat and saturated, monounsaturated, polyunsaturated, and omega-6 fatty acids were not appreciably associated with fecundability. TFA intake was associated with reduced fecundability in North American women (for the fourth quartile vs. the first, FR = 0.86, 95% confidence interval (CI): 0.71, 1.04) but not Danish women (for the fourth quartile vs. the first, FR = 1.04, 95% CI: 0.86, 1.25), though intake among Danish women was low. In North America, omega-3 fatty acid intake was associated with higher fecundability, but there was no dose-response relationship (among persons who did not use fish oil supplements: for the fourth quartile vs. the first, FR = 1.40, 95% CI: 1.13, 1.73); no association was found in Danish women, among whom low intake was rare. In the present study, high TFA intake and low omega-3 fatty acid intake were associated with reduced fecundity. PMID- 28595293 TI - Examination of Cause-of-Death Data Quality Among New York City Deaths Due to Cancer, Pneumonia, or Diabetes From 2010 to 2014. AB - The cause-of-death (COD) statement on the standard US death certificate is a valuable tool for public health practice, but its utility is impaired by reporting inaccuracies. To assess the quality of CODs reported in New York City, we developed and applied a quality measure to 3 leading CODs: cancer, pneumonia, and diabetes. The COD quality measure characterized 5 common issues with COD completion: nonspecific conditions as the underlying COD (UCOD); UCOD discrepancies; the presence of only 1 informative cause on the entire certificate; competing causes listed together on 1 line; and clinically improbable sequences. COD statements with more than 1 quality issue were defined as statements of "limited" quality. Of 82,116 deaths with cancer, diabetes, or pneumonia assigned as the UCOD in New York City from 2010 to 2014, 66.8% of pneumonia certificates were classified as "limited" quality as compared with 45.6% of cancer certificates and 32.3% of diabetes certificates. Forty percent of cancer certificates listed only 1 informative condition on the death certificate. Almost half of pneumonia certificates (45.9%) contained only enough information to assign International Classification of Diseases, Tenth Revision, code J18.9 ("unspecified pneumonia") as the UCOD, whereas most diabetes certificates contained UCOD discrepancies (25.2%). These limitations affect the quality of mortality data but may be reduced through quality improvement efforts. PMID- 28595295 TI - Fecal Microbiota Transplantation Is a New Effective Weapon to Fight Multidrug Resistant Bacteria, but Harmonization and More Data Are Needed. PMID- 28595294 TI - Coccidioidomycosis: An underreported cause of death-Arizona, 2008-2013. AB - In Arizona during 1997-2013, coccidioidomycosis increased from 21 to 90 cases/100,000 population, but coccidioidomycosis-associated deaths remained stable at 3-6 deaths/million population. We used the capture-recapture method by using death certificates and hospital discharge data to more fully estimate the total number of coccidioidomycosis-attributable deaths and compared this with published estimates. Death certificates were included if any cause of death included coccidioidomycosis; hospital discharge data deaths were included if any discharge diagnosis included coccidioidomycosis and laboratory confirmation. Among deaths during 2008-2013, we identified 529 coccidioidomycosis-attributable deaths from death certificates and 560 from hospital discharge data, with 251 deaths identified in both databases. Capture-recapture estimated 1,178 total coccidioidomycosis-attributable deaths, compared with 164 deaths (underlying cause of death) or 529 deaths (any cause of death) on death certificates. Coccidioidomycosis-attributable deaths are underreported from two- to sevenfold on Arizona death certificates, demonstrating an education need for death certifiers to document coccidioidomycosis mortality. PMID- 28595292 TI - Neonatal Outcomes Associated With Placental Abruption. AB - Placental abruption (early separation of the placenta) is associated with preterm birth and perinatal mortality, but associations with other neonatal morbidities remain understudied. We examined the association between abruption and newborn outcomes. We analyzed 223,341 singleton deliveries from the Consortium on Safe Labor study, a retrospective, multisite, observational study (2002-2008) of electronic medical records in the United States. Adjusted relative risks, incidence rate ratios, and 99% confidence intervals were estimated. Direct effects attributable to abruption were examined by conditioning on intermediates (preterm birth and small for gestational age) with sensitivity analyses. Incidence of abruption was 1.6% (n = 3,619). Abruption was associated with an elevated risk of newborn resuscitation (relative risk (RR) = 1.5, 99% confidence interval (CI): 1.5, 1.6), apnea (RR = 5.8, 99% CI: 5.1, 6.5), asphyxia (RR = 8.5, 99% CI: 5.7, 11.3), respiratory distress syndrome (RR = 6.5, 99% CI: 5.9, 7.1), neonatal intensive care unit admission (RR = 3.4, 99% CI: 3.2, 3.6), longer intensive care length of stay (incidence rate ratio = 2.0, 99% CI: 1.9, 2.2), stillbirth (RR = 6.3, 99% CI: 4.7, 7.9), and neonatal mortality (RR = 7.6, 99% CI: 5.2, 10.1). In sensitivity analyses, there was a direct effect of abruption associated with increased neonatal risks. These findings expand our knowledge of the association between abruption and perinatal and neonatal outcomes. PMID- 28595296 TI - Impact of time interval and dose rate on cell survival following low-dose fractionated exposures. AB - Enhanced cell lethality, also known as hyper-radiosensitivity, has been reported at low doses of radiation (<=0.5 Gy) in various cell lines, and is expected to be an effective cancer therapy. We conducted this study to examine the impact of time interval and dose rate of low-dose fractionated exposures with a short time interval. We evaluated the cell-survival rates of V79 and A549 cells using clonogenic assays. We performed fractionated exposures in unit doses of 0.25, 0.5, 1.0 and 2.0 Gy. We exposed the cells to 2 Gy of X-rays (i) at dose-rates of 1.0, 1.5 and 2.0 Gy/min at 1-min intervals and (ii) at a dose-rate of 2.0 Gy/min at 10-s, 1-min and 3-min intervals by fractionated exposures. Apoptosis and cell cycle analyses were also evaluated in the fractionated exposures (unit dose 0.25 Gy) and compared with single exposures by using flow cytometry. Both cell-type survival rates with fractionated exposures (unit dose 0.25 Gy) with short time intervals were markedly lower than those for single exposures delivering the same dose. When the dose rates were lower, the cytotoxic effect decreased compared with exposure to a dose-rate of 2.0 Gy/min. On the other hand, levels of apoptosis and cell cycle distribution were not significantly different between low-dose fractionated exposures and single exposures in either cell line. These results indicate that a stronger cytotoxic effect was induced with low-dose fractionated exposures with a short time interval for a given dose due to the hyper-radiosensitivity phenomenon, suggesting that dose rates are important for effective low-dose fractionated exposures. PMID- 28595300 TI - Dragon--NaturallySpeaking. PMID- 28595299 TI - Osteopathic manifesto series XII. PMID- 28595301 TI - Core Curriculum in Primary Care Series: Orthopedics/Sports Medicine. PMID- 28595298 TI - Lowered Rilpivirine Exposure During the Third Trimester of Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women. AB - Background: The use of antiretroviral therapy during pregnancy is important for control of maternal human immunodeficiency virus (HIV) disease and the prevention of perinatal HIV transmission. Physiological changes during pregnancy can reduce antiretroviral exposure. We studied the pharmacokinetics of rilpivirine 25 mg once daily in HIV-1-infected women during late pregnancy. Methods: We conducted a nonrandomized, open-label, multicenter, phase 4 study. HIV-infected pregnant women receiving rilpivirine 25 mg once daily were included. Intensive 24-hour pharmacokinetic sampling was performed in the third trimester and at least 2 weeks postpartum. Pharmacokinetic parameters were calculated by noncompartmental analysis. Results: Sixteen subjects were included. Geometric mean ratios of third trimester vs postpartum were 0.55 (90% confidence interval [CI], .46-.66) for the 24-hour area under the concentration-time curve (AUC0-24h); 0.65 (90% CI, .55 .76) for the maximum concentration; and 0.51 (90% CI, .41-.63) for the minimum observed concentration (Cmin). Four of 16 (25%) subjects had Cmin below the target concentration (0.04 mg/L) in the third trimester of pregnancy. No subtherapeutic levels were observed postpartum. No detectable viral loads were observed in this study. All newborns tested negative for HIV. No birth defects were reported. The median (range, n = 5) rilpivirine cord-to-maternal plasma concentration ratio was 0.50 (range, .35-.81). Conclusions: Rilpivirine exposure is substantially lowered during late pregnancy. Despite lower exposure, virologic suppression was maintained and no perinatal transmission was observed. Overall, these results suggest that rilpivirine 25 mg once daily may be an alternative treatment option for HIV-1-infected pregnant women who are virologically suppressed, in settings where therapeutic drug monitoring and/or close viral load monitoring are feasible to detect suboptimal antiretroviral therapy. Clinical Trials Registration: NCT00825929. PMID- 28595297 TI - FGFR2 mutations in bent bone dysplasia syndrome activate nucleolar stress and perturb cell fate determination. AB - Fibroblast Growth Factor (FGF) signaling promotes self-renewal in progenitor cells by encouraging proliferation and inhibiting cellular senescence. Yet, these beneficial effects can be hijacked by disease-causing mutations in FGF receptor (FGFR) during embryogenesis. By studying dominant FGFR2 mutations that are germline in bent bone dysplasia syndrome (BBDS), we reveal a mechanistic connection between FGFR2, ribosome biogenesis, and cellular stress that links cell fate determination to disease pathology. We previously showed that FGFR2 mutations in BBDS, which amplify nucleolar targeting of FGFR2, activate ribosomal DNA (rDNA) transcription and delay differentiation in osteoprogenitor cells and patient-derived bone. Here we find that the BBDS mutations augment the ability of FGFR2 to recruit histone-remodeling factors that epigenetically activate transcriptionally silent rDNA. Nucleolar morphology is controlled by chromatin structure, and the high levels of euchromatic rDNA induced by the BBDS mutations direct nucleolar disorganization, alter ribosome biogenesis, and activate the Rpl11-Mdm2-p53 nucleolar stress response pathway. Inhibition of p53 in cells expressing the FGFR2 mutations in BBDS rescues delayed osteoblast differentiation, suggesting that p53 activation is an essential pathogenic factor in, and potential therapeutic target for, BBDS. This work establishes rDNA as developmentally regulated loci that receive direct input from FGF signaling to balance self-renewal and cell fate determination. PMID- 28595302 TI - Cross Sectional Anatomy Tutor: An Interactive Course for Anatomy Education and Evaluation. PMID- 28595303 TI - Atlas of the Visible Human Male: Reverse Engineering of the Human Body. PMID- 28595304 TI - From the FDA: Exam guidelines issued for fen-phen users. PMID- 28595305 TI - From the FDA: Anticlotting agent approved. PMID- 28595306 TI - 1997 Editorial Consultants. PMID- 28595307 TI - Journal of the American Osteopathic Association Index to Volume 97. PMID- 28595309 TI - Intra-population variability in the drought response of a beech (Fagus sylvatica L.) population in the southwest of Europe. AB - Phenotypic variability within forest species populations is considered of special relevance for local adaptation under new environments, albeit it has been analyzed to a lesser extent than inter-population phenotypic variability. A common garden study was carried out to assess phenotypic variability in response to water stress in half-sibling families from a marginal population of Fagus sylvatica L. at its south-western range edge distribution in Europe. Two irrigation regimes were applied, well-watered (WW) seedlings and those submitted to weekly cycles of drying-rewatering of growth media. Seedling growth and their leaf functional traits were recorded during the last cycle of water stress. Most of the phenotypic changes were explained by phenotypic plasticity in response to water stress, but there was also a significant effect of family in the expression of some of the studied traits. The relationship of carbon isotope fractioning with gas exchange traits across families under WW conditions did not follow the same pattern as the phenotypic trends. The leaf net photosynthesis across families was modified by the nitrogen content on a leaf mass basis that was in turn correlated positively with leaf nitrogen isotope fractionation. The results point to an important role of leaf nitrogen in determining the intrinsic water use efficiency (WUE) across families. Variation in WUE was ruled mainly by control of stomatal conductance to water vapor under water stress, but by leaf net photosynthesis under wet conditions. Relatively high inter-family phenotypic variability in growth and functional traits were observed. Within-population phenotypic variability, and the plasticity of some of the studied traits, is of fundamental importance to cope with the harsher environments beech will have to endure in the future at different points in its distribution range. PMID- 28595310 TI - Phantom: investigating heterogeneous gene sets in time-course data. AB - Motivation: Gene set analysis is a powerful tool to study the coordinative change of time-course data. However, most existing methods only model the overall change of a gene set, yet completely overlooked heterogeneous time-dependent changes within sub-sets of genes. Results: We have developed a novel statistical method, Phantom, to investigate gene set heterogeneity. Phantom employs the principle of multi-objective optimization to assess the heterogeneity inside a gene set, which also accounts for the temporal dependency in time-course data. Phantom improves the performance of gene set based methods to detect biological changes across time. Availability and implementation: Phantom webpage can be accessed at: http://www.baylorhealth.edu/Phantom . R package of Phantom is available at https://cran.r-project.org/web/packages/phantom/index.html . Contact: jinghua.gu@bswhealth.org. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28595308 TI - Pneumococcal Capsule Synthesis Locus cps as Evolutionary Hotspot with Potential to Generate Novel Serotypes by Recombination. AB - Diversity of the polysaccharide capsule in Streptococcus pneumoniae-main surface antigen and the target of the currently used pneumococcal vaccines-constitutes a major obstacle in eliminating pneumococcal disease. Such diversity is genetically encoded by almost 100 variants of the capsule biosynthesis locus, cps. However, the evolutionary dynamics of the capsule remains not fully understood. Here, using genetic data from 4,519 bacterial isolates, we found cps to be an evolutionary hotspot with elevated substitution and recombination rates. These rates were a consequence of relaxed purifying selection and positive, diversifying selection acting at this locus, supporting the hypothesis that the capsule has an increased potential to generate novel diversity compared with the rest of the genome. Diversifying selection was particularly evident in the region of wzd/wze genes, which are known to regulate capsule expression and hence the bacterium's ability to cause disease. Using a novel, capsule-centered approach, we analyzed the evolutionary history of 12 major serogroups. Such analysis revealed their complex diversification scenarios, which were principally driven by recombination with other serogroups and other streptococci. Patterns of recombinational exchanges between serogroups could not be explained by serotype frequency alone, thus pointing to nonrandom associations between co-colonizing serotypes. Finally, we discovered a previously unobserved mosaic serotype 39X, which was confirmed to carry a viable and structurally novel capsule. Adding to previous discoveries of other mosaic capsules in densely sampled collections, these results emphasize the strong adaptive potential of the bacterium by its ability to generate novel antigenic diversity by recombination. PMID- 28595312 TI - The sub-inhibitory theory for antibiotic growth promoters. AB - Antibiotics have played a critical role in the prevention, control, and treatment of bacterial diseases in humans and animals, and as growth promoters (AGPs) when used at sub-therapeutic concentrations in animal production. Numerous hypotheses have been proposed for the effectiveness of AGPs, which have largely centered on the beneficial modulation of the intestinal microbiota. However, these hypotheses have been doubted by some researchers, as AGPs are fed at concentrations that would typically be below minimum inhibitory concentrations (sub-MIC) for the antibiotic used. More recently, pro-inflammatory immune responses have been associated with poor growth performance, and this, along with reported direct, anti-inflammatory effects of some antibiotics, have led to suggestions that reducing the nutrient cost of (intestinal) inflammation may explain the growth promoting or permitting effect of AGPs. However, doubts about antibacterial effects of AGPs, and the search for alternative explanations, overlook the sub MIC effects of antibiotics. This paper summarizes some of the reported sub-MIC effects of antibiotics and considers these in the context of helping to explain the mode of action of AGPs and effects seen in studies in vivo. This leads to suggestions for the features that alternatives to AGPs could exhibit to achieve similar performance efficacy as AGPs. PMID- 28595311 TI - Evaluation of rectum and bladder dose accumulation from external beam radiotherapy and brachytherapy for cervical cancer using two different deformable image registration techniques. AB - We evaluated dose-volume histogram (DVH) parameters based on deformable image registration (DIR) between brachytherapy (BT) and external beam radiotherapy (EBRT) that included a center-shielded (CS) plan. Eleven cervical cancer patients were treated with BT, and their pelvic and CS EBRT were studied. Planning CT images for EBRT and BT (except for the first BT, used as the reference image) were deformed with DIR to reference image. We used two DIR parameter settings: intensity-based and hybrid. Mean Dice similarity coefficients (DSCs) comparing EBRT with the reference for the uterus, rectum and bladder were 0.81, 0.77 and 0.83, respectively, for hybrid DIR and 0.47, 0.37 and 0.42, respectively, for intensity-based DIR (P < 0.05). D1 cm3 for hybrid DIR, intensity-based DIR and DVH addition were 75.1, 81.2 and 78.2 Gy, respectively, for the rectum, whereas they were 93.5, 92.3 and 94.3 Gy, respectively, for the bladder. D2 cm3 for hybrid DIR, intensity-based DIR and DVH addition were 70.1, 74.0 and 71.4 Gy, respectively, for the rectum, whereas they were 85.4, 82.8 and 85.4 Gy, respectively, for the bladder. Overall, hybrid DIR obtained higher DSCs than intensity-based DIR, and there were moderate differences in DVH parameters between the two DIR methods, although the results varied among patients. DIR is only experimental, and extra care should be taken when comparing DIR-based dose values with dose-effect curves established using DVH addition. Also, a true evaluation of DIR-based dose accumulation would require ground truth data (e.g. measurement with physical phantom). PMID- 28595313 TI - The Genome Sizes of Ostracod Crustaceans Correlate with Body Size and Evolutionary History, but not Environment. AB - Within animals, a positive correlation between genome size and body size has been detected in several taxa but not in others, such that it remains unknown how pervasive this pattern may be. Here, we provide another example of a positive relationship in a group of crustaceans whose genome sizes have not previously been investigated. We analyze genome size estimates for 46 species across the 2 most diverse orders of Class Ostracoda, commonly known as seed shrimps, including 29 new estimates made using Feulgen image analysis densitometry and flow cytometry. Genome sizes in this group range ~80-fold, a level of variability that is otherwise not seen in crustaceans with the exception of some malacostracan orders. We find a strong positive correlation between genome size and body size across all species, including after phylogenetic correction. We additionally detect evidence of XX/XO sex determination in 3 species of marine ostracods where male and female genome sizes were estimated. On average, genome sizes are larger but less variable in Order Myodocopida than in Order Podocopida, and marine ostracods have larger genomes than freshwater species, but this appears to be explained by phylogenetic inertia. The relationship between phylogeny, genome size, body size, and habitat is complex in this system and provides a baseline for future studies examining the interactions of these biological traits. PMID- 28595315 TI - DETERMINATION OF LOCAL LEVELS OF RADIATION EXPOSURE IN ORTHOPEDIC INTERVENTIONS USING STRUCTURED DOSE REPORT DATA DRAWN FROM THE HOSPITAL PICTURE ARCHIVING AND COMMUNICATION SYSTEM. AB - The aim of this study was to determine the dosimetric parameters of radiation to which orthopedic in-patients are exposed, using data drawn from the hospital's picture archiving and communication system. Data for 310 patients, relating to seven different anatomical districts, were examined. Femoral operations were divided into three types. The 75th percentile dose at the interventional reference point (IRP) exceeded 2 mGy only for femoral interventions (4.6-6.2 mGy) with 75th percentile kerma-area product (KAP) values ranging from 84.8 to 109.1 MUGy m2. The 75th percentile fluoroscopy time was longer than 1 min only for the humeral operations and the three types of femoral intervention. In general, the radiation exposure times and doses recorded in our institute were lower than those reported in the literature. The correlation between KAP and kerma at the IRP was very strong for all districts (R > 0.80). The correlation between KAP and fluoroscopy times was very strong for seven cases (R > 0.80), and strong for two (0.60 < R < 0.79). PMID- 28595314 TI - A combined meta-barcoding and shotgun metagenomic analysis of spontaneous wine fermentation. AB - Wine is a complex beverage, comprising hundreds of metabolites produced through the action of yeasts and bacteria in fermenting grape must. Commercially, there is now a growing trend away from using wine yeast (Saccharomyces) starter cultures, toward the historic practice of uninoculated or "wild" fermentation, where the yeasts and bacteria associated with the grapes and/or winery perform the fermentation. It is the varied metabolic contributions of these numerous non Saccharomyces species that are thought to impart complexity and desirable taste and aroma attributes to wild ferments in comparison to their inoculated counterparts. To map the microflora of spontaneous fermentation, metagenomic techniques were employed to characterize and monitor the progression of fungal species in 5 different wild fermentations. Both amplicon-based ribosomal DNA internal transcribed spacer (ITS) phylotyping and shotgun metagenomics were used to assess community structure across different stages of fermentation. While providing a sensitive and highly accurate means of characterizing the wine microbiome, the shotgun metagenomic data also uncovered a significant overabundance bias in the ITS phylotyping abundance estimations for the common non-Saccharomyces wine yeast genus Metschnikowia. By identifying biases such as that observed for Metschnikowia, abundance measurements from future ITS phylotyping datasets can be corrected to provide more accurate species representation. Ultimately, as more shotgun metagenomic and single-strain de novo assemblies for key wine species become available, the accuracy of both ITS amplicon and shotgun studies will greatly increase, providing a powerful methodology for deciphering the influence of the microbial community on the wine flavor and aroma. PMID- 28595316 TI - Developing a local antimicrobial resistance action plan: the Cornwall One Health Antimicrobial Resistance Group. AB - Objectives: The UK Five Year Antimicrobial Resistance (AMR) Strategy was published in September 2013 and recommended a One Health approach emphasizing the importance of collaboration to tackle AMR. We describe the inauguration of what we believe to be the first regional One Health group established in the UK. The purpose of the group was to ensure the implementation of a coordinated Cornwall wide response to the UK AMR Strategy and we describe the outputs of the group to date. Methods: The Cornwall Antimicrobial Resistance Group was set up as a sub group of the Health & Wellbeing Board's Health Protection Committee. Stakeholders reviewed the key objectives set out within the Five Year AMR strategy, identified local priorities and existing work streams within Cornwall, and completed a gap analysis. The annual work plan was developed from the gap analysis and provided a foundation for improved coordination of One Health antimicrobial stewardship (AMS) activity in Cornwall. Results: To date, outputs from the group can be arranged under the following themes: education and engagement with the public; education and engagement with healthcare workers and veterinarians; and a comprehensive AMS programme for all sectors. The group continues to grow in size with wider stakeholder engagement and increased variety of work streams. Conclusions: This unique group facilitates discussions across sectors, which has enabled the sharing of knowledge, ideas and resources, stimulated local AMS initiatives, and ensured a platform for the development of future AMR and AMS work. PMID- 28595317 TI - Relative Fundamental Frequency Distinguishes Between Phonotraumatic and Non Phonotraumatic Vocal Hyperfunction. AB - Purpose: The purpose of this article is to examine the ability of an acoustic measure, relative fundamental frequency (RFF), to distinguish between two subtypes of vocal hyperfunction (VH): phonotraumatic (PVH) and non-phonotraumatic (NPVH). Method: RFF values were compared among control individuals with typical voices (N = 49), individuals with PVH (N = 54), and individuals with NPVH (N = 35). Results: Offset Cycle 10 RFF differed significantly among all 3 groups with values progressively decreasing for controls, individuals with NPVH, and individuals with PVH. Individuals with PVH also had lower Offset Cycles 8 and 9 relative to the other 2 groups and lower RFF values for Offset Cycle 7 relative to controls. There was also a trend for lower Onset Cycle 1 RFF values for the PVH group compared with the NPVH group. Conclusions: RFF values were significantly different between controls and individuals with VH and also between the two subtypes of VH. This study adds further support to the notion that the differences between these two subsets of VH may be functional as well as structural. PMID- 28595319 TI - Distribution and developmental changes of ghrelin-immunopositive cells in the pancreas of African ostrich chicks (Struthio camelus). AB - Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHS R), is produced by multiple cell types and affects feeding behavior, metabolic regulation, and energy balance. In the mammalian pancreas, the types of endocrine cells that are immunoreactive to ghrelin vary. However, little was known about its distribution and developmental changes in the pancreas of African ostrich chicks (Struthio camelus). In the present study, the distribution, morphological characteristics, and developmental changes of ghrelin-immunopositive (ghrelin-ip) cells in the pancreas of African ostrich chicks were investigated using immunohistochemistry. Ghrelin-ip cells were found in both the pancreatic islets and acinar cell regions. The greatest number of ghrelin-ip cells were found in the pancreatic islets, and were primarily observed at the periphery of the islets; some ghrelin-ip cells were also located in the central portion of the pancreatic islets. Interestingly, from postnatal d 1 to d 90, there was a steady decrease in the number of ghrelin-ip cells in the pancreatic islets and acinar cell regions. These results clearly demonstrated that ghrelin-ip cells exist and decreased with age in the African ostrich pancreas from postnatal d 1 to d90. Thus, these findings indicated that ghrelin may be involved in the development of the pancreas in the African ostrich. PMID- 28595320 TI - Improvement in Activities of Daily Living Among Danish Centenarians?-A Comparative Study of Two Centenarian Cohorts Born 20 Years Apart. AB - Background: With the continued rise in the proportion of the oldest-old in high income countries, it is of interest to know whether the functional health of today's oldest-olds is better or worse than in previous cohorts. Using two Danish centenarian birth cohorts born 20 years apart we aimed at investigating if the later born cohort had better functioning in terms of activities of daily living (ADL). Methods: Identification, methodology, and assessment instruments were identical in the 1895-West and 1915-West Birth Cohort Studies: All persons living in the western part of Denmark and turning 100 years old in 1995 and 2015, respectively. Data were collected through structured in-home interviews. Participation rates were 74% (n = 106) and 79% (n = 238), respectively. Results: The proportion of nondisabled women of the 1915-West cohort was more than twice as high compared to the 1895-West cohort and with corresponding lower proportions of moderately and severely disabled persons (17% vs 7%, 33% vs 40% and 50% vs 53% in the 1915-West and 1895-West cohorts, respectively, p = .047). Only nonsignificant improvements were seen among men in the 1915-West cohort. In both sexes, considerably higher proportions of the latest cohort used assistive devices than the former (statistically significant for the majority of assistive devices). Conclusion: This comparative study shows improvements in reported ADL in the later born cohort of centenarians, even though only significant among women. As women constitute the majority of the oldest-olds, our findings are encouraging from a public health care view. PMID- 28595323 TI - Periorbital and Temporal Anatomy, "Targeted Fat Grafting," and How a Novel Circulatory System in Human Peripheral Nerves and Brain May Help Avoid Nerve Injury and Blindness During Routine Facial Augmentation. PMID- 28595321 TI - Mitochondrial deficits and abnormal mitochondrial retrograde axonal transport play a role in the pathogenesis of mutant Hsp27-induced Charcot Marie Tooth Disease. AB - Mutations in the small heat shock protein Hsp27, encoded by the HSPB1 gene, have been shown to cause Charcot Marie Tooth Disease type 2 (CMT-2) or distal hereditary motor neuropathy (dHMN). Protein aggregation and axonal transport deficits have been implicated in the disease. In this study, we conducted analysis of bidirectional movements of mitochondria in primary motor neuron axons expressing wild type and mutant Hsp27. We found significantly slower retrograde transport of mitochondria in Ser135Phe, Pro39Leu and Arg140Gly mutant Hsp27 expressing motor neurons than in wild type Hsp27 neurons, although anterograde movement velocities remained normal. Retrograde transport of other important cargoes, such as the p75 neurotrophic factor receptor was minimally altered in mutant Hsp27 neurons, implicating that axonal transport deficits primarily affect mitochondria and the axonal transport machinery itself is less affected. Investigation of mitochondrial function revealed a decrease in mitochondrial membrane potential in mutant Hsp27 expressing motor axons, as well as a reduction in mitochondrial complex 1 activity, increased vulnerability of mitochondria to mitochondrial stressors, leading to elevated superoxide release and reduced mitochondrial glutathione (GSH) levels, although cytosolic GSH remained normal. This mitochondrial redox imbalance in mutant Hsp27 motor neurons is likely to cause low level of oxidative stress, which in turn will contribute to, and indeed may be the underlying cause of the deficits in mitochondrial axonal transport. Together, these findings suggest that the mitochondrial abnormalities in mutant Hsp27-induced neuropathies may be a primary cause of pathology, leading to further deficits in the mitochondrial axonal transport and onset of disease. PMID- 28595322 TI - The Effects of Bit Wear on Respirable Silica Dust, Noise and Productivity: A Hammer Drill Bench Study. AB - Objectives: Hammer drills are used extensively in commercial construction for drilling into concrete for tasks including rebar installation for structural upgrades and anchor bolt installation. This drilling task can expose workers to respirable silica dust and noise. The aim of this pilot study was to evaluate the effects of bit wear on respirable silica dust, noise, and drilling productivity. Method: Test bits were worn to three states by drilling consecutive holes to different cumulative drilling depths: 0, 780, and 1560 cm. Each state of bit wear was evaluated by three trials (nine trials total). For each trial, an automated laboratory test bench system drilled 41 holes 1.3 cm diameter, and 10 cm deep into concrete block at a rate of one hole per minute using a commercially available hammer drill and masonry bits. During each trial, dust was continuously captured by two respirable and one inhalable sampling trains and noise was sampled with a noise dosimeter. The room was thoroughly cleaned between trials. Results: When comparing results for the sharp (0 cm) versus dull bit (1560 cm), the mean respirable silica increased from 0.41 to 0.74 mg m-3 in sampler 1 (P = 0.012) and from 0.41 to 0.89 mg m-3 in sampler 2 (P = 0.024); levels above the NIOSH recommended exposure limit of 0.05 mg m-3. Likewise, mean noise levels increased from 112.8 to 114.4 dBA (P < 0.00001). Drilling productivity declined with increasing wear from 10.16 to 7.76 mm s-1 (P < 0.00001). Discussion: Increasing bit wear was associated with increasing respirable silica dust and noise and reduced drilling productivity. The levels of dust and noise produced by these experimental conditions would require dust capture, hearing protection, and possibly respiratory protection. The findings support the adoption of a bit replacement program by construction contractors. PMID- 28595318 TI - Mediterranean diet and inflammaging within the hormesis paradigm. AB - A coherent set of epidemiological data shows that the Mediterranean diet has beneficial effects capable of preventing a variety of age-related diseases in which low-grade, chronic inflammation/inflammaging plays a major role, but the underpinning mechanism(s) is/are still unclear. It is suggested here that the Mediterranean diet can be conceptualized as a form of chronic hormetic stress, similar to what has been proposed regarding calorie restriction, the most thoroughly studied nutritional intervention. Data on the presence in key Mediterranean foods of a variety of compounds capable of exerting hormetic effects are summarized, and the mechanistic role of the nuclear factor erythroid 2 pathway is highlighted. Within this conceptual framework, particular attention has been devoted to the neurohormetic and neuroprotective properties of the Mediterranean diet, as well as to its ability to maintain an optimal balance between pro- and anti-inflammaging. Finally, the European Commission-funded project NU-AGE is discussed because it addresses a number of variables not commonly taken into consideration, such as age, sex, and ethnicity/genetics, that can modulate the hormetic effect of the Mediterranean diet. PMID- 28595324 TI - Bacteriophage use to control Salmonella biofilm on surfaces present in chicken slaughterhouses. AB - Foodborne diseases represent a major risk to public health worldwide. Pathogenic bacteria can live in the form of biofilm within the food industry, providing a permanent source of contamination. The aim of this study was to evaluate the influence of the types of adhesion surfaces on Salmonella biofilm formation at eight different times, and analyze the action time of a bacteriophage pool on established biofilms. Most of the samples used were classified as weak biofilm producers, with serovars Enteritidis and Heidelberg showing the highest frequency of biofilm formation. Glass and stainless steel surfaces significantly favored biofilm formation at 60 and 36 h of incubation respectively, but the polyvinyl chloride surface did not favor biofilm production, suggesting that the type of material may interfere with production. The bacteriophage pool action period focused on 3 h, but treatment of 9 h on glass surface biofilms was superior to other treatments because it affected the largest number of samples. These results suggests that some surface types and Salmonella serotypes may promote biofilm formation and indicate bacteriophages as an alternative to control biofilms. But further studies are required to prove the effectiveness and safety of bacteriophage therapy as an alternative in the antimicrobial control in the processing plants. PMID- 28595326 TI - Multiarterial grafts improve the rate of early major adverse cardiac and cerebrovascular events in patients undergoing coronary revascularization: analysis of 12 615 patients with multivessel disease. AB - OBJECTIVES: Our goal was to compare the rates of in-hospital and 30-day major adverse cardiac and cerebrovascular events (MACCE) including death, stroke, myocardial infarction and repeat revascularization in patients with multivessel disease undergoing multiarterial (MultArt) coronary artery bypass grafting (CABG) with the left internal mammary artery/saphenous vein (LIMA/SV) CABG or percutaneous coronary intervention (PCI). METHODS: From 1 January 1993 to 31 December 2009, 12 615 consecutive patients underwent isolated primary CABG (n = 6667) with LIMA/SV (n = 5712) or MultArt (n = 955) or were treated by PCI (n = 5948) with balloon angioplasty (n = 1020), bare metal stent (n = 3242), and drug eluting stent (n = 1686). We excluded patients with acute myocardial infarction. We matched the CABG group with the 3 PCI subgroups, and the PCI group with the 2 CABG subgroups. Multivariable analyses were used to evaluate the impact of CABG versus PCI and their subgroups on early MACCE. RESULTS: Unadjusted early MACCE were lower for MultArt (1.5%) than for LIMA/SV (4.5%, P < 0.001) and PCI (8.5%, P < 0.001). In matched analysis, CABG had lower early MACCE versus balloon angioplasty (4.7% vs 13.2%, P < 0.001), bare metal stent (4.3% vs 8.3%, P < 0.001), and drug-eluting stent (2.9% vs 5.5%, P = 0.008), as well as LIMA/SV versus PCI (4.6% vs 9.2%, P < 0.001) and MultArt versus PCI (1.8% vs 7.8%, P < 0.001). Stroke rate was similar in MultArt versus PCI (0.8% vs 0.3%, P = 0.18) but higher with LIMA/SV versus PCI (2.3% vs 0.4%, P < 0.001). In multivariable analysis, PCI (odds ratio 4.53, 95% confidence interval: 2.62-7.83; P < 0.001) and LIMA/SV (odds ratio 2.04, 95% confidence interval: 1.18-3.53; P < 0.011) were strong predictors of early MACCE compared with MultArt. CONCLUSIONS: MultArt confers the lowest rate of early MACCE. PMID- 28595325 TI - Maternal Lifetime Stress and Prenatal Psychological Functioning and Decreased Placental Mitochondrial DNA Copy Number in the PRISM Study. AB - Psychosocial stress contributes to placental oxidative stress. Mitochondria are vulnerable to oxidative stress, which can lead to changes in mitochondrial DNA copy number (mtDNAcn). We examined associations of maternal lifetime stress, current negative life events, and depressive and posttraumatic-stress-disorder symptom scores with placental mtDNAcn in a racially/ethnically diverse sample (n = 147) from the Programming of Intergenerational Stress Mechanisms (PRISM) study (Massachusetts, March 2011 to August 2012). In linear regression analyses adjusted for maternal age, race/ethnicity, education, prenatal fine particulate matter exposure, prenatal smoking exposure, and the sex of the child, all measures of stress were associated with decreased placental mtDNAcn (all P values < 0.05). Weighted-quantile-sum (WQS) regression showed that higher lifetime stress and depressive symptoms accounted for most of the effect on mtDNAcn (WQS weights: 0.25 and 0.39, respectively). However, among white individuals, increased lifetime stress and posttraumatic stress disorder symptoms explained the majority of the effect (WQS weights: 0.20 and 0.62, respectively) while among nonwhite individuals, lifetime stress and depressive symptoms accounted for most of the effect (WQS weights: 0.27 and 0.55, respectively). These analyses are first to link increased maternal psychosocial stress with reduced placental mtDNAcn and add to literature documenting racial/ethnic differences in the psychological sequelae of chronic stress that may contribute to maternal-fetal health. PMID- 28595327 TI - Parallel Evolution of Metazoan Mitochondrial Proteins. AB - Amino acid propensities at amino acid sites change with time due to epistatic interactions or changing environment, affecting the probabilities of fixation of different amino acids. Such changes should lead to an increased rate of homoplasies (reversals, parallelisms, and convergences) at closely related species. Here, we reconstruct the phylogeny of twelve mitochondrial proteins from several thousand metazoan species, and measure the phylogenetic distances between branches at which either the same allele originated repeatedly due to homoplasies, or different alleles originated due to divergent substitutions. The mean phylogenetic distance between parallel substitutions is ~20% lower than the mean phylogenetic distance between divergent substitutions, indicating that a variant fixed in a species is more likely to be deleterious in a more phylogenetically remote species, compared with a more closely related species. These findings are robust to artefacts of phylogenetic reconstruction or of pooling of sites from different conservation classes or functional groups, and imply that single-position fitness landscapes change at rates similar to rates of amino acid changes. PMID- 28595328 TI - Genetic Lineage Tracing in Taste Tissues Using Sox2-CreERT2 Strain. AB - Taste cells in taste buds are epithelial sensory cells. Old taste bud cells die and are replaced by new ones generated from taste stem cells. Identifying and characterizing adult taste stem cells is therefore important to understand how peripheral taste tissues are maintained. SOX2 is expressed in oral epithelium including gustatory papillae and has been proposed to be a marker of adult taste stem/progenitor cells. Nevertheless, this hypothesis has never been directly tested. Here, by single-color genetic lineage tracing using Sox2-CreERT2 strain, we reveal that all types of taste bud cells distributed throughout the oral epithelium are derived from stem cells that express SOX2. Short-term tracing shows that SOX2-positive taste stem cells actively supply taste bud cells. At the base of epithelium outside taste buds are distributed proliferation marker- and SOX2-positive cells. Consistently, taste stem cells identified by Lgr5 expression in the circumvallate papillae also express SOX2. Together, taste stem cells distributed in oral epithelia express SOX2. PMID- 28595329 TI - A mechanism for a single nucleotide intron shift. AB - Spliceosomal introns can occupy nearby rather than identical positions in orthologous genes (intron sliding or shifting). Stwintrons are complex intervening sequences, where an 'internal' intron interrupts one of the sequences essential for splicing, generating after its excision, a newly formed canonical intron defined as 'external'. In one experimentally demonstrated configuration, two alternatively excised internal introns, overlapping by one G, disrupt respectively the donor and the acceptor sequence of an external intron, leading to mRNAs encoding identical proteins. In a gene encoding a DHA1 antiporter in Pezizomycotina, we find a variety of predicted intron configurations interrupting the DNA stretch encoding a conserved peptidic sequence. Some sport a stwintron where the internal intron interrupts the donor of the external intron (experimentally confirmed for Aspergillus nidulans). In others, we found and demonstrate (for Trichoderma reesei) alternative, overlapping internal introns. Discordant canonical introns, one nt apart, are present in yet other species, exactly as predicted by the alternative loss of either of the internal introns at the DNA level from an alternatively spliced stwintron. An evolutionary pathway of 1 nt intron shift, involving an alternatively spliced stwintron intermediate is proposed on the basis of the experimental and genomic data presented. PMID- 28595331 TI - The Use of Single Stent-Assisted Coiling in Treatment of Bifurcation Aneurysms: A Multicenter Cohort Study With Proposal of a Scoring System to Predict Complete Occlusion. AB - BACKGROUND: The development of stent-assisted coiling has allowed for the endovascular treatment of wide-necked bifurcation aneurysms. A variety of options exist, and little is known about the optimal stent configuration in this setting. We report a large multicenter experience of stent-assisted coiling of bifurcations aneurysms using a single stent, with attention to factors predisposing to aneurysm recanalization. OBJECTIVE: To assess the safety and efficacy of single stent-assisted coiling, in addition to analyzing the factors associated with recanalization, and proposal of a predictive scoring scale. METHODS: A multicenter retrospective analysis of bifurcation aneurysms treated with a single stent-assisted coiling technique between 2007 and 2015 was performed. Clinical and radiographic data were collected and used to develop a scoring system to predict aneurysm occlusion. RESULTS: A total of 74 bifurcation aneurysms were treated with single stent-assisted coiling. At a median follow-up of 15.2 mo, complete occlusion or remnant neck was achieved in 90.6% of aneurysms. Aneurysm location, maximal diameter, neck size, and alpha angle were predictive of aneurysm occlusion at last follow-up. A scoring system to predict complete occlusion based on these factors was developed. An increasing score correlated with a higher rate of complete occlusion. CONCLUSION: The treatment of bifurcation aneurysm using single stent technique for stent-assisted coiling is safe and effective. Complete occlusion or remnant neck occlusion was achieved in 90.6% of cases. Class III aneurysms can be effectively treated using a single stent, while class I may require Y-stent technique. PMID- 28595330 TI - Contribution of Progranulin to Protective Lung Immunity During Bacterial Pneumonia. AB - Background: Progranulin (PGRN) is an important immunomodulatory factor in a variety of inflammatory diseases. However, its role in pulmonary immunity against bacterial infection remains unknown. Methods: Pneumonia was induced in PGRN deficient and normal wild-type mice using Pseudomonas aeruginosa or Staphylococcus aureus, and we assessed the effects of PGRN on survival, bacterial burden, cytokine and chemokine production, and pulmonary leukocyte recruitment after bacterial pneumonia. Results: Patients with community-acquired pneumonia displayed elevated PGRN levels. Likewise, mice with Gram-negative and Gram positive pneumonia had increased PGRN production in the lung and circulation. Progranulin deficiency led to increased bacterial growth and dissemination accompanied by enhanced lung injury and mortality in bacterial pneumonia, which was associated with impaired recruitment of macrophages and neutrophils in the lung. The reduced number of pulmonary macrophages and neutrophils observed in PGRN-deficient mice was related to a reduction of CCL2 and CXCL1 in the lungs after bacterial pneumonia. Importantly, therapeutic administration of PGRN improved mortality in severe bacterial pneumonia. Conclusions: This study supports a novel role for PGRN in pulmonary immunity and suggests that treatment with PGRN may be a viable therapy for bacterial pneumonia. PMID- 28595333 TI - The Rise of the Current Mortality Pattern of the United States, 1890-1930. AB - This article examines how the epidemiologic transition and the reduction of the urban mortality penalty gave rise to the current mortality regime of the United States and demonstrates how the 1918 influenza pandemic signaled its advent. This article approaches those issues through the analysis of urban-rural mortality differentials from 1890 to 1930. Until 1910, infectious diseases dwarfed degenerative diseases in leading causes of death, and generally, the more urban the location was, the higher infectious disease and overall death rates were-a direct relationship. But by 1930, degenerative diseases had eclipsed infectious diseases, and infectious disease mortality had ceased to differ between cities and rural areas. The 1918 influenza pandemic broke out toward the end of these changes, and the larger the city was, the lower influenza and overall death rates were in that year-an inverse relationship. Such gradations characterized a new mortality regime emerging in the late 1910s and foreshadowed urban-rural mortality differentials in 1930 among persons aged 45 years or older, the group whose high rates of degenerative disease death would symbolize that regime. Thus, intertwined changes in the late 19th and early 20th centuries-a shift in leading causes of death from infectious diseases to degenerative diseases and a concomitant shift from a direct relationship to an inverse relationship between urban environment and mortality-produced the current mortality regime of the United States. PMID- 28595332 TI - Ability to Discriminate Between Sustainable and Unsustainable Heat Stress Exposures-Part 1: WBGT Exposure Limits. AB - Objectives: Heat stress exposure limits based on wet-bulb globe temperature (WBGT) were designed to limit exposures to those that could be sustained for an 8 h day using limited data from Lind in the 1960s. In general, Sustainable exposures are heat stress levels at which thermal equilibrium can be achieved, and Unsustainable exposures occur when there is a steady increase in core temperature. This paper addresses the ability of the ACGIH(r) Threshold Limit Value (TLV(r)) to differentiate between Sustainable and Unsustainable heat exposures, to propose alternative occupational exposure limits, and ask whether an adjustment for body surface area improves the exposure decision. Methods: Two progressive heat stress studies provided data on 176 trials with 352 pairs of Sustainable and Unsustainable exposures over a range of relative humidities and metabolic rates using 29 participants wearing woven cotton clothing. To assess the discrimination ability of the TLV, the exposure metric was the difference between the observed WBGT and the TLV adjusted for metabolic rate. Conditional logistic regression models and receiver operating characteristic curves (ROC) along with ROC's area under the curve (AUC) were used. Four alternative models for an occupational exposure limit were also developed and compared to the TLV. Results: For the TLV, the odds ratio (OR) for Unsustainable was 2.5 per 1 degrees C-WBGT [confidence interval (CI) 2.12-2.88]. The AUC for the TLV was 0.85 (CI 0.81-0.89). For the alternative models, the ORs were also about 2.5/ degrees C WBGT, with AUCs between 0.84 and 0.88, which were significantly different from the TLV's AUC but have little practical difference. Conclusions: This study (1) confirmed that the TLV is appropriate for heat stress screening; (2) demonstrated the TLV's discrimination accuracy with an ROC AUC of 0.85; and (3) established the OR of 2.5/ degrees C-WBGT for unsustainable exposures. The TLV has high sensitivity, but its specificity is very low, which is protective. There were no important improvements with alternative exposure limits, and there was weak evidence to support metabolic rate normalized to body surface area. In sum, the TLV is protective with an appropriate margin of safety for relatively constant occupational exposures to heat stress. PMID- 28595334 TI - An Olympic Legacy? Did the Urban Regeneration Associated With the London 2012 Olympic Games Influence Adolescent Mental Health? AB - Public expenditure on large events such as the London 2012 Olympic Games is often justified by the potential legacy of urban regeneration and its associated health and well-being benefits for local communities. In the Olympic Regeneration in East London Study, we examined whether there was an association between urban regeneration related to the 2012 Games and improved mental health in young people. Adolescents aged 11-12 years attending schools in the Olympic host borough of Newham in London or in 3 adjacent comparison London boroughs completed a survey before the 2012 Games and 6 and 18 months after the Games (in 2013 and 2014, respectively). Changes in depressive symptoms and well-being between baseline and each follow-up were examined. A total of 2,254 adolescents from 25 randomly selected schools participated. Adolescents from Newham were more likely to have remained depressed between baseline and the 6- and 18-month follow-up surveys (for 6-month follow-up, relative risk = 1.78, 95% confidence interval: 1.12, 2.83; for 18-month follow-up, relative risk = 1.93, 95% confidence interval: 1.01, 3.70) than adolescents from the comparison boroughs. No differences in well-being were observed. There was little evidence that urban regeneration had any positive influence on adolescent mental health and some suggestion that regeneration may have been associated with maintenance of depressive symptoms. Such programs may have limited short-term impact on the mental health of adolescents. PMID- 28595335 TI - RESULTS FROM A NEW METHOD TO ASSESS THE OCCUPATIONAL LENS DOSE IN INTERVENTIONAL RADIOLOGY. AB - Interventional radiology procedures have always been of particular concern because of the potential high dose to the workers. Special attention has recently been given to the lens dose: in 2011 the ICRP issued the recommendation 'Statement on Tissue Reactions' where a new limit of 20 mSv in a year, averaged over defined periods of 5 years, is given. Due to the impossibility of measuring the dose directly on the eye, there is not still a general consensus on a standardized methodology to assess the lens dose, which should be at the same time reliable, robust and simple to implement in practice. The procedure described here aims to assess the lens dose using the Hp(0.07) equivalent dose measured with a dosimeter worn at chest level above the lead apron, through a correlation with the total KAP per procedure and considering the type of the protection tools used during each procedure: glasses (with lateral shields), ceiling screen, both or neither of them and the frequency of their use. PMID- 28595337 TI - Response to "The Association of Progressive Tension Sutures and Drains Seems to Decrease the Drainage Output and Seroma Formation in Abdominoplasty". PMID- 28595336 TI - Changes in serum interleukin-8 (IL-8) levels reflect and predict response to anti PD-1 treatment in melanoma and non-small-cell lung cancer patients. AB - Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. Results: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P = 0.004). In non responders, IL-8 levels significantly increased between baseline and progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients. PMID- 28595339 TI - Cardiac resynchronization therapy and electrical storm: results of the OBSERVational registry on long-term outcome of ICD patients (OBSERVO-ICD). AB - Aims: Electrical storm (ES) is a condition defined as three or more episodes of ventricular fibrillation (VF) or ventricular tachycardia (VT) within 24 h, and usually coexist with advanced heart failure in patients with structural heart disease. The aim of the present study is to test whether cardiac resynchronization therapy (CRT) can be associated with a lower incidence of ES. Methods and results: The OBSERVO-ICD (NCT02735811) is a multicentre, retrospective registry, enrolling all consecutive patients undergoing ICD or CRT D implantation from 2010 to 2012 in five Italian high-volume arrhythmia centres. Propensity score matching was used to compare two equally sized cohorts of ICD and CRT-D patients with similar characteristics. The primary endpoint was the time free from ES. Secondary endpoints were time free from unclustered VT/VF episodes and time free from ES in CRT-D patients according to clinical or echographic response. CRT-D was associated with a 45% relative risk reduction in ES when compared with ICD (5.6% vs. 12.3%; log rank P = 0.014). CRT-responders presented lower rates of ES when compared with non-responders and negative responders according to both clinical and echographic criteria (log-rank P = 0.017 and 0.023, respectively). No ES was detected in any of the 133 full responders to CRT-D. Clinical and echographic positive responses, but not CRT implant per se, were associated with lower estimate rates of unclustered VTs/VFs. Conclusion: Patients with CRT had a lower incidence of ES when compared with propensity-matched ICD patients. The long-term benefit of CRT seems to be due to the improved haemodynamics, as CRT-responders performed markedly better over a long-term follow-up. PMID- 28595338 TI - Influence of Temperature on the Reproductive and Developmental Biology of Ontsira mellipes (Hymenoptera: Braconidae): Implications for Biological Control of the Asian Longhorned Beetle (Coleoptera: Cerambycidae). AB - Ontsira mellipes Ashmead (Hymenoptera: Braconidae) is a North American parasitoid species that develops on the invasive pest, Anoplophora glabripennis (Moltschulsky) (Coleoptera: Cerambycidae), under laboratory conditions and is currently being considered as a potential new-association biocontrol agent. To develop mass-rearing protocols and field-release strategies for this parasitoid, information on its reproductive biology in relation to temperature is needed. We determined the effect of temperature (10, 15, 20, 25, and 30 degrees C) on development, survivorship, and sex ratio, and its effect on the longevity, fecundity, and host attack rates (parasitism) of adults. Developmental time for parasitoid eggs to pupae decreased from 26.7 d to 6.1 d as temperature increased from 10 degrees C to 30 degrees C. While no pupae eclosed as adults at 10 degrees C, time of adult emergence from pupae decreased from 39.7 d to 12.2 d as temperature increased from 15 degrees C to 30 degrees C. Based on estimated lower development temperature threshold (11.1 degrees C), the degree-days required for one generation was estimated at 342.9. When female parasitoids were provided with host larvae, parasitism occurred at all temperatures and was maximized at 25 degrees C. Additionally, increasing temperatures significantly reduced the preoviposition period and longevity of female O. mellipes. In addition, combining these results with temperature data from areas in the United States currently infested with A. glabripennis, we estimated that O. mellipes can complete 1.2-3.7 generations per year. Findings from this study may be considered for the future development of effective mass rearing and augmentative release strategies of O. mellipes for biological control of A. glabripennis. PMID- 28595340 TI - Ability to Discriminate Between Sustainable and Unsustainable Heat Stress Exposures-Part 2: Physiological Indicators. AB - Objectives: There are times when it is not practical to assess heat stress using environmental metrics and metabolic rate, and heat strain may provide an alternative approach. Heat strain indicators have been used for decades as tools for monitoring physiological responses to work in hot environments. Common indicators of heat strain are body core temperature (assessed here as rectal temperature Tre), heart rate (HR), and average skin temperature (Tsk). Data collected from progressive heat stress trials were used to (1) demonstrate if physiological heat strain indicators (PHSIs) at the upper limit of Sustainable heat stress were below generally accepted limits; (2) suggest values for PHSIs that demonstrate a Sustainable level of heat stress; (3) suggest alternative PHSIs; and (4) determine if metabolic rate was an effect modifier. Methods: Two previous progressive heat stress studies included 176 trials with 352 pairs of Sustainable and Unsustainable exposures over a range of relative humidities and metabolic rates using 29 participants. To assess the discrimination ability of PHSIs, conditional logistic regression and stepwise logistic regression were used to find the best combinations of predictors of Unsustainable exposures. The accuracy of the models was assessed using receiver operating characteristic curves. Results: Current recommendations for physiological heat strain limits were associated with probabilities of Unsustainable greater than 0.5. Screening limits for Sustainable heat stress were Tre of 37.5 degrees C, HR of 105 bpm, and Tsk of 35.8 degrees C. Tsk alone resulted in an area under the curve of 0.85 and the combination of Tsk and HR (area under the curve = 0.88) performed the best. The adjustment for metabolic rate was statistically significant for physiological strain index or ?Tre-sk as main predictors, but its effect modification was negligible and could be ignored. Conclusions: Based on the receiver operating characteristic curve, PHSIs (Tre, HR, and Tsk) can accurately predict Unsustainable heat stress exposures. Tsk alone or in combination with HR has a high sensitivity, and makes better discriminations than the other PHSIs under relatively constant exposure (metabolic rate and environment) for an hour or so. Screening limits with high sensitivity, however, have low thresholds that limit utility. To the extent that the observed strain is low, there is good evidence that the exposure is Sustainable. PMID- 28595342 TI - Letter: Commentary: Carotid Artery Angioplasty and Stenting Without Distal Embolic Protection Devices. PMID- 28595341 TI - Obstructive Sleep Apnea Dynamically Increases Nocturnal Plasma Free Fatty Acids, Glucose, and Cortisol During Sleep. AB - Context: Obstructive sleep apnea (OSA) is associated with diabetes and cardiovascular disease. This association may be related to metabolic changes that transpire during sleep in OSA. Objective: To examine the impact of OSA, elicited by cessation of continuous positive airway pressure (CPAP), on frequently sampled nocturnal metabolic markers including plasma free fatty acids (FFAs), glucose, insulin, triglycerides (TGs), cortisol, and lactate, as well as glucose production, oral glucose tolerance, blood pressure (BP), endothelial function, cholesterol, and high-sensitivity C-reactive protein (hsCRP). Design and Setting: Randomized crossover trial of CPAP vs CPAP withdrawal. Patients: Thirty-one patients with moderate to severe OSA acclimated to CPAP. Intervention: Patients underwent attended polysomnography while sleeping with therapeutic CPAP, or after CPAP withdrawal, in random order. Venous blood was sampled at ~20-minute intervals on both nights. In 11 patients, we assessed glucose kinetics with an infusion of 6,6-[2H2]glucose. Results: CPAP withdrawal caused recurrence of OSA associated with hypoxemia, sleep disruption, and heart rate (HR) elevation. CPAP withdrawal dynamically increased nocturnal FFA (P = 0.007), glucose (P = 0.028), and cortisol (P = 0.037), in proportion to respiratory event frequency, HR elevation, or sleep fragmentation. Diabetes predisposed to glucose elevation. CPAP withdrawal also increased systolic BP (P = 0.017) and augmentation index (P = 0.008), but did not affect insulin, TGs, glucose production, oral glucose tolerance, cholesterol, or hsCRP. Conclusion: OSA recurrence during CPAP withdrawal increases FFA and glucose during sleep, associated with sympathetic and adrenocortical activation. Recurring exposure to these metabolic changes may foster diabetes and cardiovascular disease. PMID- 28595343 TI - Sequencing, de novo assembling, and annotating the genome of the endangered Chinese crocodile lizard Shinisaurus crocodilurus. AB - The Chinese crocodile lizard, Shinisaurus crocodilurus, is the only living representative of the monotypic family Shinisauridae under the order Squamata. It is an obligate semi-aquatic, viviparous, diurnal species restricted to specific portions of mountainous locations in southwestern China and northeastern Vietnam. However, in the past several decades, this species has undergone a rapid decrease in population size due to illegal poaching and habitat disruption, making this unique reptile species endangered and listed in the Convention on International Trade in Endangered Species of Wild Fauna and Flora Appendix II since 1990. A proposal to uplist it to Appendix I was passed at the Convention on International Trade in Endangered Species of Wild Fauna and Flora Seventeenth meeting of the Conference of the Parties in 2016. To promote the conservation of this species, we sequenced the genome of a male Chinese crocodile lizard using a whole-genome shotgun strategy on the Illumina HiSeq 2000 platform. In total, we generated ~291 Gb of raw sequencing data (*149 depth) from 13 libraries with insert sizes ranging from 250 bp to 40 kb. After filtering for polymerase chain reaction duplicated and low-quality reads, ~137 Gb of clean data (*70 depth) were obtained for genome assembly. We yielded a draft genome assembly with a total length of 2.24 Gb and an N50 scaffold size of 1.47 Mb. The assembled genome was predicted to contain 20 150 protein-coding genes and up to 1114 Mb (49.6%) of repetitive elements. The genomic resource of the Chinese crocodile lizard will contribute to deciphering the biology of this organism and provides an essential tool for conservation efforts. It also provides a valuable resource for future study of squamate evolution. PMID- 28595345 TI - Supraventricular arrhythmias in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy associate with long-term outcome after catheter ablation of ventricular tachycardias. AB - Aims: This study aimed to assess the impact of supraventricular tachycardia (SVT) on long-term results of radiofrequency catheter ablation therapy of ventricular tachycardia (VT) in a large cohort of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Methods and results: Supraventricular tachycardia occurrence has been studied in patients from our ARVD/C registry (70 patients, 48 male, age 53.2 +/- 14.0, 45 patients (64.3%) with previous VT ablation). SVT were diagnosed in 26 of 70 patients (37.1%). Atrial fibrillation (AF) was the most frequent atrial arrhythmia, diagnosed in 17 patients (24.3%). In univariate analysis advanced age, clinical symptoms of heart failure, enlarged right atrium, diagnosis of significant tricuspid regurgitation (TR), and inappropriate implantable cardioverters-defibrillators therapy were associated with SVT. In binary logistic regression analysis only heart failure: hazard ratio (HR) 10.89, 95% confidence interval (95% CI) 1.08-109.96 (P = 0.043) and significant TR: HR 4.79, 95% CI 1.35-16.33 (P = 0.015) remained associated with SVT. In patients with previous VT ablation Cox multiple regression survival analysis revealed older age (>=53 years): HR 4.63, 95% CI 1.51-14.24 (P = 0.008) and SVT: HR 3.01, 95% CI 1.15-7.89 (P = 0.025) as predictors for VT recurrence during the follow-up. Conclusion: SVT and older age are associated with the recurrence of VT after catheter ablation in patients with ARVD/C. PMID- 28595344 TI - Metabolism and the Evolution of Social Behavior. AB - How does metabolism influence social behavior? This fundamental question at the interface of molecular biology and social evolution is hard to address with experiments in animals, and therefore, we turned to a simple microbial system: swarming in the bacterium Pseudomonas aeruginosa. Using genetic engineering, we excised a locus encoding a key metabolic regulator and disrupted P. aeruginosa's metabolic prudence, the regulatory mechanism that controls expression of swarming public goods and protects this social behavior from exploitation by cheaters. Then, using experimental evolution, we followed the joint evolution of the genome, the metabolome and the social behavior as swarming re-evolved. New variants emerged spontaneously with mutations that reorganized the metabolome and compensated in distinct ways for the disrupted metabolic prudence. These experiments with a unicellular organism provide a detailed view of how metabolism currency of all physiological processes-can determine the costs and benefits of a social behavior and ultimately influence how an organism behaves towards other organisms of the same species. PMID- 28595346 TI - Sedentary Behaviors and Cardiometabolic Risk: An Isotemporal Substitution Analysis. AB - Evidence suggests that time spent engaging in sedentary behaviors is associated with a greater risk of adverse cardiometabolic outcomes. We investigated the cross-sectional associations of 6 unique sedentary tasks (watching television, using the computer, completing paperwork, reading, talking on the telephone, and sitting in a car) with cardiometabolic risk factors, and also examined the effect of replacing one type of sedentary behavior with another on the level of cardiometabolic risk. Participants consisted of 3,211 individuals from the Coronary Artery Risk Development in Young Adults Study who visited the clinic between 2010 and 2011. Linear regression models examined the independent and joint associations of sedentary tasks with a composite cardiometabolic risk score, as well as with individual cardiometabolic risk factors (waist circumference, blood pressure, fasting glucose, insulin, triglycerides, and high density lipoprotein cholesterol) after adjusting for physical activity and other covariates. Replacing 2 hours of television viewing with 2 hours spent performing any other sedentary activity was associated with a lower cardiometabolic risk score of 0.06-0.09 standard deviations (all 95% confidence intervals: -0.13, 0.02). No other replacements of one type of sedentary task for another were significant. Study findings indicate that television viewing has a more adverse association with cardiometabolic risk factors than other sedentary behaviors. PMID- 28595348 TI - Has Underreporting of Cigarette Consumption Changed Over Time? Estimates Derived From US National Health Surveillance Systems Between 1965 and 2015. AB - According to survey data, the prevalence of Americans' self-reported cigarette smoking is dropping steadily. However, the accuracy of national surveys has been questioned because of declining response rates and the increasing stigmatization of smoking. We used data from 2 repeated, cross-sectional, nationally representative health surveys (National Survey on Drug Use and Health (NSDUH), 1979-2014; and National Health Interview Survey (NHIS), 1965-2015) to determine whether self-reported cigarette consumption has changed over time as a proportion of federally taxed cigarette sales. From each survey, we calculated national equivalents of annual cigarette consumption. From 1979 to 1997, the amount of cigarettes that NSDUH and NHIS respondents reported corresponded to an average of 59.5% (standard deviation (SD), 2.3%) and 65.6% (SD, 3.2%), respectively, of taxed cigarette sales. After 1997, respondents' reported smoking data corresponded to the equivalent of an average of 64.2% (SD, 5.9%) and 63.3% (SD, 2.5%), respectively, of taxed cigarette sales. NHIS figures remained steady throughout the latter period, with a decline during 2013-2015 from 65.9% to 61.1%. NSDUH figures increased steadily, exceeding those of the NHIS after 2002. Given the consistent underreporting of cigarette consumption over time, these surveys are likely not less accurate than they were previously. The recent decrease in NHIS accuracy, however, gives pause about the magnitude of the reported decline in smoking prevalence in 2014 and 2015. Improvement in the accuracy of NSDUH data is encouraging. PMID- 28595347 TI - Genetic History of Xinjiang's Uyghurs Suggests Bronze Age Multiple-Way Contacts in Eurasia. AB - The Uyghur people residing in Xinjiang, a territory located in the far west of China and crossed by the Silk Road, are a key ethnic group for understanding the history of human dispersion in Eurasia. Here we assessed the genetic structure and ancestry of 951 Xinjiang's Uyghurs (XJU) representing 14 geographical subpopulations. We observed a southwest and northeast differentiation within XJU, which was likely shaped jointly by the Tianshan Mountains, which traverses from east to west as a natural barrier, and gene flow from both east and west directions. In XJU, we identified four major ancestral components that were potentially derived from two earlier admixed groups: one from the West, harboring European (25-37%) and South Asian ancestries (12-20%), and the other from the East, with Siberian (15-17%) and East Asian (29-47%) ancestries. By using a newly developed method, MultiWaver, the complex admixture history of XJU was modeled as a two-wave admixture. An ancient wave was dated back to ~3,750 years ago (ya), which is much earlier than that estimated by previous studies, but fits within the range of dating of mummies that exhibited European features that were discovered in the Tarim basin, which is situated in southern Xinjiang (4,000 2,000 ya); a more recent wave occurred around 750 ya, which is in agreement with the estimate from a recent study using other methods. We unveiled a more complex scenario of ancestral origins and admixture history in XJU than previously reported, which further suggests Bronze Age massive migrations in Eurasia and East-West contacts across the Silk Road. PMID- 28595350 TI - Reducing Bruzzi's Formula to Remove Instability in the Estimation of Population Attributable Fraction for Health Outcomes. AB - The aim of this study was to reconcile 3 approaches to calculating population attributable fractions and attributable burden percentage: the approach of Bruzzi et al. (Am J Epidemiol. 1985;122(5):904-914.), the maximum-likelihood method of Greenland and Drescher (Biometrics. 1993;49(3):865-872.), and the multivariable method of Tanuseputro et al. (Popul Health Metr. 2015;13:5.). Using data from a statewide point prevalence survey (Western Australian Point Prevalence Survey, 2014) linked to an administrative database, we compared estimates of attributable burden percentage obtained using the contrasting methods in 6 logistic models of health outcomes from the survey, estimating 95% confidence intervals using nonparametric and weighted bootstrap approaches. Our results show that instability can arise from the fundamental algebraic construction of Bruzzi's formula, and that this instability may substantially influence the calculation of attributable burden percentage and associated confidence intervals. These observations were confirmed in a simulation study. The algebraic reduction of Bruzzi's formula to the 2 alternative methods resulted in markedly more stable estimates for population attributable fraction and attributable burden percentage in cross-sectional studies and cohort designs with fixed follow-up time. We advocate the widespread implementation of the maximum-likelihood approach and the multivariable method. PMID- 28595349 TI - Prenatal exposure to antimalarials decreases the risk of cardiac but not non cardiac neonatal lupus: a single-centre cohort study. AB - Objective: Recent studies have suggested that prenatal exposure to HCQ reduces the risk of cardiac neonatal lupus. The aim of this study is to assess if maternal intake of antimalarials (AMs) throughout pregnancy lowered the risk of cardiac and non-cardiac neonatal lupus. Methods: Consecutive children seen between 1 January 1984 to 1 October 2013 born to women with a CTD and positive anti-Ro and/or anti-La antibodies were eligible for this single-centre retrospective cohort study. A total of 315 individuals were screened and 268 participants were included. Exposure to AMs was defined as HCQ or chloroquine throughout pregnancy. Outcomes were cardiac and non-cardiac neonatal lupus. Frequentist and Bayesian analyses were performed. We hypothesized that prenatal AM exposure would decrease the risk of cardiac but not non-cardiac neonatal lupus. Results: A total of 268 pregnancies were included; 73 were exposed to AMs throughout pregnancy. Ninety-nine children developed neonatal lupus, 117 remained unaffected and 52 children did not develop cardiac neonatal lupus but could not be categorized as unaffected since their full non-cardiac neonatal lupus status was unknown. Logistic regression suggested a protective effect of AM on cardiac neonatal lupus, but results were not statistically significant [odds ratio (OR) 0.21; P = 0.07]. Bayesian analysis showed that the probability of obtaining a protective effect (OR < 1.0) for cardiac neonatal lupus was significant (98.7%). The effect of AMs on non-cardiac neonatal lupus was not significant (OR 0.78; P = 0.21). Conclusion: In this large single-centre cohort study, exposure to AMs throughout pregnancy was associated with a decreased probability of developing cardiac but not non-cardiac neonatal lupus. PMID- 28595351 TI - Cautious Interpretation of Optimal Timing of Maternal Pertussis Immunization. PMID- 28595352 TI - Neuropsychology Outcomes Following Trephine Epilepsy Surgery: The Inferior Temporal Gyrus Approach for Amygdalohippocampectomy in Medically Refractory Mesial Temporal Lobe Epilepsy. AB - BACKGROUND: Surgery is indicated in cases of mesial temporal lobe epilepsy(MTLE) that are refractory to medical management. The inferior temporal gyrus (ITG) approach provides access to the mesial temporal lobe (MTL) structures with minimal tissue disruption. Reported neuropsychology outcomes following this approach are limited. OBJECTIVE: To report neuropsychological outcomes using an ITG approach to amygdalohippocampectomy (AH) in patients with medically refractory MTLE based on a prospective design. METHODS: Fifty-four participants had Engel class I/II outcome following resection of MTL using the ITG approach. All participants had localization-related epilepsy confirmed by long-term surface video-electroencephalography and completed pre/postsurgical evaluations that included magnetic resonance imaging (MRI), Wada test or functional MRI, and neuropsychology assessment. RESULTS: Clinical semiology/video electroencephalography indicated that of the 54 patients, 28 (52%) had left MTLE and 26 (48%) had right MTLE. Dominant hemisphere resections were performed on 23 patients (43%), nondominant on 31(57%). Twenty-nine (29) had pathology-confirmed mesial temporal sclerosis (MTS). Group level analyses found declines in verbal memory for patients with language-dominant resections (P < .05). No significant decline in neuropsychological measures occurred for patients with MTS. Participants without MTS who underwent a language-dominant lobe resection exhibited a significant decline in verbal and visual memory (P < .05). Nondominant resection participants did not exhibit significant change in neuropsychology scores (P > .05). CONCLUSION: Neuropsychology outcomes of an ITG approach for selective mesial temporal resection are comparable to other selective AH techniques showing minimal adverse cognitive effects. These data lend support to the ITG approach for selective AH as an option for MTLE. PMID- 28595353 TI - Determination of Hydroxylated Polybrominated Diphenyl Ethers in Chinese Aquatic Products by LC-MS/MS. AB - In this reported work, a sensitive and reliable method for detecting 11 hydroxylated polybrominated diphenyl ethers (OH-PBDEs) was established by a combination of pressurized liquid extraction (PLE) and liquid chromatography tandem mass spectrometry (LC/MS/MS). The aquatic products (mainly crayfish and grass carp) from 12 cities in China's HuBei province were examined for the presence of the target OH-PBDEs. The analytical process involved first extracting the OH-PBDEs from the crayfish and grass carp using a PLE, followed by purification using gel permeation chromatography. To eliminate the interference from matrix, isotopic dilution was used in the quantitative analysis. Compared with the existing methods, OH-PBDEs were determined without a need for derivatizing, and it was more efficient and quicker. The condition of extraction and cleanup were also optimized. Experimental results showed that the proposed method exhibited a low detection limit of 0.04-0.2 MUg/kg, with a wide linearity range 1-400 ng/L and a good linear correlation coefficient (r2 > 0.990) using this method. These results indicated the steadiness of the established method has the advantages of high sensitivity and facile sample preparation without matrix interference. PMID- 28595354 TI - Masked Visual Analysis: Minimizing Type I Error in Visually Guided Single-Case Design for Communication Disorders. AB - Purpose: Single-case experimental designs are widely used to study interventions for communication disorders. Traditionally, single-case experiments follow a response-guided approach, where design decisions during the study are based on participants' observed patterns of behavior. However, this approach has been criticized for its high rate of Type I error. In masked visual analysis (MVA), response-guided decisions are made by a researcher who is blinded to participants' identities and treatment assignments. MVA also makes it possible to conduct a hypothesis test assessing the significance of treatment effects. Method: This tutorial describes the principles of MVA, including both how experiments can be set up and how results can be used for hypothesis testing. We then report a case study showing how MVA was deployed in a multiple-baseline across-subjects study investigating treatment for residual errors affecting rhotics. Strengths and weaknesses of MVA are discussed. Conclusions: Given their important role in the evidence base that informs clinical decision making, it is critical for single-case experimental studies to be conducted in a way that allows researchers to draw valid inferences. As a method that can increase the rigor of single-case studies while preserving the benefits of a response-guided approach, MVA warrants expanded attention from researchers in communication disorders. PMID- 28595355 TI - Risk Factors Associated With Suicide Completions Among US Enlisted Marines. AB - US enlisted Marines have experienced a substantial increase in suicide rates. We sought to identify risk factors for suicide completions among male Marines who entered basic training in San Diego, California, between June 2001 and October 2010. Suicides that occurred during active-duty military service were counted from June 1, 2001, through June 30, 2012. A total of 108,930 male Marines (66,286 deployers and 42,644 never deployed) were followed for 467,857 person-years of active-duty service time. Of the 790 deaths, 123 (15.6%) were suicides. In the final multivariate hazard model, preservice characteristics of not being a high school graduate (hazard ratio (HR) = 2.17, 95% confidence interval (CI): 1.28, 3.68) and being a smoker at the time of enlistment (HR = 1.91, 95% CI: 1.32, 2.76) were significantly associated with a higher risk for suicide completion. Diagnosed with traumatic brain injury (HR = 4.09, 95% CI: 2.08, 8.05), diagnosed with depression (HR = 2.36, 95% CI: 1.22, 4.58), and received relationship counseling (HR = 3.71, 95% CI: 1.44, 9.54) during military service were significant risks for suicide death. Deployment alone was not significantly associated with a risk for suicide death (HR = 0.53, 95% CI: 0.26, 1.05). PMID- 28595356 TI - Treatment With Bupropion and Varenicline for Smoking Cessation and the Risk of Acute Cardiovascular Events and Injuries: a Swedish Case-Crossover Study. AB - Introduction: Bupropion and varenicline are non-nicotine medications used for smoking cessation that mitigate craving and withdrawal symptoms. We aim to investigate whether these drugs increase the risk of selected acute adverse outcomes when used in medical practice. Methods: Population-based case-crossover design using data from Swedish health and administrative registers. Adult individuals diagnosed with acute myocardial infarction, stroke, suicide, suicide attempt, fall injury, or that suffered a road traffic crash from 01.10.2006 for bupropion, or from 01.03.2008 for varenicline, until 31.12.2013 were included. Different lengths of exposure periods were analyzed within the 12-week hazard period prior to the adverse outcome (1-14, 15-28, and 29-84 days). The control period was matched using the interval preceding the hazard period (85-168 days), and breaking it up into equivalent periods (85-98, 99-112, and 113-168 days). Conditional logistic regression with each case considered as one stratum was used to estimate adjusted odds ratios (OR) and confidence intervals (CI). Results: Neither medication was associated with consistent higher risks for any of the adverse outcomes. For bupropion and varenicline, respectively, in the 1-14 days hazard period, OR (95% CI) were: myocardial infarction 1.14 (0.55 to 2.34) and 1.06 (0.70 to 1.62); stroke 1.16 (0.39 to 3.47) and 1.26 (0.72 to 2.17), and traffic crashes 0.85 (0.39 to 1.85) and 1.48 (0.90 to 2.41). In the other periods, ORs were similar or even lower. For falls and suicidal events ORs were generally below one for both drugs. Conclusion: The available evidence suggests that if prescription guidelines are properly followed regarding potential contraindications both of these medications could be considered relatively safe. Implications: The reliable exposure and diagnosis assessment used in this nationwide register-based study, along with the number of cases gathered makes this sample one of the largest of its type to assess potential side effects associated with the use of these drugs. Neither medication was associated with consistent higher risks for any of the adverse outcomes studied. PMID- 28595357 TI - The Alzheimer's disease transcriptome mimics the neuroprotective signature of IGF 1 receptor-deficient neurons. AB - Seminal studies using post-mortem brains of patients with Alzheimer's disease evidenced aberrant insulin-like growth factor 1 receptor (IGF1R) signalling. Addressing causality, work in animal models recently demonstrated that long-term suppression of IGF1R signalling alleviates Alzheimer's disease progression and promotes neuroprotection. However, the underlying mechanisms remain largely elusive. Here, we showed that genetically ablating IGF1R in neurons of the ageing brain efficiently protects from neuroinflammation, anxiety and memory impairments induced by intracerebroventricular injection of amyloid-beta oligomers. In our mutant mice, the suppression of IGF1R signalling also invariably led to small neuronal soma size, indicative of profound changes in cellular homeodynamics. To gain insight into transcriptional signatures leading to Alzheimer's disease relevant neuronal defence, we performed genome-wide microarray analysis on laser dissected hippocampal CA1 after neuronal IGF1R knockout, in the presence or absence of APP/PS1 transgenes. Functional analysis comparing neurons in early stage Alzheimer's disease with IGF1R knockout neurons revealed strongly convergent transcriptomic signatures, notably involving neurite growth, cytoskeleton organization, cellular stress response and neurotransmission. Moreover, in Alzheimer's disease neurons, a high proportion of genes responding to Alzheimer's disease showed a reversed differential expression when IGF1R was deleted. One of the genes consistently highlighted in genome-wide comparison was the neurofilament medium polypeptide Nefm. We found that NEFM accumulated in hippocampus in the presence of amyloid pathology, and decreased to control levels under IGF1R deletion, suggesting that reorganized cytoskeleton likely plays a role in neuroprotection. These findings demonstrated that significant resistance of the brain to amyloid-beta can be achieved lifelong by suppressing neuronal IGF1R and identified IGF-dependent molecular pathways that coordinate an intrinsic program for neuroprotection against proteotoxicity. Our data also indicate that neuronal defences against Alzheimer's disease rely on an endogenous gene expression profile similar to the neuroprotective response activated by genetic disruption of IGF1R signalling. This study highlights neuronal IGF1R signalling as a relevant target for developing Alzheimer's disease prevention strategies. PMID- 28595358 TI - Reduced Antibody Response to Infant Measles Vaccination: Effects Based on Type and Timing of the First Vaccine Dose Persist After the Second Dose. AB - Background: The effect of age at first dose on the immunogenicity of a 2-dose pediatric schedule of measles-mumps-rubella (MMR) or measles-mumps-rubella varicella (MMRV) vaccine was assessed in children born to mostly vaccinated mothers. Methods: Immunogenicity data among children given their first measles vaccine dose between 11 and 22 months of age were pooled from 5 randomized controlled trials conducted in Europe and the United States between 2004 and 2010. Measles antibody titers were measured by enzyme-linked immunosorbent assay before and after each dose; geometric mean concentrations (GMCs) and the proportion seronegative (GMC <150 mIU/mL) were derived by age at first dose. Results: Among 5542 children given a first measles vaccine dose at 11, 12, 13-14, and 15-22 months of age, the proportion seronegative decreased from 8.5% to 3.2%, 2.4%, and 1.5%, respectively (P < .001), whereas GMCs increased with older age measles vaccine initiation (P < .001). MMRV induced higher GMCs than MMR (P < .001). First and second dose GMCs were highly correlated (Spearman coefficient = 0.8). Conclusions: As previously noted among infants born to mothers with history of wild-type measles, antibody responses among children born to vaccinated mothers were reduced based on earlier administration of their first measles vaccine dose at <=12 vs >=15 months of age. Negative effects of earlier age at first measles vaccine dose persisted after the second dose. The measles elimination goal may require a careful balance between earlier infant protection and the risk of reduced antibody responses and secondary vaccine failure among successive birth cohorts systematically initiated to measles vaccination <15 months of age. PMID- 28595360 TI - Distress from changes in physical appearance and support through information provision in male cancer patients. AB - Objective: This study aims to reveal the present situation of changes in physical appearance induced by treatment, the effects of these changes on social activities, and support from medical staff in male cancer patients. Methods: A questionnaire survey was administered to 949 male patients (response rate: 90.1%) visiting the National Cancer Center Hospital in Tokyo over 3 days in January 2015. Results: The final respondents were 823 patients (mean age: 65.3, standard deviation (SD) = 12.32). Fifty-two percent of the sample, and 79.4% of patients aged under 65 were employed. A total of 84.9% experienced changes in physical appearance, and the highest mean scores of psychological were observed for stoma (3.1) and skin eczema (2.9). A total of 66.4% reported no difference in daily life even after their physical appearance changed. However, patients younger than 65 years old who were employed experienced high social difficulties (12.5%). Many wanted to stop going to work and experienced severe distress in their social lives; 74.1% reported it is important to have the same physical appearance at work as before treatment. The majority of patients obtained information from doctors (35.2%) and consulted with their wife or partner (66.2%) regarding their appearance changes, and 5.7% did not have anyone to consult with. Conclusion: This study clarified important aspects for supporting male cancer patients: timing, content, target audience and steps of information provision. Appropriate information provision from medical staff prior to treatment can be useful in preparing patients for physical appearance changes and decreasing the severity of symptoms. PMID- 28595359 TI - Intracellular Ca2+ is important for flagellin-triggered defense in Arabidopsis and involves inositol polyphosphate signaling. AB - Cytosolic Ca2+ increase is a crucial and early step of plant immunity evoked by pathogen-associated molecular patterns (PAMPs) such as flagellin (flg). Components responsible for this increase are still not uncovered, although current models of plant immune signaling portray extracellular Ca2+ influx as paramount to flg activation of defense pathways. Work presented here provides new insights into cytosolic Ca2+ increase associated with flg-induced defense responses. We show that extracellular Ca2+ contributes more to immune responses evoked by plant elicitor peptide (Pep3) than that evoked by flg, indicating an intracellular Ca2+ source responsible for immune responses evoked by flg. Genetic impairment of the inositol polyphosphate (InsP) and G-protein signal associated with flg perception reduced flg-dependent immune responses. Previous work indicates that prior exposure of Arabidopsis plants to flg leads to an immune response reflected by less vigorous growth of a pathogenic microbe. We found that this immune response to flg was compromised in mutants lacking the ability to generate an InsP or G-protein signal. We conclude that the recruitment of intracellular Ca2+ stores by flg may involve InsP and G-protein signaling. We also found a notable difference in contribution of intracellular stores of Ca2+ to the immune signaling evoked by another PAMP, elf18 peptide, which had a very different response profile to impairment of InsP signaling. Although Ca2+ signaling is at the core of the innate immune as well as hypersensitive response to plant pathogens, it appears that the molecular mechanisms generating the Ca2+ signal in response to different PAMPs are different. PMID- 28595361 TI - Mitochondrial dysfunction underlies cognitive defects as a result of neural stem cell depletion and impaired neurogenesis. AB - Mitochondrial dysfunction is a common feature of many genetic disorders that target the brain and cognition. However, the exact role these organelles play in the etiology of such disorders is not understood. Here, we show that mitochondrial dysfunction impairs brain development, depletes the adult neural stem cell (NSC) pool and impacts embryonic and adult neurogenesis. Using deletion of the mitochondrial oxidoreductase AIF as a genetic model of mitochondrial and neurodegenerative diseases revealed the importance of mitochondria in multiple steps of the neurogenic process. Developmentally, impaired mitochondrial function causes defects in NSC self-renewal, neural progenitor cell proliferation and cell cycle exit, as well as neuronal differentiation. Sustained mitochondrial dysfunction into adulthood leads to NSC depletion, loss of adult neurogenesis and manifests as a decline in brain function and cognitive impairment. These data demonstrate that mitochondrial dysfunction, as observed in genetic mitochondrial and neurodegenerative diseases, underlies the decline of brain function and cognition due to impaired stem cell maintenance and neurogenesis. PMID- 28595364 TI - Antiretroviral unbound concentration during pregnancy: piece of interest in the puzzle? AB - Atazanavir and darunavir total concentrations (drug bound to plasma proteins plus unbound drug) progressively decrease during pregnancy. This pharmacokinetic variation leads physicians to recommend increasing doses. Conversely, the unbound concentration (Cu), i.e. the pharmacologically active form of the drug, remains unchanged. The explanation of this desynchronization lies in the fact that the clearance of the unbound form, corresponding to the intrinsic metabolic capacity of the hepatocytes, is the only factor driving Cu, and is constant during pregnancy. The attention of HIV physicians should be attracted to this aspect of pharmacokinetics, which is often incompletely understood and could lead to inadequate dose adjustment, which could then cause overexposure of the foetus for many months, with unknown consequences. PMID- 28595362 TI - Executive Function and Dysregulated Eating Behaviors in Pediatric Obesity. AB - Objective: To examine the association between caregiver proxy report of executive function (EF) and dysregulated eating behavior in children with obesity. Methods: Participants were 195 youth with obesity aged 8-17 years, and their legal guardians. Youth height, weight, demographics, depressive symptoms, eating behaviors, and EF were assessed cross-sectionally during a medical visit. Analyses of covariance, adjusted for child age, gender, race/ethnicity, standardized BMI, depressive symptoms, and family income were used to examine differences in youth EF across caregiver and youth self-report of eating behaviors. Results: Youth EF differed significantly by caregiver report of eating behavior but not youth self-report. Post hoc analyses showed that youth with overeating or binge eating had poorer EF than youth without these eating behaviors. Conclusions: Executive dysfunction, as reported by caregivers, in youth with obesity may be associated with dysregulated eating behaviors predictive of poor long-term psychosocial and weight outcomes. Further consideration of EF-specific targets for assessment and intervention in youth with obesity may be warranted. PMID- 28595363 TI - More on the Best Evolutionary Rate for Phylogenetic Analysis. AB - The accumulation of genome-scale molecular data sets for nonmodel taxa brings us ever closer to resolving the tree of life of all living organisms. However, despite the depth of data available, a number of studies that each used thousands of genes have reported conflicting results. The focus of phylogenomic projects must thus shift to more careful experimental design. Even though we still have a limited understanding of what are the best predictors of the phylogenetic informativeness of a gene, there is wide agreement that one key factor is its evolutionary rate; but there is no consensus as to whether the rates derived as optimal in various analytical, empirical, and simulation approaches have any general applicability. We here use simulations to infer optimal rates in a set of realistic phylogenetic scenarios with varying tree sizes, numbers of terminals, and tree shapes. Furthermore, we study the relationship between the optimal rate and rate variation among sites and among lineages. Finally, we examine how well the predictions made by a range of experimental design methods correlate with the observed performance in our simulations.We find that the optimal level of divergence is surprisingly robust to differences in taxon sampling and even to among-site and among-lineage rate variation as often encountered in empirical data sets. This finding encourages the use of methods that rely on a single optimal rate to predict a gene's utility. Focusing on correct recovery either of the most basal node in the phylogeny or of the entire topology, the optimal rate is about 0.45 substitutions from root to tip in average Yule trees and about 0.2 in difficult trees with short basal and long-apical branches, but all rates leading to divergence levels between about 0.1 and 0.5 perform reasonably well.Testing the performance of six methods that can be used to predict a gene's utility against our simulation results, we find that the probability of resolution, signal-noise analysis, and Fisher information are good predictors of phylogenetic informativeness, but they require specification of at least part of a model tree. Likelihood quartet mapping also shows very good performance but only requires sequence alignments and is thus applicable without making assumptions about the phylogeny. Despite them being the most commonly used methods for experimental design, geometric quartet mapping and the integration of phylogenetic informativeness curves perform rather poorly in our comparison. Instead of derived predictors of phylogenetic informativeness, we suggest that the number of sites in a gene that evolve at near-optimal rates (as inferred here) could be used directly to prioritize genes for phylogenetic inference. In combination with measures of model fit, especially with respect to compositional biases and among-site and among-lineage rate variation, such an approach has the potential to greatly improve marker choice and should be tested on empirical data. PMID- 28595365 TI - Evaluation of starter dietary digestible lysine level on broilers raised under a sex-separated or straight-run housing regime, part 2: Economics of sex separation and digestible lysine level for maximum returns. AB - The objective of this experiment was to determine the maximum net returns digestible lysine (dLys) levels (MNRL) when maintaining the ideal amino acid ratio for starter diets of broilers raised sex separate or comingled (straight run). A total of 3,240 Ross 708 chicks was separated by sex and placed in 90 pens by 2 rearing types: sex separate (36 males or 36 females) or straight-run (18 males + 18 females). Each rearing type was fed 6 starter diets (25 d) formulated to have dLys levels between 1.05 and 1.80%. A common grower diet with 1.02% of dLys was fed from 25 to 32 days. Body weight gain (BWG) and feed intake were assessed at 25 and 32 d for performance evaluation. Additionally, at 26 and 33 d, 4 birds per pen were sampled for carcass yield evaluation. Data were modeled using response surface methodology in order to estimate feed intake and whole carcass weight at 1,600 g live BW. Returns over feed cost were estimated for a 1.8-million-broiler complex of each rearing system under 9 feed/meat price scenarios. Results indicated that females needed more feed to reach market weight, followed by straight-run birds, and then males. At medium meat and feed prices, female birds had MNRL at 1.07% dLys, whereas straight-run and males had MNRL at 1.05%. As feed and meat prices increased, females had MNRL increased up to 1.15% dLys. Sex separation resulted in increased revenue under certain feed and meat prices, and before sex separation cost was deducted. When the sexing cost was subtracted from the returns, sex separation was not shown to be economically viable when targeting birds for light market BW. PMID- 28595366 TI - Conserving Phylogenetic Diversity Can Be a Poor Strategy for Conserving Functional Diversity. AB - For decades, academic biologists have advocated for making conservation decisions in light of evolutionary history. Specifically, they suggest that policy makers should prioritize conserving phylogenetically diverse assemblages. The most prominent argument is that conserving phylogenetic diversity (PD) will also conserve diversity in traits and features (functional diversity [FD]), which may be valuable for a number of reasons. The claim that PD-maximized ("maxPD") sets of taxa will also have high FD is often taken at face value and in cases where researchers have actually tested it, they have done so by measuring the phylogenetic signal in ecologically important functional traits. The rationale is that if traits closely mirror phylogeny, then saving the maxPD set of taxa will tend to maximize FD and if traits do not have phylogenetic structure, then saving the maxPD set of taxa will be no better at capturing FD than criteria that ignore PD. Here, we suggest that measuring the phylogenetic signal in traits is uninformative for evaluating the effectiveness of using PD in conservation. We evolve traits under several different models and, for the first time, directly compare the FD of a set of taxa that maximize PD to the FD of a random set of the same size. Under many common models of trait evolution and tree shapes, conserving the maxPD set of taxa will conserve more FD than conserving a random set of the same size. However, this result cannot be generalized to other classes of models. We find that under biologically plausible scenarios, using PD to select species can actually lead to less FD compared with a random set. Critically, this can occur even when there is phylogenetic signal in the traits. Predicting exactly when we expect using PD to be a good strategy for conserving FD is challenging, as it depends on complex interactions between tree shape and the assumptions of the evolutionary model. Nonetheless, if our goal is to maintain trait diversity, the fact that conserving taxa based on PD will not reliably conserve at least as much FD as choosing randomly raises serious concerns about the general utility of PD in conservation. PMID- 28595370 TI - Osteopathic manifesto series XI. PMID- 28595371 TI - AACOM update: AACOM plays role in future of medical education. PMID- 28595367 TI - Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors. AB - Objective: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well. PMID- 28595374 TI - Response: Examining quality improvement vs cost containment. PMID- 28595375 TI - CME Quiz Answers. PMID- 28595378 TI - An Alternative to the Transforaminal Cervical Epidural: A Selective Dorsal Epidural. PMID- 28595376 TI - DEIsoM: a hierarchical Bayesian model for identifying differentially expressed isoforms using biological replicates. AB - Motivation: High-throughput mRNA sequencing (RNA-Seq) is a powerful tool for quantifying gene expression. Identification of transcript isoforms that are differentially expressed in different conditions, such as in patients and healthy subjects, can provide insights into the molecular basis of diseases. Current transcript quantification approaches, however, do not take advantage of the shared information in the biological replicates, potentially decreasing sensitivity and accuracy. Results: We present a novel hierarchical Bayesian model called Differentially Expressed Isoform detection from Multiple biological replicates (DEIsoM) for identifying differentially expressed (DE) isoforms from multiple biological replicates representing two conditions, e.g. multiple samples from healthy and diseased subjects. DEIsoM first estimates isoform expression within each condition by (1) capturing common patterns from sample replicates while allowing individual differences, and (2) modeling the uncertainty introduced by ambiguous read mapping in each replicate. Specifically, we introduce a Dirichlet prior distribution to capture the common expression pattern of replicates from the same condition, and treat the isoform expression of individual replicates as samples from this distribution. Ambiguous read mapping is modeled as a multinomial distribution, and ambiguous reads are assigned to the most probable isoform in each replicate. Additionally, DEIsoM couples an efficient variational inference and a post-analysis method to improve the accuracy and speed of identification of DE isoforms over alternative methods. Application of DEIsoM to an hepatocellular carcinoma (HCC) dataset identifies biologically relevant DE isoforms. The relevance of these genes/isoforms to HCC are supported by principal component analysis (PCA), read coverage visualization, and the biological literature. Availability and implementation: The software is available at https://github.com/hao-peng/DEIsoM. Contact: pengh@alumni.purdue.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 28595377 TI - Characterization of tools to detect and enrich human and mouse O-GlcNAcase. AB - O-linked beta-N-acetylglucosamine (O-GlcNAc) is an essential regulatory post translational modification of thousands of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc is dynamically added and removed from proteins by the O-GlcNAc transferase and the O-GlcNAcase (OGA), respectively. Dysregulation of O-GlcNAc-cycling is implicated in the etiology of numerous diseases including tumorigenesis, metabolic dysfunction, and neurodegeneration. To facilitate studies focused on the role of O-GlcNAc and OGA in disease, we sought to identify commercially available antibodies that enable the enrichment of full-length OGA from lysates of mouse and human origin. Here, we report that antibodies from Abcam and Bethyl Laboratories can be used to immunoprecipitate OGA to near-saturation from human and mouse cell lysates. However, Western blotting analysis indicates that both antibodies, as well as three non commercially available antibodies (345, 346, 352), detect full-length OGA and numerous cross-reacting proteins. These non-specific signals migrate similarly to full-length OGA and are detected robustly, suggesting that the use of appropriate controls is essential to avoid the misidentification of OGA. PMID- 28595379 TI - Does the prophylactic and therapeutic use of beta-blockers in preoperative patients with tetralogy of Fallot significantly prevent and treat the occurrence of cyanotic spells? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Does the use of beta-blockers significantly prevent and treat the occurrence of cyanotic spells in preoperative infants with tetralogy of Fallot?' Altogether, 80 papers were found using the reported search, of which 6 represented the best evidence to answer the clinical question. The author, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. The participants in the papers reviewed were uncorrected (native or palliated) tetralogy of Fallot patients, all younger than 18 years of age, with some patients younger than 1 year. Each study reviewed included at least 10 patients, and all the studies were case series. Although even the most recent studies found were from 30 years ago, their data remain relevant. Several reviews reported either cases of overdosage or changes in efficacy of treatment after long-term usage. Four of the 6 case reviews demonstrated a decrease in the number of recurring cyanotic spells in at least 66% of the participants, following the introduction of beta-blockers. We can therefore conclude that the use of beta-blockers prevents the occurrence of cyanotic spells in preoperative patients with tetralogy of Fallot. There were insufficient data to establish optimum dosages or duration of treatment. PMID- 28595380 TI - Effects of stocking density on growth performance, feather growth, intestinal development, and serum parameters of geese. AB - This experiment was conducted to evaluate the effects of stocking density on the growth performance, feather growth, intestinal development, and serum parameters of geese. In total, 336 healthy, 28-day-old, male Yangzhou goslings were randomly allotted to 30 plastic wire-floor pens according to 5 stocking densities (2, 3, 4, 5 and 6 birds/m2). The results showed that with the stocking density increased from 2 birds/m2 to 6 birds/m2, the body weights of geese at 42 d (P < 0.001) and 70 d (P < 0.001) were reduced by 10.53% and 10.43% respectively, the primary feather lengths of geese at 42 d (P < 0.001) and 70 d (P = 0.021) were reduced by 20.38% and 6.62% respectively, whereas the feed/gain ratios for 28- to 42-d period and 28- to 70-d period increased from 2.50 to 2.90 (P = 0.001), and 3.80 to 4.24 (P < 0.001), respectively. The relative weights of the jejunum, ileum, and small intestine and the lengths of the jejunum, ileum, and small intestine were all adversely affected (P < 0.05) when stocking density was increased to 6 birds/m2. Serum concentrations of alkaline phosphatase (P = 0.013) and triiodothyronine (P < 0.001) decreased as the stocking density increased. The serum thyroxine concentration of geese from the 6 birds/m2 group was lower than that of geese from the other groups (P < 0.05). The reduction in thyroid hormone concentrations was similar to what was observed in growth rate. All the results suggested that high stocking density will adversely influence thyroid function and the developments of the body weight, body size, feathers, and small intestine. Under our experimental conditions, we recommend that the stocking density of geese should be kept to 5 or fewer birds/m2 to avoid the negative effects of high stocking density on geese. PMID- 28595381 TI - Enhanced Internalization of Macromolecular Drugs into Mycobacterium smegmatis with the Assistance of Silver Nanoparticles. AB - In this study, silver nanoparticles (AgNPs) were synthesized by the citrate reduction process and, with the assistance of n-hydroxysuccinimide and 1-ethyl-3 (3-dimethylaminopropyl) carbodiimide, were successfully loaded with the macromolecular drug vancomycin (VAM) to form AgNP-VAM bioconjugates. The synthesized AgNPs, VAM, and AgNP-VAM conjugate were characterized by UV-visible spectroscopy, zeta potential analysis, confocal microscopy, and transmission electron microscopy. The effect of loading VAM onto AgNPs was investigated by testing the internalization of the bioconjugate into Mycobacterium smegmatis. After treatment with the AgNP-VAM conjugate, the bacterial cells showed a significant decrease in UV absorption, indicating that loading of the VAM on AgNPs had vastly improved the drug's internalization compared with that of AgNPs. All the experimental assessments showed that, compared with free AgNPs and VAM, enhanced internalization had been successfully achieved with the AgNP-VAM conjugate, thus leading to significantly better delivery of the macromolecular drug into the M. smegmatis cell. The current research provides a new potential drug delivery system for the treatment of mycobacterial infections.. PMID- 28595382 TI - Anti-inflammatory properties of Bifidobacterium longum expressing human manganese superoxide dismutase using the TNBS-induced rats model of colitis. AB - The chronic enteritis disease ulcerative colitis (UC) is a formidable opponent, and its etiology remains unclear. Current studies have shown that oxidative stress is closely related to the pathogenesis of inflammatory bowel disease. Antioxidant enzymes, such as manganese superoxide dismutase (MnSOD),have been deemed to exert an anti-inflammatory function. Normally, oral administration of MnSOD directly leads to an incapacitation because of poor penetration and stability. To address this problem, the probiotic Bifidobacterium longum (B. longum), which naturally occurs in the intestinal flora, was engineered to secrete a biologically active human MnSOD. Then this engineered bacterium was utilized against a rat model harboring UC induced through trinitrobenzene sulfonic acid. The data showed the engineered B. longum successfully secreted a penetratin-hMn-SOD fusion protein. The bioactivity assay demonstrated that this fusion protein was delivered into Caco-2 cells and significantly decreased TNF alpha (P<0.01) and IL-6 (P<0.01) expression, as well as, ROS level (P<0.001) in LPS-induced Caco-2 cells. The rat UC model experiment indicated that the B. longum harboring rhMn-SOD (penetratin-hMn-SOD) successfully inhibited the release of cytokines like TNF-a, IL-6, IL-1beta and IL-8, and reduce MPO activity and MDA levels. The histological analysis of the colon tissue section revealed that the engineered B. longum was efficient in attenuating UC damage. These results suggested that preventing UC by the use of B. longum harboring rhMn-SOD could be an alternative choice. PMID- 28595383 TI - Cooperative Interactions between Toll-Like Receptor 2 and Toll-Like Receptor 4 in Murine Klebsiella pneumoniae Infections. AB - Klebsiella pneumoniae is an opportunistic and clinically significant emerging pathogen. We investigated the relative roles of Toll-like receptor (TLR) 2 and TLR4 in initiating host defenses against K. pneumoniae. TLR2 knockout (KO), TLR4 KO, TLR2/4 double KO (DKO), and wild-type (WT) mice were inoculated with K. pneumoniae. Mice in each group were sacrificed after either 12 or 24h, and the lungs, liver, and blood were harvested to enumerate bacterial colony-forming units (CFU). Cytokine and chemokine levels were analyzed using enzyme-linked immunosorbent assay and real-time PCR, and pneumonia severity was determined by histopathological analysis. Survival was significantly shortened in TLR4 KO and TLR2/4 DKO mice compared with that of WT mice after infection with 5 * 103 CFU. TLR2 KO mice were more susceptible to infection than WT mice after exposure to a higher infectious dose. Bacterial burdens in the lungs and liver were significantly higher in TLR2/4 DKO mice than in WT mice. Serum TNF-alpha, MCP-1, MIP-2, and nitric oxide levels were significantly decreased in TLR2/4 DKO mice relative to those in WT mice, and TLR2/4 DKO mice showed significantly decreased levels of TNF-alpha, IL-6, MCP-1, and inducible nitric oxide synthase mRNA in the lung compared with those in WT mice. Collectively, these data indicate that TLR2/4 DKO mice were more susceptible to K. pneumoniae infection than single TLR2 KO and TLR4 KO mice. These results suggest that TLR2 and TLR4 play cooperative roles in lung innate immune responses and bacterial dissemination, resulting in systemic inflammation during K. pneumoniae infection. PMID- 28595384 TI - Chiral Covalent Organic Frameworks with High Chemical Stability for Heterogeneous Asymmetric Catalysis. AB - Covalent organic frameworks (COFs) featuring chirality, stability, and function are of both fundamental and practical interest, but are yet challenging to achieve. Here we reported the metal-directed synthesis of two chiral COFs (CCOFs) by imine-condensations of enantiopure 1,2-diaminocyclohexane with C3-symmetric trisalicylaldehydes having one or zero 3-tert-butyl group. Powder X-ray diffraction and modeling studies, together with pore size distribution analysis demonstrate that the Zn(salen)-based CCOFs possess a two-dimensional hexagonal grid network with AA stacking. Dramatic enhancement in the chemical stability toward acidic (1 M HCl) and basic (9 M NaOH) conditions was observed for the COF incorporated with tert-butyl groups on the pore walls compared to the nonalkylated analog. The Zn(salen) modules in the CCOFs allow for installing multivariate metals into the frameworks by postsynthetic metal exchange. The exchanged CCOFs maintain high crystallinity and porosity and can serve as efficient and recyclable heterogeneous catalysts for asymmetric cyanation of aldehydes, Diels-Alder reaction, alkene epoxidation, epoxide ring-opening, and related sequential reactions with up to 97% ee. PMID- 28595386 TI - Solvent-Induced Molecular Folding and Self-Assembled Nanostructures of Tyrosine and Tryptophan Analogues in Aqueous Solution: Fascinating Morphology of High Order. AB - Hydrophobic derivatives of tyrosine and tryptophan, viz. octyl and dodecyl esters of tyrosine and octyl ester of tryptophan, are synthesized, and the interfacial and bulk properties in aqueous media are investigated as models for the membrane proteins. Molecular modeling by the density functional theory method is carried out to understand the molecular conformation and geometry for the purpose of determining the packing parameters. Water-induced molecular folding of the esters of both tyrosine and tryptophan, as observed using rotating frame nuclear Overhauser effect spectroscopy, indicates that the segregation of the hydrophobic and hydrophilic blocks in water is the key to the development of fascinating interfacial property displayed by the aromatic amino acid esters. The unusually high-order morphology of the aggregates, as observed using high-resolution transmission electron microscopy, is highly uncommon for single-chain amphiphiles and points to the fact that the self-assembly behavior of the present systems resembles that of block copolymers. The study of the growth of mesosized hollow aggregates with internal bilayer structures from tyrosine and tryptophan-based model systems would add to the understanding of biochemistry and biotechnology relevant to the cell membrane. The potential of biocompatible nanostructured motifs as the drug carriers is discussed. The highly functional role played by the aromatic amino acids at the membrane-water interface will be considered with the present amphiphilic models for future perspective. PMID- 28595385 TI - Bioavailability of Black Tea Theaflavins: Absorption, Metabolism, and Colonic Catabolism. AB - Data obtained with in vitro fecal incubations and a feeding study indicate black tea theaflavin and its galloyl derivatives are not absorbed in detectable amounts in either the upper or lower gastrointestinal tract. The theaflavin skeleton is comparatively resistant to degradation by colonic bacteria with a 67% recovery being obtained after a 24 h incubation, which yielded 21 phenolic and aromatic catabolites. The theaflavin galloyl moiety was removed by the microbiota, and the released gallic acid further transformed to 3-O- and 4-O-methyl gallic acids, pyrogallol-1-sulfate and pyrogallol-2-sulfate, which were excreted in urine in amounts equivalent to 94% of intake. The main urinary product potentially derived from breakdown of the theaflavin skeleton was 3-(4'-hydroxyphenyl)propionic acid. A number of the colonic catabolites originating from gallic acid and theaflavins has been reported to be bioactive in ex vivo and in vitro models with a variety of potential modes of action. PMID- 28595387 TI - Delivery of Cisplatin Anti-Cancer Drug from Carbon, Boron Nitride, and Silicon Carbide Nanotubes Forced by Ag-Nanowire: A Comprehensive Molecular Dynamics Study. AB - In this work, liberation of cisplatin molecules from interior of a nanotube due to entrance of an Ag-nanowire inside it was simulated by classical molecular dynamics method. The aim of this simulation was investigation on the effects of diameter, chirality, and composition of the nanotube, as well as the influence of temperature on this process. For this purpose, single walled carbon, boron nitride, and silicon carbide nanotube were considered. In order for a more concise comparison of the results, a new parameter namely efficiency of drug release, was introduced. The results demonstrated that the efficiency of drug release is sensitive to its adsorption on outer surface of the nanotube. Moreover, this efficiency is also sensitive to the nanotube composition and its diameter. For the effect of nanotube composition, the results indicated that silicon carbide nanotube has the least efficiency for drug release, due to its strong drug-nanotube. Also, the most important acting forces on drug delivery are van der Waals interactions. Finally, the kinetic of drug release is fast and is not related to the structural parameters of the nanotube and temperature, significantly. PMID- 28595388 TI - ADMET Evaluation in Drug Discovery. Part 17: Development of Quantitative and Qualitative Prediction Models for Chemical-Induced Respiratory Toxicity. AB - As a dangerous end point, respiratory toxicity can cause serious adverse health effects and even death. Meanwhile, it is a common and traditional issue in occupational and environmental protection. Pharmaceutical and chemical industries have a strong urge to develop precise and convenient computational tools to evaluate the respiratory toxicity of compounds as early as possible. Most of the reported theoretical models were developed based on the respiratory toxicity data sets with one single symptom, such as respiratory sensitization, and therefore these models may not afford reliable predictions for toxic compounds with other respiratory symptoms, such as pneumonia or rhinitis. Here, based on a diverse data set of mouse intraperitoneal respiratory toxicity characterized by multiple symptoms, a number of quantitative and qualitative predictions models with high reliability were developed by machine learning approaches. First, a four-tier dimension reduction strategy was employed to find an optimal set of 20 molecular descriptors for model building. Then, six machine learning approaches were used to develop the prediction models, including relevance vector machine (RVM), support vector machine (SVM), regularized random forest (RRF), extreme gradient boosting (XGBoost), naive Bayes (NB), and linear discriminant analysis (LDA). Among all of the models, the SVM regression model shows the most accurate quantitative predictions for the test set (q2ext = 0.707), and the XGBoost classification model achieves the most accurate qualitative predictions for the test set (MCC of 0.644, AUC of 0.893, and global accuracy of 82.62%). The application domains were analyzed, and all of the tested compounds fall within the application domain coverage. We also examined the structural features of the compounds and important fragments with large prediction errors. In conclusion, the SVM regression model and the XGBoost classification model can be employed as accurate prediction tools for respiratory toxicity. PMID- 28595390 TI - Electron-phonon coupling in anthracene-pyromellitic dianhydride. AB - In this study, the electron-phonon coupling constants of the mixed-stack organic semiconductor anthracene-pyromellitic dianhydride (A-PMDA) are determined from experimental resonant Raman and absorption spectra of the charge transfer (CT) exciton using a time-dependent resonant Raman model. The reorganization energies of both intermolecular and intramolecular phonons are determined and compared with theoretical estimates derived from density functional theory calculations; they are found to agree well. We found that the dominant contribution to the total reorganization energy is due to intramolecular phonons, with intermolecular phonons only contributing a small percentage. This work goes beyond prior studies of the electron-phonon coupling in A-PMDA by including the coupling of all Raman active phonons to the charge transfer exciton. The possibility of orientational disorder in A-PMDA at 80 K is inferred from the inhomogeneous broadening of the absorption line shape. PMID- 28595389 TI - Test-area surface tension calculation of the graphene-methane interface: Fluctuations and commensurability. AB - The surface tension (gamma) of methane on a graphene monolayer is calculated by using the test-area approach. By using a united atom model to describe methane molecules, strong fluctuations of surface tension as a function of the surface area of the graphene are evidenced. In contrast with the liquid-vapor interfaces, the use of a larger cutoff does not fully erase the fluctuations in the surface tension. Counterintuitively, the description of methane and graphene from the Optimized Potentials for Liquid Simulations all-atom model and a flexible model, respectively, led to a lessening in the surface tension fluctuations. This result suggests that the origin of fluctuations in gamma is due to a model-effect rather than size-effects. We show that the molecular origin of these fluctuations is the result of a commensurable organization between both graphene and methane. This commensurable structure can be avoided by describing methane and graphene from a flexible force field. Although differences in gamma with respect to the model have been often reported, it is the first time that the model drastically affects the physics of a system. PMID- 28595391 TI - Thermodiffusion as a means to manipulate liquid film dynamics on chemically patterned surfaces. AB - The model problem examined here is the stability of a thin liquid film consisting of two miscible components, resting on a chemically patterned solid substrate and heated from below. In addition to surface tension gradients, the temperature variations also induce gradients in the concentration of the film by virtue of thermodiffusion/Soret effects. We study the stability and dewetting behaviour due to the coupled interplay between thermal gradients, Soret effects, long-range van der Waals forces, and wettability gradient-driven flows. Linear stability analysis is first employed to predict growth rates and the critical Marangoni number for chemically homogeneous surfaces. Then, nonlinear simulations are performed to unravel the interfacial dynamics and possible locations of the film rupture on chemically patterned substrates. Results suggest that appropriate tuning of the Soret parameter and its direction, in conjunction with either heating or cooling, can help manipulate the location and time scales of the film rupture. The Soret effect can either potentially aid or oppose film instability depending on whether the thermal and solutal contributions to flow are cooperative or opposed to each other. PMID- 28595392 TI - Transient Raman spectra, structure, and thermochemistry of the thiocyanate dimer radical anion in water. AB - Time-resolved resonance-enhanced Stokes and anti-Stokes Raman spectra of the thiocyanate dimer radical anion, (SCN)2*-, prepared by pulse radiolysis in water, have been obtained and interpreted in conjunction with theoretical calculations to provide detailed information on the molecular geometry and bond properties of the species. The structural properties of the radical are used to develop a molecular perspective on its thermochemistry in an aqueous solution. Twenty-nine Stokes Raman bands of the radical observed in the 120-4200 cm-1 region are assigned in terms of the strongly enhanced 220 cm-1 fundamental, weakly enhanced 721 cm-1, and moderately enhanced 2073 cm-1 fundamentals, their overtones, and combinations. Calculations by range-separated hybrid density functionals (omegaB97x and LC-omegaPBE) support the spectroscopic assignments of the 220 cm-1 vibration to a predominantly SS stretching mode and the features at 721 cm-1 and 2073 cm-1 to CS and CN symmetric stretching modes, respectively. The corresponding bond lengths are 2.705 (+/-0.036) A, 1.663 (+/-0.001) A, and 1.158 (+/-0.002) A. A first order anharmonicity of 1 cm-1 determined for the SS stretching mode suggests a convergence of vibrational states at an energy of ~1.5 eV, using the Birge-Sponer extrapolation. This value, estimated for the radical confined in solvent cage, compares well with the calculated gas-phase energy of 1.26 +/- 0.04 eV required for the radical to dissociate into SCN* and SCN- fragments. The enthalpy of dissociation drops to 0.60 +/- 0.03 eV in water when solvent dielectric effects on the radical and its dissociation products upon S-S bond scission are incorporated in the calculations. No frequency shift or spectral broadening was observed between light and heavy water solvents, indicating that the motion of solvent molecules in the hydration shell has no perceptible effect on the intramolecular dynamics of the radical. The Stokes and anti-Stokes Raman frequencies were found to be identical within the experimental uncertainty, suggesting that the frequency difference between the thermally relaxed and spontaneously created vibrational states of (SCN)2*- in water is too small to be observable. PMID- 28595393 TI - A-VCI: A flexible method to efficiently compute vibrational spectra. AB - The adaptive vibrational configuration interaction algorithm has been introduced as a new method to efficiently reduce the dimension of the set of basis functions used in a vibrational configuration interaction process. It is based on the construction of nested bases for the discretization of the Hamiltonian operator according to a theoretical criterion that ensures the convergence of the method. In the present work, the Hamiltonian is written as a sum of products of operators. The purpose of this paper is to study the properties and outline the performance details of the main steps of the algorithm. New parameters have been incorporated to increase flexibility, and their influence has been thoroughly investigated. The robustness and reliability of the method are demonstrated for the computation of the vibrational spectrum up to 3000 cm-1 of a widely studied 6 atom molecule (acetonitrile). Our results are compared to the most accurate up to date computation; we also give a new reference calculation for future work on this system. The algorithm has also been applied to a more challenging 7-atom molecule (ethylene oxide). The computed spectrum up to 3200 cm-1 is the most accurate computation that exists today on such systems. PMID- 28595394 TI - Surprising behaviors in the temperature dependent kinetics of diatomic interhalogens with anions and cations. AB - Rate constants and product branching fractions of reactions between diatomic interhalogens (ICl, ClF) and a series of anions (Br-, I-) and cations (Ar+, N2+) are measured using a selected ion flow tube apparatus and reported over the temperature range 200-500 K. The efficiency of both anion reactions with ICl is 2%-3% at 300 K to yield Cl-, increasing with temperature in a manner consistent with the small endothermicities of the reactions. The anion reactions with ClF are 10%-20% efficient at 300 K to yield Cl- and also show a positive temperature dependence despite being highly exothermic. The stationary points along the anion + ClF reaction coordinates were calculated using density functional theory, showing no endothermic barriers inhibiting reaction. The observed temperature dependence can be rationalized by a decreasing dipole attraction with increasing rotational energy, but confirmation requires trajectory calculations of the systems. All four cation reactions are fairly efficient at 300 K with small positive temperature dependences, despite large exothermicities to charge transfer. Three of the four reactions proceed exclusively by dissociative charge transfer to yield Cl+. The N2+ + ClF reaction proceeds by both non-dissociative and dissociative charge transfer, with the non-dissociative channel surprisingly increasing with increasing temperature. The origins of these behaviors are not clear and are discussed within the framework of charge-transfer reactions. PMID- 28595395 TI - Quantifying fermionic decoherence in many-body systems. AB - Practical measures of electronic decoherence, called distilled purities, that are applicable to many-body systems are introduced. While usual measures of electronic decoherence such as the purity employ the full N-particle density matrix which is generally unavailable, the distilled purities are based on the r body reduced density matrices (r-RDMs) which are more accessible quantities. The r-body distilled purities are derivative quantities of the previously introduced r-body reduced purities [I. Franco and H. Appel, J. Chem. Phys. 139, 094109 (2013)] that measure the non-idempotency of the r-RDMs. Specifically, the distilled purities exploit the structure of the reduced purities to extract coherences between Slater determinants with integer occupations defined by a given single-particle basis that compose an electronic state. In this way, the distilled purities offer a practical platform to quantify coherences in a given basis that can be used to analyze the quantum dynamics of many-electron systems. Exact expressions for the one-body and two-body distilled purities are presented and the utility of the approach is exemplified via an analysis of the dynamics of oligo-acetylene as described by the Su-Schrieffer-Heeger Hamiltonian. Last, the advantages and limitations of the purity, reduced purity, and distilled purity as measures of electronic coherence are discussed. PMID- 28595396 TI - Mechanism of the fcc-to-hcp phase transformation in solid Ar. AB - We present an atomistic description of the fcc-to-hcp transformation mechanism in solid argon (Ar) obtained from transition path sampling molecular dynamics simulation. The phase transition pathways collected during the sampling for an 8000-particle system reveal three transition types according to the lattice deformation and relaxation details. In all three transition types, we see a critical accumulation of defects and uniform growth of a less ordered transition state, followed by a homogeneous growth of an ordered phase. Stacking disorder is discussed to describe the transition process and the cooperative motions of atoms in {111} planes. We investigate nucleation with a larger system: in a system of 18 000 particles, the collective movements of atoms required for this transition are facilitated by the formation and growth of stacking faults. However, the enthalpy barrier is still far beyond the thermal fluctuation. The high barrier explains previous experimental observations of the inaccessibility of the bulk transition at low pressure and its sluggishness even at extremely high pressure. The transition mechanism in bulk Ar is different from Ar nanoclusters as the orthorhombic intermediate structure proposed for the latter is not observed in any of our simulations. PMID- 28595397 TI - A quantum method for thermal rate constant calculations from stationary phase approximation of the thermal flux-flux correlation function integral. AB - This paper presents a quantum mechanical approximation to the calculation of thermal rate constants. The rate is derived from a suitable stationary phase approximation to the time integral of the thermal flux-flux correlation function. The goal is to obtain an expression that barely depends on the position of the flux operators, i.e., of the dividing surfaces, so that it can be applied also to complex systems by arbitrarily locating the dividing surfaces. The approach is tested on one and two dimensional systems where quantum effects are predominant over a wide range of temperatures. The results are quite accurate, i.e., within a few percent of the exact values for a reasonable range of dividing surface positions. PMID- 28595398 TI - Simulations of simple linoleic acid-containing lipid membranes and models for the soybean plasma membranes. AB - The all-atom CHARMM36 lipid force field (C36FF) has been tested with saturated, monounsaturated, and polyunsaturated lipids; however, it has not been validated against the 18:2 linoleoyl lipids with an unsaturated sn-1 chain. The linoleoyl lipids are common in plants and the main component of the soybean membrane. The lipid composition of soybean plasma membranes has been thoroughly characterized with experimental studies. However, there is comparatively less work done with computational modeling. Our molecular dynamics (MD) simulation results show that the pure linoleoyl lipids, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine (18:0/18:2) and 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (di-18:2), agree very well with the experiments, which demonstrates the accuracy of the C36FF for the computational study of soybean membranes. Based on the experimental composition, the soybean hypocotyl and root plasma membrane models are developed with each containing seven or eight types of linoleoyl phospholipids and two types of sterols (sitosterol and stigmasterol). MD simulations are performed to characterize soybean membranes, and the hydrogen bonds and clustering results demonstrate that the lipids prefer to interact with the lipids of the same/similar tail unsaturation. All the results suggest that these two soybean membrane models can be used as a basis for further research in soybean and higher plant membranes involving membrane-associated proteins. PMID- 28595399 TI - Modeling the nonlinear dielectric response of glass formers. AB - The recently developed pragmatical model of asymmetric double-well potentials with a finite lifetime is applied to nonlinear dielectric data in polar undercooled liquids. The viscous effects from the finite lifetime provide a crossover from the cooperative jumps of many molecules at short times to the motion of statistically independent molecules at long times. The model allows us to determine the size of cooperatively rearranging regions from nonlinear omega data and throws new light on a known inconsistency between nonlinear omega and 3omega-signals for glycerol and propylene carbonate. PMID- 28595401 TI - Thermodynamic electrophilicity. AB - We revisit the electrophilicity index proposed by Parr et al., with special emphasis on the working equations used to calculate this descriptor. We show that the standard way to obtain this reactivity index (using the conceptual density functional theory formalism) leads to several issues. In this contribution, we propose to overcome these difficulties by making use of the finite temperature grand-canonical formalism. In this way, we not only bypass the characteristic inconsistencies of the zero temperature formulation but we are able to obtain a simple exact working equation for the electrophilicity in terms of electronic structure magnitudes. PMID- 28595400 TI - Correlated natural transition orbital framework for low-scaling excitation energy calculations (CorNFLEx). AB - We present a new framework for calculating coupled cluster (CC) excitation energies at a reduced computational cost. It relies on correlated natural transition orbitals (NTOs), denoted CIS(D')-NTOs, which are obtained by diagonalizing generalized hole and particle density matrices determined from configuration interaction singles (CIS) information and additional terms that represent correlation effects. A transition-specific reduced orbital space is determined based on the eigenvalues of the CIS(D')-NTOs, and a standard CC excitation energy calculation is then performed in that reduced orbital space. The new method is denoted CorNFLEx (Correlated Natural transition orbital Framework for Low-scaling Excitation energy calculations). We calculate second order approximate CC singles and doubles (CC2) excitation energies for a test set of organic molecules and demonstrate that CorNFLEx yields excitation energies of CC2 quality at a significantly reduced computational cost, even for relatively small systems and delocalized electronic transitions. In order to illustrate the potential of the method for large molecules, we also apply CorNFLEx to calculate CC2 excitation energies for a series of solvated formamide clusters (up to 4836 basis functions). PMID- 28595402 TI - Formulation of state projected centroid molecular dynamics: Microcanonical ensemble and connection to the Wigner distribution. AB - A derivation of quantum statistical mechanics based on the concept of a Feynman path centroid is presented for the case of generalized density operators using the projected density operator formalism of Blinov and Roy [J. Chem. Phys. 115, 7822-7831 (2001)]. The resulting centroid densities, centroid symbols, and centroid correlation functions are formulated and analyzed in the context of the canonical equilibrium picture of Jang and Voth [J. Chem. Phys. 111, 2357-2370 (1999)]. The case where the density operator projects onto a particular energy eigenstate of the system is discussed, and it is shown that one can extract microcanonical dynamical information from double Kubo transformed correlation functions. It is also shown that the proposed projection operator approach can be used to formally connect the centroid and Wigner phase-space distributions in the zero reciprocal temperature beta limit. A Centroid Molecular Dynamics (CMD) approximation to the state-projected exact quantum dynamics is proposed and proven to be exact in the harmonic limit. The state projected CMD method is also tested numerically for a quartic oscillator and a double-well potential and found to be more accurate than canonical CMD. In the case of a ground state projection, this method can resolve tunnelling splittings of the double well problem in the higher barrier regime where canonical CMD fails. Finally, the state-projected CMD framework is cast in a path integral form. PMID- 28595403 TI - Colloidal diffusion over a quasicrystalline-patterned surface. AB - We report a systematic study of colloidal diffusion over a substrate with quasicrystalline-patterned holes. Silica spheres of diameter comparable to the hole diameter diffuse over the patterned substrate and experience a gravitational potential U(x, y). Using optical microscopy, we track the particle trajectories and find two distinct states: a trapped state when the particles are inside the holes and a free-diffusion state when they are on the flat surface outside the holes. The potential U(x, y) and dynamic properties of the diffusing particle, such as its mean dwell time, mean square displacement, and long-time diffusion coefficient DL, are measured simultaneously. The measured DL is in good agreement with the prediction of two theoretical models proposed for diffusion over a quasicrystal lattice. The experiment demonstrates the applications of this newly constructed potential landscape. PMID- 28595404 TI - Self-consistent field theory of polyelectrolyte brushes with finite chain extensibility. AB - Polyelectrolyte brushes are formed by charged macromolecules tethered by the end segment to a solid-liquid interface. At low ionic strength of the solution, the intermolecular electrostatic interactions lead to strong stretching of the macromolecules that may, as a result, approach the limit of their extensibility (the contour length). Here, we present an analytical theory of polyelectrolyte brushes developed within the Poisson-Boltzmann approximation which explicitly accounts for finite extensibility of the brush-forming chains. In contrast to earlier theories based on the approximation of Gaussian elasticity of the brush forming chains, the current approach enables avoiding artificial result of stretching of the chains beyond the contour length at high degrees of ionization or/and large grafting densities. PMID- 28595405 TI - Phase transformations upon doping in WO3. AB - High levels of doping in WO3 have been experimentally observed to lead to structural transformation towards higher symmetry phases. We explore the structural phase diagram with charge doping through first-principles methods based on hybrid density functional theory, as a function of doping the room temperature monoclinic phase transitions to the orthorhombic, tetragonal, and finally cubic phase. Based on a decomposition of energies into electronic and strain contributions, we attribute the transformation to a gain in energy resulting from a lowering of the conduction band on an absolute energy scale. PMID- 28595406 TI - An alternative laser driven photodissociation mechanism of pyrrole via pisigma*1/S0 conical intersection. AB - A first principles quantum dynamics study of N-H photodissociation of pyrrole on the S0-1pisigma*(A21) coupled electronic states is carried out with the aid of an optimally designed UV-laser pulse. A new photodissociation path, as compared to the conventional barrier crossing on the pisigma*1 state, opens up upon electronic transitions under the influence of pump-dump laser pulses, which efficiently populate both the dissociation channels. The interplay of electronic transitions due both to vibronic coupling and the laser pulse is observed in the control mechanism and discussed in detail. The proposed control mechanism seems to be robust, and not discussed in the literature so far, and is expected to trigger future experiments on the pisigma*1 photochemistry of molecules of chemical and biological importance. The design of the optimal pulses and their application to enhance the overall dissociation probability is carried out within the framework of optimal control theory. The quantum dynamics of the system in the presence of pulse is treated by solving the time-dependent Schrodinger equation in the semi-classical dipole approximation. PMID- 28595407 TI - On extending Kohn-Sham density functionals to systems with fractional number of electrons. AB - We analyze four ways of formulating the Kohn-Sham (KS) density functionals with a fractional number of electrons, through extending the constrained search space from the Kohn-Sham and the generalized Kohn-Sham (GKS) non-interacting v representable density domain for integer systems to four different sets of densities for fractional systems. In particular, these density sets are (I) ensemble interacting N-representable densities, (II) ensemble non-interacting N representable densities, (III) non-interacting densities by the Janak construction, and (IV) non-interacting densities whose composing orbitals satisfy the Aufbau occupation principle. By proving the equivalence of the underlying first order reduced density matrices associated with these densities, we show that sets (I), (II), and (III) are equivalent, and all reduce to the Janak construction. Moreover, for functionals with the ensemble v-representable assumption at the minimizer, (III) reduces to (IV) and thus justifies the previous use of the Aufbau protocol within the (G)KS framework in the study of the ground state of fractional electron systems, as defined in the grand canonical ensemble at zero temperature. By further analyzing the Aufbau solution for different density functional approximations (DFAs) in the (G)KS scheme, we rigorously prove that there can be one and only one fractional occupation for the Hartree Fock functional, while there can be multiple fractional occupations for general DFAs in the presence of degeneracy. This has been confirmed by numerical calculations using the local density approximation as a representative of general DFAs. This work thus clarifies important issues on density functional theory calculations for fractional electron systems. PMID- 28595408 TI - Probing the remarkable thermal kinetics of visual rhodopsin with E181Q and S186A mutants. AB - We recently reported a very unusual temperature dependence of the rate of thermal reaction of wild type bovine rhodopsin: the Arrhenius plot exhibits a sharp "elbow" at 47 degrees C and, in the upper temperature range, an unexpectedly large activation energy (114 +/- 8 kcal/mol) and an enormous prefactor (1072+/-5 s-1). In this report, we present new measurements and a theoretical model that establish convincingly that this behavior results from a collective, entropy driven breakup of the rigid hydrogen bonding networks (HBNs) that hinder the reaction at lower temperatures. For E181Q and S186A, two rhodopsin mutants that disrupt the HBNs near the binding pocket of the 11-cis retinyl chromophore, we observe significant decreases in the activation energy (~90 kcal/mol) and prefactor (~1060 s-1), consistent with the conclusion that the reaction rate is enhanced by breakup of the HBN. The results provide insights into the molecular mechanism of dim-light vision and eye diseases caused by inherited mutations in the rhodopsin gene that perturb the HBNs. PMID- 28595409 TI - Communication: A novel implementation to compute MP2 correlation energies without basis set superposition errors and complete basis set extrapolation. AB - By using a formulation based on the dynamical polarizability, we propose a novel implementation of second-order Moller-Plesset perturbation (MP2) theory within a plane wave (PW) basis set. Because of the intrinsic properties of PWs, this method is not affected by basis set superposition errors. Additionally, results are converged without relying on complete basis set extrapolation techniques; this is achieved by using the eigenvectors of the static polarizability as an auxiliary basis set to compactly and accurately represent the response functions involved in the MP2 equations. Summations over the large number of virtual states are avoided by using a formalism inspired by density functional perturbation theory, and the Lanczos algorithm is used to include dynamical effects. To demonstrate this method, applications to three weakly interacting dimers are presented. PMID- 28595410 TI - Communication: Almost error-free resolution-of-the-identity correlation methods by null space removal of the particle-hole interactions. AB - We present a method to improve upon the resolution-of-the-identity (RI) for correlation methods. While RI is known to allow for drastic speedups, it relies on a cancellation of errors. Our method eliminates the errors introduced by RI which are known to be problematic for absolute energies. In this way, independence of the error compensation assumption for relative energies is also achieved. The proposed method is based on the idea of starting with an oversized RI basis and projecting out all of its unphysical parts. The approach can be easily implemented into existing RI codes and results in an overhead of about 30%, while effectively removing the RI error. In passing, this process alleviates the problem that for many frequently employed basis sets no optimized RI basis sets have been constructed. In this paper, the theory is presented and results are discussed exemplarily for the random phase approximation and Moller-Plesset perturbation theory. PMID- 28595411 TI - Thermophysical properties of krypton-helium gas mixtures from ab initio pair potentials. AB - A new potential energy curve for the krypton-helium atom pair was developed using supermolecular ab initio computations for 34 interatomic distances. Values for the interaction energies at the complete basis set limit were obtained from calculations with the coupled-cluster method with single, double, and perturbative triple excitations and correlation consistent basis sets up to sextuple-zeta quality augmented with mid-bond functions. Higher-order coupled cluster excitations up to the full quadruple level were accounted for in a scheme of successive correction terms. Core-core and core-valence correlation effects were included. Relativistic corrections were considered not only at the scalar relativistic level but also using full four-component Dirac-Coulomb and Dirac Coulomb-Gaunt calculations. The fitted analytical pair potential function is characterized by a well depth of 31.42 K with an estimated standard uncertainty of 0.08 K. Statistical thermodynamics was applied to compute the krypton-helium cross second virial coefficients. The results show a very good agreement with the best experimental data. Kinetic theory calculations based on classical and quantum-mechanical approaches for the underlying collision dynamics were utilized to compute the transport properties of krypton-helium mixtures in the dilute-gas limit for a large temperature range. The results were analyzed with respect to the orders of approximation of kinetic theory and compared with experimental data. Especially the data for the binary diffusion coefficient confirm the predictive quality of the new potential. Furthermore, inconsistencies between two empirical pair potential functions for the krypton-helium system from the literature could be resolved. PMID- 28595412 TI - Non-adiabatic effects in F + CHD3 reactive scattering. AB - The effect of non-adiabatic transitions on the F(2P) + CHD3(nu1) -> DF + CHD2 and F(2P) + CHD3(nu1) -> HF + CD3 reactions is investigated. The dynamics of the nuclei was simulated using trajectory surface hopping and a vibronically and spin orbit coupled diabatic potential energy matrix. To facilitate the calculations, the fewest switching algorithm of Tully was adapted to the use of a complex diabatic potential energy matrix. For reactions of CHD3 with ground state fluorine atoms, F(2P3/2), the ratio between the previously computed adiabatic cross sections and the non-adiabatic ones was found to range from 1.4 to 2.1. The actual ratio depends on the translational energy and the initial vibrational state of CHD3. The total reactivity of CHD3(nu1 = 1) was found to be always larger than that of CHD3(nu1=0) mainly because of the increase in the cross sections for the HF + CD3 channel. Thus, the inclusion of non-adiabatic transitions in the theoretical treatment cannot resolve the existing disagreement between theory and experiment. Cross sections for the reaction of CHD3 with spin orbit excited fluorine atoms, F(2P1/2), were found to be significantly smaller than the ones for reaction with F(2P3/2). PMID- 28595413 TI - A simple scheme for calculating approximate transition moments within the equation of motion expectation value formalism. AB - A simple scheme for calculating approximate transition moments within the framework of the equation of motion coupled cluster method is proposed. It relies on a matrix inversion technique to calculate the excited state left eigenvectors and requires no additional cost over that of the excitation energy calculation. The new approximation gives almost identical UV-Vis spectra to that obtained using the standard equation of motion coupled cluster method with single and double excitations for molecules in a standard test set. PMID- 28595414 TI - Communication: Orientational structure manipulation in nematic liquid crystal droplets induced by light excitation of azodendrimer dopant. AB - Reversible orientational transitions in the droplets of a nematic liquid crystal (NLC) caused by the change of boundary conditions under the low intensity diode illumination are investigated. Photosensitivity of NLC is achieved by the addition of the dendrimer compound with azobenzene terminal groups. Two types of NLC droplets in glycerol are considered: the spherical droplets in the bulk of glycerol and the droplets laid-down onto the solid substrate. In the second case, the first order phase transition is revealed. The effects described can be useful for the development of highly sensitive chemical detectors and microsized photo tunable optical devices. PMID- 28595415 TI - Computational methodology for solubility prediction: Application to the sparingly soluble solutes. AB - The solubility of a crystalline substance in the solution can be estimated from its absolute solid free energy and excess solvation free energy. Here, we present a numerical method, which enables convenient solubility estimation of general molecular crystals at arbitrary thermodynamic conditions where solid and solution can coexist. The methodology is based on standard alchemical free energy methods, such as thermodynamic integration and free energy perturbation, and consists of two parts: (1) systematic extension of the Einstein crystal method to calculate the absolute solid free energies of molecular crystals at arbitrary temperatures and pressures and (2) a flexible cavity method that can yield accurate estimates of the excess solvation free energies. As an illustration, via classical Molecular Dynamic simulations, we show that our approach can predict the solubility of OPLS-AA-based (Optimized Potentials for Liquid Simulations All Atomic) naphthalene in SPC (Simple Point Charge) water in good agreement with experimental data at various temperatures and pressures. Because the procedure is simple and general and only makes use of readily available open-source software, the methodology should provide a powerful tool for universal solubility prediction. PMID- 28595416 TI - Self-intermediate scattering function analysis of supercooled water confined in hydrophilic silica nanopores. AB - We study the temperature dependence of the self-intermediate scattering function for supercooled water confined in hydrophilic silica nanopores. We simulate the simple point charge/extended model of water confined to pores of radii 20 A, 30 A, and 40 A over a temperature range of 210 K to 250 K. First, we examine the temperature dependence of the structure of the water and find that there is layering next to the pore surface for all temperatures and diameters. However, there exists a region in the center of the pore where the density is nearly constant. Using the density profile, we divide confined water into different regions and compare the dynamics of the water molecules that start in these regions. To this end, we examine the mean-squared displacement and the self intermediate scattering functions for the water hydrogens, which would allow one to connect our results with quasi-elastic neutron scattering experiments. We examine the dependence of the self-intermediate scattering function on the magnitude and direction of the wavevector, as well as the proximity to the silica surface. We also examine the rotational-translational decoupling. We find that the anisotropy of the dynamics and the rotational-translational decoupling is weakly temperature dependent. PMID- 28595418 TI - What is special about how roaming chemical reactions traverse their potential surfaces? Differences in geodesic paths between roaming and non-roaming events. AB - With the notable exception of some illustrative two-degree-of-freedom models whose surprising classical dynamics has been worked out in detail, theories of roaming have largely bypassed the issue of when and why the counterintuitive phenomenon of roaming occurs. We propose that a useful way to begin to address these issues is to look for the geodesic (most efficient) pathways through the potential surfaces of candidate systems. Although roaming manifests itself in an unusual behavior at asymptotic geometries, we found in the case of formaldehyde dissociation that it was the pathways traversing the parts of the potential surface corresponding to highly vibrationally excited reactants that were the most revealing. An examination of the geodesics for roaming pathways in this region finds that they are much less tightly defined than the geodesics in that same region that lead directly to dissociation (whether into closed-shell products or into radical products). Thus, the broader set of options available to the roaming channel gives it an entropic advantage over more conventional reaction channels. These observations suggest that what leads to roaming in other systems may be less the presence of a localized "roaming transition state," than the existence of an entire region of the potential surface conducive to multiple equivalent pathways. PMID- 28595417 TI - Albumin (BSA) adsorption onto graphite stepped surfaces. AB - Nanomaterials are good candidates for the design of novel components with biomedical applications. For example, nano-patterned substrates may be used to immobilize protein molecules in order to integrate them in biosensing units. Here, we perform long MD simulations (up to 200 ns) using an explicit solvent and physiological ion concentrations to characterize the adsorption of bovine serum albumin (BSA) onto a nano-patterned graphite substrate. We have studied the effect of the orientation and step size on the protein adsorption and final conformation. Our results show that the protein is stable, with small changes in the protein secondary structure that are confined to the contact area and reveal the influence of nano-structuring on the spontaneous adsorption, protein-surface binding energies, and protein mobility. Although van der Waals (vdW) interactions play a dominant role, our simulations reveal the important role played by the hydrophobic lipid-binding sites of the BSA molecule in the adsorption process. The complex structure of these sites, that incorporate residues with different hydrophobic character, and their flexibility are crucial to understand the influence of the ion concentration and protein orientation in the different steps of the adsorption process. Our study provides useful information for the molecular engineering of components that require the immobilization of biomolecules and the preservation of their biological activity. PMID- 28595419 TI - Deep-core photoabsorption and photofragmentation of tetrachloromethane near the Cl K-edge. AB - The fragmentation of the tetrachloromethane molecule following core-shell photoexcitation and photoionization in the neighborhood of the chlorine K-edge has been studied by using time-of-flight mass spectroscopy and monochromatic synchrotron radiation. Branching ratios for ionic dissociation were derived for all the detected ions, which are informative of the decay dynamics and photofragmentation patterns of the core-excited species. In addition, the absorption yield has been measured with a new assignment of the spectral features. The structure that appears above the Cl 1s ionization potential in the photoionization spectrum has been ascribed to the existing connection with electron-CCl4 scattering through experimental data and calculations for low energy electron-molecule cross sections. In addition, the production of the doubly ionized Cl fragment, Cl2+, as a function of the photon energy has been analysed in the terms of a simple and an appealing physical picture, the half collision model. PMID- 28595421 TI - Communication: DFT treatment of strong correlation in 3d transition-metal diatomics. AB - Bonds between, and to, transition-metal atoms often involve strong electron correlation which cannot be handled by conventional density-functional-theory approximations. The recent "B13" functional of Becke [J. Chem. Phys. 138, 074109 (2013) and J. Chem. Phys. 138, 161101 (2013)] models dynamic, static, and strong correlation in an exact-exchange-based framework. We test B13 on bond energies of transition-metal diatomics in this work, with promising results. PMID- 28595420 TI - Communication: Direct evidence for sequential dissociation of gas-phase Fe(CO)5 via a singlet pathway upon excitation at 266 nm. AB - We prove the hitherto hypothesized sequential dissociation of Fe(CO)5 in the gas phase upon photoexcitation at 266 nm via a singlet pathway with time-resolved valence and core-level photoelectron spectroscopy with an x-ray free-electron laser. Valence photoelectron spectra are used to identify free CO molecules and to determine the time constants of stepwise dissociation to Fe(CO)4 within the temporal resolution of the experiment and further to Fe(CO)3 within 3 ps. Fe 3p core-level photoelectron spectra directly reflect the singlet spin state of the Fe center in Fe(CO)5, Fe(CO)4, and Fe(CO)3 showing that the dissociation exclusively occurs along a singlet pathway without triplet-state contribution. Our results are important for assessing intra- and intermolecular relaxation processes in the photodissociation dynamics of the prototypical Fe(CO)5 complex in the gas phase and in solution, and they establish time-resolved core-level photoelectron spectroscopy as a powerful tool for determining the multiplicity of transition metals in photochemical reactions of coordination complexes. PMID- 28595423 TI - Classification of meningiomas-advances and controversies. AB - Meningiomas are the most frequent primary central nervous system (CNS) tumors. Although approximately 80% of the tumors are slow growing and benign, some subtypes are associated with a less favorable outcome. An adequate classification system aims at providing a tool for estimating recurrence and overall survival of meningioma patients. The 2016 version of the World Health Organization (WHO) classification for CNS tumors constitutes a hallmark for neuropathological tumor classification since genetic alterations and histopathology are combined for a final diagnosis. Although this mainly applies to neuroepithelial tumors in meningioma research and classification the connection of histomorphological features and genetic profiles becomes more and more evident. Here we report on advances and controversies of meningioma classification in the 2016 edition of the WHO classification of CNS tumors. Furthermore we provide an outlook how a future meningioma classification system might look like. PMID- 28595422 TI - DNA elasticity from coarse-grained simulations: The effect of groove asymmetry. AB - It is well established that many physical properties of DNA at sufficiently long length scales can be understood by means of simple polymer models. One of the most widely used elasticity models for DNA is the twistable worm-like chain (TWLC), which describes the double helix as a continuous elastic rod with bending and torsional stiffness. An extension of the TWLC, which has recently received some attention, is the model by Marko and Siggia, who introduced an additional twist-bend coupling, expected to arise from the groove asymmetry. By performing computer simulations of two available versions of oxDNA, a coarse-grained model of nucleic acids, we investigate the microscopic origin of twist-bend coupling. We show that this interaction is negligible in the oxDNA version with symmetric grooves, while it appears in the oxDNA version with asymmetric grooves. Our analysis is based on the calculation of the covariance matrix of equilibrium deformations, from which the stiffness parameters are obtained. The estimated twist-bend coupling coefficient from oxDNA simulations is G=30+/-1 nm. The groove asymmetry induces a novel twist length scale and an associated renormalized twist stiffness kappat~80 nm, which is different from the intrinsic torsional stiffness C~110 nm. This naturally explains the large variations on experimental estimates of the intrinsic stiffness performed in the past. PMID- 28595424 TI - Animal models of meningiomas. AB - Meningiomas are frequent intracranial and intraspinal tumors. They are tumors of the elderly, and meningioma growth at certain localizations, as well as recurrent tumors or primary aggressive biology may pose a therapeutic challenge. To understand the growth characteristics of meningiomas, animal models can provide insights both from a biological and therapeutical point of view. Using genetically-engineered mouse models (GEMM), it has been proven that alterations of the neurofibromatosis type 2 (NF2) gene are key steps for benign meningioma development. Aggressive meningiomas can be induced by simultaneous activation of Nf2 and the PDGF (platelet-derived growth factor)/-PDGF-Receptor (R) system, or inactivation of Tp53 and cdkn2ab in mice. However, mechanisms acting in NF2 wild type meningiomas are poorly understood so far, because appropriate models are lacking. Xenograft models have been used either by implantation of primary cultures derived from human meningiomas, or immortalized human cell lines, respectively. While the value of primary cells is limited due to low rate of overall tumor growth and slow proliferation, xenograft approaches have been shown to be helpful for the evaluation of potential medical treatment options. Future studies must incorporate new molecular meningioma tumor drivers, as well as potential treatment options based on recurrent genetic alterations into the generation of meningioma models. PMID- 28595426 TI - Patients' perceptions of palliative surgical procedures: a qualitative analysis. AB - BACKGROUND: Patients with incurable malignancies can require surgical intervention. We prospectively evaluated patients treated with palliative surgery to qualitatively assess peri-operative outcomes. METHODS: Eligible patients were assessed at a tertiary care cancer center. Demographic information and peri operative morbidity and mortality were collected. Semi-structured qualitative interviews were obtained pre-operatively and post-operatively (1 month). Qualitative evaluation was performed using content analysis and an inductive approach. RESULTS: Twenty-eight patients were approached and 20 consented to interview. Data saturation was achieved after 14 patients. Median patient age was 58% and 56% were female. Peri-operative morbidity and mortality were 44% and 22%, respectively. "No other option" was seen as a dominant pre-operative theme (14 of 18). Other pre-operative themes included a "poor understanding of prognosis and the role of surgery in overall treatment plan". Post-operative themes included a "perceived benefit from surgery" and "satisfaction with decision-making", notwithstanding significant complications. Improved understanding of prognosis and the role of surgery were described post-operatively. CONCLUSIONS: Despite limited options and a poor understanding of prognosis, many patients perceived benefit from palliative surgery. However, peri-operative mortality was substantial. A robust and thorough patient-centered discussion about individual goals for surgery should be undertaken by surgeon, patient and family prior to embarking on a palliative operation. PMID- 28595427 TI - Challenging equipotency calculation for hydromorphone after long-term intravenous application. AB - In advanced stages, most cancer patients suffer from pain which can usually be well controlled following the World Health Organization (WHO) level scheme. While the majority of patients report adequate pain relief by strong opioids (WHO III), some require an opioid rotation. Despite the existence of conversion tables, these rotations mea lead to inadequate pain control or life threatening events. Here, we report about a patient with urothelial cell carcinoma presenting in our Department of Pain Medicine with massive pain aggravation up to NRS values of 10/10 despite administration of the highest dose of intravenously applied hydromorphone. After a small single dose of the far less potent opioid piritramide with exceptionally good response, we conducted a stepwise opioid rotation from hydromorphone to piritramide within one week without any signs of abstinence or withdrawal. After the opioid rotation, we discharged the patient nearly free of pain with piritramide doses far less than equianalgesic dose tables would have recommended. Our report impressively points out that even after long-term intravenous application of highly potent opioids, new titrations are necessary for rotation to avoid overdosage and discusses several mechanisms underlying individual response to different opioids. PMID- 28595428 TI - Relationship between patient-generated subjective global assessment and survival in patients in palliative care. AB - BACKGROUND: A significant number of cancer deaths is partly due to late diagnosis of the disease at an advanced stage beyond cure. In this context, by applying the adequate tools, palliative care provides terminal cancer patients with the proper support for survival with a higher quality of life. The objective of this study was to describe the nutritional profile of terminal cancer patients and to evaluate the relationship among Patient-Generated Subjective Global Assessment (PG-SGA) score, clinical-functional characteristics and survival. METHODS: The present work is a retrospective cohort study with 104 terminal cancer patients. The Karnofsky Performance Status (KPS) was used to obtain socio-demographic data and clinical history and assess functional capacity. Furthermore, patients were classified by groups and PG-SGA score ranges. RESULTS: In the first medical consultation, the PG-SGA revealed that most patients were moderately or severely malnourished and in critical need of immediate symptom management. Functional capacity of almost half of all patients lay within a KPS score of 40 to 70. Survival analysis revealed that the median time of mortality by cancer was 5 (3.3 6.7) months. Furthermore, patients with an SGA-C, i.e., severely malnourished (P<0.001), a PG-SGA score >=9 (P=0.036) and a KPS score <=40 (P<0.001) had a lower median time of survival. CONCLUSIONS: In addition to evaluating nutritional status, the PG-SGA is directly related with survival in terminal cancer patients. The use of this tool in the studied population is of paramount importance to provide individualised and adequate support for these patients. PMID- 28595425 TI - African American elders' psychological-social-spiritual cultural experiences across serious illness: an integrative literature review through a palliative care lens. AB - Disparities in palliative care for seriously ill African American elders exist because of gaps in knowledge around culturally sensitive psychological, social, and spiritual care. The purpose of this integrative literature review is to summarize the research examining African American elders' psychological, social, and spiritual illness experiences. Of 108 articles, 60 quantitative, 42 qualitative, and 6 mixed methods studies were reviewed. Negative and positive psychological, social, and spiritual experiences were noted. These experiences impacted both the African American elders' quality of life and satisfaction with care. Due to the gaps noted around psychological, social, and spiritual healing and suffering for African American elders, palliative care science should continue exploration of seriously ill African American elders' psychological, social, and spiritual care needs. PMID- 28595430 TI - Sustained effects of acupuncture in treatment of chronic constipation. PMID- 28595429 TI - Expanding palliative care's reach in the community via the elder service agency network. AB - Over the past two decades, palliative care has established itself as a promising approach to address the complex needs of individuals with advanced illness. Palliative care is well-established in US hospitals and has recently begun to expand outside of the hospital setting to meet the needs of non-hospitalized individuals. Experts have called for the development of innovative community based models that facilitate delivery of palliative care to this target population. Elder service agencies are important partners that researchers should collaborate with to develop new and promising models. Millions of older adults receive aging network services in the U.S., highlighting the potential reach of these models. Recent health care reform efforts provide support for community based initiatives, where coordination of care and services, delivered via health and social service agencies, is highly prioritized. This article describes the rationale for developing such approaches, including efforts to educate elder service agency clients about palliative care; training agency staff in palliative care principles; building capacity for elder services providers to screen individuals for palliative care needs; embedding palliative care "champions" in agencies to educate staff and clients and coordinate access to services among those with palliative care needs; and leveraging telehealth resources to conduct comprehensive assessments by hospital palliative care teams for elder service clients who have palliative care needs. We maintain that leveraging the resources of elder service agencies could measurably expand the reach of palliative care in the community. PMID- 28595431 TI - Palliative efficacy and local control of conventional radiotherapy for lung metastases. AB - BACKGROUND: The lung is a common site of metastasis, and conventionally fractionated radiotherapy (CFRT) is commonly used to treat such metastases, usually to palliate symptoms. However, no data exists to quantify palliation or local control (LC) of CFRT for secondary lung tumors. We aimed to describe the palliative effect of CFRT for lung metastases at our institution, and compare its LC with that of stereotactic body radiation therapy (SBRT). METHODS: 182 patients received 190 courses of RT for lung metastases (99 CFRT, 91 SBRT). We characterized the proportion of CFRT patients who experienced palliation, the durability of palliative effect, and cumulative incidence of local failure (LF) using competing-risks regression. We also performed an exploratory comparison of LF between CFRT and SBRT. RESULTS: In CFRT patients, cumulative incidence of LF at 6 months and 1 year was 32% and 43%, respectively. Rate of initial palliation was 74%. Palliation rates for the most common indications were as follows: hemoptysis 86% (25/29), cough 71% (12/17), airway obstruction 66% (25/38), pain 64% (7/11). Of patients who reported palliation, 6-month and 1-year cumulative incidence of symptom recurrence was 52% and 65%, respectively. In SBRT patients, LF at 6 months and 1 year was 5.8% and 19.5%, respectively. CONCLUSIONS: CFRT effectively alleviates a variety of symptoms in lung metastases, supporting its continued use in palliation of metastatic disease. However, subsequent local progression and symptom relapse are common with CFRT. As SBRT is associated with higher rates of LC, this may be preferred in eligible patients with more favorable prognosis. PMID- 28595432 TI - Challenges and successes in non-operative management of high-grade malignant bowel obstruction. AB - Malignant bowel obstruction (MBO) occurs in between 3% and 15% of patients with cancer, and portends a poor mean survival of four weeks for patients who are not able to undergo operative intervention. Surgical interventions may be fraught with complications since these patients typically have compromised nutritional status and progressive metastatic disease burden, with tumor type and degree of aggressiveness affecting outcomes. MBO is a dynamic and difficult process to treat, with adequate pain control being limited by unpredictable enteral absorption and need for prolonged parenteral analgesia (given limited enteral access) with its inherent risks. To explore these difficulties, we report the case of a 43-year-old patient who presented with multi-level MBO from metastatic rectal carcinoma, and explore the challenges and successes of symptom management in a non-operative MBO. PMID- 28595433 TI - Managing chemotherapy-induced nausea and vomiting in head and neck cancer patients receiving cisplatin chemotherapy with concurrent radiation. AB - BACKGROUND: The purpose was to retrospectively examine the anti-emetic regimens prescribed for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) for head and neck cancer patients receiving moderate- or high-emetogenic chemotherapy (MEC/HEC) along with concurrent radiation treatment at an outpatient ambulatory care center to determine the efficacy of anti-emetics prescribed. METHODS: Consecutive patients with head and neck cancers who initiated cisplatin chemotherapy with concurrent radiation treatment between January 2013 and June 2015 were investigated. Patients' anti-emetic use and occurrence of CINV was extracted from available clinical documentation. Patients were divided into two cohorts: CISPL-HIGH (n=161), and CISPL-WEEKLY (n=38). RESULTS: A total of 199 head and neck cancer patients (158 male, 41 female) were included in the analysis (mean age =59 years). In the CISPL-HIGH cohort, 33 males (26%) and 16 females (49%) experienced CINV. In the CISPL-WEEKLY cohort, four males (13%) and two females (25%) experienced CINV. Nausea occurred in 71 patients (62 HEC and 9 MEC). The odds of achieving complete response (no nausea or vomiting) were 3.5 (P<0.0016) times more likely for patients receiving MEC. Overall, the complete response rate for the prophylaxis in MEC and HEC was 61% and 31%, respectively. Anti-emetic changes occurred in 34% and 11% of patients receiving HEC and MEC, respectively. CONCLUSIONS: In the current study CINV control for patients receiving HEC was sub-optimal. Changes to our prophylactic antiemetic regimens may help improve patient outcomes. PMID- 28595434 TI - Radiotherapy for brain metastases near the end of life in an integrated health care system. AB - BACKGROUND: To examine radiotherapy (RT) patterns-of-care and utilization at the end of life (EOL) among non-small cell lung cancer (NSCLC) patients with brain metastasis (BrM) in an integrated health care system. METHODS: Central tumor registry identified 5,133 patients diagnosed with NSCLC from 2007-2011. BrM were determined by imaging. Patient and clinical characteristics were obtained by chart abstraction. In addition to abstracted variables, graded prognostic assessment (GPA) score of 0-1 was derived by collected data and tested as a predictor of death within 14 or 30 days of RT. RESULTS: On NSCLC presentation, 10% harbored BrM while 7% developed BrM thereafter. Of 900 BrM patients, 15% were not referred for RT, with median time to death of 21 days. Median time to death for 5% not recommended RT was 48 days. Among those receiving brain RT, 11.9% died within 14 days and 23.3% (cumulatively) died within 30 days of treatment. Over 50% with GPA score 0-1 received RT, 11% within 14 days and 21% within 30 days of death; median survival of GPA score 0-1 patients was 49 days. GPA score 0-1 independently predicted for death within 30 days of RT receipt. CONCLUSIONS: BrM are common in NSCLC, and most patients are referred for brain RT. A surprising proportion of patients received treatment near the EOL, as 23% died within 30 days of RT. GPA score of 0-1 predicted for death within 30 days of treatment. RT referral, recommendation, and timing should be better tailored to life expectancy, and additional benchmarks for quality of care are needed. PMID- 28595435 TI - A fetal diagnostic center's referral rate for perinatal palliative care. AB - BACKGROUND: Fetal specialists support standardizing the practice of offering women palliative care for life limiting fetal diagnoses. However, there is little data available regarding what fetal specialists do in practice. Since 2003, our center has kept a database of all women referred for fetal complications. METHODS: Retrospective electronic chart review of pregnant women between 2006 and 2012 using UCSD's Fetal Care and Genetics Center referral database. Objectives were to determine: (I) how many high risk pregnancies referred to the University of California San Diego Medical Center (UCSD) over a 6-year period have potentially life limiting fetal diagnoses; (II) pregnancy outcome; and (III) referral rate to perinatal palliative care. RESULTS: Between July 2006 and July 2012, 1,144 women were referred to UCSD's Fetal Care and Genetics Center, a tertiary care center. Of that cohort, 332 women (29%) were diagnosed prenatally with a potentially life limiting fetal diagnosis. Most women were Hispanic or Latino, married, and had previous children. The median gestation at confirmed diagnosis was 19 weeks. Trisomy 13, Trisomy 18, and anencephaly comprised 21% of cases. The pregnancy outcome was determined in 95% cases: 56% therapeutic abortion, 16% intrauterine fetal demise, and 23% live birth. Only 11% of cases were referred to perinatal palliative care. CONCLUSIONS: The vast majority of women with potentially life limiting fetal diagnoses are not referred to perinatal palliative care. Evaluation of how to integrate palliative care into high-risk obstetrics is needed. PMID- 28595436 TI - Ethical challenges in extra corporeal membrane oxygenation use. PMID- 28595437 TI - Perceptions and types of support coming from families caring for patients suffering from advanced illness in Kinshasa, Democratic Republic of Congo. AB - BACKGROUND: Perceptions of families who take care of patients suffering from advanced illness are rarely considered in Kinshasa medical practices; nevertheless, these families are the main actors involved in such care. The objective of this present study was to illustrate, in a Congolese context, the perceptions of families on the care of patients suffering from advanced illness, and to identify the possible aids provided by healthcare facilities. METHODS: A qualitative study was performed among focus groups in six hospitals in Kinshasa. Each group included eight members. RESULTS: We gathered factors that could negatively influence the care of a patient suffering from advanced disease. Such factors included: scarcity of and inaccessibility to painkillers, economic resilience, poor quality treatment, lack of psychological counselling, seeking alternative solutions and poor communication between caregivers and patients. In contrast, the study also showed that relatives caring for these patients often receive support from the wider family and from cult members. CONCLUSIONS: This study focuses on the miscommunication between healthcare workers and patients, poor management in advanced illness as well as a lack of psychological support from caregivers. The findings can serve as basis for further research in palliative care. PMID- 28595438 TI - Should dexamethasone be standard in the prophylaxis of pain flare after palliative radiotherapy for bone metastases?-a debate. AB - Pain flare is a well-recognized side-effect of palliative radiotherapy for the treatment of painful bone metastases, with recent randomized data showing incidence rates up to 35%. The impact of pain flare has been associated with worsening immobility, anxiety, depression and quality of life. The use of dexamethasone has recently been supported as an effective option in reducing radiation-induced pain flare based on the NCIC Clinical Trials Group (NCIC CTG) Symptom Control 23 (SC.23) randomized double-blind placebo-controlled trial. Despite this, conflicting opinions exist, and standard clinical use of dexamethasone to prevent pain flare continues to be debated among clinicians. Given this controversy, two sides of the debate are presented. Although consensus has not been achieved, the choice to use dexamethasone in the prophylactic setting to reduce pain flare incidence should be a shared decision between the oncologist and patient. Factors including symptom burden, comorbidities, performance status, quality of life and radiation dose and fractionation should be taken into account on an individualized level. PMID- 28595440 TI - On the way of liberation from suffering and pain: role of hypnosis in palliative care. AB - The huge problems related to chronic, ultimately fatal diseases involve disability, pain, suffering and the perception of one's doom; this calls for reappraising the conventional concepts of health and disease, life and death, encompassing spirituality and the mystery of death beyond any limited perspective. The management of suffering and pain to enhance resilience plays a central role in palliative care (PC) and is the core of the patient-centered approach, focused on the "to care" instead of the "to cure" of the illness centered medicine. In this article, the perspectives supporting these instances are analyzed, focusing on hypnosis, to be considered as a powerful technique able to improve patient's control over mind and body (including relaxation, fairness, analgesia, improved stability of physical parameters and wellbeing). PMID- 28595441 TI - Healing, spirituality and integrative medicine. AB - Spirituality plays a prominent role in the lives of most palliative patients whether or not they formally adhere to a specific religion and belief. As a result, the palliative care team is frequently called upon to support families who are experiencing their "dark night of the soul" and struggling to make sense of their lives during a healthcare crisis. While conventional religious practices provide a source of comfort and guidance for many of our patients, a significant number of our patients do not have a strong religious community to which to turn. Over the last two decades, more people in Western countries identify themselves as spiritual but not religious and do not belong to an organized faith community. For those patients who express a strong spiritual connection or sense of 'something greater' or 'a higher power', encouraging the exploration of those feelings and beliefs through chaplains, clergypersons, or members of the interdisciplinary palliative care team can help provide context, meaning and purpose in their lives impacted by serious illness. One of the goals of effective palliative care is the facilitation of personal growth and psychological resilience in dealing with one's health challenges. Integrative medicine, also referred to as complementary and alternative medicine, provides a set of tools and philosophies intended to enhance wellness and a sense of wellbeing. Many of the modalities are derived from disciplines such as massage, acupuncture, Rei Ki, aromatherapy, and dietary supplements. The use of integrative medicine in North America is widespread and frequently not shared with one's clinician due to many patients' concerns that clinicians will disapprove of the patient's use of them. In addition to its efficacy in reducing symptoms commonly experienced by patients receiving palliative care (e.g., nausea, pain, depression, and existential suffering), integrative medicine offers non-verbal, non-cognitive avenues for many to achieve a peaceful and calm inner state. The calm state often achieved during integrative medicine treatments is similar to that seen during deep prayer or meditation. In such a transcendent or non-ordinary state of consciousness, many people experience new insights or understanding of their lives and choices they must make. Thus, integrative approaches facilitate patients attaining greater self-awareness and may meet their spiritual needs without the religious overtones that accompany traditional prayer. In so doing, patients may gain greater insight and find inner peace through simple, non-verbal approaches. PMID- 28595442 TI - Quality of life in responders after palliative radiation therapy for painful bone metastases using EORTC QLQ-C30 and EORTC QLQ-BM22: results of a Brazilian cohort. AB - BACKGROUND: Bone metastases cause pain, suffering and impaired quality of life (QoL). Palliative radiotherapy (RT) and/or chemotherapy are effective methods in controlling pain, reducing analgesics use and improving QoL. This study goal was to investigate the changes in QoL scores among patients who responded to palliative treatment. METHODS: A prospective study evaluating the role of radiation therapy in a public academic hospital in Sao Paulo-Brazil recorded patients' opioid use, pain score, Portuguese version of QLQ-BM22 and QLQ-C30 before and 2 months after radiotherapy. Analgesic use and pain score were used to calculate international pain response category. Overall response was defined as the sum of complete response (CR) and partial response (PR). CR was defined as pain score of 0 with no increase in analgesic intake whereas PR was defined as pain reduction >=2 without analgesic increase or analgesic reduction in >=25% without increase in pain at the treated site. RESULTS: From September 2014 to October 2015, 25 patients with bone metastases responded to RT or chemotherapy (1 CR, 24 PR). There were 8 male and 17 female patients. The median age of the 25 patients was 59 (range, 22 to 80) years old. Patient's primary cancer site was breast [11], prostate [5], lung [2], others [7]. For QLQ-BM 22, the mean scores of 4 categories at baseline were: pain site (PS) 39, pain characteristics (PC) 61, function interference (FI) 49 and psycho-social aspects (PA) 57. At 2 month follow up, the scores were PS 27, PC 37, FI 70 and PA 59. Statistical significant improvement (P<0.05) was seen in PS, PC, FI but not PA. In the QLQ-C30, the scores were not statistically different for all categories, except for pain that demonstrated a 33 point decrease in the median pain score domain (66 to 33). CONCLUSIONS: Responders to RT at 2 months presented improvement in BM22 and C30 pain domains, and also improvement in functional interference domain of the BM22 questionnaire. PMID- 28595443 TI - Shedding light on the fundamental mechanism underlying hypnotic analgesia. AB - Owing to the increasing importance of clinical hypnosis in pain therapy and palliative care, there is a growing interest in uncovering the mechanism underlying hypnotic analgesia. The neurophysiological findings suggest that the hypnotic state is associated with an altered operating mode of the brain that is clearly different from the normal operating mode. While in the normal operating mode a dolorogenic stimulus induces a highly synchronized large-scale activity pattern that leads to the experience of pain, the altered operating mode inhibits the synchronization of spatially divided brain regions. As a consequence, the conscious experience of pain cannot arise. In order to gain a deeper understanding of the mechanism, a novel theoretical framework is made use of. It accepts consciousness as a fundamental property of the universe and is based on the hypothesis that the whole range of phenomenal qualities is built into the frequency spectrum of a ubiquitous background field. The body of evidence supports the view that in the normal operating mode our brains act as filters that extract the plethora of phenomenal nuances selectively from this field. In the altered operating mode, which establishes under hypnotic conditions, the extraction of phenomenal qualities is partially prevented. From this perspective, hypnotic analgesia is due to an impairment of the fundamental mechanism underlying conscious perception. PMID- 28595444 TI - International access to palliative care: the need to improve. PMID- 28595445 TI - Sixty-day mortality after stereotactic radiosurgery of brain metastases-a forgotten palliative treatment outcome. PMID- 28595446 TI - Life perceptions of patients receiving palliative care and experiencing psycho social-spiritual healing. AB - BACKGROUND: It is important to identify, from the patients' perspectives, the different factors that contribute toward psycho-social-spiritual healing. METHODS: This was a qualitative study that took place at a large research center, an underserved clinic, and a community hospital. We used a needs assessment questionnaire and open-ended questions to assess the constituents of psycho social-spiritual healing: (I) how previous life experiences affected patients' present situations in dealing with their illnesses; (II) barriers to palliative care, and (III) benefits of palliative care. RESULTS: Of a total of 30 participants from 3 different study sites, 24 (80%) were receiving inpatient or outpatient palliative care at a research center. Thirteen (43%) participants were female, 10 (33%) were Black/African American, and 16 (53%) reported being on disability. While the initial shock of the diagnosis made participants feel unprepared for their illnesses, many looked to role models, previous work experiences, and spiritual as well as religious support as sources of strength and coping mechanisms. Barriers to palliative care were identified as either external (lack of proper resources) or internal (symptom barriers and perceived self-limitations). The feeling of "being seen/being heard" was perceived by many participants as the most beneficial aspect of palliative care. CONCLUSIONS: The needs assessment questionnaire and open-ended questions presented in this study may be used in clinical settings to better help patients achieve psycho-social spiritual healing through palliative care and to help clinicians learn about the person behind the patient. PMID- 28595447 TI - Therapeutic suggestions with critically ill in palliative care. AB - Suggestions can be used without formal hypnosis, especially with critically ill patients, due to their spontaneous trance state. In this paper we outline data on the effectiveness of therapeutic suggestions. We interpret the possible mechanism of therapeutic suggestions in the context of stress cognition. Basic principles of formulating suggestions are discussed and some recommended versions of non pharmacological pain control are provided. Case vignettes are given of how suggestions are used with critically ill ICU patients. PMID- 28595448 TI - Do patients receiving pelvic radiation and anti-emetics experience diarrhea and/or constipation? AB - BACKGROUND: Pelvic radiation may cause radiation enteritis, which commonly manifests as diarrhea. Radiation to the abdomen or pelvis may also cause radiation-induced nausea and vomiting (RINV) which is often treated with anti emetics such as serotonin (5-HT3) receptor antagonists (RA). However, a common side effect of these anti-emetic medications is constipation. Both diarrhea and constipation can have a significant impact on patient quality of life (QOL). The objective of this study was to assess the prevalence of diarrhea and constipation in patients receiving pelvic radiation and anti-emetics. METHODS: Patients undergoing pelvic radiation between January 2011 and March 2017 at Sunnybrook Odette Cancer Centre were enrolled in three prospective clinical trials studying the efficacy of various anti-emetics for RINV prophylaxis. Patients completed QOL questionnaires which included a single question about severity of constipation at baseline, day 5 and 10 during radiation if applicable, and day 5 and 10 after completion of radiation; severity was measured on a 4-point Likert scale ranging from 1= "not at all" to 4= "very much". Patients also recorded severity of diarrhea throughout baseline, treatment, and 10 days follow-up via daily diaries; responses were qualitative ranging from "no diarrhea" to "severe diarrhea" on a 4 point scale. RESULTS: Fifty-nine patients received pelvic radiation across the three trials. The average constipation score at baseline was 1.69 [standard deviation (SD) 0.93], and increased up to 2.33 (SD 1.03) at day 10 during treatment. Following treatment, the average score decreased to 1.61 (SD 0.80) at day 10 follow-up with the majority of patients reporting no constipation at this time (57.7%). The average diarrhea score at baseline was 1.03 (SD 0.18) and remained stable throughout treatment and follow-up. A vast majority of patients reported no diarrhea after day 10 follow-up (96.4%). CONCLUSIONS: Constipation was more prevalent than diarrhea during radiation treatment and up to day 10 after radiation to the pelvis. Approximately 42% of patients will have constipation on day 10 post radiation. Further research is needed to assess the causes of constipation including analgesics, and the effect on QOL during and shortly after palliative radiation to the pelvis. PMID- 28595449 TI - Speedy response can be achieved from palliative radiotherapy in the treatment of painful uncomplicated bone metastases. PMID- 28595450 TI - A new malyngamide from the marine cyanobacterium Moorea producens. AB - A new malyngamide (1) was isolated along with seven known compounds (2-8) from the marine cyanobacterium Moorea producens collected in Hawaii. Compound 1 represented the first reported malyngamide with a hydroxy moiety at C-7 of the characteristic fatty acid portion of the compound. Compound 1 showed cytotoxicity against L1210 cell line at an IC50 value of 2.9 mM and lethal toxicity against the shrimp Palaemon paucidens at a LD100 value of 33.3 mg/kg. The bioactivity of compound 1 was approximately 10-100 times weaker than those of isomalyngamides A and B (3, 4). These results indicated that the methoxy group at C-7 of the fatty acid section confers a degree of bioactivity in malyngamides. PMID- 28595452 TI - Taking stock of critical clues to understanding sex differences in the prevalence and recurrence of autism. PMID- 28595451 TI - Dependent Erythema of the Legs Associated With Mild Autonomic Nervous System Dysfunction. AB - INTRODUCTION: Dependent erythema or rubor is an erythematous discoloration of the limbs, most commonly associated with peripheral artery disease. We present a case of florid dependent erythema, associated with additional autonomic symptoms. METHODS: Examination and full workup of a 16-year-old healthy girl with an 8-year history of dependent erythema, chronic diarrhea, and mild hyperhidrosis. A literature search was performed to review any similar cases and generate a differential diagnosis. RESULTS: Examination of our patient showed symmetrical, asymptomatic fiery to dusky erythematous patches of the lower legs and feet, with intermittent areas of pallor. These florid changes occurred with erect posture. Resolution to near normal occurred within minutes when the patient was in the supine position. Full physical examination revealed mild erythema and hyperhidrosis of the hands. CONCLUSIONS: To our knowledge, there have been no reports of painless dependent rubor associated with sympathetic dysfunction. Literature search reports a few cases of gravitational erythema and angiodyskinesia. This case presentation is most likely part of the spectrum of dependent erythema and may shed light on the underlying aetiology. PMID- 28595454 TI - Predictors of Adults' Knowledge and Awareness of HPV, HPV-Associated Cancers, and the HPV Vaccine: Implications for Health Education. AB - High human papillomavirus (HPV) prevalence and low HPV vaccine uptake are significant public health concerns. Disparities in HPV-associated cancers and HPV vaccine uptake rates suggest the need for additional research examining factors associated with vaccine acceptance. This study assessed HPV awareness and knowledge and identified sociodemographic characteristics associated with HPV knowledge at the population level. Data from adult men ( n = 1,197) and women ( n = 1,906) who participated in the National Cancer Institute's 2014 Health Information National Trends Survey were analyzed. Multivariable regression was used to identify predictors of four HPV knowledge categories: (1) general knowledge, (2) cervical cancer knowledge, (3) "other" cancer knowledge (i.e., anal, oral, penile), and (4) vaccine knowledge. Significant gender differences in awareness and knowledge of HPV and the HPV vaccine were revealed. Most participants (>70%) knew that HPV could cause cervical cancer, but fewer (14.9% to 31.5%) knew of the association between HPV and "other" cancers. Women were more likely to report that a health care provider recommended vaccination. Significant predictors of general HPV and HPV vaccine knowledge included gender, education, income, race, and other sociodemographic characteristics. Age and income predicted cervical cancer knowledge. Knowledge of "other" HPV-associated cancers was predicted by having a child under 18 years in the household and relationship status. HPV knowledge appears to be socially patterned. Low HPV knowledge among men and some racial minorities suggests a need for further intervention. Health education should emphasize risks of noncervical HPV associated cancers. Patient-provider communication that includes education, counseling, and clear recommendations favoring vaccination may improve uptake. PMID- 28595453 TI - Chemical composition and antioxidant activities of the essential oil of Hypericum gaitii Haines - an endemic species of Eastern India. AB - The present study reports the chemical composition and antioxidant activities of the essential oil extracted from the leaves and tender branches of Hypericum gaitii Haines (Hypericaceae) - an endemic plant of Eastern India. On hydrodistillation, the fresh leaves and tender parts of H. gaitii yielded 0.43% (v/w) of pale yellowish essential oil. Gas chromatography mass spectrometry analysis revealed the presence of 40 compounds, which represent 96.9% of the total oil. Monoterpene hydrocarbons (79.3%) predominated followed by sesquiterpene hydrocarbons (12.6%). Of these, alpha-pinene (69.5%), beta caryophyllene (10.5%), sabinene (5.6%), myrcene (3.0%) and geranyl acetate (2.0%) were the main constituents. Antioxidant activities of oil were evaluated by three different systems namely 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2-azinobis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS) and reducing power assay. Essential oil exhibited moderate antioxidant activities compared to butylated hydroxytoluene (BHT) and ascorbic acid. PMID- 28595457 TI - How people with dementia and their carers adapt their homes. A qualitative study. AB - The objective was to explore the ways in which people with dementia and their carers adapt their homes, including the barriers and use of available information. Semi-structured interviews were conducted with 10 people with dementia and their informal carer. The collected data were analysed using thematic analysis. Three core themes emerged: Maintaining familiarity and coping with change, Having knowledge and finding knowledge and Meeting challenges through home adaptation. The most significant barriers to making home adaptations were lack of knowledge and maintaining familiarity. Having more information and making home modifications earlier might enable individuals with dementia to adjust to their adapted environment. PMID- 28595456 TI - Altered Brain Wiring in Parkinson's Disease: A Structural Connectome-Based Analysis. AB - Parkinson's disease (PD) is a neurodegenerative disorder that predominantly affects the motor system. Diffusion magnetic resonance imaging (MRI) has demonstrated deficits in anisotropy as well as increased diffusivity in the sub cortical structures, primarily in the substantia nigra in PD. However, the clinical spectrum of PD is not limited to motor symptoms; rather, it encompasses several nonmotor symptoms such as depression, psychosis, olfactory dysfunction, and cognitive impairment. These nonmotor symptoms underscore PD as a complex neurological disorder arising from dysfunction of several network components. Therefore, to decipher the underlying neuropathology, it is crucial to employ novel network-based methods that can elucidate associations between specific network changes. This study aimed at assessing the large-scale structural network changes in PD. Structural connectomes were computed by using probabilistic fiber tracking on diffusion MRI between 86 regions of interest. Graph theoretic analysis on the connectome was carried out at several levels of granularity: global, local (nodal), lobar, and edge wise. Our findings demonstrate lower network clustering capability, overall lower neural connectivity, and significantly reduced nodal influence of the hippocampus in PD. In addition, extensive patterns of reduced connectivity were observed within and between the temporal, parietal, and occipital areas. In summary, our findings corroborate widespread structural disconnectivity that can be potentially linked to the nonmotor symptoms in PD. PMID- 28595455 TI - A new antifungal and antiprotozoal bibenzyl derivative from Gavilea lutea. AB - A new bibenzyl derivative (4), together with two glycosylated flavonoids (1 and 2), batatasin III (3) and the phenanthrene isohircinol (5) were isolated from the aerial parts of Gavilea lutea. Their structures were elucidated on the basis of spectroscopic studies including 1D and 2D NMR, UV, IR and HRESIMS. All isolated compounds were evaluated for their antifungal activity towards Candida albicans. The new compound 4 showed inhibitory activity with a MIQ of 50 MUg. In addition, compound 4 exhibited a selective activity (IC50 = 2.3 MUg/mL) against Leishmania donovani. PMID- 28595458 TI - Continuous synthesis and anti-myocardial injury of tanshinone IIA derivatives. AB - A series of tanshinone IIA derivatives were synthesized through sulfonation, slat forming, chlorination, and amidation reactions. Meanwhile, anti-myocardial injury activity was evaluated in vitro. D8 and D9 exhibited a slightly higher anti myocardial injury (5.78, 7.46 MUM) activity compared with esmolol (8.12 MUM). In addition, they also displayed a concentration-dependent inhibition on the anti myocardial injury. PMID- 28595459 TI - Percutaneous closure of the left atrial appendage in patients with diabetes mellitus. AB - BACKGROUND: Left atrial appendage closure is a preventive treatment of atrial fibrillation-related thrombo-embolism. Patients with diabetes mellitus have increased risk for a negative outcome in percutaneous cardiac interventions. We assessed whether percutaneous left atrial appendage closure is safe and effective in patients with diabetes mellitus. METHODS: We included 78 patients (mean age of 74.4 +/- 8.3 years) with indication for left atrial appendage closure in an open label observational single-centre study. RESULTS: Patients with diabetes mellitus ( n = 31) were at higher thrombo-embolic and bleeding risk (CHA2DS2-VASc: 4.5 +/- 0.9, HAS-BLED: 4.7 +/- 0.7) compared to patients without diabetes mellitus ( n = 47, CHA2DS2-VASc: 3.5 +/- 1.0, HAS-BLED: 4.1 +/- 0.8; p < 0.001 for both). Pre- and periprocedural risk was elevated in patients with diabetes mellitus (Euro II Score: 6.6 +/- 3.7 vs 3.9 +/- 1.9, p < 0.01; Society of Thoracic Surgeons (STS) Score: 4.0 +/- 2.5 vs 2.6 +/- 1.2, p < 0.01). Procedural success was similar. Periprocedural major adverse cardiac and cerebrovascular events occurred in one patient from the control group (2.1%), whereas patients with diabetes mellitus had no events ( p = 0.672). Follow-up of 6 months revealed no bleeding complication in both groups. No stroke occurred in follow-up, and left atrial appendage flow velocity reduction (55.6 +/- 38.6 vs 51.4 +/- 19.1 cm/s, p = 0.474) and rate of postinterventional leakage in the left atrial appendage were comparable (0% vs 2.1%, p = 0.672). CONCLUSION: Despite patients with diabetes mellitus are high-risk patients, the outcome of percutaneous left atrial appendage closure is similar to patients without diabetes mellitus. PMID- 28595460 TI - Sub-inhibitory stress with essential oil affects enterotoxins production and essential oil susceptibility in Staphylococcus aureus. AB - Fourteen wild strains of Staphylococcus aureus positive for gene sea were tested for enterotoxins production and the minimum inhibitory concentration of Leptospermum scoparium, Origanum majorana, Origanum vulgare, Satureja montana and Thymus vulgaris essential oils (EOs) were determined. After this trial, bacteria stressed with sub-inhibitory concentration of each EO were tested for enterotoxins production by an immunoenzymatic assay and resistance to the same EO. Oregano oil exhibited the highest antibacterial activity followed by manuka and thyme oils. After the exposure to a sub-inhibitory concentration of EOs, strains displayed an increased sensitivity in more than 95% of the cases. After treatment with oregano and marjoram EOs, few strains showed a modified enterotoxins production, while 43% of the strains were no longer able to produce enterotoxins after treatment with manuka EO. The results obtained in this study highlight that exposure to sub-inhibitory concentration of EO modifies strains enterotoxins production and EOs susceptibility profile. PMID- 28595461 TI - An in vitro examination of the antioxidant, cytoprotective and anti-inflammatory properties of chrysin-loaded nanofibrous mats for potential wound healing applications. AB - Chrysin (Chr) is a naturally occurring flavone with a wide spectrum of biological functions including anti-cancer, anti-inflammatory and anti-oxidant properties. Due to the low bioavailability and in vivo stability of Chr at therapeutic levels for wound-healing applications, Chr-loaded PCL/PEG nanofibrous mats were successfully fabricated by optimizing the electrospinning parameters and characterized using FE-SEM and FTIR. Results of MTT showed that Human foreskin fibroblast cells (HFF-1) have more than 80% viability on Chr-loaded nanofibers. The antioxidant activity of Chr-loaded PCL/PEG electrospun nanofibers was demonstrated applying an ORAC assay and by the capability of the nanofibers to maintain the viability of HFF-1 cells on the mats under an oxidative stress condition. The Chr-blended PCL/PEG nanofibrous mats also reduced overexpression of IL-6, IL-1beta, TNF-alpha and excessive production of nitric oxide (NO) in J774A1 following stimulation by lipopolysaccharide (LPS). These results suggest that the proposed natural substance based nanofibrous mats can accelerate wound healing process with cell proliferation, antioxidative and anti-inflammatory activities. PMID- 28595462 TI - Isotopic and multielemental fingerprinting of organically and conventionally grown potatoes. AB - Two marker combinations were used for the differentiation of organically produced from conventionally produced potatoes and also for the geographical origin identification. Fifty-seven samples (from Romanian local producers or imported) were analysed from the stable isotopic (isotope ratio mass spectrometry) and elemental profile (inductively coupled plasma mass spectrometry) point of view. In order to assess the best marker combination, both isotopic and elemental experimental results were subject to chemometric analysis. The statistical tests performed were ANOVA test, Pearson correlation, principal component analysis and linear discriminant analysis (LDA). For a more comprehensive differentiation between organic vs. conventional potato samples, LDA was applied, and 94.7 % of original cases were correctly classified and the percentage obtained in cross validation procedure was 91.2 %. Regarding the geographic origin classification, LDA provided an initial classification of 96.5 %, while for cross-validation the percentage was 87.7. LDA found delta15N, Cd, Ca, Cu and Zn as best discrimination markers between organically and conventionally grown potatoes. The strongest predictors for Romania vs. foreign geographical areas along LDA were seen to be Ca, P, Co, Ni and delta13C. PMID- 28595463 TI - A new arbutin derivative from the leaves of Vaccinium dunalianum wight. AB - A new arbutin derivative, namely dunalianosides J (1), along with six known compounds, arbutin (2), robustaside A (3), 6'-O-caffeoylarbutin (4), dunalianoside D (5), kaempferol 3-O-beta-D-glucopyranoside (6) and kaempferol 3-O beta-D-sambubioside (7) were isolated from the leaves of Vaccinium dunalianum Wight (Ericaceae). The structure of 1 was elucidated by extensive 1D and 2D NMR, HR-MS and CD spectroscopic analyses. In which, kaempferol 3-O-beta-D-sambubioside (7) was isolated from the genus Vaccinium for the first time. PMID- 28595464 TI - The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. AB - OBJECTIVE: To explore the effects of baroreflex activation therapy (BAT) on hypertension in patients with treatment resistant or refractory hypertension. METHODS: This investigator-initiated randomized, double-blind, 1:1 parallel design clinical trial will include 100 patients with refractory hypertension from 6 tertiary referral hypertension centers in the Nordic countries. A Barostim Neo System will be implanted and after 1 month patients will be randomized to either BAT for 16 months or continuous pharmacotherapy (BAT off) for 8 months followed by BAT for 8 months. A second randomization will take place after 16 months to BAT or BAT off for 3 months. Eligible patients have a daytime systolic ambulatory blood pressure (ABPM) of >=145 mm Hg, and/or a daytime diastolic ABPM of >=95 mm Hg after witnessed drug intake (including >=3 antihypertensive drugs, preferably including a diuretic). RESULTS: The primary end point is the reduction in 24-hour systolic ABPM by BAT at 8 months, as compared to pharmacotherapy. Secondary and tertiary endpoints are effects of BAT on home and office blood pressures, measures of indices of cardiac and vascular structure and function during follow-up, and safety. CONCLUSIONS: This academic initiative will increase the understanding of mechanisms and role of BAT in the refractory hypertension. PMID- 28595465 TI - Community and Individual Risk Factors for Physical Child Abuse and Child Neglect: Variations by Poverty Status. AB - Families are impacted by a variety of risk and protective factors for maltreatment at multiple levels of the social ecology. Individual- and neighborhood-level poverty has consistently been shown to be associated with higher risk for child abuse and neglect. The current study sought to understand the ways in which individual- and neighborhood-level risk and protective factors affect physical child abuse and child neglect and whether these factors differed for families based on their individual poverty status. Specifically, we used a three-level hierarchical linear model (families nested within census tracts and nested within cities) to estimate the relationships between physical child abuse and child neglect and neighborhood structural factors, neighborhood processes, and individual characteristics. We compared these relationships between lower and higher income families in a sample of approximately 3,000 families from 50 cities in the State of California. We found that neighborhood-level disadvantage was especially detrimental for families in poverty and that neighborhood-level protective processes (social) were not associated with physical child abuse and child neglect for impoverished families, but that they had a protective effect for higher income families. PMID- 28595466 TI - Writing a book review. AB - Book reviews are a good way to get started with writing for a journal and this Learning and CPD activity takes you through the process of understanding the aims of book review, undertaking practice pieces through to reviewing a book and advice on the dos and don'ts of book reviewing. PMID- 28595467 TI - Remissions after third induction chemotherapy for primary non-responders with acute myeloid leukemia (AML) are uncommon and short-lived. PMID- 28595468 TI - Compositional analysis of lignocellulosic biomass: conventional methodologies and future outlook. AB - The composition and structural properties of lignocellulosic biomass have significant effects on its downstream conversion to fuels, biomaterials, and building-block chemicals. Specifically, the recalcitrance to modification and compositional variability of lignocellulose make it challenging to optimize and control the conditions under which the conversion takes place. Various characterization protocols have been developed over the past 150 years to elucidate the structural properties and compositional patterns that affect the processing of lignocellulose. Early characterization techniques were developed to estimate the relative digestibility and nutritional value of plant material after ingestion by ruminants and humans alike (e.g. dietary fiber). Over the years, these empirical techniques have evolved into statistical approaches that give a broader and more informative analysis of lignocellulose for conversion processes, to the point where an entire compositional and structural analysis of lignocellulosic biomass can be completed in minutes, rather than weeks. The use of modern spectroscopy and chemometric techniques has shown promise as a rapid and cost effective alternative to traditional empirical techniques. This review serves as an overview of the compositional analysis techniques that have been developed for lignocellulosic biomass in an effort to highlight the motivation and migration towards rapid, accurate, and cost-effective data-driven chemometric methods. These rapid analysis techniques can potentially be used to optimize future biorefinery unit operations, where large quantities of lignocellulose are continually processed into products of high value. PMID- 28595469 TI - Application of the ICRP respiratory tract model to estimate pulmonary retention of industrially sampled indium-containing dusts. AB - Inhalation of indium-containing dusts is associated with the development of indium lung disease. Workers may be exposed to several different chemical forms of indium; however, their lung dosimetry is not fully understood. We characterized the physicochemical properties and measured the lung dissolution kinetics of eight indium-containing dusts. Indium dissolution rates in artificial lung fluids spanned two orders of magnitude. We used the International Commission on Radiological Protection (ICRP) human respiratory model (HRTM) to estimate pulmonary indium deposition, retention and biokinetic clearance to blood. For a two-year (median workforce tenure at facility) exposure to respirable-sized particles of the indium materials, modeled indium clearance (>99.99% removed) from the alveolar-interstitial compartment was slow for all dusts; salts would clear in 4 years, sintered indium-tin oxide (ITO) would clear in 9 years, and indium oxide would require 48 years. For this scenario, the ICRP HRTM predicted that indium translocated to blood would be present in that compartment for 3.5-18 years after cessation of exposure, depending on the chemical form. For a 40-year exposure (working lifetime), clearance from the alveolar-interstitial compartment would require 5, 10 and 60 years for indium salts, sintered ITO and indium oxide, respectively and indium would be present in blood for 5-53 years after exposure. Consideration of differences in chemical forms of indium, dissolution rates, alveolar clearance and residence time in blood should be included in exposure assessment and epidemiological studies that rely on measures of total indium in air or blood to derive risk estimates. PMID- 28595470 TI - Twenty images over 20 years: clinical imaging and healthcare photography in the Wellcome Image Awards (WIA). AB - The Wellcome Image Awards are celebrating their 20th year of bringing us the world's most incredible science and health images this year. The 2017 winners can be seen at exhibitions to be held simultaneously across the UK, in science centres from Aberdeen to the Eden Project, as well as in Russia and South Africa. Over the last 20 years many images have featured amongst the winners and this gallery showcases the images from the contemporary clinical collection that were successful during that time. PMID- 28595472 TI - Correction to: Grzasko R, et al., Chromosome 1 amplification has similar prognostic value to del(17p13) and t(4;14)(p16;q32) in multiple myeloma patients: analysis of real-life data from the Polish Myeloma Study Group. PMID- 28595471 TI - Improved survival in multiple myeloma, with a diminishing racial gap and a widening socioeconomic status gap over three decades. AB - Multiple myeloma (MM) is estimated to have 30,280 new cases and be associated with 12,590 deaths in 2017. However, quantitative analysis for survival, based on a large population, is lacking. Data were extracted from a total of 33,170 cases from nine registry sites in the Surveillance, Epidemiology, and End Results database. The current study shows that the incidence for MM remained relatively stable between 1981 and 2010, with 4.6, 4.7, and 4.7 per 100,000 persons in each decade. In addition, survival for MM improved each decade with a larger increment in the last two decades, with a narrowing survival gap among races and a widening gap among socioeconomic status (SES) groups. The survival gap changes in races and SES groups may guide clinicians to design better treatment protocols and call for the pressing need for health-care policy to fill the gap among SES groups. PMID- 28595473 TI - CD4+CD26- lymphocytes are useful to assess blood involvement and define B ratings in cutaneous T cell lymphoma. AB - Bernengo et al. reported that >30% CD4+CD26- lymphocytes detect blood involvement in patients with mycosis fungoides (MF) and Sezary syndrome. In addition, the ISCL/EORTC suggested that this threshold might serve as a criterion for the B2 blood rating for staging. In this manuscript, we report our experience with measurement of CD4+CD26- and CD4+CD7- cells, Sezary cell counts, and aberrant T cells with diminished expression of CD2, CD3, or CD5 antigens. CD4+CD26- >=30% occurred in 15 of 373 (4.0%) patients with MF, 33 of 47 (70%) patients with erythrodermic cutaneous T cell lymphoma (ECTCL) and 2 of 54 (4%) patients with inflammatory skin diseases. CD4+CD26- measurements provided a more reliable assessment of neoplastic cell numbers in the blood than Sezary cell or CD4+CD7- percentages. CD4+CD26- measurements may be used to define B ratings for staging with B2 defined as CD4+CD26- >= 1000/MUL, plus clonality or phenotypically abnormal cells. PMID- 28595474 TI - Symptoms of depression and anxiety as predictors of physical functioning in breast cancer patients. A prospective study using path analysis. AB - BACKGROUND: Although symptoms of depression and anxiety are linked to health related quality of life (HRQoL), the nature of this relationship remained unclear. We therefore aimed to examine, in a prospective study, both possible directions of impact in this relationship. To avoid conceptual and measurement overlap between depressive and anxiety symptoms, on the one hand, and HRQoL, on the other hand, we focused on the physical functioning component of HRQoL. MATERIAL AND METHODS: We conducted a secondary analysis of a prospective cohort study with 436 female breast cancer patients (mean age 51 years). Both at baseline and after 12 months, we measured symptoms of depression and anxiety with the four-item Patient Heath Questionnaire (PHQ-4) and physical functioning with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Using path analysis, we estimated (1) the predictive value of symptoms of depression/anxiety for subsequent physical functioning and (2) the predictive value of physical functioning for subsequent symptoms of depression/anxiety, in the same model. RESULTS: Baseline symptoms of depression/anxiety predicted 1-year levels of physical functioning (depression: standardized beta = -.09, p = .024; anxiety: standardized beta = -.10, p = .009), while the reciprocal paths linking baseline physical functioning to subsequent depressive and anxiety symptoms were not significant, adjusting for the baseline scores of all outcome variables. CONCLUSIONS: Depressive and anxiety symptoms were predictors of the physical functioning component of HRQoL. Thus, if this relation is causal, treating breast cancer patients' depressive and anxiety symptoms may have a favorable impact on their self-reported physical functioning. PMID- 28595475 TI - A novel ENT iBook: what do junior doctors think? AB - Exposure to the specialty of Otolaryngology is limited. It may be consolidated by the use of an iBook as a self-study tool. The purpose of this study was to ascertain the perceptions of junior doctors on the clinical relevance of this novel educational resource. Three focus groups were formed each consisting of five junior doctors (eight female: seven male, median age 27 years). The iBook was found to be clinically relevant to the work of junior doctors, have a clear layout, with adequate interactivity and a good range of integrated multimedia elements. PMID- 28595476 TI - Obituary: Dr Leslie Bowcock, MB, ChB, HonFRPS, HonFIMI. PMID- 28595477 TI - Positive effects of plantar vibration training for the treatment of diabetic peripheral neuropathy: A pilot study. AB - PURPOSE: To evaluate the effectiveness of 8-week low-frequency plantar vibration training on patients with sensorimotor diabetic peripheral neuropathy (DPN). PARTICIPANTS: Twelve patients took part in the investigation. RESULTS: An increase of the nerve conductive velocity of soral and peroneal nerves of feet, increased postural stability, and disappearance of the pain and tingling were observed. CONCLUSION: The obtained results provide evidence for beneficial effects of 8-week plantar vibration training in patients with DPN. PMID- 28595478 TI - Validating Multidimensional Outcome Assessment Using the TBI Common Data Elements: An Analysis of the TRACK-TBI Pilot Sample. AB - The Glasgow Outcome Scale-Extended (GOSE) is often the primary outcome measure in clinical trials for traumatic brain injury (TBI). Although the GOSE's capture of global function outcome has several strengths, concerns have been raised about its limited ability to identify mild disability and failure to capture the full scope of problems patients exhibit after TBI. This analysis examined the convergence of disability ratings across a multidimensional set of outcome domains in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study. The study collected measures recommended by the TBI Common Data Elements (CDE) Workgroup. Patients presenting to 3 emergency departments with a TBI of any severity enrolled in TRACK-TBI prospectively after injury; outcome measures were collected at 3 and six months postinjury. Analyses examined frequency of impairment and overlap between impairment status across the CDE outcome domains of Global Level of Functioning (GOSE), Neuropsychological (cognitive) Impairment, Psychological Status, TBI Symptoms, and Quality of Life. GOSE score correlated in the expected direction with other outcomes (M Spearman's rho = .21 and .49 with neurocognitive and self-report outcomes, respectively). The subsample in the Upper Good Recovery (GOSE 8) category appeared quite healthy across most other outcomes, although 19.0% had impaired executive functioning (Trail Making Test Part B). A significant minority of participants in the Lower Good Recovery subgroup (GOSE 7) met criteria for impairment across numerous other outcome measures. The findings highlight the multidimensional nature of TBI recovery and the limitations of applying only a single outcome measure. PMID- 28595479 TI - Psychobiology of cumulative trauma: hair cortisol as a risk marker for stress exposure in women. AB - Childhood trauma (CT) is associated with long-lasting alterations of the hypothalamic-pituitary-adrenal (HPA) axis and elevated risk for stress exposure in adulthood. Although HPA alterations are present in the early aftermath of trauma, it remains unclear how initial HPA activity is associated with subsequent stress exposure and whether CT exposure influences the strength and direction of this association. The present study examined prospective associations between hair cortisol content (HCC) and stress exposure from baseline to 3-month follow up in young adult women with recent (i.e. past 3 months) exposure to interpersonal violence (IPV; i.e. physical or sexual assault) and non-traumatized controls. History of significant CT abuse or neglect was determined based on clinical cutoffs for a self-report CT measure: 12 women had abuse or neglect and recent IPV exposure (CT + IPV); 7 women had abuse or neglect but no IPV exposure (CT); 15 women had no history of trauma (NTC). HCC was computed for 3 cm sections reflecting cortisol secretion during the 3 months preceding the baseline assessment. The interaction of cumulative trauma and HCC predicted stress exposure over 3-month follow-up, controlling for baseline stress exposure and depressive symptoms. Simple slopes analyses revealed that lower baseline HCC predicted greater stress exposure in the CT + IPV group compared to the CT group; HCC was not associated with stress exposure in the NTC group. The present findings highlight the potential utility of HCC as a predictor of stress exposure for women with a history of childhood abuse or neglect, particularly in the context of recent IPV. Lay summary Adults with a history of CT show long-lasting alterations in major stress response systems, including the HPA axis. They are also more likely to experience stressful life events in adulthood. However, it is not clear how altered HPA activity influences risk for stress exposure and whether CT affects their relationship. The results from this study show that lower HPA activity (measured with hair cortisol) predicted greater stress exposure in women with CT - particularly for women who also experienced recent incidents involving physical or sexual assault. PMID- 28595480 TI - In vitro evaluation of cobalt oxide nanoparticle-induced toxicity. AB - Cobalt oxide (Co3O4) nanoparticles have applications in nanomedicine and nanotechnology; therefore, any possible adverse effects require thorough investigation. The present study investigated the effects of Co3O4 nanoparticles on four different cell lines: liver, HepG2 hepatocellular carcinoma cells; lung, A549 lung carcinoma cells; gastrointestinal, Caco-2 colorectal adenocarcinoma cells; and nervous system, SH-SY5Y neuroblastoma cells. A difference was observed in cell sensitivity toward Co3O4 nanoparticles. Co3O4 nanoparticles were taken up by all the cell types. However, no cell death was observed in HepG2, Caco-2, or SH-SY5Y cells; only A549 cells showed cytotoxicity at relatively high exposure concentrations. Co3O4 nanoparticles did not induce DNA damage or apoptosis in the cell lines tested except in A549. Interestingly, Co3O4 nanoparticles induced cellular oxidative damage in all cell types except Caco-2, resulting in increased malondialdehyde and 8-hydroxydeoxyguanosine levels and decreased glutathione levels. According to our results, it could be indicated that high concentrations of Co3O4 nanoparticles affected the pulmonary system but were unlikely to affect the liver, nervous system, or gastrointestinal system. Co3O4 nanoparticles might be safely used for industrial, commercial, and nanomedical applications if dose rates are adjusted depending on the route of exposure. However, further in vivo and in vitro studies are required to confirm the safety of Co3O4 nanoparticles. PMID- 28595481 TI - Retrograde Popliteal Access to Percutaneous Peripheral Intervention for Chronic Total Occlusion of Superficial Femoral Arteries. AB - OBJECTIVE: The aim of this study is to present our initial experience with the use of the retrograde popliteal artery access in patients with chronic total occlusions of superficial femoral artery (SFA). METHOD: From July 2012 to May 2014, a total of 28 patients (20 men, mean age 61.2 +/- 11.5 years) with total occlusion of the SFA and good distal runoff were treated with percutaneous atherectomy, balloon angioplasty, and stenting (mean length 165.3 +/- 57.5 mm, range 72-336 mm). All patients had severe claudication or critical limb ischemia, and most of the lesions were TransAtlantic Inter-Society Consensus classification type D (n = 21). RESULTS: Technical success was achieved in all cases. In majority (26, 92.8%) of the patients, endoluminal recanalization was possible from the popliteal access; SFA recanalization in the other 2 cases was obtained through the subintimal space. During a mean follow-up of 12.9 +/- 2.5 months, claudication, severity, rest pain, and toe ulcers improved significantly. Ankle brachial index changed from 0.54 +/- 0.11 to 0.91 +/- 0.2 at 1 year after intervention ( P < .001), and patency rates at 1, 6, and 12 months after interventions were 100%, 92.8%, and 85.7%, respectively. One pseudoaneurysm and 1 arteriovenous fistula were found in the popliteal region on duplex examinations. There were 2 in-stent restenosis and 3 occlusions during the 12-month follow-up. These occlusions were treated with reendovascular procedures. Our secondary patency rate was 96.4%. No stent fracture was observed. CONCLUSION: The retrograde popliteal artery approach under duplex guidance can be considered as safe, efficient, and the primary SFA recanalization strategy in carefully selected patients, with competitive immediate and mid-term results. PMID- 28595482 TI - Development of edible films obtained from submicron emulsions based on whey protein concentrate, oil/beeswax and brea gum. AB - Edible films with whey protein concentrate (WPC) with a lipid component, sunflower oil (O) or beeswax (W), to enhance barrier to water vapor were obtained. Brea gum was used as emulsifier and also as matrix component. In order to achieve emulsion with small and homogeneous droplet size, an ultrasonicator equipment was used after obtaining a pre-emulsion using a blender. The films were made by casting. Effects of lipid fraction on droplet size, zeta potential, mechanical properties, water vapor permeability (WVP), solubility, and optical properties were determined. The droplet size of emulsions with BG decreased when decreasing the lipid content in the formulation. The zeta potential was negative for all the formulations, since the pH was close to 6 for all of them and pI of BG is close to 2.5, and pI of beta-lactoglobulin and alpha-lactalbumin (main proteins in WPC) are 5.2 and 4.1, respectively. Increasing W or SO content in blended films reduced the tensile strength and puncture resistance significantly. BG and WPC films without lipid presented better mechanical properties. The presence of lipids decreased the WVP, as expected, and those films having BG improved this property. BG films were slightly amber as a result of the natural color of the gum. BG has shown to be a good polysaccharide for emulsifying the lipid fraction and improving the homogeneity and mechanical properties of the films with WPC and beeswax or oil. PMID- 28595483 TI - Comparative studies on polyphenolic profile and antimicrobial activity of propolis samples selected from distinctive geographical areas of Hungary. AB - The present paper reports about a comparative survey on the chemical composition, antioxidant activity and in vitro antimicrobial activity of selected propolis samples collected in Hungary. The total levels of polyphenolic compounds including flavonoids in ethanolic extracts of propolis were assessed. The major constituents of ethanolic extracts of propolis were analysed by gas chromatography/mass spectrometry analysis. Total phenolic content was determined spectrophotometrically using a Folin-Ciocalteu reagent. Free radical scavenging activities were evaluated by means of 2,2-diphenyl-1-picrylhydrazyl assay. In vitro inhibitory activity was investigated against eight different bacterial strains by agar well diffusion assay. An extensive comparison was carried out regarding general parameters and specific polyphenolic components. The experimental data led to the observation that there is considerable variability in terms of the quality and the biological value of the distinctive propolis samples. These findings confirm the hypothesis of the study; versatile experimental results are required for proper, well-reasoned, balanced and standardised industrial applications. The major flavonoid components were found to be chrysin and pinocembrin; however, versatile minor components were also detected. The total polyphenol content of ethanolic extracts of propolis ranged between 104.6 mg/g and 286.9 mg/g (gallic acid equivalent). The radical scavenging activity of ethanolic extracts of propolis varied between 101.7 mg/g and 286.9 mg/g (ascorbic acid equivalent). As the quality of propolis depends on the season, vegetation and the area of collection, marked differences were found among the different products examined in terms of both composition and general characteristics. The studied samples exhibited significant differences in term of antimicrobial activities. PMID- 28595484 TI - Kinetic modelling and optimisation of antimicrobial compound production by Candida pyralidae KU736785 for control of Candida guilliermondii. AB - Biological antimicrobial compounds from yeast can be used to address the critical need for safer preservatives in food, fruit and beverages. The inhibition of Candida guilliermondii, a common fermented beverage spoilage organism, was achieved using antimicrobial compounds produced by Candida pyralidae KU736785. The antimicrobial production system was modelled and optimised using response surface methodology, with 22.5 C and pH of 5.0 being the optimum conditions. A new concept for quantifying spoilage organism inhibition was developed. The inhibition activity of the antimicrobial compounds was observed to be at a maximum after 17-23 h of fermentation, with C. pyralidae concentration being between 0.40 and 1.25 * 109 CFU ml-1, while its maximum specific growth rate was 0.31-0.54 h-1. The maximum inhibitory activity was between 0.19 and 1.08 l contaminated solidified media per millilitre of antimicrobial compound used. Furthermore, the antimicrobial compound formation rate was 0.037-0.086 l VZI ml-1 ACU h-1, respectively. The response surface methodology analysis showed that the model developed sufficiently described the antimicrobial compound formation rate 1.08 l VZI ml-1 ACU, as 1.17 l VZI ml-1 ACU, predicted under the optimum production conditions. PMID- 28595485 TI - Strawberry puree processed by thermal, high pressure, or power ultrasound: Process energy requirements and quality modeling during storage. AB - Strawberry puree was processed for 15 min using thermal (65 C), high-pressure processing (600 MPa, 48 C), and ultrasound (24 kHz, 1.3 W/g, 33 C). These conditions were selected based on similar polyphenoloxidase inactivation (11% 18%). The specific energies required for the above-mentioned thermal, high pressure processing, and power ultrasound processes were 240, 291, and 1233 kJ/kg, respectively. Then, the processed strawberry was stored at 3 C and room temperature for 30 days. The constant pH (3.38+/-0.03) and soluble solids content (9.03 +/- 0.25 degrees Brix) during storage indicated a microbiological stability. Polyphenoloxidase did not reactivate during storage. The high-pressure processing and ultrasound treatments retained the antioxidant activity (70%-74%) better than the thermal process (60%), and high-pressure processing was the best treatment after 30 days of ambient storage to preserve antioxidant activity. Puree treated with ultrasound presented more color retention after processing and after ambient storage than the other preservation methods. For the three treatments, the changes of antioxidant activity and total color difference during storage were described by the fractional conversion model with rate constants k ranging between 0.03-0.09 and 0.06-0.22 day - 1, respectively. In resume, high pressure processing and thermal processes required much less energy than ultrasound for the same polyphenoloxidase inactivation in strawberry. While high pressure processing retained better the antioxidant activity of the strawberry puree during storage, the ultrasound treatment was better in terms of color retention. PMID- 28595486 TI - Special considerations for the diagnosis and treatment of invasive pulmonary aspergillosis. AB - INTRODUCTION: The diagnosis and treatment of invasive pulmonary aspergillosis (IPA) are ongoing challenges in clinical practice. While important advances have recently been made, including enhanced diagnostic modalities as well as novel therapeutic and prophylactic options, more effective options are urgently needed as the population of immunocompromised patients continues to expand. Areas covered: In this paper, we review novel approaches to diagnosis of IPA, including multiplex PCR, Matrix Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry and provide a detailed review of the extended-spectrum triazole isavuconazole, which was approved in 2015 to treat IPA. Expert commentary: We explore burgeoning approaches to diagnosis, including the lateral flow assay, volatile organic compounds, and artificial olfactory technology, as well as novel antifungal agents to treat IPA such as SCY-078 and F901318. PMID- 28595487 TI - Circulating Levels of Vascular Endothelial Growth Factor and Basic Fibroblastic Growth Factor in Infantile Hemangioma Versus Vascular Malformations. AB - Few preliminary reports studied the utility of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) for differentiation between infantile hemangiomas (IHs) and vascular malformations. The aim of this study was to investigate the role of serum VEGF and bFGF levels in differentiating IHs from vascular malformations and identifying the stage and clinical course of IHs. Serum levels of VEGF and bFGF were assessed in 60 infants and children with various cutaneous vascular anomalies defined in 3 groups: proliferating IHs (n = 25), involuting IHs (n = 23), and vascular malformations (n = 12), in comparison with their levels in 40 healthy matched control. Serum levels of VEGF and bFGF were significantly elevated in all groups as compared to control ( P < .001, respectively). Both proliferating and involuting IHs had comparable levels of both markers ( P > .05, respectively) that were significantly higher in comparison with vascular malformations ( P < .05, respectively). Significantly lower VEGF levels were found in IHs that had regressed spontaneously (n = 11) compared to those regressed by treatment (n = 37), ( P < .05); meanwhile, bFGF showed no significant difference between both groups ( P > .05). Using receiver operating characteristic curves, a combined use of VGEF and bFGF yielded a sensitivity of 85.42% and a specificity of 100% for differentiating IHs from vascular malformations. Serum VEGF and/or bFGF levels are increased in cutaneous vascular anomalies and can differentiate IHs from vascular malformations. None of these markers could help in identifying the stage of IHs. Low VEGF is associated with spontaneous regression of IHs. PMID- 28595488 TI - Can MRI detect pulmonary hypertension in a population pre-selected by echocardiography? AB - Background The place of magnetic resonance imaging (MRI) in the assessment of pulmonary hypertension (PH) remains controversial. Several studies proposed to use MRI to assess pulmonary pressure but the level of proof is low. Purpose To evaluate the diagnostic power of cardiac MRI within a non-selected population of patients suspected of PH after an echocardiography. Material and Methods Fifty six consecutive patients, suspected of PH after an echocardiography, were assessed with right heart catheterization and cardiac MRI (including a high temporal resolution pulmonary flow curve). We extracted from the MRI data the main parameters proposed by all precedent studies available in the literature. We looked for multivariate linear relations between those parameters and the mean pulmonary arterial pressure (mPAP), and eventually assessed with a logit regression the ability of those parameters to diagnose PH in our population. Results The multivariate model retained only two parameters: the right ventricle ejection fraction and the pulmonary trunk minimum area. The prediction of mPAP (r2 = 0.5) yielded limits of agreement of 15 mmHg. However, the prediction of PH within the population was feasible and the method yielded a specificity of 80% for a sensitivity of 100%. Conclusion The performance of MRI to assess mPAP is too low to be used as a replacement for right heart catheterization but MRI could be used as second line examination after echocardiography to avoid right heart catheterization for normal patients. PMID- 28595489 TI - A Brain Model of Disturbed Self-Appraisal in Depression. AB - OBJECTIVE: A disturbed sense of self is a core feature of depression. The medial prefrontal cortex, which has a central role in self-appraisal processes, is often implicated in the illness, although it remains unclear how functional alterations of the region contribute to the observed disturbances. The aim of this study was to clarify the role of the medial prefrontal cortex in self-appraisal processes in depression. METHOD: The authors applied a recently developed dynamic network model of self-directed cognition to functional MRI data from 71 adolescents and young adults with moderate to severe major depressive disorder, none of whom were being treated with medication, and 88 healthy control participants. Bayesian model averaging was used to determine parameter estimates for the dynamic causal models, which were compared between groups. RESULTS: While self-directed cognitive processes in the depression group were shown to rely on the same dynamic network as in the healthy control group, the medial prefrontal cortex had a "hyperregulatory" effect on the posterior cingulate cortex in the depressed group, with self-appraisal causing significantly more negative modulation of connectivity between the medial prefrontal cortex and the posterior cingulate cortex than in the control group (odds ratio=0.54, 95% CI=0.38, 0.77). This parameter was significantly inversely related with a depression factor related to poor concentration and inner tension (r=-0.32; 95% CI=-0.51, -0.08). CONCLUSIONS: The exaggerated influence of the medial prefrontal cortex on the posterior cingulate cortex in depression is a neural correlate of the disturbed self appraisal that is characteristic of the illness. PMID- 28595490 TI - The Protective Effect of Pregnancy on Risk for Drug Abuse: A Population, Co Relative, Co-Spouse, and Within-Individual Analysis. AB - OBJECTIVE: The authors sought to determine whether pregnancy is an intrinsic motivator for cessation of drug abuse. METHOD: The authors conducted prospective cohort, co-relative, co-spouse, and within-person analyses of registration for drug abuse during pregnancy among Swedish women born between 1980 and 1990 who gave birth between ages 20 and 35 (N=149,512). Drug abuse was assessed from medical, criminal, and pharmacy registries. RESULTS: In the population, rates of drug abuse were lower during pregnancy (unadjusted odds ratio=0.67, 95% CI=0.60, 0.74). Compared with population results, the negative association between pregnancy and drug abuse was moderately stronger in cousins (odds ratio=0.49, 95% CI=0.39, 0.62) and substantially stronger in siblings (odds ratio=0.35, 95% CI=0.24, 0.51) discordant for pregnancy. The estimated odds ratio for drug abuse in pregnancy-discordant monozygotic twins was even stronger, at 0.17 (95% CI=0.10, 0.31). Within individuals, the odds ratio for drug abuse while pregnant compared with an equivalent prepregnancy interval was similar to that seen in pregnancy-discordant monozygotic twins, at 0.22 (95% CI=0.19, 0.26). Compared with cohabiting fathers, mothers had a greater reduction in risk for drug abuse during pregnancy (odds ratio=0.40, 95% CI=0.34, 0.47). Pregnancy was more protective in women with low parental education and without a cohabiting, actively drug-abusing father. Compared with prepregnancy baseline, within individual analyses indicate that risk for drug abuse is also substantially reduced in the postpartum period, for example, the odds ratio for postpartum days 0-242 was 0.13 (95% CI=0.11, 0.16). CONCLUSIONS: Risk for drug abuse in women is substantially reduced during pregnancy. Multiple analyses suggest that this association is largely causal, suggesting that pregnancy is indeed a strong intrinsic motivator for drug abuse cessation. Similar strong protective effects may be present in the immediate postpartum period. Our results have implications for our etiologic models of drug abuse and especially for contingency management programs seeking to reduce drug abuse risk. PMID- 28595492 TI - Current mathematical models for cancer drug discovery. AB - INTRODUCTION: Pharmacometric models represent the most comprehensive approaches for extracting, summarizing and integrating information obtained in the often sparse, limited, and less-than-optimally designed experiments performed in the early phases of oncology drug discovery. Whilst empirical methodologies may be enough for screening and ranking candidate drugs, modeling approaches are needed for optimizing and making economically viable the learn-confirm cycles within an oncology research program and anticipating the dose regimens to be investigated in the subsequent clinical development. Areas covered: Papers appearing in the literature of approximately the last decade reporting modeling approaches applicable to anticancer drug discovery have been listed and commented. Papers were selected based on the interest in the proposed methodology or in its application. Expert opinion: The number of modeling approaches used in the discovery of anticancer drugs is consistently increasing and new models are developed based on the current directions of research of new candidate drugs. These approaches have contributed to a better understanding of new oncological targets and have allowed for the exploitation of the relatively sparse information generated by preclinical experiments. In addition, they are used in translational approaches for guiding and supporting the choice of dosing regimens in early clinical development. PMID- 28595493 TI - Genetic variation in mitochondrial cox2 of Heterakis gallinarum from poultry in Sichuan, China. AB - Heterakis gallinarum is one of the common parasitic nematodes found in the caecum of poultry. To investigate the genetic diversity and genetic structure of the H. gallinarum population in Sichuan, we amplified and sequenced the complete mitochondrial (mt) cytochrome c oxidase subunit II (cox2) gene of 59 H. gallinarum isolates from seven different geographical regions, then analyzed their genetic polymorphisms. All cox2 genes of the 59 H. gallinarum isolates were 696 bp in length, with an average A + T content of 67.1%. Fifty-nine sequences contained 34 variable sites, and were classified into 23 haplotypes (HS1-HS23). The values of haplotype diversity (Hd) and nucleotide diversity (pi) were 0.688 and 0.00288, respectively. Based on values of FST and Nm (FST = 0.01929, Nm = 12.71), there was a frequent gene flow but no significant genetic differentiation observed among the populations. The network map showed that the most prominent haplotype was HS1, and the other haplotypes (HS2-HS23) were centered on HS1 with a star-like topology, indicating that H. gallinarum had previously experienced a population expansion. To our knowledge, this is the first research on the population genetics of H. gallinarum based on mitochondrial cox2. PMID- 28595491 TI - Suicidal Behavior During Lithium and Valproate Treatment: A Within-Individual 8 Year Prospective Study of 50,000 Patients With Bipolar Disorder. AB - OBJECTIVE: Conclusions regarding lithium's antisuicidal effect for bipolar disorder have been limited due to nonrepresentative subjects and potential confounding factors, including varying severity of illness. Findings regarding the effect of valproate, the most common alternative to lithium, are inconsistent for suicidal behavior. This study investigated the associations of these two drugs with the risk of suicide-related events, and possible differences between drugs, by using within-individual designs in a register-based longitudinal cohort. METHOD: Through linkage of multiple Swedish national registers, 51,535 individuals with bipolar disorder were followed from 2005 to 2013 for treatment with lithium and valproate. Stratified Cox regression was used to estimate the hazard ratios of suicide-related events during treated periods compared with untreated periods. For significant associations between medication and suicide related events, the population attributable fraction was estimated to assess the public health impact for patients with bipolar disorder. RESULTS: During follow up, 10,648 suicide-related events occurred. The incidence rate was significantly decreased by 14% during lithium treatment (hazard ratio 0.86, 95% confidence interval [CI] 0.78-0.95) but not during valproate treatment (hazard ratio 1.02, 95% CI 0.89-1.15). The difference in hazard ratios of suicide-related events between lithium and valproate was statistically significant. Estimates of the population attributable fraction suggested that 12% (95% CI 4%-20%) of suicide related events could have been avoided if patients had taken lithium during the entire follow-up. CONCLUSIONS: The results suggest that lithium should be considered for patients with bipolar disorder with suspected suicidal intentions, although risk for suicide is only one of the considerations when providing clinical care. PMID- 28595495 TI - Lipid Based nanoformulation of lycopene improves oral delivery: formulation optimization, ex vivo assessment and its efficacy against breast cancer. AB - This study aims at developing an optimised nanostructured lipid carrier (NLC) of lycopene for efficient absorption following oral administration. The optimised formulation showed an average particle size of 121.9 +/- 3.66 nm, polydispersity index (PDI) 0.370 +/- 0.97 and zeta potential -29.0 +/- 0.83 mV. Encapsulation Efficiency (% EE) and drug loading (% DL) was found to be 84.50% +/- 4.38 and 9.54% +/- 2.65, respectively. In vitro release studies demonstrated the burst release within 4-9 h followed by sustained release over 48 h. The IC50 value of lycopene extract and optimised NLC for ABTS+* were found to be 172.37 MUg Trolox equivalent and 184.17 MUg Trolox equivalent whereas, for DPPH*, 117.76 MUg Trolox equivalent and 143.08 MUg Trolox equivalent respectively. Ex vivo studies and MTT assay revealed that the NLC had better permeation and cause sufficiently more cytotoxicity as compared to drug extract due to higher bioavailability and greater penetration. PMID- 28595494 TI - A Psychopathological Comparison between Delusional Disorder and Schizophrenia. AB - OBJECTIVE: To contribute to a better differential clinical categorisation of delusional disorder (DD) versus schizophrenia (SZ) and to add and complete evidence from previous clinical studies of DD compared to schizophrenia. METHODS: A cross-sectional study using a clinical sample of 275 patients (132 patients with DD) was studied. Patients were consecutively attending public clinics located in urban and rural areas in both Andalusia and Catalonia (Spain). All participants met DSM-IV diagnostic criteria for either DD or SZ. Data were gathered on sociodemographics, illness duration, Barona-Index estimation of intelligence quotient (IQ), and global functioning, along with a thorough psychopathological assessment using the Positive and Negative Syndrome Scale (PANSS). Comparisons between both groups were calculated using chi2, Student t, and multivariate analysis of covariance tests. RESULTS: Patients with DD were older (mean [SD], 50.3 [14.6] years vs. 36.6 [11.1] years; t = 8.597; P <= 0.0001), were more frequently married (45.4% vs. 10.8%; chi2 = 38.569; P <= 0.0001), and had a higher mean estimated premorbid IQ (111.4 vs. 105.4; t = 2.609; P <= 0.01). On the other hand, SZ patients were predominantly male (71.4% vs. 48.9%; chi2 = 14.433; P <= 0.0001) and had greater work-related disability than DD patients (20.5% vs. 50.3%; chi2 = 19.564; P <= 0.001). Overall, the DD group showed a less severe PANSS psychopathology than SZ group. Thus, total mean (SD) PANSS scores for schizophrenia and delusional disorder, respectively, were 76.2 (22.4) versus 54.1 (18.4) ( t = -8.762; P <= 0.0001). Moreover, patients with DD showed a better global functioning than those with SZ (62.7 [13.2] vs. 51.9 [16.9]; F = 44.114; P <= 0.0001). CONCLUSIONS: DD is a milder and distinct disorder compared to SZ in terms of psychopathology and global functionality. PMID- 28595497 TI - Case study - human body relay race. AB - This case presentation introduces the work of Heather Lewis, Graphic Designer from Birmingham Community Healthcare Foundation Trust, Clinical Illustration department. The graphic design team offer professional design solutions in a variety of formats such as scientific posters, banners, patient information booklets and promotional items. This particular project was requested by the Combined Community Dental Service, a Specialist Division in Birmingham. PMID- 28595496 TI - Reconstruction of input functions from a dynamic PET image with sequential administration of 15O2 and [Formula: see text] for noninvasive and ultra-rapid measurement of CBF, OEF, and CMRO2. AB - CBF, OEF, and CMRO2 images can be quantitatively assessed using PET. Their image calculation requires arterial input functions, which require invasive procedure. The aim of the present study was to develop a non-invasive approach with image derived input functions (IDIFs) using an image from an ultra-rapid O2 and C15O2 protocol. Our technique consists of using a formula to express the input using tissue curve with rate constants. For multiple tissue curves, the rate constants were estimated so as to minimize the differences of the inputs using the multiple tissue curves. The estimated rates were used to express the inputs and the mean of the estimated inputs was used as an IDIF. The method was tested in human subjects ( n = 24). The estimated IDIFs were well-reproduced against the measured ones. The difference in the calculated CBF, OEF, and CMRO2 values by the two methods was small (<10%) against the invasive method, and the values showed tight correlations ( r = 0.97). The simulation showed errors associated with the assumed parameters were less than ~10%. Our results demonstrate that IDIFs can be reconstructed from tissue curves, suggesting the possibility of using a non invasive technique to assess CBF, OEF, and CMRO2. PMID- 28595499 TI - Thermal diffusivity and perfusion constants from in vivo MR-guided focussed ultrasound treatments: a feasibility study. AB - PURPOSE: This study investigates the feasibility of non-invasively determining thermal diffusivity (alpha) and the Pennes perfusion parameter (w) from pre clinical and clinical magnetic resonance-guided focussed ultrasound (MRgFUS) temperature data. MATERIALS AND METHODS: Pre-clinical MRgFUS experiments were performed in rabbit muscle (N = 3, 28 sonications) using three-dimensional MR thermometry. Eight sonications were made in a clinical QA phantom with two dimensional thermometry. Retrospective property determination was performed on clinical uterine fibroid (N = 8, 9 sonications) and desmoid tumour (N = 4, 7 sonications) data. The property determination method fits an analytical solution to MRgFUS temperatures in the coronal MR plane, including all temperatures acquired during heating and one cooling image. When possible, additional cooling data were acquired for property determination. RESULTS: Rabbit alpha and w from Heating Data (alpha = 0.164 mm2s-1, w = 7.9 kg m-3 s-1) and Heating and Cooling Data (alpha = 0.146 mm2s-1, w = 3.3 kg m-3 s-1) were within the range of gold standard invasive measurements, with >50% reduction in variability by including cooling data. QA phantom property determination with cooling data yielded properties within 3% of expected values (alpha = 0.144 mm2s-1, w = 0.0 kg m-3 s 1), a difference that was not statistically significant (p = 0.053). Uterine fibroid (Heating Data: alpha = 0.212 mm2s-1, w = 11.0 kg m-3 s-1) and desmoid tumour (Heating & Cooling Data: alpha = 0.245 mm2s-1, w = 4.7 kg m-3 s-1) properties are feasible but lack independent verification. CONCLUSIONS: Thermal diffusivity and the Pennes perfusion parameter can be obtained from in vivo data and with clinical MRgFUS protocols. Property values are consistently improved by including cooling data. The utility of this property determination method will increase as clinical protocols implement improved temperature imaging. PMID- 28595498 TI - Associations of smoking with cardiometabolic profile and renal function in a Romanian population-based sample from the PREDATORR cross-sectional study. AB - BACKGROUND: The impact of smoking on morbidity is well known, but in Romania, limited data are available regarding the smoking prevalence and relationship with cardiometabolic profile and kidney function. OBJECTIVES: To assess the association of smoking with cardiometabolic traits and kidney function, in a Romanian population-based sample from the PREDATORR study. METHODS: PREDATORR was an epidemiological cross-sectional study. Between 2012 and 2014, participants were randomly selected from the lists of general practitioners and enrolled if they were aged 20 to 79 years, born and living in the past 10 years in Romania. Sociodemographic and lifestyle characteristics were collected through interviewer administered questionnaires. RESULTS: Overall, 2704 participants were included in the analysis, 18% of them being current smokers and 30.8% former smokers. Current smokers compared to non-smokers had higher total cholesterol (220.6 +/- 50.4 versus 213.9 +/- 86.8 mg/dl, P = 0.017), LDL-cholesterol (137.8 +/- 45.2 versus 130.7 +/- 83.7 mg/dl, P = 0.004) and glomerular filtration rate (96.9 +/- 16.8 versus 90.7 +/- 19.1 ml/min/1.73 m2, P <0.001) in women and higher triglycerides (170.7 +/- 129.8 versus 144.3 +/- 94.2 mg/dl, P = 0.007), glomerular filtration rate (97.6 +/- 17 versus 90.3 +/- 18 ml/min/1.73 m2, P < 0.001) and lower HDL cholesterol (48 +/- 15.5 versus 50.4 +/- 14.1 mg/dl, P = 0.002) in men. Active smoking was associated with hypercholesterolaemia [OR: 1.40 (95% CI: 1.01-1.96), P = 0.04] and low HDL-cholesterolaemia [OR: 1.39 (95% CI: 1.01-1.91), P = 0.04] and negatively associated with overweight/obesity [OR: 0.67 (95% CI: 0.48-0.94), P = 0.02]. Male former smokers had higher prevalence of abdominal obesity (82.4% versus 76.4%, P = 0.02), hypertriglyceridaemia (43.6% versus 35.6%, P = 0.01), hypertension (64% versus 56.4%, P = 0.01) and ischaemic vascular disease (40.5% versus 30.9%, P = 0.003) than male non-smokers. CONCLUSION: The PREDATORR study showed a high prevalence of smoking in the adult Romanian population providing data on the association of smoking with cardiometabolic traits. PMID- 28595500 TI - The Genus Patrinia: A Review of Traditional Uses, Phytochemical and Pharmacological Studies. AB - The aim of the present review is to comprehensively outline the botanical description, traditional uses, phytochemistry, pharmacology and toxicology of Patrinia, and to discuss possible trends for the further study of medicinal plants from the genus Patrinia. The genus Patrinia plays an important role in Asian medicine for the treatment of erysipelas, conjunctival congestion with swelling and pain, peri-appendicular abscesses, lung carbuncle, dysentery, leucorrhea, and postpartum disease. More than 210 chemical constituents have been isolated and identified from Patrinia plants, especially P. scabiosaefolia Fisch., P. scabra Bunge, P. villosa Juss., P. heterophylla Bunge and P. rupestris(Pall.) Juss[Formula: see text] Of these compounds, triterpenoids and saponins, iridoids, flavonoids, and lignans are the major or active constituents. Both in vitro and in vivo studies have indicated that some monomer compounds and crude extracts from the genus Patrinia possess wide pharmacological activities, including antitumor, anti-inflammatory, antibacterial, and antiviral effects. In addition, they have been shown to have valuable and positive effects on the immune and nervous system in experimental animals. There are also some reports on the clinical uses and toxicity of these species. However, few reports have been published concerning the material identification or quality control of Patrinia species, and the clinical uses and toxic effects of these plants are relatively sparse. More attention must be given to these issues. PMID- 28595501 TI - Astragaloside IV Inhibits Membrane Ca[Formula: see text] Current but Enhances Sarcoplasmic Reticulum Ca[Formula: see text] Release. AB - Astragaloside IV (AS-IV) is one of the active ingredients in Astragalus membrananceus (Huangqi), a traditional Chinese medicine. The present study investigated the effects of AS-IV on Ca[Formula: see text] handling in cardiac myocytes to elucidate its possible mechanism in the treatment of cardiac disease. The results showed that AS-IV at 1 and 10[Formula: see text][Formula: see text]M reduced KCl-induced [Ca[Formula: see text]]i increase ([Formula: see text] from 1.33[Formula: see text][Formula: see text][Formula: see text]0.04 (control, [Formula: see text] 28) to 1.22[Formula: see text][Formula: see text][Formula: see text]0.02 ([Formula: see text], [Formula: see text] 29) and 1.22[Formula: see text][Formula: see text][Formula: see text]0.02 ([Formula: see text] 0.01, [Formula: see text]), but it enhanced Ca[Formula: see text] release from SR ([Formula: see text] from 1.04[Formula: see text][Formula: see text][Formula: see text]0.01 (control, [Formula: see text]) to 1.44[Formula: see text][Formula: see text][Formula: see text]0.03 ([Formula: see text], [Formula: see text]) and 1.60[Formula: see text][Formula: see text][Formula: see text]0.04 ([Formula: see text] 0.01, [Formula: see text]0), in H9c2 cells. Similar results were obtained in native cardiomyocytes. AS-IV at 1 and 10[Formula: see text][Formula: see text]M inhibited L-type Ca[Formula: see text] current ([Formula: see text] from [Formula: see text]4.42[Formula: see text][Formula: see text][Formula: see text]0.58 pA/pF of control to [Formula: see text]2.25[Formula: see text][Formula: see text][Formula: see text]0.12 pA/pF ([Formula: see text] 0.01, [Formula: see text] 5) and [Formula: see text]1.78[Formula: see text][Formula: see text][Formula: see text]0.28 pA/pF ([Formula: see text] 0.01, [Formula: see text] 5) respectively, when the interference of [Ca[Formula: see text]]i was eliminated due to the depletion of SR Ca[Formula: see text] store by thapsigargin, an inhibitor of Ca[Formula: see text] ATPase. Moreover, when BAPTA, a rapid Ca[Formula: see text] chelator, was used, CDI (Ca[Formula: see text]-dependent inactivation) of [Formula: see text] was eliminated, and the inhibitory effects of AS-IV on ICaL were significantly reduced at the same time. These results suggest that AS-IV affects Ca[Formula: see text] homeostasis through two opposite pathways: inhibition of Ca[Formula: see text] influx through L-type Ca[Formula: see text] channel, and promotion of Ca[Formula: see text] release from SR. PMID- 28595503 TI - Histology in 3D: development of an online interactive student resource on epithelium. AB - Epithelium is an important and highly specialised tissue type that makes up the lining of inner and outer surfaces of the human body. It is proposed that a self study tool adds to efficient learning and lecturing on this complicated topic in medical curricula. This paper describes the development and evaluation of an online interactive 3D resource on epithelium for undergraduate medical students. A first evaluation was carried out by means of an online survey (n = 37). The resource was evaluated positively on the website in general, its visual contents and its value and potential for the medical curriculum. PMID- 28595502 TI - The importance of trait emotional intelligence and feelings in the prediction of perceived and biological stress in adolescents: hierarchical regressions and fsQCA models. AB - The purpose of this study is to analyze the combined effects of trait emotional intelligence (EI) and feelings on healthy adolescents' stress. Identifying the extent to which adolescent stress varies with trait emotional differences and the feelings of adolescents is of considerable interest in the development of intervention programs for fostering youth well-being. To attain this goal, self reported questionnaires (perceived stress, trait EI, and positive/negative feelings) and biological measures of stress (hair cortisol concentrations, HCC) were collected from 170 adolescents (12-14 years old). Two different methodologies were conducted, which included hierarchical regression models and a fuzzy-set qualitative comparative analysis (fsQCA). The results support trait EI as a protective factor against stress in healthy adolescents and suggest that feelings reinforce this relation. However, the debate continues regarding the possibility of optimal levels of trait EI for effective and adaptive emotional management, particularly in the emotional attention and clarity dimensions and for female adolescents. PMID- 28595504 TI - Differential Relationships Between Diabetes Knowledge Scales and Diabetes Outcomes. AB - Background Diabetes affects more than 29 million people in the US and requires daily self-management in addition to knowledge of the disease. Three knowledge assessments used are the Michigan Brief Diabetes Knowledge Test (DKT), Starr County Diabetes Knowledge Questionnaire (DKQ), and Kaiser DISTANCE Survey (DISTANCE). Purpose The purpose of the study was to test the discriminate validity of 3 diabetes knowledge scales and determine which is best associated with diabetes self-care and glycemic control. Methods Three hundred sixty-one adults with type 2 diabetes were recruited from primary care clinics. Four analyses were conducted to investigate the validity and relationships of the scale: alpha statistic to test internal validity, factor analysis to determine how much of the variance was explained, Pearson's correlation between the 3 scales, and Pearson's correlation between each scale, self-care, and outcomes. Results The DKQ had an alpha of 0.75, the DKT had an alpha of 0.49, and DISTANCE had an alpha of 0.36. The DKQ was significantly correlated with glycemic control. The DKT scale was significantly associated with general diet, the DISTANCE survey was significantly associated with exercise, and both DKT and DISTANCE were significantly associated with foot care. Conclusion Correlations among the 3 scales were modest, suggesting the scales are not measuring the same underlying construct. These findings indicate that researchers should carefully select scales appropriate for study goals or to appropriately capture the information being sought to inform practice. PMID- 28595505 TI - Wound complications after common femoral vein endophlebectomy: Influence on outcome. AB - Introduction Venous recanalization of obstructed femoral and iliac veins is associated with good results regarding the feasibility and patency rate. If the common femoral vein with its inflow vessels is involved, open surgical desobliteration or endophlebectomy has been described as a crucial part of the intervention. However, when performing the hybrid procedure, a number of specific complications have been described. We present our results after venous recanalization including an endophlebectomy, focussing on wound complications and its impact on outcome. Material and methods A retrospective analysis of prospective recorded data of all patients who underwent a hybrid procedure for chronic obstruction of iliofemoral veins between 2010 and 2015 was performed. The patients were treated by recanalization of the affected veins combined with endophlebectomy of the common femoral vein and arteriovenous fistula implantation. Data assessment focussed on complications and patency rates. Results This study includes 96 patients, thereof 58 females with a mean age of 44.1 years. The mean procedure time was 344 +/- 140 min (range 124-663). Median follow-up time was 12.5 months (2-33 months). Primary patency was 62.5% and secondary patency was 90%. Re-intervention due to early occlusion within the first 30 post-intervention days was necessary in 37.5% of all cases. Besides bleeding complications, wound complications, mainly classified as Szilagyi I, occurred in 33% of all patients. A multivariate analysis showed a significant impact of wound complications on primary as well as secondary patency rate ( p = 0.032, respectively 0.015). Conclusion Recanalization of obstructed iliac veins and/or the inferior vena cava combined with endophlebectomy of the common femoral vein and arteriovenous fistula implantation is a safe and feasible treatment option in the post-thrombotic syndrome. As wound complications are a common and associated with a significant impact on patency rate, further attempts to improve the procedure are crucial. PMID- 28595507 TI - Design, Validation, and Clinical Implementation of a Gap-Polymerase Chain Reaction Method for alpha-Thalassemia Genotyping Using Capillary Electrophoresis. AB - : alpha-Thalassemia (alpha-thal) is genetically heterogeneous with most cases caused by variably sized deletions of the HBA1 and/or HBA2 loci. In this report, we describe the development, validation, and implementation of a novel gap polymerase chain reaction (gap-PCR)/capillary electrophoresis (CE). METHOD: This assay utilizes two multiplex reactions and CE to detect the following deletions: alpha3.7 (rightward), -alpha4.2 (leftward), -(alpha)20.5, - -SEA (Southeast Asian), - -MED, - -FIL and - -THAI. Validation studies using 36 previously characterized patient samples and plasmid controls demonstrated 100.0% accuracy. Following clinical implementation, 423 patients were analyzed over 24 months. Two hundred and twenty-seven cases (46.0%) showed abnormal results including heterozygous -alpha3.7 (n = 114, 27.0%), homozygous -alpha3.7 (n = 96, 23.0%), heterozygous - -SEA (n = 9, 2.0%), heterozygous -alpha 4.2 (n = 5, 1.0%), heterozygous - -MED (n = 1, <1.0%), and compound heterozygous -alpha3.7/-alpha4.2 (n = 2, <1.0%) deletions. Correlation with red blood cell (RBC) parameters showed that patients with a deletion of two or more genes were associated with significantly lower mean corpuscular volume (MCV) and mean corpuscular hemoglobin (Hb) (MCH) levels than patients with wild-type results. This novel multiplex gap PCR protocol reliably detects the seven most common deletions giving rise to alpha-thal. Use of the fluorescently labeled CE method provides for a high throughput workflow suitable to a clinical diagnostic laboratory serving a multiethnic population. PMID- 28595508 TI - Sedative and cardiorespiratory effects of detomidine constant rate infusion in sheep. AB - The use of sheep in experiments is widespread and is increasing worldwide, and so is the need to develop species-specific anaesthetic techniques to ensure animal safety. Previous studies have mentioned several protocols involving the administration of alpha-2 adrenergic agonists in sheep; however, assessment of the efficacy and safety of these infusion techniques is still relatively new. Thus, the aim of the present study is to assess the effectiveness of detomidine constant rate infusion (CRI) in sheep by measuring the cardiovascular and respiratory parameters, blood gas variables and sedation scores. Eight adult female Santa Ines sheep received 20 ug/kg of detomidine hydrochloride intravenously as a bolus loading dose, followed by an infusion rate of 60 ug/kg/h. The heart rates and respiratory rates changed continuously during the CRI period. No arrhythmias were observed. The reduction in arterial partial pressure of oxygen (PaO2) was not significant, but one animal showed signs of hypoxaemia (minimum PaO2 of 66.9 mmHg). The arterial partial pressure of carbon dioxide (PaCO2) increased, but the animals did not become hypercapnic. The bicarbonate (HCO3-), pH and base excess (BE) tended towards metabolic alkalosis. The cardiac output (CO), stroke volume (SV), cardiac index (CI) and ejection fraction (EF%) showed no significant changes. The fractional shortening (FS%) decreased slightly, starting at T45min. Sedation scores varied between 3 (0/10) after sedation and during recovery and 7 (0/10) during CRI. We concluded that administering detomidine at an infusion rate of 60 ug/kg/h in Santa Ines sheep is a simple technique that produces satisfactory sedation for minimally invasive procedures. PMID- 28595509 TI - Rehabilitation for Individuals With Genetic Degenerative Ataxia: A Systematic Review. AB - BACKGROUND: Treatment of genetic degenerative ataxia is currently based on symptom management and maintenance of function. However, utilization of rehabilitation is limited due to a lack of evidence supporting its efficacy. OBJECTIVE: This systematic review evaluated rehabilitation interventions for individuals with genetic degenerative ataxia. In addition, long-term outcomes from rehabilitation and optimal duration and intensity of rehabilitation were examined. METHODS: A comprehensive search of 4 databases (MEDLINE, CINAHL, PEDro, and Cochrane) identified randomized, nonrandomized controlled, and cohort studies published from inception through to January 2016. The studies included at least one measure examining function, ataxia, balance, or gait. Methodological quality was assessed with the Australian National Health and Medical Research Council (NHMRC) Hierarchy of Evidence and the randomized controlled trials were rated according to the PEDro scale. RESULTS: Seventeen studies met eligibility criteria. Five randomized controlled trials were included; however, the majority were classified as level III-3 and IV studies. Of 292 participants included, 148 had autosomal dominant ataxia, and 85 had autosomal recessive ataxia. Rehabilitation interventions included coordination and balance training, multifaceted inpatient rehabilitation, a cycling regime, balance exercises with technology assisted biofeedback, respiratory muscle training, and treadmill training. Two studies examined adjuncts to rehabilitation. Fifteen of the 17 studies demonstrated a statistically significant improvement in at least 1 outcome measuring ataxia, function, gait, or balance. Less than half of the studies included assessment of long-term outcomes and follow-up time frames varied considerably. CONCLUSION: There is consistent evidence that rehabilitation improves function, mobility, ataxia, and balance in genetic degenerative ataxia. PMID- 28595510 TI - Young adults HIV-1 infected by vertical transmission in southern Brazil - Clinical, demographic, and virological features. AB - Combination antiretroviral therapy promotes longer life expectancy, making it possible for perinatally HIV-infected patients to achieve adulthood. Past therapy was not always optimized, suggesting that virological and host features may also play a role in survival. The aim of this study is to describe characteristics of HIV disease progression associated with virological features in adolescents perinatally that were HIV infected. A case series was conducted including 81 patients that were in follow-up at Hospital de Clinicas/Universidade Federal do Parana, Curitiba, Brazil. Venous blood was collected to conduct tropism and viral subtype assays. The median age was 19 years old (interquartile range 18-21), and a majority of patients were female (54.3%). Viral subtype was obtained for 66 (82%) patients, and subtypes B and C were found in 34% and 59%, respectively. Tropism assay was conducted in 55 (67%) patients: 71% were R5 and 29% X4. Distribution of viral tropism and subtype shows a significant association of subtype C with R5 tropism. Subtype C is more prevalent in southern Brazil and also in the population infected with HIV by vertical transmission. Both R5 tropism and subtype C are associated with slower progression to AIDS. The survival of these patients may be related to virological features present in a benign pattern of disease progression. PMID- 28595511 TI - Breast cancer in systemic lupus erythematosus (SLE): receptor status and treatment. AB - Objective There is a decreased risk of breast cancer in systemic lupus erythematosus (SLE) versus the general population; little is known regarding the receptor status of breast cancers in SLE, or treatment. Methods Breast cancer cases occurring after SLE diagnosis were ascertained through linkage with tumor registries. We determined breast cancer positivity for estrogen receptors (ER), progesterone receptors (PR), and/or Human Epidermal Growth Factor Receptor 2 (HER2), as well as cancer treatment. Results We obtained information on ER, PR, and/or HER2 status for 63 SLE patients with breast cancer. Fifty-three had information on ER and/or PR status; 36 of these (69%) were ER positive. Thirty six of the 63 had information on HER2 status; of these, 26 had complete information on all three receptors. Twenty-one of these 26 (81%) were HER2 negative; seven of 26(27%) were triple negative. All but one patient underwent surgery; 11.5% received both non-tamoxifen chemotherapy and radiotherapy, 16.4% radiotherapy without non-tamoxifen chemotherapy, and 14.7% received non-tamoxifen chemotherapy without radiotherapy. Conclusion ER positivity was similar to historical general population figures, with a trend toward a higher proportion of triple-negative breast cancers in SLE (possibly reflecting the relatively young age of our SLE patients). PMID- 28595512 TI - Effects of psychosocial work characteristics on hair cortisol - findings from a post-trial study. AB - Prolonged work stress, as indicated by the effort-reward imbalance (ERI) model, jeopardizes health. Cortisol represents a candidate mechanism connecting stress to ill health. However, previous findings appear inconclusive, and recommendations were made to assess work stress at multiple time points and also to investigate ERI (sub-)components. This study therefore examines the effects of two single time points, as well as the mean and change scores between time points of ERI and its components on hair cortisol concentration (HCC), a long-term cortisol measurement. Participants were 66 male factory workers (age: 40.68 +/- 6.74 years; HCC: 9.00 +/- 7.11 pg/mg), who were followed up after a stress management intervention (2006-2008). In 2008 (T1) and 2015 (T2), participants completed a 23-item ERI questionnaire, assessing effort, the three reward components (esteem, job security, job promotion) and over-commitment. In 2015, participants also provided a 3-cm hair segment close to the scalp for HCC analysis, as well as information on relevant confounders (i.e. medication intake, age, work characteristics, socioeconomic and lifestyle factors, number of stressful life events). Linear regressions revealed hardly any cross-sectional or longitudinal effect of ERI and its components on HCC. Only the change scores between T1 and T2 of job security were negatively associated with lower HCC in unadjusted (beta = -.320; p = .009) and adjusted (beta = -.288; p = .044) models. In this study, only a decrease of perceived job security over time was significantly associated with higher HCC, and other predictors were not related to this outcome. Especially after correction for multiple testing, this study revealed just a weak association of different psychosocial work measurements with HCC. Lay summary This study showed that an increase in perceived job insecurity is correlated with higher levels of the stress hormone cortisol. The higher levels of cortisol might represent a biological explanation for the negative health effects of job insecurity. The association was, however, relatively low, and more and more voices are questioning whether cortisol in hair is a reliable marker for perceived work stress. PMID- 28595513 TI - Modeling and comparative assessment of bubbling fluidized bed gasification system for syngas production - a gateway for a cleaner future in Pakistan. AB - The present study explores the potential of MSW gasification for exergy analysis and has been recently given a premier attention in a region like Pakistan where the urbanization is rapidly growing and resources are few. The plant capacity was set at 50 MW based on reference data available and the total exergetic efficiency was recorded to be 31.5 MW. The largest irreversibility distribution appears in the gasifier followed by methanation unit and CO2 capture. The effect of process temperature, equivalence ratio and MSW moisture content was explored for inspecting the variations in syngas composition, lower heating value, carbon conversion efficiency and cold gas efficiency. Special attention of the paper is paid to the comparative assessment of MSW gasification products in four regions, namely Pakistan, USA, UAE and Thailand. This extended study gave an insight into the spectrum of socioeconomic conditions with varying MSW compositions in order to explain the effect of MSW composition variance on the gasification products. PMID- 28595514 TI - The incidence and relative risk of pulmonary toxicity in patients treated with anti-PD1/PD-L1 therapy for solid tumors: a meta-analysis of current studies. AB - AIM: Monoclonal antibodies (mAbs) directed against PD-1/PD-L1 have recently entered the therapeutic algorithm of several solid tumors. Among treatment related adverse events pulmonary toxicity (PT) is of particular interest. We assess the incidence and relative risk (RR) of PT in patients treated with anti PD1/PD-L1 mAbs. RESULTS: 11 articles were selected. The incidence of any- and high-grade PT was low (2.9 and 1.0%, respectively). Compared with standard therapies, anti-PD-1 mAbs do not significantly increase the risk of both any grade (RR: 2.65; p = 0.06) and high-grade PT (RR: 1.40; p = 0.25). Of note, the RR: of developing any-grade (RR: 3.13; p < 0.0001) and high-grade (RR: 2.42; p = 0.03) PT significantly increased when excluding the Checkmate-025 trial, with everolimus as control therapy. No differences were identified between the type of mAbs, the tumor type and treatment duration for both any-grade and high-grade PT. PMID- 28595515 TI - Trans-sialidase overcomes many antigens to be used as a vaccine candidate against Trypanosoma cruzi. AB - AIM: The development of vaccines against Trypanosoma cruzi remains in an exploratory stage. Despite several antigen candidates have been evaluated, a comparison among the performance of the immunogens cannot be carried out because the available reports differ in formulations and infection model. In this work, we compared the protective capacity of seven T. cruzi antigens in the same model of five new antigens and two well-established candidates. Materials & methods: We evaluated highly immunogenic proteins that contain tandem repeats (FRA [flagelar repetitive protein], Tc3, Tc6); enzymes involved in metabolic pathways critical for parasite survival (cytosolic tryparedoxin peroxidase and tryparedoxin peroxidase); and enzymes involved in parasite invasion (trans-sialidase [TS] and cruzipain). All these antigens were formulated with Freund's adjuvant and protection against the parasite infection was assessed in BALB/c mice. RESULTS: Tc3, cytosolic tryparedoxin peroxidase, cruzipain and TS showed the best outcome after infection in survival level and parasitemia. According to these data, these groups were also assessed using the ISCOMATRIXTM adjuvant which is being used in clinical trials. CONCLUSION: Taken together, our results showed that the TS overcomes the performance of other antigens when the same model is employed, confirming that TS is a promising antigen that could be used as a vaccine against T. cruzi. PMID- 28595517 TI - Immunotherapy for pancreatic cancer: present and future. AB - Despite the identification of some efficient drugs for the treatment of metastatic pancreatic cancer, this tumor remains one of the most lethal cancers and is characterized by a strong resistance to therapies. Pancreatic cancer has some unique features including the presence of a microenvironment filled with immunosuppressive mediators and a dense stroma, which is both a physical barrier to drug penetration and a dynamic entity involved in immune system control. Therefore, the immune system has been hypothesized to play an important role in pancreatic cancer. Thus, therapies acting on innate or adaptive immunity are being investigated. Here, we review the literature, report the most interesting results and hypothesize future treatment directions. PMID- 28595516 TI - Cellular immunotherapy of cancer: an overview and future directions. AB - The clinical success of checkpoint inhibitors has led to a renaissance of interest in cancer immunotherapies. In particular, the possibility of ex vivo expanding autologous lymphocytes that specifically recognize tumor cells has attracted much research and clinical trial interest. In this review, we discuss the historical background of tumor immunotherapy using cell-based approaches, and provide some rationale for overcoming current barriers to success of autologous immunotherapy. An overview of adoptive transfer of lymphocytes, tumor infiltrating lymphocytes and dendritic cell therapies is provided. We conclude with discussing the possibility of gene-manipulating immune cells in order to augment therapeutic activity, including silencing of the immune-suppressive zinc finger orphan nuclear receptor, NR2F6, as an attractive means of overcoming tumor associated immune suppression. PMID- 28595518 TI - Humanization of chimeric anti-CD20 antibody by logical and bioinformatics approach with retention of biological activity. AB - AIM: To develop a fully bioactive humanized antibody from the chimeric rituximab for potential clinical applications using a relatively simpler and faster logical and bioinformatics approach. METHODS: From bioinformatics data, mismatched mouse amino acids in variable light and heavy chain amphipathic regions were identified and substituted with those common to human antibody framework. Appropriate synthetic DNA sequences inserted into vectors were transfected into HEK293 cells to produce the humanized antibody. RESULTS: Humanized antibodies showed specific binding to CD20 and greater cytotoxicity to cancer WIL2-NS cell proliferation than rituximab in vitro. CONCLUSION: A humanized version of rituximab with potential to be developed into a biobetter for treatment of B-cell disorders has been successfully generated using a logical and bioinformatics approach. PMID- 28595519 TI - T-cell-associated immunotherapy: a promising strategy for the treatment of hepatocellular carcinoma. PMID- 28595520 TI - A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient. AB - Programmed cell death-1 protein (PD-1) is an immune checkpoint that has gained popularity in the treatment of several advanced cancers. Inhibiting this checkpoint is known to enhance immune response, but is also known to diminish immune tolerance and to increase autoimmune toxicity. We discuss a case of rapid onset fulminant Type 1 diabetes induced by treatment with anti-programmed cell death-1 monoclonal antibody, nivolumab, in a patient with late-stage non-small cell lung adenocarcinoma. The patient had no history of previous diabetes but did reveal a high-risk genotype for Type 1 diabetes development (DR3-DQ2; DR4-DQ8). This finding supports that acute Type 1 diabetes can be an important adverse effect of immunotherapies targeting T-cell activation regulation. Because of the severity of this adverse effect, physicians should be aware of it, and studies directed to the detection of new biomarkers for early risk stratification (e.g., HLA) should be sought. PMID- 28595521 TI - A Comparative Study on Selective PPAR Modulators through Quantitative Structure activity Relationship, Pharmacophore and Docking Analyses. AB - BACKGROUND: Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. OBJECTIVE: In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi cheminformatics studies have been performed. METHODS: In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. RESULTS: It is observed that the presence of an amide fragment ( CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARalpha modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARdelta modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARgamma modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARdelta and alpha modulators, but a hydrophobic feature is the prime requirement for PPARgamma modulation. CONCLUSION: Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity. PMID- 28595524 TI - EPC dysfunction and immune networks: translating opportunities for the clinical setting in personalized medicine. AB - Cardiovascular (CV) risk stratification is suboptimal if solely based on traditional CV risk factors, since individuals with similar risk profiles could exhibit diverging CV outcomes. Thus, there is a need for new risk factors to be identified and implemented. Recent studies emphasize the relevance of the endothelial homeostasis in the control of CV risk burden, but the clinical relevance of these findings is starting to be appreciated. However, gaining insight into the actual players involved in this phenomenon would lead to the identification of novel biomarkers. Due to their central role in vascular repair, Endothelial Progenitor Cells (EPC) are promising candidates for this issue. Since excessive inflammation or imbalanced immune responses are known to underlie numerical or functional alterations of EPC, it can be speculated that these mediators may be considered as biomarkers for risk stratification. Actually, a mounting body of evidence seems to point to an inflammation-driven traditional CV risk factors-related EPC dysfunction. Therefore, in the present review we summarized the evidence highlighting a link between inflammation and immune pathways with a compromised EPC functionality, aiming to identify feasible biomarkers for risk stratification in personalized medicine schemes. PMID- 28595522 TI - Implementation of Dynamic Lighting in a Nursing Home: Impact on Agitation but not on Rest-Activity Patterns. AB - OBJECTIVE: Disturbances of circadian rest-activity rhythms in demented patients often culminate in the clinical problem of evening and nighttime agitation. The aim of the current study was to test the impact of a dynamic lighting system on agitation and rest-activity cycles in patients with dementia. METHODS: From midwinter on, a ceiling mounted dynamic lighting system was installed in the common room of a nursing home and programmed to produce high illuminance with higher blue light proportions during the day and lower illuminance without blue light in the evening. Fifteen residents with dementia were regularly assessed with the Cohen Mansfield Agitation Index (CMAI) before and after the lighting intervention. Additionally rest-activity cycles were continuously monitored for 6 months by a wrist worn activity watch. Analysis of CMAI data was performed by using the Wilcoxon-Test for matched pairs (before vs. after the lighting installation). Rest-activity data was compared with t-tests for dependent samples. The dynamic lighting significantly reduced the CMAI sum-scores from 30.2+/-5.1 to 27.9+/-2.6 (mean +/- SD; N = 12; p<0.05). Analysis of the CMAI subscores revealed that under the dynamic lighting mainly non-physically aggressive behaviors were reduced. RESULTS: Results from the rest-activity analysis did not show differences of circadian amplitude and other circadian variables before and after the lighting installation. The dynamic lighting in the living room significantly reduced agitated behavior in demented patients, indicating short-term benefits from higher daily light exposures. Whether such lighting also impacts long-term (circadian) rest-activity cycles needs to be further investigated. PMID- 28595523 TI - Blue-Enriched Lighting for Older People Living in Care Homes: Effect on Activity, Actigraphic Sleep, Mood and Alertness. AB - OBJECTIVE: Environmental (little outdoor light; low indoor lighting) and age related physiological factors (reduced light transmission through the ocular lens, reduced mobility) contribute to a light-deprived environment for older people living in care homes. METHODS: This study investigates the effect of increasing indoor light levels with blue-enriched white lighting on objective (rest-activity rhythms, performance) and self-reported (mood, sleep, alertness) measures in older people. Eighty residents (69 female), aged 86 +/- 8 yrs (mean +/- SD), participated (MMSE 19 +/- 6). Overhead fluorescent lighting was installed in communal rooms (n=20) of seven care homes. Four weeks of blue enriched white lighting (17000 K ? 900 lux) were compared with four weeks of control white lighting (4000 K ? 200 lux), separated by three weeks wash-out. Participants completed validated mood and sleep questionnaires, psychomotor vigilance task (PVT) and wore activity and light monitors (AWL). Rest-activity rhythms were assessed by cosinor, non-parametric circadian rhythm (NPCRA) and actigraphic sleep analysis. Blue-enriched (17000 K) light increased wake time and activity during sleep decreasing actual sleep time, sleep percentage and sleep efficiency (p < 0.05) (actigraphic sleep). Compared to 4000 K lighting, blue enriched 17000 K lighting significantly (p < 0.05) advanced the timing of participants' rest-activity rhythm (cosinor), increased daytime and night-time activity (NPCRA), reduced subjective anxiety (HADA) and sleep quality (PSQI). There was no difference between the two light conditions in daytime alertness and performance (PVT). CONCLUSION: Blue-enriched lighting produced some positive (increased daytime activity, reduced anxiety) and negative (increased night-time activity, reduced sleep efficiency and quality) effects in older people. PMID- 28595525 TI - Obesity-Induced Hypertension: New Insights. AB - BACKGROUND: New insights on the relationship between weight loss and hypertension and the role of the newly approved anti-obesity drugs on hypertension will be discussed Methods: Weight loss is a major factor to reduce blood pressure when a patient with excess weight is advised from the health care provider to change his lifestyle. A healthy lifestyle with reduction in body weight, reduction in caloric intake, increased fruit and vegetables consumption and reduced salt intake concomitant with an increase in physical exercise can reduce body weight and hypertension in overweight and obese patients, but not all obese are able to reduce their blood pressure and lose weight without treatment and special dietary care. Moreover, most obese people lose weight for a small period and then they regain all the weight that they have lost or even worse, they increase their weight more than before starting a diet. Newly-approved weight loss drugs have variable actions on high blood pressure. Liraglutide and phentermine/topiramate seem to reduce hypertension, while after the bupropion/naltrexone or lorcaserin use trials reported a rise in blood pressure. CONCLUSION: Reduction in body weight with treatment is not always associated with reduction in obesity induced hypertension. Weight loss treatments that exhibit sympathomimetic or adrenergic actions should be used with care and for short periods of time. PMID- 28595526 TI - Sarcopenia: An Overview on Current Definitions, Diagnosis and Treatment. AB - Sarcopenia, the progressive and generalized loss of skeletal muscle mass and strength/function associated with aging, increases the risk of a vast array of adverse health outcomes, including falls, morbidity, loss of independence, disability, and mortality. As such, sarcopenia poses a huge socioeconomic burden in developed countries. The development and implementation of effective interventions against sarcopenia are therefore a public health priority. A preliminary, fundamental step in such a process entails the agreement of researchers, healthcare professionals and policymakers around a unique operational definition of sarcopenia. This will facilitate the framing of a clear clinical entity to be incorporated in standard practice, the understanding of the underlying pathophysiology, and the identification of biological targets for drug development. PMID- 28595527 TI - Creatine Supplementation and Skeletal Muscle Metabolism for Building Muscle Mass- Review of the Potential Mechanisms of Action. AB - Creatine, a very popular supplement among athletic populations, is of growing interest for clinical applications. Since over 90% of creatine is stored in skeletal muscle, the effect of creatine supplementation on muscle metabolism is a widely studied area. While numerous studies over the past few decades have shown that creatine supplementation has many favorable effects on skeletal muscle physiology and metabolism, including enhancing muscle mass (growth/hypertrophy); the underlying mechanisms are poorly understood. This report reviews studies addressing the mechanisms of action of creatine supplementation on skeletal muscle growth/hypertrophy. Early research proposed that the osmotic effect of creatine supplementation serves as a cellular stressor (osmosensing) that acts as an anabolic stimulus for protein synthesis signal pathways. Other reports indicated that creatine directly affects muscle protein synthesis via modulations of components in the mammalian target of rapamycin (mTOR) pathway. Creatine may also directly affect the myogenic process (formation of muscle tissue), by altering secretions of myokines, such as myostatin and insulin-like growth factor 1, and expressions of myogenic regulatory factors, resulting in enhanced satellite cells mitotic activities and differentiation into myofiber. Overall, there is still no clear understanding of the mechanisms of action regarding how creatine affects muscle mass/growth, but current evidence suggests it may exert its effects through multiple approaches, with converging impacts on protein synthesis and myogenesis. PMID- 28595528 TI - Type 1 Diabetes Treatments Based on Stem Cells. AB - BACKGROUND: More than a decade ago, a new research field named Stem Cell Therapy emerged in Health Science. Initially, it was considered that cells owned a differentiation capability; however, this dogma has changed when new results have been published regarding the ability of the cells to differentiate into different cell tissue mainly due to the novel reprogramming strategies. Accordingly, cells from an adult tissue source may be potentially capable of originating cells of a very different cell type. The possibility of transplanting these cells into damaged organs has triggered many studies to understand the plasticity of stem cells. Today, we have a deeper knowledge about stem cells, however still many questions, especially about the mechanism of action, that needs to be answered. The benefit of stem cells after transplantation has been demonstrated experimentally and also in some cases clinically; however, the extent of stem cell contribution in transplanted tissue has been found to be low and a large number of evidence indicates that a trophic effect should play an important role in such benefit. A better understanding of the paracrine mechanisms involved in this process could be of great relevance in order to focus studies on endogenous cells to direct their function towards the regeneration of damaged tissue. In addition, even more sophisticated methods of reprogramming and cell transplantation have been initiated in combination with bioengineering techniques in order to enhance the potential of these cells. CONCLUSION: In the present review, we will overview the studies on stem cell and their effects in the treatment of diabetes in order to discuss the questions generated about their origin and the mechanisms that are involved in their reparative properties. PMID- 28595529 TI - Development and Optimization by Quality by Design Strategies of Frovatriptan Orally Disintegrating Tablets for Migraine Management. AB - BACKGROUND: Frovatriptan is a potent anti-migraine agent with unfavourable slow onset of action, available on the market as film-coated tablets. OBJECTIVE: Optimization, by Quality by Designs strategies, of an orally disintegrating tablet (ODT) formulation of frovatriptan aimed to make its oral administration easier and its dissolution faster than the commercial tablets, thus improving its effectiveness in migraine management. METHOD: A screening D-optimal design was applied to investigate the effects of different levels of kind and amount of ODT special excipient and disintegrant agents (identified as the critical variables) on disintegration time (DT) and % drug dissolved at 30 s (%Diss), selected as the responses to optimize. The best excipients combination, emerged by the screening step, was in-depth investigated by a Response Surface Methodology. RESULTS: A design space was defined where every combination of the selected variables fulfilled the required values for the responses with P >= 95%. In particular, the optimized formulation (Pharmaburst(r) 60% and Na alginate 15%), showed DT = 1.62+/-0.08 s and %Diss= 9.02+/-0.47%, with good agreement between measured and calculated values. Moreover, the developed ODT complied with the USP uniformity weight and drug content requirements, exhibited proper hardness and low friability, and provided 100 % dissolved drug within 5 min. CONCLUSION: A frovatriptan ODT formulation was successfully developed by Quality by Design. It represents an effective alternative to conventional tablets, allowing easier oral administration (also to paediatric and geriatric people) and very faster drug dissolution, enhancing patient compliance and facilitating an earlier treatment of migraine attacks. PMID- 28595530 TI - Encapsulation of Solid Dispersion in Solid Lipid Particles for Dissolution Enhancement of Poorly Water-Soluble Drug. AB - BACKGROUND: The aim of this research was to engineer solid dispersion lipid particles (SDSLs) in which a solid dispersion (SD) was encapsulated to form the core of solid lipid particles (SLs), thereby achieving an efficient enhancement in the dissolution of a poorly water-soluble drug. METHODS: Ultrasonication was introduced into the process to obtain micro/nanoscale SLs. The mechanism of dissolution enhancement was investigated by analysing the crystalline structure, molecular interactions, and particle size of the formulations. RESULTS: The drug release from the SD-SLs was significantly greater than that from the SD or SLs alone. This enhancement in drug release was dependent on the preparation method and the drug-topolymer ratio of the SD. With an appropriate amount of polymer in the SD, the solidification method had the potential to alter the drug crystallinity to an amorphous state, resulting in particle uniformity and molecular interactions in the SD-SLs. CONCLUSIONS: The proposed system provides a new strategy for enhancing the dissolution rate of poorly water-soluble drugs and further improving their bioavailability. PMID- 28595531 TI - Repurposed Drugs as Potential Therapeutic Candidates for the Management of Alzheimer's Disease. AB - BACKGROUND: Drug repurposing is an innovative approach as it provides new indications for already approved and established drugs. Due to high failure rates and cost involved in traditional drug development procedures, many pharmaceutical companies are primarily focusing on drug repurposing strategy. In Alzheimer disease (AD), existing therapeutic agents only provide symptomatic benefits and does not play a role in disease modification, therefore, an alternative strategy of repurposing can be used to inhibit neurodegeneracy process and other pathological complications. This review discusses the beneficial effects of available licensed drug compounds which can be used as repurposed drugs for the treatment of AD. Moreover, it includes a brief overview of current treatment strategies, including therapies based on nanotechnology and their limitations. METHODS: We attempted an organized scan of peer-reviewed research articles pertinent to licensed drugs that showed beneficial effects in Alzheimer's pathology. Our search includes in vitro studies, epidemiological data and clinical trials. In fact, we have collected, scrutinized, analyzed and discussed all the data that suggested the plausible application of repurposed drugs for the treatment of AD. RESULTS: Cholinesterase inhibitors and N-methyl-D-Aspartate receptor antagonist are available options to improve the cognitive functions of Alzheimer's patients. These drugs only help in balancing disturbed level of neurotransmitters and are not helpful in disease modification. On the other hand, the nanotechnological based approach has promised to solve some challenges, but has certain limitations such as biocompatibility issues, therefore, it requires an extensive amount of research work. As our main emphasis was on repurposed drugs, we have performed an extensive review of articles to identify compounds that have been approved by the United States Food and Drug Administration for the treatment of diseases other than Alzheimer's but might have an impact on AD modification based on clinical evidences. Amyloid clearance, tau pathology and anti-inflammatory mechanisms are potential factors that are taken into consideration for disease modification. In addition, the role of bioinformatics and in silico drug repurposing strategy is crucial in the field of drug research, and plays a significant role in the identification of potential repurposed drugs. Thus, we have also mentioned several drug repurposing computational tools that are robust and can predict reliable results based on available gene expression data. DISCUSSION: The major advantage of repurposing strategy is the identification of drug compounds with known mechanism of action, toxicology information and pharmacodynamics profiles; hence, less time is required for devising AD modification treatment. There are some issues as well with this method, which can be resolved by extending our research in this domain. CONCLUSION: AD is incurable, and there is an urgent need to find new treatments, as it is affecting the number of families and society overall. The drug repurposing approach is gaining attention in the pharmaceutical world, as it can substantially reduce the time and cost required to advance any treatment to the stage of clinical trials.. PMID- 28595532 TI - Pharmacological and Toxicological Profile of Harmane-beta-Carboline Alkaloid: Friend or Foe. AB - BACKGROUND: The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- beta-carboline alkaloid was investigated for both therapeutic and toxicological potential. METHODS: The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. RESULTS: The harmane-beta-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. CONCLUSIONS: All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing. PMID- 28595533 TI - Recent Advances of Computational Modeling for Predicting Drug Metabolism: A Perspective. AB - BACKGROUND: Absorption, Distribution, Metabolism, Excretion (ADME) properties along with drug induced adverse effects are the major reasons for the late stage failure of drug candidates as well as the cause for the expensive withdrawal of many approved drugs from the market. Considering the adverse effects of drugs, metabolism factor has great importance in medicinal chemistry and clinical pharmacology because it influences the deactivation, activation, detoxification and toxification of drugs. METHODS: Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and metabolism followed by adverse effects, as they serve the integration of information on several levels to enhance the reliability of outcomes. RESULTS AND DISCUSSION: In silico profiling of drug metabolism can help progress only those molecules along the discovery chain that is less likely to fail later in the drug discovery process. This positively impacts the very high costs of drug discovery and development. Understanding the science behind computational tools, their opportunities, and limitations is essential to make a true influence on drug discovery at different levels. If applied in a scientifically consequential way, computational tools may improve the capability to identify and evaluate potential drug molecules considering pharmacokinetic properties of drugs. CONCLUSION: Herein, current trends in computational modeling for predicting drug metabolism are reviewed highlighting new computational tools for drug metabolism prediction followed by reporting large and integrated databases of approved drugs associated with diverse metabolism issues. PMID- 28595534 TI - A Review on Pharmacokinetics of Levetiracetam in Neonates. AB - BACKGROUND: Neonatal seizures are the most common clinical manifestation of Central Nervous System (CNS) dysfunction and are associated with various neurological sequelae. There are currently no evidence-based guidelines for the management of neonatal seizures and currently used drugs such as phenobarbital, and phenytoin have limited efficacy and potential toxicities. Newer second line anticonvulsant, levetiracetam, has been used in refractory neonatal seizures despite limited data and off-label use. OBJECTIVE: In this review, we will discuss various pharmacological properties of levetiracetam when used in neonatal population. METHODS: A PubMed search for MEDLINE was undertaken to look for studies using the terms "Levetiracetam", AND "Neonates" as key words from year 1995 to January 2017. Relevant articles were selected and information was extracted about pharmacokinetics, pharmacodynamics and clinical uses of levetiracetam in neonates. RESULTS: Levetiracetam is an active, water-soluble S enantiomer of racemic pyrrolidine acetamide which exerts its antiepileptic action by binding to the synaptic vesicle protein within the brain. Metabolism of levetiracetam does not include the CYP P450 system and it is mainly eliminated through kidneys after rapid absorption. Also, no significant interactions with other drugs have been identified. Unlike other commonly used antiepileptic drugs, levetiracetam is not bound to plasma proteins, thereby, reducing the chances of toxicity and severe, life threatening side effects have not been reported. In fact, it has been shown to prevent neuro-degeneration after hypoxia/ischemia in rodent models of epilepsy. CONCLUSION: Levetiracetam has been emerging as a potential therapeutic option for refractory neonatal convulsions owing to its non hepatic elimination, linear pharmacokinetics, low protein binding and better safety profile. PMID- 28595535 TI - Current Evidence and Future Perspectives on Anti-platelet and Statin Pharmacotherapy for Patients with Symptomatic Peripheral Arterial Disease. AB - BACKGROUND: Pharmacotherapy is of increasing interest in peripheral arterial disease (PAD), with novel therapies aiming at different factors contributing to the disease. For antiplatelet therapy, there is no unanimous agreement regarding the nature or duration of optimal antiplatelet therapy so as to reduce major adverse cardiovascular and limb-related events (e.g. repeat interventions and amputations). However, evidence on novel more potent antithrombotic agents, drug combinations and personalized antiplatelet therapy for PAD patients is accumulating. Similarly, statins are now considered as a standard of care in PAD patients, due to their multiple actions which include plaque stabilization, antiinflammatory properties and regression of atheroma. CONCLUSION: This review focuses on current evidence available for various antiplatelet regimens and statin therapy for PAD and discusses future perspectives. We consider randomized controlled trials, together with the most important reviews and meta-analyses. Treatment algorithms based on currently available data. PMID- 28595537 TI - Capillaroscopic Findings in Primary Fibromyalgia. AB - INTRODUCTION: Although Raynaud's Phenomenon (RP) is observed in a significant proportion of patients with primary fibromyalgia, the available data on capillaroscopic findings in primary fibromyalgia are scarce. OBJECTIVE: The purpose of the study was to assess the capillaroscopic pattern in patients with primary fibromyalgia. PATIENTS AND METHODS: 26 patients with primary fibromyalgia (25 women and 1 man) were included in the study. Mean age was 55+/-10 years. As control groups were examined 31 patients with primary RP and 35 healthy volunteers. Capillaroscopic examination was performed with a videocapillaroscope Videocap 3.0 (DS Medica), magnification 200x with analysis of the main capillaroscopic parameters as follows: capillary distribution, shape, mean capillary diameters and length, mean capillary density, visibility of the subpapillary plexus; presence of avascular areas, microhaemorrhages and neoangiogenic capillaries. RESULTS: Symptoms of RP were observed in 65% (17/26) of the cases with primary fibromyalgia. At capillaroscopic examination, the most frequent finding in patients with primary fibromyalgia was the presence of capillary dilation in 85% (22/26) of the patients - both in cases with and without RP. However, the mean arterial and venous capillary diameters were significantly higher in the subgroup of fibromyalgia patients with clinical symptoms of RP. Of note, microvascular abnormalities characteristic of connective tissue diseases could not be observed in primary fibromyalgia patients. Analogous changes - presence of dilated capillaries - were found in 96.6% (29/30) of patients with primary RP. CONCLUSION: In our study, the most frequent capillaroscopic finding in patients with primary fibromyalgia was the presence of dilated capillary loops analogous to primary RP. Capillaroscopic signs suggestive of connective tissue disease could not be found in primary fibromyalgia patients. PMID- 28595536 TI - Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases. AB - OBJECTIVE: This review article focuses on the neuroprotective effect of drug induced hypothermia in cerebrovascular diseases and discusses its related side effects. METHOD: A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. RESULTS: Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs. PMID- 28595538 TI - Immune Cells Act as Promising Targets for the Treatment of Bone Metastasis. AB - BACKGROUND: Bone metastasis is a common complication of certain types of cancer, and unfortunately, it is still incurable to date. Immune system is a major defence against tumor cells and bone metastasis. However, the immunodeficient mouse models are widely used in most researches of bone metastasis, thereby excluding the regulatory roles of the immune system in bone metastasis. OBJECTIVE: The aim was to provide a comprehensive overview on the cellular and molecular mechanisms by which immune cells interact with tumor cells and bone cells, as well as recent related patents. METHOD: We performed a literature search of PubMed database for the current knowledge on the interaction between bone metastasis and immune system. Recent related patents were obtained from World Intellectual Property Organization (WIPO) website. RESULTS: Immune cells in the bone-tumor microenvironment include dentritic cells, monocytes/ macrophages, myeloid-derived suppressor cells, regulatory T cells, T helper cells, neutrophil, CD4+ T lymphocytes, CD8+cytotoxic T lymphocytes, and natural killer cells, et al. In addition to their well-known immunomodulatory function, recent studies revealed that immune cells could cooperate with tumor cells and bone cells to enhance bone metastasis and tumor progression. There are some patents targeting immune system to inhibit bone metastasis. CONCLUSION: Immune cells are instigated by tumor cells to enhance the occurrence and the development of bone metastasis. Taking full advantage of anti-tumor roles of immune cells may bring the promise of a possible cure for bone metastasis. PMID- 28595539 TI - Targeted Drug Delivery Systems and Their Therapeutic Applications in Cancer and Immune Pathological Conditions. AB - BACKGROUND: More than a century ago, Paul Ehrlich proposed the idea of a drug working as a "magic bullet" that selectively eliminates diseased cells without harming the surrounding normal cells. Since then, much progress has been made in this field to broaden the scope for targeted delivery of drugs. A major problem remain the toxic effects of targeted drugs on healthy cells. In order to reduce the adverse effects of chemotherapy on healthy tissues, we survey the use of recent drug delivery systems for targeted therapy. OBJECTIVE: The selective delivery of the drugs to specific diseased cells or tissues still is a daunting task. Ideally, for target drug delivery systems, the system should be made up of carriers and drugs, where carriers precisely target the desired drug. This issue covers the recent advancements in modern techniques for such purposes. RESULT AND CONCLUSION: It encompasses advances, benefits and limitations in state of art work of targeted drug delivery through hydrogels, microfluidics, nanoparticles, carbon nanotubes, polymeric micelles, liposomes, lipoprotein based drug carriers and dendrites. PMID- 28595540 TI - Apicoplast Import Protein Tic20 A Promising Therapeutic Molecular Target for Plasmodium falciparum: An In Silico Approach for Therapeutic Intervention. AB - BACKGROUND: Malaria is a lethal disease causing mortality to over millions each year. Drug resistance in the malarial parasite spurred effects to discover effective antimalarial drug targets and drugs. An objective of this current study is to identify drug targets for malarial parasite. Genes unique, non-homologous to humans and essential for parasite are identified using BLASTn by comparing genomes between parasite and host. OBJECTIVE: Further open BLASTp was used to filter the targets specific to Plasmodium species and later were subjected to gene property analysis to identify 65 potential targets. Screening of potential drug targets for the drug target properties like virulence and enzyme identified three drug targets with virulence property and eleven with enzymatic nature. METHOD: Thirteen knockouts related to potential drug targets were already tested in Plasmodium species, non-Plasmodium species and rodent malaria, lending credence to our approach. 3-D structures of 27 drug targets were predicted using I-tasser server and apicoplast import protein Tic20 is the best modeled protein. Gene ontology studies and analysis for motifs on nuclear localization signal (NLS) established apicoplast import protein Tic20 as an import protein. In silico docking studies were used to establish the druggability of apicoplast import protein Tic20. RESULT AND CONCLUSION: In silico docking studies on 3-D structure generated using I-tasser with quinine, chloroquine, artesunate into the active site of apicoplast import protein Tic20 established apicoplast import protein Tic20 as a promising therapeutic molecular target. PMID- 28595541 TI - Association of IL-12 B Gene Polymorphism with Staging of Liver Disease in Chronic HCV Patients. AB - BACKGROUND & AIMS: Cell-mediated immunity plays a critical role in viral clearance and disease progression during Hepatitis C virus (HCV) infection. Interleukin (IL)-12 is a cytokine that has been shown to be a potent antiviral cytokine. The aim of this work is to investigate the association of IL-12 B gene polymorphism with staging of liver disease in chronic HCV patients. METHODS: This cross sectional study was carried out in tropical medicine department, Tanta university hospital, Egypt, on 120 chronic HCV patients with various stages of liver disease and 30 healthy subjects served as control. All the participants were tested for IL- 12 B (p40) gene polymorphism. RESULTS: the frequency of AA genotype was higher in HCV patients with decompensated cirrhosis and in HCV patients with Hepatocellular carcinoma (HCC). However, the CC genotype was less detected in all groups, with the lowest percentage (6.6%) detected in decompensated cirrhosis and HCC patients. CONCLUSIONS: AA genotype presented more frequently in late stages of HCV chronically ill patients, while, CC genotype had no significant association with staging of liver disease and had low frequency especially in late stages of liver disease. PMID- 28595542 TI - Synthesis of 99mTc-Rifabutin: A Potential Tuberculosis Radiodiagnostic Agent. AB - BACKGROUND: Rifabutin (RFN) is bactericidal antibiotic with a very broad spectrum of activity against gram positive & gram negative organisms including Pseudomonas aeruginosa and specifically Mycobacterium tuberculosis. RFN inhibits DNA dependent RNA polymerase activity in susceptible cells. In the instant work, the therapeutic characteristics of RFN were intended for diagnostic rationale by labeling it with 99mTc (Technetium-99m). OBJECTIVE: The 99mTc labeled RFN (99mTc RFN) was investigated for labeling capacity, steadiness in saline & serum, in vitro Mycobacterium tuberculosis (MBT) uptake & distribution in MBT stained animal model rats. METHOD: It was found that 99mTc-RFN prepared by mixing 2 mg of RFN, 2.5 mCi sodium pertechnetate, 150 MUg stannous chloride at pH 5.4 gave highest yield after 30 minutes and was intact above 90 % after 240 min at room temperature in saline. RESULT: The 99mTc-RFN showed a stable profile in serum at 37 degrees C and impurities appeared up 16 h was 15.20 %. The maximum in vitro MBT uptake observed in live strain was 71.75 +/- 0.75 %. The premier uptake observed in the MBT infected site (target site) was 14.15 +/- 0.00 %, in animal model rat. CONCLUSION: Higher labeling capacity, steadiness in saline & serum, higher MBT uptake, maximum uptake in the MBT infected sites and precise imaging posed 99mTc- RFN as an alternate radio-drug for tuberculosis scintigraphy. PMID- 28595543 TI - Alkaloids and Leishmania donovani UDP-Galactopyarnosemutase: A Novel Approach in Drug Designing Against Visceral Leishmaniasis. AB - BACKGROUND: The unsatisfactory treatment options for Visceral Leishmaniasis (VL), need identification of new drug targets. Among natural products, Alkaloids have been proved to be highly effective against number of diseases. In Leishmania, UDP galactopyranosemutase (UGM) is a critical enzyme required for cell wall synthesis and thus a drug target for structure based drug designing against L. donovani. OBJECTIVE: The aim was to build the homology model of UDP galactopyransemutase and investigate the interaction of selected alkaloids with this modeled UDP galactopyranosemutase by molecular docking. METHODOLOGY: Since no crystal structure record has been found with this protein, a homology modeling was performed and a three dimensional structure of L. donovani UGM was created using MODELLER v9.9, structure quality was validated using PROCHECK and QMEAN programs which confirms that the structure is reliable. Further Molecular docking was performed with previously reported15 alkaloids. RESULTS: It was found that Protopine with a binding energy of -12.39Kcal/mole, binds at Flavin adenine dinucleotide (FAD) biding site. CONCLUSION: It was concluded that Protopine, an alkaloid could interrupt the functional aspect of L. donovani UGM and thus may be useful for drug designing studies. These finding would contribute to the understanding of the effect of drug on the parasite. PMID- 28595544 TI - Nano-carriers for the Treatment of Tuberculosis. AB - BACKGROUND: Nano size based drug delivery systems are an emerging technique with the potential to develop new strategies involving handling of drugs at the nanometer scale. There are many nano-based drug delivery systems that have been extensively reported as drug carriers for the treatment of tuberculosis. METHODS: There are numerous nano sized drug delivery systems like lipid nanoparticles, polymeric micelle, carbon nanotubes and polymeric nanoparticles that have been reported for a long time to treat diseases. There are a number of drawbacks in conventional TB dosage forms such as the development of multiple drug resistance, resulting in intolerable toxicity and high drug dose required. So, to overcome the drawbacks of conventional therapy, there is a need for a new drug delivery system with an aim to reduce the side effects of drug treatment. Nano-sized based drug delivery systems have considerable potential for the treatment of tuberculosis. These delivery systems have several advantages like high stability, high loading capacity, the feasibility of incorporation of both hydrophilic and hydrophobic drugs, and feasibility of variable routes of administration, and prolonged drug release from the matrix. These advantages enable enhanced drug solubility, bioavailability, reduced dosing frequency, high targeting, and may resolve the problem of non adherence to prescribed therapy, which is one of the major obstacles in the control of tuberculosis epidemics. CONCLUSION: This article gives an exhaustive review of patents and research papers published over the years on the challenges, the current treatment therapy of the disease faces, and potential advantages of nano sized formulations to offer more effective treatment and prevention for tuberculosis. PMID- 28595545 TI - Anticancer Polyphenols from Cultured Plant Cells: Production and New Bioengineering Strategies. AB - For many years, anticancer polyphenols have attracted significant attention as substances that prevent tumor growth and progression. These compounds are simple phenolic acids; complex phenolic acids, such as caffeoylquinic acids, rosmarinic acid and its derivatives; stilbenes (resveratrol and piceatannol); flavones; isoflavones (genistein and tectorigenin); and anthocyanins. Some compounds, such as tea and coffee polyphenols, can be produced in large quantities by traditional methods, while many others cannot. Here, we focus on the biotechnological aspects of polyphenol production by cultured plant cells and describe approaches that have been used to obtain high levels of anticancer polyphenols (resveratrol, podophyllotoxin, genistein, rosmarinic acid, lithospermic acid B, dicaffeoylquinic acids, daidzin, and others). Additionally, we provide our view on bioengineering strategies that could be important for the further improvement of cell biosynthetic characteristics. The main trend is the activation of entire biosynthetic pathways based on a comprehensive knowledge of protein-protein interaction networks involved in the regulation of polyphenol biosynthesis. As an example, we consider the jasmonate subnetwork, which will be increasingly used by plant biotechnologists. The next-generation technologies to sustained polyphenol production are likely to involve manipulations with microRNAs and reproduction of rol-gene effects. PMID- 28595546 TI - Therapeutic Proteins for Treatment of Corneal Epithelial Defects. AB - Corneal epithelial disorders take pride of place in modern ophthalmology. Defects of corneal epithelium are commonly accompanied by blurry vision, photophobia and tearing. Since cornea is the most densely innervated tissue of organisms, its disruption leads to development of a severe pain syndrome. Mild corneal erosions commonly undergo quick spontaneous recovery. Suppression of corneal wound healing due to various pathological causes results in development of severe recurrent erosions and persistent corneal defects. These pathological events can in turn lead to corneal scarring, opacification, and ulceration of cornea, and ultimately to the permanent vision impairment. The etiology of the underlying corneal diseases that commonly involves inflammatory, neurotrophic and systemic factors, should be considered for treating such defects. Therefore, the research focuse has been shifted to establish therapeutics based on proteins and peptides. Due to varied mechanisms of action, protein-based pharmaceuticals can be involved in the protection of corneal surface, mimicking tear components, stimulation of corneal wound healing, regeneration of corneal innervation, suppressing oxidative stress, inflammation and neovascularization. The active components can be naturally occurring (blood- or tear-derived) or be created de novo and optimized in order to achieve the level of activity required. Such pharmaceuticals are characterized by low toxicity and absence of systemic side-effects due to their low absorption into the bloodstream, if administrated topically. This review summarizes existing data on protein-based drugs for treatment of corneal epithelial defects that are currently under preclinical development or testing in clinical trials, or approved for medical use. PMID- 28595547 TI - Beneficial Effects of N-acetylcysteine and N-mercaptopropionylglycine on Ischemia Reperfusion Injury in the Heart. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury of the heart as a consequence of myocardial infarction or cardiac surgery represents a serious clinical problem. One of the most prominent mechanisms of I/R injury is the development of oxidative stress in the heart. In this regard, I/R has been shown to enhance the production of reactive oxygen/nitrogen species in the heart which lead to the imbalance between the pro-oxidants and antioxidant capacities of the endogenous radical-scavenging systems. OBJECTIVES: Increasing the antioxidant capacity of the heart by the administration of exogenous antioxidants is considered beneficial for the heart exposed to I/R. N-acetylcysteine (NAC) and Nmercaptopropionylglycine (MPG) are two sulphur containing amino acid substances, which belong to the broad category of exogenous antioxidants that have been tested for their protective potential in cardiac I/R injury. OBSERVATIONS: Pretreatment of hearts with both NAC and MPG has demonstrated that these agents attenuate the I/R-induced alterations in sarcolemma, sarcoplasmic reticulum, mitochondria and myofibrils in addition to improving cardiac function. While experimental studies have revealed promising data suggesting beneficial effects of NAC and MPG in cardiac I/R injury, the results of clinical trials are not conclusive because both positive and no effects of these substances have been reported on the post-ischemic recovery of heart following cardiac surgery or myocardial infarction. CONCLUSION: It is concluded that both NAC and MPG exert beneficial effects in preventing the I/Rinduced injury; however, further studies are needed to establish their effectiveness in reversing the I/R-induced abnormalities in the heart. PMID- 28595548 TI - Electrochemical Detectors in Liquid Chromatography: Recent Trends in Pharmaceutical and Biomedical Analysis. AB - Liquid chromatography (LC) coupled to an electrochemical (EC) detector is a complementary analytical tool compared to LC coupled with optical or mass spectrometry detectors (LC-MS). LC-EC can be applied to the determination of molecules difficult to be analyzed by other commercially available detectors. New EC detector design and new working electrode material have extended the scope of application in the field of pharmaceutical compounds analysis. Combining EC with LC-MS offers additional advantages compared to optical detectors in terms of drug stability and drug metabolism mimicry studies. Selected literature devoted to pharmacologically active compounds in their dosage forms, herbal drugs in natural products, drug residues in feed and/or in biological samples are reported in this review. PMID- 28595549 TI - APOC-III Antisense Oligonucleotides: A New Option for the Treatment of Hypertriglyceridemia. AB - Elevated triglyceride levels (higher than ~1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apoC-III) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. Loss of function mutations in the gene encoding apoC-III (APOC3) is associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD) while overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apoC-III concentrations), there are many patients who still have severe hypertriglyceridemia and are at increased risk for pancreatitis and potentially for CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apoC-III production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review, we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia. PMID- 28595550 TI - New Tracers and New Perspectives for Molecular Imaging in Lewy Body Diseases. AB - The term Lewy body diseases (LBDs) refers to a subset of neurodegenerative disorders that share the accumulation of the so-called Lewy bodies (LB) including: Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD later characterized by the occurrence of dementia (PDD). Moreover, multiple system atrophy (MSA) and idiopatic Rem Sleeping behaviour disorders (RBD) complete the group of synucleinopathies and have also common symptoms with respect to LBDs. The clinical diagnosis of LBDs can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by these neurodegenerative disorders, early and accurate diagnosis can lead to improved clinical management of patients. For this reason, information obtained from molecular imaging biomarkers is playing an increasingly important role in this framework. The present narrative review discusses both established milestones and new evidence on the use of molecular imaging tracers already part of the clinical practice as well as available evidence on new molecular imaging approaches in PD, PDD and DLB. PMID- 28595552 TI - Pigment Epithelium-Derived Factor: A Novel Therapeutic Target for Cardiometabolic Diseases and Related Complications. AB - Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors, serpins. It was first identified as a neuronal differentiating factor secreted by human retinal pigment epithelial cells, and then found to be the most potent inhibitor of pathological angiogenesis in mammalian eyes. Recently, PEDF has been shown not only to suppress oxidative stress and inflammatory reactions in vascular wall cells, T cells and macrophages, and adipocytes, but also to exert antithrombotic and anti fibrotic properties, thereby protecting against the development and progression of various cardiometabolic diseases and related complications. Furthermore, accumulating evidence has suggested that circulating PEDF levels may be a biomarker of severity and prognosis of these devastating disorders. Number of subjects with visceral obesity and insulin resistance is increasing, and the metabolic syndrome and its related complications, such as diabetes, nonalcoholic fatty liver disease/non-alcoholic steatohepatits, and atherosclerotic cardiovascular disease are a growing health challenge. Therefore, in this study, we review the pathophysiological role of PEDF in obesity and metabolic disorders, cardiovascular disease, diabetic eye and kidney complications, liver diseases, and reproductive system disorders, and discuss the potential clinical utility of modulating the expression and actions of PEDF for preventing these cardiometabolic disorders. We also refer to the clinical value of PEDF as a biomarker in cardiometabolic complications. PMID- 28595551 TI - NMR-based Drug Development and Improvement Against Malignant Melanoma - Implications for the MIA Protein Family. AB - The Melanoma Inhibitory Activity (MIA) protein is strongly expressed and secreted by malignant melanoma cells and was shown to promote melanoma development and invasion. The MIA protein was the first extracellular protein shown to adopt an Src homology 3 (SH3) domain-like fold in solution that can bind to fibronectin type III domains. Together with MIA, the homologous proteins OTOR (or FDP), MIA 2, and TANGO (or MIA-3) constitute a protein family of non-cytosolic and - except for fulllength TANGO and TANGO1-like (TALI) - extracellular SH3-domain containing proteins. Members of this protein family modulate collagen maturation and export, cartilage development, cell attachment in the extracellular matrix, and melanoma metastasis. These proteins may thus serve as promising targets for drug development against malignant melanoma. For the last twenty years, NMR spectroscopy has become a powerful technique in medicinal chemistry. While traditional high throughput screenings only report on the activity or affinity of low molecular weight compounds, NMR spectroscopy does not only relate to the structure of those compounds with their activity, but it can also unravel structural information on the ligand binding site on the protein at atomic resolution. Based on the molecular details of the interaction between the ligand and its target protein, the binding affinities of initial fragment hits can be further improved more efficiently in order to generate lead structures that exhibit significant therapeutic effects. The NMR-based approach promises to greatly contribute to the quest for low molecular weight compounds that ultimately could yield drugs to treat skin-related diseases such as malignant melanoma more effectively. PMID- 28595553 TI - Sulfur - Containing Amino Acids in Seizures: Current State of the Art. AB - BACKGROUND: Homocysteine and taurine are non-proteinogenic sulfur-containing amino acids with numerous important physiological roles. Homocysteine and taurine are considered to be neurotransmitters and neuromodulators, the first showing clear hyperexcitability role, while the second is known by its inhibitory and neuroprotective properties. OBJECTIVE: In this article we addressed the role of homocysteine and its related metabolite homocysteine thiolactone in the development of seizures, focusing on its experimental models in vivo, potential mechanisms of proepileptogenic activity via interactions with glutamatergic neurotransmission, sodium pump activity, oxidative stress, cholinergic system and NO-mediated neuronal signaling, as well as the pharmacological and non pharmacological approaches to modulate its proconvulsive activity. Additionally, herein we will focus on taurine neuroprotective effects linked with its anticonvulsive properties and mediated by taurine interactions with GABA-ergic and glutamatergic system and oxidative stress. PMID- 28595554 TI - Sulphur-containing Amino Acids: Protective Role Against Free Radicals and Heavy Metals. AB - BACKGROUND: Sulphur is an abundant element in biological systems, which plays an important role in processes essential for life as a constituent of proteins, vitamins and other crucial biomolecules. The major source of sulphur for humans is plants being able to use inorganic sulphur in the purpose of sulphur containing amino acids synthesis. Sulphur-containing amino acids include methionine, cysteine, homocysteine, and taurine. Methionine and cysteine are classified as proteinogenic, canonic amino acids incorporated in protein structure. Sulphur amino acids are involved in the synthesis of intracellular antioxidants such as glutathione and N-acetyl cysteine. Moreover, naturally occurring sulphur-containing ligands are effective and safe detoxifying agents, often used in order to prevent toxic metal ions effects and their accumulation in human body. METHODS: Literature search for peer-reviewed articles was performed using PubMed and Scopus databases, and utilizing appropriate keywords. RESULTS: This review is focused on sulphur-containing amino acids - methionine, cysteine, taurine, and their derivatives - glutathione and N-acetylcysteine, and their defense effects as antioxidant agents against free radicals. Additionally, the protective effects of sulphur-containing ligands against the toxic effects of heavy and transition metal ions, and their reactivation role towards the enzyme inhibition are described. CONCLUSION: Sulphur-containing amino acids represent a powerful part of cell antioxidant system. Thus, they are essential in the maintenance of normal cellular functions and health. In addition to their worthy antioxidant action, sulphur-containing amino acids may offer a chelating site for heavy metals. Accordingly, they may be supplemented during chelating therapy, providing beneficial effects in eliminating toxic metals. PMID- 28595556 TI - Iodine Prophylaxis in the Lights of the Last Recommendation of WHO on Reduction of Daily Salt Intake. AB - BACKGROUND: In 1994, International Organizations: WHO, UNICEF and ICCIDD indicat ed salt Natrium Chloride as the main carrier of iodine in the prophilaxis systems in the iodine deficient areas over the world. Following this recommendation, 24 European countries introduced the model of iodine p rop hylaxis based on the salt iodization. However in 7 European countries only - among tchem in Poland - salt iodization is mandatory as the most effective mode lon the population level. OBJECTIVE: Presenting the method for the reduction of the consumption of iodized salt and supplement ation of iodine by other iodine carriers. METHODS: Concentration of iodine in the salt has been calculated according to the daily salt consumption and WHO recommendation on the daily dose of iodine that should be supplied in different groups of age and in pregnant and breast feeding women. No relevant recent patents were available for this WHO report. RESULTS: Consumption of salt in European countries is from 8 to 11g/day/person. In Poland, it is very high 11.5g/day/person. WHO in 1996 introduced recommendation on reducing daily salt intake to 5g/day/person as Natrium is a risk factor of hypertension and some neoplastic processes. CONCLUSION: When iodized salt is the main carrier of iodine in the prophylaxis systems, additional carriers of iodine should be introduced in the food market for instant -iodized mineral water. A very important factor is the proper information and education on the population level. This action is under control of the Polish Council for Control of Iodine Deficiency Disorders [PCCIDD] established in 1991 following the example of the International Council for Control of Iodine Deficiency Disorders [ICCIDD]. PMID- 28595555 TI - Microdialysis-Assessed Adipose Tissue Metabolism in Critically Ill Patients. AB - BACKGROUND: Microdialysis is a minimally invasive technique that allows direct in situ and in vivo sampling, studies and manipulations of the interstitial/extracellular fluid/space. It has been shown to be of use mainly in acute brain injury/neurocritical care. METHODS: Microdialysis has been used to study obesity, diabetes mellitus, inflammation and pharmacokinetics at the adipose tissue level. In critically ill patients (and particularly in those with sepsis or septic shock), within days to weeks, adipose tissue shows profound alterations; under such conditions, the implementation of microdialysis can provide researchers with interesting findings. RESULTS: The well-known association between lipolysis and cortisol has been verified at the tissue level with microdialysis. Specific metabolic aberrations in critically ill patients with septic shock have been noted in adipose tissue - assessed with microdialysis before becoming evident in the systemic circulation. Measurement of the lactate to pyruvate ratio in adipose tissue - also assessed with microdialysis - in patients with septic shock has prognostic value equal to that of universally accepted clinical severity scores. CONCLUSION: Microneedle arrays have been already used to assess interstitial fluid glucose. Possibly, the implementation of microneedle and lab-on-a-chip technology, might complement the current use of microdialysis in the study of the interstitial space/adipose tissue metabolism in health and disease. PMID- 28595557 TI - Oxidative Stress, Mitochondrial Abnormalities and Proteins Deposition: Multitarget Approaches in Alzheimer's Disease. AB - Alzheimer Diseases (AD) is a multifactorial pathology characterized by a complex etiology. The hallmarks of AD, such as Abeta deposits in senile plaque and Neurofibrillary Tangles (NFT), are strongly intertwined with Reactive Oxygen Species (ROS) production and oxidative stress (OS), which are considered the common effectors of the cascade of degenerative events. An increasing body of evidence reveals that both mitochondrial abnormalities and metal accumulations synergistically act as major producers of ROS, thus contributing to neuronal toxicity. Consequently, the detrimental role of ROS production together with the neurodegenerative events involved in AD has been widely investigated as new potential therapeutic strategies. This review will concisely summarize the link between OS and the hallmarks of AD, emphasizing on their strong correlation with neurodegenerative events and elucidating the pivotal role of ROS in AD pathology. Furthermore, through this review, we will provide a short account of some of the efforts, challenges and opportunities in developing multitarget drugs by addressing ROS production, metal accumulation and protein depositions. PMID- 28595558 TI - The Role of Placental Carbonyl Reducing Enzymes in Biotransformation of Bupropion and 4-methylnitrosamino-1-(3-pyridyl)-1-butanone. AB - BACKGROUND: Bupropion (BUP) has a potential to be an effective pharmacotherapy for smoking cessation during pregnancy. Smoking during pregnancy stimulates placental carbonyl reductases that catalyze the biotransformation of BUP. 4 methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen of cigarette smoke. Carbonyl reduction of NNK into 4- methylnitrosamino-1-(3 pyridyl)-1-butanol (NNAL) constitutes a major step in NNK detoxification. Thus, placentas of pregnant smokers on BUP therapy can become a site of drug-drug interaction. Therefore, we investigated the effect of continuous exposure to BUP and cigarette smoke on the activity of placental carbonyl reductases in the formation of NNAL from NNK. METHODS: The reductive metabolism of NNK was determined using microsomal and cytosolic subcellular fractions of placentas obtained from non-smoking women treated with BUP for depression, and women not exposed to BUP: non-smokers (control) and smokers. The effect of BUP and its metabolites on the reductive metabolism of NNK was investigated using subcellular fractions of control placentas. RESULTS: The formation of NNAL from NNK by placental cytosolic fractions of heavy smokers (>=20 cigarettes per day) was lower than that of control (12.1+/-3.5 nmol.mgP-1 vs 16.5+/-6.0 nmol.mgP-1, P<0.05). While being exposed to BUP, the activity of placental carbonyl reductases remained unaffected, the formation of NNAL in the placental cytosolic fraction decreased only in the presence of high concentrations of BUP metabolites. CONCLUSION: Smoking during pregnancy decreases the detoxifying capacity of soluble carbonyl reductases towards NNK. Given the experimental conditions, exposure to BUP and its metabolites should not impede the reductive metabolism of NNK by placenta in vivo. PMID- 28595559 TI - 25-hydroxyvitamin D Correlation with Prolactin Levels and Adenoma Size in Female Patients with Newly Diagnosed Prolactin Secreting Adenoma. AB - OBJECTIVE: The present research explored the relationship of vitamin D status with prolactin levels and adenoma size in female patients with newly diagnosed prolactinoma and determination of hypovitaminosis D prevalence among female patients with prolactinoma. PATIENTS AND METHODS: We enrolled 67 female patients with newly diagnosed prolactinoma (41 with micro adenoma and 26 with macro adenoma) in this case-control study at the time of presentation. We selected 45 female subjects as a control group who were matched according to age, weight, height, body mass index and waist circumference. We investigated 25 hydroxyvitamin D, the major circulating form of vitamin D. RESULTS: Prolactinoma patients had significantly lower 25-hydroxyvitamin D levels in comparison with control subjects. Also, macroadenoma patients showed significantly lower 25 hydroxyvitamin D levels as compared to microadenomoa patients. By contrast, microadenoma patients had nonsignificant lower 25-hydroxyvitamin D levels in comparison with control subjects. Furthermore, we found prolactinoma patients with 25-hydroxyvitamin D >20.00 ng/ml showing significant differences in the prolactin levels and adenoma size when compared with those who had 25- hydroxyvitamin D <20.00 ng/ml. In regression analysis, 25-hydroxyvitamin D level was a significant predictor of adenoma size in patients diagnosed with prolactinoma. CONCLUSION: Female patients with prolactinoma have lower vitamin D levels and have higher prevalence of vitamin D insufficiency and deficiency among prolactinoma patients when compared with normal subjects. Also vitamin D deficiency in prolactinoma patients associated with larger adenoma size and higher prolactin level. Finally, 25-hydroxyvitamin D level was a statistically significant predictor of prolactinoma size but not prolactin levels. PMID- 28595560 TI - Vitamin D is Related to Markers of Vulnerable Plaque in Acute Myocardial Infarction. AB - BACKGROUND: Vitamin D is a fat soluble vitamin involved in calcium and bone metabolism; recently its deficiency has been related to cardiovascular disease. In cardiac tissue, vitamin D suppresses metalloproteinases (MMPs) expression, enzymes directly associated with vulnerable plaque. OBJECTIVE: To investigate whether the association between vitamin D and leptin is related to markers of vulnerable plaque, such as MMPs in patients with acute myocardial infarction. METHODS: We studied 66 male patients with acute myocardial infarction, undergoing primary angioplasty. Blood samples were obtained at admission and 24hs after the surgery. Leptin and vitamin D concentrations in serum and MMP-2 and -9 activities in plasma were determined. RESULTS: MMP-2 activity was increased in Vitamin D deficient/insufficient patients at admission (p=0.04) and 24 hs later (p=0.05). In a linear regression model, vitamin D explained 24% of the variance of MMP-2 activity (F=2.839 p=0.04). At admission, vitamin D correlated with serum leptin (r=-0.302 p=0.033), and explained 39.5% of its variation (F=4.432 p=0.003). CONCLUSION: In the studied population, vitamin D was inversely related to MMP-2 and leptin which are involved in coronary artery disease and acute myocardial infarction. The decrease in this hormone levels would be associated with a worse metabolic profile in acute coronary syndrome patients. PMID- 28595561 TI - Sexual Dysfunction, Cardiovascular Risk and Effects of Pharmacotherapy. AB - BACKGROUND: Sexual dysfunction affects millions of people with an increasing prevalence, worldwide. The pathophysiology of the disease shares several similarities with cardiovascular disease (CVD), including atherosclerosis, endothelial dysfunction, structural vascular damage and subclinical inflammation. Erectile dysfunction (ED) and female sexual dysfunction are common among patients with CVD and risk factors such as hypertension, diabetes, obesity and metabolic syndrome. Given the common pathogenesis of the diseases, ED is an independent prognostic factor of future ED events. Patients with overt ED or risk factors are usually treated with several drugs for the management of these conditions. Several of these drugs have been evaluated for their effect on sexual activity. RESULTS AND CONCLUSION: Among the antihypertensive drugs, diuretics and beta blockers seem to exert a detrimental impact on sexual function, with nebivolol being the only beta-blocker with favorable properties through an increase in nitric oxide bioavailability. In contrast, renin-angiotensin system inhibitors and calcium-channel blockers have a neutral effect on sexual activity. Hypoglycemic drugs have been less evaluated in the ED setting, with metformin, pioglitazone and liraglutide presenting favorable results. Statins on the other hand have not provided consistent results with observational studies suggesting a detrimental role in sexual activity and a few randomized studies indicating a neutral or even beneficial effect on erectile function. PMID- 28595562 TI - Non-viral Delivery Systems for Breast Cancer Gene Therapy. AB - INTRODUCTION: The ever-evolving field of gene therapy promises several innovative treatments for cancer. Advances in genetic modification of tumor cells and micro environment have led to the development of more effective therapeutic strategies with fewer side effects. MATERIALS & METHODS: The development of effective delivery system challenges, remains. Non-viral vectors are interesting due to their bio-safety and their ability to transfer different types of nucleic acids. Examples of these techniques are the use of oligonucleoides, liposomes, nanoparticles, inorganic material, and engineered stem cells. CONCLUSION: In this review, we focus on recent advances in the intracellular delivery of DNA and siRNA to the cancer cells with emphasis on breast cancer. PMID- 28595563 TI - Strategies on Technology Transfer and Patents Commercialization for Nanotechnology at the Spanish National Research Council. AB - : Nanoscience and nanotechnology made their appearance in the scientific scene at a time when both the economy of Spain and the Spanish Research and Innovation System were experiencing strong growth. This circumstance resulted in a remarkable development of nanoscience and nanotechnology especially in universities and public research institutions such as the Spanish National Research Council (Consejo Superior de Investigaciones Cientificas-CSIC). However, this development in academia has not been reflected in a similar increment in the transfer of knowledge to the productive sector despite several efforts and initiatives were launched. The CSIC, the main generator of scientific knowledge in Spain, has designed and implemented a series of actions in order to take advantage of the knowledge generated in nanotechnology by its research groups by mean of an appropriate transfer to both the Spanish and the international industry. METHOD: Internal methodologies used in CSIC in order to protect and commercialize nanotechnology based intellectual property as well as their effects are reviewed. The evolution of CSIC nanotechnology patents portfolio is also analyzed. RESULTS: There has been a clear increase in the patent license agreements of CSIC in the period 2002- 2015 in the field of nanotechnology. This increase is correlated to these facts: (i) Highly qualified team managing Intellectual Property issues, (ii) The presence of CSIC in international fairs, and (iii) Proactive search of companies and investors. CONCLUSION: Successful results can be achieved in technology transfer when the appropriate resources are available and properly organized with an adequate combination of efforts in knowledge protection, promotion and commercialization of technologies and support to the scientific entrepreneurs of the institution. PMID- 28595564 TI - Electric-Field-Oriented Growth of Long Hair-Like Silica Microfibrils and Derived Functional Monolithic Solids. AB - BACKGROUND: Controlled self-assembly using molecules/nanoparticles as building block materials represents an important approach for nanofabrication. METHOD: We present a "bottom-up" fabrication approach to first grow a new class of inorganic (silica) long hair-like microfibrils or microwires and then to form monolithic solid pellet that contains parallel arrays of bundled microfibrils with a controlled orientation. During the sol-gel solution processing, reactive precursor species are utilized as molecular "building blocks" for the field directed assembly growth of microfibrils driven by an electric field of pulsed direct current (dc) with controlled frequency. RESULTS: We have demonstrated a novel reactive electrofibrilation process that combines an external field with a solid-phase nucleation and growth process which in principle has no limitation on the type of reactions (such as the one here that involves sol-gel reaction chemistry) and on materials compositions (such as the example silica oxide), thus will enable bulk production of long microfibrils of wide variety of inorganic materials (other oxides or metals). Furthermore, we have fabricated uniquely architectured monolithic solid materials containing aligned microfibrils by "wet press" of the in-situ grown microfibril structure in the electric field. The consolidated monolithic slabs (1 cm * 1 cm * 3 mm) have shown anisotropic properties and desirable retention of DNA molecule fragments, thus, could serve as a platform stationary-phase materials for future development of capillary electrochromatography for biomolecule separations. CONCLUSION: Electrical field guided self-assembly is an effective approach in producing long (hair-like) ceramic microfibrils, which can be further used in consolidation fabrication of oriented structured ceramic monoliths with potential for capillary electrophoretic chromatography and other separations applications. This original work was recorded through a patent application to understand the fibril formation mechanism and its process. PMID- 28595565 TI - Gold Nanoparticles by Laser Ablation for X-Ray Imaging and Protontherapy Improvements. AB - BACKGROUND: Gold nanoparticles, 5-20 nm in diameter, were generated with a pulsed Nd: YAG laser at 1010 W/cm2 at solution concentrations ranging between 1-100 mg/ml. The incremental X-ray contrast imaging using gold nanoparticles was investigated and measured. The study was performed with the aim to enhance the massive absorption coefficient of X-ray radiation in the tumor for medical image quality and to improve traditional X-ray radiotherapy or proton therapy. A simulation of proton therapy improvement was conducted using a human ocular melanoma model, placed 3 cm behind the eye lens, and testing 60 MeV protons. Calculations suggest that the local injection of a solution containing Au-NPs may increase the proton energy released in the tumor above 50%, with the dose in the surrounding tissues leading to an increased probability of tissue healing. A discussion on recent patents in the ambit of the preparation and use of Au nanoparticles in medical imaging and therapy is presented. METHODS: Au nanoparticles were characterized using optical absorbance, X-ray fluorescence, SEM, and TEM microscopies. Biocompatible nanoparticle solutions were injected intravenously into tail veins of mice followed by X-ray imaging using 20-45 keV photons to evaluate the uptake and the clearance by different organs of the nanoparticles. RESULTS: Diagnostic X-ray images of mice in which the Au-NPs were injected showed high spatial resolution contrast of different organs having high up-take. A calculation of the dose released by X-rays, electrons and protons to the tumor site demonstrates that an increment of the order of 50% can be obtained using adapt solution concentration. CONCLUSION: The use of Au-NPs in biocompatible solutions injected in living organism permits their blood transport up to different organs. The NPs can be employed as contrast medium to enhance the medical image resolution and to prepare the cancer tissues to be exposed to ionization radiations in order to enhance the dose released to the tumor cells. This effect permits to reduce the total dose given to the patient and to increase the dose released to the tumor cells with respect to healthy ones. PMID- 28595566 TI - A Systemic Review of Adult Mesenchymal Stem Cell Sources and their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration. AB - BACKGROUND: Adult mesenchymal stem cells (MSCs) were first isolated from bone marrow by Friedenstein in 1976. These cells were clonogenic, non-haematopoietic, and able to replicate extensively in vitro. The fields of regenerative medicine and tissue engineering have grown dramatically since their inception. In the decades since, MSCs have been identified from mesoderm-, endoderm- and ectoderm derived tissues. In light of our ageing population, the need for effective cell based therapies for tissue repair and regeneration is ever-expanding. OBJECTIVES: The purpose of this systematic review was to summarise evidence from the most recent studies outlining different sources of adult MSCs and their suitability in musculoskeletal applications. METHODS: Online published articles were searched for using the PubMed/MEDLINE and Ovid databases, and relevant articles fulfilling the pre-defined eligibility criteria were analysed. RESULTS: To date, MSCs have been isolated from a number of adult tissues, including trabecular bone, adipose tissue, bone marrow, synovium, dermis, periodontal ligament, dental pulp, bursa and the umbilical cord. Bone marrow MSCs are currently considered the gold standard, with which newly discovered sources are compared on the basis of their renewal capabilities and multipotency. Furthermore, MSCs have been successful in the regeneration of osteonecrosis, osteoarthritis, bony defects, fracture remodeling and so on. CONCLUSION: Unfortunately, significant hurdles remain and will need to be overcome before tissue engineering using MSCs becomes routine in clinical practice. Thus, further research and understanding are required into the safe and effective sourcing and application of mesenchymal stem cells in musculoskeletal applications. PMID- 28595567 TI - Cartilage Tissue Regeneration: The Roles of Cells, Stimulating Factors and Scaffolds. AB - Cartilage tissue engineering is an emerging technique for the regeneration of cartilage tissue damaged as a result of trauma or disease. As the propensity for healing and regenerative capabilities of articular cartilage are limited, its repair remains one of the most challenging issues of musculoskeletal medicine. Clinical treatments intended to promote the success and complete repair of partial- and fullthickness articular cartilage defects are still unpredictable. However, one of the most exciting theories is that treatment of damaged articular cartilage can be realized with cartilage tissue engineering. This notion has prompted tissue engineering research involving cells, stimulating factors and scaffolds, either alone or in combination. With these perspectives, this review aims to present a summary of cartilage tissue engineering including development, recent progress, and major steps taken toward the regeneration of functional cartilage tissue. In addition, we discussed the role of stimulating factors, including growth factors, gene therapies, biophysical stimuli, and bioreactors, as well as scaffolds, including natural, synthetic, and nanostructured scaffolds, in cartilage tissue regeneration. Special emphasis was placed on cell source, including chondrocytes, fibroblasts, and stem cells, as an important component of cartilage tissue engineering techniques. In conclusion, continued development of cartilage tissue engineering will support future applications for patients suffering from diseased cartilage tissue problems and osteoarthritis. PMID- 28595568 TI - Differences in responses of grass carp to different types of grass carp reovirus (GCRV) and the mechanism of hemorrhage revealed by transcriptome sequencing. AB - BACKGROUND: Grass carp is an important farmed fish in China that is affected by serious disease, especially hemorrhagic disease caused by grass carp reovirus (GCRV). The mechanism underlying the hemorrhagic symptoms in infected fish remains to be elucidated. Although GCRV can be divided into three distinct subtypes, differences in the pathogenesis and host immune responses to the different subtypes are still unclear. The aim of this study was to provide a comprehensive insight into the grass carp response to different GCRV subtypes and to elucidate the mechanism underlying the hemorrhagic symptoms. RESULTS: Following infection of grass carp, GCRV-I was associated with a long latent period and low mortality (42.5%), while GCRV-II was associated with a short latent period and high mortality (81.4%). The relative copy number of GCRV-I remained consistent or decreased slightly throughout the first 7 days post infection, whereas a marked increase in GCRV-II high copy number was detected at 5 days post-infection. Transcriptome sequencing revealed 211 differentially expressed genes (DEGs) in Group I (66 up-regulated, 145 down-regulated) and 670 (386 up-regulated, 284 down-regulated) in Group II. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed significant enrichment in the terms or pathways involved in immune responses and correlating with blood or platelets. Most of the DEGs in Group I were also present in Group II, although the expression profiles differed, with most DEGs showing mild changes in Group I, while marked changes were observed in Group II, especially the interferon-related genes. Many of the genes involved in the complement pathway and coagulation cascades were significantly up-regulated at 7 days post infection in Group II, suggesting activation of these pathways. CONCLUSION: GCRV I is associated with low virulence and a long latent period prior to the induction of a mild host immune response, whereas GCRV-II is associated with high virulence, a short latent period and stimulates a strong and extensive host immune response. The complement and coagulation pathways are significantly activated at 7 days post-infection, leading to the endothelial cell and blood cell damage that result in hemorrhagic symptoms. PMID- 28595569 TI - Genome-wide comparative transcriptome analysis of CMS-D2 and its maintainer and restorer lines in upland cotton. AB - BACKGROUND: Cytoplasmic male sterility (CMS) conferred by the cytoplasm from Gossypium harknessii (D2) is an important system for hybrid seed production in Upland cotton (G. hirsutum). The male sterility of CMS-D2 (i.e., A line) can be restored to fertility by a restorer (i.e., R line) carrying the restorer gene Rf1 transferred from the D2 nuclear genome. However, the molecular mechanisms of CMS D2 and its restoration are poorly understood. RESULTS: In this study, a genome wide comparative transcriptome analysis was performed to identify differentially expressed genes (DEGs) in flower buds among the isogenic fertile R line and sterile A line derived from a backcross population (BC8F1) and the recurrent parent, i.e., the maintainer (B line). A total of 1464 DEGs were identified among the three isogenic lines, and the Rf1-carrying Chr_D05 and its homeologous Chr_A05 had more DEGs than other chromosomes. The results of GO and KEGG enrichment analysis showed differences in circadian rhythm between the fertile and sterile lines. Eleven DEGs were selected for validation using qRT-PCR, confirming the accuracy of the RNA-seq results. CONCLUSIONS: Through genome-wide comparative transcriptome analysis, the differential expression profiles of CMS D2 and its maintainer and restorer lines in Upland cotton were identified. Our results provide an important foundation for further studies into the molecular mechanisms of the interactions between the restorer gene Rf1 and the CMS-D2 cytoplasm. PMID- 28595570 TI - Plant pectin acetylesterase structure and function: new insights from bioinformatic analysis. AB - BACKGROUND: Pectins are plant cell wall polysaccharides that can be acetylated on C2 and/or C3 of galacturonic acid residues. The degree of acetylation of pectin can be modulated by pectin acetylesterase (EC 3.1.1.6, PAE). The function and structure of plant PAEs remain poorly understood and the role of the fine-tuning of pectin acetylation on cell wall properties has not yet been elucidated. RESULTS: In the present study, a bioinformatic approach was used on 72 plant PAEs from 16 species among 611 plant PAEs available in plant genomic databases. An overview of plant PAE proteins, particularly Arabidopsis thaliana PAEs, based on phylogeny analysis, protein motif identification and modeled 3D structure is presented. A phylogenetic tree analysis using protein sequences clustered the plant PAEs into five clades. AtPAEs clustered in four clades in the plant kingdom PAE tree while they formed three clades when a phylogenetic tree was performed only on Arabidopsis proteins, due to isoform AtPAE9. Primitive plants that display a smaller number of PAEs clustered into two clades, while in higher plants, the presence of multiple members of PAE genes indicated a diversification of AtPAEs. 3D homology modeling of AtPAE8 from clade 2 with a human Notum protein showed an alpha/beta hydrolase structure with the hallmark Ser-His-Asp of the active site. A 3D model of AtPAE4 from clade 1 and AtPAE10 from clade 3 showed a similar shape suggesting that the diversification of AtPAEs is unlikely to arise from the shape of the protein. Primary structure prediction analysis of AtPAEs showed a specific motif characteristic of each clade and identified one major group of AtPAEs with a signal peptide and one group without a signal peptide. A multiple sequence alignment of the putative plant PAEs revealed consensus sequences with important putative catalytic residues: Ser, Asp, His and a pectin binding site. Data mining of gene expression profiles of AtPAE revealed that genes from clade 2 including AtPAE7, AtPAE8 and AtPAE11, which are duplicated genes, are highly expressed during plant growth and development while AtPAEs without a signal peptide, including AtPAE2 and AtPAE4, are more regulated in response to plant environmental conditions. CONCLUSION: Bioinformatic analysis of plant, and particularly Arabidopsis, AtPAEs provides novel insights, including new motifs that could play a role in pectin binding and catalytic sites. The diversification of AtPAEs is likely to be related to neofunctionalization of some AtPAE genes. PMID- 28595571 TI - CottonFGD: an integrated functional genomics database for cotton. AB - BACKGROUND: Cotton (Gossypium spp.) is the most important fiber and oil crop in the world. With the emergence of huge -omics data sets, it is essential to have an integrated functional genomics database that allows worldwide users to quickly and easily fetch and visualize genomic information. Currently available cotton related databases have some weakness in integrating multiple kinds of -omics data from multiple Gossypium species. Therefore, it is necessary to establish an integrated functional genomics database for cotton. DESCRIPTION: We developed CottonFGD (Cotton Functional Genomic Database, https://cottonfgd.org ), an integrated database that includes genomic sequences, gene structural and functional annotations, genetic marker data, transcriptome data, and population genome resequencing data for all four of the sequenced Gossypium species. It consists of three interconnected modules: search, profile, and analysis. These modules make CottonFGD enable both single gene review and batch analysis with multiple kinds of -omics data and multiple species. CottonFGD also includes additional pages for data statistics, bulk data download, and a detailed user manual. CONCLUSION: Equipped with specialized functional modules and modernized visualization tools, and populated with multiple kinds of -omics data, CottonFGD provides a quick and easy-to-use data analysis platform for cotton researchers worldwide. PMID- 28595572 TI - White matter damage and systemic inflammation in Parkinson's disease. AB - BACKGROUND: Systemic inflammation and white matter (WM) alterations have been noted as effects of Parkinson's disease (PD). This study sought to evaluate WM integrity in PD patients using diffusion tensor imaging (DTI) and to assess its relationship with systemic inflammation. METHODS: Sixty-six patients with PD (23 men and 43 women) and 67 healthy volunteers (29 men and 38 women) underwent blood sampling to quantify inflammatory markers and DTI scans to determine fiber integrity. The inflammatory markers included leukocyte apoptosis, as well as cellular and serum adhesion molecules, in each peripheral blood sample. DTI related indices [including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD)] were derived from DTI scans. The resulting FA maps were compared using voxel-based statistics to determine differences between the PD and control groups. The differences in the DTI indices, clinical severity, and inflammatory markers were correlated. RESULTS: Exploratory group-wise comparison between the two groups revealed that the PD patients exhibited extensive DTI index differences. Low FA accompanied by high RD and MD, without significant differences in AD, suggesting a demyelination process, were found in the parietal, occipital, cerebellar, and insular WM of the PD patients. The declined DTI indices were significantly correlated with increased clinical disease severity, adhesion molecules, and leukocyte apoptosis. CONCLUSIONS: Patients with PD experience WM integrity damage in vulnerable regions, and these impairments are associated with increased disease severity and systemic inflammation. The possible interactions among them may represent variant neuronal injuries and their consequent processes in PD. PMID- 28595573 TI - A novel KCNQ1 nonsense variant in the isoform-specific first exon causes both jervell and Lange-Nielsen syndrome 1 and long QT syndrome 1: a case report. AB - BACKGROUND: According to previous KCNQ1 (potassium channel, voltage gated, KQT like subfamily, member 1) gene screening studies, missense variants, but not nonsense or frame-shift variants, cause the majority of long QT syndrome (LQTS; Romano-Ward syndrome [RWS]) 1 cases. Several missense variants are reported to cause RWS by a dominant-negative mechanism, and some KCNQ1 variants can cause both Jervell and Lange-Nielsen Syndrome (JLNS; in an autosomal recessive manner) and LQTS1 (in an autosomal dominant manner), while other KCNQ1 variants cause only JLNS. The human KCNQ1 gene is known to have two transcript isoforms (kidney isoform and pancreas isoform), and both isoforms can form a functional cardiac potassium channel. CASE PRESENTATION: Here, we report a novel nonsense KCNQ1 variant causing not only JLNS, but also significant QTc prolongation identical to RWS in an autosomal dominant manner. Our case study supports that haploinsufficiency in the KCNQ1 gene is causative of significant QTc prolongation identical to RWS. Interestingly, the nonsense variant (NM_000218.2:c.115G > T [p.Glu39X]) locates in exon 1a of KCNQ1, which is a kidney-isoform specific exon. The variant is located closer to the N-terminus than previously identified nonsense or frame-shift variants. CONCLUSION: To the best of our knowledge, this is the first report showing that a nonsense variant in exon 1a of KCNQ1, which is the kidney-isoform specific exon, causes JLNS. Our findings may be informative to the genetic pathogenesis of RWS and JLNS caused by KCNQ1 variants. PMID- 28595574 TI - Limitations of pulmonary embolism ICD-10 codes in emergency department administrative data: let the buyer beware. AB - BACKGROUND: Administrative data is a useful tool for research and quality improvement; however, validity of research findings based on these data depends on their reliability. Diagnoses assigned by physicians are subsequently converted by nosologists to ICD-10 codes (International Statistical Classification of Diseases and Related Health Problems, 10th Revision). Several groups have reported ICD-9 coding errors in inpatient data that have implications for research, quality improvement, and policymaking, but few have assessed ICD-10 code validity in ambulatory care databases. Our objective was to evaluate pulmonary embolism (PE) ICD-10 code accuracy in our large, integrated hospital system, and the validity of using these codes for operational and health services research using ED ambulatory care databases. METHODS: Ambulatory care data for patients (age >= 18 years) with a PE ICD-10 code (I26.0 and I26.9) were obtained from the records of four urban EDs between July 2013 to January 2015. PE diagnoses were confirmed by reviewing medical records and imaging reports. In cases where chart diagnosis and ICD-10 code were discrepant, chart review was considered correct. Physicians' written discharge diagnoses were also searched using 'pulmonary embolism' and 'PE', and patients who were diagnosed with PE but not coded as PE were identified. Coding discrepancies were quantified and described. RESULTS: One thousand, four hundred and fifty-three ED patients had a PE ICD-10 code. Of these, 257 (17.7%) were false positive, with an incorrectly assigned PE code. Among the 257 false positives, 193 cases had ambiguous ED diagnoses such as 'rule out PE' or 'query PE', while 64 cases should have had non PE codes. An additional 117 patients (8.90%) with a PE discharge diagnosis were incorrectly assigned a non-PE ICD-10 code (false negative group). The sensitivity of PE ICD-10 codes in this dataset was 91.1% (95%CI, 89.4-92.6) with a specificity of 99.9% (95%CI, 99.9-99.9). The positive and negative predictive values were 82.3% (95%CI, 80.3-84.2) and 99.9% (95%CI, 99.9-99.9), respectively. CONCLUSIONS: Ambulatory care data, like inpatient data, are subject to coding errors. This confirms the importance of ICD-10 code validation prior to use. The largest proportion of coding errors arises from ambiguous physician documentation; therefore, physicians and data custodians must ensure that quality improvement processes are in place to promote ICD-10 coding accuracy. PMID- 28595575 TI - Towards diagnostic metagenomics of Campylobacter in fecal samples. AB - BACKGROUND: The development of diagnostic metagenomics is driven by the need for universal, culture-independent methods for detection and characterization of pathogens to substitute the time-consuming, organism-specific, and often culture based laboratory procedures for epidemiological source-tracing. Some of the challenges in diagnostic metagenomics are, that it requires a great next generation sequencing depth and unautomated data analysis. RESULTS: DNA from human fecal samples spiked with 7.75 * 101-7.75 * 107 colony forming unit (CFU)/ml Campylobacter jejuni and chicken fecal samples spiked with 1 * 102-1 * 106 CFU/g Campylobacter jejuni was sequenced and data analysis was done by the metagenomic tools Kraken and CLARK. More hits were obtained at higher spiking levels, however with no significant linear correlations (human samples p = 0.12, chicken samples p = 0.10). Therefore, no definite detection limit could be determined, but the lowest spiking levels found positive were 7.75 * 104 CFU/ml in human feces and 103 CFU/g in chicken feces. Eight human clinical fecal samples with estimated Campylobacter infection loads from 9.2 * 104-1.0 * 109 CFU/ml were analyzed using the same methods. It was possible to detect Campylobacter in all the clinical samples. CONCLUSIONS: Sensitivity in diagnostic metagenomics is improving and has reached a clinically relevant level. There are still challenges to overcome before real-time diagnostic metagenomics can replace quantitative polymerase chain reaction (qPCR) or culture-based surveillance and diagnostics, but it is a promising new technology. PMID- 28595576 TI - Perceptions of quality across the maternal care continuum in the context of a health financing intervention: Evidence from a mixed methods study in rural Malawi. AB - BACKGROUND: In 2013, Malawi with its development partners introduced a Results Based Financing for Maternal and Newborn Health (RBF4MNH) intervention to improve the quality of maternal and newborn health-care services. Financial incentives are awarded to health facilities conditional on their performance and to women for delivering in the health facility. We assessed the effect of the RBF4MNH on quality of care from women's perspectives. METHODS: We used a mixed-method prospective sequential controlled pre- and post-test design. We conducted 3060 structured client exit interviews, 36 in-depth interviews and 29 focus group discussions (FGDs) with women and 24 in-depth interviews with health service providers between 2013 and 2015. We used difference-in-differences regression models to measure the effect of the RBF4MNH on experiences and perceived quality of care. We used qualitative data to explore the matter more in depth. RESULTS: We did not observe a statistically significant effect of the intervention on women's perceptions of technical care, quality of amenities and interpersonal relations. However, in the qualitative interviews, most women reported improved health service provision as a result of the intervention. RBF4MNH increased the proportion of women reporting to have received medications/treatment during childbirth. Participants in interviews expressed that drugs, equipment and supplies were readily available due to the RBF4MNH. However, women also reported instances of neglect, disrespect and verbal abuse during the process of care. Providers attributed these negative instances to an increased workload resulting from an increased number of women seeking services at RBF4MNH facilities. CONCLUSION: Our qualitative findings suggest improvements in the availability of drugs and supplies due to RBF4MNH. Despite the intervention, challenges in the provision of quality care persisted, especially with regard to interpersonal relations. RBF interventions may need to consider including indicators that specifically target the provision of respectful maternity care as a means to foster providers' positive attitudes towards women in labour. In parallel, governments should consider enhancing staff and infrastructural capacity before implementing RBF. PMID- 28595578 TI - Open questions: completing the parts list and finding the integrating signals. AB - One of the great revelations of post-genomic biology has been the extent to which essential functions and mechanisms are conserved across vast phylogenetic distances. Because of this, we can look to the fruit fly for answers to pressing open questions on the unknown functions of genes and the mechanisms of their physiological integration. PMID- 28595577 TI - Complementary and conventional providers in cancer care: experience of communication with patients and steps to improve communication with other providers. AB - BACKGROUND: Effective interdisciplinary communication is important to achieve better quality in health care. The aims of this study were to compare conventional and complementary providers' experience of communication about complementary therapies and conventional medicine with their cancer patients, and to investigate how they experience interdisciplinary communication and cooperation. METHOD: This study analyzed data from a self-administrated questionnaire. A total of 606 different health care providers, from four counties in Norway, completed the questionnaire. The survey was developed to describe aspects of the communication pattern among oncology doctors, nurses, family physicians and complementary therapists (acupuncturists, massage therapists and reflexologists/zone-therapists). Between-group differences were analyzed using chi-square, ANOVA and Fisher's exact tests. Significance level was defined as p < 0.05 without adjustment for multiple comparisons. RESULT: Conventional providers and complementary therapists had different patterns of communication with their cancer patients regarding complementary therapies. While complementary therapists advised their patients to apply both complementary and conventional modalities, medical doctors were less supportive of their patients' use of complementary therapies. Of conventional providers, nurses expressed more positive attitudes toward complementary therapies. Opportunities to improve communication between conventional and complementary providers were most strongly supported by complementary providers and nurses; medical doctors were less supportive of such attempts. A number of doctors showed lack of respect for complementary therapists, but asked for more research, guidelines for complementary modalities and training in conventional medicine for complementary therapists. CONCLUSION: For better quality of care, greater communication about complementary therapy use is needed between cancer patients and their conventional and complementary providers. In addition, more communication between conventional and complementary providers is needed. Nurses may have a crucial role in facilitating communication, as they are positive toward complementary therapies and they have more direct communication with patients about their treatment preferences. PMID- 28595580 TI - Planned home compared with planned hospital births: mode of delivery and Perinatal mortality rates, an observational study. AB - BACKGROUND: To compare the mode of delivery between planned home versus planned hospital births and to determine if differences in intervention rates could be interpreted as over- or undertreatment. METHODS: Intervention and perinatal mortality rates were obtained for 679,952 low-risk women from the Dutch Perinatal Registry (2000-2007). Intervention was defined as operative vaginal delivery and/or caesarean section. Perinatal mortality was defined as the intrapartum and early neonatal mortality rate up to 7 days postpartum. Besides adjustment for maternal and care factors, we included for additional casemix adjustment: presence of congenital abnormality, small for gestational age, preterm birth, or low Apgar score. The techniques used were nested multiple stepwise logistic regression, and stratified analysis for separate risk groups. An intention-to treat like analysis was performed. RESULTS: The intervention rate was lower in planned home compared to planned hospital births (10.9% 95% CI 10.8-11.0 vs. 13.8% 95% CI 13.6-13.9). Intended place of birth had significant impact on the likelihood to intervene after adjustment (planned homebirth (OR 0.77 95% CI. 0.75 0.78)). The mortality rate was lower in planned home births (0.15% vs. 0.18%). After adjustment, the interaction term home- intervention was significant (OR1.51 95% CI 1.25-1.84). In risk groups, a higher perinatal mortality rate was observed in planned home births. CONCLUSIONS: The potential presence of over- or under treatment as expressed by adjusted perinatal mortality differs per risk group. In planned home births especially multiparous women showed universally lower intervention rates. However, the benefit of substantially fewer interventions in the planned home group seems to be counterbalanced by substantially increased mortality if intervention occurs. PMID- 28595579 TI - Omental adipose tissue is a more suitable source of canine Mesenchymal stem cells. AB - BACKGROUND: Mesenchymal Stem Cells (MSCs) are a promising therapeutic tool in veterinary medicine. Currently the subcutaneous adipose tissue is the leading source of MSCs in dogs. MSCs derived from distinct fat depots have shown dissimilarities in their accessibility and therapeutic potential. The aims of our work were to determine the suitability of omental adipose tissue as a source of MSCs, according to sampling success, cell yield and paracrine properties of isolated cells, and compared to subcutaneous adipose tissue. RESULTS: While sampling success of omental adipose tissue was 100% (14 collections from14 donors) for subcutaneous adipose tissue it was 71% (10 collections from 14 donors). MSCs could be isolated from both sources. Cell yield was significantly higher for omental than for subcutaneous adipose tissue (38 +/- 1 vs. 30 +/- 1 CFU-F/g tissue, p < 0.0001). No differences were observed between sources regarding cell proliferation potential (73 +/- 1 vs. 74 +/- 1 CDPL) and cell senescence (at passage 10, both cultures presented enlarged cells with cytoplasmic vacuoles and cellular debris). Omental- and subcutaneous-derived MSCs expressed at the same level bFGF, PDGF, HGF, VEGF, ANG1 and IL-10. Irrespective of the source, isolated MSCs induced proliferation, migration and vascularization of target cells, and inhibited the activation of T lymphocytes. CONCLUSION: Compared to subcutaneous adipose tissue, omental adipose tissue is a more suitable source of MSCs in dogs. Since it can be procured from donors with any body condition, its collection procedure is always feasible, its cell yield is high and the MSCs isolated from it have desirable differentiation and paracrine potentials. PMID- 28595581 TI - A strategy to estimate the rate of recruitment of inflammatory cells during bovine intramammary infection under field management. AB - BACKGROUND: In most infectious diseases, among which bovine mastitis, promptness of the recruitment of inflammatory cells (mainly neutrophils) in inflamed tissues has been shown to be of prime importance in the resolution of the infection. Although this information should aid in designing efficient control strategies, it has never been quantified in field studies. METHODS: Here, a system of ordinary differential equations is proposed that describes the dynamic process of the inflammatory response to mammary pathogens. The system was tested, by principal differential analysis, on 1947 test-day somatic cell counts collected on 756 infected cows, from 50 days before to 50 days after the diagnosis of clinical mastitis. Cell counts were log-transformed before estimating recruitment rates. RESULTS: Daily rates of cellular recruitment was estimated at 0.052 (st. err. = 0.005) during health. During disease, an additional cellular rate of recruitment was estimated at 0.004 (st. err. = 0.001) per day and per bacteria. These estimates are in agreement with analogous measurements of in vitro neutrophil functions. CONCLUSIONS: Results suggest the method is adequate to estimate one of the components of innate resistance to mammary pathogens at the individual level and in field studies. Extension of the method to estimate components of innate tolerance and limits of the study are discussed. PMID- 28595582 TI - Enhancing the quality and lipid stability of chicken nuggets using natural antioxidants. AB - BACKGROUND: Current day consumers prefer natural antioxidants to synthetic antioxidants because they are more active. However, the activity generally depends on the specific condition and composition of food. The aim of this study was to investigate the effect of wheat germ oil and alpha-lipoic acid on the quality characteristics, antioxidant status, fatty acid profile, and sensory attributes of chicken nuggets. METHODS: Six types of diets were prepared for feeding the chickens to evaluate the quality of nuggets made from the leg meat of these experimental animals. These included control, diet enriched with wheat germ oil (WGO), which is a rich natural source of alpha-tocopherol (AT), diet with added AT or alpha-lipoic acid (ALA), diet with a combination of either ALA and WGO (ALA + WGO) or ALA and synthetic AT (ALA + AT). ALA has great synergism with synthetic as well as natural AT (WGO). RESULTS: The diet with WGO and ALA showed the best potential with respect to both antioxidant activity and total phenolic content. HPLC results revealed that the chicken nuggets made from WGO + ALA group showed maximum deposition of AT and ALA. The stability of the nuggets from control group was found to be significantly lower than that of nuggets from the WGO + ALA group. Total fatty acid content too was higher in the nuggets from this group. The poly unsaturated fatty acids (PUFA) were found to be higher in the nuggets from the groups fed with a combination of natural and synthetic antioxidants. CONCLUSION: It is concluded that the combination of natural and synthetic antioxidants in the animal feed exerts a synergistic effect in enhancing the stability and quality of chicken nuggets. PMID- 28595583 TI - The association between number of doctors per bed and readmission of elderly patients with pneumonia in South Korea. AB - BACKGROUND: There is an urgent need to reduce readmission of patients with pneumonia and improve quality of care. To assess the association between hospital resources and quality of care, we examined the effect of number of doctors per bed on 30-day readmission and investigated the combined effect of number of doctors per bed and number of beds. METHODS: We used nationwide cohort sample data of health insurance claims by the National Health Insurance Service (NHIS) from 2002 to 2013. Pneumonia admissions to acute care hospitals among 7446 inpatients older than 65 were examined. We conducted a multivariate Cox proportional hazard model to analyze the association between the number of doctors per bed and 30-day readmission, as well as that of pneumonia-specific 30 day readmission with the combined effects of number of doctors per bed and number of beds. RESULTS: Overall, 1421 (19.1%) patients were readmitted within 30 days and 756 (11.2%) patients were readmitted for pneumonia within 30 days. Patients with pneumonia treated by very low or low number of doctors per bed showed higher readmission (pneumonia-specific readmission: hazard ratio [HR] = 1. 406, 95% confidence interval [CI] = 1.072-1.843 for low number of doctors per bed; all cause readmissions: HR = 1.276, 95% CI = 1.026-1.587 for very low number of doctors per bed, and HR = 1.280, 95% CI = 1.064-1.540 for low number of doctors per bed). CONCLUSIONS: This empirical study showed that patients with pneumonia cared for in hospitals with more doctors were less likely to be readmitted. Pneumonia-specific 30-day readmission was also significantly associated with the combined effect of the number of doctors and the number of hospital beds. PMID- 28595585 TI - T cells bearing anti-CD19 and/or anti-CD38 chimeric antigen receptors effectively abrogate primary double-hit lymphoma cells. AB - Patients with B cell lymphomas bearing MYC translocation combined with translocation involving other genes, such as BCL2, BCL3, or BCL6, defined as double-hit lymphoma (DHL), have a poor prognosis. Recent studies expanded the concept to include double-expressing lymphoma (DEL) that co-overexpresses MYC protein with either of those proteins. Accordingly, we defined cytogenetic DHL and DEL as primary DHL. An adoptive T cell immunotherapy with a chimeric antigen receptor (CAR) has been clinically shown to exhibit cytotoxicity in refractory neoplasias. We revealed the marked cytotoxicity of anti-CD19- and/or anti-CD38 CAR T cells against primary DHL cells from patients. CD19- and/or CD38-specific T cells were co-cultured with cytogenetic DHL (n = 3) or DEL (n = 2) cells from five patients for 3 days. We examined whether T cells retrovirally transduced with each vector showed cytotoxicity against DHL cells. Anti-CD19- and/or anti CD38-CAR T cells were co-cultured with primary DHL cells at an E:T ratio of 1:2 for 3 days. Anti-CD19- and anti-CD38-CAR T cells completely abrogated these DHL cells, respectively. Anti-CD19-CAR T cells synergistically exerted collaborative cytotoxicity against these primary DHL cells with anti-CD38-CAR T cells. Therefore, refractory DHL cells can be efficiently abrogated by the clinical use of T cells with anti-CD19- and/or anti-CD38-CAR. PMID- 28595584 TI - The impact of hyperhidrosis on patients' daily life and quality of life: a qualitative investigation. AB - BACKGROUND: An understanding of the daily life impacts of hyperhidrosis and how patients deal with them, based on qualitative research, is lacking. This study investigated the impact of hyperhidrosis on the daily life of patients using a mix of qualitative research methods. METHODS: Participants were recruited through hyperhidrosis patient support groups such as the Hyperhidrosis Support Group UK. Data were collected using focus groups, interviews and online surveys. A grounded theory approach was used in the analysis of data transcripts. Data were collected from 71 participants, out of an initial 100 individuals recruited. RESULTS: Seventeen major themes capturing the impacts of hyperhidrosis were identified; these covered all areas of life including daily life, psychological well-being, social life, professional /school life, dealing with hyperhidrosis, unmet health care needs and physical impact. CONCLUSIONS: Psychosocial impacts are central to the overall impacts of hyperhidrosis, cutting across and underlying the limitations experienced in other areas of life. PMID- 28595586 TI - Between chromatin and SNPs: genetic variability and the susceptibility to acute kidney injury. PMID- 28595587 TI - Multiple gene movements into and out of haploid sex chromosomes. AB - BACKGROUND: Long-term evolution of sex chromosomes is a dynamic process shaped by gene gain and gene loss. Sex chromosome gene traffic has been studied in XY and ZW systems but no detailed analyses have been carried out for haploid phase UV sex chromosomes. Here, we explore sex-specific sequences of seven brown algal species to understand the dynamics of the sex-determining region (SDR) gene content across 100 million years of evolution. RESULTS: A core set of sex-linked genes is conserved across all the species investigated, but we also identify modifications of both the U and the V SDRs that occurred in a lineage-specific fashion. These modifications involve gene loss, gene gain and relocation of genes from the SDR to autosomes. Evolutionary analyses suggest that the SDR genes are evolving rapidly and that this is due to relaxed purifying selection. Expression analysis indicates that genes that were acquired from the autosomes have been retained in the SDR because they confer a sex-specific role in reproduction. By examining retroposed genes in Saccharina japonica, we demonstrate that UV sex chromosomes have generated a disproportionate number of functional orphan retrogenes compared with autosomes. Movement of genes out of the UV sex chromosome could be a means to compensate for gene loss from the non-recombining region, as has been suggested for Y-derived retrogenes in XY sexual systems. CONCLUSION: This study provides the first analysis of gene traffic in a haploid UV system and identifies several features of general relevance to the evolution of sex chromosomes. PMID- 28595588 TI - Erratum to Benefit of dual-chamber pacing with Closed Loop Stimulation in tilt induced cardio-inhibitory reflex syncope (BIOSync trial): study protocol for a randomized controlled trial. PMID- 28595589 TI - A comparison of approaches for adjudicating outcomes in clinical trials. AB - BACKGROUND: Incorrect classification of outcomes in clinical trials can lead to biased estimates of treatment effect and reduced power. Ensuring appropriate adjudication methods to minimize outcome misclassification is therefore essential. While there are many reported adjudication approaches, there is little consensus over which approach is best. METHODS: Under the assumption of non differential assessment (i.e. that misclassification rates are the same in each treatment arm, as would typically be the case when outcome assessors are blinded), we use simulation and theoretical results to address four different questions about outcome adjudication: (a) How many assessors should be used? (b) When is it better to use onsite or central assessment? (c) Should central assessors adjudicate all outcomes, or only suspected events? (d) Should central assessment with multiple assessors be done independently or through group consensus? RESULTS: No one adjudication approach performs optimally in all settings. The optimal approach depends on the misclassification rates of site and central assessors, and the correlation between assessors. We found: (a) there will generally be little incremental benefit to using more than three assessors and, for outcomes with very high correlation between assessors, using one assessor is sufficient; (b) when choosing between site and central assessors, the assessor with the smallest misclassification rate should be chosen; when these rates are unknown, a combination of one site assessor and two central assessors will provide good results across a range of scenarios; (c) having central assessors adjudicate only suspected events will typically increase bias, and should be avoided, unless the threshold for sending outcomes for central assessment is extremely low; (d) central assessors can adjudicate either independently or in a group, and the preferred option should be dictated by whichever is expected to have the lowest misclassification rate. CONCLUSIONS: Outcome adjudication is of critical importance to ensure validity of trial results, although no one approach is optimal across all settings. Investigators should choose the best strategy based on the specific characteristics of their trial. Regardless of the adjudication strategy chosen, assessors should be qualified and receive appropriate training. PMID- 28595590 TI - Shortcomings in snake bite management in rural Cameroon: a case report. AB - BACKGROUND: Snake bites are an important public health problem in developing countries with most bites occurring in rural areas. Severe envenomation often occurs in children and following bites to the face. Prompt administration of potent anti-venom remains the mainstay of management. However in Cameroon, the use of anti-venoms is limited by non-availability, high cost (where available) and poor mastery of treatment guidelines. CASE PRESENTATION: We present a 10-year old muslim Cameroonian child from an enclaved rural area, brought to the hospital 12 h after a snake bite to the face, with signs of severe envenomation. Despite the suboptimal anti-venom dose administered to this patient due to a stock out of this medication, supportive therapy was beneficial in ensuring a positive outcome and satisfactory recovery. CONCLUSION: This highlights snake bites as a public health problem due to the lack of snake anti-venoms in peripheral health facilities, rendering them unable to appropriately manage these cases. National health policies should encourage constant peripheral availability of anti-venoms and the institution of an intervention package for snake bite management, comprising: treatment protocol, staff training, monitoring of compliance and community education to help reduce the mortality and morbidity from snake bites. PMID- 28595591 TI - Effect of race and ethnicity on utilization and outcomes of assisted reproductive technology in the USA. AB - BACKGROUND: The purpose of this study was to determine the utilization and live birth rates of assisted reproductive technology (ART) modalities among various racial and ethnic groups in recent years. METHODS: We reviewed ART data reported to the Society for Assisted Reproductive Technologies Clinic Outcome Reporting System (SART CORS) for autologous ART and third-party ART (3ART) cycles which involved donor oocytes, sperm, embryos and gestational carrier, performed in the U.S. between 2004 and 2013. To gauge demand by various racial/ethnic groups for ART services, we examined fertility rates and demographics of the entire U.S. birth cohort over the same time interval. RESULTS: Of 1,132,844 autologous ART cycles 335,462 resulted in a live birth (29.6%). An additional, 217,030 3ART cycles resulted in 86,063 live births (39.7%). Hispanic and Black women demonstrated high fertility and lower utilization rates of autologous ART and 3ART. Caucasian and Asian women exhibited lower fertility rates and higher autologous ART and 3ART utilization. Autologous ART resulted in higher live birth rates among Caucasian and Hispanic women and lower rates among Asian and especially Black women. 3ART improved live birth rates in all races/ethnicities, though Black women experienced lower live birth rates with most modalities. Spontaneous abortion rates were higher among Black women following autologous ART and some 3ART modalities than those among Caucasian women. CONCLUSION: Utilization of ART is inversely related to fertility rates. Autologous ART produces lower live birth rates among Asian and Black women. 3ART results in relatively low live birth rates among Black women. TRIAL REGISTRATION: SART CORS #57 , Registered 5/14/2015. PMID- 28595592 TI - Computational prediction of lncRNA-mRNA interactionsby integrating tissue specificity in human transcriptome. AB - : Long noncoding RNAs (lncRNAs) play a key role in normal tissue differentiation and cancer development through their tissue-specific expression in the human transcriptome. Recent investigations of macromolecular interactions have shown that tissue-specific lncRNAs form base-pairing interactions with various mRNAs associated with tissue-differentiation, suggesting that tissue specificity is an important factor controlling human lncRNA-mRNA interactions.Here, we report investigations of the tissue specificities of lncRNAs and mRNAs by using RNA-seq data across various human tissues as well as computational predictions of tissue specific lncRNA-mRNA interactions inferred by integrating the tissue specificity of lncRNAs and mRNAs into our comprehensive prediction of human lncRNA-RNA interactions. Our predicted lncRNA-mRNA interactions were evaluated by comparisons with experimentally validated lncRNA-mRNA interactions (between the TINCR lncRNA and mRNAs), showing the improvement of prediction accuracy over previous prediction methods that did not account for tissue specificities of lncRNAs and mRNAs. In addition, our predictions suggest that the potential functions of TINCR lncRNA not only for epidermal differentiation but also for esophageal development through lncRNA-mRNA interactions. REVIEWERS: This article was reviewed by Dr. Weixiong Zhang and Dr. Bojan Zagrovic. PMID- 28595593 TI - Specialty preferences among medical students in Botswana. AB - BACKGROUND: With the establishment of a new medical college in Botswana to train generalist-doctors and specialists, we set out to explore the career preferences of medical students, factors that influence their choices and attitude to local postgraduate training. METHODS: A descriptive cross-sectional questionnaire-based study was conducted among medical students in their third to fifth year, at the Faculty of Medicine, University of Botswana. The structured, self-administered questionnaires which were hand-delivered covered demographic characteristics of responders, career choices, preferred location of specialisation and factors that influenced the choices. RESULTS: Of the 143 medical students approached, 116 (81.0%) returned completed questionnaires. Of the responders, 102 (87.9%) intend to pursue postgraduate specialisation against 2 (1.7%) who declined; 12 (10.3%) were undecided. The four most preferred specialties which constituted 68.1% were surgery (28.4%), paediatrics (19.0%), internal medicine (12.9%), obstetrics and gynaecology (7.2%). There was male preference for surgery (p = 0.04), while women were drawn more towards paediatrics and psychiatry (p = 0.04 and p = 0.01, respectively). Personal interest and aptitude was considered the most important factor among most responders (46.2%), followed by enjoyment of the posting (19.8%). A high proportion of responders 80 (69.0%) preferred to specialise abroad for better exposure/opportunities (48.3%), while for 15.5%, their preferred courses are not currently available locally. CONCLUSION: Our findings indicated that while four major specialties are preferred, significant gender differences exist with female students leaning towards non-surgical disciplines. Students prefer specialising abroad on the pretext that foreign centres offer better training opportunities, and many specialist programmes are unavailable locally. PMID- 28595594 TI - Prevalence and risk factors for latent tuberculosis infection among healthcare workers in Nampula Central Hospital, Mozambique. AB - BACKGROUND: Healthcare workers in high tuberculosis burdened countries are occupationally exposed to the tuberculosis disease with uncomplicated and complicated tuberculosis on the increase among them. Most of them acquire Mycobacterium tuberculosis but do not progress to the active disease - latent tuberculosis infection. The objective of this study was to assess the prevalence and risk factors associated with latent tuberculosis infection among healthcare workers in Nampula Central Hospital, Mozambique. METHODS: This cross-sectional study of healthcare workers was conducted between 2014 and 2015. Participants (n = 209) were administered a questionnaire on demographics and occupational tuberculosis exposure and had a tuberculin skin test administered. Multivariate linear and logistic regression tested for associations between independent variables and dependent outcomes (tuberculin skin test induration and latent tuberculosis infection status). RESULTS: The prevalence of latent tuberculosis infection was 34.4%. Latent tuberculosis infection was highest in those working for more than eight years (39.3%), those who had no BCG vaccination (39.6%) and were immunocompromised (78.1%). Being immunocompromised was significantly associated with latent tuberculosis infection (OR 5.97 [95% CI 1.89; 18.87]). Positive but non-significant associations occurred with working in the medical domain (OR 1.02 [95% CI 0.17; 6.37]), length of employment > eight years (OR 1.97 [95% CI 0.70; 5.53]) and occupational contact with tuberculosis patients (OR 1.24 [95% CI 0.47; 3.27]). CONCLUSIONS: Personal and occupational factors were positively associated with latent tuberculosis infection among healthcare workers in Mozambique. PMID- 28595595 TI - Multiplex detection in tonsillar tissue of all known human polyomaviruses. AB - BACKGROUND: In the past few years, eleven new human viruses have joined the two previously known members JCPyV and BKPyV of the Polyomaviridae family, by virtue of molecular methods. Serology data suggest that infections with human polyomaviruses (HPyVs) occur since childhood and the viruses are widespread in the general population. However, the viral persistence sites and transmission routes are by and large unknown. Our previous studies demonstrated that the four new HPyVs - KIPyV, WUPyV, MCPyV and TSPyV - were present in the tonsils, and suggested lymphoid tissue as a persistent site of these emerging human viruses. We developed a Luminex-based multiplex assay for simultaneous detection of all 13 HPyVs known, and explored their occurrence in tonsillar tissues of children and adults mostly with tonsillitis or tonsillar hypertrophy. METHODS: We set up and validated a new Luminex-based multiplex assay by using primer pairs and probes targeting the respective HPyV viral protein 1 (VP1) genes. With this assay we tested 78 tonsillar tissues for DNAs of 13 HPyVs. RESULTS: The multiplex assay allowed for simultaneous detection of 13 HPyVs with high analytical sensitivity and specificity, with detection limits of 100-102 copies per microliter, and identified correctly all 13 target sequences with no cross reactions. HPyV DNA altogether was found in 14 (17.9%) of 78 tonsils. The most prevalent HPyVs were HPyV6 (7.7%), TSPyV (3.8%) and WUPyV (3.8%). Mixed infection of two HPyVs occurred in one sample. CONCLUSIONS: The Luminex-based HPyV multiplex assay appears highly suitable for clinical diagnostic purposes and large-scale epidemiological studies. Additional evidence was acquired that the lymphoid system plays a role in HPyV infection and persistence. Thereby, shedding from this site during reactivation might take part in transmission of the newly found HPyVs. PMID- 28595596 TI - The influence of dog ownership on objective measures of free-living physical activity and sedentary behaviour in community-dwelling older adults: a longitudinal case-controlled study. AB - BACKGROUND: There is some evidence to suggest that dog ownership may improve physical activity (PA) among older adults, but to date, studies examining this, have either depended on self-report or incomplete datasets due to the type of activity monitor used to record physical activity. Additionally, the effect of dog ownership on sedentary behaviour (SB) has not been explored. The aim of the current study was to address these issues by using activPAL monitors to evaluate the influence of dog ownership on health enhancing PA and SB in a longitudinal study of independently-mobile, community-dwelling older adults. METHODS: Study participants (43 pairs of dog owners and non-dog owners, matched on a range of demographic variables) wore an activPAL monitor continuously for three, one-week data collection periods over the course of a year. Participants also reported information about their own and their dog demographics, caring responsibilities, and completed a diary of wake times. Diary data was used to isolate waking times, and outcome measures of time spent walking, time spent walking at a moderate cadence (>100 steps/min), time spent standing, time spent sitting, number of sitting events (continuous periods of sitting), and the number of and of time spent sitting in prolonged events (>30 min). For each measure, a linear mixed effects model with dog ownership as a fixed effect, and a random effects structure of measurement point nested in participant nested in pair was used to assess the effect of dog ownership. RESULTS: Owning a dog indicated a large, potentially health improving, average effect of 22 min additional time spent walking, 95%CI (12, 34), and 2760 additional steps per day, 95%CI (1667, 3991), with this additional walking undertaken at a moderate intensity cadence. Dog owners had significantly fewer sitting events. However, there were no significant differences between the groups for either the total time spent sitting, or the number or duration of prolonged sedentary events. CONCLUSIONS: The scale of the influence of dog ownership on PA found in this study, indicates that future research regarding PA in older adults should assess and report dog ownership and/or dog walking status. PMID- 28595597 TI - Label-free quantitative proteomics of Corynebacterium pseudotuberculosis isolates reveals differences between Biovars ovis and equi strains. PMID- 28595598 TI - Isolation, biochemical and molecular identification of Nocardia species among TB suspects in northeastern, Tanzania; a forgotten or neglected threat? AB - BACKGROUND: Pulmonary nocardiosis mimic pulmonary tuberculosis in most clinical and radiological manifestations. In Tanzania, where tuberculosis is one of the major public health threat clinical impact of nocardiosis as the cause of the human disease remains unknown. The objective of the present study was to isolate and identify Nocardia isolates recovered from TB suspects in Northeastern, Tanzania by using biochemical and molecular methods. METHODS: The study involved 744 sputum samples collected from 372 TB suspects from four periphery diagnostic centers in Northeastern, Tanzania. Twenty patients were diagnosed as having presumptively Nocardia infections based on microscopic, cultural characteristics and biomerieux ID 32C Yeast Identification system and confirmed using 16S rRNA and hsp65 gene specific primers for Nocardia species and sequencing. RESULTS: Biochemically, the majority of the isolates were N. asteroides (n = 8/20, 40%), N. brasiliensis (n = 4/20, 20%), N. farcinica (n = 3/20, 15%), N. nova (n = 1/20, 5%). Other aerobic actinomycetales included Streptomyces cyanescens (n = 2/20, 10%), Streptomyces griseus, Actinomadura madurae each (n = 1/20, 5%). Results of 16S rRNA and hsp65 sequencing were concordant in 15/17 (88. 2%) isolates and discordant in 2/17 (11.8%) isolates. Majority of the isolates belonged to N. cyriacigeorgica and N. farcinica, four (23.5%) each. CONCLUSIONS: Our findings suggest that Nocardia species may be an important cause of pulmonary nocardiosis that is underdiagnosed or ignored. This underscores needs to consider pulmonary nocardiosis as a differential diagnosis when there is a failure of anti-TB therapy and as a possible cause of human infections. PMID- 28595599 TI - Designing persuasive health materials using processing fluency: a literature review. AB - BACKGROUND: Health materials to promote health behaviors should be readable and generate favorable evaluations of the message. Processing fluency (the subjective experience of ease with which people process information) has been increasingly studied over the past decade. In this review, we explore effects and instantiations of processing fluency and discuss the implications for designing effective health materials. We searched seven online databases using "processing fluency" as the key word. In addition, we gathered relevant publications using reference snowballing. We included published records that were written in English and applicable to the design of health materials. RESULTS: We found 40 articles that were appropriate for inclusion. Various instantiations of fluency have a uniform effect on human judgment: fluently processed stimuli generate positive judgments (e.g., liking, confidence). Processing fluency is used to predict the effort needed for a given task; accordingly, it has an impact on willingness to undertake the task. Physical perceptual, lexical, syntactic, phonological, retrieval, and imagery fluency were found to be particularly relevant to the design of health materials. CONCLUSIONS: Health-care professionals should consider the use of a perceptually fluent design, plain language, numeracy with an appropriate degree of precision, a limited number of key points, and concrete descriptions that make recipients imagine healthy behavior. Such fluently processed materials that are easy to read and understand have enhanced perspicuity and persuasiveness. PMID- 28595600 TI - Extremely low Plasmodium prevalence in wild plovers and coursers from Cape Verde and Madagascar. AB - BACKGROUND: Relatively little is known about the prevalence of blood parasites in shorebirds, especially those breeding in the tropics. The prevalence of blood parasites of the genera Plasmodium, Haemoproteus and Leucocytozoon was assessed in blood samples from Kentish plovers and cream-coloured coursers in Cape Verde, and samples of Kittlitz's plovers, Madagascar plovers and white-fronted plovers in Madagascar. RESULTS: Only two of these samples were positive for Plasmodium: a Kittlitz's plover was infected by a generalist lineage of Plasmodium that has already been reported in Europe and Africa, while in a white-fronted plover direct sequencing revealed a previously un-described Plasmodium lineage. CONCLUSION: Potential explanations for the low prevalence of blood parasites include the scarcity of vectors in habitats used by these bird species and their resistance to parasitic infections. PMID- 28595601 TI - Multicopy plasmid integration in Komagataella phaffii mediated by a defective auxotrophic marker. AB - BACKGROUND: A commonly used approach to improve recombinant protein production is to increase the levels of expression by providing extra-copies of a heterologous gene. In Komagataella phaffii (Pichia pastoris) this is usually accomplished by transforming cells with an expression vector carrying a drug-resistance marker following a screening for multicopy clones on plates with increasingly higher concentrations of an antibiotic. Alternatively, defective auxotrophic markers can be used for the same purpose. These markers are generally transcriptionally impaired genes lacking most of the promoter region. Among the defective markers commonly used in Saccharomyces cerevisiae is leu2-d, an allele of LEU2 which is involved in leucine metabolism. Cells transformed with this marker can recover prototrophy when they carry multiple copies of leu2-d in order to compensate the poor transcription from this defective allele. RESULTS: A K. phaffii strain auxotrophic for leucine (M12) was constructed by disrupting endogenous LEU2. The resulting strain was successfully transformed with a vector carrying leu2-d and an EGFP (enhanced green fluorescent protein) reporter gene. Vector copy numbers were determined from selected clones which grew to different colony sizes on transformation plates. A direct correlation was observed between colony size, number of integrated vectors and EGFP production. By using this approach we were able to isolate genetically stable clones bearing as many as 20 integrated copies of the vector and with no significant effects on cell growth. CONCLUSIONS: In this work we have successfully developed a genetic system based on a defective auxotrophic which can be applied to improve heterologous protein production in K. phaffii. The system comprises a K. phaffii leu2 strain and an expression vector carrying the defective leu2-d marker which allowed the isolation of multicopy clones after a single transformation step. Because a linear correlation was observed between copy number and heterologous protein production, this system may provide a simple approach to improve recombinant protein productivity in K. phaffii. PMID- 28595602 TI - Assembly and use of high-density recombinant peptide chips for large-scale ligand screening is a practical alternative to synthetic peptide libraries. AB - BACKGROUND: Recombinant peptide chips could constitute a versatile complementation to state-of-the-art in situ (chemical on-chip) synthesis, particle-based printing, or pre-manufactured peptide spotting. Bottlenecks still impeding a routine implementation - from restricted peptide lengths, low diversity and low array densities to high costs - could so be overcome. METHODS: To assess overall performance, we assembled recombinant chips composed of 38,400 individual peptide spots on the area of a standard 96-well microtiter plate from comprehensive, highly diverse (>107 single clones) short random peptide libraries. RESULTS: Screening of altogether 476,160 clones against Streptavidin uncovered 2 discrete new binders: a characteristic HPQ-motif containing VSHPQAPF and a cyclic CSGSYGSC peptide. Interactions were technically confirmed by fluorescence polarization as well as biolayer-interferometry, and their potential suitability as novel detection tags evaluated by detection of a peptide-fused exemplary test protein. CONCLUSION: From our data we conclude that the presented technical pipeline can reliably identify novel hits, useful as first-generation binders or templates for subsequent ligand design plus engineering. PMID- 28595603 TI - Current and cumulative malaria infections in a setting embarking on elimination: Amhara, Ethiopia. AB - BACKGROUND: Since 2005, Ethiopia has aggressively scaled up malaria prevention and case management. As a result, the number of malaria cases and deaths has significantly declined. In order to track progress towards the elimination of malaria in Amhara Region, coverage of malaria control tools and current malaria transmission need to be documented. METHODS: A cross-sectional household survey oversampling children under 5 years of age was conducted during the dry season in 2013. A bivalent rapid diagnostic test (RDT) detecting both Plasmodium falciparum and Plasmodium vivax and serology assays using merozoite antigens from both these species were used to assess the prevalence of malaria infections and exposure to malaria parasites in 16 woredas (districts) in Amhara Region. RESULTS: 7878 participants were included, with a mean age of 16.8 years (range 0.5-102.8 years) and 42.0% being children under 5 years of age. The age-adjusted RDT-positivity for P. falciparum and P. vivax infection was 1.5 and 0.4%, respectively, of which 0.05% presented as co-infections. Overall age-adjusted seroprevalence was 30.0% for P. falciparum, 21.8% for P. vivax, and seroprevalence for any malaria species was 39.4%. The prevalence of RDT-positive infections varied by woreda, ranging from 0.0 to 8.3% and by altitude with rates of 3.2, 0.7, and 0.4% at under 2000, 2000-2500, and >2500 m, respectively. Serological analysis showed heterogeneity in transmission intensity by area and altitude and evidence for a change in the force of infection in the mid-2000s. CONCLUSIONS: Current and historic malaria transmission across Amhara Region show substantial variation by age and altitude with some settings showing very low or near-zero transmission. Plasmodium vivax infections appear to be lower but relatively more stable across geography and altitude, while P. falciparum is the dominant infection in the higher transmission, low-altitude areas. Age-dependent seroprevalence analyses indicates a drop in transmission occurred in the mid-2000s, coinciding with malaria control scale-up efforts. As malaria parasitaemia rates get very low with elimination efforts, serological evaluation may help track progress to elimination. PMID- 28595604 TI - Functionality and acceptability of a wireless fetal heart rate monitoring device in term pregnant women in rural Southwestern Uganda. AB - BACKGROUND: Over 3 million stillbirths occur annually in sub Saharan Africa; most occur intrapartum and are largely preventable. The standard of care for fetal heart rate (FHR) assessment in most sub-Saharan African settings is a Pinard Stethoscope, limiting observation to one person, at one point in time. We aimed to test the functionality and acceptability of a wireless FHR monitor that could allow for expanded monitoring capacity in rural Southwestern Uganda. METHODS: In a mixed method prospective study, we enrolled 1) non-laboring healthy term pregnant women to wear the device for 30 min and 2) non-study clinicians to observe its use. The battery-powered prototype uses Doppler technology to measure fetal cardiotocographs (CTG), which are displayed via an android device and wirelessly transmit to cloud storage where they are accessible via a password protected website. Prototype functionality was assessed by the ability to obtain and transmit a 30-min CTG. Three obstetricians independently rated CTGs for readability and agreement between raters was calculated. All participants completed interviews on acceptability. RESULTS: Fifty pregnant women and 7 clinicians were enrolled. 46 (92.0%) CTGs were successfully recorded and stored. Mean scores for readability were 4.71, 4.71 and 4.83 (out of 5) with high agreement (intra class correlation 0.84; 95% CI 0.74 to 0.91). All pregnant women reported liking or really liking the device, as well as high levels of comfort, flexibility and usefulness of the prototype; all would recommend it to others. Clinicians described the prototype as portable, flexible, easy-to-use and a time saver. Adequate education for clinicians and women also seemed to improve correct usage and minimise concerns on safety of the device. CONCLUSIONS: This prototype wireless FHR monitor functioned well in a low-resource setting and was found to be acceptable and useful to both pregnant women and clinicians. The device also seemed to have potential to improve the experience of the users compared with standard of care and expand monitoring capacity in settings where bulky, wired or traditional equipment are unreliable. Further research needs to investigate the potential impact and cost of such innovations to improve perinatal outcomes. PMID- 28595605 TI - Integrating transcriptomics and metabolomics for the analysis of the aroma profiles of Saccharomyces cerevisiae strains from diverse origins. AB - BACKGROUND: During must fermentation thousands of volatile aroma compounds are formed, with higher alcohols, acetate esters and ethyl esters being the main aromatic compounds contributing to floral and fruity aromas. The action of yeast, in particular Saccharomyces cerevisiae, on the must components will build the architecture of the wine flavour and its fermentation bouquet. The objective of the present work was to better understand the molecular and metabolic bases of aroma production during a fermentation process. For such, comparative transcriptomic and metabolic analysis was performed at two time points (5 and 50 g/L of CO2 released) in fermentations conducted by four yeast strains from different origins and/or technological applications (cachaca, sake, wine, and laboratory), and multivariate factorial analyses were used to rationally identify new targets for improving aroma production. RESULTS: Results showed that strains from cachaca, sake and wine produced higher amounts of acetate esters, ethyl esters, acids and higher alcohols, in comparison with the laboratory strain. At fermentation time T1 (5 g/L CO2 released), comparative transcriptomics of the three S. cerevisiae strains from different fermentative environments in comparison with the laboratory yeast S288c, showed an increased expression of genes related with tetracyclic and pentacyclic triterpenes metabolism, involved in sterol synthesis. Sake strain also showed upregulation of genes ADH7 and AAD6, involved in the formation of higher alcohols in the Ehrlich pathway. For fermentation time point T2 (50 g/L CO2 released), again sake strain, but also VL1 strain, showed an increased expression of genes involved in formation of higher alcohols in the Ehrlich pathway, namely ADH7, ADH6 and AAD6, which is in accordance with the higher levels of methionol, isobutanol, isoamyl alcohol and phenylethanol observed. CONCLUSIONS: Our approach revealed successful to integrate data from several technologies (HPLC, GC-MS, microarrays) and using different data analysis methods (PCA, MFA). The results obtained increased our knowledge on the production of wine aroma and flavour, identifying new gene in association to the formation of flavour active compounds, mainly in the production of fatty acids, and ethyl and acetate esters. PMID- 28595607 TI - A composite visualization method for electrophysiology-morphous merging of human heart. AB - BACKGROUND: Electrophysiological behavior is of great importance for analyzing the cardiac functional mechanism under cardiac physiological and pathological condition. Due to the complexity of cardiac structure and biophysiological function, visualization of a cardiac electrophysiological model compositively is still a challenge. The lack of either modality of the whole organ structure or cardiac electrophysiological behaviors makes analysis of the intricate mechanisms of cardiac dynamic function a difficult task. This study aims at exploring 3D conduction of stimulus and electrical excitation reactivity on the level of organ with the authentic fine cardiac anatomy structure. METHODS: In this paper, a cardiac electrical excitation propagation model is established based on the human cardiac cross-sectional data to explore detailed cardiac electrical activities. A novel biophysical merging visualization method is then presented for biophysical integration of cardiac anatomy and electrophysiological properties in the form of the merging optical model, which provides the corresponding position, spatial relationship and the whole process in 3D space with the context of anatomical structure for representing the biophysical detailed electrophysiological activity. RESULTS: The visualization result present the action potential propagation of the left ventricle within the excitation cycle with the authentic fine cardiac organ anatomy. In the visualized images, all vital organs are identified and distinguished without ambiguity. The three dimensional spatial position, relation and the process of cardiac excitation conduction and re-entry propagation in the anatomical structure during the phase of depolarization and repolarization is also shown in the result images, which exhibits the performance of a more detailed biophysical understanding of the electrophysiological kinetics of human heart in vivo. CONCLUSIONS: Results suggest that the proposed merging optical model can merge cardiac electrophysiological activity with the anatomy structure. By specifying the respective opacity for the cardiac anatomy structure and the electrophysiological model in the merging attenuation function, the visualized images can provide an in-depth insight into the biophysical detailed cardiac functioning phenomena and the corresponding electrophysiological behavior mechanism, which is helpful for further speculating cardiac physiological and pathological responses and is fundamental to the cardiac research and clinical diagnoses. PMID- 28595606 TI - Detection of a genetic footprint of the sofosbuvir resistance-associated substitution S282T after HCV treatment failure. AB - BACKGROUND: The major resistance-associated substitution for sofosbuvir (S282T) in HCV NS5B causes severe viral fitness costs and rapidly reverts back to prototype in the absence of selection pressure. Accordingly, resistance against sofosbuvir is rarely detected even in patients after treatment failure. CASE PRESENTATION: We report a case of a GT3a infected patient with viral breakthrough under SOF/DCV therapy. At the time of breakthrough the RAS S282T was predominant in NS5B and then rapidly disappeared during follow-up by week 12 after treatment. Interestingly, despite only serine was encoded in position 282 during follow-up, two distinct genetic pathways for reversion were detectable. In 31% of the quasispecies the original codon for serine was present whereas in the majority of the quasispecies an alternative codon was selected. This alternative codon usage was unique for all GT3a isolates from the HCV database and remained detectable as a genetic footprint for prior resistance selection at the RNA level for at least 6 months. CONCLUSIONS: Comparative analyses of viral sequences at the codon level before and after DAA treatment may help to elucidate the patient's history of resistance selection, which is particularly valuable for highly unfit substitutions that are detectable only for a short period of time. If such codon changes increase the risk of re-selection of resistance upon a second exposure to SOF remains to be addressed. PMID- 28595609 TI - Erratum to: High incidence of periprosthetic joint infection with propionibacterium acnes after the use of a stemless shoulder prosthesis with metaphyseal screw fixation - a retrospective cohort study of 241 patients propionibacter infections after eclipse TSA. PMID- 28595608 TI - Antimicrobial activity, toxicity and anti-inflammatory potential of methanolic extracts of four ethnomedicinal plant species from Punjab, Pakistan. AB - BACKGROUND: The plant species Aristolochia indica (AI), Melilotus indicus (MI), Tribulus terrestris (TT) and Cuscuta pedicellata (CP) are widely used in folk medicine in the villages around Chowk Azam, South Punjab, Pakistan. The aim of this study was to evaluate the antioxidant activity, phytochemical composition, and the antibacterial, antifungal, cytotoxic and anti-inflammatory potential of the four medicinal plants listed above. For CP stem, this study represents (to the best of our knowledge) the first time phytochemicals have been identified and the antioxidant and anti-inflammatory potential determined. METHODS: Phytochemicals were analyzed through chemical tests, thin layer chromatography (TLC) and spectrophotometric methods. Antioxidant activities (DPPH and H2O2) were also determined through spectrophotometric methods. Extracts were evaluated for antibacterial potential via the agar well diffusion method against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia and Acinetobacter baumannii. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by the microdilution method. Antifungal activities were tested using the agar tube dilution method against three species: Aspergillus fumigatus, Aspergillus flavus and Rhizopus oryzae. The cytotoxic potential of the plant extracts was checked using the brine shrimp assay. In vitro anti inflammatory activity of the selected plant extracts was evaluated using albumin denaturation, membrane stabilization and proteinase inhibitory assays. RESULTS: Of all the methanolic extracts tested, those from CP (stem) and TTF (T. terrestris fruit) had the highest phenolic, flavonoid and flavonol contents (497+/-4 mg GAE/g, 385+/-8 mg QE/g and 139+/-4 mg QE/g; 426+/-5 mg GAE/g, 371+/-8 mg QE/g and 138+/-6 mg QE/g, respectively) and also exhibited strong antioxidant potential in scavenging DPPH and hydrogen peroxide (IC50 values; 20+/-1 and 18+/ 0.7 MUg/mL; 92+/-2 and 26+/-2 MUg/mL, respectively). CP, TTF and TTL (T. terrestris leaf) extracts substantially inhibited the growth of the bacteria A. baumannii, S. aureus, and K. pneumonia and also exhibited the highest antifungal potential. The ranking of the plant extracts for cytotoxicity was TTF > TTL > AI > CP > MI, while the ranking for in vitro anti-inflammatory potential at a concentration of 200 MUg/mL of the selected plant extracts was CP > TTL, TTF > AI > MI. The lowest IC50 (28 MUg/mL) observed in the albumin denaturation assay was for CP. Positive correlations were observed between total phenolics, antioxidants, antibacterial, antifungal and anti-inflammatory potential of the selected plant extracts, indicating a significant contribution of phenolic compounds in the plant extracts to these activities. CONCLUSIONS: This study revealed the strong antimicrobial, antioxidant, cytotoxic and anti-inflammatory potential of the plant species CP and TT used in folk medicine. PMID- 28595610 TI - The efficacy and safety of Danggui-Sayuk-Ga-Osuyu-Saenggang-tang on Korean patients with cold hypersensitivity in the hands: study protocol for a pilot, double-blind, randomized, placebo-controlled, parallel-group clinical trial. AB - BACKGROUND: In recent years, cold hypersensitivity in the hands (CHH) has become a common ailment of women in Korea. It can lead to gynecological problems such as irregular menstruation, miscarriage, and infertility. Traditionally, Korean herbal medicine has been the primary treatment method used to balance thermoregulation in the human body; however, its effectiveness has not been confirmed through systematic study. Thus, in this trial, we will investigate the feasibility of a full randomized clinical trial, Danggui-Sayuk-Ga-Osuyu-Saenggang tang (DSGOST) in Korean women with CHH. METHODS: This study will be a pilot, multicenter, double-blind, randomized, parallel-group, two-arm, placebo controlled clinical trial. A total of 66 participants will be randomly divided into two groups, a DSGOST treatment group and a placebo control group, in a 1:1 ratio using a web-based randomization system. Each group will take DSGOST or placebo three times daily for 6 weeks. The primary outcome will be measured using Visual Analogue Scale (VAS) scores of CHH. Secondary outcomes will include changes in skin temperature of the hands, Clinical Global Impressions (CGI) scale scores, recovery rate of skin temperature of the hands after the cold stress test, and the Korean version of the WHO Quality of Life Scale, abbreviated version (WHOQOL-BREF). DISCUSSION: This trial will be the first trial to reflect the newly defined disease range of CHH which was compiled by Korean medicine expert consensus. This study will provide considerable evidence for further large scale trials and general clinical guidelines for CHH in the Korean medical field. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov, ID: NCT02645916 . Registered on 30 December 2015. PMID- 28595612 TI - Responsiveness and minimal important change of the Norwegian version of the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) in patients with subacromial pain syndrome. AB - BACKGROUND: The Disabilities of the Arm, Shoulder, and Hand questionnaire (DASH) is a valid and reliable patient-reported outcome measure (PROM). It was designed to measure physical disability and symptoms in patients with musculoskeletal disorders of the upper extremity, and is one of the most commonly used PROMs for patients with shoulder pain. The aim of this study was to examine responsiveness, the smallest detectable change (SDC) and the minimal important change (MIC) of the DASH, in line with international (COSMIN) recommendations. METHODS: The study sample consisted of 50 patients with subacromial pain syndrome, undergoing physical therapy for 3-4 months. Responsiveness to change was examined by calculating area under the receiver operating characteristic curves (AUC) and testing a priori-formulated hypothesis regarding correlations with changes in other instruments that measuring the same construct. The SDC was calculated using a test re-test protocol, and the MIC was calculated by the anchor-based MIC distribution. MIC values for patients with low and high baseline scores were also calculated. RESULTS: DASH appeared to be responsive, as it was able to distinguish patients who reported to be improved from those unchanged (AUC 0.77). All of the hypotheses were accepted. The SDC was 11.8, and the MIC was 4.4. CONCLUSION: This study shows that the Norwegian version of the DASH has good responsiveness to change and may thus be recommended to measure outcome in patients with shoulder pain in Norway. PMID- 28595611 TI - Video Game Rehabilitation for Outpatient Stroke (VIGoROUS): protocol for a multi center comparative effectiveness trial of in-home gamified constraint-induced movement therapy for rehabilitation of chronic upper extremity hemiparesis. AB - BACKGROUND: Constraint-Induced Movement therapy (CI therapy) is shown to reduce disability, increase use of the more affected arm/hand, and promote brain plasticity for individuals with upper extremity hemiparesis post-stroke. Randomized controlled trials consistently demonstrate that CI therapy is superior to other rehabilitation paradigms, yet it is available to only a small minority of the estimated 1.2 million chronic stroke survivors with upper extremity disability. The current study aims to establish the comparative effectiveness of a novel, patient-centered approach to rehabilitation utilizing newly developed, inexpensive, and commercially available gaming technology to disseminate CI therapy to underserved individuals. Video game delivery of CI therapy will be compared against traditional clinic-based CI therapy and standard upper extremity rehabilitation. Additionally, individual factors that differentially influence response to one treatment versus another will be examined. METHODS: This protocol outlines a multi-site, randomized controlled trial with parallel group design. Two hundred twenty four adults with chronic hemiparesis post-stroke will be recruited at four sites. Participants are randomized to one of four study groups: (1) traditional clinic-based CI therapy, (2) therapist-as-consultant video game CI therapy, (3) therapist-as-consultant video game CI therapy with additional therapist contact via telerehabilitation/video consultation, and (4) standard upper extremity rehabilitation. After 6-month follow-up, individuals assigned to the standard upper extremity rehabilitation condition crossover to stand-alone video game CI therapy preceded by a therapist consultation. All interventions are delivered over a period of three weeks. Primary outcome measures include motor improvement as measured by the Wolf Motor Function Test (WMFT), quality of arm use for daily activities as measured by Motor Activity Log (MAL), and quality of life as measured by the Quality of Life in Neurological Disorders (NeuroQOL). DISCUSSION: This multi-site RCT is designed to determine comparative effectiveness of in-home technology-based delivery of CI therapy versus standard upper extremity rehabilitation and in-clinic CI therapy. The study design also enables evaluation of the effect of therapist contact time on treatment outcomes within a therapist-as-consultant model of gaming and technology-based rehabilitation. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02631850 . PMID- 28595614 TI - A multicentre, randomised intervention study of the Paediatric Early Warning Score: study protocol for a randomised controlled trial. AB - BACKGROUND: Patients' evolving critical illness can be predicted and prevented. However, failure to identify the signs of critical illness and subsequent lack of appropriate action for patients developing acute and critical illness remain a problem. Challenges in assessing whether a child is critically ill may be due to children's often uncharacteristic symptoms of serious illness. Children may seem relatively unaffected until shortly before circulatory and respiratory failure and cardiac arrest. The Bedside Paediatric Early Warning Score has been validated in a large multinational study and is used in two regions in Denmark. However, healthcare professionals experience difficulties in relation to measuring blood pressure and to the lack of assessment of children's level of consciousness. In addition, is it noteworthy that in 23,288-hour studies, all seven items of the Bedside Paediatric Early Warning Score were recorded in only 5.1% of patients. This trial aims to compare two Paediatric Early Warning Score (PEWS) models to identify the better model for identifying acutely and critically ill children. The hypothesis is that the Central Denmark Region PEWS model is superior to the Bedside PEWS in terms of reducing unplanned transfers to intensive care or transfers from regional hospitals to the university hospital among already hospitalised children. METHODS/DESIGN: This is a multicentre, randomised, controlled clinical trial where children are allocated to one of two different PEWS models. The study involves all paediatric departments and one emergency department in the Central Denmark Region. The primary outcome is unplanned transfer to the paediatric intensive care unit or transfer from regional hospitals to the university hospital. Based on preliminary data, 14,000 children should be included to gain a power of 80% (with a 5% significance level) and to detect a clinically significant difference of 30% of unplanned transfers to intensive care or from regional hospitals to the paediatric department at the university department. A safety interim analysis will be performed after inclusion of 7000 patients. DISCUSSION: This is the first randomised trial to investigate two different PEWS models. This study demonstrates the safety and effectiveness of a new PEWS model and contributes to knowledge of hospitalised children's clinical deterioration. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02433327 . Registered on 27 April 2015. PMID- 28595613 TI - Developing and evaluating multimedia information resources to improve engagement of children, adolescents, and their parents with trials (TRECA study): Study protocol for a series of linked randomised controlled trials. AB - BACKGROUND: Randomised controlled trials are widely established as the best method for testing health interventions whilst minimising bias. However, recruitment and subsequent retention of children and adolescents in healthcare trials is challenging. Participant information sheets are often lengthy and difficult to read and understand. Presenting key information using multimedia may help to overcome these limitations and better support young people and their parents in deciding whether to participate in a clinical trial. METHODS: The TRECA (TRials Engagement in Children and Adolescents) study has two phases. The first phase involves a qualitative study with children and adolescents and their parents to inform the development of multimedia information resources and iterative user testing to refine the resources. The second phase will embed the use of the multimedia information resources into six host trials in the United Kingdom. Patients and parents approached to participate in the host trials will be randomly allocated to either use the multimedia information resource in conjunction with standard participant information sheets, the multimedia information resource alone, or the standard participant information sheets alone. The primary outcome will be the effect of the multimedia information resources on recruitment into trials. Other outcomes measured include the effect of multimedia information resources on retention of participants into the host trials and the impact on family members' decision-making processes, when compared to standard participant information sheets alone. DISCUSSION: This study will inform whether multimedia information resources, when developed using participatory design principles, are able to increase recruitment and retention of children and adolescents into trials. There is also the potential for patients to make better informed decisions through the use of multimedia information resources. The multimedia information resources also have the potential to assist with providing information on other healthcare decisions outside of clinical trials. TRIAL REGISTRATION: ISRCTN registry: ISRCTN73136092 (doi: 10.1186/ISRCTN73136092 ). Registered on 24 August 2016. PMID- 28595615 TI - Eph/Ephrin Signaling Controls Progenitor Identities In The Ventral Spinal Cord. AB - BACKGROUND: In the vertebrate spinal cord, motor neurons (MN) are generated in stereotypical numbers from a pool of dedicated progenitors (pMN) whose number depends on signals that control their specification but also their proliferation and differentiation rates. Although the initial steps of pMN specification have been extensively studied, how pMN numbers are regulated over time is less well characterized. RESULTS: Here, we show that ephrinB2 and ephrinB3 are differentially expressed in progenitor domains in the ventral spinal cord with several Eph receptors more broadly expressed. Genetic loss-of-function analyses show that ephrinB2 and ephrinB3 inversely control pMN numbers and that these changes in progenitor numbers correlate with changes in motor neuron numbers. Detailed phenotypic analyses by immunostaining and genetic interaction studies between ephrinB2 and Shh indicate that changes in pMN numbers in ephrin mutants are due to alteration in progenitor identity at late stages of development. CONCLUSIONS: Altogether our data reveal that Eph:ephrin signaling is required to control progenitor identities in the ventral spinal cord. PMID- 28595616 TI - Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers. AB - BACKGROUND: Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined with paclitaxel and carboplatin in patients with solid tumor cancers. METHODS: Eligible patients with advanced solid tumor cancers received oral 10 to 30 mg ridaforolimus daily for 5 consecutive days per week combined with intravenous paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] 5-6 mg/mL/min) in 3-week cycles. A standard 3 + 3 design was used to escalate doses, with predefined changes to an alternate dosing schedule and/or changes in carboplatin AUC doses based on dose-limiting toxicity (DLT). Secondary information was collected regarding response and time to progression. Patients were continued on treatment if therapy was tolerated and if stable disease or better was demonstrated. RESULTS: Thirty-one patients were consented, 28 patients were screened, and 24 patients met eligibility requirements and received treatment. Two patients were replaced for events unrelated to drug-related toxicity, resulting in 22 DLT-evaluable patients. Two grade 4 DLTs due to neutropenia were observed at dose level 1. The next cohort was changed to a predefined alternate dosing schedule (days 1-5 and 8-12). DLTs were neutropenia, sepsis, mucositis, and thrombocytopenia. The most common adverse events were neutropenia, anemia, thrombocytopenia, fatigue, alopecia, nausea, pain, and leukopenia. Twenty-four patients received a median of 4 cycles (range, 1-12). Evaluable patients for response (n = 18) demonstrated a median tumor measurement decrease of 25%. The best response in these 18 patients included 9 patients with partial response (50%), 6 with stable disease (33%), and 3 with progressive disease (17%). Thirteen of these patients received treatment for 4 or more cycles. CONCLUSIONS: Treatment with ridaforolimus combined with paclitaxel and carboplatin had no unanticipated toxicities and showed antineoplastic activity. The recommended phase II dose and schedule is ridaforolimus 30 mg (days 1-5 and 8-12) plus day 1 paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg/mL/min) on a 21-day cycle. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01256268 (trial registration date: December 1, 2010). PMID- 28595618 TI - The prevalence of the metabolic syndrome in Portugal: the PORMETS study. AB - BACKGROUND: The PORMETS study was designed to estimate the prevalence of metabolic syndrome and its determinants in the overall and administrative regions of the Portuguese mainland. METHODS: A cross-sectional study of a representative sample of non-institutionalized Portuguese adults selected from primary health care centres lists including 1695 men and 2309 women was conducted from February 2007 to July 2009. A structured questionnaire was administered, collecting information on personal medical history and socio-demographic and behavioural characteristics. Anthropometrics, blood pressure, and venous blood samples were obtained. Metabolic syndrome was defined according to three operational definitions. The prevalence ratios and their respective 95% confidence intervals were calculated using binomial generalized linear regression, with the log link function. RESULTS: The prevalence rates of metabolic syndrome in this sample of Portuguese adults were 36.5%, 49.6%, and 43.1%, using the Adult Treatment Panel III, International Diabetes Federation and Joint Interim Statement definitions, respectively. The most prevalent feature of metabolic syndrome in this sample was high blood pressure (64.3%) and the lowest was high fasting glucose (24.9%). After adjustment for age and gender, significant differences were observed for the 18 districts of the Portugal mainland. Additionally, metabolic syndrome was significantly more frequent in non-urban areas than in urban ones (p = 0.001). The prevalence of metabolic syndrome was significantly higher in women (p?0.001) and older participants (p?0.001), as well as in those who reported being housewives (p = 0.010), retired (p = 0.046) or unemployed (p = 0.024). CONCLUSIONS: This study showed that metabolic syndrome is highly prevalent in the Portuguese adult population. Regional differences in the prevalence of this syndrome were observed, and this condition was more common in non-urban areas and less favoured socio-economic categories. PMID- 28595617 TI - Quality measure and weight loss assessment in patients with type 2 diabetes mellitus treated with canagliflozin or dipeptidyl peptidase-4 inhibitors. AB - BACKGROUND: Achieving control of glycated hemoglobin (HbA1c), blood pressure (BP), and body weight (BW) remains a challenge for most patients with type 2 diabetes mellitus (T2DM). In clinical trials, canagliflozin (CANA), an inhibitor of sodium-glucose co-transporter 2, has shown significant improvement compared to some dipeptidyl peptidase-4 (DPP-4) inhibitors in the achievement of such quality measures. This study used recent electronic medical records (EMR) data to assess quality measure achievement of HbA1C, BP, and BW loss in patients treated with CANA versus DPP-4 inhibitors. METHODS: Adult patients with >=1 T2DM diagnosis and >=12 months of clinical activity (baseline) before first CANA or DPP-4 prescription (index) were identified in the QuintilesIMS Health Real-World Data EMRs-US database (03/29/2012-10/30/2015). Patients were observed from the index to last encounter. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare achievement of HbA1c < 7% (among patients <65 years old), HbA1c < 8%, systolic BP < 140 mmHg, diastolic BP < 90 mmHg, and BW loss >= 5% among patients not meeting these respective targets at baseline. RESULTS: A total of 10,702 CANA and 17,679 DPP-4 patients were selected. IPTW resulted in balanced baseline demographic, comorbidity, and disease characteristics (CANA: N = 13,793, mean age: 59.0 years; DPP-4: N = 14,588, mean age: 58.9 years). Up until 24 months post-index, CANA patients were more likely to reach an HbA1c < 7% (hazard ratio [HR] = 1.10, P = 0.007, KM rates: 42.8% vs. 40.3%), an HbA1c < 8% (HR = 1.16, P < 0.001, KM rates: 63.7% vs. 60.0%), and a BW loss >= 5% (HR = 1.46, P < 0.001, KM rates: 55.2% vs. 46.2%), compared to DPP-4 patients. Up until 12 months post-index, CANA patients were more likely to reach a systolic BP < 140 mmHg (HR = 1.07, P = 0.04, KM rates: 87.8% vs. 83.9%). but not a diastolic BP < 90 mmHg (HR = 0.95, P = 0.361), compared to DPP-4 patients. CONCLUSIONS: This retrospective study of EMR data covering up to 30 months after CANA approval (March 2013) suggests that patients initiated on CANA were more likely to reach HbA1c, systolic BP, and weight loss objectives specified by general diabetes care guidelines than patients initiated on DPP-4 inhibitors. PMID- 28595619 TI - Cytokine treatment optimises the immunotherapeutic effects of umbilical cord derived MSC for treatment of inflammatory liver disease. AB - BACKGROUND: Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC. METHODS: MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene expression analysis, surface-marker expressions, IDO activity, PGE2 secretion and inhibition of T cell proliferation and IFNgamma production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl4-induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model. RESULTS: IFN-gamma and a multiple cytokine cocktail (MC) consisting of IFN-gamma, TGFbeta and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-gamma production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-beta, TGFbeta and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl4-induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB6), ucMSC(Starv + VitB6) and ucMSC(MC) and altered bio-distribution of ucMSC(TGFbeta) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC. CONCLUSIONS: The present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation. PMID- 28595620 TI - Transcranial pulsed ultrasound facilitates brain uptake of laronidase in enzyme replacement therapy for Mucopolysaccharidosis type I disease. AB - BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a debilitating hereditary disease characterized by alpha-L-iduronidase (IDUA) deficiency and consequent inability to degrade glycosaminoglycans. The pathological accumulation of glycosaminoglycans systemically results in severe mental retardation and multiple organ dysfunction. Enzyme replacement therapy with recombinant human alpha-L iduronidase (rhIDU) improves the function of some organs but not neurological deficits owing to its exclusion from the brain by the blood-brain barrier (BBB). METHODS: We divided MPS I mice into control group, enzyme replacement group with rhIDU 2.9 mg/kg injection, enzyme replacement with one-spot ultrasound treatment group, and enzyme replacement with two-spot ultrasound treatment group, and compare treatment effectiveness between groups. All ultrasound treatments were applied on left side brain. Evans blue was used to simulate the distribution of rhIDU in the brain. RESULTS: Transcranial pulsed weakly focused ultrasound combined with microbubbles facilitates brain rhIDU delivery in MPS I mice receiving systemic enzyme replacement therapy. With intravenously injected rhIDU 2.9 mg/kg, the IDUA enzyme activity on the ultrasound treated side of the cerebral hemisphere raised to 7.81-fold that on the untreated side and to 75.84% of its normal value. Evans blue simulation showed the distribution of the delivered drug was extensive, involving a large volume of the treated cerebral hemisphere. Two-spot ultrasound treatment scheme is more efficient for brain rhIDU delivery than one-spot ultrasound treatment scheme. CONCLUSIONS: Transcranial pulsed weakly focused ultrasound can open BBB extensively and facilitates brain rhIDU delivery. This novel technology may provide a new MPS I treatment strategy. PMID- 28595621 TI - Transthoracic echocardiography: an accurate and precise method for estimating cardiac output in the critically ill patient. AB - BACKGROUND: Cardiac output (CO) monitoring is a valuable tool for the diagnosis and management of critically ill patients. In the critical care setting, few studies have evaluated the level of agreement between CO estimated by transthoracic echocardiography (CO-TTE) and that measured by the reference method, pulmonary artery catheter (CO-PAC). The objective of the present study was to evaluate the precision and accuracy of CO-TTE relative to CO-PAC and the ability of transthoracic echocardiography to track variations in CO, in critically ill mechanically ventilated patients. METHODS: Thirty-eight mechanically ventilated patients fitted with a PAC were included in a prospective observational study performed in a 16-bed university hospital ICU. CO-PAC was measured via intermittent thermodilution. Simultaneously, a second investigator used standard-view TTE to estimate CO-TTE as the product of stroke volume and the heart rate obtained during the measurement of the subaortic velocity time integral. RESULTS: Sixty-four pairs of CO-PAC and CO-TTE measurements were compared. The two measurements were significantly correlated (r = 0.95; p < 0.0001). The median bias was 0.2 L/min, the limits of agreement (LOAs) were -1.3 and 1.8 L/min, and the percentage error was 25%. The precision was 8% for CO-PAC and 9% for CO-TTE. Twenty-six pairs of DeltaCO measurements were compared. There was a significant correlation between DeltaCO-PAC and DeltaCO-TTE (r = 0.92; p < 0.0001). The median bias was -0.1 L/min and the LOAs were -1.3 and +1.2 L/min. With a 15% exclusion zone, the four-quadrant plot had a concordance rate of 94%. With a 0.5 L/min exclusion zone, the polar plot had a mean polar angle of 1.0 degrees and a percentage error LOAs of -26.8 to 28.8 degrees . The concordance rate was 100% between 30 and -30 degrees . When using CO-TTE to detect an increase in DeltaCO-PAC of more than 10%, the area under the receiving operating characteristic curve (95% CI) was 0.82 (0.62-0.94) (p < 0.001). A DeltaCO-TTE of more than 8% yielded a sensitivity of 88% and specificity of 66% for detecting a DeltaCO-PAC of more than 10%. CONCLUSION: In critically ill mechanically ventilated patients, CO-TTE is an accurate and precise method for estimating CO. Furthermore, CO-TTE can accurately track variations in CO. PMID- 28595623 TI - Effects of 1,25-dihydroxyvitamin D3 on pathological changes in rats with diabetic cardiomyopathy. AB - BACKGROUND: The role of 1,25-dihydroxyvitamin D3 (vitamin D) in the apoptosis of diabetic cardiomyopathy (DCM) is unclear. This study is to investigate the effects of vitamin D on the pathological changes in rats with DCM. METHODS: Rats were randomly divided into the control, model, and treatment groups. DCM model was established by the high-fat and -sugar diet. Plasma glucose, body weight, heart weight, heart weight index, and serum levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were determined. Heart tissue morphology was detected with histochemical staining. Expression levels of Fas and FasL were detected with RT-PCR and immunohistochemistry. RESULTS: Compared with the control group, the body weights and heart weights were significantly declined, while the plasma glucose levels and heart weight indexes were significantly elevated, in the model group (P < 0.05). However, vitamin D significantly reversed the pathological changes in DCM rats (P < 0.05). Moreover, the serum levels of LDH and CK were significantly increased in the models, which were significantly decreased by vitamin D (P < 0.05). HE staining showed that, vitamin D significantly alleviated the histological changes of myocardial cells in DCM rats. In addition, the mRNA and protein expression levels of Fas and FasL were significantly elevated in the models (P < 0.05), which were significantly declined by vitamin D (P < 0.05). CONCLUSION: Vitamin D could alleviate pathological changes, reduce Fas/FasL expression, and attenuate myocardial cell apoptosis in DCM rats, which might be used as a potential effective therapy for the disease. PMID- 28595622 TI - The evolution of trypanosomatid taxonomy. AB - Trypanosomatids are protozoan parasites of the class Kinetoplastida predominately restricted to invertebrate hosts (i.e. possess a monoxenous life-cycle). However, several genera are pathogenic to humans, animals and plants, and have an invertebrate vector that facilitates their transmission (i.e. possess a dixenous life-cycle). Phytomonas is one dixenous genus that includes several plant pathogens transmitted by phytophagous insects. Trypanosoma and Leishmania are dixenous genera that infect vertebrates, including humans, and are transmitted by hematophagous invertebrates. Traditionally, monoxenous trypanosomatids such as Leptomonas were distinguished from morphologically similar dixenous species based on their restriction to an invertebrate host. Nonetheless, this criterion is somewhat flawed as exemplified by Leptomonas seymouri which reportedly infects vertebrates opportunistically. Similarly, Novymonas and Zelonia are presumably monoxenous genera yet sit comfortably in the dixenous clade occupied by Leishmania. The isolation of Leishmania macropodum from a biting midge (Forcipomyia spp.) rather than a phlebotomine sand fly calls into question the exclusivity of the Leishmania-sand fly relationship, and its suitability for defining the Leishmania genus. It is now accepted that classic genus-defining characteristics based on parasite morphology and host range are insufficient to form the sole basis of trypanosomatid taxonomy as this has led to several instances of paraphyly. While improvements have been made, resolution of evolutionary relationships within the Trypanosomatidae is confounded by our incomplete knowledge of its true diversity. The known trypanosomatids probably represent a fraction of those that exist and isolation of new species will help resolve relationships in this group with greater accuracy. This review incites a dialogue on how our understanding of the relationships between certain trypanosomatids has shifted, and discusses new knowledge that informs the present taxonomy of these important parasites. PMID- 28595625 TI - Blood flow velocity and thickness of the choroid in a patient with chorioretinopathy associated with ocular blunt trauma. AB - BACKGROUND: Choroidal circulation hemodynamics in eyes with ocular blunt trauma has not been quantitatively examined yet. We quantitatively examined changes in choroidal blood flow velocity and thickness at the lesion site using laser speckle flowgraphy (LSFG) and enhanced depth imaging optical coherence tomography (EDI-OCT) in a patient with chorioretinopathy associated with ocular blunt trauma. CASE PRESENTATION: A 13-year-old boy developed a chorioretinal lesion with pigmentation extending from the optic disc to the superotemporal side in the right eye after ocular blunt trauma. The patient's best-corrected visual acuity (BCVA) was 0.2 in the right eye. Indocyanine green angiography showed hypofluorescence from the initial phase, with a decrease of mean blur rate (MBR) on LSFG color map, which corresponded to the chorioretinal lesion. The BCVA and foveal outer retinal morphologic abnormality spontaneously improved during follow up. MBR and choroidal thickness increased by 23-31% and 13-17 MUm at the lesion site and by 11-22% and 33-42 MUm at the fovea, respectively, during the 6-month follow-up period after baseline measurements in the affected eye. In contrast, these parameters showed little or no changes at the normal retinal site in the affected eye and the fovea in the fellow eye. CONCLUSIONS: Current data revealed that both blood flow velocity and thickness in the choroid at the lesion site decreased in the acute stage and subsequently increased together with improvements in visual function and outer retinal morphology. These results suggest that LSFG and EDI-OCT may be useful indices that can noninvasively evaluate activity of choroidal involvement in ocular blunt trauma-associated chorioretinopathy. PMID- 28595624 TI - Immunization, urbanization and slums - a systematic review of factors and interventions. AB - BACKGROUND: In 2014, over half (54%) of the world's population lived in urban areas and this proportion will increase to 66% by 2050. This urbanizing trend has been accompanied by an increasing number of people living in urban poor communities and slums. Lower immunization coverage is found in poorer urban dwellers in many contexts. This study aims to identify factors associated with immunization coverage in poor urban areas and slums, and to identify interventions to improve coverage. METHODS: We conducted a systematic review, searching Medline, Embase, Global Health, CINAHL, Web of Science and The Cochrane Database with broad search terms for studies published between 2000 and 2016. RESULTS: Of 4872 unique articles, 327 abstracts were screened, leading to 63 included studies: 44 considering factors and 20 evaluating interventions (one in both categories) in 16 low or middle-income countries. A wide range of socio economic characteristics were associated with coverage in different contexts. Recent rural-urban migration had a universally negative effect. Parents commonly reported lack of awareness of immunization importance and difficulty accessing services as reasons for under-immunization of their children. Physical distance to clinics and aspects of service quality also impacted uptake. We found evidence of effectiveness for interventions involving multiple components, especially if they have been designed with community involvement. Outreach programmes were effective where physical distance was identified as a barrier. Some evidence was found for the effective use of SMS (text) messaging services, community-based education programmes and financial incentives, which warrant further evaluation. No interventions were identified that provided services to migrants from rural areas. CONCLUSION: Different factors affect immunization coverage in different urban poor and slum contexts. Immunization services should be designed in collaboration with slum-dwelling communities, considering the local context. Interventions should be designed and tested to increase immunization in migrants from rural areas. PMID- 28595627 TI - Trends in use of and complications from intrauterine contraceptive devices and tubal ligation or occlusion. AB - BACKGROUND: Long-acting reversible contraceptives such as intrauterine devices (IUDs) are highly effective in preventing pregnancy, cost effective, and increasing in popularity. It is unclear whether changes in IUD use are associated with changes in rates of irreversible tubal sterilization. In this analysis, we evaluate changes in rates of tubal sterilization, insertion of copper or levonorgestrel (LNG) IUDs, and related complications over time. METHODS: Data were obtained from a retrospective claims database (OptumTM ClinformaticsTM Data Mart) of women aged 15 to 45 years who underwent insertion of copper or LNG IUD or tubal sterilization between 1/1/2006 and 12/31/2011. Outcomes of interest included annual rates of insertion or sterilization and annual rates of potential complications and side effects. RESULTS: The number of women included in the analysis each year ranged from 1,870,675 to 2,016,916. Between 2006 and 2011, copper IUD insertion claim rates increased from 0.18 to 0.25% and LNG IUD insertion claim rates increased from 0.63 to 1.15%, while sterilization claims decreased from 0.78 to 0.66% (P < 0.0001 for all comparisons). Increases in IUD insertion were apparent in all age groups; decreases in tubal sterilization occurred in women aged 20 to 34 years. The most common side effects and complications were amenorrhea (7.36-11.59%), heavy menstrual bleeding (4.85 15.69%), and pelvic pain (11.12-14.27%). Significant increases in claims of certain complications associated with IUD insertion or sterilization were also observed. CONCLUSION: Between 2006 and 2011, a decrease in sterilization rates accompanied an increase in IUD insertion rates, suggesting that increasing numbers of women opted for reversible methods of long-term contraception over permanent sterilization. PMID- 28595626 TI - Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-beta1 activation and myofibroblast differentiation. AB - BACKGROUND: Carbon nanotubes (CNTs) have been used in a variety of applications because of their unique properties and functions. However, many CNTs have been shown to induce lung fibrosis in experimental animals with some at a potency greater than that of silica, raising concern over possible toxic effects of CNT exposure in humans. Research into the mechanisms by which CNTs induce pulmonary fibrosis is warranted in order to facilitate the understanding, monitoring, and treatment of CNT-induced lung lesions that might occur in exposed populations. The current study focuses on investigating the role of osteopontin (OPN) in the development of lung fibrosis upon exposure to multi-walled carbon nanotubes (MWCNTs). METHODS: C57BL/6J (WT) and Opn knockout (KO) mice were exposed to MWCNTs by pharyngeal aspiration to examine the acute and chronic effects of MWCNT exposure. The role of OPN and its mode of action in lung fibrosis development were analyzed at the cellular and molecular levels in vivo and in vitro. RESULTS: OPN was highly and persistently induced in both the acute and chronic phases of the response to MWCNT exposure in mouse lungs. Comparison between WT and Opn KO mice revealed that OPN critically regulated MWCNT-induced lung fibrosis as indicated by reduced fibrotic focus formation and myofibroblast accumulation in Opn KO lungs. At the molecular level, OPN promotes the expression and activation of TGF-beta1, stimulates the differentiation of myofibroblasts from fibroblasts, and increases the production of fibrous matrix proteins in lungs and cultured lung cells exposed to MWCNTs. CONCLUSION: OPN is highly induced in CNT-exposed lungs and plays critical roles in TGF-beta1 signaling activation and myofibroblast differentiation to promote fibrosis development from MWCNT exposure. This study reveals an OPN-dependent mechanism to promote MWCNT-induced lung fibrosis. The findings raise the possibility of using OPN as a biomarker to monitor CNT exposure and as a drug target to halt fibrosis development. PMID- 28595629 TI - Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. AB - Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1 variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them. PMID- 28595630 TI - Prevalence and risk factors of poor immune recovery among adult HIV patients attending care and treatment centre in northwestern Tanzania following the use of highly active antiretroviral therapy: a retrospective study. AB - BACKGROUND: Highly Active Antiretroviral therapy (HAART) reverses the effect of Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) by durably suppressing viral replication. This allows CD4 gain to levels that are adequate enough to restore the body's capability to fight against opportunistic infections (OIs). Patients with poor immune recovery have been shown to have higher risk of developing both AIDS and non AIDS related clinical events. This study aimed at assessing the proportions and risk factors of poor immune recovery in adult HIV-infected patients on 48 months of HAART attending care and treatment center (CTC) in northwestern Tanzania. METHODS: A retrospective analysis of adult HIV patients' data attending CTC at Sekou Toure hospital and who initiated HAART between February 2004 and January 2008 was done. Poor immune recovery was defined as a CD4 count less than 350 cells/ul on follow up as used in other studies. RESULTS: A total of 734 patients were included in the study. In this study 50.25% of patients attending CTC at Sekou Toure hospital were found to have poor immune recovery. The risk of developing inadequate immune recovery was independently associated with male gender, age older than 50 years, low baseline CD4 counts, and advanced World Health Organization (WHO) clinical stage. CONCLUSIONS: Poor immune recovery is prevalent among adult HIV patients attending CTC at Sekou Toure hospital in Northwestern part of Tanzania and opportunistic infections are common in this sub group of patients. Clinicians in resource limited countries need to identify these patients timely and plan them for targeted viral assessment and close clinical follow up to improve their long term clinical outcome. PMID- 28595631 TI - Isolation of Tibet orbivirus from Culicoides and associated infections in livestock in Yunnan, China. AB - BACKGROUND: Culicoides-borne orbiviruses, such as bluetongue virus (BTV) and African horse sickness virus (AHSV), are important pathogens that cause animal epidemic diseases leading to significant loss of domestic animals. This study was conducted to identify Culicoides-borne arboviruses and to investigate the associated infections in local livestock in Yunnan, China. METHODS: Culicoides were collected overnight in Mangshi City using light traps during August 2013. A virus was isolated from the collected Culicoides and grown using baby hamster kidney (BHK-21), Vero, Madin-Darby bovine kidney (MDBK) and Aedes albopictus (C6/36) cells. Preliminary identification of the virus was performed by polyacrylamide gel (PAGE) analysis. A full-length cDNA copy of the genome was amplified and sequenced. Serological investigations were conducted in local cattle, buffalo and goat using plaque-reduction neutralization tests. RESULTS: We isolated a viral strain (DH13C120) that caused cytopathogenic effects in BHK-21, Vero, MDBK and C6/36 cells. Suckling mice inoculated intracerebrally with DH13C120 showed signs of fatal neurovirulence. PAGE analysis indicated a genome consisting of 10 segments of double-stranded RNA that demonstrated a 3-3-3-1 pattern, similar to the migrating bands of Tibet orbivirus (TIBOV). Phylogenetic analysis of the viral RNA-dependent RNA polymerase (Pol), sub-core-shell (T2, and outer core (T13) proteins revealed that DH13C120 clustered with TIBOV, and the amino acid sequences of DH13C120 virus shared more than 98% identity with TIBOV XZ0906. However, outer capsid protein VP2 and outer capsid protein VP5 shared only 43.1 and 79.3% identity, respectively, indicating that the DH13C120 virus belongs to TIBOV, and it may represent different serotypes with XZ0906. A serosurvey revealed the presence of neutralizing antibodies with 90% plaque reduction neutralization against TIBOV DH13C120 in local cattle (44%), buffalo (20%), and goat (4%). Four-fold or higher levels of TIBOV-2-neutralizing antibody titers were detected between the convalescent and acute phases of infection in local livestock. CONCLUSIONS: A new strain of TIBOV was isolated from Culicoides. This study provides the first evidence of TIBOV infection in livestock in Yunnan, China, and suggests that TIBOV could be a potential pathogen in livestock. PMID- 28595628 TI - SIX3, a tumor suppressor, inhibits astrocytoma tumorigenesis by transcriptional repression of AURKA/B. AB - BACKGROUND: SIX homeobox 3 (SIX3) is a member of the sine oculis homeobox transcription factor family. It plays a vital role in the nervous system development. Our previous study showed that the SIX3 gene is hypermethylated, and its expression is decreased in astrocytoma, but the role of SIX3 remains unknown. METHODS: Chromatin-immunoprecipitation (ChIP) and luciferase reporter assay were used to confirm the binding of SIX3 to the promoter regions of aurora kinase A (AURKA) and aurora kinase B (AURKB). Confocal imaging and co-immunoprecipitation (Co-IP) were used to detect the interaction between AURKA and AURKB. Flow cytometry was performed to assess the effect of SIX3 on cell cycle distribution. Colony formation, EdU incorporation, transwell, and intracranial xenograft assays were performed to demonstrate the effect of SIX3 on the malignant phenotype of astrocytoma cells. RESULTS: SIX3 is identified as a novel negative transcriptional regulator of AURKA and AURKB, and it decreases the expression of AURKA and AURKB in a dose-dependent manner in astrocytoma cells. Importantly, interactions between AURKA and AURKB stabilize and protect AURKA/B from degradation, and overexpression of SIX3 does not affect these interactions; SIX3 also acts as a tumor suppressor, and it increases p53 activity and expression at the post-translational level by the negative regulation of AURKA or AURKB, reduces the events of numerical centrosomal aberrations and misaligned chromosomes, and significantly inhibits the proliferation, invasion, and tumorigenesis of astrocytoma in vitro and in vivo. Moreover, experiments using primary cultured astrocytoma cells indicate that astrocytoma patients with a low expression of SIX3 and mutant p53 are more sensitive to treatment with aurora kinase inhibitors. CONCLUSION: SIX3 is a novel negative transcriptional regulator and acts as a tumor suppressor that directly represses the transcription of AURKA and AURKB in astrocytoma. For the first time, the functional interaction of AURKA and AURKB has been found, which aids in the protection of their stability, and partially explains their constant high expression and activity in cancers. SIX3 is a potential biomarker that could be used to predict the response of astrocytoma patients to aurora kinase inhibitors. PMID- 28595632 TI - A comparison of gene expression profiles in patients with coronary artery disease, type 2 diabetes, and their coexisting conditions. AB - BACKGROUND: To support a hypothesis that there is an intrinsic interplay between coronary artery disease (CAD) and type 2 diabetes (T2D), we used RNA-seq to identify unique gene expression signatures of CAD, T2D, and coexisting conditions. METHODS: After transcriptome sequencing, differential expression analysis was performed between each disordered state and normal control group. By comparing gene expression profiles of CAD, T2D, and coexisting conditions, common and specific patterns of each disordered state were displayed. To verify the specific gene expression patterns of CAD or T2D, the gene expression data of GSE23561 was extracted. RESULTS: A strong overlap of 191 genes across CAD, T2D and coexisting conditions, were mainly involved in a viral infectious cycle, anti apoptosis, endocrine pancreas development, innate immune response, and blood coagulation. In T2D-specific PPI networks involving 64 genes, TCF7L2 (Degree = 169) was identified as a key gene in T2D development, while in CAD-specific PPI networks involving 64 genes, HIF1A (Degree = 124), SMAD1 (Degree = 112) and SKIL (Degree = 94) were identified as key genes in the CAD development. Interestingly, with the provided expression data from GSE23561, the three genes were all up regulated in CAD, and SMAD1 and SKIL were specifically differentially expressed in CAD, while HIF1A was differentially expressed in both CAD and T2D, but with opposite trends. CONCLUSIONS: This study provides some evidences in transcript level to uncover the association of T2D, CAD and coexisting conditions, and may provide novel drug targets and biomarkers for these diseases. PMID- 28595633 TI - Effects of mechanical stimulation on the reprogramming of somatic cells into human-induced pluripotent stem cells. AB - BACKGROUND: Mechanical stimuli play important roles in the proliferation and differentiation of adult stem cells. However, few studies on their effects on induced pluripotent stem cells (iPSCs) have been published. METHODS: Human dermal fibroblasts were seeded onto flexible membrane-bottom plates, and infected with retrovirus expressing the four reprogramming factors OCT4, SOX2, KLF, and c-MYC (OSKM). The cells were subjected to equiaxial stretching (3% or 8% for 2, 4, or 7 days) and seeded on feeder cells (STO). The reprogramming into iPSCs was evaluated by the expression of pluripotent markers, in vitro differentiation into three germ layers, and teratoma formation. RESULTS: Equiaxial stretching enhanced reprogramming efficiency without affecting the viral transduction rate. iPSCs induced by transduction of four reprogramming factors and application of equiaxial stretching had characteristics typical of iPSCs in terms of pluripotency and differentiation potentials. CONCLUSIONS: This is the first study to show that mechanical stimuli can increase reprogramming efficiency. However, it did not enhance the infection rate, indicating that mechanical stimuli, defined as stretching in this study, have positive effects on reprogramming rather than on infection. Additional studies should evaluate the mechanism underlying the modulation of reprogramming of somatic cells into iPSCs. PMID- 28595634 TI - Generation of tooth-periodontium complex structures using high-odontogenic potential dental epithelium derived from mouse embryonic stem cells. AB - BACKGROUND: A number of studies have shown that tooth-like structures can be regenerated using induced pluripotent stem cells and mouse embryonic stem (mES) cells. However, few studies have reported the regeneration of tooth-periodontium complex structures, which are more suitable for clinical tooth transplantation. We established an optimized approach to induce high-odontogenic potential dental epithelium derived from mES cells by temporally controlling bone morphogenic protein 4 (BMP4) function and regenerated tooth-periodontium complex structures in vivo. METHODS: First, immunofluorescence and quantitative reverse transcription-polymerase chain reaction were used to identify the watershed of skin and the oral ectoderm. LDN193189 was then used to inhibit the BMP4 receptor around the watershed, followed by the addition of exogenous BMP4 to promote BMP4 function. The generated dental epithelium was confirmed by western blot analysis and immunofluorescence. The generated epithelium was ultimately combined with embryonic day 14.5 mouse mesenchyme and transplanted into the renal capsules of nude mice. After 4 weeks, the tooth-periodontium complex structure was examined by micro-computed tomography (CT) and hematoxylin and eosin (H&E) staining. RESULTS: Our study found that the turning point of oral ectoderm differentiation occurred around day 3 after the embryoid body was transferred to a common culture plate. Ameloblastin-positive dental epithelial cells were detected following the temporal regulation of BMP4. Tooth-periodontium complex structures, which included teeth, a periodontal membrane, and alveolar bone, were formed when this epithelium was combined with mouse dental mesenchyme and transplanted into the renal capsules of nude mice. Micro-CT and H&E staining revealed that the generated tooth-periodontium complex structures shared a similar histological structure with normal mouse teeth. CONCLUSIONS: An optimized induction method was established to promote the differentiation of mES cells into dental epithelium by temporally controlling the function of BMP4. A novel tooth-periodontium complex structure was generated using the epithelium. PMID- 28595635 TI - The pepper virome: natural co-infection of diverse viruses and their quasispecies. AB - BACKGROUND: The co-infection of diverse viruses in a host plant is common; however, little is known about viral populations and their quasispecies in the host. RESULTS: Here, we report the first pepper viromes that were co-infected by different types of viral genomes. The pepper viromes are dominated by geminivirus DNA-A followed by a novel carlavirus referred to as Pepper virus A. The two pepper cultivars share similar viral populations and replications. However, the quasispecies for double-stranded RNA virus and two satellite DNAs were heterogeneous and homogenous in susceptible and resistant cultivars, respectively, indicating the quasispecies of an individual virus depends on the host. CONCLUSIONS: Taken together, we provide the first evidence that the host plant resistant to viruses has an unrevealed antiviral system, affecting viral quasispecies, not replication. PMID- 28595636 TI - Two novel C-terminal frameshift mutations in the beta-globin gene lead to rapid mRNA decay. AB - BACKGROUND: The thalassemia syndromes are classified according to the globin chain or chains whose production is affected. beta-thalassemias are caused by point mutations or, more rarely, deletions or insertions of a few nucleotides in the beta-globin gene or its immediate flanking sequences. These mutations interfere with the gene function either at the transcriptional, translational or posttranslational level. METHODS: Two cases of Polish patients with hereditary hemolytic anemia suspected of thalassemia were studied. DNA sequencing and mRNA quantification were performed. Stable human cell lines which express wild-type HBB and mutated versions were used to verify that detected mutation are responsible for mRNA degradation. RESULTS: We identified two different frameshift mutations positioned in the third exon of HBB. Both patients harboring these mutations present the clinical phenotype of thalassemia intermedia and showed dominant pattern of inheritance. In both cases the mutations do not generate premature stop codon. Instead, slightly longer protein with unnatural C-terminus could be produced. Interestingly, although detected mutations are not expected to induce NMD, the mutant version of mRNA is not detectable. Restoring of the open reading frame brought back the RNA to that of the wild-type level. CONCLUSION: Our results show that a lack of natural stop codon due to the frameshift in exon 3 of beta-globin gene causes rapid degradation of its mRNA and indicate existence of novel surveillance pathway. PMID- 28595638 TI - Evaluating privacy-preserving record linkage using cryptographic long-term keys and multibit trees on large medical datasets. AB - BACKGROUND: Integrating medical data using databases from different sources by record linkage is a powerful technique increasingly used in medical research. Under many jurisdictions, unique personal identifiers needed for linking the records are unavailable. Since sensitive attributes, such as names, have to be used instead, privacy regulations usually demand encrypting these identifiers. The corresponding set of techniques for privacy-preserving record linkage (PPRL) has received widespread attention. One recent method is based on Bloom filters. Due to superior resilience against cryptographic attacks, composite Bloom filters (cryptographic long-term keys, CLKs) are considered best practice for privacy in PPRL. Real-world performance of these techniques using large-scale data is unknown up to now. METHODS: Using a large subset of Australian hospital admission data, we tested the performance of an innovative PPRL technique (CLKs using multibit trees) against a gold-standard derived from clear-text probabilistic record linkage. Linkage time and linkage quality (recall, precision and F measure) were evaluated. RESULTS: Clear text probabilistic linkage resulted in marginally higher precision and recall than CLKs. PPRL required more computing time but 5 million records could still be de-duplicated within one day. However, the PPRL approach required fine tuning of parameters. CONCLUSIONS: We argue that increased privacy of PPRL comes with the price of small losses in precision and recall and a large increase in computational burden and setup time. These costs seem to be acceptable in most applied settings, but they have to be considered in the decision to apply PPRL. Further research on the optimal automatic choice of parameters is needed. PMID- 28595637 TI - Exosome miR-371b-5p promotes proliferation of lung alveolar progenitor type II cells by using PTEN to orchestrate the PI3K/Akt signaling. AB - BACKGROUND: Pathways directing endogenous stem/progenitor cells to restore normal architecture and function of damaged/diseased lungs remain underexplored. Published data have revealed that alveolar progenitor type II cell (ATIIC) derived signaling promotes re-epithelialization of injured alveoli, yet the underlying mechanism is unknown. Here we aim to define the role of ATIIC-derived exosome miRNA signaling in controlling ATIIC-specific proliferation or differentiation in response to injury. METHODS: Pluripotent stem cell-derived cultures, which contain early lung stem/progenitor populations that can subsequently differentiate into ATIICs, were used as a model for unbiased screening and identification of ATIIC phenotype-specific exosome miRNA signaling, and human induced pluripotent stem cell-derived ATIICs (hiPSC-ATIICs) were employed to examine the molecular basis of key exosome miRNA signaling in promoting ATIIC-specific proliferation. QRT-PCR was performed to examine expression pattern of ATIIC-derived key exosome miRNA in an alveolar injury model and in injured human lungs. RESULTS: We show that human ATIIC line (A549)-derived exosome miR-371b-5p promotes ATIIC-specific proliferation, but not differentiation, in differentiating cultures of pluripotent stem cells. Using 3'UTR-driven luciferase reporters, we identified PTEN as a direct target of miR 371b-5p. Transfection of miR-371b-5p mimic into hiPSC-ATIICs leads to significantly decreased expression of endogenous PTEN, which stimulates phosphorylation of Akt and its downstream substrates, GSK3beta and FOXOs, promoting cell proliferation. While not expressed in normal ATIIC phenotypes, the exosome miR-371b-5p expression is significantly induced after hiPSC-ATIICs or hATIICs (human primary ATIICs) are subjected to bleomycin-induced injury. To rule out that the ATIIC-derived exosome-miRNAs are merely a cell culture phenomenon, we transplanted hiPSC-ATIICs into bleomycin-challenged lungs of mice, and found that the transplanted hiPSC-ATIICs engraft and express exosome miR-371b-5p, along with additional survival of numerous mouse ATIICs in bleomycin-injured lungs. Consistent with these findings, significant levels of exosome miR-371b-5p were also detected in lavage samples of patients with acute pneumonia, but not in those from patients without pulmonary disorders. CONCLUSIONS: Collectively, our data strongly suggest that ATIIC-derived exosome miR-371b-5p may serve as a niche signaling to augment ATIIC survival/proliferation, promoting re-epithelialization of injured alveoli, and thus provide a promising novel target to develop treatment for currently incurable lung diseases. PMID- 28595640 TI - Exploring the intergenerational persistence of health behaviour: an empirical study of smoking from China. AB - BACKGROUND: It is of significance to look into the intergenerational transmission of risk behaviour to explain the disparity of health. Our paper contributes to the literature by providing evidence in the context of China, focusing on smoking behaviour. METHODS: This paper studies the intergenerational transmission of smoking in the context of China using a nationally representative dataset - the China Health and Nutrition Survey (CHNS). The two-part model, the Tobit model, and the fixed effects model are utilized for the empirical analysis, respectively. RESULTS: We found a strong intergenerational persistence of health behaviour. That is, parents' smoking behaviour is positively correlated with their children's smoking initiation. CONCLUSIONS: Our study provides evidence of the intergenerational persistence of health behaviour in the case of smoking, in the world's most populous country. This has policy implications for the issue of intergenerational mobility and health education, as well as for tobacco control in China. PMID- 28595641 TI - The role of autonomy and social support in the relation between psychosocial safety climate and stress in health care workers. AB - BACKGROUND: Health care workers are exposed to psychosocial work factors. Autonomy and social support are psychosocial work factors that are related to stress, and are argued to largely result from the psychosocial safety climate within organisations. This study aimed to assess to what extent the relation between psychosocial safety climate and stress in health care workers can be explained by autonomy and social support. METHODS: In a cross-sectional study, psychosocial safety climate, stress, autonomy, co-worker support, and supervisor support were assessed using questionnaires, in a sample of health care workers (N = 277). Linear mixed models analyses were performed to assess to what extent social support and autonomy explained the relation between psychosocial safety climate and stress. RESULTS: A lower psychosocial safety climate score was associated with significantly higher stress (B = -0.21, 95% CI = -0.27 - -0.14). Neither co-worker support, supervisor support, nor autonomy explained the relation between psychosocial safety climate and stress. Taken together, autonomy and both social support measures diminished the relation between psychosocial safety climate and stress by 12% (full model: B = -0.18, 95% CI = -0.25 - -0.11). CONCLUSIONS: Autonomy and social support together seemed to bring about a small decrease in the relation between psychosocial safety climate and stress in health care workers. Future research should discern whether other psychosocial work factors explain a larger portion of this relation. TRIAL REGISTRATION: This study was registered in the Netherlands National Trial Register, trial code: NTR5527 . PMID- 28595639 TI - Diet shifts provoke complex and variable changes in the metabolic networks of the ruminal microbiome. AB - BACKGROUND: Grazing mammals rely on their ruminal microbial symbionts to convert plant structural biomass into metabolites they can assimilate. To explore how this complex metabolic system adapts to the host animal's diet, we inferred a microbiome-level metabolic network from shotgun metagenomic data. RESULTS: Using comparative genomics, we then linked this microbial network to that of the host animal using a set of interface metabolites likely to be transferred to the host. When the host sheep were fed a grain-based diet, the induced microbial metabolic network showed several critical differences from those seen on the evolved forage based diet. Grain-based (e.g., concentrate) diets tend to be dominated by a smaller set of reactions that employ metabolites that are nearer in network space to the host's metabolism. In addition, these reactions are more central in the network and employ substrates with shorter carbon backbones. Despite this apparent lower complexity, the concentrate-associated metabolic networks are actually more dissimilar from each other than are those of forage-fed animals. Because both groups of animals were initially fed on a forage diet, we propose that the diet switch drove the appearance of a number of different microbial networks, including a degenerate network characterized by an inefficient use of dietary nutrients. We used network simulations to show that such disparate networks are not an unexpected result of a diet shift. CONCLUSION: We argue that network approaches, particularly those that link the microbial network with that of the host, illuminate aspects of the structure of the microbiome not seen from a strictly taxonomic perspective. In particular, different diets induce predictable and significant differences in the enzymes used by the microbiome. Nonetheless, there are clearly a number of microbiomes of differing structure that show similar functional properties. Changes such as a diet shift uncover more of this type of diversity. PMID- 28595642 TI - Adherence to methadone maintenance treatment and associated factors among patients in Vietnamese mountainside areas. AB - BACKGROUND: Medication adherence is essential to achieve successful methadone maintenance treatment (MMT). However, treatment adherence among MMT patients in the mountainous setting in Vietnam has not been yet investigated. This study aimed to explore the medication adherence and associated factors in MMT patients in Tuyen Quang, a mountainous province. METHODS: A cross-sectional survey was conducted in two MMT clinics namely Tuyen Quang and Son Duong. Convenience sampling method was used to recruit patients. Adherence to MMT was assessed by using three questions: 1) number of days that they missed doses in the last 4 days; 2) whether they missed doses during the last weekend and 3) when they missed a dose within the last 3 months. Adherence was considered optimal if patients reported 'no' to three questions. Socioeconomic status, health status (measured by EuroQol-5 Dimensions - 5 Levels - EQ5D5L and Visual analogue scale - VAS), substance use and abuse and methods to support adherence were also collected. RESULTS: Among 241 patients, 34.4% reported optimal adherence. Self help was the most popular (89.2%) method used to support adherence. Risk factors of missing doses and suboptimal adherence included higher education and economic status; being a worker/farmer; longer duration of treatment; and suffering pain/discomfort and anxiety/depression. Protective factors were older age, having problems in usual activities/self-care, higher EQ-VAS and EQ-5D index; and reminded by mobile phone and family members. CONCLUSIONS: This study found a high sub-optimal adherence rate among MMT patients in a mountainous setting in Vietnam. Measuring adherence by using several simple items could be used periodically to monitor the treatment adherence in the clinical setting. Family and mobile phone support would have a potential role in supporting patients to adhere treatment. PMID- 28595643 TI - Planning strategies for inter-fractional robustness in pancreatic patients treated with scanned carbon therapy. AB - BACKGROUND: Managing inter-fractional anatomy changes is a challenging task in radiotherapy of pancreatic tumors, especially in scanned carbon-ion delivery. This treatment planning study aims to focus on clinically feasible solutions, such as the beam angle selection and margin design to increase the robustness against inter-fractional uncertainties. METHODS: This study included 10 patients with weekly 3D-CT imaging and physician-approved Clinical Target Volume (CTV). The study was directed to keep the CTV-coverage using six beam angle configurations in combination with different Internal Target Volume (ITV) concepts. These were: geometric-margin (symmetric 3 and 5 mm margin); range equivalent margins with an isotropic HU replacement; and to evaluate the need of asymmetric margins the water-equivalent range path (WEPL) was determined per patient from the set of CTs. Plan optimization and forward dose calculation in each week-CT were performed with the research treatment planning system TRiP98 and the plan quality evaluated in terms of CTV coverage (V95CTV) and homogeneity dose (HCTV = D5-D95). RESULTS: The beam geometry had a substantial impact on the target irradiation over the treatment course, with the single posterior or two beams showing the best average coverage of the CTV. The use of geometric margins for the more robust beam geometries showed acceptable results, with a V95CTV of (99.2 +/- 1.2)% for the 5 mm-margin. For the non-robust configurations, due to substantial changes in the radiological depth, the use of this margin results in a V95CTV that might be below 80%, only showing improvement when the range changes are included. CONCLUSIONS: Selection of adequate beam configurations and treatment margins in ion-beam therapy of pancreatic tumors is of great importance. For a single posterior beam or two beam configurations, application of geometrical margins compensate for dose degradation induced by inter fractional anatomy changes for the majority of the analyzed treatment fractions. PMID- 28595644 TI - Development of an objective gene expression panel as an alternative to self reported symptom scores in human influenza challenge trials. AB - BACKGROUND: Influenza challenge trials are important for vaccine efficacy testing. Currently, disease severity is determined by self-reported scores to a list of symptoms which can be highly subjective. A more objective measure would allow for improved data analysis. METHODS: Twenty-one volunteers participated in an influenza challenge trial. We calculated the daily sum of scores (DSS) for a list of 16 influenza symptoms. Whole blood collected at baseline and 24, 48, 72 and 96 h post challenge was profiled on Illumina HT12v4 microarrays. Changes in gene expression most strongly correlated with DSS were selected to train a Random Forest model and tested on two independent test sets consisting of 41 individuals profiled on a different microarray platform and 33 volunteers assayed by qRT-PCR. RESULTS: 1456 probes are significantly associated with DSS at 1% false discovery rate. We selected 19 genes with the largest fold change to train a random forest model. We observed good concordance between predicted and actual scores in the first test set (r = 0.57; RMSE = -16.1%) with the greatest agreement achieved on samples collected approximately 72 h post challenge. Therefore, we assayed samples collected at baseline and 72 h post challenge in the second test set by qRT-PCR and observed good concordance (r = 0.81; RMSE = -36.1%). CONCLUSIONS: We developed a 19-gene qRT-PCR panel to predict DSS, validated on two independent datasets. A transcriptomics based panel could provide a more objective measure of symptom scoring in future influenza challenge studies. Trial registration Samples were obtained from a clinical trial with the ClinicalTrials.gov Identifier: NCT02014870, first registered on December 5, 2013. PMID- 28595645 TI - Ethnobotanical survey of medicinal plants used as insects repellents in six malaria endemic localities of Cameroon. AB - BACKGROUND: The combined efforts to combat outdoor/indoor transmission of malaria parasites are hampered by the emerging vector resistance in a wide variety of malaria-endemic settings of Africa and the rest of the world, stressing the need for alternative control measures. This study aimed at documenting insect's repellent plant species used by indigenous populations of 6 localities of East, South, West and Centre regions of Cameroon. METHODS: Information was gathered through face-to-face interviews guided by a semi-structured questionnaire on the knowledge of medicinal plants with insect repellent properties. RESULTS: A total of 182 informants aged from 25 to 75 years were recruited by convenience from May to June 2015. The informants had general knowledge about insects' repellent plants (78.6%). A total of 16 plant species were recorded as insects' repellents with 50% being trees. The most cited plants were Canarium schweinfurthii (Burseraceae) (in four localities, 58/182), Elaeis guineensis (Arecaceae) (in three localities, 38/182), Chromolaena odorata (Compositae) (16/182) and Citrus limon (Rutaceae) (11/182) in two localities each. Among the repellent plant species recorded, 50% were reported to be burnt to produce in-house smokes, 31.2% were mashed and applied on the body, and 18.8% were hung in the houses. The leaf was the most commonly used plant part (52.9%), followed by the bark (17.6%). CONCLUSIONS: This study has shown that rural populations of the 6 targeted localities possess indigenous knowledge on repellent plants that are otherwise cost-effective and better choice for repelling insects including malaria transmitting mosquitoes. Meanwhile, such practices should be validated experimentally and promoted as sustainable malaria transmission control tools in the remotely located communities. PMID- 28595646 TI - Evaluation of obstetricians' surgical decision making in the management of uterine rupture. AB - BACKGROUND: Uterine rupture is an obstetric calamity with surgery as its management mainstay. Uterine repair without tubal ligation leaves a uterus that is more prone to repeat rupture while uterine repair with bilateral tubal ligation (BTL) or (sub)total hysterectomy predispose survivors to psychosocial problems like marital disharmony. This study aims to evaluate obstetricians' perspectives on surgical decision making in managing uterine rupture. METHODS: A questionnaire-based cross-sectional study of obstetricians at the 46th annual scientific conference of Society of Gynaecology and Obstetrics of Nigeria in 2012. Data was analysed by descriptive and inferential statistics. RESULTS: Seventy-nine out of 110 obstetricians (71.8%) responded to the survey, of which 42 (53.2%) were consultants, 60 (75.9%) practised in government hospitals and 67 (84.8%) in urban hospitals, and all respondents managed women with uterine rupture. Previous cesarean scars and injudicious use of oxytocic are the commonest predisposing causes, and uterine rupture carries very high incidences of maternal and perinatal mortality and morbidity. Uterine repair only was commonly performed by 38 (48.1%) and uterine repair with BTL or (sub) total hysterectomy by 41 (51.9%) respondents. Surgical management is guided mainly by patients' conditions and obstetricians' surgical skills. CONCLUSION: Obstetricians' distribution in Nigeria leaves rural settings starved of specialist for obstetric emergencies. Caesarean scars are now a rising cause of ruptures. The surgical management of uterine rupture and obstetricians' surgical preferences vary and are case scenario-dependent. Equitable redistribution of obstetricians and deployment of medical doctors to secondary hospitals in rural settings will make obstetric care more readily available and may reduce the prevalence and improve the outcome of uterine rupture. Obstetrician's surgical decision-making should be guided by the prevailing case scenario and the ultimate aim should be to avert fatality and reduce morbidity. PMID- 28595647 TI - Pubertal development in girls by breast cancer family history: the LEGACY girls cohort. AB - BACKGROUND: Pubertal milestones, such as onset of breast development and menstruation, play an important role in breast cancer etiology. It is unclear if these milestones are different in girls with a first- or second-degree breast cancer family history (BCFH). METHODS: In the LEGACY Girls Study (n = 1040), we examined whether three mother/guardian-reported pubertal milestones (having reached Tanner Stage 2 or higher (T2+) for breast and pubic hair development, and having started menstruation) differed by BCFH. We also examined whether associations between body size and race/ethnicity and pubertal milestones were modified by BCFH. We used mother/guardian reports as the primary measure of pubertal milestones, but also conducted sensitivity analyses using clinical Tanner measurements available for a subcohort (n = 204). We analyzed cross sectional baseline data with logistic regression models for the entire cohort, and longitudinal data with Weibull survival models for the subcohort of girls that were aged 5-7 years at baseline (n = 258). RESULTS: BCFH was modestly, but not statistically significantly, associated with Breast T2+ (odds ratio (OR) = 1.36, 95% confidence interval (CI) = 0.88-2.10), with a stronger association seen in the subcohort of girls with clinical breast Tanner staging (OR = 2.20, 95% CI = 0.91-5.32). In a longitudinal analysis of girls who were aged 5-7 years at baseline, BCFH was associated with a 50% increased rate of having early breast development (hazard ratio (HR) = 1.49, 95% CI = 1.0-2.21). This association increased to twofold in girls who were not overweight at baseline (HR = 2.04, 95% CI = 1.29-3.21). BCFH was not associated with pubic hair development and post menarche status. The median interval between onset of breast development and menarche was longer for BCFH+ than BCFH- girls (2.3 versus 1.7 years), suggesting a slower developmental tempo for BCFH+ girls. Associations between pubertal milestones and body size and race/ethnicity were similar in girls with or without a BCFH. For example, weight was positively associated with Breast T2+ in both girls with (OR = 1.06 per 1 kg, 95% CI = 1.03-1.10) and without (OR = 1.14 per 1 kg, 95% CI = 1.04-1.24) a BCFH. CONCLUSIONS: These results suggest that BCFH may be related to earlier breast development and slower pubertal tempo independent of body size and race/ethnicity. PMID- 28595648 TI - Investigation and management of osteoporosis in aged trauma patients: a treatment algorithm adapted to the German guidelines for osteoporosis. AB - BACKGROUND: Osteoporosis-associated fractures are of increasing importance in trauma surgery. Systematic diagnostics and treatment of osteoporosis during a hospital stay, however, remain inadequate. Therefore, a specific algorithm for diagnosing and treating osteoporosis in trauma surgery patients was developed based on the DVO (German Osteology Society) guideline for osteoporosis from 2014. METHODS: In a first step, the individuals' age and risk profile for osteoporosis is identified considering specific fractures indicating osteoporosis and risk factors assessed by a specific questionnaire. In addition, physical activity, risk of falls, dietary habits and the individuals' medication are considered. Basic osteoporosis laboratory tests, a bone densitometry by dual-energy X-ray absorptiometry (DXA) and, if needed, X-rays of the spine are carried out to identify prevalent vertebral body fractures. RESULTS: Based on the treatment algorithm adapted to the new guidelines for osteoporosis in the majority of proximal femoral fractures, treatment of osteoporosis could already be indicated without prior DXA. In case of preexisting glucocorticoid therapy, a history of previous fractures or other risk factors according to the risk questionnaire, the threshold of treatment has to be adjusted given the table of T-scores. CONCLUSIONS: The treatment algorithm for diagnosing and treating osteoporosis in in-patient trauma surgery patients can help identify high-risk patients systematically and efficiently. As a result, osteoporosis-associated fractures or failure of osteosynthesis could be reduced, yet a prospective validation of the algorithm has to be completed. PMID- 28595649 TI - Data-driven prediction of adverse drug reactions induced by drug-drug interactions. AB - BACKGROUND: The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects. METHOD: We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles. RESULTS: We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs via DDIs. This allowed us to identify potential DDI-induced ADRs not yet clinically reported. The ability of the models to quantify adverse effects between drug classes also suggests that we may be able to select drug combinations that minimize the risk of ADRs. CONCLUSION: Almost all information on DDI-induced ADRs is generated after drug approval. This situation poses significant health risks for vulnerable patient populations with comorbidities. To help mitigate the risks, we developed a robust probabilistic approach to prospectively predict DDI-induced ADRs. Based on this approach, we developed prediction models for 1,096 ADRs and used them to predict the propensity of all pairwise combinations of nearly 800 drugs to be associated with these ADRs via DDIs. We made the predictions publicly available via internet access. PMID- 28595651 TI - Psychometric limitations of the 13-item Sense of Coherence Scale assessed by Rasch analysis. AB - BACKGROUND: A person's sense of coherence (SOC) reflects their perception that the world is meaningful and predictable, and impacts their ability to deal with stressors in a health-promoting manner. A valid, reliable, and sensitive measure of SOC is needed to advance health promotion research based on this concept. The 13-item Sense of Coherence Scale (SOC-13) is widely used, but we reported in a previous evaluation its psychometric limitations when used with adults with morbid obesity. To determine whether the identified limitations were specific to that population or also generalize to other populations, we have replicated our prior study design and analysis in a new sample of adults with inflammatory bowel disease (IBD). METHODS: A sample of 428 adults with IBD completed the SOC-13 at a routine clinic visit in Norway between October 1, 2009 and May 31, 2011. Using a Rasch analysis approach, the SOC-13 and its three subscales were evaluated in terms of rating scale functioning, internal scale validity, person-response validity, person-separation reliability and differential item functioning. RESULTS: Collapsing categories at the low end of the 7-category rating scale improved its overall functioning. Two items demonstrated poor fit to the Rasch model, and once they were deleted from the scale, the remaining 11-item scale (SOC-11) demonstrated acceptable item fit. However, neither the SOC-13 nor the SOC-11 met the criteria for unidimensionality or person-response validity. While both the SOC-13 and SOC-11 were able to distinguish three groups of SOC, none of the subscales could distinguish any such groups. Minimal differential item functioning related to demographic characteristics was also observed. CONCLUSIONS: An 11-item version of the sense of coherence scale has better psychometric properties than the original 13-item scale among adults with IBD. These findings are similar to those of our previous evaluation among adults with morbid obesity and suggest that the identified limitations may exist across populations. Further refinement of the SOC scale is therefore warranted. PMID- 28595650 TI - Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner. AB - BACKGROUND: Chronic microglia-mediated inflammation and oxidative stress are well characterized underlying factors in neurodegenerative disease, whereby reactive inflammatory microglia enhance ROS production and impact neuronal integrity. Recently, it has been shown that during chronic inflammation, neuronal integrity is compromised through targeted disruption of the axon initial segment (AIS), the axonal domain critical for action potential initiation. AIS disruption was associated with contact by reactive inflammatory microglia which wrap around the AIS, increasing association with disease progression. While it is clear that chronic microglial inflammation and enhanced ROS production impact neuronal integrity, little is known about how acute microglial inflammation influences AIS stability. Here, we demonstrate that acute neuroinflammation induces AIS structural plasticity in a ROS-mediated and calpain-dependent manner. METHODS: C57BL/6J and NOX2-/- mice were given a single injection of lipopolysaccharide (LPS; 5 mg/kg) or vehicle (0.9% saline, 10 mL/kg) and analyzed at 6 h-2 weeks post-injection. Anti-inflammatory Didox (250 mg/kg) or vehicle (0.9% saline, 10 mL/kg) was administered beginning 24 h post-LPS injection and continued for 5 days; animals were analyzed 1 week post-injection. Microglial inflammation was assessed using immunohistochemistry (IHC) and RT-qPCR, and AIS integrity was quantitatively analyzed using ankyrinG immunolabeling. Data were statistically compared by one-way or two-way ANOVA where mean differences were significant as assessed using Tukey's post hoc analysis. RESULTS: LPS-induced neuroinflammation, characterized by enhanced microglial inflammation and increased expression of ROS producing enzymes, altered AIS protein clustering. Importantly, inflammation induced AIS changes were reversed following resolution of microglial inflammation. Modulation of the inflammatory response using anti-inflammatory Didox, even after significant AIS disruption occurred, increased the rate of AIS recovery. qPCR and IHC analysis revealed that expression of microglial NOX2, a ROS-producing enzyme, was significantly increased correlating with AIS disruption. Furthermore, ablation of NOX2 prevented inflammation-induced AIS plasticity, suggesting that ROS drive AIS structural plasticity. CONCLUSIONS: In the presence of acute microglial inflammation, the AIS undergoes an adaptive change that is capable of spontaneous recovery. Moreover, recovery can be therapeutically accelerated. Together, these findings underscore the dynamic capabilities of this domain in the presence of a pathological insult and provide evidence that the AIS is a viable therapeutic target. PMID- 28595652 TI - Effect of cochlear implant surgery on vestibular function: meta-analysis study. AB - IMPORTANCE: Vestibular disorders have been reported following cochlear implant (CI) surgery, but the literature shows a wide discrepancy in the reported clinical impact. The aim of this meta-analysis is to quantify the effect of CI before and after surgery on the outcomes of vestibular tests, postural stability, and subjective perception of dizziness. OBJECTIVE: To evaluate the effects of CI surgery on vestibular function in adult patients (>=18 years) with sensorineural hearing loss who underwent unilateral or bilateral implantation. DATA SOURCES: MEDLINE, PubMed, Web of Science and Cochrane Library from January 1, 1995, through July 12, 2016. STUDY SELECTION: Published studies of adult patients who received unilateral or bilateral CIs and whose vestibular function or postural stability was assessed before and after surgery. DATA EXTRACTION: From each study, test results before and after surgery were compared, for the following five tests: clinical head impulse test (HIT); bi-thermal caloric irrigation of the horizontal semicircular canal; vestibular evoked myogenic potential (VEMP); dizziness handicap inventory (DHI); and computerized dynamic posturography (CDP). RESULTS: Twenty-seven studies met all inclusion criteria. Most studies performed either bi-thermal caloric irrigation and/or VEMP, with fewer studies investigating changes in HIT, posturography or DHI. CI surgery significantly affected the results of caloric and VEMP testing. However, HIT results, posturography, and DHI, scores were not significantly affected after CI surgery. CONCLUSIONS AND RELEVANCE: CI surgery has a significant negative effect on the results of caloric as well as VEMP tests. No significant effect of CI surgery was detected in HIT, posturography, or DHI scores. Overall, the clinical effect of CI surgery on the vestibular function was found to be insignificant. Nonetheless, the potential effects of surgery on the vestibular system should be discussed with CI candidates before surgery. PMID- 28595654 TI - Dog rabies data reported to multinational organizations from Southern and Eastern African countries. AB - OBJECTIVE: Rabies is one of the viral diseases with the highest case fatality rate in humans. The main transmission route to humans is through bites, especially of infected dogs. Decisions on the allocation of resources to control and reduce the socio-economic impacts of rabies require reliable data. Several national, regional and international organizations have been gathering rabies data for more than a decade. The objective of this paper was to examine the consistencies in the number of dog rabies cases reported to different multinational organizations by Southern and Eastern African countries and to explore the presence of any time trend among the reported rabies data. RESULTS: Data was systematically extracted from the databases of the Southern and Eastern African Rabies Group-SEARG and the World Organization for Animal Health/World animal health information-OIE/WAHID. Despite differences in entities by which data have been reported to the two organisations, reported numbers were significantly correlated (Spearman's rho = 0.52, P < 0.001). The reported data did not indicate the presence of any trend in the number of reported dog rabies outbreaks. Inconsistencies in the reported numbers were observed between the databases, possibly due to the fact that human and animal health authorities report separately to the organisations involved in addition to the use of indefinite definitions of report categories set by report receiving organizations. PMID- 28595653 TI - Habitat productivity and pyrethroid susceptibility status of Aedes aegypti mosquitoes in Dar es Salaam, Tanzania. AB - BACKGROUND: Aedes aegypti (Diptera: Culicidae) is the main vector of the dengue virus globally. Dengue vector control is mainly based on reducing the vector population through interventions, which target potential breeding sites. However, in Tanzania, little is known about this vector's habitat productivity and insecticide susceptibility status to support evidence-based implementation of control measures. The present study aimed at assessing the productivity and susceptibility status of A. aegypti mosquitoes to pyrethroid-based insecticides in Dar es Salaam, Tanzania. METHODS: An entomological assessment was conducted between January and July 2015 in six randomly selected wards in Dar es Salaam, Tanzania. Habitat productivity was determined by the number of female adult A. aegypti mosquitoes emerged per square metre. The susceptibility status of adult A. aegypti females after exposure to 0.05% deltamethrin, 0.75% permethrin and 0.05% lambda-cyhalothrin was evaluated using the standard WHO protocols. Mortality rates were recorded after 24 h exposure and the knockdown effect was recorded at the time points of 10, 15, 20, 30, 40, 50 and 60 min to calculate the median knockdown times (KDT50 and KDT95). RESULTS: The results suggest that disposed tyres had the highest productivity, while water storage tanks had the lowest productivity among the breeding habitats Of A. aegypti mosquitoes. All sites demonstrated reduced susceptibility to deltamethrin (0.05%) within 24 h post exposure, with mortalities ranging from 86.3 +/- 1.9 (mean +/- SD) to 96.8 +/- 0.9 (mean +/- SD). The lowest and highest susceptibilities were recorded in Mikocheni and Sinza wards, respectively. Similarly, all sites demonstrated reduced susceptibility permethrin (0.75%) ranging from 83.1 +/- 2.1% (mean +/- SD) to 96.2 +/- 0.9% (mean +/- SD), in Kipawa and Sinza, respectively. Relatively low mortality rates were observed in relation to lambda-cyhalothrin (0.05%) at all sites, ranging from 83.1 +/- 0.7 (mean +/- SD) to 86.3 +/- 1.4 (mean +/- SD). The median KDT50 for deltamethrin, permethrin and lambda-cyhalothrin were 24.9 30.3 min, 24.3-34.4 min and 26.7-32.8 min, respectively. The KDT95 were 55.2-90.9 min for deltamethrin, 54.3-94.6 min for permethrin and 64.5-69.2 min for lambda cyhalothrin. CONCLUSIONS: The productive habitats for A. aegypti mosquitoes found in Dar es Salaam were water storage containers, discarded tins and tyres. There was a reduced susceptibility of A. aegypti to and emergence of resistance against pyrethroid-based insecticides. The documented differences in the resistance profiles of A. aegypti mosquitoes warrants regular monitoring the pattern concerning resistance against pyrethroid-based insecticides and define dengue vector control strategies. PMID- 28595655 TI - Nuclear protein in testis carcinoma of the mediastinum: a case report. AB - BACKGROUND: Nuclear protein in testis carcinoma is a rare and very aggressive undifferentiated cancer which characteristically arises in the midline of the head, neck, and mediastinum. CASE PRESENTATION: We describe the case of a 46-year old white woman admitted for superior vena cava syndrome revealing a mediastinal tumor. Pathological examination of specimens obtained by mediastinoscopy revealed an undifferentiated tumor with solid growth and positive immunoreactivity for p40 and negative immunoreactivity for cytokeratin markers. Immunohistochemical staining was positive for nuclear protein in testis, allowing the diagnosis of nuclear protein in testis midline carcinoma of the mediastinum. CONCLUSIONS: We present a rare case of mediastinal nuclear protein in testis carcinoma with diagnosis based on nuclear protein in testis protein positivity and atypical immunohistochemical features including p40 positivity and anti-cytokeratin negativity. Physicians must remain aware of the possibility of nuclear protein in testis carcinoma especially in young patients with thoracic symptoms and suspicion of neoplasm. PMID- 28595657 TI - brain-coX: investigating and visualising gene co-expression in seven human brain transcriptomic datasets. AB - BACKGROUND: The pathogenesis of neurological and mental health disorders often involves multiple genes, complex interactions, as well as brain- and development specific biological mechanisms. These characteristics make identification of disease genes for such disorders challenging, as conventional prioritisation tools are not specifically tailored to deal with the complexity of the human brain. Thus, we developed a novel web-application-brain-coX-that offers gene prioritisation with accompanying visualisations based on seven gene expression datasets in the post-mortem human brain, the largest such resource ever assembled. RESULTS: We tested whether our tool can correctly prioritise known genes from 37 brain-specific KEGG pathways and 17 psychiatric conditions. We achieved average sensitivity of nearly 50%, at the same time reaching a specificity of approximately 75%. We also compared brain-coX's performance to that of its main competitors, Endeavour and ToppGene, focusing on the ability to discover novel associations. Using a subset of the curated SFARI autism gene collection we show that brain-coX's prioritisations are most similar to SFARI's own curated gene classifications. CONCLUSIONS: brain-coX is the first prioritisation and visualisation web-tool targeted to the human brain and can be freely accessed via http://shiny.bioinf.wehi.edu.au/freytag.s/ . PMID- 28595656 TI - ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells. AB - BACKGROUND: Most melanoma patients with BRAFV600E positive tumors respond well to a combination of BRAF kinase and MEK inhibitors. However, some patients are intrinsically resistant while the majority of patients eventually develop drug resistance to the treatment. For patients insufficiently responding to BRAF and MEK inhibitors, there is an ongoing need for new treatment targets. Cellular metabolism is such a promising new target line: mutant BRAFV600E has been shown to affect the metabolism. METHODS: Time course experiments and a series of western blots were performed in a panel of BRAFV600E and BRAFWT/NRASmut human melanoma cells, which were incubated with BRAF and MEK1 kinase inhibitors. siRNA approaches were used to investigate the metabolic players involved. Reactive oxygen species (ROS) were measured by confocal microscopy and AZD7545, an inhibitor targeting PDKs (pyruvate dehydrogenase kinase) was tested. RESULTS: We show that inhibition of the RAS/RAF/MEK/ERK pathway induces phosphorylation of the pyruvate dehydrogenase PDH-E1alpha subunit in BRAFV600E and in BRAFWT/NRASmut harboring cells. Inhibition of BRAF, MEK1 and siRNA knock-down of ERK1/2 mediated phosphorylation of PDH. siRNA-mediated knock-down of all PDKs or the use of DCA (a pan-PDK inhibitor) abolished PDH-E1alpha phosphorylation. BRAF inhibitor treatment also induced the upregulation of ROS, concomitantly with the induction of PDH phosphorylation. Suppression of ROS by MitoQ suppressed PDH-E1alpha phosphorylation, strongly suggesting that ROS mediate the activation of PDKs. Interestingly, the inhibition of PDK1 with AZD7545 specifically suppressed growth of BRAF-mutant and BRAF inhibitor resistant melanoma cells. CONCLUSIONS: In BRAFV600E and BRAFWT/NRASmut melanoma cells, the increased production of ROS upon inhibition of the RAS/RAF/MEK/ERK pathway, is responsible for activating PDKs, which in turn phosphorylate and inactivate PDH. As part of a possible salvage pathway, the tricarboxylic acid cycle is inhibited leading to reduced oxidative metabolism and reduced ROS levels. We show that inhibition of PDKs by AZD7545 leads to growth suppression of BRAF-mutated and -inhibitor resistant melanoma cells. Thus small molecule PDK inhibitors such as AZD7545, might be promising drugs for combination treatment in melanoma patients with activating RAS/RAF/MEK/ERK pathway mutations (50% BRAF, 25% NRASmut, 11.9% NF1mut). PMID- 28595658 TI - Nutrient profiling for regulatory purposes. AB - In this paper, I first provide definitions of nutrient profiling and of a nutrient profile model. I set out the purposes of nutrient profiling: both general and specific. I give two examples of nutrient profile models that have been developed for regulatory purposes by the Food Standards Agency (FSA) in the UK and the WHO for its European Region - the UK FSA/Ofcom and the WHO-Euro models - and compare the way the models are constructed and function, how they have been developed, the extent to which they have been tested and validated and their use in regulation. Finally I draw some conclusions about the future use of nutrient profiling for regulatory purposes. I argue that its full potential has yet to be realised and give some reasons why. I pose some urgent research questions with respect to nutrient profiling. PMID- 28595659 TI - Uses of nutrient profiling to address public health needs: from regulation to reformulation. AB - Nutrient profiling (NP) models rate the nutritional quality of individual foods, based on their nutrient composition. Their goal is to identify nutrient-rich foods, generally defined as those that contain more nutrients than calories and are low in fat, sugar and salt. NP models have provided the scientific basis for evaluating nutrition and health claims and regulating marketing and advertising to children. The food industry has used NP methods to reformulate product portfolios. To help define what we mean by healthy foods, NP models need to be based on published nutrition standards, mandated serving sizes and open-source nutrient composition databases. Specifically, the development and testing of NP models for public health should follow the seven decision steps outlined by the European Food Safety Authority. Consistent with this scheme, the nutrient-rich food (NRF) family of indices was based on a variable number of qualifying nutrients (from six to fifteen) and on three disqualifying nutrients (saturated fat, added sugar, sodium). The selection of nutrients and daily reference amounts followed nutrient standards for the USA. The base of calculation was 418.4 kJ (100 kcal), in preference to 100 g, or serving sizes. The NRF algorithms, based on unweighted sums of percent daily values, subtracted negative (LIM) from positive (NRn) subscores (NRn - LIM). NRF model performance was tested with respect to energy density and independent measures of a healthy diet. Whereas past uses of NP modelling have been regulatory or educational, voluntary product reformulation by the food industry may have most impact on public health. PMID- 28595660 TI - HEALTH TECHNOLOGY ASSESSMENT IN TURKEY. AB - OBJECTIVES: The healthcare transformation program in Turkey has shown its success with improvements in important health indicators, increased access to healthcare services and expansion of coverage to all citizens. Turkey has been relatively able to bear the burdens associated with this due to rapid economic growth. The need for health technology assessment (HTA) was believed as a result of the expansion of coverage, pressure of new technologies, and increased expenditures. This study outlines the background and current formalization of HTA and shares the current use of HTA in decision making, while summarizing the transformation of the Turkish healthcare system for developing a high-quality, equal, and accessible care system. METHODS: We reviewed and analyzed policy changes in the Turkish healthcare system, universal health coverage, healthcare expenditures, and pricing and reimbursement policies to identify the changes leading to HTA. We reviewed existing HTA functions in Turkey and outlined their activities. Finally, we outlined a set of major challenges for HTA in Turkey over the next decade. RESULTS: HTA was formalized in Turkey in 2012-2013 with three national HTA structures and one hospital-based HTA unit. These functions currently run independent from each other. There are three major challenges in this country for HTA in the next decade: clarification of the assessment scope and methods, building a strong supporting system for HTA, and defining the role of HTA in the future vision of Turkish healthcare policy. CONCLUSION: HTA, despite challenges, has a good opportunity to develop further with clear action plans and strong political will. PMID- 28595661 TI - The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis - Corrigendum. PMID- 28595662 TI - Behavior and Evolution of Young ONset Dementia part 2 (BEYOND-II) study: an intervention study aimed at improvement in the management of neuropsychiatric symptoms in institutionalized people with young onset dementia. AB - : ABSTRACTBackground:Both neuropsychiatric symptoms (NPS) and psychotropic drug use (PDU) are common in institutionalized People with Young Onset Dementia (PwYOD) and can produce negative outcomes such as reduced quality of life and high workload. In community-dwelling PwYOD, NPS are found to be associated with unmet care needs. This emphasizes the importance of a care program for the management of NPS in institutionalized PwYOD that also addresses unmet care needs and PDU. The objectives of the Behavior and Evolution of Young ONset Dementia part 2 (BEYOND-II) study are to develop a care program for the management of NPS in institutionalized PwYOD and to evaluate its effectiveness. METHODS: The care program consists of an educational program combined with an intervention to manage NPS with the following five steps: the evaluation of psychotropic drug prescription, detection, analysis (including the detection of unmet needs), treatment and the evaluation of NPS. A stepped wedge design will be used to evaluate its effectiveness. The primary outcomes are agitation and aggression and other NPS. The secondary outcomes are PDU, quality of life, the workload of nursing staff and job satisfaction. Additionally, a process analysis and a cost consequence analysis will be conducted. CONCLUSIONS: The study protocol of the Beyond-II study describes the development, implementation and evaluation of a care program for the management of NPS in institutionalized PwYOD. This care program provides a structured method for the management of NPS, in which unmet needs and PDU are also addressed. PMID- 28595663 TI - VISIONS OF STAKEHOLDERS ABOUT INSTUTIONALIZATION OF HEALTH TECHNOLOGY ASSESSMENT IN CHILE: A QUALITATIVE STUDY. AB - OBJECTIVES: The aim of this study was to explore and describe the viewpoints and beliefs with respect to a health technology assessment (HTA) process and its institutionalization in a sample of stakeholder representatives in Chile. METHODS: A qualitative study with a descriptive design, based on the model of discourse analysis, was performed. Eighteen semi-structured interviews were conducted on nineteen Chilean representatives of stakeholders in HTA. The data analysis was based on a process of open coding that allows the contrasting of the interviewees' visions. RESULTS: From what the interviewees mentioned, a proposal to institutionalize the process of HTA is presented for Chile. The focus is on three main areas: (i) Principles to guide the HTA, (ii) Institutional Framework for Chile, and (iii) Impacts associated with their implementation process. Transparency and participation were the main principles identified. The idea of an autonomous body for HTA, independent and publicly funded, was widely supported. However, this implementation could face potential resistance from technicians and politicians, who might impose barriers to avoid their loss of decision power. CONCLUSIONS: There is a broad agreement about the importance of creating a national institution for HTA, independent and publicly funded. This study supplies relevant information for other countries that are currently undertaking a similar process. PMID- 28595665 TI - Genetic Influences on Hormonal Markers of Chronic HPA Function in Human Hair - CORRIGENDUM. PMID- 28595664 TI - Spanish-Language Adaptation of Morgeson and Humphrey's Work Design Questionnaire (WDQ). AB - Since work organizations became the subject of scientific research, how to operationalize and measure dimensions of work design has been an issue, mainly due to concerns about internal consistency and factor structure. In response, Morgeson and Humphrey (2006) built the Work Design Questionnaire -WDQ-, an instrument that identifies and measures these dimensions in different work and organizational contexts. This paper presents the instruent's adaptation into Spanish using reliability and validity analysis and drawing on a sample of 1035 Spanish workers who hold various jobs in an array of occupational categories. The total instrument's internal consistency was Cronbach's alpha of .92 and the various scales' reliability ranged from .70 to .96, except for three dimensions. There was initially a difference in the comparative fit of the two versions' factor structures, but the model with 21 work characteristics (motivational -task and knowledge-, social, and work context) showed the highest goodness of fit of the various models tested, confirming previous results from the U.S. version as well as adaptations into other languages and contexts. CFA results indicated goodness of fit of factor configurations corresponding to each of the four major categories of work characteristics, with CFI and TLI around .90, as well as SRMR and RMSEA below .08. Thus it brings to the table a reliable, valid measure of work design with clear potential applications in research as well as professional practice, applications that could improve working conditions, boost productivity, and generate more personal and professional development opportunities for workers. PMID- 28595666 TI - A Brief Cognitive Behavioural Intervention for Maladaptive Perfectionism in Students: A Pilot Study. AB - BACKGROUND: Researchers focused on developing therapeutic strategies for perfectionism given its well-established link to the onset and maintenance of several mental disorders. Meta-analytical findings provided support for the efficacy of cognitive behavioural (CB) approaches. However, most studies have focused on the efficacy of interventions, without analysing their efficiency. AIMS: To explore the feasibility of a brief (five weekly sessions) CB group intervention focused on reducing perfectionistic concerns in Argentine students. We also aimed to identify participants who benefited from the intervention and to explore their differences with non-respondents. A third aim was to explore the potential merits of the intervention in a different cultural context as this is the first attempt to adapt an English-spoken protocol to the Spanish language. METHOD: A quasi-experimental design with two time points was used. Twenty-four out of 84 participants (mean age = 27.75 years, SD = 8.3) were classified as maladaptive perfectionists. RESULTS: Paired t-tests and reliable change index comparisons revealed that most students (75%) statistically and clinically reduced their levels of perfectionistic concerns as well as their perfectionistic strivings. General distress, operationalized as anxious and depressive symptoms, was also decreased. Students who completed and responded to the intervention were more dysfunctional in academic and psychological measures at baseline than non completers and non-improvers. CONCLUSIONS: Findings support the feasibility, preliminary efficacy and efficiency of this five weekly session intervention when applied to a sample of Argentine university students. PMID- 28595667 TI - EXPERIENCES IN ADAPTING EUROPEAN NETWORK FOR HEALTH TECHNOLOGY ASSESSMENT RAPID REVIEWS TO INFORM LOCAL DECISION MAKING. AB - OBJECTIVES: The Scottish Health Technologies Group (SHTG) produces rapid reviews on nonmedicine technologies to inform advice for decision making in the National Health Service in Scotland (NHSScotland). This study describes our experiences and lessons learned in adapting for NHSScotland two rapid Relative Effectiveness Assessments (REAs) produced as part of the European Network for Health Technology Assessment (EUnetHTA) project to test collaborative preparation and then local adaptation. METHODS: The REAs were examined for their relevance to NHSScotland and the feasibility of their adaptation evaluated using a screening toolkit. Some supplementary literature searches were conducted and additional background information on epidemiology and the specific technologies was sought. To inform decision making within Scotland, it was also necessary to identify and review cost-effective analyses. RESULTS: Robust evidence reviews were delivered for NHSScotland. Time saved was less than anticipated, partly due to the need to add in health economic information, and partly because of attempts to supplement and update the EUnetHTA material. The preparation of an accompanying advice statement for NHSScotland enabled the inclusion of local contextual information. CONCLUSIONS: Collaborative production and adaptation of HTAs is feasible and would be aided by the inclusion of cost-effectiveness analyses in the original work. Agencies should develop clear processes for adapting such reviews for their context with the focus on selecting appropriate topics for adaptation, avoiding unnecessary supplementation of the original work, and ensuring local ownership of final advice. PMID- 28595668 TI - Spatiotemporal analysis of tuberculosis incidence and its associated factors in mainland China. AB - Spatiotemporal analysis is an important tool to monitor changes of tuberculosis (TB) epidemiology, identify high-risk regions and guide resource allocation. However, there are limited data on the contributing factors of TB incidence. This study aimed to investigate the spatiotemporal pattern of TB incidence and its associated factors in mainland China during 2005-2013. Global Moran's I test, Getis-Ord Gi index and heat maps were used to examine the spatial clustering and seasonal patterns. Generalized Linear Mixed Model was applied to identify factors associated with TB incidence. TB incidence presented high geographical variations with two main hot spots, while a generally consistent seasonal pattern was observed with a peak in late winter. Furthermore, we found province-level TB incidence increased with the proportion of the elderly but decreased with Gross Demographic Product per capita and the male:female ratio. Meteorological factors also influenced TB incidence. TB showed obvious spatial clustering in mainland China and both the demographic and socio-economic factors and meteorological measures were associated with TB incidence. These results provide the related information to identify the high-risk districts and the evidence for the government to develop corresponding control measures. PMID- 28595669 TI - Surges of advanced medical support associated with influenza outbreaks. AB - We utilized de-identified data to evaluate increases in four outcomes during influenza outbreak periods (IOPs) including: hospitalization, intensive care unit admission, mechanical ventilation or death for adults aged 18 years or older with medically attended acute respiratory illnesses (MAARI) admitted to any of Maryland's 50 acute-care hospitals over 12 years. Weekly numbers of positive influenza tests in the Maryland area were obtained from the US Center for Disease Control and Prevention interactive website. The fewest consecutive weeks around the peak week containing at least 85% of the positive tests defined the IOP. Weekly counts of individual study outcomes were positively correlated with regional weekly counts of positive influenza tests during all the IOPs over 12 years. Also, rate ratios comparing daily occurrences of each study outcome between the IOP and non-IOP were significantly elevated. These results confirm conclusions of previous studies that influenza outbreaks are clearly associated with deaths and increased use of advanced medical resources by patients with MAARI. These data analyses suggest that increased efforts to develop more effective influenza vaccines and therapeutics should be a priority. PMID- 28595670 TI - Healthy cognitive ageing in the Lothian Birth Cohort studies: marginal gains not magic bullet. AB - In the face of shifting demographics and an increase in human longevity, it is important to examine carefully what is known about cognitive ageing, and to identify and promote possibly malleable lifestyle and health-related factors that might mitigate age-associated cognitive decline. The Lothian Birth Cohorts of 1921 (LBC1921, n = 550) and 1936 (LBC1936, n = 1091) are longitudinal studies of cognitive and brain ageing based in Scotland. Childhood IQ data are available for these participants, who were recruited in later life and then followed up regularly. This overview summarises some of the main LBC findings to date, illustrating the possible genetic and environmental contributions to cognitive function (level and change) and brain imaging biomarkers in later life. Key associations include genetic variation, health and fitness, psychosocial and lifestyle factors, and aspects of the brain's structure. It addresses some key methodological issues such as confounding by early-life intelligence and social factors and emphasises areas requiring further investigation. Overall, the findings that have emerged from the LBC studies highlight that there are multiple correlates of cognitive ability level in later life, many of which have small effects, that there are as yet few reliable predictors of cognitive change, and that not all of the correlates have independent additive associations. The concept of marginal gains, whereby there might be a cumulative effect of small incremental improvements across a wide range of lifestyle and health-related factors, may offer a useful way to think about and promote a multivariate recipe for healthy cognitive and brain ageing. PMID- 28595671 TI - From the SAIN,LIM system to the SENS algorithm: a review of a French approach of nutrient profiling. AB - Nutrient profiling aims to classify or rank foods according to their nutritional composition to assist policies aimed at improving the nutritional quality of foods and diets. The present paper reviews a French approach of nutrient profiling by describing the SAIN,LIM system and its evolution from its early draft to the simplified nutrition labelling system (SENS) algorithm. Considered in 2010 by WHO as the 'French model' of nutrient profiling, SAIN,LIM classifies foods into four classes based on two scores: a nutrient density score (NDS) called SAIN and a score of nutrients to limit called LIM, and one threshold on each score. The system was first developed by the French Food Standard Agency in 2008 in response to the European regulation on nutrition and health claims (European Commission (EC) 1924/2006) to determine foods that may be eligible for bearing claims. Recently, the European regulation (EC 1169/2011) on the provision of food information to consumers allowed simplified nutrition labelling to facilitate consumer information and help them make fully informed choices. In that context, the SAIN,LIM was adapted to obtain the SENS algorithm, a system able to rank foods for simplified nutrition labelling. The implementation of the algorithm followed a step-by-step, systematic, transparent and logical process where shortcomings of the SAIN,LIM were addressed by integrating specificities of food categories in the SENS, reducing the number of nutrients, ordering the four classes and introducing European reference intakes. Through the French example, this review shows how an existing nutrient profiling system can be specifically adapted to support public health nutrition policies. PMID- 28595672 TI - In vitro larvicidal and in vivo anthelmintic effects of Oxalis tetraphylla (Oxalidaceae) hydroalcoholic extract against Haemonchus contortus in lambs. AB - The in vitro larvicidal and in vivo anthelmintic effects of Oxalis tetraphylla hydroalcoholic extract (HE), against Haemonchus contortus in experimentally infected lambs, were assessed. We used a microtitration plate method, comprising the following two stages. Stage 1: 20 MUl of water containing 200 sheathed H. contortus infective larvae (ShHcl) were deposited in every well of three series; then, the series 2 and 3 wells were treated with 80 MUl 1% ivermectin and O. tetraphylla HE at 20 mg/ml, respectively. Stage 2: the same procedure was performed replacing the ShHcl with exsheathed larvae (ExShHcl). Evaluations were performed after 24 and 48 h. The total numbers of dead and live larvae were counted. A second experiment evaluated the reduction in nematode egg populations in the faeces of lambs treated orally with the O. tetraphylla HE. The 27 lambs used were divided into Groups 1, 2 and 3 (n = 9), which were administered water (positive control), levamisole 1 m (7.5 mg/kg body weight (BW), as a unique dose) and O. tetraphylla HE (20 mg/kg BW), respectively. The plant HE was administered daily for 8 days. The in vitro assay showed 80.9% and 86.5% larval mortality of ShHcl after 24 and 48 h, respectively, while the corresponding mortality values for ExShHcl were 97 and 99%, respectively. The in vivo assay showed variability in the eggs/gram of faeces (epg) values; however, at the end of the trial, the average reduction in the epg values of the O. tetraphylla HE group was 45.6% (P < 0.05). Oxalis tetraphylla HE contains compounds that belong to the flavonol group with anthelmintic activity. PMID- 28595673 TI - Neonatal DNA methylation and early-onset conduct problems: A genome-wide, prospective study. AB - Early-onset conduct problems (CP) are a key predictor of adult criminality and poor mental health. While previous studies suggest that both genetic and environmental risks play an important role in the development of early-onset CP, little is known about potential biological processes underlying these associations. In this study, we examined prospective associations between DNA methylation (cord blood at birth) and trajectories of CP (4-13 years), using data drawn from the Avon Longitudinal Study of Parents and Children. Methylomic variation at seven loci across the genome (false discovery rate < 0.05) differentiated children who go on to develop early-onset (n = 174) versus low (n = 86) CP, including sites in the vicinity of the monoglyceride lipase (MGLL) gene (involved in endocannabinoid signaling and pain perception). Subthreshold associations in the vicinity of three candidate genes for CP (monoamine oxidase A [MAOA], brain-derived neurotrophic factor [BDNF], and FK506 binding protein 5 [FKBP5]) were also identified. Within the early-onset CP group, methylation levels of the identified sites did not distinguish children who will go on to persist versus desist in CP behavior over time. Overall, we found that several of the identified sites correlated with prenatal exposures, and none were linked to known genetic methylation quantitative trait loci. Findings contribute to a better understanding of epigenetic patterns associated with early-onset CP. PMID- 28595674 TI - Blunt laryngeal trauma secondary to sporting injuries. AB - BACKGROUND: Laryngeal injury after blunt trauma is uncommon, but can cause catastrophic airway obstruction and significant morbidity in voice and airway function. This paper aims to discuss a case series of sports-related blunt laryngeal trauma patients and describe the results of a thorough literature review. METHOD: Retrospective case-based analysis of laryngeal trauma referrals over six years to a tertiary laryngology centre. RESULTS: Twenty-eight patients were identified; 13 (46 per cent) sustained sports-related trauma. Most were young males, presenting with dysphonia, some with airway compromise (62 per cent). Nine patients were diagnosed with a laryngeal fracture. Four patients were managed conservatively and nine underwent surgery. Post-treatment, the majority of patients achieved good voice outcomes (83 per cent) and all had normal airway function. CONCLUSION: Sports-related neck trauma can cause significant injury to the laryngeal framework and endolaryngeal soft tissues, and most cases require surgical intervention. Clinical presentation may be subtle; a systematic approach along with a high index of suspicion is essential, as early diagnosis and treatment have been reported to improve airway and voice outcome. PMID- 28595675 TI - Is the medical treatment for arterial hypertension after primary aortic coarctation repair related to age at surgery? A retrospective cohort study. AB - BACKGROUND: Hypertension following primary coarctation repair affects up to a third of subjects. A number of studies suggest that future hypertension risk is reduced if primary repair is performed at a younger age. OBJECTIVES: The objective of this study was to evaluate the risk of future medical treatment for hypertension depending on age of primary coarctation repair. METHODS: This study was carried out at a tertiary paediatric cardiology referral centre. Retrospective database evaluation of children aged 28 days and ?12 months), and children (>12 months). Main outcome measure is the need for long-term anti hypertensive medication. The risk for re-coarctation was also evaluated. RESULTS: A total of 87 patients were analysed: 60 neonates, 17 infants, 10 children. Among them, 6.7% neonates, 29.4% infants, and 40% children required long-term anti hypertensive medications. Group differences were statistically significant (p=0.004). After adjustment for type of repair, the risk of long-term anti hypertensive therapy was 4.5 (95% confidence interval 1.2-16.9, p=0.025) and 10.5 times (95% confidence interval 2.6-42.3, p=0.001) higher if primary repair was carried out in infancy and childhood, respectively, compared with neonates. Among all, 13 patients developed re-coarctation: 21.7% in the neonatal group, 5.9% in the infant group, and 20% in the child group. We could not demonstrate a significant difference between these proportions or calculate a reliable risk for developing re-coarctation. CONCLUSIONS: Risk of medical treatment for hypertension was lowest when primary repair was carried out during the neonatal period, rising 10-fold if first operated on as a child. Knowing the likelihood of hypertension development depending on age of primary repair is useful for long term surveillance and counselling. PMID- 28595676 TI - Evaluation of the impact of 2 years of a dosing intervention on canine echinococcosis in the Alay Valley, Kyrgyzstan. AB - Echinococcosis is a re-emerging zoonotic disease in Kyrgyzstan. In 2012, an echinococcosis control scheme was started that included dosing owned dogs in the Alay Valley, Kyrgyzstan with praziquantel. Control programmes require large investments of money and resources; as such it is important to evaluate how well these are meeting their targets. However, problems associated with echinococcosis control schemes include remoteness and semi-nomadic customs of affected communities, and lack of resources. These same problems apply to control scheme evaluations, and quick and easy assessment tools are highly desirable. Lot quality assurance sampling was used to assess the impact of approximately 2 years of echinococcosis control in the Alay valley. A pre-intervention coproELISA prevalence was established, and a 75% threshold for dosing compliance was set based on previous studies. Ten communities were visited in 2013 and 2014, with 18 21 dogs sampled per community, and questionnaires administered to dog owners. After 21 months of control efforts, 8/10 communities showed evidence of reaching the 75% praziquantel dosing target, although only 3/10 showed evidence of a reduction in coproELISA prevalence. This is understandable, since years of sustained control are required to effectively control echinococcosis, and efforts in the Alay valley should be and are being continued. PMID- 28595677 TI - Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. AB - : Clinical question Is intensive blood pressure (BP) treatment (systolic BP target 110-139 mm Hg) better than standard antihypertensive treatment (systolic BP target 140-179 mm Hg) in reducing mortality and disability in patients with acute intracerebral hemorrhage (ICH)? Article chosen Qureshi AI, Palesch YY, Barsan WG, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med 2016;375(11):1033-43. OBJECTIVE: To determine the therapeutic benefit of intensive BP treatment compared to standard BP treatment in reducing death and disability after 3 months of follow-up among patients with ICH treated within 4.5 hours from onset of symptoms. PMID- 28595678 TI - A tight squeeze. PMID- 28595679 TI - Performance-based everyday functional competence measures across the adult lifespan: the role of cognitive abilities. AB - BACKGROUND: The effects of age on the ability to manage everyday functioning, crucial to ensure a healthy aging process, have been rarely examined and when, self-report measures have been used. The aim of the present study was to examine age effects across the adult lifespan in everyday functioning with two performance-based measures: the Everyday Problems Test (EPT), and the Timed Instrumental Activities of Daily Living (TIADL) tasks. The role of some crucial cognitive abilities, i.e. working memory (WM), processing speed, reasoning, vocabulary, and text comprehension in the EPT and the TIADL were also assessed to see whether or not they have a similar influence (and to what extent) in accounting for age-related effects in these two performance-based measures. METHOD: Two hundred and seventy-six healthy participants, from 40 to 89 years of age were presented with the EPT, the TIADL, as well as WM, processing speed, reasoning, text comprehension, and vocabulary tasks. RESULTS: Path models indicated an indirect effect of age and education on the EPT, which was mediated by all the cognitive variables considered, with WM and reasoning being the strongest predictors of performance. An indirect quadratic effect of age, but not of education, was found on the TIADL score, and an accelerated decline in processing speed mediated the relationship between age and the TIADL score. CONCLUSION: This study revealed age-related effects in performance-based measures, which are mediated by different cognitive abilities depending on the measure considered. The findings highlight the importance of assessing everyday functioning even in healthy older adults. PMID- 28595680 TI - Moving the Needle Just a Bit More. PMID- 28595681 TI - Donna Bartlett: Reaching Out Into the Community. PMID- 28595682 TI - Wandering: Unearthing New Tracking Devices. AB - Wandering away from home or facilities is dangerous for patients with dementia and stressful for families and caregivers when those who go missing cannot be located. Up to 60% of Alzheimer's disease patients wander, and up to 50% of those who are not found within 24 hours face serious injury or death. Currently, no effective drug therapies exist to abate wandering, which has multiple causes, but emerging technologies offer a promise of comfort in being able to easily locate a missing loved one. As of 2012, 41 states had enacted Silver Alert programs that broadcast information about missing, vulnerable adults. Numerous technologies, such as wearable global positioning system trackers and temporary barcodes worn on fingernails, exist to ease the fears of families and caregivers, locate residents, and hasten their return. While these strategies offer promise, issues of expense, effectiveness, privacy, and ethics remain. PMID- 28595683 TI - Cholecalciferol (D3) Versus Ergocalciferol (D2) in Older Adults. AB - Vitamin D is a fat-soluble vitamin that is naturally found in very few food sources. It is produced endogenously from ultraviolet light from the sun striking the skin and then triggering vitamin D synthesis and activation. Vitamin D helps promote calcium absorption in the gut, maintains adequate serum calcium and phosphate levels, promotes bone growth, modulates cell growth, and has many other roles. There have been an increasing number of people, especially in older adults, with vitamin D deficiency. This is in part a result of a reduction of sun exposure as people age, increase in use of sunscreen, and other factors. This article highlights the roles of cholecalciferol (vitamin D3) versus ergocalciferol (vitamin D2) supplementation for practicing pharmacists. PMID- 28595684 TI - Marijuana Use in the Elderly: Implications and Considerations. AB - OBJECTIVE: This article reviews the literature on the use of marijuana in the elderly. Pharmacists play an important role in the management of medications including drug use of potentially illegal drugs, including marijuana. The use of both recreational and medical marijuana has grown exponentially in the general population, including in older adults. As of 2017, marijuana for medical use is legal in 26 states and the District of Columbia. DATA SOURCES: PubMed and Internet search using the following terms: marijuana, cannabis, delta-9 tetrhydrocannabinol (THC), cannabidiol, cannabinoid, elderly, geriatric, and pharmacology. Findings are based on data collected from older adults (65 years of age and older) through August 2016. STUDY SELECTION: Because of the lack of research and funding, reputable literature on the impact of marijuana on older adults is scarce. The available evidence suggests that elderly individuals should be cautious when consuming marijuana, especially those who have certain comorbid conditions. DATA EXTRACTION: The geriatric population has a higher likelihood of having multiple comorbidities and is subject to polypharmacy. Marijuana use, medicinal or recreational, complicates the picture with additive central nervous system side effects. DATA SYNTHESIS: This article reviews the growing information on marijuana use and discusses issues to consider and cautions in usage that can apply to day-to-day clinical practice and geriatric care. The role of the pharmacist in educating patients, caregivers, and health care providers is expanding with the growing number of states that have legalized medical marijuana (26 states and the District of Columbia, as of 2017). Important education points including drug-drug interactions, drug-disease interactions, and signs and symptoms of acute overdose should be considered. CONCLUSION: With this review, pharmacists will be informed on recommendations on the use of marijuana in the older adult. Monitoring of therapy, as well as adverse effects, will be reviewed, including some legal issues and challenges. PMID- 28595685 TI - Implementing Psychopharmacology Rounds in a Nursing Facility to Improve Antipsychotic Usage. AB - OBJECTIVES: Evaluate whether implementing of pharmacy-led psychopharmacology rounds in a nursing facility will improve the rate of antipsychotic use. DESIGN: Single-center, prospective; medication use evaluation (MUE). SETTING: Rutland Nursing Home, Brooklyn, New York. PARTICIPANTS: Nursing facility residents, excluding the pediatric unit. INTERVENTIONS: Weekly interdisciplinary psychopharmacology rounds that include: clinical pharmacists, nurse managers, medical director, social workers, and administration. Antipsychotics were analyzed for all residents for appropriateness of use, proper documentation, and adequate monitoring. MAIN OUTCOME MEASURE: Assess the overall rate of reduction of antipsychotic use after implementation of psychopharmacology rounds. Secondary outcomes assessed improvements in monitoring and documentation for residents on antipsychotics. RESULTS: A total of 81 residents were evaluated over the six month MUE. Of those residents, 20 had their antipsychotics discontinued, and 11 had their antipsychotics tapered. The overall use of antipsychotics decreased from 14.6% (62/422) to 12.2% (50/411) (P = 0.285). Compliance with indications generally approved by the Centers for Medicare & Medicaid Services improved from 65% (37/57) to 85% (46/54) (P = 0.008). Matching indications on the psychiatry consult and the medication order improved from 58% (33/57) to 80% (43/54) (P = 0.015). Metabolic laboratory monitoring improved from 58% (33/57) to 83% (45/54) (P = 0.003). Improvements in timeliness of psychiatry and ophthalmology consults were not statistically significant. CONCLUSION: Implementing interdisciplinary psycho-pharmacology rounds in a nursing facility resulted in a reduction of inappropriate antipsychotic use and improved monitoring and documentation. PMID- 28595686 TI - Attitudes of Nursing Facilities' Staff Toward Pharmacy Students' Interaction with its Residents. AB - OBJECTIVE: All Appalachian College of Pharmacy second-year students undertake the longitudinal geriatric early pharmacy practice experiences (EPPE) 2 course, which involves interacting with geriatric residents in two nursing facilities over two semesters. The study investigated the nursing staff's perceptions about the rotation and the pharmacy students' interaction with nursing facility residents. STUDY DESIGN: Cross-sectional study. SETTING: Academic setting. PARTICIPANTS: 63 nursing facility staff. INTERVENTIONS: A 10-item attitude survey administered to nursing staff. MAIN OUTCOME MEASURES: Nursing staff attitude toward pharmacy students' interaction with geriatric residents during the course. RESULTS: Sixty three responses were received (84% response rate). Most respondents were female (95.2%), who occasionally interacted with pharmacy students (54.8%) and had worked at the facilities for an average of 6.8 years (standard deviation [SD] = 6.7) years. Staff reported that pharmacy students practiced interacting with geriatric residents and nursing facility staff, learned about different medications taken by residents as well as their life as a nursing facility resident. In addition, the student visits improved the mood of residents and staff's understanding of medicines, among others. Staff suggested that students spend more time with their residents in the facility as well as ask more questions of staff. CONCLUSION: The nursing facility staff generally had favorable attitudes about pharmacy students' visits in their nursing facility. Nursing facility staff noted that the geriatric rotation was a great learning experience for the pharmacy students. PMID- 28595687 TI - Solving Long-Term Care: Mission Impossible? PMID- 28595688 TI - The Efficacy of Dextran-40 as a Venous Thromboembolism Prophylaxis Strategy in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. PMID- 28595689 TI - High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. PMID- 28595690 TI - Understanding health talk in an urban Aboriginal and Torres Strait Islander primary healthcare service: a cross-sectional study. AB - Health literacy is an important determinant of health status. This cross sectional study aimed to describe the prevalence of adequate health literacy among Aboriginal and Torres Strait Islander patients or their carers including parents of sick children attending an urban primary healthcare clinic in Australia, and their experiences of communication with General Practitioners (GPs). A questionnaire, including questions from the Brief Health Literacy Screen (BHLS) and questions from the Consumer Assessment of Healthcare Providers and Systems (CAHPS): Communication with Provider, was administered to 427 participants. Descriptive statistics, Pearson's Chi-Square test and logistic regression analysis were used to describe the prevalence and risk factors associated with health literacy and any associations between the CAHPS questions and health literacy. In total, 72% of participants had adequate health literacy. An age of >=50 years was independently associated with inadequate health literacy, and completion of secondary or post-secondary schooling was protective. Communication questions that identified areas for improvement included less use of incomprehensible medical words and more frequent use of visual aids. The study provides useful information on health literacy among Aboriginal and Torres Strait Islander patients, or their carers, and their experiences of communication with GPs. Further population-based research is required to investigate the effect of health literacy on health outcomes of Aboriginal and Torres Strait Islander patients. PMID- 28595691 TI - Foreword. PMID- 28595693 TI - When Less Is Not More. PMID- 28595692 TI - Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction. AB - BACKGROUND: Dose reduction of non-vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk, whereas dose reductions without a firm indication may decrease the effectiveness of stroke prevention. OBJECTIVES: The goal of this study was to investigate NOAC dosing patterns and associated outcomes, i.e., stroke (ischemic stroke and systemic embolism) and major bleeding in patients treated in routine clinical practice. METHODS: Using a large U.S. administrative database, 14,865 patients with AF were identified who initiated apixaban, dabigatran, or rivaroxaban between October 1, 2010, and September 30, 2015. We examined use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication is not present (potential underdosing). Cox proportional hazards regression was performed in propensity score-matched cohorts to investigate the outcomes. RESULTS: Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication. CONCLUSIONS: In routine clinical practice, prescribed NOAC doses are often inconsistent with drug labeling. These prescribing patterns may be associated with worse safety with no benefit in effectiveness in patients with severe kidney disease and worse effectiveness with no benefit in safety in apixaban-treated patients with normal or mildly impaired renal function. PMID- 28595694 TI - Myocardial Damage in Patients With Deferred Stenting After STEMI: A DANAMI-3 DEFER Substudy. AB - BACKGROUND: Although some studies found improved coronary flow and myocardial salvage when stent implantation was deferred, the DANAMI-3-DEFER (Third DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction) did not show any improvement in clinical outcome in patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) and deferred stenting. OBJECTIVES: This study sought to evaluate the effect of deferred stent implantation on infarct size, myocardial salvage, and microvascular obstruction (MVO) in patients with STEMI. METHODS: In the present DANAMI-3 substudy, a total of 510 patients with STEMI were randomized to PCI with deferred versus immediate stent implantation. The patients underwent a cardiac magnetic resonance examination before discharge after the index procedure and again 3 months later. The primary endpoint was final infarct size. RESULTS: Deferred stenting did not reduce final infarct size (9% left ventricle [LV]; interquartile range [IQR]: 3% to 18% vs. 10% LV; IQR: 3% to 18%; p = 0.67). Similarly, deferred stenting was not associated with myocardial salvage index (66%; IQR: 50% to 89% vs. 67%; IQR: 49% to 88%; p = 0.80) or presence of MVO (43% vs. 42%; p = 0.78). In a post hoc analysis, stent length was the only subgroup of 7 that had an effect on outcome. In patients with a stent length >=24 mm, deferred stenting reduced the final infarct size (6% LV; IQR: 2% to 18% vs. 13% LV; IQR: 7% to 23%; p = 0.006; and p for interaction = 0.005). CONCLUSIONS: In the DANAMI-3-DEFER cardiac magnetic resonance substudy, routine deferred stenting did not reduce infarct size or MVO and did not increase myocardial salvage. These results do not support the use of routine deferred stenting in STEMI patients treated with primary PCI. (DANish Study of Optimal Acute Treatment of Patients With ST-elevation Myocardial Infarction [DANAMI-3]; NCT01435408). PMID- 28595695 TI - Is Delayed Stenting of the Culprit Artery in Patients With STEMI Ever Worth the Wait? PMID- 28595696 TI - Left Main Coronary Artery Compression in Patients With Pulmonary Arterial Hypertension and Angina. AB - BACKGROUND: Left main coronary artery (LMCA) compression is increasingly recognized as a cause of angina in pulmonary arterial hypertension (PAH). OBJECTIVES: This study aimed to evaluate the prevalence of LMCA extrinsic compression from a dilated pulmonary artery (PA) in patients with PAH and angina or angina-like symptoms, determine the usefulness of screening with computed tomography coronary angiography (CTCA), and assess the safety and efficacy of percutaneous coronary interventions (PCIs). METHODS: All patients with PAH and angina or angina-like symptoms attending the center between May 1, 2008, and December 31, 2013, underwent CTCA. Patients with confirmed LMCA stenosis on selective coronary angiography had PCI. RESULTS: Of 765 patients with PAH, 121 had angina or angina-like symptoms. Ninety-four patients had abnormal CTCA based on the relationship between the PA and the LMCA and underwent selective coronary angiography. LMCA stenosis >=50% was detected in 48 of the 94 patients. Forty five patients underwent PCI with stenting, of whom 41 had sustained angina symptom relief. The 3 other patients had surgical PA reduction plasty. Nine months after PCI, 5 patients had LMCA restenosis and PCI was successfully repeated. The best predictor of LMCA stenosis >=50% was a PA diameter >=40 mm. Rates for death or double-lung transplant and the composite rates for death, double-lung transplant, or restenosis at 36 months were 5% and 30%, respectively. CONCLUSIONS: The prevalence of LMCA compression in patients with PAH and angina is high. These results suggest that CTCA is indicated in patients with PAH and angina or angina-like symptoms. PCI was well tolerated, improved symptoms, and resulted in favorable long-term outcomes. PMID- 28595697 TI - Left Main Coronary Artery Compression in Patients With Pulmonary Arterial Hypertension. PMID- 28595699 TI - Better Understanding Quality of Life for Those Living With Marfan. PMID- 28595698 TI - Marfan Syndrome and Quality of Life in the GenTAC Registry. AB - BACKGROUND: Previous small studies suggested reduced quality of life (QOL) for people with Marfan syndrome (MFS) compared with those without MFS. The national registry of GenTAC (Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions) is a longitudinal observational cohort study of patients with conditions that predispose to thoracic aortic aneurysms and dissections, including MFS. At the time of registry enrollment, GenTAC study participants are asked to complete questionnaires about demographics, medical history, health habits, and QOL. OBJECTIVES: This study assessed QOL in GenTAC participants with MFS and identify associated factors using self-reported data. METHODS: QOL was assessed using the 4 subscales of the Physical Component Summary (PCS) of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36): physical functioning; role limitations due to physical health; bodily pain; and general health. We studied the association of QOL with self-reported demographics, health behaviors, physical impairments, surgeries, comorbid medical conditions, medications, and MFS severity. RESULTS: In the GenTAC registry, 389 adults with MFS completed the SF-36. Mean age was 41 years, 51% were men, 92% were white, and 65% were college graduates. The mean PCS composite score was 42.3. In bivariate analysis, predictors of better QOL included college education, marital status, higher household income, private health insurance, full-time employment, moderate alcohol use, fewer prior surgeries, fewer comorbid conditions, absence of depression, and less severe MFS manifestations. In a multivariable analysis, insurance status and employment remained significant predictors of QOL. CONCLUSIONS: In a large cohort of patients with MFS in the GenTAC registry, health-related QOL was below the population norm. Better QOL was independently associated with socioeconomic factors, not factors related to general health or MFS severity. PMID- 28595701 TI - Angiotensin-Converting Enzyme Inhibitors for Cardiac Allograft Vasculopathy After Heart Transplantation. PMID- 28595700 TI - Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation. AB - BACKGROUND: Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT. OBJECTIVES: This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT. METHODS: In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year. RESULTS: Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 +/- 70.5 mm3 vs. 177.3 +/- 94.3 mm3, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 +/- 14.7 to 14.4 +/- 6.3; p = 0.001) and increase in CFR (3.8 +/- 1.7 to 4.8 +/- 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 +/- 8.4 to 21.5 +/- 20.0; p = 0.72) or CFR (4.1 +/- 1.8 to 4.1 +/- 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group. CONCLUSIONS: Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363). PMID- 28595702 TI - Left Ventricular Assist Devices for Lifelong Support. AB - Continuous-flow left ventricular assist devices (LVADs) have revolutionized advanced heart failure care. These compact, fully implantable heart pumps are capable of providing meaningful increases in survival, functional capacity, and quality of life. Implantation volumes continue to grow, but several challenges remain to be overcome before LVADs will be considered as the therapy of choice for all patients with advanced heart failure. They must be able to consistently extend survival for the long term (7 to 10 years), rather than the midterm (3 to 5 years) more typical of contemporary devices; they must incorporate design elements that reduce shear stress and avoid stasis to reduce the frequent adverse events of bleeding, stroke, and pump thrombosis; and they must become more cost effective. The advancements in engineering, implantation technique, and medical management detailed in this review will highlight the progress made toward achieving lifelong LVAD support and the challenges that remain. PMID- 28595704 TI - What's in a Name? PMID- 28595703 TI - Performance on the Cardiovascular In-Training Examination in Relation to the ABIM Cardiovascular Disease Certification Examination. AB - The American College of Cardiology In-Training Exam (ACC-ITE) is incorporated into most U.S. training programs, but its relationship to performance on the American Board of Internal Medicine Cardiovascular Disease (ABIM CVD) Certification Examination is unknown. ACC-ITE scores from third-year fellows from 2011 to 2014 (n = 1,918) were examined. Covariates for regression analyses included sex, age, medical school country, U.S. Medical Licensing Examination Step, and ABIM Internal Medicine Certification Examination scores. A secondary analysis examined fellows (n = 511) who took the ACC-ITE in the first and third years. ACC-ITE scores were the strongest predictor of ABIM CVD scores (p < 0.0001), and the most significant predictor of passing (p < 0.0001). The change in ACC-ITE scores from first to third year was a strong predictor of the ABIM CVD score (p < 0.001). The ACC-ITE is strongly associated with performance on the ABIM CVD Certification Examination. PMID- 28595705 TI - A Cardiology Fellow's Guide to Patient-Centered Care. PMID- 28595706 TI - Percutaneous Mitral Valve Repair: Refining Selection Criteria. PMID- 28595708 TI - Collapse of the Aspirin Empire: Is it Diabetic Gastroparesis or Cardioprotective Paresis? PMID- 28595707 TI - Obesity-Related Changes in Cardiac Structure and Function Among Asian Men and Women. PMID- 28595709 TI - Reply: Collapse of the Aspirin Empire: Is it Diabetic Gastroparesis or Cardioprotective Paresis? PMID- 28595710 TI - Reply: Is White-Coat Hypertension Associated With Risk of Cardiovascular Diseases? PMID- 28595711 TI - Is White-Coat Hypertension Associated With Risk of Cardiovascular Diseases? PMID- 28595712 TI - Correction. PMID- 28595713 TI - Correction. PMID- 28595714 TI - Foreword. PMID- 28595717 TI - From the Editor. PMID- 28595716 TI - Combat casualty care and lessons learned from the past 100 years of war. PMID- 28595718 TI - Echocardiographic characteristics of hypertensive patients affected by transient ischemic attack: a cross-sectional study. AB - Atrial septal aneurysm (ASA), common finding in normal echocardiographies, has been described in association with transient ischemic attacks (TIAs)/strokes, as well as hypertensive end-organ damage such as left ventricular (LV) hypertrophy. Aim of this study was to assess if a cluster of echocardiographic aspects could characterize TIA hypertensive patients. A cross-sectional study on patients with history of TIA, referring to a Hypertension Center echolab, has been performed. A total of 5223 patients received transthoracic echocardiography. TIA patients were 292 (5.6%). A total of 102 age/sex-matched patients without TIA have been collected as controls. The main characteristic of TIA patients resulted ASA/bulging (B) (TIA 61%, controls 6%, P = .0001). Other aspect was LV concentric remodeling (TIA 32.3%, controls 20.8%, P = .029) and mitral flow aspects of diastolic dysfunction. After adjustment for age and hypertension, ASA/B (odds ratio [OR] = 62.4, 95% confidence interval [CI]: 13.6-73.9, P < .001), followed by LV concentric hypertrophy (OR = 2.1, 95% CI: 1.1-4.3, P = .043), was associated with a positive TIA history. A binary logistic regression performed in ASA/B patients, identified relative wall thickness as the strongest TIA associated aspect (OR = 53.4, 95% CI: 11.9-74.18, P = .001). ASA/B, common finds in general population, could carry a significant incremental possibility of association with TIA when concentric geometry, frequent hypertensive aspect, is present as well. PMID- 28595720 TI - Lessons learned from the recent history of technologies for noninvasive estimation of aortic blood pressure using transfer functions and pulse wave analysis. PMID- 28595719 TI - Effects of carvedilol or amlodipine on target organ damage in L-NAME hypertensive rats: their relationship with blood pressure variability. AB - The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor beta, tumor necrosis factor alpha, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor beta, tumor necrosis factor alpha, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats. PMID- 28595721 TI - Study of antioxidant effects on malignant glioma cells by constructing a tumor microvascular structure on microchip. AB - In this work, a three-dimensional tumor-microvascular structure was simulated on a microfluidic chip for study of antioxidants effects on malignant glioma cells in vitro. The 3D hydrogel containing lumen was constructed to co-culture endothelial cells and glioma cells to mimic tumor microvascular environment. Macroporous gelatin transglutaminase (TG) hydrogel was prepared with biological and mechanical properties suitable for cells culture and nutrient refresh. To reform a vessel structure, U87 cells were dispersed in the TG-gelatin hydrogel and HUVEC cells were seeded in the lumen of hydrogel. Three typical antioxidants (alpha-lipoic acid, catechins and ascorbic acid) have been selected to research the antioxidant effects of glioma cells in the simulative tumor microenvironment. The results showed that the HUVEC cells formed vessel presented the transportation and penetrable functions for antioxidants from lumen to glioma cells. The antioxidants displayed higher selectivity to U87 cells than HUVEC cells and alpha-lipoic acid has a strong antioxidant capacity. PMID- 28595722 TI - Knowledge integration strategies for untargeted metabolomics based on MCR-ALS analysis of CE-MS and LC-MS data. AB - In this work, two knowledge integration strategies based on multivariate curve resolution alternating least squares (MCR-ALS) were used for the simultaneous analysis of data from two metabolomic platforms. The benefits and the suitability of these integration strategies were demonstrated in a comparative study of the metabolite profiles from yeast (Saccharomyces cerevisiae) samples grown in non fermentable (acetate) and fermentable (glucose) carbon source. Untargeted metabolomics data acquired by capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry (LC-MS) were jointly analysed. On the one hand, features obtained by independent MCR-ALS analysis of each dataset were joined to obtain a biological interpretation based on the combined metabolic network visualization. On the other hand, taking advantage of the common spectral mode, a low-level data fusion strategy was proposed merging CE-MS and LC-MS data before the MCR-ALS analysis to extract the most relevant features for further biological interpretation. Then, results obtained by the two presented methods were compared. Overall, the study highlights the ability of MCR-ALS to be used in any of both knowledge integration strategies for untargeted metabolomics. Furthermore, enhanced metabolite identification and differential carbon source response detection were achieved when considering a combination of LC-MS and CE MS based platforms. PMID- 28595723 TI - Stable isotope N-phosphoryl amino acids labeling for quantitative profiling of amine-containing metabolites using liquid chromatography mass spectrometry. AB - Stable isotope chemical labeling liquid chromatography-mass spectrometry (LC-MS) is a powerful strategy for comprehensive metabolomics profiling, which can improve metabolites coverage and quantitative information for exploration of metabolic regulation in complex biological systems. In the current work, a novel stable isotope N-phosphoryl amino acids labeling strategy (SIPAL) has been successful developed for quantitative profiling of amine-containing metabolites in urine based on organic phosphorus chemistry. Two isotopic reagents, 16O2- and 18O2-N-diisopropyl phosphoryl l-alanine N-hydroxysuccinimide esters (16O/18O-DIPP L-Ala-NHS), were firstly synthesized in high yields for labeling the amine containing metabolites. The performance of SIPAL strategy was tested by analyzing standard samples including 20 l-amino acids, 10 d-amino acids and small peptides by using LC-MS. We observed highly efficient and selective labeling for SIPAL strategy within 15 min in a one-pot derivatization reaction under aqueous reaction conditions. The introduction of a neutral phosphate group at N-terminus can increase the proton affinity and overall hydrophobicity of targeted metabolites, leading to the better ionization efficiency in electrospray ionization processes and chromatographic separations of hydrophilic metabolites on reversed-phase column. Furthermore, the chiral metabolites, such as d-amino acids, could be converted to diastereomers after SIPAL and successfully separated on regular reversed-phase column. The chirality of labeled enantiomers can be determined by using different detection methods such as 31P NMR, UV, and MS, demonstrating the potential application of SIPAL strategy. In addition, absolute quantification of chiral metabolites in biological samples can be easily achieved by using SIPAL strategy. For this purpose, urine samples collected from a healthy volunteer were analyzed by using LC-ESI-Orbitrap MS. Over 300 pairs of different amine-containing metabolites have been manually identified with high relative abundance (signal-to-noise ratios greater than 10). Finally, a standard peptide could be relatively quantified by using SIPAL strategy in combination with MALDI TOF MS, suggesting the potential application of this strategy for quantitative proteomics. PMID- 28595724 TI - Sol-gel coated ion sources for liquid chromatography-direct electron ionization mass spectrometry. AB - Advances in interfacing liquid chromatography and electron ionization mass spectrometry are presented. New ion source coatings synthesized by sol-gel technology were developed and tested as vaporization surfaces in terms of peak intensity, peak width and peak delay for the liquid chromatography-direct electron ionization mass spectrometry (Direct-EI) determination of environmental pollutants like polycyclic aromatic hydrocarbons and steroids. Silica-, titania-, and zirconia-based coatings were sprayed inside the stainless steel ion source and characterized in terms of thermal stability, film thickness and morphology. Negligible weight losses until 350-400 degrees C were observed for all the materials, with coating thicknesses in the 6 (+/-1)-11 (+/-2) MUm range for optimal ionization process. The best performances in terms of both peak intensity and peak width were obtained by using the silica-based coating: the detection of the investigated compounds was feasible at low ng MUl-1 levels with a good precision (RSD < 9% for polycyclic aromatic hydrocarbons and <11% for hormones). PMID- 28595725 TI - Ultrasensitive detection of nucleic acids and proteins using quartz crystal microbalance and surface plasmon resonance sensors based on target-triggering multiple signal amplification strategy. AB - In this study, quartz crystal microbalance (QCM) and surface plasmon resonance (SPR) sensors were combined with template enhanced hybridization processes (TEHP), rolling circle amplification (RCA) and biocatalytic precipitation (BCP) for ultrasensitive detection of DNA and protein. The DNA complementary to the aptamer was released by the specific binding of the aptamer to the target protein and then hybridized with the capture probe and the assistant DNA to form a ternary "Y" junction structure. The initiation chain was generated by the template-enhanced hybridization process which leaded to the rolling circle amplification reaction, and a large number of repeating unit sequences were formed. Hybridized with the enzyme-labeled probes, the biocatalytic precipitation reaction was further carried out, resulting in a large amount of insoluble precipitates and amplifying the detection signal. Under the optimum conditions, detection limits as low as 43 aM for target DNA and 53 aM for lysozyme were achieved. In addition, this method also showed good selectivity and sensitivity in human serum. PMID- 28595726 TI - FRET-based ratiometric fluorescent probe for Cu2+ with a new indolizine fluorophore. AB - A new fluorophore indolizine was synthesized and used as a donor to construct FRET system. The chemodosimeter shows a large Stokes shifts (193 nm), high sensitivity, and high selectivity. The probe can quickly (10 min) detect Cu2+ effectively in a wide pH range from 5 to 12 and with a detection limit as low as 9.1 * 10-9 M. Furthermore, it could be used for imaging Cu2+ in living Glioma cells which demonstrated its value of practical applications in biological systems. PMID- 28595727 TI - Alternate injections coupled with flow-gated capillary electrophoresis for rapid and accurate quantitative analysis of urine samples. AB - Capillary electrophoresis (CE) is a powerful separation technique with advantages over HPLC in terms of separation efficiency, speed, and cost. However, CE suffers in poor reproducibility in quantitative chemical analysis, which is one of major drawbacks preventing its widespread use in routine analytical laboratories. Here we report a novel strategy to enhance the quantitative capability of flow-gated CE. The platform integrated dual flow branches to respectively supply a sample and its standard additions that were then alternately injected into a single capillary for rapid separations (typically 20-90 s). A micro-fabricated switch was used to enable the alternate injections. It was assumed that the analytical system maintained constant conditions during neighboring injections that served as external self-standards for quantitation. This strategy was expected to reduce uncertainties caused by the fluctuation in capillary conditions and the drift of detection systems. Experimental results demonstrated that the dual-branch flow gated CE coupled with alternate injections significantly improved the reproducibility with respect to peak height ratios under deliberate variations in injection volumes, separation voltages, optical focusing, and laser power; and thus the interday precision was ensured. To demonstrate its applicability, cyanide and amino acids in human urine were quantified rapidly with the one-point standard addition method after fluorogenic derivatization with naphthalene-2,3 dicarboxaldehyde (NDA), and the measurement accuracy was validated by determining the recovery of standard cyanide added to a urinary matrix. This strategy would be valuable to enable the quantitative capability of flow-gated CE in the measurements of a broad range of analytes, especially those lacking suited internal standards. PMID- 28595728 TI - On-line double focusing of atenolol and metoprolol in human urine using capillary electrophoresis with the aid of beta-cyclodextrin. AB - A maneuverable and sensitive on-line double focusing technique combined field amplified sample stacking (FASS) with micelle to solvent stacking (MSS) with the aid of beta-cyelodextrin (beta-CD) is developed to detect the contents of AT and ME in human urine by capillary electrophoresis (CE) with UV detector. Small amount of beta-CD not only increase the critical micelle concentration (CMC) of SDS, but also strengthen the interaction between SDS and the aimed compound by forming inclusion complexes. The result indicates that the addition of beta-CD affords 5.5- and 3.5-fold improvements for atenolol (AT) and metoprolol (ME) in sensitivity than that of in the absence of beta-CD in the double focusing system, respectively. Under the optimal conditions, about 200-fold improvement in sensitivity for analytes is achieved compared with conventional CE method. The limits of detection (LODs) at a signal-to-noise of 3 (S/N = 3) of the two beta blockers can be reached 3.3 and 3.7 ng mL-1 respectively, which are lower than minimum required performance levels (MRPLs) set by the World Anti Doping Agency. The relative standard deviations (RSDs) of peak areas of intra-day and inter-day are 3.51-3.38% and 2.34-4.28% (n = 6), respectively. AT and ME in urine without special pretreatment and additional instrument are analyzed. The recoveries are 82-98% with RSDs less than 2.0%. PMID- 28595729 TI - Diagnostic value of a simplified Pfeiffer questionnaire for polypathological patients. AB - OBJECTIVES: To analyse the correlation, sensitivity, specificity and positive predictive (PPV) and negative predictive (NPV) values of each question on the Pfeiffer questionnaire (SPMSQ) compared with the full questionnaire for polypathological patients (PPPs). METHODS: Multicentre cross-sectional study. An SPMSQ score is considered pathological if 3 or more errors are recorded. For each question and combination of 2 questions, we calculated the correlation (kappa index), sensitivity, specificity and predictive values compared with the full SPMSQ. RESULTS: Of the 1632 PPPs included (mean age, 77.9+/-9.8 years, 53% men), 1434 performed the SPMSQ (the remaining presented delirium); 39% of the PPPs were pathological. The question "What day is it today?" and the command "Count backwards by 3s from 20" obtained good correlation and NPV (85 and 89%, respectively); the combination of both increased the NPV to 97%. The question "When were you born?' achieved good correlation and greater PPV (93%). CONCLUSIONS: The combination of the question "What day is it today?" and the command "Count backwards by 3s from 20" achieved a high NPV. The question related to the date of birth achieved the highest PPV. PMID- 28595731 TI - Single nucleotide polymorphisms in an Indian cohort and association of CNTN4, MMP2 and SNTB1 variants with oral cancer. AB - Oral cancer is a high incidence cancer in India primarily due to the prevalent tobacco/areca nut chewing habits and hence a major health concern. India constitutes 26% of the global oral cancer burden. Besides the well-established risk factors, the genomic constitution of an individual plays a role in oral cancer. The aim of the current study was to analyse genomic variants represented as single nucleotide polymorphisms (SNPs), analyse their prevalence and investigate risk association of allelotypes/genotypes to oral cancers. Eleven SNPs in genes associated with biological functions were analysed in an Indian cohort (n = 1000) comprising 500 oral cancer patients and 500 long term tobacco habitues as controls, using Allelic discrimination Real-Time PCR assay with SYBR Green dye. Fisher's exact test and Odds Ratio were used for statistical analysis. Increased risk was observed for rs9849237 CC [P = 0.008; OR 1.412 (1.09-1.82)] and rs243865 CT [P = 0.004; OR 1.469 (1.13-1.90)] genotypes, whereas rs9849237 CT [P = 0.034; OR 0.755 (0.58-0.97)], rs243865 CC [P = 0.002; OR 0.669 (0.51-0.86)] and rs10090787 CC [P = 0.049; OR 0.774 (0.60-0.99)] genotypes indicated decreased risk to oral cancer. The other SNPs showed equidistribution in both groups. Our data indicated genotypes and alleles in specific SNPs rs9849237, rs243865 and rs10090787 with increased/decreased risk to oral cancer. PMID- 28595730 TI - Recurrent large genomic rearrangements in BRCA1 and BRCA2 in an Irish case series. AB - Mutations in BRCA1 and BRCA2 confer a highly increased risk of cancers, mainly of the breast and ovary. Most variants are point mutations or small insertions/deletions detectable by Sanger sequencing. Large genomic rearrangements, including deletions/duplications of multiple exons, are not routinely detectable by Sanger sequencing, but can be reliably identified by Multiplex Ligation-dependent Probe Amplification (MLPA), and account for 5-17% mutations in different populations. Comprehensive mutation testing using these two methods has been facilitated via our centre since 2005. The aim of this study was to investigate the incidence of and phenotype associated with large genomic rearrangements in BRCA1 and BRCA2 in an Irish cohort. An observational cohort study was undertaken. Patients with large genomic rearrangements in BRCA1/BRCA2 were identified from a prospectively maintained database of MLPA test results. Phenotypic and genotypic data were retrieved by chart review. Large genomic rearrangements in BRCA1 were identified in 49 families; and in BRCA2 in 7 families, representing ~11% of mutations in BRCA1/BRCA2 in Ireland. The most common large genomic rearrangement in BRCA1 was deletion of exons 1-23 (11 families, 7 from Co. Galway). Other common mutations included deletions of exon 3 (8 families) and exons 1-2 (6 families). Deletion of exons 19-20 in BRCA2 represented the familial mutation in five families, all from East Ireland (Wexford/Wicklow/Dublin). It is evident that a significant proportion of highly penetrant pathogenic variants in BRCA1 and BRCA2 will be missed if testing is limited to PCR-based Sanger sequencing alone. Screening for large genomic rearrangements in BRCA1 and BRCA2 in the routine diagnostic workflow is critical to avoid false negative results. PMID- 28595732 TI - The novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in diffuse large B-cell lymphoma. AB - An 82-year-old woman presented with generalized lymphadenopathy and skin involvement. Lymph node biopsy revealed diffuse large B-cell lymphoma with a high proliferation index. G-banding and fluorescence in situ hybridization showed a hypertetraploid karyotype with two copies of t(8;22)(q24;q11), generating the fusion of MYC and the immunoglobulin lambda chain gene (IGL), and two copies of the novel immunoglobulin heavy chain gene (IGH) translocation, t(14;15)(q32;q24). A long-distance inverse polymerase chain reaction (PCR) using nested primer combinations designed for each constant gene of IGH showed that Cgamma4 was juxtaposed to the downstream sequence of the BCL2A1 (BCL2-related protein A1) gene through the Sgamma4 switch region. As a result of t(14;15)(q32;q24), BCL2A1 and IGH Sgamma4-Cgamma4 were aligned in the same transcriptional orientation at a distance of 64 kb. Reverse transcriptase-mediated PCR showed high BCL2A1 mRNA levels in a lymphoma specimen. Since BCL2A1, mapped at 15q24.3 or 15q25.1, encodes a protein that is an anti-apoptotic member of the BCL2 protein family, we herein described the novel double-hit, t(8;22)(q24;q11)/MYC-IGL and t(14;15)(q32;q24)/IGH-BCL2A1, in which BCL2A1 is considered to play a role equivalent to that of BCL2 in the most frequent double-hit, MYC/BCL2. PMID- 28595733 TI - A novel cytogenetic and molecular characterization of renal metanephric adenoma: Identification of partner genes involved in translocation t(9;15)(p24;q24). AB - Renal metanephric adenoma (MA) is a rare benign tumor frequently misclassified when microscopic features alone are applied. The correct classification of a renal tumor is critical for diagnostic, prognostic, and therapeutic purposes. Despite the advancements in cancer genomics, up until recently relatively few genetic alterations critical to MA development have been recognized. Recent data suggest that 90% of MA have BRAFV600E mutations; the genetics of the remaining 10% are unclear. To date, only one case of a chromosomal translocation, t(9;15)(p24;q24) associated with MA has been reported. However, the potential role of the KANK1 gene, which lies near the breakpoint of the short arm of chromosome 9p24, in the etiology of MA was not examined. We identified the same cytogenetic aberration utilizing molecular cytogenetic techniques in a 22-year old female patient, and further investigated the genes involved in the translocation that might have contributed to tumorigenesis. A series of fluorescence in situ hybridization (FISH) probes identified the rearranged genes to be KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3). Mate Pair genome sequencing validated the balanced translocation between 9p24.3 and 15q25.3, involving genes KANK1 and NTRK3, respectively. BRAFV600E mutational analysis was normal. Our findings indicate that gene fusions may be one mechanism by which functionally relevant genes are altered in the development of MA. Molecular and cytogenetic analyses have elucidated a novel genetic aberration, which helps to provide a better understanding of this genomic change and assist in diagnosis and classification of new subgroups/entities in metanephric adenomas. PMID- 28595734 TI - Ethics, big data and computing in epidemiology and public health. AB - PURPOSE: This article reflects on the activities of the Ethics Committee of the American College of Epidemiology (ACE). Members of the Ethics Committee identified an opportunity to elaborate on knowledge gained since the inception of the original Ethics Guidelines published by the ACE Ethics and Standards of Practice Committee in 2000. METHODS: The ACE Ethics Committee presented a symposium session at the 2016 Epidemiology Congress of the Americas in Miami on the evolving complexities of ethics and epidemiology as it pertains to "big data." This article presents a summary and further discussion of that symposium session. RESULTS: Three topic areas were presented: the policy implications of big data and computing, the fallacy of "secondary" data sources, and the duty of citizens to contribute to big data. A balanced perspective is needed that provides safeguards for individuals but also furthers research to improve population health. Our in-depth review offers next steps for teaching of ethics and epidemiology, as well as for epidemiological research, public health practice, and health policy. CONCLUSIONS: To address contemporary topics in the area of ethics and epidemiology, the Ethics Committee hosted a symposium session on the timely topic of big data. Technological advancements in clinical medicine and genetic epidemiology research coupled with rapid advancements in data networks, storage, and computation at a lower cost are resulting in the growth of huge data repositories. Big data increases concerns about data integrity; informed consent; protection of individual privacy, confidentiality, and harm; data reidentification; and the reporting of faulty inferences. PMID- 28595735 TI - Sex-specific associations of maternal birthweight with offspring birthweight in the Omega study. AB - PURPOSE: We investigated nonlinear and offspring sex-specific associations of maternal birthweight (BW) with offspring BW among participants of the Omega study, a pregnancy cohort. METHODS: Maternal BW was modeled as a continuous variable, linear spline and binary variable indicating low birthweight (LBW; <2500 vs. >=2500 grams). Offspring BW was modeled as a continuous and binary variable in regression models. Nonlinearity was assessed using likelihood ratio tests (LRTs) in marginal linear spline models. RESULTS: For every 100-gram increase of maternal BW, offspring BW increased by 22.29 (95% CI: 17.57, 27.02) or 23.41 (95% CI: 6.87, 39.96) grams among mothers with normal BW or born macrosomic, respectively, but not among LBW mothers (beta = -8.61 grams; 95% CI: 22.88, 5.65; LRT P-value = .0005). For every 100-gram increase in maternal BW, BW of male offspring increased 23.47 (95% CI: 16.75, 30.19) or 25.21 (95% CI: 4.35, 46.07) grams among mothers with normal BW or born macrosomic, respectively, whereas it decreased 31.39 grams (95% CI: -51.63, -11.15) among LBW mothers (LRT P-value < .0001). Corresponding increases in BW of female offspring (16-22 grams) did not differ among mothers with LBW, normal BW or macrosomia (LRT P-value = .9163). CONCLUSIONS: Maternal and offspring BW associations are evident among normal BW and macrosomic mothers. These associations differ by offspring sex. PMID- 28595736 TI - Age, gender, and socioeconomic gradients in metabolic syndrome: biomarker evidence from a large sample in Taiwan, 2005-2013. AB - PURPOSE: To examine the age and gender heterogeneities in the association between socioeconomic status (SES) and the risk of metabolic syndrome (MetS) with biomarker data from Taiwan. METHODS: Subjects included 102,201 men and 112,015 women aged 25 and above, from the 2005-2013 MJ Health Survey in Taiwan. SES was measured by education and family income. MetS was defined by the Adult Treatment Panel III criteria for Asian population. Logistic regression analyses were performed by age and gender groups. RESULTS: (1) Higher education level was associated with significantly lower risk of MetS. (2) Higher income was associated with lower MetS risk among women aged under 65, but no association among men of all ages. (3) SES gradients were generally much stronger among women than among men of the same age group. (4) SES gradients reduced over the life course with the exception that income gradient remains flat among men of all ages. CONCLUSIONS: Among Chinese in Taiwan, the gender and age heterogeneities in the SES gradients in MetS are similar to those reported for Western societies. This cross-cultural convergence is broadly consistent with the general hypothesis that social conditions are fundamental causes of diseases and health disparities. PMID- 28595739 TI - From the Editor. PMID- 28595738 TI - Role of alcohol and marijuana use in the initiation of fatal two-vehicle crashes. AB - PURPOSE: To assess individual and joint effects of alcohol and marijuana on the initiation of fatal two-vehicle crashes. METHODS: Data on 14,742 culpable drivers (initiators) and 14,742 nonculpable drivers (noninitiators) involved in the same fatal two-vehicle crashes between 1993 and 2014 were obtained from the Fatality Analysis Reporting System. Multivariable conditional logistic regression models were used to assess the association of driver use of alcohol, marijuana, or both with fatal crash initiation with adjustment for demographic variables. RESULTS: Initiators were significantly more likely than non-initiators to test positive for alcohol (28.3% vs. 9.6%, P < .0001), marijuana (10.4% vs. 6.0%, P < .0001), and both substances (4.4% vs. 1.1%, P < .0001). Relative to drivers testing negative for both alcohol and marijuana, the adjusted odds ratios of fatal crash initiation were 5.37 (95% confidence interval [CI]: 4.88 to 5.92) for those testing positive for alcohol and negative for marijuana, 1.62 (95% CI: 1.43 to 1.84) for those testing positive for marijuana and negative for alcohol, and 6.39 (95% CI: 5.19 to 7.88) for those testing positive for both alcohol and marijuana. CONCLUSIONS: Alcohol and marijuana each play a significant role in fatal crash initiation. When used in combination, alcohol and marijuana appear to have a positive interaction effect on the risk of fatal crash initiation on the additive scale. PMID- 28595737 TI - Weight gain during pregnancy and the black-white disparity in preterm birth. AB - PURPOSE: To quantify the relationship between pregnancy weight gain with early and late preterm birth and evaluate whether associations differed between non Hispanic (NH) black and NH white women. METHODS: We analyzed a retrospective cohort of all live births to NH black and NH white women in the United States 2011-2015 (n = 10,714,983). We used weight gain z-scores in multiple logistic regression models stratified by prepregnancy body mass index (BMI) and race to calculate population attributable risk (PAR) percentages for the contribution of high and low pregnancy weight gain to early and late preterm birth. RESULTS: Pregnancy weight gain was related to early and late preterm birth, but associations varied by BMI and race. For early preterm birth, the PAR percentage for high pregnancy weight gain ranged from 8 to 10% in NH black women and from 6 to 8% in NH white women. There was little evidence of racial differences in late preterm birth: PAR percentages ranged from 2 to 7% in NH black women and from 3 to 7% in NH white women. CONCLUSIONS: Moderate gestational weight gain is associated with lower rate of preterm birth, with greatest reductions for early preterm birth in NH black women. PMID- 28595740 TI - Response to letter to Editor "Lessons learned from the recent history of technologies for non-invasive estimation of aortic blood pressure using transfer functions and pulse wave analysis" by Papaioannou et al. PMID- 28595741 TI - Corrigendum to position statement: Political interference in sexual and reproductive health research and health professional education [Nursing Outlook 65/2 (2017) 242-245]. PMID- 28595743 TI - The role of the complement system in hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare, but potentially life-threatening disorder, characterized by acute, recurring, and self-limiting edematous episodes of the face, extremities, trunk, genitals, upper airways, or the gastrointestinal tract. HAE may be caused by the deficiency of C1-inhibitor (C1-INH-HAE) but another type of the disease, hereditary angioedema with normal C1-INH function (nC1-INH-HAE) was also described. The patient population is quite heterogeneous as regards the location, frequency, and severity of edematous attacks, presenting large intra- and inter-individual variation. Here, we review the role of the complement system in the pathomechanism of HAE and also present an overview on the complement parameters having an importance in the diagnosis or in predicting the severity of HAE. PMID- 28595742 TI - [Internal quality control on HER2 status determination in breast cancers: Experience of a cancer center]. AB - INTRODUCTION: The implementation of an internal quality control is mandatory to guarantee the accuracy of HER2 status in invasive breast cancers. OBJECTIVES: To evaluate the impact of our quality control assurance on HER2 status results in invasive breast carcinomas from 2008 to 2014. METHODS: HER2 status was determined by immunohistochemistry as the first-line indication, completed by fluorescence in situ hybridization (FISH) for scores 2+ by immunohistochemistry. Internal quality control of HER2 status relied on the standardization of pre-analytical phases, the use of external controls with a known number of HER2 gene copies determined by FISH and continued monitoring of concordance between immunohistochemistry and FISH. RESULTS: The proportion of HER2-positive cases corresponding to scores 3+ by immunohistochemistry and 2+ amplified by FISH varied from 10.6% to 13.8% (median of 11.3%). The proportion of scores 2+ amplified by FISH varied from 13.3% to 32.7% during period of study. The rate of concordance between FISH and immunohistochemistry for score 0/1+ and 3+ cases were>=97%. Eight among 12 discordant cases were false positive resulting from errors in interpretation of immunohistochemistry (score 2+ instead of 3+). DISCUSSION: Calibration of immunohistochemistry on FISH for HER2 status contributes to limit variability of immunohistochemistry results due to technical issues or interpretation. The implementation of an external control of score 3+ on each slide enables accurate interpretation of score 2+ and 3+ by immunohistochemistry. PMID- 28595745 TI - Antithrombotic regimens in patients with atrial fibrillation and coronary artery disease after percutaneous coronary intervention: A focused review. AB - Atrial fibrillation and coronary artery disease are common comorbidities with increasing incidences worldwide. About 5-15% of atrial fibrillation patients will require coronary stenting at some point in their lives, which necessitates dual antiplatelet therapy with aspirin and a P2Y12 antagonist. Triple therapy refers to the clinical scenario in which a patient is prescribed aspirin, P2Y12 antagonist, and oral anticoagulant, usually in the setting of atrial fibrillation. Current guidelines on atrial fibrillation do not offer strong recommendations on triple therapy management. Furthermore, the optimal duration of dual antiplatelet therapy after percutaneous coronary intervention is evolving based on contemporary research and development of newer generation drug eluting stents, changing the necessary duration of triple therapy in patients with atrial fibrillation. This review will offer an in-depth survey of current guidelines, current evidence, and future studies regarding triple therapy in atrial fibrillation patients undergoing percutaneous coronary intervention. PMID- 28595744 TI - Functional electrical stimulation improves quality of life by reducing intermittent claudication. AB - OBJECTIVE: To determine if Functional Electrical Stimulation (FES) would improve ischemic pain, walking distance, and quality of life of patients with intermittent claudication. DESIGN: Single blind, randomized block, two factorial design. PATIENTS: Patients diagnosed with Peripheral Artery Disease (PAD) and intermittent claudication (IC). Ankle Brachial Index ranged 0.4-0.9 on at least one leg. Patients were randomly assigned to experimental (FES+Walk, N=13) or control (WALK, N=14) groups. INTERVENTION: Experimental group patients received FES to the dorsiflexor and plantarflexor muscles while walking for 1h/day, six days/week for eight weeks. Control group patients received similar intervention without FES. A Follow-up period of both groups lasted eight weeks. OUTCOME MEASURES: Outcome measures were taken at baseline (T0), after intervention (T1), and after follow-up (T2). Primary measures included Perceived Pain Intensity (PPI), Six minute walk (6MW), and Peripheral Arterial Disease Quality of Life (PADQOL). Secondary measures included Intermittent Claudication Questionnaire (ICQ) and Timed Up and Go (TUG). RESULTS: Group by time interactions in PPI were significant (P<0.001) with differences of 27.9 points at T1 and 36.9 points at T2 favoring the FES+Walk group. Groups difference in Symptoms and Limitations in Physical Function of the PADQOL reached significance (T1=8.9, and T2=8.3 improvements; P=0.007). ICQ was significant (T1=9.3 and T2=13.1 improvements; P=0.003). Improvement in 6MW and TUG tests were similar between groups. CONCLUSIONS AND RELEVANCE: Walking with FES markedly reduced ischemic pain and enhanced QOL compared to just walking. FES while walking may offer an effective treatment option for the elderly with PAD and Intermittent Claudication. TRIAL REGISTRATION: NIH-NIA 1R21AG048001 https://projectreporter.nih.gov/project_info_description.cfm?aid=8748641&icde=306 5377&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC. https://clinicaltrials.gov/ct2/show/NCT02384980?term=David+Embrey&rank=1. PMID- 28595746 TI - Ratio of high-sensitivity troponin to creatine kinase-MB in takotsubo syndrome. AB - BACKGROUND: Takotsubo syndrome (TT) and myocardial infarction (MI) share numerous similarities in clinical presentation, ECG modifications and biomarker elevation. We sought to determine whether the ratio of high-sensitivity cardiac troponin T (hs-TnT) to the myocardial fraction of creatine kinase (CKMB) could be a potent discriminator between TT and MI patients. METHODS: We separately present analysis of data from retrospective files and prospectively recruited patients presenting with TT (35 retrospective and 42 prospective), NSTEMI (48 retrospective and 75 prospective) and STEMI (20 retrospective and 39 prospective). We compared ratios of hs-TnT to CKMB on admission to the hospital between TT, NSTEMI and STEMI patients. Receiver operating characteristic (ROC) curves were analysed to determine optimal cut-off values. RESULTS: On admission, hs-TnT/CKMB ratio was significantly higher in TT patients than in NSTEMI and STEMI patients in both the retrospective phase (median and interquartile range, TT 0.024 [0.018-0.047] vs NSTEMI 0.009 [0.006-0.022], p<0.0001; TT vs STEMI 0.011 [0.006-0.016], p=0.0002) and the prospective cohort (median and interquartile range, TT 0.032 [0.018 0.040] vs NSTEMI 0.009 [0.006-0.015], p<0.0001; TT vs STEMI 0.009 [0.005-0.017], p<0.0001). A cut-off hs-TnT/CKMB ratio of 0.015 distinguished TT from MI with a sensitivity of 85.7% and a specificity of 67.6% (AUC 0.796; 95%CI: 0.71-0.89) in the retrospective phase. In the prospective phase, a ratio of 0.017 distinguished TT from MI with a sensitivity of 83.3% and a specificity of 78.1% (AUC 0.88; 95%CI: 0.83-0.94). CONCLUSION: hs-TnT/CKMB ratio is a novel, readily available parameter that could be used alongside clinical risk scores, other biomarkers and ECG findings to discriminate between TT and MI. PMID- 28595747 TI - Transcathether aortic valve implantation with the new repositionable self expandable Evolut R versus CoreValve system: A case-matched comparison. AB - BACKGROUND: Despite promising results following transcatheter aortic valve implantation (TAVI), several relevant challenges still remain. To overcome these issues, new generation devices have been developed. The purpose of the present study was to determine whether TAVI with the new self-expanding repositionable Evolut R offers potential benefits compared to the preceding CoreValve, using propensity matching. METHODS: Between June 2007 and November 2015, 2148 consecutive patients undergoing TAVI either CoreValve (n=1846) or Evolut R (n=302) were prospectively included in the Italian TAVI ClinicalService(r) project. For the purpose of our analysis 211 patients treated with the Evolut R were matched to 211 patients treated with the CoreValve. An independent core laboratory reviewed all angiographic procedural data and an independent clinical events committee adjudicated all events. RESULTS: Patients treated with Evolut R experienced higher 1-year overall survival (log rank test p=0.045) and a significantly lower incidence of major vascular access complications, bleeding events and acute kidney injury compared to patients treated with the CoreValve. Recapture manoeuvres to optimize valve deployment were performed 44 times, allowing a less implantation depth for the Evolut R. As a consequence, the rate of more than mild paravalvular leak and new permanent pacemaker was lower in patients receiving the Evolut R. CONCLUSION: In this matched comparison of high surgical risk patients undergoing TAVI, the use of Evolut R was associated with a significant survival benefit at 1year compared with the CoreValve. This was driven by lower incidence of periprocedural complications and higher rates of correct anatomic positioning. PMID- 28595748 TI - The Thrill of Discovery: A Personal Scientific Autobiography. PMID- 28595749 TI - Negative Emotional Verbal Memory Biases in Mild Cognitive Impairment and Late Onset Depression. AB - OBJECTIVE: Early and preferential targeting of limbic structures by Alzheimer disease (AD)-related pathology suggests emotion dysregulation may serve as a marker of AD risk. We studied emotional verbal memory in two groups at risk for AD, amnestic mild cognitive impairment (aMCI) and late-onset depression (LOD), to test the hypothesis that aMCI and LOD would be characterized by a negative bias in emotional memory, whereas cognitively normal (CN) adults would show the "positivity effect" associated with healthy aging. METHODS: Participants completed a novel test of emotional verbal memory, the Emotional Verbal Learning Test (EVeLT), consisting of a 15-item list of words with positive, negative, or neutral valence. Recall as a function of group and valence was analyzed using mixed analysis of variance. Spearman's rho was used to examine associations between EVeLT, mood, and executive function. MCI and CN participants had no current or past history of mood or anxiety disorders. aMCI participants met neuropsychological criteria for single-domain aMCI (sd-aMCI). LOD developed their first episode of depression at >=60 years of age. RESULTS: CN adults recalled more positive words, whereas sd-aMCI and LOD adults recalled more negative, relative to neutral, words on the EVeLT. Positive emotional memory and negative attitudes regarding self were inversely correlated in CN adults. CONCLUSION: sd aMCI and LOD groups show negative emotional memory biases, consistent with our hypothesis that emotion dysregulation is a signature of AD risk. PMID- 28595750 TI - The TNF-alpha of mast cells induces pro-inflammatory responses during infection with Acinetobacter baumannii. AB - Mast cells serve important roles as sentinels against bacterial infection by secreting mediators stored in granules. Much of their effectiveness depends upon recruiting and/or modulating other immune cells. The location of mast cells implies that they recognize pathogens invading tissues or mucosal tissues. Acinetobacter baumannii is a gram-negative bacterium that is considered an emerging nosocomial pathogen and causes a wide range of infections associated with high morbidity and mortality. To date, the interaction of A. baumannii with mast cells remains unclear. In this study, we demonstrated an interaction between human LAD2 mast cells and A. baumannii in vitro. When LAD2 cells were co-cultured with live A. baumannii or Pseudomonas aeruginosa PAO1 in vitro for 4h, TNF-alpha and IL-8 were produced in the culture supernatant. These inflammatory cytokines were not detected in the supernatant after the cells were treated with live bacteria without serum. Gene expression analysis showed that TNF-alpha and IL-8 mRNA expression increased in A. baumannii- and P. aeruginosa-infected LAD2 cells. Scanning electron microscopy showed that A. baumannii was tightly attached to the surface of LAD2 cells and suggested that A. baumannii may bind to FcgammaRII (CD32) on LAD2 cells. TNF-alpha in the culture supernatant from A. baumannii infected LAD2 cells, showed that PMN activation and migration increased in Boyden chamber assays. These results suggest that mast cells recognize and initiate immune responses toward A. baumannii by releasing the preformed mediator TNF alpha to activate effector neutrophils. PMID- 28595751 TI - Pancreas transplantation: 50 years of experience. AB - In December 1966, the first pancreas transplant ever was performed at the University of Minnesota. R. Lillehei and W. Kelly, transplanted a kidney and a pancreas in a diabetic patient on dialysis, getting function of both organs. Since then, the technical and immunological advances in this transplant have resulted in graft and patient survival results as the rest of the abdominal solid organ transplants. The balance of these 50 years is that more than 50,000 diabetic patients have been transplanted in more than 200 centers around the world. In our country the first transplant was performed 34 years ago in Barcelona and now 12 centers perform about 100 transplants per year. Although advances in diabetes control have been very important, pancreas transplantation continues to be the only method that allows normalization of the carbohydrates metabolism to improve the quality of life and, above all, to increase the survival of these patients. PMID- 28595753 TI - Screening of obstructive sleep apnea by STOP-BANG questionnaire in patients with epilepsy. PMID- 28595754 TI - The STOP-BANG questionnaire improves the detection of epilepsy patients at risk for obstructive sleep apnea. PMID- 28595752 TI - Improved outcome of 131I-mIBG treatment through combination with external beam radiotherapy in the SK-N-SH mouse model of neuroblastoma. AB - PURPOSE: To assess the efficacy of different schedules for combining external beam radiotherapy (EBRT) with molecular radiotherapy (MRT) using 131I-mIBG in the management of neuroblastoma. MATERIALS AND METHODS: BALB/c nu/nu mice bearing SK N-SH neuroblastoma xenografts were assigned to five treatment groups: 131I-mIBG 24h after EBRT, EBRT 6days after 131I-mIBG, EBRT alone, 131I-mIBG alone and control (untreated). A total of 56 mice were assigned to 3 studies. Study 1: Vessel permeability was evaluated using dynamic contrast-enhanced (DCE)-MRI (n=3). Study 2: Tumour uptake of 131I-mIBG in excised lesions was evaluated by gamma-counting and autoradiography (n=28). Study 3: Tumour volume was assessed by longitudinal MR imaging and survival was analysed (n=25). Tumour dosimetry was performed using Monte Carlo simulations of absorbed fractions with the radiation transport code PENELOPE. RESULTS: Given alone, both 131I-mIBG and EBRT resulted in a seven-day delay in tumour regrowth. Following EBRT, vessel permeability was evaluated by DCE-MRI and showed an increase at 24h post irradiation that correlated with an increase in 131I-mIBG tumour uptake, absorbed dose and overall survival in the case of combined treatment. Similarly, EBRT administered seven days after MRT to coincide with tumour regrowth, significantly decreased the tumour volume and increased overall survival. CONCLUSIONS: This study demonstrates that combining EBRT and MRT has an enhanced therapeutic effect and emphasizes the importance of treatment scheduling according to pathophysiological criteria such as tumour vessel permeability and tumour growth kinetics. PMID- 28595755 TI - Generic antiepileptic drug equivalence: The journey from anecdotes to evidence. PMID- 28595757 TI - Commentary: Forced thinking about hypercognitive seizures. PMID- 28595756 TI - Impact of generic substitution on levetiracetam serum concentration-A prospective study in an outpatient setting. AB - BACKGROUND: Switching patients from a branded antiepileptic drug (AED) to a generic is often challenging. Several studies have shown that considerable proportions of patients report deteriorated seizure control or increased adverse effects, enforcing a switchback to the original drug. Since tolerability and seizure control usually correlate with AED serum concentrations, we examined the fluctuation of levetiracetam (LEV) serum concentrations in patients with epilepsy before and after generic substitution. METHODS: This was an 18-week, naturalistic, open, prospective, two-center study. After a baseline period of 10 weeks, 33 outpatients on stable treatment with branded LEV (Keppra(r)) either continued with this product or were switched overnight to a generic LEV preparation (1A Pharma) for an eight-week study period. Throughout the study, patients were monitored with bi-weekly LEV serum concentration measurements and seizure diaries. RESULTS: 16 out of 33 patients were switched to a generic LEV product. No switchbacks were seen. LEV dose, LEV serum concentrations, fluctuation index and concentration/dose-ratio (C/D-ratio) were not significantly different within-group (baseline vs. study period) or between-group. Large within subject variability in serum concentrations was seen in both groups. None of the patients that were seizure-free before inclusion experienced seizures while on the generic LEV product. CONCLUSIONS: Our results show equal fluctuation of LEV serum concentrations with branded LEV and the generic LEV. Most importantly, within-subject variability was much larger than the small, non-significant differences between brands. PMID- 28595759 TI - What is "Healing"?: Reflections on Diagnostic Criteria, Nosology, and Etiology. AB - This article examines the conceptual history and contemporary usages of the term "healing." In response to longstanding definitional ambiguity, reflections are offered on what are termed the diagnostic criteria, nosology, and etiology of healing. First, a summary is provided of how healing has been defined within medicine. Second, the dimensionality of healing is discussed. Third, healing's putative determinants are outlined. For biomedicine, healing mainly concerns repair of wounds or lesions and is unidimensional. For complementary medicine, by contrast, healing has been defined alternatively as an intervention, an outcome, and a process-or all of these at once-and is multidimensional, impacting multiple systems from the cellular to the psychosocial and beyond. Notwithstanding these usages, a review of medical texts reveals that healing is rarely defined, nor is its dimensionality or determinants described. Persistent lack of critical attention to the meaning of "healing" has implications for medical research and practice. PMID- 28595758 TI - Hypercognitive seizures - Proposal of a new term for the phenomenon forced thinking in epilepsy. AB - Here we propose the term hypercognitive seizures as a descriptor for seizures that manifest as a transient mental experience of intrusive thoughts or words that do not consist mainly of reminiscence. Currently, the term forced thinking is used to describe this uncommon seizure semiology, which has also been elicited by electrical brain stimulation. The available literature on forced thinking shows discordant interpretations of its meaning, justifying the suggestion of a new descriptor. In this paper, we would like to suggest and explain the term hypercognitive seizure and argue that this type of seizure lateralizes to the dominant hemisphere. PMID- 28595760 TI - Reflections on Healing from a Nursing Perspective. PMID- 28595761 TI - Occurrence of malignant neoplasia in patients with primary hyperparathyroidism. PMID- 28595762 TI - The use of nutritional risk screening 2002 to predict prognosis in hospitalized patients with chronic obstructive pulmonary disease with respiratory failure. PMID- 28595763 TI - Checklist-Based Assessment of Procedural Skills: A Missing Piece in the Link between Medical Education Interventions and Patient Outcomes. PMID- 28595765 TI - Muehrcke Lines in an Infant. PMID- 28595764 TI - Food Allergy and Anxiety and Depression among Ethnic Minority Children and Their Caregivers. AB - OBJECTIVE: To investigate the relationship between food allergy and symptoms of anxiety and depression among ethnic minority, low socioeconomic status (SES) children and their caregivers. STUDY DESIGN: Pediatric patients ages 4-12 years with and without food allergy and their caregivers were recruited from urban pediatric outpatient clinics. Statistical analyses were used to examine the prevalence of symptoms of anxiety and depression among patients and their caregivers with and without food allergy, adjusting for asthma. RESULTS: Eighty patients ranging from ages 4 to 12 years, with a mean age of 8.1 years, and their caregivers participated in the study. Food allergy was associated with significantly higher t scores on the Multidimensional Anxiety Scale for Children (MASC) Total (P = .007), MASC Humiliation Rejection, (P = .02) and MASC Social Anxiety (P = .02) among pediatric patients, adjusting for asthma. Food allergy was not associated with child depression symptoms, nor was there a significant difference in anxiety or depression symptoms among caregivers of patients with and without food allergy. CONCLUSIONS: Food allergy appears to be associated with increased symptoms of social anxiety and higher levels of anxiety overall, but not depression, in ethnic minority children of lower socioeconomic status. This finding was not due to confounding by asthma. Food allergy was not associated with higher levels of depression or anxiety symptoms among caregivers of pediatric patients with food allergy. Future studies should investigate potential pathways between food allergy and anxiety that may be unique to children in underserved populations, and develop interventions to reduce anxiety in children with food allergy. PMID- 28595767 TI - Learning from Others: Child Health and the European Observatory on Health Systems and Policies. PMID- 28595766 TI - Improving Universal Pediatric Lipid Screening. AB - OBJECTIVE: To evaluate whether the release of national guidelines, electronic health record (EHR) modifications, and educational initiatives correlated with changes in pediatricians' universal lipid screening practices. STUDY DESIGN: Retrospective review of EHRs in an academic general pediatric practice was performed to measure the prevalence of order placement. A child was "screened" if an order was placed during a well-visit between 9 and 21 years of age. The prevalence of order placement for lipid screens on 22 374 patients from January 2010 to December 2015 was analyzed for date of order and patient age, then compared with timing of guidelines, local educational initiatives, and EHR modifications. Primary study outcome was lipid screening order placement over time. RESULTS: Order placement increased from 8.9% (95% CI 8.3%-9.5%) before any intervention to 50.0% (95% CI 48.8%-51.2%) over the last 12 months of the study period (P < .001). All age groups showed significant increases in order placement. Changes in screening were seen following guideline publications, educational initiatives, and EHR modifications (for all, P < .0001). Order completion was 69.6% (95% CI 68.9%-70.3%). The composite prevalence of screening (order placement multiplied by order completion) was 46.8% over the 6-year study period. CONCLUSIONS: Improved adherence to recommendations for universal lipid screening is possible through educational initiatives and EHR modifications. Inclusion of 12- to 16-year-old adolescents/teenagers as a targeted group for universal screening in addition to recommended age groups improved screening prevalence. Similar efforts could be applicable for implementation of other guidelines. PMID- 28595768 TI - The Pediatric Primary Care-Specialist Interface: A Call For Action. PMID- 28595769 TI - Loiasis, a Subconjunctival Manifestation. PMID- 28595770 TI - Influence of breastfeeding and iron status on mental and psychomotor development during the first year of life. AB - Breastfeeding (BF) confers numerous benefits on the developing infant in both the short and the long term including psychological development, but there are multiple other factors that must be taken into account when these relationships are studied. To analyse how breastfeeding during the first 4 months of life affects infant mental and psychomotor development (MPD) at 6 and 12 months in a group of healthy infants from a Mediterranean Spanish city considering many important potential confounds. This is a longitudinal study conducted on infants from birth until the age of 12 months. A total of 154 healthy infants were evaluated by Paediatric Unit of Sant Joan University Hospital in Reus, Spain. Type of feeding, clinical history, anthropometry, iron status and mental and psychomotor development were assessed and analysed. At 4 months, 24% of infants received BF and 26% received mixed feeding (MF). Multiple Linear Regression models were applied adjusting for potential prenatal, perinatal and postnatal confounds showing that infants who received BF for at least four months presented higher psychomotor development index (PDI) at 6 and at 12 months of age. Also, gestational age and BMI at 6m were associated positively with PDI at 6 m, and haemoglobin levels at 12m and birth height were associated with PDI and MDI at 12m (respectively). In conclusion, after the adjustment of important potential confounds, BF during at least four months and adequate infant iron status are related to better psychomotor development during the first year. No associations were found between BF and mental development. PMID- 28595771 TI - Patient Participation, Engagement and Activation: Increased emphasis on the role of patients in healthcare. PMID- 28595772 TI - Prevention of early complications and late consequences after acute pulmonary embolism: Focus on reperfusion techniques. AB - Pulmonary embolism (PE) is a major cause of acute cardiovascular mortality and long-term morbidity. Right ventricular (RV) dysfunction is the key determinant of prognosis in the acute phase of PE, and residual RV dysfunction is associated with the development of post-PE functional impairment, chronic thromboembolic disease, and higher costs of treatment over the long term. Patients with clinically overt RV failure, i.e. hemodynamic collapse at presentation (high-risk PE), necessitate immediate thrombolytic treatment to relieve the obstruction in the pulmonary circulation; surgical or catheter-directed removal of the thrombus can be an alternative option. For patients with a high risk of bleeding or active hemorrhage, or for normotensive patients with intermediate-risk PE, systemic (intravenous) standard-dose thrombolysis is not recommended since the risks of treatment outweigh its benefits. In such cases, rescue thrombolysis should be considered only if hemodynamic decompensation develops while on heparin anticoagulation. For survivors of acute PE, little is known on the possible effects of thrombolytic treatment on the risk of chronic functional and hemodynamic impairment. Catheter-directed, ultrasound-assisted, low-dose thrombolysis leads to recovery of RV dysfunction, and its safety profile appears promising. However, adequately powered prospective trials focusing on both short- and long-term clinical outcomes are needed to establish novel interventional techniques in the treatment of PE. PMID- 28595774 TI - Feasibility of using single photon counting X-ray for lung tumor position estimation based on 4D-CT. AB - PURPOSE: In stereotactic body radiation therapy of lung tumors, reliable position estimation of the tumor is necessary in order to minimize normal tissue complication rate. While kV X-ray imaging is frequently used, continuous application during radiotherapy sessions is often not possible due to concerns about the additional dose. Thus, ultra low-dose (ULD) kV X-ray imaging based on a single photon counting detector is suggested. This paper addresses the lower limit of photons to locate the tumor reliably with an accuracy in the range of state-of-the-art methods, i.e. a few millimeters. METHOD: 18 patient cases with four dimensional CT (4D-CT), which serves as a-priori information, are included in the study. ULD cone beam projections are simulated from the 4D-CTs including Poisson noise. The projections from the breathing phases which correspond to different tumor positions are compared to the ULD projection by means of Poisson log-likelihood (PML) and correlation coefficient (CC), and template matching under these metrics. RESULTS: The results indicate that in full thorax imaging five photons per pixel suffice for a standard deviation in tumor positions of less than half a breathing phase. Around 50 photons per pixel are needed to achieve this accuracy with the field of view restricted to the tumor region. Compared to CC, PML tends to perform better for low photon counts and shifts in patient setup. Template matching only improves the position estimation in high photon counts. The quality of the reconstruction is independent of the projection angle. CONCLUSIONS: The accuracy of the proposed ULD single photon counting system is in the range of a few millimeters and therefore comparable to state-of the-art tumor tracking methods. At the same time, a reduction in photons per pixel by three to four orders of magnitude relative to commercial systems with flatpanel detectors can be achieved. This enables continuous kV image-based position estimation during all fractions since the additional dose to the patient is negligible. PMID- 28595773 TI - Endoscopic endonasal management of esthesioneuroblastoma: A retrospective multicenter study. AB - OBJECTIVE: The aim of the present study was to illustrate the safety and utility of the endoscopic endonasal approach (EEA) for the treatment of esthesioneuroblastomas (ENB). METHODS: We retrospectively reviewed patients with a diagnosis of ENB between March 2008 and February 2016 at 10 tertiary referral hospitals in Japan, and assessed demographic data, stage of disease, surgical approach, outcomes and postoperative complications. RESULTS: A total of 22 patients (10 males and 12 females; mean age at presentation, 49.0 years) underwent endoscopic endonasal resection of newly diagnosed ENBs. Dulguerov staging at presentation was T1, 6 patients; T2, 9 patients; T3, 5 patients; and T4, 2 patients. As surgical procedures, unilateral resection via EEA was performed in 12 patients aiming preservation of the contralateral olfactory system, and bilateral resection via EEA was done in 10 patients. Post-operative radiotherapy was done in 20 patients. Pathological margin studies revealed margin free resections in 21 patients (95.5%). The mean period of follow-up was 44 months. Local recurrence was observed in one T2 patient 12 months after bilateral resection. All patients were alive at the last follow-up, and 21 patients showed no evidence of disease. No post-operative complications including bleeding, CSF leak and meningitis were identified. Preservation of olfactory function was achieved in 11 patients (91.7%). CONCLUSION: The results of the present study indicate the safety and utility of multilayer resection using EEA for treatment of ENBs. PMID- 28595775 TI - Surface dose measurements in and out of field: Implications for breast radiotherapy with megavoltage photon beams. AB - This study examines the difference in surface dose between flat and flattening filter free (FFF) photon beams in the context of breast radiotherapy. The surface dose was measured for 6MV, 6MV FFF, 10MV, 10MV FFF and 18MV photon beams using a thin window ionisation chamber for various field sizes. Profiles were acquired to ascertain the change in surface dose off-axis. Out-of-field measurements were included in a clinically representative half beam block tangential breast field. In the field centres of FFF beams the surface dose was found to be increased for small fields and decreased for large fields compared to flat beams. For FFF beams, surface dose was found to decrease off-axis and resulted in lower surface dose out-of-field compared to flat beams. PMID- 28595776 TI - Filamin A promotes efficient migration and phagocytosis of neutrophil-like HL-60 cells. AB - The primary defense machinery to combat inflammation involves neutrophil granulocytes which in order to execute their functions rely on the efficiency of different cellular mechanisms including adhesion, spreading, migration in different environments, and phagocytosis. These functions require an accurately regulated actin network as well as the activation and adjustment of various signaling pathways. Mammalian filamins (FLNs) comprise three highly homologous large actin-binding proteins that are obvious candidates to control these processes as FLNs have been described to play a role in migration, spreading and adhesion in a variety of different cell types. The present study analyzed the role of filamin A (FLNa) in human neutrophil-like HL-60 cells. We found a strong enrichment of FLNa at the uropod of migrating neutrophils, and show that deficiency of FLNa caused a decrease in speed of migration both in 2D and 3D that is accompanied by a reduced activation of myosin-II. In addition, we show that FLNa plays a role in neutrophil phagocytosis. We also identified a hitherto unknown interaction of FLNa with coronin 1A that is mediated by FLNa repeats 9 18. FLNa deficiency had no or only minor effects on cell adhesion and spreading. In summary, deficiency of FLNa in human neutrophil-like HL-60 cells resulted in a surprisingly subtle phenotype. Our data indicate that FLNa is not essential for the regulation of mechanical properties during migration, but contributes to motility in a modulatory manner probably through its action at the uropod. PMID- 28595777 TI - Disseminated Cryptococcus deuterogattii (AFLP6/VGII) infection in an Arabian horse from Dubai, United Arab Emirates. AB - BACKGROUND: During the past decades there has been an increase in cryptococcal infections caused by the basidiomycetous yeast species Cryptococcus gattii sensu lato, among humans and animals that live in endemic regions in Australia, Europe and the Americas. Unlike human cryptococcosis, little epidemiological data are available about C. gattii sensu lato infections in horses. CASE REPORT: A fatal case of a disseminated C. gattii sensu lato infection in an 11-year-old Arabian gelding imported from South Africa into the United Arab Emitares is reported. Tissue samples were studied by conventional mycology procedures and the obtained cryptococcal isolate was molecularly characterized by mating-type determination, amplified fragment length polymorphism (AFLP) fingerprinting, and multi-locus sequence typing (MLST). Phylogenetic analysis was performed to investigate the geographic origin of the cryptococcal isolate. The isolate was identified as Cryptococcus deuterogattii (AFLP6/VGII), mating-type alpha. Phylogenetic analysis showed that it was closely related to another C. deuterogattii isolate from the Middle East. CONCLUSIONS: A second case of a C. deuterogattii infection in the Middle East is described. It is likely that the horse acquired the infection in the Middle East, as the isolate is closely related to that of a recent human case from that region. PMID- 28595779 TI - Commentary on "Multi-Centre Study on Cardiovascular Risk Management in Patients Undergoing AAA Surveillance". PMID- 28595778 TI - An Unusual Cause of Recurrent Vomiting. PMID- 28595780 TI - The beneficial effects of zinc on diabetes-induced kidney damage in murine rodent model of type 1 diabetes mellitus. AB - Diabetes mellitus is a chronic multi-factorial metabolic disorder resulting from impaired glucose homeostasis. Zinc is a key co-factor for the correct functioning of anti-oxidant enzymes. Zinc deficiency therefore, impairs their synthesis, leading to increased oxidative stress within cells. Zinc deficiency occurs commonly in diabetic patients. The aim of this study is to investigate the effects of varying concentrations of zinc on diabetic nephropathy (DN) and the underlying mechanisms involved. FVB male mice aged 8 weeks were injected intraperitoneally with multiple low-dose streptozotocin at a concentration of 50mg/kg body weight daily for 5 days. Diabetic and age-matched control mice were treated with special diets supplemented with zinc at varying concentrations (0.85mg/kg, 30mg/kg, 150mg/kg) for 3 months. The mice were fed with zinc diets to mimic the process of oral administration of zinc in human. Zinc deficiency to some extent aggravated the damage of diabetic kidney. Feeding with normal (30mg/kg zinc/kg diet) and especially high (150mg/kg zinc/kg diet) concentration zinc could protect the kidney against diabetes-induced damage. The beneficial effects of zinc on DN are achieved most likely due to the upregulation of Nrf2 and its downstream factors NQO1, SOD1, SOD2. Zinc upregulated the expression of Akt phosphorylation and GSK-3beta phosphorylation, resulting in a reduction in Fyn nuclear translocation and export of Nrf2 to the cytosol. Thus, regular monitoring and maintaining of adequate levels of zinc are recommended in diabetic individuals in order to delay the development of DN. PMID- 28595781 TI - Comparison of the effect of dietary copper nanoparticles with copper (II) salt on bone geometric and structural parameters as well as material characteristics in a rat model. AB - Copper is required for normal functioning of all basic biochemical and physiological processes in the body. The objective of this study was to compare the effect of two different chemical forms (carbonate and nanoparticles) of Cu administered in feed mixtures to growing rats on bone geometric and structural parameters as well as material characteristics in a rat model. For this purpose, five experimental treatments were used to evaluate the effects of different levels of Cu applied in the diet as a mineral mixture (the standard dose of 6.5mg/kg diet, half the standard dose, and no Cu in mineral mixture as a negative control) and two Cu sources (CuCO3 - commonly used in rodent laboratory diets and a Cu-NP nanoparticle preparation, 40nm). There were no changes in body weight and bone morphology, but significant alteration was noted in the geometry and mechanical parameters, which was Cu-NP-dose dependent. Our study showed an increase in the ultimate load and toughness in Cu-NP-treated rats at the standard concentration. The higher values of the studied parameters prove that there was a change in bone mineralization. Although bone mineral density and content were not changed, bone tissue density and ash increased. The XRD analysis revealed that some peaks did not originate from hydroxyapatite, and they indicated existence of other mineral phases. No studies conducted so far have provided a detailed mechanical X-ray diffraction analysis of bone tissue of growing rats administered with diet containing Cu nanoparticles. This study showed that Cu-NP given in low dose increased mechanical endurance of bone, without the changes in strain and stress compared to low dose of Cu given in traditional form. PMID- 28595782 TI - Hair for a long-term biological indicator tissue for assessing the strontium nutritional status of men and women. AB - Strontium (Sr) is a trace element that closely resembles calcium metabolism. At the present time there is no available long-term biological indicator tissue for assessing the human Sr nutritional status. Here we have presented a novel concept on how to assess the Sr nutritional status by studying the frequency distribution properties of hair Sr (SrH) concentration. In this prospective, observational, cross-sectional, and exploratory epidemiological study, we analyzed SrH in 311 apparently healthy adult Croatians (123 men, 188 women). Hair strontium was analyzed by the ICP-MS. The natural frequency distribution of SrH followed the Power law, so that the data were analyzed by fitting the logistic bioassay sigmoid curve (ogive) of median derivatives. Women tend to accumulate three and a half time more SrH than men (median men 867ngg-1 vs. median women 3120ngg-1). The normal (adequate) linear physiological response range of the sigmoid curve was 351-3489ngg-1 for men and 846-8457ngg-1 for women. Values below that linear range are considered to indicate deficient Sr nutritional status, whereas values above that linear range indicate excessive strontium exposure. Hair, as a long-term, and whole blood as a short-term biological indicator tissues were not commensurable entities. Similarly, SrH accumulation was not age dependent in either men or women. Hair strontium is a reliable long-term biological indicator tissue for assessing the strontium nutritional status. PMID- 28595783 TI - Subcellular distribution of hepatic copper in beef cattle receiving high copper supplementation. AB - Previous studies of intensively reared cattle in NW Spain have reported significantly higher copper (Cu) accumulation in the liver in Holstein-Friesian (HF) animals than in Galician Blonde (GB) or GBxHF crosses when receiving a diet supplemented at the maximum Cu concentrations allowed in the EU legislation (35mg/kg). The present study aimed to evaluate whether this difference is due to the pattern of subcellular accumulation of Cu in the liver. For this purpose, liver samples from 10 GB, 9 HF and 10 GBxHF young bulls were analysed to determine the content of metallothionein (MT) and Cu and zinc (Zn) (in the liver (Cu-liver and Zn-liver) and bound to metallothionein (Cu-MT and Zn-MT)). The Cu distribution within the main subcellular compartments (nuclei, large granule, microsomes and cytosol) was also determined. Even though HF animals showed significantly higher (P<0.05) Cu concentrations in the liver (161+/-10mg/kg wet weight) compared with GB (132+/-8mg/kg), no breed-related differences were observed for any of the parameters considered in this study. Overall, the pattern of hepatic subcellular accumulation was similar to that previously described in cattle: (i) MT concentrations were lower than in other animal species but strongly related to hepatic Zn; (ii) a low proportion of Cu (6.61%) was bound to MT but this was strongly and negatively related to the Cu:Zn ratio in the liver cell; and (iii) the highest proportion of Cu (57.3%) was found in the large granule (lysosome containing) fraction. All these results indicate a low capacity of cattle to excrete Cu by the bile resulting in a high Cu accumulation in the liver cell. PMID- 28595784 TI - Cadmium triggers mitochondrial oxidative stress in human peripheral blood lymphocytes and monocytes: Analysis using in vitro and system toxicology approaches. AB - Cadmium (Cd) is a well-known heavy metal that causes environmental pollution and human health problems. Several studies attempted to assess Cd toxicity in vitro and in vivo. However, the systemic profile of cadmium toxicity has not been studied well. In the present study, we assessed the toxicity of Cd on human peripheral blood lymphocytes and monocytes and gene expression, using a system toxicological approach. Cd effect on cell viability and morphology were analyzed by MTT assay and AO/EB staining respectively. Mitochondrial membrane potential depletion and reactive oxygen singlet generation were assessed by flow cytometry. Effects of Cd treatment on gene expression were also studied. Significant reduction in cell viability and disintegration of nuclear morphology were observed in Cd-treated cells. Cd exposure enhanced the loss of mitochondrial membrane potential through oxidative stress. Dose-dependent upregulation of GSTM3 and downregulation of GSR gene expression were observed. TNF gene expression decreased as the level of Cd exposure increased. We analyzed the toxicological effects of Cd on more than 45 proteins for biological target identification. These system toxicological studies suggested that Cd induced toxicity through various biological processes such as oxidative stress, oxidation-reduction, and ROS and hydrogen peroxide generation. Additionally, Cd affects the cellular component network and modulates the expression level of oxidative stress-related genes. PMID- 28595785 TI - Comparative study of cardio-protective effects of zinc oxide nanoparticles and zinc sulfate in streptozotocin-induced diabetic rats. AB - The cardio-protective effects of zinc oxide nanoparticles (Zn NPs) against diabetes-induced cardiopathy were evaluated and compared with zinc sulfate (ZnSO4). A total of 120 Wistar rats were randomly categorized as healthy and diabetic groups. Then, the 2 groups were classified in 5 subgroups. The animals received oral supplementations containing different Zn NP (ie, doses of 1, 3, and 10mg/kg) and ZnSO4 (30mg/kg) concentrations over 8 weeks. Blood and cardiac tissue samples were collected in the different time intervals and subjected to biochemical and histopathological analysis. Zn NPs showed dual effects, as its middle dose played protective role and recovered cardiac damages evidenced by significant reduction of serum cholesterol, HDL-cholesterol, lipoprotein (a), atherogenic index, TNF-alpha, cardiac MDA, B-type natriuretic peptide and caspase 3 activity. Apoptosis indices and histopathological features also were improved. However, the highest dose was found to be toxic and resulted in aggravation of the injuries. Another interesting finding is the ability of the higher doses of Zn-NPs (3 and 10mg/kg) to elevate cardiac zinc levels above the normal range in healthy animal. ZnSO4 also helped to recuperation of the damages, but the middle dose of Zn NPs was more efficient as compared to ZnSO4. Conclusively, Zn NPs have the potential for Zn delivery in diabetic patients. PMID- 28595786 TI - Increased risk for an atypical autism diagnosis following Thimerosal-containing vaccine exposure in the United States: A prospective longitudinal case-control study in the Vaccine Safety Datalink. AB - BACKGROUND: Thimerosal is an organic-mercury (Hg)-containing compound (49.55% Hg by weight) historically added to many multi-dose vials of vaccine as a preservative and still added to some vaccines today. Concerns about the toxic effects from Thimerosal-containing childhood vaccines and the risk of an atypical autism diagnosis were evaluated in this study. METHODS: A hypothesis-testing, prospective longitudinal, case-control study assessed exposure to Hg from Thimerosal-containing hepatitis B vaccines (TM-HepB) among cases diagnosed with atypical autism (n=164) and controls (n=15,216). Automated medical records for subjects born from 1991 to 2000 and continuously enrolled in the Vaccine Safety Datalink (VSD) database were examined. RESULTS: Cases diagnosed with atypical autism were statistically significantly more likely to have received greater overall and dose-dependent exposures to Hg from TM-HepB vaccines administered within the first month of life, first two months of life, and first six months of life than the controls. Similar phenomena were observed when cases and controls were separated by gender. CONCLUSIONS: Routine childhood vaccination is an important public health tool to reduce infectious diseases. The present study provides important epidemiological evidence significantly associating increasing Hg exposure from Thimerosal-containing childhood vaccines and the subsequent risk of atypical autism diagnosis, and suggests that Thimerosal should be eliminated from vaccines. PMID- 28595787 TI - Effects of dietary chromium supplementation on muscle and bone mineral interaction in broiler chicken. AB - The study was conducted to ascertain the effects of dietary chromium chloride (CrCl3.6H2O) supplementation on mineral interaction in blood serum, leg muscles and bones of broilers at 35th day of age. For this purpose, ninety male broiler chicks were divided into three groups. One served as control (group I) while, the other two groups were supplemented with CrCl3 (group II-12.5mg/Kg feed; group III 25mg/Kg feed) from 12 to 28days of age. In serum, Cr concentration remained non significant however, Zn, and K concentrations decreased (P<0.05) with both levels of Cr-supplementation. Furthermore, in muscles Cr, Cu, Ca and Na levels remained non-significant but concentrations of Zn and K decreased (P<0.05) with feed Cr enrichment. Chromium had a substantial effect on femur and fibula Zn retention with 25mg/Kg feed supplementation while, Cr deposition decreased (P<0.05) in fibula. Femur Ca (P<0.002), Na (P<0.001) and K (P<0.05) retention was inversely proportional to both Cr concentrations in feed. In tibia, Cu and Na concentration decreased (P<0.002) with high dietary Cr supplementation. Fibular Ca and Na concentrations remained significantly (P<0.001) lower in Cr supplemented groups. Bone robusticity index was non-significant but ash to weight ratio of femur, tibia and fibula decreased (P<0.05) in group III. Chromium supplementation has a major effect on serum or muscle Zn and K deposition while bone mineral interaction shows a major thrust on Zn, Ca and Na levels. PMID- 28595788 TI - Nutritional recommendations for copper intakes should be resuscitated, reevaluated and revised. PMID- 28595789 TI - A critical review on iodine presence in drinking water access at the Saharawi refugee camps (Tindouf, Algeria). AB - Iodine content in drinking water at the Saharawi refugee camps was analysed to assess the controversy in the origin of the prevalence of goitre among this population. A review on the iodine presence in drinking water reported in the literature was conducted, along with international standards and guidelines for iodine intake and iodine concentration in drinking water were also consulted. Chinese legislation was taken as the reference standard to evaluate the iodine concentration in water as adequate (10-150MUg/L) or not (high iodine >150MUg/L and iodine excess goitre >300MUg/L). Water sampling was conducted in 2015 and 2016 at the Saharawi camps (El Aiun, Awserd, Smara, Boujador and Dakhla) and at the institutional capital of Rabouni. The water supply in the camps is organized in three zones: El Aiun and Awserd where each 'wilaya' receives treated water 20days and raw water another 20days; Smara, Rabouni and Boujador receiving treated water continuously and Dakhla receiving raw water continuously. Results show that Smara, Rabouni and Boujador have access to drinking water with adequate iodine levels, as it occurs in Dakhla where raw water meets the Chinese standard, however in El Aiun and Awserd all population should have access to treated water given the current quality of the raw water supply. External supplies of water and animal milk could be also contributing to the high iodine intake. In conclusion, the contribution of drinking water as the main source of iodine to the urinary iodine concentration (UIC) and goitre prevalence among the Saharawi refugee population is not clear. Further studies should be conducted to assess the iodine content among all the nutritional sources of the population with a detailed study on the daily intake of these foods and drinks, including UIC and goitre prevalence studies. PMID- 28595790 TI - Trace metals in fluids lining the respiratory system of patients with idiopathic pulmonary fibrosis and diffuse lung diseases. AB - Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with a poor prognosis and an undefined etiopathogenesis. Oxidative stress contributes to alveolar injury and fibrosis development and, because transition metals are essential to the functioning of most proteins involved in redox reactions, a better knowledge of metal concentrations and metabolism in the respiratory system of IPF patients may provide a valuable complementary approach to prevent and manage a disease which is often misdiagnosed or diagnosed in later stages. The present review summarizes and discusses literature data on the elemental composition of bronchoalveolar lavage (BAL), induced sputum and exhaled breath condensate (EBC) from patients affected by IPF and healthy subjects. Available data are scanty and the lack of consistent methods for the collection and analysis of lung and airways lining fluids makes it difficult to compare the results of different studies. However, the elemental composition of BAL samples from IPF patients seems to have a specific profile that can be distinguished from that of patients with other interstitial lung diseases (ILD) or control subjects. Suggestions are given towards standard sampling and analytical procedures of BAL samples, in the aim to assess typical element concentration patterns and their potential role as biomarkers of IPF. PMID- 28595792 TI - Various ketogenic diets can differently support brain resistance against experimentally evoked seizures and seizure-induced elemental anomalies of hippocampal formation. AB - In this paper the influence of two different ketogenic diets (KDs) on the seizure evoked elemental anomalies of hippocampal formation was examined. To achieve this purpose normal and pilocarpine treated rats previously fed with one of the two high fat and carbohydrate restricted diets were compared with animals on standard laboratory diet. The ketogenic ratios of the examined KDs were equal to 5:1 (KD1) and 9:1 (KD2). KD1 and standard diet fed animals presented similar patterns of seizure-evoked elemental changes in hippocampal formation. Also the analysis of behavioral data recorded after pilocarpine injection did not show any significant differences in intensity and duration of seizures between KD1 and standard diet fed animals. Higher ketogenic ratio KD2 introduced in the normal hippocampal formation prolonged changes in the accumulation of P, K, Zn and Ca. Despite this, both the intensity and duration of seizures were significantly reduced in rats fed with KD2 which suggests that its saving action on the nerve tissue may protect brain from seizure propagation. Also seizure-evoked elemental anomalies in KD2 animals were different than those observed for rats both on KD1 and standard diets. The comparison of seizure experiencing and normal rats on KD2, did not show any statistically significant differences in elemental composition of CA1 and H hippocampal areas whilst in CA3 area only Zn level changed as a result of seizures. DG was the area mostly affected by seizures in KD2 fed rats but areal densities of all examined elements increased in this hippocampal region. PMID- 28595791 TI - Association between trace elements in the environment and stroke risk: The reasons for geographic and racial differences in stroke (REGARDS) study. AB - The disparities in stroke mortality between blacks and whites, as well as the increased stroke mortality in the "stroke belt" have long been noted. The reasons for these disparities have yet to be fully explained. The association between trace element status and cardiovascular diseases, including stroke, has been suggested as a possible contributor to the disparities in stroke mortality but has not been fully explored. The purpose of this study is to investigate distributions of four trace elements (arsenic, mercury, magnesium, and selenium) in the environment in relation to stroke risk. The study population (N=27,770) is drawn from the Reasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort. Environmental distribution of each trace element was determined using data from the United States Geological Survey (USGS) and was categorized in quartiles. A proportional hazards model, adjusted for demographic data and stroke risk factors, was used to examine the association of interest. The results showed that higher selenium levels in the environment were associated with increased stroke risk, and the hazard ratio for the 4th quartile compared to the 1st quartile was 1.33 (95% CI: 1.09, 1.62). However, there was no statistically significant relationship between environmental arsenic, mercury or magnesium and the risk of stroke. Because of dietary and non-dietary exposure as well as bioavailability, further research using biomarkers is warranted to examine the association between these trace elements and the risk of stroke. PMID- 28595793 TI - Selenium modulates MMP2 expression through the TGFbeta1/Smad signalling pathway in human umbilical vein endothelial cells and rabbits following lipid disturbance. AB - BACKGROUND: A high-fat diet is a major risk factor for coronary heart diseases. Matrix metalloprotease (MMP) expression is changed in many cardiovascular diseases. Selenium, which is an important trace element in animals, has a close relationship with cardiovascular diseases. The TGFbeta1/Smad signalling pathway is ubiquitous in diverse tissues and cells, and it is also associated with the occurrence and development of cardiovascular diseases. Therefore, in this study, we aimed to determine selenium's effect on lipid metabolism, atherosclerotic plaque formation, and MMP2 expression, as well as the underlying functional mechanism. METHODS AND RESULTS: In vivo tests: 24 male New Zealand white rabbits were randomly divided into 4 groups: regular diet, high-fat diet, high-fat diet+selenium and regular diet+selenium groups. The high-fat diet induced the lipid disturbances of rabbits at week 12. Selenium supplementation lowered total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels (p<0.01). Selenium supplementation also suppressed MMP2 over expression in thoracic aortas. In vitro tests: Human umbilical vein endothelial cells (HUVECs) were treated with different concentrations of selenium or ox-LDL. Ox-LDL promoted MMP2 expression by increasing TGFbeta1, pSmad2, pSmad3 and Smad3 expression (p<0.01). Selenium attenuated MMP2 over-expression by regulating the TGFbeta1/Smad signalling pathway. CONCLUSIONS: Selenium suppressed high-fat diet induced MMP2 over-expression in vivo by improving lipid metabolism. In vitro, selenium attenuated MMP2 over-expression through the TGFbeta1/Smad signalling pathway. PMID- 28595794 TI - A systematic review and meta-analysis of the circulatory, erythrocellular and CSF selenium levels in Alzheimer's disease: A metal meta-analysis (AMMA study-I). AB - BACKGROUND: Available studies in the literature on the selenium levels in Alzheimer's disease (AD) are inconsistent with some studies reporting its decrease in the circulation, while others reported an increase or no change as compared to controls. AIM: The objective of this study was to perform a meta analysis of circulatory (plasma/serum and blood), erythrocyte and cerebrospinal fluid (CSF) selenium levels in AD compared controls. We also performed a meta analysis of the correlation coefficients (r) to demonstrate the associations between selenium and glutathione peroxidase (GPx) in AD patients. METHODS: All major databases were searched for eligible studies. We included 12 case control/observational studies reporting selenium concentrations in AD and controls. Pooled-overall effect size as standardized mean difference (SMD) and pooled r-values were generated using Review Manager 5.3 and MedCalc 15.8 software. RESULTS: Random-effects meta-analysis indicated a decrease in circulatory (SMD=-0.44), erythrocellular (SMD=-0.52) and CSF (SMD=-0.14) selenium levels in AD patients compared to controls. Stratified meta-analysis demonstrated that the selenium levels were decreased in both the subgroups with (SMD=-0.55) and without (SMD=-0.37) age matching between AD and controls. Our results also demonstrated a direct association between decreased selenium levels and GPx in AD. CONCLUSION: This meta-analysis suggests that circulatory selenium concentration is significantly lower in AD patients compared to controls and this decrease in selenium is directly correlated with an important antioxidant enzyme, the GPx, in AD. PMID- 28595795 TI - Relationship between arsenic and selenium in workers occupationally exposed to inorganic arsenic. AB - The interaction between arsenic (As) and selenium (Se) has been one of the most extensively studied. The antagonism between As and Se suggests that low Se status plays an important role in aggravating arsenic toxicity in diseases development. The objective of this study was to assess the Se contents in biological samples of inorganic As exposed workers (n=61) and in non-exposed subjects (n=52). Median (Me) total arsenic concentration in urine of exposed workers was 21.83MUg/g creat. (interquartile range (IQR) 15.49-39.77) and was significantly higher than in the control group - (Me 3.75MUg/g creat. (IQR 2.52-9.26), p<0.0001). The median serum Se concentrations in the study group and the control were: 54.20MUg/l (IQR 44.2-73.10MUg/l) and 55.45MUg/l (IQR 38.5-69.60MUg/l) respectively and did not differ significantly between the groups. In the exposed group we observed significantly higher urine concentrations of selenosugar 1 (SeSug 1) and selenosugar 3 (SeSug3) than in the control group Me: 1.68MUg/g creat. (IQR 1.25-2.97 vs Me: 1.07MUg/g creat. (IQR 0.86-1.29MUg/g), p<0.0001 for SeSug1; Me: 0.45MUg/g creat. (IQR 0.26-0.69) vs Me: 0.28MUg/g creat. (IQR 0.17 0.45MUg/g), p=0.0021). In the multivariate model, after adjusting to cofounders (age, BMI, job seniority time, consumption of fish and seafood and smoking habits) the high rate of arsenic urine wash out (measured as a sum of iAs+MMA+DMA) was significantly associated with the high total selenium urine excretion (B=0.14 (95%CI (confidence interval) 0.05-0.23)). Combination of both arsenic and selenium status to assess the risk of arsenic-induced diseases requires more studies with regard to both the analysis of speciation, genetics and the influence of factors such as nutritional status. PMID- 28595796 TI - The metal and metalloprotein profile of human plasma as biomarkers for stroke diagnosis. AB - Stroke, a major cause of disability and mortality, affects someone in the United States every 40s. Stroke biomarkers, including those that could be used as a blood test for diagnosis of stroke, have been particularly elusive. We performed a double blind study to identify human plasma biomarkers for the diagnosis of stroke, including acute ischemic stroke (AIS) and intracerebral hemorrhage (ICH). We utilized a three-track approach based on the total metal profile, the metal cofactor levels among metalloproteins, and the identification of stroke-related metalloproteins. The study included 14 case-control pairs of AIS and 23 case control pairs of ICH. Controls were matched to cases based on gender, ethnicity, and age (+/-5 years). AIS cases were statistically higher from their respective controls for protein bound co-factors Se and Cd, while unique correlations of metal cofactor concentrations among metalloproteins were identified between Pb-W, Sr-W, Pb-V, and Cu-V. ICH cases were statistically higher from their respective controls for Se and Co cofactors, whereas Cd and Pb were statistically lower. Unique correlations between metal cofactors for ICH cases were identified between Pb-W, Sr-W, Pb-V, and Cu-V. Stroke-related metalloproteins were identified, including calpain-15, protein-activated inward rectifier potassium channel 1, tau tubulin kinase 1, and voltage-dependent L-type calcium channel subunit beta-3. Linear discriminant analysis (LDA) was able to classify patients between stroke cases or controls with 93% accuracy as well as classify patients with one of the four stroke groups with 85% accuracy. Additionally, this study found utmost importance in vanadium (V) and tungsten (W) correlations for both bound and total metal concentrations, suggestive of binding to transferrin or inhibition of oxidoreductases. Future work in stroke patients will seek to quantify varying selenoproteins, including selenoprotein P and glutathione peroxidase and identified zinc finger tissue leakage proteins, and further explore the role of trace metal fluctuations with transferrin. PMID- 28595798 TI - Mineral content of smooth scallop (Flexopecten glaber) caught Canakkale, Turkey and evaluation in terms of food safety. AB - In this research, one of the most promising scallop species, smooth scallop (Flexopecten glaber) was studied. According to our findings, smooth scallop has beneficial micro and macro minerals, fat and carbohydrate just before the spawning. While the ratios protein, ash and water decreased from autumn to summer, ratio of crude fat increased till reproduction season in late spring and decreased in summer (P<0.05). In digestive glands, aluminum, bromine, cadmium, calcium, chromium, copper, iron, manganese, nickel, and zinc were detected more compared to adductor muscles (P<0.05). However; boron, magnesium and potassium were found more in adductor muscles (P<0.05) and there were no significant statistically differences in cobalt and lead (P>0.05). Most of the elements in the both tissues except K and Mg increased till summer. On the other hand, two of the most toxic metals, cadmium and aluminum were mostly accumulated in the digestive gland of smooth scallop. It is recommended that; digestive gland of scallops should be removed before consuming in terms of food safety. Besides, scallops are convenient to be processed, because of easy removal muscle tissue from internal organs. PMID- 28595797 TI - Chromium supplementation and polycystic ovary syndrome: A systematic review and meta-analysis. AB - INTRODUCTION: polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women. Some vitamins and mineral can play role in improvement of PCOS. Chromium (Cr) is an essential element in glucose and insulin homeostasis. However, findings are not consistent regarding PCOS improvement. Therefore, the purpose of this paper was to assess the effect of Cr supplementation in PCOS that have not yet fully been elucidated. METHODS: We searched ISI Web of Science, MEDLINE (1966 to June 2016), Google Scholar databases and Proquest and identified eligible papers and extracted the following terms: total testosterone, DHEAS, insulin sensitivity, fasting glucose, fasting insulin, OGTT 1h glucose, OGTT 2h glucose (mg/dL), LH (mIU/mL), FSH, DHEAS, ferriman-Galwey score (FG score). We calculated overall effect size with random effects model, between-study heterogeneity with I square (I2) statistic. Publication bias was assessed using Begg's test regression. RESULT: Totally, 7 RCTs were selected. Results indicated that Cr supplementation had a beneficial effect on BMI with effect size: -2.37 (kg/m2), 95% CI: -2.99, -1.76, p=0.001 and free testosterone concentration with effect size=-0.52 (pg/mL), 95% CI: -0.83, -0.23, p=0.001. Cr reduced fasting insulin in subgroup of studies with >10 participants with effect size: 0.86mIU/ml, 95% CI: -0.67, -0.17; p=0.001. Cr supplementation had no beneficial effects on reducing total testosterone, FG score, DHEA, FSH and LH. CONCLUSION: This systematic review and meta-analysis shows that using Cr picolinate supplementation has beneficial effects on decreasing BMI, fasting insulin and free testosterone in PCOS patients. PMID- 28595799 TI - Revision total hip arthroplasty - Salvage procedures using bone allografts in Japan. AB - Total hip arthroplasty (THA) and hemiarthroplasty have improved hip joint function of patients suffering from hip disease or trauma with excellent clinical results and long-term survivorship. Conversely, there has been an increase in the number of revision surgeries after THA and hemiarthroplasty due to bone deficiency. The reconstruction of deficient bone remains a challenging problem following THA. While performing revision surgery, we have previously classified the preoperative bone deficiency using X-ray, CT and three-dimensional CT imaging according to location and severity of the deficiencies. We then predicted the shape and amount of the required bone allograft and the type of implant. Due to the accepted reconstruction methods of bone deficiency following revision surgeries, it is important to pre-operatively assess the site and size of the bone deficiency to be repaired in the revision THA (re-THA). Bone allograft makes it possible to repair massive bone deficiency, recover bone stock, and improve long-term implant stability. Performing bone allograft will require a bone bank for harvesting, treating, and storing bone in Japan. PMID- 28595800 TI - Treatment strategy for amyloid hip arthropathy in long-term hemodialysis patients. AB - BACKGROUND: The number of hemodialysis patients has been progressively increasing in our country. On the other hand, chronic hip arthropathy associated with long term hemodialysis is a devastating problems affecting patients' quality of life. In our previous study, we proposed a classification system for radiological abnormalities seen in hemodialysis-related hip lesions. The purpose of the study was to propose the surgical strategy for hip disorders caused by long-term hemodialysis. METHODS: Patients with a history of hemodialysis for more than 10 years, 191 hip lesions in 165 consecutive patients who visited our institute due to hip symptoms. Various abnormalities were identified in 116 out of 191 hips. A retrospective assessment of the patient record and radiographs was performed for the included subjects examining the natural course of the disease process as well as the results of surgical treatment. RESULTS: Seventy-six hip lesions (69.0%) were conservatively managed at the time of the initial visit. Surgeries were performed for 75 hips (64.7%) during the study period. Among those, surgical treatment was indicated for 40 hips at the time of the initial visit. On the other hand, surgeries were performed for 35 hips during the subsequent follow-up period due to progression of the disease process. CONCLUSIONS: Based on the analysis of our surgical experiences by the retrospective chart review, we have established a flowchart of the treatment strategy for chronic hip arthropathy in long-term hemodialysis patients. STUDY DESIGN: This study is retrospective clinical study. PMID- 28595801 TI - Deregulation of hsa-miR-20b expression in TNF-alpha-induced premature senescence of human pulmonary microvascular endothelial cells. AB - miRNAs are important regulators of cellular senescence yet the extent of their involvement remains to be investigated. We sought to identify miRNAs that are involved in cytokine-induced premature senescence (CIPS) in endothelial cells. CIPS was established in young human pulmonary microvascular endothelial cells (HMVEC-Ls) following treatment with a sublethal dose (20ng/ml) of tumor necrosis factor alpha (TNF-alpha) for 15days. In parallel, HMVEC-Ls were grown and routinely passaged until the onset of replicative senescence (RS). Differential expression analysis following miRNA microarray profiling revealed an overlapped of eight deregulated miRNAs in both the miRNA profiles of RS and TNF-alpha induced premature senescence cells. Amongst the deregulated miRNAs were members of the miR 17-92 cluster which are known regulators of angiogenesis. The role of hsa-miR-20b in TNF-alpha-induced premature senescence, a paralog member of the miR 17-92 cluster, was further investigated. Biotin-labeled hsa-miR-20b captured the enriched transcripts of retinoblastoma-like 1 (RBL1), indicating that RBL1 is a target of hsa-miR-20b. Knockdown of hsa-miR-20b attenuated premature senescence in the TNF-alpha-treated HMVEC-Ls as evidenced by increased cell proliferation, increased RBL1 mRNA expression level but decreased protein expression of p16INK4a, a cellular senescence marker. These findings provide an early insight into the role of hsa-miR-20b in endothelial senescence. PMID- 28595802 TI - Can Angiomyolipomas be classified fully into three types? PMID- 28595803 TI - Enhanced bending failure strain in biological glass fibers due to internal lamellar architecture. AB - The remarkable mechanical properties of biological structures, like tooth and bone, are often a consequence of their architecture. The tree ring-like layers that comprise the skeletal elements of the marine sponge Euplectella aspergillum are a quintessential example of the intricate architectures prevalent in biological structures. These skeletal elements, known as spicules, are hair-like fibers that consist of a concentric array of silica cylinders separated by thin, organic layers. Thousands of spicules act like roots to anchor the sponge to the sea floor. While spicules have been the subject of several structure-property investigations, those studies have mostly focused on the relationship between the spicule's layered architecture and toughness properties. In contrast, we hypothesize that the spicule's layered architecture enhances its bending failure strain, thereby allowing it to provide a better anchorage to the sea floor. We test our hypothesis by performing three-point bending tests on E. aspergillum spicules, measuring their bending failure strains, and comparing them to those of spicules from a related sponge, Tethya aurantia. The T. aurantia spicules have a similar chemical composition to E. aspergillum spicules but have no architecture. Thus, any difference between the bending failure strains of the two types of spicules can be attributed to the E. aspergillum spicules' layered architecture. We found that the bending failure strains of the E. aspergillum spicules were roughly 2.4 times larger than those of the T. aurantia spicules. PMID- 28595804 TI - Techno-economic feasibility of waste biorefinery: Using slaughtering waste streams as starting material for biopolyester production. AB - The utilization of industrial waste streams as input materials for bio-mediated production processes constitutes a current R&D objective not only to reduce process costs at the input side but in parallel, to minimize hazardous environmental emissions. In this context, the EU-funded project ANIMPOL elaborated a process for the production of polyhydroxyalkanoate (PHA) biopolymers starting from diverse waste streams of the animal processing industry. This article provides a detailed economic analysis of PHA production from this waste biorefinery concept, encompassing the utilization of low-quality biodiesel, offal material and meat and bone meal (MBM). Techno-economic analysis reveals that PHA production cost varies from 1.41 ?/kg to 1.64 ?/kg when considering offal on the one hand as waste, or, on the other hand, accounting its market price, while calculating with fixed costs for the co-products biodiesel (0.97 ?/L) and MBM (350 ?/t), respectively. The effect of fluctuating market prices for offal materials, biodiesel, and MBM on the final PHA production cost as well as the investment payback time have been evaluated. Depending on the current market situation, the calculated investment payback time varies from 3.25 to 4.5years. PMID- 28595805 TI - Composting municipal biosolids in polyethylene sleeves with forced aeration: Process control, air emissions, sanitary and agronomic aspects. AB - Composting in polyethylene sleeves with forced aeration may minimize odor emissions, vectors attraction and leachates associated with open windrows. A disadvantage of this technology is the lack of mixing during composting, potentially leading to non-uniform products. In two pilot experiments using biosolids and green waste (1:1; v:v), thermophilic conditions (>45 degrees C) were maintained for two months, with successful control of oxygen levels and sufficient moisture. Emitted odors declined from 1.5-3.8*105 to 5.9*103-2.3*104 odor units m-3-air in the first 3weeks of the process, emphasizing the need of odor control primarily during this period. Therefore, composting might be managed in two phases: (i) a closed sleeve for 6-8weeks during which the odor is treated; (ii) an open pile (odor control is not necessary). Reduction of salmonella, E. coli and coliforms was effective initially, meeting the standards of "Class A" biosolids; however, total and fecal coliforms density increased after opening the second sleeve and exceeded the standard of 1000 most probable number (MPN) per g dry matter. Compost maturity was achieved in the open piles following the two sleeves and the final compost was non-phytotoxic and beneficial as a soil additive. PMID- 28595806 TI - Conversion of biowastes to biomaterial: An innovative waste management approach. AB - The study suggests that biowastes (eggshells and urine) can be potentially used as precursors to produce hydroxyapatite (HAp) biomaterial in a simple chemical process. A batch reactor was used in this work to produce HAp powder from eggshells and synthetic urine (SU). Fine powder of calcined eggshells was dissolved in water to produce aqueous calcium hydroxide. The solution was then mixed with concentrated SU in stoichiometric amounts corresponding to HAp (Ca/P molar ratio~1.67). The initial pH of the solution was alkaline (pH~8.5) and particles formed rapidly with slight mixing. Stirring the turbid solution for a longer period (72h) did not show any visual change, but the particle size decreased slightly. When the pH of the solution was adjusted to 5, the solution was initially clear, but particle formation was apparent after 48h stirring. It was noticed that at a slow stirring speed (100rpm), film formation occurred on the solution, whereas at a higher stirring speed (500rpm) no such film formation was observed. X-ray diffraction (XRD) analysis confirmed that the particles (formed at 500rpm) were an amorphous calcium phosphate (CaP). Alkaline treatment at 80 degrees C for 2h converted the amorphous CaP into HAp. Inductively coupled plasma mass spectrometry (ICP-MS) analysis of the particles (formed at 500rpm) suggested that they are calcium-deficient HAp (Ca/P molar ratio 1.58). PMID- 28595807 TI - First report of immunogenic vasculitis with Wunderlich's syndrome following influenza B infection in a previously immunocompetent woman. PMID- 28595808 TI - Regulating seclusion and restraint in health care settings: The promise of the Convention on the Rights of Persons with Disabilities. PMID- 28595809 TI - Neuroticism in child sex offenders and its association with sexual dysfunctions, cognitive distortions, and psychological complaints. AB - Studies in child sex offenders (CSO) often report deviant personality characteristics. In our study, we investigated neuroticism in CSO and tested the hypothesis that CSO with high neuroticism show more serious abuse behavior and are more likely to exhibit sexual dysfunction and cognitive distortions, as compared to CSO with low neuroticism. A sample of 40 CSO (both child sexual abusers and child sexual material users) was split into two subsamples based on their neuroticism scores, obtained by the NEO-Personality Inventory-Revised (NEO PI-R) questionnaire. Subsequently, we compared their scores in the Multiphasic Sex Inventory (MSI) questionnaire and Symptom Checklist-90-Revised (SCL-90-R). Our results show that CSO exhibited higher levels of neuroticism than controls, but were still in the normal range. In CSO, neuroticism was associated with sexual dysfunction and cognitive distortions, rather than with more severe abuse behavior. Moreover, neuroticism in this group was linked to a broad range of psychological problems and psychopathological symptoms, such as somatization or anxiety. Our findings suggest that neuroticism even below the level of personality disorder is associated with a broader range of psychological problems in CSO, which should be addressed in therapy. PMID- 28595810 TI - Successful percutaneous retrieval of embolized transcatheter left atrial appendage closure device (Watchman) using a modified vascular retrieval forceps. AB - Transcatheter closure of the left atrial appendage (LAA) is increasingly considered as an alternative to oral anticoagulation in patients with previous major bleeding or at high-risk of bleeding. Device embolization with transcatheter LAA closure is a rare complication. Most cases are asymptomatic, but it can be life threatening. Depending on the location of embolization, percutaneous retrieval is feasible. Snares are usually used for retrieval, but other devices may be used. We report the case of a 63-year gentleman who underwent an uneventful LAA closure with Watchman device and routine testing next day showed embolization to the abdominal aorta. Retrieval was performed using a modified Cook vascular retrieval forceps. PMID- 28595811 TI - Acute distal migration of a flow diverting stent. AB - The introduction of flow diverting stents, particularly for treatment of petrous to supraclinoid internal carotid artery aneurysms, has greatly impacted endovascular treatment of intracranial aneurysms. Despite their high efficacy, complications, such as ischemic events, distal hemorrhage, or problems with stent deployment, remain a significant concern. We present the first reported case of acute distal migration of a Pipeline Embolization Device (PED). A 24-year old female underwent elective placement of a PED for treatment of a left paraclinoid internal carotid artery aneurysm. Despite an uneventful intra-operative course, adequate stent placement and a normal neurologic examination immediately after placement, she demonstrated right hemiparesis shortly thereafter. Repeat angiography revealed acute distal migration of the PED and an occlusive thrombus. Thought to be secondary to chronic in-stent thrombosis, distal migration has been previously described in a delayed fashion over weeks to months. However, to our knowledge, this is the first reported case of distal flow diverter migration in an acute setting immediately following the procedure. PMID- 28595812 TI - Beyond imaging: The promise of radiomics. AB - The domain of investigation of radiomics consists of large-scale radiological image analysis and association with biological or clinical endpoints. The purpose of the present study is to provide a recent update on the status of this rapidly emerging field by performing a systematic review of the literature on radiomics, with a primary focus on oncologic applications. The systematic literature search, performed in Pubmed using the keywords: "radiomics OR radiomic" provided 97 research papers. Based on the results of this search, we describe the methods used for building a model of prognostic value from quantitative analysis of patient images. Then, we provide an up-to-date overview of the results achieved in this field, and discuss the current challenges and future developments of radiomics for oncology. PMID- 28595813 TI - Reinforcement of the colon anastomosis with cyanoacrylate glue: a porcine model. AB - BACKGROUND: Previous experimental studies on cyanoacrylate (CA) glue for the prevention of colorectal anastomotic leakage (AL) have shown promising results. The aim of this study was to investigate the effect of CA in prevention of leakage in a porcine model of ischemic colorectal AL. METHODS: Twenty-four animals were divided into four groups of six: (1)ischemic anastomosis with sufficient suture (ISCH), (2)ischemic anastomosis with sufficient suture and CA reinforcement (CA-ISCH), (3)ischemic anastomosis with insufficient suture (ISCH AI), and (4)ischemic anastomosis with insufficient suture and CA reinforcement (CA-ISCH-AI). In CA groups, N-butyl-2-cyanoacrylate was applied between the colon ends. Anastomotic bursting pressure, abscess formation, and adhesion formation were evaluated on postoperative day 7. Tissue samples were obtained for histologic evaluation of foreign body reaction. RESULTS: The AL rate was 4 of 6 (67%) in the ISCH-AI group compared with none in the other three groups. The ISCH and ISCH-AI groups had significantly higher AL scores compared with the CA groups. The mean anastomotic bursting pressure was 167 +/- 54 mm Hg in the ISCH group versus 213 +/- 43 mm Hg in the CA-ISCH-group (P = nonsignificant) and 145 +/- 102 mm Hg in the ISCH-AI group versus 187 +/- 19 mm Hg in the CA-ISCH-AI group (P = nonsignificant). The average adhesion score was significantly higher in the ISCH group than in the CA-ISCH group (4.2 +/- 1.3 versus 1.7 +/- 0.82; P = 0.019). Stricture of the anastomosis occurred only in the non-CA groups (3/12, 25%). CONCLUSIONS: Anastomotic reinforcement with CA is effective and safe to prevent leakage in a high-risk colorectal anastomosis in a porcine model. PMID- 28595814 TI - Extremity compartment syndrome following blunt trauma: a level I trauma center's 5-year experience. AB - BACKGROUND: Extremity compartment syndrome is a recognized complication of trauma. We evaluated its prevalence and outcomes at a suburban level 1 trauma center. METHODS: The trauma registry was reviewed for all blunt trauma patients aged >=18 years, admitted between 2010 and 2014. Chart review of patients with extremity compartment syndrome was performed. RESULTS: Of 6180 adult blunt trauma admissions, 83 patients developed 86 extremity compartment syndromes; two patients had compartment syndromes on multiple locations. Their (n = 83) median age was 44 years (interquartile range: 31.5-55.5). The most common mechanism of injury was motor vehicle/motor cycle accident (45.8%) followed by a fall (21.7%). The median injury severity score was 9 (interquartile range: 5-17); 65.1% had extremity abbreviate injury score >=3. Notably, 15 compartment syndromes did not have an underlying fracture. Among patients with fractures, the most commonly injured bone was the tibia, with tibial plateau followed by tibial diaphyseal fractures being the most frequent locations. Fasciotomies were performed, in order of frequency, in the leg (n = 53), forearm (n = 15), thigh (n = 9), foot (n = 5), followed by multiple or other locations. CONCLUSIONS: Extremity compartment syndrome was a relatively uncommon finding. It occurred in all extremity locations, with or without an associated underlying fracture, and from a variety of mechanisms. Vigilance is warranted in evaluating the compartments of patients with extremity injuries following blunt trauma. PMID- 28595815 TI - Adipose-derived stem cells seeded in Pluronic F-127 hydrogel promotes diabetic wound healing. AB - BACKGROUND: Chronic nonhealing wound is a multifactorial complication of diabetes that results specifically as a consequence of impaired angiogenesis and currently lacks in effective treatments. Although a stem cell-based therapy may provide a novel treatment to augment diabetic wound healing, inferior cell survival at the diabetic skin wound is one of the key causes that are responsible for the low efficacy of the stem cell therapy. MATERIALS AND METHODS: In this work, we used an injectable, biocompatible, and thermosensitive hydrogel Pluronic F-127 to encapsulate allogeneic nondiabetic adipose-derived stem cells (ADSCs) and topically applied the cells to a full-thickness cutaneous wound in the streptozotocin-induced diabetic model in rats. RESULTS: The cells seeded in the hydrogel enhanced angiogenesis (CD31 marker) and promoted the cell proliferation (Ki67 marker) at the wound site and significantly accelerated wound closure, which was accompanied by facilitated regeneration of granulation tissue. Consistently, levels of the messenger RNA expression of key angiogenesis growth factor, vascular endothelial growth factor, and key wound healing growth factor, transforming growth factor beta 1, were also upregulated in the cell-treated wounds when compared with untreated wounds. CONCLUSIONS: The results indicated that the transplantation of allogeneic ADSCs via the hydrogel improves the efficiency of cell delivery and optimizes the performance of ADSCs for augmenting diabetic wound healing. In conclusion, this ADSC-based therapy may provide a novel therapeutic strategy for the treatment of nonhealing diabetic foot ulcers. PMID- 28595816 TI - Impact of body mass index on the short-term outcomes of resected gastrointestinal stromal tumors. AB - BACKGROUND: Potentially curative treatment for gastrointestinal stromal tumors (GIST) involves resection with selective utilization of tyrosine kinase inhibitors. A potential association between obesity and GIST has been postulated as GIST is among the most common incidental findings during gastric resection for bariatric procedures. The purpose of this study is to investigate the relationship and impact of obesity on the pathologic and short-term outcomes in patients with GIST. METHODS: We performed a retrospective review of patients with resected GIST. The impact of obesity, defined as body mass index (BMI) >=30 kg/m2, on pathologic results and short-term outcomes was evaluated. RESULTS: Sixty-one patients underwent resection with a median follow-up of 26 mo (1-129 mo). Disease involved the stomach (74%), small intestine (18%), or colon/rectum (5%). Median tumor size was 6 cm, and 13 patients (21%) underwent multivisceral resection. Median BMI for the cohort was 27.2 kg/m2, and 24 patients (39%) were classified as obese based on BMI. Nonobese patients were noted to have larger primary tumors (median: 7 cm versus 5 cm, P = 0.02) and undergo multivisceral resection more frequently (32.4% versus 4.2%, P < 0.01). Short-term outcomes were similar between the groups, with a slight trend toward more postoperative complications among the obese patients. CONCLUSIONS: In this study, obese patients tended to have more favorable pathologic features. GISTs may represent another example of the "obesity paradox" in which obesity seemingly provides a protective effect. Larger studies are warranted to verify the impact of obesity on outcomes and to elucidate any underlying clinicopathologic/biologic factors. PMID- 28595817 TI - Relationships between study habits, burnout, and general surgery resident performance on the American Board of Surgery In-Training Examination. AB - BACKGROUND: The American Board of Surgery In-Training Examination (ABSITE) is used by programs to evaluate the knowledge and readiness of trainees to sit for the general surgery qualifying examination. It is often used as a tool for resident promotion and may be used by fellowship programs to evaluate candidates. Burnout has been associated with job performance and satisfaction; however, its presence and effects on surgical trainees' performance are not well studied. We sought to understand factors including burnout and study habits that may contribute to performance on the ABSITE examination. METHODS: Anonymous electronic surveys were distributed to all residents at 10 surgical residency programs (n = 326). Questions included demographics as well as study habits, career interests, residency characteristics, and burnout scores using the Oldenburg Burnout Inventory, which assesses burnout because of both exhaustion and disengagement. These surveys were then linked to the individual's 2016 ABSITE and United States Medical Licensing Examination (USMLE) step 1 and 2 scores provided by the programs to determine factors associated with successful ABSITE performance. RESULTS: In total, 48% (n = 157) of the residents completed the survey. Of those completing the survey, 48 (31%) scored in the highest ABSITE quartile (>=75th percentile) and 109 (69%) scored less than the 75th percentile. In univariate analyses, those in the highest ABSITE quartile had significantly higher USMLE step 1 and step 2 scores (P < 0.001), significantly lower burnout scores (disengagement, P < 0.01; exhaustion, P < 0.04), and held opinions that the ABSITE was important for improving their surgical knowledge (P < 0.01). They also read more frequently to prepare for the ABSITE (P < 0.001), had more disciplined study habits (P < 0.001), were more likely to study at the hospital or other public settings (e.g., library, coffee shop compared with at home; P < 0.04), and used active rather than passive study strategies (P < 0.04). Gender, marital status, having children, and debt burden had no correlation with examination success. Backward stepwise multiple regression analysis identified the following independent predictors of ABSITE scores: study location (P < 0.0001), frequency of reading (P = 0.0001), Oldenburg Burnout Inventory exhaustion (P = 0.02), and USMLE step 1 and 2 scores (P = 0.007 and 0.0001, respectively). CONCLUSIONS: Residents who perform higher on the ABSITE have a regular study schedule throughout the year, report less burnout because of exhaustion, study away from home, and have shown success in prior standardized tests. Further study is needed to determine the effects of burnout on clinical duties, career advancement, and satisfaction. PMID- 28595819 TI - Risk factors and prediction model for inpatient surgical site infection after major abdominal surgery. AB - BACKGROUND: Surgical site infections (SSIs) are a common source of postoperative morbidity and a marker of surgical quality. The ability to predict the incidence of SSIs is limited and most models have poor predictive value. We sought to identify risk factors associated with SSIs and develop a prediction model for SSIs after major abdominal surgery. METHODS: A total of 1744 patients undergoing pancreatic, hepatobiliary, and colorectal resections between January 1, 2010 and August 31, 2013 at Johns Hopkins Hospital were identified. Risk factors for any inpatient SSI (superficial and deep) were evaluated using multivariable logistic regression. RESULTS: Median patient age was 58 y (interquartile range 47, 68); surgical procedures included colorectal (59.0%), liver (26.2%), and pancreas (14.8%) resections. SSI occurred in 7.6% (n = 132) of patients. Factors associated with SSI included preoperative weight loss >4.5 kg (odds ratio [OR], 2.12; 95% confidence interval [CI], 1.06-4.25), emergency operations (OR, 2.05; 95% CI, 1.32-3.17), and colorectal resections (OR, 1.65; 95% CI, 1.13-2.43) (all P <= 0.003). Intraoperative and postoperative risk factors included estimated blood loss (EBL) >600 mL (OR, 2.23; 95% CI, 1.54-3.25), maximum respiratory rate (tachypnea) >20 breaths/min (OR, 1.74; 95% CI, 1.19-2.54), and perioperative transfusion (OR, 2.01; 95% CI, 1.33-3.04) (all P = 0.001). Intraoperative hypothermia, hyperthermia, bradycardia, tachycardia, hypotension, and hypertension were not associated with SSIs (all P > 0.05). After controlling competing risk factors, transfusion, EBL >600 mL, tachypnea, and colorectal resection were independently associated with SSIs (all P < 0.003). On the basis of the beta-coefficients in the multivariable model, an SSI scoring system was created by assigning 2 points for EBL >600 mL, 2 points for a colorectal resection, 3 points for tachypnea, and 3 points for a transfusion. The model showed good discriminatory ability to predict SSI (c-statistic = 0.7232; Akaike information criterion 875.37). CONCLUSIONS: A novel, simple 10-point SSI scoring system that incorporated perioperative risk factors such as blood transfusion, EBL, tachypnea, and the type of surgical procedure accurately stratifies patients according to SSI risk. PMID- 28595818 TI - Do-not-resuscitate orders and high-risk pediatric surgery: professional nuisance or medical necessity? AB - BACKGROUND: There is a paucity of data in the literature regarding end-of-life care and do-not-resuscitate (DNR) status of the pediatric surgical patient, although invasive procedures are frequently performed in very high risk and critically ill children. Despite significant efforts in adult medicine to enhance discussions around end-of-life care, little is known about similar endeavors in the pediatric population. METHODS: A retrospective review of the National Surgical Quality Improvement Program Pediatric database was performed. Patients aged <18 y with American Society of Anesthesiologists class 3 or greater who underwent elective surgical procedure in 2012-2013 were included. Demographic factors, principal diagnosis, associated conditions, DNR status, and mortality were extracted. Descriptive analysis was performed. RESULTS: A total of 20,164 patients met the inclusion criteria. Only 36 (0.2%) patients had a signed DNR order before surgical procedure. Of severely ill American Society of Anesthesiologists four patients, only 1% had DNR status. There were no differences in gender, race, ethnicity, or surgical specialty by the presence of a DNR order. Notably, 17.1% of children who died within this period had multiple surgical procedures performed before expiring. CONCLUSIONS: The rate of documented DNR status is extremely low in the high-risk pediatric surgical population undergoing elective surgery, even among severely ill children. Well informed end-of-life care discussions in a patient-focused approach are essential in the surgical care of children with complex medical conditions and critical illness. Better documentation of DNR discussion will also allow better tracking and benchmarking. PMID- 28595820 TI - Quality management, a directive approach to patient safety. AB - Nowadays the implementation of effective quality management systems and external evaluation in healthcare is a necessity to ensure not only transparency in activities related to health but also access to health and patient safety. The key to correctly implementing a quality management system is support from the managers of health facilities, since it is managers who design and communicate to health professionals the strategies of action involved in quality management systems. This article focuses on nursing managers' approach to quality management through the implementation of cycles of continuous improvement, participation of improvement groups, monitoring systems and external evaluation quality models (EFQM, ISO). The implementation of a quality management system will enable preventable adverse effects to be minimized or eliminated, and promote patient safety and safe practice by health professionals. PMID- 28595821 TI - Modified Inflatable Penile Prosthesis Reservoir Placement Into Space of Retzius: Comparing Outcomes in Men With or Without Prior Pelvic Surgery. AB - BACKGROUND: Traditional inflatable penile prosthesis (IPP) reservoir placement has rare but potentially serious complications including damage to local structures, and Levine and Hoeh (J Sex Med 2012;9:2759-2769) described a modified technique designed to avoid these complications. AIM: To determine whether the modified Jorgenson scissors technique is safe and effective in patients who have had prior pelvic surgery. METHODS: A retrospective chart review was performed on all patients who had a three-piece IPP placed by a single urologist from 2011 to 2015. Complication rates between the prior pelvic surgery group and the virgin pelvis group were compared using chi2 test. Differences between the two groups were considered statistically significant at a P value less than .05. OUTCOMES: Reservoir-related complication rate and rate of converting to ectopic placement. RESULTS: A total of 246 procedures were included, with 174 having no prior pelvic surgery and 72 with prior pelvic surgery. The reservoir-related complication rates were 2.8% (2 of 72) in the prior pelvic surgery group and 3.4% (6 of 174) in the virgin pelvis group. This difference was not statistically significant (P = .79). The two complications from the prior pelvic surgery cohort were inguinal hernias requiring surgical repair, which occurred in the same patient. In the virgin pelvis cohort, there were five inguinal hernias and one autoinflation. There were 16 patients who required ectopic placement of the reservoir owing to difficulty in entering the space of Retzius (SOR), 14 of whom had prior pelvic surgery. CLINICAL IMPLICATIONS: We believe this modified technique for IPP reservoir placement into the SOR is a safe alternative because the Jorgenson scissors allow perforation into the SOR away from vital structures. STRENGTHS AND LIMITATIONS: The study is limited by the fact that it is a retrospective, single center, chart review of a non-randomized surgical procedure with variable follow up in a limited number of patients. Its strength is its applicability to provide surgeons a modified technique that can be used routinely for IPP reservoir placement that appears to be safe and effective, even in men who have had prior pelvic surgery. CONCLUSION: In our experience, the modified Jorgenson scissors technique allows for safe entry into the SOR through a transverse scrotal incision and is a viable alternative to the standard SOR placement and the ectopic approach. Capoccia EM, Phelps JN, Levine LA. Modified Inflatable Penile Prosthesis Reservoir Placement Into Space of Retzius: Comparing Outcomes in Men With or Without Prior Pelvic Surgery. J Sex Med 2017;14:968-973. PMID- 28595822 TI - A multiplex restriction enzyme-PCR for unequivocal identification and differentiation of Trichostrongylus species in human samples. AB - Trichostrongylus species remain one of the major health challenges in the tropical and summer rainfall regions worldwide. Identification of strongylid species diagnostic methods is vital for obtaining a deep understanding of the epidemiology, population biology, anthelmintic treatment efficacy, and drug resistance in order to design effective parasite control strategies. We evaluated a multiplex RE-PCR for the diagnosis of key Trichostrongylus spp. Genomic DNA amplification of Trichostrongylus colubriformis, Trichostrongylus axei and Trichostrongylus vitrinus was achieved as standard sample using specific primers located in the second internal transcribed spacer (ITSII) of nuclear ribosomal DNA (rDNA). The mentioned method was based on isolation of Trichostrongylus ova from human fecal samples using Willis method, the extraction of ova genomic DNA samples, followed by rDNA ITSII PCR and one-step multiplex RE-PCR using three restriction enzymes of HinfI, DraI, and MseI. The multiplex RE-PCR technique provides a useful tool for discriminating all Trichostrongylus spp., being useful for diagnostic, epidemiological, ecological studies, and control programs. This method is rapid, especially when numerous restriction enzymes are required for species differentiation or identification. PMID- 28595823 TI - [Role of indocyanine green angiography in the management of branch retinal vein occlusions refractory to intravitreal injections: Case report]. PMID- 28595825 TI - Nursing staff's experiences of working in an evidence-based designed ICU patient room-An interview study. AB - INTRODUCTION: It has been known for centuries that environment in healthcare has an impact, but despite this, environment has been overshadowed by technological and medical progress, especially in intensive care. Evidence-based design is a concept concerning integrating knowledge from various research disciplines and its application to healing environments. OBJECTIVE: The aim was to explore the experiences of nursing staff of working in an evidence-based designed ICU patient room. METHOD: Interviews were carried out with eight critical care nurses and five assistant nurses and then subjected to qualitative content analysis. FINDINGS: The experience of working in an evidence-based designed intensive care unit patient room was that the room stimulates alertness and promotes wellbeing in the nursing staff, fostering their caring activities but also that the interior design of the medical and technical equipment challenges nursing actions. CONCLUSIONS: The room explored in this study had been rebuilt in order to create and evaluate a healing environment. This study showed that the new environment had a great impact on the caring staffs' wellbeing and their caring behaviour. At a time when turnover in nurses is high and sick leave is increasing, these findings show the importance of interior design ofintensive care units. PMID- 28595826 TI - "What happens behind the curtains?" An exploration of ICU nurses' experiences of post mortem care on patients who have died in intensive care. AB - THE AIM OF THE STUDY: The aim of this study was to explore the experiences of intensive care nurses performing post mortem care on patients who had died in an intensive care unit at a private hospital in Cape Town. The study further sets out to identify educational needs and to offer recommendations that may address these needs for this sample of nurses. METHODOLOGY AND SETTING: A qualitative research design using a descriptive method was used to explore the experiences of a purposive heterogeneous sample of six nurses who were working in an intensive care unit in a private hospital in Cape Town. DATA COLLECTION AND ANALYSIS: A semi-structured interview which was audio-taped and transcribed verbatim was employed to collect data. Colaizzi's (1978) seven step inductive method was used to formulate naive themes. Following participant feedback, three main themes emerged: care of the dead body, detachment and thanatophobia. FINDINGS: Safeguarding the integrity and physical appearance of the dead body was the major finding and of the utmost priority for the participants in this study. Regardless of how the nurses felt about death, providing professional and quality care to the dead body and the family was seen as significantly important. The nurses, whilst performing post mortem care, experienced detachment from various relationships. This comprised of the nurse detaching him/herself professionally and emotionally from the dead patient, the family and him/herself from the death experience. This 'unspoken' experience of thanatophobia became apparent when the nurses were confronted by the reality of their own deaths. CONCLUSION AND RECOMMENDATIONS: In a technological society, where answers to many questions can be pursued through science, understanding the experience of death, as opposed to dying, may be logically incomprehensible. Death remains one of the most traumatic events experienced by the patient and their family, and in some instances nurses themselves. The study has drawn attention to the nurses' experiences and in doing so; the emotional and educational needs have been identified, and in part, pedagogical offerings are recommended. PMID- 28595828 TI - [Answer to Lemoine et al. "And if it happened to children? Adapting medical care during terrorist attacks with multiple pediatric victims"]. PMID- 28595827 TI - The ovine motor cortex: A review of functional mapping and cytoarchitecture. AB - In recent years, sheep (Ovis aries) have emerged as a useful animal model for neurological research due to their relatively large brain and blood vessel size, their cortical architecture, and their docile temperament. However, the functional anatomy of sheep brain is not as well studied as that of non-human primates, rodents, and felines. For example, while the location of the sheep motor cortex has been known for many years, there have been few studies of the somatotopy of the motor cortex and there were a range of discrepancies across them. The motivation for this review is to provide a definitive resource for studies of the sheep motor cortex. This work critically reviews the literature examining the organization of the motor cortex in sheep, utilizing studies that have applied direct electrical stimulation and histological methods A clearer understanding of the sheep brain will facilitate and progress the use of this species as a scientific animal model for neurological research. PMID- 28595829 TI - [A new treatment for vascular anomalies: Six cases treated with rapamycin]. AB - Vascular anomalies (VAs) result from the defective development of the embryonic vascular system and feature dysplastic malformed vessels, which are not always apparent at birth. They do not regress over the patient's lifetime; they usually have commensurate growth during childhood and may worsen over time if not treated. VAs may cause chronic painful swelling, bleeding, functional deficits or vital structure obstruction. These patients' quality of life is usually impaired because of the chronicity and recurrence of the disease. We report on six cases of complicated VAs, refractory to current treatments, treated with rapamycin, an mTor inhibitor recently used in VAs. PMID- 28595830 TI - [Negative perceptions of the risks associated with gaming in young adolescents: An exploratory study to help thinking about a prevention program]. AB - Given the growing use of video games and the growing number of adolescents with Internet gaming disorder (IGD), prevention in this area is necessary. The objective of this study was to investigate the use and most particularly the representations of the risks associated with the use of video games in young adolescents by comparing problematic (PGs) and nonproblematic gamers (NPGs). Gender differences were also explored. Five Parisian middle schools participated in this study and 434 adolescents (231 boys, mage=13.2 years; 203 girls, mage=13.1 years) answered several questions concerning videogames (including the Game Addiction Scale). Among all participants (n=434), 37 students (n=8.8%) could be considered PGs. Of these, 29 (n=78.4%) were boys. Generally, sample students' surf and play a great deal during the week: they spend an average of 2h per day playing video games and 4h per day on the Internet. The number of screens at home is significantly higher in PGs compared to NPGs, the remaining set at a high level (n>10). Most middle school students believe that time spent on video games can have an impact on physical and mental health but they have no impact on academic performance. The two types of video games responsible for problematic use were role-play games and first-person shooter games. Most negative consequences are reported more by girls than boys: eating problems (P=.037), sleep problems (P=.040), vision problems (P=.002), conflicts with parents (P<001), loss of time (P=.003), and lack of school investment (P<.001). For all participants, the main reasons for IGD were poor academic performance, lack of friends, lack of self-confidence and family problems. In NPGs, girls reported more than boys that family problems (P=.003), lack of self-confidence (P=.005) and negative self-image (P=.007) led to IGD. The three main features of the individual with IGD reported by PGs and NPGs is the failure to stop playing, playing instead of fulfilling one's obligations and doing nothing but play. Most of the respondents believed that one can be addicted to video games and that they can have an impact on physical and mental health. Adolescents are more aware of the impact gaming generates on themselves than on their relationship with the environment (school and family). These preliminary exploratory findings indicate that preventive action could be promoted for adolescents. To promote life skills, and given that girls often report more negative consequences than boys, it seems important to include these skills in prevention programs. PMID- 28595831 TI - [Charcot-Marie-Tooth disease associated with hip dysplasia in an adolescent]. AB - Charcot-Marie-Tooth disease (CMT) is classified into hereditary motor and sensory neuropathy and can induce severe neuro-orthopaedics deformities, disabling at an early age. Hip dysplasia is present in 6% of CMT patients affecting preferentially CMT1 patients and can appear from the age of 8 years. The pathophysiological is paradoxical because we are confronted with proximal osteoarthritis deformations but genetics research brings use new trail. The main functional complaint is a hip joint pain during walking. Four orthopaedics abnormalities can be revealed by physical and radiological exam: acetabular dysplasia, femoral dysplasia, high femoral antetorsion and excentric head of femur. The natural evolution, in the absence of treatment, is an early secondary osteoarthritis. The therapeutic management should be as early as possible with preventive measures and joint health. During the symptomatic phase, the only treatment is a surgical correction. A systematic clinical examination of the hip all CMT children and a radiograph of the pelvis at the slightest clinical suspicion is recommended. PMID- 28595832 TI - Cycling around Lysine Modifications. AB - Recent studies have revealed the existence of a plethora of previously unknown protein acyl-lysine modifications, affecting the functions of targets involved in diverse cellular processes. A recent study from the Hirschey laboratory has provided new chemical insights into the mechanisms of protein acylation. PMID- 28595833 TI - A history of calcium orthophosphates (CaPO4) and their biomedical applications. AB - The historical development of a scientific knowledge on calcium orthophosphates (CaPO4) from 1770-s till 1950 is described. Many forgotten and poorly known historical facts and approaches have been extracted from old publications and then they have been analyzed, systematized and reconsidered from the modern point of view. The chosen time scale starts with the earliest available studies of 1770 s (to the best of my findings, CaPO4 had been unknown before), passes through the entire 19th century and finishes in 1950, because since then the amount of publications on CaPO4 rapidly increases and the subject becomes too broad. Furthermore, since publications of the second half of the 20th century are easily accessible, the substantial amount of them has been already reviewed by other researchers. The reported historical findings clearly demonstrate that the substantial amount of the scientific facts and experimental approaches has been known for very many decades and, in fact, the considerable quantity of relatively recent investigations on CaPO4 is just either a further development of the earlier studies or a rediscovery of the already forgotten knowledge. PMID- 28595824 TI - Zika in the Americas, year 2: What have we learned? What gaps remain? A report from the Global Virus Network. AB - In response to the outbreak of Zika virus (ZIKV) infection in the Western Hemisphere and the recognition of a causal association with fetal malformations, the Global Virus Network (GVN) assembled an international taskforce of virologists to promote basic research, recommend public health measures and encourage the rapid development of vaccines, antiviral therapies and new diagnostic tests. In this article, taskforce members and other experts review what has been learned about ZIKV-induced disease in humans, its modes of transmission and the cause and nature of associated congenital manifestations. After describing the make-up of the taskforce, we summarize the emergence of ZIKV in the Americas, Africa and Asia, its spread by mosquitoes, and current control measures. We then review the spectrum of primary ZIKV-induced disease in adults and children, sites of persistent infection and sexual transmission, then examine what has been learned about maternal-fetal transmission and the congenital Zika syndrome, including knowledge obtained from studies in laboratory animals. Subsequent sections focus on vaccine development, antiviral therapeutics and new diagnostic tests. After reviewing current understanding of the mechanisms of emergence of Zika virus, we consider the likely future of the pandemic. PMID- 28595834 TI - The completely annotated genome and comparative genomics of the Peptoniphilaceae bacterium str. ING2-D1G, a novel acidogenic bacterium isolated from a mesophilic biogas reactor. AB - The strictly anaerobic Peptoniphilaceae bacterium str. ING2-D1G (=DSM 28672=LMG 28300) was isolated from a mesophilic laboratory-scale completely stirred tank biogas reactor (CSTR) continuously co-digesting maize silage, pig and cattle manure. Based on 16S rRNA gene sequence comparison, the closest described relative to this strain is Peptoniphilus obesi ph1 showing 91.2% gene sequence identity. The most closely related species with a validly published name is Peptoniphilus indolicus DSM 20464T whose 16S rRNA gene sequence is 90.6% similar to the one of strain ING2-D1G. The genome of the novel strain was completely sequenced and manually annotated to reconstruct its metabolic potential regarding anaerobic digestion of biomass. The strain harbors a circular chromosome with a size of 1.6 Mb that contains 1466 coding sequences, 53 tRNA genes and 4 ribosomal RNA (rrn) operons. The genome carries a 28,261bp prophage insertion comprising 47 phage-related coding sequences. Reconstruction of fermentation pathways revealed that strain ING2-D1G encodes all enzymes for hydrogen, lactate and acetate production, corroborating that it is involved in the acido- and acetogenic phase of the biogas process. Comparative genome analyses of Peptoniphilaceae bacterium str. ING2-D1G and its closest relative Peptoniphilus obesi ph1 uncovered rearrangements, deletions and insertions within the chromosomes of both strains substantiating a divergent evolution. In addition to genomic analyses, a physiological and phenotypic characterization of the novel isolate was performed. Grown in Brain Heart Infusion Broth with added yeast extract, cells were spherical to ovoid, catalase- and oxidase-negative and stained Gram-positive. Optimal growth occurred between 35 and 37 degrees C and at a pH value of 7.6. Fermentation products were acetate, butanoate and carbon dioxide. PMID- 28595835 TI - The effect of resveratrol, its naturally occurring derivatives and tannic acid on the induction of cell cycle arrest and apoptosis in rat C6 and human T98G glioma cell lines. AB - Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a potent chemopreventive and potentially cancer therapeutic agent. Since rapid metabolism limits resveratrol bioavailability, derivatives less prone to metabolic transformation are being sought and tested. We evaluated the effect of resveratrol, and its analogs (pterostilbene and 3,5,4'-trimethoxystilbene) along with tannic acid, on cell cycle and apoptosis in rat C6 and human T98G glioma cells. At concentration ranges both lower and higher than IC50 calculated based on MTT assay, all these polyphenols affected the cell cycle distribution. However, resveratrol and pterostilbene increased the percentage of the cells in S phase, while trimethoxystilbene (TMS) caused a massive accumulation of cells at the G2/M phase of the cell cycle. Tannic acid had no effect on cell cycle distribution in C6 cells, but increased the number of dead cells in both glioma cell lines. The ability to induce apoptosis by tannic acid and stilbenes was confirmed by phosphatidylserine externalization, the loss of mitochondrial membrane potential and the level of cleaved caspase-3. The apoptosis rate was most significantly increased by TMS and this was related to p53 induction. These results indicate that methoxylated stilbenes are efficient inhibitors of glioma cell proliferation and apoptosis inducers and might be considered adjuvants in glioma therapy. PMID- 28595836 TI - CON4EI: Selection of the reference chemicals for hazard identification and labelling of eye irritating chemicals. AB - Assessment of the acute eye irritation potential is part of the international regulatory requirements for testing of chemicals. In the past, several prospective and retrospective validation studies have taken place in the area of serious eye damage/eye irritation testing. Success in terms of complete replacement of the regulatory in vivo Draize rabbit eye test has not yet been achieved. A very important aspect to ensure development of successful alternative test methods and/or strategies for serious eye damage/eye irritation testing is the selection of appropriate reference chemicals. A set of 80 reference chemicals was selected for the CEFIC-LRI-AIMT6-VITO CON4EI (CONsortium for in vitro Eye Irritation testing strategy) project, in collaboration with Cosmetics Europe, from the Draize Reference Database published by Cosmetics Europe based on key criteria that were set in their paper (e.g. balanced by important driver of classification and physical state). The most important goals of the CON4EI project were to identify the performance of eight in vitro alternative tests in terms of driver of classification and to identify similarities/differences between the methods in order the build a successful testing strategy that can discriminate between all UN GHS categories. This paper provides background on selection of the test chemicals. PMID- 28595837 TI - Application of Caenorhabditis elegans (nematode) and Danio rerio embryo (zebrafish) as model systems to screen for developmental and reproductive toxicity of Piperazine compounds. AB - To enable selection of novel chemicals for new processes, there is a recognized need for alternative toxicity screening assays to assess potential risks to man and the environment. For human health hazard assessment these screening assays need to be translational to humans, have high throughput capability, and from an animal welfare perspective be harmonized with the principles of the 3Rs (Reduction, Refinement, Replacement). In the area of toxicology a number of cell culture systems are available but while these have some predictive value, they are not ideally suited for the prediction of developmental and reproductive toxicology (DART). This is because they often lack biotransformation capacity, multicellular or multi- organ complexity, for example, the hypothalamus pituitary gonad (HPG) axis and the complete life cycle of whole organisms. To try to overcome some of these limitations in this study, we have used Caenorhabditis elegans (nematode) and Danio rerio embryos (zebrafish) as alternative assays for DART hazard assessment of some candidate chemicals being considered for a new commercial application. Nematodes exposed to Piperazine and one of the analogs tested showed a slight delay in development compared to untreated animals but only at high concentrations and with Piperazine as the most sensitive compound. Total brood size of the nematodes was also reduced primarily by Piperazine and one of the analogs. In zebrafish Piperazine and analogs showed developmental delays. Malformations and mortality in individual fish were also scored. Significant malformations were most sensitively identified with Piperazine, significant mortality was only observed in Piperazine and only at the higest dose. Thus, Piperazine seemed the most toxic compound for both nematodes and zebrafish. The results of the nematode and zebrafish studies were in alignment with data obtained from conventional mammalian toxicity studies indicating that these have potential as developmental toxicity screening systems. The results of these studies also provided reassurance that none of the Piperazines tested are likely to have any significant developmental and/or reproductive toxicity issues to humans when used in their commercial applications. PMID- 28595838 TI - Deciphering the loop of epithelial-mesenchymal transition, inflammatory cytokines and cancer immunoediting. AB - Tumorigenesis and tumor progression relies on the dialectics between tumor cells, the extracellular matrix and its remodelling enzymes, neighbouring cells and soluble cues. The host immune response is crucial in eliminating or promoting tumor growth and the reciprocal coevolution of tumor and immune cells, during disease progression and in response to therapy, shapes tumor fate by activating innate and adaptive mechanisms. The phenotypic plasticity is a common feature of epithelial and immune cells and epithelial-mesenchymal transition (EMT) is a dynamic process, governed by microenvironmental stimuli, critical in tumor cell shaping, increased tumor cell heterogeneity and stemness. In this review we will outline how the dysregulation of microenvironmental signaling is crucial in determining tumor plasticity and EMT, arguing how therapy resistance hinges on these dynamics. PMID- 28595840 TI - Burned Out or Bummed Out. PMID- 28595839 TI - Piezosurgery for Sagittal Split Osteotomy: Procedure Duration and Postoperative Sensory Perturbation. AB - PURPOSE: To evaluate piezosurgery for bilateral sagittal split osteotomy (BSSO) for its duration and inferior alveolar nerve (IAN) perturbation. PATIENTS AND METHODS: In this prospective randomized study, the authors evaluated 100 BSSO procedures in 50 patients. Piezoelectric (group I) and conventional (group II) osteotomies were carried out on each side of the mandible of a patient by 2 specialists. The surgeons had at least 1 year of experience using piezosurgery. The period from incision to complete splitting of the mandibular bone was recorded (ie, procedure duration). The intraoperative status (visibility and relocation) of the IAN also was recorded. The neurosensory function of the IAN was measured by the 2-point discrimination threshold and static light touch methods before surgery and postoperatively (1, 3, and 6 weeks and 6 and 12 months). Parameters were compared between the test groups by the paired t, nonparametric Wilcoxon, or chi2 test. RESULTS: Intergroup comparison showed the mean duration of osteotomy was significantly shorter for group I (17 +/- 6 vs 25 +/- 9 minutes; P < .001). The rate of intraoperative exposures of the IAN was slightly lower for group I (68%) compared with group II (81%). However, the difference was not relevant. Neurosensory disturbance and recovery of the IAN did not differ between groups. CONCLUSION: Piezoelectric osteotomy requires considerably less time than conventional mechanical approaches, but shows no advantage in preventing neurosensory perturbation. PMID- 28595841 TI - An Atypical Variant of Superolateral Dislocation of the Mandibular Condyle: A Case Report. AB - Dislocation of the mandibular condyle from the glenoid fossa can occur in anterior, posterior, lateral, and superior directions. Posterior, lateral, and superior dislocations are rare. Superolateral dislocation is seldom encountered in clinical practice. It is generally associated with fracture of the anterior or contralateral side of the mandible. The occurrence of superolateral dislocation of the condyle hooked above the zygomatic arch with an associated fracture of the medial pole of the condyle is rare and has been reported only once in the literature. This report describes another case in which the patient had superolateral dislocation of the mandibular condyle with a fractured medial pole without any associated fracture of the anterior or contralateral side of the mandible. The condyle was hooked laterally above the zygomatic arch. Open reduction of the dislocated condyle was performed and a good outcome was obtained. PMID- 28595842 TI - Preoperative implant selection for unilateral breast reconstruction using 3D imaging with the Microsoft Kinect sensor. AB - AIMS: This study aimed to investigate whether breast volume measured preoperatively using a Kinect 3D sensor could be used to determine the most appropriate implant size for reconstruction. METHODS: Ten patients underwent 3D imaging before and after unilateral implant-based reconstruction. Imaging used seven configurations, varying patient pose and Kinect location, which were compared regarding suitability for volume measurement. Four methods of defining the breast boundary for automated volume calculation were compared, and repeatability assessed over five repetitions. RESULTS: The most repeatable breast boundary annotation used an ellipse to track the inframammary fold and a plane describing the chest wall (coefficient of repeatability: 70 ml). The most reproducible imaging position comparing pre- and postoperative volume measurement of the healthy breast was achieved for the sitting patient with elevated arms and Kinect centrally positioned (coefficient of repeatability: 141 ml). Optimal implant volume was calculated by correcting used implant volume by the observed postoperative asymmetry. It was possible to predict implant size using a linear model derived from preoperative volume measurement of the healthy breast (coefficient of determination R2 = 0.78, standard error of prediction 120 ml). Mastectomy specimen weight and experienced surgeons' choice showed similar predictive ability (both: R2 = 0.74, standard error: 141/142 ml). A leave one-out validation showed that in 61% of cases, 3D imaging could predict implant volume to within 10%; however for 17% of cases it was >30%. CONCLUSION: This technology has the potential to facilitate reconstruction surgery planning and implant procurement to maximise symmetry after unilateral reconstruction. PMID- 28595845 TI - To Be or Not to Be a Multimodality Imager! PMID- 28595844 TI - Subclinical Myocardial Impairment in Metabolic Diseases. AB - Type 2 diabetes mellitus (T2DM) and obesity are important contributors to nonischemic heart failure (HF) and atrial fibrillation. There is a 2- to 5-fold increase in HF associated with T2DM, and there is a 5% in HF risk in men and 7% increment in women for every unit increment in body mass index, after adjustment for traditional cardiovascular risk factors. Likewise, the risk of atrial fibrillation increases by about 6% per unit increase in body mass index. Metabolic cardiomyopathy leads to a number of changes in cardiac structure and function that can be recognized by imaging in the asymptomatic phase, and these parameters can be used for monitoring the progression of disease or the response to therapy. The purpose of this review is to familiarize clinicians with the potential benefits of early detection of preclinical myocardial abnormalities, as well as the mechanisms that might inform interventions to prevent disease progression in patients with T2DM and obesity. PMID- 28595846 TI - Correction. PMID- 28595843 TI - Analysis of risk factors associated with unplanned reoperations following pediatric plastic surgery. AB - BACKGROUND/PURPOSE: Unplanned reoperation (UR) is an outcome measure with multiple advantages that can be used as a standardized tool to assess an institution's quality and safety of medical care. This study aimed to identify parameters associated with an increased likelihood of UR following plastic surgery in patients less than 18 years of age by using a large validated national multicenter database. METHODS/DESCRIPTION: We performed a retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) Pediatric database between 2012 and 2014 to identify pediatric patients undergoing primary plastic surgery procedures. Two cohorts were compared: patients who experienced UR and those who did not. Multiple logistic regression analysis was utilized to identify independent risk factors associated with UR. RESULTS: A total of 18,106 patients were identified in this analysis, with an overall UR rate of 0.8% (n = 137) within 30 days after surgery. Patients were on average 5.59 +/- 5.27 years of age with 9522 boys (52.6%) and 8584 girls (47.4%). The procedures most commonly associated with UR were excision of skin and subcutaneous tissue for hidradenitis (UR = 10.3%), forehead, and/or supraorbital rim reconstruction with grafts (allograft or prosthetic material, UR = 6.1%), use of multiplane external fixators (UR = 5.6%), mastectomy for gynecomastia (UR = 4.4%), and forehead and/or supraorbital rim reconstruction with autograft (3.3%). The average number of relative value units per case was 10.01 +/- 7.91. Independent risk factors for UR include inpatient procedure (p < 0.001), ASA class 3 or higher (p = 0.03), prolonged operative time (p < 0.001), and prior open wound or wound infection (p = 0.05). The most significant predictors of UR were postoperative medical and surgical complications (OR, 18.92 and 39.98, respectively, p < 0.001). CONCLUSIONS: With increasing focus on outcomes-driven healthcare, unplanned reoperation may be useful for monitoring quality across hospitals and identifying opportunities for quality improvement. This study provides the first analysis of risk factors associated with 30-day unplanned reoperations in pediatric plastic surgery. These results may aid in the informed consent process, improve patient risk assessment, counseling, and surgical planning. PMID- 28595847 TI - Interprofessional communication supporting clinical handover in emergency departments: An observation study. AB - BACKGROUND: Poor interprofessional communication poses a risk to patient safety at change-of-shift in emergency departments (EDs). The purpose of this study was to identify and describe patterns and processes of interprofessional communication impacting quality of ED change-of-shift handovers. METHODS: Observation of 66 change-of-shift handovers at two acute hospital EDs in Victoria, Australia. Focus groups with 34 nurse participants complemented the observations. Qualitative data analysis involved content and thematic methods. RESULTS: Four structural components of ED handover processes emerged represented by (ABCD): (1) Antecedents; (2) Behaviours and interactions; (3) Content; and (4) Delegation of ongoing care. Infrequent and ad hoc interprofessional communication and discipline-specific handover content and processes emerged as specific risks to patient safety at change-of-shift handovers. Three themes related to risky and effective practices to support interprofessional communications across the four stages of ED handovers emerged: 1) standard processes and practices, 2) teamwork and interactions and 3) communication activities and practices. CONCLUSIONS: Unreliable interprofessional communication can impact the quality of change-of shift handovers in EDs and poses risk to patient safety. Structured reflective analysis of existing practices can identify opportunities for standardisation, enhanced team practices and effective communication across four stages of the handover process to support clinicians to enhance local handover practices. Future research should test and refine models to support analysis of practice, and identify and test strategies to enhance ED interprofessional communication to support clinical handovers. PMID- 28595848 TI - From phase transitions to the topological renaissance: Comment on "Topodynamics of metastable brains" by Arturo Tozzi et al. PMID- 28595849 TI - On the relation between dependency distance, crossing dependencies, and parsing: Comment on "Dependency distance: a new perspective on syntactic patterns in natural languages" by Haitao Liu et al. PMID- 28595850 TI - Learning dynamics by theoretical tools of game theory: Comment on "Move me, astonish me...delight my eyes and brain: The Vienna Integrated Model of top-down and bottom-up processes in Art Perception (VIMAP) and corresponding affective, evaluative, and neurophysiological correlates" by M. Pelowski et al. PMID- 28595852 TI - Three-Dimensional Model-Based Segmentation in Echocardiography Using High Temporal Tissue and Blood Flow Information. AB - Accurate 3-D surface segmentation is a challenging task in echocardiography because of the relatively low image quality. We introduce a new method for 3-D segmentation of the endocardium involving temporal decorrelation of echo signals originating from tissue and blood using radiofrequency (RF) signals acquired in 3 D Doppler mode. Temporal features were extracted in 3-D Doppler mode, where a sequence of RF lines is recorded for each image line. Each set of RF lines is highly correlated because of the high pulse repetition frequency. However, for high blood flow, the RF signals will decorrelate over time in contrast to the endocardium, which will remain relatively highly correlated over time. These decorrelation features permit differentiation between myocardial tissue and blood flow. We describe an implementation of a 3-D segmentation model in which temporal information is used as external constraint. The model was validated in a phantom and in vivo in healthy volunteers (n = 5). The phantom study revealed that the model successfully segmented the artificial blood lumen even for low flow velocity and illustrated the sensitivity of the segmentations to flow rate. In healthy volunteers, high Dice similarity indices indicate that 3-D segmentation of the endocardial border in vivo is feasible. PMID- 28595851 TI - Delineation of Post-Procedure Ablation Regions with Electrode Displacement Elastography with a Comparison to Acoustic Radiation Force Impulse Imaging. AB - We compared a quasi-static ultrasound elastography technique, referred to as electrode displacement elastography (EDE), with acoustic radiation force impulse imaging (ARFI) for monitoring microwave ablation (MWA) procedures on patients diagnosed with liver neoplasms. Forty-nine patients recruited to this study underwent EDE and ARFI with a Siemens Acuson S2000 system after an MWA procedure. On the basis of visualization results from two observers, the ablated region in ARFI images was recognizable on 20 patients on average in conjunction with B-mode imaging, whereas delineable ablation boundaries could be generated on 4 patients on average. With EDE, the ablated region was delineable on 40 patients on average, with less imaging depth dependence. Study of tissue-mimicking phantoms revealed that the ablation region dimensions measured on EDE and ARFI images were within 8%, whereas the image contrast and contrast-to-noise ratio with EDE was two to three times higher than that obtained with ARFI. This study indicated that EDE provided improved monitoring results for minimally invasive MWA in clinical procedures for liver cancer and metastases. PMID- 28595853 TI - Acoustically Active Catheter for Intracardiac Navigation by Color Doppler Ultrasonography. AB - Navigation of intracardiac catheters by echocardiography is challenging because of the fundamental limitations of B-mode ultrasonography. We describe a catheter fitted with a piezoelectric crystal, which vibrates and produces an instantaneous marker in color flow Doppler scans. The navigation learning curve was explored first in six pigs. Accuracy and precision of targeting with the navigation marker "off" (i.e., B-mode imaging) and "on" were assessed in another six pigs. Paired comparisons confirmed significantly (p = 0.04) shorter mean distances achieved in each pig with the color Doppler marker. Pooled (mean +/- standard deviation) distance of the catheter tip from the target crystal was 5.27 +/- 1.62 mm by B mode guidance and 3.66 +/- 1.45 mm by color Doppler marker navigation. Dye injection targeted into the ischemic border zone was successful in 8 of 10 pigs. Intracardiac catheter navigation with color Doppler ultrasonography is more accurate compared with conventional guidance by B-mode imaging. PMID- 28595854 TI - Erratum to 'Intestinal colonisation with extended-spectrum cephalosporin- and colistin-resistant Enterobacteriaceae in HIV-positive individuals in Switzerland: molecular features and risk factors' [International Journal of Antimicrobial Agents 49/4 (2017) 519-521]. PMID- 28595855 TI - Dissociated time course between peak torque and total work recovery following bench press training in resistance trained men. AB - OBJECTIVE: To evaluate the time course of peak torque and total work recovery after a resistance training session involving the bench press exercise. DESIGN: Repeated measures with a within subject design. METHODS: Twenty-six resistance trained men (age: 23.7+/-3.7years; height: 176.0+/-5.7cm; mass: 79.65+/-7.61kg) performed one session involving eight sets of the bench press exercise performed to momentary muscle failure with 2-min rest between sets. Shoulder horizontal adductors peak torque (PT), total work (TW), delayed onset muscle soreness (DOMS) and subjective physical fitness were measured pre, immediately post, 24, 48, 72 and 96h following exercise. RESULTS: The exercise protocol resulted in significant pectoralis major DOMS that lasted for 72h. Immediately after exercise, the reduction in shoulder horizontal adductors TW (25%) was greater than PT (17%). TW, as a percentage of baseline values, was also less than PT at 24, 48 and 96h after exercise. Additionally, PT returned to baseline at 96h, while TW did not. CONCLUSIONS: Resistance trained men presented dissimilar PT and TW recovery following free weight bench press exercise. This indicates that recovery of maximal voluntary contraction does not reflect the capability to perform multiple contractions. Strength and conditioning professionals should be cautious when evaluating muscle recovery by peak torque, since it can lead to the repetition of a training session sooner than recommended. PMID- 28595856 TI - Component separation in the management of abdominal wall defect after laparostomy: Clinical and anatomical videos (with video). PMID- 28595857 TI - Direct control of B cells by Tregs: An opportunity for long-term modulation of the humoral response. AB - Tregs are believed to be important for maintaining self-tolerance and immune homeostasis. It is well established that Tregs maintain self-tolerance and immune homeostasis by directly suppressing and modulating the effector function of T cells. However, there are a small number of studies that suggest Tregs also directly suppress and modulate B cells. Herein we review the literature that has investigated direct action of Tregs on B cell effector function. This area of study is intriguing because it suggests Tregs may influence long-lived humoral immunity. PMID- 28595858 TI - Risk of Postoperative Venous Thromboembolism Among Pregnant Women. AB - Venous thromboembolism (VTE) is a critical complication after surgery. Although pregnancy is a known risk factor of VTE, available data on the risk of postoperative VTE are scarce. Using the American College of Surgeons National Surgical Quality Improvement Program database between 2006 and 2012, we matched 2,582 pregnant women to 103,640 nonpregnant women based on age, race, body mass index, and modified Rogers score. Pregnant women, compared with matched nonpregnant women, experienced higher incidence of VTE (0.5% vs 0.3%; odds ratio 1.93, 95% confidence interval 1.1 to 3.37, p = 0.02). Pregnant women also showed higher risk of pneumonia, ventilator dependence >=48 hours, bleeding, and sepsis than did the counterparts. In conclusion, pregnancy was associated with higher risk of VTE after surgery as well as other postoperative complications. The absolute risk difference was small, and careful evaluation against the potential risk and benefit should be given when surgical treatment is considered among pregnant women. PMID- 28595859 TI - Left Atrial Appendage Occlusion in Patients With Atrial Fibrillation and Previous Major Gastrointestinal Bleeding (from the Amplatzer Cardiac Plug Multicenter Registry). AB - History of major gastrointestinal (GI) bleeding may represent a frequent clinical indication for left atrial appendage occlusion (LAAO) in patients with non valvular atrial fibrillation (AF). This study aims to investigate the procedural safety and long-term outcome of patients with previous major GI bleeding (MGIB) who underwent LAAO. Data from the Amplatzer Cardiac Plug multicenter registry on 1,047 patients were analyzed. Patients with previous MGIB as indication for LAAO were compared with patients without previous MGIB. A total of 151 patients (14.4%) with previous MGIB were identified. Periprocedural major bleeding events were more frequent in patients with previous MGIB (4.0% vs 0.8%, p = 0.001). With an average follow-up of 1.3 years, the observed annual rate of stroke/transient ischemic attack and major bleeding for patients with previous MGIB were 2.1% (61.4% relative reduction according to the Congestive Heart failure, Hypertension, Age >=75 (doubled), Diabetes, Stroke (doubled), Vascular disease, Age 65-74, and Sex (female) [CHA2DS2-VASc] score) and 4.6% (20.1% relative reduction according to the expected rate based on the Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly (1 point each) [HAS BLED] score), respectively. In conclusion, in patients with non-valvular atrial fibrillation and previous MGIB, LAAO was associated with a low annual rate of stroke/transient ischemic attack. Periprocedural major bleeding events were more frequent in this specific population although the annual major bleeding rate showed a 20.1% relative risk reduction according to the HAS-BLED score. PMID- 28595860 TI - Diagnostic Performance of a Novel Method for Fractional Flow Reserve Computed from Noninvasive Computed Tomography Angiography (NOVEL-FLOW Study). AB - Coronary computed tomography angiography (CCTA)-derived fractional flow reserve from computed tomography (CT-FFR) may provide better diagnostic performance over CCTA alone, but the complexity of its method limits the use in clinical environment. The aim of the present study is to validate a newly developed vessel length based computational fluid dynamics scheme for the computation of FFR based on CCTA data, compare them with invasively measured FFR, and evaluate its diagnostic performance with that of CCTA. One hundred seventeen patients from 4 medical institutions who had clinically indicated invasive coronary angiography for suspected coronary artery disease (CAD) were enrolled. Invasive FFR measurement was performed in 218 vessels and these measurements were regarded as the reference standard. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CT-FFR on a per-vessel basis were 85.8%, 86.2%, 85.5%, 79.8%, and 90.3%, respectively, for CT-FFR <=0.80, and 66.1%, 75.9%, 59.5%, 55.5%, and 78.8%, respectively, for CCTA >=50%. A higher area under the receiver operating characteristic curve for CT-FFR was observed compared with CCTA (0.93 vs 0.74, p <0.0001). The CT-FFR and FFR correlated well (r = 0.76, p <0.001) with slight underestimation by CT-FFR (0.014 +/- 0.077, p = 0.007). With a novel method of vessel-length based computational fluid dynamics scheme, CT-FFR can be performed at a personal computer enhancing its applicability in clinical situation. The diagnostic accuracy of CT-FFR for the detection of functionally significant CAD was good and was superior to that of CCTA within a population of suspected CAD. PMID- 28595863 TI - Reflection, Change, and Opportunities. PMID- 28595862 TI - Safety and Efficacy of Uninterrupted Apixaban Therapy Versus Warfarin During Atrial Fibrillation Ablation. AB - Thromboembolic cerebrovascular accident remains a rare but potentially devastating complication of catheter-based atrial fibrillation (AF) ablation. Uninterrupted oral anticoagulant therapy with warfarin has become the standard of care when performing catheter-based AF ablation. Compared with warfarin, apixaban, a factor Xa inhibitor, has been shown to reduce the risk of stroke and major bleeding in nonvalvular AF. With an increase in apixaban use for stroke prophylaxis in patients with AF, there is an increased interest in the safety and efficacy of uninterrupted apixaban therapy during AF ablation. We compared the safety and efficacy of uninterrupted OA therapy with either warfarin or apixaban in all patients who underwent catheter-based AF ablation at the University of Alabama at Birmingham and at Augusta University Medical Center from January 7, 2013, to February 25, 2016. All patients underwent a transesophageal echocardiogram on the day of their ablation to assess for the presence of intracardiac thrombi. All complications were identified and classified as bleeding, thromboembolic events, or other. A total of 627 patients were analyzed as described earlier. There were 310 patients in the warfarin group and 317 patients in the apixaban group. There were 8 complications in the warfarin group and 5 complications in the apixaban group (p = 0.38). There were no thromboembolic complications in either group. In conclusion, the use of apixaban is as safe and effective as warfarin for uninterrupted OA therapy during catheter based ablation of AF. PMID- 28595861 TI - Comparison of Outcome of Coronary Artery Bypass Grafting Versus Drug-Eluting Stent Implantation for Non-ST-Elevation Acute Coronary Syndrome. AB - There is limited data comparing effectiveness of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) with drug-eluting stents in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS). We compared the long-term outcomes of the 2 revascularization strategies in 1,246 patients presented with NSTE-ACS for left main or multivessel coronary artery disease. Data were pooled from the Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients with Multivessel Coronary Artery Disease (BEST) trial, the Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus Eluting Stent in Patients with Left Main Coronary Artery Disease (PRECOMBAT) trial, and the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial. The primary outcome was a composite of death from any causes, myocardial infarction, or stroke. The baseline characteristics were similar between the 2 study groups. During the median follow-up of 60 months, the rate of the primary outcome was significantly lower with CABG than with PCI (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.56 to 0.98; p = 0.036). This difference was mainly attributed to a significant reduction in the rate of myocardial infarction (HR 0.50; 95% CI 0.31 to 0.82, p = 0.006). The superiority of CABG over PCI was consistent across the major subgroups. The individual risks of death from any causes or stroke were not different between the 2 groups. In contrast, the rate of repeat revascularization was significantly lower in the CABG group than in the PCI group (HR 0.56; 95% CI 0.41 to 0.75, p <0.001). In this study, among patients with NSTE-ACS for left main or multivessel coronary artery disease, CABG significantly reduces the risk of death from any causes, myocardial infarction, or stroke compared with PCI with drug-eluting stents. PMID- 28595864 TI - Hip strength and star excursion balance test deficits of patients with chronic ankle instability. AB - OBJECTIVES: To examine isometric hip strength in those with and without CAI, and determine the degree of Star Excursion Balance Test (SEBT) variance explained by isometric hip strength. DESIGN: Single-blinded, cross-sectional, case-control study. METHODS: Thirty individuals with CAI, 29 lateral ankle sprain (LAS) copers, and 26 healthy controls participated. We assessed dynamic postural control with the SEBT anterior (SEBT-ANT), posteromedial (SEBT-PM), and posterolateral (SEBT-PL) reaches, and isometric hip extension (EXT), abduction (ABD) and external rotation (ER) strength with hand-held dynamometry. The CAI and LAS coper groups' involved limbs and randomly selected limbs in controls were tested. Separate Kruskal-Wallis tests compared SEBT scores and isometric hip strength between groups. Backwards linear regression models determined the degree of SEBT variance explained by isometric hip strength. Statistical significance was set a priori at P<0.05. RESULTS: The CAI group had lower SEBT-ANT scores compared to LAS copers (P=0.03) and controls (P=0.03). The CAI group had lower ABD compared to LAS copers (P=0.03) and controls (P=0.02). The CAI group had lower ER compared to LAS copers (P=0.01) and controls (P=0.01). ER (R2=0.25, P=0.01) and ABD (R2=0.25, P=0.01) explained 25% of the CAI group's SEBT-PM and SEBT-PL variances, respectively. CONCLUSIONS: The CAI group had deficient dynamic postural control and isometric hip strength compared to LAS copers and controls. Additionally, the CAI group's isometric hip strength significantly influenced dynamic postural control performance. Future CAI rehabilitation strategies should consider hip muscular strengthening to facilitate improvements in dynamic postural control. PMID- 28595865 TI - Profiling of translational and rotational head accelerations in youth BMX with and without neck brace. AB - OBJECTIVES: To investigate the influence of BMX helmets and neck braces on translational and rotational accelerations in youth riders. DESIGN: Mixed model, repeated measure and correlation. METHODS: Twenty three competitive youth BMX riders classified by age group (6-9 years, 10-13 years and 14-18 years) completed 6 laps of an indoor BMX track at race pace, 3 laps without a neck brace (NB) and 3 without brace (WB). A triaxial accelerometer with gyroscope was placed behind the right ear to determine the mean number of accelerations, translational and rotational, of the head between conditions and by age group. RESULTS: Significant reductions by condition (p=0.02) and by age (p=0.04) were found for the number of accelerations, though no interactions (condition*age) were revealed. Significant increases by age (p=0.01) were revealed for translational accelerations, whilst significant increases by condition (p=0.02) were found for rotational accelerations. In addition, significant correlations were revealed between relative helmet mass and age (r=0.83; p=0.001) and relative helmet mass and number of accelerations (r=0.46; p=0.03). CONCLUSIONS: Accelerations at the head decreased with increased age, possibly due to the influence of greater stabilising musculature. Additionally, neck braces also significantly reduced the number of accelerations. However, the magnitude of accelerations may be influenced by riding dynamics. Therefore, the use of neck braces combined with strength work to develop neck strength, could aid in the reduction of head accelerations in youth BMX riders. PMID- 28595866 TI - Physical activity levels in Portuguese adolescents: A 10-year trend analysis (2006-2016). AB - OBJECTIVES: Previous studies have indicated that only a small proportion of Portuguese adolescents attain sufficient levels of physical activity for health. However, it is unknown whether the levels of moderate to vigorous physical activity (MVPA) have changed over a considerable time period in this country. Therefore, the aims of the present study were to examine the 10-year trend changes in self-reported MVPA among adolescents and also investigate differences by sex and age. DESIGN AND METHOD: This study compared two cross-sectional cohorts of youngsters aged 12-18 years, recruited in 2006 (N=1010; 461 boys and 549 girls) and in 2016 (N=1096; 461 boys and 635 girls), using identical procedures and instruments. The outcome variable, MVPA, was assessed by using the PACE+ screening measure. RESULTS: Main results showed a considerable decline in the overall levels of physical activity between 2006 and 2016 (-10.8%), as well as a small and declining proportion of adolescents achieving the international physical activity recommendations (2006: 10.7%; 2016: 8.1%). Age and sex-specific comparisons by time periods indicated that the 13- and 14-year-old male adolescents reported lower levels of MVPA in 2016 than their counterparts in 2006, and that the MVPA decline between the subgroups of 12- and 18-year-olds was higher in girls, in both 2006 and 2016. CONCLUSIONS: This study provides evidence of a secular decrease in self-reported MVPA levels among Portuguese adolescents. These results reinforce the need for interventions and policies aimed at promoting a more active lifestyle throughout adolescence. PMID- 28595867 TI - The match-to-match variation of match-running in elite female soccer. AB - OBJECTIVES: The purpose of this study was to examine the match-to-match variation of match-running in elite female soccer players utilising GPS, using full-match and rolling period analyses. DESIGN: Longitudinal study. METHODS: Elite female soccer players (n=45) from the same national team were observed during 55 international fixtures across 5 years (2012-2016). Data was analysed using a custom built MS Excel spreadsheet as full-matches and using a rolling 5-min analysis period, for all players who played 90-min matches (files=172). Variation was examined using co-efficient of variation and 90% confidence limits, calculated following log transformation. RESULTS: Total distance per minute exhibited the smallest variation when both the full-match and peak 5-min running periods were examined (CV=6.8-7.2%). Sprint-efforts were the most variable during a full-match (CV=53%), whilst high-speed running per minute exhibited the greatest variation in the post-peak 5-min period (CV=143%). Peak running periods were observed as slightly more variable than full-match analyses, with the post peak period very-highly variable. Variability of accelerations (CV=17%) and Player Load (CV=14%) was lower than that of high-speed actions. Positional differences were also present, with centre backs exhibiting the greatest variation in high-speed movements (CV=41-65%). CONCLUSIONS: Practitioners and researchers should account for within player variability when examining match performances. Identification of peak running periods should be used to assist worst case scenarios. Whilst micro-sensor technology should be further examined as to its viable use within match-analyses. PMID- 28595868 TI - Impaired hip muscle strength in patients with femoroacetabular impingement syndrome. AB - OBJECTIVES: Patients with femoroacetabular impingement (FAI) experience hip pain as well as decreased function and lowered quality of life. The aim was to compare maximal isometric and isokinetic muscle strength (MVC) during hip flexion and extension and rate of force development (RFD) during extension between patients with FAI and a matched reference group. Secondary, the aim was to compare patient hips and subgroups defined by gender and age as well as to investigate associations between hip muscle strength and self-reported outcomes. Design Cross sectional, comparative study Methods Sixty patients (36+/-9 years, 63% females) and 30 age and gender matched reference persons underwent MVC tests in an isokinetic dynamometer. RESULTS: During hip flexion and extension, patients' affected hip showed a strength deficit of 15-21% (p<0.001) and 10-25% (p<0.03) compared with reference MVC, respectively. The affected hip of the patients was significantly weaker than their contralateral hip. RFD was significantly decreased for both patient hips compared to the reference group (p<0.05). While age had less effect on MVC, female patients were more affected than male patients. Self-reported measures were associated with isometric hip muscle strength. CONCLUSIONS: Patients with FAI demonstrate decreased hip flexion and extension strength when compared to (1) reference persons and (2) their contralateral hip. There seems to be a gender specific affection which should be investigated further and addressed when planning training protocols. Furthermore, self-reported measures were associated with isometric muscle strength, which underlines the clinical importance of the reduced muscle strength. PMID- 28595869 TI - Multivariate modelling of subjective and objective monitoring data improve the detection of non-contact injury risk in elite Australian footballers. AB - OBJECTIVES: To assess the association between workload, subjective wellness, musculoskeletal screening measures and non-contact injury risk in elite Australian footballers. DESIGN: Prospective cohort study. METHODS: Across 4 seasons in 70 players from one club, cumulative weekly workloads (acute; 1 week, chronic; 2-, 3-, 4-week) and acute:chronic workload ratio's (ACWR: 1-week load/average 4-weekly load) for session-Rating of Perceived Exertion (sRPE) and GPS-derived distance and sprint distance were calculated. Wellness, screening and non-contact injury data were also documented. Univariate and multivariate regression models determined injury incidence rate ratios (IRR) while accounting for interaction/moderating effects. Receiver operating characteristics determined model predictive accuracy (area under curve: AUC). RESULTS: Very low cumulative chronic (2-, 3-, 4- week) workloads were associated with the greatest injury risk (univariate IRR=1.71-2.16, 95% CI=1.10-4.52) in the subsequent week. In multivariate analysis, the interaction between a low chronic load and a very high distance (adj-IRR=2.60, 95% CI=1.07-6.34) or low sRPE ACWR (adj-IRR=2.52, 95% CI=1.01-6.29) was associated with increased injury risk. Subjectively reporting "yes" (vs. "no") for old lower limb pain and heavy non-football activity in the previous 7 days (multivariate adj-IRR=2.01-2.25, 95% CI=1.02-4.95) and playing experience (>9 years) (multivariate adj-IRR=2.05, 95% CI=1.03-4.06) was also associated with increased injury risk, but screening data were not. Predictive capacity of multivariate models was significantly better than univariate (AUCmultivariate=0.70, 95% CI 0.64-0.75; AUCunivariate range=0.51-0.60). CONCLUSIONS: Chronic load is an important moderating factor in the workload injury relationship. Low chronic loads coupled with low or very high ACWR are associated with increased injury risk. PMID- 28595870 TI - High-speed running and sprinting as an injury risk factor in soccer: Can well developed physical qualities reduce the risk? AB - OBJECTIVES: This study investigated the association between high-speed running (HSR) and sprint running (SR) and injuries within elite soccer players. The impact of intermittent aerobic fitness as measured by the end speed of the 30-15 intermittent fitness test (30-15VIFT) and high chronic workloads (average 21-day) as potential mediators of injury risk were also investigated. DESIGN: Observational Cohort Study. METHODS: 37 elite soccer players from one elite squad were involved in a one-season study. Training and game workloads (session RPE*duration) were recorded in conjunction with external training loads (using global positioning system technology) to measure the HSR (>14.4kmh-1) and SR (>19.8kmh-1) distance covered across weekly periods during the season. Lower limb injuries were also recorded. Training load and GPS data were modelled against injury data using logistic regression. Odds ratios (OR) were calculated with 90% confidence intervals based on 21-day chronic training load status (sRPE), aerobic fitness, HSR and SR distance with these reported against a reference group. RESULTS: Players who completed moderate HSR (701-750-m: OR: 0.12, 90%CI: 0.08 0.94) and SR distances (201-350-m: OR: 0.54, 90%CI: 0.41-0.85) were at reduced injury risk compared to low HSR (<=674-m) and SR (<=165-m) reference groups. Injury risk was higher for players who experienced large weekly changes in HSR (351-455-m; OR: 3.02; 90%CI: 2.03-5.18) and SR distances (between 75-105-m; OR: 6.12, 90%CI: 4.66-8.29). Players who exerted higher chronic training loads (>=2584 AU) were at significantly reduced risk of injury when they covered 1 weekly HSR distances of 701-750m compared to the reference group of <674m (OR=0.65, 90% CI 0.27-0.89). When intermittent aerobic fitness was considered based on 30-15VIFT performance, players with poor aerobic fitness had a greater risk of injury than players with better-developed aerobic fitness. CONCLUSIONS: Exposing players to large and rapid increases in HSR and SR distances increased the odds of injury. However, higher chronic training loads (>=2584 AU) and better intermittent aerobic fitness off-set lower limb injury risk associated with these running distances in elite soccer players. PMID- 28595871 TI - Identifying a motor proficiency barrier for meeting physical activity guidelines in children. AB - OBJECTIVES: This study examined the existence of a threshold level (proficiency barrier) of actual motor competence (MC) below which a child is not likely to attain 60min of moderate-to-vigorous physical activity (MVPA) per day. DESIGN: A cross-sectional study. METHODS: Actual MC was assessed in 326 children (48.5% boys; age=9.50+/-1.24years) using the Test of Gross Motor Development-2; MVPA was measured with ActiGraph GT3X+accelerometers. Perceived MC, included as a potential mediating variable, was assessed with the Self-Perception Profile for Children. Binary logistic (mediation) regression analyses controlling for sex and a chi-squared test were used to gain insight into the relationship between (the levels of) actual MC and the percentage of children meeting the MVPA guideline. RESULTS: Actual MC significantly predicted the percentage of children meeting the guideline (B=.03, SE=.01, p<.001), even when controlling for sex. Perceived MC did not mediate this relationship. Children with high actual MC (65-100 percentile) were 2.46 (p=.003) times more likely to meet the guideline than children with low actual MC (0-27 percentile). CONCLUSIONS: The present study demonstrates the potential impact of low MC on children's MVPA levels and suggests evidence for the existence of a proficiency barrier for meeting MVPA guidelines. Almost 90% of the children whose actual MC is below the 'average' threshold do not meet the MVPA guideline. As more children with higher levels of actual MC meet the guideline than their less competent peers, it is crucial to provide opportunities to sufficiently develop children's actual MC. PMID- 28595872 TI - Distribution and diversity of marine picocyanobacteria community: Targeting of Prochlorococcus ecotypes in winter conditions (southern Adriatic Sea). AB - Adriatic, the northernmost part of the Mediterranean Sea, due its oligotrophy, topography, and hydrology dynamics, and complex circulation patterns, was suggested as an important study site for rapid climatology impacts. Its southern part is mainly oligotrophic and dominated by picophytoplankton, with cyanobacteria as main representatives. Diversity and distribution patterns of different Prochlorococcus ecotypes were investigated by molecular tools and flow cytometry during the winter convection event in the southern Adriatic (BIOTA winter cruise; February/March 2015). Phylogenetic diversity based on clone libraries of the 16S-23S ribosomal DNA ITS region, as well as flow cytometry (histograms of red fluorescence), indicated presence of 2 different Prochlorococcus in the Adriatic. HLI, as a typical clade for Mediterranean Sea, was likewise found to be dominant Prochlorococcus in the Adriatic, followed by less abundant LLI clade. In addition, Prochlorococcus were found to co-occur with diverse Synechococcus population (53% and 47% of obtained ITS sequences, respectively). Different Prochlorococcus ecotypes had similar patterns of vertical distribution, predominantly occupying upper 100m depth layer, but their distribution was clearly affected by the heterogeneity of hydrological conditions, nitrogen concentration and temperature along vertical and horizontal sampling points. Different studies pointed out that, as a consequence of climate changes, serious alteration of biological and ecological patterns are already taking place Therefore, understanding of the distribution and abundance of picophytoplankton in Adriatic, being still limited, is much needed baseline for predicting possible biogeochemical impact of future environmental changes. PMID- 28595873 TI - Borderline Sarcomas and Smooth Muscle Tumours of Uncertain Malignant Potential. AB - Borderline sarcomas and smooth muscle tumours of uncertain malignant potential (STUMP) have an unpredictable clinical behaviour with frequent local recurrences and rarely, metastases. We review the current management of common subtypes of borderline sarcomas and STUMP. PMID- 28595874 TI - Evaluation of anti-diabetic activity of glycyrrhizin-loaded nanoparticles in nicotinamide-streptozotocin-induced diabetic rats. AB - Glycyrrhizin is an active constituent of the roots and rhizomes of Glycyrrhiza glabra and has anti-hyperglycemic effects. In this study, nanoparticles (NPs) loaded with glycyrrhizin or metformin were evaluated in vivo for their anti hyperglycemic potency towards type-II diabetes in rats. The NPs were produced via the ionotropic gelation method using the biocompatible polymers chitosan and gum arabic. The polymer concentration was optimized using the 32 factorial method to acquire both minimum particle size and maximum encapsulation efficiency. The NPs were then characterized with respect to particle size, encapsulation efficiency, stability, chemical interactions, and in vitro drug dissolution profiles using spectroscopic and microscopic analysis. Furthermore, glycyrrhizin and metformin and their nanoformulations were administered for 21 successive days to diabetic rats. Glycyrrhizin-loaded NPs had significant anti-diabetic effects even though they contained approximately one quarter of the dosage relative to the pure form. PMID- 28595875 TI - Development of IgY antibodies against anti-snake toxins endowed with highly lethal neutralizing activity. AB - Snakebite envenoming is a major neglected disease related to poverty in developing countries. Treatment involves the administration of a specific antivenom serum and auxiliary therapies, if necessary. The improvement of antibodies is of great importance for the technological advancement of antivenom therapy and to reduce the morbidity and mortality associated with this medical burden. In the present study, adult hens were immunized nine times with 20MUg of B. arietans or C. d. terrificus venoms at three-week intervals between immunizations. Developing antibodies presented increasing avidity and affinity to antigenic toxin epitopes along immunization, attaining a plateau after the seventh immunization. Pooled egg yolk-purified IgY antivenom antibodies, subjected to in vitro-in vivo lethality assay using Swiss adult mice, exhibited potent venom lethal neutralizing activity. Taken together, chickens under the described immunization schedule were considered alternative candidates for antivenom production. Lower maintenance costs, a simple antibody manufacturing process and immunization suffering restrictions are additional advantages. PMID- 28595876 TI - A Diagnostic Accuracy Meta-analysis of CT and MRI for the Evaluation of Small Bowel Crohn Disease. AB - RATIONALE AND OBJECTIVES: This study aimed to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) and computed tomography (CT) in assessing small bowel (SB) Crohn disease (CD). MATERIALS AND METHODS: We systematically searched PubMed, Elsevier, ScienceDirect, Karger, Web of Science, Wiley Online Library, and Springer for studies in which CT or MRI were evaluated to assess SB CD. Bivariate random effect meta-analytic methods were used to estimate pooled sensitivity, specificity, and receiver operating characteristic curves. Diagnostic odds ratios (DORs) in a per-patient-based analysis were estimated. The area under the receiver operating characteristic curve was also calculated to measure the diagnostic accuracy. RESULTS: Twenty-one studies involving 913 patients were included in this meta-analysis. There was no significant difference observed between modalities. The diagnostic performances (lnDOR) for CT and MRI also showed no significant difference. Subgroup analysis was performed for MR imaging (MR enteroclysis, MR enterography, and CT enterography). The diagnostic performances (lnDOR) for MR enteroclysis, MR enterography, and CT enterography did not show a significant difference among them. No significant difference was found between these techniques. Deeks funnel plot asymmetry test for publication bias showed that no significant publication bias was observed in this analysis. CONCLUSIONS: This meta-analysis suggests that both MRI and CT have high diagnostic accuracy in detecting SB CD. MRI has the potential to be the first line radiation-free modality for SB CD imaging. PMID- 28595878 TI - A Northern European perspective on creating more activity friendly cities. PMID- 28595877 TI - Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. AB - Ferroptosis has recently been identified as a mode of programmed cell death. However, little is yet known about the signaling mechanism. Here, we report that lipoxygenases (LOX) contribute to the regulation of RSL3-induced ferroptosis in acute lymphoblastic leukemia (ALL) cells. We show that the glutathione (GSH) peroxidase 4 (GPX4) inhibitor RSL3 triggers lipid peroxidation, production of reactive oxygen species (ROS) and cell death in ALL cells. All these events are impeded in the presence of Ferrostatin-1 (Fer-1), a small-molecule inhibitor of lipid peroxidation. Also, lipid peroxidation and ROS production precede the induction of cell death, underscoring their contribution to cell death upon exposure to RSL3. Importantly, LOX inhibitors, including the selective 12/15-LOX inhibitor Baicalein and the pan-LOX inhibitor nordihydroguaiaretic acid (NDGA), protect ALL cells from RSL3-stimulated lipid peroxidation, ROS generation and cell death, indicating that LOX contribute to ferroptosis. RSL3 triggers lipid peroxidation and cell death also in FAS-associated Death Domain (FADD)-deficient cells which are resistant to death receptor-induced apoptosis indicating that the induction of ferroptosis may bypass apoptosis resistance. By providing new insights into the molecular regulation of ferroptosis, our study contributes to the development of novel treatment strategies to reactivate programmed cell death in ALL. PMID- 28595879 TI - Predictors of Successful Hybrid-Approach Chronic Total Coronary Artery Occlusion Stenting: An Improved Model With Novel Correlates. AB - OBJECTIVES: The aim of this study was to develop a hybrid approach-specific model to predict chronic total coronary artery occlusion (CTO) percutaneous coronary intervention success, useful for experienced but not ultra-high-volume operators. BACKGROUND: CTO percutaneous coronary intervention success rates vary widely and have improved with the "hybrid approach," but current predictive models for success have major limitations. METHODS: Data were obtained from consecutively attempted patients from 7 clinical sites (9 operators, mean annual CTO volume 61 +/- 17 cases). Angiographic analysis of 21 lesion variables was performed centrally. Statistical modeling was performed on a randomly designated training group and tested in a separate validation cohort. The primary outcome of interest was technical success. RESULTS: A total of 436 patients (456 lesions) met entry criteria. Twenty-five percent of lesions had prior failed percutaneous coronary interventions at the site. The right coronary artery was the most common location (56.4%), and mean occlusion length was 24 +/- 20 mm. The initial approach was most often antegrade wire escalation (70%), followed by retrograde (22%). Success was achieved in 79.4%. Failure was most closely correlated with presence of an ambiguous proximal cap, and in the presence of an ambiguous proximal cap, specifically defined collateral score (combination of Werner and tortuosity scores) and retrograde tortuosity. Without an ambiguous proximal cap, poor distal target, occlusion length >10 mm, ostial location, and 1 operator variable contributed. Prior failure, and Werner and tortuosity scores alone, were only weakly correlated with outcomes. The basic 7-item model predicted success, with C statistics of 0.753 in the training cohort and 0.738 in the validation cohort, the later superior (p < 0.05) to that of the J-CTO (Multicenter CTO Registry of Japan) (0.55) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) (0.61) scores. CONCLUSIONS: Success can be reasonably well predicted, but that prediction requires modification and combination of angiographic variables. Differences in operator skill sets may make it challenging to create a powerful, generalizable, predictive tool. PMID- 28595880 TI - Predictive Scores of Success in CTO PCI: There Is No Substitute for Operator Experience and Skill. PMID- 28595882 TI - Septal Ablation in Younger Patients: Is It Time to Update the Guidelines? PMID- 28595881 TI - Outcomes of Alcohol Septal Ablation in Younger Patients With Obstructive Hypertrophic Cardiomyopathy. AB - OBJECTIVES: The aim of this study was to describe the safety and outcomes of alcohol septal ablation (ASA) in younger patients with obstructive hypertrophic cardiomyopathy. BACKGROUND: The American College of Cardiology Foundation/American Heart Association guidelines reserve ASA for older patients and patients with serious comorbidities. Data on long-term age-specific outcomes after ASA are scarce. METHODS: A total of 1,197 patients (mean age 58 +/- 14 years) underwent ASA for obstructive hypertrophic cardiomyopathy. Patients were divided into young (<=50 years), middle-age (51 to 64 years), and older (>=65 years) groups. RESULTS: Thirty-day mortality and pacemaker implantation rates were lower in young compared with older patients (0.3% vs. 2% [p = 0.03] and 8% vs. 16% [p < 0.001], respectively). Ninety-five percent of young patients were in New York Heart Association functional class I or II at last follow-up. During a mean follow-up period of 5.4 +/- 4.2 years, 165 patients (14%) died. Annual mortality rates of young, middle-age, and older patients were 1%, 2%, and 5%, respectively (p < 0.01). Annual adverse arrhythmic event rates were similar in the 3 age groups at about 1% (p = 0.90). Independent predictors of mortality in young patients were age, female sex, and residual left ventricular outflow tract gradient. Additionally, young patients treated with >=2.5 ml alcohol had a higher all-cause mortality rate (0.6% vs. 1.4% per year in patients treated with <2.5 ml, p = 0.03). CONCLUSIONS: ASA in younger patients with obstructive hypertrophic cardiomyopathy was safe and effective for relief of symptoms at long-term follow up. The authors propose that the indication for ASA can be broadened to younger patients. PMID- 28595883 TI - Prognostic Impact of Revascularization in Poor-Risk Patients With Critical Limb Ischemia: The PRIORITY Registry (Poor-Risk Patients With and Without Revascularization Therapy for Critical Limb Ischemia). AB - OBJECTIVES: The authors sought to investigate the prognostic impact of revascularization for poor-risk CLI patients in real-world settings. BACKGROUND: Critical limb ischemia (CLI) is often accompanied with various comorbidities, and frailty is not rare in the population. Although previous studies suggested favorable outcomes of revascularization for CLI patients, those studies commonly included the healthier, that is, less frail patients. METHODS: This was a multicenter prospective observational study, registering patients who presented with CLI and who required assistance for their daily lives because of their disability in activities of daily living (ADL) and/or impairment of cognitive function. Revascularization was either planned (revascularization group) or not planned (non-revascularization group). The primary endpoint was 1-year survival, and was compared between the revascularization and non-revascularization groups, using the propensity score-matching method. RESULTS: Between January 2014 and April 2015, a total of 662 patients were registered, of those 100 non revascularization patients were included. A total of 625 patients (94.4%) completed the 1-year follow-up. Death was observed in 223 patients (33.7%). After propensity score matching, the 1-year survival rate was 55.9% in the revascularization group versus 51.0% in the non-revascularization group, with no significant difference (p = 0.120). In the subgroups alive at 1 year after revascularization, health-related quality of life was significantly improved compared with baseline, whereas ADL scores were unchanged from baseline and still remained significantly worse than before CLI onset. CONCLUSIONS: The 1-year overall survival rate was not significantly different between the revascularization and non-revascularization groups in poor-risk CLI patients. (Poor-Risk Patients With and Without Revascularization Therapy for Critical Limb Ischemia; [PRIORITY Registry]; UMIN000012871). PMID- 28595884 TI - Chronic Limb Ischemia: Ischemia in the Extreme. PMID- 28595886 TI - Good Intentions, Unintended Consequences? PMID- 28595885 TI - The Effect of Clinical Care Location on Clinical Outcomes After Peripheral Vascular Intervention in Medicare Beneficiaries. AB - OBJECTIVES: Modifications in reimbursement rates by Medicare in 2008 have led to peripheral vascular interventions (PVI) being performed more commonly in outpatient and office-based clinics. The objective of this study was to determine the effects of this shift in clinical care setting on clinical outcomes after PVI. BACKGROUND: Modifications in reimbursement have led to peripheral vascular intervention (PVI) being more commonly performed in outpatient hospital settings and office-based clinics. METHODS: Using a 100% national sample of Medicare beneficiaries from 2010 to 2012, we examined 30-day and 1-year rates of all-cause mortality, major lower extremity amputation, repeat revascularization, and all cause hospitalization by clinical care location of index PVI. RESULTS: A total of 218,858 Medicare beneficiaries underwent an index PVI between 2010 and 2012. Index PVIs performed in inpatient settings were associated with higher 1-year rates of all-cause mortality (23.6% vs. 10.4% and 11.7%; p < 0.001), major lower extremity amputation (10.1% vs. 3.7% and 3.5%; p < 0.001), and all-cause repeat hospitalization (63.3% vs. 48.5% and 48.0%; p < 0.001), but lower rates of repeat revascularization (25.1% vs. 26.9% vs. 38.6%; p < 0.001) when compared with outpatient hospital settings and office-based clinics, respectively. After adjustment for potential confounders, patients treated in office-based clinics remained more likely than patients in inpatient hospital settings to require repeat revascularization within 1 year across all specialties. There was also a statistically significant interaction effect between location of index revascularization and geographic region on the occurrence of all-cause hospitalization, repeat revascularization, and lower extremity amputation. CONCLUSIONS: Index PVI performed in office-based settings was associated with a higher hazard of repeat revascularization when compared with other settings. Differences in clinical outcomes across treatment settings and geographic regions suggest that inconsistent application of PVI may exist and highlights the need for studies to determine optimal delivery of PVI in clinical practice. PMID- 28595887 TI - Meta-Analysis of Strategies for Patients With Multivessel Disease Undergoing Percutaneous Coronary Intervention: Does the Timing of Staged Procedures Matter? PMID- 28595888 TI - Reply: Meta-Analysis of Strategies for Patients With Multivessel Disease Undergoing Percutaneous Coronary Intervention: Does the Timing of Staged Procedures Matter? PMID- 28595889 TI - Combined Criterion Algorithm for Computed Tomography. PMID- 28595890 TI - Reply: Combined Criterion Algorithm for Computed Tomography. PMID- 28595891 TI - Interventional Cardiology's Golden Age of Publishing. PMID- 28595892 TI - Localization of optic disc and fovea in retinal images using intensity based line scanning analysis. AB - Accurate detection of diabetic retinopathy (DR) mainly depends on identification of retinal landmarks such as optic disc and fovea. Present methods suffer from challenges like less accuracy and high computational complexity. To address this issue, this paper presents a novel approach for fast and accurate localization of optic disc (OD) and fovea using one-dimensional scanned intensity profile analysis. The proposed method utilizes both time and frequency domain information effectively for localization of OD. The final OD center is located using signal peak-valley detection in time domain and discontinuity detection in frequency domain analysis. However, with the help of detected OD location, the fovea center is located using signal valley analysis. Experiments were conducted on MESSIDOR dataset, where OD was successfully located in 1197 out of 1200 images (99.75%) and fovea in 1196 out of 1200 images (99.66%) with an average computation time of 0.52s. The large scale evaluation has been carried out extensively on nine publicly available databases. The proposed method is highly efficient in terms of quickly and accurately localizing OD and fovea structure together compared with the other state-of-the-art methods. PMID- 28595893 TI - Altered morphology of the nucleus accumbens in persistent developmental stuttering. AB - PURPOSE: Neuroimaging studies in persistent developmental stuttering repeatedly report altered basal ganglia functions. Together with thalamus and cerebellum, these structures mediate sensorimotor functions and thus represent a plausible link between stuttering and neuroanatomy. However, stuttering is a complex, multifactorial disorder. Besides sensorimotor functions, emotional and social motivational factors constitute major aspects of the disorder. Here, we investigated cortical and subcortical gray matter regions to study whether persistent developmental stuttering is also linked to alterations of limbic structures. METHODS: The study included 33 right-handed participants who stutter and 34 right-handed control participants matched for sex, age, and education. Structural images were acquired using magnetic resonance imaging to estimate volumetric characteristics of the nucleus accumbens, hippocampus, amygdala, pallidum, putamen, caudate nucleus, and thalamus. RESULTS: Volumetric comparisons and vertex-based shape comparisons revealed structural differences. The right nucleus accumbens was larger in participants who stutter compared to controls. CONCLUSION: Recent theories of basal ganglia functions suggest that the nucleus accumbens is a motivation-to-movement interface. A speaker intends to reach communicative goals, but stuttering can derail these efforts. It is therefore highly plausible to find alterations in the motivation-to-movement interface in stuttering. While behavioral studies of stuttering sought to find links between the limbic and sensorimotor system, we provide the first neuroimaging evidence of alterations in the limbic system. Thus, our findings might initialize a unified neurobiological framework of persistent developmental stuttering that integrates sensorimotor and social-motivational neuroanatomical circuitries. PMID- 28595894 TI - Arterial function parameters in patients with metabolic syndrome and severe hypertriglyceridemia. AB - BACKGROUND: Hypertriglyceridemia (hTG) is 1 of the dyslipidemia manifestations in patients with metabolic syndrome (MetS). However, for several decades, the role of hTG in cardiovascular risk was not well established. OBJECTIVE: The aim of this study was to assess the parameters of the vascular structure and function in patients with MetS and different degree of hTG. METHODS: Patients (aged 40-65 years) with MetS were divided into 3 groups by triglyceride (TG) levels according to National Cholesterol Education Program Adult Treatment Panel III Guidelines: severe hTG (TG >= 500 mg/dL), moderate hTG (TG 200-499 mg/dL), and a control (TG < 150 mg/dL) groups. Noninvasive assessment of vascular parameters (aortic augmentation index adjusted for heart rate 75 bpm [AixHR75], pulse wave velocity [PWV], flow-mediated dilatation, and common carotid artery intima-media thickness (IMT)) were performed. RESULTS: Among the 1938 patients analyzed, 1041 had hTG. Moderate hTG was observed in 90.40% (n = 941), whereas severe TG was observed in 9.6% (n = 100) of patients. Overall TG concentration was 231.17 +/- 184.23 mg/dL; in severe hTG group, TG concentration was 795.36 +/- 368.45 mg/dL, in moderate hTG group 285.20 +/- 70.86 mg/dL, and 112.48 +/- 24.80 mg/dL in control group. AIxHR75 and IMT were the lowest in the severe hTG group (P < .001 for both). Mean arterial pressure, carotid-radial PWV (9.25 +/- 1.13 vs 9.24 +/- 1.28 vs 8.91 +/- 1.28; P < .001) as well as carotid-femoral PWV (8.63 +/- 1.65 vs 8.75 +/- 1.58 vs 8.51 +/- 1.6; P = .006) were the higher in hTG groups compared with control. There were no significant differences between groups in flow-mediated dilatation (3.39 +/- 2.01 vs 3.26 +/- 2.43 vs 3.45 +/- 2.61, P = .283). CONCLUSIONS: Patients with MetS and severe hTG have lower IMT and AIxHR75 and higher PWV and mean arterial pressure. Many factors could affect arterial parameters, and more research are needed to investigate arterial parameters and hTG connection. PMID- 28595895 TI - Understanding the dissemination of appointment-based synchronization models using the CFIR framework. AB - BACKGROUND: The appointment based model (ABM) is a innovative model of pharmacy practice that combines medication synchronization with scheduled monthly appointments to improve patient medication adherence and convenience. It is being implemented in many pharmacies across the United States. OBJECTIVE: The purpose of this article is to use the Consolidated Framework for Implementation Research (CFIR) to discuss the barriers and facilitators of ABM implementation in community pharmacies while identifying priorities for additional implementation research. METHODS: A review of current evidence of ABM was examined using the five domains within the CFIR taxonomy. Interactions between these domains (the intervention, the individuals involved, the process used to implement the intervention, the inner setting, and the outer setting) and their sub domains were used to explain the current success of ABM and future barriers. RESULTS: The CFIR is an effective theoretical framework for assessing ABM. It helps identify key constructs in ABM implementation and their relationships. It also suggests future research to facilitate its adoption as a standard of pharmacy practice. CONCLUSIONS: The adoption of ABM by pharmacies will be facilitated by better evidence of its clinical and economic impact on patient health outcomes, standardization of ABM, and integrating it into current workflows. PMID- 28595897 TI - System influences on work disability due to low back pain: An international evidence synthesis. AB - Work disability due to low back pain is a significant global health concern. Current policy and practice aimed at tackling this problem is largely informed by the biopsychosocial model. Resultant interventions have demonstrated some small scale success, but they have not created a widespread decrease in work disability. This may be explained by the under-representation of the less measurable aspects in the biopsychosocial evidence base; namely the influence of relevant systems. Thus, a 'best-evidence' synthesis was conducted to collate the evidence on how compensatory (worker's compensation and disability benefits), healthcare and family systems (spouse/partner/close others) can act as obstacles to work participation for those with low back pain. Systematic searches of several scientific and grey literature sources were conducted, resulting in 1762 records. Following a systematic exclusion process, 57 articles were selected and the evidence was assessed using a system adapted from previous large-scale policy reviews conducted in this field. Results indicated how specific features of relevant systems could act as obstacles to individual efforts/interventions aimed at tackling work disability due to LBP. These findings reinforce the need for a 'whole-systems' approach, with all key players onside and have implications for the revision of current biopsychosocial-informed policy and practice. PMID- 28595896 TI - Structural Basis for the Altered PAM Recognition by Engineered CRISPR-Cpf1. AB - The RNA-guided Cpf1 nuclease cleaves double-stranded DNA targets complementary to the CRISPR RNA (crRNA), and it has been harnessed for genome editing technologies. Recently, Acidaminococcus sp. BV3L6 (AsCpf1) was engineered to recognize altered DNA sequences as the protospacer adjacent motif (PAM), thereby expanding the target range of Cpf1-mediated genome editing. Whereas wild-type AsCpf1 recognizes the TTTV PAM, the RVR (S542R/K548V/N552R) and RR (S542R/K607R) variants can efficiently recognize the TATV and TYCV PAMs, respectively. However, their PAM recognition mechanisms remained unknown. Here we present the 2.0 A resolution crystal structures of the RVR and RR variants bound to a crRNA and its target DNA. The structures revealed that the RVR and RR variants primarily recognize the PAM-complementary nucleotides via the substituted residues. Our high-resolution structures delineated the altered PAM recognition mechanisms of the AsCpf1 variants, providing a basis for the further engineering of CRISPR Cpf1. PMID- 28595898 TI - Transcriptional signatures of parasitization and markers of colony decline in Varroa-infested honey bees (Apis mellifera). AB - Extensive annual losses of honey bee colonies (Apis mellifera L.) reported in the northern hemisphere represent a global problem for agriculture and biodiversity. The parasitic mite Varroa destructor, in association with deformed wing virus (DWV), plays a key role in this phenomenon, but the underlying mechanisms are still unclear. To elucidate these mechanisms, we analyzed the gene expression profile of uninfested and mite infested bees, under laboratory and field conditions, highlighting the effects of parasitization on the bee's transcriptome under a variety of conditions and scenarios. Parasitization was significantly correlated with higher viral loads. Honey bees exposed to mite infestation exhibited an altered expression of genes related to stress response, immunity, nervous system function, metabolism and behavioural maturation. Additionally, mite infested young bees showed a gene expression profile resembling that of forager bees. To identify potential molecular markers of colony decline, the expression of genes that were commonly regulated across the experiments were subsequently assessed in colonies experiencing increasing mite infestation levels. These studies suggest that PGRP-2, hymenoptaecin, a glucan recognition protein, UNC93 and a p450 cytocrome maybe suitable general biomarkers of Varroa induced colony decline. Furthermore, the reliability of vitellogenin, a yolk protein previously identified as a good marker of colony survival, was confirmed here. PMID- 28595899 TI - [Who decides what data should be recorded in the medical history in relation to the biological origin?] AB - There is an increasing request by patients or their representatives not to have some data registered in their clinical history or if such data exists to be deleted. Without doubt, this is so because such clinical data is accessed by various professionals who in most cases are not directly involved in caring for such patients. On the other hand, such data is copied and iteratively and unnecessary reproduced in various discharge reports and others forms. The problem arises when such controversial data refer to particularly sensitive clinical aspects such as assisted reproduction techniques, which invades personal and family privacy. Therefore, the question is who determines what data should be recorded in the medical records and according to what criteria should be taken that decision? PMID- 28595900 TI - [Study of the nutritional status of patients over 65 years included in the home care program in an urban population]. AB - OBJECTIVE: To analyse the nutritional status of patients older than 65 years included in the home care program (PAD). DESIGN: Croos-sectional study. EMPLACEMENT: 3 urban health centers. PARTICIPANTS: 218 patients in the PAD. METHOD: Mini Nutritional Assessment questionnaire (MNA) was applied. Sociodemographic, anthropometric, dependency, emotional and cognitive status and analytical parameters: 57 variables were collected. Possible associations were analysed by applying the chi square and variance analysis. The level of significance was considered to be P<.05 was considered. RESULTS: The mean age was 83.9 years (SD=7.4); 34.9% were institutionalized and 80.7% were women; 21.2% of patients were malnourished and 40.1% were at risk of it. A significant association was established between poorer nutritional status and older age, lower BMI, greater dependence on basic and instrumental activities of daily living and greater cognitive impairment. The lowest mean hemoglobin, albumin, and iron levels were also associated with malnutrition and risk of malnutrition. CONCLUSIONS: More than half of PAD patients are malnourished or at risk for it, and a high proportion of them some laboratory abnormality susceptible to be corrected. Most cognitive impairment and functional dependence are closely related to malnutrition; so patients with these characteristics should receive more attention from the nutritional point of view. PMID- 28595902 TI - July 2012 (vol. 207, no. 1, page 14). PMID- 28595901 TI - Purification process for MUFA- and PUFA-based monoacylglycerols from edible oils. AB - Important health benefits have been attributed to monoacylglycerols (MAGs) due to their various physiological functions, owing to which they become candidates for use as functional foods in order to prevent the onset of certain diseases such as colon cancer. In this work, six edible oils, namely: olive, linseed, sunflower, evening primrose, DHASCO(r) and ARASCO(r) have been processed to obtain different MUFA- and PUFA- based MAGs. First, the oils were hydrolyzed by means of an enzymatic process using porcine pancreatic lipase and then the reaction products were fractionated by using a liquid chromatography column containing silica gel as stationary phase in order to purify the MAGs-enriched fraction. A second chromatography process was performed using silver nitrate coated silica gel as stationary phase, in order to obtain the different MUFA- and PUFA-based MAGs from the corresponding oils. Overall, MAGs based on oleic, linoleic, alpha-linolenic, gamma-linolenic, arachidonic and docosahexaenoic acids have been isolated in high yields and purities (92.6, 97.4, 95.3, 90.9, 100 and 95.3% purity, respectively). Positional distribution was determined by means of 1H NMR, which revealed a mix of 1(3) and 2-MAGs in variable proportions in the different MAGs. PMID- 28595903 TI - SHC004-221A1, a novel tyrosine kinase, potently inhibits T315I mutant BCR-ABL in chronic myeloid leukemia. AB - Although judicious use of tyrosine kinase inhibitors that target BCR-ABL constitutes an effective strategy for the control of chronic myeloid leukemia (CML), drug resistance is observed due to kinase domain mutations, among which a major one is BCR-ABLT315I. In this study, we identified SHC004-221A1 as a potent inhibitor of T315I and other BCR-ABL mutants. Biochemical assays demonstrated that SHC004-221A1 has an inhibitory effect on all selected BCR-ABL mutants. In vitro studies showed that SHC004-221A1 inhibited the proliferation of tumor cell lines carrying native and T315I mutant BCR-ABL. Signaling pathway analysis revealed that SHC004-221A1 inhibited the phosphorylation of STAT5 and CrkL, which contributed to the apoptosis of CML cells. In vivo studies indicated that SHC004 221A1 suppressed BCR-ALBT315I-driven tumor growth in mice. Taken together, the results of this study suggested that SHC004-221A1 may be a promising BCR-ABLT315I inhibitor for the treatment of CML. PMID- 28595904 TI - Characterization of Armitage and Yb containing granules and their relationship to nuage in ovary-derived cultured silkworm cell. AB - PIWI-interacting RNAs (piRNAs) are a class of endogenous small non-coding RNAs, which are mostly 24-32 nucleotides in length and interact specifically with PIWI subfamily of argonaute proteins. Despite the significant research progress in germ line piRNA pathway, its role in somatic cell is not well known. In Drosophila ovarian somatic cell, maturation of primary piRNA and its loading onto Piwi occurs at perinuclear Yb body. The Armitage (Armi) and Yb proteins are the major components of Yb body and specially expressed in ovarian somatic cell. Based on the reports, here we studied the BmArmi and BmYb in Bombyx mori ovary derived BmN4 cells expressing BmVasa. In this study, we show that BmArmi and BmYb co-localized with BmVasa at nuage. The helicase domains of BmArmi and BmYb are important for nuage localization. Moreover, RNAi of piRNA components reveal that BmArmi depend on BmAgo3 for nuage localization, and BmArmi and BmYb form cytoplasmic granules independently in the absence of BmVasa. Our results provide evidence that the BmArmi and BmYb coexist with BmVasa and play an important role in perinuclear nuage granules formation in ovary-derived BmN4 cell. PMID- 28595905 TI - Adiponectin regulates AQP3 via PPARalpha in human hepatic stellate cells. AB - Aquaporins (AQPs) are trans-membrane proteins which allow the movement of water and glycerol required by hepatic stellate cells (HSC) for triglyceride formation and lipid storage. Adiponectin (ADPQ) is a hormone produced by the adipose tissue, which is known to increase AQP3 expression. Since ADPQ receptor signals via the nuclear receptor PPAR we aimed to explore the role of this pathway in AQP3 regulation by ADPQ in HSC. AQP3 and CPT1alpha expression increased only after ADPQ but not rosiglitazone stimulation. In LX2 cells co-transfected with plasmids expressing PPARalpha or PPARgamma coupled to a luciferase reporter gene, only PPARalpha increased luciferase activity after ADPQ stimulation. Collectively, our findings demonstrate that ADPQ increases AQP3 expression through PPARalpha-mediated signaling in HSC. PMID- 28595906 TI - Construction of EGFR peptide gefitinib/quantum dots long circulating polymeric liposomes for treatment and detection of nasopharyngeal carcinoma. AB - Gefitinib/Quantum dots (QDs) loaded peptide long circulating liposomes (G/QDs-P LCPL) were successfully prepared for treatment and detection by fluorescence labeling for nasopharyngeal carcinoma. Gefitinib was found to have marked inhibition which is dose- and time-dependent. Hoechst 33258 florescence staining and wound-healing assay indicated that as G/QDs-P-LCPL concentration increased, HONE1 staining cells decreased, while the amount of nucleus pyknosis and karyorrhexis grew. Florescence tracing result shows that the drug mainly distributed through tumors. G-P-LCPL target the HONE1 cells and significantly increase the drug uptake efficiency so as to improve the cells inhibit rate compared with the non-targeting group. The EGFR peptide LCPL are potentially useful for drug and fluorescence labeled delivery applications. PMID- 28595907 TI - miR-141-3p functions as a tumor suppressor modulating activating transcription factor 5 in glioma. AB - Glioma is the most common malignant primary brain tumor which arises from the central nervous system. Our studies reported that an anti-apoptotic factor, activating transcription factor 5 (ATF5), is highly expressed in malignant glioma specimens and cell lines. Downregulation by dominant-negetive ATF5 could repress glioma cell proliferation and accelerate apoptosis. Here, we further investigate the upstream factor which regulates ATF5 expression. Bioinformatic analysis showed that ATF5 was a potential target of miR-141-3p. Luciferase reporter assay verified that miR-141-3p specifically targeted the ATF5 3'-UTR in glioma cells. Functional studied suggested that miR-141-3p overexpression inhibited proliferation and promoted apoptosis of glioma cells (U87MG and U251). Xenograft experiments proved the inhibition of miR-141-3p on glioma growth in vivo. Moreover, exogenous ATF5 without 3'-UTR restored the cell proliferation inhibition triggered by miR-141-3p. Taken together, we put forward that miR-141 3p is a new upstream target towards ATF5. It can serve as a crucial tumor suppressor in regulating the ATF5-regulated growth of malignant glioma. PMID- 28595908 TI - Association of angiotensin II receptor 1 and lectin-like oxidized low-density lipoprotein receptor-1 mediates the cardiac hypertrophy induced by oxidized low density lipoprotein. AB - To date the molecular mechanism of cardiac hypertrophy has not been completely elucidated. Since oxidized low-density lipoprotein (ox-LDL) is considered a risk marker for early ventricular remodeling, we speculated that ox-LDL may be related to cardiac hypertrophy. We observed the significantly upregulation of plasma ox LDL and hypertrophic responses, such as cardiomyocyte size and specific gene expressions in Apo E-/- mice fed with high fat diet, accompanied by the upregulation of AT1-R and lectin-like oxidized low-density protein receptor 1 (LOX-1). Ox-LDL treatment with neonatal rat cardiomyocyte for 24 h significantly induced similar hypertrophic responses and also upregulation of AT1-R and LOX-1. The analysis of co-immunoprecipitation and the bimolecular fluorescence complementation assay proved that LOX-1 and AT1-R could directly bind together in the presence of ox-LDL, suggesting a critical role of the association between LOX 1 and AT1-R in ox-LDL-induced cardiac hypertrophy. Furthermore, we found that the AT1-R blocker Losartan and LOX-1 neutralizing antibody through inhibiting AT1-R or LOX-1 could both decline ox-LDL-induced hypertrophic responses whereas angiotensin converting enzyme inhibitor Enalapril only partially inhibited the responses stimulated by ox-LDL. These findings suggested that ox-LDL could induce cardiac hypertrophy through the direct association of AT1-R and LOX-1. PMID- 28595909 TI - Strategies to reduce disparities in maternal morbidity and mortality: Patient and provider education. AB - A reduction in racial disparities in maternal morbidity and mortality requires effective education of both patients and providers. Although providers seem to recognize that disparities exist, there is a widespread need for improving our understanding differences in health care and outcomes and the factors that contribute to them. There are increasingly more educational materials available for the purpose of augmenting disparities education among patients and providers. However, it is important to incorporate contemporary learning methodologies and technologies to address our current knowledge deficit. Collaborative educational models with a multi-disciplinary approach to patient education will be essential. Ultimately, the comprehensive education of providers and patients will require efforts on the part of numerous stakeholders within patient care delivery models. Further investigation will be necessary to determine how best to disseminate this information to maximize the impact of patient and provider educations with the goal of eliminating disparities in maternal morbidity and mortality. PMID- 28595910 TI - Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine. AB - Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. PMID- 28595912 TI - The effect of manganese exposure in Atp13a2-deficient mice. AB - Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice. Wildtype and ATP13A2-deficient mice received saline or Mn at 5-9 or 12-19 months for 45days. Sensorimotor function was assessed starting at day 30. Autofluorescence was quantified in multiple brain regions and alpha-synuclein protein levels were determined in the ventral midbrain. Brain Mn, iron, zinc, and copper concentrations were measured in 5-9 month old mice. The results show Mn enhanced sensorimotor function, increased autofluorescence in the substantia nigra, and increased insoluble alpha-synuclein in the ventral midbrain in older ATP13A2-deficient mice. In addition, the Mn regimen used increased Mn concentration in the brain and levels were higher in Mn treated mutants than controls. These results indicate loss of ATP13A2 function leads to increased sensitivity to Mn in vivo. PMID- 28595911 TI - Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson's disease: Relevance to gene and environment interactions in metal neurotoxicity. AB - Parkinson's disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism. PMID- 28595913 TI - Performance and design considerations for an anaerobic moving bed biofilm reactor treating brewery wastewater: Impact of surface area loading rate and temperature. AB - Three 4 L anaerobic moving bed biofilm reactors (AMBBR) treated brewery wastewater with AC920 media providing 680 m2 protected surface area per m3 of media. Different hydraulic retention times (HRT; 24, 18, 12, 10, 8 and 6 h) at 40% media fill and 35 degrees C, as well as different temperatures (15, 25 and 35 degrees C) at 50% media fill and 18 h HRT were examined. Best performance at 35 degrees C and 40% media fill was observed when HRT was 18 h, which corresponded with 92% removal of soluble COD (sCOD). Organic loading rates (OLR) above 24 kg-COD m-3d-1 decreased performance below 80% sCOD removal at 35 degrees C and 40% media fill. The reason was confirmed to be that surface area loading rates (SALR) above 50 g-sCOD m-2d-1 caused excessive biofilm thickness that filled up internal channels of the media, leading to mass transfer limitations. Temperature had a very significant impact on process performance with 50% media fill and 18 h HRT. Biomass concentrations were significantly higher at lower temperatures. At 15 degrees C the mass of volatile solids (VS) was more than three times higher than at 35 degrees C for the same OLR. Biofilms acclimated to 25 degrees C and 15 degrees C achieved removal of 80% sCOD at SALR of 10 g-sCOD m-2d-1 and 1.0 g-sCOD m-2d-1, respectively. Even though biomass concentrations were higher at lower temperature, biofilm acclimated to 25 degrees C and 15 degrees C performed significantly slower than that acclimated to 35 degrees C. PMID- 28595914 TI - Ischemia-induced glomerular parietal epithelial cells hyperplasia: Commonly misdiagnosed cellular crescent in renal biopsy. AB - Ischemic pseudo-cellular crescent (IPCC) that is induced by ischemia and composed of hyperplastic glomerular parietal epithelial cells resembles cellular crescent. In this study, we aimed to assess the clinical and pathological features of IPCC in renal biopsy to avoid over-diagnosis and to determine the diagnostic basis. 4 IPCC cases diagnosed over a 4-year period (2012-2015) were evaluated for the study. Meanwhile, 5 cases of ANCA-associated glomerulonephritis and 5 cases of lupus nephritis (LN) were selected as control. Appropriate clinical data, morphology, and immunohistochemical features of all cases were retrieved. Results showed that the basement membrane of glomerulus with IPCC appeared as a concentric twisted ball, and glomerular cells of the lesion were reduced even entirely absent, and the adjacent afferent arterioles showed sclerosis or luminal stenosis. Furthermore, immune globulin deposition, vasculitis, and fibrinous exudate have not been observed in IPCC. While the cellular crescents showed diverse characteristics in both morphology and immunostaining in the control group. Therefore, these results indicated that IPCC is a sort of ischemic reactive hyperplasia and associated with sclerosis, stenosis, or obstruction of adjacent afferent arterioles, which is clearly different from cellular crescents result from glomerulonephritis. PMID- 28595915 TI - Predictive value for lymph node metastasis of epithelial-mesenchymal transition and cancer stem cell marker expression in early gastric cancer. AB - BACKGROUND: Minimally invasive therapies, including endoscopic mucosal resection or sentinel node navigation surgery, have been widely applied in early gastric cancer because of their benefits in promoting patient quality of life. However, lymph node dissection is beyond the capability of endoscopic therapy, and in sentinel node navigation surgery, the potential for skip metastasis is not negligible. Therefore, the possibility of lymph node metastasis is the most important factor to consider when deciding whether to apply the minimally invasive therapies. In the present study, the significance of epithelial mesenchymal transition and stem cell marker expression in lymph node metastasis in early gastric cancer was investigated. METHODS: We evaluated the significance of the expression of 5 epithelial mesenchymal transition-related markers (E cadherin, MMP7, S100A, Snail-1, and HGF) and 6 stem cell markers (ALDH1, SOX2, CD24, CD44, CD54, and CD133) in 119 early gastric cancer specimens using immunohistochemistry. Because protein expression is heterogeneous in gastric cancer, we analyzed the expression of these markers in two selected regions (one each at the superficial zone and the deep invasive front). RESULTS: Expression of E-cadherin, MMP7, HGF, and CD133 at the deep invasive front was associated with the absence of lymph node metastasis (P=0.013, 0.018, <0.001, and 0.026, respectively). Presence of diffuse-type component, lymphatic invasion, and lack of expression of HGF and CD133 at the deep invasive front were independent predictive markers of lymph node metastasis (P=0.019, <0.001, 0.015, and 0.047, respectively). CONCLUSIONS: Lymph node metastasis is strongly associated with expression status of HGF and CD133 at the deep invasive front, suggesting the usefulness of these proteins as independent predictive markers of lymph node metastasis in early gastric cancer. PMID- 28595916 TI - Combination of restriction endonuclease digestion with the DeltaDeltaCt method in real-time PCR to monitor etoxazole resistance allele frequency in the two-spotted spider mite. AB - Monitoring resistance allele frequency at the early stage of resistance development is important for the successful acaricide resistance management. Etoxazole is a mite growth inhibitor to which resistance is conferred by an amino acid substitution in the chitin synthase 1 (CHS1; I1017F) in T. urticae. If the susceptible allele can be specifically digested by restriction endonuclease, the DeltaDeltaCt method using real-time PCR for genomic DNA (RED-DeltaDeltaCt method) may be available for monitoring the resistance allele frequency. We tested whether the etoxazole resistance allele frequency in a pooled sample was accurately measured by the RED-DeltaDeltaCt method and validated whether the resistance variant frequency was correlated with etoxazole resistance phenotype in a bioassay. Finally, we performed a pilot test using field populations. Strong linearity of the measures by the RED-DeltaDeltaCt method with practical resistance allele frequencies; resistance allele frequency in the range between 0.5% to at least 0.75% was strictly represented. The strong linear relationship between hatchability of haploid male eggs after the etoxazole treatments (phenotype) and resistance allele frequencies in their mothers provided direct evidence that I1017F is a primary resistance factor to etoxazole in the strains used for experiments. The pilot test revealed a significant correlation between egg hatchability (including both diploid female eggs and haploid male eggs) and estimators in field populations. Consequently, we concluded that the RED DeltaDeltaCt method is a powerful tool for monitoring a resistance allele in a pooled sample. PMID- 28595918 TI - Studies on bromadiolone resistance in Rattus rattus populations from Punjab, India. AB - There are several reports on development of resistance to bromadiolone in different species of rodents around the globe, however, there is no such report involving systematic study from India. Hence, present study was carried out to investigate current status of bromadiolone resistance in house rat (Rattus rattus; n=154) collected from different poultry farms (n=8) based on feeding test, blood clotting response (BCR) test and molecular characterization of VKORC1 gene. Based on feeding test and BCR test, 28% rats were suspected to be resistant. Molecular analysis of VKORC1 gene of four suspected to be resistant rats having Prothrombin Time (PT) <70s, International Normalized Ratio (INR) <4.0 and died between 26 and 73days after treatment revealed no single nucleotide polymorphism (SNP) in nucleotide sequences. None of the sample under study showed complete nucleotide homology with previously reported nucleotide sequences of R. rattus. The sequences of VKORC1 gene under study can thus be considered as the novel sequences. Present investigation on molecular characterization of VKORC1 gene did not reveal any genetic resistance in Rattus rattus population against bromadiolone though rats could be considered resistant based on BCR and feeding tests. PMID- 28595917 TI - Assessment of toxicity and biochemical mechanisms underlying the insecticidal activity of chemically characterized Boswellia carterii essential oil against insect pest of legume seeds. AB - The present study was undertaken to investigate the insecticidal activity of chemically characterized Boswellia carterii essential oil (EO) and its mode of action against the pulse beetle Callosobruchus chinensis and C. maculatus. GC-MS analysis depicted alpha-thujene (69.16%), alpha-Pinene (7.20) and alpha Phellandrene (6.78%) as the major components of test EO. EO exhibited absolute toxicity at 0.10MUl/ml air against both C. chinensis and C. maculatus following 24h exposure. EO caused a significant reduction in oviposition and further reproductive development at LC50 doses (0.050MUl/ml to 0.066MUl/ml in air). Compared to control, a significant elevation in ROS level accompanied with impairment in enzymatic (SOD and CAT) and non-enzymatic (GSH/GSSH) antioxidant defense system has been observed in EO exposed insect pest. However, EO has no significant effect on in vivo AChE activity. An absolute protection of Vigna radiata seeds samples exposed to EO at LC90 doses was observed without affecting seed germination. The findings revealed that the B. carterii EO has strong insecticidal potential, hence, it could be recommended as a biorational alternative to synthetic insecticides. PMID- 28595919 TI - Resistance risk assessment for fludioxonil in Bipolaris maydis. AB - Bipolaris maydis (anamorph: Cochliobolus heterostrophus) is the causal agent of Southern Corn Leaf Blight (SCLB), leading to huge annually losses worldwide. Although fludioxonil, a phenylpyrrole fungicide with a broad spectrum of activity, was introduced in the 1990s, no baseline sensitivity has been established for B. maydis. One hundred field isolates were used to establish a baseline sensitivity of B. maydis against fludioxonil during 2015-2016. The results showed that the baseline sensitivity was distributed as a unimodal curve with a mean EC50 value of 0.044+/-0.022MUgmL-1. With repeated exposure to fludioxonil, a total of five fludioxonil-resistant mutants (RF>100, RF=Resistance factor) were obtained in the laboratory. Compared with the parental isolates, the five fludioxonil-resistant mutants showed decreased fitness in sporulation and virulence, and exhibited different features of sensitivity to various stresses (oxidation and osmotic pressure, cell membrane and cell wall inhibitors), but not in mycelial growth on PDA without stress amendation. The five fludioxonil resistant mutants showed a positive cross-resistance between fludioxonil and the dicarboximide fungicide procymidone, but not between fludioxonil and boscalid or fluazinam. All mutants exhibited stable resistance to fludioxonil after 10 transfers, as indicated by resistance factor values that ranged from 116.82 to 445.59. When treated with 1.0 M NaCl, all the fludioxonil-resistant mutants showed greater mycelial glycerol content than corresponding parental isolates. Sequencing alignment results of Bmos1 indicated that mutant R27-5 had a single point mutation (Z1125K), while the mutant R104 had a 34-bp deletion fragment between the codons of amino acid residues 1125 to 1236 and encodes a putative attenuated 1133-AA protein. The 34-bp deletion fragment led to not only a 11-AA deletion(DNAVNQKLAVR), but also the resulting frameshift mutation and early stop. The mutations of R27-5 and R104 were located in the Rec domain of the Bmos1 gene. No mutations at the Bmos1 were detected in the other three resistant mutants R27 1, R27-2 and R32. PMID- 28595920 TI - Tetrahydrophthalimidobenzoates as protoporphyrinogen IX oxidase inhibiting herbicides. AB - Tetrahydrophthalimidobenzoates are a class of protoporphyrinogen oxidase herbicides acting on the protoporphyrinogen oxidase enzyme. After the discovery of compound 1, a series of novel tetrahydrophthalimidobenzoate derivatives were designed and synthesized, and some synthesized compounds exhibited good herbicidal activity in controlling broadleaf weeds. The structure activity relationship of the synthesized compounds was also determined. Substitution of a fluorine atom at the 4-position of benzene ring resulted in better herbicidal activity than that with non-substitution. Among the conjunctional groups, methylene group with more methyl substitutions was the best. Consequently, compound 9 was found as the best of all in the synthesized compounds, and it is worthy of being developed not only because of its good herbicidal activity against broadleaf weeds with selectivity for maize, but also for its low toxicity to mammals. PMID- 28595921 TI - Synthesis, insecticidal activity and inhibition on topoisomerase I of 20(S)-t-Boc amino acid derivatives of camptothecin. AB - Camptothecin (CPT), a quinolone alkaloid extracted from Camptotheca acuminata Decne, exhibits potential insecticidal activities against various insect species. Our previous studies have showed that CPT induced apoptosis in Spodoptera exigua Hubner cell line and inhibited the relaxation activity of topoisomerase I (Topo I). In this study, total seven 20(S)-t-butoxy carbonyl-amino acid derivatives of CPT were synthesized and evaluated for insecticidal activities, cytotoxicity and Topo I inhibitory activities. Results showed that introduction of t-Boc amino acids to 20-position on CPT improves contact assay and cytotoxicity of most derivatives toward S. exigua but reduces inhibitory effect on relaxation activity of S. exigua Topo I. Furthermore, compounds 1d and 1g demonstrated higher level of contact activities and cytotoxicity than CPT and hydroxyl-camptothecin (HCPT), which are potential to be developed as potential insecticides targeted at more than Topo I. PMID- 28595922 TI - Fitness and inheritance of metaflumizone resistance in Plutella xylostella. AB - The diamondback moth, Plutella xylostella (L.) has developed resistance to many types of insecticides in the field. To study inheritance and fitness cost of metaflumizone resistance, a susceptible strain of diamondback moth was continuously selected with metaflumizone during 37 generations under laboratory conditions. The resistance to metaflumizone was at a high level (resistance ratios from 250.37 to 1450.47-fold). We investigated a metaflumizone resistance strain (G27) and a susceptible strain of P. xylostella, using the age-stage, two sex life table approach. Compared to the susceptible strain, egg duration, the developmental time of the first and second instar larvae, pupae duration, adult preoviposition period (APOP), total preoviposition period (TPOP), egg hatchability, the survival rate of second instar larva and the mean generation time (T) were significantly differences in the resistant strain. The resistant strain had a relative fitness of 0.78. The inheritance of metaflumizone resistance was also studied by crossing the metaflumizone resistant and susceptible populations. Results revealed an autosomal and incompletely recessive mode of inheritance for metaflumizone resistance in the resistant population of P. xylostella. The present study provided useful information for planning potential management strategies to delay development of metaflumizone resistance in P. xylostella. PMID- 28595923 TI - Microstructural and ultrastructural changes in the muscle cells of the oriental armyworm Mythimna separata Walker (Lepidoptera: Noctuidae) on treatment with wilforine. AB - This study investigated the mode of action of wilforine, an alkaloid with insecticidal properties, extracted from Tripterygium wilfordii Hook f., on the microstructure and ultrastructure of the muscle cells of larvae and adults of the oriental armyworm Mythimna separata Walker. The bioassay results showed that wilforine had oral toxicity against both M. separata larvae (LC50=63MUg/mL) and adults (LC50=36MUg/mL). The typical toxicity sign was paralysis leading to death. Both light and electron microscope observations revealed that damage to the muscle cells increased with poisoning time in larvae and adults treated with the LC80 dose of wilforine. Histopathological examinations in the muscle cells of M. separata adults showed that there were large cytoplasmic spaces, disrupted Z lines and swollen mitochondria in the muscle cells. Further, the sarcoplasmic reticulum was excessively dilated and fragmented; the nuclear membrane was ruptured; nuclear material was overflowing; and the myolemma was damaged. The similar pathological changes in the muscle cells of oriental armyworm larvae were observed, as above. In addition, a medullary sheath structure appeared and crystalline inclusion was also observed in the muscle cells of M. separata larvae. In conclusion, wilforine could induce pathological changes in the muscle cells of oriental armyworm larvae and adults, leading to their death; thus, the active site of action of wilforine maybe located in the muscle tissue of insects. PMID- 28595924 TI - Mechanisms of acaricide resistance in the cattle tick Rhipicephalus (Boophilus) microplus in Sri Lanka. AB - High tolerance of ticks to acaricides is increasingly becoming a problem to cattle farmers. Resistance status of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae)from two cattle farms of Sri Lanka were determined against different concentrations of pyrethroid permethrin, organophosphate malathion, organochlorine DDT and carbamate propoxur using Larval Packet Test (LPT) as recommended by Food and Agriculture Organization (FAO). Mechanisms of acaricide resistance were studied by conducting biochemical and PCR assays. Tick larvae were tested for the activity levels of acaricide metabolizing enzymes i.e.esterases, glutathione S-transferases (GSTs) and monooxygenases, and for altered target sites i.e.acetylcholinesterase (target site of organophosphates and carbamates) and sodium channel regulatory proteins (target site of pyrethroids and DDT). According to discriminating dosages specified by FAO for ticks both populations were 24-56% resistant to DDT. LC values showed that the both populations were susceptible to permethrin and resistant to malathion. Moderate insensitivity of AChEs and knock-down resistance (kdr) mutations were found as resistance mechanisms. GSTs and monooxygenases were not elevated. The kdr type mutation G72V (G215T in the gene) found in the sodium channel regulatory protein of R. (B.) microplus samples may be responsible for DDT resistance. Systematic and sophisticated insecticide resistance monitoring programmes and a better understanding on the mechanisms which govern resistance development are vital for future tick control programmes. PMID- 28595925 TI - Jinggangmycin-suppressed reproduction in the small brown planthopper (SBPH), Laodelphax striatellus (Fallen), is mediated by glucose dehydrogenase (GDH). AB - The small brown planthopper (SBPH), Laodelphax striatellus (Fallen), is a serious pest insect of rice, wheat, and maize in China. SBPH not only sucks plant sap but also transmits plant disease viruses, causing serious damage. These viruses include rice striped virus disease (RSV disease), black streaked dwarf, and maize rough disease virus. SBPH outbreaks are related to the overuse of pesticides in China. Some pesticides, such as triazophos, stimulate the reproduction of SBPH, but an antibiotic fungicide jinggangmycin (JGM) suppresses its reproduction. However, mechanisms of decreased reproduction of SBPH induced by JGM remain unclear. The present findings show that JGM suppressed reproduction of SBPH (?approximately 35.7%) and resulted in the down-regulated expression of glucose dehydrogenase (GDH). GDH-silenced control females (control+dsGDH) show that the number of eggs laid was reduced by 48.6% compared to control females. Biochemical tests show that the total lipid and fatty acid contents in JGM-treated and control+dsGDH females decreased significantly. Thus, we propose that the suppression of reproduction in SBPH induced by JGM is mediated by GDH via metabolic pathways. PMID- 28595926 TI - Curcumin induces autophagic cell death in Spodoptera frugiperda cells. AB - The increasing interest in the role of autophagy (type II cell death) in the regulation of insect toxicology has propelled study of investigating autophagic cell death pathways. Turmeric, the rhizome of the herb Curcuma longa (Manjal in Tamil, India and Jianghuang in Chinese) have been traditionally used for the pest control either alone or combination with other botanical pesticides. However, the mechanisms by which Curcuma longa or curcumin exerts cytotoxicity in pests are not well understood. In this study, we investigated the potency of Curcuma longa (curcumin) as a natural pesticide employing Sf9 insect line. Autophagy induction effect of curcumin on Spodoptera frugiperda (Sf9) cells was investigated using various techniques including cell proliferation assay, morphology analysis with inverted phase contrast microscope and Transmission Electron Microscope (TEM) analysis. Autophagy was evaluated using the fluorescent dye monodansylcadaverine (MDC). Cell death measurement was examined using 3-(4,5-Dimethylthiazol-2-yl)-2,5 Diphenyltetrazolium Bromide (MTT) within the concentrations of 5-15MUg/mL. Curcumin inhibited the growth of the Sf9 cells and induced autophagic cell death in a time and dose dependent manner. Staining the cells with MDC showed the presence of autophagic vacuoles while increased in a dose and time dependent manner. At the ultrastructural level transmission electron microscopy, cells revealed massive autophagy vacuole accumulation and absence of chromatin condensation. Protein expression levels of ATG8-I and ATG8-II, well-established markers of autophagy related protein were elevated in a time dependent manner after curcumin treatment. The present study proves that curcumin induces autophagic cell death in Sf9 insect cell line and this is the first report of cytotoxic effect of curcumin in insect cells and that will be utilized as natural pesticides in future. PMID- 28595927 TI - Application of fatty acids as antiviral agents against tobacco mosaic virus. AB - Numerous studies reported fatty acids (FAs) affecting basal resistance to bacterial and fungal pathogens in plants, but limited reports focused on antiviral agents. In this study, oleic acid was separated from cottonseed oil sludge by antiviral bioassay-guided methods. Antiviral activity of FAs was compared with that of Ningnanmycin. Subsequently, effects of FAs on defense related enzymes (PAL, POD) and defense-related genes (PR-1a, PR-5) were studied. FAs presented moderate antiviral activity, which is close to that of Ningnanmycin, and activities of PAL and POD were higher in oleic-acid-treated tobacco leaves than those inoculated with tobacco mosaic virus (TMV) and water treated tobacco. In oleic-acid-treated tobacco, expression levels of PR-1a and PR 5 genes rapidly increased from days 1-3. All results showed that FAs can increase resistance against TMV, and related mechanism can be attributed to activated expressions of a number of defense-related genes, suggesting that FAs can potentially act as pesticides for integrated control of plant viruses in the future. PMID- 28595928 TI - Histopathological effects of cypermethrin and Bacillus thuringiensis var. israelensis on midgut of Chironomus calligraphus larvae (Diptera: Chironomidae). AB - Pesticides are extensively used for the control of agricultural pests and disease vectors, but they also affect non-target organisms. Cypermethrin (CYP) is a synthetic pyrethroid used worldwide. Otherwise, bioinsecticides like Bacillus thuringiensis var. israelensis (Bti) have received great attention as an environmentally benign and desirable alternative. In order to evaluate the toxicity of those pesticides, Chironomus calligraphus was selected due to its high sensitivity to some toxicants. Third and fourth instars larvae were exposed to serial dilutions of CYP and Bti to determine LC50 values. In order to evaluate the potentially histopathological alterations as biomarkers, after 96-h of exposure, live larvae were fixed for histological analysis of the mid region of digestive tract. The 96-h LC50 values were 0.52 and 1.506MUg/L for CYP and Bti, respectively. Midgut histological structure of the control group showed a single layer of cubical cells with microvilli in their apical surface and a big central nucleus. The midgut epithelium of larvae exposed to a low concentration of CYP (0.037MUg/L) showed secretion activity and vacuolization while at high concentration (0.3MUg/L) cells showed a greater disorganization and a more developed fat body. On the other hand, Bti caused progressive histological damage in this tissue. Chironomus calligraphus is sensitive to Bti and CYP toxicity like other Chironomus species. The histopathological alterations could be a valuable tool to assess toxicity mechanism of different pesticides. PMID- 28595929 TI - Solvent-dependent binding interactions of the organophosphate pesticide, chlorpyrifos (CPF), and its metabolite, 3,5,6-trichloro-2-pyridinol (TCPy), with Bovine Serum Albumin (BSA): A comparative fluorescence quenching analysis. AB - Analysis of the interaction of pesticides and their metabolites with the cellular proteins has drawn considerable attention in past several years to understand the effect of pesticides on environment and mankind. In this study, we have investigated the binding interaction of Bovine Serum Albumin (BSA) with a widely used organophosphorous insecticide chlorpyrifos (CPF), and its stable metabolite, 3,5,6-trichloro-2-pyridinol (TCPy) to provide a comparative analysis of the two molecules by employing various spectroscopic techniques viz., UV-vis absorption, Circular Dichroism (CD), and Fluorescence spectroscopy. The fluorescence quenching studies of BSA emission in two different solvents viz., water and methanol in presence of CPF and TCPy have led to the revelation of several interesting facts about the pesticide-protein interaction. It has been found that both the molecules cause static quenching of BSA emission as seen from the Stern Volmer constant (Ksv) irrespective of the solvent used for the analysis. While TCPy is a stronger quencher in water, it exhibits comparable quenching capacity with CPF in methanol. The solvent dependent differential binding interaction of the two molecules finally indicates possibility of diverse bio-distribution of the pesticides within human body. The UV-vis and CD spectra of BSA in presence of the test molecules have unravelled that the molecules formed ground state complex that are highly reversible in nature and have minimal effect on the protein secondary structure. Furthermore it is also understood that structural changes of BSA in presence of CPF is significantly higher compared to that in presence of TCPY. PMID- 28595930 TI - A novel hybrid tobacco product that delivers a tobacco flavour note with vapour aerosol (Part 2): In vitro biological assessment and comparison with different tobacco-heating products. AB - This study assessed the toxicological and biological responses of aerosols from a novel hybrid tobacco product. Toxicological responses from the hybrid tobacco product were compared to those from a commercially available Tobacco Heating Product (c-THP), a prototype THP (p-THP) and a 3R4F reference cigarette, using in vitro test methods which were outlined as part of a framework to substantiate the risk reduction potential of novel tobacco and nicotine products. Exposure matrices used included total particulate matter (TPM), whole aerosol (WA), and aqueous aerosol extracts (AqE) obtained after machine-puffing the test products under the Health Canada Intense smoking regime. Levels of carbonyls and nicotine in these matrices were measured to understand the aerosol dosimetry of the products. The hybrid tobacco product tested negative across the in vitro assays including mutagenicity, genotoxicity, cytotoxicity, tumour promotion, oxidative stress and endothelial dysfunction. All the THPs tested demonstrated significantly reduced responses in these in vitro assays when compared to 3R4F. The findings suggest these products have the potential for reduced health risks. Further pre-clinical and clinical assessments are required to substantiate the risk reduction of these novel products at individual and population levels. PMID- 28595931 TI - Aripiprazole-induced adverse metabolic alterations in polyI:C neurodevelopmental model of schizophrenia in rats. AB - Schizophrenia appears to be linked to higher incidence of metabolic syndrome even in the absence of antipsychotic treatment. Atypical antipsychotics substantially differ in their propensity to induce metabolic alterations. Aripiprazole is considered to represent an antipsychotic drug with low risk of metabolic syndrome development. The aim of this study was to evaluate metabolic phenotype of neurodevelopmental polyI:C rat model and assess metabolic effects of chronic aripiprazole treatment with regard to complex neuroendocrine regulations of energy homeostasis. Polyinosinic:polycytidylic acid (polyI:C) was administered subcutaneously at a dose of 8 mg/kg in 10 ml on gestational day 15 to female Wistar rats. For this study 20 polyI:C and 20 control adult male offspring were used, randomly divided into 2 groups per 10 animals for chronic aripiprazole treatment and vehicle. Aripiprazole (5 mg/kg, dissolved tablets, ABILIFY(r)) was administered once daily via oral gavage for a month. Altered lipid profile in polyI:C model was observed and a trend towards different dynamics of weight gain in polyI:C rats was noted in the absence of significant antipsychotic treatment effect. PolyI:C model was not associated with changes in other parameters i.e. adipokines, gastrointestinal hormones and cytokines levels. Aripiprazole did not influence body weight but it induced alterations in neurohumoral regulations. Leptin and GLP-1 serum levels were significantly reduced, while ghrelin level was elevated. Furthermore aripiprazole decreased serum levels of pro-inflammatory cytokines. Our data indicate dysregulation of adipokines and gastrointestinal hormones present after chronic treatment with aripiprazole which is considered metabolically neutral in the polyI:C model of schizophrenia. PMID- 28595932 TI - Characterization of ciliate diversity in bromeliad tank waters from the Brazilian Atlantic Forest. AB - Bromeliads are a diverse group of plants that includes many species whose individuals are capable of retaining water, forming habitats called phytotelmata. These habitats harbor a diversity of organisms including prokaryotes, unicellular eukaryotes, metazoans, and fungi. Among single-celled eukaryotic organisms, ciliates are generally the most abundant. In the present study, we used Illumina DNA sequencing to survey the eukaryotic communities, especially ciliates, inhabiting the tanks of the bromeliads Aechmea gamosepala and Vriesea platynema in the Atlantic Forest of southern Brazil. Filtered sequences were clustered into distinct OTUs using a 99% identity threshold, and then assigned to phylum and genus using a BLAST-based approach (implemented in QIIME) and the SILVA reference database. Both bromeliad species harbored very diverse eukaryotic communities, with Arthropoda and Ciliophora showing the highest abundance (as estimated by the number of sequence reads). The ciliate genus Tetrahymena was the most abundant among single-celled organisms, followed by apicomplexan gregarines and the ciliate genus Glaucoma. Another interesting finding was the presence and high abundance of Trypanosoma in these bromeliad tanks, demonstrating their occurrence in this type of environment. The results presented here demonstrate a hidden diversity of eukaryotes in bromeliad tank waters, opening up new avenues for their in-depth characterization. PMID- 28595933 TI - Morphologic and phylogenetic studies of two hypotrichous ciliates, with notes on morphogenesis in Gastrostyla steinii Engelmann, 1862 (Ciliophora, Hypotrichia). AB - Two oxytrichid ciliates, Stylonychia (Metastylonychia) nodulinucleata Shi and Li, 1993 and Gastrostyla steinii Engelmann, 1862; collected from Huguangyan Maar Lake and Shenzhen Mangrove Nature Protection Area, southern China, respectively, were investigated using standard methods. The uncommon species Stylonychia (Metastylonychia) nodulinucleata can be recognized by its large body size, the conspicuous caudal cirri in vivo, and a moniliform macronucleus. We provide the first record of the small subunit ribosomal RNA (SSU rRNA) gene sequence for the species. The division of Stylonychia into two subgenera based on morphological and morphogenetic data is supported by the phylogenetic analyses, in which Stylonychia (Metastylonychia) nodulinucleata is placed as a sister branch to the clade including all the sequences of Stylonychia (Stylonychia) mytilus complex. The first brackish water population of Gastrostyla steinii is described in detail, with emphasis on its morphogenesis, which corresponds well with previous populations. In the phylogenetic trees, all the available Gastrostyla sequences, except for Gastrostyla sp. Y2 (KT780432) (probably a misidentification), nest together in the big group of the subfamily Stylonychinae with moderate to high support (ML/BI, 91%/0.95), very likely revealing the monophyly of the genus Gastrostyla. PMID- 28595934 TI - Secular Trends in Prostate Biopsy Criteria and Outcomes: The Dartmouth Experience. AB - OBJECTIVE: To evaluate trends in prostate biopsy and cancer diagnosis at a center with conservative screening practices in the pre- and post-2012 era. More restrictive prostate-specific antigen (PSA) screening guidelines have led to lower rates of screening, biopsy, and diagnosis of prostate cancer. It is not clear, however, how regions with low baseline screening rates (the Lebanon, New Hampshire hospital referral region centered on Dartmouth-Hitchcock Medical Center had the lowest rate of screening among Medicare patients in 2012) have responded to these guidelines. METHODS: We retrospectively analyzed patients who underwent prostate biopsy from January 2011 to March 2016. Demographic and clinical characteristics were analyzed by time. Multivariable analysis assessed for factors associated with higher grade cancer. RESULTS: There were 614 prostate biopsies were performed. PSA at biopsy increased with time (7.2 in 2011 vs 10.1 in 2015, P = .0085); age did not. There was a stable proportion of benign findings; proportions of low-grade disease decreased, whereas intermediate- and high-grade disease increased (2011 vs 2015: 21.1% vs 10.8% Gleason 3 + 3, 32.9% vs 43.3% >= Gleason 3 + 4, P = .0454). Factors predictive of higher grade disease included abnormal digital examination (odds ratio [OR] 2.19, P = .0076), higher PSA (OR 1.09, P = .0040), and later biopsy date (OR 1.01, P = .0469). CONCLUSION: In an environment of conservative baseline screening practices, there has been a shift in prostate biopsy criteria and outcomes, namely a rising PSA threshold for biopsy and a 50% decrease in the diagnosis of low-grade disease. Additional study is needed to ensure these trends are favorably impacting the quality of care. PMID- 28595935 TI - Predictors of Renal Functional Improvement After Pyeloplasty in Ureteropelvic Junction Obstruction: Clinical Value of Visually Assessed Renal Tissue Tracer Transit in 99mTc-mercaptoacetyltriglycine Renography. AB - OBJECTIVE: To determine the clinical value of visually assessed renal tissue transit time (TTT) in 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) renography for patients undergoing pyeloplasty. MATERIALS AND METHODS: Medical records of 164 patients who underwent dismembered pyeloplasty were retrospectively reviewed. Baseline and postoperative renal ultrasonography and 99mTc-MAG3 renography were performed. Two urologists blinded to clinical data evaluated the renography and classified TTT as timely or delayed based on visualization of the tracer in the kidney pelvis between 2 and 10 minutes. Renal functional change after pyeloplasty was compared between patients in the timely and delayed groups. RESULTS: A total of 126 patients (median age, 9 months) were evaluated after excluding patients with bilateral ureteropelvic junction obstruction, a single functioning kidney, duplicated ureter, or <3 months of follow-up. There were no differences between 89 patients with timely TTT and 37 patients with delayed TTT in mean preoperative hydronephrosis grade (3.7 vs 3.8) and pelvic diameter (3.1 cm vs 3.4 cm). Although the pre- and postoperative mean values of differential renal function (DRF) were significantly higher in the timely group than in the delayed group (47.2% vs 38.3% and 47.9% vs 44.6%), DRF change was greater in the delayed group (6.3% vs 0.6%). In multivariate analysis, delayed TTT was the only significant predictor of >5% improvement in renal function after pyeloplasty. CONCLUSION: Delayed TTT in 99mTc-MAG3 renography was a significant predictor of renal functional improvement after pyeloplasty in ureteropelvic junction obstruction. Because substantial improvement of renal function is anticipated, we recommend immediate pyeloplasty in patients with delayed TTT and decreased DRF. PMID- 28595936 TI - The Peak Site of Stone Distribution in the Upper Ureter is Unlikely the Ureteropelvic Junction: Computed Tomography Analysis of Stone Lodging Site With Respect to a Newly Identified Area of Constriction. AB - OBJECTIVE: To investigate the relationship between the upper urinary stone distribution and the "crossing point," an area of relative fixation within the upper ureter at approximately the level where the ureter crosses the gonadal vein. MATERIALS AND METHODS: We reviewed 298 consecutive patients presenting with acute renal colic, identified upper ureteral stones in computed tomography. For stones located at the "renal pelvis and upper ureter," we measured the vertebral level of each renal pelvis, crossing point, and stone. The distance between the crossing point and the stones (designated as positive if the stone was located above it) and the distance between the renal pelvis and the crossing point were measured. RESULTS: The average stone size at the "renal pelvis and upper ureter" was 6.0 +/- 3.2 mm, at "middle ureter" 5.2 +/- 1.9 mm, and at "lower ureter" 3.7 +/- 1.8 mm. Lower location was significantly correlated with smaller size (P <.001). The level of the crossing point and stone location were significantly lower on the right (P = .019, P = .033, respectively), whereas the vertebral level of the renal pelvis was not significantly different on both sides (P = .225). The mean distance between the crossing point and the stones was -5.6 +/- 18.4 mm (median: 0 mm) on the right and -4.7 +/- 19.3 mm (median: 0 mm) on the left. The mean distance between the renal pelvis and the stones was significantly longer on the right (57.2 +/- 18.5 mm and 48.2 +/- 19.1 mm) (P = .038). CONCLUSION: The crossing point is the peak site of stone distribution in the upper ureter and likely different from the traditionally identified obstruction site at the ureteropelvic junction. PMID- 28595937 TI - Application of mass transfer theory to biomarker capture by surface functionalized magnetic beads in microcentrifuge tubes. AB - In many diagnostic assays, specific biomarker extraction and purification from a patient sample is performed in microcentrifuge tubes using surface-functionalized magnetic beads. Although assay binding times are known to be highly dependent on sample viscosity, sample volume, capture reagent, and fluid mixing, the theoretical mass transport framework that has been developed and validated in engineering has yet to be applied in this context. In this work, we adapt this existing framework for simultaneous mass transfer and surface reaction and apply it to the binding of biomarkers in clinical samples to surface-functionalized magnetic beads. We discuss the fundamental fluid dynamics of vortex mixing within microcentrifuge tubes as well as describe how particles and biomolecules interact with the fluid. The model is solved over a wide range of parameters, and we present scenarios when a simplified analytical expression would be most accurate. Next, we review of some relevant techniques for model parameter estimation. Finally, we apply the mass transfer theory to practical use-case scenarios of immediate use to clinicians and assay developers. Throughout, we highlight where further characterization is necessary to bridge the gap between theory and practical application. PMID- 28595938 TI - Bifidobacteria-derived lipoproteins inhibit infection with coxsackievirus B4 in vitro. AB - The aim of the present study was to investigate the potential of bifidobacteria in protecting cells from coxsackievirus B4 (CV-B4) infection. Bifidobacterial screening identified two of five strains that protected human epithelial type 2 (HEp-2) cell viability when bifidobacteria were incubated with viral particles prior to inoculation. In contrast, no effect was shown by incubating HEp-2 cells with bifidobacteria prior to CV-B4 inoculation. Cell wall lipoprotein aggregates (LpAs) secreted by the selected strains were assayed for their antiviral activity. The two LpAs exhibited antiviral activity when they were incubated with viral particles prior to inoculation of HEp-2 cells. Recombinant LpA-derived protein exhibited identical antiviral activity. To identify the peptide sequences interacting with the virus particles, LpA proteins were aligned with the peptide sequences of the north canyon rim and puff footprint onto coxsackievirus and adenovirus receptor (CAR). The in silico molecular docking study using CV-B3 as template showed low-energy binding, indicating a stable system for the selected peptides and consequently a likely binding interaction with CV-B. Bifidobacterium longum and Bifidobacterium breve peptides homologous to the viral north rim footprint onto CAR sequence formed hydrogen bonds with several viral residues in the north rim of the canyon, which were already predicted as interacting with CAR. In conclusion, proteins from bifidobacterial LpAs can inhibit infection with CV-B4, likely through binding to the capsid amino acids that interact with CAR. PMID- 28595939 TI - Role of second-line injectable antituberculosis drugs in the treatment of MDR/XDR tuberculosis. AB - Second-line injectable antituberculosis drugs (aminoglycosides and capreomycin) are the main drugs used in the management of resistant tuberculosis. Their preserved efficacy in the case of multi-drug-resistant bacillus is counterbalanced by frequent adverse events. Adverse events are linked to the drugs themselves and to the recommended 8-month period of parenteral administration. In numerous countries facing a high incidence of multi-drug resistant tuberculosis, treatment is administered by intramuscular injection. This procedure is painful and restrictive, and therefore treatment adherence is limited. This study reports the follow-up of 11 patients diagnosed with multi drug- and extensively-resistant tuberculosis and treated with parenteral amikacin, and discusses the role of amikacin in the treatment of resistant tuberculosis. PMID- 28595940 TI - Glabridin triggers over-expression of MCA1 and NUC1 genes in Candida glabrata: Is it an apoptosis inducer? AB - The growing trends of emergence of antifungal-resistant Candida strains has recently been inspired the researchers to design new antifungal agents with novel mechanisms of action. Glabridin is an originally natural substrate with multiple biological activities which propose it as a novel anticancer, antimicrobial and antifungal agent. In the present study, the antifungal effect of glabridin against Candida glabrata isolates and its possible mechanism of action were investigated. The minimum inhibitory concentrations (MIC) for glabridin against fluconazole-resistant and fluconazole-SDD strains of C. glabrata were investigated using the Clinical and laboratory standards institute document M27 A3 and M27-S4 as a guideline. Possible alternations in the expression of two critical genes involved in yeast apoptosis, MCA1 and NUC1, were assayed by real time PCR. DNA damage and chromatin condensation was investigated using DAPI staining. Although glabridin led to a significant decrease in MICs against fluconazole-resistant C. glabrata (MIC50: 8MUg/mL), no significant decreased was shown for fluconazole-SDD strains. Therefore, a distinct azole-independent mechanism could be responsible for the inhibitory activity of glabridin. Overexpression of MCA1 and NUC1 genes in addition to DNA damage and chromatin condensation suggesting the involvement of apoptosis signaling in C. glabrata stains exposed to glabridin. This study suggests that glabridin might be considered as a novel naturally originated agent to fight against fluconazole resistance C. glabrata strains. PMID- 28595942 TI - Multicomponent access to androstano-arylpyrimidines under microwave conditions and evaluation of their anti-cancer activity in vitro. AB - Novel ring D- and A-fused pyrimidines in the androstane series were efficiently synthesized within 10-15min in polar protic solvents under microwave irradiation via two kinds of multicomponent heterocyclization reactions followed by spontaneous or promoted oxidation. The rates of the one-pot catalyst-free transformations of steroidal beta-ketoaldehydes, ammonium acetate and substituted benzaldehydes in EtOH were found to be affected slightly by the steric and electronic feature of the substituents on the aromatic ring of the arylaldehyde component and the different reactivities of rings D and A of the sterane core. At the same time, the acid-catalyzed Biginelli-type reaction of dihydrotestosterone acetate, urea and arylaldehydes, and subsequent Jones oxidation of the primarily formed dihydropyrimidinones led to the corresponding ring A-fused 1H-pyrimidin-2 ones in moderate yields independently of the substituents on the aromatic moiety. The synthesized compounds were tested in vitro on human cancer cell lines as well as on non-cancerous fibroblast cells by the MTT assay in order to investigate their biological effects. As a result of the pharmacological screen, a remarkable structure-function relationship has been observed as the acetylated Biginelli products exhibited higher toxicity compared to the deacetylated version of each compound. Furthermore, in case of three 2'-arylpyrimidine derivatives a strong prostate cancer cell specific activity has been identified. PMID- 28595943 TI - A role for G-protein coupled estrogen receptor (GPER) in estrogen-induced carcinogenesis: Dysregulated glandular homeostasis, survival and metastasis. AB - Mechanisms of carcinogenesis by estrogen center on its mitogenic and genotoxic potential on tumor target cells. These models suggest that estrogen receptor (ER) signaling promotes expansion of the transformed population and that subsequent accumulation of somatic mutations that drive cancer progression occur via metabolic activation of cathecol estrogens or by epigenetic mechanisms. Recent findings that GPER is linked to obesity, vascular pathology and immunosuppression, key events in the development of metabolic syndrome and intra tissular estrogen synthesis, provides an alternate view of estrogen-induced carcinogenesis. Consistent with this concept, GPER is directly associated with clinicopathological indices that predict cancer progression and poor survival in breast and gynecological cancers. Moreover, GPER manifests cell biological responses and a microenvironment conducive for tumor development and cancer progression, regulating cellular responses associated with glandular homeostasis and survival, invading surrounding tissue and attracting a vascular supply. Thus, the cellular actions attributed to GPER fit well with the known molecular mechanisms of G-protein coupled receptors, GPCRs, namely, their ability to transactivate integrins and EGF receptors and alter the interaction between glandular epithelia and their extracellular environment, affecting epithelial-to mesenchymal transition (EMT) and allowing for tumor cell survival and dissemination. This perspective reviews the molecular and cellular responses manifested by GPER and evaluates its contribution to female reproductive cancers as diseases that progress as a result of dysregulated glandular homeostasis resulting in chronic inflammation and metastasis. This review is organized in sections as follows: I) a brief synopsis of the current state of knowledge regarding estrogen-induced carcinogenesis, II) a review of evidence from clinical and animal-based studies that support a role for GPER in cancer progression, and III) a mechanistic framework describing how GPER-mediated estrogen action may influence the tumor and its microenvironment. PMID- 28595941 TI - Epidemiology of mucopolysaccharidoses. AB - The aim of this study was to obtain data about the epidemiology of the different types of mucopolysaccharidoses in Japan and Switzerland and to compare with similar data from other countries. Data for Japan was collected between 1982 and 2009, and 467 cases with MPS were identified. The combined birth prevalence was 1.53 per 100,000 live births. The highest birth prevalence was 0.84 for MPS II, accounting for 55% of all MPS. MPS I, III, and IV accounted for 15, 16, and 10%, respectively. MPS VI and VII were more rare and accounted for 1.7 and 1.3%, respectively. A retrospective epidemiological data collection was performed in Switzerland between 1975 and 2008 (34years), and 41 living MPS patients were identified. The combined birth prevalence was 1.56 per 100,000 live births. The highest birth prevalence was 0.46 for MPS II, accounting for 29% of all MPS. MPS I, III, and IV accounted for 12, 24, and 24%, respectively. As seen in the Japanese population, MPS VI and VII were more rare and accounted for 7.3 and 2.4%, respectively. The high birth prevalence of MPS II in Japan was comparable to that seen in other East Asian countries where this MPS accounted for approximately 50% of all forms of MPS. Birth prevalence was also similar in some European countries (Germany, Northern Ireland, Portugal and the Netherlands) although the prevalence of other forms of MPS is also reported to be higher in these countries. Birth prevalence of MPS II in Switzerland and other European countries is comparatively lower. The birth prevalence of MPS III and IV in Switzerland is higher than in Japan but comparable to that in most other European countries. Moreover, the birth prevalence of MPS VI and VII was very low in both, Switzerland and Japan. Overall, the frequency of MPS varies for each population due to differences in ethnic backgrounds and/or founder effects that affect the birth prevalence of each type of MPS, as seen for other rare genetic diseases. Methods for identification of MPS patients are not uniform across all countries, and consequently, if patients are not identified, recorded prevalence rates will be aberrantly low. PMID- 28595944 TI - IDO chronic immune activation and tryptophan metabolic pathway: A potential pathophysiological link between depression and obesity. AB - Obesity and depression are among the most pressing health problems in the contemporary world. Obesity and depression share a bidirectional relationship, whereby each condition increases the risk of the other. By inference, shared pathways may underpin the comorbidity between obesity and depression. Activation of cell-mediated immunity (CMI) is a key factor in the pathophysiology of depression. CMI cytokines, including IFN-gamma, TNFalpha and IL-1beta, induce the catabolism of tryptophan (TRY) by stimulating indoleamine 2,3-dioxygenase (IDO) resulting in the synthesis of kynurenine (KYN) and other tryptophan catabolites (TRYCATs). In the CNS, TRYCATs have been related to oxidative damage, inflammation, mitochondrial dysfunction, cytotoxicity, excitotoxicity, neurotoxicity and lowered neuroplasticity. The pathophysiology of obesity is also associated with a state of aberrant inflammation that activates aryl hydrocarbon receptor (AHR), a pathway involved in the detection of intracellular or environmental changes as well as with increases in the production of TRYCATs, being KYN an agonists of AHR. Both AHR and TRYCATS are involved in obesity and related metabolic disorders. These changes in the TRYCAT pathway may contribute to the onset of neuropsychiatric symptoms in obesity. This paper reviews the role of immune activation, IDO stimulation and increased TRYCAT production in the pathophysiology of depression and obesity. Here we suggest that increased synthesis of detrimental TRYCATs is implicated in comorbid obesity and depression and is a new drug target to treat both diseases. PMID- 28595947 TI - Comparison of Temporal Artery Versus Rectal Temperature in Emergency Department Patients Who Are Unable to Participate in Oral Temperature Assessment. AB - INTRODUCTION: In the emergency department, pediatric and geriatric patients who present with illnesses and are unable to participate in oral evaluation of temperature must undergo a rectal temperature (RT) assessment. This study asks if a temporal artery temperature (TAT) measure can supplant the RT measure. METHODS: A convenience sample, using a within-subject design, was used to evaluate the efficacy of TAT compared with RT in patients <= 3 and >= 65 years of age, who were unable to participate in oral temperature assessments. RESULTS: Instrument reliability of the TAT is adequate for both the pediatric and geriatric populations. An unadjusted TAT did not provide acceptable temperature measurements. We also found that adjusting a TAT reading by adding -17.22 degrees C (1 degrees F) rendered the TAT average (either mean or median) adequately similar to RT averages for research purposes for both pediatric and geriatric groups. DISCUSSION: No influence was detected on the differences between RT and TAT due to age, sex, or emergency severity index (ESI) score in patients or due to profession, years of education, or years of experience in caregivers for either the pediatric or geriatric groups. Furthermore, the adjusted TAT reading could detect fever in individual patients adequately in both the pediatric and geriatric groups. However, the adjusted TAT readings were too frequently divergent from RT readings to be used to measure temperature in individual patients for both pediatric and geriatric groups. PMID- 28595945 TI - Role of placebo effects in pain and neuropsychiatric disorders. AB - The placebo (and the nocebo) effect is a powerful determinant of health outcomes in clinical disease treatment and management. Efforts to completely eradicate placebo effects have shifted dynamically, as increasingly more researchers are tuned to the potentially beneficial effects of incorporating those uncontrollable placebo effects into clinical therapeutic strategies. In this review, we highlight the major findings from placebo research, elucidating the main neurobiological systems and candidate determinants of the placebo phenomenon, and illustrate a perspective that can effectively frame future research on the topic. Finally, we issue a call for increased research on the efficacy of therapeutic strategies that incorporate placebo "tools," and argue that clinical trials of the placebo response in neuropsychiatric diseases and disorders has important and far-reaching translational and clinical relevance. PMID- 28595946 TI - The effects of pessimism on cell-mediated immunity in rats. AB - We used a recently developed ambiguous-cue interpretation (ACI) paradigm to investigate whether 'optimism' and 'pessimism' as behavioural traits may be interrelated with immune functions in rodents. To this aim, in a series of ACI tests (cognitive bias screening, CBS), we identified rats that displayed 'pessimistic' and 'optimistic' traits. We found significant differences in immune biomarkers between 'optimistic' and 'pessimistic' animals. Moreover 'pessimism' was associated with significantly lower relative weight of the spleen and thymus, significantly decreased proliferative activity of splenocytes. Pessimism was associated with an increased production of interleukin-(IL)1beta and IL-4, activin A, l-selectin, interferon (IFN)-gamma and some chemokines and receptors for advanced glycation endproducts. The findings indicate an inflammatory profile in "pessimistic" animals. PMID- 28595948 TI - Healing and functional outcome of a subscapularis peel repair with a stem-based repair after total shoulder arthroplasty. AB - BACKGROUND: The purpose of this study was to evaluate functional outcome and healing of a subscapularis peel with a stem-based repair after total shoulder arthroplasty (TSA). The hypothesis was that the repair would lead to subscapularis healing in the majority of cases. METHODS: A prospective analysis was performed on a consecutive series of TSAs. Range of motion and functional outcome were assessed according to American Shoulder and Elbow Surgeons, Single Assessment Numeric Evaluation, Simple Shoulder Test, and visual analog scale scores at a minimum follow-up of 1 year. Belly-press and lift-off tests were also performed. An ultrasound evaluation assessed subscapularis healing at final follow-up. RESULTS: At a mean follow-up of 15 months, 60 patients (mean age, 64 years) were examined. Mean forward flexion improved from 115 degrees to 137 degrees . External rotation at the side improved from 27 degrees to 52 degrees , and internal rotation improved from L4 to L2 (P < .05). American Shoulder and Elbow Surgeons score improved from 34.3 to 79.8 (P < .001). Likewise, the Single Assessment Numeric Evaluation and Simple Shoulder Test scores showed significant improvement from 33.1 to 85.3 and 4.3 to 10.2, respectively (P < .001). The visual analog scale score for pain decreased from 5.8 to 0.7 (P < .001). On ultrasound examination, the subscapularis was healed intact in 55 cases (91.7%), attenuated in 3 cases (5%), and torn in 2 cases (3.3%). CONCLUSION: A stem-based repair of a subscapularis peel after TSA leads to functional improvement in the majority of cases with >90% postoperative healing of the subscapularis. PMID- 28595949 TI - Patient and physician views on the quality of care for inflammatory bowel disease after one-year follow-up: Results from SOLUTION-2, a prospective IG-IBD study. AB - BACKGROUND AND AIMS: Perception of quality of care is important in the management of patients with chronic diseases, particularly inflammatory bowel disease. AIMS AND METHODS: This longitudinal study aimed to investigate variations of the Quality of Care through the Patients' Eyes (QUOTE-IBD) questionnaire scores one year after the basal evaluation in the Studio Osservazionale quaLita cUre malatTIe crOniche intestiNali (SOLUTION-1) study. RESULTS: Of the cohort of 992 patients, 936 were evaluable. The QUOTE-IBD score overcame satisfactory levels of more than the 80%, overall and in all subdomains except for the "Continuity of Care" sub-dimension (mean, 8.3; standard deviation, 1.49), scored satisfactory only by 34% of the patients. No significant changes in satisfaction were recorded overall, or considering patients subgroups. Significant differences were found at the end of the follow-up between physicians' and patients' perceptions of quality of care, with the former over-rating their performance in "Continuity of Cares" and under-rating "Costs", "Competence", and "Accessibility" sub-domains of the score (p<0.05 for all). CONCLUSION: Perceived quality of care in a large cohort of Italian patients with inflammatory bowel disease remains unchanged after one year follow-up and was not significantly affected by disease activity or therapeutic interventions. Differences between physicians' and patients' perceptions of quality of care should be taken into account. PMID- 28595951 TI - Sumoylation regulates the transcriptional activity of different human NFAT isoforms in neurons. AB - In the nervous system, four calcium/calcineurin-regulated members of the nuclear factor of activated T-cells (NFAT) family of transcription factors, NFATc1-c4, are involved in many developmental and functional processes, such as corticogenesis, synaptogenesis, synaptic plasticity and neurotransmission, that all need precise gene regulation. Therefore it is important to understand molecular events that contribute to the regulation of the transcriptional activity of specific NFAT isoforms. Previously, we have shown that there are a number of alternative splice variants of NFAT genes expressed in the brain and that neuronal activity leads to isoform-specific transactivation capacities of different human NFAT proteins. Here we looked at the effect of sumoylation as a possible regulator of the transcriptional activity of different human NFAT isoforms in rat primary cortical and hippocampal neurons in response to membrane depolarization and compared the results to those obtained from non-neuronal HEK293-FT and BHK-21 cells in response to calcium signaling. Our results show that in primary hippocampal neurons, sumoylation represses the transcriptional activity of NFATc1, NFATc2, and NFATc3 isoforms, whereas in cortical neurons, transactivation capacity of only NFATc1 and NFATc2 is repressed by sumoylation. In non-neuronal cells, however, transcriptional activity of all four NFAT isoforms is repressed by sumoylation in HEK293-FT cells, while only NFATc1 and NFATc2 isoforms are affected by sumoylation in BHK-21 cells. Altogether, our results show that sumoylation represses the transcription activation capacities of NFAT isoforms and that the effect is cell type-specific. PMID- 28595950 TI - Luteolin attenuates interleukin-6-mediated astrogliosis in human iPSC-derived neural aggregates: A candidate preventive substance for maternal immune activation-induced abnormalities. AB - Maternal infection during pregnancy increases the risk of neurodevelopmental conditions such as autism spectrum disorders and schizophrenia in offspring. Several previous animal studies have indicated that maternal immune activation (MIA), rather than a specific pathogen, alters fetal brain development. Among them, prenatal exposure to interleukin-6 (IL-6) has been associated with behavioral and neuropathological abnormalities, though such findings remain to be elucidated in humans. We developed a human cell-based model of MIA by exposing human induced pluripotent stem cells (hiPSCs)-derived neural aggregates to IL-6 and investigated whether luteolin-a naturally occurring flavonoid found in edible plants-could prevent MIA-induced abnormalities. We generated neural aggregates from hiPSCs using the serum-free floating culture of embryoid body-like aggregates with quick reaggregation (SFEBq) method, following which aggregates were cultured in suspension. We then exposed the aggregates to IL-6 (100ng/ml) for 24h at day 51. Transient IL-6 exposure significantly increased the area ratio of astrocytes (GFAP-positive area ratio) and decreased the area ratio of early born neurons (TBR1-positive or CTIP2-positive area ratio) relative to controls. In addition, western blot analysis revealed that levels of phosphorylated STAT3 were significantly elevated in IL-6-exposed neural aggregates. Luteolin treatment inhibited STAT3 phosphorylation and counteracted IL-6-mediated increases of GFAP positive cells and reductions of TBR1-positive and CTIP2-positive cells. Our observations suggest that the flavonoid luteolin may attenuate or prevent MIA induced neural abnormalities. As we observed increased apoptosis at high concentrations of luteolin, further studies are required to determine the optimal intake dosage and duration for pregnant women. PMID- 28595952 TI - Trans-resveratrol enriched maternal diet protects the immature hippocampus from perinatal asphyxia in rats. AB - Trans-resveratrol (tRESV), a polyphenol with antioxidant properties, is common in many food sources, hence easily accessible for study as a maternal dietary supplement in perinatal asphyxia (PA). Hypoxic-ischemic encephalopathy secondary to PA affects especially vulnerable brain areas such as hippocampus and is a leading cause of neonatal morbidity. The purpose of this study is to identify new epigenetic mechanisms of brain inflammation and injury related to PA and to explore the benefit of tRESV enriched maternal diet. The hippocampal interleukin 1 beta (IL-1b), tumour necrosis factor alpha (TNFalpha) and S-100B protein, at 24 48h after 90min of asphyxia were assessed in postnatal day 6 rats whose mothers received either standard or tRESV enriched diet. The expression of non-coding microRNAs miR124, miR132, miR134, miR146 and miR15a as epigenetic markers of hippocampus response to PA was determined 24h post-asphyxia. Our results indicate that neural response to PA could be epigenetically controlled and that tRESV reduces asphyxia-related neuroinflammation and neural injury. Moreover, tRESV could increase, through epigenetic mechanisms, the tolerance to asphyxia, with possible impact on the neuronal maturation. Our data support the neuroprotective quality of tRESV when used as a supplement in the maternal diet on the offspring's outcome in PA. PMID- 28595953 TI - Inhalation of a racemic mixture (R,S)-linalool by rats experiencing restraint stress alters neuropeptide and MHC class I gene expression in the hypothalamus. AB - Some odorants have physiological and psychological effects on organisms. However, little is known about the effects of inhaling them, particularly on the central nervous system. Using DNA microarray analysis, we obtained gene expression profiles of the hypothalamus from restraint stressed rats exposed to racemic (R,S)-linalool. Hierarchical clustering across all probe sets showed that this inhalation of (R,S)-linalool influenced the expression levels of a wide range of genes in the hypothalamus. A comparison of transcription levels revealed that the inhalation of (R,S)-linalool restored the expression of 560 stress-induced probe sets to a normal status. Gene Ontology (GO) analysis showed that these genes were associated with synaptic transmission via neurotransmitters including anxiolytic neuropeptides such as oxytocin and neuropeptide Y. These genes also included several major histocompatibility complex (MHC) class I molecules necessary for neural development and plasticity. Moreover, Upstream Regulator Analysis predicted that the hormone prolactin would be activated by the inhalation of (R,S)-linalool under stress. Our results reveal some of the molecular mechanisms associated with odor inhalation in the hypothalamus in organisms under stress. PMID- 28595954 TI - A protocol for a systematic review to identify allergenic tree nuts and the molecules responsible for their allergenic properties. AB - Food regulations require that tree nuts and derived ingredients are included on food labels in order to help individuals with IgE-mediated allergies to avoid them. However, there is no consensus regarding which tree nut species should be included in this definition and specified on food labels. Allergen detection methods used for monitoring foods target allergen molecules, but it not clear which are the most relevant molecules to choose. A modified population-exposure comparators-outcome (PECO) approach has been developed to systematically review the evidence regarding (1) which allergenic tree nuts should be included in food allergen labelling lists and (2) which are the clinically relevant allergens which should be used as analytical targets. A search strategy and criteria against which the evidence will be evaluated have been developed. The resulting evidence will be used to rank tree nuts with regards their ability to cause IgE mediated allergies, and allergen molecules regarding their capacity to elicit an allergic reaction. The results of the systematic review will enable risk assessors and managers to identify tree nut species that should be included in food allergen labelling lists and ensure analytical methods for determination of allergens in foods are targeting appropriate molecules. PMID- 28595955 TI - RIFM fragrance ingredient safety assessment, 2-methyl-4(2,2,3-trimethyl-3 cyclopentenyl)butanol, CAS Registry Number 72089-08-8. PMID- 28595956 TI - Our unrequited love for natural ingredients. AB - Naturally sourced food ingredients have been the beneficiary of legal, regulatory and consumer preference as the result of a widely shared assumption of safety. However, the natural substances consumed in modernity may have little to do with the historically consumed part of the plant or even the plant itself. Further, our initial impression of a safe plant derivative may well be false as the result of the use of different growth conditions or, changes in harvesting and processing conditions that may have brought about a higher level of toxic constituents. Despite the variability of plant constituents, manufacturers' standards are set according to the content of commercially desirable properties, rather than presence of potentially toxic constituents. Why then, after all the potential reservations regarding naturals, is there such an enmity toward synthetic chemicals (including single chemical fermentation products), which have been tested in a systematic manner for potential toxic effects and whose composition is well known as the result of consistent manufacturing techniques and analytical controls? The authors will describe the paradigms used for natural products safety review and compare them with the safety criteria required for an "artificial" food ingredient. PMID- 28595958 TI - Olive phenolic compounds attenuate deltamethrin-induced liver and kidney toxicity through regulating oxidative stress, inflammation and apoptosis. AB - The purpose of this study was to evaluate the protective effect of ethanolic olive fruit extract (OFE) and its phenolic compound, oleuropein (OLE), against hepato-renal toxicity induced by deltamethrin (DEM), a synthetic pyrethroid, in Wistar rats. The kidney and liver tissues were collected after 30 days of treatment for subsequent investigation. Rats that were given DEM had a highly significant elevation in the serum biomarkers as well as hepatic and renal levels of lipid peroxidation (MDA). Additionally, a significant reduction in the total antioxidant capacity (ABTS+), superoxide dismutase (SOD) and catalase (CAT) activities was noted. This toxic effect was confirmed by histological studies and the expression levels of inflammatory (cox-2) and apoptotic genes (bcl-2 and p53). The findings for the OFE and OLEtreated groups highlighted the efficacy of olive fruit phenolic compounds as hepatic and renal-protectant in DEM-induced hepato-renal toxicity through improving the oxidative status as well as suppressing inflammation and apoptosis. Therefore, they may be used as protective natural compounds against DEM-induced hepato-renal toxicity. PMID- 28595957 TI - RIFM fragrance ingredient safety assessment, methyl anthranilate, CAS Registry Number 134-20-3. PMID- 28595959 TI - Cudratricusxanthone A attenuates renal injury in septic mice. AB - As a natural compound extracted from the roots of Cudrania tricuspidata Bureau, Cudratricusxanthone A (CTXA) is known to possess hepatoprotective, anti inflammatory, and anti-proliferative activities. This study was aimed to clarify the role of CTXA in modulating renal functional damage in a mouse model of sepsis and to elucidate its underlying mechanisms. We examined the renal protective effects of CTXA on cecal ligation and puncture (CLP)-induced renal damage by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Post-treatment with CTXA resulted in a significant reduction in the deleterious renal functions by CLP, such as elevated BUN, creatinine, and urine protein. Induction of nitric oxide synthase and excessive production of nitric acid by CLP surgery were significantly reduced by post treatment with CTXA via inhibiting nuclear factor-kappaB activation. Furthermore, the plasma levels of interleukin-6 and tumor necrosis factor-alpha were suppressed by CTXA post-treatment. Concurrently, CTXA treatment potently suppressed the CLP-induced septic lethality, rise of lipid peroxidation and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney. The present results suggested that CTXA could protect against sepsis-triggered renal injury in mice. PMID- 28595960 TI - RIFM fragrance ingredient safety assessment, benzoic acid, 2-[(1-oxopropyl)amino] , methyl ester, CAS Registry Number 25628-84-6. PMID- 28595961 TI - [Flexible bronchoscopy in octogenarians]. PMID- 28595962 TI - [Use of health-related applications on mobile devices and their association with comorbidities in older adults]. PMID- 28595963 TI - Frailty, what are we talking about? Implications for the daily clinical practice. PMID- 28595964 TI - [How to transform the concept of frailty into efficient interventions: Transversality and leadership of geriatrics]. PMID- 28595965 TI - Low Expression of Estrogen Receptor-alpha and Progesterone Receptor in Human Breast Cancer Tissues Is Associated With High-Grade Human Cytomegalovirus Protein Expression. AB - BACKGROUND: The underlying mechanisms for breast cancer (BC) are largely unknown. We investigated possible correlations between the expression levels of human cytomegalovirus (HCMV) proteins and established histopathological markers of BC, including expression of estrogen receptor (ER)-alpha, the progesterone receptor (PgR), and HER2. MATERIALS AND METHODS: We retrospectively examined paraffin embedded biopsy specimens of BC (n = 62), ductal carcinoma in situ (n = 19), and adjacent normal breast tissue (n = 42) for HCMV immediate-early protein (IE), HCMV late antigen, HCMV DNA and RNA, and investigated possible correlations between them and expression of ER-alpha, PgR, and HER2. RESULTS: HCMV DNA and RNA were detected in all examined infiltrating BCs. High-grade positivity for HCMV-IE was detected in 77% of infiltrating BCs, 39% of ductal carcinomas in situ, and 7% of tumor-free breast tissue samples. HCMV expression correlated inversely with ER alpha (P = .02) and PgR (P = .003) expression. HER2 expression was also reduced in HCMV-positive samples without reaching a level of statistical significance (P = .09). CONCLUSION: The negative correlation between high-grade expression HCMV IE and hormone receptor expression suggests a role for HCMV in hormone receptor negative BC tumors, possibly by forcing BC cells into a more aggressive phenotype. PMID- 28595966 TI - Characterization of PKACalpha enzyme kinetics and inhibition in an HPLC assay with a chromophoric substrate. AB - Here we describe a convenient, inexpensive, and non-hazardous method for the measurement of the kinase activity of the catalytic subunit of cAMP-dependent protein kinase (PKACalpha). The assay is based on the separation of a substrate peptide labeled with a strong chromophore from the phosphorylated product peptide by high-performance liquid chromatograph (HPLC) and quantification of the product ratiometrically at a wavelength in the visual spectrum (Vis). The utility and reliability of the HPLC-Vis assay were demonstrated by characterizing the kinetic parameters (KM, Vmax) of the new Rh-MAB-Kemptide substrate, a commercially prepared TAMRA-Kemptide substrate, and ATP as well as the potency (IC50, Ki) of the known PKACalpha inhibitors H89 and PKI(5-24). The advantages of this assay are that it is convenient and inexpensive, uses readily synthesized or commercially available substrates that are shelf-stable, uses a common piece of laboratory equipment, and does not require any hazardous materials such as radioactive gamma-32P-ATP. The assay format is also highly flexible and could be adapted for the testing of many different kinases by changing the peptide substrate sequence. PMID- 28595967 TI - Does the NRS Capture Changes in Communication during Inpatient Stroke Rehabilitation? AB - BACKGROUND: In Ontario, the National Rehabilitation Reporting System (NRS) is mandated for use as a measurement of change for stroke patients after admission to and discharge from rehabilitation. The NRS includes the functional independence measure (FIM) and supplementary measurement items developed by the Canadian Institute for Health Information (CIHI). Uncertainty exists regarding the efficacy of the NRS as the sole measure of outcome for communication in stroke rehabilitation patients. The use of additional speech-language pathology outcome measurement tools for this population has therefore been suggested. OBJECTIVES: This study sought to establish whether the FIM and CIHI communication items capture quantifiable gains during stroke rehabilitation and therefore whether additional measures are needed to assess outcomes. METHODS: A retrospective analysis was completed of 1252 complete data records of stroke patients discharged from inpatient rehabilitation at Hamilton Health Sciences between 2006 and 2011. RESULTS AND IMPACT: Statistically significant improvements were observed in all total matched FIM scores (M = 72.68 to M = 96.39, P < .001) and for each expression (M = 4.61 to M = 5.35, P < .001) and comprehension (M = 4.69 to M = 5.33, P < .001) subscale. The most severely affected group demonstrated the greatest gains. These findings were independent of stroke severity. Additional outcome measurement tools for communication are therefore not required to assess outcomes in rehabilitation of stroke patients, although additional research is necessary to evaluate the clinical significance of the improvements that are observed using existing measurements of change. PMID- 28595970 TI - Response to "Commentary re. Utilization of medical expulsive therapy in children: An assessment of nationwide practice patterns and outcomes". PMID- 28595969 TI - Emergence and epidemiology of Cucurbit yellow stunting disorder virus in the American Desert Southwest, and development of host plant resistance in melon. AB - Cucurbit yellow stunting disorder virus (CYSDV), emerged in the Sonoran Desert region of the southwestern USA in 2006 and has become well established. Symptoms induced by CYSDV infection include a striking interveinal chlorosis or yellowing and reduced yield and quality. The virus is transmitted by Bemisia tabaci, and the cryptic species MEAM1 has been present in the region since the early 1990s. CYSDV has now become the most economically important of the viruses affecting cucurbit production in the southwestern US. Here, we present a review of recent studies on CYSDV in the southwestern US, with implications for management of this virus throughout the world. Field surveys have established that CYSDV results in late-season infection of spring melon crops with limited economic impact; however, all summer and fall cucurbits become infected shortly after emergence due to high B. tabaci populations and abundant sources of inoculum. Studies have also demonstrated that CYSDV has an extensive host range among crops and weeds prevalent in the region. Recent studies demonstrated considerable variation in virus accumulation and transmission rates among the host plants evaluated as potential reservoirs. Cucurbit hosts had the highest CYSDV titers, were efficient sources for virus acquisition, and showed a positive correlation between titer in source plants and transmission to cucurbit plants. Non-cucurbit hosts had significantly lower CYSDV titers and varied in their capacity to serve as sources for transmission. Experiments demonstrated that multiple factors influence the efficiency with which a host plant species will be a reservoir for vector transmission of CYSDV to crops. Melon PI 313970 was identified as a new source of host plant resistance to CYSDV, in addition to the previously identified TGR 1551 (=PI 482420) and TGR 1937 (=PI 482431). Potential new sources of CYSDV resistance were identified by field screening of ca. 500 melon accessions with naturally occurring inoculum from 2007 through 2012. Host plant resistance to B. tabaci has also been identified in melon germplasm resistant to CYSDV and could be an important factor in reducing losses to CYSDV. Resistance to CYSDV is being transferred to US western shipping type cantaloupe and honeydew. PMID- 28595971 TI - Bladder debris on renal and bladder ultrasound: A significant predictor of positive urine culture. AB - BACKGROUND: Renal and bladder ultrasound (RBUS) is recommended in evaluation of children after an initial, febrile urinary tract infection. Although it is not uncommon to observe debris within the bladder lumen on sonography, the significance of this finding is uncertain. Debris may be interpreted as an indication of ongoing infection, but there have been no studies to date investigating the association of bladder debris with a positive culture. OBJECTIVE: The aim of this study was to evaluate the association of bladder debris noted at the time of RBUS with positive urine culture results obtained from a catheterized specimen, among patients undergoing RBUS and voiding cystourethrogram (VCUG) on the same day. STUDY DESIGN: We performed a retrospective cross-sectional study of 3995 patients who presented for same-day RBUS and VCUG. RBUS reports were reviewed for the presence of bladder debris, and analysis was limited to patients under 60 months of age with a catheterized urine specimen sent for culture at the time of the studies. Those with prior postnatal imaging or a diagnosis of prenatal hydronephrosis or other GU abnormalities were excluded. Thirty-four subjects with bladder debris on RBUS were identified and matched to 155 controls based on age, gender, circumcision status, and presence of vesicoureteral reflux. A positive urine culture was defined as >=50,000 colony forming units per mL of at least one organism. A conditional logistic regression model was used to evaluate the association between debris on RBUS and positive urine culture results. RESULTS: In conditional logistic regression stratifying by matching age, gender, circumcision status, and presence of vesicoureteral reflux, there was a statistically significant association between bladder debris on RBUS and positive urine culture result collected on the same day during VCUG (OR 7.88, 95% CI 1.88-33.04, p = 0.0048). This corresponds to a 688% increase in odds of positive urine culture for patients with debris (Table). DISCUSSION: This is the first study to evaluate the association between bladder debris on RBUS and positive urine culture, and it should serve as a starting point for future investigations. The study is limited in its generalizability to the sampled population; further work should evaluate the predictive value of RBUS debris among children without UTI history, with prior imaging or known genitourinary anomalies, or older children. CONCLUSION: Among children younger than 60 months old undergoing initial imaging for history of UTI, there is a significant association between bladder debris and a positive urine culture. PMID- 28595973 TI - Crash probability estimation via quantifying driver hazard perception. AB - Crash probability estimation is an important method to predict the potential reduction of crash probability contributed by forward collision avoidance technologies (FCATs). In this study, we propose a practical approach to estimate crash probability, which combines a field operational test and numerical simulations of a typical rear-end crash model. To consider driver hazard perception characteristics, we define a novel hazard perception measure, called as driver risk response time, by considering both time-to-collision (TTC) and driver braking response to impending collision risk in a near-crash scenario. Also, we establish a driving database under mixed Chinese traffic conditions based on a CMBS (Collision Mitigation Braking Systems)-equipped vehicle. Applying the crash probability estimation in this database, we estimate the potential decrease in crash probability owing to use of CMBS. A comparison of the results with CMBS on and off shows a 13.7% reduction of crash probability in a typical rear-end near-crash scenario with a one-second delay of driver's braking response. These results indicate that CMBS is positive in collision prevention, especially in the case of inattentive drivers or ole drivers. The proposed crash probability estimation offers a practical way for evaluating the safety benefits in the design and testing of FCATs. PMID- 28595972 TI - 17alpha-Ethynylestradiol alters the peritoneal immune response of gilthead seabream. AB - 17alpha-Ethynylestradiol (EE2), a synthetic estrogen used in most oral contraceptives pills and hormone replacement therapies, is found in many water bodies, where it can modulate the fish immune response. EE2 acts as an endocrine disruptor in gilthead seabream, Sparus aurata L., a marine teleost fish of great economic value in Mediterranean aquaculture, as it induces hepatic vitellogenin gene (vtg) expression. Moreover, EE2 also alters the capacity of gilthead seabream to appropriately respond to infection although it does not behave as an immunosuppressor. Nevertheless, these previous studies have mainly focused on the head kidney leukocytes and no information exists on peritoneal leukocytes, including mast cells. In the present work, juvenile gilthead seabream fish were fed a pellet diet supplemented with EE2 for 76 days and intraperitoneally injected with hemocyanin plus imject alum adjuvant at the end of EE2 treatment and 92 days later, and the peritoneal immune response was analyzed. EE2 supplementation induced vtg expression but returned to basal levels by 3 months post-treatment. Interestingly, gilthead seabream peritoneal leukocytes express the genes encoding for the nuclear estrogen receptor alpha and the G protein coupled estrogen receptor 1 and the dietary intake of EE2 induced these expression. Moreover, EE2 induced an inflammatory response in the peritoneal cavity in unvaccinated fish, which was largely maintained for several months after the cessation of the treatment. However, the impact of EE2 in vaccinated fish was rather minor and transient. Taken together, the study provides fresh information about endocrine immune disruption, focusing on peritoneal leukocytes. PMID- 28595974 TI - Amyotrophic lateral sclerosis in Huntington disease gene carrier. PMID- 28595976 TI - Hemorrhagic stroke after cannabis use in a young man. PMID- 28595975 TI - Brain molecular imaging in pharmacoresistant focal epilepsy: Current practice and perspectives. AB - This review aims to synthesize all the available data on brain molecular imaging, such as single-photon emission computed tomography (SPECT) and interictal fluorodeoxyglucose positron emission tomography (FDG-PET), in focal epilepsies. SPECT imaging is able to measure regional cerebral blood flow and its major innovation remains its ictal imaging value. On the other hand, FDG-PET, which has higher spatial resolution and lower background activity than SPECT, enables glycolytic metabolism to be identified in interictal states. Therefore, interictal FDG-PET has greater sensitivity than interictal SPECT, especially in temporal lobe epilepsies (TLEs). Thus, 18F-FDG-PET is a necessary step in the presurgical evaluation of TLEs, but also of extratemporal epilepsies (ETEs), contributing to >30% of the decision to undertake surgery. In addition, FDG-PET has particular diagnostic value in focal epilepsies showing normal magnetic resonance imaging (MRI). PET also has good prognostic value for post-surgical outcomes as well as cognitive impairment, especially in cases where the hypometabolism extent is limited. Moreover, the notion of an epileptic network is well highlighted by functional PET imaging, allowing better understanding of the pathological substrates of these disorders. Future development of quantitative analysis software and of novel radiotracers and cameras will certainly enhance its clinical usefulness. PMID- 28595977 TI - Factors influencing time between onset of signs/symptoms and referral for dementia in elderly outpatients. AB - BACKGROUND: The few studies that have focused on Time between Onset of Signs and Symptoms and Referral (TOSR) for dementia to a memory center suggest a substantial delay of 1-3 years. This delay has a negative impact on both patients' and their caregivers' quality of life. OBJECTIVE: This study aimed to evaluate this delay and the factors associated with it in a cohort of community dwelling elderly people attending a memory clinic, as well as assess the impact of the Third French National Alzheimer Plan (2008-2012). METHODS: All patients referred to the Bretonneau Memory Clinic for the first time between January 2006 (the clinic has maintained a specific database since then) and March 2016 were included in the study. RESULTS: Of the 8543 patients attending our Memory Clinic during the study period, 3353 attending for the first time and with complete data were included. Briefly, their ages were 82+/-7 years, and 67.2% were female; MMSE score was 21.2+/-6.6, IADL was 4.06+/-0.78 and the social-needs category of the Groupes Iso Ressources (GIR); Iso-Resource Group (IRG) scale was 4.04+/-0.37. The TOSR was, on average, 35.4+/-30.24 months, and increased after implementation of the Third French National Alzheimer Plan, from 26.68+/-26.28 months before 2009 to 40.08+/-31.2 months after 2009. Age and MMSE were associated with TOSR, but not the type of dementia, household composition and social characteristics. Also, there was a shorter TOSR for mild cognitive impairment than for dementia patients. CONCLUSION: Our results emphasize the need for more education and information among the general public about the early signs of cognitive impairment, especially in elderly people. PMID- 28595978 TI - Pseudolymphomatous nodular lymphoid hyperplasia of small bowel. PMID- 28595981 TI - Response to "More surprises in the global greenhouse: Human health impacts form recent toxic marine aerosol formulations, due to centennial alterations or world wide coastal food webs". PMID- 28595980 TI - Significance of beach geomorphology on fecal indicator bacteria levels. AB - Large databases of fecal indicator bacteria (FIB) measurements are available for coastal waters. With the assistance of satellite imagery, we illustrated the power of assessing data for many sites by evaluating beach features such as geomorphology, distance from rivers and canals, presence of piers and causeways, and degree of urbanization coupled with the enterococci FIB database for the state of Florida. We found that beach geomorphology was the primary characteristic associated with enterococci levels that exceeded regulatory guidelines. Beaches in close proximity to marshes or within bays had higher enterococci exceedances in comparison to open coast beaches. For open coast beaches, greater enterococci exceedances were associated with nearby rivers and higher levels of urbanization. Piers and causeways had a minimal contribution, as their effect was often overwhelmed by beach geomorphology. Results can be used to understand the potential causes of elevated enterococci levels and to promote public health. PMID- 28595982 TI - Trophic transference of microplastics under a low exposure scenario: Insights on the likelihood of particle cascading along marine food-webs. AB - Microplastics are emergent pollutants in marine environments, whose risks along food-web still need to be understood. Within this knowledge gap, MPs transference and persistence along trophic levels are key processes. We assessed the potential occurrence of these processes considering a less extreme scenario of exposure than used previously, with microplastics present only in the hemolymph of prey (the mussel Perna perna) and absent in the gut cavity. Predators were the crab Callinectes ornatus and the puffer fish Spheoeroides greeleyi. Transference of microplastics occurred from prey to predators but without evidences of particle persistence in their tissues after 10days of exposure. This suggests a reduced likelihood of trophic cascading of particles and, consequently, a reduced risk of direct impacts of microplastics on higher trophic levels. However, the contact with microplastics along food-webs is still concerning, modulated by the concentration of particles in prey and predators' depuration capacity and rate. PMID- 28595983 TI - The effects of structure on pre-mRNA processing and stability. AB - Pre-mRNA molecules can form a variety of structures, and both secondary and tertiary structures have important effects on processing, function and stability of these molecules. The prediction of RNA secondary structure is a challenging problem and various algorithms that use minimum free energy, maximum expected accuracy and comparative evolutionary based methods have been developed to predict secondary structures. However, these tools are not perfect, and this remains an active area of research. The secondary structure of pre-mRNA molecules can have an enhancing or inhibitory effect on pre-mRNA splicing. An example of enhancing structure can be found in a novel class of introns in zebrafish. About 10% of zebrafish genes contain a structured intron that forms a bridging hairpin that enforces correct splice site pairing. Negative examples of splicing include local structures around splice sites that decrease splicing efficiency and potentially cause mis-splicing leading to disease. Splicing mutations are a frequent cause of hereditary disease. The transcripts of disease genes are significantly more structured around the splice sites, and point mutations that increase the local structure often cause splicing disruptions. Post-splicing, RNA secondary structure can also affect the stability of the spliced intron and regulatory RNA interference pathway intermediates, such as pre-microRNAs. Additionally, RNA secondary structure has important roles in the innate immune defense against viruses. Finally, tertiary structure can also play a large role in pre-mRNA splicing. One example is the G-quadruplex structure, which, similar to secondary structure, can either enhance or inhibit splicing through mechanisms such as creating or obscuring RNA binding protein sites. PMID- 28595984 TI - Cell cycle pathway dysregulation in human keratinocytes during chronic exposure to low arsenite. AB - BACKGROUND: Arsenic is naturally prevalent in the earth's crust and widely distributed in air and water. Chronic low arsenic exposure is associated with several cancers in vivo, including skin cancer, and with transformation in vitro of cell lines including immortalized human keratinocytes (HaCaT). Arsenic also is associated with cell cycle dysregulation at different exposure levels in multiple cell lines. In this work, we analyzed gene expression in HaCaT cells to gain an understanding of gene expression changes contributing to transformation at an early time point. METHODS: HaCaT cells were exposed to 0 or 100nM NaAsO2 for 7weeks. Total RNA was purified and analyzed by microarray hybridization. Differential expression with fold change>=|1.5| and p-value<=0.05 was determined using Partek Genomic SuiteTM and pathway and network analyses using MetaCoreTM software (FDR<=0.05). Cell cycle analysis was performed using flow cytometry. RESULTS: 644 mRNAs were differentially expressed. Cell cycle/cell cycle regulation pathways predominated in the list of dysregulated pathways. Genes involved in replication origin licensing were enriched in the network. Cell cycle assay analysis showed an increase in G2/M compartment in arsenite-exposed cells. CONCLUSIONS: Arsenite exposure induced differential gene expression indicating dysregulation of cell cycle control, which was confirmed by cell cycle analysis. The results suggest that cell cycle dysregulation is an early event in transformation manifested in cells unable to transit G2/M efficiently. Further study at later time points will reveal additional changes in gene expression related to transformation processes. PMID- 28595985 TI - Curcumin inhibits adipogenesis induced by benzyl butyl phthalate in 3T3-L1 cells. AB - Phthalates are a group of endocrine disrupting chemicals and may have contributed to the recent global obesity health crisis. Increased adipogenesis via the peroxisome proliferator-activated receptor gamma (PPARgamma)-CCAAT-enhancer binding protein alpha (C/EBPalpha) pathway could be one critical mechanism responsible for phthalate-induced weight gain. On the other hand, curcumin has been shown to inhibit adipogenesis in cells and animal models. The present study was undertaken to evaluate, for the first time, whether curcumin could reduce adipogenesis induced by benzyl butyl phthalate (BBP) via downregulation of the PPARgamma-C/EBPalpha pathway. 3T3-L1 preadipocytes were differentiated by treating them with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine in the presence of BBP, with or without curcumin. Cells that were grown in the presence of BBP alone showed a significant increase in triacylglycerol (TG) levels. In addition, the number of Oil Red O-stained cells and the mRNA expression levels of PPARgamma, C/EBPalpha, adiponectin, and tumor necrosis factor-alpha (TNFalpha) were significantly increased. However, treatment with BBP in combination with curcumin resulted in major reductions in TG levels, the numbers of Oil Red O stained cells, and the mRNA expression levels of the four proteins. These results suggest that curcumin might be an inhibitor of BBP-induced weight gain and inflammation via stimulation of adipocyte differentiation and TNFalpha generation. Curcumin may, therefore, be a potential medication for preventing the harmful effects of phthalates. PMID- 28595986 TI - Oral foregut duplication cysts: A rare and fascinating congenital lesion. Case report and review of the literature. AB - Oral foregut duplication cysts are extremely rare lesions with approximately 57 cases reported. They are congenital cysts, located in the anterior or ventral tongue, and occur predominantly in males. They are lined by one or more types of epithelia which is limited to gastric, intestinal or respiratory epithelium. The differential diagnosis includes lymphangioma, hemangioma, ranula, epidermoid cyst, teratoma and less likely a malignant process. PMID- 28595987 TI - New data on the combined treatment of solifenacin and mirabegron in patients with overactive bladder: SYNERGY study. PMID- 28595988 TI - Updates on Corynebacterium urealyticum infection. PMID- 28595989 TI - Volume reduction outweighs biogeochemical processes in controlling phosphorus treatment in aged detention systems. AB - Stormwater detention areas (SDAs) play an important role in treating end-of-the farm runoff in phosphorous (P) limited agroecosystems. Phosphorus transport from the SDAs, including those through subsurface pathways, are not well understood. The prevailing understanding of these systems assumes that biogeochemical processes play the primary treatment role and that subsurface losses can be neglected. Water and P fluxes from a SDA located in a row-crop farm were measured for two years (2009-2011) to assess the SDA's role in reducing downstream P loads. The SDA treated 55% (497kg) and 95% (205kg) of the incoming load during Year 1 (Y1, 09-10) and Year 2 (Y2, 10-11), respectively. These treatment efficiencies were similar to surface water volumetric retention (49% in Y1 and 84% in Y2) and varied primarily with rainfall. Similar water volume and P retentions indicate that volume retention is the main process controlling P loads. A limited role of biogeochemical processes was supported by low to no remaining soil P adsorption capacity due to long-term drainage P input. The fact that outflow P concentrations (Y1=368.3MUg L-1, Y2=230.4MUg L-1) could be approximated by using a simple mixing of rainfall and drainage P input further confirmed the near inert biogeochemical processes. Subsurface P losses through groundwater were 304kg (27% of inflow P) indicating that they are an important source for downstream P. Including subsurface P losses reduces the treatment efficiency to 35% (from 61%). The aboveground biomass in the SDA contained 42% (240kg) of the average incoming P load suggesting that biomass harvesting could be a cost-effective alternative for reviving the role of biogeochemical processes to enhance P treatment in aged, P-saturated SDAs. The 20-year present economic value of P removal through harvesting was estimated to be $341,000, which if covered through a cost share or a payment for P treatment services program could be a positive outcome for both agriculture and public interests. PMID- 28595990 TI - [Using consumer panels in public health observational studies]. AB - Consumer panels are a market research method useful for gathering information about low-frequency or difficult-access customers. The objective of this field note is to explain our experience using this method in a cross-sectional public health study on the use of electronic cigarettes. After taking into account other non-probabilistic sampling techniques to obtain a huge sample of electronic cigarette users (n=600), in the end we decided to use consumer panels (recruiters) because of the relative short duration of the field work and the high representativeness of the sample. PMID- 28595991 TI - [Asbestos, an epidemic that still needs to be controlled]. PMID- 28595993 TI - Endoscopic rescue treatment in a pregnant ulcerative colitis patient with a severe colonic stricture: a conservative approach to bring the pregnancy to term. PMID- 28595992 TI - [Food industry funding and epidemiologic research in public health nutrition]. AB - The interests of the food industry to fund nutrition and health research are not limited to promoting scientific advances. Recently, several systematic reviews conducted about the effect of sugar-sweetened beverages and health outcomes have shown some biased conclusions in studies that acknowledge industry sponsorship. In this context, the Nutrition Working Group of the Spanish Epidemiology Society presented a scientific session entitled Food industry and epidemiologic research at its annual meeting. In a round table, four experts in nutrition research presented their points of view about whether the food industry should fund nutrition-related research and the related potential conflicts of interest of the food industry. All the experts agreed not only on defending independence in nutritional epidemiology regarding the design, interpretation and conclusion of their studies but also on the crucial need for guaranteed scientific rigor, scientific quality of the results and measures to protect studies against potential biases related to the conflicts of interest of funding by the food industry. Drs Perez-Farinos and Romaguera believe that the most effective way to prevent conflicts of interest would be not to allow the food industry to fund nutrition research; Drs Marcos and Martinez-Gonzalez suggested the need to establish mechanisms and strategies to prevent the potential influences of the food industry in selecting researchers or institutional sponsorship and in the analysis and results of the studies, to ensure maximum independence for researchers, as well as their professional ethics. PMID- 28595994 TI - [News techniques of pacing in congenital heart diseases]. AB - The number of children and adult with congenital heart disease requiring implantation of cardiac pacemaker or cardioverter defibrillator is constantly increasing. The lead between stimulation/defibrillation site and the generator constitutes the main weakpoint of those devices despite the numerous recent technological advances: use of bipolar probes, corticoid elution electrodes, insulation improvement, magnetic resonance imaging (MRI) compatibility. Risk of device failure remains high in this population. Long term adverse events with endovascular devices remain high. That point leads us to review our implantation strategies. We try to favour an extravascular solution whenever possible. Subcutaneous defibrillators may be proposed to patients at high risk for severe ventricular arrhythmia without cardiac pacing indication. Patients should have a rigorous pre-implantation screening procedure to minimize the increased risk of inappropriate shock. New single chamber, VVIR-type, leadless pacemakers can be implanted directly into the right ventricle. Miniaturized implantable loop recorders help in management of palpitations and syncopes: it increases diagnosis yield and helps arrhythmias burden assessment. Development of remote monitoring (implantable loop recorder, pacemaker and defibrillator) helps to reduce the incidence of adverse clinical events by providing an early detection of clinically relevant events such as arrhythmias and device failure. PMID- 28595996 TI - Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. AB - Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR. PMID- 28595995 TI - miR-146b Probably Assists miRNA-146a in the Suppression of Keratinocyte Proliferation and Inflammatory Responses in Psoriasis. AB - miR-146a inhibits inflammatory responses in human keratinocytes and in different mouse models of skin inflammation. Little is known about the role of miR-146b in the skin. In this study, we confirmed the increased expression of miR-146a and miR-146b (miR-146a/b) in the lesional skin of patients with psoriasis. The expression of miR-146a was approximately twofold higher than that of miR-146b in healthy human skin, and it was more strongly induced by stimulation of proinflammatory cytokines in keratinocytes and fibroblasts. miR-146a/b target genes regulating inflammatory responses or proliferation were altered in the skin of patients with psoriasis, among which FERMT1 was verified as a direct target of miR-146a. In silico analysis of genome-wide data from >4,000 psoriasis cases and >8,000 controls confirmed a moderate association between psoriasis and genetic variants in the miR-146a encoding gene. Transfection of miR-146a/b suppressed and inhibition enhanced keratinocyte proliferation and the expression of psoriasis related target genes. Enhanced expression of miR-146a/b-influenced genes was detected in cultured keratinocytes from miR-146a-/- and skin fibroblasts from miR 146a-/- and miR-146b-/- mice stimulated with psoriasis-associated cytokines as compared with wild-type mice. Our results indicate that besides miR-146a, miR 146b is expressed and might be capable of modulation of inflammatory responses and keratinocyte proliferation in psoriatic skin. PMID- 28595997 TI - HPV8 Field Cancerization in a Transgenic Mouse Model Is due to Lrig1+ Keratinocyte Stem Cell Expansion. AB - beta-Human papillomaviruses (HPVs) cause near ubiquitous latent skin infection within long-lived hair follicle (HF) keratinocyte stem cells. In patients with epidermodysplasia verruciformis, beta-HPV viral replication is associated with skin keratosis and cutaneous squamous cell carcinoma. To determine the role of HF keratinocyte stem cells in beta-HPV-induced skin carcinogenesis, we utilized a transgenic mouse model in which the keratin 14 promoter drives expression of the entire HPV8 early region (HPV8tg). HPV8tg mice developed thicker skin in comparison with wild-type littermates consistent with a hyperproliferative epidermis. HF keratinocyte proliferation was evident within the Lrig1+ keratinocyte stem cell population (69 vs. 55%, P < 0.01, n = 7), and not in the CD34+, LGR5+, and LGR6+ keratinocyte stem cell populations. This was associated with a 2.8-fold expansion in Lrig1+ keratinocytes and 3.8-fold increased colony forming efficiency. Consistent with this, we observed nuclear p63 expression throughout this population and the HF infundibulum and adjoining interfollicular epidermis, associated with a switch from p63 transcriptional activation isoforms to DeltaNp63 isoforms in HPV8tg skin. Epidermodysplasia verruciformis keratosis and in some cases actinic keratoses demonstrated similar histology associated with beta-HPV reactivation and nuclear p63 expression within the HF infundibulum and perifollicular epidermis. These findings would suggest that beta-HPV field cancerization arises from the HF junctional zone and predispose to squamous cell carcinoma. PMID- 28595998 TI - Targeting of CXXC5 by a Competing Peptide Stimulates Hair Regrowth and Wound Induced Hair Neogenesis. AB - The Wnt/beta-catenin pathway has been implicated in hair follicle development and hair regeneration in adults. We discovered that CXXC-type zinc finger protein 5 (CXXC5) is a negative regulator of the Wnt/beta-catenin pathway involved in hair regrowth and wound-induced hair follicle neogenesis via an interaction with Dishevelled. CXXC5 was upregulated in miniaturized hair follicles and arrector pili muscles in human balding scalps. The inhibitory effects of CXXC5 on alkaline phosphatase activity and cell proliferation were demonstrated using human hair follicle dermal papilla cells. Moreover, CXXC5-/- mice displayed accelerated hair regrowth, and treatment with valproic acid, a glycogen synthase kinase 3beta inhibitor that activates the Wnt/beta-catenin pathway, further induced hair regrowth in the CXXC5-/- mice. Disrupting the CXXC5-Dishevelled interaction with a competitor peptide activated the Wnt/beta-catenin pathway and accelerated hair regrowth and wound-induced hair follicle neogenesis. Overall, these findings suggest that the CXXC5-Dishevelled interaction is a potential target for the treatment of hair loss. PMID- 28596000 TI - The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. AB - Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage. PMID- 28596001 TI - Establishing and Validating an Ichthyosis Severity Index. AB - We designed and validated a Visual Index for Ichthyosis Severity for scale and erythema that provides (1) written descriptions of the features characteristic of each level of severity, (2) visual standards for four body sites, and (3) two distinct standards to account for different types of scale. We tested the Visual Index for Ichthyosis Severity for reliability and reproducibility using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists, and one with in-person evaluations on 85 subjects by 12 dermatologists at the Foundation for Ichthyosis and Related Skin Types conference. The validation process revealed high reliability and reproducibility for both scale and erythema. The interrater and intrarater intraclass correlation coefficients for scale were consistently near or greater than 0.7 in both settings. By contrast, the interrater reliability for erythema was higher during in-person validation compared with validation on test photographs. Our analysis indicates that the Visual Index for Ichthyosis Severity performs better in person than with photographs, an important consideration in the design of clinical trials. Power analysis predicts that a 1-point difference on this 5-step scale would be detectable with 12 subjects in each of two defined groups. This index provides a tool for clinical phenotyping and assessment of therapeutic response for many disorders of keratinization. PMID- 28595999 TI - p63 Transcription Factor Regulates Nuclear Shape and Expression of Nuclear Envelope-Associated Genes in Epidermal Keratinocytes. AB - The maintenance of a proper nuclear architecture and three-dimensional organization of the genes, enhancer elements, and transcription machinery plays an essential role in tissue development and regeneration. Here we show that in the developing skin, epidermal progenitor cells of mice lacking p63 transcription factor display alterations in the nuclear shape accompanied by a marked decrease in expression of several nuclear envelope-associated components (Lamin B1, Lamin A/C, Sun1, Nesprin-3, Plectin) compared with controls. Furthermore, chromatin immunoprecipitation-quantitative PCR assay showed enrichment of p63 on Sun1, Syne3, and Plec promoters, suggesting them as p63 targets. Alterations in the nuclei shape and expression of nuclear envelope-associated proteins were accompanied by altered distribution patterns of the repressive histone marks trimethylation on lysine 27 of histone H3, trimethylation on lysine 9 of histone H3, and heterochromatin protein 1-alpha in p63-null keratinocytes. These changes were also accompanied by downregulation of the transcriptional activity and relocation of the keratinocyte-specific gene loci away from the sites of active transcription toward the heterochromatin-enriched repressive nuclear compartments in p63-null cells. These data demonstrate functional links between the nuclear envelope organization, chromatin architecture, and gene expression in keratinocytes and suggest nuclear envelope-associated genes as important targets mediating p63-regulated gene expression program in the epidermis. PMID- 28596002 TI - Spontaneous pregnancy rates after reproductive surgery. AB - With the development of IVF procedures, the role of reproductive surgery in the management of infertile couples has been questioned. Pregnancy rates (PR) after IVF procedures are well known, but recent data on spontaneous PR after reproductive surgery are scarce. This study aimed to prospectively evaluate how often fertility is restored by reproductive surgery and to identify which independent factors influence spontaneous pregnancy after reproductive surgery. Eight hundred eighty-eight infertile women who underwent surgery for infertility were prospectively included. Women who were referred to IVF after surgery, ceased to plan pregnancy and were lost to follow-up were excluded. Spontaneous PR was analysed for 519 women. A total of 252 (48.6%) women, including 30 treated with clomiphene citrate, conceived spontaneously in the 12-18 months observation period following surgery. Multivariate logistic regression showed that woman's age (OR 0.95, 95% CI 0.90-0.99) and duration of infertility (OR 0.86, 95% CI 0.74 0.99) significantly influence spontaneous PR. Each year of infertility lowers spontaneous PR following surgery by 14% and each year of woman's age by 5%. The study shows a relatively high percentage of women conceived spontaneously after reproductive surgery. The role of reproductive surgery in the management of infertility should be re-evaluated. PMID- 28596003 TI - Empty follicle syndrome revisited: definition, incidence, aetiology, early diagnosis and treatment. AB - In this review, the definition, incidence and possible causes of empty follicle syndrome (EFS), including molecular mechanisms that may underlie the syndrome, are discussed, along with prevention and treatment options. EFS is the complete failure to retrieve oocytes after ovarian stimulation, despite apparently normal follicle development and adequate follicular steroidogenesis. Two variants of EFS have been described: the 'genuine' form (gEFS), which occurs in the presence of adequate circulating HCG levels at the time of oocyte aspiration, and the 'false' form (f-EFS), which is associated with circulating HCG below a critical threshold. Heterogeneous HCG concentration thresholds, however, have been used to define gEFS, and to date no standardization exist. The situation is unclear when GnRH-analogues are used for ovulation trigger, as the threshold circulating LH and progesterone levels used to define EFS as 'genuine' are not established. The cause of fEFS has been clearly identified as an error in HCG administration at the time of ovulation trigger; in contrast, the cause of gEFS is still unclear, although some pathogenetic hypotheses have been proposed. Optimal treatment and prognosis of these patients are still poorly understood. Large, systematic multi centre studies are needed to increase the understanding of EFS. PMID- 28596004 TI - Synthesis of dextrin-stabilized colloidal silver nanoparticles and their application as modifiers of cement mortar. AB - Various commercial dextrins were used as reducing and stabilizing agents for a novel one-step synthesis of silver nanoparticles from ammonia complexes of silver ions. As a result, stable colloids of silver were formed during the reaction with the particle size being the function of the dextrin type. The obtained colloids were characterized by UV-vis spectrophotometry, size distribution (using Non Invasive Backscatter optics) and transmission electron microscopy (TEM). The achieved results clearly indicate the possibility of low-cost production of large quantities of colloidal silver nanoparticles using materials derived from renewable sources. The resulting silver colloids can be used for different purposes, e.g. as bactericidal agents. Combination of the aforementioned properties of nanosilver particles with plasticizing properties of dextrin enables to obtain cement mortars with increased workability and enhanced compressive strength. Moreover, the obtained material is also characterized by increased immunity to adverse impact of microorganisms. PMID- 28596005 TI - Characterization of keratin microparticles from feather biomass with potent antioxidant and anticancer activities. AB - In the present study chicken feathers were hydrolyzed by chemical treatment in alkaline conditions. The pH value of feather hydrolyzed solution was amended accordingly the iso-electric precipitation. Two types of keratin microparticles KM1, KM2 were synthesized under acidic conditions at 3.5 and 5.5pH respectively. The synthesized keratin microparticles possessed uniform and round surface by scanning electron microscopy (SEM). The thermal degradation of microparticles were examined by thermogravimetry (TGA). Fourier transform infrared spectroscopy (FTIR) revealed that the extracted keratin retained the most of protein backbone. The microparticles were screened for their in vitro anticancer activities by SRB bioassay towards HeLa, SK-OV-3 and A549 cancer cell lines. Futhermore, their cytotoxicity towards healthy cell lines was analyzed having Malin Darby canine kidney (MDCK) cell lines along with in vitro antioxidant activity using DPPH and ABTS methods KM1 and KM2 showed 200.31+/-1.01 and 139.73+/-0.94, 214.16+/-0.29 and 153.92+/-0.61, 328.92+/-3.46 and 200.33+/-2.48MUg/mL of IC50 levels against HeLa, SK-OV-3, and A549 cell lines, respectively. Moreover, KM1 and KM2 demonstrated significant antioxidant potency with IC50 levels 13.15 and 9.02MUg/mL as well as 8.96 and 5.60MUg/mL in DPPH and ABTS radical scavenging bioassay, respectively. PMID- 28596007 TI - Structural profiling of wax biopolymer from Pinus roxburghii Sarg. needles using spectroscopic methods. AB - Pinus roxburghii Sarg. is the most abundant species in Himalayan region. The needles of the species largely contribute to the forest biomass and remain the major cause of forest fires leading to climate change, biodiversity loss, etc. Intriguingly, the layer of needles contains wax, a biomacromolecule with potential chemical functionalities for value addition. In the present study, a distinctive approach towards complete structural analysis of the isolated wax in its native state has been done using 1H, 13C, HSQC, HMBC, COSY, TOCSY along with GC-MS of the methyl esters of constituent fatty acids. The wax was isolated in a quantitative yield of 1.64% and analyses suggest that it is a polymer of linearly attached fatty acid esters which on hydrolysis yielded three types of omega hydroxy fatty acids viz. 12-hydroxydodecanoic acid, 14-hydroxytetradecanoic acid and 16-hydroxyhexadecanoic acid in a ratio of 1:1:2 respectively. Complete assignments for a carbonyl group, alpha-, beta- and other methylenes present in wax were achieved; corroborating the presence of polyester. In particular, identification of wax structure was accomplished through NMR; thereby providing a lead towards future structural analysis of waxes in their native form. The study would also be helpful to generate commercially important compounds derived from pine needle wax. This will offer an opportunity for utilisation of pine needle biomass: a root cause of Himalayan forest fires. PMID- 28596006 TI - Fabrication of single and bundled filament-like tissues using biodegradable hyaluronic acid-based hollow hydrogel fibers. AB - Hydrogel fibers with biodegradable and biocompatible features are useful for the fabrication of filament-like tissues. We developed cell-laden hyaluronic acid (HA)-based hollow hydrogel fibers to create single and bundled filament-like tissues. The cell-laden fibers were fabricated by crosslinking phenolic substituted hyaluronic acid (HA-Ph) in an aqueous solution containing cells through a horseradish peroxidase (HRP)-catalyzed reaction in the presence of catalase by extruding the solution in ambient flow of an aqueous solution containing H2O2. The encapsulated cells proliferated and grew within the hollow core, and the cells formed filament-like constructs in both single and bundled fibers, which were obtained by collection on a rotating cylindrical tube. Single and bundled filament-like tissues covered with an additional heterogeneous cell layer were obtained by degrading the fiber membrane using hyaluronidase after covering the fiber surface with heterogeneous cells. Cellular viability was preserved during HA-Ph hydrogel fiber fabrication and filament-like tissue formation. These results demonstrate the feasibility of HA-based hollow hydrogel fibers obtained through HRP- and catalase-mediated reactions to engineer filament like tissues. PMID- 28596008 TI - Macrophage-stimulating activities of newly isolated complex polysaccharides from Parachlorella kessleri strain KNK-A001. AB - Our previous studies demonstrated that the microalga Parachlorella kessleri (KNK A001) has immunostimulatory activities, which were observed as an increase in natural killer (NK) cell activity in mice after intraperitoneal injection or as a protective effect on a virus-infected model shrimp after oral administration. In this study, we attempted to gain insight into the constituent substances of KNK A001 that are responsible for the immunostimulatory activity. First, we obtained five polysaccharide fractions from KNK-A001 by DEAE anion exchange chromatography. Among the fractions, F5 showed the most potent induction of nitric oxide (NO) secretion in RAW264.7 cells, and both mRNA and protein expression levels of inducible NO synthase (iNOS) were increased in F5-treated RAW264.7 cells. A significant increase in the nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-kappaB) was observed in F5-treated RAW264.7 cells. F5 also induced the secretion of tumor necrosis factor (TNF)-alpha in RAW264.7 cells. Analysis using mitogen-activated protein (MAP) kinase inhibitors suggested that c-Jun N-terminal kinase (JNK) and p38 MAP kinase were mainly involved in F5-induced NO and TNF-alpha productions. The compositional analysis of F5 identified the main constituents as galactose, glucose, galacturonic acid, and mannose. Gel-filtration analysis suggested that molecular mass of F5 was approximately 400kDa. PMID- 28596010 TI - Silica hydride based phases for small molecule separations using automated liquid chromatography-mass spectrometry method development. AB - Silica hydride, or Type C silica, has been developed as an alternative chromatographic support material for liquid chromatography. There are various bonded phases available with this new support. For four such phases (Cholesterol, Bidentate C18, Diamond Hydride, and Diol), retention and selectivity behavior were investigated using liquid chromatography coupled with triple quadrupole mass spectrometry. A set of small molecules from several chemical classes of interest, and varying in their physicochemical properties, were chromatographed under both reversed-phase and aqueous normal phase modes. To screen the columns, column switching was performed using an automated platform controlled by associated software and an additional valve. A typical scouting gradient was implemented. The separation conditions were not further optimized since the goal was simply to evaluate the variable retention behavior of the phases and selectivity under generic conditions. Further, retention of the analytes were evaluated under isocratic conditions with varying percentages of organic phase to visualize the potential for dual retention modes on the same column for certain analytes. Four analytes (fentanyl, hydrocodone, hydromorphone, and matrine) showed dual mode retention behavior with all four phases. Especially, fentanyl exhibited dramatic "U-shaped" retention profiles on Cholesterol and Bidentate C18 phases. Overall, changes in the retention order between reversed phase and aqueous normal phases emphasized the potential for altered selectivity. Results showed that the Cholesterol phase provided the highest retention for most analytes compared to the other phases. The more polar Diol phase still provided good retention in reversed phase mode. Retention and selectivity were all highly reproducible. PMID- 28596009 TI - Subzero Celsius separations in three-zone temperature controlled hydrogen deuterium exchange mass spectrometry. AB - Hydrogen deuterium exchange mass spectrometry (HDX MS) reports on the conformational landscape of proteins by monitoring the exchange between backbone amide hydrogen atoms and deuterium in the solvent. To maintain the label for analysis, quench conditions of low temperature and pH are required during the chromatography step performed after protease digestion but before mass spectrometry. Separation at 0 degrees C is often chosen as this is the temperature where the most deuterium can be recovered without freezing of the typical water and acetonitrile mobile phases. Several recent reports of separations at subzero Celsius emphasize the promise for retaining more deuterium and using a much longer chromatographic gradient or direct infusion time. Here we present the construction and validation of a modified Waters nanoACQUITY HDX manager with a third temperature-controlled zone for peptide separations at subzero temperatures. A new Peltier-cooled door replaces the door of a traditional main cooling chamber and the separations and trapping column are routed through the door housing. To prevent freezing, 35% methanol is introduced post online digestion. No new pumps are required and online digestion is performed as in the past. Subzero separations, using conventional HPLC column geometry of 3MU m particles in a 1*50mm column, did not result in major changes to chromatographic efficiency when lowering the temperature from 0 to -20 degrees C. There were significant increases in deuterium recovery for both model peptides and biologically relevant protein systems. Given the higher levels of deuterium recovery, expanded gradient programs can be used to allow for higher chromatographic peak capacity and therefore the analysis of larger and more complex proteins and systems. PMID- 28596011 TI - Emmenagogue properties of Milicia excelsa (Welw.) C.C. Berg (Moraceae) based, at least in part, on its ability to correlate the activity of the hypothalamic pituitary axis to that of the ovaries. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Milicia excelsa (Welw.) C.C. Berg (Moraceae) is a medicinal plant recommended over tropical Africa as a cure for several ailments including amenorrhea. This is the hallmark of an ovarian lesion or a dysfunction of the hypothalamic-pituitary-ovarian axis which may lead to infertility, osteoporosis or endometrial cancer. However, regardless these traditional claims, no scientific report dealing with emmenagogue properties has been reported yet. AIM OF THE STUDY: To bring scientific evidence to the curative action of the plant, we proposed evaluating the effects of a root aqueous extract of Milicia excelsa on female Wistar rat sexual maturation. MATERIAL AND METHODS: The study was performed in immature (45 days old) female Wistar rats orally treated with the root aqueous extract of Milicia excelsa at doses of 14, 77 and 140mg/kg BW/day for 7 and 15 consecutive days. Genistein (10mg/kg BW) served as the reference substance. Negative control animals, treated with the vehicle, were followed up for 7, 15, 30 and 45 days and rats were aged 52, 60, 75 and 90 days at these respective days. This allowed setting the nubile age of experimental animals and to determine the impact of treatments with genistein or the aqueous extract of Milicia excelsa on the age of rat sexual maturation. Since female rats do not have menstruation and that the normal menstrual cycle occurs because of changing levels of hormones made and secreted by the ovaries in response to hormonal signals from the pituitary gland, the effects of treatments were evaluated on the pituitary production of gonadotropins, the ovarian production of estradiol and progesterone, and uterine and vaginal growths. RESULTS: The sexual maturation of untreated rats was set at 90 days old. This sexual maturation was indicated by the simultaneous elevation of gonadotropins (FSH and LH (p<0.01)) and ovarian hormones (estradiol (p<0.001) and progesterone (p<0.05)) in animals aged 90 days. Uterine and vaginal growths (p < 0.001) observed in these animals appear as the result of elevated level of estradiol. The root aqueous extract of Milicia excelsa displayed genistein-like effects and increased FSH and estradiol serum levels following both treatment periods (7 and 15 days). Estradiol serum concentration significantly increased following a 7-day treatment at the dose of 14mg/kg BW (p<0.001). This resulted in an increase in the uterine wet weight, uterine and vaginal epithelial heights (p<0.05). These results suggest that the root aqueous extract of Milicia excelsa reduced rats' sexual maturation from 90 to 52 days. Moreover, animals' body weight was not affected following treatment with Milicia excelsa. CONCLUSION: The root aqueous extract of Milicia excelsa may solve the problem of amenorrhea by synchronizing the activity of the hypothalamic pituitary axis to the ovarian production of estradiol and progesterone. The unaltered body weight following treatments justifies at least in part, the traditional use of Milicia excelsa for primary and secondary amenorrhea. PMID- 28596012 TI - Effects of positive airway pressure therapy on cardiovascular and metabolic markers in males with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular/metabolic complications. Some analytical parameters (homocysteine, glycemic and lipidic profiles) are recognized markers of these consequences. Limited data is available on the association of these markers and OSAS's severity/response to positive airway pressure therapy (PAP). MATERIAL AND METHODS: In this prospective study we analyzed polysomnographic and analytical data of male patients admitted to sleep laboratory. The aim was to evaluate metabolic/cardiovascular markers in snorers and OSAS patients, to relate with sleep parameters and PAP response. One-hundred and three patients were included, and 73 (71%) were OSAS patients. OSAS patients were similar to snorers except for higher body mass index (BMI) and dyslipidemia. Severe OSAS patients showed higher glycemia, HbA1c, insulin, and insulin resistance, and lower HDL cholesterol in comparison to mild-moderate (p<0.05, p<0.05, p<0.001, p<0.001, p<0.05, respectively). Glycemic profile and triglycerides were slightly correlated with OSAS severity. 46 OSAS patients were submitted to 6 months of PAP, with a statistical decrease in mean values of homocysteine, glycemia, total and LDL cholesterol (p<0.05, p<0.05, p<0.05, respectively), and in glycemia and LDL cholesterol in severe group only (p<0.05, p<0.05, respectively). RESULTS: This study demonstrated an association between glucose metabolism parameters and triglycerides with OSAS severity underlying the complexity of the process leading to cardiovascular/metabolic complications in this disorder. Moreover, homocysteine, glycemic and lipidic profiles changed significantly after 6 months of PAP therapy in OSAS, supporting its cardiovascular and metabolic protective effect. CONCLUSION: Our study has reinforced the importance of analytical cardiovascular/metabolic evaluation as complementary tool of diagnosis/treatment response in OSAS. PMID- 28596013 TI - Two likely targets for the anti-cancer effect of indole derivatives from cruciferous vegetables: PI3K/Akt/mTOR signalling pathway and the aryl hydrocarbon receptor. AB - Diets containing high quantities of plant foods are linked with a decreased likelihood of incidence of cancer. Several common plant-based dietary components exert effects on DNA methylation levels, and can positively influence genome stability and the transcription of tumor suppressors and oncogenes. Indole-3 carbinol (I3C) is a substance present in vegetables of the Brassicaeae family, especially broccoli, white cabbage, Brussels sprouts and cauliflower. The in vivo biological effects of I3C are ascribed to a series of oligomeric products (including 3,3'-diindolylmethane), developed under acidic conditions. I3C is one of the many natural products and bioactive compounds found in foods which have recently received much attention for its potential effects in cancer prevention and treatment. In vitro studies report that I3C suppresses the proliferation of different tumor cells, including those isolated from breast, prostate, endometrium, and colon cancers. I3C resulted to be a potent in vivo chemopreventive agent for certain hormone-dependent cancers, including breast and cervical cancer. However, the mechanisms underlying these effects are not well defined. In this review, we have analysed recent literature on the use of indole derivatives against various forms of cancer, and have identified the main signalling pathways involved in their anti-cancer effect as PI3K/Akt/mTOR and the aryl hydrocarbon receptor. PMID- 28596014 TI - Designing food structure and composition to enhance nutraceutical bioactivity to support cancer inhibition. AB - Many types of bioactive molecules found in foods ("nutraceuticals") have been shown to exert anticancer activities, including curcumin, resveratrol, polyphenols, sulforaphane, anthocyanins, genistein, quercetin and lycopene. The potential health benefits of nutraceuticals are often not realized because of their poor water solubility, chemical instability, adverse taste profile, and low oral bioavailability. Carefully designed food matrices are being developed to overcome these problems. Nutraceuticals can be isolated from their natural environment, and then incorporated into functional foods, often with the help of delivery systems (such as emulsions, nanoemulsions, liposomes, biopolymer nanoparticles, and microgels). Alternatively, the stability and bioavailability of nutraceuticals can be improved by leaving them in their natural environment, but ingesting them with a specially designed "excipient food". The structure and composition of an excipient food is controlled so as to enhance the bioaccessibilty, stability, and absorption of the nutraceuticals in the gastrointestinal tract. This review article provides an overview of some of the most important anticancer nutraceuticals found in foods, then highlights the main factors impacting their bioaccessibility, absorption and transformation. Finally, it describes different types of delivery systems and excipient systems that can be used to improve the overall bioavailability of anticancer nutraceuticals. PMID- 28596015 TI - Low-grade and high-grade endometrial stromal sarcoma: A National Cancer Database study. AB - OBJECTIVE: To provide refined prognostic information from large cohorts of women with low-grade or high-grade endometrial stromal sarcoma (ESS). METHODS: We performed an observational retrospective cohort analysis of women diagnosed with low-grade or high-grade ESS from the 1998-2013 National Cancer Database. Kaplan Meier and multivariable accelerated failure time survival analyses were performed to identify prognostic factors after multiple imputation of missing data. Recursive partitioning methods were used to rank prognostic factors in high-grade ESS. Matched cohort analyses were performed to hypothesis-test effects of adjuvant treatments. RESULTS: We identified 2414 and 1383 women with low-grade or high-grade ESS, respectively. Women with high-grade ESS had markedly decreased survival compared to women with low-grade ESS (five-year survival (95% CI): 32.6 (30.1-35.3%) versus 90.5% (89.3-91.8%), P<0.001). Among women with high-grade ESS, median survival (95% CI) was only 19.9 (17.1-22.1) months. Increased age and tumor size were associated with decreased survival in low-grade ESS. In high grade ESS, additional negative prognostic factors were distant or nodal metastasis, omission of lymphadenectomy, and pathologically-positive surgical margins (all P<0.001). Use of adjuvant chemotherapy (time ratio (TR) (95% CI): 1.36 (1.17-1.58), P<0.001) and radiotherapy (TR (95% CI): 1.57 (1.32-1.87), P<0.001) were associated with increased survival for high-grade ESS. CONCLUSION: The contrasting excellent versus poor prognosis of low-grade versus high-grade ESS, respectively, was confirmed. The best treatment of high-grade ESS is early and complete surgical resection including lymphadenectomy. Adjuvant chemotherapy and radiotherapy may increase survival of women with high-grade ESS. PMID- 28596016 TI - Multi-disciplinary summit on genetics services for women with gynecologic cancers: A Society of Gynecologic Oncology White Paper. AB - OBJECTIVE: To assess current practice, advise minimum standards, and identify educational gaps relevant to genetic screening, counseling, and testing of women affected by gynecologic cancers. METHODS: The Society of Gynecologic Oncology (SGO) organized a multidisciplinary summit that included representatives from the American College of Obstetricians and Gynecologists (ACOG), the American Society Clinical Oncology (ASCO), the National Society of Genetic Counselors (NSGC), and patient advocacy groups, BrightPink and Facing our Risk of Cancer Empowered (FORCE). Three subject areas were discussed: care delivery models for genetic testing, barriers to genetic testing, and educational opportunities for providers of genetic testing. RESULTS: The group endorsed current SGO, National Comprehensive Cancer Network (NCCN), and NSGC genetic testing guidelines for women affected with ovarian, tubal, peritoneal cancers, or DNA mismatch repair deficient endometrial cancer. Three main areas of unmet need were identified: timely and universal genetic testing for women with ovarian, fallopian tube, and peritoneal cancers; education regarding minimum standards for genetic counseling and testing; and barriers to implementation of testing of both affected individuals as well as cascade testing of family members. Consensus building among all stakeholders resulted in an action plan to address gaps in education of gynecologic oncology providers and delivery of cancer genetics care. PMID- 28596017 TI - Statin treatment is associated with survival in a nationally representative population of elderly women with epithelial ovarian cancer. AB - OBJECTIVE: Observational studies suggest that statin therapy for cardio protection is associated with improved survival in cancer patients. We sought to evaluate the impact of statin treatment on ovarian cancer survival in a nationally representative elderly population. METHODS: The linked Surveillance, Epidemiology, and End Results (SEER) registries and Medicare claims data on patients diagnosed with epithelial ovarian cancer in 2007-2009 were used to extract data on statin prescription fills, population characteristics, primary treatment, comorbidity and survival. Cox regression models were used to examine the association between statin treatment and overall survival. RESULTS: Among the 1431 ovarian cancer patients who underwent surgical resection, 609 (42.6%) filled prescriptions for statin. The majority of statin-users (89%) were prescribed a lipophilic formulation. Mean overall survival among statin-users was 32.3months compared to 28.8months for non-users (p<0.0001). A 34% reduction in death was associated with statin therapy, independent of age, race, neighborhood median household income, stage, platinum therapy and comorbid conditions (HR=0.66, 95% CI 0.55-0.81). Improved overall survival with statin use was observed for both serous (HR=0.69, 95% CI 0.54-0.87) and non-serous (HR=0.63, 95% CI 0.44-0.90) histologies. When statin treatment was categorized by lipophilicity and intensity, a significant survival benefit was limited to lipophilic statin users and those who took statins of moderate intensity. CONCLUSIONS: This SEER-Medicare analysis demonstrates improvement in overall survival with lipophilic statin use after surgery in elderly patients with epithelial ovarian cancer. A clinical trial to evaluate the impact of statin treatment in ovarian cancer survival is warranted. PMID- 28596018 TI - Considering a new domain for antimicrobial stewardship: Topical antibiotics in the open surgical wound. AB - The global push to combat the problem of antimicrobial resistance has led to the development of antimicrobial stewardship programs (ASPs), which were recently mandated by The Joint Commission and the Centers for Medicare and Medicaid Services. However, the use of topical antibiotics in the open surgical wound is often not monitored by these programs nor is it subject to any evidence-based standardization of care. Survey results indicate that the practice of using topical antibiotics intraoperatively, in both irrigation fluids and powders, is widespread. Given the risks inherent in their use and the lack of evidence supporting it, the practice should be monitored as a core part of ASPs, and alternative agents, such as antiseptics, should be considered. PMID- 28596019 TI - Risk factors of catheter-related bloodstream infection caused by Bacillus cereus: Case-control study in 8 teaching hospitals in Japan. AB - In this multicenter, matched case-control study, patients diagnosed with catheter related bloodstream infection (CRBSI) caused by Bacillus cereus (n = 108) were matched to controls (n = 269). In the multivariable analysis, administration of an amino acid preparation and an indwelling peripheral catheter were significant variables for B cereus-related CRBSI. PMID- 28596020 TI - Challenges to sustainability of hand hygiene at a rural hospital in Rwanda. AB - BACKGROUND: Many hand hygiene (HH) programs have been implemented across Sub Saharan Africa (SSA); however, most of these have been in large, referral hospitals. Our objective was to assess the impact of HH programs aimed at improving compliance at a rural hospital, and to identify unique challenges to HH sustainability. METHODS: Interventions to improve HH through providing handwashing stations, health care worker (HCW) training, and alcohol handrub were completed in 2014 and 2015. HH infrastructure, compliance, and glove use were assessed among HCWs after the intervention in 2015 and 2016. HCWs were interviewed about challenges to sustainability of HH compliance. RESULTS: Total HH compliance decreased 32.1% between 2015 and 2016 (P < .001). HH for patient protection was completed significantly less than HH for HCW protection in 2016, and HCWs appeared to substitute HH for patient protection with glove use. A high rate of physician turnover was associated with a larger decrease in HH compliance compared with nurses, and interviews suggested recruiting and retention of key personnel might play a role in HH sustainability. Availability of alcohol-based handrub in patient rooms decreased from 100% in 2015 to 79.5% in 2016 (P < .01). CONCLUSIONS: Many challenges exist to sustaining HH compliance in SSA. In rural settings, difficulty recruiting and retaining trained personnel, inconsistent availability in HH infrastructure, and variability in HCW HH training may be contributing factors. PMID- 28596021 TI - Pharmacist-driven antimicrobial stewardship in intensive care units in East China: A multicenter prospective cohort study. AB - BACKGROUND: Antimicrobial stewardship programs, particularly pharmacist-driven programs, help reduce the unnecessary use of antimicrobial agents. The objective of this study was to assess the influence of pharmacist-driven antimicrobial stewardship on antimicrobial use, multidrug resistance, and patient outcomes in adult intensive care units in China. METHOD: We conducted a multicenter prospective cohort study with a sample of 577 patients. A total of 353 patients were included under a pharmacist-driven antimicrobial stewardship program, whereas the remaining 224 patients served as controls. The primary outcome was all-cause hospital mortality. RESULTS: The pharmacist-driven antimicrobial stewardship program had a lower hospital mortality rate compared with the nonpharmacist program (19.3% vs 29.0%; P = .007). Furthermore, logistic regression analysis indicated that the pharmacist-driven program independently predicted hospital mortality (odds ratio, 0.57; 95% confidence interval, 0.36 0.91; P = .017) after adjustment. Meanwhile, this strategy had a lower rate of multidrug resistance (23.8% vs 31.7%; P = .037). Moreover, the strategy optimized antimicrobial use, such as having a shorter duration of empirical antimicrobial therapy (2.7 days; interquartile range [IQR], 1.7-4.6 vs 3.0; IQR, 1.9-6.2; P = .002) and accumulated duration of antimicrobial treatment (4.0; IQR, 2.0-7.0 vs 5.0; IQR, 3.0-9.5; P = .030). CONCLUSIONS: Pharmacist-driven antimicrobial stewardship in an intensive care unit decreased patient mortality and the emergence of multidrug resistance, and optimized antimicrobial agent use. PMID- 28596022 TI - Dipping into the Clostridium difficile pool: Are alcohol-based dispensers fomites for C difficile? AB - The purpose of this study was to evaluate alcohol-based dispensers as potential fomites for Clostridium difficile. A convenience sample of 120 alcohol-based dispensers was evaluated for the presence of C difficile either by culture or polymerase chain reaction for C difficile toxin. The results demonstrated that C difficile was not cultured, and C difficile toxin was not detected using polymerase chain reaction; however, gram-positive rods, Clostridium perfringens, Pantoea agglomerans, coagulase-negative Staphylococcus, Peptostreptococcus, Bacillus spp, and microaerophilic Streptococcus were present within the overflow basins of the alcohol-based dispensers. PMID- 28596024 TI - Child with leukemia and symptomatic pulmonary pseudoaneurysm subjected to catheterization. PMID- 28596023 TI - Prebiotics Reduce Body Fat and Alter Intestinal Microbiota in Children Who Are Overweight or With Obesity. AB - BACKGROUND & AIMS: It might be possible to manipulate the intestinal microbiota with prebiotics or other agents to prevent or treat obesity. However, little is known about the ability of prebiotics to specifically modify gut microbiota in children with overweight/obesity or reduce body weight. We performed a randomized controlled trial to study the effects of prebiotics on body composition, markers of inflammation, bile acids in fecal samples, and composition of the intestinal microbiota in children with overweight or obesity. METHODS: We performed a single center, double-blind, placebo-controlled trial of 2 separate cohorts (March 2014 and August 2014) at the University of Calgary in Canada. Participants included children, 7-12 years old, with overweight or obesity (>85th percentile of body mass index) but otherwise healthy. Participants were randomly assigned to groups given either oligofructose-enriched inulin (OI; 8 g/day; n=22) or maltodextrin placebo (isocaloric dose, controls; n=20) once daily for 16 weeks. Fat mass and lean mass were measured using dual-energy-x-ray absorptiometry. Height, weight, and waist circumference were measured at baseline and every 4 weeks thereafter. Blood samples were collected at baseline and 16 weeks, and analyzed for lipids, cytokines, lipopolysaccharide, and insulin. Fecal samples were collected at baseline and 16 weeks; bile acids were profiled using high-performance liquid chromatography and the composition of the microbiota was analyzed by 16S rRNA sequencing and quantitative polymerase chain reaction. The primary outcome was change in percent body fat from baseline to 16 weeks. RESULTS: After 16 weeks, children who consumed OI had significant decreases in body weight z-score (decrease of 3.1%), percent body fat (decrease of 2.4%), and percent trunk fat (decrease of 3.8%) compared with children given placebo (increase of 0.5%, increase of 0.05%, and decrease of 0.3%, respectively). Children who consumed OI also had a significant reduction in level of interleukin 6 from baseline (decrease of 15%) compared with the placebo group (increase of 25%). There was a significant decrease in serum triglycerides (decrease of 19%) in the OI group. Quantitative polymerase chain reaction showed a significant increase in Bifidobacterium spp. in the OI group compared with controls. 16S rRNA sequencing revealed significant increases in species of the genus Bifidobacterium and decreases in Bacteroides vulgatus within the group who consumed OI. In fecal samples, levels of primary bile acids increased in the placebo group but not in the OI group over the 16-week study period. CONCLUSIONS: In a placebo-controlled, randomized trial, we found a prebiotic (OI) to selectively alter the intestinal microbiota and significantly reduce body weight z-score, percent body fat, percent trunk fat, and serum level of interleukin 6 in children with overweight or obesity (Clinicaltrials.gov no: NCT02125955). PMID- 28596025 TI - Conjunctival air after neurosurgery. PMID- 28596026 TI - Four new iridoid glucosides containing the furan ring from the fruit of Cornus officinalis. AB - Four new and rare iridoid glucosides, cornusfuroside A-D (1-4), containing the furan ring were identified from water extract of the fruit of Cornus officinalis. These new chemical structures were determined through extensive spectroscopic analysis, including 1D and 2D NMR, IR, HRESIMS, experimental and calculated electronic circular dichroism (ECD). Notably, this study is the first report on the isolation of four iridoid glucoside structures with acetal functions in the sugar moiety. The neuroprotective effects of these compounds were also evaluated in vitro. PMID- 28596027 TI - Gelsedine-type oxindole alkaloids from Gelsemium elegans and the evaluation of their cytotoxic activity. AB - Phytochemical investigation on the 70% EtOH extract of the leaves and branches of Gelsemium elegans resulted into the isolation of five new gelsedine-type oxindole alkaloids, gelseleganins A-E (1-5). The structures of the isolated compounds were established based on 1D and 2D (1H-1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated alkaloids were tested in vitro for cytotoxic potential against seven tumor cell lines. As a result, alkaloids 3 exhibited significant cytotoxic activities against all the tested tumor cell lines with IC50 values <10MUM. PMID- 28596028 TI - Furofuran lignans from the Simpson Desert species Eremophila macdonnellii. AB - The Eremophila plant family, which occurs in the arid zones of Australia, have witnessed extensive investigation, mostly inspired by Aboriginal traditional medicine. A wide and varied biological and phytochemical profile has been reported for over 18 individual species of Australian Eremophila, although E. macdonnellii from the Simpson Desert has not yet been investigated. Isolation and elucidation of one new and six known furofuran lignans are reported. The new lignan, epimethoxypiperitol, displayed moderate anti-cancer activity against the breast cancer cell line (MCF-7). PMID- 28596029 TI - 2-Phenylnaphthalenes and a polyoxygenated cyclohexene from the stem and root extracts of Uvaria cherrevensis (Annonaceae). AB - Three new 2-phenylnaphthalene derivatives, cherrevenaphthalenes A-C (1-3), and a new polyoxygenated cyclohexene derivative, (-)-uvaribonol F (4) together with six known compounds, 5-10, were isolated from the stem and root extracts of Uvaria cherrevensis (Annonaceae). The structures of all isolated compounds were elucidated by spectroscopic analysis. The structures of 3 and 4 were further confirmed by single crystal X-ray diffraction methods. Compound 2 exhibited modest antiplasmodial activity against the P. falciparum stains TM4/8.2 and K1CB1 with IC50 values of 18.8+/-3.63 and 23.4+/-4.08MUM, respectively, and weak cytotoxicity to a Vero cell line. Furthermore, compound 4 displayed cytotoxic activity against a KB cell line with an IC50 value of 22.1+/-0.42MUM but was non cytotoxic to the Vero cell line. Compound 5 revealed stronger cytotoxicity towards the KB cell line, with an IC50 value of 5.05+/-0.86MUM and was nearly equally cytotoxic to the Vero cell line. PMID- 28596030 TI - Two, three, and four-drug regimens for HIV post-exposure prophylaxis in a North American sexual assault victim population. AB - BACKGROUND/OBJECTIVES: Due to perceived increased tolerability and compliance, and decreased cost, recent trends in practice are moving towards using fewer drugs for HIV post-exposure prophylaxis. However, there is limited literature to assess this is in the North American sexual assault victim population. METHODS: This retrospective before-and-after cohort study compared patients seen at a sexual assault care facility before and after the introduction of two and three drug post-exposure prophylaxis regimens. Our primary outcome was completion of the 28-day regimen. Secondary objectives included HIV seroconversion rates and patient reported side effects. RESULTS: Six-hundred-thirty charts from a 2-year period were reviewed, and 429 met inclusion criteria. There was no difference in completion rates of post-exposure prophylaxis between the two cohorts (50.5% vs. 51.6%). However, there were fewer reported side effects (72.2% vs. 17.6%) in the later cohort. We subsequently compared all patients in either cohort who received four-drug therapy (N=128) versus those who received two or three-drug regimens (N=47). The two or three-drug regimen group had a higher completion rate (66.0% vs. 42.2%; p=0.03), and a lower rate of reported side effects (19.1% vs. 53.9%), specifically for nausea (12.8% vs. 36.7%), constipation (0% vs. 7.9%), diarrhea (2.1% vs. 21.1%), mood changes (0% vs. 10.9%), headache (2.1% vs. 16.4%), and fatigue (6.4% vs. 26.6%). There were no HIV seroconversions in either group. CONCLUSION: Two and three-drug HIV post-exposure prophylaxis regimens are better tolerated by patients and associated with greater compliance than four-drug therapy, and could be considered in the sexual assault victim population. PMID- 28596031 TI - The current emergency medicine residency curriculum: Missing psychiatry. PMID- 28596032 TI - Clinical characteristics of external iliac artery branch injury in pelvic trauma. AB - INTRODUCTION: The clinical characteristics of an injury of external iliac artery branches in blunt pelvic trauma have not yet been sufficiently studied. We evaluated the relationship between injury characteristics and the presence of an injury to external iliac artery branches in blunt pelvic trauma. MATERIALS AND METHODS: A retrospective review of patients admitted with blunt pelvic trauma was conducted over an 11-year period. Charts were reviewed for age, gender, injury characteristics, injury severity score, length of stay in the intensive care unit, transfusion requirements, and fracture pattern. RESULTS: Of 286 blunt pelvic trauma patients, 90 patients (31%) underwent pelvic angiography. Of those patients, 10 (11%) had the injuries of the branches of external iliac artery and 88 (97%) had the injuries of the branches of internal iliac artery. Those patients with external iliac artery branch injuries were significantly associated with hemodynamic instability, when compared to those without external iliac artery branch injuries. There were no significant differences between the patients with and without external iliac artery branch injury with regard to the anatomical characteristics of pelvic trauma. CONCLUSION: Blunt pelvic trauma with hemodynamic instability may be associated with concomitant external iliac artery branch injury. PMID- 28596033 TI - Could B-type natriuretic peptides be a biomarker for trauma brain injury? A systematic review and meta-analysis. PMID- 28596034 TI - Breast implant associated anaplastic large cell lymphoma: The UK experience. Recommendations on its management and implications for informed consent. AB - BACKGROUND: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare, Non-Hodgkin lymphoma arising in the capsule of breast implants. BIA ALCL presents as a recurrent effusion and/or mass. Tumours exhibit CD30 expression and are negative for Anaplastic Lymphoma Kinase (ALK). We report the multi-disciplinary management of the UK series and how the stage of disease may be used to stratify treatment. METHODS: Between 2012 and 2016, 23 cases of BIA ALCL were diagnosed in 15 regional centres throughout the UK. Data on breast implant surgeries, clinical features, treatment and follow-up were available for 18 patients. RESULTS: The mean lead-time from initial implant insertion to diagnosis was 10 years (range: 3-16). All cases were observed in patients with textured breast implants or expanders. Fifteen patients with breast implants presented with stage I disease (capsule confined), and were treated with implant removal and capsulectomy. One patient received adjuvant chest-wall radiotherapy. Three patients presented with extra-capsular masses (stage IIA). In addition to explantation, capsulectomy and excision of the mass, all patients received neo /adjuvant chemotherapy with CHOP as first line. One patient progressed on CHOP but achieved pathological complete response (pCR) with Brentuximab Vedotin. After a mean follow-up of 23 months (range: 1-56) all patients reported here remain disease-free. DISCUSSION: BIA-ALCL is a rare neoplasm with a good prognosis. Our data support the recommendation that stage I disease be managed with surgery alone. Adjuvant chemotherapy may be required for more invasive disease and our experience has shown the efficacy of Brentuximab as a second line treatment. PMID- 28596035 TI - The pharmacokinetic and pharmacodynamic properties of site-specific pegylated genetically modified recombinant human interleukin-11 in normal and thrombocytopenic monkeys. AB - In order to improve the pharmacokinetic and pharmacodynamic properties of recombinant human interleukin-11 mutein (mIL-11) and to reduce the frequency of administration, we examined the feasibility of chemical modification of mIL-11 by methoxy polyethylene glycol succinimidyl carbonate (mPEG-SC). PEG-mIL-11 was prepared by a pH controlled amine specific method. Bioactivity of the protein was determined in a IL-11-dependent in vitro bioassay, its pharmacodynamic and pharmacokinetic properties were investigated by using normal and thrombocytopenic monkey models. N-terminus sequencing and peptide mapping analysis revealed that Lys33 is the PEGylated position for PEG-mIL-11. Bioactivity of PEG-mIL-11 assessed by B9-11 cell proliferation assay was comparable to that of mIL-11. More than 79-fold increase in area-under-the curve (AUC) and 26-fold increase in maximum plasma concentration (Cmax) was observed in pharmacokinetic analysis. Single dose administration of the PEG-mIL-11 induced blood platelets number increase and the effect duration were comparable to that of 7 to 10 consecutive daily administration of mIL-11 to the normal and thrombocytopenic monkey models. PEG-mIL-11 is a promising therapeutic for thrombocytopenia. PMID- 28596036 TI - The oriented processes for extraction and recovery of paracetamol compound across different affinity polymer membranes. Parameters and mechanisms. AB - Membrane processes represent one of the most promising technologies for separation and extraction in modern industries, because they have several advantages. Today these processes are an important research topic, including affinity polymer membranes that are highly efficient for oriented processes. Three affinity polymer membrane types containing lipophilic compounds, methyl cholate (MC) and cholic acid (CA) as extractive agents were prepared and characterized. They have been used to extract active ingredient paracetamol (acetaminophen), from concentrated solutions (0.08-0.01M). Substrate acetaminophen is an important active ingredient and its recovery as a pure compound, is very useful for the pharmaceutical industry. These affinity polymer membranes were adopted to perform experiments on a facilitated extraction process of this substrate at different medium acidities and temperatures. Macroscopic parameters, permeabilities (P) and initial fluxes (J0) for a facilitated extraction of this substrate through each membrane were determined. The results indicate that values of initial fluxes (J0) of the extracted substrate are related to its initial concentration C0 by a saturation law, which allowed to determine microscopic parameters, apparent diffusion coefficients (D*) and association constants (Kass) of formed entity (substrate - extractive agent) (ST). The results show a clear influence of temperature and acidity factors on the evolution of these parameters and membrane performances in this studied process. Activation parameters (Ea, DeltaH?, and DeltaS?) were determined and the values indicate that high performances of these membrane types are certainly related to the movement nature of the substrate across the organic phase, and the structures of the substrate and the extractive agent. PMID- 28596038 TI - Predictors of 30-day postoperative major adverse clinical events after carotid artery stenting: An analysis of the procedure-targeted American College of Surgeons National Surgical Quality Improvement Program. AB - BACKGROUND: Information about carotid artery stenting (CAS) is largely derived from clinical trials, consensus statements, and outcomes comparisons between CAS and carotid endarterectomy. Given these limitations, the goal of this study was to identify risk factors for adverse outcomes after CAS among hospitals participating in the CAS-targeted American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). METHODS: Our study sample consisted of patients from the 2012 to 2015 CAS-targeted ACS NSQIP data set. The primary outcome variable was 30-day postoperative incidence of major adverse clinical events (MACEs; death, myocardial infarction/arrhythmia, ipsilateral stroke/transient ischemic attack). Univariable and multivariable analyses were performed to identify patient and procedural characteristics associated with MACEs. RESULTS: A total of 448 patients undergoing CAS for carotid artery stenosis were identified in the 2012 to 2015 CAS-targeted ACS NSQIP data set as eligible for analysis. The incidence of postoperative MACEs was 8.4% for symptomatic patients and 5.4% for asymptomatic patients. On multivariable analysis, independent predictors of MACEs included age >=80 years, female sex, black race, presence of chronic obstructive pulmonary disease, active tobacco use (protective), and use of more than one stent. CONCLUSIONS: The rate of major postoperative events in preoperatively asymptomatic patients is higher than the threshold recommended by the American Heart Association guidelines. Elderly patients (>=80 years), female patients, and black patients as well as those receiving more than one stent are at increased risk of negative outcome after CAS. PMID- 28596037 TI - Development and evaluation of an oral fast disintegrating anti-allergic film using hot-melt extrusion technology. AB - The main objective of this novel study was to develop chlorpheniramine maleate orally disintegrating films (ODF) using hot-melt extrusion technology and evaluate the characteristics of the formulation using in vitro and in vivo methods. Modified starch with glycerol was used as a polymer matrix for melt extrusion. Sweetening and saliva-simulating agents were incorporated to improve palatability and lower the disintegration time of film formulations. A standard screw configuration was applied, and the last zone of the barrel was opened to discharge water vapors, which helped to manufacture non-sticky, clear, and uniform films. The film formulations demonstrated rapid disintegration times (6 11s) and more than 95% dissolution in 5min. In addition, the films had characteristic mechanical properties that were helpful in handling and storage. An animal model was employed to determine the taste masking of melt-extruded films. The lead film formulation was subjected to a human panel for evaluation of extent of taste masking and disintegration. PMID- 28596039 TI - Assessment of aortic wall thrombus predicts outcomes of endovascular repair of complex aortic aneurysms using fenestrated and branched endografts. AB - OBJECTIVE: The goal of this study was to investigate the correlation between atherothrombotic aortic wall thrombus (AWT) and clinical outcomes in patients treated by fenestrated-branched endovascular aortic repair (F-BEVAR) and present a new classification system for assessment of AWT burden. METHODS: The clinical data of 301 patients treated for pararenal and thoracoabdominal aortic aneurysms (TAAAs) by F-BEVAR was reviewed. The study excluded 89 patients with extent I to III TAAA because of extensive laminated thrombus within the aneurysm sac. Computed tomography angiograms were analyzed in all patients to determine the location, extent, and severity of atherothrombotic AWT. The aorta was divided into three segments: ascending and arch (A), thoracic (B) and renal-mesenteric (C). Volumetric measurements (cm3) of AWT were performed using TeraRecon software (TeraRecon Inc, Foster City, Calif). These volumes were used to create an AWT index by dividing the AWT volume from the total aortic volume. A classification system was proposed using objective assessment of the number of affected segments, thrombus type, thickness, area, and circumference. Clinical outcomes included 30-day mortality, neurologic and gastrointestinal complications, renal events (Risk, Injury, Failure, Loss of kidney function, End-stage renal disease [RIFLE]), and solid organ infarction. RESULTS: The study included 212 patients, 169 men (80%) and 43 women (20%), with a mean age of 76 +/- 7 years. A total of 700 renal-mesenteric arteries were incorporated (3.1 +/- 1 vessels/patient). AWT was classified as mild in 98 patients (46%) and was considered moderate or severe in 114 (54%). There was one death (0.5%) at 30 days. Solid organ infarction was present in 50 patients (24%), and acute kidney injury occurred in 45 patients (21%) by RIFLE criteria. An association with higher AWT indices was found for time to resume enteral diet (P = .0004) and decline in renal function (P = .0003). Patients with acute kidney injury 2 by RIFLE criterion had significantly higher (P = .002) AWT index scores in segment B. Spinal cord injury occurred in three patients (1.4%) and stroke in four (1.9%), but were not associated with the AWT index. Severity of AWT using the new proposed classification system correlated with the AWT index in all three segments (P < .001). Any of the end points occurred in 35% of the patients with mild and in 53% of those with moderate or severe AWT (P = .016). CONCLUSIONS: AWT predicts solid organ infarction, renal function deterioration, and longer time to resume enteral diet after F-BEVAR of pararenal and type IV TAAAs. Evaluation of AWT should be part of preoperative planning and decision making for selection of the ideal method of treatment in these patients. PMID- 28596040 TI - Low level exposure to crude oil impacts avian flight performance: The Deepwater Horizon oil spill effect on migratory birds. AB - In 2010, the Deepwater Horizon oil spill released 134 million gallons of crude oil into the Gulf of Mexico making it the largest oil spill in US history. The three month oil spill left tens of thousands of birds dead; however, the fate of tens of thousands of other migratory birds that were affected but did not immediately die is unknown. We used the homing pigeon as a surrogate species for migratory birds to investigate the effects of a single external oiling event on the flight performance of birds. Data from GPS data loggers revealed that lightly oiled pigeons took significantly longer to return home and spent more time stopped en route than unoiled birds. This suggests that migratory birds affected by the oil spill could have experienced long term flight impairment and delayed arrival to breeding, wintering, or crucial stopover sites and subsequently suffered reductions in survival and reproductive success. PMID- 28596041 TI - Data sharing statements for clinical trials: a requirement of the International Committee of Medical Journal Editors. PMID- 28596042 TI - Interleukin 23 inhibitors for psoriasis: not just another number. PMID- 28596044 TI - Incidence, recurrence and risk factors of hernias following stoma reversal. AB - BACKGROUND: To determine the incidence and risk factors for stoma site (SSH) and incisional (IH) hernias following stoma reversal as well as their recurrence following repair. METHODS: A cohort of VA Surgical Quality Improvement Program patients undergoing stoma reversal from 2002 to 2014 were evaluated at a single institution. Variables were selected a priori and evaluated by univariate analyses. RESULTS: Of 114 stoma reversals, 63 utilized a midline approach. The incidence of SSH and IH was 9.6% and 31.7% over a median follow-up of 5.7 (0.5 14) and 4.0 (0.1-14) years, respectively. Five SSH and 10 IH were repaired with no recurrences. Myofascial release and superficial surgical site infections (SSI) were associated with SSH while body mass index, preoperative radiotherapy, American Society of Anesthesiologists classification >=3, operative duration >=2.5 h and deep SSIs were associated with IH. CONCLUSIONS: Incisional hernia incidence after stoma reversal is high for both the stoma site and midline. Risk factors differ for each hernia type. A low recurrence rate exists in short term follow-up following repair of a hernia occurrence. PMID- 28596045 TI - Comorbidity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study. AB - BACKGROUND: Previous studies have shown evidence of comorbid conditions in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). OBJECTIVE: To estimate the prevalence of comorbidities and assess their associations using a nationwide population-based database of a Spanish CFS/ME cohort. METHOD: A nationally representative, retrospective, cross-sectional cohort study (2008 2015) assessed 1757 Spanish subjects who met both the 1994 Centers for Disease Control and Prevention/Fukuda definition and 2003 Canadian Criteria for CFS/ME. Sociodemographic and clinical data, comorbidities, and patient-reported outcome measures at baseline were recorded. A cluster analysis based on baseline clinical variables was performed to classify patients with CFS/ME into 5 categories according to comorbidities. A multivariate logistic regression analysis was conducted adjusting for potential confounding effects such as age and sex; response and categorical predictor variables were also assessed. RESULTS: A total of 1757 CFS/ME patients completed surveys were collected. We identified 5 CFS/ME clusters: group 1-fibromyalgia, myofascial pain, multiple chemical hypersensitivity, sicca syndrome, epicondylitis, and thyroiditis; group 2 alterations of ligaments and subcutaneous tissue, hypovitaminosis D, psychopathology, ligamentous hyperlaxity, and endometriosis. These 2 subgroups comprised mainly older women, with low educational level, unemployment, high levels of fatigue, and poor quality of life; group 3-with hardly any comorbidities, comprising mainly younger women, university students or those already employed, with lower levels of fatigue, and better quality of life; group 4-poorly defined comorbidities; and group 5-hypercholesterolemia. CONCLUSION: Over 80% of a large population-based cohort of Spanish patients with CFS/ME presented comorbidities. Among the 5 subgroups created, the most interesting were groups 1-3. Future research should consider multidisciplinary approaches for the management and treatment of CFS/ME with comorbid conditions. PMID- 28596043 TI - Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. AB - BACKGROUND: Tildrakizumab is a high-affinity, humanised, IgG1 kappa antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis. METHODS: We did two three-part, parallel group, double blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement >=10%, Physician's Global Assessment [PGA] score >=3, and Psoriasis Area and Severity Index [PASI] score >=12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (<=90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with >=2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. FINDINGS: reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0.0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0.0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0.0001 for comparisons of both tildrakizumab groups vs placebo; p<0.0001 for 200 mg vs etanercept and p=0.0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0.0001 for comparisons of both tildrakizumab groups vs placebo; p=0.0031 for 200 mg vs etanercept and p=0.0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. INTERPRETATION: In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to severe chronic plaque psoriasis. FUNDING: Merck & Co. PMID- 28596046 TI - Capacity Evaluation Requests in the Medical Setting: A Retrospective Analysis of Underlying Psychosocial and Ethical Factors. AB - BACKGROUND: Psychosocial and ethical variables influence physicians in requesting decision-making capacity (DMC) evaluations. Previous authors have classified certain DMC evaluation requests as "unwarranted" when there is no explicit suspicion or evidence that the patient might lack DMC. OBJECTIVE: To explore psychosocial and ethical reasons motivating both "warranted" and "unwarranted" DMC evaluation requests by physicians in the medical setting. METHODS: A retrospective electronic health record review was approved by the institutional review board. All psychiatric consultation requests identified as DMC evaluation requests between January 1, 2012 and December 31, 2012 were assessed independently by 2 reviewers. Each reviewer identified each DMC evaluation request as "warranted" vs "unwarranted." Unwarranted DMC evaluation requests were defined as those lacking explicit suspicion that the patient might lack DMC or those with explicit evidence of a patient with blatantly impaired DMC. We hypothesized that most (over half) DMC evaluation requests would be deemed unwarranted. Descriptive statistics, chi-square/Fisher exact tests, and t test/ANOVA were used. RESULTS: A total of 146 DMC evaluations were reviewed, and 83 (56.8%) of these were deemed unwarranted. Of these, most were likely driven by a previous neuropsychiatric disturbance (p < 0.001). Various other psychosocial and ethical patterns were identified (i.e., the practice of defensive medicine and guardianship concerns). CONCLUSION: Over half of DMC evaluation requests in a general medical setting were unwarranted. Many such requests were motivated by unarticulated psychosocial and ethical factors. DMC evaluation requests appear to serve as a means for indirectly resolving various psychosocial and ethical dilemmas beyond assessing DMC itself. Implications and future directions are discussed. PMID- 28596047 TI - Successful percutaneous closure of a residual atrial septal defect due to device failure. AB - A 39-year-old woman underwent uneventful percutaneous occlusion of an ostium secundum atrial septal defect (ASD) with a 22 mm Ultrasept ASD Occluder(r). Transesophageal echocardiography (TEE) performed two years after implantation revealed a de novo residual left-to-right shunt through the correctly implanted device. Three-dimensional transesophageal echocardiography (3D TEE) further clarified this finding by showing a perforation of the device membrane coating. The patient underwent transcatheter closure of the residual shunt with a 20 mm Ultrasept PFO(r) device. The procedure was guided by fluoroscopy and real-time 3D TEE. At the end of the procedure 3D TEE documented correct device deployment with complete defect coverage and absence of residual shunt. PMID- 28596048 TI - Impact of antigens, adjuvants and strains on sexually dimorphic antibody response to vaccines in mice. AB - Sexually dimorphic antibody response to vaccines has long been noticed. In addition to sex hormones, other factors such as antigens, adjuvants and strains of mice, as shown by indirect evidence, could also impact the sexual dimorphism. To clarify this, we immunized both gender mice of distinct strains with inactivated FMDV or HBsAg with or without adjuvants, and detected the specific antibody response of the mice. We found that in absence of adjuvants, the recombinant HBsAg but not the inactivated FMDV induced enhanced IgG antibody response in the female BALB/c mice. The o/w emulsion could facilitate the HBsAg to induce the comparable level of IgG antibodies in the male BALB/c mice as that in the females. The o/w emulsion rather than ISA206, a w/o/w emulsion, could assist the inactivated FMDV to induce higher levels of IgM antibodies in the female BALB/c mice. Moreover, the sexually dimorphic antibody response varied among the ICR, BALB/c and the F1 (BALB/c * C57BL/6) mice. Thus the data suggest that antigens, adjuvants and strains all impact the sexually dimorphic antibody response to vaccines and may provide insights for developing gender-based vaccines. PMID- 28596049 TI - Modern science for better quality control of medicinal products "Towards global harmonization of 3Rs in biologicals": The report of an EPAA workshop. AB - This article summarizes the outcome of an international workshop organized by the European Partnership for Alternative Approaches to Animal Testing (EPAA) on Modern science for better quality control of medicinal products: Towards global harmonization of 3Rs in biologicals. As regards the safety testing of biologicals, the workshop participants agreed to actively encourage the deletion of abnormal toxicity tests and target animal batch safety tests from all relevant legal requirements and guidance documents (country-specific guidelines, pharmacopoeia monographs, WHO recommendations). To facilitate the global regulatory acceptance of non-animal methods for the potency testing of, e.g., human diphtheria and tetanus vaccines and veterinary swine erysipelas vaccines, international convergence on the scientific principles of the use of appropriately validated in vitro assays for replacing in vivo methods was identified as an overarching goal. The establishment of scientific requirements for new assays was recognized as a further means to unify regulatory approaches in different jurisdictions. It was recommended to include key regulators and manufacturers early in the corresponding discussions. Manufacturers and responsible expert groups, e.g. at the European Directorate for the Quality of Medicines and Health Care of the Council of Europe or the European Medicines Agency, were invited to consider leadership for international collaboration. PMID- 28596050 TI - Histological evaluation of effectiveness of platelet-rich fibrin on healing of sinus membrane perforations: A preclinical animal study. AB - The aim of this study was to evaluate the effectiveness of platelet-rich fibrin (PRF) in repairing of Schneiderian membrane perforations in rabbit maxillary sinus. A total of 42 female New Zealand rabbits were randomly divided into two groups. Symmetrical bony defects were created 1 cm in diameter and the sinus membranes were exposed. The Schneiderian membranes were elevated in both sinuses and each membrane was perforated with a 1 cm incision. No treatment was applied to the right perforations in both groups. Left-sided perforations were closed with collagen membrane in the first group and PRF membrane in the other group. Seven animals randomly selected from each group were sacrificed at weeks 1, 2 and 4 in order to be able to examine the amounts of lymphocytes, fibroblasts, veins, and collagen fibers in the area where the membranes were applied. Histological analyses showed that there were no statistically significant differences between the collagen membrane and the PRF membrane in the healing of sinus perforation area. PRF may be considered as an alternative application to collagen membrane in sinus membrane perforations. PMID- 28596051 TI - Functions of AT1 and AT2 angiotensin receptors in the paraventricular nucleus of the rat, correlating single-unit and cardiovascular responses. AB - The paraventricular hypothalamic nucleus (PVN) is a complex structure with both neuroendocrine and autonomic functions including cardiovascular control. The PVN contains angiotensin II (AngII) immunoreactive cells, fibers, as well as AT1 and AT2 receptors of AngII. We microinjected AngII into the PVN of normotensive anesthetized rats and simultaneously recorded blood pressure, heart rate (HR) and single-unit responses. The roles of AT1 and AT2 receptors in these responses were also evaluated. Microinjection of AngII into the PVN produced a short excitatory single-unit response and two types of pressor responses: short duration with a decrease in HR and long with an increase in HR. Microinjection of losartan, an AT1 antagonist, into the PVN produced two response types, attenuation and augmentation of the pressor and firing rate responses to AngII. Microinjection of PD123319, an AT2 antagonist, into the PVN greatly attenuated pressor and single unit response to AngII, indicating that the pressor response was mediated through AT2 receptors too. In conclusion, microinjection of AngII into the PVN stimulates neurons resulting in an increase in firing rate and consequently produces a short or long pressor response. These responses were mediated through AT1 and AT2 receptors; however, AT1 receptor may produce inhibition too. The results suggest that AngII of the PVN may be a neurotransmitter playing a role in arterial pressure regulation. PMID- 28596052 TI - A Solitary Pulmonary Nodule of Unexpected Etiology. PMID- 28596053 TI - The assessment of portal-tract healing after knee arthroscopy. AB - OBJECTIVE: The aim of this study was to analyse the pattern of portal-tract healing, to compare the healing time of anteromedial and anterolateral portal tracts and to assess the impact of portal-tract delayed healing on the post operative sub-acute and chronic anterior knee tenderness. METHODS: The study included 104 patients (68 males and 36 females; mean age: 49 +/- 3.16 years (range; 17-66)) who have undergone knee arthroscopy. Puncture wounds were divided into two groups, (1) anteromedial and (2) anterolateral groups. Each group contained 104 portal-tracts. Healing of portal tracts was evaluated using sequential superficial ultrasonographic examinaitons. Visual analogue scale (VAS) was used to measure pain related to delayed tract healing and its association with the post-operative sub-acute and chronic anterior knee tenderness. RESULTS: Anteromedial and anterolateral tracts total healing time average values were 47 days and 28 days respectively. The VAS average values of anteromedial tracts after 2 weeks, one month, three months, six months and one year were 8.2, 6.3, 4, 1.9 and 0.6 respectively, and for the anterolateral tracts 7.4, 5.5, 2.8, 1.2 and 0.2 respectively. A statistical significance was detected between the two groups at the first and third months with P values 0.042 and 0.0035 respectively. CONCLUSIONS: Anteromedial tracts closed later than anterolateral tracts. Both portal-tracts delayed closure is a potential for post-operative sub-acute and chronic anterior knee tenderness after arthroscopic surgery. Four grades of tract healing were recognized. Portal-tract ultrasonography is advised in persistent post-operative sub-acute and chronic anterior knee tenderness. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 28596054 TI - A potent and selective natriuretic peptide receptor-3 blocker 11-mer peptide created by hybridization of musclin and atrial natriuretic peptide. AB - The natriuretic peptide (NP) system is a critical endocrine, autocrine, and paracrine system and has been investigated for potential use against cardiovascular and metabolic diseases. The clearance of NPs is regulated by the proteolysis of neutral endopeptidase (NEP) and by endocytosis via natriuretic peptide receptor-3 (NPR3). A linear NPR3-selective peptide, [Cha8]-ANP(7-16)-NH2 (1), showed potent binding affinity for NPR3 but poor predicted chemical stability due to its free thiol group. A 12-mer peptide (9) without a thiol group was designed by the hybridization of two NPR3-binding peptides: a linear ANP fragment peptide analog and musclin, a murine member of the bHLH family of transcription factors, possessed high binding affinity and strict selectivity for NPR3. To increase the proteolytic resistance of 9, amino acid substitutions at the cleavage sites led to hydroxyacetyl-[d-Phe5,d-Hyp7,Cha8,d Ser9,Hyp11,Arg(Me)14]-ANP(5-15)-NHCH3 (23), showing high and selective binding affinity for NPR3 over NPR1 and excellent stability in mouse serum. Compound 23 increased intracellular cGMP concentrations in primary cultured adipocytes, and continuous administration induced substantial plasma cGMP elevation in mice, suggesting its potential to clarify the physiological role of NPR3 and its therapeutic application. PMID- 28596055 TI - Posterior Aortic Root Enlargement During Aortic Valve Replacement: Role of Intraoperative Transesophageal Echocardiography. PMID- 28596056 TI - Development and initial validation of a sensory threshold examination protocol (STEP) for phenotyping canine pain syndromes. AB - OBJECTIVE: To study the feasibility and test-retest repeatability of a sensory threshold examination protocol (STEP) and report the quantitative sensory threshold distributions in healthy dogs. STUDY DESIGN: Prospective, observational, cohort study. ANIMALS: Twenty-five healthy client-owned dogs. METHODS: Tactile sensitivity test (TST) (von Frey filaments), mechanical thresholds (MT with 2, 4 and 8 mm probes), heat thresholds (HT) and responsiveness to cold stimulus (CT at 0 degrees C) were quantitatively assessed for five body areas (BAs; tibias, humeri, neck, thoracolumbar region and abdomen) in a randomized order on three different occasions. Linear mixed model and generalized linear mixed models were used to evaluate the effects of body weight category, age, sex, BA, occasion, feasibility score and investigator experience. Test-retest repeatability was evaluated with the intra-class correlation coefficient. RESULTS: The STEP lasted 90 minutes without side effects. The BA affected most tests (p <= 0.001). Higher thresholds and longer cold latencies were scored in the neck (p <= 0.024) compared to other BAs. Weight category affected all thresholds (p <= 0.037). Small dogs had lower MT (~1.4 N mean difference) and HT (1.1 degrees C mean difference) than other dogs (p <= 0.029). Young dogs had higher HT than adults (2.2 degrees C mean difference) (p = 0.035). Gender also affected TST, MT and HT (p < 0.05) (females versus males: TST odds ratio = 0.5, MT = 1.3 N mean difference, HT = 2.2 degrees C mean difference). Repeatability was substantial to moderate for all tests, but poor for TST. There was no difference in thresholds between occasions, except for CT. Test-retest repeatability was slightly better with the 2 mm MT probe compared to other diameters and improved with operator experience. CONCLUSIONS AND CLINICAL RELEVANCE: The STEP was feasible, was well tolerated and showed substantial test retest repeatability in healthy dogs. Further validation is needed in dogs suffering pain. PMID- 28596057 TI - Erratum to "Feasibility of automatic evaluation of clinical rules in general practice" [Int. J. Med. Inform. 100 (2017) 90-94]. PMID- 28596058 TI - Adolescents' unhealthy eating habits are associated with meal skipping. AB - OBJECTIVE: Meal consumption and diet quality are important for healthy development during adolescence. The aim of this study was to determine the association between meal habits and diet quality in Brazilian adolescents. METHODS: A school-based, cross-sectional study was conducted in 2008 with a probabilistic sample of adolescents ages 14 to 19 y (N = 1139) from high schools in central-western Brazil. Consumption of breakfast, morning snack, lunch, afternoon snack, and dinner was assessed to evaluate adolescents' meal profile. The Brazilian Healthy Eating Index-Revised (BHEI-R) was calculated to evaluate diet quality. The association between meal profile and BHEI-R (global estimates and components) was assessed using multivariate linear regression models. RESULTS: Diet was characterized by unhealthy eating: a low consumption of fruits, vegetables, and milk/dairy, and a high consumption of fats and sodium. An unsatisfactory meal profile was observed in 14% of adolescents, whereas daily consumption of breakfast, lunch, and dinner was reported by 47%, 78%, and 52% of adolescents, respectively. Meal profile was positively associated with diet quality. Daily consumption of breakfast was associated with higher BHEI-R scores, lower sodium intake, and greater consumption of fruits and milk/dairy. Daily consumption of lunch was associated with greater consumption of vegetables and "meats, eggs, and legumes," whereas consumption of dinner was associated with an increased consumption of "whole fruits." CONCLUSION: This study showed a parallelism between daily consumption of meals with healthier eating and greater adherence to traditional Brazilian food habits. Skipping meals was associated with a low-quality diet, especially concerning to the low consumption of fruits and vegetables and a high intake of sodium and calories from solid fats, added sugars, and alcoholic beverages. Therefore, the adoption of regular meal habits may help adolescents improve their diet quality. PMID- 28596059 TI - Development and validation of a pancreatic injury mortality score (PIMS) based on 473 consecutive patients treated at a level 1 trauma center. AB - BACKGROUND: This study sought to develop a pancreatic injury mortality score (PIMS) to identify patients at greatest risk of in-hospital mortality after a major pancreatic injury. METHODS: The study used data from a prospective database of 473 patients treated for pancreatic injuries between January 1990 and December 2015. Two thirds of the patients were assigned to the derivation cohort and one third to the validation cohort. Clinical correlates of in-hospital death were identified and considered in stepwise logistic regression analyses that identified the factors included in the risk index. RESULTS: Five variables, age >55, shock on admission, a vascular injury, number of associated injuries and American Association for the Study of Trauma (AAST) pancreatic injury scale correlated with in-hospital death and were used to calculate PIMS. The final score ROC in the derivation dataset was 0.84 (95% CI 0.79-0.89) and in the validation dataset was 0.91 (95% CI 0.84-0.97), which were comparable (p = 0.1). Finally, cut-off scores were used to generate three risk groups and the rate of mortality within the low (PIMS 0-4), medium (PIMS 5-9), and high risk (PIMS 10 20) groups were not significantly different. The scoring system was tested in a validation cohort and showed good calibration and discrimination for in-hospital mortality. CONCLUSIONS: We have derived and validated the PIMS, a novel organ specific risk prediction score calculated from five variables for in-hospital mortality following major pancreatic trauma. PIMS is simple, quick and easily understandable, increases clinical risk prediction for patients with complex pancreatic and can be used as a benchmark for survival. PMID- 28596060 TI - [Medical prevention and treatment of radiation-induced pulmonary complications]. AB - Radiation-induced lung injuries mainly include the (acute or sub-acute) radiation pneumonitis, the lung fibrosis and the bronchiolitis obliterans organizing pneumonia (BOOP). The present review aims at describing the diagnostic process, the current physiopathological knowledge, and the available (non dosimetric) preventive and curative treatments. Radiation-induced lung injury is a diagnosis of exclusion, since clinical, radiological, or biological pathognomonic evidences do not exist. Investigations should necessarily include a thoracic high resolution CT-scan and lung function tests with a diffusing capacity of the lung for carbon monoxide. No treatment ever really showed efficacy to prevent acute radiation-induced lung injury, or to treat radiation-induced lung fibrosis. The most promising drugs in order to prevent radiation-induced lung injury are amifostine, angiotensin-converting-enzyme inhibitors and pentoxifylline. Inhibitors of collagen synthesis are currently tested at a pre-clinical stage to limit the radiation-induced lung fibrosis. Regarding available treatments of radiation-induced pneumonitis, corticoids can be considered the cornerstone. However, no standardized program or guidelines concerning the initial dose and the gradual tapering have been scientifically established. Alternative treatments can be prescribed, based on clinical cases reporting on the efficacy of immunosuppressive drugs. Such data highlight the major role of the lung dosimetric protection in order to efficiently prevent radiation-induced lung injury. PMID- 28596061 TI - Ecological assessment of an algaecidal naphthoquinone derivate for the mitigation of Stephanodiscus within a mesocosm. AB - The novel eco-friendly algaecidal naphthoquinone derivate was used to control harmful algal bloom causing species Stephanodiscus and, its effect was assessed on other undesired and non-targeted microbial communities. We conducted a mesocosm experiment to investigate the effects of this novel algaecide on native microbial communities rearing in water collected from Nakdonggang River. Upon treatment of the mesocosm with the naphthoquinone derivate the concentration of Chl-a decreased from 20.4 MUg L-1 to 9.5 MUg L-1 after 2 days. The turbidity has also shown decrement (exhibited 15.5 NTU on the 7th day). The concentrations of DOC and phosphate in the treatment were slightly higher than those in the control due to the decomposition of dead Stephanodiscus, whereas the DO and pH in the treated condition were slightly lower than those in the control; which was due to increment of organic acids and higher degradation activity. Results showed that bacterial abundance were not significantly different but community composition were slightly different as revealed by NGS (Next generation sequencing). The variation in HNF (Heterotrophic nanoflagellates) revealed that the bacterial community composition changed following the change in bacterial abundance. During the treatment, the abundance of Stephanodiscus was significantly reduced by more than 80% after 6 days, and the abundance of ciliates and the dominant species, Halteria grandinella, had shown marked decline. The abundance of zooplankton sharply decreased to 5 ind. L-1on the 8th day but increased again by the end of the study period. The Shannon-Wiener diversity index of phytoplankton, ciliates and zooplankton in the treated mesocosm increased significantly after 4, 7 and 8 days, respectively. The marked changes in the ecosystem structure were observed in treatment compare to control. However, the beneficial microalgal populations were not affected which indicated possibility of restoration of treated ecosystem and regain of healthy community structure after certain period. PMID- 28596062 TI - Inflammation in tendinopathy. AB - Pain and functional limitation are frequent in symptomatic tendinopathy. The essential lesion of tendinopathy is a failed healing response. Understanding the cellular and molecular mechanisms involved in a failed healing response during the early stages of pathogenesis of tendinopathy would help to develop new and effective treatments. The role of inflammation in the development of tendon pathologies has been revived during the last few years, in particular during the first phases of tendinopathies, when "early tendinopathy" may not be clinically evident. This review outlines the possible molecular events that occur in the first phases of tendinopathy onset, stressing the role of pro-inflammatory cytokines, proteolytic enzymes, growth factors and healing genes in the development of tendon disorders. PMID- 28596063 TI - Closing the Loop between Nodding Syndrome and Onchocerca Infection. PMID- 28596064 TI - Nodding Syndrome in the Spotlight - Placing Recent Findings in Perspective. AB - Nodding syndrome (NS) is a debated scientific topic. A recently published study suggests that NS is an autoimmune disorder based on findings of cross-reacting antibodies between neuronal structures and a protein present in Onchocerca volvulus (OV). In our opinion, the proposed causal relationship between OV infection and NS has yet to be demonstrated and, instead, OV infection in NS may be opportunistic. PMID- 28596065 TI - Patterns of Inpatient Care and Readmission Rates (30-day, 3-month and 1-year) in Myocardial Infarction in Spain. Differences Between STEMI and NSTEMI. PMID- 28596066 TI - Tools or Toys? The 20-Year Anniversary of the Nonfluoroscopic Mapping System Dilemma. PMID- 28596067 TI - Architecture and functioning of child and adolescent mental health services: a 28 country survey in Europe. AB - The WHO Child and Adolescent Mental Health Atlas, published in 2005, reported that child and adolescent mental health services (CAMHS) in Europe differed substantially in their architecture and functioning. We assessed the characteristics of national CAMHS across the European Union (EU), including legal aspects of adolescent care. Using an online mapping survey aimed at expert(s) in each country, we obtained data for all 28 countries in the EU. The characteristics and activities of CAMHS (ie, availability of services, inpatient beds, and clinicians and organisations, and delivery of specific CAMHS services and treatments) varied considerably between countries, as did funding sources and user access. Neurodevelopmental disorders were the most frequent diagnostic group (up to 81%) for people seen at CAMHS (data available from only 13 [46%] countries). 20 (70%) countries reported having an official national child and adolescent mental health policy, covering young people until their official age of transition to adulthood. The heterogeneity in resource allocation did not seem to match epidemiological burden. Substantial improvements in the planning, monitoring, and delivery of mental health services for children and adolescents are needed. PMID- 28596068 TI - Meaning of activation energy in phospholipid multibilayers phase transitions. AB - The question of the activation energy of phase transitions in lyotropic liquid crystal phases of model phospholipid membranes was considered. In our experiments, we obtained DSC thermograms of hydrated DPPC and DMPC at different scanning rates, and activation energy values were determined by a modification of Kissinger non-isothermal kinetics method. Using this approach the equivalent order of reaction corresponding to the phase transition can be determined alongside the activation energy. The cooperativity of both main transition and pre-transition was shown to be strongly dependent on scanning rate, asymptotically tending to a certain value at high rates, which corresponds to the number of lipid molecules in two concentric layers of hexagonal tiling. Changes in pretransition activation energy are shown to be proportional to changes in the system volume during the pretransition process, while the tail-length dependent part of the main transition activation energy is proportional to the jump in the number of gauche isomers. PMID- 28596069 TI - Validation of the EFFECT questionnaire for competence-based clinical teaching in residency training in Lithuania. AB - BACKGROUND AND AIM: In 2013, all residency programs at the Lithuanian University of Health Sciences were renewed into a competency-based medical education curriculum. To assess the quality of clinical teaching in residency training, we chose the EFFECT (evaluation and feedback for effective clinical teaching) questionnaire designed and validated at the Radboud University Medical Centre in the Netherlands. The aim of this study was to validate the EFFECT questionnaire for quality assessment of clinical teaching in residency training. MATERIALS AND METHODS: The research was conducted as an online survey using the questionnaire containing 58 items in 7 domains. The questionnaire was double-translated into Lithuanian. It was sent to 182 residents of 7 residency programs (anesthesiology reanimathology, cardiology, dermatovenerology, emergency medicine, neurology, obstetrics and gynecology, physical medicine and rehabilitation). Overall, 333 questionnaires about 146 clinical teachers were filled in. To determine the item characteristics and internal consistency (Cronbach's alpha), the item and reliability analyses were performed. Furthermore, confirmatory factor analysis (CFI) was performed using a model for maximum-likelihood estimation. RESULTS: Cronbach's alpha within different domains ranged between 0.91 and 0.97 and was comparable with the original version of the questionnaire. Confirmatory factor analysis demonstrated satisfactory model-fit with CFI of 0.841 and absolute model fit RMSEA of 0.098. CONCLUSIONS: The results suggest that the Lithuanian version of the EFFECT maintains its original validity and may serve as a valid instrument for quality assessment of clinical teaching in competency-based residency training in Lithuania. PMID- 28596070 TI - SM = SM: The Interface of Systems Medicine and Sexual Medicine for Facing Non Communicable Diseases in a Gender-Dependent Manner. AB - INTRODUCTION: Complex non-communicable diseases (NCDs), including cancer, cardiovascular disease, obesity, diabetes, and chronic respiratory disorders, are major causes of morbidity and mortality globally. The complexity of NCDs requires innovative, integrated, and interdisciplinary approaches for diagnosis, treatment, and prevention by adopting the new paradigm called systems medicine. A growing body of evidence suggests that sexual dysfunction in general and erectile and lubrication dysfunctions in particular are, in a sex-dependent manner, efficient predictors of overall systemic well-being. However, the relation between systems medicine and sexual medicine is not well defined. AIM: To demonstrate that in combating the major NCDs, sexual health can be used as a surrogate marker of systemic health and can facilitate the diagnosis, treatment, and prevention of NCDs. METHODS: A comprehensive review of peer-reviewed publications on the topic was performed through a PubMed search. MAIN OUTCOME MEASURES: Because there is a strong biological basis for the developmental origins of health and disease not only in the early phases of development but also later in life, the identification of appropriate biomarkers is essential for monitoring these timelines and trajectories for better understanding NCD processes, risk stratification for NCD intervention, and prevention. RESULTS: In this review, I propose a novel approach in which sexual medicine can be used as a new tool to understand and manage NCDs and as a marker of systemic health. Moreover, the multipronged application of systems medicine to pathophysiologic changes leading to sexual dysfunction might sustain the growth of a young science such as sexual medicine. CONCLUSION: This multilevel approach has the potential to suggest novel avenues for the comprehensive management of NCDs and sexual dysfunction in a sex-dependent manner. Jannini EA. SM = SM: The Interface of Systems Medicine and Sexual Medicine for Facing Non-Communicable Diseases in a Gender-Dependent Manner. Sex Med Rev 2017;5:349-364. PMID- 28596071 TI - Genetic and metabolic engineering approaches for the production and delivery of L asparaginases: An overview. AB - L-asparaginase is one of the protein drugs for countering leukemia and lymphoma. A major challenge in the therapeutic potential of the enzyme is its immunogenicity, low-plasma half-life and glutaminase activity that are found to be the reasons for toxicities attributed to asparaginase therapy. For addressing these challenges, several research and developmental activities are going on throughout the world for an effective drug delivery for treatment of cancer. Hence there is an urgent need for the development of asparaginase with improved properties for efficient drug delivery. The strategies selected should be economically viable to ensure the availability of the drug at low cost. The current review addresses various strategies adopted for the production of asparaginase from different sources, approaches for increasing the therapeutic efficiency of the protein and new drug delivery systems for L-asparaginase. PMID- 28596072 TI - Surface display of synthetic phytochelatins on Saccharomyces cerevisiae for enhanced ethanol production in heavy metal-contaminated substrates. AB - The aim of this work was to study the feasibility of surface displaying synthetic phytochelatin (EC) on Saccharomyces cerevisiae to overcome the inhibitory effect of heavy metals on ethanol production. Via the fusion of a gene encoding EC to an alpha-agglutinin gene, the engineered S. cerevisiae was able to successfully display EC on its surface. This surface engineered yeast strain exhibited an efficient cadmium adsorption capability and a remarkably enhanced cadmium tolerance. Moreover, its ethanol production efficiency was significantly improved as compared to a control strain in the presence of cadmium. Similar results could also be observed in the presence of other metals, such as nickel, lead and copper. Overall, this method allows simultaneous biorefinery and heavy metal removal when using heavy metal-contaminated biomass as raw materials. PMID- 28596073 TI - Metabolic engineering of Enterobacter aerogenes for 2,3-butanediol production from sugarcane bagasse hydrolysate. AB - The pathway engineering of Enterobacter aerogenes was attempted to improve its production capability of 2,3-butanediol from lignocellulosic biomass. In the medium containing glucose and xylose mixture as carbon sources, the gene deletion of pflB improved 2,3-butanediol carbon yield by 40%, while the deletion of ptsG increased xylose consumption rate significantly, improving the productivity at 12 hr by 70%. The constructed strain, EMY-22-galP, overexpressing glucose transporter (galP) in the triple gene knockout E. aerogenes, ldhA, pflB, and ptsG, provided the highest 2,3-butanediol titer and yield at 12 hr flask cultivation. Sugarcane bagasse was pretreated with green liquor, a solution containing Na2CO3 and Na2SO3 and was hydrolyzed by enzymes. The resulting hydrolysate was used as a carbon source for 2,3-butanediol production. After 72 hr in fermentation, the yield of 0.395g/g sugar was achieved, suggesting an economic production of 2,3-butanediol was possible from lignocellulosic biomass with the metabolically engineered strain. PMID- 28596074 TI - Introduction of an acetyl-CoA carboxylation bypass into Escherichia coli for enhanced free fatty acid production. AB - This study investigated the effect of the methylmalonyl-CoA carboxyltransferase (MMC) of Propionibacterium freudenreichii on production of free fatty acid (FFA) in Escherichia coli. Overexpression of the MMC exhibited a 44% increase in FFA titer. Co-overexpression of MMC and phosphoenolpyruvate carboxylase (PPC), which supplies the MMC precursor, further improved the titer by 40%. Expression of malic enzyme (MaeB) led to a 23% increase in FFA titer in the acetyl-CoA carboxylase (ACC)-overexpressing cells, but no increase in the MMC-overexpressing cells. The highest FFA production in the MMC-overexpressing strain was achieved through the addition of aspartic acid, which can be converted into oxaloacetate (OAA), resulting in a 120% increased titer compared with that in the ACC overexpressing strain. These findings demonstrate that MMC provides an alternative pathway for malonyl-CoA synthesis and increases fatty acid production. PMID- 28596075 TI - Nitrogen removal and nitrogen functional gene abundances in three subsurface wastewater infiltration systems under different modes of aeration and influent C/N ratios. AB - Matrix DO, nitrogen removal and nitrogen functional gene abundances in non aerated (NA), continuously aerated (CA) and intermittently aerated (IA) subsurface wastewater infiltration systems (SWISs) under different influent C/N ratios were studied. Aeration created aerobic condition in 50cm depth and did not change anoxic or anaerobic condition in 80 and 110cm depths, which enhanced NH4+ N and TN removal and the enrichment of nitrogen removal functional genes (amoA, nxrA, narG, napA, nirK, nirS, qnorB and nosZ) compared to NA SWIS, especially under high influent C/N ratio. High TN removal rate (89.6%) was obtained in IA SWIS under the influent C/N ratio of 12, which was higher than that in CA SWIS (87.1%). The results suggested that intermittent aeration was a reliable option to achieve high TN removal in SWISs, especially under high influent C/N ratio. PMID- 28596076 TI - Genetic modification: A tool for enhancing beta-glucosidase production for biofuel application. AB - Beta-glucosidase (BGL) is a rate-limiting enzyme for cellulose hydrolysis as it acts in the final step of lignocellulosic biomass conversion to convert cellobiose into glucose, the final end product. Most of the fungal strains used for cellulase production are deficient in BGL hence BGL is supplemented into cellulases to have an efficient biomass conversion. Genetic engineering has enabled strain modification to produce BGL optimally with desired properties to be employed for biofuel applications. It has been cloned either directly into the host strains lacking BGL or into another expression system, to be overexpressed so as to be blended into BGL deficient cellulases. In this article, role of genetic engineering to overcome BGL limitations in the cellulase cocktail and its significance for biofuel applications has been critically reviewed. PMID- 28596077 TI - Long-term bio-H2 and bio-CH4 production from food waste in a continuous two-stage system: Energy efficiency and conversion pathways. AB - Anaerobic digestion is a well-established technology for treating organic waste, but it is still under challenge for food waste due to process stability problems. In this work, continuous H2 and CH4 production from canteen food waste (FW) in a two-stage system were successfully established by optimizing process parameters. The optimal hydraulic retention time was 5d for H2 and 15d for CH4. Overall, around 59% of the total COD in FW was converted into H2 (4%) and into CH4 (55%). The fluctuations of FW characteristics did not significantly affect process performance. From the energy point view, the H2 reactor contributed much less than the methane reactor to total energy balance, but it played a key role in maintaining the stability of anaerobic treatment of food waste. Microbial characterization indicated that methane formation was through syntrophic acetate oxidation combined with hydrogenotrophic methanogenesis pathway. PMID- 28596078 TI - Identification of an oxytocinase/vasopressinase-like leucyl-cystinyl aminopeptidase (LNPEP) in teleost fish and evidence for hypothalamic mRNA expression linked to behavioral social status. AB - The vasotocin/vasopressin and isotocin/mesotocin/oxytocin family of nonapeptides regulate social behaviors and physiological functions associated with reproductive physiology and osmotic balance. While experimental and correlative studies provide evidence for these nonapeptides as modulators of behavior across all classes of vertebrates, mechanisms for nonapeptide inactivation in regulating these functions have been largely overlooked. Leucyl-cystinyl aminopeptidase (LNPEP) - also known as vasopressinase, oxytocinase, placental leucine aminopeptidase (P-LAP), and insulin-regulated aminopeptidase (IRAP) - is a membrane-bound zinc-dependent metalloexopeptidase enzyme that inactivates vasopressin, oxytocin, and select other cyclic polypeptides. In humans, LNPEP plays a key role in the clearance of oxytocin during pregnancy. However, the evolutionary diversity, expression distribution, and functional roles of LNPEP remain unresolved for other vertebrates. Here, we isolated and sequenced a full length cDNA encoding a LNPEP-like polypeptide of 1033 amino acids from the ovarian tissue of Amargosa pupfish, Cyprinodon nevadensis. This deduced polypeptide exhibited high amino acid identity to human LNPEP both in the protein's active domain that includes the peptide binding site and zinc cofactor binding motif (53.1% identity), and in an intracellular region that distinguishes LNPEP from other aminopeptidases (70.3% identity). Transcripts encoding this LNPEP enzyme (lnpep) were detected at highest relative abundance in the gonads, hypothalamus, forebrain, optic tectum, gill and skeletal muscle of adult pupfish. Further evaluation of lnpep transcript abundance in the brain of sexually-mature pupfish revealed that lnpep mRNAs were elevated in the hypothalamus of socially subordinate females and males, and at lower abundance in the telencephalon of socially dominant males compared to dominant females. These findings provide evidence of an association between behavioral social status and hypothalamic lnpep transcript abundance and suggest that variation in the rate of VT/IT peptide inactivation by LNPEP may be a contributing component in the mechanism whereby nonapeptides regulate social behavior. PMID- 28596080 TI - Physical Strain: A New Perspective on Walking in Cerebral Palsy. AB - OBJECTIVES: To describe (1) physical strain of walking, (2) the proportion of participants walking above the anaerobic threshold, and (3) 4 phenotypes of physical strain of walking on the basis of deviations in aerobic capacity and walking energy cost (EC) in children and adolescents with cerebral palsy (CP). DESIGN: Cohort study. SETTING: Academic medical center. PARTICIPANTS: A sample (N=57) of participants (n=37; mean age, 13.5+/-4.0y) with CP (Gross Motor Function Classification System [GMFCS] levels I [n=13], II [n=17], and III [n=7]) and typically developing (TD) participants (n=20; mean age, 11.8+/-3.5y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Oxygen consumption (Vo2walk), speed, and EC were determined during walking at a comfortable speed. Peak oxygen consumption (Vo2peak) and anaerobic threshold were measured during a maximal cycling exercise test. Aerobic capacity was reduced if lower than the 10th percentile, and EC was increased if higher than 3SD. Physical strain was defined as follows: (Vo2walk/Vo2peak)*100. RESULTS: Participants with CP had a higher physical strain (GMFCS level I, 55%+/-12% GMFCS level II, 62%+/-17%; GMFCS level III, 78%+/-14%) than did TD participants (40%+/-11%) (P<.001). Forty-three percent of participants with CP showed a Vo2walk at or above their anaerobic threshold as compared with 10% of TD participants (P=.007). Phenotypes showed that a reduced Vo2peak (n=9) or an increased EC (n=9) lead to an 18% to 20% higher physical strain, whereas a combination (n=12) leads to a 40% increase. CONCLUSIONS: Children and adolescents with CP walk at a high physical strain, approximating intense exercise and a considerable proportion walks close to or above their anaerobic threshold, probably explaining fatigue and reduced walking distance. Both an increased EC and a reduced Vo2peak contribute to high physical strain in children or adolescents with CP. The different causes of high physical strain in individuals with CP require different intervention strategies. PMID- 28596081 TI - Vitamin K2 improves developmental competency and cryo-tolerance of in vitro derived ovine blastocyst. AB - Vitamin K2 (VK2), acts as an electron carrier in mitochondria and thereby effects reactive oxygen species (ROS) and ATP production. This study evaluates role of VK2 on in vitro developmental competency and cryo-survival of pre-implantation ovine embryos. Initially the optimal and beneficial concentration of VK2 on compaction and blastocyst formation rates was defined (0.1 MUM). Subsequently, it was shown that 0.1 MUM VK2, at blastocyst stage, reduces H2O2 production, increase the expression of mitochondrial related gene and improved embryos quality. We further assessed presence VK2 supplementation before and/or after vitrification of in vitro derived blastocysts. Our results reveal that presence of VK2 before and after vitrification improves rates of blastocysts re-expansion (88.19+/- 3.37% vs 73.68+/- 1.86%, P < 0.05) and hatching (49.55+/- 4.37% vs 32.7+/- 3.32%) compared to control group. These observation were consistent with reduction in H2O2 production and improved in expression of mitochondrial related genes. However, VK2 before or after vitrification, not only had no positive effect on these two parameters, but also significantly reduced these parameters. Therefore, in concordance with pervious report in bovine, we show that VK2 supplementation post genomic activation (Day 3-7) improved developmental competency of ovine in vitro derived embryos. We also showed that presence of VK2 after vitrification improves the cryo-survival of ovine embryos. PMID- 28596082 TI - Restless legs syndrome and cardiovascular disease: a research roadmap: A response. PMID- 28596079 TI - Avian genomics lends insights into endocrine function in birds. AB - The genomics era has brought along the completed sequencing of a large number of bird genomes that cover a broad range of the avian phylogenetic tree (>30 orders), leading to major novel insights into avian biology and evolution. Among recent findings, the discovery that birds lack a large number of protein coding genes that are organized in highly conserved syntenic clusters in other vertebrates is very intriguing, given the physiological importance of many of these genes. A considerable number of them play prominent endocrine roles, suggesting that birds evolved compensatory genetic or physiological mechanisms that allowed them to survive and thrive in spite of these losses. While further studies are needed to establish the exact extent of avian gene losses, these findings point to birds as potentially highly relevant model organisms for exploring the genetic basis and possible therapeutic approaches for a wide range of endocrine functions and disorders. PMID- 28596083 TI - Organ donation in cardiac arrest patients treated with extracorporeal CPR: A single centre observational study. AB - AIM OF THE STUDY: In a consecutive cohort of cardiac arrest (CA) treated with extracorporeal cardiopulmonary resuscitation (eCPR), we describe the incidence of brain death (BD), the eligibility for organ donation and the short-term follow-up of the transplanted organs. METHODS: All refractory in- and out-of-hospital CA admitted to our Cardiac Intensive Care Unit between January 2011 and September 2016 treated with eCPR were enrolled in the study. RESULTS: 112 CA patients received eCPR. 82 (73.2%) died in hospital, 25 BD (22.3%) and 57 for other causes (50.9%). At the time of first neurological evaluation after rewarming, variables related to evolution to BD were a lower GCS (3 [3-3] vs. 8 [3-11], p<0.001), a higher level of neuron specific enolase (269.3+/-49.4 vs. 55.2+/-37.2ng/ml, p<0.001), a higher presence of EEG indices of poor outcome (84% vs. 15%, p<0.001), absence of brainstem reflexes (p<0.001), absence of bilateral N20 SSEPS waves (66.7% vs. 3.7%, p<0.001). None of BD patients present a normal CT scan (at 2.5+/-2days), with 85% prevalence of diffuse hypoxic injury and a mean grey/white matter ratio of 1.1+/-0.1. Rate of donation in BD patients was 56%, with 39 donated organs: 23 kidneys, 12 livers, and 4 lungs. 89.74% of the transplanted organs reached an early good functional recovery. CONCLUSION: In refractory CA patients treated with eCPR, the prevalence of BD is high. This population has a high potential for considering organ donation. Donated organs have a good outcome. PMID- 28596084 TI - Stem cell evolutionary paradigm and cell engineering. AB - Studying hematopoietic and mesenchymal stem cells for almost three decades revealed some similarities between the stem cell entity and the single-celled eukaryotes exhibiting the anaerobic/facultative aerobic metabolic features. A careful analysis of nowadays knowledge concerning the early eukaryotic evolution allowed us to reveal some analogies between stem cells in the metazoan tissues and the single-celled eukaryotes which existed during the first phase of eukaryotes evolution in mid-Proterozoic era. In fact, it is possible to trace the principle of the self-renewal back to the first eukaryotic common ancestor, the first undifferentiated nucleated cell possessing the primitive, mostly anaerobically-respiring mitochondria and a capacity to reproduction by a simple cell division "a l'identique". Similarly, the diversification of these single cell eukaryotes and acquiring of complex life cycle allowed/conditioned by the increase of O2 in atmosphere (and consequently in the water environment) represents a prototype for the phenomenon of commitment/differentiation. This point of view allowed to predict the ex-vivo behavior of stem cells with respect to the O2 availability and metabolic profile which enabled to conceive the successful protocols of stem cell expansion and ex vivo conditioning based on "respecting" this relationship between the anaerobiosis and stemness. In this review, the basic elements of this paradigm and a possible application in cell engineering were discussed. PMID- 28596085 TI - Brief hyperopic defocus or form deprivation have varying effects on eye growth and ocular rhythms depending on the time-of-day of exposure. AB - It is generally accepted that myopic defocus is a more potent signal to the emmetropization system than hyperopic defocus: one hour per day of myopic defocus cancels out 11 h of hyperopic defocus. However, we have recently shown that the potency of brief episodes of myopic defocus at inhibiting eye growth depends on the time of day of exposure. We here ask if this will also be true of the responses to brief periods of hyperopic defocus: may integration of the signal depend on time of day? If so, are the rhythms in axial length and choroidal thickness altered? Hyperopic defocus: Birds had one eye exposed to hyperopic defocus by the wearing of -10D lenses for 2 or 6 h at one of 3 times of day for 5 days: Morning (7 am - 9 am: n = 13; 7 am - 1 pm: n = 6), Mid-day (12 pm - 2 pm: n = 20; 10 am - 4 pm: n = 8), or Evening (7 pm - 9 pm: n = 12; 2 pm - 8 pm: n = 11). A separate group wore monocular lenses continually as a control (n = 12). Form deprivation: Birds wore a diffuser over one eye for 2 h at one of 3 times of day for 5 days: Morning (n = 12); Mid-day (n = 19) or Evening (n = 6). For all groups, ocular dimensions were measured using high-frequency A-scan ultrasonography at noon on the first day, under inhalation anesthesia. On day 5, eye dimensions were re-measured at 12 pm, and refractive errors were measured using a Hartinger's refractometer. A subset of birds in the 2-h lens group (morning, n = 8; mid-day, n = 8; evening, n = 6), and the deprivation group (n = 6 per time point), were also measured at 6 pm, 12 am, 6 am and 12 pm on the last day of exposure, to obtain the parameters of the diurnal rhythms in axial length and choroidal thickness. The effects of 2 h of defocus depended on time of day of exposure: it stimulated eye growth when exposure was in the morning and inhibited it when it was at mid-day (change in vitreous chamber, X-C; ANOVA p < 0.0005; 120 MUm vs -77 MUm/5d, respectively; t-tests: p = 0.001; p = 0.01; post-hoc tests: p = 0.002). For mid-day, experimental eyes were more hyperopic (1.4 D; p < 0.0001). Similar to 2 h defocus, 6 h exposures at mid-day inhibited growth and produced hyperopia (X-C: -167 MUm; t-test p = 0.005; RE: 1.8 D; p = 0.03). The effects of 2 h of FD were similar to those of hyperopic defocus in inhibiting growth for mid day exposures, but FD inhibited growth for the morning exposures as well (Axial length: X-C: Morning: -122 MUm; mid-day: -92 MUm; ttests p = 0.006 and p = 0.016 respectively). Experimental eyes were more hyperopic (1.8 D; 1.0 D; p < 0.05). The rhythms in axial length were altered for the morning exposures in both conditions. Form deprivation in the morning, which caused inhibition, caused the phases of the two rhythms to shift toward one another (peaks at 6:00 am and 10:45 am for choroid and axial length respectively). Our findings imply that the retinal "integrator", and/or scleral growth regulator exhibit diurnal rhythms. Furthermore, they suggest that reading activities early in the day may be contraindicated in school children at risk of becoming myopic. PMID- 28596087 TI - Enabling the sustainable Faecal Sludge Management service delivery chain-A case study of dense settlements in Kigali, Rwanda. AB - The lack of access to basic sanitation is a global concern and alarmingly prevalent in low- and middle- income countries. In the densely populated settlements of these countries, on-site sanitation systems are usually the only feasible option because dwellers there have no sewers in place to connect to. Using on-site sanitation facilities results in an accumulation of faecal sludge which needs to be properly managed to ensure the well-being of the users as well as the surrounding environment. Unfortunately, often the conditions for faecal sludge management (FSM) within dense settlements are adverse and thus hamper sustainable FSM. We use the normative framework of the FSM enabling environment to gather empirical evidence from densely populated settlements of Kigali city in Rwanda to examine current FSM practices and the extent to which these are being influenced and affected by the setting within which they are taking place. The analysis of the study findings confirms that the existing conditions for FSM in these settlements are inadequate. The specific constraints that hinder the achievement of sustainable FSM include limited government focus on the sanitation sector, high turnover of staff in relevant government institutions, pit sludge management is not placed on the sanitation projects agenda, the existing relevant bylaws are not pro-poor oriented, a lack of clear responsibilities, a lack of relevant local professional training opportunities, unaffordability of FSM services and an inhibition to discuss FSM. Drawing on the involved stakeholders' own perceptions and suggestions, we identify possible approaches to overcome the identified constraints and to allow all actors in the FSM chain to contribute effectively to the management of faecal sludge in densely populated low-income urban settlements. Finally, our study also presents a contribution to the theoretical conceptualisation of the enabling environment for sustainable FSM. PMID- 28596086 TI - Use, microbiological effectiveness and health impact of a household water filter intervention in rural Rwanda-A matched cohort study. AB - Unsafe drinking water is a substantial health risk contributing to child diarrhoea. We investigated impacts of a program that provided a water filter to households in rural Rwandan villages. We assessed drinking water quality and reported diarrhoea 12-24 months after intervention delivery among 269 households in the poorest tertile with a child under 5 from 9 intervention villages and 9 matched control villages. We also documented filter coverage and use. In Round 1 (12-18 months after delivery), 97.4% of intervention households reported receiving the filter, 84.5% were working, and 86.0% of working filters contained water. Sensors confirmed half of households with working filters filled them at least once every other day on average. Coverage and usage was similar in Round 2 (19-24 months after delivery). The odds of detecting faecal indicator bacteria in drinking water were 78% lower in the intervention arm than the control arm (odds ratio (OR) 0.22, 95% credible interval (CrI) 0.10-0.39, p<0.001). The intervention arm also had 50% lower odds of reported diarrhoea among children <5 than the control arm (OR=0.50, 95% CrI 0.23-0.90, p=0.03). The protective effect of the filter is also suggested by reduced odds of reported diarrhoea-related visits to community health workers or clinics, although these did not reach statistical significance. PMID- 28596088 TI - Interleukin 6 may be related to indoleamine 2,3-dioxygense function in M2 macrophages treated with small dense LDL particles. AB - Macrophages are known as important immune cells involved in the improvement of atherosclerosis plaques. The M2 macrophages are beneficial because scavenging the non-functional components in vessel sub-endothelial space. In this study, we investigated the effects of small dense LDL (sdLDL) on the changes of indoleamine 2,3-dioxygense (IDO) and interleukin (IL6) in the differentiated M2 macrophages. The patients were selected from who underwent coronary artery angiography. The monocytes were isolated from the whole blood samples of healthy (<5% stenosis) and patient (>70% stenosis; SVD, 2VD and 3VD) subjects and, were differentiated into M2 macrophages. The IDO gene expression, activity and IL6 values were measured by RT-qPCR, colorimetry and ELISA techniques, respectively. In contrast with healthy group, the IDO gene expression and activity were significantly reduced in SVD and 2VD groups (P<0.05). Furthermore, they were conversely associated to secretion of IL6. In conclusion, the data suggested that inflammatory responses in M2 macrophages differentiated from monocytes of patients after treatment of sdLDL may be related to the reduced IDO function. PMID- 28596089 TI - PRKCH regulates hematopoietic stem cell function and predicts poor prognosis in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) cells often co-opt normal hematopoietic stem cell (HSC) programs to drive neoplastic proliferation, and HSC-related gene expression signatures have been identified as biomarkers for poor prognosis in AML patients. We sought to identify new regulators of HSCs and AML cells from previously published HSC and leukemia stem cell (LSC) gene expression signatures. We identified PRKCH (protein kinase C eta) as a gene that is highly expressed in both mouse and human HSCs, as well as in LSCs from independent cohorts of AML patients. Prkch deletion in mice resulted in impaired HSC function. PRKCH was most highly expressed in undifferentiated (FAB M0) subtype AML, and high expression correlated with TP53 and RUNX1 mutations, high-risk cytogenetic features, and poor overall survival. Prkch deletion in an Flt3-ITD/Runx1 mutant mouse AML model did not extend survival. Thus, PRKCH is necessary for normal HSC function; its expression predicts poor survival in AML patients, but it is not required for AML to develop. PMID- 28596091 TI - Human papillomavirus vaccines: WHO position paper, May 2017-Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations on the use of human papillomavirus (HPV) vaccines excerpted from the WHO position paper on Human papillomavirus vaccines: WHO position paper, May 2017, published in the Weekly Epidemiological Record [1]. This position paper replaces the 2014 WHO position paper on HPV vaccines [2]. The position paper focuses primarily on the prevention of cervical cancer, but also considers the broader spectrum of cancers and other diseases preventable by HPV vaccination. It incorporates recent developments concerning HPV vaccines, including the licensure of a nonavalent (9 valent) vaccine and recent data on vaccine effectiveness, and provides guidance on the choice of vaccine. New recommendations are proposed regarding vaccination strategies targeting girls only or both girls and boys, and vaccination of multiple birth cohorts [3]. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of HPV vaccines were discussed by SAGE in October 2016; evidence presented at these meetings can be accessed at: www.who.int/immunization/sage/meetings/2016/october/presentations_background_docs en/. PMID- 28596090 TI - Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013. AB - Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD(r)). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-gamma ELISPOT activity, CD4+ T-cells and a TH1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI) trial. PMID- 28596093 TI - A pilot study evaluating the association between physical activity and cognition among individuals with Parkinson's disease. AB - BACKGROUND: Few studies have examined the association between daily physical activity and cognitive function among older adults with Parkinson's disease (PD). OBJECTIVE: Here we evaluate the association between accelerometer-assessed physical activity and cognition among older patients with PD. METHODS: Cognition assessed via the Montreal Cognitive Assessment (MoCA). Moderate-to-vigorous physical activity (MVPA) was assessed via accelerometry over a 1-2 week monitoring period. RESULTS: After adjusting for motor impairment severity, for every 1 min/day increase in MVPA, participants had a 0.09 unit increase in MoCA determined cognitive function (beta = 0.09; 95% CI: -0.003-0.19; P = 0.05). When further adjusting for motor impairment, age and gender, results were unchanged (beta = 0.09; 95% CI: 0.004-0.19; P = 0.04). CONCLUSION: The present study provides suggestive evidence of a favorable association between daily physical activity behavior and cognitive function among adults with PD. PMID- 28596092 TI - Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. AB - PURPOSE: This guideline presents evidence-based recommendations for stereotactic body radiation therapy (SBRT) in challenging clinical scenarios in early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The American Society for Radiation Oncology convened a task force to perform a systematic literature review on 4 key questions addressing: (1) application of SBRT to operable patients; (2) appropriate use of SBRT in tumors that are centrally located, large, multifocal, or unbiopsied; (3) individual tailoring of SBRT in "high-risk" clinical scenarios; and (4) SBRT as salvage therapy after recurrence. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength. RESULTS: Although few randomized trials have been completed for SBRT, strong consensus recommendations based on extensive, consistent publications were generated for several questions, including recommendations for fractionation for central tumors and surgery versus SBRT in standard-risk medically operable patients with early-stage NSCLC. Lower quality evidence led to conditional recommendations on use of SBRT for tumors >5 cm, patients with prior pneumonectomy, T3 tumors with chest wall invasion, synchronous multiple primary lung cancer, and as a salvage therapy after prior radiation therapy. These areas of moderate- and low-quality evidence highlight the importance of clinical trial enrollment as well as the role of prospective data registries. CONCLUSIONS: SBRT has an important role to play in treating early-stage NSCLC, particularly for medically inoperable patients with limited other treatment options. Shared decision-making with patients should be performed in all cases to ensure the patient understands the risks related to SBRT, the side effects, and the alternative treatments available. PMID- 28596094 TI - Physical activity of rurally residing children with a disability: A survey of parents and carers. AB - BACKGROUND: Children residing in rural areas face unique barriers to physical activity participation. Further, while children with a disability who reside in metropolitan areas face barriers hindering physical activity, rurally residing children with a disability may face the augmented combination of these barriers that could have negative health implications. Parents are often the key advocates for children with disabilities and are likely to have valuable insight into the opportunities and barriers to physical activity for their child. OBJECTIVE: The aim of this study was to investigate parents' perceptions of physical activity opportunities for their child with a disability in a rural area. METHODS: A mixed method survey examining parent's perceptions of their child's physical activity and possible barriers to participation was mailed to rurally residing parents of children with a disability. Quantitative data were analyzed descriptively using frequencies and proportions. Qualitative data were analyzed using qualitative content analysis. RESULTS: There were 34 completed surveys, a response rate of 37%. Participants' responses indicated 74% of children were not meeting daily recommendations of physical activity. Participation barriers including emotional, physical and environmental issues. Three main themes emerged from qualitative data; segregation, access to facilities and resources and barriers specific to the child. CONCLUSION: The children in this study were from rural areas and face similar barriers to children in metropolitan areas. However, they are also confronted with the same barriers children without a disability in rural areas face, participating in physical activity. This may have detrimental effects on their health and development. PMID- 28596095 TI - Framing childhood mental disorders within the context of disability. PMID- 28596096 TI - Hearing loss and associated medical conditions among individuals 65 years and older. AB - BACKGROUND: Hearing loss is prevalent, but few studies have investigated its associations with common medical conditions. OBJECTIVE: The objective was to assess the prevalence of medical conditions among individuals with hearing loss, compared to those without hearing loss, in people aged 65 years and older. METHODS: The National Health Interview Survey (NHIS) collects data on a variety of health-related topics, including disability. Three years of NHIS data (2011 2013; unweighted n = 53,111) were pooled to examine subpopulations of individuals with hearing loss. Comparisons were made between adults aged 65 and older with, and without, self-reported hearing loss. Statistical analysis included descriptive frequencies, Chi-square tests, and multiple logistic regressions. The outcomes of interest included self-reported diagnosis of arthritis, cardiovascular disease, diabetes, high blood pressure, emphysema, stroke, cancer, asthma, multiple chronic conditions, health status, and obesity. RESULTS: Hearing loss prevalence was nearly 37%. After adjusting for sociodemographics, smoking status, and disability, hearing loss was independently associated with the following conditions: arthritis (OR 1.41; 1.27-1.57), cancer (OR 1.35; 1.21-1.5), cardiovascular disease (OR 1.48; 1.33-1.66), diabetes (OR 1.16; 1.03-1.31), emphysema (OR 1.41; 1.14-1.74), high blood pressure (OR 1.29; 1.17-1.43), and stroke (OR 1.39; 1.12-1.66). There was an association with worse health status over the past year (OR 1.5 (1.3-1.73). CONCLUSIONS: Hearing loss among older individuals is independently associated with increased disease burden and poorer self-reported health. Future studies are needed to investigate the mechanistic nature of these associations, and whether improved access to hearing healthcare surveillance can reduce the overall health burden among these individuals. PMID- 28596098 TI - Acoustic Analysis of Voice and Electroglottography in Patients With Laryngopharyngeal Reflux. AB - BACKGROUND: Laryngopharyngeal reflux (LPR) refers to the flow of gastric acid content into the laryngopharynx. It has been reported that 10% of the patients consulting an otolaryngologist present with this condition. Signs of LPR can be identified during flexible or rigid laryngoscopy. The Voice Handicap Index (VHI) is a reliable tool for detecting the impact of voice disorders, and acoustic assessment of voice including acoustic analysis of voice (AAV) and electroglottography (EGG) provide objective data of voice production and voice disorders. OBJECTIVE: This study aimed to describe changes in AAV, EGG, and VHI in patients who present with LPR compared with a matched control group of healthy subjects. MATERIALS AND METHODS: Seventeen patients with LPR were studied. A group of healthy subjects matched by age and gender without any history of voice disorder, LPR, or gastroesophageal reflux disease was assembled. Both groups of patients were studied by VHI, flexible laryngoscopy, AAV, and EGG. RESULTS: All patients with LPR demonstrated abnormal VHI values. Shimmer, jitter, open quotient, and irregularity were significantly increased in the patients with LPR. Nonsignificant correlations were found between VHI scores and abnormal acoustic parameters in patients with LPR. CONCLUSIONS: Although abnormal acoustic parameters of patients with LPR were not predictive of the overall VHI score, the abnormal acoustic parameters of patients with LPR suggest a decrease in adequate laryngeal control during phonation. PMID- 28596099 TI - "Cold-Steel" Phonosurgery of Reinke Edema Evaluated by the Multidimensional Voice Program. AB - OBJECTIVES: "Cold-steel" phonosurgery (PS) of Reinke edema is challenging, as the delicate structures of the vocal folds are difficult to preserve. This study aimed to evaluate the results of PS using the Multidimensional Voice Program (MDVP) . MATERIALS AND METHODS: From 2003 to 2007, 76 consecutive patients with Reinke edema were treated with PS for the first time. Reliable MDVP data were available in 37 female patients with both pre- and postoperative values in 14 patients. Voice quality and outcome after PS were evaluated by jitter, shimmer, soft phonation index, and fundamental frequency (f0) using MDVP, videostroboscopy, and a five-step voice outcome score. RESULTS: In the 14 patients, the mean f0 increased from 172 to 222 (P = 0.01), and jitter decreased from 2.03 to 1.17 (P = 0.04) 3 months postoperatively. Vocal fold grading based on videostroboscopy correlated significantly with jitter (P = 0.01). Patients with high preoperative values of jitter, shimmer, or soft phonation index had larger reductions than those with normal values. All had a postoperative reduction of the edemas. The mean voice outcome score increased postoperatively. None of the 37 patients reported complications, but seven patients were reoperated. Preoperatively, 95% of the 37 patients were smokers and only 9 (24%) changed smoking habits. Pre- or postoperative voice therapy was used in 23 (62%) patients. CONCLUSIONS: f0 and jitter by MDVP adequately reflected the postoperative voice improvement and reduction of the edema. Removal of large amounts of edematous tissue, many years of vocal abuse, and unchanged smoking habits may prevent optimal results. PMID- 28596097 TI - Menstrual Cycle, Vocal Performance, and Laryngeal Vascular Appearance: An Observational Study on 17 Subjects. AB - OBJECTIVE: To assess the anatomical and functional features of the vocal folds during different phases of the female menstrual cycle. METHODS: An observational study of 17 healthy fertile female volunteers not using hormonal contraception was carried out. Each volunteer underwent two examinations: first, during the early days of the menstrual cycle when progesterone levels are low (p-depletion), and second, during premenstruation when progesterone levels are high (p-peak). The workup included blood hormone levels, Voice Handicap Index, acoustic analysis, rigid telescopy, stroboscopy, and narrow band imaging. The videos were evaluated by blinded observers. RESULTS: The participants' mean age was 31.7 +/- 5.6 (range 23-43). Progesterone levels were 13- to 45-fold higher in p-peak relative to p-depletion. No significant differences were detected in Voice Handicap Index scores, stroboscopic reports, or acoustic analysis between p-peak and p-depletion examinations. Analyzing the rigid telescopy and narrow band imaging videos, the observers tended to estimate the different laryngeal subsites more vascularized during the p-peak examination. Moreover, this tendency was significantly correlated with blood progesterone levels during the p-depletion examinations; the lower the blood progesterone levels were during p-depletion, the higher the probability for the observers to estimate the p-peak examinations more vascularized (P value = 0.024). CONCLUSIONS: Alterations in laryngeal vascular characteristics are evident throughout the menstrual cycle and may suggest increased congestion during premenstrual days. Variations in progesterone levels during the menstrual cycle correlate with laryngeal vascular changes. Hormone-related alterations in vocal folds' vascularity may have a role in the variability of vocal performance in certain women. PMID- 28596100 TI - Aerodynamic Patterns in Patients With Voice Disorders: A Retrospective Study. AB - OBJECTIVE: A recently published retrospective chart review of aerodynamic profiles of women with primary muscle tension dysphonia by Gillespie et al (2013) identified various relationships between mean airflow rate (MFR) and estimated subglottal pressure (est-Psub). The current retrospective study expanded the diagnostic categories to include all voice disorders referred for voice therapy. Three research questions were proposed: (1) Are there differences in the MFR and the est-Psub compared with the normal control group? (2) Within the disordered population, are there different variations in the pairing of MFR and est-Psub? (3) If these variations exist, are they diagnosis specific? METHODS: A retrospective chart review of patients seen for acoustic and aerodynamic voice assessment at the Emory Voice Center between January 1, 2013 and December 31, 2014, were examined for aerodynamic measures of est-Psub and MFR; of these, 192 met the inclusion criteria. Simple t test, two-step cluster analysis, and analysis of variance, as well as Tukey multiple comparisons, were performed using R and SPSS. RESULTS: Mean est-Psub was significantly greater in the group with voice disorder than in the control group (P value < 0.001). However, no statistical significance was found when comparing the MFR with the control group (P value <0.59). Nine possible pairings of MFR and est-Psub were found. Sufficient evidence was not found to detect significant differences in these pairings across diagnostic groups. CONCLUSION: With regard to the rate and interrelationships of MFR and est-Psub, the findings of this study are similar to those of Gillespie et al, that is, MFR and est-Psub are not determinate of diagnosis. PMID- 28596101 TI - Utility of Laryngeal High-speed Videoendoscopy in Clinical Voice Assessment. AB - OBJECTIVE: This study aimed to assess the utility of laryngeal high-speed videoendoscopy (HSV) as a clinical tool. DESIGN: This is a prospective study of 151 patients. METHODS: A total of 151 adult patients (52 male, 99 female) underwent both videoendoscopy with stroboscopy (videostroboscopy) and HSV examination as part of a routine clinical voice assessment. At the time of the examination, ratings for videostroboscopy were reported in the clinical report. Next, the clinicians reviewed the HSV examination and indicated the changes in ratings of HSV relative to videostroboscopy. Finally, the clinical reports were reviewed by a clinician not involved in data collection or clinical care of the patients and noted differences between videostroboscopy and HSV clinical ratings, and resulting diagnoses were identified and grouped. RESULTS: Ratings of all vibratory features showed change between videostroboscopy and HSV. Mucosal wave and amplitude of vibration showed the largest percentage change, respectively, in 74% and 53% of the reports. They were followed by the features of glottal closure (36%), phase closure (32%), glottal edge (25%), and phase symmetry (21%). Ratings of supraglottic compression and vocal fold vertical level showed the least change between videostroboscopy and HSV. Changes in initial diagnosis owing to the inclusion of HSV were indicated in 7% of the cases. CONCLUSIONS: HSV may be an important laryngeal imaging technique for functional assessment of the pathophysiology of certain voice disorders. HSV could enable important refinements in the diagnosis and management of vocal fold pathology. PMID- 28596102 TI - Evolution of the fusogenic activity of the receptor FGFRL1. AB - FGFRL1 is a transmembrane receptor that can induce the fusion of CHO cells to multinucleated syncytia. This cell fusion activity has been attributed to the extracellular Ig3 domain of the receptor. We investigated how the fusogenic activity evolved during the evolution of animals. We found that the Ig3 domain from humans, mice, chicken and fish stimulates fusion of CHO cells, while the Ig3 domain from lancelet and sea urchin does not. It is therefore conceivable that the fusogenic activity of FGFRL1 developed during the evolution of vertebrates. Bony fish contain two copies of the FGFRL1 gene because they have undergone a whole-genome duplication. One of the corresponding proteins (FGFRL1a) induces cell-cell fusion, while the other (FGFRL1b) does not. Analysis of chimeric constructs and in vitro mutagenesis suggested that FGFRL1b has lost its fusogenic activity after duplication. A rescue experiment supported this conclusion. When four amino acids were changed, the Ig3 domain of FGFRL1b was converted into an active, fusogenic protein comparable to FGFRL1a. The four amino acids are located in a hydrophobic pocket of the Ig3 domain. It is likely that this hydrophobic pocket interacts with a target molecule on the membrane of adjacent cells to induce cell-cell fusion. PMID- 28596103 TI - Training General Practitioners to Detect Probable Mental Disorders in Young People During Health Risk Screening. AB - PURPOSE: The purpose of the study is to investigate whether a training intervention increases general practitioners' (GPs) detection sensitivity for probable mental disorders in young people. METHODS: Forty general practices were randomized to an intervention (29 GPs) or comparison arm (49 GPs). Intervention GPs participated in 9 hours of interactive training on youth-friendly care, psychosocial health risk screening, and responding to risk-taking behavior with motivational interviewing approaches, followed by practice visits assisting with integration of screening processes and tools. Youth aged 14-24 years attending GPs underwent a computer-assisted telephone interview about their consultation and psychosocial health risks. Having a "probable mental disorder" was defined as either scoring high on Kessler's scale of psychological distress (K10) or self perceived mental illness. Other definitions tested were high K10; self-perceived mental illness; and high K10 and self-perceived mental illness. Psychosocial health risk screening rates, detection sensitivity, and other accuracy parameters (specificity, positive predictive value, and negative predictive value) were estimated. RESULTS: GPs' detection sensitivity improved after the intervention if having probable mental disorder was defined as high K10 score and self-perceived mental illness (odds ratio: 2.81; 95% confidence interval: 1.23-6.42). There was no significant difference in sensitivity of GPs' detection for our preferred definition, high K10 or self-perceived mental illness (.37 in both; odds ratio: .93; 95% confidence interval: .47-1.83), and detection accuracy was comparable (specificity: .84 vs. .87, positive predictive values: .54 vs. .60, and negative predictive values: .72 vs. .72). CONCLUSIONS: Improving recognition of mental disorder among young people attending primary care is likely to require a multifaceted approach targeting young people and GPs. PMID- 28596104 TI - Effect of stratum corneum heterogeneity, anisotropy, asymmetry and follicular pathway on transdermal penetration. AB - The impact of the complex structure of the stratum corneum on transdermal penetration is not yet fully described by existing models. A quantitative and thorough study of skin permeation is essential for chemical exposure assessment and transdermal delivery of drugs. The objective of this study is to analyze the effects of heterogeneity, anisotropy, asymmetry, follicular diffusion, and location of the main barrier of diffusion on percutaneous permeation. In the current study, the solution of the transient diffusion through a two-dimensional anisotropic brick-and-mortar geometry of the stratum corneum is obtained using the commercial finite element program COMSOL Multiphysics. First, analytical solutions of an equivalent multilayer geometry are used to determine whether the lipids or corneocytes constitute the main permeation barrier. Also these analytical solutions are applied for validations of the finite element solutions. Three illustrative compounds are analyzed in these sections: diethyl phthalate, caffeine and nicotine. Then, asymmetry with depth and follicular diffusion are studied using caffeine as an illustrative compound. The following findings are drawn from this study: the main permeation barrier is located in the lipid layers; the flux and lag time of diffusion through a brick-and-mortar geometry are almost identical to the values corresponding to a multilayer geometry; the flux and lag time are affected when the lipid transbilayer diffusivity or the partition coefficients vary with depth, but are not affected by depth-dependent corneocyte diffusivity; and the follicular contribution has significance for low transbilayer lipid diffusivity, especially when flux between the follicle and the surrounding stratum corneum is involved. This study demonstrates that the diffusion is primarily transcellular and the main barrier is located in the lipid layers. PMID- 28596106 TI - Mechanisms of axon regeneration: The significance of proteoglycans. AB - BACKGROUND: Therapeutics specific to neural injury have long been anticipated but remain unavailable. Axons in the central nervous system do not readily regenerate after injury, leading to dysfunction of the nervous system. This failure of regeneration is due to both the low intrinsic capacity of axons for regeneration and the various inhibitors emerging upon injury. After many years of concerted efforts, however, these hurdles to axon regeneration have been partially overcome. SCOPE OF REVIEW: This review summarizes the mechanisms regulating axon regeneration. We highlight proteoglycans, particularly because it has become increasingly clear that these proteins serve as critical regulators for axon regeneration. MAJOR CONCLUSIONS: Studies on proteoglycans have revealed that glycans not only assist in the modulation of protein functions but also act as main players-e.g., as functional ligands mediating intracellular signaling through specific receptors on the cell surface. By regulating clustering of the receptors, glycans in the proteoglycan moiety, i.e., glycosaminoglycans, promote or inhibit axon regeneration. In addition, proteoglycans are involved in various types of neural plasticity, ranging from synaptic plasticity to experience dependent plasticity. GENERAL SIGNIFICANCE: Although studies on proteins have progressively facilitated our understanding of the nervous system, glycans constitute a new frontier for further research and development in this field. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28596105 TI - Multifunctional nanodiamonds in regenerative medicine: Recent advances and future directions. AB - With recent advances in the field of nanomedicine, many new strategies have emerged for diagnosing and treating diseases. At the forefront of this multidisciplinary research, carbon nanomaterials have demonstrated unprecedented potential for a variety of regenerative medicine applications including novel drug delivery platforms that facilitate the localized and sustained release of therapeutics. Nanodiamonds (NDs) are a unique class of carbon nanoparticles that are gaining increasing attention for their biocompatibility, highly functional surfaces, optical properties, and robust physical properties. Their remarkable features have established NDs as an invaluable regenerative medicine platform, with a broad range of clinically relevant applications ranging from targeted delivery systems for insoluble drugs, bioactive substrates for stem cells, and fluorescent probes for long-term tracking of cells and biomolecules in vitro and in vivo. This review introduces the synthesis techniques and the various routes of surface functionalization that allow for precise control over the properties of NDs. It also provides an in-depth overview of the current progress made toward the use of NDs in the fields of drug delivery, tissue engineering, and bioimaging. Their future outlook in regenerative medicine including the current clinical significance of NDs, as well as the challenges that must be overcome to successfully translate the reviewed technologies from research platforms to clinical therapies will also be discussed. PMID- 28596107 TI - A novel function for glucocerebrosidase as a regulator of sterylglucoside metabolism. AB - BACKGROUND: Sterols are major cell membrane lipids, and in many organisms they are modified with glucose to generate sterylglucosides. Glucosylation dramatically changes the functional properties of sterols. The formation of sterylglucosides from sterols in plants, fungi, and bacteria uses UDP-glucose as a glucose donor. By contrast, sterylglucoside biosynthesis in mammals is catalyzed by the transglucosylation activity of glucocerebrosidases, with glucosylceramide acting as the glucose donor. Recent success in isolation and structural determination of sterylglucosides in the vertebrate central nervous system shows that transglucosylation also occurs in vivo. These analyses also revealed that sterylglucoside aglycons are composed of several cholesterol related metabolites, including a plant-type sitosteryl. SCOPE OF REVIEW: In this review, we discuss the biological functions and metabolism of sterylglucosides. We also summarize new findings from studies on the metabolism of vertebrate sterylglucosides and review the circumstances underlying the recent discovery of sterylglucosides in vertebrate brain. Finally, we discuss the role of sterylglucosides in a variety of neurodegenerative disorders such as Gaucher disease and Parkinson's disease. MAJOR CONCLUSIONS: The biological significance of UDP-glucose-independent sterol glucosylation is still unknown, but it is plausible that glucosylation may provide sterols with novel biological functions. Even though sterol glucosylation is a simple reaction, it can dramatically change the physical properties of sterols. GENERAL SIGNIFICANCE: Sterylglucosides may play roles in various physiological processes and in the pathogenesis of different diseases. Arriving at a better understanding of them at the organ and cellular level may open up new approaches to developing therapeutics for a variety of diseases. This article is part of a Special Issue entitled Neuro glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa. PMID- 28596108 TI - Association Between EGFR T790M Status and Progression Patterns During Initial EGFR-TKI Treatment in Patients Harboring EGFR Mutation. AB - BACKGROUND: Emergence of the T790M point mutation in exon 20 of the epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to investigate the association between T790M mutation status and the progression patterns during EGFR-TKI treatment. METHODS: We reviewed 181 patients with advanced non-small cell lung cancer harboring EGFR mutation, who were evaluated for T790M mutation status after initial EGFR-TKI failure (gefitinib, erlotinib, or afatinib). We retrospectively investigated the patient characteristics, initial EGFR-TKI response, T790M mutation status, subsequent treatment after initial EGFR-TKIs, timing of re-biopsy, and progression patterns during the EGFR-TKI treatment. RESULTS: After the resistance to the EGFR-TKIs, the T790M mutation was identified in 87 (48%) of 181 patients. Seventy-three (40%) patients had solitary lesion progression, and 108 (60%) had multiple lesion progression during the initial EGFR-TKI treatment. The prevalence of the T790M mutation was significantly greater in patients with solitary lesion progression than those with multiple lesion progression (58% vs. 24%; P < .0001). The overall response rate and progression-free survival on initial EGFR-TKIs were significantly better in patients who acquired T790M after failure of EGFR-TKIs than those without T790M (overall response rate, 80% vs. 60%; P = .0033 and progression-free survival, 11.4 vs. 9.3 months; P = .0050). The multivariate analysis showed that gender, initial EGFR-TKI response, and progression patterns were significantly associated with T790M mutation status. DISCUSSION: The progression patterns during initial EGFR-TKIs and initial EGFR-TKI response are associated with the T790M mutation. PMID- 28596109 TI - Cytotherapy with M1-polarized macrophages ameliorates liver fibrosis by modulating immune microenvironment in mice. AB - BACKGROUND & AIMS: Macrophages play vital roles in chronic liver injury, and have been tested as a tool for cytotherapy in liver fibrosis. However, macrophages possess ontogenic and functional heterogeneities. Some subsets are pro-fibrotic, whereas others are anti-fibrotic. This study aimed to clarify which macrophage subset is efficient for cytotherapy in liver fibrosis and to elucidate the underlying mechanisms. METHODS: Liver fibrosis was induced in mice by carbon tetrachloride injection or bile duct ligation. Bone-marrow-derived macrophages (BMDMs) were polarized into M0, M1, or M2 macrophages, respectively. BMDMs were infused into mice through the tail vein at different stages of fibrogenesis. Fibrosis progression, hepatic cell populations, and related molecular changes were evaluated. RESULTS: Both M0 and M1 BMDMs significantly ameliorated liver fibrosis, but M1 exhibited stronger therapeutic effects than M0. M2 macrophages were not effective on liver fibrosis. M1 macrophages reduced the number and activation of hepatic stellate cells (HSCs), which could be attributed at least partly to increased HSC apoptosis. M1 macrophages enhanced the recruitment of endogenous macrophages into fibrotic liver, which displayed the phenotype of Ly6Clo restorative macrophages and produced matrix metalloproteinases (MMPs) and hepatic growth factor (HGF) to enhance collagen degradation and hepatocyte proliferation, respectively. M1 macrophages also increased the number of total and activated natural killer (NK) cells in the fibrotic liver, which released TNF related apoptosis-inducing ligand (TRAIL), inducing HSC apoptosis. CONCLUSIONS: M1 macrophages, which modulate the immune microenvironment to recruit and modify the activation of endogenous macrophages and NK cells, are effective for cytotherapy in experimental liver fibrosis. Lay summary: M1 Bone marrow-derived macrophages (BMDMs) exhibit a stronger therapeutic effect by modulating the hepatic microenvironment to recruit and modify the activation of endogenous macrophages and natural killer (NK) cells, which likely lead to hepatic stellate cells (HSCs) apoptosis and hampered fibrogenesis. PMID- 28596112 TI - Aggregation of biological particles under radial directional guidance. AB - Many biological environments display an almost radially-symmetric structure, allowing proteins, cells or animals to move in an oriented fashion. Motivated by specific examples of cell movement in tissues, pigment protein movement in pigment cells and animal movement near watering holes, we consider a class of radially-symmetric anisotropic diffusion problems, which we call the star problem. The corresponding diffusion tensor D(x) is radially symmetric with isotropic diffusion at the origin. We show that the anisotropic geometry of the environment can lead to strong aggregations and blow-up at the origin. We classify the nature of aggregation and blow-up solutions and provide corresponding numerical simulations. A surprising element of this strong aggregation mechanism is that it is entirely based on geometry and does not derive from chemotaxis, adhesion or other well known aggregating mechanisms. We use these aggregate solutions to discuss the process of pigmentation changes in animals, cancer invasion in an oriented fibrous habitat (such as collagen fibres), and sheep distributions around watering holes. PMID- 28596110 TI - Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease. AB - BACKGROUND & AIM: Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. METHODS: Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jalpha18 wild-type (Lck-CD1dTgJalpha18+; type I NKT cell sufficient) and Jalpha18 deficient (Lck-CD1dTgJalpha18o, type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. RESULTS: Lck-CD1dTgJalpha18o and Lck-CD1dTgJalpha18+ mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in Th1-skewing and impaired Th2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. CONCLUSIONS: Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a Th1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the development of chronic autoimmune liver disease. PMID- 28596111 TI - High fat diet disrupts endoplasmic reticulum calcium homeostasis in the rat liver. AB - BACKGROUND & AIMS: Disruption to endoplasmic reticulum (ER) calcium homeostasis has been implicated in obesity, however, the ability to longitudinally monitor ER calcium fluctuations has been challenging with prior methodologies. We recently described the development of a Gaussia luciferase (GLuc)-based reporter protein responsive to ER calcium depletion (GLuc-SERCaMP) and investigated the effect of a high fat diet on ER calcium homeostasis. METHODS: A GLuc-based reporter cell line was treated with palmitate, a free fatty acid. Rats intrahepatically injected with GLuc-SERCaMP reporter were fed a cafeteria diet or high fat diet. The liver and plasma were examined for established markers of steatosis and compared to plasma levels of SERCaMP activity. RESULTS: Palmitate induced GLuc SERCaMP release in vitro, indicating ER calcium depletion. Consumption of a cafeteria diet or high fat pellets correlated with alterations to hepatic ER calcium homeostasis in rats, shown by increased GLuc-SERCaMP release. Access to ad lib high fat pellets also led to a corresponding decrease in microsomal calcium ATPase activity and an increase in markers of hepatic steatosis. In addition to GLuc-SERCaMP, we have also identified endogenous proteins (endogenous SERCaMPs) with a similar response to ER calcium depletion. We demonstrated the release of an endogenous SERCaMP, thought to be a liver esterase, during access to a high fat diet. Attenuation of both GLuc-SERCaMP and endogenous SERCaMP was observed during dantrolene administration. CONCLUSIONS: Here we describe the use of a reporter for in vitro and in vivo models of high fat diet. Our results support the theory that dietary fat intake correlates with a decrease in ER calcium levels in the liver and suggest a high fat diet alters the ER proteome. Lay summary: ER calcium dysregulation was observed in rats fed a cafeteria diet or high fat pellets, with fluctuations in sensor release correlating with fat intake. Attenuation of sensor release, as well as food intake was observed during administration of dantrolene, a drug that stabilizes ER calcium. The study describes a novel technique for liver research and provides insight into cellular processes that may contribute to the pathogenesis of obesity and fatty liver disease. PMID- 28596113 TI - Evolution of delayed dispersal and subsequent emergence of helping, with implications for cooperative breeding. AB - Cooperative breeding occurs when individuals help raise the offspring of others. It is widely accepted that help displayed by cooperative breeders emerged only after individuals' tendency to delay dispersal had become established. We use this idea as a basis for two inclusive-fitness models: one for the evolution of delayed dispersal, and a second for the subsequent emergence of helpful behavior exhibited by non-breeding individuals. We focus on a territorial species in a saturated environment, and allow territories to be inherited by non-breeding individuals who have delayed dispersal. Our first model predicts that increased survivorship and increased fecundity both provide an incentive to non-breeding individuals to delay dispersal, and stay near their natal territory for some period of time. Predictions from the first model can be well understood by ignoring complications arising from competition among relatives. Our second model shows that effects on relatives play a primary role in the advantage of helping. In addition, the second model predicts that increased survivorship and fecundity promote the emergence of help. Together, our models lead us to conclude that the emergence of cooperative-breeding systems is made easier by life-history features associated with high survivorship and fecundity. We discuss the implications of our conclusions for life-history-based hypotheses of cooperative breeding and social evolution. PMID- 28596114 TI - Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5ch and AAV1. AB - In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5ch) and AAV1 for repeated liver-targeted gene delivery. To develop a relevant model, we immunized animals with a high dose of AAV5ch-human secreted embryonic alkaline phosphatase (hSEAP) that generates high levels of anti-AAV5ch NAB. Secondary liver transduction with the same dose of AAV1-human factor IX (hFIX) in the presence of high levels of anti-AAV5ch NAB proved to be successful because expression/activity of both reporter transgenes was observed. This is the first time that two different transgenes are shown to be produced by non-human primate (NHP) liver after sequential administration of clinically relevant doses of both AAV5ch and AAV1. The levels of transgene proteins achieved after delivery with AAV5ch and AAV1 illustrate the possibility of both serotypes for liver targeting. Furthermore, transgene DNA and RNA biodistribution patterns provided insight into the potential cause of decrease or loss of transgene protein expression over time in NHPs. PMID- 28596116 TI - Mechanisms of Neurofeedback: A Computation-theoretic Approach. AB - Neurofeedback training is a form of brain training in which information about a neural measure is fed back to the trainee who is instructed to increase or decrease the value of that particular measure. This paper focuses on electroencephalography (EEG) neurofeedback in which the neural measures of interest are the brain oscillations. To date, the neural mechanisms that underlie successful neurofeedback training are still unexplained. Such an understanding would benefit researchers, funding agencies, clinicians, regulatory bodies, and insurance firms. Based on recent empirical work, an emerging theory couched firmly within computational neuroscience is proposed that advocates a critical role of the striatum in modulating EEG frequencies. The theory is implemented as a computer simulation of peak alpha upregulation, but in principle any frequency band at one or more electrode sites could be addressed. The simulation successfully learns to increase its peak alpha frequency and demonstrates the influence of threshold setting - the threshold that determines whether positive or negative feedback is provided. Analyses of the model suggest that neurofeedback can be likened to a search process that uses importance sampling to estimate the posterior probability distribution over striatal representational space, with each representation being associated with a distribution of values of the target EEG band. The model provides an important proof of concept to address pertinent methodological questions about how to understand and improve EEG neurofeedback success. PMID- 28596115 TI - Differential dendritic remodeling in prelimbic cortex of male and female rats during recovery from chronic stress. AB - Chronic stress produces differential dendritic remodeling of pyramidal neurons in medial prefrontal cortex of male and female rats. In males, this dendritic remodeling is reversible. However, the timeline of recovery, as well as the potential for reversibility in females, is unknown. Here, we examined dendritic recovery of pyramidal neurons in layer II-II of prelimbic cortex in male and female rats following chronic restraint stress (3h/day for 10days). Dendritic morphology and spine density were analyzed immediately following the cessation of stress, or following a 7- or 10-day recovery period. Chronic stress produced apical dendritic retraction in males, which was coupled with a decrease in the density of stubby spine on apical dendrites. Further, following a 10-day recovery period, the morphology of neurons from stressed rats resembled that of unstressed rats. Male rats given a 7-day recovery period had apical dendritic outgrowth compared to unstressed rats. Immediately after cessation of stress, females showed only minimal dendritic remodeling. The morphology of neurons in stressed females resembled those of unstressed rats following only 7days of recovery, at which time there was also a significant increase in stubby spine density. Males and females also showed different changes in baseline corticosterone concentrations during recovery. These findings not only indicate that dendritic remodeling in prelimbic cortex following chronic stress is different between males and females, but also suggest chronic stress induces differential hypothalamic-pituitary-adrenal axis dysregulation in males and females. These differences may have important implications for responses to subsequent stressors. PMID- 28596117 TI - Disrupted white matter structural networks in healthy older adult APOE epsilon4 carriers - An international multicenter DTI study. AB - The epsilon4 allelic variant of the Apolipoprotein E gene (APOE epsilon4) is the best-established genetic risk factor for late-onset Alzheimer's disease (AD). White matter (WM) microstructural damages measured with Diffusion Tensor Imaging (DTI) represent an early sign of fiber tract disconnection in AD. We examined the impact of APOE epsilon4 on WM microstructure in elderly individuals from the multicenter European DTI Study on Dementia. Voxelwise statistical analysis of fractional anisotropy (FA), mean diffusivity, radial and axial diffusivity (MD, radD and axD respectively) was carried out using Tract-Based Spatial Statistics. Seventy-four healthy elderly individuals - 31 APOE epsilon4 carriers (APOE epsilon4+) and 43 APOE epsilon4 non-carriers (APOE epsilon4-) -were considered for data analysis. All the results were corrected for scanner acquisition protocols, age, gender and for multiple comparisons. APOE epsilon4+ and APOE epsilon4- subjects were comparable regarding sociodemographic features and global cognition. A significant reduction of FA and increased radD was found in the APOE epsilon4+ compared to the APOE epsilon4- in the cingulum, in the corpus callosum, in the inferior fronto-occipital and in the inferior longitudinal fasciculi, internal and external capsule. APOE epsilon4+, compared to APOE epsilon4- showed higher MD in the genu, right internal capsule, superior longitudinal fasciculus and corona radiate. Comparisons stratified by center supported the results obtained on the whole sample. These findings support previous evidence in monocentric studies indicating a modulatory role of APOE E4 allele on WM microstructure in elderly individuals at risk for AD suggesting early vulnerability and/or reduced resilience of WM tracts involved in AD. PMID- 28596118 TI - Neuroprotective role of GABAB receptor modulation against streptozotocin-induced behavioral and biochemical abnormalities in rats. AB - Stimulation as well as inhibition of GABAB (Gamma amino butyric acid) receptors has been reported to show beneficial effects in Alzheimer's disease (AD). Experimental evidences suggest that the use of GABAergic agents could influence learning and memory. The present study was designed to investigate the possible role of GABAB receptors in streptozotocin (STZ)-induced behavioral and biochemical abnormalities in rats. Herein STZ was infused (3mg/kg) bilaterally on alternate days (day 1 and day 3) to produce experimental dementia in rats. STZ infused rats were then treated with baclofen (GABABR agonist) 5 and 10mg/kg i.p. and CGP35348 (GABABR antagonist) 25 and 50mg/kg i.p. one week following STZ infusion for 15days. Cognitive functions were assessed by using Morris water maze (MWM) and object recognition task (ORT). Levels of malondialdehyde (MDA.), reduced glutathione (GSH), andacetylcholinesterase (AChE) were determined to evaluate oxidative stress and cholinergic function. STZ-infused rats showed decreased memory retention, elevated levels of MDA, increased AChE activity, reduced GSH levels. The combination of STZ with increasing doses of Baclofen further induced a higher decrease in memory retention and increase in oxidative stress. CGP35348 restored cognitive functions and AChE activity in STZ-infused rats. The cognitive enhancement following CGP35348 may be due to its ability to restore cholinergic, serotonergic and dopaminergic function, and its antioxidant activity. Therefore, it would be safe to conclude that the pharmacological blockade of GABAB receptors would be therapeutic in the management of cognitive disorders such as Alzheimer's disease. PMID- 28596119 TI - Alterations of M1 and M4 acetylcholine receptors in the genetically dystonic (dtsz) hamster and moderate antidystonic efficacy of M1 and M4 anticholinergics. AB - Striatal cholinergic dysfunction has been suggested to play a critical role in the pathophysiology of dystonia. In the dtsz hamster, a phenotypic model of paroxysmal dystonia, M1 antagonists exerted moderate antidystonic efficacy after acute systemic administration. In the present study, we examined the effects of the M4 preferring antagonist tropicamid and whether long-term systemic or acute intrastriatal injections of the M1 preferring antagonist trihexyphenidyl are more effective in mutant hamsters. Furthermore, M1 and M4 receptors were analyzed by autoradiography and immunohistochemistry. Tropicamide retarded the onset of dystonic attacks, as previously observed after acute systemic administration of trihexyphenidyl. Combined systemic administration of trihexyphenidyl (30mg/kg) and tropicamide (15mg/kg) reduced the severity in acute trials and delayed the onset of dystonia during long-term treatment. In contrast, acute striatal microinjections of trihexyphenidyl, tropicamid or the positive allosteric M4 receptor modulator VU0152100 did not exert significant effects. Receptor analyses revealed changes of M1 receptors in the dorsomedial striatum, suggesting that the cholinergic system is involved in abnormal striatal plasticity in dtsz hamsters, but the pharmacological data argue against a crucial role on the phenotype in this animal model. However, antidystonic effects of tropicamide after systemic administration point to a novel therapeutic potential of M4 preferring anticholinergics for the treatment of dystonia. PMID- 28596122 TI - Trends and regional variations in provision of contraception methods in a commercially insured population in the United States based on nationally proposed measures. AB - OBJECTIVES: Three measures to assess the provision of effective contraception methods among reproductive-aged women have recently been endorsed for national public reporting. Based on these measures, this study examined real-world trends and regional variations of contraceptive provision in a commercially insured population in the United States. STUDY DESIGN: Women 15-44years old with continuous enrollment in each year from 2005 to 2014 were identified from a commercial claims database. In accordance with the proposed measures, percentages of women (a) provided most effective or moderately effective (MEME) methods of contraception and (b) provided a long-acting reversible contraceptive (LARC) method were calculated in two populations: women at risk for unintended pregnancy and women who had a live birth within 3 and 60days of delivery. RESULTS: During the 10-year period, the percentages of women at risk for unintended pregnancy provided MEME contraceptive methods increased among 15-20-year-olds (24.5%-35.9%) and 21-44-year-olds (26.2%-31.5%), and those provided a LARC method also increased among 15-20-year-olds (0.1%-2.4%) and 21-44-year-olds (0.8%-3.9%). Provision of LARC methods increased most in the North Central and West among both age groups of women. Provision of MEME contraceptives and LARC methods to women who had a live birth within 60days postpartum also increased across age groups and regions. CONCLUSIONS: This assessment indicates an overall trend of increasing provision of MEME contraceptive methods in the commercial sector, albeit with age group and regional variations. If implemented, these proposed measures may have impacts on health plan contraceptive access policy. PMID- 28596120 TI - Myelin-induced inhibition in a spiral ganglion organ culture - Approaching a natural environment in vitro. AB - The performance of a cochlear implant depends on the defined interaction between afferent neurons of the spiral ganglion and the inserted electrode. Neurite outgrowth can be induced by neurotrophins such as brain-derived neurotrophic factor (BDNF) via tropomyosin kinase receptor B (TrkB). However, neurotrophin signaling through the p75 neurotrophin receptor (p75) inhibits neurite outgrowth in the presence of myelin. Organotypic cultures derived from postnatal (P3-5) mice were used to study myelin-induced inhibition in the cochlear spiral ganglion. Neurite outgrowth was analyzed and quantified utilizing an adapted Sholl analysis. Stimulation of neurite outgrowth was quantified after application of BDNF, the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) and a selective inhibitor of the Rho-associated kinase (Y27632), which inhibits the p75 pathway. Myelin-induced inhibition was assessed by application of myelin associated glycoprotein (MAG-Fc) to stimulate the inhibitory p75 pathway. Inhibition of neurite outgrowth was achieved by the selective TrkB inhibitor K252a. Stimulation of neurite outgrowth was observed after treatment with BDNF, 7,8 DHF and a combination of BDNF and Y27632. The 7,8-DHF-induced growth effects could be inhibited by K252a. Furthermore, inhibition of neurite outgrowth was observed after supplementation with MAG-Fc. Myelin-induced inhibition could be overcome by 7,8-DHF and the combination of BDNF and Y27632. In this study, myelin induced inhibition of neurite outgrowth was established in a spiral ganglion model. We reveal that 7,8-DHF is a viable novel compound for the stimulation of neurite outgrowth in a myelin-induced inhibitory environment. The combination of TrkB stimulation and ROCK inhibition can be used to overcome myelin inhibition. PMID- 28596123 TI - New clinical performance measures for contraceptive care: their importance to healthcare quality. AB - OBJECTIVES: The National Quality Forum (NQF) recently endorsed the first clinical performance measures for contraceptive care. We present data demonstrating that the measures meet the NQF's criterion "importance to measure and report." STUDY DESIGN: We summarized national contraceptive care initiatives, epidemiologic data documenting the reproductive health burden and the scientific literature examining the association between contraceptive use and unintended pregnancy. In addition, we analyzed contraceptive use data from the National Survey of Family Growth (2013-2015) and the Pregnancy Risk Assessment Monitoring System (2012 2013). RESULTS: Five Federal agencies lead national initiatives, and two Institute of Medicine reports highlight the centrality of reproductive health outcomes for the health of women and infants. Two literature reviews demonstrate that the type of contraception used is associated with risk of unintended pregnancy. Fifty-three percent of adolescents (15-19years) and 40% of adult women (20-44years) at risk of unintended pregnancy are not using a most or moderately effective contraceptive method; in the postpartum period, one third of adolescents (<=19years) and 44% of adult women (>=20years) are not using these methods. CONCLUSIONS: The new contraceptive care measures meet the NQF criterion for "importance to measure and report." The measures are based on evidence that contraceptive use is associated with reproductive health outcomes, and there is a substantial performance gap in the use of most and moderately effective methods. IMPLICATIONS: Using the new contraceptive care measures may motivate providers to increase access to contraceptive care, thereby improving health outcomes. PMID- 28596121 TI - One-year continuation of copper or levonorgestrel intrauterine devices initiated at the time of emergency contraception. AB - OBJECTIVE(S): This study compares 1-year intrauterine device (IUD) continuation among women presenting for emergency contraception (EC) and initiating the copper (Cu T380A) IUD or the levonorgestrel (LNG) 52 mg IUD plus 1.5 mg oral LNG. STUDY DESIGN: This cohort study enrolled 188 women who presented at a single family planning clinic in Utah between June 2013 and September 2014 and selected either the Cu T380A IUD or LNG 52 mg IUD plus oral LNG for EC. Trained personnel followed participants by phone, text or e-mail for 12 months or until discontinuation occurred. We assessed reasons for discontinuation and used Cox proportional hazard models, Kaplan-Meier estimates and log-rank tests to assess differences in continuation rates between IUDs. RESULTS: One hundred seventy-six women received IUDs; 66 (37%) chose the Cu T380A IUD and 110 (63%) chose the LNG 52 mg IUD plus oral LNG. At 1 year, we accounted for 147 (84%) participants, 33 (22%) had requested removals, 13 (9%) had an expulsion and declined reinsertion, 3 (2%) had a pregnancy with their IUD in place and 98 (67%) were still using their device. Continuation rates did not differ by IUD type; 60% of Cu T380A IUD users and 70% of LNG 52 mg IUD plus oral LNG users were still using their device at 12 months (adjusted hazard ratio 0.72, 95% confidence interval 0.40-1.3). CONCLUSION(S): Two-thirds of women who chose IUD placement at the EC clinical encounter continued use at 1 year. Women initiating Cu T380A IUD and LNG 52 mg IUD had similar 1-year continuation rates. These findings support same-day insertion of IUDs for women who are seeking EC and would like to use a highly effective reversible method going forward. IMPLICATIONS: Providing IUD options for EC users presents an opportunity to increase availability of highly effective contraception. PMID- 28596124 TI - Detection of Aichi virus genotype B in two lines of wastewater treatment processes. AB - Enteric viruses are released in important quantities into the environment where they can persist for a very long time. At very low doses, they can cause human gastroenteritis, and are responsible for a substantial number of waterborne diseases. The aims of this study were multiple: firstly, to study the circulation of Aichi viruses (AiV) in wastewater sampled at the scale of a pilot wastewater treatment plant; secondly, to evaluate the performance of two wastewater treatment procedures, as natural oxidizing lagoons and rotating Biodisks, concerning the AiV removal; and finally, to determine the different type of AiV genotype found during this study. Hence, the pilot wastewater treatment plant is principally irrigated by the wastewater of three neighbouring clinics. Wastewater samples were collected during 2011 from the two lines of biological treatment procedures. AiV detection in wastewater were achieved using the Reverse Transcription Polymerase Chain Reaction (RT-PCR) technique, and the identification of AiV genotype was realized by the direct sequencing of PCR products. The result revealed that AiV strains were identified in 50% (n = 51) of the wastewater samples. A significant increase of the AiV detection frequency was registered from upstream to downstream of the five ponds constituting the natural oxidizing lagoon process, and at the exit of the rotating Biodisks procedure. All detected AiV strains showed the highest nucleotide sequence identity to genotype B that has been recently observed in patients in Asia. This finding represented the first Tunisian survey that revealed and mentioned the first detection of AiV genotype B in sewage and by the same argued for a noticeable resistance or survival of this type of virus in the two lines of treatment considered. PMID- 28596125 TI - Biomarkers in Psychiatry: Between myth and clinical reality. PMID- 28596126 TI - Reaction time, processing speed and sustained attention in schizophrenia: impact on social functioning. AB - INTRODUCTION: Previous studies have linked processing speed with social cognition and functioning of patients with schizophrenia. A discriminant analysis is needed to determine the different components of this neuropsychological construct. This paper analyzes the impact of processing speed, reaction time and sustained attention on social functioning. MATERIAL AND METHODS: 98 outpatients between 18 and 65 with DSM-5 diagnosis of schizophrenia, with a period of 3 months of clinical stability, were recruited. Sociodemographic and clinical data were collected, and the following variables were measured: processing speed (Trail Making Test [TMT], symbol coding [BACS], verbal fluency), simple and elective reaction time, sustained attention, recognition of facial emotions and global functioning. RESULTS: Processing speed (measured only through the BACS), sustained attention (CPT) and elective reaction time (but not simple) were associated with functioning. Recognizing facial emotions (FEIT) correlated significantly with scores on measures of processing speed (BACS, Animals, TMT), sustained attention (CPT) and reaction time. The linear regression model showed a significant relationship between functioning, emotion recognition (P=.015) and processing speed (P=.029). CONCLUSIONS: A deficit in processing speed and facial emotion recognition are associated with worse global functioning in patients with schizophrenia. PMID- 28596127 TI - Does the environment affect suicide rates in Spain? A spatiotemporal analysis. AB - INTRODUCTION: Suicide is an important public health problem, it represents one of the major causes of unnatural death, and there are many factors that affect the risk of suicidal behaviour. The present study analyzes the temporal and spatial variations of mortality by suicide in Spain and its relationship with gross domestic product (GDP) per capita. MATERIAL AND METHODS: A retrospective study was performed, in which deaths by suicide, sex and age group in 50 Spanish provinces between 2000 and 2012 were analyzed. The annual trend of suicide mortality was assessed using Kendall's tau-b correlation coefficient. Seasonality and monthly and weekly behaviour were evaluated by performing the ANOVA test and the Bonferroni adjustment. Finally, the relationship between GDP per capita and suicide was studied. RESULTS: Between 2000 and 2012, 42,905adult people died by suicide in Spain. The annual average incidence rate was 95 suicides per million population. The regions located in the south and in the northwest of the country registered the highest per capita mortality rates. There is a decreasing trend in mortality by suicide over the period studied (CC=-.744; P=.0004) in adults over the age of 64, and a seasonal behaviour was identified with summer maximum and autumn minimum values (f=.504; P<.0001). The regions with the highest GDP per capita showed the lowest mortality by suicide (r=-.645; P<.0001) and the relationship is stronger among older age groups. CONCLUSIONS: Mortality by suicide does not follow a homogenous geographical distribution in Spain. Mortality in men was higher than in women. Over the period of study, there has been a decrease in mortality by suicide in Spain in adults over the age of 64. The seasonal cycle of suicides and the inverse relationship with GDP per capita found in this study, provide information which may be used as a tool for developing prevention and intervention strategies. PMID- 28596128 TI - Sweetpotato weevil, Cylas formicarius (Fab.) (Coleoptera: Brentidae) avoids its host plant when a virulent Metarhizium anisopliae isolate is present. AB - Metarhizium anisopliae has a wide range of coleopteran hosts, including weevils. Some susceptible insects are known to modify their behavior to prevent infection, typically detecting virulent strains by olfaction, and avoiding physical contact with sources of infection. Laboratory olfactometer assays were conducted on the sweetpotato weevil Cylas formicarius to test the hypothesis that insects would avoid a more virulent strain of M. anisopliae when presented with a strain of low virulence or an untreated control. When adult weevils were allowed to choose between paired test arenas containing sweetpotato roots and M. anisopliae isolates on agar cores, weevils avoided arenas with the highly virulent isolate QS155, showing a preference for either roots with uninoculated agar cores or cores with the low virulence isolate QS002-3. When roots or whole sweetpotato plants were inoculated with M. anisopliae, the preferences of weevils remained broadly similar; weevils were repelled by the highly virulent isolate QS155 when tested against either QS002-3 or uninoculated roots and plants, however weevils were not repelled by the low virulence isolate QS002-3 tested against uninoculated controls. When single-sex groups of weevils were tested separately in the olfactometer using uninoculated whole plants and plants treated with isolate QS155, males and females responded similarly and statistically identical preferences were found for the untreated plants. When weevils were released singly at different times of the day the response time for males was significantly shorter in the afternoon compared to the morning. Males were always significantly faster to respond to olfactory stimuli than females. Understanding factors that may lead to avoidance of virulent M. anisopliae strains by C. formicarius will be an essential part of developing an 'attract-and-infect' strategy for the management of C. formicarius. PMID- 28596129 TI - Sync to link: Endorphin-mediated synchrony effects on cooperation. AB - Behavioural synchronization has been shown to facilitate social bonding and cooperation but the mechanisms through which such effects are attained are poorly understood. In the current study, participants interacted with a pre-recorded confederate who exhibited different rates of synchrony, and we investigated three mechanisms for the effects of synchrony on likeability and trusting behaviour: self-other overlap, perceived cooperation, and opioid system activation measured via pain threshold. We show that engaging in highly synchronous behaviour activates all three mechanisms, and that these mechanisms mediate the effects of synchrony on liking and investment in a Trust Game. Specifically, self-other overlap and perceived cooperation mediated the effects of synchrony on interpersonal liking, while behavioural trust was mediated only by change in pain threshold. These results suggest that there are multiple compatible pathways through which synchrony influences social attitudes, but endogenous opioid system activation, such as beta-endorphin release, might be important in facilitating economic cooperation. PMID- 28596130 TI - Celebrating 100 years of Developmental Biology at the Hubrecht Institute. PMID- 28596131 TI - Control of anterior pituitary cell excitability by calcium-activated potassium channels. AB - In anterior pituitary endocrine cells, large (BK), small (SK) and intermediate (IK) conductance calcium activated potassium channels are key determinants in shaping cellular excitability in a cell type- and context-specific manner. Indeed, these channels are targeted by multiple signaling pathways that stimulate or inhibit cellular excitability. BK channels can, paradoxically, both promote electrical bursting as well as terminate bursting and spiking dependent upon intrinsic BK channel properties and proximity to voltage gated calcium channels in somatotrophs, lactotrophs and corticotrophs. In contrast, SK channels are predominantly activated by calcium released from intracellular IP3-sensitive calcium stores and mediate membrane hyperpolarization in cells including gonadotrophs and corticotrophs. IK channels are predominantly expressed in corticotrophs where they limit membrane excitability. A major challenge for the future is to determine the cell-type specific molecular composition of calcium activated potassium channels and how they control anterior pituitary hormone secretion as well as other calcium-dependent processes. PMID- 28596132 TI - CRUSADE Score is Superior to Platelet Function Testing for Prediction of Bleeding in Patients Following Coronary Interventions. AB - Hypothetically, diminished platelet reactivity (PR) during dual antiplatelet therapy (DAPT) should cause extra major bleeding events (MBE), although definite evidence is lacking. Multiple scores have been proposed to stratify bleeding risk, but their predictive value during DAPT is unclear. We compared the performance of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) with PR testing to predict MBE in Korean patients with acute coronary syndrome. We screened 1105, and included 903 consecutive patients who underwent coronary interventions. All patients received DAPT, while MBE were assessed by BARC scale. Admission platelet reactivity was assessed with VerifyNow Analyzer simultaneously with CRUSADE score, and MBE were collected at 1month and at 1year post stenting. There were a total of 113 (11%) MBE at 1month, and extra 41(5%) MBE at 1year. At 1month MBE prediction was superior by CRUSADE score (AUC: 0.816, 95% CI: 0.79 0.84, p<0.0001), compared to PR (AUC: 0.605, 95% CI: 0.572-0.637, p=0.0007). Moreover, CRUSADE score remains the independent predictor of MBE by multivariate analyses (OR=2.94, 95% CI: 2.18-3.96, p<0.0001). At 1year MBE also correlated, but were not significantly different between admission CRUSADE score (AUC: 0.62, 95% CI: 0.58 0.66, p=0.0183) and PR (AUC: 0.674, 95% CI: 0.63-0.71, p=0.002). We conclude that MBE are more common in real life than reported in clinical trials. CRUSADE score was superior to PR testing for predicting short term, but not 1year MBE in Korean patients undergoing percutaneous coronary intervention and treated with DAPT. PMID- 28596133 TI - Nuclear Factor I/B: A Master Regulator of Cell Differentiation with Paradoxical Roles in Cancer. AB - Emerging evidence indicates that nuclear factor I/B (NFIB), a transcription factor required for proper development and regulation of cellular differentiation in several tissues, also plays critical roles in cancer. Despite being a metastatic driver in small cell lung cancer and melanoma, it has become apparent that NFIB also exhibits tumour suppressive functions in many malignancies. The contradictory contributions of NFIB to both the inhibition and promotion of tumour development and progression, corroborates its diverse and context dependent roles in many tissues and cell types. Considering the frequent involvement of NFIB in cancer, a better understanding of its multifaceted nature may ultimately benefit the development of novel strategies for the management of a broad spectrum of malignancies. Here we discuss recent findings which bring to light NFIB as a crucial and paradoxical player in cancer. PMID- 28596135 TI - Administration of an oxytocin receptor antagonist attenuates sexual motivation in male rats. AB - In male rats, oxytocin impacts both sexual arousal and certain types of consummatory sexual behaviors. However, the role of oxytocin in the motivational aspects of sexual behavior has received limited attention. Given the role that oxytocin signaling plays in consummatory sexual behaviors, it was hypothesized that pharmacological attenuation of oxytocin signaling would reduce sexual motivation in male rats. Sexually experienced Long-Evans male rats were administered either an oxytocin receptor antagonist (L368,899 hydrochloride; 1mg/kg) or vehicle control into the intraperitoneal cavity 40min prior to placement into the center chamber of a three-chambered arena designed to assess sexual motivation. During the 20-minute test, a sexually experienced stimulus male rat and a sexually receptive stimulus female rat were separately confined to smaller chambers that were attached to the larger end chambers of the arena. However, physical contact between test and stimulus rats was prevented by perforated dividers. Immediately following the sexual motivation test, test male rats were placed with a sexually receptive female to examine consummatory sexual behaviors. Although both drug and vehicle treated rats exhibited a preference for the female, treatment with an oxytocin receptor antagonist decreased the amount of time spent with the female. There were no differences between drug and vehicle treated rats in either general activity, exploratory behaviors, the amount of time spent near the stimulus male rat, or consummatory sexual behaviors. Extending previous findings, these results indicate that oxytocin receptors are involved in sexual motivation in male rats. PMID- 28596134 TI - A Critical Role of Zinc Importer AdcABC in Group A Streptococcus-Host Interactions During Infection and Its Implications for Vaccine Development. AB - Bacterial pathogens must overcome host immune mechanisms to acquire micronutrients for successful replication and infection. Streptococcus pyogenes, also known as group A streptococcus (GAS), is a human pathogen that causes a variety of clinical manifestations, and disease prevention is hampered by lack of a human GAS vaccine. Herein, we report that the mammalian host recruits calprotectin (CP) to GAS infection sites and retards bacterial growth by zinc limitation. However, a GAS-encoded zinc importer and a nuanced zinc sensor aid bacterial defense against CP-mediated growth inhibition and contribute to GAS virulence. Immunization of mice with the extracellular component of the zinc importer confers protection against systemic GAS challenge. Together, we identified a key early stage host-GAS interaction and translated that knowledge into a novel vaccine strategy against GAS infection. Furthermore, we provided evidence that a similar struggle for zinc may occur during other streptococcal infections, which raises the possibility of a broad-spectrum prophylactic strategy against multiple streptococcal pathogens. PMID- 28596136 TI - Paclitaxel loaded phospholipid-based gel as a drug delivery system for local treatment of glioma. AB - Paclitaxel (PTX) is a chemotherapeutic agent and has been widely used in clinic against human cancer. However, it has limited application in brain tumor treatment due to the poor penetration of blood brain barrier. Local delivery system is a promising carrier of PTX in the treatment of glioma. A biodegradable phospholipid-based gel (PG) system was developed for intratumoral injection and evaluated in brain glioma-bearing mice model. PTX loaded PG was composed of phospholipid, ethanol, medium chain triglyceride, triacetin and PTX. It was prepared by a very simple method. The system was a transparent solution with good fluidity, while turned into a gel after phase-transition when ethanol diffused. Both in vitro dissolution and in vivo imaging study proved the sustained release effect of PG system. In vivo tolerability study showed a better tolerability after mice treated with PTX PG compared with free PTX. The survival time of brain glioma-bearing mice after treatment with PTX PG was significantly prolonged compared with mice treated by free PTX (P<0.05). In conclusion, this study developed a novel PG based local PTX delivery system with simple preparation method, good tolerability and high therapeutic efficacy. It has a great potential to improve the clinical management of glioma. PMID- 28596137 TI - Reshaping antibiotics through hydrophobic drug-bile acid ionic complexation enhances activity against Staphylococcus aureus biofilms. AB - The antibiotic era is on the verge of a profound change and facing a ground shaking crisis. The frequent failures of antibiotic treatments are often associated with biofilm formation, which is responsible for chronic infections, exacerbation as well as reinfection. So far, albeit the large number of valuable strategies employed to combat biofilm formation, little success has been recorded. In this work, we propose a simple approach, based on hydrophobic ionic complexation with the bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), to enhance anti-biofilm activity of well-known antibiotics, namely kanamycin (K), amikacin (A) and vancomycin (V). Activity was evaluated against Staphylococcus aureus ATCC 29213 and six methicillin-resistant clinical isolates. The formation of a 1:4 ADCA and KDCA and 1:1 VUDCA complexes was confirmed by 1HNMR, in silico molecular dynamics simulations, as well as thermal, spectrophotometric and HPLC analyses. The complexes showed higher inhibition of S. aureus growth compared to parent drugs and a concentration-independent biofilm inhibition and dispersion capacity in the order KDCA > ADCA >>VUDCA, even at concentrations ten-fold below the MIC. S. aureus growth inhibition evaluated upon treatment with bile acid-drug sequential addition and the complexes as well as the measured complex stability in solution suggest a bile acid carrier role. The complexes showed in vivo toxicity only at 10*MIC concentration on the chicken embryo chorioallantoic membrane model in the order KDCA < ADCA < VUDCA. KDCA was safe at all concentrations. Although several aspects to be addressed, this approach is promising due to its simplicity, the proved in vitro anti-biofilm activity enhancement and tolerability. A potential pulmonary drug delivery application is envisaged. PMID- 28596138 TI - Preparation, characterization, and cytotoxicity studies of niclosamide loaded mesoporous drug delivery systems. AB - Recent reports on the anticancer potential of niclosamide have opened new avenues for anticancer treatment. Niclosamide belongs to the BCS class II, which is indicative of poor solubility and dissolution rate limited absorption. The aim of this study was to improve the dissolution rate of the drug by mesoporous drug delivery system. Porous silica grades (ordered and nonordered) with different pore size, pore volume and surface area were used in the study. The drug was loaded on silica carriers by the solvent evaporation method and characterized by BET surface area analysis, SEM, P-XRD, DSC, and FTIR. A discriminatory dissolution medium was developed for performing the in vitro dissolution of niclosamide. In comparison to the plain drug, all silica based formulations showed improvement in the dissolution rate. Maximum enhancement in the dissolution rate was observed in 1:2 drug:carrier loading ratio when compared to 1:1 ratio. Different properties of mesoporous silica like structural geometry, pore size and microenvironment pH demonstrated a significant impact on drug release from the formulations. Cytotoxicity of the optimized mesoporous formulations of niclosamide was explored in HCT-116, HCT-15, NCI, MDA-MB-231 and A549 cancer cell lines. Nearly 3 fold and 2 fold increase in% cytotoxicity of drug loaded Syloid-244 and Sylysia 350 at 1:2 ratio respectively, were observed when compared to the plain drug. PMID- 28596139 TI - Effects of cyclodextrins on the chemical stability of drugs. AB - Cyclodextrins (CDs) are enabling pharmaceutical excipients that can enhance both solubility and stability of wide variety of drugs in aqueous solutions through formation of drug/CD inclusion complexes where apolar moieties of the drug molecules are located inside the CD cavity. In properly designed pharmaceutical formulations CDs will improve physiochemical properties of lipophilic drugs without affecting their intrinsic ability to permeate biological membranes. Here the effect of CD complexes on the chemical stability of drugs is reviewed. Numerous studies shown that in aqueous solutions CD complexation can hamper hydrolysis, oxidation, photodegradation, isomerization and enzyme catalyzed degradation of dissolved drugs. However, some drugs, such as beta-lactam antibiotics, can under certain conditions undergo CD catalyzed degradation in aqueous solutions. Also, some drugs that are stabilized by CDs in aqueous solutions are destabilized by the same CDs in solid dosage forms. Thus, the effects of CDs on drug stability have to be tested and verified in the final drug formulation and under the recommended storage conditions. PMID- 28596140 TI - Formation, characterization and pH dependence of rifampicin: heptakis(2,6-di-O methyl)-beta-cyclodextrin complexes. AB - Rifampicin (Rif) is a broad spectrum antibiotic used as a first line agent in the treatment of mycobacterial infections. However, its low solubility and reduced stability in water limit its bioavailability, thus requiring the use of complex formulations. Here, we present a systematic study of Rif in complex with a methylated cyclodextrin, heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB), in phosphate buffer using a combination of nuclear magnetic resonance (NMR) and steady-state UV-vis spectroscopic methods. An increase in the stability and solubility of Rif in complex with DIMEB was observed in buffered solutions (phosphate, PBS). At neutral pH the presence of three distinguishable binding sites was revealed, demonstrating that DIMEB forms predominantly a stable 1:1 (K~3000M-1) complex at the piperazine site of Rif, while at acidic pH the binding constant decreases significantly (K~400M-1) due to protonation of the piperazine, thus inducing a release of Rif. The reported results provide new and relevant information for the stability and solubility of Rif in aqueous solution when forming a complex with DIMEB. Furthermore they contribute to clarify Rif interactions with cyclodextrin carriers, thus providing the basis for the development of new methylated cyclodextrin that can efficiently encapsulate and deliver Rif and derivatives of its family. PMID- 28596141 TI - Delivery of cyclodextrin polymers to bacterial biofilms - An exploratory study using rhodamine labelled cyclodextrins and multiphoton microscopy. AB - Cyclodextrin (CD) polymers are interesting nanoparticulate systems for pharmaceutical delivery; however, knowledge regarding their applications towards delivery into complex microbial biofilm structures is so far limited. The challenge is to demonstrate penetration and transport through the biofilm and its exopolysaccharide matrix. The ideal functionalization for penetration into mature biofilms is unexplored. In this paper, we present a novel set of rhodamine labelled betaCD-polymers, with different charge moieties, i.e., neutral, anionic, and cationic, and explore their potential delivery into mature Staphylococcus epidermidis biofilms using multiphoton laser scanning microscopy (MPM). The S. epidermidis biofilms, being a medically relevant model organism, were stained with SYTO9. By using MPM, three-dimensional imaging and spectral investigation of the distribution of the betaCD-polymers could be obtained. It was found that the cationic betaCD-polymers showed significantly higher integration into the biofilms, compared to neutral and anionic functionalized betaCDs. None of the carriers presented any inherent toxicity to the biofilms, meaning that the addition of rhodamine moiety does not affect the inertness of the delivery system. Taken together, this study demonstrates a novel approach by which delivery of fluorescently labelled CD nanoparticles to bacterial biofilms can be explored using MPM. Future studies should be undertaken investigating the potential in using cationic functionalization of CD based delivery systems for targeting anti-microbial effects in biofilms. PMID- 28596142 TI - Amphiphilic cyclodextrin nanoparticles. AB - Cyclodextrins are cyclic oligosaccharides obtained by enzymatic digestion of starch. The alpha-, beta- and gamma- cyclodextrins contain respectively 6, 7 and 8 glucopyranose units, with primary and secondary hydroxyl groups located on the narrow and wider rims of a truncated cone shape structure. Such structure is that of a hydrophobic inner cavity with a hydrophilic outer surface allowing to interact with a wide range of molecules like ions, protein and oligonucleotides to form inclusion complexes. Many cyclodextrin applications in the pharmaceutical area have been widely described in the literature due to their low toxicity and low immunogenicity. The most important is to increase the solubility of hydrophobic drugs in water. Chemically modified cyclodextrin derivatives have been synthesized to enhance their properties and more specifically their pharmacological activity. Among these, amphiphilic derivatives were designed to build organized molecular structures, through selfassembling systems or by incorporation in lipid membranes, expected to improve the vectorization in the organism of the drug-containing cyclodextrin cavities. These derivatives can form a variety of supramolecular structures such as micelles, vesicles and nanoparticles. The purpose of this review is to summarize applications of amphiphilic cyclodextrins in different areas of drug delivery, particularly in protein and peptide drug delivery and gene delivery. The article highlights important amphiphilic cyclodextrin applications in the design of novel delivery systems like nanoparticles. PMID- 28596143 TI - Towards quality assessed characterization of nanomaterial: Transfer of validated protocols for size measurement by dynamic light scattering and evaluation of zeta potential by electrophoretic light scattering. AB - Quality control analysis of nanomaterials has been identified as a major issue to pursue their development in different industrial fields including nanomedicine. One difficulty is the lack of standardized and validated protocols suitable to achieve their characterization. In a previous work, we have developed standardized protocols for the evaluation of the size and zeta potential of nanomaterials based on methods described in the ISO standard and have performed validation of each one. The present work was aimed to transfer these protocols in three independent receiving laboratories. No official guideline was described in the literature to achieve such a transfer. A comparative study for receiving laboratories equipped with the same instrument as the sending laboratory was designed based on the Code of Federal Regulation edited by the Food and Drug Administration. For the receiving laboratory equipped with an instrument working at a different wavelength, a new validation was designed and applied. Corresponding statistical methods were used for the analysis of the results. A successful transfer of the protocols in all receiving laboratories was achieved. All laboratories recorded consistent results applying in blind the protocol of size measurements on two samples of nanomaterials from which included one reference. PMID- 28596144 TI - Serum protein expression profiling and bioinformatics analysis in workers occupationally exposed to chromium (VI). AB - Cr(VI) is widely-recognized as occupational and environmental contaminant, but the precise underlying mechanisms of Cr(VI) induced carcinogenic toxicity remain to be elucidated. Among kinds of toxic mechanisms, alteration of protein profiling usually elaborate a key mechanism of Cr(VI) induced toxicity and carcinogenesis. Large-scale proteins changes can reflect the onset or progression of carcinogenic toxicity, and potential serum protein biomarkers of Cr(VI) exposure. To gain an insight into the serum proteins expression profiling in chromate workers and find potential novel serum proteins biomarkers of Cr(VI) exposure, 107 male participants from a chromate production plant were recruited into the study. Questionnaire was applied to collect personal information and occupational history. Chromium concentration in blood (CrB) was measured to evaluate the participants' internal exposure. Serum proteins profiling and bioinformatics analysis were performed to explore differentially expressed proteins, proteins-chemical interaction network, critical proteins nodes related to the signaling pathways among 16 controls and 25 exposure workers in the first stage. ELISA tests were applied to verify the critical interested proteins nodes in the remaining 41 exposure workers and 25 controls. The results showed that the CrB levels in the control group were significantly lower than that in the exposure group (P<0.05). 44 significantly differentially expressed serum proteins formed 16 significant signaling pathways and a complex proteins-chemical interaction network, which associated with the immune system and extracellular matrix organization. C reactive protein (CRP), sonic hedgehog protein (SHH) and calcium located at critical nodes in proteins-chemical interaction network. There was a significant negative correlation between serum CRP level and CrB (P<0.05), and a significant positive correlation between SHH concentrations and CrB (P<0.05), which indicated that CRP and SHH might be as the potential novel biomarkers of Cr(VI) exposure. Also, the current study preliminarily paved the way to further functional studies to understand the underlying mechanisms and novel serum biomarkers of Cr(VI) exposure. PMID- 28596145 TI - Supporting Homework Compliance in Cognitive Behavioural Therapy: Essential Features of Mobile Apps. AB - Cognitive behavioral therapy (CBT) is one of the most effective psychotherapy modalities used to treat depression and anxiety disorders. Homework is an integral component of CBT, but homework compliance in CBT remains problematic in real-life practice. The popularization of the mobile phone with app capabilities (smartphone) presents a unique opportunity to enhance CBT homework compliance; however, there are no guidelines for designing mobile phone apps created for this purpose. Existing literature suggests 6 essential features of an optimal mobile app for maximizing CBT homework compliance: (1) therapy congruency, (2) fostering learning, (3) guiding therapy, (4) connection building, (5) emphasis on completion, and (6) population specificity. We expect that a well-designed mobile app incorporating these features should result in improved homework compliance and better outcomes for its users. PMID- 28596146 TI - The Role of Web-Based Health Information in Help-Seeking Behavior Prior to a Diagnosis of Lung Cancer: A Mixed-Methods Study. AB - BACKGROUND: Delays to diagnosis in lung cancer can lead to reduced chance of survival, and patients often wait for several months before presenting symptoms. The time between first symptom recognition until diagnosis has been theorized into three intervals: symptom appraisal, help-seeking, and diagnostic interval (here: "pathway to diagnosis"). Interventions are needed to reduce delays to diagnosis in lung cancer. The Web has become an important lay health information source and could potentially play a role in this pathway to diagnosis. OBJECTIVE: Our overall aim was to gain a preliminary insight into whether Web-based information plays a role in the pathway to diagnosis in lung cancer in order to assess whether it may be possible to leverage this information source to reduce delays to diagnosis. METHODS: Patients diagnosed with lung cancer in the 6 months before study entry completed a survey about whether (and how, if yes) they had used the Web to appraise their condition prior to diagnosis. Based on survey responses, we purposively sampled patients and their next-of-kin for semistructured interviews (24 interviews; 33 participants). Interview data were analyzed qualitatively using Framework Analysis in the context of the pathway to diagnosis model. RESULTS: A total of 113 patients completed the survey (age: mean 67.0, SD 8.8 years). In all, 20.4% (23/113) reported they or next-of-kin had researched their condition online before the diagnosis. The majority of searches (20/23, 87.0%) were conducted by or with the help of next-of-kin. Interview results suggest that patients and next-of-kin perceived an impact of the information found online on all three intervals in the time to diagnosis. In the appraisal interval, participants used online information to evaluate symptoms and possible causes. In the help-seeking interval, the Web was used to inform the decision of whether to present to health services. In the diagnostic interval, it was used to evaluate health care professionals' advice, to support requests for further investigation of symptoms, and to understand medical jargon. Within this interval, we identified two distinct subintervals (before/after relevant diagnostic tests were initiated), in which the Web reportedly played different roles. CONCLUSIONS: Because only 20.4% of the sample reported prediagnosis Web searches, it seems the role of the Web before diagnosis of lung cancer is at present still limited, but this proportion is likely to increase in the future, when barriers such as unfamiliarity with technology and unwillingness to be informed about one's own health are likely to decrease. Participants' perceptions suggest that the Web can have an impact on all three intervals in the pathway to diagnosis. Thus, the Web may hold the potential to reduce delays in the diagnostic process, and this should be explored in future research and interventions. Our results also suggest a division of the diagnostic interval into two subintervals may be useful. PMID- 28596147 TI - A Mobile Phone-Based Health Coaching Intervention for Weight Loss and Blood Pressure Reduction in a National Payer Population: A Retrospective Study. AB - BACKGROUND: The prevalence of obesity and associated metabolic conditions continue to be challenging and costly to address for health care systems; 71% of American adults were overweight, with 35% of men and 40% of women diagnosed with obesity in 2014. Digital health coaching is an innovative approach to decreasing the barriers of cost and accessibility of receiving health coaching for the prevention and management of chronic disease in overweight or obese individuals. OBJECTIVE: To evaluate the early impact of a mobile phone-based health coaching service on weight loss and blood pressure management in a commercially insured population. METHODS: This was a retrospective study using existing registry data from a pilot commercial collaboration between Vida Health and a large national insurance provider, which enrolled adult members who were overweight (body mass index >25 kg/m2) and able to engage in a mobile phone-based coaching intervention. Participants received 4 months of intensive health coaching via live video, phone, and text message through the Vida Health app. Participants were also provided with a wireless scale, pedometer, and blood pressure cuff. Of the 1012 enrolled, 763 (75.40%) participants had an initial weight upon enrollment and final weight between 3 and 5 months from enrollment; they served as our intervention group. There were 73 participants out of the 1012 (7.21%) who had weight data 4 months prior to and after Vida coaching, who served as the matched-pair control group. RESULTS: Participants in the intervention group lost an average of 3.23% total body weight (TBW) at 4 months of coaching and 28.6% (218/763) intervention participants achieved a clinically significant weight loss of 5% or more of TBW, with an average of 9.46% weight loss in this cohort. In the matched-pair control group, participants gained on average 1.81% TBW in 4 months without Vida coaching and lost, on average, 2.47% TBW after 4 months of Vida coaching, demonstrating a statistically significant difference of 4.28% in mean percentage weight change (P<.001). Among 151 intervention participants with blood pressure data, 112 (74.2%) had a baseline blood pressure that was above the goal (systolic blood pressure >120 mmHg); 55 out of 112 (49.1%) participants improved their blood pressure at 4 months by an entire hypertensive stage-as defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. CONCLUSIONS: Mobile phone app based health coaching interventions can be an acceptable and effective means to promote weight loss and improve blood pressure management in overweight or obese individuals. Given the ubiquity of mobile phones, digital health coaching may be an innovative solution to decreasing barriers of access to much-needed weight management interventions for obesity. PMID- 28596148 TI - The Second Victim Phenomenon After a Clinical Error: The Design and Evaluation of a Website to Reduce Caregivers' Emotional Responses After a Clinical Error. AB - BACKGROUND: Adverse events (incidents that harm a patient) can also produce emotional hardship for the professionals involved (second victims). Although a few international pioneering programs exist that aim to facilitate the recovery of the second victim, there are no known initiatives that aim to raise awareness in the professional community about this issue and prevent the situation from worsening. OBJECTIVE: The aim of this study was to design and evaluate an online program directed at frontline hospital and primary care health professionals that raises awareness and provides information about the second victim phenomenon. METHODS: The design of the Mitigating Impact in Second Victims (MISE) online program was based on a literature review, and its contents were selected by a group of 15 experts on patient safety with experience in both clinical and academic settings. The website hosting MISE was subjected to an accreditation process by an external quality agency that specializes in evaluating health websites. The MISE structure and content were evaluated by 26 patient safety managers at hospitals and within primary care in addition to 266 frontline health care professionals who followed the program, taking into account its comprehension, usefulness of the information, and general adequacy. Finally, the amount of knowledge gained from the program was assessed with three objective measures (pre- and posttest design). RESULTS: The website earned Advanced Accreditation for health websites after fulfilling required standards. The comprehension and practical value of the MISE content were positively assessed by 88% (23/26) and 92% (24/26) of patient safety managers, respectively. MISE was positively evaluated by health care professionals, who awarded it 8.8 points out of a maximum 10. Users who finished MISE improved their knowledge on patient safety terminology, prevalence and impact of adverse events and clinical errors, second victim support models, and recommended actions following a severe adverse event (P<.001). CONCLUSIONS: The MISE program differs from existing intervention initiatives by its preventive nature in relation to the second victim phenomenon. Its online nature makes it an easily accessible tool for the professional community. This program has shown to increase user's knowledge on this issue and it helps them correct their approach. Furthermore, it is one of the first initiatives to attempt to bring the second victim phenomenon closer to primary care. PMID- 28596149 TI - Measuring Audience Engagement for Public Health Twitter Chats: Insights From #LiveFitNOLA. AB - BACKGROUND: Little empirical evidence exists on the effectiveness of using Twitter as a two-way communication tool for public health practice, such as Twitter chats. OBJECTIVE: We analyzed whether Twitter chats facilitate engagement in two-way communications between public health entities and their audience. We also describe how to measure two-way communications, incoming and outgoing mentions, between users in a protocol using free and publicly available tools (Symplur, OpenRefine, and Gephi). METHODS: We used a mixed-methods approach, social network analysis, and content analysis. The study population comprised individuals and organizations participating or who were mentioned in the first #LiveFitNOLA chat, during a 75-min period on March 5, 2015, from 12:00 PM to 1:15 PM Central Time. We assessed audience engagement in two-way communications with two metrics: engagement ratio and return on engagement (ROE). RESULTS: The #LiveFitNOLA chat had 744 tweets and 66 participants with an average of 11 tweets per participant. The resulting network had 134 network members and 474 engagements. The engagement ratios and ROEs for the #LiveFitNOLA organizers were 1:1, 40% (13/32) (@TulanePRC) and 2:1, -40% (-25/63) (@FitNOLA). Content analysis showed information sharing (63.9%, 314/491) and health information (27.9%, 137/491) as the most salient theme and sub-theme, respectively. CONCLUSIONS: Our findings suggest Twitter chats facilitate audience engagement in two-way communications between public health entities and their audience. The #LiveFitNOLA organizers' engagement ratios and ROEs indicated a moderate level of engagement with their audience. The practical significance of the engagement ratio and ROE depends on the audience, context, scope, scale, and goal of a Twitter chat or other organized hashtag-based communications on Twitter. PMID- 28596150 TI - Pain Improvement With Novel Combination Analgesic Regimens (PAIN-CARE): Randomized Controlled Trial Protocol. AB - BACKGROUND: Neuropathic pain (NP) (including painful diabetic neuropathy, postherpetic neuralgia, etc) affects approximately 7% to 8% of the population and is associated with a devastating symptom burden as well as a profound economic impact for patients, their families, and the health care system. Current therapies have limited efficacy and dose-limiting adverse effects (AEs). Rational combination therapy with carefully selected NP drugs has shown potential for measurable improvements in pain relief, quality of life, and health care use. Today, over half of NP patients concurrently receive 2 or more analgesics but combination use is based on little evidence. Research is urgently needed to identify safer, more effective combinations. OBJECTIVE: We hypothesize that analgesic combinations containing at least 1 nonsedating agent would be as safe but more effective than either monotherapy without increasing overall AEs because of additive pain relief. Pregabalin (PGB), a sedating anticonvulsant, is proven effective for NP; the antioxidant alpha-lipoic acid (ALA) is one of the only nonsedating systemic agents proven effective for NP. Thus, we will conduct a clinical trial to compare a PGB+ALA combination to each monotherapy for NP. METHODS: Using a double-blind, double-dummy, crossover design, 54 adults with NP will be randomly allocated to 1 of 6 sequences of treatment with PGB, ALA and PGB+ALA combination. During each of 3 different treatment periods, participants will take 2 sets of capsules containing (1) ALA or placebo and (2) PGB or placebo for 31 days, followed by an 11-day taper/washout period. The primary outcome will be mean daily pain intensity (0-10) at maximally tolerated dose (MTD) during each period. Secondary outcomes, assessed at MTD, will include global improvement, adverse events, mood, and quality of life. RESULTS: Participant recruitment is expected to begin September 1, 2017. The proposed trial was awarded external peer reviewed funding by the Canadian Institutes of Health Research (Canada) on July 15, 2016. CONCLUSIONS: This trial will provide rigorous evidence comparing the efficacy of a PGB+ALA combination to PGB alone and ALA alone in the treatment of NP. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN14577546; http://www.isrctn.com/ISRCTN14577546?q=&filters=conditionCategory:Signs%20and%20S mptoms,trialStatus: Ongoing,recruitmentCountry:Canada&sort=&offset=1&totalResults=2&page=1&pageSize=1 &searchType=basic-search (Archived by WebCite at http://www.webcitation.org/6qvHFDc6m). PMID- 28596151 TI - Survey on advance care planning of Italian outpatients on chronic haemodialysis. AB - OBJECTIVES: The clinical practice guidelines published by the Renal Physicians Association (USA) recommend instituting advance care planning (ACP) for patients with end-stage renal disease. Studies on this issue are lacking in Italy. Our aim was to determine the attitudes of patients on ACP in our dialysis centre. METHODS: We performed a cross-sectional survey. We recruited patients on maintenance haemodialysis (HD) at Hemodialysis Center of Universita Cattolica del Sacro Cuore, from 1 March 2014 to 31 March 2015. The only exclusion criterion was inability to give an informed consent. Patients completed a questionnaire concerning their treatment preferences in three hypothetical disease scenarios: persistent vegetative state, advanced dementia, severe terminal illness; for each patients, we also collected clinical, functional and socioeconomic data. RESULTS: Thirty-four HD outpatients completed the study questionnaire. The majority of respondents (85%) considered information about prognosis, health conditions and treatment options, including withdrawing dialysis, as very important and 94% of respondents considered treatment of uraemic/dialytic symptoms the most important issue. In the health scenarios provided, dialysis was the treatment least withheld. Dependence on instrumental activities of daily living (0.048) and higher Charlson Comorbidity Index scores (p=0.035) were associated with continuing dialysis in at least one scenario. CONCLUSIONS: ACP should be tailored to patients' value, culture and preferences. A significant proportion of patients, however, do not want to be involved in end of life decisions. Frail elderly patients, in particular, are not inclined to interrupt dialysis, despite poor quality of life or a poor prognosis. PMID- 28596152 TI - Bullous pemphigoid and pemphigus vulgaris. PMID- 28596153 TI - Immunohistochemistry on old archival paraffin blocks: is there an expiry date? AB - Few studies have focused on antigen preservation in formalin-fixed and paraffin embedded (FFPE) tissue in old archival material and additional studies are required, especially considering that these samples are an irreplaceable resource for scientific and clinical research. The purpose of this study is to verify antigen preservation in FFPE tissue samples stored for several decades. From the pathology archives, FFPE blocks were selected dating back to the 1960s, 1970s, 1980s, 1990s, 2000s and 2010. A panel of 12 antibodies was applied and immunoreactivities were compared. While cytoplasmic antigens showed no reduction in immunostaining intensity over time, membrane and nuclear antigens presented reduced staining intensity in older blocks. In particular, the nuclear antigen, Ki67 and CD31 showed the most pronounced antigen decay in the oldest archival blocks. In order to test possible antigen recovery, deep sectioning and lengthening of heat pretreatment were applied. Both strategies partially recover antigenicity, but their simultaneous application shows the best results. PMID- 28596154 TI - 3D printed pathological sectioning boxes to facilitate radiological-pathological correlation in hepatectomy cases. AB - Radiogenomics promises to identify tumour imaging features indicative of genomic or proteomic aberrations that can be therapeutically targeted allowing precision personalised therapy. An accurate radiological-pathological correlation is critical to the process of radiogenomic characterisation of tumours. An accurate correlation, however, is difficult to achieve with current pathological sectioning techniques which result in sectioning in non-standard planes. The purpose of this work is to present a technique to standardise hepatic sectioning to facilitateradiological-pathological correlation. We describe a process in which three-dimensional (3D)-printed specimen boxes based on preoperative cross sectional imaging (CT and MRI) can be used to facilitate pathological sectioning in standard planes immediately on hepatic resection enabling improved tumour mapping. We have applied this process in 13 patients undergoing hepatectomy and have observed close correlation between imaging and gross pathology in patients with both unifocal and multifocal tumours. PMID- 28596155 TI - Better research flattens the J shaped curve. PMID- 28596156 TI - Noninvasive Interrogation of Cancer Metabolism with Hyperpolarized 13C MRI. AB - This review will highlight recent advances in hyperpolarized 13C MR spectroscopic imaging, which can be used to noninvasively interrogate tumor metabolism. After providing an overview of MR and hyperpolarization, we will discuss the latest advances in data acquisition techniques. Next, we will shift our focus to hyperpolarized probe design and provide an overview of the latest hyperpolarized 13C MR spectroscopic imaging probes developed in the last several years. PMID- 28596157 TI - 18F-FDG PET and CT Scans Detect New Imaging Patterns of Response and Progression in Patients with Hodgkin Lymphoma Treated by Anti-Programmed Death 1 Immune Checkpoint Inhibitor. AB - The response evaluation criteria in patients with Hodgkin lymphoma (HL) were designed for the assessment of chemotherapy and targeted molecular agents. We investigated the accuracy of 3-mo 18F-FDG PET/CT for the identification of HL patients responding to immune-checkpoint blockade by anti-programmed death 1 antibodies (anti-PD1). We also reported the frequency of new immune patterns of response and progression. Methods: Retrospectively, we recruited consecutive HL patients treated by anti-PD1 (pembrolizumab or nivolumab) at Gustave Roussy from 2013 to 2015. 18F-FDG PET/CT and contrast-enhanced CT scans were acquired every 3 mo. We recorded the best overall response according to the International Harmonization Project Cheson 2014 criteria and LYmphoma Response to Immunomodulatory therapy Criteria (LYRIC) (2016 revised criteria). Patients achieving an objective response at any time during the anti-PD1 treatment were classified as responders. Results: Sixteen relapsed or refractory classic HL patients were included. The median age was 39 y (age range, 19-69 y). The median previous lines of therapy was 6 (range, 3-13). The mean follow-up was 22.6 mo. Nine of 16 patients (56%) achieved an objective response. Two deaths occurred due to progressive disease at 7 mo. 18F-FDG PET/CT detected all responders at 3 mo and reclassified best overall response in 5 patients compared with CT alone. A decrease in tumor metabolism and volume (SUVmean, metabolic tumor volume) and increase in healthy splenic metabolism at 3 mo were observed in responders (area under the curve > 0.85, P < 0.04). Five of 16 patients (31%) displayed new imaging patterns related to anti-PD1; we observed 2 transient progressions consistent with indeterminate response according to the LYRIC (2016) (IR2b at 14 mo and IR3 at 18 mo) and 3 patients with new lesions associated with immune related adverse events. Conclusion: Three-month 18F-FDG PET/CT scans detected HL patients responding to anti-PD1. New patterns were encountered in 31% of patients, emphasizing the need for further evaluation in larger series and close collaboration between imaging and oncology specialists on a per-patient basis. PMID- 28596158 TI - Molecular Imaging of Human Embryonic Stem Cells Stably Expressing Human PET Reporter Genes After Zinc Finger Nuclease-Mediated Genome Editing. AB - Molecular imaging is indispensable for determining the fate and persistence of engrafted stem cells. Standard strategies for transgene induction involve the use of viral vectors prone to silencing and insertional mutagenesis or the use of nonhuman genes. Methods: We used zinc finger nucleases to induce stable expression of human imaging reporter genes into the safe-harbor locus adeno associated virus integration site 1 in human embryonic stem cells. Plasmids were generated carrying reporter genes for fluorescence, bioluminescence imaging, and human PET reporter genes. Results: In vitro assays confirmed their functionality, and embryonic stem cells retained differentiation capacity. Teratoma formation assays were performed, and tumors were imaged over time with PET and bioluminescence imaging. Conclusion: This study demonstrates the application of genome editing for targeted integration of human imaging reporter genes in human embryonic stem cells for long-term molecular imaging. PMID- 28596159 TI - In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study. AB - Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18F-fluoromisonidazole (18F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (18F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization. PMID- 28596161 TI - Five minutes with . . . Lynne Jones. PMID- 28596163 TI - Meet the First Authors. PMID- 28596160 TI - Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. AB - We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin-angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5+/-1.3 to 7.5%+/-1.0%, 82.5+/-20.2 to 80.6+/-20.9 kg, 143+/-8 to 128+/-14 mm Hg, 78+/-10 to 67+/-9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6+/-58.9 to 29.2+/-60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin-angiotensin system in patients with type 2 diabetes. PMID- 28596164 TI - CASAAV Technology to Examine Regulators of Heart Failure: Cause or Effect. PMID- 28596165 TI - Aging, Smooth Muscle Vitality, and Aortic Integrity. PMID- 28596166 TI - I'll Have the Rigor, but Hold the Mortis. PMID- 28596168 TI - Myocardial Injury as a New Target for Cell Therapy in Patients With Chronic Heart Failure: When Something Bad Is Actually Good? PMID- 28596167 TI - Psychosocial Factors and Cardiovascular Disease Risk: An Opportunity in Women's Health. PMID- 28596169 TI - I'll Take My Science Spicy, Please. PMID- 28596170 TI - John Canty Jr: A Full Life, Both at Home and in the Lab. PMID- 28596171 TI - Amyloid Cardiomyopathy: Disease on the Rise. PMID- 28596172 TI - Stem Cell Therapy: Healing or Hype? Why Stem Cell Delivery Doesn't Work. PMID- 28596173 TI - Forging the Fate of Cellular Therapies for Cardiovascular Disease. PMID- 28596174 TI - Induced Pluripotent Stem Cells 10 Years Later: For Cardiac Applications. AB - Induced pluripotent stem cells (iPSCs) are reprogrammed cells that have features similar to embryonic stem cells, such as the capacity of self-renewal and differentiation into many types of cells, including cardiac myocytes. Although initially the reprogramming efficiency was low, several improvements in reprogramming methods have achieved robust and efficient generation of iPSCs without genomic insertion of transgenes. iPSCs display clonal variations in epigenetic and genomic profiles and cellular behavior in differentiation. iPSC derived cardiac myocytes (iPSC cardiac myocytes) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models, and are useful for drug discovery and toxicology testing. In addition, iPSC cardiac myocytes can help with patient stratification in regard to drug responsiveness. Furthermore, they can be used as source cells for cardiac regeneration in animal models. Here, we review recent progress in iPSC technology and its applications to cardiac diseases. PMID- 28596176 TI - Letter by Balligand and Michel Regarding Article, "Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent". PMID- 28596177 TI - Response by Simpson et al to Letter Regarding Article, "Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent". PMID- 28596178 TI - Circulation Research "In This Issue" Anthology. PMID- 28596179 TI - A young goalkeeper with buttock pain and fever. PMID- 28596180 TI - The non-combatant status: importance and implications for medical personnel. AB - Under the laws of armed conflict military medics are deemed non-combatants, and as such are subject to certain protections and limitations. The non-combatant status is defined in the famous Geneva Conventions, which form the basis of the international law of armed conflict. The protections afforded to medical personnel in armed conflict are a result of the need to protect and treat the sick and injured during times of hostility. This paper describes the history and legal development of the non-combatant status, and summarises the importance and implications of the contents of the Geneva Conventions that are relevant to medical personnel as non-combatants. We conclude that, despite scope for criticism of its relevance in contemporary operations, the non-combatant status for medical personnel highlights our commitment to alleviating suffering in armed conflict, and provides a vital legal basis to protect those who serve to treat the sick and injured. The ultimate beneficiaries of this protected status for medical personnel are our patients themselves. This paper also aims to stimulate debate and discussion of the importance of the non-status amongst military medical personnel. PMID- 28596181 TI - Evolution of poor reporting and inadequate methods over time in 20 920 randomised controlled trials included in Cochrane reviews: research on research study. AB - Objective To examine how poor reporting and inadequate methods for key methodological features in randomised controlled trials (RCTs) have changed over the past three decades.Design Mapping of trials included in Cochrane reviews.Data sources Data from RCTs included in all Cochrane reviews published between March 2011 and September 2014 reporting an evaluation of the Cochrane risk of bias items: sequence generation, allocation concealment, blinding, and incomplete outcome data.Data extraction For each RCT, we extracted consensus on risk of bias made by the review authors and identified the primary reference to extract publication year and journal. We matched journal names with Journal Citation Reports to get 2014 impact factors.Main outcomes measures We considered the proportions of trials rated by review authors at unclear and high risk of bias as surrogates for poor reporting and inadequate methods, respectively.Results We analysed 20 920 RCTs (from 2001 reviews) published in 3136 journals. The proportion of trials with unclear risk of bias was 48.7% for sequence generation and 57.5% for allocation concealment; the proportion of those with high risk of bias was 4.0% and 7.2%, respectively. For blinding and incomplete outcome data, 30.6% and 24.7% of trials were at unclear risk and 33.1% and 17.1% were at high risk, respectively. Higher journal impact factor was associated with a lower proportion of trials at unclear or high risk of bias. The proportion of trials at unclear risk of bias decreased over time, especially for sequence generation, which fell from 69.1% in 1986-1990 to 31.2% in 2011-14 and for allocation concealment (70.1% to 44.6%). After excluding trials at unclear risk of bias, use of inadequate methods also decreased over time: from 14.8% to 4.6% for sequence generation and from 32.7% to 11.6% for allocation concealment.Conclusions Poor reporting and inadequate methods have decreased over time, especially for sequence generation and allocation concealment. But more could be done, especially in lower impact factor journals. PMID- 28596182 TI - Toward uniform standards for pharmacy technicians: Summary of the 2017 Pharmacy Technician Stakeholder Consensus Conference. PMID- 28596184 TI - Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. PMID- 28596185 TI - Response to: Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis by Kremer and Weinblatt. PMID- 28596183 TI - Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D. AB - Food intake induces synthesis of N-acylphosphatidylethanolamines (NAPEs) in the intestinal tract. While NAPEs exert leptin-like (leptogenic) effects, including reduced weight gain and food intake, the mechanisms by which NAPEs induce these leptogenic effects remain unclear. One key question is whether intestinal NAPEs act directly on cognate receptors or first require conversion to N acylethanolamides (NAEs) by NAPE-hydrolyzing phospholipase D (NAPE-PLD). Previous studies using Nape-pld-/- mice were equivocal because intraperitoneal injection of NAPEs led to nonspecific aversive effects. To avoid the aversive effects of injection, we delivered NAPEs and NAEs intestinally using gut bacteria synthesizing these compounds. Unlike in wild-type mice, increasing intestinal levels of NAPE using NAPE-synthesizing bacteria in Nape-pld-/- mice failed to reduce food intake and weight gain or alter gene expression. In contrast, increasing intestinal NAE levels in Nape-pld-/- mice using NAE-synthesizing bacteria induced all of these effects. These NAE-synthesizing bacteria also markedly increased NAE levels and decreased inflammatory gene expression in omental adipose tissue. These results demonstrate that intestinal NAPEs require conversion to NAEs by the action of NAPE-PLD to exert their various leptogenic effects, so that the reduced intestinal NAPE-PLD activity found in obese subjects may directly contribute to excess food intake and obesity. PMID- 28596175 TI - Calcium Signaling and Cardiac Arrhythmias. AB - There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndromes, including catecholaminergic polymorphic ventricular tachycardia, congenital long QT syndrome, and hypertrophic cardiomyopathy. In addition, acquired deficits of multiple Ca2+-handling proteins can contribute to the pathogenesis of arrhythmias in patients with various types of heart disease. In this review article, we will first review the key role of Ca2+ in normal cardiac function-in particular, excitation-contraction coupling and normal electric rhythms. The functional involvement of Ca2+ in distinct arrhythmia mechanisms will be discussed, followed by various inherited arrhythmia syndromes caused by mutations in Ca2+-handling proteins. Finally, we will discuss how changes in the expression of regulation of Ca2+ channels and transporters can cause acquired arrhythmias, and how these mechanisms might be targeted for therapeutic purposes. PMID- 28596186 TI - Hepatitis B virus testing and linkage to care in a Canadian urban tertiary referral centre: a retrospective cohort study. AB - BACKGROUND: Despite universal vaccination, chronic hepatitis B virus (HBV) infection remains a public health concern in North America owing to immigration. We aimed to characterize the number of people with a positive result of testing for HBV surface antigen (HBsAg) in Calgary, a large urban Canadian health care region, and to assess whether recommended laboratory tests and specialist consultation were done for those identified as HBsAg-positive. METHODS: Based on laboratory and Alberta Health Services administrative data, we identified all adults (age > 18 yr) with a positive HBsAg test result from Jan. 1 to Dec. 31, 2014 within the Calgary Zone. Demographic and relevant laboratory data were extracted within 6 months of a positive HBsAg test result, and referral to hepatology (2011-2014) was identified from data on referral to a centralized clinic. Parametric and nonparametric statistical methods were used for analyses. RESULTS: We identified 1214 HBsAg-positive people (584 women [48.1%]; median age 44 [interquartile range (IQR) 36-55] yr). A total of 1192 people (98.2%) had alanine aminotransferase testing (median level 23 [IQR 16-34] U/L; 117 [9.8%] with elevated levels), 682 (56.2%) had testing for HBV DNA (median level 2.8 [IQR 2.1-3.8] logIU/mL), 630 (51.9%) had HBV e antigen testing (negative result in 548 [87.0%]), and 145 (11.9%) had HBV e antibody testing (positive result in 111 [76.6%]). Overall, 144 people (11.9%) received anti-HBV treatment, and 390 (32.1%) were referred to a hepatologist. INTERPRETATION: Many HBsAg-positive people in Calgary did not receive the recommended laboratory assessments. The results highlight the necessity of continual public health efforts to screen for chronic HBV infection in Canada and to ensure adequate follow-up in order to reach the World Health Organization's goal of viral hepatitis elimination by 2030. PMID- 28596187 TI - Functional Connectivity in Virally Suppressed Patients with HIV-Associated Neurocognitive Disorder: A Resting-State Analysis. AB - BACKGROUND AND PURPOSE: HIV-associated neurocognitive disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre combination antiretroviral era and in patients without HIV suppression, HIV associated neurocognitive disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated neurocognitive disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated neurocognitive disorder in the context of HIV viral suppression in both blood and CSF. MATERIALS AND METHODS: Eighteen patients with active HIV-associated neurocognitive disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network. RESULTS: There were significant group differences between the control and HIV-associated neurocognitive disorder groups in the salience (0.26 versus 0.14, t = 2.6978, df = 25, P = .0123) and executive networks (0.52 versus 0.32, t = 2.2372, df = 25, P = .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks. CONCLUSIONS: Active HIV-associated neurocognitive disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker. PMID- 28596188 TI - Retrospective Validation of a Computer-Assisted Quantification Model of Intracerebral Hemorrhage Volume on Accuracy, Precision, and Acquisition Time, Compared with Standard ABC/2 Manual Volume Calculation. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage accounts for 6.5%-19.6% of all acute strokes. Initial intracerebral hemorrhage volume and expansion are both independent predictors of clinical outcomes and mortality. Therefore, a rapid, unbiased, and precise measurement of intracerebral hemorrhage volume is a key component of clinical management. The most commonly used method, ABC/2, results in overestimation. We developed an interactive segmentation program, SegTool, using a novel graphic processing unit, level set algorithm. Until now, the speed, bias, and precision of SegTool had not been validated. MATERIALS AND METHODS: In a single stroke academic center, 2 vascular neurologists and 2 neuroradiologists independently performed a test-retest experiment that involved repeat measurements of static, unchanging intracerebral hemorrhage volumes on CT from 76 intracerebral hemorrhage cases. Measurements were made with SegTool and ABC/2. True intracerebral hemorrhage volumes were estimated from a consensus of repeat manual tracings by 2 operators. These data allowed us to estimate measurement bias, precision, and speed. RESULTS: The measurements with SegTool were not significantly different from the true intracerebral hemorrhage volumes, while ABC/2 overestimated volume by 45%. The interrater measurement variability with SegTool was 50% less than that with ABC/2. The average measurement times for ABC/2 and SegTool were 35.7 and 44.6 seconds, respectively. CONCLUSIONS: SegTool appears to have attributes superior to ABC/2 in terms of accuracy and interrater reliability with a 9-second delay in measurement time (on average); hence, it could be useful in clinical trials and practice. PMID- 28596190 TI - To tPA or Not to tPA, That Is the Question. PMID- 28596189 TI - Reliability of White Matter Microstructural Changes in HIV Infection: Meta Analysis and Confirmation. AB - BACKGROUND: Diffusion tensor imaging has been widely used to measure HIV effects on white matter microarchitecture. While many authors have reported reduced fractional anisotropy and increased mean diffusivity in HIV, quantitative inconsistencies across studies are numerous. PURPOSE: Our aim was to evaluate the consistency across studies of HIV effects on DTI measures and then examine the DTI reliability in a longitudinal seropositive cohort. DATA SOURCES: Published studies and investigators. STUDY SELECTION: The meta-analysis included 16 cross sectional studies reporting fractional anisotropy and 12 studies reporting mean diffusivity in the corpus callosum. DATA ANALYSIS: Random-effects meta-analysis was used to estimate study standardized mean differences and heterogeneity. DTI longitudinal reliability was estimated in seropositive participants studied before and 3 and 6 months after beginning treatment. DATA SYNTHESIS: Meta analysis revealed lower fractional anisotropy (standardized mean difference, 0.43; P < .001) and higher mean diffusivity (standardized mean difference, 0.44; P < .003) in seropositive participants. Nevertheless, between-study heterogeneity accounted for 58% and 66% of the observed variance (P < .01). In contrast, the longitudinal cohort fractional anisotropy was higher and mean diffusivity was lower in seropositive participants (both, P < .001), and fractional anisotropy and mean diffusivity measures were very stable during 6 months, with intraclass correlation coefficients all >0.96. LIMITATIONS: Many studies pooled participants with varying treatments, ages, and disease durations. CONCLUSIONS: HIV effects on WM microstructure had substantial variations that could result from acquisition, processing, or cohort-selection differences. When acquisition parameters and processing were carefully controlled, the resulting DTI measures did not show high temporal variation. HIV effects on WM microstructure may be age-dependent. The high longitudinal reliability of DTI WM microstructure measures makes them promising disease-activity markers. PMID- 28596191 TI - Perfusion MR Imaging Using a 3D Pulsed Continuous Arterial Spin-Labeling Method for Acute Cerebral Infarction Classified as Branch Atheromatous Disease Involving the Lenticulostriate Artery Territory. AB - BACKGROUND AND PURPOSE: Branch atheromatous disease is a stroke subtype considered a risk factor for early neurologic deterioration. Meanwhile, crossed cerebellar diaschisis is thought to be influenced by the degree and location of supratentorial perfusion abnormalities and is associated with the clinical outcome in the case of an ischemic stroke. In this article, our aim was to clarify the utility of using a whole-brain 3D pulsed continuous arterial spin labeling method as an imaging biomarker for predicting neurologic severity in branch atheromatous disease. MATERIALS AND METHODS: Twenty-three patients with branch atheromatous disease in the lenticulostriate artery territory were enrolled. All patients underwent MR imaging, including DWI, 3D-TOF-MRA, and 3D arterial spin-labeling. We measured the asymmetry index of CBF in the affected area (branch atheromatous disease), the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis), and the DWI infarct volume in the lenticulostriate artery territory. We also compared each parameter with the initial NIHSS score with the Pearson correlation coefficient. RESULTS: Among the 23 patients, we found no correlation between NIHSS score and the asymmetry index of CBF in the affected area (branch atheromatous disease) (r = -0.027, P = .724), whereas the asymmetry index of the contralateral cerebellar hemisphere (crossed cerebellar diaschisis) and DWI infarct volumes were significantly correlated with NIHSS score (r = 0.515, P = .012; r = 0.664, P = .001, respectively). CONCLUSIONS: In patients with branch atheromatous disease, 3D arterial spin-labeling can detect crossed cerebellar diaschisis, which is correlated with the degree of neurologic severity. PMID- 28596192 TI - The Impact of Conscious Sedation versus General Anesthesia for Stroke Thrombectomy on the Predictive Value of Collateral Status: A Post Hoc Analysis of the SIESTA Trial. AB - BACKGROUND AND PURPOSE: Radiologic selection criteria to identify patients likely to benefit from endovascular stroke treatment are still controversial. In this post hoc analysis of the recent randomized Sedation versus Intubation for Endovascular Stroke TreAtment (SIESTA) trial, we aimed to investigate the impact of sedation mode (conscious sedation versus general anesthesia) on the predictive value of collateral status. MATERIALS AND METHODS: Using imaging data from SIESTA, we assessed collateral status with the collateral score of Tan et al and graded it from absent to good collaterals (0-3). We examined the association of collateral status with 24-hour improvement of the NIHSS score, infarct volume, and mRS at 3 months according to the sedation regimen. RESULTS: In a cohort of 104 patients, the NIHSS score improved significantly in patients with moderate or good collaterals (2-3) compared with patients with no or poor collaterals (0-1) (P = .011; mean, -5.8 +/- 7.6 versus -1.1 +/- 10.7). Tan 2-3 was also associated with significantly higher ASPECTS before endovascular stroke treatment (median, 9 versus 7; P < .001) and smaller mean infarct size after endovascular stroke treatment (median, 35.0 versus 107.4; P < .001). When we differentiated the population according to collateral status (0.1 versus 2.3), the sedation modes conscious sedation and general anesthesia were not associated with significant differences in the predictive value of collateral status regarding infarction size or functional outcome. CONCLUSIONS: The sedation mode, conscious sedation or general anesthesia, did not influence the predictive value of collaterals in patients with large-vessel occlusion anterior circulation stroke undergoing thrombectomy in the SIESTA trial. PMID- 28596193 TI - MR Imaging Diagnosis of Diencephalic-Mesencephalic Junction Dysplasia in Fetuses with Developmental Ventriculomegaly. AB - Diencephalic-mesencephalic junction dysplasia is a rare malformation characterized by a poorly defined junction between the diencephalon and the mesencephalon, associated with a characteristic butterfly-like contour of the midbrain (butterfly sign). This condition may be variably associated with other brain malformations, including callosal abnormalities and supratentorial ventricular dilation, and is a potential cause of developmental hydrocephalus. Here, we have reported 13 fetuses with second-trimester obstructive ventriculomegaly and MR features of diencephalic-mesencephalic junction dysplasia, correlating the fetal imaging with available pathology and/or postnatal data. The butterfly sign can be clearly detected on axial images on fetal MR imaging, thus allowing for the prenatal diagnosis of diencephalic mesencephalic junction dysplasia, with possible implications for the surgical management of hydrocephalus and parental counseling. PMID- 28596194 TI - Influence of Ultra-Low-Dose and Iterative Reconstructions on the Visualization of Orbital Soft Tissues on Maxillofacial CT. AB - BACKGROUND AND PURPOSE: Dose reduction on CT scans for surgical planning and postoperative evaluation of midface and orbital fractures is an important concern. The purpose of this study was to evaluate the variability of various low dose and iterative reconstruction techniques on the visualization of orbital soft tissues. MATERIALS AND METHODS: Contrast-to-noise ratios of the optic nerve and inferior rectus muscle and subjective scores of a human cadaver were calculated from CT with a reference dose protocol (CT dose index volume = 36.69 mGy) and a subsequent series of low-dose protocols (LDPs I-4: CT dose index volume = 4.18, 2.64, 0.99, and 0.53 mGy) with filtered back-projection (FBP) and adaptive statistical iterative reconstruction (ASIR)-50, ASIR-100, and model-based iterative reconstruction. The Dunn Multiple Comparison Test was used to compare each combination of protocols (alpha = .05). RESULTS: Compared with the reference dose protocol with FBP, the following statistically significant differences in contrast-to-noise ratios were shown (all, P <= .012) for the following: 1) optic nerve: LDP-I with FBP; LDP-II with FBP and ASIR-50; LDP-III with FBP, ASIR-50, and ASIR-100; and LDP-IV with FBP, ASIR-50, and ASIR-100; and 2) inferior rectus muscle: LDP-II with FBP, LDP-III with FBP and ASIR-50, and LDP-IV with FBP, ASIR 50, and ASIR-100. Model-based iterative reconstruction showed the best contrast to-noise ratio in all images and provided similar subjective scores for LDP-II. ASIR-50 had no remarkable effect, and ASIR-100, a small effect on subjective scores. CONCLUSIONS: Compared with a reference dose protocol with FBP, model based iterative reconstruction may show similar diagnostic visibility of orbital soft tissues at a CT dose index volume of 2.64 mGy. Low-dose technology and iterative reconstruction technology may redefine current reference dose levels in maxillofacial CT. PMID- 28596195 TI - e-ASPECTS Correlates with and Is Predictive of Outcome after Mechanical Thrombectomy. AB - BACKGROUND AND PURPOSE: The e-ASPECTS software is a tool for the automated use of ASPECTS. Our aim was to analyze whether baseline e-ASPECT scores correlate with outcome after mechanical thrombectomy. MATERIALS AND METHODS: Patients with ischemic strokes in the anterior circulation who were admitted between 2010 and 2015, diagnosed by CT, and received mechanical thrombectomy were included. The ASPECTS on baseline CT was scored by e-ASPECTS and 3 expert raters, and interclass correlation coefficients were calculated. The e-ASPECTS was correlated with functional outcome (modified Rankin Scale) at 3 months by using the Spearman rank correlation coefficient. Unfavorable outcome was defined as mRS 4-6 at 3 months, and a poor scan was defined as e-ASPECTS 0-5. RESULTS: Two hundred twenty patients were included, and 147 (67%) were treated with bridging protocols. The median e-ASPECTS was 9 (interquartile range, 8-10). Intraclass correlation coefficients between e-ASPECTS and raters were 0.72, 0.74, and 0.76 (all, P < .001). e-ASPECTS (Spearman rank correlation coefficient = -0.15, P = .027) correlated with mRS at 3 months. Patients with unfavorable outcome had lower e ASPECTS (median, 8; interquartile range, 7-10 versus median, 9; interquartile range, 8-10; P = .014). Sixteen patients (7.4%) had a poor scan, which was associated with unfavorable outcome (OR, 13.6; 95% CI, 1.8-104). Independent predictors of unfavorable outcome were e-ASPECTS (OR, 0.79; 95% CI, 0.63-0.99), blood sugar (OR, 1.01; 95% CI, 1.004-1.02), atrial fibrillation (OR, 2.64; 95% CI, 1.22-5.69), premorbid mRS (OR, 1.77; 95% CI, 1.21-2.58), NIHSS (OR, 1.11; 95% CI, 1.04-1.19), general anesthesia (OR, 0.24; 95% CI, 0.07-0.84), failed recanalization (OR, 8.47; 95% CI, 3.5-20.2), and symptomatic intracerebral hemorrhage (OR, 25.8; 95% CI, 2.5-268). CONCLUSIONS: The e-ASPECTS correlated with mRS at 3 months and was predictive of unfavorable outcome after mechanical thrombectomy, but further studies in patients with poor scan are needed. PMID- 28596196 TI - Effect of Retrievable Stent Size on Endovascular Treatment of Acute Ischemic Stroke: A Multicenter Study. AB - BACKGROUND AND PURPOSE: In clinical practice, stent diameter is one of the variable properties important for endovascular treatment. A consensus guideline for stent retriever size selection has yet to be established. The aim of this study was to investigate the effects of different diameters of Solitaire retrievers on outcomes. MATERIALS AND METHODS: Of 628 patients enrolled from the Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke Registry, 256 were treated with the Solitaire 4-mm device and 372, with the 6-mm device. We matched patients treated with the 2 stent sizes using propensity score analysis. The successful outcome was reperfusion as measured by the modified Thrombolysis in Cerebral Infarction score immediately postprocedure and the dichotomized modified Rankin Scale score at 90 days. Symptomatic intracerebral hemorrhage and in-hospital mortality were also recorded. RESULTS: After propensity score analysis, group outcomes did not differ. In addition, in patients with atherosclerosis-related occlusion, a higher reperfusion rate (P = .021) was observed in the Solitaire 4 group, as well as a shorter time interval (P = .002) and fewer passes (P = .025). Independent predictors of successful reperfusion in patients with atherosclerotic disease on logistic analysis were the small stent (OR, 3.217; 95% CI, 1.129-9.162; P = .029) and the propensity score acting as a covariate (OR, 52.84; 95% CI, 3.468-805.018; P = .004). CONCLUSIONS: We found no evidence of a differential effect of intra-arterial therapy based on the size of Solitaire retrievers. In patients with atherosclerotic disease, favorable reperfusion was associated with deployment of a small stent. PMID- 28596197 TI - First evidence of genotype-phenotype correlations in Gorlin syndrome. AB - BACKGROUND: Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS. METHODS: We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation. RESULTS: Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004). CONCLUSION: We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant. PMID- 28596198 TI - Pituitary abscess. AB - Pituitary abscess is an uncommon pituitary lesion. Its clinical diagnosis can be difficult to distinguish from other pituitary lesions. This pathology is characterised by vague symptoms of headaches, generalised tiredness and hypopituitarism manifestations. A history of recent meningitis, paranasal sinusitis or head surgery can be a suggestive of the source of infection.A 20 year-old man was admitted to neurosurgery department with complain of headache, fatigue, polyuria, polydipsia, blurred vision and sexual dysfunction. MRI of the head revealed a suprasellar mass that was centrally hyperintense lesion on T2 weighted images with peripheral hypointensity and isointense centrally on T1 images with peripheral hyperintensity images. Treatment of this lesion pituitary abscess was surgical drainage of the pituitary area through a trans-sphenoidal approach and broad spectrum antibiotic therapy with ceftriaxone, metronidazole and vancomycin for 6 weeks. The patient continues to have pituitary insufficiency and treated with oral hydrocortisone.Although pituitary abscess is a rare condition, it should always be kept in mind when evaluating a patient with hypopituitarism. After the diagnosis, the surgery and antibiotics should be commenced rapidly. The outcome is usually good with proper treatment. PMID- 28596199 TI - Mediastinal seminoma presenting with superior vena cava syndrome. AB - We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease. PMID- 28596200 TI - A case of a chronic salmonella infection following Roux-en-Y gastric bypass surgery, treated successfully by a laparoscopic cholecystectomy. AB - We report a case of chronic infection caused by Salmonella and cured by a laparoscopic cholecystectomy after Roux-en-Y gastric bypass (RYGB) surgery for obesity. This patient presented with a 2-year history of chronic abdominal pain, loose stools and excessive weight loss. Her stool and urine cultures were positive for Salmonella Despite multiple courses of antibiotics, she remained positive.After undergoing a laparoscopic cholecystectomy, the patient became asymptomatic and stools remained negative. In chronic carriers for Salmonella, the gall bladder is the common reservoir for the bacteria and removing it is usually curative.The possibility that the source of the may be in the biliary limb of her bariatric procedure and not in the gall bladder remained a concern.In patients who have had a RYGB, cholecystectomy is an effective treatment.All patients presenting with abdominal symptoms following RYGB should have stool and urine cultures taken as part of their work up. PMID- 28596201 TI - Isolated gastric sarcoidosis: a rare entity. AB - We present a case of isolated granulomatous gastritis in a 21-year-old woman. Initial symptoms included nausea, vomiting and inability to tolerate oral intake. An upper oesophagogastroduodenoscopy revealed nodular and thickened mucosa with histological findings of granulomatous gastritis. Infectious, inflammatory and malignant causes were excluded prior to making a diagnosis of gastric sarcoidosis. PMID- 28596202 TI - Persistent lesion hyperintensity on brain diffusion-weighted MRI is an early sign of intravascular lymphoma. AB - A 63-year-old man presented with right-sided hemianopia and unsteady gait. Brain MRI revealed multiple hyperintense infarct-like lesions on diffusion-weighted images (DWI). Hyperintensity persisted in some of these lesions even after 6 weeks, although his symptoms were ameliorated then. The patient developed episodic dizziness and a transient event of apraxia at 18 weeks after the first episode. Brain MRI revealed additional hyperintense lesions on DWI, which persisted even after 7 weeks. Eventually, the patient manifested cauda equina syndrome 39 weeks after the first episode. Brain MRI showed the presence of new lesions in addition to the persistent hyperintense lesions on DWI over 21 weeks in the right frontal lobe. Based on laboratory findings and the pathological assessment of bone marrow and random skin biopsies, the patient was diagnosed with intravascular lymphoma (IVL). Persistent hyperintense lesions on DWI of brain MRI may precede the clinical exacerbation of IVL. PMID- 28596203 TI - Surgical management of isolated mesenteric autoimmune disease: addressing the spectrum of IgG4-related disease and sclerosing mesenteritis. AB - IgG4-related disease (IgG4-RD) is a rare form of autoimmune sclerosing disease, characterised by elevated serum IgG4 and tissue IgG4 levels, specific histopathological findings, multiorgan involvement and adequate response to glucocorticoid treatment. The low incidence and the heterogeneous nature of the disease has made consensus on diagnostic criteria for IgG4-RD difficult. Whether sclerosing mesenteritis (SM) is considered a manifestation of IgG4-RD is strongly debated. We present the case of a patient with a history of rheumatoid arthritis who presented with a calcified abdominal mass. She was found to have an isolated, pedunculated mesenteric mass positive for IgG4 and concurrently elevated serum IgG4 levels. Clinical features did not classify her disease as either SM or IgG4 RD as currently described in consensus statements. Concurrent diagnoses of IgG4 RD, SM and other autoimmune disorders, as well as postoperative recommendations for resected isolated IgG4-positive masses, are discussed. PMID- 28596204 TI - Malignant hypertension as a rare cause of thrombotic microangiopathy. AB - Malignant hypertension can occasionally be associated with microangiopathic haemolytic anaemia. A 38-year-old male presented with nausea, vomiting, loss of appetite and oliguria for 2 weeks. He was diagnosed with hypertensive emergency with cardiac and renal dysfunction. Interestingly, further workup was diagnostic for the presence of thrombotic microangiopathy (TMA): haemoglobin =12.7 g/dL, indirect bilirubin =2.0 mg/dL, haptoglobin <=6 mg/dL, platelet count =121 000/MUL and schistocytes on peripheral smear. At the outset, the cause of TMA was unclear. Patient denied having diarrhoea, making haemolytic uremic syndrome less likely. A normal ADAMTS13 activity test ruled out thrombotic thrombocytopaenic purpura. Malignant hypertension induced TMA was highest on the differential and plasma exchange was deferred. Renal biopsy revealed features of TMA and malignant nephrosclerosis. Patient eventually became dialysis dependent. Aggressive blood pressure control was obtained with multiple medications. PMID- 28596205 TI - Congenital prepubic sinus (an epispadiac variant of dorsal urethral duplication) with dorsal penile curvature in an adult man: a rare association. AB - Urethral duplication is among a very rare congenital disorder with multiple anatomical variants reported. Urethral duplication of complete type is usually diagnosed during childhood with urinary incontinence or double urinary stream as common presentation. However, patients with incomplete urethral duplication usually present with intermittent mucous discharge from the accessory urethral opening. A 20-year-old man presented to us with intermittent mucous discharge from the accessory opening along with dorsal penile curvature making sexual intercourse very difficult. The epispadiac urethral tract with proximal fibrous tract was excised, and the dorsal penile curvature was corrected by ventral plication, implicating that the fibrous cord may be the causative factor for the development of dorsal curvature. PMID- 28596206 TI - Primary myeloid sarcoma of small bowel. PMID- 28596207 TI - Delayed progression of bull's eye maculopathy. AB - Chloroquine-induced maculopathy may progress years after drug cessation and an apparent period of visual stability. Both doctor and patients should be fully aware of the risks of retinal toxicity, including delayed onset and progression. It is therefore crucial that regular monitoring continues in affected patients, long after the initial diagnosis of maculopathy. PMID- 28596208 TI - Intrahepatic fetus: unusual image of an intratumoural haemorrhage. PMID- 28596209 TI - Intake of dairy foods and risk of Parkinson disease. AB - OBJECTIVE: To prospectively examine the association between commonly consumed dairy products and the risk of Parkinson disease (PD) in women and men. METHODS: Analyses were based on data from 2 large prospective cohort studies, the Nurses' Health Study (n = 80,736) and the Health Professionals Follow-up Study (n = 48,610), with a total of 26 and 24 years of follow-up, respectively. Both US based studies were conducted via mailed biennial questionnaires. Dietary intake was assessed with food frequency questionnaires administered repeatedly over the follow-up period. Incident cases of PD (n = 1,036) were identified via questionnaires and subsequently confirmed by reviewing medical records. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on total milk intake and PD risk and 1 study on total dairy intake and PD risk. RESULTS: While total dairy intake was not significantly associated with PD risk in our cohorts, intake of low-fat dairy foods was associated with PD risk. The pooled, multivariable-adjusted hazard ratio (HR) comparing people who consumed at least 3 servings of low-fat dairy per day to those who consumed none was 1.34 (95% confidence interval [CI] 1.01-1.79, p trend = 0.04). This association appeared to be driven by an increased risk of PD associated with skim and low-fat milk (HR 1.39, 95% CI 1.12-1.73, p trend <0.01). Results were similar in women and men (p for heterogeneity >0.05). In the meta analysis, the pooled relative risk comparing extreme categories of total milk intake was 1.56 (95% CI 1.30-1.88), and the association between total dairy and PD became significant (HR 1.27, 95% CI 1.04-1.55). CONCLUSIONS: Frequent consumption of dairy products appears to be associated with a modest increased risk of PD in women and men. PMID- 28596210 TI - Patients With Diabetes Without Significant Angiographic Coronary Artery Disease Have the Same Risk of Myocardial Infarction as Patients Without Diabetes in a Real-World Population Receiving Appropriate Prophylactic Treatment. AB - OBJECTIVE: The risk of myocardial infarction (MI) in patients with diabetes is greater than for patients without diabetes. Consequently, prophylactic treatment is recommended for patients with diabetes and risk factors for ischemic heart disease. We aimed to estimate the risk of adverse cardiac events in patients with and without diabetes with and without coronary artery disease (CAD) after coronary angiography (CAG). RESEARCH DESIGN AND METHODS: A population-based cohort of patients registered in the Western Denmark Heart Registry who underwent CAG between 1 January 2003 and 31 December 2012 was stratified according to the presence or absence of obstructive CAD and diabetes. End points were death, cardiac death, and MI. Unadjusted and adjusted rate ratios (RRs) were calculated by using patients without diabetes and without CAD as the reference group. RESULTS: We included 93,866 patients of whom 12,544 (13.4%) had diabetes at the time of CAG. Median follow-up was 4.1 years. Patients with and without diabetes without obstructive CAD had the same adjusted risk of death (RR 1.03 [95% CI 0.92 1.15]), cardiac death (RR 1.21 [95% CI 0.90-1.64]), and MI (RR 0.88 [95% CI 0.65 1.17]). Patients with diabetes without CAD were more often treated with statins (75.3% vs. 46.0%) and aspirin (65.7% vs. 52.7%) than patients without diabetes and CAD. CONCLUSIONS: In a real-world population, patients with diabetes with high rates of statin and aspirin treatment had the same risk of cardiovascular events as patients without diabetes in the absence of angiographically significant CAD. PMID- 28596212 TI - Rapid growth causes abnormal vaterite formation in farmed fish otoliths. AB - Sagittal otoliths are essential components of the sensory organs that enable all teleost fish to hear and maintain balance, and are primarily composed of calcium carbonate. A deformity, where aragonite (the normal crystal form) is replaced with vaterite, was first noted over 50 years ago but its underlying cause is unresolved. We evaluated the prevalence of vateritic otoliths from two captive rearing studies which suggested that fast growth, due to environmental rather than genetic control, led to vaterite development. We then tested this by varying light and temperature to create phenotypes with different growth rates, which resulted in fast growers (5 times larger) having 3 times more vaterite than slow growers. A decrease in either the ratio of otolith matrix proteins (otolin-1/OMM 64) or [Ca2+]/[CO32-] may explain why fast growth causes vaterite deposition. As vaterite decreases hearing sensitivity, reducing growth rates in hatcheries may improve the welfare of farmed fish and increase the success of conservation efforts. PMID- 28596211 TI - Low levels of extracellular glucose limit cardiac anaerobic metabolism in some species of fish. AB - There is a wide interspecific range in plasma glucose levels in teleosts from less than 0.5 to greater than 10 mmol l-1 Here we assessed how glucose availability influences glucose metabolism in hearts of Atlantic cod (Gadus morhua), rainbow trout (Oncorhynchus mykiss), lumpfish (Cyclopterus lumpus) and short-horned sculpin (Myoxocephalus scorpius) under normoxic and hypoxic conditions. These species had plasma glucose levels of 5.1, 4.8, 0.9 and 0.5 mmol l-1, respectively. Rates of glucose metabolism and lactate production were determined in isolated hearts perfused with medium containing physiological levels of glucose. Under normoxic conditions there was no significant difference in rates of either glucose metabolism (average 15 nmol g-1 min-1) or lactate production (average 30 nmol g-1 min-1) across species. Under hypoxia (12% of air saturation) there were significant increases in rates of glucose metabolism and lactate production in hearts from Atlantic cod (glucose-130; lactate-663 nmol g-1 min-1) and rainbow trout (glucose-103; lactate-774 nmol g-1 min-1); however, there was no change in rate of glucose metabolism in hearts from either lumpfish or short-horned sculpin and only increases in lactate production to rates much lower than the other species. Furthermore, Atlantic cod hearts perfused with medium containing low non-physiological levels of glucose (0.5 mmol l-1) had the same rates of glucose metabolism under normoxic and hypoxic treatments. Anaerobic metabolism supported by extracellular glucose is compromised in fish with low levels of plasma glucose, which in turn may decrease performance under oxygen limiting conditions at the whole-animal level. PMID- 28596213 TI - Chamber music: an unusual Helmholtz resonator for song amplification in a Neotropical bush-cricket (Orthoptera, Tettigoniidae). AB - Animals use sound for communication, with high-amplitude signals being selected for attracting mates or deterring rivals. High amplitudes are attained by employing primary resonators in sound-producing structures to amplify the signal (e.g. avian syrinx). Some species actively exploit acoustic properties of natural structures to enhance signal transmission by using these as secondary resonators (e.g. tree-hole frogs). Male bush-crickets produce sound by tegminal stridulation and often use specialised wing areas as primary resonators. Interestingly, Acanthacara acuta, a Neotropical bush-cricket, exhibits an unusual pronotal inflation, forming a chamber covering the wings. It has been suggested that such pronotal chambers enhance amplitude and tuning of the signal by constituting a (secondary) Helmholtz resonator. If true, the intact system - when stimulated sympathetically with broadband sound - should show clear resonance around the song carrier frequency which should be largely independent of pronotum material, and change when the system is destroyed. Using laser Doppler vibrometry on living and preserved specimens, microcomputed tomography, 3D-printed models and finite element modelling, we show that the pronotal chamber not only functions as a Helmholtz resonator owing to its intact morphology but also resonates at frequencies of the calling song on itself, making song production a three resonator system. PMID- 28596215 TI - Reproductive and metabolic state differences in olfactory responses to amino acids in a mouth brooding African cichlid fish. AB - Olfaction mediates many crucial life-history behaviors such as prey detection, predator avoidance, migration and reproduction. Olfactory function can also be modulated by an animal's internal physiological and metabolic states. While this is relatively well studied in mammals, little is known about how internal state impacts olfaction in fishes, the largest and most diverse group of vertebrates. Here we apply electro-olfactograms (EOGs) in the African cichlid fish Astatotilapia burtoni to test the hypothesis that olfactory responses to food related cues (i.e. l-amino acids; alanine and arginine) vary with metabolic, social and reproductive state. Dominant males (reproductively active, reduced feeding) had greater EOG magnitudes in response to amino acids at the same tested concentration than subordinate males (reproductively suppressed, greater feeding and growth rates). Mouth brooding females, which are in a period of starvation while they brood fry in their mouths, had greater EOG magnitudes in response to amino acids at the same tested concentration than both recovering and gravid females that are feeding. Discriminant function analysis on EOG magnitudes also grouped the male (subordinate) and female (recovering, gravid) phenotypes with higher food intake together and distinguished them from brooding females and dominant males. The slope of the initial negative phase of the EOG also showed intra-sexual differences in both sexes. Our results demonstrate that the relationship between olfaction and metabolic state observed in other taxa is conserved to fishes. For the first time, we provide evidence for intra-sexual plasticity in the olfactory response to amino acids that is influenced by fish reproductive, social and metabolic state. PMID- 28596214 TI - Changes in mechanical work during neural adaptation to asymmetric locomotion. AB - Minimizing whole-body metabolic cost has been suggested to drive the neural processes of locomotor adaptation. Mechanical work performed by the legs should dictate the major changes in whole-body metabolic cost of walking while providing greater insight into temporal and spatial mechanisms of adaptation. We hypothesized that changes in mechanical work by the legs during an asymmetric split-belt walking adaptation task could explain previously observed changes in whole-body metabolic cost. We predicted that subjects would immediately increase mechanical work performed by the legs when first exposed to split-belt walking, followed by a gradual decrease throughout adaptation. Fourteen subjects walked on a dual-belt instrumented treadmill. Baseline trials were followed by a 10-min split-belt adaptation condition with one belt running three times faster than the other. A post-adaptation trial with both belts moving at 0.5 m s-1 demonstrated neural adaptation. As predicted, summed mechanical work from both legs initially increased abruptly and gradually decreased over the adaptation period. The initial increase in work was primarily due to increased positive work by the leg on the fast belt during the pendular phase of the gait cycle. Neural adaptation in asymmetric split-belt walking reflected the reduction of pendular phase work in favor of more economical step-to-step transition work. This may represent a generalizable framework for how humans initially and chronically learn new walking patterns. PMID- 28596217 TI - General practitioners' views of clinically led commissioning: cross-sectional survey in England. AB - OBJECTIVES: Involving general practitioners (GPs) in the commissioning/purchasing of services has been an important element in English health policy for many years. The Health and Social Care Act 2012 handed responsibility for commissioning of the majority of care for local populations to GP-led Clinical Commissioning Groups (CCGs). In this paper, we explore GP attitudes to involvement in commissioning and future intentions for engagement. DESIGN AND SETTING: Survey of a random sample of GPs across England in 2015. METHOD: The Eighth National GP Worklife Survey was distributed to GPs in spring 2015. Responses were received from 2611 respondents (response rate = 46%). We compared responses across different GP characteristics and conducted two sample tests of proportions to identify statistically significant differences in responses across groups. We also used multivariate logistic regression to identify the characteristics associated with wanting a formal CCG role in the future. RESULTS: While GPs generally agree that they can add value to aspects of commissioning, only a minority feel that this is an important part of their role. Many current leaders intend to quit in the next 5 years, and there is limited appetite among those not currently in a formal role to take up such a role in the future. CCGs were set up as 'membership organisations' but only a minority of respondents reported feeling that they had 'ownership' of their local CCG and these were often GPs with formal CCG roles. However, respondents generally agree that the CCG has a legitimate role in influencing the work that they do. CONCLUSION: CCGs need to engage in active succession planning to find the next generation of GP leaders. GPs believe that CCGs have a legitimate role in influencing their work, suggesting that there may be scope for CCGs to involve GPs more fully in roles short of formal leadership. PMID- 28596216 TI - Effect of Ischemia Duration and Protective Interventions on the Temporal Dynamics of Tissue Composition After Myocardial Infarction. AB - RATIONALE: The impact of cardioprotective strategies and ischemia duration on postischemia/reperfusion (I/R) myocardial tissue composition (edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction) is not well understood. OBJECTIVE: To study the effect of ischemia duration and protective interventions on the temporal dynamics of myocardial tissue composition in a translational animal model of I/R by the use of state-of the-art imaging technology. METHODS AND RESULTS: Four 5-pig groups underwent different I/R protocols: 40-minute I/R (prolonged ischemia, controls), 20-minute I/R (short-duration ischemia), prolonged ischemia preceded by preconditioning, or prolonged ischemia followed by postconditioning. Serial cardiac magnetic resonance (CMR)-based tissue characterization was done in all pigs at baseline and at 120 minutes, day 1, day 4, and day 7 after I/R. Reference myocardium at risk was assessed by multidetector computed tomography during the index coronary occlusion. After the final CMR, hearts were excised and processed for water content quantification and histology. Five additional healthy pigs were euthanized after baseline CMR as reference. Edema formation followed a bimodal pattern in all 40-minute I/R pigs, regardless of cardioprotective strategy and the degree of intramyocardial hemorrhage or microvascular obstruction. The hyperacute edematous wave was ameliorated only in pigs showing cardioprotection (ie, those undergoing short-duration ischemia or preconditioning). In all groups, CMR-measured edema was barely detectable at 24 hours postreperfusion. The deferred healing-related edematous wave was blunted or absent in pigs undergoing preconditioning or short-duration ischemia, respectively. CMR-measured infarct size declined progressively after reperfusion in all groups. CMR-measured myocardial salvage, and the extent of intramyocardial hemorrhage and microvascular obstruction varied dramatically according to CMR timing, ischemia duration, and cardioprotective strategy. CONCLUSIONS: Cardioprotective therapies, duration of index ischemia, and the interplay between these greatly influence temporal dynamics and extent of tissue composition changes after I/R. Consequently, imaging techniques and protocols for assessing edema, myocardium at risk, infarct size, salvage, intramyocardial hemorrhage, and microvascular obstruction should be standardized accordingly. PMID- 28596219 TI - Diabetes prevention model spurs new Medicare billing opportunity. PMID- 28596220 TI - New drugs and dosage forms. PMID- 28596218 TI - Health-related shame: an affective determinant of health? AB - Despite shame being recognised as a powerful force in the clinical encounter, it is underacknowledged, under-researched and undertheorised in the contexts of health and medicine. In this paper we make two claims. The first is that emotional or affective states, in particular shame, can have a significant impact on health, illness and health-related behaviours. We outline four possible processes through which this might occur: (1) acute shame avoidance behaviour; (2) chronic shame health-related behaviours; (3) stigma and social status threat and (4) biological mechanisms. Second, we postulate that shame's influence is so insidious, pervasive and pernicious, and so critical to clinical and political discourse around health, that it is imperative that its vital role in health, health-related behaviours and illness be recognised and assimilated into medical, social and political consciousness and practice. In essence, we argue that its impact is sufficiently powerful for it to be considered an affective determinant of health, and provide three justifications for this. We conclude with a proposal for a research agenda that aims to extend the state of knowledge of health related shame. PMID- 28596221 TI - FDA approves edaravone for amyotrophic lateral sclerosis. PMID- 28596223 TI - Need for specific-gravity values in adopting gravimetric measurement in sterile compounding. PMID- 28596224 TI - Medication mismanagement using the rivaroxaban demonstration pack. PMID- 28596225 TI - Increased warfarin requirements in a patient with chronic hepatitis C infection receiving sofosbuvir and ribavirin. AB - PURPOSE: A case of increased warfarin requirements during treatment with sofosbuvir and ribavirin for chronic hepatitis C virus (HCV) infection is reported. SUMMARY: A 63-year-old white man receiving long-term anticoagulation with warfarin for atrial fibrillation and a history of cardioembolic stroke was initiated in September 2014 on a 12-week course of sofosbuvir 400 mg orally daily and weight-based ribavirin 600 mg orally twice daily for HCV genotype 2 infection. Before starting this treatment regimen, the patient had been stable on warfarin 52.5 mg weekly, with therapeutic International Normalized Ratio (INR) values. During the 12-week course of sofosbuvir and ribavirin, the patient's dose of warfarin progressively increased from 52.5 to 77.5 mg weekly due to subtherapeutic INRs, with the first adjustment in the warfarin dose occurring 9 days after initiation of HCV treatment. Three weeks after completion of the sofosbuvir and ribavirin regimen, the patient's INR was 3.06, and his warfarin dose was then decreased to 70 mg weekly. The patient continued with this warfarin dosage until 18 weeks after completion of his HCV regimen. The dosage was then decreased to 65 mg weekly after an INR of 3.86. Three weeks later, his INR was 2.19, and warfarin 65 mg weekly was continued. As of June 2016, the patient has continued to require warfarin 62.5-65 mg weekly to maintain a therapeutic INR. CONCLUSION: A 63-year-old man on a stable dose of warfarin experienced a decrease in INR values after the initiation of a 12-week course of sofosbuvir and ribavirin for the treatment of chronic HCV infection. PMID- 28596226 TI - Autoimmune hemolytic anemia associated with trimethoprim-sulfamethoxazole use. AB - PURPOSE: A case report of drug-induced immune hemolytic anemia (DIIHA) triggered by exposure to trimethoprim-sulfamethoxazole is presented along with a brief review of the pathophysiology of DIIHA and diagnostic considerations. SUMMARY: A 58-year-old woman recently initiated on trimethoprim-sulfamethoxazole for treatment of a urinary tract infection presented to the emergency department with generalized weakness and fatigue. Initial laboratory studies were significant for the following values: hemoglobin concentration, 5.6 g/dL (reference range, 12-15 g/dL); mean corpuscular volume, 116.9 MUm3 (reference range, 80-100 MUm3); and reticulocyte count, 16% (reference range, 0.5-1.5%). An elevated serum lactate dehydrogenase concentration (646 U/L [reference range, 50-150 U/L]) and a low haptoglobin concentration (<10 mg/dL [reference range, 30-200 mg/dL]) indicated a hemolytic process. A peripheral blood smear revealed spherocytosis. Serologic testing showed antibodies to both immunoglobulin G (IgG) and complement component C3b. An antibody identification panel was nonspecifically positive for a warm reacting autoantibody (IgG). The combination of clinically evident hemolytic anemia, recent exposure to a newly initiated drug, and serologic evidence strongly suggested DIIHA. Trimethoprim-sulfamethoxazole was promptly discontinued, a total of 6 units of packed red blood cells were transfused, and the patient was treated with methylprednisolone sodium succinate. Clinical and hematologic improvements were observed within a few days. Results of follow-up antibody screening and direct antiglobulin testing 4 weeks after discharge were negative. CONCLUSION: A 58-year-old woman developed warm autoimmune hemolytic anemia after receiving trimethoprim-sulfamethoxazole for 5 days. PMID- 28596227 TI - Outcomes with perioperative fat emulsions containing omega-3 fatty acid: A meta analysis of randomized controlled trials. AB - PURPOSE: Results of a meta-analysis of data from clinical studies comparing patient outcomes and hospital length of stay (LOS) in surgical patients receiving fish oil (FO)-containing i.v. fat emulsions (IVFEs) versus non-FO-containing IVFEs are presented. METHODS: Computerized searches of the MEDLINE, Embase, and Coch rane CENTRAL databases were performed in August 2014 to identify English language articles on randomized controlled trials (RCTs) comparing FO-containing and non-FO-containing IVFEs in adult surgical patients receiving parenteral nutrition. Selected articles were analyzed for methodological and publication bias and study heterogeneity (I2 statistic). RESULTS: Data from 19 RCTs (total n = 1,167) were included in the meta-analysis. Compared with use of non-FO containing IVFEs (products based in soybean oil [SO], medium-chain triglycerides, or olive oil), use of FO-containing IVFEs was associated with reduced infectious morbidity (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.30-0.65; p < 0.0001; I2 = 0%); the effect size was greatest for FO-containing versus SO-based IVFEs. Relative to use of SO-based IVFEs, use of FO-containing IVFEs was associated with a significant reduction in hospital LOS (weighted mean difference, -2.70 days; 95% CI, -3.60 to -1.79 days; p < 0.00001; I2 = 0%). CONCLUSION: The results of the meta-analysis indicated that FO-containing IVFEs could improve infectious morbidity and LOS. The overall effect of reducing infectious morbidity and LOS was found to be the greatest in comparison with the SO-based IVFEs. PMID- 28596229 TI - Implementation of a proton pump inhibitor stewardship program. AB - PURPOSE: The development and implementation of a proton pump inhibitor (PPI) stewardship program at a single institution are described. SUMMARY: Due to the overuse of PPIs and the increasing awareness of the adverse drug events associated with long-term PPI therapy, the pharmacy and internal medicine services of a medical center implemented a PPI stewardship program. All patients admitted to the internal medicine service were evaluated by the PPI stewardship team to determine if they had an appropriate indication for PPI continuation in the hospital as well as after discharge. If patients did not meet specified criteria for continuation of PPI use during hospitalization, PPI therapy was suspended and replaced by as-needed acid suppressive therapy, and the patients received discharge counseling regarding the implemented medication regimen changes. Challenges encountered during program development included establishing appropriate criteria for PPI continuation and determining the best method for discontinuing PPIs in order to reduce the risk of rebound hyperacidity. CONCLUSION: In an effort to reduce unnecessary PPI use, a PPI stewardship program was developed and implemented to ensure appropriate continuation of PPIs for patients admitted and discharged from an internal medicine service. PMID- 28596228 TI - Development and implementation of a residency project advisory board. AB - PURPOSE: The development and implementation of a residency project advisory board (RPAB) to manage multiple pharmacy residents' yearlong projects across several residency programs are described. SUMMARY: Preceptor and resident feedback during our annual residency program review and strategic planning sessions suggested the implementation of a more-coordinated approach to the identification, selection, and oversight of all components of the residency project process. A panel of 7 department leaders actively engaged in residency training and performance improvement was formed to evaluate the residency project process and provide recommendations for change. These 7 individuals would eventually constitute the RPAB. The primary objective of the RPAB at Aurora Health Care is to provide oversight and a structured framework for the selection and execution of multiple residents' yearlong projects across all residency programs within our organization. Key roles of the RPAB include developing expectations, coordinating residency project ideas, and providing oversight and feedback. The development and implementation of the RPAB resulted in a significant overhaul of our entire yearlong resident project process. Trends toward success were realized after the first year of implementation, including consistent expectations, increased clarity and engagement in resident project ideas, and more projects meeting anticipated endpoints. CONCLUSION: The development and implementation of an RPAB have provided a framework to optimize the organization, progression, and outcomes of multiple pharmacy resident yearlong projects in all residency programs across our pharmacy enterprise. PMID- 28596230 TI - A life undefined by cancer. PMID- 28596232 TI - Professional Policies Approved by the 2017 ASHP March Virtual House of Delegates. PMID- 28596233 TI - Adaptable interaction between aquaporin-1 and band 3 reveals a potential role of water channel in blood CO2 transport. AB - Human CO2 respiration requires rapid conversion between CO2 and HCO3- Carbonic anhydrase II facilitates this reversible reaction inside red blood cells, and band 3 [anion exchanger 1 (AE1)] provides a passage for HCO3- flux across the cell membrane. These 2 proteins are core components of the CO2 transport metabolon. Intracellular H2O is necessary for CO2/HCO3- conversion. However, abundantly expressed aquaporin 1 (AQP1) in erythrocytes is thought not to be part of band 3 complexes or the CO2 transport metabolon. To solve this conundrum, we used Forster resonance energy transfer (FRET) measured by fluorescence lifetime imaging (FLIM-FRET) and identified interaction between aquaporin-1 and band 3 at a distance of 8 nm, within the range of dipole-dipole interaction. Notably, their interaction was adaptable to membrane tonicity changes. This suggests that the function of AQP1 in tonicity response could be coupled or correlated to its function in band 3-mediated CO2/HCO3- exchange. By demonstrating AQP1 as a mobile component of the CO2 transport metabolon, our results uncover a potential role of water channel in blood CO2 transport and respiration.-Hsu, K., Lee, T.-Y., Periasamy, A., Kao, F.-J., Li, L.-T., Lin, C.-Y., Lin, H.-J., Lin, M. Adaptable interaction between aquaporin-1 and band 3 reveals a potential role of water channel in blood CO2 transport. PMID- 28596235 TI - Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up-regulation of fibronectin. AB - Epidermal growth factor receptor (EGFR) activation is a major cause of metastasis in such cancers as head and neck squamous cell carcinoma (HNSCC); however, whether the metabolic enzyme, pyruvate dehydrogenase kinase 1 (PDK1), mediates EGF-enhanced HNSCC metastasis remains unclear. Of interest, we found that EGF induced PDK1 expression in HNSCC. Tumor cell transformation induced by EGF was repressed by PDK1 knockdown, and the down-regulation of PDK1 expression or inhibition of its activity significantly blocked EGF-enhanced cell migration and invasion. In addition, depletion of PDK1 impeded EGF-enhanced binding of HNSCC cells to endothelial cells as well as the metastatic seeding of tumor cells in lungs. PDK1 depletion inhibited EGF-induced matrix metalloproteinase-1 (MMP-1), MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Furthermore, PDK1 overexpression induced MMP-1, MMP-2, MMP-3, MMP-9, and fibronectin expression and Rac1/cdc42 activation. Of interest, depletion of fibronectin inhibited PDK1-enhanced MMP-1-3 and MMP-9 expression as well as Rac1/cdc42 activation and tumor invasion. These results demonstrate that EGF induced PDK1 expression enhances HNSCC metastasis via activation of the fibronectin signaling pathway. Inhibition of PDK1 may be a potential strategy for the treatment of EGFR-mediated HNSCC metastasis.-Hsu, J.-Y., Chang, J.-Y., Chang, K.-Y., Chang, W.-C., Chen B.-K. Epidermal growth factor-induced pyruvate dehydrogenase kinase 1 expression enhances head and neck squamous cell carcinoma metastasis via up-regulation of fibronectin. PMID- 28596234 TI - Cathepsin B as a potential cystatin M/E target in the mouse hair follicle. AB - Deficiency of the cysteine protease inhibitor cystatin M/E (Cst6) in mice leads to disturbed epidermal cornification, impaired barrier function, and neonatal lethality. We report the rescue of the lethal skin phenotype of ichq (Cst6 deficient; Cst6-/-) mice by transgenic, epidermis-specific, reexpression of Cst6 under control of the human involucrin (INV) promoter. Rescued Tg(INV Cst6)Cst6ichq/ichq mice survive the neonatal phase, but display severe eye pathology and alopecia after 4 mo. We observed keratitis and squamous metaplasia of the corneal epithelium, comparable to Cst6-/-Ctsl+/- mice, as we have reported in other studies. We found the INV promoter to be active in the hair follicle infundibulum; however, we did not observe Cst6 protein expression in the lower regions of the hair follicle in Tg(INV-Cst6)Cst6ichq/ichq mice. This result suggests that unrestricted activity of proteases is involved in disturbance of hair follicle biology, eventually leading to baldness. Using quenched activity based probes, we identified mouse cathepsin B (CtsB), which is expressed in the lower regions of the hair follicle, as an additional target of mouse Cst6. These data suggest that Cst6 is necessary to control CtsB activity in hair follicle morphogenesis and highlight Cst6-controlled proteolytic pathways as targets for preventing hair loss.-Oortveld, M. A. W., van Vlijmen-Willems, I. M. J. J., Kersten, F. F. J., Cheng, T., Verdoes, M., van Erp, P. E. J., Verbeek, S., Reinheckel, T., Hendriks, W. J. A. J., Schalkwijk, J., Zeeuwen, P. L. J. M. Cathepsin B as a potential cystatin M/E target in the mouse hair follicle. PMID- 28596236 TI - Acute Hypoglycemia in Healthy Humans Impairs Insulin-Stimulated Glucose Uptake and Glycogen Synthase in Skeletal Muscle: A Randomized Clinical Study. AB - Hypoglycemia is the leading limiting factor in glycemic management of insulin treated diabetes. Skeletal muscle is the predominant site of insulin-mediated glucose disposal. Our study used a crossover design to test to what extent insulin-induced hypoglycemia affects glucose uptake in skeletal muscle and whether hypoglycemia counterregulation modulates insulin and catecholamine signaling and glycogen synthase activity in skeletal muscle. Nine healthy volunteers were examined on three randomized study days: 1) hyperinsulinemic hypoglycemia (bolus insulin), 2) hyperinsulinemic euglycemia (bolus insulin and glucose infusion), and 3) saline control with skeletal muscle biopsies taken just before, 30 min after, and 75 min after insulin/saline injection. During hypoglycemia, glucose levels reached a nadir of ~2.0 mmol/L, and epinephrine rose to ~900 pg/mL. Hypoglycemia impaired insulin-stimulated glucose disposal and glucose clearance in skeletal muscle, whereas insulin signaling in glucose transport was unaffected by hypoglycemia. Insulin-stimulated glycogen synthase activity was completely ablated during hyperinsulinemic hypoglycemia, and catecholamine signaling via cAMP-dependent protein kinase and phosphorylation of inhibiting sites on glycogen synthase all increased. PMID- 28596238 TI - Loss of beta-PIX inhibits focal adhesion disassembly and promotes keratinocyte motility via myosin light chain activation. AB - During healing of the skin, the cytoskeleton of keratinocytes and their matrix adhesions, including focal adhesions (FAs), undergo reorganization. These changes are coordinated by small GTPases and their regulators, including the guanine nucleotide exchange factor beta-PIX (also known as ARHGEF7). In fibroblasts, beta PIX activates small GTPases, thereby enhancing migration. In keratinocytes in vitro, beta-PIX localizes to FAs. To study beta-PIX functions, we generated beta PIX knockdown keratinocytes. During wound closure of beta-PIX knockdown cell monolayers, disassembly of FAs is impaired, and their number and size are increased. In addition, in the beta-PIX knockdown cells, phosphorylated myosin light chain (MLC; also known as MYL2) is present not only in the leading edge of cells at the wound front, but also in the cells following the front, while p21 activated kinase 2 (PAK2), a regulator of MLC kinase (MYLK), is mislocalized. Inhibition or depletion of MYLK restores FA distribution in beta-PIX knockdown cells. Traction forces generated by beta-PIX knockdown cells are increased relative to those in control cells, a result consistent with an unexpected enhancement in the migration of single beta-PIX knockdown cells and monolayers of such cells. We propose that targeting beta-PIX might be a means of promoting epithelialization of wounds in vivo. PMID- 28596237 TI - The SNARE Protein Syntaxin-1a Plays an Essential Role in Biphasic Exocytosis of the Incretin Hormone Glucagon-Like Peptide 1. AB - Exocytosis of the hormone glucagon-like peptide 1 (GLP-1) by the intestinal L cell is essential for the incretin effect after nutrient ingestion and is critical for the actions of dipeptidyl peptidase 4 inhibitors that enhance GLP-1 levels in patients with type 2 diabetes. Two-photon microscopy revealed that exocytosis of GLP-1 is biphasic, with a first peak at 1-6 min and a second peak at 7-12 min after stimulation with forskolin. Approximately 75% of the exocytotic events were represented by compound granule fusion, and the remainder were accounted for by full fusion of single granules under basal and stimulated conditions. The core SNARE protein syntaxin-1a (syn1a) was expressed by murine ileal L cells. At the single L-cell level, first-phase forskolin-induced exocytosis was reduced to basal (P < 0.05) and second-phase exocytosis abolished (P < 0.05) by syn1a knockout. L cells from intestinal-epithelial syn1a-deficient mice demonstrated a 63% reduction in forskolin-induced GLP-1 release in vitro (P < 0.001) and a 23% reduction in oral glucose-stimulated GLP-1 secretion (P < 0.05) in association with impairments in glucose-stimulated insulin release (by 60%; P < 0.01) and glucose tolerance (by 20%; P < 0.01). The findings identify an exquisite mechanism of metered secretory output that precisely regulates release of the incretin hormone GLP-1 and hence insulin secretion after a meal. PMID- 28596239 TI - Electrophoresis of cell membrane heparan sulfate regulates galvanotaxis in glial cells. AB - Endogenous electric fields modulate many physiological processes by promoting directional migration, a process known as galvanotaxis. Despite the importance of galvanotaxis in development and disease, the mechanism by which cells sense and migrate directionally in an electric field remains unknown. Here, we show that electrophoresis of cell surface heparan sulfate (HS) critically regulates this process. HS was found to be localized at the anode-facing side in fetal neural progenitor cells (fNPCs), fNPC-derived astrocytes and brain tumor-initiating cells (BTICs), regardless of their direction of galvanotaxis. Enzymatic removal of HS and other sulfated glycosaminoglycans significantly abolished or reversed the cathodic response seen in fNPCs and BTICs. Furthermore, Slit2, a chemorepulsive ligand, was identified to be colocalized with HS in forming a ligand gradient across cellular membranes. Using both imaging and genetic modification, we propose a novel mechanism for galvanotaxis in which electrophoretic localization of HS establishes cell polarity by functioning as a co-receptor and provides repulsive guidance through Slit-Robo signaling. PMID- 28596240 TI - Control of mitochondrial homeostasis by endocytic regulatory proteins. AB - Mitochondria play essential roles in cellular energy processes, including ATP production, control of reactive oxygen species (ROS) and apoptosis. While mitochondrial function is regulated by the dynamics of fusion and fission, mitochondrial homeostasis remains incompletely understood. Recent studies implicate dynamin-2 and dynamin-related protein-1 (Drp1, also known as DNM1L), as GTPases involved in mitochondrial fission. Here, we identify the ATPase and endocytic protein EHD1 as a novel regulator of mitochondrial fission. EHD1 depletion induces a static and elongated network of mitochondria in the cell. However, unlike dynamin-2 and Drp1, whose depletion protects cells from staurosporine-induced mitochondrial fragmentation, EHD1-depleted cells remain sensitive to staurosporine, suggesting a different mechanism for EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either by Mul1-mediated ubiquitylation and degradation of the fusion protein Mfn2, or by removal of inactive Drp1 from the mitochondrial membrane. We demonstrate that EHD1 and its interaction partner rabankyrin-5 interact with the retromer complex to influence mitochondrial dynamics, likely by inducing VPS35-mediated removal of inactive Drp1 from mitochondrial membranes. Our study sheds light on mitochondrial dynamics, expanding a new paradigm of endocytic protein regulation of mitochondrial homeostasis. PMID- 28596242 TI - Smooth muscle function and myosin polymerization. AB - Smooth muscle is able to function over a much broader length range than striated muscle. The ability to maintain contractility after a large length change is thought to be due to an adaptive process involving restructuring of the contractile apparatus to maximize overlap between the contractile filaments. The molecular mechanism for the length-adaptive behavior is largely unknown. In smooth muscle adapted to different lengths we quantified myosin monomers, basal and activation-induced myosin light chain (MLC) phosphorylation, shortening velocity, power output and active force. The muscle was able to generate a constant maximal force over a two fold length range when it was allowed to go through isometric contraction/relaxation cycles after each length change (length adaptation). In the relaxed state, myosin monomer concentration and basal MLC phosphorylation decreased linearly, while in the activated state activation induced MLC phosphorylation and shortening velocity/power output increased linearly with muscle length. The results suggest that recruitment of myosin monomers and oligomers into the actin filament lattice (where they form force generating filaments) occurs during muscle adaptation to longer length, with the opposite occurring during adaptation to shorter length. PMID- 28596241 TI - Disruption of Rab8a and Rab11a causes formation of basolateral microvilli in neonatal enteropathy. AB - Misplaced formation of microvilli to basolateral domains and intracellular inclusions in enterocytes are pathognomonic features in congenital enteropathy associated with mutation of the apical plasma membrane receptor syntaxin 3 (STX3). Although the demonstrated binding of Myo5b to the Rab8a and Rab11a small GTPases in vitro implicates cytoskeleton-dependent membrane sorting, the mechanisms underlying the microvillar location defect remain unclear. By selective or combinatory disruption of Rab8a and Rab11a membrane traffic in vivo, we demonstrate that transport of distinct cargo to the apical brush border rely on either individual or both Rab regulators, whereas certain basolateral cargos are redundantly transported by both factors. Enterocyte-specific Rab8a and Rab11a double-knockout mouse neonates showed immediate postnatal lethality and more severe enteropathy than single knockouts, with extensive formation of microvilli along basolateral surfaces. Notably, following an inducible Rab11a deletion from neonatal enterocytes, basolateral microvilli were induced within 3 days. These data identify a potentially important and distinct mechanism for a characteristic microvillus defect exhibited by enterocytes of patients with neonatal enteropathy. PMID- 28596245 TI - Computerised cognitive-behavioural therapy for adults with intellectual disability: randomised controlled trial. AB - BackgroundDespite the evidence base for computer-assisted cognitive-behavioural therapy (CBT) in the general population, it has not yet been adapted for use with adults who have an intellectual disability.AimsTo evaluate the utility of a CBT computer game for adults who have an intellectual disability.MethodA 2 * 3 (group * time) randomised controlled trial design was used. Fifty-two adults with mild to moderate intellectual disability and anxiety or depression were randomly allocated to two groups: computerised CBT (cCBT) or psychiatric treatment as usual (TAU), and assessed at pre-treatment, post-treatment and 3-month follow-up. Forty-nine participants were included in the final analysis.ResultsA significant group * time interaction was observed on the primary outcome measure of anxiety (Glasgow Anxiety Scale for people with an Intellectual Disability), favouring cCBT over TAU, but not on the primary outcome measure of depression (Glasgow Depression Scale for people with a Learning Disability). A medium effect size for anxiety symptoms was observed at post-treatment and a large effect size was observed after follow-up. Reliability of Change Indices indicated that the intervention produced clinically significant change in the cCBT group in comparison with TAU.ConclusionsAs the first application of cCBT for adults with intellectual disability, this intervention appears to be a useful treatment option to reduce anxiety symptoms in this population. PMID- 28596244 TI - Weight cycling and the subsequent onset of type 2 diabetes mellitus: 10-year cohort studies in urban and rural Japan. AB - OBJECTIVE: To investigate how weight cycling (gaining and losing weight) affects the risk of diabetes. DESIGN: Cohort studies. SETTING: Primary healthcare in urban and rural Japan. PARTICIPANTS: 20 708 urban and 9670 rural residents. PRIMARY OUTCOME MEASURES: ORs for diabetes in those with weight loss, weight loss gain, stable weight, weight gain-loss and weight gain over 10 years. Weight gain and loss were defined as a change of more than +/-4% from baseline weight. RESULTS: In the urban region, the ORs relative to the stable group for the loss gain and gain-loss groups were 0.63 (95% CI 0.45 to 0.89) and 0.51 (95% CI 0.32 to 0.82) for men and 0.72 (95% CI 0.39 to 1.34) and 1.05 (95% CI 0.57 to 1.95) for women. In the rural region, they were 1.58 (95% CI 0.78 to 3.17) and 0.44 (95% CI 0.15 to 1.29) in men and 0.41 (95% CI 0.12 to 1.44) and 0.77 (95% CI 0.28 to 2.14) in women. The ORs for an increase in weight between 5 and 10 kg from the age of 20 years were 1.54 (95% CI 1.03 to 2.30) in men and 0.96 (95% CI 0.55 to 1.65) in women. CONCLUSIONS: In Japan, weight cycling was associated with a significant reduction in the risk of diabetes for men from urban regions. The associations were unclear for women from urban regions and both men and women from rural regions. These results differ from those in Western studies, probably because of differences in diet, insulin secretion and sensitivity and weight consciousness. PMID- 28596246 TI - Cancer mortality in patients with schizophrenia: systematic review and meta analysis. AB - BackgroundPrevious studies have reported conflicting results on the association between schizophrenia and cancer mortality.AimsTo summarise available evidence and quantify the association between schizophrenia and cancer mortality using meta-analysis.MethodWe systematically searched literature in the PubMed and Embase databases. Risk estimates and 95% confidence intervals reported in individual studies were pooled using the DerSimonian-Laird random-effects model.ResultsWe included 19 studies in the meta-analysis. Among them, 15 studies reported standardised mortality ratios (SMRs) comparing patients with schizophrenia with the general population, and the pooled SMR was 1.40 (95% CI 1.29-1.52, P < 0.001). The other four studies reported hazard ratios (HRs) comparing individuals with schizophrenia with those without schizophrenia; the pooled HR was 1.51 (95% CI 1.13-2.03, P = 0.006).ConclusionsPatients with schizophrenia are at a significantly increased risk of cancer mortality compared with the general population or individuals without schizophrenia. PMID- 28596250 TI - The risks of folic acid to the nervous system in vitamin B12 deficiency: rediscovered in the era of folic acid fortification policies. PMID- 28596249 TI - Maternal autoimmunity: risk of neurodevelopmental and neuropsychiatric outcomes. PMID- 28596247 TI - Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. AB - Objective To assess the impact of incretin based treatment on all cause mortality in patients with type 2 diabetes.Design Systematic review and meta-analysis of randomised trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov.Eligibility criteria Randomised controlled trials that compared glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors with placebo or active anti-diabetic drugs in patients with type 2 diabetes.Data collection and analysis Paired reviewers independently screened citations, assessed risk of bias of included studies, and extracted data. Peto's method was used as the primary approach to pool effect estimates from trials, sensitivity analyses were carried out with other statistical approaches, and meta-regression was applied for six prespecified hypotheses to explore heterogeneity. The GRADE approach was used to rate the quality of evidence.Results 189 randomised controlled trials (n=155 145) were included, all of which were at low to moderate risk of bias; 77 reported no events of death and 112 reported 3888 deaths among 151 614 patients. Meta analysis of 189 trials showed no difference in all cause mortality between incretin drugs versus control (1925/84 136 v 1963/67 478; odds ratio 0.96, 95% confidence interval 0.90 to 1.02, I2=0%; risk difference 3 fewer events (95% confidence interval 7 fewer to 1 more) per 1000 patients over five years; moderate quality evidence). Results suggested the possibility of a mortality benefit with GLP-1 agonists but not DPP-4 inhibitors, but the subgroup hypothesis had low credibility. Sensitivity analyses showed no important differences in the estimates of effects.Conclusions Current evidence does not support the suggestion that incretin based treatment increases all cause mortality in patients with type 2 diabetes. Further studies are warranted to examine if the effect differs between GLP-1 agonists versus DPP-4 inhibitors. PMID- 28596248 TI - Examining the language and behavioural profile in FTD and ALS-FTD. AB - BACKGROUND: A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS FTD) is indistinguishable from that of bvFTD alone. METHODS: A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. RESULTS: A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p=0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups. CONCLUSIONS: Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD. PMID- 28596251 TI - Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis. AB - OBJECTIVE: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers. METHODS: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI). RESULTS: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p<0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, rho=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, rho=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI. CONCLUSIONS: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease. PMID- 28596252 TI - Success in bone marrow failure? Novel therapeutic directions based on the immune environment of myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are clonal neoplasms of aging that are associated with BM failure, related cytopenias, fatigue, susceptibility to infections, bruising, bleeding, a shortened lifespan, and a propensity for leukemic transformation. Most frail, elderly patients are not candidates for curative allogeneic BM transplantations and instead receive expectant management, supportive blood transfusions, or empirical, nontargeted therapy. It has been known for some time that MDS arises in an abnormal BM immune environment; however, connections have only recently been established with recurring MDS associated mutations. Understanding how mutant clones alter and thrive in the immune environment of marrow failure at the expense of normal hematopoiesis opens the door to novel therapeutic strategies that are aimed at restoring immune and hematopoietic balance. Several examples are highlighted in this review. Haploinsufficiency of microRNAs 145 and 146a in MDS with chromosome 5q deletions leads to derepression of TLR4 signaling, dysplasia, and suppression of normal hematopoiesis. Moreover, mutations of TET2 or DNMT3A-regulators of cytosine methylation-are among the earliest in myeloid cancers and are even found in healthy adults with cryptic clonal hematopoiesis. In innate immune cells, TET2 and DNMT3A mutations impair the resolution of inflammation and production of type I IFNs, respectively. Finally, a common result of MDS-associated mutations is the inappropriate activation of the NLRP3 inflammasome, with resultant pyroptotic cell death, which favors mutant clone expansion. In summary, MDS-associated mutations alter the BM immune environment, which provides a milieu that is conducive to clonal expansion and leukemic progression. Restoring this balance may offer new therapeutic avenues for patients with MDS. PMID- 28596253 TI - Getting Practical About Recertification. PMID- 28596254 TI - Keeping Up in the Community. PMID- 28596255 TI - Thrombotic Thrombocytopenic Purpura Associated With Pegylated Interferon Alfa-2a Use in a Patient With Polycythemia Vera. AB - Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV. Our patient had a low ADAMTS13 level due to an inhibitor, which normalized after withholding pegIFNa and initiating treatment for TTP with therapeutic plasma exchange and corticosteroids. She experienced refractory TTP, necessitating treatment with rituximab and splenectomy. Postsplenectomy, she developed a high platelet count, warranting the need to restart treatment for PV. However, JAK2V617F allelic burden by real-time PCR was 0.7%, indicating that the increased platelet count was likely secondary to splenectomy. Therefore, we elected to monitor her counts and JAK2V617F allelic burden closely. With this case report, we hope to alert treating physicians that TTP should be considered as a complication of pegIFNa therapy in PV and that prompt discontinuation of the drug with necessary treatment should be instituted to prevent fatal complications. PMID- 28596257 TI - Developments in Molecular Testing and Biosimilars. AB - Molecular testing and biosimilars offer the potential for increased access to targeted treatment options and reduction in healthcare costs, but come with significant challenges in ensuring patient access to innovation in cancer care while maintaining safe, effective, ethical, and affordable treatment options. As providers, payers, patients, and the larger healthcare systems become inundated with a wide variety of molecular diagnostics and an increased number of biosimilars coming to market, it will be important to understand regulatory guidance and policy implications relating to the appropriateness of molecular testing and the clinical use of biosimilars in cancer care. In September 2016, NCCN hosted the Molecular Testing and Biosimilars Policy Summit to address the challenges, issues, and opportunities in both the molecular testing and biosimilar landscapes. Keynote presentations and panelists further discussed the status and future of molecular testing and biosimilars within the oncology space, as well as patient access and education needs moving forward. PMID- 28596256 TI - NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017. AB - The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer. PMID- 28596258 TI - Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution. AB - Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend that patients with clinical stage I/II breast cancer undergo advanced imaging for staging only when symptomatic. Regardless, many asymptomatic patients undergo chest CT. The goal of this study was to assess the use and results of chest CT in these patients at an NCCN Member Institution. Methods: Patients with breast cancer diagnosed between 1998 and 2012 were identified in a prospectively maintained database. All patients with clinical stage I/II disease who did not receive neoadjuvant chemotherapy were included. Data collected included demographics, tumor size, node status, chest CT within 6 months of diagnosis, imaging findings, need for additional workup, and identification of metastatic disease. Appropriate statistical tests were used for analysis. Results: From 1998 to 2012, 3,321 patients were diagnosed with early-stage breast cancer. Of these, 2,062 (62.1%) had clinical stage I breast cancer at diagnosis and 1,259 (37.9%) had stage II; 227 patients (11%) with stage I and 456 (36.2%) with stage II breast cancer received staging chest CT. Of patients undergoing CT, 184 (26.9%) were found to have pulmonary nodules, which measured <=5 mm for 128 patients (69.6%), 5 to 10 mm for 46 patients (25.0%), 11 to 20 mm for 6 patients (3.2%), and >=20 mm for 4 patients (2.2%). Patients undergoing chest CT for staging subsequently underwent a mean of 2.34 (range, 0-16) additional CTs in follow-up. Of all patients undergoing chest CT for staging, only 9 (1.3%) were ultimately diagnosed with pulmonary metastases at an average of 25 months (range, 0-97) after initial staging chest CT. Conclusions: A significant percentage of patients with stage I/II breast cancer underwent unnecessary chest CT as part of their initial workup. Nearly one-third of these patients were found to have pulmonary nodules, but only 1.3% were ever diagnosed with pulmonary metastases. Adherence to NCCN Guidelines will reduce the excessive use of CT chest imaging. PMID- 28596259 TI - Morphologic and Molecular Characteristics of De Novo AML With JAK2 V617F Mutation. AB - Background:JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next generation sequencing. The control group consisted of 12 patients with JAK2 wild type (wt) AML matched for age, sex, and diagnosis. Results: We identified 11 patients (0.5%) with JAK2 V617F, with a median age at diagnosis of 72.5 years (range, 36-90 years). Ten neoplasms were classified as AML with myelodysplasia related changes and 1 as AML with t(8;21)(q22;q22). All JAK2mut AML cases showed at least bilineage dysplasia, 7 of 11 showed fibrosis, 8 of 11 had an abnormal karyotype, and 5 had deletions or monosomy of chromosomes 5 and 7. Using the European LeukemiaNet (ELN) classification, 9 patients (82%) with JAK2mut AML were intermediate-2 and adverse risk. Cases of JAK2mut AML did not have mutations in other activating signaling pathways (P=.013); 7 (64%) showed additional mutations in at least one gene involving DNA methylation and/or epigenetic modification. Patients with JAK2mut AML had a significantly higher median BM granulocyte percentage (12% vs 3.5%; P=.006) and a higher frequency of ELN intermediate-2 and adverse risk cytogenetics (P=.04) compared with those with JAK2wt AML. JAK2mut AML showed higher circulating blasts, but this difference was not significant (17% vs 5.5%; P=not significant). No difference was seen in the median overall survival rate of patients with JAK2mut AML versus those with JAK2wt AML (14 vs 13.5 months, respectively). Conclusions: De novo JAK2mut AML is rare and frequently found in patients with dysplasia, BM fibrosis, and abnormal karyotype with intermediate- or high-risk features; gene mutations in DNA methylation and epigenetic-modifying pathways; and absence of gene mutations in activating signaling pathways. PMID- 28596260 TI - Evaluating the NCCN Clinical Criteria for Recommending BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer. AB - Background: Mutations in the BRCA1 and BRCA2 genes predispose individuals to a significantly elevated risk for breast and ovarian cancers. Identification of these individuals allows for proper screening, management, and testing of at-risk relatives. NCCN has established clinical criteria for recommending BRCA1/2 testing. Patients and Methods: A retrospective chart review of 1,123 patients with breast cancer was performed to evaluate the positive predictive values (PPVs) of 14 individual criteria for predicting BRCA1/2 mutations. Results: Two criteria had PPVs significantly below 10%. Only 2 of 115 patients who were recommended for testing based solely on the criterion of "diagnosed with breast cancer at <=45 years of age" had pathogenic mutations at a PPV of 1.6% (95% CI, 0.2%-6.0%). Additionally, 0 of 37 individuals who underwent testing based on the criterion, "diagnosed with breast cancer at any age with >=2 close blood relatives with breast cancer at any age" tested positive (95% CI, 0%-9%). Overall, meeting >1 criterion has a PPV of 12%, whereas meeting only 1 criterion has a PPV of 3.2% (95% CI, 1.6%-5.7%), significantly below 10% (P<.0001) for predicting BRCA1/2 positivity. Conclusions: Patients with breast cancer meeting >1 criterion constitute a population significantly enriched for BRCA1/2 mutations, whereas those meeting only 1 criterion test positive at a rate similar to unselected patients with breast cancer. These data will inform ongoing discussions regarding how to best implement BRCA1/2 genetic testing. PMID- 28596261 TI - Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. AB - The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim. PMID- 28596262 TI - Optimal Surveillance Strategies After Surgery for Renal Cell Carcinoma. AB - One in 5 patients who undergo surgical resection for clinically localized renal cell carcinoma (RCC) develop local and/or distant recurrences which, when detected early, may be amenable to salvage local and systemic therapies. When considering that approximately half of these recurrences will occur during the first 2 years, a clear rationale exists for optimizing surveillance strategies after surgery. Although there is a notable dearth of high-quality data on this subject, clinical principles can guide clinicians as they attempt to balance the burden of surveillance strategies with potential clinical benefit. The objective of this review is to summarize the evidence regarding optimal surveillance protocols after surgery for RCC. We provide an overview of the rationale supporting surveillance after surgery, a summary of the American Urological Association and NCCN guidelines, reasons against routine long-term surveillance, surveillance costs, and ancillary issues, such as the utility of bone scan, PET/CT scan, and surveillance after thermoablation. PMID- 28596263 TI - Integrating Immunotherapy Into the Management of Renal Cell Carcinoma. AB - Before 2005, systemic treatment of metastatic renal cell carcinoma (RCC) was limited to a few minimally effective options. Since then, new agents have emerged targeting the vascular endothelial growth factor and mTOR pathways, which has improved outcomes for patients. Options increased even further beginning in 2015 with 3 new agents, including the addition of nivolumab, the first immune checkpoint inhibitor to demonstrate improved survival in RCC. RCC has long been considered a malignancy with immunogenic potential, and nivolumab offers the potential for durable responses in some patients with a generally tolerable toxicity profile. With so many drugs available to clinicians and patients, properly integrating immune checkpoint blockade (ICB) into the treatment paradigm is challenging. Additionally, emerging research with other ICB agents, as well as ongoing trials of combination strategies, is likely to further impact clinical decision-making. This article attempts to provide some context to inform systemic treatment decisions in the current landscape, with a particular emphasis on the role of immunotherapy, outlines the ongoing immunotherapy research in RCC, and discusses how treatment may evolve. PMID- 28596264 TI - Evidence-Based Guidelines: Optimizing Imaging in Cancer Care. PMID- 28596266 TI - NCCN News. PMID- 28596267 TI - Adaptations of motoneuron properties after weight-lifting training in rats. AB - Resistance training, with repeated short-term and high-intensity exercises, is responsible for an increase in muscle mass and force. The aim of this study was to determine whether such training induces adaptations in the electrophysiological properties of motoneurons innervating the trained muscles and to relate these adaptive changes to previous observations made on motor unit contractile properties. The study was performed on adult male Wistar rats. Animals from the training group were subjected to a 5-wk voluntary progressive weight-lifting program, whereas control rats were restricted to standard cage activity. Intracellular recordings from lumbar spinal motoneurons were made under pentobarbital anesthesia. Membrane properties were measured, and rhythmic firing of motoneurons was analyzed. Strength training evoked adaptive changes in both slow- and fast-type motoneurons, indicating their increased excitability. A shorter spike duration, a higher input resistance, a lower rheobase, a decrease in the minimum current required to evoke rhythmic firing, an increase in the maximum frequencies of the early-state firing (ESF) and the steady-state firing (SSF), and an increase in the respective slopes of the frequency-current (f/I) relationship were observed in fast motoneurons of the trained group. The increase in the maximum ESF and SSF frequencies and an increase in the SSF f/I slope were also present in slow motoneurons. Higher maximum firing rates of motoneurons as well as higher discharge frequencies evoked at the same level of intracellular depolarization current imply higher levels of tetanic forces developed by motor units over the operating range of force production after strength training.NEW & NOTEWORTHY Neuronal responses to weight-lifting training can be observed in altered properties of both slow and fast motoneurons. Motoneurons of trained animals are more excitable, require lower intracellular currents to evoke rhythmic firing, and have the ability to evoke higher maximum discharge frequencies during repetitive firing. PMID- 28596268 TI - Application of Euclidean distance mapping for assessment of basement membrane thickness distribution in asthma. AB - Abnormal thickening of the airway basement membrane is one of the hallmarks of airway remodeling in asthma. The present protocols for measuring the basement membrane involve the use of stained tissue sections and measurements of the basement membrane thickness at certain intervals, followed by the calculation of the geometric mean thickness for each airway. This report describes an automated, unbiased approach which uses color segmentation to identify structures of interest on stained sections and Euclidean distance mapping to measure the thickness distribution of airway structures. This method was applied to study the thickness distribution of the basement membrane and airway epithelium in lungs donated for research from seven nonasthmatic and eight asthmatic age- and sex matched donors. A total of 60 airways were assessed. We report that the thickness and thickness distribution of the basement membrane and airway epithelium are increased in large and small airways of asthmatics compared with nonasthmatics. Using this method we were able to demonstrate the heterogeneity in the thickness of the basement membrane and airway epithelium within individual airways of asthmatic subjects. This new computational method enables comprehensive and objective quantification of airway structures, which can be used to quantify heterogeneity of airway remodeling in obstructive lung diseases such as asthma and chronic obstructive pulmonary disease.NEW & NOTEWORTHY The described application of Euclidean distance mapping provides an unbiased approach to study the extent and thickness distribution of changes in tissue structures. This approach will enable researchers to use computer-aided analysis of structural changes within lung tissue to understand the heterogeneity of airway remodeling in lung diseases. PMID- 28596270 TI - Timing of postexercise carbohydrate-protein supplementation: roles of gastrointestinal blood flow and mucosal cell damage on gastric emptying in humans. AB - It is well known that protein ingestion immediately after exercise greatly stimulates muscle protein synthesis during the postexercise recovery phase. However, immediately after strenuous exercise, the gastrointestinal (GI) mucosa is frequently injured by hypoperfusion in the organ/tissue, possibly resulting in impaired GI function (e.g., gastric emptying; GE). The aim of this study was to examine the effect of GI blood flow on the GE rate. Eight healthy young subjects performed an intermittent supramaximal cycling exercise for 30 min, which consisted of a 120% Vo2peak for 20 s, followed by 20 W for 40 s. The subjects ingested 300 ml of a nutrient drink containing carbohydrate-protein at either 5 min postexercise in one trial (PE-5) or 30 min postexercise in another trial (PE 30). In the control trial (Con), the subjects ingested the same drink without exercise. The celiac artery blood flow (CABF) and superior mesenteric artery blood flow (SMABF) and GE rate were assessed by ultrasonography. Before drink ingestion in PE-5, CABF significantly decreased from baseline, whereas in PE-30, it returned to baseline. Following drink ingestion in PE-5, CABF did not change from baseline, but it significantly increased in PE-30 and Con. SMABF increased significantly later in PE-5 than in PE-30 and Con. The GE rate was consistently slower in PE-5 than in PE-30 and Con. In conclusion, the CABF response after exercise seems to modulate the subsequent GE rate and SMABF response.NEW & NOTEWORTHY A carbohydrate-protein drink was ingested at either 5 min (i.e., profoundly decreased celiac artery blood flow; CABF) or 30 min (i.e., already recovered CABF) postexercise. In the 5-min postexercise trial, the gastric emptying (GE) rate and superior mesenteric artery blood flow (SMABF) response were slower than those in the 30-min postexercise trial. The GE rate and SMABF response may be altered depending on the postexercise CABF response. PMID- 28596271 TI - Extracting aerobic system dynamics during unsupervised activities of daily living using wearable sensor machine learning models. AB - Physical activity levels are related through algorithms to the energetic demand, with no information regarding the integrity of the multiple physiological systems involved in the energetic supply. Longitudinal analysis of the oxygen uptake (Vo2) by wearable sensors in realistic settings might permit development of a practical tool for the study of the longitudinal aerobic system dynamics (i.e., Vo2 kinetics). This study evaluated aerobic system dynamics based on predicted Vo2 data obtained from wearable sensors during unsupervised activities of daily living (MUADL). Thirteen healthy men performed a laboratory-controlled moderate exercise protocol and were monitored for ~6 h/day for 4 days (MUADL data). Variables derived from hip accelerometer (ACCHIP), heart rate monitor, and respiratory bands during MUADL were extracted and processed by a validated random forest regression model to predict Vo2. The aerobic system analysis was based on the frequency-domain analysis of ACCHIP and predicted Vo2 data obtained during MUADL. Optimal samples for frequency domain analysis (constrained to <=0.01 Hz) were selected when ACCHIP was higher than 0.05 g at a given frequency (i.e., participants were active). The temporal characteristics of predicted Vo2 data during MUADL correlated with the temporal characteristics of measured Vo2 data during laboratory-controlled protocol ([Formula: see text] = 0.82, P < 0.001, n = 13). In conclusion, aerobic system dynamics can be investigated during unsupervised activities of daily living by wearable sensors. Although speculative, these algorithms have the potential to be incorporated into wearable systems for early detection of changes in health status in realistic environments by detecting changes in aerobic response dynamics. NEW & NOTEWORTHY The early detection of subclinical aerobic system impairments might be indicative of impaired physiological reserves that impact the capacity for physical activity. This study is the first to use wearable sensors in unsupervised activities of daily living in combination with novel machine learning algorithms to investigate the aerobic system dynamics with the potential to contribute to models of functional health status and guide future individualized health care in the normal population. PMID- 28596272 TI - Exercise training in heart failure: which training modality works best? PMID- 28596269 TI - Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke. AB - It has been suggested that medications can increase heat stroke (HS) susceptibility/severity. We investigated whether the nonsteroidal anti inflammatory drug (NSAID) indomethacin (INDO) increases HS severity in a rodent model. Core temperature (Tc) of male, C57BL/6J mice (n = 45) was monitored continuously, and mice were given a dose of INDO [low dose (LO) 1 mg/kg or high dose (HI) 5 mg/kg in flavored treat] or vehicle (flavored treat) before heating. HS animals were heated to 42.4 degrees C and euthanized at three time points for histological, molecular, and metabolic analysis: onset of HS [maximal core temperature (Tc,Max)], 3 h of recovery [minimal core temperature or hypothermia depth (HYPO)], and 24 h of recovery (24 h). Nonheated (control) animals underwent identical treatment in the absence of heat. INDO (LO or HI) had no effect on physiological indicators of performance (e.g., time to Tc,Max, thermal area, or cooling time) during heating or recovery. HI INDO resulted in 45% mortality rate by 24 h (HI INDO + HS group). The gut showed dramatic increases in gross morphological hemorrhage in HI INDO + HS in both survivors and nonsurvivors. HI INDO + HS survivors had significantly lower red blood cell counts and hematocrit suggesting significant hemorrhage. In the liver, HS induced cell death at HYPO and increased inflammation at Tc,Max, HYPO, and 24 h; however, there was additional effect with INDO + HS group. Furthermore, the metabolic profile of the liver was disturbed by heat, but there was no additive effect of INDO + HS. This suggests that there is an increase in morbidity risk with INDO + HS, likely resulting from significant gut injury.NEW & NOTEWORTHY This paper suggests that in a translational mouse model, NSAIDs may be counterindicated in situations that put an individual at risk of heat injury. We show here that a small, single dose of the NSAID indomethacin before heat stroke has a dramatic and highly damaging effect on the gut, which ultimately leads to increased systemic morbidity. PMID- 28596273 TI - Novel analysis of 4DCT imaging quantifies progressive increases in anatomic dead space during mechanical ventilation in mice. AB - Increased dead space is an important prognostic marker in early acute respiratory distress syndrome (ARDS) that correlates with mortality. The cause of increased dead space in ARDS has largely been attributed to increased alveolar dead space due to ventilation/perfusion mismatching and shunt. We sought to determine whether anatomic dead space also increases in response to mechanical ventilation. Mice received intratracheal lipopolysaccharide (LPS) or saline and mechanical ventilation (MV). Four-dimensional computed tomography (4DCT) scans were performed at onset of MV and after 5 h of MV. Detailed measurements of airway volumes and lung tidal volumes were performed using image analysis software. The forced oscillation technique was used to obtain measures of airway resistance, tissue damping, and tissue elastance. The ratio of airway volumes to total tidal volume increased significantly in response to 5 h of mechanical ventilation, regardless of LPS exposure, and airways demonstrated significant variation in volumes over the respiratory cycle. These findings were associated with an increase in tissue elastance (decreased lung compliance) but without changes in tidal volumes. Airway volumes increased over time with exposure to mechanical ventilation without a concomitant increase in tidal volumes. These findings suggest that anatomic dead space fraction increases progressively with exposure to positive pressure ventilation and may represent a pathological process.NEW & NOTEWORTHY We demonstrate that anatomic dead space ventilation increases significantly over time in mice in response to mechanical ventilation. The novel functional lung-imaging techniques applied here yield sensitive measures of airway volumes that may have wide applications. PMID- 28596275 TI - Skeletal muscle morphology, protein synthesis, and gene expression in Ehlers Danlos syndrome. AB - Patients with Ehlers-Danlos syndrome (EDS) are known to have genetically impaired connective tissue and skeletal muscle symptoms in form of pain, fatigue, and cramps; however earlier studies have not been able to link these symptoms to morphological muscle changes. We obtained skeletal muscle biopsies in patients with classic EDS [cEDS; n = 5 (Denmark)+ 8 (The Netherlands)] and vascular EDS (vEDS; n = 3) and analyzed muscle fiber morphology and content (Western blotting and muscle fiber type/area distributions) and muscle mRNA expression and protein synthesis rate (RT-PCR and stable isotope technique). The cEDS patients did not differ from healthy controls (n = 7-11) with regard to muscle fiber type/area, myosin/alpha-actin ratio, muscle protein synthesis rate, or mRNA expression. In contrast, the vEDS patients demonstrated higher expression of matrix proteins compared with cEDS patients (fibronectin and MMP-2). The cEDS patients had surprisingly normal muscle morphology and protein synthesis, whereas vEDS patients demonstrated higher mRNA expression for extracellular matrix remodeling in skeletal musculature compared with cEDS patients.NEW & NOTEWORTHY This study is the first of its kind to systematically investigate muscle biopsies from Ehlers-Danlos patients, focusing on muscle structure and function. These patients suffer from severe muscle symptoms, but in our study they show surprisingly normal muscle findings, which points toward indirect muscle symptoms originating from the surrounding connective tissue. These findings have basal physiological importance and implications for future physiotherapeutic treatment options for these patients. PMID- 28596276 TI - Comparing the cytotoxicity of electronic cigarette fluids, aerosols and solvents. AB - BACKGROUND: As thousands of electronic cigarette (e-cigarette) refill fluids continue to be formulated and distributed, there is a growing need to understand the cytotoxicity of the flavouring chemicals and solvents used in these products to ensure they are safe. The purpose of this study was to compare the cytotoxicity of e-cigarette refill fluids/solvents and their corresponding aerosols using in vitro cultured cells. METHODS: E-cigarette refill fluids and do it-yourself products were screened in liquid and aerosol form for cytotoxicity using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. The sensitivity of human pulmonary fibroblasts, lung epithelial cells (A549) and human embryonic stem cells to liquids and aerosols was compared. Aerosols were produced using Johnson Creek's Vea cartomizer style e-cigarette. RESULTS: A hierarchy of potency was established for the aerosolised products. Our data show that (1) e-cigarette aerosols can produce cytotoxic effects in cultured cells, (2) four patterns of cytotoxicity were found when comparing refill fluids and their corresponding aerosols, (3) fluids accurately predicted aerosol cytotoxicity 74% of the time, (4) stem cells were often more sensitive to aerosols than differentiated cells and (5) 91% of the aerosols made from refill fluids containing only glycerin were cytotoxic, even when produced at a low voltage. CONCLUSIONS: Our data show that various flavours/brands of e-cigarette refill fluids and their aerosols are cytotoxic and demonstrate the need for further evaluation of e-cigarette products to better understand their potential health effects. PMID- 28596274 TI - Dietary nitrate restores compensatory vasodilation and exercise capacity in response to a compromise in oxygen delivery in the noncompensator phenotype. AB - Recently, dietary nitrate supplementation has been shown to improve exercise capacity in healthy individuals through a potential nitrate-nitrite-nitric oxide pathway. Nitric oxide has been shown to play an important role in compensatory vasodilation during exercise under hypoperfusion. Previously, we established that certain individuals lack a vasodilation response when perfusion pressure reductions compromise exercising muscle blood flow. Whether this lack of compensatory vasodilation in healthy, young individuals can be restored with dietary nitrate supplementation is unknown. Six healthy (21 +/- 2 yr), recreationally active men completed a rhythmic forearm exercise. During steady state exercise, the exercising arm was rapidly transitioned from an uncompromised (below heart) to a compromised (above heart) position, resulting in a reduction in local pressure of -31 +/- 1 mmHg. Exercise was completed following 5 days of nitrate-rich (70 ml, 0.4 g nitrate) and nitrate-depleted (70 ml, ~0 g nitrate) beetroot juice consumption. Forearm blood flow (in milliliters per minute; brachial artery Doppler and echo ultrasound), mean arterial blood pressure (in millimeters of mercury; finger photoplethysmography), exercising forearm venous effluent (ante-cubital vein catheter), and plasma nitrite concentrations (chemiluminescence) revealed two distinct vasodilatory responses: nitrate supplementation increased (plasma nitrite) compared with placebo (245 +/- 60 vs. 39 +/- 9 nmol/l; P < 0.001), and compensatory vasodilation was present following nitrate supplementation (568 +/- 117 vs. 714 +/- 139 ml ? min-1 ? 100 mmHg-1; P = 0.005) but not in placebo (687 +/- 166 vs. 697 +/- 171 min-1 ? 100 mmHg-1; P = 0.42). As such, peak exercise capacity was reduced to a lesser degree (-4 +/- 39 vs. -39 +/- 27 N; P = 0.01). In conclusion, dietary nitrate supplementation during a perfusion pressure challenge is an effective means of restoring exercise capacity and enabling compensatory vasodilation.NEW & NOTEWORTHY Previously, we identified young, healthy persons who suffer compromised exercise tolerance when exercising muscle perfusion pressure is reduced as a result of a lack of compensatory vasodilation. The ability of nitrate supplementation to restore compensatory vasodilation in such noncompensators is unknown. We demonstrated that beetroot juice supplementation led to compensatory vasodilation and restored perfusion and exercise capacity. Elevated plasma nitrite is an effective intervention for correcting the absence of compensatory vasodilation in the noncompensator phenotype. PMID- 28596277 TI - The liver in regulation of iron homeostasis. AB - The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. PMID- 28596278 TI - HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype is associated with a high risk of asparaginase hypersensitivity in acute lymphoblastic leukemia. AB - Hypersensitivity reactions are the most frequent dose-limiting adverse reactions to Escherichia coli-derived asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. The aim of the present study was to identify associations between sequence-based Human Leukocyte Antigen Class II region alleles and asparaginase hypersensitivity in a Hungarian ALL population. Four digit typing of HLA-DRB1 and HLA-DQB1 loci was performed in 359 pediatric ALL patients by using next-generation sequencing method. Based on genotypic data of the two loci, haplotype reconstruction was carried out. In order to investigate the possible role of the HLA-DQ complex, the HLA-DQA1 alleles were also inferred. Multivariate logistic regression analysis and a Bayesian network-based approach were applied to identify relevant genetic risk factors of asparaginase hypersensitivity. Patients with HLA-DRB1*07:01 and HLA-DQB1*02:02 alleles had significantly higher risk of developing asparaginase hypersensitivity compared to non-carriers [P=4.56*10-5; OR=2.86 (1.73-4.75) and P=1.85*10-4; OR=2.99 (1.68 5.31); n=359, respectively]. After haplotype reconstruction, the HLA-DRB1*07:01 HLA-DQB1*02:02 haplotype was associated with an increased risk. After inferring the HLA-DQA1 alleles the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-DQB1*02:02 haplotype was associated with the highest risk of asparaginase hypersensitivity [P=1.22*10 5; OR=5.00 (2.43-10.29); n=257]. Significantly fewer T-cell ALL patients carried the HLA-DQB1*02:02 allele and the associated haplotype than did pre-B-cell ALL patients (6.5%; vs. 19.2%, respectively; P=0.047). In conclusion, we identified a haplotype in the Human Leukocyte Antigen Class II region associated with a higher risk of asparaginase hypersensitivity. Our results confirm that variations in HLA D region might influence the development of asparaginase hypersensitivity. PMID- 28596279 TI - Feasibility study of online yoga for symptom management in patients with myeloproliferative neoplasms. PMID- 28596280 TI - Extracellular vesicles of bone marrow stromal cells rescue chronic lymphocytic leukemia B cells from apoptosis, enhance their migration and induce gene expression modifications. AB - Interactions between chronic lymphocytic leukemia (CLL) B cells and the bone marrow (BM) microenvironment play a major function in the physiopathology of CLL. Extracellular vesicles (EVs), which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in CLL / microenvironment interactions. In the present study, EVs purified by ultracentrifugation from BM mesenchymal stromal cell (BM-MSC) cultures were added to CLL B cells. After their integration into CLL B cells, we observed a decrease of leukemic cell spontaneous apoptosis and an increase in their chemoresistance to several drugs, including fludarabine, ibrutinib, idelalisib and venetoclax after 24 hours. Spontaneous (P=0.0078) and stromal cell derived factor 1alpha -induced migration capacities of CLL B cells were also enhanced (P=0.0020). A microarray study highlighted 805 differentially expressed genes between leukemic cells cultured with or without EVs. Of these, genes involved in the B-cell receptor pathway such as CCL3/4, EGR1/2/3, and MYC were increased. Interestingly, this signature presents important overlaps with other microenvironment stimuli such as B-cell receptor stimulation, CLL/nurse-like cells co-culture or those provided by a lymph node microenvironment. Finally, we showed that EVs from MSCs of leukemic patients also rescue leukemic cells from spontaneous or drug-induced apoptosis. However, they induce a higher migration and also a stronger gene modification compared to EVs of healthy MSCs. In conclusion, we show that EVs play a crucial role in CLL B cells/BM microenvironment communication. PMID- 28596281 TI - Hemoglobin concentration, total hemoglobin mass and plasma volume in patients: implications for anemia. AB - In practice, clinicians generally consider anemia (circulating hemoglobin concentration < 120 g.l-1 in non-pregnant females and < 130 g.l-1 in males) as due to impaired hemoglobin synthesis or increased erythrocyte loss or destruction. Rarely is a rise in plasma volume relative to circulating total hemoglobin mass considered as a cause. But does this matter? We explored this issue in patients, measuring hemoglobin concentration, total hemoglobin mass (optimized carbon monoxide rebreathing method) and thereby calculating plasma volume in healthy volunteers, surgical patients, and those with inflammatory bowel disease, chronic liver disease or heart failure. We studied 109 participants. Hemoglobin mass correlated well with its concentration in the healthy, surgical and inflammatory bowel disease groups (r=0.687-0.871, P<0.001). However, they were poorly related in liver disease (r=0.410, P=0.11) and heart failure patients (r=0.312, P=0.16). Here, hemoglobin mass explained little of the variance in its concentration (adjusted R2=0.109 and 0.052; P=0.11 and 0.16), whilst plasma volume did (R2 change 0.724 and 0.805 in heart and liver disease respectively, P<0.0001). Exemplar patients with identical (normal or raised) total hemoglobin masses were diagnosed as profoundly anemic (or not) depending on differences in plasma volume that had not been measured or even considered as a cause. The traditional inference that anemia generally reflects hemoglobin deficiency may be misleading, potentially resulting in inappropriate tests and therapeutic interventions to address 'hemoglobin deficiency' not 'plasma volume excess'. Measurement of total hemoglobin mass and plasma volume is now simple, cheap and safe, and its more routine use is advocated. PMID- 28596282 TI - Chlorambucil plus rituximab as front-line therapy for elderly and/or unfit chronic lymphocytic leukemia patients: correlation with biologically-based risk stratification. PMID- 28596284 TI - Prognostic biopsy of choroidal melanoma: an optimised surgical and laboratory approach. AB - BACKGROUND: Accurate survival prognostication for patients with uveal melanoma (UM) enables effective patient counselling and permits personalised systemic surveillance for the early detection of metastases and, in high-risk patients, enrolment in any trials of systemic adjuvant therapy. The aim of this work is to determine the success of prognostic UM tumour biopsy using an improved surgical approach and optimised sample handling workflow. METHODS: Patients with UM treated by primary radiotherapy between 2011 and 2013 and who underwent a prognostic biopsy with cytology, multiplex ligation-dependent probe amplification and/or microsatellite analysis were included. The main outcomes and measures were success of cytology and genetic studies, and surgical complications. RESULTS: The cohort comprised 232 patients with UM having a median age of 59 years (range, 25 82) at treatment. The median largest basal diameter was 11.4 mm (range, 4.1-20.8) and tumour height was 3.4 mm (range, 0.7-10.3). Ciliary body involvement was noted in 42 cases. Treatment consisted of Ru-106 brachytherapy in 151 cases (65%) and proton beam radiotherapy in 81 cases (35%). With improvements in surgical techniques and laboratory methods over time, cytology success increased from 92% (131/142) to 99% (89/90) and the numbers of samples with sufficient DNA for genetic testing increased from 79% (104/131) to 93% (83/89). Overall, chromosome 3 loss was noted in 64/187 (34%) cases. Surgical complications, including transient localised bleeding, vitreous haemorrhage and retinal perforation, decreased over time. Eight patients required additional surgery. CONCLUSIONS: Improved surgical techniques and laboratory methods yielded successful cytology and genetic information in the majority of cases. PRECIS: Analysis of data from 232 patients with uveal melanoma undergoing prognostic tumour biopsy demonstrated that improved surgical techniques and laboratory methods yielded successful cytology and genetic information in 99% and 89% of cases, respectively. PMID- 28596283 TI - Combined targeting of STAT3 and STAT5: a novel approach to overcome drug resistance in chronic myeloid leukemia. AB - In chronic myeloid leukemia, resistance against BCR-ABL1 tyrosine kinase inhibitors can develop because of BCR-ABL1 mutations, activation of additional pro-oncogenic pathways, and stem cell resistance. Drug combinations covering a broad range of targets may overcome resistance. CDDO-Me (bardoxolone methyl) is a drug that inhibits the survival of leukemic cells by targeting different pro survival molecules, including STAT3. We found that CDDO-Me inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines and primary leukemic cells, including cells harboring BCR-ABL1T315I or T315I+ compound mutations. Furthermore, CDDO-Me was found to block growth and survival of CD34+/CD38- leukemic stem cells (LSC). Moreover, CDDO-Me was found to produce synergistic growth-inhibitory effects when combined with BCR-ABL1 tyrosine kinase inhibitors. These drug-combinations were found to block multiple signaling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. However, CDDO-Me was also found to increase the expression of heme-oxygenase-1, a heat-shock-protein that triggers drug resistance and cell survival. We therefore combined CDDO-Me with the heme oxygenase-1 inhibitor SMA-ZnPP, which also resulted in synergistic growth inhibitory effects. Moreover, SMA-ZnPP was found to sensitize BCR-ABL1+ cells against the combination 'CDDO-Me+ tyrosine kinase inhibitor'. Together, combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in BCR-ABL1+ cells, including stem cells and highly resistant sub-clones expressing BCR ABL1T315I or T315I-compound mutations. Whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia remains to be elucidated. PMID- 28596285 TI - Vitreomacular adhesion or vitreomacular traction may affect antivascular endothelium growth factor treatment for neovascular age-related macular degeneration. AB - OBJECTIVE: The aim of this review is to determine whether vitreomacular adhesion (VMA) or vitreomacular traction (VMT) has an influence on the outcomes of antivascular endothelium growth factor (anti-VEGF) treatment neovascular age related macular degeneration (nAMD). METHODS: A systematic literature search was performed in Pubmed.gov, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wanfang, SinoMed and ClinicalTrials.gov up to 30 June 2016 to identify eligible studies. RESULTS: Nine studies and 2212 participants were finally identified. At month 6, the mean improvement in best-corrected visual acuity (BCVA) and mean decline in central retinal thickness (CRT) of the VMA/VMT(+) group was less than that of the VMA/VMT(-) group (95% CI -3.05 to 0.96 letters, p=0.0002; 15.53 to 32.98 MUm, p<0.00001; respectively); at month 12, there was a small or only marginally significant difference (-0.01 to 2.00 letters, p=0.05; 0.17 to 23.7 MUm, p=0.05; respectively) between the groups. During the 12 months, however, the VMA/VMT(+) group required more injections ((0.25 to 0.95), p=0.0008). CONCLUSIONS: In using anti-VEGF drugs to treat nAMD, clinicians should take into account the fact that concurrent VMA or VMT might antagonise the efficacy of anti-VEGF drugs during the early stage of treatment. PMID- 28596286 TI - One-year outcome of intravitreal ziv-aflibercept therapy for non-responsive neovascular age-related macular degeneration. AB - AIM: To evaluate 12-month outcome of intravitreal ziv-aflibercept (IVZ) therapy in eyes with neovascular age-related macular degeneration (nAMD) that are non responsive to bevacizumab and ranibizumab. METHODS: This retrospective study included 16 eyes (14 patients) with nAMD who were on prior treatment with bevacizumab and ranibizumab and were treated with as-needed IVZ (1.25 mg/0.05 mL) for 12 months. The primary outcome measure was the mean change in best corrected visual acuity (BCVA) and secondary outcome measures included mean change in central macular thickness (CMT), retinal pigment epithelial detachment (RPED) heights, longest treatment free interval, presence of subretinal fluid (SRF) and intraretinal fluid (IRF) and adverse events. RESULTS: There was no change in the mean logarithm of minimum angle of resolution (logMAR) BCVA at baseline and following treatment with IVZ therapy (p=0.978). The mean number of IVZ injections during 12 months was 5.9+/-3.3, and the mean number of antivascular endothelial growth factors (VEGFs) injections prior to switching to IVZ was 8.4+/-4.7. The mean treatment free interval was longer during IVZ therapy (114.4+/-67.1 days) compared with 76.3+/-54.6 days before IVZ therapy (p=0.03). Five (31.25%) eyes had visual gains of at least 0.1 logMAR, 3 (18.75%) eyes had stable BCVA (within 0.1 logMAR) and 8 (50%) eyes had BCVA decline of at least 0.1 logMAR. There was no significant difference in the mean CMT, RPED heights and presence of IRF and SRF at 12 months compared with baseline. No adverse events were noted. CONCLUSION: IVZ increased the treatment free interval in non-responders but no significant change in visual and anatomic outcomes. PMID- 28596287 TI - Incidence and prevalence of uveitis in South Korea: a nationwide cohort study. AB - AIM: To evaluate the incidence and prevalence of uveitis and associated risk factors in South Korea. METHODS: For this retrospective national cohort study, approximately 1 000 000 Korean residents were randomly selected from the Korean National Health Insurance Service database. Uveitis was defined according to the Korean Classification of Diseases. The uveitis incidence and prevalence were calculated. Sociodemographic factors and comorbidities associated with uveitis were evaluated via Cox proportional regression models. RESULTS: A total of 1 094 440 subjects were evaluated over 7 051 346 person-years (mean follow-up: 6.44 years). Overall, 7447 newly developed uveitis cases were identified during the period of 2007-2013; the average incidence of uveitis was 10.6 per 10 000 person years (95% CI 10.3 to 10.8). The average incidences of anterior and non-anterior uveitis were 9.0 and 1.5 per 10 000 person-years, respectively. The prevalence rates of uveitis, anterior uveitis and non-anterior uveitis were 17.3, 15.0 and 2.3 per 10 000 persons, respectively, during the period of 2007-2013. Increasing age, male sex, residing in a relatively rural area and high income were associated with uveitis, along with Behcet's disease, juvenile idiopathic arthritis, ankylosing spondylitis, systemic lupus erythematous, ulcerative colitis and tuberculosis. CONCLUSIONS: The overall incidence of uveitis in Korea was similar to those reported in Taiwan and the USA. Despite a potentially inaccurate disease definition, claims data may be useful for monitoring the substantial uveitis burden in South Korea. PMID- 28596289 TI - Paediatric sepsis, the under-recognised killer: quality improvement initiative of outreach teaching in paediatric sepsis. AB - Sepsis is the leading cause of child's death, yet it is well known that the rapid initiation of simple, timely interventions reduces morbidity and mortality. This paper shares our findings on the barriers doctors in training have identified to delivering such care. We also share the results of a pilot paediatric intensive care unit outreach teaching programme designed to directly address these highlighted concerns. PMID- 28596288 TI - Should exercises be painful in the management of chronic musculoskeletal pain? A systematic review and meta-analysis. AB - BACKGROUND: Chronic musculoskeletal disorders are a prevalent and costly global health issue. A new form of exercise therapy focused on loading and resistance programmes that temporarily aggravates a patient's pain has been proposed. The object of this review was to compare the effect of exercises where pain is allowed/encouraged compared with non-painful exercises on pain, function or disability in patients with chronic musculoskeletal pain within randomised controlled trials. METHODS: Two authors independently selected studies and appraised risk of bias. Methodological quality was evaluated using the Cochrane risk of bias tool, and the Grading of Recommendations Assessment system was used to evaluate the quality of evidence. RESULTS: The literature search identified 9081 potentially eligible studies. Nine papers (from seven trials) with 385 participants met the inclusion criteria. There was short- term significant difference in pain, with moderate quality evidence for a small effect size of 0.27 (-0.54 to -0.05) in favour of painful exercises. For pain in the medium and long term, and function and disability in the short, medium and long term, there was no significant difference. CONCLUSION: Protocols using painful exercises offer a small but significant benefit over pain-free exercises in the short term, with moderate quality of evidence. In the medium and long term there is no clear superiority of one treatment over another. Pain during therapeutic exercise for chronic musculoskeletal pain need not be a barrier to successful outcomes. Further research is warranted to fully evaluate the effectiveness of loading and resistance programmes into pain for chronic musculoskeletal disorders. PROSPERO REGISTRATION: CRD42016038882. PMID- 28596290 TI - Yeast genetic interaction screen of human genes associated with amyotrophic lateral sclerosis: identification of MAP2K5 kinase as a potential drug target. AB - To understand disease mechanisms, a large-scale analysis of human-yeast genetic interactions was performed. Of 1305 human disease genes assayed, 20 genes exhibited strong toxicity in yeast. Human-yeast genetic interactions were identified by en masse transformation of the human disease genes into a pool of 4653 homozygous diploid yeast deletion mutants with unique barcode sequences, followed by multiplexed barcode sequencing to identify yeast toxicity modifiers. Subsequent network analyses focusing on amyotrophic lateral sclerosis (ALS) associated genes, such as optineurin (OPTN) and angiogenin (ANG), showed that the human orthologs of the yeast toxicity modifiers of these ALS genes are enriched for several biological processes, such as cell death, lipid metabolism, and molecular transport. When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for ALS therapy. The toxicity modifiers identified in this study may deepen our understanding of the pathogenic mechanisms of ALS and other devastating diseases. PMID- 28596292 TI - The PDE4 inhibitor CHF-6001 and LAMAs inhibit bronchoconstriction-induced remodeling in lung slices. AB - Combination therapy of PDE4 inhibitors and anticholinergics induces bronchoprotection in COPD. Mechanical forces that arise during bronchoconstriction may contribute to airway remodeling. Therefore, we investigated the impact of PDE4 inhibitors and anticholinergics on bronchoconstriction-induced remodeling. Because of the different mechanism of action of PDE4 inhibitors and anticholinergics, we hypothesized functional interactions of these two drug classes. Guinea pig precision-cut lung slices were preincubated with the PDE4 inhibitors CHF-6001 or roflumilast and/or the anticholinergics tiotropium or glycopyorrolate, followed by stimulation with methacholine (10 MUM) or TGF-beta1 (2 ng/ml) for 48 h. The inhibitory effects on airway smooth muscle remodeling, airway contraction, and TGF-beta release were investigated. Methacholine-induced protein expression of smooth muscle-myosin was fully inhibited by CHF-6001 (0.3-100 nM), whereas roflumilast (1 uM) had smaller effects. Tiotropium and glycopyrrolate fully inhibited methacholine-induced airway remodeling (0.1-30 nM). The combination of CHF-6001 and tiotropium or glycopyrrolate, in concentrations partially effective by themselves, fully inhibited methacholine-induced remodeling in combination. CHF-6001 did not affect airway closure and had limited effects on TGF-beta1-induced remodeling, but rather, it inhibited methacholine-induced TGF-beta release. The PDE4 inhibitor CHF-6001, and to a lesser extent roflumilast, and the LAMAs tiotropium and glycopyrrolate inhibit bronchoconstriction-induced remodeling. The combination of CHF-6001 and anticholinergics was more effective than the individual compounds. This cooperativity might be explained by the distinct mechanisms of action inhibiting TGF-beta release and bronchoconstriction. PMID- 28596293 TI - The uncoupling of autophagy and zinc homeostasis in airway epithelial cells as a fundamental contributor to COPD. AB - The proper regulation of zinc (Zn) trafficking proteins and the cellular distribution of Zn are critical for the maintenance of autophagic processes. However, there have been no studies that have examined Zn dyshomeostasis and the disease-related modulation of autophagy observed in the airways afflicted with chronic obstructive pulmonary disease (COPD). We hypothesized that dysregulated autophagy in airway epithelial cells (AECs) is related to Zn dysregulation in cigarette smoke (CS)-induced COPD. We applied a human ex vivo air-liquid interface model, a murine model of smoke exposure, and human lung tissues and investigated Zn, ZIP1, and ZIP2 Zn-influx proteins, autophagy [microtubule associated 1A/1B-light chain-3 (LC3), Beclin-1], autophagic flux (Sequestosome), apoptosis [Bcl2; X-linked inhibitor of apoptosis (XIAP), poly (ADP)-ribose polymerase (PARP)], and inflammation [thymic stromal lymphopoietin (TSLP), regulated on activation, normal T cell expressed and secreted (RANTES), and IL 1beta]. Lung tissues from CS-exposed mice exhibit reduced free-Zn in AECs, with elevated ZIP1 and diminished ZIP2 expression. Interestingly, increased LC3 colocalized with ZIP1, suggesting an autophagic requirement for free-Zn to support its catabolic function. In human AECs, autophagy was initiated but was unable to efficiently degrade cellular debris, as evidenced by stable Beclin-1 and increased LC3-II, but with a concomitant elevation in Sequestosome. Autophagic dysfunction due to CS exposure coupled with Zn depletion also induced apoptosis, with the reduction of antiapoptotic and antiautophagic proteins Bcl2 and XIAP and PARP cleavage. This was accompanied by an increase in RANTES and TSLP, an activator of adaptive immunity. We conclude that the uncoupling of Zn trafficking and autophagy in AECs constitutes a fundamental disease-related mechanism for COPD pathogenesis and could provide a new therapeutic target. PMID- 28596294 TI - The metalloproteinase ADAM8 promotes leukocyte recruitment in vitro and in acute lung inflammation. AB - Alveolar leukocyte recruitment is a hallmark of acute lung inflammation and involves transmigration of leukocytes through endothelial and epithelial layers. The disintegrin and metalloproteinase (ADAM) 8 is expressed on human isolated leukocytic cells and can be further upregulated on cultured endothelial and epithelial cells by proinflammatory cytokines. By shRNA-mediated knockdown we show that leukocytic ADAM8 is required on monocytic THP-1 cells for chemokine induced chemotaxis as well as transendothelial and transepithelial migration. Furthermore, ADAM8 promotes alphaL-integrin upregulation and THP-1 cell adhesion to endothelial cells. On endothelial cells ADAM8 enhances transendothelial migration and increases cytokine-induced permeability. On epithelial cells the protease facilitates migration in a wound closure assay but does not affect transepithelial leukocyte migration. Blood leukocytes and bone marrow-derived macrophages (BMDM) from ADAM8-deficient mice show suppressed chemotactic response. Intranasal application of LPS to mice is accompanied with ADAM8 upregulation in the lung. In this model of acute lung inflammation ADAM8 deficient mice are protected against leukocyte infiltration. Finally, transfer experiments of BMDM in mice indicate that ADAM8 exerts a promigratory function predominantly on leukocytes. Our study provides in vitro and in vivo evidence that ADAM8 on leukocytes holds a proinflammatory function in acute lung inflammation by promoting alveolar leukocyte recruitment. PMID- 28596291 TI - DDX54 regulates transcriptome dynamics during DNA damage response. AB - The cellular response to genotoxic stress is mediated by a well-characterized network of DNA surveillance pathways. The contribution of post-transcriptional gene regulatory networks to the DNA damage response (DDR) has not been extensively studied. Here, we systematically identified RNA-binding proteins differentially interacting with polyadenylated transcripts upon exposure of human breast carcinoma cells to ionizing radiation (IR). Interestingly, more than 260 proteins, including many nucleolar proteins, showed increased binding to poly(A)+ RNA in IR-exposed cells. The functional analysis of DDX54, a candidate genotoxic stress responsive RNA helicase, revealed that this protein is an immediate-to early DDR regulator required for the splicing efficacy of its target IR-induced pre-mRNAs. Upon IR exposure, DDX54 acts by increased interaction with a well defined class of pre-mRNAs that harbor introns with weak acceptor splice sites, as well as by protein-protein contacts within components of U2 snRNP and spliceosomal B complex, resulting in lower intron retention and higher processing rates of its target transcripts. Because DDX54 promotes survival after exposure to IR, its expression and/or mutation rate may impact DDR-related pathologies. Our work indicates the relevance of many uncharacterized RBPs potentially involved in the DDR. PMID- 28596295 TI - Genetic variance is associated with susceptibility for cigarette smoke-induced DAMP release in mice. AB - Chronic obstructive pulmonary disease (COPD) is characterized by unresolved neutrophilic airway inflammation and is caused by chronic exposure to toxic gases, such as cigarette smoke (CS), in genetically susceptible individuals. Recent data indicate a role for damage-associated molecular patterns (DAMPs) in COPD. Here, we investigated the genetics of CS-induced DAMP release in 28 inbred mouse strains. Subsequently, in lung tissue from a subset of strains, the expression of the identified candidate genes was analyzed. We tested whether small interfering RNA-dependent knockdown of candidate genes altered the susceptibility of the human A549 cell line to CS-induced cell death and DAMP release. Furthermore, we tested whether these genes were differentially regulated by CS exposure in bronchial brushings obtained from individuals with a family history indicative of either the presence or absence of susceptibility for COPD. We observed that, of the four DAMPs tested, double-stranded DNA (dsDNA) showed the highest correlation with neutrophilic airway inflammation. Genetic analyses identified 11 candidate genes governing either CS-induced or basal dsDNA release in mice. Two candidate genes (Elac2 and Ppt1) showed differential expression in lung tissue on CS exposure between susceptible and nonsusceptible mouse strains. Knockdown of ELAC2 and PPT1 in A549 cells altered susceptibility to CS extract induced cell death and DAMP release. In bronchial brushings, CS-induced expression of ENOX1 and ARGHGEF11 was significantly different between individuals susceptible or nonsusceptible for COPD. Our study shows that genetic variance in a mouse model is associated with CS-induced DAMP release, and that this might contribute to susceptibility for COPD. PMID- 28596296 TI - Dietary saccharides and sweet tastants have differential effects on colonization of Drosophila oocytes by Wolbachia endosymbionts. AB - Wolbachia bacteria are widespread, maternally transmitted endosymbionts of insects. Maintenance of sufficient Wolbachia titer in maternal germline cells is required for transmission efficacy. The mechanisms that regulate Wolbachia titer are not well understood; however, dietary sucrose was reported to elevate oocyte Wolbachia titer in Drosophila melanogaster whereas dietary yeast decreased oocyte titer. To further investigate how oocyte Wolbachia titer is controlled, this study analyzed the response of wMel Wolbachia to diets enriched in an array of natural sugars and other sweet tastants. Confocal imaging of D. melanogaster oocytes showed that food enriched in dietary galactose, lactose, maltose and trehalose elevated Wolbachia titer. However, oocyte Wolbachia titers were unaffected by exposure to the sweet tastants lactulose, erythritol, xylitol, aspartame and saccharin as compared to the control. Oocyte size was generally non responsive to the nutrient-altered diets. Ovary size, however, was consistently smaller in response to all sugar- and sweetener-enriched diets. Furthermore, most dietary sugars administered in tandem with dietary yeast conferred complete rescue of oocyte titer suppression by yeast. All diets dually enriched in yeast and sugar also rescued yeast-associated ovary volume changes. This indicates oocyte colonization by Wolbachia to be a nutritionally sensitive process regulated by multiple mechanistic inputs. PMID- 28596298 TI - Sex differences in pulmonary vascular control: focus on the nitric oxide pathway. AB - Although the incidence of pulmonary hypertension is higher in females, the severity and prognosis of pulmonary vascular disease in both neonates and adults have been shown to be worse in male subjects. Studies of sex differences in pulmonary hypertension have mainly focused on the role of sex hormones. However, the contribution of sex differences in terms of vascular signaling pathways regulating pulmonary vascular function remains incompletely understood. Consequently, we investigated pulmonary vascular function of male and female swine in vivo, both at rest and during exercise, and in isolated small pulmonary arteries in vitro, with a particular focus on the NO-cGMP-PDE5 pathway. Pulmonary hemodynamics at rest and during exercise were virtually identical in male and female swine. Moreover, NO synthase inhibition resulted in a similar degree of pulmonary vasoconstriction in male and female swine. However, NO synthase inhibition blunted bradykinin-induced vasodilation in pulmonary small arteries to a greater extent in male than in female swine. PDE5 inhibition resulted in a similar degree of vasodilation in male and female swine at rest, while during exercise there was a trend towards a larger effect in male swine. In small pulmonary arteries, PDE5 inhibition failed to augment bradykinin-induced vasodilation in either sex. Finally, in the presence of NO synthase inhibition, the pulmonary vasodilator effect of PDE5 inhibition was significantly larger in female swine both in vivo and in vitro. In conclusion, the present study demonstrated significant sex differences in the regulation of pulmonary vascular tone, which may contribute to understanding sex differences in incidence, treatment response, and prognosis of pulmonary vascular disease. PMID- 28596299 TI - Postexercise essential amino acid supplementation amplifies skeletal muscle satellite cell proliferation in older men 24 hours postexercise. AB - Aged skeletal muscle has an attenuated and delayed ability to proliferate satellite cells in response to resistance exercise. The mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway is a focal point for cell growth, however, the effect of postexercise mTORC1 activation on human skeletal muscle satellite cell (SC) proliferation is unknown. To test the proliferative capacity of skeletal muscle SC in aging muscle to a potent mTORC1 activator (i.e., EAA; essential amino acids) we recruited older (~72y) men to conduct leg resistance exercise (8setsx10reps) without (-EAA; n = 8) and with (+EAA: n = 11) ingestion of 10 g of EAA 1 h postexercise. Muscle biopsies were taken before exercise (Pre) and 24 h postexercise (Post) for assessment of expression and fiber type-specific Pax7+ SC, Ki67+Pax7+ SC and MyoD+ SC -EAA did not show an increase in Pax7+ satellite cells at Post(P > 0.82). Although statistical significance for an increase in Pax7 + SC at 24 h post-RE was not observed in +EAA versus -EAA, we observed trends for a treatment difference (P < 0.1). When examining the change from Pre to Post trends were demonstrated (#/myofiber: P = 0.076; and %/myonuclei: P = 0.065) for a greater increase in +EAA versus -EAA Notably, we found an increase SC proliferation in +EAA, but not -EAA with increase in Ki67+ SC and MyoD+ cells (P < 0.05). Ki67+ SC also exhibited a significant group difference Post (P < 0.010). Pax7+ SC in fast twitch myofibers did not change and were not different between groups (P > 0.10). CDK2, MEF2C, RB1 mRNA only increased in +EAA (P < 0.05). Acute muscle satellite cell proliferative capacity may be partially rescued with postexercise EAA ingestion in older men. PMID- 28596301 TI - Modeling elucidates how refractory period can provide profound nonlinear gain control to graded potential neurons. AB - Refractory period (RP) plays a central role in neural signaling. Because it limits an excitable membrane's recovery time from a previous excitation, it can restrict information transmission. Classically, RP means the recovery time from an action potential (spike), and its impact to encoding has been mostly studied in spiking neurons. However, many sensory neurons do not communicate with spikes but convey information by graded potential changes. In these systems, RP can arise as an intrinsic property of their quantal micro/nanodomain sampling events, as recently revealed for quantum bumps (single photon responses) in microvillar photoreceptors. Whilst RP is directly unobservable and hard to measure, masked by the graded macroscopic response that integrates numerous quantal events, modeling can uncover its role in encoding. Here, we investigate computationally how RP can affect encoding of graded neural responses. Simulations in a simple stochastic process model for a fly photoreceptor elucidate how RP can profoundly contribute to nonlinear gain control to achieve a large dynamic range. PMID- 28596302 TI - Carcinoid heart disease. AB - Rare neuroendocrine tumours (NETs) that most commonly arise in the gastrointestinal tract can lead to carcinoid syndrome and carcinoid heart disease. Patients with carcinoid syndrome present with vasomotor changes, hypermotility of the gastrointestinal system, hypotension and bronchospasm. Medical therapy for carcinoid syndrome, typically with somatostatin analogues, can help control symptoms, inhibit tumour progression and prolong survival. Carcinoid heart disease occurs in more than 50% of these patients and is the initial presentation of carcinoid syndrome in up to 20% of patients. Carcinoid heart disease has characteristic findings of plaque-like deposits composed of smooth muscle cells, myofibroblasts, extracellular matrix and an overlying endothelial layer which can lead to valve dysfunction. Valvular dysfunction can lead to oedema, ascites and right-sided heart failure. Medical therapy of carcinoid heart disease is limited to symptom control and palliation. Valve surgery for carcinoid heart disease should be considered for symptomatic patients with controlled metastatic carcinoid syndrome. A multidisciplinary approach is needed to guide optimal management. PMID- 28596300 TI - Clear Cell Renal Cell Carcinoma is linked to Epithelial-to-Mesenchymal Transition and to Fibrosis. AB - Clear cell renal cell carcinoma (ccRCC) represents the most common type of kidney cancer with high mortality in its advanced stages. Our study aim was to explore the correlation between tumor epithelial-to-mesenchymal transition (EMT) and patient survival. Renal biopsies of tumorous and adjacent nontumorous tissue were taken with a 16 g needle from our patients (n = 26) undergoing partial or radical nephrectomy due to ccRCC RNA sequencing libraries were generated using Illumina TruSeq(r) Access library preparation protocol and TruSeq Small RNA library preparation kit. Next generation sequencing (NGS) was performed on Illumina HiSeq2500. Comparative analysis of matched sample pairs was done using the Bioconductor Limma/voom R-package. Liquid chromatography-tandem mass spectrometry and immunohistochemistry were applied to measure and visualize protein abundance. We detected an increased generic EMT transcript score in ccRCC Gene expression analysis showed augmented abundance of AXL and MMP14, as well as down-regulated expression of KL (klotho). Moreover, microRNA analyses demonstrated a positive expression correlation of miR-34a and its targets MMP14 and AXL Survival analysis based on a subset of genes from our list EMT-related genes in a publicly available dataset showed that the EMT genes correlated with ccRCC patient survival. Several of these genes also play a known role in fibrosis. Accordingly, recently published classifiers of solid organ fibrosis correctly identified EMT affected tumor samples and were correlated with patient survival. EMT in ccRCC linked to fibrosis is associated with worse survival and may represent a target for novel therapeutic interventions. PMID- 28596303 TI - Prevalence and predictors of intracranial aneurysms in patients with bicuspid aortic valve. AB - OBJECTIVE: To determine the prevalence and outcomes of intracranial aneurysm (IA) in patients with bicuspid aortic valve (BAV). METHODS: Retrospective review of patients with BAV who underwent brain MR angiography at the Mayo Clinic from 1994 to 2013. RESULTS: There were 678 patients included in this study-mean age 57+/-13 years, men 480 (71%), mean follow-up 10+/-3 years (5913 patient-years). Coarctation of aorta (COA) was present in 154 (23%) patients.There were 59 IAs identified in 52 of 678 patients (7.7%). IA was present in 20/154 patients (12.9%) with COA and 32/524 patients (5.7%) without COA (p<0.001). For the patients without COA, female gender and right-left cusp fusion were risks factors for IA in women after adjustment for all potential variables (HR 1.76, CI 1.31 to 2.68, p=0.03). There was no significant trend in the risk for IA across age tertiles: age <=40 years versus 41-60 years (HR 1.19, p=0.34), and age 41-60 years versus 61-80 years (HR 1.06, p=0.56).Among the 52 patients with IA, enlargement occurred in three patients (6%), rupture in two patients (4%) and four patients (8%) underwent coil embolisation. For the 626 patients without IA at baseline, no patient developed IA over 7+/-2 years of imaging follow-up. CONCLUSIONS: BAV is associated with a higher prevalence of IA compared to the general population, and this risk is higher in patients with COA, right-left cusp fusion and female gender. PMID- 28596304 TI - PCSK9 inhibition and atherosclerotic cardiovascular disease prevention: does reality match the hype? AB - Within this review we look at whether the potential provided by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition for prevention of atherosclerotic cardiovascular disease matches the excitement generated. Two fully human monoclonal antibodies to PCSK9 are currently licenced for clinical use both in the USA and the European Union: evolocumab and alirocumab. These reduce low-density lipoprotein cholesterol by over 50% across a range of populations and were generally found to have a safety profile comparable with placebo. The development programme for a third humanised monoclonal antibody, bococizumab, was terminated early due to the presence of neutralising antibodies reducing its efficacy over time. Results from the first cardiovascular outcomes trial, FOURIER, have demonstrated significant reductions in cardiovascular events in a population with stable cardiovascular disease over a 2-year period. The ODYSSEY OUTCOMES trial comparing alirocumab to placebo is expected to report in 2018 and provide cardiovascular outcome data in a post acute coronary syndrome population. Monoclonal antibodies have an injection burden of 12-26 injections per year. An alternative approach to reducing PCSK9 is to inhibit translation of the messenger RNA for PCSK9. The phase II ORION-1 study using inclisiran, a small interference RNA to PCSK9, suggested that two doses of inclisiran produced time averaged reductions in LDL cholesterol of 50% over 9 months. The ORION-4 cardiovascular outcome trial will assess the cardiovascular benefits of two injections per year using inclisiran. With further outcome trials expected, appropriate patient selection will be key considering the higher drug costs of these therapies. PMID- 28596305 TI - Genotype-phenotype correlations in Marfan syndrome. PMID- 28596306 TI - Mendelian randomisation in cardiovascular research: an introduction for clinicians. AB - Understanding the causal role of biomarkers in cardiovascular and other diseases is crucial in order to find effective approaches (including pharmacological therapies) for disease treatment and prevention. Classical observational studies provide naive estimates of the likely role of biomarkers in disease development; however, such studies are prone to bias. This has direct relevance for drug development as if drug targets track to non-causal biomarkers, this can lead to expensive failure of these drugs in phase III randomised controlled trials. In an effort to provide a more reliable indication of the likely causal role of a biomarker in the development of disease, Mendelian randomisation studies are increasingly used, and this is facilitated by the availability of large-scale genetic data. We conducted a narrative review in order to provide a description of the utility of Mendelian randomisation for clinicians engaged in cardiovascular research. We describe the rationale and provide a basic description of the methods and potential limitations of Mendelian randomisation. We give examples from the literature where Mendelian randomisation has provided pivotal information for drug discovery including predicting efficacy, informing on target-mediated adverse effects and providing potential new evidence for drug repurposing. The variety of the examples presented illustrates the importance of Mendelian randomisation in order to prioritise drug targets for cardiovascular research. PMID- 28596307 TI - Plants transfer lipids to sustain colonization by mutualistic mycorrhizal and parasitic fungi. AB - Arbuscular mycorrhizal (AM) fungi facilitate plant uptake of mineral nutrients and draw organic nutrients from the plant. Organic nutrients are thought to be supplied primarily in the form of sugars. Here we show that the AM fungus Rhizophagus irregularis is a fatty acid auxotroph and that fatty acids synthesized in the host plants are transferred to the fungus to sustain mycorrhizal colonization. The transfer is dependent on RAM2 (REQUIRED FOR ARBUSCULAR MYCORRHIZATION 2) and the ATP binding cassette transporter-mediated plant lipid export pathway. We further show that plant fatty acids can be transferred to the pathogenic fungus Golovinomyces cichoracerum and are required for colonization by pathogens. We suggest that the mutualistic mycorrhizal and pathogenic fungi similarly recruit the fatty acid biosynthesis program to facilitate host invasion. PMID- 28596310 TI - Pittsburgh myth, Paris reality. PMID- 28596309 TI - Guanine glycation repair by DJ-1/Park7 and its bacterial homologs. AB - DNA damage induced by reactive carbonyls (mainly methylglyoxal and glyoxal), called DNA glycation, is quantitatively as important as oxidative damage. DNA glycation is associated with increased mutation frequency, DNA strand breaks, and cytotoxicity. However, in contrast to guanine oxidation repair, how glycated DNA is repaired remains undetermined. Here, we found that the parkinsonism-associated protein DJ-1 and its bacterial homologs Hsp31, YhbO, and YajL could repair methylglyoxal- and glyoxal-glycated nucleotides and nucleic acids. DJ-1-depleted cells displayed increased levels of glycated DNA, DNA strand breaks, and phosphorylated p53. Deglycase-deficient bacterial mutants displayed increased levels of glycated DNA and RNA and exhibited strong mutator phenotypes. Thus, DJ 1 and its prokaryotic homologs constitute a major nucleotide repair system that we name guanine glycation repair. PMID- 28596311 TI - Fatty acids in arbuscular mycorrhizal fungi are synthesized by the host plant. AB - Plants form beneficial associations with arbuscular mycorrhizal fungi, which facilitate nutrient acquisition from the soil. In return, the fungi receive organic carbon from the plants. The transcription factor RAM1 (REQUIRED FOR ARBUSCULAR MYCORRHIZATION 1) is crucial for this symbiosis, and we demonstrate that it is required and sufficient for the induction of a lipid biosynthetic pathway that is expressed in plant cells accommodating fungal arbuscules. Lipids are transferred from the plant to mycorrhizal fungi, which are fatty acid auxotrophs, and this lipid export requires the glycerol-3-phosphate acyltransferase RAM2, a direct target of RAM1. Our work shows that in addition to sugars, lipids are a major source of organic carbon delivered to the fungus, and this is necessary for the production of fungal lipids. PMID- 28596313 TI - Erratum for the Report "A nontoxic pain killer designed by modeling of pathological receptor conformations" by V. Spahn, G. Del Vecchio, D. Labuz, A. Rodriguez-Gaztelumendi, N. Massaly, J. Temp, V. Durmaz, P. Sabri, M. Reidelbach, H. Machelska, M. Weber, C. Stein. PMID- 28596312 TI - Tuning quantum nonlocal effects in graphene plasmonics. AB - The response of electron systems to electrodynamic fields that change rapidly in space is endowed by unique features, including an exquisite spatial nonlocality. This can reveal much about the materials' electronic structure that is invisible in standard probes that use gradually varying fields. Here, we use graphene plasmons, propagating at extremely slow velocities close to the electron Fermi velocity, to probe the nonlocal response of the graphene electron liquid. The near-field imaging experiments reveal a parameter-free match with the full quantum description of the massless Dirac electron gas, which involves three types of nonlocal quantum effects: single-particle velocity matching, interaction enhanced Fermi velocity, and interaction-reduced compressibility. Our experimental approach can determine the full spatiotemporal response of an electron system. PMID- 28596308 TI - Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. AB - The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin. PMID- 28596315 TI - News at a glance. PMID- 28596314 TI - The dishonest HONEST Act. PMID- 28596316 TI - Oldest members of our species discovered in Morocco. PMID- 28596317 TI - Romanian researchers decry sudden power grab. PMID- 28596319 TI - Data Check: Critics challenge NIH finding that bigger labs aren't necessarily better. PMID- 28596318 TI - Circular DNA throws biologists for a loop. PMID- 28596320 TI - Rethinking the dreaded r-word. PMID- 28596321 TI - India resurrects forgotten leprosy vaccine. PMID- 28596323 TI - Saving the 'God of ugly things'. PMID- 28596322 TI - Can U.S. states and cities overcome Paris exit? PMID- 28596324 TI - Science reads for the summer of '17. PMID- 28596325 TI - Nanomaterials for stimulating nerve growth. PMID- 28596326 TI - From sequence to color. PMID- 28596327 TI - Poisons, antidotes, and selfish genes. PMID- 28596328 TI - Specific repair by discerning macrophages. PMID- 28596329 TI - De-extinction, nomenclature, and the law. PMID- 28596330 TI - Fund global health: Save lives and money. PMID- 28596331 TI - Minority investigators lack NIH funding. PMID- 28596332 TI - The limits of carbon reduction roadmaps. PMID- 28596333 TI - Repair and Regeneration. PMID- 28596334 TI - Self-repairing cells: How single cells heal membrane ruptures and restore lost structures. AB - Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. However, these repair activities can also be observed at the single-cell level. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. This Review presents current understanding in wound healing and regeneration as two distinct aspects of cellular self-repair by examining a few model organisms that have displayed robust repair capacity, including Xenopus oocytes, Chlamydomonas, and Stentor coeruleus Although many open questions remain, elucidating how cells repair themselves is important for our mechanistic understanding of cell biology. It also holds the potential for new applications and therapeutic approaches for treating human disease. PMID- 28596335 TI - Inflammation and metabolism in tissue repair and regeneration. AB - Tissue repair after injury is a complex, metabolically demanding process. Depending on the tissue's regenerative capacity and the quality of the inflammatory response, the outcome is generally imperfect, with some degree of fibrosis, which is defined by aberrant accumulation of collagenous connective tissue. Inflammatory cells multitask at the wound site by facilitating wound debridement and producing chemokines, metabolites, and growth factors. If this well-orchestrated response becomes dysregulated, the wound can become chronic or progressively fibrotic, with both outcomes impairing tissue function, which can ultimately lead to organ failure and death. Here we review the current understanding of the role of inflammation and cell metabolism in tissue regenerative responses, highlight emerging concepts that may expand therapeutic perspectives, and briefly discuss where important knowledge gaps remain. PMID- 28596336 TI - Regenerating optic pathways from the eye to the brain. AB - Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect the eyes to the brain, fail to regenerate after damage, eventually leading to blindness. Here, we review research on regeneration and repair of the optic system. Intrinsic developmental growth programs can be reactivated in RGCs, neural activity can enhance RGC regeneration, and functional reformation of eye to-brain connections is possible, even in the adult brain. Transplantation and gene therapy may serve to replace or resurrect dead or injured retinal neurons. Retinal prosthetics that can restore vision in animal models may too have practical power in the clinical setting. Functional restoration of sight in certain forms of blindness is likely to occur in human patients in the near future. PMID- 28596338 TI - Why radiation causes dry mouth. PMID- 28596339 TI - Sighting of magnetic Majorana fermions? PMID- 28596340 TI - Designing molecular disorder. PMID- 28596337 TI - Cardiac regeneration strategies: Staying young at heart. AB - The human heart is continually operating as a muscular pump, contracting, on average, 80 times per minute to propel 8000 liters of blood through body tissues each day. Whereas damaged skeletal muscle has a profound capacity to regenerate, heart muscle, at least in mammals, has poor regenerative potential. This deficiency is attributable to the lack of resident cardiac stem cells, combined with roadblocks that limit adult cardiomyocytes from entering the cell cycle and completing division. Insights for regeneration have recently emerged from studies of animals with an elevated innate capacity for regeneration, the innovation of stem cell and reprogramming technologies, and a clearer understanding of the cardiomyocyte genetic program and key extrinsic signals. Methods to augment heart regeneration now have potential to counteract the high morbidity and mortality of cardiovascular disease. PMID- 28596341 TI - Teaching sulfur and phosphorus to share. PMID- 28596343 TI - Local macrophage clean-up. PMID- 28596342 TI - Comets contributed to Earth's atmosphere. PMID- 28596344 TI - Polycomb steps to inactivate X. PMID- 28596346 TI - Plasmodium leftovers cause bone loss. PMID- 28596345 TI - A clue to a drug's neurotoxicity? PMID- 28596348 TI - Tracing development of the dendritic cell lineage. PMID- 28596347 TI - Bacterial sensing mechanism revealed. PMID- 28596349 TI - Swapping boron acids for carbon acids. PMID- 28596350 TI - Selfish genetic interactions in nematodes. PMID- 28596351 TI - General relativity weighs a white dwarf. PMID- 28596352 TI - Moving beyond mice for vaccine studies. PMID- 28596353 TI - From glassy carbon to mixed carbon. PMID- 28596354 TI - DNA damage linked to fitness loss in aging. PMID- 28596355 TI - HIV reprograms progenitor cells. PMID- 28596356 TI - Down to the guts of climate change. PMID- 28596357 TI - A learning environment designed for experts. PMID- 28596358 TI - Wheels do more than go round and round. PMID- 28596359 TI - Old cancer drugs with a modern mechanism. PMID- 28596360 TI - A checkup on density functional theory. PMID- 28596361 TI - Neutron scattering in the proximate quantum spin liquid alpha-RuCl3. AB - The Kitaev quantum spin liquid (KQSL) is an exotic emergent state of matter exhibiting Majorana fermion and gauge flux excitations. The magnetic insulator alpha-RuCl3 is thought to realize a proximate KQSL. We used neutron scattering on single crystals of alpha-RuCl3 to reconstruct dynamical correlations in energy momentum space. We discovered highly unusual signals, including a column of scattering over a large energy interval around the Brillouin zone center, which is very stable with temperature. This finding is consistent with scattering from the Majorana excitations of a KQSL. Other, more delicate experimental features can be transparently associated with perturbations to an ideal model. Our results encourage further study of this prototypical material and may open a window into investigating emergent magnetic Majorana fermions in correlated materials. PMID- 28596362 TI - Palladium-catalyzed carbon-sulfur or carbon-phosphorus bond metathesis by reversible arylation. AB - Compounds bearing aryl-sulfur and aryl-phosphorus bonds have found numerous applications in drug development, organic materials, polymer science, and homogeneous catalysis. We describe palladium-catalyzed metathesis reactions of both compound classes, each of which proceeds through a reversible arylation manifold. The synthetic power and immediate utility of this approach are demonstrated in several applications that would be challenging to achieve by means of traditional cross-coupling methods. The C(sp2)-S bond metathesis protocol was used in the depolymerization of a commercial thermoplastic polymer and in the late-stage derivatization of a drug. The C(sp2)-P variant led to the convenient preparation of a variety of phosphorus heterocycles, including a potential chiral ligand and fluorescent organic materials, via a ring-closing transformation. PMID- 28596363 TI - Polymeric peptide pigments with sequence-encoded properties. AB - Melanins are a family of heterogeneous polymeric pigments that provide ultraviolet (UV) light protection, structural support, coloration, and free radical scavenging. Formed by oxidative oligomerization of catecholic small molecules, the physical properties of melanins are influenced by covalent and noncovalent disorder. We report the use of tyrosine-containing tripeptides as tunable precursors for polymeric pigments. In these structures, phenols are presented in a (supra-)molecular context dictated by the positions of the amino acids in the peptide sequence. Oxidative polymerization can be tuned in a sequence-dependent manner, resulting in peptide sequence-encoded properties such as UV absorbance, morphology, coloration, and electrochemical properties over a considerable range. Short peptides have low barriers to application and can be easily scaled, suggesting near-term applications in cosmetics and biomedicine. PMID- 28596364 TI - Xenon isotopes in 67P/Churyumov-Gerasimenko show that comets contributed to Earth's atmosphere. AB - The origin of cometary matter and the potential contribution of comets to inner planet atmospheres are long-standing problems. During a series of dedicated low altitude orbits, the Rosetta Orbiter Spectrometer for Ion and Neutral Analysis (ROSINA) on the Rosetta spacecraft analyzed the isotopes of xenon in the coma of comet 67P/Churyumov-Gerasimenko. The xenon isotopic composition shows deficits in heavy xenon isotopes and matches that of a primordial atmospheric component. The present-day Earth atmosphere contains 22 +/- 5% cometary xenon, in addition to chondritic (or solar) xenon. PMID- 28596365 TI - PCGF3/5-PRC1 initiates Polycomb recruitment in X chromosome inactivation. AB - Recruitment of the Polycomb repressive complexes PRC1 and PRC2 by Xist RNA is an important paradigm for chromatin regulation by long noncoding RNAs. Here, we show that the noncanonical Polycomb group RING finger 3/5 (PCGF3/5)-PRC1 complex initiates recruitment of both PRC1 and PRC2 in response to Xist RNA expression. PCGF3/5-PRC1-mediated ubiquitylation of histone H2A signals recruitment of other noncanonical PRC1 complexes and of PRC2, the latter leading to deposition of histone H3 lysine 27 methylation chromosome-wide. Pcgf3/5 gene knockout results in female-specific embryo lethality and abrogates Xist-mediated gene repression, highlighting a key role for Polycomb in Xist-dependent chromosome silencing. Our findings overturn existing models for Polycomb recruitment by Xist RNA and establish precedence for H2AK119u1 in initiating Polycomb domain formation in a physiological context. PMID- 28596368 TI - Research on a razor's edge. PMID- 28596366 TI - Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. AB - A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10 2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system. PMID- 28596369 TI - HIV prevalence and related risk behaviours in female seasonal farm workers in Souss Massa Draa, Morocco: results from a cross-sectional survey using cluster based sampling. AB - OBJECTIVES: To determine prevalence of HIV and HIV-related behaviours in female seasonal farm workers (FSFWs) in two provinces of Souss Massa Draa (SMD) region in Morocco. SMD has a higher burden of HIV compared with other parts of Morocco and is characterised by a substantial aggregation of FSFW. METHODS: We carried out a cross-sectional HIV biobehavioural survey using cluster-based sampling of farms in the provinces Chtouka Ait Baha and Taroudant Ouled Teima in 2014. HIV testing was done using the Determine HIV-1/2 rapid test and reactive specimens were tested using ELISA and western blot. Collected data were post hoc weighted for region-based stratification and adjusted for clustering effects using complex survey functions of SPSS (V.21). RESULTS: Among those eligible to participate, the response rate was 92.8%. HIV prevalence was 0.9% (95% CI 0.4% to 2.4%) among 520 recruited participants. A high proportion of respondents (67.7%) had no education. Ever having sex was reported by 79.8% and among these, 12.7% ever exchanged sex for money or goods. Sixty-one per cent reported condom use at most recent commercial vaginal sex in the past 12 months. STI symptom recognition was found to be low because 62.4% and 46.8% of FSFW could not report any STI symptoms in men and women, respectively. Twenty-seven per cent of respondents had an HIV test in the past 12 months. In multivariable analysis, those with primary or higher education (adjusted OR (aOR)=2.38, 95% CI 1.33 to 4.27) and those who participated in an HIV educational session at their workplace (aOR=11.00, 95% CI 3.99 to 30.31) had higher odds of ever been tested for HIV. CONCLUSIONS: Although we found a relatively low HIV prevalence among FSFW in SMD, HIV interventions should be intensified, in particular, in a subgroup of women who are involved in sex work. PMID- 28596372 TI - Human Blood Monocyte Subsets: A New Gating Strategy Defined Using Cell Surface Markers Identified by Mass Cytometry. AB - OBJECTIVE: Human monocyte subsets are defined as classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16+). Alterations in monocyte subset frequencies are associated with clinical outcomes, including cardiovascular disease, in which circulating intermediate monocytes independently predict cardiovascular events. However, delineating mechanisms of monocyte function is hampered by inconsistent results among studies. APPROACH AND RESULTS: We use cytometry by time-of-flight mass cytometry to profile human monocytes using a panel of 36 cell surface markers. Using the dimensionality reduction approach visual interactive stochastic neighbor embedding (viSNE), we define monocytes by incorporating all cell surface markers simultaneously. Using viSNE, we find that although classical monocytes are defined with high purity using CD14 and CD16, intermediate and nonclassical monocytes defined using CD14 and CD16 alone are frequently contaminated, with average intermediate and nonclassical monocyte purity of ~86.0% and 87.2%, respectively. To improve the monocyte purity, we devised a new gating scheme that takes advantage of the shared coexpression of cell surface markers on each subset. In addition to CD14 and CD16, CCR2, CD36, HLA-DR, and CD11c are the most informative markers that discriminate among the 3 monocyte populations. Using these additional markers as filters, our revised gating scheme increases the purity of both intermediate and nonclassical monocyte subsets to 98.8% and 99.1%, respectively. We demonstrate the use of this new gating scheme using conventional flow cytometry of peripheral blood mononuclear cells from subjects with cardiovascular disease. CONCLUSIONS: Using cytometry by time-of-flight mass cytometry, we have identified a small panel of surface markers that can significantly improve monocyte subset identification and purity in flow cytometry. Such a revised gating scheme will be useful for clinical studies of monocyte function in human cardiovascular disease. PMID- 28596373 TI - Mitochondrial Oxidative Stress Promotes Atherosclerosis and Neutrophil Extracellular Traps in Aged Mice. AB - RATIONALE: Mitochondrial oxidative stress (mitoOS) has been shown to be increased in various cell types in human atherosclerosis and with aging. However, the role of cell type-specific mitoOS in atherosclerosis in the setting of advanced age and the molecular mechanisms remains to be determined in vivo. OBJECTIVE: The aim of this study was to examine the role of myeloid cell mitoOS in atherosclerosis in aged mice. APPROACH AND RESULTS: Lethally irradiated low-density lipoprotein receptor-deficient mice (Ldlr-/-) were reconstituted with bone marrow from either wild-type or mitochondrial catalase (mCAT) mice. mCAT transgenic mice contain ectopically expressed human catalase gene in mitochondria, which reduces mitoOS. Starting at the age of 36 weeks, mice were fed the Western-type diet for 16 weeks. We found that mitoOS in lesional myeloid cells was suppressed in aged mCAT >Ldlr-/- chimeric mice compared with aged controls, and this led to a significant reduction in aortic root atherosclerotic lesion area despite higher plasma cholesterol levels. Neutrophil extracellular traps (NETs), a proinflammatory extracellular structure that contributes to atherosclerosis progression, were significantly increased in the lesions of aged mice compared with lesions of younger mice. Aged mCAT->Ldlr-/- mice had less lesional neutrophils and decreased NETs compared with age-matched wild-type->Ldlr-/- mice, whereas young mCAT-> and wild-type->Ldlr-/- mice had comparable numbers of neutrophils and similar low levels of lesional NETs. Using cultured neutrophils, we showed that suppression of mitoOS reduced 7-ketocholesterol-induced NET release from neutrophils of aged but not younger mice. CONCLUSIONS: MitoOS in lesional myeloid cells enhanced atherosclerosis development in aged mice, and this enhancement was associated with increased lesional NETs. Thus, mitoOS-induced NET formation is a potentially new therapeutic target to prevent atherosclerosis progression during aging. PMID- 28596374 TI - LRP1-Dependent BMPER Signaling Regulates Lipopolysaccharide-Induced Vascular Inflammation. AB - OBJECTIVE: Bacterial endotoxin (lipopolysaccharide)-mediated sepsis involves dysregulated systemic inflammation, which injures the lung and other organs, often fatally. Vascular endothelial cells act as both targets and mediators of lipopolysaccharide-induced inflammatory responses. Dysfunction of endothelium results in increases of proinflammatory cytokine production and permeability leakage. BMPER (bone morphogenetic protein-binding endothelial regulator), an extracellular modulator of bone morphogenetic protein signaling, has been identified as a vital component in chronic endothelial inflammatory responses and atherosclerosis. However, it is unclear whether BMPER also regulates inflammatory response in an acute setting such as sepsis. To address this question, we investigated the role of BMPER during lipopolysaccharide-induced acute lung injury. APPROACH AND RESULTS: Mice missing 1 allele of BMPER (BMPER+/- mice used in the place of BMPER-/- mice that die at birth) were used for lipopolysaccharide challenge. Lipopolysaccharide-induced pulmonary inflammation and injury was reduced in BMPER+/- mice as shown by several measures, including survival rate, infiltration of inflammatory cells, edema, and production of proinflammatory cytokines. Mechanistically, we have demonstrated that BMPER is required and sufficient for the activation of nuclear factor of activated T cells c1. This BMPER-induced nuclear factor of activated T cells activation is coordinated by multiple signaling pathways, including bone morphogenetic protein-independent low density lipoprotein receptor-related protein 1-extracellular signal-regulated kinase activation, calcineurin signaling, and low-density lipoprotein receptor related protein 1beta-mediated nuclear factor 45 nuclear export in response to BMPER treatment. CONCLUSIONS: We conclude that BMPER plays a pivotal role in pulmonary inflammatory response, which provides new therapeutic options against sepsis shock. The new signaling pathway initiated by BMPER/low-density lipoprotein receptor-related protein 1 axis broadens our understanding about BMPER's role in vascular homeostasis. PMID- 28596375 TI - NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice-Brief Report. AB - OBJECTIVE: Inflammasomes are multiprotein complexes, and their activation has been associated with cardiovascular disease. Inflammasome activation leads to secretion of caspase-1 by innate immune cells, resulting in the activation of interleukin-1beta. Recently, a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, was described. In this study, we investigated the effect of MCC950 on atherosclerotic lesion development in apoE-/- mice. APPROACH AND RESULTS: First, we determined the efficacy of MCC950 in vitro. Bone marrow derived macrophages and dendritic cells were stimulated with lipopolysaccharide and cholesterol crystals resulting in high levels of interleukin-1beta release, which was inhibited by MCC950. In vivo MCC950 treatment reduced lipopolysaccharide-induced interleukin-1beta secretion, without affecting the tumor necrosis factor-alpha response. Subsequently, atherosclerotic plaques were induced in Western-type diet fed apoE-/- mice by semiconstrictive perivascular collar placement at the carotid arteries, after which the mice received MCC950 (10 mg/kg) or vehicle control 3* per week intraperitoneally for 4 weeks. After euthanize, atherosclerotic plaque size and volume were quantified in hematoxylin eosin-stained 10-um cryosections throughout the artery. MCC950 treatment significantly reduced the development of atherosclerotic lesions as determined by maximal stenosis, average plaque size, and plaque volume. Although the amount of collagen and the necrotic core size were not affected, the number of macrophages in the plaque was significantly reduced on treatment. In addition, VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA expression was significantly reduced in the carotids of MCC950-treated mice. CONCLUSIONS: These findings show that specific inhibition of the NLRP3 inflammasome using MCC950 can be a promising therapeutic approach to inhibit atherosclerotic lesion development. PMID- 28596376 TI - Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A. AB - OBJECTIVE: To establish the cellular source of plasma factor (F)XIII-A. APPROACH AND RESULTS: A novel mouse floxed for the F13a1 gene, FXIII-Aflox/flox (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.Flox cross abolished platelet FXIII-A and reduced plasma FXIII-A to 23+/-3% (P<0.001). However, the effect of platelet factor 4-cre on plasma FXIII-A was exerted outside of the megakaryocyte lineage because plasma FXIII-A was not reduced in the Mpl-/- mouse, despite marked thrombocytopenia. In support of this, platelet factor 4-cre depleted FXIII-A mRNA in brain, aorta, and heart of floxed mice, where FXIII-Apos cells were identified as macrophages as they costained with CD163. In the integrin alphaM-cre.Flox and the double copy lysozyme 2-cre.cre.Flox crosses, plasma FXIII-A was reduced to, respectively, 75+/-5% (P=0.003) and 30+/-7% (P<0.001), with no change in FXIII-A content per platelet, further consistent with a macrophage origin of plasma FXIII-A. The change in plasma FXIII-A levels across the various mouse genotypes mirrored the change in FXIII-A mRNA expression in aorta. Bone marrow transplantation of FXIII A+/+ bone marrow into FXIII-A-/- mice both restored plasma FXIII-A to normal levels and replaced aortic and cardiac FXIII-A mRNA, while its transplantation into FXIII-A+/+ mice did not increase plasma FXIII-A levels, suggesting that a limited population of niches exists that support FXIII-A-releasing cells. CONCLUSIONS: This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor. PMID- 28596377 TI - Trowaglerix Venom Polypeptides As a Novel Antithrombotic Agent by Targeting Immunoglobulin-Like Domains of Glycoprotein VI in Platelet. AB - OBJECTIVE: Currently prescribed antiplatelet drugs have 1 common side effect-an increased risk of hemorrhage and thrombocytopenia. On the contrary, bleeding defects associated with glycoprotein VI (GPVI) expression deficiency are usually slightly prolonged bleeding times. However, GPVI antagonists are lacking in clinic. APPROACH AND RESULTS: Using reverse-phase high-performance liquid chromatography and sequencing, we revealed the partial sequence of trowaglerix alpha subunit, a potent specific GPVI-targeting snaclec (snake venom C-type lectin protein). Hexapeptide (Troalpha6 [trowaglerix a chain hexapeptide, CKWMNV]) and decapeptide (Troalpha10) derived from trowaglerix specifically inhibited collagen-induced platelet aggregation through blocking platelet GPVI receptor. Computational peptide design helped to design a series of Troalpha6/Troalpha10 peptides. Protein docking studies on these decapeptides and GPVI suggest that Troalpha10 was bound at the lower surface of D1 domain and outer surface of D2 domain, which was at the different place of the collagen binding site and the scFv (single-chain variable fragment) D2-binding site. The newly discovered site was confirmed by inhibitory effects of polyclonal antibodies on collagen-induced platelet aggregation. This indicates that D2 domain of GPVI is a novel and important binding epitope on GPVI-mediated platelet aggregation. Troalpha6/Troalpha10 displayed prominent inhibitory effect of thrombus formation in fluorescein sodium-induced platelet thrombus formation of mesenteric venules and ferric chloride-induced carotid artery injury thrombosis model without prolonging the in vivo bleeding time. CONCLUSIONS: We develop a novel antithrombotic peptides derived from trowaglerix that acts through GPVI antagonism with greater safety-no severe bleeding. The binding epitope of polypeptides on GPVI is novel and important. These hexa/decapeptides have therapeutic potential for developing ideal small-mass GPVI antagonists for arterial thrombogenic diseases. PMID- 28596379 TI - Using exhaled CO2 to guide initial respiratory support at birth: a randomised controlled trial. AB - IMPORTANCE: A sustained inflation (SI) provided at birth might reduce bronchopulmonary dysplasia (BPD). OBJECTIVE: This study aims to examine whether an SI-guided exhaled carbon dioxide (ECO2) compared with positive pressure ventilation (PPV) alone at birth decreases BPD. DESIGN: Randomised controlled trial. Infants were randomly allocated to either SI (SI group) or PPV (PPV group). PARTICIPANTS: Participants of this study include infants between 23+0 and 32+6 weeks gestation with a need for PPV at birth. INTERVENTION: Infants randomised into the SI group received an initial SI with a peak inflation pressure (PIP) of 24 cmH2O over 20 s. The second SI was guided by the amount of ECO2. If ECO2 was <=20 mm Hg, a further SI of 20 s was delivered. If ECO2 was >20 mm Hg the second SI was 10 s. Infants randomised into the PPV group received mask PPV with an initial PIP of 24 cmH2O. PRIMARY OUTCOMES: Reduction in BPD defined as the need for respiratory support or supplemental oxygen at corrected gestational age of 36 weeks. RESULTS: SI (n=76) and PPV (n=86) group had similar rates of BPD (23% vs 33%, p=0.090, not statistically significant). The duration of mechanical ventilation was significantly reduced with SI versus PPV (63 (10 246) hours versus 204 (17-562) hours, respectively (p=0.045)). No short-term harmful effects were identified from two SI lasting up to 40 s (eg, pneumothorax, intraventricular haemorrhage or patent ductus arteriosus). CONCLUSION: Preterm infants <33 weeks gestation receiving SI at birth had lower duration of mechanical ventilation and similar incidence of BPD compared with PPV. Using ECO2 to guide length of SI is feasible. TRIAL REGISTRATION NUMBER: NCT01739114; Results. PMID- 28596380 TI - Identification of oxidative modifications of hemopexin and their predicted physiological relevance. AB - Hemopexin protects against heme toxicity in hemolytic diseases and conditions, sepsis, and sickle cell disease. This protection is sustained by heme-hemopexin complexes in biological fluids that resist oxidative damage during heme-driven inflammation. However, apo-hemopexin is vulnerable to inactivation by reactive nitrogen (RNS) and oxygen species (ROS) that covalently modify amino acids. The resultant nitration of amino acids is considered a specific effect reflecting biological events. Using LC-MS, we discovered low endogenous levels of tyrosine nitration in the peptide YYCFQGNQFLR in the heme-binding site of human hemopexin, which was similarly nitrated in rabbit and rat hemopexins. Immunoblotting and selective reaction monitoring were used to quantify tyrosine nitration of in vivo samples and when hemopexin was incubated in vitro with nitrating nitrite/myeloperoxidase/glucose oxidase. Significantly, heme binding by hemopexin declined as tyrosine nitration proceeded in vitro Three nitrated tyrosines reside in the heme-binding site of hemopexin, and we found that one, Tyr-199, interacts directly with the heme ring D propionate. Investigating the oxidative modifications of amino acids after incubation with tert-butyl hydroperoxide and hypochlorous acid in vitro, we identified additional covalent oxidative modifications on four tyrosine residues and one tryptophan residue of hemopexin. Importantly, three of the four modified tyrosines, some of which have more than one modification, cluster in the heme-binding site, supporting a hierarchy of vulnerable amino acids. We propose that during inflammation, apo-hemopexin is nitrated and oxidated in niches of the body containing activated RNS- and ROS generating immune and endothelial cells, potentially impairing hemopexin's protective extracellular antioxidant function. PMID- 28596381 TI - A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. AB - Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein-coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice, renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist INT-767 induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-beta expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF alpha, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease. PMID- 28596384 TI - Complete Genome Sequence of an Aquaculture-Associated Phage, FL-1, Infecting Flavobacterium spp. AB - FL-1, a myophage of Flavobacterium, was found to have a 53-kb genome with 87 putative coding sequences. PMID- 28596382 TI - A new long noncoding RNA (lncRNA) is induced in cutaneous squamous cell carcinoma and down-regulates several anticancer and cell differentiation genes in mouse. AB - Keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. Although some of the early events involved in this pathology have been identified, the subsequent steps leading to tumor development are poorly defined. We demonstrate here that the development of mouse tumors induced by the concomitant application of a carcinogen and a tumor promoter (7,12 dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), respectively) is associated with the up-regulation of a previously uncharacterized long noncoding RNA (lncRNA), termed AK144841. We found that AK144841 expression was absent from normal skin and was specifically stimulated in tumors and highly tumorigenic cells. We also found that AK144841 exists in two variants, one consisting of a large 2-kb transcript composed of four exons and one consisting of a 1.8-kb transcript lacking the second exon. Gain- and loss-of function studies indicated that AK144841 mainly inhibited gene expression, specifically down-regulating the expression of genes of the late cornified envelope-1 (Lce1) family involved in epidermal terminal differentiation and of anticancer genes such as Cgref1, Brsk1, Basp1, Dusp5, Btg2, Anpep, Dhrs9, Stfa2, Tpm1, SerpinB2, Cpa4, Crct1, Cryab, Il24, Csf2, and Rgs16 Interestingly, the lack of the second exon significantly decreased AK144841's inhibitory effect on gene expression. We also noted that high AK144841 expression correlated with a low expression of the aforementioned genes and with the tumorigenic potential of cell lines. These findings suggest that AK144841 could contribute to the dedifferentiation program of tumor-forming keratinocytes and to molecular cascades leading to tumor development. PMID- 28596385 TI - Complete Genome of Avian coronavirus Vaccine Strains Ma5 and BR-I. AB - Avian coronavirus (AvCoV) is a ubiquitous multiple-serotype pathogen of poultry, and its control is mainly based on the use of vaccines. We report here the previously unknown full genomes of the Ma5 (27,652 nucleotides [nt]) and BR-I (27,618 nt) AvCoV vaccine strains of the GI-1 (Massachusetts) and GI-11 (Brazil) types. PMID- 28596383 TI - Reinvestigation of the biological activity of d-allo-ShK protein. AB - ShK toxin from the sea anemone Stichodactyla helianthus is a 35-residue protein that binds to the Kv1.3 ion channel with high affinity. Recently we determined the X-ray structure of ShK toxin by racemic crystallography, in the course of which we discovered that d-ShK has a near-background IC50 value ~50,000 times lower than that of the l-ShK toxin. This lack of activity was at odds with previously reported results for an ShK diastereomer designated d-allo-ShK, for which significant biological activity had been observed in a similar receptor blocking assay. As reported, d-allo-ShK was made up of d-amino acids, but with retention of the natural stereochemistry of the chiral side chains of the Ile and Thr residues, i.e. containing d-allo-Ile and d-allo-Thr along with d-amino acids and glycine. To understand its apparent biological activity, we set out to chemically synthesize d-allo-ShK and determine its X-ray structure by racemic crystallography. Using validated allo-Thr and allo-Ile, both l-allo-ShK and d allo-ShK polypeptide chains were prepared by total chemical synthesis. Neither the l-allo-ShK nor the d-allo-ShK polypeptides folded, whereas both l-ShK and d ShK folded smoothly under the same conditions. Re-examination of NMR spectra of the previously reported d-allo-ShK protein revealed that diagnostic Thr and Ile signals were the same as for authentic d-ShK. On the basis of these results, we conclude that the previously reported d-allo-ShK was in fact d-ShK, the true enantiomer of natural l-ShK toxin, and that the apparent biological activity may have arisen from inadvertent contamination with trace amounts of l-ShK toxin. PMID- 28596386 TI - Genome Sequence of Serratia marcescens Phage BF. AB - Phages infecting Serratia marcescens, a common causative agent of nosocomial infections, have potential therapeutic applications. Here, we report the complete genome of the novel S. marcescens phage BF, representing the third-largest phage genome sequenced to date. PMID- 28596387 TI - Draft Genome Sequences of Eight Crimean-Congo Hemorrhagic Fever Virus Strains. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a geographically widespread RNA virus with a high degree of genomic diversity that complicates sequence-based diagnostics. Here, we sequenced eight CCHFV strains for improved assay design and deposition into FDA-ARGOS, the FDA's pathogen database for development and verification of next generation sequencing assays. PMID- 28596388 TI - Draft Genome Sequences of Two Staphylococcus aureus Strains Isolated in Succession from a Case of Bacteremia. AB - Staphylococcus aureus strains MEH1 and MEH7 were successively isolated from the blood of a patient with recurrent bacteremia. The submitted draft genomes of strains MEH1 and MEH7 are 2,914,972 and 2,911,704 bp, respectively. PMID- 28596389 TI - Complete Genome Sequence of Bacillus subtilis J-5, a Potential Biocontrol Agent. AB - Bacillus subtilis J-5 was isolated from tomato rhizosphere soil and exhibited strong inhibitory activity against Botrytis cinerea To shed light on the molecular mechanism underlying the biological control on phytopathogens, the whole genome of this strain was sequenced. Genes encoding antimicrobial compounds and the regulatory systems were identified in the genome. PMID- 28596390 TI - Draft Genome of Halomonas lionensis RHS90T, a Stress-Tolerant Gammaproteobacterium Isolated from Mediterranean Sea Sediments. AB - Members of the genus Halomonas are physiologically versatile and harbor ecological adaptations enabling the colonization of contrasted environments. We present here the draft genome of Halomonas lionensis RHS90T, isolated from Mediterranean Sea sediments. Numerous genes related to stress tolerance, DNA repair, or external signal-sensing systems were predicted, which could represent selective advantages of this marine bacterium. PMID- 28596391 TI - Draft Genome Report of Bacillus altitudinis SORB11, Isolated from the Indian Sector of the Southern Ocean. AB - Here, we present the draft genome sequence of Bacillus altitudinis SORB11, which is tolerant to UV radiation. The strain was isolated from the Indian sector of the Southern Ocean at a depth of 3.8 km. The genome sequence information reported here for B. altitudinis SORB11 gives the basis of its UV resistance mechanism and provides data for further comparative studies with other bacteria resistant to UV radiation. PMID- 28596392 TI - Fourteen Draft Genome Sequences for the First Reported Cases of Azithromycin Resistant Neisseria gonorrhoeae in Ireland. AB - Here, we report the draft genome assemblies of 14 azithromycin-resistant Neisseria gonorrhoeae clinical isolates, representing the first such strains identified in Ireland. Among these isolates are the first reported highly resistant strains (MIC >256 mg/liter), which both belonged to the ST1580 sequence type. PMID- 28596393 TI - Genome Sequence of Geothermobacter sp. Strain EPR-M, a Deep-Sea Hydrothermal Vent Iron Reducer. AB - Geothermobacter sp. strain EPR-M was isolated from a hydrothermal vent on the East Pacific Rise and has been shown to participate in the reduction of Fe(III) oxides. Here, we report its 3.73-Mb draft genome sequence. PMID- 28596394 TI - Complete Genome Sequence of a Novel Goose Parvovirus Isolated in Sichuan Province, China, in 2016. AB - Here, we report the complete genome sequence of the novel goose parvovirus (NGPV) strain SC16 (NGPV-SC16), which was isolated from Sichuan Province, China, in 2016 and is a cause of the newly emerging beak atrophy and dwarfism syndrome in ducklings and a moderately pathogenic GPV-related parvovirus. The whole genome of strain NGPV-SC16 was 5,109 nucleotides long. PMID- 28596378 TI - Molecular definitions of autophagy and related processes. AB - Over the past two decades, the molecular machinery that underlies autophagic responses has been characterized with ever increasing precision in multiple model organisms. Moreover, it has become clear that autophagy and autophagy-related processes have profound implications for human pathophysiology. However, considerable confusion persists about the use of appropriate terms to indicate specific types of autophagy and some components of the autophagy machinery, which may have detrimental effects on the expansion of the field. Driven by the overt recognition of such a potential obstacle, a panel of leading experts in the field attempts here to define several autophagy-related terms based on specific biochemical features. The ultimate objective of this collaborative exchange is to formulate recommendations that facilitate the dissemination of knowledge within and outside the field of autophagy research. PMID- 28596396 TI - Genome Sequence of a Novel Human Gammapapillomavirus Isolated from Skin. AB - A new human gammapapillomavirus (HPV_MTS2) genome was isolated and fully cloned from a skin swab. The L1 open reading frame of HPV_MTS2 was 79% and 80% identical to those of its closest relatives, HPV type 149 (species Gamma-7 of the genus Gammapapillomavirus) and HPV isolate Dysk2 (GenBank accession no. KX781281), respectively, thus qualifying it as a new HPV type. PMID- 28596395 TI - Complete Genome Sequence of Vibrio coralliilyticus 58, Isolated from Pacific Oyster (Crassostrea gigas) Larvae. AB - We report here the complete genome of Vibrio coralliilyticus strain 58, which was originally isolated from inactive Pacific oyster (Crassostrea gigas) larvae in Japan. The assembled genome consisted of two chromosomes and one plasmid. These data will provide valuable information and important insights into the biodiversity of this organism. PMID- 28596397 TI - First Detection of Avian Lineage H7N2 in Felis catus. AB - In December 2016, influenza A (H7N2) was first detected among cats in the New York City shelter system with subsequent widespread transmission. The sequence of the first clinical isolate, A/feline/New York/16-040082-1/2016(H7N2), and its genetic similarity to the live bird market lineage of H7N2 low-pathogenicity avian influenza are described. PMID- 28596398 TI - Metagenomic 16S rRNA Sequencing Analysis of Pacific Oyster (Crassostrea gigas) Microbiota from the Puget Sound Region in the United States. AB - This is the first study analyzing Pacific oyster microbiota in the Puget Sound estuarine system using a next-generation sequencing method. Taxonomic analysis indicated that Tenericutes, Chlamydiae, Proteobacteria, and Firmicutes were the most abundant phyla. Small numbers of operational taxonomic units (OTUs) belonging to the Vibrio genus were detected in all the oyster microbiome samples. PMID- 28596400 TI - Complete Genome Sequences of Five Representative Staphylococcus aureus ST398 Strains from Five Major Sequence Heterogeneity Groups of a Diverse Isolate Collection. AB - Staphylococcus aureus sequence type 398 (ST398) is a rapidly emerging livestock associated strain causing zoonotic disease in humans. The course of pathogen evolution remains unclear, prompting whole-genome comparative studies in attempts to elucidate this issue. We present the full, annotated genomes of five newly isolated representative ST398 strains from five major sequence heterogeneity groups of our diverse isolate collection. PMID- 28596399 TI - Whole-Genome Sequence of Coxiella burnetii Nine Mile RSA439 (Phase II, Clone 4), a Laboratory Workhorse Strain. AB - Here, we report the whole-genome sequence of Coxiella burnetii Nine Mile RSA439 (phase II, clone 4), a laboratory strain used extensively to investigate the biology of this intracellular bacterial pathogen. The genome consists of a 1.97 Mb chromosome and a 37.32-kb plasmid. PMID- 28596401 TI - Draft Genome Sequence of Pseudomonas chlororaphis ATCC 9446, a Nonpathogenic Bacterium with Bioremediation and Industrial Potential. AB - Pseudomonas chlororaphis strain ATCC 9446 is a biocontrol-related organism. We report here its draft genome sequence assembled into 35 contigs consisting of 6,783,030 bp. Genome annotation predicted a total of 6,200 genes, 6,128 coding sequences, 81 pseudogenes, 58 tRNAs, 4 noncoding RNAs (ncRNAs), and 41 frameshifted genes. PMID- 28596402 TI - Complete Genome Sequence of the Methicillin-Resistant Staphylococcus aureus Colonizing Strain M92. AB - M92 is a methicillin-resistant Staphylococcus aureus (MRSA) colonizing strain belonging to ST239-MRSA-III. It frequently shows local nasal colonization in our hospital staff, but has never been associated with infection. We sequenced the complete genome of M92, in order to compare it to highly virulent MRSA strains to gain insight into MRSA virulence factors. PMID- 28596403 TI - Three Draft Genome Sequences of the Bacterial Plant Pathogen Ralstonia solanacearum, Isolated in Georgia. AB - Ralstonia solanacearum, the causative agent of bacterial wilt, is a devastating bacterial plant pathogen with a wide range of hosts. We report here the first draft genome sequences for three strains of Ralstonia solanacearum isolated from infected potato, tomato, and pepper plants in Georgia. PMID- 28596404 TI - Complete Genome Sequence of Human Echovirus 20 Strain 812/YN/CHN/2010, Associated with Severe Hand-Foot-and-Mouth Disease. AB - Human echovirus 20 (E-20) belongs to the Human enterovirus B (HEV-B) species and is often detected in nonpolio enterovirus cases of acute flaccid paralysis. We determined the complete genome of strain 812/YN/CHN/2010, isolated from a child with severe hand-foot-and-mouth disease in Yunnan, China, in 2010. PMID- 28596405 TI - Genome Sequence of Paracoccus contaminans LMG 29738T, Isolated from a Water Microcosm. AB - We announce here the complete genome sequence of Paracoccus contaminans LMG 29738T, which we recently isolated from a contaminated water microcosm. The genome consists of a 2.94-Mb chromosome and a 94-kb plasmid. To our knowledge, we provide the first DNA methylation analysis of a Paracoccus species. PMID- 28596406 TI - Draft Genome Sequences of Enterobacter cloacae Strains CAPREx E7 and CAPREx E2-2. AB - Enterobacter cloacae strains CAPREx E7 and CAPREx E2-2 were isolated from Ghanaian yams at a London market. The draft genome sequences indicate that the two strains are similar, with genomes of 5,042,838 and 5,039,930 bp and 56.19% and 55.05% G+C content, respectively. Both strains encoded three different beta lactamases, including one of the AmpC family. PMID- 28596407 TI - Complete Genome Sequence of Burkholderia cenocepacia CR318, a Phosphate Solubilizing Bacterium Isolated from Corn Root. AB - Here, we report the complete genome sequence of the phosphate-solubilizing bacterium Burkholderia cenocepacia CR318, consisting of three circular chromosomes of 3,511,146 bp, 3,097,552 bp, and 1,056,069 bp. The data presented will facilitate further insight into the mechanisms of phosphate solubilization and its application for agricultural and ecological sustainability. PMID- 28596408 TI - Draft Genome Sequence of Serratia proteamaculans MFPA44A14-05, a Model Organism for the Study of Meat and Seafood Spoilage. AB - In this study, we present a draft genome sequence of Serratia proteamaculans MFPA44A14-05. This strain was isolated from a spoiled organic modified-atmosphere packed beef carpaccio. The draft genome sequence will contribute to the understanding of the role of the S. proteamaculans species in meat and seafood spoilage. PMID- 28596409 TI - Draft Genome Sequence of a Sequence Type 398 Methicillin-Resistant Staphylococcus aureus Isolate from a Danish Dairy Cow with Mastitis. AB - Livestock-associated (LA) methicillin-resistant Staphylococcus aureus (MRSA) strains of sequence type 398 (ST398) colonize both humans and various livestock species. In 2016, an ST398 LA-MRSA isolate (Sa52) was collected from a Danish dairy cow with mastitis, and here, we report the draft genome sequence of strain Sa52. PMID- 28596410 TI - Genome Sequences for Streptomyces spp. Isolated from Disease-Suppressive Soils and Long-Term Ecological Research Sites. AB - We report here the high-quality genome sequences of three Streptomyces spp. isolated as part of a long-term study of microbial soil ecology. Streptomyces sp. strain GS93-23 was isolated from naturally disease-suppressive soil (DSS) in Grand Rapids, MN, and Streptomyces sp. strains S3-4 and 3211-3 were isolated from experimental plots in the Cedar Creek Ecosystem Science Reserve (CCESR). PMID- 28596411 TI - Draft Genome Sequences of Salmonella Lysozyme Gene Knockout Mutants. AB - Lysozyme enzymes hydrolyze the beta-1,4-glycosidic bond in oligosaccharides. These enzymes are part of a broad group of glucoside hydrolases that are poorly characterized; however, they are important for growth and are being recognized as emerging virulence factors. This is the release of four lysozyme-encoding-gene deletion mutants in Salmonella enterica serovar Typhimurium LT2. PMID- 28596412 TI - Draft Genome Sequence of Leifsonia sp. Strain NCR5, a Rhizobacterium Isolated from Cadmium-Contaminated Soil. AB - We report here the draft genome sequence of Leifsonia sp. strain NCR5, a Gram positive actinomycete isolated from Carpobrotus rossii (Haw.) Schwantes rhizosphere. The de novo genome of Leifsonia sp. strain NCR5 was assembled with 69 scaffolds and a G+C content of 69%, was 4.2 Mb in length, and contained 3,952 coding sequences. PMID- 28596413 TI - Correction for Compant et al., "Draft Genome Sequence of the Root-Colonizing Fungus Trichoderma harzianum B97". PMID- 28596414 TI - Letter to the editor: Treating nonalcoholic fatty liver disease with statins. Are all statins equal? PMID- 28596415 TI - Hemolytic Uremic Syndrome in Pregnancy and Postpartum. AB - BACKGROUND: Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy associated hemolytic uremic syndrome. RESULTS: Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). CONCLUSIONS: Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants. PMID- 28596417 TI - Nephrotic Syndrome Post-Kidney Transplant. PMID- 28596416 TI - A Kidney Graft Survival Calculator that Accounts for Mismatches in Age, Sex, HLA, and Body Size. AB - BACKGROUND AND OBJECTIVES: Outcomes for transplants from living unrelated donors are of particular interest in kidney paired donation (KPD) programs where exchanges can be arranged between incompatible donor-recipient pairs or chains created from nondirected/altruistic donors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using Scientific Registry of Transplant Recipients data, we analyzed 232,705 recipients of kidney-alone transplants from 1998 to 2012. Graft failure rates were estimated using Cox models for recipients of kidney transplants from living unrelated, living related, and deceased donors. Models were adjusted for year of transplant and donor and recipient characteristics, with particular attention to mismatches in age, sex, human leukocyte antigens (HLA), body size, and weight. RESULTS: The dependence of graft failure on increasing donor age was less pronounced for living-donor than for deceased-donor transplants. Male donor-to-male recipient transplants had lower graft failure, particularly better than female to male (5%-13% lower risk). HLA mismatch was important in all donor types. Obesity of both the recipient (8%-18% higher risk) and donor (5%-11% higher risk) was associated with higher graft loss, as were donor-recipient weight ratios of <75%, compared with transplants where both parties were of similar weight (9%-12% higher risk). These models are used to create a calculator of estimated graft survival for living donors. CONCLUSIONS: This calculator provides useful information to donors, candidates, and physicians of estimated outcomes and potentially in allowing candidates to choose among several living donors. It may also help inform candidates with compatible donors on the advisability of joining a KPD program. PMID- 28596419 TI - Intratumor Heterogeneity: Novel Approaches for Resolving Genomic Architecture and Clonal Evolution. AB - High-throughput genomic technologies have revealed a remarkably complex portrait of intratumor heterogeneity in cancer and have shown that tumors evolve through a reiterative process of genetic diversification and clonal selection. This discovery has challenged the classical paradigm of clonal dominance and brought attention to subclonal tumor cell populations that contribute to the cancer phenotype. Dynamic evolutionary models may explain how these populations grow within the ecosystem of tissues, including linear, branching, neutral, and punctuated patterns. Recent evidence in breast cancer favors branching and punctuated evolution driven by genome instability as well as nongenetic sources of heterogeneity, such as epigenetic variation, hierarchal tumor cell organization, and subclonal cell-cell interactions. Resolution of the full mutational landscape of tumors could help reconstruct their phylogenetic trees and trace the subclonal origins of therapeutic resistance, relapsed disease, and distant metastases, the major causes of cancer-related mortality. Real-time assessment of the tumor subclonal architecture, however, remains limited by the high rate of errors produced by most genome-wide sequencing methods as well as the practical difficulties associated with serial tumor genotyping in patients. This review focuses on novel approaches to mitigate these challenges using bulk tumor, liquid biopsies, single-cell analysis, and deep sequencing techniques. The origins of intratumor heterogeneity and the clinical, diagnostic, and therapeutic consequences in breast cancer are also explored. Mol Cancer Res; 15(9); 1127-37. (c)2017 AACR. PMID- 28596418 TI - ERRalpha Maintains Mitochondrial Oxidative Metabolism and Constitutes an Actionable Target in PGC1alpha-Elevated Melanomas. AB - The uncontrolled growth of tumors provides metabolic dependencies that can be harnessed for therapeutic benefit. Although tumor cells exhibit these increased metabolic demands due to their rapid proliferation, these metabolic processes are general to all cells, and furthermore, targeted therapeutic intervention can provoke compensatory adaptation that alters tumors' characteristics. As an example, a subset of melanomas depends on the transcriptional coactivator PGC1alpha function to sustain their mitochondrial energy-dependent survival. However, selective outgrowth of resistant PGC1alpha-independent tumor cells becomes endowed with an augmented metastatic phenotype. To find PGC1alpha dependent components that would not affect metastasis in melanomas, an unbiased proteomic analyses was performed and uncovered the orphan nuclear receptor ERRalpha, which supports PGC1alpha's control of mitochondrial energetic metabolism, but does not affect the antioxidant nor antimetastatic regulatory roles. Specifically, genetic or pharmacologic inhibition of ERRalpha reduces the inherent bioenergetic capacity and decreases melanoma cell growth, but without altering the invasive characteristics. Thus, within this particularly aggressive subset of melanomas, which is characterized by heighted expression of PGC1alpha, ERRalpha specifically mediates prosurvival functions and represents a tangible therapeutic target.Implications: ERRalpha, a druggable protein, mediates the bioenergetic effects in melanomas defined by high PGC1alpha expression, suggesting a rational means for therapeutic targeting of this particularly aggressive melanoma subtype. Mol Cancer Res; 15(10); 1366-75. (c)2017 AACR. PMID- 28596422 TI - Interruptions in medication administration: are we asking the right questions? PMID- 28596421 TI - Higher glucocorticoid replacement doses are associated with increased mortality in patients with pituitary adenoma. AB - OBJECTIVE: Patients with secondary adrenal insufficiency (AI) have an excess mortality. The objective was to investigate the impact of the daily glucocorticoid replacement dose on mortality in patients with hypopituitarism due to non-functioning pituitary adenoma (NFPA). METHODS: Patients with NFPA were followed between years 1997 and 2014 and cross-referenced with the National Swedish Death Register. Standardized mortality ratio (SMR) was calculated with the general population as reference and Cox-regression was used to analyse the mortality. RESULTS: The analysis included 392 patients (140 women) with NFPA. Mean +/- s.d. age at diagnosis was 58.7 +/- 14.6 years and mean follow-up was 12.7 +/- 7.2 years. AI was present in 193 patients, receiving a mean daily hydrocortisone equivalent (HCeq) dose of 20 +/- 6 mg. SMR (95% confidence interval (CI)) for patients with AI was similar to that for patients without, 0.88 (0.68-1.12) and 0.87 (0.63-1.18) respectively. SMR was higher for patients with a daily HCeq dose of >20 mg (1.42 (0.88-2.17)) than that in patients with a daily HCeq dose of 20 mg (0.71 (0.49-0.99)), P = 0.017. In a Cox-regression analysis, a daily HCeq dose of >20 mg was independently associated with a higher mortality (HR: 1.88 (1.06-3.33)). Patients with daily HCeq doses of <=20 mg had a mortality risk comparable to patients without glucocorticoid replacement and to the general population. CONCLUSION: Patients with NFPA and AI receiving more than 20 mg HCeq per day have an increased mortality. Our data also show that mortality in patients substituted with 20 mg HCeq per day or less is not increased. PMID- 28596420 TI - Analysis of Posttranslational Activation of Alternative Oxidase Isoforms. AB - Mitochondrial alternative oxidase (AOX) in plants is a non-proton-motive ubiquinol oxidase that is activated by redox mechanisms and 2-oxo acids. A comparative analysis of the AOX isoenzymes AOX1A, AOX1C, and AOX1D from Arabidopsis (Arabidopsis thaliana) revealed that cysteine residues, CysI and CysII, are both involved in 2-oxo acid activation, with AOX1A activity being more increased by 2-oxo acids than that of AOX1C and AOX1D. Substitution of cysteine in AOX1A by glutamate mimicked its activation by pyruvate or glyoxylate, but not in AOX1C and AOX1D. CysIII, only present in AOX1A, is not involved in activation by reduction or metabolites, but substitutions at this position affected activity. AOX1A carrying a serine residue at position CysI was activated by succinate, while correspondingly substituted variants of AOX1C and AOX1D were insensitive. Activation by glutamate at CysI and CysII is consistent with the formation of the thiohemiacetal, while succinate activation after changing CysI to serine suggests hemiacetal formation. Surprisingly, in AOX1A, replacement of CysI by alanine, which cannot form a (thio)hemiacetal, led to even higher activities, pointing to an alternative mechanism of activation. Taken together, our results demonstrate that AOX isoforms are differentially activated and that activation at CysI and CysII is additive. PMID- 28596424 TI - S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF kappaB activity during disease progression. AB - Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by accumulation of clonal B lymphocytes, resulting from a complex balance between cell proliferation and apoptotic death. Continuous crosstalk between cancer cells and local/distant host environment is required for effective tumor growth. Among the main actors of this dynamic interplay between tumoral cells and their microenvironment are the nano-sized vesicles called exosomes. Emerging evidence indicates that secretion, composition, and functional capacity of exosomes are altered as tumors progress to an aggressive phenotype. In CLL, no data exist exploring the specific changes in the proteomic profile of plasma-derived exosomes from patients during disease evolution. We hereby report for the first time different proteomic profiles of plasma exosomes, both between indolent and progressive CLLs as well as within the individual patients at the onset of disease and during its progression. Next, we focus on the changes of the exosome protein cargoes, which are found exclusively in patients with progressive CLL after disease progression. The alterations in the proteomic cargoes underline different networks specific for leukemia progression related to inflammation, oxidative stress, and NF-kappaB and phosphatidylinositol 3-kinase/AKT pathway activation. Finally, our results suggest a preponderant role for the protein S100 A9 as an activator of the NFkappaB pathway during CLL progression and suggest that the leukemic clone can generate an autoactivation loop through S100-A9 expression, NF-kappaB activation, and exosome secretion. Collectively, our data propose a new pathway for NF-kappaB activation in CLL and highlight the importance of exosomes as extracellular mediators promoting tumor progression in CLL. PMID- 28596423 TI - Integration of over 9,000 mass spectrometry experiments builds a global map of human protein complexes. AB - Macromolecular protein complexes carry out many of the essential functions of cells, and many genetic diseases arise from disrupting the functions of such complexes. Currently, there is great interest in defining the complete set of human protein complexes, but recent published maps lack comprehensive coverage. Here, through the synthesis of over 9,000 published mass spectrometry experiments, we present hu.MAP, the most comprehensive and accurate human protein complex map to date, containing > 4,600 total complexes, > 7,700 proteins, and > 56,000 unique interactions, including thousands of confident protein interactions not identified by the original publications. hu.MAP accurately recapitulates known complexes withheld from the learning procedure, which was optimized with the aid of a new quantitative metric (k-cliques) for comparing sets of sets. The vast majority of complexes in our map are significantly enriched with literature annotations, and the map overall shows improved coverage of many disease associated proteins, as we describe in detail for ciliopathies. Using hu.MAP, we predicted and experimentally validated candidate ciliopathy disease genes in vivo in a model vertebrate, discovering CCDC138, WDR90, and KIAA1328 to be new cilia basal body/centriolar satellite proteins, and identifying ANKRD55 as a novel member of the intraflagellar transport machinery. By offering significant improvements to the accuracy and coverage of human protein complexes, hu.MAP (http://proteincomplexes.org) serves as a valuable resource for better understanding the core cellular functions of human proteins and helping to determine mechanistic foundations of human disease. PMID- 28596427 TI - The time is right for an international PCD disease registry: insight and ongoing research activities. PMID- 28596425 TI - Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6. AB - Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear. We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P = .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P = .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms. PMID- 28596426 TI - Pulmonary exacerbation in adults with bronchiectasis: a consensus definition for clinical research. AB - There is a need for a clear definition of exacerbations used in clinical trials in patients with bronchiectasis. An expert conference was convened to develop a consensus definition of an exacerbation for use in clinical research.A systematic review of exacerbation definitions used in clinical trials from January 2000 until December 2015 and involving adults with bronchiectasis was conducted. A Delphi process followed by a round-table meeting involving bronchiectasis experts was organised to reach a consensus definition. These experts came from Europe (representing the European Multicentre Bronchiectasis Research Collaboration), North America (representing the US Bronchiectasis Research Registry/COPD Foundation), Australasia and South Africa.The definition was unanimously approved by the working group as: a person with bronchiectasis with a deterioration in three or more of the following key symptoms for at least 48 h: cough; sputum volume and/or consistency; sputum purulence; breathlessness and/or exercise tolerance; fatigue and/or malaise; haemoptysis AND a clinician determines that a change in bronchiectasis treatment is required.The working group proposes the use of this consensus-based definition for bronchiectasis exacerbation in future clinical research involving adults with bronchiectasis. PMID- 28596428 TI - Nonalcoholic fatty liver disease and COPD: is it time to cross the diaphragm? PMID- 28596429 TI - The challenge of defining exacerbation in bronchiectasis. PMID- 28596430 TI - A long way to go after the initial experience with balloon pulmonary angioplasty. PMID- 28596431 TI - Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease. AB - Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-alpha levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities. PMID- 28596432 TI - Obstructive sleep apnoea and related comorbidities in incident idiopathic pulmonary fibrosis. AB - The objectives of this prospective study were: 1) to determine the prevalence and determinants of obstructive sleep apnoea (OSA) in patients with newly diagnosed idiopathic pulmonary fibrosis (IPF); 2) to determine whether OSA was associated with cardiovascular disease (CVD) as well as increased oxidative stress and levels of IPF biomarkers in the blood.A group of 45 patients with newly diagnosed IPF attended polysomnography. The prevalence of CVD and the severity of coronary artery calcification were investigated by high-resolution computed tomography. The levels of 8-hydroxydeoxyguanosine (8-OH-DG) and various IPF biomarkers in the blood were compared between patients with no or mild OSA (apnoea-hypopnoea index (AHI) <15 events.h-1), with moderate OSA (15 <=AHI <30 events.h-1) and with severe OSA (AHI >=30 events.h-1).The prevalence of moderate-to-severe OSA and severe OSA was 62% and 40%, respectively. AHI did not correlate with demographic or physiological data. All patients with severe OSA had a medical history of CVD, versus 41.2% and 40% of those with no or mild OSA, or with moderate OSA, respectively (p<0.0001). Ischaemic heart disease (IHD) and moderate-to-severe coronary artery calcifications were strongly associated with severe OSA. The 8-OH DG and matrix metalloproteinase-7 serum levels were significantly increased in the severe OSA group.Moderate-to-severe OSA is highly prevalent in incident IPF and severe OSA is strongly associated with the presence of CVD, particularly IHD. PMID- 28596433 TI - Childhood factors associated with complete and clinical asthma remission at 25 and 49 years. PMID- 28596434 TI - Treatment outcomes of MDR-TB and HIV co-infection in Europe. PMID- 28596436 TI - Checkpoint inhibition in CNS lymphoma. PMID- 28596435 TI - Balloon pulmonary angioplasty for inoperable patients with chronic thromboembolic pulmonary hypertension: the initial German experience. AB - Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention.BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%.BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk-benefit assessments. PMID- 28596437 TI - Rusty neutrophils in beta-thalassemia: no traction! PMID- 28596438 TI - Lost in translation: RP and GATA1 mutations in DBA. PMID- 28596440 TI - Villada G, Vega F. Clusters of paracortical plasmacytoid dendritic cells in lupus lymphadenitis. Blood. 2017;129(13):1884. PMID- 28596439 TI - Double-heart sign. PMID- 28596441 TI - Brivaracetam and levetiracetam dose adjustments leading to behavioural adverse effects. PMID- 28596442 TI - An unusual but classic cause of hand numbness: Pancoast tumour. PMID- 28596443 TI - Mounier-Kuhn syndrome. PMID- 28596444 TI - Pattern of medication errors among inpatients in a resource-limited hospital setting. AB - PURPOSE OF THE STUDY: There are limited studies on medication errors in South Asian and South East Asian regions. To bridge this gap, we assessed prescribing errors and selected medicine administration errors among inpatients, and the level of acknowledgement of prescribing errors by specialist physicians in a resource-limited hospital setting. STUDY DESIGN: The study was conducted in two medical wards of a hospital in Sri Lanka. Prescribing errors were identified among medicines prescribed in the latest prescription of randomly selected inpatients. Medical notes, medication histories and clinic notes were information sources. Consistency of medicine administration according to prescribing instructions was assessed by matching prescriptions with medicine charts. The level of acknowledgement of prescribing errors by specialist physicians of study wards was assessed by questionnaire. RESULTS: Prescriptions of 400 inpatients (2182 medicines) were analysed. There were 115 patients with at least one medication error. Among the 400 patients, 32.5% (n=130) were prescribing errors. The most frequent types of prescribing errors were 'wrong frequency' (10.3%, n=41), 'prescribing duplications' (10%, n=40), 'prescribing unacceptable medicine combinations' (6%, n=24) and 'medicine omissions' (4.3%, n=17). Medicine charts of 10 patients were inconsistent with prescribing instructions. Wrong medicine administration frequencies were common. The levels of acknowledgment of prescribing errors by the two specialist physicians were 75.5% and 90.9%, respectively. CONCLUSIONS: Prescribing and medicine administration errors happen in resource-limited hospitals. Errors related to dosing regimen and failing to document medicines prescribed or administered to patients in their records were particularly high. PMID- 28596445 TI - Development of a New Care Model for Hospitalized Children With Medical Complexity. AB - Children with medical complexity are a rapidly growing inpatient population with frequent, lengthy, and costly hospitalizations. During hospitalization, these patients require care coordination among multiple subspecialties and their outpatient medical homes. At a large freestanding children's hospital, a new inpatient model of care was developed in an effort to consistently provide coordinated, family-centered, and efficient care. In addition to expanding the multidisciplinary team to include a pharmacist, dietician, and social worker, the team redesign included: (1) medication reconciliation rounds, (2) care coordination rounds, and (3) multidisciplinary weekly handoff with outpatient providers. During weekly medication reconciliation rounds, the team pharmacist reviews each patient's current medications with the team. In care coordination rounds, the team collaborates with unit care managers to identify discharge needs and complete discharge tasks. Finally, at the end of the week, the outgoing hospital medicine attending physician hands off patient care to the incoming attending with input from the team's pharmacist, dietician, and social worker. Families and providers noted improvements in care coordination with the new care model. Remaining challenges include balancing resident autonomy and attending supervision, as well as supporting providers in delivering care that can be emotionally challenging. Aspects of this care model could be tested and adapted at other hospitals that care for children with medical complexity. Additionally, future work should study the impact of inpatient complex care models on patient health outcomes and experience. PMID- 28596446 TI - Reducing Uncertainty: Predictors of Stopping Chemotherapy Early and Shortened Survival Time in Platinum Resistant/Refractory Ovarian Cancer-The GCIG Symptom Benefit Study. AB - BACKGROUND: Clinicians and patients often overestimate the benefits of chemotherapy, and overall survival (OS), in platinum resistant/refractory ovarian cancer (PRROC). This study sought to determine aspects of health-related quality of life and clinicopathological characteristics before starting chemotherapy that were associated with stopping chemotherapy early, shortened survival, and death within 30 days of chemotherapy. MATERIALS AND METHODS: This study enrolled women with PRROC before starting palliative chemotherapy. Health-related quality of life was measured with EORTC QLQ-C30/QLQ-OV28. Chemotherapy stopped within 8 weeks of starting was defined as stopping early. Logistic regression was used to assess univariable and multivariable associations with stopping chemotherapy early and death within 30 days of chemotherapy; Cox proportional hazards regression was used to assess associations with progression-free and OS. RESULTS: Low baseline global health status (GHS), role function (RF), physical function (PF), and high abdominal/gastrointestinal symptom (AGIS) were associated with stopping chemotherapy early (all p < .007); low PF and RF remained significant after adjusting for clinicopathological factors (both p < .0401). Most who stopped chemotherapy early had Eastern Cooperative Oncology Group Performance Score 0-1 at baseline (79%); PF, RF, and GHS remained independently significant predictors of stopping chemotherapy early in this subgroup. Death within 30 days of chemotherapy occurred in 14%. Low GHS, RF, and PF remained significantly associated with death within 30 days of chemotherapy after adjusting for clinicopathological factors (all p < .012). CONCLUSION: Women with low GHS, RF, or PF before starting chemotherapy were more likely to stop chemotherapy early, with short OS. Self-ratings of GHS, RF, and PF could improve patient-clinician communication regarding prognosis and help decision-making in women considering chemotherapy for PRROC. IMPLICATIONS FOR PRACTICE: Measuring aspects of health related quality of life when considering further chemotherapy in platinum resistant/refractory ovarian cancer (PRROC) could help identify women with a particularly poor prognosis who are unlikely to benefit from chemotherapy and could therefore be spared unnecessary treatment and toxicity in their last months of life. Self-ratings of global health status, role function, and physical function could improve patient-clinician communication regarding prognosis and help decision-making in women considering chemotherapy for PRROC. PMID- 28596447 TI - Impact of Thrombus Length on Outcomes After Intra-Arterial Aspiration Thrombectomy in the THERAPY Trial. AB - BACKGROUND AND PURPOSE: Increasing thrombus length (TL) impedes recanalization after intravenous (IV) thrombolysis. We sought to determine whether the clinical benefit of aspiration thrombectomy relative to IV r-tPA (recombinant tissue-type plasminogen activator) may be greater at longer TL. METHODS: THERAPY was a randomized trial of aspiration thrombectomy plus IV r-tPA versus IV r-tPA alone in large-vessel stroke patients with prospective TL measurement >=8 mm. In this post hoc study, we evaluated the association of TL with trial end points and potential endovascular treatment effect, using univariate, multivariable, and multiplicative interaction analyses. RESULTS: TL data were available for all 108 patients (28% internal carotid artery, 62% M1, and 10% M2). Median TL was 14.0 mm (interquartile range, 9.7-19.5 mm). Longer TL was associated with worse outcome (90-day modified Rankin Scale score: odds ratio, 1.24 per 5-mm TL increment; 95% confidence interval, 1.04-1.52; P=0.02), even after adjusting for key outcome predictors (adjusted P=0.004). Longer TL was also associated with more serious adverse events (adjusted P=0.01), more symptomatic hemorrhages (adjusted P=0.03), and increased mortality (adjusted P=0.01). No significant relationship was observed between TL and angiographic reperfusion (modified thrombolysis in cerebral ischemia 2b-3), but greater TL was associated with longer endovascular procedural times (rho=0.36; P=0.045). Increasing TL was associated with greater aspiration thrombectomy treatment effect (interaction term P=0.03). This might be related to a potentially stronger adverse effect of increasing TL on 90-day modified Rankin Scale for patients treated with IV r-tPA (rho=0.39; P=0.01) compared with intra-arterial therapy (rho=0.20; P=0.165). CONCLUSIONS: Ischemic stroke patients with longer symptomatic thrombi have worse 90-day clinical outcomes but may have a greater relative benefit of aspiration thrombectomy over IV r-tPA alone. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01429350. PMID- 28596448 TI - Association of Vegetable Nitrate Intake With Carotid Atherosclerosis and Ischemic Cerebrovascular Disease in Older Women. AB - BACKGROUND AND PURPOSE: A short-term increase in dietary nitrate (NO3-) improves markers of vascular health via formation of nitric oxide and other bioactive nitrogen oxides. Whether this translates into long-term vascular disease risk reduction has yet to be examined. We investigated the association of vegetable derived nitrate intake with common carotid artery intima-media thickness (CCA IMT), plaque severity, and ischemic cerebrovascular disease events in elderly women (n=1226). METHODS: Vegetable nitrate intake, lifestyle factors, and cardiovascular disease risk factors were determined at baseline (1998). CCA-IMT and plaque severity were measured using B-mode carotid ultrasound (2001). Complete ischemic cerebrovascular disease hospitalizations or deaths (events) over 14.5 years (15 032 person-years of follow-up) were obtained from the West Australian Data Linkage System. RESULTS: Higher vegetable nitrate intake was associated with a lower maximum CCA-IMT (B=-0.015, P=0.002) and lower mean CCA IMT (B=-0.012, P=0.006). This relationship remained significant after adjustment for lifestyle and cardiovascular risk factors (P<=0.01). Vegetable nitrate intake was not a predictor of plaque severity. In total 186 (15%) women experienced an ischemic cerebrovascular disease event. For every 1 SD (29 mg/d) higher intake of vegetable nitrate, there was an associated 17% lower risk of 14.5-year ischemic cerebrovascular disease events in both unadjusted and fully adjusted models (P=0.02). CONCLUSIONS: Independent of other risk factors, higher vegetable nitrate was associated with a lower CCA-IMT and a lower risk of an ischemic cerebrovascular disease event. PMID- 28596449 TI - Noninvasive Ventilatory Correction in Patients With Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND PURPOSE: Even though current guidelines suggest that noninvasive ventilatory correction (NIVC) could be considered for acute ischemic stroke patients with obstructive sleep apnea, available evidence is conflicting, with no adequately powered randomized clinical trial being available to date. METHODS: We conducted a systematic review and meta-analysis of all available literature data evaluating the effect of NIVC on neurological improvement (based on decrease in National Institutes of Health Stroke Scale score), vascular events (recurrent stroke, transient ischemic attack, myocardial infarction and unstable angina), and mortality during the follow-up period. RESULTS: We identified 4 randomized clinical trials and 1 prospectively matched observational cohort, comprising a total of 389 patients (59.8% males, mean age: 64.4 years). The risk of both performance and detection bias was considered high in most of the included randomized clinical trials because of the lack of blinding in participants, personnel and/or outcome assessors. The mean decrease in National Institutes of Health Stroke Scale scores during the first (<=30) days of acute ischemic stroke was found to be greater in NIVC-treated patients in comparison to controls (standardized mean difference, 0.38; 95% confidence interval, 0.11-0.66; P=0.007). However, no significant differences were detected between NIVC-treated acute ischemic stroke patients and controls on both the risk of vascular events (risk ratio, 0.53; 95% confidence interval, 0.25-1.14; P=0.11) and mortality (risk ratio, 0.71; 95% confidence interval, 0.37-1.36; P=0.30). No evidence of heterogeneity (I2=0%; P for Cochran Q>0.50) or publication bias were detected in all analyses. CONCLUSIONS: NIVC seems to be associated with greater short-term neurological improvement in acute ischemic stroke patients with obstructive sleep apnea. This finding deserves further investigation within the settings of an adequately powered, sham-control, randomized clinical trial. PMID- 28596450 TI - Endovascular Therapies for Acute Ischemic Stroke in Children. PMID- 28596453 TI - Response by de Ridder et al to Letter Regarding Article, "PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2) Results of a Randomized, Double-Blind Placebo Controlled Clinical Trial". PMID- 28596452 TI - Effect of Long-Term Vascular Care on Progression of Cerebrovascular Lesions: Magnetic Resonance Imaging Substudy of the PreDIVA Trial (Prevention of Dementia by Intensive Vascular Care). AB - BACKGROUND AND PURPOSE: This study aimed to evaluate the effect of a nurse-led multidomain cardiovascular intervention on white matter hyperintensity (WMH) progression and incident lacunar infarcts in community-dwelling elderly with hypertension. METHODS: The preDIVA trial (Prevention of Dementia by Intensive Vascular Care) was an open-label, cluster-randomized controlled trial in community-dwelling individuals aged 70 to 78 years. General practices were assigned by computer-generated randomization to 6-year nurse-led, multidomain intensive vascular care or standard care. Of 3526 preDIVA participants, 195 nondemented participants with a systolic blood pressure >=140 mm Hg were consecutively recruited to undergo magnetic resonance imaging at 2 to 3 and 5 to 6 years after baseline. WMH volumes were measured automatically, lacunar infarcts assessed visually, blinded to treatment allocation. RESULTS: One hundred and twenty-six participants were available for longitudinal analysis (64 intervention and 62 control). Annual WMH volume increase in milliliter was similar for intervention (mean=0.73, SD=0.84) and control (mean=0.70, SD=0.59) participants (adjusted mean difference, -0.08 mL; 95% confidence interval, -0.30 to 0.15; P=0.50). Analyses suggested greater intervention effects with increasing baseline WMH volumes (P for interaction=0.03). New lacunar infarcts developed in 6 (9%) intervention and 2 (3%) control participants (odds ratio, 2.2; 95% confidence interval, 0.4-12.1; P=0.36). CONCLUSIONS: Nurse-led vascular care in hypertensive community-dwelling older persons did not diminish WMH accumulation over 3 years. However, our results do suggest this type of intervention could be effective in persons with high WMH volumes. There was no effect on lacunar infarcts incidence but numbers were low. CLINICAL TRIAL INFORMATION: URL: http://www.isrctn.com/ISRCTN29711771. Unique identifier: ISRCTN29711771. PMID- 28596451 TI - Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study. AB - BACKGROUND AND PURPOSE: Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. METHODS: We measured serum IGF-1 levels in 757 elderly individuals (mean age 79+/-5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990-1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. RESULTS: During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09-5.06; P=0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist-hip ratio for the association between IGF-1 and ischemic stroke (P<0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist-hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P=0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37-0.95; P=0.031) lower risk of incident ischemic stroke, respectively. CONCLUSIONS: IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance. PMID- 28596454 TI - Association Between Previous Use of Antiplatelet Therapy and Intracerebral Hemorrhage Outcomes. AB - BACKGROUND AND PURPOSE: Although the use of antiplatelet therapy (APT) is associated with the risk of intracerebral hemorrhage (ICH), there are limited data on prestroke APT and outcomes, particularly among patients on combination APT (CAPT). We hypothesized that the previous use of antiplatelet agents is associated with increased mortality in ICH. METHODS: We analyzed data of 82 576 patients with ICH who were not on oral anticoagulant therapy from 1574 Get with the Guidelines-Stroke hospitals between October 2012 and March 2016. Patients were categorized as not on APT, on single-APT (SAPT), and CAPT before hospital presentation with ICH. We described baseline characteristics, comorbidities, hospital characteristics and outcomes, overall and stratified by APT use. RESULTS: Before the diagnosis of ICH, 65.8% patients were not on APT, 29.5% patients were on SAPT, and 4.8% patients were on CAPT. There was an overall modest increased in-hospital mortality in the APT group versus no APT group (24% versus 23%; adjusted odds ratio, 1.05; 95% confidence interval, 1.01-1.10). Although patients on SAPT and CAPT were older and had higher risk profiles in terms of comorbidities, there was no significant difference in the in-hospital mortality among patients on SAPT versus those not on any APT (23% versus 23%; adjusted odds ratio, 1.01; 95% confidence interval, 0.97-1.05). However, in hospital mortality was higher among those on CAPT versus those not on APT (30% versus 23%; adjusted odds ratio, 1.50; 95% confidence interval, 1.39-1.63). CONCLUSIONS: Our study suggests that among patients with ICH, previous use of CAPT, but not SAPT, was associated with higher risk for in-hospital mortality. PMID- 28596455 TI - Letter by Poppe et al Regarding Article, "Emergent Carotid Stenting After Thrombectomy in Patients With Tandem Lesions". PMID- 28596456 TI - Response by Behme to Letter Regarding Article, "Emergent Carotid Stenting After Thrombectomy in Patients With Tandem Lesions". PMID- 28596457 TI - Statin Adherence Is Associated With Reduced Recurrent Stroke Risk in Patients With or Without Atrial Fibrillation. AB - BACKGROUND AND PURPOSE: Outpatient statin use reduces the risk of recurrent ischemic stroke among patients with stroke of atherothrombotic cause. It is not known whether statins have similar effects in ischemic stroke caused by atrial fibrillation (AFib). METHODS: We studied outpatient statin adherence, measured by percentage of days covered, and the risk of recurrent ischemic stroke in patients with or without AFib in a 21-hospital integrated healthcare delivery system. RESULTS: Among 6116 patients with ischemic stroke discharged on a statin over a 5 year period, 1446 (23.6%) had a diagnosis of AFib at discharge. The mean statin adherence rate (percentage of days covered) was 85, and higher levels of percentage of days covered correlated with greater degrees of low-density lipoprotein suppression. In multivariable survival models of recurrent ischemic stroke over 3 years, after controlling for age, sex, race/ethnicity, medical comorbidities, and hospital center, higher statin adherence predicted reduced stroke risk both in patients without AFib (hazard ratio, 0.78; 95% confidence interval, 0.63-0.97) and in patients with AFib (hazard ratio, 0.59; 95% confidence interval, 0.43-0.81). This association was robust to adjustment for the time in the therapeutic range for international normalized ratio among AFib subjects taking warfarin (hazard ratio, 0.61; 95% confidence interval, 0.41 0.89). CONCLUSIONS: The relationship between statin adherence and reduced recurrent stroke risk is as strong among patients with AFib as it is among patients without AFib, suggesting that AFib status should not be a reason to exclude patients from secondary stroke prevention with a statin. PMID- 28596459 TI - Letter by Noubiap and Kamtchum-Tatuene Regarding Article, "PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo Controlled Clinical Trial". PMID- 28596458 TI - Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events. AB - BACKGROUND AND PURPOSE: Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). METHODS: We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. alpha-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes <=7 days after presentation and 6 months later. RESULTS: We enrolled 365 patients with IS and 32 with TIA. alpha-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at <=7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6 month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. CONCLUSIONS: In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes. PMID- 28596461 TI - Classification of pulmonary pathology from breath sounds using the wavelet packet transform and an extreme learning machine. AB - BACKGROUND: Auscultation is a medical procedure used for the initial diagnosis and assessment of lung and heart diseases. From this perspective, we propose assessing the performance of the extreme learning machine (ELM) classifiers for the diagnosis of pulmonary pathology using breath sounds. METHODS: Energy and entropy features were extracted from the breath sound using the wavelet packet transform. The statistical significance of the extracted features was evaluated by one-way analysis of variance (ANOVA). The extracted features were inputted into the ELM classifier. RESULTS: The maximum classification accuracies obtained for the conventional validation (CV) of the energy and entropy features were 97.36% and 98.37%, respectively, whereas the accuracies obtained for the cross validation (CRV) of the energy and entropy features were 96.80% and 97.91%, respectively. In addition, maximum classification accuracies of 98.25% and 99.25% were obtained for the CV and CRV of the ensemble features, respectively. CONCLUSION: The results indicate that the classification accuracy obtained with the ensemble features was higher than those obtained with the energy and entropy features. PMID- 28596462 TI - [Pure Amnesia]. AB - Pure amnesia (amnesic syndrome) is an organic brain syndrome characterized by impairment in episodic memory, with either an anterograde or sometimes retrograde loss of memories. Although episodic memory is impaired, semantic memory, immediate memory, and procedural memory are preserved. The Papez circuit is a network of nerve fibers and nerve centers that starts and ends in the hippocampus travelling by way of the fornix, mammillary bodies, anterior thalamic nuclei, cingulate gyrus, and parahippocampal gyrus. A lesion restricted to this circuit often produces pure amnesia. Regions concerned with the Yakovlev circuit also have an important role in memory. Clinical cases of pure amnesia caused by cerebrovascular disease presented following brain imaging and resulted from various different lesions. The cases identified were predominantly thalamic amnesia and hippocampal amnesia. Thalamic amnesia often resulted from an infarction in the territory of the thalamotuberal artery and paramedian thalamic artery although thalamic hemorrhage in medial portion of thalamus also produced pure amnesia. Hippocampal amnesia usually occurred following an infarction in the temporal branches of posterior cerebral artery. Cases of retrosplenial amnesia caused by subcortical hematoma and infarction in the retrosplenial region are also described. In addition, cases of pure amnesia resulting from an infarction in the fornix, mammillary body hemorrhage, and caudate hemorrhage are also shown. PMID- 28596463 TI - [Prosopometamorphopsia]. AB - Facial perception relies on both configural processing and analytical processing. Seventeen years ago, Haxby and colleagues proposed an influential neural model in which a core system and an extended system were involved in facial processing. Herein, first analyze configural processing on the basis of the Haxby model. We review previous findings from published electrophysiological and neuroimaging studies, and describe previously reported clinical cases, and finally we discuss our own clinical cases an findings. Based on this work we have sketched out a new framework for facial perception suggesting that suggests that the extended system includes more widely distributed regions than originally expected. PMID- 28596460 TI - Role of Improved Vascular Health in the Declining Incidence of Dementia. PMID- 28596464 TI - [Music Processing in the Brain: Neuropsychological Approach Through Findings of Patients with Amusia]. AB - Less than 100 cases of amusia have been reported. The sites of lesion in these patients have been located in the right, left, and bilateral cerebral hemisphere(s); therefore the lateralization of amusia is not as clear as that of aphasia. Among them, pure amusia, the selective loss of musical ability due to acquired brain damage, was observed only in nine cases. The cases of pure amusia included right superior and middle temporal gyrus lesion involvement. By comparing the lesion sites and symptoms of pure amusia, it might be assumed that the right superior/middle temporal gyrus participates in the perception and expression of melody. In 2011, the selective loss of the experience of musical emotion was termed musical anhedonia by the presenting author. Only four cases of musical anhedonia have been reported, and in those the cortical and subcortical regions of the right temporoparietal area were commonly damaged. It was supposed that musical anhedonia was caused by the disconnection between the right auditory association cortices and the insula. Based on the results of the assessment of healthy young participants, there have been many reports of congenital amusia or musical anhedonia by musical psychologists. Further studies are needed in order to determine whether these diseases actually exist. PMID- 28596465 TI - [Somatoparaphrenia]. AB - Somatoparaphrenia (SP) typically occurs after a right-hemisphere stroke, where the patient refers to his/her hemiplegic left hand as belonging to someone else. In this report, we review the literature for the brain structures affected in SP. We also report three cases with varying degrees of SP: a typical case, one case where SP affected the visceral sensations, and one case where a concurring psychiatric condition lead to a very complex, bizarre delusion. PMID- 28596466 TI - [Clocks, Behavior, and Cognition]. AB - The nerve center responsible for controlling our circadian rhythm is located in a cluster of cells known as the suprachiasmatic nucleus in the hypothalamus. Various physiological functions such as sleep, arousal, blood pressure, body temperature, and hormone secretion are regulated in a 24-hour rhythm by this circuit. Somatic cells of other organs have a peripheral clock gene and by synchronizing the rhythm of the central and peripheral clocks, it is possible to live a healthy life. Due to aging and degenerative disease, circadian rhythm gradually collapses. Factors that can contribute to this include reduced expression of the time gene associated with photo stimulation, a reduction in neurotransmitter levels, and reduced melatonin production. Biological clocks play an important role in our emotions, cognitive function, and behavior. Sleep disorders and metabolic disease related to the circadian rhythm affect metabolic and endocrine activities via the autonomic nervous system and the intestinal bacterial flora. Shift work disorder is associated with insomnia and excessive drowsiness as individuals often work during their sleeping hours. Now time management is placed at the center of our society, and it is important to evaluate the medical risk of engaging in shift work. In frontotemporal dementia (FTD), the stereotypical behaviors may be associated with time. In some patients, multiple timed behaviors occupy a considerable part of the patient's daily life. Stereotypical behaviors in FTD are often considered in contrast to obsessive compulsive disease (OCD). Studies of OCD have found a close correlation between clinical symptoms, cognitive function, and brain function. PMID- 28596467 TI - [Embolic Stroke of Undetermined Source]. AB - A new clinical construct, embolic stroke of undetermined source (ESUS) was established as a therapeutically relevant entity, which are defined as a non lacunar infarction without proximal arterial stenosis or cardioembolic sources, with a clear indication for anticoagulation, especially with direct oral anticoagulant (DOAC). The possible embolic sources include covert atrial fibrillation, arterial stenosis with <50%, low-risk emboligenic cardiac sources, aortic plaque, cancer-associated, and paradoxical embolism. As its diagnosis is based on exclusive process, ESUS comprises heterogeneous pathologies. Though current Japanese guideline recommends antiplatelets for non-cardioembolic stroke, ESUS may benefits from anticoagulants. Randomized trials testing DOAC for the secondary prevention of ESUS are currently ongoing. PMID- 28596468 TI - [The Unitary Psychosis Theory]. AB - Since E. Kraepelin isolated schizophrenia and bipolar disorder as heterogeneous diseases, attempts to categorize mental illnesses have continued to the DSM-5. Meanwhile, cases of psychosis occurring as a result of neurosyphilis have been reported. Whilst in some cases it is useful to divide mental illnesses, in others imposing such classifications may be not be feasible. Since 2008 numerous papers have been published showing that the same genes are related to an increased incidence of several psychiatric diseases including intellectual disorder, autism, ADHD, schizophrenia, bipolar disorder, and depression. This suggests that the theory that these are separate and heterogeneous diseases should be rejected. Aside from the categorical classification in the DSM, it is desirable to create new diagnostic criteria that capture mental illness as a spectrum. PMID- 28596469 TI - [A Case of Takayasu Arteritis with Acute Bilateral Occlusion of the Internal Carotid Arteries]. AB - A 38-year-old woman developed disturbance of consciousness and quadriplegia. Magnetic resonance images showed scattered acute infarcts in both hemispheres and bilateral occlusion of the intracranial artery (ICA). Immediate mechanical thrombectomy restored the patency of the ICA. Contrast-enhanced computed tomography revealed bilateral wall thickening of the abdominal aorta and the iliac arteries. This finding and an elevated erythrocyte sedimentation rate supported the diagnosis of Takayasu arteritis. Here, we thus report a rare case of Takayasu arteritis with acute bilateral occlusion of the internal carotid arteries. PMID- 28596470 TI - [Epidural Emphysema Associated with Diabetic Nonketotic Hyperosmolar Coma]. PMID- 28596481 TI - Mislocalization of centromeric histone H3 variant CENP-A contributes to chromosomal instability (CIN) in human cells. AB - Chromosomal instability (CIN) is a hallmark of many cancers and a major contributor to tumorigenesis. Centromere and kinetochore associated proteins such as the evolutionarily conserved centromeric histone H3 variant CENP-A, associate with centromeric DNA for centromere function and chromosomal stability. Stringent regulation of cellular CENP-A levels prevents its mislocalization in yeast and flies to maintain genome stability. CENP-A overexpression and mislocalization are observed in several cancers and reported to be associated with increased invasiveness and poor prognosis. We examined whether there is a direct relationship between mislocalization of overexpressed CENP-A and CIN using HeLa and chromosomally stable diploid RPE1 cell lines as model systems. Our results show that mislocalization of overexpressed CENP-A to chromosome arms leads to chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit. CENP-A overexpressing cells showed altered localization of centromere and kinetochore associated proteins such as CENP-C, CENP-T and Nuf2 leading to weakened native kinetochores as shown by reduced interkinetochore distance and CIN. Importantly, our results show that mislocalization of CENP-A to chromosome arms is one of the major contributors for CIN as depletion of histone chaperone DAXX prevents CENP-A mislocalization and rescues the reduced interkinetochore distance and CIN phenotype in CENP-A overexpressing cells. In summary, our results establish that CENP-A overexpression and mislocalization result in a CIN phenotype in human cells. This study provides insights into how overexpression of CENP-A may contribute to CIN in cancers and underscore the importance of understanding the pathways that prevent CENP-A mislocalization for genome stability. PMID- 28596482 TI - Aging-dependent DNA hypermethylation and gene expression of GSTM1 involved in T cell differentiation. AB - This study investigated whether aging was associated with epigenetic changes of DNA hypermethylation on immune gene expression and lymphocyte differentiation. We screened CG sites of methylation in blood leukocytes from different age populations, picked up genes with age-related increase of CG methylation content more than 15%, and validated immune related genes with CG hypermethylation involved in lymphocyte differentiation in the aged population. We found that 12 genes (EXHX1a?? IL-10a?? TSP50a?? GSTM1a??SLC5A5a??SPI1a??F2Ra??LMO2a??PTPN6a??FGFR2a??MMP9a??MET) were associated with promoter or exon one DNA hypermethylation in the aged group. Two immune related genes, GSTM1 and LMO2, were chosen to validate its aging-related CG hypermethylation in different leukocytes. We are the first to validate that GSTM1_P266 and LMO2_E128 CG methylation contents in T lymphocytes but not polymorphonuclear cells (PMNs) or mononuclear cells (MNCs) were significantly increased in the aged population. The GSTM1 mRNA expression in T lymphocytes but not PMNs or MNCs was inversely associated with the GSTM1 CG hypermethylation levels in the aged population studied. Further studies showed that lower GSTM1 CG methylation content led to the higher GSTM1 mRNA expression in T cells and knockdown of GSTM1 mRNA expression decreased type 1 T helper cell (Th1) differentiation in Jurkat T cells and normal adult CD4 T cells. The GSTM1_P266 hypermethylation in the aged population associated with lower GSTM1 mRNA expression was involved in Th1 differentiation, highlighting that modulation of aging-associated GSTM1 methylation may be able to enhance T helper cell immunity in the elders. PMID- 28596485 TI - Rumen-derived lipopolysaccharide provoked inflammatory injury in the liver of dairy cows fed a high-concentrate diet. AB - Rumen-derived lipopolysaccharide (LPS) is translocated from the rumen into the bloodstream when subacute ruminal acidosis (SARA) occurs following long-term feeding with a high-concentrate (HC) diet in dairy cows. The objective of this study was to investigate the mechanism of inflammatory responses in the liver caused by HC diet feeding. We found that SARA was induced in dairy cows when rumen pH below 5.6 lasted for at least 3 h/d with HC diet feeding. Also, the LPS levels in the portal and hepatic veins were increased significantly and hepatocytes were impaired as well as the liver function was inhibited during SARA condition. Meanwhile, the mRNA expression of immune genes including TNF receptor associated factor 6 (TRAF6), nuclear factor-kappa B (NF-kappaB), p38 mitogen activated protein kinase (MAPK), extracellular regulated protein kinases (ERK) MAPK, Interleukin-1 (IL-1) and serum amyloid A (SAA) in the liver were significantly increased in SARA cows. Moreover, the phosphorylation level of NF kappaB p65 and p38 MAPK proteins in the liver and the concentration of Tumor Necrosis Factor (TNF-alpha), Interleukin-1beta (IL-1beta) and Interleukin-6 (IL 6) in peripheral blood were obviously increased under SARA condition. In conclusion, the inflammatory injury in the liver caused by LPS that traveled from the digestive tract to the liver through the portal vein after feeding with a HC diet. PMID- 28596511 TI - Effect of Alprazolam on Redox Status in Renal Transplantation Donors and Recipients. AB - BACKGROUND Benzodiazepines are the most popular premedication drugs thought to act through the GABA/benzodiazepine receptor complex and alprazolam is one of the most potent benzodiazepines that have a quick onset. While there is a growing body of evidence supporting alprazolam in the amelioration of redox status in animals, no study has been performed concerning its antioxidant activity in humans. The purpose of this investigation was to determine the effect of alprazolam on redox status. MATERIAL AND METHODS This study was a four-group randomized controlled trial. Participants were recruited from Acibadem University Acibadem International Hospital and included a convenience sample of 82 donors and recipients undergoing renal transplantation. Patients were randomly divided into four groups. While donors and recipients in experimental groups (G1 and G3) were administered alprazolam 0.5 mg orally one hour before the operation, those in control groups (G2 and G4) were not. Serum advanced oxidative protein products, total thiol, free hemoglobin, ischemic modified albumin, and sialic acid levels at different time points were measured to evaluate the redox status. RESULTS All oxidative stress parameters were higher in the alprazolam premedication groups (G1, G3) at all time points than in the control groups (G2, G4). Basal values of oxidative parameters (at time point T1) in patients with CKD (G3, G4) were lower than in healthy donors (G1, G2). CONCLUSIONS Alprazolam premedication in donors and end-stage renal failure patients undergoing renal transplantation does not improve redox homeostasis but further experimental studies are needed. PMID- 28596487 TI - ZNF131 suppresses centrosome fragmentation in glioblastoma stem-like cells through regulation of HAUS5. AB - Zinc finger domain genes comprise ~3% of the human genome, yet many of their functions remain unknown. Here we investigated roles for the vertebrate-specific BTB domain zinc finger gene ZNF131 in the context of human brain tumors. We report that ZNF131 is broadly required for Glioblastoma stem-like cell (GSC) viability, but dispensable for neural progenitor cell (NPC) viability. Examination of gene expression changes after ZNF131 knockdown (kd) revealed that ZNF131 activity notably promotes expression of Joubert Syndrome ciliopathy genes, including KIF7, NPHP1, and TMEM237, as well as HAUS5, a component of Augmin/HAUS complex that facilitates microtubule nucleation along the mitotic spindle. Of these genes only kd of HAUS5 displayed GSC-specific viability loss. Critically, HAUS5 ectopic expression was sufficient to suppress viability defects of ZNF131 kd cells. Moreover, ZNF131 and HAUS5 kd phenocopied each other in GSCs, each causing: mitotic arrest, centrosome fragmentation, loss of Augmin/HAUS complex on the mitotic spindle, and loss of GSC self-renewal and tumor formation capacity. In control NPCs, we observed centrosome fragmentation and lethality only when HAUS5 kd was combined with kd of HAUS2 or HAUS4, demonstrating that the complex is essential in NPCs, but that GSCs have heightened requirement. Our results suggest that GSCs differentially rely on ZNF131-dependent expression of HAUS5 as well as the Augmin/HAUS complex activity to maintain the integrity of centrosome function and viability. PMID- 28596512 TI - Paricalcitol as an Antiproteinuric Agent Can Result in the Deterioration of Renal and Heart Function in a Patient with Fabry Disease. AB - BACKGROUND Fabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal a galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria. CASE REPORT We present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function. CONCLUSIONS Despite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug. PMID- 28596513 TI - Bidirectional Pull-Back Technique for Retrieval of Strut-Embedded Cylinder-Shaped Filters in Inferior Vena Cava. AB - BACKGROUND IVC filters have been widely accepted as an effective method to prevent pulmonary embolism (PE) in patients with deep venous thrombosis (DVT). However, the placement of IVC filters is associated with significant complications and filter retrieval can be challenging when the filter struts are embedded into the caval wall. MATERIAL AND METHODS Over 26 months, we reviewed the safety and efficacy of the bidirectional pull-back technique for removing strut-embedded IVC filters in 15 consecutive patients. Retrieval procedural data such as in-dwell time, retrieval time, and fluoroscopy time were recorded. Clinical outcomes and procedure-related complications were evaluated by venography or enhanced computed tomography. Histologic tissue was analyzed to reveal the pathologic effects of chronic filter implantation. All patients underwent routine clinical follow-up at a mean time of 12 months (range, 8-14 months). RESULTS Technical success of filter retrieval was achieved in 100%, with mean implantation of 46.6 days (range, 27-66 days). Filter types were as follows: OptEase (n=11) and Aegisy (n=4). The mean retrieval time and fluoroscopy time were 21.43+/-5.42 min and 7.63+/-2.67 min, respectively. Immediate postprocedure venography showed no procedure-related complications. Thirteen patients discontinued previously prescribed lifelong anticoagulation. There were no long term complications during follow-up. CONCLUSIONS The bidirectional pull-back technique is safe and efficient for filter retrieval. This complex technique can be particularly useful in selected patients to remove strut-embedded cylindrical shaped IVC filters previously considered irretrievable. PMID- 28596490 TI - A genetic polymorphism repurposes the G-protein coupled and membrane-associated estrogen receptor GPER to a transcription factor-like molecule promoting paracrine signaling between stroma and breast carcinoma cells. AB - GPER is a membrane-associated estrogen receptor of the family of G-protein coupled receptors. For breast cancer, the contribution of GPER to promoting the proliferation and migration of both carcinoma cells and cancer-associated fibroblasts (CAFs) in response to estrogen and other agonists has extensively been investigated. Intriguingly, GPER was previously found to be localized to the nucleus in one isolate of breast CAFs. Moreover, this nuclear GPER was shown to bind regulatory sequences of cancer-relevant target genes and to induce their expression. We decided to find out what induces the nuclear localization of GPER, how general this phenomenon is, and what its functional significance is. We discovered that interfering with N-linked glycosylation of GPER, either by mutation of the predicted glycosylation sites or pharmacologically with tunicamycin, drives GPER into the nucleus. Surveying a small set of CAFs from breast cancer biopsies, we found that a relatively common single nucleotide polymorphism, which results in the expression of a GPER variant with the amino acid substitution P16L, is associated with the nuclear localization of GPER. GPER with P16L fails to be glycosylated, presumably because of a conformational effect on the nearby glycosylation sites. GPER P16L is defective for membrane-associated signaling, but instead acts like an estrogen-stimulated transcription factor. In CAFs, it induces the secretion of paracrine factors that promote the migration of carcinoma cells. This raises the possibility that the GPER P16L polymorphism could be a risk factor for breast cancer. PMID- 28596514 TI - Genome-wide identification and characterization of phased small interfering RNA genes in response to Botrytis cinerea infection in Solanum lycopersicum. AB - Phased small interfering RNAs (phasiRNAs) are encoded by a novel class of genes known as phasiRNA producing (PHAS) genes. These genes play important regulatory roles by targeting protein coding transcripts in plant species. In this study, 91 regions were identified as potential PHAS loci in tomato, with additional evidence that seven of them can be triggered by five miRNAs. Among the identified loci, 51 were located in genic regions, and the remaining 40 were located in intergenic regions. The transient overexpression of PHAS15 and PHAS26 demonstrated that phasiRNAs predicted by PhaseTank were indeed generated from their respective PHAS loci. Using sRNA-seq data from B. cinerea-infected tomato leaves, we identified 50 B. cinerea-responsive phasiRNAs with increased abundance and five with decreased abundance. Moreover, 164 targets of these differentially expressed phasiRNAs were predicted, and 94 of them were confirmed experimentally using degradome data. Gene ontology analysis of the targets revealed an enrichment of genes with functions related to defense responses and signaling regulation. These results suggest that a large number of endogenous siRNAs, such as phasiRNAs, have not yet been identified in tomato and underscore the urgent need to systematically identify and functionally analyze siRNAs in tomato. PMID- 28596515 TI - Characterization of a new murine cell line of sarcomatoid hepatocellular carcinoma and its application for biomarker/therapy development. AB - Sarcomatoid hepatocellular carcinoma (SHC) is a rare type of HCC with significantly poorer survival than ordinary HCC. Little is known about the mechanism associated with SHC and its biomarkers and therapy. Here, we established a mouse liver cancer cell line and designated as Ymac-1. A sarcomatous appearance was observed in the allograft tumor arose from Ymac-1. Liver-secreted plasma proteins were found in Ymac-1 cultured supernatant by proteomics analysis. The positive staining of CK7, CK8, Vimentin and the suppressed expression of AFP indicated that Ymac-1 is a SHC cell line. Compared to its original tumor, an elevated level of EMT markers, N-cadherin and Vimentin, was found in Ymac-1. Ymac-1 displayed a higher migration rate and side population percentage than a mouse ordinary HCC cell line-Hepa1-6. Microarray analysis was performed to identify potential biomarkers/therapeutic targets for SHC. G6pd, a vital enzyme in pentose phosphate pathway, is highly expressed in Ymac-1. Depletion of G6pd in Ymac-1 reduced CD133 expression and sphere formation. Positive correlations between G6PD and CD133 were observed in human specimen. Higher expression of both G6PD and CD133 in tumor were associated with poor survival. In summary Ymac-1 can be a useful SHC cell model for novel biomarker and therapy development. PMID- 28596516 TI - mTFkb: a knowledgebase for fundamental annotation of mouse transcription factors. AB - Transcription factors (TFs) are well-known important regulators in cell biology and tissue development. However, in mouse, one of the most widely-used model species, currently the vast majority of the known TFs have not been functionally studied due to the lack of sufficient annotations. To this end, we collected and analyzed the whole transcriptome sequencing data from more than 30 major mouse tissues and used the expression profiles to annotate the TFs. We found that the expression patterns of the TFs are highly correlated with the histology of the tissue types thus can be used to infer the potential functions of the TFs. Furthermore, we found that as many as 30% TFs display tissue-specific expression pattern, and these tissue-specific TFs are among the key TFs in their corresponding tissues. We also observed signals of divergent transcription associated with many TFs with unique expression pattern. Lastly, we have integrated all the data, our analysis results as well as various annotation resources to build a web-based database named mTFkb freely accessible at htt p://www.m yogenesisdb.org/mTFkb/ . We believe that mTFkb could serve as a useful and valuable resource for TF studies in mouse. PMID- 28596517 TI - Prenatal chromium exposure and risk of preterm birth: a cohort study in Hubei, China. AB - Few studies have investigated the association of environmental chromium exposure and preterm birth in general population. This study was designed to investigate whether maternal chromium exposure during pregnancy is associated with reduced gestational age or risk of preterm birth using the data from Healthy Baby Cohort study conducted in Hubei, China between 2012 and 2014 (n = 7290). Chromium concentrations in maternal urine samples collected at delivery were measured with inductively coupled plasma mass spectrometry. Tertiles of chromium concentrations was negatively associated with gestational age in multivariable linear regression analyses [beta (95% CI): low = reference; middle = -0.67 days (-1.14, -0.20); high = -2.30 days (-2.93, -1.67); p trend <0.01]. Logistic regression analyses also indicated that higher maternal chromium [adjusted odds ratio (OR) (95% CI): 1.55(0.99, 2.42) for the medium tertile; 1.89(1.13, 3.18) for the highest tertile; p trend <0.01] was associated with increased risk of preterm birth. The associations appeared to be more pronounced in male infants (adjusted OR (95% CI): 2.54 (1.29, 4.95) for the medium tertile; 2.92 (1.37, 6.19) for the highest tertile; p trend <0.01). Our findings suggest maternal exposure to higher chromium levels during pregnancy may potentially increase the risk of delivering preterm infants, particularly for male infants. PMID- 28596520 TI - A Comprehensive Prediction Model of Hydraulic Extended-Reach Limit Considering the Allowable Range of Drilling Fluid Flow Rate in Horizontal Drilling. AB - Hydraulic extended-reach limit (HERL) model of horizontal extended-reach well (ERW) can predict the maximum measured depth (MMD) of the horizontal ERW. The HERL refers to the well's MMD when drilling fluid cannot be normally circulated by drilling pump. Previous model analyzed the following two constraint conditions, drilling pump rated pressure and rated power. However, effects of the allowable range of drilling fluid flow rate (Q min <= Q <= Q max ) were not considered. In this study, three cases of HERL model are proposed according to the relationship between allowable range of drilling fluid flow rate and rated flow rate of drilling pump (Q r ). A horizontal ERW is analyzed to predict its HERL, especially its horizontal-section limit (L h ). Results show that when Q min <= Q r <= Q max (Case I), L h depends both on horizontal-section limit based on rated pump pressure (L h1 ) and horizontal-section limit based on rated pump power (L h2 ); when Q min < Q max < Q r (Case II), L h is exclusively controlled by L h1 ; while L h is only determined by L h2 when Q r < Q min < Q max (Case III). Furthermore, L h1 first increases and then decreases with the increase in drilling fluid flow rate, while L h2 keeps decreasing as the drilling fluid flow rate increases. The comprehensive model provides a more accurate prediction on HERL. PMID- 28596518 TI - Recombinant human plasma phospholipid transfer protein (PLTP) to prevent bacterial growth and to treat sepsis. AB - Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis. PMID- 28596519 TI - The Connection of the Genetic, Cultural and Geographic Landscapes of Transoxiana. AB - We have analyzed Y-chromosomal variation in populations from Transoxiana, a historical region covering the southwestern part of Central Asia. We studied 780 samples from 10 regional populations of Kazakhs, Uzbeks, Turkmens, Dungans, and Karakalpaks using 35 SNP and 17 STR markers. Analysis of haplogroup frequencies using multidimensional scaling and principal component plots, supported by an analysis of molecular variance, showed that the geographic landscape of Transoxiana, despite its distinctiveness and diversity (deserts, fertile river basins, foothills and plains) had no strong influence on the genetic landscape. The main factor structuring the gene pool was the mode of subsistence: settled agriculture or nomadic pastoralism. Investigation of STR-based clusters of haplotypes and their ages revealed that cultural and demic expansions of Transoxiana were not closely connected with each other. The Arab cultural expansion introduced Islam to the region but did not leave a significant mark on the pool of paternal lineages. The Mongol expansion, in contrast, had enormous demic success, but did not impact cultural elements like language and religion. The genealogy of Muslim missionaries within the settled agricultural communities of Transoxiana was based on spiritual succession passed from teacher to disciple. However, among Transoxianan nomads, spiritual and biological succession became merged. PMID- 28596521 TI - Soil nematodes show a mid-elevation diversity maximum and elevational zonation on Mt. Norikura, Japan. AB - Little is known about how nematode ecology differs across elevational gradients. We investigated the soil nematode community along a ~2,200 m elevational range on Mt. Norikura, Japan, by sequencing the 18S rRNA gene. As with many other groups of organisms, nematode diversity showed a high correlation with elevation, and a maximum in mid-elevations. While elevation itself, in the context of the mid domain effect, could predict the observed unimodal pattern of soil nematode communities along the elevational gradient, mean annual temperature and soil total nitrogen concentration were the best predictors of diversity. We also found nematode community composition showed strong elevational zonation, indicating that a high degree of ecological specialization that may exist in nematodes in relation to elevation-related environmental gradients and certain nematode OTUs had ranges extending across all elevations, and these generalized OTUs made up a greater proportion of the community at high elevations - such that high elevation nematode OTUs had broader elevational ranges on average, providing an example consistent to Rapoport's elevational hypothesis. This study reveals the potential for using sequencing methods to investigate elevational gradients of small soil organisms, providing a method for rapid investigation of patterns without specialized knowledge in taxonomic identification. PMID- 28596522 TI - Enhancing Optical Forces in InP-Based Waveguides. AB - Cantilever sensors are among the most important microelectromechanical systems (MEMS), which are usually actuated by electrostatic forces or piezoelectric elements. Although well-developed microfabrication technology has made silicon the prevailing material for MEMS, unique properties of other materials are overlooked in this context. Here we investigate optically induced forces exerted upon a semi-insulating InP waveguide suspended above a highly doped InP:Si substrate, in three different regimes: the epsilon-near-zero (ENZ), with excitation of surface plasmon polaritons (SPPs) and phonons excitation. An order of magnitude amplification of the force is observed when light is coupled to SPPs, and three orders of magnitude amplification is achieved in the phonon excitation regime. In the ENZ regime, the force is found to be repulsive and higher than that in a waveguide suspended above a dielectric substrate. Low losses in InP:Si result in a big propagation length. The induced deflection can be detected by measuring the phase change of the light when passing through the waveguide, which enables all-optical functioning, and paves the way towards integration and miniaturization of micro-cantilevers. In addition, tunability of the ENZ and the SPP excitation wavelength ranges, via adjusting the carrier concentration, provides an extra degree of freedom for designing MEMS devices. PMID- 28596523 TI - Extrasynaptic NMDA receptor dependent long-term potentiation of hippocampal CA1 pyramidal neurons. AB - In the adult mouse hippocampus, NMDA receptors (NMDARs) of CA1 neurons play an important role in the synaptic plasticity. The location of NMDARs can determine their roles in the induction of long-term potentiation (LTP). However, the extrasynaptic NMDARs (ES-NMDARs) dependent LTP haven't been reported. Here, through the use of a 5-Hz stimulation and MK-801 (an irreversible antagonist of NMDARs) in the CA1 neurons of adult mice hippocampal slices, synaptic NMDARs were selectively inhibited and NMDAR-mediated excitatory postsynaptic currents were not recovered. We found that a robust LTP was induced by 3-train 100-Hz stimulation when the synaptic NMDARs and extrasynaptic NR2B containing NMDARs were blocked, but not in the any of the following conditions: blocking of all NMDARs (synaptic and extrasynaptic), blocking of the synaptic NMDARs, and blocking of the synaptic NMDARs and extrasynaptic NR2A-containing NMDARs. The results indicate that this LTP is ES-NMDARs dependent, and NR2B-containing ES NMDARs modulates the threshold of LTP induction. PMID- 28596525 TI - Mathematical modeling and stability analysis of Pine Wilt Disease with optimal control. AB - This paper presents and examine a mathematical system of equations which describes the dynamics of pine wilt disease (PWD). Firstly, we examine the model with constant controls. Here, we investigate the disease equilibria and calculate the basic reproduction number of the disease. Secondly, we incorporate time dependent controls into the model and then analyze the conditions that are necessary for the disease to be controlled optimally. Finally, the numerical results for the model are presented. PMID- 28596524 TI - Association between Carotid Plaque and Cognitive Impairment in Chinese Stroke Population: The SOS-Stroke Study. AB - We aimed to investigate the association between carotid plaques and cognitive impairment among patients with acute ischemic stroke, and to assess key clinical implications. In the Acute Ischemic Stroke Study, patients who received a cognitive testing and underwent complete carotid artery ultrasound scans were included. Cognitive function was measured by the mini-mental state examination. The cross-sectional relationships between cognitive impairment and carotid plaques were evaluated using multivariate logistic regression analysis. Of the 3116 patients included in this study, 826 (26.51%) patients were diagnosed with cognitive impairment. After adjusting for potential confounders, patients with >=2 carotid plaques (odds ratio [OR] = 1.47; 95% confidence interval [CI]: 1.19 1.82), patients with >=2 number of carotid arteries with plaque (OR = 1.48; 95% CI: 1.19-1.84) and patients with hypoechoic plaque (OR = 2.05; 95% CI: 1.24-3.38) are more likely to have cognitive impairment. In this acute ischemic stroke population, the number of carotid plaques, the number of carotid arteries with plaque and plaque stability are all associated with cognitive impairment. PMID- 28596526 TI - Mechanistic roles of microRNAs in hepatocarcinogenesis: A study of thioacetamide with multiple doses and time-points of rats. AB - Environmental chemicals exposure is one of the primary factors for liver toxicity and hepatocarcinoma. Thioacetamide (TAA) is a well-known hepatotoxicant and could be a liver carcinogen in humans. The discovery of early and sensitive microRNA (miRNA) biomarkers in liver injury and tumor progression could improve cancer diagnosis, prognosis, and management. To study this, we performed next generation sequencing of the livers of Sprague-Dawley rats treated with TAA at three doses (4.5, 15 and 45 mg/kg) and four time points (3-, 7-, 14- and 28-days). Overall, 330 unique differentially expressed miRNAs (DEMs) were identified in the entire TAA-treatment course. Of these, 129 DEMs were found significantly enriched for the "liver cancer" annotation. These results were further complemented by pathway analysis (Molecular Mechanisms of Cancer, p53-, TGF-beta-, MAPK- and Wnt signaling). Two miRNAs (rno-miR-34a-5p and rno-miR-455-3p) out of 48 overlapping DEMs were identified to be early and sensitive biomarkers for TAA-induced hepatocarcinogenicity. We have shown significant regulatory associations between DEMs and TAA-induced liver carcinogenesis at an earlier stage than histopathological features. Most importantly, miR-34a-5p is the most suitable early and sensitive biomarker for TAA-induced hepatocarcinogenesis due to its consistent elevation during the entire treatment course. PMID- 28596527 TI - Identification of commonly altered genes between in major depressive disorder and a mouse model of depression. AB - The heterogeneity of depression (due to factors such as varying age of onset) may explain why biological markers of major depressive disorder (MDD) remain uncertain. We aimed to identify gene expression markers of MDD in leukocytes using microarray analysis. We analyzed gene expression profiles of patients with MDD (age >=50, age of depression onset <50) (N = 10, depressed state; N = 13, remitted state). Seven-hundred and ninety-seven genes (558 upregulated, 239 downregulated when compared to those of 30 healthy subjects) were identified as potential markers for MDD. These genes were then cross-matched to microarray data obtained from a mouse model of depression (676 genes, 148 upregulated, 528 downregulated). Of the six common genes identified between patients and mice, five genes (SLC35A3, HIST1H2AL, YEATS4, ERLIN2, and PLPP5) were confirmed to be downregulated in patients with MDD by quantitative real-time polymerase chain reaction. Of these genes, HIST1H2AL was significantly decreased in a second set of independent subjects (age >=20, age of onset <50) (N = 18, subjects with MDD in a depressed state; N = 19, healthy control participants). Taken together, our findings suggest that HIST1H2AL may be a biological marker of MDD. PMID- 28596529 TI - Physical mechanism for biopolymers to aggregate and maintain in non-equilibrium states. AB - Many human or animal diseases are related to aggregation of proteins. A viable biological organism should maintain in non-equilibrium states. How protein aggregate and why biological organisms can maintain in non-equilibrium states are not well understood. As a first step to understand such complex systems problems, we consider simple model systems containing polymer chains and solvent particles. The strength of the spring to connect two neighboring monomers in a polymer chain is controlled by a parameter s with s -> infinity for rigid-bond. The strengths of bending and torsion angle dependent interactions are controlled by a parameter s A with s A -> -infinity corresponding to no bending and torsion angle dependent interactions. We find that for very small s A , polymer chains tend to aggregate spontaneously and the trend is independent of the strength of spring. For strong springs, the speed distribution of monomers in the parallel (along the direction of the spring to connect two neighboring monomers) and perpendicular directions have different effective temperatures and such systems are in non equilibrium states. PMID- 28596528 TI - Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter. AB - Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model. PMID- 28596530 TI - Axin2-expressing cells differentiate into reparative odontoblasts via autocrine Wnt/beta-catenin signaling in response to tooth damage. AB - In non-growing teeth, such as mouse and human molars, primary odontoblasts are long-lived post-mitotic cells that secrete dentine throughout the life of the tooth. New odontoblast-like cells are only produced in response to a damage or trauma. Little is known about the molecular events that initiate mesenchymal stem cells to proliferate and differentiate into odontoblast-like cells in response to dentine damage. The reparative and regenerative capacity of multiple mammalian tissues depends on the activation of Wnt/beta-catenin signaling pathway. In this study, we investigated the molecular role of Wnt/beta-catenin signaling pathway in reparative dentinogenesis using an in vivo mouse tooth damage model. We found that Axin2 is rapidly upregulated in response to tooth damage and that these Axin2-expressing cells differentiate into new odontoblast-like cells that secrete reparative dentine. In addition, the Axin2-expressing cells produce a source of Wnt that acts in an autocrine manner to modulate reparative dentinogenesis. PMID- 28596531 TI - RF1 attenuation enables efficient non-natural amino acid incorporation for production of homogeneous antibody drug conjugates. AB - Amber codon suppression for the insertion of non-natural amino acids (nnAAs) is limited by competition with release factor 1 (RF1). Here we describe the genome engineering of a RF1 mutant strain that enhances suppression efficiency during cell-free protein synthesis, without significantly impacting cell growth during biomass production. Specifically, an out membrane protease (OmpT) cleavage site was engineered into the switch loop of RF1, which enables its conditional inactivation during cell lysis. This facilitates extract production without additional processing steps, resulting in a scaleable extract production process. The RF1 mutant extract allows nnAA incorporation at previously intractable sites of an IgG1 and at multiple sites in the same polypeptide chain. Conjugation of cytotoxic agents to these nnAAs, yields homogeneous antibody drug conjugates (ADCs) that can be optimized for conjugation site, drug to antibody ratio (DAR) and linker-warheads designed for efficient tumor killing. This platform provides the means to generate therapeutic ADCs inaccessible by other methods that are efficient in their cytotoxin delivery to tumor with reduced dose-limiting toxicities and thus have the potential for better clinical impact. PMID- 28596532 TI - High-Throughput Analysis of in-vitro LFP Electrophysiological Signals: A validated workflow/software package. AB - Synchronized brain activity in the form of alternating epochs of massive persistent network activity and periods of generalized neural silence, has been extensively studied as a fundamental form of circuit dynamics, important for many cognitive functions including short-term memory, memory consolidation, or attentional modulation. A key element in such studies is the accurate determination of the timing and duration of those network events. The local field potential (LFP) is a particularly attractive method for recording network activity, because it allows for long and stable recordings from multiple sites, allowing researchers to estimate the functional connectivity of local networks. Here, we present a computational method for the automatic detection and quantification of in-vitro LFP events, aiming to overcome the limitations of current approaches (e.g. slow analysis speed, arbitrary threshold-based detection and lack of reproducibility across and within experiments). The developed method is based on the implementation of established signal processing and machine learning approaches, is fully automated and depends solely on the data. In addition, it is fast, highly efficient and reproducible. The performance of the software is compared against semi-manual analysis and validated by verification of prior biological knowledge. PMID- 28596534 TI - Circulating 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) levels are associated with hyperglycemia and beta cell dysfunction in a Chinese population. AB - Several recent clinical studies have suggested that the levels of circulating 3 carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) are significantly higher in patients with gestational diabetes mellitus (GDM), impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM). This study recruited a total of 516 participants. The following patient populations were enrolled: 99 newly diagnosed cases with T2DM, 219 cases with prediabetes [82 with isolated impaired glucose tolerance (I - IGT), 66 with isolated impaired fasting glucose (I - IFG) and 71 with impaired glucose tolerance and impaired fasting glucose (IGT + IFG)], and 198 cases with normal glucose tolerance [NGT, including 99 first-degree relatives of type 2 diabetes patients (FDRs) and 99 non-FDRs]. We investigated the circulating CMPF levels in subjects with different glucose metabolism statuses and examined the potential link between CMPF and beta cell function. Our results indicate that the serum CMPF levels were elevated in the prediabetes, T2DM, and FDRs groups compared to the NGT group. Additionally, the serum CMPF concentrations were independently and negatively associated with the triglyceride levels and Stumvoll first-phase insulin secretion index. Cumulatively, our findings suggest that the circulating CMPF levels can predict glycolipid metabolism disorders. Furthermore, elevated serum CMPF concentrations may determine hyperglycemia and beta cell dysfunction. PMID- 28596535 TI - Identification and characterization of roles for Puf1 and Puf2 proteins in the yeast response to high calcium. AB - Members of the yeast family of PUF proteins bind unique subsets of mRNA targets that encode proteins with common functions. They therefore became a paradigm for post-transcriptional gene control. To provide new insights into the roles of the seemingly redundant Puf1 and Puf2 members, we monitored the growth rates of their deletions under many different stress conditions. A differential effect was observed at high CaCl2 concentrations, whereby puf1Delta growth was affected much more than puf2Delta, and inhibition was exacerbated in puf1Deltapuf2Delta double knockout. Transcriptome analyses upon CaCl2 application for short and long terms defined the transcriptional response to CaCl2 and revealed distinct expression changes for the deletions. Intriguingly, mRNAs known to be bound by Puf1 or Puf2 were affected mainly in the double knockout. We focused on the cell wall regulator Zeo1 and observed that puf1Deltapuf2Delta fails to maintain low levels of its mRNA. Complementarily, puf1Deltapuf2Delta growth defect in CaCl2 was repaired upon further deletion of the Zeo1 gene. Thus, these proteins probably regulate the cell-wall integrity pathway by regulating Zeo1 post transcriptionally. This work sheds new light on the roles of Puf proteins during the cellular response to environmental stress. PMID- 28596536 TI - Enhanced Thermal Conductivity and Dielectric Properties of Iron Oxide/Polyethylene Nanocomposites Induced by a Magnetic Field. AB - Iron Oxide (Fe3O4) nanoparticles were deposited on the surface of low density polyethylene (LDPE) particles by solvothermal method. A magnetic field was introduced to the preparation of Fe3O4/LDPE composites, and the influences of the magnetic field on thermal conductivity and dielectric properties of composites were investigated systematically. The Fe3O4/LDPE composites treated by a vertical direction magnetic field exhibited a high thermal conductivity and a large dielectric constant at low filler loading. The enhancement of thermal conductivity and dielectric constant is attributed to the formation of the conductive chains of Fe3O4 in LDPE matrix under the action of the magnetic field, which can effectively enhance the heat flux and interfacial polarization of the Fe3O4/LDPE composites. Moreover, the relatively low dielectric loss and low conductivity achieved are attributed to the low volume fraction of fillers and excellent compatibility between Fe3O4 and LDPE. Of particular note is the dielectric properties of Fe3O4/LDPE composites induced by the magnetic field also retain good stability across a wide temperature range, and this contributes to the stability and lifespan of polymer capacitors. All the above-mentioned properties along with the simplicity and scalability of the preparation for the polymer nanocomposites make them promising for the electronics industry. PMID- 28596537 TI - Transcriptome sequencing of Tessaratoma papillosa antennae to identify and analyze expression patterns of putative olfaction genes. AB - Studies on insect olfaction have increased our understanding of insect's chemosensory system and chemical ecology, and have improved pest control strategies based on insect behavior. In this study, we assembled the antennal transcriptomes of the lychee giant stink bug, Tessaratoma papillosa, by using next generation sequencing to identify the major olfaction gene families in this species. In total, 59 odorant receptors, 14 ionotropic receptors (8 antennal IRs), and 33 odorant binding proteins (28 classic OBPs and 5 plus-C OBPs) were identified from the male and female antennal transcriptomes. Analyses of tissue expression profiles revealed that all 59 OR transcripts, 2 of the 8 antennal IRs, and 6 of the 33 OBPs were primarily expressed in the antennae, suggesting their putative role in olfaction. The sex-biased expression patterns of these antenna predominant genes suggested that they may have important functions in the reproductive behavior of these insects. This is the first report that provides a comprehensive resource to future studies on olfaction in the lychee giant stink bug. PMID- 28596538 TI - Stable synthesis of few-layered boron nitride nanotubes by anodic arc discharge. AB - Boron nitride nanotubes (BNNTs) were successfully synthesized by a dc arc discharge using a boron-rich anode as synthesis feedstock in a nitrogen gas environment at near atmospheric pressure. The synthesis was achieved independent of the cathode material suggesting that under such conditions the arc operates in so-called anodic mode with the anode material being consumed by evaporation due to the arc heating. To sustain the arc current by thermionic electron emission, the cathode has to be at sufficiently high temperature, which for a typical arc current density of ~100 A/cm2, is above the boron melting point (2350 K). With both electrodes made from the same boron-rich alloy, we found that the arc operation unstable due to frequent sticking between two molten electrodes and formation of molten droplets. Stable and reliable arc operation and arc synthesis were achieved with the boron-rich anode and the cathode made from a refractory metal which has a melting temperature above the melting point of boron. Ex-situ characterization of synthesized BNNTs with electron microscopy and Raman spectroscopy revealed that independent of the cathode material, the tubes are primarily single and double walled. The results also show evidence of root-growth of BNNTs produced in the arc discharge. PMID- 28596533 TI - Breaking barriers to novel analgesic drug development. AB - Acute and chronic pain complaints, although common, are generally poorly served by existing therapies. This unmet clinical need reflects a failure to develop novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms, and the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities for developing novel therapeutic strategies and revisiting existing targets, including modulating ion channels, enzymes and G-protein-coupled receptors. PMID- 28596539 TI - Zebrafish as an animal model in epilepsy studies with multichannel EEG recordings. AB - Despite recent interest in using zebrafish in human disease studies, sparked by their economics, fecundity, easy handling, and homologies to humans, the electrophysiological tools or methods for zebrafish are still inaccessible. Although zebrafish exhibit more significant larval-adult duality than any other animal, most electrophysiological studies using zebrafish are biased by using larvae these days. The results of larval studies not only differ from those conducted with adults but also are unable to delicately manage electroencephalographic montages due to their small size. Hence, we enabled non invasive long-term multichannel electroencephalographic recording on adult zebrafish using custom-designed electrodes and perfusion system. First, we exploited demonstration of long-term recording on pentylenetetrazole-induced seizure models, and the results were quantified. Second, we studied skin electrode impedance, which is crucial to the quality of signals. Then, seizure propagations and gender differences in adult zebrafish were exhibited for the first time. Our results provide a new pathway for future neuroscience research using zebrafish by overcoming the challenges for aquatic organisms such as precision, serviceability, and continuous water seepage. PMID- 28596540 TI - Preparation and in vivo characterization of 51MnCl2 as PET tracer of Ca2+ channel mediated transport. AB - Manganese has long been employed as a T1-shortening agent in magnetic resonance imaging (MRI) applications, but these techniques are limited by the biotoxicity of bulk-manganese. Positron emission tomography (PET) offers superior contrast sensitivity compared with MRI, and recent preclinical PET studies employing 52gMn (t1/2: 5.6 d, beta+: 29%) show promise for a variety of applications including cell tracking, neural tract tracing, immunoPET, and functional beta-cell mass quantification. The half-life and confounding gamma emissions of 52gMn are prohibitive to clinical translation, but the short-lived 51Mn (t1/2: 46 min, beta+: 97%) represents a viable alternative. This work develops methods to produce 51Mn on low-energy medical cyclotrons, characterizes the in vivo behavior of 51MnCl2 in mice, and performs preliminary human dosimetry predictions. 51Mn was produced by proton irradiation of electrodeposited isotopically-enriched 54Fe targets. Radiochemically isolated 51MnCl2 was intravenously administered to ICR mice which were scanned by dynamic and static PET, followed by ex vivo gamma counting. Rapid blood clearance was observed with stable uptake in the pancreas, kidneys, liver, heart, and salivary gland. Dosimetry calculations predict that 370 MBq of 51Mn in an adult human male would yield an effective dose equivalent of approximately 13.5 mSv, roughly equivalent to a clinical [18F]-FDG procedure. PMID- 28596542 TI - Leukocyte Bim deficiency does not impact atherogenesis in ldlr -/- mice, despite a pronounced induction of autoimmune inflammation. AB - Proapoptotic Bcl-2 family member Bim is particularly relevant for deletion of autoreactive and activated T and B cells, implicating Bim in autoimmunity. As atherosclerosis is a chronic inflammatory process with features of autoimmune disease, we investigated the impact of hematopoietic Bim deficiency on plaque formation and parameters of plaque stability. Bim -/- or wild type bone marrow transplanted ldlr -/- mice were fed a Western type diet (WTD) for 5 or 10 weeks, after which they were immunophenotyped and atherosclerotic lesions were analyzed. Bim -/- transplanted mice displayed splenomegaly and overt lymphocytosis. CD4+ and CD8+ T cells were more activated (increased CD69 and CD71 expression, increased interferon gamma production). B cells were elevated by 147%, with a shift towards the pro-atherogenic IgG-producing B2 cell phenotype, resulting in a doubling of anti-oxLDL IgG1 antibody titers in serum of bim -/- mice. Bim -/- mice displayed massive intraplaque accumulation of Ig complexes and of lesional T cells, although this did not translate in changes in plaque size or stability features (apoptotic cell and macrophage content). The surprising lack in plaque phenotype despite the profound pro-atherogenic immune effects may be attributable to the sharp reduction of serum cholesterol levels in WTD fed bim -/- mice. PMID- 28596543 TI - The electromigration effect revisited: non-uniform local tensile stress-driven diffusion. AB - The electromigration (EM) effect involves atomic diffusion of metals under current stressing. Recent theories of EM are based on the unbalanced electrostatic and electron-wind forces exerted on metal ions. However, none of these models have coupled the EM effect and lattice stability. Here, we performed in situ current-stressing experiments for pure Cu strips using synchrotron X-ray diffractometry and scanning electron microscopy and ab initio calculations based on density functional theory. An intrinsic and non-uniform lattice expansion - larger at the cathode and smaller at the anode, is identified induced by the flow of electrons. If this electron flow-induced strain is small, it causes an elastic deformation; while if it is larger than the yield point, diffusion as local stress relaxation will cause the formation of hillocks and voids as well as EM induced failure. The fundamental driving force for the electromigration effect is elucidated and validated with experiments. PMID- 28596541 TI - Association of maternal and fetal LEPR common variants with maternal glycemic traits during pregnancy. AB - Recent studies suggested that maternal and placental leptin receptor (LEPR) may be involved in maternal glucose metabolism in pregnancy. To identify maternal and fetal LEPR common variants influencing gestational glycemic traits, we performed association study of 24-28-week maternal fasting glucose, glucose 1 hour after the consumption of a 50-g oral glucose load, fasting insulin and indices of beta cell function (HOMA-beta) and insulin resistance (HOMA-IR) in 1,112 unrelated women and their children. Follow-up of 36 LEPR loci identified 3 maternal loci (rs10889567, rs1137101 and rs3762274) associated with fasting glucose, these 3 fetal loci associated with fasting insulin and HOMA1-IR, as well as these 3 maternal-fetal loci combinations associated with HOMA2-beta. We also demonstrated association of maternal locus rs7554485 with HOMA2-beta and HOMA2-IR, maternal locus rs10749754 with fasting glucose, fetal locus rs10749754 with HOMA2-IR. However, these associations were no longer statistically significant after Bonferroni correction. In conclusion, our results first revealed multiple associations between maternal and fetal LEPR common variants and gestational glycemic traits. These associations did not survive Bonferroni correction. These corrections are overly conservative for association studies. We therefore believe the influence of these nominally significant variants on gestational glycometabolism will be confirmed by additional studies. PMID- 28596544 TI - Robust tribo-mechanical and hot corrosion resistance of ultra-refractory Ta-Hf-C ternary alloy films. AB - In this work we report the hot corrosion properties of binary and ternary films of the Ta-Hf-C system in V2O5-Na2SO4 (50%wt.-50%wt.) molten salts at 700 degrees C deposited on AISI D3 steel substrates. Additionally, the mechanical and nanowear properties of the films were studied. The results show that the ternary alloys consist of solid solutions of the TaC and HfC binary carbides. The ternary alloy films have higher hardness and elastic recoveries, reaching 26.2 GPa and 87%, respectively, and lower nanowear when compared to the binary films. The corrosion rates of the ternary alloys have a superior behavior compared to the binary films, with corrosion rates as low as 0.058 MUm/year. The combination and tunability of high hardness, elastic recovery, low nanowear and an excellent resistance to high temperature corrosion demonstrates the potential of the ternary Ta-Hf-C alloy films for applications in extreme conditions. PMID- 28596545 TI - Rapid on-site monitoring of Legionella pneumophila in cooling tower water using a portable microfluidic system. AB - Legionnaires' disease, predominantly caused by the bacterium Legionella pneumophila, has increased in prevalence worldwide. The most common mode of transmission of Legionella is inhalation of contaminated aerosols, such as those generated by cooling towers. Simple, rapid and accurate methods to enumerate L. pneumophila are required to prevent the spread of this organism. Here, we applied a microfluidic device for on-chip fluorescent staining and semi-automated counting of L. pneumophila in cooling tower water. We also constructed a portable system for rapid on-site monitoring and used it to enumerate target bacterial cells rapidly flowing in the microchannel. A fluorescently-labelled polyclonal antibody was used for the selective detection of L. pneumophila serogroup 1 in the samples. The counts of L. pneumophila in cooling tower water obtained using the system and fluorescence microscopy were similar. The detection limit of the system was 104 cells/ml, but lower numbers of L. pneumophila cells (101 to 103 cells/ml) could be detected following concentration of 0.5-3 L of the water sample by filtration. Our technique is rapid to perform (1.5 h), semi-automated (on-chip staining and counting), and portable for on-site measurement, and it may therefore be effective in the initial screening of Legionella contamination in freshwater. PMID- 28596546 TI - Electro-Forming and Electro-Breaking of Nanoscale Ag Filaments for Conductive Bridging Random-Access Memory Cell using Ag-Doped Polymer-Electrolyte between Pt Electrodes. AB - Ag-doped polymer (polyethylene oxide: PEO) conductive-bridging-random-access memory (CBRAM) cell using inert Pt electrodes is a potential electro-forming free CBRAM cells in which electro-forming and electro-breaking of nanoscale (16~22-nm in diameter) conical or cylindrical Ag filaments occurs after a set or reset bias is applied. The dependency of the morphologies of the Ag filaments in the PEO polymer electrolyte indicates that the electro-formed Ag filaments bridging the Pt cathode and anode are generated by Ag+ ions drifting in the PEO polymer electrolyte toward the Pt anode and that Ag dendrites grow via a reduction process from the Pt anode, whereas electro-breaking of Ag filaments occurs through the oxidation of Ag atoms in the secondary dendrites and the drift of Ag+ ions toward the Pt cathode. The Ag doping concentration in the PEO polymer electrolyte determines the bipolar switching characteristics; i.e., the set voltage slightly decreases, while the reset voltage and memory margin greatly increases with the Ag doping concentration. PMID- 28596547 TI - Echo-Planar J-resolved Spectroscopic Imaging using Dual Read-outs: Implementation and Quantitation of Human Brain Metabolites. AB - Attempts have been made to reduce the total scan time in multi-dimensional J resolved spectroscopic imaging (JRESI) using an echo-planar (EP) readout gradient, but acquisition duration remains a limitation for routine clinical use in the brain. We present here a significant acceleration achieved with a 4D EP JRESI sequence that collects dual phase encoded lines within a single repetition time (TR) using two bipolar read-out trains. The performance and reliability of this novel 4D sequence, called Multi-Echo based Echo-Planar J-resolved Spectroscopic Imaging (ME-EP-JRESI), was evaluated in 10 healthy controls and a brain phantom using a 3 T MRI/MRS scanner. The prior knowledge fitting (ProFit) algorithm, with a new simulated basis set consisting of macromolecules and lipids apart from metabolites of interest, was used for quantitation. Both phantom and in-vivo data demonstrated that localization and spatial/spectral profiles of metabolites from the ME-EP-JRESI sequence were in good agreement with that of the EP-JRESI sequence. Both in the occipital and temporal lobe, metabolites with higher physiological concentrations including Glx (Glu+Gln), tNAA (NAA+NAAG), mI all had coefficient of variations between 9-25%. In summary, we have implemented, validated and tested the ME-EP-JRESI sequence, demonstrating that multi-echo acquisition can successfully reduce the total scan duration for EP-JRESI sequences. PMID- 28596548 TI - Sortase A-mediated crosslinked short-chain dehydrogenases/reductases as novel biocatalysts with improved thermostability and catalytic efficiency. AB - (S)-carbonyl reductase II (SCRII) from Candida parapsilosis is a short-chain alcohol dehydrogenase/reductase. It catalyses the conversion of 2 hydroxyacetophenone to (S)-1-phenyl-1,2-ethanediol with low efficiency. Sortase was reported as a molecular "stapler" for site-specific protein conjugation to strengthen or add protein functionality. Here, we describe Staphylococcus aureus sortase A-mediated crosslinking of SCRII to produce stable catalysts for efficient biotransformation. Via a native N-terminal glycine and an added GGGGSLPETGG peptide at C-terminus of SCRII, SCRII subunits were conjugated by sortase A to form crosslinked SCRII, mainly dimers and trimers. The crosslinked SCRII showed over 6-fold and 4-fold increases, respectively, in activity and k cat/K m values toward 2-hydroxyacetophenone compared with wild-type SCRII. Moreover, crosslinked SCRII was much more thermostable with its denaturation temperature (Tm) increased to 60 degrees C. Biotransformation result showed that crosslinked SCRII gave a product optical purity of 100% and a yield of >99.9% within 3 h, a 16-fold decrease in transformation duration with respect to Escherichia coli/pET-SCRII. Sortase A-catalysed ligation also obviously improved Tms and product yields of eight other short-chain alcohol dehydrogenases/reductases. This work demonstrates a generic technology to improve enzyme function and thermostability through sortase A-mediated crosslinking of oxidoreductases. PMID- 28596549 TI - Synthesis of porous polymer/tissue paper hybrid membranes for switchable oil/water separation. AB - The unusually broad physical and chemical property window of ionic liquids allows for a wide range of applications, which gives rise to the recent spring-up of ionic liquid-based functional materials. Via solvothermal copolymerization of a monomeric ionic liquid and divinylbenzene in the presence of a tissue paper in autoclave, we fabricated a flexible porous polymer/paper hybrid membrane. The surface areas of the hybrid membranes depend on the weight fraction of the copolymer impregnated inside the tissue paper. The as-prepared hybrid membrane shows controlled surface wettability in terms of ethanol wetting and ethanol removal by harsh drying condition. This unique property provides the hybrid membrane with switchable oil/water separation function, thus of practical values for real life application. PMID- 28596550 TI - Booster immunizations with DNA plasmids encoding HER-2/neu prevent spontaneous mammary cancer in HER-2/neu transgenic mice over life span. AB - Cancer vaccines are less effective at old than at young age because of immunosenescence. Besides, in preliminary observations we showed that the immunization with HER-2/neu DNA plasmid in transgenic young mice (standard immunization, SI) delays but not abrogate spontaneous mammary tumours progressively appearing during aging. In this study we evaluated whether booster immunizations (BI) of HER-2/neu transgenic mice with HER-2/neu DNA plasmids every 6 (ECD6), 3 (ECD3), or 1.5 (ECD1.5) months after SI induce a protective immunity that could be maintained over life span. The long term BI significantly improved the effect of SI increasing the number of tumour free mice at 110 weeks of age from 13% (SI) to 58% (BI). Both the number and the volume of tumour masses were reduced in BI than in SI groups. The protective effect of BI was associated with increased antibody production with isotype switching to IgG2a, augmented CD4 T cells, and increased in vivo cytotoxicity of HER-2/neu specific cytotoxic T lymphocytes, mainly in ECD1.5 and ECD3 groups. The transfer of sera from ECD1.5 mice to untreated HER-2/neu mice highly protected against tumour development than sera from SI mice. We conclude that BI induce a protective immunity effective over life span. PMID- 28596551 TI - Automated segmentation of human cervical-supraclavicular adipose tissue in magnetic resonance images. AB - Human brown adipose tissue (BAT), with a major site in the cervical supraclavicular depot, is a promising anti-obesity target. This work presents an automated method for segmenting cervical-supraclavicular adipose tissue for enabling time-efficient and objective measurements in large cohort research studies of BAT. Fat fraction (FF) and R2* maps were reconstructed from water-fat magnetic resonance imaging (MRI) of 25 subjects. A multi-atlas approach, based on atlases from nine subjects, was chosen as automated segmentation strategy. A semi automated reference method was used to validate the automated method in the remaining subjects. Automated segmentations were obtained from a pipeline of preprocessing, affine registration, elastic registration and postprocessing. The automated method was validated with respect to segmentation overlap (Dice similarity coefficient, Dice) and estimations of FF, R2* and segmented volume. Bias in measurement results was also evaluated. Segmentation overlaps of Dice = 0.93 +/- 0.03 (mean +/- standard deviation) and correlation coefficients of r > 0.99 (P < 0.0001) in FF, R2* and volume estimates, between the methods, were observed. Dice and BMI were positively correlated (r = 0.54, P = 0.03) but no other significant bias was obtained (P >= 0.07). The automated method compared well with the reference method and can therefore be suitable for time-efficient and objective measurements in large cohort research studies of BAT. PMID- 28596553 TI - Hematopoietic Id Deletion Triggers Endomyocardial Fibrotic and Vascular Defects in the Adult Heart. AB - Inhibitor of DNA binding (Id) proteins play important roles in regulating cardiac development via paracrine signaling. Id1/Id3 knockout mice die at mid-gestation with multiple cardiac defects. Single Id knockout studies have not reported cardiomyopathies. To bypass embryonic lethality we used Tie2CRE-mediated recombination to conditionally delete Id1 against global Id3 ablation (Id cDKOs), which develops adult-onset dilated cardiomyopathy. We confirm upregulation of thrombospondin-1 (TSP1) in Id cDKO hearts. Colocalization studies reveal increased TSP1 expression in the vicinity of endothelial cells and near regions of endocardial fibrosis/disruption. Downstream fibrotic molecules were upregulated. Endocardial capillary density was reduced with evidence of vascular distention. Treatment of Id cDKO cardiac explants with LSKL, a peptide antagonist of TSP1 activation of TGFbeta, reversed the increased expression of fibrotic molecules. We conducted bone marrow transplant experiments in which we transferred bone marrow cells from Id cDKO mice into lethally irradiated WT mice. The majority of WT recipients of Id cDKO bone marrow cells phenocopied Id cDKO cardiac fibrosis 4 months post-transplantation. Injection of LSKL into adult Id cDKO mice led to downregulation of fibrotic molecules. The results prompt caution when bone marrow transfers from individuals potentially carrying mutations in the Id axis are applied in clinical settings. PMID- 28596552 TI - Genome-wide survey of switchgrass NACs family provides new insights into motif and structure arrangements and reveals stress-related and tissue-specific NACs. AB - NAC proteins comprise of a plant-specific transcription factor (TF) family and play important roles in plant development and stress responses. Switchgrass (Panicum virgatum) is the prime candidate and model bioenergy grass across the world. Excavating agronomically valuable genes is important for switchgrass molecular breeding. In this study, a total of 251 switchgrass NAC (PvNACs) family genes clustered into 19 subgroups were analyzed, and those potentially involved in stress response or tissue-specific expression patterns were pinpointed. Specifically, 27 PvNACs were considered as abiotic stress-related including four membrane-associated ones. Among 40 tissue-specific PvNACs expression patterns eight factors were identified that might be relevant for lignin biosynthesis and/or secondary cell wall formation. Conserved functional domains and motifs were also identified among the PvNACs and potential association between these motifs and their predicted functions were proposed, that might encourage experimental studies to use PvNACs as possible targets to improve biomass production and abiotic stress tolerance. PMID- 28596554 TI - Salt intake, blood pressure, and socioeconomic disparities among government employees in Sri Lanka: a cross-sectional study. AB - Our study estimated salt intake, examined the association between blood pressure (BP) and salt intake, and explored the socioeconomic variations in salt intake among administrators (government employees). This is a cross-sectional study. We studied 168 randomly selected administrators aged 30-60 years attached to government offices in Colombo, Sri Lanka. Self-administered questionnaire gathered information on socio-demographic, work-related information, lifestyle practices, and medical history. BP, 24-hour urine collection, and anthropometric indices were measured. Mean salt intake levels measured by 24-hour Sodium (Na) excretion in hypertensives and non-hypertensives were 202.56 (SD +/- 85.45) mmol/day and 176.79 (SD +/- 82.02) mmol/day, respectively. A 100-mmol increase in sodium was associated with an average increase of 3.1 (95 per cent CI 2-4.2) mmHg in systolic BP and 1.8 (95 per cent CI 0.89-2.6) mmHg in diastolic BP. Higher salt intake was found in managerial assistants (12.38 +/- 5.0 g) compared with senior officers (10.84 +/- 4.9 g). Salt intake among these administrators was alarmingly high. High salt intake was positively associated with hypertension and more prevalent in lower socioeconomic strata. PMID- 28596555 TI - Controlled functional expression of the bacteriocins pediocin PA-1 and bactofencin A in Escherichia coli. AB - The bacteriocins bactofencin A (class IId) and pediocin PA-1 (class IIa) are encoded by operons with a similarly clustered gene organization including a structural peptide, an immunity protein, an ABC transporter and accessory bacteriocin transporter protein. Cloning of these operons in E. coli TunerTM (DE3) on a pETcoco-2 derived vector resulted in successful secretion of both bacteriocins. A corresponding approach, involving the construction of vectors containing different combinations of these genes, revealed that the structural and the transporter genes alone are sufficient to permit heterologous production and secretion in this host. Even though the accessory protein, usually associated with optimal disulfide bond formation, was not required for bacteriocin synthesis, its presence did result in greater pediocin PA-1 production. The simplicity of the system and the fact that the associated bacteriocins could be recovered from the extracellular medium provides an opportunity to facilitate protein engineering and the overproduction of biologically-active bacteriocins at industrial scale. Additionally, this system could enable the characterization of new bacteriocin operons where genetic tools are not available for the native producers. PMID- 28596556 TI - Indoxyl sulfate (IS)-mediated immune dysfunction provokes endothelial damage in patients with end-stage renal disease (ESRD). AB - Progressive renal failure causes uremia-related immune dysfunction, which features a chronic inflammatory milieu. Given the central role of end-stage renal disease (ESRD)-related immune dysfunction in the pathogenesis of cardiovascular diseases (CVDs), much attention has been focused on how uremic toxins affect cellular immunity and the mechanisms underlying pathogenesis of atherosclerosis in ESRD patients. Here, we investigated the characteristics of monocytes and CD4+ T cells in ESRD patients and the immune responses induced by indoxyl sulfate (IS), a key uremic toxin, in order to explore the pathogenic effects of these cells on vascular endothelial cells. In ESRD patients, monocytes respond to IS through the aryl hydrocarbon receptor (AhR) and consequently produce increased levels of TNF-alpha. Upon stimulation with TNF-alpha, human vascular endothelial cells produce copious amounts of CX3CL1, a chemokine ligand of CX3CR1 that is highly expressed on CD4+CD28-T cells, the predominantly expanded cell type in ESRD patients. A migration assay showed that CD4+CD28- T cells were preferentially recruited by CX3CL1. Moreover, activated CD4+CD28- T cells exhibited cytotoxic capability allowing for the induction of apoptosis in HUVECs. Our findings suggest that in ESRD, IS-mediated immune dysfunction may cause vascular endothelial cell damage and thus, this toxin plays a pivotal role in the pathogenesis of CVD. PMID- 28596557 TI - Burkholderia pseudomallei in a lowland rice paddy: seasonal changes and influence of soil depth and physico-chemical properties. AB - Melioidosis, a severe infection with the environmental bacterium Burkholderia pseudomallei, is being recognised increasingly frequently. What determines its uneven distribution within endemic areas is poorly understood. We cultured soil from a rice field in Laos for B. pseudomallei at different depths on 4 occasions over a 13-month period. We also measured physical and chemical parameters in order to identify associated characteristics. Overall, 195 of 653 samples (29.7%) yielded B. pseudomallei. A higher prevalence of B. pseudomallei was found at soil depths greater than the 30 cm currently recommended for B. pseudomallei environmental sampling. B. pseudomallei was associated with a high soil water content and low total nitrogen, carbon and organic matter content. Our results suggested that a sampling grid of 25 five metre square quadrats (i.e. 25 * 25 m) should be sufficient to detect B. pseudomallei at a given location if samples are taken at a soil depth of at least 60 cm. However, culture of B. pseudomallei in environmental samples is difficult and liable to variation. Future studies should both rely on molecular approaches and address the micro-heterogeneity of soil when investigating physico-chemical associations with the presence of B. pseudomallei. PMID- 28596560 TI - Decision and coordination of low-carbon supply chain considering technological spillover and environmental awareness. AB - We focus on the impacts of technological spillovers and environmental awareness in a two-echelon supply chain with one-single supplier and one-single manufacturer to reduce carbon emission. In this supply chain, carbon abatement investment becomes one of key factors of cutting costs and improving profits, which is reducing production costs in the components and products-the investment from players in supply chain. On the basis of optimality theory, the centralized and decentralized models are respectively established to investigate the optimal decisions and profits. Further, setting the players' profits of the decentralized scenario as the disagreement points, we propose a bargaining-coordination contract through revenue-cost sharing to enhance the performance. Finally, by theoretical comparison and numerical analysis, the results show that: (i) The optimal profits of players and supply chain improve as technological spillovers and environmental awareness increase, and the profits of them in the bargaining coordination contract are higher than that in the decentralized scenario; (ii) Technological spillovers between the players amplify the impact of "free-ride" behavior, in which the supplier always incentives the manufacturer to improve carbon emission intensity, but the cooperation will achieves and the profits will improve only when technological spillovers and environmental awareness are great; (iii) The contract can effectively achieve coordinated supply chain, and improve carbon abatement investment. PMID- 28596559 TI - Facile Synthesis ZnS/ZnO/Ni(OH)2 Composites Grown on Ni Foam: A Bifunctional Materials for Photocatalysts and Supercapacitors. AB - A facile one-step hydrothermal reaction was employed to synthesis an integrated bifunctional composite composed by a network structure of ZnS/ZnO/Ni(OH)2 nanosheets with ZnS/ZnO nanospheres in situ growing on Ni foam. The synergistic effect of these three substances make the composite having both improved electrochemical performances and photocatalytic activity. The ZnS/ZnO/Ni(OH)2 4mmol shows a high specific capacitance of 1173.8 F g-1 at 1 A g-1, as well as good rate capability and relatively stable cyclability. Using as photocatalyst, the methyl orange dye in solution can be completely decomposed under ultraviolet visible radiation in about 80 min. And the composite is easy to be repeatedly used because bulk Ni foam was used as a carrier. Such a bifunctional composite material provides a new insight for energy storage and utilization as well as the water pollution treatment. PMID- 28596558 TI - Association of increased Treg and Th17 with pathogenesis of moyamoya disease. AB - Immuno-inflammation has been shown to play a pivotal role in the pathogenesis of moyamoya disease (MMD). However, how did circulating Treg/Th17 cells involve in MMD patients remains unclear. 26 MMD, 21 atherothrombotic stroke, and 32 healthy controls were enrolled in this study. MMD patients have a significantly higher percentage of circulating Treg and Th17 cells as well as their dominantly secreting cytokines than other groups (P < 0.0001), whereas no difference was found in the ratio of Treg/Th17 between patients in MMD and atherothrombotic stroke group or control subjects (P = 0.244). However, the increased Treg in MMD patients which were enriched with FrIII Treg cells had deficient suppressive functions (P = 0.0017) compared to healthy volunteers. There was a positive correlation between Treg or TGF-beta and MMD Suzuki's stage. And the level of circulating Treg was as an independent factor associated with MMD stage. Besides, TGF-beta was also correlated with the increased expression of VEGF in MMD patients. Our findings indicated an important involvement of circulating Treg in the pathogenic development of MMD and TGF-beta in Treg induced VEGF. PMID- 28596561 TI - A Risk Model based on Ultrasound, Ultrasound Elastography, and Histologic Parameters for Predicting Axillary Lymph Node Metastasis in Breast Invasive Ductal Carcinoma. AB - To develop a risk model for predicting axillary lymph node metastasis (LNM) in patients with breast invasive ductal carcinoma (IDCs) using ultrasound (US), US elastography of virtual touch tissue imaging (VTI) and virtual touch tissue imaging & quantification (VTIQ), and histologic parameters. This study included 162 breast IDCs in 162 patients. Univariate and multivariate analyses were used to identify the risk factors and a risk model was created. The results found that 64 (39.5%) of 162 patients had axillary LNMs. The risk score (RS) for axillary LNM was defined as following: RS = 1.3 * (if lesion size >=20 mm) + 2.6 * (if taller than wide shape) + 2.2 * (if VTI score >=5) + 3.9 * (if histological grade III) + 1.9 * (if positive C-erbB-2). The rating system was divided into 6 stages (i.e. Stage I, Stage II, Stage III, Stage IV, Stage V, and Stage VI) and the associated risk rates in terms of axillary LNM were 0% (0/19), 6.1% (2/33), 7.7% (3/39), 65.5% (19/29), 92.3% (24/26), and 100% (16/16), respectively. The risk model for axillary LNM established in the study may facilitate subsequent treatment planning and management in patients with breast IDCs. PMID- 28596562 TI - Characterizing haploinsufficiency of SHELL gene to improve fruit form prediction in introgressive hybrids of oil palm. AB - The fundamental trait in selective breeding of oil palm (Eleais guineensis Jacq.) is the shell thickness surrounding the kernel. The monogenic shell thickness is inversely correlated to mesocarp thickness, where the crude palm oil accumulates. Commercial thin-shelled tenera derived from thick-shelled dura * shell-less pisifera generally contain 30% higher oil per bunch. Two mutations, sh MPOB (M1) and sh AVROS (M2) in the SHELL gene - a type II MADS-box transcription factor mainly present in AVROS and Nigerian origins, were reported to be responsible for different fruit forms. In this study, we have tested 1,339 samples maintained in Sime Darby Plantation using both mutations. Five genotype-phenotype discrepancies and eight controls were then re-tested with all five reported mutations (sh AVROS , sh MPOB , sh MPOB2 , sh MPOB3 and sh MPOB4 ) within the same gene. The integration of genotypic data, pedigree records and shell formation model further explained the haploinsufficiency effect on the SHELL gene with different number of functional copies. Some rare mutations were also identified, suggesting a need to further confirm the existence of cis-compound mutations in the gene. With this, the prediction accuracy of fruit forms can be further improved, especially in introgressive hybrids of oil palm. Understanding causative variant segregation is extremely important, even for monogenic traits such as shell thickness in oil palm. PMID- 28596563 TI - The performance of the SEPT9 gene methylation assay and a comparison with other CRC screening tests: A meta-analysis. AB - The SEPT9 gene methylation assay is the first FDA-approved blood assay for colorectal cancer (CRC) screening. Fecal immunochemical test (FIT), FIT-DNA test and CEA assay are also in vitro diagnostic (IVD) tests used in CRC screening. This meta-analysis aims to review the SEPT9 assay performance and compare it with other IVD CRC screening tests. By searching the Ovid MEDLINE, EMBASE, CBMdisc and CJFD database, 25 out of 180 studies were identified to report the SEPT9 assay performance. 2613 CRC cases and 6030 controls were included, and sensitivity and specificity were used to evaluate its performance at various algorithms. 1/3 algorithm exhibited the best sensitivity while 2/3 and 1/1 algorithm exhibited the best balance between sensitivity and specificity. The performance of the blood SEPT9 assay is superior to that of the serum protein markers and the FIT test in symptomatic population, while appeared to be less potent than FIT and FIT DNA tests in asymptomatic population. In conclusion, 1/3 algorithm is recommended for CRC screening, and 2/3 or 1/1 algorithms are suitable for early detection for diagnostic purpose. The SEPT9 assay exhibited better performance in symptomatic population than in asymptomatic population. PMID- 28596564 TI - Rainbow trapping in a chirped three-dimensional photonic crystal. AB - Light localization and intensity enhancement in a woodpile layer-by-layer photonic crystal, whose interlayer distance along the light propagation direction is gradually varied, has been theoretically predicted and experimentally demonstrated. The phenomenon is shown to be related to the progressive slowing down and stopping of the incident wave, as a result of the gradual variation of the local dispersion. The light localization is chromatically resolved, since every frequency component is stopped and reflected back at different positions along the crystal. It has been further discussed that the peculiar relation between the stopping position and the wave vector distribution can substantially increase the enhancement factor to more than two orders of magnitude. Compared to previously reported one- and two-dimensional photonic crystal configurations, the proposed scheme has the advantage of reducing the propagation losses by providing a three-dimensional photonic bandgap confinement in all directions. The slowing down and localization of waves inside photonic media can be exploited in optics and generally in wave dynamics, in many applications that require enhanced interaction of light and matter. PMID- 28596565 TI - Inhibiting STAT3 signaling is involved in the anti-melanoma effects of a herbal formula comprising Sophorae Flos and Lonicerae Japonicae Flos. AB - A herbal formula (SL) comprising Sophorae Flos and Lonicerae Japonicae Flos was traditionally used to treat melanoma. Constitutively active signal transducer and activator of transcription 3 (STAT3) has been proposed as a therapeutic target in melanoma. Here we investigated whether an ethanolic extract of SL (SLE) exerted anti-melanoma activities by inhibiting STAT3 signaling. B16F10 allograft model, A375 and B16F10 cells were employed to assess the in vivo and in vitro anti melanoma activities of SLE. A375 cells stably expressing STAT3C, a constitutively active STAT3 mutant, were used to determine the role of STAT3 signaling in SLE's anti-melanoma effects. Intragastric administration of SLE (1.2 g/kg) potently inhibited melanoma growth in mice and inhibited STAT3 phosphorylation in the tumors. In cultured cells, SLE dramatically reduced cell viability, induced apoptosis, suppressed migration and invasion, and restrained STAT3 activation and nuclear localization. STAT3C overexpression in A375 cells diminished SLE's effects on cell viability, apoptosis and invasion. Collectively, SLE exerted potent anti-melanoma effects partially by inhibiting STAT3 signaling. This study provides pharmacological justification for the traditional use of this formula in treating melanoma, and suggests that SLE has the potential to be developed as a modern alternative and/or complimentary agent for melanoma treatment and prevention. PMID- 28596566 TI - High-dose maternal folic acid supplementation before conception impairs reversal learning in offspring mice. AB - Maternal folic acid (FA) supplementation prior to and during gestation is recommended for the prevention of neural tube closure defects in the developing embryo. Prior studies, however, suggested that excessive FA supplementation during gestation can be associated with toxic effects on the developing organism. Here, we address whether maternal dietary folic acid supplementation at 40 mg/kg chow (FD), restricted to a period prior to conception, affects neurobehavioural development in the offspring generation. Detailed behavioural analyses showed reversal learning impairments in the Morris water maze in offspring derived from dams exposed to FD prior to conceiving. Furthermore, offspring of FD dams showed minor and transient gene expression differences relative to controls. Our data suggest that temporary exposure of female germ cells to FD is sufficient to cause impaired cognitive flexibility in the subsequent generation. PMID- 28596568 TI - Influence of rovibrational excitation on the non-diabatic state-to-state dynamics for the Li(2p) + H2 -> LiH + H reaction. AB - The non-adiabatic state-to-state dynamics of the Li(2p) + H2 -> LiH + H reaction has been studied using the time-dependent wave packet method, based on a set of diabatic potential energy surfaces recently developed by our group. Integral cross sections (ICSs) can be increase more than an order of magnitude by the vibrational excitation of H2, whereas the ICSs are barely affected by the rotational excitation of H2. Moreover, ICSs of the title reaction with vibrationally excited H2 decrease rapidly with increasing collision energy, which is a typical feature of non-threshold reaction. This phenomenon implies that the title reaction can transformed from an endothermic to an exothermic reaction by vibrational excitation of H2. With the increase of the collision energy, the sideways and backward scattered tendencies of LiH for the Li(2p) + H2(v = 0, j = 0, 1) -> LiH + H reactions are enhanced slightly, while the backward scattering tendency of LiH for the Li(2p) + H2(v = 1, j = 0) -> LiH + H reaction becomes remarkably weakened. For the reaction with vibrationally excited H2 molecule, both direct and indirect reaction mechanism exist simultaneously. PMID- 28596567 TI - The Methylation Capacity of Arsenic and Insulin Resistance are Associated with Psychological Characteristics in Children and Adolescents. AB - The goal of the present study was to compare the influence of the methylation capacity of arsenic, as well as insulin resistance on psychological characteristics of school students from elementary and junior high school. 296 elementary and 318 junior high school students participated in health examinations, completed questionnaires and determined their concentrations of urinary arsenic species and psychological characteristics. Insulin resistance was determined by means of the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). We found that HOMA-IR values were significantly related to increased score of the depression and anger after adjusted for age, gender, schools, father's educational levels, mother's educational levels, BMI, body fat, and urinary creatinine in all students. Anxiety scores and depression scores of junior high school children were significantly higher compared to elementary school children, but lower in disruptive behavior scores. HOMA-IR levels were significantly inversely related to self-concept scores in junior high school students. A greater urinary inorganic arsenic percentage (iAs%) was marginally significantly related to a higher depression score in junior high school students. This is the first study to show a relationship between HOMA-IR levels or urinary arsenic profiles and psychological distress in school students from elementary and junior high school. PMID- 28596569 TI - Targeting Bacillus anthracis toxicity with a genetically selected inhibitor of the PA/CMG2 protein-protein interaction. AB - The protein-protein interaction between the human CMG2 receptor and the Bacillus anthracis protective antigen (PA) is essential for the transport of anthrax lethal and edema toxins into human cells. We used a genetically encoded high throughput screening platform to screen a SICLOPPS library of 3.2 million cyclic hexapeptides for inhibitors of this protein-protein interaction. Unusually, the top 3 hits all contained stop codons in the randomized region of the library, resulting in linear rather than cyclic peptides. These peptides disrupted the targeted interaction in vitro; two act by binding to CMG2 while one binds PA. The efficacy of the most potent CMG2-binding inhibitor was improved through the incorporation of non-natural phenylalanine analogues. Cell based assays demonstrated that the optimized inhibitor protects macrophages from the toxicity of lethal factor. PMID- 28596570 TI - An Alcaligenes strain emulates Bacillus thuringiensis producing a binary protein that kills corn rootworm through a mechanism similar to Cry34Ab1/Cry35Ab1. AB - Crops expressing Bacillus thuringiensis (Bt)-derived insecticidal protein genes have been commercially available for over 15 years and are providing significant value to growers. However, there remains the need for alternative insecticidal actives due to emerging insect resistance to certain Bt proteins. A screen of bacterial strains led to the discovery of a two-component insecticidal protein named AfIP-1A/1B from an Alcaligenes faecalis strain. This protein shows selectivity against coleopteran insects including western corn rootworm (WCR). Transgenic maize plants expressing AfIP-1A/1B demonstrate strong protection from rootworm injury. Surprisingly, although little sequence similarity exists to known insecticidal proteins, efficacy tests using WCR populations resistant to two different Cry proteins show that AfIP-1A/1B and mCry3A differ in their mode of action while AfIP-1A/1B and the binary Cry34Ab1/Cry35Ab1 protein share a similar mode. These findings are supported by results of competitive binding assays and the similarity of the x-ray structure of AfIP-1A to Cry34Ab1. Our work indicates that insecticidal proteins obtained from a non-Bt bacterial source can be useful for developing genetically modified crops and can function similarly to familiar proteins from Bt. PMID- 28596571 TI - The Role of TRPC6 in the Neuroprotection of Calycosin Against Cerebral Ischemic Injury. AB - Our previous studies have provided evidences that calycosin can protect the brain from ischemia/reperfusion injury, but its mechanisms is not fully understand. Transient receptor potential canonical 6 (TRPC6) has a critical role in promoting neuronal survival against cerebral ischemic injury. The aim of the present study is to test whether calycosin protects against cerebral ischemic injury through TRPC6-CREB pathway. In vivo, rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h and then treated with different doses of calycosin at the onset of reperfusion. In vitro, primary cultured neurons were treated by calycosin, then exposed to 2 h oxygen glucose deprivation (OGD) followed by 24 h reoxygenation. Our results showed that treatment with calycosin protected against ischemia-induced damages by increasing TRPC6 and P-CREB expression and inhibiting calpain activation. The neuroprotection effect of calycosin was diminished by inhibition or knockdown of TRPC6 and CREB. These findings indicated that the potential neuroprotection mechanism of calycosin was involved with TRPC6-CREB pathway. PMID- 28596572 TI - Inhibition of androgen receptor promotes CXC-chemokine receptor 7-mediated prostate cancer cell survival. AB - The atypical C-X-C chemokine receptor 7 (CXCR7) has been implicated in supporting aggressive cancer phenotypes in several cancers including prostate cancer. However, the mechanisms driving overexpression of this receptor in cancer are poorly understood. This study investigates the role of androgen receptor (AR) in regulating CXCR7. Androgen deprivation or AR inhibition significantly increased CXCR7 expression in androgen-responsive prostate cancer cell lines, which was accompanied by enhanced epidermal growth factor receptor (EGFR)-mediated mitogenic signaling, promoting tumor cell survival through an androgen independent signaling program. Using multiple approaches we demonstrate that AR directly binds to the CXCR7 promoter, suppressing transcription. Clustered regularly interspaced short palindromic repeats (CRISPR) directed Cas9 nuclease mediated gene editing of CXCR7 revealed that prostate cancer cells depend on CXCR7 for proliferation, survival and clonogenic potential. Loss of CXCR7 expression by CRISPR-Cas9 gene editing resulted in a halt of cell proliferation, severely impaired EGFR signaling and the onset of cellular senescence. Characterization of a mutated CXCR7-expressing LNCaP cell clone showed altered intracellular signaling and reduced spheroid formation potential. Our results demonstrate that CXCR7 is a potential target for adjuvant therapy in combination with androgen deprivation therapy (ADT) to prevent androgen-independent tumor cell survival. PMID- 28596573 TI - Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices. AB - Neutrophil trafficking in tissues critically regulates the body's immune response. Neutrophil migration can either play a protective role in host defense or cause health problems. Fibroblast growth factor 23 (FGF23) is a known biomarker for chronic kidney disease (CKD) and was recently shown to impair neutrophil arrest on endothelium and transendothelial migration. In the present study, we further examined the effect of FGF23 on human blood neutrophil chemotaxis using two new microfluidic devices. Our results showed that chemotaxis of FGF23 pre-treated neutrophils to a fMLP gradient, in the presence or absence of a uniform FGF23 background, is quantitatively lower compared to the control cells. This effect is accompanied with a stronger drifting of FGF23 pre-treated cells along the flow. However, without the FGF23 pre-treatment, the FGF23 background only reduces chemotaxis of transmigrated cells through the thin barrier channel to the fMLP gradient. The effect of FGF23 on neutrophil migration and the correlation between multiple cell migration parameters are further revealed by chemotactic entropy and principle component analysis. Collectively, these results revealed the effect of FGF23 on weakening neutrophil chemotaxis, which shed light on FGF23 mediated neutrophil migration with direct disease relevance such as CKD. PMID- 28596574 TI - Estimation of the thermocapillary force and its applications to precise droplet control on a microfluidic chip. AB - Droplet control through the use of light-induced thermocapillary effects has recently garnered attention due to its non-intrusive and multifunctional nature. An important issue in droplet control is the estimation of the thermocapillary force. The purpose of the present study is to estimate the thermocapillary force and propose empirical equations between the force and simply measurable key parameters such as droplet diameter and power of heat source. In addition, we aim to shift the droplet trajectory and develop an on-demand droplet routing system based on the estimation of the thermocapillary force. We illuminated a continuous phase with a 532 nm laser beam to minimize possible damage or property changes to target molecules contained within droplets. A mixture of light-absorbing material and oleic acid was used for the continuous phase fluid, while deionized water (DI water) was used for the dispersed phase fluid. We proposed empirical equations to estimate the thermocapillary force, which was then applied to precise droplet shifting and routing. We found that the shifting distance was linearly proportional to the thermocapillary force, and that an on-demand droplet routing system resulted in a success rate greater than 95%. PMID- 28596575 TI - Infectious pancreatic necrosis virus enters CHSE-214 cells via macropinocytosis. AB - Infectious pancreatic necrosis virus (IPNV) is a non-enveloped virus belonging to the Birnaviridae family. IPNV produces an acute disease in salmon fingerlings, with high mortality rates and persistent infection in survivors. Although there are reports of IPNV binding to various cells, the viral receptor and entry pathways remain unknown. The aim of this study was to determine the endocytic pathway that allows for IPNV entry. We observed that IPNV stimulated fluid uptake and virus particles co-localysed with the uptake marker dextran in intracellular compartments, suggesting a role for macropinocytosis in viral entry. Consistent with this idea, viral infection was significantly reduced when the Na+/H+ exchanger NHE1 was inhibited with 5-(N-Ethyl-N-isopropyl) amiloride (EIPA). Neither chlorpromazine nor filipin complex I affected IPNV infection. To examine the role of macropinocytosis regulators, additional inhibitors were tested. Inhibitors of the EGFR pathway and the effectors Pak1, Rac1 and PKC reduced viral infection. Together, our results indicate that IPNV is mainly internalized into CHSE-214 cells by macropinocytosis. PMID- 28596576 TI - Knee subchondral bone perfusion and its relationship to marrow fat and trabeculation on multi-parametric MRI and micro-CT in experimental CKD. AB - The pathogenesis of chronic kidney disease (CKD) is multifactorial. In the progression of CKD arthropathy, arteriosclerosis may alter the knee subchondral bone marrow by altering blood flow through the bone vasculature. Herein, multi parametric MRI assessment, including dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), magnetic resonance spectroscopy (MRS), MRI T2*, contrast enhanced MR angiography (CE-MRA), and micro-CT were applied in a rodent nephrectomy model to: 1) investigate the blood perfusion of subchondral bone marrow and its relationship to fat water content and trabeculation pattern in CKD and 2) demonstrate the feasibility of using multi-parametric MRI parameters as imaging biomarkers to evaluate the disease's progression. Two groups of rats in our study underwent either 1) no intervention or 2) 5/6 nephrectomy. We found that in the CKD group, perfusion amplitude A and elimination constant k el values were significantly decreased, and vascular permeability k ep was significantly increased. MRS showed that fat fraction (FF) was significantly lower, water fraction (WF) was significantly higher in the CKD group. Micro-CT showed a significant loss of trabecular bone. Knee subchondral bone marrow perfusion deficiency in experimental CKD may be associated with decreased fat content, increased water content, and sparse trabeculation. PMID- 28596577 TI - Development of an efficient vector system for gene knock-out and near in-cis gene complementation in the sugarcane smut fungus. AB - Sporisorium scitamineum is the causative agent responsible for smut disease of sugarcane worldwide. However, lack of efficient gene manipulation system makes this fungus much behind the type model of the smut fungi in molecular biology. Here, we report the development of a CRISPR/Cas9 and T-DNA based dual vector system that allowed efficient knock-out or knock-in of a gene of interest in the S. scitamineum in a site-specific manner. By using Mfa2, a key player in the mating event in S. scitamineum as a tester gene, site-specific insertions of the introduced fragments were achieved both for Mfa2 knockout and complementation. Of particular advantage of this system is the simplicity of selection and identification for the desired transformants by using drug resistance coupled with PCR. This system greatly facilitates the gene function study in S. scitamineum, and could potentially be used for other basidiomycete fungi. PMID- 28596579 TI - Preparing local strain patterns in graphene by atomic force microscope based indentation. AB - Patterning graphene into various mesoscopic devices such as nanoribbons, quantum dots, etc. by lithographic techniques has enabled the guiding and manipulation of graphene's Dirac-type charge carriers. Graphene, with well-defined strain patterns, holds promise of similarly rich physics while avoiding the problems created by the hard to control edge configuration of lithographically prepared devices. To engineer the properties of graphene via mechanical deformation, versatile new techniques are needed to pattern strain profiles in a controlled manner. Here we present a process by which strain can be created in substrate supported graphene layers. Our atomic force microscope-based technique opens up new possibilities in tailoring the properties of graphene using mechanical strain. PMID- 28596580 TI - Flower induction, microscope-aided cross-pollination, and seed production in the duckweed Lemna gibba with discovery of a male-sterile clone. AB - Duckweed species have a great potential to develop into fast-growing crops for water remediation and bioenergy production. Seed production and utilization of hybrid vigour are essential steps in this process. However, even in the extensively-studied duckweed species, Lemna gibba, flower primordia were often aborted prior to maturation. Salicylic acid (SA) and agar solidification of the medium promoted flower maturation and resulted in high flowering rates in L. gibba 7741 and 5504. Artificial cross-pollination between individuals of L. gibba 7741 yielded seeds at high frequencies unlike that in L. gibba 5504. In contrast to clone 7741, the anthers of 5504 did not dehisce upon maturation, its artificially released pollen grains had pineapple-like exine with tilted spines. These pollens were not stained by 2,5-diphenylmonotetrazoliumbromide (MTT) and failed to germinate. Therefore, clone 5504 is male sterile and has potential application with respect to hybrid vigour. Moreover, pollination of flowers of 5504 with 7741 pollen grains resulted in intraspecific hybrid seeds, which was confirmed by inter-simple sequence repeat (ISSR) markers. These hybrid seeds germinated at a high frequency, forming new clones. PMID- 28596578 TI - Transgenic overexpression of GTP cyclohydrolase 1 in cardiomyocytes ameliorates post-infarction cardiac remodeling. AB - GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial fibrosis, and phosphorylated p38 mitogen activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility, tetrahydrobiopterin, the dimers of nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial fibrosis and increases anterior wall thickness and cardiac contractility after infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated p38 mitogen-activated protein kinase and elevates tetrahydrobiopterin levels, the dimerization and phosphorylation of neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling proteins in post-infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-infarction cardiac remodeling is attributable to preservation of neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins, and identify a new therapeutic target for cardiac remodeling after infarction. PMID- 28596581 TI - The homology gene BtDnmt1 is Essential for Temperature Tolerance in Invasive Bemisia tabaci Mediterranean Cryptic Species. AB - The Bemisia tabaci Mediterranean (MED) cryptic species has been rapidly invading most parts of the world owing to its strong ecological adaptability, particularly its strong resistance to temperature stress. Epigenetic mechanisms play important roles in mediating ecological plasticity. In particular, DNA methylation has been the focus of attempts to understand the mechanism of phenotypic plasticity. The relationship between temperature and DNA methylation and how it affects the adaptability of invasive insects remain unknown. To investigate the temperature resistance role of DNA methyltransferase 1 (Dnmt1) in MED, we cloned and sequenced BtDnmt1 homology and identified its functions under various temperature conditions. The full-length cDNA of MED BtDnmt1 homology was 5,958 bp and has a 4,287 bp open reading frame that encodes a 1,428-amino-acid protein. BtDnmt1 mRNA expression levels were significantly down-regulated after feeding with dsRNA. Furthermore, after feeding with dsBtDnmt1, the MED adults exhibited significantly higher mortality under temperature stress conditions than the controls, suggesting that MED BtDnmt1 homology plays an essential role in the temperature tolerance capacity of MED. Our data improve our understanding of the temperature resistance and temperature adaptability mechanisms that have allowed the successful invasion and colonization of various environments by this alien species. PMID- 28596582 TI - Cell Sheets of Co-cultured Endothelial Progenitor Cells and Mesenchymal Stromal Cells Promote Osseointegration in Irradiated Rat Bone. AB - Irradiated bone has a greater risk of implant failure than nonirradiated bone. The purpose of this study was to investigate the influence of cell sheets composed of co-cultured bone marrow mesenchymal stromal cells (BMSCs) and endothelial progenitor cells (EPCs) on implant osseointegration in irradiated bone. Cell sheets (EPCs, BMSCs or co-cultured EPCs and BMSCs) were wrapped around titanium implants to make cell sheet-implant complexes. The co-cultured group showed the highest osteogenic differentiation potential in vitro, as indicated by the extracellular matrix mineralization and the expression of osteogenesis related genes at both mRNA and protein levels. The co-cultured cells promoted ectopic bone formation as indicated by micro-computed tomography (Micro-CT) and histological analysis. In the irradiated tibias of rats, implants of the co cultured group showed enhanced osseointegration by Micro-CT evaluation and histological observation. Co-cultured EPCs and BMSCs also up-regulated the expression of osteogenesis related genes in bone fragments in close contact with implants. In conclusion, cell sheets of co-cultured EPCs and BMSCs could promote osseous healing around implants and are potentially useful to improve osseointegration process for patients after radiotherapy. PMID- 28596583 TI - Dynamic Contrast-enhanced MRI in Renal Tumors: Common Subtype Differentiation using Pharmacokinetics. AB - Preoperative renal tumor subtype differentiation is important for radiology and urology in clinical practice. Pharmacokinetic data (K trans & V e, etc.) derived from dynamic contrast-enhanced MRI (DCE-MRI) have been used to investigate tumor vessel permeability. In this prospective study on DCE-MRI pharmacokinetic studies, we enrolled patients with five common renal tumor subtypes: clear cell renal cell carcinoma (ccRCC; n = 65), papillary renal cell carcinoma (pRCC; n = 12), chromophobic renal cell carcinoma (cRCC; n = 9), uroepithelial carcinoma (UEC; n = 14), and fat-poor angiomyolipoma (fpAML; n = 10). The results show that K trans of ccRCC, pRCC, cRCC, UEC and fpAML (0.459 +/- 0.190 min-1, 0.206 +/- 0.127 min-1, 0.311 +/- 0.111 min-1, 0.235 +/- 0.116 min-1, 0.511 +/- 0.159 min-1, respectively) were different, but V e was not. K trans could distinguish ccRCC from non-ccRCC (pRCC & cRCC) with a sensitivity of 76.9% and a specificity of 71.4%, respectively, as well as to differentiate fpAML from non-ccRCC with a sensitivity of 100% and a specificity of 76.2%, respectively. Our findings suggest that DCE-MRI pharmacokinetics are promising for differential diagnosis of renal tumors, especially for RCC subtype characterization and differentiation between fpAML and non-ccRCC, which may facilitate the treatment of renal tumors. PMID- 28596584 TI - RCAN-11R peptide provides immunosuppression for fully mismatched islet allografts in mice. AB - Calcineurin inhibitors have been used for transplant therapy. However, the inhibition of calcineurin outside the immune system has a number of side effects. We previously developed a cell-permeable inhibitor of NFAT (nuclear factor of activated T cells) using the polyarginine peptide delivery system. This peptide (11R-VIVIT) selectively interferes with calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase and provides immunosuppression for fully mismatched islet allografts in mice. However, our recent study showed that 11R-VIVIT affected cell viability in vitro when it was used at higher concentration because of the VIVIT sequence. The aim of this study is to develop a safer NFAT inhibitor (RCAN-11R) that does not affect cell viability, and which is less toxic than calcineurin inhibitors. The minimal sequence of the protein family of regulators of calcineurin (RCAN) that is responsible for the inhibition of calcineurin-NFAT signaling was recently characterized. The peptide could selectively interfere with the calcineurin-NFAT interaction without affecting the activity of calcineurin phosphatase, similar to 11R-VIVIT. RCAN-11R did not affect cell viability when it was used at a higher concentration than the toxic concentration of 11R-VIVIT. RCAN-11R could therefore be useful as a therapeutic agent that is less toxic than current drugs or 11R-VIVIT. PMID- 28596585 TI - Tetraploid embryonic stem cells can contribute to the development of chimeric fetuses and chimeric extraembryonic tissues. AB - Our study examined the in vivo chimeric and survival capacities of chimeras created by injecting tetraploid embryonic stem cells (ESCs) expressing green fluorescent protein (GFP) into diploid embryos. At 3.5 days post-coitum (dpc) and 4.5 dpc, the tetraploid ESCs were able to contribute to the inner cell mass (ICM) just as diploid ESCs tagged with GFP. At 6.5 dpc, 8.0 dpc and 10.5 dpc, the tetraploid ESCs manifested in the same location as the diploid ESCs. The GFP cells in the extraembryonic tissues and fetuses of tetraploid ESC chimeras were tetraploid as determined by fluorescence activated cell sorting (FACS). Furthermore, tetraploid ESCs contributed to the development of the placenta, embryolemma and umbilical cord at 13.5 dpc and 16.5 dpc; however, very less GFP cells were found in the fetuses of tetraploid ESC chimeras. We further found that the proliferation of tetraploid ESCs was slower than that of diploid ESCs. In addition, the relative mRNA expression in the three germ layers and the trophoblast was abnormal in the EBs of tetraploid ESCs compared with diploid ESCs. In short, slower proliferation and abnormal differentiation potential of tetraploid ESCs might be two of the reasons for their poor survival and chimeric capacities. PMID- 28596586 TI - Storage of neural histamine and histaminergic neurotransmission is VMAT2 dependent in the zebrafish. AB - Monoaminergic neurotransmission is greatly dependent on the function of the vesicular monoamine transporter VMAT2, which is responsible for loading monoamines into secretory vesicles. The role of VMAT2 in histaminergic neurotransmission is poorly understood. We studied the structure and function of the histaminergic system in larval zebrafish following inhibition of VMAT2 function by reserpine. We found that reserpine treatment greatly reduced histamine immunoreactivity in neurons and an almost total disappearance of histamine-containing nerve fibers in the dorsal telencephalon and habenula, the most densely innervated targets of the hypothalamic histamine neurons. The reserpine treated larvae had an impaired histamine-dependent dark-induced flash response seen during the first second after onset of darkness, implying that function of the histaminergic network is VMAT2 dependent. Levels of histamine and other monoamines were decreased in reserpine treated animals. This study provides conclusive evidence of the relevance of VMAT2 in histaminergic neurotransmission, further implying that the storage and release mechanism of neural histamine is comparable to that of other monoamines. Our results also reveal potential new insights about the roles of monoaminergic neurotransmitters in the regulation of locomotion increase during adaptation to darkness. PMID- 28596587 TI - Histones H3 and H4 require their relevant amino-tails for efficient nuclear import and replication-coupled chromatin assembly in vivo. AB - Concomitant chromatin assembly and DNA duplication is essential for cell survival and genome integrity, and requires newly synthesized histones. Although the N terminal domains of newly synthesized H3 and H4 present critical functions, their requirement for replication-coupled chromatin assembly is controversial. Using the unique capability of the spontaneous internalization of exogenous proteins in Physarum, we showed that H3 and H4 N-tails present critical functions in nuclear import during the S-phase, but are dispensable for assembly into nucleosomes. However, our data revealed that chromatin assembly in the S-phase of complexes presenting ectopic N-terminal domains occurs by a replication-independent mechanism. We found that replication-dependent chromatin assembly requires an H3/H4 complex with the relevant N-tail domains, suggesting a concomitant recognition of the two histone domains by histone chaperones. PMID- 28596588 TI - Optimization of a CRISPR/Cas9-mediated Knock-in Strategy at the Porcine Rosa26 Locus in Porcine Foetal Fibroblasts. AB - Genetically modified pigs have important roles in agriculture and biomedicine. However, genome-specific knock-in techniques in pigs are still in their infancy and optimal strategies have not been extensively investigated. In this study, we performed electroporation to introduce a targeting donor vector (a non-linearized vector that did not contain a promoter or selectable marker) into Porcine Foetal Fibroblasts (PFFs) along with a CRISPR/Cas9 vector. After optimization, the efficiency of the EGFP site-specific knock-in could reach up to 29.6% at the pRosa26 locus in PFFs. Next, we used the EGFP reporter PFFs to address two key conditions in the process of achieving transgenic pigs, the limiting dilution method and the strategy to evaluate the safety and feasibility of the knock-in locus. This study demonstrates that we establish an efficient procedures for the exogenous gene knock-in technique and creates a platform to efficiently generate promoter-less and selectable marker-free transgenic PFFs through the CRISPR/Cas9 system. This study should contribute to the generation of promoter-less and selectable marker-free transgenic pigs and it may provide insights into sophisticated site-specific genome engineering techniques for additional species. PMID- 28596589 TI - Fusaric Acid immunotoxicity and MAPK activation in normal peripheral blood mononuclear cells and Thp-1 cells. AB - Fusaric acid (FA), a food-borne mycotoxin, is a potent divalent metal chelator. The human immune system is complex and susceptible to environmental insult however, the immunotoxity of FA remains unknown. We investigated the immunotoxicity of FA on human peripheral blood mononuclear cells (PBMCs) and Thp 1 cells. FA was cytotoxic to PBMCs (IC50-240.8 MUg/ml) and Thp-1 (IC50-107.7 MUg/ml) cells at 24 h. FA induced early apoptosis but significantly decreased caspase activity in PBMCs, a characteristic of paraptosis. In Thp-1 cells, FA induced apoptosis and increased caspase -9 and -3/7 activities. In PBMCs, FA maintained mitochondrial membrane potential and decreased protein expression of Bax whilst increasing expression of p-Bcl-2; FA induced oxidative stress and depleted ATP levels in both cell types. In Thp-1 cells, FA increased mitochondrial membrane depolarization and decreased p-Bcl-2 expression. In PBMCs, FA significantly up-regulated the MAPK protein expression of p-ERK and p-JNK but down-regulated p-p38 expression. In Thp-1 cells, FA up-regulated MAPK protein expression of p-ERK whilst p-JNK and p-p38 expression were down-regulated. In conclusion FA induced programmed cell death and altered MAPK signaling in healthy PBMCs and Thp-1 cells strongly suggesting a possible mechanism of FA induced immunotoxicity in vitro. PMID- 28596591 TI - Widom Lines in Binary Mixtures of Supercritical Fluids. AB - Recent experiments on pure fluids have identified distinct liquid-like and gas like regimes even under supercritical conditions. The supercritical liquid-gas transition is marked by maxima in response functions that define a line emanating from the critical point, referred to as Widom line. However, the structure of analogous state transitions in mixtures of supercritical fluids has not been determined, and it is not clear whether a Widom line can be identified for binary mixtures. Here, we present first evidence for the existence of multiple Widom lines in binary mixtures from molecular dynamics simulations. By considering mixtures of noble gases, we show that, depending on the phase behavior, mixtures transition from a liquid-like to a gas-like regime via distinctly different pathways, leading to phase relationships of surprising complexity and variety. Specifically, we show that miscible binary mixtures have behavior analogous to a pure fluid and the supercritical state space is characterized by a single liquid gas transition. In contrast, immiscible binary mixture undergo a phase separation in which the clusters transition separately at different temperatures, resulting in multiple distinct Widom lines. The presence of this unique transition behavior emphasizes the complexity of the supercritical state to be expected in high-order mixtures of practical relevance. PMID- 28596590 TI - A comprehensive analysis and annotation of human normal urinary proteome. AB - Biomarkers are measurable changes associated with the disease. Urine can reflect the changes of the body while blood is under control of the homeostatic mechanisms; thus, urine is considered an important source for early and sensitive disease biomarker discovery. A comprehensive profile of the urinary proteome will provide a basic understanding of urinary proteins. In this paper, we present an in-depth analysis of the urinary proteome based on different separation strategies, including direct one dimensional liquid chromatography-tandem mass spectrometry (LC/MS/MS), two dimensional LC/MS/MS, and gel-eluted liquid fraction entrapment electrophoresis/liquid-phase isoelectric focusing followed by two dimensional LC/MS/MS. A total of 6085 proteins were identified in healthy urine, of which 2001 were not reported in previous studies and the concentrations of 2571 proteins were estimated (spanning a magnitude of 106) with an intensity based absolute quantification algorithm. The urinary proteins were annotated by their tissue distribution. Detailed information can be accessed at the "Human Urine Proteome Database" (www.urimarker.com/urine). PMID- 28596593 TI - Improving randomness characterization through Bayesian model selection. AB - Random number generation plays an essential role in technology with important applications in areas ranging from cryptography to Monte Carlo methods, and other probabilistic algorithms. All such applications require high-quality sources of random numbers, yet effective methods for assessing whether a source produce truly random sequences are still missing. Current methods either do not rely on a formal description of randomness (NIST test suite) on the one hand, or are inapplicable in principle (the characterization derived from the Algorithmic Theory of Information), on the other, for they require testing all the possible computer programs that could produce the sequence to be analysed. Here we present a rigorous method that overcomes these problems based on Bayesian model selection. We derive analytic expressions for a model's likelihood which is then used to compute its posterior distribution. Our method proves to be more rigorous than NIST's suite and Borel-Normality criterion and its implementation is straightforward. We applied our method to an experimental device based on the process of spontaneous parametric downconversion to confirm it behaves as a genuine quantum random number generator. As our approach relies on Bayesian inference our scheme transcends individual sequence analysis, leading to a characterization of the source itself. PMID- 28596592 TI - Sequence variant at 4q25 near PITX2 associates with appendicitis. AB - Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 * 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk. PMID- 28596594 TI - Magnifying narrow-band imaging of gastric mucosal morphology predicts the H. pylori-related epigenetic field defect. AB - DNA methylation is associated with "field defect" in the gastric mucosa. To characterize "field defect" morphologically, we examined DNA methylation of non neoplastic gastric mucosa in relation to their morphology seen by narrow-band imaging (NBI) with magnifying endoscopy. Magnifying NBI of non-neoplastic gastric body was classified as follows: normal-small and round pits with uniform subepithelial capillary networks; type 1-a little enlarged round pits with indistinct subepithelial capillary networks; type 2-remarkably enlarged pits with irregular vessels; and type 3-clearly demarcated oval or tubulovillous pits with bulky coiled or wavy vessels. Methylation of nine candidate genes (MYOD1, SLC16A12, GDNF, IGF2, MIR 124A1, CDH1, PRDM5, RORA and MLF1) were determined by bisulfite pyrosequencing. Infinium HumanMethylation450 array was used to characterize the methylation of >450,000 CpG sites. Mean Z score methylation of nine genes positively correlated with the changes of mucosal patterns from normal to types 1, 2, and 3 (P < 0.0001). Genome-wide analysis showed that development of mucosal patterns correlated with methylation accumulation especially at CpG islands. Genes with promoter CpG islands that were gradually methylated with the development of mucosal patterns significantly enriched the genes involved in zinc related pathways. The results indicates that gastric mucosal morphology predicts a "field defect" in this tissue type. Accumulation of DNA methylation is associated with "field defect" in the non-neoplastic gastric mucosa. Endoscopic identification of "field defect" has important implications for preventing gastric cancer. Our results suggest that magnifying NBI of gastric mucosal morphology predicts a "field defect" in the gastric mucosa. PMID- 28596595 TI - Mitochondrial biogenesis dysfunction and metabolic dysfunction from a novel mitochondrial tRNAMet 4467 C>A mutation in a Han Chinese family with maternally inherited hypertension. AB - To investigate the relationship between mitochondrial DNA (mtDNA) and hypertension as well as the mechanism involved in mitochondrial metabolic dysfunction. We identified a novel tRNAMet C4467A mutation in a Han Chinese family with hypertension. The maternal members presented with increased glucose, total cholesterol, low-density lipoprotein, and serum sodium as well as decreased potassium compared with non-maternal members (P < 0.05). Segregation analysis showed this mutation was maternally inherited. We analyzed lymphocyte cell lines derived from three maternal and three non-maternal family members. Reactive oxygen species production in the mutant cell lines was 114.5% higher compared with that in controls (P < 0.05) while ATP was 26.4% lower. The mitochondrial membrane potential of the mutated cell lines was 26.2% lower than that in controls (P < 0.05). Oxygen consumption rates were decreased in the mutant cell lines (P < 0.05). The activation of caspase-3/7 was 104.1% higher in the mutant cell lines compared with controls (P < 0.05). The expression of voltage-dependent anion channel (VDAC), Bax and apoptosis-inducing factor (AIF) in the mutant cell lines was higher compared with that in controls, with the increased colocalization of VDAC and Bax. Therefore, this mutation contributes to oxidative stress and mitochondrial biogenesis dysfunction, which may be involved in the pathogenesis of hypertension. PMID- 28596596 TI - Optical mapping of neuronal activity during seizures in zebrafish. AB - Mapping neuronal activity during the onset and propagation of epileptic seizures can provide a better understanding of the mechanisms underlying this pathology and improve our approaches to the development of new drugs. Recently, zebrafish has become an important model for studying epilepsy both in basic research and in drug discovery. Here, we employed a transgenic line with pan-neuronal expression of the genetically-encoded calcium indicator GCaMP6s to measure neuronal activity in zebrafish larvae during seizures induced by pentylenetretrazole (PTZ). With this approach, we mapped neuronal activity in different areas of the larval brain, demonstrating the high sensitivity of this method to different levels of alteration, as induced by increasing PTZ concentrations, and the rescuing effect of an anti-epileptic drug. We also present simultaneous measurements of brain and locomotor activity, as well as a high-throughput assay, demonstrating that GCaMP measurements can complement behavioural assays for the detection of subclinical epileptic seizures, thus enabling future investigations on human hypomorphic mutations and more effective drug screening methods. Notably, the methodology described here can be easily applied to the study of many human neuropathologies modelled in zebrafish, allowing a simple and yet detailed investigation of brain activity alterations associated with the pathological phenotype. PMID- 28596598 TI - Application of high rate integrated anaerobic-aerobic/biogranular activated carbon sequencing batch reactor (IAnA-BioGACSBR) for treating strong municipal landfill leachate. AB - The aim of the present study is to evaluate the application of high rate integrated anaerobic-aerobic/biogranular activated carbon sequencing batch reactor (IAnA-BioGACSBR) to treat raw strong leachate from open dumping of municipal solid waste. The influence of two important and effective independent variables, COD concentrations and volumetric filling rate with GAC, onto the leachate treatment were investigated. Three responses such as TKN, BOD and COD were considered for evaluating the interaction of parameters. The results showed that maximum BOD5 removal of 98.9% in anaerobic zone and 99% in aerobic zone was obtained at the highest values of COD (~30000 mg/L) and filling ratio (~50%). The highest values of COD removal efficiency were found to be 98.54% and 98%, at COD rate of 10000 mg/L and GAC of 35%, respectively. The highest removal values of TKN was 77.2% and 78.9% in anaerobic and aerobic zone, respectively. Under optimal conditions, compared with the SBR and the GAC-SBR performances, results reveal that the application of the GAC-SBR has shown better effluent characteristics. Based on the results, it can be asserted that the application of the high rate IAnA-BioGACSBR for the treatment of biodegradable landfill leachate was more effective. PMID- 28596597 TI - Smart Microparticles with a pH-responsive Macropore for Targeted Oral Drug Delivery. AB - The development of a smart microencapsulation system programmed to actively respond to environmental pH change has long been recognized a key technology in pharmaceutical and food sciences. To this end, we developed hollow microparticles (MPs) with self-controlled macropores that respond to environmental pH change, using an Oil-in-Water emulsion technique, for oral drug delivery. We observed that freeze-drying of MPs induced closure of macropores. The closing/opening behavior of macropores was confirmed by exposing MPs encapsulating different ingredients (sulforhodamine b, fluorescent nanoparticles, and lactase) to simulated gastrointestinal (GI) fluids. MPs maintained their intact, closed pore structure in gastric pH, and subsequent exposure to intestinal pH resulted in pore opening and ingredients release. Further, MPs displayed higher protection (>15 times) than commercial lactase formulation, indicating the protective ability of the system against harsh GI conditions. This study showed development of a hybrid MP system combining the advantages of solid particles and hollow capsules, exhibiting easy solvent-free loading mechanism and smart protection/release of encapsulates through controllable macropores. Ultimately, our MPs system strives to usher a new research area in smart drug delivery systems and advance the current oral drug delivery technology by solving major challenges in targeted delivery of pH-sensitive therapeutics. PMID- 28596599 TI - The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma. AB - The Warburg effect is a metabolic hallmark of cancer. Tumor cells rapidly adjust their energy source to glycolysis in order to efficiently proliferate in a hypoxic environment, but the mechanism underlying this switch remains incompletely understood. Here, we show that hypoxia potently induces the down regulation of miR-125a expression in hepatocellular carcinoma (HCC) cells and tumors. Furthermore, we demonstrate that miR-125a could decrease the production of lactate, the uptake of glucose, and the levels of ATP and reactive oxygen species (ROS) in HCC cells. We investigated the molecular mechanism through which miR-125a inhibits HCC glycolysis and identified hexokinase II (HK2) as a direct target gene of miR-125a. Finally, we revealed that the miR-125a/HK2 axis is functionally important for regulating glycolysis of HCC cell and progression of cancer in vitro and in vivo. In summary, our findings demonstrate for the first time that hypoxia-down-regulated miR-125a regulated HCC glycolysis and carcinogenesis by targeting hexokinase HK2, a key glycolytic enzyme for the Warburg effect, and add a new dimension to hypoxia-mediated regulation of cancer metabolism. PMID- 28596600 TI - Detection of DNA Amplicons of Polymerase Chain Reaction Using Litmus Test. AB - We report on a new colorimetric DNA detection method that takes advantage of the power of polymerase chain reaction (PCR) and the simplicity of the classic litmus test. The strategy makes use of a modified set of primers for PCR to facilitate ensuing manipulations of resultant DNA amplicons: their tagging with urease and immobilization onto magnetic beads. The amplicon/urease-laden beads are then used to hydrolyze urea, resulting in the increase of pH that can be conveniently reported by a pH-sensitive dye. We have successfully applied this strategy for the detection of two hypervirulent strains of the bacterium Clostridium difficile that are responsible for the recent increase in the global incidence and severity of C. difficile infections. Furthermore, the viability of this test for diagnostic applications is demonstrated using clinically validated stool samples from C. difficile infected patients. PMID- 28596601 TI - Ebbinghaus figures that deceive the eye do not necessarily deceive the hand. AB - In support of the visual stream dissociation hypothesis, which states that distinct visual streams serve vision-for-perception and vision-for-action, visual size illusions were reported over 20 years ago to 'deceive the eye but not the hand'. Ever since, inconclusive results and contradictory interpretations have accumulated. Therefore, we investigated the effects of the Ebbinghaus figure on repetitive aiming movements with distinct dynamics. Participants performed a Fitts' task in which Ebbinghaus figures served as targets. We systematically varied the three parameters which have been shown to influence the perceived size of the Ebbinghaus figure's target circle, namely the size of the target, its distance to the context circles and the size of the context circles. This paper shows that movement is significantly affected by the context size, but, in contrast to perception, not by the other two parameters. This is especially prominent in the approach phase of the movement towards the target, regardless of the dynamics. To reconcile the findings, we argue that different informational variables are used for size perception and the visual control of movements irrespective of whether certain variables induce (perceptual) illusions. PMID- 28596602 TI - Measuring multisensory integration: from reaction times to spike counts. AB - A neuron is categorized as "multisensory" if there is a statistically significant difference between the response evoked, e.g., by a crossmodal stimulus combination and that evoked by the most effective of its components separately. Being responsive to multiple sensory modalities does not guarantee that a neuron has actually engaged in integrating its multiple sensory inputs: it could simply respond to the stimulus component eliciting the strongest response in a given trial. Crossmodal enhancement is commonly expressed as a proportion of the strongest mean unisensory response. This traditional index does not take into account any statistical dependency between the sensory channels under crossmodal stimulation. We propose an alternative index measuring by how much the multisensory response surpasses the level obtainable by optimally combining the unisensory responses, with optimality defined as probability summation under maximal negative stochastic dependence. The new index is analogous to measuring crossmodal enhancement in reaction time studies by the strength of violation of the "race model inequality', a numerical measure of multisensory integration. Since the new index tends to be smaller than the traditional one, neurons previously labeled as "multisensory' may lose that property. The index is easy to compute and it is sensitive to variability in data. PMID- 28596603 TI - Nanorobotic System iTRo for Controllable 1D Micro/nano Material Twisting Test. AB - In-situ micro/nano characterization is an indispensable methodology for material research. However, the precise in-situ SEM twisting of 1D material with large range is still challenge for current techniques, mainly due to the testing device's large size and the misalignment between specimen and the rotation axis. Herein, we propose an in-situ twist test robot (iTRo) to address the above challenges and realize the precise in-situ SEM twisting test for the first time. Firstly, we developed the iTRo and designed a series of control strategies, including assembly error initialization, triple-image alignment (TIA) method for rotation axis alignment, deformation-based contact detection (DCD) method for sample assembly, and switch control for robots cooperation. After that, we chose three typical 1D material, i.e., magnetic microwire Fe74B13Si11C2, glass fiber, and human hair, for twisting test and characterized their properties. The results showed that our approach is able to align the sample to the twisting axis accurately, and it can provide large twisting range, heavy load and high controllability. This work fills the blank of current in-situ mechanical characterization methodologies, which is expected to give significant impact in the fundamental nanomaterial research and practical micro/nano characterization. PMID- 28596604 TI - miR-143 and miR-145 disrupt the cervical epithelial barrier through dysregulation of cell adhesion, apoptosis and proliferation. AB - Molecular mechanisms regulating preterm birth (PTB)-associated cervical remodeling remain unclear. Prior work demonstrated an altered miRNA profile, with significant increases in miR-143 and miR-145, in cervical cells of women destined to have a PTB. The study objective was to determine the effect of miR-143 and miR 145 on the cervical epithelial barrier and to elucidate the mechanisms by which these miRNAs modify cervical epithelial cell function. Ectocervical and endocervical cells transfected with miR-negative control, miR-143 or miR-145 were used in cell permeability and flow cytometry assays for apoptosis and proliferation. miR-143 and miR-145 target genes associated with cell adhesion, apoptosis and proliferation were measured. Epithelial cell permeability was increased in miR-143 and miR-145 transfected cervical epithelial cells. Cell adhesion genes, JAM-A and FSCN1, were downregulated with overexpression of miR 143 and miR-145. miR-143 and miR-145 transfection decreased cervical cell number by increasing apoptosis and decreasing cell proliferation through initiation of cell cycle arrest. Apoptosis genes, BCL2 and BIRC5, and proliferation genes, CDK1 and CCND2, were repressed by miR-143 and miR-145. These findings suggest that miR 143 and miR-145 play a significant role in cervical epithelial barrier breakdown through diverse mechanisms and could contribute to premature cervical remodeling associated with PTB. PMID- 28596606 TI - Yolk removal generates hatching asynchrony in snake eggs. AB - Hatching synchrony is wide-spread amongst egg-laying species and is thought to enhance offspring survival, notably by diluting predation risks. Turtle and snake eggs were shown to achieve synchronous hatching by altering development rates (where less advanced eggs may accelerate development) or by hatching prematurely (where underdeveloped embryos hatch concurrently with full-term embryos). In Natricine snakes, smaller eggs tend to slow down metabolism throughout incubation in order to hatch synchronously with larger eggs. To explore the underlying mechanism of this phenomenon we experimentally manipulated six clutches, where half of the eggs were reduced in mass by removing 7.2% of yolk, and half were used as the control. The former experienced higher heart rates throughout the incubation period, hatched earlier and produced smaller hatchlings than the latter. This study supports the idea that developmental rates are related to egg mass in snake eggs and demonstrates that the relationship can be influenced by removing yolk after egg-laying. The shift in heart rates however occurred in the opposite direction to expected, with higher heart rates in yolk-removed eggs resulting in earlier hatching rather than lower heart rates resulting in synchronous hatching, warranting further research on the topic. PMID- 28596605 TI - Microenvironmental cooperation promotes early spread and bistability of a Warburg like phenotype. AB - We introduce an in silico model for the initial spread of an aberrant phenotype with Warburg-like overflow metabolism within a healthy homeostatic tissue in contact with a nutrient reservoir (the blood), aimed at characterizing the role of the microenvironment for aberrant growth. Accounting for cellular metabolic activity, competition for nutrients, spatial diffusion and their feedbacks on aberrant replication and death rates, we obtain a phase portrait where distinct asymptotic whole-tissue states are found upon varying the tissue-blood turnover rate and the level of blood-borne primary nutrient. Over a broad range of parameters, the spreading dynamics is bistable as random fluctuations can impact the final state of the tissue. Such a behaviour turns out to be linked to the re cycling of overflow products by non-aberrant cells. Quantitative insight on the overall emerging picture is provided by a spatially homogeneous version of the model. PMID- 28596607 TI - A loose endosperm structure of wheat seed produced under low nitrogen level promotes early germination by accelerating water uptake. AB - Water uptake is the fundamental requirement for the initiation and completion of seed germination that is a vital phase in the life cycle of seed plants. We found that seeds produced under four nitrogen levels showed significantly different germination speed. The objective of this study was to study the mechanism of rapid seed germination and explore which pathways and genes play critical roles in radicle protrusion. Anatomical data revealed that seed protein content affected endosperm structure of seeds. Moreover, scanning electron microscope maps showed that faster germinated seeds had a looser endosperm structure compared with other seeds. Subsequently, high throughout RNA-seq data were used to compare the transcriptomes of imbibed seeds with different germination speed. Gene ontology (GO) term enrichment analysis revealed that cell wall metabolism related genes significantly up-regulated in faster germinated seeds. In these genes, the top four were chitinase that had about fourfold higher expression in faster germinated seeds. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that faster germinated seeds had enhanced expression in glutathione metabolism. By combining these results, we propose a model for nitrogen fertilizer affects germination speed of wheat seed, which provide new insights into seed germination. PMID- 28596608 TI - The dynamics of resting fluctuations in the brain: metastability and its dynamical cortical core. AB - In the human brain, spontaneous activity during resting state consists of rapid transitions between functional network states over time but the underlying mechanisms are not understood. We use connectome based computational brain network modeling to reveal fundamental principles of how the human brain generates large-scale activity observable by noninvasive neuroimaging. We used structural and functional neuroimaging data to construct whole- brain models. With this novel approach, we reveal that the human brain during resting state operates at maximum metastability, i.e. in a state of maximum network switching. In addition, we investigate cortical heterogeneity across areas. Optimization of the spectral characteristics of each local brain region revealed the dynamical cortical core of the human brain, which is driving the activity of the rest of the whole brain. Brain network modelling goes beyond correlational neuroimaging analysis and reveals non-trivial network mechanisms underlying non-invasive observations. Our novel findings significantly pertain to the important role of computational connectomics in understanding principles of brain function. PMID- 28596609 TI - Land use alters arbuscular mycorrhizal fungal communities and their potential role in carbon sequestration on the Tibetan Plateau. AB - Loss of belowground biodiversity by land-use change can have a great impact on ecosystem functions, yet appropriate investigations remain rare in high-elevation Tibetan ecosystems. We compared arbuscular mycorrhizal (AM) fungal communities in arable soils with those in native forest and grassland in southeast Tibet and investigated their potential contribution to carbon sequestration. The AM fungi were abundant and diverse. AM fungal diversity was significantly higher in grassland than in forest or arable land. Significant differences in AM fungal community composition were found among different land use types. The relative abundance of operational taxonomic units (OTUs) in forest and grassland were positively related to glomalin-related soil protein (GRSP), soil organic carbon, macroaggregates, and the unprotected and physically protected carbon, while the AM fungal community in arable soils was dominated by a few OTUs which were positively linked to soil pH. Changes in GRSP content were closely related to water-stable macroaggregates and carbon storage in grassland and forest soils but not in arable soil. Given the inevitable trend toward agricultural management this study emphasizes the need to implement effective agricultural practices that can enhance AM fungal activity to maintain soil quality and carbon sequestration for the sustainable development of this fragile ecosystem. PMID- 28596610 TI - Comprehensive study of excess phosphate response reveals ethylene mediated signaling that negatively regulates plant growth and development. AB - Excess Phosphorus (P) in agriculture is causing serious environmental problems like eutrophication of lakes and rivers. Unlike the enormous information available for phosphate starvation response (P0), very few information is available for the effect of excess phosphate Pi on plants. Characterization of Excess Phosphate Response (EPiR) is essential for designing strategies to increase phosphate accumulation and tolerance. We show a significant modulation in the root developmental plasticity under the increasing supply of excess Pi. An excess supply of 20 mM Pi (P20) produces a shallow root system architecture (RSA), reduces primary root growth, root apical meristem size, and meristematic activity in Arabidopsis. The inhibition of primary root growth and development is indeterminate in nature and caused by the decrease in number of meristematic cortical cells due to EPiR. Significant changes occurred in metal nutrients level due to excess Pi supply. A comparative microarray investigation of the EPiR response reveals a modulation in ethylene biosynthesis and signaling, metal ions deficiency response, and root development related genes. We used ethylene insensitive or sensitive mutants to provide more evidence for ethylene-mediated signaling. A new role of EPiR in regulating the developmental responses of plants mediated by ethylene has been demonstrated. PMID- 28596611 TI - Design and deposition of a metal-like and admittance-matching metamaterial as an ultra-thin perfect absorber. AB - A stratiform metamaterial, comprising metal and dielectric thin films, exhibits both near-perfect antireflection and strong light extinction to function as a perfect and ultra-thin light absorber. The equivalent admittance and extinction coefficient of the metamaterial are tailored using a visual method that is based on an admittance diagram. A five-layered metamaterial was designed and deposited with a total thickness of 260 nm on a mirror to exhibit strong and wide angle absorption over wavelengths from 400 nm to 2000 nm. A seven-layered metamaterial with a total thickness of less than 200 nm was designed and deposited to have equivalent admittance around unity and an extinction coefficient that is comparable to that of metal. Such a metal-like metamaterial exhibits low reflectivity so couples most visible light energy into the films and dissipates energy with an equivalent skin depth of less than 55 nm over visible wavelengths. PMID- 28596612 TI - Alignment of liquid crystals by polymers with residual amounts of solvents. AB - The homogeneous nematic layers in liquid crystal cells with treated surfaces are affected by orientational transitions in the electric, magnetic, or temperature fields. The liquid crystal structures formed on solid or liquid surfaces find limited application in identifying the liquid-crystal states by the textures observed in polarized light. The use of surfaces prepared from polymer solutions makes it possible to significantly broaden the range of application of the liquid crystal structures. We investigate the structures with the continuous transformation of the nematic director orientation from radial to planar, which were formed by the polycarbonate surface in the presence of different residual solvents. The structures contained the disclination lines that aligned either by a plate rubbed to provide the homogeneous planar orientation in the LC layer or by a magnetic field applied along the polycarbonate film during the structure formation. The orientational transitions caused by surface treatment, temperature, and electric or magnetic fields in these structures are observed. The comparison of temperature critical distance as well as electric and magnetic coherence lengths with equilibrium length calculated from the expression for the free energy of the nematic is performed. The electro-optical characteristics of the nematic structures are obtained. PMID- 28596613 TI - Effect of climate warming on the annual terrestrial net ecosystem CO2 exchange globally in the boreal and temperate regions. AB - The net ecosystem CO2 exchange is the result of the imbalance between the assimilation process (gross primary production, GPP) and ecosystem respiration (RE). The aim of this study was to investigate temperature sensitivities of these processes and the effect of climate warming on the annual terrestrial net ecosystem CO2 exchange globally in the boreal and temperate regions. A database of 403 site-years of ecosystem flux data at 101 sites in the world was collected and analyzed. Temperature sensitivities of rates of RE and GPP were quantified with Q 10, defined as the increase of RE (or GPP) rates with a temperature rise of 10 degrees C. Results showed that on the annual time scale, the intrinsic temperature sensitivity of GPP (Q 10sG ) was higher than or equivalent to the intrinsic temperature sensitivity of RE (Q 10sR ). Q 10sG was negatively correlated to the mean annual temperature (MAT), whereas Q 10sR was independent of MAT. The analysis of the current temperature sensitivities and net ecosystem production suggested that temperature rise might enhance the CO2 sink of terrestrial ecosystems both in the boreal and temperate regions. In addition, ecosystems in these regions with different plant functional types should sequester more CO2 with climate warming. PMID- 28596614 TI - The Arctic in the Twenty-First Century: Changing Biogeochemical Linkages across a Paraglacial Landscape of Greenland. AB - The Kangerlussuaq area of southwest Greenland encompasses diverse ecological, geomorphic, and climate gradients that function over a range of spatial and temporal scales. Ecosystems range from the microbial communities on the ice sheet and moisture-stressed terrestrial vegetation (and their associated herbivores) to freshwater and oligosaline lakes. These ecosystems are linked by a dynamic glacio fluvial-aeolian geomorphic system that transports water, geological material, organic carbon and nutrients from the glacier surface to adjacent terrestrial and aquatic systems. This paraglacial system is now subject to substantial change because of rapid regional warming since 2000. Here, we describe changes in the eco- and geomorphic systems at a range of timescales and explore rapid future change in the links that integrate these systems. We highlight the importance of cross-system subsidies at the landscape scale and, importantly, how these might change in the near future as the Arctic is expected to continue to warm. PMID- 28596616 TI - Using Social Network Measures in Wildlife Disease Ecology, Epidemiology, and Management. AB - Contact networks, behavioral interactions, and shared use of space can all have important implications for the spread of disease in animals. Social networks enable the quantification of complex patterns of interactions; therefore, network analysis is becoming increasingly widespread in the study of infectious disease in animals, including wildlife. We present an introductory guide to using social network-analytical approaches in wildlife disease ecology, epidemiology, and management. We focus on providing detailed practical guidance for the use of basic descriptive network measures by suggesting the research questions to which each technique is best suited and detailing the software available for each. We also discuss how using network approaches can be used beyond the study of social contacts and across a range of spatial and temporal scales. Finally, we integrate these approaches to examine how network analysis can be used to inform the implementation and monitoring of effective disease management strategies. PMID- 28596615 TI - Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs. AB - Reporting progress against targets for international biodiversity agreements is hindered by a shortage of suitable biodiversity data. We describe a cost effective system involving Reef Life Survey citizen scientists in the systematic collection of quantitative data covering multiple phyla that can underpin numerous marine biodiversity indicators at high spatial and temporal resolution. We then summarize the findings of a continental- and decadal-scale State of the Environment assessment for rocky and coral reefs based on indicators of ecosystem state relating to fishing, ocean warming, and invasive species and describing the distribution of threatened species. Fishing impacts are widespread, whereas substantial warming-related change affected some regions between 2005 and 2015. Invasive species are concentrated near harbors in southeastern Australia, and the threatened-species index is highest for the Great Australian Bight and Tasman Sea. Our approach can be applied globally to improve reporting against biodiversity targets and enhance public and policymakers' understanding of marine biodiversity trends. PMID- 28596617 TI - Metaresearch for Evaluating Reproducibility in Ecology and Evolution. AB - Recent replication projects in other disciplines have uncovered disturbingly low levels of reproducibility, suggesting that those research literatures may contain unverifiable claims. The conditions contributing to irreproducibility in other disciplines are also present in ecology. These include a large discrepancy between the proportion of "positive" or "significant" results and the average statistical power of empirical research, incomplete reporting of sampling stopping rules and results, journal policies that discourage replication studies, and a prevailing publish-or-perish research culture that encourages questionable research practices. We argue that these conditions constitute sufficient reason to systematically evaluate the reproducibility of the evidence base in ecology and evolution. In some cases, the direct replication of ecological research is difficult because of strong temporal and spatial dependencies, so here, we propose metaresearch projects that will provide proxy measures of reproducibility. PMID- 28596618 TI - Development of a cross-cultural HPV community engagement model within Scotland. AB - OBJECTIVE: To examine cultural barriers and participant solutions regarding acceptance and uptake of the human papillomavirus (HPV) vaccine from the perspective of Black African, White-Caribbean, Arab, Indian, Bangladeshi and Pakistani young people. METHODS: In total, 40 young people from minority ethnic communities in Scotland took part in a qualitative study, involving seven focus groups and four paired interviews, to explore their views and experiences of the HPV vaccine. Using critical discursive psychology, the analysis focused on young people's accounts of barriers and enablers to information, access and uptake of the HPV vaccination programme. RESULTS: Participants suggested innovative strategies to tackle intergenerational concerns, information design and accessibility, and public health communications across diverse contexts. A cross cultural community engagement model was developed, embracing diversity and contradiction across different ethnic groups. This included four inter-related strategies: providing targeted and flexible information for young people, vaccine provision across the life-course, intergenerational information and specific cross-cultural communications. CONCLUSION: This is the first HPV cross-cultural model inductively derived from accounts of young people from different ethnic communities. We recommend public health practitioners and policymakers consider using the processes and strategies within this model to increase dialogue around public engagement, awareness and receptivity towards HPV vaccination. PMID- 28596619 TI - Signs of Change? At-Home and Breadwinner Parents' Housework and Child-Care Time. AB - We analyze American Time Use Survey (ATUS) data to examine patterns in domestic work among at-home and breadwinner parents to further gauge how time availability, relative earnings, and gender shape time use in couples with extreme differences in earnings and work hours. We find that involvement in female-typed housework is an important driver of overall housework time. It is counter-normative housework behavior by at-home fathers that shapes conclusions about how time availability, relative resources, and gender influence parents' housework. While time availability appears to shape child care in comparable ways across parents, mothers are more engaged in child care than similarly-situated fathers. Overall, our comparisons point to the importance of distinguishing among gender-normative housework tasks and accounting for differences in engagement on work and non-work days. Our results also provide a basis for assessing the social significance of growing numbers of parents in work-family roles that are not gender-normative. PMID- 28596621 TI - Brachiopods from the Silberberg Formation (Late Eocene to Early Oligocene) of Atzendorf, Central Germany. AB - Six brachiopod species, i.e., Discradisca sp., Cryptopora sp., Pliothyrina sp. cf. P. grandis (Blumenbach, 1803), Terebratulina tenuistriata (Leymerie, 1846), Rhynchonellopsis nysti (Bosquet, 1862), and Orthothyris pectinoides (von Koenen, 1894), have been identified in the Late Eocene to Early Oligocene Silberberg Formation of Atzendorf, Central Germany. The species R. nysti and O. pectinoides dominate the studied assemblage. Rhynchonellopsis is here transferred from the family Cancellothyrididae to Chlidonophoridae because it has a loop without united crural processes. Orthothyris pectinoides has a brachial skeleton of chlidonophorid type, but its transverse band is incomplete. In species composition, the assemblage from Atzendorf differs from other Paleogene and Neogene European assemblages by the absence of megathyridids and dominance of chlidonophorids, indicating a relatively deep environment. PMID- 28596620 TI - Respiratory oxygen consumption in the seagrass Zostera marina varies on a diel basis and is partly affected by light. AB - The seagrass Zostera marina is an important marine ecosystem engineer, greatly influencing oxygen and carbon fluctuations in temperate coastal areas. Although photosynthetically driven gas fluxes are well studied, the impact of the plant's mitochondrial respiration on overall CO2 and O2 fluxes in marine vegetated areas is not yet understood. Likewise, the gene expression in relation to the respiratory pathway has not been well analyzed in seagrasses. This study uses a combined approach, studying respiratory oxygen consumption rates in darkness simultaneously with changes in gene expression, with the aim of examining how respiratory oxygen consumption fluctuates on a diel basis. Measurements were first made in a field study where samples were taken directly from the ocean to the laboratory for estimations of respiratory rates. This was followed by a laboratory study where measurements of respiration and expression of genes known to be involved in mitochondrial respiration were conducted for 5 days under light conditions mimicking natural summer light (i.e., 15 h of light and 9 h of darkness), followed by 3 days of constant darkness to detect the presence of a potential circadian clock. In the field study, there was a clear diel variation in respiratory oxygen consumption with the highest rates in the late evening and at night (0.766 and 0.869 umol O2 m-2 s-1, respectively). These repetitive diel patterns were not seen in the laboratory, where water conditions (temperature, pH, and oxygen) showed minor fluctuations and only light varied. The gene expression analysis did not give clear evidence on drivers behind the respiratory fluxes; however, expression levels of the selected genes generally increased when the seagrass was kept in constant darkness. While light may influence mitochondrial respiratory fluxes, it appears that other environmental factors (e.g., temperature, pH, or oxygen) could be of significance too. As seagrasses substantially alter the proportions of both oxygen and inorganic carbon in the water column and respiration is a great driver of these alterations, we propose that acknowledging the presence of respiratory fluctuations in nature should be considered when estimating coastal carbon budgets. As dark respiration in field at midnight was approximately doubled from that of midday, great over-, or underestimations of the respiratory carbon dioxide release from seagrasses could be made if values are just obtained at one specific time point and considered constant. PMID- 28596622 TI - The trace fossil Lepidenteron lewesiensis: a taphonomic window on diversity of Late Cretaceous fishes. AB - The trace fossil Lepidenteron lewesiensis (Mantell 1822) provides an exceptional taphonomic window to diversity of fishes as shown for the Upper Cretaceous of Poland, in the Middle Turonian-Lower Maastrichtian deposits of the Opole Trough, Miechow Trough, Mazury-Podlasie Homocline, and SE part of the Border Synclinorium. Lepidenteron lewesiensis is an unbranched burrow lined with small fish scales and bones, without a constructed wall. It contains scales, vertebrae, and bones of the head belonging to ten taxa of teleostean fishes: two undetermined teleosteans, six undetermined Clupeocephala, one Dercetidae, and one undetermined euteleostean. The preservation of fish remains suggests that fishes were pulled down into the burrow by an animal, probably by eunicid polychaetes. PMID- 28596623 TI - Fish-otoliths from the marine-brackish water transition from the Middle Miocene of the Belgrade area, Serbia. AB - We describe here the first fossil otoliths from the Middle Miocene (Badenian and Sarmatian) of Belgrade, Serbia. They were obtained from Lower Badenian outcrops at Slanci and from upper Badenian and Sarmatian sediments recovered from four shallow wells near the village of Barajevo. The otoliths from the Lower Badenian of Slanci represent fishes typical for an open marine environment, characterized primarily by the mesopelagic families Myctophidae and Bregmacerotidae, a faunal composition that is also well known from other time equivalent locations in the Central Paratethys. The upper Badenian and Sarmatian composition of the fish fauna, in contrast, is dominated by otoliths of the family Gobiidae, indicating a sharp environmental shift from open marine to shallow water, probably slightly brackish environments, which is also confirmed by the faunal composition of mollusks, foraminifera, and ostracods. Most of the gobiid genera identified in the samples from Barajevo represent small fishes of the so-called sand gobies with Ponto-Caspian affinities, such as Economidichthys, Knipowitschia, or Pomatoschistus, or are entirely endemic to the Ponto-Caspian Basin, such as Hyrcanogobius. Another group of endemic Ponto-Caspian gobies is the first fossil record interpreted to represent the genus Proterorhinus. These and other finds currently being investigated indicate that the origin of the extant, rich, endemic gobiid fauna of the Ponto-Caspian Basin dates back to a crucial time in the development of Paratethys during the Middle Miocene when it segregated from the Mediterranean with the onset of phases of low salinity in the basin. In addition, we briefly discuss the distribution of certain gobiid species during Late Badenian and Sarmatian as it begins to emerge. The following new taxa are described based on fossil otoliths: Hyrcanogobius hesperis n.sp. and Proterorhinus vasilievae n.sp. PMID- 28596624 TI - Late Cretaceous crinoids (Echinodermata) from the southwestern margin of the Holy Cross Mts. (southern Poland) and phylogenetic relationships among bourgueticrinids. AB - A systematic account of crinoids from the Upper Coniacian-Lower Campanian of the southwestern margin of the Holy Cross Mountains in southern Poland is presented. Seven crinoid taxa [Marsupites testudinarius (von Schlotheim), Bourgueticrinus ellipticus (Miller), Bourgueticrinus sp., I.? granosus Valette, Isocrinus? sp., Nielsenicrinus carinatus Roemer and Austinocrinus bicoronatus (von Hagenow)] are described and illustrated. The new material from Poland extends down the stratigraphic range of Austinocrinus bicoronatus to the Lower Campanian. Morphometric data support that Bourgueticrinus ellipicus and B.? suedicus are conspecific. Taphonomy and paleoecology of recorded crinoid assemblages are discussed. Phylogeny of Cretaceous bourgueticrinids is also revisited. PMID- 28596625 TI - Antecedents and near-term consequences for interdisciplinary dissertators. AB - Given the complexity of questions studied by academicians, institutions are increasingly encouraging interdisciplinary research to tackle these problems; however, neither the individual-level pathways leading to the pursuit of interdisciplinary research nor the resulting market outcomes have been closely examined. In this study, we focus attention on the individuals who complete interdisciplinary dissertations to ask "who are they and how do they fare after earning the PhD?" Since interdisciplinary research is known to be relatively risky among academics, we examine demographic variables that are known to be associated in other contexts with risk-taking before considering whether interdisciplinarians' outcomes are different upon graduating. First among our three main findings, students whose fathers earned a college degree demonstrated a 1.3% higher probability of pursuing interdisciplinary research. Second, the probability that non-citizens pursue interdisciplinary dissertation work is 4.6% higher when compared with US citizens. Third, individuals who complete an interdisciplinary dissertation tend to earn approximately 2% less in the year after graduation; however, mediation analyses show that the decision to become a postdoctoral researcher accounts for the apparent salary penalty. Our findings shed light on the antecedents and near-term consequences for individuals who complete interdisciplinary dissertations and contribute to broader policy debates concerning supports for academic career paths. PMID- 28596626 TI - A theoretical model of the relationship between the h-index and other simple citation indicators. AB - Of the existing theoretical formulas for the h-index, those recently suggested by Burrell (J Informetr 7:774-783, 2013b) and by Bertoli-Barsotti and Lando (J Informetr 9(4):762-776, 2015) have proved very effective in estimating the actual value of the h-index Hirsch (Proc Natl Acad Sci USA 102:16569-16572, 2005), at least at the level of the individual scientist. These approaches lead (or may lead) to two slightly different formulas, being based, respectively, on a "standard" and a "shifted" version of the geometric distribution. In this paper, we review the genesis of these two formulas-which we shall call the "basic" and "improved" Lambert-W formula for the h-index-and compare their effectiveness with that of a number of instances taken from the well-known Glanzel-Schubert class of models for the h-index (based, instead, on a Paretian model) by means of an empirical study. All the formulas considered in the comparison are "ready-to use", i.e., functions of simple citation indicators such as: the total number of publications; the total number of citations; the total number of cited paper; the number of citations of the most cited paper. The empirical study is based on citation data obtained from two different sets of journals belonging to two different scientific fields: more specifically, 231 journals from the area of "Statistics and Mathematical Methods" and 100 journals from the area of "Economics, Econometrics and Finance", totaling almost 100,000 and 20,000 publications, respectively. The citation data refer to different publication/citation time windows, different types of "citable" documents, and alternative approaches to the analysis of the citation process ("prospective" and "retrospective"). We conclude that, especially in its improved version, the Lambert-W formula for the h-index provides a quite robust and effective ready-to use rule that should be preferred to other known formulas if one's goal is (simply) to derive a reliable estimate of the h-index. PMID- 28596627 TI - Data sets for author name disambiguation: an empirical analysis and a new resource. AB - Data sets of publication meta data with manually disambiguated author names play an important role in current author name disambiguation (AND) research. We review the most important data sets used so far, and compare their respective advantages and shortcomings. From the results of this review, we derive a set of general requirements to future AND data sets. These include both trivial requirements, like absence of errors and preservation of author order, and more substantial ones, like full disambiguation and adequate representation of publications with a small number of authors and highly variable author names. On the basis of these requirements, we create and make publicly available a new AND data set, SCAD zbMATH. Both the quantitative analysis of this data set and the results of our initial AND experiments with a naive baseline algorithm show the SCAD-zbMATH data set to be considerably different from existing ones. We consider it a useful new resource that will challenge the state of the art in AND and benefit the AND research community. PMID- 28596628 TI - Identification of successful mentoring communities using network-based analysis of mentor-mentee relationships across Nobel laureates. AB - Skills underlying scientific innovation and discovery generally develop within an academic community, often beginning with a graduate mentor's laboratory. In this paper, a network analysis of doctoral student-dissertation advisor relationships in The Academic Family Tree indicates the pattern of Nobel laureate mentoring relationships is non-random. Nobel laureates had a greater number of Nobel laureate ancestors, descendants, mentees/grandmentees, and local academic family, supporting the notion that assortative processes occur in the selection of mentors and mentees. Subnetworks composed entirely of Nobel laureates extended across as many as four generations. Several successful mentoring communities in high-level science were identified, as measured by number of Nobel laureates within the community. These communities centered on Cambridge University in the latter nineteenth century and Columbia University in the early twentieth century. The current practice of building web-based academic networks, extended to include a wider variety of measures of academic success, would allow for the identification of modern successful scientific communities and should be promoted. PMID- 28596629 TI - Letter to the Editor: About the quality and impact of scientific articles. AB - It is argued that counting the total number of times a scientific article is cited by others, does neither result in a proxy for its cognitive impact nor for its quality. One would have to distinguish at least substitutable and fundamental references. A supposed correlation between peer review assessments and citation counts is conceptually problematic, because peer review includes objective as well as subjective considerations (convictions). With refined methods, however, a differential citation analysis might be able in the future to answer if a given article did or did not have positive cognitive impact on subsequent research. PMID- 28596630 TI - How to allocate limited healthcare resources: Lessons from the introduction of antiretroviral therapy in rural Mozambique. AB - Proper allocation of limited healthcare resources is a challenging task for policymakers in developing countries. Allocation of and access to these resources typically varies based on how need is defined, thus determining how individuals access and acquire healthcare. Using the introduction of antiretroviral therapy in southern Mozambique as an example, we examine alternative definitions of need for rural populations and how they might impact the allocation of this vital health service. Our results show that how need is defined matters when allocating limited healthcare resources and the use of need-based metrics can help ensure more optimal distribution of services. PMID- 28596631 TI - Identification of uranium signatures relevant for nuclear safeguards and forensics. AB - The paper describes the applicability of different characteristics (signatures) in nuclear safeguards and forensics for assessment of uranium material provenance in terms of production process. The study follows a uranium ore concentrate production from an ore to a U3O8 product. It turned out that rare-earth elemental pattern, radiochronometry (age of ore body and material production date), sulphur and organic impurities are useful to find out the origin or history of the material, while certain trace-elements and isotopics of Pb or Sr were found to be inconclusive. The results will be important to understand the signatures in nuclear safeguards and forensics. PMID- 28596632 TI - 'Of course we are on Facebook': Use and non-use of social media among Swedish and Norwegian politicians. AB - While plenty of research has provided important insights into the uses of the Internet by politicians during elections, a relatively scarce amount of work has looked into these uses outside of such parliamentary events. This article seeks to remedy this lack of research by presenting a study on the 'routine' uses of two of the currently most popular social media services - Facebook and Twitter. Focusing on politicians elected to the national parliaments of Norway and Sweden, the article employs novel methodologies for data collection and statistical analyses in order to provide an overarching, structural view of the day-to-day social media practices of Scandinavian politicians. Findings indicate that use levels are rather low for both services - the median amount of tweets sent and messages posted on Facebook is close to one per day. Further analyses reveal that the most active politicians could be labelled as 'underdogs', as they are more likely to be younger, in opposition and out of the political limelight. PMID- 28596633 TI - Beyond Hybrid Licenses-Strategies for Post Patent Expiration Payments in the United States1. PMID- 28596634 TI - A three-step reconstruction method for fluorescence molecular tomography based on compressive sensing. AB - Fluorescence molecular tomography (FMT) is a promising tool for real time in vivo quantification of neurotransmission (NT) as we pursue in our BRAIN initiative effort. However, the acquired image data are noisy and the reconstruction problem is ill-posed. Further, while spatial sparsity of the NT effects could be exploited, traditional compressive-sensing methods cannot be directly applied as the system matrix in FMT is highly coherent. To overcome these issues, we propose and assess a three-step reconstruction method. First, truncated singular value decomposition is applied on the data to reduce matrix coherence. The resultant image data are input to a homotopy-based reconstruction strategy that exploits sparsity via l1 regularization. The reconstructed image is then input to a maximum-likelihood expectation maximization (MLEM) algorithm that retains the sparseness of the input estimate and improves upon the quantitation by accurate Poisson noise modeling. The proposed reconstruction method was evaluated in a three-dimensional simulated setup with fluorescent sources in a cuboidal scattering medium with optical properties simulating human brain cortex (reduced scattering coefficient: 9.2 cm-1, absorption coefficient: 0.1 cm-1) and tomographic measurements made using pixelated detectors. In different experiments, fluorescent sources of varying size and intensity were simulated. The proposed reconstruction method provided accurate estimates of the fluorescent source intensity, with a 20% lower root mean square error on average compared to the pure-homotopy method for all considered source intensities and sizes. Further, compared with conventional l2 regularized algorithm, overall, the proposed method reconstructed substantially more accurate fluorescence distribution. The proposed method shows considerable promise and will be tested using more realistic simulations and experimental setups. PMID- 28596635 TI - An Investigation of Low-Dose 3D Scout Scans for Computed Tomography. AB - PURPOSE: Commonly 2D scouts or topograms are used prior to CT scan acquisition. However, low-dose 3D scouts could potentially provide additional information for more effective patient positioning and selection of acquisition protocols. We propose using model-based iterative reconstruction to reconstruct low exposure tomographic data to maintain image quality in both low-dose 3D scouts and reprojected topograms based on those 3D scouts. METHODS: We performed tomographic acquisitions on a CBCT test-bench using a range of exposure settings from 16.6 to 231.9 total mAs. Both an anthropomorphic phantom and a 32 cm CTDI phantom were scanned. The penalized-likelihood reconstructions were made using Matlab and CUDA libraries and reconstruction parameters were tuned to determine the best regularization strength and delta parameter. RMS error between reconstructions and the highest exposure reconstruction were computed, and CTDIW values were reported for each exposure setting. RMS error for reprojected topograms were also computed. RESULTS: We find that we are able to produce low-dose (0.417 mGy) 3D scouts that show high-contrast and large anatomical features while maintaining the ability to produce traditional topograms. CONCLUSIONS: We demonstrated that iterative reconstruction can mitigate noise in very low exposure CT acquisitions to enable 3D CT scout. Such additional 3D information may lead to improved protocols for patient positioning and acquisition refinements as well as a number of advanced dose reduction strategies that require localization of anatomical features and quantities that are not provided by simple 2D topograms. PMID- 28596636 TI - No-gold-standard evaluation of image-acquisition methods using patient data. AB - Several new and improved modalities, scanners, and protocols, together referred to as image-acquisition methods (IAMs), are being developed to provide reliable quantitative imaging. Objective evaluation of these IAMs on the clinically relevant quantitative tasks is highly desirable. Such evaluation is most reliable and clinically decisive when performed with patient data, but that requires the availability of a gold standard, which is often rare. While no-gold-standard (NGS) techniques have been developed to clinically evaluate quantitative imaging methods, these techniques require that each of the patients be scanned using all the IAMs, which is expensive, time consuming, and could lead to increased radiation dose. A more clinically practical scenario is where different set of patients are scanned using different IAMs. We have developed an NGS technique that uses patient data where different patient sets are imaged using different IAMs to compare the different IAMs. The technique posits a linear relationship, characterized by a slope, bias, and noise standard-deviation term, between the true and measured quantitative values. Under the assumption that the true quantitative values have been sampled from a unimodal distribution, a maximum likelihood procedure was developed that estimates these linear relationship parameters for the different IAMs. Figures of merit can be estimated using these linear relationship parameters to evaluate the IAMs on the basis of accuracy, precision, and overall reliability. The proposed technique has several potential applications such as in protocol optimization, quantifying difference in system performance, and system harmonization using patient data. PMID- 28596638 TI - Policy entrepreneurship in UK central government: The behavioural insights team and the use of randomized controlled trials. AB - What factors explain the success of the UK Cabinet Office's Behavioural Insights Team? To answer this question, this article applies insights from organizational theory, particularly accounts of change agents. Change agents are able-with senior sponsorship-to foster innovation by determination and skill: they win allies and circumvent more traditional bureaucratic procedures. Although Behavioural Insights Team is a change agent-maybe even a skunkworks unit-not all the facilitating factors identified in the literature apply in this central government context. Key factors are its willingness to work in a non-hierarchical way, skills at forming alliances, and the ability to form good relationships with expert audiences. It has been able to promote a more entrepreneurial approach to government by using randomized controlled trials as a robust method of policy evaluation. PMID- 28596637 TI - Wild chimpanzees' use of single and combined vocal and gestural signals. AB - ABSTRACT: We describe the individual and combined use of vocalizations and gestures in wild chimpanzees. The rate of gesturing peaked in infancy and, with the exception of the alpha male, decreased again in older age groups, while vocal signals showed the opposite pattern. Although gesture-vocal combinations were relatively rare, they were consistently found in all age groups, especially during affiliative and agonistic interactions. Within behavioural contexts rank (excluding alpha-rank) had no effect on the rate of male chimpanzees' use of vocal or gestural signals and only a small effect on their use of combination signals. The alpha male was an outlier, however, both as a prolific user of gestures and recipient of high levels of vocal and gesture-vocal signals. Persistence in signal use varied with signal type: chimpanzees persisted in use of gestures and gesture-vocal combinations after failure, but where their vocal signals failed they tended to add gestural signals to produce gesture-vocal combinations. Overall, chimpanzees employed signals with a sensitivity to the public/private nature of information, by adjusting their use of signal types according to social context and by taking into account potential out-of-sight audiences. We discuss these findings in relation to the various socio-ecological challenges that chimpanzees are exposed to in their natural forest habitats and the current discussion of multimodal communication in great apes. SIGNIFICANCE STATEMENT: All animal communication combines different types of signals, including vocalizations, facial expressions, and gestures. However, the study of primate communication has typically focused on the use of signal types in isolation. As a result, we know little on how primates use the full repertoire of signals available to them. Here we present a systematic study on the individual and combined use of gestures and vocalizations in wild chimpanzees. We find that gesturing peaks in infancy and decreases in older age, while vocal signals show the opposite distribution, and patterns of persistence after failure suggest that gestural and vocal signals may encode different types of information. Overall, chimpanzees employed signals with a sensitivity to the public/private nature of information, by adjusting their use of signal types according to social context and by taking into account potential out-of-sight audiences. PMID- 28596639 TI - How does single party dominance influence civil society organisations' engagement strategies? Exploratory analysis of participative mainstreaming in a 'regional' European polity. AB - A raft of United Nations Treaties, European Union Directives and domestic laws oblige governments in 180 + countries to apply the Participative Democratic Model of mainstreaming equalities to public administration by involving those targeted by equality initiatives at all stages in their design and delivery. Notwithstanding Participative Democratic Model's deeply political nature, extant work has overlooked how governing party turnover influences civil society organisations' (CSOs) strategies. Here, this lacuna is addressed using a negative 'extreme case study' research design involving qualitative accounts from civil society organisations in Wales, a 'regional' European polity characterised by one party dominance. The findings reveal how the absence of turnover distorts the Participative Democratic Model in relation to diverse factors including: strategic bridging, extraparliamentary politics, cognitive locks and party institutionalisation. Inter alia, the wider contribution of this analysis lies in showing the importance of turnover to effective engagement, the 'pathologies' associated with one-party dominance and the need for adaptive civil society strategies tailored to prevailing electoral politics and governing party turnover in liberal democracies. PMID- 28596640 TI - Working with layers: The governance and regulation of healthcare quality in an institutionally layered system. AB - Institutional arrangements used to steer public policies have increasingly become layered. Inspired by the literature on institutional layering and institutional work, this paper aims to make a contribution to our understanding of institutional layering. We do so by studying an interesting case of layering: the Dutch hospital sector. We focus on the actors responsible for the internal governance (Board of Directors and Supervisory Boards) and the external regulation (the Healthcare Inspectorate) of hospitals. In the paper, we explore the institutional work of these actors, more specifically how institutional work results from and is influenced by institutional layering and how this in turn influences the institutional makeup of both healthcare organizations and their institutional context. Our approach allowed us to see that layering changes the activities of actors in the public sector, can be used to strengthen one's position but also presents actors with new struggles, which they in turn can try to overcome by relating and using the institutionally layered context. Layering and institutional work are therefore in continuous interaction. Combining institutional layering with a focus on the lived experiences of actors and their institutional work makes it possible to move into the layered arrangement and better understand its consequences. PMID- 28596643 TI - Platelets: Pathophysiological Relevance and Therapeutic Potential. PMID- 28596641 TI - Gene Electrotransfer of Plasmid-Encoding IL-12 Recruits the M1 Macrophages and Antigen-Presenting Cells Inducing the Eradication of Aggressive B16F10 Murine Melanoma. AB - Cancer immunotherapy is currently one of the leading approaches in cancer treatment. Gene electrotransfer of plasmids encoding interleukin 12 (IL-12) into the cells leads to the production of IL-12, which drives immune cell polarization to an antitumoral response. One of the cell types that shows great promise in targeting tumor cells under the influence of IL-12 cytokine milieu is that of macrophages. Therefore, the aim of this study was to evaluate gene electrotransfer of antibiotic resistance-free plasmid DNA-encoding murine IL-12 (mIL-12) in mice bearing aggressive B16F10 murine melanoma. IL-12 electrotransfer resulted in the complete long-term eradication of the tumors. Serum mIL-12 and murine interferon gamma (mIFNgamma) were increased after IL-12 gene electrotransfer. Further on, hematoxylin and eosin (HE) staining showed increased infiltration of immune cells that lasted from day 4 until day 14. Immunohistochemistry (IHC) staining of F4/80, MHCII, and CD11c showed higher positive staining in the IL-12 gene electrotransfer group than in the control groups. Immune cell infiltration into the tumors and the high density of MHCII- and CD11c-positive cells suggest an antitumor polarization of macrophages and the presence of antigen-presenting cells that contributes to the important antitumor effectiveness of IL-12. PMID- 28596642 TI - A Double-Blinded Randomized Study Investigating a Possible Anti-Inflammatory Effect of Saxagliptin versus Placebo as Add-On Therapy in Patients with Both Type 2 Diabetes And Stable Coronary Artery Disease. AB - BACKGROUND: Promising results regarding potential anti-inflammatory and antiatherosclerotic effects of gliptins have been reported. Our aim was to investigate whether saxagliptin treatment modifies expression of inflammatory markers, primarily in peripheral blood mononuclear cells (PBMCs) and in circulating leukocytes in patients with stable coronary artery disease (CAD) and T2DM. METHODS: Patients (n = 12) were randomized to saxagliptin 5 mg daily or placebo for 3 months. Samples were taken at baseline and end of study in fasting state prior to intake of medications. PBMCs were isolated and cryopreserved at 150 degrees C until ex vivo exposed to 1 ng/mL of lipopolysaccharide (LPS) for 4 hours. Gene expression was performed with custom-designed TaqMan(r) Arrays and relative quantification by real-time PCR (RT-qPCR). RESULTS: HbA1c was reduced in the saxagliptin-treated group compared to that in the change with placebo (p = 0.042). In unstimulated PBMCs and in circulating leukocytes, we observed a significant increase in IL-10 expression in the saxagliptin group (p = 0.043, both), significantly different from that in the placebo (p = 0.009 and p = 0.032, resp.). No between group differences in changes were observed in any of the selected proinflammatory markers. CONCLUSION: In our small cohort of patients with combined T2DM and CAD, a possible anti-inflammatory effect of saxagliptin, observed in the present study by upregulation of IL-10 in leukocytes, needs to be confirmed in larger studies. PMID- 28596644 TI - Highlights of Multiple Myeloma at the Annual Meeting of American Society of Hematology, 2016. AB - This review discusses the landmark studies in the field of multiple myeloma (MM) which were presented at American society of hematology annual meeting, 2016. There were contrary results from two large phase III trials (one from US and one from Europe) that evaluated the role of additional interventions like tandem autologous transplant (ASCT) and consolidation after induction therapy followed by ASCT in newly diagnosed MM (NDMM) patients, but there were critical differences between the two studies. Novel agents like carfilzomib and ixazomib proved to be of benefit when used as induction and post ASCT consolidation and maintenance in NDMM. The early data on subcutaneous administration of daratumumab (DARA) looked promising. The high rate of minimal residual disease negativity after using DARA even in relapsed/refractory MM (RRMM) setting reinforces the benefit of targeting CD38. The responses seen with venetoclax in RRMM with t(11;14)(high BCL-2, low BCL-XL and MCL-1) and selinexor in penta-refractory myeloma which fulfills the FDA category of unmet need, opens up newer options for these patients. BCMA CAR-T infusion shows encouraging results in advanced refractory myeloma patients. PMID- 28596645 TI - Platelet Derived Biomaterials for Therapeutic Use: Review of Technical Aspects. AB - Whole blood is composed of both cellular and plasma components, providing a rich source of therapeutic products. Of late, platelet derived biomaterial (platelet rich plasma) consisting of plasma proteins and platelets are increasingly being used for various indications. Protocols for preparation and nomenclature of this biomaterial vary widely amongst authors and are often not well defined. Additionally, they are not uniformly documented in the literature, making results difficult to compare or replicate. In this paper we review the evolution and type of these products available for clinical use. Further we will discuss the scientific rational and technical aspects in preparation of these platelet biomaterials in order to administer them in various fields of medicine. PMID- 28596646 TI - Evaluation of Bone Marrow Microvessel Density in Patients with Aplastic Anemia. AB - Bone marrow microenvironment plays a crucial role in the growth of hemopoietic cells and bone marrow function, which in turn depends on an intact microvasculature. Our study assesses the microvessel density (MVD) in the bone marrow of aplastic anemia (AA) patients, compares with MVD of controls and MVD among the different types of AA. Bone marrow specimens from 60 patients with AA and 17 controls were studied. There were 33 patients with non severe AA (NSAA), 12 patients with severe AA (SAA) and 15 patients with very severe AA (VSAA). MVD was calculated on sections stained immunohistochemically for CD34. The mean bone marrow MVD in AA group was 1.28 +/- 0.36, being significantly lower than that in control group (6.80 +/- 1.59, p < 0.001). MVD of SAA and NSAA patients were 1.16 +/- 0.35 and 1.49 +/- 0.27, respectively, being significantly different (p = 0.003). MVD of VSAA was 0.93 +/- 0.25 and the difference with NSAA is significant, however there was no significant difference between SAA and VSAA. Bone marrow MVD is low in AA patients and is likely to have a role in pathophysiology of bone marrow failure. Proangiogenic agents together with specific therapy might accelerate the recovery of hematopoiesis in AA patients. PMID- 28596647 TI - Audio Vestibular Status in CML Patients on Imatinib Mesylate with Review of Literature. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm occasionally presenting with features of leukostasis as primary symptoms. Hearing loss is occasionally reported in CML patients. Further whether Imatinib mesylate has any effect on vestibular functions is not known. We conducted a preliminary study to assess hearing pattern in patients with CML on long term TKI therapy. This is a single center, cross sectional study from northern-India. Patients of CML who were on regular Tyrosine kinase inhibitors (TKI) therapy for at least 6 months underwent audiovestibular evaluation . A total of 44 CML patients on TKI therapy were assessed over a period of 6 months. The median age of the patients was 41 years, the mean duration of TKI therapy was 36 months. Four patients were found to have otological disorder clinically. On pure tone audiometry of 88 ears normal hearing pattern were found with at low and mid frequencies. There was a down sloping type of curve at higher frequencies in PTA in most of the patients. Cold caloric tests in 42 patients were found as equal response in both ears. We conclude from this preliminary study that there are no audio vestibular dysfunctions amongst patients of CML on TKI. It's a negative study wherein we have ruled out any auditory deficits secondary to Imatinib therapy. Further studies are required to evaluate the audiometric profile in CML patients before Imatinib therapy and to be compared with the patients already on Imatinib in a large cohort. PMID- 28596648 TI - The Impact of Mean Platelet Volume (MPV) and JAK-2 Mutation on Thrombosis in Chronic Myeloproliferative Diseases. AB - Thrombosis and bleeding are the main complications of chronic myeloproliferative diseases. Mean platelet volume (MPV) is an important indicator of the platelet activation. The aim of the present study was to assess the interrelationships between MPV, JAK-2 gene mutation and thromboembolic events in patients with ET and PV. Patients with ET (n = 60) and PV (n = 46) were compared to the secondary erythrocytosis group (n = 19); and a control group of age and sex matched healthy volunteers (n = 52). Besides demographic, clinical and laboratory data; thrombotic and hemorrhagic events were recorded for each patient. Platelet counts, MPV and JAK2 mutations were studied; and their relation with thromboembolic events were investigated using SPSS program for statistical analysis. There was no significant difference between groups regarding age (p = 0.188). Mean platelet count was significantly higher in ET group than other groups (p < 0.0001). Mean platelet count in PV group was significantly higher than control (p < 0.0001) and secondary erythrocytosis groups (p < 0.0001). In the ET group, MPV values were significantly lower than the control group and PV group. In the ET group, those with thromboembolia had lower platelet counts. There was no relation between MPV and thromboembolic event rate in PV, ET and secondary erithrocytosis groups; while no event was recorded in the control group. There was no relation between thromboembolic event rate and JAK 2 mutation. The association of JAK-2 mutation and high MPV especially in ET and PV groups does not contribute to the thromboembolic events. PMID- 28596649 TI - Use of Surrogate Samples to Monitor pH During High dose Methotrexate Therapy. AB - High dose methotrexate (Mtx) therapy is commonly used in hemato-oncological practice. Alkalization of urine is a part of high dose methotrexate therapy for preventing crystallization in urine to avert renal insufficiency. Alkalization is monitored by urine pH at regular intervals. Oral pH has occasionally been used as a surrogate for oral mucositis. To compare and correlate pH of various body secretions (venous blood, oral salivary, lacrimal and urine) among patients undergoing alkalization with intravenous sodium bicarbonate during high dose methotrexate therapy. A prospective single center study in patients with hematological malignancies receiving Mtx > 1.5 g/m2 over 4-24 h. Patients were assessed for pH (from all 4 body fluids) at regular time intervals (q8 h) starting 6 h-prior and 48 h-post initiation of Mtx therapy. Mean pH of urine/oral was compared to surrogate samples. The mean oral pH was 6.9 (SD 0.65), the mean urinary pH was 7.59 (SD 0.773) the mean pH by venous blood gas analysis (venous pH) was 7.388 (SD 0.059), the mean lacrimal pH was 7.4536 (SD 0.527). Repeated measures ANOVA suggests that pH of different body fluids differ and cannot be used interchangeably [F (2.417, 309.361) = 54.89, p < 0.0005]. There was no statistically significant correlation between any other pair of assessed body fluids. On paired t test only the means of venous pH and urinary pH did not differ statistically (p 0.056). Venous pH significantly correlated with urinary pH but the strength of correlation was weak (r 0.184; p 0.037). pH of different body fluids is statistically different even when sampled simultaneously thus the pH of one fluid cannot be substituted for other. Based on this study we cannot substitute urinary pH with any other body fluids presently in patients undergoing high dose methotrexate and alkalization except in rare circumstances when venous pH can be used as a poor surrogate for urinary pH in situations where urinary pH cannot be monitored due to any reason. There was no surrogate for oral pH among the studied body fluids. PMID- 28596650 TI - Role of Plasma Fibrinogen in Diagnosis and Prediction of Short Term Outcome in Neonatal Sepsis. AB - The study was carried out to determine the role of plasma fibrinogen in diagnosis of neonatal sepsis and to evaluate its role in predicting short term outcome. Sixty five neonates with clinical features suggestive of neonatal sepsis were included in this study. Seventy five neonates served as the control group. Plasma fibrinogen, prothrombin time, activated partial thromboplastin time and platelet counts were performed in all the neonates. Cut-off value of plasma fibrinogen for diagnosis of neonatal sepsis was determined with the help of receiver operating characteristic curve. Plasma fibrinogen level was found to be significantly higher among neonates with sepsis when compared to neonates in control group (p < 0.0001). It had sensitivity of 70.8 %, specificity of 82.7 %, positive predictive value (PPV) of 72.3 % and negative predictive value (NPV) of 81.6 % for diagnosis of neonatal sepsis at cut-off value of 301.90 mg/dL. When neonates with septic shock and/or disseminated intravascular coagulation (DIC) were excluded from study population, sensitivity and NPV rose to 91.9 % and 95.4 % at the same cut off value while specificity and PPV remained the same. Lower level of plasma fibrinogen was detected in neonates with septic shock and/or DIC (p < 0.0001) and in neonates who died (p < 0.0001). Hence plasma fibrinogen can serve as an effective tool in diagnostic work up of neonatal sepsis as well as in assessing development of complications and outcome. PMID- 28596651 TI - Bacteremia During Early Post-allogeneic Hematopoietic Stem Cell Transplantation Period: A Single Center Experience. AB - Bacteremia is a significant complication of allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to study bacteremia occurring during early post transplant period at Bone Marrow Transplantation Unit of Ain Shams University regarding its risk factors and impact on survival. Patients performing allogeneic HSCT were followed up for occurrence of bacteremia. Survival status was assessed at 180 days post-transplant. Bacteremia occurred in 53.3 % of patients. On univariate analysis, CD34 +ve cell dose (P = 0.004), duration of neutropenia (P = 0.018), time interval between day of stem cell infusion and day of neutrophil engraftment (P = 0.043) and > 1 apheresis days (P = 0.040) were associated with higher rates of bacteremia. On multivariate analysis, CD34 +ve cell dose (P = 0.002) and apheresis day number (P = 0.038) remained significant. There was significant difference between patients who developed bacteremia and those who did not regarding overall survival (OS) (P = 0.042). Patients developing bacteremia caused by Gram negative bacteria (GNB) had lower OS than Gram positive bacteria (GPB) (P < 0.001). In conclusion, stem cell dose and apheresis day number influence bacteremia risk. Also, Gram negative bacteremia has negative impact on allogeneic transplant recipient survival rates. PMID- 28596652 TI - Changing Trends in the Use of Granulocyte Transfusions in Neutropenic Children with Sepsis in India. AB - We present our data on granulocyte transfusions in children undergoing treatment for cancer and HSCT at our centre and their changing indications. In this retrospective observational analysis of children who received granulocytes from 2007 to 2015, we divided children receiving granulocytes into two groups-the first from January 2007 till December 2013 and the second from January 2014 till December 2015. This division is based on the change in our policy to use granulocytes within 48 h of septicemia as the incidence of drug resistant bacterial strains had increased at our centre. Data on 72 children with febrile neutropenia treated with 230 granulocyte infusions was analyzed. From 2007 to 2013 (n = 48/72), 27/48 (56 %) had culture proven sepsis of which 14 (51 %) were carbapenem resistant gram negative bacilli. 11 of the 27 children survived the crisis (41 %). We then changed our policy to transfuse granulocytes early during sepsis. From 2014 to 2015 (n = 24/72) 22 patients had culture proven sepsis (91 %) of which 20 had carbapenem resistant gram negative bacilli. 12/22 (54 %) with culture proven sepsis survived the episode. The survival rate improved from 41 % in first group to 54 % after early intervention with granulocytes (P value 0.0347). Despite the increased incidence of resistant bacteria during the period of 2014-2015, early use of granulocytes improved survival rate from 41 to 54 %. This intervention cannot be taken in isolation and needs to be offered early in parallel with appropriate antibiotics. PMID- 28596653 TI - Neonatal Outcomes of Pregnancy with Immune Thrombocytopenia. AB - Neonates born to mothers with immune thrombocytopenia (ITP) have an increased risk for neonatal thrombocytopenia and hemorrhagic complications. The aim of this study was to determine the maternal and neonatal outcomes of pregnancies with ITP and also to identify risk factors that predicts neonatal thrombocytopenia. We performed a retrospective analysis of 40 pregnancies with ITP and their 40 neonates. Among the 40 neonates, thrombocytopenia (platelet count of less than 150 * 109/L) was detected in 15 neonates (37.5 %) whom 8 of them had severe thrombocytopenia (platelet count of less than 50 * 109/L). Ten of the 15 neonates with thrombocytopenia required treatment to increase the platelet counts. There was statistically significant association between neonatal thrombocytopenia and maternal splenectomy history and maternal duration of thrombocytopenia. There was no statistically significant correlation between maternal platelet count and neonatal platelet count. Clinicians should pay special attention in these neonates because of risk for development of neonatal thrombocytopenia. Maternal and neonatal outcomes in patients with idiopathic thrombocytopenic purpura is generally good. PMID- 28596654 TI - Is There a Relationship Between CXCR4 Gene Expression and Prognosis of Immune Thrombocytopenia in Children? AB - Immune thrombocytopenia (ITP) is a common autoimmune disorder characterized by decreased platelet count (thrombocytopenia) and bleeding symptoms due to production of autoantibodies against platelets. Chemokines are molecules inducing chemotaxis and play an important role in megakaryopoiesis, including CXCR4 chemokine receptor. CXCR4 is expressed on cells of megakaryocytic series, especially platelets, and triggers several mechanisms in these cells. The purpose of this study was to evaluate the pattern of CXCR4 gene changes upon diagnosis and after treatment and its comparison with laboratory findings in peripheral blood samples from newly diagnosed ITP patients. 35 newly diagnosed patients with ITP and 35 healthy controls were enrolled in this study. CXCR4 gene expression was investigated before and after treatment using real-time PCR. HPRT gene was used as the reference gene to calculate the expression rate of CXCR4 as CXCR4/HPRT ratio. CXCR4 gene expression upon diagnosis and after treatment in peripheral blood plasma of ITP patients showed a significant decrease in comparison with the control group while its expression did not change before and after treatment. No significant correlation was found between the expression of this gene and laboratory parameters. Due to unpredictable course of ITP in patients and the possibility of its progress to refractory form, accurate choice of a biomarker is essential for evaluating prognosis and detection of resistant forms. PMID- 28596655 TI - A Correlation of the Platelet Count with D-Dimer Levels as an Indicator for Component Therapy in Children with Dengue Hemorrhagic Fever. AB - Dengue Fever (DF) may evolve into two life threatening forms-Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). DHF is associated with increased vascular permeability and plasma leakage causing thrombocytopenia and loss of clotting factors into the third space and may result in bleeding initially due to thrombocytopenia and later due to disseminated intravascular coagulation (DIC), often as a terminal event. Prompt recognition and treatment of minor bleeds in DF children with incipient DIC with component therapy may be associated with improved survival while failure to do so is usually catastrophic. A sensitive marker for early DIC is the presence of D-dimer (DD) in the blood. To determine the correlation between the severity of thrombocytopenia and early DIC in children with DHF. The impact of additional factors like age and shock will also be evaluated. Case control prospective study of 60 DHF sero -positive children (1 15 years) with thrombocytopenia. After clinical evaluation they were divided into two equal groups based on the degree of thrombocytopenia (more than/less than 30,000/mm3). PT/APTT and DD levels were estimated in all children of both groups and statistical correlation was done. There was no significant difference in the DD levels between the two groups. However, children in either group, presenting with clinical features of shock and thrombocytopenia had significantly higher DD levels. Empirical component therapy in children with DHF based purely on their low platelet counts may not be justified. However, in DHF children with thrombocytopenia and features of shock, aggressive component therapy may prevent subsequent bleeding and may be justified. PMID- 28596656 TI - Assessment of Heart and Liver Iron Overload in Thalassemia Major Patients Using T2* Magnetic Resonance Imaging. AB - Accumulation of excess iron in heart can lead to cardiac dysfunction, which is the most common cause of death in thalassemia major patients. Biopsy is an invasive procedure and therefore not an ideal option to assess iron load. However, standard/usual non-invasive methods, such as ferritin measurement, have some limitations and the results show poor correlations with iron load. Magnetic Response Imaging (MRI-T2*), as a non-invasive and reliable method for iron load assessment in organs such as liver and heart, can be suggested as a favorable alternative. This cross-sectional study was implemented in Thalassemia and Hemophilia Clinic Center (Sarvar) affiliated with Mashhad University of Medical Sciences, Mashhad, Iran, from 2012 to 2013. After the approval of the research protocol by the local ethic committee, laboratory tests, including CBC and serum ferritin, were carried out, and echocardiography and heart and liver MRI-T2* were performed. All statistical analysis was done through SPSS software (version 11.5), using independent sample t test and Pearson's correlation coefficient test. A P value <=0.05 was considered to be significant. 88 patients with the mean (+/-SD) age of 21.2 (+/-5.6) years, (range 11-37 years) were observed. Iron load was assessed using MRI-T2* with the following results: Out of 88 patients, 48.9 % had mild to severe cardiac siderosis, and 75.2 % had mild to severe liver siderosis. We demonstrated a correlation between liver MRI-T2* and serum ferritin, and heart MRI-T2* and ejection fraction. However, no correlation between liver and heart MRI-T2* was observed. Heart and liver siderosis is a common and serious problem in thalassemia major patients, and MRI-T2* as a sensitive and non-invasive technique can be used for early/timely detection of siderosis and good therapeutic monitoring in these patients. PMID- 28596657 TI - Increased Level of Factor VIII and Physiological Inhibitors of Coagulation in Patients with Sickle Cell Disease. AB - Sickle cell disease (SCD) is a hemoglobinopathy characterized by hemolysis, oxidative stress, and vaso-occlusive crises. Thromboembolism also remains a serious complication and probably underestimated in the SCD. Our objective was to seek the existence of hemostasis abnormalities that predispose to thrombosis such as elevation of FVIII and Physiological inhibitors of coagulation deficiency. We studied 81 patients with SCD, including 32 homozygous S/S, 20 double heterozygous S/beta thalassemia and 29 heterozygous S/A. Controls AA were in number 60. For each patient and control we assayed the physiological coagulation inhibitors (Protein C, Protein S and Antithrombin) and the clotting FVIII. We found a significant increase in FVIII in all phenotypes of SCD compared to controls. Also, a significant decrease in levels of protein C and S was observed in patients with sickle cell homozygous or double heterozygous S beta Thalassemia compared to controls. As against, for antithrombin no difference was observed between patients and controls. These hemostasis abnormalities therefore reflect the existence of a pro thrombotic state in sickle cell disease that can explain the increase of incidence of thrombosis in this pathology. Factor VIII clotting consistently high in SCD may well be a prime therapeutic target in the treatment of thrombotic manifestations of this disease. PMID- 28596658 TI - Usefulness of Reticulocyte Parameters for Diagnosis of Hereditary Spherocytosis in Children. AB - Innovations in laboratory equipment have enabled a widening of the spectrum of hematological parameters obtained from single measurements of peripheral blood samples, including reticulocyte parameters. The usefulness of reticulocytes indices to confirm the diagnosis of pediatric anemia was analyzed in this study. The study group consisted of 163 children, aged 1 month-17 years, with anemia. Complete blood count extended with an analysis of reticulocyte parameters were measured using a Beckman Coulter LH 750. The mean sphered corpuscular volume (MSCV) in the group of children with hereditary spherocytosis (HS) was 66.71 +/- 8.45 fL, whereas in other anemic patients MSCV was 87.76 +/- 11.22 fL, p < 0.0001. In HS children the average mean corpuscular volume of red blood cells was higher than the MSCV value, while an inverse correlation was observed in the group of children with other anemias, p < 0.0001. A significant difference was found between the ratio of absolute reticulocyte count and IRF fraction (Ret#/IRF)-0.6 +/- 0.28 in the HS group and 0.23 +/- 0.16 in the non-HS group, respectively. Our results suggest that analysis of reticulocyte parameters is useful in the diagnosis of anemia and should be included in the routine CBC analysis in anemic children. PMID- 28596660 TI - Facts and Fallacies of Kidd Antibodies: Experience in a Tertiary Care Hospital in North India. AB - We have analyzed the method used in our laboratory to detect the most elusive, clinically significant alloantibody: the Kidd alloantibodies and find the most convenient procedure. A retrospective analysis of the method used in our laboratory for determining Kidd alloantibodies from January 2013 to May 2015 was conducted. The details of the event that sensitized the patient for red cell antibody formation and procedure used to detect the alloantibody were retrieved from the departmental records. Of 405 red cell antibody identification cases, 24 (5.9 %) had Kidd antibody (anti-Jka in 12: 50 % cases; anti-Jkb in 4: 16.7 % cases; multiple antibodies in 8: 32 % cases). Thirteen of 24 patients (54.2 %) had autocontrol positive of which 6 cases needed adsorption procedures whereas antibody/ies could be identified without adsorption procedure in the remaining 7 cases. All the 7 cases had autocontrol of 1+ strength. Of the 11 patients (45.8 %) with autocontrol negative, the antibody was identified using solid phase in 7 cases whereas tube panels were also used in the remaining 4 cases. Kidd alloantibodies though deceptive can be identified by sensitive techniques like the solid phase and simple but laborious techniques using the tube cell panels. Depending upon the reaction strength of the autocontrol, the routine autoadsorption process may be skipped and tube cell enzyme treated cells or solid phase techniques be used to get the results. PMID- 28596659 TI - Patterns of Adverse Transfusion Reactions in a Tertiary Care Centre of North India: A Step Towards Hemovigilance. AB - Transfusion of blood and blood products is a double edged sword, so it should be used judiciously. The primary aim of the centralized Haemovigilance Program is to improve transfusion safety. To determine the incidence of adverse transfusion reactions (ATRs) in recipients of blood and blood components. Prospective study from January 2014 till April 2015 was done. ATRs reported to the Department of Transfusion Medicine were recorded and analyzed on the basis of their clinical features and lab tests. During the study period 25,099 units of blood and blood components were transfused and 100 ATRs (0.40 %) were reported. The incidence of febrile nonhemolytic transfusion reactions (FNHTR) was maximum (73 %) followed by allergic reactions (24 %), bacterial sepsis (1 %), hypotension due to ACE inhibitors (1 %) and acute hemolytic transfusion reaction (AHTR) (1 %). Of all the reported ATRs, 76 % occurred with packed red cells, 15 % occurred with whole blood, while platelets and Fresh Frozen Plasma transfusions were responsible for 8 % and 1 %, respectively. The majority of the reactions were FNHTRs followed by allergic reactions. Reporting of all adverse events and continuous medical education to medical and paramedical staff will help in strengthening hemovigilance system. PMID- 28596661 TI - What is it really? Anti-G or Anti-D plus Anti-C: Clinical Significance in Antenatal Mothers. AB - G antigen of Rh blood group system is present either along with D and/or C positive red cells. Hence, [serologically anti-G presents with the similar picture as that of multiple antibodies (anti-D + anti-C). Differentiating them is important as anti-D + anti-C causes severe hemolytic disease of the fetus and newborn than anti-G. In pregnancies with anti-G alone, alloimmunization due to D antigen could be prevented by prophylactic administration of RhIg. Differentiating between anti-D + C from anti-G in alloimmunized pregnant mothers becomes essential. Sera from antenatal mothers, whose antibody identification by 11-cell panel gave a pattern for anti-D and anti-C were selected. Extended phenotyping for Rh system was performed for these antenatal cases. Differential adsorption and elution testing using R2R2 cells initially and r'r cells subsequently were performed to distinguish anit-G from anti-D + anti-C. Antibody titers of these antibodies were determined and their clinical outcome in the newborn was followed. A pattern suggestive of anti D and anti C on antibody identification were observed in six antenatal cases. On further workup 50 % of them confirmed to have anti G. Antibody titers of anti-G and anti-C were lower than that of Anti-D. All newborns were sensitized in vivo and the antibody specificity in them were confirmed with elution studies. The mothers who had only anti-G were subsequently administered with an appropriate dose of RhIg.Differential adsorption and elution studies help in identifying anti-G and distinguishing it from anti-D plus anti-C, thus helping in better patient management. PMID- 28596663 TI - Novel e8a2 BCR/ABL Fusion Transcript in Case of a Myeloproliferative Neoplasm. AB - Main objective of this work was to confirm the occurrence of rare BCR-ABL fusion variant involving the a2 region of the ABL gene and e8 of BCR gene in a patient of Myeloproliferative neoplasm positive for t(9;22) translocation but negative for common major and minor breakpoint cluster regions. A patient with elevated white blood cell count was subjected to classical cytogenetics, FISH as well as RT-PCR testing using commercial kits as well as published primers and in house testing protocol. The translocation event in chromosome 9 and 22 could be successfully detected. BCR/ABL dual color, dual fusion probe generated a classical balanced translocation scenario within the nucleus. In RT-PCR we found an unexpectedly large amplification band around 1700 bp, which is consistent with e8a2 transcript. Nine metaphases showed 46,XY,t(9;22)(q34;q11.2)[9] by cytogenetic. A rare e8a2 break point in the BCR-ABL gene in myeloproliferative neoplasm disease detected in India. It also emphasizes the utility of cytogenetic and FISH for primary diagnosis of any neoplasm in blood. Our Patient detected rare BCR-ABL fusion variant e8a2 was on imatinib 400 mg since last 3 months. After 3 months fluorescent in situ analysis and reverse transcriptase pcr analysis showed negative results. PMID- 28596662 TI - Rh and Kell Phenotype Matched Blood Versus Randomly Selected and Conventionally Cross Matched Blood on Incidence of Alloimmunization. AB - There is paucity of literature regarding efficacy of transfusion of Rh and Kell matched blood in reducing alloimmunization risk among non-chronically transfused patients. A prospective study to compare efficacy of Rh and Kell phenotype matched blood over randomly selected and conventionally cross-matched blood on the incidence of alloimmunization in patients undergoing cardiac surgery was carried out in the Department of Transfusion Medicine at Indraprastha Apollo Hospitals, New Delhi, from 1st September, 2013 to 31st December, 2014. Two groups, A and B of 250 each were studied. Group A received ABO, Rh and Kell phenotype matched units. Group B received units matched only for ABO and Rh D. Retrospective analysis for antigenic exposures was done. Alloimmunization rate was evaluated for both groups after 72 h and 4 weeks and compared. A p value <=0.05 was considered statistically significant. None of the patients in Group A were alloimmunized. In Group B, 119 patients received antigenic stimulus (single antigen stimuli- 93; multiple- 26). The probability of a patient being exposed was 52.4 %. At 6 weeks post transfusion, one patient developed 'Anti-E' and had received 'E' stimulus once. The rate of alloimmunization was 0.4 % in group B, 0.8 % overall and the risk of alloimmunization per unit transfused was 0.17 %. Non responders were 99.16 %. The study did not reach statistical significance (p = 0.238). Majority of our population are non-responders therefore, the resources and time can be reserved for providing Rh and Kell matched units for multiply transfused patients. PMID- 28596664 TI - Bullous Pyoderma Gangrenosum Associated with Hairy Cell Leukemia and Its Complete Response to Cladribine Therapy. AB - Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis seen in association with systemic disorders including hematologic malignancies. Hairy cell leukemia (HCL) however, is an unusual association of PG. We describe a 49-year old lady who presented to our hematology clinic with easy fatiguability and ulcerative skin lesions of 6 months duration. Examination revealed pallor and massive splenomegaly. Indurated, ulcerated lesion with undermined edges and necrotic base was observed on left thigh. Investigations revealed pancytopenia and bone marrow examination identified typical hairy cells. Flow cytometry of marrow aspirate was suggestive of classical HCL. BRAF V600E mutation was detected in peripheral blood by reverse transcriptase polymerase chain reaction. Skin biopsy revealed neutrophilic dermatosis and findings classical of bullous PG. Cladribine therapy (0.09 mg/kg/day by continuous intravenous infusion for 7 days) led to remission of both HCL and PG after a duration of 4 weeks. Cladribine monotherapy in a case of PG with HCL may avoid the additional immunosuppresion risk imposed by treating PG separately with corticosteroids. Immunosuppressive role of cladribine might be helpful in treating PG concurrent with HCL. PMID- 28596665 TI - Langerhans Cell Histiocytosis (LCH) of the Tonsil in Adult Patient: An Uncommon Disease at an Uncommon Site. AB - Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal neoplastic proliferation of normal antigen presenting cell (APC), the Langerhans cell. Most cases occur in childhood and the disease is rare in adults. LCH can involve solitary organ or can present as a multi-system disease in children. In adults, isolated pulmonary LCH is the commonest presentation. Tonsillar infiltration as a sole manifestation is extremely rare. We herewith report a case with isolated tonsillar involvement by LCH in an adult patient. PMID- 28596666 TI - Enoxaparin Induced Skin Lesions in Pregnancy: A Rare But Clinically Recognizable Association. AB - We report the case of a 29 year old pregnant female who experienced itching with erythematous plaques on prophylactic enoxaparin for recurrent fetal losses. These lesions generalized on rechallenge but erythema and itching gradually resolved after 4 weeks of discontinuation. Cutaneous adverse events with heparin have been reported (Villanueva et al. in Actas Dermosifiliogr 103:816-819, 2012; Neloska et al. in Acta Dermatovenerol Croat 23:223-224, 2015; Maldonado et al. in Clin Exp Dermatol 37:707-711, 2012; Schindewolf et al. in Lancet 380:1867-1879, 2012; Tassava and Warkentin in Am J Hematol 90:747-750, 2015), some specifically with enoxaparin (Villanueva et al. 2012; Neloska et al. 2015). PMID- 28596667 TI - Air Bubbles Produced During Rapid Blood Warming with Inline Blood Warmer Leading to Panic of Air Embolism. PMID- 28596668 TI - Venous Thrombosis in Hematopoietic Stem Cell Transplantation. PMID- 28596669 TI - Horner's Syndrome in a Case of Granulocytic Sarcoma. PMID- 28596670 TI - Growth Factor Variation in Two Types of Autologous Platelet Biomaterials: PRP Versus PRF. AB - Autologous platelet biomaterials represent a key source of cytokines and growth factors extensively used for clinical and surgical applications involving tissue regeneration; wound healing and tissue repair. In this communication we discuss the growth factors released by activated platelet rich plasma (PRP) and platelet rich fibrin (PRF) releasate. Our study highlights that significantly higher growth factors (TGF-beta1) are released by activated PRP as compared to releasate of PRF. The various growth factors released by both platelet products are significantly higher than the baseline concentration in the whole blood and have different bio-mechanism hence should be individualized as per the clinical indication. PMID- 28596671 TI - Autologous Blood Transfusion as a Life Saving Measure for a Trauma Patient with Fracture Femur and Drug Induced Hemolytic Anemia: A Case Report. AB - A positive direct antiglobulin test has been reported in 1:1000 to 1:14,000 blood donors and 1-15 % of hospital patients. Drugs may cause a positive direct antiglobulin test result and/or immune-mediated haemolysis with an incidence of approximately 1 in a 1 million population. Our aim is to highlight the importance of following strict transfusion protocols and management insight in a direct antiglobulin test positive patient showing incompatibility with multiple units possibly due to drug induced immune haemolytic anaemia (DIIHA). We also aim to highlight importance of autologous blood transfusion in an orthopaedic procedure in which homologous transfusion may be needed. We are presenting case of a 36 year old male with alleged h/o of road traffic accident with comminuted intra articular fracture of the distal femur. He had h/o of ankylosing spondylitis since last 20 years on medication with indomethacin and methotrexate. A review of the literature was performed which showed use of drug methotrexate as an uncommon clinical entity for DIIHA; sporadic reports exist in the medical literature to support this view. The review of the literature in combination with our own data showed methotrexate can be a cause of DIIHA. We therefore advocate proper immunohaematological work up and use of autologous blood for management of at risk-patients of DIIHA. PMID- 28596672 TI - Clinically Significant IgM Anti-Cw: A Rare Report. PMID- 28596673 TI - Power Spectral Density Analysis of Electrocorticogram Recordings during Cerebral Hypothermia in Neonatal Seizures. AB - BACKGROUND: Neonatal seizures (NS) are the most common form of neurological dysfunction observed in newborns. PURPOSE: The purpose of this study in newborn piglets was to determine the effect of cerebral hypothermia (CH) on neural activity during pharmacologically induced NS. We hypothesized that the neuroprotective effects of CH would preserve higher frequencies observed in electrocorticogram (ECoG) recordings. METHODS: Power spectral density was employed to determine the levels of brain activity in ECoGs to quantitatively assess the power of each frequency observed in neurological brain states of delta, theta, alpha, and beta-gamma frequencies. RESULT: The most significant reduction of power occurs in the lower frequency band of delta-theta-alpha of CH cohorts, while t score probabilities imply that high-frequency brain activity in the beta-gamma range is preserved in the CH population. CONCLUSION: While the overall power density decreases over time in both groups, the decrease is to a lesser degree in the CH population. PMID- 28596675 TI - Cautiously using natural medicine to treat liver problems. AB - Natural medicine is a system of therapy that administrates natural agents and their derivatives to treat human diseases. This medicine has been used to treat many kinds of human diseases for thousands of years. The treatment protocols of natural medicine are integrative in nature, and are required to utilize the most appropriate therapies to address the needs of the individual patient. Because of the relative convenience, safety and efficacy, natural medicine is now increasing worldwide. Naturopathic doctors are licensed in many areas of the world and regulated partly by law in these areas, which is quite different from various other forms of complementary and alternative medicine. Liver diseases, such as hepatitis, liver cirrhosis and liver carcinoma, are serious health problems worldwide. Nearly half of the natural agents used in treatment of liver diseases today are natural products and their derivatives. Although natural medicine is beneficial and safe, physicians should pay close attention to the potential side effects of the naturopathic agents, which lead to liver injury, interstitial pneumonia and acute respiratory failure. Therefore, when administrating naturopathic protocols to patients for the treatment of liver diseases, we should try our best to prevent and avoid as much as possible the negative impact of these medicines. This article highlights the current practice and recommended improvement of natural medicines in the treatment of liver diseases and gives some specific examples to emphasize the prevention and management of adverse reactions of the natural agents and suggests that natural medicine should be cautiously used to treat liver problems. PMID- 28596674 TI - Follow-up after curative resection for gastric cancer: Is it time to tailor it? AB - There is still no consensus on the follow-up frequency and regimen after curative resection for gastric cancer. Moreover, controversy exists regarding the utility of follow-up in improving survival, and the recommendations of experts and societies vary considerably. The main reason to establish surveillance programs is to diagnose tumor recurrence or metachronous cancers early and to thereby provide prompt treatment and prolong survival. In the setting of gastric malignancies, other reasons have been put forth: (1) the detection of adverse effects of a previous surgery, such as malnutrition or digestive sequelae; (2) the collection of data; and (3) the identification of psychological and/or social problems and provision of appropriate support to the patients. No randomized controlled trials on the role of follow-up after curative resection of gastric carcinoma have been published. Herein, the primary retrospective series and systematic reviews on this subject are analyzed and discussed. Furthermore, the guidelines from international and national scientific societies are discussed. Follow-up is recommended by the majority of institutions; however, there is no real evidence that follow-up can improve long-term survival rates. Several studies have demonstrated that it is possible to stratify patients submitted to curative gastrectomy into different classes according to the risk of recurrence. Furthermore, promising studies have identified several molecular markers that are related to the risk of relapse and to prognosis. Based on these premises, a promising strategy will be to tailor follow-up in relation to the patient and tumor characteristics, molecular marker status, and individual risk of recurrence. PMID- 28596676 TI - Renin angiotensin system in liver diseases: Friend or foe? AB - In the last three decades, the understanding of the renin angiotensin system (RAS) has been changed by the discoveries of functional local systems, novel biologically active peptides, additional specific receptors, alternative pathways of angiotensin (Ang) II generation, and new roles for enzymes and precursor components other than those in Ang II synthesis. In this regard, the discovery that Ang-(1-7) opposes the pressor, proliferative, pro-fibrotic, and pro inflammatory effects mediated by Ang II has contributed to the realization that the RAS is composed of two axes. The first axis consists of the angiotensin converting enzyme (ACE), with Ang II as the end product, and the angiotensin type 1 (AT1) receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to the production of Ang-(1-7), with the Mas receptor as the main effector conveying the vasodilatory, anti-proliferative, anti-fibrotic, and anti-inflammatory effects of Ang-(1-7). Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases. In this manuscript, we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications, including hemodynamic changes and hepatorenal syndrome. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed. PMID- 28596679 TI - Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line. AB - AIM: To determine how a normal human colon cell line reacts to microbial challenge as a way to study oxidative stress-induced responses associated with inflammatory bowel disease. METHODS: Normal human colon epithelial cells (ATCC(r) CRL.1790TM) were stimulated with either heat killed E. coli or heat killed murine cecal contents (HKC) and examined for several relevant biomarkers associated with inflammation and oxidative stress including cytokine production, mitochondrial autophagy and oxidant status. TNFalpha, IL-1beta and IL-8 protein concentrations were measured within the supernatants. Fluorescent microscopy was performed to quantify the production of reactive oxygen species (ROS) using an oxidation responsive fluorogenic probe. Mitochondrial morphology and mitochondrial membrane potential was assessed by dual staining using COXIV antibody and a dye concentrating in active mitochondria. Mitochondrial ROS scavenger was used to determine the source of ROS in stimulated cells. Autophagy was detected by staining for the presence of autophagic vesicles. Positive controls for autophagy and ROS/RNS experiments were treated with rapamycin and chloroquine. Mitochondrial morphology, ROS production and autophagy microscopy experiments were analyzed using a custom acquisition and analysis microscopy software (ImageJ). RESULTS: Exposing CRL.1790 cells to microbial challenge stimulated cells to produce several relevant biomarkers associated with inflammation and oxidative stress. Heat killed cecal contents treatment induced a 10-12 fold increase in IL-8 production by CRL.1790 cells compared to unstimulated controls at 6 and 12 h (P < 0.001). Heat killed E. coli stimulation resulted in a 4-5 fold increase in IL-8 compared to the unstimulated control cells at each time point (P < 0.001). Both heat killed E. coli and HKC stimulated robust ROS production at 6 (P < 0.001), and 12 h (P < 0.01). Mitochondrial morphologic abnormalities were detected at 6 and 12 h based on reduced mitochondrial circularity and decreased mitochondrial membrane potential, P < 0.01. Microbial stimulation also induced significant autophagy at 6 and 12 h, P < 0.01. Lastly, blocking mitochondrial ROS generation using mitochondrial specific ROS scavenger reversed microbial challenge induced mitochondrial morphologic abnormalities and autophagy. CONCLUSION: The findings from this study suggest that CRL.1790 cells may be a useful alternative to other colon cancer cell lines in studying the mechanisms of oxidative stress events associated with intestinal inflammatory disorders. PMID- 28596677 TI - Relationship between adipose tissue dysfunction, vitamin D deficiency and the pathogenesis of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Its pathogenesis is complex and not yet fully understood. Over the years many studies have proposed various pathophysiological hypotheses, among which the currently most widely accepted is the "multiple parallel hits" theory. According to this model, lipid accumulation in the hepatocytes and insulin resistance increase the vulnerability of the liver to many factors that act in a coordinated and cooperative manner to promote hepatic injury, inflammation and fibrosis. Among these factors, adipose tissue dysfunction and subsequent chronic low grade inflammation play a crucial role. Recent studies have shown that vitamin D exerts an immune-regulating action on adipose tissue, and the growing wealth of epidemiological data is demonstrating that hypovitaminosis D is associated with both obesity and NAFLD. Furthermore, given the strong association between these conditions, current findings suggest that vitamin D may be involved in the relationship between adipose tissue dysfunction and NAFLD. The purpose of this review is to provide an overview of recent advances in the pathogenesis of NAFLD in relation to adipose tissue dysfunction, and in the pathophysiology linking vitamin D deficiency with NAFLD and adiposity, together with an overview of the evidence available on the clinical utility of vitamin D supplementation in cases of NAFLD. PMID- 28596680 TI - Role of AXL in invasion and drug resistance of colon and breast cancer cells and its association with p53 alterations. AB - AIM: To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy. METHODS: We used 14 cell lines, including 3 isogenic pairs carrying mutant/knockout p53, to gain insight into the relationship between AXL and TP53. These included HCT116, HCT116.p53 mutant, RKO, and RKO.p53-/- lines (all from colon cancers) as well as breast cancer cell lines MCF7 and 1001 (MCF7-p53 mutant clone). HeLa cell line was used as a positive control for epithelial to mesenchymal transition (EMT). AXL expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7. AXL siRNA silencing was performed and followed by collagen invasion assay. Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents (doxorubicin for breast cancer cells; 5FU or irinotecan for colon cancer cells). RESULTS: We showed that the introduction of p53 mutations or knockout increased expression levels of AXL in isogenic cells compared to the matching p53 wild-type parental cells. Overall, we found a trend for correlation between the potential EMT candidate AXL, p53 alterations, and EMT markers in colorectal and breast cancers. The expression of AXL in RKO cells, a rare colon cancer cell line with inactive Wnt signaling, suggests that the AXL oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation. AXL silencing in the TP53 mutant isogenic cell lines 1001, HCT116.p53 mutant and RKO.P53-/- was > 95% efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells. AXL silencing showed a subtle trend to restore colon cancer cell sensitivity to 5FU or irinotecan. Importantly, AXL expressing cells developed more invasive potential after exposure to chemotherapy compared to the AXL-silenced cells. CONCLUSION: AXL is influenced by p53 status and could cause the emergence of aggressive clones after exposure to chemotherapy. These findings could have applications in cancer management. PMID- 28596678 TI - Recent advances in the management of pruritus in chronic liver diseases. AB - Pruritus is a symptom found in patients with chronic liver diseases, especially cholestatic liver diseases such as primary biliary cholangitis. This symptom impairs patient quality of life by disturbing sleep and may lead to consideration of liver transplantation. Mechanisms implicated in pruritus have been associated with the peripheral and central nervous systems, leading to the development of various therapeutic options. Little evidence for the efficacy of most of these treatments is currently available, indicating a need for further investigations. PMID- 28596681 TI - Effects of heme oxygenase-1-modified bone marrow mesenchymal stem cells on microcirculation and energy metabolism following liver transplantation. AB - AIM: To investigate the effects of heme oxygenase-1 (HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) on the microcirculation and energy metabolism of hepatic sinusoids following reduced-size liver transplantation (RLT) in a rat model. METHODS: BMMSCs were isolated and cultured in vitro using an adherent method, and then transduced with HO-1-bearing recombinant adenovirus to construct HO-1/BMMSCs. A rat acute rejection model following 50% RLT was established using a two-cuff technique. Recipients were divided into three groups based on the treatment received: normal saline (NS), BMMSCs and HO-1/BMMSCs. Liver function was examined at six time points. The levels of endothelin-1 (ET-1), endothelial nitric-oxide synthase (eNOS), inducible nitric-oxide synthase (iNOS), nitric oxide (NO), and hyaluronic acid (HA) were detected using an enzyme-linked immunosorbent assay. The portal vein pressure (PVP) was detected by Power Lab ML880. The expressions of ET-1, iNOS, eNOS, and von Willebrand factor (vWF) protein in the transplanted liver were detected using immunohistochemistry and Western blotting. ATPase in the transplanted liver was detected by chemical colorimetry, and the ultrastructural changes were observed under a transmission electron microscope. RESULTS: HO-1/BMMSCs could alleviate the pathological changes and rejection activity index of the transplanted liver, and improve the liver function of rats following 50% RLT, with statistically significant differences compared with those of the NS group and BMMSCs group (P < 0.05). In term of the microcirculation of hepatic sinusoids: The PVP on POD7 decreased significantly in the HO-1/BMMSCs and BMMSCs groups compared with that of the NS group (P < 0.01); HO-1/BMMSCs could inhibit the expressions of ET-1 and iNOS, increase the expressions of eNOS and inhibit amounts of NO production, and maintain the equilibrium of ET-1/NO (P < 0.05); and HO-1/BMMSCs increased the expression of vWF in hepatic sinusoidal endothelial cells (SECs), and promoted the degradation of HA, compared with those of the NS group and BMMSCs group (P < 0.05). In term of the energy metabolism of the transplanted liver, HO-1/BMMSCs repaired the damaged mitochondria, and improved the activity of mitochondrial aspartate aminotransferase (ASTm) and ATPase, compared with the other two groups (P <0.05). CONCLUSION: HO-1/BMMSCs can improve the microcirculation of hepatic sinusoids significantly, and recover the energy metabolism of damaged hepatocytes in rats following RLT, thus protecting the transplanted liver. PMID- 28596682 TI - Diabetes recurrence after metabolic surgeries correlates with re-impaired insulin sensitivity rather than beta-cell function. AB - AIM: To investigate factors causing diabetes recurrence after sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB). METHODS: SG and DJB were performed on rats with diabetes induced by high-fat diet (HFD) and streptozotocin (STZ). HFD was used to induce diabetes recurrence at 4 wk postoperatively. Body weight, oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA IR), insulin signaling [IR, insulin receptor substrate (IRS)1, IRS2, phosphatidylinositol 3-kinase and AKT in liver and skeletal muscle], oral glucose stimulated insulin secretion, beta-cell morphology (mass, apoptosis and insulin secretion), glucagon-like peptide (GLP)-1, PYY and ghrelin were compared among SG rats with common low-fat diet (SG-LFD), SG with HFD (SG-HFD), DJB rats with LFD (DJB-LFD), DJB with HFD (DJB-HFD) and sham-operation with LFD (Sham) at targeted postoperative times. RESULTS: SG and DJB resulted in significant improvement in glucose tolerance, lower HOMA-IR, up-regulated hepatic and muscular insulin signaling, higher levels of oral glucose-stimulated insulin secretion, bigger beta-cell mass, higher immunofluorescence intensity of insulin, fewer transferase mediated dUTP-biotin 3' nick end-labeling (TUNEL)-positive beta cells and higher postprandial GLP-1 and PYY levels than in the Sham group. The improvement in glucose tolerance was reversed at 12 wk postoperatively. Compared with the SG-LFD and DJB-LFD groups, the SG-HFD and DJB-HFD groups showed higher HOMA-IR, down regulated hepatic and muscular insulin signaling, and more TUNEL-positive beta cells. No significant difference was detected between HFD and LFD groups for body weight, glucose-stimulated insulin secretion, beta-cell mass, immunofluorescence intensity of insulin, and postprandial GLP-1 and PYY levels. Fasting serum ghrelin decreased in SG groups, and there was no difference between HFD-SG and LFD-SG groups. CONCLUSION: HFD reverses the improvement in glucose homeostasis after SG and DJB. Diabetes recurrence may correlate with re-impaired insulin sensitivity, but not with alterations of beta-cell function and body weight. PMID- 28596683 TI - Polymorphisms of microRNA target genes IL12B, INSR, CCND1 and IL10 in gastric cancer. AB - AIM: To evaluate associations between miRNA target genes IL12B, INSR, CCND1 and IL10 polymorphisms and gastric cancer (GC) in European population. METHODS: Gene polymorphisms were analyzed in 508 controls and 474 GC patients from 3 tertiary centers in Germany, Lithuania and Latvia. Controls were patients from the out patient departments, who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy. Gastric cancer (GC) patients had histopathological verification of gastric adenocarcinoma. Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells. IL12B T>G (rs1368439), INSR T>C (rs1051690), CCND1 A>C (rs7177) and IL10 T>C (rs3024498) SNPs were genotyped by the real-time polymerase chain reaction. Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex, age and country of birth. RESULTS: We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690. The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls (23.26% and 19.19% respectively, P = 0.028). CT genotype was also more prevalent in patients compared to control group (38.48% and 30.12% respectively, P < 0.021). Logistic regression analysis revealed that only one polymorphism (rs1051690 in INSR gene) was associated with increased risk of GC. Carriers of CT genotype had higher odds of GC when compared to CC genotype (OR = 1.45, 95%PI: 1.08-1.95, P = 0.01). Similar association was observed in a dominant model for INSR gene, where comparison of TT+CT vs CC genotypes showed an increased risk of GC (OR = 1.44, 95%PI: 1.08-1.90, P = 0.01). Other analyzed SNPs were not associated with the presence of GC. CONCLUSION: INSR rs1051690 SNP is associated with increased risk of GC, while polymorphisms in IL12B, CCND1 and IL10 genes are not linked with the presence of GC. PMID- 28596684 TI - Insulin-like growth factor-1, IGF binding protein-3, and the risk of esophageal cancer in a nested case-control study. AB - AIM: To assess the relationship between serum levels of insulin-like growth factor-1 (IGF1)/IGF-binding protein-3 (IGFBP3) and the risk of esophageal carcinoma. METHODS: We assessed the relationship between the serum levels of these molecules and the risk of esophageal cancer in a prospective, nested case control study of participants from the Japan Collaborative Cohort Study. A baseline survey was conducted from 1988 to 1990. Of the 110585 enrolled participants, 35% donated blood samples. Those who had been diagnosed with esophageal cancer were considered cases for nested case-control studies. A conditional logistic model was used to estimate odds ratios for the incidence of esophageal cancer associated with serum IGF1 and IGFBP3 levels. RESULTS: Thirty one cases and 86 controls were eligible for the present assessment. The molar ratio of IGF1/IGFBP3, which represents the free and active form of IGF1, was not correlated with the risk of esophageal carcinoma. A higher molar difference between IGFBP3 and IGF1, which estimates the free form of IGFBP3, was associated with a decreased risk of esophageal carcinoma (P = 0.0146), and people in the highest tertile had the lowest risk (OR = 0.107, 95%CI: 0.017-0.669). After adjustment for body mass index, tobacco use, and alcohol intake, the molar difference of IGFBP3-IGF1 was inversely correlated with the risk of esophageal carcinoma (P = 0.0150). CONCLUSION: The free form of IGFBP3, which is estimated by this molar difference, may be inversely associated with esophageal cancer incidence. PMID- 28596685 TI - Tumor-associated autoantibodies are useful biomarkers in immunodiagnosis of alpha fetoprotein-negative hepatocellular carcinoma. AB - AIM: To determine the prevalence and diagnostic value of autoantibodies in alpha fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). METHODS: Fifty-six serum samples from AFP-negative HCC cases, 86 from AFP-positive HCC cases, 168 from chronic liver disease cases, and 59 from normal human controls were included in this study. Autoantibodies to nucleophosmin (NPM)1, 14-3-3zeta and mouse double minute 2 homolog (MDM2) proteins in AFP-negative HCC serum were evaluated by enzyme-linked immunosorbent assay. Partially positive sera were further evaluated by western blotting. Immunohistochemistry was used to detect the expression of three tumor-associated antigens (TAAs) in AFP-negative HCC and normal control tissues. RESULTS: The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%, 19.6% and 19.6%, which was significantly higher than in the chronic liver disease cases and normal human controls (P < 0.01) as well as AFP-positive HCC cases. The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6% to 21.4%, and the specificity was approximately 95%. When the three autoantibodies were combined, the sensitivity reached 30.4% and the specificity reached 91.6%. CONCLUSION: Autoantibodies to NPM1, 14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC. PMID- 28596687 TI - Relationship between use of selective serotonin reuptake inhibitors and irritable bowel syndrome: A population-based cohort study. AB - AIM: To investigate the relationship between selective serotonin reuptake inhibitor (SSRI) use and the subsequent development of irritable bowel syndrome (IBS). METHODS: This retrospective, observational, population-based cohort study collected data from Taiwan's National Health Insurance Research Database. A total of 19653 patients newly using SSRIs and 78612 patients not using SSRIs, matched by age and sex at a ratio of 1:4, were enrolled in the study from January 1, 2000 to December 31, 2010. The patients were followed until IBS diagnosis, withdrawal from the National Health Insurance system, or the end of 2011. We analyzed the effects of SSRIs on the risk of subsequent IBS using Cox proportional hazards regression models. RESULTS: A total of 236 patients in the SSRI cohort (incidence, 2.17/1000 person-years) and 478 patients in the comparison cohort (incidence, 1.04/1000 person-years) received a new diagnosis of IBS. The mean follow-up period from SSRI exposure to IBS diagnosis was 2.05 years. The incidence of IBS increased with advancing age. Patients with anxiety disorders had a significantly increased adjusted hazard ratio (aHR) of IBS (aHR = 1.33, 95%CI: 1.11-1.59, P = 0.002). After adjusting for sex, age, urbanization, family income, area of residence, occupation, the use of anti-psychotics and other comorbidities, the overall aHR in the SSRI cohort compared with that in the comparison cohort was 1.74 (95%CI: 1.44-2.10; P < 0.001). The cumulative incidence of IBS was higher in the SSRI cohort than in the non-SSRI cohort (log rank test, P < 0.001). CONCLUSION: SSRI users show an increased risk of subsequent diagnosis of IBS in Taiwan. PMID- 28596686 TI - Clinical course of ulcerative colitis patients who develop acute pancreatitis. AB - AIM: To investigate the clinical course of ulcerative colitis (UC) patients who develop acute pancreatitis. METHODS: We analyzed 3307 UC patients from the inflammatory bowel disease registry at Asan Medical Center from June 1989 to May 2015. The clinical course of UC patients who developed acute pancreatitis was compared with that of non-pancreatitis UC patients. RESULTS: Among 51 patients who developed acute pancreatitis, 13 (0.40%) had autoimmune, 10 (0.30%) had aminosalicylate-induced, and 13 (1.73%) had thiopurine-induced pancreatitis. All 13 patients with autoimmune pancreatitis (AIP) had type 2 AIP. Two (15.4%) patients had pre-existing AIP, and three (23.1%) patients developed AIP and UC simultaneously. Compared to non-pancreatitis patients, AIP patients had UC diagnosed at a significantly younger age (median, 22.9 years vs 36.4 years; P = 0.001). AIP and aminosalicylate-induced pancreatitis patients had more extensive UC compared to non-pancreatitis patients. All patients with pancreatitis recovered uneventfully, and there were no recurrences. Biologics were used more frequently in aminosalicylate- and thiopurine-induced pancreatitis patients compared to non-pancreatitis patients [adjusted OR (95%CI), 5.16 (1.42-18.67) and 6.90 (1.83-25.98), respectively]. Biologic utilization rate was similar among AIP and non-pancreatitis patients [OR (95%CI), 0.84 (0.11-6.66)]. Colectomy rates for autoimmune, aminosalicylate-induced, and thiopurine-induced pancreatitis, and for non-pancreatitis patients were 15.4% (2/13), 20% (2/10), 15.4% (2/13), and 7.3% (239/3256), respectively; the rates were not significantly different after adjusting for baseline disease extent. CONCLUSION: Pancreatitis patients show a non-significant increase in colectomy, after adjusting for baseline disease extent. PMID- 28596688 TI - Laparoscopic management of gastric gastrointestinal stromal tumors: A retrospective 10-year single-center experience. AB - AIM: To determine the feasibility, safety, and oncological outcome of laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) based on favorable or unfavorable location. METHODS: Our hospital database included 207 patients who underwent laparoscopic removal of gastric GISTs from January 2004 to September 2015. Patient demographics, clinical presentation, surgery, histopathology, postoperative course, and oncological outcomes were reviewed and analyzed. RESULTS: Gastric GIST in favorable locations was present in 81/207 (39.1%) cases, and in unfavorable locations in 126/207 (60.9%) cases. Overall mean tumor size was 3.28 +/- 1.82 cm. No conversions occurred, and complete R0 resection was achieved in 207 (100%) cases. There were three incidences of iatrogenic tumor rupture. The feasibility and safety of laparoscopic surgery were comparable in both groups with no statistical difference between unfavorable and favorable location groups, respectively: for operative time: 83.86 +/- 44.41 vs 80.77 +/- 36.46 min, P = 0.627; conversion rate: 0% vs 0%; estimated blood loss: 27.74 +/- 45.2 vs 29.59 +/- 41.18 mL, P = 0.780; tumor rupture during surgery: 0.90% vs 2.82%, P = 0.322; or postoperative complications: 3.74% vs 7.04%, P = 0.325. The follow-up period recurrence rate was 1.89% with no significant differences between the two groups (3.03% vs 0%, P = 0.447). Overall 5-year survival rate was 98.76% and survival rates were similar between the two groups: 98.99% vs 98.39%, P = 0.623 (unfavorable vs favorable, respectively). CONCLUSION: The laparoscopic approach for gastric GISTs is safe and feasible with well accepted oncological surgical outcomes. Strategies for laparoscopic resection should be selected according to the location and size of the tumor. Laparoscopic treatment of gastric GISTs in unfavorable locations should not be restricted in gastrointestinal centers. PMID- 28596689 TI - Short health scale: A valid measure of health-related quality of life in Korean speaking patients with inflammatory bowel disease. AB - AIM: To evaluate the short health scale (SHS), a new, simple, four-part visual analogue scale questionnaire that is designed to assess the impact of inflammatory bowel disease (IBD) on health-related quality of life (HRQOL), in Korean-speaking patients with IBD. METHODS: The SHS was completed by 256 patients with Crohn's disease (CD) and ulcerative colitis (UC). Individual SHS items were correlated with inflammatory bowel disease questionnaire (IBDQ) dimensions and with disease activity to assess validity. Test-retest reliability, responsiveness and patient or disease characteristics with probable association with high SHS scores were analyzed. RESULTS: Of 256 patients with IBD, 139 (54.3%) had UC and 117 (45.7%) had CD. The correlation coefficients between SHS questions about "symptom burden", "activities of daily living", and "disease-related worry" and their corresponding dimensions in the IBDQ ranged from 0.62 to 0.71, compared with correlation coefficients ranging from -0.45 to -0.61 for their non corresponding dimensions. There was a stepwise increase in SHS scores, with increasing disease activity in both CD and UC (all P values < 0.001). Reliability was confirmed with test-retest correlations ranging from 0.68 to 0.90 (all P values < 0.001). Responsiveness was confirmed with the patients who remained in remission. Their SHS scores remained unchanged, except for the SHS dimension "disease-related worry". In the multivariate analysis, female sex was associated with worse "general well-being" (OR = 2.28, 95%CI: 1.02-5.08) along with worse disease activity. CONCLUSION: The SHS is a valid and reliable measure of HRQOL in Korean-speaking patients with IBD. PMID- 28596690 TI - Continuing episodes of pain in recurrent acute pancreatitis: Prospective follow up on a standardised protocol with drugs and pancreatic endotherapy. AB - AIM: To assess the outcomes of drug therapy (DT) followed by pancreatic endotherapy for continuing painful episodes in recurrent acute pancreatitis. METHODS: DT comprised of pancreatic enzymes and anti-oxidants failing which, endotherapy (ET; pancreatic sphincterotomy and stent placement) was done. The frequency of pain, its visual analogue score (VAS), quality of life (QoL), serum C peptide and faecal elastase were compared between baseline and after 1 year of follow up in all patients and in the two subgroups on DT and ET. Response was defined as at least 50% reduction in the severity of pain to below a score of 5. RESULTS: Of the thirty nine patients analysed, 21 (53.9%) responded to DT and 18 (46.1%) underwent ET. The VAS for pain (7.0 +/- 2.0 vs 1.3 +/- 2.5, P < 0.001) and the number of days with pain per month decreased [1.0 (1.0, 2.0) vs 1.0 (0.0, 1.0), P < 0.001], and the QoL scores [55.0 (44.0, 66.0) vs 38.0 (32.00, 51.00), P < 0.01] improved significantly during follow up. Similar significant improvements were seen in patients in the subgroups of DT and ET except for QoL in ET. The serum C-peptide (P = 0.001) and FE (P < 0.001) levels improved significantly in the entire group and in the two subgroups of patients except for the C peptide levels in patients on DT. CONCLUSION: A standardised protocol of DT, followed by ET decreased the intensity and frequency of pain in recurrent acute pancreatitis, enhanced QoL and improved pancreatic function. PMID- 28596691 TI - Nissen fundoplication vs proton pump inhibitors for laryngopharyngeal reflux based on pH-monitoring and symptom-scale. AB - AIM: To compare the outcomes between laparoscopic Nissen fundoplication (LNF) and proton pump inhibitors (PPIs) therapy in patients with laryngopharyngeal reflux (LPR) and type I hiatal hernia diagnosed by oropharyngeal pH-monitoring and symptom-scale assessment. METHODS: From February 2014 to January 2015, 70 patients who were diagnosed with LPR and type I hiatal hernia and referred for symptomatic assessment, oropharyngeal pH-monitoring, manometry, and gastrointestinal endoscopy were enrolled in this study. All of the patients met the inclusion criteria. All of the patients underwent LNF or PPIs administration, and completed a 2-year follow-up. Patients' baseline characteristics and primary outcome measures, including comprehensive and single symptoms of LPR, PPIs independence, and satisfaction, and postoperative complications were assessed. The outcomes of LNF and PPIs therapy were analyzed and compared. RESULTS: There were 31 patients in the LNF group and 39 patients in the PPI group. Fifty-three patients (25 in the LNF group and 28 in the PPI group) completed reviews and follow-up. Oropharyngeal pH-monitoring parameters were all abnormal with high acid exposure, a large amount of reflux, and a high Ryan score, associated reflux symptom index (RSI) score. There was a significant improvement in the RSI and LPR symptom scores after the 2-year follow-up in both groups (P < 0.05), as well as typical symptoms of gastroesophageal reflux disease. Improvement in the RSI (P < 0.005) and symptom scores of cough (P = 0.032), mucus (P = 0.011), and throat clearing (P = 0.022) was significantly superior in the LNF group to that in the PPI group. After LNF and PPIs therapy, 13 and 53 patients achieved independence from PPIs therapy (LNF: 44.0% vs PPI: 7.14%, P < 0.001) during follow-up, respectively. Patients in the LNF group were more satisfied with their quality of life than those in the PPI group (LNF: 62.49 +/- 28.68 vs PPI: 44.36 +/- 32.77, P = 0.004). Body mass index was significantly lower in the LNF group than in the PPI group (LNF: 22.2 +/- 3.1 kg/m2vs PPI: 25.1 +/- 2.9 kg/m2, P = 0.001). CONCLUSION: Diagnosis of LPR should be assessed with oropharyngeal pH-monitoring, manometry, and the symptom-scale. LNF achieves better improvement than PPIs for LPR with type I hiatal hernia. PMID- 28596692 TI - Diagnosis of eosinophilic gastroenteritis is easily missed. AB - AIM: To analyze the clinical characteristics of eosinophilic gastroenteritis (EGE) and to investigate the situations of missed diagnosis of EGE. METHODS: First, the clinical characteristics of 20 EGE patients who were treated at our hospital were retrospectively summarized. Second, 159 patients who underwent gastroscopy and 211 patients who underwent colonoscopy were enrolled. The pathological diagnosis showed only chronic inflammation in their medical records. The biopsy slides of these patients were reevaluated to determine the number of infiltrating eosinophils in order to assess the probability of a missed diagnosis of EGE. Finally, 122 patients who experienced refractory upper gastrointestinal symptoms for at least one month were recruited. At least 6 biopsy specimens were obtained by gastroscopy, and the number of eosinophils that had infiltrated was evaluated. Those who met the pathological diagnostic criteria of EGE underwent further examination to confirm the diagnosis of EGE. The probability of a missed diagnosis of EGE was prospectively investigated. RESULTS: Among the 20 patients with EGE, mucosal EGE was found in 15 patients, muscular EGE was found in 3 patients and serosal EGE was found in 2 patients. Abdominal pain was the most common symptom. The number of peripheral blood eosinophils was elevated in all 20 patients, all of whom were sensitive to corticosteroids. Second, among the 159 patients who underwent gastroscopy, 7 (4.40%) patients met the criteria for pathological EGE (eosinophil count >= 25/HPF). Among the 211 patients who underwent colonoscopy, 9 (4.27%) patients met the criteria for pathological EGE (eosinophil count >= 30/HPF). No patients with eosinophil infiltration were diagnosed with EGE in clinical practice before or after endoscopy. Although these patients did not undergo further examination to exclude other diseases that can also lead to gastrointestinal eosinophil infiltration, these might be the cases where the diagnosis of EGE was missed. Finally, among the 122 patients with refractory upper gastrointestinal symptoms, eosinophil infiltration was seen in 7 patients (5.74%). The diagnosis of EGE was confirmed in all 7 patients after the exclusion of other diseases that can also lead to gastrointestinal eosinophil infiltration. A positive correlation was observed between the duration of the symptoms and the risk of EGE (r = 0.18, P < 0.01). The patients whose symptoms persisted longer than 6 mo more readily developed EGE. None of the patients were considered to have EGE by their physicians before endoscopy. CONCLUSION: Although EGE is a rare inflammatory disorder, it is easily misdiagnosed. When a long history of abdominal symptoms fails to improve after conventional therapy, EGE should be considered. PMID- 28596693 TI - Fecal microbiota transplantation cured epilepsy in a case with Crohn's disease: The first report. AB - Fecal microbiota transplantation (FMT) is a promising strategy that involves reconstruction of gut microbiota. Recently, it has been considered as a treatment of Crohn's disease (CD) and certain neurological diseases. Here, to the best of our knowledge, we report the first case that used FMT to achieve remission of intestinal and neurological symptoms in a girl with CD and a 17-year history of epilepsy. During the 20 mo of follow-up, FMT has proved its efficacy in preventing relapse of seizures after withdrawing the antiepileptic drugs. Furthermore, this finding highlights the role of microbiota-gut-brain axis and inspires a novel treatment for epilepsy through remodeling gut microbiota. PMID- 28596694 TI - The natural algorithmic approach of mixed trigonometric-polynomial problems. AB - The aim of this paper is to present a new algorithm for proving mixed trigonometric-polynomial inequalities of the form [Formula: see text] by reducing them to polynomial inequalities. Finally, we show the great applicability of this algorithm and, as an example, we use it to analyze some new rational (Pade) approximations of the function cos2x and to improve a class of inequalities by Yang. The results of our analysis could be implemented by means of an automated proof assistant, so our work is a contribution to the library of automatic support tools for proving various analytic inequalities. PMID- 28596695 TI - Skew log-concavity of the Boros-Moll sequences. AB - Let [Formula: see text] be a triangular array of numbers. We say that [Formula: see text] is skew log-concave if for any fixed n, the sequence [Formula: see text] is log-concave. In this paper, we show that the Boros-Moll sequences are almost skew log-concave. PMID- 28596696 TI - On bounds involving k-Appell's hypergeometric functions. AB - In this paper, we derive a new extension of Hermite-Hadamard's inequality via k Riemann-Liouville fractional integrals. Two new k-fractional integral identities are also derived. Then, using these identities as an auxiliary result, we obtain some new k-fractional bounds which involve k-Appell's hypergeometric functions. These bounds can be viewed as new k-fractional estimations of trapezoidal and mid point type inequalities. These results are obtained for the functions which have the harmonic convexity property. We also discuss some special cases which can be deduced from the main results of the paper. PMID- 28596697 TI - Wavelet transforms on Gelfand-Shilov spaces and concrete examples. AB - In this paper, we study the continuity properties of wavelet transforms in the Gelfand-Shilov spaces with the use of a vanishing moment condition. Moreover, we also compute the Fourier transforms and the wavelet transforms of concrete functions in the Gelfand-Shilov spaces. PMID- 28596698 TI - Child Behavior Problems, Teacher Executive Functions, and Teacher Stress in Head Start Classrooms. AB - RESEARCH FINDINGS: The current article explores the relationship between teachers' perceptions of child behavior problems and preschool teacher job stress, as well as the possibility that teachers' executive functions moderate this relationship. Data came from 69 preschool teachers in 31 early childhood classrooms in 4 Head Start centers and were collected using Web-based surveys and Web-based direct assessment tasks. Multilevel models revealed that higher levels of teachers' perceptions of child behavior problems were associated with higher levels of teacher job stress and that higher teacher executive function skills were related to lower job stress. However, findings did not yield evidence for teacher executive functions as a statistical moderator. PRACTICE OR POLICY: Many early childhood teachers do not receive sufficient training for handling children's challenging behaviors. Child behavior problems increase a teacher's workload and consequently may contribute to feelings of stress. However, teachers' executive function abilities may enable them to use effective, cognitive-based behavior management and instructional strategies during interactions with students, which may reduce stress. Providing teachers with training on managing challenging behaviors and enhancing executive functions may reduce their stress and facilitate their use of effective classroom practices, which is important for children's school readiness skills and teachers' health. PMID- 28596699 TI - Examination of a newly developed mobile dry scrubber (DS) for coal mine dust control applications. AB - The Office of Mine Safety and Health Research of the U.S. National Institute for Occupational Safety and Health (NIOSH OMSHR) conducted laboratory testing of a self-tramming, remotely controlled mobile Dry Scrubber (DS) that J.H. Fletcher and Co. developed under a contract with NIOSH OMSHR to reduce the exposure of miners to airborne dust. The scrubber was found to average greater than 95 percent dust removal efficiency with disposable filters, and 88 and 90 percent, respectively, with optional washable filters in their prewash and post-wash test conditions. Although the washable filters can be reused, washing them generated personal and downstream respirable dust concentrations of 1.2 and 8.3 mg/m3, respectively, for a 10-min washing period. The scrubber's velocity-pressure regulated variable-frequency-drive fan maintained relatively consistent airflow near the targeted 1.42 and 4.25 m3/s (3,000 and 9,000 ft3/min) airflow rates during most of the laboratory dust testing until reaching its maximum 60-Hz fan motor frequency or horsepower rating at 2,610 Pa (10.5 in. w.g.) of filter differential pressure and 3.97 m3/s (8,420 ft3/min) of scrubber airflow quantity. Laboratory sound level measurements of the scrubber showed that the outlet side of the scrubber was noisier, and the loaded filters increased sound levels compared with clean filters at the same airflow quantities. With loaded filters, the scrubber reached a 90 dB(A) sound level at 2.83 m3/s (6,000 ft3/min) of scrubber airflow, indicating that miners should not be overexposed in relation to MSHA's permissible exposure level - under Title 30 Code of Federal Regulations Part 62.101- of 90 dB(A) at or below this airflow quantity. The scrubber's washable filters were not used during field-testing because of their lower respirable dust removal efficiency and the airborne dust generated by filter washing. Field-testing the scrubber with disposable filters at two underground coal mine sections showed that it could clean a portion of the section return air and provide dust reduction of about 50 percent at the face area downstream of the continuous-miner operation. PMID- 28596700 TI - Using software to predict occupational hearing loss in the mining industry. AB - Powerful mining systems typically generate high-level noise that can damage the hearing ability of miners. Engineering noise controls are the most desirable and effective control for overexposure to noise. However, the effects of these noise controls on the actual hearing status of workers are not easily measured. A tool that can provide guidance in assigning workers to jobs based on the noise levels to which they will be exposed is highly desirable. Therefore, the Pittsburgh Mining Research Division (PMRD) of the U.S. National Institute for Occupational Safety and Health (NIOSH) developed a tool to estimate in a systematic way the hearing loss due to occupational noise exposure and to evaluate the effectiveness of developed engineering controls. This computer program is based on the ISO 1999 standard and can be used to estimate the loss of hearing ability caused by occupational noise exposures. In this paper, the functionalities of this software are discussed and several case studies related to mining machinery are presented to demonstrate the functionalities of this software. PMID- 28596701 TI - Exploring Differential Effects Across Two Decoding Treatments on Item-Level Transfer in Children with Significant Word Reading Difficulties: A New Approach for Testing Intervention Elements. AB - In English, gains in decoding skill do not map directly onto increases in word reading. However, beyond the Self-Teaching Hypothesis (Share, 1995), little is known about the transfer of decoding skills to word reading. In this study, we offer a new approach to testing specific decoding elements on transfer to word reading. To illustrate, we modeled word-reading gains among children with reading disability (RD) enrolled in Phonological and Strategy Training (PHAST) or Phonics for Reading (PFR). Conditions differed in sublexical training with PHAST stressing multi-level connections and PFR emphasizing simple grapheme-phoneme correspondences. Thirty-seven children with RD, 3rd - 6th grade, were randomly assigned 60 lessons of PHAST or PFR. Crossed random-effects models allowed us to identify specific intervention elements that differentially impacted word-reading performance at posttest, with children in PHAST better able to read words with variant vowel pronunciations. Results suggest that sublexical emphasis influences transfer gains to word reading. PMID- 28596702 TI - Document retrieval on repetitive string collections. AB - Most of the fastest-growing string collections today are repetitive, that is, most of the constituent documents are similar to many others. As these collections keep growing, a key approach to handling them is to exploit their repetitiveness, which can reduce their space usage by orders of magnitude. We study the problem of indexing repetitive string collections in order to perform efficient document retrieval operations on them. Document retrieval problems are routinely solved by search engines on large natural language collections, but the techniques are less developed on generic string collections. The case of repetitive string collections is even less understood, and there are very few existing solutions. We develop two novel ideas, interleaved LCPs and precomputed document lists, that yield highly compressed indexes solving the problem of document listing (find all the documents where a string appears), top-k document retrieval (find the k documents where a string appears most often), and document counting (count the number of documents where a string appears). We also show that a classical data structure supporting the latter query becomes highly compressible on repetitive data. Finally, we show how the tools we developed can be combined to solve ranked conjunctive and disjunctive multi-term queries under the simple [Formula: see text] model of relevance. We thoroughly evaluate the resulting techniques in various real-life repetitiveness scenarios, and recommend the best choices for each case. PMID- 28596703 TI - Black holes in multi-fractional and Lorentz-violating models. AB - We study static and radially symmetric black holes in the multi-fractional theories of gravity with q-derivatives and with weighted derivatives, frameworks where the spacetime dimension varies with the probed scale and geometry is characterized by at least one fundamental length [Formula: see text]. In the q derivatives scenario, one finds a tiny shift of the event horizon. Schwarzschild black holes can present an additional ring singularity, not present in general relativity, whose radius is proportional to [Formula: see text]. In the multi fractional theory with weighted derivatives, there is no such deformation, but non-trivial geometric features generate a cosmological-constant term, leading to a de Sitter-Schwarzschild black hole. For both scenarios, we compute the Hawking temperature and comment on the resulting black-hole thermodynamics. In the case with q-derivatives, black holes can be hotter than usual and possess an additional ring singularity, while in the case with weighted derivatives they have a de Sitter hair of purely geometric origin, which may lead to a solution of the cosmological constant problem similar to that in unimodular gravity. Finally, we compare our findings with other Lorentz-violating models. PMID- 28596704 TI - Learning while (re)configuring: Business model innovation processes in established firms. AB - This study addresses the question of how established organizations develop new business models over time, using a process research approach to trace how four business model innovation trajectories unfold. With organizational learning as analytical lens, we discern two process patterns: "drifting" starts with an emphasis on experiential learning and shifts later to cognitive search; "leaping," in contrast, starts with an emphasis on cognitive search and shifts later to experiential learning. Both drifting and leaping can result in radical business model innovations, while their occurrence depends on whether a new business model takes off from an existing model and when it goes into operation. We discuss the implications of these findings for theory on business models and organizational learning. PMID- 28596705 TI - Evolving user needs and late-mover advantage. AB - We propose a generalized NK-model of late-mover advantage where late-mover firms leapfrog first-mover firms as user needs evolve over time. First movers face severe trade-offs between the provision of functionalities in which their products already excel and the additional functionalities requested by users later on. Late movers, by contrast, start searching when more functionalities are already known and typically come up with superior product designs. We also show that late-mover advantage is more probable for more complex technologies. Managerial implications follow. PMID- 28596708 TI - Riots of the Other: An analysis of societal reactions to contemporary riots in disadvantaged neighbourhoods in the Netherlands. AB - In this article I argue that there has been a change in the dynamics of riots in the Netherlands from the escalated political protests of the 1960s, 1970s and 1980s to public disturbances in disadvantaged neighbourhoods that lack a clearly articulated political component in the last two decades. This article examines the societal reactions such recent 'riots' evoke and the means by which the demarcated autonomous and exogenous groups are designated as 'the rioters' through a process of 'Othering'. It examines the 2007 'Slotervaart riot' as an exemplary case of such recent 'riots' in the Netherlands. It concludes that placing the focus on demarcated groups of Others during recent 'riots' in the Netherlands allowed broader social problems to be placed outside the 'normal' or 'pure' societal body. PMID- 28596709 TI - Crimmigration in Europe. PMID- 28596707 TI - Red cell distribution width (RDW) as a biomarker for respiratory failure in a pediatric ICU. AB - BACKGROUND: The red cell distribution width (RDW) is a widely available, inexpensive, and highly reproducible test that reflects the range of the red cell sizes. Any process that releases reticulocytes in the circulation will result in an increase in RDW. Elevated RDW values are linked to worsened pulmonary function in the adult population. We performed a retrospective cohort study to describe the association between RDW and respiratory failure in critically ill children in a in a pediatric intensive care unit (PICU) in a tertiary university hospital. SUBJECTS: All patients admitted between January 2009 and June 2015 were considered eligible for inclusion. METHODS: Retrospective cohort study. RESULTS: In total, 960 patients were included in the cohort analysis. Of those patients, 149 (15.5%) had elevated RDW values. RDW on admission was associated with lower 28 day ventilator-free days. The highest quintile of RDW was associated with the need for mechanical ventilation, even when correcting for anaemia, age and Pediatric Risk of Mortality (PRISM) scores. In the subgroup of ventilated patients, RDW was associated with nadir PaO2/FiO2(P/F) ratios. CONCLUSION: The RDW value on admission of our PICU patients is associated with a greater need for invasive mechanical ventilation, lower 28 day ventilator-free days and lower nadir P/F ratios in the patients with highest RDW values on admission. RDW may be a valuable, cheap and universally available, prognostic parameter for respiratory dysfunction in the PICU. PMID- 28596710 TI - Crimmigration checks in the internal border areas of the EU: Finding the discretion that matters. AB - Internal borders are a major but understudied site of crimmigration as most scholarship has focused on external borders (Van der Woude and Van Berlo, 2015). Internal borders were supposed to disappear under the principle of free movement within the European Union. But today we see EU member states policing the borders inside Schengen, checking identification, verifying passage, and regulating mobility in so-called 'gray zones'. This article investigates this type of policing within the EU, focusing on the case of the Netherlands. It argues that the policing of internal borders is highly dependent upon discretionary power, a significant factor in the crimmigration process that we do not know enough about. Following Hawkins (1992, 2003), Schneider (1992), and Bushway and Forst (2013) on discretion and discretionary decision-making, we examine the interaction between decisions by law-makers and policy-makers that create discretionary space for law enforcement officials on the ground, and the way in which these street-level bureaucrats perceive the discretionary space attributed to them. By zeroing in on the interaction between these two actors, we aim to find the discretionary decision that matters the most in terms of explaining the crimmigration practices, offering a more holistic and interdisciplinary approach to border control. We discuss the implications of this power and the consequences for the European Project as such. PMID- 28596711 TI - Framing migration and the process of crimmigration: A systematic analysis of the media representation of unauthorized immigrants in the Netherlands. AB - In this article we examine whether the proposal to criminalize illegal stay in the Netherlands was preceded by increased negative media attention for unauthorized immigrants. Using a corpus linguistics approach, we carried out a quantitative discourse analysis of all newspaper articles on unauthorized migrants over a period of 15 years. Our results show that the amount of media coverage actually strongly decreased in the years before the proposal, and this coverage was moreover increasingly less negative. This study thus nuances the somewhat popular belief that unauthorized migrants are increasingly portrayed in negative ways and shows that the framing of migrants as criminals is a more diffuse process in which the media seem to follow rather than fuel politics and policy. PMID- 28596712 TI - Child sexual exploitation and youth offending: A research note. AB - Links between child sexual exploitation (CSE) and youth offending should be better recognised, according to these preliminary research findings from the UK. Data from a leading CSE service provider and Youth Offending Team were analysed for the period 2001-2010 inclusive. Of CSE victims, 40 percent had offending records and recidivism rates were high. Together they committed 1586 offences - 5 percent of all local youth crime. Male and female offending behaviour differed significantly. The types of offences identified were potentially symptomatic of CSE. Referral to CSE services typically post-dated arrest, indicating that children were recognised first as offenders. Challenges in researching the interactions between these two complex issues are discussed. This study has important implications for youth justice policy and practice, both nationally and internationally. PMID- 28596706 TI - Regulating STING in health and disease. AB - The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases. This review will summarise the recent structural and functional findings of STING, and discuss how STING research has promoted the development of novel therapeutic approaches and experimental tools to improve treatment of tumour and autoimmune diseases. PMID- 28596715 TI - 2015 TMS William Hume-Rothery Award and Symposium. PMID- 28596713 TI - Performances of Different Fragment Sizes for Reduced Representation Bisulfite Sequencing in Pigs. AB - BACKGROUND: Reduced representation bisulfite sequencing (RRBS) has been widely used to profile genome-scale DNA methylation in mammalian genomes. However, the applications and technical performances of RRBS with different fragment sizes have not been systematically reported in pigs, which serve as one of the important biomedical models for humans. The aims of this study were to evaluate capacities of RRBS libraries with different fragment sizes to characterize the porcine genome. RESULTS: We found that the MspI-digested segments between 40 and 220 bp harbored a high distribution peak at 74 bp, which were highly overlapped with the repetitive elements and might reduce the unique mapping alignment. The RRBS library of 110-220 bp fragment size had the highest unique mapping alignment and the lowest multiple alignment. The cost-effectiveness of the 40-110 bp, 110 220 bp and 40-220 bp fragment sizes might decrease when the dataset size was more than 70, 50 and 110 million reads for these three fragment sizes, respectively. Given a 50-million dataset size, the average sequencing depth of the detected CpG sites in the 110-220 bp fragment size appeared to be deeper than in the 40-110 bp and 40-220 bp fragment sizes, and these detected CpG sties differently located in gene- and CpG island-related regions. CONCLUSIONS: In this study, our results demonstrated that selections of fragment sizes could affect the numbers and sequencing depth of detected CpG sites as well as the cost-efficiency. No single solution of RRBS is optimal in all circumstances for investigating genome-scale DNA methylation. This work provides the useful knowledge on designing and executing RRBS for investigating the genome-wide DNA methylation in tissues from pigs. PMID- 28596714 TI - Response to "The Use of Meta-Analysis to Compare and Select Offender Risk Instruments". PMID- 28596716 TI - Cognitive Reactivity: Cultural Adaptation and Psychometric Testing of the Persian Version of the Leiden Index of Depression Sensitivity Revised (LEIDS-R) in an Iranian Sample. AB - Cognitive reactivity (CR) to the experimental induction of sad mood has been found to predict relapse in recovered depressed patients. The Leiden Index of Depression Sensitivity Revised (LEIDS-R) is a self-report measure of CR. The aim of the present study was to establish the validity and reliability of the Persian version of the LEIDS-R. The participants were recovered depressed and non depressed Iranian individuals (n = 833). The analyses included content validation, factor analysis, construct validity, and reliability testing. Preliminary construct validation analysis confirmed that factor analysis was appropriate for the Persian version of the LEIDS-R. Factor analysis displayed similar factor loadings to the original English version. The total internal consistency of the translated version, which was assessed using Cronbach's alpha coefficient, was equal to 0.90. The test-retest reliability of the total score was equal to that of the test-retest conducted after a two-week interval at 0.94. Content validity, face validity, and construct validity, as well as reliability analysis were all found to be satisfactory for the Persian version of the LEIDS R. The Persian version of the LEIDS-R appears to be valid and reliable for use in future studies, and has properties comparable to the original version and to that obtained in previous studies. PMID- 28596718 TI - Mass spectrometry based metabolomics for in vitro systems pharmacology: pitfalls, challenges, and computational solutions. AB - INTRODUCTION: Mass spectrometry based metabolomics has become a promising complement and alternative to transcriptomics and proteomics in many fields including in vitro systems pharmacology. Despite several merits, metabolomics based on liquid chromatography mass spectrometry (LC-MS) is a developing area that is yet attached to several pitfalls and challenges. To reach a level of high reliability and robustness, these issues need to be tackled by implementation of refined experimental and computational protocols. OBJECTIVES: This study illustrates some key pitfalls in LC-MS based metabolomics and introduces an automated computational procedure to compensate for them. METHOD: Non-cancerous mammary gland derived cells were exposed to 27 chemicals from four pharmacological classes plus a set of six pesticides. Changes in the metabolome of cell lysates were assessed after 24 h using LC-MS. A data processing pipeline was established and evaluated to handle issues including contaminants, carry over effects, intensity decay and inherent methodology variability and biases. A key component in this pipeline is a latent variable method called OOS-DA (optimal orthonormal system for discriminant analysis), being theoretically more easily motivated than PLS-DA in this context, as it is rooted in pattern classification rather than regression modeling. RESULT: The pipeline is shown to reduce experimental variability/biases and is used to confirm that LC-MS spectra hold drug class specific information. CONCLUSION: LC-MS based metabolomics is a promising methodology, but comes with pitfalls and challenges. Key difficulties can be largely overcome by means of a computational procedure of the kind introduced and demonstrated here. The pipeline is freely available on www.github.com/stephanieherman/MS-data-processing. PMID- 28596717 TI - Integration of metabolomic and transcriptomic networks in pregnant women reveals biological pathways and predictive signatures associated with preeclampsia. AB - INTRODUCTION: Preeclampsia is a leading cause of maternal and fetal mortality worldwide, yet its exact pathogenesis remains elusive. OBJECTIVES: This study, nested within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), aimed to develop integrated omics models of preeclampsia that have utility in both prediction and in the elucidation of underlying biological mechanisms. METHODS: Metabolomic profiling was performed on first trimester plasma samples of 47 pregnant women from VDAART who subsequently developed preeclampsia and 62 controls with healthy pregnancies, using liquid-chromatography tandem mass spectrometry. Metabolomic profiles were generated based on logistic regression models and assessed using Received Operator Characteristic Curve analysis. These profiles were compared to profiles from generated using third trimester samples. The first trimester metabolite profile was then integrated with a pre-existing transcriptomic profile using network methods. RESULTS: In total, 72 (0.9%) metabolite features were associated (p<0.01) with preeclampsia after adjustment for maternal age, race, and gestational age. These features had moderate to good discriminatory ability; in ROC curve analyses a summary score based on these features displayed an area under the curve (AUC) of 0.794 (95%CI 0.700, 0.888). This profile retained the ability to distinguish preeclamptic from healthy pregnancies in the third trimester (AUC:0.762 (95% CI 0.663, 0.860)). Additionally, metabolite set enrichment analysis identified common pathways, including glycerophospholipid metabolism, at the two time-points. Integration with the transcriptomic signature refined these results suggesting a particular role for lipid imbalance, immune function and the circulatory system. CONCLUSIONS: These findings suggest it is possible to develop a predictive metabolomic profile of preeclampsia. This profile is characterized by changes in lipid and amino acid metabolism and dysregulation of immune response and can be refined through interaction with transcriptomic data. However validation in larger and more diverse populations is required. PMID- 28596719 TI - A methodology for elucidating regulatory mechanisms leading to changes in lipid profiles. AB - INTRODUCTION: It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations. OBJECTIVES: This work simplifies this process. METHODS: A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids. RESULTS: The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1-an mRNA stabiliser. CONCLUSION: This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations. PMID- 28596720 TI - AAV-Mediated Gene Supplementation Therapy in Achromatopsia Type 2: Preclinical Data on Therapeutic Time Window and Long-Term Effects. AB - Achromatopsia type 2 (ACHM2) is a severe, inherited eye disease caused by mutations in the CNGA3 gene encoding the alpha subunit of the cone photoreceptor cyclic nucleotide-gated (CNG) channel. Patients suffer from strongly impaired daylight vision, photophobia, nystagmus, and lack of color discrimination. We have previously shown in the Cnga3 knockout (KO) mouse model of ACHM2 that gene supplementation therapy is effective in rescuing cone function and morphology and delaying cone degeneration. In our preclinical approach, we use recombinant adeno associated virus (AAV) vector-mediated gene transfer to express the murine Cnga3 gene under control of the mouse blue opsin promoter. Here, we provide novel data on the efficiency and permanence of such gene supplementation therapy in Cnga3 KO mice. Specifically, we compare the influence of two different AAV vector capsids, AAV2/5 (Y719F) and AAV2/8 (Y733F), on restoration of cone function, and assess the effect of age at time of treatment on the long-term outcome. The evaluation included in vivo analysis of retinal function using electroretinography (ERG) and immunohistochemical analysis of vector-driven Cnga3 transgene expression. We found that both vector capsid serotypes led to a comparable rescue of cone function over the observation period between 4 weeks and 3 months post treatment. In addition, a clear therapeutic effect was present in mice treated at 2 weeks of age as well as in mice treated at 3 months of age at the first assessment at 4 weeks after treatment. Importantly, the effect extended in both cases over the entire observation period of 12 months post treatment. However, the average ERG amplitude levels differed between the two groups, suggesting a role of the absolute age, or possibly, the associated state of the degeneration, on the achievable outcome. In summary, we found that the therapeutic time window of opportunity for AAV-mediated Cnga3 gene supplementation therapy in the Cnga3 KO mouse model extends at least to an age of 3 months, but is presumably limited by the condition, number and topographical distribution of remaining cones at the time of treatment. No impact of the choice of capsid on the therapeutic success was detected. PMID- 28596721 TI - Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini Review. AB - Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB1) represents the most relevant target molecule of cannabinoids so far. One main function of central CB1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade of CB1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB1-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB1 activation but also contributing to control of feeding behavior will be introduced. PMID- 28596723 TI - The 11S Proteasomal Activator REGgamma Impacts Polyglutamine-Expanded Androgen Receptor Aggregation and Motor Neuron Viability through Distinct Mechanisms. AB - Spinal and bulbar muscular atrophy (SBMA) is caused by expression of a polyglutamine (polyQ)-expanded androgen receptor (AR). The inefficient nuclear proteasomal degradation of the mutant AR results in the formation of nuclear inclusions containing amino-terminal fragments of the mutant AR. PA28gamma (also referred to as REGgamma) is a nuclear 11S-proteasomal activator with limited proteasome activation capabilities compared to its cytoplasmic 11S (PA28alpha, PA28beta) counterparts. To clarify the role of REGgamma in polyQ-expanded AR metabolism, we carried out genetic and biochemical studies in cell models of SBMA. Overexpression of REGgamma in a PC12 cell model of SBMA increased polyQ expanded AR aggregation and contributed to polyQ-expanded AR toxicity in the presence of dihydrotestosterone (DHT). These effects of REGgamma were independent of its association with the proteasome and may be due, in part, to the decreased binding of polyQ-expanded AR by the E3 ubiquitin-ligase MDM2. Unlike its effects in PC12 cells, REGgamma overexpression rescued transgenic SBMA motor neurons from DHT-induced toxicity in a proteasome binding-dependent manner, suggesting that the degradation of a specific 11S proteasome substrate or substrates promotes motor neuron viability. One potential substrate that we found to play a role in mutant AR toxicity is the splicing factor SC35. These studies reveal that, depending on the cellular context, two biological roles for REGgamma impact cell viability in the face of polyQ-expanded AR; a proteasome binding-independent mechanism directly promotes mutant AR aggregation while a proteasome binding dependent mechanism promotes cell viability. The balance between these functions likely determines REGgamma effects on polyQ-expanded AR-expressing cells. PMID- 28596722 TI - Unique Structural Features of Membrane-Bound C-Terminal Domain Motifs Modulate Complexin Inhibitory Function. AB - Complexin is a small soluble presynaptic protein that interacts with neuronal SNARE proteins in order to regulate synaptic vesicle exocytosis. While the SNARE binding central helix of complexin is required for both the inhibition of spontaneous fusion and the facilitation of synchronous fusion, the disordered C terminal domain (CTD) of complexin is specifically required for its inhibitory function. The CTD of worm complexin binds to membranes via two distinct motifs, one of which undergoes a membrane curvature dependent structural transition that is required for efficient inhibition of neurotransmitter release, but the conformations of the membrane-bound motifs remain poorly characterized. Visualizing these conformations is required to clarify the mechanisms by which complexin membrane interactions regulate its function. Here, we employ optical and magnetic resonance spectroscopy to precisely define the boundaries of the two CTD membrane-binding motifs and to characterize their conformations. We show that the curvature dependent amphipathic helical motif features an irregular element of helical structure, likely a pi-bulge, and that this feature is important for complexin inhibitory function in vivo. PMID- 28596725 TI - A Ternary Brain-Computer Interface Based on Single-Trial Readiness Potentials of Self-initiated Fine Movements: A Diversified Classification Scheme. AB - In recent years, the readiness potential (RP), a type of pre-movement neural activity, has been investigated for asynchronous electroencephalogram (EEG)-based brain-computer interfaces (BCIs). Since the RP is attenuated for involuntary movements, a BCI driven by RP alone could facilitate intentional control amid a plethora of unintentional movements. Previous studies have mainly attempted binary single-trial classification of RP. An RP-based BCI with three or more states would expand the options for functional control. Here, we propose a ternary BCI based on single-trial RPs. This BCI classifies amongst an idle state, a left hand and a right hand self-initiated fine movement. A pipeline of spatio temporal filtering with per participant parameter optimization was used for feature extraction. The ternary classification was decomposed into binary classifications using a decision-directed acyclic graph (DDAG). For each class pair in the DDAG structure, an ordered diversified classifier system (ODCS-DDAG) was used to select the best among various classification algorithms or to combine the results of different classification algorithms. Using EEG data from 14 participants performing self-initiated left or right key presses, punctuated with rest periods, we compared the performance of ODCS-DDAG to a ternary classifier and four popular multiclass decomposition methods using only a single classification algorithm. ODCS-DDAG had the highest performance (0.769 Cohen's Kappa score) and was significantly better than the ternary classifier and two of the four multiclass decomposition methods. Our work supports further study of RP based BCI for intuitive asynchronous environmental control or augmentative communication. PMID- 28596726 TI - Ability to Gain Control Over One's Own Brain Activity and its Relation to Spiritual Practice: A Multimodal Imaging Study. AB - Spiritual practice, such as prayer or meditation, is associated with focusing attention on internal states and self-awareness processes. As these cognitive control mechanisms presumably are also important for neurofeedback (NF), we investigated whether people who pray frequently (N = 20) show a higher ability of self-control over their own brain activity compared to a control group of individuals who rarely pray (N = 20). All participants underwent structural magnetic resonance imaging (MRI) and one session of sensorimotor rhythm (SMR, 12 15 Hz) based NF training. Individuals who reported a high frequency of prayer showed improved NF performance compared to individuals who reported a low frequency of prayer. The individual ability to control one's own brain activity was related to volumetric aspects of the brain. In the low frequency of prayer group, gray matter volumes in the right insula and inferior frontal gyrus were positively associated with NF performance, supporting prior findings that more general self-control networks are involved in successful NF learning. In contrast, participants who prayed regularly showed a negative association between gray matter volume in the left medial orbitofrontal cortex (Brodmann's area (BA) 10) and NF performance. Due to their regular spiritual practice, they might have been more skillful in gating incoming information provided by the NF system and avoiding task-irrelevant thoughts. PMID- 28596727 TI - Executive Mechanisms for Thinking about Negative Situations in Both Cooperative and Non-Cooperative Contexts. AB - Mentalizing is a fundamental aspect of social cognition that includes understanding the mental states of others. This process involves the participation of a well-defined set of brain regions. However, it is still unknown how different contextual situations, such as previous cooperative or non cooperative interactions, can modulate the brain activity related to the inference of others' mental states. Hence, this study investigated whether a previous social interaction can modulate the neural mechanisms involved in a way to response to inferred mental states of cooperators and non-cooperators in positive vs. negative emotional situations. Participants first engaged in a Dictator game with cooperator and non-cooperator confederates. Then, in an fMRI setup, participants had to infer the mental states of the cooperator and non cooperator confederates under positive and negative situations. Results showed that in addition to the mentalizing network, inferring mental states recruited occipital and cerebellar areas in the cooperative context. A differential pattern of activity that depended on the emotional valence of the situation was also detected, i.e., negative situations recruited prefrontal cortex (PFC) in both contexts, while temporal regions were recruited only for the non-cooperative context. Overall, these results suggest that our previous experiences with others modulate the brain activity related to the inferences we make about their mental states in specific emotional situations. PMID- 28596724 TI - Recent Advances in Translational Magnetic Resonance Imaging in Animal Models of Stress and Depression. AB - Magnetic resonance imaging (MRI) is a valuable translational tool that can be used to investigate alterations in brain structure and function in both patients and animal models of disease. Regional changes in brain structure, functional connectivity, and metabolite concentrations have been reported in depressed patients, giving insight into the networks and brain regions involved, however preclinical models are less well characterized. The development of more effective treatments depends upon animal models that best translate to the human condition and animal models may be exploited to assess the molecular and cellular alterations that accompany neuroimaging changes. Recent advances in preclinical imaging have facilitated significant developments within the field, particularly relating to high resolution structural imaging and resting-state functional imaging which are emerging techniques in clinical research. This review aims to bring together the current literature on preclinical neuroimaging in animal models of stress and depression, highlighting promising avenues of research toward understanding the pathological basis of this hugely prevalent disorder. PMID- 28596728 TI - Have Standard Tests of Cognitive Function Been Misappropriated in the Study of Cognitive Enhancement? AB - In the past decade, there has emerged a vast research literature dealing with attempts to harness brain plasticity in older adults, with a view to improving cognitive function. Since cognitive training (CT) has shown restricted utility in this regard, attention has increasingly turned to interventions that use adjunct procedures such as motor training or physical activity (PA). As evidence builds that these have some efficacy, it becomes necessary to ensure that the outcome measures being used to infer causal influence upon cognitive function are subjected to appropriate critical appraisal. It has been highlighted previously that the choice of specific tasks used to demonstrate transfer to the cognitive domain is of critical importance. In the context of most intervention studies, standardized tests and batteries of cognitive function are de rigueur. The argument presented here is that the latent constructs to which these tests relate are not usually subject to a sufficient level of analytic scrutiny. We present the historical origins of some exemplar tests, and give particular consideration to the limits on explanatory scope that are implied by their composition and the nature of their deployment. In addition to surveying the validity of these tests when used to appraise intervention-related changes in cognitive function, we also consider their neurophysiological correlates. In particular, we argue that the broadly distributed brain activity associated with the performance of many tests of cognitive function, extending to the classical motor networks, permits the impact of interventions based on motor training or PA to be better understood. PMID- 28596729 TI - Detection and Evaluation of Spatio-Temporal Spike Patterns in Massively Parallel Spike Train Data with SPADE. AB - Repeated, precise sequences of spikes are largely considered a signature of activation of cell assemblies. These repeated sequences are commonly known under the name of spatio-temporal patterns (STPs). STPs are hypothesized to play a role in the communication of information in the computational process operated by the cerebral cortex. A variety of statistical methods for the detection of STPs have been developed and applied to electrophysiological recordings, but such methods scale poorly with the current size of available parallel spike train recordings (more than 100 neurons). In this work, we introduce a novel method capable of overcoming the computational and statistical limits of existing analysis techniques in detecting repeating STPs within massively parallel spike trains (MPST). We employ advanced data mining techniques to efficiently extract repeating sequences of spikes from the data. Then, we introduce and compare two alternative approaches to distinguish statistically significant patterns from chance sequences. The first approach uses a measure known as conceptual stability, of which we investigate a computationally cheap approximation for applications to such large data sets. The second approach is based on the evaluation of pattern statistical significance. In particular, we provide an extension to STPs of a method we recently introduced for the evaluation of statistical significance of synchronous spike patterns. The performance of the two approaches is evaluated in terms of computational load and statistical power on a variety of artificial data sets that replicate specific features of experimental data. Both methods provide an effective and robust procedure for detection of STPs in MPST data. The method based on significance evaluation shows the best overall performance, although at a higher computational cost. We name the novel procedure the spatio-temporal Spike PAttern Detection and Evaluation (SPADE) analysis. PMID- 28596730 TI - Integration of Continuous-Time Dynamics in a Spiking Neural Network Simulator. AB - Contemporary modeling approaches to the dynamics of neural networks include two important classes of models: biologically grounded spiking neuron models and functionally inspired rate-based units. We present a unified simulation framework that supports the combination of the two for multi-scale modeling, enables the quantitative validation of mean-field approaches by spiking network simulations, and provides an increase in reliability by usage of the same simulation code and the same network model specifications for both model classes. While most spiking simulations rely on the communication of discrete events, rate models require time-continuous interactions between neurons. Exploiting the conceptual similarity to the inclusion of gap junctions in spiking network simulations, we arrive at a reference implementation of instantaneous and delayed interactions between rate-based models in a spiking network simulator. The separation of rate dynamics from the general connection and communication infrastructure ensures flexibility of the framework. In addition to the standard implementation we present an iterative approach based on waveform-relaxation techniques to reduce communication and increase performance for large-scale simulations of rate-based models with instantaneous interactions. Finally we demonstrate the broad applicability of the framework by considering various examples from the literature, ranging from random networks to neural-field models. The study provides the prerequisite for interactions between rate-based and spiking models in a joint simulation. PMID- 28596731 TI - Gait Is Associated with Cognitive Flexibility: A Dual-Tasking Study in Healthy Older People. AB - Objectives: To analyze which gait parameters are primarily influenced by cognitive flexibility, and whether such an effect depends on the walking condition used. Design: Cross-sectional analysis. Setting: Tubingen evaluation of Risk factors for Early detection of Neurodegenerative Disorders. Participants: A total of 661 non-demented individuals (49-80 years). Measurements: A gait assessment with four conditions was performed: a 20 m walk at convenient speed (C), at fast speed (F), at fast speed while checking boxes (FB), and while subtracting serial 7s (FS). Seven gait parameters from a wearable sensor-unit (McRoberts, Netherlands) were compared with delta Trail-Making-Test (dTMT) values, which is a measure of cognitive flexibility. Walking strategies of good and poor dTMT performers were compared by evaluating the patterns of gait parameters across conditions. Results: Five parameters correlated significantly with the dTMT in the FS condition, two parameters in the F and FB condition, and none in the C condition. Overall correlations were relatively weak. Gait speed was the gait parameter that most strongly correlated with the dTMT (r2 = 7.4%). In good, but not poor, dTMT performers differences between FB and FS were significantly different in variability-associated gait parameters. Conclusion: Older individuals need cognitive flexibility to perform difficult walking conditions. This association is best seen in gait speed. New and particularly relevant for recognition and training of deficits is that older individuals with poor cognitive flexibility have obviously fewer resources to adapt to challenging walking conditions. Our findings partially explain gait deficits in older adults with poor cognitive flexibility. PMID- 28596732 TI - Moderating Effects of Cortisol on Neural-Cognitive Association in Cognitively Normal Elderly Subjects. AB - Cortisol homeostasis is important for healthy brain and cognitive aging. The aim of the current study is to investigate the role of serum cortisol levels in the relationship between regional brain volumes and cognitive processing speed in a group of cognitively normal elderly subjects. Forty-one healthy elderly participants were from a parallel longitudinal study. The reported data in this study reflects baseline measurements. Whole-brain anatomical scanning was performed using a 3.0 Tesla Philips Medical Systems Achieva scanner. Cognitive processing speed was assessed by the digit-symbol and symbol search tests, from the Chinese version of the Wechsler Adult Intelligence Scale-third edition (WAIS III). Serum cortisol levels (sampled in the late morning) were measured by ELISA kits. Whole-brain regression analysis revealed that serum cortisol levels positively predicted the white matter volumes (WMV) of the right thalamus, the gray matter volumes (GMV) of the left thalamus and right cerebellar tonsil, and negatively predicted the WMV and GMV of the left middle temporal gyrus (MTG) in 41 healthy elderly participants. Furthermore, serum cortisol significantly moderated the relationship between the GMV of the left MTG and processing speed, as well as the GMV of the left thalamus and processing speed. This study provided the first piece of evidence supporting serum cortisol levels in moderating the relationship between regional brain volumes and processing speed in healthy elderly subjects. This observation enriches our understanding of the role of cortisol in brain morphology and cognitive functioning. PMID- 28596733 TI - Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People. AB - Blood brain barrier (BBB) plays a crucial role in maintaining homeostasis of microenvironment that is essential to neural function of the central nervous system (CNS). When facing various extrinsic or intrinsic stimuli, BBB is damaged which is an early event in pathogenesis of a variety of neurological diseases in old patients including acute and chronic cerebral ischemia, Alzheimer's disease and etc. Treatments that could maintain the integrity of BBB may prevent neurological diseases following various stimuli. Old people often face a common stress of sepsis, during which lipopolysaccharide (LPS) is released into circulation and the integrity of BBB is damaged. Of note, there is a significant decrease of melatonin level in old people and animal. Melatonin has been shown to preserves BBB integrity and permeability via a variety of pathways: inhibition of matrix metalloproteinase-9 (MMP-9), inhibition of NADPH oxidase-2, and impact on silent information regulator 1 (SIRT1) and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. More important, a recent study showed that melatonin supplementation alleviates LPS induced BBB damage in old mice through activating AMP-activated protein kinase (AMPK) and inhibiting gp91phox, suggesting that melatonin supplementation may help prevent neurological diseases through maintaining the integrity of BBB in old people. PMID- 28596734 TI - Characterization and Expression of Sphingosine 1-Phosphate Receptors in Human and Rat Heart. AB - Aim: Sphingosine 1-phosphate (S1P), sphingolipid derivatives are known anti inflammatory, anti-apoptotic, and anti-oxidant agent. S1P have been demonstrated to have a role in the cardiovascular system. The purpose of this study was to understand the precise expression and distribution of S1P receptors (S1PRs) in human and rat cardiovascular tissues to know the significance and possible implementation of our experimental studies in rat models. Methods and Results: In this study, we investigated the localization of S1PRs in human heart samples from cardiac surgery department, University of Verona Hospital and rat samples. Immunohistochemical investigation of paraffin-embedded sections illustrated diffused staining of the myocardial samples from human and rat. The signals of the human heart were similar to those of the rat heart in all chambers of the heart. The immunohistochemical expression levels correlated well with the results of RT-PCR-based analysis and western blotting. We confirmed by all techniques that S1PR1 expressed strongly as compared to S1PR3, and are uniformly distributed in all chambers of the heart with no significant difference in human and rat myocardial tissue. S1PR2 expression was significantly weak while S1PR4 and S1PR5 were not detectable in RT-PCR results in both human and rat heart. Conclusion: These results indicate that experimental studies using S1PR agonists on rat models are more likely to have a potential for translation into clinical studies, and second important information revealed by this study is, S1P receptor agonist can be used for cardioprotection in global ischemia-reperfusion injury. PMID- 28596735 TI - Diet Composition and Variability of Wild Octopus vulgaris and Alloteuthis media (Cephalopoda) Paralarvae: a Metagenomic Approach. AB - The high mortality of cephalopod early stages is the main bottleneck to grow them from paralarvae to adults in culture conditions, probably because the inadequacy of the diet that results in malnutrition. Since visual analysis of digestive tract contents of paralarvae provides little evidence of diet composition, the use of molecular tools, particularly next generation sequencing (NGS) platforms, offers an alternative to understand prey preferences and nutrient requirements of wild paralarvae. In this work, we aimed to determine the diet of paralarvae of the loliginid squid Alloteuthis media and to enhance the knowledge of the diet of recently hatched Octopus vulgaris paralarvae collected in different areas and seasons in an upwelling area (NW Spain). DNA from the dissected digestive glands of 32 A. media and 64 O. vulgaris paralarvae was amplified with universal primers for the mitochondrial gene COI, and specific primers targeting the mitochondrial gene 16S gene of arthropods and the mitochondrial gene 16S of Chordata. Following high-throughput DNA sequencing with the MiSeq run (Illumina), up to 4,124,464 reads were obtained and 234,090 reads of prey were successfully identified in 96.87 and 81.25% of octopus and squid paralarvae, respectively. Overall, we identified 122 Molecular Taxonomic Units (MOTUs) belonging to several taxa of decapods, copepods, euphausiids, amphipods, echinoderms, molluscs, and hydroids. Redundancy analysis (RDA) showed seasonal and spatial variability in the diet of O. vulgaris and spatial variability in A. media diet. General Additive Models (GAM) of the most frequently detected prey families of O. vulgaris revealed seasonal variability of the presence of copepods (family Paracalanidae) and ophiuroids (family Euryalidae), spatial variability in presence of crabs (family Pilumnidae) and preference in small individual octopus paralarvae for cladocerans (family Sididae) and ophiuroids. No statistically significant variation in the occurrences of the most frequently identified families was revealed in A. media. Overall, these results provide new clues about dietary preferences of wild cephalopod paralarvae, thus opening up new scenarios for research on trophic ecology and digestive physiology under controlled conditions. PMID- 28596736 TI - Claudin Loss-of-Function Disrupts Tight Junctions and Impairs Amelogenesis. AB - Claudins are a family of proteins that forms paracellular barriers and pores determining tight junctions (TJ) permeability. Claudin-16 and -19 are pore forming TJ proteins allowing calcium and magnesium reabsorption in the thick ascending limb of Henle's loop (TAL). Loss-of-function mutations in the encoding genes, initially identified to cause Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC), were recently shown to be also involved in Amelogenesis Imperfecta (AI). In addition, both claudins were expressed in the murine tooth germ and Claudin-16 knockout (KO) mice displayed abnormal enamel formation. Claudin-3, an ubiquitous claudin expressed in epithelia including kidney, acts as a barrier-forming tight junction protein. We determined that, similarly to claudin-16 and claudin-19, claudin-3 was expressed in the tooth germ, more precisely in the TJ located at the apical end of secretory ameloblasts. The observation of Claudin-3 KO teeth revealed enamel defects associated to impaired TJ structure at the secretory ends of ameloblasts and accumulation of matrix proteins in the forming enamel. Thus, claudin-3 protein loss-of-function disturbs amelogenesis similarly to claudin-16 loss-of-function, highlighting the importance of claudin proteins for the TJ structure. These findings unravel that loss-of-function of either pore or barrier-forming TJ proteins leads to enamel defects. Hence, the major structural function of claudin proteins appears essential for amelogenesis. PMID- 28596737 TI - Commentary: Validation of a Ramp Running Protocol for Determination of the True VO2max in Mice. PMID- 28596738 TI - Intensity- and Duration-Based Options to Regulate Endurance Training. AB - The regulation of endurance training is usually based on the prescription of exercise intensity. Exercise duration, another important variable of training load, is rarely prescribed by individual measures and mostly set from experience. As the specific exercise duration for any intensity plays a substantial role regarding the different kind of cellular stressors, degree, and kind of fatigue as well as training effects, concepts integrating the prescription of both intensity and duration within one model are needed. An according recent approach was the critical power concept which seems to have a physiological basis; however, the mathematical approach of this concept does not allow applying the three zones/two threshold model of metabolism and its different physiological consequences. Here we show the combination of exercise intensity and duration prescription on an individual basis applying the power/speed to distance/time relationship. The concept is based on both the differentiation of intensities by two lactate or gas exchange variables derived turn points, and on the relationship between power (or velocity) and duration (or distance). The turn points define three zones of intensities with distinct acute metabolic, hormonal, and cardio-respiratory responses for endurance exercise. A maximal duration exists for any single power or velocity such as described in the power-duration relationship. Using percentages of the maximal duration allows regulating fatigue, recovery time, and adaptation for any single endurance training session. Four domains of duration with respect to induced fatigue can be derived from maximal duration obtained by the power-duration curve. For any micro-cycle, target intensities and durations may be chosen on an individual basis. The model described here is the first conceptual framework of integrating physiologically defined intensities and fatigue related durations to optimize high-performance exercise training. PMID- 28596740 TI - Ultrasound Imaging of Mouse Fetal Intracranial Hemorrhage Due to Ischemia/Reperfusion. AB - Despite vast improvement in perinatal care during the 30 years, the incidence rate of neonatal encephalopathy remains unchanged without any further Progress towards preventive strategies for the clinical impasse. Antenatal brain injury including fetal intracranial hemorrhage caused by ischemia/reperfusion is known as one of the primary triggers of neonatal injury. However, the mechanisms of antenatal brain injury are poorly understood unless better predictive models of the disease are developed. Here we show a mouse model for fetal intracranial hemorrhage in vivo developed to investigate the actual timing of hypoxia-ischemic events and their related mechanisms of injury. Intrauterine growth restriction mouse fetuses were exposed to ischemia/reperfusion cycles by occluding and opening the uterine and ovarian arteries in the mother. The presence and timing of fetal intracranial hemorrhage caused by the ischemia/reperfusion were measured with histological observation and ultrasound imaging. Protein-restricted diet increased the risk of fetal intracranial hemorrhage. The monitoring of fetal brains by ultrasound B-mode imaging clarified that cerebral hemorrhage in the fetal brain occurred after the second ischemic period. Three-dimensional ultrasound power Doppler imaging visualized the disappearance of main blood flows in the fetal brain. These indicate a breakdown of cerebrovascular autoregulation which causes the fetal intracranial hemorrhage. This study supports the fact that the ischemia/reperfusion triggers cerebral hemorrhage in the fetal brain. The present method enables us to noninvasively create the cerebral hemorrhage in a fetus without directly touching the body but with repeated occlusion and opening of the uterine and ovarian arteries in the mother. PMID- 28596739 TI - RANK/RANKL/OPG Signalization Implication in Periodontitis: New Evidence from a RANK Transgenic Mouse Model. AB - Periodontitis is based on a complex inflammatory over-response combined with possible genetic predisposition factors. The RANKL/RANK/OPG signaling pathway is implicated in bone resorption through its key function in osteoclast differentiation and activation, as well as in the inflammatory response. This central element of osteo-immunology has been suggested to be perturbed in several diseases, including periodontitis, as it is a predisposing factor for this disease. The aim of the present study was to validate this hypothesis using a transgenic mouse line, which over-expresses RANK (RTg) and develops a periodontitis-like phenotype at 5 months of age. RTg mice exhibited severe alveolar bone loss, an increased number of TRAP positive cells, and disorganization of periodontal ligaments. This phenotype was more pronounced in females. We also observed dental root resorption lacunas. Hyperplasia of the gingival epithelium, including Malassez epithelial rests, was visible as early as 25 days, preceding any other symptoms. These results demonstrate that perturbations of the RANKL/RANK/OPG system constitute a core element of periodontitis, and more globally, osteo-immune diseases. PMID- 28596741 TI - Commentary: A Neural Basis for the Acquired Capacity for Suicide. PMID- 28596742 TI - Assessing the Growth of Ethical Banking: Some Evidence from Spanish Customers. AB - Aristotle, who, having predated Adam Smith by 2000 years, deserves to be recognized as the world's first economist (Solomon, 1995), distinguished between two different senses of what we call economics: oikonomikos, or household trading, which he approved of and considered essential to the working of any even slightly complex society, and chrematisike, or trade for profit, which he considered selfish and utterly devoid of virtue, calling those who engaged in such practices "parasites". Of course, consumers do not purchase and invest for solely economic reasons (Polanyi, 1944). Interest in ethics in economics has been the subject of continuous study. In this regard, the recent financial crisis has had not only economic, but also social, psychological, political, and ethical consequences, which have impacted the financial and banking system. Consumers are no longer drawn only by the economic return but also by ethical factors. Ethical banking is on the rise. This paper aims to explain the reasons for the growth in ethical banking and to answer the following questions: can banking consumers investors change the characterization of the banking system? Can ethical banking gain ground on traditional banking? And is ethical banking really effective? To this end, it will examine the Spanish case, using econometric causal regression models to identify the reasons why consumers decide to invest in ethical banking and determine its role in the Spanish economy. PMID- 28596743 TI - General and Food-Specific Inhibitory Control As Moderators of the Effects of the Impulsive Systems on Food Choices. AB - The present study aimed to extend the application of the reflective-impulsive model to restrained eating and explore the effect of automatic attention (impulsive system) on food choices. Furthermore, we examined the moderating effects of general inhibitory control (G-IC) and food-specific inhibitory control (F-IC) on successful and unsuccessful restrained eaters (US-REs). Automatic attention was measured using "the EyeLink 1000," which tracked eye movements during the process of making food choices, and G-IC and F-IC were measured using the Stop-Signal Task. The results showed that food choices were related to automatic attention and that G-IC and F-IC moderated the predictive relationship between automatic attention and food choices. Furthermore, among successful restrained eaters (S-REs), automatic attention to high caloric foods did not predict food choices, regardless of whether G-IC or F-IC was high or low. Whereas food choice was positively correlated with automatic attention among US-REs with poor F-IC, this pattern was not observed in those with poor G-IC. In conclusion, the S-REs had more effective self-management skills and their food choices were affected less by automatic attention and inhibitory control. Unsuccessful restrained eating was associated with poor F-IC (not G-IC) and greater automatic attention to high caloric foods. Thus, clinical interventions should focus on enhancing F-IC, not G-IC, and on reducing automatic attention to high caloric foods. PMID- 28596744 TI - Commentary: The Social Dilemma of Autonomous Vehicles. PMID- 28596745 TI - Negative Affectivity Predicts Lower Quality of Life and Metabolic Control in Type 2 Diabetes Patients: A Structural Equation Modeling Approach. AB - Introduction: It is essential to consider the clinical assessment of psychological aspects in patients with Diabetes Mellitus (DM), in order to prevent potentially adverse self-management care behaviors leading to diabetes related complications, including declining levels of Quality of Life (QoL) and negative metabolic control. Purpose: In the framework of Structural Equation Modeling (SEM), the specific aim of this study is to evaluate the influence of distressed personality factors as Negative Affectivity (NA) and Social Inhibition (SI) on diabetes-related clinical variables (i.e., QoL and glycemic control). Methods: The total sample consists of a clinical sample, including 159 outpatients with Type 2 Diabetes Mellitus (T2DM), and a control group composed of 102 healthy respondents. All participants completed the following self- rating scales: The Type D Scale (DS14) and the World Health Organization QoL Scale (WHOQOLBREF). Furthermore, the participants of the clinical group were assessed for HbA1c, disease duration, and BMI. The observed covariates were BMI, gender, and disease duration, while HbA1c was considered an observed variable. Results: SEM analysis revealed significant differences between groups in regards to the latent construct of NA and the Environmental dimension of QoL. For the clinical sample, SEM showed that NA had a negative impact on both QoL dimensions and metabolic control. Conclusions: Clinical interventions aiming to improve medication adherence in patients with T2DM should include the psychological evaluation of Type D Personality traits, by focusing especially on its component of NA as a significant risk factor leading to negative health outcomes. PMID- 28596746 TI - A Systematic Review of Psychosocial Interventions to Cancer Caregivers. AB - Objective: To systematically review the effect of psychosocial interventions on improving QoL, depression and anxiety of cancer caregivers. Methods: We conducted a systematic review of psychosocial interventions among adult cancer caregivers published from 2011 to 2016. PsycINFO, PubMed, Proquest, Cochrane Library, Embase, Applied Social Sciences Index and Abstracts (ASSIA), Cumulative Index to Nursing and Allied Health Literature, Social Sciences Citation Index (SSCI) and EBSCO, China National Knowledge Infrastructure (CNKI) and WANFANG were searched. Inclusion criteria were: randomized controlled trails (RCTs); psychosocial intervention to cancer caregivers; psychosocial health indicators including quality of life, depression or anxiety. Results: 21 studies out of 4,666 identified abstracts met inclusion criteria, including 19 RCTs. The intervention modes fell into the following nine categories: family connect intervention, self determination theory-based intervention (SDT), cognitive behavioral therapy (CBT), emotion-focused therapy (EFT), comprehensive health enhancement support system (CHESS), FOCUS programme, existential behavioral therapy (EBT), telephone interpersonal counseling (TIP-C), problem-solving intervention (COPE). Conclusion: paired-intervention targeting self-care and interpersonal connections of caregivers and symptom management of patients is effective in improving quality of life and alleviating depression of cancer caregivers while music therapy is helpful for reducing anxiety of cancer caregivers. PMID- 28596747 TI - Personality Styles of German-Speaking Psychotherapists Differ from a Norm, and Male Psychotherapists Differ from Their Female Colleagues. AB - Variables pertaining to the person of the psychotherapist have been neglected in psychotherapy research for some time. Concerning personality in particular, however, research has mostly focused on its relation with the psychotherapist's choice of method, or differences between the various major therapy approaches. That is, psychotherapists were compared to each other without specifying how exactly psychotherapists are in comparison to "ordinary people." We wanted to know: Are there specific personality styles that distinguish psychotherapists from the norm? A sample of 1,027 psychotherapists from Germany, Austria, and Switzerland filled out the short version of the Personality Style and Disorder Inventory (PSDI-S) via online survey. The PSDI-S is a self-report questionnaire that assesses 14 personality styles, partly related to the non-pathological equivalents of classifiable personality disorders. The psychotherapists were compared to a normative sample of 3,392 people of different professions. The results could be divided into three groups: (1) Large differences in four personality styles that might contribute to relationship skills and may enable psychotherapists to put their own personal opinion aside, show empathy and appreciation, open themselves to the emotional experience of the patient, and provide a trusting relationship. (2) Moderate differences in seven personality styles that are equally indicative of the professional social skills of the psychotherapists, i.e., they were neither submissive nor passive, not excessively helpful, but also not too self-assertive. (3) Hardly any or no differences regarding a charming (histrionic) style, optimism, and conscientiousness. Gender specific results revealed that male psychotherapists differed from their female colleagues, but they did so differently than men and women in the normative sample do. The main limitations were that we relied on self-report and did not statistically control for gender, age, and education, when comparing to the norm. As a conclusion, German-speaking psychotherapists show personality styles that we interpret as functional for psychotherapeutic practice but this needs corroboration from studies that use different methods and measures. PMID- 28596748 TI - The Infant Version of the Laboratory Temperament Assessment Battery (Lab-TAB): Measurement Properties and Implications for Concepts of Temperament. AB - We describe large-sample research using the Infant Laboratory Temperament Assessment Battery (Lab-TAB; Goldsmith and Rothbart, 1996) in 1,076 infants at 6 and 12 months of age. The Lab-TAB was designed to assess temperament dimensions through a series of episodes that mimic everyday situations. Our goal is to provide guidelines for scoring Lab-TAB episodes to derive temperament composites. We also present a set of analyses examining mean differences and stability of temperament in early infancy, gender differences in infant temperament, as well as a validation of Lab-TAB episodes and composites with parent reported Infant Behavior Questionnaire (IBQ; Rothbart, 1981) scales. In general, laboratory observed temperament was only modestly related to parent reported temperament. However, temperament measures were significantly stable across time and several gender differences that align with previous research emerged. In sum, the Lab-TAB usefully assesses individual differences in infant emotionality. PMID- 28596749 TI - Measures of Dogs' Inhibitory Control Abilities Do Not Correlate across Tasks. AB - Inhibitory control, the ability to overcome prepotent but ineffective behaviors, has been studied extensively across species, revealing the involvement of this ability in many different aspects of life. While various different paradigms have been created in order to measure inhibitory control, only a limited number of studies have investigated whether such measurements indeed evaluate the same underlying mechanism, especially in non-human animals. In humans, inhibitory control is a complex construct composed of distinct behavioral processes rather than of a single unified measure. In the current study, we aimed to investigate the validity of inhibitory control paradigms in dogs. Sixty-seven dogs were tested in a battery consisting of frequently used inhibitory control tests. Additionally, dog owners were asked to complete an impulsivity questionnaire about their dog. No correlation of dogs' performance across tasks was found. In order to understand whether there are some underlying behavioral aspects explaining dogs' performance across tests, we performed principle component analyses. Results revealed that three components (persistency, compulsivity and decision speed) explained the variation across tasks. The questionnaire and dogs' individual characteristics (i.e., age and sex) provided only limited information for the derived components. Overall, results suggest that no unique measurement for inhibitory control exists in dogs, but tests rather measure different aspects of this ability. Considering the context-specificity of inhibitory control in dogs and most probably also in other non-human animals, extreme caution is needed when making conclusions about inhibitory control abilities based on a single test. PMID- 28596750 TI - Self-Concept in Childhood: The Role of Body Image and Sport Practice. AB - The purpose of this study was to explore the differences in satisfaction with body image depending on whether the subject practices organized sport or not, as well as the gender of the children. In addition, the study aims to examine the role of body image and the practice of organized sport on the process of building the academic, social, emotional, family and physical dimensions of self-concept in childhood. To do so, a sample of 944 pupils was used. These children were attending primary school in different centers of the Autonomous Community of Extremadura (Spain) and were between 9 and 12 years of age. The main results of the study show that three out of every four children participating in this study were not satisfied with their figure and one out of every five was very dissatisfied. The satisfaction or dissatisfaction with the figure was similar in boys and girls, although it could be appreciated that the ideal body image is partly conditioned by gender stereotypes. The children most satisfied with their body image had a greater academic and physical self-concept. The children that practiced organized sports had a greater physical and emotional self-concept. The children most dissatisfied with their body image and practiced organized sports had a lower family self-concept. All these findings are discussed with reference to previous research literature. PMID- 28596751 TI - How Do Discrepancies between Victimization and Rejection Expectations in Gay and Bisexual Men Relate to Mental Health Problems? AB - Introduction: Victimization and rejection expectations predict mental health problems in gay and bisexual men. Furthermore, it was shown that victimization predicts rejection expectations. Nevertheless, the levels of these two variables do not necessarily correspond as indicated by low inter-correlations, resulting in the question "How do discrepancies in the two variables relate to mental health problems?" This study tests if non-corresponding levels of victimization and rejection expectations in gay and bisexual men relate to mental health problems differently than corresponding levels of victimization and rejection expectations. It furthermore tests for linear and curvilinear relationships between victimization, rejection expectations, and mental health problems. Methods: Data from N = 1423 gay and bisexual men were obtained online. Victimization and rejection expectations were tested for discrepant values (differing 0.5 SD or more) and those that were in agreement (differing less than 0.5): 33.7% of participants were in agreement, 33.0% reported higher rejection expectations than victimization, and 33.3% v.v. Then, a polynomial regression and a surface analysis were conducted. Results: Discrepant values in victimization and rejection expectations or the direction of the discrepancy did not relevantly predict mental health problems. Findings indicate that victimization and rejection expectations predict mental health problems linearly as well as convexly (upward curving) in gay and bisexual men. Discussion: This study replicates findings that gay and bisexual men with more experiences of victimization and rejection expectations demonstrated more mental health problems. Furthermore, this study is the first one to find a convex relationship between these predictors and mental health problems, implicating that disproportionally high mental health problems exist in those gay and bisexual men with high levels of victimization and rejection expectations. On the other hand, discrepancies between these two variables do not predict mental health problems. Future studies are needed to test for replication of our findings. PMID- 28596753 TI - Auditory Processing after Early Left Hemisphere Injury: A Case Report. AB - Few studies have addressed the long-term outcomes of early brain injury, especially after hemorrhagic stroke. This is the first study to report a case of acquired auditory processing disorder in a 10-year-old child who had a severe left hemorrhagic cerebral infarction at 13 months of age, compromising nearly all of the left temporal lobe. This case, therefore, is an excellent and rare opportunity to investigate the presence of neural plasticity of central auditory system in a developing brain followed severe brain damage. After assuring normal functioning of the peripheral auditory system, a series of behavioral auditory processing tests was applied in dichotic and monaural listening conditions and with verbal and non-verbal stimuli. For all verbal dichotic tasks (dichotic digits, competing words, and sentences tests), good performance on the left ear, especially for Dichotic digits test (100%), and zero performance on the right ear were observed. For monaural low-redundancy tests, the patient also exhibited good performance for auditory figure-ground and time-compressed sentences tests in the left ear. In the right ear, a very poor performance was observed, but slightly better than the same in Dichotic tasks. Impaired performance was also observed in the LiSN test in terms of spatial advantage and, for the Pitch Pattern Sequence test, the only non-verbal test applied, the patient had performance within the normal range in both ears. These results are interpreted taking into consideration the anatomical location of stroke lesion and also the influence of hemispheric specialization for language on auditory processing performance. PMID- 28596752 TI - The Retina in Multiple System Atrophy: Systematic Review and Meta-Analysis. AB - BACKGROUND: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. METHODS: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. RESULTS: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 MUm (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 um (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. CONCLUSION: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected. PMID- 28596754 TI - Angiotensins and Huntington's Disease: A Study on Immortalized Progenitor Striatal Cell Lines. AB - Neurons from mouse models of Huntington's disease (HD) exhibit altered electrophysiological properties, potentially contributing to neuronal dysfunction and neurodegeneration. The renin-angiotensin system (RAS) is a potential contributor to the pathophysiology of neurodegenerative diseases. However, the role of angiotensin II (Ang II) and angiotensin (1-7) has not been characterized in HD. We investigated the influence of Ang II and angiotensin (1-7) on total potassium current using immortalized progenitor mutant huntingtin-expressing (Q111) and wild-type (Q7) cell lines. Measurements of potassium current were performed using the whole cell configuration of pCLAMP. The results showed that (1) the effect of Ang II administered to the bath caused a negligible effect on potassium current in mutant Q111 cells compared with wild-type Q7 cells and that intracellular administration of Ang II reduced the potassium current in wild type but not in mutant cells; (2) the small effect of Ang II was abolished by losartan; (3) intracellular administration of Ang II performed in mutant huntingtin-expressing Q111 cells revealed a negligible effect of the peptide on potassium current; (4) flow cytometer analysis indicated a low expression of Ang II AT1 receptors in mutant Q111 cells; (5) mutant huntingtin-expressing striatal cells are highly sensitive to Ang (1-7) and that the effect of Ang (1-7) is related to the activation of Mas receptors. In conclusion, mutant huntingtin expressing cells showed a negligible effect of Ang II on potassium current, a result probably due to the reduced expression of AT1 receptors at the surface cell membrane. In contrast, administration of Ang (1-7) to the bath showed a significant decline of the potassium current in mutant cells, an effect dependent on the activation of Mas receptors. Ang II had an intracrine effect in wild-type cells and Ang (1-7) exerted a significant effect in mutant huntingtin-expressing striatal cells. PMID- 28596755 TI - Genetic Diversity and Virulence Determinants of Escherichia coli Strains Isolated from Patients with Crohn's Disease in Spain and Chile. AB - Adherent-invasive Escherichia coli (AIEC) strains are genetically variable and virulence factors for AIEC are non-specific. FimH is the most studied pathogenicity-related protein, and there have been few studies on other proteins, such as Serine Protease Autotransporters of Enterobacteriacea (SPATEs). The goal of this study is to characterize E. coli strains isolated from patients with Crohn's disease (CD) in Chile and Spain, and identify genetic differences between strains associated with virulence markers and clonality. We characterized virulence factors and genetic variability by pulse field electrophoresis (PFGE) in 50 E. coli strains isolated from Chilean and Spanish patients with CD, and also determined which of these strains presented an AIEC phenotype. Twenty-six E. coli strains from control patients were also included. PFGE patterns were heterogeneous and we also observed a highly diverse profile of virulence genes among all E. coli strains obtained from patients with CD, including those strains defined as AIEC. Two iron transporter genes chuA, and irp2, were detected in various combinations in 68-84% of CD strains. We found that the most significant individual E. coli genetic marker associated with CD E. coli strains was chuA. In addition, patho-adaptative fimH mutations were absent in some of the highly adherent and invasive strains. The fimH adhesin, the iron transporter irp2, and Class-2 SPATEs did not show a significant association with CD strains. The V27A fimH mutation was detected in the most CD strains. This study highlights the genetic variability of E. coli CD strains from two distinct geographic origins, most of them affiliated with the B2 or D E. coli phylogroups and also reveals that nearly 40% of Chilean and Spanish CD patients are colonized with E.coli with a characteristic AIEC phenotype. PMID- 28596756 TI - Grand Challenge in Plant Virology: Understanding the Impact of Plant Viruses in Model Plants, in Agricultural Crops, and in Complex Ecosystems. PMID- 28596757 TI - Time-Resolved Tracking of Mutations Reveals Diverse Allele Dynamics during Escherichia coli Antimicrobial Adaptive Evolution to Single Drugs and Drug Pairs. AB - Understanding the evolutionary processes that lead to antibiotic resistance can help to achieve better treatment strategies. Yet, little is known about the dynamics of the resistance alleles during adaptation. Here, we use population sequencing to monitor genetic changes in putative resistance loci at several time points during adaptive evolution experiments involving five different antibiotic conditions. We monitor the mutational spectra in lineages evolved to be resistant to single antibiotics [amikacin (AMK), chloramphenicol (CHL), and ciprofloxacin (CIP)], as well as antibiotic combinations (AMK + CHL and CHL + CIP). We find that lineages evolved to antibiotic combinations exhibit different resistance allele dynamics compared with those of single-drug evolved lineages, especially for a drug pair with reciprocal collateral sensitivity. During adaptation, we observed interfering, superimposing and fixation allele dynamics. To further understand the selective forces driving specific allele dynamics, a subset of mutations were introduced into the ancestral wild type enabling differentiation between clonal interference and negative epistasis. PMID- 28596759 TI - BSocial: Deciphering Social Behaviors within Mixed Microbial Populations. AB - Ecosystem functionality depends on interactions among populations, of the same or different taxa, and these are not just the sum of pairwise interactions. Thus, know-how of the social interactions occurring in mixed-populations are of high interest, however they are commonly unknown due to the limitations posed in tagging each population. The limitations include costs/time in tediously fluorescent tagging, and the number of different fluorescent tags. Tag-free strategies exist, such as high-throughput sequencing, but ultimately both strategies require the use of expensive machinery. Our work appoints social behaviors on individual strains in mixed-populations, offering a web-tool (BSocial http://m4m.ugr.es/BSocial.html) for analyzing the community framework. Our quick and cheap approach includes the periodic monitoring of optical density (OD) from a full combinatorial testing of individual strains, where number of generations and growth rate are determined. The BSocial analyses then enable us to determine how the addition/absence of a particular species affects the net productivity of a microbial community and use this to select productive combinations, i.e., designate their social effect on a general community. Positive, neutral, or negative assignations are applied to describe the social behavior within the community by comparing fitness effects of the community against the individual strain. The usefulness of this tool for selection of optimal inoculum in biofilm-based methyl tert-butyl ether (MTBE) bioremediation was demonstrated. The studied model uses seven bacterial strains with diverse MTBE degradation/growth capacities. Full combinatorial testing of seven individual strains (triplicate tests of 127 combinations) were implemented, along with MTBE degradation as the desired function. Sole observation of highest species fitness did not render the best functional outcome, and only when strains with positive and neutral social assignations were mixed (Rhodococcus ruber EE6, Agrobacterium sp. MS2 and Paenibacillus etheri SH7), was this obtained. Furthermore, the use of positive and neutral strains in all its combinations had a significant higher degradation mean (x1.75) than exclusive negative strain combinations. Thus, social microbial processes benefit bioremediation more than negative social microbial combinations. The BSocial webtool is a great contributor to the study of social interactions in bioremediation processes, and may be used in other natural or synthetic habitat studies. PMID- 28596758 TI - A Functional Metagenomic Analysis of Tetracycline Resistance in Cheese Bacteria. AB - Metagenomic techniques have been successfully used to monitor antibiotic resistance genes in environmental, animal and human ecosystems. However, despite the claim that the food chain plays a key role in the spread of antibiotic resistance, metagenomic analysis has scarcely been used to investigate food systems. The present work reports a functional metagenomic analysis of the prevalence and evolution of tetracycline resistance determinants in a raw-milk, blue-veined cheese during manufacturing and ripening. For this, the same cheese batch was sampled and analyzed on days 3 and 60 of manufacture. Samples were diluted and grown in the presence of tetracycline on plate count milk agar (PCMA) (non-selective) and de Man Rogosa and Sharpe (MRS) agar (selective for lactic acid bacteria, LAB). DNA from the cultured bacteria was then isolated and used to construct four fosmid libraries, named after the medium and sampling time: PCMA 3D, PCMA-60D, MRS-3D, and MRS-60D. Clones in the libraries were subjected to restriction enzyme analysis, PCR amplification, and sequencing. Among the 300 fosmid clones analyzed, 268 different EcoRI restriction profiles were encountered. Sequence homology of their extremes clustered the clones into 47 groups. Representative clones of all groups were then screened for the presence of tetracycline resistance genes by PCR, targeting well-recognized genes coding for ribosomal protection proteins and efflux pumps. A single tetracycline resistance gene was detected in each of the clones, with four such resistance genes identified in total: tet(A), tet(L), tet(M), and tet(S). tet(A) was the only gene identified in the PCMA-3D library, and tet(L) the only one identified in the PCMA-60D and MRS-60D libraries. tet(M) and tet(S) were both detected in the MRS-3D library and in similar numbers. Six representative clones of the libraries were sequenced and analyzed. Long segments of all clones but one showed extensive homology to plasmids from Gram-positive and Gram-negative bacteria. tet(A) was found within a sequence showing strong similarity to plasmids pMAK2 and pO26-Vir from Salmonella enterica and Escherichia coli, respectively. All other genes were embedded in, or near to, sequences homologous to those of LAB species. These findings strongly suggest an evolution of tetracycline resistance gene types during cheese ripening, which might reflect the succession of the microbial populations. The location of the tetracycline resistance genes in plasmids, surrounded or directly flanked by open reading frames encoding transposases, invertases or mobilization proteins, suggests they might have a strong capacity for transference. Raw-milk cheeses should therefore be considered reservoirs of tetracycline resistance genes that might be horizontally transferred. PMID- 28596760 TI - In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment. AB - Pseudomonas aeruginosa is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing P. aeruginosa pathogenicity. One of its QS systems employs Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signal molecules. Both activate the transcriptional regulator MvfR (Multiple Virulence Factor Regulator), also called PqsR, driving the production of QS molecules as well as toxins and biofilm formation. The aim of this work was to elucidate the effects of QS inhibitors (QSIs), such as MvfR antagonists and PqsBC inhibitors, on the biosynthesis of the MvfR-regulated small molecules 2' aminoacetophenone (2-AA), dihydroxyquinoline (DHQ), HHQ, PQS, and 4-hydroxy-2 heptylquinoline-N-oxide (HQNO). The employed synthetic MvfR antagonist fully inhibited pqs small molecule formation showing expected sigmoidal dose-response curves for 2-AA, HQNO, HHQ and PQS. Surprisingly, DHQ levels were enhanced at lower antagonist concentrations followed by a full suppression at higher QSI amounts. This particular bi-phasic profile hinted at the accumulation of a biosynthetic intermediate resulting in the observed overproduction of the shunt product DHQ. Additionally, investigations on PqsBC inhibitors showed a reduction of MvfR natural ligands, while increased 2-AA, DHQ and HQNO levels compared to the untreated cells were detected. Moreover, PqsBC inhibitors did not show any significant effect in PA14 pqsC mutant demonstrating their target selectivity. As 2-AA is important for antibacterial tolerance, the QSIs were evaluated in their capability to attenuate persistence. Indeed, persister cells were reduced along with 2-AA inhibition resulting from MvfR antagonism, but not from PqsBC inhibition. In conclusion, antagonizing MvfR using a dosage capable of fully suppressing this QS system will lead to a favorable therapeutic outcome as DHQ overproduction is avoided and bacterial persistence is reduced. PMID- 28596761 TI - A Highlight for Non-Escherichia coli and Non-Salmonella sp. Enterobacteriaceae in Dairy Foods Contamination. PMID- 28596762 TI - Species Distribution and Prevalence of Putative Virulence Factors in Mesophilic Aeromonas spp. Isolated from Fresh Retail Sushi. AB - Aeromonas spp. are ubiquitous bacteria that have received increasing attention as human pathogens because of their widespread occurrence in food, especially seafood and vegetables. The aim of this work was to assess the species identity and phylogenetic relationship of 118 Aeromonas strains isolated from fresh retail sushi from three producers, and to characterize the isolates with respect to genetic and phenotypic virulence factors. We also evaluate the potential hazard associated with their presence in ready-to-eat seafood not subjected to heat treatment. Mesophilic Aeromonas salmonicida was most prevalent (74%), followed by A. bestiarum (9%), A. dhakensis (5%), A. caviae (5%), A. media (4%), A. hydrophila (2%), and A. piscicola (1%). All isolates were considered potentially pathogenic due to the high prevalence of genes encoding hemolysin (hlyA) (99%), aerolysin (aerA) (98%), cytotoxic enterotoxin (act) (86%), heat-labile cytotonic enterotoxin (alt) (99%), and heat-stable cytotonic enterotoxin (ast) (31%). The shiga-like toxins 1 and 2 (stx-1 and stx-2) were not detected. Moreover, there was heterogeneity in toxin gene distribution among the isolates, and the combination of act/alt/hlyA/aerA was most commonly detected (63%). beta-hemolysis was species-dependent and observed in 91% of the isolates. All A. media and A. caviae strains were non-hemolytic. For isolates belonging to this group, lack of hemolysis was possibly related to the absence of the act gene. Swimming motility, linked to adhesion and host invasion, occurred in 65% of the isolates. Partial sequencing of the gyrB gene demonstrated its suitability as a genetic marker for Aeromonas species identification and for assessment of the phylogenetic relationship between the isolates. The gyrB sequence divergence within a given species ranged from 1.3 to 2.9%. A. bestiarum, A. salmonicida, and A. piscicola were the most closely related species; their sequences differed by 2.7-3.4%. The average gyrB sequence similarity between all species was 93%, demonstrating its acceptable taxonomic resolution. The presence of multiple species of potential pathogenic Aeromonas in fresh retail sushi raises new food safety issues related to the increased consumption of ready-to-eat food composed of raw ingredients. PMID- 28596763 TI - Methanogenic Community Was Stable in Two Contrasting Freshwater Marshes Exposed to Elevated Atmospheric CO2. AB - The effects of elevated atmospheric CO2 concentration on soil microbial communities have been previously recorded. However, limited information is available regarding the response of methanogenic communities to elevated CO2 in freshwater marshes. Using high-throughput sequencing and real-time quantitative PCR, we compared the abundance and community structure of methanogens in different compartments (bulk soil, rhizosphere soil, and roots) of Calamagrostis angustifolia and Carex lasiocarpa growing marshes under ambient (380 ppm) and elevated CO2 (700 ppm) atmospheres. C. lasiocarpa rhizosphere was a hotspot for potential methane production, based on the 10-fold higher abundance of the mcrA genes per dry weight. The two marshes and their compartments were occupied by different methanogenic communities. In the C. lasiocarpa marsh, archaeal family Methanobacteriaceae, Rice Cluster II, and Methanosaetaceae co-dominated in the bulk soil, while Methanobacteriaceae was the exclusively dominant methanogen in the rhizosphere soil and roots. Families Methanosarcinaceae and Methanocellaceae dominated in the bulk soil of C. angustifolia marsh. Conversely, Methanosarcinaceae and Methanocellaceae together with Methanobacteriaceae dominated in the rhizosphere soil and roots, respectively, in the C. angustifolia marsh. Elevated atmospheric CO2 increased plant photosynthesis and belowground biomass of C. lasiocarpa and C. angustifolia marshes. However, it did not significantly change the abundance (based on mcrA qPCR), diversity, or community structure (based on high-throughput sequencing) of methanogens in any of the compartments, irrespective of plant type. Our findings suggest that the population and species of the dominant methanogens had weak responses to elevated atmospheric CO2. However, minor changes in specific methanogenic taxa occurred under elevated atmospheric CO2. Despite minor changes, methanogenic communities in different compartments of two contrasting freshwater marshes were rather stable under elevated atmospheric CO2. PMID- 28596764 TI - The Structural and Functional Capacity of Ruminal and Cecal Microbiota in Growing Cattle Was Unaffected by Dietary Supplementation of Linseed Oil and Nitrate. AB - Microorganisms in the digestive tract of ruminants differ in their functionality and ability to use feed constituents. While cecal microbiota play an important role in post-rumen fermentation of residual substrates undigested in the rumen, limited knowledge exists regarding its structure and function. In this trial we investigated the effect of dietary supplementation with linseed oil and nitrate on methane emissions and on the structure of ruminal and cecal microbiota of growing bulls. Animals were allocated to either a CTL (control) or LINNIT (CTL supplemented with 1.9% linseed and 1.0% nitrates) diet. Methane emissions were measured using the GreenFeed system. Microbial diversity was assessed using amplicon sequencing of microbial genomic DNA. Additionally, total RNA was extracted from ruminal contents and functional mcrA and mtt genes were targeted in amplicon sequencing approach to explore the diversity of functional gene expression in methanogens. LINNIT had no effect on methane yield (g/kg DMI) even though it decreased methane production by 9% (g/day; P < 0.05). Methanobrevibacter- and Methanomassiliicoccaceae-related OTUs were more abundant in cecum (72 and 24%) compared to rumen (60 and 11%) irrespective of the diet (P < 0.05). Feeding LINNIT reduced the relative abundance of Methanomassiliicoccaceae mcrA cDNA reads in the rumen. Principal component analysis revealed significant differences in taxonomic composition and abundance of bacterial communities between rumen and cecum. Treatment decreased the relative abundance of a few Ruminococcaceae genera, without affecting global bacterial community structure. Our research confirms a high level of heterogeneity in species composition of microbial consortia in the main gastrointestinal compartments where feed is fermented in ruminants. There was a parallel between the lack of effect of LINNIT on ruminal and cecal microbial community structure and functions on one side and methane emission changes on the other. These results suggest that the sequencing strategy used here to study microbial diversity and function accurately reflected the absence of effect on methane phenotypes in bulls treated with linseed plus nitrate. PMID- 28596765 TI - Enzymatic Degradation of Aromatic and Aliphatic Polyesters by P. pastoris Expressed Cutinase 1 from Thermobifida cellulosilytica. AB - To study hydrolysis of aromatic and aliphatic polyesters cutinase 1 from Thermobifida cellulosilytica (Thc_Cut1) was expressed in P. pastoris. No significant differences between the expression of native Thc_Cut1 and of two glycosylation site knock out mutants (Thc_Cut1_koAsn and Thc_Cut1_koST) concerning the total extracellular protein concentration and volumetric activity were observed. Hydrolysis of poly(ethylene terephthalate) (PET) was shown for all three enzymes based on quantification of released products by HPLC and similar concentrations of released terephthalic acid (TPA) and mono(2-hydroxyethyl) terephthalate (MHET) were detected for all enzymes. Both tested aliphatic polyesters poly(butylene succinate) (PBS) and poly(3-hydroxybutyrate-co-3 hydroxyvalerate) (PHBV) were hydrolyzed by Thc_Cut1 and Thc_Cut1_koST, although PBS was hydrolyzed to significantly higher extent than PHBV. These findings were also confirmed via quartz crystal microbalance (QCM) analysis; for PHBV only a small mass change was observed while the mass of PBS thin films decreased by 93% upon enzymatic hydrolysis with Thc_Cut1. Although both enzymes led to similar concentrations of released products upon hydrolysis of PET and PHBV, Thc_Cut1_koST was found to be significantly more active on PBS than the native Thc_Cut1. Hydrolysis of PBS films by Thc_Cut1 and Thc_Cut1_koST was followed by weight loss and scanning electron microscopy (SEM). Within 96 h of hydrolysis up to 92 and 41% of weight loss were detected with Thc_Cut1_koST and Thc_Cut1, respectively. Furthermore, SEM characterization of PBS films clearly showed that enzyme tretment resulted in morphological changes of the film surface. PMID- 28596766 TI - T Lymphocytes Influence the Mineralization Process of Bone. AB - Bone is a unique organ able to regenerate itself after injuries. This regeneration requires the local interplay between different biological systems such as inflammation and matrix formation. Structural reconstitution is initiated by an inflammatory response orchestrated by the host immune system. However, the individual role of T cells and B cells in regeneration and their relationship to bone tissue reconstitution remain unknown. Comparing bone and fracture healing in animals with and without mature T and B cells revealed the essential role of these immune cells in determining the tissue mineralization and thus the bone quality. Bone without mature T and B cells is stiffer when compared to wild-type bone thus lacking the elasticity that helps to absorb forces, thus preventing fractures. In-depth analysis showed dysregulations in collagen deposition and osteoblast distribution upon lack of mature T and B cells. These changes in matrix deposition have been correlated with T cells rather than B cells within this study. This work presents, for the first time, a direct link between immune cells and matrix formation during bone healing after fracture. It illustrates specifically the role of T cells in the collagen organization process and the lack thereof in the absence of T cells. PMID- 28596767 TI - Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential. AB - Natural killer T cells carrying a highly conserved, semi-invariant T cell receptor (TCR) [invariant natural killer T (iNKT) cells] are a subset of unconventional T lymphocytes that recognize glycolipids presented by CD1d molecules. Although CD1d is expressed on a variety of hematopoietic and non hematopoietic cells, dendritic cells (DCs) are key presenters of glycolipid antigen in vivo. When stimulated through their TCR, iNKT cells rapidly secrete copious amounts of cytokines and induce maturation of DCs, thereby facilitating coordinated stimulation of innate and adaptive immune responses. The bidirectional crosstalk between DCs and iNKT cells determines the functional outcome of iNKT cell-targeted responses and iNKT cell agonists are used and currently being evaluated as adjuvants to enhance the efficacy of antitumor immunotherapy. This review illustrates mechanistic underpinnings of reciprocal DCs and iNKT cell interactions and discusses how those can be harnessed for cancer therapy. PMID- 28596768 TI - African Trypanosomes Undermine Humoral Responses and Vaccine Development: Link with Inflammatory Responses? AB - African trypanosomosis is a debilitating disease of great medical and socioeconomical importance. It is caused by strictly extracellular protozoan parasites capable of infecting all vertebrate classes including human, livestock, and game animals. To survive within their mammalian host, trypanosomes have evolved efficient immune escape mechanisms and manipulate the entire host immune response, including the humoral response. This report provides an overview of how trypanosomes initially trigger and subsequently undermine the development of an effective host antibody response. Indeed, results available to date obtained in both natural and experimental infection models show that trypanosomes impair homeostatic B-cell lymphopoiesis, B-cell maturation and survival and B-cell memory development. Data on B-cell dysfunctioning in correlation with parasite virulence and trypanosome-mediated inflammation will be discussed, as well as the impact of trypanosomosis on heterologous vaccine efficacy and diagnosis. Therefore, new strategies aiming at enhancing vaccination efficacy could benefit from a combination of (i) early parasite diagnosis, (ii) anti-trypanosome (drugs) treatment, and (iii) anti-inflammatory treatment that collectively might allow B cell recovery and improve vaccination. PMID- 28596769 TI - C1 Complex: An Adaptable Proteolytic Module for Complement and Non-Complement Functions. AB - Complement C1 is the defining component of the classical pathway. Within the C1qC1r2C1s2 complex, C1q functions as a molecular scaffold for C1r2C1s2 and C1q binding to its ligands activates these two serine proteases. The classic C1q ligands are antigen-bound antibodies and activated C1s cleaves C4 and C2 to initiate the complement cascade. Recent studies suggest broad C1 functions beyond the complement system. C1q binds to the Frizzled receptors to activate C1s, which cleaves lipoprotein receptor-related protein 6 to trigger aging-associated Wnt receptor signaling. C1q binds to apoptotic cells and the activated C1 proteases cleave nuclear antigens. C1s also cleaves MHC class I molecule and potentially numerous other proteins. The diversity of C1q ligands and C1 protease substrates renders C1 complex versatile and modular so that it can adapt to multiple molecular and cellular processes besides the complement system. PMID- 28596770 TI - A Phase 1 Human Immunodeficiency Virus Vaccine Trial for Cross-Profiling the Kinetics of Serum and Mucosal Antibody Responses to CN54gp140 Modulated by Two Homologous Prime-Boost Vaccine Regimens. AB - A key aspect to finding an efficacious human immunodeficiency virus (HIV) vaccine is the optimization of vaccine schedules that can mediate the efficient maturation of protective immune responses. In the present study, we investigated the effect of alternate booster regimens on the immune responses to a candidate HIV-1 clade C CN54gp140 envelope protein, which was coadministered with the TLR4 agonist glucopyranosyl lipid A-aqueous formulation. Twelve study participants received a common three-dose intramuscular priming series followed by a final booster at either 6 or 12 months. The two homologous prime-boost regimens were well tolerated and induced CN54gp140-specific responses that were observed in both the systemic and mucosal compartments. Levels of vaccine-induced IgG subclass antibodies correlated significantly with FcgammaR engagement, and both vaccine regimens were associated with strikingly similar patterns in antibody titer and FcgammaR-binding profiles. In both groups, identical changes in the antigen (Ag)-specific IgG-subclass fingerprint, leading to a decrease in IgG1 and an increase in IgG4 levels, were modulated by booster injections. Here, the dissection of immune profiles further supports the notion that prime-boost strategies are essential for the induction of diverse Ag-specific HIV-1 responses. The results reported here clearly demonstrate that identical responses were effectively and safely induced by both vaccine regimens, indicating that an accelerated 6-month regimen could be employed for the rapid induction of immune responses against CN54gp140 with no apparent impact on the overall quality of the induced immune response. (This study has been registered at http://ClinicalTrials.gov under registration no. NCT01966900.). PMID- 28596772 TI - Epigenetic Regulation of Matrix Metalloproteinase-1 and -3 Expression in Mycobacterium tuberculosis Infection. AB - In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between -2,001 and -2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance. PMID- 28596771 TI - Regulation of T Cell Trafficking by Enzymatic Synthesis of O-Glycans. AB - Selectins constitute a family of oligosaccharide binding proteins that play critical roles in regulating the trafficking of leukocytes. In T cells, L selectin (CD62L) controls the capacity for naive and memory T cells to actively survey peripheral lymph nodes, whereas P- and E-selectin capture activated T cells on inflamed vascular endothelium to initiate extravasation into non lymphoid tissues. The capacity for T cells to interact with all of these selectins is dependent on the enzymatic synthesis of complex O-glycans, and thus, this protein modification plays an indispensable role in regulating the distribution and homing of both naive and previously activated T cells in vivo. In contrast to neutrophils, O-glycan synthesis is highly dynamic in T cell populations and is largely controlled by extracellular stimuli such as antigen recognition or signaling though cytokine receptors. Herein, we review the basic principles of enzymatic synthesis of complex O-glycans, discuss tools and reagents for studying this type of protein modification and highlight our current understanding of how O-glycan synthesis is regulated and subsequently impacts the trafficking potential of diverse T cell populations. PMID- 28596773 TI - Molecular Link between Leaf Coloration and Gene Expression of Flavonoid and Carotenoid Biosynthesis in Camellia sinensis Cultivar 'Huangjinya'. AB - 'Huangjinya' is an excellent albino tea germplasm cultivated in China because of its bright color and high amino acid content. It is light sensitive, with yellow leaves under intense light while green leaves under weak light. As well, the flavonoid and carotenoid levels increased after moderate shading treatment. However, the mechanism underlying this interesting phenomenon remains unclear. In this study, the transcriptome of 'Huangjinya' plants exposed to sunlight and shade were analyzed by high-throughput sequencing followed by de novo assembly. Shading 'Huangjinya' made its leaf color turn green. De novo assembly showed that the transcriptome of 'Huangjinya' leaves comprises of 127,253 unigenes, with an average length of 914 nt. Among the 81,128 functionally annotated unigenes, 207 differentially expressed genes were identified, including 110 up-regulated and 97 down-regulated genes under moderate shading compared to full light. Gene ontology (GO) indicated that the differentially expressed genes are mainly involved in protein and ion binding and oxidoreductase activity. Antioxidation-related pathways, including flavonoid and carotenoid biosynthesis, were highly enriched in these functions. Shading inhibited the expression of flavonoid biosynthesis associated genes and induced carotenoid biosynthesis-related genes. This would suggest that decreased flavonoid biosynthetic gene expression coincides with increased flavonoids (e.g., catechin) content upon moderate shading, while carotenoid levels and biosynthetic gene expression are positively correlated in 'Huangjinya.' In conclusion, the leaf color changes in 'Huangjinya' are largely determined by the combined effects of flavonoid and carotenoid biosynthesis. PMID- 28596774 TI - Tube-Wise Diagnostic Microarray for the Multiplex Characterization of the Complex Plant Pathogen Ralstonia solanacearum. AB - Ralstonia solanacearum is a well-known agricultural and ecological threat worldwide. The complexity of the R. solanacearum species complex (Rssc) represents a challenge for the accurate characterization of epidemiological strains by official services and research laboratories. The majority of protocols only focus on a narrow range of strains; however, this species complex includes strains that represent major constraints and are under strict regulation. The main drawback associated with the current methods of detecting and characterizing Rssc strains is their reliance on combining different protocols to properly characterize the strains at the ecotype level, which require time and money. Therefore, we used microarray technology (ArrayTube) to develop a standard protocol, which characterizes 17 major groups of interest in the Rssc, in a single multiplex reaction. These 17 majors groups are linked with a phylogenetic assignation (phylotypes, sequevars), but also with an ecotype assignation associated with a range of hosts (e.g., brown rot, Moko). Probes were designed with a 50-mer length constraint and thoroughly evaluated for any flaws or secondary structures. The strains are characterized based on a DNA extraction from pure culture. Validation data showed strong intra-repeatability, inter repeatability, and reproducibility as well as good specificity. A hierarchical analysis of the probe groups is suitable for an accurate characterization. Compared with single marker detection tests, the method described in this paper addresses efficiently the issue of combining several tests by testing a large number of phylogenetic markers in a single reaction assay. This custom microarray (RsscAT) represents a significant improvement in the epidemiological monitoring of Rssc strains worldwide, and it has the potential to provide insights for phylogenetic incongruence of Rssc strains based on the host of isolation and may be used to indicate potentially emergent strains. PMID- 28596776 TI - Genome-Wide Association Mapping of Loci Associated with Plant Growth and Forage Production under Salt Stress in Alfalfa (Medicago sativa L.). AB - Salinity tolerance is highly desirable to sustain alfalfa production in marginal lands that have been rendered saline. In this study, we used a diverse panel of 198 alfalfa accessions for mapping loci associated with plant growth and forage production under salt stress using genome-wide association studies (GWAS). The plants were genotyped using genotyping-by-sequencing (GBS). A greenhouse procedure was used for phenotyping four agronomic and physiological traits affected by salt stress, including dry weight (DW), plant height (PH), leaf chlorophyll content (LCC), and stomatal conductance (SC). For each trait, a stress susceptibility index (SSI) was used to evaluate plant performance under stressed and non-stressed conditions. Marker-trait association identified a total of 42 markers significantly associated with salt tolerance. They were located on all chromosomes except chromosome 2 based on the alignment of their flanking sequences to the reference genome (Medicago truncatula). Of those identified, 13 were associated with multiple traits. Several loci identified in the present study were also identified in previous reports. BLAST search revealed that 19 putative candidate genes linked to 24 significant markers. Among them, B3 DNA binding protein, Thiaminepyrophosphokinase and IQ calmodulin-binding motif protein were identified among multiple traits in the present and previous studies. With further investigation, these markers and candidates would be useful for developing markers for marker-assisted selection in breeding programs to improve alfalfa cultivars with enhanced tolerance to salt stress. PMID- 28596777 TI - Physiological Responses and Yield of Wheat Plants in Zinc-Mediated Alleviation of Drought Stress. AB - To evaluate the physiological responses of wheat to zinc (Zn) fertilizer application under drought stress, pot, and field experiments were conducted on wheat plants grown under different soil moistures and treated with soil and foliar Zn applications. Photosynthetic characteristics, antioxidant content, Zn element concentration, and the transcription level of genes involved in antioxidant biosynthesis were analyzed. Zn application increased SPAD and Fv/Fm of wheat flag leaves, while decreased lipid peroxidation levels and H2O2 content. Zn application increased the antioxidant content (ascorbate, reduced glutathione, total phenolic, and total flavonoid) of wheat flag leaves, and enhanced the relative expression levels of two antioxidant enzyme genes, four ascorbate glutathione cycle genes, and two flavonoid biosynthesis pathway genes under drought stress. Soil Zn application increased grain yield and Zn concentration by 10.5 and 15.8%, 22.6 and 9.7%, and 28.2 and 32.8% under adequate water supply, moderate drought, and severe drought, respectively. Furthermore, foliar application of Zn in the field increased grain yield and grain Zn concentration under both adequate water supply and rain-fed conditions. Zn plays a role in alleviating wheat plant drought stress by Zn-mediated increase in photosynthesis pigment and active oxygen scavenging substances, and reduction in lipid peroxidation. Furthermore, Zn fertilizer could regulate multiple antioxidant defense systems at the transcriptional level in response to drought. PMID- 28596775 TI - Abnormal Endogenous Repression of GA Signaling in a Seedless Table Grape Cultivar with High Berry Growth Response to GA Application. AB - Gibberellin (GA) application is routinely used in the table grape industry to increase berry size and cluster length. Although grapevine cultivars show a wide range of growth responsiveness to GA3 application, the reasons for these differences is unclear. To shed light on this issue, two commercial grapevine cultivars with contrasting berry response to GA were selected for comparative analysis, in which we tested if the differences in response: (1) is organ specific or cultivar-related; (2) will be reflected in qualitative/quantitative differences in transcripts/proteins of central components of GA metabolism and signaling and levels of GA metabolites. Our results showed that in addition to the high response of its berries to GA, internodes and rachis of cv. Black finger (BF) presented a greater growth response compared to that of cv. Spring blush (SB). In agreement, the results exposed significant quantitative differences in GA signaling components in several organs of both cultivars. Exceptionally higher level of all three functional VvDELLA proteins was recorded in young BF organs, accompanied by elevated VvGID1 expression and lower VvSLY1b transcripts. Absence of seed traces, low endogenous GA quantities and lower expression of VvGA20ox4 and VvGA3ox3 were also recorded in berries of BF. Our results raise the hypothesis that, in young organs of BF, low expression of VvSLY1b may be responsible for the massive accumulation of VvDELLA proteins, which then leads to elevated VvGID1 levels. This integrated analysis suggests causal relationship between endogenous mechanisms leading to anomalous GA signaling repression in BF, manifested by high quantities of VvDELLA proteins, and greater growth response to GA application. PMID- 28596778 TI - Glycolysis Is Dynamic and Relates Closely to Respiration Rate in Stored Sugarbeet Roots. AB - Although respiration is the principal cause of the loss of sucrose in postharvest sugarbeet (Beta vulgaris L.), the internal mechanisms that control root respiration rate are unknown. Available evidence, however, indicates that respiration rate is likely to be controlled by the availability of respiratory substrates, and glycolysis has a central role in generating these substrates. To determine glycolytic changes that occur in sugarbeet roots after harvest and to elucidate relationships between glycolysis and respiration, sugarbeet roots were stored for up to 60 days, during which activities of glycolytic enzymes and concentrations of glycolytic substrates, intermediates, cofactors, and products were determined. Respiration rate was also determined, and relationships between respiration rate and glycolytic enzymes and metabolites were evaluated. Glycolysis was highly variable during storage, with 10 of 14 glycolytic activities and 14 of 17 glycolytic metabolites significantly altered during storage. Changes in glycolytic enzyme activities and metabolites occurred throughout the 60 day storage period, but were greatest in the first 4 days after harvest. Positive relationships between changes in glycolytic enzyme activities and root respiration rate were abundant, with 10 of 14 enzyme activities elevated when root respiration was elevated and 9 glycolytic activities static during periods of unchanging respiration rate. Major roles for pyruvate kinase and phosphofructokinase in the regulation of postharvest sugarbeet root glycolysis were indicated based on changes in enzymatic activities and concentrations of their substrates and products. Additionally, a strong positive relationship between respiration rate and pyruvate kinase activity was found indicating that downstream TCA cycle enzymes were unlikely to regulate or restrict root respiration in a major way. Overall, these results establish that glycolysis is not static during sugarbeet root storage and that changes in glycolysis are closely related to changes in sugarbeet root respiration. PMID- 28596779 TI - Characterization of Aldehyde Oxidase (AO) Genes Involved in the Accumulation of Carotenoid Pigments in Wheat Grain. AB - Aldehyde Oxidase (AO) enzyme (EC 1.2.3.1) catalyzes the final steps of carotenoid catabolism and it is a key enzyme in the abscisic acid (ABA) biosynthesis. AO isoforms are located in the cytosolic compartment of tissues in many plants, where induce the oxidation of aldehydes into carboxylic acid, and in addition, catalyze the hydroxylation of some heterocycles. The goal of the present study was to characterize the AO genes involved in the accumulation of carotenoid pigments in wheat grain, an important quantitative trait controlled by multiple genes. The cDNAs corresponding to the four AO isoforms from Arabidopsis thaliana and five AO isoforms from Brachypodium distachyon were used as query in 454 sequence assemblies data for Triticum aestivum cv. Chinese Spring (https://urgi.versailles.inra.fr/blast/blast.php) to obtain the partial or whole orthologous wheat AO sequences. Three wheat isoforms, designated AO1, AO2, and AO3 were located on the chromosome groups 2, 5, and 7, respectively, and mapped on two consensus wheat maps by SNP markers located within the AO gene sequences. To validate the possible relationships between AO3 genes and carotenoid accumulation in wheat, the expression levels of AO-A3 and AO-B3 gene were determined during the kernel maturation stage of two durum wheat cultivars, Ciccio and Svevo, characterized by a low and high carotenoid content, respectively. Different AO-A3 gene expression values were observed between the two cultivars indicating that the AO-A3 allele present in Ciccio was more active in carotenoid degradation. A gene marker was developed and can be used for marker assisted selection in wheat breeding programs. PMID- 28596780 TI - Katanin Effects on Dynamics of Cortical Microtubules and Mitotic Arrays in Arabidopsis thaliana Revealed by Advanced Live-Cell Imaging. AB - Katanin is the only microtubule severing protein identified in plants so far. Previous studies have documented its role in regulating cortical microtubule organization during cell growth and morphogenesis. Although, some cell division defects are reported in KATANIN mutants, it is not clear whether or how katanin activity may affect microtubule dynamics in interphase cells, as well as the progression of mitosis and cytokinesis and the orientation of cell division plane (CDP). For this reason, we characterized microtubule organization and dynamics in growing and dividing cotyledon cells of Arabidopsis ktn1-2 mutant devoid of KATANIN 1 activity. In interphase epidermal cells of ktn1-2 cortical microtubules exhibited aberrant and largely isotropic organization, reduced bundling and showed excessive branched microtubule formation. End-wise microtubule dynamics were not much affected, although a significantly slower rate of microtubule growth was measured in the ktn1-2 mutant where microtubule severing was completely abolished. KATANIN 1 depletion also brought about significant changes in preprophase microtubule band (PPB) organization and dynamics. In this case, many PPBs exhibited unisided organization and splayed appearance while in most cases they were broader than those of wild type cells. By recording PPB maturation, it was observed that PPBs in the mutant narrowed at a much slower pace compared to those in Col-0. The form of the mitotic spindle and the phragmoplast was not much affected in ktn1-2, however, the dynamics of both processes showed significant differences compared to wild type. In general, both mitosis and cytokinesis were considerably delayed in the mutant. Additionally, the mitotic spindle and the phragmoplast exhibited extensive rotational motions with the equatorial plane of the spindle being essentially uncoupled from the division plane set by the PPB. However, at the onset of its formation the phragmoplast undergoes rotational motion rectifying the expansion of the cell plate to match the original cell division plane. Conclusively, KATANIN 1 contributes to microtubule dynamics during interphase, regulates PPB formation and maturation and is involved in the positioning of the mitotic spindle and the phragmoplast. PMID- 28596781 TI - Polycomb Group Proteins RING1A and RING1B Regulate the Vegetative Phase Transition in Arabidopsis. AB - Polycomb group (PcG) protein-mediated gene silencing is a major regulatory mechanism in higher eukaryotes that affects gene expression at the transcriptional level. Here, we report that two conserved homologous PcG proteins, RING1A and RING1B (RING1A/B), are required for global H2A monoubiquitination (H2Aub) in Arabidopsis. The mutation of RING1A/B increased the expression of members of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) gene family and caused an early vegetative phase transition. The early vegetative phase transition observed in ring1a ring1b double mutant plants was dependent on an SPL family gene, and the H2Aub status of the chromatin at SPL locus was dependent on RING1A/B. Moreover, mutation in RING1A/B affected the miRNA156a mediated vegetative phase transition, and RING1A/B and the AGO7-miR390-TAS3 pathway were found to additively regulate this transition in Arabidopsis. Together, our results demonstrate that RING1A/B regulates the vegetative phase transition in Arabidopsis through the repression of SPL family genes. PMID- 28596782 TI - Chloroplast- or Mitochondria-Targeted DEAD-Box RNA Helicases Play Essential Roles in Organellar RNA Metabolism and Abiotic Stress Responses. AB - The yields and productivity of crops are greatly diminished by various abiotic stresses, including drought, cold, heat, and high salinity. Chloroplasts and mitochondria are cellular organelles that can sense diverse environmental stimuli and alter gene expression to cope with adverse environmental stresses. Organellar gene expression is mainly regulated at posttranscriptional levels, including RNA processing, intron splicing, RNA editing, RNA turnover, and translational control, during which a variety of nucleus-encoded RNA-binding proteins (RBPs) are targeted to chloroplasts or mitochondria where they play essential roles in organellar RNA metabolism. DEAD-box RNA helicases (RHs) are enzymes that can alter RNA structures and affect RNA metabolism in all living organisms. Although a number of DEAD-box RHs have been found to play important roles in RNA metabolism in the nucleus and cytoplasm, our understanding on the roles of DEAD box RHs in the regulation of RNA metabolism in chloroplasts and mitochondria is only at the beginning. Considering that organellar RNA metabolism and gene expression are tightly regulated by anterograde signaling from the nucleus, it is imperative to determine the functions of nucleus-encoded organellar RBPs. In this review, we summarize the emerging roles of nucleus-encoded chloroplast- or mitochondria-targeted DEAD-box RHs in organellar RNA metabolism and plant response to diverse abiotic stresses. PMID- 28596784 TI - INDY-A New Link to Metabolic Regulation in Animals and Humans. AB - The Indy (I'm Not Dead Yet) gene encodes the fly homolog of the mammalian SLC13A5 citrate transporter. Reduced expression of the Indy gene in flies and worms extends their longevity. INDY is expressed in the plasma membrane of metabolically active tissues. Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction. Reducing INDY activity prevents weight gain in flies, worms, and mice, and counteracts the negative effects of age or a high fat diet on metabolism and insulin sensitivity. The metabolic effects of reducing INDY activity are the result of reduced cytoplasmic citrate. Citrate is a key metabolite and has a central role in energy status of the cell by effecting lipid and carbohydrate metabolism and energy production. Thereby newly described drugs that reduce INDY transporting activity increase insulin sensitivity and reduce hepatic lipid levels via its effect on hepatic citrate uptake. A recent report presented the first direct link between increased hepatic levels of human INDY, insulin resistance, and non-alcoholic fatty liver disease in obese humans. Similarly increased hepatic mIndy levels were observed in non-human primates fed on a high fat diet for 2 years. This effect is mediated via the stimulatory effect of the interleukin-6/Stat3 pathway on mINDY hepatic expression. These findings make INDY a potential and very promising target for the treatment of metabolic disorders in humans. PMID- 28596783 TI - Analysis of EF-Hand Proteins in Soybean Genome Suggests Their Potential Roles in Environmental and Nutritional Stress Signaling. AB - Calcium ion (Ca2+) is a universal second messenger that plays a critical role in plant responses to diverse physiological and environmental stimuli. The stimulus specific signals are perceived and decoded by a series of Ca2+ binding proteins serving as Ca2+ sensors. The majority of Ca2+ sensors possess the EF-hand motif, a helix-loop-helix structure which forms a turn-loop structure. Although EF-hand proteins in model plant such as Arabidopsis have been well described, the identification, classification, and the physiological functions of EF-hand containing proteins from soybean are not systemically reported. In this study, a total of at least 262 genes possibly encoding proteins containing one to six EF hand motifs were identified in soybean genome. These genes include 6 calmodulins (CaMs), 144 calmodulin-like proteins (CMLs), 15 calcineurin B-like proteins, 50 calcium-dependent protein kinases (CDPKs), 13 CDPK-related protein kinases, 2 Ca2+- and CaM-dependent protein kinases, 17 respiratory burst oxidase homologs, and 15 unclassified EF-hand proteins. Most of these genes (87.8%) contain at least one kind of hormonal signaling- and/or stress response-related cis-elements in their -1500 bp promoter regions. Expression analyses by exploring the published microarray and Illumina transcriptome sequencing data revealed that the expression of these EF-hand genes were widely detected in different organs of soybean, and nearly half of the total EF-hand genes were responsive to various environmental or nutritional stresses. Quantitative RT-PCR was used to confirm their responsiveness to several stress treatments. To confirm the Ca2+-binding ability of these EF-hand proteins, four CMLs (CML1, CML13, CML39, and CML95) were randomly selected for SDS-PAGE mobility-shift assay in the presence and absence of Ca2+. Results showed that all of them have the ability to bind Ca2+. This study provided the first comprehensive analyses of genes encoding for EF-hand proteins in soybean. Information on the classification, phylogenetic relationships and expression profiles of soybean EF-hand genes in different tissues and under various environmental and nutritional stresses will be helpful for identifying candidates with potential roles in Ca2+ signal-mediated physiological processes including growth and development, plant-microbe interactions and responses to biotic and abiotic stresses. PMID- 28596786 TI - Impact of ultrasound examination shortly after kidney transplantation. AB - BACKGROUND: Ultrasound is routinely performed at our transplant unit within the first 48 h of kidney transplantation (KTX). The objective of this study was to evaluate the association of ultrasound results and, in particular, elevated resistance indices (RIs) with the occurrence of surgical complications and allograft outcomes. METHODS: The study included all kidney allograft recipients undergoing transplantation at our center between January 2010 and December 2011 (N = 329). Ultrasound examination was performed on 315 recipients (95.7%). RESULTS: Delayed graft function was more common in subjects with a high RI (>=0.7) than in patients with an RI < 0.7 (47.2 vs. 28.2%; p = 0.032). A lack of arterial signal was detected in eight patients (2.5%), of whom five had a vascular complication that required surgical therapy. In 12 patients (3.8%), RI was 1 without any other signs of vascular impairment. Even though such values can be a sign of venous thrombosis, no case was observed in any of these patients. CONCLUSIONS: The results of our study suggest that ultrasound evaluation of the transplanted kidney shortly after transplantation is a valuable tool not only for detecting vascular complications but also as a predictor of graft outcome regarding delayed graft function. PMID- 28596787 TI - Clinical Usefulness of the VS Classification System Using Magnifying Endoscopy with Blue Laser Imaging for Early Gastric Cancer. AB - BACKGROUND: Blue laser imaging (BLI) enables the acquisition of more information from tumors' surfaces compared with white light imaging. Few reports confirm the validity of magnifying endoscopy (ME) with BLI (ME-BLI) for early gastric cancer (EGC). We aimed to assess the detailed endoscopic findings from EGCs using ME BLI. METHODS: We enrolled 386 consecutive patients with 417 EGCs that were diagnosed using ME-BLI and resected by endoscopic submucosal dissection. Using the VS classification system, three highly experienced endoscopists (HEEs) and three less experienced endoscopists (LEEs) evaluated the demarcation line (DL), microsurface pattern (MSP), and microvascular pattern (MVP) within the endoscopic images of EGCs obtained using ME-BLI, assigning high-confidence (HC) or low confidence (LC) levels. We investigated the clinicopathological features associated with each confidence level. RESULTS: The HEEs' evaluations determined the presence of DL in 99%, irregular MSP in 96%, and irregular MVP in 96%, and the LEEs' evaluations determined the presence of DL in 98%, irregular MSP in 95%, and irregular MVP in 95% of the EGCs. When DL was present, HC levels in the Helicobacter pylori- (H. pylori-) eradicated group and noneradicated group were evident in 65% and 89%, a difference that was significant (p < 0.001). CONCLUSIONS: In the diagnosis of EGC with ME-BLI, the VS classification system with ME-NBI can be applied, but identifying the DL after H. pylori was difficult. PMID- 28596788 TI - Factors Requiring Adjustment in the Interpretation of Serum Carcinoembryonic Antigen: A Cross-Sectional Study of 18,131 Healthy Nonsmokers. AB - Serum carcinoembryonic antigen (CEA) is a well-known tumor marker for colorectal adenocarcinoma. However, CEA levels can be influenced by various nonmalignant conditions. A retrospective, cross-sectional study was performed including 18,131 healthy nonsmokers who underwent health check-ups with evaluation of the serum CEA level. In the training set, multivariate analysis revealed that the log transformed CEA level had positive relationships with age (regression coefficient (r) = 0.005, P < 0.001), white blood cell (WBC) count (r = 0.007, P = 0.016), hemoglobin (HB, r = 0.016, P < 0.001), aspartate aminotransferase (AST, r = 0.002, P = 0.005), creatinine (r = 0.076, P = 0.038), and glycosylated hemoglobin (HbA1c, r = 0.052, P < 0.001); body mass index (BMI, r = -0.007, P < 0.001) showed a negative correlation. The results for age, BMI, WBC count, HB, AST, and HbA1c were validated in the test set. We were able to construct the following model to predict the log-transformed CEA level: log (CEA + 0.51) = -0.204 - 0.051 (gender) + 0.005 (age) - 0.006 (BMI) + 0.008 (WBC count) + 0.016 (HB) + 0.002 (AST) + 0.062 (creatinine) + 0.054 (HbA1c). For colorectal cancer prediction, the model with the observed CEA and adjusted CEA levels had significantly high predictive power (AUC 0.756, P < 0.001) than the model only including the observed CEA level (AUC 0.693, P < 0.001). Factors influencing serum CEA levels should be adjusted before clinical interpretation to increase the predictive value of CEA. PMID- 28596785 TI - Oxidative stress and angiogenesis in primary hyperparathyroidism. AB - BACKGROUND: The inappropriate elevation of parathormone (PTH), which regulates the process of angiogenesis in parathyroid tissue, causes the changes of activity of enzymes responsible for the removal of free radicals. Parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT) lowers the level of PTH and leads to the reduction of risk of cardiovascular and all-cause mortality by normalization of the antioxidant status. Therefore, the aims of the study were to assess the activity of antioxidant enzymes and free radical reaction products in patients after parathyroidectomy, and to evaluate the correlation between the systemic oxidative stress and angiogenic parameters. MATERIALS AND METHODS: Patients with PHPT treated surgically were enrolled into the study. Total antioxidant capacity (TAC), total oxidative status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), ceruloplasmin (CER), lipid hydroperoxides (LHP) and malondialdehyde (MDA) were measured before and after parathyroidectomy. The immunohistological expression of angiogenic factors in parathyroid specimens was assessed by the BrightVision method from ImmunoLogic using murine monoclonal anti-human: anti-VEGF, anti-CD31 and anti-CD106 antibodies. RESULTS: The significant increase of TAC, CER, reduction of TOS, MDA, SOD, especially for cytoplasmic form, and significant decrease of OSI, LHP were observed after PTX. There was no significant correlation between changes of oxidative stress markers and angiogenic parameters: VEGF, CD-31, CD-106 in parathyroid tissue. The correlation level was low and medium. CONCLUSIONS: Parathyroidectomy causes down regulation of lipid peroxidation processes and leads to reduction of oxidative stress in patients with PHPT. The decrease in the OSI is the results of down regulation of oxidative stress in the postoperative period. The change of the antioxidant status has no impact on angiogenesis processes in parathyroid tissue. PMID- 28596789 TI - Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children's Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations. AB - BACKGROUND: Some, however not all, children with growth hormone deficiency (GHD) reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF I) is the main mediator of GH anabolic effects. OBJECTIVE: The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. METHODS: The analysis comprised 26 children with GHD, aged 5.7-15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1) with lower IGF-I/IGFBP-3 molar ratio and (2) with higher IGF I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1-16.6 yrs, of normal height and body mass. RESULTS: GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. CONCLUSIONS: A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis. PMID- 28596790 TI - High Doses of Halotolerant Gut-Indigenous Lactobacillus plantarum Reduce Cultivable Lactobacilli in Newborn Calves without Increasing Its Species Abundance. AB - To elucidate the ecological effect of high oral doses of halotolerant (resistant to table salt) indigenous-gut bacteria on other commensals early in life, we conducted a culture-based study to quantify the effect of intestinal Lactobacillus plantarum strain of bovine origin (with remarkable aerobic growth capabilities and inhibitory activity against Escherichia coli O157:H7 and F5) on clinical health and gut lactobacilli/coliforms in newborn calves. In a double blind placebo-randomized trial twelve colostrum-fed calves, consecutively born at a farm, were fed L. plantarum within 12 hours from birth at low (107-8 CFU/day) or high concentrations (1010-11) or placebo (q24 h, 5 d; 10 d follow-up). We developed a 2.5% NaCl-selective culture strategy to facilitate the enumeration of L. plantarum-strain-B80, and tested 384 samples (>1,152 cultures). L. plantarum B80-like colonies were detected in a large proportion of calves (58%) even before their first 24 hours of life indicating endemic presence of the strain in the farm. In contrast to studies where human-derived Lactobacillus LGG or rhamnosus had notoriously high, but short-lived, colonization, we found that L. plantarum colonized stably with fecal shedding of 6 +/- 1 log10.g-1 (irrespective of dose, P > 0.2). High doses significantly reduced other fecal lactic acid bacteria (e.g., lactobacilli, P < 0.01) and slightly reduced body weight gain in calves after treatment. For the first time, a halotolerant strain of L. plantarum with inhibitory activity against a human pathogen has the ability to inhibit other lactobacilli in vivo without changing its species abundance, causing transintestinal translocation, or inducing clinical disease. The future selection of probiotics based on halotolerance may expand therapeutic product applicability. PMID- 28596792 TI - A case series evaluating the serological response of adult asthma patients to the 23-valent pneumococcal polysaccharide vaccine. AB - BACKGROUND: Asthma is an independent risk factor for invasive pneumococcal disease; however, the immune response of adult asthma patients to pneumococcal vaccination is unknown. We explore the serologic response of patients with moderate to severe asthma to the 23-valent pneumococcal polysaccharide vaccine (PPSV23). METHODS: Seventeen moderate to severe adult asthma patients that had not been vaccinated against pneumococcus over the 5 previous years were prospectively recruited from a tertiary care asthma clinic. Serum was analyzed for the presence of antibodies to five capsular polysaccharide (CP) antigens (6B, 9V, 19A, 19F, 23F) before and 4 weeks after PPSV23 vaccination. RESULTS: There was a wide variability in baseline anti-CP antibody concentrations. Other than for serotype 19A, our patients frequently have baseline anti-CP antibody concentrations below 1 ug/mL (35% for serotype 19F, 41% for serotypes 9V and 23F, and 59% for serotype 6B). All post-vaccination geometric mean antibody concentrations were significantly higher than baseline. In the 31 tests where the baseline antibody concentration was <1 ug/mL, 77.4% had at least a twofold increase post-vaccination. Despite this, a large proportion of post-vaccination anti-CP antibody concentrations remained <1 ug/mL (51.6% of tests). Nine patients had at least one anti-CP antibody concentration <1 ug/mL post-vaccination. There was no difference between these patients and the remaining eight patients in demographic or clinical variables. CONCLUSIONS: Patients with moderate to severe asthma have variable baseline and low post-vaccination antibody concentrations to common CP antigens included in the PPSV23 vaccine. The clinical relevance of these observations remains to be determined since the threshold concentration in adults required for clinical protection from invasive pneumococcal disease is uncertain. PMID- 28596793 TI - Comparative Analysis of Tongue Indices between Patients with and without a Self Reported Yin Deficiency: A Cross-Sectional Study. AB - We investigated the hypothesis that Yin-deficient patients have a reddened tongue with less coating. We screened 189 participants aged 20 to 49 years, complaining of headache. To classify patients in terms of Yin deficiency, we used two self reporting Yin-deficiency questionnaires (Yin-Deficiency Questionnaire and Yin Deficiency Scale) and diagnosis by a doctor. Based on the tests, a total of 33 subjects were assigned to a Yin-deficient group and 33 subjects were assigned to a nondeficient control group. Tongue images were acquired using a computerized tongue diagnostic system, for evaluating tongue indices. The tongue coating percentage and tongue redness were calculated as the mean a* value of both the whole tongue area (WT a*) and the tongue body area (TB a*). The tongue coating percentage of the Yin-deficient group (34.79 +/- 10.76) was lower than that of the nondeficient group (44.13 +/- 14.08). The WT a* value of the Yin-deficient group (19.39 +/- 1.52) was significantly higher than that of the nondeficient group (18.21 +/- 2.06). However, the difference in the TB a* value between the two groups was not significant. In conclusion, we verified that Yin-deficient patients had less tongue coating and tended to have a more reddish tongue than nondeficient patients. PMID- 28596794 TI - Efficacy and Safety of an Herbal Therapy in Patients with Amnestic Mild Cognitive Impairment: A 24-Week Randomized Phase III Trial. AB - OBJECTIVE: In the 24-week randomized, double-blind, double-placebo, parallel controlled trial, we aimed to test the effects of herbal therapy with amnestic mild cognitive impairment (aMCI). METHODS: A total of 324 patients with aMCI entered a 2-week placebo run-in period followed by 24 weeks' treatment of either (a) herbal capsule (5 shenwu capsules/administration, 3 times/day) and placebo identical to donepezil tablets (n = 216) or (b) donepezil (5 mg/day) and placebo identical to herbal capsule (n = 108). RESULTS: Herbal therapy showed a significant improvement on the primary efficacy measure, measured by Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog), and showed a mean decrease from baseline of 4.23 points at the endpoint, without a significant difference from the donepezil group. Secondary efficacy measurement of the Logical Memory II Delayed Story Recall subtest (DSR) showed modest improvement in those taking herbal capsule compared to baseline, and there was no significant difference from donepezil group. The frequency of adverse events was much less in the herbal therapy group than the donepezil. CONCLUSION: Herbal therapy demonstrated a significant improvement in cognition and memory, which were similar to the donepezil in patients with aMCI. Herbal therapy was safe and well tolerated. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov NCT01451749. PMID- 28596791 TI - In Utero Stem Cell Transplantation: Potential Therapeutic Application for Muscle Diseases. AB - Muscular dystrophies, myopathies, and traumatic muscle injury and loss encompass a large group of conditions that currently have no cure. Myoblast transplantations have been investigated as potential cures for these conditions for decades. However, current techniques lack the ability to generate cell numbers required to produce any therapeutic benefit. In utero stem cell transplantation into embryos has been studied for many years mainly in the context of hematopoietic cells and has shown to have experimental advantages and therapeutic applications. Moreover, patient-derived cells can be used for experimental transplantation into nonhuman animal embryos via in utero injection as the immune response is absent at such early stages of development. We therefore propose in utero transplantation as a potential method to generate patient-derived humanized skeletal muscle as well as muscle stem cells in animals for therapeutic purposes as well as patient-specific drug screening. PMID- 28596795 TI - Optimization of Extraction Process for Antidiabetic and Antioxidant Activities of Kursi Wufarikun Ziyabit Using Response Surface Methodology and Quantitative Analysis of Main Components. AB - By using extraction yield, total polyphenolic content, antidiabetic activities (PTP-1B and alpha-glycosidase), and antioxidant activity (ABTS and DPPH) as indicated markers, the extraction conditions of the prescription Kursi Wufarikun Ziyabit (KWZ) were optimized by response surface methodology (RSM). Independent variables were ethanol concentration, extraction temperature, solid-to-solvent ratio, and extraction time. The result of RSM analysis showed that the four variables investigated have a significant effect (p < 0.05) for Y1, Y2, Y3, Y4, and Y5 with R2 value of 0.9120, 0.9793, 0.9076, 0.9125, and 0.9709, respectively. Optimal conditions for the highest extraction yield of 39.28%, PTP-1B inhibition rate of 86.21%, alpha-glycosidase enzymes inhibition rate of 96.56%, and ABTS inhibition rate of 77.38% were derived at ethanol concentration 50.11%, extraction temperature 72.06 degrees C, solid-to-solvent ratio 1 : 22.73 g/mL, and extraction time 2.93 h. On the basis of total polyphenol content of 48.44% in this optimal condition, the quantitative analysis of effective part of KWZ was characterized via UPLC method, 12 main components were identified by standard compounds, and all of them have shown good regression within the test ranges and the total content of them was 11.18%. PMID- 28596796 TI - Hesperidin Protects against Acute Alcoholic Injury through Improving Lipid Metabolism and Cell Damage in Zebrafish Larvae. AB - Alcoholic liver disease (ALD) is a series of abnormalities of liver function, including alcoholic steatosis, steatohepatitis, and cirrhosis. Hesperidin, the major constituent of flavanone in grapefruit, is proved to play a role in antioxidation, anti-inflammation, and reducing multiple organs damage in various animal experiments. However, the underlying mechanism of resistance to alcoholic liver injury is still unclear. Thus, we aimed to investigate the protective effects of hesperidin against ALD and its molecular mechanism in this study. We established an ALD zebrafish larvae model induced by 350 mM ethanol for 32 hours, using wild-type and transgenic line with liver-specific eGFP expression Tg (lfabp10alpha:eGFP) zebrafish larvae (4 dpf). The results revealed that hesperidin dramatically reduced the hepatic morphological damage and the expressions of alcohol and lipid metabolism related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, and fads2 compared with ALD model. Moreover, the findings demonstrated that hesperidin alleviated hepatic damage as well, which is reflected by the expressions of endoplasmic reticulum stress and DNA damage related genes (chop, gadd45alphaa, and edem1). In conclusion, this study revealed that hesperidin can inhibit alcoholic damage to liver of zebrafish larvae by reducing endoplasmic reticulum stress and DNA damage, regulating alcohol and lipid metabolism. PMID- 28596797 TI - Causality in cancer research: a journey through models in molecular epidemiology and their philosophical interpretation. AB - In the last decades, Systems Biology (including cancer research) has been driven by technology, statistical modelling and bioinformatics. In this paper we try to bring biological and philosophical thinking back. We thus aim at making different traditions of thought compatible: (a) causality in epidemiology and in philosophical theorizing-notably, the "sufficient-component-cause framework" and the "mark transmission" approach; (b) new acquisitions about disease pathogenesis, e.g. the "branched model" in cancer, and the role of biomarkers in this process; (c) the burgeoning of omics research, with a large number of "signals" and of associations that need to be interpreted. In the paper we summarize first the current views on carcinogenesis, and then explore the relevance of current philosophical interpretations of "cancer causes". We try to offer a unifying framework to incorporate biomarkers and omic data into causal models, referring to a position called "evidential pluralism". According to this view, causal reasoning is based on both "evidence of difference-making" (e.g. associations) and on "evidence of underlying biological mechanisms". We conceptualize the way scientists detect and trace signals in terms of information transmission, which is a generalization of the mark transmission theory developed by philosopher Wesley Salmon. Our approach is capable of helping us conceptualize how heterogeneous factors such as micro and macro-biological and psycho-social are causally linked. This is important not only to understand cancer etiology, but also to design public health policies that target the right causal factors at the macro-level. PMID- 28596798 TI - Work-related floors as injury hazards - a nationwide pilot project analyzing floors in theatres and education establishments in Germany. AB - BACKGROUND: An adequate dance floor is said to prevent injuries. On the basis of scientific research, numerous recommendations regarding an adequate dance floor have been developed. Up to the present, however, studies have still been lacking into how far these recommendations have already been implemented in theatres with regular dance productions and/or in-house dance ensembles. The aim of this study is to analyze a nationwide survey on dance floors of theatres and education establishments in Germany. METHODS: A questionnaire-based survey on existence and type of floors in the various dance-related working areas was carried out at theatres and education establishments institutions (n = 86 institutions (n = 76 theatres, n = 10 education establishments). References as to region, size of dance ensembles and dance styles performed were created. RESULTS: Of all education establishments, 75.3% were equipped with a sprung sub-floor in the ballet studios. In contrast, sprung sub-floors were only found in 29.7% of the working areas, the stage AND ballet studios in theatres. The percentage of theatres providing sprung sub-floors in all rooms used by dancers is even lower. Considering all dance-related work areas, larger ensembles (>30 dancers) were offered better conditions regarding floors than smaller ensembles (p > 0.001). No significant tendencies were found regarding regions or dance styles. CONCLUSION: Recommendations concerning an appropriate dance floor have only partly been realized. Besides secured finances for reinstallation, further education of responsible officials and artists is essential. However, accrediting dance as own genre in theatres is the indispensable prerequisite. PMID- 28596800 TI - A comparative study of the prevalence and correlates of psychiatric disorders in Almajiris and public primary school pupils in Zaria, Northwest Nigeria. AB - BACKGROUND: 'Almajiris' are children and adolescents sent far away from their homes to study in Islamic schools under the care of Muslim scholars. Over the years, there has been a decline in the capacity of the scholars to cater to these pupils. Consequently, Almajiris spend significant periods of time on the streets begging and carrying out menial jobs to earn a living thereby increasing their risk for physical and mental disorders. The aim of this study was to compare the prevalence of psychiatric disorders among Almajiris and public primary school pupils in Zaria. METHODS: A comparative cross-sectional design was utilized to compare 213 Almajiris and 200 public primary school children and adolescents aged between 5 and 19 years. All participants were administered a Socio-demographic questionnaire and the Schedule for Affective Disorders and Schizophrenia for School-aged Children Present and Lifetime Version (K-SADS-PL). Data were analyzed using Chi square tests and logistic regression. RESULTS: The current prevalence of psychiatric disorders among Almajiris and public school pupils was 57.7 and 37.0% respectively. After adjusting for age and family characteristics, Almajiris were significantly more likely to have any psychiatric diagnosis, depression, enuresis, substance use, and post traumatic stress disorder but less likely to have separation anxiety disorder than the public school pupils. CONCLUSION: Psychiatric disorders are more prevalent among Almajiris and public primary school pupils in Northwest Nigeria than found in other prevalence studies with a significantly higher rate among the Almajiris. Joint efforts need to be made by the Government and Civil Society organizations including religious groups towards reforming the Almajiri education system and the provision of programmes aimed at reducing the prevalence of psychiatric disorders in both Almajiris and the school pupils. PMID- 28596801 TI - Tobacco in post-conflict settings: the case of Iraq. AB - Tobacco is the leading cause of preventable death in the world, claiming six million lives each year. Although smoking prevalence is decreasing in high-income countries, many low- and middle-income countries, particularly fragile and post conflict nations such as Iraq, are still seeing prevalence rates rising. With the evidence of higher rates of nicotine dependence in conflict and post-conflict areas, the tobacco problem only becomes more difficult for Iraq, which finds itself involved in conflicts lasting years, if not decades. Terrorism and unstable governments, as well as Big Tobacco, create large roadblocks on the route to adequate tobacco control. However, some tobacco control efforts have been successful in other post-conflict settings, demonstrating that with good governance, many of these roadblocks can be overcome. This review explores the context of tobacco control strategies in Iraq, identifies problems/issues, and discusses possible resolutions using some examples from other post-conflict countries. PMID- 28596799 TI - The rate of success of the conservative management of liver trauma in a developing country. AB - BACKGROUND: The conservative treatment of liver trauma has made important progress over the last 10 years at the Trauma University Hospital in Tirana, Albania. The percentage of success was 58.7%. The aims of this study were to analyze the conservative treatment of liver trauma and to compare the results with those in the literature. METHODS: This study was conducted prospectively from January 2009 to December 2012. We analyzed 173 patients admitted to our hospital with liver trauma. Liver injuries were evaluated according to the American Association for the Surgery of Trauma and the World Society of Emergency Surgery classification, while the anatomic gravity of the associated injuries was defined using the Injury Severity Score system. The potential mortality was estimated with the Revised Trauma Score. RESULTS: Out of the 173 patients with liver trauma, 83.2% were male. The main cause of liver trauma was motor vehicle crashes (50.9%). Blunt trauma was the cause of liver injury in 129 cases (74.6%), and penetrating trauma occurred in 44 cases (25.4%). Initially, the decision was to manage 88 cases (50.9%) via the conservative approach. Of these, 73 cases (42.2%) were successfully treated with conservative treatment, while in 15 cases (17.2%), this approach failed. The success rate of conservative treatment by grade of injuries was as follows: grade I (38.4%), grade II (30.1%), grade III (28.8%), and grade IV (2.7%). The likelihood of the success of conservative treatment had a significant correlation with the grade of the liver injury (p < 0.00001), associated intra-abdominal injuries (p = 0.00051), and complications (z = 2.3169, p = 0.02051). The overall mortality rate of liver trauma was 13.2%. CONCLUSIONS: The likelihood of success in using conservative treatment had a significant correlation with the grade of liver injury and associated intra abdominal injuries. The limited hospital resources and low level of consensus on conservative treatment had a negative impact on the level of success. PMID- 28596802 TI - Nursing diagnoses in adult/elderly patients undergoing outpatient antineoplastic chemotherapy: a review. AB - OBJECTIVE: To search in the scientific literature for nursing diagnoses identified in adult/elderly patients undergoing antineoplastic chemotherapy in an outpatient setting. METHODS: Review of studies published in Portuguese, English, or Spanish which were searched in five electronic databases in March 2016, using the descriptors nursing process, nursing diagnosis, neoplasms, drug therapy and hospital outpatient clinic. RESULTS: In the four studies selected for review, 40 nursing diagnoses were identified, namely unbalanced nutrition, less than body requirements, risk of deficient fluid volume, diarrhoea, fatigue, impaired home maintenance, deficient knowledge, disturbed body image, interrupted family processes, ineffective sexuality pattern, anxiety, powerlessness, fear, readiness for enhanced religiosity, risk of infection, impaired dentition, risk of impaired skin integrity, acute pain, and nausea. CONCLUSIONS: The nursing diagnoses identified can support the selection of interventions and the creation of nursing guidelines in outpatient oncology services. PMID- 28596803 TI - Volumetric arc therapy for total scalp irradiation: case report for a recurrent basal cell carcinoma of the scalp. AB - Total scalp irradiation may be used to treat numerous conditions including squamous and basal cell carcinomas. These conditions are relatively uncommon and patients are frequently treated with palliative intent. In this report, we describe a volumetric arc therapy technique using photon beams for curative intent in an 84 years old patient with recurrent basal cell carcinoma of the scalp. Dose was 50Gy (2Gy per session) to the planning target volume (PTV) followed by a 10 Gy boost to the macroscopic disease on the forehead. A custom made 1 cm superflab bolus helmet was used. Toxicities only consisted of Grade-1 transient radiation dermatitis and alopecia. A sustained clinical response was observed at 6 months follow-up. Volumetric arc therapy (VMAT) may offer an effective alternative modality to treat patients with very extensive scalp lesions as described in this case report. PMID- 28596804 TI - Bringing a humanistic approach to cancer clinical trials. AB - In this article, we describe some practical aspects that promote the humanisation of clinical research. Actions are not limited to improving the communication skills of medical staff but also include maintenance of care continuity, accessible written information, and application of theoretic models such as shared decision-making and management of stress in decision-making under uncertainty. We believe that a comprehensive strategy will increase patients' motivation to participate in and adhere to clinical research. PMID- 28596805 TI - Ataxia-Telangiectasia patients get a rare chance to meet the experts at a dedicated workshop in IFOM (the FIRC Institute of Molecular Oncology). AB - Ataxia telangiectasia (A-T) is a genetic syndrome characterized by cerebellar degeneration, telangiectasia, immunodeficiency and cancer predisposition. A-T occurs in between 1 in 40,000 and 1 in 100,000 live births. The first symptoms normally occur in early childhood when the infant begins to walk. Affected children have immunodeficiency and an increased predisposition for cancers. A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. PMID- 28596807 TI - Aqueous SARA ATRP using Inorganic Sulfites. AB - Aqueous supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) using inorganic sulfites was successfully carried out for the first time. Under optimized conditions, a well-controlled poly[oligo(ethylene oxide) methyl ether acrylate] (POEOA) was obtained with <30 ppm of soluble copper catalyst using tris(2-pyridylmethyl)amine (TPMA) ligand in the presence of an excess of halide salts (e.g. NaCl). Inorganic sulfites (e.g. Na2S2O4) were continuously fed into the reaction mixture. The mechanistic studies proved that these salts can activate alkyl halides directly and regenerate the activator complex. The effects of the feeding rate of the SARA agent (inorganic sulfites), ligand and its concentration, halide salt and its concentration, sulfite used, and copper concentration, were systematically studied to afford fast polymerizations rates while maintaining the control over polymerization. The kinetic data showed linear first-order kinetics, linear evolution of molecular weights with conversion, and polymers with narrow molecular weight distributions (D ~1.2) during polymerization even at relatively high monomer conversions (~80%). "One-pot" chain extension and "one-pot" block copolymerization experiments proved the high chain-end functionality. The polymerization could be directly regulated by starting or stopping the continuous feeding of the SARA agent. Under biologically relevant conditions, the aqueous SARA ATRP using inorganic sulfites was used to synthesize a well-defined protein-polymer hybrid by grafting of P(OEOA480) from BSA-O-[iBBr]30. PMID- 28596806 TI - Custom-made foot orthoses: an analysis of prescription characteristics from an Australian commercial orthotic laboratory. AB - BACKGROUND: Foot orthoses are widely used in the prevention and treatment of foot disorders. The aim of this study was to describe characteristics of custom-made foot orthosis prescriptions from a Australian podiatric orthotic laboratory. METHODS: One thousand consecutive foot orthosis prescription forms were obtained from a commercial prescription foot orthosis laboratory located in Melbourne, Victoria, Australia (Footwork Podiatric Laboratory). Each item from the prescription form was documented in relation to orthosis type, cast correction, arch fill technique, cast modifications, shell material, shell modifications and cover material. Cluster analysis and discriminant function analysis were applied to identify patterns in the prescription data. RESULTS: Prescriptions were obtained from 178 clinical practices across Australia and Hong Kong, with patients ranging in age from 5 to 92 years. Three broad categories ('clusters') were observed that were indicative of increasing 'control' of rearfoot pronation. A combination of five variables (rearfoot cast correction, cover shape, orthosis type, forefoot cast correction and plantar fascial accommodation) was able to identify these clusters with an accuracy of 70%. Significant differences between clusters were observed in relation to age and sex of the patient and the geographic location of the prescribing clinician. CONCLUSION: Foot orthosis prescriptions are complex, but can be broadly classified into three categories. Selection of these prescription subtypes appears to be influenced by both patient factors (age and sex) and clinician factors (clinic location). PMID- 28596808 TI - Saturated hydrogen saline ameliorates lipopolysaccharide-induced acute lung injury by reducing excessive autophagy. AB - The pathogenesis of acute lung injury (ALI) induced by lipopolysaccharide (LPS) involves excessive pulmonary inflammation and oxidative stress. In turn, autophagy is associated with inflammatory diseases and organ dysfunction, and studies have demonstrated that LPS treatment may trigger autophagy. Thus, excessive autophagy may stimulate the strong inflammatory response observed in the development of LPS-induced ALI. Saturated hydrogen saline may alleviate LPS induced ALI by inhibiting autophagy, however its underlying mechanisms of action remain unknown. It has been suggested that saturated hydrogen saline may downregulate expression of nuclear factor (NF)-kappaB, leading to a decrease in Beclin-1 transcription and inhibition of autophagy. Inhibition of autophagy also occurs via the phosphorylation of Unc-51-like autophagy activating kinase 1 and autophagy-related protein-13 by mechanistic target of rapamycin, which in turn may be upregulated by saturated hydrogen saline. In addition, signaling pathways involving heme oxygenase-1 and p38 mitogen-activated protein kinase are associated with the alleviative effects of saturated hydrogen saline on LPS induced autophagy. The present review focuses on potential molecular mechanisms regarding the effects of saturated hydrogen saline in the reduction of autophagy during LPS-induced ALI. PMID- 28596811 TI - Genetic Engineering and Human Mental Ecology: Interlocking Effects and Educational Considerations. AB - This paper describes some likely semiotic consequences of genetic engineering on what Gregory Bateson has called "the mental ecology" (1979) of future humans, consequences that are less often raised in discussions surrounding the safety of GMOs (genetically modified organisms). The effects are as follows: an increased 1) habituation to the presence of GMOs in the environment, 2) normalization of empirically false assumptions grounding genetic reductionism, 3) acceptance that humans are capable and entitled to decide what constitutes an evolutionary improvement for a species, 4) perception that the main source of creativity and problem solving in the biosphere is anthropogenic. Though there are some tensions between them, these effects tend to produce self-validating webs of ideas, actions, and environments, which may reinforce destructive habits of thought. Humans are unlikely to safely develop genetic technologies without confronting these escalating processes directly. Intervening in this mental ecology presents distinct challenges for educators, as will be discussed. PMID- 28596810 TI - Simulation of shear bands with Soft PARticle Code (SPARC) and FE. AB - The aim of this paper is to numerically investigate the development, thickness and orientation of shear bands, in biaxial test with two approaches towards solving problems of continuum mechanics, namely the meshless "Soft PARticle" method and the mesh based Finite Element method. Soft PArticle Code (SPARC) is a straightforward collocation numerical method based on strong formulation, in which a first order polynomial basis is adopted for the evaluation of spatial derivatives in partial differential equations. A novel nonlinear constitutive model- barodesy for clay, is adopted in this study. The biaxial test, which involves homogeneous, and later inhomogeneous localized deformation is simulated using the Soft PArticle Code and the Finite Element method. The inclination and thickness of the shear bands are evaluated and analysed with the earlier experimental, theoretical and numerical investigations. Furthermore, simulation results are compared and presented to demonstrate the advantages and limitations of SPARC in comparison to FE method. PMID- 28596809 TI - Viscum album (L.) in experimental animal tumors: A meta-analysis. AB - Mistletoe (Viscum album L.) has been used as complementary anticancer treatment for ~100 years. Although the clinical efficacy of mistletoe in cancer and associated survival benefits remain contested, several studies point to its effectiveness and others have reported antitumor and immunomodulatory properties. In the present review, a search was conducted for original articles reporting the outcomes of treatments for experimental animal tumors with mistletoe. The inclusion criteria were: Publication in English, from 1996 onwards and in peer reviewed journals included in the database PubMed. The parameters analyzed were: Provenance and time of publication, rationale, methods (animal species used, mistletoe preparation, treatment protocol, tumor lineage, blinding, randomization, controls and concomitant treatments), outcomes and investigated mechanisms of action. A total of 37 studies met the inclusion criteria. The quality of the studies was adequate in the terms of sample size and use of controls, and the only animal species employed were mice and rats. However, few studies reported having performed random allocation and none reported blinding. There was wide variation in the type and preparation of mistletoe used, route of administration, regimen, tumor type and the mechanism of action assessed. A temporal trend was identified; earlier studies sought to establish the antitumor effect of mistletoe and its possible mechanisms, cytotoxicity and immunomodulation in particular, whereas the later ones tended to focus more on biologically active principles, genomics and oxidative stress. A total of 32/37 studies reported an antitumor effect, 3 of which had mixed results. A total of 2 studies did not detect any antitumor effect and a further 2 found stimulation of tumor growth in the treated groups. One study did not assess antitumor effects, investigating immunomodulation action instead. The quality of the studies was satisfactory and the majority reported positive outcomes. Nevertheless, there is a great deal of methodological heterogeneity among the studies, which precludes conclusive comparisons. Based on these results, the present authors strongly suggest developing guidelines for reporting in vivo mistletoe cancer treatment experiments. PMID- 28596812 TI - Hydrogen Chemical Configuration and Thermal Stability in Tungsten Disulfide Nanoparticles Exposed to Hydrogen Plasma. AB - The chemical configuration and interaction mechanism of hydrogen adsorbed in inorganic nanoparticles of WS2 are investigated. Our recent approaches of using hydrogen activated by either microwave or radiofrequency plasma dramatically increased the efficiency of its adsorption on the nanoparticles surface. In the current work we make an emphasis on elucidation of the chemical configuration of the adsorbed hydrogen. This configuration is of primary importance as it affects its adsorption stability and possibility of release. To get insight on the chemical configuration, we combined the experimental analysis methods with theoretical modeling based on the density functional theory (DFT). Micro-Raman spectroscopy was used as a primary tool to elucidate chemical bonding of hydrogen and to distinguish between chemi- and physisorption. Hydrogen adsorbed in molecular form (H2) was clearly identified in all the plasma-hydrogenated WS2 nanoparticles samples. It was shown that the adsorbed hydrogen is generally stable under high vacuum conditions at room temperature, which implies its stability at the ambient atmosphere. A DFT model was developed to simulate the adsorption of hydrogen in the WS2 nanoparticles. This model considers various adsorption sites and identifies the preferential locations of the adsorbed hydrogen in several WS2 structures, demonstrating good concordance between theory and experiment and providing tools for optimizing of hydrogen exposure conditions and the type of substrate materials. PMID- 28596813 TI - Three Eras in Global Tobacco Control: How Global Governance Processes Influenced Online Tobacco Control Networking. AB - Online networks can serve as a platform to diffuse policy innovations and enhance global health governance. This study focuses on how shifts in global health governance may influence related online networks. We compare social network metrics (average degree centrality [AVGD], density [D] and clustering coefficient [CC]) of Globalink, an online network of tobacco control advocates, across three eras in global tobacco control governance; pre-Framework Convention on Tobacco Control (FCTC) policy transfer (1992-1998), global regime formation through the FCTC negotiations (1999-2005), and philanthropic funding through the Bloomberg Initiative (2006-2012). Prior to 1999, Globalink was driven by a handful of high income countries (AVGD=1.908 D=0.030, CC=0.215). The FCTC negotiations (1999 2005) corresponded with a rapid uptick in the number of countries represented within Globalink and new members were most often brought into the network through relationships with regional neighbors (AVGD=2.824, D=0.021, CC=0.253). Between 2006 and 2012, the centrality of the US in the network increases significantly (AVGD=3.414, D=0.023, CC=0.310). The findings suggest that global institutionalization through WHO, as with the FCTC, can lead to the rapid growth of decentralized online networks. Alternatively, private initiatives, such as the Bloomberg Initiative, can lead to clustering in which a single source of information gains increasing influence over an online network. PMID- 28596814 TI - Enhancement of Mitochondrial Transfer by Antioxidants in Human Mesenchymal Stem Cells. AB - Excessive reactive oxygen species is the major component of a harsh microenvironment after ischemia/reperfusion injury in human tissues. Combined treatment of N-acetyl-L-cysteine (NAC) and L-ascorbic acid 2-phosphate (AAP) promoted the growth of human mesenchymal stem cells (hMSCs) and suppressed oxidative stress-induced cell death by enhancing mitochondrial integrity and function in vitro. In this study, we aimed to determine whether NAC and AAP (termed MCA) could enhance the therapeutic potential of hMSCs. We established a coculture system consisting of MCA-treated and H2O2-treated hMSCs and investigated the role of tunneling nanotubes (TNTs) in the exchange of mitochondria between the 2 cell populations. The consequences of mitochondria exchange were assessed by fluorescence confocal microscopy and flow cytometry. The results showed that MCA could increase the mitochondrial mass, respiratory capacity, and numbers of TNTs in hMSCs. The "energized" mitochondria were transferred to the injured hMSCs via TNTs, the oxidative stress was decreased, and the mitochondrial membrane potential of the H2O2-treated hMSCs was stabilized. The transfer of mitochondria decreased the expression of S616 phosphorylated dynamin-related protein 1, a protein that dictates the fragmentation/fission of mitochondria. Concurrently, MCA also enhanced mitophagy in the coculture system, implicating that damaged mitochondria were eliminated in order to maintain cell physiology. PMID- 28596815 TI - Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue. AB - AIM: To investigate genotype variation among induced pluripotent stem cell (iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS: Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer (OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using next-generation sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants (SNVs) (missense, nonsense, and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbSNP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer. RESULTS: In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer (stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the non-cancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived from cancerous tissue. These results suggest that the traceability and preference of the starting single cells being derived from pre-cancer (stem) cells, stroma cells such as cancer-associated fibroblasts, and immune cells that co-existed in the tissues along with the mature cancer cells. CONCLUSION: The genotypes of iPSC lines derived from heterogeneous cancer tissues can provide information on the type of starting cell that the iPSC line was generated from. PMID- 28596816 TI - Coffee: The magical bean for liver diseases. AB - Coffee has long been recognized as having hepatoprotective properties, however, the extent of any beneficial effect is still being elucidated. Coffee appears to reduce risk of hepatocellular carcinoma, reduce advancement of fibrotic disease in a variety of chronic liver diseases, and perhaps reduce ability of hepatitis C virus to replicate. This review aims to catalog the evidence for coffee as universally beneficial across a spectrum of chronic liver diseases, as well as spotlight opportunities for future investigation into coffee and liver disease. PMID- 28596817 TI - Cardiovascular assessment in liver transplant for non-alcoholic steatohepatitis patients: What we do, what we should do. AB - Non-alcoholic fatty liver disease (NAFLD) is increasing considerably due to the current lifestyle, which means that it is becoming one of the main indications for liver transplantation. On the other hand, there is a strong association between NAFLD and cardiovascular disease. This has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness, leading to cardiovascular events and, ultimately, mortality. According to the liver transplant guidelines, screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years old. However, there are no specific recommendations in NAFLD patients requiring a liver transplantation, despite its well-known cardiovascular risk association. Many studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or nutritionists. Also, the incidence of cardiovascular disease is also increased in NAFLD patients in the post-transplantation period in comparison with other etiologies, because of the pre-existent risk factors together with the immunosuppressive therapy. Therefore, an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in NAFLD patients requiring a liver transplantation. PMID- 28596818 TI - Trend of hepatocellular carcinoma incidence after Bayesian correction for misclassified data in Iranian provinces. AB - AIM: To study the trend of hepatocellular carcinoma incidence after correcting the misclassification in registering cancer incidence across Iranian provinces in cancer registry data. METHODS: Incidence data of hepatocellular carcinoma were extracted from Iranian annual of national cancer registration reports 2004 to 2008. A Bayesian method was implemented to estimate the rate of misclassification in registering cancer incidence in neighboring province. A beta prior is considered for misclassification parameter. Each time two neighboring provinces were selected to be entered in the Bayesian model based on their expected coverage of cancer cases which is reported by medical university of the province. It is assumed that some cancer cases from a province that has an expected coverage of cancer cases lower than 100% are registered in their neighboring facilitate province with more than 100% expected coverage. RESULTS: There is an increase in the rate of hepatocellular carcinoma in Iran. Among total of 30 provinces of Iran, 21 provinces were selected to be entered to the Bayesian model for correcting the existed misclassification. Provinces with more medical facilities of Iran are Tehran (capital of the country), Razavi Khorasan in north east of Iran, East Azerbaijan in north-west of the country, Isfahan in central part and near to Tehran, Khozestan and Fars in south and Mazandaran in north of the Iran, had an expected coverage more than their expectation. Those provinces had significantly higher rates of hepatocellular carcinoma than their neighboring provinces. In years 2004 to 2008, it was estimated to be on average 34% misclassification between North Khorasan province and Razavi Khorasan, 43% between South Khorasan province and Razavi Khorasan, 47% between Sistan and balochestan province and Razavi Khorasan, 23% between West Azerbaijan province and East Azerbaijan province, 25% between Ardebil province and East Azerbaijan province, 41% between Hormozgan province and Fars province, 22% betweenChaharmahal and bakhtyari province and Isfahan province, 22% between Kogiloye and boyerahmad province and Isfahan, 22% between Golestan province and Mazandaran province, 43% between Bushehr province and Khozestan province, 41% between Ilam province and Khuzestan province, 42% between Qazvin province and Tehran province, 44% between Markazi province and Tehran, and 30% between Qom province and Tehran. CONCLUSION: Accounting and correcting the regional misclassification is necessary for identifying high risk areas and planning for reducing the cancer incidence. PMID- 28596819 TI - Usefulness of the MESH score in a European hepatocellular carcinoma cohort. AB - The Barcelona Clinic Liver Cancer classification is the most widely - used hepatocellular carcinoma (HCC) staging system because it is simple, precise and linked to a treatment algorithm based on randomized studies. But each group includes a broad spectrum of tumors, with limited therapeutic options, particularly for intermediate and advanced stages. Consequently, different additional scoring systems have been proposed to refine the prognosis and/or to improve the management. But until now, there is no consensus. Liu et al proposes a new scoring system, based on a large HCC cohort, with patients at different stages, treated using diverse modalities. This score includes six parameters used in current practice. It is simple to calculate, reliable, with an ability to predict survival superior to other systems, which also works with our European HCC cohort. The MESH score may be especially useful to differentiate subgroups with different prognosis for each treatment modality. PMID- 28596821 TI - Turbine Blade Illusion. AB - In January 2017, a large wind turbine blade was installed temporarily in a city square as a public artwork. At first sight, media photographs of the installation appeared to be fakes - the blade looks like it could not really be part of the scene. Close inspection of the object shows that its paradoxical visual appearance can be attributed to unconscious assumptions about object shape and light source direction. PMID- 28596823 TI - Atypical presentation of sigmoid carcinoma. AB - Colorectal carcinoma is common worldwide and its metastasis represents the main cause of mortality related to the disease. Inguinal metastization of this tumor has been considered almost impossible, owing to colon anatomy and its cranial lymphatic drainage. We report the case of a 63-year-old man submitted to laparoscopical sigmoid colectomy, due a sigmoid adenocarcinoma. During follow-up, a right inguinal lymphadenopathy with 25 mm was detected. Fine needle aspiration biopsy revealed that it was a colon adenocarcinoma metastasis, and thus the patient underwent an inguinal lymphadenectomy. The histological study confirmed metastatic adenocarcinoma of the colon and the patient was submitted to 5 fluouracil and oxaliplatin chemotherapy. This case coursed with metastasis to the right inguinal region; although, the pathophysiological mechanism involved is difficult to understand. There are no solid data for the management of these patients. Inguinal lymphadenectomy and chemotherapy, proved to be effective. PMID- 28596822 TI - Ethmoid malformation associated with pediatric nasal polyposis and allergic fungal sinusitis. AB - A 17-year-old female with allergic fungal sinusitis and nasal polyposis presented with epistaxis in the emergency room. On examination, right-sided proptosis and irregular nasal obstruction were observed in the right nasal cavity. CT imaging revealed massive right-sided polyposis and significant ipsilateral malformation with boney architecture preservation of the ethmoidal labyrinth and lamina papyracea. The patient was treated surgically with symptomatic improvement. These findings indicate a unique malformation of the ethmoid while the patient was in development. To the authors' knowledge, this anatomical malformation has not been previously described in the literature. Physicians should implement diagnostic procedures early if nasal polyposis and allergic fungal sinusitis is suspected in pediatric patients, especially with periocular involvement, to mitigate the risk of boney malformations of the sinuses. PMID- 28596824 TI - Primary extrahepatic bile duct neuroendocrine tumor with obstructive jaundice masquerading as a Klatskin tumor. AB - Neuroendocrine tumors (NETs) of the extrahepatic bile duct are extremely rare and reported infrequently in the literature. These tumors are difficult to diagnose preoperatively, and the prognosis is variable, often determined by extent of disease, tumor grade and resectability. This case report presents a 45-year-old male with history of biliary obstruction relieved by endobiliary stents with common hepatic duct stricture just above the cystic duct, thought to be a Klatskin's cholangiocarcinoma. Final pathological examination was consistent with primary extrahepatic NET. PMID- 28596820 TI - Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome. AB - BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics. PMID- 28596827 TI - Erratum to: Arrhythmogenic right ventricular cardiomyopathy secondary to adipose infiltration as a cause of episodic collapse in a horse. AB - [This corrects the article DOI: 10.1186/s13620-015-0052-3.]. PMID- 28596826 TI - Field evaluation of the efficacy of common anthelmintics used in the control of gastrointestinal nematodes of sheep in Dabat district, Northwest Ethiopia. AB - BACKGROUND: Gastrointestinal nematode (GIN) infections are the main impediments that restrict the welfare and productivity of small ruminant in the world. Effective management of GINs in grazing sheep relies heavily on the use of highly efficacious anthelmintic drugs. However, anthelmintic resistance is becoming a significant concern in the world, and this phenomenon severely threatens the potential utilisation of this control strategy. Therefore, this study was conducted 1) to evaluate the efficacy of commonly used anthelmintic on GINs in naturally infected sheep and 2) to assess the farmers' perception on anthelmintics utilisation practices in Dabat district, Northwest Ethiopia. METHODS: One hundred twenty nematode infected sheep were used in this study. Sheep were selected based on the egg count (>=150 eggs per gram of faeces). The animals were allocated randomly into four groups (30 animals per group). Group-I, II and III were treated with Albendazole, Tetramisole, and Ivermectin, respectively. The 4th group was left untreated (as control). Faecal samples were collected on day 0 (before treatment), on day 3, 7, 10 and 14 (post-treatment). The modified McMaster technique was used for quantifying the eggs. Faecal egg count reduction test (FECRT) was applied to determine the efficacy of anthelmintic at day 14 (post-treatment). In addition, a questionnaire survey was conducted on 100 randomly selected sheep owners. RESULTS: All anthelmintics tested revealed significant (P < 0.05) reduction in nematode egg excretion in the sheep post-treatment. Faecal egg count reduction (FECR) levels for Albendazole, Tetramisole, and Ivermectin were 97.2, 98.9 and 97.7%, respectively. Post treatment egg counts and percentage reduction of egg counts were not significantly different (P > 0.05) among the treatment groups. The nematode genera identified before treatment were Haemonchus, Trichostrongylus, Cooperia, Trichuris, Teladorsagia, Bunostomum, and Strongyloides. Haemonchus and Trichostrongylus were detected after treatment with Albendazole and Ivermectin. The questionnaire survey revealed that Albendazole was the most commonly (90%) used anthelmintic to treat nematodes in sheep, followed by Tetramisole (36%) and Tetraclozan (Tetramisole-Oxyclozanide combination) (20%). Respondents expressed that anthelmintic selection was made based on veterinarian prescription (84%), colour (27%), efficacy (4%), price affordability (1%) and availability (1%). CONCLUSION: This study demonstrated that the tested anthelmintics had an acceptable level of efficacy against GINs of sheep. PMID- 28596825 TI - Kv1.3 channel blocker (ImKTx88) maintains blood-brain barrier in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Disruption of blood-brain barrier (BBB) and subsequent infiltration of auto-reactive T lymphocytes are major characteristics of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Kv1.3 channel blockers are demonstrated potential therapeutic effects on MS patients and EAE models, maybe via reducing activation of T cells. However, it remains to be explored whether Kv1.3 channel blockers maintain integrity of BBB in MS model. RESULTS: In this study, ImKTx88, a highly selective Kv1.3 channel blocker, was used to determine the role of Kv1.3 channel in the pathogenesis of EAE, particularly in the maintenance of BBB. ImKTx88 ameliorated pathological severity in the EAE rats, and reduced extravasation into CNS. ImKTx88 also ameliorated the severity of loss or redistribution of tight junction proteins, and inhibited over expression of ICAM-1 and VCAM-1 in the brain from EAE rats. Furthermore ImKTx88 protection was associated with activation of Ang-1/Tie-2 axis, and might be due to decreased IL-17 production. CONCLUSIONS: ImKTx88 may be a novel therapeutic agent for MS treatment by stabilizing the BBB. PMID- 28596830 TI - The effect of switching from oral low-dose aripiprazole to aripiprazole once monthly 300 mg on the quality of life in three patients with schizophrenia. AB - BACKGROUND: Schizophrenia is a chronic disease that requires long-term management with antipsychotics; however, an important barrier to the success of long-term treatment is drug noncompliance, which increases the risk of recurrence and hospitalization. Second-generation long-acting injectable antipsychotics have improved drug adherence, and the pharmacological effects of the drugs, and therefore, have become useful treatment options. METHODS: We report on three schizophrenia patients who switched from oral low-dose aripiprazole to aripiprazole once-monthly 300 mg. We examined the efficacy and safety of aripiprazole once-monthly 300 mg, as well as its influence on quality of life, from baseline to 20 weeks after aripiprazole once-monthly 300 mg treatment. RESULTS: Aripiprazole once-monthly 300 mg did not exacerbate the depressive and negative symptoms, and extrapyramidal symptoms were improved, which may have helped improve the quality of life. CONCLUSION: The results suggest the efficacy of aripiprazole once-monthly 300 mg in maintenance treatment for schizophrenia when mental symptoms are stable. PMID- 28596829 TI - An unusual case of primary hepatic lymphoma with dramatic but unsustained response to bendamustine plus rituximab and literature review. AB - OBJECTIVES: Primary hepatic lymphoma is an uncommon cause of hepatic space occupying lesions. METHODS: We describe the case of a 73-year-old man with primary hepatic lymphoma, who presented with a low-grade fever and lower limb weakness which had progressed in the past 2 months. RESULTS: Abdominal ultrasound and computed tomography showed multiple small hepatic tumors. Echo-guided biopsy of the hepatic tumor demonstrated primary hepatic diffuse large B cell lymphoma. Moreover, bone marrow was uninvolved, but the bone marrow smear disclosed hemophagocytosis, which is uncommon in diffuse large B cell lymphoma. Chemotherapy with bendamustine and rituximab treatment was initiated with a dramatic response: hepatic tumors markedly shrank in size shown by follow-up computed tomography and the patient returned to his normal life. Nevertheless, the response was sustained for only 8 months. Finally, the disease resisted further chemotherapy and this patient died of a severe Klebsiella pneumoniae infection. CONCLUSION: Chemotherapy with bendamustine and rituximab has shown a dramatic, but not durable, response in the present case with old age and multiple comorbidities. PMID- 28596831 TI - Ofatumumab-associated acute pneumonitis: Not new but still the first case. AB - Ofatumumab is an anti-CD20 humanized monoclonal antibody utilized in the treatment of several clinical conditions resistant to other treatments. In spite there was a general expectation that ofatumumab was less toxic compared to rituximab, side effects have been reported that resemble those of its anti-CD20 chimeric precursor. Here, we describe the first case of Ofatumumab associate lung injury occurring in a 14-year-old boy affected by nephrotic syndrome dependent to prednisone plus cyclosporine A who had been treated with the dose of drug utilized in nephrotic syndrome (1500 mg/173 m2). The patient developed the full blown picture of rituximab associated lung injury (RALI) after 45 days from ofatumumab infusion at the end of the steroid tapering: severe exertional dyspnea, mild fever and cyanosis, with CT scan showing diffuse ground glass areas in both lungs and DLCO (diffusing capacity of transfer factor of the lung for carbon monoxide) test suggestive for reduction of CO diffusion. Clinical outcome was good with rapid improvement and normalization of all parameters without any specific therapy. After 60 days, chest CT and CO diffusion tests were normal. In conclusion, we describe here the first case of acute pneumonitis associated with ofatumumab that presents the same clinical, laboratory, and radiology features of the lung injury reported for rituximab. Like RALI occurring in patients treated for nephrotic syndrome, this case had a mild clinical expression and recovered in a few months. PMID- 28596832 TI - Mechanical and vasomotor properties of piglet isolated middle cerebral artery. AB - Piglets are often used as experimental models for studying cerebrovascular responses in newborn infants. However, the mechanical characteristics of piglets' middle cerebral arteries (MCA) are not well characterized. Additionally, the vessels' response to dopamine, the most commonly used vasopressor in newborns, is not characterized in piglets' MCA. Finally, the influence of preterm birth on the dopamine response is not known. The aim of this current was to compare by wire myography the active and passive mechanical characteristics and dopamine concentration-response relations of MCAs isolated from preterm and term newborn piglets. Second-order branches of the MCA with a diameter <400 MUm were chosen for study. The active and passive mechanical properties were comparable between vessels from six preterm (90% gestation, nsegments = 11) and nine term (nsegments = 22) newborn piglets. The response to increasing concentrations of dopamine was biphasic, starting with vasodilation in the 1 nmol/L-0.3 MUmol/L concentration range followed by vasoconstriction at higher concentrations. The response was very similar between the two groups. In conclusion, the mechanical properties of the MCA as well as the response to dopamine were comparable between term and 90% gestation preterm piglets. PMID- 28596833 TI - Absorption, distribution, metabolism, and excretion of [14C]-dasotraline in humans. AB - Dasotraline is a dopamine and norepinephrine reuptake inhibitor, and the early clinical trials show a slow absorption and long elimination half-life. To investigate the absorption, distribution, metabolism, and excretion of dasotraline in humans, a single dose of [14C]-dasotraline was administered to eight healthy male adult volunteers. At 35 days, 90.7% of the dosed radioactivity was recovered in the urine (68.3%) and feces (22.4%). The major metabolic pathways involved were: (1) amine oxidation to form oxime M41 and sequential sulfation to form M42 or glucuronidation to form M43; (2) N-hydroxylation and sequential glucuronidation to form M35; (3) oxidative deamination to form (S) tetralone; (4) mono-oxidation of (S)-tetralone and sequential glucuronidation to form M31A and M32; and (5) N-acetylation to form (1R,4S)-acetamide M102. A total of 8 metabolites were detected and structurally elucidated with 4 in plasma (M41, M42, M43, and M35), 7 in urine (M41, M42, M43, M31A, M32, M35, and (S) tetralone), and 3 in feces (M41, (S)-tetralone, and (1R,4S)-acetamide). The 2 most abundant circulating metabolites were sulfate (M42) and glucuronide (M43) conjugates of the oxime of dasotraline, accounting for 60.1% and 15.0% of the total plasma radioactivity, respectively; unchanged dasotraline accounted for 8.59%. The oxime M41 accounted for only 0.62% of the total plasma radioactivity and was detected only at early time points. M35 was a minor glucuronide metabolite, undetectable by radioactivity but identified by mass spectrometry. The results demonstrate that dasotraline was slowly absorbed, and extensively metabolized by oxidation and subsequent phase II conjugations. The findings from this study also demonstrated that metabolism of dasotraline by humans did not produce metabolites that may cause a safety concern. PMID- 28596836 TI - Characterizing QT interval prolongation in early clinical development: a case study with methadone. AB - Recently, we have shown how pharmacokinetic-pharmacodynamic (PKPD) modeling can be used to assess the probability of QT interval prolongation both in dogs and humans. A correlation between species has been identified for a drug-specific parameter, making it possible to prospectively evaluate nonclinical signals. Here, we illustrate how nonclinical data on methadone can be used to support the evaluation of dromotropic drug effects in humans. ECG and drug concentration data from a safety pharmacology study in dogs were analyzed using nonlinear mixed effects modeling. The slope of the PKPD model describing the probability of QT interval prolongation was extrapolated from dogs to humans and subsequently combined with methadone pharmacokinetic data as input for clinical trial simulations. Concentration versus time profiles were simulated for doses between 5 and 500 mg. Predicted peak concentrations in humans were then used as reference value to assess the probability of an increase in QT interval of >=5 and >=10 ms. Point estimates for the slope in dogs suggested low probability of >=10 ms prolongation in humans, whereas an effect of approximately 5 ms increase is predicted when accounting for the 90% credible intervals of the drug-specific parameter in dogs. Interspecies differences in drug disposition appear to explain the discrepancies between predicted and observed QT prolonging effects in humans. Extrapolation of the effects of racemic compound may not be sufficient to describe the increase in QT interval observed after administration of methadone to patients. Assessment of the contribution of enantioselective metabolism and active metabolites is critical. PMID- 28596837 TI - Genome-wide DNA methylation profiling of CpG islands in a morpholino anthracycline derivative-resistant leukemia cell line: p38alpha as a novel candidate for resistance. AB - Effective leukemia treatment is seriously hampered by drug resistance. We previously showed that aberrant methylation of the topoisomerase II alpha gene causes altered gene expression and acquired drug resistance in etoposide resistant leukemia cells. In this study, we analyzed the genome-wide methylation status in resistant leukemia cells. We used MX2, which is a morpholino anthracycline derivative that functions as a topoisomerase II alpha inhibitor. We established a human myelogenous leukemia cell line (K562/P) and a related cell line with resistance to MX2 (K562/MX2). Using these cell lines, we investigated the genome-wide methylation status, compared expression profiles with a microarray, and analyzed the data using Gene Ontology and key node analysis. We demonstrate that the MX2-resistant cell line was globally hypermethylated. Gene Ontology analysis identified genes involved in the immunological response and gene silencing that were responsible for methylation-related altered gene expression in drug-resistant cells. Key node analysis showed that p38alpha mitogen-activated protein kinase was a novel enzyme involved in MX2-related resistance. p38 kinase activity in resistant cells was increased compared to MX2 sensitive parent cells. Blocking p38alpha activity using inhibitors and p38alpha knock down with small interfering RNA restored the sensitivity to MX2 in resistant cells with a decrease in p38 kinase activity as well as decreased expression of p38alpha mRNA and phosphorylated p38alpha protein. These findings may lead to a new strategy for treatment of drug-resistant leukemia cells. PMID- 28596834 TI - Acute cocaine exposure elicits rises in calcium in arousal-related laterodorsal tegmental neurons. AB - Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT. Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels of synaptic DA, but via a different pharmacological action than cocaine, induced calcium spiking with similar profiles. Although large differences in spiking were not noted in an animal model associated with a heightened proclivity of acquiring addiction-related behavior, the prenatal nicotine exposed mouse (PNE), subtle differences in cocaine's effect on calcium spiking were noted, indicative of a reduction in action of cocaine in the LDT associated with exposure to nicotine during gestation. When taken together, our data indicate that acute actions of cocaine do include effects on LDT cells. Considering the role of intracellular calcium in cellular excitability, and of the LDT in addiction circuitry, our data suggest that cocaine effects in this nucleus may contribute to the high addiction potential of this drug. PMID- 28596835 TI - Chronic diazepam administration increases the expression of Lcn2 in the CNS. AB - Benzodiazepines (BZDs), which bind with high affinity to gamma-aminobutyric acid type A receptors (GABAA-Rs) and potentiate the effects of GABA, are widely prescribed for anxiety, insomnia, epileptic discharge, and as anticonvulsants. The long-term use of BZDs is limited due to adverse effects such as tolerance, dependence, withdrawal effects, and impairments in cognition and learning. Additionally, clinical reports have shown that chronic BZD treatment increases the risk of Alzheimer's disease. Unusual GABAA-R subunit expression and GABAA-R phosphorylation are induced by chronic BZD use. However, the gene expression and signaling pathways related to these effects are not completely understood. In this study, we performed a microarray analysis to investigate the mechanisms underlying the effect of chronic BZD administration on gene expression. Diazepam (DZP, a BZD) was chronically administered, and whole transcripts in the brain were analyzed. We found that the mRNA expression levels were significantly affected by chronic DZP administration and that lipocalin 2 (Lcn2) mRNA was the most upregulated gene in the cerebral cortex, hippocampus, and amygdala. Lcn2 is known as an iron homeostasis-associated protein. Immunostained signals of Lcn2 were detected in neuron, astrocyte, microglia, and Lcn2 protein expression levels were consistently upregulated. This upregulation was observed without proinflammatory genes upregulation, and was attenuated by chronic treatment of deferoxamine mesylate (DFO), iron chelator. Our results suggest that chronic DZP administration regulates transcription and upregulates Lcn2 expression levels without an inflammatory response in the mouse brain. Furthermore, the DZP-induced upregulation of Lcn2 expression was influenced by ambient iron. PMID- 28596838 TI - Botulinum Neurotoxins Serotypes A and B induce paralysis of mouse striated and smooth muscles with different potencies. AB - To address the scarcity of direct comparison of botulinum neurotoxin serotypes activity on smooth versus striatal muscle, we have studied the action of BoNT/A1 and BoNT/B1 on ex vivo preparations of both muscle types. We have set up and characterized a model of neurogenic contractions in the isolated mouse bladder, and used this model to explore the effects of the two serotypes on contractions evoked by electrical field stimulation. Both toxins were also tested in the mouse phrenic nerve hemidiaphragm assay, to compare their potency in smooth versus striated muscle. The characterization of the model of neurogenic contractions in the isolated mouse bladder indicates that about half of the activity is driven by purinergic signaling, and about half by cholinergic signaling. Furthermore, we find that BoNT/B1 is more potent than BoNT/A1 in inhibiting activity in the mouse detrusor smooth muscle preparation, but that both toxins have comparable potency on the striated muscle activity of the phrenic nerve hemidiaphragm model. We also show that these findings are mouse strain independent. In conclusion, the established mouse bladder detrusor smooth muscle model is able to discriminate between different botulinum neurotoxin serotypes and could be a useful preclinical tool to explore the pathophysiology of bladder overactivity, as well as the effects of new therapeutic candidates. It is interesting to note that the high proportion of purinergic transmission driving detrusor contractions in this model is similar to that seen in neurodetrusor overactivity disease, making this model relevant with regard to pathophysiological interest. PMID- 28596839 TI - Structure-specific effects of lipidated oxytocin analogs on intracellular calcium levels, parental behavior, and oxytocin concentrations in the plasma and cerebrospinal fluid in mice. AB - Oxytocin (OT) is a neuroendocrine nonapeptide that plays an important role in social memory and behavior. Nasal administration of OT has been shown to improve trust in healthy humans and social interaction in autistic subjects in some clinical trials. As a central nervous system (CNS) drug, however, OT has two unfavorable characteristics: OT is short-acting and shows poor permeability across the blood-brain barrier, because it exists in charged form in the plasma and has short half-life. To overcome these drawbacks, an analog with long-lasting effects is required. We previously synthesized the analog, lipo-oxytocin-1 (LOT 1), in which two palmitoyl groups are conjugated to the cysteine and tyrosine residues. In this study, we synthesized and evaluated the analogs lipo-oxytocin-2 (LOT-2) and lipo-oxytocin-3 (LOT-3), which feature the conjugation of one palmitoyl group at the cysteine and tyrosine residues, respectively. In human embryonic kidney-293 cells overexpressing human OT receptors, these three LOTs demonstrated comparably weak effects on the elevation of intracellular free calcium concentrations after OT receptor activation, compared to the effects of OT. The three LOTs and OT exhibited different time-dependent effects on recovery from impaired pup retrieval behavior in sires of CD38-knockout mice. Sires treated with LOT-1 showed the strongest effect, whereas others had no or little effects at 24 h after injection. These results indicated that LOTs have structure specific agonistic effects, and suggest that lipidation of OT might have therapeutic benefits for social impairment. PMID- 28596840 TI - Novel SGLT2 inhibitor: first-in-man studies of antisense compound is associated with unexpected renal effects. AB - The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium-glucose cotransporter-2 (SGLT2) mRNA expression. It is developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administration of the drug were planned to be evaluated in healthy volunteers in a single-ascending-dose study (50-400 mg) and a multiple-ascending-dose study (6 weeks; weekly doses of 50-400 mg with loading dose regimen of three doses during the first week). The study was halted early because increases in serum creatinine occurred in the subjects participating in the 100 mg multiple-dose cohort. The pronounced changes in serum creatinine were accompanied by increased urinary excretion of beta-2-microglobulin and KIM1. The possible mechanisms for these findings remain elusive and are in contrast to preclinical findings as comparable treatment with ISIS 388626 of animals did not reveal similar changes. Although exposure was limited, there was an indication that glucosuria increased upon active treatment. Before the concept of antisense mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations. PMID- 28596841 TI - Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. AB - Emerging viruses such as HIV, dengue, influenza A, SARS coronavirus, Ebola, and other viruses pose a significant threat to human health. Majority of these viruses are responsible for the outbreaks of pathogenic lethal infections. To date, there are no effective therapeutic strategies available for the prophylaxis and treatment of these infections. Chloroquine analogs have been used for decades as the primary and most successful drugs against malaria. Concomitant with the emergence of chloroquine-resistant Plasmodium strains and a subsequent decrease in the use as antimalarial drugs, other applications of the analogs have been investigated. Since the analogs have interesting biochemical properties, these drugs are found to be effective against a wide variety of viral infections. As antiviral action, the analogs have been shown to inhibit acidification of endosome during the events of replication and infection. Moreover, immunomodulatory effects of analogs have been beneficial to patients with severe inflammatory complications of several viral diseases. Interestingly, one of the successful targeting strategies is the inhibition of HIV replication by the analogs in vitro which are being tested in several clinical trials. This review focuses on the potentialities of chloroquine analogs for the treatment of endosomal low pH dependent emerging viral diseases. PMID- 28596843 TI - Magnitude and predictors of antiretroviral treatment failure among HIV-infected children in Fiche and Kuyu hospitals, Oromia region, Ethiopia: a retrospective cohort study. AB - The objective of the study was to assess the magnitude and predictors of first line antiretroviral treatment failure among HIV-infected children. A retrospective cohort study was conducted between January 2006 and December 2015. All pediatric patients of <15 years old and who took at least 6 months of ART in Fiche and Kuyu hospitals of Oromia region, Ethiopia were included in the study. Collected data were entered and analyzed using SPSS version 20. Multivariable logistic regression was employed to identify predictors of treatment failure. Data of 269 children were analyzed and majority (53.9%) of the children were males with a mean age of 9.8 +/- 3.64 years. Based on the two WHO criteria, overall ART failure was found to be 51 (18.8%), of which 33 (12.26%) had clinical and 18 (6.69%) had immunologic failures. The mean time to the detection of treatment failure was 41 +/- 24.96 months. Children's age between 6 and 9 years (AOR = 0.26, 95% CI: 0.09, 0.72) was protective toward treatment failure, while lost to follow-up (AOR = 7.54, 95% CI: 2.35, 24.16), died (AOR = 22.22, 95% CI: 3.75, 131.54), transferred out (AOR = 3.34, 95% CI: 1.41, 7.87), suboptimal adherence to ART (AOR = 4.85, 95% CI: 1.82, 12.93), baseline CD4 count of <50 cells/mm3 (AOR = 4.28, 95% CI: 3.49, 5.9), and WHO advanced clinical stage (AOR = 2.46, 95% CI: 1.14, 5.31) were found to be predictors of treatment failure. The study revealed that the treatment failure is high and the mean time to develop treatment failure is short. The predictors for treatment failure were suboptimal adherence, lost to follow-up, transferred out, initial CD4 count <50 cells/mm3, initial WHO stages 3 and 4. On the other hand, being in the age of 6-9 years is protective from developing treatment failure as compared to the other age category. PMID- 28596844 TI - Let's get to work. PMID- 28596845 TI - Global Mental Health: how do we make it 'global'? PMID- 28596846 TI - Promise of Systems Research in reducing burden of Mental Health. PMID- 28596842 TI - Effects of resveratrol on drug- and carcinogen-metabolizing enzymes, implications for cancer prevention. AB - Resveratrol is a polyphenol found in grape skins and peanuts that has demonstrated many health benefits including protection against aging, cardiovascular and metabolic disease, neurological decline, and cancer. The anticancer properties of resveratrol have been attributed to a variety of mechanisms, including its general inhibition of phase I metabolism and induction of phase II metabolism. The effects of resveratrol on these enzymes, however, are still unclear, as in vitro evidence often contrasts with animal studies and clinical trials. Reasons for these variances could include the low bioavailability of resveratrol and the effects of resveratrol metabolites. Due to resveratrol's interactions with drug-metabolizing enzymes and drug transporters, individuals concurrently taking pharmacological doses of resveratrol with other supplements or medications could potentially experience nutrient-drug interactions. This review summarizes the known effects of resveratrol and its main metabolites on drug metabolism in order to help characterize which populations might benefit from resveratrol for the prevention of cancer, as well as those that may need to avoid supplementation due to potential drug interactions. PMID- 28596847 TI - What can be done to reduce the burden of mental health problems globally? PMID- 28596848 TI - Pulling at the Roots: Broadening Our Perspective on Mental Disorder Aetiology. PMID- 28596849 TI - Learners without borders. PMID- 28596850 TI - Improving Malawian teachers' mental health knowledge and attitudes: an integrated school mental health literacy approach. AB - BACKGROUND: Mental health literacy is foundational for mental health promotion, prevention, stigma reduction and care. Integrated school mental health literacy interventions may offer an effective and sustainable approach to enhancing mental health literacy for educators and students globally. METHODS: Through a Grand Challenges Canada funded initiative called 'An Integrated Approach to Addressing the Issue of Youth Depression in Malawi and Tanzania', we culturally adapted a previously demonstrated effective Canadian school mental health curriculum resource (the Guide) for use in Malawi, the African Guide: Malawi version (AGMv), and evaluated its impact on enhancing mental health literacy for educators (teachers and youth club leaders) in 35 schools and 15 out-of-school youth clubs in the central region of Malawi. The pre- and post-test study designs were used to assess mental health literacy - knowledge and attitudes - of 218 educators before and immediately following completion of a 3-day training programme on the use of the AGMv. RESULTS: Results demonstrated a highly significant and substantial improvement in knowledge (p < 0.0001, d = 1.16) and attitudes (p < 0.0001, d = 0.79) pertaining to mental health literacy in study participants. There were no significant differences in outcomes related to sex or location. CONCLUSIONS: These positive results suggest that an approach that integrates mental health literacy into the existing school curriculum may be an effective, significant and sustainable method of enhancing mental health literacy for educators in Malawi. If these results are further found to be sustained over time, and demonstrated to be effective when extended to students, then this model may be a useful and widely applicable method for improving mental health literacy among both educators and students across Africa. PMID- 28596851 TI - Autism: a (key) piece of the global mental health puzzle. PMID- 28596852 TI - Executive function and attention-deficit/hyperactivity disorder in Ugandan children with perinatal HIV exposure. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is among the most commonly diagnosed mental disorders in childhood and is associated with substantial deficits in executive functioning and lost academic and occupational attainment. This study evaluates symptoms of ADHD and their association with neurocognitive deficits in a cohort of rural Ugandan children who were born to HIV-infected mothers. METHODS: We assessed ADHD symptoms and executive function (including memory and attention) in a non-clinical sample of children born to HIV infected mothers in rural eastern Uganda. Analyses included assessments of the psychometric properties, factor structure, and convergent and discriminant validity of the ADHD measure (ADHD-Rating Scale-IV); and executive function deficits in children meeting symptom criteria for ADHD. RESULTS: 232 children [54% female; mean age 7.8 years (s.d. 2.0)] were assessed for ADHD and executive function deficits. The ADHD measure showed good internal consistency (alpha = 0.85.) Confirmatory factor analysis showed an acceptable fit for the diagnostic and statistical manual of mental disorders (DSM-5) two-factor model. Subjects meeting DSM-5 symptom criteria for ADHD had worse parent-rated executive function on six out of seven subscales. CONCLUSIONS: Our results demonstrate structural validity of the ADHD measure with this population, strong associations between ADHD symptom severity and poorer executive function, and higher levels of executive function problems in perinatally HIV-exposed Ugandan children with ADHD. These findings suggest that ADHD may be an important neurocognitive disorder associated with executive function problems among children in sub Saharan African settings where perinatal HIV exposure is common. PMID- 28596853 TI - Cross-cultural child and adolescent psychiatry research in developing countries. AB - Mental disorders are currently a major source of morbidity among children and youth globally. The bulk of the epidemiological data about childhood mental health morbidity currently comes from the industrialized countries which paradoxically host a small (about 20%) proportion of global children and youth population. As the world seek to generate more data on the mental health of the teeming children and youth population in low- and middle-income countries (LMICs), cross-cultural issues need be considered. This consideration is imperative for reasons which include the high level of ethno-diversity in LMICs; the contextual issues in the conceptualization of normal (and abnormal) childhood across cultures, the cross-cultural nuances in risk and protective factors, and the plurality of nature and expression of childhood psychopathology. As much as it is imperative to do so, advancing cross-cultural child and adolescent research in LMICs will need to overcome challenges such as inclusive sampling and cultural validation of instruments developed in the industrialized countries of the West. Funding, technical resources, and publication bias are other potential challenges. These issues are appraised in this narrative review and some ways forward are proffered. PMID- 28596854 TI - Designing and evaluating Brain Powered Games for cognitive training and rehabilitation in at-risk African children. AB - BACKGROUND: Valid, reliable, accessible, and cost-effective computer-training approaches can be important components in scaling up educational support across resource-poor settings, such as sub-Saharan Africa. The goal of the current study was to develop a computer-based training platform, the Michigan State University Games for Entertainment and Learning laboratory's Brain Powered Games (BPG) package that would be suitable for use with at-risk children within a rural Ugandan context and then complete an initial field trial of that package. METHODS: After game development was completed with the use of local stimuli and sounds to match the context of the games as closely as possible to the rural Ugandan setting, an initial field study was completed with 33 children (mean age = 8.55 +/- 2.29 years, range 6-12 years of age) with HIV in rural Uganda. The Test of Variables of Attention (TOVA), CogState computer battery, and the Non Verbal Index from the Kaufman Assessment Battery for Children, 2nd edition (KABC II) were chosen as the outcome measures for pre- and post-intervention testing. The children received approximately 45 min of BPG training several days per week for 2 months (24 sessions). RESULTS: Although some improvements in test scores were evident prior to BPG training, following training, children demonstrated clinically significant changes (significant repeated-measures outcomes with moderate to large effect sizes) on specific TOVA and CogState measures reflecting processing speed, attention, visual-motor coordination, maze learning, and problem solving. CONCLUSIONS: Results provide preliminary support for the acceptability, feasibility, and neurocognitive benefit of BPG and its utility as a model platform for computerized cognitive training in cross-cultural low resource settings. PMID- 28596855 TI - Infant Mental Health Research in Africa: a call for action for research in the next 10 years. AB - BACKGROUND: Less than 3% of articles published in the peer reviewed literature include data from low- and middle-income countries - where 90% of the world's infants live. METHODS: In this paper, we discuss the context of infancy in Africa and the conditions of adversity obtaining in Africa. RESULTS: We discuss the implications of poverty on parenting, and linked to this outline the impact of maternal depression on infant development. CONCLUSIONS: We outline three features of the field of infant mental health research in Africa, and issue a call for action about what we believe is needed in order to develop the field in the next decade. PMID- 28596856 TI - Establishing the feasibility of assessing the mental health of children displaced by the Syrian conflict. AB - BACKGROUND: In the humanitarian crisis context of conflict zones, collecting data is essential for identifying and addressing the mental health needs of refugee children to avoid mass suffering. This study tested the feasibility of recruiting refugees caring for children and using established and brief parent-report questionnaires in a challenging context to collect mental health data on refugee children displaced by Syria's conflict. METHODS: Caregivers of 4-10-year olds attending primary schools run by non-governmental organisation (NGO) Generation Freedom in and near refugee camps on the Syrian-Turkish border were invited to complete the Pediatric Emotional Distress Scale (PEDS) and Strengths and Difficulties Questionnaire (SDQ). RESULTS: It was possible to reach 144 adult refugees caring for children with research participation information and use informed consent procedures. A total of 106 caregivers completed the questionnaires yielding a good return rate (74%). Eighty-two (77.4%) caregivers had complete data on the PEDS and 61 (57.5%) on the SDQ. Almost half (49%) of the children met the clinical cut-off for being anxious/withdrawn and 62% for being fearful rated using the PEDS and 45% for SDQ rated emotional symptoms. More than a third had clinical levels of behavioural problems on both scales. CONCLUSIONS: It proved feasible to collect child mental health data in challenging conditions in the context of the Syrian crisis with support from a local NGO providing humanitarian assistance. The PEDS performed better than the SDQ in this context. High levels of emotional distress and behavioural problems in children reiterate the urgent need for evidence-based psychosocial support. PMID- 28596857 TI - Immunological correlates of behavioral problems in school-aged children living with HIV in Kayunga, Uganda. AB - BACKGROUND: HIV can affect the neuropsychological function of children, including their behavior. We aim to identify immunological correlates of behavioral problems among children living with HIV in Uganda. METHODS: Children participating in a parent randomized control trial in Kayunga, Uganda were assessed with the Behavior Rating Inventory of Executive Function (BRIEF) and the Child Behavior Checklist (CBCL). We constructed simple and multiple linear regression models to identify immunological correlates of behavioral problems. RESULTS: A total of 144 children living with HIV (50% male) with a mean age of 8.9 years [Standard Deviation (s.d.) = 1.9] were included in the analysis. Eighty two children were on antiretroviral therapy. Mean CD4 cell count % was 35.1 cells/MUl (s.d. = 15.0), mean CD4 cell activation 5.7% (s.d. = 5.1), mean CD8 cell activation was 17.5% (s.d. = 11.2) and 60 children (41.7%) had a viral load of <4000 copies/ml. In the adjusted models for the BRIEF, higher scores were associated with higher viral loads (abeta = 16.7 * 10-6, 95% CI -5.00 * 10-6 to 28.4 * 10-6), specifically on the behavioral regulation index. Higher mean CD8 activation % was associated with higher scores on the Externalizing Problems and Total Problems scales of the CBCL (abeta = 0.17, 95% CI 0.04-0.31 and abeta = 0.15, 95% CI 0.00-0.28, respectively). CONCLUSIONS: Poorer behavioral outcomes were associated with higher viral loads while higher CD8 activation was associated with poorer emotional and behavioral outcomes. Complete immunological assessments for children living with HIV could include commonly used viral and immunological parameters to identify those at higher risk of having negative behavior outcomes and who would benefit the most from behavioral interventions. PMID- 28596858 TI - Exploring women's fear of childbirth in a high maternal mortality setting on the Arabian Peninsula. AB - BACKGROUND: Few studies from low-income countries have addressed women's fear of childbirth (FOC) although likely to affect women during both pregnancy and childbirth. The aim of this study was to explore FOC in a high maternal mortality setting in the Arab region, Yemen. METHODS: A multi-stage (stratified-purposive random) sampling process was used. We interviewed 220 women with childbirth experience in urban/rural Yemen. Answers to the question 'Were you afraid of giving birth?' were analyzed using qualitative content analysis. RESULTS: Women perceived childbirth as a place of danger. Fear of death and childbirth complications stemming from previous traumatic childbirth and traumatic experience in the community was rampant. Husbands' and in-laws' disappointment in a girl infant constituted a strong sociocultural component of FOC. Women's perception of living in tension 'between worlds' of tradition and modernity reinforced fear of institutional childbirth. Women without FOC gave reasons of faith, social belonging and trust in either traditional or modern childbirth practice, past positive experience of childbirth and the desire for social status associated with children. CONCLUSIONS: The numerous maternal and infant deaths have a strong impact on women's FOC. Antenatal care has an important role in reducing fear including that of institutional childbirth and in strengthening a couple in welcoming a female infant. Staff should be sensitized to the fears of both husband and wife and women be allowed support during childbirth. Within the scope of the Millennium Development Goals and strengthening of reproductive mental health programs, FOC urgently needs to be addressed. PMID- 28596859 TI - Stemming the tide: promoting mental health and preventing mental disorders in low and middle-income countries. AB - The first World Health Organization's global action plan for mental health recognizes the importance of mental health promotion and prevention of mental disorders, through the inclusion of one of four objectives focused on this crucial area of research and practice. This paper aims to provide an 'aerial view' of the field of mental health promotion and prevention of mental disorders with a focus on low- and middle-income countries. Starting with reasons why promotion and prevention need to take center stage in global mental health efforts, the paper provides a framework and four general principles to guide such efforts: a socio-ecological perspective (place); an inter-sectoral and interdisciplinary approach (collaboration), a developmental perspective (timing), and a participatory and empowerment approach (strengths), or PaCTS. Evidence based examples of mental health promotion, universal, selective, and indicated prevention are described. PMID- 28596860 TI - A systematic review of online interventions for mental health in low and middle income countries: a neglected field. AB - BACKGROUND: Low and middle income countries (LMICs) are facing an increase of the impact of mental health problems while confronted with limited resources and limited access to mental health care, known as the 'mental health gap'. One strategy to reduce the mental health gap would be to utilize the internet to provide more widely-distributed and low cost mental health care. We undertook this systematic review to investigate the effectiveness and efficacy of online interventions in LMICs. METHODS: We systematically searched the data-bases PubMed, PsycINFO, JMIR, and additional sources. MeSH terms, Thesaurus, and free text keywords were used. We included all randomized controlled trials (RCTs) of online interventions in LMICs. RESULTS: We found only three articles reported results of RCTs on online interventions for mental health conditions in LMICs, but none of these interventions was compared with an active control condition. Also, the mental health conditions were diverse across the three studies. CONCLUSIONS: There is a dearth of studies examining the effect of online interventions in LMICs, so we cannot draw a firm conclusion on its effectiveness. However, given the effectiveness of online interventions in high income countries and sharp increase of internet access in LMICs, online interventions may offer a potential to help reduce the 'mental health gap'. More studies are urgently needed in LMICs. PMID- 28596861 TI - Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health Programme for providing innovative mental health care in rural communities in India. AB - BACKGROUND: India has few mental health professionals to treat the large number of people suffering from mental disorders. Rural areas are particularly disadvantaged due to lack of trained health workers. Ways to improve care could be by training village health workers in basic mental health care, and by using innovative methods of service delivery. The ongoing Systematic Medical Appraisal, Referral and Treatment Mental Health Programme will assess the acceptability, feasibility and preliminary effectiveness of a task-shifting mobile-based intervention using mixed methods, in rural Andhra Pradesh, India. METHOD: The key components of the study are an anti-stigma campaign followed by a mobile-based mental health services intervention. The study will be done across two sites in rural areas, with intervention periods of 1 year and 3 months, respectively. The programme uses a mobile-based clinical decision support tool to be used by non physician health workers and primary care physicians to screen, diagnose and manage individuals suffering from depression, suicidal risk and emotional stress. The key aim of the study will be to assess any changes in mental health services use among those screened positive following the intervention. A number of other outcomes will also be assessed using mixed methods, specifically focussed on reduction of stigma, increase in mental health awareness and other process indicators. CONCLUSIONS: This project addresses a number of objectives as outlined in the Mental Health Action Plan of World Health Organization and India's National Mental Health Programme and Policy. If successful, the next phase will involve design and conduct of a cluster randomised controlled trial. PMID- 28596862 TI - Attention deficit hyperactivity disorder symptom self-report in adults in Kenya and its associated risk factors, an analysis from a household survey in a demographic surveillance site. AB - BACKGROUND: There have been no household surveys of adult attention deficit and hyperactivity disorder (ADHD) in Kenya, and only one in sub-Saharan Africa. METHODS: Data on ADHD was used from a household survey of mental disorders and their associated risk factors conducted in Maseno area (population 70 805), near Lake Victoria in Kenya, using a demographic surveillance site as the sample frame, as part of a wider survey of mental health, malaria and immunity A total of 1190 households were selected, and 1158 adult participants consented to the study while 32 refused to participate in the study interviews, giving a response rate of 97.3%. ADHD symptoms were assessed with the WHO Adult ADHD Self-Report Scale (ASRS) Screener. RESULTS: This survey found that the overall prevalence of ADHD using the ASRS was 13.1%. This suggests a high level of ADHD in the Kenyan population which needs to be further investigated for its impact on adult mental health. In the adjusted analysis, increased odds ratios (ORs) were found in those with higher assets (OR 1.7, p = 0.023), those with life events (OR 2.4, p = 0.001 for those with 2-3 life events and OR 2.6, p < 0.001 for those with 4 or more life events), and those with common mental disorders (OR 2.3, p = 0.001). CONCLUSION: The study demonstrates the magnitude of ADHD symptoms as a public health issue, relevant for health worker training, and the importance of further research into its prevalence in adults and associated risk factors. PMID- 28596863 TI - Parents make the difference: a randomized-controlled trial of a parenting intervention in Liberia. AB - BACKGROUND: The objective of this study was to evaluate the impact of a brief parenting intervention, 'Parents Make the Difference'(PMD), on parenting behaviors, quality of parent-child interactions, children's cognitive, emotional, and behavioral wellbeing, and malaria prevention behaviors in rural, post conflict Liberia. METHODS: A sample of 270 caregivers of children ages 3-7 were randomized into an immediate treatment group that received a 10-session parent training intervention or a wait-list control condition (1:1 allocation). Interviewers administered baseline and 1-month post-intervention surveys and conducted child-caregiver observations. Intent-to-treat estimates of the average treatment effects were calculated using ordinary least squares regression. This study was pre-registered at ClinicalTrials.gov (NCT01829815). RESULTS: The program led to a 55.5% reduction in caregiver-reported use of harsh punishment practices (p < 0.001). The program also increased the use of positive behavior management strategies and improved caregiver-child interactions. The average caregiver in the treatment group reported a 4.4% increase in positive interactions (p < 0.05), while the average child of a caregiver assigned to the treatment group reported a 17.5% increase (p < 0.01). The program did not have a measurable impact on child wellbeing, cognitive skills, or household adoption of malaria prevention behaviors. CONCLUSIONS: PMD is a promising approach for preventing child abuse and promoting positive parent-child relationships in low resource settings. PMID- 28596864 TI - Alternative approaches for studying humanitarian interventions: propensity score methods to evaluate reintegration packages impact on depression, PTSD, and function impairment among child soldiers in Nepal. AB - BACKGROUND: Ethical, logistical, and funding approaches preclude conducting randomized control trials (RCTs) in some humanitarian crises. A lack of RCTs and other intervention research has contributed to a limited evidence-base for mental health and psychosocial support (MHPS) programs after disasters, war, and disease outbreaks. Propensity score methods (PSMs) are an alternative analysis technique with potential application for evaluating MHPS programs in humanitarian emergencies. METHODS: PSMs were used to evaluate impacts of education reintegration packages (ERPs) and other (vocational or economic) reintegration packages (ORPs) v. no reintegration programs on mental health of child soldiers. Propensity scores were used to determine weighting of child soldiers in each of the three treatment arms. Multiple linear regression was used to estimate adjusted changes in symptom score severity on culturally validated measures of depression, post-traumatic stress disorder (PTSD), and functional impairment from baseline to 1-year follow-up. RESULTS: Among 258 Nepali child soldiers participating in reintegration programs, 54.7% completed ERP and 22.9% completed ORP. There was a non-significant reduction in depression by 0.59 (95% CI -1.97 to 0.70) for ERP and by 0.60 (95% CI -2.16 to 0.96) for ORP compared with no treatment. There were non-significant increases in PTSD (1.15, 95% CI -1.55 to 3.86) and functional impairment (0.91, 95% CI -0.31 to 2.14) associated with ERP and similar findings for ORP (PTSD: 0.66, 95% CI -2.24 to 3.57; functional impairment (1.05, 95% CI -0.71 to 2.80). CONCLUSION: In a humanitarian crisis in which a non-randomized intervention assignment protocol was employed, the statistical technique of PSMs addressed differences in covariate distribution between child soldiers who received different integration packages. Our analysis did not demonstrate significant changes in psychosocial outcomes for ERPs and ORPs. We suggest the use of PSMs in evaluating non-randomized interventions in humanitarian crises when non-randomized conditions are not utilized. PMID- 28596865 TI - Information for global mental health. AB - BACKGROUND: Information is needed for development of mental health (MH) services; and particularly in low- and middle-income countries (LAMICs), where the MH systems are relatively weak. World Health Organization (WHO) has worked intensively during the last 15 years for developing a strategy in the field of MH information. METHODS: The paper analyzes WHO instruments developed in this area [MH Atlas series and WHO Assessment Instrument for Mental Health Systems (WHO AIMS)]. RESULTS: Data from Atlas series and WHO-AIMS demonstrated that the role of information is often neglected at all the steps: from data collection and processing to analysis, dissemination and utilization, particularly in LAMIC. By implementing several sets of feasible MH indicators WHO has technically supported the improvement of the MH information systems in LAMICs. CONCLUSIONS: In the last few years the importance of information in MH has increased and has been successfully highlighted; but a lot of work still needs to be done for achieving a minimum set of MH indicators and reliable data that can be used by both high income countries and LAMIC. PMID- 28596866 TI - Intersectoral policy for severe and persistent mental illness: review of approaches in a sample of high-income countries. AB - BACKGROUND: It is increasingly recognised that intersectoral linkages between mental health and other health and support sectors are essential for providing effective care for individuals with severe and persistent mental illness. The extent to which intersectoral collaboration and approaches to achieve it are detailed in mental health policy has not yet been systematically examined. METHODS: Thirty-eight mental health policy documents from 22 jurisdictions in Australia, New Zealand, the United Kingdom, Ireland and Canada were identified via a web search. Information was extracted and synthesised on: the extent to which intersectoral collaboration was an objective or guiding principle of policy; the sectors acknowledged as targets for collaboration; and the characteristics of detailed intersectoral collaboration efforts. RESULTS: Recurring themes in objectives/guiding principles included a whole of government approach, coordination and integration of services, and increased social and economic participation. All jurisdictions acknowledged the importance of intersectoral collaboration, particularly with employment, education, housing, community, criminal justice, drug and alcohol, physical health, Indigenous, disability, emergency and aged care services. However, the level of detail provided varied widely. Where detailed strategies were described, the most common linkage mechanisms were joint service planning through intersectoral coordinating committees or liaison workers, interagency agreements, staff training and joint service provision. CONCLUSIONS: Sectors and mechanisms identified for collaboration were largely consistent across jurisdictions. Little information was provided about strategies for accountability, resourcing, monitoring and evaluation of intersectoral collaboration initiatives, highlighting an area for further improvement. Examples of collaboration detailed in the policies provide a useful resource for other countries. PMID- 28596867 TI - Mental health disabilities and human rights protections. AB - BACKGROUND: Around the world, reports regularly expose persistent and systemic human rights violations of patients in mental health services and facilities, and of those who are unable to access needed supports. A number of factors contribute - political will; the range and quality of services available; public and professional attitudes to mental health; stigma; health professionals' training and expertise; and available resources. METHODS: This paper examines one of the main determinants, the legal framework. This sets the parameters for mental health policies and services and for applicable human rights norms and standards that can be realized in practice. RESULTS: We provide an overview of international human rights instruments in relation to mental health disabilities, and of the major human rights violations in this area. Key implications for mental health law reform are drawn with a particular focus on discrimination and coercive interventions. The major challenges posed by the UN Convention on the Rights of Persons with Disabilities (2006) are examined. Current mental health laws, to greater or lesser degrees, fail to meet the newly required standards. We discuss reforms based on 'generic law' and 'legal capacity' principles that seek to meet those standards. CONCLUSIONS: We outline some emergent and promising examples of reform. The role of civil society and the importance of the standing of those with mental health disabilities in this process is noted. PMID- 28596868 TI - Patterns of individual coping, engagement with social supports and use of formal services among a five-country sample of resilient youth. AB - BACKGROUND: Although resilience among victims of child abuse is commonly understood as a process of interaction between individuals and their environments, there have been very few studies of how children's individual coping strategies, social supports and formal services combine to promote well being. METHOD: For this study, we conducted a multi-phase analysis of a qualitative dataset of 608 interviews with young people from five countries using grounded theory strategies to build a substantive theory of young people's service and support use patterns. We started with an analysis of ten interviews (two from each country) and then compared these findings to patterns found in each country's full dataset. RESULTS: The substantive theory that emerged explains young people's transience between individual coping strategies (cognitive and behavioral), reliance on social supports (family members, peers and teachers), and engagement with formal service providers whose roles are to provide interventions and case management. Young people's patterns of navigation were shown to be contingent upon the individual's risk exposure, his or her individual capacity to cope, and the quality of the formal and informal supports and services that are available and accessible. CONCLUSION: Differing amounts of formal resources in low-, middle- and high-income countries influence patterns of service use. Implications for better coordination between formal mental health services and social supports are discussed. PMID- 28596870 TI - Strengths-based community action as a source of resilience for children affected by armed conflict. AB - Psychosocial and mental health supports for war-affected children frequently are limited by a deficits focus. Current research and practice indicate the value of a strengths-based approach that supports children's resilience and supports a positive environment for children and builds on existing strengths. This paper analyzes how community-based child protection mechanisms are a cornerstone of prevention efforts, and views community-based action as a particularly valuable source for strengths-based support for war-affected children. It shows how collective planning and action on behalf of vulnerable children create high levels of community ownership and effective, sustainable supports for children. It suggests that significant work lies ahead in strengthening the evidence base regarding the effectiveness of strengths-based approaches and in transforming practice away from expert-driven approaches toward community-driven action. PMID- 28596869 TI - 'It is not the State's fault that we have a person like this': relations, institutions and the meaning of 'rights' to carers of People with Psychosocial Disabilities in Chile. AB - BACKGROUND: The UN Convention on the Rights of Persons with Disabilities (CRPD) has been adopted by national governments to advance the interests and wellbeing of people with psychosocial disabilities (PPSD). It is often assumed that the adoption of a 'rights' framework will advance the dignity and autonomy of PPSD. However, little is known about how families and communities understand 'rights'. The present paper, based on research conducted in Santiago, Chile, takes a contextual approach to rights, asking: How do family carers of PPSD understand and use the idea of 'rights'? How does the context of caregiving shape families' understanding of rights? METHODS: Four focus groups were conducted with a total of 25 family carers (predominantly mothers) of people diagnosed with schizophrenia and other severe neuropsychiatric conditions. Thematic analysis was conducted. RESULTS: Carers' experience of caregiving was marked by isolation, stigmatization, a lack of support and mistreatment by public services. Their family networks did not provide sustained help and support, and the public services they had used were characterized by scarce resources and inadequate support. Carers did not refer to rights of dignity or autonomy. Given an unsupportive context, and worries about who would care for their child after the carer's death, their primary interest in 'rights' was a right to guaranteed, long term care. While carers endorsed the idea of universal, state-supported rights, appeals to compassion and the exchange of favours were spoken of as the most effective strategies for gaining a minimum level of services and support. CONCLUSIONS: Carers' understandings, framed against a background of unmet needs and shaped by a history of unsatisfactory interactions with services and institutions, do not resonate with the principles of the CRPD. We suggest an expanded, relational struggle for rights that acknowledges the role of families and the tensions surrounding the distribution of rights within the family. PMID- 28596871 TI - PEPFAR support of alcohol-HIV prevention activities in Namibia and Botswana: a framework for investigation, implementation and evaluation. AB - BACKGROUND: The association between harmful use of alcohol and HIV infection is well documented. To address this dual epidemic, the US President's Emergency Plan for AIDS Relief (PEPFAR) developed and implemented a multi-pronged approach primarily in Namibia and Botswana. We present the approach and preliminary results of the public health investigative and programmatic activities designed, initiated and supported by PEPFAR to combat the harmful use of alcohol and its association as a driver of HIV morbidity and mortality from 2008 to 2013. APPROACH: PEPFAR supported comprehensive alcohol programming using a matrix model approach that combined the socio-ecological framework and the Alcohol Misuse Prevention and Intervention Continuum. This structure enabled seven component objectives: (1) to quantify harmful use of alcohol through rapid assessments; (2) to develop and evaluate alcohol-based interventions; (3) to promote screening programs and alcohol abuse resource services; (4) to support stakeholder networks; (5) to support policy interventions and (6) structural interventions; and (7) to institutionalize universal prevention messages. DISCUSSION: Targeted PEPFAR support for alcohol activities resulted in several projects to address harmful alcohol use and HIV. Components are graphically conceptualized within the matrix model, demonstrating the intersections between primary, secondary and tertiary prevention activities and individual, interpersonal, community, and societal factors. Key initiative successes included leveraging alcohol harm prevention activities that enabled projects to be piloted in healthcare settings, schools, communities, and alcohol outlets. Primary challenges included the complexity of multi-sectorial programming, varying degrees of political will, and difficulties monitoring outcomes over the short duration of the program. PMID- 28596872 TI - At the intersection of lay and professional social networks: how community ties shape perceptions of mental health treatment providers. AB - BACKGROUND: The therapeutic alliance is a critical determinant of individuals' persistence and outcomes in mental health treatment. Simultaneously, individuals' community networks shape decisions about whether, when, and what kind of treatment are used. Despite the similar focus on social relationship influence for individuals with serious mental illness, each line of research has maintained an almost exclusive focus on either 'inside' (i.e. treatment) networks or 'outside' (i.e. community) networks, respectively. METHOD: For this study, we integrate these important insights by employing a network-embedded approach to understand the therapeutic alliance. Using data from the Indianapolis Network Mental Health Study (INMHS, n = 169, obs = 2206), we target patients experiencing their first major contact with the mental health treatment system. We compare patients' perceptions of support resources available through treatment providers and lay people, and ask whether evaluations of interpersonal dimensions of the therapeutic alliance are contingent on characteristics of community networks. RESULTS: Analyses reveal that providers make up only 9% of the whole social network, but are generally perceived positively. However, when community networks are characterized by close relationships and frequent contact, patients are significantly more likely to report that treatment providers offer useful advice and information. Conversely, when community networks are in conflict, perceptions of treatment providers are more negative. CONCLUSION: Community-based social networks are critical for understanding facilitators of and barriers to effective networks inside treatment, including the therapeutic alliance. Implications for community-based systems of care are discussed in the context of the USA and global patterns of deinstitutionalization and community reintegration. PMID- 28596873 TI - Post-traumatic stress disorder and major depression in conflict-affected populations: an epidemiological model and predictor analysis. AB - BACKGROUND: Despite significant research examining mental health in conflict affected populations we do not yet have a comprehensive epidemiological model of how mental disorders are distributed, or which factors influence the epidemiology in these populations. We aim to derive prevalence estimates specific for region, age and sex of major depression, and PTSD in the general populations of areas exposed to conflict, whilst controlling for an extensive range of covariates. METHODS: A systematic review was conducted to identify epidemiological estimates of depression and PTSD in conflict-affected populations and potential predictors. We analyse data using Bayesian meta-regression techniques. RESULTS: We identified 83 studies and a list of 34 potential predictors. The age-standardised pooled prevalence of PTSD was 12.9% (95% UI 6.9-22.9), and major depression 7.6% (95% UI 5.1-10.9) - markedly lower than estimated in previous research but over two-times higher than the mean prevalence estimated by the Global Burden of Disease Study [3.7% (95% UI 3.0-4.5) and 3.5% (95% UI 2.9-4.2) for anxiety disorders and MDD, respectively]. The age-patterns reveal sharp prevalence inclines in the childhood years. A number of ecological variables demonstrated associations with prevalence of both disorders. Symptom scales were shown to significantly overestimate prevalence of both disorders. Finding suggests higher prevalence of both disorders in females. CONCLUSION: This study provides, for the first time, age specific estimates of PTSD and depression prevalence adjusted for an extensive range of covariates and is a significant advancement on our current understanding of the epidemiology in conflict-affected populations. PMID- 28596875 TI - How useful are randomized controlled trials in a rapidly changing world? PMID- 28596874 TI - Overview evidence on interventions for population suicide with an eye to identifying best-supported strategies for LMICs. AB - Globally, over 800 000 people died by suicide in 2012 and there are indications that for each adult who died of suicide there were likely to be many more attempting suicide. There are many millions of people every year who are affected by suicide and suicide attempts, taking into consideration the family members, friends, work colleagues and communities, who are bereaved by suicide. In the WHO Mental Health Action Plan 2013-2020, Member States committed themselves to work towards the global target of reducing the suicide rate in countries by 10% by 2020. Hence, the first-ever WHO report on suicide prevention, Preventing suicide: a global imperative, published in September 2014, is a timely call to take action using effective evidence-based interventions. Their relevance for low- and middle income countries is discussed in this paper, highlighting restricting access to means, responsible media reporting, introducing mental health and alcohol policies, early identification and treatment, training of health workers, and follow-up care and community support following a suicide attempt. PMID- 28596876 TI - Does poverty alleviation decrease depression symptoms in post-conflict settings? A cluster-randomized trial of microenterprise assistance in Northern Uganda. AB - BACKGROUND: By 2009, two decades of war and widespread displacement left the majority of the population of Northern Uganda impoverished. METHODS: This study used a cluster-randomized design to test the hypothesis that a poverty alleviation program would improve economic security and reduce symptoms of depression in a sample of mostly young women. Roughly 120 villages in Northern Uganda were invited to participate. Community committees were asked to identify the most vulnerable women (and some men) to participate. The implementing agency screened all proposed participants, and a total of 1800 were enrolled. Following a baseline survey, villages were randomized to a treatment or wait-list control group. Participants in treatment villages received training, start-up capital, and follow-up support. Participants, implementers, and data collectors were not blinded to treatment status. RESULTS: Villages were randomized to the treatment group (60 villages with 896 participants) or the wait-list control group (60 villages with 904 participants) with an allocation ration of 1:1. All clusters participated in the intervention and were included in the analysis. The intent-to treat analysis included 860 treatment participants and 866 control participants (4.1% attrition). Sixteen months after the program, monthly cash earnings doubled from UGX 22 523 to 51 124, non-household and non-farm businesses doubled, and cash savings roughly quadrupled. There was no measurable effect on a locally derived measure of symptoms of depression. CONCLUSIONS: Despite finding large increases in business, income, and savings among the treatment group, we do not find support for an indirect effect of poverty alleviation on symptoms of depression. PMID- 28596877 TI - Applications of the epidemiological modelling outputs for targeted mental health planning in conflict-affected populations: the Syria case-study. AB - BACKGROUND: Epidemiological models are frequently utilised to ascertain disease prevalence in a population; however, these estimates can have wider practical applications for informing targeted scale-up and optimisation of mental health services. We explore potential applications for a conflict-affected population, Syria. METHODS: We use prevalence estimates of major depression and post traumatic stress disorder (PTSD) in conflict-affected populations as inputs for subsequent estimations. We use Global Burden of Disease (GBD) methodology to estimate years lived with a disability (YLDs) for depression and PTSD in Syrian populations. Human resource (HR) requirements to scale-up recommended packages of care for PTSD and depression in Syria over a 15-year period were modelled using the World Health Organisation mhGAP costing tool. Associated avertable burden was estimated using health benefit analyses. RESULTS: The total number of cases of PTSD in Syria was estimated at approximately 2.2 million, and approximately 1.1 million for depression. An age-standardised major depression rate of 13.4 (95% UI 9.8-17.5) YLDs per 1000 Syrian population is estimated compared with the GBD 2010 global age-standardised YLD rate of 9.2 (95% UI 7.0-11.8). HR requirements to support a linear scale-up of services in Syria using the mhGAP costing tool demonstrates a steady increase from 0.3 FTE in at baseline to 7.6 FTE per 100 000 population after scale-up. Linear scale-up over 15 years could see 7-9% of disease burden being averted. CONCLUSION: Epidemiological estimates of mental disorders are key inputs into determining disease burden and guiding optimal mental health service delivery and can be used in target populations such as conflict-affected populations. PMID- 28596878 TI - Mental health system governance in Nigeria: challenges, opportunities and strategies for improvement. AB - INTRODUCTION: A health systems approach to understanding efforts for improving health care services is gaining traction globally. A component of this approach focuses on health system governance (HSG), which can make or mar the successful implementation of health care interventions. Very few studies have explored HSG in low- and middle-income countries, including Nigeria. Studies focusing on mental health system governance, are even more of a rarity. This study evaluates the mental HSG of Nigeria with a view to understanding the challenges, opportunities and strategies for strengthening it. METHODOLOGY: This study was conducted as part of the project, Emerging Mental Health Systems in Low and Middle Income Countries (Emerald). A multi-method study design was utilized to evaluate the mental HSG status of Nigeria. A situational analysis of the health policy and legal environment in the country was performed. Subsequently, 30 key informant interviews were conducted at national, state and district levels to explore the country's mental HSG. RESULTS: The existing policy, legislative and institutional framework for HSG in Nigeria reveals a complete exclusion of mental health in key health sector documents. The revised mental health policy is however promising. Using the Siddiqi framework categories, we identified pragmatic strategies for mental health system strengthening that include a consideration of existing challenges and opportunities within the system. CONCLUSION: The identified strategies provide a template for the subsequent activities of the Emerald Programme (and other interventions), towards strengthening the mental health system of Nigeria. PMID- 28596879 TI - Human rights principles in developing and updating policies and laws on mental health. AB - The World Health Organization's Mental Health Action Plan 2013-2020 stipulates human rights as a cross-cutting principle (WHO, 2013) and foresees global targets to update policies as well as mental health laws in line with international and regional human rights instruments. The international human rights agreements repeatedly refer to health, including mental health. The most pertinent provisions related to mental health are enshrined in the 2006 Convention on the Rights of Persons with Disabilities (CRPD), which sets out human rights in an accessible and inclusive fashion to ensure the equal participation of persons with disabilities. The inconclusive description of disability in the treaty overtly refers to 'mental impairment' as part of an explicitly evolving understanding of disability. This text sketches some of the underlying concepts as they apply to the realm of mental health: non-discrimination of persons with disabilities and measures that should be taken to ensure accessibility in a holistic understanding; removal of social and attitudinal barriers as much as communication and intellectual barriers but also institutional hurdles. The CRPD's paradigm shift away from framing disability mainly through deficits towards a social understanding of disability as the result of interaction and focusing on capacity is the core on which the provision of mental health services at community level to enable participation in society shall be ensured. Questions of capacity, also to make decisions and the possible need for support in so doing, are sketched out. PMID- 28596880 TI - Key influences in the design and implementation of mental health information systems in Ghana and South Africa. AB - INTRODUCTION: Strengthening of mental health information systems (MHIS) is essential to monitor and evaluate mental health services in low and middle-income countries. While research exists assessing wider health management information systems, there is limited published evidence exploring the design and implementation of MHIS in these settings. This paper aims to identify and assess the key factors affecting the design and implementation of MHIS, as perceived by the key stakeholders in Ghana and South Africa. METHODS: We report findings from the Mental Health and Poverty Project, a 5-year research programme implemented within four African countries. The MHIS strengthening in South Africa and Ghana included two related components: intervention and research. The intervention component aimed to strengthen MHIS in the two countries, and the research component aimed to document interventions in each country, including the key influences. Data were collected using semi structured interviews with key stakeholders and reviews of key documents and secondary data from the improved MHIS. We analyzed the qualitative data using a framework approach. RESULTS: Key components of the MHIS intervention involved the introduction of a redesigned patient registration form, entry into computers for analysis every 2 months by clinical managerial staff, and utilization of data in hospital management meetings in three psychiatric hospitals in Ghana; and the introduction of a new set of mental health indicators and related forms and tally sheets at primary care clinics and district hospitals in five districts in the KwaZulu-Natal and Northern Cape provinces in South Africa. Overall, the key stakeholders perceived the MHIS strengthening as an effective intervention in both countries with an enhanced set of indicators in South Africa and introduction of a computerized system in Ghana. DISCUSSION: Influences on the design and implementation of MHIS interventions in Ghana and South Africa relate to resources, working approaches (including degree of consultations during the design stage and communication during implementation stage) and the low priority of mental health. Although the influencing factors represent similar categories, more influences were identified on MHIS implementation, compared with the design stage. Different influences appear to be related within, and across, the MHIS design and implementation and may reinforce or negate each other thus leading to the multiplier or minimization effects. The wider context, similar to other studies, is important in ensuring the success of such interventions. CONCLUSION: Future MHIS strengthening interventions can consider three policy implications which emerged from our analysis and experience: enhancing consultations during the intervention design, better consideration of implementation challenges during design, and better recognition of relations between different influences. PMID- 28596881 TI - The ethics of mental health survey research in low- and middle- income countries. PMID- 28596882 TI - Scaling up interventions for depression in sub-Saharan Africa: lessons from Zimbabwe. AB - BACKGROUND: There is a dearth of information on how to scale-up evidence-based psychological interventions, particularly within the context of existing HIV programs. This paper describes a strategy for the scale-up of an intervention delivered by lay health workers (LHWs) to 60 primary health care facilities in Zimbabwe. METHODS: A mixed methods approach was utilized as follows: (1) needs assessment using a semi-structured questionnaire to obtain information from nurses (n = 48) and focus group discussions with District Health Promoters (n = 12) to identify key priority areas; (2) skills assessment to identify core competencies and current gaps of LHWs (n = 300) employed in the 60 clinics; (3) consultation workshops (n = 2) with key stakeholders to determine referral pathways; and (4) in-depth interviews and consultations to determine funding mechanisms for the scale-up. RESULTS: Five cross-cutting issues were identified as critical and needing to be addressed for a successful scale-up. These included: the lack of training in mental health, unavailability of psychiatric drugs, depleted clinical staff levels, unavailability of time for counseling, and poor and unreliable referral systems for people suffering with depression. Consensus was reached by stakeholders on supervision and support structure to address the cross-cutting issues described above and funding was successfully secured for the scale-up. CONCLUSION: Key requirements for success included early buy-in from key stakeholders, extensive consultation at each point of the scale up journey, financial support both locally and externally, and a coherent sustainability plan endorsed by both government and private sectors. PMID- 28596883 TI - The 12-item WHO Disability Assessment Schedule II as an outcome measure for treatment of common mental disorders. AB - BACKGROUND: Common mental disorders (CMD) are among the most significant contributors to disability worldwide. Patient-reported disability outcomes should be included as a key metric in the comparative assessment of value across global mental health interventions. This study aims to evaluate the validity of a widely used, cross-cultural tool - the 12-item World Health Organization Disability Assessment Schedule II (WHODAS) - as a functional outcome measure for CMD treatment. METHODS: The study population includes 1024 participants with CMD enrolled in the MANAS trial in India. CMD was assessed using the Revised Clinical Interview Schedule (CIS-R). Disability was assessed using the 12-item WHODAS II plus a measure of disability days. This analysis presents the correlations between these disability items and CMD symptom severity at 2 months after enrollment (convergent validity) and the items' associations with CMD recovery 4 months later (external responsiveness). RESULTS: All items showed a positive correlation of disability with CMD symptom severity (p < 0.001). The WHODAS items of 'standing,' 'household responsibilities,' and 'emotional disturbance' explained the most variance in CMD symptom severity. Improvements in 'disability days,' 'emotional disturbance,' 'standing,' 'household responsibilities,' 'day-to day work,' and 'concentrating' were significantly associated with CMD recovery over follow-up. CONCLUSIONS: Further research is recommended on a CMD-specific WHODAS subscale comprised of the six WHODAS items found to be most strongly associated with CMD severity and recovery. This shorter, CMD-specific disability subscale would critically serve as a common metric to compare intervention impact on patient-centered outcomes and, in turn, to allocate global mental health resources efficiently. PMID- 28596884 TI - Daily bread: a novel vehicle for dissemination and evaluation of psychological first aid for families exposed to armed conflict in Syria. AB - BACKGROUND: Risks to the mental health of children and families exposed to conflict in Syria are of such magnitude that research identifying how best to deliver psychological first aid is urgently required. This study tested the feasibility of a novel approach to large-scale distribution of information and data collection. METHODS: Routine humanitarian deliveries of bread by a bakery run by a non-governmental organisation (NGO) were used to distribute parenting information leaflets and questionnaires to adults looking after children in conflict zones inside Syria. Study materials were emailed to a project worker in Turkey. Leaflets and questionnaires requesting feedback were transported alongside supplies to a bakery in Syria, and then packed with flatbreads. Three thousand bread-packs were distributed, from three distribution points to which questionnaires were returned, and then taken to Turkey and dispatched to the UK. FINDINGS: Notwithstanding delays, 3000 leaflets and questionnaires were successfully distributed over 2 days. Questionnaire return yielded 1783 responses, a 59.5% return rate. Overall ratings of the usefulness of the leaflet were 1060 (59.5%) 'quite a lot' and 339 (19.0%) 'a great deal'. Content analysis was used to code 400 respondent comments. Four themes emerged; positive comments about the leaflet, suggestions for modifications, descriptions of children's needs and the value respondents placed on faith. INTERPRETATION: Findings indicate the willingness of NGO staff and volunteers to assist in research, the remarkable willingness of caregivers to respond and the value of brief advice. It demonstrates the scope for using existing humanitarian routes to distribute information and receive feedback even in high-risk settings. PMID- 28596885 TI - Overcrowding as a risk factor for domestic violence and antisocial behaviour among adolescents in Ejigbo, Lagos, Nigeria. AB - BACKGROUND: The objective was to investigate the relationships between overcrowding, domestic violence, and antisocial behaviour in a sample of adolescents in Lagos metropolitan area, Nigeria. Possible gender differences and differences due to religious affiliation concerning domestic violence and antisocial behaviour were also investigated. METHOD: A questionnaire was filled in by 238 Nigerian adolescents, 12-20 years of age; the sample included 122 females (m = 15.1 years, s.d. = 2.0) and 116 males (m = 15.8 years, s.d. = 2.0). The respondents were from junior and senior secondary schools in Ejigbo and surrounding cities (Isolo, Egbe and Ago-Palace Lagos). Six scales were included: adolescents as victims of adult and sibling aggression, respectively, witnessing of domestic violence, parental negativity towards adolescents, antisocial behaviour among adolescents and poverty in the home. Overcrowding, gender and religious affiliation served as independent variables. RESULTS: According to a multivariate analysis of variance with level of poverty as covariate, overcrowding showed significant associations with four of five scales measuring aggressive and antisocial behaviours. Gender and religion were associated with three variables each. However, multiple regression analyses revealed that overcrowding tended to partial out the effects of both gender and religion showing that overcrowding was the most important factor determining negative outcomes. CONCLUSIONS: The results have implications for housing policies in Nigeria. Moreover, these results may also have implications for research and policy making in other nations and parts of the world. PMID- 28596886 TI - Reducing the stigma of mental illness. AB - This paper presents a narrative review of anti-stigma programming using examples from different countries to understand and describe current best practices in the field. Results highlight the importance of targeting the behavioural outcomes of the stigmatization process (discrimination and social inequity), which is consistent with rights-based or social justice models that emphasize social and economic equity for people with disabilities (such as equitable access to services, education, work, etc.). They also call into question large public education approaches in favour of more targeted contact-based interventions. Finally, to add to the research base on best practices, anti-stigma programs are encouraged to create alliances with university researchers in order to critically evaluate their activities and build better, evidence informed practices. PMID- 28596887 TI - Economic, social and mental health impacts of an economic intervention for female sexual violence survivors in Eastern Democratic Republic of Congo. AB - BACKGROUND: Conflict-affected communities face poverty and mental health problems, with sexual violence survivors at high risk for both given their trauma history and potential for exclusion from economic opportunity. To address these problems, we conducted a randomized controlled trial of a group-based economic intervention, Village Savings and Loans Associations (VSLA), for female sexual violence survivors in the Democratic Republic of Congo. METHODS: In March 2011, 66 VSLA groups, with 301 study participants, were randomized to the VSLA program or a wait-control condition. Data were collected prior to randomization, at 2 months post-program in June 2012, and 8-months later for VSLA participants only. Outcome data included measures of economic and social functioning and mental health severity. VSLA program effect was derived by comparing intervention and control participants' mean changes from baseline to 2-month follow-up. RESULTS: At follow-up, VSLA study women reported significantly greater per capita food consumption and significantly greater reductions in stigma experiences compared with controls. No other study outcomes were statistically different. At 8-month follow-up, VSLA participants reported a continued increase in per capita food consumption, an increase in economic hours worked in the prior 7 days, and an increase in access to social resources. CONCLUSIONS: While female sexual violence survivors with elevated mental symptoms were successfully integrated into a community-based economic program, the immediate program impact was only seen for food consumption and experience of stigma. Impacts on mental health severity were not realized, suggesting that targeted mental health interventions may be needed to improve psychological well-being. PMID- 28596888 TI - Validity and diagnostic accuracy of the Luganda version of the 9-item and 2-item Patient Health Questionnaire for detecting major depressive disorder in rural Uganda. AB - BACKGROUND: The prevalence of depression in rural Ugandan communities is high and yet detection and treatment of depression in the primary care setting is suboptimal. Short valid depression screening measures may improve detection of depression. We describe the validation of the Luganda translated nine- and two item Patient Health Questionnaires (PHQ-9 and PHQ-2) as screening tools for depression in two rural primary care facilities in Eastern Uganda. METHODS: A total of 1407 adult respondents were screened consecutively using the nine-item Luganda PHQ. Of these 212 were randomly selected to respond to the Mini International Neuropsychiatric Interview diagnostic questionnaire. Descriptive statistics for respondents' demographic characteristics and PHQ scores were generated. The sensitivity, specificity and positive predictive values (PPVs), and area under the ROC curve were determined for both the PHQ-9 and PHQ-2. RESULTS: The optimum trade-off between sensitivity and PPV was at a cut-off of ?5. The weighted area under the receiver Operating Characteristic curve was 0.74 (95% CI 0.60-0.89) and 0.68 (95% CI 0.54-0.82) for PHQ-9 and PHQ-2, respectively. CONCLUSION: The Luganda translation of the PHQ-9 was found to be modestly useful in detecting depression. The PHQ-9 performed only slightly better than the PHQ-2 in this rural Ugandan Primary care setting. Future research could improve on diagnostic accuracy by considering the idioms of distress among Luganda speakers, and revising the PHQ-9 accordingly. The usefulness of the PHQ-2 in this rural population should be viewed with caution. PMID- 28596889 TI - Challenges and opportunities to improve autism services in low-income countries: lessons from a situational analysis in Ethiopia. AB - BACKGROUND: Little has been reported about service provision for children with autism in low-income countries. This study explored the current service provision for children with autism and their families in Ethiopia, the existing challenges and urgent needs, and stakeholders' views on the best approaches to further develop services. METHODS: A situational analysis was conducted based on (i) qualitative interviews with existing service providers; (ii) consultation with a wider group of stakeholders through two stakeholder workshops; and (iii) information available in the public domain. Findings were triangulated where possible. RESULTS: Existing diagnostic and educational services for children with autism are scarce and largely confined to Ethiopia's capital city, with little provision in rural areas. Families of children with autism experience practical and psychosocial challenges, including severe stigma. Informants further raised the lack of culturally and contextually appropriate autism instruments as an important problem to be addressed. The study informants and local stakeholders provided several approaches for future service provision expansion, including service decentralisation, mental health training and awareness raising initiatives. CONCLUSIONS: Services for children with autism in Ethiopia are extremely limited; appropriate care for these children is further impeded by stigma and lack of awareness. Ethiopia's plans to scale up mental healthcare integrated into primary care provide an opportunity to expand services for children with autism and other developmental disorders. These plans, together with the additional strategies outlined in this paper can help to address the current service provision gaps and may also inform service enhancement approaches in other low-income countries. PMID- 28596890 TI - Acceptability of internet interventions for youth mental health in Vietnam. AB - BACKGROUND: Despite high levels of mental illness, Vietnamese youth have limited access to mental health care. Internet interventions, evidence-based psychotherapy treatments delivered through the internet, have the potential to increase access to mental health for youth in Vietnam. This study explored the perceptions of youths and parents toward internet interventions for youth mental health. METHODS: Four focus groups were conducted with youths (n = 20) and parents (n = 20) in Danang, Vietnam. The Technology Acceptance Model was used a framework for focus group questions. The data were analyzed using direct content analysis. RESULTS: Most youths and parents agreed that the internet serves well as a care delivery model. Participants expressed that the web would be useful for psychoeducation and sharing and receiving information with others. Both groups reported lack of awareness of web-based interventions and logistical concerns regarding access as main barriers. In addition, many parents were concerned about internet addiction. Specific adaptations in Vietnam such as standalone internet service centers and partnering with local organizations may benefit uptake of internet interventions. CONCLUSION: This study suggests that internet-based programs for youth mental health, particularly interventions incorporating psychoeducation and social networking components, will be well received in Vietnam. Barriers need to be addressed to successfully implement internet-based treatment. Future initiatives should incorporate acceptance models to improve development of internet interventions for youth. PMID- 28596891 TI - Local perceptions of the impact of group interpersonal psychotherapy in rural Uganda. AB - BACKGROUND: This study investigated local perceptions of changes stemming from a long-standing Group Interpersonal Psychotherapy (IPT-G) program for the treatment of depression in rural Uganda. The study was conducted in a low-income, severely HIV/AIDS-affected area where in 2001 the prevalence of depression was estimated at 21% among adults. METHOD: Data were collected using free-listing and key informant qualitative interviews. A convenience sample of 60 free-list respondents was selected from among IPT-G participants, their families, and other community members from 10 Ugandan villages. Twenty-two key informants and six IPT G facilitators were also interviewed. RESULTS: Content analysis yielded five primary categories of change in the community related to the IPT-G program: (1) improved school attendance for children; (2) improved productivity; (3) improved sanitation in communities; (4) greater cohesion among community members; and (5) reduced conflict in families. Community members and IPT-G facilitators suggested that as depression remitted, IPT-G participants became more hopeful, motivated and productive. CONCLUSION: Results suggest that providing treatment for depression in communities with high depression prevalence rates may lead to positive changes in a range of non-mental health outcomes. PMID- 28596892 TI - Process and implementation of Audio Computer Assisted Self-Interviewing (ACASI) assessments in low resource settings: a case example from Zambia. AB - BACKGROUND: Studies from low- and middle-income countries (LMIC) indicate that the use of audio computer-assisted self-interviewing (ACASI) is associated with more accurate reporting of sensitive behaviors (e.g. substance use and sexual risk behaviors) compared with interviewer-administered questionnaires. There is a lack of published information on the process of designing, developing, and implementing ACASI in LMIC. In this paper we describe our experience implementing an ACASI system for use with a population of orphans and vulnerable children in Zambia. METHODS: A questionnaire of mental health, substance use, and HIV risk behaviors was converted into an ACASI system, tested in pilot and validity studies, and implemented for use in a randomized controlled trial. Successes, barriers, and challenges associated with each stage in the development and implementation of ACASI are described. RESULTS: We were able to convert a lengthy and complex survey into an ACASI system that was feasible for use in Zambia. Lessons learned include the importance of: (1) piloting the written and electronic versions; (2) proper and extensive training for study assessors to use ACASI and for those doing voice recordings; and (3) attention to logistics such as appropriate space, internet, and power. CONCLUSIONS: We found that ACASI was feasible and acceptable in Zambia with proper planning, training, and supervision. Given mounting evidence indicating that ACASI provides more accurate self-report data and immediate data download compared with interview-administered measures, it may be an effective and economical alternative for behavioral health research studies in LMIC. PMID- 28596894 TI - Sustainable development goals and mental health: learnings from the contribution of the FundaMentalSDG global initiative. PMID- 28596895 TI - Global Mental Health: sharing and synthesizing knowledge for sustainable development. AB - Global mental health (GMH) is a growing domain with an increasing capacity to positively impact the world community's efforts for sustainable development and wellbeing. Sharing and synthesizing GMH and multi-sectoral knowledge, the focus of this paper, is an important way to support these global efforts. This paper consolidates some of the most recent and relevant 'context resources' [global multi-sector (GMS) materials, emphasizing world reports on major issues] and 'core resources' (GMH materials, including newsletters, texts, conferences, training, etc.). In addition to offering a guided index of materials, it presents an orientation framework (global integration) to help make important information as accessible and useful as possible. Mental health colleagues are encouraged to stay current in GMH and global issues, to engage in the emerging agendas for sustainable development and wellbeing, and to intentionally connect and contribute across sectors. Colleagues in all sectors are encouraged to do likewise, and to take advantage of the wealth of shared and synthesized knowledge in the GMH domain, such as the materials featured in this paper. PMID- 28596893 TI - The potential of low-intensity and online interventions for depression in low- and middle-income countries. AB - The World Health Organization (WHO) reports that low- and middle-income countries (LMICs) are confronted with a serious 'mental health gap', indicating an enormous disparity between the number of individuals in need of mental health care and the availability of professionals to provide such care (WHO in 2010). Traditional forms of mental health services (i.e. face-to-face, individualised assessments and interventions) are therefore not feasible. We propose three strategies for addressing this mental health gap: delivery of evidence-based, low-intensity interventions by non-specialists, the use of transdiagnostic treatment protocols, and strategic deployment of technology to facilitate access and uptake. We urge researchers from all over the world to conduct feasibility studies and randomised controlled studies on the effect of low-intensity interventions and technology supported (e.g. online) interventions in LMICs, preferably using an active control condition as comparison, to ensure we disseminate effective treatments in LMICs. PMID- 28596896 TI - Head injury in asylum seekers and refugees referred with psychological trauma. AB - OBJECTIVE: Individuals who seek asylum are frequently fleeing violent persecution and may experience head injury (HI). However, little is known about the prevalence of HI in asylum seekers and refugees (ASR) despite the potential for HI to significantly affect cognitive and emotional functioning and to compromise asylum outcomes. This preliminary study investigates the prevalence of HI in ASR referred to a complex psychological trauma service. METHOD: Participants were 115 adult ASR referred to a community psychological trauma service with moderate to severe mental health problems associated with psychological trauma. They were screened for a history of HI using a questionnaire developed for the study. Interpreters were used when required. RESULTS: The overall prevalence of HI was 51%. At least 38% of those with HI had a moderate-severe HI that could cause persisting disability. In 53% of those with HI, the cause was torture, human trafficking or domestic violence. Repeat HI can have cumulative effects on function; it was common, and was reported in 68% of those with HI. An injury to the head was not known to mental health clinicians prior to screening in 64% of cases. CONCLUSION: The emotional and cognitive consequences of HI in ASR may increase the vulnerability of this disadvantaged group, and can be associated with neurobehavioural problems affecting daily life and may compromise asylum outcomes. Routine screening for HI in ASR is needed, as are links to neuropsychology and brain injury services for advice, assessment and intervention. PMID- 28596897 TI - Monitoring and evaluating capacity building activities in low and middle income countries: challenges and opportunities. AB - BACKGROUND: Lower and middle income countries (LMICs) are home to >80% of the global population, but mental health researchers and LMIC investigator led publications are concentrated in 10% of LMICs. Increasing research and research outputs, such as in the form of peer reviewed publications, require increased capacity building (CB) opportunities in LMICs. The National Institute of Mental Health (NIMH) initiative, Collaborative Hubs for International Research on Mental Health reaches across five regional 'hubs' established in LMICs, to provide training and support for emerging researchers through hub-specific CB activities. This paper describes the range of CB activities, the process of monitoring, and the early outcomes of CB activities conducted by the five research hubs. METHODS: The indicators used to describe the nature, the monitoring, and the early outcomes of CB activities were developed collectively by the members of an inter hub CB workgroup representing all five hubs. These indicators included but were not limited to courses, publications, and grants. RESULTS: Results for all indicators demonstrate a wide range of feasible CB activities. The five hubs were successful in providing at least one and the majority several courses; 13 CB recipient-led articles were accepted for publication; and nine grant applications were successful. CONCLUSIONS: The hubs were successful in providing CB recipients with a wide range of CB activities. The challenge remains to ensure ongoing CB of mental health researchers in LMICs, and in particular, to sustain the CB efforts of the five hubs after the termination of NIMH funding. PMID- 28596898 TI - Service and Policy implication of substance use disorders among adolescents in juvenile correctional facilities in Lagos, Nigeria. AB - BACKGROUND: Lack of relevant data has continued to militate against the development of policy and practice toward identification and treatment of alcohol/substance abuse among adolescents coming in contact with the juvenile justice system in Nigeria. This study aims to provide such data, including its policy/practice implications. METHODS: One hundred and seventy eight (178) adolescents, who are representative of adolescents within the youth correctional services of Lagos jurisdiction, were interviewed using the alcohol and substance abuse section of the Kiddies' Schedule for Affective Disorders and Schizophrenia. RESULTS: The lifetime prevalence rate of abuse of/dependence on any of alcohol or other substances was 22.5% (alcohol, 12.3%; illicit substance, 17.9%). Males were overrepresented among those with any substance use disorder, with gendered prevalence rate as high as 35%. Having had a lived-experience of being a street child was the single most significant independent factor (Odds ratio (OR), 8.4; p = 0.007) associated with lifetime alcohol substance use disorder. CONCLUSIONS: Substance use disorder is highly prevalent among adolescents within the juvenile justice systems in Lagos Nigeria. There is need for deliberate incorporation of alcohol and substance abuse screening and intervention as part of individual care plan in youth correctional facilities in Nigeria. Practical steps toward achieving this were drawn from local reality and international best practices. PMID- 28596899 TI - Mental disorders in pregnancy and 5-8 years after delivery. AB - BACKGROUND: Even though mental disorders represent a major public health problem for women and respective children, there remains a lack of epidemiological longitudinal studies to assess the psychological status of women throughout pregnancy and later in life. This epidemiological cohort study assessed the relationship between mental disorders of 409 Brazilian women in pregnancy and 5-8 years after delivery. METHODS: The women were followed from 1997 to 2000 at 17 health services, and subsequently from 2004 to 2006 at their homes. Mental disorders were investigated by the Perceived Stress Scale-PSS, General Health Questionnaire-GHQ and State-Trait Anxiety Inventories-STAI. The relationship between scores of the PSS, GHQ and STAI 5-8 years after delivery and in pregnancy was assessed by multivariate linear regression analysis, controlling for the following confounders: maternal age, education, per capita income, family size, work, marital status and body mass index. RESULTS: Scores of the PSS, GHQ and STAI 5-8 years after delivery were positively associated with scores of the PSS, GHQ and STAI in the three trimesters of pregnancy, and inversely associated with maternal age and per capita income (adj. R2 varied from 0.15 to 0.37). PSS, GHQ and STAI scores in the 3rd trimester of pregnancy were positively associated with scores of the PSS, GHQ and STAI in the 1st and 2nd trimesters of pregnancy (adj. R2 varied from 0.31 to 0.65). CONCLUSIONS: The results of this study reinforce the urgency to integrate mental health screening into routine primary care for pregnant and postpartum women. PMID- 28596901 TI - Developing mental health research in sub-Saharan Africa: capacity building in the AFFIRM project. AB - BACKGROUND: There remains a large disparity in the quantity, quality and impact of mental health research carried out in sub-Saharan Africa, relative to both the burden and the amount of research carried out in other regions. We lack evidence on the capacity-building activities that are effective in achieving desired aims and appropriate methodologies for evaluating success. METHODS: AFFIRM was an NIMH funded hub project including a capacity-building program with three components open to participants across six countries: (a) fellowships for an M.Phil. program; (b) funding for Ph.D. students conducting research nested within AFFIRM trials; (c) short courses in specialist research skills. We present findings on progression and outputs from the M.Phil. and Ph.D. programs, self-perceived impact of short courses, qualitative data on student experience, and reflections on experiences and lessons learnt from AFFIRM consortium members. RESULTS: AFFIRM delivered funded research training opportunities to 25 mental health professionals, 90 researchers and five Ph.D. students across 6 countries over a period of 5 years. A number of challenges were identified and suggestions for improving the capacity-building activities explored. CONCLUSIONS: Having protected time for research is a barrier to carrying out research activities for busy clinicians. Funders could support sustainability of capacity-building initiatives through funds for travel and study leave. Adoption of a train-the trainers model for specialist skills training and strategies for improving the rigor of evaluation of capacity-building activities should be considered. PMID- 28596900 TI - Poverty and suicide research in low- and middle-income countries: systematic mapping of literature published in English and a proposed research agenda. AB - Approximately 75% of suicides occur in low- and middle-income countries (LMICs) where rates of poverty are high. Evidence suggests a relationship between economic variables and suicidal behaviour. To plan effective suicide prevention interventions in LMICs we need to understand the relationship between poverty and suicidal behaviour and how contextual factors may mediate this relationship. We conducted a systematic mapping of the English literature on poverty and suicidal behaviour in LMICs, to provide an overview of what is known about this topic, highlight gaps in literature, and consider the implications of current knowledge for research and policy. Eleven databases were searched using a combination of key words for suicidal ideation and behaviours, poverty and LMICs to identify articles published in English between January 2004 and April 2014. Narrative analysis was performed for the 84 studies meeting inclusion criteria. Most English studies in this area come from South Asia and Middle, East and North Africa, with a relative dearth of studies from countries in Sub-Saharan Africa. Most of the available evidence comes from upper middle-income countries; only 6% of studies come from low-income countries. Most studies focused on poverty measures such as unemployment and economic status, while neglecting dimensions such as debt, relative and absolute poverty, and support from welfare systems. Most studies are conducted within a risk-factor paradigm and employ descriptive statistics thus providing little insight into the nature of the relationship. More robust evidence is needed in this area, with theory-driven studies focussing on a wider range of poverty dimensions, and employing more sophisticated statistical methods. PMID- 28596902 TI - The effect of gender norms on the association between violence and hope among girls in the Democratic Republic of the Congo. AB - BACKGROUND: Girls at early stages of adolescence are vulnerable to violence victimization in humanitarian contexts, but few studies examine factors that affect girls' hope in these settings. We assessed attitudes toward traditional gender norms as an effect modifier of the relationship between violence exposure and future orientation in displaced girls. METHODS: Secondary analysis, using multivariable regression of cross-sectional data from girls ages 10-14 in South Kivu, Democratic Republic of the Congo. Key variables of interest were attitudes toward intimate partner violence (IPV), Children's Hope Scale (CHS) score, and exposure to physical, emotional, and sexual violence within the last 12 months. Additional covariates included age, educational status, and territory. RESULTS: The interaction of exposure to violence and attitudes toward IPV magnified the association between violence exposure and lower CHS score for physical violence (beta = -0.09, p = 0.040) and unwanted sexual touching (beta = -0.20, p = 0.003) among girls age 10-14, when adjusting for other covariates. The interaction of exposure to violence and attitudes toward IPV magnified the association between violence exposure and lower CHS score for forced sex (beta = -0.22, p = 0.016) among girls age 13-14, when adjusting for covariates. Findings for emotional violence, any form of sexual violence, and coerced sex trended toward lower CHS scores for girls who reported higher acceptance of IPV, but did not reach significance. CONCLUSIONS: Findings support the utility of gender norms transformative programming in increasing resilience of girls who have experienced sexual violence in humanitarian contexts. PMID- 28596903 TI - LATIN-MH: a model for building research capacity within Latin America. AB - BACKGROUND: Latin America Treatment and Innovation Network in Mental Health (LATIN-MH) is a research hub located in Brazil and Peru that conducts a research project to help reduce the treatment gap in mental health in Latin America (LA). Besides its research core, LATIN-MH has a Capacity Building (CB) component that aims to help young researchers receive the specific training to contribute to the growing scientific production in mental health in LA. METHODS: LATIN-MH proposal in CB includes a series of actions to prepare professionals in the research area. The main proposals are described here, which include online study groups, promotion of scientific meetings, hands-on training in different levels and sharing of information. RESULTS: LATIN-MH CB activities are at its initial stages but the proposed activities were well evaluated by the participants. The first participating fellows who finished their fellowships are contributing elsewhere in the mental treatment and human resources formation area. CONCLUSION: The repercussion of LATIN-MH actions in CB and its evaluation, particularly on the formation of human resources and dissemination of information, show that the hub is contributing to the critic formation of young researchers and the circulation of important information. PMID- 28596904 TI - RedeAmericas: building research capacity in young leaders for sustainable growth in community mental health services in Latin America. AB - The purpose of this paper is to describe the development and initial accomplishments of a training program of young leaders in community mental health research as part of a Latin American initiative known as RedeAmericas. RedeAmericas was one of five regional 'Hubs' funded by the National Institute of Mental Health (NIMH) to improve community mental health care and build mental health research capacity in low- and middle-income countries. It included investigators in six Latin American cities - Santiago, Chile; Medellin, Colombia; Rio de Janeiro, Brazil; and Cordoba, Neuquen, and Buenos Aires in Argentina - working together with a team affiliated with the Global Mental Health program at Columbia University in New York City. One component of RedeAmericas was a capacity-building effort that included an Awardee program for early career researchers in the mental health field. We review the aims of this component, how it developed, and what was learned that would be useful for future capacity building efforts, and also comment on future prospects for maintaining this type of effort. PMID- 28596906 TI - Pattern of impairments and late diagnosis of autism spectrum disorder among a sub Saharan African clinical population of children in Nigeria. AB - BACKGROUND: Autism spectrum disorder (ASD) is a complex group of neurodevelopmental disorders. Studies conducted among Africans living outside the continent indicate that African children are more likely than Caucasian children to have a late diagnosis of ASD. There is a dearth of information on this topic among children with ASD living in Africa. METHODS: To determine the pattern of impairments and age at diagnosis in ASD, sixty Nigerian children with a diagnosis of ASD were recruited from a neurodevelopmental clinic. DSM-V criteria were used to make a diagnosis of ASD, while a symptom checklist for ASD was used to determine the pattern of impairments in ASD. RESULTS: Ages of the children ranged from 2 to 17 years with a mean age of 9.45 +/- 4.33 years with the majority of them (75%) being 12 years or younger. All the children (100%) with ASD exhibited poor eye contact, difficulty in mixing with other children and inability to consistently respond to his/her name. More than a half of them (55%) lack verbal communication. Impairments that were uncommon are in the areas of object attachment (20.0%), odd postures (26.7%) and inappropriate facial expression (30.0%). Mean age at the observation of ASD features was 17.0 +/- 6.7 months. Mean age at diagnosis of ASD was 9.00 +/- 4.30 years. The mean time lag from a parental concern of ASD features to seeking specialist care was 85 months and to diagnosis was 91 months. CONCLUSIONS: Core symptoms/impairments of ASD are present in Nigerian children but a late diagnosis is common. PMID- 28596905 TI - Mental health training for secondary school teachers in Haiti: a mixed methods, prospective, formative research study of feasibility, acceptability, and effectiveness in knowledge acquisition. AB - BACKGROUND: Engagement and training of educators in student mental health holds promise for promoting access to care as a task sharing strategy but has not been well-studied in low-income regions. METHODS: We used a prospective and convergent mixed methods design to evaluate a customized school mental health 21/2 day training for teachers in rural Haiti (n = 22) as the initial component of formative research developing a school-based intervention to promote student mental health. Training prepared teachers to respond to student mental health needs by providing psychoeducational and practical support to facilitate access to care. We examined level of participation and evaluated feasibility, acceptability, and perceived effectiveness by calculating mean scores on self report Likert-style items eliciting participant experience. We examined effectiveness of the training on improving mental health knowledge and attitudes by comparing mean scores on an assessment administered pre- and post-training. Finally, we examined self-report written open-ended responses and focus group discussion (FGD) interview data bearing on perceived feasibility, acceptability, and effectiveness to contextualize participant ratings of training and to identify recommendations for enhancing the utility of mental health training locally for educators. RESULTS: Mean scores of knowledge and attitudes significantly improved between the pre-test and post-tests; e.g., knowledge improved from 58% correct at baseline to 68% correct on the second post-test (p = 0.039). Mean ratings of the training were favorable across all categories and FGD data demonstrated widespread participant endorsement of training acceptability and effectiveness; participants recommended extending the duration and number of training sessions. CONCLUSIONS: Findings support feasibility, acceptability, and a limited scope of effectiveness of brief mental health training for secondary school teachers in Haiti. Further development of approaches to engage teachers in promoting school mental health through training is warranted. PMID- 28596907 TI - Implementing mhGAP training to strengthen existing services for an internally displaced population in Pakistan. AB - BACKGROUND: In 2014, over a million people were internally displaced after the launch of a military operation in North Waziristan, a tribal region on Pakistan's side of the Durand Line. Despite security concerns and restrictions, a collaborative mental health and psychosocial support initiative was undertaken in the district of Bannu. Monthly mental health camps were conducted for a period of 6 months by a multidisciplinary mental health team. The initiative also helped to assess mental health needs and plan training for primary care staff to strengthen existing resources. METHODS: As part of this initiative, Mental Health Gap Action Programme (mhGAP) training was conducted for physicians and psychosocial staff in the affected district. This marked the first instance of implementing these guidelines in Pakistan following a humanitarian crisis. This paper describes the training process including the adaptation of the mhGAP curriculum, training of trainers, training workshops for primary care staff and an analysis of results of pre- and post-testing of their knowledge about common mental disorders using a 25 item questionnaire. RESULTS: The gaps in knowledge of primary care physicians in recognizing and managing common mental disorders were clearly identified. The mean pre- and post-test scores of the participants were 15.43, 62% (p value 0.000, s.d. 4.05) and 19.48, 78% (p value 0.000, s.d. 3.13) respectively, which showed significant improvement. CONCLUSIONS: Despite the challenges of a humanitarian crisis, mhGAP guidelines can be successfully implemented to train primary care physicians in in low- and middle-income countries such as Pakistan. However, the dearth of primary care resources can hinder the complete integration of mental health services into primary healthcare. PMID- 28596908 TI - Integrating mental health care into primary care systems in low- and middle income countries: lessons from PRIME and AFFIRM. PMID- 28596910 TI - Research capacity strengthening in South Asia: based on the experience of South Asian Hub for Advocacy, Research and Education on Mental Health (SHARE). AB - The South Asian Hub for Advocacy, Research and Education (SHARE) was a five-year National Institute of Mental Health (NIMH)-funded program that aimed to stimulate the research base for task-shifting mental health interventions to address the mental health treatment gap in low and middle-income countries. During its 5 years (2011-2016) SHARE made notable accomplishments, including providing 20 studentships for short courses and ten fellowships to conduct mentored study, developing a new humanitarian research training course, implementing distance learning courses, creating an online repository of training materials, creation of a network of public health researchers at different career stages in South Asia, strengthening of partnerships amongst institutions of SHARE network and supporting its member's to produce peer reviewed publications. Furthermore, additional research capacity building and research grants leveraged on SHARE network were secured. The salient lessons learned in the 5-year program were that research capacity-building opportunities need to be tailored to the local context, as SHARE sought to develop and support courses that can build the capacities in specific areas identified as weak in the South Asian region. Mentoring was recognized as a critical component for which innovative and effective models of mentoring in the region need to be developed. Diverse platforms and mediums ought to be utilized to deliver the research training programs. Finally, research capacity-building program requires collaborative efforts of multiple stakeholders working locally, nationally and globally to attain the maximum impact in a region. PMID- 28596909 TI - Developing a scalable training model in global mental health: pilot study of a video-assisted training Program for Generalist Clinicians in Rural Nepal. AB - BACKGROUND: In low- and middle-income countries, mental health training often includes sending few generalist clinicians to specialist-led programs for several weeks. Our objective is to develop and test a video-assisted training model addressing the shortcomings of traditional programs that affect scalability: failing to train all clinicians, disrupting clinical services, and depending on specialists. METHODS: We implemented the program -video lectures and on-site skills training- for all clinicians at a rural Nepali hospital. We used Wilcoxon signed-rank tests to evaluate pre- and post-test change in knowledge (diagnostic criteria, differential diagnosis, and appropriate treatment). We used a series of 'Yes' or 'No' questions to assess attitudes about mental illness, and utilized exact McNemar's test to analyze the proportions of participants who held a specific belief before and after the training. We assessed acceptability and feasibility through key informant interviews and structured feedback. RESULTS: For each topic except depression, there was a statistically significant increase (Delta) in median scores on knowledge questionnaires: Acute Stress Reaction (Delta = 20, p = 0.03), Depression (Delta = 11, p = 0.12), Grief (Delta = 40, p < 0.01), Psychosis (Delta = 22, p = 0.01), and post-traumatic stress disorder (Delta = 20, p = 0.01). The training received high ratings; key informants shared examples and views about the training's positive impact and complementary nature of the program's components. CONCLUSION: Video lectures and on-site skills training can address the limitations of a conventional training model while being acceptable, feasible, and impactful toward improving knowledge and attitudes of the participants. PMID- 28596911 TI - Mental health provision in schools: approaches and interventions in 10 European countries. AB - BACKGROUND: The role of schools in providing community-based support for children's mental health and well-being is widely accepted and encouraged. Research has mainly focused on designing and evaluating specific interventions and there is little data available regarding what provision is available, the focus and priorities of schools and the professionals involved in providing this support. The current study presents these data from schools in 10 European countries. METHODS: Online survey of 1466 schools in France, Germany, Ireland, Netherlands, Poland, Serbia, Spain, Sweden, UK and Ukraine. The participating countries were chosen based on their geographical spread, diversity of political and economic systems, and convenience in terms of access to the research group and presence of collaborators. RESULTS: Schools reported having more universal provision than targeted provision and there was greater reported focus on children who already have difficulties compared with prevention of problems and promotion of student well-being. The most common interventions implemented related to social and emotional skills development and anti-bullying programmes. Learning and educational support professionals were present in many schools with fewer schools reporting involvement of a clinical specialist. Responses varied by country with 7.4-33.5% between-country variation across study outcomes. Secondary schools reported less support for parents and more for staff compared with primary schools, with private schools also indicating more staff support. Schools in rural locations reported less student support and professionals involved than schools in urban locations. CONCLUSION: The current study provides up-to-date and cross-country insight into the approaches, priorities and provision available for mental health support in schools; highlighting what schools prioritise in providing mental health support and where coverage of provision is lacking. PMID- 28596912 TI - Induced migration of endothelial cells into 3D scaffolds by chemoattractants secreted by pro-inflammatory macrophages in situ. AB - Cell migration in scaffolds plays a crucial role in tissue regeneration, which can better mimic cell behaviors in vivo. In this study, a novel model has been proposed on controlling 3D cell migration in porous collagen-chitosan scaffolds with various pore structures under the stimulation of inflammatory cells to mimic the angiogenesis process. Endothelial cells (ECs) cultured atop the scaffolds in the Transwell molds which were placed into a well of a 24-well culture plate were promoted to migrate into the scaffolds by chemoattractants such as vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-alpha) secreted by the pro-inflammatory macrophages incubated in the well culture plate. The phenotype of macrophages was mediated by 50 ng/ml interferon-gamma (IFN gamma) and different concentrations of lipopolysaccharide (LPS, 150-300 ng/ml). The cell migration depth had a positive correlation with LPS concentration, and thereby the TNF-alpha concentration. The ECs migrated easier to a deeper zone of the scaffolds prepared at - 10oC (187 MUm in pore diameter) than that at - 20oC (108 MUm in pore diameter) as well. The method provides a useful strategy to study the 3D cell migration, and is helpful to reveal the vascularization process during wound healing in the long run. PMID- 28596913 TI - Polyanhydride micelles with diverse morphologies for shape-regulated cellular internalization and blood circulation. AB - Biodegradable amphiphilic poly (ethylene glycol) (PEG) based ether-anhydride terpolymer, consisting of PEG, 1, 3-bis (p-carboxyphenoxy) propane (CPP) and sebacic acid (SA), namely PEG-CPP-SA terpolymer, was employed to self-assemble into micelles by adding water into a solution of the terpolymer in tetrahydrofuran (THF). The shape of polyanhydride micelles can be regulated by simply adjusting the water addition rate, where spherical, rod-like and comb-like micelles can obtained under water addition rate of 20, 3 and 1 ml/h, respectively. The effect of micellar morphologies on the cellular internalization and intracellular distribution were characterized qualitatively with cervical cancer cells (HeLa cells) and hepatoma cells (HepG2 cells) by fluorescence microscopy, confocal laser scanning microscopy (CLSM), flow cytometry (FCM) and transmission electron microscopy (TEM). The results reveal that the cellular uptake of micelles are micelle-shape-dependent (rod-like micelles may possess the highest cellular internalization rate) and cell-type-specific. Each endocytic pathway can make a contribution to this process in different degree. Moreover, blood circulation experiments of these micelles were carried out, demonstrating that comb-like micelles have a relatively longer blood circulating feature, which may due to its irregular shape help to increase the sensitivity to fluid forces and allows them to tumble and align with the blood flow. PMID- 28596914 TI - Cytotoxic effects of docetaxel as a candidate drug of drug-eluting stent on human umbilical vein endothelial cells and the signaling pathway of cell migration inhibition, adhesion delay and shape change. AB - Docetaxel (DTX), a paclitaxel analogue, can efficiently inhibit proliferation of vascular smooth muscle cells and has broadly been used as an antiangiogenesis drug. However, as a candidate drug of drug-eluting stent, the effects of DTX on human umbilical vein endothelial cells (HUVECs) are still not well understood. Herein, we investigated the effects of DTX on proliferation, apoptosis, adhesion, migration and morphology of HUVECs in vitro. We found that DTX had the cytostatic and cytotoxic effects at low and high concentrations, respectively. DTX could inhibit the proliferation and migration of HUVECs, induce HUVECs apoptosis, delay HUVECs adhesion and decrease spreading area and aspect ratio of individual cells. The signaling pathway that DTX led to the migration inhibition, adhesion delay and shape change of HUVECs is the VE-cadherin mediated integrin beta1/FAK/ROCK signaling pathway. The study will provide a theoretical basis for the clinical application of DTX. PMID- 28596917 TI - Assessment of Vascular Change Using Swept-Source Optical Coherence Tomography Angiography: A New Theory Explains Central Visual Loss in Behcet's Disease. AB - OBJECTIVE: To evaluate retinal vascular structural change in ocular Behcet's using optical coherence tomography angiography (OCTA) and fluorescein angiography (FA). METHODS: An analytic cross-sectional study of 37 eyes of 21 Behcet's uveitic patients was performed. Foveal retinal thickness (FRT), perifoveal hypoperfusion areas in superficial capillary plexus (SCP), and deep capillary plexus (DCP) were measured with swept-source optical coherence tomography and OCTA. FA images were used for assessing the vascular features and correlation. RESULTS: Twenty-one patients were enrolled (52.4% males). The average age at onset was 36.7 +/- 12.93 years. The median of disease duration was 5 years (1 25). FRT was 118.1 +/- 52.35 MUm, which correlated with visual acuity (95% CI 60.47, -13.92). Using OCTA, the area of hypoperfusion in SCP (0.47 +/- 0.17 mm2) was smaller than that in DCP (1.94 +/- 3.87 mm2) (p < 0.001). Superficial to deep capillary plexus nonperfusion (SCP : DCP) ratio was 0.57 +/- 0.27 which had the positive coefficient correlation with visual acuity (95% CI -0.644, -0.015). CONCLUSIONS: OCTA is an alternative noninvasive method to monitor macular ischemia in Behcet. Behcet's uveitis affects DCP more than SCP. Decreasing SCP : DCP ratio and decrease FRT correlates with poor visual acuity. Macular ischemia and DCP loss can be found early and can explain vision loss in Behcet. PMID- 28596915 TI - The effect of mechanical loads on the degradation of aliphatic biodegradable polyesters. AB - Aliphatic biodegradable polyesters have been the most widely used synthetic polymers for developing biodegradable devices as alternatives for the currently used permanent medical devices. The performances during biodegradation process play crucial roles for final realization of their functions. Because physiological and biochemical environment in vivo significantly affects biodegradation process, large numbers of studies on effects of mechanical loads on the degradation of aliphatic biodegradable polyesters have been launched during last decades. In this review article, we discussed the mechanism of biodegradation and several different mechanical loads that have been reported to affect the biodegradation process. Other physiological and biochemical factors related to mechanical loads were also discussed. The mechanical load could change the conformational strain energy and morphology to weaken the stability of the polymer. Besides, the load and pattern could accelerate the loss of intrinsic mechanical properties of polymers. This indicated that investigations into effects of mechanical loads on the degradation should be indispensable. More combination condition of mechanical loads and multiple factors should be considered in order to keep the degradation rate controllable and evaluate the degradation process in vivo accurately. Only then can the degradable devise achieve the desired effects and further expand the special applications of aliphatic biodegradable polyesters. PMID- 28596918 TI - Physical Activity and Quality of Life in Retinitis Pigmentosa. AB - PURPOSE: Aerobic exercise has been found to be neuroprotective in animal models of retinal degeneration. This study aims to report physical activity levels in patients with RP and investigate the relationship between physical activity and vision-related quality-of-life (QOL). MATERIALS AND METHODS: A retrospective study of adult patients with RP examined in 2005-2014. Physical activity levels were assessed using the Godin Exercise Questionnaire. The NEI-Visual Function Questionaire-25 (VFQ-25), SF-36 General Health survey, and Pepper Assessment Tool for Disability (PAT-D) were administered. RESULTS: 143 patients participated. 81 (56.6%) patients were classified as "active" and 62 (43.4%) as "insufficiently active" by Godin score. VFQ-25 revealed statistically significant differences between the active and insufficiently active patients, including overall visual function (53.3 versus 45.1, p = 0.010), color vision (73.8 versus 52.9, p < 0.001), and peripheral vision (34.3 versus 23.8, p = 0.021). The physical component of the SF-36 and the PAT-D survey also demonstrated statistically significant differences (47.2 versus 52.9, p = 0.002; 24.3 versus 30.0, p = 0.010). Active patients had a higher initial Goldmann visual field (GVF) score (74.8 versus 60.1 degrees, p = 0.255) and final GVF score (78.7 versus 47.1 degrees, p = 0.069) but did not reach statistical significance. CONCLUSIONS: In RP, increased physical activity is associated with greater self-reported visual function and QOL. PMID- 28596916 TI - The use of bioactive peptides to modify materials for bone tissue repair. AB - It has been well recognized that the modification of biomaterials with appropriate bioactive peptides could further enhance their functions. Especially, it has been shown that peptide-modified bone repair materials could promote new bone formation more efficiently compared with conventional ones. The purpose of this article is to give a general review of recent studies on bioactive peptide modified materials for bone tissue repair. Firstly, the main peptides for inducing bone regeneration and commonly used methods to prepare peptide-modified bone repair materials are introduced. Then, current in vitro and in vivo research progress of peptide-modified composites used as potential bone repair materials are reviewed and discussed. Generally speaking, the recent related studies have fully suggested that the modification of bone repair materials with osteogenic related peptides provide promising strategies for the development of bioactive materials and substrates for enhanced bone regeneration and the therapy of bone tissue diseases. Furthermore, we have proposed some research trends in the conclusion and perspectives part. PMID- 28596920 TI - Patient Factors Predicting Weight Loss after Roux-en-Y Gastric Bypass. AB - OBJECTIVE: The purpose of this study was to identify preoperative factors predicting weight loss following Roux-en-Y gastric bypass (RYGB) surgery. MATERIAL AND METHODS: 281 patients subjected to RYGB between January 2006 and June 2012 were included. Demographic, physical, and socioeconomic factors were assessed with regression analysis. Dependent variable was percent of excess weight loss (% EWL) at follow-up. RESULTS: Follow-up data at one year was available in 96%, at two years in 88%, and at three years in 65% of the patients. Mean EWL was 72.5%. The success rate (defined as >=60% EWL) at 1 year was 73% and at 2 years 74% and was 71% after 3 years. An earlier onset of obesity and high preoperative BMI were independently associated with unsuccessful weight loss at 1 year follow-up. At 2-year follow-up, an association between unsuccessful weight loss and psychiatric disorder, diabetes, hypertension, and preoperative BMI was seen. At 3-year follow-up no statistically significant associations were detected. CONCLUSIONS: RYGB provides successful weight loss for most patients. The results from this study indicate that an earlier age of onset of obesity, high preoperative BMI, psychiatric disorder, diabetes, and hypertension are associated with unsuccessful weight loss. PMID- 28596919 TI - Rho-Kinase/ROCK as a Potential Drug Target for Vitreoretinal Diseases. AB - Rho-associated kinase (Rho-kinase/ROCK) was originally identified as an effector protein of the G protein Rho. Its involvement in various diseases, particularly cancer and cardiovascular disease, has been elucidated, and ROCK inhibitors have already been applied clinically for cerebral vasospasm and glaucoma. Vitreoretinal diseases including diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinoapthy are still a major cause of blindness. While anti-VEGF therapy has recently been widely used for vitreoretinal disorders due to its efficacy, attention has been drawn to new unmet needs. The importance of ROCK in pathological vitreoretinal conditions has also been elucidated and is attracting attention as a potential therapeutic target. ROCK is involved in angiogenesis and hyperpermeability and also in the pathogenesis of various pathologies such as inflammation and fibrosis. It has been expected that ROCK inhibitors will become new molecular target drugs for vitreoretinal diseases. This review summarizes the recent progress on the mechanisms of action of ROCK and their applications in disease treatment. PMID- 28596921 TI - Practices of Breast Self-Examination and Associated Factors among Female Debre Berhan University Students. AB - BACKGROUND: Breast cancer is the most prevalent form of cancer in Ethiopia of all female cancers. It is considered to be a progressive disease with a poor prognosis if detected late. Breast self-examination is an important prevention method of breast cancer. This study was aimed at assessing practice and associated factors of breast self-examination (BSE) among female Debre Berhan University students in Ethiopia. METHODS: A cross-sectional study was conducted in 2015 among 420 using self-administrated questionnaire. Multistage sampling technique was used to select the study participants. Bivariate and multivariate logistic regression analysis were done. RESULTS: Majority of the study participants, 338 (84.5%), were between 20 and 24 years old with the mean age of 21.1 +/- 1.65. Only 14 (3.5%) had family history of breast cancer. Two hundred fifty-six (64%) of the participants had heard about BSE and 30.25% had good knowledge about BSE. Mass media were the most common source of information about breast cancer. Few of the participants (28.3%) had performed BSE. Lack of knowledge on how to perform BSE was cited as the main reason for not practicing BSE. Knowing how to perform, when to perform, and position to perform BSE and having a perception that BSE is important and useful to detect breast cancer were significant predictors of practices of BSE. CONCLUSIONS: This study revealed that most of the participants had low knowledge and practice of BSE. Therefore, it important to develop health educational programs in the university to raise awareness about BSE and breast cancer so as to practice self-breast examination. PMID- 28596923 TI - Unilateral Dilated Pupil and Spontaneous Cardiac Arrest with Successful Bystander Resuscitation. AB - A 75-year-old man collapsed on a golf course and received cardiopulmonary resuscitation from a bystander, including the use of a public automated external defibrillator (AED). The AED was discharged once, with return of spontaneous circulation. An air ambulance crew found the patient haemodynamically stable, with no acute abnormalities on a 12-lead ECG. He had reduced consciousness and a dilated left pupil. On contacting the patient's wife by telephone, she said that he had fallen and hit his head earlier that day. The crew decided to convey the patient to a Major Trauma Centre that had both neurosurgical and cardiology specialist services (rather than the nearest hospital) so that both traumatic brain injury and cardiac pathologies could be addressed if required. A head CT was normal, but coronary angiography demonstrated occlusion of two coronary arteries. These were successfully treated with stenting, and the patient went home two weeks later. He informed medical staff that his left pupil has been permanently dilated since he was a boy following a traumatic ocular injury. This case illustrates the utility of early deployment of an AED as well as the importance of an accurate history and emergency decision-making by prehospital personnel. PMID- 28596924 TI - An Unusual Case of Pancreatic Metastasis from Squamous Cell Carcinoma of the Lung Diagnosed by EUS-Guided Fine Needle Biopsy. AB - We report a case of a 70-year-old man who presented with abdominal pain and weight loss, with initial imaging showing simultaneous mass lesions in the pancreas and lungs along with extensive lymphadenopathy in the thorax up to the left supraclavicular region. Core biopsies of the left supraclavicular lymph node showed squamous cell carcinoma, which required differentiation between secondary and primary pancreatic neoplasms. Endoscopic ultrasound-guided sampling using a novel fine needle biopsy system was key to making a definite histological diagnosis and determining the best treatment plan. PMID- 28596925 TI - Foreign Body Moves Retrograde through Ileocecal Valve during Colonoscopy. AB - Ingestion of foreign bodies and particularly of button or/and cylindrical batteries is frequent in children and adults with underlying psychiatric diseases. We present a case of a 30-year-old woman with unstable borderline disorder, where overall 4 button and 2 cylindrical batteries were endoscopically removed from her digestive system. During the last session of colonoscopy a peculiar incident was observed, as a cylindrical battery of 15 mm diameter and 43 mm length moved retrograde through ileocecal valve into the small bowel. The foreign body removal from terminal ileum was effective and safe using an endoscopic loop. This report suggests that endoscopic insertion in terminal ileum should be attempted in every colonoscopy session conducted under the indication of foreign body removal, as the possibility of retrograde movement of even large foreign bodies in the colon and through ileocecal valve is given. PMID- 28596926 TI - Invasive Mucormycosis Induced Pneumopericardium: A Rare Cause of Pneumopericardium in an Immunocompromised Patient. AB - Mucor and Rhizopus cause life-threatening infections primarily involving the lungs and sinuses, which disseminate very rapidly by necrosis and infarction of the contiguous tissues. We present a case of a 64-year-old African American posttransplant patient who presented with a productive cough and weight loss. He had a past surgical history of renal transplant for renal cell carcinoma and was on dual immunosuppressive therapy, that is, mycophenolate and tacrolimus. During his hospital stay, he developed a pneumopericardium due to the direct extension of a lung lesion. The diagnosis was made by radiological imaging and PCR result which was consistent with Mucor species. He was treated with antifungal therapy. The purpose of this report is to highlight the unusual association of mucormycosis with pneumopericardium. PMID- 28596928 TI - Pulmonary Embolism due to Inferior Vena Cava Compression by a Retroperitoneal Hematoma after Endovascular Repair of a Ruptured Abdominal Aortic Aneurysm. AB - We report a case of a patient with a residual hematoma compressing the inferior vena cava after endovascular aneurysm repair (EVAR), which led to a pulmonary embolism (PE). A 65-year-old man underwent emergent EVAR for a ruptured aortic aneurysm in the right retroperitoneal region. He developed sudden chest pain at midnight of the fifth day after EVAR, and computed tomography demonstrated a massive PE. He subsequently went into cardiopulmonary arrest. This case suggested that abdominal complications due to a residual hematoma, including deep vein thrombosis and PE, should be considered in addition to compartment syndrome. PMID- 28596922 TI - Noradrenergic Modulation of Cognition in Health and Disease. AB - Norepinephrine released by the locus coeruleus modulates cellular processes and synaptic transmission in the central nervous system through its actions at a number of pre- and postsynaptic receptors. This transmitter system facilitates sensory signal detection and promotes waking and arousal, processes which are necessary for navigating a complex and dynamic sensory environment. In addition to its effects on sensory processing and waking behavior, norepinephrine is now recognized as a contributor to various aspects of cognition, including attention, behavioral flexibility, working memory, and long-term mnemonic processes. Two areas of dense noradrenergic innervation, the prefrontal cortex and the hippocampus, are particularly important with regard to these functions. Due to its role in mediating normal cognitive function, it is reasonable to expect that noradrenergic transmission becomes dysfunctional in a number of neuropsychiatric and neurodegenerative diseases characterized by cognitive deficits. In this review, we summarize the unique role that norepinephrine plays in prefrontal cortical and hippocampal function and how its interaction with its various receptors contribute to cognitive behaviors. We further assess the changes that occur in the noradrenergic system in Alzheimer's disease, Parkinson's disease, attention-deficit/hyperactivity disorder, and schizophrenia and how these changes contribute to cognitive decline in these pathologies. PMID- 28596927 TI - Necrotizing Pseudomonas aeruginosa Community-Acquired Pneumonia: A Case Report and Review of the Literature. AB - Lung cavities are not typically associated with community-acquired pneumonia (CAP). CAP due to P. aeruginosa is rare and even less commonly causes necrotizing pneumonia. We report a case of P. aeruginosa CAP that progressed to necrotizing pneumonia and was eventually fatal. Procalcitonin (PCT) has been well investigated in guiding antibiotic therapy (especially CAP) in adults. In this case, PCT at presentation and sequentially was negative. We discuss this caveat and present hypotheses as to the sensitivity and specificity of PCT and C reactive protein (CRP) in these patients. To better characterize P. aeruginosa CAP, we undertook a review of cases indexed in PubMed from 2001 to 2016 (n = 9). The data reveal that risk factors for P. aeruginosa CAP include smoking, alcohol use, obstructive lung disease, sinusitis, and hot tub use. The route of infection for P. aeruginosa CAP remains unknown. One of the most interesting findings on reviewing cases was that P. aeruginosa CAP involves the right upper lobe in the vast majority. We suggest that when physicians in the community see patients with distinctly upper lobe necrotizing or cavitary pneumonia, they should consider P. aeruginosa in their differential diagnosis. Further studies are needed to clarify route of infection, role of PCT and CRP, and optimal therapy including drug and duration. PMID- 28596929 TI - Influence of Resistance Training on Neuromuscular Function and Physical Capacity in ALS Patients. AB - OBJECTIVES: The present study aimed to explore the effect of resistance training in patients with amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motor neuron loss and muscle weakness. MATERIALS AND METHODS: Following a 12-week "lead-in" control period, a population of ALS patients from Funen, Denmark, completed a 12-week resistance training program consisting of 2-3 sessions/week. Neuromuscular function (strength and power) and voluntary muscle activation (superimposed twitch technique) were evaluated before and after both control and training periods. Physical capacity tests (chair rise and timed up and go), the revised ALS functional rating scale (ALSFRS-R) scores, and muscle cross sectional area (histology) were also assessed. RESULTS: Of twelve ALS patients assessed for eligibility, six were included and five completed the study. Training did not significantly affect the ALSFRS-R score, and loss of neuromuscular function (strength and power) increased following the training period. However, an improved functionality (chair rise) and an increase in greatly hypertrophied type II fibres combined with an increase in atrophied fibres following the training period compared to the control period were observed. CONCLUSION: In this small study, the present form of resistance training was unable to attenuate progressive loss of neuromuscular function in ALS, despite some changes in physical capacity and morphology. PMID- 28596930 TI - Baby-Led Weaning: The Evidence to Date. AB - PURPOSE OF REVIEW: Infants are traditionally introduced to solid foods using spoon-feeding of specially prepared infant foods. RECENT FINDINGS: However, over the last 10-15 years, an alternative approach termed 'baby-led weaning' has grown in popularity. This approach involves allowing infants to self-feed family foods, encouraging the infant to set the pace and intake of the meal. Proponents of the approach believe it promotes healthy eating behaviour and weight gain trajectories, and evidence is starting to build surrounding the method. This review brings together all empirical evidence to date examining behaviours associated with the approach, its outcomes and confounding factors. SUMMARY: Overall, although there is limited evidence suggesting that a baby-led approach may encourage positive outcomes, limitations of the data leave these conclusions weak. Further research is needed, particularly to explore pathways to impact and understand the approach in different contexts and populations. PMID- 28596931 TI - A Systematic Review of Methods for Increasing Vegetable Consumption in Early Childhood. AB - PURPOSE OF REVIEW: This study aims to synthesise the body of research investigating methods for increasing vegetable consumption in 2- to 5-year-old children, while offering advice for practitioners. RECENT FINDINGS: Repeated exposure is a well-supported method for increasing vegetable consumption in early childhood and may be enhanced with the inclusion of non-food rewards to incentivise tasting. Peer models appear particularly effective for increasing 2-5 year-olds' vegetable consumption. There is little evidence for the effectiveness of food adaptations (e.g. flavour-nutrient learning) for increasing general vegetable intake among this age group, although they show some promise with bitter vegetables. SUMMARY: This review suggests that practitioners may want to focus their advice to parents around strategies such as repeated exposure, as well as the potential benefits of modelling and incentivising tasting with non food rewards. Intervention duration varies greatly, and considerations need to be made for how this impacts on success. PMID- 28596932 TI - Are There Sensitive Periods for Food Acceptance in Infancy? AB - PURPOSE OF REVIEW: A sensitive period in development is one in which it is easier for learning to take place; the behaviour can however still be learned at a later stage, but with more difficulty. This is in contrast to a critical period, a time at which a behaviour must be learned, and if this window of opportunity is missed, then the behaviour can never be acquired. Both might determine food acceptance in childhood. RECENT FINDINGS: There is evidence to support the idea of a sensitive period for the introduction of tastes, a critical period for the introduction of textures and for the development of oral motor function, and a possible critical period for the introduction of new foods but only in children where there is an innate disposition to develop early and extreme disgust responses. SUMMARY: There are both sensitive and critical periods in the acquisition of food preferences. PMID- 28596934 TI - Gel performance in rheology and profile control under low-frequency vibration: coupling application of physical and chemical EOR techniques. AB - Flowing gel plugging and low-frequency vibration oil extraction technology have been widely applied in low-permeability formation. High probability of overlapping in action spheres of two technologies might lead to poor operating efficiency during gel injection. Study on flowing gel rheological properties under low-frequency vibration was essential, which was carried out indoor with viscosity measurement. Potential dynamic mechanisms were analyzed for the rheological variation. Under low-frequency vibration, gel rheological properties were found to be obviously influenced, with vibration delaying gel cross-linking in induction period, causing a two-stage gel viscosity change in acceleration period, and decreasing gel strength in stable period. Surface of gel system under vibration presented different fluctuating phenomenon from initial harmonic vibrating to heterogeneous fluctuating (droplet separation might appear) to final harmonic vibrating again. Dynamic displacement in unconsolidated sand pack revealed that low-frequency vibration during gel injection might be a measure to achieve deep profile control, with the gel injection depth increased by 65.8 % compared with the vibration-free sample. At last, suggestions for field test were given in the paper to achieve lower injection friction and better gel plugging efficiency. PMID- 28596933 TI - Lung Organoids and Their Use To Study Cell-Cell Interaction. AB - PURPOSE OF REVIEW: The lung research field has pioneered the use of organoids for the study of cell-cell interactions. RECENT FINDINGS: The use of organoids for airway basal cells is routine. However, the development of organoids for the other regions of the lung is still in its infancy. Such cultures usually rely on cell-cell interactions between the stem cells and a putative niche cell for their growth and differentiation. SUMMARY: The use of co-culture organoid systems has facilitated the in vitro cultivation of previously inaccessible stem cell populations, providing a novel method for dissecting the molecular requirements of these cell-cell interactions. Future technology development will allow the growth of epithelial-only organoids in more defined media and also the introduction of specific non-epithelial cells for the study of cell interactions. These developments will require an improved understanding of the epithelial and non-epithelial cell types present in the lung and their lineage relationships. PMID- 28596935 TI - Green synthesis of enzyme/metal-organic framework composites with high stability in protein denaturing solvents. AB - OBJECTIVES: Enzyme/metal-organic framework composites with high stability in protein denaturing solvents were reported in this study. RESULTS: Encapsulation of enzyme in metal-organic frameworks (MOFs) via co-precipitation process was realized, and the generality of the synthesis was validated by using cytochrome c, horseradish peroxidase, and Candida antarctica lipase B as model enzymes. The stability of encapsulated enzyme was greatly increased after immobilization on MOFs. Remarkably, when exposed to protein denaturing solvents including dimethyl sulfoxide, dimethyl formamide, methanol, and ethanol, the enzyme/MOF composites still preserved almost 100% of activity. In contrast, free enzymes retained no more than 20% of their original activities at the same condition. This study shows the extraordinary protecting effect of MOF shell on increasing enzyme stability at extremely harsh conditions. CONCLUSION: The enzyme immobilized in MOF exhibited enhanced thermal stability and high tolerance towards protein denaturing organic solvents. PMID- 28596936 TI - New Bioengineering Breakthroughs and Enabling Tools in Regenerative Medicine. AB - PURPOSE OF REVIEW: In this review, we provide a general overview of recent bioengineering breakthroughs and enabling tools that are transforming the field of regenerative medicine (RM). We focus on five key areas that are evolving and increasingly interacting including mechanobiology, biomaterials and scaffolds, intracellular delivery strategies, imaging techniques, and computational and mathematical modeling. RECENT FINDINGS: Mechanobiology plays an increasingly important role in tissue regeneration and design of therapies. This knowledge is aiding the design of more precise and effective biomaterials and scaffolds. Likewise, this enhanced precision is enabling ways to communicate with and stimulate cells down to their genome. Novel imaging technologies are permitting visualization and monitoring of all these events with increasing resolution from the research stages up to the clinic. Finally, algorithmic mining of data and soft matter physics and engineering are creating growing opportunities to predict biological scenarios, device performance, and therapeutic outcomes. SUMMARY: We have found that the development of these areas is not only leading to revolutionary technological advances but also enabling a conceptual leap focused on targeting regenerative strategies in a holistic manner. This approach is bringing us ever more closer to the reality of personalized and precise RM. PMID- 28596939 TI - Undifferentiated Pleomorphic Sarcoma and the Importance of Considering the Oncogenic and Immune-Suppressant Role of the Human T-Cell Lymphotropic Virus Type 1: A Case Report. AB - INTRODUCTION: Soft-tissue sarcomas account for 0.7% of all malignant tumors, with an incidence rate of 3 per 100,000 persons/year. The undifferentiated pleomorphic sarcoma (UPS) with giant cells, a high grade tumor of soft tissue, is very unusual, especially in young adults before the age of 40. Human T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus, classified as group 1 human carcinogens by The International Agency for Research on Cancer, that causes an aggressive malignancy known as adult T-cell lymphoma/leukemia and a progressive chronic inflammatory neurological disease named HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 causes accumulation of genetic mutations in the host genome that could contribute to cellular transformation, one of the oncogenic features of HTLV-1. CASE REPORT: We describe a case of a young woman with UPS who suffered from HAM/TSP with 3 years of evolution. In 2013, the patient started with neurological symptoms: weakness in the legs and bladder dysfunction. One year later, the patient developed a mild paraparesis in both extremities, anti-HTLV-1 antibodies were detected in plasma and in cerebrospinal fluid, and HAM/TSP was confirmed. In November 2015, a benign ganglion cyst was first suspected without intervention and by March 2016 a sarcoma was diagnosed. Three weeks after surgical resection, the tumor aroused in deep tissue and behaved aggressively, implicating a curative wide resection of the fibula, joint reconstruction, and soft-tissue graft. Histopathological examination confirmed UPS with giant cells. CONCLUDING REMARKS: The unapparent subclinical immunodeficiency state due to HTLV-1 infection deserves to be considered in order to carefully monitor the possibility of developing any type of cancer. Besides, reaching an accurate and timely diagnosis of UPS can be challenging due to the difficulty in diagnosis/classification and delayed consultation. In this particular case, considering the high grade of UPS and the progressive invalidating myelopathy caused by HTLV-1, treatment should be carefully evaluated to positively impact on the patient's life expectancy. PMID- 28596937 TI - Harnessing the Potential of Human Pluripotent Stem Cells and Gene Editing for the Treatment of Retinal Degeneration. AB - PURPOSE OF REVIEW: A major cause of visual disorders is dysfunction and/or loss of the light-sensitive cells of the retina, the photoreceptors. To develop better treatments for patients, we need to understand how inherited retinal disease mutations result in the dysfunction of photoreceptors. New advances in the field of stem cell and gene editing research offer novel ways to model retinal dystrophies in vitro and present opportunities to translate basic biological insights into therapies. This brief review will discuss some of the issues that should be taken into account when carrying out disease modelling and gene editing of retinal cells. We will discuss (i) the use of human induced pluripotent stem cells (iPSCs) for disease modelling and cell therapy; (ii) the importance of using isogenic iPSC lines as controls; (iii) CRISPR/Cas9 gene editing of iPSCs; and (iv) in vivo gene editing using AAV vectors. RECENT FINDINGS: Ground-breaking advances in differentiation of iPSCs into retinal organoids and methods to derive mature light sensitive photoreceptors from iPSCs. Furthermore, single AAV systems for in vivo gene editing have been developed which makes retinal in vivo gene editing therapy a real prospect. SUMMARY: Genome editing is becoming a valuable tool for disease modelling and in vivo gene editing in the retina. PMID- 28596940 TI - Histone Deacetylase Inhibitor Treatment Increases the Expression of the Plasma Membrane Ca2+ Pump PMCA4b and Inhibits the Migration of Melanoma Cells Independent of ERK. AB - Several new therapeutic options emerged recently to treat metastatic melanoma; however, the high frequency of intrinsic and acquired resistance among patients shows a need for new therapeutic options. Previously, we identified the plasma membrane Ca2+ ATPase 4b (PMCA4b) as a metastasis suppressor in BRAF-mutant melanomas and found that mutant BRAF inhibition increased the expression of the pump, which then inhibited the migratory and metastatic capability of the cells. Earlier it was also demonstrated that histone deacetylase inhibitors (HDACis) upregulated PMCA4b expression in gastric, colon, and breast cancer cells. In this study, we treated one BRAF wild-type and two BRAF-mutant melanoma cell lines with the HDACis, SAHA and valproic acid, either alone, or in combination with the BRAF inhibitor, vemurafenib. We found that HDACi treatment strongly increased the expression of PMCA4b in all cell lines irrespective of their BRAF mutational status, and this effect was independent of ERK activity. Furthermore, HDAC inhibition also enhanced the abundance of the housekeeping isoform PMCA1. Combination of HDACis with vemurafenib, however, did not have any additive effects on either PMCA isoform. We demonstrated that the HDACi-induced increase in PMCA abundance was coupled to an enhanced [Ca2+]i clearance rate and also strongly inhibited both the random and directional movements of A375 cells. The primary role of PMCA4b in these characteristic changes was demonstrated by treatment with the PMCA4-specific inhibitor, caloxin 1c2, which was able to restore the slower Ca2+ clearance rate and higher motility of the cells. While HDAC treatment inhibited cell motility, it decreased only modestly the ratio of proliferative cells and cell viability. Our results show that in melanoma cells the expression of both PMCA4b and PMCA1 is under epigenetic control and the elevation of PMCA4b expression either by HDACi treatment or by the decreased activation of the BRAF-MEK-ERK pathway can inhibit the migratory capacity of the highly motile A375 cells. PMID- 28596938 TI - Genome-Edited T Cell Therapies. AB - PURPOSE OF REVIEW: Alternative approaches to conventional drug-based cancer treatments have seen T cell therapies deployed more widely over the last decade. This is largely due to their ability to target and kill specific cell types based on receptor recognition. Introduction of recombinant T cell receptors (TCRs) using viral vectors and HLA-independent T cell therapies using chimeric antigen receptors (CARs) are discussed. This article reviews the tools used for genome editing, with particular emphasis on the applications of site-specific DNA nuclease mediated editing for T cell therapies. RECENT FINDINGS: Genetic engineering of T cells using TCRs and CARs with redirected antigen-targeting specificity has resulted in clinical success of several immunotherapies. In conjunction, the application of genome editing technologies has resulted in the generation of HLA-independent universal T cells for allogeneic transplantation, improved T cell sustainability through knockout of the checkpoint inhibitor, programmed cell death protein-1 (PD-1), and has shown efficacy as an antiviral therapy through direct targeting of viral genomic sequences and entry receptors. SUMMARY: The combined use of engineered antigen-targeting moieties and innovative genome editing technologies have recently shown success in a small number of clinical trials targeting HIV and hematological malignancies and are now being incorporated into existing strategies for other immunotherapies. PMID- 28596941 TI - Highly Specific and Effective Targeting of EGFRvIII-Positive Tumors with TandAb Antibodies. AB - To harness the cytotoxic capacity of immune cells for the treatment of solid tumors, we developed tetravalent, bispecific tandem diabody (TandAb) antibodies that recognize EGFRvIII, the deletion variant III of the epidermal growth factor receptor (EGFR), and CD3 on T-cells, thereby directing immune cells to eliminate EGFRvIII-positive tumor cells. Using phage display, we identified scFv antibodies selectively binding to EGFRvIII. These highly EGFRvIII-specific, fully human scFv were substantially improved by affinity maturation, achieving KDs in the picomolar range, and were used to construct a set of bispecific EGFRvIII targeting TandAbs with a broad range of binding and cytotoxic properties. These antibodies exhibited an exquisite specificity for a distinguished epitope in the N-terminal portion of EGFRvIII, as shown on recombinant antigen in Western Blot, SPR, and ELISA, as well as on antigen-expressing cells in FACS assays, and did not bind to the wild-type EGFR. High-affinity EGFRvIII/CD3 TandAbs were most potent in killing assays, displaying cytotoxicity toward EGFRvIII-expressing CHO, F98 glioma, or human DK-MG cells with EC50 values in the range of 1-10 pM in vitro. They also demonstrated dose-dependent growth control in vivo in an EGFRvIII-positive subcutaneous xenograft tumor model. Together with the tumor exclusive expression of EGFRvIII, the EGFRvIII/CD3 TandAbs' high specificity and strictly target-dependent activation with no off-target activity provide an opportunity to target tumor cells and spare normal tissues, thereby reducing the side effects associated with other anti-EGFR therapies. In summary, EGFRvIII/CD3 TandAbs are highly attractive therapeutic antibody candidates for selective immunotherapy of EGFRvIII-positive tumors. PMID- 28596942 TI - Phenol-Soluble Modulin Toxins of Staphylococcus haemolyticus. AB - Coagulase-negative staphylococci (CoNS) are important nosocomial pathogens and the leading cause of sepsis. The second most frequently implicated species, after Staphylococcus epidermidis, is Staphylococcus haemolyticus. However, we have a significant lack of knowledge about what causes virulence of S. haemolyticus, as virulence factors of this pathogen have remained virtually unexplored. In contrast to the aggressive pathogen Staphylococcus aureus, toxin production has traditionally not been associated with CoNS. Recent findings have suggested that phenol-soluble modulins (PSMs), amphipathic peptide toxins with broad cytolytic activity, are widespread in staphylococci, but there has been no systematic assessment of PSM production in CoNS other than S. epidermidis. Here, we identified, purified, and characterized PSMs of S. haemolyticus. We found three PSMs of the beta-type, which correspond to peptides that before were described to have anti-gonococcal activity. We also detected an alpha-type PSM that has not previously been described. Furthermore, we confirmed that S. haemolyticus does not produce a delta-toxin, as results from genome sequencing had indicated. All four S. haemolyticus PSMs had strong pro-inflammatory activity, promoting neutrophil chemotaxis. Notably, we identified in particular the novel alpha-type PSM, S. haemolyticus PSMalpha, as a potent hemolysin and leukocidin. For the first time, our study describes toxins of this important staphylococcal pathogen with the potential to have a significant impact on virulence during blood infection and sepsis. PMID- 28596943 TI - In vitro Evaluation of the Colistin-Carbapenem Combination in Clinical Isolates of A. baumannii Using the Checkerboard, Etest, and Time-Kill Curve Techniques. AB - The worldwide increase in the emergence of carbapenem resistant Acinetobacter baumannii (CRAB) calls for the investigation into alternative approaches for treatment. This study aims to evaluate colistin-carbapenem combinations against Acinetobacter spp., in order to potentially reduce the need for high concentrations of antibiotics in therapy. This study was conducted on 100 non duplicate Acinetobacter isolates that were collected from different patients admitted at Saint George Hospital-University Medical Center in Beirut. The isolates were identified using API 20NE strips, which contain the necessary agents to cover a panel of biochemical tests, and confirmed by PCR amplification of blaOXA-51-like. Activities of colistin, meropenem and imipenem against Acinetobacter isolates were determined by ETEST and microdilution methods, and interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. In addition, PCR amplifications of the most common beta lactamases contributing to carbapenem resistance were performed. Tri locus PCR-typing was also performed to determine the international clonality of the isolates. Checkerboard, ETEST and time kill curves were then performed to determine the effect of the colistin-carbapenem combinations. The synergistic potential of the combination was then determined by calculating the Fractional Inhibitory Concentration Index (FICI), which is an index that indicates additivity, synergism, or antagonism between the antimicrobial agents. In this study, 84% of the isolates were resistant to meropenem, 78% to imipenem, and only one strain was resistant to colistin. 79% of the isolates harbored blaOXA-23-like and pertained to the International Clone II. An additive effect for the colistin carbapenem combination was observed using all three methods. The combination of colistin-meropenem showed better effects as compared to colistin-imipenem (p < 0.05). The colistin-meropenem and colistin-imipenem combinations also showed a decrease of 2.6 and 2.8-fold, respectively in the MIC of colistin (p < 0.001). Time kill assays additionally showed synergistic effects for a few isolates, and no bacterial re-growth was detected following a 24 h incubation. Our study showed that the combination of colistin with carbapenems could be a promising antimicrobial strategy in treating CRAB infections and potentially lowering colistin toxicity related to higher doses used in colistin monotherapy. PMID- 28596944 TI - CodY Regulates Thiol Peroxidase Expression as Part of the Pneumococcal Defense Mechanism against H2O2 Stress. AB - Streptococcus pneumoniae is a facultative anaerobic pathogen. Although it maintains fermentative metabolism, during aerobic growth pneumococci produce high levels of H2O2, which can have adverse effects on cell viability and DNA, and influence pneumococcal interaction with its host. The pneumococcus is unusual in its dealing with toxic reactive oxygen species (ROS) in that it neither has catalase nor the global regulators of peroxide stress resistance. Previously, we identified pneumococcal thiol peroxidase (TpxD) as the key enzyme for enzymatic removal of H2O2, and showed that TpxD synthesis is up-regulated upon exposure to H2O2. This study aimed to reveal the mechanism controlling TpxD expression under H2O2 stress. We hypothesize that H2O2 activates a transcription factor which in turn up-regulates tpxD expression. Microarray analysis revealed a pneumococcal global transcriptional response to H2O2. Mutation of tpxD abolished H2O2-mediated response to high H2O2 levels, signifying the need for an active TpxD under oxidative stress conditions. Bioinformatic tools, applied to search for a transcription factor modulating tpxD expression, pointed toward CodY as a potential candidate. Indeed, a putative 15-bp consensus CodY binding site was found in the proximal region of tpxD-coding sequence. Binding of CodY to this site was confirmed by EMSA, and genetic engineering techniques demonstrated that this site is essential for TpxD up-regulation under H2O2 stress. Furthermore, tpxD expression was reduced in a DeltacodY mutant. These data indicate that CodY is an activator of tpxD expression, triggering its up-regulation under H2O2 stress. In addition we show that H2O2 specifically oxidizes the 2 CodY cysteines. This oxidation may trigger a conformational change in CodY, resulting in enhanced binding to DNA. A schematic model illustrating the contribution of TpxD and CodY to pneumococcal global transcriptional response to H2O2 is proposed. PMID- 28596945 TI - Treatment with pCramoll Alone and in Combination with Fluconazole Provides Therapeutic Benefits in C. gattii Infected Mice. AB - Cryptococcus gattii is one of the main causative agents of cryptococcosis in immunocompetent individuals. Treatment of the infection is based on the use of antimycotics, however, the toxicity of these drugs and the increase of drug resistant strains have driven the search for more effective and less toxic therapies for cryptococcosis. pCramoll are isolectins purified from seeds of Cratylia mollis, a native forage plant from Brazil, which has become a versatile tool for biomedical application. We evaluated the effect of pCramoll alone and in combination with fluconazole for the treatment of mice infected with C. gatti. pCramoll alone or in combination with fluconazole increased the survival, reduced the morbidity and improved mice behavior i.e., neuropsychiatric state, motor behavior, autonomic function, muscle tone and strength and reflex/sensory function. These results were associated with (i) decreased pulmonary and cerebral fungal burden and (ii) increased inflammatory infiltrate and modulatory of IFNgamma, IL-6, IL-10, and IL-17A cytokines in mice treated with pCramoll. Indeed, bone marrow-derived macrophages pulsed with pCramoll had increased ability to engulf C. gattii, with an enhanced production of reactive oxygen species and decrease of intracellular fungal proliferation. These findings point toward the use of pCramoll in combination with fluconazole as a viable, alternative therapy for cryptococcosis management. PMID- 28596946 TI - Non-high-density lipoprotein fractions are strongly associated with the presence of metabolic syndrome independent of obesity and diabetes: a population-based study among Iranian adults. AB - BACKGROUND: Non-HDL-C as a valuable predictor of premature atherosclerosis, coronary events like first Myocardial infarction and cardiovascular mortality has a high accuracy of measurement both in fasting and non-fasting individuals. Metabolic syndrome (MetS) can promote the development of diabetes mellitus, endothelial dysfunction and atherosclerosis. A common pathway for cross linking of metabolic abnormalities and non-HDL-C has been suggested. In this study we aimed to describe the potential association between non-HDL cholesterol fractions and metabolic syndrome. METHODS: Data of third national surveillance of the risk factors of non-communicable diseases (SuRFNCD-2007) were analyzed. We defined metabolic syndrome (MetS) according to the Adult Treatment Panel III (ATPIII) and International Diabetes Federation (IDF) criteria for 2125 subjects aging 25-64 years. The receiver operating characteristic (ROC) curves were used to determine the optimal cut-points for the diagnosis of MetS. The curves were depicted for non-high-density lipoprotein cholesterol (non-HDL-C) and difference of total non HDL-C and LDL-C (Differential cholesterol or Diff-C) as predictors of MetS. Logistic regression was also performed in a complex sample analysis scheme. RESULTS: The area under the curve (AUC) with 95% Confidence intervals of total non-HDL-C was computed. Values were 0.693 (0.670-0.715) for IDF-defined MetS and 0.719 (0.697-0.740) for ATPIII criteria. The optimal non-HDL-C cut-point we recommend for both criteria is 153.50 mg/dl (sensitivity: 75.7%, specificity: 57.2%, with ATPIII; sensitivity: 73.2%, specificity: 57.1%, with IDF). Using IDF criteria, the accuracy of predictors were greater in non-diabetic subjects. AUC of Diff-C in DM (-) vs. DM (+) were 0.786 (0.765-0.807) vs. 0.627(0.549-0.705). Adults with high non-HDL-C were 4.42 times more likely to have ATPIII-defined MetS (>=190 vs. < 190 mg/dL). Elevated Diff-C corresponded to increased risk of the MetS (ORs: 10.71 and 26.29 for IDF and ATP III criteria, respectively. All P values <0.001). CONCLUSIONS: A significant robust association exists between non HDL-C and MetS whether applying conventional or new thresholds. PMID- 28596948 TI - Standardization of 123I-meta-iodobenzylguanidine myocardial sympathetic activity imaging: phantom calibration and clinical applications. AB - PURPOSE: Myocardial sympathetic imaging with 123I-meta-iodobenzylguanidine (123I mIBG) has gained clinical momentum. Although the need for standardization of 123I mIBG myocardial uptake has been recognized, the availability of practical clinical standardization approaches is limited. The need for standardization includes the heart-to-mediastinum ratio (HMR) and washout rate with planar imaging, and myocardial defect scoring with single-photon emission computed tomography (SPECT). METHODS: The planar HMR shows considerable variation due to differences in collimator design. These camera-collimator differences can be overcome by cross-calibration phantom experiments. The principles of these cross calibration phantom experiments are summarized in this article. 123I-mIBG SPECT databases were compiled by Japanese Society of Nuclear Medicine working group. Literature was searched based on the words "123I-mIBG quantification method", "standardization", "heart-to-mediastinum ratio", and its application to "risk model". RESULTS: Calibration phantom experiments have been successfully performed in Japan and Europe. The benefit of these cross-calibration phantom experiments is that variation in the HMR between institutions is minimized including low energy, low-medium-energy and medium-energy collimators. The use of myocardial 123I-mIBG SPECT can be standardized using 123I-mIBG normal databases as a basis for quantitative evaluation. This standardization method can be applied in cardiac event prediction models. CONCLUSION: Standardization of myocardial 123I mIBG outcome parameters may facilitate a universal implementation of myocardial 123I-mIBG scintigraphy. PMID- 28596950 TI - Review: Quality of Life in Children with Non-cystic Fibrosis Bronchiectasis. AB - Non-cystic fibrosis bronchiectasis (NCFB) has gained renewed interest, due to its increasing health-care burden. Annual mortality statistics in England and Wales showed that under 1,000 people die from bronchiectasis each year, and this number is increasing by 3% yearly. Unfortunately, there is a severe lack of well powered, randomized controlled trials to guide clinicians how to manage NCFB effectively. Quality-of-life (QOL) measures in NCFB are an important aspect of clinical care that has not been studied well. Commonly used disease-specific questionnaires in children with NCFB are the St George's Respiratory Questionnaire, Short Form-36, the Leicester Cough Questionnaire, and the Parent Cough-Specific Quality of Life questionnaire (PC-QOL). Of these, only the PC-QOL can be used in young children, as it is a parent-proxy questionnaire. We reviewed pediatric studies looking at QOL in children with NCFB and cystic fibrosis. All types of airway clearance techniques appear to be safe and have no significant benefit over each other. Number of exacerbations and hospitalizations correlated with QOL scores, while symptom subscales correlated with lung function, worse QOL, frequent antibiotic requirements, and duration of regular follow-up in only one study. There was a correlation between QOL and age of diagnosis in children with primary ciliary dyskinesia. Other studies have shown no relationship between QOL scores and etiology of NCFB as well as CT changes. As for treatments, oral azithromycin and yoga have demonstrated some improvement in QOL scores. In conclusion, more studies are required to accurately determine important factors contributing to QOL. PMID- 28596949 TI - New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals. AB - PURPOSE: This short review aims to cover the more recent and promising developments of carbon-11 (11C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging. METHODS: A survey of the literature was undertaken to identify articles focusing on methodological development in 11C chemistry and their use within novel radiopharmaceutical preparation. However, since 11C labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000-2016) and articles in English. RESULTS: From the literature, it is clear that the majority of 11C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of 11C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of 11C-labeled carbonyl groups, where organic bases are utilized as [11C]carbon dioxide-fixation agents. The second method of clinical importance is a low-pressure 11C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react [11C]carbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to 11C-labeled products. CONCLUSION: Radiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and 11C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy 11C-labeling methods with clinical relevance to the field of PET radiochemistry. PMID- 28596953 TI - Tuberculosis Treatment Completion in a United States/Mexico Binational Context. AB - BACKGROUND: Tuberculosis (TB) remains a salient public health issue along the U.S./Mexico border. This study seeks to identify the social and structural factors, which are associated with TB disease burden in the binational geographic region. Identification of barriers of treatment completion provides the necessary framework for developing evidence-based interventions that are culturally relevant and context specific for the U.S./Mexico border region. METHODS: Retrospective study of data extracted from medical charts (n = 439) from Yuma County Health Department (YCHD) (n = 160) and Centro de Salud San Luis Rio Colorado (n = 279). Patients currently accessing TB treatment at either facility were excluded from the study. Chi-square, unadjusted odds ratios, and logistic regression were utilized to identify characteristics associated with successful TB treatment in this population. FINDINGS: The study population was predominantly male (n = 327). Females were more likely to complete TB treatment (OR = 3.71). The absence of drug use and/or the absence of an HIV positive diagnosis were found to be predictors of TB treatment completion across both clinical sites. Forty-four percent (43.59%) (n = 85) TB patients treated at CDS San Luis did not complete treatment versus 40.35% (n = 49) of TB patients who did not complete treatment at YCHD. Moving from the area or being deported was the highest category (20.78%) for incomplete TB treatment in the population (n = 64) across both clinical sites. PMID- 28596952 TI - Neurodevelopmental Delay Diagnosis Rates Are Increased in a Region with Aerial Pesticide Application. AB - A number of studies have implicated pesticides in childhood developmental delay (DD) and autism spectrum disorder (ASD). The influence of the route of pesticide exposure on neurodevelopmental delay is not well defined. To study this factor, we examined ASD/DD diagnoses rates in an area near our regional medical center that employs yearly aerial pyrethroid pesticide applications to combat mosquito borne encephalitis. The aim of this study was to determine if areas with aerial pesticide exposure had higher rates of ASD/DD diagnoses. This regional study identified higher rates of ASD/DD diagnoses in an area with aerial pesticides application. Zip codes with aerial pyrethroid exposure were 37% more likely to have higher rates of ASD/DD (adjusted RR = 1.37, 95% CI = 1.06-1.78, p = 0.02). A Poisson regression model controlling for regional characteristics (poverty, pesticide use, population density, and distance to medical center), subject characteristics (race and sex), and local birth characteristics (prematurity, low birthweight, and birth rates) identified a significant relationship between aerial pesticide use and ASD/DD rates. The relationship between pesticide application and human neurodevelopment deserves additional study to develop safe and effective methods of mosquito prevention, particularly as communities develop plans for Zika virus control. PMID- 28596951 TI - Early-Life Host-Microbiome Interphase: The Key Frontier for Immune Development. AB - Human existence can be viewed as an "animal in a microbial world." A healthy interaction of the human host with the microbes in and around us heavily relies on a well-functioning immune system. As development of both the microbiota and the host immune system undergo rapid changes in early life, it is not surprising that even minor alterations during this co-development can have profound consequences. Scrutiny of existing data regarding pre-, peri-, as well as early postnatal modulators of newborn microbiota indeed suggest strong associations with several immune-mediated diseases with onset far beyond the newborn period. We here summarize these data and extract overarching themes. This same effort in turn sets the stage to guide effective countermeasures, such as probiotic administration. The objective of our review is to highlight the interaction of host immune ontogeny with the developing microbiome in early life as a critical window of susceptibility for lifelong disease, as well as to identify the enormous potential to protect and promote lifelong health by specifically targeting this window of opportunity. PMID- 28596954 TI - Assessment of Health Needs in Children with Congenital Upper Limb Differences in Nicaragua: Community Case Study. AB - Congenital anomalies are prevalent in Nicaragua, and disability is estimated to be 10% in the general population. We studied children with congenital upper limb differences, as they are vulnerable to disability. This case study documents a collaborative effort between American and Nicaraguan orthopedic surgeons to determine unmet health needs of children with congenital upper limb differences at Hospital Manuel de Jesus Rivera ("La Mascota" Hospital) in Nicaragua, with the goal of developing programs that successfully address these needs within the context of the priorities of the community. Participants were recruited during one of the biannual pediatric hand specialty clinics held by a partnership of pediatric hand surgeons and occupational therapists under the auspices of Health Volunteers Overseas (La Brigada de las Manos, or "La Brigada") and Nicaraguan orthopedic surgeons. Structured interviews were performed with 34 parents or caregivers of patients with the diagnosis of a congenital upper limb difference. Parents were asked to rank the social, economic, environmental, and biological factors that determine health according to priority. Using the Hanlon Method for prioritizing health problems, in consultation with local providers and the program director of La Brigada, five needs were identified: (1) improvements in access to specialized care from hand surgeons and (2) rehabilitation specialists; (3) improvements in upper extremity function; (4) access to transportation; and (5) improvement in physical activity and sports participation. Based on the results of this needs assessment, we learned that some of the needs were already part of the ongoing work of the partnership, but in addition, more needs became evident; for that reason, local health care providers and members of La Brigada identified potential solutions to these needs and are currently working to translate these in future interventions. PMID- 28596947 TI - Molecular mechanisms of hypoxia in cancer. AB - PURPOSE: Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. METHODS: A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. RESULTS: A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. CONCLUSION: Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised. PMID- 28596956 TI - Commentary: PET/MR Versus PET/CT Imaging: Impact on the Clinical Management of Small-Bowel Crohn's Disease. PMID- 28596955 TI - Flux-Enabled Exploration of the Role of Sip1 in Galactose Yeast Metabolism. AB - 13C metabolic flux analysis (13C MFA) is an important systems biology technique that has been used to investigate microbial metabolism for decades. The heterotrimer Snf1 kinase complex plays a key role in the preference Saccharomyces cerevisiae exhibits for glucose over galactose, a phenomenon known as glucose repression or carbon catabolite repression. The SIP1 gene, encoding a part of this complex, has received little attention, presumably, because its knockout lacks a growth phenotype. We present a fluxomic investigation of the relative effects of the presence of galactose in classically glucose-repressing media and/or knockout of SIP1 using a multi-scale variant of 13C MFA known as 2-Scale 13C metabolic flux analysis (2S-13C MFA). In this study, all strains have the galactose metabolism deactivated (gal1Delta background) so as to be able to separate the metabolic effects purely related to glucose repression from those arising from galactose metabolism. The resulting flux profiles reveal that the presence of galactose in classically glucose-repressing conditions, for a CEN.PK113-7D gal1Delta background, results in a substantial decrease in pentose phosphate pathway (PPP) flux and increased flow from cytosolic pyruvate and malate through the mitochondria toward cytosolic branched-chain amino acid biosynthesis. These fluxomic redistributions are accompanied by a higher maximum specific growth rate, both seemingly in violation of glucose repression. Deletion of SIP1 in the CEN.PK113-7D gal1Delta cells grown in mixed glucose/galactose medium results in a further increase. Knockout of this gene in cells grown in glucose-only medium results in no change in growth rate and a corresponding decrease in glucose and ethanol exchange fluxes and flux through pathways involved in aspartate/threonine biosynthesis. Glucose repression appears to be violated at a 1/10 ratio of galactose-to-glucose. Based on the scientific literature, we may have conducted our experiments near a critical sugar ratio that is known to allow galactose to enter the cell. Additionally, we report a number of fluxomic changes associated with these growth rate increases and unexpected flux profile redistributions resulting from deletion of SIP1 in glucose-only medium. PMID- 28596957 TI - Heterogeneous Vascular Bed Responses to Pulmonary Titanium Dioxide Nanoparticle Exposure. AB - A growing body of research links engineered nanomaterial (ENM) exposure to adverse cardiovascular endpoints. The purpose of this study was to evaluate the impact of ENM exposure on vascular reactivity in discrete segments so that we may determine the most sensitive levels of the vasculature where these negative cardiovascular effects are manifest. We hypothesized that acute nano-TiO2 exposure differentially affects reactivity with a more robust impairment in the microcirculation. Sprague-Dawley rats (8-10 weeks) were exposed to nano-TiO2via intratracheal instillation (20, 100, or 200 ug suspended per 250 uL of vehicle) 24 h prior to vascular assessments. A serial assessment across distinct compartments of the vascular tree was then conducted. Wire myography was used to evaluate macrovascular active tension generation specifically in the thoracic aorta, the femoral artery, and third-order mesenteric arterioles. Pressure myography was used to determine vascular reactivity in fourth- and fifth-order mesenteric arterioles. Vessels were treated with phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Nano-TiO2 exposure decreased endothelium dependent relaxation in the thoracic aorta and femoral arteries assessed via ACh by 53.96 +/- 11.6 and 25.08 +/- 6.36%, respectively. Relaxation of third-order mesenteric arterioles was impaired by 100 and 20 ug nano-TiO2 exposures with mean reductions of 50.12 +/- 8.7 and 68.28 +/- 8.7%. Cholinergic reactivity of fourth- and fifth-order mesenteric arterioles was negatively affected by nano-TiO2 with diminished dilations of 82.86 +/- 12.6% after exposure to 200 ug nano-TiO2, 42.6 +/- 12.6% after 100 ug nano-TiO2, and 49.4 +/- 12.6% after 20 ug nano-TiO2. Endothelium-independent relaxation was impaired in the thoracic aorta by 34.05 +/ 25% induced by exposure to 200 ug nano-TiO2 and a reduction in response of 49.31 +/- 25% caused by 100 ug nano-TiO2. Femoral artery response was reduced by 18 +/- 5%, while third-order mesenteric arterioles were negatively affected by 20 ug nano-TiO2 with a mean decrease in response of 38.37 +/- 10%. This is the first study to directly compare the differential effect of ENM exposure on discrete anatomical segments of the vascular tree. Pulmonary ENM exposure produced macrovascular and microvascular dysfunction resulting in impaired responses to endothelium-dependent, endothelium-independent, and adrenergic agonists with a more robust dysfunction at the microvascular level. These results provide additional evidence of an endothelium-dependent and endothelium-independent impairment in vascular reactivity. PMID- 28596958 TI - Circulating Cellular Adhesion Molecules and Cognitive Function: The Coronary Artery Risk Development in Young Adults Study. AB - OBJECTIVE: Higher circulating concentrations of cellular adhesion molecules (CAMs) can be used as markers of endothelial dysfunction. Given that the brain is highly vascularized, we assessed whether endothelial function is associated with cognitive performance. METHOD: Within the Coronary Artery Risk Development in Young Adults (CARDIA) Study, excluding N = 54 with stroke before year 25, we studied CAMs among N = 2,690 black and white men and women in CARDIA year 7 (1992 1993, ages 25-37) and N = 2,848 in CARDIA year 15 (2000-2001, ages 33-45). We included subjects with levels of circulating soluble CAMs measured in year 7 or 15 and cognitive function testing in year 25 (2010-2011, ages 43-55). Using multiple regression analysis, we evaluated the association between CAMs and year 25 cognitive test scores: Rey Auditory Verbal Learning Test (RAVLT, memory), Digit Symbol Substitution Test (DSST, speed of processing), and the Stroop Test (executive function). RESULT: All CAM concentrations were greater in year 15 vs. year 7. Adjusting for age, race, sex, education, smoking, alcohol, diet, physical activity, participants in the fourth vs. the first quartile of CARDIA year 7 of circulating intercellular adhesion molecule-1 (ICAM-1) scored worse on RAVLT, DSST, and Stroop Test (p <= 0.05) in CARDIA year 25. Other CAMs showed little association with cognitive test scores. Findings were similar for ICAM-1 assessed at year 15. Adjustment for possibly mediating physical factors attenuated the findings. CONCLUSION: Higher circulating ICAM-1 at average ages 32 and 40 was associated with lower cognitive skills at average age 50. The study is consistent with the hypothesis that endothelial dysfunction is associated with worse short term memory, speed of processing, and executive function. PMID- 28596959 TI - Oral Bioavailability and Plasma Disposition of Pefloxacin in Healthy Broiler Chickens. AB - The pharmacokinetics of pefloxacin after single 10 mg/kg BW intravenous (IV) and oral doses were studied in healthy broiler chickens. For 24 h, serial blood samples were obtained after IV and oral administration. Concentrations of pefloxacin and its major metabolite N-demethyl pefloxacin (norfloxacin) were measured by use of high-performance liquid chromatography. The plasma concentrations-time data were found to fit a two-compartment open model. For pefloxacin, the elimination half-life (t1/2beta) was 8.44 +/- 0.48 and 13.18 +/- 0.82 h after IV and oral administration, respectively. After single oral dose, pefloxacin was rapidly absorbed with an absorption half-life (t1/2a) and TMAX of 0.87 +/- 0.07 and 2.01 +/- 0.12 h, respectively. Maximum plasma concentration (CMAX) was 4.02 +/- 0.31 ug/mL. Oral bioavailability of pefloxacin was found to be 70 +/- 2%. Pefloxacin was converted to N-demethyl pefloxacin (norfloxacin). This metabolite represented 5% of the parent drug plasma concentrations. The maximal plasma concentration (CMAX) of N-demethyl pefloxacin (norfloxacin) was calculated as 0.19 +/- 0.01 mg/mL. The t1/2beta of N-demethyl pefloxacin after oral pefloxacin administration was 10.93 +/- 0.80 h. The results indicate that an oral dose of 10 mg pefloxacin/kg BW, every 24 h, should be effective in treatment of the most systemic infections in poultry. PMID- 28596960 TI - Acinetobacter baumannii Infection in Transfusion Dependent Thalassemia Patients with Sepsis. AB - PURPOSE: To identify the Acinetobacter baumannii infection among transfusion dependent thalassemia patients. METHODS: A quantitative approach was employed to assess Acinetobacter baumannii infection in transfusion dependent thalassemia patients. Samples were collected from 916 patients, which have shown bacterial growth on MacConkey and blood agar culture media. A. baumannii strains were identified by microbiological methods and Gram's staining. API 20 E kit (Biomerieux, USA) was used for final identification. RESULTS: From 916 cultured blood specimens, 107 (11.6%) showed growth of A. baumannii. Serum ferritin in thalassemic patients without bacterial infections was 3849.5 +/- 1513.5 ug/L versus 6413.5 +/- 2103.9 ug/L in those with bacterial infections (p = 0.0001). Acinetobacter baumannii infected patients have shown higher serum ferritin levels (p = 0.0001). Serum ferritin in thalassemic patients was 3849.5 +/- 1513.5 ug/L versus 6413.5 +/- 2103.9 ug/L in those with bacterial infections (p = 0.0001). Acinetobacter baumannii infected patients showed high serum ferritin levels (p = 0.0001). The clinical symptoms have been found with A. baumannii +ve with a mean and standard deviation of 47 (5.1%) and A. baumannii -ve with mean and standard deviation of 60 (6.5%). CONCLUSION: Isolation of asymptomatic A. baumannii from the thalassemia patients shows an alarming situation of bacterial infections. A continuous surveillance of transfusion dependent thalassemia patients is recommended for bacterial sepsis. PMID- 28596961 TI - First Insight into the Molecular Epidemiology of Mycobacterium tuberculosis Isolates from the Minority Enclaves of Southwestern China. AB - Yunnan is a province located in southwestern China. The aim of this study was to investigate the genetic diversity of Mycobacterium tuberculosis (MTB) strains circulating in Yunnan Province. We used spoligotyping and a 12-locus high resolution VNTR set to identify a total of 271 MTB isolates collected from six prefectures' Yunnan. All the 271 patients were classified as 11 different ethnic groups, including 133 Han patients (49.1%) and 138 minority patients (50.9%). Spoligotyping analyses revealed that the largest two spoligotypes were SIT1 (Beijing family, n = 136) and SIT53 (T family, n = 35). Statistical analysis indicated that the proportion of Beijing genotype in Qujing was significantly higher than that in the ethnic enclaves (P <= 0.01). Compared with the percentage of Beijing-family isolates from patients under 25 years of age (72.7%), those from patients aged 45~64 years (44.6%, P < 0.01) and older than 64 years (48.1%) (P = 0.04) were significantly lower. Beijing genotype strains (23.8%, 36/151) showed higher clustering rate than non-Beijing genotype strains (16/120, 13.3%, P = 0.029). In conclusion, our data demonstrated that the Beijing genotype was the predominant genotype in Yunnan Province. The distribution of Beijing genotype strains showed geographic diversity. In addition, Beijing genotype was associated with recent transmission rather than drug resistance. PMID- 28596962 TI - A Novel ECG Eigenvalue Detection Algorithm Based on Wavelet Transform. AB - This study investigated an electrocardiogram (ECG) eigenvalue automatic analysis and detection method; ECG eigenvalues were used to reverse the myocardial action potential in order to achieve automatic detection and diagnosis of heart disease. Firstly, the frequency component of the feature signal was extracted based on the wavelet transform, which could be used to locate the signal feature after the energy integral processing. Secondly, this study established a simultaneous equations model of action potentials of the myocardial membrane, using ECG eigenvalues for regression fitting, in order to accurately obtain the eigenvalue vector of myocardial membrane potential. The experimental results show that the accuracy of ECG eigenvalue recognition is more than 99.27%, and the accuracy rate of detection of heart disease such as myocardial ischemia and heart failure is more than 86.7%. PMID- 28596964 TI - Oxidative Stress-Induced DNA Damage by Manganese Dioxide Nanoparticles in Human Neuronal Cells. AB - Metal nanoparticles have been extensively used in industry as well as in biomedical application. In this work, we have evaluated the toxic potential of manganese dioxide (MnO2) nanoparticles (MNPs) on human neuronal (SH-SY5Y) cells. Cellular toxicity due to MNPs (0, 10, 30, and 60 MUg/ml) on the SH-SY5Y cell was observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutral red uptake (NRU) tests. MNPs produced reactive oxygen species (ROS) and declined in mitochondrial membrane potential in the SH-SY5Y cell in dose and duration dependent manner. Moreover, lipid peroxide (LPO), superoxide dismutase (SOD), and catalase (CAT) activities were increased and glutathione was reduced in dose and time dependent manner. A significant upgrade in Hoechst 33342 fluorescence intensity (chromosome condensation) and phosphatidylserine translocation (apoptotic cell) was visualized in cells treated with MNPs for 48 h. On the other hand, caspase-3 activity was increased due to MNPs in SH-SY5Y cells. DNA strand breaks were determined by alkaline single cell gel electrophoresis assay (Comet Assay) and maximum fragmentation of DNA produced due to MNPs (60 MUg/ml) for 48 hours. This result provides a basic mechanism of induction of apoptosis and toxicity by MNPs in SH-SY5Y cells. PMID- 28596963 TI - Prion Diagnosis: Application of Real-Time Quaking-Induced Conversion. AB - Prions composed of pathogenic scrapie prion protein (PrPSc) are infectious pathogens that cause progressive neurological conditions known as prion diseases or transmissible spongiform encephalopathies. Although these diseases pose considerable risk to public health, procedures for early diagnosis have not been established. One of the most recent attempts at sensitive and specific detection of prions is the real-time quaking-induced conversion (RT-QuIC) method, which measures the activity of PrPSc aggregates or amyloid formation triggered by PrPSc seeds in the presence of recombinant PrP. In this review, we summarize prions, prion diseases, and current approaches to diagnosis, including the principle, conditions for assay performance, and current diagnostic applications of RT-QuIC. PMID- 28596965 TI - The Fibularis (Peroneus) Tertius Muscle in Humans: A Meta-Analysis of Anatomical Studies with Clinical and Evolutionary Implications. AB - Being considered an exclusive human structure for a long time, fibularis tertius (FT) is believed to have a secondary function of foot dorsiflexion and eversion. This study is an attempt to approach the issue from an anatomical perspective. A systematic literature search identified 35 studies (7601 legs) which met the inclusion criteria. The weighted results of FT presence were as follows: an "adult cadaveric" frequency of 93.2% and a clinical frequency of 80%. The most common FT origin and insertion sites were the distal half of fibula and the base of the 5th metatarsal, respectively. In 95% of cases, an accessory fibular muscle was detected when FT was lacking. We demonstrated that the discrepancy found between the adult cadaveric and clinical frequency values would point out a probable bias in interpreting previous kinesiological results. On an evolutionary level, comparative anatomy demonstrated a very low FT prevalence among monkeys while reaching a frequency of 30% in gorillas, the only non-human apes having an almost exclusive terrestrial locomotion. The consistent prevalence among humans and the presence of similar functional muscles when it is missing would support an essential role of FT during the phylogenetic development of the erect bipedal posture and probably during gait. PMID- 28596966 TI - Prevalence of Malnutrition and Associated Factors among Children in Rural Ethiopia. AB - BACKGROUND: Child malnutrition continues to be the leading public health problem in developing countries. In Ethiopia, malnutrition is a leading cause of child illness and death. Recently the composite index of anthropometric failure (CIAF) has been implemented to measure the prevalence of malnutrition. This index presents a more complete picture compared with the previous conventional indices. In this study, CIAF was used to determine the prevalence of malnutrition among children aged 0-59 months in rural Ethiopia. METHODS: Data was extracted from the 2014 Ethiopian Mini Demographic and Health Survey (EMDHS) for this study. A total of 3095 children were included in the analysis. The composite index of anthropometric failure (CIAF) was used to measure the nutritional status of the children. Logistic regression was fitted, to identify factors associated with malnutrition among children in rural Ethiopia, using STATA 13. RESULT: The prevalence of malnutrition among rural children in Ethiopia was 48.5%. Age of the children, preceding birth interval, educated status of mother, wealth status, and region were factors independently associated with nutritional status of children in rural Ethiopia. CONCLUSION: The prevalence of malnutrition among children in rural Ethiopia was high. A child older than 12 months, having uneducated mother, living in a household with poor wealth status, born with short birth interval, and living in some region of the country are associated with increased odds of being malnourished. PMID- 28596968 TI - Piper betle L. Modulates Senescence-Associated Genes Expression in Replicative Senescent Human Diploid Fibroblasts. AB - Piper betle (PB) is a traditional medicine that is widely used to treat different diseases around Asian region. The leaf extracts contain various bioactive compounds, which were reported to have antidiabetic, antibacterial, anti inflammatory, antioxidant, and anticancer effects. In this study, the effect of PB aqueous extracts on replicative senescent human diploid fibroblasts (HDFs) was investigated by determining the expressions of senescence-associated genes using quantitative PCR. Our results showed that PB extracts at 0.4 mg/ml can improve cell proliferation of young (143%), presenescent (127.3%), and senescent (157.3%) HDFs. Increased expressions of PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were observed in senescent HDFs compared to young and/or presenescent HDFs. Treatment with PB extracts modulates the transcriptional profile changes in senescent HDFs. By contrast, expressions of SOD1 increased, whereas GPX1, PRDX6, TP53, CDKN2A, PAK2, and MAPK14 were decreased in PB-treated senescent HDFs compared to untreated senescent HDFs. In conclusion, this study indicates the modulation of PB extracts on senescence-associated genes expression of replicative senescent HDFs. Further studies warrant determining the mechanism of PB in modulating replicative senescence of HDFs through these signaling pathways. PMID- 28596967 TI - Prdx6 Upregulation by Curcumin Attenuates Ischemic Oxidative Damage via SP1 in Rats after Stroke. AB - BACKGROUND: The role of Peroxiredoxin 6 (Prdx6) in brain ischemia remains unclear. Curcumin (Cur) treatment elicits neuroprotective effects against cerebral ischemic injury, and the associated mechanisms may involve Prdx6. In this study, we investigated whether Prdx6 and the transcription factor specific protein 1 (SP1) were involved in the antioxidant effect of Cur after stoke. METHODS: Focal cerebral ischemic injury was induced by transient middle cerebral artery occlusion for 2 hours in male Sprague-Dawley rats treated with or without Prdx6 siRNA. Expression of Prdx6 in the penumbra was assessed by Real-Time PCR (RT-PCR), Western blot analysis, and immunoflourescent staining. In addition, infarct volume, neurological deficit score, and oxidative stress were evaluated. Prdx6 levels were also determined in the presence and absence of SP1 antagonist mithramycin A (MTM-A). RESULTS: Cur treatment upregulated Prdx6 protein expression and the number of Prdx6-positive neuronal cells 24 hours after reperfusion. Cur treatment also attenuated oxidative stress and induced neuroprotective effects against ischemic damage, whereas the beneficial effects of Cur treatment were lost in animals treated with Prdx6-siRNA. Prdx6 upregulation by Cur treatment was abolished by SP1 antagonists MTM. CONCLUSIONS: Prdx6 upregulation by Cur treatment attenuates ischemic oxidative damage through SP1 induction in rats after stroke. This represents a novel mechanism of Cur induced neuroprotection against cerebral ischemia. PMID- 28596969 TI - Twelve-Year Follow-Up of Laser In Situ Keratomileusis for Moderate to High Myopia. AB - PURPOSE: To assess the long-term clinical outcomes of conventional laser in situ keratomileusis (LASIK) for moderate to high myopia. METHODS: We retrospectively examined sixty-eight eyes of 37 consecutive patients who underwent conventional LASIK for the correction of myopia (-3.00 to -12.75 diopters (D)). At 3 months and 1, 4, 8, and 12 years postoperatively, we assessed the safety, efficacy, predictability, stability, mean keratometry, central corneal thickness, and adverse events. RESULTS: The safety and efficacy indices were 0.82 +/- 0.29 and 0.67 +/- 0.37, respectively, 12 years postoperatively. At 12 years, 53% and 75% of the eyes were within 0.5 and 1.0 D, respectively, of the targeted correction. Manifest refraction changes of -0.74 +/- 0.99 D occurred from 3 months to 12 years after LASIK (p < 0.001). We found a significant correlation of refractive regression with the changes in keratometric readings from 3 months to 12 years postoperatively (Pearson correlation coefficient, r = -0.28, p = 0.02), but not with the changes in central corneal thickness (r = -0.08, p = 0.63). No vision threatening complications occurred in any case. CONCLUSIONS: Conventional LASIK offered good safety outcomes during the 12-year observation period. However, the efficacy and the predictability gradually decreased with time owing to myopic regression in relation to corneal steepening. PMID- 28596970 TI - Type 2 Diabetes in Young Females Results in Increased Serum Amyloid A and Changes to Features of High Density Lipoproteins in Both HDL2 and HDL3. AB - Persons with type 2 diabetes mellitus (T2DM) have an elevated risk of atherosclerosis. High-density lipoproteins (HDL) normally protect against cardiovascular disease (CVD), but this may be attenuated by serum amyloid A (SAA). In a case-control study of young females, blood samples were compared between subjects with T2DM (n = 42) and individuals without T2DM (n = 42). SAA and apolipoprotein AI (apoAI) concentrations, paraoxonase-1 (PON-1), cholesteryl ester transfer protein (CETP), and lecithin-cholesterol acyltransferase (LCAT) activities were measured in the serum and/or HDL2 and HDL3 subfractions. SAA concentrations were higher in T2DM compared to controls: serum (30 mg/L (17, 68) versus 15 mg/L (7, 36); p = 0.002), HDL2 (1.0 mg/L (0.6, 2.2) versus 0.4 mg/L (0.2, 0.7); p < 0.001), and HDL3, (13 mg/L (8, 29) versus 6 mg/L (3, 13); p < 0.001). Serum-PON-1 activity was lower in T2DM compared to that in controls (38,245 U/L (7025) versus 41,109 U/L (5690); p = 0.043). CETP activity was higher in T2DM versus controls in HDL2 (232.6 MUmol/L (14.1) versus 217.1 MUmol/L (25.1); p = 0.001) and HDL3 (279.5 MUmol/L (17.7) versus 245.2 MUmol/L (41.2); p < 0.001). These results suggest that individuals with T2DM have increased SAA related inflammation and dysfunctional HDL features. SAA may prove to be a useful biomarker in T2DM given its association with elevated CVD risk. PMID- 28596971 TI - Soluble Urokinase Receptor and the Kidney Response in Diabetes Mellitus. AB - Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. DN typically manifests by glomerular hyperfiltration and microalbuminuria; then, the disease progresses to impaired glomerular filtration rate, which leads to ESRD. Treatment options for DN include the strict control of blood glucose levels and pressure (e.g., intraglomerular hypertension). However, the search for novel therapeutic strategies is ongoing. These include seeking specific molecules that contribute to the development and progression of DN to potentially interfere with these "molecular targets" as well as with the cellular targets within the kidney such as podocytes, which play a major role in the pathogenesis of DN. Recently, podocyte membrane protein urokinase receptor (uPAR) and its circulating form (suPAR) are found to be significantly induced in glomeruli and sera of DN patients, respectively, and elevated suPAR levels predicted diabetic kidney disease years before the occurrence of microalbuminuria. The intent of this review is to summarize the emerging evidence of uPAR and suPAR in the clinical manifestations of DN. The identification of specific pathways that govern DN will help us build a more comprehensive molecular model for the pathogenesis of the disease that can inform new opportunities for treatment. PMID- 28596973 TI - Quadriceps Strength in Patients With Isolated Cartilage Defects of the Knee: Results of Isokinetic Strength Measurements and Their Correlation With Clinical and Functional Results. AB - BACKGROUND: Recent studies have found a significant deficit of maximum quadriceps strength after autologous chondrocyte implantation (ACI) of the knee. However, it is unclear whether muscular strength deficits in patients with cartilage damage exist prior to operative treatment. PURPOSE: To isokinetically test maximum quadriceps muscle strength and quantify the impact of possible strength deficits on functional and clinical test results. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: To identify clinically relevant muscular strength deficits, 24 patients (5 females, 19 males; mean age, 34.5 years; body mass index, 25.9 kg/m2) with isolated cartilage defects (mean onset, 5.05 years; SD, 7.8 years) in the knee joint underwent isokinetic strength measurements. Maximal quadriceps strength was recorded in 3 different testing modes: pure concentric contraction (flexors and extensors alternating work; con1), concentric-eccentric (only the extensors work concentrically and eccentrically; con2), and eccentric contraction in the alternating mode (ecc). Results were compared for functional performance (single-leg hop test), pain scales (visual analog scale [VAS], numeric rating scale [NRS]), self-reported questionnaires (International Knee Documentation Committee [IKDC], Knee Injury and Osteoarthritis Outcome Scale [KOOS]), and defect size (cm2). RESULTS: Compared with the uninjured leg, significantly lower quadriceps strength was detected in the injured leg in all isokinetic working modes (con1 difference, 27.76 N.m [SD 17.47; P = .003]; con2 difference, 21.45 N.m [SD, 18.45; P =.025]; ecc difference, 29.48 N.m [SD, 21.51; P = .001]), with the largest deficits found for eccentric muscle performance. Moderate negative correlations were observed for the subjective pain scales NRS and VAS. The results of the IKDC and KOOS questionnaires showed low, nonsignificant correlations with findings in the isokinetic measurement. Moreover, defect sizes (mean, 3.13 cm2) were of no importance regarding the prediction of the strength deficit. The quadriceps strength deficit between the injured and the uninjured leg was best predicted by the results of the single-leg hop test. CONCLUSION: Patients with isolated cartilage defects of the knee joint have significant deficits in quadriceps muscle strength of the injured leg compared with the uninjured leg. The single-leg hop test may be used to predict quadriceps strength deficits. Future research should address whether preoperative strength training in patients with cartilage defects of the knee could be effective and should be taken into consideration in addition to surgical treatment. PMID- 28596974 TI - Magnetic Resonance Imaging Appearance of the Hip Musculature After Arthroscopic Labral-Level Iliopsoas Tenotomies. AB - BACKGROUND: Iliopsoas (IP) muscle atrophy is a known consequence of open IP tenotomy, but the severity of IP muscle atrophy that occurs after arthroscopic labral-level IP tenotomies has not been documented. PURPOSE: To document the severity of muscle atrophy that occurs in the iliacus, psoas, and adjacent hip musculature after arthroscopic labral-level IP tenotomy. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-eight patients who had magnetic resonance arthrograms (MRAs) obtained prior to and 3 months to 5 years after arthroscopic labral-level IP tenotomies are the basis of this report. The pre- and postoperative MRAs of each patient were examined in consensus by 2 musculoskeletal radiologists who graded the postoperative muscle atrophy from 0 (no fatty infiltration) to 4 (>75% fatty infiltration) and noted any compensatory muscle hypertrophy or abnormal IP tendon morphology. Patients also were assessed with the Byrd 100-point modified Harris Hip Scoring system (MHHS) preoperatively and at the time of their postoperative MRA. RESULTS: Postoperative MRAs were obtained on average 1.7 years (range, 3 months to 5 years) after hip arthroscopy. None of the patients had muscle atrophy on their preoperative MRAs. In contrast, 89% of patients had iliacus and psoas muscle atrophy on their postoperative MRAs, but only 2 (7%) developed grade 4 atrophy, and the majority (64%) had either grade 1 (n = 15) or no atrophy (n = 3). In addition, there were no significant differences in the MHHS of the patients with mild (grades 0-1), moderate (grades 2-3), or severe (grade 4) postoperative atrophy. Postoperative MRAs also demonstrated low-grade atrophy (grades 1-2) in the quadratus femoris (n = 5) and rectus femoris (n = 1) muscles, and 16 patients (57%) had distortion of the tendon, but none had a gap in their tendon. CONCLUSION: A majority of patients (89%) developed IP muscle atrophy after arthroscopic labral-level IP tenotomies, and although this percentage was similar (89% vs 90%) to that reported with lesser trochanteric IP tenotomies, the patients did not (1) develop atrophy of the gluteus maximus and vastus lateralis muscles, (2) have chronic IP tendon disruption, or (3) develop the severity of IP atrophy (55% grade 4 vs 7% grade 4) that has been reported after arthroscopic lesser trochanteric IP tenotomies. PMID- 28596972 TI - Targets of Neutrophil Influx and Weaponry: Therapeutic Opportunities for Chronic Obstructive Airway Disease. AB - Neutrophils are important effector cells of antimicrobial immunity in an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), there is excessive infiltration and activation of neutrophils, subsequent production of reactive oxygen species, and release of serine proteases, matrix metalloproteinases, and myeloperoxidase resulting in collateral damage as the cells infiltrate into the tissue. Increased neutrophil survival through dysregulated apoptosis facilitates continued release of neutrophil-derived mediators to perpetuate airway inflammation and tissue injury. Several target mechanisms have been investigated to address pathologic neutrophil biology and thereby provide a novel therapy for respiratory disease. These include neutrophil influx through inhibition of chemokine receptors CXCR2, CXCR1, and PI3Kgamma signaling and neutrophil weaponry by protease inhibitors, targeting matrix metalloproteinases and neutrophil serine proteases. In addition, neutrophil function can be modulated using selective PI3Kdelta inhibitors. This review highlights the latest advances in targeting neutrophils and their function, discusses the opportunities and risks of neutrophil inhibition, and explores how we might better develop future strategies to regulate neutrophil influx and function for respiratory diseases in dire need of novel effective therapies. PMID- 28596975 TI - Patient Satisfaction After Biceps Tenotomy. AB - BACKGROUND: Biceps tenotomy and tenodesis are frequently performed for proximal biceps lesions; however, there continues to be debate as to which method is superior. This study examined patient-reported outcomes after biceps tenotomy. HYPOTHESIS: Biceps tenotomy in the setting of concomitant shoulder pathology is a reasonable option with high satisfaction rates and a low incidence of pain and cramping in middle-aged to older individuals. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 104 patients (mean age, 63.5 years; range, 40-81 years) were evaluated at the time of surgery and at a mean follow-up of 38.4 months (range, 22-57 months). Biceps tenotomy was performed as a component of more extensive shoulder surgery in all patients. Patient satisfaction, frequency of cramping and spasms, biceps pain, weakness, and cosmetic deformity were evaluated at over 1-year follow-up. RESULTS: Ninety-one percent of patients were satisfied or very satisfied with their surgical outcome, and 95% would have their surgery again. Three patients who reported being unsatisfied or very unsatisfied had either advanced glenohumeral arthritis or an irreparable rotator cuff tear. Cosmetic deformity occurred in 13% of patients. Twenty percent reported spasms and cramping in their biceps, and 19% reported some biceps pain; however, frequency of spasms and cramping was typically once weekly, and biceps pain was reported as severe or very severe in only 2 patients. Subjective biceps weakness was reported in 17% of patients. Age had no effect on outcome measures, and female sex was associated with less limitation and greater satisfaction after tenotomy compared with men. CONCLUSION: Our results indicate that patient reported downsides to biceps tenotomy were usually mild and/or infrequent and did not affect patient satisfaction. We conclude that biceps tenotomy is a viable option that can lead to a high rate of patient satisfaction and outcomes in middle-aged to older individuals undergoing shoulder surgery with biceps pathology. PMID- 28596976 TI - Endogenous Brain Repair: Overriding intrinsic lineage determinates through injury induced micro-environmental signals. AB - Adult human neurogenesis has generated excitement over the last 2 decades with the idea that endogenous adult stem cells could act as a potential cell source for brain repair after injury. Indeed, many forms of experimentally induced brain injury including stroke and excitotoxic lesioning can promote proliferation from the subventricular zone and mobilise neuroblasts and oligodendrocyte progenitor cells to migrate through brain parenchyma to damaged regions. However the failure of neuroblasts to mature into appropriate neuronal subtypes for cell replacement has been an issue. Recent work by our group and others has indicated that micro environmental signals released from areas of cell loss may be able to override intrinsic gene expression lineages and covert neuroblasts into oligodendrocyte progenitor cells. This commentary will discuss the enhanced fate plasticity of both adult neural progenitors and parenchymal NG2 cells after injury, and the importance of understanding brain-injury induced micro-environmental signals in the quest toward promoting endogenous regeneration after injury. PMID- 28596977 TI - Different forms of structural plasticity in the adult olfactory bulb. AB - The adult olfactory bulb (OB) continuously receives new interneurons that integrate into the functional neuronal network and that play an important role in odor information processing and olfactory behavior. Adult neuronal progenitors are derived from neural stem cells in the subventricular zone (SVZ) bordering the lateral ventricle. They migrate long distances along the rostral migratory stream (RMS) toward the OB where they differentiate into interneurons, mature, and establish synapses with tufted or mitral cells (MC), the principal neurons in the OB. The plasticity provided by both adult-born and pre-existing early-born neurons depends on the formation and pruning of new synaptic contacts that adapt the functioning of the bulbar network to changing environmental conditions. However, the formation of new synapses occurs over a long time scale (hours days), whereas some changes in environmental conditions can occur more rapidly, requiring a much faster adjustment of neuronal networks. A new form of structural remodeling of adult-born, but not early-born, neurons was recently brought to light. This plasticity, which is based on the activity-dependent relocation of mature spines of GCs toward the dendrites of active principal cells, may allow a more rapid adjustment of the neuronal network in response to quick and persistent changes in sensory inputs. In this mini-review we discuss the different forms of structural plasticity displayed by adult-born and early-born neurons and the possibility that these different forms of structural remodeling may fulfill distinct roles in odor information processing. PMID- 28596978 TI - Multiple roles of Ulk4 in neurogenesis and brain function. AB - Neurogenesis is essential for proper brain formation and function, and abnormal neural proliferation is an underlying neuropathology of many brain disorders. Recent advances on adult neurogenesis demonstrate that neural stem cells (NSCs) at the subventricular zone (SVZ) are largely derived during mid-embryonic neurogenesis from a subset of cells, which slow down in their pace of cell division,1 become quiescent cells and can be reactivated in need.2 The NSCs at birth constitute the stem cell pool for both postnatal oligodendrogenesis3 and adult neurogenesis.1,2 However, little is known about factors that control the size of NSC pool. The article published in Stem Cells on Jun 14, 2016 by Liu and colleagues described a member of the Unc-51-like serine/threonine kinase family, Ulk4, which plays a critical role in regulating the NSC pool size.4 Authors presented evidence of cell cycle-dependent Ulk4 expression in vitro and in vivo, and reduced NSC pool in targetedly disrupted Ulk4 newborn mice, with disturbed pathways of cell cycle regulation and WNT signaling (Fig. 1), suggesting that ULK4 may be associated with neurodevelopmental, neuropsychiatric as well as neurodegenerative diseases. PMID- 28596980 TI - Prediabetes: The Variation between HbA1c and Fasting Plasma Glucose. AB - PURPOSE: The prevalence of Diabetes Type 2 is on the rise internationally. Currently, Fasting Plasma Glucose (FPG) and HbA1c are both used to determine if an individual is diabetic or prediabetic. We aimed to describe the prevalence of diabetes, prediabetes, and glycemic control in a population-based sample of elderly Hispanic and non-Hispanic White participants in New Mexico. METHODS: To do this, we compared HbA1c with FPG using Chi-Square analysis across gender and ethnicity to provide information for future health care policy. We also performed non-parametric regression using a locally weighted smoothing technique to investigate the relationship between FPG and HbA1c levels. RESULTS: Our analysis identifies a large variation between the sensitivity of HbA1c and FPG in the identification of both prediabetes and diabetes. Interestingly, 95% of diabetics defined by FPG are also defined by HbA1c, representing overlap between the two measures. When comparing the prevalence of prediabetes between the two measures, the overlap of FPG with HbA1c was only 30% and HbA1c identifies more individuals as prediabetic than FPG. Prevalence of diabetes was also higher when defined by HbA1c compared to FPG and the overall agreement between HbA1c and FPG appears to be poor particularly by sex and ethnicity (K=0.22-0.34). Glycemic control was poor overall with Hispanics displaying a larger amount of uncontrolled diabetes. CONCLUSION: We compared HbA1c and FPG by gender and ethnicity and showed both measures of diabetes differ in their sensitivity across ethnic groups. Our results suggest that using HbA1c, rather than FPG, results in higher rates of prediabetes and diabetes, a finding with numerous implications for health care practice. PMID- 28596979 TI - The expanding role of the Ehmt2/G9a complex in neurodevelopment. AB - Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue- and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment. PMID- 28596981 TI - Differentiating Nonoccupational Postexposure Prophylaxis Seroconverters and Non Seroconverters in a Community-Based Clinic in Los Angeles, California. AB - BACKGROUND: Nonoccupational postexposure prophylaxis (nPEP) is a 28-day regimen of antiretroviral medications taken within 72 hours of human immunodeficiency virus (HIV) exposure to prevent HIV acquisition. Although nPEP has been recommended since 1998, few studies have analyzed the characteristics that distinguish nPEP failures (seroconverters) and successes (non-seroconverters). METHODS: This retrospective study analyzed all nPEP courses prompted by sexual exposure that were prescribed at the Los Angeles LGBT Center between March 2010 and July 2014. Fisher exact tests and logistic regressions were used to determine characteristics that distinguished nPEP seroconverters from non-seroconverters. RESULTS: Of the nPEP courses administered, 1744 had a follow-up visit for HIV testing within 24 weeks of exposure and 17 individuals seroconverted. Seven reported a known re-exposure, 8 self-reported only condom-protected sex subsequent to the initial exposure, and 2 reported abstinence since the exposure. In multivariable analyses, seroconverters were more likely than non seroconverters to report methamphetamine use, incomplete medication adherence, and nPEP initiation later in the 72-hour window. CONCLUSIONS: Nonoccupational postexposure prophylaxis is an important emergency tool for HIV prevention. Our findings corroborate that timing of the initial nPEP dose is an important predictor of seroconversion. Although the current study did not offer the initial nPEP dose at the beginning of the visit, use of this fast-track dosing schedule will ensure that the first dose is taken as early as possible postexposure and may lower the likelihood for seroconversion. Furthermore, we recommend systematic screening for substance use because these individuals may be well suited for pre exposure prophylaxis given their sustained risk. PMID- 28596982 TI - Evidence of the Effectiveness of Primary Brachial Plexus Surgery in Infants With Obstetric Brachial Plexus Palsy-Revisited. AB - A recent systematic review questioned the effectiveness of primary surgery in infants with obstetric brachial plexus palsy. At our center, the indication for primary surgery in infants with upper Erb's obstetric palsy is the lack of active elbow flexion at age 4 months. The current study compares the outcome of motor recovery in 2 groups of infants with upper Erb's palsy: one group (n = 9) treated surgically between age 4 and 5 months, and another group (n = 9) treated conservatively despite the lack of active elbow flexion at age 4 months. The only reason for not doing the surgery in the latter group was refusal by the parents. The scores of motor recovery were collected at the 2-year follow-up visit, and they were significantly better in the surgical group. The study demonstrates the effectiveness of primary surgery in infants with upper Erb's obstetric palsy compared to conservative management. PMID- 28596983 TI - Prospective randomized comparison of a 22G core needle using standard versus capillary suction for EUS-guided sampling of solid pancreatic masses. AB - BACKGROUND AND STUDY AIMS: The optimal technique for sampling pancreatic lesions with a 22 G Procore needle (pc) is unknown. The aims of this study were to evaluate the 22 Gpc using standard suction technique (SST) and capillary suction technique (CST) and compare diagnostic adequacy of 22 Gpc with the standard 25 G needle. PATIENTS AND METHODS: Sixty consecutive patients referred for EUS-FNA of a solid pancreatic mass were prospectively evaluated. All patients underwent 2 passes with a standard 25 G needle for cytologic analysis. The first group of 30 patients underwent a single pass with the 22 Gpc needle using SST for cytology and histology. The second group underwent a single pass with the 22 Gpc needle using CST. The sequence of passes was randomized. The diagnostic adequacy of each pass was graded by 2 cytopathologists blinded to technique and needle type for comparison. RESULTS: For a cytologic diagnosis with 22 Gpc, an adequate sample was obtained in 82.8 % SST vs. 80.0 % CST ( P = 0.79). For a histologic diagnosis with 22 Gpc, an adequate sample was obtained in 70.4 % SST vs. 69.0 % CST ( P = 0.91). A single pass with 22 Gpc provided comparable results to a single pass with the 25 G needle for a cytologic diagnosis; both were superior to a single 22 Gpc pass for a histologic diagnosis. Two passes with the 25 G needle provided a diagnostic specimen in 95.0 % vs 81.4 % with one pass using 22 Gpc ( P = 0.01). CONCLUSIONS: No significant difference in diagnostic adequacy was observed between techniques for the 22 Gpc. Two passes with a 25 G needle performed better than 1 pass with 22 Gpc. (NCT01598194). PMID- 28596984 TI - Use of a novel shorter minimum caliber needle for creating endoscopic tattoos for preoperative localization: a comparative ex vivo study. AB - BACKGROUND AND STUDY AIMS : In colorectal cancer surgery, inadvertent deep injections during endoscopic tattooing can cause India ink leakage into the peritoneum, leading to complications or to poor visualization of the surgical plane. This ex vivo animal study compared the use of novel shorter, minimum caliber needles versus conventional injection needles for endoscopic tattooing. ANIMALS AND METHODS : Four endoscopists used the novel needles and conventional needles to make ten endoscopic tattoos (five tattoos/needle type/endoscopist) in harvested porcine rectum using a saline test-injection method. India ink leakage and the success of the tattoo (i. e. visible, < 40 mm, plus no India ink leakage) were compared. RESULTS : India ink leakage was observed for 30 % (6/20) of the conventional needle tattoos but for none of the novel needle tattoos ( P = 0.02). Tattoos created using the novel needles were more successful than those made with the conventional needles: 18/20 (90 %) vs. 11/20 (55 %); P = 0.01. CONCLUSIONS : The use of novel shorter minimum caliber needles may be safe and effective for endoscopic tattooing for preoperative localization prior to colorectal cancer surgery. PMID- 28596985 TI - Linked color imaging improves the visibility of colorectal polyps: a video study. AB - BACKGROUND/STUDY AIM: Linked color imaging (LCI) by a laser endoscope (Fujifilm Co, Tokyo, Japan) is a novel narrow band light observation. In this study, we aimed to investigate whether LCI could improve the visibility of colorectal polyps using endoscopic videos. PATIENTS AND METHODS: We prospectively recorded videos of consecutive polyps 2 - 20 mm in size diagnosed as neoplastic polyps. Three videos, white light (WL), blue laser imaging (BLI)-bright, and LCI, were recorded for each polyp by one expert. After excluding inappropriate videos, all videos were evaluated in random order by two experts and two non-experts according to a published polyp visibility score from four (excellent visibility) to one (poor visibility). Additionally, the relationship between polyp visibility scores in LCI and various clinical characteristics including location, size, histology, morphology, and preparation were analyzed compared to WL and BLI bright. RESULTS: We analyzed 101 colorectal polyps (94 neoplastic) in 66 patients (303 videos). The mean polyp size was 9.0 +/- 8.1 mm and 54 polyps were non-polypoid. The mean polyp visibility scores for LCI (2.86 +/- 1.08) were significantly higher than for WL and BLI-bright (2.53 +/- 1.15, P < 0.001; 2.73 +/- 1.47, P < 0.041). The ratio of poor visibility (score 1 and 2) was significantly lower in LCI for experts and non-experts (35.6 %, 33.6 %) compared with WL (49.6 %, P = 0.015, 50.5 %, P = 0.046). The polyp visibility scores for LCI were significantly higher than those for WL for all of the factors. With respect to the comparison between BLI-bright and WL, the polyp visibility scores for BLI-bright were not higher than WL for right-sided location, < 10 mm size, sessile serrated adenoma and polyp histology, and poor preparation. For those characteristics, LCI improved the lesions with right-sided location, SSA/P histology, and poor preparation significantly better than BLI. CONCLUSIONS: LCI improved polyp visibility compared to WL for both expert and non-expert endoscopists. It is useful for improving polyp visibility in any location, any size, any morphology, any histology, and any preparation level. PMID- 28596986 TI - International core curriculum for capsule endoscopy training courses. AB - Capsule endoscopy (CE) has become a first-line noninvasive tool for visualisation of the small bowel (SB) and is being increasingly used for investigation of the colon. The European Society of Gastrointestinal Endoscopy (ESGE) guidelines have specified requirements for the clinical applications of CE. However, there are no standardized recommendations yet for CE training courses in Europe. The following suggestions in this curriculum are based on the experience of European CE training courses directors. It is suggested that 12 hours be dedicated for either a small bowel capsule endoscopy (SBCE) or a colon capsule endoscopy (CCE) course with 4 hours for an introductory CCE course delivered in conjunction with SBCE courses. SBCE courses should include state-of-the-art lectures on indications, contraindications, complications, patient management and hardware and software use. Procedural issues require approximately 2 hours. For CCE courses 2.5 hours for theoretical lessons and 3.5 hours for procedural issued are considered appropriate. Hands-on training on reading and interpretation of CE cases using a personal computer (PC) for 1 or 2 delegates is recommended for both SBCE and CCE courses. A total of 6 hours hands-on session- time should be allocated. Cases in a SBCE course should cover SB bleeding, inflammatory bowel diseases (IBD), tumors and variants of normal and cases with various types of polyps covered in CCE courses. Standardization of the description of findings and generation of high quality reports should be essential parts of the training. Courses should be followed by an assessment of trainees' skills in order to certify readers' competency. PMID- 28596987 TI - Biodegradable Polyphosphazene-Based Blends for Regenerative Engineering. AB - : The occurrence of musculoskeletal tissue injury or disease and the subsequent functional impairment is at an alarming rate. It continues to be one of the most challenging problems in the human health care. Regenerative engineering offers a promising transdisciplinary strategy for tissues regeneration based on the convergence of tissue engineering, advanced materials science, stem cell science, developmental biology and clinical translation. Biomaterials are emerging as extracellular-mimicking matrices designed to provide instructive cues to control cell behavior and ultimately, be applied as therapies to regenerate damaged tissues. Biodegradable polymers constitute an attractive class of biomaterials for the development of scaffolds due to their flexibility in chemistry and the ability to be excreted or resorbed by the body. Herein, the focus will be on biodegradable polyphosphazene-based blend systems. The synthetic flexibility of polyphosphazene, combined with the unique inorganic backbone, has provided a springboard for more research and subsequent development of numerous novel materials that are capable of forming miscible blends with poly (lactide-co glycolide) (PLAGA). Laurencin and co-workers has demonstrated the exploitation of the synthetic flexibility of Polyphosphazene that will allow the design of novel polymers, which can form miscible blends with PLAGA for biomedical applications. These novel blends, due to their well-tuned biodegradability, and mechanical and biological properties coupled with the buffering capacity of the degradation products, constitute ideal materials for regeneration of various musculoskeletal tissues. LAY SUMMARY: Regenerative engineering aims to regenerate complex tissues to address the clinical challenge of organ damage. Tissue engineering has largely focused on the restoration and repair of individual tissues and organs, but over the past 25 years, scientific, engineering, and medical advances have led to the introduction of this new approach which involves the regeneration of complex tissues and biological systems such as a knee or a whole limb. While a number of excellent advanced biomaterials have been developed, the choice of biomaterials, however, has increased over the past years to include polymers that can be designed with a range of mechanical properties, degradation rates, and chemical functionality. The polyphosphazenes are one good example. Their chemical versatility and hydrogen bonding capability encourages blending with other biologically relevant polymers. The further development of Polyphosphazene-based blends will present a wide spectrum of advanced biomaterials that can be used as scaffolds for regenerative engineering and as well as other biomedical applications. PMID- 28596988 TI - NAFLD Susceptibility Genes and their Association with Type 2 Diabetes and Obesity in a New Mexico Population. AB - OBJECTIVE: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that increase the risk of developing non-alcoholic fatty liver disease (NAFLD). One purpose of this study was to determine the frequencies of NAFLD susceptibility SNPs in a non-Hispanic white and Hispanic population who attended a clinic in northeast Albuquerque, NM. Another goal was to determine associations with selected indicators in this New Mexican population. METHODS: This cohort study involving 168 volunteer subjects in the NM population (88 non Hispanic whites, 63 Hispanics, 4 Native Americans, 11 Asian Americans, 2 unreported ethnicity). Eight SNPs within 6 NAFLD susceptibility genes including PNPLA3 (rs738409), LYPLAL1 (rs12137855), APOC3 (rs2854116, rs2854117), GCKR (rs780094, rs741038), FABP2 (rs1799883), PEMT (rs7946) were analyzed by genotyping using the TaqMan genotyping assay (Applied Biosystems, Foster City, CA). Statistical analyses were carried out using statistical package SAS 9.3. RESULTS: The NAFLD allele frequencies were similar in non-Hispanic whites and Hispanics except for PNPLA3 (rs738409), FABP2 (rs1799883), and PEMT (rs7946). Eight SNPs in 5 NAFLD susceptibility genes were significantly associated OR marginally associated with selected indicators for NAFLD, metabolic syndrome, overweight, obesity, insulin resistance, type 2 diabetes, hypertension, dyslipidemia. No SNPs were significantly associated with the same indicator in both the non-Hispanic white and Hispanic groups. CONCLUSIONS: In this population of non-Hispanic whites and Hispanics, there were only heterozygotes for the APOC3 derived alle le whereas for all other genes tested, both heterozygotes and homozygotes were found. Associations of alleles with indicators of chronic disease were different in non-Hispanic whites compared to Hispanics. PMID- 28596989 TI - Both RAD5-dependent and independent pathways are involved in DNA damage associated sister chromatid exchange in budding yeast. AB - Sister chromatids are preferred substrates for recombinational repair after cells are exposed to DNA damage. While some agents directly cause double-strand breaks (DSBs), others form DNA base adducts which stall or impede the DNA replication fork. We asked which types of DNA damage can stimulate SCE in budding yeast mutants defective in template switch mechanisms and whether PCNA polyubiquitination functions are required for DNA damage-associated SCE after exposure to potent recombinagens. We measured spontaneous and DNA damage associated unequal sister chromatid exchange (uSCE) in yeast strains containing two fragments of his3 after exposure to MMS, 4-NQO, UV, X rays, and HO endonuclease-induced DSBs. We determined whether other genes in the pathway for template switching, including UBC13, MMS2, SGS1, and SRS2 were required for DNA damage-associated SCE. RAD5 was required for DNA damage-associated SCE after exposure to UV, MMS, and 4-NQO, but not for spontaneous, X-ray-associated, or HO endonuclease-induced SCE. While UBC13, MMS2, and SGS1 were required for MMS and 4NQO-associated SCE, they were not required for UV-associated SCE. DNA damage associated recombination between his3 recombination substrates on non-homologous recombination was enhanced in rad5 mutants. These results demonstrate that DNA damaging agents that cause DSBs stimulate SCE by RAD5-independent mechanisms, while several potent agents that generate bulky DNA adducts stimulate SCE by multiple RAD5-dependent mechanisms. We suggest that DSB-associated recombination that occurs in G2 is RAD5-independent. PMID- 28596990 TI - Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain. AB - The mechanisms underlying the rapidly reversible brain swelling described in patients with cerebral malaria (CM) are unknown. Using a 1.5-Tesla (T) magnetic resonance imaging (MRI) scanner, we undertook an observational study in Rourkela, India, of 11 Indian patients hospitalized with CM and increased brain volume. Among the 11 cases, there were 5 adults and 6 children. All patients had reduced consciousness and various degrees of cortical swelling at baseline. The latter was predominately posterior in distribution. The findings on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were consistent with vasogenic edema in all cases. Reversibility after 48 to 72 h was observed in >90% of cases. DWI/ADC mismatch suggested the additional presence of cytotoxic edema in the basal nuclei of 5 patients; all of these had perfusion parameters consistent with vascular engorgement and not with ischemic infarcts. Our results suggest that an impairment of the blood-brain barrier is responsible for the brain swelling in CM. In 5 cases, vasogenic edema occurred in conjunction with changes in the basal nuclei consistent with venous congestion, likely to be caused by the sequestration of Plasmodium falciparum-infected erythrocytes. While both mechanisms have been individually postulated to play an important role in the development of CM, this is the first demonstration of their concurrent involvement in different parts of the brain. The clinical and radiological characteristics observed in the majority of our patients are consistent with posterior reversible encephalopathy syndrome (PRES), and we show for the first time a high frequency of PRES in the context of CM. IMPORTANCE The pathophysiology and molecular mechanisms underlying cerebral malaria (CM) are still poorly understood. Recent neuroimaging studies demonstrated that brain swelling is a common feature in CM and a major contributor to death in pediatric patients. Consequently, determining the precise mechanisms responsible for this swelling could open new adjunct therapeutic avenues in CM patients. Using an MRI scanner with a higher resolution than the ones used in previous reports, we identified two distinct origins of brain swelling in both adult and pediatric patients from India, occurring in distinct parts of the brain. Our results support the hypothesis that both endothelial dysfunction and microvascular obstruction by Plasmodium falciparum-infected erythrocytes make independent contributions to the pathogenesis of CM, providing opportunities for novel therapeutic interventions. PMID- 28596992 TI - Lip prints- A study of its uniqueness among students of MediCiti Medical College. AB - BACKGROUND: "Cheiloscopy" is a technique that deals with lip prints. The pattern of fine creases on the lips are unique to the individual. They are similar to finger prints and useful in crime investigation. AIMS AND OBJECTIVES: To study the uniqueness, prevalence, and gender significance of lip print patterns in human subjects. MATERIALS AND METHODS: The study was conducted on 100 randomly selected male and female undergraduate medical students. The lip print of each subject was obtained and its pattern was analyzed according to Suzuki and Tsuchihashi classification. RESULTS: The study showed that Type I lip pattern was the commonest. CONCLUSION: Our study has added to confirmation of the distinctiveness of cheiloscopy, which can be used as an additional tool for identification. Studies on lip prints being very scanty, our findings add significantly to the meager literature on this subject. Further in-depth studies to establish prevalence of patterns in lip prints will certainly help as useful evidence in forensic investigations. PMID- 28596991 TI - Long Persistence of a Streptococcus pneumoniae 23F Clone in a Cystic Fibrosis Patient. AB - Streptococcus pneumoniae isolates of serotype 23F with intermediate penicillin resistance were recovered on seven occasions over a period of 37 months from a cystic fibrosis patient in Berlin. All isolates expressed the same multilocus sequence type (ST), ST10523. The genome sequences of the first and last isolates, D122 and D141, revealed the absence of two phage-related gene clusters compared to the genome of another ST10523 strain, D219, isolated earlier at a different place in Germany. Genomes of all three strains carried the same novel mosaic penicillin-binding protein (PBP) genes, pbp2x, pbp2b, and pbp1a; these genes were distinct from those of other penicillin-resistant S. pneumoniae strains except for pbp1a of a Romanian S. pneumoniae isolate. All PBPs contained mutations that have been associated with the penicillin resistance phenotype. Most interestingly, a mosaic block identical to an internal pbp2x sequence of ST10523 was present in pbp2x of Streptococcus mitis strain B93-4, which was isolated from the same patient. This suggests interspecies gene transfer from S. pneumoniae to S. mitis within the host. Nearly all genes expressing surface proteins, which represent major virulence factors of S. pneumoniae and are typical for this species, were present in the genome of ST10523. One exception was the hyaluronidase gene hlyA, which contained a 12-nucleotide deletion within the promoter region and an internal stop codon. The lack of a functional hyaluronidase might contribute to the ability to persist in the host for an unusually long period of time. IMPORTANCEStreptococcus pneumoniae is a common resident in the human nasopharynx. However, carriage can result in severe diseases due to a unique repertoire of pathogenicity factors that are rare in closely related commensal streptococci. We investigated a penicillin-resistant S. pneumoniae clone of serotype 23F isolated from a cystic fibrosis patient on multiple occasions over an unusually long period of over 3 years that was present without causing disease. Genome comparisons revealed an apparent nonfunctional pneumococcus-specific gene encoding a hyaluronidase, supporting the view that this enzyme adds to the virulence potential of the bacterium. The 23F clone harbored unique mosaic genes encoding penicillin resistance determinants, the product of horizontal gene transfer involving the commensal S. mitis as donor species. Sequences identical to one such mosaic gene were identified in an S. mitis strain from the same patient, suggesting that in this case S. pneumoniae played the role of donor. PMID- 28596993 TI - Segmenting subregions of the human hippocampus on structural magnetic resonance image scans: An illustrated tutorial. AB - BACKGROUND: The hippocampus plays a central role in cognition, and understanding the specific contributions of its subregions will likely be key to explaining its wide-ranging functions. However, delineating substructures within the human hippocampus in vivo from magnetic resonance image scans is fraught with difficulties. To our knowledge, the extant literature contains only brief descriptions of segmentation procedures used to delineate hippocampal subregions in magnetic resonance imaging/functional magnetic resonance imaging studies. METHODS: Consequently, here we provide a clear, step-by-step and fully illustrated guide to segmenting hippocampal subregions along the entire length of the human hippocampus on 3T magnetic resonance images. RESULTS: We give a detailed description of how to segment the hippocampus into the following six subregions: dentate gyrus/Cornu Ammonis 4, CA3/2, CA1, subiculum, pre/parasubiculum and the uncus. Importantly, this in-depth protocol incorporates the most recent cyto- and chemo-architectural evidence and includes a series of comprehensive figures which compare slices of histologically stained tissue with equivalent 3T images. CONCLUSION: As hippocampal subregion segmentation is an evolving field of research, we do not suggest this protocol is definitive or final. Rather, we present a fully explained and expedient method of manual segmentation which remains faithful to our current understanding of human hippocampal neuroanatomy. We hope that this 'tutorial'-style guide, which can be followed by experts and non-experts alike, will be a practical resource for clinical and research scientists with an interest in the human hippocampus. PMID- 28596994 TI - Recurrent Post-Ablation Paroxysmal Atrial Fibrillation Shares Substrates With Persistent Atrial Fibrillation : An 11-Center Study. AB - INTRODUCTION: The role of atrial fibrillation (AF) substrates is unclear in patients with paroxysmal AF (PAF) that recurs after pulmonary vein isolation (PVI). We hypothesized that patients with recurrent post-ablation (redo) PAF despite PVI have electrical substrates marked by rotors and focal sources, and structural substrates that resemble persistent AF more than patients with (de novo) PAF at first ablation. METHODS: In 175 patients at 11 centers, we compared AF substrates in both atria using 64 pole-basket catheters and phase mapping, and indices of anatomical remodeling between patients with de novo or redo PAF and first ablation for persistent AF. RESULTS: Sources were seen in all patients. More patients with de novo PAF (78.0%) had sources near PVs than patients with redo PAF (47.4%, p=0.005) or persistent AF (46.9%, p=0.001). The total number of sources per patient (p=0.444), and number of non-PV sources (p=0.701) were similar between groups, indicating that redo PAF patients had residual non-PV sources after elimination of PV sources by prior PVI. Structurally, left atrial size did not separate de novo from redo PAF (49.5+/-9.5 vs. 49.0+/-7.1mm, p=0.956) but was larger in patients with persistent AF (55.2+/-8.4mm, p=0.001). CONCLUSIONS: Patients with paroxysmal AF despite prior PVI show electrical substrates that resemble persistent AF more closely than patients with paroxysmal AF at first ablation. Notably, these subgroups of paroxysmal AF are indistinguishable by structural indices. These data motivate studies of trigger versus substrate mechanisms for patients with recurrent paroxysmal AF after PVI. PMID- 28596995 TI - Cardiac Myosin Binding Protein-C Autoantibodies are Potential Early Indicators of Cardiac Dysfunction and Patient Outcome in Acute Coronary Syndrome. AB - The degradation and release of cardiac myosin binding protein-C (cMyBP-C) upon cardiac damage may stimulate an inflammatory response and autoantibody (AAb) production. We determined whether the presence of cMyBP-C-AAbs associated with adverse cardiac function in CVD patients. Importantly, cMyBP-C-AAbs were significantly detected in ACS patient sera upon arrival to the emergency department, particularly in STEMI patients. Patients positive for cMyBP-C-AAbs had a reduced LVEF and elevated levels of clinical biomarkers of MI. We conclude that cMyBP-C-AAbs may serve as early predictive indicators of deteriorating cardiac function and patient outcome in ACS patients prior to the infarction. PMID- 28596996 TI - Global variation in gene expression and the value of diverse sampling. AB - The genomics era has accelerated our understanding of how genetic and epigenetic factors influence both normal variable traits and disease risk in humans. However, the majority of "omics" studies have focused on individuals living in urban centers, primarily from Europe and Asia, neglecting much of the genetic and environmental variation that exists across worldwide populations. Comparative studies of gene regulation in ethnically diverse populations are informing our understanding of how evolutionary forces have shaped the genetic and molecular mechanisms underlying complex traits, and studying gene expression in different environmental contexts is enabling the dissection of disease-related pathways such as immune response. Such approaches are vital to the equitable application of genomics and medicine. PMID- 28596997 TI - The Charles Schepens Lecture: Management Options for Vitreomacular Traction: Use an Individualized Approach. AB - PURPOSE: To present the management options for vitreomacular traction (VMT) and to recommend an individualized approach to treatment selection. DESIGN: Presented at the American Academy of Ophthalmology Annual Meeting, 2016, Chicago, October 15, 2016 (The Charles Schepens Lecture). PARTICIPANTS: None. METHODS: Review of published literature and clinical trials. MAIN OUTCOME MEASURES: Visual and anatomic outcomes of various treatment options for VMT were reviewed. RESULTS: The management options for VMT include pars plana vitrectomy, pneumatic vitreolysis, enzymatic vitreolysis, and observation. The surgical management using pars plana vitrectomy offers the most effective approach for VMT, but there are inherent risks and cost issues. Pneumatic vitreolysis is reported to be cost effective and may be an anatomically successful nonsurgical option for management. Enzymatic vitreolysis with intravitreal ocriplasmin is another nonsurgical option, but both short- and long-term side effects may occur. Observation in selected patients can be associated with stable visual outcomes during long-term follow-up. CONCLUSIONS: The final management decision should be individualized for specific patients depending on the patient's clinical findings, potential risks, probable benefits, and costs of each option. PMID- 28596998 TI - Perpendicular magnetic anisotropy of two-dimensional Rashba ferromagnets. AB - We compute the magnetocrystalline anisotropy energy within two-dimensional Rashba models. For a ferromagnetic free-electron Rashba model, the magnetic anisotropy is exactly zero regardless of the strength of the Rashba coupling, unless only the lowest band is occupied. For this latter case, the model predicts in-plane anisotropy. For a more realistic Rashba model with finite band width, the magnetic anisotropy evolves from in-plane to perpendicular and back to in-plane as bands are progressively filled. This evolution agrees with first-principles calculations on the interfacial anisotropy, suggesting that the Rashba model captures energetics leading to anisotropy originating from the interface provided that the model takes account of the finite Brillouin zone. The results show that the electron density modulation by doping or an external voltage is more important for voltage-controlled magnetic anisotropy than the modulation of the Rashba parameter. PMID- 28596999 TI - Opportunities and Challenges in Realizing Universal Access to Obstetric Ultrasound in Sub-Saharan Africa. AB - The potential benefits of obstetric ultrasound have yet to be fully realized in sub-Saharan Africa (SSA), despite the region bearing the greatest burden of poor perinatal outcomes. We reviewed the literature for challenges and opportunities of universal access to obstetric ultrasound and explored what is needed to make such access an integral component of maternity care in order to address the massive burden of perinatal morbidity and mortality in SSA. Original peer reviewed literature was searched in various electronic databases using a 'realist' approach. While the available data were inconclusive, they identify many opportunities for potential future research on the subject within the region that can help build a strong case to justify the provision of universal access to ultrasound as an integral component of comprehensive antenatal care. PMID- 28597001 TI - Calcified Liver Metastases from a Neuroendocrine Tumor of the Lung (Atypical Carcinoid) - A Case Report. AB - Pulmonary neuroendocrine tumors (NETs) are rare tumors with an incidence rate of 0.2-2/100 000 population/year in Western countries (M. E. Caplin et al. Ann Oncol 2015; 26:1604-20). They account for 1-2% of all neoplasms of the lung and constitute one-fourth to one-third of all NETs. Atypical carcinoids are far less common than typical carcinoids and predominantly occur in male smokers aged 50 70 years. Most pulmonary NETs are asymptomatic due to their peripheral location. Surgical resection is the treatment of choice. Medical management should take hormone-related symptoms into account. PMID- 28597000 TI - Intraoperative Ultrasound as a Screening Modality for the Detection of Liver Metastases during Resection of Primary Colorectal Cancer - A Systematic Review. AB - Colorectal cancer (CRC) is one of the most common cancer diseases worldwide. One in 4 patients with CRC will have a disseminated disease at the time of diagnosis and often in the form of synchronous liver metastases. Studies suggest that up to 30% of patients have non-recognized hepatic metastases during primary surgery for CRC. Intraoperative ultrasonography examination (IOUS) of the liver to detect liver metastases was considered the gold standard during open CRC surgery. Today laparoscopic surgery is the standard procedure, but laparoscopic ultrasound examination (LUS) is not performed routinely. Aim To perform a systematic review of the test performance of IOUS and LUS regarding the detection of synchronous liver metastases in patients undergoing surgery for primary CRC. Method The literature was systematically reviewed using the search engines: PubMed, Cochrane, Embase and Google. 21 studies were included in the review and the key words: intraoperative ultrasound, laparoscopic ultrasound, staging colon and rectum cancer. Results Intraoperative ultrasound showed a higher sensitivity, specificity, positive predictive value and overall accuracy for the detection liver metastases during surgery for primary CRC, compared to preoperative imaging modalities (ultrasound, computed tomography (CT) and contrast-enhanced computed tomography (CE-CT)). LUS showed a higher detection rate for liver metastases compared to CT, CE-CT and magnetic resonance imaging (MRI). Conclusion This systematic review found that both IOUS and LUS had a higher detection rate regarding liver metastases during primary CRC surgery, especially liver metastases<10 mm in diameter, when compared to US, CT, CE-CT and MRI. PMID- 28597002 TI - Littre Hernia: A Rare Case of an Incarcerated Meckel's Diverticulum. AB - A Meckel's diverticulum is a remnant of the vitelline duct, which leads to the formation of a true diverticulum containing all layers of the small intestine. The diverticulum can contain ectopic gastric, duodenal or pancreatic tissue and is the most common congenital anomaly of the gastrointestinal tract with estimates of prevalence ranging from 0.3% to 3%. The condition is usually clinically silent. In children the most common complication is gastrointestinal bleeding caused by ulceration due to the acid secretion by ectopic gastric mucosa. PMID- 28597003 TI - Endothelin: Ominous Player in Breast Cancer. PMID- 28597005 TI - Acid Etching with Modified Phosphoric Acid to Increase the Longevity of the Bonded Interface. AB - PURPOSE: To evaluate the effect of three phosphoric acids modified with chlorhexidine (CHX), benzalkonium chloride (BAC), or proanthocyanidins (PRO) and one conventional phosphoric acid (CON) on the immediate (24 h; IM) and 1-year composite-dentin microtensile bond strength (MUTBS) and nanoleakage (NL), using an etch-and-rinse adhesive. MATERIALS AND METHODS: A flat dentin surface was exposed on 28 caries-free extracted molars, which were then randomly assigned to four groups (n = 7). After etching and rinsing with one phosphoric acid per group, the adhesive (Adper Single Bond 2) was applied on a moist dentin surface. Composite buildups (Filtek Z350) were constructed incrementally and bonded stick specimens (0.8 mm2) were prepared and submitted to the microtensile test (0.5 mm/min) immediately (24 h) or after 1 year of water storage. For nanoleakage, 2 bonded sticks from each tooth at each storage period were immersed in 50 wt% ammoniacal silver nitrate, polished, and analyzed by SEM in backscattered mode. Data were submitted to a two-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: After 1 year, stable MUTBS values were observed only for the modified phosphoric acids (CHX, BAC, and PRO). Also, NL was more evident in the CON group than in the CHX, BAC and PRO groups (p < 0.05) after 1-year water storage. CONCLUSIONS: Compared to the control, the phosphoric acid etchants which contained protease inhibitors (CHX, BAC and PA) promoted the stability of composite-dentin microtensile bond strength and showed less nanoleakage after 1 year of water storage. They represent an effective way of prolonging the stability of the composite-dentin bonds without creating an additional bonding step. PMID- 28597004 TI - Increased Binding of Apolipoproteins A-I and E4 to Triglyceride-Rich Lipoproteins is linked to Induction of Hypertriglyceridemia. AB - Hypertriglyceridemia (HTG) is an independent factor of atherosclerotic cardiovascular disease and a hallmark of many metabolic disorders. However, the molecular etiology of HTG is still largely unknown. In mice, severe HTG may be induced by expression of specific mutants of apolipoprotein (apo) A-I or wild type (WT) apoE4. Expression of a certain apoE4 mutant results in mild HTG, while expression of another apoE4 mutant or WT apoA-I results in normal plasma triglyceride (TG) levels. Biophysical studies of the apoA-I and apoE4 forms associated with HTG help better understand the molecular mechanisms of induction of HTG by these proteins. The studies show that the apoA-I and apoE4 forms that induce HTG have a destabilized and more loosely folded conformation in solution than their counterparts not associated with HTG. Disruption of the protein salt bridge networks by the mutations is likely responsible for the observed structural changes. Each apoA-I and apoE4 form that induced HTG show enhanced binding to model TG-rich particles. HTG appeared to positively correlate with the apolipoprotein ability to bind to TG-rich particles. This implies that in vivo, the conformational changes in the apolipoproteins that induce HTG facilitate their binding to plasma TG-rich lipoproteins. We discuss metabolic pathways leading to the development of HTG that may result from enhanced binding of the apolipoproteins to TG-rich lipoproteins in circulation. While various factors may be involved in the development of HTG in humans, it is possible that structural alterations that increase affinity of apolipoproteins to TG-rich lipoproteins may contribute to some cases of this disorder. PMID- 28597006 TI - Effect of Final Irrigation Protocol and Etching Mode on Bond Strength of a Multimode Adhesive in the Root Canal. AB - PURPOSE: To analyze the effects of ethanol for final post space irrigation and etching mode on the bond strength of fiber posts luted with a mild multimode adhesive (pH 2.3) as compared with a reference group using a self-adhesive resin cement (SAR). MATERIALS AND METHODS: Human anterior teeth were endodontically treated. After post space preparation, the root canals were irrigated using 1% sodium hypochlorite (NaOCl) applied with passive ultrasonic irrigation, followed by either distilled water (control) or distilled water and ethanol 99% as final post space irrigation. Fiber posts were luted using Futurabond U in self-etch mode (FU-SE), Futurabond U in etch-and-rinse mode (FU-ER), or Futurabond DC (SE) in combination with a dual-curing core buildup material (Grandio Core, all VOCO); alternatively, posts were inserted using a self-adhesive composite cement (RelyX Unicem 2, 3M ESPE). Bond strengths were evaluated using push-out tests following thermocycling (TC) and storage in 0.9% NaCl for 3 months. RESULTS: Mean push-out bond strengths (MPa) were significantly affected by the luting system (p < 0.0005) but not by the irrigation protocol (p = 0.068; ANOVA), although a significant interaction between the factors "luting agent" and "pre-treatment" was observed. FU E&R (21.28 [4.34]) and RX (20.12 [7.32]) revealed significantly higher bond strengths compared to FU SE (15.9 [6.02]), whereas F DC (18.8 [6.9]) did not differ significantly from all other groups. Ethanol pre-treatment increased bond strength in the apical part of the root canal for all materials, with the exception of FU E&R. CONCLUSION: Mild multimode adhesives exhibit comparable mean bond strengths to a SAR cement within the root canal for luting fiber posts if applied in an etch-and-rinse mode. Using this approach, ethanol application has no positive effects on bond strength. PMID- 28597007 TI - Tensile Bond Strength of So-called Universal Primers and Universal Multimode Adhesives to Zirconia and Lithium Disilicate Ceramics. AB - PURPOSE: To test the bond strength and durability after artificial aging of so called universal primers and universal multimode adhesives to lithium disilicate or zirconia ceramics. MATERIALS AND METHODS: A total of 240 ceramic plates, divided into two groups, were produced and conditioned: 120 acid-etched lithium disilicate plates (IPS e.max CAD) and 120 air-abraded zirconia plates (Zenostar T). Each group was divided into five subgroups (n = 24), and a universal restorative primer or multimode universal adhesive was used for each subgroup to bond plexiglas tubes filled with a composite resin to the ceramic plate. The specimens were stored in water at 37 degrees C for 3 days without thermal cycling, or for 30 or 150 days with 7500 or 37,500 thermal cycles between 5 degrees C and 55 degrees C, respectively. All specimens then underwent tensile bond strength testing. RESULTS: Initially, all bonding systems exhibited high TBS, but some showed a significant reduction after 30 and 150 days of storage. After 3, 30, and 150 days, Monobond Plus, which contains silane and phosphate monomer, showed significantly higher bond strengths than the other universal primer and adhesive systems. CONCLUSIONS: The bond strength to lithium disilicate and zirconia ceramic is significantly affected by the bonding system used. Using a separate primer containg silane and phosphate monomer provides more durable bonding than do silanes incorporated in universal multimode adhesives. Only one of five so-called universal primers and adhesives provided durable bonding to lithium disilicate and zirconia ceramic. PMID- 28597008 TI - Effect of Reduced Phosphoric Acid Pre-etching Times ?on Enamel Surface Characteristics and Shear Fatigue Strength Using Universal Adhesives. AB - PURPOSE: To examine the effect of reduced phosphoric acid pre-etching times on enamel fatigue bond strength of universal adhesives and surface characteristics by using atomic force microscopy (AFM). MATERIALS AND METHODS: Three universal adhesives were used in this study (Clearfil Universal Bond [C], G-Premio Bond [GP], Scotchbond Universal Adhesive [SU]). Four pre-etching groups were employed: enamel pre-etched with phosphoric acid and immediately rinsed with an air-water spray, and enamel pre-etched with phosphoric acid for 5, 10, or 15 s. Ground enamel was used as the control group. For the initial bond strength test, 15 specimens per etching group for each adhesive were used. For the shear fatigue test, 20 specimens per etching group for each adhesive were loaded using a sine wave at a frequency of 20 Hz for 50,000 cycles or until failure occurred. Initial shear bond strengths and fatigue shear strengths of composite adhesively bonded to ground and pre-etched enamel were determined. AFM observations of ground and pre-etched enamel were also conducted, and surface roughness as well as surface area were evaluated. RESULTS: The initial shear bond strengths and fatigue shear strengths of the universal adhesives in the pre-etched groups were significantly higher than those of the control group, and were not influenced by the pre etching time. Significantly higher surface roughness and surface area of enamel surfaces in pre-etched groups were observed compared with those in the control group. While the surface area was not significantly influenced by etching time, surface roughness of the enamel surfaces in the pre-etched groups significantly increased with pre-etching time. CONCLUSIONS: The results of this in vitro study suggest that reduced phosphoric acid pre-etching times do not impair the fatigue bond strength of universal adhesives. Although fatigue bond strength and surface area were not influenced by phosphoric-acid etching times, surface roughness increased with increasing etching time. PMID- 28597009 TI - Dimethyl Sulfoxide Wet-bonding Technique May Improve the Quality of Dentin Bonding. AB - PURPOSE: To investigate the effect of the dimethyl-sulfoxide wet-bonding technique on composite-dentin bonds and to explore its potential mechanism. MATERIALS AND METHODS: Thirty human third molars were segmented, ground, etched, and randomly divided into three groups according to the following pretreatments: 1. water; 2. ethanol; 3. 50% (v/v) dimethyl sulfoxide (DMSO). Then, Single Bond 2 was applied and composite buildups were constructed. After 24 h of water storage or 10,000 cycles of thermocycling, the microtensile bond strength (MTBS) and nanoleakage were measured. Contact angle measurement, Masson's trichrome staining, and in situ zymography were used to explore the possible action mechanism of DMSO on adhesive-dentin interfaces. RESULTS: DMSO pretreatment prevented the decline of thermocycled MTBS (p < 0.05) without affecting the immediate MTBS (p > 0.05) compared to the water wet-bonded group. Nanoleakage expression in the thermocycled DMSO wet-bonded group was also less than that in the thermocycled water-wet group (p < 0.05). Moreover, DMSO decreased the contact angle of the dentin surfaces (p < 0.05), reduced the amount of collagen exposure (p < 0.05), and decreased the collagenolytic activity in the hybrid layer (p < 0.05). CONCLUSION: The 50% DMSO pretreatment was effective in increasing the wettability of the etched dentin surface, promoting the penetration of the adhesive monomer, and enhancing the stability of the dentin collagen at the adhesive- dentin interface. All these changes may lead to higher quality dentin bonds, suggesting that DMSO wet bonding is a viable alternative to improve the durability of dentin bonding. PMID- 28597010 TI - Smartphone-based colorimetric detection via machine learning. AB - We report the application of machine learning to smartphone-based colorimetric detection of pH values. The strip images were used as the training set for Least Squares-Support Vector Machine (LS-SVM) classifier algorithms that were able to successfully classify the distinct pH values. The difference in the obtained image formats was found not to significantly affect the performance of the proposed machine learning approach. Moreover, the influence of the illumination conditions on the perceived color of pH strips was investigated and further experiments were conducted to study the effect of color change on the learning model. Non-integer pH levels are identified as their nearest integer pH values, whereas the test results for integer pH levels using JPEG, RAW and RAW-corrected image formats captured under different lighting conditions lead to perfect classification accuracy, sensitivity and specificity, which proves that colorimetric detection using machine learning based systems is able to adapt to various experimental conditions and is a great candidate for smartphone-based sensing in paper-based colorimetric assays. PMID- 28597011 TI - ChemComm trials double-blind peer review option. PMID- 28597012 TI - A high-performance enzyme entrapment platform facilitated by a cationic polymer for the efficient electrochemical sensing of ethanol. AB - Entrapment is one of the major approaches for enzyme immobilization; however, it suffers a few critical drawbacks including leakage and high mass transfer resistance to substrates. To address these challenges, herein we report on a new facile and effective enzyme entrapment platform using a special cationic polymer, poly(2-(dimethylamino)ethyl methacrylate) (MADQUAT) on a single-wall carbon nanotube and reduced graphene oxide (SWCNT-rGO) nanohybrid thin film. To demonstrate this new approach, alcohol dehydrogenase (ADH) is employed as a model enzyme for the entrapment toward the design of an efficient electrochemical biosensor for the detection of ethanol. MADQUAT possesses strong electrostatic affinity with various negatively charged biomolecules; and our FTIR study has shown that there are no structural changes in the enzyme following the entrapment, with an excellent secondary structure association (r = 0.92). Our electrochemical measurements have shown that the entrapped ADH exhibits high ability to exchange electrons in the presence of the NAD+/NADH cofactor and that the SWCNT-rGO nanohybrid significantly enhances the biocatalytic activity of the immobilized ADH and the electrochemical oxidation of NADH in comparison with either SWCNTs or rGO. The ethanol biosensor developed in this study exhibits a fast response, wide linearity range, high sensitivity (26.27 MUA mM-1 cm-2), remarkable low limit of detection (0.16 MUM), high selectivity and high stability. The optimized biosensor has been further tested with real samples including wine, beer and blood alcohol, showing promising analytical and biomedical applications. PMID- 28597017 TI - Folliculotropic Mycosis Fungoides with Skewed T-cell Receptor CDR3 Motif: Suggestive of Lipid-antigen Selection? AB - Folliculotropic mycosis fungoides (FMF), a variant of mycosis fungoides (MF) with distinct clinical features, is characterized by infiltration of malignant T cells in hair follicles. This raises the hypothesis that antigens in the hair follicle may contribute to the pathogenesis of FMF. T-cell receptor beta gene (TRB) sequences as well as dendritic cell subsets in patients with FMF (n = 21) and control patients with MF (n = 20) were studied to explore this hypothesis. A recurrent usage of the TRB junctional genes TRBJ2-1 and TRBJ2-7 was found in patients with FMF compared with those with MF. These genes contribute to an amino acid motif in the complementarity-determining region 3 (CDR3) of the T-cell receptor. This motif was previously found in T cells stimulated by lipids bound to CD1 on antigen-presenting cells. Additional immunohistochemical analysis revealed abundant CD1c- and CD1a- expressing dendritic cells in FMF. The combined findings support a role for lipid-antigen stimulation in FMF. PMID- 28597018 TI - Robotic devices and brain-machine interfaces for hand rehabilitation post-stroke. AB - OBJECTIVE: To review the state of the art of robotic-aided hand physiotherapy for post-stroke rehabilitation, including the use of brain-machine interfaces. Each patient has a unique clinical history and, in response to personalized treatment needs, research into individualized and at-home treatment options has expanded rapidly in recent years. This has resulted in the development of many devices and design strategies for use in stroke rehabilitation. METHODS: The development progression of robotic-aided hand physiotherapy devices and brain-machine interface systems is outlined, focussing on those with mechanisms and control strategies designed to improve recovery outcomes of the hand post-stroke. A total of 110 commercial and non-commercial hand and wrist devices, spanning the 2 major core designs: end-effector and exoskeleton are reviewed. RESULTS: The growing body of evidence on the efficacy and relevance of incorporating brain-machine interfaces in stroke rehabilitation is summarized. The challenges involved in integrating robotic rehabilitation into the healthcare system are discussed. CONCLUSION: This review provides novel insights into the use of robotics in physiotherapy practice, and may help system designers to develop new devices. PMID- 28597019 TI - A Large Skin-colored Nodule on the Plantar Foot: A Quiz. Melanoma associated with germline BAP1 mutation. PMID- 28597020 TI - Pemphigus Vulgaris Persistently Localized to the Nose with Local and Systemic Response to Topical Steroids. AB - is missing (Short communication). PMID- 28597021 TI - Bortezomib Does Not Prevent the Occurrence of Kaposi's Sarcoma in Patients with Haematological Malignancies: Two Case Reports. AB - is missing (Short communication). PMID- 28597022 TI - Increased Interleukin-19 Expression in Cutaneous T-cell Lymphoma and Atopic Dermatitis. AB - Interleukin-19 (IL-19), a pro-inflammatory cytokine known to stimulate the production of T helper type 2 (Th2) cytokines, is induced by IL-17A and highly expressed in the lesional skin of psoriasis and atopic dermatitis (AD). This aim of this study was to investigate whether IL-19 is involved in cutaneous T-cell lym-phoma (CTCL) and AD. IL-19 levels were significantly higher in the sera of patients with AD and those with advanced-stage CTCL than in normal controls, correlating significantly with clinical disease markers. IL-19 mRNA levels in lesional skin of both diseases were significantly elevated. Immunohistochemical staining revealed that IL-19 was expressed in the epidermis of AD skin and CTCL skin. In vitro, IL-17A and IL-4 increased IL-19 mRNA expression in human keratinocytes. Thus, IL-19 was increased in the sera and skin of AD and CTCL. These results suggest that IL-19 is important for bridging Th17 to Th2 in these diseases. PMID- 28597023 TI - Rare Ingestive Food Allergy to Mushroom Boletus badius. AB - is missing (Short communication). PMID- 28597025 TI - Abscopal Effect of Local Irradiation Treatment for Diffuse Large B-cell Lymphoma. AB - is missing (Short communication). PMID- 28597024 TI - Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice. AB - The mTOR (mechanistic target of rapamycin) inhibitor rapamycin has long been known for its immune suppressive properties, but it has shown limited therapeutic success when given systemically to patients with psoriasis. Recent data have shown that the mTOR pathway is hyperactivated in lesional psoriatic skin, which probably contributes to the disease by interfering with maturation of keratinocytes. This study investigated the effect of topical rapamycin treatment in an imiquimod-induced psoriatic mouse model. The disease was less severe if the mice had received rapamycin treatment. Immunohistological analysis revealed that rapamycin not only prevented the activation of mTOR signalling (P-mTOR and P-S6 levels), but almost normalized the expression of epidermal differentiation markers. In addition, the influx of innate immune cells into the draining lymph nodes was partially reduced by rapamycin treatment. These data emphasize the role of mTOR signalling in the pathogenesis of psoriasis, and support the investigation of topical mTOR inhibition as a novel anti-psoriatic strategy. PMID- 28597026 TI - Primary Cutaneous Aggressive Epidermotropic CD8+ T-cell Lymphoma with Brain Involvement and Mimicking Dermatomyositis. PMID- 28597027 TI - [Low-flow low-gradient aortic valve stenosis : Current evidence]. AB - Many patients with severe aortic stenosis have a "low-flow, low-gradient" aortic stenosis. The management of these patients can be quite difficult, as these patients often show impairment of the left ventricle, which can lead to false measurements of the severity of stenosis and also leads to a higher risk during aortic valve replacement. More diagnostic tools than only standard echocardiography are needed to correctly differentiate true severe aortic stenosis from pseudo severe aortic stenosis. PMID- 28597028 TI - [Aphasia: a neuronal network disorder]. AB - Language processing requires the coordinated interaction of local and distant neural populations within distributed networks of the temporal, frontal and parietal brain regions. Poststroke aphasia is the consequence of both local as well as remote dysfunction within language-specific and domain-general networks. Language recovery, in turn, rests on reorganization processes within these networks. These comprise the resolution of an acute network failure (i. e. diaschisis), the subacute activation of right hemisphere homologous regions and the gradual reintegration of left hemisphere remote and perilesional areas. The application of unifocal noninvasive brain stimulation over these regions provides a means of modulating neural plasticity in order to enhance the reorganization processes underlying language recovery. The lack of knowledge as to the optimal stimulation site, the appropriate stimulation protocol and the proper timing of interventions might explain the only marginal effects of brain stimulation adjunct to speech and language therapy. In addition, individually different contributions of left and right hemisphere regions to recovery due to heterogeneous lesion sites among patients limit the possibility to identify general principles for brain stimulation. The assumption that aphasia is not only the consequence of the focal effect of a brain lesion but arises from remote dysfunctions within associated functional networks ignites the concept for individualized, potentially multifocal therapeutic network modulation. PMID- 28597029 TI - [Shared decision-making in acute psychiatric medicine : Contraindication or a challenge?] AB - BACKGROUND: The concept of shared decision-making (SDM) has existed since the 1990s in multiple fields of somatic medicine but has only been poorly applied in psychiatric clinical routine despite broad acceptance and promising outcomes in clinical studies on its positive effects. MATERIALS AND METHODS: The concept itself and its practicability in mental health are carefully assessed and strategies for its future implementation in psychiatric medicine are presented in this article. Ongoing clinical studies probing some of those strategies are further outlined. RESULTS AND DISCUSSION: On top of the ubiquitous shortage of time in clinical routine, psychiatrists report their concern about patients' limited abilities in sharing decisions and their own fear of potentially harmful decisions resulting from a shared process. Misinterpretation of shared decision making restricting the health care professional to rather an informed choice scenario and their own adhesion to the traditional paternalistic decision-making approach further add to SDM's underutilization. Those hurdles could be overcome by communication skill workshops for all mental health care professionals, including nursing personnels, psychologists, social workers and physicians, as well as the use of decision aids and training courses for patients to motivate and empower them in sharing decisions with the medical staff. By this, the patient-centered treatment approach demanded by guidelines, carers and users could be further facilitated in psychiatric clinical routine. PMID- 28597030 TI - [Genetic risk factors for neuropsychiatric disorders]. PMID- 28597031 TI - The prevalence of incidental findings on computed tomography of the abdomen/pelvis in pediatric trauma patients. AB - PURPOSE: Computed tomography scans of the abdomen/pelvis (CTAP) in the adult population may reveal findings unrelated to the injury, such as a mass; the occurrence of incidental findings in pediatric patients remains unknown. This study aims to determine the percentage of pediatric trauma patients with incidental findings. METHODS: Data regarding consecutive 250 patients who underwent CTAP during their evaluation were retrieved from our level 1 pediatric trauma center trauma registry. Interpretations were reviewed for mention of incidental findings. Records for patients with incidental findings were examined to determine what further evaluation occurred. RESULTS: Nine patients were excluded due to incomplete records. Of the remaining 241 patients, 114 incidental findings were identified among 86 (35.7%) patients. There were 47 clinically significant incidental findings, occurring in 41 (17%) patients. Seven patients (8.1%) had further workup of their findings; Three (3.5%) went on to have an operation (two patients with ureteropelvic junction obstruction and one with high riding testicle). No potential tumors were found in this population. Incidental findings were mentioned in 25.5% of discharge summaries. CONCLUSIONS: Pediatric trauma CTAP reveals incidental findings at a lower rate than in their adult counterparts. Documentation of findings should be improved for optimal care of the injured child. PMID- 28597032 TI - [Leishmaniasis : Diagnosis and therapy]. AB - The delayed appearance of a papule after returning from travelling hints towards the diagnosis cutaneous leishmaniasis. Histologically, a granulomatous inflammatory response is seen, and using Giemsa staining, intracellular parasites can be visualized within histiocytes. Polymer chain reaction (PCR) from the tissue or subsequent cultures not only aids in excluding other differential diagnoses, but also in the identification of the causing Leishmania subspecies. The latter is important for the choice of the optimal therapeutic regimen. PMID- 28597033 TI - Topography of neurovascular structures in relation to round window and how it relates to cochlear implantation. AB - PURPOSE: The purpose of this investigation was to evaluate the distances and angles on basal turn of cochlea in relation to round window at which the jugular bulb, internal carotid artery and facial nerve are at maximal risk and their implications in cochlear implantation (CI). METHODS: Fifty-four cadaveric temporal bones were microdissected to expose the basal turn of cochlea, the carotid canal, the facial canal and the jugular fossa. The points were marked on the basal turn of cochlea, where there was minimum distance of basal turn of cochlea from the roof of the jugular fossa (point a), carotid canal (point b) and facial canal (point c). The distances and angles of these points from the round window were measured. RESULTS: The points a, b and c were at mean (range) distances of 2.8 mm (1.3-4.1 mm), 8.4 mm (6.5-10.4 mm) and 16.4 mm (12.5-20.5 mm) and at mean angles of 30 degrees (15 degrees -45 degrees ), 111 degrees (71 degrees -136 degrees ) and 284 degrees (255 degrees -315 degrees ), respectively, from the round window. CONCLUSIONS: This study highlights that 2.8 +/- 0.5 mm (30 +/- 5.40), 8.4 +/- 1 mm (111 +/- 12.70) and 16.4 +/- 1.7 mm (284 +/- 13.5) from the round window are the high-risk points on the basal turn of the cochlea for the jugular bulb, internal carotid artery and facial nerve, respectively. A wide range found for each parameter indicates that it is mandatory to evaluate these distances in each CI patient on preoperative radiographs to avoid intraoperative injury to these vital structures. PMID- 28597034 TI - Ultrasound visualization of an underestimated structure: the bicipital aponeurosis. AB - PURPOSE: We established a detailed sonographic approach to the bicipital aponeurosis (BA), because different pathologies of this, sometimes underestimated, structure are associated with vascular, neural and muscular lesions; emphasizing its further implementation in routine clinical examinations. METHODS: The BA of 100 volunteers, in sitting position with the elbow lying on a suitable table, was investigated. Patients were aged between 18 and 28 with no history of distal biceps injury. Examination was performed using an 18-6 MHz linear transducer (LA435; system MyLab25 by Esaote, Genoa, Italy) utilizing the highest frequency, scanned in two planes (longitudinal and transverse view). In each proband, scanning was done with and without isometric contraction of the biceps brachii muscle. RESULTS: The BA was characterized by two clearly distinguishable white lines enveloping a hypoechoic band. In all longitudinal images (plane 1), the lacertus fibrosus was clearly seen arising from the biceps muscle belly, the biceps tendon or the myotendinous junction, respectively. In transverse images (plane 2) the BA spanned the brachial artery and the median nerve in all subjects. In almost all probands (97/100), the BA was best distinguishable during isometric contraction of the biceps muscle. CONCLUSION: With the described sonographic approach, it should be feasible to detect alterations and unusual ruptures of the BA. Therefore, we suggest additional BA scanning during clinical examinations of several pathologies, not only for BA augmentation procedures in distal biceps tendon tears. PMID- 28597035 TI - Focus on immunocompromised patients. PMID- 28597037 TI - Erratum to: Population pharmacokinetic modelling of doxorubicin and doxorubicinol in children with cancer: is there a relationship with cardiac troponin profiles? PMID- 28597036 TI - Outpatient Drainmanagement of patients with clinically relevant Postoperative Pancreatic Fistula (POPF). AB - PURPOSE: Postoperative pancreatic fistula (POPF) is a common complication after pancreatic surgery associated with extended hospitalization, increased medical costs, and reduced quality of life. The aim of the present study was to analyze the feasibility of ambulatory drainage and develop an ambulatory management algorithm. METHODS: Patients with POPF grade B or C (according to the ISGPF classification) between Jan. 2005 and Dec. 2014 that required persistent drainage were identified from a prospectively collected database. Postoperative events and clinical outcomes were retrospectively analyzed. RESULTS: A total of 132 out of 887 patients (14.8%) developed a POPF (grade B or C), and 45 (34.1%) were discharged from the hospital with percutaneous drainage. For patients with grade B fistulas, the mean hospital stay was significantly shorter compared to patients with grade C fistulas (mean 27.7 vs. 40 days; p = 0.0285). About 40% of patients with ambulatory drainage developed a complication, but only 28.9% required readmission. Of those, 52.9% did not require specific treatment and 26.3% were treated with a new drain placement. None of the patients developed major complications, and there was no difference in the frequency of complications between the two groups (p = 0.872). The duration of drain persistence was significantly shorter for patients with grade B fistulas than for those with grade C fistulas (52.2 vs. 85.9 days; p = 0.0007). CONCLUSIONS: Ambulatory drainage management is feasible in selected patients. No severe complications occurred during ambulatory drainage management. A management algorithm is recommended as this could possibly reduce medical costs and improve quality of life. PMID- 28597038 TI - The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway. AB - PURPOSE: Evidence indicates that the cardiac glycoside oleandrin exhibits cytotoxic activity against several different types of cancer. However, the specific mechanisms underlying oleandrin-induced anti-tumor effects remain largely unknown. The present study examined the anti-cancer effect and underlying mechanism of oleandrin on human colon cancer cells. METHODS: The cytotoxicity and IC50 of five small molecule compounds (oleandrin, neriifolin, strophanthidin, gitoxigenin, and convallatoxin) in human colon cancer cell line SW480 cells and normal human colon cell line NCM460 cells were determined by cell counting and MTT assays, respectively. Apoptosis was determined by staining cells with annexin V-FITC and propidium iodide, followed by flow cytometry. Intracellular Ca2+ was determined using Fluo-3 AM,glutathione (GSH) levels were measured using a GSH detection kit,and the activity of caspase-3, -9 was measured using a peptide substrate. BAX, pro-caspase-3, -9, cytochrome C and BCL-2 expression were determined by Western blotting. RESULTS: Oleandrin significantly decreased cell viabilities in SW480, HCT116 and RKO cells. The IC50 for SW480 cells was 0.02 uM, whereas for NCM460 cells 0.56 uM. More interestingly, the results of flow cytometry showed that oleandrin potently induced apoptosis in SW480 and RKO cells. Oleandrin downregulated protein expression of pro-caspase-3, -9, but enhanced caspase-3, -9 activities. These effects were accompanied by upregulation of protein expression of cytochrome C and BAX, and downregulation of BCL-2 protein expression in a concentration-dependent manner. Furthermore, oleandrin increased intracellular Ca2+ concentration, but decreased GSH concentration in the cells. CONCLUSIONS: The present results suggest that oleandrin induces apoptosis in human colorectal cancer cells via the mitochondrial pathway. Our findings provide new insight into the mechanism of anti-cancer property of oleandrin. PMID- 28597040 TI - Phase II study of induction gemcitabine and S-1 followed by chemoradiotherapy and systemic chemotherapy using S-1 for locally advanced pancreatic cancer. AB - PURPOSE: S-1 has systemic activity for locally advanced pancreatic cancer (LAPC). Here, the efficacy and safety of induction gemcitabine (GEM) and S-1 (GS) followed by chemoradiotherapy (CRT) and systemic chemotherapy using S-1 for LAPC were assessed. METHODS: The treatment consisted of four cycles of induction GS (S 1 60, 80, or 100 mg/day based on body surface area for 14 days every 3 weeks plus GEM 1000 mg/m2 on days 8 and 15), followed by S-1 (80, 100, or 120 mg/day based on body surface area on days 1-14 and 22-35) and concurrent radiotherapy (50.4 Gy in 28 fractions). Maintenance chemotherapy with S-1 was started 1-4 weeks after CRT until disease progression or unacceptable toxicity was observed. The primary endpoint was 1-year survival. RESULTS: A total of 30 patients with LAPC were enrolled. The median survival and progression-free survival were 21.3 and 12.7 months, respectively. Overall survival rates at 1, 2, 3, and 4 years were 73.3, 36.7, 23.3, and 16.7%, respectively. The median survival of 23 patients who received CRT was 22.9 months, with a 3-year survival rate of 30.4%. The two most common grade 3 or 4 adverse events during induction GS were neutropenia (63.3%) and biliary tract infection (20%). Toxicities during CRT or maintenance chemotherapy were generally mild. CONCLUSIONS: This regimen was feasible and highly active resulting in encouraging survival in patients with LAPC. Further investigations are warranted to elucidate the effectiveness of this treatment strategy in future studies. Clinical trials information: UMIN000006332. PMID- 28597039 TI - Clinical significance of systemic chemotherapy after curative resection of metachronous pulmonary metastases from colorectal cancer. AB - PURPOSE: The use of systemic chemotherapy after resection remains controversial in patients with resectable metachronous pulmonary metastases from colorectal cancer (CRC). This retrospective study compared systemic chemotherapy with observation alone after resection of pulmonary metastases from CRC. METHODS: Between 2001 and 2015, 91 patients with metachronous pulmonary metastases underwent curative surgical resection at five centers. Patients with stage IV at diagnosis were excluded. Overall survival (OS) was defined as the time from pulmonary resection until death. The disease-free interval (DFI) was defined as the time from pulmonary resection until recurrence or death. RESULTS: Among the 91 patients, 63 were in the chemotherapy group, while 28 were in the observation alone group. The characteristics were similar between the two groups, except for the carcinoembryonic antigen level after pulmonary metastases and the use of adjuvant treatment after resection of the primary tumor. With a median follow-up duration of 46 months (11-126), the estimated 5-year DFI and OS rates were 32.8 and 61.4%, respectively. The chemotherapy following pulmonary resection was not significantly associated with the DFI (p = 0.416) and OS (p = 0.119). CONCLUSION: Systemic chemotherapy after pulmonary resection was not found to have a significant effect on survival. PMID- 28597041 TI - Efficacy and safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel for high-risk head and neck cancer patients in Japan. AB - PURPOSE: To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin. PATIENTS AND METHODS: The eligibility criteria required stage III-IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy. RESULTS: Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed. CONCLUSION: Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin intolerant patients. PMID- 28597042 TI - Cisplatin induces expression of drug resistance-related genes through c-jun N terminal kinase pathway in human lung cancer cells. AB - PURPOSE: Change of multidrug resistance-related genes (e.g., lung resistance protein, LRP) and overexpression of anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are responsible for cisplatin resistance. In our study, we investigated the mechanism by which cisplatin induces LRP, Bcl-2, Bcl-xL, XIAP, and Survivin expression in human lung adenocarcinoma A549 cells and human H446 small cell lung cancer cells at mRNA and protein levels. METHODS: In our study, cell proliferation was assessed with CCK-8 assays, and cell apoptosis was assessed with flow cytometric analysis and Annexin-V/PI staining. qPCR was used to complete RNA experiments. Protein expression was assessed with Western blotting. RESULTS: Cisplatin increased Bcl-2, LRP, and Survivin expression, but decreased Bcl-xL and XIAP expression in a dose-dependent manner. Preincubation with JNK specific inhibitor, SP600125, significantly inhibited these genes' expression at mRNA and protein levels, enhanced chemosensitivity of lung cancer cells to cisplatin, and promoted cisplatin-induced apoptosis. CONCLUSION: Our data suggest that the JNK signaling pathway plays an important role in cisplatin resistance. Lung resistance protein (LRP) and anti-apoptotic genes (Bcl-2, Bcl-Xl, XIAP, Survivin) are involved in the process. The results reminded us of a novel therapy target for lung cancer treatment. PMID- 28597043 TI - Prognostic factors in patients with advanced biliary tract cancer treated with first-line gemcitabine plus cisplatin: retrospective analysis of 740 patients. AB - PURPOSE: Biliary tract cancer (BTC) is a heterogeneous group of diseases comprising intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer. Although gemcitabine plus cisplatin (GEMCIS) was established as the standard first-line chemotherapy based on the ABC-02 trial, more data are needed to define the clinical course of BTC and its prognostic factors with the standard GEMCIS treatment. METHODS: Between April 2010 and June 2016, 740 patients with histologically documented cholangiocarcinoma and gallbladder cancer were treated with first-line GEMCIS in Asan Medical Center, Seoul, Korea. RESULTS: In 389 patients with measurable disease (53%), the objective response rate was 13% (n = 50) and there was no significant difference between primary tumor sites (p = 0.45). With a median follow-up duration of 27.3 months (95% CI 24.2-30.5), the median PFS and OS were 5.2 months (95% CI 4.7-5.6) and 10.4 months (95% CI 9.6 11.2), respectively. In multivariate analysis, male gender (female versus male, hazard ratio [HR] 0.83), baseline CA 19-9 level (elevated versus normal, HR 1.31), initially metastatic disease (versus locally advanced disease, HR 1.92), poor performance status (2 versus 0-1, HR 1.45), and measurable disease by RECIST criteria (versus non-measurable, HR 1.40) were significantly associated with a poorer OS (all p < 0.05). CONCLUSIONS: Our retrospective analysis of a large number of patients in a real-world setting found comparable efficacy outcomes to the ABC-02 trial. The prognostic factors identified here may help to predict clinical outcomes and design future clinical trials for advanced BTC. PMID- 28597044 TI - Indocyanine green visualization "during" craniotomy for moyamoya disease. PMID- 28597045 TI - Biocontrol activity of a cold-adapted yeast from Tibet against gray mold in cherry tomato and its action mechanism. AB - Cold-adapted biocontrol yeast was selected from four yeast isolates from Tibet against gray mold of cherry tomato in cold storage. The strain numbered LB2 showed the best biocontrol activity and identified as Cryptococcus laurentii. Competition for nutrient, space, and induced fruit resistance was also its antagonistic mechanism. Compared with C. laurentii from sea-level place, the reason why LB2 had a better biocontrol activity was studied. More trehalose and proline in cell of LB2 made it exhibit a better cellular activity at low temperature, such as higher population dynamics in the wounds of cherry tomato and more biocontrol-related enzyme secretion, chitinase and beta-glucanase. The better oxidative stress tolerance was another characteristic of LB2. Maybe because of the ideal culture condition, there was no obvious difference between these two yeasts in the growth in vitro test at low temperature. Although the same phenomenon existed in the low pH stress test, LB2 still had higher cell concentration under this stress. Comparative transcriptomics method was also applied to analyze the cell activity of LB2 and C. laurentii at different temperatures. The results showed that more active response in the intracellular structure and intracellular metabolic process to cold temperature made LB2 had a better activity. The present study indicated a possibility to select cold-adapted biocontrol yeast from Tibet and also showed its primary action mechanism. PMID- 28597050 TI - Is there a role for sentinel node biopsy in the pre-operative ultrasound positive axilla? AB - Axillary management in breast cancer is becoming increasingly conservative. This approach is based on the identification of low axillary burden on sentinel node biopsy (SNB). The modern practice of routine pre-operative axillary ultrasound has meant that patients are 'fast tracked' to axillary node clearance (ANC) in the presence of a histologically confirmed positive axilla. This practice reduces the number of patients undergoing SNB compared to the original trials, which evaluated the role of SNB, and those assessing safety of omission of ANC in low axillary burden. The risk of depriving patients with low axillary burden the opportunity to avoid ANC as a consequence of pre-operative ultrasound is discussed. PMID- 28597046 TI - Molecular cloning and expression analysis of major intrinsic protein gene in Chlamydomonas sp. ICE-L from Antarctica. AB - Major intrinsic proteins (MIPs) form channels facilitating the passive transport of water and other small polar molecules across membranes. In this study, the complete open reading frame (ORF) of CiMIP1 (GenBank ID KY316061) encoding one kind of MIPs in the Antarctic ice microalga Chlamydomonas sp. ICE-L is successfully cloned using RACE. In addition, the expression patterns of CiMIP1 gene under different conditions of temperature and salinity are determined by qRT PCR. The ORF of CiMIP1 gene encodes 308 amino acids, and the deduced amino acid sequence shows 74% homology with Chlamydomonas reinhardtii CrMIP1 (GenBank number 159471952). Phylogenetic analysis reveals that algal MIPs are divided into seven groups, and it is speculated that CiMIP1 most likely belongs to the MIPD subfamily. In addition, we are surprised to find that a third NPA motif exists at the carboxy terminus of the target protein except for two highly conserved ones. Expression analysis shows that the transcriptional levels of CiMIP1 gene are upregulated under either lower temperature or higher temperature and high salinity. In summary, the results together have provide new insights into the newly discovered gene in green algae and lay the foundation for further studies on the adaptation mechanism of Chlamydomonas sp. ICE-L to abiotic stresses. PMID- 28597051 TI - Effects of Backpacker Use, Pack Stock Trail Use, and Pack Stock Grazing on Water Quality Indicators, Including Nutrients, E. coli, Hormones, and Pharmaceuticals, in Yosemite National Park, USA. AB - We investigated how visitor-use affects water quality in wilderness in Yosemite National Park. During the summers of 2012-2014, we collected and analyzed surface water samples for water-quality indicators, including fecal indicator bacteria Escherichia coli, nutrients (nitrogen, phosphorus, carbon), suspended sediment concentration, pharmaceuticals, and hormones. Samples were collected upstream and downstream from different types of visitor use at weekly to biweekly intervals and during summer storms. We conducted a park-wide synoptic sampling campaign during summer 2014, and sampled upstream and downstream from meadows to evaluate the mitigating effect of meadows on water quality. At pack stock stream crossings, Escherichia coli concentrations were greater downstream from crossings than upstream (median downstream increase in Escherichia coli of three colony forming units 100 mL-1), with the greatest increases occurring during storms (median downstream increase in Escherichia coli of 32 CFU 100 mL-1). At backpacker use sites, hormones, and pharmaceuticals (e.g., insect repellent) were detected at downstream sites, and Escherichia coli concentrations were greater at downstream sites (median downstream increase in Escherichia coli of 1 CFU 100 mL 1). Differences in water quality downstream vs. upstream from meadows grazed by pack stock were not detectable for most water-quality indicators, however, Escherichia coli concentrations decreased downstream, suggesting entrapment and die-off of fecal indicator bacteria in meadows. Our results indicate that under current-use levels pack stock trail use and backpacker use are associated with detectable, but relatively minor, effects on water quality, which are most pronounced during storms. PMID- 28597052 TI - On the Ground or in the Air? A Methodological Experiment on Crop Residue Cover Measurement in Ethiopia. AB - Maintaining permanent coverage of the soil using crop residues is an important and commonly recommended practice in conservation agriculture. Measuring this practice is an essential step in improving knowledge about the adoption and impact of conservation agriculture. Different data collection methods can be implemented to capture the field level crop residue coverage for a given plot, each with its own implication on survey budget, implementation speed and respondent and interviewer burden. In this paper, six alternative methods of crop residue coverage measurement are tested among the same sample of rural households in Ethiopia. The relative accuracy of these methods are compared against a benchmark, the line-transect method. The alternative methods compared against the benchmark include: (i) interviewee (respondent) estimation; (ii) enumerator estimation visiting the field; (iii) interviewee with visual-aid without visiting the field; (iv) enumerator with visual-aid visiting the field; (v) field picture collected with a drone and analyzed with image-processing methods and (vi) satellite picture of the field analyzed with remote sensing methods. Results of the methodological experiment show that survey-based methods tend to underestimate field residue cover. When quantitative data on cover are needed, the best estimates are provided by visual-aid protocols. For categorical analysis (i.e., >30% cover or not), visual-aid protocols and remote sensing methods perform equally well. Among survey-based methods, the strongest correlates of measurement errors are total farm size, field size, distance, and slope. Results deliver a ranking of measurement options that can inform survey practitioners and researchers. PMID- 28597054 TI - [Benign tumours of the musculoskeletal system]. PMID- 28597055 TI - ? PMID- 28597053 TI - Community exposure and vulnerability to water quality and availability: a case study in the mining-affected Pazna Municipality, Lake Poopo Basin, Bolivian Altiplano. AB - Assessing water sources for drinking and irrigation along with community vulnerability, especially in developing and rural regions, is important for reducing risk posed by poor water quality and limited water availability and accessibility. We present a case study of rural mining-agricultural communities in the Lake Poopo Basin, one of the poorest regions on the Bolivian Altiplano. Here, relatively low rainfall, high evaporation, salinization and unregulated mining activity have contributed to environmental degradation and water issues, which is a situation facing many Altiplano communities. Social data from 72 households and chemical water quality data from 27 surface water and groundwater sites obtained between August 2013 and July 2014 were used to develop locally relevant vulnerability assessment methodologies and ratings with respect to water availability and quality, and Chemical Water Quality Hazard Ratings to assess water quality status. Levels of natural and mining-related contamination in many waters (CWQHR >= 6; 78% of assessed sites) mean that effective remediation would be challenging and require substantial investment. Although waters of fair to good chemical quality (CWQHR <= 5; 22% of assessed sites) do exist, treatment may still be required depending on use, and access issues remain problematic. There is a need to comply with water quality legislation, improve and maintain basic water supply and storage infrastructure, build and operate water and wastewater treatment plants, and adequately and safely contain and treat mine waste. This study serves as a framework that could be used elsewhere for assessing and mitigating water contamination and availability affecting vulnerable populations. PMID- 28597056 TI - A space-jump derivation for non-local models of cell-cell adhesion and non-local chemotaxis. AB - Cellular adhesion provides one of the fundamental forms of biological interaction between cells and their surroundings, yet the continuum modelling of cellular adhesion has remained mathematically challenging. In 2006, Armstrong et al. proposed a mathematical model in the form of an integro-partial differential equation. Although successful in applications, a derivation from an underlying stochastic random walk has remained elusive. In this work we develop a framework by which non-local models can be derived from a space-jump process. We show how the notions of motility and a cell polarization vector can be naturally included. With this derivation we are able to include microscopic biological properties into the model. We show that particular choices yield the original Armstrong model, while others lead to more general models, including a doubly non-local adhesion model and non-local chemotaxis models. Finally, we use random walk simulations to confirm that the corresponding continuum model represents the mean field behaviour of the stochastic random walk. PMID- 28597058 TI - [Flexion and extension osteotomy of the knee]. AB - OBJECTIVES: Flexion and extension osteotomy of the knee for symptomatic malalignment in the sagittal plane. INDICATIONS: Congenital/posttraumatic bony deficiencies in flexion/pathologic hyperextension in the knee. Additional treatment for ligament reconstruction. CONTRAINDICATIONS: Absolute: Infection, critical soft tissue situation, circulatory disorders. Relative: Osteoporosis, heavy smoker, obesity, reduced patient compliance. SURGICAL TECHNIQUE: Diagnostic arthroscopy of the knee. If the malposition is located at the proximal tibia, an extending or flexing high tibial osteotomy with correction of the tibial slope is carried out. If the malalignment is referred to the distal femur, the adjustment is performed by a distal femoral osteotomy. POSTOPERATIVE MANAGEMENT: Partial weight bearing with 20 kg for the first 6 postoperative weeks. Due to the tuberositas tibiae osteotomy, it is necessary to restrict the movement of the knee for the first 6 weeks. RESULTS: Between 2015 and 2016, 11 patients (2 female, 9 male) were treated with a flexion or extension osteotomy of the knee. Of these patients, 2 had symptomatic hyperflexion, 7 had restriction of movement with an exaggerated tibial slope, and 2 patients had an extension deficiency according to a malalignment of the distal femur. After surgery, the symptomatic pathologic movement of the knee was improved in every patient. One patient had pseudarthrosis during the healing process, which required a second operation with reosteosynthesis and bony grafting. These results are also reflected in an improvement of the preoperative IKDC score from 52.7 (range 37-82) to 1 year postoperative 75.8 (range 67-84). The Lysholm score increased from preoperative 40.2 (range 15-73) to postoperative 84.3 (range 68-91). PMID- 28597059 TI - [Malignant melanoma of the urinary bladder]. AB - Primary malignant melanoma of the genitourinary tract is a rare lesion. We report the case of a 52-year-old man with primary manifestation of metastatic melanoma in the bladder. Multimodal therapy with transurethral tumor resection and systemic interferon/dacarbazine was not successful and the patient died 18 months later. Currently immune checkpoint inhibitors, CTLA-4 (cytotoxic T lymphocyte antigen-4) and PD-L1 are currently being tested in phase III studies and show long-lasting response in the case of classical melanoma manifestations. PMID- 28597057 TI - An L-Glutamine Transporter Isoform for Neurogenesis Facilitated by L-Theanine. AB - L-Theanine (=gamma-glutamylethylamide) is an amino acid ingredient in green tea with a structural analogy to L-glutamine (L-GLN) rather than L-glutamic acid (L GLU), with regards to the absence of a free carboxylic acid moiety from the gamma carbon position. L-theanine markedly inhibits [3H]L-GLN uptake without affecting [3H]L-GLU uptake in cultured neurons and astroglia. In neural progenitor cells with sustained exposure to L-theanine, upregulation of the L-GLN transporter isoform Slc38a1 expression and promotion of both proliferation and neuronal commitment are seen along with marked acceleration of the phosphorylation of mammalian target of rapamycin (mTOR) and relevant downstream proteins. Stable overexpression of Slc38a1 leads to promotion of cellular growth with facilitated neuronal commitment in pluripotent embryonic carcinoma P19 cells. In P19 cells stably overexpressing Slc38a1, marked phosphorylation is seen with mTOR and downstream proteins in a fashion insensitive to the additional stimulation by L theanine. The green tea amino acid L-theanine could thus elicit pharmacological actions to up-regulate Slc38a1 expression for activation of the mTOR signaling pathway required for cell growth together with accelerated neurogenesis after sustained exposure in undifferentiated neural progenitor cells. In this review, I summarize a novel pharmacological property of the green tea amino acid L-theanine for embryonic and adult neurogenesis with a focus on the endogenous amino acid analog L-GLN. A possible translational strategy is also discussed on the development of dietary supplements and nutraceuticals enriched of L-theanine for the prophylaxis of a variety of untoward impairments and malfunctions seen in patients with different neurodegenerative and/or neuropsychiatric disorders. PMID- 28597060 TI - [Early bilateral nephrectomy in neonatal autosomal recessive polycystic kidney disease : Improved prognosis or unnecessary effort?] AB - BACKGROUND: Neonatal autosomal recessive polycystic kidney disease (ARPKD) is associated with giant kidneys, lung hypoplasia, pulmonal hypertension, and end stage renal failure. Depending on the study, mortality is reported to range between 20 and 80%. OBJECTIVES: Does bilateral nephrectomy improve survival? PATIENTS AND METHODS: Between 2010 and 2016, we treated 7 children with prenatally diagnosed ARPKD. All had a planned delivery by cesarean section. After birth, oscillated ventilation with nitrogen enrichment was initiated to achieve maximum oxygenation and to decrease pumonary hypertension. All children had bilateral massive kidney hyperplasia (length 13-16 cm). RESULTS: Nephrectomy on one side was performed within 72 h together with placement of a peritoneal dialysis catheter in the intensive care unit. Contralateral nephrectomy was performed after 1-2 weeks when the child was stabilized by dialysis. In 2 children, kidney transplantation has already been performed and they are doing fine. One child died after 10 months due to infection. The other children are stable on home peritoneal dialysis awaiting transplantation. CONCLUSIONS: Early bilateral nephrectomy in neonatal ARPKD is feasible, but requires distinctive care at a pediatric intensive care unit and a high amount of organizational efforts to treat these children adequately in the first few days. In our experience, the procedure is a promising approach to improve ventilation and enable dialysis. However, kidney transplantation, best from a living donor, is required within the first years of life. PMID- 28597061 TI - Progressive accumulation of autofluorescent granules in macrophages in rat striatum after systemic 3-nitropropionic acid: a correlative light- and electron microscopic study. AB - A variety of tissue biomolecules and intracellular structures are known to be autofluorescent. However, autofluorescent signals in brain tissues often confound analysis of the fluorescent markers used for immunohistochemistry. While investigating tissue and cellular pathologies induced by 3-nitropropionic acid, a mitochondrial toxin selective for striatal neurons, we encountered many autofluorescent signals confined to the lesion core. These structures were excited by blue (wavelength = 488 nm) and yellow-orange (555 nm), but not by red (639 nm) or violet (405 nm) lasers, indicating that this autofluorescence overlaps with the emission spectra of commonly used fluorophores. Almost all of the autofluorescence was localized in activated microglia/macrophages, while reactive astrocytes emitted no detectable autofluorescence. Amoeboid brain macrophages filled with autofluorescent granules revealed very weak expression of the microglial marker, ionized calcium-binding adaptor molecule 1 (Iba1), while activated microglia with evident processes and intense Iba1 immunoreactivity contained scant autofluorescent granules. In addition, immunolabeling with two lysosomal markers, ED1/CD68 and lysosomal-associated membrane protein 1, showed a pattern complementary with autofluorescent signals in activated microglia/macrophages, implying that the autofluorescent structures reside within cytoplasm free of intact lysosomes. A correlative light- and electron-microscopic approach finally revealed the ultrastructural identity of the fluorescent granules, most of which matched to clusters of lipofuscin-like inclusions with varying morphology. Thus, autofluorescence in the damaged brain may reflect the presence of lipofuscin-laden brain macrophages, which should be taken into account when verifying any fluorescent signals that are likely to be correlated with activated microglia/macrophages after brain insults. PMID- 28597063 TI - Limited Post-observation Period in Pediatric Outpatient Ultrasound-Guided Liver Biopsies. AB - PURPOSE: We retrospectively studied whether a limited 2 h post-biopsy observation period after a percutaneous outpatient ultrasound-guided liver biopsy is a sufficient monitoring period for children. MATERIALS AND METHODS: This study is an IRB-approved retrospective cohort review of consecutive outpatient percutaneous ultrasound-guided liver biopsies from June 01, 2014, to June 30, 2016. A total of 198 biopsies in 192 patients (85 females and 113 males) underwent an outpatient ultrasound-guided liver biopsy between June 01, 2014, and June 30, 2016 (age range 3 weeks-18 years, mean 11.6 years). Outpatient biopsies were performed with a limited patient observation time [median (IQR) observation 2.25 (0.83) h]. RESULTS: Adequate histopathology was obtained in 99% (197/198) of cases. Only one case was determined by a pathologist as not sufficient to render a diagnosis. 84% (166/198) of the biopsies were performed with a 16G needle, and 16% (32/198) were performed with an 18G needle. Overall, seven complications were detected (3.5% of all biopsies, 7/198) in seven patients. All complications detected were minor, 1.5% (3/198) were categorized as SIR A and 2% (4/198) as SIR B. The most common complication included pain after biopsy (4/198), followed by rash at the biopsy site (3/198). No major complications were detected in our sample. CONCLUSION: In a consecutive cohort of children, the use of a limited 2 h observation period after an ultrasound-guided percutaneous biopsy was a sufficient monitoring period for complications. Additionally, we did not observe a high proportion of patients returning for follow-up medical care after discharge due to complications. PMID- 28597064 TI - Magnetic Resonance Signal Intensity Ratio Measurement Before Uterine Artery Embolization: Ability to Predict Fibroid Size Reduction. AB - PURPOSE: To evaluate whether the magnetic resonance imaging (MRI) signal intensity (SI) ratio between the dominant fibroid and the periphery striated muscle can predict fibroid volume reduction >50% after uterine fibroid embolization (UFE). MATERIALS AND METHODS: From October 2013 until May 2016, 52 patients were included in this prospective study. The SI ratio before UFE was calculated using circular region of interests placed on the dominant fibroid and the iliac muscle. The SI fibroid-to-iliac muscle ratio was calculated as SI of the dominant fibroid/SI of the iliac muscle on T1-, T2-, and T1 post-contrast weighted sequences. The dominant fibroid volume was measured and analyzed before and after UFE. RESULTS: In all, 46 patients who completed the three-month follow up MRI were available for analysis. The correlation between SI fibroid-to-muscle ratio at the T2-weighted sequence and imaging volume reduction outcome was statistically significant (p < 0.002). All other parameters showed no statistically significant reduction in fibroid volume: (p < 0.68) for SI ratio at T1-weighted, (p < 0.13) for SI ratio at T1 post-contrast, and (p < 0.58) for fibroid volume. Spearman's rank showed positive correlation (r = 0.439, p < 0.003) between the fibroid-to-muscle SI ratio on T2-weighted sequence. The area under curve (AUC) for SI fibroid-to-muscle ratio on T2-weighted sequence was 0.776. For the other parameters, the AUC values were 0.512, 0.671, and 0.578, respectively. CONCLUSION: SI dominant fibroid-to-muscle ratio at T2-weighted sequence before UFE was significantly related to dominant fibroid volume reduction after UFE and may be used for better patient selection. PMID- 28597062 TI - An anther-specific gene PhGRP is regulated by PhMYC2 and causes male sterility when overexpressed in petunia anthers. AB - KEY MESSAGE: An anther-specific GRP gene, regulated by PhMYC2 , causes a significant reduction of male fertility when overexpressed in petunia, and its promoter is efficient in genetic engineering of male-sterile lines. Glycine-rich proteins (GRPs) play important roles in plant anther development; however, the underlying mechanisms and related regulatory networks are poorly understood. In this study, a novel glycine-rich family gene designated as PhGRP was isolated from Petunia hybrida 'Fantasy Red'. The qRT-PCR analysis showed that it expressed specifically in anthers, and its expression peaked earlier than those well-known tapetum-specific genes, such as TA29, and several genes with the classic cis regulatory element 'anther-box' in petunia during its anther development. The male fertility was significantly reduced in PhGRP overexpression lines, due to the abnormal formation of pollen wall. The PhGRP promoter (pPhGRP) could drive the GUS genes expressing specifically in the anthers of the transgenic Arabidopsis plants, indicating that the anther-specific characteristic of this promoter was conserved. In addition, when pPhGRP was used to drive the expression of BARNASE, complete male-sterile petunia lines were created without changes in vegetative organs and floral parts other than anthers. Finally, when pPhGRP was used as the bait to screen a yeast-one-hybrid (Y1H) library, a transcription factor (PhMYC2) belonging to the bHLH family was successfully selected, and the binding between pPhGRP and PhMYC2 was validated both by Y1H and dual-luciferase reporter assay. Overall, these results suggest that PhGRP, which is a male fertility-related gene that expresses specifically in anthers, is regulated by PhMYC2 and whose promoter can be used as an effective tool in the creation of male-sterile lines. PMID- 28597066 TI - Effects of Fat Grafting Containing Stem Cells in Microstomia and Microcheilia Derived from Systemic Sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease with multisystem involvement, dominated by a general fibrosis. The early stage of the disease is associated with progressive damage to microcirculation, particularly in the respiratory tract, the gastrointestinal tract and skin. The face assumes a typical appearance characterized by microstomia (reduction of mouth opening) and microcheilia (thinning of the lips). These conditions cause a considerable reduction in performance status of patients. We treated them by fat grafting, rich in adipose stem cells, and we evaluated through time clinical, functional and aesthetic evaluation of oral pathology associated with SSc. MATERIALS AND METHOD: From September 2014 to May 2016, we enrolled and treated seven patients in the plastic, reconstructive and aesthetic surgery clinic. Through time, we evaluated the following parameters: evaluation of mouth opening (maximum opening in superior-inferior and lateral directions) and lip thicknesses, both measured by doctors of the aforementioned operating unit; variation in the quality of life as perceived by patients according to the MHISS scale (Mouth Handicap Systemic Sclerosis); variation in severity of labial fibrosis assessed by microscopic analysis of pre- and post-fat transfer samples in the pathology clinic; safety of the protocol, according to the management of side effects resulting from the procedure; aesthetic evaluation, made by external observers and non-experts in the field, on pre- and post-operative photographs. RESULTS AND CONCLUSIONS: We reported satisfying results, both functionally and aesthetically, for all parameters except one, for which the sample size might have proven critical. These data should be a starting point for further experimental research and clinical trials. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 28597067 TI - Old Drugs May Be Good Friends but Always Under Prerequisites. PMID- 28597065 TI - Cellular and molecular pathways of structural damage in rheumatoid arthritis. AB - Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilage. PMID- 28597068 TI - Genetic diversity of human papillomavirus types 35, 45 and 58 in cervical cancer in Brazil. AB - In Brazil, most studies of intra-type variants of human papillomavirus (HPV) have focused on HPV16 and HPV18, but other high-risk HPV types have not been studied. Here, we report the prevalence of lineages and variants of HPV35, HPV45 and HPV58 in cervical cancers from the Amazonian and Southeast Brazilian regions. The most frequent sublineages were A1 for HPV35, B2 for HPV45, and A2 for HPV58. The Southeast region had a higher frequency of the B2 sublineage of HPV45, and for HPV35, the genetic and nucleotide sequence diversity were higher in the Southeast region, suggesting that regional factors are influencing the diversity and lineage prevalence. PMID- 28597069 TI - An updated proposal for classification of infectious salmon anemia virus strains. AB - Biological databases contain a wealth of valuable information that can contribute to the enrichment of virtually any area. However, the exponential growth of information together with its dissemination through virtual networks has become a double-edged sword, promoting synonymy that leads to confusion and chaos. Organization of data is a big effort that must be accompanied by clarity, both in the deposited data and in the publications arising from them. In this report, an effort is made to organize the information related to infectious salmon anemia virus and its classification based on the variability of genomic segment 6. PMID- 28597070 TI - The KISS1 metastasis suppressor appears to reverse the Warburg effect by shifting from glycolysis to mitochondrial beta-oxidation. AB - : The shift by cancer cells toward aerobic glycolysis (Warburg effect) confers selective advantages by utilizing nutrients (e.g., lipids, amino acids, and nucleotides) to build biomass. Lipogenesis is generally enhanced, and its inhibition diminishes proliferation and survival. Re-expression of the metastasis suppressor KISS1 in human melanoma cells results in greater mitochondrial biogenesis, inhibition of glycolysis, utilization of beta-oxidation to provide energy, elevated oxidation of exogenous fatty acids, and increased expression of early-phase lipogenesis genes at both mRNA and protein levels. Correspondingly, the energy sensor AMPKbeta is phosphorylated, resulting in inhibitory phosphorylation of acetyl-CoA carboxylase (ACC), which is linked to enhanced beta oxidation. Furthermore, PGC1alpha is required for KISS1-mediated phosphorylation of ACC and metastasis suppression. Collectively, these data further support the linkages between macromolecular metabolism and metastasis. KEY MESSAGES: * KISS1 alters fatty acid metabolism. * There may be connections between metastasis and metabolism. * PGC1alpha appears to be downstream mediator of KISS1 metastasis suppression. PMID- 28597071 TI - The novel tool of cell reprogramming for applications in molecular medicine. AB - Recent discoveries in the field of stem cell biology have enabled scientists to "reprogram" cells from one type to another. For example, it is now possible to place adult skin or blood cells in a dish and convert them into neurons, liver, or heart cells. It is also possible to literally "rejuvenate" adult cells by reprogramming them into embryonic-like stem cells, which in turn can be differentiated into every tissue and cell type of the human body. Our ability to reprogram cell types has four main implications for medicine: (1) scientists can now take skin or blood cells from patients and convert them to other cells to study disease processes. This disease modeling approach has the advantage over animal models because it is directly based on human patient cells. (2) Reprogramming could also be used as a "clinical trial in a dish" to evaluate the general efficacy and safety of newly developed drugs on human patient cells before they would be tested in animal models or people. (3) In addition, many drugs have deleterious side effects like heart arrhythmias in only a small and unpredictable subpopulation of patients. Reprogramming could facilitate precision medicine by testing the safety of already approved drugs first on reprogrammed patient cells in a personalized manner prior to administration. For example, drugs known to sometimes cause arrhythmias could be first tested on reprogrammed heart cells from individual patients. (4) Finally, reprogramming allows the generation of new tissues that could be grafted therapeutically to regenerate lost or damaged cells. PMID- 28597073 TI - Beta cell heterogeneity: an evolving concept. AB - Beta cells are primarily defined by their ability to produce insulin and secrete it in response to appropriate stimuli. It has been known for some time, however, that beta cells are not functionally identical to each other and that the rates of insulin synthesis and release differ from cell to cell, although the functional significance of this variability remains unclear. Recent studies have used heterogeneous gene expression to isolate and evaluate different subpopulations of beta cells and to demonstrate alterations in these subpopulations in diabetes. In the last few years, novel technologies have emerged that permit the detailed evaluation of the proteome (e.g. time-of-flight mass spectroscopy, [CyTOF]) and transcriptome (e.g. massively parallel RNA sequencing) at the single-cell level, and tools for single beta cell metabolomics and epigenomics are quickly maturing. The first wave of single beta cell proteome and transcriptome studies were published in 2016, giving a glimpse into the power, but also the limitations, of these approaches. Despite this progress, it remains unclear if the observed heterogeneity of beta cells represents stable, distinct beta cell types or, alternatively, highly dynamic beta cell states. Here we provide a concise overview of recent developments in the emerging field of beta cell heterogeneity and the implications for our understanding of beta cell biology and pathology. PMID- 28597074 TI - Early metabolic markers identify potential targets for the prevention of type 2 diabetes. AB - AIMS/HYPOTHESIS: The aims of this study were to evaluate systematically the predictive power of comprehensive metabolomics profiles in predicting the future risk of type 2 diabetes, and to identify a panel of the most predictive metabolic markers. METHODS: We applied an unbiased systems medicine approach to mine metabolite combinations that provide added value in predicting the future incidence of type 2 diabetes beyond known risk factors. We performed mass spectrometry-based targeted, as well as global untargeted, metabolomics, measuring a total of 568 metabolites, in a Finnish cohort of 543 non-diabetic individuals from the Botnia Prospective Study, which included 146 individuals who progressed to type 2 diabetes by the end of a 10 year follow-up period. Multivariate logistic regression was used to assess statistical associations, and regularised least-squares modelling was used to perform machine learning-based risk classification and marker selection. The predictive performance of the machine learning models and marker panels was evaluated using repeated nested cross-validation, and replicated in an independent French cohort of 1044 individuals including 231 participants who progressed to type 2 diabetes during a 9 year follow-up period in the DESIR (Data from an Epidemiological Study on the Insulin Resistance Syndrome) study. RESULTS: Nine metabolites were negatively associated (potentially protective) and 25 were positively associated with progression to type 2 diabetes. Machine learning models based on the entire metabolome predicted progression to type 2 diabetes (area under the receiver operating characteristic curve, AUC = 0.77) significantly better than the reference model based on clinical risk factors alone (AUC = 0.68; DeLong's p = 0.0009). The panel of metabolic markers selected by the machine learning-based feature selection also significantly improved the predictive performance over the reference model (AUC = 0.78; p = 0.00019; integrated discrimination improvement, IDI = 66.7%). This approach identified novel predictive biomarkers, such as alpha tocopherol, bradykinin hydroxyproline, X-12063 and X-13435, which showed added value in predicting progression to type 2 diabetes when combined with known biomarkers such as glucose, mannose and alpha-hydroxybutyrate and routinely used clinical risk factors. CONCLUSIONS/INTERPRETATION: This study provides a panel of novel metabolic markers for future efforts aimed at the prevention of type 2 diabetes. PMID- 28597075 TI - Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study. AB - AIMS/HYPOTHESIS: The aim of this prospective nationwide study was to examine antenatal pregnancy care and pregnancy outcomes in women with type 1 and type 2 diabetes, and to describe changes since 2002/2003. METHODS: This national population-based cohort included 3036 pregnant women with diabetes from 155 maternity clinics in England and Wales who delivered during 2015. The main outcome measures were maternal glycaemic control, preterm delivery (before 37 weeks), infant large for gestational age (LGA), and rates of congenital anomaly, stillbirth and neonatal death. RESULTS: Of 3036 women, 1563 (51%) had type 1, 1386 (46%) had type 2 and 87 (3%) had other types of diabetes. The percentage of women achieving HbA1c < 6.5% (48 mmol/mol) in early pregnancy varied greatly between clinics (median [interquartile range] 14.3% [7.7-22.2] for type 1, 37.0% [27.3-46.2] for type 2). The number of infants born preterm (21.7% vs 39.7%) and LGA (23.9% vs 46.4%) were lower for women with type 2 compared with type 1 diabetes (both p < 0.001). The prevalence rates for congenital anomaly (46.2/1000 births for type 1, 34.6/1000 births for type 2) and neonatal death (8.1/1000 births for type 1, 11.4/1000 births for type 2) were unchanged since 2002/2003. Stillbirth rates are almost 2.5 times lower than in 2002/2003 (10.7 vs 25.8/1000 births for type 1, p = 0.0012; 10.5 vs 29.2/1000 births for type 2, p = 0.0091). CONCLUSIONS/INTERPRETATION: Stillbirth rates among women with type 1 and type 2 diabetes have decreased since 2002/2003. Rates of preterm delivery and LGA infants are lower in women with type 2 compared with type 1 diabetes. In women with type 1 diabetes, suboptimal glucose control and high rates of perinatal morbidity persist with substantial variations between clinics. DATA AVAILABILITY: Further details of the data collection methodology, individual clinic data and the full audit reports for healthcare professionals and service users are available from http://content.digital.nhs.uk/npid . PMID- 28597072 TI - Normal and altered pre-mRNA processing in the DMD gene. AB - Splicing of pre-mRNA is a crucial regulatory stage in the pathway of gene expression controlled by multiple post- and co-transcriptional mechanisms. The large Duchenne muscular dystrophy gene encoding the protein dystrophin provides a striking example of the complexity of human pre-mRNAs. In this review, we summarize the current state of knowledge about canonical and non-canonical splicing in the DMD pre-mRNA, with a focus on mechanisms that take place in the full-length transcript isoform expressed in human skeletal muscle. In particular, we highlight recent work demonstrating that multi-step events are required for long DMD intron removal. The role of temporary intron retention in the occurrence of alternative splicing events is also discussed. Even though the proportion of splicing mutations is lower than reported in other genes, a great diversity of splicing defects linked to point mutations, but also large genomic rearrangements are observed in the DMD gene. We provide an overview of the molecular mechanisms underlying aberrant splicing in patients with Duchenne or Becker muscular dystrophy, and we also detail how alternative splicing can serve as a disease modifier in patients by changing the outcome of the primary defect. PMID- 28597077 TI - Is Rosai-Dorfman disease a reactve process? Detection of a MAP2K1 L115V mutation in a case of Rosai-Dorfman disease. PMID- 28597076 TI - Juxtapapillary and circumpapillary choroidal melanoma: globe-sparing treatment outcomes with iodine-125 notched plaque brachytherapy. AB - PURPOSE: Managing juxtapapillary and circumpapillary choroidal melanoma with brachytherapy is challenging because of technical complications with accurate plaque placement and high radiation toxicity given tumor proximity to the optic nerve. We evaluated our center's experience using ultrasound-guided, Iodine (I) 125 notched plaque brachytherapy for treating choroidal melanoma contiguous with (juxtapapillary) and at least partially surrounding the optic disc (circumpapillary). METHODS: All cases of choroidal melanoma treated with I-125 notched plaque brachytherapy at our center from September 2003-December 2013 were retrospectively reviewed. Only patients with >=18 months of follow-up who had lesions contiguous with the optic disc (0 mm of separation) were included. The tumor apex prescription dose was 85 Gy. Outcomes evaluated included local control, distant metastasis-free survival (DMFS), cancer-specific survival (CSS), overall survival (OS), visual acuity, and radiation toxicity. RESULTS: Thirty four patients were included with a median follow-up of 44.1 months (range 18.2 129.0). AJCC T-category was T1 in 58.8%, T2 in 26.5%, and T3 in 14.7%. Median circumferential optic disc involvement was 50% (range 10%-100%). Eye retention was achieved in 94.1%. Actuarial 2- and 4-year rates of local recurrence were 3.1% and 7.6%, DMFS were 97.0% and 88.5%, CSS were 97.0% and 92.8%, and OS were 97.0% and 88.9%, respectively. In addition, 23.5% had visual acuity >=20/200 at last follow-up. CONCLUSIONS: I-125 notched plaque brachytherapy provides high eye preservation rates with acceptable longer-term post-treatment visual outcomes. Based on our experience, choroidal melanoma directly contiguous with and partially encasing the optic disc may be effectively treated with this technique. PMID- 28597078 TI - Spectrum of genetic mutations in de novo PUNLMP of the urinary bladder. AB - Our group and others have previously demonstrated the presence of TERT promoter mutations (TERT-mut) in 60-80% of urothelial carcinomas and some of their histologic variants. Five other genes have been frequently implicated in bladder cancer: FGRF3, TP53, PIK3CA, HRAS, and CDKN2A. In the current study, we sought to determine the prevalence of mutations in TERT and these five other genes in de novo papillary urothelial neoplasms of low malignant potential (PUNLMP) of the urinary bladder. A retrospective search of our archives for PUNLMP was performed and 30 de novo cases were identified and included in the study. We found mutations in TERT (TERT-mut) and FGFR3 (FGFR3-mut) to be the most common alterations in the cohort (63 and 60%, respectively). The majority of the TERT mut-positive tumors (84%) had a g.1295228C > T alteration with the remaining tumors demonstrating g.1295250C > T. Approximately one fourth of tumors had TP53 mutations. These findings support the potential utility of a uniform genetic mutation panel to detect bladder cancers of various subtypes. PMID- 28597079 TI - MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism. AB - Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR 28 mark the first epigenetic changes observed between sporadic and MEN1 associated PHPT. PMID- 28597080 TI - Intratumoral Fusobacterium nucleatum abundance correlates with macrophage infiltration and CDKN2A methylation in microsatellite-unstable colorectal carcinoma. AB - Fusobacterium nucleatum (Fn), a specific species of gut microbiota, has been suggested to be enriched in the microsatellite instability-high (MSI-H) molecular subtype of colorectal carcinomas (CRCs). However, the clinicopathologic and molecular factors that interact with Fn in MSI-H CRCs are poorly understood. In this study, 16S ribosomal RNA gene DNA sequence of Fn was quantitatively measured by real-time polymerase chain reaction in tumor DNA samples from a total of 160 surgically resected MSI-H CRC tissues. Each case was classified into one of the three categories based on the Fn DNA amount: Fn-high, Fn-low, and Fn-negative. The clinicopathologic and molecular associations of Fn in MSI-H CRCs were statistically analyzed. Among the 160 MSI-H CRC samples, 15 (9%), 92 (58%), and 53 (33%) cases were Fn-high, Fn-low, and Fn-negative, respectively. Compared with Fn-low/negative tumors, Fn-high MSI-H CRCs were significantly associated with a high density of CD68+ tumor-infiltrating macrophages (P = 0.019) and promoter CpG island hypermethylation of the CDKN2A (p16) gene (P = 0.008). There were also tendencies toward associations of Fn-high with the BRAF V600E mutation (P = 0.047) and active Crohn-like lymphoid reactions (P = 0.052) in MSI-H CRCs. However, Fn-high was not significantly associated with CD3+ T cell density, CD163+ M2 macrophage density or PD-L1 expression status. In conclusion, high amounts of intratumoral Fn are correlated with increased macrophage infiltration and CDKN2A promoter methylation in MSI-H CRCs. PMID- 28597081 TI - Effects of bright and blue light on acoustic reaction time and maximum handgrip strength in male athletes: a randomized controlled trial. AB - PURPOSE: To assess which type of evening light exposure has the greatest effect on reaction time and maximum handgrip strength. These were pre-specified secondary outcomes in a trial which primarily investigated the influence of light on cycling performance. METHODS: Seventy-four male athletes were allocated at random to either bright light (BRIGHT), monochromatic blue light (BLUE), or a control condition (CONTROL). Light exposure lasted for 60 min and started 17 h after the individual midpoint of sleep. Reaction time, handgrip strength, and melatonin levels were measured before and after the light exposure. We used analysis of covariance to compare the groups with respect to the investigated outcomes. RESULTS: Two participants had to be excluded retrospectively. The remaining 72 participants had a median age of 23 years. The adjusted difference in reaction time was -1 ms [95% confidence interval (CI) -8, 6] for participants in BRIGHT and 2 ms (95% CI -5, 9) for participants in BLUE, both relative to participants in CONTROL. The adjusted difference in handgrip strength was 0.9 kg (95% CI -1.5, 3.3) for participants in BRIGHT and -0.3 kg (95% CI -2.7, 2.0) for participants in BLUE, both relative to participants in CONTROL. After the light exposure, 17% of participants in BRIGHT, 22% in BLUE, and 29% in CONTROL showed melatonin concentrations of 2 pg/ml or higher. CONCLUSIONS: The results suggest that bright light might reduce melatonin levels but neither bright nor blue light exposure in the evening seem to improve reaction time or handgrip strength in athletes. PMID- 28597082 TI - [Difficulties with children of abnormal weight]. PMID- 28597084 TI - [Current state and perspectives in university pathology]. PMID- 28597083 TI - Anal fistula surgery: what are the patients expecting from the surgeon? PMID- 28597085 TI - ? PMID- 28597086 TI - Influence of a Former Mining Area in the Heavy Metals Concentrations in Blood of Free-Living Mediterranean Pond Turtles (Mauremys leprosa). AB - The objective of this study was to assess metal exposure in the Mediterranean Pond Turtle (Mauremys leprosa) inhabiting a watercourse in an ancient mining district polluted by different metals ("Rambla de Las Moreras", southeastern Spain) and included in the Ramsar Convention. For this purpose, mercury (Hg), lead (Pb), copper (Cu), zinc (Zn) and cadmium (Cd) were analysed in blood samples from 42 M. leprosa healthy adults (27 males and 13 females). The highest median concentrations were found for Zn, followed by Cu, Pb, Hg and Cd (366, 33, 9, 0.83 and 0.14 ug/dL, respectively). Although the literature regarding toxic metals in freshwater turtles is relatively scarce, Pb may cause deleterious effects in our population. In general, males presented higher levels than females, which could be due to maternal transfer during egg formation. The significant correlations between Cu-Cd and Cu-Hg suggest the implication of an efficient mechanism of detoxification involving metallothioneins. PMID- 28597087 TI - Phylogenetic and pathogenic characterization of a pigeon paramyxovirus type 1 isolate reveals cross-species transmission and potential outbreak risks in the northwest region of China. AB - Pigeon paramyxovirus type-1 (PPMV-1) is enzootic in pigeons, causing severe economic loss in the poultry industry in many countries. However, the exact epidemic process of PPMV-1 transmission is still unclear. In this study, we analyzed the complete genome of the PPMV-1/SX-01/15 isolate. Sequence results show that the virus genome contains 15,192 nucleotides, with the gene order 3'-NP P-M-F-HN-L-5'. Phylogenetic analysis revealed that this genome belongs to subgenotype VIc in class II. The mean death time (MDT) and intracerebral pathogenicity index (ICPI) were 62.4 h and 1.13, respectively, indicating that this isolate is a mesogenic PPMV-1 strain. To our knowledge, this is the first report of a subgenotype VIc mesogenic PPMV-1 strain circulating in commercial pigeon flocks in the northwest region of China. In a comparative infection experiment, the morbidity and mortality rates were 100% and 80%, respectively, in 4-week-old pigeons, whereas they were 50% and 30%, respectively, in 5-week-old chickens. Furthermore, this virus caused severe neurological symptoms in a 4-week old pigeon and mild neurological symptoms in a 5-week-old chicken. A histopathological examination of the brain showed a classical nonsuppurative encephalitis lesion. The pattern of viral shedding, and viral load, and virus distribution differed between infected chickens and pigeons. Genomic characteristics suggest that there was cross-species transmission of PPMV-1 subgenotype VIc in this region at least from the years 2006 to 2015. PMID- 28597088 TI - Viral polymerase inhibitors T-705 and T-1105 are potential inhibitors of Zika virus replication. AB - Since 2015, 69 countries and territories have reported evidence of vector-borne Zika virus (ZIKV) transmission. Currently, there are no effective licensed vaccines or drugs available for the treatment or prevention of ZIKV infection. We tested a series of compounds for their ability to inhibit ZIKV replication in cell culture. The compounds in T-705 (favipiravir) and T-1105 were found to have antiviral activity, suggesting that these compounds are promising candidates for further development as specific antiviral drugs against ZIKV. PMID- 28597089 TI - VOSalophen: a vanadium complex with a stilbene derivative-induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis. AB - In our previous work, we demonstrated the promising in vitro effect of VOSalophen, a vanadium complex with a stilbene derivative, against Leishmania amazonensis. Its antileishmanial activity has been associated with oxidative stress in L. amazonensis promastigotes and L. amazonensis-infected macrophages. In the present study, the mechanism involved in the death of parasites after treatment with VOSalophen, as well as in vivo effect in the murine model cutaneous leishmaniasis, has been investigated. Promastigotes of L. amazonensis treated with VOSalophen presented apoptotic cells features, such as cell volume decrease, phosphatidylserine externalization, and DNA fragmentation. An increase in autophagic vacuoles formation in treated promastigotes was also observed, showing that autophagy also may be involved in the death of these parasites. In intracellular amastigotes, DNA fragmentation was observed after treatment with VOSalophen, but this effect was not observed in host cells, highlighting the selective effect of this vanadium complex. In addition, VOSalophen showed activity in the murine model of cutaneous leishmaniasis, without hepatic and renal damages. The outcome described here points out that VOSalophen had promising antileishmanial properties and these data also contribute to the understanding of the mechanisms involved in the death of protozoa induced by metal complexes. PMID- 28597090 TI - Ethnic and Gender Differences in Preferred Activities among Maori and non-Maori of Advanced age in New Zealand. AB - This study explored active aging for older Maori and non-Maori by examining their self-nominated important everyday activities. The project formed part of the first wave of a longitudinal cohort study of aging well in New Zealand. Maori aged 80 to 90 and non-Maori aged 85 were recruited. Of the 937 participants enrolled, 649 answered an open question about their three most important activities. Responses were coded under the World Health Organization's International Classification of Functioning, Disability and Health (ICF), Activities and Participation domains. Data were analyzed by ethnicity and gender for first in importance, and all important activities. Activity preferences for Maori featured gardening, reading, walking, cleaning the home, organized religious activities, sports, extended family relationships, and watching television. Gendered differences were evident with walking and fitness being of primary importance for Maori men, and gardening for Maori women. Somewhat similar, activity preferences for non-Maori featured gardening, reading, and sports. Again, gendered differences showed for non-Maori, with sports being of first importance to men, and reading to women. Factor analysis was used to examine the latent structural fit with the ICF and whether it differed for Maori and non-Maori. For Maori, leisure and household activities, spiritual activities and interpersonal interactions, and communicating with others and doing domestic activities were revealed as underlying structure; compared to self-care, sleep and singing, leisure and work, and domestic activities and learning for non Maori. These findings reveal fundamental ethnic divergences in preferences for active aging with implications for enabling participation, support provision and community design. PMID- 28597091 TI - Prognosis After Sublobar Resection of Small-sized Non-small Cell Lung Cancer with Visceral Pleural or Lymphovascular Invasion. AB - BACKGROUND: Although standard surgical treatment of stage I non-small cell lung cancer (NSCLC) is lobectomy, sublobar resection may be elected for small-sized (<=2 cm) peripheral tumors. Our aim was examine the need for completion lobectomy in the event of confirmed pleural or lymphovascular invasion after sublobar resection of NSCLC. METHODS: A total of 271 consecutive patients undergoing curative resection of stage I NSCLC <=2 cm were reviewed retrospectively, analyzing clinicopathologic findings and survival times of those with invasion positive (visceral pleural or lymphovascular invasion) or invasion-negative (neither visceral pleural nor lymphovascular invasion) tumors by surgical approach (sublobar resection vs lobectomy). RESULTS: Aside from age and pulmonary function, clinicopathologic characteristics of the patient subsets did not differ significantly, nor did 5-year recurrence-free survival rates of surgical subsets (sublobar resection vs lobectomy) in respective tumor groups (invasion-positive 78.9 vs 79.8%, p = 0.928; invasion-negative 80.2 vs 85.4%, p = 0.505). In multivariate analysis, dissected lymph node count was the sole parameter significantly impacting recurrence of stage I invasion-positive NSCLC (hazard ratio = 0.914, 95% confidence interval 0.845-0.988; p = 0.023). Sublobar resection was not a risk factor for recurrence. CONCLUSIONS: Survival rates for patients with small-sized (<=2 cm) NSCLC and visceral pleural or lymphovascular invasion did not differ significantly, whether sublobar resection or lobectomy was done. Hence, completion lobectomy is unnecessary in this setting. PMID- 28597094 TI - [Autopsy in oncology : Treatment validation in cancer centers and clinical cancer registries]. AB - The legal recognition of autopsy as a tool of quality assurance will strengthen its importance especially in the care of cancer patients. However, this confidence is relativized by the consideration of the assessment of the autopsy in various effective nonlegislative regulations. This consideration shows that in contrast to earlier years autopsy does not play a major role in the most important programs for the certification of cancer centers or for clinical cancer registration. If clinical autopsy is to play a more important role in the future, then in addition to improving and standardizing its quality the implementation into these systems of quality management is indispensable. PMID- 28597092 TI - Factors associated with changes in health-related quality of life in children with cystic fibrosis during 1-year follow-up. AB - : There are limited data on health-related quality of life (HRQoL) changes over time in children with cystic fibrosis (CF). We investigated associations between clinical and treatment variables with changes in HRQoL during 1 year. Forty-nine children with CF aged 6-18 years were followed in this multicentre, observational cohort study during 1 year. HRQoL was measured by the validated disease specific cystic fibrosis questionnaire-revised (CFQ-R). The CFQ-R total score as well as most domain scores improved significantly (8.0 points and [3.3-31.7] points respectively) during the one-year follow-up. Age at baseline demonstrated a strong longitudinal association with the change of CFQ-R total score (2.853 points decrease of CFQ-R total score per year increase in age) and several domain scores. Below 12 years of age, CFQ-R total score improved in most children, whereas a deterioration was observed in most children above 12 years. The number of PEx was associated with an increase of treatment burden score (4.466 points decrease per extra PEx). CONCLUSION: In the group as a whole, HRQoL improved significantly over time. However, changes over time were significantly influenced by age: below 12 years of age, HRQoL improved in most patients whereas a deterioration was observed in most children >12 years. Strategies how to preserve or ideally to improve HRQoL in adolescence should be developed. What is known: * Quality of life in patient with CF is diminished * Although CF is a chronic disease, longitudinal data on QoL in children with CF are scarce. What is new: * Below 12 years of age, quality of life improved in most children during the 1 year follow-up whereas a deterioration in quality of life was observed in most children above 12 years. * the treatment burden score of QoL correlated with the exacerbation rate. PMID- 28597093 TI - [Pediatric salivary gland tumors and tumor-like lesions]. AB - Salivary gland tumors and tumor-like lesions in the pediatric population are uncommon. They comprise a heterogeneous group of infectious/inflammatory and neoplastic conditions. Pediatric salivary neoplasms include benign tumors of mesenchymal or epithelial origin as well as malignancies of epithelial (carcinomas), mesenchymal (sarcoma) or hematolymphoid (lymphoma) derivation. Infectious/inflammatory conditions and hematolymphoid malignancies may represent either genuine parenchymal pathology or conditions involving intraglandular lymph nodes of the parotid glands (intraglandular lymphadenopathy and intraglandular nodal lymphomas). Pediatric sialadenitis may be of diverse etiologies including viral (mumps, CMV, HIV, etc.), bacterial, autoimmune (juvenile Sjogren syndrome) or idiopathic (chronic recurrent juvenile sialectatic sialadenitis). Angiomatous lesions (juvenile capillary hemangioma, lymphangioma and vascular malformation) and pleomorphic adenomas represent the most common pediatric benign mesenchymal and benign epithelial tumors, respectively. The vast majority of salivary gland carcinomas in children and adolescents represent low-grade mucoepidermoid carcinomas followed by acinic cell and adenoid cystic carcinomas (together >80% of carcinomas). Other malignant neoplasms include (rhabdomyo-) sarcomas, malignant lymphomas and very rarely sialoblastomas. This long differential diagnosis list of etiologically and biologically highly heterogeneous entities, their shared clinical presentation as "salivary gland enlargement" and the significant differences in their therapeutic strategies and prognosis underline the need for careful assessment to identify the correct diagnosis. Diagnosis is mainly based on a set of typical clinical and imaging features, serological/microbiological findings and, in selected cases, histomorphological characteristics in biopsy specimens. PMID- 28597095 TI - Natural and anthropic effects on hydrochemistry and major and trace elements in the water mass of a Spanish Pyrenean glacial lake set. AB - This study presents the key hydrochemical characteristics and concentration levels of major (Ca, Mg, Na, Si, K, Sr, Fe) and trace (Ba, Sc, Cr, Mn, Al, As, Li, Co, Cu, U, Pb, Hg, Au, Sn, Zn, Cd, Ag, Ni) elements in the water mass of four selected Pyrenean cirque glacial lakes (Sabocos, Banos, Truchas and Escalar tarns) with different catchment features, between 2010 and 2013. Resulting data set is statistically analyzed to discriminate between the natural or anthropic origin of the elements. Analyses indicate that in all cases, the main source of most major and trace elements is geological weathering, being thus individual bedrock composition the main driver of differences between lakes. Several anthropogenic sources of airborne Cu, Sc, Co, and Cr must be also considered. The shallowness of the lake is also a factor that may influence element cycling and concentration levels in its water mass. Concentrations of anthropogenic elements were low, comparable to those reported in other glacial lakes, way below the WHO, US EPA, EC, and Spanish legal limits for drinking water quality, indicating the absence of serious pollution. Toxic heavy metals Cd, Pb, Hg, and Zn were not detected in any of the tarns. PMID- 28597096 TI - A social choice-based methodology for treated wastewater reuse in urban and suburban areas. AB - Reusing treated wastewater for supplying water demands such as landscape and agricultural irrigation in urban and suburban areas has become a major water supply approach especially in regions struggling with water shortage. Due to limited available treated wastewater to satisfy all water demands, conflicts may arise in allocating treated wastewater to water users. Since there is usually more than one decision maker and more than one criterion to measure the impact of each water allocation scenario, effective tools are needed to combine individual preferences to reach a collective decision. In this paper, a new social choice (SC) method, which can consider some indifference thresholds for decision makers, is proposed for evaluating and ranking treated wastewater and urban runoff allocation scenarios to water users in urban and suburban areas. Some SC methods, namely plurality voting, Borda count, pairwise comparisons, Hare system, dictatorship, and approval voting, are applied for comparing and evaluating the results. Different scenarios are proposed for allocating treated wastewater and urban runoff to landscape irrigation, agricultural lands as well as artificial recharge of aquifer in the Tehran metropolitan Area, Iran. The main stakeholders rank the proposed scenarios based on their utilities using two different approaches. The proposed method suggests ranking of the scenarios based on the stakeholders' utilities and considering the scores they assigned to each scenario. Comparing the results of the proposed method with those of six different SC methods shows that the obtained ranks are mostly in compliance with the social welfare. PMID- 28597097 TI - Does trade openness affect CO2 emissions: evidence from ten newly industrialized countries? AB - This paper examines whether the hypothetical environmental Kuznet curve (EKC) exists or not and investigates how trade openness affects CO2 emissions, together with real GDP and total primary energy consumption. The study sample comprises ten newly industrialized countries (NICs-10) from 1971 to 2013. The results support the existence of hypothetical EKC and indicate that trade openness negatively and significantly affects emissions, while real GDP and energy do positive effects of emissions. Moreover, the empirical results of short-run causalities indicate feedback hypothetical linkage of real GDP and trade, unidirectional linkages from energy to emissions, and from trade to energy. The error correction terms (ECTs) reveal in the long run, feedback linkages of emissions, real GDP, and trade openness, while energy Granger causes emissions, real GDP, and trade, respectively. The study recommendations are that our policymakers should encourage and expand the trade openness in these countries, not only to restrain CO2 emissions but also to boost their growth. PMID- 28597099 TI - Commentary on: Men and women show similar survival rates after breast cancer. PMID- 28597098 TI - Maximized complexity in miniaturized brains: morphology and distribution of octopaminergic, dopaminergic and serotonergic neurons in the parasitic wasp, Trichogramma evanescens. AB - The parasitic wasp, Trichogramma evanescens, is an extremely small insect, with a body length as small as 0.3 mm. To facilitate this miniaturization, their brains may have evolved to contain smaller neural components and/or reduced neural complexity than larger insects. Here, we study whether the size and number of neurons are reduced in the miniaturized brain of T. evanescens, focusing on neurons that express serotonin (5HT), octopamine (OA) and dopamine (DA). We provide the first description of the distribution, projection patterns and number of 5HT-, OA- and DA-like immunoreactive cell bodies in T. evanescens and compare our observations with descriptions of much larger insects. The brains of T. evanescens contain comparable numbers of monoaminergic neurons to those of larger insects. Serotonergic neurons appear to be especially conserved; most of the clusters contain a similar number of neurons to those described in Apis mellifera and Drosophila melanogaster. This maintained complexity may have been facilitated by miniaturization of neuron size. However, many dopaminergic and some octopaminergic neuron clusters in T. evanescens contain fewer neurons than in larger insects. Modification of the complexity of these monoaminergic systems may have been necessary to maintain neuron functionality during brain miniaturization in T. evanescens. Our results reveal some of the evolutionary adaptations that may enable behavioural and cognitive complexity with respect to miniaturized brains. PMID- 28597101 TI - Erratum to: GABA content within medial prefrontal cortex predicts the variability of fronto-limbic effective connectivity. PMID- 28597100 TI - Sucrose-induced plasticity in the basolateral amygdala in a 'comfort' feeding paradigm. AB - A history of intermittent, limited sucrose intake (LSI) attenuates the hypothalamic-pituitary-adrenocortical (HPA) axis stress response, and neuronal activity in the basolateral amygdala (BLA) is necessary for this HPA-dampening. LSI increases the expression of plasticity-associated genes in the BLA; however, the nature of this plasticity is unknown. As BLA principal neuron activity normally promotes HPA responses, the present study tests the hypothesis that LSI decreases stress-excitatory BLA output by decreasing glutamatergic and/or increasing GABAergic inputs to BLA principal neurons. Male rats with unlimited access to chow and water were given additional access to 4 ml of sucrose (30%) or water twice daily for 14 days, and BLA structural and functional plasticity was assessed by quantitative dual immunolabeling and whole-cell recordings in brain slices. LSI increased vesicular glutamate transporter 1-positive (glutamatergic) appositions onto parvalbumin-positive inhibitory interneurons, and this was accompanied by increased expression of pCREB, a marker of neuronal activation that is mechanistically linked with plasticity, within parvalbumin interneurons. LSI also increased the paired-pulse facilitation of excitatory, but not inhibitory synaptic inputs to BLA principal neurons, without affecting postsynaptic excitatory or miniature excitatory and inhibitory postsynaptic currents, suggesting a targeted decrease in the probability of evoked synaptic excitation onto these neurons. Collectively, these results suggest that LSI decreases BLA principal neuron output by increasing the excitatory drive to parvalbumin inhibitory interneurons, and decreasing the probability of evoked presynaptic glutamate release onto principal neurons. Our data further imply that palatable food consumption blunts HPA stress responses by decreasing the excitation-inhibition balance and attenuating BLA output. PMID- 28597102 TI - Effects of progressive resistance training and weight loss versus weight loss alone on inflammatory and endothelial biomarkers in older adults with type 2 diabetes. AB - PURPOSE: Type 2 diabetes has been associated with an increase in inflammatory and endothelial biomarkers, which are associated with an increased risk of cardiovascular disease and diabetes-related complications. This study examined the effects of high-intensity progressive resistance training (PRT) with moderate weight loss (WL) versus WL alone on inflammatory and endothelial biomarkers in older overweight adults with type 2 diabetes. METHODS: This was a 12-month randomized controlled trial in which 36 inactive, overweight adults aged 60-80 years with poorly controlled type 2 diabetes were randomized to 6 months of supervised PRT + WL or stretching (sham) exercise plus WL followed by 6 months of home-training without dietary modification. Fasted blood samples were collected at baseline and subsequent 3-month intervals with the following inflammatory [interleukin (IL)-10, IL-6, tumor necrosis factor (TNF)-alpha, adiponectin] and endothelial markers [resistin and intercellular adhesion molecule (ICAM)-1)] assessed. RESULTS: No significant within-group changes or between-group differences were detected for any inflammatory or endothelial biomarker following the 6-month supervised exercise and WL phase. There was a greater reduction in IL 10 at 9 months in the PRT + WL relative to WL group (P = 0.033). There was also a greater reduction in TNF-alpha at 9 and 12 months in the PRT + WL relative to WL group (P = 0.026 and P = 0.024, respectively). Serum adiponectin increased in the PRT + WL relative to WL group after 12 months (P = 0.036). All results were adjusted for baseline values, age, weight, sex, diabetes duration, medication use and any change in medication. CONCLUSIONS: Long-term participation in PRT, independent of change in weight, can result in some improvements in certain inflammatory markers in older overweight adults with type 2 diabetes. PMID- 28597103 TI - The effects of strength training versus ski-ergometer training on double-poling capacity of elite junior cross-country skiers. AB - PURPOSE: To compare the effects of strength training versus ski-ergometer training on double-poling gross efficiency (GE), maximal speed (V max), peak oxygen uptake ([Formula: see text]) for elite male and female junior cross country skiers. METHODS: Thirty-three elite junior cross-country skiers completed a 6-week training-intervention period with two additional 40-min training sessions per week. The participants were matched in pairs and within each pair randomly assigned to either a strength-training group (STR) or a ski-ergometer training group (ERG). Before and after the intervention, the participants completed three treadmill roller-skiing tests to determine GE, V max, and [Formula: see text]. Mixed between-within subjects analysis of variance (ANOVA) was conducted to evaluate differences between and within groups. Paired samples t tests were used as post hoc tests to investigate within-group differences. RESULTS: Both groups improved their V max and [Formula: see text] expressed absolutely (all P < 0.01). For the gender-specific sub-groups, it was found that the female skiers in both groups improved both V max and [Formula: see text] expressed absolutely (all P < 0.05), whereas the only within-group differences found for the men were improvements of V max in the STR group. No between-group differences were found for any of the investigated variables. CONCLUSIONS: Physiological and performance-related variables of importance for skiers were improved for both training regimes. The results demonstrate that the female skiers' physiological adaptations to training, in general, were greater than those of the men. The magnitude of the physiological adaptations was similar for both training regimes. PMID- 28597104 TI - [Upper abdominal pain, nausea, and vomiting in a 63-year-old woman]. AB - We present a case of myotonic dystrophy type I and its complications including cholangitis and cardiac arrhythmias. The therapy options focus on the consequences of the disease and result in an endoscopic retrograde cholangiography (ERC) and implantation of an implantable cardioverter defibrillator (ICD). Myotonic dystrophy is a disease which results in a loss of smooth and skeletal muscle cells leading to multiple consequences such as gastrointestinal symptoms and cardiac manifestations. PMID- 28597105 TI - Role of Aspirin in Breast Cancer Survival. AB - Chemotherapy and hormonal therapy have significantly decreased breast cancer mortality, although with considerable side effects and financial costs. In the USA, over three million women are living after a breast cancer diagnosis and are eager for new treatments that are low in toxicity and cost. Multiple observational studies have reported improved breast cancer survival with regular aspirin use. Furthermore, pooled data from five large randomized trials of aspirin for cardiovascular disease showed that subjects on aspirin had decreased risk of cancer mortality and decreased risk of metastatic cancer. Although the potential mechanism for aspirin preventing breast cancer is not known, possible pathways may involve platelets, inflammation, cyclooxygenase (COX) 2, hormones, or PI3 kinase. This review article summarizes the current epidemiologic and clinical trial evidence as well as possible underlying mechanisms that justify current phase III randomized trials of aspirin to improve breast cancer survival. PMID- 28597106 TI - Relative Ascites Polymorphonuclear Cell Count Indicates Bacterascites and Risk of Spontaneous Bacterial Peritonitis. AB - BACKGROUND AND AIMS: Absolute polymorphonuclear (PMN) counts in ascites define spontaneous bacterial peritonitis (SBP), a severe form of bacterial infection in liver cirrhosis. Bacterascites, another form of ascites infection, can progress to SBP or may resolve spontaneously but is not reflected by absolute PMN counts. We investigated whether the relative ascites PMN count (the absolute PMN count divided by the absolute leukocyte count) provides additional information to detect bacterascites or predict SBP. METHODS: Hospitalized patients with liver cirrhosis requiring paracentesis were stratified with respect to a diagnosis of bacterascites and SBP with a prospective follow-up for 1 year. Diagnostic power of relative PMN counts in ascites was evaluated by receiver operating characteristics curves. RESULTS: At inclusion, we observed 28/269 (10%) and 43/269 (16%) episodes of BA and SBP, respectively. Unlike absolute PMN counts, relative PMN counts in ascites were significantly elevated in bacterascites (p = 0.001). During follow-up, 16 and 30 further episodes of BA and SBP were detected, respectively. Relative PMN counts increased significantly once patients developed BA (p = 0.001). At a threshold of 0.20 for the relative PMN count, sensitivity, specificity, positive and negative predictive values for bacterascites which required antibiotic treatment were 83, 75, 26 and 98%, respectively (p < 0.001). Furthermore, a relative PMN count in ascites >=0.13 and MELD score >17 was independent factors associated with occurrence of SBP during follow-up. CONCLUSION: The relative PMN count is a cheap immunological marker linked to bacterascites and future SBP, which may help to stratify patients according to their risk of infection. PMID- 28597108 TI - Prevalence of histological features of idiopathic noncirrhotic portal hypertension in general population: a retrospective study of incidental liver biopsies. AB - BACKGROUND: Idiopathic noncirrhotic portal hypertension (INCPH) is associated with histologic changes secondary to obliterative portal venopathy without cirrhosis. We studied the prevalence of individual histological features of INCPH in liver biopsies obtained incidentally during unrelated elective procedures and in elective liver biopsies with the diagnosis of fatty liver disease. METHODS: A total of 53 incidental liver biopsies obtained intraoperatively during unrelated elective procedures and an additional 28 elective biopsies with the diagnosis of fatty liver disease without portal hypertension and cirrhosis were studied. Various histologic features of INCPH were evaluated. RESULTS: Shunt vessel (30%), phlebosclerosis (27%), increased number of portal vessels (19%) and incomplete septa (17%) were common in these liver biopsies after confounding factors such as co-existing fatty liver disease or fibrosis were excluded. At least one feature of INCPH was noted in 90% of the biopsies. Eight (10%) biopsies showed 5-6 features of INCPH. In total, 11 (14%) of 81 patients had risk factors associated with INCPH, including hypercoagulability, autoimmune disease, exposure to drugs, and infections. No patient had portal hypertension at the end of the follow-up. CONCLUSION: The histologic features of INCPH are seen in incidental liver biopsies and fatty liver disease without portal hypertension. Ten percent of the biopsies show 5-6 features of INCPH without portal hypertension. Interpreting histologic features in the right clinical context is important for proper patient care. PMID- 28597107 TI - Microscopic Colitis Evolved Into Inflammatory Bowel Diseases Is Characterized by Increased Th1/Tc1 Cells in Colonic Mucosal Lamina Propria. AB - BACKGROUND: An association between microscopic colitis (MC), i.e., lymphocytic colitis (LC) and collagenous colitis (CC), and inflammatory bowel diseases (IBD) has been noticed. A subset of MC cases may evolve into IBD, and IBD in remission may present as MC in a histologic pattern. Moreover, MC and IBD may coexist in different regions of the bowel. A link between MC and IBD in their pathogenesis is, therefore, suggested. Abnormal mucosal immunity is likely the key. METHODS: We reviewed 2324 MC cases in Calgary over 14 years and identified 20 cases evolved into IBD (IBD transformers). 13 of them were further investigated for colonic mucosal lamina propria mononuclear cells (LPMNCs), as opposed to 22 cases whose MC resolved. On their index colonic biopsy immunohistochemistry was performed to detect major T cell subsets characterized by key cytokines and master transcription factors (IFNgamma and T-bet for Th1/Tc1, GATA-3 for Th2/Tc2, IL-17 and RORc for Th17/Tc17, FoxP3 for Treg/Tcreg) as well as TNFalpha+ cells (partly representing Th1). LPMNCs positive for each marker were counted (average number per high-power field). RESULTS: IBD transformers had increased IFNgamma+, T-bet+, TNF-alpha+, and GATA-3+ LPMNCs compared to the MC-resolved cases. The LC to-IBD subgroup had increased IFNgamma+ and GATA-3+ cells compared to the LC resolved subgroup. The CC-to-IBD subgroup had increased T-bet+, TNF-alpha+, and GATA-3+ cells compared to the CC-resolved subgroup. Among MC-resolved patients, more TNF-alpha+ and RORc+ cells were seen in LC than in CC. CONCLUSION: Th1/Tc1- and TNFalpha-producing cells, and likely a subset of Th2/Tc2 cells as well, may be involved in the MC-to-IBD transformation. PMID- 28597110 TI - Acculturation matters in the relation between ambivalence over emotional expressions and well-being among Chinese American breast cancer survivors. AB - PURPOSE: Ambivalence over emotional expression (AEE) is the inner conflict of desiring emotion expression and fearing consequence of emotion expression. Few studies to date have examined the effects of AEE within an ethnic group that prioritizes emotional self-control. The present study examined the associations between AEE and well-being (viz., quality of life and depressive symptoms) as a function of acculturation among a sample of Chinese American breast cancer survivors. METHODS: Ninety-six Chinese breast cancer survivors (M age = 54.64 years old, SD = 7.98) were recruited from Southern California. Participants filled out a paper-pen questionnaire containing the Ambivalence over Emotional Expression Questionnaire (AEQ), the Functional Assessment of Cancer Therapy Breast (FACT-B), and the Center for Epidemiologic Studies Depression Scale-Short Form (CESD-10). RESULTS: Acculturation was a statistically significant moderator of the relations between AEE and depressive symptoms, and a statistically marginally significant moderator of the relations between AEE and quality of life. Simple slopes revealed that AEE was negatively associated with quality of life (B = -.45, p < .001) and depressive symptoms (B = .20, p < .001) for women with high acculturation, but not associated for women with low acculturation (Bs = -.15 and .04, ps > .05, for quality of life and depressive symptoms, respectively). CONCLUSIONS: These results suggest that less acculturated Chinese breast cancer survivors are protected by Chinese cultural values of emotional self-control and restraint, and thus do not experience the detrimental effects of AEE on their depressive symptoms and quality of life. Implications are discussed. PMID- 28597111 TI - Equilibrium mappings in polar-isotropic confined active particles. AB - Despite their fundamentally nonequilibrium nature, the individual and collective behavior of active systems with polar propulsion and isotropic interactions (polar-isotropic active systems) are remarkably well captured by equilibrium mapping techniques. Here we examine two signatures of equilibrium systems --the existence of a local free energy function and the independence of the coarse grained behavior on the details of the microscopic dynamics-- in polar-isotropic active particles confined by hard walls of arbitrary geometry at the one-particle level. We find that boundaries that possess concave regions make the density profile strongly dynamics-dependent and give it a nonlocal dependence on the geometry of the confining box. This in turn constrains the scope of equilibrium mapping techniques in polar-isotropic active systems. PMID- 28597109 TI - Race-specific associations between health-related quality of life and cellular aging among adults in the United States: evidence from the National Health and Nutrition Examination Survey. AB - PURPOSE: Poor health-related quality of life (HRQOL) could lead to higher morbidity and mortality through telomere attrition or accelerated cellular aging. We conducted a cross-sectional analysis to examine the relationship between four dimensions of HRQOL and leukocyte telomere length (LTL) among a nationally representative sample of 3547 US adults (>=20 years) using the data from the 2001 2002 National Health and Nutrition Examination Survey. METHOD: We used HRQOL survey information collected on individuals' self-rated general health, recent physical health, recent mental health, and recent activity limitation. Telomere length was assessed using quantitative polymerase chain reaction. Multiple linear regressions were used to estimate the relationship between each dimension of HRQOL and log-transformed values of LTL with adjustment for sample weights and design effects. RESULTS: HRQOL-race interactions were significant, and the results were stratified by race. After controlling for demographic factors, disease conditions, and lifestyle variables, worse general health was significantly associated with shorter LTL for Blacks (coefficient, beta: -0.022, 95% Confidence Interval, 95% CI: -0.03 to -0.01), but not for Whites or Mexican Americans. Unwell physical health was associated with shorter telomere length for Whites (beta: -0.005, 95% CI: -0.01 to -0.001) only. Unwell mental health showed no significant association with LTL in any race. CONCLUSIONS: Although longitudinal studies are needed to prove causality, our findings suggest that HRQOL could be associated with LTL shortening. We also found a possible racial difference in this association and recommend additional multiethnic studies to confirm this and to understand the reasons and consequences of this difference. PMID- 28597112 TI - Serial magnetic resonance study in super refractory status epilepticus: progressive involvement of striatum and pallidus is a possible predictive marker of negative outcome. AB - Super refractory status epilepticus (SRSE) is a life-threatening condition in which seizures do not respond to third-line anticonvulsant drug therapy. SRSE is associated with high mortality. How often SRSE occurs, what are the risk factors leading to this condition, and what is the effect on clinical outcome of failure to control seizures are poorly defined. Several studies have evaluated magnetic resonance imaging (MRI) findings in status epilepticus (SE), confirming that SE may directly cause selective neuronal necrosis due to excitotoxic mechanisms, as described in clinical case reports and experimental models. The aim of our study is to illustrate, in a case of SRSE, MRI signal changes during time and to describe which cerebral structures are early involved in this difficult clinical condition. We investigated with serial MRI study a patient affected by childhood generalized epilepsy who developed SRSE of unknown etiology during adulthood. MRI scans showed brain signal changes according to progressive electro-clinical worsening, particularly an early involvement of striatum/pallidus. An extended literature exists about transient MRI changes in SE, but not enough about SRSE, because of the difficulties in executing serial MRI studies in patients with such risky condition. MRI findings in SRSE must be investigated with particular care in order to detect early changes in basal ganglia that could suggest severe prognosis. PMID- 28597114 TI - A visual timeline tool for tracking mood and medication perinatally in affective disorders. PMID- 28597113 TI - Headache in children and dynamic thiol/disulfide balance evaluation with a new method. AB - Headache is one of the most common causes of presentation to the physician in children. We aimed to evaluate the dynamic thiol/disulfide homeostasis with a new method in children with headache and also to investigate the relationship between the headache type, pain severity and duration in our study. We included 40 patients diagnosed with migraine, 40 patients diagnosed with tension-type headache (TTH) and 40 healthy children in the study. No significant difference was found between the total thiol, native thiol, and disulfide levels of the patient and control groups. However, the disulfide/native thiol and disulfide/total thiol ratios were higher in the migraine group than in the TTH and control groups. No correlation was found between the Pediatric Migraine Disability Assessment (PedMIDAS) score and the headache duration and any of the thiol/disulfide parameters. A negative correlation was found between the total thiol and native thiol levels and the PedMIDAS score in the TTH group. Migraine and TTH patients have different effect to thiol/disulfide homeostasis. PMID- 28597115 TI - Psychiatric outcomes after hysterectomy in women with uterine myoma: a population based retrospective cohort study. AB - Controversy regarding psychological or psychiatric outcomes following hysterectomy still exists. The purpose of this study was to investigate the risk of postoperative psychiatric disorders in women with hysterectomy compared to that in women with uterus-conserving surgery for myomas by using population-based data from South Korea. This study was designed as a retrospective cohort study. We analyzed the National Health Insurance Service National Sample Cohort data including all administrative medical claims from 2002 to 2013. The study population, consisting of 9581 women, was defined as those diagnosed with uterine myoma who underwent medical procedures. The association between psychiatric and mood disorders and hysterectomy was assessed using Cox proportional hazard regression. During the study period, 1381 (14.4%) women experienced psychiatric disorders and 374 (3.9%) experienced mood disorders. The hazard ratio (HR) for psychiatric disorder was higher in women after hysterectomy than in women after uterus-conserving procedures (adjusted HR = 1.44; 95% CI = 1.27-1.64, p < 0.0001). In addition, the HR for mood disorders in women after hysterectomy was significantly higher than in women after uterus-conserving procedures (adjusted HR = 1.62; 95% CI = 1.26-2.08, p = 0.0002). Our study suggests that hysterectomy increased the risk of psychiatric disorders compared to uterus-conserving procedures in women with uterine myoma. Considering these findings, more focus on psychological responses in women following hysterectomy is needed, and appropriate psychosocial support or provisioning of information before or after procedures could reduce psychological distress. PMID- 28597117 TI - Oral dexamethasone decreases postoperative pain, swelling, and trismus more than diclofenac following third molar removal: a randomized controlled clinical trial. AB - PURPOSE: The aim of this study was to compare the anti-inflammatory potential of two pharmacotherapy protocols based on the parameters of pain, trismus, and swelling, after extraction of third molars. METHODS: Thirty patients selected with symmetrical impaction of third molars were submitted to surgical procedures in both sides in different times. For one group, dexamethasone was used for 3 days, and for another group diclofenac sodium was also used for the same period. The main variables analyzed were the visual analogue pain scale (VAS), but others were also analyzed such as swelling and trismus, which were submitted to statistical analysis. RESULTS: The results had no difference regarding the length of procedures (p = 0.986) and the pain in the immediate and 4-h postoperative period (p = 0.723 and 0.541). The rescue analgesic consumption was higher (p < 0.05) when using the protocol with diclofenac sodium. The variables mouth opening (p < 0.05) and swelling (p < 0.05) were significantly better when using the protocol with dexamethasone in the postoperative period. CONCLUSIONS: Medical protocol with the use of dexamethasone in the postoperative period was more effective in controlling pain, trismus, and swelling, after the extraction of third molars, when compared to diclofenac sodium. PMID- 28597116 TI - Secretory leukocyte protease inhibitor regulates human periodontal ligament cell production of pro-inflammatory cytokines. AB - OBJECTIVE: Regulation of immune-like cell properties of periodontal ligament (PDL) cells is not understood. We investigate the importance of secretory leukocyte protease inhibitor (SLPI) for production of pro-inflammatory cytokines in human PDL cells. MATERIALS AND METHODS: PDL cells were isolated from teeth extracted for orthodontic reasons. Cellular location of SLPI was investigated by immunocytochemistry. Cytokine transcript and protein expression were assessed by quantitative real-time RT-PCR and Western blotting. SLPI gene activity was knocked-down by siRNA. NF-kappaB signaling was assessed by measuring IkappaBalpha, and phosphorylated p65 and p105 protein expression. RESULTS: PDL cells showed cytoplasmic expression of SLPI. Cellular expression level of SLPI negatively correlated to LPS-induced stimulation of IL-6 and MCP-1. Both SLPI gene activity and protein were reduced by about 70% in PDL cells treated with SLPI siRNA compared to cells treated with non-coding construct. Treatment with SLPI siRNA was associated with up-regulation of both basal and LPS-stimulated IL 6, MCP-1 and TLRs mRNA expression. The up-regulation of MCP-1 transcript in SLPI siRNA-treated cells was confirmed on protein level. SLPI siRNA-treatment enhanced the phosphorylated NF-kappaB p105 protein expression. CONCLUSIONS: SLPI regulates PDL cell pro-inflammatory cytokine expression and modulates NF-kappaB signaling, suggesting that SLPI governs the immune cell-like properties of PDL cells. PMID- 28597118 TI - CORR Insights(r): Prolotherapy Induces an Inflammatory Response in Human Tenocytes In Vitro. PMID- 28597119 TI - Highlights lecture EANM 2016: "Embracing molecular imaging and multi-modal imaging: a smart move for nuclear medicine towards personalized medicine". AB - The 2016 EANM Congress took place in Barcelona, Spain, from 15 to 19 October under the leadership of Prof. Wim Oyen, chair of the EANM Scientific Committee. With more than 6,000 participants, this congress was the most important European event in nuclear medicine, bringing together a multidisciplinary community involved in the different fields of nuclear medicine. There were over 600 oral and 1,200 poster or e-Poster presentations with an overwhelming focus on development and application of imaging for personalized care, which is timely for the community. Beyond FDG PET, major highlights included progress in the use of PSMA and SSTR receptor-targeted radiopharmaceuticals and associated theranostics in oncology. Innovations in radiopharmaceuticals for imaging pathologies of the brain and cardiovascular system, as well as infection and inflammation, were also highlighted. In the areas of physics and instrumentation, multimodality imaging and radiomics were highlighted as promising areas of research. PMID- 28597120 TI - Long-term prognostic implications of myocardial perfusion imaging in octogenarians: an all-comer, cohort study. AB - PURPOSE: Evaluation of the long-term prognostic value of myocardial perfusion imaging (MPI) in octogenarians. METHODS: Six hundred and twenty-nine octogenarians [51% previous myocardial infarction (MI) or revascularization] who underwent single-isotope MPI (78% 201Tl, 22% 99mTc-tetrofosmin) with exercise (38% Bruce, 2% leg ergometry) or pharmacologic (58% adenosine, 2% dobutamine) stress were studied. All patients had LVEF determined by echocardiography within 1 month from MPI. Myocardial perfusion scoring was performed on a 17-segment LV model with a 5-point grading system and three summed stress score (SSS)-based risk categories were formed [high-(SSS > 12), low-(SSS < 4), medium]. Prospective follow-up was performed to document all-cause (ACD), cardiac death (CD), MI, and revascularization. Revascularization was used to censor follow-up in survival analysis regarding ACD, CD, and CD/MI. For analysis of the CD, MI, or late revascularization (LR) composite, only revascularizations within 3 months from MPI (early revascularizations) were used for censoring. RESULTS: After 9.3 years there were 187 ACDs, 86 CDs, 28 MIs, and 77 revascularizations, including 28 early revascularizations. Adjusting for LVEF and stress-modality type, SSS was identified as an independent predictor of ACD [HR 1.03 (1.01-1.05)], CD [HR 1.05 (1.03-1.08)], CD,MI [HR 1.05 (1.02-1.07)], and CD,MI or LR [HR 1.05 (1.03-1.07)] (p <= 0.001 in all cases). Increased lung uptake had independent prognostic value only for the CD, MI, or LR end-point [HR 3 (1.2-7.7), p = 0.02]. Survival modeling demonstrated that LVEF and SSS, but not non-perfusion scintigraphic data provided incremental prognostic value over pre-test available clinical and historical information for all end-points. Differences between Kaplan-Meier survival curves of SSS-based risk groups were significant for all end-points (p < 0.001 in all cases). CONCLUSIONS: In octogenarians, MPI provides effective long term risk stratification, regardless of stress type used or underlying cardiac function. PMID- 28597122 TI - Nanoparticle-in-gel system for delivery of vitamin C for topical application. AB - Hyperpigmentation is a dermal condition of melanocyte proliferation, induced by various factors like ultraviolet radiation producing reactive oxygen species, DNA damage, and apoptosis. The application of topical antioxidants through the different type of formulations can help to prevent oxidative damage to the skin. L-ascorbic acid (vitamin C) is a water-soluble compound and the most abundant antioxidant in human skin, but this vitamin is unstable and loses its potency with poor formulation strategies. Nanotechnology has been effectively used to promote stability and therapeutic activity of various drug molecules. With this context, the objective of the work was set to formulate a topical delivery system of vitamin C nanoparticles incorporated into the polymeric gel. Vitamin C (50 mg) was loaded into ethyl cellulose nanoparticles, of varying concentrations (50-250 mg), by the solvent evaporation method and subsequently incorporated into hydroxypropyl methyl cellulose gels (3, 5, and 7%). The formulations were characterized for various physico-chemical properties such as particle size, drug content, entrapment efficiency, and drug-polymer interactions. In vitro, drug release studies were conducted by using dialysis bag method and Franz diffusion cell for the nanoparticles and gel formulations, respectively. The optimized formulation exhibited sustained release over 8 h. The ex vivo skin permeation studies were performed and the amount of drug retained and released through the skin were determined. The results obtained from the study proved the potentiality and suitability of this novel system to treat hyperpigmentation. PMID- 28597121 TI - Current research priorities in perioperative intensive care medicine. AB - INTRODUCTION: Surgical treatments are offered to more patients than ever before, and increasingly to older patients with chronic disease. High-risk patients frequently require critical care either in the immediate postoperative period or after developing complications. The purpose of this review was to identify and prioritise themes for future research in perioperative intensive care medicine. METHODS: We undertook a priority setting process (PSP). A panel was convened, drawn from experts representing a wide geographical area, plus a patient representative. The panel was asked to suggest and prioritise key uncertainties and future research questions in the field of perioperative intensive care through a modified Delphi process. Clinical trial registries were searched for on going research. A proposed "Population, Intervention, Comparator, Outcome" (PICO) structure for each question was provided. RESULTS: Ten key uncertainties and future areas of research were identified as priorities and ranked. Appropriate intravenous fluid and blood component therapy, use of critical care resources, prevention of delirium and respiratory management featured prominently. CONCLUSION: Admissions following surgery contribute a substantial proportion of critical care workload. Studies aimed at improving care in this group could have a large impact on patient-centred outcomes and optimum use of healthcare resources. In particular, the optimum use of critical care resources in this group is an area that requires urgent research. PMID- 28597124 TI - Relative atherosclerotic plaque volume by CT coronary angiography trumps conventional stenosis assessment for identifying flow-limiting lesions. AB - The new methods for diagnosing the ischemia with coronary computed tomographic angiography (CTA) as a noninvasive test have been investigated. To compare the relative plaque volume to quantitative CTA and quantitative coronary angiography (QCA) for detecting flow-limiting coronary artery stenoses. We studied 49 patients with 55 intermediate lesions (30-69% diameter stenosis) who underwent CTA, coronary angiography (CAG), and FFR. CTA and QCA measures included lesion length, percent diameter stenosis (%DS), minimal lumen diameter (MLD), target main vessel percent plaque volume (%PV), lesion %PV, target main vessel percent lumen volume (%LV), and lesion %LV. FFR <=0.80 was considered diagnostic of a flow-limiting lesion. The area under the receiver-operating characteristic curve (AUC) was used to determine the accuracy of detecting flow-limiting lesions. We also investigated the AUC of discrimination of flow-limiting lesion according to calcium score. Eighteen of 55 lesions (32.7%) had an FFR <=0.80. Only vessel %PV differentiated between lesions with and without flow obstruction (67.6 vs. 62.7%, p = 0.018). The AUC for vessel %PV was greatest (0.76; 95% CI 0.61-0.87). The AUC for the discrimination of the flow-limiting lesions according to low calcium score (<=400) improved to 0.82 (95% CI 0.57-0.94). In intermediate coronary artery stenoses, vessel %PV is more accurate than conventional stenosis assessment for detecting flow-limiting lesions. In low calcium score, vessel %PV is more useful for diagnosis of ischemic heart disease compared with conventional quantitative measures. PMID- 28597123 TI - Vaginal drug delivery for the localised treatment of cervical cancer. AB - Cervical cancer is usually treated by surgery, with the more advanced cancers requiring adjuvant chemotherapy or radiotherapy. The location of the cervix makes it easily accessible through the vagina for the localised delivery of chemotherapeutic drugs. Localised delivery has the advantage of direct delivery to the site of action resulting in a lower dose having to be required and a reduction in systemic side effects. This approach would be advantageous for fertility sparing surgery, whereby localised delivery could be used to reduce tumour size allowing for a much smaller tumour to be removed, reducing the risk of preterm birth. Furthermore, localised delivery could be used after surgery to reduce the risk of recurrence, which is significantly higher in fertility sparing surgery compared to standard surgery. In this paper, we discuss the number of vaginal dosage forms that have investigated for this purpose, including tablets, rings, bioadhesive and cervical caps. APIs under investigation have ranged from well-established chemotherapeutic drugs to more experimental compounds. PMID- 28597125 TI - New insight to estimate under-expansion after stent implantation on bifurcation lesions using optical coherence tomography. AB - Optical coherence tomography (OCT) allows full volumetric segmentation of the lumen. However, for the estimation of stent under-expansion we still rely on the conventional method (CM) of single cross-sectional narrowing compared with reference vessel, likely masking true lesion significance, especially for bifurcations and tapered vessels. We, therefore, suggest a novel concept of volumetric metrics that take into account vessel tapering and major side branches and is capable of obtaining ideal lumen area for every frame of the stent by OCT. Forty-four patients with bifurcation lesions were enrolled. In volumetric metrics, expansion index was calculated as [(actual lumen area/ideal lumen area) * 100] in all frames. While minimum expansion index (MEI) was often located in the proximal segment to the major side branch, minimum stent area (MSA) by CM was frequently located in the distal segment (p < 0.001). Furthermore, the frequency of the under-expansion was significantly greater in newly metrics compared with CM [21 (47.7%) and 11 (25.0%), p = 0.045]. New metrics changed the presence of the under-expansion in 40.9% (18/44) of patients and the locations of MEI and MSA were different in 72.7% (32/44) of cases. Volumetric assessment enables to more accurately assess stent under-expansion. PMID- 28597126 TI - Healthcare and disease burden among refugees in long-stay refugee camps at Lesbos, Greece. AB - OBJECTIVES: To assess current medical problems at two Greek refugee sites at Lesbos island (Camp Moria and Caritas hotel), to explore which care is needed and to assess how the provided healthcare can be improved. DESIGN: In this dynamic cohort study all consecutive patients who visited doctors from the Boat Refugee Foundation were included. OUTCOME: Treatment Rates (TR) with 95% Confidence Intervals (95% CI) were calculated for all major health issues. Additionally, the provided health care was evaluated using the SPHERE project standards. RESULTS: During the observation period of 30 March 2016 to 15 May 2016, 2291 persons were followed for a total of 289 person years (py). The median age of patients was 23.0 (IQR 8-38) years, 30.0% was aged <18. The healthcare demand was high with 3.6 patient visits per py. Upper respiratory tract infections were most commonly diagnosed with a TR of 89.6/100py (95% CI 78.7-10.1) followed by dental problems (TR 18.0/100py, 95% CI 13.1-22.9). The rate of suicide attempts was high at TR 1.4/100py (95% CI 0.03-2.8), and many psychological problems were diagnosed, TR 19.4/100py (95% CI 14.3-24.4). Major health care threats are the lack of a vaccination program, inadequate sanitation and hygiene, and severe overcrowding. CONCLUSIONS: This study can help policy makers and Non-Governmental Organizations decide which health care is needed most in the current European refugee crisis. There is an urgent need for mental and dental healthcare. Furthermore, it is crucial that vaccination programs are initiated and "hotspot" camps should transform in camps designed for long-stay situations. PMID- 28597128 TI - The MO-meatocanalplasty: a modification of the M-meatoplasty to address the superior quadrants and the bony canal. AB - The meatoplasty of the external auditory canal is a frequently performed otologic procedure in recurrent otitis externa, eczema or frequent accumulation of cerumen due to a narrow meatus of the external ear canal. Numerous surgical techniques have been described. The M-meatoplasty described by Mirck for addressing the external meatus is widely used. However, this technique does not sufficiently enlarge the external ear canal in all cases. Specifically in patients where the ear canal narrowing is most prominent in the postero- and/or anterosuperior quadrants of the lateral meatus the technique needs some modifications. In these cases, an oblique conversion of the M-meatoplasty, the MO-meatocanalplasty, is useful. In cases where the bony canal is also narrow this modification allows for a bony canalplasty while avoiding a retro-auricular approach. The MO meatocanalplasty can be used in combination with myringoplasty and tympanoplasty. PMID- 28597130 TI - Erratum to: The Differential Contributions of Conceptual Representation Format and Language Structure to Levels of Semantic Abstraction Capacity. PMID- 28597129 TI - Transcanal surgery for vestibular schwannomas: a pictorial review of radiological findings, surgical anatomy and comparison to the traditional translabyrinthine approach. AB - : The most popular approaches for vestibular schwannoma (VS) removal are retrosigmoid, middle cranial fossa and translabyrinthine (TL). All require a certain degree of invasivity, bone removal, or brain manipulation. Recently, the authors described the transcanal transpromontorial approaches (TTA), which allow the inner ear to be accessed directly through the external auditory canal (EAC), either with a microscopic (Expanded TTA, or ExpTTA) or even an exclusive endoscopic technique (Endoscopic TTA, or EndoTTA). The advantages compared to traditional approaches are a direct view of the internal auditory canal (IAC) from lateral to medial, very little or no superficial tissue dissection and very little petrous bone drilling. In summary, from an anatomical point of view, they could be considered to be minimally invasive approaches. The radiologic outcome and the anatomical correspondence of these new approaches are described so as to share with the readers the possible radiologic findings and to compare and differentiate them from classic transpetrous approaches such as the TL approach. LEVEL OF EVIDENCE: 4. PMID- 28597127 TI - The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement. AB - Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity. PMID- 28597131 TI - Applied Problem Solving in Children with ADHD: The Mediating Roles of Working Memory and Mathematical Calculation. AB - The difficulties children with ADHD experience solving applied math problems are well documented; however, the independent and/or interactive contributions of cognitive processes underlying these difficulties are not fully understood and warrant scrutiny. The current study examines two primary cognitive processes integral to children's ability to solve applied math problems: working memory (WM) and math calculation skills (i.e., the ability to utilize specific facts, skills, or processes related to basic math operations stored in long-term memory). Thirty-six boys with ADHD-combined presentation and 33 typically developing (TD) boys aged 8-12 years old were administered multiple counterbalanced tasks to assess upper (central executive [CE]) and lower level (phonological [PH STM] and visuospatial [VS STM] short-term memory) WM processes, and standardized measures of mathematical abilities. Bias-corrected, bootstrapped mediation analyses revealed that CE ability fully mediated between-group differences in applied problem solving whereas math calculation ability partially mediated the relation. Neither PH STM nor VS STM was a significant mediator. When modeled together via serial mediation analysis, CE in tandem with math calculation ability fully mediated the relation, explained 79% of the variance, and provided a more parsimonious explication of applied mathematical problem solving differences among children with ADHD. Results suggest that interventions designed to address applied math difficulties in children with ADHD will likely benefit from targeting basic knowledge of math facts and skills while simultaneously promoting the active interplay of these skills with CE processes. PMID- 28597132 TI - Lung involvement in "stable" undifferentiated connective tissue diseases: a rheumatology perspective. AB - Previous studies of the occurrence of interstitial lung disease (ILD) in undifferentiated connective tissue diseases (UCTD) were conducted in patients admitted to Respiratory Medicine Units. The aim of the present prospective study was to investigate lung involvement in UCTD patients admitted to a Rheumatology Unit. Eighty-one consecutive UCTD patients were enrolled in the study. Each patient underwent history and physical examination, routine laboratory investigations, antinuclear antibody (ANA) profiling, B-mode echocardiography, and lung function study according to previously reported methods. Lung high resolution computed tomography (HRCT) was performed in patients who provided informed consent. Six patients (7.4%) had a history of grade II dyspnea. Three of them had a DLCO ranging from 42 to 55% of the predicted value; and a HRCT documented ILD with a non-specific interstitial pneumonia (NSIP) pattern. Symptoms in the other three patients were due to cardiac disease. None of the 75 asymptomatic patients, had relevant findings at physical examination, 26/75 had a DLCO <80% (<70% in 10 cases). Of these, 3 of the 30 patients who underwent lung HRCT were affected by NSIP-ILD. Six of the 81 enrolled were affected by ILD, which was symptomatic in three patients. A higher percentage of patients had a reduced DLCO. The latter finding may reflect a preradiographic ILD or a preechocardiographic pulmonary vascular disease. PMID- 28597134 TI - Digital tomosynthesis as a new diagnostic tool for assessing of chronic gout arthritic feet and ankles: comparison of plain radiography and computed tomography. AB - This aimed to compare the three radiographic methods of digital tomosynthesis (DT), plain radiography, and computed tomography (CT) for evaluating changes in feet of patients with chronic gouty arthritis. Two independent radiologists read the plain radiography, DT, and CT images of 30 male patients with gout. The degrees of erosion and joint space narrowing were scored using the Sharp-van der Heijde scoring method in 18 foot joints, which consisted of four proximal interphalangeal and one interphalangeal joint of the first toe, five metatarsophalangeal, five tarsometatarsal, and three naviculo-cuneiform joints of the foot. DT showed high reproducibility [0.929 for intraobserver intraclass correlation coefficient (ICC) and 0.838 for interobserver ICC]. DT showed similar results to those of CT and superior results to those of plain radiography for evaluating radiographic damage [mean total score, 8.5 +/- 14.6 (+/-standard deviation) for plain radiography, 12.9 +/- 12.4 for DT, and 12.6 +/- 11.2 for CT]. This study showed that DT is a good method for evaluating radiographic changes in patients with gout. Further research is needed to apply DT to actual clinical settings. PMID- 28597133 TI - Real-life 10-year retention rate of first-line anti-TNF drugs for inflammatory arthritides in adult- and juvenile-onset populations: similarities and differences. AB - The aim of this study is to retrospectively analyze 10-year drug survival of first-line TNF inhibitor (TNFi) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) patients, comparing withdrawal rates and discontinuation pattern between adult- and juvenile-onset populations. RA, AS, PsA, and JIA patients treated with infliximab, etanercept, or adalimumab as first TNFi between 1999 and 2015 were extracted from a local registry. Drug survival up to 10-year follow-up was evaluated by the Kaplan-Meier method and compared according to age (adult vs juvenile onset), TNFi agent, and discontinuation reason by a stratified log-rank test. Three hundred sixty JIA (205 etanercept, 66 adalimumab, and 89 infliximab) and 951 (607 RA, 188 AS, and 156 PsA) adult patients (464 infliximab, 262 adalimumab, and 225 etanercept) were included. After exclusion of systemic-onset JIA (18.5%), overall 10-year retention rate was 31.8%, with no difference between adult- and juvenile-onset patients (32.1 and 30.2%, respectively; HR 0.938 [95% CI 0.782-1.125]). Etanercept showed the highest drug survival in adult-onset population (p < 0.0001 vs both monoclonal antibodies) and infliximab the lowest in juvenile-onset population (p = 0.005 vs adalimumab and p < 0.0001 vs etanercept). Inefficacy was the most frequent reason for TNFi withdrawal in adult population (29.75%) with a significantly higher risk of discontinuation than in juvenile-onset subgroup (HR 1.390 [95% CI 1.060-1.824]). Serious infections and malignancies caused TNFi withdrawal only in adult whereas gastrointestinal, neuropsychiatric, and ocular complications quite only in juvenile patients. Despite a similar 10-year drug survival, adult- and juvenile-onset subpopulations showed a significantly different pattern of TNFi reasons for discontinuation. PMID- 28597135 TI - GLIS3 rs7020673 and rs10758593 polymorphisms interact in the susceptibility for type 1 diabetes mellitus. AB - AIMS: The transcription factor Gli-similar 3 (GLIS3) plays a key role in the development and maintenance of pancreatic beta cells as well as in the regulation of Insulin gene expression in adults. Accordingly, genome-wide association studies identified GLIS3 as a susceptibility locus for type 1 diabetes mellitus (T1DM) and glucose metabolism traits. Therefore, the aim of this study was to replicate the association of the rs10758593 and rs7020673 single nucleotide polymorphisms (SNPs) in the GLIS3 gene with T1DM in a Brazilian population. METHODS: Frequencies of the rs7020673 (G/C) and rs10758593 (A/G) SNPs were analyzed in 503 T1DM patients (cases) and in 442 non-diabetic subjects (controls). Haplotypes constructed from the combination of these SNPs were inferred using a Bayesian statistical method. RESULTS: Genotype and allele frequencies of rs7020673 and rs10758593 SNPs did not differ significantly between case and control groups. However, the frequency of >=3 minor alleles of the analyzed SNPs in haplotypes was higher in T1DM patients compared to non-diabetic subjects (6.2 vs. 1.6%; P = 0.001). The presence of >=3 minor alleles remained independently associated with risk of T1DM after adjustment for T1DM high-risk HLA DR/DQ haplotypes, age and ethnicity (OR = 3.684 95% CI 1.220-11.124). Moreover, levels of glycated hemoglobin seem to be higher in T1DM patients with rs10758593 A/A genotype than patients carrying the G allele of this SNP (P = 0.038), although this association was not kept after Bonferroni correction. CONCLUSIONS: Our results indicate that individually the rs7020673 and rs10758593 SNPs are not significantly associated with T1DM but seem to interact in the predisposition for this disease. PMID- 28597136 TI - Tactile motion lacks momentum. AB - The displacement of the final position of a moving object in the direction of the observed motion path, i.e. an overestimation, is known as representational momentum. It has been described both in the visual and the auditory domain, and is suggested to be modality-independent. Here, we tested whether a representational momentum can also be demonstrated in the somatosensory domain. While the cognitive literature on representational momentum suggests that it can, previous work on the psychophysics of tactile motion perception would rather predict an underestimation of the perceived endpoint of a tactile stimulus. Tactile motion stimuli were applied on the left and the right dorsal forearms of 32 healthy participants, who were asked to indicate the subjectively perceived endpoint of the stimulation. Velocity, length and direction of the trajectory were varied. Contrary to the prediction based on the representational momentum literature, participants in our experiment significantly displaced the endpoint against the direction of movement (underestimation). The results are thus compatible with previous psychophysical findings on the perception of tactile motion. Further studies combining paradigms from classical psychophysics and cognitive psychology will be needed to resolve the apparently paradoxical predictions by the two literatures. PMID- 28597137 TI - Investigation of the Potential Health Benefits as Lipase Inhibitor and Antioxidant of Leopoldia comosa (L.) Parl.: Variability of Chemical Composition of Wild and Cultivated Bulbs. AB - There is a great interest in the nutritional value of vegetables and fruits and how the habitat affects nutritive and biological properties. In vitro studies here reported were performed to evaluate the inhibitory activity of formulations from edible plant on pancreatic lipase. The aim of this study was also to evaluate the biovariability of L. comosa (L.) Parl. bulbs from Italy. The wild bulbs were compared with the same cultivated species that are commonly commercialized to identify samples with the best quality for a potential therapeutic application. Hydroalcoholic extract and polar fraction of wild bulbs showed a very important pancreatic lipase inhibitory activity, with IC50 values of 0.166 +/- 0.005 and 0.153 +/- 0.005 mg/mL, respectively. In order to characterize the extracts, gas chromatography associated with mass spectrometry (GC/MS) analysis was performed, revealing the predominance of palmitic acid. Phenolic and flavonoid composition was also evaluated. L. comosa extract obtained from wild bulbs demonstrated both antioxidant and anti-obesity activities that might be attributed to a wide range of present phenolic compounds. PMID- 28597138 TI - Advances in renal genetic diagnosis. AB - Most genetic disorders are clinically and genetically heterogeneous. Next generation sequencing (NGS) has revolutionized the field and is providing rapidly growing insights into the pathomechanism of hereditary nephropathies. Current best-practice guidelines for most hereditary nephropathies include genetic diagnostics. The increasing number of genes that have to be considered in patients with hereditary nephropathies is often challenging when addressed by conventional techniques and largely benefits from NGS-based approaches that allow the parallel analysis of all disease genes in a single test at relatively low cost, e.g., by the use of multi-gene panels. Knowledge of the underlying genotype is of advantage in discussions with regard to transplantation and therapeutic options. Further, genetics may aid the early detection and treatment of renal and extrarenal complications and the reduction of invasive procedures. An accurate genetic diagnosis is crucial for genetic counselling, provides information about the recurrence risk and may help to improve the clinical management of patients and their families. The bottleneck in genetics is no longer the primary wet lab process but the interpretation of the obtained genetic data, which is by far the most challenging and work-intensive part of the analysis. This can only be managed in a multidisciplinary setting that brings together expert knowledge in genetics and the respective medical field. In the future, bench and bedside benefits can be expected from this kind of digitized medicine. PMID- 28597140 TI - Erratum to: Peri-interventional neurological complication rates in patients undergoing carotid artery stenting depend on the side of the stenosis treated. PMID- 28597139 TI - Hypoxia and Bone Metastatic Disease. AB - PURPOSE OF REVIEW: This review highlights our current knowledge of oxygen tensions in the bone marrow, and how low oxygen tensions (hypoxia) regulate tumor metastasis to and colonization of the bone marrow. RECENT FINDINGS: The bone marrow is a relatively hypoxic microenvironment, but oxygen tensions fluctuate throughout the marrow cavity and across the endosteal and periosteal surfaces. Recent advances in imaging have made it possible to better characterize these fluctuations in bone oxygenation, but technical challenges remain. We have compiled evidence from multiple groups that suggests that hypoxia or hypoxia inducible factor (HIF) signaling may induce spontaneous metastasis to the bone and promote tumor colonization of bone, particularly in the case of breast cancer dissemination to the bone marrow. We are beginning to understand oxygenation patterns within the bone compartment and the role for hypoxia and HIF signaling in tumor cell dissemination to the bone marrow, but further studies are warranted. PMID- 28597141 TI - Apparent metabolizable energy value of whole date palm (Phoenix dactylifera L.) and its possible use as a feedstuff for aged laying hens. AB - This study was conducted to evaluate the feeding value of whole date palm (WDP) with and without enzyme supplementation on aged laying hen's performance. Apparent metabolizable energy value of WDP was determined by the total collection method using ten adult leghorn cockerels. WDP was substituted with a corn-soybean meal basal diet at 40% level, and then the metabolizable energy of this experimental diet and basal diet was determined. After that, a total number of 256 Bovanz 95-week-old hens were randomly allocated into eight groups consisting of four replicates of eight birds each, based on a 4 * 2 factorial arrangement of the treatments. Eight iso-caloric and iso-nitrogenous experimental diets including one corn-soybean meal-based control diet and two, three, and four corn soybean meal-based diets included 70, 140, and 210 g/kg ground WDP, respectively. Each of the diets supplemented with two levels of an enzyme (0.0 and 0.07 g/kg Natozim Plus). There was no significant difference in feed intake, feed conversion ratio, egg production, egg mass, eggshell thickness, and Haugh unit among the treatments (P > 0.05). However, yolk color score significantly decreased as dietary WDP level increased. The serum biochemical metabolites were not significantly affected by WDP and enzyme supplementation (P > 0.05). There were no significant differences in the relative weight of different organs except for abdominal fat. Our findings show that using WDP up to 21% of the diet was more economic and had no adverse effect on productive performance and serum metabolites of laying hens. However, WDP had an adverse effect on yolk color which can be ameliorated by carotenoid supplementation. PMID- 28597142 TI - Simple Mindreading Abilities Predict Complex Theory of Mind: Developmental Delay in Autism Spectrum Disorders. AB - Theory of mind (ToM) is impaired in individuals with autism spectrum disorders (ASD). The aims of this study were to: (i) examine the developmental trajectories of ToM abilities in two different mentalizing tasks in children with ASD compared to TD children; and (ii) to assess if a ToM simple test known as eyes-test could predict performance on the more advanced ToM task, i.e. comic strip test. Based on a sample of 37 children with ASD and 55 TD children, our results revealed slower development at varying rates in all ToM measures in children with ASD, with delayed onset compared to TD children. These results could stimulate new treatments for social abilities, which would lessen the social deficit in ASD. PMID- 28597143 TI - Sexual Orientation, Gender Identity, and Romantic Relationships in Adolescents and Adults with Autism Spectrum Disorder. AB - This study compared sexual orientation and romantic relationship experience in a large sample of adolescents and adults with autism spectrum disorder (ASD) (n = 675) and general population peers (n = 8064). Gender identity was explored in the ASD group in relation to assigned gender at birth. Compared to general population peers, more people with ASD, especially women, reported sexual attraction to both same- and opposite-sex partners. About half of the participants with ASD was in a relationship (heterosexual in most cases) and most of them lived with their partner. A notable number of autistic participants, again more women than men, reported gender non-conforming feelings. Attention to gender identity and sexual diversity in education and clinical work with people with ASD is advised. PMID- 28597144 TI - Multicolor Flow Cytometry for the Diagnosis of Primary Immunodeficiency Diseases. AB - PURPOSE: Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs. METHODS: Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood. RESULTS: Multicolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X HIGM, AT, WAS, HIES, and CMCD. CONCLUSIONS: Immunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs. PMID- 28597145 TI - Quality of Life, Treatment Beliefs, and Treatment Satisfaction in Children Treated for Primary Immunodeficiency with SCIg. AB - Despite the development of subcutaneous treatment, children and adolescents with primary immunodeficiency (PID) are vulnerable to a lower quality of life (QoL) than non-clinical participants. Comparisons have been offered in rare reports with limited sample sizes. No description is available of treatment beliefs and treatment satisfaction with standard tools. The objective of this study was to describe a large sample of patients with pediatric PID on QoL, treatment beliefs and satisfaction, and identify perceived benefits and issues of treatment both in children and parents. A mail-back survey was conducted in 60 patients with PID treated with subcutaneous Ig and their parents from a clinic in Montreal (QC, Canada). We used the standardized tools to assess for QoL levels, beliefs of necessity and concerns with treatment, and dimensions of satisfaction. We collected and coded perceived benefits and issues through open-ended questions. We found lower QoL in children with PID than in healthy non-clinical participants (median d = 0.40) and similar QoL levels to children with cancer (median d = 0.12). Participants considered their treatment as less necessary and able to control the illness and less convenient than patients with other conditions. Children were more prone to consider the treatment as convenient (69 vs. 47% p = .028) but reported more discomfort (24 vs. 10% p = .043) than parents. Results suggest a lower-than-expected QoL in pediatric PID. Aspects of the illness and treatment are probably unclear to patients and their families, as necessity beliefs were lower than expected. Educational strategies should be developed and assessed to address this issue. PMID- 28597147 TI - MiR-338-3p inhibits TNF-alpha-induced lipogenesis in human sebocytes. AB - OBJECTIVE: To suppress TNF-alpha-induced lipogenesis in sebocytes (associated with acne development) with microRNA-338-3p (miR-338-3p) and to explore the underlying mechanisms. RESULTS: TNF-alpha increased lipid droplet formation in sebocytes which were used as in vitro model of inflammation-induced acne. Flow cytometry and TLC assays validated that miR-338-3p could suppress TNF-alpha induced lipid droplet formation, down-regulate the expression of PREX2a, and inactivate AKT signaling in sebocytes. In addition, suppression of AKT activity by the PI3 K and AKT inhibitors diminished TNF-alpha-induced lipogenesis. PREX2a siRNA mimics the effects of miR-338-3p on AKT phosphorylation and lipogenesis. PREX2a overexpression consistently restored lipogenesis and AKT phosphorylation attenuated by miR-338-3p. CONCLUSIONS: MiR-338-3p suppresses the TNF-alpha induced lipogenesis in sebocytes by targeting PREX2a and down-regulating PI3K/AKT signaling. PMID- 28597148 TI - Medicolegal Sidebar: Resident Physician Liability. PMID- 28597146 TI - Human IkappaBalpha Gain of Function: a Severe and Syndromic Immunodeficiency. AB - Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IkappaBalpha, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IkappaBalpha, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-kappaB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional alpha/beta T cells, and a lack of circulating gamma/delta T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IkappaBalpha underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT. PMID- 28597149 TI - The renal pathological findings in Japanese HIV-infected individuals with CKD: a clinical case series from a single center. AB - BACKGROUND: Chronic kidney diseases (CKD) have emerged as a significant cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). However, the detailed study of renal pathological findings currently remains unclear in these Japanese patients. METHODS: A retrospective cohort study was undertaken to investigate renal pathological findings between January 1996 and July 2016. Our study included 20 Japanese HIV-infected patients with CKD; 10 cases had undergone renal biopsies, and 10 cases had undergone autopsies, respectively. Moreover, in the 10 biopsied patients, their clinical courses as well as renal outcomes after renal biopsy were also reviewed. RESULTS: All of the patients had received combination antiretroviral therapy (cART). The 10 biopsy cases (mean age, 54 +/- 14 years and duration of cART, 8 +/- 5 years) included three cases of diabetic nephropathy (DMN), two of IgA nephropathy, two of cART induced tubulointerstitial nephritis (TIN), one of minimal change disease, one case of only finding intrarenal arterioles, and one case without abnormal findings. Among those patients, their clinical courses were preferable except for in the DMN cases. In the autopsy cases (mean age, 52 +/- 10 years and duration of cART, 5 +/- 5 years), no distinct mesangial or membranous abnormalities were detected. Mild to moderate tubulointerstitial atrophies were observed in six cases. Intrarenal arteriosclerosis was identified in nine cases, and the proportion of global glomerulosclerosis seen was 8.4 +/- 12.5%/100 glomeruli. CONCLUSION: DMN and cART-induced TIN was noted in the biopsy cases. In the autopsy cases, renal arteriosclerosis, global glomerulosclerosis, and tubulointerstitial atrophy were remarkable. Early diagnosis of kidney diseases should be crucial to introduce optimal management, including controlling rigorous comorbidities and appropriate use of cART, to prevent further progression of CKD. PMID- 28597150 TI - Erratum to: Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients. PMID- 28597151 TI - Outcomes and prognostic factors for relapsed or refractory lymphoma patients in phase I clinical trials. AB - Background Although safety and prognostic factors for overall survival (OS) have been extensively studied in Phase I clinical trials on patients with solid tumours, data on lymphoma trials are scarce. Here, we investigated safety, outcomes and prognostic factors in relapsed or refractory lymphoma patients included in a series of Phase I trials. Method and patients All consecutive adult patients with recurrent/refractory lymphoma enrolled in 26 Phase I trials at a single cancer centre in France between January 2008 and June 2016 were retrospectively assessed. Results 133 patients (males: 65%) were included in the analysis. The median (range) age was 65 (23-86). Aggressive non-Hodgkin, indolent non-Hodgkin and Hodgkin types accounted for 64%, 25% and 11% of the patients, respectively. The patients had received a median (range) of 3 (1-13) lines of treatment prior to trial entry. The median [95% confidence interval] progression free survival and OS times were 3.0 [1.8-3.6] and 17.8 [12.7-30.4] months, respectively. High-grade toxicity (grade 3 or higher, according to the National Cancer Institute's Common Terminology Criteria for Adverse Events classification) was experienced by 56 of the 133 patients (42%) and was related to the investigational drug in 44 of these cases (79%). No toxicity-related deaths occurred. Dose-limiting toxicity (DLT) was encountered in 11 (9%) of the 116 evaluable patients. High-grade toxicity occurred during the DLT period for 34 of the 56 patients (61%) and after the DLT period in the remaining 22 (39%). The main prognostic factors for poor OS were the histological type (i.e. tumour aggressiveness), an elevated serum LDH level, and a low serum albumin level. Early withdrawal from a trial was correlated with the performance status score, the histological type and the serum LDH level. The overall objective response and disease control rates were 24% and 57%, respectively. Conclusion Performance status, LDH, albumin and histological type (tumour aggressiveness) appear to be the most relevant prognostic factors for enrolling Phase I participants with relapsed or refractory lymphoma. 39% of the patients experienced a first high grade toxic event after the dose-limiting toxicity period, suggesting that the conventional concept of dose-limiting toxicity (designed for chemotherapy) should be redefined in the era of modern cancer therapies. PMID- 28597153 TI - Erratum to: A molecular phylogenetic framework for Bacillus subtilis using genome sequences and its application to Bacillus subtilis subspecies stecoris strain D7XPN1, an isolate from a commercial food-waste degrading bioreactor. PMID- 28597154 TI - COD reduction of textile effluent in three-phase fluidized bed bioreactor using Pseudomonas aureofaciens and Escherichia coli. AB - This paper investigated the effect of mixed cultures of Pseudomonas aureofaciens and Escherichia coli and air as gas on degradation of chemical oxygen demand (COD) in three-phase inverse fluidized beds (TPIFBs) for textile effluents with initial COD of 1200 ppm (effluent 1) and 640 ppm (effluent 2). Investigators focused on the importance of different design of gas spargers of the TPIFB for checking its effect on COD reduction performance. For this purpose, four different gas spargers were fabricated for gas flow entry into bioreactor with different % open area: Gas sparger 1 (18% open area), sparger 2 (10.42% open area), sparger 3 (8.077% open area) and sparger 4 (1.53% open area). These percentage open area decided the amount of gas flow in a unit time in batch studies, which in turn rely mainly on superficial gas velocity. The reduction in COD was measured at two different superficial gas velocity (0.00343 and 0.004068 m/s) and at two ratio of static bed height to diameter (H/D) of 0.5 and 0.25 in an aerobic mode. Textile effluent 1 resulted in 98.07% COD reduction with sparger 3 and discharged at 23.14 ppm in 28 h. Textile effluent 2 resulted in 96.5% COD reduction with sparger 2 and discharged at 22.4 ppm in 22 h. The resulting COD values of Effluent 1 and effluent 2 were in range of discharge limit and resulted at a low gas velocity of 0.00343 m/s and low H/D ratio of 0.25. The gas holdup correlation was found to be epsilon g = 0.0064 U g0.98 . PMID- 28597155 TI - Discriminatory power of rbcL barcode locus for authentication of some of United Arab Emirates (UAE) native plants. AB - DNA barcoding of United Arab Emirates (UAE) native plants is of high practical and scientific value as the plants adapt to very harsh environmental conditions that challenge their identification. Fifty-one plant species belonged to 22 families, 2 monocots, and 20 eudicots; a maximum number of species being legumes and grasses were collected. To authenticate the morphological identification of the wild plant taxa, rbcL and matK regions were used in the study. The primer universality and discriminatory power of rbcL is 100%, while it is 35% for matK locus for these plant species. The sequences were submitted to GenBank; accession numbers were obtained for all the rbcL sequences and for 6 of matK sequences. We suggest rbcL as a promising barcode locus for the tested group of 51 plants. In the present study, an inexpensive, simple method of identification of rare desert plant taxa through rbcL barcode is being reported. PMID- 28597152 TI - Glycosylation engineering of therapeutic IgG antibodies: challenges for the safety, functionality and efficacy. AB - Glycosylation of the Fc region of IgG has a profound impact on the safety and clinical efficacy of therapeutic antibodies. While the biantennary complex-type oligosaccharide attached to Asn297 of the Fc is essential for antibody effector functions, fucose and outer-arm sugars attached to the core heptasaccharide that generate structural heterogeneity (glycoforms) exhibit unique biological activities. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for the development and quality control of therapeutic antibodies, and glycan profiles of the Fc are recognized as critical quality attributes. In the past decade our understanding of the influence of glycosylation on the structure/function of IgG-Fc has grown rapidly through X-ray crystallographic and nuclear magnetic resonance studies, which provides possibilities for the design of novel antibody therapeutics. Furthermore, the chemoenzymatic glycoengineering approach using endoglycosidase-based glycosynthases may facilitate the development of homogeneous IgG glycoforms with desirable functionality as next-generation therapeutic antibodies. Thus, the Fc glycans are fertile ground for the improvement of the safety, functionality, and efficacy of therapeutic IgG antibodies in the era of precision medicine. PMID- 28597156 TI - Molecular characterization of indigenous Bacillus thuringiensis strains isolated from Kashmir valley. AB - Bacillus thuringiensis (Bt) being an eco-friendly bioinsecticide is effectively used in pest management strategies and, therefore, isolation and identification of new strains effective against a broad range of target pests is important. In the present study, new indigenous B. thuringiensis strains were isolated and investigated so that these could be used as an alternative and/or support the current commercial strains/cry proteins in use. For this, 159 samples including soil, leaf and spider webs were collected from ten districts of Kashmir valley (India). Of 1447 bacterial strains screened, 68 Bt strains were identified with 4 types of crystalline inclusions. Crystal morphology ranking among the Bt strains was spherical (69.11%) > spore attached (8.82%) > rod (5.88%) = bipyramidal (5.88%) > spherical plus rod (4.41%) > spherical plus bipyramidal (2.94%) = cuboidal (2.94%). SDS-PAGE investigation of the spore-crystal mixture demonstrated Bt strains contained proteins of various molecular weights ranging from 150 to 28 kDa. Insecticidal activity of the 68 indigenous Bt strains against Spodoptera litura neonates showed that Bt strain SWK1 strain had the highest mortality. Lepidopteron active genes (cry1, cry2Ab, cry2Ab) were present in six Bt strains. Further, analysis of a full-length cry2A gene (~1.9 kb) by PCR-RFLP in strain SWK1 revealed that it was a new cry2A gene in Bt strain SWK1 and was named as cry2Al1 (GenBank Accession No. KJ149819.1) using the Bt toxin nomenclature ( http://www.btnomenclature.info ). Insect bioassays with neonate larvae of S. litura and H. armigera showed that the purified Cry2Al1 is toxic to S. litura with LC50 2.448 ug/ml and H. armigera with LC50 3.374 ug/ml, respectively. However, it did not produce any mortality in third instar larvae of Aedes aegypti, Culex quinquefasciatus and Anopheles stephensi larvae/pupae insects (100 ug/ml) at 28 +/- 2 degrees C and 75 to 85% relative humidity under a photoperiod of 14L:10D. PMID- 28597157 TI - Optimization of cultivation conditions for biotechnological production of lipid by Rhodotorula kratochvilovae (syn, Rhodosporidium kratochvilovae) SY89 for biodiesel preparation. AB - Rhodotorula kratochvilovae (syn, Rhodosporidium kratochvilovae) SY89, an oleaginous yeast, isolated from Ethiopian soil, was grown under nitrogen-limited media. The capacity this with respect to biomass production, lipid yield and lipid content was evaluated. The influence of inoculum size, carbon sources, variations in glucose concentration, nitrogen sources, C/N ratio, pH, temperature, agitation, and aeration rate and incubation period were investigated. Inoculum size of 10% v/v, glucose as a carbon source at 50 g/L glucose, 0.50 g/L yeast extract and 0.31 g/L (NH4)2SO4, C/N ratio of 120, pH 5.5, incubation temperature of 30 degrees C, 225 rpm, 0.2 as aeration ratio and 144 h of incubation were found to be optimum conditions for lipid production. Then the yeast was grown in a batch bioreactor by combining the different optimized parameters together. Under the optimized conditions, the yeast gave maximum biomass (15.34 +/- 1.47 g/L), lipid yield (8.60 +/- 0.81 g/L) and lipid content (56.06 +/- 1.70%). The dominant fatty acids exhibited in order of their relative abundance (%w/w), were oleic, palmitic, linoleic, stearic, linolenic and palmitoleic acids. The concentration of saturated and monounsaturated fatty acids adds up 78.63 +/- 2.19%. This suggests that this strain could be used as a good feedstock for biodiesel production. PMID- 28597159 TI - Metabolite analysis of endophytic fungi from cultivars of Zingiber officinale Rosc. identifies myriad of bioactive compounds including tyrosol. AB - Endophytic fungi associated with rhizomes of four cultivars of Zingiber officinale were identified by molecular and morphological methods and evaluated for their activity against soft rot pathogen Pythium myriotylum and clinical pathogens. The volatile bioactive metabolites produced by these isolates were identified by GC-MS analysis of the fungal crude extracts. Understanding of the metabolites produced by endophytes is also important in the context of raw consumption of ginger as medicine and spice. A total of fifteen isolates were identified from the four varieties studied. The various genera identified were Acremonium sp., Gliocladiopsis sp., Fusarium sp., Colletotrichum sp., Aspergillus sp., Phlebia sp., Earliella sp., and Pseudolagarobasidium sp. The endophytic community was unique to each variety, which could be due to the varying host genotype. Fungi from phylum Basidiomycota were identified for the first time from ginger. Seven isolates showed activity against Pythium, while only two showed antibacterial activity. The bioactive metabolites identified in the fungal crude extracts include tyrosol, benzene acetic acid, ergone, dehydromevalonic lactone, N-aminopyrrolidine, and many bioactive fatty acids and their derivatives which included linoleic acid, oleic acid, myristic acid, n-hexadecanoic acid, palmitic acid methyl ester, and methyl linoleate. The presence of these varying bioactive endophytic fungi may be one of the reasons for the differences in the performance of the different ginger varieties. PMID- 28597158 TI - Fabrication, optimization, and characterization of noble silver nanoparticles from sugarcane leaf (Saccharum officinarum) extract for antifungal application. AB - Metal nanoparticles obtained from green route are gaining significant prominence as a result of their potential applications in nanomedicine and material engineering. Overall metal nanoparticles studied, silver nanoparticles (AgNPs) clutch prominent place in nanoparticles research field. Herein, we have reported the green synthesis of Saccharum officinarum leaf biomass extract-mediated synthesis of AgNPs. Initial nanoparticle production was confirmed by visual observation as color change from light yellow to bright brown color with yellow shade and spectrophotometrically at 450 nm and the various reaction conditions were optimized. The FTIR spectra of the biomass extract and synthesized AgNPs authorized the presence of phyto constituents as capping agent. The High Resolution-Transmission Electron Microscopy (HR-TEM) analyses confirm the morphology and the average particle size of AgNPs as ~28.2 nm. The crystalline nature oxide state and mean particle diameter of AgNPs were confirmed by X-ray diffraction (XRD) analysis, Selected Area Electron Diffraction (SAED) pattern and face-centered cubic (FCC). The obtained AgNPs show moderate to good antifungal activity against Phytophthora capsici, Colletotrichum acutatum and Cladosporium fulvum as 10, 12 and 14 mm zones of inhibition against synthesized AgNPs at 250 MUg/well, respectively. PMID- 28597160 TI - Purification and characterization of a newly serine protease inhibitor from Rhamnus frangula with potential for use as therapeutic drug. AB - Protease inhibitors from plants are well known to be potent inhibitors of the growth of bacteria, fungi, and even certain viruses which make them excellent candidates for use as the lead compounds for the development of novel antimicrobial agents for applications in medicine. In this study, Rhamnus frangula was selected as a protease inhibitor source. The maximum recovery of the protease inhibitor against trypsin was recorded in the crude extract made in 0.1 M phosphate buffer (pH 7.0) and isolated from the mature leaves. Then, the protease inhibitor designated as RfIP1 was purified to homogeneity by Sephadex G50 with an apparent molecular mass of 22.5 kDa and its N-terminal sequence exhibited a high degree of homology with known serine protease inhibitor sequences. The RfIP1 displayed maximal activity at pH 7 and 37 degrees C. It maintained almost 80% of its maximal activity through a large pH range. The thermo-stability of RfIP1 was markedly enhanced by BSA, CaCl2, and sorbitol, whereas the addition of Mg2+, Zn2+, NaTDC, SDS, DTT, and beta-ME significantly promoted inhibitory activity. The protease inhibitor displayed high inhibitory activity toward some known proteases (cathepsin B, chymotrypsin, collagenase, thrombin, and trypsin) that have more importance in pharmaceutical industry and it acted as potent inhibitor of some commercially proteases from Aspergillus oryzae, Bacillus sp, and Bacillus licheniformis. The protease inhibitor also possessed an appreciable antibacterial effect against both Gram-positive and Gram negative bacteria. PMID- 28597161 TI - Improved activity of beta-cyclodextrin glycosyltransferase from Bacillus sp. N 227 via mutagenesis of the conserved residues. AB - beta-Cyclodextrin glycosyltransferase (beta-CGTase) belongs to the alpha-amylase family of enzymes and converts starch to cyclic oligosaccharides called beta cyclodextrins (beta-CD). The beta-CGTase from alkalophilic Bacillus sp. N-227 was separately mutagenized to give three site-directed beta-CGTase mutants, Y127F, R254F and D355R, that showed enhanced cyclization activity towards a starch substrate from 1.64 to 2.1-folds. Kinetic studies indicate that the mutants had higher affinity towards the substrate than the wild type beta-CGTase. The Y127F mutant had the highest affinity which was indicated by the lowest K m of 15.30 mM and the highest catalytic activity. Increasing hydrophobicity around the catalytic center appeared to favor the cyclization activity of the mutants. The beta-CGTase and the three mutants showed optimal enzyme activity at 60 degrees C and pH 6.0. All the enzymes were stable for at least 60 min across a wide pH range (5.0-7.0). PMID- 28597162 TI - A modified protocol yields high-quality RNA from highly mucilaginous Dioscorea tubers. AB - Extraction of RNA from Dioscorea is difficult because of rich mucilage and secondary metabolite content. High-quality RNA is required for RT-PCR and transcriptome analysis. Different protocols and common extraction kits were used for RNA extraction in Dioscorea, but the results were not satisfactory. A CTAB based protocol with lithium chloride precipitation yielded good quality RNA. The RNA isolated using this protocol was successfully used for RT-PCR and transcriptome sequencing experiments. Mucilage content varies at different developmental stages of Dioscorea and the present protocol was effective in isolating RNA from such samples. Although the protocol was originally modified for tuber tissues, it can be used also for extraction of RNA from rhizome, root, shoot and leaf. PMID- 28597163 TI - Shift in microbial group during remediation by enhanced natural attenuation (RENA) of a crude oil-impacted soil: a case study of Ikarama Community, Bayelsa, Nigeria. AB - Acute and chronic pollution of environments with crude oil does not bode well for biota living within the vicinity of polluted environments. This is due to environmental and public health concerns on the negative impact of crude oil pollution on living organisms. Enhancing microbial activities by adding nutrients and other amendments had proved effective in pollutant removal during bioremediation. This study was carried out to determine how microbial group respond during remediation by enhanced natural attenuation (RENA) during a field scale bioremediation. Crude oil-polluted soil samples were collected (before, during, and after remediation) from a site undergoing remediation by enhanced natural attenuation (RENA) at Ikarama Community, Bayelsa State, Nigeria, and were analyzed for total petroleum hydrocarbon (TPH), polyaromatic hydrocarbon (PAH), and a shift in microbial community. The gas chromatography-flame ionization detector (GC-FID) results showed that the pollutant concentrations (TPH and PAH) reduced by 98 and 85%, respectively, after the remediation. Culturable hydrocarbon utilizing bacteria (CHUB) was highest (8.3 * 104 cfu/g) for sample collected during the remediation studies, whilst sample collected after remediation had low CHUB (6.1 * 104 cfu/g) compared to that collected before remediation (7.7 * 104 cfu/g). Analysis of 16S rRNA of the isolated CHUB showed they belonged to eight bacterial genera namely: Achromobacter, Alcaligenes, Azospirillus, Bacillus, Lysinibacillus, Ochrobactrum, Proteus, and Pusillimonas, with Alcaligenes as the dominant genus. In this study, it was observed that the bacterial community shifted from mixed group (Gram-positive and -negative) before and during the remediation, to only the latter group after the remediation studies. The betaproteobacteria groups were the dominant isolated bacterial phylotype. This study showed that RENA is an effective method of reducing pollutant concentration in crude oil-polluted sites, and could be applied to other polluted sites in the Niger Delta region of Nigeria to mitigate the devastating effects of crude oil pollution. PMID- 28597164 TI - Recombinant expression, characterization and application of a dihydrolipoamide dehydrogenase with diaphorase activity from Bacillus sphaericus. AB - Diaphorases are flavin-containing enzymes with potential applications in biotransfomation reactions, biosensor design and in vitro diagnostic tests. In this communication, we describe recombinant expression, characterization and application of a lipoamide dehydrogenase (DLD) with diaphorase activity from a strain of Bacillus sphaericus. The DLD gene consisting of 1413 bp encoding a protein of 470 amino acids was expressed in Escherichia coli BL21 (DE3) and the recombinant enzyme was characterized. B. sphaericus DLD catalyzed the reduction of NAD+ by dihydrolipoamide and exhibited NADH-dependent diaphorase activity. The molecular weight of purified enzyme was about 50 kDa, and determined to be a monomeric protein. Diaphorase was active and stable from pH 7.0 to 9.0 with an optimal activity at pH 8.5. It showed its maximal activity at temperature of 30 degrees C and was almost stable at temperatures between 25 and 30 degrees C. Different metal ions and inhibitors showed no influence on the activity of target enzyme. The K m and V max values for NADH were estimated to be 0.33 mM and 200.0 U/ml, respectively. Moreover, recombinant B. sphaericus diaphorase exhibited considerable potential to be used as a component of diagnostic tests for the quantification of metabolites. In conclusion, considering the properties of diaphorase from B. sphaericus PAD-91, it can have potential application as a diagnostic enzyme. PMID- 28597165 TI - Proteomic characterization and bio-informatic analysis of differentially expressed E. coli Nissle 1917 proteins with response to cocoti wine stress. AB - The present study emphases the comparative proteomic analysis of Escherichia coli Nissle 1917 under cocoti palm wine stress and identified differentially expressed proteins. Protein samples were analyzed by 2-D, MALDI-TOF combined with MS access. In 2-D electrophoresis, eight differentially expressed proteins were identified: five up-regulated, two down-regulated and one newly expressed protein. Protein spots were digested with trypsin for MALDI-TOF-MS analysis; protein sequences were obtained from MASCOT search. Sequences were aligned with template using Swiss Model server. Phyre-2 was used to predict homology modeling, RasMol was used to analyze the modeling structures, PSVS server was utilized to validate the protein structure by Ramachandran's plot analysis, physical and chemical properties were analyzed using ProtParam server, Phylogenetic tree was constructed by Mega4. UniProt search helps to find protein functional information of differentially expressed proteins, involved in catalytic activities, regulation mechanisms, DNA damage stimulus, anti-termination and termination process, protein binding, electron transport mechanism, and cell signaling process functions. A detailed exploration of the proteins under cocoti palm wine stress have provided the composition, structure and functions of the expressed proteins for further investigation. PMID- 28597166 TI - Sex allocation in gynodioecious Cyananthus delavayi differs between gender morphs and soil quality. AB - KEY MESSAGE: Sex allocation in Cyananthus delavayi. Gynodioecy, where females and hermaphrodites coexist in the same natural population, is particularly suitable for predicting the ecological pressures that drive the stability of gender polymorphism. Since females have a disadvantage in that they only contribute to the next generation via ovules, they should gain an advantage via other means, of which resource allocation is an important component. Thus, to study their sex allocation is very helpful to understand how the dimorphic sexual system is maintained in natural systems. We studied the sex allocation patterns and reproductive output of the gynodioecious Cyananthus delavayi in three populations with different soil qualities (organic matter, N, P and K). The hermaphroditic flowers and pistils were much larger than those of female individuals. Although both gender morphs invested similar biomass in the pistils, females allocated more of their resource pool to the seed production, while hermaphrodites allocated more to pollinator advertisement. The pollen production of hermaphrodites did not differ between populations, suggesting that pollen production by hermaphrodites was not limited by soil nutrients. Fruit set of females, but not hermaphrodites, decreased with declining soil quality, whereas seeds per fruit of both females and hermaphrodites were highest in poor soils. Overall, this study shows that females achieve greater reproductive success by allocating more of their resource pool to enhancing seed production, which should favor their presence in gynodioecious populations. The hermaphrodites achieve reproductive success from both pollen and seed production, and unnecessarily reduce their allocation to pollen production. Soil quality should explain, at least partially, the sexual allocation patterns. Furthermore, some of our findings contradict previous hypotheses, thus adding a new example to the body of research on plant sex allocation and the development of future theories. PMID- 28597167 TI - Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy. AB - Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 * 109/L) (P < 0.001) and high PB blast (>30 * 109/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index >=95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established. PMID- 28597169 TI - Erratum to: Good adherence to imatinib therapy among patients with chronic myeloid leukemia-a single-center observational study. PMID- 28597170 TI - Mathematical Model of Interaction Between Bacteriocin-Producing Lactic Acid Bacteria and Listeria. Part 1: Steady States and Thresholds. AB - Mathematical modeling is an important tool to assessing quantitative conjectures and to answer specific questions. In the modeling, we assume that a competitor represented by a lactic acid bacterium produces antimicrobial compounds (substances that kill microorganisms or inhibit their growth), such as lactic acid and bacteriocins, with some cost to its own growth. Bacteriocins are protein compounds with antimicrobial effect against related species and bacteria such as Listeria monocytogenes, which is foodborne pathogen that cause listeriosis. From the analysis of the model, we found the thresholds which determine the existence of multiple equilibria and we studied their stability, in order to evaluate the interaction between lactic acid bacteria and L. monocytogenes. PMID- 28597168 TI - Treatment of refractory autoimmune hemolytic anemia with venetoclax in relapsed chronic lymphocytic leukemia with del(17p). PMID- 28597171 TI - Hypopituitarism is associated with lower oxytocin concentrations and reduced empathic ability. AB - PURPOSE: Central diabetes insipidus is characterised by arginine vasopressin deficiency. Oxytocin is structurally related to vasopressin and is synthesised in the same hypothalamic nuclei, thus we hypothesised that patients with acquired central diabetes insipidus and anterior hypopituitarism would display an oxytocin deficiency. Moreover, psychological research has demonstrated that oxytocin influences social and emotional behaviours, particularly empathic behaviour. We therefore further hypothesised that central diabetes insipidus patients would perform worse on empathy-related tasks, compared to age-matched and gender matched clinical control (clinical control-isolated anterior hypopituitarism) and healthy control groups. METHOD: Fifty-six participants (age 46.54 +/- 16.30 yrs; central diabetes insipidus: n = 20, 8 males; clinical control: n = 15, 6 males; healthy control: n = 20, 7 males) provided two saliva samples which were analysed for oxytocin and completed two empathy tasks. RESULTS: Hypopituitary patients (both central diabetes insipidus and clinical control groups) had significantly lower oxytocin concentrations compared to healthy control participants. Hypopituitary patients also performed significantly worse on both the reading the mind in the eyes task and the facial expression recognition task compared to healthy control participants. Regression analyses further revealed that central diabetes insipidus patients' oxytocin concentrations significantly predicted their performance on easy items of the reading the mind in the eyes task. CONCLUSIONS: Hypopituitarism may therefore be associated with reduced oxytocin concentrations and impaired empathic ability. While further studies are needed to replicate these findings, our data suggest that oxytocin replacement may offer a therapeutic approach to improve psychological well-being in patients with hypopituitarism. PMID- 28597172 TI - The P2X7 receptor is not essential for development of imiquimod-induced psoriasis like inflammation in mice. AB - Psoriasis is a chronic inflammatory skin disorder, characterised by epidermal hyperplasia (acanthosis) and leukocyte infiltration of the skin. Current therapies are inadequate, highlighting the need for new therapeutic targets. The P2X7 receptor is implicated in the pathogenesis of psoriasis. This study investigated the role of P2X7 in imiquimod (IMQ)-induced psoriasis-like inflammation. Topically applied IMQ caused twofold greater ear swelling in BALB/c mice compared to C57BL/6 mice, which encode a partial loss-of-function missense mutation in the P2RX7 gene. However, there was no difference in histological skin pathology (acanthosis and leukocyte infiltration) between the two strains. IMQ treatment up-regulated P2X7 expression in skin from both mouse strains. Additionally, IMQ induced ATP release from cultured human keratinocytes, a process independent of cell death. Injection of the P2X7 antagonist Brilliant Blue G (BBG) but not A-804598 partly reduced ear swelling compared to vehicle injected control mice. Neither antagonist altered skin pathology. Moreover, no difference in ear swelling or skin pathology was observed between C57BL/6 and P2X7 knock-out (KO) mice. Flow cytometric analysis of IMQ-treated skin from C57BL/6 and P2X7 KO mice demonstrated similar leukocyte infiltration, including neutrophils, macrophages and T cells. In conclusion, this study demonstrates that P2X7 is not essential for development of IMQ-induced psoriasis-like inflammation but does not exclude a role for this receptor in psoriasis development in humans or other mouse models of this disease. PMID- 28597174 TI - Unlicensed and off-label use of drugs in pediatric surgical units at tertiary care hospitals of Pakistan. AB - Background Unlicensed and off-label prescribing practice is global dilemma around the world. This pioneering study was designed to determine unlicensed and off label use of drug in surgical wards of tertiary care hospitals of Pakistan. Objective To assess unlicensed and off-label use of drugs in pediatric surgical unit at three tertiary care hospitals in Peshawar, Pakistan. Setting Two government and one private tertiary care hospitals in Pakistan. Method Drug profiles of 895 patients from three different clinical settings were evaluated for unlicensed and off-label use of drugs using Micromedex DRUGDEX. Main outcome measure Characteristics of the unlicensed and off-label drug prescriptions. Result Total of 3168 prescribed drugs were analyzed in this study. Indication (38.7%) and dose (34.8%) were the most frequent off-label categories. In comparison with the corresponding reference categories, infants and children, male patients and having less than five prescribed drugs were significant predictors of unlicensed prescriptions. In comparison with the corresponding reference categories, significant predictors of off-label drug prescribing were children younger than two year, children between 2-12 years, patient staying at hospital less than 5 days and patients having less than five prescribed drugs. Conclusion The prevalence of unlicensed and off-label drug prescriptions are high at pediatric surgical ward of tertiary care hospitals. More awareness of the efficacy and safety of drugs are required in pediatrics. In addition, new formulations with advanced dosing for children are also required to minimize the risk of adverse outcomes. PMID- 28597175 TI - Distribution of CYP2C19 polymorphisms in Mongolian and Han nationals and the choice of specific antiplatelet drugs. AB - Background Individualized medication reviews may improve our understanding of the distribution of CYP2C19 polymorphisms in ethnic populations. Objective To evaluate differences in CYP2C19 gene polymorphisms between Mongolian and Han nationals and determine the effect of adjustments of antiplatelet treatments according to the genetic profile in patients undergoing percutaneous coronary intervention (PCI). Setting Prospective, observational, single-center study. Methods 397 patients diagnosed with acute coronary syndrome were enrolled. Additionally, 186 patients undergoing PCI were given different treatments according to their CYP2C19 genotypes. Patients with the genotype of an extensive metabolizers (EMs; *1/*1) were co-administered aspirin 100 mg/day and clopidogrel 75 mg/day, following a loading dose of 300 mg; intermediate metabolizers (IMs; e.g., *1/*2 and *1/*3) and poor metabolizers (PMs; e.g., *2/*2 and *2/*3) were administered a loading dose of 180 mg ticagrelor, followed by a maintenance dose of 90 mg twice a day. Results In Mongolians, 60.79% of patients were EMs, which was significantly higher than that in Han nationals (P = 0.002). In Han individuals, 62.14% of patients were IMs and PMs, which was significantly higher than that in Mongolians (P < 0.05). Three patients died, and the frequency of adverse events during follow-up was significantly higher in patients given conventional treatment than in patients given tailored treatment (P = 0.039). However, differences in metabolism subtypes did not affect the incidence of adverse reactions. Conclusions There were differences in CYP2C19 polymorphisms between Mongolians and Hans. Effective, safe therapy was achieved by tailoring antiplatelet drug therapy based on genotype. PMID- 28597173 TI - Problems, interventions, and their outcomes during the routine work of hospital pharmacists in Bosnia and Herzegovina. AB - Background In the last 30 years, activities of hospital pharmacists have gone through significant changes. Pharmacists are increasingly involved in patient care. Objectives To explore drug-related and logistic problems, interventions, and their outcomes during routine everyday work of hospital pharmacists. Setting Institute for physical medicine and rehabilitation, Banja Luka, Bosnia and Herzegovina. Methods In the period of January 2013-October 2015 a prospective observational study was performed. Medical doctors, nurses, therapists, and patients addressed pharmacists, face-to-face or by telephone, with drug-related problems (DRPs) and/or logistic issues. Main outcome measure Type of DRP or logistic issue, intervention, outcome, initiator and time spent for solving the problem were documented for each consultation. Results Out of 1515 interventions, 48.8% were aimed at solving DRPs. The most common DRPs were the recommendation of a drug or dose and need for additional information about drugs. Drug price and supply were the most prevalent logistic issues. DRPs were more frequently initiated by medical doctors and required more time to solve the problem compared to logistic issues (Mann-Whitney U test, p <= 0.001, respectively). The acceptance rate of interventions to solve DRPs (83.7%) was lower compared to logistic issues (95.2%; p <= 0.001). Conclusions Hospital pharmacists were faced with an approximately equal number of DRPs and logistic issues during their routine everyday work. The overall acceptance rate of pharmacists' interventions was high, and the results of our study indicate that there is a need for more involvement of hospital pharmacists in Bosnia and Herzegovina in clinical activities. Impact on practice. PMID- 28597176 TI - Self-management research of asthma and good drug use (SMARAGD study): a pilot trial. AB - Background Community pharmacists play an important role in supporting patients for optimal drug use. Objective To assess the effectiveness of monitoring in asthma patients with inhaled corticosteroids (ICS) on disease control. Setting Asthma patients using ICS were invited from two intervention (IG) and two control pharmacies (CG). Method Participating patients completed questionnaires at the study start and at 6-month follow-up, including the Control of Allergic Rhinitis and Asthma Test (CARAT) questionnaire. IG patients completed the CARAT questionnaire every 2 weeks and received counselling on disease management, ICS adherence, and inhalation technique when scores were suboptimal, deteriorating, or absent. For Turbuhaler users, additional electronic monitoring (EMI) was available, with daily alerts for ICS intake. Main outcome measure As the primary outcome, CARAT scores at follow-up were compared between IG and CG using linear regression. As secondary outcome, refill adherence was compared using logistic regression. Results From March to July 2015, we enrolled 39 IG and 41 CG patients. At follow-up, CARAT scores did not differ between IG and CG (-0.19; 95% confidence interval [CI], -2.57 to 2.20), neither did patient numbers with ICS adherence >80% (0.82; 95% CI, 0.28-2.37). Among EMI users, CARAT scores did not differ, but ICS adherence >80% showed a 4.52-fold increase (95% CI, 1.56-13.1) compared with EMI nonusers. Conclusion Among community-dwelling asthma patients, pharmacist monitoring did not affect CARAT scores, but EMI use showed improved ICS refill adherence. PMID- 28597177 TI - Dynamical Systems Modeling of Couple Interaction: a New Method for Assessing Intervention Impact Across the Transition to Parenthood. AB - This study explored the use of dynamical systems modeling techniques to evaluate self- and co-regulation of affect in couples' interactions before and after the transition to parenthood, and the impact of the Family Foundations program on these processes. Thirty-four heterosexual couples, randomized to intervention and control conditions, participated in videotaped dyadic interaction tasks at pretest (during pregnancy) and posttest (1 year after birth). Husbands' and wives' positivity and negativity were micro-coded throughout interactions. Individual negativity set-points, self-regulation, and partner co-regulatory processes during interactions were examined using a coupled oscillators model. Regarding self-regulatory processes, men exhibited amplification of negativity at the prenatal assessment that did not change at the postnatal assessment; women demonstrated no significant damping or amplification at pretest and a marginally significant change towards greater amplification at the postnatal assessment. In terms of partner-influenced regulatory dynamics, men's positive behaviors changed from damping to amplifying women's negative behaviors in the control group following the transition to parenthood, but exerted an even stronger damping effect on women's negative behaviors in the intervention group. The study highlights the advantages of dynamic modeling approaches in testing specific hypotheses in the study of self- and co-regulatory couple dynamics and demonstrates the potential of studying dynamic processes to further understanding of developmental and intervention-related change mechanisms. PMID- 28597178 TI - Comment on: "Assessing Pruritus in Hidradenitis Suppurativa: A Cross-Sectional Study". PMID- 28597179 TI - Comment on: Facial Hyperpigmentation in Skin of Color: Special Considerations and Treatment. PMID- 28597180 TI - Author's Reply to Cohen: Facial Hyperpigmentation in Skin of Color: Special Considerations and Treatment. PMID- 28597181 TI - Clinical Signs, Pathophysiology and Management of Cutaneous Side Effects of Anti Tumor Necrosis Factor Agents. AB - Approximately one in four patients treated with anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab, and golimumab) develops cutaneous adverse events, typically months to years after the initiation of treatment, with xerosis cutis, eczema (often psoriasiform), psoriasis, palmoplantar pustulosis, cutaneous infections, alopecia, and skin cancer being the most frequently encountered. The typical skin lesion of anti-tumor necrosis factor (TNF)-treated patients is orange-red psoriasiform eczema affecting the flexures, genitalia, scalp, or face, with high susceptibility to bacterial superinfection with Staphylococcus aureus. When adequate dermatological treatment is administered to patients with skin lesions receiving anti-TNF treatment, the discontinuation of anti-TNF agents is only rarely required. Smoking, female sex, and Crohn's disease are most frequently observed as risk factors for anti-TNF-induced cutaneous adverse events. The underlying pathophysiology is still poorly understood, but epidermal permeability barrier dysfunction, increased susceptibility to bacterial superinfection, and cytokines derived from T helper (Th) 1 (interferon-gamma), Th17 cells (interleukin [IL]-17A and IL-22), plasmocytic dendritic cells (interferon-alpha), and keratinocytes (IL-36gamma and IL-17C) appear to play a role. In this review, we describe the clinical characteristics, risk factors, pathophysiology, and management of cutaneous adverse events of patients treated with anti-TNF agents. In addition, we try to give some practical guidance on how to prevent and manage the skin changes in anti-TNF-treated patients, based on our own experience with dermatological care in a large cohort of inflammatory bowel disease patients receiving anti-TNF therapy. PMID- 28597182 TI - Apremilast: A Novel Oral Treatment for Psoriasis and Psoriatic Arthritis. AB - Psoriasis is a chronic immune-mediated disease associated with several co morbidities and negative impacts on a patient's quality of life. Despite the advances in biologic therapy, there are still unmet needs in the treatment of psoriasis, as current treatments are limited in terms of long-term efficacy, tolerability, safety, route of administration, and cost. Apremilast is an oral, small-molecule phosphodiesterase 4 inhibitor that works intracellularly by blocking the degradation of cyclic adenosine 3',5'-monophosphate, resulting in increased intracellular cyclic adenosine 3',5'-monophosphate levels in phosphodiesterase 4-expressing cells. This inhibition results in the reduced expression of proinflammatory mediators, and an increased expression of anti inflammatory mediators, providing apremilast with an anti-inflammatory rather than immunosuppressive mode of action. Apremilast offers a novel therapeutic option for patients with psoriasis and psoriatic arthritis and may fulfill some of the unmet needs in patients with psoriasis. Potential advantages of apremilast include moderate activity for both psoriasis and psoriatic arthritis and efficacy in difficult-to-treat forms of psoriasis, a good safety profile, no need of laboratory prescreening or ongoing monitoring for laboratory parameters, owing to the absence of organ toxicity, a potentially advantageous weight loss effect, and a convenient oral administration and dosing. Cost effectiveness and health economics considerations will be decisive in determining the ultimate place of apremilast in the therapeutic armamentarium for psoriasis. PMID- 28597183 TI - Discrepancies between NCCN and ESMO guidelines in the management of anal cancer: a qualitative review. AB - There is an ever-growing need, with the ongoing developments in research and the progress towards patient centered care, to delineate standardized protocols of management of anal cancer. However, guidelines from different societies show some degree of disagreement. This is a systematic review of the literature to identify similarities and discrepancies between the guidelines for the management of anal cancer drafted by the European Society for Medical Oncology (ESMO) and by the National Comprehensive Cancer Network (NCCN). We found essentially similar management for investigation, diagnosis, chemotherapy regimens, and radiotherapy doses in both ESMO and NCCN recommendations in the management of anal cancer. There were few differences, which included the levels of evidence and grades of recommendations, the delineation of radiotherapy fields, and the treatment of the elderly and personalized medicine based on genetics. The follow-up regime is also marginally different in the first 2 years. Even if the observed differences may be justified by a different implementation of evidence-based medicine among different countries for particular management modalities of anal cancer, we identified the grey areas which need further study. In addition, these facets should be assessed more carefully when planning future guidelines. PMID- 28597184 TI - Epithelial membrane protein-2 (EMP2) promotes angiogenesis in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is associated with an extremely poor clinical prognosis. One pathologic hallmark of GBM is excessive vascularization with abnormal blood vessels. Extensive investigation of anti-angiogenic therapy as a treatment for recurrent GBM has been performed. Bevacizumab, a monoclonal anti-vascular endothelial growth factor A (VEGF-A), suggests a progression-free survival benefit but no overall survival benefit. Developing novel anti-angiogenic therapies are urgently needed in controlling GBM growth. In this study, we demonstrate tumor expression of epithelial membrane protein-2 (EMP2) promotes angiogenesis both in vitro and in vivo using cell lines from human GBM. Mechanistically, this pro-angiogenic effect of EMP2 was partially through upregulating tumor VEGF-A levels. A potential therapeutic effect of a systemic administration of anti-EMP2 IgG1 on intracranial xenografts was observed resulting in both significant reduction of tumor load and decreased tumor vasculature. These results suggest the potential for anti-EMP2 IgG1 as a promising novel anti-angiogenic therapy for GBM. Further investigation is needed to fully understand the molecular mechanisms how EMP2 modulates GBM pathogenesis and progression and to further characterize anti-EMP2 therapy in GBM. PMID- 28597185 TI - Neural Correlates of Sensory Hyporesponsiveness in Toddlers at High Risk for Autism Spectrum Disorder. AB - Altered patterns of sensory responsiveness are a frequently reported feature of Autism Spectrum Disorder (ASD). Younger siblings of individuals with ASD are at a greatly elevated risk of a future diagnosis of ASD, but little is known about the neural basis of sensory responsiveness patterns in this population. Younger siblings (n = 20) of children diagnosed with ASD participated in resting electroencephalography (EEG) at an age of 18 months. Data on toddlers' sensory responsiveness were obtained using the Sensory Experiences Questionnaire. Correlations were present between hyporesponsiveness and patterns of oscillatory power, functional connectivity, and signal complexity. Our findings suggest that neural signal features hold promise for facilitating early identification and targeted remediation in young children at risk for ASD. PMID- 28597186 TI - Problem Behaviors in Autism Spectrum Disorder: Association with Verbal Ability and Adapting/Coping Skills. AB - Data from the Autism Inpatient Collection was used to examine the relationship between problem behaviors and verbal ability, which have generally, though not universally, been highly associated. In a comparison of 169 minimally-verbal and 177 fluently-verbal 4 to 20-year-old psychiatric inpatients with ASD, the severity of self-injurious behavior, stereotyped behavior, and irritability (including aggression and tantrums) did not significantly differ, when controlling for age and NVIQ. Verbal ability was not strongly related to the severity of problem behaviors. However, lower adapting/coping scores were significantly associated with increasing severity of each type of problem behavior, even when accounting for verbal ability. Interventions to develop adapting/coping mechanisms may be important for mitigation of problem behaviors across the spectrum of individuals with ASD. PMID- 28597187 TI - Examining the Role of Race, Ethnicity, and Gender on Social and Behavioral Ratings Within the Autism Diagnostic Observation Schedule. AB - The Autism Diagnostic Observation Schedule (ADOS) is widely used to assess symptoms of autism spectrum disorder (ASD). Given well-documented differences in social behaviors across cultures, this study examined whether item-level biases exist in ADOS scores across sociodemographic groups (race, ethnicity, and gender). We examined a subset of ten ADOS items among participants (N = 2458). Holding level of overall ADOS behavioral symptoms constant, we found significant item level bias (measurement noninvariance) for race and ethnicity on three ADOS items. Item-level bias was not apparent across gender. Although the magnitude of bias was small, our findings highlight the need to reevaluate norms and operational definitions used in assessments to increase ASD diagnostic accuracy among culturally-diverse groups. PMID- 28597188 TI - Modulation of Global and Local Processing Biases in Adults with Autistic-like Traits. AB - Previous work shows that doing a continuous performance task (CPT) shifts attentional biases in neurotypical individuals towards global aspects of hierarchical Navon figures by selectively activating right hemisphere regions associated with global processing. The present study examines whether CPT can induce similar modulations of attention in individuals with high levels of autistic traits who typically show global processing impairments. Participants categorized global or local aspects of Navon figures in pre- and post-CPT blocks. Post-CPT, high trait individuals showed increased global interference during local categorization. This result suggests that CPT may be useful for temporarily enhancing global processing in individuals with high levels of autistic traits and possibly those diagnosed with autism. PMID- 28597190 TI - The prevalence of REM-related obstructive sleep apnoea is reduced by the AASM 2012 hypopnoea criteria. AB - PURPOSE: The variations in reported prevalence of rapid eye movement-related obstructive sleep apnoea (REM-OSA) have been attributed to different definitions, although the effect of hypopnoea criteria has not been previously investigated. METHODS: Within this retrospective study, 134 of 382 consecutive patients undertaking polysomnography (PSG) for the suspicion of OSA met the inclusion criteria. PSGs were scored using both the 2007 AASM recommended hypopnoea criteria (AASM2007Rec) and the 2012 AASM recommended hypopnoea criteria (AASM2012Rec). For each hypopnoea criteria, REM-OSA patients were grouped as REM related [either as REM-predominant OSA (rpOSA) or REM-isolated OSA (riOSA)] or non-stage-specific OSA (nssOSA). Outcome measures (SF-36, FOSQ and DASS-21) were also compared between groups. RESULTS: Incorporation of the AASM2012Rec criteria compared to the AASM2007Rec criteria increased the apnoea-hypopnoea index (AHI) for NREM and REM sleep but decreased the AHIREM/AHINREM ratio from 1.9 to 1.3 (p < 0.001). It also decreased the prevalence of riOSA [15.7 vs 2.2% (p < 0.001) for AASM2007Rec and AASM2012Rec, respectively]. The prevalence of rpOSA remained the same for each hypopnoea criteria although the prevalence of nssOSA increased with the AASM2012Rec hypopnoea criteria [53.0 vs 66.4% (p < 0.006) for AASM2007Rec and AASM2012Rec, respectively]. There were no differences in clinical symptoms between the groups, irrespective of hypopnoea criteria used. CONCLUSIONS: This study demonstrates that in comparison with AASM2007Rec, the AASM2012Rec hypopnoea criteria reduce the prevalence of riOSA but not rpOSA by reducing the ratio of REM respiratory events and NREM respiratory events. PMID- 28597189 TI - A podocyte view of membranous nephropathy: from Heymann nephritis to the childhood human disease. AB - Membranous nephropathy (MN) is characterized by an accumulation of immune deposits on the subepithelial side of the glomerular basement membrane, which results in complement activation and proteinuria. Since 2002, several major antigens of the podocyte have been identified in human MN, the first one being neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. This discovery opened the field to the major advances that have occurred since then in the pathophysiology and treatment of MN. It is remarkable that experimental models such as Heymann nephritis and cationic bovine serum albumin-induced MN in the rabbit predicted the pathomechanisms of the human glomerulopathy. The podocyte is at the center of the pathogenesis of MN either by providing a source of endogenous antigens or by creating an environment favorable to deposition and accumulation of immune complexes containing exogenous (non-podocyte) antigens. The podocyte is also a victim of complement activation and antibody blocking activity against enzymes or receptors. A search for innovative drugs aimed at protecting this cell against complement activation and the effects of prolonged ER stress has become a priority. PMID- 28597191 TI - Theoretical analysis of the binding of iron(III) protoporphyrin IX to 4 methoxyacetophenone thiosemicarbazone via DFT-D3, MEP, QTAIM, NCI, ELF, and LOL studies. AB - Thiosemicarbazones display diverse pharmacological properties, including antimalarial activities. Their pharmacological activities have been studied in depth, but little of this research has focused on their antimalarial mode of action. To elucidate this antimalarial mechanism, we investigated the nature of the interactions between iron(III) protoporphyrin IX (Fe(III)PPIX) and the thione thiol tautomers of 4-methoxyacetophenone thiosemicarbazone (MAPTSC). Dispersion corrected density functional theory (DFT-D3), the quantum theory of atoms in molecules (QTAIM), the noncovalent interaction (NCI) index, the electron localization function (ELF), the localized orbital locator (LOL), and thermodynamic calculations were employed in this work. Fe(III)PPIX-MAPTSC binding is expected to inhibit hemozoin formation, thereby preventing Fe(III)PPIX detoxification in plasmodia. Preliminary studies geared toward the identification of atomic binding sites in the thione-thiol tautomers of MAPTSC were carried out using molecular electrostatic potential (MEP) maps and conceptual DFT-based local reactivity indices. The thionic sulfur and the 2 N-azomethine nitrogen/thiol sulfur of, respectively, the thione and thiol tautomers of MAPTSC were identified as the most favorable nucleophilic sites for electrophilic attack. The negative values of the computed Fe(III)PPIX-MAPTSC binding energies, enthalpies, and Gibbs free energies are indicative of the existence and stability of Fe(III)PPIX-MAPTSC complexes. MAPTSC-Fe(III) coordinate bonds and strong hydrogen bonds (N-H...O) between the NH2 group in MAPTSC and the C=O group in one propionate side chain of Fe(III)PPIX are crucial to Fe(III)PPIX-MAPTSC binding. QTAIM, NCI, ELF, and LOL analyses revealed a subtle interplay of weak noncovalent interactions dominated by dispersive-like van der Waals interactions between Fe(III)PPIX and MAPTSC that stabilize the Fe(III)PPIX-MAPTSC complexes. PMID- 28597193 TI - Concentrate supplementations of grazing pregnant Kalahari Red goats: Effects on pregnancy variables, reproductive performance, birth types and weight of kids. AB - A study was conducted for 22 weeks to determine the effects of concentrate supplementations at three crude protein (CP) levels, i.e. low protein diet-LPD 12.42% CP (124.93 g day-1); medium protein diet-MPD 14.18% CP (145.87 g day-1) and high protein diet-HPD 16.35% CP (168.19 g day-1) on some pregnancy variables, reproductive performance, birth types and weight of kids kidded by pregnant Kalahari Red goats grazed on Chloris gayana. Thirty-three matured Kalahari Red goats of first parity within age range of 2 to 21/2 years with an average body weight of 38.10 +/- 1.13 kg were randomly allotted to the diets with 11 goats per treatment. Data obtained were subjected to analysis of variance in a completely randomised design. It was observed that goats fed HPD had the highest (p < 0.05) values for products of pregnancy (10.35 kg) taken within 24hour before kidding and foetal growth rate (88.37 g day-1) during pregnancy. Goats fed MPD had the lowest values (p < 0.05) of 9.28 kg and 80.07 g day-1 for each of the respective parameters. Afterbirth weight was also the highest and lowest (p < 0.05) for goats supplemented with HPD (3.38 kg) and MPD (3.04 kg), respectively. On the other hand, MPD-supplemented goats had the highest values (p < 0.05) for litter size (2.14) and litter weight (6.80 kg) at birth, the value which was the least for HPD supplementation. From the results obtained from this study, it could be concluded that concentrate diet supplementation with 14.18% CP improved litter size and weight at birth with resultant reduction in weights of pregnancy variables of pregnant Kalahari Red goats grazed on Rhodes grass. PMID- 28597194 TI - A social Bouba/Kiki effect: A bias for people whose names match their faces. AB - The "bouba/kiki effect" is the robust tendency to associate rounded objects (vs. angular objects) with names that require rounding of the mouth to pronounce, and may reflect synesthesia-like mapping across perceptual modalities. Here we show for the first time a "social" bouba/kiki effect, such that experimental participants associate round names ("Bob," "Lou") with round-faced (vs. angular faced) individuals. Moreover, consistent with a bias for expectancy-consistent information, we find that participants like targets with "matching" names, both when name-face fit is measured and when it is experimentally manipulated. Finally, we show that such bias could have important practical consequences: An analysis of voting data reveals that Senatorial candidates earn 10% more votes when their names fit their faces very well, versus very poorly. These and similar cross-modal congruencies suggest that social judgment involves not only amodal application of stored information (e.g., stereotypes) to new stimuli, but also integration of perceptual and bodily input. PMID- 28597192 TI - Pre-banking microbial contamination of donor conjunctiva and storage medium for penetrating keratoplasty. AB - PURPOSE: The aims of this study were to investigate the incidence of positive donor tissue cultures before transfer to preservation medium (OptisolTM-GS) for penetrating keratoplasty, to verify the efficacy of antibiotics contained in OptisolTM-GS by examining the drug susceptibility and to assess the relationship between the results of our microbial assessments as well as donor factors and the incidence of contamination. METHODS: We conducted a retrospective, cross sectional study using Juntendo Eye Bank records for all corneal transplantations. Two hundred donor conjunctiva harvestings and storage medium (EP-II(r)) cultures were performed between July 2008 and June 2011. We analyzed the associations between donor factors (age, gender, history of cataract surgery, death-to preservation interval, cause of death) and contamination rates using multivariate analysis by the generalized estimating equation model. RESULTS: We obtained positive bacterial cultures from 154 of the 200 eyes (77.0%). The isolated bacteria were indigenous, such as coagulase-negative Staphylococci, Corynebacterium sp., and methicillin-resistant Staphylococcus aureus (MRSA). There was significant resistance to levofloxacin (18 eyes, 9.0%) and gentamicin (12 eyes, 6.0%), and no vancomycin-resistant bacteria were detected. The donor factors did not correlate with the prevalence of bacterial contamination in our criteria. CONCLUSIONS: Pre-banking microbial assessment allows for microbial detection, bacterial susceptibility and resistance testing. This is useful for developing preservation mediums containing effective spectrum antibiotic agents for high quality control of corneal banking. PMID- 28597195 TI - Identification of epitopes on nonstructural protein 7 of porcine reproductive and respiratory syndrome virus recognized by monoclonal antibodies using phage display technology. AB - Nonstructural protein 7 (nsp7) of porcine reproductive and respiratory syndrome virus (PRRSV) is considered to be a suitable reagent for the development of serological diagnostic assays. It can be expressed as a soluble recombinant protein in Escherichia coli, and its antibody response may continue up to 202 days post-infection. Furthermore, the region encoded by nsp7 is highly homologous among various strains within the genotype, and the results of nsp7-based enzyme linked immunosorbent assay (ELISA) showed high agreement with previous Idexx ELISA results. All these evidences suggest the existence of important epitopes on nsp7, though the characteristics of these epitopes remain unclear. In the present study, we prepared three monoclonal antibodies against nsp7 protein and used them to screen the epitope-distribution characteristics of PRRSV nsp7 protein by phage display technology. We identified a linear epitope NAWGDEDRLN at amino acids 153 162 type II PRRSV nsp7beta subunit. This newly defined epitope showed excellent reactivity with PRSSV-positive serum samples. These results further our understanding of the antigenic structure of nsp7 protein, and provide efficient reagents for PRRSV serological tests. PMID- 28597196 TI - Draft genome sequence of the potato pathogen Rhizoctonia solani AG3-PT isolate Ben3. AB - The basidiomycetes fungus Rhizoctonia solani AG3 is responsible for black scurf disease on potato and occurs in each potato growing area world-wide. In this study, the draft genome sequence of the black scurf pathogen R. solani AG3-PT isolate Ben3 is presented. The genome sequence of R. solani AG3-PT isolate Ben3 consists of 1385 scaffolds. These scaffolds amount to a size of approx. 51 Mb. Considering coverage analyses of contigs, the size of the diploid genome was estimated to correspond to 116 Mb. Gene prediction by applying AUGUSTUS (3.2.1.) resulted in 12,567 identified genes. Based on automatic annotation using GenDBE, genes potentially encoding cellulases and enzymes involved in secondary metabolite synthesis were identified in the R. solani AG3-PT isolate Ben3 genome. Comparative analyses including the R. solani AG3 isolate Rhs1AP, also originating from potato, revealed first insights into core genes shared by both isolates and unique determinants of each isolate. PMID- 28597197 TI - Effect of environmental stress on cell surface and membrane fatty acids of Lactobacillus plantarum. AB - Adhesion has been regarded as one of the basic features of probiotics. We undertake this study in the aim to give new insight about the change in cellular physiological state under heat and acid treatments of Lactobacillus plantarum. Different cell properties have been investigated such as adhesive ability to abiotic surfaces, the cell surface hydrophobicity and the fatty acids profiles. The results of cell surface properties and Gas chromatography analysis demonstrated a modification in term adhesive ability and fatty acid (FA) composition of the tested strain under stressful conditions. In fact, after the exposure of the strain to heat and acid treatments, an increase in the hydrophobicity level and the adhesion capacity on HeLa cells was shown. Our findings revealed that high temperature and low pH change the fatty acids profiles of the treated cells, especially the proportions of unsaturated and saturated fatty acid. In this context, our data revealed that the unsaturated FA to-saturated FA ratio was increased significantly (P < 0.05) for stressed strains compared with control cells. The results of the present finding suggest that the tested strain have suffered changes like the modifications on bacterial membrane as a cellular response to survive the hard environmental conditions, allowing them to withstand harsh conditions and sudden environmental changes to survive under. PMID- 28597198 TI - Long-term treatment of Cushing's disease with pasireotide: 5-year results from an open-label extension study of a Phase III trial. AB - BACKGROUND: Treating hypercortisolism in patients with Cushing's disease after failed surgery often requires chronic medication, underlining the need for therapies with favourable long-term efficacy and safety profiles. METHODS: In a randomised, double-blind study, 162 adult patients with persistent/recurrent or de novo Cushing's disease received pasireotide. Patients with mean urinary free cortisol at/below the upper limit of normal or clinical benefit at month 12 could continue receiving pasireotide during an open-ended, open-label phase, the outcomes of which are described herein. RESULTS: Sixteen patients received 5 years of pasireotide treatment. Among these, median (95% confidence interval) percentage change from baseline in mean urinary free cortisol was -82.6% (-89.0, 41.9) and -81.8% (-89.8, -67.4) at months 12 and 60. Eleven patients had mean urinary free cortisol <= upper limit of normal at month 60. Improvements in clinical signs were sustained during long-term treatment. The safety profile of pasireotide at 5 years was similar to that reported after 12 months. Fifteen of 16 patients experienced a hyperglycaemia-related adverse event; glycated haemoglobin levels were stable between months 6 and 60. Adverse events related to hyperglycaemia, bradycardia, gallbladder/biliary tract, and liver safety were most likely to first occur by month 6; adverse event severity did not tend to worsen over time. CONCLUSIONS: This represents the longest prospective trial of a medical therapy for Cushing's disease to date. A subset of patients treated with pasireotide maintained biochemical and clinical improvements for 5 years, with no new safety signals emerging. These data support the use of pasireotide as an effective long-term therapy for some patients with Cushing's disease. PMID- 28597199 TI - Predictors of Diabetes Fatalism Among Arabs: A Cross-Sectional Study of Lebanese Adults with Type 2 Diabetes. AB - Fatalism is a grounded cultural belief that is common among Arabs and is known to hinder self-care in chronic diseases including diabetes (Nabolsi and Carson in Scand J Caring Sci 25(4):716-724, 2011). The purpose of this study is to identify predictors of diabetes fatalism in this population. Data on 280 Lebanese patients with type 2 diabetes (mean age 58.24 +/- 13.48 years; mean HbA1c 7.90 +/- 1.90%; 53.76% females) recruited from one hospital in greater Beirut, Lebanon, and from the community using snowballing technique were examined. Multiple linear regression was used to assess the independent association between diabetes fatalism and demographic and patient characteristics. Age (beta = -.14, 95% CI .27, -.002), BMI (beta = .35, 95% CI .15; .54), level of education (beta = -3.98, 95% CI -7.64; -.32) and number of diabetes problems (beta = -5.03, 95% CI -9.89; .18) were significantly associated with diabetes fatalism in the regression model. The combination of demographic and patient characteristics accounted for 14.5% of the variance in diabetes fatalism scores' change. Patients with type 2 diabetes who exhibited more fatalistic attitudes were younger, of lower education levels, had higher BMI and had fewer diabetes comorbidities. Such findings are crucial for healthcare practitioners to identify fatalistic patients and to tailor culturally appropriate strategies in diabetes management. Further studies are warranted to explore other potential determinants of diabetes fatalism with larger sample and non-Lebanese Arabic population. PMID- 28597200 TI - The Lesion Analysis of Cholinergic Neurons in 5XFAD Mouse Model in the Three Dimensional Level of Whole Brain. AB - Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer's disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain. PMID- 28597202 TI - Erratum to: Design of a Lentiviral Vector for the Inducible Expression of MYC: A New Strategy for Construction Approach. PMID- 28597201 TI - Methane alleviates carbon tetrachloride induced liver injury in mice: anti inflammatory action demonstrated by increased PI3K/Akt/GSK-3beta-mediated IL-10 expression. AB - The inflammatory response plays an important role in carbon tetrachloride (CCl4) induced acute liver injury and methane has been shown to exert beneficial effects on inflammation-associated diseases. Thus, we investigated the potential protective effects of methane-rich saline (MS) on CCl4-induced acute liver injury and explored the underlying mechanism. A CCl4-induced acute liver injury model was established by injection of CCl4 (0.6 ml/kg, ip) in mice followed by treatment with MS (16 ml/kg, ip), 24 h later. All groups of mice were sacrificed and blood and liver tissues were collected. Serum aminotransferase, necrotic areas, and inflammatory cell infiltration in liver slices were enhanced after CCl4 treatment but decreased with MS treatment. IL-6, TNF-alpha, IL-1beta, IFN gamma, ICAM-1, CXCL1, MPO, NF-kappaB p65, ERK, JNK, and MAPK P38, expression in serum or liver homogenate were greater after CCl4 treatment but comparatively less after MS treatment. Only IL-10 increased after MS treatment. Anti-IL10 blockade (1.5 mg/kg) restored MS-mediated attenuated phosphorylation of NF KbB/MAPK and the protective effect of MS was abolished for all indices examined. The PI3K inhibitor, wortmannin had the same effects on MS as anti-IL-10 antibody. MS also induced phosphorylation of GSK-3beta and AKT in CCl4-treated mice. After pre-treatment with wortmannin (0.7 mg/kg), phosphorylation of GSK-3beta and AKT proteins were reduced compared to its solvent control group-DMSO-treated animals. Thus, the data provide evidence that MS may activate the PI3K-AKT-GSK-3beta pathway to induce IL-10 expression and produce anti-inflammatory effects via the NF-kappaB and MAPK pathways. The findings provide a new pharmacological strategy for management of inflammatory response after acute liver injury. PMID- 28597203 TI - Assessing Patient Activation among High-Need, High-Cost Patients in Urban Safety Net Care Settings. AB - We sought to examine the literature using the Patient Activation Measure (PAM) or the Patient Enablement Instrument (PEI) with high-need, high-cost (HNHC) patients receiving care in urban safety net settings. Urban safety net care management programs serve low-income, racially/ethnically diverse patients living with multiple chronic conditions. Although many care management programs track patient progress with the PAM or the PEI, it is not clear whether the PAM or the PEI is an effective and appropriate tool for HNHC patients receiving care in urban safety net settings in the United States. We searched PubMed, EMBASE, Web of Science, and PsycINFO for articles published between 2004 and 2015 that used the PAM and between 1998 and 2015 that used the PEI. The search was limited to English-language articles conducted in the United States and published in peer reviewed journals. To assess the utility of the PAM and the PEI in urban safety net care settings, we defined a HNHC patient sample as racially/ethnically diverse, low socioeconomic status (SES), and multimorbid. One hundred fourteen articles used the PAM. All articles using the PEI were conducted outside the U.S. and therefore were excluded. Nine PAM studies (8%) included participants similar to those receiving care in urban safety net settings, three of which were longitudinal. Two of the three longitudinal studies reported positive changes following interventions. Our results indicate that research on patient activation is not commonly conducted on racially and ethnically diverse, low SES, and multimorbid patients; therefore, there are few opportunities to assess the appropriateness of the PAM in such populations. Investigators expressed concerns with the potential unreliability and inappropriate nature of the PAM on multimorbid, older, and low-literacy patients. Thus, the PAM may not be able to accurately assess patient progress among HNHC patients receiving care in urban safety net settings. Assessing progress in the urban safety net care setting requires measures that account for the social and structural challenges and competing demands of HNHC patients. PMID- 28597204 TI - [Descemetectomy : An alternative to transplantation?] AB - Due to rising demand worldwide it is becoming increasingly more difficult to satisfy the needs for human corneal transplants. At this point transplantation is the only possible cure for endothelial diseases, such as Fuchs endothelial dystrophy. In this article we present descemetectomy, a circumscribed removal of Descemet's membrane (DMx) without subsequent transplantation, as new possible treatment option on the basis of a clinical case. PMID- 28597205 TI - [Spontaneous intraocular hemorrhage under oral anticoagulation : Apixaban in comparison to phenprocoumon]. AB - BACKGROUND: To determine and compare the frequency of intraocular hemorrhage in patients who underwent oral anticoagulation with apixaban or phenprocoumon. METHODS: A retrospective analysis of patients under oral anticoagulant medication (apixaban or phenprocoumon) seen between January 2015 and June 2015 at the department of ophthalmology, University of Muenster Medical Center was performed. Vitreal or retinal hemorrhage in addition to clinical information including age, gender, best corrected visual acuity, concomitant diseases, concomitant medication and therapy were obtained. Bleeding frequency in both groups was compared using Fisher's exact test. RESULTS: A total of 172 patients were included with a mean age = 74.0 +/- 10.6 years, 57.0% (n = 98) male and 43.0% (n = 74) female. In the phenprocoumon group 147 patients (3.4%, n = 5) developed a retinal or vitreal hemorrhage. In the apxiban group 25 patients (36%, n = 9) developed a retinal or vitreal hemorrhage. There was a significant correlation between the group and bleeding risk (p < 0.001). CONCLUSION: There was a significant correlation between medication (apixaban vs. phenprocoumon) and bleeding risk in this study population. Further studies with more patients especially in patients with a high risk of hemorhage, age-related macular degeneration (AMD) and proliferative diabetic retinopathy are needed. PMID- 28597207 TI - In memory of Marco Leonardi. PMID- 28597206 TI - Effect of strut distribution on neointimal coverage of everolimus-eluting bioresorbable scaffolds: an optical coherence tomography study. AB - The thick struts of bioresorbable vascular scaffolds (BRS) are associated with changes in wall shear stress and contribute to neointimal proliferation. We aimed to evaluate the relationship between the BRS strut distribution and the neointimal proliferation. 50 lesions underwent optical coherence tomography, 12 months after BRS implantation. Scaffold area and neointimal thickness were evaluated in each cross-sectional area (CSA). Scaffold eccentricity was defined as follows: (maximum diameter - minimum diameter) * 100/maximum diameter. CSAs of BRS were divided into four quadrants. The maximal neointimal thickness (Maximal NIT), Minimal-NIT and the number of struts in each quadrant were measured. The number of struts were classified as 1, 2, 3 and >= 4. Furthermore, the mean-NIT acquired in each quadrant was divided by the average-NIT of all struts in the same CSA, which was defined as the unevenness score. In addition, Maximal-NIT minus Minimal-NIT was divided by the average-NIT of all struts in the same CSA, which was defined as heterogenicity of neointimal proliferation. There was a significant difference in the association between the number of struts and not only the unevenness score (no. of strut = 1 (N = 440), unevenness score 1.04 +/- 0.34; 2 (N = 696), 0.98 +/- 0.27; 3 (N = 994), 0.96 +/- 0.23; >=4 (N = 1202), 1.04 +/- 0.22, P < 0.01) but also Maximal-NIT and Minimal-NIT. Furthermore, a significant correlation was observed between scaffold eccentricity in each CSA and the heterogeneity of neointimal proliferation in the same CSA (N = 892, R = 0.38, p = 0.01). Crowding of struts is associated with increased neointimal proliferation after BRS implantation. The scaffold eccentricity causes heterogeneity of neointimal proliferation. PMID- 28597208 TI - Subject-specific regional measures of water diffusion are associated with impairment in chronic spinal cord injury. AB - PURPOSE: We aimed to identify non-invasive imaging parameters that can serve as biomarkers for the integrity of the spinal cord, which is paramount to neurological function. Diffusion tensor imaging (DTI) indices are sensitive to axonal and myelin damage, and have strong potential to serve as such biomarkers. However, averaging DTI indices over large regions of interest (ROIs), a common approach to analyzing the images of injured spinal cord, leads to loss of subject specific information. We investigated if DTI-tractography-driven, subject specific demarcation approach can yield measures that are more specific to impairment. METHODS: In 18 individuals with chronic spinal cord injury (SCI), subject-specific demarcation of the injury region was performed using DTI tractography, which yielded three regions relative to injury (RRI; regions superior to, at, and below injury epicenter). DTI indices averaged over each RRI were correlated with measures of residual motor and sensory function, obtained using the International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI). RESULTS: Total ISNCSCI score (ISNCSCI-tot; sum of ISNCSCI motor and sensory scores) was significantly (p < 0.05) correlated with fractional anisotropy and axial and radial diffusivities. ISNCSCI-tot showed strongest correlation with indices measured from the region inferior to the injury epicenter (IRRI), the degree of which exceeded that of those measured from the entire cervical cord-suggesting contribution from Wallerian degeneration. CONCLUSION: DTI tractography-driven, subject-specific injury demarcation approach provided measures that were more specific to impairment. Notably, DTI indices obtained from the IRRI region showed the highest specificity to impairment, demonstrating their strong potential as biomarkers for the SCI severity. PMID- 28597209 TI - Molecular Dynamics Simulation Reveals Unique Interplays Between a Tarantula Toxin and Lipid Membranes. AB - Tarantula toxins compose an important class of spider toxins that target ion channels, and some are known to interact with lipid membranes. In this study, we focus on a tarantula toxin, Jingzhaotoxin-III (JZTx-III) that specifically targets the cardiac voltage-gated sodium channel Na[Formula: see text]1.5 and is suspected to be able to interact with lipid membranes. Here, we use an all-atom model and long-term molecular dynamics simulations to investigate the interactions between JZTx-III and lipid membranes of different compositions. Trajectory analyses show that JZTx-III has no substantial interaction with the neutral 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipids, but binds to membranes containing negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3 [phospho-rac-(1-glycerol)] (POPG). The most intriguing observations in our simulation are the different interactions between the toxin and the membrane in the mixed and pure POPG membrane systems. The POPC/POPG mixed membrane undergoes a phase transition to a rippled phase upon binding of the toxin, while the pure POPG membrane has no apparent change. Moreover, the binding of JZTx-III to both of the mixture and the pure POPG membrane systems induce small conformational changes. The sequence alignment shows that JZTx-III may not partition into the lipid bilayer due to the mutations of a C-terminal hydrophobic residue and some charged residues that affect toxin orientation. Taken together, JZTx-III and lipid membranes have unique effects on each other that may facilitate the specific binding of JZTx-III to Na[Formula: see text]1.5. This computational study also enriches our understanding of the potential complex interactions between spider toxins and lipid membranes. PMID- 28597210 TI - Multiple Desmoplastic Cellular Neurothekeomas in Child: Report of the First Oral Case and Review of the Literature. AB - Cellular neurothekeomas (CNs) are distinctive benign tumors of uncertain histogenesis, with predilection for the skin of the head and neck region. We describe the first case of multiple desmoplastic CNs (DCNs) affecting the oral cavity in a 9-year-old girl. Histopathologic evaluation showed a proliferation of spindle and epithelioid cells, forming nests and bundles, supported by exuberant fibrous stroma, as well as scattered multinucleated floret-like giant cells. The tumor cells were immunopositive for vimentin, CD63, CD56, whereas AE1/AE3, S100, CD34, alpha-SMA, GFAP, EMA, CD57 and NSE were negative. Ki-67 was <2%. Multiple DCNs should be considered in the differential diagnosis of oral nodular lesions. PMID- 28597212 TI - A purely green synthesis of silver nanoparticles using Carica papaya, Manihot esculenta, and Morinda citrifolia: synthesis and antibacterial evaluations. AB - Green procedure for synthesizing silver nanoparticles (AgNPs) is currently considered due to its economy and toxic-free effects. Several existing works on synthesizing AgNPs using leaves extract still involve the use of physical or mechanical treatment such as heating or stirring, which consume a lot of energy. To extend and explore the green extraction philosophy, we report here the synthesis and antibacterial evaluations of a purely green procedure to synthesize AgNPs using Carica papaya, Manihot esculenta, and Morinda citrifolia leaves extract without the aforementioned additional treatment. The produced AgNPs were characterized using the ultraviolet-visible spectroscopy, field emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy, and antibacterial investigations. For antibacterial tests, two bacteria namely Escherichia coli and Bacillus cereus were selected. The presently employed method has successfully produced spherical AgNPs having sizes ranging from 9 to 69 nm, with plasmonic characteristics ranging from 356 to 485 nm, and energy-dispersive X-ray peak at approximately 3 keV. In addition, the smallest particles can be produced when Manihot esculenta leaves extract was applied. Moreover, this study also confirmed that both the leaves and synthesized AgNPs exhibit the antibacterial capability, depending on their concentration and the bacteria type. PMID- 28597211 TI - Characterization and use of Equine Bone Marrow Mesenchymal Stem Cells in Equine Cartilage Engineering. Study of their Hyaline Cartilage Forming Potential when Cultured under Hypoxia within a Biomaterial in the Presence of BMP-2 and TGF beta1. AB - Articular cartilage presents a poor capacity for self-repair. Its structure function are frequently disrupted or damaged upon physical trauma or osteoarthritis in humans. Similar musculoskeletal disorders also affect horses and are the leading cause of poor performance or early retirement of sport- and racehorses. To develop a therapeutic solution for horses, we tested the autologous chondrocyte implantation technique developed on human bone marrow (BM) mesenchymal stem cells (MSCs) on horse BM-MSCs. This technique involves BM-MSC chondrogenesis using a combinatory approach based on the association of 3D culture in collagen sponges, under hypoxia in the presence of chondrogenic factors (BMP-2 + TGF-beta1) and siRNA to knockdown collagen I and HtrA1. Horse BM MSCs were characterized before being cultured in chondrogenic conditions to find the best combination to enhance, stabilize, the chondrocyte phenotype. Our results show a very high proliferation of MSCs and these cells satisfy the criteria defining stem cells (pluripotency-surface markers expression). The combination of BMP-2 + TGF-beta1 strongly induces the chondrogenic differentiation of MSCs and prevents HtrA1 expression. siRNAs targeting Col1a1 and Htra1 were functionally validated. Ultimately, the combined use of specific culture conditions defined here with specific growth factors and a Col1a1 siRNAs (50 nM) association leads to the in vitro synthesis of a hyaline-type neocartilage whose chondrocytes present an optimal phenotypic index similar to that of healthy, differentiated chondrocytes. Our results lead the way to setting up pre-clinical trials in horses to better understand the reaction of neocartilage substitute and to carry out a proof-of-concept of this therapeutic strategy on a large animal model. PMID- 28597213 TI - [3-D mapping of ventricular tachycardia in patients with dilative cardiomyopathy]. AB - Catheter ablation of ventricular tachycardia (VT) is gaining in importance. The current guidelines suggest considering catheter ablation for VT even in patients with a single sustained and documented episode. This is also underlined by recent data indicating that absence of VT predicts lower mortality and longer transplant free survival. The majority of patients with VTs have a history of prior myocardial infarction; in a smaller proportion, patients present with dilated cardiomyopathy. The latter has a less structured scar pattern which makes it more complicated to apply efficient ablation strategies. Data have shown that the probability of VT recurrence after catheter ablation is higher and an epicardial access more frequently required. Algorithms and strategies to improve catheter ablation results have been developed and evaluated especially on patients with dilated cardiomyopathy (DCM) to further improve outcomes. The present article will strive to acquaint the reader with the current strategies and state of knowledge. PMID- 28597214 TI - [Diagnosis of ischemia and revascularization in patients with ventricular tachyarrhythmia]. AB - Sustained ventricular tachyarrhythmia usually occurs on the basis of structural heart disease, particularly coronary heart disease (CAD). Although monomorphic ventricular tachycardia (VT) appears mainly in patients with CAD, it is typically not triggered by acute ischemia, in contrast to polymorphic VT or ventricular fibrillation (VF). To judge if VT is caused by acute ischemia is even more difficult in context with an elevated highly sensitive troponin T which is generally elevated in sustained VT because tachycardia in chronic stable coronary artery sclerosis causes a mismatch between increased oxygen demand and limited oxygen supply. Therefore, acute coronary angiography and revascularization may frequently not be necessary in monomorphic VT, will usually not improve rhythm stabilization, and may lead to misinterpretation of monomorphic VT being caused by a coronary stenosis. This can lead to withholding antiarrhythmic therapy after revascularization since it is assumed that the cause of VT has been treated. On the other hand, acute coronary angiography and revascularization are useful in polymorphic VT/VF, ECG signs of ischemia, or typical chest pain before occurrence of VT/VF. Coronary angiography should also be performed in patients with VT with newly diagnosed reduced left ventricular function and before catheter ablation. PMID- 28597215 TI - Pharmacodynamics of Insulin Preparations Administered in Different Subcutaneous Injection Sites: Are There Differences Between Healthy Subjects Versus Diabetic Patients? PMID- 28597216 TI - Pharmacokinetic Properties of Fast-acting Insulin Aspart Administered in Different Subcutaneous Injection Regions: Response to the commentary by Nuggehally R. Srinivas. PMID- 28597217 TI - Context modulation of learned attention deployment. AB - In three experiments, we investigated the contextual control of attention in human discrimination learning. In each experiment, participants initially received discrimination training in which the cues from Dimension A were relevant in Context 1 but irrelevant in Context 2, whereas the cues from Dimension B were irrelevant in Context 1 but relevant in Context 2. In Experiment 1, the same cues from each dimension were used in Contexts 1 and 2, whereas in Experiments 2 and 3, the cues from each dimension were changed across contexts. In each experiment, participants were subsequently shifted to a transfer discrimination involving novel cues from either dimension, to assess the contextual control of attention. In Experiment 1, measures of eye gaze during the transfer discrimination revealed that Dimension A received more attention than Dimension B in Context 1, whereas the reverse occurred in Context 2. Corresponding results indicating the contextual control of attention were found in Experiments 2 and 3, in which we used the speed of learning (associability) as an indirect marker of learned attentional changes. Implications of our results for current theories of learning and attention are discussed. PMID- 28597218 TI - Uncovering a New Moral Dilemma of Economic Optimization in Biotechnological Processing. AB - The trend of emerging biorefineries is to process the harvest as efficiently as possible and without any waste. From the most valuable phytomass, refined medicines, enzymes, dyes and other special reactants are created. Functional foods, food ingredients, oils, alcohol, solvents, plastics, fillers and a wide variety of other chemical products follow. After being treated with nutrient recovery techniques (for fertilizer production), biofuels or soil improvers are produced from the leftovers. Economic optimization algorithms have confirmed that such complex biorefineries can be financially viable only when a high degree of feedstock concentration is included. Because the plant material is extremely voluminous before processing, the farming intensity of special plants increases in the nearest vicinity of agglomerations where the biorefineries are built for logistical reasons. Interdisciplinary analyses revealed that these optimization measures lead to significantly increased pollen levels in neighbouring urban areas and subsequently an increased risk of allergies, respectively costs to the national health system. A new moral dilemma between the shareholder's profit and public interest was uncovered and subjected to disputation. PMID- 28597219 TI - Advocacy Science: Explaining the Term with Case Studies from Biotechnology. AB - The paper discusses the use of term 'advocacy science' which is communication of science which goes beyond simple reporting of scientific findings, using the case study of biotechnology. It argues that advocacy science should be used to distinguish the engagement of modern civil society organizations to interpret scientific knowledge for their lobbying. It illustrates how this new communicative process has changed political discourse in science and general perception of the role of science in contemporary society. PMID- 28597220 TI - The Value of Darkness: A Moral Framework for Urban Nighttime Lighting. AB - The adverse effects of artificial nighttime lighting, known as light pollution, are emerging as an important environmental issue. To address these effects, current scientific research focuses mainly on identifying what is bad or undesirable about certain types and uses of lighting at night. This paper adopts a value-sensitive approach, focusing instead on what is good about darkness at night. In doing so, it offers a first comprehensive analysis of the environmental value of darkness at night from within applied ethics. A design for values orientation is utilized to conceptualize, define, and categorize the ways in which value is derived from darkness. Nine values are identified and categorized via their type of good, temporal outlook, and spatial characteristics. Furthermore, these nine values are translated into prima facie moral obligations that should be incorporated into future design choices, policy-making, and innovations to nighttime lighting. Thus, the value of darkness is analyzed with the practical goal of informing future decision-making about urban nighttime lighting. PMID- 28597221 TI - Editorial Board Self-Publishing Rates in Czech Economic Journals. AB - This article investigates whether editorial board members of selected economic journals publish their research papers in their 'own' journal. Journals were selected from the Journal Citation Report(r) from the categories Business; Business, Finance; and Economics. Only research articles published between 2012 and 2015 were included in the analysis. We recorded ratios concerning the share of articles authored by editorial board members, the share of editorial board members publishing in their own journals and ratios representing their publication output. The average share of articles authored by editorial board members ranges from 0.6 to 17.5%. The average share of editorial board members publishing in their own journals ranges from 5.6 to 24.4%. Considering only editorial board members publishing in their own journals, the share of their articles in their journals ranges from 8.2 to 71.4%. While the share of board members publishing only in their own journals, to the number of board members publishing in their own journals, the ratio in a quarter of journals is equal to zero, with a maximum reach of 85.7%. All observed ratios are significantly positively correlated with the gap between impact factor and impact factor without Journal Self Cites; and negatively correlated with the Article Influence Score. A cluster of journals in which a high proportion of editorial board members publish and simultaneously these members publish in their own journal at a high rate was identified. PMID- 28597222 TI - Development and Preliminary Validation of a New Measure of Values in Scientific Work. AB - In this paper we describe the development and initial psychometric evaluation of a new measure, the values in scientific work (VSW). This scale assesses the level of importance that investigators attach to different VSW. It taps a broad range of intrinsic, extrinsic, and social values that motivate the work of scientists, including values specific to scientific work (e.g., truth and integrity) and more classic work values (e.g., security and prestige) in the context of science. Notably, the values represented in this scale are relevant to scientists regardless of their career stage and research focus. We administered the VSW and a measure of global values to 203 NIH-funded investigators. Exploratory factor analyses suggest the delineation of eight VSW, including autonomy, research ethics, social impact, income, collaboration, innovation and growth, conserving relationships, and job security. These VSW showed predictable and distinct associations with global values. Implications of these findings for work on research integrity and scientific misconduct are discussed. PMID- 28597223 TI - The Irrelevance of the Risk-Uncertainty Distinction. AB - Precautionary Principles are often said to be appropriate for decision-making in contexts of uncertainty such as climate policy. Contexts of uncertainty are contrasted to contexts of risk depending on whether we have probabilities or not. Against this view, I argue that the risk-uncertainty distinction is practically irrelevant. I start by noting that the history of the distinction between risk and uncertainty is more varied than is sometimes assumed. In order to examine the distinction, I unpack the idea of having probabilities, in particular by distinguishing three interpretations of probability: objective, epistemic, and subjective probability. I then claim that if we are concerned with whether we have probabilities at all-regardless of how low their epistemic credentials are then we almost always have probabilities for policy-making. The reason is that subjective and epistemic probability are the relevant interpretations of probability and we almost always have subjective and epistemic probabilities. In contrast, if we are only concerned with probabilities that have sufficiently high epistemic credentials, then we obviously do not always have probabilities. Climate policy, for example, would then be a case of decision-making under uncertainty. But, so I argue, we should not dismiss probabilities with low epistemic credentials. Rather, when they are the best available probabilities our decision principles should make use of them. And, since they are almost always available, the risk-uncertainty distinction remains irrelevant. PMID- 28597224 TI - High-speed broadband monitoring of cell viscoelasticity in real time shows myosin dependent oscillations. AB - Study of the dynamic evolutions of cell viscoelasticity is important as during cell activities such as cell metastasis and invasion, the rheological behaviors of the cells also change dynamically, reflecting the biophysical and biochemical connections between the outer cortex and the intracellular structures. Although the time variations of the static modulus of cells have been investigated, few studies have been reported on the dynamic variations of the frequency-dependent viscoelasticity of cells. Measuring and monitoring such dynamic evolutions of cells at nanoscale can be challenging as the measurement needs to meet two objectives inherently contradictory to each other-the measurement must be broadband (to cover a large frequency spectrum) but also rapid (to capture the time-elapsed changes). In this study, we exploited a recently developed control based nanomechanical protocol of atomic force microscope to monitor in real time the dynamic evolutions of the viscoelasticity of live human prostate cancer cells (PC-3 cells) and study its dependence on myosin activities. We found that the viscoelasticity of PC-3 cells, followed the power law, and oscillated at a period of about 200 s. Both the amplitude and the frequency of the oscillation strongly depended on the intracellular calcium and blebbistatin-sensitive motor proteins. PMID- 28597225 TI - A multicenter, retrospective, observational study of the clinical outcomes and risk factors for relapse of ulcerative colitis at 1 year after leukocytapheresis. AB - BACKGROUND: Extracorporeal leukocytapheresis (LCAP) is effective for inducing remission of ulcerative colitis (UC). This retrospective observational study aimed to evaluate the clinical outcome at 1 year and identify risk factors for relapse of UC after LCAP. METHODS: Patients with active UC treated with LCAP between 2010 and 2012 were enrolled from 54 medical facilities in Japan. Clinical data evaluated at 1 year after the last LCAP session included the incidence of relapse, 1-year cumulative relapse-free rate, risk factors for relapse, and history of re-induction treatment following relapse. Relapse was defined by the addition of treatment to induce remission. The primary endpoint was the 1-year cumulative relapse-free rate. Secondary endpoints were risk factors for relapse and outcomes of re-induction treatment after relapse. RESULTS: For 314 patients, the 1-year cumulative relapse-free rate was 63.6%. Following LCAP, a Lichtiger clinical activity index (CAI) of 3 or 4 and high leukocyte count (cut-off value: 7790/mm3) were associated with a greater risk of relapse. Intensive LCAP (>=4 sessions within the first 2 weeks) was associated with favorable long-term outcomes in corticosteroid-refractory patients. The response rate was 85.1% among 30 patients who required re-treatment with LCAP. CONCLUSIONS: The majority of patients (>60%) with UC treated with LCAP achieved clinical remission within 1 year and remained relapse-free. A higher Lichtiger CAI and leukocyte count following LCAP were risk factors for relapse. Re-induction therapy with LCAP was effective for relapse of UC. PMID- 28597226 TI - Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model. AB - BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). OBJECTIVE: We examined the feasibility of a 2 month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. METHODS: The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. RESULTS: Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study. CONCLUSION: These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2 month (q8wk) dose interval option for the treatment of schizophrenia. PMID- 28597227 TI - A hemoglobin adduct as a biomarker for the internal exposure to the rodent carcinogen furfuryl alcohol. AB - Furfuryl alcohol is a common food contaminant, which is formed by acid- and heat catalyzed degradation of fructose and glucose. Its carcinogenic effect in rodents originates most likely from sulfotransferase (SULT)-catalyzed conversion into the mutagenic sulfate ester 2-sulfoxymethylfuran. In this study, a protein adduct biomarker was sought for the medium-term internal exposure to furfuryl alcohol. A UPLC-MS/MS screening showed that the adduct N-((furan-2-yl)methyl)-Val (FFA-Val) at the N-terminus of hemoglobin is a valid target analyte. The Val cleavage by fluorescein isothiocyanate-mediated Edman degradation yielded 3-fluorescein-1 (furan-2-ylmethyl)-5-(propan-2-yl)-2-thioxoimidazolidin-4-one (FFA-Val-FTH), which was characterized by 1H and 13C NMR spectroscopy. An isotope-dilution method for the quantification of FFA-Val-FTH by UPLC-MS/MS was developed. It was used to study the adduct formation in furfuryl alcohol-treated FVB/N mice and the influence of ethanol and the alcohol dehydrogenase (ADH) inhibitor 4 methylpyrazole on the adduct levels. The administration of 400 mg/kg body weight furfuryl alcohol alone led to 12.5 and 36.7 pmol FFA-Val/g Hb in blood samples of male and female animals, respectively. The co-administration of 1.6 g ethanol/kg body weight increased FFA-Val levels by 1.4-fold in males and by 1.5-fold in females. The co-administration of 100 mg 4-methylpyrazole/kg body weight had a similar effect on the adduct levels. A high correlation was observed between adduct levels in hemoglobin and in hepatic DNA samples determined in the same animal experiment. This indicated that FFA-Val is a valid biomarker for the internal exposure to 2-sulfoxymethylfuran, which may be suitable to monitor furfuryl alcohol exposure also in humans. PMID- 28597229 TI - Couch modelling for volumetric modulated arc therapy (VMAT). AB - The aim of this work was to investigate the impact of the accuracy of a certain couch model on the overall accuracy of the dose calculation. For this purpose two models of the Varian Exact Couch (Varian Medical Systems, Palo Alto, CA, USA) for use in the planning of volumetric modulated arc therapy (VMAT) were created in Monaco 5.1 (Elekta, Stockholm, Sweden). The first was a simplistic model, with the relative electron densities (ED) of structures based entirely on CT Hounsfield units (HU). The second couch model was obtained by assigning the appropriate EDs to the relevant couch structures. Instead of getting EDs from the CT scan using the Hounsfield units to ED conversion, the second approach was to determine the optimal ED iteratively. The values accepted for the second couch model were the EDs that produced the best agreement between Monaco calculations and the measured couch attenuation. Finally, the performance of the two couch models in clinical prostate VMAT plans was compared. PMID- 28597230 TI - Both sides now: diagnostic imaging medical physics in two hemispheres. PMID- 28597228 TI - SGLT2-I in the Hospital Setting: Diabetic Ketoacidosis and Other Benefits and Concerns. AB - PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the newest class of antihyperglycemic agents. They are increasingly being prescribed in the outpatient diabetic population. In this review, we examine the risks and benefits of continuation and initiation of SGLT2 inhibitors in the inpatient setting. RECENT FINDINGS: There are currently no published data regarding safety and efficacy of SGLT2 inhibitor use in the hospital. Outpatient data suggests that SGLT2 inhibitors have low hypoglycemic risk. They also decrease systolic blood pressure and can prevent cardiovascular death. The EMPA-REG study also showed a decrease in admissions for acute decompensated heart failure. There have been increasing cases of diabetic ketoacidosis, and specifically the euglycemic manifestation, associated with SGLT2 inhibitors use. We present two cases of inpatient SGLT2 inhibitor use, one of continuation of outpatient therapy and one of new initiation of therapy. We then discuss potential risks and methods to mitigate these as well as benefits of these medications in the inpatient setting. We cautiously suggest the use of SGLT2 inhibitors in the hospital. However, these must be used judiciously and the practitioner must be aware of euglycemic diabetic ketoacidosis and its risk factors in this population. PMID- 28597231 TI - Development of an In Vitro PIV Setup for Preliminary Investigation of the Effects of Aortic Compliance on Flow Patterns and Hemodynamics. AB - The aorta with its compliance plays a major role in hemodynamics as it saves a portion of ejected blood during systole which is then released in diastole. The aortic compliance decreases with increasing age, which is related to several cardiovascular imparities and diseases. Changes in flow patterns and pressure curves, due to varying aortic compliance, are difficult to investigate in vivo. As a result, the aim of the present work was to develop an in vitro setup enabling standardized investigations on the effect of compliance changes on flow patterns and pressure curves. Therefore an experimental setup with an anatomically correct silicone phantom of the aortic arch was developed, suitable for optical flow measurements under pulsatile inflow conditions. The setup was developed for precise adjustments of different compliances and optical flow measurements. Particle image velocimetry measurements were carried out downstream of the aortic valve in the center plane perpendicular to the valve with compliance adjusted between 0.62 * 10-3 to 1.82 * 10-3 mmHg-1. Preliminary results of the in vitro investigations showed that decreases in compliance results in significant increases in pressure changes with respect to time (dp/dt) and altered pressure curves in the aortic arch. In terms of flow, an increased aortic stiffness lead to higher mean velocities and decreased vortex development in the aortic sinuses. As in vivo validation and translation remains difficult, the results have to be considered as preliminary in vitro insights into the mechanisms of (age-related) compliance changes. PMID- 28597232 TI - Factors Associated to Medication Consumption Among the Immigrant Population Residing in Spain. AB - We aimed to determine the prevalence of medication use by the immigrant population residing in Spain, and to identify the factors associated with this consumption. Descriptive cross-sectional study was performed using secondary data retrieved from the 2012 Spanish National Health Survey (SNHS). Using logistic multivariate regression analysis, three models were generated: one for immigrants from high income countries (HIC), another for immigrants from low income countries (LIC), and a third one for the native population. The prevalence of total consumption of medicinal products is greater in the native population (61.75%) than in the immigrant population (HIC: 56.22%; LIC: 48.55%). Analgesics are the most consumed drugs in all the groups. Greater medication consumption is associated with being female, being of an advanced age (immigrants from HIC: AOR 9.75, for older than 75 years), the presence of chronic disease, a perception of bad health (HIC: AOR 3.48) and the use of emergency services (LIC immigrants: AOR 1.68). Medicine consumption in the immigrant population living in Spain is lower than in the native population. The factors associated with this consumption are similar; however, LIC immigrants who needed healthcare services and did not receive them presented a greater probability of consuming medicinal products. PMID- 28597234 TI - An automated approach to measuring child movement and location in the early childhood classroom. AB - Children's movement is an important issue in child development and outcome in early childhood research, intervention, and practice. Digital sensor technologies offer improvements in naturalistic movement measurement and analysis. We conducted validity and feasibility testing of a real-time, indoor mapping and location system (Ubisense, Inc.) within a preschool classroom. Real-time indoor mapping has several implications with respect to efficiently and conveniently: (a) determining the activity areas where children are spending the most and least time per day (e.g., music); and (b) mapping a focal child's atypical real-time movements (e.g., lapping behavior). We calibrated the accuracy of Ubisense point by-point location estimates (i.e., X and Y coordinates) against laser rangefinder measurements using several stationary points and atypical movement patterns as reference standards. Our results indicate that activity areas occupied and atypical movement patterns could be plotted with an accuracy of 30.48 cm (1 ft) using a Ubisense transponder tag attached to the participating child's shirt. The accuracy parallels findings of other researchers employing Ubisense to study atypical movement patterns in individuals at risk for dementia in an assisted living facility. The feasibility of Ubisense was tested in an approximately 90 min assessment of two children, one typically developing and one with Down syndrome, during natural classroom activities, and the results proved positive. Implications for employing Ubisense in early childhood classrooms as a data-based decision-making tool to support children's development and its potential integration with other wearable sensor technologies are discussed. PMID- 28597235 TI - AGSuite: Software to conduct feature analysis of artificial grammar learning performance. AB - To simplify the problem of studying how people learn natural language, researchers use the artificial grammar learning (AGL) task. In this task, participants study letter strings constructed according to the rules of an artificial grammar and subsequently attempt to discriminate grammatical from ungrammatical test strings. Although the data from these experiments are usually analyzed by comparing the mean discrimination performance between experimental conditions, this practice discards information about the individual items and participants that could otherwise help uncover the particular features of strings associated with grammaticality judgments. However, feature analysis is tedious to compute, often complicated, and ill-defined in the literature. Moreover, the data violate the assumption of independence underlying standard linear regression models, leading to Type I error inflation. To solve these problems, we present AGSuite, a free Shiny application for researchers studying AGL. The suite's intuitive Web-based user interface allows researchers to generate strings from a database of published grammars, compute feature measures (e.g., Levenshtein distance) for each letter string, and conduct a feature analysis on the strings using linear mixed effects (LME) analyses. The LME analysis solves the inflation of Type I errors that afflicts more common methods of repeated measures regression analysis. Finally, the software can generate a number of graphical representations of the data to support an accurate interpretation of results. We hope the ease and availability of these tools will encourage researchers to take full advantage of item-level variance in their datasets in the study of AGL. We moreover discuss the broader applicability of the tools for researchers looking to conduct feature analysis in any field. PMID- 28597233 TI - How Have You Been? or ?Como estas?: Does Language of Interview Influences Self Rated Health Among Hispanic Subgroups? AB - This paper reports language differences in poor/fair self-rated health (SRH) among adults from six Hispanic groups in the United States. Data are from the cross-sectional 1997-2013 National Health Interview Survey (NHIS). The total sample of Hispanic adults with valid information for the variables considered in the study (n = 156,374) included Mexican-Americans (Mex-Am; n = 43,628), Mexicans (n = 55,057), Puerto Ricans (n = 14,631), Cubans (n = 8,041), Dominicans (from Dominican Republican, n = 4,359) and Other Hispanics (n = 30,658). We compared percentage of the population that reported poor/fair SRH among Hispanic individuals by language of interview and across origins using bivariate tests of association. Multivariable logistic regression analysis was used to study the odds of reporting poor/fair SRH based on language among the overall population and each group. Among the six Hispanic origins Puerto Ricans (15.92%), Cubans (16.36%) and Dominicans (15.32%) reported poor/fair SRH at higher levels than the overall sample (12.32%). In the logistic regression model adjusting potential covariates, those interviewed in Spanish were at higher odds of reporting poor/fair SRH than those interviewed in English (OR = 1.47, p < 0.0001). In the stratified analysis, Mexican-Americans were the only group where language of interview did not affect the odds of reporting poor/fair SRH. There are differences by Hispanic origin for reporting poor/fair SRH, and also by language of interview. Achieving accurate measurement of health status among Hispanics is a concern for all researchers, in particular those who study differences in health status by race/ethnicity in the United States. Future, research should account for Hispanic background and language of interviews. PMID- 28597236 TI - Bayesian analysis of the piecewise diffusion decision model. AB - Most past research on sequential sampling models of decision-making have assumed a time homogeneous process (i.e., parameters such as drift rates and boundaries are constant and do not change during the deliberation process). This has largely been due to the theoretical difficulty in testing and fitting more complex models. In recent years, the development of simulation-based modeling approaches matched with Bayesian fitting methodologies has opened the possibility of developing more complex models such as those with time-varying properties. In the present work, we discuss a piecewise variant of the well-studied diffusion decision model (termed pDDM) that allows evidence accumulation rates to change during the deliberation process. Given the complex, time-varying nature of this model, standard Bayesian parameter estimation methodologies cannot be used to fit the model. To overcome this, we apply a recently developed simulation-based, hierarchal Bayesian methodology called the probability density approximation (PDA) method. We provide an analysis of this methodology and present results of parameter recovery experiments to demonstrate the strengths and limitations of this approach. With those established, we fit pDDM to data from a perceptual experiment where information changes during the course of trials. This extensible modeling platform opens the possibility of applying sequential sampling models to a range of complex non-stationary decision tasks. PMID- 28597237 TI - Energy conserving thermoregulatory patterns and lower disease severity in a bat resistant to the impacts of white-nose syndrome. AB - The devastating bat fungal disease, white-nose syndrome (WNS), does not appear to affect all species equally. To experimentally determine susceptibility differences between species, we exposed hibernating naive little brown myotis (Myotis lucifugus) and big brown bats (Eptesicus fuscus) to the fungus that causes WNS, Pseudogymnoascus destructans (Pd). After hibernating under identical conditions, Pd lesions were significantly more prevalent and more severe in little brown myotis. This species difference in pathology correlates with susceptibility to WNS in the wild and suggests that survival is related to different host physiological responses. We observed another fungal infection, associated with neutrophilic inflammation, that was equally present in all bats. This suggests that both species are capable of generating a response to cold tolerant fungi and that Pd may have evolved mechanisms for evading host responses that are effective in at least some bat species. These host-pathogen interactions are likely mediated not just by host physiological responses, but also by host behavior. Pd-exposed big brown bats, the less affected species, spent more time in torpor than did control animals, while little brown myotis did not exhibit this change. This differential thermoregulatory response to Pd infection by big brown bat hosts may allow for a more effective (or less pathological) immune response to tissue invasion. PMID- 28597238 TI - Context Matters: Team and Organizational Factors Associated with Reach of Evidence-Based Psychotherapies for PTSD in the Veterans Health Administration. AB - Evidence-based psychotherapies for PTSD are often underused. The objective of this mixed-method study was to identify organizational and clinic factors that promote high levels of reach of evidence-based psychotherapies for PTSD 10 years into their dissemination throughout the Veterans Health Administration. We conducted 96 individual interviews with staff from ten outpatient PTSD teams at nine sites that differed in reach of evidence-based psychotherapies for PTSD. Major themes associated with reach included clinic mission, clinic leader and staff engagement, clinic operations, staff perceptions, and the practice environment. Strategies to improve reach of evidence-based psychotherapies should attend to organizational and team-level factors. PMID- 28597239 TI - Relationship between reticuloendothelial systems' FDG uptake level and clinicopathological features in patient with invasive ductal breast cancer. AB - PURPOSE: The reticuloendothelial system (RES) is a part of the immune system and plays a major role in the protection of against diseases. We thought that FDG PET/CT may show the degree of systemic immune response induced with malignancy in the organs with the high RES activity. Our objective is to investigate FDG uptake levels of high RES activity organs (liver, spleen, bone marrow) in invasive ductal breast cancer and to evaluate the association with the clinicopathological features. METHODS: In the present study, 193 patients with invasive ductal breast cancer who performed FDG-PET/CT were categorized according to the clinicopathological features including age, tumor size, axillary nodal status, histological grade, the presence of lymphavascular invasion, receptor status, Ki 67 proliferation index and biological subgroup. Also, a control group of 100 subjects were identified for comparison with breast cancer patients. We analyzed the relation of FDG uptake levels in high RES activity organs and clinicopathological features in patients. RESULTS: There was a statistically significant difference of SUVmax of the liver, spleen, and bone marrow between cancer and control groups (P < 0.0001). We found that high SUVmax in liver, spleen and bone marrow were significantly correlated with worse prognostic clinicopathological features in patient with invasive ductal breast cancer. CONCLUSIONS: FDG uptake level in high RES activity organs is associated with the presence of tumor, and also directly relating clinicopathological features for patients with invasive ductal breast cancer. PMID- 28597242 TI - [The basics of knee osteotomy : Clinical examination, analysis of the deformity and correction planning]. AB - Clinical results of knee osteotomies are good. A precise preoperative analysis of the deformity in three dimensions and accurate planning of the correction osteotomy is essential. All pathologies of the knee and the surrounding joints must be considered. The opening wedge technique and locking plate systems have improved accuracy and reliability. An analysis of deformities and the planning of their correction is presented in this article. Access to the extent of the correction according to the level of degeneration has proven useful in clinical praxis. Digital storage of the planning is recommended for legal reasons. PMID- 28597240 TI - MR arthrography of the hip: evaluation of isotropic 3D intermediate-weighted FSE and hybrid GRE T1-weighted sequences. AB - PURPOSE: To compare the diagnostic performance of three-dimensional (3D) intermediate-weighted FSE (IW-3D) and 3D hybrid T1-weighted sequences (Hy-3D) and 2D fast-spin-echo sequences (FSE) in diagnosing chondral and labral lesions at 1.5 Tesla hip MR arthrography (MRA). MATERIALS AND METHODS: Institutional review board approval was obtained and informed consent was waived. Ninety-two consecutive patients were evaluated. Chondral and labral lesions were retrospectively and independently evaluated by two radiologists. Intra-operative findings were used as the reference standard (arthroscopy = 73, open surgery = 19). Sensitivity (Se), specificity (Sp), and accuracy (Acc) values that obtained were compared using McNemar test. A value of p < 0.05 was considered statistically significant. Inter-observer agreement was calculated using kappa statistics. RESULTS: Surgeons revealed 81 labrum and 44 chondral lesions, respectively. The highest Se, Sp, and Acc for Reader 1 were 96.3, 90.9, and 95.6%, respectively, in evaluating labral lesions (by reading 2D data set) and 90.9, 100, and 95.7% in evaluating chondral lesions (by reading IW-3D images). The highest Se, Sp, and Acc for Reader 2 were 93.8, 81.8, and 92.4% in evaluating labral lesions (using 2D images) and 88.6, 97.9, and 93.5%, respectively, in evaluating chondral lesions (using Hy-3D). The difference of diagnostic accuracy achieved was not significant (p > 0.05). A near-perfect inter-observer agreement was achieved by reading 2D data set (k = 0.88) and Hy-3D (k = 0.83) and IW-3D (k = 0.85). CONCLUSIONS: At 1.5 Tesla hip MRA, the accuracy of IW-3D and Hy-3D images was not significantly higher than the 2D sequences in evaluating acetabular labrum and chondral lesions. PMID- 28597241 TI - Biocontrol of the toxigenic plant pathogen Fusarium culmorum by soil fauna in an agroecosystem. AB - In 2011 and 2013, a field experiment was conducted in a winter wheat field at Adenstedt (northern Germany) to investigate biocontrol and interaction effects of important members of the soil food web (Lumbricus terrestris, Annelida; Folsomia candida, Collembola and Aphelenchoides saprophilus, Nematoda) on the phytopathogenic fungus Fusarium culmorum in wheat straw. Therefore, soil fauna was introduced in mesocosms in defined numbers and combinations and exposed to either Fusarium-infected or non-infected wheat straw. L. terrestris was introduced in all faunal treatments and combined either with F. candida or A. saprophilus or both. Mesocosms filled with a Luvisol soil, a cover of different types of wheat straw and respective combinations of faunal species were established outdoors in the topsoil of a winter wheat field after harvest of the crop. After a time span of 4 and 8 weeks, the degree of wheat straw coverage of mesocosms was quantified to assess its attractiveness for the soil fauna. The content of Fusarium biomass in residual wheat straw and soil was determined using a double-antibody sandwich (DAS)-ELISA method. In both experimental years, the infected wheat straw was incorporated more efficiently into the soil than the non infected control straw due to the presence of L. terrestris in all faunal treatments than the non-infected control straw. In addition, Fusarium biomass was reduced significantly in all treatments after 4 weeks (2011: 95-99%; 2013:15 54%), whereupon the decline of fungal biomass was higher in faunal treatments than in non-faunal treatments and differed significantly from them. In 2011, Fusarium biomass of the faunal treatments was below the quantification limit after 8 weeks. In 2013, a decline of Fusarium biomass was observed, but the highest content of Fusarium biomass was still found in the non-faunal treatments after 8 weeks. In the soil of all treatments, Fusarium biomass was below the quantification limit. The earthworm species L. terrestris revealed a considerable potential as an effective biocontrol agent contributing to a sustainable control of a Fusarium plant pathogen in wheat straw, thus reducing the infection risk for specific plant diseases in arable fields. PMID- 28597243 TI - Probing the catalytic site of rabbit muscle glycogen phosphorylase using a series of specifically modified maltohexaose derivatives. AB - Glycogen phosphorylase (GP) is an allosteric enzyme whose catalytic site comprises six subsites (SG1, SG-1, SG-2, SG-3, SG-4, and SP) that are complementary to tandem five glucose residues and one inorganic phosphate molecule, respectively. In the catalysis of GP, the nonreducing-end glucose (Glc) of the maltooligosaccharide substrate binds to SG1 and is then phosphorolyzed to yield glucose 1-phosphate. In this study, we probed the catalytic site of rabbit muscle GP using pyridylaminated-maltohexaose (Glcalpha1-4Glcalpha1-4Glcalpha1 4Glcalpha1-4Glcalpha1-4GlcPA, where GlcPA = 1-deoxy-1-[(2-pyridyl)amino]-D glucitol]; abbreviated as PA-0) and a series of specifically modified PA-0 derivatives (Glc m -AltNAc-Glc n -GlcPA, where m + n = 4 and AltNAc is 3 acetoamido-3-deoxy-D-altrose). PA-0 served as an efficient substrate for GP, whereas the other PA-0 derivatives were not as good as the PA-0, indicating that substrate recognition by all the SG1 -SG-4 subsites was important for the catalysis of GP. By comparing the initial reaction rate toward the PA-0 derivatives (V derivative) with that toward PA-0 (V PA-0), we found that the value of V derivative/V PA-0 decreased significantly as the level of allosteric activation of GP increased. These results suggest that some conformational changes have taken place in the maltooligosaccharide-binding region of the GP catalytic site during allosteric regulation. PMID- 28597244 TI - Seasonal and flight-related variation of galectin expression in heart, liver and flight muscles of yellow-rumped warblers (Setophaga coronata). AB - Galectins, a family of multifunctional glycan-binding proteins, are proposed as biomarkers of cellular stress responses. Avian migration is an energetically challenging physical stress, which represents a physiological model of muscular endurance exercises. This study assesses change in galectin gene expression profiles associated with seasonal variation in migratory state and endurance flight in yellow-rumped warblers (Setophaga coronata). Bioinformatics analysis and real-time qPCR were used to analyse the expression of galectins in flight muscle, heart and liver tissues of 15 warblers separated into three groups of winter unflown, and fall migratory flown/unflown birds. Five transcripts similar to chicken and human galectins -1, -2, -3, -4, and -8 were identified in warbler tissues. The expression of these galectins showed no seasonal changes between two experimental groups of birds maintained under unflown winter and fall conditions indicating a minor role of galectins in preparation for migration. However, endurance flight led to a significant elevation of galectin-1 and galectin-3 mRNAs in flight muscles and galectin-3 mRNA in heart tissue while no changes were observed in liver. Different changes were observed for the level of O GlcNAcylated proteins, which were elevated in flight muscles under winter conditions. These results suggest that secreted galectin-1 and galectin-3 may be active in repair of bird muscles during and following migratory flight and serve as molecular biomarkers of recent arrival from migratory flights in field studies. PMID- 28597245 TI - Protein kinase CK2 regulates redox homeostasis through NF-kappaB and Bcl-xL in cardiomyoblasts. AB - Oxygen consumption is particularly elevated in cardiac cells as they are equipped with a large number of mitochondria and high levels of respiratory chain components. Consequently, production of reactive oxygen species (ROS) is tightly controlled as an imbalance in redox reactions can lead to irreversible cellular damage. siRNA-mediated down-regulation of protein kinase CK2 has been implicated in the accumulation of ROS in cells. The present study was undertaken in order to investigate the role of CK2 in redox homeostasis in cardiomyoblasts. We found that inhibition or silencing of CK2 causes elevated levels of ROS, notably superoxide radical, and this is accompanied by suppression of NF-kappaB transcriptional activity and mitochondrial dysfunction. We show that CK2 regulates the expression of manganese superoxide dismutase, the enzyme catalyzing the dismutation of superoxide, in cancer cells but not in cardiomyoblasts. Furthermore, we report evidence that impaired expression of CK2 results in destabilization of the Bcl-2 mammalian homolog Bcl-xL, which is known to stabilize the mitochondrial membrane potential, through a mechanism involving disruption of the chaperone function of heat shock protein 90. Analysis of differential mRNA expression related to oxidative stress revealed that CK2 silencing caused a statistically significant deregulation of four genes associated with the oxidative damage, i.e., Fmo2, Ptgs1, Dhcr24, and Ptgs2. Overall, the results reported here are consistent with the notion that CK2 plays a role in conferring protection against oxidative stress by positively regulating pro-survival signaling molecules and the protein folding machinery in cardiomyoblasts. PMID- 28597246 TI - Criminal Justice Contact, Stressors, and Obesity-Related Health Problems Among Black Adults in the USA. AB - Criminal justice contact-defined as lifetime arrest, parole, or incarceration, seems to exacerbate chronic conditions, and those who are most likely to have had contact with the criminal justice system, such as Black adults, often already have pre-existing disproportionately high rates of stress and chronic conditions due to the social determinants of health that affect underrepresented minorities. Findings from this study suggest that there is a mechanism that links the stressors among Black adults manifested by such factors as family, financial, neighborhood, and personal problems with criminal justice contact to obesity related health status. Using the National Survey of American Life (NSAL), modified Poisson regression analyses were used to determine the association between criminal justice contact, stressors, and obesity-related health problems among a national sample of Black adults (n = 5008). In the full model, the odds of experiencing obesity-related health problems for Black adults who had criminal justice contact was reduced (PR, 1.23 to 1.14) and not statistically significant. Black adults who reported experiencing family stressors (PR, 1.21; 95% CI, 1.08, 1.36), financial stressors (PR, 1.30; 95% CI, 1.16, 1.47), and personal stressors (PR, 1.16; 95% CI, 1.02, 1.31) were statistically significant and higher than those who reported not experiencing any of these stressors; neighborhood stressors was not statistically significant. The evidence suggests a relationship between the stressors associated with criminal justice contact and obesity related health status. These findings emphasize the need to further explore the family, financial, and personal stressors for Black adults with criminal justice contact in order to further our understanding of their obesity-related health problems.?. PMID- 28597247 TI - Pre-operative predictors of post-operative falls in people undergoing total hip and knee replacement surgery: a prospective study. AB - INTRODUCTION: Pain and disability often persist following hip (THR) and knee replacement (TKR) surgery predisposing patients to increased risk of falling. This study identified pre-operative predictors for post-operative falls in TKR and THR patients, and the incidence and circumstances of falls in the 12 months post-surgery. MATERIALS AND METHODS: A survey was undertaken of patients before THR and TKR, and was repeated 12 months post-operation. The survey included (1) medical history and medications usage, (2) pain and function, (3) health-related and physical activity and (4) fear of falls and history of falls questionnaires. Patients were classified as 'fallers' (>=1 fall) or 'non-fallers' based on prospectively documented falls in the 12 months post-surgery. Binary logistic regression was conducted to identify independent pre-operative predictors of incident falls status. RESULTS: Eighty-two of the 243 participants (33.7%) reported >=1 fall in the 12 months post-operatively [60 (34.1%) patients following TKR and 22 (32.8%) following THR]. The logistic regression model was statistically significant, chi 2 = 24.731, p < 0.001, the model explaining 22% of the variance in falls, and correctly classifying 73.7% of cases as fallers or non fallers. Reduced SF-36v2 general health sub-scale, increased planned physical activity and previous falls in the preceding year were predictors of falls. Those reporting >=1 fall pre-operatively were three times more likely to fall post operatively. CONCLUSION: People awaiting hip or knee joint replacement surgery might present with complex conditions that predispose them to greater risk of falling post-operation. Review of general health and history of falling is recommended pre-operatively to identify patients at risk. PMID- 28597248 TI - The Soul, as an Uninhibited Mental Activity, is Reduced into Consciousness by Rules of Quantum Physics. AB - This paper is an effort to describe, in neuroscientific terms, one of the most ambiguous concepts of the universe-the soul. Previous efforts to understand what the soul is and where it may exist have accepted the soul as a subjective and individual entity. We will make two additions to this view: (1) The soul is a result of uninhibited mental activity and lacks spatial and temporal information; (2) The soul is an undivided whole and, to become divided, the soul has to be reduced into unconscious and conscious mental events. This reduction process parallels the maturation of the frontal cortex and GABA becoming the main inhibitory neurotransmitter. As examples of uninhibited mental activity, we will discuss the perceptual differences of a newborn, individuals undergoing dissociation, and individuals induced by psychedelic drugs. Then, we will explain the similarities between the structure of the universe and the structure of the brain, and we propose that consideration of the rules of quantum physics is necessary to understand how the soul is reduced into consciousness. PMID- 28597250 TI - Peer teaching as a means of enhancing communication skills in anaesthesia training: trainee perspectives. AB - PURPOSE: The purpose of this study is to introduce peer teaching of communication skills to first-year anaesthesia trainees in Ireland and to evaluate their perception of this teaching modality. METHODS: Seventy-nine first-year anaesthesia trainees participated in a novel peer-led communication skills programme over a 2-year period (Y1, Y2). A Likert scaling questionnaire was developed to explore trainee perception of the peer teaching programme. RESULTS: Of the 79 respondents (36 in Y1 and 43 in Y2), 99% either agreed or strongly agreed that the peer teachers were successful in their role. Ninety-two percent requested formal peer teaching in other areas of training. The trainees regarded a peer teacher as an appropriate information provider (92%), role model (88%), planner (88%) and facilitator (94%), but less so as an assessor (70%). The most consistently stated strength of peer teaching was the relatability of peer teachers with their lack of experience cited as the main weakness. Eighty percent of participants preferred peer teaching to regular expert teaching. CONCLUSION: This study highlights the positive attitudes of first-year anaesthesia trainees towards a novel peer teaching programme in communication skills. This author recommends that peer teaching is further developed within postgraduate medical programmes to maximise learning for trainees in the student and teacher roles and to redistribute the teaching burden within clinical departments. PMID- 28597249 TI - Differential regulation of protein phosphatase 1 (PP1) isoforms in human heart failure and atrial fibrillation. AB - Protein phosphatase 1 (PP1) is a key regulator of important cardiac signaling pathways. Dysregulation of PP1 has been heavily implicated in cardiac dysfunctions. Accordingly, pharmacological targeting of PP1 activity is considered for therapeutic intervention in human cardiomyopathies. Recent evidence from animal models implicated previously unrecognized, isoform-specific activities of PP1 in the healthy and diseased heart. Therefore, this study examined the expression of the distinct PP1 isoforms PP1alpha, beta, and gamma in human heart failure (HF) and atrial fibrillation (AF) and addressed the consequences of beta-adrenoceptor blocker (beta-blocker) therapy for HF patients with reduced ejection fraction on PP1 isoform expression. Using western blot analysis, we found greater abundance of PP1 isoforms alpha and gamma but unaltered PP1beta levels in left ventricular myocardial tissues from HF patients as compared to non-failing controls. However, expression of all three PP1 isoforms was higher in atrial appendages from patients with AF compared to patients with sinus rhythm. Moreover, we found that in human failing ventricles, beta-blocker therapy was associated with lower PP1alpha abundance and activity, as indicated by higher phosphorylation of the PP1alpha-specific substrate eIF2alpha. Greater eIF2alpha phosphorylation is a known repressor of protein translation, and accordingly, we found lower levels of the endoplasmic reticulum (ER) stress marker Grp78 in the very same samples. We propose that isoform specific targeting of PP1alpha activity may be a novel and innovative therapeutic strategy for the treatment of human cardiac diseases by reducing ER stress conditions. PMID- 28597252 TI - Clinical practice guidelines of the French Association for Supportive Care in Cancer and the French Society for Psycho-oncology: refusal of treatment by adults afflicted with cancer. AB - PURPOSE: The study's purpose was to develop practical guidelines for assessment and management of refusal of treatment by adults afflicted with cancer. METHODS: The French Association for Supportive Care in Cancer and the French Society for Psycho-oncology gathered a task force that applied a consensus methodology to draft guidelines studied predisposing situations, the diagnosis, regulatory aspects, and the management of refusal of treatment by adults afflicted with cancer. RESULTS: We propose five guidelines: (1) be aware of the conditions/profiles of patients most often associated with refusal of treatment so as to adequately underpin the care and support measures; (2) understand the complexity of the process of refusal and knowing how to accurately identify the type and the modalities of the refused treatments; (3) apply a way to systematically analyze refusal, thereby promoting progression from a situation of disaccord toward a consensual decision; (4) devise procedures, according to the legal context, to address refusal of treatment that safeguards the stakeholders in situations of sustained disaccord; and (5) know the indications for ethical collective decision-making. CONCLUSION: The quality of the relationship between patients and health professionals, and the communication between them are essential components involved in reaching a point of consent or refusal of treatment. A process of systematic analysis of refusal is recommended as the only way to ensure that all of the physiological, psychological, and contextual elements that are potentially involved are taken into account. PMID- 28597251 TI - Occurrence of Multiple Sclerosis After Drug Exposure: Insights From Evidence Mapping. AB - INTRODUCTION: The role of drugs in the occurrence of multiple sclerosis (MS) is perceived to be insufficiently investigated. OBJECTIVE: The aim of this study was to map and assess the evidence on MS occurrence after drug exposure, in order to identify possible signals of causal association. METHODS: A search strategy was performed in MEDLINE and Embase as of July 2016; references consistent with the aim of the study were analysed to extract relevant measures of causal association between drugs and MS. The Newcastle-Ottawa Scale and appropriate guidelines from the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) were used to assess the quality of included studies. RESULTS: After screening 832 articles, 58 were selected (of which 14 were found by checking the reference lists of reviews): 30 case reports and case series, 24 longitudinal studies and four randomized controlled trials. Seven longitudinal studies had good (at least 7 out of 9) quality scores, whereas case reports/case series presented several limitations. Half of included articles focused on immunomodulatory drugs (etanercept, infliximab and adalimumab), especially in case reports/series, suggesting an association with MS occurrence. Contraceptives and antibacterials were investigated in some population-based studies, without definite results. CONCLUSION: A heterogeneous pharmacological profile of identified classes emerged. Low strength of evidence and conflicting results highlighted the difficulties in addressing the possible contribution of drugs in MS occurrence. Methodological advances are needed, especially to control the confounding role of underlying disease for specific drug classes. PMID- 28597255 TI - ? PMID- 28597253 TI - Effectiveness of a standardized patient education program on therapy-related side effects and unplanned therapy interruptions in oral cancer therapy: a cluster randomized controlled trial. AB - PURPOSE: Oral agents for cancer treatment are increasingly prescribed due to their benefits. However, oral cancer medications are difficult to handle and have a considerable potential for side effects. This type of therapy requires a high level of self-management competence by the patient. A standardized patient education program provided by physicians and oncology nurses may positively influence the handling of oral agents. The aim of the study was to evaluate the impact of a standardized patient education program provided by specially trained oncology nurses on therapy management regarding side effects and unplanned therapy interruptions. METHODS: One hundred sixty-five patients from 28 office based oncology practices from all over Germany participated in this cluster randomized controlled study. Patients of both intervention (n = 111) and standard care groups (n = 54) received the usual oncologist counseling; in addition, the patients from the intervention group (k = 17 practices) received an education from specially trained oncology nurses. The time of observation was 3 months per patient. RESULTS: The patients of the intervention group reported fewer side effects (skin rash, pain, fatigue, nausea, vomiting). Patients in the standard care group interrupted the therapy more frequently without informing their oncologist, compared to the intervention group. CONCLUSIONS: Patients benefit from a standardized patient education program provided by specially trained oncology nurses. They tend to handle side effects and critical situations better. PMID- 28597254 TI - Changes in structure and function of bacterial communities during coconut leaf vermicomposting. AB - To understand bacterial community dynamics during the vermicomposting of lignin rich coconut leaves using an indigenous isolate of an epigeic earthworm, Eudrilus sp., we employed amplicon-based pyrosequencing of the V1 to V3 region of the 16S rRNA genes. Total community DNA was isolated from two separate vermicomposting tanks in triplicate at four different stages of the process: pre-decomposition (15th day), initial vermicomposting (45th day), 50-70% vermicomposting (75th day) and mature vermicompost (105th day). Alpha diversity measurements revealed an increase in bacterial diversity till the 75th day, which then declined in the mature vermicompost. Beta diversity comparisons showed formation of distinct, stage-specific communities. In terms of relative abundance, the Acidobacteria, Actinobacteria, Chloroflexi, Gemmatimonadetes, Nitrospirae, Planctomycetes, TM7 and WS3 groups increased until the 50-70% vermicomposting stage (p = 0.05). During the same time, the abundance of Bacteroidetes and Proteobacteria decreased. In contrast, the levels of Firmicutes increased throughout the 105-day vermicomposting process. The distribution of the most abundant OTUs revealed that each stage of the vermicomposting process possessed its own unique microbiome. Predictions based on the OTUs present by PICRUSt suggested a functional shift in the microbiome during vermicomposting. Enzymes and pathways of lipid and lignin metabolism were predicted to be initially abundant, but by the end of the process, biosynthesis of secondary metabolites and plant beneficial properties were enriched. The study revealed that bacterial communities undergo a continuous change throughout the vermicomposting process and that certain OTUs associated with specific stages could be targets for further improvements in the process. PMID- 28597256 TI - ? PMID- 28597257 TI - ? PMID- 28597258 TI - ? PMID- 28597259 TI - ? PMID- 28597260 TI - ? PMID- 28597261 TI - [HCV healing also in HIV infected patients]. PMID- 28597262 TI - [On stage with HIV]. PMID- 28597263 TI - [Prophylaxis on sexually transmittable diseases in people living with HIV: advice, testing, treatment]. PMID- 28597264 TI - [HIV pre-exposure prophylaxis in women]. PMID- 28597265 TI - [HIV Pre-Exposure prophylaxis (PrEP) in men]. PMID- 28597266 TI - [Long-acting shot against HIV]. PMID- 28597267 TI - [What can new substances offer?] PMID- 28597268 TI - [Finally the therapy worked]. PMID- 28597269 TI - [New therapy preservers the kidney]. PMID- 28597271 TI - ? PMID- 28597270 TI - [Vaccines for people living with HIV/AIDS]. PMID- 28597274 TI - ? PMID- 28597272 TI - ? PMID- 28597273 TI - ? PMID- 28597275 TI - ? PMID- 28597276 TI - ? PMID- 28597277 TI - ? PMID- 28597279 TI - ? PMID- 28597280 TI - [Treatment of HIV-infected patients: metabolism, bone, cardiovascular - what is part of routine care?] PMID- 28597281 TI - Gangrenous cholecystitis: innovative laparoscopic techniques to facilitate subtotal fenestrating cholecystectomy when a critical view of safety cannot be achieved. AB - BACKGROUND: Gangrenous cholecystitis is associated with a higher conversion rate of conversion from laparoscopic to open than acute non-gangrenous cholecystitis. New strategies and techniques are needed to decrease conversion rates and improve outcomes. METHODS: In this article, we provide a richly detailed, illustrated description of a modified fundus-first technique that we have developed over the last 15 years and now use routinely with rare conversions. We also compared outcomes of laparoscopic (LC) and open (OC) approaches for pathologically confirmed gangrenous cholecystitis in 146 patients during 1995-2005, the first 10 years during which these two approaches were performed contemporaneously at our institution on comparable patients. RESULTS: Among the 142 patients that met the inclusion criteria, laparoscopic procedures were started in 112 (79%) of these patients, with successful completion in 72 resulting in an overall conversion rate of 36%. During the last 5 years, however, in cases where the described laparoscopic technique was used, no patient has required conversion. The laparoscopic LC group had shorter average ICU stay (p < 0.05) and overall length of stay (2 vs 6 days, p < 0.001). Intraoperative cholangiography was completed in 37 of 72 LC patients (52%) versus 6 of 30 OC (20%). In five of the LC patients, a filling defect was seen on the cholangiogram and laparoscopic transcystic common bile duct stones, thereby avoiding a second anesthetic and endoscopic procedure. CONCLUSIONS: In the setting of severe inflammation, a number of procedural modifications can be incorporated to allow the surgeon to approach dissection of the gangrenous gallbladder using a flexible operative plan designed to optimize safe completion of this challenging procedure, with the expected improvement in surgical outcomes. PMID- 28597282 TI - The general surgeon's perspective of rectus diastasis. A systematic review of treatment options. AB - BACKGROUND: Diastasis of the rectus abdominis muscles (DRAM) is characterised by thinning and widening of the linea alba, combined with laxity of the ventral abdominal musculature. This causes the midline to "bulge" when intra-abdominal pressure is increased. Plastic surgery treatment for DRAM has been thoroughly evaluated, though general surgical treatments and the efficacy of physiotherapy remain elusive. The aim of this systematic literature review is to evaluate both general surgical and physiotherapeutic treatment options for restoring DRAM in terms of postoperative complications, patient satisfaction, and recurrence rates. METHOD: MEDLINE(r), Embase, PubMed, PubMed Central(r), The cochrane central registry of controlled trials (CENTRAL), Google Scholar, and the Physiotherapy Evidence Database (PEDro) were searched using the following terms: 'rectus diastasis', 'diastasis recti', 'midline', and 'abdominal wall'. All clinical studies concerning general surgical or physiotherapeutic treatment of DRAM were eligible for inclusion. RESULT: Twenty articles describing 1.691 patients (1.591 surgery/100 physiotherapy) were included. Surgical interventions were classified as plication techniques (313 patients; 254 open/59 laparoscopic), modified hernia repair techniques (68 patients, all open), and combined hernia & DRAM techniques (1.210 patients; 1.149 open/40 hybrid). The overall methodological quality was low. Plication techniques with interrupted sutures and mesh reinforcement were applied most frequently for DRAM repair. Open repairs were performed in 85% of patients. There was no difference in postoperative complications or recurrence rate after laparoscopic or open procedures, or between plication and modified hernia repair techniques. Physiotherapy programmes were unable to reduce IRD in a relaxed state. Though reduction of IRD during muscle contraction was described. CONCLUSION: Both plication-based methods and hernia repair methods are used for DRAM repair. Based on the current literature, no clear distinction in recurrence rate, postoperative complications, or patient reported outcomes can be made. Complete resolution of DRAM, measured in a relaxed state, following a physiotherapy training programme is not described in current literature. Physiotherapy can achieve a limited reduction in IRD during muscle contraction, though the impact of this finding on patient satisfaction, cosmesis, or function outcome is unclear. PMID- 28597283 TI - Transumbilical laparoscopic-assisted appendectomy in children: is it worth it? AB - INTRODUCTION: Transumbilical laparoscopic-assisted appendectomy (TULAA) is the technique of choice for all types of appendicitis in our Department. It combines the advantages of laparoscopy (global vision and minimally invasion) and open surgery (lower cost). The objective was to assess the results of our TULAA series and compare them to the results of standard laparoscopic appendectomies (SLA) performed during the same period. METHODS: Retrospective review of total appendectomies performed since TULAA introduction (September 2003 to December 2015) with statistic analysis of the results. RESULTS: A total of 1309 patients underwent TULAA approach, but 126 (9.6%) needed reconversion to open appendectomy, 1 (0.08%) to SLA, and 9 (0.7%) introduction of a second port. Mean age and weight of patients was 121.5 +/- 36 months and 37.6 +/- 14 kg, respectively. Mean operative time was 40.9 +/- 15.5 min, ranging from 11 to 110. All types of appendicitis were present, with 394 being complicated (29.9%). Postoperative complications were seen in 168 patients (14.3%), 37 being readmitted (3.2%), and only five needing reintervention (Two intestinal occlusions and three abscess debridement). When comparing TULAA and SLA, there were no significant differences in the length of hospitalization, time to tolerate soft diet, analgesic requirements, and complications depending on the type of appendicitis, but TULAA was significantly faster and cheaper (average 900?). CONCLUSIONS: In our hands, TULAA has shown to be effective, easy to learn, and fast to perform. Low surgical cost is probably its principal advantage, which might be encouraging in times of crisis. PMID- 28597284 TI - Comparison of single-incision laparoscopic percutaneous extraperitoneal closure (SILPEC) and open repair for pediatric inguinal hernia: a single-center retrospective cohort study of 2028 cases. AB - BACKGROUD: Recently, laparoscopic percutaneous extraperitoneal closure (LPEC) has gained increased popularity for pediatric inguinal hernia repair. To improve cosmesis, we developed single incision LPEC (SILPEC). The aim of this study was to assess the safety and feasibility of SILPEC compared with traditional open repair (OR). METHODS: This was a single-center retrospective cohort study of 2028 children who underwent inguinal hernia repair between April 2005 and August 2014. Nine hundred and ninety-five patients underwent OR and 1033 patients underwent SILPEC. Medical records were reviewed with respect to operative time, recurrence, incidence of contralateral metachronous inguinal hernia (CMIH), and complications. Patient satisfaction with cosmetic result was also investigated using questionnaires sent by mail. RESULTS: All SILPEC procedures were completed without conversion. Operative time was longer in the SILPEC group than in the OR group for both unilateral and bilateral surgery regardless of sex (unilateral male: p = 0.0006, unilateral female: p < 0.0001, bilateral male: p < 0.0001, bilateral female: p < 0.0001). There was no statistically significant difference in recurrence rate (p = 0.43). The incidence of CMIH was significantly higher in the OR than in the SILPEC group (p < 0.0001). No postoperative testicular atrophy was found in either group. There was no statistically significant difference in ascending testis (p = 0.09), but the frequency of surgical site infection was higher in the SILPEC than in the OR group (p = 0.0013). According to the questionnaire, operative scar was more invisible in the SILPEC than in the OR group (p < 0.0001), but both procedures had equally high levels of satisfaction for cosmetic results (p = 0.58). CONCLUSION: SILPEC proved to be a safe and feasible procedure compared with OR with an equally low recurrence rate, more effectiveness for preventing CMIH, and more invisible scar. PMID- 28597285 TI - Impaired laparoscopic performance of novice surgeons due to phone call distraction: a single-centre, prospective study. AB - BACKGROUND: Distractions such as phone calls during laparoscopic surgery play an important role in many operating rooms. The aim of this single-centre, prospective study was to assess if laparoscopic performance is impaired by intraoperative phone calls in novice surgeons. METHODS: From October 2015 to June 2016, 30 novice surgeons (medical students) underwent a laparoscopic surgery training curriculum including two validated tasks (peg transfer, precision cutting) until achieving a defined level of proficiency. For testing, participants were required to perform these tasks under three conditions: no distraction (control) and two standardised distractions in terms of phone calls requiring response (mild and strong distraction). Task performance was evaluated by analysing time and accuracy of the tasks and response of the phone call. RESULTS: In peg transfer (easy task), mild distraction did not worsen the performance significantly, while strong distraction was linked to error and inefficiency with significantly deteriorated performance (P < 0.05). Precision cutting (difficult task) was not slowed down by mild distraction, but surgical and cognitive errors were significantly increased when participants were distracted (P < 0.05). Compared to mild distraction, participants reported a more severe subjective disturbance when they were diverted by strong distraction (P < 0.05). CONCLUSION: Our data reveals that phone call distractions result in impaired laparoscopic performance under certain circumstances. To ensure patient safety, phone calls should be avoided as far as possible in operating rooms. PMID- 28597286 TI - What are the differences in the outcome of laparoscopic axial (I) versus paraesophageal (II-IV) hiatal hernia repair? AB - INTRODUCTION: Comparison of elective laparoscopic repair of axial vs paraesophageal hiatal hernias reveals relevant differences in both the patient collectives and the complexity of the procedures. MATERIALS AND METHODS: The present uni- and multivariable analysis of data from the Herniamed Registry compares the outcome for 2047 (67.3%) (type I) axial with 996 (32.7%) (types II IV) paraesophageal primary hiatal hernias following laparoscopic repair. RESULTS: Compared with the patients with axial hiatal hernias, patients with paraesophageal hiatal hernia were nine years older, had a higher ASA score (ASA III/IV: 34.8 vs 13.7%; p < 0.001), and more often at least one risk factor (38.8 vs 21.4%; p < 0.001). This led in the univariable analysis to significantly more general postoperative complications (6.0 vs 3.0%; p < 0.001). Reflecting the greater complexity of the procedures used for laparoscopic repair of paraesophageal hiatal hernias, significantly higher intraoperative organ injury rates (3.7 vs 2.3%; p = 0.033) and higher postoperative complication-related reoperation rates (2.1 vs 1.1%; p = 0.032) were identified. Univariable analysis did not reveal any significant differences in the recurrence and pain rates on one-year follow-up. Multivariable analysis did not find any evidence that the use of a mesh had a significant influence on the recurrence rate. CONCLUSION: Surgical repair of paraesophageal hiatal hernia calls for an experienced surgeon as well as for corresponding intensive medicine competence because of the higher risks of general and surgical postoperative complications. PMID- 28597287 TI - Comparison of endoscopic sphincterotomy techniques after Billroth II gastrectomy using a novel mechanical simulator. AB - BACKGROUND AND AIMS: A postsurgical anatomy renders endoscopic sphincterotomy (EST) more challenging. Although different EST techniques for such a situation exist, comparative studies are lacking. The aim of the study was to compare the efficacy of different EST techniques using a novel mechanical simulator. METHODS: Ten expert endoscopists performed 6 different EST techniques on a novel mechanical Billroth II (BII) simulator in a random sequence. The EST techniques were (1) standard sphincterotome used with a side-viewing endoscope, (2) BII sphincterotome used with a side-viewing endoscope, (3) needle-knife EST guided by biliary endoprosthesis used with a side-viewing endoscope, (4) standard sphincterotome used with a forward-viewing endoscope, (5) BII sphincterotome used with a forward-viewing endoscope, and (6) needle-knife EST guided by biliary endoprosthesis used with a forward-viewing endoscope. The results of videotaped ESTs were evaluated by a blinded expert and duration for each EST modality was calculated. RESULTS: Needle-knife EST guided by endoprosthesis was rated superior to EST using a BII sphincterotome (p = 0.017) or a standard sphincterotome (p < 0.001). EST using the BII sphincterotome was significantly faster than EST with the needle knife (p = 0.004) and the standard sphincterotome (p = 0.005). There were no differences between the use of a forward-viewing endoscope and a side viewing endoscope. CONCLUSION: In an ex vivo model for EST in B II gastrectomy needle-knife EST guided by endoprosthesis achieved superior ratings in comparison to the use of a BII sphincterotome, although it was more time-consuming. A standard sphincterotome should not be used for such a procedure. PMID- 28597289 TI - Erratum to: Colorimetric Detection of Acetyl Xylan Esterase Activities. PMID- 28597288 TI - Safety and efficacy of endoscopic submucosal dissection of large (>=3 cm) subepithelial tumors located in the cardia. AB - BACKGROUND: Upper gastrointestinal subepithelial tumors (SETs) may harbor potential malignancy. Although it is well recognized that large SETs should be resected, the treatment strategy remains controversial. Compared to surgical resection, endoscopic resection has many advantages such as less invasive, shorter hospital stay, lower costs, and better quality of life. However, Endoscopic resection of large SETs in the cardia is challenging. The purpose of this study was to evaluate the safety and efficacy of endoscopic submucosal dissection (ESD) in the treatment of such SETs. METHODS: A total of 41 patients with large SETs (>=3 cm in diameter) located in the cardia were involved in the study. All patients underwent ESD. Data on therapeutic outcomes and follow-up were collected, for analysis of risk factors of complication rates. RESULTS: The average tumor size was 4.7 +/- 1.7 cm. The average procedure time was 69.3 +/- 32.7 min and the average postoperative hospital stay was 3.5 +/- 1.1 days. A total of 41 tumors were removed successfully, in which 35 were leiomyomas, three were gastrointestinal stromal tumors, two were lipomas, and one was gastritis cystica profunda. The en bloc resection rate was 90.2%, and was significantly higher for tumors with a round or oval shape (100%) than for those with an irregular shape (75.0%) (P < 0.05). Five patients experienced complications (12.2%), all of which were managed conservatively. The complication rates were significantly higher in patients with a tumor originating from the deep muscularis propria layer and demonstrating a trans-cardia growth pattern. No residual or tumor recurrence was observed and no stricture occurred during the follow-up period (average, 26.7 +/- 18.4 months). CONCLUSIONS: ESD is safe and effective to curatively remove most large SETs in the cardia, and may serve as an accurate histopathology measurement to direct future therapy. PMID- 28597290 TI - Erratum to: Identification and Characterisation of a Novel Pathogenic Mutation in the Human Lipodystrophy Gene AGPAT2 : C48R: A Novel Mutation in AGPAT2. PMID- 28597292 TI - [Osteotomy around the knee]. PMID- 28597291 TI - Multiple drug transporters mediate the placental transport of sulpiride. AB - Sulpiride is a typical antipsychotic drug for the treatment of schizophrenia, depression and other psychological disorders. It has been proven that a small amount of sulpiride could cross the human placenta using an ex vivo placental perfusion model. However, the placental transfer mechanism has not been elucidated. Considering the structure of sulpiride, we speculated that the transporters expressed in placenta might be involved in sulpiride uptake across the blood-placenta barrier. The aim of our study was to determine which transporters contributed to the placental transfer of sulpiride. Our results revealed that sulpiride was a substrate of human organic cation transporter (hOCT) 3, human multidrug resistance protein (hMDR) 1 and human breast cancer resistance protein (hBCRP) using transfected cells expressing respective transporters. In addition, the accumulation of sulpiride in BeWo cells (a human choriocarcinoma cell line) was obviously affected by inhibitors of carnitine/organic cation transporter (OCTN) 2, MDR1 and BCRP. The accumulation of sulpiride in primary human trophoblast cells was obviously affected by inhibitors of OCT3, OCTN1 and OCTN2. The above results indicate that hOCTN1 and hOCTN2 likely contribute to the sulpiride uptake from maternal circulation to trophoblast cells, while hMDR1 and hBCRP mediate the efflux from trophoblast cells to maternal circulation, and hOCT3 probably is involved in the bidirectional transport of sulpiride between the placenta and fetal blood. PMID- 28597293 TI - Reducing uncertainty in sustainable interpersonal service relationships: the role of aesthetics. AB - Sustainable interpersonal service relationships (SISRs) are the outcome of a design process that supports situated meaningful interactions between those being served and those in service. Service design is not just directed to simply satisfy the ability to perceive the psychological state of others, but more importantly, it should aim at preserving these relationships in relation to the contextual requirements that they functionally need, in order to be or remain sustainable. However, SISRs are uncertain since they have many possibilities to be in error in the sense that the constructed, situated meanings may finally be proven unsuccessful for the anticipations and the goals of those people engaged in a SISR. The endeavor of this paper is to show that aesthetic behavior plays a crucial role in the reduction of the uncertainty that characterizes such relationships. Aesthetic behavior, as an organized network of affective and cognitive processes, has an anticipatory evaluative function with a strong influence on perception by providing significance and value for those aspects in SISRs that exhibit many possibilities to serve goals that correspond to sustainable challenges. Thus, aesthetic behavior plays an important role in the construction of meanings that are related to both empathic and contextual aspects that constitute the entire situation in which a SISR takes place. Aesthetic behavior has a strong influence in meaning-making, motivating the selection of actions that contribute to our initial goal of interacting with uncertainty, to make the world a bit less puzzling and, thus, to improve our lives, or in other words, to design. PMID- 28597294 TI - Grasping occluded targets: investigating the influence of target visibility, allocentric cue presence, and direction of motion on gaze and grasp accuracy. AB - Participants executed right-handed reach-to-grasp movements toward horizontally translating targets. Visual feedback of the target when reaching, as well as the presence of additional cues placed above and below the target's path, was manipulated. Comparison of average fixations at reach onset and at the time of the grasp suggested that participants accurately extrapolated the occluded target's motion prior to reach onset, but not after the reach had been initiated, resulting in inaccurate grasp placements. Final gaze and grasp positions were more accurate when reaching for leftward moving targets, suggesting individuals use different grasp strategies when reaching for targets traveling away from the reaching hand. Additional cue presence appeared to impair participants' ability to extrapolate the disappeared target's motion, and caused grasps for occluded targets to be less accurate. Novel information is provided about the eye-hand strategies used when reaching for moving targets in unpredictable visual conditions. PMID- 28597295 TI - Evolution of intrinsic disorder in eukaryotic proteins. AB - Conformational flexibility conferred though regions of intrinsic structural disorder allows proteins to behave as dynamic molecules. While it is well-known that intrinsically disordered regions can undergo disorder-to-order transitions in real-time as part of their function, we also are beginning to learn more about the dynamics of disorder-to-order transitions along evolutionary time-scales. Intrinsically disordered regions endow proteins with functional promiscuity, which is further enhanced by the ability of some of these regions to undergo real time disorder-to-order transitions. Disorder content affects gene retention after whole genome duplication, but it is not necessarily conserved. Altered patterns of disorder resulting from evolutionary disorder-to-order transitions indicate that disorder evolves to modify function through refining stability, regulation, and interactions. Here, we review the evolution of intrinsically disordered regions in eukaryotic proteins. We discuss the interplay between secondary structure and disorder on evolutionary time-scales, the importance of disorder for eukaryotic proteome expansion and functional divergence, and the evolutionary dynamics of disorder. PMID- 28597296 TI - Behaviour of intrinsically disordered proteins in protein-protein complexes with an emphasis on fuzziness. AB - Intrinsically disordered proteins (IDPs) do not, by themselves, fold into a compact globular structure. They are extremely dynamic and flexible, and are typically involved in signalling and transduction of information through binding to other macromolecules. The reason for their existence may lie in their malleability, which enables them to bind several different partners with high specificity. In addition, their interactions with other macromolecules can be regulated by a variable amount of chemically diverse post-translational modifications. Four kinetically and energetically different types of complexes between an IDP and another macromolecule are reviewed: (1) simple two-state binding involving a single binding site, (2) avidity, (3) allovalency and (4) fuzzy binding; the last three involving more than one site. Finally, a qualitative definition of fuzzy binding is suggested, examples are provided, and its distinction to allovalency and avidity is highlighted and discussed. PMID- 28597299 TI - Letter to the Editor concerning "The surgical algorithm for the AOSpine thoracolumbar spine injury classification system" by A. R. Vaccaro et al. Eur Spine J (2016);25(4):1087-1094. PMID- 28597300 TI - Proximal junctional kyphosis in adult scoliosis: comparison of four radiological predictor models. AB - OBJECTIVE: The objective of this retrospective study is to identify the best immediate postoperative radiological predictors for the occurrence of proximal junctional kyphosis (PJK). Four proposed methods will be explored. METHODS: A homogeneous database of adult scoliosis from multiple centers was used. Patients with whole spine X-rays at the required follow-up (FU) periods were included. Spinal and pelvic parameters were measured and calculated to compare four predictive methods: Method 1: assessment of the global sagittal alignment (GSA); Method 2: restoration of the theoretical values of lumbar lordosis (LL) and thoracic kyphosis (TK) according to pelvic incidence (PI); Method 3: evaluation of TK + LL, and Method 4: restoration of the apex of sagittal LL to its theoretical values according to various spine shapes in Roussouly Classification. PJK occurrence was assessed at the last FU radiograph. RESULTS: 250 patients were included; mean age was 56.67 years and mean FU was 2.5 years. PJK occurred in 25.6% of cases. PJK occurred in 19.9% in patients with a GSA <45 degrees and in 29.9% where GSA >45 degrees (p = 0.04, OR = 1.71). Restoring the sagittal apex of the LL to its theoretical values according to PI deceased PJK to 13.5% compared to 38.9% in the other cases (p = 0.01, OR = 4.6). The two other described methods (2 and 3) were not significant predictors. DISCUSSION: The comparison between the four predictive methods showed that a GSA >45 degrees and restoration of sagittal apex of lordosis according to PI, were the most predictive methods for PJK in ASD. The latter had a higher predictive value. Our findings could prove useful in effective preoperative planning in ASD surgery to reduce PJK rates. LEVEL OF EVIDENCE: Level IV. PMID- 28597301 TI - Osteoarthritis and spontaneous fusion of facet joints after percutaneous instrumentation in thoracolumbar fractures. AB - PURPOSE: This retrospective study determined the rate of osteoarthritis and spontaneous facet joint fusion and analyzed risk factors related to patient characteristics, fracture type or surgical technique on pre- and postoperative CT after percutaneous instrumentation in thoracolumbar fractures. METHODS: 1050 facet joints adjacent to screws in 148 patients (15-85 years) with thoracolumbar fractures were analyzed with an average time between CTs of 12.3 months. Screw diameters, lengths and cement augmentation were recorded. Facet joint violation by screw trajectory and by insertion depth was classified in three grades. Pre- and postoperative osteoarthritis was graded as absent, minor or severe and postoperative facet joint fusion as absent, partial or complete. RESULTS: The facet violation rate was moderate in 15.4% and severe in 0.6% according to screw trajectory, and 11.0 and 0.6%, respectively, according to insertion depth. Osteoarthritis was preoperatively rated moderate in 9.6% and severe in 1.2%. A progression was evidenced in 79 facet joints (7.5%). Screw cement augmentation was the main predictive factor (p < 0.0001). Partial fusion was evidenced in 2.6% and complete fusion in 1% of facet joints. Risk factors were: BMI (p = 0.0002), age (p = 0.0013), preoperative osteoarthritis (p = 0.0005), time between 2 CTs (p = 0.0001), B-type fractures (p = 0.0005), concomitant anterior fusion (p = 0.0034). CONCLUSIONS: Occurrence or worsening of osteoarthritis was mainly observed in elderly patients with cement-augmented screws and spontaneous facet fusion in elderly patients with high BMI and preoperative osteoarthritis, or in anteriorly fused B-type injuries. Thus, percutaneous instrumentation can safely be removed after fracture consolidation in younger patients while preserving facet joints. PMID- 28597298 TI - Conditionally disordered proteins: bringing the environment back into the fold. AB - For many proteins, biological function requires the folding of the polypeptide chain into a unique and persistent tertiary structure. This review concerns proteins that adopt a specific tertiary structure to function, but are otherwise partially or completely disordered. The biological cue for protein folding is environmental perturbation or minor post-translational modification. Hence, we term these proteins conditionally disordered. Many of these proteins recognize and bind other molecules, and conditional disorder has been hypothesized to allow for more nuanced control and regulation of binding processes. However, this remains largely unproven. The sequences of conditionally disordered proteins suggest their propensity to fold; yet, under the standard laboratory conditions, they do not do so, which may appear surprising. We argue that the surprise results from the failure to consider the role of the environment in protein structure formation and that conditional disorder arises as a natural consequence of the marginal stability of the folded state. PMID- 28597297 TI - Intrinsic protein disorder in oncogenic KRAS signaling. AB - How Ras, and in particular its most abundant oncogenic isoform K-Ras4B, is activated and signals in proliferating cells, poses some of the most challenging questions in cancer cell biology. In this paper, we ask how intrinsically disordered regions in K-Ras4B and its effectors help promote proliferative signaling. Conformational disorder allows spanning long distances, supports hinge motions, promotes anchoring in membranes, permits segments to fulfil multiple roles, and broadly is crucial for activation mechanisms and intensified oncogenic signaling. Here, we provide an overview illustrating some of the key mechanisms through which conformational disorder can promote oncogenesis, with K-Ras4B signaling serving as an example. We discuss (1) GTP-bound KRas4B activation through membrane attachment; (2) how farnesylation and palmitoylation can promote isoform functional specificity; (3) calmodulin binding and PI3K activation; (4) how Ras activates its RASSF5 cofactor, thereby stimulating signaling of the Hippo pathway and repressing proliferation; and (5) how intrinsically disordered segments in Raf help its attachment to the membrane and activation. Collectively, we provide the first inclusive review of the roles of intrinsic protein disorder in oncogenic Ras-driven signaling. We believe that a broad picture helps to grasp and formulate key mechanisms in Ras cancer biology and assists in therapeutic intervention. PMID- 28597302 TI - The impact of hypertension on the occurrence of postoperative spinal epidural hematoma following single level microscopic posterior lumbar decompression surgery in a single institute. AB - PURPOSE: Postoperative spinal epidural hematoma (PSEH) is one of the most hazardous complications after spine surgery. A recent study has reported that a >=50 mmHg increase in systolic blood pressure after extubation was a significant risk factor for symptomatic PSEH. In this paper, the impact of hypertension on PSEH occurrence was investigated. METHODS: Among a total of 2468 patients who underwent single level microscopic posterior decompression surgery for lumbar spinal stenosis in a single institute, 15 (0.6%) received evacuation surgery for PSEH. Those 15 patients were investigated statistically compared with a randomly selected control group (n = 46) using the Mann-Whitney U test and multiple logistic regression analysis. RESULTS: The univariate analysis showed that there were no significant differences in age, gender, BMI, pre-operative anti-coagulant usage, intraoperative blood loss, operation time, and the rate of patients who received pre-operative hypertension treatment. However, there were significant differences in the rate of patients who showed high blood pressure at admission (66.7 vs 6.5%) and >50 mmHg increases in blood pressure after extubation (53.3 vs 17.4%) in the univariate analysis. Moreover, postoperatively, there was a statistical difference in the amount of post-operative drainage. Multiple logistic regression analysis showed that high blood pressures at admission and poor postoperative drainage were the essential risk factors. CONCLUSIONS: Our results demonstrate that the pre-operative high blood pressure value was the most essential risk factor for PSEH, although there was no difference in the preoperative hypertension treatment. Consequently, management of pre-operative blood pressure and post-operative drainage will be crucial for preventing PSEH. PMID- 28597303 TI - Current pathogenic Escherichia coli foodborne outbreak cases and therapy development. AB - Food contamination by pathogenic microorganisms has been a serious public health problem and a cause of huge economic losses worldwide. Foodborne pathogenic Escherichia coli (E. coli) contamination, such as that with E. coli O157 and O104, is very common, even in developed countries. Bacterial contamination may occur during any of the steps in the farm-to-table continuum from environmental, animal, or human sources and cause foodborne illness. To understand the causes of the foodborne outbreaks by E. coli and food-contamination prevention measures, we collected and investigated the past 10 years' worldwide reports of foodborne E. coli contamination cases. In the first half of this review article, we introduce the infection and symptoms of five major foodborne diarrheagenic E. coli pathotypes: enteropathogenic E. coli (EPEC), Shiga toxin-producing E. coli/enterohemorrhagic E. coli (STEC/EHEC), Shigella/enteroinvasive E. coli (EIEC), enteroaggregative E. coli (EAEC), and enterotoxigenic E. coli (ETEC). In the second half of this review article, we introduce the foodborne outbreak cases caused by E. coli in natural foods and food products. Finally, we discuss current developments that can be applied to control and prevent bacterial food contamination. PMID- 28597304 TI - Improved Tet-On and Tet-Off systems for tetracycline-regulated expression of genes in Candida. AB - Tetracycline-regulated expression of genes is often used for functional analysis of Candida albicans genes. However, the widely used Tet-On system has certain limitations such as prolonged lag time (up to 8 h) for induction and non-uniform expression among the cells. We speculated that poor expression of tetracycline controlled transactivator (Tet-transactivator) from CaADH1 promoter could be responsible for this, and thus compared the effect of expressing this protein under the control of CaADH1, CaTDH3 and CaRP10 promoters on the expression of GFP from the TET promoter. Only CaRP10 promoter facilitated a more uniform and rapid induction of GFP. However, a high concentration of doxycycline was needed for induction, which is not desirable for assessing certain phenotypes. Tet-Off systems are known to require a low concentration of doxycycline, but a limitation of the widely used Tet-Off system for C. albicans is the use of CaENO1 promoter, which is known to be repressed in the presence of gluconeogenic carbon source, for expression of transactivator. Thus, we have converted the above-mentioned Tet On systems to Tet-Off systems by site-directed mutagenesis of the Tet transactivator. Compared to the Tet-On systems, the Tet-Off systems required about 200-fold less concentration of doxycycline for modulation of gene expression. Only the Tet-Off system with CaRP10 promoter driving the expression of transactivator allowed rapid and high level expression of GFP compared to those with CaADH1 or CaTDH3 promoters. The utility of CaRP10 based Tet-On and Tet Off systems was further validated by the conditional expression of the CaTUP1 gene. We have also adapted these systems for use with Candida tropicalis and find that the Tet-Off system is functional in this species. The Tet systems reported here will be useful for conditional expression of genes in C. albicans as well as C. tropicalis. PMID- 28597305 TI - The 2 micron plasmid: a selfish genetic element with an optimized survival strategy within Saccharomyces cerevisiae. AB - Since its discovery in the early 70s, the 2 micron plasmid of Saccharomyces cerevisiae continues to intrigue researchers with its high protein-coding capacity and a selfish nature yet high stability, earning it the title of a 'miniaturized selfish genetic element'. It codes for four proteins (Rep1, Rep2, Raf1, and Flp) vital for its own survival and recruits several host factors (RSC2, Cohesin, Cse4, Kip1, Bik1, Bim1, and microtubules) for its faithful segregation during cell division. The plasmid maintains a high-copy number with the help of Flp-mediated recombination. The plasmids organize in the form of clusters that hitch-hike the host chromosomes presumably with the help of the plasmid-encoded Rep proteins and host factors such as microtubules, Kip1 motor, and microtubule-associated proteins Bik1 and Bim1. Although there is no known yeast cell phenotype associated with the 2 micron plasmid, excessive copies of the plasmid are lethal for the cells, warranting a tight control over the plasmid copy number. This control is achieved through a combination of feedback loops involving the 2 micron encoded proteins. Thus, faithful segregation and a concomitant tightly controlled plasmid copy number ensure an optimized benign parasitism of the 2 micron plasmid within budding yeast. PMID- 28597306 TI - Maintenance of remission with combination etanercept-DMARD therapy versus DMARDs alone in active rheumatoid arthritis: results of an international treat-to-target study conducted in regions with limited biologic access. AB - In this transglobal, randomized, double-blind, placebo-controlled, treat-to target study, the maintenance of efficacy was compared between biologic-and biologic-free-disease-modifying antirheumatic drug (DMARD) combination regimens after low disease activity (LDA) was achieved with biologic DMARD induction therapy. Patients with moderate-to-severe rheumatoid arthritis despite methotrexate therapy received open-label etanercept 50 mg subcutaneously once weekly plus methotrexate with or without other conventional synthetic (cs) DMARDs for 24 weeks. Patients achieving LDA [disease activity score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) <3.2] at week 24 were randomized to receive etanercept-methotrexate combination therapy or placebo-methotrexate combination therapy, with or without other csDMARDs, for 28 weeks. In the open label period, 72% of patients achieved DAS28-ESR LDA at week 24. Patients enrolled in the double-blind period had long-standing rheumatoid arthritis and high disease activity at baseline (mean duration, 8.1 years; DAS28-ESR, 6.4). In the etanercept and placebo combination groups, 44% versus 17% achieved DAS28-ESR LDA and 34 versus 13% achieved DAS28-ESR remission at week 52 (p < 0.001). Adverse events were reported in 37 and 43%, serious adverse events in 0 and 4%, and serious infections in 0 and 2% in these groups, respectively, in the double blind period. After induction of response with etanercept combination therapy following a treat-to-target approach in patients with long-standing rheumatoid arthritis and high disease activity at baseline, the etanercept combination regimen was significantly more effective in maintaining LDA and remission than a biologic-free regimen. ClinicalTrials.gov identifier. NCT01578850. PMID- 28597308 TI - Randomized Controlled Trial of Adding Telephone Follow-Up to an Occupational Rehabilitation Program to Increase Work Participation. AB - Purpose Transfer from on-site rehabilitation to the participant's daily environment is considered a weak link in the rehabilitation chain. The main objective of this study is to see if adding boosted telephone follow-up directly after completing an occupational rehabilitation program effects work participation. Methods A randomized controlled study included participants with chronic pain, chronic fatigue or common mental disorders on long-term sick leave. After completing 31/2 weeks of acceptance and commitment therapy based occupational rehabilitation, participants were randomized to boosted follow-up or a control group before returning to their daily environment. The intervention was delivered over 6 months by on-site RTW coordinators mainly via telephone. Primary outcome was RTW categorized as participation in competitive work >=1 day per week on average over 8 weeks. Results There were 213 participants of mean age 42 years old. Main diagnoses of sick leave certification were mental disorders (38%) and musculoskeletal disorders (30%). One year after discharge the intervention group had 87% increased odds (OR 1.87, 95% confidence interval 1.06-3.31, p = 0.031), of (re)entry to competitive work >=1 day per week compared with the controls, with similar positive results for sensitivity analysis of participation half time (>=2.5 days per week). The cost of boosted follow-up was 390.5 EUR per participant. Conclusion Participants receiving boosted RTW follow-up had higher (re)entry to competitive work >=1 day per week at 1 year when compared to the control group. Adding low-cost boosted follow-up by telephone after completing an occupational rehabilitation program augmented the effect on return-to-work. PMID- 28597310 TI - Scientific Paper Abstracts Presented at the Society of Abdominal Radiology 2017 Annual Scientific Meeting and Educational Course (March 26-31, 2017, Hollywood, Florida). PMID- 28597307 TI - Optimization of biological therapy in rheumatoid arthritis patients: outcomes from the CREATE registry after 2 years of follow-up. AB - : The current strategy for managing rheumatoid arthritis (RA) focuses on achieving clinical remission. Once remission is achieved and sustained over time, the most efficient strategy is dose optimization. This work describes the results of dose optimization after 2 years of follow-up in patients with RA treated with biological therapy and identifies predictive variables of response. Cohort: patients from the CREATE registry who, as of 1 November 2013, had been in clinical remission (DAS28 <=2.6) for at least 6 months. INTERVENTION: Dose optimization was 20-50% of the standard dose. Outcome measurement were effectiveness (percentage of patients who continued to meet criteria for clinical remission) and efficiency (dose reduction and mean savings). Sixty-eight patients with RA were optimized, with initial mean DAS28 of 2.2 +/- 0.7. After 2 years of follow-up, the mean DAS28 was 2.4 +/- 0.7, a non-statistically significant difference. Twenty-eight patients (41.2%) continued in clinical remission with dose optimization after 2 years. Mean survival time was 14.2 months (95% CI 12.0 16.5). Of the 40 patients who needed to return to a standard dose, 57.5% managed to achieve remission again at 2 years. Mean dose reduction at 2 years was 21.17%, reaching a mean saving of ?5576 +/- 5099 per patient. In actual clinical practice, over 40% of patients with established RA who had been in sustained clinical remission managed to continue in remission 2 years after receiving optimized doses. The savings achieved was about 21% of the actual direct health costs for patients in the CREATE registry. PMID- 28597309 TI - Choroid plexus cauterization on treatment of hydranencephaly and maximal hydrocephalus. AB - INTRODUCTION: The standard treatment for hydranencephaly and maximal hydrocephalus consists of inserting shunts, although complications frequently occur. Choroid plexus cauterization (CPC) is an alternative, but its long-term efficacy and the factors associated with the success and failure of controlling head circumference (HC) are not well defined. OBJECTIVE: This study aims to evaluate the long-term efficacy and factors related to the success rate of CPC in the treatment of hydranencephaly and maximal hydrocephalus. METHOD: Forty-two children with maximal hydrocephalus and hydranencephaly underwent CPC from 2006 to 2014 and were retrospectively evaluated. Children with less than 3 months of follow-up were excluded. The long-term efficacy and success rate of possible variables (i.e., sex, type of malformation, type of surgery performed, treatment hospital, age, and HC at the time of surgery and birth) were evaluated. RESULTS: Thirty-four children were considered for the effectiveness analysis. Treatment was successful in 24 children (70.6%), and failure occurred in 10 children (29.4%). Failure was detected soon after the endoscopic procedure (average 116 days). There was no difference in effectiveness when comparing the age at the moment of surgery (p = 0.473), type of malformation (p = 1), HC at birth (0.699), and HC at the time of surgery (p = 0.648). The surgical death rate was 7.14%. CONCLUSION: Endoscopic CPC was a valid procedure used to treat hydranencephaly and maximal hydrocephaly, and it was effective in 70.6% of cases, with an average follow-up period of 32 months. When failures occurred, they occurred early. None of the analyzed variables interfered with the success of the treatment. PMID- 28597311 TI - Integrated Process for Ethanol, Biogas, and Edible Filamentous Fungi-Based Animal Feed Production from Dilute Phosphoric Acid-Pretreated Wheat Straw. AB - Integration of wheat straw for a biorefinery-based energy generation process by producing ethanol and biogas together with the production of high-protein fungal biomass (suitable for feed application) was the main focus of the present study. An edible ascomycete fungal strain Neurospora intermedia was used for the ethanol fermentation and subsequent biomass production from dilute phosphoric acid (0.7 to 1.2% w/v) pretreated wheat straw. At optimum pretreatment conditions, an ethanol yield of 84 to 90% of the theoretical maximum, based on glucan content of substrate straw, was observed from fungal fermentation post the enzymatic hydrolysis process. The biogas production from the pretreated straw slurry showed an improved methane yield potential up to 162% increase, as compared to that of the untreated straw. Additional biogas production, using the syrup, a waste stream obtained post the ethanol fermentation, resulted in a combined total energy output of 15.8 MJ/kg wheat straw. Moreover, using thin stillage (a waste stream from the first-generation wheat-based ethanol process) as a co-substrate to the biogas process resulted in an additional increase by about 14 to 27% in the total energy output as compared to using only wheat straw-based substrates. ?. PMID- 28597313 TI - Cellular response in the tick feeding site in crossbred cattle artificially infested by Rhipicephalus microplus. AB - Ticks and tick-borne diseases are of global importance and can cause serious economic losses to cattle-raising businesses. However, only few attempts have been made to describe the relationships between various cellular immune components and tick counts of, and therefore resistance to, Rhipicephalus microplus. The present study evaluated the late inflammatory cellular response and dermal dendritic cells at the attachment site in naturally presensitized bovines, artificially infested by R. microplus ticks. Twenty-two crossbred (Holstein * Gir) male experimental cattle were artificially infested with approximately 10,000 larvae of R. microplus. Parasitic infestation was determined by counting the engorged female ticks (4.5-8.0 mm in diameter) at the 21st day after artificial infestation. Biopsies (6 mm) were taken prior to the infestation and along with the tick count from the right pinna of each animal, and examined with histological techniques and immunohistochemistry using S100 protein. Inflammatory cell counts were conducted in the sections stained with the May Grunwald Giemsa technique, and immunostained dermal dendritic cells were evaluated and classified in scores ranging from 0 to 4. An average of 39.2 ticks per animal was found. Eosinophils (47.8%) constituted the major portion of the cellular infiltrate, followed by mononuclear cells (28.3%), neutrophils (14.4%), and basophils (0% to approximately 2%). The dendritic cell count shows a considerable population in the dermis, with pre- and post-infestation mean scores of 1.54 and 1.89, respectively; these scores were not significantly different. Our results pointed out the importance of the cellular response in the cattle resistance to ticks. PMID- 28597312 TI - [Management of chronic pain using extended release tilidine : Quality of life and implication of comedication on tilidine metabolism]. AB - BACKGROUND AND OBJECTIVES: The synthetic opioid tilidine is often used in chronic pain treatment. However, the activation via metabolism in patients with concomitant medication and reduced liver or kidney function is not thoroughly investigated. We therefore studied pain treatment efficacy, health-related quality of live and the metabolism of tilidine in patients with chronic pain. METHODS AND MATERIALS: In all, 48 patients, who were on a stable dose of oral prolonged release tilidine for at least 7 days, were included in this observational multicenter study. Liver and kidney function were assessed in routine blood samples, concentrations of tilidine, nortilidine and bisnortilidine were determined using a validated LC/MS/MS method. Comedication was registered and patients experience with regard to quality of life, pain, gastrointestinal symptoms and adverse events was assessed in standardised questionnaires. RESULTS: On average a daily dose of 180 mg tilidine was taken. Dose normalized plasma concentrations of the active metabolite nortilidine ranged between 1.6 ng/ml and 76.5 ng/ml (mean 29.2 +/- 25.1 ng/ml). Ratios between tilidine and nortilidine were on average 0.28 (median = 0.13, standard deviation = 0.67). Patients were on 1 to 14 different concomitant medications. About 66% of the patients had sufficient pain treatment. Almost no opioid-induced constipation was observed. Only few patients had decreased kidney or liver function which did not result in elevated nortilidine concentrations. CONCLUSION: Pain treatment using tilidine resulted in variable nortilidine concentrations which are obviously not strongly influenced by comedication or reduced liver or kidney function. Only a few side effects were observed with almost no opioid-induced constipation. PMID- 28597314 TI - Deltamethrin as inductor agent of precocious ovarian degeneration in Rhipicephalus sanguineus s.l. (Acari: Ixodidae) ticks. AB - The cosmopolitan species Rhipicephalus sanguineus s.l. is one of the most widely distributed ticks all over the world. These ectoparasites are vectors of several pathogens and cause significant direct damage to their hosts. The biological success of these ectoparasites has been attributed to their ovaries and salivary glands, organs that ensure their survival in various environmental conditions. The importance of the ovaries in ticks is that, after mating, the individuals are able to lay approximately three thousand eggs. The present study had the objective to demonstrate the effects of deltamethrin obtained from the product Butox P CE 25(r) (MSD Saude Animal, Sao Paulo, Brazil) on the ovarian development of R. sanguineus s.l. females. The chemical was tested in the concentrations of 25, 50, 100 and 200 ppm (respectively 80, 40, 20 and 10 times lower than the recommended by the manufacturer). Through the application of histological techniques and HE staining, the results showed that the deltamethrin was potentially able to modify the morphophysiology of the oocytes in all developmental stages, interfering in the vitellogenesis, causing intense vacuolation, cytoplasmic disorganization, and alterations in the chorion secretion. In addition, the chemical affected the germ vesicle of some oocytes, causing damages and hypertrophy, fragmenting the chromatin and forming bodies strongly stained by hematoxylin. Therefore, this study confirmed that the deltamethrin had an important action on the reproductive system of the R. sanguineus s.l. females, causing the precocious structural disorganization of the germ cells, consequently preventing the generation of new individuals. PMID- 28597315 TI - Fiber-type distribution in insect leg muscles parallels similarities and differences in the functional role of insect walking legs. AB - Previous studies have demonstrated that myofibrillar ATPase (mATPase) enzyme activity in muscle fibers determines their contraction properties. We analyzed mATPase activities in muscles of the front, middle and hind legs of the orthopteran stick insect (Carausius morosus) to test the hypothesis that differences in muscle fiber types and distributions reflected differences in their behavioral functions. Our data show that all muscles are composed of at least three fiber types, fast, intermediate and slow, and demonstrate that: (1) in the femoral muscles (extensor and flexor tibiae) of all legs, the number of fast fibers decreases from proximal to distal, with a concomitant increase in the number of slow fibers. (2) The swing phase muscles protractor coxae and levator trochanteris, have smaller percentages of slow fibers compared to the antagonist stance muscles retractor coxae and depressor trochanteris. (3) The percentage of slow fibers in the retractor coxae and depressor trochanteris increases significantly from front to hind legs. These results suggest that fiber-type distribution in leg muscles of insects is not identical across leg muscles but tuned towards the specific function of a given muscle in the locomotor system. PMID- 28597317 TI - Erratum to: Plasma exchange response in 34 patients with severe optic neuritis. PMID- 28597316 TI - Substrate translocation involves specific lysine residues of the central channel of the conjugative coupling protein TrwB. AB - Conjugative transfer of plasmid R388 requires the coupling protein TrwB for protein and DNA transport, but their molecular role in transport has not been deciphered. We investigated the role of residues protruding into the central channel of the TrwB hexamer by a mutational analysis. Mutations affecting lysine residues K275, K398, and K421, and residue S441, all facing the internal channel, affected transport of both DNA and the relaxase protein in vivo. The ATPase activity of the purified soluble variants was affected significantly in the presence of accessory protein TrwA or DNA, correlating with their behaviour in vivo. Alteration of residues located at the cytoplasmic or the inner membrane interface resulted in lower activity in vivo and in vitro, while variants affecting residues in the central region of the channel showed increased DNA and protein transfer efficiency and higher ATPase activity, especially in the absence of TrwA. In fact, these variants could catalyze DNA transfer in the absence of TrwA under conditions in which the wild-type system was transfer deficient. Our results suggest that protein and DNA molecules have the same molecular requirements for translocation by Type IV secretion systems, with residues at both ends of the TrwB channel controlling the opening-closing mechanism, while residues embedded in the channel would set the pace for substrate translocation (both protein and DNA) in concert with TrwA. PMID- 28597318 TI - The relationship between progressive motor deficits and lesion location in patients with single infarction in the lenticulostriate artery territory. AB - As the corticospinal tracts cross the lenticulostriate artery (LSA) territory at the posterior segment, we hypothesized that posteriorly located infarctions of the LSA may be associated with progressive motor deficits. We prospectively studied 519 consecutive patients with LSA infarctions who entered our hospital within 24 h after onset. We categorized patients into two groups in terms of progress: no progress and progress. Progress was defined as worsening by 1 point or more in the National Institutes of Health Stroke Scale (NIHSS), some of which recovered afterward or thoroughly progressed. LSA infarctions on the first DWI were divided into proximal type and distal (group 1) type. The proximal type was further divided into anterior (group 2), intermediate (group 3) and posterior (group 4) type according to the middle point of antero-posterior diameter of the lateral ventricle. There were 109 patients who showed progress that accounted for 21.0% of all patients. The number of patients who progressed is as follows: distal type 65 (23.8%), anterior type 31 (36.0%), intermediate type 26 (56.5%) and posterior type 97 (85.0%). The Cochran-Armitage test showed a significant increase through group 1 to group 4 (p < 0.0001). Independent predictive factors for progress were male (OR 0.57, p = 0.0107), higher NIHSS on admission (>=4) (OR 3.02, p < 0.0001), intermediate proximal type (OR 3.3, p = 0.0007) and posterior proximal type (OR 16.4, p < 0.0001). The more posterior the infarct location, the more frequent was the progress that occurred, probably due to the anatomical fact that corticospinal tracts crossed the LSA territory at the posterosuperior quadrant. PMID- 28597319 TI - Erratum to: Biliary Intraductal Papillary Mucinous Neoplasm: the "Thread Sign". PMID- 28597322 TI - Sustained attention to a predictable, unengaging Go/No-Go task shows ongoing development between 6 and 11 years. AB - Response time variability (RTV) is a useful measure of sustained attention; however, little is known about developmental changes in RTV at different temporal frequencies. Thirty-five 6-year-olds, 31 8-year-olds, and 37 10-year-olds completed the fixed-sequence Sustained Attention to Response Task on three occasions, six months apart. Fast Fourier Transform and ex-Gaussian analyses of response time (RT) data assessed momentary fluctuations in RT, gradual changes in RT, and very long responses, thought to reflect attentional control fluctuations, slow-shifting arousal, and infrequent lapses in attention, respectively. A half by-half analysis measured within-occasion time-on-task effects. The 10-to 11-year olds performed with less momentary fluctuations in RT, fewer long responses, and fewer commission and omission errors than the younger groups. This group performed well in the first half of the task but showed time-on-task effects on measures of momentary fluctuations in RT, very long responses, target sensitivity (d'), and commission errors. The 6- to 7-year-olds performed less well than the older groups, and showed time-on-task effects, on almost all measures. The 8- to- 9-year-olds mostly performed at an intermediate level compared with the other groups; however, this group performed with a similar level of momentary fluctuations in RT and very long responses as the 6- to 7-year-olds. These findings indicate that there is ongoing maturation of various aspects of sustained attention on a predictable task, with a period of relative stability in performance between 8 and 9 years of age. PMID- 28597320 TI - Diagnostic Laparoscopy Prior to Neoadjuvant Therapy in Pancreatic Cancer Is High Yield: an Analysis of Outcomes and Costs. AB - BACKGROUND: There is currently no standardized regimen for management of borderline resectable pancreatic cancer (BRPC), and treatment includes varying sequences of surgery, chemotherapy, and/or radiation. This study examines the diagnostic yield and cost of performing staging diagnostic laparoscopy (SDL) prior to neoadjuvant therapy (NAT) in BRPC. METHODS: Sequential patients treated for BRPC between January 2010 and October 2013 were included. SDL was adopted in a staged fashion due to surgeon preference, and included biopsy of visible lesions and washings for cytology. Cost ratios (CRs) were calculated to compare the direct cost of the SDL versus no-SDL groups and to compare patients with positive versus negative SDL. RESULTS: Of 116 patients evaluated for BRPC, 75 patients underwent SDL and 19 (25%) revealed occult metastatic disease. Sixteen patients had a positive biopsy and three had positive cytology alone. There was no difference in overall treatment cost (CR 0.95, 95% CI 0.62-1.37), oncologic treatment (CR 0.66, 95% CI 0.32-1.23), or remaining surgical treatment (CR 1.14, 95% CI 0.77-1.71) for patients who underwent SDL compared to those who did not. Patients with a positive SDL incurred lower overall cost compared to those with a negative SDL (CR 0.23, 95% CI 0.16-0.32) due to lack of further surgery or radiation, and less intensive chemotherapy regimens. CONCLUSIONS: SDL prior to NAT is a useful adjunct to CT to diagnose occult metastatic disease in BRPC. PMID- 28597323 TI - Stent-induced flow disturbances in the ipsilateral external carotid artery following internal carotid artery stenting: a temporary cause of jaw claudication. AB - BACKGROUND: We hypothesize that stenting of the internal carotid artery can immediately impede blood flow to the external carotid artery by either plaque shift or stent coverage of the ostium, and thereby cause ischemic symptoms like ipsilateral jaw claudication. METHODS: Thirty-three patients with high-grade asymptomatic stenosis of the internal carotid artery who underwent endovascular treatment were examined by ultrasound of the external carotid artery and performed an exercise test by chewing chewing gum synchronously to an electronic metronome for 3 min. Tests were performed before, the day after, and 1 week after the stenting procedure. Claudication time was defined as the timespan until occurrence of pain of the masseter muscle and/or chewing dyssynchrony to the metronome for more than 15 s. Ten patients with an isolated, atherosclerotic stenosis of the external carotid artery served as controls. RESULTS: A significantly reduced claudication time (in seconds) was recorded in patients who underwent carotid artery stenting compared to baseline values; median 89 (interquartile range, IQR, 57 to 124) vs. median 180 (IQR 153 to 180; p < 0.001). By categorization of the flow velocity at the external carotid artery into faster or slower as 200 cm/sec, the effect was even accentuated. Stenting values showed improvement 1 week after but did not return to baseline levels. No respective changes were found in controls. CONCLUSION: Stenting of the internal carotid artery lead to ipsilateral flow deterioration at the external carotid artery resulting in temporary jaw claudication. This impairment attenuated over the time and was significantly reduced after 1 week. PMID- 28597324 TI - Gender differences in moral judgment and the evaluation of gender-specified moral agents. AB - Whether, and if so, how exactly gender differences are manifested in moral judgment has recently been at the center of much research on moral decision making. Previous research suggests that women are more deontological than men in personal, but not impersonal, moral dilemmas. However, typical personal and impersonal moral dilemmas differ along two dimensions: Personal dilemmas are more emotionally salient than impersonal ones and involve a violation of Kant's practical imperative that humans must never be used as a mere means, but only as ends. Thus, it remains unclear whether the reported gender difference is due to emotional salience or to the violation of the practical imperative. To answer this question, we explore gender differences in three moral dilemmas: a typical personal dilemma, a typical impersonal dilemma, and an intermediate dilemma, which is not as emotionally salient as typical personal moral dilemmas, but contains an equally strong violation of Kant's practical imperative. While we replicate the result that women tend to embrace deontological ethics more than men in personal, but not impersonal, dilemmas, we find no gender differences in the intermediate situation. This suggests that gender differences in these type of dilemmas are driven by emotional salience, and not by the violation of the practical imperative. Additionally, we also explore whether people think that women should behave differently than men in these dilemmas. Across all three dilemmas, we find no statistically significant differences about how people think men and women should behave. PMID- 28597325 TI - The impossibility of reliably determining the authenticity of desires: implications for informed consent. AB - It is sometimes argued that autonomous decision-making requires that the decision maker's desires are authentic, i.e., "genuine," "truly her own," "not out of character," or similar. In this article, it is argued that a method to reliably determine the authenticity (or inauthenticity) of a desire cannot be developed. A taxonomy of characteristics displayed by different theories of authenticity is introduced and applied to evaluate such theories categorically, in contrast to the prior approach of treating them individually. The conclusion is drawn that, in practice, the authenticity of desires cannot be reliably determined. It is suggested that authenticity should therefore not be employed in informed consent practices in healthcare. PMID- 28597326 TI - Identification of bakanae disease resistance loci in japonica rice through genome wide association study. AB - BACKGROUND: Bakanae disease, caused by seed-borne Fusarium species, mainly F. fujikuroi, is a rice disease whose importance is considerably increasing in several rice growing countries, leading to incremental production losses. RESULTS: A germplasm collection of japonica rice was screened for F. fujikuroi resistance, allowing the identification of accessions with high-to-moderate levels of resistance to bakanae. A GWAS approach uncovered two genomic regions highly associated with the observed phenotypic variation for response to bakanae infection on the short arm of chromosome 1 (named as qBK1_628091) and on the long arm of chromosome 4 (named as qBK4_31750955). High levels of phenotypic resistance to bakanae were associated to the cumulated presence of the resistant alleles at the two resistance loci, suggesting that they can provide useful levels of disease protection in resistance breeding. A fine comparison with the genomic positions of qBK1_628091 and qBK4_31750955 with respect to the QTLs for bakanae resistance reported in the literature suggests that the resistant loci here described represent new genomic regions associated to F. fujikuroi resistance. A search for candidate genes with a putative role in bakanae resistance was conducted considering all the annotated genes and F. fujikuroi related DEGs included in the two genomic regions highlighting several gene functions that could be involved in resistance, thus paving the way to the functional characterization of the resistance loci. CONCLUSIONS: New effective sources for bakanae resistance were identified on rice chromosomes 1 and 4 and tools for resistance breeding are provided. PMID- 28597327 TI - The Role of the Corpus Callosum in Pediatric Dysphagia: Preliminary Findings from a Diffusion Tensor Imaging Study in Children with Unilateral Spastic Cerebral Palsy. AB - The purpose of this study is to determine the relationship between the structural integrity of the corpus callosum (CC) and clinical feeding/swallowing performance in children with unilateral spastic cerebral palsy (USCP). Twenty children with USCP, (11 males, 5.11-17.6 yoa) were assessed via the Dysphagia Disorder Survey (DDS) and diffusion tensor imaging. Children were grouped into left hemisphere lesion (LHL; n = 13) and right hemisphere lesion (RHL; n = 7) groups. DTI variables analyzed for three CC regions (anterior, middle, posterior) were: fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and fibers count. Children with RHL presented with higher clinical dysphagia severity (p = 0.03). Six of seven children with RHL had lesions affecting periventricular/subcortical areas, and 8/13 children with LHL had lesions affecting the sensorimotor cortex. In the LHL group, as FA and fiber count of the anterior CC decreased and RD increased (all indicating reduced CC structural integrity), signs of dysphagia increased (r = -0.667, p = 0.013; r = -0.829, p <= 0.001; r = 0.594, p = 0.032, respectively). Reduced fiber count in the middle and posterior CC was also significantly associated with increased DDS scores (r = 0.762, p = 0.002; r = -0.739, p = 0.004, respectively). For the RHL group no significant correlations were observed. We provide preliminary evidence that corpus callosum integrity correlates with feeding/swallowing performance in children with USCP, especially when cortical sensorimotor areas of the left hemisphere are impacted. In this sample, CC integrity appeared to enable interhemispheric cortical plasticity for swallowing, but was not as critical when intrahemispheric connections were disrupted, as seen in the RHL group. PMID- 28597329 TI - Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia lymphoma in Japan: interim results of postmarketing all-case surveillance. AB - We present the interim results of a postmarketing all-case surveillance study in patients with C-C chemokine receptor 4 (CCR4)-positive, relapsed or refractory adult T-cell leukemia-lymphoma (ATL) treated with the anti-CCR4 monoclonal antibody mogamulizumab since its 2012 launch in Japan. The safety and efficacy analysis populations comprised 484 and 442 patients, respectively. The ATL subtype was acute in 58.9% and lymphoma in 34.2% of patients. All patients were scheduled to receive intravenous infusions of mogamulizumab (1.0 mg/kg) once weekly for eight weeks, alone or in combination with other modalities. Adverse drug reactions (ADRs) were reported in 74.0% of patients, of which 35.7% were serious and 6.2% were fatal. The priority survey items of infusion-related reaction, skin disorder, infection, immune disorder, and tumor lysis syndrome were reported in 29.3, 34.3, 22.1, 3.5, and 2.5% of patients, respectively. Graft versus-host disease was reported in 25/42 patients who received mogamulizumab before allogeneic hematopoietic stem cell transplantation. The best overall response rate was 57.7% overall, 57.5% in patients treated with mogamulizumab alone, and 58.2% in patients treated with combination therapy. This surveillance indicates that mogamulizumab shows acceptable tolerability in practice; however, because of the risk of serious/fatal ADRs, patients administered mogamulizumab should be carefully monitored. PMID- 28597328 TI - The comprehensive complication index (CCI) is a more sensitive complication index than the conventional Clavien-Dindo classification in radical gastric cancer surgery. AB - BACKGROUND: The comprehensive complication index (CCI) integrates all complications of the Clavien-Dindo classification (CDC) and offers a metric approach to measure morbidity. The aim of this study was to evaluate the CCI at a high-volume center for gastric cancer surgery and to compare the CCI to the conventional CDC. METHODS: Clinical factors were collected from the prospective complication data of gastric cancer patients who underwent radical gastrectomy at Seoul National University Hospital from 2013 to 2014. CDC and CCI were calculated, and risk factors were investigated. Correlations and generalized linear models of hospital stay were compared between the CCI and CDC. The complication monitoring model with cumulative sum control-CCI (CUSUM-CCI) was displayed for individual surgeons, for comparisons between surgeons, and for the institution. RESULTS: From 1660 patients, 583 complications in 424 patients (25.5%) were identified. The rate of CDC grade IIIa or greater was 9.7%, and the overall CCI was 5.8 +/- 11.7. Age, gender, Charlson score, combined resection, open method, and total gastrectomy were associated with increased CCI (p < 0.05). The CCI demonstrated a stronger relationship with hospital stay (rho = 0.721, p < 0.001) than did the CDC (rho = 0.634, p < 0.001). For prolonged hospital stays (>=30 days), only the CCI showed a moderate correlation (rho = 0.544, p = 0.024), although the CDC did not. The CUSUM-CCI model displayed dynamic time-event differences in individual and comparison monitoring models. In the institution monitoring model, a gradual decrease in the CCI was observed. CONCLUSIONS: The CCI is more strongly correlated with postoperative hospital stay than is the conventional CDC. The CUSUM-CCI model can be used for the continuous monitoring of surgical quality. PMID- 28597330 TI - The utility of superb microvascular imaging for monitoring low-velocity venous flow following pancreas transplantation: report of a case. AB - Vascular thrombosis is a major complication after pancreas transplantation. Because delays in detecting thrombosis often result in graft failure, monitoring blood flow is crucial. Periodic evaluation using color Doppler ultrasonography is mostly performed for monitoring blood flow in the grafted pancreas. However, conventional color Doppler imaging has limited capability to visualize low velocity blood flow. Superb microvascular imaging (SMI) is a novel ultrasound Doppler technique that is especially sensitive in detecting low-velocity flow. Herein, the authors describe the utility of SMI for monitoring splenic venous blood flow not detected by conventional color Doppler ultrasonography after pancreas transplantation. Ultrasonographic evaluation was performed every 4-6 h for 2 weeks after pancreas transplantation. SMI was used for detecting venous blood flow that was not clearly visible by conventional color Doppler imaging. The greater part of venous blood flow was undetectable by conventional color Doppler imaging, especially in the horizontal regions of the splenic vein. However, SMI clearly described venous flow at all points, even immediately after transplantation and when the patient developed hypotension due to massive bleeding complications. SMI is an extremely useful tool for monitoring venous flow after pancreas transplantation and does not require contrast agents. PMID- 28597332 TI - Comparing the use of live trees and deadwood for larval foraging by aye-ayes (Daubentonia madagascariensis) at Kianjavato and Torotorofotsy, Madagascar. AB - Aye-aye (Daubentonia madagascariensis) feeding behavior has become synonymous with deadwood foraging. However, deadwood is not always the most frequently used substrate, as some aye-ayes use live trees more often to access invertebrates. We sought to compare the frequency of aye-aye invertebrate foraging in deadwood and live trees to better understand their feeding behaviors. We followed two male aye ayes at Kianjavato, a heavily disturbed habitat in southeastern Madagascar, from October 2013 to October 2014, and one male and one female aye-aye at Torotorofotsy, a continuous forest in eastern Madagascar, from July 2014 to December 2015. We collected feeding data by recording the behavior of a focal aye aye every 5 min for a total of 373 h at Kianjavato and 383 h at Torotorofotsy. Our results showed no difference in the amount of deadwood used between the individuals. However, there was a significant difference in the amount of live tree feeding between the female at Torotorofotsy and one of the males at Kianjavato. We conclude that feeding on invertebrates in live trees is more important to aye-ayes than previously realized and that aye-ayes are exceedingly flexible in their invertebrate feeding behaviors, adjusting to their habitat by using various substrates. PMID- 28597331 TI - Inhibition Efficiency in Highly Proficient Bilinguals and Simultaneous Interpreters: Evidence from Language Switching and Stroop Tasks. AB - The present behavioral study aimed to examine the impact of language control expertise on two domain-general control processes, i.e. active inhibition of competing representations and overcoming of inhibition. We compared how Simultaneous Interpreters (SI) and Highly Proficient Bilinguals-two groups assumed to differ in language control capacity-performed executive tasks involving specific inhibition processes. In Experiment 1 (language decision task), both active and overcoming of inhibition processes are involved, while in Experiment 2 (bilingual Stroop task) only interference suppression is supposed to be required. The results of Experiment 1 showed a language switching effect only for the highly proficient bilinguals, potentially because overcoming of inhibition requires more cognitive resources than in SI. Nevertheless, both groups performed similarly on the Stroop task in Experiment 2, which suggests that active inhibition may work similarly in both groups. These contrasting results suggest that overcoming of inhibition may be harder to master than active inhibition. Taken together, these data indicate that some executive control processes may be less sensitive to the degree of expertise in bilingual language control than others. Our findings lend support to psycholinguistic models of bilingualism postulating a higher-order mechanism regulating language activation. PMID- 28597333 TI - The Role of Leadership Support in a Church-Based Cancer Education Implementation Study. AB - Leadership plays a role in the success of an organization's initiatives. We examined church leaders' support-as perceived by lay community health advisor (CHA) interventionists-and implementation outcomes in a cancer early detection trial. CHAs perceived that their pastors: helped promote the intervention (M = 3.1/4, SD 1.2) and attended about half (M = 1.6/3, SD 1.3) the workshops. CHAs used marginally more techniques to recruit members when they perceived pastors were engaged in promoting the program (r s = .44, p = .08). Pastor attendance was positively associated with member enrollment (r s = .50, p < .05). Pastor support may be related to receptivity of both CHAs and congregants to engage in church health promotion. PMID- 28597335 TI - Effect of endoskeleton stent graft design on pulse wave velocity in patients undergoing endovascular repair of the aortic arch. AB - PURPOSE: Pulse wave velocity (PWV), which measures vascular stiffness, is a powerful predictor of cardiovascular event. Treatment of aneurysms with endovascular prosthesis has been reported to increase PWV. The purpose of this study was to evaluate whether an endoskeleton stent graft design has less effect on PWV than the exoskeleton stent graft design. METHODS: Between July 2008 and September 2016, 74 patients underwent endovascular treatment of aortic arch aneurysm in our institution. PWV before and after surgery were compared between those who underwent treatment with Najuta, an endoskeleton stent graft (n = 51), and those treated with other commercially available exoskeleton stent grafts (n = 23). RESULTS: Preoperative PWV (endoskeleton: 2004 +/- 379.2 cm/s vs. exoskeleton: 2083 +/- 454.5 cm/s, p = 0.47) was similar between the two groups. Factors that were associated with preoperative PWV were age (r = 0.37, 95% CI 0.15-0.56, p = 0.002) and mean arterial pressure (r = 0.53, 95% CI 0.34-0.68, p < 0.001). There was a significant increase in PWV in patients treated by exoskeleton stent grafts (before: 2083 +/- 454.5 cm/s vs. after: 2305 +/- 479.7 cm/s, p = 0.023) while endoskeleton stent graft showed no change in PWV (before: 2003 +/- 379.2 vs. after: 2010 +/- 521.1, p = 0.56). In a multivariate analysis, mean arterial pressure (coef 17.5, 95% CI 6.48-28.59, p = 0.002) and exoskeleton stent graft (coef 359.4, 95% CI 89.36-629.43, p = 0.010) were independently associated with PWV after surgery. CONCLUSIONS: Physiological changes after endovascular treatment should be considered including effect on vascular stiffness. Endoskeleton stent graft may provide aneurysm repair with minimum effect in PWV after surgery. PMID- 28597336 TI - Design features of offshore oil production platforms influence their susceptibility to biocorrosion. AB - Offshore oil-producing platforms are designed for efficient and cost-effective separation of oil from water. However, design features and operating practices may create conditions that promote the proliferation and spread of biocorrosive microorganisms. The microbial communities and their potential for metal corrosion were characterized for three oil production platforms that varied in their oil water separation processes, fluid recycling practices, and history of microbially influenced corrosion (MIC). Microbial diversity was evaluated by 16S rRNA gene sequencing, and numbers of total bacteria, archaea, and sulfate-reducing bacteria (SRB) were estimated by qPCR. The rates of 35S sulfate reduction assay (SRA) were measured as a proxy for metal biocorrosion potential. A variety of microorganisms common to oil production facilities were found, but distinct communities were associated with the design of the platform and varied with different locations in the processing stream. Stagnant, lower temperature (<37 degrees C) sites in all platforms had more SRB and higher SRA compared to samples from sites with higher temperatures and flow rates. However, high (5 mmol L-1) levels of hydrogen sulfide and high numbers (107 mL-1) of SRB were found in only one platform. This platform alone contained large separation tanks with long retention times and recycled fluids from stagnant sites to the beginning of the oil separation train, thus promoting distribution of biocorrosive microorganisms. These findings tell us that tracking microbial sulfate-reducing activity and community composition on off-shore oil production platforms can be used to identify operational practices that inadvertently promote the proliferation, distribution, and activity of biocorrosive microorganisms. PMID- 28597334 TI - JAK-STAT signaling regulation of chicken embryonic stem cell differentiation into male germ cells. AB - The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is crucial in chicken germ stem cell differentiation, but its role in the regulation of germ cell differentiation is unknown. To address this, cucurbitacin I or interleukin 6 was used to inhibit or activate JAK-STAT signaling during embryonic stem cells (ESCs) differentiation. The expression of downstream JAK-STAT signaling molecules was assessed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). PAS, and immunohistochemical staining of frozen sections was used to determine the appearance of primordial germ cells (PGCs) and, later, spermatogonial stem cells (SSCs) during gonadal development. Inhibition of the JAK-STAT signaling resulted in decreased expression of JAK2 and STAT3 as well as of PGCs markers; moreover, the proportion of CVH and C-KIT positive cells as well as the yield of PGCs were remarkably decreased, and the gonad was smaller than that of control samples. Conversely, activation of JAK-STAT resulted in increased expression of JAK2 and STAT3 as well as that of PGC marker CVH. In addition, the proportion of CVH and C KIT-positive cells as well as the PGC yield was increased, and the gonad was significantly larger than that from control samples. Collectively, our results suggested that JAK-STAT effectively promoted the formation of PGCs in the genital ridge during early embryogenesis in vivo and played a positive role in the regulation of ESC to SSC differentiation in vitro, with JAK2 and STAT3 functioning as pivotal factors for intracellular signal transduction. PMID- 28597337 TI - Brain reward responses to food stimuli among female monozygotic twins discordant for BMI. AB - : Obese individuals are characterized by altered brain reward responses to food. Despite the latest discovery of obesity-associated genes, the contribution of environmental and genetic factors to brain reward responsiveness to food remains largely unclear. Sixteen female monozygotic twin pairs with a mean BMI discordance of 3.96 +/- 2.1 kg/m2 were selected from the Netherlands Twin Register to undergo functional MRI scanning while watching high- and low-calorie food and non-food pictures and during the anticipation and receipt of chocolate milk. In addition, appetite ratings, eating behavior and food intake were assessed using visual analog scales, validated questionnaires and an ad libitum lunch. In the overall group, visual and taste stimuli elicited significant activation in regions of interest (ROIs) implicated in reward, i.e. amygdala, insula, striatum and orbitofrontal cortex. However, when comparing leaner and heavier co-twins no statistically significant differences in ROI-activations were observed after family wise error correction. Heavier versus leaner co-twins reported higher feelings of hunger (P = 0.02), cravings for sweet food (P = 0.04), body dissatisfaction (P < 0.05) and a trend towards more emotional eating (P = 0.1), whereas caloric intake was not significantly different between groups (P = 0.3). Our results suggest that inherited rather than environmental factors are largely responsible for the obesity-related altered brain responsiveness to food. Future studies should elucidate the genetic variants underlying the susceptibility to reward dysfunction and obesity. CLINICAL TRIAL REGISTRATION NUMBER: NCT02025595. PMID- 28597338 TI - Joint representation of consistent structural and functional profiles for identification of common cortical landmarks. AB - In the brain mapping field, there have been significant interests in representation of structural/functional profiles to establish structural/functional landmark correspondences across individuals and populations. For example, from the structural perspective, our previous studies have identified hundreds of consistent DICCCOL (dense individualized and common connectivity-based cortical landmarks) landmarks across individuals and populations, each of which possess consistent DTI-derived fiber connection patterns. From the functional perspective, a large collection of well characterized HAFNI (holistic atlases of functional networks and interactions) networks based on sparse representation of whole-brain fMRI signals have been identified in our prior studies. However, due to the remarkable variability of structural and functional architectures in the human brain, it is challenging for earlier studies to jointly represent the connectome-scale structural and functional profiles for establishing a common cortical architecture which can comprehensively encode both structural and functional characteristics across individuals. To address this challenge, we propose an effective computational framework to jointly represent the structural and functional profiles for identification of consistent and common cortical landmarks with both structural and functional correspondences across different brains based on DTI and fMRI data. Experimental results demonstrate that 55 structurally and functionally common cortical landmarks can be successfully identified. PMID- 28597339 TI - The clinical behavior of sinonasal inverted papilloma with cellular dysplasia: case series and review of the literature. AB - The prognosis and recurrence rate of inverted papilloma (IP) with concomitant cellular dysplasia are not well-delineated. Demographic, clinical and imaging data of all patients who were surgically treated for sinonasal inverted papilloma (SNIP) in our center between 1996 and 2013 were reviewed. Data regarding the coexistence of dysplastic changes or malignancy within the resected tissues were also retrieved. After the exclusion of malignant cases and patients who were lost for follow-up, 92 patients were included in the study. Five patients had coexisting cellular dysplasia (4.7%), four of them had severe dysplasia and one had mild-to-moderate dysplasia. All four cases with severe dysplasia recurred, three were primarily treated endoscopically and one by external approach. Only the case with mild to moderate dysplasia which had been treated by subcranial approach did not recur. Patients with dysplasia had significantly higher recurrence rate than patients without dysplasia (80 vs. 14%, p = 0.019). This significant relation between histology and recurrence remained even after adjustment to tumor extent. The adjusted odd ratio of dysplasia (dysplasia vs. no dysplasia) is 9.7, p = 0.043. SNIP with dysplasia should be treated aggressively and followed closely. The histopathologic investigation of SNIP specimens should always note the presence of dysplasia and its severity. Further investigation on the clinical behavior of SNIP with dysplasia is needed. Multicenter studies are warranted due to the rarity of dysplastic SNIP. PMID- 28597340 TI - Upregulation of heat-shock proteins in larvae, but not adults, of the flesh fly during hot summer days. AB - Heat-shock proteins (HSPs) are highly expressed when organisms are exposed to thermal stresses. The HSPs are considered to play significant roles in thermal adaptation because they function as molecular chaperones facilitating proper protein synthesis. The expression of HSPs under field conditions, however, has not been evaluated much, and their importance, based on the ecological contexts in nature, is still unclear. We investigated this aspect in the larvae and adults of the flesh fly, Sarcophaga similis. These larvae spend their larval life in the carrion or faeces of vertebrates; therefore, they are less mobile and are occasionally exposed to high temperature. In contrast, the adults of this species can fly and, therefore, they are highly mobile. Massive transcription of Hsps was detected both in the larvae and adults in a laboratory heat-shock experiment. The larvae in the field showed no or less Hsp production on thermally mild days, whereas considerable upregulation of Hsp expression was detected on days with high temperature. The adults can also be exposed to thermal stress as high as 40 degrees C or higher in the field. However, most of the flies showed no or less Hsp expression. The observations in the experimental cage under field conditions revealed behavioural thermoregulation of adults through microhabitat selection. The present study demonstrates ontogenetic alteration of the strategy to overcome thermal stress in an insect; in the field, less mobile larvae use physiological protection against heat (HSP production), whereas highly mobile adults avoid the stress behaviourally (through microhabitat selection). PMID- 28597342 TI - Enhancing Adherence to Care in the HIV Care Continuum: The Barrier Elimination and Care Navigation (BEACON) Project Evaluation. AB - Interventions are needed to address each phase of the HIV care continuum in order to improve health outcomes and reduce likelihood of HIV transmission. The purpose of this study was to assess the impact of a community- and clinic-based intervention designed and implemented to reengage individuals who were lost to HIV care. Eligible participants had either never engaged in HIV care or had not had a medical visit for at least 12 months. Participants enrolled in a community- and clinic-based intervention that included intensive case management, access to a community nurse and peer navigator, as well as emergency stabilization funds. Data were collected at baseline and 6-month time points by the case managers; which included sociodemographics, general health, abstracted HIV viral loads and CD4 cell counts from their medical records. Descriptive and GEE analyses were conducted to assess changes from baseline to 6 months. A total of 322 participants enrolled over a 5-year period, of whom the majority were male (n = 250) and African American with a mean age of 42.0 years. After 6 months of the intervention, there was a significant increase of individuals who had undetectable HIV viral loads and their median CD4 cell counts increased (p < 0.01 for both). General health improved as well (p < 0.01). It is clear that this method of engagement, while staff intensive, is successful at engaging and retaining individuals in HIV care at least through 6 months. PMID- 28597341 TI - In Silico Prediction and Validation of Gfap as an miR-3099 Target in Mouse Brain. AB - MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms (miRDB, miRanda, TargetScan, and DIANA-micro-T-CDS) with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms (324 genes) were subjected to DAVID bioinformatics analysis to understand their overall functional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization (ISH) expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes (Dnmt3a, Gabpa, Gfap, Itga4, Lxn, Smad7, and Tbx18) having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset. PMID- 28597343 TI - Safer Conception for Couples Affected by HIV: Structural and Cultural Considerations in the Delivery of Safer Conception Care in Uganda. AB - In countries with high HIV prevalence and high fertility desires, the rights of HIV-affected couples to have children are a pressing issue. Conception among people living with HIV carries risks for both horizontal and vertical HIV transmission. In Uganda ~100,000 HIV-infected women become pregnant annually. Providers face a number of challenges to preventing HIV transmission, reducing unplanned pregnancies, and ensuring safer conception. We report findings from interviews with 27 HIV-affected couples (54 individuals) in Uganda. We explored key cultural and structural factors shaping couples' childbearing decisions. Our data reveal a complex intersection of gender norms, familial expectations, relationship dynamics, and HIV stigma influencing their decisions. Participants provided insights regarding provider bias, stigma, and the gendering of reproductive healthcare. To reduce horizontal transmission HIV and family planning clinics must address men's and women's concerns regarding childbearing with specific attention to cultural and structural challenges. PMID- 28597344 TI - Implementation of Evidence-Based HIV Interventions for Gay, Bisexual, and Other Men Who Have Sex with Men. AB - The Centers for Disease Control and Prevention provides trainings to support implementation of five evidence-based HIV prevention interventions (EBIs) for men who have sex with men (MSM): d-up: Defend Yourself!; Many Men, Many Voices; Mpowerment; Personalized Cognitive Counseling; and Popular Opinion Leader. We evaluated trainees' implementation of these EBIs and, using multivariable logistic regression, examined factors associated with implementation. Approximately 43% of trainees had implemented the EBIs for which they received training. Implementation was associated with working in community-based organizations (vs. health departments or other settings); acquiring training for Mpowerment or Popular Opinion Leader (vs. Personalized Cognitive Counseling); having >=3 funding sources (vs. one); and having (vs. not having) sufficient time and necessary EBI resources. Findings suggest that implementation may vary by trainee characteristics, especially those related to employment setting, EBI training, funding, and perceived implementation barriers. Efforts that address these factors may help to improve EBI implementation among trainees. PMID- 28597345 TI - Antimicrobial effect of OKCEL(r) H-D prepared from oxidized cellulose. AB - The antimicrobial effect of OKCEL(r) H-D, a topical, absorbable hemostatic textile prepared from oxidized cellulose, was tested. Testing by dilution and diffusion methods was conducted on a spectrum of 27 select microorganisms, including also antibiotic-resistant strains. OKCEL(r) H-D showed inhibitory effects on nearly all tested bacteria. In testing using the dilution suspension method, the majority of bacteria showed decrease in cell density by 7-8 orders of magnitude after just 6 h of exposure. For clinical isolates of antibiotic resistant strains, a reduction occurred after 24 h of exposure. In testing the antimicrobial effects of OKCEL(r) H-D by the dilution method was least effective on spore-forming Bacillus subtilis, for which no antimicrobial effect was detected after 48 h, and on Mycobacterium smegmatis, for which the number of cells decreased by four orders of magnitude only after 24 h. By the diffusion method, inhibition zones were recorded for nearly all test microorganisms except for Staphylococcus aureus, M. smegmatis, and Listeria monocytogenes. No growth beneath the tested OKCEL(r) H-D material was recorded, however, even for the latter-named bacteria strains, which attests to its good inhibitory effect. PMID- 28597346 TI - The rate of facial nerve dysfunction and time to recovery after intraparotid and extraparotid facial nerve exposure and protection in head and neck cutaneous tumor surgery. AB - BACKGROUND: Most patients with head and neck skin tumors present with normal facial nerve function. A common treatment strategy for these patients is facial nerve preservation surgery, although the degree to which the nerve is successfully preserved is still unclear. Data on the incidence and recovery of facial nerve dysfunction are woefully lacking in the field of dermato-oncology. METHODS: In 23 patients with normal preoperative facial nerve function, we retrospectively reviewed twenty-six head and neck surgical interventions that included facial nerve exposure and protection, focusing particularly on the differences in outcome between intraparotid and extraparotid exposure of the facial nerve branches. RESULTS: Eleven of the 26 cases (42.4%) developed transient paresis, but only one (3.8%) developed permanent paresis. Of 41 dissected facial nerve branches, 14 developed transient paresis (34.1%) and one, a marginal mandibular branch, developed permanent paresis (2.4%). The branches most susceptible to developing paresis were the temporal (4/6 branches, 66.7%) and marginal mandibular branches (8/17 branches, 47.1%). Although the rate of paresis was higher, and ensuing recovery period slightly longer in the extraparotid dissection group compared to the intraparotid dissection group, there were no statistically significant differences between the two groups. The extraparotid and intraparotid rates of paresis were 48% (11/23 branches) and 21.1% (4/19 branches), respectively, P = 0.139; and the average recovery periods were 10.3 and 9.3 weeks, respectively, P = 0.64. CONCLUSIONS: The functional outcome, regardless of the different sites of facial nerve exposure, was almost always either complete facial nerve sparing or transient dysfunction that resolved within 6 months. PMID- 28597347 TI - Contribution of Molecular Allergen Analysis in Diagnosis of Milk Allergy. AB - PURPOSE OF REVIEW: We sought to describe the available evidence supporting the utilization of the molecular allergen analysis (MAA) for diagnosis and management of cow milk protein allergy (CMPA). RECENT FINDINGS: Cow milk proteins are among the most common food allergens in IgE- and non-IgE-mediated food allergic disorders in children. Most individuals with CMPA are sensitized to both caseins and whey proteins. Caseins are more resistant to high temperatures compared to whey proteins. MAA is not superior to the conventional diagnostic tests based on the whole allergen extracts for diagnosis of CMPA. However, MAA can be useful in diagnosing tolerance to extensively heated milk proteins in baked foods. Children with CMPA and high levels of casein IgE are less likely to tolerate baked milk compared to children with low levels of casein IgE. Specific IgE-binding patterns to casein and betalactoglobulin peptides may predict the natural course of CMPA and differentiate subjects who are more likely to develop CMPA at a younger age versus those with a more persistent CMPA. Specific IgE-binding patterns to casein and beta-lactoglobulin peptides may also predict response to milk OITand identify patientsmost likely to benefit fromOIT. PMID- 28597348 TI - Pelvic inlet shape measured by three-dimensional pelvimetry is a predictor of the operative time in the anterior resection of rectal cancer. AB - PURPOSE: We evaluated pelvic shape as a predictor of the surgical outcome of anterior resection in patients with rectal cancer. METHODS: In total, 228 patients who had undergone anterior resection (R0 resection and double-stapling anastomosis) for rectal cancer from 2005 to 2014 were included in this study. The anteroposterior (AP) and transverse (T) diameters of the pelvic inlet and outlet and pelvic depth were analyzed on three-dimensional volume-rendered images, and the AP/T ratio was calculated. Univariate and multivariate analyses were performed to determine the predictive significance of the operative time and intraoperative blood loss as surgical outcomes. RESULTS: No difference was observed between the inlet AP/T and patient sex ratios, but the other pelvic dimensions were significantly shorter in males than in females. The univariate analysis revealed that the operative time was significantly correlated with the inlet T diameter and that it tended to be correlated with the outlet T diameter and the inlet AP/T ratio. A multivariate analysis adjusted for operation-related factors revealed that the inlet AP/T ratio was the only independent risk factor for an extended operative time (p = 0.036). None of the pelvic dimensions were independent risk factors for increased blood loss. CONCLUSION: The shape of the pelvic inlet may be useful for predicting the operative time. PMID- 28597349 TI - Perioperative allogenic blood transfusion is a poor prognostic factor after hepatocellular carcinoma surgery: a multi-center analysis. AB - PURPOSE: The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients. METHODS: We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score. RESULTS: Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P < 0.001) and multivariate analyses (risk ratio 1.521, P = 0.011). After matching the different distributions using propensity scores, perioperative blood transfusion was found to be a poor prognostic factor for HCC patients. CONCLUSIONS: In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores. PMID- 28597351 TI - Psychological outcomes of injection port therapy in children and adolescents with type 1 diabetes and their primary caregivers. PMID- 28597350 TI - Short- and long-term outcomes of the Frey procedure for chronic pancreatitis: a single-center experience and summary of outcomes in Japan. AB - PURPOSE: To evaluate the short- and long-term outcomes of the Frey procedure for chronic pancreatitis (CP). METHODS: The subjects of this study were 12 patients who underwent the Frey procedure for CP between January, 2000 and December, 2016. We assessed pain relief, weight gain, and exocrine/endocrine insufficiency during follow-up. RESULTS: The study population comprised 11 men and 1 woman (91.7% vs. 8.3%; mean age, 50.3 +/- 6.8 years; range 39-61 years). Pancreatitis was caused by alcohol in 9 (75%) patients and was idiopathic in 3 (25%) patients. The mean follow-up period was 82.5 +/- 46.5 months (range 16.9-152.1 months). There was no operative mortality, but three patients (25%) suffered postoperative morbidity. All patients were pain-free at the time of discharge. There was no case of new onset diabetes mellitus after surgery, although one patient (8.3%) suffered exocrine insufficiency. The body weight and body mass index of all patients improved during follow-up. Only one patient continued to suffer pain in the long term. CONCLUSION: The findings of this long-term follow-up of patients who underwent the Frey procedure suggest that it offers effective pain relief and is a safe technique for the management of CP. PMID- 28597353 TI - Bringing the Family in through the Back Door: the Stealthy Expansion of Family Care in Asian and European Long-Term Care Policy. AB - In the era of global ageing, amid political concerns about increasing care needs and long-term sustainability of current care regimes, most high-income economies are seeking to minimise the use of institutional care and to expand formal home care for their older populations. In long-term care reforms, concerns about public funding, formal providers and the paid care workforce are foremost. However, an integral yet hidden part of all these reforms is the stealthily growing role of family carers. This article aims to identify and spell out how developments in formal home care bring about different modes of increasing, encouraging and necessitating family care inputs, across welfare states. Using secondary sources, three different modes were identified, and the article outlines the logic of each mechanism, drawing on illustrative examples of policy dynamics in both European and Asian countries. Family care inputs have increased through policy changes that are not explicitly or primarily about family care, but rather about expansion or changes in formal care. In some cases, this is explicit, in other cases something that happens 'through the back door'. Nonetheless, in all cases there are implications for the family caregivers' time, health and employment options. Future studies are needed to examine longitudinal trends from a comparative perspective to confirm our findings and elucidate how government commitments to formal home care provision and financing interact with the changing nature and volume of family caregiving. PMID- 28597352 TI - Role of Inflammatory Diseases in Hypertension. AB - Chronic inflammatory diseases (CID) are characterized by an increased risk of cardiovascular (CV) morbidity and mortality. Several mechanisms, including early acceleration of subclinical atherosclerotic damage, inflammatory markers and immune system deregulation factors, have been demonstrated to strictly interplay for development and progression of atherosclerosis. Moreover, traditional CV risk factors are likely to explain at least some of the excess of CV risk in these patients. Among traditional CV risk factors, compelling evidence suggests a higher incidence and prevalence of hypertension in patients with CID in comparison to the general population. Moreover, hypertension represents an important predictor of CV events in these patients. Pathogenic mechanisms underlying the rise of blood pressure in CID are multifactorial and still poorly investigated. Indeed, multiple disease-related factors may affect blood pressure control in these patients and hypertension may affect disease prognosis and increase CV risk. Better knowledge of the complex interplay between hypertension and CID will be important to elucidate pathogenic mechanisms and to improve CV outcome in these patients. Aim of this review is to highlight available evidence on the relationship between hypertension and CID and to elucidate the multiple factors that may affect blood pressure control in these disorders. PMID- 28597355 TI - Minimal Device Encrustation on Vesair Intravesical Balloons in the Treatment of Stress Urinary Incontinence: Analysis of Balloons Removed from Women in the SOLECT Trial. AB - INTRODUCTION: Encrustation of urinary biomaterials is common; however, the incidence of surface deposition on the Vesair(r) intravesical pressure attenuation balloon has not been previously reported. The purpose of this analysis is to determine the incidence and potential risk factors for encrustation of the Vesair intravesical balloon. METHODS: The SOLECT trial is a prospective randomized controlled trial conducted at several European centers to evaluate the safety and efficacy of the Vesair balloon for the treatment of female stress urinary incontinence (SUI). Women included in the study demonstrated SUI symptoms for more than 12 months without complicating factors, such as history of recurrent urinary tract infections or nephrolithiasis. All balloons removed from women enrolled in the SOLECT trial were analyzed for surface characteristics and encrustation. Surface deposition severity was quantified and composition analyzed with infrared spectroscopy and scanning electron microscopy. Incidence of surface deposition was tabulated and risk factors analyzed. RESULTS: One hundred and five balloons removed from 75 women were included in this analysis. Measurable stone deposition of less than 1.5 mm was found on four balloons (3.8%), surface granules were noted on 42 (40.0%), surface film on 11 (10.5%), and both granules and film on two (1.9%). Analysis identified calcium oxalate both in measurable encrustation deposits as well as those with surface granulation. Pooled analysis found that dwell time was a risk factor for calcium deposition. CONCLUSION: The rate of encrustation on the Vesair intravesical balloon is low and does not appear to increase the rate of adverse outcomes or reduce clinical efficacy. FUNDING: Solace Therapeutics, Inc. PMID- 28597354 TI - Pharmacologic Considerations for Pediatric Sedation and Anesthesia Outside the Operating Room: A Review for Anesthesia and Non-Anesthesia Providers. AB - Understanding the pharmacologic options for pediatric sedation outside the operating room will allow practitioners to formulate an ideal anesthetic plan, allaying anxiety and achieving optimal immobilization while ensuring rapid and efficient recovery. The authors identified relevant medical literature by searching PubMed, MEDLINE, Embase, Scopus, Web of Science, and Google Scholar databases for English language publications covering a period from 1984 to 2017. Search terms included pediatric anesthesia, pediatric sedation, non-operating room sedation, sedation safety, and pharmacology. As a narrative review of common sedation/anesthesia options, the authors elected to focus on studies, reviews, and case reports that show clinical relevance to modern day sedation/anesthesia practice. A variety of pharmacologic agents are available for sedation/anesthesia in pediatrics, including midazolam, fentanyl, ketamine, dexmedetomidine, etomidate, and propofol. Dosing ranges reported are a combination of what is discussed in the reviewed literature and text books along with personal recommendations based on our own practice. Several reports reveal that ketofol (a combination of ketamine and propofol) is quite popular for short, painful procedures. Fospropofol is a newer-generation propofol that may confer advantages over regular propofol. Remimazolam combines the pharmacologic effects of remifentanil and midazolam. A variety of etomidate derivatives such as methoxycarbonyl-etomidate, carboetomidate, methoxycarbonyl-carboetomidate, and cyclopropyl-methoxycarbonyl metomidate are in development stages. The use of nitrous oxide as a mild sedative, analgesic, and amnestic agent is gaining popularity, especially in the ambulatory setting. Utilizing a dedicated and experienced team to provide sedation enhances safety. Furthermore, limiting sedation plans to single-agent pharmacy appears to be safer than using multi agent plans. PMID- 28597357 TI - Health care needs and service use among male prison inmates in the United States: A multi-level behavioral model of prison health service utilization. AB - BACKGROUND: The purpose of this study is to apply Andersen's Behavioral Model of Health Service Use to men's prisons to assess the direct and indirect effects of inmate predisposing characteristics through multiple types of need. Also examined are the effects of prison-specific enabling factors and the variation in use of health services across prisons. This study uses a nationally representative U.S. sample of men incarcerated in state prisons (n = 8816) and generalized structural equation and multilevel modeling. Five types of need-medical condition, illness, dental problem, unintentional injury, and intentional injury-are assessed for their association with use of health services. RESULTS: Findings indicate that a number of inmate predisposing (age, race, education) and vulnerability (mood/anxiety disorder,) characteristics are associated with use of health services but are partially mediated by enabling and need factors. Each type of medical need has strong direct effects with mood/anxiety disorder emerging as the strongest total effect (including both direct effects and indirect effects through need). There is significant variation in rates of health service utilization across prisons that is not accounted for by the prison-level factors included in the multilevel model. CONCLUSIONS: The varying patterns of health service use across prisons suggest that incarceration may be an important circumstance that shapes health. In other words, where someone is incarcerated may influence their ability to access and use services in response to medical need. It is important that prisons provide integrated services for inmates with mood/anxiety disorder given high comorbidity with other health conditions. PMID- 28597356 TI - Structural insight into the role of Gln293Met mutation on the Peloruside A/Laulimalide association with alphabeta-tubulin from molecular dynamics simulations, binding free energy calculations and weak interactions analysis. AB - Peloruside A (PLA) and Laulimalide (LAU) are novel microtubule-stabilizing agents with promising properties against different cancer types. These ligands share a non-taxoid binding site at the outer surface of beta-tubulin and promote microtubule stabilization by bridging two adjacent alphabeta-tubulin dimers from parallel protofilaments. Recent site-directed mutagenesis experiments confirmed the existence of a unique beta-tubulin site mutation (Gln293Met) that specifically increased the activity of PLA and caused resistance to LAU, without affecting the stability of microtubules in the absence of the ligands. In this work, fully atomistic molecular dynamics simulations were carried out to examine the PLA and LAU association with native and mutated alphabeta-tubulin in the search for structural and energetic evidence to explain the role of Gln293Met mutation on determining the activity of these ligands. Our results revealed that Gln293Met mutation induced the loss of relevant LAU-tubulin contacts but exerted negligible changes in the interaction networks responsible for PLA-tubulin association. Binding free energy calculations (MM/GBSA and MM/PBSA), and weak interaction analysis (aNCI) predicted an increased affinity for PLA, and a weakened association for LAU after mutation, thus suggesting that Gln293Met mutation exerts its action by a modulation of drug-tubulin interactions. These results are valuable to increase understanding about PLA and LAU activity and to assist the future design of novel agents targeting the PLA/LAU binding pocket. PMID- 28597359 TI - Trends in prescribing rate of statins at discharge and modifiable factors in patients with atherosclerotic cardiovascular disease. AB - Tremendous effort has been invested in reducing the prevalence of atherosclerotic cardiovascular disease (ASCVD) in China. Meanwhile, accumulating evidence has emerged to show the benefits of statins in the prevention of cardiovascular disease. The present study investigated the change trends of statins prescription at discharge among patients with ASCVD in recent years, differences across subtypes of ASCVD, and associated factors. The study included 51,972 patients with a discharge diagnosis of ASCVD who were hospitalized in West China Hospital from 2008 to 2014. Trends of statins prescription rates between subtypes of ASCVD were compared and potential influential factors were explored. The overall statins prescription rate in patients with ASCVD was 58.8%. Adjusted odds ratios (ORs) of increase in prescription rate per year were 1.15 (95% CI 1.13-1.17, p < 0.001), 1.14 (95% CI 1.10-1.17, p < 0.001), 1.19 (95% CI 1.16-1.23; p < 0.001), 1.14 (95% CI 1.09-1.19; p < 0.001), and 1.13 (95% CI 1.09-1.17; p < 0.001) for ASCVD, coronary artery disease, cerebrovascular disease, peripheral arterial disease (PAD), and polyvascular disease, respectively; no significant differences in trends were detected among ASCVD subtypes. However, statins prescription rates were persistently lower in cerebrovascular disease and PAD than the other two subtypes. Discharge departments, together with other physician-related and patient-related characteristics were associated with statins utilization. In conclusion, between 2008 and 2014, statins prescription rate in patients with ASCVD was not optimal. The increasing trends in statins prescription among patients with ASCVD subtypes were similar but the differences did not decrease. Consciousness of integrated and successive medical care should be strengthened in China. PMID- 28597360 TI - Diabetes, eating disorders and body image in young adults: an exploratory study about "diabulimia". AB - PURPOSE: The purpose of this study was to compare disordered eating (DE) and body image dissatisfaction (BID) among young adults with type 1 diabetes and their peers without diabetes, to investigate the consequences of diabetes for food, body image and weight in individuals with diabetes and to identify the behavior of insulin omission as a weight loss strategy. METHODS: Fifty-five young adults with diabetes and 73 without diabetes (ages 18-30) completed self-report questionnaires to evaluate their behaviors, attitudes and feelings related to eating disorders and their perceptions about body image. The participants with diabetes were asked to answer a questionnaire with open and closed questions developed specifically for this study. RESULTS: No significant differences between participants with and without diabetes in relation to BID and DE were found. The results demonstrated several changes resulting from diabetes in terms of food, body image and weight that interfere with the day-to-day life of individuals with diabetes; 7.3% of these participants reported insulin omission as a weight loss strategy. CONCLUSIONS: This study emphasizes the importance of research on DE in the population with diabetes and their prevention, screening and treatment. In particular, it is essential to give more attention to insulin omission as a compensatory behavior that is inappropriate and harmful to health. LEVEL OF EVIDENCE: Level III, case-control analytic study. PMID- 28597361 TI - Modified Distribution-Free Goodness-of-Fit Test Statistic. AB - Covariance structure analysis and its structural equation modeling extensions have become one of the most widely used methodologies in social sciences such as psychology, education, and economics. An important issue in such analysis is to assess the goodness of fit of a model under analysis. One of the most popular test statistics used in covariance structure analysis is the asymptotically distribution-free (ADF) test statistic introduced by Browne (Br J Math Stat Psychol 37:62-83, 1984). The ADF statistic can be used to test models without any specific distribution assumption (e.g., multivariate normal distribution) of the observed data. Despite its advantage, it has been shown in various empirical studies that unless sample sizes are extremely large, this ADF statistic could perform very poorly in practice. In this paper, we provide a theoretical explanation for this phenomenon and further propose a modified test statistic that improves the performance in samples of realistic size. The proposed statistic deals with the possible ill-conditioning of the involved large-scale covariance matrices. PMID- 28597358 TI - Working Towards an Appropriate Use of Ibuprofen in Children: An Evidence-Based Appraisal. AB - Ibuprofen is the most widely used non-steroidal anti-inflammatory drug (NSAID) for the treatment of inflammation, mild-to-moderate pain and fever in children, and is the only NSAID approved for use in children aged >=3 months. Its efficacy and safety profile have led to its increasing use in paediatric care, even without medical prescription. However, an increase of suspected adverse reactions to ibuprofen has been noted in concomitance with the raised, often medically unsupervised, consumption of the drug. The purpose of this work was a critical review of the paediatric literature over the last 15 years on side effects and adverse events associated with ibuprofen, in order to highlight circumstances associated with higher risks and to promote safe and appropriate use of this drug. The literature from 2000 to date demonstrates that gastrointestinal events are rare, but (when they occur) include both upper and lower digestive tract lesions. Dehydration plays an important role in triggering renal damage, so ibuprofen should not be given to patients with diarrhoea and vomiting, with or without fever. Likewise, ibuprofen should never be administered to patients who are sensitive to it or to other NSAIDs. It is contraindicated in neonates and in children with wheezing and persistent asthma and/or during varicella. Most of the analysed studies reported adverse events when ibuprofen was being used for fever symptoms or flu-like syndrome. Ibuprofen should not be used as an antipyretic, except in rare cases. Ibuprofen remains the drug of first choice in the treatment of inflammatory pain in children. PMID- 28597362 TI - A System-Wide Approach to Physician Efficiency and Utilization Rates for Non Operating Room Anesthesia Sites. AB - There has been little in the development or application of operating room (OR) management metrics to non-operating room anesthesia (NORA) sites. This is in contrast to the well-developed management framework for the OR management. We hypothesized that by adopting the concept of physician efficiency, we could determine the applicability of this clinical productivity benchmark for physicians providing services for NORA cases at a tertiary care center. We conducted a retrospective data analysis of NORA sites at an academic, rural hospital, including both adult and pediatric patients. Using the time stamps from WiseOR(r) (Palo Alto, CA), we calculated site utilization and physician efficiency for each day. We defined scheduling efficiency (SE) as the number of staffed anesthesiologists divided by the number of staffed sites and stratified the data into three categories (SE < 1, SE = 1, and SE >1). The mean physician efficiency was 0.293 (95% CI, [0.281, 0.305]), and the mean site utilization was 0.328 (95% CI, [0.314, 0.343]). When days were stratified by scheduling efficiency (SE < 1, =1, or >1), we found differences between physician efficiency and site utilization. On days where scheduling efficiency was less than 1, that is, there are more sites than physicians, mean physician efficiency (95% CI, [0.326, 0.402]) was higher than mean site utilization (95% CI, [0.250, 0.296]). We demonstrate that scheduling efficiency vis-a-vis physician efficiency as an OR management metric diverge when anesthesiologists travel between NORA sites. When the opportunity to scale operational efficiencies is limited, increasing scheduling efficiency by incorporating different NORA sites into a "block" allocation on any given day may be the only suitable tactical alternative. PMID- 28597363 TI - A Portable Optical Recording Device Simulating CO2 Angiography for Training Purposes. PMID- 28597364 TI - Potential Application of Nanoemulsions for Skin Delivery of Pomegranate Peel Polyphenols. AB - Pomegranate peel and seeds have demonstrated to possess antioxidant compounds with potential application to protect the skin against the ultraviolet radiation damage. However, the photoprotection activity is dependent on the amount of these compounds that reach the viable skin layers. In this paper, we describe the in vitro skin permeation and retention of the major pomegranate peel polyphenols using Franz diffusion cells, after entrapping a ethyl acetate fraction (EAF) from Punica granatum peel extract into nanoemulsions (NEs) prepared with pomegranate seed oil (PSO) or medium chain triglyceride oil (MCT). The in vitro skin permeation of gallic acid (GA), ellagic acid (EA), and punicalagin (PC) was evaluated using a HPLC-DAD validated method. After 8 h of skin permeation, all polyphenol compounds were mostly retained in the skin and did not reach the receptor compartment. However, a 2.2-fold enhancement of the retained amount of gallic acid in the stratum corneum was verified after EAF-loaded NEs are applied, when compared with the free EAF. GA and EA were delivered to the viable epidermis and dermis only when nanoemulsions were applied onto the skin. The mean retained amounts of GA and EA in the EP and DE after applying the EAF-loaded PSO-NE were 1.78 and 1.36 MUg cm-2 and 1.10 and 0.97 MUg cm-2, respectively. Similar values were obtained after applying the EAF-loaded MCT-NE. The skin permeation results were supported by the confocal microscopy images. These results evidenced the promising application of nanoemulsions to deliver the pomegranate polyphenols into the deeper skin layers. PMID- 28597367 TI - Erratum to: Moclobemide: An update of its pharmacological properties and therapeutic use. PMID- 28597365 TI - A novel pathogenic frameshift variant of CD3E gene in two T-B+ NK+ SCID patients from Turkey. AB - Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency, which is characterized by the dysfunction and/or absence of T lymphocytes. Early diagnosis of SCID is crucial for overall survival, and if it remains untreated, SCID is often fatal. Next-generation sequencing (NGS) has become a rapid, high-throughput technology, and has already been proven to be beneficial in medical diagnostics. In this study, a targeted NGS panel was developed to identify the genetic variations of SCID by using SmartChip-TE technology, and a novel pathogenic frameshift variant was found in the CD3E gene. Sanger sequencing has confirmed the segregation of the variant among patients. We found a novel deletion in the CD3E gene (NM000733.3:p.L58Hfs*9) in two T-B+ NK+ patients. The variant was not found in the databases of dbSNP, ExAC, and 1000G. One sibling in family I was homozygous and the rest of the family members were heterozygous for this variant. T cell receptor excision circle (TREC) and kappa deleting recombination excision circle (KREC) analyses were performed for T and B cell maturation. TRECs were not detected in both patients and the KREC copy numbers were similar to the other family members. In addition, heterozygous family members showed decreased TREC levels when compared with the wild-type sibling, indicating that carrying this variant in one allele does not cause immunodeficiency, but does effect T cell proliferation. Here, we report a novel pathogenic frameshift variant in CD3E gene by using targeted NGS panel. PMID- 28597366 TI - Finite element model predicts the biomechanical performance of cervical disc replacement and fusion hybrid surgery with various geometry of ball-and-socket artificial disc. AB - PURPOSE: Few finite element studies have investigated changes in cervical biomechanics with various prosthesis design parameters using hybrid surgery (HS), and none have investigated those combined different HS strategies. The aim of our study was to investigate the effect of ball-and-socket prosthesis geometry on the biomechanical performance of the cervical spine combined with two HS constructs. METHODS: Two HS strategies were conducted: (1) ACDF at C4-C5 and anterior cervical disc replacement (ACDR) at C5-C6 (ACDF/ACDR), and (2) ACDR/ACDF. Three different prostheses were used for each HS strategy: prosthesis with the core located at the center of the inferior endplate with a radius of 5 mm (BS-5) or 6 mm (BS-6), or with a 5 mm radius core located 1 mm posterior to the center of the inferior endplate (PBS-5). Flexion and extension motions were simulated under displacement control. RESULTS: The flexion motions in supra- and infra-adjacent levels increased in all cases. The corresponding extension motions increased with all prostheses in ACDR/ACDF group. The stiffness in flexion and extension increased with all HS models, except for the extension stiffness with ACDF/ACDR. The facet stresses between the index and infra-adjacent level in ACDR/ACDF were significantly greater than those in the intact model . The stresses on the BS-5 UHMWPE core were greater than the yield stress. CONCLUSION: The core radii and position did not significantly affect the moments, ROM, and facet stress in extension. However, the moments and ROM in flexion were easily affected by the position. The results implied that the large core radii and posterior core position in ACDR designs may reduce the risk of subsidence and wear in the long term as they showed relative low stress . The ACDF/ACDR surgery at C4-C6 level may be an optimal treatment for avoiding accelerating the degeneration of adjacent segments. PMID- 28597368 TI - Health-Related Resource-Use Measurement Instruments for Intersectoral Costs and Benefits in the Education and Criminal Justice Sectors. AB - BACKGROUND: Intersectoral costs and benefits (ICBs), i.e. costs and benefits of healthcare interventions outside the healthcare sector, can be a crucial component in economic evaluations from the societal perspective. Pivotal to their estimation is the existence of sound resource-use measurement (RUM) instruments; however, RUM instruments for ICBs in the education or criminal justice sectors have not yet been systematically collated or their psychometric quality assessed. This review aims to fill this gap. METHODS: To identify relevant instruments, the Database of Instruments for Resource Use Measurement (DIRUM) was searched. Additionally, a systematic literature review was conducted in seven electronic databases to detect instruments containing ICB items used in economic evaluations. Finally, studies evaluating the psychometric quality of these instruments were searched. RESULTS: Twenty-six unique instruments were included. Most frequently, ICB items measured school absenteeism, tutoring, classroom assistance or contacts with legal representatives, police custody/prison detainment and court appearances, with the highest number of items listed in the Client Service Receipt Inventory/Client Sociodemographic and Service Receipt Inventory/Client Service Receipt Inventory-Children's Version (CSRI/CSSRI/CSRI C), Studying the Scope of Parental Expenditures (SCOPE) and Self-Harm Intervention, Family Therapy (SHIFT) instruments. ICBs in the education sector were especially relevant for age-related developmental disorders and chronic diseases, while criminal justice resource use seems more important in mental health, including alcohol-related disorders or substance abuse. Evidence on the validity or reliability of ICB items was published for two instruments only. CONCLUSION: With a heterogeneous variety of ICBs found to be relevant for several disease areas but many ICB instruments applied in one study only (21/26 instruments), setting-up an international task force to, for example, develop an internationally adaptable instrument is recommended. PMID- 28597369 TI - First report of real-time monitoring of coagulation function potential and IgG subtype of anti-FVIII autoantibodies in a child with acquired hemophilia A associated with streptococcal infection and amoxicillin. AB - We describe an 8-year-old boy with acquired hemophilia A (AHA) associated with streptococcal infection and amoxicillin. Laboratory data revealed low factor VIII activity (FVIII:C, 1.5 IU/dl), and FVIII inhibitor (15.9 BU/ml). Comprehensive coagulation function assays, including rotation thromboelastometry (ROTEM(r)), revealed a markedly prolonged clotting time. Thrombin and plasmin generation (TG/PG) appeared to be moderately impaired. The inhibitor epitope of his anti FVIII autoantibody recognized light and heavy chains. He was treated with Novoseven(r) and prednisolone, resulting in rapid improvement. ROTEM showed the return of coagulation time to normal level on day 20, and TG gradually improved. PG was moderately reduced in the clinical early phase, but improved at day 20. The patient's IgG subtype was IgG4 at onset. IgG1 was transiently positive on day 20, but negative on day 46. FVIII inhibitor gradually decreased and was completely absent after day 46, along with the elevated FVIII:C. IgG4 was again elevated on day 83, followed by a rapid decrease, indicative of the presence of non-neutralizing antibody, which remains currently undetected. We for the first time report changes in comprehensive coagulation function and IgG subtype of anti FVIII antibody in a rare pediatric case of AHA. PMID- 28597370 TI - Micropropagation of Ajuga species: a mini review. AB - The genus Ajuga L., belonging to Lamiaceae family, is widespread. The demand for Ajuga species has risen sharply because of their medicinal, ornamental, and pharmacological properties. These wide-ranging plants are being rapidly depleted due to over-collection for ornamental and medicinal purposes, as well as by habitat destruction and deforestation. Ajuga boninsimae, A. bracteosa, A. ciliate, A. genevensis, A. incisa, A. makinoi, A. multiflora, A. pyramidalis, A. shikotanensis, A. reptans, and A. vestita are categorized and protected as endangered plants. In vitro plant culture has therefore emerged for the conservation and mass clonal propagation of rare plants. This mini-review covers the current in vitro scenario in the propagation of Ajuga species. Adventitious or axillary shoots are initiated on the leaf, petiole and internodes, as well as roots, nodes, and shoot tip explants. Shoot induction is predominantly dependent on plant growth regulators added to the culture medium. Full- or half-strength Murashige and Skoog medium with or without auxin is used for in vitro rooting. Rooted shoots need to be acclimatized in the greenhouse with an estimated 82-100% survival rate. PMID- 28597371 TI - Uptake and biotransformation of pure commercial microcystin-LR versus microcystin LR from a natural cyanobacterial bloom extract in the aquatic fungus Mucor hiemalis. AB - OBJECTIVES: To evaluate the remediation efficiency of Mucor hiemalis by comparing media elimination, uptake, and biotransformation of microcystin-LR with exposure to pure toxin versus a crude bloom extract. RESULTS: With exposure to the extract, the elimination rate of microcystin-LR from the media, which was 0.28 ng MC-LR l-1 h-1, was significantly higher compared to that achieved with exposure to the pure toxin (0.16 ng MC-LR l-1 h-1) after 24 h. However, intracellular breakdown of microcystin-LR was significantly lower in the extract exposed pellets compared to the pure toxin treated fungal pellets over time. This coincided with reduced intracellular glutathione S-transferase activity with crude extract exposure which could be responsible for the detection of only the glutathione conjugate of microcystin-LR. CONCLUSION: This paper signifies the importance of using laboratory exposure scenarios which resemble conditions in nature to fully understand and evaluate remediation efficiency. There is merit in using M. hiemalis for mycoremediation of cyanotoxins in surface waters. PMID- 28597372 TI - miR-599 inhibits proliferation and invasion of glioma by targeting periostin. AB - OBJECTIVE: To explore the molecular mechanism of microRNA-599(miR-599) in the migration and invasion of glioma. RESULT: Clinicopathological characteristics of 33 patients were analyzed. Based on reverse transcription-PCR, miR-599 was down regulated in glioma tissues compared with adjacent normal brain tissues (P < 0.001). Moreover, negative correlations between miR-599 and periostin protein expression in glioma tissues (P < 0.01) and necrosis by magnetic resonance imaging (P < 0.05) were observed. Transwell and wound healing assays showed that overexpression of miR-599 inhibited glioma cell migration and invasion. miR-599 down-regulated periostin expression by targeting the 3'-untranslated region. Additionally, re-expression of periostin partial reversed the suppressive effect of miR-599 on migration and invasion in vitro and in vivo. CONCLUSION: microRNA 599 inhibits proliferation and invasion by down-regulating periostin expression in vitro and in vivo. PMID- 28597373 TI - Giving Patients a Meaningful Voice in European Health Technology Assessments: The Role of Health Preference Research. PMID- 28597374 TI - Giving Patients a Meaningful Voice in United States Regulatory Decision Making: The Role for Health Preference Research. PMID- 28597375 TI - Preferences for Health Interventions: Improving Uptake, Adherence, and Efficiency. PMID- 28597376 TI - Health Valuation: Demonstrating the Value of Health and Lifespan. PMID- 28597377 TI - Health Preference Research: An Overview. PMID- 28597378 TI - Assessment of Individual Patient Preferences to Inform Clinical Practice. PMID- 28597379 TI - Valuing health risk in agriculture: a choice experiment approach to pesticide use in China. AB - This paper presents a choice experiment approach to investigate farmers' valuations for health risk changes associated with pesticide use in Anqiu County, China. An empirical comparison on the disparity between farmers' willingness to pay (WTP) for a health risk reduction and willingness to accept (WTA) for the same risk increase is also conducted. Respondents were randomly assigned into the WTP group or the WTA group. Four attributes (health consequence, baseline risk, risk change size, and price) were identified and included. The results show that cancer consequence due to pesticide use decreases the utility of the farmer. A higher baseline risk has a higher WTP to reduce the risk and a higher probability of receiving compensation. If the health risk change size is bigger, it will result in a higher WTP and higher compensation. Household income, education, and age have significant and positive impacts on farmers' WTP. Farmers who are more educated or female are more likely to accept the compensation scheme if health risks increase. The marginal WTA for the same risk change is about two times higher than the marginal WTP. The findings of this study can contribute to the literature comparing people's WTP and WTA in a discrete choice experiment on valuing health risk changes associated with pesticide use. PMID- 28597381 TI - The removal efficiency of constructed wetlands filled with the zeolite-slag hybrid substrate for the rural landfill leachate treatment. AB - The removal efficiencies of two horizontal subsurface flow constructed wetlands (HSSF CWs, down-flow (F1) and up-flow (F2)) filled with the zeolite-slag hybrid substrate for the rural landfill leachate treatment were investigated. The adsorption experiment was conducted to evaluate the potential of zeolite and slag as the wetland substrate. The effects of distance variations along the longitudinal profile of wetland bed on pollutant removal were assessed by sampling at four locations (inlet, outlet, 0.55 m, and 1.10 m from the inlet). During the operation time, the influent and effluent concentrations of chemical oxygen demand (COD), ammonia nitrogen (NH3-N), total nitrogen (TN), heavy metals, and polycyclic aromatic hydrocarbon (PAH) were measured. The results showed that the constructed wetlands were capable of removing COD, 20.5-48.2% (F1) and 18.6 61.2% (F2); NH3-N, 84.0-99.9% (F1) and 93.5-99.2% (F2); TN, 80.3-92.1% (F1) and 80.3-91.2% (F2); and heavy metals, about 90% (F1 and F2). The zeolite-slag hybrid substrate performed excellent removal efficiency for the nitrogen and heavy metals. The inlet area was the most active region of leachate removal. The up flow constructed wetland (F2) has a higher removal efficiency for the PAH compounds. The significant removal efficiency illustrated that the rural landfill leachate can be treated using the horizontal subsurface flow constructed wetland filled with the zeolite-slag hybrid substrate. PMID- 28597380 TI - Maternal-embryonic metabolic and antioxidant response of Chapalichthys pardalis (Teleostei: Goodeidae) induced by exposure to 3,4-dichloroaniline. AB - Chapalichthys pardalis is a viviparous fish, microendemic to the Tocumbo Region in the state of Michoacan, Mexico. Despite the peculiar type of reproduction of goodeid fish and their mother-embryo interaction, the effects on embryos induced by maternal exposure to aquatic xenobiotics are still unknown. The objective of the present work was to determine the maternal-embryonic metabolic and antioxidant response of C. pardalis exposed to 3,4-dichloroaniline (3,4-DCA), a compound considered highly noxious to the environment because of its high toxicity and persistence, which has been used as reference toxicant in toxicological bioassays. We determined the median lethal concentration (LC50, 96 h) and then exposed pregnant females to 3.3, 2.5, and 0.5 mg L-1 of 3,4-DCA (equivalent to LC1, LC0.01, and LC50/10, respectively) during 21 days. We assessed the activity of antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), macromolecules content (proteins, lipids, carbohydrates), glucose, and lactate concentration, as well as the oxidative damage, by measuring thiobarbituric acid reactive substances, and protein oxidation. To interpret results, we used the integrated biomarker response (IBRv2). The average LC50 was of 5.18 mg L-1 (4.8-5.5 mg L-1; p = 0.05). All females exposed to concentrations of 3.3 and 2.5 mg L-1 lost 100% of the embryos during the bioassay, whereas those exposed to 0.5 mg L-1 showed alterations in the antioxidant activity and oxidative damage, being the embryos and the maternal liver the most affected, with IBRv2 values of 10.09 and 9.21, respectively. Damage to macromolecules was greater in embryos and the maternal liver, with IBRv2 of 16.14 and 8.40, respectively. We conclude that exposure to xenobiotics, like 3,4-DCA, in species with a marked maternal-embryonic interaction represents a potential risk for the development and survival of the descendants, thereby, potentially affecting the future of the population. PMID- 28597382 TI - Performance and microbial community dynamics of electricity-assisted sequencing batch reactor (SBR) for treatment of saline petrochemical wastewater. AB - High-salinity wastewater is often difficult to treat by common biological technologies due to salinity stress on the bacterial community. Electricity assisted anaerobic technologies have significantly enhanced the treatment performance by alleviating the impact of salinity stress on the bacterial community, but electricity-assisted aerobic technologies have less been reported. Herein, a novel bio-electrochemistry system has been designed and operated in which a pair of stainless iron mesh-graphite plate electrodes were installed into a sequencing batch reactor (SBR, designated as S1) to strengthen the performance of saline petrochemical wastewater under aerobic conditions. The removal efficiency of phenol and chemical oxygen demand (COD) in S1 were 94.1 and 91.2%, respectively, on day 45, which was clearly higher than the removal efficiency of a single SBR (S2) and an electrochemical reactor (S3), indicating that a coupling effect existed between the electrochemical process and biodegradation. A certain amount of salinity (<=8000 mg/L) could enhance the treatment performance in S1 but weaken that in S2. Illumina sequencing revealed that microbial communities in S1 on days 45 and 91 were richer and more diverse than in S2, which suggests that electrical stimulation could enhance the diversity and richness of the microbial community, and reduce the negative effect of salinity on the microorganisms and enrich some salt-adapted microorganisms, thus improve the ability of S1 to respond to salinity stress. This novel bio-electrochemistry system was shown to be an alternative technology for the high saline petrochemical wastewater. PMID- 28597383 TI - Green biotransformations catalysed by enzyme-inorganic hybrid nanoflowers in environmentally friendly ionic solvents. AB - Environmentally friendly ionic solvents such as (a) ionic liquids (ILs) formulated with hydroxyl ammonium cations and various carboxylic acid anions and (b) choline chloride or ethyl ammonium chloride-based deep eutectic solvents (DES) were tested as media for hydrolytic and synthetic reactions catalysed by lipase-inorganic hybrid nanoflowers. The nature of ionic solvents used has a significant effect on the hydrolytic and synthetic activity of the immobilized lipase, as well as on its stability and reusability. In choline chloride-based DES, the activity and especially the operational stability of the biocatalyst are significantly increased compared to those observed in buffer, indicating the potential application of these solvents as green media for various biocatalytic processes of industrial interest. PMID- 28597384 TI - Toxicity against Drosophila melanogaster and antiedematogenic and antimicrobial activities of Alternanthera brasiliana (L.) Kuntze (Amaranthaceae). AB - Bioactive phytocompounds are studied by several bioactivities demonstrated, as their cytotoxic effects. The aim of this work was to evaluate the phytochemical profile, the toxic effect using the Drosophila melanogaster animal model and the anti-inflammatory and antimicrobial effect of the Alternanthera brasiliana (EEAB) ethanol extract. The phytochemical profile was performed using HPLC. The cytotoxic effect was evaluated in vivo using D. melanogaster. The anti inflammatory effect was determined by neurogenic and antiedematogenic assays, and the antimicrobial activity was assayed using a microdilution method to determine the minimum inhibitory concentration (MIC) of the EEAB alone and in association with antibiotics. The main compound identified on the EEAB was luteolin (1.93%). Its cytotoxic effect was demonstrated after 24 h in the concentrations of 10, 20 and 40 mg/mL. The extract demonstrated an antiedematogenic effect, with a reduction of the edema between 35.57 and 64.17%. The MIC of the extract was >=1.024 MUg/mL, thus being considered clinically irrelevant. However, when the EEAB was associated with gentamicin, a synergism against all bacterial strains assayed was observed: Staphylococcus aureus (SA10), Escherichia coli (EC06) and Pseudomonas aeruginosa (PA24). Due to these results, the EEAB demonstrated a low toxicity in vivo and anti-inflammatory and synergistic activities. These are promising results, mainly against microbial pathogens, and the compounds identified can be a source of carbon backbones for the discovery and creation of new drugs. PMID- 28597385 TI - Cadmium accumulation characteristics of low-cadmium rice (Oryza sativa L.) line and F1 hybrids grown in cadmium-contaminated soils. AB - Cadmium (Cd) pollution has threatened severely to food safety and human health. A pot experiment and a field experiment were conducted to investigate the difference of Cd accumulation between rice (Oryza sativa L.) lines and F1 hybrids in Cd-contaminated soils. The adverse effect on biomass of rice lines was greater than that of F1 hybrids under Cd treatments in the pot experiment. The variations of Cd concentration among rice cultivars in different organs were smaller in stem and leaf, but larger in root and ear. Average proportion of Cd in root of F1 hybrids was 1.39, 1.39, and 1.16 times higher than those of rice lines at the treatment of 1, 2, and 4 mg Cd kg-1 soil, respectively. Cd concentrations in ear of F1 hybrids were significantly lower than rice lines with the reduction from 29.24 to 50.59%. Cd concentrations in brown rice of all F1 hybrids were less than 0.2 mg kg-1 at 1 mg Cd kg-1 soil, in which Lu98A/YaHui2816, 5406A/YaHui2816, and C268A/YaHui2816 could be screened out as cadmium-safe cultivars (CSCs) for being safe even at 2 mg Cd kg-1 soil. C268A/YaHui2816 showed the lowest Cd concentration in root among F1 hybrids, while Lu98A/YaHui2816 and 5406A/YaHui2816 showed lower capability of Cd translocation from root to shoot under Cd exposure, which eventually caused the lower Cd accumulation in brown rice. The lower level of Cd translocation contributed to reducing the accumulation of Cd in brown rice had been validated by the field experiment. Thus, Lu98A/YaHui2816, 5406A/YaHui2816, and C268A/YaHui2816 could be considered as potential CSCs to cultivate in Cd-contaminated soils (<2 mg Cd kg-1 soil). PMID- 28597386 TI - Ozone alters the feeding behavior of the leaf beetle Agelastica coerulea (Coleoptera: Chrysomelidae) into leaves of Japanese white birch (Betula platyphylla var. japonica). AB - High mixing ratios of ground-level O3 threaten trophic interactions. In the present study, we conducted laboratory assays, where insect larvae and adults were not directly exposed to O3, to test the feeding behavior and attraction of the coleopteran leaf beetle Agelastica coerulea to early and late leaves of Japanese white birch (Betula platyphylla var. japonica) treated with ambient or elevated O3 levels. We found that overwintered adults were not deterred from grazing elevated O3-treated leaves, but rather preferred them than ambient O3 treated ones. We also found that the feeding behavior of 2nd instar larvae fed on early or late leaves was not influenced by the O3 treatment of the leaves when larvae could choose leaves. These observations of the adults and larvae feeding preferences contradict prior observations in the field conditions where the insects avoided leaves in O3-enriched atmosphere. Since adults preferred elevated O3-exposed leaves in the present laboratory assays, it is worthy of further investigations whether adults change their grazing preference so as to ensure the leaf palatability as a feeding source for their larvae. Hence, new direction towards detailed ovipositional behavior surveys under field conditions is encouraged. PMID- 28597387 TI - Ozone-UV-catalysis based advanced oxidation process for wastewater treatment. AB - A bench-scale advanced oxidation (AO) reactor was investigated for the degradation of six pollutants (2-naphthol, phenol, oxalic acid, phthalate, methylene blue, and D-glucose) in a model wastewater at with the aim to test opportunities for the further upscale to industrial applications. Six experimental conditions were designed to completely examine the experimental reactor, including photolysis, photocatalysis, ozonation, photolytic ozonation, catalytic ozonation, and photocatalytic ozonation. The stationary catalyst construction was made from commercially available TiO2 nanopowder by mounting it on a glass support and subsequently characterized for morphology (X-ray diffraction analysis and scanning electron microscopy) as well as durability. The ozone was generated in a dielectrical barrier discharge reactor using air as a source of oxygen. The degradation efficiency was estimated by the decrease in total organic carbon (TOC) concentration as well as toxicity using Daphnia magna, and degradation by-products by ultra-performance liquid chromatography-mass spectrometry. The photocatalytic ozonation was the most effective for the treatment of all model wastewater. The photocatalytic ozonation was most effective against ozonation and photolytic ozonation at tested pH values. A complete toxicity loss was obtained after the treatment using photocatalytic ozonation. The possible degradation pathway of the phthalate by oxidation was suggested based on aromatic ring opening reactions. The catalyst used at this experiment confirmed as a durable for continuous use with almost no loss of activity over time. The design of the reactor was found to be very effective for water treatment using photocatalytic ozonation. Such design has a high potential and can be further upscaled to industrial applications due to the simplicity and versatility of manufacturing and maintenance. PMID- 28597388 TI - Treatment of tannery effluent by passive uptake-parametric studies and kinetic modeling. AB - Galactomyces geotrichum was utilized as a potential biosorbent for the treatment of tannery effluent under controlled environmental conditions. Tannery effluent treatment was studied through parametric experiments to study the effect of effluent pH (3.0-10.0), initial COD (1100-4400 mg/L), and biosorbent dosage (0.3 3.0 g/L).The zeta potential of the biosorbent was determined and found to influence the optimal pH. Increase in effluent COD values resulted in decreased COD removal percentages which attributed to limited availability of surface active sites. The equation relating the COD removal efficiency and biosorbent dose was proposed. Two popular kinetic models, namely pseudo-second order and power function models, were employed to the experimental data. Pseudo-second order model proved to be a good fit with high values of regression coefficient (R 2 > 0.960). Potential application of a fungal biosorption process was explored and the optimal process parameters were identified. PMID- 28597389 TI - Enhanced Fenton-like degradation of TCE in sand suspensions with magnetite by NTA/EDTA at circumneutral pH. AB - The present study investigated the degradation of trichloroethylene (TCE) in sand suspensions by Fenton-like reaction with magnetite (Fe3O4) in the presence of various chelators at circumneutral pH. The results showed that ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA) greatly improved the rate of TCE degradation, while [S,S]-ethylenediaminedisuccinic acid (s,s-EDDS), malonate, citrate, and phytic acid (IP6) have minimal effects on TCE degradation. Quenching tests suggested that TCE was mainly degraded by hydroxyl radical (HO.) attack, with about 90% inhibition on TCE degradation by the addition of HO. scavenger 2-propanol. The presence of 0.1-0.5% Fe3O4/sand (w/w) contributed to 40% increase in TCE degradation rates. In particular, the use of chelators can avoid high concentrations of H2O2 required for the Fenton-like reaction with Fe3O4, and moreover improve the stoichiometric efficiencies of TCE degradation to H2O2 consumption. The suitable concentrations of chelators (EDTA and NTA) and H2O2 were suggested to be 0.5 and 20 mM, respectively. Under the given conditions, degradation rate constants of TCE were obtained at 0.360 h-1 with EDTA and 0.526 h-1 with NTA, respectively. Enhanced degradation of TCE and decreased usage of H2O2 in this investigation suggested that Fenton-like reaction of Fe3O4 together with NTA (or EDTA) may be a promising process for remediation of TCE-contaminated groundwater. PMID- 28597391 TI - Desorption of micropollutant from spent carbon filters used for water purifier. AB - In this study, to examine the accumulated micropollutants in the spent carbon filter used in the water purifier, first, the method to desorb micropollutant from the activated carbon was developed and optimized. Then, using this optimized desorption conditions, we examined which micropollutants exist in spent carbon filters collected from houses in different regions in Korea where water purifiers were used. A total of 11 micropollutants (caffeine (CFF), acetaminophen (ACT), sulfamethazine (SMA), sulfamethoxazole (SMZ), metoprolol (MTP), carbamazepine (CBM), naproxen (NPX), bisphenol-A (BPA), ibuprofen (IBU), diclofenac (DCF), and triclocarban (TCB)) were analyzed using LC/MS-MS from the spent carbon filters. CFF, NPX, and DCF had the highest detection frequencies (>60%) in the carbon filters (n = 100), whereas SMA, SMZ, and MTP were only detected in the carbon filters, but not in the tap waters (n = 25), indicating that these micropollutants, which exist less than the detection limit in tap water, were accumulated in the carbon filters. The regional micropollutant detection patterns in the carbon filters showed higher levels of micropollutants, especially NPX, BPA, IBU, and DCF, in carbon filters collected in the Han River and Nakdong River basins where large cities exist. The levels of micropollutants in the carbon filter were generally lower in the regions where advanced oxidation processes (AOPs) were employed at nearby water treatment plants (WTPs), indicating that AOP process in WTP is quite effective in removing micropollutant. Our results suggest that desorption of micropollutant from the carbon filter used can be a tool to identify micropollutants present in tap water with trace amounts or below the detection limit. PMID- 28597392 TI - Packaging of implantable accelerometers to monitor epicardial and endocardial wall motion. AB - Acceleration signals, collected from the inner and the outer heart wall, offer a mean of assessing cardiac function during surgery. Accelerometric measurements can also provide detailed insights into myocardial motion during exploratory investigations. Two different implantable accelerometers to respectively record endocardial and epicardial vibrations, have been developed by packaging a commercially available capacitive transducer. The same coating materials have been deposited on the two devices to ensure biocompatibility of the implants: Parylene-C, medical epoxy and Polydimethylsiloxane (PDMS). The different position specific requirements resulted in two very dissimilar sensor assemblies. The endocardial accelerometer, that measures accelerations from the inner surface of the heart during acute animal tests, is a 2 mm-radius hemisphere fixed on a polymethyl methacrylate (PMMA) rod to be inserted through the heart wall. The epicardial accelerometer, that monitors the motion of the outer surface of the heart, is a three-legged structure with a stretchable polytetrafluoroethylene (PTFE) reinforcement. This device can follow the continuous motion of the myocardium (the muscular tissue of the heart) during the cardiac cycle, without hindering its natural movement. Leakage currents lower than 1 MUA have been measured during two weeks of continuous operation in saline. Both transducers have been used, during animal tests, to simultaneously record and compare acceleration signals from corresponding locations on the inner and the outer heart wall of a female sheep. PMID- 28597393 TI - Brigatinib: First Global Approval. AB - Brigatinib (ALUNBRIGTM) is a small molecule antineoplastic anaplastic lymphoma kinase (ALK) inhibitor being developed by ARIAD Pharmaceuticals (a wholly-owned subsidiary of Takeda Pharmaceutical Company). In April 2017 brigatinib received accelerated approval in the USA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The development of resistance to crizotinib is a therapeutic challenge that has led to the development of second-generation ALK inhibitors such as brigatinib, which have activity against treatment-resistant ALK mutants. This article summarizes the milestones in the development of brigatinib leading to this first global approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. PMID- 28597390 TI - Effects of nanoparticles in species of aquaculture interest. AB - Recently, it was observed that there is an increasing application of nanoparticles (NPs) in aquaculture. Manufacturers are trying to use nano-based tools to remove the barriers about waterborne food, growth, reproduction, and culturing of species, their health, and water treatment in order to increase aquaculture production rates, being the safe-by-design approach still unapplied. We reviewed the applications of NPs in aquaculture evidencing that the way NPs are applied can be very different: some are direclty added to feed, other to water media or in aquaculture facilities. Traditional toxicity data cannot be easily used to infer on aquaculture mainly considering short-term exposure scenarios, underestimating the potential exposure of aquacultured species. The main outputs are (i) biological models are not recurrent, and in the case, testing protocols are frequently different; (ii) most data derived from toxicity studies are not specifically designed on aquaculture needs, thus contact time, exposure concentrations, and other ancillary conditions do not meet the required standard for aquaculture; (iii) short-term exposure periods are investigated mainly on species of indirect aquaculture interest, while shrimp and fish as final consumers in aquaculture plants are underinvestigated (scarce or unknown data on trophic chain transfer of NPs): little information is available about the amount of NPs accumulated within marketed organisms; (iv) how NPs present in the packaging of aquacultured products can affect their quality remained substantially unexplored. NPs in aquaculture are a challenging topic that must be developed in the near future to assure human health and environmental safety. Graphical abstract ?. PMID- 28597394 TI - Invasive Candidiasis in Brescia, Italy: Analysis of Species Distribution and Antifungal Susceptibilities During Seven Years. AB - The aims of this study were to evaluate the epidemiology of nosocomial candidemia in a large teaching hospital in Brescia, Italy, and the in vitro antifungal susceptibility of isolates. We analyzed 196 isolates causing fungemia in patients admitted in our hospital, between January 2009 and December 2015. Strains were identified by VITEK 2 and MALDI-TOF MS. MICs were determined by Sensititre Yeast OneTM. The resistance was defined by using the revised CLSI breakpoints/epidemiological cutoff values to assign susceptibility or wild type to systemic antifungal agents. Most infections were caused by Candida albicans (60%), Candida parapsilosis (15%), Candida glabrata (12%) and Candida tropicalis (6%). The susceptibility rate for fluconazole was 96.5%. Non-Candida species isolates exhibited full susceptibilities to echinocandins according to CLSI breakpoints. Amphotericin B demonstrated excellent activity against all Candida species. Local epidemiological and antifungal susceptibility studies are necessary in order to improve empirical treatment guidelines. PMID- 28597395 TI - Correlates and catalysts of hominin evolution in Africa. AB - Hominin evolution in the African Pliocene and Pleistocene was accompanied and mediated by changes in the abiotic and biotic spheres. It has been hypothesized that such environmental changes were catalysts of hominin morphological evolution and speciations. Whereas there is little doubt that ecological changes were relevant to shaping the trajectories of mammalian evolution, testing specific hypotheses with data from the fossil record has yielded ambiguous results regarding environmental disruption as a primary catalyst. Proposed mechanisms for abiotic and biotic causes of evolution are not always consistent with the timing and trends exhibited by the African fossil record of hominins and other mammals. Analyses of fossil and genetic data suggest that much of hominin evolution, and by extension mammalian evolution, was autocatalytic, driven by feedback loops within a species or lineage, irrespective of changes in the external environment. PMID- 28597396 TI - TRPV4 Activation Contributes Functional Recovery from Ischemic Stroke via Angiogenesis and Neurogenesis. AB - The endothelial transient receptor potential cation channel subfamily V member 4 (TRPV4) plays a crucial role in vascular remodeling; however, TRPV4-mediated angiogenesis after ischemic neuronal death as a neurorestorative strategy has not yet been thoroughly examined. In this study, we first tested whether TRPV4 activation can improve functional recovery in rats subjected to transient brain ischemia. The possible mechanisms for TRPV4 activation-promoted functional recovery were explored. A TRPV4 agonist, 4alpha-phorbol 12,13-didecanoate (4alpha PDD), was intravenously injected via the tail vein at 6 h and 1, 2, 3, 4 days after ischemic stroke. The treatment reduced infarct volume by almost 50% (14.7 +/- 3.7 vs. 29.2 +/- 6.2%; p < 0.0001) and improved functional outcomes (p = 0.03) on day 5. To explore the therapeutic mechanism, we measured endothelial nitric oxide synthase (eNOS) expression and phosphorylation, vascular endothelial growth factor A (VEGFA) signaling, and neural stem/progenitor cells (NPCs). TRPV4 activation significantly increased eNOS expression and phosphorylation (serine 1177) by more than 2-fold in the ischemic region. The expressions of VEGFA and VEGF receptor-2 were significantly higher in the treated animals, especially an increase of the proangiogenic VEGFA164a isoform while a decrease of the antiangiogenic VEGFA165b isoform. We evaluated angiogenesis by detecting microvessel density in ischemic region. Using the immunohistochemistry staining, we found that 4alpha-PDD treatment caused a 3.4-fold increase of microvessel density (p < 0.0001). In addition, NPC proliferation and migration in the ischemic hemisphere were increased by 3-fold and 5-fold, respectively. In conclusion, our data suggest that TRPV4 activation by 4alpha-PDD may improve poststroke functional improvement through angiogenesis and neurogenesis. PMID- 28597397 TI - Protein Kinase Cdelta Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene. AB - Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cdelta (PKCdelta) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA induced increase in phospho-PKCdelta expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCdelta expression and phospho ERK1/2 expression. Since PKCdelta knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1 overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCdelta expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCdelta KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCdelta inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCdelta expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCdelta expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCdelta, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCdelta and GPx-1 genes to restore cognitive function. PMID- 28597398 TI - Determination of Brain-Regional Blood Perfusion and Endogenous cPKCgamma Impact on Ischemic Vulnerability of Mice with Global Ischemia. AB - Conventional protein kinase C (cPKC)gamma participated in cerebral hypoxic preconditioning-induced neuroprotection and affected the neurological outcome of ischemic stroked mice. As an independent predictor of ischemic stroke, the internal carotid artery occlusion (ICAO)-caused brain-regional ischemic injury may worsen the neurological outcome of patients. However, the brain-regional ischemic vulnerability and its underlying mechanism remain unclear. In this study, the bilateral ICAO (BICAO) model was applied in cPKCgamma wild type (WT) and knockout (KO) mice to determine the cPKCgamma impact on brain-regional ischemic vulnerability. The arterial spin labeling (ASL) imaging results showed that 7 days BICAO-induced global ischemia could cause significant blood perfusion loss in prefrontal cortex (69.13%), striatum (61.69%), hypothalamus (67.36%), hippocampus (69.82%) and midbrain (40.53%) of WT mice, along with neurological deficits. Nissl staining and Western blot results indicated that hypothalamus and midbrain had more severe neural cell loss than prefrontal cortex, striatum and hippocampus, which negatively coincided with endogenous cPKCgamma protein levels but not blood perfusion loss and cPKCgamma membrane translocation levels. Furthermore, we found that cPKCgamma KO significantly aggravated the neuron loss in prefrontal cortex, striatum and hippocampus and abolish the regional ischemic vulnerability by using immunofluorescent staining with neuron-specific marker NeuN. Similarly, cPKCgamma KO also significantly increased Caspase-3, -8 and -9 cleavage levels in prefrontal cortex, striatum, hippocampus, hypothalamus and midbrain of mice with 24 h BICAO. These results suggested that hypothalamus and midbrain are more vulnerable to ischemia, and endogenous cPKCgamma affects the regional ischemic vulnerability through modulating Caspase-8 and -9 dependent cell apoptosis. PMID- 28597399 TI - Effects of Levosimendan on Patients with Heart Failure Complicating Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: The prognosis for patients with heart failure (HF), including cardiogenic shock (CS), complicating acute coronary syndrome (ACS) remains poor. OBJECTIVE: This study aimed to review the relevant literature and evaluate whether levosimendan was associated with better clinical outcomes in these patients. METHODS: We searched PubMed, EMBASE, and the Cochrane library databases for randomized controlled trials that investigated levosimendan compared with any control in patients with HF/CS complicating ACS. RESULTS: A total of 1065 patients from nine trials were included in this study. Analysis showed that levosimendan significantly reduced total mortality and the incidence of worsening HF. In patients with HF-ACS, levosimendan was associated with reduced mortality. In patients with CS-ACS, no significant difference was observed between the two groups. Levosimendan contributed to significantly reduced mortality when compared with placebo, but no significant reduction was seen compared with dobutamine. Compared with controls, levosimendan decreased pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac index, with no significant difference observed between the groups in terms of heart rate. Levosimendan non significantly increased the risk of hypotension but did not increase the risk of ischemic episodes, sinus tachycardia, atrial fibrillation, or ventricular arrhythmias. CONCLUSION: Levosimendan appears to be a promising drug to reduce mortality and worsening HF in patients with HF/CS-ACS. It appears to provide hemodynamic benefit and was associated with an increased risk of hypotension. PMID- 28597400 TI - Gynecologic oncologists' attitudes and practices relating to integrative medicine: results of a nationwide AGO survey. AB - PURPOSE: The growing popularity and acceptance of integrative medicine is evident both among patients and among the oncologists treating them. As little data are available regarding health-care professionals' knowledge, attitudes, and practices relating to the topic, a nationwide online survey was designed. METHODS: Over a period of 11 weeks (from July 15 to September 30, 2014) a self administered, 17-item online survey was sent to all 676 members of the Research Group on Gynecological Oncology (Arbeitsgemeinschaft Gynakologische Onkologie) in the German Cancer Society. The questionnaire items addressed the use of integrative therapy methods, fields of indications for them, advice services provided, level of specific qualifications, and other topics. RESULTS: Of the 104 respondents (15.4%) using integrative medicine, 93% reported that integrative therapy was offered to breast cancer patients. The second most frequent type of tumor in connection with which integrative therapy methods were recommended was ovarian cancer, at 80% of the participants using integrative medicine. Exercise, nutritional therapy, dietary supplements, herbal medicines, and acupuncture were the methods the patients were most commonly advised to use. CONCLUSION: There is considerable interest in integrative medicine among gynecological oncologists, but integrative therapy approaches are at present poorly implemented in routine clinical work. Furthermore there is a lack of specific training. Whether future efforts should focus on extending counseling services on integrative medicine approaches in gynecologic oncology or not, have to be discussed. Evidence-based training on integrative medicine should be implemented in order to safely guide patients in their wish to do something by themselves. PMID- 28597401 TI - Biomechanical evaluation of the risk of secondary fracture around short versus long cephalomedullary nails. AB - INTRODUCTION: For proximal femur fractures, long cephalomedullary nails (CMNs) are often selected to avoid a diaphyseal stress riser at the tip of a shorter nail. Secondary peri-implant fracture rates for long and short CMN have not been shown to differ clinically. This study biomechanically compares both CMN in a cadaveric model. METHODS: Ten matched pairs of cadaveric femora with short or long CMN were axially loaded and internally rotated to failure. RESULTS: Resulting fractures involved distal interlocking screws of the short and long CMN. Energy and rotation to failure were significantly greater for short CMN. Torque at failure trended higher for short CMN but not significantly. No statistical difference was detected in stiffness of the short and long CMN. DISCUSSION: A greater risk of secondary fracture is not indicated for short versus long CMN under torsional stress. Short CMN may be suitable in the younger patient. PMID- 28597402 TI - Metastatic bone disease from breast cancer: a review of minimally invasive techniques for diagnosis and treatment. AB - Skeletal-related events in patients with metastatic bone disease include intractable severe pain, pathologic fracture, spinal cord and nerve compression, hypercalcemia and bone marrow aplasia. In patients with breast cancer, the skeleton is the most frequent site for metastases. Treatment options for metastatic bone disease in these patients include bisphosphonates, chemotherapeutic agents, opioids, hormonal therapy, minimally invasive/interventional and surgical techniques. Interventional oncology techniques for breast cancer patients with bone metastases include diagnostic (biopsy) and therapeutic (palliative and curative) approaches. In the latter, percutaneous ablation, augmentation and stabilization are included. The purpose of this article is to describe the basic concepts of biopsy, ablation, embolization and peripheral skeleton augmentation techniques in patients with metastatic bone disease from breast carcinoma. The necessity for a tailored approach applying different techniques for different cases and locations will be addressed. PMID- 28597404 TI - Relevance of microRNA 21 in Different Types of Hypertension. AB - Hypertension (HTN) is a chronic medical condition that commonly affects the aging population worldwide. The prevalence of HTN is increasing in developing countries and is one of the leading causes of death in older individuals. HTN results from a complex interplay of genetic and environmental factors. Besides, HTN can result in various other health complications such as stroke and chronic kidney diseases, if not treated. Although various studies have explained the underlying mechanisms in the pathogenesis of HTN, limited information is available on their biomarkers. MicroRNAs (miRNAs) are RNA molecules that have been recognized as key regulators for HTN. miR-21 is a common microRNA that is has been reported to be significantly upregulated in HTN individuals. Hence, miR-21 can be a potential therapeutic target for HTN. The number of studies related to miR-21 on hypertension is limited. Therefore, the main thrust of this paper is to provide an overview of the current clinical evidence and significance of miR-21 in HTN. PMID- 28597403 TI - Resistant Hypertension: Mechanisms and Treatment. AB - PURPOSE OF REVIEW: Emerging evidence suggests that multiple mechanisms may be responsible for the development of treatment-resistant hypertension (TRH). This review aims to summarize recent data on potential mechanisms of resistance and discuss current pharmacotherapeutic options available in the management of TRH. RECENT FINDINGS: Excess sodium and fluid retention, increased activation of the renin-angiotensin-aldosterone system, and heightened activity of the sympathetic nervous system appear to play an important role in development of TRH. Emerging evidence also suggests a role for arterial stiffness and, potentially, gut dysbiosis. Therapeutic approaches for TRH should include diuretic optimization and the addition of aldosterone antagonists as the preferred fourth agent in most patients. Further therapeutic approaches may be guided by the suspected underlying mechanism of TRH in conjunction with other patient-specific factors. The pathophysiology of TRH is multifaceted; however, increasing evidence supports several mechanisms that may be targeted to improve blood pressure control among patients with TRH. Further studies are needed to determine whether such approaches may be more effective than usual care. PMID- 28597406 TI - Clinical significance of extra-coronary arterial calcifications. PMID- 28597405 TI - Hyperbilirubinemia, Hypertension, and CKD: the Links. AB - PURPOSE OF REVIEW: This review aims to highlight recent advances on the role of hyperbilirubinemia in hypertension and chronic kidney disease, with a focus on the pathophysiological mechanisms explaining the protective effects of bilirubin. An overview of pharmacologic induction of hyperbilirubinemia will also be discussed. RECENT FINDINGS: The findings depict a protective role of bilirubin in the development of hypertension and cardiovascular diseases. Hyperbilirubinemia is also negatively correlated with the development and progression of chronic kidney disease. Commonly used drugs play a role in pharmacologic induction of hyperbilirubinemia. Bilirubin is therefore an exciting target for new therapeutic interventions for its antioxidant properties can be pivotal in the management of hypertension and in preventing and halting the progression of chronic kidney disease. Longitudinal studies are warranted to evaluate the prospective association between bilirubin levels and incident hypertension and chronic kidney disease in the general population. Interventions to induce hyperbilirubinemia need to be explored as a novel therapeutic approach in fighting disease burden. PMID- 28597407 TI - Resistance wheel exercise from mid-life has minimal effect on sciatic nerves from old mice in which sarcopenia was prevented. AB - The ability of resistance exercise, initiated from mid-life, to prevent age related changes in old sciatic nerves, was investigated in male and female C57BL/6J mice. Aging is associated with cellular changes in old sciatic nerves and also loss of skeletal muscle mass and function (sarcopenia). Mature adult mice aged 15 months (M) were subjected to increasing voluntary resistance wheel exercise (RWE) over a period of 8 M until 23 M of age. This prevented sarcopenia in the old 23 M aged male and female mice. Nerves of control sedentary (SED) males at 3, 15 and 23 M of age, showed a decrease in the myelinated axon numbers at 15 and 23 M, a decreased g-ratio and a significantly increased proportion of myelinated nerves containing electron-dense aggregates at 23 M. Myelinated axon and nerve diameter, and axonal area, were increased at 15 M compared with 3 and 23 M. Exercise increased myelinated nerve profiles containing aggregates at 23 M. S100 protein, detected with immunoblotting was increased in sciatic nerves of 23 M old SED females, but not males, compared with 15 M, with no effect of exercise. Other neuronal proteins showed no significant alterations with age, gender or exercise. Overall the RWE had no cellular impact on the aging nerves, apart from an increased number of old nerves containing aggregates. Thus the relationship between cellular changes in aging nerves, and their sustained capacity for stimulation of old skeletal muscles to help maintain healthy muscle mass in response to exercise remains unclear. PMID- 28597410 TI - Teaching Trauma and Narrative: Using Salinger's For Esme-with Love and Squalor. PMID- 28597408 TI - Single-cell RNA-sequencing of the brain. AB - Single-cell RNA-sequencing (scRNA-seq) is revolutionizing our understanding of the genomic, transcriptomic and epigenomic landscapes of cells within organs. The mammalian brain is composed of a complex network of millions to billions of diverse cells with either highly specialized functions or support functions. With scRNA-seq it is possible to comprehensively dissect the cellular heterogeneity of brain cells, and elucidate their specific functions and state. In this review, we describe the current experimental methods used for scRNA-seq. We also review bioinformatic tools and algorithms for data analyses and discuss critical challenges. Additionally, we summarized recent mouse brain scRNA-seq studies and systematically compared their main experimental approaches, computational tools implemented, and important findings. scRNA-seq has allowed researchers to identify diverse cell subpopulations within many brain regions, pinpointing gene signatures and novel cell markers, as well as addressing functional differences. Due to the complexity of the brain, a great deal of work remains to be accomplished. Defining specific brain cell types and functions is critical for understanding brain function as a whole in development, health, and diseases. PMID- 28597409 TI - Progression and Persistence of Neurotoxicity Induced by MDMA in Dopaminergic Regions of the Mouse Brain and Association with Noradrenergic, GABAergic, and Serotonergic Damage. AB - The amphetamine-related drug 3,4-methylenedioxymethamphetamine (MDMA) is known to induce neurotoxic damage in dopaminergic regions of the mouse brain. In order to characterize how the number of administrations influenced the severity of MDMA induced dopaminergic damage and to describe the localization and persistence of this damage, we evaluated the changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) in different regions of the mouse brain. Moreover, we investigated whether dopaminergic damage was associated with noradrenergic, GABAergic, and serotonergic damage, by evaluating the changes in noradrenaline transporter (NET), glutamic acid decarboxylase-67 (GAD-67), and serotonin transporter (SERT). Mice received 14, 28, or 36 MDMA administrations (10 mg/kg twice a week) and were sacrificed at different time points (postnatal days 85, 110, 138, or 214) for immunohistochemical evaluation. Mice receiving 28 administrations showed reduced levels of DAT-positive fibers in caudate-putamen (CPu) and medial prefrontal cortex (mPFC) and reduced levels of TH-positive nigral neurons. These mice also displayed increased NET-positive hippocampal fibers, reduced GAD-67-positive neurons in CPu and hippocampus, and reduced GAD 67-positive fibers in mPFC. Similar effects of MDMA on DAT, TH, and GAD-67 were found in mice receiving 36 administrations, which also displayed reduced levels of striatal, cortical, and hippocampal TH-immunoreactive fibers. The reductions in dopaminergic markers and GAD-67 persisted at 3 months after MDMA discontinuation. Finally, MDMA never modified the levels of SERT. These results provide further insight into the localization and persistence of MDMA-induced dopaminergic damage and show that this effect may associate with GABAergic but not noradrenergic or serotonergic damage. PMID- 28597411 TI - Comparative proteomic analysis of alfalfa revealed new salt and drought stress related factors involved in seed germination. AB - Salinity and drought are two major environmental factors that limit the growth and yield of many forage crops in semi-arid and arid regions. Alfalfa (Medicago sativa L.) is one of the most important forage crops in many countries. We aim to investigate the molecular mechanisms of alfalfa in response to salt and drought stresses in this study. Physiological and proteomic analyses were applied to examine the Zhongmu NO.3 alfalfa seed germination stage with 200 mM NaCl and 180 g.L-1 polyethylene glycol (PEG) treatments. The germination ability of the seed and the accumulation of osmotic solutes were quite different between the NaCl and PEG treatments. More than 800 protein spots were detected by proteomics technology on two-dimensional electrophoresis (2-DE) gels. The abundance of twenty-eight proteins were decreased or increased after salt and drought stress. Seventeen of these proteins were identified and classified into six functional categories through mass spectrometry (MS). The six groups involved in salt- and PEG-mediated stress included defense response, energy metabolism, protein synthesis and degradation, oxidative stress, carbohydrate metabolism-associated proteins, and unknown proteins. We discovered that some proteins related to carbohydrate metabolism and energy production increased in abundance under salt- and PEG-mediated drought stress. This demonstrates a common mechanism of energy consumption during abiotic stresses. Further study of these proteins with unknown function will provide insights into the molecular mechanisms of abiotic stress and the discovery of new candidate markers. PMID- 28597412 TI - Association of A-604G ghrelin gene polymorphism and serum ghrelin levels with the risk of obesity in a mexican population. AB - Obesity is a metabolic disorder that has a multifactorial etiology and affects millions of people worldwide. Ghrelin, a hormone coded by the GHRL gene, plays a role in human body composition and appetite. Single nucleotide polymorphisms (SNPs) of the GHRL gene have been associated with obesity and metabolic disorders. To evaluate the association of A-604G SNP of GHRL promoter region with serum ghrelin levels and the risk of obesity in a Mexican population. Two hundred and fifty individuals were enrolled and classified as obese or control subjects (CS) according to BMI. DNA samples, anthropometric measurements and biochemical parameters were obtained from all subjects. The A-604G SNP was genotyped using PCR-RFLPs technique. Ghrelin levels were measured using a commercial enzyme immunoassay. The G/G genotype was more frequent among obese individuals (p < 0.0001) when compared to CS. The G/A genotype and A allele were associated with protection against obesity (OR 0.29, p < 0.0001; OR 0.39, p < 0.0001 respectively), the A allele remained significant after adjusting for age and gender (OR: 0.25, p < 0.0001). Serum ghrelin levels were higher in obese patients (p = 0.004) than in CS, however, significance was lost after adjustment for age (p = 0.088). The G/G genotype was associated with higher levels of serum ghrelin (p = 0.02) independently of the effect of age. The G/G genotype of the A-604G SNP in the GHRL gene is associated with altered serum ghrelin levels and obesity. The A allele was also associated with protection against obesity in this study. PMID- 28597414 TI - Effects of light-emitting diode supplementary lighting on the winter growth of greenhouse plants in the Yangtze River Delta of China. AB - BACKGROUND: The winter in the Yangtze River Delta area of China involves more than 1 month of continuous low temperature and poor light (CLTL) weather conditions, which impacts horticultural production in an unheated greenhouse; however, few greenhouses in this area are currently equipped with a heating device. The low-cost and long-living light-emitting diode (LED) was used as an artificial light source to explore the effects of supplementary lighting during the dark period in CLTL winter on the vegetative characteristics, early yield, and physiology of flowering for pepper plants grown in a greenhouse without heating. Two LED lighting sets were employed with different light source to provide 65 MUmol m-2 s-1 at night: (1) LED-A: red LEDs (R, peak wavelength 660 nm) and blue LEDs (B, peak wavelength 460 nm) with an R:B ratio of 6:3; and (2) LED-B: R and B LEDs at an R:B ratio of 8:1. Plants growth parameters and chlorophyll fluorescence characteristics were compared between lighting treatments and the control group. RESULTS: Plants' yield and photosynthesis ability were improved by LED-A. Pepper grown under the LED-A1 strategy showed a 303.3 % greater fresh weight of fruits and a 501.3 % greater dry mass compared with the control group. Plant leaves under LED-A1 showed maximum efficiency of the light quantum yield of PSII, electron transfer rate, and the proportion of the open fraction of PSII centers, with values 113.70, 114.34, and 211.65 % higher than those of the control group, respectively, and showed the lowest rate constant of thermal energy dissipation of all groups. LED-B was beneficial to the plant height and stems diameter of the pepper plants more than LED-A. CONCLUSIONS: These results can serve as a guide for environment control and for realizing low energy consumption for products grown in a greenhouse in the winter in Southern China. PMID- 28597413 TI - Late-onset ornithine transcarbamylase deficiency associated with hyperammonemia. AB - The urea cycle converts ammonia and produces urea. One form of urea cycle abnormality is ornithine transcarbamylase (OTC) deficiency. This hereditary disorder is associated with hyperammonemia. OTC deficiency commonly appears during neonatal and early childhood life and is rare in adults. We report a 69 year-old man who presented at the local hospital with 3-day loss of appetite, early morning vomiting, and state of confusion. Blood ammonia was 293 MUg/dl. At 2-3 h after admission, the patient went into a deep coma. He was intubated and admitted immediately to the intensive care unit. Treatment, including sustained hemodialysis, failed to lower blood ammonia level. His grandchild died of OTC deficiency at 6 year of age. Computed tomography, magnetic resonance imaging and esophagogastroduodenoscopy showed no abnormalities. On admission to our hospital, he complained of vomiting and disturbance of consciousness, hyperammonemia, and normal anion gap. Genetic analysis showed A208T mutation. The deceased grandchild with OTC deficiency also had the same mutation. Long-term hemodialysis coupled with administration of L-arginine and lactulose resulted in improvement of blood ammonia level. Early diagnosis and treatment of adult-onset OTC deficiency are essential to avoid serious complications. PMID- 28597416 TI - Phytochemical studies for quantitative estimation of iridoid glycosides in Picrorhiza kurroa Royle. AB - BACKGROUND: Picrorhiza kurroa Royle commonly known as 'Kutki or Kutaki' is an important medicinal plant in Ayurvedic system of medicine and has traditionally been used to treat disorders of the liver and upper respiratory tract. The plant is the principle source of iridoid glycosides, picrosides I, II and kutkoside used in various herbal drug formulations mainly as strong hepatoprotective and immune-modulatory compound. The species has become endangered to near extinction due to the unregulated collection from the wild, slower plant growth and ecological destruction of natural habitats. There is a severe shortage of plant material, while the market demand is ever increasing. Hence, it is very important to apply a simple and precise analytical method to determine and validate the concentration of the major bioactive constituents in different populations of this plant species for development of a high yielding chemotype for large scale production and its commercial exploitation on scientific lines. RESULTS: This study assessed and validated a fast and reliable chromatography method for the determination of picroside-I and picroside-II in different populations of this priortized medicinal plant species. Separation and resolution of picrosides was carried out on a reversed phase (C-18) column by using a mobile phase of methanol and water (40:60 v/v). The detection of picrosides was carried out at 270 nm. The average levels of these two major marker compounds in all the seven accessions showed significant quantitative variation (ANOVA, p < 0.05) between mean levels of marker compounds and their accumulation in different parts of the plant viz. roots, rhizomes and leaves. The highest content of pk-I was found in the accession from Gurez altitude (3750 masl) while the highest content of pk-II was found in accession from Keller (Shopian) altitude (3300 masl) demonstrate that picroside accusation is directly correlated with altitudinal variation. The method was validated in terms of linearity, accuracy and precision (within- and between-assay variation). CONCLUSION: A simple chromatographic method with the ability to separate both the major chemical constituents effectively in different herbal extracts of P. kurroa and other related species has been standardized and validated, which is more suitable for regular and normal analysis of picrosides in different herbal formulations. The paper accomplish that picroside concentration in different samples showed significant variation based on altitude and other agroclimatic factors, which can be useful in the selection and collection of superior genotypes with higher concentration of these marker compounds. PMID- 28597415 TI - Effects of CuO nanoparticles on Lemna minor. AB - BACKGROUND: Copper dioxide nanoparticles (NPs), which is a kind of important and widely used metal oxide NP, eventually reaches a water body through wastewater and urban runoff. Ecotoxicological studies of this kind of NPs effects on hydrophyte are very limited at present. Lemna minor was exposed to media with different concentrations of CuO NPs, bulk CuO, and two times concentration of Cu2+ released from CuO NPs in culture media. The changes in plant growth, chlorophyll content, antioxidant defense enzyme activities [i.e., peroxidase (POD), catalase (CAT), superoxide dismutase (SOD) activities], and malondialdehyde (MDA) content were measured in the present study. The particle size of CuO NPs and the zeta potential of CuO NPs and bulk CuO in the culture media were also analyzed to complementally evaluate their toxicity on duckweed. RESULT: Results showed that CuO NPs inhibited the plant growth at lower concentration than bulk CuO. L. minor roots were easily broken in CuO NPs media under the experimental condition, and the inhibition occurred only partly because CuO NPs released Cu2+ in the culture media. The POD, SOD, and CAT activities of L. minor increased when the plants were exposed to CuO NPs, bulk CuO NPs and two times the concentration of Cu2+ released from CuO NPs in culture media, but the increase of these enzymes were the highest in CuO NPs media among the three kinds of materials. The MDA content was significantly increased compared with that of the control from 50 mg L-1 CuO NP concentration in culture media. CONCLUSION: CuO NPs has more toxicity on L. minor compared with that of bulk CuO, and the inhibition occurred only partly because released Cu2+ in the culture media. The plant accumulated more reactive oxygen species in the CuO NP media than in the same concentration of bulk CuO. The plant cell encountered serious damage when the CuO NP concentration reached 50 mg L-1 in culture media. The toxicology of CuO NP on hydrophytes must be considered because that hydrophytes are the basic of aquatic ecosystem. PMID- 28597417 TI - Elevation gradient of soil bacterial communities in bamboo plantations. AB - BACKGROUND: Elevation trends of macro organisms have long been well studied. However, whether microbes also exhibit such patterns of elevation change is unknown. Here, we investigated the changes in bamboo forest soil bacterial communities along six elevation gradients, from 600 to 1800 m a.s.l. in Mt. Da an, a subtropical montane area in Nantou county at central Taiwan. RESULTS: Data from 16S rRNA gene clone libraries revealed that more than 70 % of the six communities contained Acidobacteria and Proteobacteria, although the relative abundance differed. Nonmetric multidimensional scaling analysis of the distribution of operational taxonomic units showed differences in bamboo soil bacterial communities across gradients. The bacterial communities at 1000 and 1200 m showed greater diversity than the communities at both lower (600 and 800 m) and higher (1400 and 1800 m) elevations. In contrast to the bacterial community trend, soil C and N and microbial biomass properties increased linearly with elevation. CONCLUSION: The bamboo soil bacterial community could interact with multiple factors such as soil organic matter content and temperature, for differences in composition and diversity with change in elevation. PMID- 28597418 TI - Influence of LED light spectra on in vitro somatic embryogenesis and LC-MS analysis of chlorogenic acid and rutin in Peucedanum japonicum Thunb.: a medicinal herb. AB - BACKGROUND: Peucedanum japonicum Thunb, an important medicinal herb is reported to possess pharmacological properties such as anti-obesity, anti-oxidant, anti inflammatory, anti-bacterial, anti-diabetic and anti-platelet aggregation. The present study aimed to develop an in vitro plant regeneration system of P. japonicum via somatic embryogenesis and to analyse chlorogenic acid and rutin contents in a few commercially available plant products of P. japonicum in Japan and Taiwan markets, and tissue culture plants derived from somatic embryos. RESULTS: Induction of somatic embryogenesis could be achieved when root derived calli after three subcultures were transferred from Murashige Skoog's salts and vitamins (MS basal) medium with 2,4-dichlorophenoxyacetic acid (2,4-D) (0.1-5 mg/L) to a medium with abscisic acid (ABA) (0.5-4 mg/L), or exposed to eight different light spectra provided by light-emitting diode (LED) sources. Concentrations of ABA and LED light spectra had an influence on number of somatic embryos induced and proliferation of callus. Development of secondary somatic embryos and conversion of embryos to plantlets was achieved on a medium with ABA, or their exposure to red or blue lights in a special incubation chamber. Four months old tissue culture plants derived from somatic embryos showed significantly higher levels of chlorogenic acid (10.5 mg/g dw) compared to commercial product sold in Japanese market (0.55 mg/g dw). However, rutin was absent in tissue culture plants in contrast to commercial sample (0.33 mg/g dw). CONCLUSION: In this report, we describe in vitro plant regeneration system in P. japonicum via somatic embryogenesis and production of chlorogenic acid in tissue culture plants. The present study has application in further tissue culture propagation of elite plant material with high chlorogenic acid content, and identification of high yielding plants with the LC-MS method. PMID- 28597419 TI - Culm height development, biomass accumulation and carbon storage in an initial growth stage for a fast-growing moso bamboo (Phyllostachy pubescens). AB - BACKGROUND: The purpose of this study was to predict culm height development and to evaluate biomass accumulation and carbon storage in the initial growth stage of moso bamboos (Phyllostachys pubescens). A total of 30 bamboos were sampled based on their diameter at breast height (DBH). I predicted the culm heights daily based on the Richards growth function for these bamboo samples. After they reached their maximum heights, the biomass and carbon storage were determined. RESULTS: The results showed that the Richards function accurately simulated the height growth of bamboos and that the growth potential of culm heights increased with increasing DBH classes. In contrast, the time when the maximum growth rate occurred (t max ) appeared to not be influenced by DBH classes and was close to 20 days for all DBH classes. The culms arrived at their maximum heights in about 40 days regardless of DBH class. In addition, astonishing biomass accumulation and carbon storage was found during this period, and the aboveground biomass and carbon storage were predicted to be 3.44-17.33 and 1.58-8.04 kg culm-1 for moso bamboos, respectively. The allometric model was used to predict the relationships between DBH and aboveground biomass in this stage. CONCLUSIONS: I compared the biomass accumulation between this stage and the entire yield period (5 years) and found that the bamboos accumulated three-fourths of their biomass for the entire yield period in only 40 days. This revealed that biomass accumulation and carbon storage mainly occurs in the initial growth stage for individual moso bamboos. PMID- 28597420 TI - Lead heavy metal toxicity induced changes on growth and antioxidative enzymes level in water hyacinths [Eichhornia crassipes (Mart.)]. AB - BACKGROUND: Lead (Pb) heavy metal pollution in water bodies is one of the serious problems across the world. This study was designed to find out the effect of Pb toxicity on physiological and biochemical changes in Eichhornia crassipes (water hyacinth) seedlings. RESULTS: The plant growth was significantly inhibited (50%) at 1000 mg/L Pb concentration. Accumulation of Pb was higher in root than in shoot tissues. The maximum level of Pb accumulation was noticed in roots (5.45%) followed by petiole (2.72%) and leaf tissues (0.66%). Increasing the Pb concentration gradually decreased the chlorophyll content. Intracellular distribution of Pb was also studied using SEM-EDX, where the Pb deposition was observed in both root and leaf tissues. MDA content increased in both the leaf and root tissues up to the 400 mg/L Pb treatment and slightly decreased at higher concentrations. The activity of antioxidative enzymes, such as APX and POX, positively correlated with Pb treatment, while in the case of SOD and CAT enzymes increased up to 800 mg/L treatment and then slightly decreased at higher concentration in both leaf and root tissues. CONCLUSIONS: These results suggest that water hyacinth plants have efficient mechanism to tolerate Pb toxicity, as evidenced by an increased level of antioxidative enzymes. Results clearly indicate that water hyacinth is a feasible plant for hyperaccumulation of heavy metals from polluted wetlands. PMID- 28597421 TI - Nitrogen deficiency impacts on leaf cell and tissue structure with consequences for senescence associated processes in Brassica napus. AB - Improvement of nutrient use efficiency is a major goal for several crop plants, especially Brassica napus. Indeed, the low nitrogen use efficiency (NUE) in this crop results in negative economic and ecological consequences. The low NUE of oilseed rape is mainly due to low remobilization of nitrogen from vegetative parts to growing organs. Remobilization of leaf nitrogen takes place during senescence, a process known to strongly modify cell and tissue structure. This study focused on the impact of moderate N depletion, expected to induce 30 % reduction of seed yield, on these structural modifications. Two genotypes (Aviso and Express) were studied, with different tolerance of nitrogen depletion, evaluated through seed yield and dry mass production. Structural modifications of leaf cells and tissues were investigated through NMR relaxometry and light microscopy. Lower tolerance of N depletion was associated with higher impact on senescence associated structural modification pattern. The link between leaf structure modifications and nutrient remobilization is discussed. It is proposed that leaf structure monitoring during senescence through NMR device could be developed to select genotypes with high NUE. PMID- 28597422 TI - BnaABF2, a bZIP transcription factor from rapeseed (Brassica napus L.), enhances drought and salt tolerance in transgenic Arabidopsis. AB - BACKGROUND: Abiotic stresses such as drought and salt stresses have a negative effect on the growth and productivity of plants. Improvement of stress tolerance through genetic engineering in plants has been reported in intense studies. Transcription factors play vital roles in plant adaptation to stresses by regulating expression of a great deal of target genes. A family of Arabidopsis basic region leucine zipper (bZIP) transcription factors that can recognize and bind to the abscisic acid (ABA)-responsive elements (ABREs) in promoter is named as ABRE binding factors (ABFs)/ABRE binding proteins (AREBs). They play a key role in the regulation of expression of downstream stress-responsive genes in ABA signalling. Genetic transformation of ABF/ABRE transcription factors has been suggested to be an effective approach for engineering stress-tolerant plants. However, whether the ABF/ABRE transcription factors are able to be used for generating stress-tolerant rapeseed plants has not yet been studied. RESULTS: BnaABF2, encoding a bZIP transcription factor, was cloned from rapeseed in this study. Subcellular localization and transactivation analyses showed that BnaABF2 was localized to the nucleus with transactivation activity in plant cells. BnaABF2 gene expression was induced by drought and salt stresses and BnaABF2 positively functions in ABA signalling during the vegetative stage. Overexpression of BnaABF2 was found to render drought and salt tolerance to Arabidopsis plants. The resistance of the BnaABF2-expressing transgenic plants to drought and salt stresses is due to reduced water-loss rate and expression of stress-responsive genes such as RD29B, RAB18 and KIN2. The expression of RD29B, RAB18 and KIN2 regulated by BnaABF2 is involved in an ABA-dependent stress signalling. CONCLUSIONS: Identification of the positive role of rapeseed BnaABF2 in plant tolerance to drought and salt provides evidence for ability of engineering stress-tolerant rapeseed plants by genetic transformation of BnaABF2. PMID- 28597423 TI - Illumina-based transcriptomic profiling of Panax notoginseng in response to arsenic stress. AB - BACKGROUND: Panax notoginseng, a famous herbal medicine, has recently attracted great attention on its safety and quality since P. notoginseng can accumulate and tolerate As from growing environment. For the purpose of understanding As damage to the quality of P. notoginseng as well as corresponding tolerance mechanisms, genes involved in As stress response were identified using Illumina sequencing. RESULTS: Totally 91,979,946 clean reads were generated and were de novo assembled into 172,355 unigenes. A total of 81,575 unigenes were annotated in at least one database for their functions, accounting for 47.34 %. By comparative analysis, 1725 differentially expressed genes (DEGs, 763 up-regulated/962 down-regulated) were identified between As stressed plant (HAs) and control plant (CK), among which 20 DEGs were further validated by real-time quantitative PCR (qRT-PCR). In the upstream and downstream steps of biosynthesis pathways of ginsenosides and flavonoids, 7 genes encoding key enzymes were down-regulated in HAs. Such down regulations were also revealed in pathway enrichment analysis. Genes encoding transporters (transporters of ABC, MATE, sugar, oligopeptide, nitrate), genes related to hormone metabolism (ethylene, ABA, cytokinin) and genes related to arsenic accumulation (HXT, NRAMP, MT and GRX) were differentially expressed. The up-regulated genes included those of oxidative stress-related protein (GSTs, thioredoxin), transcription factors (HSFs, MYBs) and molecular chaperones (HSP). CONCLUSIONS: The down-regulation of biosynthesis of ginsenoside and flavonoid indicated that As accumulation in P. notoginseng can cause not only safety hazard, but also qualitative losses. Aside from the results of arsenic content of seedling roots, the ability of P. notoginseng to over-accumulate arsenic can also be explained by the differential expression of genes of HXT, NRAMP, MT and GRX. To illustrate the detoxification mechanism of P. notoginseng, differential expression of genes encoding oxidative-related proteins, transcription factors, molecular chaperones, transporters and hormone were revealed in our study, which agreed with those reported in Arabidopsis to a certain extent, indicating P. notoginseng and Arabidopsis shared some common detoxification mechanisms in response to As stress. The longer As treatment in our study may account for the smaller quantity of related DEGs and smaller degree of expression differences of certain DEGs compared with those of Arabidopsis. PMID- 28597424 TI - Endocarps of menispermaceous plants in Taiwan. AB - BACKGROUND: The fruits of the family Menispermaceae are drupes, and because the drupe endocarps are morphologically diverse, they are generally used to classify members of this family. There is a lack of detailed knowledge of Menispermaceae endocarps in Taiwan. Therefore, in this study, the endocarps of seven genera and 14 species were dissected, and their morphological characters were photographed and described. Furthermore, a key for the 14 species based on the endocarps features, as well as a key of the studied genera, is proposed. RESULTS: The endocarp types comprise a straight shape in Tinospora dentata Diels and a horseshoe shape in the other 13 species. In general, the genus Cyclea bears two dorsal crests with 16 small spines, although there are about 25 spines in Cyclea insularis (Makino) Hatusima. The genus Cocculus has a dorsal convex endocarp with a subannular. In Taiwan, the endocarp of Sinomenium acutum (Thunb.) Rehder & E. H. Wilson has up to 26 transverse ridges, without spines on the crest and might be categorized under the genus Menispermum. Transverse endocarp ridges are found in Stephania cephalantha Hayata and Stephania tetrandra S. Moore, whereas transverse endocarp strips are found in Stephania japonica (Thunb.) Miers, Stephania longa Lour. and Stephania merrillii Diels. CONCLUSION: We believe that the descriptions and photographs of the endocarp traits of T. dentata, which is endemic to Taiwan, will provide more evidence for further studies on extant and fossil species. PMID- 28597425 TI - Virus-induced plasma membrane aquaporin PsPIP2;1 silencing inhibits plant water transport of Pisum sativum. AB - BACKGROUND: Aquaporins (AQPs) are known to facilitate water transport across cell membranes, but the role of a single AQP in regulating plant water transport, particularly in plants other than Arabidopsis remains largely unexplored. In the present study, a virus-induced gene silencing (VIGS) technique was employed to suppress the expression of a specific plasma membrane aquaporin PsPIP2;1 of Pea plants (Pisum sativum), and subsequent effects of the gene suppression on root hydraulic conductivity (Lpr), leaf hydraulic conductivity (K leaf ), root cell hydraulic conductivity (Lprc), and leaf cell hydraulic conductivity (Lplc) were investigated, using hydroponically grown Pea plants. RESULTS: Compared with control plants, VIGS-PsPIP2;1 plants displayed a significant suppression of PsPIP2;1 in both roots and leaves, while the expression of other four PIP isoforms (PsPIP1;1, PsPIP1;2, PsPIP2;2, and PsPIP2;3) that were simultaneously monitored were not altered. As a consequence, significant declines in water transport of VIGS-PsPIP2;1 plants were observed at both organ and cell levels, i.e., as compared to control plants, Lpr and K leaf were reduced by 29 %, and Lprc and Lplc were reduced by 20 and 29 %, respectively. CONCLUSION: Our results demonstrate that PsPIP2;1 alone contributes substantially to root and leaf water transport in Pea plants, and highlight VIGS a useful tool for investigating the role of a single AQP in regulating plant water transport. PMID- 28597426 TI - Anti-hepatitis, antioxidant activities and bioactive compounds of Dracocephalum heterophyllum extracts. AB - BACKGROUND: Dracocephalum heterophyllum was a traditional Tibetan medicine possesses various pharmacological effects involved in anti-inflammatory, antibacterial activities. However, its anti-hepatitis, antioxidant activity and bioactive compounds have not been reported, the objective of this research work was to investigate the pharmacological activity and bioactive compounds of D. heterophyllum extracts. RESULTS: In the present study, the anti-hepatics and antioxidant activities of four D. heterophyllum extracts (i.e. petroleum ether extracts, ethyl acetate extracts, n-BuOH extracts, and water extracts) were conducted. The main chemical constituent of petroleum ether and ethyl acetate extracts were also isolated using chromatographic techniques and identified by NMR spectroscopic methods. The anti-hepatitis assay showed that the petroleum ether and ethyl acetate extracts of D. heterophyllum significantly prolonged the mean survival times and reduced the mortality of mouse hepatitis model induced by concanavalin A (ConA). The levels of alanine transaminase, aspartate transaminase in blood serum could be decreased obviously by ethyl acetate extracts compared with ConA group (P < 0.01). The histological analysis demonstrated that the ethyl acetate extracts could inhibit apoptosis and necrosis caused by ConA. In addition, the antioxidant activities of the four extracts of D. heterophyllum were measured by DPPH assay, ABTS assay, anti-lipidperoxidation assay, ferric reducing antioxidant power assay, ferrous metal ions chelating assay and determination of total phenolic contents. The results showed that the ethyl acetate extract had the highest antioxidant activities, followed by petroleum ether extract. Finally, nine mainly compounds were isolated from the Petroleum ether and ethyl acetate extracts, including four triterpenes: oleanolic acid (1), ursolic acid (2), pomolic acid (3), 2alpha- hydroxyl ursolic acid (4), three flavonoids: apigenin-7-O-rutinoside (5), luteolin (8), diosmetin (9) and two phenolic acids: rosmarinic acid (6), methyl rosmarinate (7). CONCLUSION: The Ethyl acetate extract of D. heterophyllum had the highest anti-hepatitis and antioxidants activities, followed by petroleum ether extract. The bioactive substances may be triterpenes, flavonoids and phenolic acids, the ethyl acetate extracts of D. heterophyllum may be possible candidates in developing anti hepatitis medicine. PMID- 28597427 TI - Morphological and physiological responses of Heteropogon contortus to drought stress in a dry-hot valley. AB - BACKGROUND: Heteropogon contortus is a valuable pasture species that is widely used for vegetation restoration in dry-hot valleys of China. However, to date, its morphological and physiological responses to drought, and the underlying mechanisms are not well understood. This study was aimed to investigate the morphological and physiological changes of H. contortus under drought stress during the dry-hot season. Heteropogon contortus was planted in pots and subjected to four levels of soil water treatments: above 85 % (control), 70-75 % (light stress), 55-60 % (moderate stress) or 35-40 % (severe stress) of field capacity. RESULTS: Within the total stress period (0-29 days), H. contortus grew rapidly in the light stress, whereas severe stress had a negative impact on growth. Aboveground biomass decreased together with increasing drought stress, whereas root biomass increased. Consequently, the root/shoot ratio of the severe stress treatment increased by 80 % compared to that of the control treatment. The ratio of bound water/free water (BW/FW) was the most sensitive parameter to drought and showed a value under severe stress that was 152.83 % more than that in the control treatment. Although leaf water potential (LWP) and leaf relative water content (RWC) decreased with progressive water stress, H. contortus managed to maintain a relatively high RWC (nearly 70 %) in the severe stress condition. We also detected a significant reduction (below 0.6) in the ratio of variable fluorescence/maximum fluorescence (Fv/Fm) in the severe stress treatment. CONCLUSIONS: Our results show that H. contortus adapts to drought mainly by avoidance mechanisms, and its morphological and physiological characteristics are inhibited under severe stress, but can recover at a certain time after re watering. These findings might help limited water resources to be fully used for vegetation management in the studied region. PMID- 28597428 TI - Mapping quantitative trait loci for fruit traits and powdery mildew resistance in melon (Cucumis melo). AB - BACKGROUND: Fruit characters affect consumer preferences and the market value of melons is determined by fruit quality. Most fruit quality-related traits are controlled by multiple genes, and are influenced by environmental factors. Furthermore, powdery mildew is another limiting factor in melon production. To develop new melon cultivars with disease resistance and high quality fruits using the molecular marker-assisted breeding strategy, identification of quantitative trait loci for fruit quality and disease resistance is required. RESULTS: The F2 populations from the cross of TARI-08874 (Cucumis melo ssp. melo) and 'Bai-li gua' (C. melo ssp. agrestis) were used to map the quantitative trait loci (QTLs) for fruit-related traits and powdery mildew resistance in two trials. All traits were significantly different (P < 0.05) between parents. The generated linkage map consisted of twelve major linkage groups (LGs), spanning 626.1 cM in total, with an average distance of 8.3 cM between flanking markers. Nineteen QTLs were detected for seven melon traits, among which ten QTLs were localized to the same positions as the corresponding QTLs described in other studies. Four of these QTLs were detected in both trials. The results of identified QTLs in this study suggested that fruit size in the tested populations were mainly determined by fruit diameter and flesh thickness. All of the major QTLs for fruit diameter and flesh thickness were identified on LG5 and LG11. Four QTLs identified responsible for netting width of fruit rind were co-localized with the QTLs for netting density, suggesting similar genetic mechanisms affecting these two traits. Additionally, only one major QTL for powdery mildew resistance was detected on LG2, and it was closely linked to a simple sequence repeat (SSR) marker CMBR120 which was identified in a previous study. CONCLUSION: Because the netting feature is a crucial factor for external appearance of fruits in Asia market, we focus on mining the genetic information of fruit netting. This is the first report of QTL mapping to netting width. Furthermore, new QTLs were identified for netting density (qND4, qND6, and qND7) and netting width (qNW2, qNW4, qNW6, and qNW7) successfully. In addition, novel QTLs for fruit diameter (qFD5), flesh thickness (qFT11) were also detected. PMID- 28597429 TI - Embryology of two mycoheterotrophic orchid species, Gastrodia elata and Gastrodia nantoensis: ovule and embryo development. AB - BACKGROUND: Gastrodia elata, a famous herbal medicine, has been received great attention on its treatments of headache, vertigo and epilepsy. Gastrodia nantoensis is a newly described species from central Taiwan with potential medicinal value. Gastrodia species are fully mycoheterotrophic orchids, and the courses of their seed development are more rapid as compared to the chlorophyllous orchids. A better understanding of their reproductive biology would provide insights into the propagation and conservation of the mycoheterotrophic orchid species. RESULTS: Based on the histological and histochemical investigations, we observed some notable features in ovule and embryo development. First, only the archesporial cell and/or megasporocyte are present within their ovaries at the time of anthesis. Second, their suspensors consist of a single cell and their mature embryos consist of a gradient of small to large cells. Nile red staining of a globular embryo reveals the presence of cuticular material in the surface wall of embryo proper and the lateral walls of suspensor cell, indicating that the basal wall of suspensor cell is the major route for nutrient supply from maternal tissues to embryo proper. Third, their seed coats are derived from a single integument, and lignin but not cuticular material is present in the outer most layer of seed coat and persists through seed maturation. CONCLUSIONS: The faster seed development of Gastrodia species is due to the speedy courses of ovule and embryo development. In the mature seeds, the presence of a differentiated apical zone in embryo proper suggests the easy to-germinate character. This study provides basic knowledge for further molecular studies on embryo development and symbiotic germination of Gastrodia species. PMID- 28597430 TI - Identification of drought stress related proteins from 1Sl(1B) chromosome substitution line of wheat variety Chinese Spring. AB - BACKGROUND: Wheat, one of the most important crops, has a detrimental effect on both yield and quality under drought stress. As our preliminary experiment showed that the Chinese Spring wheat-Aegilops longissima chromosome substitution line CS 1Sl (1B) had a better drought tolerance than CS, the substitution line CS-1Sl(1B) was used to identify drought stress related proteins by means of a comparative proteome approach in this work. Our present study aimed to explore the gene resources for drought resistance in 1Sl genome. RESULT: Our results showed that drought stress induced downregulation of relative water and chlorophyll contents and the upregulation of proline content, and further influencing grain filling shortening and significant decrease of plant height, B-type starch granule numbers, grain number and weight. In total, 25 grain albumin and globulin protein spots were found to be specifically encoded by the 1Sl chromosome. In addition, 17 protein spots respected 13 unique proteins were identified by MALDI-TOF/TOF MS, which were mainly involved in adverse defense and gluten quality. Among them, ascorbate peroxidase, serpin-Z2B and alpha-amylase/trypsin inhibitor were upregulated under drought stress. These proteins play important roles in plant drought defenses through various metabolic pathways. CONCLUSION: Our results indicate that the 1Sl chromosome of Aegilops longissima has potential gene resources that could be useful for improving wheat drought resistance. PMID- 28597431 TI - Antioxidant responses and photosynthetic behaviors of Kappaphycus alvarezii and Kappaphycus striatum (Rhodophyta, Solieriaceae) during low temperature stress. AB - BACKGROUND: Kappaphycus are farmed in tropical countries as raw material for carrageenan, which is widely used in food industry. The sea area available for farming is one limiting factor in the production of seaweeds. Though cultivation is spreading into subtropical regions, the lower seawater temperature is an important problem encountered in subtropical regions for the farming of Kappaphycus. This research of physiological response to low temperature stress will be helpful for screening Kappaphycus strains for growth in a lower temperature environment. RESULTS: Responses of antioxidant systems and photosystem II (PSII) behaviors in Kappaphycus alvarezii and Kappaphycus striatum were evaluated during low temperature treatments (23, 20, 17 degrees C). Compared with the controls at 26 degrees C, the H2O2 concentrations increased in both species when the thalli were exposed to low temperatures (23, 20, 17 degrees C), but these increases were much greater in K. striatum than in K. alvarezii thalli, suggesting that K. striatum suffered more oxidative stress. The activities of some important antioxidant enzymes (e.g. superoxide dismutase and ascorbate peroxidase) and the hydroxyl free radical scavenging capacity were substantially higher at 23, 20 and 17 degrees C than at the control 26 degrees C in K. alvarezii, indicating that the antioxidant system of K. alvarezii enhanced its resistance to low temperature. However, no significant increases of antioxidant enzymes activities were observed at 20 and 17 degrees C in K. striatum. In addition, both the maximal efficiency of PSII photochemistry (FV/Fm) and the performance index (PIABS) decreased significantly in K. striatum at 23 degrees C, indicating that the photosynthetic apparatus was damaged at 23 degrees C. In contrast, no significant decreases of either FV/Fm or PIABS were observed in K. alvarezii at 23 degrees C. CONCLUSIONS: It is concluded that K. alvarezii has greater tolerance to low temperature than K. striatum. PMID- 28597432 TI - Harpin Hpa1 promotes flower development in Impatiens and Parochetus plants. AB - BACKGROUND: The harpin protein Hpa1 has multiple beneficial effects in plants, promoting plant growth and development, increasing crop yield, and inducing plant resistance to pathogens and insect pests. In these effects, the 10-40 residue fragment (Hpa110-42) isolated from the Hpa1 sequence is 1.3 to 7.5-fold more effective than the full length. RESULTS: This study extends the beneficial effects of Hpa1 and Hpa110-42 to flower development in three species of the garden balsam Impatiens and the garden scoparius Parochetus communis plant. The external application of Hpa1 or Hpa110-42 to the four ornamental plants had three effects, i.e., promoting flower growth, retarding senescence of fully expanded flowers, and increasing anthocyanin concentrations in those flowers and therefore improving their ornamental visages. Based on quantitative comparisons, Hpa110-42 was at least 17 and 42 % more effective than Hpa1 to increase anthocyanin concentrations and to promote the growth of flowers or delay their senescence. CONCLUSION: Our results suggest that Hpa1 and especially Hpa110-42 have a great potential of horticultural application to increase ornamental merits of the different garden plants. PMID- 28597433 TI - Interspecific associations of dominant tree populations in a virgin old-growth oak forest in the Qinling Mountains, China. AB - BACKGROUND: Understanding interspecific associations in old-growth forests will help to reveal mechanisms of interspecific replacement in the process of forest development and provide a theoretical basis for vegetation restoration and reestablishment. In this study, we analyzed interspecific associations of eleven dominant tree populations of varying development stages in an old-growth oak forest stand in the Qinling Mountains, China. We examined overall interspecific associations (multiple species) and pairwise interspecific associations (two species). RESULTS: Interspecific competition was intense during forest development and was the main factor driving succession. Community structure appears to become more stable over time which supports the harsh-benign hypothesis that interspecific competition is more common in stable sites. CONCLUSION: Old growth oak (Quercus spp.) forests are distributed widely around the world in part due to oak being a typical K-selected species. K-selected species produce fewer, high-quality offspring with higher survival rates, strong competitive ability, and longevity. The resulting distribution shifted from clumped to random, likely as a result of intense interspecific competition creating ecological niche differentiation. PMID- 28597434 TI - Ectopic expression of Lc differentially regulated anthocyanin biosynthesis in the floral parts of tobacco (Nicotiana tobacum L.) plants. AB - BACKGROUND: Anthocyanins are the conspicuous pigments of flowering plants and participate in several aspects of plant development and defense, such as seeds and pollens dispersal. Leaf colour (Lc) is the first basic/helix-loop-helix (bHLH) transcription factor controlling anthocyanin biosynthesis isolated from maize (Zea mays L.). Ectopic expression of maize Lc enhanced anthocyanin biosynthesis in many plants including tobacco (Nicotiana tobacum L.). However, the molecular regulatory mechanism of anthocyanin biosynthesis in the different floral parts of tobacco remains largely unknown. Therefore, the molecular and biochemical characterization of anthocyanin biosynthesis were investigated in the flowers of both wild type and Lc-transgenic tobacco plants. RESULTS: At the reproductive stage, with respect to the different parts of the flowers in wild type SR1, the calyxes and the pistils were green, and the petals and the filaments showed light pink pigmentation; the Lc-transgenic tobacco exhibited light red in calyxes and crimson in petals and in filaments respectively. Correspondingly, the total anthocyanin contents (TAC) in calyxes, petals and filaments of Lc-transgenic plants were much higher than that of the counterparts in SR1. Though the TAC in anthers of Lc-transgenic plants was low, it was still significantly higher than that of SR1. SR1 has almost the same TAC in the pistils as Lc-transgenic plants. Consistent with the intense phenotype and the increased TAC, Lc was weakly expressed in the calyxes and strongly expressed in petals and filaments of Lc-transgenic plants, while Lc was not detected in SR1. The expression level of NtAN2 in petals was similar between SR1 and Lc-transgenic lines. In agreement with the expression profile of Lc, both early (NtCHS) and late anthocyanin-biosynthetic genes (NtDFR, NtF3'H, and NtANS) were coordinately up-regulated in the counterparts of flowers. HPLC analysis demonstrated that the cyanidin (Cya) deposition was mainly responsible for the intense pigmentation of Lc-transgenic tobacco. CONCLUSIONS: Ectopic expression of Lc greatly enhanced both early- and late- anthocyanin-biosynthetic gene expression, and therefore resulted in the Cya-based TAC increase in the calyxes, the filaments and the petals in tobacco plants. PMID- 28597435 TI - Micro-morphological study of Evolvulus spp. (Convolvulaceae): the old world medicinal plants. AB - BACKGROUND: Several medicinal properties have been reported for plants in the genus Evolvulus, such as a brain tonic and antifungal from Evolvulus alsinoides, and a sedative and an anthelmintic from Evolvulus nummularius. Therefore, the correct identification of the source plants is critically important. The aim of this research was to investigate the micromorphology of two Evolvulus taxa used for herbal medicines compared with one worldwide ornamental species by using peeling, paraffin embedding, acetolysis, and SEM methods in order to support species identification. RESULTS: Our findings indicate that all taxa share several common features, such as a single layer of epidermis on both sides of leaf surfaces, sinuous anticlinal epidermal cell walls, anomocytic, paracytic or laterocytic stomata, and capitate glandular trichomes. Y-shaped hairs were found in two species but not in E. nummularius. Similarly, isobilateral mesophyll occurs in both E. alsinoides and Evolvulus glomeratus, but a dorsiventral mesophyll is present in E. nummularius. Stems consist of a single layer of epidermis, one to four chlorenchyma layers, one to seven layers of cortical cells and a bicollateral bundle with pith in the center. The seed coat epidermal cell shapes were irregular or polygonal with raised and undulated anticlinal boundaries, and folded or flattened to concave periclinal walls. Pollens of all taxa are monads, spheroidally shaped with 28-47 um diameter, and 15-pantocolpate apertures type with microechinate ornamentation. CONCLUSIONS: An identification key to species is constructed based on leaf anatomy and seed coat characters. This data can be used in other subjects such as pharmaceutical botany, organic chemistry, taxonomy and horticulture, in terms of species identification. PMID- 28597436 TI - Activity and expression of ADP-glucose pyrophosphorylase during rhizome formation in lotus (Nelumbo nucifera Gaertn.). AB - BACKGROUND: Lotus root is a traditional and popular aquatic vegetable in China. Starch is an important component of the rhizome and directly affects the quality of processed products. ADP -glucose pyrophosphorylase (AGPase) is a rate-limiting enzyme associated with starch biosynthesis in plants. Therefore, in the present study, AGPase activity and NnAGP expression during rhizome development of lotus were analyzed. RESULTS: Among 15 cultivars analyzed, the contents of amylose and total starch in the rhizome were highest in 'Mei Ren Hong'. 'Su Zhou' and 'Zhen Zhu' showed the lowest amylose, amylopectin and total starch contents. In the rhizome, activity of AGPase was highest at the middle swelling stage of development, and higher activity was observed in the 'Hou ba' leaf and terminational leaf at the same stage. Three AGPase genes, comprising two large subunit genes (NnAGPL1 and NnAGPL2) and one small subunit gene (NnAGPS), were isolated and identified. The deduced amino acid sequences showed 40.5 % similarity among the three genes. Full-length genomic DNA sequences of NnAGPL1, NnAGPL2, and NnAGPS were 4841, 11,346 and 4169 bp, respectively. Analysis of the temporal and spatial expression patterns revealed that the transcription levels of NnAGPL1 and NnAGPS were higher in the rhizome, followed by the 'Hou ba' leaf, whereas NnAGPL2 was significantly detected in the 'Hou ba' leaf and terminational leaf. The initial swelling stage of rhizome development was accompanied by the highest accumulation of mRNAs of NnAGPL1, whereas expression of NnAGPL2 was not detected during rhizome development. The transcript level of NnAGPS was highest at the initial swelling stage compared with the other rhizome developmental stages. Transcription of NnAGPL1, NnAGPL2, and NnAGPS was induced within 24 h after treatment with exogenous sucrose. The mRNA level of NnAGPL1 and NnAGPS was increased by exogenous ABA, whereas transcription of NnAGPL2 was not affected by ABA. CONCLUSIONS: The three AGPase genes display marked differences in spatial and temporal expression patterns. Regulation of AGPase in relation to starch synthesis in lotus is indicated to be complex. PMID- 28597437 TI - Salt tolerance of a wild ecotype of vetiver grass (Vetiveria zizanioides L.) in southern China. AB - BACKGROUND: Vetiver grass (Vetiveria zizanioides L.) is widely used in more than 120 countries for land management (e.g. rehabilitation of saline lands). A wild ecotype of vetiver grass was found in southern China in the 1950s, but little is known about its adaptability to saline stress. For the purpose of understanding its tolerance to salinity as well as corresponding tolerance mechanisms, in a greenhouse with natural lighting, seedlings were grown in culture solutions and subjected to a range of NaCl concentrations for 18 days. RESULTS: Compared to no NaCl treatment, 200 mM NaCl significantly reduced leaf water potential, leaf water content, leaf elongation rate, leaf photosynthetic rate and plant relative growth rate and increased leaf malondialdehyde (MDA) content, but the parameters showed only slight reduction at 150 mM NaCl. In addition, salinity caused an increase in the activity of antioxidant enzymes in leaves. Moreover, increasing NaCl levels significantly increased Na+ but decreased K+ concentrations in both roots and leaves. The leaves had higher K+ concentrations at all NaCl levels, but lower Na+ concentrations compared to the roots, thereby maintaining higher K+/Na+ ratio in leaves. CONCLUSIONS: Our results showed that the salinity threshold of this wild vetiver grass is about 100 mM NaCl, i.e. highly tolerant to salt stress. This wild vetiver grass has a high ability to exclude Na+ and retain K+ in its leaves, which is a critical strategy for salt tolerance. PMID- 28597439 TI - Erratum to: Micro-morphological study of Evolvulus spp. (Convolvulaceae): the old world medicinal plants. PMID- 28597438 TI - Effect of light regime and provenance on leaf characteristics, growth and flavonoid accumulation in Cyclocarya paliurus (Batal) Iljinskaja coppices. AB - BACKGROUND: As a highly valued and multiple function tree species, Cyclocarya paliurus is planted and managed for timber production and medical use. However, limited information is available on its genotype selection and cultivation for growth and phytochemicals. Responses of growth and secondary metabolites to light regimes and genotypes are useful information to determine suitable habitat conditions for the cultivation of medicinal plants. RESULTS: Both light regime and provenance significantly affected the leaf characteristics, leaf flavonoid contents, biomass production and flavonoid accumulation per plant. Leaf thickness, length of palisade cells and chlorophyll a/b decreased significantly under shading conditions, while leaf areas and total chlorophyll content increased obviously. In the full light condition, leaf flavonoid contents showed a bimodal temporal variation pattern with the maximum observed in August and the second peak in October, while shading treatment not only reduced the leaf content of flavonoids but also delayed the peak appearing of the flavonoid contents in the leaves of C. paliurus. Strong correlations were found between leaf thickness, palisade length, monthly light intensity and measured flavonoid contents in the leaves of C. paliurus. Muchuan provenance with full light achieved the highest leaf biomass and flavonoid accumulation per plant. CONCLUSIONS: Cyclocarya paliurus genotypes show diverse responses to different light regimes in leaf characteristics, biomass production and flavonoid accumulation, highlighting the opportunity for extensive selection in the leaf flavonoid production. PMID- 28597440 TI - Efficient and heritable transformation of Phalaenopsis orchids. AB - BACKGROUND: Phalaenopsis orchid (Phal. orchid) is visually attractive and it is important economic floriculture species. Phal. orchids have many unique biological features. However, investigation of these features and validation on their biological functions are limited due to the lack of an efficient transformation method. RESULTS: We developed a heritable and efficient Agrobacterium- mediated transformation using protocorms derived from tetraploid or diploid Phal. orchids. A T-DNA vector construct containing eGFP driven by ubiquitin promoter was subjected to transformation. An approximate 1.2-5.2 % transformation rate was achieved. Genomic PCR confirmed that hygromycin selection marker, HptII gene and target gene eGFP were integrated into the orchid genome. Southern blotting indicated a low T-DNA insertion number in the orchid genome of the transformants. Western blot confirmed the expression of eGFP protein in the transgenic orchids. Furthermore, the GFP signal was detected in the transgenic orchids under microscopy. After backcrossing the pollinia of the transgenic plants to four different Phal. orchid varieties, the BC1 progenies showed hygromycin resistance and all surviving BC1 seedlings were HptII positive in PCR and expressed GFP protein as shown by western blot. CONCLUSIONS: This study demonstrated a stable transformation system was generated for Phal. orchids. This useful transformation protocol enables functional genomics studies and molecular breeding. PMID- 28597441 TI - Accumulation of catechins and expression of catechin synthetic genes in Camellia sinensis at different developmental stages. AB - BACKGROUND: Catechins are the main polyphenol compounds in tea (Camellia sinensis). To understand the relationship between gene expression and product accumulation, the levels of catechins and relative expressions of key genes in tea leaves of different developmental stages were analyzed. RESULTS: The amounts of catechins differed significantly in leaves of different stages, except for gallocatechin gallate. Close correlations between the expression of synthesis genes and the accumulation of catechins were identified. Correlation analysis showed that the expressions of chalcone synthase 1, chalcone synthase 3, anthocyanidin reductase 1, anthocyanidin reductase 2 and leucoanthocyanidin reductase genes were significantly and positively correlated with total catechin contents, suggesting their expression may largely affect total catechin accumulation. Anthocyanidin synthase was significantly correlated with catechin. While both ANRs and LAR were significantly and positively correlated with the contents of (-)-epigallocatechin gallate and (-)-epicatechin gallate. CONCLUSION: Our results suggest synergistic changes between the expression of synthetic genes and the accumulation of catechins. Based on our findings, anthocyanidin synthase may regulate earlier steps in the conversion of catechin, while the anthocyanidin reductase and leucoanthocyanidin reductase genes may both play important roles in the biosynthesis of galloylated catechins. PMID- 28597442 TI - Effects of adjacent land-use types on the distribution of soil organic carbon stocks in the montane area of central Taiwan. AB - BACKGROUND: Soil organic carbon (SOC) stocks can be altered through reforestation and cropping. We estimated the effects of land use on SOC stocks after natural deciduous forests replaced by crops and coniferous plantations by examining the vertical distribution of SOC stocks at different depth intervals in an adjacent Oolong tea (Camellia sinensis L.) plantation, Moso bamboo (Phyllostachys pubescens) forest, Japanese cedar (Cryptomeria japonica) forest, and Taiwania (Taiwania cryptomerioides) forest in central Taiwan. The main soil characteristics, soil nitrogen (N) content, and soil carbon to nitrogen (C/N) ratio were also determined. RESULTS: Different land uses resulted in significantly higher bulk density, lower cation exchange capacity, SOC, soil N, soil C/N ratio, and SOC stocks in croplands compared to forestlands. Due to the long-term application of chemical fertilizers, a significantly lower soil pH was found in the tea plantation. Croplands had a lower soil C/N ratio because of less C input into the soil and a higher mineralization rate of organic carbon during cultivation. Similar SOC stocks were found in Taiwania and Japanese cedar forests (148.5 and 151.8 Mg C ha-1, respectively), while the tea plantation had comparable SOC stocks to the bamboo forest (101.8 and 100.5 Mg C ha-1, respectively). Over 40% of SOC stocks was stored in croplands and over 56% was stored in forestland within the upper 10 cm of soil. CONCLUSIONS: Coniferous plantations can contribute to a higher SOC stock than croplands, and a significant difference can be found in the top 0-5 cm of soil. PMID- 28597443 TI - Phenologic variation of major triterpenoids in regular and white Antrodia cinnamomea. AB - BACKGROUND: Antrodia cinnamomea and its host Cinnamomum kanehirae are both endemic species unique to Taiwan. Many studies have confirmed that A. cinnamomea is rich in polysaccharides and triterpenoids that may carry medicinal effects in anti-cancer, anti-inflammation, anti-hypertension, and anti-oxidation. Therefore it is of interest to study the chemical variation of regular orange-red strains and white strains, which included naturally occurring and blue-light induced white A. cinnamomea. RESULTS: The chemical profiles of A. cinnamomea extracts at different growth stages were compared using thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). The TLC and HPLC profiles indicated that specific triterpenoids varied between white and regular strains. Moreover, the compounds of blue-light induced white strain were similar to those of naturally occurring white strain but retained specific chemical characteristics in more polar region of the HPLC chromatogram of regular strain. CONCLUSIONS: Blue-light radiation could change color of the regular A. cinnamomea from orange-red to white by changing its secondary metabolism and growth condition. Naturally occurring white strain did not show a significantly different composition of triterpenoid profiles up to eight weeks old when compared with the triterpenoid profiles of the regular strain at the same age. The ergostane-type triterpenoids were found existing in both young mycelia and old mycelia with fruiting body in artificial agar-plate medium culture, suggesting a more diversified biosynthetic pathway in artificial agar-plate culture rather than wild or submerged culture. PMID- 28597444 TI - Endoreduplication as a part of flower ontogeny in Trifolium pratense cultivars. AB - BACKGROUND: Endoreduplication appears in numerous plant species and plays a vital role during ontogeny. The presence of polyploid cells in an otherwise diploid organism is tied specifically to the taxonomy, ecology and physiology of the studied specimen. Little is known about the changes in endopolyploidy levels of floral organs during their development. In order to uncover the workings of endoreduplication in polysomatic species, our study examines flowers of T. pratense in three ontogenetic stages by means of flow cytometry. RESULTS: Cultivar 'Manuela' is characterized by the presence of 2C-8C and 'Dajana' 2C-16C nuclei. In general, the frequencies of nuclei only slightly changed during development. Endopolyploidy levels represented by endoreduplication index (EI) in the 'Manuela' sepals and stamens showed statistical differences between young and old stages, other organs of both cultivars between stages are not statistically different. Significant differences between 'Manuela' and 'Dajana' cultivars were found only in sepals of I. stage, and in petals and carpels of III. stage. Cultivars showed a similar pattern of endopolyploidy. However, a considerable decrease in EI 'Manuela' petals and carpels at III. stage was detected as opposed to 'Dajana'. Overall, a higher endoreduplication index is distinctive for organs of the 'Dajana' cultivar. CONCLUSIONS: In this study we prove the permanent presence of endopolyploid cells in the floral organs of T. pratense throughout their development. PMID- 28597445 TI - Developmental program impacts phenological plasticity of spring wheat under drought. AB - BACKGROUND: Developing drought-tolerant crops critically depends on the efficient response of a genotype to the limited water availability, a trait known as phenological plasticity. Our understanding of the phenological plasticity remains limited, in particular, about its relationships with plant developmental program. Here, we examined the plastic response of spring wheat at tillering, booting, heading, and anthesis stages to constant or periodic drought stress. The response was assessed by morphological and physiological parameters including symptoms. RESULTS: The dynamics of morphological symptoms were indicators of the plasticity identification of drought. We found that spring wheat exhibits higher phenological plasticity during tillering stage followed by the heading stage, while booting and anthesis stages are the most sensitive. Also, the adaptive response is thought to be influenced with the plant height genes. Furthermore, periodic stress caused more pronounced inhibition of yield than the constant stress, with limited resistance resolution under long period. CONCLUSIONS: Our study shows the importance of considering the phenological plasticity in designing screens for drought tolerance in spring wheat and proposes tillering as the most informative stage for capturing genotypes with tolerance to limit water availability. PMID- 28597446 TI - Ontogenetic characterization of sporangium and spore of Huperzia serrata: an anti aging disease fern. AB - BACKGROUND: Huperzia serrata is a medicinal plant used in Traditional Chinese Medicine, which has been used to prevent against aging diseases. It is mainly propagated by spores and grows extremely slowly. Due to severe harvest, it is a highly endangered species. In this report, we characterize ontogenesis of sporangia and spores that are associated with propagation. A wild population of H. serrata plants is localized in western Hunan province, China and protected by Chinese Government to study its development (e.g. sporangia and spores) and ecology. Both field and microscopic observations were conducted for a few of years. RESULTS: The development of sporangia from their initiation to maturation took nearly 1 year. Microscopic observations showed that the sporangial walls were developed from epidermal cells via initiation, cell division, and maturation. The structure of the mature sporangial wall is composed of one layer of epidermis, two middle layers of cells, and one layer of tapetum. Therefore, the sporangium is the eusporangium type. Spore development is characterized into six stages, initiation from epidermal cell and formation of sporogenous cells, primary sporogenous cell, secondary sporogenous cell, spore mother cell, tetrad, and maturation. CONCLUSION: The sporangial development of H. serrata belongs to the eusporangium type. The development takes approximately 1 year period from the initiation to the maturation. These data are useful for improving propagation of this medicinal plant in the future. PMID- 28597447 TI - Carbon dioxide assimilation and photosynthetic electron transport of tea leaves under nitrogen deficiency. AB - BACKGROUND: Tea plant is famed in humid and sub-humid of tropical regions, sub tropical regions, and is a leaf-harvested crop. Nitrogen is the most important nutrient for increasing quality of tea leaves. Therefore, large amounts of nitrogen fertilizer are increasingly applied by tea farmers. Appropriate application of nitrogen fertilizer aroused people's concern. This research of physiological response to N deficiency stress will be helpful for appropriate application of nitrogen fertilizer for tea farmers and elucidate a mechanistic basis for the reductions in carbon dioxide (CO2) assimilation. RESULTS: To elucidate a mechanistic basis for the reductions in carbon dioxide (CO2) assimilation under nitrogen (N) deficiency tea leaves, changes in chlorophyll (Chl), carbohydrates, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) and chlorophyll fluorescence transient were examined together with six N treatment (0, 50, 100, 300, 1200 or 6000 MUM N). Root, stem and leaves dry weight (DW) increased as N supply increased from 0 to 300 MUM, then remained unchanged. The reductions in CO2 assimilation of N-deficient leaves paralleled with high intercellular CO2 concentration. Rubisco activity, protein and Chl content increased linearly or curvilinearly over the range of leaf N content examined except unchanged as leaf N from 2.15 to 2.79 g m-2. Chlorophyll fluorescence transient from N-deficient leaves displayed a depression at the P-step, accompanied by a new step at about 150 MUs (L-step). Fv/Fm, REo/ETo, ETo/ABS, Sm, ETo/CSo, PIabs, PItot, abs, were decreased in N-deficient leaves but increased DIo/CSo, DIo/RC and DIo/ABS. Regressive analysis showed that CO2 assimilation decreased linearly or curvilinearly with decreasing initial rubisco, PIabs and Leaf Chl, respectively. Therefore, we concluded the decreased photosynthetic electron transport capacity, leaf chl content and initial rubisco activity are probably the main factors contributing to decreased CO2 assimilation under N deficiency. CONCLUSIONS: The decreased photosynthetic electron transport capacity, leaf Chl content and initial rubisco activity are probably the main factors contributing to decreased CO2 assimilation under N deficiency. PMID- 28597448 TI - Antioxidants, anti-inflammatory, and antidiabetic effects of the aqueous extracts from Glycine species and its bioactive compounds. AB - BACKGROUND: The aim of this study was to examine the possible antioxidant, anti inflammatory, and antidiabetic effects of the aqueous extracts from three Glycine species. In HPLC analysis, the chromatograms of three Glycine species were established. Flavonoid-related compounds might be important bioactive compounds in Glycine species. RESULTS: The results showed that the aqueous extract of Glycine tabacina (AGTa) had the strongest antioxidant activity compared with the other Glycine species extracts. We also found that AGTa had higher contents of total polyphenol compounds and flavonoids than the other extracts. We also have investigated the anti-inflammatory effects of the three Glycine species using lipopolysaccharide (LPS)-stimulated mouse macrophage (RAW264.7) ex vivo. When RAW264.7 macrophages were treated with different concentrations of three Glycine species together with LPS, a significant concentration-dependent inhibition of NO production was detected. The aqueous extract of Glycine max (AGM) had the strongest anti-inflammatory activity in comparison with the other Glycine species extracts. Western blotting revealed that three Glycine species blocked protein expression of iNOS and cyclooxygenase-2 (COX-2) in LPS-stimulated RAW264.7 macrophages, significantly. The antidiabetic activities of the three Glycine species were studied in vitro using alpha-glucosidase and aldose reductase (AR) inhibitory methods. AGTa had the highest inhibitory activities on alpha glucosidase and aldose reductase, with IC50 of 188.1 and 126.42 MUg/mL, respectively. The bioactive compounds, genistein and daidzein, had high inhibitory activities on antioxidant, anti-inflammatory, alpha-glucosidase and aldose reductase. CONCLUSIONS: These results suggest that Glycine species might be a good resource for future development of antioxidant, anti-inflammatory and antidiabetic heath foods. PMID- 28597449 TI - Physiological targets of salicylic acid on Artemisia aucheri BOISS as a medicinal and aromatic plant grown under in vitro drought stress. AB - BACKGROUND: Artemisia aucheri BOISS is a medicinal and aromatic plant, which is endemic to mountainous areas of Iran and surroundings. In this study, we investigated the alleviating effects of salicylic acid (SA) pretreatment (0.01 and 0.1 mM) on A. aucheri under in vitro drought stress induced by 2 and 4% polyethylene glycol (PEG/6000). RESULTS: Plants exposed to PEG stress showed higher levels of H2O2, MDA and electrolyte leakage compared with control. While SA pretreatment decreased these parameters under PEG stress significantly. The activity of CAT, POD, APX, SOD and GR positively changed with PEG and more induction in activity of antioxidant enzymes was observed in SA-pretreated plants under PEG stress. Furthermore, ASA, GSH and their redox ratios (ASC/DHA and GSH/GSSG) enhanced with SA pretreatments. Analysis of our data revealed that MDA, DHA and H2O2 were the best targets for SA under in vitro PEG treatment for A. aucheri plants. CONCLUSIONS: Salicylic acid as a signal molecule mitigated adverse effects of PEG-simulated drought stress on A. aucheri under in vitro condition by improving the activity of antioxidant enzymes. In addition, protective role of SA was also related to promotion of ascorbate-glutathione cycle. PMID- 28597451 TI - [Outcomes vs. Attributable Outcomes: Rational Choice Theory Must Take a Stance Towards Action Theory]. AB - The reply concentrates on advancing again my third thesis, which has not directly been taken up by Breyer and Kliemt. The thesis says that both criticisms against the Rule of Rescue - the irrationality objection, which Breyer and Kliemt try to defend, and the objection that the Rule is discriminatory, which they do not defend - are the results of insufficient action-theoretical reflection. I argue that Breyer's and Kliemt's objection to the Rule, unstable as it is in their comment, is not even clearly identifiable if they do not take a stance towards the central question: Do they want to - and, if so, can they consistently - incorporate people's interest in taking account of the attributability of an outcome to a decision maker into their utility concept? PMID- 28597450 TI - Effect of Visible Light on Vasospasticity of Post-Subarachnoid Hemorrhage Cerebrospinal Fluid. AB - Background and Objective Cerebral vasospasm (CV) is a serious complication of subarachnoid hemorrhage (SAH) with high morbidity and mortality rates. The mechanism of CV has not been determined. There are many theories related to this unsolved issue, one of which supports CV as a two-stage phenomenon from a pathophysiologic perspective. The first stage consists of inhibition of neuronal nitric oxide synthase by oxyhemoglobin, which results in a decrease of nitric oxide (NO) production. The second stage consists of an increase in the levels of asymmetric dimethylarginine through bilirubin oxidation products (BOXes), which are oxidized by-products of hemoglobin metabolism. These in turn inhibit endothelial nitric oxide synthase (eNOS), which results in the blockage of the second NO production mechanism. BOXes are sensitive to visible light, as is their precursor bilirubin. The hypothesis of CV prevention using the photosensitivity of BOXes was tested in this study. Material and Methods Cerebrospinal fluid (CSF) obtained from two patients with SAH was divided in half and either exposed to a standard dose of visible light or not exposed to any light. The CSF was spectrophotometrically investigated and the concentration of BOXes was measured. A comparison between CSF samples exposed to light and not exposed to light was made. Using two groups of 16 rats each, the vasospastic effect of the CSF exposed and not exposed to light on arteries of the cortical surface was measured. The cortex was exposed using the cranial window. Results Spectrophotometric analysis revealed that the concentration of BOXes in the CSF decreased significantly after being exposed to visible light (p < 0.001). There was a significant difference of the vasospastic effect of CSF on exposed cortical arteries (p < 0.001). Conclusion The concentration of BOXes and the vasospastic effect of CSF taken from patients with SAH were significantly reduced after being exposed to visible light if compared with CSF not exposed to light. PMID- 28597452 TI - Impact of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio and the Hypertriglyceremic-Waist Phenotype to Predict the Metabolic Syndrome and Insulin Resistance. AB - Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations. PMID- 28597453 TI - The Association Between Normal Range TSH and Lipid Profile. AB - Dyslipidemia in thyroid dysfunction is mostly attributed to thyrotropin (TSH) levels, especially in subclinical disorders, but the exact role of TSH in dyslipidemia has not been explained. A total of 3 020 subjects who remained euthyroid in 3 phases of the Tehran Thyroid study were enrolled and divided according to quartiles of TSH as: Q1 (0.32-1.02), Q2 (1.02-1.53), Q3 (1.53-2.27), and Q4 (2.27-5.06). General Linear model was used to determine whether there was a significant correlation between subjects' lipid profile and quartiles of TSH from 1st to 2nd and from 1st to 3rd phase. Mean TC, LDL-C level and median TG were significantly higher for Q1 in all study phases. All lipid parameters of participants after 6 years (3rd phase study) except LDL-C were significantly varied in different TSH groups. Highest levels of TC, TG and HDL-C were observed in Q4. Thus, irrespective of TC and LDL-C in Q1 and Q4 (participants with the lowest and highest limit of TSH within the normal range), the difference in lipid parameters in middle of normal TSH range was not significant. Normal range TSH levels have a statistically significant effect on lipid profile, but the effect size is not clinically significant. PMID- 28597454 TI - Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A. AB - In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2-O-methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds (1, 4, and 6) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2-4. Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these (4 and 6) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results. PMID- 28597455 TI - Hereditary Neuropathies: Update 2017. PMID- 28597456 TI - [Hypothyreosis after Hemithyroidectomy - surprisingly frequent complication in aftercare]. AB - BACKGROUND: Hemithyroidectomy is a frequent treatment for thyroid nodules. Postoperative hypothyroidism is an often underestimated complication. We studied the incidence, time, symptoms and risk factors of postoperative hypothyroidism. MATERIAL AND METHODS: 127 Patients were analyzed in a retrospective chart review and with a structured assessment of the general practitioners and endocrinologists. Patients were classified according to the postoperative TSH as hypothyroid (>4.0 mU/L) or euthyroid (0.4-4.0 mU/L). Thyroid hormone was assessed at 4-6 Weeks, 6 months and 1 year. RESULTS: 55 patients (43 %) had postoperative hypothyroidism and 72 (57%) stayed euthyroid during follow up. The hypothyroidism occured during the first 2 months in 39 patients (71 %), between 2-6 months in 13 patients (24 %) and between 6-12 months in 3 patients (5 %). 33 patients (60 %) with hypothyroidism were asymptomatic and 16 patients (29 %) had symptoms. Preoperative TSH level was significantly higher in the hypothyroid group (1.64) compared to the euthyroid group (1.13, P = 0.0017). The other variables as age, gender, preoperative levels of T3, T4, Calcium and PTH showed no significant difference. CONCLUSION: Postoperative hypothyroidism is an important complication after hemithyroidectomy which should not be missed. Preoperative elevated TSH level is a riskfactor for postoperative hypothyroidism. All Patients after hemithyroidectomy should have postoperative TSH assessment after 4-6 weeks, 6 months and 12 months. PMID- 28597457 TI - Safeguarding Infant Brains: A Multidisciplinary Challenge-Results of a Survey, Update on Current Scientific Evidence, and Recommendations on How to Deal with Possible Anesthetic Drug Neurotoxicity. AB - INTRODUCTION: Potential neurotoxicity of anesthetic drugs has been among the most intensively discussed issue in pediatric anesthesia for more than 10 years. It remains unclear how far this discussion has reached the European pediatric surgical community. Our aim was to investigate the thoughts of pediatric surgeons regarding this topic. In addition, we provide an update on the current scientific evidence regarding neurotoxicity together with recommendations for clinical practice. MATERIALS AND METHODS: A web-based survey to assess the thoughts of practicing European pediatric surgeons regarding neurotoxicity and how it may have influenced their daily practice of pediatric surgery was launched via the European Pediatric Surgeons' Association Web site. RESULTS: A total of 72 responses could be analyzed. A majority of the respondents were interested in the topic but felt a need to further explore it. Thirty-one respondents have changed their daily practice of pediatric surgery due to potential anesthetic drug toxicity. Eighteen respondents reported to be concerned about neurotoxicity, 29 held a neutral position, and 8 were not concerned. Twenty-seven respondents found it a shared responsibility of the surgeon and the anesthesiologist to deal with the neurotoxicity issue. The majority of respondents found a necessity for further research on anesthetic drug neurotoxicity, assigning the highest priority to prospective longitudinal human studies and the lowest to animal studies. CONCLUSION: The neurotoxicity question has reached the pediatric surgical community. Currently available scientific data do not support the theory of anesthetic drug-induced neurotoxicity in young children. Recent interdisciplinary clinical research focuses on neurodevelopmental outcome after surgery in neonates and infants. The European Safe Anesthesia For Every Tot initiative suggests focusing on proper conduct of anesthesia in children rather than on possible anesthetic drug neurotoxicity. PMID- 28597458 TI - Clinical Scoring Systems in Thrombotic Microangiopathies. PMID- 28597460 TI - Thromboprophylaxis in Cancer Patients Undergoing Surgery. PMID- 28597459 TI - Novel (Oral) Anticoagulant Challenges in Surgery. PMID- 28597461 TI - Serum Concentration of Growth Differentiation Factor-15 Is Independently Associated with Global Platelet Function and Higher Fibrinogen Values in Adult Healthy Subjects. PMID- 28597463 TI - Hemostasis in Pediatric Cardiac Surgery. PMID- 28597464 TI - ? PMID- 28597462 TI - Heparin-Induced Thrombocytopenia in Cardiac Surgery Patients. PMID- 28597465 TI - ? PMID- 28597466 TI - Suppression of the vacuolar invertase gene delays senescent sweetening in chipping potatoes. AB - BACKGROUND: Potato chip processors require potato tubers that meet quality specifications for fried chip color, and color depends largely upon tuber sugar contents. At later times in storage, potatoes accumulate sucrose, glucose, and fructose. This developmental process, senescent sweetening, manifests as a blush of color near the center of the fried chip, becomes more severe with time, and limits the storage period. Vacuolar invertase (VInv) converts sucrose to glucose and fructose and is hypothesized to play a role in senescent sweetening. To test this hypothesis, senescent sweetening was quantified in multiple lines of potato with reduced VInv expression. RESULTS: Chip darkening from senescent sweetening was delayed by about 4 weeks for tubers with reduced VInv expression. A strong positive correlation between frequency of dark chips and tuber hexose content was observed. Tubers with reduced VInv expression had lower hexose to sucrose ratios than controls. CONCLUSION: VInv activity contributes to reducing sugar accumulation during senescent sweetening. Sucrose breakdown during frying may contribute to chip darkening. Suppressing VInv expression increases the storage period of the chipping potato crop, which is an important consideration, as potatoes with reduced VInv expression are entering commercial production in the USA. (c) 2017 Society of Chemical Industry. PMID- 28597468 TI - Interaction of anorexia and cultural beliefs in infant malnutrition in Mali. AB - Anorexia, the lack of a normal appetite or refusal to eat, has been reported among infants and young children worldwide. Many factors can contribute to anorexia, including a monotonous diet, chronic malnutrition, zinc deficiency, disease, anxiety, intestinal parasites, and sores in the mouth. At the same time, ethnographic research reveals wide variation in how, and to what extent, caretakers control food consumption (both quality and quantity) in infants generally, and how they deal with anorexia specifically. In some cultures, children are given considerable autonomy in deciding what and how much food to eat, even when anorectic. In other groups, Children's diets are closely monitored by adult caretakers and anorectic children are urged, or even forced, to eat. Theoretically, the potential for wildespread malnutrition and accompanying growth failure, even in the presence of adequate dietary resources, will be highest in populations which exhibit an interaction of (1) multiple conditions leading to anorexia and (2) cultural beliefs which allow children autonomy in food consumption decisions. Research in Mali provides examples of the potential consequences of the combination for child growth. PMID- 28597469 TI - Brief Reviews. PMID- 28597467 TI - Development of indicators for evaluating the appropriate use of triazoles for invasive fungal disease: A Delphi panel survey. AB - WHAT IS KNOWN AND OBJECTIVES: Triazoles including fluconazole, itraconazole, voriconazole and posaconazole are now widely used, whereas in some countries, they are reportedly used in inappropriate way frequently; thus, it is clearly a matter of urgency to regulate the use of triazole drugs. Several studies have made good attempts to evaluate antifungal use, but they did not cover the entire medication process. This study aimed to establish indicators for the appropriate use of triazoles for invasive fungal disease, so as to produce a reference for evaluating and standardizing the rational application of triazole antifungals. METHODS: A comprehensive analysis and literature review were conducted to construct an evaluation system for indications, therapeutic timing, duration of drug usage, drug dosage, administration method, drug interactions, medication in specific populations and pharmaceutical care. A Delphi questionnaire was designed based on the preliminary evaluation of an indicator system that comprised eight primary indicators, 29 secondary indicators and 54 tertiary indicators. A Delphi panel survey was completed by 28 and 26 experts in the first and second rounds, respectively, via e-mail. Agreement was considered to be reached when the median score was in the top tertile (4 or 5), and 80% of panel scores were in the top tertile. The experts mainly comprised physicians and clinical pharmacists from different regions. Based on expert opinions, the evaluation indicator system was modified and the final version was established. RESULTS: The response rate was high in the first and second rounds, at 100% and 93%, respectively, as was the dependability coefficient (0.83). The expert opinions resulted in four secondary indicators and nine tertiary indicators being deleted, and 10 tertiary indicators being modified. After the two rounds of the Delphi survey, the final established system of indicators comprised eight primary indicators, 25 secondary indicators and 45 tertiary indicators. WHAT IS NEW AND CONCLUSIONS: Contrasted with previous studies that have only focused on a subset of indicators, this research establishes comprehensive indicators for evaluating the use of triazoles for invasive fungal disease and which cover most of the medication process: indications, therapeutic timing, duration of drug usage, drug dosage, administration method, drug interactions, medication in specific populations and pharmaceutical care. The indicators can reflect the characteristic of triazoles throughout the process of clinical administration for an invasive fungal disease, and it will be helpful as references when hospital administrators are regulating the use of antifungals. PMID- 28597470 TI - Breast conservation for male breast cancer: Case report of intraoperative radiation. AB - Male breast cancer (MBC) comprises <1% of all breast cancers in the United States. MBC is typically treated with total mastectomy while the majority of female breast cancer is treated with breast conservation therapy combined with various forms of radiation. One method that has developed over the last two decades is the use of intraoperative radiation therapy (IORT) as a type of accelerated partial breast irradiation to direct the treatment field to the tumor bed. Since overall prognosis and systemic therapy recommendations for MBC are similar to breast cancer in women, we describe the first case of MBC treated with BCS and IORT. Our patient is a 62-year-old male who was found to have a right breast 1.6 cm palpable mass at the 10:00 position 1 cm radially from the nipple. Core biopsy demonstrated invasive ductal carcinoma, moderately differentiated, estrogen and progesterone receptor positive, and Her 2 Negative. The patient had a strong desire for breast conservation, and needed to minimize daily radiation treatments due to his work schedule. After discussion among our multidisciplinary tumor board, we felt this patient to be suitable for BCS and IORT given his age, favorable tumor subtype, size, and clinically early stage breast cancer. A right axillary sentinel lymph node biopsy and central lumpectomy was performed. The INTRABEAM device (Carl Zeiss Meditec, Oberkochen, Germany) was utilized for radiation delivery. The patient had negative margins on his final pathology. The postoperative course was uneventful and at the 6 month follow-up visit there were no issues and he had an excellent cosmetic outcome. BCS and IORT is an option in appropriately selected male patients with favorable subtype early stage breast cancer. PMID- 28597471 TI - Gabapentin for chronic neuropathic pain in adults. AB - BACKGROUND: Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000. OBJECTIVES: To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain in adults. SEARCH METHODS: For this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables. MAIN RESULTS: We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%). AUTHORS' CONCLUSIONS: Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review. PMID- 28597472 TI - Aroma-volatile profile of black morel (Morchella importuna) grown in Israel. AB - BACKGROUND: A headspace solid-phase microextraction method with gas chromatography-mass spectrometry was used to profile the aroma volatiles of mature fruiting bodies of Morchella importuna grown in Israel. RESULTS: We tentatively identified 40 aroma compounds and seven unknown volatiles. The M. importuna aroma profile consisted of 14 aldehydes, six alcohols, 10 methyl esters, four heterocyclic/sulfur compounds, 10 carbohydrates and three other compounds (i.e. one acid, one ketone and one butyl ester). The most abundant volatiles were carbohydrates, with a total relative peak area of 29.3%, followed by alcohols (27.7%), aldehydes (21.6%), methyl esters (10.8%), heterocyclic/sulfur compounds (3.1%) and other compounds (5.8%). The 8-carbon (C8) compounds imparting typical mushroom-like aroma were very abundant in M. importuna, accounting for 27.9% of the total peak area and including, amongst others, 1-octen-3-ol (80% of total C8), octanal and 2-octenal (Z- and E-). CONCLUSION: The aroma volatile profile of morels has much in common with that of other mushrooms, with a few unique characteristics. To our knowledge, this is the first detailed report of the aroma profile of M. importuna. (c) 2017 Society of Chemical Industry. PMID- 28597473 TI - Body fat distribution: Associations with socioeconomic status in the Hispanic health and nutrition examination survey. AB - Three indices derived from principal components analysis of four skinfold measurements were studied in relation to socioeconomic status (SES; income and education) in men and women of the U.S. Hispanic Health and Nutrition Examination Survey (HHANES). The three indices were fatness (PC1), central body fat distribution (PC2), and "centralized obesity" (PC1 + PC2). The well-known inverse relation of fatness (PC1) with SES was demonstrated in women. This relationship tended to be positive in men, but not consistently so within the three Hispanic groups (Puerto Rican, Cuban, Mexican-Americans) studied. A negative association of central body fat distribution (PC2) was also evident in both sexes and in all three groups except in Puerto Rican men, in whom the relationship was no longer significant after age adjustments. The third index combined information on both fatness level and central distribution. It was strongly related to SES in women but not in men. PMID- 28597474 TI - ZEB1 expression is a potential indicator of invasive endometriosis. AB - INTRODUCTION: Although endometriosis is a benign disease, it shares some features with cancers, such as invasiveness and the potential to metastasize. This study sought to investigate the epithelial-mesenchymal transition status in human endometriotic lesions. MATERIAL AND METHODS: Thirteen endometriosis patients and 10 control women without endometriosis undergoing surgery for benign indications were recruited. We examined the expression of E-cadherin, vimentin, and epithelial-mesenchymal transition-induced transcriptional factors, such as Snail and ZEB1, by immunohistochemistry. We evaluated the expression of each marker in epithelial cells of both endometriotic lesions (ovarian endometrioma, deep infiltrating endometriosis, adenomyosis) and normal endometria. The correlation between ZEB1 expression and serum level of CA125 was also investigated. RESULTS: Immunohistochemical analysis revealed that although E-cadherin, vimentin, and Snail were expressed in epithelia of normal endometria and endometriotic lesions, ZEB1 expression was only expressed in epithelia of endometriotic lesions. Additionally, ZEB1 was most frequently observed in epithelial cells of invasive endometriosis. The endometriosis patients with high serum CA125 level were more likely to have ZEB1-positive lesions. CONCLUSIONS: This is the first observation of ZEB1 expression in epithelial cells of benign disease. The preferential expression of ZEB1 in epithelial cells of endometriotic lesions suggests that these cells may have, at least in part, a higher level of mesenchymal features possibly via ZEB1-driven epithelial-mesenchymal transition than normal endometria and that ZEB1 can be a potential indicator of invasiveness or severity of endometriosis. PMID- 28597475 TI - Program considerations for integration of nutrition and family planning: Beliefs around maternal diet and breastfeeding within the context of the nutrition transition in Egypt. AB - In Egypt, rising maternal overweight and obesity is consistent with the transition to westernized diets and a growing reliance on energy-dense, low nutrient foods. Although the first 1,000 days of life are the focus of many programmes designed to prevent many forms of malnutrition, little attention has been paid to maternal dietary practices and weight gain during pregnancy. This study used in-depth interviews with pregnant women (N = 40), lactating women (N = 40), and nonlactating women (N = 40) to gain an understanding of behaviours, perceptions, and cultural beliefs in relation to maternal dietary intake during pregnancy, lactation, and nonlactation; weight gain during pregnancy; birth spacing; and family planning. Study findings reveal that food choice was driven by affordability, favoured foods, or foods considered appropriate for a specific life stage (pregnant, lactating, and nonlactating). Knowledge of weight gain during pregnancy is limited, especially with regards to excessive weight gain during pregnancy. Diet is often modified during lactation to support breast milk production, and a normal diet resumed when breastfeeding ceases. Within the context of breastfeeding, the lactational amenorrhea method provides an opportunity to improve exclusive breastfeeding practices, maternal diet during lactation, and the transition to other family planning methods by 6 months postpartum. Health care providers should discuss limiting maternal consumption of low nutrient foods such as junk foods, soda, and teas during pregnancy and postpartum. Dietary counselling should accompany information on appropriate weight gain during pregnancy and exercise to prevent excessive weight gain, in the context of the nutrition transition. PMID- 28597476 TI - Safe fluoroquinolones prophylaxis in blood cancer patients with chemotherapy induced neutropenia and Glucose-6-Phosphate-Dehydrogenase deficiency. AB - WHAT IS KNOWN AND OBJECTIVE: Bacterial infections are the leading causes of morbidity and mortality in haematologic patients with chemotherapy-induced neutropenia. The only strategy shown to be effective in reducing febrile neutropenia incidence is fluoroquinolone prophylaxis, but the safety of this class of drugs in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD-), the most common human enzyme defect, is still controversial because of the claimed association with acute haemolytic anaemia. METHODS: We retrospectively analysed 242 patients treated with 628 intensive chemotherapy courses. Of these, 59 patients were with G6PD-. All patients underwent fluoroquinolone prophylaxis and were transfused according to our single-unit transfusion policy. The principal endpoint was the incidence of acute haemolytic anaemia. Secondary endpoints included the incidence of febrile neutropenia, microbiologically and clinically documented infection (MDI and CDI) and the incidence of Gram-positive or Gram-negative infections. RESULTS AND DISCUSSIONS: No episode of acute haemolytic anaemia was observed in the entire cohort. The incidence of MDI and CDI was similar, but the incidence of invasive fungal disease (IFD; P<.0001, HR 11.4, 95%CI 3.5-37.05) and Candida sepsis (P=.008, HR 37, 95%CI 2.01-680.9) was higher in patients with G6PD-. Interestingly, we observed a reduced incidence of febrile neutropenia in patients with G6PD- (P=.01, HR 0.46, 95%CI 0.25-0.8). WHAT IS NEW AND CONCLUSIONS: Our data suggest that fluoroquinolone prophylaxis in patients with G6PD-, treated with intensive chemotherapy, is feasible and safe. Our findings on the incidence of IFD and febrile neutropenia suggest that G6PD may be important in susceptibility to opportunistic pathogens and host response in neutropenic patients. PMID- 28597477 TI - Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (DeltaE9) mice. AB - AIMS: Alzheimer's disease (AD), a progressive development dementia, is increasingly impacting patients' living conditions worldwide. Despite medical care and funding support, there are still no highly individualized drugs and practical strategies for clinical prevention and treatment. Developmentally regulated brain protein (abbreviated as Drebrin or Dbn, also known as Dbn1 in mouse) exists in neurons, especially in dendrites, and is an actin-binding protein that modulates synaptic morphology and long-term memory. However, the majority of previous studies have focused on its upstream proteins and neglected the impact Drebrin has on behavior and AD in vivo. METHODS: Here, we tracked the behavioral performances of 4-, 8-, 12-, and 16-month-old AD mice and investigated the expression level of Drebrin in their hippocampi. A Pearson correlation analysis between Drebrin levels and behavioral data was performed. Subsequently, 2-month-old AD mice were injected with rAAV-zsGreen-Dbn1 vector, composing the APP/PS1-Dbn1 group, and sex- and age-matched AD mice were injected with rAAV tdTomato vector to serve as the control group. All mice were conducted behavioral tests and molecular detection 6 months later. RESULTS: (i) The expression of Drebrin is decreased in the hippocampus of aged AD mice compared with that of age matched WT and young adult AD mice; (ii) cognitive ability of APP/PS1 mice decreases with age; (iii) Drebrin protein expression in the hippocampus correlates with behavioral performance in different aged AD mice; (iv) cognitive ability improved significantly in APP/PS1-Dbn1 mice; (v) the expression level of Drebrin in APP/PS1-Dbn1 mouse hippocampus was significantly increased; (vi) the pathological lesion of AD was alleviated in APP/PS1-Dbn1 mice; (vii) the filamentous actin (F-actin) and microtubule-associated protein 2(MAP-2) in APP/PS1-Dbn1 mice were notably more than control mice. CONCLUSION: In this study, an effective expression of Drebrin improves cognitive abilities and alleviates lesions in an AD mouse model. These results may provide some valid resources for therapy and research of AD. PMID- 28597479 TI - Tuning the Reactivity of Functionalized Diallylic Alcohols: Bronsted versus Lewis Acid Catalysis. AB - The chemodivergent reactivity of bifunctional, enol thioether-containing diallylic alcohols in acidic medium is disclosed, highlighting the difference between strong Lewis acid and mild Bronsted acid catalysis. In the presence of bismuth(III) triflate, allylic alcohol activation affords diversely substituted cyclopentenones in a Nazarov-type electrocyclization, whereas activation of the thioenol ether by p-toluenesulfonic acid provides an entry to alpha-sulfenylated beta,gamma-unsaturated ketones. Both methods represent a facile access to the corresponding products under mild conditions, using inexpensive and non-toxic catalytic systems. PMID- 28597478 TI - Safety of the use of group A plasma in trauma: the STAT study. AB - BACKGROUND: Use of universally ABO-compatible group AB plasma for trauma resuscitation can be challenging due to supply limitations. Many centers are now using group A plasma during the initial resuscitation of traumatically injured patients. This study was undertaken to evaluate the impact of this practice on mortality and hospital length of stay (LOS). STUDY DESIGN AND METHODS: Seventeen trauma centers using group A plasma in trauma patients of unknown ABO group participated in this study. Eligible patients were group A, B, and AB trauma patients who received at least 1 unit of group A plasma. Data collected included patient sex, age, mechanism of injury, Trauma Injury Severity Score (TRISS) probability of survival, and number of blood products transfused. The main outcome of this study was in-hospital mortality differences between group B and AB patients compared to group A patients. Data on early mortality (<=24 hr) and hospital LOS were also collected. RESULTS: There were 354 B and AB patients and 809 A patients. The two study groups were comparable in terms of age, sex, TRISS probability of survival, and total number of blood products transfused. The use of group A plasma during the initial resuscitation of traumatically injured patients of unknown ABO group was not associated with increased in-hospital mortality, early mortality, or hospital LOS for group B and AB patients compared to group A patients. CONCLUSION: These results support the practice of issuing thawed group A plasma for the initial resuscitation of trauma patients of unknown ABO group. PMID- 28597480 TI - Public Understanding of Ebola Risks: Mastering an Unfamiliar Threat. AB - Ebola was the most widely followed news story in the United States in October 2014. Here, we ask what members of the U.S. public learned about the disease, given the often chaotic media environment. Early in 2015, we surveyed a representative sample of 3,447 U.S. residents about their Ebola-related beliefs, attitudes, and behaviors. Where possible, we elicited judgments in terms sufficiently precise to allow comparing them to scientific estimates (e.g., the death toll to date and the probability of dying once ill). Respondents' judgments were generally consistent with one another, with scientific knowledge, and with their self-reported behavioral responses and policy preferences. Thus, by the time the threat appeared to have subsided in the United States, members of the public, as a whole, had seemingly mastered its basic contours. Moreover, they could express their beliefs in quantitative terms. Judgments of personal risk were weakly and inconsistently related to reported gender, age, education, income, or political ideology. Better educated and wealthier respondents saw population risks as lower; females saw them as higher. More politically conservative respondents saw Ebola as more transmissible and expressed less support for public health policies. In general, respondents supported providing "honest, accurate information, even if that information worried people." These results suggest the value of proactive communications designed to inform the lay public's decisions, thoughts, and emotions, and informed by concurrent surveys of their responses and needs. PMID- 28597482 TI - Physical growth of Ecuadorian Chachi Amerindians. AB - Measurments of height, weight, arm circumference, and triceps and subscapular skinfolds were collected on 457 Ecuadorian Chachi Amerindians between the ages of 4 and 64 years. Compared to US reference values, the Chachi are very small in terms of height-for-age, but have normal or above normal weight-for-height. The Chachi are also in the lower part of the distribution of body size among South American Indians. In terms of body composition, Chachi arm circumferences and triceps skinfolds are below the US 50th percentile. The estimated upper arm muscle area of Chachi males is below the US median, but Chachi females older than the age of 15 have arm muscle areas exceeding the US median. One reason for the greater arm muscle area of adult Chachi females may be that they perform much more physical activity involving the upper body than do US women. Problems in the interpretation of anthropometric indicators of nutritional status among South American Indian populations limit the conclusions about Chachi nutritional status that can be drawn from these results. PMID- 28597481 TI - Peripartum cardiomyopathy in Denmark: a retrospective, population-based study of incidence, management and outcome. AB - AIM: Population-based European studies of peripartum cardiomyopathy (PPCM) are few. We aimed to estimate the nationwide incidence and outcome of PPCM in Denmark during 2005-2014. METHODS AND RESULTS: The Danish National Birth Register and the Danish National Patient Register were linked and searched for cardiomyopathy and heart failure ICD-10 diagnoses in a period of nine months before to 12 months after a delivery from 1 January 2005 through 31 December 2014. Diagnoses were validated and additional data were extracted from patient charts. A total of 61 women met the inclusion criteria equalling 1 in 10 149 deliveries. The majority recovered left ventricular systolic function within one year, but 14.8% suffered a major adverse event with 3.3% mortality, 8.2% mechanical circulatory support requirement and/or heart transplantation and 4.9% persistent severe heart failure. Half of the women had a concomitant hypertensive disorder of pregnancy, and this subgroup had a milder course of the disease. Baseline left ventricular ejection fraction (LVEF) was the only significant predictor of LVEF 10-14 months after diagnosis, and cabergoline therapy to inhibit lactation predicted the dichotomous outcome of complete recovery (LVEF >=55%). CONCLUSION: The first validated, population-based European estimate of PPCM incidence is 1 in 10 149 deliveries, which places Denmark between American and Japanese estimates. Clinical outcome in the cohort was similar to those reported in recent cohorts. Women with concomitant hypertensive disorder of pregnancy had a milder course of PPCM. Baseline LVEF predicted LVEF 10-14 months after diagnosis and cabergoline predicted complete recovery. PMID- 28597484 TI - Body composition estimates using different measurement techniques in a sample of highland subsistence farmers in Guatemala. AB - This study aims at assessing the accuracy of estimates of body composition provided by bioimpedance (BIA) equations developed for U.S. populations when applied to a sample of Guatemalan farmers. If these equations were shown to have low validity, the second objective was to develop more accurate estimates of fat free mass (FFM). One hundred males and females 19 to 45 years of age were randomly selected from four rural communities in the Western Highlands of Guatemala. Bioimpedance equations explained 59 and 33% of the variation in FFM, with a RMSE of 2.7 and 2.8 kg in males and females, respectively. Body fat (BF) predictions had a lower R2 . Using the "all possible regressions" procedure, the best subset for prediction of FFM used anthropometric and BIA variables as predictors. The best model for men and women included only anthropometric variables: 75% of the variance in FFM for men and 70% of the variance in women was explained by this model. The RMSE was 2.1 and 1.9 kg for both groups, respectively. It is concluded that FFM can be estimated from anthropometric dimensions with a high degree of accuracy and use of BIA does not provide more valid estimates. PMID- 28597483 TI - International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. AB - ISSUES: Non-injectable naloxone formulations are being developed for opioid overdose reversal, but only limited data have been published in the peer-reviewed domain. Through examination of a hitherto-unsearched database, we expand public knowledge of non-injectable formulations, tracing their development and novelty, with the aim to describe and compare their pharmacokinetic properties. APPROACH: (i) The PatentScope database of the World Intellectual Property Organization was searched for relevant English-language patent applications; (ii) Pharmacokinetic data were extracted, collated and analysed; (iii) PubMed was searched using Boolean search query '(nasal OR intranasal OR nose OR buccal OR sublingual) AND naloxone AND pharmacokinetics'. KEY FINDINGS: Five hundred and twenty-two PatentScope and 56 PubMed records were identified: three published international patent applications and five peer-reviewed papers were eligible. Pharmacokinetic data were available for intranasal, sublingual, and reference routes. Highly concentrated formulations (10-40 mg mL-1 ) had been developed and tested. Sublingual bioavailability was very low (1%; relative to intravenous). Non concentrated intranasal spray (1 mg mL-1 ; 1 mL per nostril) had low bioavailability (11%). Concentrated intranasal formulations (>=10 mg mL-1 ) had bioavailability of 21-42% (relative to intravenous) and 26-57% (relative to intramuscular), with peak concentrations (dose-adjusted Cmax = 0.8-1.7 ng mL-1 ) reached in 19-30 min (tmax ). IMPLICATIONS: Exploratory analysis identified intranasal bioavailability as associated positively with dose and negatively with volume. CONCLUSION: We find consistent direction of development of intranasal sprays to high-concentration, low-volume formulations with bioavailability in the 20-60% range. These have potential to deliver a therapeutic dose in 0.1 mL volume. [McDonald R, Danielsson Glende O, Dale O, Strang J. International patent applications for non-injectable naloxone for opioid overdose reversal: Exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 2017;00:000-000]. PMID- 28597486 TI - Recent Progress on Localized Field Enhanced Two-dimensional Material Photodetectors from Ultraviolet-Visible to Infrared. AB - Two-dimensional (2D) materials have drawn tremendous attention in recent years. Being atomically thin, stacked with van der Waals force and free of surface chemical dangling bonds, 2D materials exhibit several distinct physical properties. To date, 2D materials include graphene, transition metal dichalcogenides (TMDS), black phosphorus, black P(1-x) Asx , boron nitride (BN) and so forth. Owing to their various bandgaps, 2D materials have been utilized for photonics and optoelectronics. Photodetectors based on 2D materials with different structures and detection mechanisms have been established and present excellent performance. In this Review, localized field enhanced 2D material photodetectors (2DPDs) are introduced with sensitivity over the spectrum from ultraviolet, visible to infrared in the sight of the influence of device structure on photodetector performance instead of directly illustrating the detection mechanisms. Six types of localized fields are summarized. They are: ferroelectric field, photogating electric field, floating gate induced electrostatic field, interlayer built-in field, localized optical field, and photo-induced temperature gradient field, respectively. These localized fields are proved to effectively promote the detection ability of 2DPDs by suppressing background noise, enhancing optical absorption, improving electron-hole separation efficiency, amplifying photoelectric gain and/or extending the detection range. PMID- 28597485 TI - Comparison of haemostatic function of PAS-C-platelets vs. plasma-platelets in reconstituted whole blood using impedance aggregometry and thromboelastography. AB - BACKGROUND AND OBJECTIVES: There are concerns about the haemostatic function of platelets stored in platelet additive solution (PAS). Aim of this study was to compare the haemostatic function of PAS-C-platelets to plasma-platelets in reconstituted whole blood. MATERIALS AND METHODS: In our experiment, whole blood was reconstituted with red blood cells, solvent-detergent (SD) plasma and either PAS-C-platelets or plasma-platelets (n = 7) in a physiological ratio. On storage days 2, 5, 8 and 13, the agonist-induced aggregation (multiple electrode aggregometry), clot formation (thromboelastography) and agonist-induced CD62P responsiveness (flow cytometry) were measured. RESULTS: Samples with PAS-C platelets showed significantly lower aggregation than plasma-platelets when induced with adenosine diphosphate, -6 U (95% confidence interval: -8; -4) or thrombin receptor-activating protein, -15 U (-19; -10). Also when activated with collagen and ristocetin, the PAS-C-platelets showed less aggregation, although not statistically significant. All samples with PAS-C-platelets showed significantly lower agonist-induced CD62P responsiveness than samples with plasma platelets. However, there was no difference regarding all TEG parameters. CONCLUSION: Our findings demonstrate that the function - aggregation and CD62P responsiveness - of PAS-C-platelets in reconstituted whole blood is inferior to that of plasma-platelets, which may have implications in the setting of massive transfusions. PMID- 28597487 TI - Dietary change and adolescent growth among the Bundi (Gende-speaking) people of Papua New Guinea. AB - In the 1960's, the Bundi had a pattern of slow growth, delayed maturation, and small adult body size due to malnutrition. Since then, improved transportation, wage income, cash cropping, and migration have changed dietary patterns for the Bundi. The purpose of our study was to assess the effects of this general increase in protein and energy intakes on adolescent growth. The data were collected in 1984. Subscapular skinfold thicknesses among rural Bundi children measured in 1984 and 1967 confirm that nutritional status has improved, although current means for height and weight are still below the NCHS 5th percentile. Rural Bundi measure in 1984 were compared to the 1967 data for differences in height and weight. For both sexes, there were increases in growth status and/or the tempo of growth in height and weight. Urban- rural comparisons further contrast the effects of improved nutrition. For males and females, significant differences between urban and rural groups are found mainly in the age range of the adolescent growth spurt. These findings suggest earlier maturation of urban adolescents. Although interpretation of cross-sectional growth data cannot be conclusive, these results suggest that the tempo of growth is the best indicator of nutritional status during adolescenc. PMID- 28597488 TI - Primary breast angiosarcoma in young women from the same geographic region in a short period of time: Only a coincidence or an increased risk? PMID- 28597489 TI - Development of a web-based application and multicountry analysis framework for assessing interdicted infections and cost-utility of screening donated blood for HIV, HCV and HBV. AB - BACKGROUND AND OBJECTIVES: Most countries test donations for HIV, HCV and HBV using serology with or without nucleic acid testing (NAT). Cost-utility analyses provide information on the relative value of different screening options. The aim of this project was to develop an open access risk assessment and cost-utility analysis web-tool for assessing HIV, HCV and HBV screening options (http://www.isbtweb.org/working-parties/transfusion-transmitted-infectious diseases/). An analysis for six countries (Brazil, Ghana, the Netherlands, South Africa, Thailand and USA) was conducted. MATERIALS AND METHODS: Four strategies; (1) antibody assays (Abs) for HIV and HCV + HBsAg, (2) antibody assays that include antigens for HIV and HCV (Combo) + HBsAg, (3) NAT in minipools of variable size (MP NAT) and (4) individual donation (ID) NAT can be evaluated using the tool. Country-specific data on donors, donation testing results, recipient outcomes and costs are entered using the online interface. Results obtained include the number infections interdicted using each screening options, and the (incremental and average) cost-utility of the options. RESULTS: In each of the six countries evaluated, the use of antibody assays is cost effective or even cost saving. NAT has varying cost-utility depending on the setting, and where adopted, the incremental cost-utility exceeds any previously defined or proposed threshold in each country. CONCLUSION: The web-tool allows an assessment of infectious units interdicted and value for money of different testing strategies. Regardless of gross national income (GNI) per capita, countries appear willing to dedicate healthcare resources to blood supply safety in excess of that for other sectors of health care. PMID- 28597491 TI - Hippocampal neurogenesis and pattern separation: A meta-analysis of behavioral data. AB - The generation of new neurons in the hippocampus of adult mammals has become a widely accepted phenomenon, but the functional significance of the adult neurogenesis in the hippocampus is not fully understood. One of the main hypotheses currently investigated suggests that neurogenesis contributes to pattern separation in the dentate gyrus. Many behavioral studies were conducted aiming to test this hypothesis using rodents as animal model. In those studies, researches ablated neurogenesis in the animals and subsequently evaluate them in tests of behavioral pattern separation, that is, behaviors that are thought to rely on the computational process of pattern separation. The results of these studies are varied, with most supporting a role for neurogenesis in pattern separation, but some others not. To address this controversy we performed a systematic review and meta-analysis of studies evaluating the effect of neurogenesis ablation on behavioral pattern separation. Analysis results indicated that most of the literature in the topic is surprisingly consistent and, although there are two studies with divergent results, the bulk of the literature supports an effect of hippocampal neurogenesis on behavioral pattern separation. We discuss those findings in light of other behavioral effects of hippocampal neurogenesis ablation, limitations of behavioral data and other lines of evidence about the effect of hippocampal neurogenesis in the dentate gyrus. PMID- 28597490 TI - Downregulation of USP32 inhibits cell proliferation, migration and invasion in human small cell lung cancer. AB - OBJECTIVES: Ubiquitin specific protease 32 (USP32) is a highly conserved but uncharacterized gene, which has been reported to be associated with growth of breast cancer cells. However, the role of USP32 in human small cell lung cancer (SCLC) has not been uncovered. The aim of this study was to investigate and evaluate the clinical significance of USP32 in patients with SCLC. MATERIALS AND METHODS: Expression of USP32 was firstly investigated using public online data sets and then determined in SCLC tissues and cell lines using quantitative real time PCR, Western blotting and immunohistochemical staining. SCLC cells were transfected with a small-interfering RNA targeting USP32 mRNA and analysed for cell viability, proliferation ability, cell cycle distribution, apoptosis and invasion. RESULTS: USP32 was found to be overexpressed in SCLC tissues compared with normal tissues. High USP32 expression was significantly correlated with disease stage and invasion. In vitro experiments demonstrated that silencing of USP32 caused a significant decrease in the proliferation and migration rate of cells. Furthermore, USP32 silencing arrested cell cycle progression at G0/G1 phase via decreasing CDK4/Cyclin D1 complex and elevating p21. In addition, downregulation of USP32 significantly induced cell apoptosis by activating cleaved caspase-3 and cleaved PARP, as well as inhibiting cell invasiveness via altering epithelial mesenchymal transition expression. CONCLUSIONS: Our results suggest for the first time that USP32 is important for SCLC progression and might be a potential target for molecular therapy of SCLC. PMID- 28597492 TI - Dependability and precision of anthropometric measures in a longitudinal field study in an Egyptian village. AB - Reliability and its components, precision and dependability, are analyzed for a complex dataset involving longitudinal anthropometric measurements on subjects of varying ages in an Egyptian village setting. Results are compared with other published datasets. Technical error of measurement is similar to or compares favorably with other datasets for both adults and children. Overall reliability is strongly influenced by dependability coefficients, which are calculated in this analysis over relatively longer time periods (2 weeks for young children and longer for older individuals) than in other comparable datasets. It is evident that some components of the theoretical construct of imprecision, i.e., measurement error derived from variation over longer periods of time in factors contributing to accuracy, are actually captured in the analytical component of variance called undependability. PMID- 28597493 TI - Seeking, accepting and declining help for emotional distress in cancer: A systematic review and thematic synthesis of qualitative evidence. AB - Many individuals affected by cancer who experience emotional distress report not wanting help. This review aims to understand why individuals affected by cancer seek, accept or decline help for emotional distress and what influences these actions. A systematic review and thematic synthesis of the qualitative literature was conducted. Using pre-defined search terms, four electronic databases were searched from January 2000 to May 2016. Pre-determined inclusion and exclusion criteria were then applied. Identified papers were quality appraised. In total, 32 papers were included in the synthesis. Four themes emerged from data synthesis: attaining normality-the normality paradox; being emotionally literate; perceptions of help; needs-support gap. Attaining normality is ideographic, context dependent and temporally situated; some individuals maintain normality by not seeking/declining help whereas others seek/accept help to achieve a new normality. Thus, attaining normality paradoxically functions to explain both why individuals sought/accepted help or did not seek/declined help. Data indicate that a context dependent, systems thinking approach is merited to enhance psychosocial care. In particular, clinicians must actively explore the personal context of an individual's distress to ensure that help desired and help offered are mutually understood. Further research must address the limitations of the current evidence base to advance theoretical understanding. PMID- 28597494 TI - Unexpectedly low frequency of BRCA1/2 deleterious mutations in Japanese patients with breast cancer. PMID- 28597495 TI - Ageing and memory medication: social rationales and consumption practices. AB - This article focuses on the social rationales underlying the consumption or rejection of medication for memory by the elderly. Our analysis is set within the wider frame of the current use of psychopharmaceuticals for the enhancement of everyday performance, discussing its relationship to new cultures of ageing. Our results, from a recently concluded study, point to different patterns of investment in memory in old age. On the one hand, we found a willingness to consume medication for memory - a heterogeneous disposition split between the imaginary of disease and that of performance enhancement. On the other hand, we found a cultural resistance and scepticism towards the use of psychopharmaceuticals for performance purposes. This suggests that a new frame of psychopharmaceuticalization of old age - represented by memory medication - is prompting different rationales, ranging from consumption to resistance. PMID- 28597496 TI - Elevated anti-Mullerian hormone in lean women may not indicate polycystic ovarian syndrome. AB - BACKGROUND: Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder with clinical features shared with functional hypogonadotrophic hypogonadism (FHH). AIM: To investigate the usefulness of an elevated (>40 pmol/L) anti-Mullerian hormone (AMH) in identifying PCOS and distinguishing PCOS from FHH. MATERIALS AND METHODS: 141 patients with an elevated AMH and body mass index either <20 kg/m2 (lean) or >30 kg/m2 (obese) were selected and three subgroups analysed - obese, lean, lean with suspected FHH. FHH was diagnosed clinically, incorporating diet, weight and exercise history; confirmatory tests included pituitary MRIs, progestin challenges and endometrial thickness measurements. PCOS features of oligo/anovulation, polycystic ovarian morphology (PCOm) and hyperandrogenism were determined by clinical history, pelvic ultrasound, free androgen index and physical examination, respectively. Features of PCOS and blood levels of AMH, follicle-stimulating hormone, luteinising hormone, sex hormone binding globulin (SHBG) and testosterone were compared between subgroups. RESULTS: Of 141 patients with elevated AMH, 76 were obese and 65 lean. Greater than one-third of lean women had the clinical picture of FHH. Elevated AMH predicted PCOm and menstrual irregularity across all subgroups but uniquely associated with hyperandrogenism in the obese. Median AMH levels were similar among FHH and non-FHH women. Median SHBG levels were significantly higher (111 +/- 73 vs 56 +/- 31, P < 0.001) in lean women with FHH compared to those without FHH. CONCLUSIONS: PCOS and FHH share common features of elevated AMH levels, oligo-anovulation and polycystic ovarian morphology. AMH did not assist in differentiating FHH from PCOS. A higher SHBG level shows promise as a discriminatory finding in FHH. PMID- 28597499 TI - Lupus in the far east: a modern epidemic. AB - Systemic lupus erythematosus (SLE) is a diverse and heterogeneous disease with much variation between different ethnicities. Although more severe and prevalent in non-Caucasian populations, the bulk of evidence regarding 'Asian lupus' had traditionally been extrapolated from studies on patient minorities in the West. Lupus research in Asia has since grown exponentially and now takes a leading role in improving the care for SLE patients worldwide. With recent advances, particularly from studies in population-specific phenotyping, genome-wide association studies, lupus nephritis and innovative treatment modalities, we now have an expanding understanding of both the basic science and clinical management of SLE. Upcoming breakthroughs from growing multi-ethnic cohorts and international collaborations will likely bring further important ramifications for SLE management in the near future. PMID- 28597498 TI - Different implications of the dorsal and ventral hippocampus on contextual memory retrieval after stress. AB - This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24 h-test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four-hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty-four hours later, nonstressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time-course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to nonstressed mice. Moreover, local infusion of the anesthetic lidocaine into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in nonstress and stress conditions whereas lidocaine infusion into the dHPC induced in nonstressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in nonstress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction. PMID- 28597497 TI - Right ventricular dysfunction in left-sided heart failure with preserved versus reduced ejection fraction. AB - BACKGROUND: Right ventricular (RV) dysfunction is recognized as a major prognostic factor in left-sided heart failure (HF). However, the relative contribution of RV dysfunction in HF with preserved (HFpEF) vs. reduced ejection fraction (HFrEF) is unclear. METHODS AND RESULTS: Right ventricular longitudinal strain (RVLS), tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) were determined by echocardiography in 657 age- and gender-matched groups of patients with HFpEF [left ventricular ejection fraction (LVEF) >=50%; n=219] and HFrEF (LVEF <50%; n=219) and in controls without HF (n=219) from an Asian population-based cohort study. Across control to HFpEF and HFrEF groups, RV function deteriorated as measured by RVLS (-26.7 +/- 5%, -22.7+/-6.6% and -18.2 +/- 6.7%, respectively) and TAPSE (21.0 +/- 3.9, 17.5 +/- 5.1 and 14.7 +/- 4.7 mm, respectively), whereas PASP increased (26.8 +/- 7.1, 34.5 +/- 11.9 and 39.3 +/- 16.2 mmHg, respectively) (all P<0.001). Controlling for PASP in control, HFpEF and HFrEF subjects, the magnitude of RVLS/PASP (-1.06 +/- 0.32, -0.75 +/- 0.32 and -0.56 +/- 0.36, respectively) and TAPSE/PASP ratios (0.83 +/- 0.23, 0.54 +/- 0.24 and 0.55 +/- 0.29, respectively) similarly decreased across groups. Right ventricular dysfunction (by both TAPSE and RVLS) was independently associated with left ventricular systolic dysfunction and atrial fibrillation, but not with PASP. Among patients with HF, both TAPSE/PASP and RVLS/PASP ratios were related to the composite endpoint of all-cause death and HF hospitalization, even after multivariable adjustment [hazard ratio (HR) 0.33; 95% confidence interval (CI) 0.14-0.74 and HR 3.09; 95% CI 1.52-6.26, respectively], with no difference between HFrEF and HFpEF. CONCLUSIONS: Right ventricular dysfunction is present in HFpEF and is even more pronounced in HFrEF for any given degree of pulmonary hypertension. It is independently predicted by left ventricular dysfunction but not by PASP. Right ventricular-arterial coupling is prognostically important in HF regardless of LVEF. PMID- 28597500 TI - Heroin abuse during pregnancy: Effects on perinatal outcome and early childhood growth. AB - Heroin abuse during pregnancy is associated with 1) fetal growth retardation and neonatal withdrawal syndrome in infants and 2) an increased frequency of abruptio placentae, sexually transmitted diseases, and other complications in mothers. Based on the findings of several small cohort studies, postnatal growth and development of infants whose mothers were addicted to heroin during pregnancy appears to fall within normal variation. In the present study, information about use of heroin and other substances during pregnancy in relation to neonatal outcome was analyzed in 47 heroin-abusing mothers and 80 control women and their respective infants. In addition medical record information was available for postnatal growth follow-up of 28 (58%) of heroin-exposed children and 22 (27.5%) of control infants. Infants born to heroin addicts in this study were significantly (P<.01) smaller at birth but exhibited no increase in the frequency of congenital anomalies compared with controls. Similar to findings of previous investigators, postnatal development of infants born to addicts was not delayed. PMID- 28597501 TI - Influence of prepregnant body mass and weight gain for gestation on spontaneous preterm delivery and duration of gestation during adolescent pregnancy. AB - We examined the influence of two measures of maternal nutritional status: prepregnant body mass (kilograms/meter2 ) and Weight gain during pregnancy (adjusted for duration of gestation) on spontaneous preterm delivery (<37 completed Weeks' gestation) and duration of gestation, as well as on low birthweight (<2,500 grams) and small-for-gestational-age (SGA) in pregnant adolescents. Inadequate Weight gain for gestation increased the risk of spontaneous preterm delivery when prematurity was reckoned by the obstetric estimate (Adjusted Odds Ratio, AOR = 1.75 95% CI 1.22-2.50) or from the mother's LMP (AOR = 1.49 95% CI 1.10-2.02). In linear models, gestation duration was significantly reduced, by more than half a week, when reckoned from eiter estimate of gestation. However, the association between preterm birth or gestation duration and prepregnancy body mass was not consistent and depended on the method of estimating gestation. Low birthweight and SGA were each significantly associated with inadequate weight gain during pregnancy as well as with prepregnant body mass. These results suggest that current maternal nutritional status, as measured by weight gain during pregnancy, may influence preterm delivery and gestation duration. The inconsistent results obtained with prepregnancy body mass may reflect a size bias inherent in the obstetric estimate of gestation, rather than effects of prepregnant maternal nutritional status on gestation. PMID- 28597502 TI - Synergistic Impacts of Electrolyte Adsorption on the Thermoelectric Properties of Single-Walled Carbon Nanotubes. AB - Single-walled carbon nanotubes are promising candidates for light-weight and flexible energy materials. Recently, the thermoelectric properties of single walled carbon nanotubes have been dramatically improved by ionic liquid addition; however, controlling factors remain unsolved. Here the thermoelectric properties of single-walled carbon nanotubes enhanced by electrolytes are investigated. Complementary characterization with absorption, Raman, and X-ray photoelectron spectroscopy reveals that shallow hole doping plays a partial role in the enhanced electrical conductivity. The molecular factors controlling the thermoelectric properties of carbon nanotubes are systematically investigated in terms of the ionic functionalities of ionic liquids. It is revealed that appropriate ionic liquids show a synergistic enhancement in conductivity and the Seebeck coefficient. The discovery of significantly precise doping enables the generation of thermoelectric power factor exceeding 460 uW m-1 K-2 . PMID- 28597504 TI - Gold(Core)-Lead(Shell) Nanoparticle-Loaded Titanium(IV) Oxide Prepared by Underpotential Photodeposition: Plasmonic Water Oxidation. AB - Underpotential photodeposition of Pb yields an ultrathin shell layer on the Au(111) surface of Au nanoparticle(NP)-loaded TiO2 (Au/TiO2 ) with heteroepitaxial nanojunctions. The localized surface plasmon resonance of Au/TiO2 undergoes no damping with the Pb-shell formation, and the Pb shell offers resistance to aerobic oxidation. Mesoporous films comprising the Au(core) Pb(shell) NP-loaded TiO2 and unmodified Au/TiO2 were formed on fluorine-doped tin oxide (FTO) electrode. Using them as the photoanode, photoelectrochemical cells were fabricated, and the photocurrent was measured under illumination of simulated sunlight. The photocurrent for water splitting is dramatically enhanced by the Pb-shell formation. The photoelectrochemical measurements of the hot electron lifetime and density functional theory calculations for model clusters indicate that the Pb-shell effect originates from the charge separation enhancement. PMID- 28597503 TI - Prognostic model for brain metastases from lung adenocarcinoma identified with epidermal growth factor receptor mutation status. AB - BACKGROUND: Several indices have been developed to predict survival of brain metastases (BM) based on prognostic factors. However, such models were designed for general brain metastases from different kinds of cancers, and prognostic factors vary between cancers and histological subtypes. Recently, studies have indicated that epidermal growth factor receptor (EGFR) mutation status may be a potential prognostic biological factor in BM from lung adenocarcinoma. Thus, we sought to define the role of EGFR mutation in prognoses and introduce a prognostic model specific for BM from lung adenocarcinoma. METHODS: Data of 256 patients with BM from lung adenocarcinoma identified with EGFR mutations were collected. Independent prognostic factors were confirmed using a Cox regression model. The new prognostic model was developed based on the results of multivariable analyses. The score of each factor was calculated by six-month survival. Prognostic groups were divided into low, medium, and high risk based on the total scores. The prediction ability of the new model was compared to the three existing models. RESULTS: EGFR mutation and Karnofsky performance status were independent prognostic factors and were thus integrated into the new prognostic model. The new model was superior to the three other scoring systems regarding the prediction of three, six, and 12-month survival by pairwise comparison of the area under the curve. CONCLUSION: Our proposed prognostic model specific for BM from lung adenocarcinoma incorporating EGFR mutation status was valid in predicting patient survival. Further verification is warranted, with prospective testing using large sample sizes. PMID- 28597505 TI - Renal effects of an emergency department chloride-restrictive intravenous fluid strategy in patients admitted to hospital for more than 48 hours. AB - OBJECTIVE: Patients commonly receive i.v. fluids in the ED. It is still unclear whether the choice of i.v. fluids in this setting influences renal or patient outcomes. We aimed to assess the effects of restricting i.v. chloride administration in the ED on the incidence of acute kidney injury (AKI). METHODS: We conducted a before-and-after trial with 5008 consecutive ED-treated hospital admissions in the control period and 5146 consecutive admissions in the intervention period. During the control period (18 February 2008 to 17 August 2008), patients received standard i.v. fluids. During the intervention period (18 February 2009 to 17 August 2009), we restricted all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes (KDIGO) staging to define AKI. RESULTS: Stage 3 of KDIGO-defined AKI decreased from 54 (1.1%; 95% confidence interval [CI] 0.8-1.4) to 30 (0.6%; 95% CI 0.4-0.8) (P = 0.006). The rate of renal replacement therapy did not change, from 13 (0.3%; 95% CI 0.2-0.4) to 8 (0.2%; 95% CI 0.1-0.3) (P = 0.25). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stage 3 (hazard ratio 1.82; 95% CI 1.13-2.95; P = 0.01). On sensitivity assessment after removing repeat admissions, KDIGO stage 3 remained significantly lower in the intervention period compared with the control period (P = 0.01). CONCLUSION: In a before-and-after trial, a chloride-restrictive strategy in an ED was associated with a significant decrease in the incidence of stage 3 of KDIGO-defined AKI. PMID- 28597507 TI - Percutaneous ultrasound-guided cholecystocentesis: complications and association of ultrasonographic findings with bile culture results. AB - OBJECTIVES: To retrospectively evaluate cases presented for percutaneous ultrasound-guided cholecystocentesis for associated complications, identify risk factors associated with complications and to assess ultrasonographic findings and relate these to bacterial culture results. METHODS: Data on 300 patients presented for percutaneous ultrasound-guided cholecystocentesis were retrospectively collected and ultrasonographic images were assessed for defined structural changes. The incidence of major complications was determined. Multi variable multi-level logistic regression was used to investigate the association of ultrasonographic findings with positive bile culture. RESULTS: Three hundred percutaneous ultrasound-guided cholecystocentesis procedures performed in 201 dogs and 51 cats were included; 35 patients had the procedure performed more than once. The overall incidence of major complications was 8 of 300 procedures (2.7%). Bile peritonitis occurred in 2 of 300 procedures (0.7%). An ultrasonographically abnormal gall bladder was found in 52% of cases and had a sensitivity, specificity and accuracy of 82, 55.7 and 61.5% respectively, to predict a positive bile culture. CLINICAL SIGNIFICANCE: Percutaneous ultrasound guided cholecystocentesis is overall a safe technique when carried out in selected patients. Abnormal ultrasonographic findings are only a fair predictor of a positive bile culture. PMID- 28597506 TI - Skeletal myofiber vascular endothelial growth factor is required for the exercise training-induced increase in dentate gyrus neuronal precursor cells. AB - KEY POINTS: Peripheral vascular endothelial growth factor (VEGF) is necessary for exercise to stimulate hippocampal neurogenesis. Here we report that skeletal myofiber VEGF directly or indirectly regulates exercise-signalled proliferation of neuronal precursor cells. Our results found skeletal myofiber VEGF to be necessary for maintaining blood flow through hippocampal regions independent of exercise training state. This study demonstrates that skeletal myofiber VEGF is required for the hippocampal VEGF response to acute exercise. These results help to establish the mechanisms by which exercise, through skeletal myofiber VEGF, affects the hippocampus. ABSTRACT: Exercise signals neurogenesis in the dentate gyrus of the hippocampus. This phenomenon requires vascular endothelial growth factor (VEGF) originating from outside the blood-brain barrier, but no cellular source has been identified. Thus, we hypothesized that VEGF produced by skeletal myofibers plays a role in regulating hippocampal neuronal precursor cell proliferation following exercise training. This was tested in adult conditional skeletal myofiber-specific VEGF gene-ablated mice (VEGFHSA-/- ) by providing VEGFHSA-/- and non-ablated (VEGFf/f ) littermates with running wheels for 14 days. Following this training period, hippocampal cerebral blood flow (CBF) was measured by functional magnetic resonance imaging (fMRI), and neuronal precursor cells (BrdU+/Nestin+) were detected by immunofluorescence. The VEGFf/f trained group showed improvements in both speed and endurance capacity in acute treadmill running tests (P < 0.05). The VEGFHSA-/- group did not. The number of proliferating neuronal precursor cells was increased with training in VEGFf/f (P < 0.05) but not in VEGFHSA-/- mice. Endothelial cell (CD31+) number did not change in this region with exercise training or skeletal myofiber VEGF gene deletion. However, resting blood flow through the hippocampal region was lower in VEGFHSA-/- mice, both untrained and trained, than untrained VEGFf/f mice (P < 0.05). An acute hypoxic challenge decreased CBF (P < 0.05) in untrained VEGFf/f , untrained VEGFHSA-/- and trained VEGFHSA-/- mice, but not trained VEGFf/f mice. VEGFf/f , but not VEGFHSA-/- , mice were able to acutely run on a treadmill at an intensity sufficient to increase hippocampus VEGF levels. These data suggest that VEGF expressed by skeletal myofibers may directly or indirectly regulate both hippocampal blood flow and neurogenesis. PMID- 28597508 TI - A Graphene Quantum Dots-Hypochlorite Hybrid System for the Quantitative Fluorescent Determination of Total Antioxidant Capacity. AB - Antioxidants play a major part in the prevention and impairment of oxidative stress-induced damages and diseases. Evaluating the antioxidants activity/capacity in food and biological fluid is proved to be useful for the diagnosis and treatment of these oxidative stress-induced diseases. Herein, a graphene quantum dots (GQDs)-hypochlorite system to detect the antioxidants including nonenzymatic and enzymatic antioxidants in the biological fluid is proposed. The detection principle is based on the fact that antioxidants can protect the fluorescence of GQDs from hypochlorite-caused quenching by acting as the scavengers of hypochlorite. The GQDs-hypochlorite system allows the accurate quantification of the total antioxidant capacity (TAC) of commercial drinks as well as the extracellular superoxide dismutase (SOD) secretion upon stimulation of cytokines or hyperglycemia. This system shows the excellent analytical recoveries for commercial drinks (>89.9%) and good consistency with ELISA testing for SOD secretion in cell-conditioned medium. These results demonstrate the ability and reliability of the GQD-hypochlorite system for detecting and quantifying TAC in real drinks and complex biological fluids. PMID- 28597509 TI - Child and adolescent risk factors that differentially predict violent versus nonviolent crime. AB - While most research on the development of antisocial and criminal behavior has considered nonviolent and violent crime together, some evidence points to differential risk factors for these separate types of crime. The present study explored differential risk for nonviolent and violent crime by investigating the longitudinal associations between three key child risk factors (aggression, emotion dysregulation, and social isolation) and two key adolescent risk factors (parent detachment and deviant peer affiliation) predicting violent and nonviolent crime outcomes in early adulthood. Data on 754 participants (46% African American, 50% European American, 4% other; 58% male) oversampled for aggressive-disruptive behavior were collected across three time points. Parents and teachers rated aggression, emotion dysregulation, and social isolation in fifth grade (middle childhood, age 10-11); parents and youth rated parent detachment and deviant peer affiliation in seventh and eighth grade (early adolescence, age 12-14) and arrest data were collected when participants were 22 23 years old (early adulthood). Different pathways to violent and nonviolent crime emerged. The severity of child dysfunction in late childhood, including aggression, emotion dysregulation, and social isolation, was a powerful and direct predictor of violent crime. Although child dysfunction also predicted nonviolent crime, the direct pathway accounted for half as much variance as the direct pathway to violent crime. Significant indirect pathways through adolescent socialization experiences (peer deviancy) emerged for nonviolent crime, but not for violent crime, suggesting adolescent socialization plays a more distinctive role in predicting nonviolent than violent crime. The clinical implications of these findings are discussed. PMID- 28597510 TI - Urinary tract washing specimens containing atypical urothelial tissue fragments are significantly associated with urothelial neoplasia. AB - BACKGROUND: We previously found that the presence of atypical urothelial tissue fragments (AUTF) was associated with an increased risk of high-grade urothelial carcinoma (HGUC) but not low-grade urothelial neoplasia (LGUN) in voided urine (VU) specimens. However, we subsequently found that patients with LGUN were more likely to have cytologic atypia in urinary washing (UW) specimens, suggesting that cytologic atypia found in UW specimens might be associated with both LGUN and HGUC. In this study, we retrospectively examined UW specimens containing AUTF to determine whether they were associated with HGUC, LGUN, or both HGUC and LGUN. METHODS: 1173 UW specimens and any follow up biopsies were identified over a 10 year period and the presence of AUTF was recorded based on the original clinical diagnosis. RESULTS: The presence of AUTF in UW specimens was significantly associated with high-risk indeterminate diagnosis or definitive diagnosis of HGUC (P < .001). In addition, AUTF specimens were significantly associated with a neoplastic diagnosis of low-grade urothelial carcinoma (LGUC) or HGUC on subsequent biopsies when compared to specimens lacking AUTF (P = .047). The overall rate of CIS/HGUC in specimens with AUTF was 33.0 vs. 13.5% for specimens without AUTF (P = .051). CONCLUSIONS: Urothelial tissue fragments (UTF) found in UW specimens should be examined for the presence of cytomorphological atypia, as the presence of AUTF almost triples the risk of HGUC. As opposed to what has been found in VU specimens, AUTF in UW specimens is also associated with an increased risk of LGUN. PMID- 28597511 TI - Successful Treatment of Enterohemorrhagic Escherichia coli-Induced Acute Encephalopathy and Hemolytic-Uremic Syndrome With Polymyxin-B Direct Hemoperfusion. PMID- 28597512 TI - Vortex Fluidic Chemical Transformations. AB - Driving chemical transformations in dynamic thin films represents a rapidly thriving and diversifying research area. Dynamic thin films provide a number of benefits including large surface areas, high shearing rates, rapid heat and mass transfer, micromixing and fluidic pressure waves. Combinations of these effects provide an avant-garde style of conducting chemical reactions with surprising and unusual outcomes. The vortex fluidic device (VFD) has proved its capabilities in accelerating and increasing the efficiencies of numerous organic, materials and biochemical reactions. This Minireview surveys transformations that have benefited from VFD-mediated processing, and identifies concepts driving the effectiveness of vortex-based dynamic thin films. PMID- 28597513 TI - Complexity in Acid-Base Titrations: Multimer Formation Between Phosphoric Acids and Imines. AB - Solutions of Bronsted acids with bases in aprotic solvents are not only common model systems to study the fundamentals of proton transfer pathways but are also highly relevant to Bronsted acid catalysis. Despite their importance the light nature of the proton makes characterization of acid-base aggregates challenging. Here, we track such acid-base interactions over a broad range of relative compositions between diphenyl phosphoric acid and the base quinaldine in dichloromethane, by using a combination of dielectric relaxation and NMR spectroscopy. In contrast to what one would expect for an acid-base titration, we find strong deviations from quantitative proton transfer from the acid to the base. Even for an excess of the base, multimers consisting of one base and at least two acid molecules are formed, in addition to the occurrence of proton transfer from the acid to the base and simultaneous formation of ion pairs. For equimolar mixtures such multimers constitute about one third of all intermolecular aggregates. Quantitative analysis of our results shows that the acid-base association constant is only around six times larger than that for the acid binding to an acid-base dimer, that is, to an already protonated base. Our findings have implications for the interpretation of previous studies of reactive intermediates in organocatalysis and provide a rationale for previously observed nonlinear effects in phosphoric acid catalysis. PMID- 28597515 TI - Activation-Dependent Breathing in a Flexible Metal-Organic Framework and the Effects of Repeated Sorption/Desorption Cycling. AB - A non-interpenetrated metal-organic framework with a paddle-wheel secondary building unit has been activated by direct thermal evacuation, guest exchange with a volatile solvent, and supercritical CO2 drying. Conventional thermal activation yields a mixture of crystalline phases and some amorphous content. Exchange with a volatile solvent prior to vacuum activation produces a pure breathing phase with high sorption capacity, selectivity for CO2 over N2 and CH4 , and substantial hysteresis. Supercritical drying can be used to access a guest free open phase. Pressure-resolved differential scanning calorimetry was used to confirm and investigate a systematic loss of sorption capacity by the breathing phase as a function of successive cycles of sorption and desorption. A corresponding loss of sample integrity was not detectable by powder X-ray diffraction analysis. This may be an important factor to consider in cases where flexible MOFs are earmarked for industrial applications. PMID- 28597514 TI - Macrophage Migration Inhibitory Factor Induces Inflammation and Predicts Spinal Progression in Ankylosing Spondylitis. AB - OBJECTIVE: To investigate the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of ankylosing spondylitis (AS). METHODS: Patients who met the modified New York criteria for AS were recruited for the study. Healthy volunteers, rheumatoid arthritis patients, and osteoarthritis patients were included as controls. Based on the annual rate of increase in modified Stoke AS Spine Score (mSASSS), AS patients were classified as progressors or nonprogressors. MIF levels in serum and synovial fluid were quantitated by enzyme linked immunosorbent assay. Predictors of AS progression were evaluated using logistic regression analysis. Immunohistochemical analysis of ileal tissue was performed to identify MIF-producing cells. Flow cytometry was used to identify MIF-producing subsets, expression patterns of the MIF receptor (CD74), and MIF induced tumor necrosis factor (TNF) production in the peripheral blood. MIF induced mineralization of osteoblast cells (SaOS-2) was analyzed by alizarin red S staining, and Western blotting was used to quantify active beta-catenin levels. RESULTS: Baseline serum MIF levels were significantly elevated in AS patients compared to healthy controls and were found to independently predict AS progression. MIF levels were higher in the synovial fluid of AS patients, and MIF producing macrophages and Paneth cells were enriched in their gut. MIF induced TNF production in monocytes, activated beta-catenin in osteoblasts, and promoted the mineralization of osteoblasts. CONCLUSION: Our findings indicate an unexplored pathogenic role of MIF in AS and a link between inflammation and new bone formation. PMID- 28597516 TI - Introductory remarks: Influence of nutritional status on growth-perspectives from field and clinic. PMID- 28597517 TI - Sociogeographic variation in the physical fitness of a cross-sectional sample of Flemish girls 13 to 18 years of age. AB - Three aspects of physical fitness-somatic characteristics, motor fitness, and sport participation-of girls from different sociogeographic origins of Belgium were contrasted. The sample consisted of a cross-sectional sample of 4,528 Flemish girls 13 to 18 years of age, who were classified by dwelling area as rural, semi-urban, and urban. Somatic characteristics included 16 anthropometric dimensions, skeletal maturity, and somatotype. Motor fitness was assessed by 10 tests. Sociocultural background information and the level of sport participation were investigated by questionnaire and interview. Data were analysed via one-way analyses of variance and growth curves were plotted to compare the sociogeographic differentiation patterns in physical fitness variables. The results show small motor and somatic differences between rural and urban youngsters, which is explained by the process of conurbation. However, urban girls were significantly more involved in sports than their rural counterparts. This is most probably due to greater sport involvement of parents from urban girls and/or the differences in available sport facilities. PMID- 28597518 TI - Heterogeneity among populations for familial aggregation of blood pressure. AB - A simple model of familial aggregation was applied to age-sex corrected systolic (SBP) and diastolic (DBP) blood pressure data from two separate studies: The Quebec Family Study and the Tecumseh Community Health Study. Examination of the familial correlations suggested heterogeneity across studies in all DBP correlations, but for SBP only spouse correlations were higher in Quebec. Fitting the path model to the data revealed that the only source of heterogeneity for SBP was in spouse resemblance (u), which was significant in Quebec but could be dropped from the model in Tecumseh. For SBP, no further heterogeneity was detected, with the vertical transmission being compatible with (but not evidence for) purely polygenic inheritance (i.e., tauf = taum = 1/2). Familiality estimates (t2 ) for SBP were quite high (nearly 40%), and extra sibling resemblance was significant. For DBP, heterogeneity was detected in all parameters of the model except for spouse resemblance. Common sibship environmental effects (b) were of little importance in Tecumseh but were highly significant in Quebec. Vertical transmission from mothers (taum ) could be fixed at 1/2 in Tecumseh but was only about half as large in Quebec, and familiality estimates were higher in Quebec (nearly 60%) than in Tecumseh (about 25%). One source of the heterogeneity for SBP was due to cohabitation, which positively impacted on sibling correlations. The source of the sample heterogeneity in DBP may be through environmental factors which have a smaller impact in Tecumseh than in Quebec, although genetic heterogeneity could not be ruled out. Differences in the study designs, as well as differences in the two populations, could account for the heterogeneity detected. PMID- 28597519 TI - Feasibility study on robot-assisted retinal vascular bypass surgery in an ex vivo porcine model. AB - PURPOSE: To describe a new robot-assisted surgical system for retinal vascular bypass surgery (RVBS) and to compare the success rate with freehand RVBS. METHODS: A robot-assisted system for retinal microsurgery was constructed to include two independent robotic arms. A 23-gauge light probe and an intraocular forceps were affixed to the arm end effectors to perform the intraocular manipulation. Harvested porcine eyes were introduced to be established animal models of closed-sky eyeballs after that pars plana vitrectomy using temporary keratoprosthesis was performed by a skilful surgeon. Retinal vascular bypass surgery (RVBS) was performed by an inexperienced ophthalmologist to test the ease of use. A stainless steel wire (45-MUm pipe diameter) was used as an artificial vessel. Before RVBS, the wires were prepositioned at the retinal surface of the eyes. The Control group (n = 20) underwent freehand RVBS, and the Experimental group (n = 20) underwent robot-assisted RVBS. To create the simulated bypass, the distal end of the wire was inserted into the selected vessel and advanced ~4 mm away from the optic disc. If successful, then the proximal wire end was inserted and advanced ~2 mm towards the optic disc. The difference in the success rate for the freehand and robot-assisted procedures was analysed by the chi-square test. RESULTS: The success rate for the freehand RVBS was 5% (1/20 eyes). In contrast, the robot-assisted success rate was 35% (7/20) of eyes (p < 0.05). CONCLUSION: This study demonstrated the feasibility of robot-assisted RVBS in ex vivo porcine eyes. The robotic system increased the accuracy and stability of manipulation by eliminating freehand tremor, leading to a higher surgical success rate. PMID- 28597520 TI - The impact of vaccination on RBC alloimmunization in a murine model. AB - Emerging data in animal models and humans suggest that pathogen-associated and damage-associated molecular patterns variably impact RBC alloantibody formation. In this study, we tested the hypothesis that vaccinations may enhance immune responses to transfused RBCs. The Pneumovax23 vaccine decreased the magnitude of anti-KEL alloimmunization in a murine model, whereas the hepB vaccine did not impact the response; RBC transfusion did not alter immune responses to either vaccine. These data highlight the complexities of the intersection of innate and adaptive immunity and suggest that future studies investigating the pathways through which inflammation impacts alloimmunization are warranted. PMID- 28597521 TI - Erratum. PMID- 28597523 TI - Corrigendum: Formation Mechanism of the First Carbon-Carbon Bond and the First Olefin in the Methanol Conversion into Hydrocarbons. PMID- 28597524 TI - Loosening of Lipid Packing Promotes Oligoarginine Entry into Cells. AB - Despite extensive use of arginine-rich cell-penetrating peptides (CPPs)-including octaarginine (R8)-as intracellular delivery vectors, mechanisms for their internalization are still under debate. Lipid packing in live cell membranes was characterized using a polarity-sensitive dye (di-4-ANEPPDHQ), and evaluated in terms of generalized polarization. Treatment with membrane curvature-inducing peptides led to significant loosening of the lipid packing, resulting in an enhanced R8 penetration. Pyrenebutyrate (PyB) is known to facilitate R8 membrane translocation by working as a hydrophobic counteranion. Interestingly, PyB also actively induced membrane curvature and perturbed lipid packing. R8 is known to directly cross cell membranes at elevated concentrations. The sites of R8 influx were found to have looser lipid packing than surrounding areas. Lipid packing loosening is proposed as a key factor that governs the membrane translocation of CPPs. PMID- 28597525 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 26/2017. PMID- 28597526 TI - Primum non nocere: the dangers of deferring heart failure therapy. PMID- 28597527 TI - Nanoscale Chemical Imaging of Interfacial Monolayers by Tip-Enhanced Raman Spectroscopy. AB - We report an investigation of interfacial fluorinated hydrocarbon (carboxylic fantrip) monolayers by nanoscale imaging using tip-enhanced Raman spectroscopy (TERS) and density functional theory (DFT) calculations. By comparing TERS images of a sub-monolayer prepared by spin-coating and a pi-pi-stacked monolayer on Au(111) in which the molecular orientation is confined, specific Raman peaks shift and line widths narrow in the transferred LB monolayer. Based on DFT calculations that take into account dispersion corrections and surface selection rules, these specific effects are proposed to originate from pi-pi stacking and molecular orientation restriction. TERS shows the possibility to distinguish between a random and locked orientation with a spatial resolution of less than 10 nm. This work combines experimental TERS imaging with theoretical DFT calculations and opens up the possibility of studying molecular orientations and intermolecular interaction at the nanoscale and molecular level. PMID- 28597528 TI - Enhancement of recovery from mental illness with l-methylfolate supplementation. AB - People suffering from depression, schizophrenia, and dementia often have measurably lower levels of serum folate compared to people not experiencing psychiatric disorders. Augmentation of SSRI and SNRI antidepressant medications with l-methylfolate has been demonstrated to increase their effectiveness and onset of action. Even the use of l-methylfolate as a stand-alone monotherapy has been observed to exert antidepressant properties. The role of folate in mental illness has been known for many decades, but the strategic use of l-methylfolate supplementation has not yet been accepted as a standard regimen. It is the proposal of this paper that advanced nurse practitioners should consider the use of l-methylfolate as an adjunct to antidepressant medications at the initiation of therapy as part of a standard regimen in their clinical practice. PMID- 28597529 TI - Potassium-Based Dual Ion Battery with Dual-Graphite Electrode. AB - A potassium ion battery has potential applications for large scale electric energy storage systems due to the abundance and low cost of potassium resources. Dual graphite batteries, with graphite as both anode and cathode, eliminate the use of transition metal compounds and greatly lower the overall cost. Herein, combining the merits of the potassium ion battery and dual graphite battery, a potassium-based dual ion battery with dual-graphite electrode is developed. It delivers a reversible capacity of 62 mA h g-1 and medium discharge voltage of ~3.96 V. The intercalation/deintercalation mechanism of K+ and PF6- into/from graphite is proposed and discussed in detail, with various characterizations to support. PMID- 28597530 TI - Relationship between clinical parameters and linear growth in children with cystic fibrosis. AB - Mixed longitudinal height data from 1,170 cystic fibrosis patients seen at Rainbow Babies and Childrens Hospital in Cleveland form the basis for this analysis. As a group, the patients experience growth retardation throughout the growth cycle, with median height values below the 25th percentile of NCHS standards until late adolescence. Median height increments are also below normal standards until age 16 years in boys and 14 years in girls. Based on these results, it appears that some CF patients have very delayed adolescent growth spurts, and continue to grow into early adulthood. Pancreataic-enzyme-sufficient patients have greater height-for-age percentiles than enzyme-deficient patients after 9 years of age. The overall difference between enzyme-sufficient and enzyme deficient patients is not statistically significant (P=0.058), perhaps because of small sample size for the enzyme-sufficient group (n=19). The correlation between pulmonary status assessed from lung X-rays and height increment peaks at age 10 years in girls and age 15 years in boys, with significant negative correlation occurring after age 16 years in both sexes. Although both pancreatic enzyme deficiency and lung disease appear to have some effect on linear growth in CF, especially during adolescence, these two factors explain a relatively small portion of the variation in growth percentiles. PMID- 28597531 TI - Attitudes in Australia on the upscheduling of over-the-counter codeine to a prescription-only medication. AB - INTRODUCTION AND AIMS: In December 2016, the Australian Therapeutic Goods Administration announced that over-the-counter (OTC) codeine would be available by prescription-only in February 2018. Prior to this announcement, the authors aimed to evaluate attitudes among Australian codeine consumers, pharmacists and general medical practitioners (GP) towards the proposed upscheduling of OTC codeine. DESIGN AND METHODS: Public Therapeutic Goods Administration submissions on codeine upscheduling were assessed, and a brief questionnaire was developed to assess the common issues raised. Participants (354 codeine consumers; 220 pharmacists; 120 GPs) completed a web-based questionnaire. Comparisons of attitudes on specific statements related to codeine upscheduling were made between consumers who were in support and those who opposed the proposal and between pharmacists and GPs. Regression models were conducted to examine correlates of attitudes towards codeine restriction. RESULTS: Most consumer, pharmacist and a third of GP respondents opposed the upscheduling of codeine. Consumers, on average, questioned whether the proposed intervention would address the intended targets of minimising codeine-related side effects and risk of codeine dependence. Like consumers, pharmacists indicated concern around whether codeine restriction would address concerns of associated harm and dependence, as well as the burden regular GP appointments would create in terms of finances for consumers and time for GPs. GPs themselves, did not support these views. DISCUSSION AND CONCLUSIONS: Consumer responses identify key targets for educational campaigns when codeine is rescheduled, particularly around effective alternatives to OTC codeine. Additionally, contrasting views of pharmacists and GPs reinforce the importance of pharmacovigilance in evaluating the effectiveness of codeine restriction, once implemented. [McCoy J, Bruno R, Nielsen S. Attitudes in Australia on the upscheduling of over-the-counter codeine to a prescription only medication. Drug Alcohol Rev 2017;00:000-000]. PMID- 28597533 TI - ERRATUM. PMID- 28597532 TI - Substrate characterization and catheter ablation in patients with scar-related ventricular tachycardia using ultra high-density 3-D mapping. AB - BACKGROUND: Ablation of scar-related ventricular tachycardia (VT), especially in noninducible VT or hemodynamically unstable patients, can be challenging. Thus, we evaluated feasibility of an ultra high-density 3-D mapping approach to characterize the ventricular substrate and, if possible, to map VT. METHODS AND RESULTS: Twenty-two patients (67 +/- 2 years, mean LV-EF 36 +/- 3%) with both ischemic and nonischemic cardiomyopathy and documented VT underwent mapping and catheter ablation using a 64-electrode mini-basket catheter. Substrate characterization included ultra high-density voltage maps, identification of areas of slow conduction and late potentials. Whenever VT was inducible activation mapping was performed. In 13 of 22 patients, the presumed clinical VT (in 16 of 22 any VT) was inducible. A total of 50 maps were generated (22 substrate maps, 28 during VT), mapping time was 33 +/- 4 minutes, number of points was 10,937 +/- 1,923. Low voltage areas were related with the site of origin in all mapped VT. Isochronal maps indicated areas of slow conduction in 14 of 22 patients, all in border zone scar. In 95% of patients, late potentials were found. Mapping time during VT was 9 +/- 2 minutes, number of points 6,740 +/- 1,140. Covered cycle length was 82 +/- 5% (16 re-entry, 10 focal, and two undetermined). During 4 months follow-up, 90% remained free from VT recurrence. CONCLUSION: Ultra high-density mapping in patients with scar-related VT is feasible, safe and enables detailed insight into tachycardia mechanisms. Critical sites can be identified (1) by precise substrate characterization when VT is not inducible or hemodynamically not tolerated and (2) during short lasting episodes of VT in order to guide catheter ablation. PMID- 28597534 TI - Whole-genome patterns of linkage disequilibrium across flycatcher populations clarify the causes and consequences of fine-scale recombination rate variation in birds. AB - Recombination rate is heterogeneous across the genome of various species and so are genetic diversity and differentiation as a consequence of linked selection. However, we still lack a clear picture of the underlying mechanisms for regulating recombination. Here we estimated fine-scale population recombination rate based on the patterns of linkage disequilibrium across the genomes of multiple populations of two closely related flycatcher species (Ficedula albicollis and F. hypoleuca). This revealed an overall conservation of the recombination landscape between these species at the scale of 200 kb, but we also identified differences in the local rate of recombination despite their recent divergence (<1 million years). Genetic diversity and differentiation were associated with recombination rate in a lineage-specific manner, indicating differences in the extent of linked selection between species. We detected 400 3,085 recombination hotspots per population. Location of hotspots was conserved between species, but the intensity of hotspot activity varied between species. Recombination hotspots were primarily associated with CpG islands (CGIs), regardless of whether CGIs were at promoter regions or away from genes. Recombination hotspots were also associated with specific transposable elements (TEs), but this association appears indirect due to shared preferences of the transposition machinery and the recombination machinery for accessible open chromatin regions. Our results suggest that CGIs are a major determinant of the localization of recombination hotspots, and we propose that both the distribution of TEs and fine-scale variation in recombination rate may be associated with the evolution of the epigenetic landscape. PMID- 28597535 TI - Epidemiology of campylobacteriosis in Denmark 2000-2015. AB - Campylobacter is the most frequently occurring cause of bacterial gastroenteritis in Europe. Unlike other zoonotic diseases, European-wide incidences of Campylobacter infections have increased during the past decade, resulting in a significant disease burden. In Denmark, campylobacteriosis is notifiable by laboratory and a unique registration system of electronic transfer and storage of notified Campylobacter cases linked to the national person register of age, gender and geographical location allows collection of comprehensive case data. Using national surveillance data, we describe Campylobacter infections in Denmark from 2000 to 2015, focusing on age-specific incidences, geography, seasonality and outbreaks. During the observed period, a total of 60,725 Campylobacter infections were registered with a mean annual incidence of 69.3 cases/100,000 population. From 2000 to 2014, the incidence of campylobacteriosis decreased by 20%, followed by an apparent increase of 20% from 2014 to 2015. Approximately one third of cases were travel-related. Incidences were highest in males, young adults aged 20-29 years and children under 5 years of age. Generally, children under 10 years of age living in rural areas were at higher risk of infection. Infection patterns were seasonal with an increase from May to October, peaking in August. Outbreaks were identified each year, including four large waterborne outbreaks which all occurred following heavy rainfall events. For the most part, patterns of Campylobacter infection in Denmark during 2000 to 2015 remained remarkably constant and followed what is known about the disease with respect to demographic, temporal and spatial characteristics. To establish better targeted prevention and control measures, the current knowledge gaps regarding both Campylobacter microbiology (degree of clonal diversity and clustering) and the importance of different risk factors (food versus environment/climate) need to be filled. PMID- 28597536 TI - Timing of solid food introduction and association with later childhood overweight and obesity: The IDEFICS study. AB - This study investigated associations between timing of solid food introduction and childhood obesity and explored maternal characteristics influencing early feeding practices. Cross-sectional data from children 2-9 years (n = 10,808; 50.5% boys) residing in 8 European countries of the IDEFICS study (2007-2008) were included. Late solid food introduction (>=7 months of age) was associated with an increased prevalence of later childhood overweight/obesity among exclusively breastfed children (OR [odds ratio]: 1.38, 95% CI [confidence interval] [1.01, 1.88]). In contrast, early solid food introduction (<4 months of age) was associated with lower prevalence of overweight/obesity among children that ceased exclusive breastfeeding earlier than 4 months (OR: 0.63, 95% CI [0.47, 0.84]). Children that were introduced to solids right after 6 months exclusive breastfeeding and continued to receive breastmilk (>=12 months) were less likely to become overweight/obese (OR: 0.67, 95% CI [0.51, 0.88]) compared to children that discontinued to receive breastmilk. Analyses were adjusted for age, sex, country, birth weight, parental education level, parental body mass index, tobacco use in pregnancy, gestational weight gain, and gestational diabetes. Underweight mothers, overweight mothers, mothers who reported daily smoking during pregnancy, and low-educated mothers were less likely to follow recommendations on breastfeeding and timely solids introduction. Future studies should examine whether guidelines for solid food introduction timing have to distinguish between exclusively breastfed, formula fed, and too early exclusive breastfeeding-ceased infants. There is also need for more prospective studies; recall bias was an important current limitation. In conclusion, health professionals should emphasize benefits of breastfeeding and appropriate solid food introduction, especially to mothers that are less likely to follow recommendations. PMID- 28597538 TI - Bone cortical area in the evaluation of nutrition and activity levels. AB - This study compares the differing impacts of nutrition and habitual activities on cortical area. While nutrition should have a systemic effect on cortical area, activities are more likely to result to localized changes in either cortical area, its distribution, or both. Two groups from the Southeastern United States were examined here: Archaic hunter-gatherers and Mississippian agriculturalists. Cross-sectional area and strength were greater in the femora alone of agricultural males. Agricultural females showed no increases in cortical area, but nonetheless had greater strength in both the arms and legs. In addition, in spite of significantly lower cortical area at one site-the proximal humerus agricultural females maintained bone strength at this level. These findings suggest that most of the differences seen in cross-sectional area and structure are due to changing activities associated with the introduction of agriculture, although nutrition probably had a constraining effect on cortical area in agricultural females. Finally, in order to distinguish between the effects of diet and activities, it is best to examine more than a single bone and to consider both cortical area and its distribution, rather than area alone. PMID- 28597537 TI - The challenge of complex drug use: Associated use of codeine-containing medicines and new psychoactive substances in a European cross-sectional online population. AB - OBJECTIVE: Misuse of codeine-containing medicines in combination with new psychoactive substances (NPS) is inadequately described. This study characterises codeine consumption amongst NPS users and non-NPS users to provide warning of health issues. METHODS: Online survey conducted between July 2015 and March 2016. RESULTS: Out of 340 respondents, residing in a country in Europe and using codeine recently, 63.8% were female. Mean age: 34.9 years (SD = 12.4). Substance use included NPS (18.5%) and illicit controlled drugs (55.9%). Factors relating to codeine use found to significantly predict NPS use were consuming codeine extracted from combination tablets (OR = 16.79, 95% CI [8.67, 32.51]), obtaining codeine from friends, family, and acquaintances (OR = 3.98, 95% CI [1.82, 8.7]), use of illicit controlled drugs (OR = 34.99, 95% CI [8.39, 145.94]) and use of codeine to experience euphoria (OR = 6.41, 95% CI [3.42, 12.04]). CONCLUSIONS: Amongst NPS users, codeine is less likely to be used daily but more likely to be used for recreational purposes. Smaller populations engaging in high-risk use exist who take multiple drugs in high doses. Combinations of misused codeine and NPS highlight the need for policy to respond to a more complex drug situation. PMID- 28597539 TI - Developmental effects of antipsychotic drugs on serotonin receptor subtypes. AB - Antipsychotic medications are increasingly prescribed to pediatric and adolescent patients with psychotic diseases in spite of limited knowledge on the long-term effects of dissimilar antipsychotic drugs on developing brain. In this study, we quantified the levels of two major serotonin 5-HT1A , and 5-HT2A receptors in brain regions of developing rats after 3 weeks of treatment with typical (fluphenazine) and atypical (clozapine and olanzapine) antipsychotics, and compared to similarly treated adult rats treated with olanzapine, risperidone, and quetiapine examined in previous studies. Fluphenazine, clozapine, and olanzapine all increased 5-HT1A receptors in medial prefrontal cortex (MPC) and dorsolateral frontal cortex (DFC) of juvenile and adult rats. Clozapine and olanzapine also increased 5-HT1A labeling in hippocampal CA1 and CA3 regions of juvenile but not adult animals. Repeated treatments with clozapine and olanzapine, but not fluphenazine, decreased 5-HT2A receptors in MPC and DFC in developing and mature animals. In addition, both clozapine and olanzapine selectively reduced 5-HT2A labeling in hippocampal CA1 and CA3 regions of juvenile animals. These findings suggest that forebrain 5-HT receptor subtypes in juvenile animals are more sensitive than adults to the long-term effects of antipsychotic drugs, which may account for differences in clinical effects of antipsychotic drugs between young vs. adult psychiatric patients. PMID- 28597540 TI - Urbanization-dependent gradients in stature among polish conscripts in 1976 and 1986. AB - On the basis of two successive surveys of 19-year-old Polish conscripts, one in 1976 and another in 1986, secular trends in stature and the relationship between stature and population size of locality of habitation were examined. In spite of the serious economic crisis in the early 1980s and a rather abrupt cessation of the trend towards earlier menarche in Poland between 1977 and 1987, the trend towards taller stature continued unabated and was intense (2.0 cm in the general population). In 1976, stature decreased systematically with decreasing population size in the following order: (1) cities over 500,000, (2) cities between 100,000 and 500,000, (3) towns between 25,000 and 100,000, (4) towns below 25,000, and (5) villages. A similar gradient persisted in the 1986 survey. In 1986, about one half of the total statural gradient was accounted for by the gap between rural conscripts and those next on the urbanization scale, i.e., conscripts from the smallest towns, and the magnitude of this gap was unaltered during the decade. However, the rural-large city gap has declined from 3.6 cm in 1976 to 2.8 cm in 1986. The relative shortness of rural conscripts and the tallness of their large city age peers are consistent with the pattern of social variation in stature and maturation rate observed among Polish school children and with the country's postwar economic and social history. PMID- 28597541 TI - Restless roosts: Light pollution affects behavior, sleep, and physiology in a free-living songbird. AB - The natural nighttime environment is increasingly polluted by artificial light. Several studies have linked artificial light at night to negative impacts on human health. In free-living animals, light pollution is associated with changes in circadian, reproductive, and social behavior, but whether these animals also suffer from physiologic costs remains unknown. To fill this gap, we made use of a unique network of field sites which are either completely unlit (control), or are artificially illuminated with white, green, or red light. We monitored nighttime activity of adult great tits, Parus major, and related this activity to within individual changes in physiologic indices. Because altered nighttime activity as a result of light pollution may affect health and well-being, we measured oxalic acid concentrations as a biomarker for sleep restriction, acute phase protein concentrations and malaria infection as indices of immune function, and telomere lengths as an overall measure of metabolic costs. Compared to other treatments, individuals roosting in the white light were much more active at night. In these individuals, oxalic acid decreased over the course of the study. We also found that individuals roosting in the white light treatment had a higher probability of malaria infection. Our results indicate that white light at night increases nighttime activity levels and sleep debt and affects disease dynamics in a free living songbird. Our study offers the first evidence of detrimental effects of light pollution on the health of free-ranging wild animals. PMID- 28597543 TI - Epidemiological differences among birth weight and gestational age subgroups of newborns. AB - For a sample of 16,113 women who received prenatal care from the Guatemalan Social Security Institute Hospital, we described the distribution of birth weight and gestational age subgroups and the association between known epidemiologic risk factors and the odds for 1) an appropriate-weight-for-gestational-age preterm vs. a small-for-gestational-age term infant, 2) a small-for-gestational age preterm vs. a small-for-gestational-age term infant, and 3) a normal ponderal index vs. a low ponderal index term small-for-gestational-age infant. We found that low maternal income, education, height (3147 cm), prepregnancy weight (347.8 kg), and weight gain during pregnancy (30.72 kg) were associated with a greater odds for birth of a term small-for-gestational-age infant (particularly those with a normal ponderal index) than for the birth of a preterm appropriate-weight for-gestational-age infant. Conversely, medical and pregnancy-related complications were associated with greater odds for a preterm birth of an appropriate- or a small-for-gestational-age infant. Implications of these findings for interventions and research are discussed. PMID- 28597542 TI - The efficacy and safety of gemcitabine, cisplatin, prednisone, thalidomide versus CHOP in patients with newly diagnosed peripheral T-cell lymphoma with analysis of biomarkers. AB - We compared the efficacy and safety of gemcitabine, cisplatin, prednisone and thalidomide (GDPT) with standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) for patients with newly diagnosed peripheral T-cell lymphoma (PTCL) in a prospective randomized controlled and open-label clinical trial. Between July 2010 and June 2016, 103 patients were randomly allocated into two groups, of whom 52 were treated with GDPT therapy and 51 with CHOP therapy. The 2-year progression-free survival (PFS) and overall survival (OS) rates were better in the GDPT group than in the CHOP group (57% vs. 35% for 2-year PFS, P = 0.0035; 71% vs 50% for 2-year OS, P = 0.0001). The complete remission rate (CRR) and the overall response rate (ORR) in the GDPT group were higher than in the CHOP group (52% vs. 33%, P = 0.044 for CRR; 67% vs. 49%, P = 0.046 for ORR). Haemocytopenia was the predominant adverse effect, and acute toxicity was moderate, tolerable and well managed in both arms. mRNA expression of ERCC1, RRM1, TUBB3 and TOP2A genes varied among patients but the difference did not reach statistical significance, mainly due to the relatively small sample size. The precise characters of these biomarkers remain to be identified. In conclusion, GDPT is a promising new regimen as potential first-line therapy against PTCL. This study was registered at www.clinicaltrials.gov as #NCT01664975. PMID- 28597544 TI - Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation. AB - The folding of newly synthesized proteins in the endoplasmic reticulum (ER) is assisted by ER-resident chaperone proteins. BiP (immunoglobulin heavy-chain binding protein), a member of the HSP70 family, plays a central role in protein quality control. The chaperone function of BiP is regulated by its intrinsic ATPase activity, which is stimulated by ER-resident proteins of the HSP40/DnaJ family, including ERdj3. Here, we report that two closely related proteins, SDF2 and SDF2L1, regulate the BiP chaperone cycle. Both are ER-resident, but SDF2 is constitutively expressed, whereas SDF2L1 expression is induced by ER stress. Both luminal proteins formed a stable complex with ERdj3 and potently inhibited the aggregation of different types of misfolded ER cargo. These proteins associated with non-native proteins, thus promoting the BiP-substrate interaction cycle. A dominant-negative ERdj3 mutant that inhibits the interaction between ERdj3 and BiP prevented the dissociation of misfolded cargo from the ERdj3-SDF2L1 complex. Our findings indicate that SDF2 and SDF2L1 associate with ERdj3 and act as components in the BiP chaperone cycle to prevent the aggregation of misfolded proteins, partly explaining the broad folding capabilities of the ER under various physiological conditions. PMID- 28597545 TI - Cimifugin suppresses allergic inflammation by reducing epithelial derived initiative key factors via regulating tight junctions. AB - Cimifugin is a bioactive component of Saposhnikovia divaricata, a Chinese herb for treating allergy. Our previous studies demonstrated that cimifugin inhibited allergic inflammation efficiently. This study aims to determine the mechanism of cimifugin on epithelial cells in allergic inflammation. Mice were sensitized and challenged with FITC to establish type 2 atopic dermatitis (AD) model. The initial stage of AD model, in which mice were just sensitized with FITC, was established in vivo and immortalized human epidermal (HaCaT) cells were utilized in vitro. Initiative key cytokines, TSLP and IL-33, were measured by ELISA, the junctions in ECs were observed by electron microscopy and TJs (CLDN-1, occludin and CLDND1) were assessed by Western blot, immunohistochemistry and immunofluorescence. The results showed that TSLP and IL-33 were inhibited significantly by cimifugin in the initial stage of AD model. Simultaneously, cimifugin reduced the separated gap among the epithelial cells and increased the expression of TJs. Similar effects on TSLP/IL-33 and TJs were obtained in vitro. The effect of cimifugin on TSLP decreased significantly when expression of CLDN1 was interfered with siRNA and this implied cimifugin inhibits initiative cytokines through restoring TJs. Furthermore, cimifugin administered only in the initial stage obviously attenuated the ultimate allergic inflammation, which indicate that impacts of cimifugin in the initial stage on TSLP/IL-33 and TJs are sufficient for suppressing allergic inflammation. This study not only revealed the mechanisms of cimifugin, but also indicated the possibility of initiative key cytokines and TJs as therapeutic targets. PMID- 28597547 TI - Controlled Growth of Monocrystalline Organo-Lead Halide Perovskite and Its Application in Photonic Devices. AB - Organo-lead halide perovskites (OHPs) have recently emerged as a new class of exceptional optoelectronic materials, which may find use in many applications, including solar cells, light emitting diodes, and photodetectors. More complex applications, such as lasers and electro-optic modulators, require the use of monocrystalline perovskite materials to reach their ultimate performance levels. Conventional methods for forming single crystals of OHPs like methylammonium lead bromide (MAPbBr3 ) afford limited control over the product morphology, rendering the assembly of defined microcavity nanostructures difficult. We overcame this by synthesizing for the first time (MA)[PbBr3 ]?DMF (1), and demonstrating its facile transformation into monocrystalline MAPbBr3 microplatelets. The MAPbBr3 microplatelets were tailored into waveguide based photonic devices, of which an ultra-low propagation loss of 0.04 dB MUm-1 for a propagation distance of 100 MUm was demonstrated. An efficient active electro-optical modulator (AEOM) consisting of a MAPbBr3 non-linear arc waveguide was demonstrated, exhibiting a 98.4 % PL intensity modulation with an external voltage of 45 V. This novel synthetic approach, as well as the demonstration of effective waveguiding, will pave the way for developing a wide range of photonic devices based on organo-lead halide perovskites. PMID- 28597548 TI - Equitable Access Is Not a Secondary Goal of Organ Allocation. PMID- 28597549 TI - Lexical-processing efficiency leverages novel word learning in infants and toddlers. AB - Children who rapidly recognize and interpret familiar words typically have accelerated lexical growth, providing indirect evidence that lexical processing efficiency (LPE) is related to word-learning ability. Here we directly tested whether children with better LPE are better able to learn novel words. In Experiment 1, 17- and 30-month-olds were tested on an LPE task and on a simple word-learning task. The 17-month-olds' LPE scores predicted word learning in a regression model, and only those with relatively good LPE showed evidence of learning. The 30-month-olds learned novel words quite well regardless of LPE, but in a more difficult word-learning task (Experiment 2), their LPE predicted word learning ability. These findings suggest that LPE supports word-learning processes, especially when learning is difficult. PMID- 28597546 TI - Endothelin-1 receptor blockade as new possible therapeutic approach in multiple myeloma. AB - New effective treatments are needed to improve outcomes for multiple myeloma (MM) patients. Receptors with restricted expression on plasma cells (PCs) represent attractive new therapeutic targets. The endothelin-1 (EDN1) axis, consisting of EDN1 acting through EDN-receptor A (EDNRA) and B (EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM. PMID- 28597550 TI - Technical error of mesiodistal diameters for the permanent and deciduous dentition. AB - Method errors and reliabilities are given for mesiodistal measurements of the permanent and deciduous dentitions. Method errors, describing random measurement error, range between 0.04 and 0.12 mm. Reliabilities, describing the proportion of true variance to true plus error variance, are lowest for measurements taken on the canines. Mesiodistal measurements of the incisors are more reliable than those taken on the (pre)molars. The different reliability estimates reflect disparities in true rather than error variance. The method error and reliability statistics serve different purposes and lead to different interpretations. PMID- 28597551 TI - Testis-specific isoform of Na/K-ATPase (ATP1A4) regulates sperm function and fertility in dairy bulls through potential mechanisms involving reactive oxygen species, calcium and actin polymerization. AB - Traditional bull breeding soundness evaluation (BBSE) eliminates bulls that are grossly abnormal; however, bulls classified as satisfactory potential breeders still vary in field fertility, implying submicroscopic differences in sperm characteristics. The testis-specific isoform of Na/K-ATPase (ATP1A4) is involved in regulation of sperm motility and capacitation in bulls through well established enzyme activity and signaling functions. The objective was to determine ATP1A4 content, activity and their relationship to post-thaw sperm function and field fertility, using semen samples from low-fertility (LF) and high-fertility (HF) Holstein bulls (n = 20 each) with known FERTSOL rates (measure of field fertility, based on non-return rate). Frozen-thawed sperm from HF bulls had increased ATP1A4 content and activity compared to LF bulls. Furthermore, post-thaw sperm from HF bulls had increased tyrosine phosphorylation, ROS, F-actin content, and low intracellular calcium compared to LF bulls. Subsequent incubation of HF bull sperm with ouabain (a specific ligand of Na/K-ATPase) further augmented the post-thaw increase in tyrosine phosphorylation, ROS production, and F-actin content, whereas the increase in intracellular calcium was still low compared to LF bull sperm. ATP1A4 content and activity, ROS, F-actin and calcium were significantly correlated with fertility. In conclusion, we inferred that ATP1A4 content and activity differed among dairy bulls with satisfactory semen characteristics and that ATP1A4 may regulate sperm function through mechanisms involving ROS, F-actin and calcium in frozen-thawed sperm of HF and LF dairy bulls. PMID- 28597552 TI - Branched chain alpha-ketoacid dehydrogenase kinase 111-130, a T cell epitope that induces both autoimmune myocarditis and hepatitis in A/J mice. AB - INTRODUCTION: Organ-specific autoimmune diseases are believed to result from immune responses generated against self-antigens specific to each organ. However, when such responses target antigens expressed promiscuously in multiple tissues, then the immune-mediated damage may be wide spread. METHODS: In this report, we describe a mitochondrial protein, branched chain alpha-ketoacid dehydrogenase kinase (BCKDk ) that can act as a target autoantigen in the development of autoimmune inflammatory reactions in both heart and liver. RESULTS: We demonstrate that BCKDk protein contains at least nine immunodominant epitopes, three of which, BCKDk 71-90, BCKDk 111-130 and BCKDk 141-160, were found to induce varying degrees of myocarditis in immunized mice. One of these, BCKDk 111 130, could also induce hepatitis without affecting lungs, kidneys, skeletal muscles, and brain. In immunogenicity testing, all three peptides induced antigen specific T cell responses, as verified by proliferation assay and/or major histocompatibility complex class II/IAk dextramer staining. Finally, the disease inducing abilities of BCKDk peptides were correlated with the production of interferon-gamma, and the activated T cells could transfer disease to naive recipients. CONCLUSIONS: The disease induced by BCKDk peptides could serve as a useful model to study the autoimmune events of inflammatory heart and liver diseases. PMID- 28597553 TI - Attenuated positive psychotic symptoms and the experience of anhedonia. AB - BACKGROUND: Deficits in anticipatory pleasure have been consistently shown among chronic, first-episode, and clinical high risk for psychosis populations, but much less attention has been given to non-clinical individuals experiencing attenuated positive psychotic symptoms (APPS). METHODS: Young adults (N = 1839) were administered the Temporal Experience of Pleasure Scale, which measures anticipatory and consummatory pleasure, and the Prodromal Questionnaire, which measures APPS. Analyses examined (1) total APPS endorsed and (2) comparisons of groups experiencing APPS that were endorsed as distressing (distressing APPS = D APPS; experiencing more D-APPS = high-D-APPS, a potentially more clinically meaningful group; experiencing fewer D-APPS = low-D-APPS). RESULTS: Results indicated that anticipatory, but not consummatory, pleasure deficits were associated with elevated APPS. Additionally, the high-D-APPS group exhibited significantly less anticipatory pleasure compared with the low-D-APPS group, but did not differ in consummatory pleasure. CONCLUSION: Our results mirror findings in schizophrenia samples and suggest that anticipatory pleasure deficits occur along the entire continuum of psychotic experiences. PMID- 28597554 TI - Clinical outcomes in a specialist male genital skin clinic: prospective follow-up of 600 patients. AB - It is important to assess outcomes for medical interventions in order to focus scarce resources on outcomes with a known positive benefit. An open, observational study was performed to assess the clinical outcomes of 600 male patients with a genital skin problem attending a specialist secondary care dermatology facility. Patients were mainly referred by general practitioners and genitourinary medicine physicians. Outcome was measured at 3 and 6 months, and was determined by clinical examination and assessment of patient symptoms. The mean age of the group was 45.3 years. The commonest diagnoses were lichen sclerosus (30.5%), balanitis (17.3%), eczema (12.8%), lichen planus (7.3%), psoriasis (7.2%) and benign lesions (5.5%). The commonest presenting symptoms were genital rash (43%), genital soreness, pain or burning (17.5%), and penile lesions (15.7%). Lichen sclerosus and all forms of balanitis were more common in uncircumcised patients, whereas lichen planus was more common in circumcised males. Short-term outcome was excellent, with 11.5% of patients being reassured and discharged on their first visit, and after 6 months 58% of all patients were clear and 12% had improved. Only 4.5% reported no improvement in symptoms. Diagnostic biopsy demonstrated malignant or premalignant lesions in nearly a fifth of those having a procedure. Close working with urological and genitourinary medicine colleagues is important to manage the various aspects of male health. PMID- 28597555 TI - Harnessing Scientific and Technological Advances to Improve Equity in Kidney Allocation Policies. AB - We reported that current assignment of HLA-DQ is a barrier to organ allocation. Here we simulated the impact of incorporating HLA-DQ antigens and antibodies as A/B and alphabeta allelic variants, respectively, on calculated panel reactive antibody (cPRA) and probability of finding potential compatible donors (PCD). A cohort of 1224 donors and 2075 sensitized candidates was analyzed using HLA DQalphabeta allelic (study) versus serologic (current practice) nomenclature. A significant (p < 10-4 ) decrease in cPRA was observed with higher impact for male versus female, and first transplant versus retransplant (p < 10-4 ), affecting mostly patients with moderate cPRA (30-80%). Consequently, the number of patients qualifying for 100% cPRA points according to the United Network for Organ Sharing Kidney Allocation System decreased by 37%. More critically, by using allelic versus serologic nomenclature for HLA-DQ, the number of PCDs for all patients was increased, with male and first-transplant patients showing a higher expansion compared with female and retransplants. Patients of blood group O showed the highest benefit. The goal of reporting unacceptable antigens is to improve accuracy of virtual crossmatching and increase the likelihood of finding immunologically compatible donors. Our simulation provides strong support for the need to re-evaluate the use of allele typing and how HLA-DQ antigens and antibodies are incorporated into allocation policies to ensure equity. PMID- 28597556 TI - Seasonality and weight gain during the first year of life. AB - A comparison is made between weight increments at 0-3, 4-6, 7-9, and 10-12 months of life between infants born in the fall, winter, spring, and summer seasons in Sui Lin, Taiwan. The focus of the study is on (1) whether in a tropical region the effects of seasonality on weight gain interact with the developmental stage of the infant and (2) whether these interactions are partly regulated by the growth history of the infant. The main hypothesis is that the highest growth velocities will occur in the dry, cold months of the year (fall and winter) and the lowest velocities will occur in the hot, rainy months (spring and summer). The highest and lowest mean birth weights were recorded in the spring and summer seasons, respectively. Season had no effect on weight gain during 0-3 months; on the other hand, birth weight and length were significantly related to weight gain during this 0-3 month period. In the last two seasons of the first year, the highest weight increments occurred in the fall and the lowest occurred in the spring and summer. At the end of the 12 months of life there were no weight differences between cohorts. PMID- 28597558 TI - "Miro" in Parkinson's disease: Here, there, everywhere! PMID- 28597559 TI - What Would Dr. James Parkinson Think Today? Tau and Other Imaging Possibilities in Parkinson's Disease. PMID- 28597557 TI - Adaptive Deep Brain Stimulation for Movement Disorders: The Long Road to Clinical Therapy. AB - Continuous high-frequency DBS is an established treatment for essential tremor and Parkinson's disease. Current developments focus on trying to widen the therapeutic window of DBS. Adaptive DBS (aDBS), where stimulation is dynamically controlled by feedback from biomarkers of pathological brain circuit activity, is one such development. Relevant biomarkers may be central, such as local field potential activity, or peripheral, such as inertial tremor data. Moreover, stimulation may be directed by the amplitude or the phase (timing) of the biomarker signal. In this review, we evaluate existing aDBS studies as proof-of principle, discuss their limitations, most of which stem from their acute nature, and propose what is needed to take aDBS into a chronic setting. (c) 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 28597561 TI - Relationship of disease characteristics and nutritional status to patterns of growth in children with Crohn disease. AB - Crohn disease is one type of inflammatory bowel disease with frequent occurrence before maturity. Many children with Crohn disease experience linear growth retardation. However, the prevalence and contribution of various factors to growth failure have not been adequately investigated. The purpose of the present study was to estimate the prevalence of growth deficiency by using multiple criteria based on longitudinal data and to simulatneously evaluate the contribution of disease, demographic, and treatment characteristics to the growth failure in this group of children. A sample of 78 patients assessed retrospectively and 41 patients followed prospectively were drawn from the Children's Hospital of Philadelphia Division of Gastroenterology and Nutrition. Data on growth, nutritional status (hematocrit and albumin levels), disease characteristics (severity, site, duration, and age of onset), and steroid dosage were collected for both groups. For the prospective sample, measurements of height, weight, and four skinfold thicknesses were taken. A 24 hour recall and 3 day food record estimated kcal intake. Parental size was taken by report from the accompanying caregiver. When three criteria were used, prevalence of growth retardation was 67% in the retrospective group, higher than most available figures. In the prospective sample, reductions in height adjusted for midparental size were greater than those for weight, and depletion of lower body fat was greater than that of upper body fat. Multiple regression analyses showed that degree of growth retardation as measured by the parent adjusted z score for height was associated with higher steroid dosage and later age of disease onset, but not disease severity or the anatomical site of the disease. Of the nutritional status variables, degree of growth retardation was most closely associated with degree of reduction in lower body fat stores. PMID- 28597560 TI - l-Dopa responsiveness is associated with distinctive connectivity patterns in advanced Parkinson's disease. AB - BACKGROUND: Neuronal loss and dopamine depletion alter motor signal processing between cortical motor areas, basal ganglia, and the thalamus, resulting in the motor manifestations of Parkinson's disease. Dopamine replacement therapy can reverse these manifestations with varying degrees of improvement. METHODS: To evaluate functional connectivity in patients with advanced Parkinson's disease and changes in functional connectivity in relation to the degree of response to l dopa, 19 patients with advanced Parkinson's disease underwent resting-state functional magnetic resonance imaging in the on-medication state. Scans were obtained on a 3-Tesla scanner in 3 * 3 * 2.5 mm3 voxels. Seed-based bivariate regression analyses were carried out with atlas-defined basal ganglia regions as seeds, to explore relationships between functional connectivity and improvement in the motor section of the UPDRS-III following an l-dopa challenge. False discovery rate-corrected P was set at < 0.05 for a 2-tailed t test. RESULTS: A greater improvement in UPDRS-III scores following l-dopa administration was characterized by higher resting-state functional connectivity between the prefrontal cortex and the striatum (P = 0.001) and lower resting-state functional connectivity between the pallidum (P = 0.001), subthalamic nucleus (P = 0.003), and the paracentral lobule (supplementary motor area, mesial primary motor, and primary sensory areas). CONCLUSIONS: Our findings show characteristic basal ganglia resting-state functional connectivity patterns associated with different degrees of l-dopa responsiveness in patients with advanced Parkinson's disease. l Dopa exerts a graduated influence on remapping connectivity in distinct motor control networks, potentially explaining some of the variance in treatment response. (c) 2017 International Parkinson and Movement Disorder Society. PMID- 28597565 TI - BTN3A1-antibodies and phosphoantigens: TCRVgamma9Vdelta2 "see" the difference. AB - Human blood gammadelta T lymphocytes express TCRVgamma9Vdelta2 and respond to nonpeptide phosphoantigens (PAgs) by a mysterious mechanism involving the BTN3A1 (CD277) molecule . BTN3A1 is a butyrophilin-like protein related to CD80, PD-L1, and MHC, and is either a presenting or a co-stimulatory molecule for PAgs. Although the precise roles and molecular interactions with the TCRVgamma9Vdelta2 are currently not determined, it is commonly thought that all TCRVgamma9Vdelta2 lymphocytes 'see' PAg and BTN3A1 together, presumably in a single molecular recognition event. But whether this recognition event could be reproduced in a simplified model was not addressed in previous studies. In this issue, Starick et al. (Eur. J. Immunol. 2017. 47: 982-992) compared the response of three TCRVgamma9Vdelta2 pairs of murine and human cell transfectants to PAg and anti BTN3A1 antibodies using IL-2 release as a readout. The authors found that although the two murine transfectants responded similarly to either stimuli, one murine TCRVgamma9Vdelta2 transfectant reacted to PAgs but not to anti-BTN3A1 (mAb 20.1). Human transductants behave in a similar fashion, demonstrating that TCRVgamma9Vdelta2 lymphocytes differentiate PAg and BTN3A1 signals, while species of the transductants unmask this differential sensitivity. Indeed, understanding the puzzling mode of antigen recognition by gammadelta T lymphocytes will be essential for developing gammadelta T-cell-based immunotherapies, and the authors of this study now demonstrate that TCRVgamma9Vdelta2 lymphocytes are able to differentiate the PAg and BTN3A1 stimuli. PMID- 28597567 TI - Longitudinal principal component analysis of somatic and motor characteristics. AB - Longitudinal principal component analysis was applied to the study of growth patterns of several somatic and motor characteristics. The data are from the "Leuven Growth Study of Belgian Boys," in which six annual observations were made. Peak growth velocity and age at peak growth velocity for each variable were estimated. The results for height show three components sufficient to provide an adequate representation of the original information. The first component can be interpreted as a growth distance component, which characterizes the general position of an individual growth curve relative to the average growth curve during the period analyzed. Components 2 and 3 reflect fluctuations in percentile level during the age period studied and can be conceived as indices of stability. Component 2 provides additional information about the age at peak height velocity; component 3 characterizes variation in peak height velocity. These interpretations can, in general, be assumed for the other characteristics analyzed. PMID- 28597566 TI - Navigating air travel and cardiovascular concerns: Is the sky the limit? AB - As the population ages and our ability to care for patients with cardiac disease improves, an increasing number of passengers with cardiovascular conditions will be traveling long distances. Many have had cardiac symptoms, recent interventions, devices, or surgery. Air travel is safe for most individuals with stable cardiovascular disease. However, a thorough understanding of the physiologic changes during air travel is essential given the potential impact on cardiovascular health and the risk of complications in passengers with preexisting cardiac conditions. It is important for clinicians to be aware of the current recommendations and precautions that need to be taken before and during air travel for passengers with cardiovascular concerns. PMID- 28597562 TI - Reprogramming progeria fibroblasts re-establishes a normal epigenetic landscape. AB - Ideally, disease modeling using patient-derived induced pluripotent stem cells (iPSCs) enables analysis of disease initiation and progression. This requires any pathological features of the patient cells used for reprogramming to be eliminated during iPSC generation. Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of patients with HGPS and controls, including one family trio. HGPS patient-derived iPSCs are nearly indistinguishable from controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles, and can differentiate into affected cell lineages recapitulating disease progression, despite the nuclear aberrations, altered gene expression, and epigenetic landscape inherent to the donor fibroblasts. These analyses demonstrate the power of iPSC reprogramming to reset the epigenetic landscape to a revitalized pluripotent state in the face of widespread epigenetic defects, validating their use to model the initiation and progression of disease in affected cell lineages. PMID- 28597568 TI - Influence of nutritional status on growth. PMID- 28597582 TI - YGA 2017 poster presentations. PMID- 28597571 TI - Growth of Filipino infants who differ in body proportions at birth. AB - Growth of infants who differ in body proportions at birth was followed during the first 12 months of life. The sample of 2,695 infants from Metropolitan Cebu, in the Central Philippines, was divided into five groups based on a cross tabulation of low-birth-weight(LBW) status (2,500 g or less) with low (<10th percentile), adequate (10th-90th percentile) or high (>90th percentile)Rohre's Index (RI). The groups exhibited significant differences in growth patterns. The importance of these groups, which reflect weight and body proportions of the infant at birth as a determinant of attained size at 2, 6, and 12 months of age, was evaluated by using multivariate techniques which took into consideration other factors known to affect growth. Results show that intergroup differences in growth patterns and attained size occur because of (1) differences in postnatal growth potential represented by weight and body proportions at birth, (2) differences in the important biological inputs that affect postnatal growth (such as feeding practices and morbidity), and (3) differences in the effects of inputs on growth. Infants who are LBW but well proportioned are most likely to remain small during the first year of life, while those with a low RI at birth are more capable of catch-up growth. PMID- 28597569 TI - Cross-sectional relations of whole-blood miRNA expression levels and hand grip strength in a community sample. AB - MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community-based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed-effects regression modeling of grip strength (kg) versus continuous miRNA 'Cq' values and versus binary miRNA expression was performed. We conducted an integrative miRNA-mRNA coexpression analysis and examined the enrichment of biologic pathways for the top miRNAs associated with grip strength. Grip strength was lower in women than in men and declined with age with a mean 44.7 (10.0) kg in men and 26.5 (6.3) kg in women. Among 299 miRNAs interrogated for association with grip strength, 93 (31%) had FDR q value < 0.05, 54 (18%) had an FDR q value < 0.01, and 15 (5%) had FDR q value < 0.001. For almost all miRNA-grip strength associations, increasing miRNA concentration is associated with increasing grip strength. miR-20a-5p (FDR q 1.8 * 10-6 ) had the most significant association and several among the top 15 miRNAs had links to skeletal muscle including miR-126-3p, miR-30a-5p, and miR-30d 5p. The top associated biologic pathways included metabolism, chemokine signaling, and ubiquitin-mediated proteolysis. Our comprehensive assessment in a community-based sample of miRNAs in blood associated with grip strength provides a framework to further our understanding of the biology of muscle strength. PMID- 28597570 TI - Pharmaco-toxicological effects of the novel third-generation fluorinate synthetic cannabinoids, 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice. In vitro and in vivo studies. AB - INTRODUCTION: 5F-ADBINACA, AB-FUBINACA, and STS-135 are 3 novel third-generation fluorinate synthetic cannabinoids that are illegally marketed as incense, herbal preparations, or research chemicals for their psychoactive cannabis-like effects. METHODS: The present study aims at investigating the in vitro and in vivo pharmacological activity of 5F-ADBINACA, AB-FUBINACA, and STS-135 in male CD-1 mice, comparing their in vivo effects with those caused by the administration of Delta9 -THC and JWH-018. In vitro competition binding experiments revealed a nanomolar affinity and potency of the 5F-ADBINACA, AB-FUBINACA, and STS-135 on mouse and human CB1 and CB2 receptors. Moreover, these synthetic cannabinoids induced neurotoxicity in murine neuro-2a cells. RESULTS: In vivo studies showed that 5F-ADBINACA, AB-FUBINACA, and STS-135 induced hypothermia; increased pain threshold to both noxious mechanical and thermal stimuli; caused catalepsy; reduced motor activity; impaired sensorimotor responses (visual, acoustic, and tactile); caused seizures, myoclonia, and hyperreflexia; and promoted aggressiveness in mice. Behavioral and neurological effects were fully prevented by the selective CB1 receptor antagonist/inverse agonist AM 251. Differently, the visual sensory response induced by STS-135 was only partly prevented by the AM 251, suggesting a CB1 -independent mechanism. CONCLUSIONS: For the first time, the present study demonstrates the pharmaco-toxicological effects induced by the administration of 5F-ADBINACA, AB-FUBINACA, and STS-135 in mice and suggests their possible detrimental effects on human health. PMID- 28597585 TI - Psychosocial functioning in adolescents with and without borderline personality disorder. AB - OBJECTIVE: Little is known about the psychosocial functioning of adolescents with borderline personality disorder (BPD). The main objective of this paper is to compare the psychosocial functioning of a group of adolescents with BPD to a group of psychiatrically healthy adolescents. METHODS: The present cross sectional study included 104 adolescent inpatients with BPD, compared with 60 age matched psychiatrically healthy comparison subjects. All participants were rigorously diagnosed using three semi-structured interviews: the Structured Clinical Interview for DSM-IV Childhood Diagnoses, the Revised Diagnostic Interview for Borderlines and the Childhood Interview for DSM-IV Borderline Personality. All subjects were also interviewed using the adolescent version of the Background Information Schedule to assess multiple facets of psychosocial functioning. RESULTS: Adolescents with BPD rated their relationships with their parents as significantly less positive, were more likely to date, but spent more time alone than their healthy counterparts. In addition, adolescents with BPD reported significantly more problems at work and school (i.e. lower frequency of having a good work or school history, higher frequency of being suspended or expelled from school) and significantly lower rates of participation in extra curricular activities than their healthy counterparts. CONCLUSIONS: Taken together, the results of this study suggest that adolescents with BPD are more impaired in both the social and vocational areas of functioning than psychiatrically healthy comparison subjects. They might also suggest that an overlooked area of strength concerns their relationships with peers. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28597586 TI - Association of lung cancer death rates by parish with migration rate by age group. AB - Geographic distribution of cancer incidence, as judged from death certificates in Louisiana, shows evidence of strong epidemiological forces. Inspection of data on migration and lung cancer frequency shows them to be associated. Inmigrants account for a majority of the lung cancer deaths. Under assumptions of phenotypic complexity stemming from both genetic and environmental components, we used a multiple regression technique to test the significance of this association. Given the nature of the data and the assumptions of the analysis, there was a reasonable level of significance, suggesting that inmigration of older persons may be largely responsible for higher cancer rates in some parishes (counties) in Louisiana. PMID- 28597587 TI - The role of skin ulceration in breast carcinoma staging and outcome. AB - Breast carcinoma with skin ulceration (SU) is considered a locally advanced disease. The purpose of the study is to investigate if SU is an independent adverse factor. Breast carcinoma patients with SU (n=111) were included in the study. A subset (n=38, study cohort) was matched with cases that had no SU (n=38, matched cohort); the survival analyses were compared between these groups. Then, cases (n=80) were staged independent from SU into stage I, II or III. Disease free survival (DFS) and overall survival (OS) were analyzed. Patients with larger tumors tended to present with distant metastases more often than patients with smaller tumors (P=.004). In the matched cases, the 5-year DFS probability was 53% for the study cohort and 58% for the matched cohort; and for OS 75% for the study cohort and 84% for the matched cohort with no statistical significant difference. However, there was a trend towards worse DFS for the patients whose tumors had SU. When the cases were staged based on tumor size and node status (I, II or III), the OS was statistically significant (P=.047) but not the DFS (P=.195). Relatively small tumors with SU had an extent of disease similar to that observed in patients with early stages disease. The survival analysis suggests that SU may not be an adverse factor. However, more cases are needed to further examine this finding. PMID- 28597588 TI - Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: A perspective on glucose-lowering interventions. AB - Type 2 diabetes is a leading cause of cardiovascular disease (CVD). Observational studies have consistently shown an association between glycaemic level and risk of major adverse cardiovascular events (MACE); however, intervention studies have provided limited evidence supporting a reduction in the cardiovascular burden of diabetes through intensive glucose control. In the present review, we aimed to examine the concept of cumulative glycaemic exposure with regard to protection against CVD in diabetes. We address how we can move from a binary approach in trials, to a more quantitative approach based on differences in cumulative glycaemic exposure. We plotted the association between differing glycaemic exposures between study arms and the hazard ratio for MACE in randomized controls trials comparing intensive with conventional glycaemic control in type 2 diabetes. We found a strikingly strong correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained for trials comparing antidiabetes drugs with placebo. The results suggest that a minimum study duration and a minimum gain in glycated haemoglobin (HbA1c) reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantitative perspective in that respect. The present analysis underlines that the duration of the intensification of glycemic control, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision-making. PMID- 28597589 TI - Enhanced decomposition of stable soil organic carbon and microbial catabolic potentials by long-term field warming. AB - Quantifying soil organic carbon (SOC) decomposition under warming is critical to predict carbon-climate feedbacks. According to the substrate regulating principle, SOC decomposition would decrease as labile SOC declines under field warming, but observations of SOC decomposition under warming do not always support this prediction. This discrepancy could result from varying changes in SOC components and soil microbial communities under warming. This study aimed to determine the decomposition of SOC components with different turnover times after subjected to long-term field warming and/or root exclusion to limit C input, and to test whether SOC decomposition is driven by substrate lability under warming. Taking advantage of a 12-year field warming experiment in a prairie, we assessed the decomposition of SOC components by incubating soils from control and warmed plots, with and without root exclusion for 3 years. We assayed SOC decomposition from these incubations by combining inverse modeling and microbial functional genes during decomposition with a metagenomic technique (GeoChip). The decomposition of SOC components with turnover times of years and decades, which contributed to 95% of total cumulative CO2 respiration, was greater in soils from warmed plots. But the decomposition of labile SOC was similar in warmed plots compared to the control. The diversity of C-degradation microbial genes generally declined with time during the incubation in all treatments, suggesting shifts of microbial functional groups as substrate composition was changing. Compared to the control, soils from warmed plots showed significant increase in the signal intensities of microbial genes involved in degrading complex organic compounds, implying enhanced potential abilities of microbial catabolism. These are likely responsible for accelerated decomposition of SOC components with slow turnover rates. Overall, the shifted microbial community induced by long-term warming accelerates the decomposition of SOC components with slow turnover rates and thus amplify the positive feedback to climate change. PMID- 28597590 TI - In Vitro Evaluation of Pediatric Hollow-Fiber Membrane Oxygenators on Hemodynamic Performance and Gaseous Microemboli Handling: An International Multicenter/Multidisciplinary Approach. AB - The objective of this study was to compare the hemodynamic performances and gaseous microemboli (GME) handling ability of two pediatric oxygenators in a simulated pediatric cardiopulmonary bypass (CPB) model and the importance of adding an arterial filter in the circuit. The circuit consisted of a Braile Infant oxygenator or a Maquet Quadrox-I Pediatric oxygenator without integrated arterial filter (parallel arrangement), 1/4 in. ID tubing A-V loop, and a 12-Fr arterial cannula, primed with lactated Ringer's solution and packed red blood cells. Trials were conducted at flow rates ranging from 500 to 2000 mL/min (500 mL/min increment) at 35 degrees C and 28 degrees C. Real-time pressure and flow data were recorded using a custom-based data acquisition system. For GME testing, 5 cc of air was manually injected into the venous line. GME were recorded using the Emboli Detection and Classification Quantifier (EDAC) System. An additional experiment using a separate arterial filter was conducted. There was no difference in the mean circuit pressure, pressure drop, total hemodynamic energy level, and energy loss between the two oxygenators. The venous line pressures were higher in the Braile than in the Quadrox group during all trials (P <0.01). GME count and volume at pre-/post oxygenator and pre-cannula sites in the Quadrox were lower than the Braile group at high flow rates (P < 0.05). In the additional experiment, an arterial filter captured a significant number of microemboli at all flow rates. The Braile Infant oxygenator has a matched hemodynamic characteristic with the Quadrox-i Pediatric oxygenator. The Quadrox-i has a better GME handling ability compared with the Braile Infant oxygenator. Regardless of type of oxygenator an additional arterial filter decreases the number of GME. PMID- 28597591 TI - Morphological Variation in Anuran Limbs: Constraints and Novelties. AB - Anurans have three primary types of locomotion: walking, jumping, and swimming. Additionally, they may dig, climb, grasp, etc. All adult anurans have four limbs, with four fingers on the hands and five toes on the feet. We summarized and updated knowledge on the interspecific variation within anuran limbs, then discuss how developmental constraints (e.g., in size) and novelties may have influenced anuran diversification through the locomotion. We analyze morphological variation from limb bud stages up to the final limb form resulting from certain skeletal organization and growth. We find limited morphometric variations in the skeleton of different developmental modules (i.e., skull, trunk, urostyle, limbs) indicate that the anuran body shape is largely constrained. We identify specializations of the stylopodium, zeugopodium, and proximal carpals/tarsals that have evolved to facilitiate saltatorial locomotion. We show that the anuran prepollex and prehallux are not vestigial digits and that they have come to serve specialized function. Medial rotation of the manus in anurans appears to have evolved to help distribute the force of impact upon landing at the end of a jump. Additional skeletal elements in anuran limbs are intercalary elements and sesamoids. The intercalary elements appear within neobatrachians and are integrated with digital pads in lineages capable of locomotion on smooth vertical surfaces. They have allowed arboreal anurans to occupy a wide range of arboreal habitats. PMID- 28597593 TI - From the ADAA President. PMID- 28597592 TI - Refractive outcome after pars plana vitrectomy for macular hole in pseudophakic eyes. PMID- 28597594 TI - Technology and mental health. PMID- 28597595 TI - Early weight gain in pregnant adolescents and fetal outcome. AB - While the contribution of total maternal gain to birthweight is well described, less is known about whether there are specific effects of early weight gain. Early weight gain adequacy may be a particular problem among teenage gravidas who are more likely to have low prepregnant weight and in developing countries where chronic undernutrition is endemic. We studied the effects of early weight gain adequacy on infant birthweight in a geographical cohort of 1,790 adolescents from Camden County, New Jersey. Weight gain was calculated for prepregnant weight to 24 weeks' gestation and 24 weeks to delivery. Inadequate early weight gain was defined as gains less than 4.3 kg and inadequate late gains as averaging less than 400 gm/week from 24 weeks' gestation to delivery. In regressions predicting birthweight outcome, we found significant independent effects of timing of weight gain inadequacy. Early inadequate gains were associated with a -186.6 +/- 31.6 gm decrement in birthweight that was not diminished even when later weight gains were compensatory. Late inadequate (-154.4 +/- 29.3 gm) and inadequate gains both early and later (-298.6 +/- 49.1 gm) were also associated with birthweight decrements. However, overweight (body mass index >24.5) appeared to buffer some of the effects of inadequate weight gains, reducing the decrement to about -100 gm. Protocols that seek to improve infant outcomes should focus on early weight gain during pregnancy. Affecting weight gain only late in pregnancy may not be able to substantially reduce the risk of fetal growth retardation. PMID- 28597596 TI - New roles for neuronal estrogen receptors. AB - Estrogens encompass steroid hormones which display physiological roles not only in the female reproductive system but also in other organ systems of non reproductive controls, including the peripheral and central nervous systems. Traditionally, estrogen signals in neurons through a "genomic pathway": binding to estrogen receptors (ERs) which then interact with nuclear estrogen response elements to initiate transcription. This effect is usually delayed at onset (within several hours to days) and prolonged in duration. In addition to these classical ERs, recent data suggest that other ERs function through pregenomic signaling pathways. Estrogen's pregenomic pathways cause intracellular changes within seconds to minutes and go through a novel, 7-transmembrane spanning G protein-coupled receptor (GPER, formerly known as GPR30). In this review, we will briefly cover the cellular and molecular mechanisms of GPER and then discuss newly discovered roles of GPER in cognition, depression, homeostasis, pain processing, and other associated neuronal functions. PMID- 28597599 TI - Growth status of children in rural Mali: Implications for nutrition education programs. AB - In conjunction with a rural development project, a cross-sectional anthropometric survey and ethnographic research were conducted in six rural villages in southern Mali where food is generally sufficient. A total of 1,132 individuals were measured, and individual and group interviews concerning dietary habits and intra familial food distribution patterns were conducted. In this paper, data on the growth status of children under 12 years of age (N=575) are reported and analyzed. As defined by inadequate growth, rates of malnutrition are extremely high in this population. Deficits in growth peak among the 2 year olds, with 67% falling more than 2 SD below the NCHS/WHO standard for weight-for-age, and 53% falling more than 2SD below the standard for height-for-age. Deficits in weight for-height are highest among the 1 year olds, with 32% falling more than 2 SD below the NCHS/WHO standards. From birth to 23 months, the correlation between age (in months) and weight-for-age z-scores is -.63 (P=.0001). Between 24 and 47 months, the correlation improves, to +.36 (P=.0004), indicating that children experience some catch-up growth. By the age of 11 years, they still have not recovered fully from the combination of poor nutrition and infections in early childhood, however, and malnutrition continues to be a problem throughout childhood. Iodine deficiency is also a problem in two of the six villages. Interview data confirm earlier findings in Mali regarding child feeding practices, specifically, that infants and young children are expected to feed themselves, and that the best foods are reserved for adults. These findings have important implications for the design and implementation of nutrition education programs in southern Mali. PMID- 28597597 TI - Sinus hypoplasia in the cystic fibrosis rat resolves in the absence of chronic infection. AB - BACKGROUND: Sinus hypoplasia is a hallmark characteristic in cystic fibrosis (CF). Chronic rhinosinusitis (CRS) is nearly universal from a young age, impaired sinus development could be secondary to loss of the cystic fibrosis transmembrane conductance regulator (CFTR) or consequences of chronic infection during maturation. The objective of this study was to assess sinus development relative to overall growth in a novel CF animal model. METHODS: Sinus development was evaluated in CFTR-/- and CFTR+/+ rats at 3 stages of development: newborn; 3 weeks; and 16 weeks. Microcomputed tomography (microCT) scanning, cultures, and histology were performed. Three-dimensional sinus and skull volumes were quantified. RESULTS: At birth, sinus volumes were decreased in CFTR-/- rats compared with wild-type rats (mean +/- SEM: 11.3 +/- 0.85 mm3 vs 14.5 +/- 0.73 mm3 ; p < 0.05), despite similar weights (8.4 +/- 0.46 gm vs 8.3 +/- 0.51 gm; p = 0.86). CF rat weights declined by 16 weeks (378.4 +/- 10.6 gm vs 447.4 +/- 15.9 gm; p < 0.05), sinus volume increased similar to wild-type rats (201.1 +/- 3.77 gm vs 203.4 +/- 7.13 gm; p = 0.8). The ratio of sinus volume to body weight indicates hypoplasia present at birth (1.37 +/- 0.12 vs 1.78 +/- 0.11; p < 0.05) and showed an increase compared with CFTR+/+ animals by 16 weeks (0.53 +/- 0.02 vs 0.46 +/- 0.02; p < 0.05). Rats did not develop histologic evidence of chronic infection. CONCLUSION: CF rat sinuses are smaller at birth, but develop volumes similar to wild-type rats with maturation. This suggests that loss of CFTR may confer sinus hypoplasia at birth, but normal development ensues without chronic sinus infection. PMID- 28597598 TI - Rosa rugosa flavonoids alleviate myocardial ischemia reperfusion injury in mice by suppressing JNK and p38 MAPK. AB - OBJECTIVE: Although Rosa rugosa has been applied for preventing coronary artery disease, the pharmacological mechanism is little explored. In this study, the effects and mechanisms of Rosa rugosa flavonoids (RRF) on myocardial ischemia reperfusion injury (MIRI) were investigated. METHODS: Mice were pretreated by intragastric administration of 600 mg/kg RRF for 7 days. Then MIRI was induced by 45 minutes coronary artery ligation and 3 hours reperfusion. Myocardial infarct size (MIS) and histopathology, activities of myocardial enzymes, and effects of RRF on inflammation and apoptosis were evaluated. RESULTS: Pretreating the mice with RRF significantly reduced MIS and inhibited activity of plasma myocardial enzymes. Activity of the enzymes associated with anti-oxidation, SOD, and TEAC, and mRNA expression of NOX2 were significantly elevated. RRF pretreatment significantly decreased the translocation of p65 from the cytoplasm into the nucleus and reduced the expression of the pro-inflammatory cytokines, IL-6 and IL 1beta. RRF pretreatment also significantly prevented the expression of caspase-3 and Bax, and increased the expression of Bcl-2. And RRF inhibited the phosphorylation of JNK and p38 MAPK. CONCLUSIONS: RRF significantly inhibited MIRI through anti-oxidative, anti-inflammatory, and anti-apoptosis effects, and mechanisms were associated with its inhibition on phosphorylation of JNK and p38 MAPK. PMID- 28597600 TI - Iridium-Catalyzed Enantioselective Allylic Substitution of Aliphatic Esters with Silyl Ketene Acetals as the Ester Enolates. AB - Enantioselective allylic substitution with enolates derived from aliphatic esters under mild conditions remains challenging. Herein we report iridium-catalyzed enantioselective allylation reactions of silyl ketene acetals, the silicon enolates of esters, to form products containing a quaternary carbon atom at the nucleophile moiety and a tertiary carbon atom at the electrophile moiety. Under relatively neutral conditions, the allylated aliphatic esters were obtained with excellent regioselectivity and enantioselectivity. These products were readily converted into primary alcohols, carboxylic acids, amides, isocyanates, and carbamates, as well as tetrahydrofuran and gamma-butyrolactone derivatives, without erosion of enantiomeric purity. PMID- 28597601 TI - Endothelial alterations in 712 keratoconus patients. AB - PURPOSE: To investigate the effect of the severity of keratoconus on the corneal endothelium using specular microscopy. METHODS: Seven hundred and twelve eyes from the Homburg Keratoconus Center (HKC) database were included in this retrospective study. Corneal endothelium was evaluated using the Tomey EM-3000 specular microscope. Keratoconus-related topographic and tomographic data were obtained from Scheimpflug-based tomography (Oculus Pentacam(r) HR). Eyes were classified into stages 0 (healthy) to 4 (severe keratoconus) according to the Topographic Keratoconus Classification (TKC). Subgroups were analysed based on contact lens (CL) type (none/rigid/soft). RESULTS: The frequencies of keratoconus stages 0/1/2/3/4 according to TKC were 169/94/206/166/77. The endothelial cell density (ECD) for the endothelial cell area for TKC 0/1/2/3/4 was 2611/2624/2557/2487/2401 cells per mm2 and the coefficient of variation (CV) was 40.9/40.0/41.6/46.2/49.0%, respectively. The more severe the keratoconus stage, the lower the endothelial cell count (p < 0.001) and the higher the CV (p < 0.001). No contact lens wearing was noted in 207 eyes (NoCL), rigid CL in 200 (RCL) and soft CL in 54 (SCL). CD for NoCL/RCL/SCL was 2523/2533/2644 per mm2 and CV was 41.8/54.1/43.1%, respectively. A significant difference in CV was found between NoCL and RCL (p = 0.02), and no significant difference in CV was found between NoCL and SCL (p = 0.07). Endothelial cell density (ECD) did not differ significantly between NoCL and RCL or SCL. CONCLUSION: Endothelial cell density (ECD) decreases and CV increases significantly with increasing tomographic severity of keratoconus. In patients with RCL compared to eyes without CL wear, we found a statistically significantly higher CV in the endothelial cell size. PMID- 28597602 TI - Multifunctional Hyperbolic Nanogroove Metasurface for Submolecular Detection. AB - Metasurface serves as a promising plasmonic sensing platform for engineering the enhanced light-matter interactions. Here, a hyperbolic metasurface with the nanogroove structure in the subwavelength scale is designed. This metasurface is able to modify the wavefront and wavelength of surface plasmon wave with the variation of the nanogroove width or periodicity. At the specific optical frequency, surface plasmon polaritons are tightly confined and propagated with a diffraction-free feature due to the epsilon-near-zero effect. Most importantly, the groove hyperbolic metasurface can enhance the plasmonic sensing with an ultrahigh phase sensitivity of 30 373 deg RIU-1 and Goos-Hanchen shift sensitivity of 10.134 mm RIU-1 . The detection resolution for refractive index change of glycerol solution is achieved as 10-8 RIU based on the phase measurement. The detection limit of bovine serum albumin (BSA) molecule is measured as low as 0.1 * 10-18 m (1 * 10-19 mol L-1 ), which corresponds to a submolecular detection level (0.13 BSA mm-2 ). As for low-weight biotin molecule, the detection limit is estimated below 1 * 10-15 m (1 * 10-15 mol L-1 , 1300 biotin mm-2 ). This enhanced plasmonic sensing performance is two orders of magnitude higher than those with current state-of-art plasmonic metamaterials and metasurfaces. PMID- 28597603 TI - Nematodes, exotic earthworms and nitrogen addition: interactions between global change factors lead to cancellation effects. AB - Photos from the experiment described in Shao et al. (): (a) the endogeic (i.e. earthworms that typically live in the soil, burrowing horizontally to acquire nutrients) earthworm Pontoscolex corethrurus that was added to the plots; (b) P. corethrurus in a quiescence state in response to drought; (c) set-up of the control plots (i.e. no earthworms, ambient nitrogen) used in this experiment. [Colour figure can be viewed at wileyonlinelibrary.com] In Focus: Shao, Y., Zhang, W., Eisenhauer, N., Liu, T., Xiong, Y., Liang, C. & Fu, S. (2017) Nitrogen deposition cancels out exotic earthworm effects on plant-feeding nematode communities. Journal of Animal Ecology, 86, 708-717. In this issue of Journal of Animal Ecology, Shao et al. () explored how N addition and exotic earthworms interacted to impact on the plant-feeding nematode community. They demonstrate that exotic earthworm presence alone increased the abundance of less harmful plant-feeding nematodes and decreased the abundance of the more harmful plant feeding nematodes. However, in plots receiving both exotic earthworms and N addition, such earthworm effects on the nematode community were negated. These findings pull focus on the need to simultaneously consider multiple global change factors (e.g. exotic species invasions and N deposition) when making predictions about how such factors might affect above- and below-ground interactions and thereby alter ecosystem function. PMID- 28597604 TI - Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial. AB - OBJECTIVE: To investigate the efficacy and safety of lesinurad in combination with febuxostat in a 12-month phase III trial in patients with tophaceous gout. METHODS: Patients with serum urate (UA) >=8.0 mg/dl (>=6.0 mg/dl with urate lowering therapy) and >=1 measurable target tophus were given febuxostat 80 mg/day for 3 weeks before randomization to receive lesinurad (200 or 400 mg daily) or placebo in addition to the febuxostat. The primary end point was the proportion of patients achieving a serum UA level of <5.0 mg/dl (month 6). The key secondary end point was the proportion of patients with complete resolution of >=1 target tophus (month 12). Other end points included the percentage change in total target tophi area. Safety assessments included adverse events and laboratory data. RESULTS: Patients (n = 324) were predominantly male, with a mean age of 54.1 years. Significantly more patients achieved the serum UA target by month 6 with the addition of lesinurad 400 mg (76.1%; P < 0.0001), but not 200 mg (56.6%; P = 0.13), to the febuxostat therapy as compared with febuxostat alone (46.8%). At all other time points, significantly more patients in the lesinurad 200 mg group achieved the serum UA target. The number of patients with complete tophus resolution was not different between groups. Treatment with lesinurad (200 mg and 400 mg) plus febuxostat reduced the total target tophi area as compared with febuxostat alone (50.1% and 52.9% versus 28.3%, respectively; P < 0.05). Safety was generally comparable with that of febuxostat alone, except for higher rates of predominantly reversible elevations in the serum creatinine level, particularly with lesinurad 400 mg. CONCLUSION: Treatment with lesinurad in combination with febuxostat demonstrated superior lowering of serum UA levels as compared with febuxostat alone, with clinically relevant added effects on tophi and an acceptable safety profile with lesinurad 200 mg in patients with tophaceous gout warranting additional therapy. PMID- 28597605 TI - Skinfold thicknesses, body circumferences and their relationship to age, sex, and socioeconomic status in adults from Northwest India. AB - Subcutaneous fatness, measured anthropometrically, was analyzed in a sample of 651 males and females, 18-49 years of age, of high and low socioeconomic status (SES) from the Chandigarh zone of Northwest India. There were significant differences between lower and upper SES males and females. In general, all groups tend to show increases in indicators of fatness between the 18-29 and the 30-39 year age groups. However, there was less consistency across groups between 30-39 and 40-49 years. There is no difference in sexual dimorphism between SES groups. Means of lower SES subjects are approximately 1 S.D. below those of U.S. reference data. Using the body mass index as a criterion, no lower SES individuals were classified as overweight or obese. In the upper SES sample, 12.1% were classified as overweight. PMID- 28597606 TI - The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets. AB - AIMS: The prescription of optimal medical therapy for heart failure is often delayed despite compelling evidence of a reduction in mortality. We calculated the absolute risk resulting from delayed prescription of therapy. For comparison, we established the threshold applied by clinicians when discussing the risk for death associated with an intervention, and the threshold used in official patient information leaflets. METHODS AND RESULTS: We undertook a meta-analysis of randomized controlled trials to calculate the excess mortality caused by deferral of medical therapy for 1 year. Risk ratios for angiotensin-converting enzyme inhibitors, beta-blockers and aldosterone antagonists were 0.80, 0.73 and 0.77, respectively. In patients who might achieve a 1-year survival rate of 90% if treated, a 1-year deferral of treatment reduced survival to 78% (i.e. an annual absolute increase in mortality of 12 in 100 patients). This corresponds to an additional absolute mortality risk per month of 1%. A survey of clinicians carried out to establish the risk threshold at which they would obtain written consent showed the majority (85%) sought written consent for interventions associated with a 12-fold lower mortality risk: one in 100 patients. A systematic review of UK patient information leaflets to establish the magnitude of risk considered sufficient to be stated explicitly showed that leaflets begin to mention death at a ~18 000-fold lower mortality risk of just 0.0007 in 100 patients. CONCLUSIONS: Deferring heart failure treatment for 1 year carries far greater risk than the level at which most doctors seek written consent, and 18 000 times more risk than the level at which patient information leaflets begin to mention death. PMID- 28597608 TI - Advanced Photoacoustic Imaging Applications of Near-Infrared Absorbing Organic Nanoparticles. AB - Progress of nanotechnology in recent years has stimulated fast development of nanoparticles in biomedical research. Photoacoustic (PA) imaging as an emerging non-invasive technique in molecular imaging has improved imaging depth relative to conventional optical imaging, demonstrating great potential in clinical applications. The convergence of nanotechnology and PA imaging has enabled a broad spectrum of new opportunities in fundamental biology and translation medicine. This review focuses on the recent advances of organic nanoparticles in PA imaging applications. Near-infrared absorbing organic nanoparticles are classified and discussed according to their different imaging applications, which include tumor imaging, gastrointestinal imaging, sentinel lymph node imaging, disease microenvironment imaging and real-time drug imaging. The chemistry and PA properties of organic nanoparticles are discussed in details to highlight their own merits, and their challenges and perspectives in PA imaging are also discussed. PMID- 28597607 TI - Immaturity of insulin secretion by pancreatic islets isolated from one human neonate. AB - Human beta-cells are functionally mature by the age of 1 year. The timeline and mechanisms of this maturation are unknown owing to the exceptional availability of testable tissue. Here, we report the first in vitro study of insulin secretion by islets from a 5-day-old newborn. Glucose was inefficient alone, but induced insulin secretion, which was concentration-dependent, showed a biphasic time course and was of similar magnitude as in infant islets when beta-cell cyclic adenosine monophosphate was raised by forskolin. Tolbutamide alone was effective in low glucose, but its effect was not augmented by high glucose. Metabolic amplification by glucose was thus inoperative, in contrast to amplification by cyclic adenosine monophosphate. Newborn islets showed high basal insulin secretion that could be inhibited by diazoxide or omission of CaCl2 . Postnatal acquisition of functional maturity by human beta-cells implicates control of basal secretion and production of metabolic signals able to activate both triggering and amplifying pathways of insulin secretion. PMID- 28597610 TI - A commingling analysis of obesity in the Tecumseh community health study. AB - A commingling analysis of the distributions of obesity as quantified by Quetelet's index, triceps skinfold, suprailiac skinfold, umbilical skinfold, subscapular skinfold, a trunk-extremity ratio of skinfold measurements and Quetelet-adjusted trunk-extremity ratio was performed in a population of 9,226 individuals living in Tecumseh, Michigan, during 1962-1965. For all but the (non Quetelet-adjusted) trunk-extremity ratio, two or three distributions were needed to fit the data adequately even after performing a power transformation to eliminate skewness. Although this evidence is compatible with a major gene effect, segregation analyses of these data using the unified, mixed model are necessary to resolve whether the commingling is due to a major gene. PMID- 28597609 TI - Transaminase Levels and Hepatic Events During Tocilizumab Treatment: Pooled Analysis of Long-Term Clinical Trial Safety Data in Rheumatoid Arthritis. AB - OBJECTIVE: To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long-term tocilizumab treatment for rheumatoid arthritis in clinical trials. METHODS: Data were pooled from patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease-modifying antirheumatic drugs [DMARDs]) in phase III or IV clinical trials, long-term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient-years of tocilizumab exposure for this pooled analysis. RESULTS: Overall, 16,204.8 patient-years of tocilizumab exposure (mean +/- SD duration of exposure 3.9 +/- 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1-3* ULN in 59%/55% of patients, >3-5* ULN in 8.9%/3.3% of patients, and >5* ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3* ULN occurred in 7.7%/3.6% of patients, and >=2 consecutive elevations >3* ULN occurred in 1.9%/0.4% of patients. Elevations >3* ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient-years [95% confidence interval 0.02-0.09]) occurred in the tocilizumab studies. CONCLUSION: Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended. PMID- 28597611 TI - Recordings and Analysis of Atomic Ledge and Dislocation Movements in InGaAs to Nickelide Nanowire Phase Transformation. AB - The formation of low resistance and self-aligned contacts with thermally stable alloyed phases is a prerequisite for realizing reliable functionality in ultrascaled semiconductor transistors. Detailed structural analysis of the phase transformation accompanying contact alloying can facilitate contact engineering as transistor channels approach a few atoms across. Original in situ heating transmission electron microscopy studies are carried out to record and analyze the atomic scale dynamics of contact alloy formation between Ni and In0.53 Ga0.47 As nanowire channels. It is observed that the nickelide reacts on the In0.53 Ga0.47 As (111) || Ni2 In0.53 Ga0.47 As (0001) interface with atomic ledge propagation along the Ni2 In0.53 Ga0.47 As [101-0] direction. Ledges nucleate as a train of strained single-bilayers and propagate in-plane as double-bilayers that are associated with a misfit dislocation of b->=2c3[0001]. The atomic structure is reconstructed to explain this phase transformation that involves collective gliding of three Shockley partials in In0.53 Ga0.47 As lattice to cancel out shear stress and the formation of misfit dislocations to compensate the large lattice mismatch in the newly formed nickelide phase and the In0.53 Ga0.47 As layers. This work demonstrates the applicability of interfacial disconnection (ledge + dislocation) theory in a nanowire channel during thermally induced phase transformation that is typical in metal/III-V semiconductor reactions. PMID- 28597613 TI - The use of steroids by gym athletes: an attempt to diagnose the problem scale and possible causes. AB - BACKGROUND: Anabolic-androgenic steroids (AAS) are said to be frequently used by both professional and amateur athletes. In addition to having a negative impact on health, steroids defy the concept of fair play. The aim of the study was to evaluate the scale of the problem related to using anabolic-androgenic steroids (AAS) by gym athletes and to analyze possible causes. METHODS: The study involved 435 participants aged between 18-66 (mean age 27.49+/-7.48). Out of them, 61.4% were male and 38.6% were female. The subjects were divided into two groups: Group A included 154 (35.4%) amateur and recreational athletes and group B included 281 (64.6%) professional athletes concerned with fitness, bodybuilding and powerlifting. A survey prepared by the authors was conducted in the study, and it consisted of 23 closed questions about AAS use, body confidence, and exercise dependence. In addition, a stadiometer and a body composition analyzer were utilized to take necessary measurements. RESULTS: Between 1-23% of group A participants admitted to using AAS. For group B, it was between 7-30%. Males were reported to use AAS more frequently than females in both groups. With regard to group A, differences in body confidence and exercise dependence were found between males using and not using AAS. Exercise dependence was reported to be different between group A and group B participants. This was true for both males and females. Also, it was shown that group A and group B females differed in terms of metabolic age, body mass and body composition (fat mass, fat-free mass, muscle mass, and total body water). CONCLUSIONS: Most gym athletes do not use AAS. Amateur athletes tend to use AAS more frequently than professional athletes. Factors that contribute to AAS use are: male gender, low body confidence, young age, and long training. PMID- 28597614 TI - The effects of two different explosive strength training programs on vertical jump performance in basketball. AB - BACKGROUND: The aim of this study was to compare the effects of two different training programs oriented to improve vertical jump performance and leg stiffness in basketball players. METHODS: Fifty-eight male basketball players were involved, divided into three age groups (senior, U19 and U17). Subsequently, within any age group, the players were randomLy divided into two training groups, respectively performing a 16-week "hang-clean" training program (HCL), and a "half-squat" training program (HSQ), lasting for the same duration. HCL was based on the hang clean exercise and included also jump rope training; HSQ was based on the half squat exercise and included also speed ladder training. The squat jump (SJ), the countermovement jump without and with arm swing, and with one step approach (respectively, CMJ, CMJS, and TCMJS) and explosive strength indices obtained with a leg stiffness test were assessed pre- and post-training. RESULTS: In senior and U19 athletes both training programs involved an improvement of Vertical Jump performance, with some differences between different age groups. Instead, for the U17 players, only the HSQ led to an enhancement of SJ and TCMJS. Significant enhancement of leg stiffness was observed only in U19 and U17 groups after training. CONCLUSIONS: The present study showed that the programs based on the hang-clean and half squat allowed to improve explosive strength in basketball training. However, only HSQ was effective for the U17 group. Thus, the present findings demonstrate that specific training programs should be designed according to the age of the players. PMID- 28597612 TI - Age-dependent changes in physical performance and body composition in community dwelling Japanese older adults. AB - BACKGROUND: The aim of this study was to describe the age-dependent changes in the parameters of physical performance and body composition in Japanese older adults who are independently dwelling in the community. We also examined whether the age-dependent changes differ among physical performance and body composition parameters. METHODS: Cross-sectional data from 10 092 community-dwelling older adults (mean age 73.6 years; 5296 women) were analyzed. The measures of physical performance included hand-grip strength, the five-times-sit-to-stand test, and walking speed. Body composition parameters (body weight, fat mass, and appendicular skeletal muscle mass) were measured with a bioelectrical impedance analyser. Correlations between age and the physical performance and body composition parameters were tested. The T-scores of physical performance and body composition measurements were calculated and presented according to 5-year age groups to examine the differences in age-dependent changes in physical performance and body composition parameters. RESULTS: All physical performance measures significantly decreased with aging. The cumulative mean T-scores according to age group showed different age-dependent changes between body mass index (BMI) and appendicular skeletal muscle mass index (ASMI) (cumulative mean T score change of BMI and ASMI of -5.7 to -2.9 and -12.7 to -12.1, respectively). The slope declines in age-associated changes were greater in grip strength (beta = -0.77, 95% confidence interval = -0.82 to -0.76) for men and in walking speed (beta = -0.95, 95% confidence interval = -0.99 to -0.90) for women. CONCLUSIONS: The patterns of age-dependent decreases in physical performance measures differed among parameters and between sexes. There is a possibility of a difference in the age-related slope patterns among parameters; decreases in grip strength in men and walking speed in women may be more prominent with advancing age. Furthermore, the decrease in ASMI with age is more striking than that of BMI. PMID- 28597615 TI - Aerobic physical exercise and negative compensation of non-exercise physical activity in post-menopause: a pilot study. AB - BACKGROUND: Sedentarism is a risk factor for mortality that is independent of physical exercise. As indicated in the literature, there is negative compensation of non-exercise physical activity due to exercise training. The aim was to investigate potential predictor variables of physical activity compensation in post-menopausal women beginning aerobic physical exercise training. METHODS: One hundred and three post-menopausal women (mean age, 58.31+/-5.33 years) were eligible for the study. Metabolic markers were measured (plasma leptin, insulin, glucose), together with cardiovascular parameters and body composition. Daily physical activity was recorded objectively. Following baseline measurements, participants walked at moderate intensity on 4 days/week, for 13 weeks. RESULTS: Baseline mean intensity of daily physical activity and leptin-to-fat mass ratio (L/FMkg) were independently and negatively correlated with variations in non exercise physical activity. High L/FMkg was associated with negative compensation of non-exercise physical activity due to aerobic physical exercise. The same was shown for participants starting their exercise training who showed high daily physical activity. CONCLUSIONS: Knowledge of both L/FMkg and baseline spontaneous physical activity of participants in exercise training are important to programme physical exercise interventions and to prevent negative non-exercise physical activity compensation due to exercise training. PMID- 28597616 TI - Comparison of the movement patterns between small- and large-sided game training and competition in professional soccer players. AB - BACKGROUND: The purpose of this investigation was to compare the movement patterns of professional soccer players during a small-sided game (SSG), a large sided game (LSG), and a competitive friendly match (FM). METHODS: Fourteen professional players participated in three training routines with a similar relative pitch area per player. The SSG and LSG consisted of 8 repetitions of 4 min game play, interspersed by 2 minutes of active recovery, and their data were compared to the first 32 minutes of a FM. All movement patterns from walking to sprint running were recorded using 10-Hz GPS devices while player perception of exertion was recorded via visual analogue scale, post-trial. RESULTS: Total running distance (3852+/-405 vs. 3359+/-429 and 3088+/-414 m), running distance at 5-6.9 m/s (222+/-98 vs. 75+/-53 and 49+/-35 m) and maximal running speed (7.0+/-0.7 vs. 6.1+/-0.4 and 6.0+/-0.7 m/s) were significantly greater during FM than for SSG and LSG. However, the number of accelerations (462+/-16 vs. 458+/-12 vs. 422+/-15) and decelerations (733+/-31 vs. 692+/-24 vs. 609+/-27), and the rating of perceived exertion (8+/-1 vs. 7+/-1 vs. 5+/-1) were significantly greater during SSG compared to LSG and FM. CONCLUSIONS: Although smaller game based training routines do not replicate exactly the movement patterns of a competitive match, they can increase the execution of short-term and high intensity movements for specialized training in professional soccer players. PMID- 28597617 TI - Iron monitoring of male and female rugby sevens players over an international season. AB - BACKGROUND: Given the likely influence that high training loads, contact-induced hemolysis and female-specific requirements have on the incidence of iron deficiency, characterizing the direction and magnitude of fluctuations in iron status over an international season is important for managing player health and physical performance in rugby sevens. METHODS: Australian national male (N.=27) and female (N.=23) rugby sevens players undertook blood tests at pre-season, mid season, and end-season. Hemoglobin (Hb), hematocrit (Hct), ferritin, transferrin and transferrin saturation were quantified. Female athletes also reported oral contraceptive use and a subset (N.=7) provided 7-day food diaries to quantify iron intake. RESULTS: Male players typically had a three-fold higher ferritin concentration than females. Pre-season ferritin concentrations in male (151+/-66 ug/L) and female (51+/-24 ug/L) players declined substantially (~20%) by mid season but recovered by end-season. Over the season 23% of female players were classified as iron deficient (ferritin <30 ug/L) and prescribed supplementation. The greatest incidence of iron deficiency in female players occurred mid-season (30%). Oral contraception and dietary iron intake had an unclear influence on female players' ferritin concentration, while age was largely positively correlated (r=0.66+/-~0.33). CONCLUSIONS: Given the relatively low ferritin concentrations evident in female rugby sevens players, and the potential for a further decline midway through a season when physical load may be at its highest, 6-monthly hematological reviews are suggested in combination with dietary management. Annual screening may be beneficial for male players, with further monitoring only when clinically indicated. PMID- 28597618 TI - The effects of resistance training, overtraining, and early specialization on youth athlete injury and development. AB - INTRODUCTION: In 2014, 60 million youth ages 6-18 participated in some form of generalized athletics. Around 3.5 million children are injured annually participating in organized sport or recreational activities. While sound physical education can decrease the burden of youth sports injuries, the median annual physical education budget of $ 764 for USA elementary, middle, and high schools may not allow enough flexibility to apply evidenced-based guidelines. EVIDENCE ACQUISITION: The topics were selected after a careful review of the 2016 National Strength and Conditioning Association Position Statement on Long-Term Athletic Development. Articles used to summarize the topics were located by using and cross-referencing sources from this statement. PubMed searches were also conducted using the key words "youth sports injuries," "early sports specialization," "training and maturation," "training versus developmental stage," and "long-term athletic development." EVIDENCE SYNTHESIS: Youth resistance training has been shown to decrease not only the risk of injury, but also of the development of diabetes and metabolic syndrome. Adequate recovery time also decreases injury risk, and resources such as the RESTQ-Sport are available to help coaches identify stress-recovery imbalances, which can be detected two months before an athlete becomes overreached. Through early detection of overtraining, a significant proportion of overuse injuries can be prevented. Early specialization causes fewer muscle groups to be worked and increased repetition, theoretically increasing the risk of injury and early sport dropout. Prior to puberty, increased neuronal activation and adaptation can be achieved through focusing on agility, balance and coordination, thus taking advantage of increased synaptoplasticity. In these early years, neuronal stimulation is more important than muscle hypertrophy, which plays a greater role in athletic development after puberty. CONCLUSIONS: A substantial proportion of youth injuries are preventable. Coaches and physical educators who correctly understand and apply the principles outlined in this review can help youth under their supervision engage in healthy training for sport. PMID- 28597619 TI - Gender-related cardiac dimension differences between female and male professional soccer players. AB - BACKGROUND: The aim of this study was to determine if cardiac hypertrophy differs between professional female and male soccer players. METHODS: Twenty-two female and 20 male professional soccer players, and their respective non-athlete controls (22 females and 19 males) were submitted to an echocardiogram. RESULTS: Females had a shorter left ventricular intracavitary diameter and wall thicknesses than males in both groups. However, these differences disappeared when cardiac dimensions were expressed relative to body mass area (P>0.05). Compared to their respective controls, female and male soccer players had a longer (P<0.05) left ventricular end-systolic diameter (female: 1.87+/-0.16 vs. 1.77+/-0.15 cm/m2 and male: 1.83+/-0.21 vs. 1.73+/-0.16 cm/m2), left ventricular end-diastolic diameter (female: 2.86+/-0.25 vs. 2.74+/-0.22 cm/m2 and male: 2.81+/-0.26 vs. 2.55+/-0.66 cm/m2), left ventricular posterior wall thickness (female: 0.44+/-0.06 vs. 0.39+/-0.04 cm/m2 and male: 0.43+/-0.04 vs. 0.39+/-0.10 cm/m2), left ventricular septal wall thickness (female: 0.47+/-0.06 vs. 0.41+/ 0.04 cm/m2 and male: 0.45+/-0.04 vs. 0.40+/-0.11 cm/m2), and left ventricular mass index (female: 91.8+/-22.1 vs. 72.3+/-10.5 g/m2 and male: 121.7+/-20.3 vs. 99.8+/-13.8 g/m2 ). CONCLUSIONS: Part of the gender differences in cardiac dimensions might be attributed to differences in body dimension. Soccer training increases cardiac dimensions even with BSA correction and females seem to have similar left ventricle remodeling compared to males. PMID- 28597620 TI - Critical velocity in swimmers of different ages. AB - BACKGROUND: In swimming one of the most employed training speed among coaches is the non-invasive theoretical critical velocity (TCV) defined as the velocity that can be maintained continuously without exhaustion. METHODS: We calculated the 4 mmol/L lactate critical velocity (MCV) in a group of swimmers of different ages (young, elite and master), and compared results to the predicted TCV defined starting from the 200 and 400 m freestyle best seasonal performances. A steady state test consisted in 20 repetitions of 100 m each was performed to study the effect of the imposed MCV in the three athletes' categories. RESULTS: TCV mean values resulted slightly higher than MCV mean values. A strong correlation between TCV and MCV was found considering the whole sample (r=0.96, P<0.001), the Masters (r=0.97, P<0.001) and the Elite (r=0.93, P<0.01). Lactate concentration of the three groups after the steady-state test was 4.2 mmol/L, 3.3 mmol/L and 4.9 mmol/L respectively for young, elite and master groups. CONCLUSIONS: TCV is a reliable, practical and quick parameter that well approximate the anaerobic threshold pace. MCV underestimated the fixed 4 mmol/L lactate threshold pace in the elite swimmers and overestimate it in the master swimmers. Further investigation is needed to understand more in detail TCV applicability for athletes of different ages. PMID- 28597621 TI - Hemodynamic adaptation to training in visually-impaired professional tandem cyclists. AB - BACKGROUND: Cycling is one of the disciplines with the greatest training-induced volumetric changes in cardiovascular systems. The aim of the study was to evaluate the hemodynamic adaptation to 7-month routine training in athletes with and without severe visual impairment. METHODS: The study involved 26 men: visually-impaired (VI) (N.=13; 37+/-12.2 years) and properly-sighted (PS) (N.=13; 41+/-12.8 years) elite tandem-cycling athletes. They underwent hemodynamic variables monitoring at rest and during exercise test by impedance cardiography (ICG), before (in the middle of the transition period) and after 7-month cycling training (at the beginning of the competitive period). RESULTS: At baseline, there were no statistically significant differences in hemodynamic variables between studied groups (P>0.05) apart from ejection fraction (EF) (P=0.010). After training, there was an increase in SVpeak (for PS: 146.46+/-7.10 mL vs. 169.69+/-5.19 mL; for VI: 147.53+/-9.55 mL vs. 160.07+/-12.27 mL), COpeak (for PS: 26.21+/-1.32 L/min vs. 30.65+/-0.94 L/min; for VI: 25.08+/-1.72 L/min vs. 27.95+/-2.17 L/min) and EFpeak (for PS: 65.46+/-2.04% vs. 71.92+/-2.36%; for VI: 61.46+/-2.19% vs. 65.538+/-2.895%). The decrease in HRrest (for PS: 74.91+/-2.8 bpm vs. 69.61+/-3.3 bpm; for VI: 76.7+/-3.8 bpm vs. 72.22+/-3.2 bpm) and SVRpeak (for PS: 311.92+/-20.48 PRU vs. 263.00+/-11.69 PRU; for VI: 365.46+/-24.26 PRU vs. 315.38+/-19.07 PRU) was also noted. CONCLUSIONS: VI and PS tandem cyclists showed similar improvement in majority of hemodynamic variables (mainly volumetric changes). Severe visual impairment does not limit health benefits of regular physical activity. This could be the starting point to motivate inactive VI people to physical activity. PMID- 28597622 TI - The effect of training load on neuromuscular performance, muscle soreness and wellness during an in-season non-competitive week in elite rugby athletes. AB - BACKGROUND: In the elite rugby setting, it is critical to understand the effects of training load on the levels of fatigue, soreness and readiness of the athletes. METHODS: The training load, wellness, neuromuscular markers of fatigue and various perceptual measures of soreness of 16 elite rugby athletes were monitored during a training week. Training load was obtained for field training sessions, extra conditioning and gym-based sessions. Perceptual fatigue was obtained every morning from a 5-item wellness questionnaire and a questionnaire on the muscle soreness of 9 different muscle sites from each side of the body. Neuromuscular performance was obtained from a countermovement jump. RESULTS: Although the training performed on day 4 had a significantly (P<0.05) greater load in comparison to training days 1 and 2, muscle soreness and neuromuscular performance were more adversely effected after the cumulative workloads of days 1 and 2. Moreover, the effect of training load on muscle soreness was only evident in the lower body muscles. Data from the present study also suggest that two days off training are adequate for complete recovery from a high load training week in elite rugby athletes. There were no significant differences in soreness ratings between left and right sides for any of the 9 muscles sites. CONCLUSIONS: There was a clear effect of training load on soreness and neuromuscular fatigue, with greater fatigue following two training days in a row when compared to a single training day. Monitoring soreness from different lower body muscle sites may provide important information that relates to the fatigue levels of rugby athletes and therefore it is recommended to be included as part of the training load monitoring protocol. PMID- 28597623 TI - Impact of a stewardship program on bacteraemia in adult inpatients. AB - OBJECTIVE: Bloodstream infections (BSIs) are associated with considerable morbidity and mortality among inpatients. The aim of this study was to evaluate the impact of a stewardship program on clinical and antimicrobial therapy-related outcomes in patients with bacteraemia. METHODS: Single-centre, before-and-after quasi-experimental study in adult inpatients. Over 1 January 2013 to 31 June 2013 all patients aged 18 years or older with a bacteraemia (interven-tion group, N=200) were compared to a historical cohort (1 Janu-ary 2012 to 31 December 2012) (control group, N=200). RESULTS: Following blood culture results and adjusting for potential confounders, the stewardship program was associated with more changes to antibiotic regimens (adjusted odds ratio [ORa]: 4.6, 95% CI 2.9, 7.4), more adjustments to antimicrobial therapy (ORa: 2.4, 95% CI 1.5, 3.8), and better source control in the first five days (ORa 1.6, 95% CI: 1.0, 2.7). In the subgroup that initially received inappropriate empiric treatment (n=138), the intervention was associated with more antibiotic changes (OR: 3.9, 95% CI: 1.8, 8.5) and a better choice of definitive antimicrobial therapy (OR 2.3 95% CI: 1.2, 4.6). There were also more antibiotic changes in the subgroups with both Gram negative (OR: 2.8, 95% CI: 1.6, 4.9; n=217) and Gram-positive (OR: 4.6, 95% CI: 1.8, 9.9; n=135) bacteraemia among those receiving the intervention, while the Gram-positive subgroup also received more appropriate definitive antimicrobial therapy (OR: 3.9, 95% CI: 1.8, 8.8). CONCLUSIONS: The stewardship program improved treatment of patients with bacteraemia and appropriateness of therapy. PMID- 28597624 TI - That blasted research. PMID- 28597625 TI - Treatment of stroke. PMID- 28597626 TI - People we meet. PMID- 28597628 TI - ? PMID- 28597627 TI - ? PMID- 28597629 TI - ? PMID- 28597630 TI - ? PMID- 28597631 TI - [Physical activity and weight reduction]. PMID- 28597632 TI - ? PMID- 28597633 TI - Spontaneous intracerebral haemorrhages in Vestfold county. AB - BACKGROUND: Limited information is available on the incidence and progress of spontaneous intracerebral haemorrhages in Norway. The objective of this article is to describe the frequency of and the prognosis for such haemorrhages in a geographically well-defined population. MATERIAL AND METHOD: All patients admitted to Vestfold Hospital with a first-time spontaneous intracerebral haemorrhage during the period from 1 September 2010 to 31 May 2014 were included. Age, gender, risk factors, haemorrhaged volume, treatment and mortality were registered. For survivors, the use of nursing and rehabilitation resources was identified, as were neurological function and the ability to cope with daily activities after three months. RESULTS: A total of 182 patients (102 men) were included. The incidence of first-time intracerebral haemorrhages amounted to 20.5/100 000/year. Altogether 25.8 % used anticoagulants prior to the haemorrhage, and 38.5 % used a platelet inhibitor. After two days 23.0 % had died, while the 30-day mortality amounted to 39.6 %. Warfarin use was associated with a significantly increased 90-day mortality when compared to no anticoagulation treatment (p = 0.002). Of those patients who were alive 90 days after their intracerebral haemorrhage, 50.0 % functioned very well according to their Barthel score, and 67.6 % had returned to their own homes. INTERPRETATION: First-time spontaneous intracerebral haemorrhage is a serious event with high mortality. PMID- 28597634 TI - Prehospital path in acute stroke. AB - BACKGROUND: Too few patients with acute stroke receive thrombolytic therapy owing to the limited time window for treatment and prehospital delay. The purpose of this study is to describe the prehospital path for patients with acute stroke and, in particular, what distinguishes patients who contact the Emergency Medical Communication Centre (EMCC) from those who contact their general practitioner (GP) or Out-of-hours (OOH) services. MATERIAL AND METHOD: Patients with acute cerebral infarction and intracerebral haemorrhage admitted to the Stroke Unit, Department of Neurology, Akershus University Hospital, were included. Data on the prehospital path (prehospital delay, medical contacts) were collected over the period 15 April 2009 - 1 April 2010. RESULTS: A total of 299 patients were included in the study. The median age was 75 years and 48.5 % were women. In all, 63.9 % of patients with acute stroke called the EMCC, and 93.7 % of these were taken directly to hospital by ambulance. Of those who called the GP's office or OOH services, 60.7 % were asked to go to the GP's office or OOH services in person. Patients who called and attended the GP's office or OOH services had milder neurological deficits (p < 0.001) and longer patient delay (p = 0.018) than those who called the EMCC. INTERPRETATION: Six out of ten patients who contacted the primary health care services were asked to go to the GP's office/OOH services in person, which resulted in unnecessary delay. The findings from this study may indicate a need for specific training of this group of health care professionals in the prompt handling of patients with possible stroke. PMID- 28597635 TI - Modern treatment of metastatic prostate cancer. AB - The treatment of prostate cancer with remote metastases has advanced greatly in recent years. Treatment options are dependent on the extent of the metastases, the patient's general condition and wishes, and the treatment response. We present an overview of the latest options for systemic treatment of patients with metastatic prostate cancer, based on availability in Norway. PMID- 28597636 TI - A woman in her thirties with breast cancer and bilateral goitre. PMID- 28597637 TI - How can we support the parents of children with a life-shortening disease? PMID- 28597638 TI - [#thatfeeling]. PMID- 28597639 TI - ? PMID- 28597640 TI - ? PMID- 28597641 TI - ? PMID- 28597642 TI - ? PMID- 28597643 TI - ? PMID- 28597644 TI - ? PMID- 28597645 TI - ? PMID- 28597646 TI - ? PMID- 28597649 TI - Single center experience with extracranial carotid aneurysm open repair. AB - BACKGROUND: Our aim is to report our single center experience with extracranial carotid artery aneurysms (ECAA) open repair. METHODS: A retrospective review was performed including the perioperative and postoperative data of all patients who underwent ECAA repair between 2008 and 2015. The operative technique was based on aneurysm size, anatomical features and operative risk. RESULTS: Fourteen patients (6 men and 8 women, mean age +/- 60.5 years) were admitted for ECAA. Thirteen patients (92.8%) were submitted to ECCA open repair while in one patient (7.2%) conservative treatment was realized. Bilateral lesions and concomitant internal carotid artery (ICA) kinking was observed in 2 cases (13%). Seven patients (54%) were asymptomatic at diagnosis and ECCA localization involved ICA in 9 cases (69.2%). Aneurysmectomy with end-to-end anastomosis was perfomed in 2 cases (15.3%), patch arterioplasty in 2 cases (15.3%), prosthetic graft interposition in 3 cases (23.0%), autologous vein graft bypass in 2 cases (15.3%) and artery ligation with distal ICA arteriorraphy in one case (7.6%). No perioperative deaths, major neurological complications and surgical reinterventions were recorded. Overall survival at a mean follow-up of 19.6 months (range, 0-52 months) was 100%. CONCLUSIONS: ECAA open repair represents a safe surgical option, with lower prevalence of complications and no need for reintervention in high volume centers. PMID- 28597647 TI - ? PMID- 28597648 TI - ? PMID- 28597650 TI - Foolproof Method for Fast and Reversible Switching of Water-Droplet Adhesion by Magnetic Gradients. AB - Reversible switching of water-droplet adhesion on solid surfaces is of great significance for smart devices, such as microfluidics. In this work, we designed a foolproof method for fast and reversible magnet-controlled switching of water droplet adhesion surfaces by doping iron powders in soft poly(dimethylsiloxane). The water adhesion is adjusted by magnetic field-induced structure changes, avoiding complex chemical or physical surface design. The regulation process is so convenient that only tens of milliseconds are needed. The on-site responsive mechanism extends its use to unusual curved surfaces. Moreover, the excellent reversibility and stability make the film an ideal candidate for real-time applications. PMID- 28597651 TI - In Operando Investigation of Electrical Coupling of Photosystem 1 and Photosystem 2 by Means of Bipolar Electrochemistry. AB - Electrochemical communication between two photobioelectrochemical half-cells based on photosystem 1 and photosystem 2 is investigated in operando. The driving force for the electron-transfer reactions is applied in a wireless mode using bipolar electrochemistry with the actual electrode potentials being self regulated by the redox processes. Four parameters are assessed to understand the overall performance and elucidate the limiting reactions of the photobioelectrochemical cell. In addition to the potential differences for oxidation and reduction reactions, the current flowing between the half-cells as well as in situ collection of locally evolved O2 by photosystem 2 using a positioned scanning electrochemical microscopy tip are evaluated. In this way, changes in the enzymatic performances as a result of inactivation of either of the protein complexes or variations in the external conditions are monitored. PMID- 28597652 TI - Comment on "Impact of Adsorption on Scanning Electrochemical Microscopy Voltammetry and Implications for Nanogap Measurements": Assessment of Heterogeneous Self-Exchange Reaction at Conductor and Insulator. PMID- 28597653 TI - Overexpression of ATP-Binding Cassette Subfamily G Member 2 Confers Resistance to Phosphatidylinositol 3-Kinase Inhibitor PF-4989216 in Cancer Cells. AB - Deregulated activation of phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently found in human cancers, which plays a key role in promoting cancer proliferation and resistance to anticancer therapies. Therefore, developing inhibitors targeting key components of the PI3K/Akt/mTOR signaling pathway has great clinical significance. PF-4989216 is a novel, orally available small-molecule drug that was developed to selectively inhibit the PI3K/Akt/mTOR signaling pathway and subsequent cancer cell proliferation. PF-4989216 exhibited potent and selective inhibition against PI3K kinase activity in preclinical small-cell lung cancer (SCLC) models, and was especially effective against the proliferation of SCLCs harboring PIK3CA mutation. Unfortunately, in addition to innate resistance mechanisms, drug extrusion by the efflux pumps may also contribute to the development of acquired resistance to PI3K inhibitors in cancer cells. The overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2 is one of the most common mechanisms for reducing intracellular drug concentration and developing multidrug resistance, which remains a substantial challenge to the effective treatment of cancer. In this study, we report the discovery of ABCG2 overexpression as a mechanism of resistance to PI3K inhibitor PF-4989216 in human cancer cells. We demonstrated that the inhibition of Akt and downstream S6RP phosphorylation by PF 4989216 were significantly reduced in ABCG2-overexpressing human cancer cells. Moreover, overexpression of ABCG2 in various cancer cell lines confers significant resistance to PF-4989216, which can be reversed by an inhibitor or competitive substrate of ABCG2, indicating that ABCG2-mediated transport alone can sufficiently reduce the intracellular concentration of PF-4989216. PMID- 28597654 TI - OMS-2-Supported Cu Hydroxide-Catalyzed Benzoxazoles Synthesis from Catechols and Amines via Domino Oxidation Process at Room Temperature. AB - In the presence of manganese oxide octahedral molecular sieve (OMS-2) supported copper hydroxide Cu(OH)x/OMS-2, aerobic synthesis of benzoxazoles from catechols and amines via domino oxidation/cyclization at room temperature is achieved. This heterogeneous benzoxazoles synthesis initiated by the efficient oxidation of catechols over Cu(OH)x/OMS-2 tolerates a variety of substrates, especially amines containing sensitive groups (hydroxyl, cyano, amino, vinyl, ethynyl, ester, and even acetyl groups) and heterocycles, which affords functionalized benzoxazoles in good to excellent yields by employing low catalyst loading (2 mol % Cu). The characterization and plausible catalytic mechanism of Cu(OH)x/OMS-2 are described. The notable features of our catalytic protocol such as the use of air as the benign oxidant and EtOH as the solvent, mild conditions, ease of product separation, being scalable up to the gram level, and superior reusability of catalyst (up to 10 cycles) make it more practical and environmentally friendly for organic synthesis. PMID- 28597655 TI - Identification and Characterization of 3-epi-Rotundone, a Novel Stereoisomer of Rotundone, in Several Kinds of Fruits. AB - A novel stereoisomer of rotundone, 3-epi-rotundone, was identified in the aroma of grapefruit, orange, apple, and mango. 3-epi-Rotundone was prepared by the isomerization of rotundone, and its structural elucidation was confirmed by comparing the 1D and 2D nuclear magnetic resonance and nuclear Overhauser effect spectroscopy spectra with those of rotundone. The odor thresholds of rotundone and 3-epi-rotundone in water were determined by a triangle test as 5 and 19100 ng/kg, respectively. The odor of 3-epi-rotundone was evaluated as woody, spicy, peppery, citrus, grapefruit-like, powdery, and celery-like, which was a greater range of odor characteristics than that for rotundone. Results of odor evaluation of 3-epi-rotundone revealed that its unique organoleptic properties, which were odor description (woody, spicy, and peppery), anosmic properties in neat form, and strong adaptation, were similar to those of rotundone. 3-epi-Rotundone might be a valuable substance to apply new types of woody, peppery, and spicy notes. PMID- 28597656 TI - Enhancing Mechanical and Thermal Properties of Epoxy Nanocomposites via Alignment of Magnetized SiC Whiskers. AB - This research is focused on the fabrication and properties of epoxy nanocomposites containing magnetized SiC whiskers (MSiCWs). To this end, we report an original strategy for fabrication of magnetically active SiCWs by decorating the whiskers with magnetic (iron oxide) nanoparticles via polymer polymer (poly(acrylic acid)/poly(2-vinyl pyridine)) complexation. The obtained whiskers demonstrated a substantial magnetic response in the polymerizing epoxy resin, with application of only a 20 mT (200 G) magnetic field. We also found that the whiskers chemically reacted with the epoxy resin, causing formation of an extended interphase near the boundary of the whiskers. The SiC whiskers oriented with the magnetic field demonstrated positive effects on the behavior of epoxy-based nanocomposites. Namely, the aligned MSiCWs enhanced the thermomechanical properties of the materials significantly above that of the neat epoxy and epoxy nanocomposite, with randomly oriented whiskers. PMID- 28597657 TI - Coupled Lattice Polarization and Ferromagnetism in Multiferroic NiTiO3 Thin Films. AB - Polarization-induced weak ferromagnetism (WFM) was demonstrated a few years back in LiNbO3-type compounds, MTiO3 (M = Fe, Mn, Ni). Although the coexistence of ferroelectric polarization and ferromagnetism has been demonstrated in this rare multiferroic family before, first in bulk FeTiO3, then in thin-film NiTiO3, the coupling of the two order parameters has not been confirmed. Here, we report the stabilization of polar, ferromagnetic NiTiO3 by oxide epitaxy on a LiNbO3 substrate utilizing tensile strain and demonstrate the theoretically predicted coupling between its polarization and ferromagnetism by X-ray magnetic circular dichroism under applied fields. The experimentally observed direction of ferroic ordering in the film is supported by simulations using the phase-field approach. Our work validates symmetry-based criteria and first-principles calculations of the coexistence of ferroelectricity and WFM in MTiO3 transition metal titanates crystallizing in the LiNbO3 structure. It also demonstrates the applicability of epitaxial strain as a viable alternative to high-pressure crystal growth to stabilize metastable materials and a valuable tuning parameter to simultaneously control two ferroic order parameters to create a multiferroic. Multiferroic NiTiO3 has potential applications in spintronics where ferroic switching is used, such as new four-stage memories and electromagnetic switches. PMID- 28597658 TI - Layer Control of Tubular Graphene for Corrosion Inhibition of Nickel Wires. AB - Corrosion protection of complex surface is an active area of research due to its importance to commercial applications such as electrochemical fabrication. However, conventional coatings exhibit limited conductivity, thermal stability, and durability and are thus not suitable. Recent work has shown the potential of graphene, a two-dimensional carbon allotrope, for corrosion protection. The studies, however, limited themselves to simple planar geometries that provide limited insight in the applicability to relevant morphologies such as mesh electrodes and roughened surfaces. We here study the corrosion protection ability of tubular graphene (TG) on Ni-wires as a model system for such complex geometries. TG-covered Ni wires of approximately 50 MUm diameters were produced by the annealing of cellulose acetate (CA) on Ni. The high quality of the TG coating was confirmed by Raman spectroscopy, scanning electron microscopy, and electrical measurements. We show that the graphene layer number could be controlled by adjusting the CA membrane quantity. We found a direct relation between the degree of corrosion inhibition with the variation of graphene layer number. The increase of graphene layers on a Ni surface could enhance its corrosion inhibition in acidic, basic, and marine environments, which shows the potential of our approach for future applications. PMID- 28597659 TI - Vibrational Spectroscopy and Proton Transfer Dynamics in Protonated Oxalate. AB - The dynamics and infrared spectroscopic signatures of proton transfer in protonated oxalate (p-Oxa) are studied using classical and quantum dynamics. The intermolecular interactions are described by a force field suitable to follow proton transfer. This allows to carry out multiple extended classical molecular dynamics (MD) and ring polymer MD simulations from which the infrared spectrum is determined. Simulations at 600 K sample the quantum mechanical ground state probability distribution and best reproduce the experimentally observed maximum absorption wavelength and part of the line shape. Comparison with the experimentally measured spectrum provides an estimate for the barrier height for proton transfer which can not be determined directly from experiment. A barrier of 4.2 kcal/mol is found to best reproduce the position and width of the infrared absorption of the transferring proton in p-Oxa and also leads to an infrared (IR) spectrum in good agreement with experiment for the deuterated species d-Oxa. A novel means to capture the two resonance forms of oxalate depending on the localization of the excess proton on either CO moiety is found to yield improved results for the spectroscopy in the framework region between 1000 and 2000 cm-1. PMID- 28597660 TI - Monolayer Bismuthene-Metal Contacts: A Theoretical Study. AB - Bismuthene, a bismuth analogue of graphene, has a moderate band gap, has a high carrier mobility, has a topological nontriviality, has a high stability at room temperature, has an easy transferability, and is very attractive for electronics, optronics, and spintronics. The electrical contact plays a critical role in an actual device. The interfacial properties of monolayer (ML) bismuthene in contact with the metal electrodes spanning a wide work function range in a field-effect transistor configuration are systematically studied for the first time by using both first-principles electronic structure calculations and quantum transport simulations. The ML bismuthene always undergoes metallization upon contact with the six metal electrodes owing to a strong interaction. According to the quantum transport simulations, apparent metal-induced gap states (MIGSs) formed in the semiconductor-metal interface give rise to a strong Fermi-level pinning. As a result, the ML bismuthene forms an n-type Schottky contact with Ir/Ag/Ti electrodes with electron Schottky barrier heights (SBHs) of 0.17, 0.22, and 0.25 eV, respectively, and a p-type Schottky contact with Pt/Al/Au electrodes with hole SBHs of 0.09, 0.16, and 0.38 eV, respectively. The effective channel length of the ML bismuthene transistors is also significantly reduced by the MIGSs. However, the MIGSs are eliminated and the effective channel length is increased when ML graphene is used as an electrode, accompanied by a small hole SBH of 0.06 eV (quasi-Ohmic contact). Hence, an insight is provided into the interfacial properties of the ML bismuthene-metal composite systems and a guidance is provided for the choice of metal electrodes in ML bismuthene devices. PMID- 28597661 TI - Metal-free Oxidative Coupling of Aromatic Alkenes with Thiols Leading to (E) Vinyl Sulfones. AB - A facile I2O5-mediated direct oxidative coupling of aromatic alkenes with thiols toward vinyl sulfones has been developed under metal-free conditions. This methodology provides a convenient and efficient approach to various (E)-vinyl sulfones from readily available starting materials with excellent regioselectivity. The present oxidative coupling reaction, not only expands the scope of functionalization of alkenes with thiols, but also makes it a practical and powerful complement to traditional methods for the synthesis of (E)-vinyl sulfones. PMID- 28597663 TI - Enhancement of Light Absorption in Photovoltaic Devices using Textured Polydimethylsiloxane Stickers. AB - We designed and fabricated a random-size inverted-pyramid-structured polydimethylsiloxane (RSIPS-PDMS) sticker to enhance the light absorption of solar cells and thus increase their efficiency. The fabricated sticker was laminated onto bare glass and crystalline silicon (c-Si) surfaces; consequently, low solar-weighted reflectance values were obtained for these surfaces (6.88 and 17.2%, respectively). In addition, we found that incident light was refracted at the PDMS-air interface of each RSIPS, which redirected the incident power and significantly increased the optical path length in the RSIPS-PDMS sticker which was 14.7% greater than that in a flat-PDMS sticker. Moreover, we investigated power reflection and propagation through the RSIPS-PDMS sticker using a finite difference time-domain method. By attaching an RSIPS-PDMS sticker onto both an organic solar cell (OSC) based on a glass substrate and a c-Si solar cell, the power conversion efficiency of the OSC and the c-Si solar cell were increased from 8.57 to 8.94% and from 16.2 to 17.9%, respectively. Thus, the RSIPS-PDMS sticker is expected to be universally applicable to the surfaces of solar cells to enhance their light absorption. PMID- 28597664 TI - [Addictive substances in fatal cases of fall/jump from height]. AB - The aim of the study is to analyse causes of fatal cases of falls from height focusing on the occurrence of addictive substances. The authors performed a retrospective analysis of cases dealing with falls/jumps autopsied at the Institutes of Forensic Medicine in Bratislava in the years 2005-2014 accounting for a catchment area with approximately 1.2 m population. Selection criteria were met in 360 cases, i.e. approximately 4 % of all cases autopsied. There were 68 % of men and 32 % of women involved. The age interval ranged from 10 up to 93 years (mean age 50 years). Addictive substances were found in a total of 32 % of cases, ethanol alone in 22 % of cases. The cases were divided into groups according to the cause as follows: accidental falls (24%) also involving occupational accidents (11 %), jumps in suicidal ideation (63 %) and cases with the unspecified cause of falling (13 %). Most of the cases with detected addictive substances were in the group of suicidal jumps (35 %). In this group, 32 % of patients were treated for psychiatric disorders. The most common diagnosis was a depressive disorder and schizophrenia. In the group of occupational accidents, ethanol was found in 25 % of cases. The results of the study show that it is essential to pay more attention to psychiatric patients as not even regular psychiatric care and treatment can always prevent suicide. Accordingly, there is a need to strictly monitor the ban on alcohol consumption at work and the observance of safety regulations for working at heights, and thus to minimise the occurrence of falls with fatal outcomes. PMID- 28597662 TI - Chitosan/Hyaluronic Acid Nanoparticles: Rational Design Revisited for RNA Delivery. AB - Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation). The RNA avidity for chitosan showed-as expected-an inverse relationship: higher avidity-higher polyplex stability-lower transfection efficiency. The avidity of chitosan for RNA appears to lead to opposite effects: higher avidity-higher polyplex stability but also higher transfection efficiency. Surprisingly, the best transfecting particles were those with the lowest propensity for RNA release, although this might be a misleading relationship: for example, the same macromolecular parameters that increase avidity can also boost chitosan's endosomolytic activity, with a strong enhancement in transfection. The performance of these nonviral vectors appears therefore difficult to predict simply on the basis of carrier- or payload-related variables, and a more holistic consideration of the journey of the nanoparticle, from cell uptake to cytosolic bioavailability of payload, is needed. It is also noteworthy that the nanoparticles used in this study showed optimal performance under slightly acidic conditions (pH 6.4), which is promising for applications in a tumoral extracellular environment. It is also worth pointing out that under these conditions we have for the first time successfully delivered mRNA with chitosan/HA nanoparticles. PMID- 28597665 TI - [Injuries associated with cardiopulmonary resuscitation in non-survivors after out-of-hospital cardiac arrest (autopsy study)]. AB - The aim of the present study is to investigate incidence and seriousness of CPR associated injuries on a cohort of CPR non-survivors after out-of-hospital cardiac arrest in the Moravian-Silesian region. In total, 80 persons were included in the study within the study period (2012 - 2015). CPR-associated injuries were identified in 75 (93.7 %) persons, multiple injuries were found in 73 persons. Spectrum of identified injuries covered skin injuries of the upper half of the body, head and neck injuries, rare abdominal injuries and very frequent thorax injuries. Sternal fractures were found in 53 (63.3 %) persons. Rib fractures were identified in 59 (73.0 %) persons; rib fractures were usually multiple (mean number of broken ribs was 7.6 per person). Intra-thoracic injuries were diagnosed in 33 (41.2 %) persons - findings of lung contusions and lacerations, transmural heart contusions, hemothorax and hemopericard. The vast majority of identified intra-thoracic injuries were considered clinically relevant (provided the fact that return of spontaneous circulation had been achieved). Intraabdominal injuries (liver and spleen injuries) were identified in 15 (18.7 %) of persons. Vast majority of these injuries was clinically irrelevant. We have found clinically serious injuries (spleen rupture and liver dilacerations) in 3 (3.7 %) persons. Outcomes of our study suggest that CPR associated injuries are very common, usually multiple, and in some cases they might be even potentially lethal (if return of spontaneous circulation is achieved).Key words: cardiopulmonary resuscitation - cardiac arrest - injuries - autopsy study - sternal and rib fractures. PMID- 28597667 TI - [Giant cell-rich lesions of bone and their differential diagnosis]. AB - Giant cell-rich lesions form a heterogeneous group of reactive and truly neoplastic processes with diverse clinical presentation and biological behavior. Common to all of them are variably numerous multinucleated osteoclast-like giant cells and the presence of mononuclear stroma. Based on the histological picture alone it is sometimes impossible to reliably distinguish certain tumors from each other. The pathologist has to know the patient's age, the exact localization, tumor growth dynamics and its radiographic characteristics. Secondary reactive changes occur frequently and these can completely alter the morphology of the lesion and thus overshadow the underlying neoplasm. Reparative changes in a pathological fracture may histologically mimic primary bone malignancy. Immunohistochemistry helps only in select cases and molecular genetic methods still have very limited utility for the diagnosis of giant cell-rich tumors. It is necessary to correlate the microscopic features of the lesion with clinical and radiological findings. A correct diagnosis is of paramount importance for proper treatment and prognosis. PMID- 28597666 TI - [Methodology of injury compensation and Government Regulation of injury compensation in reflection in the Constitutional Court decision]. AB - After the new Civil Code had come into force, the Compensation Statute lost the efficiency. The injury compensation should not have been provided according medical report with respect to the Compensation Statute but according decency basis. So the Highest Court has accepted the Methodology of compensation. The article deals with the first reflection of the Methodology in the judicature of the Constitutional Court as well as the opinion of the Constitutional Court of the Government Statute which regulates the injury compensation in labour law. The Metodology of compensation is based on the ICF (International Classification of Functioning, Disability and Health), while the Compensation Statute was based on the etiology principe. ICF is a classification of health and health-related domains. As the functioning and disability of an individual occurs in a context, ICF also includes a list of environmental factors. ICF is the WHO framework for measuring health and disability at both individual and population levels. PMID- 28597668 TI - Hybrid peripheral nerve sheath tumors: A review. AB - Hybrid peripheral nerve sheath tumors (HPNST) are relatively recently described tumors. With ongoing research, a considerable amount of important findings have been made, much of which has substantial clinical implications. However, a comprehensive review of the whole topic has not been published in the literature so far. In the presented manuscript, the various hybrid tumors are discussed separately with a special emphasis on the morphological and immunohistochemical findings as well as on their association with tumor syndromes. PMID- 28597669 TI - [Myxoid tumors of soft tissues]. AB - Myxoid tumours of soft tissue represent a heterogeneous spectrum of lesions with variable biological behaviour, from completely benign to highly aggressive malignancies. Myxoid tumours share abundant myxoid extracellular matrix, overlapping histopathologic features and immunohistochemical findings, with resulting diagnostic problems. This review article attempts to give the most complete list possible, with the characterization of gross and microscopic features, relevant immunohistochemical and molecular biology findings and to outline differential diagnosis. PMID- 28597670 TI - [Identification of an optimal algorithm for effective diagnostics of non-small cell lung cancer with ALK gene rearrangement - implementation of the method and practical experiences with routine diagnostics]. AB - The aim of the retrospective part of the study was a) to select an optimal clone of immunohistochemical (IHC) antibody against the ALK protein with specificity and sensitivity high enough to use this antibody as a screening method for selecting non-small cell lung cancer (NSCLC) cases for fluorescence in situ hybridization (FISH) testing of ALK gene rearrangement and b) to determine the diagnostic yield of "small" biopsies i.e. endobronchial, transbronchial and transthoracic biopsies and cytoblocks for ALK gene rearrangement testing. The best IHC method of ALK protein detection (clone D5F3, dilution 1:100, Cell Signaling Technology, Danvers, MA, USA) was then verified in prospective routine testing of patients with NSCLC. ALK status was correlated with tumor morphology and clinical data. In the retrospective part of the study, 170 EGFR-nonmutated cases of NSCLC were IHC and FISH tested. In the prospective part, 557 cases of NSCLC were tested by IHC and 76 by FISH. There were 8/154 (5.2%) cases with ALK gene rearrangement detected in the retrospective part and 24/557(4.3 %) in the prospective part. Sensitivity and specificity of the best IHC method were 100 % and 99 % in the retrospective part and 100 % and 80 % in the prospective part. The diagnostic yield of "small" biopsies was between 74 - 80 % retrospectively, depending on IHC variant, and 88 % prospectively. No case with ALK gene rearrangement detected prospectively had EGFR mutation. A high diagnostic yield confirms that ALK status testing can be used in this type of specimen. A prevalence of 5.2 % in the retrospective part (EGFR-nonmutated cases) and 4.3 % in the prospective part (without known EGFR mutation status), tumor morphology (solid and acinar type, mucinous type or at least partial mucin production (extra and/or intracellular) as well as lower average age and male/female ratio of patients with ALK positive tumors in the prospective part (57.5 y vs. 65.2 y, 8 men and 16 women vs. 336 men and 197 women) are consistent with global data. PMID- 28597671 TI - Mature teratoma of the uterine corpus: A case report. AB - We report a case of a 37-year old female with a mature teratoma of the uterine corpus presented by metrorrhagia. Grossly, the tumor was polypoid without apparent invasion into the myometrium. Microscopically, the tumor consisted of disorganized mature neural tissue intermingled with nodular foci of cartilaginous tissue, groups of seromucionous glands and ciliated columnar respiratory epithelium. Fifteen months after the diagnosis, the patient showed no signs of tumor relapse. Then she was lost for a follow-up. Teratoma of the uterine corpus is rare; to the best of our knowledge only about 20 cases have been reported to date. PMID- 28597672 TI - Pancreas Burkitt primary lymphoma in pediatric age. AB - We present an the case of an eight-year-old Portuguese boy with no history of traveling, admitted with non-specific abdominal pain. An analytic study revealed high levels of lipase and amylase. Ultrasound, abdominal computerized tomography (CT), and an abdominal magnetic resonance imaging (MRI), were performed. The imaging findings are suggestive of a pancreatic tumor which is an extremely rare entity in children. A biopsy was performed by opened surgery and identified a Burkitt lymphoma. PMID- 28597673 TI - Portal air embolism after endoscopic retrograde cholangiopancreatography. AB - The authors present an uncommon case of portal venous gas and contrast opacification that occured during endoscopic retrograde cholangiopancreatography. This report demonstrates that portal vein cannulation may be a source of confusion because the guided wire trajectory inside the portal vein may be similar to that of the biliary, and a contrast washout/opacified portal vein may be misinterpreted as an incompletely filled bile duct. PMID- 28597674 TI - Diverticulitis of the cecal appendix: a case report. AB - Appendicular diverticulosis is a rare condition. It is important to know its insidious form of presentation for its early diagnosis and treatment, thus diminishing morbimortality. In case of incidental findings, an appendicectomy will be performed to prevent complications and the development of malignancy. PMID- 28597675 TI - Artifacts of the common bile duct caused by duodenal metallic hemoclip on magnetic resonance cholangiopancreatography. AB - Magnetic resonance cholangiography (MRCP) is a non-invasive and highly sensitive diagnostic modality for pancreatobiliay lesions, which can replace the role of Endoscopic Retrograde Cholangiopancreatography (ERCP). However metallic components can lead to misinterpretation of the images of MRCP. Here we present a case of a duodenal metal hemoclip, producing a susceptibility artifact of pathologic lesion in the common bile duct on MRCP. PMID- 28597676 TI - Dorsal inflammatory mass secondary to lost stones after laparoscopic cholecystectomy. AB - The most frequent intraabdominal complication after lost stones are abscesses, which account for 65% of complications. The main risk factors are: old age, male gender, surgical difficulty, leakage of lithiasis of more than 1.5 cm or more than 15 stones, perihepatic location and pigmented gallstones. We report the case of a 73-year-old man with a medical history of hypertension, diabetes, chronic kidney failure and laparoscopic cholecystectomy. PMID- 28597677 TI - Endoscopic management of afferent loop syndrome caused by enteroliths and anastomotic stricture. A case report. AB - Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Causes of afferent loop obstruction include adhesions, internal hernias, intestinal strictures or malignancy. Obstruction caused by enteroliths is rare and usually requires surgery. We present the case of a 90 year-old man with a Billroth-II performed 50 years earlier and three acute pancreatitis. He presented with acute abdominal pain, without signs of pancreatitis. Upper digestive endoscopy revealed a punctiform anastomotic stricture of the afferent loop. Fluoroscopy-guided contrast injection showed a dilated loop with multiple filling defects. After through-the-scope balloon dilation, multiple calculi similar to gallstones were observed in the afferent loop and were removed with a basket. There were no signs of choledochoduodenal fistula or abnormalities in the ampulla of Vater, leading us to assume the formation of intestinal calculi. This case represents a rare cause of ALS, emphasizing the possibility of solely endoscopic treatment. The stone was removed and the anastomotic stricture which was the underlying cause of the enterolith formation was treated by endoscopy. Endoscopic management of enterolith-related ALS is technically difficult and rarely reported. To our knowledge, there are two cases in which electrohydraulic lithotripsy was used to fragment a large enterolith in the afferent loop. This includes one report of failed endoscopic retrieval of an enterolith and in another case a perforation after an attempt to grasp the stone with a basket. ALS has multiple causes and non-specific clinical manifestations. We highlight the importance of high clinical suspicion and individualized treatment according to the patient's condition, severity, ALS etiology and locally available treatment possibilities. PMID- 28597678 TI - A giant hiatal hernia and intrathoracic pancreas. AB - Transhiatal herniation of the pancreas is an extremely rare condition, with only a few more than ten cases reported. Most patients are symptomatic at initial presentation and multi-detector computed tomography allows a detailed visualization of the anatomy and size of the diaphragmatic defect. Surgical repair is recommended for symptomatic cases. PMID- 28597679 TI - Successful extracorporeal shock wave lithotripsy (ESWL) treatment of a symptomatic massive biliary stone proximal to an anastomotic biliary stricture. AB - Postoperative benign biliary stricture in the anastomotic site is one of the most common complications of biliary-enteric anastomosis, with a rate of 6.87% after 2 13 years of follow-up. If untreated, biliary strictures can induce other complications such as recurrent cholangitis, intrahepatic stones, pancreatitis and secondary biliary cirrhosis. We report our experience with extracorporeal shock wave lithotripsy (ESWL) in a patient with a massive symptomatic stone proximal to an anastomotic biliary stricture. PMID- 28597680 TI - Fishbone impaction in the colon. AB - Postoperative benign biliary stricture in the anastomotic site is one of the most common complications of biliary-enteric anastomosis, with a rate of 6.87% after 2 13 years of follow-up. If untreated, biliary strictures can induce other complications such as recurrent cholangitis, intrahepatic stones, pancreatitis and secondary biliary cirrhosis. We report our experience with extracorporeal shock wave lithotripsy (ESWL) in a patient with a massive symptomatic stone proximal to an anastomotic biliary stricture. PMID- 28597681 TI - Mesenteric-portal axis thrombosis and deep venous thrombosis in a patient with inferior vena cava agenesis. AB - Splenoportal axis thrombosis not associated with cirrhosis or neoplasms has a prevalence lower than 5 per 10,000 people. An etiologic factor responsible for portal thrombosis is finally identified in most cases, usually systemic thrombogenic factors or predisposing local factors. However, despite a detailed study of all etiologic factors, up to 30% of cases are eventually considered as idiopathic in origin. We report the case of a 41-year-old patient who presented with abdominal pain and lower extremity edema. The patient was diagnosed with portal and mesenteric-portal confluence thrombosis, bilateral deep venous thrombosis and right lumbar vein thrombosis based on an abdominal CT scan. This was associated with a likely congenital inferior vena cava agenesis. This malformation is present in approximately 5% of patients with deep vein thrombosis even though it represents a rare cause of portal thrombosis. The fact that several thromboses developed simultaneously makes this a unique and isolated case in the current literature as no similar cases have been reported thus far. PMID- 28597682 TI - A bronchobiliary fistula due to giant hydatid cyst. AB - Intrathoracic rupture of hydatid cyst of the liver is a rare but severe complication of echinococcal disease. It represent a serious condition responsible for lesions at 3 levels: hepatic, diaphragmatic, and pulmonary. Early diagnosis and management of septic associated complications are essential. We present the case of a 55 year old female patient with a giant hydatid cyst type CE 2 based on WHO Classification, communicating with the biliary tree and with a massive extension to the right hemithorax. PMID- 28597683 TI - Recurrent hyperammonemic encephalopathy. Embolization of the portosystemic shunt. AB - We present the case of a recurrent hyperammonaemic encephalopathy due to a portosystemic shunt that was successfully treated by embolization. PMID- 28597684 TI - Protection against shigellosis caused by Shigella dysenteriae serotype 4 in guinea pigs using Escherichia albertii DM104 as a live vaccine candidate strain. AB - Recently, we reported the induction of protective immunity by environmental Escherichia albertii strain DM104 against Shigella dysenteriae in guinea pig model. In this study, we assessed three different immunization routes, such as intranasal, oral, and intrarectal routes, and revealed differences in immune responses by measuring both the serum IgG and mucosal IgA antibody titers. Protective efficacy of different routes of immunization was also determined by challenging immunized guinea pigs against live S. dysenteriae. It was found that intranasal immunization showed promising results in terms of antibody response and protective efficacy. All these results reconfirm our previous findings and additionally point out that the intranasal immunization of the environmental E. albertii strain DM104 in guinea pig model can be a better live vaccine candidate against shigellosis. PMID- 28597685 TI - A gain-of-function mutation of STAT1: A novel genetic factor contributing to chronic mucocutaneous candidiasis. AB - Heterozygous gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) have increasingly been identified as a genetic cause of autosomal-dominant (AD) chronic mucocutaneous candidiasis (CMC). In this article, we describe a 33-year-old man who experienced chronic refractory candidiasis, recurrent otitis media, and pneumonia resulting in bronchiectasis, severe oral and esophageal candidiases with strictures associated with hypothyroidism and immune hemolytic anemia. His son also suffered from persistent candidiasis, chronic diarrhea, poor weight gain, and pneumonia that resulted in his demise because of sepsis. The immunological workup showed that an inverse CD4/CD8 ratio and serum immunoglobulins were all within normal ranges. The laboratory data revealed failure in response to Candida lymphocyte transformation test. In addition, by Sanger sequencing method, we found a heterozygous mutation, Thr385Met (T385M), located in the DNA-binding domain of STAT1, which was previously shown to be GOF. These findings illustrate the broad and variable clinical phenotype of heterozygous STAT1 GOF mutations. However, more clinical information and phenotype-genotype studies are required to define the clinical phenotype caused by AD STAT1 GOF. PMID- 28597686 TI - Three new flavanoids from artificially induced dragon's blood of Dracaena cambodiana. AB - Three new flavanoids, (2R)-7,4'-dihydroxy-8-methylflavan (1), (2R)-7,4'-dihydroxy 6-methylflavan (2), and (3R)-7,3',4'-trihydroxyhomoisoflavan (3), together with seven known compounds (4-10), were isolated from artificially induced dragon's blood of Dracaena cambodiana, and their structures were determined based on HR ESI-MS and extensive spectroscopic techniques (UV, IR, 1D-, and 2D-NMR). Compound 2 exhibited weak cytotoxicity against BEL-7402 cells line with the IC50 value of 39.2 MUM. In addition, compound 3 showed significant acetylcholinesterase (AChE) inhibitory activity. PMID- 28597688 TI - The availability and accessibility of basic concept vocabulary in AAC software: a preliminary study. AB - Core vocabulary lists obtained through the analyses of children's utterances include a variety of basic concept words. Supporting young children who use augmentative and alternative communication (AAC) to develop their understanding and use of basic concepts is an area of practice that has important ramifications for successful communication in a classroom environment. This study examined the availability of basic concept words across eight frequently used, commercially available AAC language systems, iPad(c) applications, and symbol libraries used to create communication boards. The accessibility of basic concept words was subsequently examined using two AAC language page sets and two iPad applications. Results reveal that the availability of basic concept words represented within the different AAC language programs, iPad applications, and symbol libraries varied but was limited across programs. However, there is no significant difference in the accessibility of basic concept words across the language program page sets or iPad applications, generally because all of them require sophisticated motor and cognitive plans for access. These results suggest that educators who teach or program vocabulary in AAC systems need to be mindful of the importance of basic concept words in classroom settings and, when possible, enhance the availability and accessibility of these words to users of AAC. PMID- 28597687 TI - Comparison of Calcaneal Exposure Through the Extensile Lateral and Sinus Tarsi Approaches. AB - : The purpose of this study was to compare the exposure of the posterior facet with the extensile lateral (EL) approach compared with the sinus tarsi (ST) approach. We hypothesized that the ST approach will provide a similar exposure of the posterior calcaneal facet. A total of 8 sequential ST then EL approaches were performed on cadavers. Calcaneal landmarks were identified by visualization or palpation. Calibrated digital photographs of the posterior facet and lateral calcaneal body were obtained from standardized positions and used to calculate the exposed surface area. No significant difference was found in the average square area of the posterior facet exposed with the 2 approaches. Significantly more of the lateral calcaneal body was seen with the EL approach. Excluding the posterior facet superomedial quadrant, all the landmarks were visualized in 100% of approaches. The superomedial corner was visualized in significantly more of the cadavers with the EL approach and was palpable in 12.5% of the remaining cadavers in both approaches. Whereas the ST approach exposes less of the lateral wall of the calcaneus, it exposes similar amounts of the posterior facet when compared with the EL approach. LEVELS OF EVIDENCE: Therapeutic, Level V. PMID- 28597689 TI - Circulating endothelial cells and their subsets: novel biomarkers for cancer. AB - Angiogenesis contributes to the growth of solid tumors. Antiangiogenic agents are widely used in various cancers and considerable efforts have been made in the development of novel biomarkers that can predict the outcome of an anticancer treatment. Of those, circulating endothelial cells (CECs) and their subsets constitute a surrogate tool for monitoring disease activity. However, owing to the lack of standardization on the phenotypes and detection of CECs and their subsets, results have always been inconsistent and uninterpretable. In this review, we focus on the biological characteristics in terms of physiology, phenotypes and detection of CECs along with their subsets; review the current scenario of CEC enumeration as a surrogate biomarker in clinical oncology; and explore their future potential applications. PMID- 28597690 TI - DNA methylation and copy number variation analyses of human embryonic stem cell derived neuroprogenitors after low-dose decabromodiphenyl ether and/or bisphenol A exposure. AB - The polybrominated diphenyl ether flame retardants decabromodiphenyl ether (BDE 209) and bisphenol A (BPA) are environmental contaminants that can cross the placenta and exert toxicity in the developing fetal nervous system. Copy number variants (CNVs) play a role in a number of genetic disorders and may be implicated in BDE-209/BPA teratogenicity. In this study, we found that BDE-209 and/or BPA exposure decreased neural differentiation efficiency of human embryonic stem cells (hESCs), although there was a >90% induction of neuronal progenitor cells (NPCs) from exposed hESCs. However, the mean of CNV numbers in the NPCs with BDE-209 + BPA treatment was significantly higher compared to the other groups, whereas DNA methylation was lower and DNA methyltransferase(DNMT1 and DNMT3A) expression were significantly decreased in all of the BDE-209 and/or BPA treatment groups compared with the control groups. The number of CNVs in chromosomes 3, 4, 11, 22, and X in NPCs with BDE-209 and/or BPA exposure was higher compared to the control group. In addition, CNVs in chromosomes 7, 8, 14, and 16 were stable in hESCs and hESCs-derived NPCs irrespective of BDE-209/BPA exposure, and CNVs in chromosomes 20 q11.21 and 16 p13.11 might be induced by neural differentiation. Thus, BDE-209/BPA exposure emerges as a potential source of CNVs distinct from neural differentiation by itself. BDE-209 and/or BPA exposure may cause genomic instability in cultured stem cells via reduced activity of DNA methyltransferase, suggesting a new mechanism of human embryonic neurodevelopmental toxicity caused by this class of environmental toxins. PMID- 28597691 TI - Safety and Efficacy of Pegfilgrastim When Given Less Than 14 Days Before the Next Chemotherapy Cycle: Review of Every 14-Day Chemotherapy Regimen Containing 5-FU Continuous Infusion. AB - BACKGROUND: Pegfilgrastim should not be given <14 days from the next chemotherapy because of concerns for cytopenias. Some clinicians are prescribing pegfilgrastim to be given <14 days in patients receiving 5-fluorouracil continuous infusion (5 FUCI) regimens. OBJECTIVE: To determine the effectiveness and safety of pegfilgrastim administered <14 days from the next chemotherapy in patients receiving 5-FUCI administered >46 hours. METHODS: Single-institution retrospective cohort study of patients who received 5-FUCI administered >46 hours from June 2013 to December 2015. The unit of measurement was chemotherapy cycles. End points included the safety and efficacy of giving pegfilgrastim <14 days from the next chemotherapy (Pegfilgrastim-Less-Than-14-Days-Group) and comparing that to pegfilgrastim given >=14 days (Pegfilgrastim-More-Than-14-Days-Group), filgrastim only (Filgrastim-Group), and no colony stimulating factors (No-CSF Group). Generalized estimating equations (GEEs) were used to compare mean absolute neutrophil count (ANC) and white blood cell count (WBC). Poisson regression models with GEE were used to estimate relative risk (RR) for neutropenia. RESULTS: There were no incidences of neutropenia, febrile neutropenia (FN), or hospitalizations for FN with the Pegfilgrastim-Less-Than-14 Days-Group. There was also a high mean ANC of 9.9 (5.7) * 109/L. Mean ANC and WBC were statistically significantly less with the Filgrastim-Group, No-CSF-Group, and Pegfilgrastim-More-Than-14-Days-Group compared with the Pegfilgrastim-Less Than-14-Days-Group. The Filgrastim-Group and the No-CSF-Group had a 32% (1.10 1.56, P = 0.002) and 8% (1.04-1.12, P < 0.001) increased risk of incidence of neutropenia, respectively, compared with the Pegfilgrastim-Less-Than-14-Days Group. The risk of incidence of neutropenia was the same with the Pegfilgrastim More-Than-14-Days-Group and Pegfilgrastim-Less-Than-14-Days-Group (0.95-1.04, P = 0.821). CONCLUSION: This study shows a promising possibility that administering pegfilgrastim <14 days from the next chemotherapy cycle could be a safe and effective practice. However, better controlled clinical trials are needed. PMID- 28597692 TI - Are Traditional Remedies Useful in Management of Fibromyalgia and Chronic Fatigue Syndrome? A Review Study. AB - Fibromyalgia and chronic fatigue syndrome are disorders that often occur simultaneously and are characterized by widespread pain and persistent fatigue. The patients are associated with disability and impairment social and physical functions. There are many remedies in traditional Persian medicine suggested for management of the disease complaints. The aim of this study was to investigate the clinical presentations and pathophysiology of disorders with the basic and principal textbook of traditional Persian medicine written by Avicenna ( Canon of Medicine). According to Persian medicine, the term E'aya can be matched by mentioned disorders. Avicenna believed that strenuous activities play an important role in the beginning of some types of fatigue. He classified fatigue into 4 groups, and in each type the clinical symptoms varied. The multifaceted entity of fibromyalgia and chronic fatigue syndrome in Persian medicine and conventional medicine suggests multidisciplinary therapies in management of these disabling disorders. PMID- 28597694 TI - Everyday functioning of people with Parkinson's disease and impairments in executive function: a qualitative investigation. AB - PURPOSE: Executive function is the key area of cognitive impairment in Parkinson's disease. This study investigated how cognitive difficulties impact on everyday life of people with Parkinson's disease and their carers, and whether they explicitly mention executive-type difficulties. METHODS: Semistructured interviews with 11 people with Parkinson's disease and six carers were analyzed thematically. People with Parkinson's disease performed within the normal range on cognitive screening tests, but all had abnormal scores on tests of executive function. RESULTS: Despite relatively mild executive deficits and no global cognitive impairment, participants described executive-type difficulties as well as a range of problems in other cognitive domains, such as memory, processing speed and apathy. Cognitive difficulties had a far-reaching impact on everyday life and their significance depended on personal circumstances, such as the level of responsibilities of the person with Parkinson's disease and the extent of available support. CONCLUSIONS: By presenting subjective accounts of living with Parkinson's disease and cognitive difficulties, this study improves our understanding of how the observed level of cognitive impairment translates into everyday functioning. The study results have implications for recognizing cognitive difficulties and for planning support for people with Parkinson's disease and their families, and can help identify ways of promoting effective self-management. Implications for rehabilitation Treatment of Parkinson's disease tends to focus on the movement disorder, meaning that cognitive difficulties and their impact can be overlooked. Participants in this study had only relatively mild executive deficits but described a range of cognitive problems, including executive-type difficulties. Cognitive difficulties have an emotional impact and can cause a range of challenges in everyday life, adding to the burden of physical symptoms of Parkinson's disease. Results of this study provide insights into how executive functions impairments translate into everyday difficulties in Parkinson's disease and have implications for planning support for people with Parkinson's disease and their families. PMID- 28597693 TI - The effects of mental practice combined with modified constraint-induced therapy on corticospinal excitability, movement quality, function, and activities of daily living in persons with stroke. AB - PURPOSE: Studies on to what extent the combined therapy of modified constraint induced movement therapy and mental practice is more effective than modified constraint-induced movement therapy alone are lacking. This study aims to compare the effects of the combined therapy with modified constraint-induced movement therapy alone on corticospinal excitability, quality of the movement of the affected upper extremity, upper motor functions, and performance of the affected arm in daily life of hemiplegic stroke patients. METHODS: The participants comprised 14 people who had suffered stroke and were randomly divided into two groups. All participants participated in modified constraint-induced movement therapy, while only the experimental group partook in additional mental practice. Both groups were tested for corticospinal excitability, quality of movement, hand function, and activities of daily living. RESULTS: Both groups showed significant improvement in the movement quality of reaching and performance of activities of daily living. In the experimental group, functional improvement of the upper limb was also observed. The improvements in corticospinal excitability, upper extremity function, and performance in daily activities were significantly greater in the experimental group compared to the control group. CONCLUSIONS: This study confirmed that the combined therapy produces more effective improvement in corticospinal excitability, upper limb function, and performance in daily activities. The combined therapy of mental practice and modified constraint-induced movement therapy could be used as a clinically useful intervention. Implications for rehabilitation Modified constraint-induced movement therapy could be used as an intervention method for people with stroke to make improvements in the quality of movement and performance in activities of daily livings with the affected side. With additional mental practice, upper extremity functions improve, and changes in neurological, functional and performance in daily lives are greater compared to modified constraint-induced movement therapy without mental practice. Impact of mental practice has on rehabilitation should not be underestimated. PMID- 28597695 TI - MicroRNAs in HPV associated cancers: small players with big consequences. AB - INTRODUCTION: MicroRNAs (miRs) are short (~20 nucleotides) non-coding ribonuecleic acids (ncRNAs) known to be involved in cellular processes such as proliferation, differentiation, immune response, pathogenicity and tumourigenesis, among many others. The regulatory mechanisms exerted by miRs have been implicated in many cancers, including Human Papillomavirus (HPV)-associated cancers. Areas covered: In this review, the authors discuss the involvement of miRs (-143, -375, -21, -200, -296 etc.) that have been shown to be dysregulated in HPV-associated cancers. This review also encompasses both intracellular and exosomal miRs, and their potential as diagnostic biomarkers in saliva and blood. The authors have also attempted to dissect the functional impact of miRs on cellular processes such as changes in cellular polarity, loss of apoptosis and tumour suppression, and unchecked and uncontrolled cell cycle regulation, all of which ultimately lead to aberrant cellular proliferation. Expert commentary: Identification of dysregulated miRs in HPV-associated cancers opens up new opportunities to develop diagnostic, therapeutic and prognostic biomarkers. Studies on global expression patterns of miRs dysregulated in HPV-associated cancers can be instrumental in developing broader therapeutic strategies. Therapies like anti-miR, miR-replacement and those based on alternative natural products targeting miRs, need to be improved and better synchronized to be cost effective and have better treatment outcomes. PMID- 28597696 TI - "Not always a straight path": patients' perspectives following anterior cruciate ligament rupture and reconstruction. AB - PURPOSE: To explore patients' perspectives following anterior cruciate ligament rupture and subsequent reconstructive surgery. METHODS: A qualitative study design was employed, using validated questionnaires, interviews and general inductive methodology. Semi-structured interviews were conducted with five men and four women who had undergone an anterior cruciate ligament reconstruction in the past 6-36 months. Participants completed the Knee Osteoarthritis Outcome Score and the Tegner Activity Score. Descriptive statistics were used to analyze quantitative data. Interviews were recorded, transcribed and analyzed using the general inductive approach to develop key themes. RESULTS: Participants had not returned to pre-injury knee-related activity levels (Tegner score: 7 pre-injury; 4 current). The theme of a disruptive "journey" emerged with two sub-themes of "loss of identity" and "life at the present," influenced positively and negatively by "support systems" and experience with the "care pathway." This unequivocally negative experience resulted in irrevocable changes to their lives, reflected by current lower knee-related quality of life. CONCLUSIONS: Anterior cruciate ligament injury and rehabilitation thereof have a profound influence in the individual's identity. The results imply that a broader approach is needed within the rehabilitation process to address psychosocial factors, in addition to physical impairments and function. Implications for rehabilitation Anterior cruciate ligament rupture has a profound influence on patients' understanding of their individual identity. Support systems the patients have in place influence the patients' experience of the care pathway. Understanding psychosocial responses and implementing appropriate strategies and interventions for these may be critical for rehabilitation of these patients. PMID- 28597698 TI - Cavernous sinus fungal infection: a rare case. AB - Intracranial fungal infection of the cavernous sinus is a condition that usually affects immunocompromised individuals and is rarely seen in immunocompetent individuals. It is a potentially life threatening condition which requires prompt treatment. Here we present a case of an immunocompetent patient with a fungal infection of the cavernous sinus. PMID- 28597697 TI - Effectiveness of assisted and unassisted cough capacity in amyotrophic lateral sclerosis patients. AB - : Decreased cough capacity during a respiratory infection is one of the main causes of acute respiratory failure and hospitalisation in amyotrophic lateral sclerosis (ALS). OBJECTIVE: To determine whether a respiratory measurement could identify the effectiveness of cough capacity in ALS during a respiratory infection. METHODS: This was a prospective study of all ALS patients who were treated at a respiratory care unit due to a respiratory infection from 2012 to 2016. The effectiveness of unassisted and assisted coughing was evaluated and respiratory function tests were performed during the acute episode. RESULTS: Forty-eight ALS patients were enrolled, with only four having an effective unassisted cough. The variable which predicted unassisted cough effectiveness was peak cough flow (PCF) (OR 4499.27; 95%CI 3.60-3219086.19; p = 0.022) with a cut off point of 2.77 L/s (166 L/min). For manually assisted coughing, the predictor of cough effectiveness was manually assisted PCF (cut-off point of 2.82-169 L/min) (OR 2198.602; 95% CI 3.750-1351691.42; p = 0.019). Mechanically assisted PCF (cut-off point of 2.95-177 L/min) was found to be the predictor of mechanically assisted coughing effectiveness (OR 23.40; 95% CI 2.11-258.96; p = 0.010). CONCLUSIONS: During a respiratory infection in ALS patients, the effectiveness of assisted and unassisted cough capacity depends on the PCF generated. PMID- 28597700 TI - Engineering of a novel optimized platform for sublingual delivery with novel characterization tools: in vitro evaluation and in vivo pharmacokinetics study in human. AB - The aim of this work was to develop a novel and more efficient platform for sublingual drug delivery using mosapride citrate (MSP) as a model drug. The engineering of this delivery system had two stages, the first stage was tuning of MSP physicochemical properties by complexation with pure phosphatidylcholine or phosphatidylinositol enriched soybean lecithin to form MSP-phospholipid complex (MSP-PLCP). Changes in physicochemical properties were assessed and the optimum MSP-PLCP formula was then used for formulation into a flushing resistant platform using two mucoadhesive polymers; sodium alginates and sodium carboxymethylcellulose at different concentrations. Design of experiment approach was used to characterize and optimize the formulated flushing resistant platform. The optimized formulation was then used in a comparative pharmacokinetics study with the market formulation in human volunteers. Results showed a marked change in MSP physicochemical properties of MSP-PLCP compared to MSP. Addition of mucoadhesive polymers to flushing resistant platform at an optimum concentration balanced between desired mucoadhesive properties and a reasonable drug release rate. The optimized formulation showed significantly a superior bioavailability in humans when compared to the market sublingual product. Finally, the novel developed sublingual flushing resistant platform offers a very promising and efficient tool to extend the use of sublingual route and widen its applications. PMID- 28597699 TI - Chelation therapy in cardiovascular disease: an update. AB - INTRODUCTION: The off-label use of chelation therapy (disodium edetate or EDTA) for prevention of cardiovascular disease (CVD) is widespread, despite the lack of convincing evidence for efficacy or approval from the Food and Drug Administration. After the publication of results from the National Institute of Health-sponsored Trial to Assess Chelation Therapy (TACT), a randomized controlled trial (RCT) in patients after myocardial infarction (MI), there is a renewed interest in clarifying the role of this treatment modality for patients with coronary artery disease. Areas covered: This narrative review highlights the evidence from observational studies and RCT in assessing the effect of chelation therapy on cardiovascular outcomes and potential for adverse effects or harm. Expert commentary: Although encouraging results were reported in TACT, the evidence is insufficient to recommend the routine use of chelation therapy even in the post-MI diabetic subgroup, which appeared to benefit. The ongoing TACT2 trial may clarify its use in post-MI diabetic patients. Unsubstantiated claims of chelation therapy as an effective treatment of atherosclerosis should be avoided and patients made aware of the inadequate evidence for efficacy and potential adverse effects, especially the harm that can occur if used as a substitute for proven therapies. PMID- 28597701 TI - Upper limb and eye movement coordination during reaching tasks in people with stroke. AB - PURPOSE: To enhance understanding of the relationship between upper limb and eye movements during reaching tasks in people with stroke. METHODS: Eye movements were recorded from 10 control participants and 8 chronic stroke participants during a visual orienting task (Experiment 1) and a series of reaching tasks (Experiment 2). Stroke participants completed the reaching tasks using (i) their less impaired upper limb, (ii) their more impaired upper limb without support, and (iii) their more impaired upper limb, with support (SaeboMAS gravitational support and/or electrical stimulation). Participants were tested individually and completed both experiments in the same session. RESULTS: Oculomotor control and the coordination between the upper limb and the oculomotor system were found to be intact in stroke participants when no limb movements were required, or when the less impaired upper limb was used. However, when the more impaired upper limb was used, success and accuracy in reaching decreased and patterns of eye movements changed, with an observed increase in eye movements to the limb itself. With upper limb support, patterns of hand-eye coordination were found to more closely resemble those of the control group. CONCLUSION: Deficits in upper limb motor systems result in changes in patterns of eye movement behavior during reaching tasks. These changes in eye movement behavior can be modulated by providing upper limb support. Implications for Rehabilitation Deficits in upper limb motor systems can result in changes in patterns of eye movement behavior during reaching tasks. Upper limb support can reduce deficits in hand-eye coordination. Stroke rehabilitation outcomes should consider motor and oculomotor performance. PMID- 28597702 TI - Recent progress on curcumin-based therapeutics: a patent review (2012-2016). Part II: curcumin derivatives in cancer and neurodegeneration. AB - INTRODUCTION: Curcumin, the main bioactive compound found in the rhizome of Curcuma longa L., is considered a 'privileged structure', due to its ability to modulate different signaling pathways involved in the pathogenesis of several diseases. Unfortunately, its poor pharmacodynamic and pharmacokinetic properties, mainly related to chemical instability, low solubility and rapid metabolism, greatly reduce its therapeutic potential. In the last years a number of derivatives were developed and patented, aimed both at improving its multifaceted biological profile and overcoming its undesired effects. Areas covered: This review summarizes the patent literature of the last five years dealing with synthetic curcumin-related compounds in cancer and neurodegeneration, properly designed in order to avoid the so-called 'dark side of curcumin', and to take advantage of the beneficial properties of this molecule, worth to be further exploited to obtain effective therapeutics. Expert opinion: Due to the synergistic binding to several networked targets, curcumin turned out to be suitable for polypharmacological approaches, and its 'privileged structure' could also provide the key scaffold to develop novel multipotent drugs useful for treating multifactiorial pathologic conditions such as cancer and neurodegeneration. PMID- 28597704 TI - Foundation year one training in neurosurgery: achieving competency a 5-year review. AB - INTRODUCTION: F1 doctors are a rare breed in Neurosurgery, featuring in only 4 out of 40 UK centres. It is widely perceived that Neurosurgery would only provide a highly specialised experience for F1s, limiting the opportunity to achieve the core practical and clinical competencies as highlighted by the United Kingdom Foundation Programme (UKFPO). Additionally, Health Education England have increased the number of community placements such as General Practice and Psychiatry further limiting F1 placements offered in specialities like Neurosurgery. AIMS: We sought to acquire the views, experiences and true perspectives of training from F1 doctors in our neurosurgery centre. Importantly, we wanted to determine whether Neurosurgery provides sufficient opportunities to achieve mandatory core foundation competencies. METHODS: We invited all F1s (27) to complete a secure-web based online questionnaire comprising nine domains of training. Responses: We had an overall response rate of 96%. Ninety-six per cent of our F1s valued this placement, gaining skills that could be transferred to other specialities. Eighty-eight per cent found the post to be of similar or greater value in comparison to their other F1 posts and 66% would recommend this post to others. Ninety-two per cent of F1s felt they were adequately supervised and regular informal feedback was offered in order to ensure acquisition of core competences. Fourty-four per cent of F1s were involved in post-graduate academia. All trainees attended their mandatory F1 teaching although attendance to additional departmental teaching was limited. DISCUSSION: Trainees found that Neurosurgery provided a generalised exposure not a specialised one. Ninety-two per cent felt Neurosurgery had provided sufficient educational opportunities to achieve their required competencies. Importantly, all trainees managed to achieve their core generic competencies. F1 placements in Neurosurgery are highly beneficial to both trainee and service. The placement provides more than sufficient educational opportunities to help meet mandatory training requirements. F1 doctors also augment the number of junior doctors supporting the neurosurgical service. PMID- 28597703 TI - Scoring model to predict outcome in critically ill cirrhotic patients with acute respiratory failure: comparison with MELD scoring models and CLIF-SOFA score. AB - BACKGROUND: Critically ill cirrhotic patients have a high mortality, particularly with concomitant respiratory failure on admission. There are no specific models in use for mortality risk assessment in critically ill cirrhotic patients with acute respiratory failure (CICRF). The aim is to develop a risk prediction model specific to CICRF in order to quantify the severity of illness. METHODS: We analyzed 949 CICRF patients extracted from the MIMIC-III database. The novel model (ARF-CLIF-SOFA) was developed from the CLIF-SOFA score. Cox regression analysis and AUROC were implemented to test the predictive accuracy, compared with existing scores including the CLIF-SOFA score and MELD-related scores. RESULTS: ARF-CLIF-SOFA contains PaO2/FiO2 ratio, lactate, MAP, vasopressor therapy, bilirubin and creatinine (1 point each; score range: 0-6). Based on our patient cohort, the ARF-CLIF-SOFA score had good predictive accuracy for predicting the 30-, 90-day and 1-year mortality (AUROC = 0.767 at 30-day, 0.768 at 90-day, 0.765 at 1-year, respectively). Additionally, the performance of the ARF-CLIF-SOFA is superior to existing scores (all P < 0.001). CONCLUSION: The ARF CLIF-SOFA score can be considered a CICRF specific score with a better predictive accuracy compared to the existing scores. PMID- 28597705 TI - Evaluation of Applying a Combination of Red Cell Indexes and Formulas to Differentiate beta-Thalassemia Trait from Iron Deficiency Anemia in the Thai Population. AB - Red cell indexes and formulas have been established as simple, fast, and inexpensive tools to differentiate beta-thalassemia (beta-thal) trait from iron deficiency anemia. However, none of them showed 100.0% sensitivity and specificity. Moreover, one index may show greater sensitivity and specificity in one population but is ineffective in another population. This study evaluated the diagnostic reliability of a combination of two red cell indexes [red blood cell (RBC) and red blood cell distribution width (RDW)] and nine formulas called '11T score' for differentiation of beta-thal trait and iron deficiency anemia in the Thai population. A total of 103 cases, 67 beta-thal trait and 36 iron deficiency anemia, Thai subjects with microcytic hypochromic anemia [mean corpuscular volume (MCV) <80.0 fL and mean corpuscular hemoglobin (Hb) (MCH) <27.0 pg] were involved in this retrospective study. The results showed that the 11T score with a cutoff value of 7 was able to discriminate between beta-thal trait and iron deficiency anemia with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and efficiency (EFF) higher than 70.0%. It also had 85.4% of correctly identified cases and the highest value of Youden's Index (YI) (73.8%) when compared to the 11T score with other cutoff values (5, 6, 8 and 9) and other indexes. Thus, the 11T score with the cutoff value of 7 could be used to differentiate beta-thal trait from iron deficiency anemia in the Thai population. PMID- 28597706 TI - Outcomes following rescue cerclage in twin pregnancies. AB - OBJECTIVE: Our aim was to compare perinatal outcomes in twin pregnancies complicated by premature asymptomatic cervical dilatation treated with rescue cerclage and expectant management. METHODS: A retrospective cohort study was conducted at a single tertiary referral center between 2003 and 2014 and included all women with twins found to have a dilated cervix with intact membranes before 25-week gestation. Pregnancy outcomes were compared between women with rescue cerclage and those managed expectantly. A total of 36 women were eligible for the study, 27 (75.0%) of whom had a rescue cerclage compared to 9 (25.0%) women managed expectantly. Student's t-test was used to compare continuous variables between the groups and the chi-square and Fisher's exact tests were used for categorical variables as appropriate. Statistical analysis was performed with the SPSS v21.0 software (IBM Corp; Armonk, NY). Differences were considered significant when the p value was less than .05. RESULTS: Among the 27 women with a rescue cerclage, the mean gestational age at time of cerclage insertion was 21.5 +/- 2.6 weeks. The intervention and control groups were similar with respect to the degree of cervical dilatation at presentation (2.6 +/- 1.3 versus 3.0 +/- 1.5 cm, p = .5). Women in the cerclage group gave birth at a more advanced gestation (28.9 +/- 6.1 versus 24.2 +/- 2.6 weeks, respectively, p = .03) and were less likely to give birth at <34 and <28 weeks (66.7 versus 100.0%, p = .046, and 59.3 versus 100.0%, p = .02, respectively). The mean latency from the placement of cerclage to delivery was 7.3 +/- 5.5 weeks. Similar findings were observed when analysis was limited to women with cervical dilatation of <=3 cm at presentation. CONCLUSIONS: In asymptomatic women with twin pregnancies and cervical dilatation before 25 weeks of gestation, rescue cerclage can prolong pregnancy and improve perinatal outcomes when compared to expectant management. PMID- 28597707 TI - CT-guided radiofrequency ablation of spinal osteoblastoma: treatment and long term follow-up. AB - OBJECTIVE: Osteoblastoma (OB) is a painful, rare, benign bone tumour usually observed in young populations, and this condition involves the spine in up to one third of cases. We sought to focus on the minimally invasive treatment of spinal OB with radiofrequency ablation (RFA) under computed tomography (CT) guidance. When performed near the spinal cord, surgery can lead to instability of the spine, sometimes requiring additional interventions to stabilise the segments involved, and can cause the precocious onset of arthrosis or other degenerative diseases. The results were evaluated both clinically and with the aid of diagnostic imaging techniques during a 5-year follow-up study. MATERIALS AND METHODS: Eleven patients affected by spinal OB were treated in a single session with biopsy and CT-guided RFA. Pre- and post-evaluations of the patients were performed both clinically and with CT and magnetic resonance imaging (MRI). RESULTS: Complete success in terms of pain relief was achieved in all patients. Additional treatments were not required in any patients. There were no complications. During follow-up, neither complications nor pathological findings related to the treatment were observed. CONCLUSIONS: Our experience demonstrates that RFA for spinal OB is safe and effective. One of the main advantages of this technique is represented by its lower grade of invasiveness compared with that for potentially hazardous surgical manoeuvres. PMID- 28597708 TI - Balance and walking performance are improved after resistance and aerobic training in persons with chronic stroke. AB - PURPOSE: To investigate the effect of different types of physical training on balance performance and whether improved balance correlates with improved walking performance. METHODS: Forty eight participants with chronic stroke were randomly assigned to aerobic training on cycle ergometer (AT-group), resistance training of the lower extremities (RT-group), or sham training of upper extremities (ST group). Participants exercised 3 d/week for 12 weeks. Balance (Berg Balance Scale), peak oxygen uptake rate, isometric knee extensor strength, maximal gait speed, and 6 minute walk test were measured at baseline and after 12 weeks. RESULTS: Training specific effects were observed; the AT-group improved peak oxygen uptake rate by 15.5 (6.0-25.0)%, the RT-group improved non-paretic knee extensor strength by 35.1 (18.3-51.9)% and the ST-group improved non-paretic knee extensor strength by 8.9 (0.7-17.1)%. All groups improved balance (6.0 (95% CI: 3.2-8.8)%), maximal gait speed (10.2 (6.5-14.0)%), and 6 minute walk distance (12.4 (8.8-15.9)%) but balance improvements did not correlate with improvements in muscle strength, peak oxygen uptake rate, or walking. CONCLUSIONS: Physical exercise improves balance and walking performance, but improved balance is not a prerequisite for functional improvements in chronic stroke. Implications for Rehabilitation Aerobic training and progressive resistance training show small significant improvements in balance and walking, indicating a possible clinical relevance of these training modalities. Improvements in balance may not be a prerequisite for improvements in walking distance when assistive devices are allowed during walking tests. PMID- 28597709 TI - Philippine Academy of Rehabilitation Medicine emergency basic relief and medical aid mission project (November 2013-February 2014): the role of physiatrists in Super Typhoon Haiyan. AB - BACKGROUND: Physiatrists have provided humanitarian assistance in recent large scale global natural disasters. Super Typhoon Haiyan, the deadliest and most costly typhoon in modern Philippine history, made landfall on 8 November 2013 resulting in significant humanitarian needs. METHODS: Philippine Academy of Rehabilitation Medicine physiatrists conducted a project of 23 emergency basic relief and medical aid missions in response to Super Typhoon Haiyan from November 2013 to February 2014. The final mission was a medical aid mission to the inland rural community of Burauen, Leyte. Summary data were collected, collated, and tabulated; project and mission evaluation was performed. RESULTS: During the humanitarian assistance project, 31,254 basic relief kits containing a variety of food and non-food items were distributed and medical services including consultation, treatment, and medicines were provided to 7255 patients. Of the 344 conditions evaluated in the medical aid mission to Burauen, Leyte 85 (59%) were physical and rehabilitation medicine conditions comprised of musculoskeletal (62 [73%]), neurological (17 [20%]), and dermatological (6 [7%]) diagnoses. Post mission and project analysis resulted in recommendations and programmatic changes to strengthen response in future disasters. Physiatrists functioned as medical providers, mission team leaders, community advocates, and in other roles. CONCLUSIONS: This physiatrist-led humanitarian assistance project met critical basic relief and medical aid needs of persons impacted by Super Typhoon Haiyan, demonstrating significant roles performed by physiatrists in response to a large scale natural disaster. Resulting disaster programing changes and recommendations may inform a more effective response by PARM mission teams in the Philippines as well as by other South-Eastern Asia teams comprising rehabilitation professionals to large-scale, regional natural disasters. Implications for rehabilitation Large scale natural disasters including tropical cyclones can have a catastrophic impact on the affected population. In response to Super Typhoon Haiyan, physiatrists representing the Philippine Academy of Rehabilitation Medicine conducted a project of 23 emergency basic relief and medical aid missions from November 2013 to February 2014. Project analysis indicates that medical mission teams responding in similar settings may expect to evaluate a significant number of physical medicine and rehabilitation conditions. Medical rehabilitation with participation by rehabilitation professionals including rehabilitation doctors is essential to the emergency medical response in large-scale natural disasters. PMID- 28597710 TI - Comparing treatment options for chronic inflammatory neuropathies and choosing the right treatment plan. AB - INTRODUCTION: Chronic inflammatory neuropathies are disorders caused by an immune response to peripheral nerve. They include chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and neuropathy associated with anti-MAG IgM monoclonal gammopathy and other less frequent neuropathies. Several immune therapies have been proven to be effective in these neuropathies even if the best therapeutic option is still unsettled. Areas covered: The authors reviewed the literature to compare the efficacy and safety of currently used immune therapies in these neuropathies. The authors also analyzed the effect of other immune suppressive agents and of biological agents including rituximab, eculizumab, natalizumab, alemtuzumab and fingolimod that were found effective in other autoimmune diseases. Expert commentary: Despite the reported efficacy of a number of new immune therapies in some patients with immune mediated neuropathies, their efficacy has not been so far confirmed in randomized controlled studies. High-dose intravenous immunoglobulin (IVIg) (and subcutaneous immunoglobulin [SCIg] for maintenance treatment), steroids and plasma exchange remain the only therapy of proven efficacy in CIDP, IVIg in MMN and, with certain limits, rituximab and, occasionally plasma exchange in neuropathy associated with anti-MAG antibodies. New biological agents are also on the horizon but their efficacy needs to be proved in controlled studies. PMID- 28597711 TI - Embryo culture using a time-lapse monitoring system improves live birth rates compared with a conventional culture system: a prospective cohort study. AB - In this prospective cohort study, the effects of a time-lapse monitoring system on embryo quality and clinical pregnancy outcomes were assessed. A total of 608 patients undergoing in vitro fertilization between April 2013 and June 2014 at our institution were recruited for this study and group-matched into a time-lapse monitoring (TLM) (N = 304) or a standard incubator (SI) (N = 304). The patients' characteristics in the TLM and SI groups were not significantly different. The TLM group showed a significantly higher transferable embryo ratio at Day 3 (61.65% vs. 52.87%; p < 0.0010, RR =1.10 [1.02, 1.19]), a higher number of transferable embryos (4.71 +/- 2.38 vs. 4.09 +/- 2.35; p = 0.0053, SMD =0.26 [0.06, 0.46]) and number of good-quality embryos cryopreserved at Day 3 (2.72 +/- 2.35 vs. 2.11 +/- 2.33; p = 0.0056, SMD =0.26 [0.06, 0.46]). In addition, the implantation and clinical pregnancy rates were not statistically significant between the TLM and SI groups. However, the TLM group had a higher ongoing pregnancy rate (67.32% vs. 57.22%; p = 0.0410) and live birth rate (65.37% vs. 55%; p = 0.0380) compared with the SI group. The observed beneficial effects could be the result of a more stable environment provided by the TLM system. PMID- 28597712 TI - Blockade and knock-out of CALHM1 channels attenuate ischemic brain damage. AB - Overactivation of purinergic receptors during cerebral ischemia results in a massive release of neurotransmitters, including adenosine triphosphate (ATP), to the extracellular space which leads to cell death. Some hypothetical pathways of ATP release are large ion channels, such as calcium homeostasis modulator 1 (CALHM1), a membrane ion channel that can permeate ATP. Since this transmitter contributes to postischemic brain damage, we hypothesized that CALHM1 activation may be a relevant target to attenuate stroke injury. Here, we analyzed the contribution of CALHM1 to postanoxic depolarization after ischemia in cultured neurons and in cortical slices. We observed that the onset of postanoxic currents in neurons in those preparations was delayed after its blockade with ruthenium red or silencing of Calhm1 gene by short hairpin RNA, as well as in slices from CALHM1 knockout mice. Subsequently, we used transient middle cerebral artery occlusion and found that ruthenium red, a blocker of CALHM1, or the lack of CALHM1, substantially attenuated the motor symptoms and reduced significantly the infarct volume. These results show that CALHM1 channels mediate postanoxic depolarization in neurons and brain damage after ischemia. Therefore, targeting CALHM1 may have a high therapeutic potential for treating brain damage after ischemia. PMID- 28597713 TI - Back to life with checkpoint inhibitors in Hodgkin lymphoma. AB - Cancer can escape the immune system through different mechanisms. One of which is the expression of program death ligand-1 (PD-L1). This ligand binds to programmed cell death 1 receptor on activated T cells, subsequently leading to inhibition of the immune response. Nivolumab is a novel antibody that binds to programmed cell death 1 and prevents such immune tolerance. Several recently published clinical trials confirmed the clinical efficacy of single agent nivolumab in pretreated patients with different cancer types. Publications on nivolumab in Hodgkin lymphoma are very scarce. We report on a 30-year-old man with stage IVB Hodgkin lymphoma, who failed nine lines of treatments including high-dose chemotherapy and autologous stem cell transplantation and brentuximab vedotin. He reached a major response after four cycles of nivolumab and got married. The available literature is being reviewed. Pre-treated Hodgkin lymphoma is amenable to novel immunotherapy. Nivolumab induces clinically meaningful responses with excellent tolerance. The drug enriches our treatment options by reviving the immune system response against cancer. Further clinical studies are needed to determine the effectiveness on a large patients' cohort. PMID- 28597714 TI - A case report: Urolithiasis, hydronephrosis, and acute kidney injury in pregnancy. PMID- 28597715 TI - Effect of menstrual phase on the surgical treatment of ovarian cysts. AB - This study aimed to determine whether the menstrual cycle affects operative bleeding and postoperative ovarian reserve in patients undergoing laparoscopic ovarian cystectomy. A total of 155 patients who had undergone laparoscopic ovarian cystectomy were classified into the follicular phase (n = 84) and luteal phase (n = 71) of the menstrual cycle. The primary outcome measures were operative blood loss and the rate of decline in ovarian reserve, as calculated by measuring serial serum anti-Mullerian hormone (AMH) levels preoperatively and 3 months postoperatively. No significant difference in the baseline demographics, operative blood loss (p = .984), the rate of decline in ovarian reserve (p = .945), and other surgical outcomes were observed between both the groups. These results demonstrate that the menstrual cycle had no influence on the operative blood loss and ovarian reserve during laparoscopic ovarian cystectomy. Therefore, the menstrual cycle is not an important factor to determine the optimal timing of ovarian cystectomy. Impact statement What is already known on this subject?: The menstrual cycle results in periodic changes in haemostasis and blood flow in the reproductive organs. What do the results of this study add?: These results demonstrate that the menstrual cycle had no influence on the operative blood loss and ovarian reserve during laparoscopic ovarian cystectomy. What are the implications of these findings for clinical practice and/or further research?: The menstrual cycle is not an important factor to determine the optimal timing of ovarian cystectomy. PMID- 28597716 TI - Postmortem Whole Exome Sequencing Identifies Novel EIF2B3 Mutation With Prenatal Phenotype in 2 Siblings. AB - OBJECTIVE: We describe 2 male siblings with a severe, prenatal phenotype of vanishing white matter disease and the impact of whole exome sequencing on their diagnosis and clinical care. METHODS: The 2 children underwent detailed clinical characterization, through clinical and laboratory testing, as well as prenatal and postnatal imaging. Biobanked blood from the 2 siblings was submitted for whole exome sequencing at Baylor Laboratories. RESULTS: Both male children had abnormal prenatal neuroimaging and suffered precipitous, fatal neurologic decline. Neuropathologic findings included subependymal pseudocysts, microcalcifications, and profound lack of brain myelin and sparing of peripheral nerve myelin. A novel homozygous mutation in the EIF2B3 gene (c.97A>G [p.Lys33Glu]) was found in both children; both parents were heterozygous carriers. The family subsequently conceived a healthy child via in vitro fertilization with preimplantation mutation screening. CONCLUSION: These histories expand the prenatal phenotype of eIF2b-related disorders and poignantly illustrate the impact that unbiased genomic sequencing can have on the diagnosis and medical decision making for families affected by childhood neurodegenerative disorders. PMID- 28597717 TI - Physician-Modified Thoracic Stent-Grafts for the Treatment of Aortic Arch Lesions. AB - PURPOSE: To evaluate outcomes of physician-modified thoracic stent-grafts for the treatment of aortic arch aneurysms. METHODS: A retrospective dual-center analysis was performed involving 36 patients (mean age 74.7+/-9 years, range 58-91; 27 men) with an aortic arch lesion who were treated between November 2013 and June 2016 using physician-modified thoracic stent-grafts. Half of the patients had a degenerative aneurysm; the remainder had type B dissection (n=9), traumatic transection (n=3), type Ia endoleak after previous endografting (n=5), or aortoesophageal fistula (n=1). All patients were considered to be at high surgical risk. Patients were treated using an aortic arch stent-graft with a single fenestration (n=24) or a proximal scallop (n=12); zone 0 was involved in 16 patients, zone 1 in 9, and zone 2 in 11. The modified thoracic stent-graft was deployed after supra-aortic branch revascularization in 24 (67%) patients. RESULTS: Mean time required for stent-graft modifications was 18 minutes (range 14-21). Technical success was obtained in all cases with no type I endoleak. One (3%) patient had a stroke without permanent sequelae. The 30-day mortality was 6%. During a mean follow-up of 11.4+/-6 months (range 2-36), there were no conversions to open repair. The overall mortality was 14%; aorta-related mortality was 6%. CONCLUSION: Our experience suggests that physician-modified thoracic stent-grafts are feasible for aortic arch lesions and provide encouraging results in the short term. Durability concerns will need to be assessed. PMID- 28597718 TI - Effect of Working Memory Updating Training on Retrieving Symptoms of Children With Learning Disabilities. AB - Working memory (WM) deficiency is a primary reason for the poor academic performance of children with learning disabilities (LDs). Studies have shown that the WM of typical children could be improved through training, and WM training contributes to improving their fluid intelligence and academic achievement. However, few studies have investigated WM training for children with LDs, and results have been inconsistent. The present study examined the long-term effects of WM updating training and whether it can mitigate LD symptoms. Fifty-four children with LDs were recruited and divided randomly into a training or control group. The training group underwent adaptive running WM training for 20 days. Before and after training, the 2 groups completed a 2-back task, a digit span task (forward and backward), Raven's Standard Progressive Matrices test, and a scholastic attainment test (Chinese and math). The tests were repeated 6 months later. The results showed that, as compared with the controls, the training group exhibited significant improvements in the digit backward span task, 2-back task, and Raven's Standard Progressive Matrices. The math scores of the training group improved significantly by 6 months after the training. The results of this study suggest that WM updating training could mitigate the cognitive deficits of LDs and improve the WM capacity, fluid intelligence, and math scores of children with LDs. Moreover, the training effects could be maintained for at least 6 months. PMID- 28597719 TI - Sentinel lymph node biopsy to exclude lymphatic spread in placental site trophoblastic tumour. PMID- 28597720 TI - The Predictive Validity of the Static-99, Static-99R, and Static-2002/R: Which One to Use? AB - The use of Static tools (Static-99, Static-99R, Static-2002, and Static-2002R) in risk decision making involving sexual offenders is widespread internationally. This study compared the predictive accuracy and incremental validity of four Static risk measures in a sample of 621 Australian sexual offenders. Results indicated that approximately 45% of the sample recidivated (with 18.8% committing sexual offenses). All of the Static measures investigated yielded moderate predictive validity for sexual recidivism, which was comparable with other Australian and overseas studies. Area under the curve (AUC) values for the four measures across the 5-, 10-, and 15-year intervals ranged from .67 to .69. All of the Static measures discriminated quite well between low-risk and high-risk sexual offenders but less well for the moderate risk categories. When pitted together, none of the tools accounted for additional variance in sexual recidivism, above and beyond what the other measures accounted for. The overall results provide support for the use of Static measures as a component of risk assessment and decision making with Australian sexual offending populations. The limitations of this study and recommendations for further research are also discussed. PMID- 28597721 TI - Dynamics of problem setting and framing in citizen discussions on synthetic biology. AB - Synthetic biology is an emerging scientific field where engineers and biologists design and build biological systems for various applications. Developing synthetic biology responsibly in the public interest necessitates a meaningful societal dialogue. In this article, we argue that facilitating such a dialogue requires an understanding of how people make sense of synthetic biology. We performed qualitative research to unravel the underlying dynamics of problem setting and framing in citizen discussions on synthetic biology. We found that most people are not inherently for or against synthetic biology as a technology or development in itself, but that their perspectives are framed by core values about our relationships with science and technology and that sensemaking is much dependent on the context and general feelings of (dis)content. Given that there are many assumptions focused on a more binary idea of the public's view, we emphasize the need for frame awareness and understanding in a meaningful dialogue. PMID- 28597722 TI - Foodborne botulism in the Faroe Islands in a two-decade period. PMID- 28597723 TI - Minimal activity of nanoparticle albumin-bound (nab) paclitaxel in relapsed or refractory lymphomas: results of a phase-I study. AB - Compared with solvent-based taxanes, nanoparticle albumin-bound (nab(r)) paclitaxel has demonstrated improved efficacy and tolerability in several solid tumor malignancies. Studies evaluating nab paclitaxel in patients with lymphoma are lacking. In this planned phase-I/phase-II study, we sought to determine the safety and efficacy of nab-paclitaxel in patients with relapsed/refractory (R/R) lymphoma. Eligible patients (R/R to >=2 prior systemic therapies) received weekly nab-paclitaxel on days 1, 8 and 15 every 28 days. Dosing was initiated at 100 mg/m2 with dose escalations in 25 mg/m2 increments up to 150 mg/m2 in a classic 3 + 3 design. Twenty heavily pretreated patients (median 5 prior regimens), including 65% with refractory disease, enrolled. The maximum dose tested was well tolerated and grade 3/4 hematologic adverse events (neutropenia 25%, thrombocytopenia 20% and anemia 15%) were modest. The overall response rate was 10% with two partial responses, leading to a decision to close the study prematurely. PMID- 28597724 TI - Motivations and Features of Co-Parenting an Infant With Complex Congenital Heart Disease. AB - This study described co-parenting motivations and quality of co-parenting features for parents of infants with complex congenital heart disease (CCHD), including differences over time by illness severity. Existing transcripts of parenting experience at infant age 1 and 12 months for 23 parent couples were analyzed using directed content analysis. Data were quantitized for additional description. Six co-parenting motivations and five co-parenting features were identified. Two co-parenting motivations had not been previously described: Developing the Co-Parenting Relationship and Maintaining the Couple Relationship. Variability in quality of co-parenting features was evident. However, the majority of parents showed high ratings. Motivations and quality of co-parenting features changed over time and were related to illness severity. Our findings increase the understanding of what parents are working on as a couple to parent an infant with CCHD and the quality of this co-parenting. Several questions for further study are presented. PMID- 28597725 TI - Physicians' Voices: What Skills and Supports Are Needed for Effective Practice in an Integrated Delivery System? A Case Study of Kaiser Permanente. AB - Payers are demanding that US health care become more accountable and integrated, posing new demands for physicians and the organizations that partner with them. We conducted focus groups with 30 physicians in a large integrated delivery system who had previous experience practicing in less integrated settings and asked about skills they need to succeed in this environment. Physicians identified 3 primary skills: orienting to teams and systems, engaging patients as individuals and as a panel, and integrating cost awareness into practice. Physicians also expressed a high level of trust that the system was designed to help them provide better care. This belief appeared to make the new demands and mental shifts tolerable, even welcome, standing in contrast to research showing widespread physician distrust of their institutional settings. Physicians' new skills and the system features that promote trust are described in the article and should be a focus for systems transitioning to a more integrated, accountable model. PMID- 28597726 TI - Migration kinetics of four photo-initiators from paper food packaging to solid food simulants. AB - The migration behaviour of four photo-initiators (BP, EHA, MBP and Irgacure 907) was studied by 'printing' onto four different food-packaging materials (Kraft paper, white cardboard, Polyethylene (PE)-coated paper and composite paper) and tracking movement into the food simulant: Tenax-TA (porous polymer 2,6-diphenyl furan resin). The results indicated that the migration of the photo-initiators was related to the molecular weight and log Ko/w of each photo-initiator. At different temperatures, the migration rates of the photo-initiators were different in papers with different thicknesses. The amount of each photo initiator found in the food was closely related to the food matrix. The Weibull model was used to predict the migration load into the food simulants by calculating the parameters tau and beta and determining the relationship of the two parameters with temperature and paper thickness. The established Weibull model was then used to predict the migration of each photo-initiator with respect to different foods. A two-parameter Weibull model fitted the actual situation, with some deviation from the actual migration amount. PMID- 28597727 TI - Influence of Groundnut bud necrosis virus on the Life History Traits and Feeding Preference of Its Vector, Thrips palmi. AB - The effect of Groundnut bud necrosis virus (GBNV) infection on the life history traits of its vector, Thrips palmi, and its feeding preference on GBNV-infected plants were studied. A significant difference was observed in the developmental period (first instar to adult) between the GBNV-infected and healthy thrips, wherein the developmental period of GBNV-infected thrips was decreased. However, there was no effect on the other parameters such as preadult mortality, adult longevity, and fecundity. Further investigation on a settling and feeding choice assay of T. palmi to GBNV-infected and healthy plants showed that T. palmi preferred GBNV-infected cowpea plants more than the healthy cowpea plants. This preference was also noticed for leaf disks from GBNV-infected cowpea, groundnut, and tomato plants. PMID- 28597728 TI - Theorization and an Empirical Investigation of the Component-Based and Developmental Text Writing Fluency Construct. AB - We discuss a component-based, developmental view of text writing fluency, which we tested using data from children in Grades 2 and 3. Text writing fluency was defined as efficiency and automaticity in writing connected texts, which acts as a mediator between text generation (oral language), transcription skills, and writing quality. We hypothesized that in the beginning phase, text writing fluency would be largely constrained by transcription skills (spelling and handwriting), while at a later phase, oral language would make an independent contribution to text writing fluency. Furthermore, we hypothesized that text writing fluency would have a stronger relationship with writing quality at a later phase than at an earlier phase. We operationalized text writing fluency using two curriculum-based measurement writing scores: percentage correct word sequences and correct minus incorrect word sequences. Results revealed that in Grade 2, only transcription skills were uniquely related to text writing fluency, whereas in Grade 3, oral language was also related to text writing fluency. Text writing fluency was weakly related to writing quality in Grade 2 but strongly related to writing quality in Grade 3, over and above oral language and transcription skills. In both grades, oral language and handwriting fluency were independently related to writing quality. Theoretical and practical implications are discussed. PMID- 28597729 TI - Effects of high- and low-energy radial shock waves therapy combined with physiotherapy in the treatment of rotator cuff tendinopathy: a retrospective study. AB - PURPOSE: The aim of this study was to investigate the efficacy of high- and low energy radial shock waves combined with physiotherapy for rotator cuff tendinopathy patients. METHODS: Data from rotator cuff tendinopathy patients received high- or low-energy radial shock waves combined with physiotherapy or physiotherapy alone were collected. The Constant and Murley score and visual analog scale score were collected to assess the effectiveness of treatment in three groups at 4, 8, 12, and 24 weeks. RESULTS: In total, 94 patients were involved for our retrospective study. All groups showed remarkable improvement in the visual analog scale and Constant and Murley score compared to baseline at 24 weeks. The high-energy radial shock waves group had more marked improvement in the Constant and Murley score compared to the physiotherapy group at 4 and 8 weeks and at 4 weeks when compared with low-energy group. Furthermore, high energy radial shock waves group had superior results on the visual analog scale at 4, 8, and 12 weeks compared to low-energy and physiotherapy groups. CONCLUSIONS: This retrospective study supported the usage of high-energy radial shock waves as a supplementary therapy over physiotherapy alone for rotator cuff tendinopathy by relieving the symptoms rapidly and maintaining symptoms at a satisfactory level for 24 weeks. Implications for Rehabilitation High-energy radial shock waves can be a supplemental therapy to physiotherapy for rotator cuff tendinopathy. We recommend the usage of high-energy radial shock waves during the first 5 weeks, at an interval of 7 days, of physiotherapy treatment. High-energy radial shock waves treatment combined with physiotherapy can benefit rotator cuff tendinopathy by relieving symptoms rapidly and maintain these improvements at a satisfactory level for quite a long time. PMID- 28597730 TI - Early Results of the Bolton Treovance Endograft in the Treatment of Abdominal Aortic Aneurysms. AB - PURPOSE: To present early results with the Treovance aortic stent-graft in the treatment of abdominal aortic aneurysms (AAAs). METHODS: Between October 2013 and January 2016, 35 consecutive AAA patients (mean age 74+/-7.7 years; 32 men) were treated with Treovance. The maximum diameter of the treated AAA was 60+/-9 cm. Nine (25%) patients presented with concomitant iliac aneurysms. Seven (20%) AAAs had infrarenal neck angulation >60 degrees . The infrarenal neck length and diameter were 21.6+/-12.6 mm and 25.7+/-4.6 mm, respectively. Sixteen (45%) AAAs had a reversed tapered neck contour. Six (17%) and 9 (25%) patients showed severe or moderate iliac tortuosity, respectively. Primary endpoints were endoleak, reintervention, and aneurysm-related death. RESULTS: Primary technical success was 94% due to 2 intraoperative type Ia endoleaks, which were successfully treated with a proximal aortic extension (100% assisted primary technical success). Local dissection was encountered in 5 (7%) of 70 femoral artery access sites in 4 patients. During a mean 12-month follow-up (range 6-24), clinical success was 97%. No type I or III endoleak, death, AAA rupture, open conversion, or device-related serious adverse events were documented. Four type II endoleaks were detected; one resolved spontaneously at 12 months and 2 remained stable, while one associated with AAA sac enlargement was treated successfully with embolization of the lumbar arteries (3% reintervention rate). CONCLUSION: Treovance shows accurate deployment even through angulated and tortuous iliac vessels and presents satisfactory conformability in highly angulated necks with acceptable clinical results. Future development to lower the profile and increase the flexibility of its delivery system will enhance its applicability in cases of narrow access vessels. PMID- 28597731 TI - New perspectives for chronic pain treatment: a patent review (2010-2016). AB - INTRODUCTION: Chronic pain is a major problem of public health worldwide and is responsible for the increase in health costs. The therapeutic options available in the market for the treatment of chronic pain are often rather ineffective due to; the high number of adverse reactions, tolerance and dependence, reducing the quality of life, pharmacotherapy adherence and functional capacity. Hence, several studies have been conducted in the search for new treatment alternatives for chronic pain syndromes. Areas covered: This review brings together the therapeutic patents published over the past six years reporting the discovery of new drugs for the treatment of chronic pain, based on the perspective that these compounds are candidates for the management of chronic pain conditions. Expert opinion: Over the past 6 years, several pharmaceutical companies, as well as universities and researchers, have synthesized a series of compounds, which have been shown to be effective in controlling chronic pain in preclinical studies. These findings nurture the hope of discovering new therapeutic options for chronic pain. However, such studies are in early stages and there is a long and hard path to be followed until these compounds can become chemical entities available to the public. PMID- 28597732 TI - Severe aortic regurgitation of quadricuspid aortic valve. PMID- 28597733 TI - Interrupted aortic arch in a 58-year-old patient. PMID- 28597734 TI - Platelets and cardiovascular risk. AB - Atherosclerosis and its late sequels are still the number one cause of death in Western societies. Platelets are a driving force not only during the genesis of atherosclerosis, but especially in its late stages, as evidenced by complications such as arterial thrombosis, myocardial infarction, and ischaemic stroke. Platelets are small, anucleate blood elements of critical importance in cardiovascular disease, a major cause of morbidity and mortality. Numerous risk scores exist to identify healthy individuals at increased risk of developing atherosclerosis and cardiovascular disease. However, markers of cardiovascular risk not routinely assessed (i.e. platelet activity, mean platelet volume and P selectin) may also contribute to be useful in calculating cardiovascular risk. The present review and meta-analysis summarizes the evidence for measuring platelet function indices to identify patients at risk of developing cardiovascular events. PMID- 28597735 TI - Early changes of left atrial function in chronic asymptomatic alcoholics by two dimensional speckle-tracking echocardiography. AB - Background Chronic excessive alcohol intake has been reported as a possible cause of dilated cardiomyopathy. Two-dimensional speckle-tracking echocardiography (2D STE) is a novel method for the angle-independent and objective quantification of myocardial deformation. This study sought to assess left atrial function changes among alcoholics related to the duration of heavy drinking by 2D-STE. Methods We classified 92 asymptomatic alcoholics into mild, moderate and severe groups. Thirty age-matched controls were also recruited. We measured left atrial (LA) phasic volumes (max, min and pre-atrial contraction volume) using Simpson's method in apical four-chamber view. Passive emptying (LAPEF) and active emptying (LAAEF) indices were calculated. Global longitudinal strain rate (SRs) during left ventricular (LV) ejection, early diastolic strain rate (SRe) during LV early diastole and peak negative strain rate (SRa) after the P-wave were also obtained by averaging all atrial segments. Results The alcoholics had larger LA volumes (max, min and pre-atrial contraction volume) since moderate stage (P < 0.01). LAPEF, SRs SRe, and E/A ratio showed progressive decrease according to the grades of alcoholism. The differences between the groups were significant, beginning from the moderate group (P < 0.01). During LAAEF, SRa values increased with the disease severity up to moderate alcoholics and then deteriorated significantly in severe alcoholics (P < 0.01). Conclusions These data suggest that 2D-STE may be considered a promising tool for the early detection of impairment of LA function in alcoholics. PMID- 28597736 TI - Venous stenosis and occlusion in the presence of endocardial leads in patients referred for transvenous lead extraction. AB - Objective The aim of this study was to evaluate the incidence of venous stenosis and occlusion (VSO) in patients referred for transvenous lead extraction (TLE) with regard to the indications for this treatment and to analyse the influence of VSO on efficacy, complications and technical challenges of TLE procedures. Methods The material consists of 133 consecutive TLE procedure records. The contrast venography examination of the ipsilateral access vein was performed prior to the operation. The whole study population was divided into two subgroups, based on the presence (subgroup I) or absence (subgroup II) of VSO. Results Phlebography was performed in 133 patients with age ranging from 25.7 to 86.1 years, 44 female (33.1%). The VSO was confirmed in 48 (36.1%) patients - subgroup I. Most of the patients were referred to TLE due to non-infectious reasons (100 pts-75.2%). The absence of VSO was observed substantially more frequently in patients with diabetes (P = 0.02). Procedural success rate reached 93.3% in subgroup I and 98.8% in subgroup II (P = 0.1). There was no significant difference in the use of advanced tools and alternative access sites. Conclusion The presence of VSO can be expected in one third of patients referred for lead extraction. There is no association between indication for TLE (infected or noninfected lead extraction) and the incidence of VSO. Diabetes proved to have a protective effect on venous patency in the previously mentioned group. VSO does not influence the effectiveness, safety, and the use of additional tools during TLE procedures. PMID- 28597737 TI - Extension of catheter ablation and outcome for ventricular tachycardia or premature ventricular contractions from the right ventricular outflow tract. AB - Objective We aimed to determine whether the extension of ablation could influence the ablation outcome for ventricular tachycardia (VT)/premature ventricular contractions (PVCs) from the right ventricular outflow tract (RVOT). Methods and results The radiofrequency catheter ablation results of 33 VT/6 frequent PVCs from the RVOT were analysed. The ablation extension was divided into 3 categories from the final successful ablation point with the earliest activation: (I) focal ablation (15 cases); ablation at 1 or 2 points; (II) focal with extended ablation (12 cases); focal and surrounding area ablation (maximum <=1 cm) after elimination of clinical VT/PVCs; and (III) broad ablation (12 cases); continued broad ablation (maximum >1 cm) after elimination of clinical VT/PVCs. Acute termination was defined as the complete elimination and non-inducibility of clinical VT/PVCs during the procedure. For the mean follow-up of 12.8 months, the recurrence rate was not significantly different among the groups (P = 0.49). The mean procedure time was longer in group II, but ablation times and complication rates were not different among the groups. When acute termination was achieved, the overall recurrence rate was 7.6%. However, when confirming absence of the clinical VT/PVCs using 24-hour Holter monitoring immediately after the procedure, the recurrence rate was 2.7%. Conclusions Ablation extension did not affect ablation outcome of VT/PVCs from the RVOT. Confirmation of absence of clinical VT/PVCs using 24-hour Holter monitoring immediately after the procedure could guarantee long-term success. PMID- 28597738 TI - Improved diagnostic accuracy when combining computed tomography angiography and corrected coronary opacification in patients with coronary stents. AB - Background The accuracy of coronary computed tomography angiography (CCTA) is sub optimal in patients with coronary stents. Methods that can increase its diagnostic accuracy are desirable. Objective A proof-of-concept study was undertaken to determine if corrected coronary opacification (CCO) differences can improve the accuracy of CCTA in stented coronary arteries. Methods PCI patients who underwent both CCTA and invasive coronary angiography (ICA) within 3 months were analyzed. Coronary luminal attenuation values (normalized to the aorta) were measured proximally and distally to coronary stents. CCO differences were evaluated for ability to predict (i) stenosis on invasive angiography, (ii) abnormal resting coronary flow as measured by the corrected thrombolysis in myocardial infarction (TIMI) frame count (cTFC), and (iii) the combination of abnormal resting flow and significant stenosis on invasive angiography. Results Twenty-nine stented coronary arteries (n = 25, mean age =61.4 years, men =80.0%) were assessed. In stented coronary vessels, CCO identified stenosis (>= 70%) with an area under the curve of 0.767 (P = 0.021). CCO predicted abnormal resting coronary flow with high accuracy (AUC =0.867, P = 0.002). Combined CCTA/CCO identified both abnormal cTFC and stenosis >=70% on ICA (functionally significant stenosis) with diagnostic accuracy of 92.3%. In contrast, CCTA visual assessment alone had lower diagnostic accuracy of 66.7% for identifying functionally significant stenosis. Conclusion CCO differences are predictive of abnormal resting flow and consequently, in-stent restenosis. Incorporation of this technique may improve the specificity of CCTA in PCI patients. PMID- 28597739 TI - One-year and longer dual antiplatelet therapy after an acute coronary syndrome: a Belgian position paper. AB - Acute coronary syndrome patients receive DAPT up to one year after their initial event. Exceptions to the guideline-recommended one-year rule, however, are not uncommon. The reasoning behind shorter treatments, such as unacceptable bleeding risk or urgent surgery, should be well documented in the patient's charts and discharge letter. Based on recent evidence, patients at high risk for repetitive events should continue on low-dose ticagrelor without a significant interruption at one year and indefinitely in the absence of excess bleeding risk. As there is currently no reimbursement, policy makers and insurers should be made aware of the continuing risk and unmet clinical need in this patient population. Nevertheless, many unsolved questions need to be answered, both through additional analyses from recent trials such as PEGASUS-TIMI 54 or DAPT, as well as new carefully designed clinical studies. PMID- 28597741 TI - Belgian Society of Cardiology 36th Annual Congress. PMID- 28597740 TI - Pocket haematoma after cardiac electronic device implantation in patients receiving antiplatelet and anticoagulant treatment: a single-centre experience. AB - Objective In modern cardiology practice, implantation of cardiac electronic devices in patients taking anticoagulant or antiplatelet therapy is a common clinical scenario. Bleeding complications are of particular concern in this patient population and pocket haematoma is one of the most frequent complications. We sought to determine the relationship between periprocedural antiplatelet/anticoagulant therapy and pocket haematoma formation in patients undergoing cardiac implantable electronic device (CIED) implantation. Methods We conducted a retrospective study including 232 consecutive patients undergoing CIED implantation in the department of cardiology of the Medipol University Hospital. Patients were divided into six groups: clopidogrel group (n = 12), acetylsalicylic acid (ASA) group (n = 73), ASA + clopidogrel group (n = 29), warfarin group (n = 34), warfarin + ASA group (n = 21) and no antiplatelet anticoagulant therapy group as the control group (n = 63). CIED implantations were stratified under four subtitles including implantable cardioverter/defibrillator (ICD), cardiac resynchronization therapy (CRT), permanent pacemaker and the last group as either device upgrade or generator replacement. Results The mean age of the patients was 63 +/- 14 years and 140 patients were male (60.3%). A pocket haematoma was documented in 6 of 232 patients (2.6%). None of the patients with pocket haematoma needed pocket exploration or blood transfusion. The type of the device did not have a significant effect on pocket haematoma incidence (P = 0.250). Univariate logistic regression showed that platelet level and ASA plus clopidogrel use were significantly associated with haematoma frequency after CIED implantations, respectively (OR: 0.977, CI 95% [0.958-0.996]; OR: 16.080, CI 95% [2.801 92.306]). Multivariate analysis revealed that dual antiplatelet treatment (beta = 3.016, P = 0.002, OR: 2.410, 95% CI [3.042-136.943]) and baseline platelet level (beta = -0.027, p:0.025, OR: 0.974, 95% CI [0.951-0.997]) were independent risk factors for pocket haematoma formation. Conclusion Dual antiplatelet therapy and low platelet levels significantly increased the risk of pocket haematoma formation in patients undergoing CIED implantations. PMID- 28597742 TI - Left ventricular hypertrophy and papillary fibroelastoma in a patient with a MYBPC3 gene mutation. PMID- 28597743 TI - One-year results of primary stenting for TASC II D lesions of the superficial femoral and popliteal arteries. AB - Objective This study aimed to evaluate the safety and the efficacy of primary stenting to treat Trans-Atlantic Inter-Society Consensus II (TASC) D femoropopliteal lesions. Background Advances in wire, balloon and stent design have been reported to improve the durability of stenting of longer femoropopliteal lesions. Methods A total of 57 limbs of 53 patients with Rutherford stage 3 to 6 due to TASC D femoropopliteal lesions were treated with a self-expanding nitinol stent in a prospective, single-centre, observational study. End points of interest included primary and secondary patency, target lesion revascularization, in-stent restenosis, major adverse cardiovascular events, Rutherford class improvement and change in walking capacity at 1 year. Results A total of 53 patients (57 lesions) were treated with a self-expanding nitinol stent and final procedural success was 91.2%. The median length of the treated segment was 330 +/- 96 mm. The median stented segment was 366 +/- 71 mm and the mean number of the stents was 2.1 +/- 0.9. At 1 year, primary and secondary patency rates were 63.9% and 82.1%, respectively. Major adverse cardiovascular events occurred in 11 patients (22.9%), and[[strike_start]] [[strike_end]]significant benefits were observed in Rutherford class and walking distance (both P < 0.001). Conclusions Primary implantation of self-expanding nitinol stents for the treatment of TASC D femoropopliteal lesions appears to be safe and effective, especially in patients who have multiple co-morbidities and a high risk for surgical bypass. The risk of restenosis was higher when long stenting was extended to the popliteal artery. PMID- 28597744 TI - Noninvasive techniques for the diagnosis of anomalous origin of the left coronary artery from the pulmonary artery in adult patients. AB - Background Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital cardiac anomaly which requires surgical treatment, which improves left ventricular function and clinical outcomes. The definitive diagnosis of ALCAPA is based on coronary angiography, however, noninvasive visualization of the origin of the coronary artery is often helpful in the diagnosis of ALCAPA. Objectives The purpose of this study was to evaluate noninvasive techniques for the diagnosis of ALCAPA, and present the clinical outcomes in adults after surgical correction of ALCAPA. Methods Medical charts of five patients with ALCAPA treated at the John Paul II Hospital in Cracow between 2004 and 2012 were analyzed retrospectively. Noninvasive imaging techniques were used to visualize coronary vessels preoperatively. Patients were followed one year after the operation with echocardiograms and assessment of the New York Heart Association functional class. Results Computed tomography showed ALCAPA in four patients. Magnetic resonance imaging showed abnormal left ventricle remodeling suggestive of ischemia of the anterior cardiac wall. Myocardial perfusion imaging revealed ischemia of the middle and periapical segments of the anterior and anterolateral wall of the left ventricle in two patients. Postoperatively, patients had symptomatic improvement, but there was no statistically significant difference in mean ejection fraction. Conclusions Noninvasive techniques can be used to visualize the origin of the coronary arteries and characterize their morphology. Long-term follow-up of adult patients after surgical correction of ALCAPA is not well documented in the literature, but surgical treatment revealed beneficial short-term effects and symptoms relief. PMID- 28597745 TI - Editorial. PMID- 28597746 TI - Incomplete Shone's complex: adult age diagnosis. PMID- 28597747 TI - "Uneven-sized eyes" sign on echocardiography in a young girl with pulmonary artery sling and tracheal bronchus. PMID- 28597748 TI - Hypereosinophilic cardiac disease. AB - Hypereosinophilia may be due to several aetiologies. Cardiac complications are not uncommon, whatever the causes. Clinical presentations of hypereosinophilic cardiac diseases may vary widely from asymptomatic form to fatal necrotic myocarditis or irreversible restrictive cardiomyopathy. As a major cause of morbidity and mortality, diagnosis of cardiac involvement is crucial. Until recently the diagnosis was exclusively based on cardiac biopsy. Nowadays, multimodal cardiac imaging, including echocardiography and cardiac magnetic resonance imaging, is the cornerstone of the diagnosis. Cardiac magnetic resonance imaging has emerged as a very useful tool for the diagnosis allowing precise tissue characterization. It has even been proposed as a surrogate to cardiac biopsy. It should be systematically performed in case of hypereosinophilia. Early and appropriate treatment is crucial to avoid the evolution toward irreversible cardiac lesions. These treatments are symptomatic but should also be adapted to the underlying diseases. PMID- 28597749 TI - A stalactite in the aorta. Abnormal calcification in a patient with pseudoxanthoma elasticum. PMID- 28597750 TI - MUC1 induces tamoxifen resistance in estrogen receptor-positive breast cancer. AB - INTRODUCTION: Tamoxifen, as an essential therapeutic tool in the treatment of estrogen receptor-positive breast cancer, has been available for the past three decades and is currently being utilized as a chemo-preventive agent for patients at high risk for breast carcinoma. However, the induction of chemo-resistance during therapy has indicated a significant challenge with regards to this agent. Areas covered: This review enumerates the role of MUC1-C proto-oncogene in tamoxifen resistance and describes a number of signaling pathways by which MUC1-C would mediate the development of resistance. Finally, recent clinical studies conducted on the magnitude of MUC1 in inducing tamoxifen resistance are described. Expert commentary: Mucin 1, or MUC1, is aberrantly overexpressed on the entire tumor cell surface of most human cancers. Thus, it may result in the upregulation of several signaling pathways, such as growth cascades related to receptor tyrosine kinases (RTK), beta-catenin and E-cadherin, as well as promoting gene transcription of Ras-related protein Rab-31 in order to mediate tumor growth control in response to tamoxifen. On the contrary, MUC1 suppresses apoptotic events, which in turn impresses upon cell fate. Also, it has been demonstrated that silencing MUC1-C proto-oncogene is associated with increased sensitivity to tamoxifen-induced growth inhibitors. PMID- 28597751 TI - The Modified Borg Dyspnea Scale does not predict hospitalization in pulmonary arterial hypertension. AB - Background Breathlessness is the most common symptom reported by patients with pulmonary arterial hypertension (PAH). The Modified Borg Dyspnea Scale (MBS) is routinely obtained during the six-minute walk test in the assessment of PAH patients, but it is not known whether the MBS predicts clinical outcomes such as hospitalizations in PAH. Methods We performed a retrospective study of World Health Organization (WHO) Group 1 PAH patients followed at our center. The dates of the first three MBS and hospitalizations that occurred within three months of a documented MBS were collected. Marginal Cox hazard regression modeling was used to assess for a relationship between MBS and all-cause as well as PAH-related hospitalization. Results A total of 50 patients were included; most (92%) were functional class III/IV, 44% and 65% were treatment-naive prior to their first MBS and hospitalization, respectively. The first recorded MBS was inversely correlated with the first recorded six-minute walk distance (6MWD) (r = -0.41, P < 0.01) but did not track with WHO functional class (r = 0.07, P = 0.63). MBS did not predict all-cause (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.76-1.08; P = 0.28) or PAH-related hospitalization (HR, 1.04; 95% CI, 0.89-1.23; P = 0.61), though there was a strong relationship between 6MWD and PAH-related hospitalization ( P = 0.01). These findings persisted after multivariable adjustment. Conclusions Breathlessness as assessed by MBS does not predict all cause or PAH-related hospitalization. Robust and validated patient-reported outcomes are needed in pulmonary vascular disease. PMID- 28597752 TI - Withdrawal of long-term epoprostenol therapy in pulmonary arterial hypertension (PAH). AB - Once initiated for pulmonary arterial hypertension (PAH), epoprostenol treatment usually needs to be delivered for an indefinite duration. It is possible that some participants could be transitioned from epoprostenol to oral therapies. We retrospectively evaluated eight PAH participants transitioned from epoprostenol to PAH oral drugs. The criteria for epoprostenol withdrawal were: (1) persistent improvement of clinic and hemodynamic status; (2) stable dose of epoprostenol for the last three months; and (3) the participant's preference for oral therapy after evaluation of risk-benefit. We evaluated the clinical, functional, and hemodynamic status at baseline, at withdrawal, and after the transition to oral PAH therapy. The transition was completed in all eight participants. Four participants had a complete successful transition (CT) with a stable clinical and hemodynamic course and four participants had a partial successful transition (PT) remaining stable clinically, with a mild hemodynamic worsening, but without need to re-initiate epoprostenol therapy. The four CT participants were treated with epoprostenol for a shorter period of time (CT group: 35 +/- 30 versus PT group: 79 +/- 49 months, P = 0.08). Mean epoprostenol dosage was lower in the CT group (CT group: 15 +/- 1.5 ng/kg/min versus PT group: 24 +/- 11 ng/kg/min, P = 0.09). Safe withdrawal of epoprostenol treatment and transition to oral PAH therapy was possible in a small and highly selected group of participants. The majority of these participants had a porto-pulmonary PAH or PAH associated to HIV infection. PMID- 28597753 TI - Circulatory power and ventilatory power over time under goal-oriented sequential combination therapy for pulmonary arterial hypertension. AB - Many therapeutic options are available for patients with pulmonary arterial hypertension (PAH). However, little is known about the effects of sequential combination therapy on exercise capacity. Here we monitored exercise capacity by cardiopulmonary exercise testing (CPX) and observed the benefit of using a peak VO2 cutoff of 15 mL/kg/min to guide combination therapy. Thirty patients newly diagnosed with PAH were treated with goal-oriented sequential combination therapy. Endothelin receptor antagonists (ERA) were the first-line treatment, with phosphodiesterase type 5 inhibitors (PDE-5i) as the preferred combination partner. The patients underwent cardiac catheterization at baseline and after 12 months and CPX at baseline and after three, six, and 12 months. Circulatory power (CP) was defined as the product of peak O2 uptake and peak systolic blood pressure (SBP); ventilatory power (VP) was defined as peak SBP divided by the minute ventilation-CO2 production slope. After 12 months, ERA had been administered to 100% of the study patients and PDE-5i to 82%. Mean CP at baseline and after three, six, and 12 months was 1807, 2063, 2248, and 2245 mmHg.min/mL/kg, respectively, and mean VP was 2.93, 3.53, 4.16, and 3.68 mmHg, respectively. CP was greater after 6 months than at baseline ( P = 0.047); VP was greater after three months than at baseline ( P = 0.019) and further improved at six months compared with three months ( P = 0.040). Therefore, repeated CPX assessment, including measurement of CP and VP, can provide useful information regarding the efficacy of goal-oriented treatment for PAH. PMID- 28597754 TI - Characteristics of pediatric pulmonary hypertension trials registered on ClinicalTrials.gov. AB - The investigation of pediatric pulmonary hypertension (PH) drugs has been identified as a high priority by the United States National Institutes of Health (NIH). Studying pediatric PH is challenging due to the rare and heterogeneous nature of the disease. We sought to define the pediatric PH clinical trials landscape, to evaluate areas of trial success or failure, and to identify potential obstacles to the study of pediatric PH drugs. Interventional pediatric (ages 0-17 years) PH trials registered on ClinicalTrials.gov from June 2005 through December 2014 were analyzed. There were 45 pediatric PH trials registered during the study period. Median (IQR) projected trial enrollment was 40 (24-63), with seven trials (16%) targeting > 100 participants. Industry was the most common trial sponsor (n = 23, 50%), with only two (4.4%) NIH-sponsored trials. Phosphodiesterase inhibitors were the most frequently studied drug (n = 18, 39%). Single group study designs were used in 44% (n = 20) with an active comparator (parallel, factorial, or cross-over designs) in 25 trials, including 22 with randomization and ten that were double-blinded. Study outcomes varied markedly with inconsistent use of known surrogate and composite endpoints. One-third of trials (n = 15, 33%) were terminated, predominantly due to poor participant enrollment. Of the 17 completed trials, 11 had published results and only three efficacy trials met their primary endpoint. There are unique challenges to drug development in pediatric PH, including enrolling patients, identifying appropriate study endpoints, and conducting randomized, controlled, double-blind trials where the likelihood of meeting the study endpoint is optimized. PMID- 28597755 TI - Assessment of microRNA and gene dysregulation in pulmonary hypertension by endoarterial biopsy. AB - MicroRNAs (miRNAs) may regulate a number of genes, each of which may have a variety of functions. We utilized an endoarterial biopsy catheter to assess the dysregulation of miRNAs in a porcine shunt model of pulmonary hypertension (PH). Two Yucatan micropigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Endoarterial biopsy samples were obtained at baseline, and at regular intervals during the progression of PH. RNA, isolated from biopsy samples, was analyzed by Illumina miRNA expression microarrays (containing ~1200 human miRNAs), Affymetrix Porcine GeneChips, Bioconductor, and GeneSpring. We examined a total of 925 genes in a PH whole genome microarray. Biopsy samples showed that 39 miRNAs were downregulated and 34 miRNAs were upregulated compared to baseline. The number of PH-associated genes reported to be controlled by each of the dysregulated miRNAs was in the range of 1-113. The five miRNAs that had the largest number of PH-associated genes were: miR-548c-3p, miR-520d-3p, miR 130a-5p, miR-30a-3p, and miR-let-7g-3p. Several of the dysregulated miRNAs have been associated with molecular pathways and biologic processes involved in PH. Among 29 miRNAs, which were predicted to be dysregulated by a systems biology approach, we found four that were dysregulated in our porcine shunt model. An endoarterial biopsy technique was successful in showing that a large number of miRNAs are dysregulated in a porcine shunt model of PH. Many of these miRNAs control multiple PH-associated genes, molecular pathways, and biologic processes. Endoarterial biopsy offers potential experimental and clinical diagnostic value. PMID- 28597756 TI - Lack of elevation in plasma levels of pro-inflammatory cytokines in common rodent models of pulmonary arterial hypertension: questions of construct validity for human patients. AB - Translational research depends on the relevance of animal models and how well they replicate human disease. Here, we investigated plasma levels of three important pro-inflammatory cytokines (TNFalpha, IL-6, and MCP-1), known to be elevated in human pulmonary arterial hypertension (PAH), and systematically assessed their levels in PAH patients compared to five different rodent models of pulmonary hypertension (PH). A consistent immunoassay platform (Luminex xMAP) and source (Millipore) was used to measure all specimens. PAH patients (n = 29) exhibited significant elevations in all three cytokines (median [IQR] pg/mL; TNFalpha, 7.0 [4.8-11.7]; IL-6, 9.2 [3.8-17.2]; MCP-1, 109 [65-142]) versus healthy participants (n = 20) (median [IQR] pg/mL; TNFalpha, 3.0 [2.0-3.6]; IL-6, 1.7 [0.5-7.2]; MCP-1, 79 [49-93]. In contrast, mice with PH established after three weeks of hypoxia (n = 18) or SU5416 plus hypoxia (n = 20) showed no significant change in their plasma cytokine levels versus controls (n = 16), based on three to four independent experiments per group. Similarly, plasma cytokine levels were not elevated in rats with PH established three weeks after monocrotaline (n = 23), eight weeks after SU5416 alone (n = 10) or six to eight weeks after SU5416 plus hypoxia (n = 21) versus controls (n = 36 rats), based on three to eight independent experiments per group. Positive biologic control specimens from sepsis patients (n = 9), cecal-ligation and puncture (CLP)-induced septic mice (n = 6), and lipopolysaccharide-induced septic rats (n = 4) showed robust elevations in all three cytokines. This study suggests that animal models commonly used for the development of novel diagnostic and therapeutic approaches for PAH may have limited construct validity with respect to markers of systemic immune activation seen in human patients. PMID- 28597758 TI - Longitudinal change in pulmonary arterial capacitance as an indicator of prognosis and response to therapy and in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic progressive disease that leads to right heart failure and death. Pulmonary arterial capacitance (PAC), defined as stroke volume divided by the pulmonary pulse pressure, has been identified as a prognostic factor in PAH. The impact of changes in PAC over time, however, is unclear. We evaluated changes in PAC over time to determine if such changes predicted transplant-free survival. A single-center retrospective study of consecutive group 1 PAH patients who had two or more right heart catheterizations (RHC) between January 2007 and June 2016 was undertaken. Hemodynamic data, clinical data, and outcomes were collected. Univariate and multivariate Cox proportional-hazards modelling to identify the contribution of risk factors for a composite outcome of death or lung transplantation was done. Mixed-effects logistic regression was performed to investigate the association between the change in PAC value over time and the composite outcome. A P value < 0.05 was considered significant. In total, 109 consecutive patients with a total of 300 RHC data were identified. PAC correlated inversely with functional status ( P < 0.001) and inversely with pulmonary vascular resistance ( P < 0.001). PAC values increased with the addition of new PAH-specific medications. Mixed effects logistic regression modeling using longitudinal data showed that a decrease in PAC over the study period was associated with increased mortality and transplantation (adjusted P = 0.039) over the study period. Change in PAC was a better predictor of outcome over the study period than baseline PAC or changes in other hemodynamic or clinical parameters. Decreases in PAC were predictive of increased mortality or transplantation in patients with group 1 PAH. There was a trend towards increased PAC in response to the addition of a PAH-specific medication. Our data support the use of PAC as a therapeutic target in PAH. PMID- 28597759 TI - Follow-up tricuspid annular plane systolic excursion predicts survival in pulmonary arterial hypertension. AB - Few studies have examined the utility of serial echocardiography in the evaluation, management, and prognosis of patients with pulmonary arterial hypertension (PAH). Therefore, we sought to evaluate the prognostic significance of follow-up tricuspid annular plane systolic excursion (TAPSE) in PAH. We prospectively studied 70 consecutive patients with PAH who underwent baseline right heart catheterization (RHC) and transthoracic echocardiogram, who survived to follow-up echocardiogram after initiation of PAH therapy. Baseline TAPSE was 1.6 +/- 0.5 cm which increased to 2.0 +/- 0.4 cm on follow-up ( P < 0.0001). The cohort was dichotomized by TAPSE at one-year follow-up: Group 1 (n = 37): follow up TAPSE >= 2 cm; Group 2 (n = 33): follow-up TAPSE < 2 cm. Group 1 participants were significantly more likely to reach WHO functional class I-II status and achieve a higher six-minute walk distance on follow-up. Of the 68 patients who survived more than one year, 18 died (26.5%) over a median follow-up of 941 days (range, 3-2311 days), with significantly higher mortality in Group 2 versus Group 1 (41.9% vs. 13.5%; P = 0.003). While baseline TAPSE stratified at 2 cm did not predict survival in this cohort, TAPSE >= 2 cm at follow-up strongly predicted survival in bivariable models (hazard ratio, 0.21; 95% confidence interval, 0.08 0.60). In conclusion, follow-up TAPSE >= 2 cm is a prognostic marker and potential treatment target in a PAH population. PMID- 28597757 TI - The cancer theory of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) remains a mysterious killer that, like cancer, is characterized by tremendous complexity. PAH development occurs under sustained and persistent environmental stress, such as inflammation, shear stress, pseudo-hypoxia, and more. After inducing an initial death of the endothelial cells, these environmental stresses contribute with time to the development of hyper-proliferative and apoptotic resistant clone of cells including pulmonary artery smooth muscle cells, fibroblasts, and even pulmonary artery endothelial cells allowing vascular remodeling and PAH development. Molecularly, these cells exhibit many features common to cancer cells offering the opportunity to exploit therapeutic strategies used in cancer to treat PAH. In this review, we outline the signaling pathways and mechanisms described in cancer that drive PAH cells' survival and proliferation and discuss the therapeutic potential of antineoplastic drugs in PAH. PMID- 28597760 TI - Late-onset pulmonary arterial hypertension in repaired D-transposition of great arteries: an uncommon complication. AB - Late-onset pulmonary arterial hypertension (PAH) is a rare but fatal complication in patients with childhood surgical repair of dextro-transposition of great arteries (D-TGA), especially with the Mustard and Senning procedures. The pathogenic mechanisms of PAH in patients with repaired D-TGA are not well understood and treatment is not standardized. In this manuscript, we present a case of late-onset PAH in an adult D-TGA patient after Mustard repair and discuss the pathogenic mechanisms, diagnosis, and treatment of pulmonary hypertension in repaired D-TGA. PMID- 28597761 TI - Metabolic and Functional Evaluation of the Heart and Lungs in Pulmonary Hypertension by Gated 2-[18F]-Fluoro-2-deoxy-D-glucose Positron Emission Tomography. AB - Pulmonary hypertension (PH) is associated with a metabolic shift towards glycolysis in both the right ventricle and lung. This results in increased glucose uptake to compensate for the lower energy yield of glycolysis, which creates a potential for 2-[18F] fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to be a useful tool in the evaluation of participants with PH. We investigated the utility of PET for PH by comparing FDG-PET uptake in the right ventricle and lungs in 30 participants with PH and eight healthy controls and correlating these measurements with echocardiographic (ECHO) measurements and other traditional assessments commonly used in PH. All participants underwent gated FDG-PET scanning in the fasting state, ECHO, six-minute walk test (6MWT), and blood draw for NT-proBNP. Participants also completed the CAMPHOR questionnaire. Right ventricular (RV) end-diastolic and end-systolic volumes, RV ejection fraction, and FDG uptake by PET were significantly different between PH and healthy controls and strongly correlated with plasma NT-proBNP levels and RV ECHO parameters including TAPSE, RV systolic pressure, Tei index, and global peak systolic strain. In addition, lung standardized uptake value (SUV) was also found to be significantly higher in participants with PH than healthy controls. However, lung SUV did not show any significant correlations with NT-proBNP levels, 6MWT, or functional and pressure measurements by ECHO. In this study, we demonstrated the ability to evaluate both lung and right heart metabolism and function in PH by using a single gated FDG-PET scan. PMID- 28597762 TI - The safety and pharmacokinetics of rapid iloprost aerosol delivery via the BREELIB nebulizer in pulmonary arterial hypertension. AB - The BREELIB nebulizer was developed for iloprost to reduce inhalation times for patients with pulmonary arterial hypertension (PAH). This multicenter, randomized, unblinded, four-part study compared inhalation time, pharmacokinetics, and acute tolerability of iloprost 5 ug at mouthpiece delivered via BREELIB versus the standard I-Neb nebulizer in 27 patients with PAH. The primary safety outcome was the proportion of patients with a maximum increase in heart rate (HR) >= 25% and/or a maximum decrease in systolic blood pressure >= 20% within 30 min after inhalation. Other safety outcomes included systolic, diastolic, and mean blood pressure, HR, oxygen saturation, and adverse events (AEs). Median inhalation times were considerably shorter with BREELIB versus I Neb (2.6 versus 10.9 min; n = 24). Maximum iloprost plasma concentration and systemic exposure (area under the plasma concentration-time curve) were 77% and 42% higher, respectively, with BREELIB versus I-Neb. Five patients experienced a maximum systolic blood pressure decrease >= 20%, four with BREELIB (one mildly and transiently symptomatic), and one with I-Neb; none required medical intervention. AEs reported during the study were consistent with the known safety profile of iloprost. The BREELIB nebulizer offers reduced inhalation time, good tolerability, and may improve iloprost aerosol therapy convenience and thus compliance for patients with PAH. PMID- 28597763 TI - Open label study of ambrisentan in patients with exercise pulmonary hypertension. AB - A growing body of evidence suggests that exercise pulmonary hypertension (ePH) is an early form of pulmonary arterial hypertension (PAH). Identifying the disease at an early, potentially more responsive phase, and initiating treatment may improve functional status and prevent progression to severe forms of PAH. This was a single-center, open-label six-month treatment trial to evaluate the effect of ambrisentan on pulmonary hemodynamics and exercise capacity in ePH utilizing invasive cardiopulmonary exercise testing (iCPET). After six months of treatment with ambrisentan, patients repeated iCPET; exercise capacity, symptoms, and pulmonary hemodynamics were reassessed. Twenty-two of 30 patients completed the treatment phase and repeat iCPET. After six months of treatment there was a significant decline in peak exercise mPAP (-5.2 +/- 5.6 mmHg, P = 0.001), TPG ( 7.1 +/- 8.0 mmHg, P = 0.001), PVR (-0.9 +/- 0.7 Woods units, P = 0.0002), and Ca vO2 (-1.8 +/- 2.3 mL/dL, P = 0.0002), with significant increases in peak PCWP (+2.9 +/- 5.6 mmHg, P = 0.02), PVC (+0.8 +/- 1.4 mL/mmHg, P = 0.03), and CO (+2.3 +/- 1.4 L/min, P = 0.0001). A trend toward increased VO2max (+4.4 +/- 2.6% predicted, P = 0.07) was observed. In addition, there were improvements in 6MWD and WHO FC after 24 weeks. Our findings suggest that treatment of ePH with ambrisentan results in improved pulmonary hemodynamics and functional status over a six-month period. Treatment of ePH may prevent the progression of vascular remodeling and development of established PAH. PMID- 28597764 TI - MicroCT analysis of vascular morphometry: a comparison of right lung lobes in the SUGEN/hypoxic rat model of pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling within the lung. Clinical computed tomography (CT) scans are routinely used to aid in PAH diagnosis. Animal models, including the Sugen-hypoxic rat model (SU/hyp), of PAH closely mimic human PAH development. We have previously used micro-computed tomography (microCT) to find extensive right lung vascular remodeling in the SU/hyp. We hypothesized that the individual right lung lobes may not contribute equally to overall lung vascular remodeling. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) and subsequently exposed to chronic hypoxic conditions (10% O2) for three weeks. Following perfusion of the lung vasculature with an opaque resin (Microfil), the right lung lobes were microCT-imaged with a 10-um voxel resolution and 3D morphometry analysis was performed separately on each lobe. As expected, we found a significantly lower ratio of vascular volume to total lobe volume in the SU/hyp compared with the control, but only in the distal lobes (inferior: 0.23 [0.21-0.30] versus 0.35 [0.27-0.43], P = 0.02; accessory: 0.27 [0.25-0.33] versus 0.37 [0.29-0.43], P = 0.06). Overall, we observed significantly fewer continuous blood vessels and reduced vascular density while having greater vascular lumen diameters in the distal lobes of both groups ( P < 0.05). In addition, the vascular separation within the SU/hyp lobes and the vascular surface area to volume ratio were significantly greater in the SU/hyp lobes compared with controls ( P < 0.03). Results for the examined parameters support the overall extensive vascular remodeling in the SU/hyp model and suggest this may be lobe-dependent. PMID- 28597765 TI - Poor survival in patients with scleroderma and pulmonary hypertension due to heart failure with preserved ejection fraction. AB - Pulmonary hypertension due to heart failure with preserved ejection fraction (PH HFpEF) has been poorly studied in patients with systemic sclerosis (SSc). We sought to compare clinical characteristics and survival of SSc patients with PH HFpEF (SSc-PH-HFpEF) versus pulmonary arterial hypertension (SSc-PAH). We hypothesized that patients with SSc-PH-HFpEF have a similar poor overall prognosis compared with patients with SSc-PAH when matched for total right ventricular load. The analysis included 117 patients with SSc-PH (93 with SSc-PAH versus 24 with SSc-PH-HFpEF) enrolled prospectively in the Johns Hopkins PH Registry. We examined baseline demographics and hemodynamics at diagnostic right heart catheterization (RHC), two-dimensional echocardiographic characteristics, six-minute walking distance (6MWD), treatment modalities, and laboratory values (serum NT-proBNP, creatinine, uric acid, and sodium), and assessed survival. Demographics and clinical features were similar between the two groups. Baseline RHC showed significantly higher pulmonary and right heart pressures in the SSc-PH HFpEF compared with the SSc-PAH group. Trans-pulmonary gradient (TPG), however, was equally elevated without significant difference between the groups. SSc-PH HFpEF patients had left atrial enlargement on echocardiography compared with SSc PAH patients. No significant differences were found between groups for 6MWD, NT proBNP, and other laboratory values. Although overall median survival time was 4.6 years with no difference in mortality rate between the two groups (SSc-PH HFpEF versus SSc-PAH: 75% versus 59%; P = 0.26), patients with SSc-PH-HFpEF had a twofold increased risk of death compared with SSc-PAH patients after adjusting for hemodynamics. Concomitant intrinsic pulmonary vascular disease and HFpEF likely contribute to very poor survival in patients with SSc-PH-HFpEF. PMID- 28597768 TI - Corrigendum. PMID- 28597766 TI - Identifying "super responders" in pulmonary arterial hypertension. AB - Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called "super responders." This was first recognized among PAH patients with acute vasodilator response during invasive hemodynamic testing, a subset of whom have dramatically improved survival when treated with calcium channel blocker (CCB) therapy. Retrospective studies have now suggested a sex discrepancy in response to endothelin receptor antagonists (ERA) and phosphodiesterase inhibitors, and more recently a few studies have found genomic associations with response to CCBs and ERAs. With increasing availability of "omics" technologies, recognition of these "super responders," combined with careful clinical and molecular phenotyping, will lead to advances in pharmacogenomics, precision medicine, and continued improvements in survival among PAH patients. PMID- 28597767 TI - Increased mortality from complications of pulmonary hypertension in patients undergoing transcatheter aortic valve replacement. AB - Aortic stenosis (AS) leads to pulmonary hypertension (PH) and right ventricle (RV) failure. Our goal was to describe mortality related to postoperative complications in PH patients undergoing transcatheter aortic valve replacement (TAVR). Ninety-three TAVR patients were analyzed (controls, sPAP < 50 mmHg; cases, sPAP >= 50 mmHg). Significant findings in cases included increased mortality (365 days), post-TAVR atrioventricular block (AVB) and acute kidney injury (AKI), and increased mean length of stay (LOS). This novel study highlights complications of PH as independent risk factors for death and significant morbidity post TAVR. Optimization of preoperative volume status and RV afterload reduction, while addressing AVB and AKI, may play a vital role in reducing mortality and LOS. PMID- 28597769 TI - A systematic review of transition studies of pulmonary arterial hypertension specific medications. AB - Pulmonary arterial hypertension (PAH) is a progressive potentially fatal disease. Multiple pharmacologic options are now available, which facilitated transitions between different therapeutic options, although the evidence for such transitions has not been well described. We sought to review the evidence supporting the safety and/or efficacy of transitioning between PAH-specific medications. We performed a systematic review of all published studies in the Medline database between 1 January 2000 and 30 June 2016 reporting on any transition between the currently Food and Drug Administration (FDA)-approved PAH-specific medications. Studies reporting on three or more adult patients published in the English language reporting on transitions between FDA-approved PAH medications were extracted and tabulated. Forty-one studies met the selection criteria, nine of which included less than eight patients (and thus were reported separately in the supplement), for a total of 32 studies. Transitioning from parenteral epoprostenol to parenteral treprostinil appears to be safe and efficacious in patients who have less severe disease and more favorable hemodynamics. Transitioning from a prostacyclin analogue to an oral medication may be successful in patients who have favorable hemodynamics and stable disease. There is conflicting evidence supporting the transition from a parenteral to an inhaled prostacyclin analogue, even in patients who are on background oral therapy. Currently, the only evidence in support of transitioning between oral PDE5 inhibitors is from sildenafil to tadalafil. Patients on higher doses of sildenafil are more likely to fail. In patients with liver abnormalities due to bosentan or sitaxentan, the transition to ambrisentan appears to be safe and can result in clinical improvement. Studies regarding PAH medication transitions are limited. Patients who have less severe disease, better functional status, and are on lower medications doses may be more successful at transitioning. PMID- 28597770 TI - Pulmonary arterial hypertension: Specialists' knowledge, practices, and attitudes of genetic counseling and genetic testing in the USA. AB - Pulmonary arterial hypertension (PAH) is characterized by obstruction of pre capillary pulmonary arteries, which leads to sustained elevation of pulmonary arterial pressure. Identifying those at risk through early interventions, such as genetic testing, may mitigate disease course. Current practice guidelines recommend genetic counseling and offering genetic testing to individuals with heritable PAH, idiopathic PAH, and their family members. However, it is unclear if PAH specialists follow these recommendations. Thus, our research objective was to determine PAH specialists' knowledge, utilization, and perceptions about genetic counseling and genetic testing. A survey was designed and distributed to PAH specialists who primarily work in the USA to assess their knowledge, practices, and attitudes about the genetics of PAH. Participants' responses were analyzed using parametric and non-parametric statistics and groups were compared using the Wilcoxon rank sum test. PAH specialists had low perceived and actual knowledge of the genetics of PAH, with 13.2% perceiving themselves as knowledgeable and 27% actually being knowledgeable. Although these specialists had positive or ambivalent attitudes about genetic testing and genetic counseling, they had poor utilization of these genetic services, with almost 80% of participants never or rarely ordering genetic testing or referring their patients with PAH for genetic counseling. Physicians were more knowledgeable, but had lower perceptions of the value of genetic testing and genetic counseling compared to non-physicians ( P < 0.05). The results suggest that increased education and awareness is needed about the genetics of PAH as well as the benefits of genetic testing and genetic counseling for individuals who treat patients with PAH. PMID- 28597771 TI - First-in-child use of the oral selective prostacyclin IP receptor agonist selexipag in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. Selexipag is a selective prostacyclin receptor agonist with vasodilatory, anti proliferative, anti-inflammatory, and pro-angiogenic properties. However, no clinical data on its therapeutic use in children with PAH are currently available. Here, we report the case of a 12-year-old girl who presented in World Health Organization (WHO) functional class III and right ventricular (RV) failure with recurrent syncope, dizziness, and progressive fatigue for two years. Cardiac catheterization revealed severe precapillary PAH: mean right atrial pressure (RAP) = 10-13 mmHg, right ventricular end-diastolic pressure (RVEDP) = 13 mmHg, left ventricular end-diastolic pressure (LVEDP) = 7 mmHg, mean pulmonary arterial pressure (PAP) = 81 mmHg, and mean aorta ascendens pressure = 89 mmHg. The pulmonary vascular resistance index (PVRi) was 25.2 WU * m2. An oral combination therapy was started with a phosphodiesterase type 5 inhibitor (sildenafil 3 * 20 mg) and an endothelin-1 receptor antagonist (bosentan 2 * 62.5 mg). No significant clinical/hemodynamic improvement was seen after nine months of dual therapy, so that the patient was transferred to our institution. We agreed upon the off-label add-on use of oral selexipag. Within ten days, we up-titrated selexipag to a final (max. adult) dose of 1600 mcg twice daily. After six months, the patient had: (1) decrease in PVR index, pulmonary artery acceleration time, RAP, RVEDP, right atrial/RV size; (2) re-gain of vasoreactivity; and (3) improvement of cardiac index, 6-minute walking distance, functional class, body weight, and CAMPHOR score. Our encouraging results suggest the consideration of off-label use of oral selexipag in children with severe PAH, preferably in a protocol-driven prospective study. PMID- 28597772 TI - Right ventricular ST-elevation myocardial infarction as a cause of death in idiopathic pulmonary arterial hypertension. AB - A 32-year-old woman with advanced idiopathic pulmonary arterial hypertension (PAH), treated with oral tadalafil and intravenous epoprostenol, presented with typical angina pectoris of one day's duration. Her electrocardiogram, previously typical of pulmonary hypertension, revealed an acute ST-elevation myocardial infarction in the anterior precordial leads. She had a prior coronary angiogram, in preparation for lung transplantation, that revealed normal coronary arteries. Urgent coronary angiography showed acute occlusion of several acute marginal coronary branches that feed the right ventricle (RV). Coronary angioplasty and stenting was unable to adequately restore coronary perfusion. Despite support, she developed progressive cardiogenic shock and died three days later. This is an unusual complication of PAH. PMID- 28597773 TI - Prostacyclins have no direct inotropic effect on isolated atrial strips from the normal and pressure-overloaded human right heart. AB - Prostacyclins are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostacyclins on right heart function are still not clarified. The aim of this study was to investigate the possible direct inotropic properties of clinical available prostacyclin mimetics in the normal and the pressure-overloaded human right atrium. Trabeculae from the right atrium were collected during surgery from chronic thromboembolic pulmonary hypertension (CTEPH) patients with pressure-overloaded right hearts, undergoing pulmonary thromboendarterectomy (n = 10) and from patients with normal right hearts operated by valve replacement or coronary bypass surgery (n = 9). The trabeculae were placed in an organ bath, continuously paced at 1 Hz. They were subjected to increasing concentrations of iloprost, treprostinil, epoprostenol, or MRE-269, followed by isoprenaline to elicit a reference inotropic response. The force of contraction was measured continuously. The expression of prostanoid receptors was explored through quantitative polymerase chain reaction (qPCR). Iloprost, treprostinil, epoprostenol, or MRE-269 did not alter force of contraction in any of the trabeculae. Isoprenaline showed a direct inotropic response in both trabeculae from the pressure-overloaded right atrium and from the normal right atrium. Control experiments on ventricular trabeculae from the pig failed to show an inotropic response to the prostacyclin mimetics. qPCR demonstrated varying expression of the different prostanoid receptors in the human atrium. In conclusion, prostacyclin mimetics did not increase the force of contraction of human atrial trabeculae from the normal or the pressure-overloaded right heart. These data suggest that prostacyclin mimetics have no direct inotropic effects in the human right atrium. PMID- 28597775 TI - Dobutamine stress MRI in pulmonary hypertension: relationships between stress pulmonary artery relative area change, RV performance, and 10-year survival. AB - In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RACREST, RACSTRESS, and DeltaRAC (RAC STRESS - RAC REST) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n'vv [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n'vv on ten-year survival were determined using Kaplan-Meier analysis. PH patients with a low DeltaRAC (<-2.6%) had a worse long-term survival (log-rank P = 0.045, HR for death = 4.46 [95% CI = 1.08-24.5]) than those with DeltaRAC >= -2.6%. Given the small sample, these data should be interpreted with caution; however, low DeltaRAC was associated with an increase in stress diastolic PA area indicating proximal PA stiffening. Associations of borderline significance were observed between low RACSTRESS and low n'vvSTRESS, Deltaeta'VV, and DeltaRVEF. Further studies are required to validate the potential prognostic impact of DeltaRAC and the biomechanics potentially connecting low DeltaRAC to shorter survival. Such studies may facilitate development of novel PH therapies targeted to the proximal PA. PMID- 28597776 TI - The Pulmonary Vascular Research Institute celebrates its first decade. PMID- 28597774 TI - Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Throughout the past 20 years, numerous specific pharmacologic agents, including phosphodiesterase-5 inhibitors, endothelin receptor antagonists, prostaglandins, and more recently, soluble guanylate cyclase stimulators and selective IP prostacyclin receptor agonist, have emerged for the treatment of PAH. Early clinical trials were typically of short-term duration, comparing the effects of PAH-targeted therapies versus placebo and using exercise tolerance as the primary endpoint in most trials. A meta-analysis of these trials documented a reduction in short-term mortality of ~40% with monotherapy. More recently, we have witnessed a progressive shift in PAH study designs using longer event-driven trials comparing the effects of upfront and sequential combination therapy on clinical worsening that is perceived as a more clinically relevant outcome measure. Recent meta-analyses also documented that combination therapy significantly reduced the risk of clinical worsening by ~35% compared with monotherapy alone. In this review article, we will discuss the evolution of treatments and clinical trial design in the field of PAH over the past decades with a special focus on combination therapy and its current role in the management of PAH. We will also detail unresolved questions regarding the future of PAH patients' care and the challenges of future clinical trials. PMID- 28597777 TI - Improved metabolism and redox state with a novel preservation solution: implications for donor lungs after cardiac death (DCD). AB - Lungs donated after cardiac death (DCD) are an underutilized resource for a dwindling donor lung transplant pool. Our study investigates the potential of a novel preservation solution, Somah, to better preserve statically stored DCD lungs, for an extended time period, when compared to low-potassium dextran solution (LPD). We hypothesize that Somah is a metabolically superior organ preservation solution for hypothermic statically stored porcine DCD lungs, possibly improving lung transplant outcomes. Porcine DCD lungs (n = 3 per group) were flushed with and submerged in cold preservation solution. The lungs were stored up to 12 h, and samples were taken from lung tissue and the preservation medium throughout. Metabolomic and redox potential were analyzed using high performance liquid chromatography, mass spectrometry, and RedoxSYS(r), comparing substrate and pathway utilization in both preservation solutions. Glutathione reduction was seen in Somah but not in LPD during preservation. Carnitine, carnosine, and n-acetylcarnosine levels were elevated in the Somah medium compared with LPD throughout. Biopsies of Somah exposed lungs demonstrated similar trends after 2 h, up to 12 h. Adenosine gradually decreased in Somah medium over 12 h, but not in LPD. An inversely proportional increase in inosine was found in Somah. Higher oxidative stress levels were measured in LPD. Our study suggests suboptimal metabolic preservation in lungs stored in LPD. LPD had poor antioxidant potential, cytoprotection, and an insufficient redox potential. These findings may have immediate clinical implications for human organs; however, further investigation is needed to evaluate DCD lung preservation in Somah as a viable option for transplant. PMID- 28597779 TI - Phosphodiesterase type 5 inhibitor to riociguat transition is associated with hemodynamic and symptomatic improvement in pulmonary hypertension. AB - Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. We studied the clinical and hemodynamics effects of transitioning 12 pulmonary hypertension patients from Phosphodiesterase type 5 inhibitor (PDE5i) to riociguat, and demonstrated a significant increase in cardiac index, fall in pulmonary vascular resistance, and improvement in functional class with this switch. Switch from PDE5i to riociguat appeared to be safe and fairly well tolerated in most patients. PMID- 28597778 TI - Genomic stability of pulmonary artery endothelial colony-forming cells in culture. AB - Pulmonary vascular remodeling, including proliferation and migration of pulmonary artery endothelial cells (PAEC), is a pathologic hallmark of pulmonary arterial hypertension (PAH). Multiple studies have shown evidence of increased levels of DNA damage and lineage-specific genetic changes in PAH lung vascular cells, suggesting increased genomic instability. Highly proliferative endothelial colony forming cell (ECFC) clones can be isolated from PAEC. Here we utilized ECFC to track chromosomal copy number of 20 PAH and eight control clones across serial passages using genome-wide microarrays. All PAH clones were genomically stable for at least 20-22 population doublings. At very late passages, ECFC developed a highly aneuploid karyotype, but this was generally associated with senescence and was common to both PAH and controls. We also utilized ECFC to isolate the chromosomally abnormal cells from a mixed population of PAH PAEC. Analysis of PAEC harboring two different changes affecting chromosomes 1 and X demonstrated that both abnormalities were present in the same clone, indicating they originated in a common ancestral cell. In a second case, with a partial duplication of chromosome 17, clones carrying the duplication were more frequent at later passages than chromosomally normal clones from the same PAEC culture, suggesting the rearrangement may confer a proliferative advantage. Overall, this small study suggests that endothelial cells from PAH lungs are stable in culture, but that when chromosome abnormalities do occur, they may confer a selective advantage that allows expansion of the abnormal cell population and could contribute to lung vascular remodeling in vivo. PMID- 28597781 TI - Editorial. PMID- 28597780 TI - Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis. AB - Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. An unbiased cluster analysis was performed on 17 baseline clinical variables of PAH patients from the FREEDOM-M, FREEDOM-C, and FREEDOM-C2 randomized trials of oral treprostinil versus placebo. Participants were either treatment-naive (FREEDOM-M) or on background therapy (FREEDOM-C, FREEDOM-C2). We tested for association of clusters with outcomes and interaction with respect to treatment. Primary outcome was 6-minute walking distance (6MWD) change. We included 966 participants with 12-week (FREEDOM-M) or 16-week (FREEDOM-C and FREEDOM-C2) follow-up. Four patient clusters were identified. Compared with Clusters 1 (n = 131) and 2 (n = 496), Clusters 3 (n = 246) and 4 (n = 93) patients were older, heavier, had worse baseline functional class, 6MWD, Borg Dyspnea Index, and fewer years since PAH diagnosis. Clusters also differed by PAH etiology and background therapies, but not gender or race. Mean treatment effect of oral treprostinil differed across Clusters 1-4 increased in a monotonic fashion (Cluster 1: 10.9 m; Cluster 2: 13.0 m; Cluster 3: 25.0 m; Cluster 4: 50.9 m; interaction P value = 0.048). We identified four distinct clusters of PAH patients based on common patient characteristics. Patients who were older, diagnosed with PAH for a shorter period, and had worse baseline symptoms and exercise capacity had the greatest response to oral treprostinil treatment. PMID- 28597782 TI - Unroofed coronary sinus with cardiac veins. PMID- 28597783 TI - Reverse cardiac remodelling after lung transplantation in Eisenmenger syndrome. PMID- 28597784 TI - The impact of non-dipper circadian rhythm of blood pressure on left ventricular hypertrophy in patients with non-dialysis chronic kidney disease. AB - Objective The aim of this study was to investigate the correlation between non dipper circadian rhythm of blood pressure (BP) and left ventricular hypertrophy (LVH) in patients with chronic kidney disease (CKD). Methods and results All 257 patients with stage 1 to 5 CKD were enrolled in the study and classified into a CKD1-3 group and a CKD4-5 group according to renal function. The parameters and circadian rhythm of BP were measured by a GE Marquette Tonoport V Eng dynamic sphygmomanometer, and cardiac structure was examined by echocardiography. The incidence of abnormal circadian BP rhythm (non-dipper rhythm) was quite high (75.4% in all enrolled patients and 71.3% in the patients with normal BP levels) in CKD patients and increased with the deterioration of renal function. Changes of cardiac structure such as LVH in patients with non-dipper BP were more distinct than in patients with dipper BP. The development of left ventricular mass index (LVMI) correlated positively with the incidence of non-dipper BP rhythm. Multiple regression analysis showed that 24-h systolic BP (beta = 0.417, P < 0.01), triglycerides (TG) (beta = -0.132, P = 0.007), Hb (beta = -0.394, P = 0.016) and gender (beta = 0.158, P = 0.039) were independent risk factors of LVMI. Conclusions The incidence of non-dipper circadian rhythm of blood pressure was quite high in CKD patients and increased with the deterioration of renal function. Non-dipper circadian rhythm of BP is closely related with LVMI. PMID- 28597785 TI - Unroofed coronary sinus: multi-modality evaluation. PMID- 28597786 TI - Percutaneous tricuspid valve-in-ring implantation in a systemic sclerosis patient with pulmonary arterial -hypertension. PMID- 28597787 TI - Major depressive disorder is associated with fragmented QRS. AB - Objective There is a close link between major depressive disorder (MDD) and cardiovascular disease (CVD). Increasing oxidative stress, changes in hypothalamic-pituitary-adrenal axis and platelet clotting cascade may lead to subclinical myocardial damage in MDD patients without overt CVD. The aim of the study was to investigate whether MDD is associated with fragmented QRS (fQRS) on electrocardiogram (ECG) which may reflect myocardial fibrosis/scarring and ischaemia. Methods and results A total of 66 MDD patients without overt CVD and 35 age- and sex-matched control subjects were enrolled in this study. Twelve-lead surface ECGs were analysed for the presence of fQRS and echocardiographic examination was performed for each individual. Multivariate logistic regression analysis was used to assess the relationship between MDD and fQRS. The baseline characteristics in terms of age, gender, body mass index and cardiovascular risk factors were comparable in the groups (all P values >0.05). Left ventricular ejection fraction, left ventricular wall thickness and diastolic blood pressure were also similar in the two groups. The presence of fQRS was more prevalent (P < 0.001) and SBP values (P = 0.007) were higher in patients with MDD compared to controls. Moreover, multivariate binary logistic regression analysis indicated the recurrent MDD as the only independent predictor of fQRS on ECG (beta =0.196, 95% CI 0.046 - 0.827, P = 0.014). Conclusion The presence of fQRS on the ECG is associated with MDD, and may be a beneficial tool for detecting subclinical cardiac damage in this population. PMID- 28597788 TI - The non-fluoroscopic navigation reduces significantly not only the fluoroscopic exposure during catheter ablation of the cavotricuspid isthmus but the total radiofrequency time as well. AB - Objective The non-fluoroscopic navigation (NFN) is known to reduce the fluoroscopic time during catheter ablation of various arrhythmias. We aimed to study the impact of NFN over several procedural parameters during radiofrequency (RF) catheter ablation of the cavo-tricuspid isthmus (CTI) in patients with CTI dependent atrial flutter. Methods Data about 124 consecutive patients with CTI ablation performed were retrospectively collected. The patients were divided into two groups: (1) ablation with two diagnostic catheters deployed in the coronary sinus and around the tricuspid annulus (NFN-, n = 62); (2) ablation with the same two catheters plus NFN system using cutaneous patches (NFN+, n = 62). Several procedural parameters were analysed. The non-parametric Mann-Whitney test was used for statistical analysis. A P-value <0.05 was considered significant. Results Acute success was achieved in 122 patients (98.4%), recurrences of atrial flutter were observed in 11 patients (8.9%). There were no significant differences between the NFN + and NFN- groups in the procedural duration (169.6 vs 157.6 min) and the recurrences (6.5 vs 11.3%). In the NFN + group the fluoroscopic time was shorter (9.4 vs 16.7 min), DAP was lower (2,128.3 vs 4,129.9 MUGy*m2), the total RF time was shorter (1,870.5 vs 2,335.5 sec), R < 0.05 for all parameters. Conclusions NFN reduces significantly not only the x-ray exposure but the total RF time as well. It does not influence the procedural duration and the recurrence rate. The acute and long-term success of catheter ablation of CTI is high irrespective of the use of NFN. PMID- 28597789 TI - Reduction in electrocardiographic lateral precordial voltage after subcutaneous implantable cardioverter-defibrillator implantation. PMID- 28597790 TI - Septal thrombus following blunt cardiac injury. PMID- 28597791 TI - Value of latent outflow obstruction to predict clinical course of patients with hypertrophic cardiomyopathy. AB - Objective The frequency, significance and prognostic value of left ventricle obstruction (LVO) induced with provocation (latent LVO) is controversial for hypertrophic cardiomyopathy (HC) patients. This study was designed to assess the value of latent LVO in predicting the clinical course in 101 patients with HC. Methods and results Patients were followed for a mean of 82 +/- 48 months (range 2 to 148 months) for clinical end points defined as a composite of cardiovascular death resuscitated cardiac arrest, appropriate defibrillator shock or hospitalization due to worsening of heart failure symptoms. Presence of LVO (hazard ratio 3.63; 95% confidence interval, 1.85 to 7.12; P = 0.0001) and log NT proBNP levels (hazard ratio, 1.40; 95% confidence interval, 1.14 to 1.72; P = 0.001) were the independent variables associated with an increased risk of experiencing clinical end points. HC patients with latent LVO have a trend toward decreased survival when compared with HC patients without LVO (log rank P = 0.027), but better survival than patients with resting LVO (log rank P = 0.007). HC patients with NT-proBNP levels <1,000 pg/ml had also better survival. LVO and NT-proBNP levels are the major determinants of clinical end points in patients with HC. Conclusions Evaluation of patients without resting LVO to demonstrate latent obstruction is of critical importance in respect of outcome and selection of patients for septal reduction therapies, so routine provocative testing with physiological exercise and measurement of NT-proBNP is recommended in this patient population for risk stratification. PMID- 28597792 TI - Implications of the calcium-sensing receptor in ischemia/reperfusion. AB - The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) which was first isolated from bovine parathyroid glands. Its complex structure has been well characterized, which helped to better understand its function. The CaSR activity can be modulated by various ligands, either activators (also called "calcimimetics") or inhibitors (or "calcilytics"). The main role of the CaSR concerns Ca2+ homeostasis. In bone, intestine and kidney, the CaSR acts as a sensor for extracellular ionized Ca2+ concentration ([Ca2+]e) to keep it stable. Such a homeostatic function is well illustrated by human inherited diseases caused by mutations in CASR gene, characterized by Ca2+ balance disturbances. Interestingly, the CaSR is also expressed in numerous tissues which are not directly involved in Ca2+ regulation. There, the CaSR has been implicated in regulatory pathways, including cell proliferation, differentiation and apoptosis. Moreover, recent observations suggest that the CaSR may be involved in ischaemia/reperfusion (I/R) cascades. In cardiomyocytes, the expression and activation of the CaSR are significantly induced at the time of I/R, which induces apoptotic pathways. Likewise, the activation of the CaSR in I/R in brain, liver and kidney has been associated with increased cell death and aggravated structural and functional damage. The present review summarizes these observations and hypothesizes a novel therapeutic option targeting the CaSR in I/R. PMID- 28597793 TI - The effectiveness of CRT on improvement of survival of heart failure patients in real life clinical settings. AB - Objectives Prolongation of QRS (>= 120 ms) in patients with heart failure (HF) is associated with higher all-cause mortality than in those with narrow QRS. The aim of our study was to compare the survival of patients with HF and wide QRS after cardiac resynchronization therapy (CRT) with survival of HF patients with narrow QRS and to assess factors predictive of non-response to CRT. Methods We enrolled 680 patients with advanced HF and optimal pharmacologic therapy. All patients were assigned according to duration of QRS complex and implanted device. We acquired two groups. A first group, patients with wide QRS and implanted CRT-D (CRT-D group, n = 354) and a second group, patients having narrow QRS and implanted single/dual chamber ICD (ICD group, n = 326). The primary outcome was death from any cause. The response to CRT was defined as an increase of EF at least by 5% and/or reduction of LVEDD at least by 10%. Results The primary outcome was reached by 84 (23.7%) patients in the CRT-D group and 69 (21.2%) patients in the ICD group. We did not find a statistically significant difference in survival rate between the CRT-D and ICD group [P = 0.44; hazard ratio (HR) 1.132]. Conclusion Survival of patients with HF and wide QRS after CRT implantation is comparable to those with HF and narrow QRS. Coronary artery disease and QRS width less than 145 ms increase risk of non-response to CRT 2.2 and 2.9 times, respectively. PMID- 28597794 TI - Narrow QRS tachycardia with AV response from 2:1 to 1:1. What is the mechanism? PMID- 28597795 TI - Pseudo-aneurysm as rare complication after pacemaker implantation. PMID- 28597796 TI - A1166C polymorphism of the angiotensin II type 1 receptor gene contributes to hypertension susceptibility: evidence from a meta-analysis. AB - Background The angiotensin II type 1 receptor (AT1R) gene is a prime candidate for polymorphisms that could contribute to hypertension. A polymorphism in the 3' untranslated region, leading to the transversion of adenine to cytosine at position 1166, has been the most-studied variant. However, the results have been inconsistent, and we therefore performed a meta-analysis to evaluate the association of this polymorphism with hypertension. Methods We conducted an extended a computer-based literature search of PubMed and Web of Knowledge up to November 30, 2015. The extracted data were analysed statistically, and pooled odds ratios with 95% confidence intervals were calculated to assess the strengths of associations using Review Manager software (version 5.2). Results After removing 5 studies that were not consistent with the Hardy-Weinberg equilibrium, we finally collected 41 case-control studies involving 11,837 cases and 11,020 controls to evaluate the association between AT1R polymorphisms and hypertension. We found that the risk of hypertension was higher for allele C than for allele A under the codominant model, significantly higher for genotype CC + AC than for genotype AA under the dominant model, and significantly higher for genotype CC + AC in Caucasians. Conclusion This meta-analysis suggests that the AT1R 1166 CC + AC genotype consistently confers susceptibility to hypertension and that early preventive measures should be applied in clinical settings according to patient genotypes. PMID- 28597797 TI - Percutaneous intervention for central shunts: new routes, new strategies. AB - Introduction In traditional locations, the standard Blalock-Taussig shunt presents numerous technical difficulties for percutaneous intervention. We changed our strategy to a central type shunt (Laks-type) with end-to-side pulmonary and side-to-side aortic anastomosis. The aim of this study was to determine whether this modified strategy would allow easier percutaneous manipulation in patients with small pulmonary arteries. Methods All children with a stretchable central vascular graft who required any form of percutaneous intervention were prospectively enrolled in the study. Results Eleven infants were evaluated a median time of 3 months (range 0.9-4.4) following initial shunt placement; the median weight at intervention was 5.7 kg (range: 4.0 - 10.0). All shunts (100%) were easily and swiftly entered without the need for special catheters or co-axial systems. In four patients other interventions in distal pulmonary arteries were first performed: cutting balloon treatment in three and balloon angioplasty of peripheral pulmonary artery stenosis in one. The shunts were then augmented with a stent with a diameter increasing from 3.5 +/- 0.4 mm to 4.7 +/- 0.8 mm and saturation increasing from 76% (range: 69-88) to 84% (range: 77-88) (P < 0.05). Several months later, two children required further interventions that could easily be performed via the stented shunts. No complications were observed. Conclusions The Laks-type shunt provides easy access for percutaneous procedures of the distal pulmonary arteries including cutting balloons; this shunt can predictably be expanded to augment pulmonary flow. This study highlights how co-operation between the interventionalist and the surgeon can improve strategies to manage these difficult patients. PMID- 28597799 TI - Primary cardiac synovial sarcoma and dual-source cardiac computed tomography findings. PMID- 28597798 TI - Ultrafiltration versus intravenous loop diuretics in patients with acute decompensated heart failure: a meta-analysis of clinical trials. AB - Background Intravenous loop diuretics are the first-line therapy for acute decompensated heart failure (ADHF) but many patients are discharged with unresolved congestion resulting in higher re-hospitalization and mortality rates. Ultrafiltration (UF) is a promising intervention for ADHF. However, studies comparing UF to diuretics have been inconsistent in their clinical outcomes. Methods A comprehensive literature search was performed. Trials were included if they met the following criteria: (1) randomization with a control group, (2) comparison of UF with a loop diuretic, and (3) a diagnosis of ADHF. Results When compared to diuretics, UF was associated with a reduced risk of clinical worsening (odds ratio (OR) 0.57, 95% CI: 0.38-0.86, P-value 0.007), increased likelihood for clinical decongestion (OR 2.32, 95% CI: 1.09-4.91, P-value 0.03) with greater weight (0.97 Kg, 95% CI: 0.52-1.42, P-value <0.0001) and volume reduction (1.11 L, 95% CI: 0.68-1.54, P-value <0.0001). The overall risk of re hospitalization (OR 0.92, 95% CI: 0.62-1.38, P-value 0.70), return to emergency department (OR 0.69, 95% CI: 0.44-1.08, P-value 0.10) and mortality (OR 0.99, 95% CI: 0.60-1.62, P-value 0.97) were not significantly improved by UF treatment. Conclusions UF is associated with significant improvements in clinical decongestion but not in rates of re-hospitalization or mortality. PMID- 28597800 TI - Effect of dobutamine stress echocardiography on serum heart fatty acid binding protein levels. AB - Objective Heart fatty acid binding protein (HFABP) is a low-molecular-weight free protein that is abundant in the intracytoplasmic space of myocytes. Due to its unique features, serum HFABP levels may increase in myocardial ischaemia. The aim of this study was to evaluate the effect of myocardial ischaemia induced by dobutamine stress echocardiography (DSE) on serum HFABP levels. Methods and results A total of 30 consecutive patients with suspected myocardial ischaemia underwent DSE examination. HFABP levels were measured immediately before and 1 hour after DSE. HFABP rose significantly in individuals in the DSE positive group (1.66 +/- 1.18 ng/ml vs 2.65 +/- 1.34 ng/ml, P = 0.004), but remained unchanged in the DSE negative group (1.61 +/- 0.77 ng/ml vs 1.85 +/- 0.76 ng/ml, P = 0.066). Conclusion Serum HFABP levels increased significantly at 1 hour in the presence of ischaemia induced by DSE in patients with stable clinical coronary syndromes. No such increase was evident in the absence of ischaemia. PMID- 28597802 TI - Very late stent thrombosis and longitudinal stent deformation. PMID- 28597801 TI - Subtraction coronary CT angiography clarifies in-stent restenosis of a three layer stent segment. PMID- 28597803 TI - Prognostic value of galectin-3 on admission in Chinese patients with heart failure: a prospective observational study. AB - Objective We performed a prospective observational study to explore the prognostic value of plasma galectin-3, a biomarker for fibrosis and inflammation, in Chinese patients with heart failure (HF). Methods and results Galectin-3, N terminal pro B-type natriuretic peptide (NT-proBNP) and other clinically related variables were measured in consecutive HF patients in Beijing Hospital. Specifically, galectin-3 was detected by an enzyme-linked immunosorbent assay. The primary end point was major adverse cardiac events (MACE), including all cause mortality or readmission at the end of follow-up. The secondary end point was all-cause mortality. The adjusted hazard ratio (HR) was determined by COX regression model. In total, 272 patients were included in this study with a median age of 77 years, of whom 55.9% were male. During a median follow-up of 584 (415-813) days, 53 patients (19.5%) died and 103 patients (37.9%) died and/or required readmission. Plasma galectin-3 levels by tertiles were associated with an increased risk for the primary end point (P < 0.001). Kaplan-Meier survival curves showed that the third tertile of galectin-3 was associated with an increased rate of MACE, compared with the first and second tertiles, with the log rank P < 0.001 and P = 0.001, respectively. In addition, the multivariate COX regression model showed that the highest tertile of galectin-3 was associated with an increased risk for MACE (HR =2.13, 95% confidence interval: 1.24-3.68, P = 0.006), compared with the lowest tertile after adjustment for age, NT-proBNP, creatinine, uric acid, albumin, haemoglobin, and estimated glomerular filtration rate (eGFR). Conclusion Plasma galectin-3 is an independent predictor of all cause mortality and/or readmission in Chinese patients with HF. PMID- 28597804 TI - Effect of biodegradable polymer drug-eluting stents versus biocompatible polymer everolimus-eluting stents: a meta-analysis. AB - OBJECTIVE: Biocompatible polymer everolimus-eluting stents (EES) are associated with risk of stent thrombosis (ST); biodegradable polymer drug-eluting stents (BP DES) were designed to reduce these risks. However, the long-term benefits are not completely clear. METHOD: We undertook a meta-analysis of randomized studies identified in systematic searches of MEDLINE, EMBASE, and the Cochrane Database. Primary outcome was the risk of ST. RESULTS: Twelve studies (11,692 patients) were included. Overall, compared with EES, BP-DES were associated with a broadly equivalent risk of definite and probable ST (OR, 0.91; 95% CI, 0.55 to 1.50; P = 0.71; I2 = 0.0%), early ST (OR, 2.25; 95% CI, 0.78 to 6.47; P = 0.13; I2 = 0.0%), late ST (OR, 3.57; 95% CI, 0.42 to 30.58; P = 0.25; I2 = 0.0%) and very late ST (OR, 0.50; 95% CI, 0.05 to 5.52; P = 0.57). Meanwhile, there was no significant difference in all-cause mortality (OR, 1.07; 95% CI, 0.86 to 1.32; P = 0.54; I2 = 0.0%), myocardial infarction (OR, 1.07; 95% CI, 0.88 to 1.30; P = 0.47; I2 = 0.0%), target vessel revascularization (OR, 1.02; 95% CI, 0.86 to 1.21; P = 0.80; I2 = 12.0%), and major adverse cardiac events (OR, 1.04; 95% CI, 0.93 to 1.16; P = 0.53; I2 = 0.0%). Furthermore, angiographic data showed that in-stent and in segment late luminal loss were similar between the two groups. CONCLUSIONS: Compared with biocompatible polymer EES, biodegradable polymer stents appear to have equivalent clinical benefits. PMID- 28597805 TI - Efficacy of sequential three-step empirical therapy for chronic cough. AB - BACKGROUND: Empirical three-step therapy has been proved in just one hospital. This study aimed to demonstrate applicability of the sequential empirical three step therapy for chronic cough in different clinical settings. METHODS: Sequential empirical three-step therapy was given to patients with chronic cough in one tertiary and three secondary care respiratory clinics. Recruiters were initially treated with methoxyphenamine compound as the first-step therapy, followed by corticosteroids as the second-step therapy and the combination of a proton-pump inhibitor and a prokinetic agent as the third-step therapy. The efficacy of the therapy was verified according to the changes in cough symptom score between pre- and post-treatment, and compared among the different clinics. RESULTS: In total 155 patients in one tertiary clinic and 193 patients in secondary care clinics were recruited. The total dropout ratio is significantly higher in the secondary care clinics than that in the tertiary clinic (9.3% versus 3.2%, p = 0.023). The therapeutic success rate for cough was 38.7% at first-step therapy, 32.3% at second-step therapy and 20.0% at third-step therapy in the tertiary clinic, and comparable to corresponding 49.7%, 31.1% and 4.1% in secondary care clinics. Furthermore, the overall cough resolution rate was not significantly different (91.0% versus 85.0%, p = 0.091). However, the efficacy of the third-step therapy is much higher (20.0% versus 4.1%, p = 0.001) in the tertiary clinic than in the secondary care clinics. CONCLUSIONS: Sequential empirical three-step therapy is universally efficacious and useful for management of chronic cough in different clinical settings. PMID- 28597806 TI - Sinonasal organised haematoma: clinical features and successful application of modified transnasal endoscopic medial maxillectomy. AB - OBJECTIVE: Although organised haematoma often induces bone thinning and destruction similar to malignant diseases, the aetiology of organised haematoma and the optimal treatment remain unclear. This paper presents the clinical features of individuals with organised haematoma, and describes cases in which a novel modified approach was successfully applied for resection of organised haematoma in the maxillary sinus. METHOD: Pre-operative examination data were evaluated retrospectively. Modified transnasal endoscopic medial maxillectomy was employed. RESULTS: Fourteen patients with organised haematoma were treated. Contrast-enhanced computed tomography showed heterogeneous enhancement in all patients. Eight patients underwent modified transnasal endoscopic medial maxillectomy, without complications such as facial numbness, tooth numbness, facial tingling, lacrimation and eye discharge. Dissection of the apertura piriformis and anterior maxillary wall was not necessary for any of these eight patients. No recurrence was observed. CONCLUSION: Pre-operative examinations can be helpful in determining the likelihood of organised haematoma. Modified transnasal endoscopic medial maxillectomy appears to be a safe and effective method for organised haematoma resection. PMID- 28597808 TI - Activation delay-induced mechanical dyssynchrony in single-ventricle heart disease. AB - We present the case of an infant with a single functional ventricle who developed ventricular dysfunction and heart failure due to an electrical activation delay and dyssynchrony. Earlier recognition of this potentially reversible aetiology may have changed her poor outcome. PMID- 28597807 TI - Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases. PMID- 28597809 TI - Discontinuation of contact precautions with the introduction of universal daily chlorhexidine bathing. AB - Contact precautions are a traditional strategy to prevent transmission of methicillin-resistant Staphylococcus aureus (MRSA). Chlorhexidine bathing is increasingly used to decrease MRSA burden and transmission in intensive care units (ICUs). We sought to evaluate a hospital policy change from routine contact precautions for MRSA compared with universal chlorhexidine bathing, without contact precautions. We measured new MRSA acquisition in ICU patients and surveyed for MRSA environmental contamination in common areas and non-MRSA patient rooms before and after the policy change. During the baseline and chlorhexidine bathing periods, the number of patients (453 vs. 417), ICU days (1999 vs. 1703) and MRSA days/1000 ICU days (109 vs. 102) were similar. MRSA acquisition (2/453 vs. 2/457, P = 0.93) and environmental MRSA contamination (9/474 vs. 7/500, P = 0.53) were not significantly different between time periods. There were 58% fewer contact precaution days in the ICU during the chlorhexidine period (241/1993 vs. 102/1730, P < 0.01). We found no evidence that discontinuation of contact precautions for patients with MRSA in conjunction with adoption of daily chlorhexidine bathing in ICUs is associated with increased MRSA acquisition among ICU patients or increased MRSA contamination of ICU fomites. Although underpowered, our findings suggest this strategy, which has the potential to reduce costs and improve patient safety, should be assessed in similar but larger studies. PMID- 28597810 TI - Fungi as a Source of Food. AB - In this article, we review some of the best-studied fungi used as food sources, in particular, the cheese fungi, the truffles, and the fungi used for drink fermentation such as beer, wine, and sake. We discuss their history of consumption by humans and the genomic mechanisms of adaptation during artificial selection. PMID- 28597812 TI - Microbial Impact on Host Metabolism: Opportunities for Novel Treatments of Nutritional Disorders? AB - Malnutrition is the cause of major public health concerns worldwide. On the one hand, obesity and associated pathologies (also known as the metabolic syndrome) affect more than 10% of the world population. Such pathologies might arise from an elevated inflammatory tone. We have discovered that the inflammatory properties of high-fat diets were linked to the translocation of lipopolysaccharide (LPS). We proposed a mechanism associating the gut microbiota with the onset of insulin resistance and low-grade inflammation, a phenomenon that we called "metabolic endotoxemia." We and others have shown that bacteria as well as host-derived immune-related elements control microbial communities and eventually contribute to the phenotype observed during diet-induced obesity, diabetes, and metabolic inflammation. On the other hand, undernutrition is one of the leading causes of death in children. A diet poor in energy and/or nutrients causes incomplete development of the gut microbiota and may profoundly affect energy absorption, initiating stunted growth, edema, and diarrhea. In this review, we discuss how changes in microbiota composition are associated with obesity and undernutrition. We also highlight that opposite consequences exist in terms of energy absorption from the diet (obesity versus undernutrition), but interestingly the two situations share similar defects in term of diversity, functionality, and inflammatory potential. PMID- 28597813 TI - Therapeutic Opportunities in the Vaginal Microbiome. AB - The reproductive tract of females lies at the core of humanity. The immensely complex process that leads to successful reproduction is miraculous yet invariably successful. Microorganisms have always been a cause for concern for their ability to infect this region, yet it is other, nonpathogenic microbial constituents now uncovered by sequencing technologies that offer hope for improving health. The universality of Lactobacillus species being associated with health is the basis for therapeutic opportunities, including through engineered strains. The manipulation of these and other beneficial constituents of the microbiota and their functionality, as well as their metabolites, forms the basis for new diagnostics and interventions. Within 20 years, we should see significant improvements in how cervicovaginal health is restored and maintained, thus providing relief to the countless women who suffer from microbiota-associated disorders. PMID- 28597811 TI - Mycobacterium tuberculosis in the Face of Host-Imposed Nutrient Limitation. AB - Coevolution of pathogens and host has led to many metabolic strategies employed by intracellular pathogens to deal with the immune response and the scarcity of food during infection. Simply put, bacterial pathogens are just looking for food. As a consequence, the host has developed strategies to limit nutrients for the bacterium by containment of the intruder in a pathogen-containing vacuole and/or by actively depleting nutrients from the intracellular space, a process called nutritional immunity. Since metabolism is a prerequisite for virulence, such pathways could potentially be good targets for antimicrobial therapies. In this chapter, we review the current knowledge about the in vivo diet of Mycobacterium tuberculosis, with a focus on amino acid and cofactors, discuss evidence for the bacilli's nutritionally independent lifestyle in the host, and evaluate strategies for new chemotherapeutic interventions. PMID- 28597814 TI - Killing Mycobacterium tuberculosis In Vitro: What Model Systems Can Teach Us. AB - Tuberculosis is one of the most successful human diseases in our history due in large part to the multitude of virulence factors exhibited by the causative agent, Mycobacterium tuberculosis. Understanding the pathogenic nuances of this organism in the context of its human host is an ongoing topic of study facilitated by isolating cells from model organisms such as mice and non-human primates. However, M. tuberculosis is an obligate intracellular human pathogen, and disease progression and outcome in these model systems can differ from that of human disease. Current in vitro models of infection include primary macrophages and macrophage-like immortalized cell lines as well as the induced pluripotent stem cell-derived cell types. This article will discuss these in vitro model systems in general, what we have learned so far about utilizing them to answer questions about pathogenesis, the potential role of other cell types in innate control of M. tuberculosis infection, and the development of new coculture systems with multiple cell types. As we continue to expand current in vitro systems and institute new ones, the knowledge gained will improve our understanding of not only tuberculosis but all infectious diseases. PMID- 28597816 TI - Sex and the Imperfect Fungi. AB - Approximately 20% of species in the fungal kingdom are only known to reproduce by asexual means despite the many supposed advantages of sexual reproduction. However, in recent years, sexual cycles have been induced in a series of emblematic "asexual" species. We describe how these discoveries were made, building on observations of evidence for sexual potential or "cryptic sexuality" from population genetic analyses; the presence, distribution, and functionality of mating-type genes; genome analyses revealing the presence of genes linked to sexuality; the functionality of sex-related genes; and formation of sex-related developmental structures. We then describe specific studies that led to the discovery of mating and sex in certain Candida, Aspergillus, Penicillium, and Trichoderma species and discuss the implications of sex including the beneficial exploitation of the sexual cycle. We next consider whether there might be any truly asexual fungal species. We suggest that, although rare, imperfect fungi may genuinely be present in nature and that certain human activities, combined with the genetic flexibility that is a hallmark of the fungal kingdom, might favor the evolution of asexuality under certain conditions. Finally, we argue that fungal species should not be thought of as simply asexual or sexual, but rather as being composed of isolates on a continuum of sexual fertility. PMID- 28597815 TI - DksA-HapR-RpoS axis regulates haemagglutinin protease production in Vibrio cholerae. AB - DksA acts as a co-factor for the intracellular small signalling molecule ppGpp during the stringent response. We recently reported that the expression of the haemagglutinin protease (HAP), which is needed for shedding of the cholera pathogen Vibrio cholerae during the late phase of infection, is significantly downregulated in V. cholerae ?dksA mutant (?dksAVc) cells. So far, it has been shown that HAP production by V. cholerae cells is critically regulated by HapR and also by RpoS. Here, we provide evidence that V. cholerae DksA (DksAVc) positively regulates HapR at both the transcriptional and post-transcriptional levels. We show that in ?dksAVc cells the CsrB/C/D sRNAs, required for the maintenance of intracellular levels of hapR transcripts during the stationary growth, are distinctly downregulated. Moreover, the expression of exponential phase regulatory protein Fis, a known negative regulator of HapR, was found to continue even during the stationary phase in ?dksAVc cells compared to that of wild-type strain, suggesting another layer of complex regulation of HapR by DksAVc. Extensive reporter construct-based and quantitative reverse-transcriptase PCR (qRT-PCR) analyses supported that RpoS is distinctly downregulated at the post-transcriptional/translational levels in stationary phase-grown ?dksAVc cells. Since HAP expression through HapR and RpoS is stationary phase-specific in V. cholerae, it appears that DksAVc is also a critical stationary phase regulator for fine tuning of the expression of HAP. Moreover, experimental evidence provided in this study clearly supports that DksAVc is sitting at the top of the hierarchy of regulation of expression of HAP in V. cholerae. PMID- 28597817 TI - Decreased pro-inflammatory immune responses during recurrent acute HCV infections in HIV co-infected patients. AB - Patients in high-risk groups continue to transmit the hepatitis C virus (HCV) and frequently experience reinfections. Since little is known regarding the immune response to HCV during reinfection, we compared primary and consecutive acute HCV infections in patients with an HIV infection, and focused on the cytokine bridging innate to adaptive immunity. We observed that the serum levels of IL 12p40, MIP-1beta, MIG and IP-10 increased during primary acute HCV infection, but not during subsequent secondary acute reinfections. The weaker pro-inflammatory cytokine responses observed during HCV reinfections suggest more limited secondary acute immune responses, which may prevent damage to the infected liver. PMID- 28597818 TI - Enhanced pathogenicity and neurotropism of mouse-adapted H10N7 influenza virus are mediated by novel PB2 and NA mutations. AB - The H10 subtype of avian influenza viruses (AIVs) circulates globally in wild birds and poultry, and this subtype has been shown to be increasingly prevalent in China. Among the various H10 viruses, H10N7 AIVs have caused repeated mammal and human infections. To investigate their genetic adaptation in mammals, we generated a mouse-adapted avian H10N7 variant (A/mallard/Beijing/27/2011-MA; BJ27 MA) which exhibited increased virulence in mice compared to wild-type virus and acquired neurotropism. Sequencing showed the absence of the widely recognized mammalian adaptation markers of E627K and D701N in PB2 in the mouse-adapted strain; instead, five amino acid mutations were identified: E158G and M631L in PB2; G218E in haemagglutinin (H3 numbering); and K110E and S453I in neuraminidase (NA). The neurovirulence of the BJ27-MA virus necessitated the combined presence of the PB2 and NA mutations. Mutations M631L and E158G of PB2 and K110E of NA were required to mediate increased virus replication and severity of infection in mice and mammalian cells. PB2-M631L was functionally the most dominant mutation in that it strongly upregulated viral polymerase activity and played a critical role in the enhancement of virus replication and disease severity in mice. K110E mutation in NA, on the other hand, significantly promoted NA enzymatic activity. These results indicate that the novel mutations in PB2 and NA genes are critical for the adaptation of H10N7 AIV in mice, and they could serve as molecular signatures of virus transmission to mammalian hosts, including humans. PMID- 28597819 TI - Phage exposure causes dynamic shifts in the expression states of specific phase variable genes of Campylobacter jejuni. AB - Phase variation (PV) creates phenotypic heterogeneity at high frequencies and in a reversible manner. This phenomenon allows bacteria to adapt to a variety of different environments and selective pressures. In Campylobacterjejuni this reversible adaptive process is mediated by mutations in homopolymeric G/C tracts. Many C. jejuni-specific phages are dependent on phase-variable surface structures for successful infection. We previously identified the capsular polysaccharide (CPS) moiety, MeOPN-GalfNAc, as a receptor for phage F336 and showed that phase variable expression of the transferase for this CPS modification, cj1421, and two other phase-variable CPS genes generated phage resistance in C. jejuni. Here we investigate the population dynamics of C. jejuni NCTC11168 when exposed to phage F336 in vitro using a newly described method - the 28-locus-CJ11168 PV analysis. Dynamic switching was observed in the ON/OFF states of three phase-variable CPS genes, cj1421, cj1422 and cj1426, during phage F336 exposure, with the dominant phage-resistant phasotype differing between cultures. Although loss of the phage receptor was predominately observed, several other PV events also led to phage resistance, a phenomenon that increases the chance of phage-resistant subpopulations being present in any growing culture. No other PV genes were affected and exposure to phage F336 resulted in a highly specific response, only selecting for phase variants of cj1421, cj1422 and cj1426. In summary, C. jejuni may benefit from modification of the surface in multiple ways to inhibit or reduce phage binding, thereby ensuring the survival of the population when exposed to phages. PMID- 28597821 TI - The Mycobiome: Impact on Health and Disease States. AB - The term "microbiome" refers to microorganisms (microbiota) and their genomes (metagenome) coexisting with their hosts. Some researchers coined the term "second genome" to underscore the importance of the microbiota and its collective metagenome on their host's health and/or disease. It is now undeniable that the commensal fungal microorganisms, alongside the other components of the microbiota, play a central role in association with the human host. In recognition, projects were launched nationally and internationally to unify efforts to characterize the microbiome and elucidate the functional role of the microbiota and the mechanism(s) by which these organisms and their metabolites (metabolome) may affect health and disease states. In this article, we will highlight the role of the fungal community as an indispensable component of the microbiome. PMID- 28597822 TI - Fungi that Infect Humans. AB - Fungi must meet four criteria to infect humans: growth at human body temperatures, circumvention or penetration of surface barriers, lysis and absorption of tissue, and resistance to immune defenses, including elevated body temperatures. Morphogenesis between small round, detachable cells and long, connected cells is the mechanism by which fungi solve problems of locomotion around or through host barriers. Secretion of lytic enzymes, and uptake systems for the released nutrients, are necessary if a fungus is to nutritionally utilize human tissue. Last, the potent human immune system evolved in the interaction with potential fungal pathogens, so few fungi meet all four conditions for a healthy human host. Paradoxically, the advances of modern medicine have made millions of people newly susceptible to fungal infections by disrupting immune defenses. This article explores how different members of four fungal phyla use different strategies to fulfill the four criteria to infect humans: the Entomophthorales, the Mucorales, the Ascomycota, and the Basidiomycota. Unique traits confer human pathogenic potential on various important members of these phyla: pathogenic Onygenales comprising thermal dimorphs such as Histoplasma and Coccidioides; the Cryptococcus spp. that infect immunocompromised as well as healthy humans; and important pathogens of immunocompromised patients-Candida, Pneumocystis, and Aspergillus spp. Also discussed are agents of neglected tropical diseases important in global health such as mycetoma and paracoccidiomycosis and common pathogens rarely implicated in serious illness such as dermatophytes. Commensalism is considered, as well as parasitism, in shaping genomes and physiological systems of hosts and fungi during evolution. PMID- 28597823 TI - Made for Each Other: Ascomycete Yeasts and Insects. AB - Fungi and insects live together in the same habitats, and many species of both groups rely on each other for success. Insects, the most successful animals on Earth, cannot produce sterols, essential vitamins, and many enzymes; fungi, often yeast-like in growth form, make up for these deficits. Fungi, however, require constantly replenished substrates because they consume the previous ones, and insects, sometimes lured by volatile fungal compounds, carry fungi directly to a similar, but fresh, habitat. Yeasts associated with insects include Ascomycota (Saccharomycotina, Pezizomycotina) and a few Basidiomycota. Beetles, homopterans, and flies are important associates of fungi, and in turn the insects carry yeasts in pits, specialized external pouches, and modified gut pockets. Some yeasts undergo sexual reproduction within the insect gut, where the genetic diversity of the population is increased, while others, well suited to their stable environment, may never mate. The range of interactions extends from dispersal of yeasts on the surface of insects (e.g., cactus-Drosophila-yeast and ephemeral flower communities, ambrosia beetles, yeasts with holdfasts) to extremely specialized associations of organisms that can no longer exist independently, as in the case of yeast-like symbionts of planthoppers. In a few cases yeast-like fungus-insect associations threaten butterflies and other species with extinction. Technical advances improve discovery and identification of the fungi but also inform our understanding of the evolution of yeast-insect symbioses, although there is much more to learn. PMID- 28597824 TI - Mycobacterial Biofilms: Revisiting Tuberculosis Bacilli in Extracellular Necrotizing Lesions. AB - Under detergent-free in vitro conditions, Mycobacterium tuberculosis, the etiological agent of tuberculosis in humans, spontaneously forms organized multicellular structures called biofilms. Moreover, in vitro biofilms of M. tuberculosis are more persistent against antibiotics than their single-cell planktonic counterparts, thereby raising questions about the occurrence of biofilms in the host tissues and their significance in persistence during chemotherapy of tuberculosis. In this article, we present arguments that extracellular M. tuberculosis in necrotizing lesions likely grows as biofilms. PMID- 28597820 TI - Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions. AB - The emergence and spread of drug-resistant pathogens, and our inability to develop new antimicrobials to combat resistance, have inspired scientists to seek out new targets for drug development. The Mycobacterium tuberculosis complex is a group of obligately aerobic bacteria that have specialized for inhabiting a wide range of intracellular and extracellular environments. Two fundamental features in this adaptation are the flexible utilization of energy sources and continued metabolism in the absence of growth. M. tuberculosis is an obligately aerobic heterotroph that depends on oxidative phosphorylation for growth and survival. However, several studies are redefining the metabolic breadth of the genus. Alternative electron donors and acceptors may provide the maintenance energy for the pathogen to maintain viability in hypoxic, nonreplicating states relevant to latent infection. This hidden metabolic flexibility may ultimately decrease the efficacy of drugs targeted against primary dehydrogenases and terminal oxidases. However, it may also open up opportunities to develop novel antimycobacterials targeting persister cells. In this review, we discuss the progress in understanding the role of energetic targets in mycobacterial physiology and pathogenesis and the opportunities for drug discovery. PMID- 28597826 TI - Pathology of Tuberculosis: How the Pathology of Human Tuberculosis Informs and Directs Animal Models. AB - Tuberculosis (TB) is a chronic inflammatory disease caused by the pathogenic bacterium Mycobacterium tuberculosis. A wide variety of host- and pathogen associated variables influence the clinical manifestation of TB in different individuals within the human population. As a consequence, the characteristic granulomatous lesions that develop within the lung are heterogeneous in size and cellular composition. Due to the lack of appropriate tissues from human TB patients, a variety of animal models are used as surrogates to study the basic pathogenesis and to test experimental vaccines and new drug therapies. Few animal models mimic the clinical course and pathological response of M. tuberculosis seen in the naturally occurring disease in people. In particular, post-primary TB, which accounts for the majority of cases of active TB and is responsible for transmission between individuals via aerosol exposers, cannot be reproduced in animals and therefore cannot be adequately modeled experimentally. This article describes a new paradigm that explains the pathogenesis of post-primary TB in humans. This new evidence was derived from histological examination of tissues from patients with different stages of M. tuberculosis infection and that had not been treated with antimicrobial drugs. Gaining a better understanding of this unique stage of TB disease will lead to more effective treatment, diagnostic, and prevention strategies. PMID- 28597828 TI - 3D Hepatic Ultrasonography-A Detailed Imaging Modality. PMID- 28597825 TI - Fungal Sex: The Basidiomycota. AB - Fungi of the Basidiomycota, representing major pathogen lineages and mushroom forming species, exhibit diverse means to achieve sexual reproduction, with particularly varied mechanisms to determine compatibilities of haploid mating partners. For species that require mating between distinct genotypes, discrimination is usually based on both the reciprocal exchange of diffusible mating pheromones, rather than sexes, and the interactions of homeodomain protein signals after cell fusion. Both compatibility factors must be heterozygous in the product of mating, and genetic linkage relationships of the mating pheromone/receptor and homeodomain genes largely determine the complex patterns of mating-type variation. Independent segregation of the two compatibility factors can create four haploid mating genotypes from meiosis, referred to as tetrapolarity. This condition is thought to be ancestral to the basidiomycetes. Alternatively, cosegregation by linkage of the two mating factors, or in some cases the absence of the pheromone-based discrimination, yields only two mating types from meiosis, referred to as bipolarity. Several species are now known to have large and highly rearranged chromosomal regions linked to mating-type genes. At the population level, polymorphism of the mating-type genes is an exceptional aspect of some basidiomycete fungi, where selection under outcrossing for rare, intercompatible allelic variants is thought to be responsible for numbers of mating types that may reach several thousand. Advances in genome sequencing and assembly are yielding new insights by comparative approaches among and within basidiomycete species, with the promise to resolve the evolutionary origins and dynamics of mating compatibility genetics in this major eukaryotic lineage. PMID- 28597827 TI - Inflammatory Bowel Disease in Childhood and Adolescence. AB - BACKGROUND: The incidence of inflammatory bowel disease (IBD) in childhood and adolescence is 5-11 cases per 100 000 persons per year, corresponding to a new diagnosis of IBD in 800-1470 patients in Germany each year. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, including guidelines from Germany and abroad. RESULTS: Children and adolescents with IBD often have extensive involvement and an aggressive course of disease. Nonetheless, infliximab and adalimumab are the only biological agents that have been approved for this group of patients. In Crohn's disease, exclusive enteral nutrition is the treatment of first choice for inducing a remission. Patients with (peri-)anal fistulae are treated primarily with infliximab. Corticosteroids and aminosalicylates should be used with caution. In contrast, children and adolescents with ulcerative colitis are treated with either aminosalicylates or prednisolone to induce a remission. As a rule, maintenance pharmacotherapy with thiopurines in Crohn's disease and severe ulcerative colitis, or with aminosalicylates in mild to moderate ulcerative colitis, is indicated for several years, at least until the end of puberty. Patients with refractory disease courses are treated with methylprednisolone, anti-TNF-alpha-antibodies, and/or calcineurin inhibitors. The spectrum of surgical interventions is the same as for adults. Specific aspects of the treatment of children and adolescents with IBD include adverse drug effects, the areas of nutrition, growth, and development, and the structured transition to adult medicine. CONCLUSION: Children and adolescents with IBD or suspected IBD should be cared for by pediatric gastroenterologists in a center where such care is provided. Individualized treatment with multidisciplinary, family-oriented longterm care is particularly important. Drug trials in children and adolescents are needed so that the off label use of drugs to patients in this age group can be reduced. PMID- 28597830 TI - Response to a wild poliovirus type 2 (WPV2)-shedding event following accidental exposure to WPV2, the Netherlands, April 2017. AB - On 3 April 2017, a wild poliovirus type 2 (WPV2) spill occurred in a Dutch vaccine manufacturing plant. Two fully vaccinated operators with risk of exposure were advised on stringent personal hygiene and were monitored for virus shedding. Poliovirus (WPV2-MEF1) was detected in the stool of one, 4 days after exposure, later also in sewage samples. The operator was isolated at home and followed up until shedding stopped 29 days after exposure. No further transmission was detected. PMID- 28597829 TI - Urogenital Infection as a Risk Factor for Male Infertility. AB - BACKGROUND: Infections of the genital tract are considered common causes of male fertility disorders, with a prevalence of 6-10%. Most of the affected men are asymptomatic. The diagnostic evaluation is based mainly on laboratory testing. Inconsistent diagnostic criteria have been applied to date, and this may explain the controversial debate about the role of infection and inflammation in the genital tract as a cause of infertility. The risk of an irreversible fertility disorder should not be underestimated. METHODS: This review is based on pertinent publications retrieved by a selective literature search in PubMed, including guidelines from Germany and abroad and systematic review articles. RESULTS: The main causes of inflammatory disease of the male genital tract are ascending sexually transmitted infections (STIs) and uropathogens. Chronic prostatitis has no more than a limited influence on ejaculate variables. By contrast, approximately 10% of men who have had acute epididymitis develop persistent azoospermia thereafter, and 30% have oligozoospermia. Obstruction of the excurrent ducts can ensue, as can post-infectious disturbances of spermatogenesis. The differential diagnostic evaluation includes the determination of testicular volumes, hormone concentrations, and ejaculate variables. Epidemiological data are lacking with regard to infertility after primary orchitis of infectious origin; however, up to 25% of testicular biopsies obtained from infertile men reveal focal inflammatory reactions. Multiple studies have suggested a deleterious effect of leukocytes and inflammatory mediators on sperm para - meters. On the other hand, the clinical significance of bacteriospermia remains unclear. CONCLUSION: Any suspicion of an infectious or inflammatory disease in the male genital tract should prompt a systematic diagnostic evaluation and appropriate treatment. For patients with obstructive azoospermia, the etiology and site of the obstruction determine the surgical approach to be taken. In the near future, the elucidation of underlying pathophysiological mechanisms and the identification of suitable biomarkers may enable new strategies for conservative treatment. PMID- 28597833 TI - ? PMID- 28597831 TI - Ongoing haemolytic uraemic syndrome (HUS) outbreak caused by sorbitol-fermenting (SF) Shiga toxin-producing Escherichia coli (STEC) O157, Germany, December 2016 to May 2017. AB - We report an ongoing, protracted and geographically dispersed outbreak of haemolytic uraemic syndrome (HUS) and gastroenteritis in Germany, involving 30 cases since December 2016. The outbreak was caused by the sorbitol-fermenting immotile variant of Shiga toxin-producing (STEC) Escherichia coli O157. Molecular typing revealed close relatedness between isolates from 14 cases. One HUS patient died. Results of a case-control study suggest packaged minced meat as the most likely food vehicle. Food safety investigations are ongoing. PMID- 28597832 TI - Development and validation of the HCV-MOSAIC risk score to assist testing for acute hepatitis C virus (HCV) infection in HIV-infected men who have sex with men (MSM). AB - Current guidelines recommend hepatitis C virus (HCV) testing for HIV-infected men who have sex with men (MSM) with ongoing risk behaviour, without specifying the type of risk behaviour. We developed and validated the HCV-MOSAIC risk score to assist HCV testing in HIV-infected MSM. The risk score consisted of six self reported risk factors identified using multivariable logistic regression using data from the Dutch MOSAIC study (n = 213, 2009-2013). Area under the ROC curve (AUC), sensitivity, specificity, post-test-probability-of-disease and diagnostic gain were calculated. The risk score was validated in case-control studies from Belgium (n = 142, 2010-2013) and the United Kingdom (n = 190, 2003-2005) and in cross-sectional surveys at a Dutch sexually transmitted infections clinic (n = 284, 2007-2009). The AUC was 0.82; sensitivity 78.0% and specificity 78.6%. In the validation studies sensitivity ranged from 73.1% to 100% and specificity from 56.2% to 65.6%. The post-test-probability-of-disease ranged from 5.9% to 20.0% given acute HCV prevalence of 1.7% to 6.4%, yielding a diagnostic gain of 4.2% to 13.6%. The HCV-MOSAIC risk score can successfully identify HIV-infected MSM at risk for acute HCV infection. It could be a promising tool to improve HCV testing strategies in various settings. PMID- 28597835 TI - [Optimization of the final lingual occlusion: an analysis]. AB - INTRODUCTION: The objectives of orthodontic treatment are to achieve a functional, aesthetic and sustainable occlusion. However, its analysis is often limited to the study of its buccal side, easy to check in mouth. Yet, the lingual occlusion is also of paramount importance. MATERIAL AND METHOD: After calling to mind the ideal static objectives of treatment, described by some authors and defined by some scientific societies, this article studies the different supports for the analysis of lingual static occlusion and proposes a new protocol for the carving of orthodontic casts. RESULTS: The lingual occlusion end-of-treatment objectives lack details, whether by the scientific societies or literature, although we possess simple ways to study them. DISCUSSION: The lingual part of occlusion is rarely studied in our daily practice, particularly because its analysis cannot be achieved by a direct intraoral examination. However, it is of major importance in the success and stability of our treatments. PMID- 28597834 TI - [Magnetic resonance imaging artefacts and fixed orthodontic attachments]. AB - OBJECTIVES: Orthodontic appliances are often removed before magnetic resonance imaging (MRI) scans because they are known to produce artefacts. The purpose of this study was to find the exact indications for removal of various fixed attachments when imaging four specific areas of the head and neck. MATERIALS AND METHODS: Sixty patients requiring an MRI scan of the head for medical reasons volunteered for this investigation. One of four different types of fixed attachments (stainless steel brackets, titanium brackets, ceramic brackets with metal slots, and stainless steel retainers) were assigned to a patient. Each patient had two scans at 1.5 T: with an "empty wax jig" and with a wax jig including the attachment. Archwires were not investigated as they are easily removed before a scan. Two radiologists evaluated the scans of each patient and each of the four areas under investigation: maxillary sinus, oral cavity, temporomandibular joints and posterior cerebral fossa. RESULTS: Stainless steel brackets always caused non-interpretability of all anatomic areas (100 per cent). Titanium brackets, ceramic brackets with metal slots, and stainless steel retainers caused artefact in the oral cavity only (for 20, 16.65, and 86.65 per cent of the subjects). CONCLUSIONS: Our results show that ceramic brackets with metal slots and titanium brackets do not always have to be removed before MRI scans of the head and neck, depending on the area under investigation. Metal fixed retainers should only be removed if the oral cavity itself is under investigation. Stainless steel brackets should always be removed before MRI scans of the head and neck. PMID- 28597836 TI - A propos d'un cas de resorptions radiculaires severes en orthodontie : quelle etiologie et quelle prise en charge?Orthodontics and root resorptions: a clinical case. AB - INTRODUCTION: Root resorptions are, with white spots, some of the inconveniences caused by orthodontic treatments. Although they are rare, they should not be ignored despite the many benefits gained by orthodontic treatment. Contrary to white spots, which are controllable by good dental hygiene, root resorptions can occur despite patient cooperation. Orthodontists should be aware of this phenomenon and make regular radiologic controls a priority for detection "before, during and after" treatment. MATERIAL AND METHOD: After literary references, the presentation of the case report will illustrate the role of the orthodontist in the preservation and care of teeth damaged by impacted cuspids. DISCUSSION: The discussion will focus on the prevention and the interception of those phenomena, the etiologic research on these cases, on medical supervision and prognostic for damaged teeth. CONCLUSION: Before the conclusion, we will evoke the contribution of the cone-beam in the diagnosis of root resorption. PMID- 28597837 TI - [Effectiveness of selective alveolar decortication in accelerating orthodontic treatment: a systematic review]. AB - INTRODUCTION: The number of scientific publications on accelerating orthodontic treatment, and especially surgical alveolar corticotomies techniques, has grown exponentially over the years. The objective of this systematic literature review was to assess the effectiveness of these corticotomies basing on human studies. MATERIAL AND METHOD: The review was conducted from Medline and Web of Science Core Collection to identify prospective controlled clinical trials with duration of orthodontic treatment or the tooth movement rate for primary endpoint. RESULTS: Eleven studies respected all inclusion criteria. Six investigated the duration of treatment and found shorter values in experimental group than in control group, with a gain of 8 to 34 weeks. Five investigated the tooth movement rate and found 2.3 times higher values on average during the first month in experimental groups, 1.9 times during the second and third months, and 1.3 times during the fourth month. The technique also seemed to decrease the risk of root resorption and improve molar anchorage. Moreover, it exhibited good periodontal tolerance. CONCLUSION: Current literature highlights the effectiveness of surgical decortications during the first three to four months after surgery. Longer prospective studies are needed to assess their long term effects. PMID- 28597838 TI - [Collaboration between periodontics and orthodontics: interest of alveolar corticotomies and piezocision. Review of literature]. AB - INTRODUCTION: Orthodontics in adults must adapt to certain particularities especially related to the decrease or absence of growth and the prevalence of periodontal damage in this population. This review of the literature aims to assess the effects of alveolar corticotomies on accelerating or facilitating tooth movements in different types of orthodontic movements, to compare results obtained by classical technique with those obtained by piezocision and analyze their impact on periodontal tissues in the long term. MATERIAL AND METHODS: Research was performed with Medline, Embase and Cochrane databases, beginning in January 2000. Every study, selected through its title and abstract, was then evaluated through its full content. A total of 65 studies were included. RESULTS: All studies showed that corticotomies temporarily facilitate accelerated orthodontic tooth movement, with minimal complications. No periodontal lesion, loss of pulpal vitality or severe root resorption were reported. DISCUSSION: Only a few studies have examined control groups treated with conventional orthodontics. Corticotomy allows temporary acceleration of orthodontic tooth movement. Piezocision is less invasive and performed in certain indications; it also lightens the postoperative complications. However, the fact that using alveolar corticotomies significantly decreases the treatment time remains uncertain, due to the lack of significant data. Further prospective randomized clinical studies are necessary to analyze more precisely the decrease in the overall treatment time, improved periodontal support and stability of orthodontic treatment results in the long term following the alveolar corticotomies. PMID- 28597839 TI - [Timing of alveolar bone graft and sequences of canine eruption in cases of cleft lip and palate: a systematic review]. AB - INTRODUCTION: The alveolar bone graft (ABG) is an important phase in the surgical treatment of cleft lip and palate (CLP). The purpose of alveolar bone grafting is to eliminate oronasal fistulas, restore the continuity of the maxilla and provide optimal periodontal support for spontaneous eruption of permanent canines adjacent to the cleft. The purpose of this systematic review was to determine the ideal timing of the ABG that would achieve these goals. MATERIAL AND METHODS: Databases consulted were MEDLINE, Embase et EBSCOhost, using keywords present in the MeSH: [cleft lip and palate] and [alveolar bone graft] and [tooth eruption]. Selection criteria included retrospective studies, prospective studies and meta analyzes dating from January 2005, with available full text. RESULTS: Among 105 references, 9 articles met our selection criteria. ABG carried out before or just after the eruption of permanent canines adjacent to the cleft, between 8 and 12 years old, has the best success rate of the transplant (71% to 89%) and the lowest risk of canine inclusion (5% to 19%). CONCLUSION: According to literature data, the optimal timing of ABG that provide best results is located between 8 and 12 years, before or just after the eruption of permanent canines adjacent to the cleft. However, this timing could be modified by the multidisciplinary team according priorities, particularly aesthetic, defined for each child. PMID- 28597841 TI - J'ai lu pour vous. PMID- 28597840 TI - [How to treat hypoplasia of the lateral upper incisors by canine substitution : a clinical case]. AB - INTRODUCTION: Facing a patient with a morphological or numerical disorder of the lateral upper incisors (mainly pegged or missing incisor), the orthodontist has to choose between two treatment options : either spatial planning for a prosthetic restoration, or space closure with substitution of the lateral incisors by canines; the choice depends on the clinical context we are faced with. Each treatment option has its advantages and disadvantages and it is hard to tip the balance in one direction or another. MATERIAL AND METHOD: This article illustrates the rationale for therapeutic management of space closure, in a patient with skeletal class III, with hypoplastic and peg-shaped upper lateral incisors. PMID- 28597842 TI - Adjunctive lacosamide for focal epilepsy: an open-label trial evaluating the impact of flexible titration and dosing on safety and seizure outcomes. AB - To evaluate the safety and effectiveness of lacosamide in a real-life setting with the use of a flexible dose titration schedule and individualised maintenance doses up to the maximum approved dose of 400 mg/day. Adults with a diagnosis of focal seizures, with or without secondary generalization, were enrolled in this open-label Phase IV trial (NCT01235403). Lacosamide was initiated at 100 mg/day (50 mg bid) and uptitrated over a 12-week period to 200, 300 or 400 mg/day, based on safety and seizure control. Although dose increases were to be in increments of 100 mg/day, intermediate doses were permitted at each escalation step for one week for patients known to be particularly sensitive to starting new AEDs. After receiving a stable, effective dose for three weeks, patients entered the 12-week maintenance period. Primary outcomes were incidence of treatment-emergent adverse events (TEAEs) and withdrawal due to TEAEs. Seizure outcomes, all secondary, were median focal seizure frequency, >=50% reduction in focal seizure frequency, and seizure freedom. One hundred patients with a mean age of 44 years were enrolled and 74 completed the trial. The incidence of TEAEs was 64.0% (n=100), with the most frequently reported (>=5% of patients) being dizziness, headache, and asthenia. Fourteen patients withdrew due to TEAEs, most frequently due to dizziness (six patients; 6.0%), vomiting (two patients; 2%), and tremor (two patients; 2%). Among patients with baseline and maintenance phase seizure data (n=75), median reduction in focal seizure frequency from baseline was 69.7% and the >=50% responder rate was 69.3%. Among 74 patients who completed the maintenance phase, 21 (28.4%) were seizure-free. Flexible lacosamide dosing in this open-label trial was associated with a favourable tolerability and safety profile; the nature of the TEAEs was consistent with that observed in previous pivotal trials. Treatment with lacosamide was also associated with effective seizure control. PMID- 28597843 TI - Dynamical predictors of an imminent phenotypic switch in bacteria. AB - Single cells can stochastically switch across thresholds imposed by regulatory networks. Such thresholds can act as a tipping point, drastically changing global phenotypic states. In ecology and economics, imminent transitions across such tipping points can be predicted using dynamical early warning indicators. A typical example is 'flickering' of a fast variable, predicting a longer-lasting switch from a low to a high state or vice versa. Considering the different timescales between metabolite and protein fluctuations in bacteria, we hypothesized that metabolic early warning indicators predict imminent transitions across a network threshold caused by enzyme saturation. We used stochastic simulations to determine if flickering predicts phenotypic transitions, accounting for a variety of molecular physiological parameters, including enzyme affinity, burstiness of enzyme gene expression, homeostatic feedback, and rates of metabolic precursor influx. In most cases, we found that metabolic flickering rates are robustly peaked near the enzyme saturation threshold. The degree of fluctuation was amplified by product inhibition of the enzyme. We conclude that sensitivity to flickering in fast variables may be a possible natural or synthetic strategy to prepare physiological states for an imminent transition. PMID- 28597844 TI - Study of gelatin as an effective energy absorbing layer for laser bioprinting. AB - Laser-induced forward transfer printing, also commonly known as laser printing, has been widely implemented for three-dimensional bioprinting due to its unique orifice-free nature during printing. However, the printing quality has the potential to be further improved for various laser bioprinting applications. The objectives of this study are to investigate the feasibility of using gelatin as an energy absorbing layer (EAL) material for laser bioprinting and its effects on the quality of printed constructs, bioink printability, and post-printing cell viability and process-induced DNA damage. The gelatin EAL is applied between the quartz support and the coating of build material, which is to be printed. Printing quality can be improved by EAL-assisted laser printing when using various alginate solutions (1%, 2%, and 4%) and cell-laden bioinks (2% alginate and 5 * 106 cells ml-1 in cell culture medium). The required laser fluence is also reduced due to a higher absorption coefficient of gelatin gel, in particular when to achieve the best printing type/quality. The post-printing cell viability is improved by ~10% and DNA double-strand breaks are reduced by ~50%. For all the build materials investigated, the gelatin EAL helps reduce the droplet size and average jet velocity. PMID- 28597845 TI - Significantly enhanced mechanical properties in AlN helix. AB - To safely and reliably use aluminum nitride (AlN) helices in the fabrication of novel micro/nanodevices, it is very important to know their mechanical properties. Herein, we investigate the mechanical properties of individual AlN helices using an in situ tensile-bending test. Tensile tests reveal that an AlN helix has an average epsilon of ~4.7 +/- 0.8% elastic deformation before a typical brittle fracture occurs. The bending test shows a two-step mechanical feature-linear-elastic followed by an elastic-plastic process-with an average epsilon bent of ~54.5 +/- 0.6%. Our results provide direct cognition about the mechanical properties of AlN helices and their benefit to the design of AlN-based flexible micro/nanodevices. PMID- 28597846 TI - Single-trial effective brain connectivity patterns enhance discriminability of mental imagery tasks. AB - OBJECTIVE: The majority of the current approaches of connectivity based brain computer interface (BCI) systems focus on distinguishing between different motor imagery (MI) tasks. Brain regions associated with MI are anatomically close to each other, hence these BCI systems suffer from low performances. Our objective is to introduce single-trial connectivity feature based BCI system for cognition imagery (CI) based tasks wherein the associated brain regions are located relatively far away as compared to those for MI. APPROACH: We implemented time domain partial Granger causality (PGC) for the estimation of the connectivity features in a BCI setting. The proposed hypothesis has been verified with two publically available datasets involving MI and CI tasks. MAIN RESULTS: The results support the conclusion that connectivity based features can provide a better performance than a classical signal processing framework based on bandpass features coupled with spatial filtering for CI tasks, including word generation, subtraction, and spatial navigation. These results show for the first time that connectivity features can provide a reliable performance for imagery-based BCI system. SIGNIFICANCE: We show that single-trial connectivity features for mixed imagery tasks (i.e. combination of CI and MI) can outperform the features obtained by current state-of-the-art method and hence can be successfully applied for BCI applications. PMID- 28597847 TI - Mapping the fine structure of cortical activity with different micro-ECoG electrode array geometries. AB - OBJECTIVE: Innovations in micro-electrocorticography (uECoG) electrode array manufacturing now allow for intricate designs with smaller contact diameters and/or pitch (i.e. inter-contact distance) down to the sub-mm range. The aims of the present study were: (i) to investigate whether frequency ranges up to 400 Hz can be reproducibly observed in uECoG recordings and (ii) to examine how differences in topographical substructure between these frequency bands and electrode array geometries can be quantified. We also investigated, for the first time, the influence of blood vessels on signal properties and assessed the influence of cortical vasculature on topographic mapping. APPROACH: The present study employed two uECoG electrode arrays with different contact diameters and inter-contact distances, which were used to characterize neural activity from the somatosensory cortex of minipigs in a broad frequency range up to 400 Hz. The analysed neural data were recorded in acute experiments under anaesthesia during peripheral electrical stimulation. MAIN RESULTS: We observed that uECoG recordings reliably revealed multi-focal cortical somatosensory response patterns, in which response peaks were often less than 1 cm apart and would thus not have been resolvable with conventional ECoG. The response patterns differed by stimulation site and intensity, they were distinct for different frequency bands, and the results of functional mapping proved independent of cortical vascular. Our analysis of different frequency bands exhibited differences in the number of activation peaks in topographical substructures. Notably, signal strength and signal-to-noise ratios differed between the two electrode arrays, possibly due to their different sensitivity for variations in spatial patterns and signal strengths. SIGNIFICANCE: Our findings that the geometry of uECoG electrode arrays can strongly influence their recording performance can help to make informed decisions that maybe important in number of clinical contexts, including high-resolution brain mapping, advanced epilepsy diagnostics or brain machine interfacing. PMID- 28597848 TI - Effects of soft interactions and bound mobility on diffusion in crowded environments: a model of sticky and slippery obstacles. AB - Crowded environments modify the diffusion of macromolecules, generally slowing their movement and inducing transient anomalous subdiffusion. The presence of obstacles also modifies the kinetics and equilibrium behavior of tracers. While previous theoretical studies of particle diffusion have typically assumed either impenetrable obstacles or binding interactions that immobilize the particle, in many cellular contexts bound particles remain mobile. Examples include membrane proteins or lipids with some entry and diffusion within lipid domains and proteins that can enter into membraneless organelles or compartments such as the nucleolus. Using a lattice model, we studied the diffusive movement of tracer particles which bind to soft obstacles, allowing tracers and obstacles to occupy the same lattice site. For sticky obstacles, bound tracer particles are immobile, while for slippery obstacles, bound tracers can hop without penalty to adjacent obstacles. In both models, binding significantly alters tracer motion. The type and degree of motion while bound is a key determinant of the tracer mobility: slippery obstacles can allow nearly unhindered diffusion, even at high obstacle filling fraction. To mimic compartmentalization in a cell, we examined how obstacle size and a range of bound diffusion coefficients affect tracer dynamics. The behavior of the model is similar in two and three spatial dimensions. Our work has implications for protein movement and interactions within cells. PMID- 28597849 TI - Association between diacylglycerol kinase kappa variants and hypospadias susceptibility in a Han Chinese population. AB - Previous genome-wide association studies have identified variants in the diacylglycerol kinase kappa (DGKK) gene associated with hypospadias in populations of European descent. However, no variants of DGKK were confirmed to be associated with hypospadias in a recent Han Chinese study population, likely due to the limited number of single-nucleotide polymorphisms (SNPs) included in the analysis. In this study, we aimed to address the inconsistent results and evaluate the association between DGKK and hypospadias in the Han Chinese population through a more comprehensive analysis of DGKK variants. We conducted association analyses for 17 SNPs in or downstream of DGKK with hypospadias among 322 cases (58 mild, 113 moderate, 128 severe, and 23 unknown) and 1008 controls. Five SNPs (rs2211122, rs4554617, rs7058226, rs7063116, and rs5915254) in DGKK were significantly associated with hypospadias (P < 0.05), with odds ratios (ORs) of 1.64-1.76. When only mild and moderate cases were compared to controls, 10 SNPs in DGKK were significant (P < 0.05), with ORs of 1.56-2.13. No significant SNP was observed when only severe cases were compared to controls. This study successfully implicated DGKK variants in hypospadias risk among a Han Chinese population, especially for mild/moderate cases. Severe forms of hypospadias are likely due to other genetic factors. PMID- 28597851 TI - Care for mental disorders and promotion of mental well-being in South-East Asia. PMID- 28597850 TI - The role of peroxisome proliferator-activated receptor gamma in prostate cancer. AB - Despite great progress in the detection and treatment of prostate cancer, this disease remains an incredible health and economic burden. Although androgen receptor (AR) signaling plays a key role in the development and progression of prostate cancer, aberrations in other molecular pathways also contribute to the disease, making it essential to identify and develop drugs against novel targets, both for the prevention and treatment of prostate cancer. One promising target is the peroxisome proliferator-activated receptor gamma (PPARgamma) protein. PPARgamma was originally thought to act as a tumor suppressor in prostate cells because agonist ligands inhibited the growth of prostate cancer cells; however, additional studies found that PPARgamma agonists inhibit cell growth independent of PPARgamma. Furthermore, PPARgamma expression increases with cancer grade/stage, which would suggest that it is not a tumor suppressor but instead that PPARgamma activity may play a role in prostate cancer development and/or progression. Indeed, two new studies, taking vastly different, unbiased approaches, have identified PPARgamma as a target in prostate cancer and suggest that PPARgamma inhibition might be useful in prostate cancer prevention and treatment. These findings could lead to a new therapeutic weapon in the fight against prostate cancer. PMID- 28597852 TI - Mental health policies in South-East Asia and the public health role of screening instruments for depression. AB - The World Health Organization (WHO) South-East Asia Region, which contributes one quarter of the world's population, has a significant burden due to mental illnesses. Mental health has been a low priority in most countries of the region. Although most of these countries have national mental health policies, implementation at ground level remains a huge challenge. Many countries in the region lack mental health legislation that can safeguard the rights of people with mental illnesses, and governments have allocated low budgets for mental health services. It is imperative that concerned authorities work towards scaling up both financial and human resources for effective delivery of mental health services. Policymakers should facilitate training in the field of mental health and aim towards integrating mental health services with primary health care, to reduce the treatment gap. Steps should also be taken to develop a robust mental health information system that can provide baseline information and insight about existing mental health services and help in prioritization of the mental health needs of the individual countries. Although evidence-based management protocols such as the WHO Mental Health Gap Action Programme (mhGAP) guidelines facilitate training and scaling up of care in resource-limited countries, the identification of mental disorders like depression in such settings remains a challenge. Development and validation of brief psychiatric screening instruments should be prioritized to support such models of care. This paper illustrates an approach towards the development of a new culturally adapted instrument to identify depression that has scope for wider use in the WHO South-East Asia Region. PMID- 28597853 TI - Depression and physical noncommunicable diseases: The need for an integrated approach. AB - Depression is globally the third-leading cause of disability in terms of disability-adjusted life-years. Depression in patients with diseases such as cancer, diabetes mellitus, stroke or cardiovascular disease is 2-4-fold more prevalent than in people who do not have physical noncommunicable diseases, and may have a more prolonged course. The significant burden due to depression that is comorbid with chronic physical disease, coupled with limited resources, makes it a major public health challenge for low- and middle-income countries. Given the bidirectional relation between depression and chronic physical disease, the clear way forward in managing this population of patients is via a system in which mental health care is integrated with primary care. Central to this integrated approach is the Collaborative Care Model, adapted to the local sociocultural context. In this model, care is jointly led by the primary care physician, supported by a case manager and a mental health professional. Various successful initiatives in low- and middle-income countries may be used as templates for collaborative care in other low-resource settings. The model involves a range of interwoven components, such as capacity-building, task sharing, task-shifting, developing good referral and linkage systems, anti-stigma initiatives and lifestyle modifications. Policies based on adoption of this approach would not only directly address depression that is comorbid with physical noncommunicable disease but also facilitate achievement of Sustainable Development Goal 3, to "ensure healthy lives and promote well-being for all at all ages". PMID- 28597854 TI - Decentralizing provision of mental health care in Sri Lanka. AB - In the past, mental health services in Sri Lanka were limited to tertiary-care institutions, resulting in a large treatment gap. Starting in 2000, significant efforts have been made to reconfigure service provision and to integrate mental health services with primary health care. This approach was supported by significant political commitment to establishing island-wide decentralized mental health care in the wake of the 2004 tsunami. Various initiatives were consolidated in The mental health policy of Sri Lanka 2005-2015, which called for implementation of a comprehensive community-based, decentralized service structure. The main objectives of the policy were to provide mental health services of good quality at primary, secondary and tertiary levels; to ensure the active involvement of communities, families and service users; to make mental health services culturally appropriate and evidence based; and to protect the human rights and dignity of all people with mental health disorders. Significant improvements have been made and new cadres of mental health workers have been introduced. Trained medical officers (mental health) now provide outpatient care, domiciliary care, mental health promotion in schools, and community mental health education. Community psychiatric nurses have also been trained and deployed to supervise treatment adherence in the home and provide mental health education to patients, their family members and the wider community. A total of 4367 mental health volunteers are supporting care and raising mental health literacy in the community. Despite these important achievements, more improvements are needed to provide more timely intervention, combat myths and stigma, and further decentralize care provision. These, and other challenges, will be targeted in the new mental health policy for 2017-2026. PMID- 28597855 TI - Post-disaster mental health and psychosocial support: Experience from the 2015 Nepal earthquake. AB - On 25 April 2015, an earthquake of magnitude 7.8 struck Nepal, which, along with the subsequent aftershocks, killed 8897 people, injured 22 303 and left 2.8 million homeless. Previous efforts to provide services for mental health and psychological support (MHPSS) in humanitarian settings in Nepal have been largely considered inadequate and poorly coordinated. Immediately after the earthquake, the Government of Nepal declared a state of emergency and the health sector started to respond. The immediate response to the earthquake was coordinated following the Inter-Agency Standing Committee (IASC) cluster approach. One month after the disaster, integrated MHPSS subclusters were initiated to coordinate the activities of many national and international, governmental and nongovernmental, partners. These activities were largely conducted on an ad-hoc basis, owing to lack of focus on MHPSS in the health sector's contingency plan for emergencies. The mental health subcluster attempted to implement a mental health response according to World Health Organization and IASC guidelines. The MHPSS response highlighted many strengths and weaknesses of Nepal's mental health system. This provides an opportunity to "build back better" through reform of mental health services. A strategic response to the lessons of the 2015 earthquake will deliver both improved population mental health and increased preparedness for the future. PMID- 28597856 TI - Challenges and opportunities in suicide prevention in South-East Asia. AB - Suicide is a global public health problem, with over 800 000 people worldwide dying by suicide in 2012, according to the World Health Organization (WHO). The WHO South-East Asia Region is especially affected, with 39% of global suicides occurring in the 11 countries in this region. Women are a particularly vulnerable population, for a variety of social and cultural reasons. In India specifically, deaths by suicide for women peak in the age range 15-29 years. There is sufficient evidence to show that reduction of easy access to means of suicide is an effective prevention strategy. A common method of suicide in the region is by ingestion of pesticides. Strategies that have targeted limiting access to pesticides as a means of preventing suicide, such as the use of central storage and locked boxes, have shown promising results. Given the limited human and economic resources in these countries, it is essential to involve all stakeholders, including health services, voluntary and community organizations, teachers, social workers, traditional healers and other gatekeepers, in suicide prevention. A multisectoral approach, specifically targeting women and reducing easy access to pesticides, should be the way forward to reducing suicides in this region. In addition, more research is needed, to identify cost-effective and sustainable strategies. PMID- 28597857 TI - Services for depression and suicide in Thailand. AB - Depression, together with suicide is an important contributor to the burden of disease in Thailand. Until recently, depression has been significantly under recognized in the country. The lack of response to this health challenge has been compounded by a low level of access to standard care, constraints on mental health personnel and inadequate dissemination of knowledge in caring for people with these disorders. In the past decade, significant work has been undertaken to establish a new evidence-based surveillance and care system for depression and suicide in Thailand that operates at all levels of health-care provision nationwide. The main components of the integrated system are: (i) community-level screening for depression in at-risk groups, using a two-question tool; (ii) assessment of the severity of depression using a nine-question scale; (iii) diagnosis and treatment by general practitioners; (iv) psychosocial care provided by psychiatric nurses; (v) continuous care for relapse and suicide prevention; and (vi) promotion of mental well-being and prevention of depression in at-risk populations. Factors such as appropriate financial mechanisms, capacity-building programmes for health-care workers, and robust treatment guidelines have contributed to the success and sustainability of this comprehensive surveillance and care system. By 2016, more than 14 million people at risk had been screened for depression and received mental health education; more than 1.7 million people with depression had received psychosocial interventions; 0.7 million diagnosed patients had received antidepressants; and 0.8 million were being followed up for relapse and suicide prevention. The application of this surveillance and care system has led to an enormous increase in the accessibility of standard care for people with depressive disorders, from 5.1% of those with depressive disorders in 2009 to 48.5% in 2016. PMID- 28597859 TI - Suicide burden and prevention in Nepal: The need for a national strategy. AB - Suicide is a major cause of deaths worldwide and is a key public health concern in Nepal. Although routine national data are not collected in Nepal, the available evidence suggests that suicide rates are relatively high, notably for women. In addition, civil conflict and the 2015 earthquake have had significant contributory effects. A range of factors both facilitate suicide attempts and hinder those affected from seeking help, such as the ready availability of toxic pesticides and the widespread, although erroneous, belief that suicide is illegal. Various interventions have been undertaken at different levels in prevention and rehabilitation but a specific long-term national strategy for suicide prevention is lacking. Hence, to address this significant public health problem, a multisectoral platform of stakeholders needs to be established under government leadership, to design and implement innovative and country contextualized policies and programmes. A bottom-up approach, with active and participatory community engagement from the start of the policy- and strategy formulation stage, through to the design and implementation of interventions, could potentially build grass-roots public ownership, reduce stigma and ensure a scaleable and sustainable response. PMID- 28597858 TI - Policy and governance to address depression and suicide in Bhutan: The national suicide-prevention strategy. AB - Suicide and mental disorders are a growing public health issue in Bhutan, due in part to a rapidly transitioning society. The burden of suicide has been recognized by the Royal Government of Bhutan and, as a result, it introduced the country's first ever national suicide-prevention plan in 2015. The 3-year action plan takes a holistic approach to making suicide-prevention services a top social priority, through strengthening suicide-prevention policies, promoting socially protective measures, mitigating risk factors and reaching out to individuals who are at risk of suicide or affected by incidents of suicide. This article documents Bhutan's policy and governance for addressing depression and suicide within the context of its national suicide-prevention strategy, examines progress and highlights lessons for future directions in suicide prevention. Since the endorsement of the 3-year action plan by the prime minister's cabinet, the implementation of suicide-prevention measures has been accelerated through a high level national steering committee. Activities include suicide-prevention actions by sectors such as health, education, monastic communities and police; building capacity of gatekeepers; and improving the suicide information system to inform policies and decision-making. Suicide-prevention activities have become the responsibility of local governments, paving the way for suicide prevention as an integral mandate across sectors and at grass-root levels in the Kingdom of Bhutan. PMID- 28597860 TI - Co-occurring depression and alcohol-use disorders in South-East Asia: A narrative review. AB - Depression and alcohol-use disorders frequently co-occur and the presence of one augments the adverse consequences of the other. This article reviews and synthesizes the available literature on depression and alcohol-use disorders from the World Health Organization (WHO) South-East Asia Region, with respect to epidemiology, screening instruments, interventions and services, and policy. In common with other low- and middle-income settings, data from this region on co occurring depression and alcohol-use disorders are scarce. The wide variations in language and cultural diversity within the countries of this region further make the identification and management of people with co-occurring depression and alcohol-use disorders a major challenge. A range of interventions for individuals with the two disorders have been studied. However, most of this work has been done in high-income countries, highlighting the need to explore the effectiveness and cost effectiveness of various pharmacological and non-pharmacological interventions in the WHO South-East Asia Region. Much of this region comprises low-resource settings, with a dearth of trained personnel and resources. Flexible transdiagnostic approaches, delivered by community health workers and integrated into primary health care may be a pragmatic approach. Such services should form part of strengthened national responses to alcohol-related public health problems across the region. PMID- 28597861 TI - Suicide and depression in the World Health Organization South-East Asia Region: A systematic review. AB - Background Depression is the most common comorbid psychiatric disorder in people who die by suicide and 39% of global suicides occur in the World Health Organization (WHO) South-East Asia Region. The aim of this systematic review was to identify, for countries of this region, first the prevalence of depression among people who (i) die by, or (ii) attempt, suicide, and second, the proportion of people with depression who attempt or die by suicide. Methods PubMed, PsycINFO, EMBASE and Google Scholar were searched, together with five available national databases, for quantitative research papers published in English between 1956 and 4 September 2016 from the 11 countries of the WHO South-East Asia Region. Results The 19 articles that met the predefined eligibility criteria were from five countries: Bangladesh (1), India (12), Indonesia (1), Sri Lanka (3) and Thailand (2); no eligible papers from the remaining countries of the region were retrieved. Eight studies, from Bangladesh, India, Indonesia and Sri Lanka, reported the prevalence of depression among people who had died by suicide. The study settings varied, as did the proportion of depression recorded (6.9-51.7%), and the study sample sizes ranged from 27 to 372. Eight studies from India and one from Sri Lanka investigated depression among people who had attempted suicide. Using a range of screening and diagnostic tools, the reported prevalence of depression ranged between 22.0% and 59.7%. The study sample sizes ranged from 56 to 949. Only two articles were found, both from Thailand, that reported on suicide in people with depression. Conclusion Despite the high burden of mortality of suicide in the WHO South-East Asia Region, evidence on the relation between suicide and depression is scarce. There is a need to understand this phenomenon better, in order to inform suicide-prevention strategies in the region. PMID- 28597862 TI - Alcohol consumption among adults in Bangladesh: Results from STEPS 2010. AB - Background Alcohol use is a risk factor for the development of noncommunicable diseases. National data are needed to assess the prevalence of alcohol use in the Bangladeshi population. The objective of this study was to describe the prevalence and patterns of alcohol use among men and women of rural and urban areas of Bangladesh. Additionally, predictors of ever alcohol use were also identified. Methods A nationally representative cross-sectional survey (STEPS 2010) was conducted on 9275 adults between November 2009 and April 2010. Participants were selected using multi-stage random cluster sampling. Data on several risk factors for noncommunicable diseases, including alcohol use, were collected by an interviewer-administered questionnaire. Results Among the total population, 5.6% (n = 519) reported to have ever drunk alcohol and 94.4% (8756) were lifetime abstainers; 2.0% (n = 190) of participants reported to have drunk alcohol within the last 12 months. Of these, 94.7% (n = 180) were men. Only 0.9% (n = 87) of the total population had drunk alcohol within the last 30 days and were categorized as current drinkers. Among current drinkers, 77.0% (n = 67) were defined as binge drinkers, having had at least one episode of heavy drinking in this time period; 92.0% (n = 80) were current smokers and 59.8% (n = 52) had either no formal education or less than primary school education. Ever alcohol use was more common among men, those who live in urban areas and smokers. Conclusion Alcohol use is low in Bangladesh; however, those who do use alcohol frequently binge drink, which is a public health concern. Targeted efforts should be made on these specific groups, to control and prevent the continued use of alcohol in Bangladesh. PMID- 28597863 TI - Perinatal care practices in home deliveries in rural Bangalore, India: A community-based, cross-sectional survey. AB - Background A slowing in the decline in neonatal mortality in India has hindered progress made in reducing overall child mortality. The persisting use of unsafe home deliveries and harmful neonatal care practices may contribute to this stagnation in neonatal mortality rates. Methods A community-based cross-sectional study of mothers residing in rural Bangalore, India, who had given birth within 42 days of the day of home visit was done during 2013-2014. Trained health workers interviewed women who delivered at home about perinatal care practices. The questionnaire used was adapted from previous studies assessing perinatal care practices according to World Health Organization guidelines. Descriptive analyses of perinatal practices were reported as frequencies. The association of various factors with the outcomes clean cord care, thermal care and early initiation of breastfeeding were assessed using multivariate logistic regression analyses. Results Of a total of 2230 deliveries, 945 (42.4%) took place in hospitals, while the remainder were at home (57.6%). Among home deliveries, only 30.6% were attended by a skilled worker; a safe-delivery kit was used in 40.6% and 47.1% of attendants had washed their hands before delivery. In most cases (94.6%), the umbilical cord was cut after delivery of the placenta and a non-sterile instrument was used in 26.6% of births. Harmful practices of applications on the cord stump (35.0%), bathing within 6 h (61.6%), pre-lacteal feeding (30.8%) and delayed initiation of breastfeeding (73.3%) were reported. Wrapping was usually delayed, and most (64.7%) neonates were wrapped between 10 min and 60 min after birth. Being Hindu was positively associated with good perinatal care practices, and attending antenatal care at least once was associated with clean cord care and early breastfeeding. Having a trained birth attendant at delivery was associated only with clean cord care. Having a medical doctor/nurse in attendance was associated with only early initiation of breastfeeding. Being a member of a scheduled caste/tribe was positively associated with clean cord care and thermal care. Conclusion Appropriate and culturally acceptable behaviour-change communication strategies are needed to improve delivery and neonatal care practices in Bangalore. PMID- 28597864 TI - Motivating and demotivating factors for community health workers: A qualitative study in urban slums of Delhi, India. AB - Background Community health workers play an important role in delivering health care services, especially to underserved populations in low- and middle-income countries. They have been shown to be successful in providing a range of preventive, promotive and curative services. This qualitative study investigated the factors motivating or demotivating community health workers in urban settings in Delhi, India. Methods In this sub-study of the ANCHUL (Ante Natal and Child Healthcare in Urban Slums) implementation research project, four focus-group discussions and nine in-depth interviews were conducted with community health workers and medical officers. Utilizing a reflexive and inductive qualitative methodology, the data set was coded, to allow categories of motivating and demotivating factors to emerge. Results Motivating factors identified were: support from family members for their work, improved self-identity, job satisfaction and a sense of social responsibility, prior experiences of ill health, the opportunity to acquire new skills and knowledge, social recognition and status conferred by the community, and flexible work and timings. Negative experiences in the community and at health centres, constraints in the local health system in response to the demand generated by the community health workers, and poor pay demotivated community health workers in this study, even causing some to quit their jobs. Conclusion Community-health-worker programmes that focus on ensuring the technical capacity of their staff may not give adequate attention to the factors that motivate or discourage these workers. As efforts get under way to ensure universal access to health care, it is important that these issues are recognized and addressed, to ensure that community health worker programmes are effective and sustainable. PMID- 28597865 TI - Adoption of the 2015 World Health Organization guidelines on antiretroviral therapy: Programmatic implications for India. AB - The therapeutic and preventive benefits of early initiation of antiretroviral therapy (ART) for HIV are now well established. Reflecting new research evidence, in 2015 the World Health Organization (WHO) recommended initiation of ART for all people living with HIV (PLHIV), irrespective of their clinical staging and CD4 cell count. The National AIDS Control Programme (NACP) in India is currently following the 2010 WHO ART guidelines for adults and the 2013 guidelines for pregnant women and children. This desk study assessed the number of people living with HIV who will additionally be eligible for ART on adoption of the 2015 WHO recommendations on ART. Data routinely recorded for all PLHIV registered under the NACP up to 31 December 2015 were analysed. Of the 250 865 individuals recorded in pre-ART care, an estimated 135 593 would be eligible under the WHO 2013 guidelines. A further 100 221 would be eligible under the WHO 2015 guidelines. Initiating treatment for all PLHIV in pre-ART care would raise the number on ART from 0.92 million to 1.17 million. In addition, nearly 0.07 million newly registered PLHIV will become eligible every year if the WHO 2015 guidelines are adopted, of which 0.028 million would be attributable to implementation of the WHO 2013 guidelines alone. In addition to drugs, there will be a need for additional CD4 tests and tests of viral load, as the numbers on ART will increase significantly. The outlay should be seen in the context of potential health-care savings due to early initiation of ART, in terms of the effect on disease progression, complications, deaths and new infections. While desirable, adoption of the new guidance will have significant programmatic and resource implications for India. The programme needs to plan and strengthen the service-delivery mechanism, with emphasis on newer and innovative approaches before implementation of these guidelines. PMID- 28597866 TI - Delivery of antiretroviral treatment services in India: Estimated costs incurred under the National AIDS Control Programme. AB - Competing domestic health priorities and shrinking financial support from external agencies necessitates that India's National AIDS Control Programme (NACP) brings in cost efficiencies to sustain the programme. In addition, current plans to expand the criteria for eligibility for antiretroviral therapy (ART) in India will have significant financial implications in the near future. ART centres in India provide comprehensive services to people living with HIV (PLHIV): those fulfilling national eligibility criteria and receiving ART and those on pre-ART care, i.e. not on ART. ART centres are financially supported (i) directly by the NACP; and (ii) indirectly by general health systems. This study was conducted to determine (i) the cost incurred per patient per year of pre-ART and ART services at ART centres; and (ii) the proportion of this cost incurred by the NACP and by general health systems. The study used national data from April 2013 to March 2014, on ART costs and non-ART costs (human resources, laboratory tests, training, prophylaxis and management of opportunistic infections, hospitalization, operational, and programme management). Data were extracted from procurement records and reports, statements of expenditure at national and state level, records and reports from ART centres, databases of the National AIDS Control Organisation, and reports on use of antiretroviral drugs. The analysis estimates the cost for ART services as US$ 133.89 (?8032) per patient per year, of which 66% (US$ 88.66, ?5320) is for antiretroviral drugs and 34% (US$ 45.23, ?2712) is for non-ART recurrent expenditure, while the cost for pre-ART care is US$ 33.05 (?1983) per patient per year. The low costs incurred for patients in ART and pre-ART care services can be attributed mainly to the low costs of generic drugs. However, further integration with general health systems may facilitate additional cost saving, such as in human resources. PMID- 28597867 TI - Prognostic Significance of a Micropapillary Pattern in Pure Mucinous Carcinoma of the Breast: Comparative Analysis with Micropapillary Carcinoma. AB - BACKGROUND: Mucinous carcinoma of the breast is an indolent tumors with a favorable prognosis; however, micropapillary features tend to lead to aggressive behavior. Thus, mucinous carcinoma and micropapillary carcinoma exhibit contrasting biologic behaviors. Here, we review invasive mucinous carcinoma with a focus on micropapillary features and correlations with clinicopathological factors. METHODS: A total of 64 patients with invasive breast cancer with mucinous or micropapillary features were enrolled in the study. Of 36 pure mucinous carcinomas, 17 (47.2%) had micropapillary features and were termed mucinous carcinoma with micropapillary features (MUMPC), and 19 (52.8%) had no micropapillary features and were termed mucinous carcinoma without micropapillary features. MUMPC were compared with 15 invasive micropapillary carcinomas (IMPC) and 13 invasive ductal and micropapillary carcinomas (IDMPC). RESULTS: The clinicopathological factors of pure mucinous carcinoma and MUMPC were not significantly different. In contrast to IMPC and IDMPC, MUMPC had a low nuclear grade, lower mitotic rate, higher expression of hormone receptors, negative human epidermal growth factor receptor 2 (HER2) status, lower Ki-67 proliferating index, and less frequent lymph node metastasis (p < .05). According to univariate analyses, progesterone receptor, HER2, T-stage, and lymph node metastasis were significant risk factors for overall survival; however, only T-stage remained significant in a multivariate analysis (p < .05). CONCLUSIONS: In contrast to IMPC and IDMPC, the micropapillary pattern in mucinous carcinoma does not contribute to aggressive behavior. However, further analysis of a larger series of patients is required to clarify the prognostic significance of micropapillary patterns in mucinous carcinoma of the breast. PMID- 28597868 TI - Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients. AB - BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients. METHODS: To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival. RESULTS: PR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5 year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses. CONCLUSIONS: Loss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients. PMID- 28597869 TI - The qualitative orientation in medical education research. AB - Qualitative research is very important in educational research as it addresses the "how" and "why" research questions and enables deeper understanding of experiences, phenomena and context. Qualitative research allows you to ask questions that cannot be easily put into numbers to understand human experience. Getting at the everyday realities of some social phenomenon and studying important questions as they are really practiced helps extend knowledge and understanding. To do so, you need to understand the philosophical stance of qualitative research and work from this to develop the research question, study design, data collection methods and data analysis. In this article, I provide an overview of the assumptions underlying qualitative research and the role of the researcher in the qualitative process. I then go on to discuss the type of research objectives which are common in qualitative research, then introduce the main qualitative designs, data collection tools, and finally the basics of qualitative analysis. I introduce the criteria by which you can judge the quality of qualitative research. Many classic references are cited in this article, and I urge you to seek out some of these further reading to inform your qualitative research program. PMID- 28597871 TI - Development an instrument assessing residents' attitude towards professionalism lapses in training. AB - PURPOSE: Medical professionalism is a fundamental competency for all physicians and continuous development of professionalism during residency training is crucial. The purpose of this study was to develop an instrument assessing residents' attitudes toward unprofessional behaviors. METHODS: A questionnaire survey was conducted in cooperation with the Korea Resident Association from May to July 2013. A total of 317 residents from seven university-affiliated hospitals in South Korea participated in the survey. RESULTS: In the exploratory factor analysis, seven factors were extracted from the data; factor loadings of the 44 items ranged between 0.40 and 0.89. Through iterative discussion, three items below 0.45 were deleted and one additional item was removed due to its irrelevance. Twelve items included in Factor 1 were divided into two different categories. A final version of the questionnaire containing 40 items in eight categories was assessed using confirmatory factor analysis. It was deemed to have a good fit; the root mean square error of approximation and comparative fit index were 0.07 and 0.9, respectively. The reliability (Cronbach's alpha) of the inventory was 0.97. CONCLUSION: The items of this instrument encompass a broad range of residents' behaviors in clinical practice, research, and publication. In addition, it includes some types of misconduct that can be considered unique features of the authors' cultural backgrounds. We recommend this instrument as an assessment tool to diagnose residents' perceptions and attitudes towards professionalism lapses and to provide insight regarding potential improvement in professionalism education. PMID- 28597870 TI - Potential bias factors that affect the course evaluation of students in preclinical courses. AB - PURPOSE: We aim to identify what potential bias factors affected students' overall course evaluation, and to observe what factors should be considered in the curriculum evaluation system of medical schools. METHODS: This study analyzed students' ratings of preclinical instructions at the Ajou University School of Medicine. The ratings of instructions involved 41 first-year and 45 second-year medical students. RESULTS: There was a statistically significant difference between years of study and ratings' scoring. Learning difficulty, learning amount, student assessment, and teacher preparation from second-year students were significantly higher than first-year students (p<0.05). The analysis results revealed that student assessment was the predictor of ratings from first-year students, while teacher preparation was the predictor of ratings from second-year students. CONCLUSION: We found significant interactions between year of study and the students' rating results. We were able to confirm that satisfaction of instructions factors perceived by medical students were different for the characteristics of courses. Our results may be an important resource for evaluating preclinical curriculums. PMID- 28597872 TI - Flipped-learning course design and evaluation through student self-assessment in a predental science class. AB - PURPOSE: This study explores how to design a flipped classroom for a predental science course and evaluate its course through student self-assessment in order to provide practical implications for flipped learning in an undergraduate level. METHODS: Second- and third-year predental students in the Seoul National University School of Dentistry enrolled in Biodiversity and Global Environment, a 15-week, three-credit course based on a flipped learning model. At the end of the course, the students were asked to rate their self-directed learning, attitude toward social media, discussion skills, learning readiness, and class satisfaction. Out of the 82 predental students, 61 (74.3%) answered the survey. Pearson correlation and multivariate regression analyses were employed to examine the relationship between the self-rated measurements and the performance scores. RESULTS: The majority of the students felt somewhat more prepared than the medium level before the class (mean score of 3.17 out of 5.00), whereas they expressed relatively low preference concerning social media use and attitude (mean score of 2.49). Thus, it was found that learning readiness was significantly associated with both discussion skills and class satisfaction. In particular, multivariate regression analysis confirmed that learning readiness had a significant influence on learning outcomes. CONCLUSION: This study offered insights into how to design a flipped learning course in terms of predental students' preference and their learning readiness. Although learning success in a flipped classroom depends on the students' self-perceived level of preparedness, much still remains to be achieved in order to apply social media benefits in a flipped learning context. PMID- 28597873 TI - Do medical students generate sound arguments during small group discussions in problem-based learning?: an analysis of preclinical medical students' argumentation according to a framework of hypothetico-deductive reasoning. AB - PURPOSE: Hypothetico-deductive reasoning (HDR) is an essential learning activity and a learning outcome in problem-based learning (PBL). It is important for medical students to engage in the HDR process through argumentation during their small group discussions in PBL. This study aimed to analyze the quality of preclinical medical students' argumentation according to each phase of HDR in PBL. METHODS: Participants were 15 first-year preclinical students divided into two small groups. A set of three 2-hour discussion sessions from each of the two groups during a 1-week-long PBL unit on the cardiovascular system was audio recorded. The arguments constructed by the students were analyzed using a coding scheme, which included four types of argumentation (Type 0: incomplete, Type 1: claim only, Type 2: claim with data, and Type 3: claim with data and warrant). The mean frequency of each type of argumentation according to each HDR phase across the two small groups was calculated. RESULTS: During small group discussions, Type 1 arguments were generated most often (frequency=120.5, 43%), whereas the least common were Type 3 arguments (frequency=24.5, 8.7%) among the four types of arguments. CONCLUSION: The results of this study revealed that the students predominantly made claims without proper justifications; they often omitted data for supporting their claims or did not provide warrants to connect the claims and data. The findings suggest instructional interventions to enhance the quality of medical students' arguments in PBL, including promoting students' comprehension of the structure of argumentation for HDR processes and questioning. PMID- 28597875 TI - Mentoring for career development. PMID- 28597876 TI - Metal-free radical trifluoromethylation of beta-nitroalkenes through visible light photoredox catalysis. AB - A catalytic method for functional group interconversion is immensely important in modern sciences. Here, we report an efficient catalytic conversion of nitroalkenes to highly stereoselective 1-trifluoromethylalkenes at room temperature. This unprecedented metal-free photocatalytic strategy is simple and operates under visible-light irradiation using the commercially available CF3 source. PMID- 28597874 TI - Evaluation of an extracurricular program for students interested in rural and public health. AB - PURPOSE: The problem regarding the geographic imbalance of the physician workforce has been a long-standing problem in South Korea. Additionally, rural medicine and public health have been marginalized across whole undergraduate curriculums. The aim of this study was to evaluate the effectiveness of an extracurricular program targeting medical students interested in rural and public health. METHODS: A 2-day extracurricular program was held twice in 2015 and 2016. A total of 53 students were selected among eighty students who voluntarily applied to participate in the program. The effectiveness of the program was evaluated by pre- and post-program surveys. RESULTS: The overall satisfaction for the program was 5.35 out of 6. The participants showed a significant improvement in perception of the clerkship experience in a rural and public health care setting as well as the importance of rural medicine and public health in South Korea. CONCLUSION: In conclusion, this study showed the acceptability of a short term extracurricular program for medical students interested in rural and public health. PMID- 28597877 TI - Comparison of the electrochemical performance of iron hexacyanoferrate with high and low quality as cathode materials for aqueous sodium-ion batteries. AB - In this work, high quality iron hexacyanoferrate nanocubes (HQ-PB NCs) were synthesized through a simple hydrothermal method and then investigated as cathode electrode materials for aqueous sodium-ion batteries (SIBs), which displayed a much enhanced electrochemical performance compared with the PB nanoparticles with low quality (LQ-PB NPs). The HQ-PB NCs could be promising cathode materials for aqueous SIBs. PMID- 28597878 TI - Incorporation studies of clickable ceramides in Jurkat cell plasma membranes. AB - The incorporation properties of ceramide analogues for click chemistry in Jurkat T cells were investigated. The analogues varied in the acyl chain length and the position of the functional group for click chemistry. Fluorescence microscopy studies including anisotropy and quenching experiments showed significant differences in the accessibility of the functional group indicating different incorporation properties into the plasma membrane. PMID- 28597882 TI - Quantifying the exchange coupling in linear copper porphyrin oligomers. AB - Linear pi-conjugated porphyrin oligomers are of significant current interest due to their potential applications as molecular wires. In this study we investigate electronic communication in linear butadiyne-linked copper porphyrin oligomers by electron paramagnetic resonance (EPR) spectroscopy via measurement of the exchange interaction, J, between the copper(ii) centers. The contributions of dipolar and exchange interactions to the frozen solution continuous wave (cw) EPR spectra of the compounds with two or more copper porphyrin units were explicitly accounted for in numerical simulations using a spin Hamiltonian approach. It is demonstrated that a complete numerical simulation of the powder spectrum of a large spin system with a Hamiltonian dimension of 26 244 and beyond can be made feasible by simulating the spectra in the time domain. The exchange coupling in the Cu2 dimer (CuCu distance 1.35 nm) is of the order of tens of MHz (H = 2JS1.S2) and is strongly modulated by low-energy molecular motions such as twisting of the molecule. PMID- 28597880 TI - The transient manifold structure of the p53 extreme C-terminal domain: insight into disorder, recognition, and binding promiscuity by molecular dynamics simulations. AB - The p53 tumour suppressor is a transcription activator that signals for cell cycle arrest and apoptosis. In its active form p53 is a tetramer, with each monomer organised in domains with different degrees of structural stability, ranging from the well folded DNA-binding domain (DBD) and tetramerization domain (TET), to the intrinsically disordered transactivation domain (TAD), and extreme C-terminal domain (CTD). Compared to all other domains, the structure/function relationship of the p53-CTD within the full-length p53 tetramer is still poorly understood due to its high degree of conformational disorder. Meanwhile, the structure of p53-CTD-like peptides has been well characterized when in complex with a variety of receptors, where, as other intrinsically disordered regions (IDR), it adopts specific, while diverse, conformations. Receptor-specific folding is likely to occur upon binding, either from a random coil, or as a result of an initial recognition of a pre-formed structural motif, known as molecular recognition feature (MoRF), selected by the receptor within the conformational ensemble of the IDP in solution. In this latter case, MoRFs act as nucleation sites, favouring the initiation of the folding process within the binding site. In this work we show the results of over 20 MUs of cumulative molecular dynamics (MD) simulations of a 22 residue peptide unbound in solution with sequence corresponding to the p53-CTD 367-388 section. Such extensive sampling allowed us to identify and characterize the structure of specific sets of minimal structural MoRFs within the p53-CTD peptide conformational ensemble at equilibrium. These motifs are short, involving only 3 to 4 residues, and specifically localized within the peptide sequence. Corresponding patterns of secondary structure propensity along the p53-CTD sequence are also predicted by disorder prediction calculations. Based on these findings we discuss how the structural complementarity of specific minimal structural MoRFs to the binding site of different receptors could regulate the p53-CTD binding promiscuity. PMID- 28597879 TI - To cage or to be caged? The cytotoxic species in ruthenium-based photoactivated chemotherapy is not always the metal. AB - In metal-based photoactivated chemotherapy (PACT), two photoproducts are generated by light-triggered photosubstitution of a metal-bound ligand: the free ligand itself and an aquated metal complex. By analogy with cisplatin, the aquated metal complex is usually presented as the biologically active species, as it can typically bind to DNA. In this work, we show that this qualitative assumption is not necessarily valid by comparing the biological activity, log P, and cellular uptake of three ruthenium-based PACT complexes: [Ru(bpy)2(dmbpy)]2+, [Ru(bpy)2(mtmp)]2+, and [Ru(Ph2phen)2(mtmp)]2+. For the first complex, the photoreleased dmbpy ligand is responsible for the observed phototoxicity, whereas the second complex is not phototoxic, and for the third complex it is the ruthenium bis-aqua photoproduct that is the sole cytotoxic species. PMID- 28597883 TI - The effect of hydroxyl on the solution behavior of a quaternary ammonium gemini surfactant. AB - The adsorption and viscoelastic properties of a micellar solution of 2-hydroxyl propanediyl-1,3-bis(hexadecyldimethylammonium bromide), abbreviated as 16-3OH-16, have been investigated by surface tension and rheological measurements. Meanwhile, an aqueous solution of propanediyl-1,3-bis(hexadecyldimethylammonium bromide), abbreviated as 16-3-16, was also examined. From the steady state and oscillatory rheological results, a notable difference in shear viscosities between the two systems was observed. Zeta potentials and size distributions confirm the change in the potentials and hydrodynamic diameters, and these results are in good agreement with the rheological results. The differences of the two solutions were attributed to the effect of the hydroxyl group on the spacer of 16-3OH-16. Molecular dynamic simulations and density functional theory (DFT) calculations were performed to investigate the non-covalent interactions in the solution and the difference between the molecular orbitals and the electrostatic potentials. Our research shows that a more uniform distribution of positive charges around the spacer could result in a more effective electrostatic screening effect between the charged headgroups, and promote the formation of a worm-like micelle. Also, hyperconjugation becomes stronger when the hydroxyl group is introduced on the spacer of the gemini molecule. PMID- 28597884 TI - A neural network potential energy surface for the NaH2 system and dynamics studies on the H(2S) + NaH(X1Sigma+) -> Na(2S) + H2(X1Sigmag+) reaction. AB - In order to study the dynamics of the reaction H(2S) + NaH(X1Sigma+) -> Na(2S) + H2(X1Sigmag+), a new potential energy surface (PES) for the ground state of the NaH2 system is constructed based on 35 730 ab initio energy points. Using basis sets of quadruple zeta quality, multireference configuration interaction calculations with Davidson correction were carried out to obtain the ab initio energy points. The neural network method is used to fit the PES, and the root mean square error is very small (0.00639 eV). The bond lengths, dissociation energies, zero-point energies and spectroscopic constants of H2(X1Sigmag+) and NaH(X1Sigma+) obtained on the new NaH2 PES are in good agreement with the experiment data. On the new PES, the reactant coordinate-based time-dependent wave packet method is applied to study the reaction dynamics of H(2S) + NaH(X1Sigma+) -> Na(2S) + H2(X1Sigmag+), and the reaction probabilities, integral cross-sections (ICSs) and differential cross-sections (DCSs) are obtained. There is no threshold in the reaction due to the absence of an energy barrier on the minimum energy path. When the collision energy increases, the ICSs decrease from a high value at low collision energy. The DCS results show that the angular distribution of the product molecules tends to the forward direction. Compared with the LiH2 system, the NaH2 system has a larger mass and the PES has a larger well at the H-NaH configuration, which leads to a higher ICS value in the H(2S) + NaH(X1Sigma+) -> Na(2S) + H2(X1Sigmag+) reaction. Because the H(2S) + NaH(X1Sigma+) -> Na(2S) + H2(X1Sigmag+) reaction releases more energy, the product molecules can be excited to a higher vibrational state. PMID- 28597885 TI - A simple self-assembly strategy for ultrahigh surface area nitrogen-doped porous carbon nanospheres with enhanced adsorption and energy storage performances. AB - A class of novel N-doped porous carbon nanospheres (PCNSs) with ultrahigh surface areas (e.g., Langmuir surface area = 3219 m2 g-1) and large templated mesopore diameters (up to 18.6 nm) was synthesized based upon a simple yet efficient copolymerization-induced self-assembly process of aniline/pyrrole co-monomers and block copolymer templates. The PCNSs exhibited enhanced adsorption properties towards creatinine and superior lithium-sulfur battery performances. PMID- 28597886 TI - Photoelectrical properties of CdS/CdSe core/shell QDs modified anatase TiO2 nanowires and their application for solar cells. AB - Anatase TiO2 nanowire (NW) films modified with inverted type-I CdS/CdSe core/shell structure QDs have been successfully prepared by the post synthesis ligand-assisted technique. Surface photovoltage (SPV), transient photovoltage (TPV) and transient photocurrent (TPC) measurements demonstrate that CdS/CdSe core/shell structure QD-sensitized TiO2 NWs electrodes favor photoexicited electron injection and charge transfer due to the special photo-electronic features of CdS/CdSe core/shell structure QDs. With a polysulfide electrolyte, the maximum conversion efficiency was 2.18% for CdS/CdSe QDs with the CdSe shell being 4.4 nanometers thick; a PCE of 0.07% for CdS QDs and a PCE of 0.63% for CdSe QDs were obtained under illumination at 100 mW cm-2. The results reveal that the CdS/CdSe core/shell structure QDs sensitized TiO2 NW electrodes have promising applications in solar cells. PMID- 28597887 TI - Revealing the structure and functionality of graphene oxide and reduced graphene oxide/pyrene carboxylic acid interfaces by correlative spectral and imaging analysis. AB - A high-end correlated spectral and imaging multianalysis, adapted for bidimensional systems, is presented here to analyze graphene oxide (GO) and reduced GO (rGO) modified with pyrene carboxylic acid (PCA). Confocal Raman mapping was used next to two-photon excited Fluorescence Lifetime Imaging Microscopy (FLIM) to characterize the distribution of PCA on GO and rGO and compared to UV-vis and X-ray Photoelectron Spectroscopy (XPS) analysis of the materials. Raman imaging clearly highlights the difference in the spatial distribution of PCA molecules on GO and rGO. Two-photon excited FLIM helped in gaining insight into the elusive phenomena and effects occurring at the GO-PCA interface level. Apart from the charge transfer effects from PCA molecules to GO, the GO structure depends on the molecular orientation and the spatial distribution of PCA molecules identified by different sp2 network domains in Raman mapping. Heating of GO-PCA results in an enhancement of the sp2 network presumably as the PCA aromatic core becomes fused into the GO nanosheets whilst enriching the resulting rGO nanosheets with carboxyl functionalities. This "healing" effect observed in rGO-PCA might be of high importance for applications using rGO-PCA matrices and interfaces in particular for electrical devices. PMID- 28597888 TI - Determining oxidative stability of battery electrolytes: validity of common electrochemical stability window (ESW) data and alternative strategies. AB - Increasing the operation voltage of electrochemical energy storage devices is a viable measure to realize higher specific energies and energy densities. A sufficient oxidative stability of electrolytes is the predominant requirement for successful high voltage applicability. The common method to investigate oxidative stability of LIB electrolytes is related to determination of the electrochemical stability window (ESW), on e.g. Pt or LiMn2O4 electrodes. However, the transferability of the obtained results to practical systems is questionable for several reasons. In this work, we evaluated the validity of the potentiodynamic based ESW method by comparing the obtained data with the results of galvanostatic based techniques, applied on commercial positive electrodes. We demonstrated that the oxidative stabilities, determined by the two techniques, are in good accordance with each other. However, the investigation of electrolytes being incompatible to Li metal, renders conventional ESW measurements useless when metallic Li is used as counter - and reference electrode in the ESW setup. For this reason, we introduced an alternative setup based on Li4Ti5O12 full cells. On the example of a butyronitrile-based electrolyte, we finally demonstrated that this electrolyte is not only reductively but also oxidatively less stable than common LiPF6/organic carbonate based electrolytes. PMID- 28597889 TI - Molecular dynamics simulations of solvent-exfoliation and stabilization of graphene with the assistance of compressed carbon dioxide and pyrene-polyethylene glycol. AB - In this work we carried out molecular dynamics (MD) simulations to explore the mechanism of solvent-exfoliation and stabilization of graphene in the presence of (compressed) carbon dioxide (cpCO2), p-xylene and pyrene-polyethylene glycol (Py PEG) polymers. We studied the role of each component in graphene exfoliation and stabilization by setting different experimental variables. The simulation results show that the cpCO2 molecules played a "wedge" role in the exfoliation process, firstly wedging into the interlayer, and then helping solvent molecules to insert into the interlayer. The solvent molecules between the graphene sheets are the main reasons that graphene exfoliation is achieved. And the Py-PEG polymer chains mainly act as stabilizers to prevent the exfoliated graphene sheets from restacking. This work provides detailed theoretical clues to better understand the mechanism of exfoliation and stabilization of graphene. PMID- 28597891 TI - A novel banded structure ceramic phosphor for high-power white LEDs. AB - A novel banded structure ceramic phosphor has been fabricated in this research. This structure provides a convenient and effective method for regulating the full spectrum. It has the advantage of being able to adjust the intensity of all three primary colors independently, regardless of the mutual absorption among different active ions. PMID- 28597890 TI - An in vivo study on bone formation behavior of microporous granular calcium phosphate. AB - This study was developed based on in vivo investigation of microporous granular biomaterials based on calcium phosphates, involving matrices of beta-tricalcium phosphate (beta-TCP), hydroxyapatite (HA), biphasic compositions of both phases and a control group. The physicochemical characterization of materials was carried out by X-Ray diffraction (DRX) and mercury porosimetry. Biodegradability, bioactivity and neoformation processes were investigated by Raman spectroscopy, scanning electron microscopy (SEM) and polarized light conducted on biopsies obtained from in vivo tests for periods of 90 and 180 days. These were performed to evaluate the behavior of granular microporous compositions in relation to bone neoformation. Through the performance obtained from in vivo assays, excellent osseointegration and bone tissue neoformation were observed. The results are encouraging and show that the microporous granular biomaterials of HA, beta-TCP and biphasic compositions show similar results with perfect osseointegration. Architectures simulating a bone structure can make the difference between biomaterials for bone tissue replacement and repair. PMID- 28597892 TI - An unexpected rearrangement of pyrazolium halides based on N-N bond cleavage: synthesis of 1,2-dihydropyrimidines. AB - The rearrangement of pyrazolium halides was observed, giving 1,2 dihydropyrimidines in good to high yields. A broad scope of pyrazolium halides bearing various N-substituted benzyls or alkyls can be utilized. A mechanistic study using isotope labelling experiments suggested that the present rearrangement proceeds through an ylide formation/ring cleavage/ring closure pathway to yield the observed product. PMID- 28597893 TI - Observing the dynamic "hot spots" on two-dimensional Au nanoparticles monolayer film. AB - Interparticle spacing was controlled by evaporating water on 2D Au nanoparticles arrays. Relationships among SERS effect, SPR catalysis, and gap distance were experimentally and theoretically studied. PMID- 28597894 TI - Deciphering the aqueous chemistry of glyoxal oxidation with hydrogen peroxide using molecular imaging. AB - Aqueous surfaces after photochemical and dark reactions of glyoxal and hydrogen peroxide (H2O2) have been studied using a microfluidic reactor coupled with an in situ liquid time-of-flight secondary ion mass spectrometry (ToF-SIMS) for the first time. Spectral principal component analysis was used to determine similarities and differences among various photochemical aging and dark reaction samples and controls. Compared with previous results using bulk solutions, our unique liquid surface molecular imaging approach provided observations of glyoxal hydration (i.e., first and secondary products), oxidation products (i.e., glyoxylic acid, oxalic acid, formic acid, tartaric acid), oligomers, cluster ions, and water clusters with sub-micrometer spatial resolution. Observations of oxidation products give the physical foundation to deduce new reaction pathways at the aqueous surface. The first chemical mapping of water cluster changes between dark and photochemical aging suggests that glyoxal oxidation affects the hydrophobicity and water microenvironment at the surface, influencing the particle's ability of reactive uptake and subsequent cloud condensation nucleation and/or ice nucleation activation. Moreover, SIMS three-dimensional chemical mapping has made it possible to visualize the surface mixing state for the first time. We potentially provide a new method to investigate complex surface chemistry as an important source of aqueous secondary organic aerosol (aqSOA) formation in atmospheric chemistry. PMID- 28597895 TI - Investigation of plasmon resonance in metal/dielectric nanocavities for high efficiency photocatalytic device. AB - Photocatalytic nanostructures loaded with metallic nanoparticles are being considered as a potential candidate for designing efficient water splitting devices. Here, we aim to unveil the plasmonic behavior of a device made of Au TiO2 nanostructures through in-depth investigations combining electron energy loss spectroscopy (EELS) and cathodoluminescence (CL). The experiments confirm the existence of Au bulk plasmon excitation, intrinsic interband transitions, and plasmon losses over a wide range of energies (0.6-2.4 eV). Depending on the size and the shape of the obtained nanostructures, such as fishing hook (FH), asymmetric nanorod (AR), and a/symmetric nanoparticles, in our devices, the dephasing times and the quality factors of the modes vary. Finite difference time domain simulations were then carried out on FH and AR structures. These simulations indicate good agreement between the electric field enhancement and the obtained plasmon excitation as observed in EELS. Moreover, the plasmonic activity obtained by CL and EELS was correlated with the photocurrent measurements recorded with the device, which confirmed that the localized plasmons in Au generate hot electrons and enhance the photoresponse of the device. This study confirms the functionality of the metal dielectric photocatalyst device over a wide range of wavelengths ranging from UV to near IR. PMID- 28597896 TI - Direct catalytic enantioselective Mannich-type reaction of alpha,alpha dithioacetonitriles with imines using chiral bis(imidazoline)-Pd complexes. AB - The first highly enantioselective reaction of alpha,alpha-dithioacetonitriles with imines has been developed. Good yields and enantioselectivity were observed for the reaction of various imines using chiral bis(imidazoline) catalysts. The obtained products can be converted into beta-aminonitrile or 1,3-diaminoketone. PMID- 28597897 TI - Correction: Stable small bubble clusters in two-dimensional foams. AB - Correction for 'Stable small bubble clusters in two-dimensional foams' by Kai Zhang et al., Soft Matter, 2017, DOI: . PMID- 28597898 TI - Maxwell-Stefan diffusion coefficient estimation for ternary systems: an ideal ternary alcohol system. AB - The Maxwell-Stefan model is a popular diffusion model originally developed to model diffusion of gases, which can be considered thermodynamically ideal mixtures, although its application has been extended to model diffusion in non ideal liquid mixtures as well. A drawback of the model is that it requires the Maxwell-Stefan diffusion coefficients, which are not based on measurable quantities but they have to be estimated. As a result, numerous estimation methods, such as the Darken model, have been proposed to estimate these diffusion coefficients. However, the Darken model was derived, and is only well defined, for binary systems. This model has been extended to ternary systems according to two proposed forms, one by R. Krishna and J. M. van Baten, Ind. Eng. Chem. Res., 2005, 44, 6939-6947 and the other by X. Liu, T. J. H. Vlugt and A. Bardow, Ind. Eng. Chem. Res., 2011, 50, 10350-10358. In this paper, the two forms have been analysed against the ideal ternary system of methanol/butan-1-ol/propan-1-ol and using experimental values of self-diffusion coefficients. In particular, using pulsed gradient stimulated echo nuclear magnetic resonance (PGSTE-NMR) we have measured the self-diffusion coefficients in various methanol/butan-1-ol/propan-1 ol mixtures. The experimental values of self-diffusion coefficients were then used as the input data required for the Darken model. The predictions of the two proposed multicomponent forms of this model were then compared to experimental values of mutual diffusion coefficients for the ideal alcohol ternary system. This experimental-based approach showed that the Liu's model gives better predictions compared to that of Krishna and van Baten, although it was only accurate to within 26%. Nonetheless, the multicomponent Darken model in conjunction with self-diffusion measurements from PGSTE-NMR represents an attractive method for a rapid estimation of mutual diffusion in multicomponent systems, especially when compared to exhaustive MD simulations. PMID- 28597899 TI - Mechanochemical synthesis of two-dimensional aromatic polyamides. AB - Herein we report a facile mechanochemical synthesis of 2D aromatic polyamides (2DAPAs) under solvent-free and room temperature conditions for the first time. The solvent-free conditions are found to be key to the successful synthesis of 2DAPAs. These micrometer-size 2DAPAs have ultrathin graphene-like structures and are highly crystalline, solvent dispersible and thermally stable up to 400 degrees C. PMID- 28597900 TI - Correction: Dynamic nuclear polarization in a magnetic resonance force microscope experiment. AB - Correction for 'Dynamic nuclear polarization in a magnetic resonance force microscope experiment' by Corinne E. Isaac et al., Phys. Chem. Chem. Phys., 2016, 18, 8806-8819. PMID- 28597901 TI - A perspective for investigating photo-induced molecular dynamics from within with femtosecond free electron lasers. AB - Photo-induced molecular dynamics can now be investigated using free electron lasers (FELs) whose attributes are unprecedented brightness, few femtosecond pulses duration and in the near future few hundreds of attosecond pulse duration. These relatively new tools are utilized to investigate photon-induced physical and chemical processes by ionizing inner-shell electrons and thus unlocking molecular dynamics from within. PMID- 28597902 TI - Scalable and practical synthesis of clickable Cu-chelating azides. AB - A convenient and effective synthetic access to chelating azides was designed enabling the preparation of efficient clickable fluorescent derivatives. The comparison of the reactivity of these chelating azides to regular azides showcased the striking superiority of such derivatives for labeling applications. PMID- 28597903 TI - A near-infrared organic photosensitizer for use in dye-sensitized photoelectrochemical water splitting. AB - Dye-sensitized photoelectrochemical cells (DSPECs) composed of a new near infrared BODIPY dye D1 that is co-deposited with a ruthenium water oxidation catalyst C1 have been fabricated. The devices at pH 7.2 showed an excellent Faradaic efficiency of H2 production (65.8%) that was 5.4 times larger than that of a triphenylamine photosensitizer D2 and C1-coadsorbed cell. PMID- 28597904 TI - Engineering tough, highly compressible, biodegradable hydrogels by tuning the network architecture. AB - By precisely tuning the network architecture, tough, highly compressible hydrogels were engineered. The hydrogels were made by interconnecting high functionality hydrophobic domains through linear tri-block chains, consisting of soft hydrophilic middle blocks, flanked with flexible hydrophobic blocks. In showing their applicability, the efficient encapsulation and prolonged release of hydrophobic drugs were achieved. PMID- 28597905 TI - Stroke prevention in atrial fibrillation: Past, present and future. Comparing the guidelines and practical decision-making. AB - Concepts and our approaches to stroke prevention in atrial fibrillation (AF) have changed markedly over the last decade. There has been an evolution over the approach to stroke and bleeding risk assessment, as well as new treatment options. An increasing awareness of AF has led to calls to improve the detection of and population screening for AF. Stroke and bleeding risk assessment continues to evolve, and the ongoing debate on balance between simplicity and practicality, against precision medicine will continue. In this review article, we provide an overview of past, present and the (likely) future concepts and approaches to stroke prevention in AF. We propose three simple steps (the Birmingham '3-step') that offers a practical management pathway to help streamline and simplify decision-making for stroke prevention in patients with AF. PMID- 28597906 TI - Platelet receptors as therapeutic targets: Past, present and future. AB - Anti-platelet drugs reduce arterial thrombosis after plaque rupture and erosion, prevent stent thrombosis and are used to prevent and treat myocardial infarction and ischaemic stroke. Some of them may also be helpful in treating less frequent diseases such as thrombotic thrombocytopenic purpura. The present concise review aims to cover current and future developments of anti-platelet drugs interfering with the interaction of von Willebrand factor (VWF) with glycoprotein (GP) Ibalpha, and directed against GPVI, GPIIb/IIIa (integrin alphaIIbbeta3), the thrombin receptor PAR-1, and the ADP receptor P2Y12. The high expectations of having novel antiplatelet drugs which selectively inhibit arterial thrombosis without interfering with normal haemostasis could possibly be met in the near future. PMID- 28597907 TI - Mindfulness-based cognitive therapy for severely fatigued multiple sclerosis patients: A waiting list controlled study. AB - BACKGROUND: Fatigue is the most common symptom in multiple sclerosis. Evidence based treatment options are scarce. OBJECTIVE: To study the feasibility and potential effectiveness of mindfulness-based cognitive therapy in severely fatigued multiple sclerosis patients. METHODS: Non-randomized pilot study with a wai-ting list control period including 59 multiple sclerosis patients with severe fatigue. PRIMARY OUTCOME MEASURE: fatigue severity subscale of the Checklist Individual Strength-20. Secondary measures: Hospital Anxiety and Depression Scale, Life Satisfaction Questionnaire, subscale sleep of the Symptom Checklist 90, Cognitive Failure Questionnaire, Fatigue Catastrophizing Scale, Coping Inventory of Stressful Situations, and Five Facet Mindfulness Questionnaire-Short Form. Measurements were taken before treatment (double baseline), after treatment, and at follow-up (3 months). RESULTS: Adherence rate was 71%. Eight out of 10 participants who completed the intervention were satisfied with the intervention. Significant time effects were found for 7 out of 11 outcome measures (p = 0.006 to < 0.001). The effect size was moderate for all outcome measures that were significant post-treatment and/or at follow-up (N2 = 0.10 0.17). Improvements were maintained at follow-up. Of the completers, 46% showed a clinically relevant change regarding fatigue. CONCLUSION: Mindfulness-based cognitive therapy is feasible in severely fatigued multiple sclerosis patients and has positive results in the reduction of severe fatigue and several psychological factors. PMID- 28597908 TI - Chronic pain, depression and quality of life in individuals with spinal cord injury: Mediating role of participation. AB - OBJECTIVE: To test the hypotheses that: (i) pain is associated with depressive symptoms and quality of life; and (ii) participation restriction, satisfaction, and frequency mediate these relationships. DESIGN: Population-based, cross sectional study. SUBJECTS/PATIENTS: Community-dwelling individuals with spinal cord injury (n = 1,549). METHODS: Hypotheses were tested in individuals with at least moderate chronic pain on the spinal cord injury - Secondary Conditions Scale (n = 834), applying structural equation modelling to data for spinal cord injury subgroups related to lesion severity (paraplegia, tetraplegia, complete, incomplete) and time since injury (<= 10 vs >= 10 years). Model parameters included pain intensity (numerical rating scale), participation frequency, restriction, satisfaction (Utrecht Scale of Evaluation of Rehabilitation Participation; USER-Participation), depressive symptoms (5-item Mental Health Index of the Short Form Health Survey; MHI-5), and 5 selected quality of life items (World Health Organization Quality of Life Scale; WHOQoL-BREF). RESULTS: Structural equation models confirmed associations of pain with depressive symptoms and quality of life, as well as the mediating role of participation restriction and low satisfaction with participation. These findings were apparent in individuals with tetraplegia or complete lesion and in those <= 10 years since paraplegia or incomplete injury. CONCLUSION: Unrestricted or satisfactory participation was found to be a crucial resource for individuals living less than 10 years with a more severe spinal cord injury, since it represents buffering potential for the negative effects of chronic pain on mental health and quality of life. PMID- 28597909 TI - Diagnostic and therapeutic guidelines for gastro-entero-pancreatic neuroendocrine neoplasms (recommended by the Polish Network of Neuroendocrine Tumours). AB - Progress in the diagnostics and therapy of gastro-entero-pancreatic (GEP) neuroendocrine neoplasms (NEN), the published results of new randomised clinical trials, and the new guidelines issued by the European Neuroendocrine Tumour Society (ENETS) have led the Polish Network of Neuroendocrine Tumours to update the 2013 guidelines regarding management of these neoplasms. We present the general recommendations for the management of NENs, developed by experts during the Third Round Table Conference - Diagnostics and therapy of gastro-entero pancreatic neuroendocrine neoplasms: Polish recommendations in view of current European recommenda-tions, which took place in December 2016 in Zelechow near Warsaw. Drawing from the extensive experience of centres dealing with this type of neoplasms, we hope that we have managed to develop the optimal management system, applying the most recent achievements in the field of medicine, for these patients, and that it can be implemented effectively in Poland. These management guidelines have been arranged in the following order: gastric and duodenal NENs (including gastrinoma); pancreatic NENs; NENs of the small intestine and appendix, and colorectal NENs. PMID- 28597910 TI - A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7-CAG Expansion Loci in the Indian and Mexican Population. AB - Spinocerebellar ataxia type 7 (SCA7) is a rare neurogenetic disorder caused by highly unstable CAG repeat expansion mutation in coding region of SCA7. We aimed to understand the effect of diverse ATXN7 cis-element in correlation with CAG expansion mutation of SCA7. We initially performed an analysis to identify the haplotype background of CAG expanded alleles using eight bi-allelic single nucleotide polymorphisms (SNPs) flanking an ATXN7-CAG expansion in 32 individuals from nine unrelated Indian SCA7 families and 88 healthy controls. Subsequent validation of the findings was performed in 89 ATXN7-CAG mutation carriers and in 119 unrelated healthy controls of Mexican ancestry. The haplotype analyses showed a shared haplotype background and C allele of SNP rs6798742 (approximately 6 kb from the 3'-end of CAG repeats) is in complete association with expanded, premutation, intermediate, and the majority of large normal (>=12) CAG allele. The C allele (ancestral/chimp allele) association was validated in SCA7 subjects and healthy controls from Mexico, suggesting its substantial association with CAG expanded and expansion-prone chromosomes. Analysis of rs6798742 and other neighboring functional SNPs within 6 kb in experimental datasets (Encyclopedia of DNA Elements; ENCODE) shows functional marks that could affect transcription as well as histone methylation. An allelic association of the CAG region to an intronic SNP in two different ethnic and geographical populations suggests a -cis factor-dependent mechanism in ATXN7 CAG-region expansion. PMID- 28597911 TI - Digitizing Medicines for Remote Capture of Oral Medication Adherence Using Co encapsulation. AB - High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories. PMID- 28597912 TI - Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus. AB - OBJECTIVE: To evaluate acute and long-term effects of intravenous brivaracetam (BRV) and BRV + diazepam (DZP) combination treatment in a rat model of self sustaining status epilepticus (SSSE). METHODS: Rats were treated with BRV (10 mg/kg) 10 min after initiation of perforant path stimulation (PPS) as early treatment; or BRV (10-300 mg/kg), DZP (1 mg/kg), or BRV (0.3-10 mg/kg) + DZP (1 mg/kg) 10 min after the end of PPS (established SSSE). Seizure activity was recorded electrographically for 24 h posttreatment (acute effects), and for 1 week at 6-8 weeks or 12 months' posttreatment (long-term effects). All treatments were compared with control rats using one-way analysis of variance (ANOVA) and Bonferroni's test, or Kruskal--Wallis and Dunn's multiple comparison tests, when appropriate. RESULTS: Treatment of established SSSE with BRV (10-300 mg/kg) resulted in dose-dependent reduction in SSSE duration and cumulative seizure time, achieving statistical significance at doses >=100 mg/kg. Lower doses of BRV (0.3-10 mg/kg) + low-dose DZP (1 mg/kg) significantly reduced SSSE duration and number of seizures. All control rats developed spontaneous recurrent seizures (SRS) 6-8 weeks after SSSE, whereas seizure freedom was noted in 2/10, 5/10, and 6/10 rats treated with BRV 200 mg/kg, 300 mg/kg, and BRV 10 mg/kg + DZP, respectively. BRV (10-300 mg/kg) showed a dose-dependent trend toward reduction of SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at 300 mg/kg. Combination of BRV (10 mg/kg) + DZP significantly reduced SRS frequency, cumulative seizure time, and spike frequency. In the 12-month follow-up study, BRV (0.3-10 mg/kg) + low-dose DZP markedly reduced SRS frequency, cumulative seizure time, and spike frequency, achieving statistical significance at some doses. Early treatment of SSSE with BRV 10 mg/kg significantly reduced long-term SRS frequency. SIGNIFICANCE: These findings support clinical evaluation of BRV for treatment of status epilepticus or acute repetitive seizures. PMID- 28597914 TI - Computed tomographic features of urinary bladder torsion in two dogs. AB - Urinary bladder torsion is rare in dogs. It is characterised by rotation of the organ along its longitudinal axis and is potentially life-threatening because of urinary flow obstruction with subsequent urine retention, hydroureter, hydronephrosis and azotaemia. This report describes the computed tomographic features of urinary bladder torsion in two dogs. In both cases, the hallmark indicative of torsion was the "whirl sign," originating from the twisted pelvic urethra and urinary bladder neck encircling the ureters, blood vessels and bladder ligaments in a characteristic spiral pattern. The imaging features correlated well with surgical findings, demonstrating high sensitivity of computed tomography in the preoperative diagnosis of urinary bladder torsion. PMID- 28597913 TI - Inherent vulnerabilities in monoaminergic pathways predict the emergence of depressive impairments in an animal model of chronic epilepsy. AB - The objective was to determine whether the depression comorbid with epilepsy could be predicted based on inherent premorbid patterns of monoaminergic transmission. In male Wistar rats, despair-like and anhedonia-like behaviors were examined using forced swimming and taste preference tests, respectively. Serotonergic raphe nucleus (RN)-prefrontal cortex (PFC) and dopaminergic ventral tegmental area (VTA)-nucleus accumbens (NAcc) pathways were interrogated by fast scan cyclic voltammetry (FSCV). The assays were performed before and 2 months after pilocarpine status epilepticus. In a subset of naive rats, FSCV, coupled with the intensity-dependent stimulation paradigm, detected specific deviations in each pathway (six rats for RN-PFC and seven rats for VTA-NAcc, with overlap in two, of 19 total subjects) in the absence of behavioral impairments. During epilepsy, animals with preexisting deviations in RN-PFC invariably developed despair, and rats with deviations in VTA-NAcc developed anhedonia. Serotonergic and dopaminergic pathways, respectively, showed signs of explicit deterioration. We suggest that epilepsy triggers decompensations in the already vulnerable depression-relevant neuronal circuits, which culminate in depression. The established connection between the identified specific signatures in monoamine transmission in naive rats and specific symptoms of epilepsy-associated depression may help in understanding causes of comorbidity and in developing its early biomarkers. PMID- 28597916 TI - Implementing a nursing systems framework in a developing country. AB - AIM: To test the effect on patient mortality of implementing a nursing systems framework across a national health system. BACKGROUND: There have been five previous observational studies that have tested the effect of a nursing systems framework on clinical outcomes for patients. Implementation of a nursing systems framework in the health system of a developing country has not been evaluated. DESIGN: Quasi-experimental (before and after) study. METHOD: A nursing systems framework consisting of six themes: (i) Professionalisation; (ii) Education; (iii) Structure; (iv) Quality of nursing care; (v) An academic health system; and (vi) Communication (Professional), was implemented across the national health system of Qatar in March 2015. Routine administrative data were extracted (March 2014-February 2016) for elective admissions. Our primary and secondary outcomes were, respectively, all cause mortality at discharge and readmission to hospital (within 28 days of discharge). We split the data into two time periods: before (March 2014-February 2015) and after (March 2015-February 2016) the implementation of the nursing systems framework. Multivariable regression modelling was used to examine the effect of the framework on patient mortality, after adjusting for key confounding variables (patient age, episode acuity, intensive care admission and length of stay). FINDINGS: Data were extracted for 318 548 patients (year 1 = 130 829; year 2 = 187 725). After adjusting for confounding, there was a significant association between the implementation of the nursing systems framework, mortality and readmission. CONCLUSION AND IMPLICATIONS FOR NURSING POLICY AND PRACTICE: Our observations suggest that the implementation of a nursing systems framework may be important in improving outcomes for patients in emerging health systems. PMID- 28597915 TI - Dissecting LSD1-Dependent Neuronal Maturation in the Olfactory Epithelium. AB - Neurons in the olfactory epithelium (OE) each express a single dominant olfactory receptor (OR) allele from among roughly 1,000 different OR genes. While monogenic and monoallelic OR expression has been appreciated for over two decades, regulators of this process are still being described; most recently, epigenetic modifiers have been of high interest as silent OR genes are decorated with transcriptionally repressive trimethylated histone 3 lysine 9 (H3K9me3) whereas active OR genes are decorated with transcriptionally activating trimethylated histone 3 lysine 4 (H3K4me3). The lysine specific demethylase 1 (LSD1) demethylates at both of these lysine residues and has been shown to disrupt neuronal maturation and OR expression in the developing embryonic OE. Despite the growing literature on LSD1 expression in the OE, a complete characterization of the timing of LSD1 expression relative to neuronal maturation and of the function of LSD1 in the adult OE have yet to be reported. To fill this gap, the present study determined that LSD1 (1) is expressed in early dividing cells before OR expression and neuronal maturation and decreases at the time of OR stabilization; (2) colocalizes with the repressor CoREST (also known as RCOR1) and histone deacetylase 2 in these early dividing cells; and (3) is required for neuronal maturation during a distinct time window between activating reserve stem cells (horizontal basal cells) and Neurogenin1 (+) immediate neuronal precursors. Thus, this study clarifies the role of LSD1 in olfactory neuronal maturation. PMID- 28597917 TI - Prediction of specific depressive symptom clusters in youth with epilepsy: The NDDI-E-Y versus Neuro-QOL SF. AB - OBJECTIVE: Proper assessment and early identification of depressive symptoms are essential to initiate treatment and minimize the risk for poor outcomes in youth with epilepsy (YWE). The current study examined the predictive utility of the Neurological Disorders Depression Inventory-Epilepsy for Youth (NDDI-E-Y) and the Neuro-QOL Depression Short Form (Neuro-QOL SF) in explaining variance in overall depressive symptoms and specific symptom clusters on the gold standard Children's Depression Inventory-2 (CDI-2). METHODS: Cross-sectional study examining 99 YWE (female 68, mean age 14.7 years) during a routine epilepsy visit, who completed self-report measures of depressive symptoms, including the NDDI-E-Y, CDI-2, and the Neuro-QOL SF. Caregivers completed a measure of seizure severity. All sociodemographic and medical information was evaluated through electronic medical record review. RESULTS: After accounting for seizure and demographic variables, the NDDI-E-Y accounted for 45% of the variance in the CDI-2 Total score and the CDI-2 Ineffectiveness subscale. Furthermore, the NDDI-E-Y predicted CDI-2 Total scores and subscales similarly, with the exception of explaining significantly more variance in the CDI-2 Ineffectiveness subscale compared to the Negative Mood subscale. The NDDI-E-Y explained greater variance compared to Neuro-QOL SF across the Total (48% vs. 37%) and all CDI-2 subscale scores; however, the NDDI-E-Y emerged as a stronger predictor of only CDI-2 Ineffectiveness. Both the NDDI-E-Y and Neuro-QOL SF accounted for the lowest amount of variance in CDI-2 Negative Mood. Sensitivity was poor for the Neuro-QOL SF in predicting high versus low CDI 2 scores. SIGNIFICANCE: The NDDI-E-Y has strong psychometrics and can be easily integrated into routine epilepsy care for quick, brief screening of depressive symptoms in YWE. PMID- 28597918 TI - Inflammation in the developing rat modulates astroglial reactivity to seizures in the mature brain. AB - Astrocytes participate in neuronal development and excitability, and produce factors enhancing or suppressing inflammatory processes occurring due to neurodegenerative diseases, such as epilepsy. Seizures, in turn, trigger the release of inflammatory mediators, causing structural and functional changes in the brain. Therefore, it appears reasonable to determine whether generalized inflammation at developmental periods can affect astrocyte reactivity to epileptic seizures occurring in the adult brain. Lipopolysaccharide (LPS) was injected in 6- or 30-day-old rats (P6 or P30, respectively). At the age of 2 months, seizures were induced, and pilocarpine and morphological changes of astrocytes located within the hippocampal formation were assessed. Additionally, expression of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), aquaporin 4 (AQP4), and inwardly rectifying potassium channel Kir 4.1 (Kir4.1) was determined using Western blots. The animal group given LPS on P6 displayed maximal susceptibility to pilocarpine-induced seizures, significantly higher than the group that received LPS on P30. In the immunohistologically examined hippocampal formation, the GFAP-immunoreactive area was not affected by LPS alone. However, it was reduced following seizures in naive controls but not in LPS-pretreated rats. Increases in the ramification of astrocytic processes were detected only in adult rats given LPS on P30, not on P6. Seizures abolished the effects. Following seizures, the process ramification showed no significant change in the two LPS-treated rat groups, whereas it was significantly reduced in the dentate gyrus of LPS-untreated controls. Glial fibrillary acidic protein (GFAP) expression showed no changes induced with LPS alone and rose slightly after seizures. AQP4 content was lower in rats given LPS on P6 and was seizure resistant in the two LPS-treated groups, contrary to a decrease in untreated controls. GS expression was not affected by LPS treatments and was reduced after seizures without an intergroup difference. Kir4.1 underwent highly significant increases in all groups experiencing seizures, but LPS alone had no effect. It can be concluded that the generalized inflammatory status led to some important changes in astrocytes reflected, in part at least by permanent modifications of their morphology and molecular profile. Moreover, the previously experienced inflammation prevented the cells from much stronger changes in response to seizures observed in adult untreated controls. The obtained results point to a link between the activation of astrocytes by transient systemic inflammation occurring during the developmental period and their subsequent reactivity to seizures, which may play an important role in the functional features of the brain, including its susceptibility to seizures. PMID- 28597919 TI - An Open-Label Dose-Finding Study of Allopurinol to Target Defined Reduction in Urate Levels in Hemodialysis Patients. PMID- 28597920 TI - A Case of Nonfatal Intoxication Associated with the Recreational use of Diphenidine. AB - Diphenidine is a dissociative drug that shows several psychotropic effects including euphoria, shifts in perception of reality, hallucinations, and transient anterograde amnesia. In this study, a case of acute intoxication occurring after diphenidine intake is reported. A 30-year-old Caucasian male was hospitalized after he was found in a confused and agitated state and unable to communicate. The physical examination displayed tachycardia, miotic pupils, and increased both body temperature and respiratory rate. After a liquid-liquid extraction procedure, GC/MS analysis revealed the presence of diphenidine in plasma and urine at concentrations of 308 and 631 ng/mL, respectively. Methylphenidate and diclazepam were also detected in the plasma. The clinical progress of the patient was favorable, and his symptoms were cured with a symptomatic treatment. The combined circumstantial elements and toxicological results of the case reported revealed the occurrence of an acute intoxication ascribable to the recreational abuse of diphenidine. PMID- 28597921 TI - Feasibility of Canine Detection of Mass Storage Devices: A Study of Volatile Organic Compounds Emanating from Electronic Devices Using Solid Phase Microextraction. AB - Detection of canines are well-known to be valuable in the location of contraband, such as explosives or narcotics. More recently, canines have been trained and utilized in the detection of concealed mass storage devices that might contain evidence of illegal activity such as child pornography. To lay the analytical foundation for this detection work, research was carried out to determine the volatile organic compounds associated with mass storage devices (MSD) that could be used by trained canines for detection. Headspace analysis of a variety of electronic devices was performed using solid phase microextraction (SPME) with gas chromatography/mass spectrometry (GC/MS). Analyses found several volatile compounds common to SIM and SD cards, as well as USB drives, including 2 propenenitrile, styrene, isophorone, hydroxycyclohexyl phenyl ketone, and 2 furanmethanol, tetrahydro. Results indicated that mass storage devices do have a characteristic odor profile making detection with minimal false alerts feasible for trained canines. PMID- 28597922 TI - Pharmacokinetic Characterization and Dose Selection of a Novel Sumatriptan Nasal Spray Formulation, DFN-02. AB - This 3-way, single-dose, randomized crossover study evaluated the pharmacokinetics (PK) and dose proportionality of 5-, 10-, and 15-mg doses of intranasal sumatriptan (DFN-02) coformulated with a permeation enhancer (DDM) in 18 healthy adults. The objective was to determine which DFN-02 dose approximates the PK of a 6-mg dose of sumatriptan delivered via subcutaneous injection in the deltoid muscle of the arm. Sumatriptan plasma concentrations peaked with DFN-02 between 10 and 15 minutes postdose, declining thereafter, with a t1/2 of about 2.5 hours; mean Cmax and AUC0-infinity values increased linearly across doses. After DFN-02 doses of 5, 10, and 15 mg, mean Cmax was 40.7 +/- 14.2, 71.2 +/- 22.1, and 101.0 +/- 49.5 ng/mL, and mean AUC0-infinity was 49.9 +/- 20.6, 87.1 +/- 31.2, and 120.5 +/- 53.3 ng.h/mL, respectively. The increase in sumatriptan bioavailability was less than dose-proportional among the DFN-02 doses studied. Based on the established PK of a 6-mg subcutaneous sumatriptan injection (mean Tmax , 12 minutes; mean Cmax , 74 +/- 15 ng/mL in the deltoid area of the arm) and the peak and time to peak sumatriptan concentrations of the DFN-02 doses tested, a 10-mg dose of DFN-02 was found to be the closest match. Overall, DFN-02 was well tolerated at doses of 5 to 15 mg, and no new safety concerns were identified. PMID- 28597923 TI - Mucinous adenocarcinoma in association with hidradenitis suppurativa. PMID- 28597924 TI - Introduction. PMID- 28597925 TI - Validation of a procedure to quantify oxolinic acid, danofloxacin, ciprofloxacin and enrofloxacin in selected meats by micellar liquid chromatography according to EU Commission Decision 2002/657/EC. AB - The suitability of an analytical method to determine oxolinic acid, danofloxacin, ciprofloxacin and enrofloxacin in edible tissues, based on micellar liquid chromatography coupled with fluorescence detection, to be applied in chicken, turkey, duck, lamb, goat, rabbit and horse muscle, is described. The method was fully matrix-matched in-lab revalidated, for each antimicrobial drug and meat, following the guidelines of the EU Commission Decision 2002/657/EC. The permitted limits were the maximum residue limits stated by the EU Commission Regulation 37/2010. The results obtained for the studied validation parameters were in agreement with the guidelines: selectivity (the antibiotics were resolved), linearity (r2 > 0.995), limit of detection (0.004-0.02 mg/kg), limits of quantification (0.01-0.05 mg/kg), calibration range (up to 0.5 mg/kg), recovery (89.5-105.0%), precision (<8.3%), decision limit, detection capability, ruggedness, stability and application to incurred samples. The method was found to be able to provide reliable concentrations with low uncertainty within a large interval, including the maximum residue limits, and then was useful to find out prohibited contaminated samples. The method did not require to be adapted for these matrices, and then it maintained its interesting advantages: short-time, eco-friendly, safe, inexpensive, easy-to-conduct, minimal manipulation and useful for routine analysis. PMID- 28597926 TI - Effect of hospital-wide interventions to optimize albumin use in a tertiary hospital. AB - WHAT IS KNOWN AND OBJECTIVE: Albumin has been frequently used as a therapeutic agent based on previous recommendations that are mostly controversial. Considering limited evidence-based indications, common inappropriate albumin use in many hospitals necessitates prompt educational and regulatory interventions. We performed this study to assess the effect of a hospital-wide programme to optimize albumin use in a tertiary referral university-affiliated hospital. METHODS: This study was conducted in three 45-day phases, separated by two sequential interventions: guideline implementation and albumin order-sheet consideration. We evaluated albumin use and assessed its appropriateness in each phase at baseline, after guideline implementation and after order-sheet consideration. RESULTS: We recorded 100, 93 and 71 albumin orders for 100, 84 and 66 patients during the first, second and third phases, respectively. The adjusted number of albumin orders (used albumin vials) was 94.9 (1481.7 vials), 80.8 (1037.6 vials) and 66 (1219 vials) in the first, second and third phases of the study, respectively. Albumin orders with appropriate indication increased significantly over the three phases of the study (OR=1.5, P=.008). The frequency of inappropriate orders reduced significantly from the first phase to the third phase (58%-27%, P=.007). WHAT IS NEW AND CONCLUSION: The pattern and amount of albumin use changed following guideline implementation and order-sheet consideration, and inappropriate albumin use was reduced in our hospital. There was still room for improvement, particularly for indications that were not included in the guideline. Hence, a more comprehensive guideline, frequent audit, feedback and interactive educational approaches might be necessary to achieve results that are of a greater magnitude. PMID- 28597928 TI - Disseminated papular lesions as a unique manifestation heralding bacille Calmette Guerin infection in a patient with T-B+NK- severe combined immunodeficiency. PMID- 28597927 TI - The prevalence of anxiety and associated factors in persons with epilepsy. AB - The objectives of this study were to estimate the prevalence of, and factors associated with, anxiety in epilepsy. We conducted a cross-sectional analysis using data from the Neurological Disease and Depression Study. The prevalence of anxiety and associated factors were assessed using descriptive statistics and logistic regression. Of the total sample (n = 250 patients), nearly 40.0% of participants had anxiety according to the Hospital Anxiety and Depression Scale. The most prevalent symptom of anxiety was "worrying thoughts" (35.6%). After adjustment for age and sex, depression (odds ratio [OR] = 8.97, 95% confidence interval [CI] = 4.38-18.40), medication side effects (OR = 1.79, 95% CI = 1.04 3.05), smoking (OR = 4.35, 95% CI = 2.27-8.31), and illicit substance use (OR = 2.42, 95% CI = 1.18-4.96) were significantly associated with higher odds of anxiety, whereas higher education (OR = 0.47, 95% CI = 0.28-0.80) was associated with lower odds of anxiety. Furthermore, participants with anxiety reported more severe epilepsy, debilitating seizures, and overall lower quality of life. Evidence from our study reveals a high prevalence of anxiety in persons with epilepsy and that anxiety is associated with a variety of negative outcomes. These findings further emphasize the need for more studies to understand the impact of anxiety and its relationship with various sociodemographic and clinical factors. PMID- 28597929 TI - Next-generation sequencing of oncogenes and tumor suppressor genes in odontogenic myxomas. AB - BACKGROUND: Mutations previously considered drivers of malignant neoplasms also occur in benign tumors. From the biological perspective, the study of malignant and benign neoplasms is equally relevant. The study of rare tumors contributes to the understanding of the more common ones, as both could share the same hallmark genetic drivers. The identification of driver mutations in benign tumors is facilitated by the fact that they harbor quiet genomes. Pathogenic mutations have being described in benign epithelial odontogenic tumors, such as ameloblastomas and adenomatoid odontogenic tumors. However, the molecular pathogenesis of odontogenic myxoma (OM), a benign aggressive ectomesenchymal tumor, is still poorly characterized, precluding the development of personalized therapy. Aiming to find druggable genetic mutations, we investigated in OM mutations in 50 genes commonly mutated in cancer. METHODS: We used targeted next-generation sequencing to interrogate over 2,800 COSMIC mutations in OM. RESULTS: Missense single nucleotide variants were detected in KDR, TP53, PIK3CA, KIT, JAK3; however, these did not include pathogenic mutations. CONCLUSION: These aggressive tumors do not harbor pathogenic mutations in genes commonly mutated in human cancers or if they do, these mutations probably occur in a low proportion of cases. PMID- 28597930 TI - Infection control guidelines for optometrists 2016. AB - BACKGROUND: This paper provides an updated version of the paper: Infection control guidelines for optometrists 2007. METHODS: Information from peer-reviewed journal articles, guidelines from professional societies, and government health department and other websites and instructions from equipment manufacturers were considered in determining infection risk factors in optometric practice. They were used to revise the recommendations on disinfection, sterilisation and reprocessing procedures for instrumentation and other equipment used in optometric practice as well as personal infection control measures to be undertaken by staff. RESULTS AND CONCLUSIONS: Optometrists and optometric practice staff should adopt measures to minimise the risk of transmission of infection. These include appropriate hand-washing, staff vaccinations, single use instruments/equipment, appropriate disposal of waste, appropriate methods of reprocessing where items are reused, routine employment of standard infection control precautions and application of more rigorous procedures for individuals who are known to be infected or immuno-suppressed. Information provided to patients regarding infection control procedures in topical drug administration, contact lens wear and use of eye make-up are additional considerations for optometrists. PMID- 28597931 TI - An in vitro study of the long non-coding RNA TUG1 in tongue squamous cell carcinoma. AB - BACKGROUND: This study sought to study the expression of the long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) in tongue squamous cell carcinoma (TSCC) and reveal its possible function. METHODS: qRT-PCR was used to evaluate 27 samples of fresh TSCC tissues and adjacent normal tongue tissues. siRNA technology was employed to downregulate TUG1 expression in CAL-27 and SCC-9 cell lines. The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was utilized to assess cell proliferation ability; apoptosis and cell cycle phases were analysed via flow cytometry. RESULTS: qRT-PCR findings indicated that the lncRNA TUG1 was upregulated in TSCC tissues compared with adjacent normal tongue tissues (P<.05). After TUG1 expression was downregulated using siRNA technology, cell proliferation was significantly inhibited (P<.05), and the number of cells in S phase was reduced (P<.05). CONCLUSION: The lncRNA TUG1 may represent a potential oncogene in TSCC. PMID- 28597933 TI - Death due to a rare complication of colonoscopy and the potential medicolegal implications. AB - A 64-year-old woman was found dead at home after undergoing a screening colonoscopy. At autopsy, 1.9 L of blood was discovered within her abdominal cavity. The only major abnormality was nontraumatic avulsion of the splenic capsule. This was the only identifiable abnormality capable of causing the severe hemoperitoneum and demise of the patient. Although rare, splenic capsule avulsion is a recognized complication of colonoscopy. Many have theorized that it results from excessive traction on the splenocolic ligament resulting in a tear of the splenic capsule. Most patients present within the first 24 hours after the procedure with nonspecific symptoms, and many patients may not seek medical attention. The paucity of the literature in the area of splenic capsular avulsion after colonoscopy reinforces the importance of reporting known cases, and by doing so raise awareness of this rare but devastating complication of an otherwise beneficial screening procedure. PMID- 28597932 TI - Low-Cost Zeta Potentiometry Using Solute Gradients. AB - The zeta potential is an electric potential in the Debye screening layer of an electrolyte, which represents a key physicochemical surface property in various fields ranging from electrochemistry to pharmaceuticals. Thus, characterizing the zeta potential is essential for many applications, but available measurement techniques are limited. Electrophoretic light scattering is typically used to measure the zeta potential of particles in suspension, whereas zeta potential measurements of a solid wall in solution rely on either streaming potential or electroosmotic mobility measurement techniques, both of which are expensive and sophisticated. Here, a simple, robust method to simultaneously measure the zeta potential of particles in suspension and solid walls is presented. The method uses solute gradients to induce particle and fluid motions via diffusiophoresis and diffusioosmosis, respectively, which are both sensitive to the zeta potential of the particle and the wall. By visualizing the particle dynamics, both zeta potentials can be determined independently. Finally, a compact microscope is used to demonstrate low-cost zeta potentiometry that allows measurement of both particle and wall zeta potentials, which suggests a cost-effective tool for pharmaceuticals as well as for educational purposes. PMID- 28597934 TI - A comparison of four porewater sampling methods for metal mixtures and dissolved organic carbon and the implications for sediment toxicity evaluations. AB - Evaluations of sediment quality conditions are commonly conducted using whole sediment chemistry analyses but can be enhanced by evaluating multiple lines of evidence, including measures of the bioavailable forms of contaminants. In particular, porewater chemistry data provide information that is directly relevant for interpreting sediment toxicity data. Various methods for sampling porewater for trace metals and dissolved organic carbon (DOC), which is an important moderator of metal bioavailability, have been employed. The present study compares the peeper, push point, centrifugation, and diffusive gradients in thin films (DGT) methods for the quantification of 6 metals and DOC. The methods were evaluated at low and high concentrations of metals in 3 sediments having different concentrations of total organic carbon and acid volatile sulfide and different particle-size distributions. At low metal concentrations, centrifugation and push point sampling resulted in up to 100 times higher concentrations of metals and DOC in porewater compared with peepers and DGTs. At elevated metal levels, the measured concentrations were in better agreement among the 4 sampling techniques. The results indicate that there can be marked differences among operationally different porewater sampling methods, and it is unclear if there is a definitive best method for sampling metals and DOC in porewater. Environ Toxicol Chem 2017;36:2906-2915. Published 2017 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 28597935 TI - Failure rates of artificial dermis products in treatment of diabetic foot ulcer: A systematic review and network meta-analysis. AB - Diabetic foot ulcer (DFU) is a frequent complication in diabetic patients, occurring in up to 25% of those affected. Among the treatments available to clinicians, the use of bioengineered skin substitutes is an attractive alternative. Artificial dermis functions as a matrix, covering the wound and supporting healing and reconstruction of the lost tissue. This study was aimed at reviewing the use of five regeneration matrices (namely, Integra, Nevelia, Matriderm, Pelnac, and Renoskin) as reported by clinical trials. We searched Medline, Embase, ISI Web of Science, Scopus, and Cochrane Central Register of Controlled Trials databases for relevant studies. Risk of failure rates was analysed by relative risk ratio method and complete ulcer healing was studied using network meta-analysis. Thirteen studies (12 randomized clinical trials and one cohort study) were eligible for analysis. The network meta-analysis based on a single study for Matriderm and 12 studies for other products showed that Matriderm was statistically inferior in achieving complete ulcer healing, as compared to all other products combined. In the second phase analysis, which was limited to three studies using artificial dermis products, there was a 57% reduction in the risk of reepithelialization failure for DFU patients who used Matriderm or Pelnac, compared to those who used Pelnac with basic fibroblast growth factor spray or skin grafting. The data showed an overall low failure rate suggesting that these bioengineered skin products provide a suitable support and microenvironment for healing of DFUs with low ulcer recurrence rates. This systematic review with meta-analysis highlights the pressing need for more studies investigating the safety, efficacy and failure rates of regeneration matrices in the treatment of DFUs. PMID- 28597937 TI - Frustration-guided motion planning reveals conformational transitions in proteins. AB - Proteins exist as conformational ensembles, exchanging between substates to perform their function. Advances in experimental techniques yield unprecedented access to structural snapshots of their conformational landscape. However, computationally modeling how proteins use collective motions to transition between substates is challenging owing to a rugged landscape and large energy barriers. Here, we present a new, robotics-inspired motion planning procedure called dCC-RRT that navigates the rugged landscape between substates by introducing dynamic, interatomic constraints to modulate frustration. The constraints balance non-native contacts and flexibility, and instantaneously redirect the motion towards sterically favorable conformations. On a test set of eight proteins determined in two conformations separated by, on average, 7.5 A root mean square deviation (RMSD), our pathways reduced the Calpha atom RMSD to the goal conformation by 78%, outperforming peer methods. We then applied dCC-RRT to examine how collective, small-scale motions of four side-chains in the active site of cyclophilin A propagate through the protein. dCC-RRT uncovered a spatially contiguous network of residues linked by steric interactions and collective motion connecting the active site to a recently proposed, non canonical capsid binding site 25 A away, rationalizing NMR and multi-temperature crystallography experiments. In all, dCC-RRT can reveal detailed, all-atom molecular mechanisms for small and large amplitude motions. Source code and binaries are freely available at https://github.com/ExcitedStates/KGS/. PMID- 28597936 TI - The beneficial metabolic effects of insulin sensitizers are not attenuated by mitochondrial pyruvate carrier 2 hypomorphism. AB - NEW FINDINGS: What is the central question of this study? The antidiabetic effects of thiazolidinedione (TZD) drugs may be mediated in part by a molecular interaction with the constituent proteins of the mitochondrial pyruvate carrier complex (MPC1 and MPC2). We examined the ability of a mutant mouse strain expressing an N-terminal truncation of MPC2 (Mpc2Delta16 mice) to respond to TZD treatment. What is the main finding and its importance? The response of Mpc2Delta16 mice to TZD treatment was not significantly different from that of wild-type C57BL6/J control animals, suggesting that the 16 N-terminal amino acids of MPC2 are dispensable for the effects of TZD treatment. Rosiglitazone and pioglitazone are thiazolidinedione (TZD) compounds that have been used clinically as insulin-sensitizing drugs and are generally believed to mediate their effects via activation of the peroxisome proliferator-activated receptor gamma (PPARgamma). Recent work has shown that it is possible to synthesize TZD compounds with potent insulin-sensitizing effects and markedly diminished affinity for PPARgamma. Both clinically used TZDs and investigational PPARgamma sparing TZDs, such as MSDC-0602, interact with the mitochondrial pyruvate carrier (MPC) and inhibit its activity. The MPC complex is composed of two proteins, MPC1 and MPC2. Herein, we used mice expressing a hypomorphic MPC2 protein missing 16 amino acids in the N-terminus (Mpc2Delta16 mice) to determine the effects of these residues in mediating the insulin-sensitizing effects of TZDs in diet induced obese mice. We found that both pioglitazone and MSDC-0602 elicited their beneficial metabolic effects, including improvement in glucose tolerance, attenuation of hepatic steatosis, reduction of adipose tissue inflammation and stimulation of adipocyte browning, in both wild-type and Mpc2Delta16 mice after high-fat diet feeding. In addition, truncation of MPC2 failed to attenuate the interaction between TZDs and the MPC in a bioluminescence resonance energy transfer-based assay or to affect the suppression of pyruvate-stimulated respiration in cells. Collectively, these data suggest that the interaction between TZDs and MPC2 is not affected by loss of the N-terminal 16 amino acids nor are these residues required for the insulin-sensitizing effects of these compounds. PMID- 28597938 TI - Epigenetics in natural animal populations. AB - Phenotypic plasticity is an important mechanism for populations to buffer themselves from environmental change. While it has long been appreciated that natural populations possess genetic variation in the extent of plasticity, a surge of recent evidence suggests that epigenetic variation could also play an important role in shaping phenotypic responses. Compared with genetic variation, epigenetic variation is more likely to have higher spontaneous rates of mutation and a more sensitive reaction to environmental inputs. In our review, we first provide an overview of recent studies on epigenetically encoded thermal plasticity in animals to illustrate environmentally-mediated epigenetic effects within and across generations. Second, we discuss the role of epigenetic effects during adaptation by exploring population epigenetics in natural animal populations. Finally, we evaluate the evolutionary potential of epigenetic variation depending on its autonomy from genetic variation and its transgenerational stability. Although many of the causal links between epigenetic variation and phenotypic plasticity remain elusive, new data has explored the role of epigenetic variation in facilitating evolution in natural populations. This recent progress in ecological epigenetics will be helpful for generating predictive models of the capacity of organisms to adapt to changing climates. PMID- 28597940 TI - "Undoing" (or Symbolic Reversal) at Homicide Crime Scenes. AB - A closed case file review of a nonrandom national sample of 975 homicides disclosed 11 cases (1.13%) of undoing, wherein offenders engaged in crime scene behavior that has been considered an attempt to symbolically reverse the murder. The frequency of the various methods of undoing involved the use of blankets to cover the victim's body (55%), positioning the body (55%), use of a bed or couch (42%), washing the body (36%), using pillows (36%), as well as removing clothing and adding other types of adornments (27%). Ten of the 11 offenders were male, and one was female; all 12 victims were female. Ten of the 12 victims were family members or relationship intimates. These findings are consistent with prior reports which concluded that the motivation for undoing behavior is an attempt to compensate for guilt or remorse for having committed the homicide. PMID- 28597941 TI - Knotting of a urethral catheter. PMID- 28597939 TI - Precision oncology based on omics data: The NCT Heidelberg experience. AB - Precision oncology implies the ability to predict which patients will likely respond to specific cancer therapies based on increasingly accurate, high resolution molecular diagnostics as well as the functional and mechanistic understanding of individual tumors. While molecular stratification of patients can be achieved through different means, a promising approach is next-generation sequencing of tumor DNA and RNA, which can reveal genomic alterations that have immediate clinical implications. Furthermore, certain genetic alterations are shared across multiple histologic entities, raising the fundamental question of whether tumors should be treated by molecular profile and not tissue of origin. We here describe MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a clinically applicable platform for prospective, biology-driven stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors. We illustrate how a standardized workflow for selection and consenting of patients, sample processing, whole exome/genome and RNA sequencing, bioinformatic analysis, rigorous validation of potentially actionable findings, and data evaluation by a dedicated molecular tumor board enables categorization of patients into different intervention baskets and formulation of evidence-based recommendations for clinical management. Critical next steps will be to increase the number of patients that can be offered comprehensive molecular analysis through collaborations and partnering, to explore ways in which additional technologies can aid in patient stratification and individualization of treatment, to stimulate clinically guided exploratory research projects, and to gradually move away from assessing the therapeutic activity of targeted interventions on a case-by-case basis toward controlled clinical trials of genomics-guided treatments. PMID- 28597942 TI - Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients. AB - Gene fusions resulting from structural rearrangements are an established mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350 single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211 pediatric cancer patients were evaluated for copy number alterations (CNAs) associated with gene fusions. Karyotype or fluorescence in situ hybridization studies were performed in 42% of the patients. Ten percent of the bone marrow or solid tumor specimens had SNP array-associated CNAs suggestive of a gene fusion. Alterations involving ETV6, ABL1-NUP214, EBF1-PDGFRB, KMT2A(MLL), LMO2-RAG, MYH11 CBFB, NSD1-NUP98, PBX1, STIL-TAL1, ZNF384-TCF3, P2RY8-CRLF2, and RUNX1T1-RUNX1 fusions were detected in the bone marrow samples. The most common alteration among the low-grade gliomas was a 7q34 tandem duplication resulting in a KIAA1549 BRAF fusion. Additional fusions identified in the pediatric brain tumors included FAM131B-BRAF and RAF1-QKI. COL1A1-PDGFB, CRTC1-MAML2, EWSR1, HEY1, PAX3- and PAX7 FOXO1, and PLAG1 fusions were determined in a variety of solid tumors and a novel potential gene fusion, FGFR1-USP6, was detected in an aneurysmal bone cyst. The identification of these gene fusions was instrumental in tumor diagnosis. In contrast to hematologic and solid tumors in adults that are predominantly driven by mutations, the majority of hematologic and solid tumors in children are characterized by CNAs and gene fusions. Chromosomal microarray analysis is therefore a robust platform to identify diagnostic and prognostic markers in the clinical setting. PMID- 28597944 TI - A Quantum-mechanical Study of the Binding Pocket of Proteorhodopsin: Absorption and Vibrational Spectra Modulated by Analogue Chromophores. AB - Proteorhodopsin is a light-driven proton pumping membrane protein related to bacteriorhodopsin. It contains an all-trans retinal A1 chromophore covalently bound to a lysine residue via a protonated Schiff base. In this study, we exploited density functional theory (DFT) calculations to investigate the retinal binding pocket in the dark state and after mimicking photoisomerization. The model of the binding pocket is constructed incrementally by adding the residues near the retinal that are necessary to ensure a stable protonated Schiff base. The presence of a few water molecules near the Schiff base turns out to be an essential feature of the model. The absorption properties are then studied using time-dependent DFT (TDDFT) and compared to experimental data to further validate the structural model and to assess the accuracy of the computational setting. It is shown that TDDFT is able to reproduce the main absorption peak accurately and to quantitatively determine the spectral shift induced by substituting the native all-trans retinal A1 chromophore with different retinal analogues. Moreover, ab initio molecular dynamics simulations are performed to investigate the vibrational spectra of our models before and after isomerization. Specific differences in the vibrational spectra are identified that provide further insight into experimental FTIR difference spectra. PMID- 28597943 TI - Identification of Eight Synthetic Cannabinoids, Including 5F-AKB48 in Seized Herbal Products Using DART-TOF-MS and LC-QTOF-MS as Nontargeted Screening Methods. AB - Synthetic cannabinoids are sprayed onto plant material and smoked for their marijuana-like effects. Clandestine manufacturers modify synthetic cannabinoid structures by creating closely related analogs. Forensic laboratories are tasked with detection of these analog compounds, but targeted analytical methods are often thwarted by the structural modifications. Here, direct analysis in real time coupled to accurate mass time-of-flight mass spectrometry (DART-TOF-MS) in combination with liquid chromatography quadruple time-of-flight mass spectrometry (LC-QTOF-MS) are presented as a screening and nontargeted confirmation method, respectively. Methanol extracts of herbal material were run using both methods. Spectral data from four different herbal products were evaluated by comparing fragmentation pattern, accurate mass and retention time to available reference standards. JWH-018, JWH-019, AM2201, JWH-122, 5F-AKB48, AKB48-N-(4-pentenyl) analog, UR144, and XLR11 were identified in the products. Results demonstrate that DART-TOF-MS affords a useful approach for rapid screening of herbal products for the presence and identification of synthetic cannabinoids. PMID- 28597945 TI - Specific psychosocial exposures for workers' mental health: A population-based study. AB - BACKGROUND: In order to plan interventions it is important to obtain evidence on the relation between a health outcome and specific exposures. However, there are few studies that identify the effect of specific psychosocial work exposures on poor mental health. This is the aim of this study. METHODS: Population-based cross-sectional study in Catalonia. We estimated prevalence ratios (PR) of minor psychiatric disorder associated with several psychosocial work exposures. RESULTS: The items with highest PR were "Are there times when you need to be at work and at home at the same time?" (PR = 1.81), "Are you worried about a variation in your salary?" (PR = 1.77), "Is your work emotionally demanding?" (PR = 1.65) and "Are you worried about it being difficult for you to find another job if you became unemployed?" (PR = 1.51). CONCLUSIONS: This study could be useful in order to begin planning interventions on specific psychosocial exposures to protect mental health in the workplace. PMID- 28597947 TI - The feasibility of a pragmatic distance-based intervention to increase physical activity in lung cancer survivors. AB - The purpose of this study was to investigate the feasibility and preliminary efficacy of a pragmatic distance-based intervention designed to increase physical activity (PA) participation in lung cancer survivors. Fourteen lung cancer survivors were recruited via invitation from the State Cancer Registry to join a 12-week PA intervention of print materials paired with brief telephone follow-up. Outcome measures of feasibility, PA participation and quality of life (QoL) were assessed at baseline, post-intervention and follow-up via telephone interview. Eligibility, recruitment and attrition rates were 16%, 58% and 29% respectively. No adverse events were reported; however, pain scores worsened following the intervention (median change -3.6, IQR -8.0, 0.0). Average intervention adherence was 91% with low median ratings of participation burden (i.e., all items 1/7) and high trial evaluation (i.e., all items 7/7). Post-intervention, median change in self-reported moderate and vigorous PA was 84 min (IQR -22, 188), and several domains of QoL improved. However, for both of these outcomes, improvements were not maintained at follow-up. Our findings suggest that this pragmatic distance based intervention was safe, had good adherence rates, and indicate potential for improving short-term PA and QoL in lung cancer survivors. Additional strategies are needed to improve other indicators of feasibility, particularly recruitment, retention and long-term maintenance of improvements. Australian New Zealand Clinical Trials Registration: ACTRN12612000085875. PMID- 28597946 TI - Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes. AB - BACKGROUND: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody negative type 1 diabetes (T1D). OBJECTIVES: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D. METHODS: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers. RESULTS: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis. CONCLUSIONS: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers. PMID- 28597948 TI - Identification of a Carbonized Body Using Implanted Surgical Plates: The Importance of Computed Tomography. AB - In addition to clinical examination, forensic odontologists can use diagnostic imaging as an auxiliary method for identification. This paper reports a case where forensic odontologists from the Afranio Peixoto Legal Medicine Institute in Rio de Janeiro (Brazil) positively identified a carbonized and partially calcined body using oral and maxillofacial imaging. The cadaver showed several metallic plates fixed with metallic screws on bones of the neurocranium and viscerocranium. Family members provided spiral computed tomography scans of the skull and a panoramic radiograph that were acquired after an accident that required surgical procedures. Comparative analysis between the clinical exam and the maxillofacial images demonstrated complete coincidence, confirming the victim's identity. Dactyloscopy, which is the most commonly used method of identification, was not possible because of the body carbonization. Thus, diagnostic imaging, especially computed tomography, was essential for elucidation of this case. PMID- 28597950 TI - Vicinal Difunctionalization of Alkenes through a Multicomponent Reaction with the Insertion of Sulfur Dioxide. AB - A four-component reaction of aryldiazonium tetrafluoroborates, sulfur dioxide, alkenes, and hydroxylamines under mild conditions is accomplished. No catalyst or additive is needed for the vicinal difunctionalization of alkenes with the insertion of sulfur dioxide. Not only DABCO?(SO2 )2 (DABCO=1,4 diazabicyclo[2.2.2]octane) but also potassium metabisulfite (K2 S2 O5 ) is effective in this transformation. The multicomponent reaction proceeds efficiently at room temperature with broad substrate scope, leading to the corresponding products in good yields. PMID- 28597949 TI - Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity. AB - OBJECTIVE: The relationship between patterns of islet autoantibodies at diagnosis and specificity of the first islet autoantibody at the initiation of autoimmunity was analyzed with the aim of identifying patterns informative of the primary autoantibodies. METHODS: Information about a single first autoantibody at seroconversion and autoantibody data at diagnosis were available for 128 children participating in the follow-up cohort of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Autoantibody data at diagnosis and genotyping results were also obtained from children in the Finnish Pediatric Diabetes Register (FPDR). RESULTS: Insulin autoantibodies (IAA) were the most common primary antibodies (N = 68), followed by those for glutamic acid decarboxylase (GADA; N = 38), IA-2 antigen (IA-2A; N = 13), and zinc transporter 8 (ZnT8A; N = 9), whereas at diagnosis, IA-2A were most frequent (N = 103), followed by IAA (N = 78), ZnT8A (N = 73), and GADA (N = 71). Accordingly, the presence of many specific autoantibodies at diagnosis was due to the secondary antibodies appearing after primary antibodies, and in some cases, the primary autoantibody, most often IAA, had already disappeared at the time of diagnosis. Many of the autoantibody combinations present at diagnosis could be assembled into groups associated with either IAA or GADA as first autoantibodies. These combinations, in children diagnosed below the age of 10 years in the FPDR, were found to be strongly associated with risk genotypes in either INS (IAA first) or IKZF4-ERBB3 (GADA first) genes. CONCLUSIONS: Autoantibody patterns at diagnosis may be informative on primary autoantibodies initiating autoimmunity in young children developing type 1 diabetes. PMID- 28597951 TI - Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis. AB - : Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+ CD127+ CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood-derived CD4+ CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+ CD127+ CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+ CD127+ CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+ CD127+ CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. CONCLUSION: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570-1584). PMID- 28597952 TI - Efficacy of Combined Sous Vide-Microwave Cooking for Foodborne Pathogen Inactivation in Ready-to-Eat Chicory Stems. AB - There is a variety of different food processing methods, which can be used to prepare ready-to-eat foods. However, the need to preserve the freshness and nutritional qualities leads to the application of mild technologies which may be insufficient to inactivate microbial pathogens. In this work, fresh chicory stems were packed under a vacuum in films, which were transparent to microwaves. These were then exposed to microwaves for different periods of time. The application of sous vide microwave cooking (SV-MW, 900 W, 2450 MHz), controlled naturally occurring mesophilic aerobic bacteria, yeasts and molds for up to 30 d when vacuum-packed vegetables were stored at 4 degrees C. In addition, the process lethality of the SV-MW 90 s cooking was experimentally validated. This treatment led to 6.07 +/- 0.7 and 4.92 +/- 0.65 log cfu/g reduction of Escherichia coli and Listeria monocytogenes inoculated over the chicory stems (100 g), respectively. With an initial load of 9 log cfu/g for both pathogens, less than 10 cfu/g of surviving cells were found after 90 s cooking. This shows that short-time microwave cooking can be used to effectively pasteurize vacuum-packed chicory stems, achieving >5 log cfu/g reduction of E. coli and L. monocytogenes. PMID- 28597953 TI - A clip domain serine protease involved in moulting in the silkworm, Bombyx mori: cloning, characterization, expression patterns and functional analysis. AB - Clip domain serine proteases (CLIPs), characterized by one or more conserved clip domains, are essential components of extracellular signalling cascades in various biological processes, especially in innate immunity and the embryonic development of insects. Additionally, CLIPs may have additional non-immune functions in insect development. In the present study, the clip domain serine protease gene Bombyx mori serine protease 95 (BmSP95), which encodes a 527-residue protein, was cloned from the integument of B. mori. Bioinformatics analysis indicated that BmSP95 is a typical CLIP of the subfamily D and possesses a clip domain at the N terminus, a trypsin-like serine protease (tryp_spc) domain at the C terminus and a conserved proline-rich motif between these two domains. At the transcriptional level, BmSP95 is expressed in the integument during moulting and metamorphosis, and the expression pattern is consistent with the fluctuating 20-hydroxyecdysone (20E) titre in B. mori. At the translational level, BmSP95 protein is synthesized in the epidermal cells, secreted as a zymogen and activated in the moulting fluid. Immunofluorescence revealed that BmSP95 is distributed into the old endocuticle in the moulting stage. The expression of BmSP95 was upregulated by 20E. Moreover, expression of BmSP95 was downregulated by pathogen infection. RNA interference-mediated silencing of BmSP95 led to delayed moulting from pupa to moth. These results suggest that BmSP95 is involved in integument remodelling during moulting and metamorphosis. PMID- 28597954 TI - Exposure to Bordetella pertussis adenylate cyclase toxin affects integrin mediated adhesion and mechanics in alveolar epithelial cells. AB - BACKGROUND INFORMATION: The adenylate cyclase (CyaA) toxin is a major virulent factor of Bordetella pertussis, the causative agent of whooping cough. CyaA toxin is able to invade eukaryotic cells where it produces high levels of cyclic adenosine monophosphate (cAMP) affecting cellular physiology. Whether CyaA toxin can modulate cell matrix adhesion and mechanics of infected cells remains largely unknown. RESULTS: In this study, we use a recently proposed multiple bond force spectroscopy (MFS) with an atomic force microscope to assess the early phase of cell adhesion (maximal detachment and local rupture forces) and cell rigidity (Young's modulus) in alveolar epithelial cells (A549) for toxin exposure <1 h. At 30 min of exposure, CyaA toxin has a minimal effect on cell viability (>95%) at CyaA concentration of 0.5 nM, but a significant effect (~81%) at 10 nM. MFS performed on A549 for three different concentrations (0.5, 5 and 10 nM) demonstrates that CyaA toxin significantly affects both cell adhesion (detachment forces are decreased) and cell mechanics (Young's modulus is increased). CyaA toxin (at 0.5 nM) assessed at three indentation/retraction speeds (2, 5 and 10 MUm/s) significantly affects global detachment forces, local rupture events and Young modulus compared with control conditions, while an enzymatically inactive variant CyaAE5 has no effect. These results reveal the loading rate dependence of the multiple bonds newly formed between the cell and integrin-specific coated probe as well as the individual bond kinetics which are only slightly affected by the patho-physiological dose of CyaA toxin. Finally, theory of multiple bond force rupture enables us to deduce the bond number N which is reduced by a factor of 2 upon CyaA exposure (N ~ 6 versus N ~ 12 in control conditions). CONCLUSIONS: MFS measurements demonstrate that adhesion and mechanical properties of A549 are deeply affected by exposure to the CyaA toxin but not to an enzymatically inactive variant. This indicates that the alteration of cell mechanics triggered by CyaA is a consequence of the increase in intracellular cAMP in these target cells. SIGNIFICANCE: These results suggest that mechanical and adhesion properties of the cells appear as pertinent markers of cytotoxicity of CyaA toxin. PMID- 28597955 TI - Dispersal enhances beta diversity in nectar microbes. AB - Dispersal is considered a key driver of beta diversity, the variation in species composition among local communities, but empirical tests remain limited. We manipulated dispersal of nectar-inhabiting bacteria and yeasts via flower visiting animals to examine how dispersal influenced microbial beta diversity among flowers. Contrary to the prevailing view that dispersal lowers beta diversity, we found beta diversity was highest when dispersal was least limited. Our analysis suggested that this unexpected pattern might have resulted from stronger priority effects under increased dispersal. Dispersal is highly stochastic, generating variability in species arrival history and consequently the potential for community divergence via priority effects, in these and likely many other microbial, plant, and animal communities. Yet most previous experiments eliminated this possibility. We suggest that the positive effects of dispersal on beta diversity, like the one we report here, may have been greatly underappreciated. PMID- 28597956 TI - A post-GWAS confirming GPAT3 gene associated with pig growth and a significant SNP influencing its promoter activity. AB - Our previous genome-wide association study revealed that a SNP, ASGA0040372, located upstream of glycerol-3-phosphate acyltransferase 3 (GPAT3), is related to growth traits in Duroc pigs. In this study, we aimed to extensively investigate the genetic variation of GPAT3 and to further verify the contribution of ASGA0040372 to growth traits and its effect on promoter activity. Our data, obtained based on gene cloning and rapid amplification of cDNA ends experiments, showed that there are 14 exons and three alternative splicing variants. Five SNPs were detected, including ASGA0040372 and four novel SNPs. Furthermore, the five SNPs obtained were used to confirm their genetic effects on pig growth by an association study in a Duroc pig population. The results indicated that three SNPs (ASGA0040372, RS331766122 and RS346215414) are highly associated with average daily gain or days to 100 kg traits (P-value < 0.05). Subsequent analysis suggested that the promoter region of GPAT3 gene, from -950 to -500 bp, exhibited the highest activity. We also observed that ASGA0040372 (A/G) alleles have significantly different effects on promoter transcriptional activities, which leads to differential expression of GPAT3. Taken together, we conclude that the GPAT3 gene is associated with pig growth and that ASGA0040372 influences promoter activity of GPAT3 in pig. PMID- 28597958 TI - Pristine DNA Hydrogels from Biotechnologically Derived Plasmid DNA. AB - DNA hydrogels are of great interest for a variety of biomedical applications owing to their biocompatibility and biodegradability but the advantages of DNA hydrogels have not been exploited yet because of their limited availability. Thus far, DNA hydrogels have been prepared from synthetically derived building blocks, and their production on large scale would be far too expensive. As an alternative, here the generation of DNA hydrogels from plasmid DNA is reported. Plasmid DNA can be prepared on large scale at reasonable costs by a fermentation process. The desired linear DNA building blocks are then obtained from the plasmid DNA by enzymatic digestion. Gel formation is carried out by covalent bond formation between individual building blocks via enzymatic ligation. The generation of pristine DNA hydrogels from plasmid DNA is thus presented for the first time. The viscoelastic properties of the hydrogels were studied by rheology, which confirmed that the gels have storage moduli G' of >100 Pa. PMID- 28597957 TI - Early childhood infections precede development of beta-cell autoimmunity and type 1 diabetes in children with HLA-conferred disease risk. AB - BACKGROUND: The etiology of type 1 diabetes (T1D) is largely unknown. Infections and microbial exposures are believed to play a role in the pathogenesis and in the development of islet autoimmunity in genetically susceptible individuals. OBJECTIVE: To assess the relationships between early childhood infections, islet autoimmunity, and progression to T1D in genetically predisposed children. METHODS: Children with human leukocyte antigen (HLA)-conferred disease susceptibility (N=790; 51.5% males) from Finland (n = 386), Estonia (n = 322), and Russian Karelia (n = 82) were observed from birth up to the age of 3 years. Children attended clinical visits at the age of 3, 6, 12, 18, 24, and 36 months. Serum samples for analyzing T1D-associated autoimmune markers were collected and health data recorded during the visits. RESULTS: Children developing islet autoimmunity (n = 46, 5.8%) had more infections during the first year of life (3.0 vs 3.0, mean rank 439.1 vs 336.2; P = .001) and their first infection occurred earlier (3.6 vs 5.0 months; P = .005) than children with no islet autoimmunity. By May 2016, 7 children (0.9%) had developed T1D (progressors). Compared with non-diabetic children, T1D progressors were younger at first infection (2.2 vs 4.9 months; P = .004) and had more infections during the first 2 years of life (during each year 6.0 vs 3.0; P = .001 and P = .027, respectively). By 3 years of age, the T1D progressors had twice as many infections as the other children (17.5 vs 9.0; P = .006). CONCLUSIONS: Early childhood infections may play an important role in the pathogenesis of T1D. Current findings may reflect either differences in microbial exposures or early immunological aberrations making diabetes-prone children more susceptible to infections. PMID- 28597959 TI - Nonlinear Change Processes During Psychotherapy Characterize Patients Who Have Made Multiple Suicide Attempts. AB - Research suggests that multiple suicide attempters experience considerable variability in suicide ideation and longer-duration suicidal crises, which suggests the possibility of two states of stability (one low risk and one high risk). To date, however, few studies have examined nonlinear change processes in suicide ideation among patients. In a sample of 76 active duty U.S. Army soldiers receiving brief cognitive behavioral therapy for acute suicide risk, we examined differences in the ebb and flow of suicide ideation among multiple attempters, first-time attempters, and ideators. Results indicated that multiple attempters were characterized by two states of stability corresponding to low and high intensity suicide ideation; these states were separated by a region of instability corresponding to moderate intensity suicide ideation. In contrast, ideators and first-time attempters were characterized by only a single state of stability corresponding to low intensity suicide ideation. Among patients who have made multiple suicide attempts, suicide ideation may function as a bimodal rather than a continuous construct. PMID- 28597961 TI - Non-housekeeping, non-essential GroEL (chaperonin) has acquired novel structure and function beneficial under stress in cyanobacteria. AB - GroELs which are prokaryotic members of the chaperonin (Cpn)/Hsp60 family are molecular chaperones of which Escherichia coli GroEL is a model for subsequent research. The majority of bacterial species including E. coli and Bacillus subtilis have only one essential groEL gene that forms an operon with the co chaperone groES gene. In contrast to these model bacteria, two or three groEL genes exist in cyanobacterial genomes. One of them, groEL2, does not form an operon with the groES gene, whereas the other(s) does. In the case of cyanobacteria containing two GroEL homologs, one of the GroELs, GroEL1, substitutes for the native GroEL in an E. coli cell, but GroEL2 does not. Unlike the E. coli GroEL, GroEL2 is not essential, but it plays an important role which is not substitutable by GroEL1 under stress. Regulation of expression and biochemical properties of GroEL2 are different/diversified from GroEL1 and E. coli GroEL in many aspects. We postulate that the groEL2 gene has acquired a novel, beneficial function especially under stresses and become preserved by natural selection, with the groEL1 gene retaining the original, house-keeping function. In this review, we will focus on difference between the two GroELs in cyanobacteria, and divergence of GroEL2 from the E. coli GroEL. We will also compare cyanobacterial GroELs with the chloroplast Cpns (60alpha and 60beta) which are thought to be evolved from the cyanobacterial GroEL1. Chloroplast Cpns appear to follow the different path from cyanobacterial GroELs in the evolution after gene duplication of the corresponding ancestral groEL gene. PMID- 28597960 TI - Prevalence of malocclusion in individuals with and without intellectual disability: A comparative study. AB - OBJECTIVE: The aim of this study was to compare the prevalence malocclusion between individuals with intellectual disability (ID) and a control group without disability (NID). METHODS: A total of 202 individuals (123 with ID and 79 with no impairment) were included in the study. Data were collected through oral examinations using the Angle classification of malocclusion and the dental aesthetic index (DAI). RESULTS: According to Angle's classification of malocclusion, it was found that 37.6% of all participants presented malocclusion. Class II malocclusion was the most common form of malocclusion in both groups, whereas class III cases were present almost exclusively in ID group (91.7%). The mean DAI score was 30.85 (+/- 13.7), being higher in the ID group (32.80) than in the control group (27.81; p = 0.003). A total of 45 (22.3%) participants had DAI scores of 36 and above, which indicate a handicapping malocclusion requiring mandatory orthodontic treatment. From those needing mandatory orthodontic treatment, the majority (84.4%) belonged to ID group. Mandibular irregularity (56.4%) and incisal segment crowding (45%) were the most common features of the malocclusion. Linear regression indicates that having an intellectual disability predicts severe or very severe malocclusion. CONCLUSIONS: In this study, the prevalence of malocclusion was found to be higher and more severe in intellectual disabled participants. The dental practitioner should understand the particular relevance of this problem especially in patients with intellectual disabilities where impaired oral functions and poor appearance may further complicate oral health and increase negative social responses. PMID- 28597962 TI - An unusual clinical presentation of lupus erythematosus tumidus localized on the thigh. AB - A 44-year-old woman with seronegative polyarthritis presented with a 2-year history of a solitary, bluish-red, oedematous, nonscaly, annular and partially reticulated macule on her right thigh. Histopathological findings revealed perivascular and periadnexal lymphocytic infiltrate in the dermis. Alcian blue and colloidal iron stains highlighted mucinous deposit in the upper and mid dermis. Direct immunofluorescence showed a linear deposit of IgG and C3 along the basement membrane zone. Antinuclear antibody was positive at a titre of 1 : 80, with homogenous and speckled patterns. Except for its unusual localization and lack of photosensitivity, our case had the clinical and histopathological features of lupus erythematosus tumidus. These characteristics were also reminiscent of reticular erythematous mucinosis and erythema annulare centrifugum, both of which are considered to be associated with cutaneous lupus erythematosus (CLE). Hydroxychloroquine 200 mg daily led to improvement of the skin lesion. The unusual clinical presentation of our case emphasizes the heterogeneity of clinical manifestations of CLE. PMID- 28597964 TI - Interleukin-10 receptor mutation presenting with severe nappy ulceration and infantile inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) can be divided into Crohn disease, ulcerative colitis and inflammatory bowel disease unclassified (IBDU). In most patients, these disorders present in adolescence or early adulthood. Patients with infantile IBD can have an associated underlying immunodeficiency disorder caused by a mutation in interleukin (IL)-10 or its receptor. We describe a child presenting with intractable bloody diarrhoea since 2 weeks of age and with severe nappy ulceration, who was ultimately diagnosed as having inflammatory bowel disease (IBD) due to an immunodeficiency in the IL-10 receptor. This report highlights the importance of considering this rare immunodeficiency in patients with infantile IBD presenting with severe perianal disease to a dermatologist. PMID- 28597965 TI - Fracture resistance of zirconia-based all-ceramic crowns after bur adjustment. AB - Intra-oral grinding is often required to optimize occlusion of all-ceramic restorations. The effect of burs of different grit size on the fracture resistance of veneered zirconia crowns was investigated in this study. Forty eight standardized zirconia copings were produced. The ceramic veneer was designed with a positive ellipsoidal defect on the palatal aspect of the crowns. To simulate adjustment of dental restorations by burs, this palatal defect was removed by use of three different diamond-coated burs with grit sizes 46, 107, or 151 MUm (fine, medium, or coarse, respectively). Each different grit size of bur was used to grind 16 crowns. All crowns were then polished and surface roughness was measured. Half of the specimens underwent thermomechanical aging (10,000 thermocycles between 6.5 degrees C and 60 degrees C) and 1.2 million cycles of chewing simulation (F = 108 N). A linear regression model was computed to test the effect of aging and grinding grit size at a level of significance of alpha = 0.05. Fracture loads increased with decreasing grit size. Grit size and aging had a significant effect on the fracture resistance of the crowns. Use of fine and coarse burs for intra-oral adjustments resulted in different fracture resistance of veneered zirconia crowns. Coarse burs should be avoided in the final stage of grinding before polishing. PMID- 28597966 TI - Diurnal variation in outcomes after out-of-hospital cardiac arrest in Asian communities: The Pan-Asian Resuscitation Outcomes Study. AB - OBJECTIVE: The present study aimed to determine whether the time of out-of hospital cardiac arrest (OHCA) is associated with survival rate and neurological outcome after OHCA, as well as to compare the effect size of time of OHCA across six Asian regions. METHODS: We collected data from the Pan-Asian Resuscitation Outcomes Study registry, six Asian regions (Tokyo, Osaka, Aichi, Seoul, Taipei and Singapore) from 2009 to 2012. Adult OHCA cases were divided depending on the arrest time: I (00.01-06.00 hours), II (06.01-12.00 hours), III (12.01-18.00 hours) and IV (18.01-24.00 hours). Using a multivariable logistic regression analysis, we compared the outcomes of survival and good neurological recovery. RESULTS: Of 65 413 cases treated by the emergency medical service, 36 706 (56.1%) cases were analysed. There was the lowest OHCA incidence in time block I. Compared with time block I, the adjusted odds ratios and 95% confidence intervals for the standardised survival rate were 1.6 (1.3-1.9) in time block II, 1.4 (1.2 1.7) in time block III and 1.2 (1.0-1.4) in time block IV. Regarding the good neurological recovery rate, compared with time block I, the adjusted odds ratios and 95% confidence intervals were 1.9 (1.5-2.4) in time block II, 1.7 (1.3-2.1) in time block III and 1.4 (1.1-1.7) in time block IV. However, in the subgroup analysis, there were regional differences between Japan and the other regions. CONCLUSIONS: We found diurnal similarities in OHCA occurrence, as well as differences in survival rate and good neurological recovery rate among Asian regions. PMID- 28597963 TI - miR-181a and miR-150 regulate dendritic cell immune inflammatory responses and cardiomyocyte apoptosis via targeting JAK1-STAT1/c-Fos pathway. AB - The immune inflammatory response plays a crucial role in many cardiac pathophysiological processes, including ischaemic cardiac injury and the post infarction repair process. MicroRNAs (miRNAs) regulate the development and function of dendritic cells (DCs), which are key players in the initiation and regulation of immune responses; however, the underlying regulatory mechanisms remain unclear. Here, we used the supernatants of necrotic primary cardiomyocytes (Necrotic-S) to mimic the myocardial infarction (MI) microenvironment to investigate the role of miRNAs in the regulation of DC-mediated inflammatory responses. Our results showed that Necrotic-S up-regulated the DC maturation markers CD40, CD83 and CD86 and increased the production of inflammatory cytokines, concomitant with the up-regulation of miR-181a and down-regulation of miR-150. Necrotic-S stimulation activated the JAK/STAT pathway and promoted the nuclear translocation of c-Fos and NF-kappaB p65, and silencing of STAT1 or c-Fos suppressed Necrotic-S-induced DC maturation and inflammatory cytokine production. The effects of Necrotic-S on DC maturation and inflammatory responses, its activation of the JAK/STAT pathway and the induction of cardiomyocyte apoptosis under conditions of hypoxia were suppressed by miR-181a or miR-150 overexpression. Taken together, these data indicate that miR-181a and miR-150 attenuate DC immune inflammatory responses via JAK1-STAT1/c-Fos signalling and protect cardiomyocytes from cell death under conditions of hypoxia. PMID- 28597967 TI - Anidulafungin for the treatment of candidaemia caused by Candida parapsilosis: Analysis of pooled data from six prospective clinical studies. AB - Concerns with echinocandin use for infections caused by Candida parapsilosis complex species have driven the need for data to support echinocandin clinical efficacy in such patients. Data from six prospective studies were pooled to assess efficacy and safety of anidulafungin in patients with candidaemia caused by C. parapsilosis. Patient-level data were pooled from patients with microbiologically confirmed candidaemia due to C. parapsilosis treated with anidulafungin. Patients received a 200 mg intravenous (IV) loading dose of anidulafungin (day 1) and 100 mg daily thereafter. IV treatment could be switched to oral azole therapy after >=5 or >=10 days. Primary endpoint was global response at end of IV therapy (EOIVT). Seventy patients had candidaemia caused by C. parapsilosis. Global response was 77.1% (95% CI: 67.3, 87.0) at EOIVT and 70.0% (95% CI: 59.3, 80.7) at end of treatment. Three of 55 isolates (with MICs available) were resistant to anidulafungin (MIC >=8 mg/L). All-cause mortality was 5.7% (n=4/70) by day 14 and 14.3% (n=10/70) by day 28. IV anidulafungin was effective for the treatment of C. parapsilosis candidaemia in this population, consistent with efficacy previously demonstrated for other Candida species. (ClinicalTrials.gov identifiers: NCT00496197, NCT00548262, NCT00537329, NCT00689338, NCT00806351, NCT00805740). PMID- 28597968 TI - Genetic epidemiology of familial Mediterranean fever through integrative analysis of whole genome and exome sequences from Middle East and North Africa. AB - Familial Mediterranean fever (FMF), an autosomal recessive and rare autoinflammatory disease is caused by genetic mutations in the MEFV gene and is highly prevalent in the Mediterranean basin. Although the carrier frequency of specific disease variants in the MEFV gene has been reported from isolated studies, a comprehensive view of variants in the Mediterranean region has not been possible due to paucity of data. The recent availability of whole-genome and whole-exome datasets prompted us to study the genetic epidemiology of MEFV variants in the region. We assembled data from 5 datasets encompassing whole genome and whole-exome datasets for 2115 individuals from multiple subpopulations in the region and also created a compendium for MEFV genetic variants, which were further systematically annotated as per the American College of Medical Genetics and Genomics (ACMG) guidelines. Our analysis points to significant differences in allele frequencies in the subpopulations, and the carrier frequency for MEFV genetic variants in the population to be about 8%. The MEFV gene appears to be under natural selection from our analysis. To the best of our knowledge, this is the most comprehensive study and analysis of population epidemiology of MEFV gene variants in the Middle East and North African populations. PMID- 28597969 TI - The Role of Epigenetic Regulation and Pluripotency-Related MicroRNAs in Differentiation of Pancreatic Stem Cells to Beta Cells. AB - In this study, we aimed to research the effects of class-I HDACs and glucose on differentiation of pancreatic islet derived mesenchymal stem cells (PI-MSCs) to beta cells. Beta cell differentiation determined by flow cytometric analysis and gene expression levels of PDX1, PAX4, PAX6, NKX6.1, NGN3, INS2, and GLUT2. As a result the valproic acid, is an inhibitor of class-I HDACs, caused the highest beta cell differentiation in PI-MSCs. However, the cells in this group were at early stages of differentiation. Glucose co-administration to this group carried the differentiation to higher levels, but these newly formed beta cells were not functional. Moreover, reduction in the levels of pluripotency factors that Oct3/4, c-Myc, and Nanog were parallel to beta cell differentiation. Also, the levels of HDAC1 and acetylated H3/H4 were increased and methylated H3 was decreased by VPA treatment. In addition, we have detected over expression in genes of miR-18a-5p, miR-19b-5p, miR-30d-3p, miR-124, miR-146a-5p, miR-184, miR 335, and miR-433-5p in parallel to beta cell differentiation. As the conclusion, this study is important for understanding the epigenetic mechanism that controls the beta cell differentation and it suggests new molecules that can be used for diagnosis, and treatment of diabetes. J. Cell. Biochem. 119: 455-467, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28597970 TI - Simultaneous determination of eight short-chain aliphatic amines in drug substances by HPLC with diode array detection after derivatization with halonitrobenzenes. AB - Short-chain aliphatic amines are a class of hazardous impurities in drug substances. A simple method, involving derivatization followed by high performance liquid chromatography with diode array detection, has been developed for residue determination of eight aliphatic amines simultaneously in drug substances. Different halonitrobenzenes derivatization reagents were systematically compared. As a result, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene was selected since the derivatization effectively shifted the absorption wavelength to the visible region (400-450 nm), where most drug substances, impurities and even the derivatization reagent absorb very weakly. Due to the redshift effect, interference was minimized and adequately low limits of quantitation were reached (0.24-0.80 nmol/mL). Moreover, the derivatization reaction was readily carried out in dimethyl sulfoxide at room temperature for 1 h using N,N-diisopropylethylamine as catalyst to achieve the highest yield. Without any pre-treatment, the derivatives were analyzed by high-performance liquid chromatography with diode array detection. The high stability of the derivatives within 24 h at room temperature (RSD<1.04%) further facilitated the simultaneous preparation and consecutive analysis of quantities of samples. Finally, the proposed method was successfully applied for residue determination of eight aliphatic amines simultaneously in eight drug substance samples. This study could be helpful for the routine analysis and residue control of aliphatic amines in drug substances. PMID- 28597971 TI - Diagnosis of congenital hyperinsulinism: Biochemical profiles during hypoglycemia. AB - OBJECTIVES: To define the ranges of biochemical markers during hypoglycemia for the diagnosis of congenital hyperinsulinism (CHI), using high sensitivity insulin assays. SUBJECTS: A total of 298 patients with CHI and 58 control patients with non-hyperinsulinemic hypoglycemia, who were diagnosed after 2007. METHODS: The levels of biochemical markers (glucose, insulin, beta-hydroxybutyrate [BHB], free fatty acids [FFA], lactate, ammonia) at the time of hypoglycemia were analyzed along with the maximal glucose infusion rate (GIR) to maintain euglycemia and clinical outcomes. RESULTS: Median levels of blood glucose in patients with CHI and in controls were 30 and 46 mg/dL, while insulin levels were 9.90 and undetectable (<.5) MUU/mL, respectively. Similarly, median levels of BHB were 17.5 and 3745 umol/L, and those of FFA were 270.5 and 2660 umol/L, respectively. For patients after 5 months, cutoffs of insulin >1.25 MUU/mL, BHB < 2000 umol/L, and FFA < 1248 umol/L predicted CHI with sensitivities of 97.5, 96.2, and 95.2% and specificities of 84.2, 89.3, and 92.3%, respectively. Maximal GIR in the CHI groups tended to decrease with age. In addition, decreased gestational age, low birth weight, and elevated lactate at hypoglycemia were significantly more common in patients who were off treatment within 100 days without pancreatectomy. CONCLUSIONS: After introduction of high-sensitive assays, the diagnostic value of insulin was improved, allowing for more efficient cutoffs to be set for diagnosis of CHI. Premature birth, low birth weight and elevated lactate might be helpful in predicting early remission of hypoglycemia. PMID- 28597972 TI - A Novel Interacting Protein SERP1 Regulates the N-Linked Glycosylation and Function of GLP-1 Receptor in the Liver. AB - Glucagon-like peptide 1 (GLP-1) exerts multiple effects on metabolism through its receptor, GLP-1R, in the liver. Activation and transduction of GLP-1R require complex interactions of largely unknown accessory proteins, and these processes are crucial to the response to endoplasmic reticulum (ER) stress. Using the membrane-based split ubiquitin yeast two-hybrid system (MYTH) and a human liver cDNA library, we obtained the human GLP-1R interactome and identified SERP1 as a potential interacting protein based on its ability to stabilize membrane proteins and facilitate N-linked glycosylation. GLP-1R and SERP1 were co-expressed in HEK 293 cells, and their interaction was confirmed by co-immunoprecipitation. We then found that overexpression of SERP1 could rescue GLP-1R glycosylation after application of tunicamycin to block N-linked glycosylation. SERP1 overexpression also attenuated exendin-4-stimulated cAMP accumulation and AMPK activation. However, the glycosylation and function of mutant GLP-1R, in which all three sites for N-linked glycosylation were mutated, were not increased with overexpression of SERP1. Moreover, as a GLP-1R interactor, SERP1 could also partly reverse the accumulation of tunicamycin-induced ER stress. Taken together, our findings identify a group of proteins that interact with GLP-1R and show that one specific interacting protein, SERP1, has an important role in facilitating the glycosylation of GLP-1R and rescuing its activities after ER stress induced by tunicamycin. J. Cell. Biochem. 118: 3616-3626, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28597973 TI - Safety, Tolerability, and Pharmacokinetics of Single and Multiple Oral Doses of an Omega-3-Carboxylic Acid Formulation in Healthy Male Japanese Subjects: A Phase 1 Single-Blind, Randomized, Placebo-Controlled Trial. AB - OM3-CA (omega-3-carboxylic acids) is a complex mixture of omega-3 carboxylic acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which is approved in the United States for the treatment of hypertriglyceridemia. As part of its clinical development in Japan, we performed a phase 1 study to investigate the safety, tolerability, and pharmacokinetics after single and multiple doses of OM3-CA in healthy male Japanese subjects. Eighteen Japanese subjects were allocated to receive 2 or 4 g/day OM3-CA, or placebo (n = 6 per group). In addition, 6 white subjects received 4 g/day OM3-CA. The primary objective was to determine the safety and tolerability of OM3-CA. Plasma concentrations of EPA and DHA were adjusted for baseline values for pharmacokinetic analysis. Overall, OM3-CA was well tolerated in healthy Japanese subjects. Two Japanese subjects in each group and 5 white subjects experienced adverse events (AEs). Alanine aminotransferase increase was the most common AE in Japanese subjects, also seen with placebo, and diarrhea was the most common AE in white subjects. The maximum plasma concentrations of EPA and DHA were observed 5 6 hours postdose. The pharmacokinetic profiles of EPA and DHA after administration of OM3-CA were comparable between Japanese and white subjects. PMID- 28597974 TI - A simple cell transport device keeps culture alive and functional during shipping. AB - Transporting living complex cellular constructs through the mail while retaining their full viability and functionality is challenging. During this process, cells often suffer from exposure to suboptimal life-sustaining conditions (e.g. temperature, pH), as well as damage due to shear stress. We have developed a transport device for shipping intact cell/tissue constructs from one facility to another that overcomes these obstacles. Our transport device maintained three different cell lines (Caco2, A549, and HepG2 C3A) individually on transwell membranes with high viability (above 97%) for 48 h under simulated shipping conditions without an incubator. The device was also tested by actual overnight shipping of blood brain barrier constructs consisting of human induced pluripotent brain microvascular endothelial cells and rat astrocytes on transwell membranes to a remote facility (approximately 1200 miles away). The blood brain barrier constructs arrived with high cell viability and were able to regain full barrier integrity after equilibrating in the incubator for 24 h; this was assessed by the presence of continuous tight junction networks and in vivo-like values for trans-endothelial electrical resistance (TEER). These results demonstrated that our cell transport device could be a useful tool for long distance transport of membrane-bound cell cultures and functional tissue constructs. Studies that involve various cell and tissue constructs, such as the "Multi-Organ-on-Chip" devices (where multiple microscale tissue constructs are integrated on a single microfluidic device) and studies that involve microenvironments where multiple tissue interactions are of interest, would benefit from the ability to transport or receive these constructs. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1257-1266, 2017. PMID- 28597975 TI - Domestic Predation of an Elder: A Fatal Dog Attack Case. AB - We present the case of a 91-year-old woman lived alone at her home with two domestic dogs, that is,, a Labrador Retriever and a Staffordshire Bull Terrier and found dead. The investigation of the scene revealed that the Bull Terrier's jawbone and chest were covered with blood. The autopsy revealed multiple, histologically confirmed, life-threatening skin and bone lacerations without scavenging marks. The punctures and tearing of each of the wounds on the skin were compatible with bites. A left humeral fracture and multiple fractures of the right facial bones were observed. The death was attributed to external hemorrhages due to several dog bites. A veterinary physical and behavioral examination indicated that the Bull Terrier was involved in the attack. A domestic predation hypothesis was deemed here most likely due to the presence of food supplies at the scene, the dog's previous history of attack, and the breed of the dog. PMID- 28597976 TI - Vesiculobullous eruption in a patient receiving psoralen ultraviolet A (PUVA) treatment for prurigo nodules: a case of PUVA-aggravated pemphigoid nodularis. PMID- 28597977 TI - Identification of the missing mitochondrial methyltransferase of citrate synthase. AB - Read the Original article at doi: 10.1002/1873-3468.12649. PMID- 28597978 TI - Pharmacokinetics of Sulfadoxine and Pyrimethamine for Intermittent Preventive Treatment of Malaria During Pregnancy and After Delivery. AB - Sulfadoxine/pyrimethamine is recommended for intermittent preventative treatment of malaria during pregnancy. Data from 98 women during pregnancy and 77 after delivery in four African countries were analyzed using nonlinear mixed-effects modeling to characterize the effects of pregnancy, postpartum duration, and other covariates such as body weight and hematocrit on sulfadoxine/pyrimethamine pharmacokinetic properties. During pregnancy, clearance increased 3-fold for sulfadoxine but decreased by 18% for pyrimethamine. Postpartum sulfadoxine clearance decreased gradually over 13 weeks. This finding, together with hematocrit-based scaling of plasma to whole-blood concentrations and allometric scaling of pharmacokinetics parameters with body weight, enabled site-specific differences in the pharmacokinetic profiles to be reduced significantly but not eliminated. Further research is necessary to explain residual site-specific differences and elucidate whether dose-optimization, to address the 3-fold increase in clearance of sulfadoxine in pregnant women, is necessary, viable, and safe with the current fixed dose combination of sulfadoxine/pyrimethamine. PMID- 28597979 TI - On the relationship between residue structural environment and sequence conservation in proteins. AB - Residues that are crucial to protein function or structure are usually evolutionarily conserved. To identify the important residues in protein, sequence conservation is estimated, and current methods rely upon the unbiased collection of homologous sequences. Surprisingly, our previous studies have shown that the sequence conservation is closely correlated with the weighted contact number (WCN), a measure of packing density for residue's structural environment, calculated only based on the Calpha positions of a protein structure. Moreover, studies have shown that sequence conservation is correlated with environment related structural properties calculated based on different protein substructures, such as a protein's all atoms, backbone atoms, side-chain atoms, or side-chain centroid. To know whether the Calpha atomic positions are adequate to show the relationship between residue environment and sequence conservation or not, here we compared Calpha atoms with other substructures in their contributions to the sequence conservation. Our results show that Calpha positions are substantially equivalent to the other substructures in calculations of various measures of residue environment. As a result, the overlapping contributions between Calpha atoms and the other substructures are high, yielding similar structure-conservation relationship. Take the WCN as an example, the average overlapping contribution to sequence conservation is 87% between Calpha and all-atom substructures. These results indicate that only Calpha atoms of a protein structure could reflect sequence conservation at the residue level. PMID- 28597980 TI - Efficient Flexible Solar Cell based on Composition-Tailored Hybrid Perovskite. AB - Organic-inorganic hybrid perovskites (OIHPs) are new photoactive layer candidates for lightweight and flexible solar cells due to their low-temperature process capability; however, the reported efficiency of flexible OIHP devices is far behind those achieved on rigid glass substrates. Here, it is revealed that the limiting factor is the different perovskite film deposition conditions required to form the same film morphology on flexible substrates. An optimized perovskite film composition needs a different precursor ratio, which is found to be essential for the formation of high-quality perovskite films with longer radiative carrier recombination lifetime, smaller density of trap states, reduced precursor residue, and uniform and pin-hole free films. A record efficiency of 18.1% is achieved for the flexible perovskite solar-cell devices made on an indium tin oxide/poly(ethylene terephthalate) substrate via a low temperature (<=100 degrees C) solution process. PMID- 28597981 TI - Reflections on patient involvement in research and clinical practice: A secondary analysis of women's perceptions and experiences of egg aspiration in fertility treatment. AB - The importance of patient involvement is increasing in healthcare, and initiatives are constantly implemented to reach the ideal of involved and educated patients. This secondary analysis was initially embedded in a randomized controlled study where the aim was to gain insight into perceptions and experiences within a group of women undergoing fertility treatment through two focus group interviews. In this secondary analysis, we investigated how patient involvement was strived for in both clinical practice and research. During the analysis, it became apparent that the women exercised and maintained a clear perspective on their hope for a child, Project Child, while the interviewer pursued a treatment perspective, Project Treatment. Despite different perspectives, the conversation during the interviews seemed effortless, and it became apparent how the interviewer and the participants were actually focusing partly on the same, but primarily on different issues but without addressing or acknowledging this. Knowledge and awareness of the difference in perspectives is important when healthcare professionals seek to involve patients both in clinical practice and in research. Patient involvement in both research and clinical practice has shown to be a challenge and entails that pathways are organized and decisions shared by healthcare professionals. PMID- 28597982 TI - Rare case of Epstein-Barr virus-associated early gastric cancer with multiple synchronous intramucosal lesions. PMID- 28597983 TI - Celecoxib for rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis is a systemic auto-immune disorder that causes widespread and persistent inflammation of the synovial lining of joints and tendon sheaths. Presently, there is no cure for rheumatoid arthritis and treatment focuses on managing symptoms such as pain, stiffness and mobility, with the aim of achieving stable remission and improving mobility. Celecoxib is a selective non-steroidal anti-inflammatory drug (NSAID) used for treatment of people with rheumatoid arthritis. OBJECTIVES: To assess the benefits and harms of celecoxib in people with rheumatoid arthritis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and clinical trials registers (ClinicalTrials.gov and the World Health Organization trials portal) to May 18, 2017. We also searched the reference and citation lists of included studies. SELECTION CRITERIA: We included prospective randomized controlled trials (RCTs) that compared oral celecoxib (200 mg and 400 mg daily) versus no intervention, placebo or a traditional NSAID (tNSAID) in people with confirmed rheumatoid arthritis, of any age and either sex. We excluded studies with fewer than 50 participants in each arm or had durations of fewer than four weeks treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included eight RCTs with durations of 4 to 24 weeks, published between 1998 and 2014 that involved a total of 3988 adults (mean age = 54 years), most of whom were women (73%). Participants had rheumatoid arthritis for an average of 9.2 years. All studies were assessed at high or unclear risk of bias in at least one domain. Overall, evidence was assessed as moderate-to-low quality. Five studies were funded by pharmaceutical companies. Celecoxib versus placeboWe included two studies (N = 873) in which participants received 200 mg daily or 400 mg daily or placebo. Participants who received celecoxib showed significant clinical improvement compared with those receiving placebo (15% absolute improvement; 95% CI 7% to 25%; RR 1.53, 95% CI 1.25 to 1.86; number needed to treat to benefit (NNTB) = 7, 95% CI 5 to 13; 2 studies, 873 participants; moderate to low quality evidence).Participants who received celecoxib reported less pain than placebo treated people (11% absolute improvement; 95% CI 8% to 14%; NNTB = 4, 95% CI 3 to 6; 1 study, 706 participants) but results were inconclusive for improvement in physical function (MD -0.10, 95% CI 0.29 to 0.10; 1 study, 706 participants).In the celecoxib group, 15/293 participants developed ulcers, compared with 4/99 in the placebo group (Peto OR 1.26, 95% CI 0.44 to 3.63; 1 study, 392 participants; low quality evidence). Nine (of 475) participants in the celecoxib group developed short-term serious adverse events, compared with five (of 231) in the placebo group (Peto OR 0.87 (0.28 to 2.69; 1 study, 706 participants; low quality evidence).There were fewer withdrawals among people who received celecoxib (163/475) compared with placebo (130/231) (22% absolute change; 95% CI 16% to 27%; RR 0.61, 95% CI 0.52 to 0.72; 1 study, 706 participants).Cardiovascular events (myocardial infarction, stroke) were not reported. However, regulatory agencies warn of increased cardiovascular event risk associated with celecoxib. Celecoxib versus tNSAIDsSeven studies (N = 2930) compared celecoxib and tNSAIDs (amtolmetin guacyl, diclofenac, ibuprofen, meloxicam, nabumetone, naproxen, pelubiprofen); one study included comparisons of both placebo and tNSAIDs (N = 1149).There was a small improvement, which may not be clinically significant, in numbers of participants achieving ACR20 criteria response in the celecoxib group compared to tNSAIDs (4% absolute improvement; 95% CI 0% less improvement to 8% more improvement; RR 1.10, 95% CI 0.99 to 1.23; 4 studies, 1981 participants). There was a lack of evidence of difference between participants in the celecoxib and tNSAID groups in terms of pain or physical function. Results were assessed at moderate-to-low quality evidence (downgraded due to risk of bias and inconsistency).People who received celecoxib had a lower incidence of gastroduodenal ulcers >= 3 mm (34/870) compared with those who received tNSAIDs (116/698). This corresponded to 12% absolute change (95% CI 11% to 13%; RR 0.22, 95% CI 0.15 to 0.32; 5 studies, 1568 participants; moderate quality evidence). There were 7% fewer withdrawals among people who received celecoxib (95% CI 4% to 9%; RR 0.73, 95% CI 0.62 to 0.86; 6 studies, 2639 participants).Results were inconclusive for short-term serious adverse events and cardiovascular events (low quality evidence). There were 17/918 serious adverse events in people taking celecoxib compared to 42/1236 among people who received placebo (Peto OR 0.71; 95% CI 0.39 to 1.28; 5 studies, 2154 participants). Cardiovascular events were reported in both celecoxib and placebo groups in one study (149 participants). AUTHORS' CONCLUSIONS: Celecoxib may improve clinical symptoms, alleviate pain and contribute to little or no difference in physical function compared with placebo. Celecoxib was associated with fewer numbers of participant withdrawals. Results for incidence of gastroduodenal ulcers (>= 3 mm) and short-term serious adverse events were uncertain; however, there were few reported events for either.Celecoxib may slightly improve clinical symptoms compared with tNSAIDs. Results for reduced pain and improved physical function were uncertain. Particpants taking celecoxib had lower incidence of gastroduodenal ulcers (>= 3 mm) and there were fewer withdrawals from trials. Results for cardiovascular events and short-term serious adverse events were also uncertain.Uncertainty about the rate of cardiovascular events between celecoxib and tNSAIDs could be due to risk of bias; another factor is that these were small, short-term trials. It has been reported previously that both celecoxib and tNSAIDs increase cardiovascular event rates. Our confidence in results about harms is therefore low. Larger head-to-head clinical trials comparing celecoxib to other tNSAIDs is needed to better inform clinical practice. PMID- 28597985 TI - Alkali Metal Chlorine and Bromine Carbenoids: Their Thermal Stability and Structural Properties. AB - The synthesis and structures of a series of M/X carbenoids of the type [Ph2 P(S)]2 CMX with M=Li, Na, and K and X=Cl and Br are reported, amongst the first isolated Na/Br and K/Br carbenoids. NMR spectroscopic as well as crystallographic studies showed distinct differences between the lithium carbenoids and their heavier congeners. In the solid state, all carbenoids showed no direct metal carbon interaction, but an interaction between the metal and the halogen atom. This contact is only very weak in the case of the Li/Br carbenoid, but much more pronounced in the corresponding potassium and sodium compounds. Nevertheless, these interactions did not significantly influence the stability of the carbenoids by weakening the C-X bond and facilitating the MX elimination. As such all compounds were found to be stable up to approximately 60 degrees C in solution. Hence, M-X interactions-albeit being an essential feature for the structure formation of carbenoids-are not the only criterion determining the stability of such compounds. In the present systems, the stabilization by the thiophosphinoyl moieties is more important than the metal/halogen combination. PMID- 28597986 TI - Tensions in the personal world of the nurse family carer: A phenomenological approach. AB - The incidence of chronic illness is growing globally. As a result, there are fiscal and social implications for health delivery. Alongside the increased burden on health resources is the expectation that someone within the family will assume the responsibility of carer for those who are chronically ill. The expectation to assume the role of carer may be amplified for family members who are also nurses. Currently, there is little research that investigates the impact of nurses who are carers for family with a chronic illness. Consequently, this qualitative study, based on face-to-face and telephone dialogue, was conducted using unstructured interviews. A phenomenological-hermeneutic approach utilizing the hermeneutic circle was employed to understand the meaning of the transcriptions. Hermeneutic phenomenology inspired by Heideggerian philosophy was used as a framework to clarify themes and build ways of understanding the phenomenon of 'Being' a nurse and a family carer. Themes identified in the analysis of the study included a personal world, a professional world and a practical world. This paper explicates the findings from examination of the personal world of 'Being' a nurse who is also a family carer. Analysis revealed there were three facets to this way of 'Being': a shared experience, a caring experience and a fraught experience. The findings of the study disclosed that participants were informed by experiences that were both enriching and conflicting. These insights can enlighten healthcare professionals to the tensions which exist for nurses who care for family so that these considerations are incorporated into individualized and effective family-centred care. PMID- 28597984 TI - Dual inhibition of BDNF/TrkB and autophagy: a promising therapeutic approach for colorectal cancer. AB - Colorectal cancer (CRC) is the most common digestive cancer in the Western world. Despite effective therapies, resistance and/or recurrence frequently occur. The present study investigated the impact of two survival pathways-neurotrophic factors (TrkB/BDNF) and autophagy-on cell fate and tumour evolution. In vitro studies were performed on two CRC cell lines, SW480 (primary tumour) and SW620 (lymph node invasion), which were also used for subcutaneous xenografts on a nude mouse model. In addition, the presence of neurotrophic factors (NTs) and autophagy markers were assessed in tissue samples representative of different stages. On the basis of our previous study (which demonstrated that TrkB overexpression is associated with prosurvival signaling in CRC cells), we pharmacologically inhibited NTs pathways with K252a. As expected, an inactivation of the PI3K/AKT pathway was observed and CRC cells initiated autophagy. Conversely, blocking the autophagic flux with chloroquine or with ATG5-siRNA overactivated TrkB/BDNF signaling. In vitro, dual inhibition improved the effectiveness of single treatment by significantly reducing metabolic activity and enhancing apoptotic cell death. These findings were accentuated in vivo, in which dual inhibition induced a spectacular reduction in tumour volume following long-term treatment (21 days for K252a and 12 days for CQ). Finally, significant amounts of phospho-TrkB and LC3II were found in the patients' tissues, highlighting their relevance in CRC tumour biology. Taken together, our results show that targeting NTs and autophagy pathways potentially constitutes a new therapeutic approach for CRC. PMID- 28597987 TI - Trafficking and localisation to the plasma membrane of Nav 1.5 promoted by the beta2 subunit is defective due to a beta2 mutation associated with Brugada syndrome. AB - BACKGROUND INFORMATION: Cardiac channelopathies arise by mutations in genes encoding ion channel subunits. One example is Brugada Syndrome (BrS), which causes arrhythmias and sudden death. BrS is often associated with mutations in SCN5A, encoding Nav 1.5, the alpha subunit of the major cardiac voltage-gated sodium channel. This channel forms a protein complex including one or two associated beta subunits as well as other proteins. RESULTS: We analysed regulation of Nav 1.5 localisation and trafficking by beta2, specifically, Nav 1.5 arrival to the cell surface. We used polarised Madin-Darby canine kidney (MDCK) cells and mouse atria-derived HL-1 cells, which retain phenotypic features of adult cardiomyocytes. In both, Nav 1.5 was found essentially intracellular, mainly in the endoplasmic reticulum, whereas beta2 localised to the plasma membrane, and was restricted to the apical surface in MDCK cells. A fraction of beta2 interacted with Nav 1.5, despite their limited overlap. Importantly, beta2 promoted Nav 1.5 localisation to the cell surface. Both beta2 WT and the BrS associated mutation D211G (substitution of Asp for Gly) effectively reached the plasma membrane. Strikingly, however, beta2 D211G was defective in promoting Nav 1.5 surface localisation. CONCLUSIONS: Our data sustain that beta2 promotes surface localisation of Nav 1.5, which can be affected due to beta2 mutations associated with channelopathies. SIGNIFICANCE: Our findings add to the understanding of beta2 role in Nav 1.5 trafficking and localisation, which must influence cell excitability and electrical coupling in the heart. This study will contribute to knowledge on development of arrhythmias. PMID- 28597989 TI - Discrimination and resilience and the needs of people who identify as Transgender: A narrative review of quantitative research studies. AB - AIMS AND OBJECTIVES: To examine discrimination and resilience experiences of people who identify as transgender and establish potential health service responses. BACKGROUND: People who identify as transgender face many challenges in society in terms of the knowledge, understanding and acceptance of a person's gender identity. DESIGN: A narrative review of quantitative empirical research. METHODS: A comprehensive search of CINAHL, MEDLINE, PsycINFO and Sociological Abstracts electronic databases from 2006-2016 was conducted. RESULTS: The search yielded 1,478 papers and following the application of rigorous inclusion and exclusion criteria a total of 19 papers were included in the review. The findings reveal that there is a need to ensure that the needs of transgender people are represented, fully integrated and clearly linked to outcomes that improve their health and quality of life. CONCLUSIONS: Discrimination experiences can result in poorer health outcomes; however, many people have developed resilience and positive coping strategies. RELEVANCE TO CLINICAL PRACTICE: Nurses need to recognise and respond appropriately to the care and treatment needs of this population. Comprehensive nursing assessments and plans of care that encompass all aspects of the person should be in place supported by clear policy guidelines and evidence-based research. The education requirements of practitioners are outlined. PMID- 28597988 TI - Estimating apparent maximum muscle stress of trunk extensor muscles in older adults using subject-specific musculoskeletal models. AB - Maximum muscle stress (MMS) is a critical parameter in musculoskeletal modeling, defining the maximum force that a muscle of given size can produce. However, a wide range of MMS values have been reported in literature, and few studies have estimated MMS in trunk muscles. Due to widespread use of musculoskeletal models in studies of the spine and trunk, there is a need to determine reasonable magnitude and range of trunk MMS. We measured trunk extension strength in 49 participants over 65 years of age, surveyed participants about low back pain, and acquired quantitative computed tomography (QCT) scans of their lumbar spines. Trunk muscle morphology was assessed from QCT scans and used to create a subject specific musculoskeletal model for each participant. Model-predicted extension strength was computed using a trunk muscle MMS of 100 N/cm2 . The MMS of each subject-specific model was then adjusted until the measured strength matched the model-predicted strength (+/-20 N). We found that measured trunk extension strength was significantly higher in men. With the initial constant MMS value, the musculoskeletal model generally over-predicted trunk extension strength. By adjusting MMS on a subject-specific basis, we found apparent MMS values ranging from 40 to 130 N/cm2 , with an average of 75.5 N/cm2 for both men and women. Subjects with low back pain had lower apparent MMS than subjects with no back pain. This work incorporates a unique approach to estimate subject-specific trunk MMS values via musculoskeletal modeling and provides a useful insight into MMS variation. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:498-505, 2018. PMID- 28597990 TI - Temporal dynamics of relative abundances and bacterial succession in chronic wound communities. AB - Polymicrobial bacterial infection is an important factor contributing to wound chronicity. Consequently, clinicians frequently adopt a biofilm-based wound care approach, in which wounds are treated utilizing DNA sequencing information about microbial communities. While more successful than treatment not using community information, there is little information about temporal dynamics of wound communities and optimal approaches over the course of treatment. To characterize these dynamics, temporal analysis over three sampling points was conducted for 167 chronic wounds. Across sampling intervals, wound communities from the same patients changed in composition, and most commonly shared less than 50% of observed species. There was a significant relationship between community similarity and time between sampling. Classifying wounds into state types, we found that communities frequently transitioned from Pseudomonas or Staphylococcus dominated, into a highly variable state type. Although low abundance microbial species are typically disregarded due to uncertainty of biological importance, we found that 80% of wound microbiomes included common or dominant species at subsequent time points that were in low abundance in earlier samples. Moreover, these species were often those known to frequently infect wounds. Results document compositional shifts through the course of treatment and suggest that routine consideration of low abundance species may improve biofilm-based wound care. Moreover, findings indicate that integrating ecological modeling to understand wound microbiome succession may lead to more informed therapy. PMID- 28597992 TI - Systemic ALA-PDT effectively blocks the development of psoriasis-like lesions and alleviates leucocyte infiltration in the K14-VEGF transgenic mouse. AB - BACKGROUND: Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders. In spite of significant advances in the treatment of psoriasis, more effective and safer therapeutic strategies are still needed. Photodynamic therapy (PDT) is a method of light treatment that is being used increasingly in the treatment of dermatological diseases. AIM: To evaluate the therapeutic effects of systemic 5-aminolaevulinic acid (ALA)-PDT on psoriasis and to explore its potential mechanism of action. METHODS: We investigated the therapeutic effects of systemic ALA-PDT in K14-vascular endothelial growth factor (VEGF) transgenic homozygous mice, an animal model of psoriasis, which has many clinical and histopathological characteristics similar to those of human psoriasis. Using haematoxylin and eosin staining, immunohistochemistry and real time quantitative PCR respectively, we assessed the changes in psoriasis-like lesions, cellular infiltration of T cells, dendritic cells (DCs) and neutrophils, and the mRNA expression of the inflammatory cytokines interleukin (IL)-17 and interferon (IFN)-gamma in the lesions. RESULTS: Systemic ALA-PDT blocked the development of psoriasis-like lesions and moderately attenuated the histopathological changes in K14-VEGF transgenic mice. Furthermore, systemic ALA PDT produced an obvious reduction in infiltration of T cells, CD11c+ DCs and neutrophils in psoriasis-like lesions. In addition, systemic ALA-PDT also significantly decreased the mRNA expression of IL-17 and IFN-gamma. CONCLUSIONS: We suggest that the mechanism of systemic ALA-PDT in this psoriasis-like model might be associated with selective damage to abnormal T helper (Th)1 and Th17 cells, and reduction of the inflammatory cytokines IL-17 and IFN-gamma. These observations partly explain the potential mechanism of systemic ALA-PDT in psoriasis and other inflammatory skin diseases. PMID- 28597991 TI - Lack of linear correlation between dynamic and steady-state cerebral autoregulation. AB - KEY POINTS: For correct application and interpretation of cerebral autoregulation (CA) measurements in research and in clinical care, it is essential to understand differences and similarities between dynamic and steady-state CA. The present study found no correlation between dynamic and steady-state CA indices in healthy older adults. There was variability between individuals in all (steady-state and dynamic) autoregulatory indices, ranging from low (almost absent) to highly efficient CA in this healthy population. These findings challenge the assumption that assessment of a single CA parameter or a single set of parameters can be generalized to overall CA functioning. Therefore, depending on specific research purposes, the choice for either steady-state or dynamic measures or both should be weighed carefully. ABSTRACT: The present study aimed to investigate the relationship between dynamic (dCA) and steady-state cerebral autoregulation (sCA). In 28 healthy older adults, sCA was quantified by a linear regression slope of proportionate (%) changes in cerebrovascular resistance (CVR) in response to proportionate (%) changes in mean blood pressure (BP) induced by stepwise sodium nitroprusside (SNP) and phenylephrine (PhE) infusion. Cerebral blood flow (CBF) was measured at the internal carotid artery (ICA) and vertebral artery (VA) and CBF velocity at the middle cerebral artery (MCA). With CVR = BP/CBF, Slope-CVRICA , Slope-CVRVA and Slope-CVRiMCA were derived. dCA was assessed (i) in supine rest, analysed with transfer function analysis (gain and phase) and autoregulatory index (ARI) fit from spontaneous oscillations (ARIBaseline ), and (ii) with transient changes in BP using a bolus injection of SNP (ARISNP ) and PhE (ARIPhE ). Comparison of sCA and dCA parameters (using Pearson's r for continuous and Spearman's rho for ordinal parameters) demonstrated a lack of linear correlations between sCA and dCA measures. However, comparisons of parameters within dCA and within sCA were correlated. For sCA slope-CVRVA with Slope-CVRiMCA (r = 0.45, P < 0.03); for dCA ARISNP with ARIPhE (rho = 0.50, P = 0.03), ARIBaseline (rho = 0.57, P = 0.03) and PhaseLF (rho = 0.48, P = 0.03); and for GainVLF with GainLF (r = 0.51, P = 0.01). By contrast to the commonly held assumption based on an earlier study, there were no linear correlations between sCA and dCA. As an additional observation, there was strong inter-individual variability, both in dCA and sCA, in this healthy group of elderly, in a range from low to high CA efficiency. PMID- 28597994 TI - Corneal sensitivity and tear production in 108 horses with ocular disease. AB - PURPOSE: To compare corneal sensitivity and tear production in horses with keratitis to horses with other ocular disease. METHOD: Retrospective medical record review was used to identify equine patients presented during a 1-year period for an ocular complaint who had Schirmer Tear Test (STT) or Corneal Touch Threshold (CTT) measured. Variables studied included patient age and sex; affected eye; category of presenting ocular complaint (keratitis vs. other ocular complaint); STT; and CTT. Patients with a complaint of ulcerative keratitis, immune-mediated keratitis, and stromal abscess were categorized in the keratitis group. Patients with a complaint of uveitis, as well as lid, lens, or retinal disease, were categorized in the group having other ocular disease. For patients presenting more than once in 2013, only the first visit at which STT or CTT was measured was included. For patients with bilateral disease, STT and CTT of both eyes were averaged. RESULTS: A total of 108 patients were included, 45 with keratitis and 63 with other ocular disease. Average age was 13.65 years, with more males (77) than females (31). Adjusted for age, STT in affected eyes did not differ significantly between the two groups (keratitis = 29.92 mm/min; other ocular disease = 27.96 mm/min), but CTT was significantly lower in patients with keratitis (33.78 mm) than in patients with other ocular disease (40.10 mm). CONCLUSIONS: Corneal sensitivity may be decreased in patients with keratitis. It is not known whether this is a cause or an effect of corneal disease. PMID- 28597993 TI - One-Step Extraction and Hydrolysis of Flavonoid Glycosides in Rape Bee Pollen Based on Soxhlet-Assisted Matrix Solid Phase Dispersion. AB - INTRODUCTION: Flavonoids are frequently found as glycosylated derivatives in plant materials. To determine contents of flavonoid aglycones in these matrices, procedures for the extraction and hydrolysis of flavonoid glycosides are required. The current sample preparation method is both labour and time consuming. OBJECTIVE: Develop a modified matrix solid phase dispersion (MSPD) procedure as an alternative methodology for the one-step extraction and hydrolysis of flavonoid glycosides. METHOD: HPLC-DAD was applied for demonstrating the one-step extraction and hydrolysis of flavonoids in rape bee pollen. The obtained contents of flavonoid aglycones (quercetin, kaempferol, isorhamnetin) were used for the optimisation and validation of the method. RESULTS: The extraction and hydrolysis were accomplished in one step. The procedure completes in 2 h with silica gel as dispersant, a 1:2 ratio of sample to dispersant, and 60% aqueous ethanol with 0.3 M hydrochloric acid as the extraction solution. The relative standard deviations (RSDs) of repeatability were less than 5%, and the recoveries at two fortified levels were between 88.3 and 104.8%. CONCLUSION: The proposed methodology is simple and highly efficient, with good repeatability and recovery. Compared with currently available methods, the present work has advantages of using less time and labour, higher extraction efficiency, and less consumption of the acid catalyst. This method may have applications for the one-step extraction and hydrolysis of bioactive compounds from plant materials. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28597995 TI - K+ -Responsive Block Copolymer Micelles for Targeted Intracellular Drug Delivery. AB - In this work, a novel type of block copolymer micelles with K+ -responsive characteristics for targeted intracellular drug delivery is developed. The proposed smart micelles are prepared by self-assembly of poly(ethylene glycol)-b poly(N-isopropylacry-lamide-co-benzo-18-crown-6-acrylamide) (PEG-b-P(NIPAM-co B18C6Am)) block copolymers. Prednisolone acetate (PA) is successfully loaded into the micelles as the model drug, with loading content of 4.7 wt%. The PA-loaded micelles display a significantly boosted drug release in simulated intracellular fluid with a high K+ concentration of 150 * 10-3 m, as compared with that in simulated extracellular fluid. Moreover, the in vitro cell experiments indicate that the fluorescent molecules encapsulated in the micelles can be delivered and specifically released inside the HSC-T6 and HepG2 cells responding to the increase of K+ concentration in intracellular compartments, which confirms the successful endocytosis and efficient K+ -induced intracellular release. Such K+ responsive block copolymer micelles are highly potential as new-generation of smart nanocarriers for targeted intracellular delivery of drugs. PMID- 28597996 TI - Sensitization of melanoma cells to temozolomide by overexpression of microRNA 203 through direct targeting of glutaminase-mediated glutamine metabolism. AB - BACKGROUND: Malignant melanoma (MM) is an aggressive malignancy, which accounts for 80% of skin cancer-related deaths and is notably resistant to conventional chemotherapeutic agents. One of the most common treatments for melanoma is surgery, followed by various combinations of chemotherapy drugs. AIM: To investigate the role of microRNA (miR)-203 in sensitivity of MM cells to the chemotherapy drug temozolomide (TMZ). METHODS: Using quantitative reverse transcription PCR, we measured the expression of miR-203 in an MM cell line. Cell viability of MM cells in response to TMZ treatment was measured by MTT assay. Glutamine metabolism and level of glutaminase (GLS) were assessed. RESULTS: We found that miR-203 was significantly downregulated by TMZ treatment in human MM cells. In addition, miR-203 expression was lower in TMZ-resistant MM cells compared with parental cells. Interestingly, glutamine metabolism and GLS expression were higher in TMZ-resistant cells, and TMZ-resistant cells exhibited more glutamine dependency than TMZ-sensitive MM cells. We also identified GLS as a downstream target gene of miR-203, which binds directly to the 3' untranslated region of GLS. Overexpression of miR-203 was associated with decreased GLS expression and sensitization to TMZ in vitro. Re-expression of GLS in miR-203 overexpressing MM cells markedly rescued miR-203-mediated suppression of these events. Finally, we found a significant negative correlation between miR-203 and GL, with downregulation of miR-203 and upregulation of GLS in tissues from patients with MM. CONCLUSION: Taken together, our results demonstrate that overexpression of miR-203 sensitizes MM cells to TMZ by targeting GLS, providing new insights into the development of anti-tumour agents for patients with chemotherapy-resistant MM. PMID- 28597997 TI - An under-recognized, life-threatening complication of atopic dermatitis. PMID- 28597998 TI - A novel mechanical mitral valve replacement using Sapien XT. AB - PATIENT PRESENTATION: We report the case of a 66 year old female who presented to our institution fourteen years after receiving a St. Jude Mechanical Mitral Valve Replacement. She presented in refractory NYHA class IV congestive heart failure with comorbidities of acute renal failure, liver failure, and mental status changes. She was found to have immobility of one of the mitral valve disks with resultant severe mitral stenosis with a mean pressure gradient of 12 mmHg. EVALUATION AND MANAGEMENT: The patient was found to have an STS predicted mortality of 39% with redo surgical MVR, and evaluation by the valve team led to a recommendation of a hybrid surgical and transcatheter procedure. The patient underwent femoral bypass and hypothermia with a sternotomy and left atrial approach. The mechanical discs were removed utilizing needle drivers without removal of the St. Jude ring. Subsequently, a 26 mm Edwards Sapien XT valve was deployed under direct and fluoroscopic visualization. The patient had an event free post-operative course, and one year following the procedure has had an outstanding clinical response with NYHA class II congestive heart failure. Her echocardiogram reveals normal valve function with a MPG of 4 mmHg without mitral regurgitation. CONCLUSION: Transatrial hybrid TMVR within the ring of a St. Jude mechanical mitral valve appears to be a feasible procedure which may be used in the future to decrease morbidity and mortality associated with high-risk redo-MVR in patients with mechanical mitral valve prostheses. PMID- 28597999 TI - A rapid and easy protein N-terminal profiling strategy using (N Succinimidyloxycarbonylmethyl)tris(2,4,6-trimethoxyphenyl)phosphonium bromide (TMPP) labeling and StageTip. AB - Protein N-terminal profiling is crucial when characterizing biological functions and provides proteomic evidences for genome reannotations. However, most of the current N-terminal enrichment approaches involve multiple chemical derivatizations and chromatographic separation processes which are time consuming and can contribute to N-terminal peptide losses. In this study, a fast, one-step approach utilizing (N-Succinimidyloxycarbonylmethyl)tris(2,4,6 trimethoxyphenyl)phosphonium bromide (TMPP) derivatization and StageTip separation was developed to enhance N-terminal peptide enrichment and analysis. Based on the characteristics of TMPP-derivatized samples, such as a higher hydrophobicity and increased likelihood to produce a and b ions in collision induced dissociation or HCD fragmentation modes, first the SDS-PAGE was optimized to increase protein loading and gel entry and to remove unbound TMPP. Then, this process was combined with a simplified StageTip separation and a new scoring criterion (considering a, b and y ions) to identify more TMPP-modified N-terminal spectra. When utilizing a low amount of starting material (~20 MUg protein), a total of 581 yeast N-terminal peptides were identified, with 485 of them being TMPP modified, in only about one third of the general experimental time. It is hoped that the workflow constructed herein will provide a fast and practical strategy for N-terminomic studies. PMID- 28598000 TI - Peptidomic Analysis of Maternal Serum to Identify Biomarker Candidates for Prenatal Diagnosis of Tetralogy of Fallot. AB - Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease. To identify endogenous peptides possibly involved in the progression of TOF, we performed comparative peptidomic profiling of maternal serum between normal fetuses and fetuses suffering from TOF. A total of 278 differentially expressed peptides, including 94 over-expressed peptides and 184 under-expressed peptides, originating from 227 protein precursors were identified by liquid chromatography/mass spectrometry (LC/MS) in maternal serum of fetuses with TOF compared to normal controls. Further, ingenuity pathway analysis (IPA) was used to identify putative roles for these peptides in cardiovascular development. Two peptides were derived from functional domains of proteins involved in heart development and associated with TOF; these may represent candidate bioactive peptides involved in TOF. These peptides may be related to the pathologic changes in the heart associated with TOF, and may be useful as novel biomarkers for prenatal diagnosis of TOF. J. Cell. Biochem. 119: 468-477, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28598001 TI - 3D Printing Technology in Planning Thumb Reconstructions with Second Toe Transplant. AB - OBJECTIVE: To report preoperative planning using 3D printing to plan thumb reconstructions with second toe transplant. METHODS: Between December 2013 and October 2015, the thumbs of five patients with grade 3 thumb defects were reconstructed using a wrap-around flap and second toe transplant aided by 3D printing technology. CT scans of hands and feet were analyzed using Boholo surgical simulator software (www.boholo.com). This allowed for the creation of a mirror image of the healthy thumb using the uninjured thumb. Using 3D images of the reconstructed thumb, a model of the big toe and the second toe was created to understand the dimensions of the donor site. This model was also used to repair the donor site defect by designing appropriate iliac bone and superficial circumflex iliac artery flaps. The polylactic acid model of the donor toes and reconstructed thumb was produced using 3D printing. Surgically, the wrap-around flap of the first dorsal metatarsal artery and vein combined with the joint and bone of the second toe was based upon the model donor site. Sensation was reconstructed by anastomosing the dorsal nerve of the foot and the plantar digital nerve of the great toe. Patients commenced exercises 2 weeks after surgery. RESULTS: All reconstructed thumbs survived, although partial flap necrosis occurred in one case. This was managed with regular dressing changes. Patients were followed up for 3-15 months. The lengths of the reconstructed thumbs are 34-49 mm. The widths of the thumb nail beds are 16-19 mm, and the thickness of the digital pulp is 16-20 mm. The thumb opposition function was 0 1.5 cm; the extension angle was 5 degrees -20 degrees (mean, 16 degrees ), and the angle of flexion was 38 degrees -55 degrees (mean, 47 degrees ). Two-point discrimination was 9-11 mm (mean, 9.6 mm). The reconstructed thumbs had good appearance, function and sensation. Based on the criteria set forth by the Standard on Approval of Reconstructed Thumb and Finger Functional Assessment of the Chinese Medical Association, the results were considered excellent for four cases and good for one case. The success rate was 100%. CONCLUSIONS: When planning a wrap-around flap and second toe transplant to reconstruct a thumb, both the donor and recipient sites can be modeled using 3D printing. This can shorten the operative time by supplying digital and accurate schematics for the operation. It can also optimize the function and appearance of the reconstructed thumb while minimizing damage to the donor site. PMID- 28598002 TI - A DNA-Programmed Liposome Fusion Cascade. AB - Chemically engineered and functionalized nanoscale compartments are used in bottom-up synthetic biology to construct compartmentalized chemical processes. Progressively more complex designs demand spatial and temporal control over entrapped species. Here, we address this demand with a DNA-encoded design for the successive fusion of multiple liposome populations. Three individual stages of fusion are induced by orthogonally hybridizing sets of membrane-anchored oligonucleotides. Each fusion event leads to efficient content mixing and transfer of the recognition unit for the subsequent stage. In contrast to fusion protein-dependent eukaryotic vesicle processing, this artificial fusion cascade exploits the versatile encoding potential of DNA hybridization and is generally applicable to small and giant unilamellar vesicles. This platform could thus enable numerous applications in artificial cellular systems and liposome-based synthetic pathways. PMID- 28598003 TI - Editorial: The Effect of Ethnicity on Cardiovascular Outcomes in Systemic Lupus Erythematosus Is Perhaps Not a Paradox. PMID- 28598006 TI - Issue Information - IFA. PMID- 28598004 TI - Higher maternal vitamin D concentrations are associated with longer leukocyte telomeres in newborns. AB - Gestational vitamin D insufficiency is related with increased risks of various diseases and poor health outcomes later in life. Telomere length at birth or early in life is known to be a predictor of individual health. Both vitamin D and telomere length are related with various health conditions, and vitamin D concentrations are associated with leukocyte telomere lengths in women. We investigated the association between maternal vitamin D concentrations and newborn leukocyte telomere lengths. This cross-sectional study included 106 healthy pregnant women without adverse obstetric outcomes and their offspring. We examined the maternal age, weight before pregnancy, health behaviours, and nutritional intakes, along with each newborn's sex and birthweight, and we measured maternal height, telomere length, total white blood cell count, and glycosylated haemoglobin as covariates. Pearson's correlation coefficients were calculated to evaluate the relationship between the baseline variables and newborn leukocyte telomere lengths. To confirm that there was an independent association between newborn leukocyte telomere lengths and maternal vitamin D concentrations, we performed a stepwise multiple linear regression analysis. Newborn leukocyte telomere lengths correlated positively with maternal leukocyte telomere lengths (r = .76, p < .01), maternal 25-hydroxyvitamin D concentrations (r = .72, p < .01), maternal energy intakes (r = .22, p = .03), and newborn body weights (r = .51, p < .01). In the multivariate model, newborn leukocyte telomere lengths were associated with maternal vitamin D concentrations (beta = .33, p < .01). These findings suggest that the maternal vitamin D concentration during pregnancy may be a significant determinant of the offspring's telomere length. PMID- 28598007 TI - Large-scale study of clinical and biochemical characteristics of Chinese patients diagnosed with Krabbe disease. AB - Krabbe disease (KD) is a rare disease caused by the deficiency of beta galactocerebrosidase. This study investigated 22 unrelated Chinese patients, including their clinical presentations, plasma psychosine levels and beta galactocerebrosidase gene mutations. We found the late-onset form of KD present in 82% of the patients in our study, which was more prevalent than in patients from other populations. Plasma psychosine levels were elevated in KD, which were correlated with the severity of clinical presentations. Sanger sequencing identified 8 novel mutations, including 7 missense mutations, p.H253Y, p.S259L, p.P318L, p.F350V, p.T428A, p.L530P, p.G586D, and 1 splicing mutation, c.1251+1G>A. Quantitative real-time polymerase chain reaction (PCR) and multiplex ligation-dependent probe amplification identified a novel exon 12 and 14 deletion, separately. Next generation sequencing, applied at the final step, revealed 2 missense mutant alleles missed using Sanger sequencing. The most common mutation in Chinese population is p.P154H, which accounts for 20.5% of alleles. Consistent with the higher prevalence of the late-onset form of KD, missense mutations predominated in our study, different with the common mutation types in Europe and Japan. This work was the first large-scale study of Chinese KD patients describing their clinical, biochemical and genetic characteristics, which furthered our understanding of this classical neurological lysosomal storage disease. PMID- 28598005 TI - Higher concentrations of dithranol appear to induce hair growth even in severe alopecia areata. AB - Alopecia areata (AA) is the commonest autoimmune cause of non-scarring alopecia. Topical treatments including corticosteroids and irritants maybe beneficial. Studies report variable hair regrowth with dithranol (anthralin) but all used low concentrations (0.1-1.25%) and inconsistent measurements of AA severity. We report retrospective data (2005-2014) of 102 patients who had failed ultra-potent topical steroids and were referred to a specialist hair clinic for treatment with dithranol up to 3%. The severity of alopecia areata tool was used and participants graded as mild (<25%), moderate (>25 to 75%), and severe (>75%) hair loss. Compared with baseline any and at-least 50% hair regrowth [72%, 68%, 50% and 61.5%, 48.4%, 37.5%, in mild, moderate and severe AA respectively] occurred in all groups (median treatment duration 12 months). Twenty-nine patients (28.4%) were discharged with complete regrowth; with no difference in proportions in severity groups (33.3%, 29%, and 21.9%) but in the period to discharge [7.9, 6.3, and 29.4 months (p-values <.05)] for mild, moderate, and severe AA. Treatment trials of 12 months with dithranol at higher concentrations may be an option in patients who failed potent topical or intra-lesional steroids) regardless of AA severity. Randomized trials (of less staining formulations) of dithranol are warranted. PMID- 28598008 TI - A persistent umbilical nodule. PMID- 28598009 TI - Development of overuse tendinopathy: A new descriptive model for the initiation of tendon damage during cyclic loading. AB - Tendinopathic tissue has long been characterized by changes to collagen microstructure. However, initial tendon damage from excessive mechanical loading a hallmark of tendinopathy development-could occur at the nanoscale level of collagen fibrils. Indeed, it is on this scale that tenocytes interact directly with tendon matrix, and excessive collagen fibril damage not visible at the microscale could trigger a degenerative cascade. In this study, we explored whether initiation of tendon damage during cyclic loading occurs via a longitudinal compression-induced buckling mechanism of collagen fibrils leading to nanoscale kinkband development. Two groups of tendons were cyclically loaded to equivalent peak stresses. In each loading cycle, tendons in one group were unloaded to the zero displacement mark, while those in the other group were unloaded to a nominal level of tension, minimizing the potential for fibril buckling. Tendons that were unloaded to the zero displacement mark ruptured significantly sooner during cyclic loading (1,446 +/- 737 vs. 4,069 +/- 1,129 cycles), indicating that significant fatigue damage is accrued in the low stress, toe region of the load-deformation response. Ultrastructural analysis using scanning electron microscopy of tendons stopped after 1,000 cycles showed that maintaining a nominal tension slowed the accumulation of kinkbands, supporting a longitudinal compression-induced buckling mechanism as the basis for kinkband development. Based on our results, we present a new descriptive model for the initiation of tendon damage during cyclic loading. The so-called Compression of Unrecovered Elongation or CUE Model may provide useful insight into the development of tendinopathy. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:467-476, 2018. PMID- 28598011 TI - An Evolutionary Concept Analysis of Compassion Fatigue. AB - PURPOSE: The purpose of this article is to fill the need for an updated concept analysis of compassion fatigue. METHODS: This review used Rodgers' Evolutionary Model to direct the analysis of 25 papers published between 2005 and 2015. This review focused strictly on healthcare providers in the formal healthcare setting. CONCLUSIONS: The authors provided an analysis of the evolution of compassion fatigue and identified surrogate terms, attributes and defining characteristics, and antecedents and consequences of the term, true to Rodgers' Evolutionary Model. Related terms are also discussed and a brief case model is provided. CLINICAL RELEVANCE: A better understanding of compassion fatigue will allow researchers and clinicians to identify its causes, prevention, and treatment. This could impact the rate at which healthcare providers leave clinical practice and their ability to compassionately engage with patients. PMID- 28598010 TI - DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression. AB - Recently, a large number of studies have focused on the important role of long non-coding RNAs (lncRNAs) in metabolism and development and have found that abnormal lncRNA expression is associated with the pathogenesis and development of many diseases. The lncRNA DLEU1 is involved in many solid tumours and haematological malignancies. However, its role in epithelial ovarian carcinoma (EOC) and the associated molecular mechanisms has not been reported. In this study, quantitative reverse transcription-PCR (qRT-PCR) demonstrated higher lncRNADLEU1 expression in EOC tissues than in normal tissues. Plasmid transfection of DLEU1 to up-regulate its expression in the ovarian cancer cell lines A2780 and OVCAR3 increased cell proliferation, migration, and invasion, while inhibited apoptosis. Nude mouse xenograft assay demonstrated that DLEU1 overexpression promoted tumour growth in vivo. QRT-PCR showed decreased miR-490 3p expression, while Western blotting demonstrated increased its target genes CDK1, cyclinD1 and SMARCD1, as well as matrix metalloproteinase-2 (MMP2), Bcl-xL and P70S6K protein expression, respectively. Short interfering RNA silencing of DLEU1 produced opposite results, where qRT-PCR showed increased miR-490-3p expression. The dual-luciferase reporter assay revealed a direct interaction between DLEU1 and miR-490-3p. MiR-490-3p plays a tumour suppressor role in epithelial ovarian cancer by targeting CDK1 regulation and influencing SMARCD1 and cyclin D1 (CCND1) expressions. Therefore, we suggest that through interaction with miR-490-3p, DLEU1 may influence the expression of CDK1, CCND1 and SMARCD1 protein, subsequently promoting the development and progression of EOC. PMID- 28598012 TI - Meta-analysis: Association of Helicobacter pylori infection with Parkinson's diseases. AB - BACKGROUND: The results from observational studies on the relationship between helicobacter pylori (H. pylori) infection and Parkinson's disease remain controversial. A meta-analysis was conducted to evaluate the association between helicobacter pylori infection and Parkinson's disease. METHODS: A comprehensive literature search was performed on relevant studies published from January 1983 to January 2017 in PubMed, Web of Science and EMBASE databases. The fixed or random effects model was used to pool the odds ratio with 95% confidence interval from individual studies. Publication bias was estimated by Egger's test and the funnel plot. RESULTS: Eight eligible studies involving 33 125 participants were included in this meta-analysis. Compared with the no helicobacter pylori infected person, the pooled odds ratio of Parkinson's disease in helicobacter pylori infected person was 1.59 (95% confidence interval: 1.37-1.85). In subgroup analyzes, the combined odds ratios were 1.96 (1.23-3.12) in Asia, 1.55 (1.32 1.82) in Europe, 1.59 (1.35-1.88) in case-control studies, 1.56 (1.01-2.39) in cross-sectional studies, 1.56 (1.32-1.85) in studies with confounders adjusted, and 1.71 (1.21-2.43) in studies with no confounder adjusted, respectively. CONCLUSIONS: This meta-analysis indicated that H. pylori infection might be associated with the risk of Parkinson's disease. PMID- 28598013 TI - 3D Nitrogen-Anion-Decorated Nickel Sulfides for Highly Efficient Overall Water Splitting. AB - Developing non-noble-metal electrocatalysts with high activity and low cost for both the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is of paramount importance for improving the generation of H2 fuel by electrocatalytic water-splitting. This study puts forward a new N-anion-decorated Ni3 S2 material synthesized by a simple one-step calcination route, acting as a superior bifunctional electrocatalyst for the OER/HER for the first time. The introduction of N anions significantly modifies the morphology and electronic structure of Ni3 S2 , bringing high surface active sites exposure, enhanced electrical conductivity, optimal HER Gibbs free-energy (DeltaGH* ), and water adsorption energy change (DeltaGH2O* ). Remarkably, the obtained N-Ni3 S2 /NF 3D electrode exhibits extremely low overpotentials of 330 and 110 mV to reach a current density of 100 and 10 mA cm-2 for the OER and HER in 1.0 m KOH, respectively. Moreover, an overall water-splitting device comprising this electrode delivers a current density of 10 mA cm-2 at a very low cell voltage of 1.48 V. Our finding introduces a new way to design advanced bifunctional catalysts for water splitting. PMID- 28598014 TI - Nurses' experience of the transfer of ICU patients to general wards: A great responsibility and a huge challenge. AB - AIMS AND OBJECTIVES: The aim of the study was to describe nurses' experiences of patients' transition from ICUs to general wards and their suggestions for improvements. BACKGROUND: In the ICU, the most seriously ill patients with life threatening conditions and multiple organ dysfunction syndromes are cared for and carefully monitored by specially trained professionals using advanced techniques for the prevention of failure of vital functions. The transfer of ICU patients to general wards means a change from a high to a lower level, including the loss of one-to-one nursing and a reduction of visible monitoring equipment and general close attention. DESIGN: A qualitative descriptive design. METHODS: Eight nurses from three different inpatient units in Norway, five from a university hospital and three from a local hospital were selected through a convenience sample. Interviews with open questions were conducted, and qualitative content analysis was used to explore the data. RESULTS: Nurses' experiences were described in one main category: ICU patients' transition-a great responsibility and a huge challenge, and two generic categories: (i) a challenging transition for nurses, patients and relatives and (ii) dialogue and competencies as tools for improvement, with six subcategories. CONCLUSION: A number of factors affected patient care, such as poor cooperation, communication, reporting, expertise and clinical gaze. It was clear that the general wards had major challenges, and a number of improvements were suggested. RELEVANCE TO CLINICAL PRACTICE: This study shows that there is still a gap between the ICU and general wards and that nurses continue to struggle with this. It is therefore important that the managers responsible for the quality of care together with the professionals take seriously the criticism in the present and previous studies and work towards a safe transition for patients. PMID- 28598015 TI - Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy. AB - OBJECTIVE: To determine the utility of skin biopsies as a biomarker of disease severity in subjects with amyloid neuropathy. METHODS: Five groups of patients were studied: (1) transthyretin (TTR) familial amyloidotic polyneuropathy (FAP; n = 20), (2) TTR mutation carriers without peripheral neuropathy (TTR-noPN; n = 10), (3) healthy controls (n = 20), (4) diabetic neuropathy disease controls (n = 20), and (5) patients with light-chain (AL) amyloid (n = 2). All subjects underwent neurological examination and 3mm skin biopsies. Sections were stained with anti-PGP9.5, anti-TTR, and Congo red. Intraepidermal (IENFD), sweat gland (SGNFD), and pilomotor nerve fiber densities (PMNFD) were measured. Correlations between the amount of amyloid present (amyloid burden), fiber subtype, and Neuropathy Impairment Score in the Lower Limbs (NIS-LL) were evaluated. RESULTS: IENFD, SGNFD, and PMNFD were all significantly reduced in TTR-FAP patients versus healthy controls, whereas TTR-noPN subjects had intermediate reductions. Lower nerve fiber densities were associated with NIS-LL (p < 0.001). Congo red staining revealed brilliant red amyloid deposits confirmed by apple-green birefringence within dermal collagen, sweat glands, and arrector pili that engulfed axons. The diagnostic sensitivity and specificity to detect amyloid in skin were 70% and 100%. Both AL amyloidosis and 2 of 10 TTR-noPN subjects were Congo red-positive. Amyloid burden correlated with IENFD (r = -0.63), SGNFD (r = -0.67), PMNFD (r = 0.50), and NIS-LL (r = -0.57). Wild-type TTR staining was less prominent in TTR FAP patients. INTERPRETATION: Cutaneous amyloid was detected in 70% of TTR-FAP and 20% of TTR-noPN subjects. Amyloid burden correlated strongly with reductions in IENFD, SGNFD, PMNFD, and NIS-LL. Skin is an attractive tissue to establish an amyloid diagnosis, and amyloid burden has potential as a biomarker to detect treatment effect in TTR-FAP drug trials. Ann Neurol 2017;82:44-56. PMID- 28598018 TI - Enantioselective Hydroazidation of Trisubstituted Non-Activated Alkenes. AB - A one-pot procedure for the enantioselective hydroazidation of non-activated trisubstituted alkenes is described. Hydroboration with monoisopinocampheylborane (IpcBH2 ) provides dialkylboranes that are in situ selectively converted into monoalkyl-substituted catecholboranes; these undergo radical azidation upon treatment with benzenesulfonyl azide and a radical initiator. Enantiomerically enriched azides were thus obtained in yields of 59-81 % and enantioselectivities of up to 94:6 e.r. (98:2 e.r. if the intermediate dialkylborane is purified by crystallization). A rapid access to enantiomerically pure (+)-rodocaine is also described. The use of other arenesulfonyl radical traps enables enantioselective hydroallylation, hydrosulfanylation, and hydrobromination reactions with yields of 71-86 %. PMID- 28598016 TI - Race/Ethnicity and Cardiovascular Events Among Patients With Systemic Lupus Erythematosus. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is more prevalent and results in more severe outcomes among blacks, Asians, and Hispanics than among whites. Cardiovascular disease (CVD) is the leading cause of death among SLE patients. We undertook this study to examine racial/ethnic variations in risk of CVD events among SLE patients. METHODS: Within the Medicaid Analytic eXtract from 2000 to 2010, we identified patients ages 18-65 years with SLE (>=3 International Classification of Diseases, Ninth Revision 710.0 codes, >=30 days apart) and with >=12 months of continuous enrollment. Subjects were followed up from the index date to the first CVD event (myocardial infarction [MI] or stroke), death, disenrollment, loss to follow-up, or end of follow-up period. Race/ethnicity specific annual CVD event rates were calculated. Cox regression models estimated hazard ratios (HRs) with 95% confidence intervals (95% CIs), accounting for competing risk of death and adjusting for baseline demographics and comorbidities. RESULTS: Of 65,788 SLE patients, 93.1% were women and ~42% were black, 38% were white, 16% were Hispanic, 3% were Asian, and 1% were American Indian/Alaska Native. Mean +/- SD follow-up was 3.8 +/- 3.1 years. CVD event rates were highest among blacks (incidence rate [IR] 10.57 [95% CI 9.96-11.22]) and lowest among Asians (IR 6.63 [95% CI 4.97-8.85]). After multivariable adjustment, risk of CVD events was increased among blacks (HR 1.14 [95% CI 1.03 1.26]) compared to whites. Hispanics and Asians had a lower risk of MI (HR 0.61 [95% CI 0.48-0.77] and HR 0.57 [95% CI 0.34-0.96], respectively), while blacks and Hispanics had a higher risk of stroke (HR 1.31 [95% CI 1.15-1.49] and HR 1.22 [95% CI 1.03-1.44], respectively). CONCLUSION: Among SLE patients enrolled in Medicaid, the risk of MI was lower among Hispanics and Asians compared to whites, while the risk of stroke was elevated among blacks and Hispanics compared to whites. PMID- 28598017 TI - A novel RNA polymerase-binding protein that interacts with a sigma-factor docking site. AB - Sporulation in Bacillus subtilis is governed by a cascade of alternative RNA polymerase sigma factors. We previously identified a small protein Fin that is produced under the control of the sporulation sigma factor sigmaF to create a negative feedback loop that inhibits sigmaF -directed gene transcription. Cells deleted for fin are defective for spore formation and exhibit increased levels of sigmaF -directed gene transcription. Based on pull-down experiments, chemical crosslinking, bacterial two-hybrid experiments and nuclear magnetic resonance chemical shift analysis, we now report that Fin binds to RNA polymerase and specifically to the coiled-coil region of the beta' subunit. The coiled-coil is a docking site for sigma factors on RNA polymerase, and evidence is presented that the binding of Fin and sigmaF to RNA polymerase is mutually exclusive. We propose that Fin functions by a mechanism distinct from that of classic sigma factor antagonists (anti-sigma factors), which bind directly to a target sigma factor to prevent its association with RNA polymerase, and instead functions to inhibit sigmaF by competing for binding to the beta' coiled-coil. PMID- 28598019 TI - Authors' reply to the letter by Nguyen et al. PMID- 28598020 TI - Comment on a paper by Palmlof et al. entitled 'Expectations of recovery: A prognostic factor in patients with neck pain undergoing manual therapy treatment'. PMID- 28598021 TI - Onset of Kaposi sarcoma and Merkel cell carcinoma during low-dose steroid therapy for rheumatic polymyalgia. PMID- 28598022 TI - Skin resistance to UVB-induced oxidative stress and hyperpigmentation by the topical use of Lactobacillus helveticus NS8-fermented milk supernatant. AB - AIMS: In this study, we investigated the preventive properties of the supernatant of Lactobacillus helveticus NS8-fermented milk (NS8-FS) against UV light-induced skin oxidative damage and hyperpigmentation. METHODS AND RESULTS: NS8-FS exhibited significant radical scavenging activity in tests with ABST+ and DPPH scavenging methods, and as well strongly inhibited 3-morpholinosydnonimine (Sin 1)-induced ROS generation in HaCat keratinocytes. Unexpectedly, NS8-FS was found to inhibit melanin production in B16F10 melanoma cells and to exhibit inhibitory effects both to the enzymatic activity of tyrosinase (TYR) and the expression of proteins required for melanin synthesis. In SKH-1 hairless mice, topical application of NS8-FS alleviated UVB-induced skin photodamage, including the improvement of the appearance of epidermal thickness, transepidennal water loss and lipid peroxidation levels. In the tanning guinea pig model, the whitening effect of NS8-FS was demonstrated using Masson-Fontana staining and TYR staining. Furthermore, NS8-FS was shown to stimulate the nuclear translocation and activation of the Nrf2 protein, along with recovery of antioxidant enzyme activities. CONCLUSION: NS8-FS exhibits the protective capacities against UV light-induced skin oxidative damage and hyperpigmentation. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings indicate the potential of cell-free fermented products of lactic acid bacteria in topical photoprotection. PMID- 28598024 TI - Facile and Reversible Formation of Iron(III)-Oxo-Cerium(IV) Adducts from Nonheme Oxoiron(IV) Complexes and Cerium(III). AB - Ceric ammonium nitrate (CAN) or CeIV (NH4 )2 (NO3 )6 is often used in artificial water oxidation and generally considered to be an outer-sphere oxidant. Herein we report the spectroscopic and crystallographic characterization of [(N4Py)FeIII -O CeIV (OH2 )(NO3 )4 ]+ (3), a complex obtained from the reaction of [(N4Py)FeII (NCMe)]2+ with 2 equiv CAN or [(N4Py)FeIV =O]2+ (2) with CeIII (NO3 )3 in MeCN. Surprisingly, the formation of 3 is reversible, the position of the equilibrium being dependent on the MeCN/water ratio of the solvent. These results suggest that the FeIV and CeIV centers have comparable reduction potentials. Moreover, the equilibrium entails a change in iron spin state, from S=1 FeIV in 2 to S=5/2 in 3, which is found to be facile despite the formal spin-forbidden nature of this process. This observation suggests that FeIV =O complexes may avail of reaction pathways involving multiple spin states having little or no barrier. PMID- 28598023 TI - Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway. AB - Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-beta1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV-augmented bleomycin-induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild-type or Src-deficient were exposed to low tidal volume (VT ) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non-ventilated mice were used as control groups. Following bleomycin exposure in wild-type mice, high VT MV induced substantial increases in microvascular permeability, TGF-beta1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of alpha-smooth muscle actin and decreased staining of E-cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src-deficient mice, dampened the MV augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV-augmented EMT and pulmonary fibrosis after bleomycin-induced ALI, partly by inhibiting the Src pathway. PMID- 28598025 TI - A Diary Study of Self-Compassion, Upward Social Comparisons, and Body Image Related Outcomes. AB - BACKGROUND: Self-compassion may protect individuals experiencing poor body image and associated maladaptive outcomes. The purpose of the study was to examine within-person associations (whilst controlling for between-person differences) between appearance-related self-compassion, appearance-related threats (operationalised as upward appearance comparisons), and body image-related variables, namely, social physique anxiety, drive for thinness, and body dissatisfaction. METHODS: A diary methodology was used whereby young women (n = 126; Mage = 21.26) responded to brief online surveys three times per day (11am, 3pm, and 7pm) every second day for one week (i.e. a total of 12 measurement points). RESULTS: Results of mixed linear modeling revealed that both state appearance-related upward comparisons and self-compassion independently predicted all three outcomes in a positive and negative fashion, respectively. No significant interaction effects between state appearance-related upward comparisons and self-compassion were found. CONCLUSIONS: The results suggested that appearance-based self-compassion was important, not just when there was a potential threat to body image via upward appearance comparisons. The findings highlight the importance of fostering self-compassion on a daily level. PMID- 28598026 TI - Altered Expression of MicroRNAs in Rheumatoid Arthritis. AB - Rheumatoid arthritis is one of the most common types of inflammatory joint diseases. Women, smokers, and people with positive family history are more susceptible to this disease. Diagnostic criteria include at least one swollen joint that has not been caused by other diseases. MicroRNAs are non-coding RNAs that are evolutionarily conserved and have a length of 18-25 nucleotides. MicroRNAs control gene expression at the post-transcriptional level via promoting mRNA degradation or translational repression. Recognition of alterations in microRNA status and their respective targets, may offer an opportunity to better identify the pathways that are involved in the etiopathogenesis of autoimmune diseases. It has been suggested that microRNAs may serve as potential biomarkers for both diagnosis and prognosis of autoimmune diseases. Here, we review the available evidence on the deregulations of microRNA expression in rheumatoid arthritis. More precisely, this review focuses on the microRNA involved in T cell regulation and gives perspectives on the use of this microRNA as biomarkers of diagnosis, prognosis, or intervention efficacy. J. Cell. Biochem. 119: 478-487, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28598027 TI - A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents. AB - AIM: To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). METHODS: The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. RESULTS: ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. CONCLUSIONS: ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity. PMID- 28598030 TI - Corrigendum. PMID- 28598029 TI - Assessing the stability and suitability of haematology parameters for diagnosing and monitoring iron deficiency. PMID- 28598028 TI - Antitumor evaluation and multiple analysis on different extracted fractions of the root of Cynanchum auriculatum Royle ex Wight. AB - The root of Cynanchum auriculatum (C. auriculatum) Royle ex Wight has been shown to possess various pharmacological effects and has recently attracted much attention with respect to its potential role in antitumor activity. The C-21 steroidal glycosides are commonly accepted as the major active ingredients of C. auriculatum. In this study, the antitumor abilities of different extracted fractions of the root bark and the root tuber of C. auriculatum were investigated by using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in human cancer cell lines HepG2 and SMMC-7721. The results showed that the chloroform and ethyl acetate fractions of the root tuber suppressed tumor cell growth strongly. To identify and characterize the chemical constituents of different active fractions, an ultra high performance liquid chromatography with triple-quadrupole tandem mass spectrometry method was developed for the simultaneous quantitation of eight C-21 steroidal glycosides. The analysis revealed that the C-21 steroidal glycosides were concentrated in the chloroform and ethyl acetate fractions, and the total contents of different fractions in the root tuber were significantly higher than those of corresponding ones in the root bark. Furthermore, the C-21 steroidal glycosides based on different types of aglucones were prone in different medicinal parts of C. auriculatum. PMID- 28598031 TI - Laparoscopic segmental duodenectomy for a gastrointestinal stromal tumor located in the second portion of the duodenum: A case report. AB - Gastrointestinal stromal tumors of the duodenum are rare. For benign tumors, premalignant lesions, or malignant potential tumors located in the second portion of the duodenum close to the papilla of Vater, pancreaticoduodenectomy is sometimes performed. A case of laparoscopic segmental duodenectomy for a gastrointestinal stromal tumor at the second portion of the duodenum is reported. The surgical procedure was performed as follows: first, the second portion of the duodenum was separated from the pancreatic head; second, the duodenum was cut off with the linear stapler after having confirmed preservation of the papilla by intraoperative endoscopy; and third, reconstruction was carried out by a side-to side duodenojejunostomy. Laparoscopic segmental duodenectomy for duodenal gastrointestinal stromal tumors is thought to be advantageous compared with pancreaticoduodenectomy in terms of low burden and organ function preservation. The present procedure is feasible for benign or low-malignant tumors that do not infiltrate outside of the duodenal walls. PMID- 28598032 TI - The relationship between species richness and ecosystem variability is shaped by the mechanism of coexistence. AB - Theory relating species richness to ecosystem variability typically ignores the potential for environmental variability to promote species coexistence. Failure to account for fluctuation-dependent coexistence may explain deviations from the expected negative diversity-ecosystem variability relationship, and limits our ability to predict the consequences of increases in environmental variability. We use a consumer-resource model to explore how coexistence via the temporal storage effect and relative nonlinearity affects ecosystem variability. We show that a positive, rather than negative, diversity-ecosystem variability relationship is possible when ecosystem function is sampled across a natural gradient in environmental variability and diversity. We also show how fluctuation-dependent coexistence can buffer ecosystem functioning against increasing environmental variability by promoting species richness and portfolio effects. Our work provides a general explanation for variation in observed diversity-ecosystem variability relationships and highlights the importance of conserving regional species pools to help buffer ecosystems against predicted increases in environmental variability. PMID- 28598033 TI - Decision making in anomalous aortic origin of a coronary artery. AB - Anomalous aortic origin of a coronary artery (AAOCA) is the second most common cause of sudden cardiac death (SCD) in young athletes in United States. The exact pathophysiological mechanisms of SCD are unknown. There is lack of long-term outcome data on repaired and unrepaired AAOCA and our current risk stratification scheme for these patients is suboptimal. These patients are evaluated in a nonuniform manner across institutions in United States, and even by different providers residing in the same institution. The main objective of this article is to use what is known and unknown about this disease and to provide a possible framework that can help workup and manage patients with AAOCA in a more consistent fashion. PMID- 28598035 TI - Genetic study of early-onset Graves' disease in the Chinese Han population. AB - Graves' disease (GD) is a complex autoimmune disorder in which genetic and environmental factors are both involved in the pathogenesis. Early-onset patients have a shorter exposure time to environmental factors and are, therefore, good models to help understand the genetic architecture of GD. Based on previous studies of early-onset GD, 11 single nucleotide polymorphisms (SNPs) and their related SNPs (R2 > .6), SNPs located within a +/-1-Mb region of the FOXP3 gene, and 20 validated GD-risk SNPs were selected and screened for genotyping in 3735 GD and 4893 control patients to investigate whether early-onset GD is a subtype of GD with distinct susceptibility genes. Ultimately, we did not confirm the reported genetic markers of early-onset GD in our Chinese Han population but found that a GD-risk SNP located in the human leukocyte antigen class I region rs4947296-was more strongly correlated with early-onset GD than non-early-onset GD. In addition, heterogeneity analysis of GD patients suggests that it may be more reasonable to define early-onset GD as an onset age <=20 years. PMID- 28598036 TI - GmTIR1/GmAFB3-based auxin perception regulated by miR393 modulates soybean nodulation. AB - Auxins play important roles in the nodulation of legumes. However, the mechanism by which auxin signaling regulates root nodulation is largely unknown. In particular, the role of auxin receptors and their regulation in determinate nodule development remains elusive. We checked the expression pattern of the auxin receptor GmTIR1/GmAFB3 genes in soybean. We analyzed the functions of GmTIR1/AFB3 in the regulation of rhizobial infection and nodule number, and also tested the functions of miR393 during nodulation and its relationship with GmTIR1/AFB3. The results showed that GmTIR1 and GmAFB3 genes exhibit diverse expression patterns during nodulation and overexpression of GmTIR1 genes significantly increased inflection foci and eventual nodule number. GmTIR1/AFB3 genes were post-transcriptionally cleaved by miR393 family and knock-down of the miR393 family members significantly increased rhizobial infection and the nodule number. Overexpression of the mutated form of GmTIR1C at the miR393 cleavage site that is resistant to miR393 cleavage led to a further increase in the number of infection foci and nodules, suggesting that miR393s modulate nodulation by directly targeting GmTIR1C. This study demonstrated that GmTIR1- and GmAFB3 mediated auxin signaling, that is spatio-temporally regulated by miR393, plays a crucial role in determinate nodule development in soybean. PMID- 28598037 TI - Atypical neurofibromatosis type 1 with unilateral limb hypertrophy mimicking overgrowth syndrome. AB - Neurofibromatosis type 1 (NF1; OMIM 162200), a dominantly inherited multitumor syndrome, results from mutations in the Neurofibromin 1 (NF1) gene. We present the case of a Hungarian woman with the clinical phenotype of NF1 over her whole body and the clinical features of unilateral overgrowth involving her entire left leg. This unusual phenotype suggested either the atypical form of NF1 or the coexistence of NF1 and overgrowth syndrome. Direct sequencing of the genomic DNA isolated from peripheral blood revealed a novel frameshift mutation (c.5727insT, p.V1909fsX1912) in the NF1 gene. Next-generation sequencing of 50 oncogenes and tumour suppressor genes, performed on the genomic DNAs isolated from tissue samples and peripheral blood, detected only wild-type sequences. Based on these results, we concluded that the patient is affected by an unusual phenotype of NF1, and that the observed unilateral overgrowth of the left leg might be a rare consequence of the identified c.5727insT mutation. PMID- 28598034 TI - Hepatitis E in southern Vietnam: Seroepidemiology in humans and molecular epidemiology in pigs. AB - Viral pathogens account for a significant proportion of the burden of emerging infectious diseases in humans. The Wellcome Trust-Vietnamese Initiative on Zoonotic Infections (WT-VIZIONS) is aiming to understand the circulation of viral zoonotic pathogens in animals that pose a potential risk to human health. Evidence suggests that human exposure and infections with hepatitis E virus (HEV) genotypes (GT) 3 and 4 results from zoonotic transmission. Hypothesising that HEV GT3 and GT4 are circulating in the Vietnamese pig population and can be transmitted to humans, we aimed to estimate the seroprevalence of HEV exposure in a population of farmers and the general population. We additionally performed sequence analysis of HEV in pig populations in the same region to address knowledge gaps regarding HEV circulation and to evaluate if pigs were a potential source of HEV exposure. We found a high prevalence of HEV GT3 viral RNA in pigs (19.1% in faecal samples and 8.2% in rectal swabs) and a high HEV seroprevalence in pig farmers (16.0%) and a hospital-attending population (31.7%) in southern Vietnam. The hospital population was recruited as a general-population proxy even though this particular population subgroup may introduce bias. The detection of HEV RNA in pigs indicates that HEV may be a zoonotic disease risk in this location, although a larger sample size is required to infer an association between HEV positivity in pigs and seroprevalence in humans. PMID- 28598038 TI - Biphasic Effect of ATP on In Vitro Mineralization of Dental Pulp Cells. AB - Dental pulp cells release adenosine triphosphate (ATP) in response to intrapulpal pressure and the amount released depends on the magnitude of the pressure. ATP regulates the differentiation of stem cells into adipocytes and osteoblasts. However, it is unknown whether extracellular ATP influences the stemness and osteogenic differentiation of stem cells from human exfoliated deciduous teeth (SHEDs). Therefore, this study investigated the effects of extracellular ATP at a low (0.1 MUM) and high (10 MUM) concentration on the stemness and osteogenic differentiation of SHEDs. Cells were cultured in either growth medium or osteogenic medium with or without 0.1-10 MUM ATP. In growth medium, both concentrations of ATP increased the mRNA expression of pluripotent and osteogenic markers. In contrast, in osteogenic medium, 0.1 MUM ATP enhanced in vitro mineralization, whereas 10 MUM ATP inhibited this process. In addition, 10 MUM ATP stimulated the mRNA expression and activity of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), an enzyme that regulates the phosphate/pyrophosphate ratio. Thus, depending on the growth condition and its concentration, ATP stimulated stemness and in vitro mineralization or inhibited mineralization. In growth medium, both ATP concentrations stimulated pluripotent and osteogenic marker gene expression. However, in osteogenic medium, a biphasic effect was found on in vitro mineralization; the low concentration stimulated, whereas the high concentration inhibited, mineralization. We propose that ATP released due to mechanical stress modulates the stemness and differentiation of SHEDs. J. Cell. Biochem. 119: 488-498, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 28598039 TI - The Synthesis and Evaluation of Fluoro-, Trifluoromethyl-, and Iodomuscimols as GABA Agonists. AB - Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (alpha1 beta2 gamma2 ) and extrasynaptic (alpha4 beta2 gamma) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (alpha4 beta2 gamma) receptor. PMID- 28598040 TI - Doing the Research that Informs Practice: A Retrospective View of One Group's Attempt to Study The Teaching and Learning of Organic Chemistry. AB - The idea that the focus of educational research should be on results that can inform the practice of teaching has been an implicit assumption for so many years that one would be hard-pressed to trace it back to an individual source. At one time, the people doing such research in STEM disciplines were faculty in schools or colleges of education who focused on K-12 classrooms and looked for ideas, concepts, and principles that would be valid across a range of STEM disciplines. Eventually, this research was done on college- or university-level students, as well, and there was a shift toward what has been called discipline-based educational research (DBER) that looks at the problems associated with the teaching and learning of a given discipline, such as chemistry. This paper will discuss the results of research on problem-solving in chemistry that has been done in our research group, with particular emphasis on the challenges of teaching and learning organic chemistry. The goal of this paper is to show what can happen when one listens carefully to students and begins to appreciate the difference between what we think we have taught and what the students learned. The examples we will use have the potential for convincing those of us who teach chemistry to rethink what we do in our classes to find better ways of helping our students understand the material we are trying to teach. Although this paper will focus on results from the second-year organic chemistry course, similar results have been observed in both inorganic and physical chemistry, as well as biochemistry courses. PMID- 28598041 TI - The Double Trouble: PVD and Peripheral Neuropathy in Diabetes. PMID- 28598043 TI - Clinical Profile of Hypertensive Emergencies in an Intensive Care Unit. AB - AIMS AND OBJECTIVE: To study the prevalence of hypertensive emergencies in an ICU set up and to study the clinical presentation of hypertensive emergencies related to cardiovascular, neurological and renovascular system. METHODS: Type of Study: Cross-sectional, descriptive study. DURATION OF STUDY: Two years from 1st December 2011 till 30th November 2013. SAMPLE SIZE: 50 patients of hypertensive emergencies admitted to the intensive care unit of Dr. V.M. Govt. Medical College, Solapur were studied. Inclusion criteria All patients above 18 years of age. Systolic blood pressure > 180 mmHg Diastolic blood pressure > 120 mm Hg Exclusion criteria Pregnancy Patients with diabetes mellitus We classified as hypertensive emergencies all cases in which the increase in blood pressure was associated with one or more of the following types of acute or ongoing end-organ damage: hypertensive encephalopathy; stroke (cerebral infarction or intracerebral or subarachnoid hemorrhage, transient ischemic attack); acute pulmonary edema, left ventricular failure; acute myocardial infarction or unstable angina, progressive renal insufficiency features suggestive of retinopathy. All these conditions were diagnosed clinically or by approprriate diagnostic tests. CONCLUSIONS: most common presenting complaint in patients was breathlessness seen in 17 patients (34%), followed by neurological deficit in 14 patients (28%). Thirteen patients (26%) had complaints of headache, whereas 12 (24%) patients complained of chest pain on admission. Other symptoms included vomiting, giddiness, psychomotor agitation, and decreased urine output. Out of a total of 4076 admissions during the study period in the intensive care unit we had 50 cases of hypertensive emergencies with prevalence of 1.22% in our intensive care unit. Most common organ involvement was the retina followed by cardiovascular system, renal and then the central nervous system. PMID- 28598042 TI - Peripheral Vascular Disease in Patients with Diabetic Foot Ulcers - An Emerging Trend: A Prospective Study from North India. AB - BACKGROUND: Diabetic foot ulcer is one of the chronic complications of diabetes mellitus (DM) with 25% of patients with diabetes developing a foot ulcer during their lifetime leading to amputation. Diabetic foot is classified into 2 main types: neuropathic ulcers (NPU) and neuro-ischemic ulcer (NIU) where in addition to neuropathy peripheral vascular disease (PVD) is also present. AIMS: We aimed to a) assess the prevalence of Peripheral vascular disease (PVD) in patients of type 2 diabetes mellitus (T2DM) presenting with New Diabetic Foot ulcers (DFU). b) To compare the clinical profile and risk factors responsible for development of NPU and NIU in North Indian population. SETTING AND DESIGN: Cross sectional study conducted on first 100 T2DM patients presenting with new DFU in tertiary referral institute for one year period from August 2012 to July 2013. METHODS AND MATERIAL: Detailed relevant clinical history including age, sex and duration of diabetes, history of smoking and hypertension (HTN) and prevalence of other complications like retinopathy, nephropathy, coronary artery disease (CAD) and stroke was obtained. Patients were examined for neuropathy, loss of pulsations, ankle brachial pressure index (ABI) and investigated for HbA1C, blood urea nitrogen (BUN) and serum creatinine. Statistical analysis used: t test, Fisher exact test and univariate analysis. RESULTS: NIU was present in 30 and NPU in 70 out of 100 patients. NIU were commoner among males as compared to females (21/64 males vs 9/36 females). Strong association of smoking (20/30 patients), hypertension (24/30 patients) and longer duration of DM (14 vs 8 years) with NIU was found. Even other complications of DM like CAD (8/30 patients), stroke (4/30 patients), retinopathy (24/30 patients) and nephropathy (15/30 patients) were more prevalent in patients with NIU. CONCLUSIONS: Prevalence of PVD is 30% in our study which is more than previous studies showing an increasing trend. NPU are two times more common than NIU. Hypertensive male patients with smoking habits and longer duration of T2DM are most prone to develop NIU. NIU share the similar risk factors with CAD and coexist with other complications of DM which should be looked for and treated. PMID- 28598044 TI - A Study of Prehospital Delay Patterns in Acute Myocardial Infarction in an Urban Tertiary Care Institute in Mumbai. AB - OBJECTIVE: There is now increasing awareness about the need for early diagnosis in patients presenting with chest pain. Pre-hospital delay remains a major hurdle in the institution of early reperfusion therapy, which is crucial in salvaging 'at-risk' myocardium and reducing adverse cardiovascular events following ST elevation myocardial infarction (STEMI). This study aims to determine the incidence and the determinants of delayed presentation STEMI and the potential impact of such delay on adverse cardiovascular outcomes. METHODS: We prospectively evaluated all patients who were admitted in the emergency department of our hospital with STEMI from March 2014 to February 2016. Data was collected sequentially at the time of admission, discharge and during follow-up. Patients were evaluated with serial ECGs, continuous ECG monitoring and echocardiography. RESULTS: Out of 1386 patients with STEMI, delayed presentation was seen in 1148 (> 2 hrs) and 805 (> 4 hrs) patients. The duration from onset of symptoms to the presentation in the emergency room (pre-hospital delay) was 228 +/- 341minutes.The door to needle time was 34 +/- 24 minutes. The major factors for pre-hospital delay were misinterpretation of symptoms (45%) and transportation problems (27%). CONCLUSIONS: The problem of pre-hospital delay continues to remain a major hurdle in initiating timely reperfusion therapy in patients with acute STEMI. Lack of awareness and poor transportation facilities are the major contributors. It should be the goal of STEMI care programmes of the future to make a concerted effort to addressing these factors, in order to optimize the benefit of reperfusion therapy for this high risk group of patients. PMID- 28598045 TI - Soft Drinks Consumption and the Risk of Nonalcoholic Fatty Liver Disease. AB - INTRODUCTION: The increased consumption of sugar-sweetened beverages (SSBs) has been implicated in the increased incidence of obesity and metabolic syndrome Little of the research on sugar-sweetened beverage intake has examined the consumption patterns of sugared beverages by college students, despite the vulnerabilities of this population to weight gain. The current study sought to characterize sugar-sweetened beverage intake of undergraduate students who belong to high socio-economic strata and to study its correlation with presence of non alcoholic fatty liver disease. MATERIAL AND METHODS: In a cross sectional, a self reported questionnaire based study about soft drink consumption (>=2/day, 1/day, <1/day). That included undergraduate medical students. Anthropometry and blood pressure were recorded and fasting glucose, insulin and lipid profile and abdominal ultrasonography for the presence of fatty liver was assessed. RESULTS: A total of 242 students were studied. The students in group 1 (>=2/day) had significantly higher BMI, waist circumference and diastolic blood pressure than students of other groups. They also had higher triglycerides, fasting insulin, HOMA-IR and significantly lower levels of HDL-cholesterol. Overall (40%) students had metabolic syndromes in group 1 compared to 8% and 3% in other groups while presence of NAFLD was observed in 75%, 16% and 4% in three groups respectively. Duration of soft drink consumption had positive correlation with presence of NAFLD. CONCLUSIONS: Substantial consumption of soft drinks is leading to increased obesity and cardio-metabolic risk factors in young adults. Artificially sweetened diet soft drinks have been posed as a healthier alternative due to their lack of calories but they do not guarantee protection against non-alcoholic fatty liver disease. PMID- 28598047 TI - Awareness and Outcome of Changing Trends in Clinical Profile of Dengue Fever: A Retrospective Analysis of Dengue Epidemic from January to December 2014 at a Tertiary Care Hospital. AB - BACKGROUND: Dengue fever is caused by mosquito-borne arboviral infection that has become a public health concern globally. Recently, an alarming rise of dengue has also been seen in India. Hence the study was undertaken to know profile of clinical manifestations and laboratory findings during the evolution of dengue fever. METHODS: In this study, retrospective data analysis was done in 216 seropositive dengue patients admitted between January to December 2014 in department of medicine at a north Indian care hospital. The tests analyzed were blood counts, serum electrolytes, liver function tests, kidney function tests, chest x-ray and other relevant investigations. RESULTS: Males were commonly affected and the most exposed age group was found to be18-35 years. The seropositive case rate for dengue was 56% for NS1 antigen and 36% for IgM. There was rural dominancy of cases with a peak in September. Fever was the most common clinical feature followed by headache, myalgia, backache, nausea and abdominal pain. Petechia was most common haemorrhagic manifestation. Common laboratory findings included 89.35% decreased Platelet counts (<100 000/cmm), 67.59% increased hematocrit (>45%) and 58.33% deranged liver function test. There was no reported mortality in dengue. CONCLUSIONS: From prompt and proper treatment could prevent deaths in moderate and severe dengue. Atypical presentations of dengue should be kept in mind so as not to miss the cases. Increased community awareness and vector control measures need to be strengthened during peri-monsoon period to reduce burden of dengue cases. PMID- 28598046 TI - Correlation and Comparison of Epicardial Adipose Tissue with Sagittal Abdominal Diameter and Other Anthropometric and Biochemical Variables of Metabolic syndrome. AB - OBJECTIVE: 1) To determine relation of epicardial adipose tissue (EAT) thickness with sagittal abdominal diameter (SAD) and other anthropometric measurements in metabolic syndrome (MetS). 2) To determine relation of epicardial adipose tissue with biochemical variables of metabolic syndrome. METHODS: Cases were recruited from the patients attending OPD in New Medical College Hospital, Govt. Medical College, Kota, Rajasthan, India between March 2015 to February 2016. Informed consent was obtained from all participants after taking permission from hospital ethical committee. Patients were categorized as cases and controls according to IDF criteria for MetS. We obtained receiver operating characteristic (ROC) curve of EAT for determination of cut-off values. RESULTS: Epicardial adipose tissue thickness had significant positive correlation with fasting blood sugar (r = 0.49), sagittal abdominal diameter(r = 0.48), body mass index (r = 0.47), LDL cholesterol(r = 0.34), waist circumference (r = 0.33), waist hip ratio (r = 0.32), triglycerides (r= 0.31) and total cholesterol (r = 0.29). Epicardial adipose tissue thickness had significant negative correlation to HDL cholesterol (r = -0.34). EAT thickness (cm) was greater in metabolic syndrome cases (0.515 +/ 0.07 vs 0.338 +/- 0.06; p < 0.0001). Optimal cut off of EAT in metabolic syndrome is 0.425 cm according to ROC curve at which test is 96% sensitive and 83 % specific. CONCLUSIONS: EAT has shown good correlation with SAD and other anthropometric measurements as well as biochemical parameters of metabolic syndrome. Optimal cut off value of EAT to predict metabolic syndrome is 0.425 cm. FBS and Triglycerides are more closely associated with EAT. HDL Cholesterol is better correlated to SAD while LDL cholesterol is best correlated to WC. PMID- 28598048 TI - Hepatotoxicity in HIV Patients, An Observational Study in Patients from Tertiary Care Centre of Western India. AB - OBJECTIVE: HIV AIDS has currently become a chronic manageable condition with HAART, but with its chronicity and lifelong therapy currently the adverse drug reactions to these drugs are the main concern for any treating physician. Hepatotoxicity is one of the prime concerns of any physician managing HIV patients. We observe a number of patients reporting hepatotoxicity in our cohort and this had great impact on the efficacy and intake of the HAART drugs, this led us to explore this area and to find out the prevalence and etiologies in our cohort. METHODS: Thus we conducted this observational study to determine the prevalence of hepatotoxicity, the various etiologies for hepatotoxicity and assess HAART as the etiology of hepatotoxicity .The study was conducted in the virology department after obtaining ethics committee approval and incompliance with ICH, GCP guidelines. The study was conducted over a span of 3 months and data was collected and analyzed. RESULTS: Data of 178 Subjects was considered for evaluation of which 10 were excluded due to incomplete information. 168 patients with hepatotoxicity were assessed in the study, the prevalence of hepatotoxicity in our cohort was around 2.25%. Of the 168 patients 111 were male and 57 were female.52 patients were on Antituberculosis therapy (ATT) and thus 30.95% was the incidence rate of hepatotoxicity due to ATT. 23.80% (40 out of 168) were alcoholic and hence it was the etiological agent. HAART as the etiology was observed in 5 patients,2.97%being the incidence .Hepatitis B as the causative agent for hepatotoxicity was observed in 3.57% patients. CONCLUSIONS: We thus concluded that ATT and alcoholism are major areas of concern in HIV patients and thus a strict monitoring is warranted while prescribing ATT at the same time deaddiction is equally important. HAART induced hepatotoxicity is observed only in a small section of patients and thus these drugs need not be attributed as culprits blindly and put to disrepute. PMID- 28598049 TI - Diabetes Drug Prescription Pattern and Awareness Among Health Care Providers in Sub-Himalayan Region of India: A Population Based Study. AB - BACKGROUND: To determine the pattern of diabetic drug prescription and awareness about diabetes among primary health providers in the rural areas of Himachal Pradesh situated in the western Himalayas at an elevation range from 350 meters (1,148ft) to 6900 meters (22,966ft) above sea level. METHODS AND MATERIAL: Study was conducted in 20 rural areas of Himachal Pradesh, located 50 to 400 Km from state capital, at 2200 to 10,000 feet altitude. Non-pregnant diabetic adults were surveyed through 31 diabetic camps. Detailed history, weight, height, waist circumference, body mass index recorded. Fasting or random blood glucose, glycated hemoglobin, lipid profile measured and blood pressure recorded. RESULTS: 894 diabetic patients were included in the study (59.83% male) with the mean age of 52.94+/-6.78 years. Two in three patients were on oral hypoglycemic agents (OHAs), and one in three on alternative approaches for diabetes control. Among OHAs, sulphonylureas (SU) were the most commonly prescribed oral agents in 76.09% of patients followed by metformin in 23.87%. Glibenclamide was the most commonly prescribed SU in 44.60%. Amlodipine and atenolol was the commonest anti hypertensive drug prescribed in 77.85% either in combination or as individual drug. Only 10.59% were on lipid lowering therapy. For primary care providers glycemic target was the mainstay of diabetes treatment with little emphasis on blood pressure control and no emphasis on lipid reduction. CONCLUSIONS: Sulphonylureas were the commonest anti-diabetic drug prescribed by the primary care providers followed by metformin. Insulin was prescribed to 2.23% only. Combination of amlodipine and atenolol was the commonest anti-hypertensive drugs prescribed and only 10% of patients were prescribed statin. PMID- 28598050 TI - Consensus Document on Home Nebulization for Maintenance Treatment of Obstructive Airway Diseases: A Joint Initiative by the National Allergy Asthma Bronchitis Institute (NAABI) and Chest Research Foundation (CRF). AB - Recent years have seen an increase in the use of nebulizers for delivering maintenance therapy in obstructive airway diseases (OADs) such as asthma and chronic obstructive pulmonary disease (COPD). The probable factors associated with this increase at home are: convenience of drug delivery, technological advances making the nebulizer equipment more efficient and portable, increase in the prevalence of OADs and the ageing population which may impact the optimal use of handheld inhalers such as pressurized metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). Although there is increase in the use of maintenance therapy with nebulization, there has been no such increase in the evidence base available for the appropriate use of nebulizers. The last international guidelines were published in 2001. Hence there is a need to address this knowledge gap especially with the widespread use of home nebulization in India. With this objective, we organized a consensus meeting to address certain critical questions pertaining to the use of nebulizers for maintenance treatment in OADs. This article presents the findings of the consensus panel on the use of maintenance treatment of OADs with nebulization at home. PMID- 28598052 TI - Survival Analysis. PMID- 28598051 TI - Prevention and Management of Acute Kidney Injury: What a Physician Should Know. AB - The incidence of acute kidney injury (AKI) has been increasing worldwide. The increase is attributable not only to ageing population with multiple comorbidities, polypharmacy, increasing use of contrast for diagnostic and therapeutic procedures but also to the fact that now it is being recognized more often. The 'Zero by 25' initiative by International Society of Nephrology aims at preventing all avoidable deaths from AKI worldwide by the year 2025. It calls for greater awareness about management of AKI among primary care physicians. In last few years, various concepts have emerged regarding prevention and management of AKI. This review aims at consolidating and applying these concepts to the '5R approach' for management of AKI introduced by Lewington. PMID- 28598053 TI - Healer on Death Bed: How and Why? Revive Him Please! PMID- 28598054 TI - Right Atrial Myxoma. PMID- 28598055 TI - The "Mexican Hat" Sign in Osmotic Demyelination Syndrome. PMID- 28598056 TI - Neuro-Behcet's Disease Presenting as a Young Stroke. AB - Neuro-Behcet's disease (NBD) is a rare neurological manifestation of the systemic small vessel vasculitis called Behcet's disease. It can present in various ways with predilection for the brain stem, thalamo- hypothalamic regions, cerebellum and basal ganglia. In this case, we describe a case of young stroke that was later attributed to NBD. PMID- 28598057 TI - Macrophage Activation Syndrome. AB - Macrophage Activation Syndrome (MAS) occurs as a severe life-threatening complication of several chronic rheumatic diseases. It is more frequent with systemic onset juvenile arthritis and adult onset Still's disease.1 It can be primary, infection related, malignancy associated or autoimmune3. We report a case of Macrophage Activation Syndrome presenting as pyrexia of unknown origin (PUO) and pancytopenia in the absence of any known triggering factor. PMID- 28598058 TI - Successful Treatment of BK Virus Hemorrhagic Cystitis (HC) Post Allogenic Hematopoietic Stem Cell Transplantation with Low Dose Cidofovir. AB - BK virus (BKV) hemorrhagic cystitis (HC) is a serious cause of morbidity and mortality after allogeneic hematopoietic SCT (allo-HSCT) in patients with hematological malignancies. Around half of allogenic HSCT patients present with BKV viruria at some point after HSCT; about 5-40% of these patients subsequently develop active HC. Supportive care including bladder irrigation, blood transfusions and symptomatic pain management remains the mainstay of therapy; the acyclic nucleoside analogue cidofovir is currently the front-line drug for BKV-HC treatment. Here we report the first case of severe hemorrhagic cystitis from India who was successfully treated with low dose cidofovir therapy. PMID- 28598059 TI - Cardiac Abscess with Ventricular Aneurysm Secondary to Old Myocardial Infarction. AB - Myocardial Abscess (MA) is a rare life threatening condition mostly occurring secondary to underlying infective endocarditis. But it can also be found secondary to septicemia with some unknown focus of sepsis in the body. Development of MA as a consequence of left ventricular aneurysm (LVA) secondary to myocardial infarction is very rare. We report the case of 56 year old male, who presented with high grade fever and leukocytosis. On detailed evaluation, he was found to have a myocardial abscess with underlying LVA. PMID- 28598060 TI - Spontaneous Pneumothorax in H1N1 Infection. AB - Spontaneous pneumothorax is a very rare entity in H1N1 infection unless it is co existent with other respiratory conditions especially COPD. The other factors are old age, children below 5 years and patients with ILD. The mortality rate goes high with pulmonary illness complicated by H1N1 infection in smokers and in pregnant women. This is the first reported case of H1N1 infection with Spontaneous Pneumothorax in India. PMID- 28598061 TI - Bullous Pemphigoid as a Harbinger of Metastatic Cholangiocarcinoma - A Rarity. AB - Bullous pemphigoid (BP) is an autoimmune blistering disorder of the skin first described in 1953. A decade later, antibodies were described targeting the cutaneous basement membrane zone. The association of Bullous pemphigoid with malignancy is debatable1 but reported in many case reports.2-6 We report a 79 year old male with cholangiocarcinoma that presented with bullous pemphigoid as a paraneoplastic phenomenon. PMID- 28598062 TI - Atypical Variants of Takotsubo Cardiomyopathy: Twin Case Reports. AB - Takotsubo cardiomyopathy (TTC) is a well-known entity. We present two rare presentations of the same. Our first patient was diagnosed to have hypertrophic cardiomyopathy with ventricular tachycardia (VT), for which an ICD had been implanted. He later developed acute TTC with a large left ventricular (LV) apical thrombus. Our second patient was a 59 year old lady diagnosed to have TTC 2 years ago, from which she had recovered completely. She recently developed a recurrence of the same. PMID- 28598063 TI - Squamous Cell Carcinoma of Oesophagus with Tracheo- Esophageal Fistula, Pulmonary Tuberculosis and Hyperthyroidism in 16 yrs Old Female. AB - This case of a 16-year-old female with moderately-differentiated squamous cell carcinoma of the esophagus with tracheo-esophageal fistula, hyperthyroidism and sputum positive pulmonary tuberculosis with RNTCP Category 1 DOTS is reported because of its rarity. The patient presented with cough, vomiting, weight loss and respiratory distress. PMID- 28598064 TI - Emphysematous Gastritis with Air in Portal Venous System. AB - Emphysematous gastritis is a rare but severe form of phlegmonous gastritis caused by gastric mucosal disruption and infection of stomach wall by gas-forming bacteria. Ingestion of corrosive substances is the most common predisposing factor, followed by alcohol abuse, abdominal surgery, diabetes and immunosuppression. Patients usually present with abdominal pain, vomiting, diarrhea, constipation and/or gastro-intestinal hemorrhage. Characteristic radiological findings include presence of gas in the gastric wall. Management of this condition includes broad-spectrum antibiotics and supportive therapy. Outcome of emphysematous gastritis is frequently fatal due to septic shock and multi-organ failure. We report a case of a 65 years old male who presented with fever and upper abdominal tenderness. He had history of uncontrolled diabetes and chronic alcohol intake. Radiological investigations revealed air within the gastric wall, portal vein, liver and spleen. Despite initial improvement with conservative management, patient succumbed due to sepsis and shock. PMID- 28598065 TI - Malignant Pleural Effusion with Filariasis. AB - The occurrence of microfilaria in pleural fluid is rare. Filarial lung involvement occurs in the form of Tropical Pulmonary Eosinophilia with pulmonary infiltrates and peripheral eosinophilia. We report a 74-year-old male patient, non smoker who was admitted to our hospital with breathlessness and chest discomfort of two weeks duration. He had, eosinophilia and deranged renal function. X-ray chest revealed massive left sided pleural effusion. Pleural fluid analysis revealed atypical cells and pleural fluid cytology showed microfilaria (Wuchereria bancrofti), which were also found on peripheral smear. PMID- 28598067 TI - Is this the Right Direction for Dengue Fever Research in India? PMID- 28598066 TI - Invention of Contraceptive Pill. PMID- 28598068 TI - Early Recognition of Malaria or Dengue in Thrombocytopenic Febrile Illness. PMID- 28598069 TI - Intractable Vomiting and Hiccups as a Presenting Symptom of Neuromyelitis Optica Spectrum Disorder. PMID- 28598070 TI - [Helminth derived Immunomodulatory Glycan LNFP3 Impairs Pathogenesis of Peripheral Neuropathic Pain and Spinal Glial Activation]. AB - OBJECTIVES: To investigate the effect of helminth-derived immunomodulatory glycan lacto-N-fucopentaose3(LNFP3) on the pathogenesis of neuropathic pain and spinal glial activation in the corresponding time windows after adult rat tibial nerve permanent transection (modified spared nerve injury, mSNI). METHODS: Ten weeks old male adult Sprague-Dawley (SD) rats weighing 250-300 g were randomly grouped into four groups: sham-operated group (n =6), mSNI group (n =6), mSNI plus bovine serum albumin (BSA) group (n =12) and mSNI plus LNFP3 group (n=12). Rats were subjected to surgical operation or sham operation on the right tibial nerves and were intraperitoneal injected BSA or LNEP3-BSA conjugates by the group design. Animals from each group (n=6 per group) were subjected to the plantar test,von Frey hairs test, pinprick test and acetone test for critical evaluation of region specific pain responses on the plantar sural and saphenous skin territories of ipsilateral and contralateral hindpaws after injuries. Transverse frozen sections of L3-4 spinal cords from the remaining animals of mSNI plus BSA group and mSNI plus LNFP3 group 7 and 14 d after injury (n=3 for each time point per group)were prepared and subjected to immunofluorescent staining of microglia/macrophage marker [cluster of differentiation molecule 11b (CD11b)] and astrocyte marker [glial fibrillary acidic protein (GFAP)], for analysis of spinal glial activation. RESULTS: After adult rat mSNI, early systematic administration of LNFP3 significantly but not completely attenuated region-specific pathological pain evoked by mechanical and thermal stimuli on the sural and saphenous skin territories of rat hindpaw plantar surfaces in acute (4/5 d after injuries) and subacute (7/8 d and 14/15 d after injuries) phases. Meanwhile, in the ipsilateral spinal cord dorsal horns, this early systematic treatment inhibited microglia/macrophage activation 7 d after injury and astrocyte activation 7 and 14 d after injury. CONCLUSIONS: Early systematic administration of LNFP3 impairs the pathogenesis (acute induction and chronic transition) of neuropathic pain and spinal glial activation in the corresponding time windows after adult rat mSNI. PMID- 28598071 TI - [Early Systemic Administration of IL-10 Inhibits Neuropathic Pain in Adult Rats with Tibial Nerve Injury]. AB - OBJECTIVES: To determine the effect of early systemic administration of IL-10 on peripheral neuropathic pain induced by tibial nerve permanent transection [modified spared nerve injury (mSNI)]in adult rats. METHODS: Male adult Sprague Dawley (SD) rats (ten-week old, 250-300 g) with mSNI were randomly divided into mSNI, sham-operated, IL-10 intervention (intraperitoneal injection), PBS intervention (intraperitoneal injection) groups, each containing six rats. Intraperitoneally injections (IL-10 or PBS) were given immediately after surgeries for a single regime with a dosage of 500 uL (0.1 mg/mL). Plantar test, von Frey hairs test, pinprick test and acetone test were performed before and after tibial nerve injuries (0 d, 4/5 d, 7/8 d, 14/15 d) to evaluate region specific pain responses of the rats on the plantar sural and saphenous skin territories of ipsilateral and contralateral hindpaws. The hindpaw position (on 8 d) of six additional rats with standard SNI was compared with those with mSNI. RESULTS: The rats with standard SNI showed an eversion posture of hindpaws, more prominent than those with mSNI. Region-specific pathological pain evoked by mechanical and thermal stimuli on the sural and saphenous skin territories of the plantar surfaces of rat hindpaws was demonstrated on the ipsilateral rather than contralateral hindpaws. This effect was shown in the rats with mSNI but not in those with sham operations. Compared with PBS, early intraperitoneal injection of IL-10 significantly and persistently attenuated either allodynia or hyperalgesia in the rats with mSNI. CONCLUSIONS: Tibial nerve permanent transection models of adult rats can be used as a simple but useful rodent model of peripheral neuropathic pain. Early systemic administration of IL-10 impairs the pathogenesis of neuropathic pain induced by tibial nerve injuries. PMID- 28598072 TI - [The Effects of NF-kappaB Signalling on the TNF-alpha induced Ratios of MMPs to TIMPs in Chondrocytes]. AB - OBJECTIVES: To explore the influence of the NF-kappaB inhibitor (bay11-7082) on tumor necrosis factor-alpha (TNF-alpha)-induced different ratios of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in chondrocytes. METHODS: Chondrocytes were isolated from the knee joint of a 1-day old mouse by trypsin digestion method. Hematoxylin-Eosin (HE) stain was used to show the morphology of isolated chondrocytes; Semi-quantitative PCR was applied to analyze the influence of bay11-7082 on gene expressions of TNF-alpha-induced MMPsand TIMPsin chondrocytes; Zymography was used to elucidate activities of the gelatinases induced by TNF-alpha and/or bay11-7082. RESULTS: TNF-alpha up regulated gene expressiosn of the MMPsand TIMPs(P<0.05). The ratios of MMPs/TIMPswere mostly increased except the part of MMP-1. Bay11-7082 could reduce TNF-alpha-induced MMPsand TIMPsgene expressions, and could make the increased ratio of MMPs/TIMPsdropped to the normal level of chondrocytes. Similar results were observed at the protein level of the gelatinases by zymography. CONCLUSIONS: TNF-alpha-induced high ratios of MMPs/TIMPs could partiallyexplain over degradation of cartilage extracellular matrix in osteoarthritis (OA). Blockage of NF-kappaB with bay11-7082 might provide a possible therapeutic strategy for the OA deterioration. PMID- 28598073 TI - [Effects of FGF-21 on Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells in High Glucose Environment]. AB - OBJECTIVES: To determine the effect of fibroblast growth factor-21(FGF-21)on the osteogenic differention of human bone mesenchymal stem cells (hBMSCs) exposed to a hyperglycemia condition in vitro. METHODS: hBMSCs were isolated from adult bone marrows, and identified by Alizarin red and oil red O staining. The expressions of immunophenotype were analysed using flow cytometry (CD105, CD90, CD73, CD44).HBMSCs were divided into control group[glucose (Glu) concentration of 5.5 mmol/L], Glu A, B, C groups(Glu 16.5, 25, 40 mmol/L), FGF-21 group (Glu 5.5mmol/ L+ FGF-21 ),Glu B+ FGF-21 group, and Glu B +FGF-21+cell mitogen activated protein kinase (MAPK) blocker (PD98059, SP600125 ,and SB203580) groups. The effect of FGF 21 on the differentiation of hBMSCs was detected using indicators as follows: alkaline phosphatase(ALP)on day 14, mRNA expressions ofALP, osteocalcin(OCN)and Runx2, protein expressions and phosphorylation of extracellular signal regulated kinase (ERK), mitogen-activated protein kinase(P38) and c-Jun N-terminal kinases(JNK) on day 21. RESULTS: hBMSCs differentiated into osteoblast cells and lipocyte. The hBMSCs were identified by flow cytometry.Compared with control group, significant increases of ALP mRNA, OCN mRNA and Runx2mRNA levels, as well as phosphorylation of ERK, P38 and JNK were observed in Glu A, B, C groups.Compared with Glu B group, ALP, OCN and Runx2 mRNA levels, and phosphorylation of ERK, P38 and JNK were decreased in Glu B+FGF-21 group .Compared with Glu B+FGF-21 group, ALP and Runx2 mRNA levels, and phosphorylation of ERK, JNK and P38 were decreased in Glu B +FGF-21 +MAPK blocker groups. CONCLUSIONS: High glucose could promote the biomineralization of hBMSCs. FGF-21 in high glucose environment could inhibit the osteogenic differentiation of hBMSCs. PMID- 28598074 TI - [Sodium Ferulate Attenuates Oxidative Stressvia Suppressing NALP3 Inflammasome and ERK Signal Pathway]. AB - OBJECTIVES: Study the gene and protein expression of NACHT-PYD-containing protein 3 (NALP3) inflammasome and extracellular regulated protein kinase (ERK), the intervention effects of sodium ferulate (SF) in human lung epithelial cells A549 under oxidative stress, and to investigate the possible mechanism. METHODS: Human lung epithelial cells A549 cultured in vitro were divided into 6 groups, including control group,H2O2(200 umol/L) group, SF group (400 ug/mL), caspase-1 blockers (Z-VAD) group (Z-VAD 20 umol/L+H2O2200 umol/L), ERK blockers (PD98059) group (PD98059 50 umol/L+H2O2 200 umol/L), and SF+H2O2 group (SF 400 ug/mL+H2O2 200 umol/L). Fluorescent quantitative real-time PCR (qRT-PCR) was performed to detect the mRNA levels of caspase-1 and NALP3, the expression of caspase-1, NALP3, phosphorylated ERK p-ERK, ERK protein were evaluated by Western blot. The level of interleukin-1 beta (IL-1beta) were detected by ELISA. RESULTS: Compared with the control group,H2O2 not only increased the mRNA and protein expression levels of caspase-1 and NALP3 and the protein expression levels of p-ERK/ERK, but also enhanced the secretion of IL-1beta in human lung epithelial cells A549 (P<0.05),while SF group showed no statistic significance of those indicators above (P>0.05). The Z-VAD group, the PD98059 group and the SF+H2O2 group resisted the effects of H2O2 on A549 cells by decreasing the mRNA and protein expressions of caspase-1 and NALP3,and the protein expression of p-ERK/ERK, as well as reducing the secretion of IL-1beta(P<0.05),when compared with the H2O2 group. CONCLUSIONS: SF may reduce the expression of caspase-1, NALP3 and IL-1beta by inhibiting ERK, so as to reduce the inflammation caused by oxidative stress. PMID- 28598075 TI - [The Protective Effect of Tanshinone IIA on Oxygen-glucose Deprivation and Reperfusion Injury of MicrogliaThrough the NLRP3 Inflammatory Signaling Pathway]. AB - OBJECTIVES: To investigate the protective effect of Tanshinone IIA (TSA) on oxygen-glucose deprivation and reperfusion (OGD/R) injury of BV-2 cell and its NLRP3 inflammatory signaling pathway. METHODS: The highest expression level of NLPR3 in BV-2 cells was detected by Western blot after oxygen-glucose deprivation (OGD) for 3 h and reperfusion for different time, to determine the most suitable reperfusion time. Cell viability of TSA (0-2.5 ug/mL) treatment was detected by CCK8 assay to determine the maximum effect concentration of TSA. In TSA 0 (also called OGD group), 0.5, 1.0, 2.0 ug/mL groups, expression levels of NLRP3 and caspase-1 were detected by Western blot, while IL-1beta and IL-18 in culture medium of those groups were detected by ELISA assay. RESULTS: The highest expression level of NLRP3 came to 12 h of reperfusion. The maximum effective concentration of TSA was 2.0 ug/mL. The expression levels of NLRP3, caspase-1, IL 1beta and IL-18 decreased with the increase of TSA concentration. CONCLUSIONS: TSA can inhibit the expression of protein and cytokines of NLRP3 inflammatory signaling pathway in OGD/R BV-2 cells, which may be one of the molecular mechanisms of the protective effect of TSA on OGD/R cells. PMID- 28598076 TI - [Effect of RUNX3 on the Expression of Smad4 in T24 Bladder Cancer Cell Line]. AB - OBJECTIVES: To examine the effects of RUNX3 on cell proliferation and apoptosis and the expression level of Smad4 mRNA in the bladder cancer cell line of T24 by transfection with recombinant plasmid of pIRES-EGFP-RUNX3. METHODS: The recombinant plasmid of pIRES-EGFP-RUNX3 was constructed successfully. Cultured T24 cells were divided into three groups, including control group, empty vector group,and recombinant plasmid group. The cells in empty vector group and recombinant plasmid group were respectively transfected by pIRES-EGFP and pIRES EGFP-RUNX3 The cells were harvested at 24 h after the transfection, the variation of cell morphology was examined by fluorescence microscopy. The cell apoptosis was detected by flow cytometry. The expression level of RUNX3 and Smad4 mRNA was measured by RT-PCR. RESULTS: Cell death was observed in two transfection groups. At 24 h after transfection,the apoptosis rate was (3.23+/-0.45)% in control group, (8.98+/-1.62)% in empty vector group and (43.61+/-2.69)% in recombinant plasmid group. The expression level of RUNX3 mRNA was 2.79+/-0.36,detected only in recombinant plasmid group, which was significantly up-regulated compared with the other two groups (P<0.05). CONCLUSIONS: The expression level of Smad4 mRNA was up-regulated by transfection with pIRES-EGFP-RUNX3,which also inhibited cell proliferation and promoted cell apoptosis.The tumor suppressor gene of RUNX3 could regulate the bladder cancer cell proliferation and apoptosis by TGF beta/Smad signaling pathway. PMID- 28598077 TI - [The Effect of Ruxolitinib on the Expression of VEGF and HIF-1alpha in Leukemia HEL Cells]. AB - OBJECTIVES: To investigate the effect of Ruxolitinib on the expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1alpha) in HEL cells. METHODS: he HEL cells were treated with Ruxolitinib in different concentrations (1 nmol/L, 5 nmol/L, 10 nmol/L, 50 nmol/L, 100 nmol/L, 500 nmol/L). The growth inhibition of Ruxolitinib on HEL cells was detected by CCK-8 assay;the mRNA expression level ofJAK2 were measured by RT-PCR and the protein level of p-JAK2, VEGF, HIF-1alpha were observed by Western blot after treated with Ruxolitinib for 24,48,72 h. Chick chorioallantoic membrane (CAM) test was used to testify the effect of Ruxolitinib on angiogenesis. RESULTS: Ruxolitinib with different concentrations could inhibit HEL cells proliferation. RT-PCR showed that the mRNA level ofJAK2 decreased in a concentration-dependent manner and Western blot demonstrated that the expression levels of p-JAK2, VEGF and HIF-1alpha were lower in Ruxolitinib treatment groups than those in control group (P<0.05) after HEL cells were treated with different concentrations of Ruxolitinib for 24,48,72 h. Ruxolitinib significantly suppressed blood vessels'formation in CAM. CONCLUSIONS: Ruxolitinib can inhibit VEGF, HIF-1alpha expression and angiogenesis of HEL leukemia cells by inhibiting JAK2 pathway. PMID- 28598078 TI - [The Transmission of KPC-2 Gene in Klebsiella Species]. AB - OBJECTIVES: To explore the mechanisms of imipenem resistance inKlebsiella spp. and the transmission of Klebsiella pneumoniae Carbapenemase-2(KPC-2) gene in Klebsiella species. METHODS: The imipenem resistant Klebsiella pneumoniae and Klebsiella oxytoca were isolated in the West China Hospital of Sichuan University in 2009/2010 and 2012/2013. Their minimal inhibitory concentration (MIC) was determined by agar dilution method. CARB ChromID plate and improved Hodge test were undertaken to detect carbapenemases resistant phenotype. PCR method was used for detecting KPC-2 gene. Plasmid transmission was detected by plasmid conjugation tests. The homology of the plasmids and the strains was analyzed using random amplified polymorphic DNA (RAPD) and enterobacterial repetitive intergenic consensus PCR(ERIC-PCR) methods. RESULTS: Three strains of Klebsiella oxytoca collected in 2009/2010 and 7 Klebsiella pneumoniae collected in 2012/2013 developed carbapenemases resistance, all of which carried KPC-2 gene. The 3 KPC-2 positive plasmids isolated from Klebsiella oxytoca transited to recipient organisms and showed homology with the 7 KPC-2 gene positive plasmids isolated from Klebsiella pneumoniae. The ERIC-PCR showed homology of the 7 KPC positive Klebsiella pneumoniae. CONCLUSIONS: Carbapenemases inKlebsiella spp with expressed KPC-2 gene contribute to the development of resistance in this hospital. The transmission of KPC-2 plasmid in Klebsiella oxytoca may cause imipenem resistance in Klebsiella pneumonia. The horizontal transmission may be the main mechanism in the spread of imipenem resistance inKlebsiella spp. PMID- 28598079 TI - [Effects of Different Concentrations of Glucose on the Osteogenic Differentiation of Orofacial Bone Mesenchymal Stem Cells]. AB - OBJECTIVES: To determine the effects of different concentrations of glucose on the proliferation and osteogenic differentiation of orofacial bonemesenchymal stem cells (OFMSCs). METHODS: OFMSCs were primarily cultured and identified in vitro to undergo osteogenic/adipogenic/chondrogenic differentiation. The cells were exposed to osteogenic medium containing different levels of glucose: 5.5,11,16.5,25,44 mmol/L. The cell activity and proliferation index were measured using a cell counting kit (CCK)-8 and flow cytometry. The alkaline phosphatase (ALP) activity of the cells was measured at the 4th and 7th day. Alizarin red staining was carried out at the 21st day. RT-PCR detecting osteogenesis-related gene Runx2 and Osterix mRNA expression was performed at the 4th, 7th, 14th and 21st day. RESULTS: Osteogenesis induced calcium nodes was observed with Alizarin red staining at the 21st day. Adipogenic induced red lipid droplets was observed with Oil Red O staining at the 14th day. Chondrogenic induced blue cytoplasm was observed with Alcian blue staining at the 14th day. With 5.5 to 25 mmol/L glucose,OFMSCs proliferation was promoted.But when the concentration of glucose continued to increase (from 25 to 44 mmol/L),OFMSCs proliferation significantly reduced.The ALP activity decreased with glucose in a concentration-dependent manner ( P<0.05). Osteogenesis induced Alizarin red staining and mineralization showed at the 21st day. The calcium nodes and mineralization quantity decreased with glucose in a concentration-dependent manner ( P<0.05).The cells exposed to 5.5 mmol/L glucose had a higher level of expression of Runx2 and Osterix mRNA than the others (P<0.05).The experssion of Runx2 and Osterix mRNA in all groups showed a trend of rising first, followed by an obvious down regulation. CONCLUSIONS: With certain limits,OFMSC proliferation is promoted by glucose. Osteogenic differentiation is inhibited by glucose in a concentration-dependent manner. PMID- 28598080 TI - [Expression of CXCR7 in Gastric Cancer Cells and Its Effect on the Migration and Invasion of SGC-7901 Cells]. AB - OBJECTIVES: To determine the expression of chemokine (C-X-C motif) receptor 7 (CXCR7) in five gastric cancer cell lines with various degrees of differentiation, and the effect of silencing CXCR7 on the migration and invasion of SGC-7901 cells. METHODS: The expression of CXCR7 in gastric cell lines (HGC 27, MGC-803, SGC-7901, BGC-823 and MKN-28) was detected by Western bolt and RT PCR. The SGC-7901 cells were transfected with liposome of CXCR7 siRNA to silence CXCR7 gene, and then treated with stromal-derived factor-1 (SDF-1)-the ligand of CXCR7. Transwell assay was used for determining the migratory and invasive ability of SGC-7901 cells in the four groups: NC siRNA, NC siRNA+SDF-1, CXCR7 siRNA and CXCR7 siRNA+SDF-1. RESULTS: CXCR7 was expressed in the five gastric cancer cell lines, with the highest intensity in SGC-7901. The migrated and invasive cells increased in the NC siRNA+SDF-1 group and reduced in the CXCR7 siRNA group compared with the NC siRNA group (P<0.05). The CXCR7-siRNA+SDF-1 group had less migrated and invasive cells than the NC siRNA+SDF-1 group (P<0.05). CONCLUSIONS: CXCR7 is highly expressed in SGC-7901. SDF-1 promotes the migratory and invasive capability of SGC-7901 cells, but such an effect can be inhibited by silencing it with CXCR7siRNA. PMID- 28598081 TI - [MiR-183 Regulates Proliferation of SW1990 Pancreatic Cancer Cell Line by Targeting PDCD4]. AB - OBJECTIVES: To investigate the effect of miR-183 on the cell proliferation in SW1990 pancreatic cancer cell line by targeting programmed cell death factor 4(PDCD4). METHODS: The SW1990 pancreatic cancer cells were transfected with miR 183 mimics and inhibitors at different concentrations, the alteration of PDCD4 levels was observed at specific concentrations by qPCR and Western blot. The cellular proliferation of transfected cells was determined by MTT assay. The distribution of cell cycle and apoptosis was examined by flow cytometry (FCM) and Hoechst 33258 staining. The expression of B-cell lymphoma(bcl-2) was evaluated by Western blot. RESULTS: The miR-183 mimic and inhibitor (at concentrations of 50 nmol/L or 150 nmol/L) showed significantly increasing or decreasing effects on the levels ofmiR-183 respectively. The expression of PDCD4 was downregulated in the cells transfected with miR-183 mimics, while significantly upregulated in the cells treated with miR-183 inhibitors. Western blot showed that miR-183 inhibitors resulted in a marked decrease in the expression levels of bcl-2. The growth of SW1990 cells was obviously inhibited after anti-miR-183 treatment, while an increase of apoptosis cells proportion and cell cycle G0/G1 arrest were observed after miR-183 inhibitors transfection. CONCLUSIONS: The miR-183 inhibitors could restrain cell proliferation, promote cell apoptosis and increase G0/G1 arrest in SW1990 pancreatic cancer cells, which may be possibly through targeting PDCD4. PMID- 28598082 TI - [Expression of Micro-RNA 218 in Cervical Cancer and Its Effect on Proliferation, Apoptosis and Invasion of HeLa Cells]. AB - OBJECTIVES: To investigate the expression and clinical significance of microRNA 218(miR-218)in human cervical cancer and the effects ofmiR-218 on proliferation, cell apoptosis and invasion of HeLa cells. METHODS: QRT-PCR was used to detect the expression ofmiR-218 in 23 cases of normal cervical tissues and 114 cases of cervical cancer, and the relationship between the expression and the clinicopathological features was analyzed; HeLa cells were devided into three groups: non transfection (control group), transfected with empty liposomes negative control goup (NC group), transfected with miR-218 mimic (miR-218M group). The cell growth inhibiting ratio of HeLa cells was assessed by MTT assay. Fluorescence activated cell sorting was used to measure cell apoptosis. Changes of cell migration ability were detected by wound healing test and Transwell assay. QRT-PCR and Western blot were used to detect the expression of Bcl-2, Bax, NF-kappaB and E-cadherin, respectively. RESULTS: The expression ofmiR-218 in cervical cancer was down regulated, and there were significant differences in the different pathological types, stages, lymph node metastasis and interstitial infiltration in cervical cancer tissues ( P<0.01); After being transfected with miR-218 mimic, the proliferation of HeLa cells was significantly inhibited. The ability of invasion was decreased. QRT-PCR and Western blot showed that after being transfected with miR-218 mimic, the expression levels of Bcl-2 mRNA and protein were down-regulated and Bax mRNA and protein expression levels were increased, E-cadherin mRNA and protein expression were up-regulated, but NF kappaB mRNA and protein expression were down-regulated. CONCLUSIONS: he low expression of miR-218 is correlated with the poor clinicopathological features in human cervical cancer. MiR-218 overexpression reduces cancer cell proliferation and induces apoptosis and inhibits cell migration, suggesting that miR-218 may play a key role in the progression of human cervical cancer. PMID- 28598083 TI - [Expressions of Spinal Macrophage Colony Stimulating Factor and Its Receptor CSF 1R in the Development ofComplicated Regional Pain Symptom I]. AB - OBJECTIVES: To study the changes of mechanical allodynia and temperature hyperalgesia, as well as the expression of the spinal macrophage colony stimulating factor (M-CSF) and its receptor CSF-1R during the development of complicated regional pain symptom I(CRPS I). METHODS: The animal model of CRPS I was established using prolonged ischemia-reperfusion injury of rodent left hindpaw. The mechanical allodynia and temperature hyperalgesia of ipsilateral hindpaw were continuously measured for 14 d after reperfusion, and the expressions of spinal M-CSF and CSF-1R in ipsilateral spinal cord horn were measured with immunofluorescence technique on day 3, day 7 and day 14 after reperfusion. RESULTS: The thresholds of mechanical allodynia and temperature hyperalgesia of ipsilateral hindpaw were significantly decreased (P<0.05). M-CSF was secreted by the astrocytes. CSF-1R was primarily distributed on the microglia. The immunofluorescence intensities of M-CSF and CSF-1R in ipsilateral spinal cord horn were significantly increased on day 7 and day 14 after reperfusion (P<0.05). CONCLUSIONS: The ischemia-reperfusion injury simulated pain syndrome in CRPS I and increased the expressions of spinal M-CSF and CSF-1R. PMID- 28598084 TI - [Effect of Electroacupuncture with Near-to-bone Needling to Chondrocyte Apoptosis and Proliferation on the Knee Osteoarthritis Model]. AB - OBJECTIVES: To study the effect of electroacupuncture with near-to-bone needling on the proliferation and apoptosis of knee osteoarthritis. METHODS: Totally 40 New Zealand rabbits were randomly divided into two groups, the normal group (A, n =10) and the modeling group (n =30). Hulth-Telhag method was applied 30 rabbits to establish rabbit left knee osteoarthritis model, and evaluated by X-ray after 6 weeks. Then divided the 30 modeling rabbits into electroacupuncture with near to-bone needling group (C,n =10), electroacupuncture with ordinary needling group (D,n =10) and model group (B ,n =10) randomly. Four treatments (5 d as one course of treatment) were applied to C group and D group, respectively. At the end of the experiment, modeling situation was detected by X-ray, pathological changes of cartilage was detected by HE staining ,and apoptosis of chondrocytes was checked by TUNEL staining; mRNA expressions of Caspase-3 and proliferating cell unclear antigen (PCNA) in chondrocytes were detected by RT-PCR; protein expressions of Caspase-3, PCNA, Bcl-2 and Bax in chondrocytes were detected by Western blot. RESULTS: HE stain demonstrated that the chondrocytes of A group,C group and D group were arranged in a more regular and smooth surface when compared with B group. The expressions of Bcl-2 and PCNA in C and D groups were higher than those of B group, but the expression of Caspase-3 and Bax were lower, when evaluated with Western blot;increased expressions of PCNA and Bcl-2 but decreased expressions of Caspase-3 and Bax in C group were also noticed when compared with D group. RT-PCR results demonstrated that when compared with B group, the expression of PCNA mRNA were increased but Caspase-3 mRNA were decreased in C and D groups; compared with D group, the expression of PCNA mRNA were increased but Caspase-3 mRNA were decreased in C group. CONCLUSIONS: The electroacupuncture with near-to-bone needling method is superior to the electroacupuncture with ordinary needling in decreasing apoptosis and promoting proliferation of chondrocytes. PMID- 28598085 TI - [Inhibitory Effects of Sphingosine-1-phosphate Receptor-2 on Vascular Permeability in Mice]. AB - OBJECTIVES: To determine the effect of sphingosine-1-phosphate receptor 2 (S1PR2) on vascular permeability in mice. METHODS: Acute lung injury models of mice were constructed with intra-tracheal administration of lipopolysaccharide (LPS) and compared with the controls with intra-tracheal administration of saline. The effect of S1PR2 on vascular permeability was observed by detecting leakage of Evans blue into lung tissues, pulmonary vascular leakage of fluorescein isothiocyanate (FITC)-dextran, and the wet/dry mass ratio of lungs. The effect of vascular endothelial growth factor (VEGF) on vascular endothelial permeability was detected by Miles analysis. RESULTS: LPS injections induced significant Evans blue leakage, FITC-dextran pulmonary vascular leakage and pulmonary edema, which appeared to be more serious in S1PR2-deleted mice compared with those in wild type mice. LPS enhanced Evans blue leakage associated with VEGF in a dose dependent way in both S1PR2-deleted mice and wild type mice. But the vascular permeability response in subcutaneous tissues induced by VEGF was higher in S1PR2 deleted mice than that in wild-type mice. CONCLUSIONS: S1PR2 is involved in endothelial cell barrier protections, which inhibits vascular permeability. PMID- 28598086 TI - [High Mobility Group Chromosomal Protein N2 Inhibit Cervical Cancer Transplanted in Nude Mice]. AB - OBJECTIVES: To study the effect of high mobility group chromosomal protein N2 on inhibiting cervical cancer in nude mice. METHODS: Model of cervical cancer were established in nude mice. They were randomly divided into 4 groups including negative control group, HMGN2 group, cisplatin group and HMGN2 with cisplatin group. After 4 injections, the tumor size were calculated and tumor tissues were stained by haematoxylin eosin (HE) staining. RESULTS: Transplated tumor models were established successfully. The tumor sizes of negative control group [(0.38+/ 0.12) cm3] were significantly lower than those of HMGN2 group [(0.14+/-0.07)cm3, cisplatin group [(0.11+/-0.06) cm3] and HMGN2 combined with cisplatin group[(0.11+/-0.07) cm3]. No differences were detected in HMGN2 group, cisplatin group and HMGN2 with cisplatin group in tumor sizes. The tumor inhibition rates of HMGN2 group, cisplatin group and HMGN2 with cisplatin group were 0.62+/-0.18, 0.71+/-0.17 and 0.70+/-0.18, respectively. The necrosis area were smaller in negative control group than in other three groups by HE staining. CONCLUSIONS: HMGN2 has a significant inhibitory effect on transplanted cervical cancer in nude mice. PMID- 28598087 TI - [Bioinformatic Analysis of Differentially Expressed Genes Involved in the Post hypoxic Ischemic Brain Damage of Newborn Rats]. AB - OBJECTIVES: To analyze the differentially expressed genes (DEGs) in cerebral cortices of rats which were seven weeks after neonatal hypoxic ischemic brain damage (HIBD) and elucidate the biological significance of the DEGs. METHODS: The gene expression profile of GSE37777, including 4 HI samples subjected to HIBD and 4 normal controls, was downloaded from the Gene Expression Omnibus database (GEO). DEGs were screened using the R package in HIBD groups compared with normal controls. Pathway enrichment analysis was carried out using the Cytoscape plug-in ClueGO+Cluepedia and a functionally grouped pathway network of DEGs was constructed and analyzed. Besides, the protein-protein interaction (PPI) network was constructed with the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized using Cytoscape. RESULTS: A total of 973 DEGs were identified in HIBD group compared with the control group, including 599 up regulated and 374 down-regulated genes. Furthermore, a functionally grouped pathway network of DEGs was constructed and hedgehog signaling pathway were identified. Shh and Dhh which were Hedgehog signaling pathway-related genes and the Wnt signaling pathway-related genes Wnt1, Wnt2B, and Wnt5 were up-regulated in HIBD group. Furthermore, Ccnd1, Shh, Ret and Gli3 were hub proteins in the PPI network and up-regulated Shh and Dhh, down-regulated Ccnd1 and Gli3 were noticed. CONCLUSIONS: Our results showed that Hedgehog and Wnt signaling pathway may be activated HIBD group. Additionally, Shh and Ret which were related to the repair process of brain damage were up-regulated. Continuous repair process may exist in the cerebral cortices of rats which were seven weeks after neonatal HIBD. PMID- 28598088 TI - [Study on the Characteristics of Bone in Type-2 Diabetic Rats by Micro-CT]. AB - OBJECTIVES: To study the characteristics of bone in type 2 diabetic rats using micro-CT. METHODS: Sixteen male Sprague Dawley(SD) rats, aged 8 week-old, were randomly divided into normal group and experimental group (n =10). Afer being fed with high-fat chow, the rats in experimental group were given low-dose streptozotocin (STZ,30 mg/kg) to induce type 2 diabetic disease. Serum glucose, insulin and tissue sections of pancreas is used to evaluate the effect of type 2 diabetic rat model. The characteristics of bone in the two groups were measured and compared by micro-CT. RESULTS: Compared with normal group (n =10), the experimental group (n =9) had the body mass and serum glucose increased significantly (P<0.05). The level of serum insulin was equivalent in two groups(P>0.05). Pancreatic tissue section staining showed in experimental group islet morphology was irregular, edge boundary was blur and islet cells were saperated with increasing fiber tissue. The bone volume of normal and experimental groups were (0.194 2+/-2.332)%, and (0.080 7+/-1.952)%, respectively. Trabecular thickness (unit:mm) were 0.052 9+/-0.004 5 and 0.043 6+/ 0.002 4, respectively. Trabecular number (unit:mm-1) were 3.668 8+/-0.134 5, and 1.851 7+/-0.288 8, respectively ( P<0.05), while trabecular space (unit:mm) were 0.219 6+/-0.072 1 and 0.496 5+/-0.076 4, respectively( P<0.05). Bone tissue morphology metrology test results was consistent with the results of micro-CT. CONCLUSIONS: The diabetic rat model showed declined bone volume and trabecular density, trabecular number. Micro-CT may be more intuitive in bone quality inspection to reflect the characteristics of bone microstructure morphology. PMID- 28598089 TI - [Expressions of MACC1, Snail, and KISS-1 Proteins in Infiltrating Breast Carcinoma and Its Clinicopathological Features]. AB - OBJECTIVES: To investigate the protein expressions of metastasis-associated in colon cancer 1 (MACC1), KISS-1 (a cancer ruppressor gene) and Snail (the marker of epithelial-mesenchymal transition) in infiltrating breast carcinoma (IBC) and explore the role of them in invasion, metastasis and prognosis in IBC. METHODS: Expressions of MACC1, Snail and KISS-1 were examined by immunohistochemistry in 250 specimens of IBC and 80 specimens of normal breast tissues. Their clinicopathological features were analyzed, and their influence on patients' survival was identified. RESULTS: The positive rate of MACC1, Snail and KISS-1 in normal breast tissues and IBC tissues was 7.5%, 5.0%, 87.5% and 63.6%, 58.8%, 38.0%, respectively. And there was a significant difference between the IBC group and control group ( P<0.05). The positive expressions of MACC1, Snail and KISS-1 were significantly different in different TNM stages, lymph node metastasis, types and grades of tumor ( P<0.05). The survival time of positive KISS-1 group was significantly longer than that of negative group ( P<0.001); the survival time was significantly shorter in positive MACC1 group or Snail group than that of negative groups (both P<0.001). Cox regression analysis indicated that the positive expressions of MACC1, Snail and negative expression of KISS-1 were independent risk factors of IBC (P<0.05). CONCLUSIONS: Abnormal expression of MACC1, Snail and KISS-1 should be involved in the invasion and metastasis of IBC. The combined detection in the expressions of MACC1, Snail and KISS-1 at the early stage may play an important role in predicting the progression and prognosis of IBC. PMID- 28598090 TI - [The Association Between Bone Morphogenic Protein-4 and in-situ Saphenous Vein Graft Pathology in Diabetic Patients Undergoing Coronary Revascularization]. AB - OBJECTIVES: This study was designed to assess the expression levels of bone morphogenic protein-4 (BMP4) in saphenous veins harvested from diabetic patients undergoing coronary artery bypass grafting (CABG), and to investigate its association with in-situ morphological and pathological changes within the venous wall. METHODS: From January 2013 to December 2014, forty patients with type 2 diabetes mellitus (DM) and risk factors matched non-DM controls (n =40) were enrolled prospectively. Of the 40 DM patients, 24 had noninsulin-dependent diabetes (NIDM) and the remaining 16 had insulin-dependent diabetes (IDM). Segments of saphenous vein without surgical dilatation from these 80 patients were obtained. Vessel wall characteristics were evaluated by hematoxylin-eosin (HE) staining, and the expression and distribution of BMP4 was assessed by Western blot assay and immunohistochemistry analysis. RESULTS: The intimal and medial thickness of the saphenous veins harvested from DM patients were higher than those from non-DM controls. Compared with non-DM patients, the expression level of BMP4 was significantly elevated in diabetic veins ( P<0.05), and BMP4 was highly expressed in smooth muscle cells located in the medial layer. Moreover, the expression levels of BMP4 in diabetic veins were significantly correlated with intimal thickness (r =0.655, P<0.01), intimal area (r =0.684, P<0.01), medial thickness (r =0.642, P<0.01) and medial area (r =0.692, P<0.01). CONCLUSIONS: The pre-existing intimal and medial hyperplasia were significantly correlated with the high expression levels of BMP4 in saphenous veins harvested from diabetic patients, implying a potential role of BMP4 in the progression of vein graft stenotic diseases in this cohort of post-CABG patients. Future studies were warranted in investigating novel therapeutic strategy targeting at BMP4 for improving long-term vein graft patency. PMID- 28598091 TI - [Layer-specific Analysis in Patients with ST Segment Elevation Myocardial Infarction]. AB - OBJECTIVES: To evaluate left ventricular wall function after ST segment elevation myocardial infarction(STEMI) by layer-specific analysis and determine if the layer-specific parameters can predict left ventricular remodeling(LVR). METHODS: Thirty nine patients with first STEMI who had successful primary percutaneous coronary intervention(P-PCI) were studied, while 30 healthy individuals were included as normal control. Echocardiographic examinations were performed in STEMI patients within 48 h after P-PCI (before follow-up) and 6 months later (follow-up). Three dimensional cardiac function and longitudinal, circumferential 3-layer strain were analyzed. RESULTS: In STEMI, longitudinal endocardial strain was higher than epicardial strain (P<0.01), circumferential strain decreased from endocardium to epicardium gradually (P<0.01). Longitudinal and circumferential 3 layer strain at follow-up was higher than that before follow-up (P<0.01), but lower than that in control group( P<0.05). LVR group had lower longitudinal and circumferential 3-layer strain (P<0.05). Longitudinal epicardial strain was the independent predictor of LVR(odds ratio:3.332,95% confidence interval:1.124 3.882,P=0.03), the cut off value of -9% yielded 89.5% sensitivity and 70.2% specificity. CONCLUSIONS: Strain decreased from endocardium to epicardium within 48 h after P-PCI in STEMI. Myocardial function was lower in LVR group. Longitudinal epicardial strain could be employed as an independent predictor of LVR after STEMI. PMID- 28598092 TI - [Risk Prediction of Feeding Intolerance in Preterm Infants]. AB - OBJECTIVES: To identify risk factors associated with feeding intolerance (FI) in preterm infants. METHODS: Preterm infants treated in the neonatal unit of a hospital from August 2014 to January 2015 were recruited in this study. A clinical observation table was developed based on the reactive scope model. Data in relation to predictive homeostasis, reactive homeostasis, homeostatic overload, homeostatic failure and other aspects were collected and compared between those with and without FI.Alogistic regression model was established to determine predictors of FI. RESULTS: 1.A total of 207 preterm infants were included in the study: 125 male and 82 female. They had an average gestational age of (33.48+/-1.66) weeks (ranging from 27+2 to 37 weeks) and an average birth body mass of (2 019.55+/-334.38) g(ranging from 830 g to 3 120 g).2.The incidence of FI was 33.8%. FI in preterm infants often occurred during the period of being fed within 72 h.The main clinical manifestation of FI was gastric retentionin early-preterm infants and emesis in late-preterm infants.3.Gestational age, birth body mass, fetal distress, aminophylline application, intrauterine infection, breast milk feeding and interval between stools were associated with FI. Gestational age and birth body mass were found to be significant protectors of FI in the logistic regression model. FI declined with increased gestational age and birth body mass. Fetal distress, aminophylline application, and >3 d interval between stools were found to be significant risks of FI in the logistic regression model.4.The prediction model had a 92.73% forecast generation rate of return, with 97.14% sensitivity,88.32%specificity, and 91.30% accuracy. CONCLUSIONS: Low gestational age, low birth body mass, fetal distress,aminophylline application, and >3 d interval between stools are independent risk factors associate with FI. The prediction model can identify high risk cases of FI. PMID- 28598093 TI - [Genotype Distribution of 1 998 Strains of Hepatitis C Virus in West China Hospital of Sichuan University from 2009 to 2013]. AB - OBJECTIVES: To investigate hepatitis C virus (HCV) genotype distribution detected in West China Hospital of Sichuan University. METHODS: We analyzed genotype distribution data on HCV infected patients who had information of HCV genotypes from January 2009 to December 2013 diagnosed in West China Hospital of Sichuan University. RESULTS: Five genotypes and 15 genetic subtypes of HCV were found among the 1 998 cases, and 4 of the patients were infected with mixed HCV subtype. Among those genotypes and genetic subtypes, genotype 1a was detected in 8 cases (0.40%), genotype 1b in 1 368 cases (68.47%), genotype 1c in 18 cases (0.90%), genotype 2a in 78 cases (3.90%), genotype 2b in 1 case (0.05%), genotype 2i in 16 cases (0.80%), genotype 3a in 291 cases (14.56%), genotype 3b in 154 cases (7.71%), genotype 3k in 4 cases (0.20%), genotype 5a in 1 case (0.05%), genotype 6a in 50 cases (2.50%), genotype 6b in 3 cases (0.15%), genotype 6h in 1 case (0.05%), genotype 6n in 1 case (0.05%), mixed-genotype 1b/1c in 1 case (0.05%), mixed-genotype 1b/6h in 1 case (0.05%), mixed-genotype 2c/2a in 1 case (0.05%), and mixed-genotype 3b/3k in 1 case (0.05%). The distribution of five main HCV genetic subtypes on gender had no statistical significance (P>0.05), and its distribution on people with different ages had statistical significance ( P<0.05). CONCLUSIONS: The major genotypes of HCV were 1b (predominant), 3a, 3b, 2a, 6a in patients diagnosed in West China Hospital of Sichuan University, with the existence of single-genotype 1a, 1c, 2b, 2i, 3k, 5a, 6b, 6h, 6n and mixed genotype 1b/1c, 1b/6h, 2c/2a, 3b/3k, indicating the diversity of HCV genotype. PMID- 28598094 TI - [Ecological Trendofthe Incidence of Tuberculosis in Mianyang City During 2004 2013]. AB - OBJECTIVES: To determine the trend of the incidence of tuberculosis (TB) in Mianyang City during 2004-2013 and its ecological determinants. METHODS: Linear correlations between TB incidence and ecological factors were analyzed using the data collected in Mianyang City from 2004 to 2013. A multivariate linear regression model was established to determine the ecological predictors of TB incidence. RESULTS: The incidence of TB in Mianyang City decreased over the period of 2004-2013. Economic development and increased health resources were negatively correlated with TB incidence. Population density was positively correlated with TB incidence. A multivariate linear regression equationon TB incidence (y) was established with the independent variables (x1 to x10) forming a component (using principal component analysis) to eliminate multicollinearity: y=117.692-1.467x1-1.145x2-1.961x3-4.777x4-2.690x5-6.181x6+82.234x7-2.721x8 0.351x9-0.382x10. The incidence of TB decreased with the increases of real GDP per capita (x1), average wage of workers(x2), per capita disposable income of urban residents (x3), rural per capita net income (x4), per capita consumption expenditure of urban residents (x5), per capita living consumption expenditure of rural residents (x6), number of licensed (assistant) physicians per thousand population (x8), urbanization rate (x9),and per capita housing construction area of urban (x10),while it increased with the increase of density of population (x7). CONCLUSIONS: Socio-economic development, health resources and population density are predictors of TB incidence. PMID- 28598095 TI - [Depressive Symptoms in the Mid- and Old-aged People in China]. AB - OBJECTIVES: To determine the prevalence and determinants of depressive symptoms in the mid- and old-aged people in China. METHODS: Data were extracted from the 2013 China Health and Retirement Longitudinal Study (CHARLS),which containthe Center Epidemiologic Studies-Depression scale(CES-D). Binary logistic regression models were developed to identify factors associated with the prevalence of depression symptoms. These included socio-economic status of the respondents (gender, age, education),health-related factors (chronic diseases, disability, accident injury, and fall in recent two years),and family events over the past two years (deaths of a parent, spouse or child). RESULTS: About 31.9% of respondents had depressive symptoms, with a mean CES-D score of 8.0+/-4.9.Women and those who were younger than 75 years, widowed, resided in a rural area, had low levels of education, and suffered from multiple chronic conditions were more likely to have depressive symptoms than the others. CONCLUSIONS: High prevalence of depressive symptoms in the mid- and old-aged population in China is evident, which is associated with the health and socio-economic status of the population. PMID- 28598096 TI - [Catastrophic Health Expenditure before and after Compensations from the New Rural Cooperative Medical Scheme in Rural Zigong of Sichuan Province]. AB - OBJECTIVES: To estimate catastrophic health expenditure (CHE) of rural families in Zigong, and to determine the main influencing factors of CHE. METHODS: CHE was estimated using indicators such as occurrence and average deviations. The influencing factors of CHE were identified through binary logistic regression. RESULTS: We found 6.37% catastrophic health payment headcount, 1.13% mean catastrophic payment gap, and 17.80% mean positive gap after compensations. Compensations from the new rural cooperative medical scheme (NCMS) led to a reduction of 74.81% catastrophic health payment headcount for hospitalization costs and 48.00% catastrophic health payment headcount for outpatient costs, respectively. The numbers of hospitalizations in a family, presence of patients with chronic diseases, per capita household income, and numbers of family members with a job were found to be predictors of CHE. CONCLUSIONS: Rural families that have patients with chronic diseases are vulnerable to CHE.The government should develop policies to ease the financial burdens of the families with a high accumulated health expenditure over time. PMID- 28598097 TI - [Correlation Between Gross Motor Function and Risk Factors in Children with Cerebral Palsy:an Epidemiology Study in Chengdu]. AB - OBJECTIVES: To investigate the correlation between gross motor function and risk factors in children with cerebral palsy(CP). METHODS: We included the children aged 2-12 years old who were diagnosed with CP and registered in Chengdu Federation of Disabled Persons in 20 districts of Chengdu. Gross motor function was estimated by gross motor function classification system (CMFCS). Risk factors of the CP children were investigated retrospectively. Univariate and multivariate logistic regression analyses were used to analysis the correlation of the CP risk factors and GMFCS grades in the children with CP. RESULTS: A total of 333 children were identified with a male to female ratio of 1.15,an average age of (6.32+/-2.74) years old, and dominated in 6-<12 age group (197 cases,59.16%) and spastic CP (228 cases,68.47%).Thirty risk factors for CP were included, among which the majors were listed as premature delivery (185 cases,55.56%),low body mass (150 cases,45.05%),and neonatal hypoxic-ischemic encephalopathy (104 cases,31.23%).No risk factors of CP were found correlating with GMFCS grades by univariate logistic regression analysis. Stepwise multiple logistic regression analysis showed no risk factors of CP in the regression equation. CONCLUSIONS: The risk factors of CP can not be used to predict the severity of gross motor function of children with CP. PMID- 28598098 TI - [Improving Primary Culture of Pulmonary Microvascular Endothelial Cells of Rats]. AB - OBJECTIVES: To improve the culturing method of pulmonary microvascular endothelial cells (PMEVCs) of SD rats. METHODS: The culturing processes in regard to obtaining peripheral lung tissue, attaching tissue block,preparing medium and subculturing were modified.These included an injection of heparin sodium before anesthesia, abdominal bleeding, opening of chest when breathing stopped, improvement of operational details, reduction of pollution by adding penicillin and streptomycin, discard of tissues after 48 h of primary culturing, remove of fibroblasts by a second digestion, and identification of cells using a fluorescence microscope for binding with lectin from BSI (FITC-BSI).An inverted microscope was used to observe the morphological characteristics of PMEVCs. RESULTS: Purified PMEVCs were obtained,which displayed a polygon or short fusiform, exhibiting a typical cobblestone-like morphology. The morphology of PMVECs turned into swirling or long fusiform following subculture or changes in culture conditions. The results of FITC-BSI assay showed that more than 90% cells were stained with green fluorescence. CONCLUSIONS: Purified PMEVCs with a good growth state and subculture stability can be obtained using the modified method. PMID- 28598099 TI - [Emulsified Sevoflurane Selectively Blocking Spinal Cord and Brain in Rabbit Model]. AB - OBJECTIVES: To establish the rabbits model of selectively anesthetized brain and spinal cord and to explore the skeletal muscle relaxation sites of sevoflurane. METHODS: Sixteen adult male New Zealand white rabbits were randomly assigned to the experiment. The upper torso systemic circulation and the lower torso bypass circulation were independently established by the ligation of thoracic aorta at T12-L1 level. Sevoflurane was administered to the upper or lower torso through lungs or oxygenator to selectively anesthetized brain or spinal cord (mainly lumbar and sacro-coccygeal region). Sevoflurane concentration from end-tidal (represented the brain) and oxygenator outlet (represented the spinal cord) was measured by an anesthetic gas analyzer. The concentration and partial pressure of sevoflurane in carotid artery (represented the brain) and abdominal aorta (represented the spinal cord) were determined using a gas chromatograph with the two-stage headspace equilibration method. RESULTS: When 1.5 mininum alveolar concentration (MAC) sevoflurane was administrated via lungs, the concentration and partial pressure of sevoflurane in the carotid artery were significantly higher than those in the abdominal aorta (P<0.05), with the end-tidal sevoflurane concentration higher than that of oxygenator outlet ( P<0.05), which indicated sevoflurane concentration and partial pressure in brain were higher than those in spinal cord. When 1.5 MAC sevoflurane was delivered via oxygenator,the indicators were conversed ( P<0.05), which indicated sevoflurane concentration and partial pressure in spinal cord were higher than those in brain. CONCLUSIONS: Based on the unique blood supply to the spinal cord of New Zealand white rabbits, we successfully established selectively anesthetized brain and spinal cord rabbit models. PMID- 28598100 TI - [Construction and Identification of the cDNA Expression Library for Human Esophageal Cancer Cells]. AB - OBJECTIVES: To construct a cDNA phage expression library for human esophageal cancer cells. METHODS: After the total RNA were obtained from esophageal cancer cells, the mRNA were separated with magnetic beads adsorption method, and the single-strand and double-strand cDNA were synthesized through reverse transcription. With the undesirable cDNA fragments removed, the remaining cDNA (linked withEcoR1 aptamer and phosphorylated its 5'end) combined with the carrier of T7 Select10-3b. The recombinant phage were packaged in vitro for preliminary cDNA library. PCR was used to identify the size of inserted cDNA. RESULTS: The constructed original cDNA phage expression library for human esophageal cancer cells was consisted of 2.01*106 pfu/mL bacteriophages with a recombination rate of 100%. The length of the inserted cDNA fragments were range from 300 bp to 1 500 bp. CONCLUSIONS: The cDNA phage expression library of human esophageal cell is successfully constructed to meet the currently recognized standards, and can be well used to screen cDNA-cloned genes of human esophageal cancer antigens by serological analysis of recombinantly expressed cDNA clone (SEREX). PMID- 28598101 TI - [Pancreatic beta-cell Functions Measured by Continuous Glucose Monitoring in Han Chinese with Varied Degree of Glucose Tolerance]. AB - OBJECTIVES: To compare the pancreatic beta-cell functions of Han people between those with normal glucose tolerance (NGT),prediabetes (PD),and newly-diagnosed type 2 diabetes mellitus (NDDM), and to evaluate the value of the continuous glucose monitoring system (CGMS) in determining beta-cell functions. METHODS: A total of 169 volunteers of Han people (20-75 years old, 72 male and 97 female) without diagnosed diabetes were given 75-g oral glucose tolerance test (OGTT) and insulin release tests. The body mass index (BMI) of the participants ranged from 18.5 to 28.0 kg/m2.They were categorized into NGT (n=87), PD (n=52) and NDDM (n=30) groupsaccording to the World Health Organization (WHO) 1999 criteria.Blood samples were taken to test triglyceride(TG),total cholesterol (TC),and glycosylated hemoglobin A1c (HbA1c). The participants were also given a 72 h continuous glucose monitoring. The beta-cell functions were calculated using the OGTT and insulin release test results, which included homeostasis model assessment insulin resistance (HOMA-IR),homeostasis model assessment beta-cell function (HOMA-B),basic secretion, early phase secretion, and second phase secretion. The area under the curve of glucose (AUC-G) was estimated through the CGMS.A multivariate stepwise regression model was developed to identify predictors of beta-cell functions. RESULTS: Significant differences in age,BMI,HOMA-IR,HOMA-B,AUC-G, basic secretion, early phase secretion and second phase secretion were found between the NGT and PD groups (P<0.05) and between the NGT and NDDM groups (P<0.05). Differences in AUC-G and basic secretion and early phase secretion were found between the PD and NDDM groups (P<0.05),but not in age, BMI, HOMA-IR, HOMA-B, and second phase secretion.The multivariate stepwise regression analysis showed that HOMA-B (standardized partical regression coefficient beta=-0.244,P=0.001), basic secretion (beta=-0.355,P<0.001), and HbA1c (beta=0.638,P<0.001) contributed significantly to the AUC-G. CONCLUSIONS: beta-cell functions decline in those with prediabetes, which appears first at the second phase secretion. Changes in beta-cell secretion functions are more obvious than in insulin resistance during the progression from PD to NDDM.AUC-G can be a better indicator of impaired beta-cellfunctions. PMID- 28598102 TI - [The Diagnostic Value of Double Contrast Enhanced Ultrasound in Colorectal Neoplasms]. AB - OBJECTIVES: To determine the value of double contrast enhanced ultrasound (DCEUS) in detecting colorectal neoplasms. METHODS: The conventional abdominal ultrasound and DCEUS (hydrocolonal ultrasound+intravenous contrast-enhanced ultrasonography) were performed in 77 patients with 79 colorectal tumors. The clinical, ultrasonic and pathological data of the patients were reviewed. RESULTS: The conventional abdominal ultrasound detected 32 colorectal tumors (32/79, with a sensitivity of 40.1%), compared with 68 tumors found in DCEUS (68/79, with a sensitivity of 86.1%). The tumors were located accurately in 21.9%(7/32) and 88.2%(60/68) cases for the conventional abdominal ultrasound and DCEUS, respectively ( P<0.05). DCEUS accurately located 94.4%(51/54)cased with colon neoplasm. Two types of enhancing modes were found with colorectal neoplasm: entirely homogeneous enhancing and heterogeneous enhancing perpendicularly from the serosal part to the mucosal part. The enhancing modes were associated with the morphology of neoplasm. Thirty-nine segmented-thickened tumors were found with perpendicularly enhancing from the serosal surface to the mucosal surface, while 29 protruding tumors were found with enhancing from their pedicles or fund. CONCLUSIONS: DCEUS has higher detection sensitivity and location accuracy than conventional ultrasound. PMID- 28598103 TI - [Safety and Tolerance of Healthy People to Injection of Astragalosides-a New Drug for Coronary Heart Disease]. AB - OBJECTIVES: To assess the safety and tolerance of healthy volunteers to as tragalosides injection (AGI), and to determine a safe dose range for phase II clinical trial. METHODS: A total of 62 healthy volunteers participated in this study, with 26 being given a single AGI of 100 mL, 200 mL, 300 mL, 400 mL, 500 mL, or 600 mL and 36 subjects being given 500 mL, 400 mL, 200 mL or 300 mL of AGI once a day for 7 d. Discomfortsymptoms, vital signs and safety problems were recorded 3 d and 7 d after the administration of AGI. The results were analyzed. RESULTS: Of the 62 participants, 40 adverse events (AEs) were reported by 31 participants, which included 23 mild adverse reactions (ADRs) and 4 moderate ADRs. Nine AEs were reported by 9 participants with single AGI, including 7 ADRs. Fourteen AEs were reported by 10 participants with 500 mL and 400 mL multiple AGI, including 12 ADRs occurred in 9 participants.Seventeen AEs were reported by 12 participants with 300 mL and 300 mL multiple AGI, including 3 mild ADRs. The main ADRs included abnormal liver function [slightly elevated glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST),and serum total bilirubin (TBil)], low blood potassium, increased urine red blood cell count, rash, and phlebitis. CONCLUSIONS: The maximum tolerance is 600 mL for single-dose treatment, and 400 mL for multiple-dose (7 d). The dose guidance given in this study should be examined its effects and safety in patients with coronary heart disease in phase II clinical trial. PMID- 28598104 TI - [Association of nt3434A→G Mutation in Mitochondrial DNA ND1 Gene with Diabetes Mellitus]. AB - OBJECTIVES: To study the association of nt3434 A→G mutation in mitochondrial DNA NADH dehydrogenase 1 subunit (ND1) gene with diabetes mellitus. METHODS: PCR-RFLP was used to detect the nt3434 A→G variant of mtDNA ND1 gene in 216 diabetic patients and 203 healthy control individuals. Characteristics of mutation and clinical indicators in nt3434A→G family were analyzed. RESULTS: nt3434A→G mutation was detected in one diabetic patient but not found in NC group. This patient had low insulin secretion, low BMI, and elevated serum lactate acids. No significant difference was found in the mutation frequencies between these two groups. nt3434 A→G mutation was also detected in this patient's sister and daughter, who were normal glucose tolerance and had slightly elevated serum lactate acids levels. CONCLUSIONS: Further investigation would be helpful to answer whether nt3434A→G mutation of mitochondrial DNA ND1 gene is associated with an increased risk of diabetes. PMID- 28598106 TI - [The Protective Effect of Inhibition of PARP-1 on Inflammation Induced by PM2.5 in Human Bronchial Epithelial Cell Line.] AB - OBJECTIVES: To explore whether the inhibition of poly ADP-ribose polymerase 1(PARP-1) could attenuated inflammation induced by fine particulate matter (PM2.5) in human bronchial epithelial cell line. METHODS: Cell viability was detected by Trypan Blue assay after incubated with PM2.5 for 24 h.PM2.5 doses no more than 600 MUg/mL were utilized in the following experiments.In order to observe how PARP-1 would effect the expression of nuclear factor-kappaB p65 and inducible nitric oxide synthase (iNOS),cells were respectively treated with 600 MUg/mL PM2.5,10 MUmol/L 4-amino-1, 8-naphthalimide (4-AN),600 MUg/mL PM2.5+10 MUmol/L 4-AN or DMSO.Western blot assay was used to estimate the protein expression of PARP-1,p65 in nuclear and iNOS in cytoplasm.Nitric acid enzyme reduction assay was used to determine the production of nitric oxide (NO). RESULTS: As the PM2.5 concentration increased,the cell viability decreased,while the expression of PARP-1,p65,iNOS and NO increased significantly (P<0.05).After pretreatment of 4-AN for 24 h,the expression of PARP-1,p65,iNOS and NO almost decreased to the normal level(P>0.05). CONCLUSIONS: Inflammation triggered by PM2.5 could be attenuated by the inhibition of PAPR-1,which involved the block of transcriptional activity of NF-kappaB for inflammatory mediator. PMID- 28598105 TI - [Genetic Recombiniation and Protein Expression Detection of Listeria-based tuberculosis Vaccine Candidates.] AB - OBJECTIVES: Genetic construction of tuberculosis vaccine candidates based on Listeria(L.) monocytogenes,L.ivanovii,and evaluation their protein expression,in order to provide a novel method for research on tuberculosis controlling. METHODS: Two kinds of gene cassettes carrying tuberculosis antigen encoding gene Rv3875 or Rv0129c were inserted into targeting vector harboring L.monocytogenes,L.ivanovii homologous sequences via genetic connection methods and plasmid transformation technology in vitro.Targeting plasmids were electroporated into L.monocytogenes,L.ivanovii,and the recombinant strains were experienced serial passage at 42 degrees C and 30 degrees C.Subsequently,the tuberculosis antigen gene cassettes in targeting plasmids were integrated into L.monocytogenes and L.ivanovii attenuated strain (knocking out of virulence gene actA and plcB) and L.ivanovii wild type strain by homologous recombination and gene targeting technology.The recombinant strains were screened by blue-white spot and antibiotic resistance test;the intracellular and extracellular proteins of the recombinant strains were tested by Western blot. RESULTS: Five recombination strains carried antigen gene cassette were constructed,and the recombinant genome were confirmed by PCR and sequencing.No erythromycin resistance gene was found in 5 strains,which was coincident to expection.Recombination strains Li-Rv0129c,Li-DeltaactAplcB-Rv0129c and Li DeltaactAplcB-Rv3875 expressed Mycobacterium tuberculosis antigenic protein,Ag85C or ESAT-6,as expected.But L.monocytogenes strains did not express proper antigenic protein. CONCLUSIONS: Three novel L.ivanovii-based tuberculosis vaccine candicates,carrying Mycobacterium tuberculosis Rv0129c antigen gene cassette (coding for Ag85C) or Rv3875 gene cassette (coding for ESAT-6),and expressing relevant antigenic proteins have been successfully selected. PMID- 28598107 TI - [The Antitumor Effects of Fisetin on Ovarian Cancer in vitro and in vivo.] AB - OBJECTIVES: We attempted to survey the inhibit effect of fisetin with human ovarian cancer cell line SKOV3 and the xenograft and the mechanism of the effect. METHODS: The ovarian cancer cell line SKOV3 treated by fisetin were observed directly under the transmission electronmicroscope (TEM);MTT assay was used to determine cell viability.Flow cytometry was used to analyze the apoptosis in ovarian cancer cell line SKOV3.In addition,we established an ovarian cancer athymicnude rat model.We observed the neoplasia and progression after fisetin treatment.The proliferation and apoptosis of athymic nude rat model were evaluated by testing Bcl-2,Bax and poly-ADP-ribose polyerase (PARP) expression through Western blot. RESULTS: The chromatin were brought together and the apoptotic bodies were detected in SKOV3 cells under transmission electron microscope after the treatment by fisetin.MTT assay indicated that fisetin inhibited ovarian cancer cell proliferation in a dose-dependent manner.The flow cytometry data demonstrated that the apoptosis might induct in SKOV3 cells after treatment by fisetin.In athymic rude rat model,under the influence of fisetin,tumor volume and tumor mass were significantly decreased.Western blot demonstrated that treatment with higher concentration of fisetin resulted in a significant decrease of Bcl-2 and a significant increase of Bax.The apoptosis proteins PARP was cut apparently. CONCLUSIONS: The results provided the first insight into antitumor anti-proliferative and the induction of apoptosis efficacy of fisetin against ovarian cancer in vitro and in vivo.All data suggested a safe promising therapeutic potential of fisetin in ovarian cancer treatment. PMID- 28598108 TI - [HPV E7 Function in DNA Damage Response of Cervical Intraepithelial Neoplasia.] AB - OBJECTIVES: To determine the function of human papillomavirus (HPV) E7 in DNA damage response of cervical intraepithelial neoplasia (CIN) 3 cells. METHODS: Samples of CIN 3 and child foreskin tissues were collected,with pathologically confirmed HPV positive and negative,respectively.Collagenase A was used for digesting tissues prior to primary culture.The HPV negative cells were infected with lentivirus E7 and pLV.Proteins(53BP1,NBS1,BRCA1 and RPA32) responsive to DNA double break damages were detected by indirect immunofluorescent staining after 0 8 h treatment with X-ray (2 or 5 Gy). RESULTS: After treatment with 2 or 5 Gy X ray,53BP1,NBS1,BRCA1 and RPA32 foci in HPV+ cells increased compared with HPV- cells (P<0.05).Less 53BP1,RPA32,BRCA1 and NBS1 foci positive cells (foci>5) were found in E7 infected cells than in pLV infected cells(P<0.05).Both of them reached the peak at 6 h (2 Gy) or 4 h (5 Gy). CONCLUSIONS: We have successfully established a model to detect the function of HPV E7 in DNA damage response using primary culture of CIN fibroblasts.With the progression of CIN,HPV E7 can inhibit DNA double break repair. PMID- 28598109 TI - [The Study of Decitabine Effect on the Endometrial Carcinoma Xenografted in Nude Mice.] AB - OBJECTIVES: To explore the effect of the demethylation drug 5-Aza-CdR on endometrial carcinoma xenografted in nude mice. METHODS: Randomly assigned the mice into decitabine (AZA),cisplatin (DDP),medroxyprogesterone acetate (MPA),AZA+DDP,AZA+MPA,DDP+MPA and model groups (three in each group) after building the models of xenografted tumor by transplanting the HEC-1B cells on nude mice,and dealt them respectively with corresponding drugs (1 MUg/g,single or combination) in the experiment groups and normal saline in model group (injected per 3 d,8 injections in total).Then the tumor inhibitory rates in different groups were calculated.The methylation and protein expression of RASSF1A gene was estimated by methylation specific PCR (MSP) and Western blot respectively,and apoptosis situation of carcinoma cell was estimated by tunel. RESULTS: Inhibitory rate in AZA+DDP group was the highest,and the lowest was AZA group.RASSF1A gene promoter region methylation levels of AZA,AZA+DDP and AZA+MPA groups significantly reduced and showed obvious demethylation stripes while other groups mainly showed the methylation stripes.The differences of RASSF1A protein expression between AZA,AZA+DDP and AZA+MPA groups were not statistical significant (P>0.05),but the three were higher than model group (P<0.05);there was no statistically significant difference respectively in the DDP,MPA,DDP+ MPA groups compared with that of model group (P>0.05).In the comparison of apoptosis index,model group was the lowest,followed by the three single medicine groups,and the highest was three combination groups (P<0.05). CONCLUSIONS: Demethylation drug 5-Aza-CdR in endometrial cancer treatment has a great potential clinical application value by reversing the abnormal methylation of RASSF1A gene,restoring biological functions of RASSF1A protein and strengthening the efficacy of DDP and MPA. PMID- 28598110 TI - [Microbial Community Structure on the Root Surface of Patients with Periodontitis.] AB - OBJECTIVES: To study the microbial community structure on the root surface of patients with periodontitis. METHODS: Bacterial plaque and tissues from the root neck (RN group),root middle (RM group) and root tine (RT group) of six teeth with mobility 3 in one patient with periodontitis were sampled.The V3V4 region of 16S rRNA was sequenced on the Illumina MiSeq platform.The microbial community structure was analyzed by Mothur,Qiime and SPSS software. RESULTS: The principal component analysis (PCoA) results indicated that the RM samples had a similar microbial community structure as that of the RT samples,which was significant different from that of the RN samples.Thirteen phyla were detected in the three groups of samples,which included 7 dominant phyla.29 dominant genera were detected in 184 genera.The abundance of Bacteroidetes_[G-6] and Peptostre ptococcaceae_[XI][G-4] had a positive correlation with the depth of the collection site of samples (P<0.05),while the abundance of Prevotella,Selenomonas,Corynebacterium and Olsenella had a negative correlation with the depth of the collection site of samples (P<0.05). CONCLUSIONS: There is region-specificity of microbial community structure on the root surface of patients with periodontitis. PMID- 28598111 TI - [The Alterations in Expression of the Synaptophysin in Rat Brain Trauma Injury Model-an Experimental Study.] AB - OBJECTIVES: To study the rat brain trauma injury model and investigate the rules of transformation of expression of synaptophysin and its relationship between histology and radiology alternation after brain trauma injury. METHODS: 24 SD male rats aged three months were randomly divided into 4 groups,including a control group of 6 rats.The experimental group rats were received operation to build free falling brain trauma injury model.The rat were analyzed at 2,4,8 weeks after injury.The experimental group rat were killed after CT scan and functional evaluation,histological changes were measured through HE staining.Synaptophysin were observed by using immunofluorescence method and Western blot. RESULTS: After brain injury the functional evaluation of rat showed dysneuria.Edema and necrosis in neurons and local congestion at 24 h after injury,necrosis and solubility liquefaction at 2 weeks after injury,and histological defects at 4 weeks and 8 weeks after injury,were observed in HE staining in experimental group.The significant cerebral low density shadows at 24 h after injury,lightened in 2 weeks after injury,and disappeared at 4 weeks and 8 weeks after injury,left only the bone defects in CT images.Expression of synaptophysin in brain tissue was decreased from 2 weeks after injury and it was mild increased at 8 weeks after injury evaluated by immunofluorescence method and Western blot. CONCLUSIONS: The functional evaluation,histological and CT scan result indicate that we have built the rat brain trauma injury model successfully.The damage of synapse was correlated with histological and radiological result.The expression of synaptophysin was decreased form acute stage and gradually increased until 8 weeks after injury.This study can be applied as control in research of nerve regeneration after brain trauma injury. PMID- 28598112 TI - [Effects of Fluoxetine on Nogo Expression and Collagen Production with Decrease of Pulmonary Artery Pressure in Rats with Right Ventricular Failure.] AB - OBJECTIVES: To investigate the effect of fluoxetine on neurite growth inhibitor (Nogo) expession and collagen production of cardiac tissue in rats with right heart failure and pulmonary hypertension. METHODS: Thirty one male SD rats were randomly divided into the treatment group,right heart failure group and normal control group.The rats in the treatment group and right heart failure group received intrapertioneal injection of monocrotaline (MCT,60 mg/kg) to induce pulmonary hypertension and right heart failure.After 21 days,the rats in treatment group were given fluoxetine of 10 mg/(kg*d) by gavage per day for 21 days,the rats in the other two groups were given saline.HE staining was used to observe the pulmonary artery and right ventricular myocardial tissue in rats.The collagen formation in right ventricular myocardium was observed by Masson staining.The expressions of Nogo-A, Nogo-B,type1collagen and type 3 collagen mRNA in myocardium were measured by real-time fluorescence quantitative PCR,while the semi quantitative measurement of Nogo protein level was detected by Western blot. RESULTS: After the intervention of fluoxetine,pulmonary artery stenosis was significantly reduced,myocardial tissue lesion decreased,collagen synthesis decreased in right ventricular myocardium.RT-PCR showed that mRNA of Nogo-A decreased,and mRNA of Nogo-B increased (P<0.05).Western blot showed that the expression of Nogo-A protein decreased,while Nogo-B1 protein expression increased (P<0.05),Nogo-B2 expression was not significantly changed (P>0.05). CONCLUSIONS: Nogo may affect the collagen synthesis in right heart failure,and partly involved in myocardial fibrosis. PMID- 28598113 TI - [Effects of Huoxue Dingxuan Capsule Glare on Vertebral Artery Blood Flow,Plasma PAI and t-PA in CSA Rat Models.] AB - OBJECTIVES: To determine the effects of Huoxue Dingxuan Capsule on vertebral artery blood flow,plasma plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in rats with cervical spondylosis of vertebral artery type (CSA). METHODS: Ninety healthy male Wistar rats were equally and randomly divided into control,model and treatment groups.The rats in the model and treatment groups were subject to composite modeling manufacturing CSA.The treatment group was given six-week interventions with Huoxue Dingxuan capsule 4 weeks after the modeling.Vertebral artery blood flow,plasma PAI,and t-PA contents were detected before modeling,prior to the interventions,and post interventions. RESULTS: Before the interventions,the rats in the model and treatment groups had significantly lower blood flow of vertebral artery than the controls (P<0.05).The model rats also had increased serum PAI and t-PA contents (P<0.01).After the interventions,significantly higher vertebral blood flow was found in the treatment group compared with the controls (P<0.05).After the interventions,increased serum PAI and t-PA contents were observed in the rats in the model group (P<0.01);whereas,decreased serum PAI and t-PA contents were observed in the rats in the treatment group (P<0.01).The treatment group had lower levels of serum PAI and t-PA contents than the model group (P<0.01). CONCLUSIONS: Huoxue Dingxuan Capsule glare can improve the blood flow of vertebral artery and reduce serum PAI and t-PA contents. PMID- 28598114 TI - [Effects of Lung Ventilation Perfusion Imaging Examination on Pregnant Outcomes of Rabbits.] AB - OBJECTIVES: To examine the pregnancy outcomes of rabbits being subjected to pulmonary ventilation perfusion imaging examinations. METHODS: Pregnant rabbits were randomly divided into two groups: control group and experimental (lung ventilation-perfusion scintigraphy) group.The pregnancy outcomes were measured using indicators of miscarriage,premature birth,and stillbirth,as well as malformations and developmental abnormalities of offspring over a three-month period. RESULTS: No significant differences in miscarriage,premature birth,and stillbirth were found between the two groups.No obvious deformity appearances in the offspring were observed.The two groups showed no statistically significant differences in fetal progeny-intrauterine growth and developmental indicators measured by body mass,head circumference,abdominal circumference and length. CONCLUSIONS: Lung ventilation-perfusion scintigraphy examination has no effects on pregnant outcomes measured by miscarriage,premature birth,stillbirth,fetal teratogenicity and fetal growth. PMID- 28598115 TI - [Expression of miR-429 and Its Target Gene HSPA4L in Sperms from Asthenospermia Patients.] AB - OBJECTIVES: To investigate the expression of miR-429 and its target gene heat shock protein A4L (HSPA4L) in sperms from asthenospermia patients. METHODS: Twenty semen samples from healthy and fertile adults and 20 semen samples from asthenospermia patients were collected,and normal sperm parameters were defined according to World Health Organization criteria.The expression levels of miR-429 and HSPA4L mRNA were determined by qRT-PCR,and the bioinformatics tool (Targetscan) was used to predict the target of miR-429.Luciferase reporter assay and transfection study were performed to confirm target gene of miR-429.The expression levels of HSPA4L mRNA and protein were further determined by qRT-CPR and Western blot,respectively. RESULTS: The motility and viability of sperms from asthenospermia patients were lower than that in control group,and miR-429 was up regulated in sperms from asthenospermia patients.Bioinformatics analysis revealed that HSPA4L was a target of miR-429.Luciferase reporter assay and transfection study further confirmed that miR-429 suppresses the expressions of HSPA4L mRNA and protein via directly targeting HSPA4L 3'UTR.Results from clinical samples also demonstrated that HSPA4L mRNA and protein were down-regulated in sperms from asthenospermia patients and the expression level of miR-429 was inversely correlated with the expression level of HSPA4L mRNA (r=-0.725, P<0.05). CONCLUSIONS: miR-429 is up-regulated in sperms from asthenospermia patients,and it may modulate the motility and viability of sperms via suppressing the expression of HSPA4L. PMID- 28598116 TI - [Optimal Ovulation Induction in Polycystic Ovary Syndrome Resistant to Clomiphene Citrate or Letrozole.] AB - OBJECTIVES: To investigate the optimal ovulation induction with the combination of combining letrozole(LE),clomiphene citrate (CC),and human menopausal gonadotropin (HMG) in polycystic ovary syndrome(PCOS) patients resistant to CC or LE. METHODS: Two hundreds nine PCOS patients (209 cycles) resistant to CC or LE were randomly divided into three groups: CC+HMG group (59 cycles),LE+HMG group (72 cycles) and LE+CC group (78 cycles).The patients in LE+CC group unable to form the dominant follicle after 54 cycles were enrolled into LE+CC+HMG group.Maximum follicle diameter (MFD),endometrial thickness,number of follicles (diameter>1.4 cm),the level of serum estradiol (E2) were measured on the day of HMG administration.Also these results were observed and compared including the duration of treatment,dosage of HMG,number of ovulated follicles,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate,twinning rate,and ectopic pregnancy rate. RESULTS: The ovulation rate was significantly lower in LE+CC group (30.77%) (P<0.05),but similar in the other three groups.The number of >1.4 cm follicles and ovulated follicles,ovulation duration and E2 concentration in LE+CC group were also at a lower level (P<0.05).The patients in LE+CC+HMG group showed higher E2 level and more HMG consumption (P<0.05).There was no statistical difference in endometrial thickness,MFD,clinical pregnancy rate,biochemical pregnancy rate,early abortion rate and twinning rate among these groups (P>0.05).No severe ovarian hyperstimulation syndrome (OHSS) or luteinized unruptured follicle (LUF) occurred. CONCLUSIONS: Combintion of LE with CC could achieve 1/3 ovulation induction in PCOS resistant to CC or LE alone.When both combined with HMG,the induction of ovulation could be significantly higher than LE+HMG and CC+HMG,while the risk of multiple pregnancy and OHSS was reduced. PMID- 28598117 TI - [Expression Level of Membrane-associated Proteins Numb in Epithelial Ovarian Carcinoma and Its Relationship with Ovarian Cancer Stem Cell Markers CD117, CD133, ALDH1.] AB - OBJECTIVES: To explore the expression level of membrane-associated protein Numb in epithelial ovarian carcinoma and its relationship with ovarian cancer stem cell markers CD117,CD133,acetaldehyde dehydrogenase 1(ALDH1). METHODS: A total of 136 patients who had ovarian tumors and 22 patients who had not ovarian tumors in Department of Gynaecology and Obstetrics,West China Second University Hospital,Sichuan University were chosen as the study subjects.According to the histopathologic examination results,they were divided into epithelial ovarian carcinoma group (n=92),ovarian borderline tumor group (n=23),ovarian benign tumor group (n=21) and normal ovary group (n=22).Expression levels of Numb protein,CD117,CD133 and ALDH1 in ovarian tissue were detected by immunohistochemical SP method and these several kinds of protein expression differences and correlation statistical analysis were performend. RESULTS: 1 The positive expression rate of Numb protein in epithelial ovarian carcinoma group was higher than that in benign tumor or normal ovary group,also Numb protein positive expression rate in ovarian borderline tumor group was higher than that in normal ovary group,and the differences were statistically significant (P<0.05).2 Numb protein positive expression rate in ovarian tissue in patients with epithelial ovarian carcinoma FIGO stage1-2 was lower than that in stage 3 4,also the same in no lymph nodes metastasis compared with lymph nodes invasion,and the differences of positive expression rate were statistically significant (P<0.05).While there were no significant differences among different age,histopathological types,pathological grades and residual tumor size (P>0.05).3 There was no correlation between Numb protein and CD117 and CD133 positive expression rate in epithelial ovarian carcinoma tissue [correlation coefficient (r)=0.116,P=0.261; r=0.083,P=0.425].However,the positive expression rate of Numb protein and ALDH1 was positively correlated (r=0.296,P=0.261). CONCLUSIONS: The expression of Numb protein may involve in the occurrence,invasion and mechanisms of ovarian cancer,positively correlated with ovarian cancer stem cell markers ALDH1,and may affect the prognosis of patients. PMID- 28598118 TI - [The Evaluation Value of Methylation Status of CpG Island of SFRP1 and LINE1 Gene Promoter Area in the Prognosis of Hepatocellular Carcinoma.] AB - OBJECTIVES: To investigate the relationship between aberrant promoter CpG islands methylation status of secreted frizzled related protein 1 (SFRP1) and long intersper sed nuclear element 1 (LINE1) gene and clinicopathologic parameters to determine their prognosis value for hepatocellular carcinoma (HCC). METHODS: 105 cases of HCC and 50 cases of normal people plasma were collected,and then the promoter hypermethylation status of SFRP1 and hypormethylation status of LINE1 were examined by methylation specific PCR (MSP); The relationship between SFRP1/LINE1 methylation status and patients' clinicopathologic factors was analyzed;The association between SFRP1/LINE1 methylation status and disease-free survival and overall survival was analyzed by Kaplan-Meier curves,the log-rank test,and multivariate Cox regression. RESULTS: SFRP1 gene promoter CpG islands hypermethylation and LINE1 gene promoter CpG islands hypomethylation were found in 59.05% (62/105) and 66.67% (70/105) of 105 cancerous plasma cases,repectively,SFRP1 hypermethylation status and LINE1 hypomethylation status in plasma of HCC account for 43.81%(62/105) and no positive methylation cases were detected in normal cases;The hypermethylation status of SFRP1 and hypomethylation status of LINE1 gene were related with HBsAg and alpha fetoprotein (AFP) level;There was statistically significant difference between CpG islands hypermethylation of two genes and disease-free survival rate and overall survival rate;The group patients with SFRP1 hypermethylation positive and LINE1 hypomethylation positive demonstrated the worst prognosis while the group with SFRP1 hypermethylation negative and LINE1 hypomethylation negative had the best prognosis. CONCLUSIONS: The promoter methylation of SFRP1 and LINE1 is correlated with the occurrence and development of HCC.SFRP1 and LINE1 might be potential and reliable biomarkers for predicting prognosis in HCC patients. PMID- 28598119 TI - [Aortic and Mitral Annuli Coupling and Its Association with Cardiac Function in Patients with Dilated Cardiomyopathy.] AB - OBJECTIVES: To compare the mitral and aortic annuli excursion (AE) and aortomitral angle (AMA) variations between patients with and without dilated cardiomyopathy (DCM) using speckle tracking echocardiography (STE),and determine the role of annuli dynamics and coupling behaviors in the left ventricular function. METHODS: Thirty-five patients with DCM and thirty-five age and sex matched healthy adults underwent transthoracic echocardiographic examinations.In the parasternal long-axis view,the AE and AMA variations were measured using Philips QLAB 9.0 software.In the apical four chamber view,the left ventricular ejection fraction (LVEF),longitudinal,circumferential,and radial strain were measured using Tomtec Arene 1.0 software. RESULTS: The DCM patients had significantly smaller AE and AMAmax-min,bigger AMAmax and AMAmin,and varied cardiac cycle compared with the healthy adults.The AMA of DCM patients increased to its maximal value earlier in diastole with little variation.AE was positively correlated with LVEF and multidirectional strain.AMAmax and AMAmin were negatively correlated with AE,LVEF and multidirectional strain (P<0.05).Significant correlations were also found between AMAmax-min and AE,LVEF and multidirectional strain (P<0.05). CONCLUSIONS: AE,AMA,LVEF and multidirectional strain can be quantified using STE.The coupling of mitral and aortic annuli in DCM patients is abnormal and correlated well with left ventricular systolic function.AE and AMA can be conveniently used for estimation of integral and regional cardiac function. PMID- 28598120 TI - [Characteristics and Clinical Significance of Outer Retinal Tubulation in Wet Age macular Degeneration Treated by Anti-vascular Endothelial Growth Factor Through Optical Coherence Tomography.] AB - OBJECTIVES: To determine the characteristics and clinical significance of outer retinal tabulation (ORT) in wet age-related macular degeneration (wAMD) treated by anti-vascular endothelial growth factor (anti-VEGF) through optical coherence tomography (OCT). METHODS: The 35 wAMD patients with 39 ORT eyes treated by anti VEGF were examined by OCT to determine the morphological features and evolution of the ORTs over time and their response to anti-VEGF. RESULTS: ORTs were located in the places that exudation or edema had happened in the outer nuclear layer of retina.38 ORTs remained stable on both quantity and morphology.One ORT became invisible temporarily and then reappeared. CONCLUSIONS: ORTs are reconstructed by photoreceptor cells that have survived after outer retina damages.There is no connection between anti-VEGF treatment and ORT formation. PMID- 28598121 TI - [Regional Homogeneity Changes in Patients with Social Anxiety Disorders after Cognitive Behavioral Therapy.] AB - OBJECTIVES: To examine the altered spontaneous brain activity in patients with social anxiety disorders (SAD) before and after cognitive behavior therapy (CBT),and determine the neuromechanism of formation,treatment and recovery of SAD. METHODS: Fifteen SAD patients were treated with an eight-week group CBT.The patients underwent functional magnetic resonance imaging (fMRI) at resting state before and after the treatments.Eighteen healthy controls (HC) were recruited and underwent a baseline fMRI scan.The regional homogeneity (ReHo) of the patients was compared with the healthy controls.Before the baseline scanning,all participants were assessed with the Liebowitz Social Anxiety Scale(LSAS),the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD). RESULTS: All participants were right-handed.10 males and 4 females were in the patient group,with mean age of (27.07+/-8.11) years.13 males and 5 females were in the HC group,with mean age of (26.28+/-2.42) years.There was no difference for gender and age while significant differences were found in LSAS,HAMA,HAMD between patients and controls (P<0.01).After 8 weeks of group CBT,clinical assessments significantly decreased (P<0.05) in patients group.Compared with HC,the pre-treatment SAD patients showed significantly increased ReHo in right cerebellum lobe at baseline [(P<0.05,with Gaussian random field (GRF) correction]; but the difference became insignificant after the group CBT.The post-treatment patients showed increased ReHo in left putamen and right caudate compared with their pre-treatment conditions (P<0.05,with GRF correction).Pre-post ReHo change in right cerebellum posterior in patients was positively correlated with pre-post change of LSAS-fear scores (r=0.62,P=0.015). CONCLUSIONS: The activity of cerebellum might be one of the potential biomakers to modulate the treatment effect of CBT in SAD,which provides a basis for further investigation into the pathophysiology of SAD. PMID- 28598122 TI - [Adverse Drug Reactions in Sichuan Children During 2012-2014.] AB - OBJECTIVES: To determine the characteristics of adverse drug reactions (ADRs) in children. METHODS: Reported ADRs in the patients aged from 0-18 years were extracted from the 2012-2014 Sichuan ADR surveillance system.The time trend,category of ADRs [system organ class (SOC)],outcomes,and demographic characteristics of the patients were analyzed. RESULTS: The reported paediatric ADRs increased over time;most occurred in males (7 709,56.40%) and preschool children (5 928,43.37%).The majorities involved intravenous drips (8 492,62.13%) and skin and appendages (7 510,55.10%).About 267 (1.95%) cases were deemed as serious ADRs,most (120,44.94%) involving whole body consequences.The majority (13 515,98.87%) of patients recovered.But deaths (5,0.04%) were also reported. CONCLUSIONS: Pediatric ADRs are associated with young age (less than 5 years old) and intravenous drips.Serious ADRs should be identified for early interventions. PMID- 28598123 TI - [Advances of Molecular Diagnostic Techniques Application in Clinical Diagnosis.] AB - Over the past 20 years,clinical molecular diagnostic technology has made rapid development,and became the most promising field in clinical laboratory medicine.In particular,with the development of genomics,clinical molecular diagnostic methods will reveal the nature of clinical diseases in a deeper level,thus guiding the clinical diagnosis and treatments.Many molecular diagnostic projects have been routinely applied in clinical works.This paper reviews the advances on application of clinical diagnostic techniques in infectious disease,tumor and genetic disorders,including nucleic acid amplification,biochip,next-generation sequencing,and automation molecular system,and so on. PMID- 28598124 TI - [The Targeted Regulating Role of Has-miR-577 and Has-miR-583 on Gene FGF-21 Detected by the Dual Luciferase Reporter System.] AB - OBJECTIVES: To determine the targeted regulating role of has-miR-577 and has-miR 583 on the expression of fibroblast growth factor 21 (FGF-21) based on a constructed luciferase reporter FGF-21 gene vector. METHODS: The site of has-miR 577 and has-miR-583 target genes FGF-21 were predicted by the bioinformatics analyzing tools online.FGF-21 gene fragments,combined with has-miR-577 or has-miR 583 sequences and mutant sequences,were designed and synthesized.The wild type (psiCHECK2-FGF-21) and mutant (psiCHECK2-FGF-21-mut) luciferase reporter gene carriers were constructed.The relevant plasmids [hsa-miR-577mimics,hsa-miR-583 mimics or miR negative control (miR-NC)] and luciferase reporter gene carrier (wild type or mutant ) were co-transfected into 293T cells.The luciferase reporter system was used to detect the luciferase activity.The effects of has-miR 577 and has-miR-583 on the expression of FGF-21 were observed. RESULTS: The double enzyme electrophoresis and sequencing results showed that the gene fragment size and sequences of the wild type (psiCHECK2-FGF-21) and mutant (psiCHECK2-FGF-21-mut) carriers met expectations of the experiment.The luciferase assays revealed that has-miR-577 and has-miR-583 significantly diminished luciferase activity from the reporter vector containing 3'UTR of FGF-21 (P<0.05),whereas no suppression of luciferase activity was found in the mutant (psiCHECK2-FGF-21-mut). CONCLUSIONS: FGF-21 gene can be targeted by has-miR-577 and has-miR-583. PMID- 28598125 TI - [Association of Gene Polymorphisms in Wnt Signal Pathway with Tuberculosis in Chinese Tibetan Population.] AB - OBJECTIVES: To determine the correlation between gene polymorphisms in Wnt signal pathway and susceptibility of Chinese Tibetan people to tuberculosis. METHODS: A total of 488 active tuberculosis patients and 454 healthy subjects(control) were enrolled in this case-control study.Five single nucleotide polymorphisms (SNPs) in Wnt signal pathway (rs4135385 in CTNNB1 gene,rs11001553 in DKK1 gene,rs56900803 in WIF1 gene,rs7832767 in SFRP1 gene and rs11079571 in AXIN2 gene) were genotyped using MassARRAY method.The genotype and allele distributions of these loci were determined using SPSS19.0 and SNP stats software.Significant SNPs were measured in the co-dominant,dominant and recessive genetic models.The polymorphism distributions of Chinese Tibetans were compared with those of Chinese Han populations. RESULTS: The genotype distributions of all SNPs coincided with the Hardy-Weinberg equilibrium in the 2 groups.The frequencies of genotype and allele of rs7832767 in SFRP1 gene were significantly different (P=0.004,0.002,respectively) between the Tibetan patients with tuberculosis and the Tibetan healthy controls.Compared with C allele carriers,those carrying T allele of rs7832767 showed increased risk of tuberculosis [odds ratio (OR)=1.260,95% confidence interval (CI):1.086-1.471,P=0.002].The co dominant,dominant and recessive models of this locus were also associated with higher risk of tuberculosis.No significant differences in genotype and allele distributions were observed for the other four SNP loci (P all>0.05).The distribution of rs4135385 in CTNNB1 gene in the Chinese Tibetan population differed from the Han population (P=0.035 for genotype,0.021 for allele).There were no obvious differences in genotype and allele distributions for the other four SNPs between the Tibetan and Han populations (P all >0.05). CONCLUSIONS: SFRP1 gene polymorphism in Wnt signal pathway is associated with tuberculosis susceptibility in Chinese Tibetan population.The distribution of CTNNB1 gene polymorphism differs between Chinese Tibetan and Han populations. PMID- 28598126 TI - [FLT3 Gene Expression and Its Clinical Significance in Acute Myeloid Leukemia.] AB - OBJECTIVES: To determine the correlation between fms-like tyrosine kinase 3 gene (FLT3) expression and FLT3-internal tandem duplication (ITD) mutations in acute myeloid leukemia patients,and the association between expression of FLT3 gene and clinical and laboratory features of patients. METHODS: The expression of FLT3 mRNA in bone marrow (BM) leukemic cells of 128 acute myeloid leukemia (AML) patients was measured by real-time PCR.The patients were divided into two groups using the 35% FLT3 expression as a cut-off point.The associations between the expression level of FLT3 and clinical and laboratory features of patients were analyzed. RESULTS: The patients had a FLT3 gene expression level of 0.01-180.68 (mean 14.65) at the initial diagnosis,with AML-M1 the most expressed and AML-M6 the least expressed,but without statistical significance.The patients with a high level of FLT3 gene expression had higher peripheral blood white blood cell count (WBC) (P<0.01) and were more likely to become anemic and febrile (P<0.05).WBC [regression coefficient (B)=1.508,odds ratio (OR)=4.518,95% confidence interval(CI):1.465-13.390,P=0.009] and anemia (B=2.142,OR=8.513,95%CI:3.201 22.644,P<0.001)were predictors of higher expression of FLT3.The patients with high levels of FLT3 gene expression had lower complete remission rate (32/83),compared with those (36/44) with low levels of FLT3 gene expression (P<0.05).The Cox regression analysis showed that the patients with higher levels of FLT3 gene expression had a higher risk of death (B=1.338, relative risk=3.810, 95%CI:1.820-7.947,P<0.001).The Kaplan-Meier analysis showed that the patients with higher levels of FLT3 gene expression had lower survival time (56.63%) than those with lower levels of FLT3 expression (70.45%,P<0.05). CONCLUSIONS: FLT3 gene has adverse impacts on complete remission of AML.High expression of FLT3 gene is associated with poor prognosis of patients with AML. PMID- 28598127 TI - [Correlations Between AML1-ETO Fusion Gene and Clinical Features of Acute Myeloid Leukemia in Sichuan.] AB - OBJECTIVES: To determine the correlations between AML1-ETO fusion gene and clinical characteristics of patients with AML,and its association with the prognosis of AML-M2. METHODS: Medical records of 94 AML-M2 cases with positive AML1-ETO fusion gene and 51 AML-M2 cases with negative AML1-ETO gene were retrospective reviewed.Their clinical characteristics,treatment responses and prognostic outcomes were compared. RESULTS: No significant differences in the clinical symptoms,predominantly anemia,fever and hemorrhage,were found between the AML1-ETO fusion gene positive and negative AML-M2 (P>0.05).However,lower levels of red blood cell (RBC) and platelet (PLT),and higher levels of ratio of grain to red,percentage of bone marrow granulocyte (NC),CD34,human leukocyte antigen DR (HLA-DR),CD56 and CD19 were found in those with positive AML1-ETO fusion gene (P<0.05).The efficacy of treatments and survival curves showed no significant differences between the two groups (P>0.05).CD56 and original percentage of bone marrow granulocyte were predictors of poor long-term survival.Complete remission was the only predictor of better long-term survival. CONCLUSIONS: AML1-ETO fusion gene is neither associated with clinical symptoms,nor with survival and long term prognosis in Sichuan.As many factors affect the efficacy of treatments and prognosis of AML-M2,stratified analysis is needed to determine the role of AML1-ETO. PMID- 28598128 TI - [Molecular Features of SMA-related Genes in Spinal Muscular Atrophy Patients of Han Nationality in Southwest China.] AB - OBJECTIVES: To investigate the molecular features of spinal muscular atrophy (SMA) related genes in SMA patients of Han nationality of southwest of China. METHODS: We collected 62 unrelated patients of SMA and 50 unrelated healthy individuals in this study.The copy numbers of survival motor neuron gene (SMN) and uronal-apoptosis inhibitory protein gene (NAIP) were measured by using multiplex ligation-dependent probe amplification (MLPA). RESULTS: Of 62 patients,the copy number of SMA1-4 were 30.65% (19/62),41.94%(26/62),16.13% (10/62),11.29% (7/62),respectively.The deletion of SMN1 exon 7 accounts for 98.38% (61/62).The deletion of SMN1 exon 8 accounts for 82.26% (51/62).Among SMA 1 patients,the homozygous deletion of NAIP exon 5 accounts for 68.42% (13/19) and heterzygous deletion accounts for 26.32% (5/19).Among SMA2-4patients,the homozygous deletion of NAIP exon 5 accounts for 13.95% (6/43) and heterzygous deletion accounts for 62.79% (27/43).Furthermore,68.42% (13/19) patients of SMA1have 1 copy and 2 copies of SMN2 gene,84.62% (22/26) patients of SMA 2 have more than 2 copies of SMN2 gene,90.00% (9/10) SMA3 and 85.71% (6/7) SMA4 have over 2 copies of SMN2 gene and even have 5 and 6 copy of SMN2 gene. CONCLUSIONS: The deletion of SMN1 gene is the main cause of SMA,and the change of SMN2 and NAIP copy number can affect the severity of SMA. PMID- 28598129 TI - [Genotype of Thalassemia in Han Chinese and Tibetans in Sichuan Province,China.] AB - OBJECTIVES: To investigate the carrying rates and genotype distribution of thalassemia gene in Han people and Tibetans in Sichuan district. METHODS: A total of 1 147 Han adults and 613 adult Tibetans were included in this study.Hematological parameters were measured with Sysmex XE-2100 automatic blood cell analyzer.Alpha thalassemia and beta thalassemia gene analyses were further performed on samples with a mean corpuscular volume (MCV) <85 fL and a mean corpuscular hemoglobin (MCH) <27 pg.Multiplex ligation-dependent probe amplification (MLPA) and reverse dot blot assays were used for detecting deletional mutations of alpha globin gene and non-deletional mutations of alpha globin and beta globin genes,respectively. RESULTS: About 1.48% (17/1 147) Han people carried alpha thalassemia gene,with --SEA/alphaalpha as the most common genotype; 1.39% (16/1 147) carried beta thalassemia gene,with CD17 and IVS-2-654 as the most common genotype.There were 2 cases with both alpha and beta thalassemia.Low MCH (<27 pg) was found in all 33 cases with positive thalassemia genes.However,5 people with positive thalassemia genes had higher than 80 fL MCV,with the highest reaching 83.7 fL.Out of 613 Tibetans,only one was found to have positive thalassemia genes. CONCLUSIONS: Sichuan Han population carry a high level of thalassemia genes,with various genotypes and pathogenic gene mutation types.Han people with < 84 fL MCV and <27 pg MCH were recommended for thalassemia gene screening.Tibetans were not recommended for routine screening of thalassemia. PMID- 28598130 TI - [Radiation Dose of Body Surface at Sensitive Organs and Its Protective Precaution in Head CT Scanning:Initial Experience.] AB - OBJECTIVES: To investigate the radiation dose of body surface at sensitive organs using different protective precaution in head CT scanning. METHODS: The standard phantom received head routine sequence scanning with dual-source computed tomography.The phantoms were scanned with three different protective precaution:group A (without protective clothing),group B (wearing lead collar and cover lead clothes),group C (wearing lead collar and clothes without cuffs).The thermoluminescence dosimeters (TLD) was placed on the body surface corresponding to sensitive organs to measure radiation dose. RESULTS: The volume of CT dose index (CTDIvol) and dose length product (DLP) in group A,B and C were same,44.06 mGy and 634 mGy*cm,respectively.There was no statistic significant difference between group A,B and C of radiation dose in non-protective region (P=0.712).The radiation dose in the neck region under the cover of lead collar in group A,B and C were (2.57 +/- 0.65) mGy,(2.30 +/- 1.10) mGy and (2.48 +/- 0.90) mGy,respectively,without statistic significant difference between groups (P=0.816).However,the radiation dose in abdominal region of group A was (0.66+/ 0.37) mGy,which was significantly higher than that of group B [(0.18 +/- 0.18) mGy] and group C [(0.18+/-0.16) mGy],The radiation dose in dorsal region of group A was (0.55+/-0.43) mGy,which was significantly higher than that of group B [(0.28+/-0.22) mGy],while that of group C [(0.14+/-0.12) mGy] was significantly lower than group B. CONCLUSIONS: Compared to traditional lead coverage,lead collar and cloth can decrease the radiation dose of body surface and sensitive organs in head scan with dual source CT. PMID- 28598131 TI - [Clinical Characteristics of Autonomic Dysfunction in Hypertensive Patients with Minor Ischemic Stroke.] AB - OBJECTIVES: To investigate clinical characteristics of autonomic dysfunction (AD) in hypertensive patients with minor ischemic stroke (MIS). METHODS: Sixty hypertensive patients with MIS (observation group) and 60 age-matched hypertensive patients (control group) were recruited in our study.The clinical data of the patients were collected.Autonomic symptoms were accessed using the Scale for Outcomes in Parkinson disease-Autonomic (SCOPA-AUT).Depression was evaluated with Hamilton Depression Scale (HAM-D) .Age,heart beat rate,concomitant diseases,SCOPA-AUT,and HAM-D were analyzed between the two groups. RESULTS: Compared with the control group,the observation group showed an increased incidence of orthostatic hypotension,depression,SCOPA-AUT and HAM-D score.Logistic regression showed HAM-D score>8 [standard partial regression coefficent (beta)=0.142,odds ratio (OR)=3.251,P=0.009] and age>60 yr.(beta=0.180,OR=1.972, P=0.003) were independent risk factors for AD. CONCLUSIONS: AD is common in hypertensive patients with MIS and depression is probably the potential etiology. PMID- 28598133 TI - [Therapeutic Efficacy of Qingre Jiedu and Huoxue Huayu Recipe in Prednisone dependant Patients with Chronic Primary Immune Thrombocytopenic Purpura.] AB - OBJECTIVES: To observe the clinical efficacy of Qingre Jiedu and Huoxue Huayu Recipe on the prednisone-dependant patients with chronic primary immune thrombocytopenic purpura (CPITP). METHODS: Fifty prednisone-dependant CPITP patients were treated with Qingre Jiedu and Huoxue Huayu Recipe orally one dose a day,the dosage of prednisone for these patients was tapered according to the monitoring result of blood platelet count (BPC).The therapeutic efficacy in these patients was evaluated before and after Chinese medicine treatment over 4 weeks. RESULTS: After the treatment of chinese medicine,BPC was increased from (28.6+/ 22.5) *109 L-1 to (81.8+/-56.5)*109 L-1 (P<0.05).The dosage of prednisone was decreased from (28.1+/-15.2) mg/d to (8.0+/-9.4) mg/d (P<0.05).Complement response,response and no response rate were 2%,10% and 88% before Chinese medicine treatment,which were 30%, 46% and 24% after Chinese medicine treatment,respectively (P<0.05). CONCLUSIONS: Qingre Jiedu and Huoxue Huayu Recipe could be effective in the treatment of prednisone-dependant patients with CPITP,and could decrease the dosage of prednisone. PMID- 28598134 TI - The International Health Regulations (IHR) - 10 years of global public health security. PMID- 28598135 TI - Japanese encephalitis: surveillance and immunization in Asia and the Western Pacific, 2016. PMID- 28598132 TI - [Effect of Sleep in Early Pregnancy on Gestational Diabetes: a Prospective Study.] AB - OBJECTIVES: To investigate the influence of sleep status in early pregnant women on the occurrence of gestational diabetes mellitus (GDM). METHODS: In this prospective study,542 pregnant women in early pregnancy were selected as subjects.The sleep time,insomnia,pre-gestational body mass and basic information of the subjects were collected by the trained investigators through questionnaire.At the 24th to 28th pregnant week,the body mass of each subject was measured and oral glucose tolerance test (OGTT) was conducted.The diagnosis of GDM was followed the guidelines of diagnose and treatment of gestational diabetes mellitus in China (2014).A non-conditional logistic regression method was adopted to analyze the correlation between sleep status of early pregnant women and the occurrence of GDM. RESULTS: The numbers of subjects in sleep deficiency group,sleep sufficiency group and sleep excessive group were 16 (2.95%),268 (49.45%) and 258 (47.60%),respectively.The incidences of GDM for sleep deficiency group,sleep sufficient group,and sleep excessive group were 62.50%(10/16),25.75%(69/268) and 22.09% (57/258),respectively,the difference was statistically significant (chi2=11.280,P<0.05).Compared with either sleep sufficiency or sleep excessive group,sleep deficiency group had higher GDM occurrence rate with statistically significant (chi2=8.410,11.218,P<0.017).Insomnia subjects in early pregnancy were 137 (25.28%).The incidences of GDM in insomnia group and normal group were 32.12% and 22.72% respectively,the difference was statistically significant (chi2=4.813, P<0.05).After adjusting the confounding factors [age,education,pre-pregnant body mass index (BMI),gained body mass in early and medium pregnancy,family history of type-2 diabetes,gravidity,parity,smoke,drink,exercise and occupation],non conditional logistic regression results show that sleep deficiency for early pregnant women was an independent risk factor for the occurrence of GDM [odds ratio (OR)=7.38,95% confidence interval (CI): 2.25-24.17].However,the association between insomnia and the occurrence of GDM was not found. CONCLUSIONS: Sleep deficiency in early pregnancy may be a risk factor for the occurrence of GDM. PMID- 28598136 TI - Early detection of recurrence or progression disease in patients with ovarian cancer after primary debulking surgery. Correlation between CT findings and CA 125 levels. AB - BACKGROUND: There are no standard approaches for follow up in advanced ovarian cancer (AOC) patients; the aim of this study is to evaluate correlation between computed tomography (CT) and CA 125 levels to assess early detection of recurrence or progression disease (PD). METHODS: We included 76 patients with AOC, who had prior debulking surgery, starting first or second line of chemotherapy and underwent follow-up CT examinations. Evaluation of tumor response to treatment by imaging was assessed using RECIST 1.1. Site of relapse was classified as: abdomen, chest and neck (observed in the upper chest scans). RESULTS: Change in CA 125 levels was calculated in respect previous evaluation at the end of treatment for each patient. The most suitable cut-offs could be identified in an increase in CA 125 levels >10.5% (sensitivity: 67.9%; specificity: 83.6%; LR+: 4.1; LR-: 0.4) in order to predict PD and in a change of -0.5% in order to exclude PD (sensitivity 83.0%; specificity: 69.6%; LR+: 2.7; LR : 0.2). Site of relapse was abdomen (58.5%), abdomen and chest (33.9%), chest (3.8%), chest and neck (1.9%), and abdomen, chest and neck (1.9%). CONCLUSIONS: Increase in CA 125 levels >10.5% could be sufficiently predictive of PD requiring CT examination. Change of -0.5% is sufficiently predictive of absence of PD. Increase <10.5% and >0.5% needs clinical correlation to establish correct timing and extension of CT examination. Attention must be played in reducing number and extent of CT examinations to reduce exposure dose. PMID- 28598137 TI - The effectiveness of psychosocial assessment in the detection and management of postpartum depression: a systematic review. AB - INTRODUCTION: Perinatal mental disorders remain a public health concern. A psychosocial assessment gives a comprehensive understanding of a woman's circumstances by identifying risk factors that affect the overall mental state and function of the woman. The aim was to evaluate the current international evidence regarding the effectiveness of psychosocial assessments in the detection and management of postpartum depression. EVIDENCE ACQUISITION: Six health related databases were systematically searched from January 2000 to June 2016. Full papers reporting the effectiveness of psychosocial assessment on the detection and management of postpartum depression were included. A data extraction form was designed and piloted on two studies. Data were extracted on study design, population, study context, intervention/s and outcome/s. The methods of all the studies selected were critically appraised using the Quality Assessment Tool for Quantitative Studies. EVIDENCE SYNTHESIS: A total of 692 citations were found. Four randomized control trials (RCTs) met full inclusion criteria and qualified for full paper review and data extraction. Due to the heterogeneity of the data retrieved a narrative synthesis was carried out. Overall, when compared to routine care, psychosocial assessments were found to be sensitive to detect risk factors associated with postnatal depression. Results from two of the included studies reported no statistically significant difference in outcomes amongst those who screened positive and received the intervention compared to those who screened positive and were given standard care. CONCLUSIONS: Presently there is a paucity of published data on the effectiveness of psychosocial assessment in the detection and management of postnatal depression and results show conflicting evidence. Further RCTs are recommended to further elucidate the effectiveness of psychosocial assessments. PMID- 28598138 TI - Unexplained infertility: live-birth's prognostic factors to determine the ART management. AB - BACKGROUND: The purpose of this retrospective observational study was to identify prognostic factors that lead to a live birth (LB) in couples with unexplained infertility in order to define the best assisted-reproductive technique (ART) strategy. METHODS: Prognostic factors of couples with unexplained infertility managed initially with gonadotropin intrauterine inseminations (IUI) at a single university fertility center were analyzed. Infertility was not considered "unexplained" in case of mild male infertility and suspicion of diminished ovarian reserve (FSH>10 IU/L). ART management consisted to start with IUI cycles and then, if failure, to propose in vitro fertilization (IVF). Couples were compared according to the results of IUI cycles in terms of LB. RESULTS: Between January 2011 and July 2015, 133 couples with unexplained infertility were included (320 IUI cycles). The average age of women was 31.6+/-4.6 years and the average number of IUI per couple was 2.4+/-1.2. The IUI live birth rate (LBR) was 37.6%, with an average of 2 cycles to obtain a pregnancy. For 63 couples, no pregnancy occurred after IUI cycles. The prognostic factors of the two groups "LB after IUI" vs. "no LB after IUI" were not statistically different. The remaining 20 couples had a spontaneous pregnancy with a LB. Cumulative LBR, including spontaneous and ART pregnancies, was 65.7%. Of the 63 couples with no LB after IUI, 33.3% dropped-out from infertility treatments before starting IVF. CONCLUSIONS: To avoid couple's drop-out, we advise to start infertility treatment for unexplained infertility with two IUI before undergoing IVF if IUI failure. PMID- 28598139 TI - Mini-sling efficacy in obese versus non-obese patients for treatment of stress urinary incontinence. AB - BACKGROUND: The impact of obesity on single-incision has been object of concerns. The aim of the study was to compare the outcomes of MiniArc single-incision sling in normal weight, overweight and obese patients. METHODS: This retrospective study analyzed women with proven stress urinary incontinence (SUI). Patients were divided into three groups according to BMI: normal weight (group A), overweight (group B) and obese (group C). Objective cure rate was assessed with stress test and subjective cure rate was determined by ICIQ-SF and PGI-I scores. Postoperative overactive bladder syndrome and voiding symptoms were recorded. RESULTS: One hundred ninety-two patients were analyzed (A=97; B=68; C=27). Mean follow-up was 23.2 months without differences among groups. Estimated blood loss and operative time were not influenced by BMI. No bladder perforation were observed. Objective cure rate (A=87.6%; B=86.8%; C=81.5%) and subjective outcomes resulted similar irrespective of BMI class. De novo onset of overactive bladder syndrome and voiding symptoms were reported without significant differences among groups. CONCLUSIONS: The current study showed that single-incision sling Miniarc seems to be an effective treatment irrespective of BMI. Operative data, complications, objective and subjective outcomes were similar for normal weight, overweight and obese women. PMID- 28598140 TI - Biomarker profiling of plasma samples utilizing RANDOX biochip array technology. AB - RANDOX Biochip Array Technology offers an efficient, cost-effective method of measuring multiple analytes on a large number of samples in biologic fluids. This innovative technology has proven extremely useful in the profiling of markers in a number of different disease states. Biochip arrays have also shown promise in clinical trials, offering rapid evaluation of multiple markers and circulating levels of the analyte with only a small sample. This biochip technology has broad applications in clinical, pharmaceutical, toxicological, immunologic and microbiologic areas. This technique offers parallel profiling and will have great value in personalized and precision medicine. The aim of this manuscript is to explore the recent and future utility of biochips for profiling marker levels in different diseased populations using RANDOX's Biochip Array Technology. PMID- 28598141 TI - Evaluation of cerebral perfusion by contrast-enhanced ultrasound at low mechanical index in cerebral ischemia rat model. AB - BACKGROUND: No data is available for brain low mechanical index (low-MI) contrast enhanced ultrasound (CEUS). This study aimed to assess low-MI CEUS for cerebral ischemia in rats. METHODS: Twenty adult Wistar rats were divided to the brain ischemia (N.=12) and sham (N.=8) groups. A Logiq E9 (GE; ML6-15 probe) was used. Bolus injection of SonoVue (Bracco) at 3.6 mL/kg was performed. Cerebral perfusion was evaluated using time to peak (TTP) and area under the curve (AUC) of time-intensity curves (TIC). RESULTS: There was a decrease in peak systolic BFV of anterior cerebral and middle cerebral arteries in ischemic rats and a sharp increase in peak systolic BFV of basilar artery compared with sham rats (all P<0.01). Microbubble enhancement occurred in the Willis circle, followed by diencephalon and telencephalon. The AUC and TTP of the region of interest at telencephalon were significantly different between the two groups; in addition, the differences with the diencephalon were also significant (all P<0.01). There were differences in AUC and TTP between the telencephalon and diencephalon of the same group (all P<0.05). CONCLUSIONS: Real-time low-MI CEUS could sensitively demonstrate dynamic microbubble enhancement in brain tissues and allows semi quantitative assessment of cerebral perfusion after ischemic brain injury using TIC. PMID- 28598142 TI - Arthroscopic eminoplasty: a new choice of treatment for TMJ internal derangement. AB - BACKGROUND: Temporomandibular joint (TMJ) internal derangement is a common disabling disorder that is often underestimated by society. The main goal of our study was to show the clinic improvement experienced by patients that underwent arthroscopic eminoplasty as a treatment for TMJ in our center. METHODS: Nineteen patients (1 male, 18 females) agreed to participate voluntarily in our study. These patients presented signs and symptoms of TMJ internal derangement and pathological MRI images, and underwent arthroscopic eminoplasty in our center. A patient database was created to record Wilkes stages, type of surgical intervention, complications, and preoperative and postoperative pain and mouth opening. RESULTS: Our data showed that TMJ pain (measured 6 months before surgery) was higher (M=7.44, SD=1.44; t(18)=8.37, P<0.01) than the pain registered eighteen months after surgery (M=3.10, SD=2.40). Moreover, postoperative mouth opening (M=33.6 SD=7.92) was greater than preoperative mouth opening. CONCLUSIONS: The results indicate that this technique is effective in reducing pain and increasing mouth opening with minimal postoperative morbidity. Specifically, this technique minimizes the stress suffered by the joint disc at the narrowest points of joint space and increases articular stability. PMID- 28598143 TI - Composite Polymer Electrolytes with Li7La3Zr2O12 Garnet-Type Nanowires as Ceramic Fillers: Mechanism of Conductivity Enhancement and Role of Doping and Morphology. AB - Composite polymer solid electrolytes (CPEs) containing ceramic fillers embedded inside a polymer-salt matrix show great improvements in Li+ ionic conductivity compared to the polymer electrolyte alone. Lithium lanthanum zirconate (Li7La3Zr2O12, LLZO) with a garnet-type crystal structure is a promising solid Li+ conductor. We show that by incorporating only 5 wt % of the ceramic filler comprising undoped, cubic-phase LLZO nanowires prepared by electrospinning, the room temperature ionic conductivity of a polyacrylonitrile-LiClO4-based composite is increased 3 orders of magnitude to 1.31 * 10-4 S/cm. Al-doped and Ta-doped LLZO nanowires are also synthesized and utilized as fillers, but the conductivity enhancement is similar as for the undoped LLZO nanowires. Solid-state nuclear magnetic resonance (NMR) studies show that LLZO NWs partially modify the PAN polymer matrix and create preferential pathways for Li+ conduction through the modified polymer regions. CPEs with LLZO nanoparticles and Al2O3 nanowire fillers are also studied to elucidate the role of filler type (active vs passive), LLZO composition (undoped vs doped), and morphology (nanowire vs nanoparticle) on the CPE conductivity. It is demonstrated that both intrinsic Li+ conductivity and nanowire morphology are needed for optimal performance when using 5 wt % of the ceramic filler in the CPE. PMID- 28598144 TI - Use of Mass Spectrometric Vapor Analysis To Improve Canine Explosive Detection Efficiency. AB - Canines remain the gold standard for explosives detection in many situations, and there is an ongoing desire for them to perform at the highest level. This goal requires canine training to be approached similarly to scientific sensor design. Developing a canine training regimen is made challenging by a lack of understanding of the canine's odor environment, which is dynamic and typically contains multiple odorants. Existing methodology assumes that the handler's intention is an adequate surrogate for actual knowledge of the odors cuing the canine, but canines are easily exposed to unintentional explosive odors through training material cross-contamination. A sensitive, real-time (~1 s) vapor analysis mass spectrometer was developed to provide tools, techniques, and knowledge to better understand, train, and utilize canines. The instrument has a detection library of nine explosives and explosive-related materials consisting of 2,4-dinitrotoluene (2,4-DNT), 2,6-dinitrotoluene (2,6-DNT), 2,4,6 trinitrotoluene (TNT), nitroglycerin (NG), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), pentaerythritol tetranitrate (PETN), triacetone triperoxide (TATP), hexamethylene triperoxide diamine (HMTD), and cyclohexanone, with detection limits in the parts-per-trillion to parts-per-quadrillion range by volume. The instrument can illustrate aspects of vapor plume dynamics, such as detecting plume filaments at a distance. The instrument was deployed to support canine training in the field, detecting cross-contamination among training materials, and developing an evaluation method based on the odor environment. Support for training material production and handling was provided by studying the dynamic headspace of a nonexplosive HMTD training aid that is in development. These results supported existing canine training and identified certain areas that may be improved. PMID- 28598145 TI - Redox Induced Configurational Isomerization of Bisphosphine-Tricarbonyliron(I) Complexes and the Difference a Ferrocene Makes. AB - The tricarbonyliron (TCFe) complexes Fe(CO)3(dppf) and Fe(CO)3(dppp), where dppf = 1,1'-bis(diphenylphosphino)ferrocene and dppp = 1,3 bis(diphenylphosphino)propane, exhibit redox activity that induces configurational isomerization. The presence of the ferrocenyl (Fc) group stabilizes higher oxidized forms of TCFe. Using spectroelectrochemistry (IR, UV vis, Mossbauer, and EPR) and computational analysis, we can show that the Fc in the backbone of the dppf ligand tends to form a weak dative bond to the electrophilic TCFeI and TCFeII species. The open shell TCFeI intermediate was stabilized by the distribution of spin between the two Fe centers (Fc and TCFe), whereas lacking the Fc moiety resulted in highly reactive TCFeI species. The [Fe(CO)3(dppf)]+ cation adopts two possible configurations, square-pyramidal (without an Fe-Fe interaction) and trigonal-bipyramidal (containing an Fe-Fe interaction). The two configurations are in equilibrium with the trigonal bipyramidal configuration being enthalpically favored (DeltaH = -7 kJ mol-1). There is an entropic penalty (DeltaS = -20 J mol-1) due to tilting of the Cp (cyclopentadienide) rings of the dppf moieties by ~8 degrees . Additionally, the terminal iron hydride [FeH(CO)3(dppf)]BF4 was formed by protonation with a strong acid (HBF4.Et2O). PMID- 28598146 TI - Uranyl Carbonate Complexes in Aqueous Solution and Their Ligand NMR Chemical Shifts and 17O Quadrupolar Relaxation Studied by ab Initio Molecular Dynamics. AB - Dynamic structural effects, NMR ligand chemical shifts, and 17O NMR quadrupolar relaxation rates are investigated in the series of complexes UO22+, UO2(CO3)34-, and (UO2)3(CO3)66-. Car-Parrinello molecular dynamics (CPMD) is used to simulate the dynamics of the complexes in water. NMR properties are computed on clusters extracted from the CPMD trajectories. In the UO22+ complex, coordination at the uranium center by water molecules causes a decrease of around 300 ppm for the uranyl 17O chemical shift. The final value of this chemical shift is within 40 ppm of the experimental range. The UO2(CO3)34- and (UO2)3(CO3)66- complexes show a solvent dependence of the terminal carbonate 17O and 13C chemical shifts that is less pronounced than that for the uranyl oxygen atom. Corrections to the chemical shift from hybrid functionals and spin-orbit coupling improve the accuracy of chemical shifts if the sensitivity of the uranyl chemical shift to the uranyl bond length (estimated at 140 ppm per 0.1 A from trajectory data) is taken into consideration. The experimentally reported trend in the two unique 13C chemical shifts is correctly reproduced for (UO2)3(CO3)66-. NMR relaxation rate data support large 17O peak widths, but remain below those noted in the experimental literature. Comparison of relaxation data for solvent-including versus solvent-free models suggest that carbonate ligand motion overshadows explicit solvent effects. PMID- 28598147 TI - X-ray Crystallographic Structure of a Giant Double-Walled Peptide Nanotube Formed by a Macrocyclic beta-Sheet Containing Abeta16-22. AB - This paper describes the supramolecular assembly of a macrocyclic beta-sheet containing residues 16-22 of the beta-amyloid peptide, Abeta. X-ray crystallography reveals that the macrocyclic beta-sheet assembles to form double walled nanotubes, with an inner diameter of 7 nm and outer diameter of 11 nm. The inner wall is composed of an extended network of hydrogen-bonded dimers. The outer wall is composed of a separate extended network of beta-barrel-like tetramers. These large peptide nanotubes pack into a hexagonal lattice that resembles a honeycomb. The complexity and size of the peptide nanotubes rivals some of the largest tubular biomolecular assemblies, such as GroEL and microtubules. These observations demonstrate that small amyloidogenic sequences can be used to build large nanostructures. PMID- 28598149 TI - Taking the Silver Bullet Colloidal Silver Particles for the Topical Treatment of Biofilm-Related Infections. AB - Biofilms are aggregates of bacteria residing in a self-assembled matrix, which protects these sessile cells against external stress, including antibiotic therapies. In light of emerging multidrug-resistant bacteria, alternative strategies to antibiotics are emerging. The present study evaluated the activity of colloidal silver nanoparticles (AgNPs) of different shapes against biofilms formed by Staphylococcus aureus (SA), methicillin-resistant SA (MRSA), and Pseudomonas aeruginosa (PA). Colloidal quasi-spherical, cubic, and star-shaped AgNPs were synthesized, and their cytotoxicity on macrophages (THP-1) and bronchial epithelial cells (Nuli-1) was analyzed by the lactate dehydrogenase assay. The antibiofilm activity was assessed in vitro by the resazurin assay and in an in vivo infection model in Caenorhabditis elegans. Cubic and star-shaped AgNPs induced cytotoxicity, while quasi-spherical AgNPs were not toxic. Quasi spherical AgNPs showed substantial antibiofilm activity in vitro with 96% (+/ 2%), 97% (+/-1%), and 98% (+/-1%) biofilm killing of SA, MRSA, and PA, respectively, while significantly reducing mortality of infected nematodes. The in vivo antibiofilm activity was linked to the accumulation of AgNPs in the intestinal tract of C. elegans as observed by 3D X-ray tomography. Quasi spherical AgNPs were physically stable in suspension for over 6 months with no observed loss in antibiofilm activity. While toxicity and stability limited the utilization of cubic and star-shaped AgNPs, quasi-spherical AgNPs could be rapidly synthesized, were stable and nontoxic, and showed substantial in vitro and in vivo activity against clinically relevant biofilms. Quasi-spherical AgNPs hold potential as pharmacotherapy, for example, as topical treatment for biofilm related infections. PMID- 28598150 TI - High-Yield Site-Specific Conjugation of Fibroblast Growth Factor 1 with Monomethylauristatin E via Cysteine Flanked by Basic Residues. AB - Site-specific conjugation is a leading trend in the development of protein conjugates, including antibody-drug conjugates (ADCs), suitable for targeted cancer therapy. Here, we present a very efficient strategy for specific attachment of a cytotoxic drug to fibroblast growth factor 1 (FGF1), a natural ligand of FGF receptors (FGFRs), which are over-expressed in several types of lung, breast, and gastric cancers and are therefore an attractive molecular target. Recently, we showed that FGF1 fused to monomethylauristatin E (vcMMAE) was highly cytotoxic to cells presenting FGFRs on their surface and could be used as a targeting agent alternative to an antibody. Unfortunately, conjugation via maleimide chemistry to endogenous FGF1 cysteines or a cysteine introduced at the N-terminus proceeded with low yield and led to nonhomogeneous products. To improve the conjugation, we introduced a novel Lys-Cys-Lys motif at either FGF1 terminus, which increased cysteine reactivity and allowed us to obtain an FGF1 conjugate with a defined site of conjugation and a yield exceeding 95%. Using FGFR-expressing cancer lines, we confirmed specific cytotoxity of the obtained C terminal FGF1-vcMMAE conjugate and its selective endocytososis as compared with FGFR1-negative cells. This simple and powerful approach relying on the introduction of a short sequence containing cysteine and positively charged amino acids could be used universally to improve the efficiency of the site-specific chemical modification of other proteins. PMID- 28598148 TI - Effect of a K72A Mutation on the Structure, Stability, Dynamics, and Peroxidase Activity of Human Cytochrome c. AB - We test the hypothesis that Lys72 suppresses the intrinsic peroxidase activity of human cytochrome c, as observed previously for yeast iso-1-cytochrome c [McClelland, L. J., et al. (2014) Proc. Natl. Acad. Sci. U. S. A. 111, 6648 6653]. A 1.25 A X-ray structure of K72A human cytochrome c shows that the mutation minimally affects structure. Guanidine hydrochloride denaturation demonstrates that the K72A mutation increases global stability by 0.5 kcal/mol. The K72A mutation also increases the apparent pKa of the alkaline transition, a measure of the stability of the heme crevice, by 0.5 unit. Consistent with the increase in the apparent pKa, the rate of formation of the dominant alkaline conformer decreases, and this conformer is no longer stabilized by proline isomerization. Peroxidase activity measurements show that the K72A mutation increases kcat by 1.6-4-fold at pH 7-10, an effect larger than that seen for the yeast protein. X-ray structures of wild type and K72A human cytochrome c indicate that direct interactions of Lys72 with the far side of Omega-loop D, which are seen in X-ray structures of horse and yeast cytochrome c and could suppress peroxidase activity, are lacking. Instead, we propose that the stronger effect of the K72A mutation on the peroxidase activity of human versus yeast cytochrome c results from relief of steric interactions between the side chains at positions 72 and 81 (Ile in human vs Ala in yeast), which suppress the dynamics of Omega loop D necessary for the intrinsic peroxidase activity of cytochrome c. PMID- 28598152 TI - Continuous-Ink, Multiplexed Pen-Plotter Approach for Low-Cost, High-Throughput Fabrication of Paper-Based Microfluidics. AB - There is an unmet need for high-throughput fabrication techniques for paper-based microanalytical devices, especially in limited resource areas. Fabrication of these devices requires precise and repeatable deposition of hydrophobic materials in a defined pattern to delineate the hydrophilic reaction zones. In this study, we demonstrated a cost- and time-effective method for high-throughput, easily accessible fabrication of paper-based microfluidics using a desktop pen plotter integrated with a custom-designed multipen holder. This approach enabled simultaneous printing with multiple printing heads and, thus, multiplexed fabrication. Moreover, we proposed an ink supply system connected to commercial technical pens to allow continuous flow of the ink, thereby increasing the printing capacity of the system. We tested the use of either hot- or cold laminating layers to improve (i) the durability, stability, and mechanical strength of the paper-based devices and (ii) the seal on the back face of the chromatography paper to prevent wetting of the sample beyond the hydrophilic testing region. To demonstrate a potential application of the paper-based microfluidic devices fabricated by the proposed method, colorimetric urine assays were implemented and tested: nitrite, urobilinogen, protein, blood, and pH. PMID- 28598153 TI - Molecular Precursors for ZnO Nanoparticles: Field-Assisted Synthesis, Electrophoretic Deposition, and Field-Effect Transistor Device Performance. AB - Zinc complexes with multidentate Schiff base ligands are suitable precursors for ZnO in microwave-assisted transformation reactions. [Bis(acetylacetonato)ethylenediimine]zinc(II) and [bis(methylacetoacetato)ethylenediimine]zinc(II) have been synthesized with high purity and good yield from the direct reaction of the respective diimine ligand with diethylzinc in tetrahydrofuran. The thermal decay is studied by thermogravimetry coupled with online infrared spectroscopy. The ceramization reaction in ethoxyethanol yields stable dispersions of spherical ZnO nanoparticles with very small particle sizes (around 5-6 nm), which can be employed for coating and thin-film deposition processes. Field-effect transistors (FETs) composed of thin films fabricated from these semiconducting ZnO particles possess charge-carrier mobilities of 6.0 * 10-3 and 5.4 * 10-2 cm2/(V s) after processing at 350 and 450 degrees C, respectively. Electrophoretic deposition affords dense film coatings composed of these ZnO nanoparticles with thicknesses of 30-90 nm on ITO (indium tin oxide) glass-electrodes. The positive zeta potentials of the ZnO nanoparticles in these dispersions are in agreement with the electrocoating process at the cathode. PMID- 28598151 TI - Active Targeting of the Nucleus Using Nonpeptidic Boronate Tags. AB - Active intracellular transport is a central mechanism in cell biology, directed by a limited set of naturally occurring signaling peptides. Here, we report the first nonpeptide moiety that recruits intracellular transport machinery for nuclear targeting. Proteins synthetically modified with a simple aromatic boronate motif are actively trafficked to the nucleus via the importin alpha/beta pathway. Significantly, proteins too large to passively diffuse through nuclear pores were readily imported into the nucleus through this boronate-mediated pathway. The use of this simple motif to provide active intracellular targeting provides a promising strategy for directing subcellular localization for therapeutic and fundamental applications. PMID- 28598155 TI - Dissolution Trapping of Carbon Dioxide in Heterogeneous Aquifers. AB - The geologic architecture in sedimentary reservoirs affects the behavior of density-driven flow and the dispersion of CO2-rich brine. The spatial organization and connectivity of facies types play an important role. Low permeability facies may suppress fingering and reduce vertical spreading, but may also increase transverse mixing. This is more pronounced when geologic structures create preferential flow pathways through connected facies types. We perform high resolution simulations of three-dimensional (3D) heterogeneous formations whose connectivity cannot be represented in two-dimensional models consistent with percolation theory. This work focuses on the importance of 3D facies-based heterogeneity and connectivity on advection-diffusion transport of dissolved CO2. Because the dissolution of CO2 and the subsequent density increase of brine are the driving force for gravitational instabilities, we model the phase behavior with the accurate cubic-plus-association equation-of-state, which accounts for the self-association of polar water molecules and the cross-association between CO2 and water. Our results elucidate how the spatial organization of facies affects the dynamics of CO2 convective mixing. Scaling relations for the evolution of a global dispersion-width provide insights that can be universally applied. The results suggest that the long-term evolution and scaling of dispersion are surprisingly similar for homogeneous and (binary and multiscale) heterogeneous porous media. PMID- 28598154 TI - 3D-Printable Bioactivated Nanocellulose-Alginate Hydrogels. AB - We describe herein a nanocellulose-alginate hydrogel suitable for 3D printing. The composition of the hydrogel was optimized based on material characterization methods and 3D printing experiments, and its behavior during the printing process was studied using computational fluid dynamics simulations. The hydrogel was biofunctionalized by the covalent coupling of an enhanced avidin protein to the cellulose nanofibrils. Ionic cross-linking of the hydrogel using calcium ions improved the performance of the material. The resulting hydrogel is suitable for 3D printing, its mechanical properties indicate good tissue compatibility, and the hydrogel absorbs water in moist conditions, suggesting potential in applications such as wound dressings. The biofunctionalization potential was shown by attaching a biotinylated fluorescent protein and a biotinylated fluorescent small molecule via avidin and monitoring the material using confocal microscopy. The 3D-printable bioactivated nanocellulose-alginate hydrogel offers a platform for the development of biomedical devices, wearable sensors, and drug releasing materials. PMID- 28598156 TI - Ultrafast Self-Assembly of Sub-10 nm Block Copolymer Nanostructures by Solvent Free High-Temperature Laser Annealing. AB - Laser spike annealing was applied to PS-b-PDMS diblock copolymers to induce short time (millisecond time scale), high-temperature (300 to 700 degrees C) microphase segregation and directed self-assembly of sub-10 nm features. Conditions were identified that enabled uniform microphase separation in the time frame of tens of milliseconds. Microphase ordering improved with increased temperature and annealing time, whereas phase separation contrast was lost for very short annealing times at high temperature. PMMA brush underlayers aided ordering under otherwise identical laser annealing conditions. Good long-range order for sub-10 nm cylinder morphology was achieved using graphoepitaxy coupled with a 20 ms dwell laser spike anneal above 440 degrees C. PMID- 28598157 TI - Pseudoknot Formation Seeds the Twister Ribozyme Cleavage Reaction Coordinate. AB - The twister RNA is a recently discovered nucleolytic ribozyme that is present in both bacteria and eukarya. While its biological role remains unclear, crystal structure analyses and biochemical approaches have revealed critical features of its catalytic mechanism. Here, we set out to explore dynamic aspects of twister RNA folding along the cleavage reaction coordinate. To do so, we have employed both bulk and single-molecule fluorescence resonance energy transfer (FRET) methods to investigate a set of twister RNAs with labels strategically positioned at communicating segments. The data reveal that folding of the central pseudoknot (T1), the most crucial structural determinant to promote cleavage, exhibits reversible opening and closing dynamics at physiological Mg2+ concentration. Uncoupled folding, in which T1 formation precedes structuring for closing of stem P1, was confirmed using pre-steady-state three-color smFRET experiments initiated by Mg2+ injection. This finding suggests that the folding path of twister RNA requires proper orientation of the substrate prior to T1 closure such that the U5 A6 cleavage site becomes embraced to achieve its cleavage competent conformation. We also find that the cleaved 3'-fragment retains its compacted pseudoknot fold, despite the absence of the phylogenetically conserved stem P1, rationalizing the poor turnover efficiency of the twister ribozyme. PMID- 28598159 TI - Palladium-Promoted Neutral 1,4-Brook Rearrangement/Intramolecular Allylic Cyclization Cascade Reaction: A Strategy for the Construction of Vinyl Cyclobutanols. AB - A cascade reaction to build vinyl cyclobutanol rings through activation of vinyl epoxides by palladium, followed by 1,4-Brook rearrangement and intramolecular cyclization with a palladium complex of the resulting carbon anion, is described. Through this cascade reaction, several highly substituted cyclobutanol substrates were achieved in good yields with high stereoselectivities. PMID- 28598158 TI - Selective and Scalable Perfluoroarylation of Nitroalkanes. AB - Functionalized per- and polyfluoroarenes are important building blocks, with many industrially and medicinally important molecules containing them. Nucleophilic aromatic substitution can be employed as a quick and straightforward way to synthesize these building blocks. While many methods to derivatize fluoroarenes exist that use heteroatom centered nucleophiles, there are fewer methods that use carbon centered nucleophiles, and of those many are poorly defined. This work presents the SNAr reaction of nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition was probed using both DFT calculations and experimentally via halogen exchange. PMID- 28598160 TI - A Double Decarboxylation in Superfolder Green Fluorescent Protein Leads to High Contrast Photoactivation. AB - A photoactivatable variant of superfolder green fluorescent protein (GFP) was created by replacing the threonine at position 203 with aspartic acid. Photoactivation by exposure of this mutant to UV light resulted in conversion of the fluorophore from the neutral to the negatively charged form, accompanied by a ~95-fold increase in fluorescence under 488 nm excitation. Mass spectrometry before and after exposure to UV light revealed a change in mass of 88 Da, attributed to the double decarboxylation of Glu 222 and Asp 203. Kinetics studies and nonlinear power-dependence of the initial rate of photoconversion indicated that the double decarboxylation occurred via a multiphoton absorption process at 254 nm. In addition to providing a photoactivatable GFP with robust folding properties, a detailed mechanistic understanding of this double decarboxylation in GFP will lead to a better understanding of charge transfer in fluorescent proteins. PMID- 28598161 TI - Ruthenium-Catalyzed Synthesis of Fused Tricyclic 1H-2,3-Dihydropyrimido[1,2 a]quinolines in One Step. AB - A novel ruthenium-catalyzed intramolecular cyclization of a nitrile and an azetidine was developed to achieve a one-step synthesis of the fused tricyclic 1H 2,3-dihydropyrimido[1,2-a]quinoline, which is the core skeleton for more than 100 natural pyoverdines and is also responsible for their fluorescence. PMID- 28598162 TI - Linear Response Theory for Water Transport Through Dry Nanopores. AB - Porous two-dimensional crystals like graphene have the potential to revolutionize reverse-osmosis membrane technology. The permeability is a common figure of merit that describes the ease with which water flows through a membrane. For two dimensional crystals, the permeability can be orders of magnitude higher than it is in conventional reverse-osmosis membranes. We apply our Gaussian Dynamics nonequilibrium molecular dynamics simulation method to very hydrophobic two dimensional membranes and find that the current-pressure drop relationship becomes nonlinear. In this regime, the conventional permeability is an inadequate descriptor of the passage process, and the transport mechanism becomes a two-step one. The backing pressure first causes the pore to wet, and after it reaches a threshold pressure, water transport takes place from the wet state. We recover a simple description of the transport process by applying linear response theory with respect to the wet reference state rather than the dry one. A macroscopic thermodynamic argument supports our mechanistic description and predicts the wetting threshold pressure as a function of the contact angle. PMID- 28598163 TI - Structural Color Patterns on Paper Fabricated by Inkjet Printer and Their Application in Anticounterfeiting. AB - Inkjet-printed structural color patterns have attracted great attention in recent years because of their broadly promising applications. However, the patterns are usually fabricated on pretreated plastic substrates. Herein a convenient inkjet printing method was developed to fabricate large-scale computer-designed structural color patterns on photo paper without any treatment using inks containing monodisperse CdS spheres. By this strategy, not only were the single color and multicolor structural color patterns on paper successfully obtained, but also invisible photonic anticounterfeiting was achieved without any external stimuli. The key point of this anticounterfeiting technique is printing patterns and the background with inks containing uniformed CdS spheres with different diameters but similar intrinsic colors, so that the invisible patterns can be observed clearly by simply changing the viewing angle. The invisible and visible can be realized without the change of intrinsic structure, and the patterns are all solids. The patterns will have long lifetime and good durability, which is beneficial for their practical usage. PMID- 28598164 TI - Asymmetric Syntheses of Amaryllidaceae Alkaloids (-)-Crinane and (+)-4a Dehydroxycrinamabine. AB - A palladium-catalyzed asymmetric allyl-allyl cross-coupling reaction to construct the chiral quaternary carbon center of crinane alkaloids has been developed. On the basis of an efficient approach, the enantioselective synthesis of (-)-crinane (1) is presented, and the first asymmetric total synthesis of (+)-4a dehydroxycrinamabine (2) was achieved by subsequent oxidation, 1,4-conjugate addition, RCM reaction, reductive amination, and Pictet-Spengler reaction. The method provided an alternative strategy for the syntheses of crinane alkaloids and other Amaryllidaceae natural products. PMID- 28598165 TI - Phosphine-Catalyzed Domino beta/gamma-Additions of Benzofuranones with Allenoates: A Method for Unsymmetrical 3,3-Disubstituted Benzofuranones. AB - A phosphine-catalyzed domino process of benzofuranones with allenoates has been developed which furnishes highly functionalized unsymmetrical 3,3-disubstituted benzofuranones in synthetically useful yields. The mechanism for the transformation is a tandem beta-umpolung/gamma-umpolung process. PMID- 28598166 TI - Resolving the Iron Phthalocyanine Redox Transitions for ORR Catalysis in Aqueous Media. AB - Metal macrocycles are among the most important catalytic systems in electrocatalysis and biocatalysis owing to their rich redox chemistry. Precise understanding of the redox behavior of metal macrocycles in operando is essential for fundamental studies and practical applications of this catalytic system. Here we present electrochemical data for the representative iron phthalocyanine (FePc) in both aqueous and nonaqueous media coupled with in situ Raman and X-ray absorption analyses to challenge the traditional notion of the redox transition of FePc at the low potential end in aqueous media by showing that it arises from the redox transition of the ring. Our data unequivocally demonstrate that the electron is shuttled to the Pc ring via the Fe(II)/Fe(I) redox center. The Fe(II)/Fe(I) redox transition of FePc in aqueous media is indiscernible by normal spectroscopic methods owing to the lack of a suitable axial ligand to stabilize the Fe(I) state. PMID- 28598167 TI - Closer versus Long Range Interaction Effects on the Non-Arrhenius Behavior of Quasi-Resonant O2 + N2 Collisions. AB - We report in this paper an investigation on energy transfer processes from vibration to vibration and/or translation in thermal and subthermal regimes for the O2 + N2 system performed using quantum-classical calculations on different empirical, semiempirical, and ab initio potential energy surfaces. In particular, the paper focuses on the rationalization of the non-Arrhenius behavior (inversion of the temperature dependence) of the quasi-resonant vibration-to-vibration energy transfer transition rate coefficients at threshold. To better understand the microscopic nature of the involved processes, we pushed the calculations to the detail of the related cross sections and analyzed the impact of the medium and long-range components of the interaction on them. Furthermore, the variation with temperature of the dependence of the quasi-resonant rate coefficient on the vibrational energy gap between initial and final vibrational states and the effectiveness of quantum-classical calculations to overcome the limitations of the purely classical treatments were also investigated. These treatments, handled in an open molecular science fashion by chaining data and competencies of the various laboratories using a grid empowered molecular simulator, have allowed a rationalization of the dependence of the computed rate coefficients in terms of the distortion of the O2-N2 configuration during the diatom-diatom collisions. A way of relating such distortions to a smooth and continuous progress variable, allowing a proper evolution from both long to closer range formulation of the interaction and from its entrance to exit channel (through the strong interaction region) relaxed graphical representations, is also discussed in the paper. PMID- 28598169 TI - Reunderstanding the Fluorescent Behavior of Four-Coordinate Monoboron Complexes Containing Monoanionic Bidentate Ligands. AB - We demonstrated for the first time that, at temperatures below the melting point of a given polar solvent, the emission of some four-coordinate monoboron complexes containing monoanionic bidentate (NO) ligands shifted to lower wavelengths, but no such shift was observed for studies conducted in nonpolar solvents. This means that the emission from a polar solvent appears at shorter wavelengths if compared with that from a nonpolar solvent when the measurement was performed at low temperatures, a phenomenon totally different from that observed for conventional solvatochromic fluorophores. The finding was rationalized by considering the temperature-dependent conformational relaxation of the tetrahedron monoboron complexes from their local excited (LE) state to their relaxed excited (RE) state. Further studies revealed that variating the structure of the chelating ligands could result in remarkable changes in the fluorescent colors of the monoboron complexes. However, changing the structure of other two monodentate ligands showed little effect upon the fluorescence property of the compounds. Therefore, it is anticipated that the monoboron complexes may be taken as a platform to construct a variety of functional molecular systems via alternating the structure of the chelating ligand and that of the monodentate ligand. As an example, naphthalene was introduced as a monodentate ligand, and independent emissions from naphthalene unit and the other part of the monoboron complex as well as intramolecular energy transfer between them were observed. It is believed that the present work provides a new insight into the monoboron complexes, laying the foundation for them to be explored for developing novel molecular systems. PMID- 28598168 TI - Diastereoselective Au-Catalyzed Allene Cycloisomerizations to Highly Substituted Cyclopentenes. AB - Site- and regiocontrolled Au-catalyzed allene carbocyclizations furnish highly substituted cyclopentenes in >1:1 dr. Significant substitution on the substrate is tolerated, with potential to install five contiguous stereocenters after alkene functionalization. Major challenges include identifying a Au/Cu catalyst that controls both the relative rates of allene epimerization/cyclization and the facial selectivity in addition of a metal enolate to the allene. Experiments to achieve stereodivergent cyclizations and transform key cyclopentenes into useful synthetic building blocks are described. PMID- 28598171 TI - Exotic Physics and Chemistry of Two-Dimensional Phosphorus: Phosphorene. AB - Phosphorene, the monolayer form of black phosphorus, is the most recent addition to graphene-like van der Waals two-dimensional (2D) systems. Due to its several interesting properties, namely its tunable direct band gap, high carrier mobility, and unique in-plane anisotropy, it has emerged as a promising candidate for electronic and optoelectronic devices. Phosphorene (Pn) reveals a much richer phase diagram than graphene, and it comprises the two forms namely the stapler clip like (black Pn, alpha form) and chairlike (blue Pn, beta form) structures. Regardless of its favorable properties, black Pn suffers from instability in oxygen and water, which limits its successful applications in electronic devices. In this Perspective, the cause of structural diversity of Pn, which leads to different properties of both black and blue Pn, is discussed. We provide possible solutions for protecting phosphorene from chemical degradation and its applications in the field of energy storage namely for Li and Na ion batteries. PMID- 28598170 TI - Synthesis of (1 -> 2)-S-Linked Saccharides and S-Linked Glycoconjugates via a Palladium-G3-XantPhos Precatalyst Catalysis. AB - Buchwald-Hartwig-Migita cross-coupling of 1-thiosugars with 2-iodoglycals has been accomplished under mild and operationally simple reaction conditions through the use of Pd-G3 XantPhos palladacycle precatalyst. This new methodology has been successfully applied to a variety of alpha- or beta-mono-, di-, and polythiosugar derivatives to synthesize efficiently a series of (1 -> 2)-S-linked thiosaccharides and S-linked glycoconjugates, which are difficult to synthesize by classical methods. PMID- 28598172 TI - Feasibility of Photosensitized Reactions with Secondary Organic Aerosol Particles in the Presence of Volatile Organic Compounds. AB - The ability of a complex mixture of organic compounds found in secondary organic aerosol (SOA) to act as a photosensitizer in the oxidation of volatile organic compounds (VOCs) was investigated. Different types of SOAs were produced in a smog chamber by oxidation of various biogenic and anthropogenic VOCs. The SOA particles were collected from the chamber onto an inert substrate, and the resulting material was exposed to 365 nm radiation in an air flow containing ~200 ppbv of limonene vapor. The mixing ratio of limonene and other VOCs in the flow was observed with a proton transfer reaction time-of-flight mass spectrometer (PTR-ToF-MS). The photosensitized uptake of limonene was observed for several SOA materials, with a lower limit for the reactive uptake coefficient on the scale of ~10-5. The lower limit for the uptake coefficient under conditions of Los Angeles, California on the summer solstice at noon was estimated to be on the order of ~10-6. Photoproduction of oxygenated VOCs (OVOCs) resulting from photodegradation of the SOA material also occurred in parallel with the photosensitized uptake of limonene. The estimated photosensitized limonene uptake rates by atmospheric SOA particles and vegetation surfaces appear to be too small to compete with the atmospheric oxidation of limonene by the hydroxyl radical or ozone. However, these processes could play a role in the leaf boundary layer where concentrations of oxidants are depleted and concentrations of VOCs are enhanced relative to the free atmosphere. PMID- 28598173 TI - Nanocrystal Width Controls Fibrinogen Orientation and Assembly Kinetics on Poly(butene-1) Surfaces. AB - From the view of biomedical relevance, it is known that a specific arrangement of surface-immobilized human plasma fibrinogen (HPF) molecules is required to retain their biological functionality. Here, we demonstrate a topographical effect of chemically identical isotactic poly(butene-1) (iPB-1) semicrystalline nanostructures on the adsorption behavior, i.e., conformation change and orientation of HPF molecules. Using the distinct crystallization of iPB-1 under different shear conditions, polymer thin films consisting of needle-like crystals (NLCs) or shish-kebab crystals (SKCs) having lateral dimension, i.e., width, smaller than or comparable to the HPF major axis, respectively, were fabricated. The protein adsorption kinetic studies by quartz crystal microbalance with dissipation (QCM-D) revealed surface-dependent packing density and assembly configuration of HPF. High-resolution imaging disclosed a "side-on" protein adsorption and anisotropic network formation on the NLCs. With a 2-fold orientation analysis performed at both "single" protein and multiprotein levels, we quantitatively proved the preferential alignment of adsorbed HPF molecules with respect to the axial direction of the NLCs. Remarkably, the iPB-1 surface with SKCs perturbed the "end-to-end" protein-protein interactions and thus hindered the network formation. The distinguished adsorption behavior of HPF molecules on iPB-1 surfaces is explained by the physical effect of crystal width, which is additionally supported by the synergistic effect of crystal curvature and aspect ratio. Our studies provide fundamental insight into purely topography controlled self-assembly of HPF molecules, which might be further exploited in creating topographically defined implant surfaces for preventing protein aggregation related disorders. PMID- 28598174 TI - General Approach to Five-Membered Nitrogen Heteroaryl C-Glycosides Using a Palladium/Copper Cocatalyzed C-H Functionalization Strategy. AB - A general approach to the synthesis of diverse heteroaryl-C-Delta1,2-glycosides has been developed by employing the Pd(OAc)2/CuI cocatalyzed direct cross coupling of five-membered nitrogen heterocycles with 1-iodoglycals in a C-H activation manner. Using this method, 27 examples of heteroaryl-C-Delta1,2 glycosides, containing indoles, thiazoles, benzothiazoles, imidazoles, benzimidazoles, and benzoxazoles as aglycones were obtained in 43-99% yield. PMID- 28598175 TI - Naphthoquinones of Sinningia reitzii and Anti-inflammatory/Antinociceptive Activities of 8-Hydroxydehydrodunnione. AB - Chemical investigation of the tubers of Sinningia reitzii led to the isolation of five new naphthoquinones, 8-hydroxydehydrodunnione (1), 7-hydroxydehydrodunnione (2), 5-hydroxy-6,7-dimethoxy-alpha-dunnione (3), 5-hydroxy-6,7-dimethoxydunniol (4), and 8-hydroxy-7-methoxy-2-O-methylstreptocarpone (5). Three known naphthoquinones, 7-hydroxy-alpha-dunnione, 8-hydroxydunnione, and 6,8-dihydroxy-7 methoxy-2-O-methyldunniol, were also identified. When tested for anti inflammatory activity in a mouse model, compound 1 (50-500 pg/paw) reduced the edema induced by carrageenan in a dose-dependent fashion. The highest dose showed a similar inhibition to that observed for the positive control dexamethasone. At lower doses (5-10 pg/paw), 1 also dose dependently reduced the mechanical hyperalgesia induced by carrageenan. Compound 1 (15 pg/paw) abolished the mechanical hyperalgesia induced by prostaglandin E2 and dopamine, but not that induced by dibutyryl cyclic AMP. Dipyrone (320 MUg/paw) completely abolished the hyperalgesia induced by these algogens. Additionally, compound 1 did not alter heat-induced nociception. These results suggest that this new naphthoquinone exhibits important anti-inflammatory and antinociceptive activities, which is dissimilar to that of most known analgesics. PMID- 28598177 TI - Finally in Italy the School of Specialisation in Paediatric Dentistry! AB - After over two decades of discussions, promises and indecisions, the year 2016 marked the birth of the School of Specialisation in Paediatric Dentistry, which is now a reality. The importance of dental post-graduate specialisation schools has been debated since the Degree Course in Dentistry was established. Previously, in Italy only two dental branches - Oral Surgery and Orthodontics - had obtained the recognition that a School of Specialisation entails. Today, with specific training and the newly- established hyper-specialisation in Paediatric Dentistry, the future of the profession is brighter than ever. This will allow dental professionals to provide the best cure to our young patients but it especially marks and recognises the importance of prevention in general. Having established a Specialty School in Paediatric Dentistry is also important to keep the pace with the other European countries where this postgraduate course has been already offered for many years. In my opinion, training professionals with a solid specialisation based both on cultural insights and hands-on clinical activities translates into the possibility of making true prevention. The ultimate goal of paediatric dentists, as well as paediatricians, is certainly to treat young patients but also and above all to accompany them toward an adulthood possibly free of pathologies. With an eye to a future where Paediatric Dentistry will be at the core of dental and orthodontic prevention, I wish great success to all the many specialisation schools established within the Italian Universities. PMID- 28598176 TI - Reaction Kinetics of Phenolic Antioxidants toward Photoinduced Pyranine Free Radicals in Biological Models. AB - 8-Hydroxy-1,3,6-pyrenetrisulfonic acid (pyranine, PyOH) free radicals were induced by laser excitation at visible wavelengths (470 nm). The photochemical process involves photoelectron ejection from PyO- to produce PyO* and PyO*- with maxima absorption at 450 and 510 nm, respectively. The kinetic rate constants for phenolic antioxidants with PyO*, determined by nanosecond time-resolved spectroscopy, were largely reliant on the ionic strength depending on the antioxidant phenol/phenolate dissociation constant. Further, the apparent rate constant measured in the presence of Triton X100 micelles was influenced by the antioxidant partition between the micelle and the dispersant aqueous media but limited by its exit rates from the micelle. Similarly, the rate reaction between ascorbic acid and PyO* was markedly affected by the presence of human serum albumin responding to the dynamic of the ascorbic acid binding to the protein. PMID- 28598178 TI - Multidisciplinary approach to the treatment of double bilateral upper permanent incisors in a young boy. AB - BACKGROUND: A double tooth is a rare developmental anomaly referring to the fusion of two adjacent tooth buds or the gemination of a single bud. CASE REPORT: This case report describes the multidisciplinary approach to an 11-year-old patient with two double upper permanent incisors. The clinical intraoral examination showed a mixed dentition with bilateral double maxillary central incisors, molar Class I malocclusion and palatal ectopy of two lateral upper incisors. Computed tomography of the upper dental arch revealed the presence of double central incisors with two distinct roots. The clinical choice consisted of an innovative treatment including surgical, endodontic, orthodontic and restorative treatments. This management protocol produced good aesthetic, healthy and functional results that were stable also two years post-treatment. PMID- 28598179 TI - In vivo and in vitro comparison of ICDAS II, DIAGNOdent pen, CarieScan PRO and SoproLife camera for occlusal caries detection in primary molar teeth. AB - AIM: This research was aimed to investigate the in vivo and in vitro performance of traditional and novel methods in the detection of occlusal caries in primary teeth. MATERIALS AND METHODS: One hundred twenty primary molar teeth were assessed by two examiners both in vivo using ICDAS II, radiographic examination, DIAGNOdent pen, CarieScan PRO and SoproLife camera and in vitro using the mentioned diagnostic methods except radiographic examination. In addition, in vitro examinations were repeated 2 weeks later. After sectioning and evaluation under stereomicroscope, the lesion depth was determined with Downer's histological criteria. Sensitivity, specificity, positive and negative predictive value, accuracy and area under the ROC curve were calculated at D1 and D3 thresholds. The intra- and inter-examiners' reproducibility were analysed using Cohen's kappa statistics and intraclass correlation coefficient. RESULTS: Intra- and inter-examiner repeatability were high for all methods. While ICDAS and SoproLife camera showed the highest sensitivity value at D1 and D3 thresholds in vivo, radiographic examination showed the lowest sensitivity values. While ICDAS and SoproLife camera showed the highest sensitivity values at D3 threshold in vitro, CarieScan PRO showed the lowest sensitivity value. CONCLUSION: The ICDAS II method could be sufficient alone in diagnosis of occlusal caries of primary teeth. However, SoproLife camera may be useful in monitoring caries lesions. PMID- 28598180 TI - Evaluation of the Self-Adjusting File system (SAF) for the instrumentation of primary molar root canals: a micro-computed tomographic study. AB - AIM: The Self-Adjusting File (SAF) system has been recommended for use in permanent teeth since it offers more conservative and effective root-canal preparation when compared to traditional rotary systems. However, no study had evaluated the usage of SAF in primary teeth. The aim of this study was to evaluate and compare the use of SAF, K file (manual instrumentation) and Profile (traditional rotary instrumentation) systems for primary-tooth root-canal preparation in terms of instrumentation time and amounts of dentin removed using micro-computed tomography (μCT) technology. MATERIALS AND METHODS: Study Design: The study was conducted with 60 human primary mandibular second molar teeth divided into 3 groups according to instrumentation technique: Group I: SAF (n=20); Group II: K file (n=20); Group III; Profile (n=20). Teeth were embedded in acrylic blocks and scanned with a μCT scanner prior to instrumentation. All distal root canals were prepared up to size 30 for K file,.04/30 for Profile and 2 mm thickness, size 25 for SAF; instrumentation time was recorded for each tooth, and a second μCT scan was performed after instrumentation was complete. Amounts of dentin removed were measured using the three-dimensional images by calculating the difference in root-canal volume before and after preparation. Data was statistically analysed using the Kolmogorov-Smirnov and Kruskal-Wallis tests. RESULTS: Manual instrumentation (K file) resulted in significantly more dentin removal when compared to rotary instrumentation (Profile and SAF), while the SAF system generated significantly less dentin removal than both manual instrumentation (K file) and traditional rotary instrumentation (Profile) (p<.05). Instrumentation time was significantly greater with manual instrumentation when compared to rotary instrumentation (p<.05), whereas instrumentation time did not differ significantly between the Profile and SAF systems. CONCLUSION: Within the experimental conditions of the present study, the SAF seems as a useful system for root-canal instrumentation in primary molars because it removed less dentin than other systems, which is especially important for the relatively thin-walled canals of primary teeth, and because it involves less clinical time, which is particularly important in the treatment of paediatric patients. PMID- 28598181 TI - A new method for deep caries treatment in primary teeth using ozone: a retrospective study. AB - AIM: The aim of this study was to assess the effectiveness of a new protocol for deep caries treatment in deciduous teeth based on: 1) the incomplete removal of carious dentin tissue; 2) the use of new technology (ozone) for the disinfection of carious dentine; 3) the creation of a peripheral seal in healthy tissue for bonding procedures with rubber dam isolation. MATERIALS AND METHODS: From a personal database, authors selected 50 consecutive patients (28 males, 22 females; mean age 5.8 ± 1.7 years) in whom this new protocol was applied on posterior deciduous molars, for a total of 94 restorations. RESULTS: Regular follow- ups were performed at 3, 6 and 12 months by a second operator, who was asked to rate each restoration as success or failure. The success rate at 12 months was 93,62% (n. 88/94 restorations), similar to that reported in the literature for pulpotomy. CONCLUSION: The deciduous teeth considered for this study, if treated conventionally, would have probably been subjected to pulpotomy, because of the extension of the carious lesions. The proposed protocol, through the use of ozone, proved to be an excellent alternative, with the fundamental advantage of saving dental tissue and preventing the invasion of the pulp chamber. PMID- 28598182 TI - Masticatory parameters of children with and without clinically diagnosed caries in permanent dentition. AB - AIM: Mastication turns food into a bolus and prepares it for chemical digestion. Any condition affecting tooth structure and position may have an impact on mastication. The aim of this study is to compare masticatory performance (MP) and maximum bite force (MBF) between children with and without clinically visible caries in permanent first molars. MATERIALS AND METHODS: The study was conducted with 50 children in good general condition aged 12-14 years (25 girls, 25 boys) with no orthodontic/skeletal anomalies and no missing teeth due to dental trauma or extraction. Maximum bite force was measured bilaterally using strain gauge sensors. Masticatory performance was evaluated by silicone tablet comminution test. RESULTS: Masticatory performance was superior in caries-free children when compared to children with caries. Maximum bite force values in children with and without caries were not statistically different. CONCLUSIONS: Caries reduces masticatory performance. Therefore, treatment is crucial for masticatory efficiency. PMID- 28598183 TI - Dental fear/anxiety among children and adolescents. A systematic review. AB - AIM: The aim of this paper was to review the published scientific literature to quantify the prevalence and mean score of dental fear/anxiety (DFA) in children/adolescents and its variation according to several variables. MATERIALS AND METHODS: Cross- sectional and cohort studies published from 2000 to 2014, that measured DFA in children /adolescents (aged 0-19 years), in the general population, or visiting private or public dental services (general or pediatric) or attending school and kindergarten, were searched, with specific terms, in 3 electronic databases (Medline, Embase, Web Of Science). Primary data, collected with specific questionnaires of demonstrated reliability and/or validity, were extracted. RESULTS: After screening 743 abstracts and evaluating 164 full-text publications, 36 articles were selected. Dental fear/anxiety prevalence rates were 12.2%, 10.0%, 12.2%,11.0% and 20.0% for the CFSS-DS, DAS, MDAS, DFS, and DFSS-SF scores, respectively. In the studies that used MCDAS Dental fear/prevalence rates varied from 13.3% to 29.3%. In the studies that used CFSS DS ratings, the prevalence and the mean score of dental fear/anxiety was lower in Northern Europe than the remaining countries, the prevalence decreased with increasing age and the frequency was higher in females than males. CONCLUSIONS: Dental fear/anxiety is a common problem in children/adolescents worldwide, therefore, new strategies to overcome this relevant children/adolescent condition should be encouraged. PMID- 28598185 TI - Three-dimensional longitudinal changes of maxilla and mandible morphology during the predental period. AB - AIM: The purpose of this study was to longitudinally analyse the morphology of maxilla and mandible over time in infants using a three-dimensional (3D) surface scanner. MATERIALS AND METHODS: Seventeen Japanese full-term infants participated in the study. Dental plaster models were fabricated every 3 months from 1 month of age to 12 months. The plaster models were scanned using the 3D surface scanner to create 3D models. The arch width, arch length, arch angle, palatal depth and palatal area of the 3D models were analysed. RESULTS: The arch width and length of maxilla and mandible increased as the arch angle decreased. The arch width and length of the maxilla were greater than those of the mandible. The total alveolar ridge morphology increased in size in the occlusal view, with marked growth in the sagittal direction. The palatal depth remained virtually unchanged although the palatal area increased as a result of buccal growth of the alveolar ridge. CONCLUSIONS: The morphological growth pattern of the maxilla and mandible in infants can be evaluated quantitatively using 3D analysis. Knowledge about the healthy development of children and their orofacial growth patterns during the predental period can be applied as an index for diagnostic criteria. PMID- 28598184 TI - Surface electromyography before and after orthognathic surgery and condylectomy in active laterognathia: a case report. AB - BACKGROUND: Condylar hyperplasia is a rare bone disease characterised by excessive development of mandibular condyle, which can lead to the development of asymmetric facial deformity together with malocclusion, mandibular deviation, TMJ and masticatory musculoskeletal system dysfunction. There is not a treatment protocol universally accepted. In order to determine the correct management, treatment and intervention timing of these patients, morphological examinations should be coupled with functional assessments. CASE REPORT: In the present case report, morphological (bone scintigraphy; orthopantomography; posteroanterior and lateral cephalograms; 3D facial photographs) and functional (surface electromyography of masseter and temporalis muscles) quantitative data of a 20 year-old male patient affected by unilateral condylar hyperplasia are presented. The patient underwent a surgical treatment with high unilateral condylectomy associated to a maxillary Le Fort I osteotomy; as well as orthodontic treatment before and after surgery. Facial morphology and masticatory muscles activity were assessed before surgery and followed-up 6, 12 and 24 months after surgery. Twenty four months after surgery, all electromyographic values were normal, and soft tissue facial asymmetry was negligible at 3D assessment. CONCLUSION: Surface electromyography joins a set of clinical and morphological diagnostic tests that help the surgeon in planning the operation and managing the post-surgical patient. PMID- 28598186 TI - Dentoskeletal features in mixed dentition children with displaced maxillary canines in a southern Italian population. AB - AIM: To analyse the prevalence and the distribution of displaced, buccal/palatal maxillary canines, and the association with sagittal and vertical skeletal relationships in a southern Italian population. MATERIALS AND METHODS: Consecutive records of patients were examined. Inclusion criteria were: age 7-12 years, 1-2 cervical vertebral maturation (CVM) stage, initial dental casts, intraoral photographs, panoramic, lateral and periapical radiographs. Subjects with at least one canine in Lindauer II, III or IV sector and/or α angle >31° were included in displaced maxillary canine (DMC) group, whereas those with both canines in sector I and α angle ≤31° were used as control group (CTR). According to canine bulges and/or x-ray examinations, DMC were then divided in palatal and buccal displaced canines (PDC/BDC). Sagittal and vertical skeletal relationships were evaluated using ANB and SN/GoMe angles. Chi square tests were performed to compare the prevalence rates of skeletal features. RESULTS: The sample consisted of 123 children, 40 DMC and 83 CTR. The DMC group included 11 PDC and 29 BDC subjects. The M:F ratio was 1:3 in PDC and BDC, 1:1 in CTR group. The unilateral-to-bilateral ratio was 1:1 and 3:1 in PDC and BDC subjects. The most common sector combination regarding unilateral and bilateral displacements was "II" and "II,II". PDC occurred more in Class I and in hyperdivergents, whereas BDC in Class I or II and in normodivergents. CONCLUSIONS: DMC occurred more often in females than in males. BDC was more common than PDC and unilateral displacements occurred more frequently than bilateral ones. No significant correlation with skeletal features was observed. PMID- 28598187 TI - Dental intrinsic green pigmentation from primary to mixed dentition: clinical and histological findings. AB - AIM: The aim of this report is to present a case of a child with green pigmentation of the primary dentition caused by bilirubin elevation due to choleostasis during neonatal life, and the 5-year follow-up. CASE REPORT: The case presented initially with bands of green pigmentation of all primary teeth in a pattern that followed the time of their calcification, with those formed earlier being more severely affected. Fading of the green pigmentation was detected during the follow-up, while erupted lower permanent incisors were normal. Histological findings of an exfoliated primary incisor showed a green line at the enamel-dentine junction with the external surface of the dentine showing a band of variable width and irregularly arranged tubules. CONCLUSION: Bilirubin green pigmentation of primary teeth follows a chronological pattern and its intensity fades with time. Overlying enamel in affected areas may appear thinner. PMID- 28598188 TI - How serious is Molar Incisor Hypomineralisation (MIH) among 8- and 9-year-old children in Bosnia-Herzegovina? A clinical study. AB - AIM: To determine the prevalence of MIH in 8- and 9 year-old children in the city of Kljuc, Bosnia-Herzegovina, and to describe the distribution and severity of the affected teeth. MATERIALS AND METHODS: Study design: All 8- and 9-year-olds (n=104) living in Kljuc (born 2004/2005) were invited to participate, and 103 were examined by a calibrated clinician. Written, informed consent was obtained from all participants' relatives, as well as a questionnaire designed to assess potential risk indicators. Index teeth were all permanent first molars and incisors (12 teeth). Opacities (>1mm), post eruptive breakdown (PEB), atypical restorations and previous extractions caused by MIH were registered. RESULTS: The prevalence of MIH was 11.7% (n=12), significantly higher for girls than for boys (14.6% vs. 9.7%; p<0.05). The maxillary first molars and incisors were 1.8 (p<0.02) and 2.3 (p<0.05) times more frequently affected than the mandibular ones, respectively. Seven (30%) of the affected molars had opacities, 8 (35%) had PEB and 8 (35%) atypical restorations. No molars had been extracted due to MIH. The use of penicillin due to adenoid infections in the first 5 years was associated with a higher prevalence of MIH (41.7% vs. 19.6%). CONCLUSIONS: The prevalence of MIH (11.7%) supports the data previously published from Bosnia Herzegovina. Girls had higher prevalence of MIH than boys; first molars and incisors in the maxilla were almost twice as often affected as in the mandible. Use of penicillin in the first 5 years was associated with a higher prevalence. PMID- 28598189 TI - Translation and validation of the italian version of the Psychosocial Impact of Dental Aesthetics Questionnaire (pidaq) among adolescents. AB - AIM: The Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) is a valid tool aiming to evaluate the self-reported influence of dental aesthetics on quality of life. This questionnaire was developed in English for young adults, and later translated and validated with an Italian population. A new version of the questionnaire was recently introduced to be used in adolescents (11-17 years- old), but it had not been translated in Italian yet. Hence, the purpose of this study was to translate, cross-culturally adapt and validate the PIDAQ for adolescents, for its use among Italian subjects. METHODS: To develop the Italian PIDAQ, the original version was translated, back-translated, cross-culturally adapted and pre-tested. Afterwards, the Italian PIDAQ was administered to a convenience sample of 677 subjects, aged 11-17 years, together with two other written questionnaires: the Aesthetic Component of the Index of Orthodontic Treatment Need (IOTN-AC) and the Perception of Occlusion Scale (POS), which are instruments dedicated to assess the self-reported degree of malocclusion. A one way ANOVA was performed to assess the difference between groups, within each PIDAQ factor, according to POS and IOTN-AC scores. The correlation between PIDAQ factors and POS/IOTN-AC scores was measured as Spearman's rank correlation. The internal consistency was assessed as Cronbach's alpha coef?cient (α), and the test-retest reproducibility as Intra-Class Correlation Coef?cient (ICC). RESULTS: The one-way ANOVA showed that all the factors of the self- reported impact of dental aesthetics on quality of life significantly increased as the degree of malocclusion worsened (P<0.001). Furthermore, all the factors showed statistically significant correlations with both IOTN-AC and POS scores. The α ranged between 0.79 and 0.90, and the ICC ranged between 0.93-0.97. CONCLUSION: The Italian adolescent PIDAQ showed good reliability and validity. The psychometric properties of this version of the questionnaire support its use for the assessment of the psychosocial impact of dental aesthetics among Italian adolescents. PMID- 28598190 TI - Paediatric laser dentistry. Part 2: Hard tissue laser applications. AB - AIM: Erbium lasers can provide effective and minimally invasive caries removal in children. The bonding phase remains a critic step as well as the choice of material. Glass ionomers exhibits lower bonding properties in laser irradiated teeth compared to the conventional method or to composite and resin modified glass ionomer. Laser can also provide effective decontamination and coagulation effects in vital and non vital pulp therapy of primary teeth, improving and simplifying the cleaning and disinfecting steps. PMID- 28598191 TI - No time like the present - two hundred years of Parkinson's disease. PMID- 28598192 TI - Evaluation of a human neural stem cell culture method for prediction of the neurotoxicity of anti-epileptics. AB - Human neural stem cells have been proposed as an in vitro model to predict neurotoxicity. In this study, the potential of in vitro cultures of human-derived neurospheres to predict the effects of various anti-epileptic drugs (sodium valproate, phenytoin, carbamazepine and phenobarbitone) was evaluated. In general, these drugs had no significant effects on cell viability, total cellular protein, and neuronal process length at low doses, but at high doses these parameters were reduced significantly. Therapeutic doses of sodium valproate and phenytoin had a clear effect on neurosphere size and cell migration, with a significant reduction in both parameters when compared with the control group. The other drugs (carbamazepine and phenobarbitone) reduced neurosphere size and cell migration only at higher doses. The expression levels of glial fibrillary protein and tubulin III, which were used to identify astrocytes and neuronal cells, respectively, were reduced in a dose-dependent manner that became significant at high doses. The levels of glial fibrillary protein did not indicate any occurrence of reactive astrocytosis. PMID- 28598193 TI - Sample size estimation for pilot animal experiments by using a Markov Chain Monte Carlo approach. AB - The statistical determination of sample size is mandatory when planning animal experiments, but it is usually difficult to implement appropriately. The main reason is that prior information is hardly ever available, so the assumptions made cannot be verified reliably. This is especially true for pilot experiments. Statistical simulation might help in these situations. We used a Markov Chain Monte Carlo (MCMC) approach to verify the pragmatic assumptions made on different distribution parameters used for power and sample size calculations in animal experiments. Binomial and normal distributions, which are the most frequent distributions in practice, were simulated for categorical and continuous endpoints, respectively. The simulations showed that the common practice of using five or six animals per group for continuous endpoints is reasonable. Even in the case of small effect sizes, the statistical power would be sufficiently large (>= 80%). For categorical outcomes, group sizes should never be under eight animals, otherwise a sufficient statistical power cannot be guaranteed. This applies even in the case of large effects. The MCMC approach demonstrated to be a useful method for calculating sample size in animal studies that lack prior data. Of course, the simulation results particularly depend on the assumptions made with regard to the distributional properties and effects to be detected, but the same also holds in situations where prior data are available. MCMC is therefore a promising approach toward the more informed planning of pilot research experiments involving the use of animals. PMID- 28598194 TI - The use of neurocomputational models as alternatives to animal models in the development of electrical brain stimulation treatments. AB - Recent publications call for more animal models to be used and more experiments to be performed, in order to better understand the mechanisms of neurodegenerative disorders, to improve human health, and to develop new brain stimulation treatments. In response to these calls, some limitations of the current animal models are examined by using Deep Brain Stimulation (DBS) in Parkinson's disease as an illustrative example. Without focusing on the arguments for or against animal experimentation, or on the history of DBS, the present paper argues that given recent technological and theoretical advances, the time has come to consider bioinspired computational modelling as a valid alternative to animal models, in order to design the next generation of human brain stimulation treatments. However, before computational neuroscience is fully integrated in the translational process and used as a substitute for animal models, several obstacles need to be overcome. These obstacles are examined in the context of institutional, financial, technological and behavioural lock-in. Recommendations include encouraging agreement to change long-term habitual practices, explaining what alternative models can achieve, considering economic stakes, simplifying administrative and regulatory constraints, and carefully examining possible conflicts of interest. PMID- 28598195 TI - White paper and colourful language: Toward a realistic view of animal research. PMID- 28598196 TI - Derivation and Validation of a Prognostic Model to Predict 6-Month Mortality in an Intensive Care Unit Population. AB - RATIONALE: Identification of terminally ill patients in the intensive care unit (ICU) would facilitate decision making and timely palliative care. OBJECTIVES: To develop and validate a patient-specific integrated prognostic model to predict 6 month mortality in medical ICU patients. METHODS: A longitudinal prospective cohort study of temporally split samples of 1,049 consecutive medical ICU patients in a tertiary care hospital was performed. For each patient, we collected demographic data, Acute Physiology and Chronic Health Evaluation III score, Charlson comorbidity index, intensivist response to a surprise question (SQ; "Would I be surprised if this patient died in the next 6 months?") on admission, and vital status at 6 months. RESULTS: Between November 2013 and May 2015, derivation and validation cohorts of 500 and 549 consecutive patients were studied to develop a multivariate logistic regression model. In the multivariate logistic regression model, Charlson comorbidity index (P = 0.033), Acute Physiology and Chronic Health Evaluation III score (P < 0.001), and SQ response (P < 0.001) were predictors of vital status at 6 months. The odds of dying within 6 months were significantly higher when the SQ was answered "no" than when it was answered "yes" (odds ratio, 7.29; P < 0.001). The c-statistic for the derivation and validation cohorts were 0.832 (95% confidence interval, 0.795-0.870) and 0.84 (95% confidence interval, 0.806-0.875), respectively. CONCLUSIONS: Our integrated prognostic model, which includes the SQ, has strong discrimination and calibration to predict 6-month mortality in medical ICU patients. This model can aid clinicians in identifying ICU patients who may benefit from the integration of palliative care into their treatment. PMID- 28598198 TI - Usefulness of ischemia-modified albumin in predicting oxidative stress in patients with vitiligo. AB - AIM: To investigate the emphasis of oxidative stress in the pathogenesis of vitiligo through an evaluation of ischemia-modified albumin (IMA). Results/methodology: IMA was of higher statistical significance in patients than in the control group (IMA: 0.57 +/- 0.2 vs 0.52 +/- 0.2 DeltaABSU; p < 0.0001). IMA (p < 0.0001; OR: 8.9; 95% CI = 3.1-26.1) was found as an independent predictor of oxidative stress. Increases in affected body surface area and age were found to be independent risk factors for IMA. The sensitivity, specificity and positive and negative predictive values and capacity of IMA were higher than other studied biomarkers. DISCUSSION/CONCLUSION: IMA can be detected in the condition of oxidative stress in vitiligo; it has great potential as a biomarker of said condition, when compared with other studied biomarkers. PMID- 28598197 TI - Hypersensitivity Pneumonitis: Perspectives in Diagnosis and Management. PMID- 28598200 TI - Correction to: Murugaian et al., Novel mutations in calcium sensing receptor gene in tropical chronic pancreatitis in India. PMID- 28598199 TI - Phytoremediation of domestic wastewater using a hybrid constructed wetland in mountainous rural area. AB - The purpose of this study is to evaluate the efficiency of hybrid constructed wetlands (HCWs) in a rural mountainous area. The experiment was set up in small rural community named Tidili within the region of Marrakech, Morocco. The wastewater treatment plant was composed of three vertical flow constructed wetlands (VFCWs) working in parallel, followed by two parallel horizontal subsurface flow constructed wetlands (HFCWs), with hydraulic loading rates of 0.5 and 0.75 m3/m2.d, respectively. The two units were planted with Phragmites australis at a density of 4 plants/m2. Wastewater samples were collected at the inlet of the storage tank and at the outlet of the whole system (VFCWs, HFCWs) stages. The main removal percentages of total suspended solids (TSS), biochemical oxygen demand measured in a 5-day test (BOD5), chemical oxygen demand (COD), total nitrogen, and total phosphorus were respectively 95%, 93%, 91%, 67%, and 62%. The system showed a very high capacity to remove total coliforms, fecal coliforms, and fecal streptococci (4.46, 4.31, and 4.10 Log units, respectively). Artificial neural networks (ANNs) were used to model the quality parameters (TSS, BOD5, COD) and total coliforms and fecal streptococci. Based on the obtained results, the ANN model could be considered as an efficient tool to predict the studied phytoremediation performances using HCWs. PMID- 28598201 TI - Fate of heavy metals in vertical subsurface flow constructed wetlands treating secondary treated petroleum refinery wastewater in Kaduna, Nigeria. AB - This study examined the performance of pilot-scale vertical subsurface flow constructed wetlands (VSF-CWs) planted with three indigenous plants, i.e. Typha latifolia, Cyperus alternifolius, and Cynodon dactylon, in removing heavy metals from secondary treated refinery wastewater under tropical conditions. The T. latifolia-planted VSF-CW had the best heavy metal removal performance, followed by the Cyperus alternifolius-planted VSF-CW and then the Cynodon dactylon-planted VSF-CW. The data indicated that Cu, Cr, Zn, Pb, Cd, and Fe were accumulated in the plants at all the three VSF-CWs. However, the accumulation of the heavy metals in the plants accounted for only a rather small fraction (0.09-16%) of the overall heavy metal removal by the wetlands. The plant roots accumulated the highest amount of heavy metals, followed by the leaves, and then the stem. Cr and Fe were mainly retained in the roots of T. latifolia, Cyperus alternifolius, and Cynodon dactylon (TF < 1), meaning that Cr and Fe were only partially transported to the leaves of these plants. This study showed that VSF-CWs planted with T. latifolia, Cyperus Alternifolius, and Cynodon dactylon can be used for the large scale removal of heavy metals from secondary refinery wastewater. PMID- 28598202 TI - Evaluation of the effect of time dependent dosing on pharmacokinetic and pharmacodynamics of amlodipine in normotensive and hypertensive human subjects. AB - In clinical practice, circadian rhythms play a prominent role in pharmacokinetics and cell responses to therapy, hence necessitating in designing a defined protocol for drug administration. Clinical evidence for chronopharmacological behavior of cardiovascular active drugs in human subjects has been limited for amlodipine. Hence, the present study was undertaken to study the chronopharmacokinetic and chronopharmacodynamic phenomena of amlodipine and evaluate the effect of time of dosage in hypertensive subjects. Single oral dose of amlodipine was administered to the hypertensive/normotensive subjects either morning or evening to assess the pharmacokinetic profile after morning dosing or evening dosing, respectively. PK parameters obtained revealed that Tmax was shorter and Cmax was greater after evening dosing than the morning dosing in both hypertensive and normotensive subjects. These observations were comparable with the hypothesis that amlodipine is absorbed rapidly when it is given during the night time. Also, the changes in systolicBP, DiastolicBP, and heart rate in comparison to the respective circadian baseline values were markedly different depending on the time and dosing. SBP and HR were significantly reduced after evening dosing with slight difference in measurement of DBP in hypertensive patients. Hence, it can be concluded that prescription of antihypertensive medications containing amlodipine, to be administered at night offers highly efficacious means to control BP without the need to increase either the dose or number of medications. The current treatment strategy method involves delivery of medications, so that they are synchronized in time to biological need that varies according to the chronobiology of the targeted tissues. PMID- 28598204 TI - Hygienic Status Assessment of Two Lamb Slaughterhouses in Spain. AB - A total of 180 lamb carcasses and 200 inert surfaces were sampled in two commercial abattoirs (plants A and B) from northwest Spain. A higher (P < 0.001) average microbial load (log CFU per square centimeter) on lamb carcasses was observed for total viable counts (TVC; 2.74 +/- 1.15) than for Enterobacteriaceae (2.21 +/- 1.16). Different microbial counts were found on carcasses from plants A and B, both for TVC (2.56 +/- 0.96 versus 3.18 +/- 1.47, respectively; P < 0.001) and Enterobacteriaceae (2.09 +/- 0.97 versus 2.50 +/- 1.61, respectively; P < 0.05). High correlations (P < 0.001) were observed for TVC and Enterobacteriaceae in both plants A (r = 0.708) and B (r = 0.912). The percentages of unsatisfactory daily mean log values for carcasses, according to European Union Regulation (EC) No 2073/2005, were 0.0 (TVC) and 30.8 (Enterobacteriaceae) in plant A and 10.0 (TVC) and 40.0 (Enterobacteriaceae) in plant B. Average counts for inert surfaces were all lower than 10 CFU/cm2 (TVC) or 1 CFU/cm2 (Enterobacteriaceae). The need to improve hygienic practices in order to adhere to the European Union microbiological performance criteria is emphasized. The detected different microbial counts between slaughterhouses could be attributed to differences in external hygiene of livestock and in the number of slaughterhouse workers. Microbiological analysis of carcasses and surfaces allows detection of hygienic concerns in the overall process. PMID- 28598203 TI - Prevalence and Mechanism of Fluoroquinolone Resistance in Escherichia coli Isolated from Swine Feces in Korea. AB - In this study, we investigated the prevalence and fluoroquinolone (FQ) resistance mechanisms in Escherichia coli isolated from swine fecal samples. E. coli isolates were collected from 171 (72.2%) of 237 swine fecal samples. Of these, 59 isolates (34.5%) were confirmed as FQ-resistant E. coli by the disk diffusion method. Of the FQ-resistant isolates, three major FQ resistance mechanisms were investigated. Of the 59 isolates, plasmid-mediated quinolone resistance genes were detected in 9 isolates (15.3%). Efflux pump activity was found in 56 isolates (94.9%); however, this was not correlated with the increased FQ resistance measured by determining the MIC. Point mutations in quinolone resistance-determining regions were the main cause of FQ resistance. All 59 ciprofloxacin-resistant isolates had mutations in quinolone resistance determining regions; of these 59 isolates, all (100%) had mutations in gyrA, 58 (98.3%) had mutations in parC, 22 (37.3%) had mutations in parE, and none had mutations in gyrB. The predominant mutation type was double mutation in gyrA (Ser83Leu plus mutation in aspartic acid 87), and all FQ-resistant isolates (except one) that had mutations in parC or parE also had double mutations in gyrA. Importantly, the frequencies of multidrug-resistant and extended-spectrum beta-lactamase-producing E. coli were significantly higher in the high ciprofloxacin MIC group in this study. Compared with previous studies in Korea, the prevalence of FQ resistance and plasmid-mediated quinolone resistance genes had increased considerably in swine. Although the use of FQ as a feed additive is prohibited in Korea, use for self-treatment and therapeutic purposes has been increasing, which may be responsible for the higher FQ resistance rate observed in this study. Therefore, prudent use of FQ on animal farms is warranted to reduce the evolution of FQ-resistant bacteria in the animal industry. PMID- 28598205 TI - Neurofilament light chain protein as a marker of neuronal injury: review of its use in HIV-1 infection and reference values for HIV-negative controls. AB - INTRODUCTION: Several CSF biomarkers of neuronal injury have been studied in people living with HIV. At this time, the most useful is the light subunit of the neurofilament protein (NFL). This major structural component of myelinated axons is essential to maintain axonal caliber and to facilitate effective nerve conduction. CSF concentrations of NFL provide a sensitive marker of CNS injury in a number of neurological diseases, including HIV-related neuronal injury. Areas Covered: In this review, the authors describe CSF NFL concentrations across the spectrum of HIV-infection, from its early acute phase to severe immunosuppression, with and without neurological conditions, and with and without antiretroviral treatment (n = 516). Furthermore, in order to provide more precise estimates of age-related upper limits of CSF NFL concentrations, the authors present data from a large number (n = 359) of HIV-negative controls. Expert Commentary: Recently a new ultrasensitive diagnostic assay for quantification of NFL in plasma has been developed, providing a convenient way to assess neuronal damage without having to perform a lumbar puncture. This review also considers our current knowledge of plasma NFL in HIV CNS infection. PMID- 28598207 TI - The Relationship Between Single-Nucleotide Polymorphisms, the Expression of DNA Damage Response Genes, and Hepatocellular Carcinoma in a Polish Population. AB - The molecular mechanism of hepatocellular carcinoma (HCC) is related to DNA damage caused by oxidative stress products induced by hepatitis B virus (HBV) or C (HCV) infection and exposure to environmental pollutants. Single-nucleotide polymorphisms (SNPs) of DNA damage response (DDR) genes may influence individual susceptibility to environmental risk factors and affect DNA repair efficacy, which, in turn, can influence the risk of HCC. The study evaluates a panel of 15 SNPs in 11 DDR genes (XRCC1, XRCC3, XPD, MUTYH, LIG1, LIG3, hOGG1, PARP1, NFIL1, FEN1, and APEX1) in 65 HCC patients, 50 HBV- and 50 HCV-infected non-cancerous patients, and 50 healthy controls. It also estimates the mRNA expression of nine DDR genes in cancerous and adjacent healthy liver tissues. Two of the investigated polymorphisms (rs1052133 and rs13181) were associated with HCC risk. For all investigated genes, the level of mRNA was significantly lower in HCC cancer tissue than in non-cancerous liver tissue. Seven of the investigated polymorphisms were statistically related to gene expression in cancer tissues. The disruption of DDR genes may be responsible for hepatocellular transformation in HCV-infected patients. PMID- 28598206 TI - A Novel In Vitro Human Granuloma Model of Sarcoidosis and Latent Tuberculosis Infection. AB - Many aspects of pathogenic granuloma formation are poorly understood, requiring new relevant laboratory models that represent the complexity (genetics and diversity) of human disease. To address this need, we developed an in vitro model of granuloma formation using human peripheral blood mononuclear cells (PBMCs) derived from patients with active sarcoidosis, latent tuberculosis (TB) infection (LTBI), or normal healthy control subjects. PBMCs were incubated for 7 days with uncoated polystyrene beads or beads coated with purified protein derivative (PPD) or human serum albumin. In response to PPD-coated beads, PBMCs from donors with sarcoidosis and LTBI formed robust multicellular aggregates resembling granulomas, displaying a typical T-helper cell type 1 immune response, as assessed by cytokine analyses. In contrast, minimal PBMC aggregation occurred when control PBMCs were incubated with PPD-coated beads, whereas the response to uncoated beads was negligible in all groups. Sarcoidosis PBMCs responded to human serum albumin-coated beads with modest cellular aggregation and inflammatory cytokine release. Whereas the granuloma-like aggregates formed in response to PPD coated beads were similar for sarcoidosis and LTBI, molecular profiles differed significantly. mRNA expression patterns revealed distinct pathways engaged in early granuloma formation in sarcoidosis and LTBI, and they resemble molecular patterns reported in diseased human tissues. This novel in vitro human granuloma model is proposed as a tool to investigate mechanisms of early granuloma formation and for preclinical drug discovery research of human granulomatous disorders. Clinical trial registered with www.clinicaltrials.gov (NCT01857401). PMID- 28598209 TI - The significance of early warning in chronic myeloid leukemia. PMID- 28598208 TI - Characterization and Spatiotemporal Expression of Klf4 in Large Yellow Croaker Larimichthys crocea. AB - As one of transcription factors and pluripotency factors, Klf4 plays a crucial role in regulation of cellular processes. In this article, we characterized Klf4 of large yellow croaker (Lc-Klf4), which encodes a 452-amino acid protein (Lc Klf4) with three highly conserved C2H2 zinc fingers. Lc-Klf4 shares high conservative functions in teleosts with the closest relationship with Stegastes partitus. The spatiotemporal expression showed that Lc-Klf4 was expressed widely in adult tissues with gender difference as follows: brain>gill>eye>heart in female; heart>testis>gill>brain in male; male>female in heart, gill, and testis; and female>male in eye. During growth, the highest expression level of Lc-Klf4 was at 635 dph (days posthatching) in testis and at 270 dph and 635 dph in brain. Besides, Lc-Klf4 was widely and highly distributed in different developmental spermatids especially in spermatocytes. The expression of Lc-Klf4 in embryos was exhibited zygotically beginning from late gastrula stage with high level in closure of blastopore stage and appearance of optic vesicle stage. This expression pattern was supported by whole-mount in situ hybridization with high expression in back and head of late embryos. In conclusion, the spatiotemporal expression patterns of Lc-Klf4 illustrated that Klf4 involves in spermatogenesis, embryogenesis, and adult physiological processes. PMID- 28598211 TI - Pleural Diseases: Saline Irrigation in Pleural Infection, Epidemiology of Pneumothorax, and Bevacizumab in Mesothelioma. PMID- 28598210 TI - eHealth for inflammatory bowel disease self-management - the patient perspective. AB - BACKGROUND: Electronic health (eHealth) solutions may help address the growing pressure on IBD outpatient services as they encompass a component of self management. However, information regarding patients' attitudes towards the use of eHealth solutions in IBD is lacking. OBJECTIVE: The aim of this study was to evaluate eHealth technology use and explore the perspectives of IBD patients on what constitutes the ideal eHealth solution to facilitate self-management. METHODS: A mixed methods qualitative and quantitative analysis of the outcomes of a discussion forum and an online survey conducted at a tertiary hospital in Melbourne, Australia between November 2015 and January 2016 was undertaken. RESULTS: Eighteen IBD patients and parents participated in the discussion forum. IBD patients expressed interest in eHealth tools that are convenient and improve access to care, communication, disease monitoring and adherence. Eighty six patients with IBD responded to the online survey. A majority of patients owned a mobile phone (98.8%), had access to the internet (97.7%), and felt confident entering data onto a phone or computer (73.3%). Most patients (98.8%) were willing to use at least one form of information and communication technology to help manage their IBD. Smartphone apps and internet websites were the two most preferred technologies to facilitate IBD self-management. CONCLUSIONS: This study demonstrates the willifngness of patients to engage with eHealth as a potential solution to facilitate IBD self-management. Future development and testing of eHealth solutions should be informed by all major stakeholders including patients to maximise their uptake and efficacy to facilitate IBD self-management. PMID- 28598212 TI - Blood protein biomarkers as diagnostic tool for ischemic stroke: a systematic review. AB - AIM: This systematic review provides a summary of the blood protein biomarkers that have been studied for the diagnosis of acute ischemic stroke. MATERIALS & METHODS: An extensive MEDLINE (using PubMed) and Web of Knowledge search was performed. From the 354 articles found, 42 were eligible for further analysis and 25 protein biomarkers were examined. RESULTS: Though many candidate blood-based protein biomarkers were examined, only two could significantly differentiate ischemic stroke patients from healthy controls, stroke mimics and hemorrhagic stroke patients. CONCLUSION: The blood protein biomarkers, brain natriuretic peptide (BNP) and S100B, were promising biomarkers in diagnosing ischemic stroke. They could be used in cases of diagnostic uncertainty and/or when less experienced healthcare personnel are involved. PMID- 28598213 TI - Characterization and degradation potential of diesel-degrading bacterial strains for application in bioremediation. AB - Bioremediation of polluted soils is a promising technique with low environmental impact, which uses soil organisms to degrade soil contaminants. In this study, 19 bacterial strains isolated from a diesel-contaminated soil were screened for their diesel-degrading potential, biosurfactant (BS) production, and biofilm formation abilities, all desirable characteristics when selecting strains for re inoculation into hydrocarbon-contaminated soils. Diesel-degradation rates were determined in vitro in minimal medium with diesel as the sole carbon source. The capacity to degrade diesel range organics (DROs) of strains SPG23 (Arthobacter sp.) and PF1 (Acinetobacter oleivorans) reached 17-26% of total DROs after 10 days, and 90% for strain GK2 (Acinetobacter calcoaceticus). The amount and rate of alkane degradation decreased significantly with increasing carbon number for strains SPG23 and PF1. Strain GK2, which produced BSs and biofilms, exhibited a greater extent, and faster rate of alkane degradation compared to SPG23 and PF1. Based on the outcomes of degradation experiments, in addition to BS production, biofilm formation capacities, and previous genome characterizations, strain GK2 is a promising candidate for microbial-assisted phytoremediation of diesel contaminated soils. These results are of particular interest to select suitable strains for bioremediation, not only presenting high diesel-degradation rates, but also other characteristics which could improve rhizosphere colonization. PMID- 28598215 TI - Enhanced atrazine removal by hydrophyte-bacterium associations and in vitro screening of the isolates for their plant growth-promoting potential. AB - Emergent hydrophytes Acorus calamus, Typha latifolia, and Phragmites karka and epiphytic root bacteria isolated from their rhizoplanes were exposed to atrazine (5 and 10 mg l-1) individually and in plant-bacterium combination for 15 days hydroponically. It was observed that A. calamus-Pseudomonas sp. strain, the ACB combination, was best in decontamination, showing 91% and 87% removal of 5 and 10 mg l-1 atrazine. Plant-bacterium association led to significant increase in atrazine decontamination as compared to decontamination by either plant or bacterium alone, indicating a synergistic action of the hydrophytes and isolates which led to enhanced atrazine removal. To the best of our knowledge this is the first report on the potential of plant-bacterium combinations for atrazine decontamination. The isolates showed augmented growth in the presence of plants and were able to alleviate atrazine stress in them. These isolates exhibited plant growth-promoting traits such as auxin, siderophore, Poly(3-hydroxybutyric acid)/succinogycan, ammonia, catalase production and solubilization of inorganic phosphate in vitro. The use of plant-bacterium mutualistic symbiosis for atrazine mitigation is a relatively simple, inexpensive, and clean technique and this phytoremediation-rhizoremediation combination is suggested to be tried on field to establish their potential for clean-up of contaminated sites. PMID- 28598214 TI - Exosomal miRNAs as biomarkers in the diagnosis of liver disease. AB - Liver disease is a primary cause of liver-related morbidity and mortality worldwide. Currently, histological examination is the gold standard for diagnosis and classification of liver disease; however, due to its several drawbacks, including the risk of complications and sampling variability, noninvasive diagnostic options are favorable. Exosomal miRNAs have recently been considered as an important source of medical biomarkers due to being widely distributed in body fluids. This review summarizes existing concepts related to the origin, mode of transportation and possible functions of exosomal miRNAs, and recent findings on the role of exosomal miRNAs in liver diseases and development of exosomal miRNA-based diagnostic biomarkers in the primary forms of liver diseases. PMID- 28598216 TI - The Impact of Partial Factorial Invariance on Cross-Group Comparisons. AB - This study explored the impact of partial factorial invariance on cross-group comparisons of latent variables, including latent means, latent variances, structural relations (or correlations) with other constructs, and regression coefficients as predicting external variables. The results indicate that the estimates of factor mean differences are sensitive to violations of invariance on both factor loadings and intercepts. Noninvariant factor loadings were also found to influence the cross-group comparisons of factor variances and regression coefficients (slopes, in the raw metric) with external variables. However, cross group comparisons of standardized slopes and interfactor correlations were not subject to noninvariance. Under conditions of partial invariance, we further compared the performance of four different model specification strategies. In general, fitting partially invariant models with all noninvariant parameters that were freely estimated yielded more accurate estimates of the parameters of interest. The implications of the major findings of this work, as well as recommendations and guidelines for future empirical researchers, are discussed below. PMID- 28598217 TI - Influence of biochar and compost on phytoremediation of oil-contaminated soil. AB - The use of pyrolyzed carbon, biochar, as a soil amendment is of potential interest for improving phytoremediation of soil that has been contaminated by petroleum hydrocarbons. To examine this question, the research reported here compared the effects of biochar, plants (mesquite tree seedlings), compost and combinations of these treatments on the rate of biodegradation of oil in a contaminated soil and the population size of oil-degrading bacteria. The presence of mesquite plants significantly enhanced oil degradation in all treatments except when biochar was used as the sole amendment without compost. The greatest extent of oil degradation was achieved in soil planted with mesquite and amended with compost (44% of the light hydrocarbon fraction). Most probable number assays showed that biochar generally reduced the population size of the oil-degrading community. The results of this study suggest that biochar addition to petroleum contaminated soils does not improve the rate of bioremediation. In contrast, the use of plants and compost additions to soil are confirmed as important bioremediation technologies. PMID- 28598218 TI - What's New in Noninvasive Ventilation: Factors Associated with Failure, Patterns of Use in Acute Asthma, and the Role of New Interfaces. PMID- 28598219 TI - Recent approaches to ameliorate selectivity and sensitivity of enzyme based cholesterol biosensors: a review. AB - The healthcare area is often reluctant to execute new technology unless they are proven to be safe, constructive and secure. Eventually, an aspiration stands for providing point-of-care testing service to allow a better estimation of the biochemical levels of a patient that entails an insistent remedial action. With increasing mortality rate due to cardiovascular diseases (CVDs) in present scenario, it has become the need of hour to develop more advance methods for their diagnosis, so that it can be determined at sensitive levels and can be prevented from being fatal. Elevated level of cholesterol in blood stream is one of the utmost risk factors which lead to CVDs. Discernible from the vast research in this field, worth of cholesterol biosensors is already recognized and flourished in the clinical analysis of brain and cardiac vascular diseases. It necessitates unremitting progress in the development of biosensing technology towards fabrication, miniaturization and multiplexing ability of cholesterol quantification devices so that they can endow with lab-on-chip-analysis systems to the medical field. Different strategies have been meticulously explored for the engineering of cholesterol biosensors utilizing nanocomposites, conducting polymers, nanotubes and nanoparticles. Foremost, this article reviews the contemporary evolution in cholesterol biosensors, which encompass various strategies for immobilization of enzymes and roles of various matrices and artificial mediators used for the biosensor fabrication. Still there remains an enormous challenge to congregate the demands of performance and yield in a cost effective manner for its application in successful treatments of CVDs. PMID- 28598220 TI - Bone and cortical bone thickness of mandibular buccal shelf for mini-screw insertion in adults. AB - OBJECTIVE: To analyze the buccal bone thickness, bone depth, and cortical bone depth of the mandibular buccal shelf (MBS) to determine the most suitable sites of the MBS for mini-screw insertion. MATERIALS AND METHODS: The sample included cone-beam computed tomographic (CBCT) records of 30 adult subjects (mean age 30.9 +/- 7.0 years) evaluated retrospectively. All CBCT examinations were performed with the i-CAT CBCT scanner. Each exam was converted into DICOM format and processed with OsiriX Medical Imaging software. Proper view sections of the MBS were obtained for quantitative and qualitative evaluation of bone characteristics. RESULTS: Mesial and distal second molar root scan sections showed enough buccal bone for mini-screw insertion. The evaluation of bone depth was performed at 4 and 6 mm buccally to the cementoenamel junction. The mesial root of the mandibular second molar at 4 and 6 mm showed average bone depths of 18.51 mm and 14.14 mm, respectively. The distal root of the mandibular second molar showed average bone depths of 19.91 mm and 16.5 mm, respectively. All sites showed cortical bone depth thickness greater than 2 mm. CONCLUSIONS: Specific sites of the MBS offer enough bone quantity and adequate bone quality for mini screw insertion. The insertion site with the optimal anatomic characteristics is the buccal bone corresponding to the distal root of second molar, with screw insertion 4 mm buccal to the cementoenamel junction. Considering the cortical bone thickness of optimal insertion sites, pre-drilling is always recommended in order to avoid high insertion torque. PMID- 28598221 TI - The beneficial effects of renin-angiotensin system blockades on 2 year outcomes in coronary artery ectasia patients. AB - OBJECTIVES: This study was designed to investigate the impact of renin angiotensin system blockade (RASB) therapy with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on the outcomes of coronary artery ectasia (CAE). METHODS: The CAE patients identified by coronary angiography from our center were consecutively enrolled. We obtained the baseline discharge prescription of RASB from the medical records system and conducted follow-up through telephone interviews. Cox regression models, propensity score and subgroup analysis were used to assess the impact of RASB on all-cause mortality and non-fatal myocardial infarction. Both the unadjusted and adjusted Kaplan Meier curves stratified by RASB therapy were plotted. RESULTS: There were 595 patients with CAE in total and 333 (56.0%) were prescribed RASB therapy. Over a 2 year follow-up time, 16 all-cause deaths and 10 non-fatal myocardial infarctions were identified. Those patients treated with RASB had a significantly lower all cause mortality and non-fatal myocardial infarction rate with an adjusted hazard ratio of 0.32 (95% confidence interval: 0.13 to 0.77, p = .011). The outcome benefits of RASB therapy were further confirmed in the propensity score analysis and subgroup analysis. CONCLUSIONS: This observational study suggests that RASB therapy is associated with a lower risk of all-cause mortality and non-fatal myocardial infarction in patients with CAE. PMID- 28598222 TI - PFCA uptake and translocation in dominant wheat species (Triticum aestivum L.). AB - The comparative uptake of four perfluorinated carboxylic acids (PFCAs) by wheat (Triticum aestivum L.) grown in nutrient solution was investigated. Wheat is the main food crop in northern China and may become a potential pathway of human exposure to these PFCAs. The uptake of four PFCAs from water at a fixed concentration (1 MUg/mL) increased over time, approaching a steady state, and except for the short-chain perfluorobutanoic acid, most of the total mass of each of the PFCAs taken up by wheat was found to be at the root. The root concentration factor (RCF) and shoot/root concentration factor (SRCF) were calculated, and with the increase in carbon chain length, the RCFs increased but SRCFs decreased, which indicated that long-chain PFCAs had stronger root uptake and weaker translocation capacities than short-chain PFCAs. In addition, pH could obviously impact the uptake of four PFCAs in the roots and shoots of wheat, and the highest concentrations were found at pH = 7 when the pH increased from 4 to 10. PMID- 28598225 TI - A novel voxel-wise lesion segmentation technique on 3.0-T diffusion MRI of hyperacute focal cerebral ischemia at 1 h after permanent MCAO in rats. AB - To assess hyperacute focal cerebral ischemia in rats on 3.0-Tesla diffusion weighted imaging (DWI), we developed a novel voxel-wise lesion segmentation technique that overcomes intra- and inter-subject variation in apparent diffusion coefficient (ADC) distribution. Our novel technique involves the following: (1) intensity normalization including determination of the optimal type of region of interest (ROI) and its intra- and inter-subject validation, (2) verification of focal cerebral ischemic lesions at 1 h with gross and high-magnification light microscopy of hematoxylin-eosin (H&E) pathology, (3) voxel-wise segmentation on ADC with various thresholds, and (4) calculation of dice indices (DIs) to compare focal cerebral ischemic lesions at 1 h defined by ADC and matching H&E pathology. The best coefficient of variation was the mode of the left hemisphere after normalization using whole left hemispheric ROI, which showed lower intra- (2.54 +/- 0.72%) and inter-subject (2.67 +/- 0.70%) values than the original. Focal ischemic lesion at 1 h after middle cerebral artery occlusion (MCAO) was confirmed on both gross and microscopic H&E pathology. The 83 relative threshold of normalized ADC showed the highest mean DI (DI = 0.820 +/- 0.075). We could evaluate hyperacute ischemic lesions at 1 h more reliably on 3-Tesla DWI in rat brains. PMID- 28598224 TI - Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. AB - RATIONALE: Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs' effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer. OBJECTIVES: To determine the effects of human MSCs on macrophage function in the ARDS environment and to elucidate the mechanisms of these effects. METHODS: Human monocyte-derived macrophages (MDMs) were studied in noncontact coculture with human MSCs when stimulated with LPS or bronchoalveolar lavage fluid (BALF) from patients with ARDS. Murine alveolar macrophages (AMs) were cultured ex vivo with/without human MSC-derived EVs before adoptive transfer to LPS-injured mice. MEASUREMENTS AND MAIN RESULTS: MSCs suppressed cytokine production, increased M2 macrophage marker expression, and augmented phagocytic capacity of human MDMs stimulated with LPS or ARDS BALF. These effects were partially mediated by CD44-expressing EVs. Adoptive transfer of AMs pretreated with MSC-derived EVs reduced inflammation and lung injury in LPS-injured mice. Inhibition of oxidative phosphorylation in MDMs prevented the modulatory effects of MSCs. Generating dysfunctional mitochondria in MSCs using rhodamine 6G pretreatment also abrogated these effects. CONCLUSIONS: In the ARDS environment, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype through EV-mediated mitochondrial transfer. MSC induced changes in macrophage phenotype critically depend on enhancement of macrophage oxidative phosphorylation. AMs treated with MSC-derived EVs ameliorate lung injury in vivo. PMID- 28598223 TI - Mitochondria in chronic obstructive pulmonary disease and lung cancer: where are we now? AB - Recent advances in mitochondrial biogenesis have provided the emerging recognition that mitochondria do much more than 'simply providing energy for cellular function'. Currently, a constantly improving understanding of the mitochondrial structure and function has been providing valuable insights into the contribution of defects in mitochondrial metabolism to various human diseases, including chronic obstructive pulmonary disease and lung cancer. The growing interest in mitochondria research led to development of new biomedical fields in the two main smoking-related lung diseases. However, there is considerable paucity in our understanding of mechanisms by which mitochondrial dynamics regulate lung diseases. In this review, we will discuss our current knowledge on the role of mitochondrial dysfunction in the pathogenesis of chronic obstructive pulmonary disease and non-small-cell lung cancer. PMID- 28598226 TI - MTOR controls genesis and autophagy of GABAergic interneurons during brain development. AB - Interneuron progenitors in the ganglionic eminence of the ventral telencephalon generate most cortical interneurons during brain development. However, the regulatory mechanism of interneuron progenitors remains poorly understood. Here, we show that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) regulates proliferation and macroautophagy/autophagy of interneuron progenitors in the developing ventral telencephalon. To investigate the role of MTOR in interneuron progenitors, we conditionally deleted the Mtor gene in mouse interneuron progenitors and their progeny by using Tg(mI56i-cre,EGFP)1Kc/Dlx5/6 Cre-IRES-EGFP and Nkx2-1-Cre drivers. We found that Mtor deletion markedly reduced the number of interneurons in the cerebral cortex. However, relative positioning of cortical interneurons was normal, suggesting that disruption of progenitor self-renewal caused the decreased number of cortical interneurons in the Mtor-deleted brain. Indeed, Mtor-deleted interneuron progenitors showed abnormal proliferation and cell cycle progression. Additionally, we detected a significant activation of autophagy in Mtor-deleted brain. Our findings suggest that MTOR plays a critical role in the regulation of cortical interneuron number and autophagy in the developing brain. PMID- 28598227 TI - Integration of a Palliative Care Intervention into Community Practice for Lung Cancer: A Study Protocol and Lessons Learned with Implementation. AB - BACKGROUND: A notable gap in the evidence base for outpatient palliative care (PC) for cancer is that most trials were conducted in specialized oncology or academic centers with limited translation and further evaluation in "real-world" settings. Health systems are desperate for guidance regarding the most effective and sustainable PC service models. OBJECTIVE: Describe the study protocol to evaluate the dissemination of a previously tested nurse-led PC intervention (PCI) for patients with lung cancer and their family caregiver in community-based settings, lessons learned in adapting and implementing the PCI, and implications for future dissemination-translational efforts Design: Two-group, prospective sequential, quasi-experimental design with Phase 1 (Usual care) followed by Phase 2 (Intervention) setting/subjects. Three Kaiser Permanente Southern California sites. Patients with stage 2-4 nonsmall cell lung cancer and their caregiver. MEASUREMENTS: Standard measures of quality of life (QOL; FACT-L, FACIT- SP12, City of Hope Family QOL), symptom burden, distress, and caregiver preparedness and perceived burden. RESULTS: Adaptations were made to the PCI (comprehensive patient/caregiver assessment, interdisciplinary care planning, and patient/caregiver education) to harmonize with existing workflows, minimize burden to patients, caregivers, and the PC team, and maximize chances of sustainability. Implementation facilitators include external competitive pressures, internal readiness, and adaptability of the PCI. Barriers include the changing lung cancer therapeutic landscape and perceived need for PC support by patients and providers, insufficient staffing, and people-dependent processes. CONCLUSIONS: Efforts to disseminate and implement previously tested PC models into real-world community practices need to be more realistic and consider the local context. PMID- 28598228 TI - HDAC6 inhibition disrupts maturational progression and meiotic apparatus assembly in mouse oocytes. AB - Histone deacetylases (HDACs) have been implicated in diverse biologic processes including transcriptional regulation, signal transduction, and developmental control. However, the role of HDAC6 in mammalian oocytes remains unknown. In the present study, by using Tubastatin A (TubA), a selective HDAC6 inhibitor, we examined the effects of HDAC6 on maturational progression and meiotic apparatus in mouse oocytes. We found that HDAC6 inhibition results in maturation arrest and disruption of spindle morphology and chromosome alignment. In line with this observation, confocal microscopy revealed that kinetochore-microtubule attachment, a critical mechanism controlling chromosome movement, is compromised in TubA-treated oocytes markedly. Moreover, we noted that HDAC6 inhibition significantly increases the acetylation levels of alpha-tubulin in mouse oocytes, which may be associated with the defective phenotypes of TubA-treated oocytes by altering microtubule stability and dynamics. In sum, we discover a novel function of HDAC6 during oocyte maturation and suggest a potential pathway modulating meiotic apparatus assembly. PMID- 28598229 TI - Autophagy in natural and therapy-driven anticancer immunosurveillance. AB - Autophagy is primordial for the maintenance of metabolic and genetic homeostasis in all eukaryotic organisms. Owing to its cell-intrinsic effects, autophagy robustly inhibits malignant transformation, yet can support the progression of established neoplasms as well as their resistance to conventional treatments. The notion that autophagy inhibition sensitizes neoplastic cells to chemotherapy and radiation therapy rivals with the capacity of autophagy to contribute to natural and therapy-driven anticancer immunosurveillance via a multitude of mechanisms. Indeed, autophagy ensures an optimal release of immunostimulatory signals by dying cancer cells and hence boosts their capacity to initiate an immune response. Moreover, autophagy is important for the activity of several components of the immune system involved in tumor recognition and elimination, including antigen-presenting cells and CD8+ cytotoxic T lymphocytes. In this review, we discuss how cancer cells disable autophagy to bypass immune control and how strategies aiming to enhance autophagy can be envisaged to improve the efficacy of immunogenic cancer therapies. PMID- 28598231 TI - Effect of Ursolic Acid on Metabolic Syndrome, Insulin Sensitivity, and Inflammation. AB - To evaluate the effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation, a randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients (30-60 years) with a diagnosis of metabolic syndrome without treatment. They were randomly assigned to two groups of 12 patients, each to receive orally 150 mg of ursolic acid or homologated placebo once a day for 12 weeks. Before and after the intervention, the components of metabolic syndrome, insulin sensitivity (Matsuda index), and inflammation profile (interleukin-6 and C-reactive protein) were evaluated. After ursolic acid administration, the remission of metabolic syndrome occurred in 50% of patients (P = .005) with significant differences in body weight (75.7 +/- 11.5 vs. 71 +/- 11 kg, P = .002), body mass index (BMI) (29.9 + 3.6 vs. 24.9 +/- 1.2 kg/m2, P = .049), waist circumference (93 +/- 8.9 vs. 83 + 8.6 cm, P = .008), fasting glucose (6.0 +/- 0.5 vs. 4.7 +/- 0.4 mmol/L, P = .002), and insulin sensitivity (3.1 +/- 1.1 vs. 4.2 +/- 1.2, P = .003). Ursolic acid administration leads to transient remission of metabolic syndrome, reducing body weight, BMI, waist circumference and fasting glucose, as well as increasing insulin sensitivity. PMID- 28598233 TI - Functional impairment in RHOT1/Miro1 degradation and mitophagy is a shared feature in familial and sporadic Parkinson disease. AB - Mitophagy is a conserved and highly regulated process of selective degradation crucial in maintaining normal cellular physiology. Genetic defects and cellular aberrations affecting mitophagy have been associated with the development of Parkinson disease. In their recently published article (highlighted in a punctum in this issue of the journal) Hsieh et al. present a putative mitophagy marker, which serves as a mechanistic link between sporadic and familial Parkinson disease. PMID- 28598230 TI - Protective mechanism of FSH against oxidative damage in mouse ovarian granulosa cells by repressing autophagy. AB - Oxidative stress-induced granulosa cell (GCs) death represents a common reason for follicular atresia. Follicle-stimulating hormone (FSH) has been shown to prevent GCs from oxidative injury, although the underlying mechanism remains to be elucidated. Here we first report that the suppression of autophagic cell death via some novel signaling effectors is engaged in FSH-mediated GCs protection against oxidative damage. The decline in GCs viability caused by oxidant injury was remarkably reduced following FSH treatment, along with impaired macroautophagic/autophagic flux under conditions of oxidative stress both in vivo and in vitro. Blocking of autophagy displayed similar levels of suppression in oxidant-induced cell death compared with FSH treatment, but FSH did not further improve survival of GCs pretreated with autophagy inhibitors. Further investigations revealed that activation of the phosphoinositide 3-kinase (PI3K) AKT-MTOR (mechanistic target of rapamycin [serine/threonine kinase]) signaling pathway was required for FSH-mediated GCs survival from oxidative stress-induced autophagy. Additionally, the FSH-PI3K-AKT axis also downregulated the autophagic response by targeting FOXO1, whereas constitutive activation of FOXO1 in GCs not only abolished the protection from FSH, but also emancipated the autophagic process, from the protein level of MAP1LC3B-II to autophagic gene expression. Furthermore, FSH inhibited the production of acetylated FOXO1 and its interaction with Atg proteins, followed by a decreased level of autophagic cell death upon oxidative stress. Taken together, our findings suggest a new mechanism involving FSH-FOXO1 signaling in defense against oxidative damage to GCs by restraining autophagy, which may be a potential avenue for the clinical treatment of anovulatory disorders. PMID- 28598232 TI - Exercise reestablishes autophagic flux and mitochondrial quality control in heart failure. AB - We previously reported that facilitating the clearance of damaged mitochondria through macroautophagy/autophagy protects against acute myocardial infarction. Here we characterize the impact of exercise, a safe strategy against cardiovascular disease, on cardiac autophagy and its contribution to mitochondrial quality control, bioenergetics and oxidative damage in a post myocardial infarction-induced heart failure animal model. We found that failing hearts displayed reduced autophagic flux depicted by accumulation of autophagy related markers and loss of responsiveness to chloroquine treatment at 4 and 12 wk after myocardial infarction. These changes were accompanied by accumulation of fragmented mitochondria with reduced O2 consumption, elevated H2O2 release and increased Ca2+-induced mitochondrial permeability transition pore opening. Of interest, disruption of autophagic flux was sufficient to decrease cardiac mitochondrial function in sham-treated animals and increase cardiomyocyte toxicity upon mitochondrial stress. Importantly, 8 wk of exercise training, starting 4 wk after myocardial infarction at a time when autophagy and mitochondrial oxidative capacity were already impaired, improved cardiac autophagic flux. These changes were followed by reduced mitochondrial number:size ratio, increased mitochondrial bioenergetics and better cardiac function. Moreover, exercise training increased cardiac mitochondrial number, size and oxidative capacity without affecting autophagic flux in sham-treated animals. Further supporting an autophagy mechanism for exercise-induced improvements of mitochondrial bioenergetics in heart failure, acute in vivo inhibition of autophagic flux was sufficient to mitigate the increased mitochondrial oxidative capacity triggered by exercise in failing hearts. Collectively, our findings uncover the potential contribution of exercise in restoring cardiac autophagy flux in heart failure, which is associated with better mitochondrial quality control, bioenergetics and cardiac function. PMID- 28598234 TI - Design and evaluation of novel topical formulation with olive oil as natural functional active. AB - Currently, the innovative skin research is focused on the development of novel topical formulations loaded with natural functional actives. The health benefits of olive oil are unsurpassed and many others are revealed as research studies allow the understanding of its unlimited properties. Olive oil has a protective toning effect on skin, but it is not transported effectively into its layers. Aiming the development of a cosmetic formulation for skin photoprotection and hydration, we have prepared and characterized macro-sized particles, made of a hydrogel polymer, loaded with olive oil. Alginate beads were uniform in shape, with minimal oil leakage, offering interesting prospects for encapsulation of lipophilic and poorly stable molecules, like olive oil. In vitro photoprotection and in vivo tolerance tests were in favor of this application. Thus, this study suggests that the incorporation of the olive oil-loaded particles into a cream formulation provides strong moisturizing properties and a photoprotective potential, when applied to healthy subjects. PMID- 28598235 TI - Lift and cut: Anti-host autophagy mechanism of Legionella pneumophila. AB - RavZ, an effector protein of pathogenic Legionella pneumophila, inhibits host macroautophagy/autophagy by deconjugation of lipidated LC3 proteins from phosphatidylethanolamine (PE) on the autophagosome membrane. The mechanism for how RavZ specifically recognizes and deconjugates the lipidated LC3s is not clear. To understand the structure-function relationship of LC3-deconjugation by RavZ, we prepared semisynthetic LC3 proteins modified with different fragments of PE or 1-hexadecanol (C16). We find that RavZ activity is strictly dependent on the conjugated PE structure and RavZ extracts LC3-PE from the membrane before deconjugation. Structural and biophysical analysis of RavZ-LC3 interactions suggest that RavZ initially recognizes LC3-PE on the membrane via its N-terminal LC3-interacting region (LIR) motif. RavZ specifically targets to autophagosome membranes by interaction with phosphatidylinositol 3-phosphate (PtdIns3P) via its C-terminal domain and association with membranes via the hydrophobic alpha3 helix. The alpha3 helix is involved in extraction of the PE moiety and docking of the fatty acid chains into the lipid-binding site of RavZ, which is related in structure to that of the phospholipid transfer protein Sec14. The LIR interaction and lipid binding facilitate subsequent proteolytic cleavage of LC3-PE. The findings reveal a novel mode of host-pathogen interaction. PMID- 28598236 TI - Destructive cellular paths underlying familial and sporadic Parkinson disease converge on mitophagy. AB - The knowledge gap separating the molecular and cellular underpinnings of Parkinson disease (PD) and its pathology hinders treatment innovation. Adding to this difficulty is the lack of a reliable biomarker for PD. Our previous studies identify a link of 2 PD proteins, PINK1/PRKN Parkin to a mitochondrial motor adaptor RHOT1/Miro-1, which mediates mitochondrial motility and mitophagy. Here we review our recent paper showing that a third PD protein, LRRK2, also targets RHOT1 and regulates mitophagy, and pathogenic LRRK2 disrupts this function. Notably, we discover impairments in RHOT1 and mitophagy in sporadic PD patients with no known genetic backgrounds, pointing to RHOT1-mediated mitophagy as a convergent pathway in PD. This novelty opens new doors in PD research toward RHOT1-based therapy and biomarker development. PMID- 28598237 TI - Homocysteine as a Diagnostic and Etiopathogenic Factor in Children with Autism Spectrum Disorder. AB - Substantial characteristics of autism are cognitive and psychophysical disorders. Etiopathogenetic factors are thought to be responsible for development of autism in children with genetic predisposition as well as have their effect on the severity of the disorders. The main problem of early identification of patients affected by autism spectrum disorder is that there are no clear diagnostic criteria. The aim of our study was assessment of hair magnesium and serum homocysteine concentrations in children with autism. The presented work is a continuation of previous study in which we investigated the influence of disturbances in magnesium and homocysteine levels in children with autism, performed on a new, larger group of patients. One hundred and forty children had hair magnesium levels analyzed, as well as blood serum levels of homocysteine and magnesium. Hair magnesium analysis was performed using a flame atomic absorption spectrometer, blood serum homocysteine determination was performed using a radioimmunological method, and blood serum magnesium level was determined using a biochemical method. Our research showed normal magnesium blood levels and significantly high homocysteine levels and very low hair magnesium levels. Low concentration of hair magnesium progresses with age. Our hypothesis is that magnesium deficiency, as a relevant epigenetic factor, might be decreasing methylation of homocysteine, therefore decreasing genome transcription and lowering the synaptic plasticity. We suggest that analysis of hair magnesium and serum homocysteine levels might be useful in identification of children with autism spectrum disorder, as well as control of its treatment. Obtained results and performed analysis might therefore justify supplementation of magnesium among children with autism. PMID- 28598239 TI - The Prospective Evaluation of the Net Effect of Red Blood Cell Transfusions in Routine Provision of Palliative Care. AB - BACKGROUND: Red Blood Cell (RBC) transfusions are commonly used in palliative care. RBCs are a finite resource, transfusions carry risks, and the net effect (benefits and harms) is poorly defined for people with life-limiting illnesses. OBJECTIVE: To examine the indications and effects of RBC transfusion in palliative care patients. DESIGN: This international, multisite, prospective consecutive cohort study. SETTING/SUBJECTS: Palliative care patients undergoing RBC transfusion. MEASUREMENTS: Target symptoms (fatigue, breathlessness, generalized weakness, or dizziness) were assessed before transfusion and at day 7 by treating clinicians, using National Cancer Center Institute Common Terminology Criteria for Adverse Events. Assessment of harms was made at day 2. RESULTS: One hundred and one transfusions with day 7 follow-up were collected. Median age was 72.0 (interquartile range 61.5-83.0) years, 58% men, and mean Australia-modified Karnofsky Performance Status (AKPS) of 48 (standard deviation [SD] 17). A mean 2.1 (SD 0.6) unit was tranfused. The target symptoms were fatigue (61%), breathlessness (16%), generalized weakness (12%), dizziness (6%), or other (5%). Forty-nine percent of transfusions improved the primary target symptom, and 78% of transfusions improved at least one of the target symptoms. Harms were infrequent and mild. An AKPS of 40%-50% was associated with higher chances of symptomatic benefit in the target symptom; however, no other predictors of response were identified. CONCLUSIONS: In the largest prospective consecutive case series to date, clinicians generally reported benefit, with minimal harms. Ongoing work is required to define the optimal patient- and clinician-reported hematological and functional outcome measures to optimize the use of donor blood and to minimize transfusion-associated risk. PMID- 28598238 TI - NLRC3 regulates cellular proliferation and apoptosis to attenuate the development of colorectal cancer. AB - Nucleotide-binding domain, leucine-rich-repeat-containing proteins (NLRs) are intracellular innate immune sensors of pathogen-associated and damage-associated molecular patterns. NLRs regulate diverse biologic processes such as inflammatory responses, cell proliferation and death, and gut microbiota to attenuate tumorigenesis. In a recent publication in Nature, we identified NLRC3 as a negative regulator of PI3K-mTOR signaling and characterized its potential tumor suppressor function. Enterocytes lacking NLRC3 cannot control cellular proliferation because they are unable to suppress activation of PI3K-mTOR signaling pathways. In this Extra-View, we explore possible mechanisms through which NLRC3 regulates cellular proliferation and cell death. Besides interacting with PI3K, NLRC3 associates with TRAF6 and mTOR, confirming our recent finding that NLRC3 negatively regulates the PI3K-mTOR axis. Herein, we show that NLRC3 suppresses c-Myc expression and activation of PI3K-AKT targets FoxO3a and FoxO1 in the colon of Nlrc3-/- mice, suggesting that additional signaling pathways contribute to increased cellular proliferation. Moreover, NLRC3 suppresses colorectal tumorigenesis by promoting cellular apoptosis. Genes encoding intestinal stem cell markers BMI1 and OLFM4 are upregulated in the colon of Nlrc3 /- mice. Herein, we discuss recent findings and explore mechanisms through which NLRC3 regulates PI3K-mTOR signaling. Our studies highlight the therapeutic potential of modulating NLRC3 to prevent and treat cancer. PMID- 28598242 TI - Antithrombotic Effect of Fermented Ophiopogon japonicus in Thrombosis-Induced Rat Models. AB - In this study, the antithrombotic and thrombolytic ability of second fermented extract of Ophiopogon japonicus (FEOJ) was verified in thrombosis-induced rats. Thrombosis was induced by oral administration of 2% carrageenan for 4 weeks. Five experimental groups (n = 9/group) involved in the study were control group, thrombosis group, low-dose FEOJ group (2 mL/kg, low-dose Ophiopogon japonicus [LOJ]), middle-dose FEOJ group (6 mL/kg, medium-dose Ophiopogon japonicus [MOJ]), and high-dose FEOJ group (12 mL/kg, high-dose Ophiopogon japonicus [HOJ]). The clotting time (CT), bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FBG) were assessed in blood samples, and histological studies were performed on liver and lung tissues. The results demonstrated delayed CT only in MOJ and HOJ groups and delayed BT in all FEOJ groups compared with those in thrombosis and control groups (P < .05). Similarly, APTT was significantly delayed only in MOJ and HOJ groups, and PT was significantly delayed in all FEOJ groups, compared with those in control and thrombosis groups (P < .05). Although concentrations of FBG were similar in control, thrombosis, and LOJ groups, the tendency for decreased concentration of FBG (statistically nonsignificant) in MOJ and HOJ groups has been observed. Histological examination of livers and lungs revealed that thrombosis was partially improved in FEOJ group compared with the thrombosis group. In conclusion, CT, BT, PT, and APTT were prolonged in FEOJ group more than in control and thrombosis groups, thereby, depicting antithrombotic and thrombolytic effects. However, concentration-dependent effects of FEOJ were more prominent in MOJ and HOJ groups than in the LOJ group. PMID- 28598241 TI - Critical histone post-translational modifications for centromere function and propagation. AB - The centromere is a critical genomic region that enables faithful chromosome segregation during mitosis, and must be distinguishable from other genomic regions to facilitate establishment of the kinetochore. The centromere-specific histone H3-variant CENP-A forms a special nucleosome that functions as a marker for centromere specification. In addition to the CENP-A nucleosomes, there are additional H3 nucleosomes that have been identified in centromeres, both of which are predicted to exhibit specific features. It is likely that the composite organization of CENP-A and H3 nucleosomes contributes to the formation of centromere-specific chromatin, termed 'centrochromatin'. Recent studies suggest that centrochromatin has specific histone modifications that mediate centromere specification and kinetochore assembly. We use chicken non-repetitive centromeres as a model of centromeric activities to characterize functional features of centrochromatin. This review discusses our recent progress, and that of various other research groups, in elucidating the functional roles of histone modifications in centrochromatin. PMID- 28598240 TI - Classical autophagy proteins LC3B and ATG4B facilitate melanosome movement on cytoskeletal tracks. AB - Macroautophagy/autophagy is a dynamic and inducible catabolic process that responds to a variety of hormonal and environmental cues. Recent studies highlight the interplay of this central pathway in a variety of pathophysiological diseases. Although defective autophagy is implicated in melanocyte proliferation and pigmentary disorders, the mechanistic relationship between the 2 pathways has not been elucidated. In this study, we show that autophagic proteins LC3B and ATG4B mediate melanosome trafficking on cytoskeletal tracks. While studying melanogenesis, we observed spatial segregation of LC3B labeled melanosomes with preferential absence at the dendritic ends of melanocytes. This LC3B labeling of melanosomes did not impact the steady-state levels of these organelles but instead facilitated their intracellular positioning. Melanosomes primarily traverse on microtubule and actin cytoskeletal tracks and our studies reveal that LC3B enables the assembly of microtubule translocon complex. At the microtubule-actin crossover junction, ATG4B detaches LC3B from melanosomal membranes by enzymatic delipidation. Further, by live imaging we show that melanosomes transferred to keratinocytes lack melanocyte specific LC3B. Our study thus elucidates a new role for autophagy proteins in directing melanosome movement and reveal the unconventional use of these proteins in cellular trafficking pathways. Such crosstalk between the central cellular function and housekeeping pathway may be a crucial mechanism to balance melanocyte bioenergetics and homeostasis. PMID- 28598244 TI - Accumulation of undegraded autophagosomes by expression of dominant-negative STX17 (syntaxin 17) mutants. AB - Macroautophagy/autophagy, which is one of the main degradation systems in the cell, is mediated by a specialized organelle, the autophagosome. Purification of autophagosomes before fusion with lysosomes is important for both mechanistic and physiological studies of the autophagosome. Here, we report a simple method to accumulate undigested autophagosomes. Overexpression of the autophagosomal Qa SNARE STX17 (syntaxin 17) lacking the N-terminal domain (NTD) or N-terminally tagged GFP-STX17 causes accumulation of autophagosomes. A HeLa cell line, which expresses GFP-STX17DeltaNTD or full-length GFP-STX17 under the control of the tetracycline-responsive promoter, accumulates a large number of undigested autophagosomes devoid of lysosomal markers or early autophagy factors upon treatment with doxycycline. Using this inducible cell line, nascent autophagosomes can be easily purified by OptiPrep density-gradient centrifugation and immunoprecipitation. This novel method should be useful for further characterization of nascent autophagosomes. PMID- 28598245 TI - Factors associated with stress in families of children with autism spectrum disorder. AB - PURPOSE: The purpose of this study was to identify key factors associated with severe stress in families raising a child with autism spectrum disorder (ASD). METHODS: Questionnaires were mailed to families with one or more children with a diagnosis of ASD. Data from 543 surveys were analyzed using univariate and multivariate logistic regression. RESULTS: Forty-four percent (n = 241) of the caregivers reported severe family stress related to raising a child with ASD. Severe family stress was associated with (1) reduced ability to socialize; (2) not having accessed individual therapy; (3) negative co-parent relationships; and (4) high out of pockets costs due to the child's ASD. The specific ASD diagnosis, comorbid conditions, socio-demographic variables, and social support were not associated with severe family stress. CONCLUSION: The findings of the current study highlight the importance of a systemic approach to family stress, whereby individual, family, and ecological factors are investigated. PMID- 28598246 TI - The effect of ISAba1-mediated adeN gene disruption on Acinetobacter baumannii pathogenesis. PMID- 28598243 TI - Advances in arterial spin labelling MRI methods for measuring perfusion and collateral flow. AB - With the publication in 2015 of the consensus statement by the perfusion study group of the International Society for Magnetic Resonance in Medicine (ISMRM) and the EU-COST action 'ASL in dementia' on the implementation of arterial spin labelling MRI (ASL) in a clinical setting, the development of ASL can be considered to have become mature and ready for clinical prime-time. In this review article new developments and remaining issues will be discussed, especially focusing on quantification of ASL as well as on new technological developments of ASL for perfusion imaging and flow territory mapping. Uncertainty of the achieved labelling efficiency in pseudo-continuous ASL (pCASL) as well as the presence of arterial transit time artefacts, can be considered the main remaining challenges for the use of quantitative cerebral blood flow (CBF) values. New developments in ASL centre around time-efficient acquisition of dynamic ASL-images by means of time-encoded pCASL and diversification of information content, for example by combined 4D-angiography with perfusion imaging. Current vessel-encoded and super-selective pCASL-methodology have developed into easily applied flow-territory mapping methods providing relevant clinical information with highly similar information content as digital subtraction angiography (DSA), the current clinical standard. Both approaches seem therefore to be ready for clinical use. PMID- 28598247 TI - A long-range flexible billboard model of gene activation. AB - Gene regulation is fundamentally important for the coordination of diverse biologic processes including homeostasis and responses to developmental and environmental stimuli. Transcription factor (TF) binding sites are one of the major functional subunits of gene regulation. They are arranged in cis-regulatory modules (CRMs) that can be more active than the sum of their individual effects. Recently, we described a mechanism of glucocorticoid (GC)-induced gene regulation in which the glucocorticoid receptor (GR) binds coordinately to multiple CRMs that are 10s of kilobases apart in the genome. In those results, the minority of GR binding sites appear to involve direct TF:DNA interactions. Meanwhile, other GR binding sites in a cluster interact with those direct binding sites to tune their gene regulatory activity. Here, we consider the implications of those and related results in the context of existing models of gene regulation. Based on our analyses, we propose that the billboard and regulatory grammar models of cis regulatory element activity be expanded to consider the influence of long-range interactions between cis-regulatory modules. PMID- 28598250 TI - Telehealth Centers: A Proposal of a Theoretical Model for Evaluation. AB - BACKGROUND: Telehealth is a form of assistance support and continuing education for professionals who work in Primary Healthcare. INTRODUCTION: The implementation of the Brazilian Telehealth Program has extended the need for evaluation of its results to improve its use and benefits. Thus, it is necessary to systematize the theory, principals, and guidelines that guide the program organization, its activities, and resources. The objective of this study is to propose a theoretical model of functioning and organization for telehealth centers of the Brazilian Telehealth Program. MATERIALS AND METHODS: A study that combined bibliographic, documental research and empiric data to systematize information, which are the basis functioning of the program, and verify the availability of telehealth centers in Brazil. RESULTS: The results were the construction of a theoretical model that demonstrated the evaluability of the object and the definition of methodological paths to continue the evaluation research that respond with fragilities and potentialities. DISCUSSION: In Brazil, there is public funding for telehealth activities offered by telehealth centers linked to the Ministry of Health. Its operation is guided by support for training and assistance activities, enabling qualification and strengthening of professionals to improve patient care and increase access. The transformation of reality is possible and favored by the articulation of teaching and service. More research is needed to evaluate these services offered. Theoretical guidance through modeling is fundamental to qualify the evaluation. CONCLUSION: The theoretical model is an important tool to qualify and optimize the evaluative research process. PMID- 28598249 TI - Recall and decay of consent information among parents of infants participating in a randomized controlled clinical trial using an audio-visual tool in The Gambia. AB - Communicating essential research information to low literacy research participants in Africa is highly challenging, since this population is vulnerable to poor comprehension of consent information. Several supportive materials have been developed to aid participant comprehension in these settings. Within the framework of a pneumococcal vaccine trial in The Gambia, we evaluated the recall and decay of consent information during the trial which used an audio-visual tool called 'Speaking Book', to foster comprehension among parents of participating infants. The Speaking Book was developed in the 2 most widely spoken local languages. Four-hundred and 9 parents of trial infants gave consent to participate in this nested study and were included in the baseline assessment of their knowledge about trial participation. An additional assessment was conducted approximately 90 d later, following completion of the clinical trial protocol. All parents received a Speaking Book at the start of the trial. Trial knowledge was already high at the baseline assessment with no differences related to socio economic status or education. Knowledge of key trial information was retained at the completion of the study follow-up. The Speaking Book (SB) was well received by the study participants. We hypothesize that the SB may have contributed to the retention of information over the trial follow-up. Further studies evaluating the impact of this innovative tool are thus warranted. PMID- 28598248 TI - Enamel matrix derivative enhances the proliferation and osteogenic differentiation of human periodontal ligament stem cells on the titanium implant surface. AB - Periodontal ligament stem cells (PDLSCs) have mesenchymal-stem-cells-like qualities, and are considered as one of the candidates of future clinical application in periodontal regeneration therapy. Enamel matrix derivative (EMD) is widely used in promoting periodontal regeneration. However, the effects of EMD on the proliferation and osteogenic differentiation of human PDLSCs grown on the Ti implant surface are still no clear. Therefore, this study examined the effects of EMD on human PDLSCs in vitro. Human PDLSCs were isolated from healthy participants, and seeded on the surface of Ti implant disks and stimulated with various concentrations of EMD. Cell proliferation was determined with Cell Counting Kit-8 (CCK-8). The osteogenic differentiation of PDLSCs was evaluated by the measurement of alkaline phosphatase (ALP) activity, Alizarin red staining, and real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. The results indicated that EMD at concentrations (5-60 ug/ml) increased the viability and proliferation of PDLSCs. The treatment with 30 and 60 ug/ml of EMD significantly elevated ALP activity, augmented mineralized nodule formation and calcium deposition, and upregulated the mRNA and protein levels of Runx-2 and osteocalcin (OCN) in the PDLSCs grown on the Ti surface. Further investigation found that EMD treatment did not change the protein levels of phosphatidylinositol-3-kinase (PI3K), p-PI3K, Akt and mTOR, but significantly upregulated the phosphorylated levels of Akt and mTOR. Collectively, these results suggest that EMD stimulation can promote the proliferation and osteogenic differentiation of PDLSCs grown on Ti surface, which is possibly associated with the activation of Akt/mTOR signaling pathway. PMID- 28598251 TI - Molecular Characterization of Methicillin-Resistant Staphylococcus aureus Isolated from Australian Animals and Veterinarians. AB - This study aimed to determine the frequency and molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) from Australian animals and whether animal-derived MRSA was similar to that from Australian veterinarians. A total of 1,080 clinical coagulase positive Staphylococcus isolates from Australian animals were collected during 2013. Sixteen (4%) of 360 S. aureus isolates were MRSA. Most MRSA came from companion animals, while none came from livestock. MRSA isolates were characterized using whole genome sequencing. ST22 IV (EMRSA-15) was the most common clone in dogs and cats. Clonal complex (CC) 8 was most common in horses. Most ST22-IV isolates were resistant to ciprofloxacin. Animal-derived MRSA genomes were interrogated for the presence of host-specific genetic markers (staphylokinase gene [scn], chemotaxis-inhibiting proteins gene [chp], staphylococcal complement inhibitor gene [sak], enterotoxin A gene [sea], and Von Willebrand Factor binding protein gene [vwb]). A subset of MRSA genomes previously collected from Australian veterinarians was also interrogated. There was no clear pattern in the distribution of host-specific markers among animal and veterinarian isolates. Animal- and veterinarian-derived MRSA were intermingled in the phylogenetic tree. The absence of MRSA in Australian livestock is in stark contrast with its presence in livestock from other countries. Possible explanations include Australia's geographic isolation, the absence of live animal importation into Australia, and most notably, the restrictions placed on the use of antimicrobials of critical importance in Australian livestock. PMID- 28598252 TI - Mutation of nucleotides around the +1 position of type 3 polymerase III promoters: The effect on transcriptional activity and start site usage. AB - Type 3 RNA polymerase III (Pol III) promoters are widely used for the expression of small RNAs such as short hairpin RNA and guide RNA in the popular RNAi and CRISPR-Cas gene regulation systems. Although it is generally believed that type 3 Pol III promoters use a defined transcription start site (+1 position), most man made promoter constructs contain local sequence alterations of which the impact on transcription efficiency and initiation accuracy is not known. For three human type 3 Pol III promoters (7SK, U6, and H1), we demonstrated that the nucleotides around the +1 position affect both the transcriptional efficiency and start site selection. Human 7SK and U6 promoters with A or G at the +1 position efficiently produced small RNAs with a precise +1 start site. The human H1 promoter with +1A or G also efficiently produced small RNAs but from multiple start sites in the 3/-1 window. These results provide new insights for the design of vectors for accurate expression of designed small RNAs for research and therapeutic purposes. PMID- 28598253 TI - Androgen receptor and miR-206 regulation in prostate cancer. AB - In the United States, prostate cancer is the second leading cause of cancer related deaths among men with an approximately 220,000 patients diagnosed with the disease in 2015. Prostate cancer is a hormone-driven tumor, and a common therapy is androgen-deprivation therapy (ADT) that involves anti-androgen treatments and/or castration therapy. Understanding the molecular basis for androgen-independent tumors is crucial toward developing new therapies for these patients. Understanding how androgen receptor itself functions is an important step in elucidating this process. Androgen receptor (AR), NR3C4, is a nuclear hormone receptor and functions as a DNA-binding transcription factor that regulates the expression of protein-coding genes. Translocation of AR to improper gene promoter elements or DNA-binding sites can result in an alteration in gene expression and thus normal prostate function. Therefore, it is crucial to understand which AR-promoter interactions are drivers of disease, as compared to promiscuous or benign AR-binding interactions. While a large portion of our genome is considered a gene desert, it is now appreciated that these regions of the genome contain non-coding RNA genes such as microRNAs (miRNAs). These non coding RNAs have enormous regulatory potential, as they post-transcriptionally regulate gene expression by binding to messenger RNAs (mRNAs) to promote degradation or intervention of translational processes. In this review, we focus specifically on the notion that mis-regulation of non-coding RNAs such as miRNAs by improper AR-DNA binding are an important component that promotes prostate cancer. We also highlight the role of miR-206 and the interaction of miR-206 and AR within this process, given this is a miRNA known to be regulated by hormones in both breast and prostate cancer. PMID- 28598254 TI - Archaeal RNA polymerase arrests transcription at DNA lesions. AB - Transcription elongation is not uniform and transcription is often hindered by protein-bound factors or DNA lesions that limit translocation and impair catalysis. Despite the high degree of sequence and structural homology of the multi-subunit RNA polymerases (RNAP), substantial differences in response to DNA lesions have been reported. Archaea encode only a single RNAP with striking structural conservation with eukaryotic RNAP II (Pol II). Here, we demonstrate that the archaeal RNAP from Thermococcus kodakarensis is sensitive to a variety of DNA lesions that pause and arrest RNAP at or adjacent to the site of DNA damage. DNA damage only halts elongation when present in the template strand, and the damage often results in RNAP arresting such that the lesion would be encapsulated with the transcription elongation complex. The strand-specific halt to archaeal transcription elongation on modified templates is supportive of RNAP recognizing DNA damage and potentially initiating DNA repair through a process akin to the well-described transcription-coupled DNA repair (TCR) pathways in Bacteria and Eukarya. PMID- 28598257 TI - What's Worth Talking About? Information Theory Reveals How Children Balance Informativeness and Ease of Production. AB - Of all the things a person could say in a given situation, what determines what is worth saying? Greenfield's principle of informativeness states that right from the onset of language, humans selectively comment on whatever they find unexpected. In this article, we quantify this tendency using information theoretic measures and report on a study in which we tested the counterintuitive prediction that children will produce words that have a low frequency given the context, because these will be most informative. Using corpora of child-directed speech, we identified adjectives that varied in how informative (i.e., unexpected) they were given the noun they modified. In an initial experiment ( N = 31) and in a replication ( N = 13), 3-year-olds heard an experimenter use these adjectives to describe pictures. The children's task was then to describe the pictures to another person. As the information content of the experimenter's adjective increased, so did children's tendency to comment on the feature that adjective had encoded. Furthermore, our analyses suggest that children balance informativeness with a competing drive to ease production. PMID- 28598255 TI - The regulatory role of miRNAs on VDR in breast cancer. AB - Triple negative breast cancer (TNBC) has been associated with the lack of three hormone receptors; estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2). However, a host of other steroid hormone receptors such as vitamin D receptor (VDR) is present in TNBC, and the role of these hormone receptors in breast tumorigenesis is unclear. The levels of microRNAs (miRNAs) are also expressed differently than in normal mammary epithelial cells. miRNAs are regulatory RNAs involved in various cellular functions, mainly gene silencing. Here, we reviewed the literature surrounding miRNAs in breast cancer, and performed in silico analysis to determine whether there was a correlation between levels of VDR in relation to miRNAs important in breast cancer development and tumorigenesis. We identified three miRNAs of interest, specifically, miR-23, miR-124, and miR-125. Through this research we determined the possibility that these miRNAs play an important role in controlling VDR activity and by virtue the development of breast cancer. PMID- 28598259 TI - SEPP1 and SEP15 gene polymorphisms and susceptibility to breast cancer. PMID- 28598256 TI - Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination. AB - Two large pivotal phase III studies demonstrated the efficacy of the tetravalent dengue vaccine (CYD-TDV; Dengvaxia(r), Sanofi Pasteur) against all dengue serotypes. Here we present an unprecedented integrated summary of the immunogenicity of CYD-TDV to identify the parameters driving the neutralizing humoral immune response and evolution over time. We summarized the immunogenicity profiles of a 3-dose schedule of CYD-TDV administered 6 months apart across 10 phase II and 6 phase III trials undertaken in dengue endemic and non-endemic countries. Dengue neutralizing antibody titers in sera were determined at centralized laboratories using the 50% plaque reduction neutralization test (PRNT50) at baseline, 28 d after the third dose, and annually thereafter for up to 4 y after the third dose in some studies. CYD-TDV elicits neutralizing antibody responses against all 4 dengue serotypes; geometric mean titers (GMTs) increased from baseline to post-dose 3. GMTs were influenced by several parameters including age, baseline dengue seropositivity and region. In the 2 pivotal studies, GMTs decreased initially during the first 2 y post-dose 3 but appear to stabilize or slightly increase again in the third year. GMTs persisted 1.2-3.2-fold higher than baseline levels for up to 4 y post-dose 3 in other studies undertaken in dengue endemic countries. Our integrated analysis captures the fullness of the CYD-TDV immunogenicity profile across studies, age groups and regions; by presenting the available data in this way general trends and substantial outliers within each grouping can be easily identified. CYD-TDV elicits neutralizing antibody responses against all dengue serotypes, with differences by age and endemicity, which persist above baseline levels in endemic countries. PMID- 28598260 TI - Comparison of the Acceptance of Telemonitoring for Glucose Management Between South Korea and China. AB - BACKGROUND: Telemonitoring is used for glucose management and support in many countries. A better understanding of the differences in telemonitoring acceptance based on regional characteristics is needed. Therefore, we compared the acceptance of telemonitoring for glucose management among patients in South Korea and China. MATERIALS AND METHODS: This study used data from Korean (n = 81) and Chinese (n = 92) subjects with type 2 diabetes. We used two independent sample t tests to compare patients' perceptions of telemonitoring and multiple regression analysis to determine the factors that affected their behavioral intentions to use telemonitoring. We conducted Wilcoxon signed rank tests to assess the differences in hemoglobin A1c (HbA1c) levels from baseline to follow-up. RESULTS: Although Korean and Chinese patients had positive perceptions of the services, different factors influenced their behavioral intentions to use them. In South Korea, performance expectations and social influences were significantly associated with intention to use telemonitoring. Patients younger than 50 years showed a significant decrease in HbA1c levels at month 6 (p < 0.05). In China, effort expectancy and facilitating conditions were significantly associated with intention to use. In addition, subjects in all age groups exhibited a significant decrease in HbA1c levels at all follow-up points (p < 0.001). CONCLUSION: Telemonitoring was a supportive intervention in improving blood sugar levels among patients with diabetes in South Korea and China, but the factors influencing its use varied. We provide practical guidance for developing telemonitoring for glucose management that considers the distinct characteristics of different countries. PMID- 28598258 TI - The epidemiology of supernumerary teeth and the associated molecular mechanism. AB - Supernumerary teeth are common clinical dental anomalies. Although various studies have provided abundant information regarding genes and signaling pathways involved in tooth morphogenesis, which include Wnt, FGF, BMP, and Shh, the molecular mechanism of tooth formation, especially for supernumerary teeth, is still unclear. In the population, some cases of supernumerary teeth are sporadic, while others are syndrome-related with familial hereditary. The prompt and accurate diagnosis of syndrome related supernumerary teeth is quite important for some distinctive disorders. Mice are the most commonly used model system for investigating supernumerary teeth. The upregulation of Wnt and Shh signaling in the dental epithelium results in the formation of multiple supernumerary teeth in mice. Understanding the molecular mechanism of supernumerary teeth is also a component of understanding tooth formation in general and provides clinical guidance for early diagnosis and treatment in the future. PMID- 28598262 TI - Strigolactones in the Rhizosphere: Friend or Foe? AB - Strigolactones are well-known endogenous plant hormones that play a major role in planta by influencing different physiological processes. Moreover, ex planta, strigolactones are important signaling molecules in root exudates and function as host detection cues to launch mutualistic interactions with arbuscular mycorrhizal fungi in the rhizosphere. However, parasitic plants belonging to the Orobanchaceae family hijacked this communication system to stimulate their seed germination when in close proximity to the roots of a suitable host. As a result, the secretion of strigolactones by the plant can have both favorable and detrimental outcomes. Here, we discuss these dual positive and negative effects of strigolactones and we provide a detailed overview on the role of these molecules in the complex dialogs between plants and different organisms in the rhizosphere. PMID- 28598261 TI - Neurotoxicity of alkylated polycyclic aromatic compounds in human neuroblastoma cells. AB - Polycyclic aromatic compounds (PAC) are ubiquitous environmental pollutants originating from incomplete combustion processes. While the toxicity of parent PAC such as benzo[a]pyrene (BaP) is well characterized, effects of other alkyl PAC dibenzothiophene (DBT) and retene (Ret) are not well established. The aim of this study was to examine the underlying relative neurotoxic mechanisms attributed to BaP (parent PAH), DBT and Ret (alkyl-PACs) using human neuroblastoma SK-N-SH cells. The lethal concentrations (LC10 and LC20) were found at approximately 10 uM and 40 uM, respectively after 24-h exposure of SK-N-SH cells. It was hypothesized that PAC trigger reactive oxygen species (ROS) production, leading to activation of apoptotic signaling pathways. Differentiated neuronal cells were treated with three compounds at (0.5-40 uM) for 24 h. There was a significant concentration-dependent increase in levels of ROS, even at sub lethal levels of 1 uM Ret. The mitochondrial membrane potential (MMP) was significantly decreased. Real-time RT-PCR results showed up-regulation of pro apoptotic genes and down-regulation of antioxidative genes expression in BaP-, DBT-, and Ret-treated SK-N-SH cells. Cytochrome c protein levels and lipid peroxidation (LPO) were also significantly elevated in a concentration-related manner. Data demonstrated that BaP-, DBT-, or Ret-induced neuronal cell damage involved oxidative stress generation through mitochondria-mediated apoptosis pathway. Alkyl-PAC also exhibited higher potency in ROS induction and reduction of MMP than parent PAC. These findings may be important for environmental risk assessment attributed to exposure to PAC. PMID- 28598264 TI - Letter to the Editor. Subdural collections in infants: trauma or not trauma? PMID- 28598263 TI - The Phenylalanine Ammonia Lyase Gene LjPAL1 Is Involved in Plant Defense Responses to Pathogens and Plays Diverse Roles in Lotus japonicus-Rhizobium Symbioses. AB - Phenylalanine ammonia lyase (PAL) is important in the biosynthesis of plant secondary metabolites that regulate growth responses. Although its function is well-established in various plants, the functional significance of PAL genes in nodulation is poorly understood. Here, we demonstrate that the Lotus japonicus PAL (LjPAL1) gene is induced by Mesorhizobium loti infection and methyl-jasmonate (Me-JA) treatment in roots. LjPAL1 altered PAL activity, leading to changes in lignin contents and thicknesses of cell walls in roots and nodules of transgenic plants and, hence, to structural changes in roots and nodules. LjPAL1-knockdown plants (LjPAL1i) exhibited increased infection thread and nodule numbers and the induced upregulation of nodulin gene expression after M. loti infection. Conversely, LjPAL1 overexpression delayed the infection process and reduced infection thread and nodule numbers after M. loti inoculation. LjPAL1i plants also exhibited reduced endogenous salicylic acid (SA) accumulation and expression of the SA-dependent marker gene. Their infection phenotype could be partially restored by exogenous SA or Me-JA application. Our data demonstrate that LjPAL1 plays diverse roles in L. japonicus-rhizobium symbiosis, affecting rhizobial infection progress and nodule structure, likely by inducing lignin modification, regulating endogenous SA biosynthesis, and modulating SA signaling. PMID- 28598265 TI - Robot-assisted endoscopic third ventriculostomy: institutional experience in 9 patients. AB - OBJECTIVE The endoscopic third ventriculostomy (ETV) is an established and effective treatment for obstructive hydrocephalus. In its most common application, surgeons plan their entry point and the endoscope trajectory for the procedure based on anatomical landmarks, then control the endoscope freehand. Recent studies report an incidence of neural injuries as high as 16.6% of all ETVs performed in North America. The authors have introduced the ROSA system to their ETV procedure to stereotactically optimize endoscope trajectories, to reduce risk of traction on neural structures by the endoscope, and to provide a stable mechanical holder of the endoscope. Here, they present their series in which the ROSA system was used for ETVs. METHODS At the authors' institution, they performed ETVs with the ROSA system in 9 consecutive patients within an 8 month period. Patients had to have a favorable expected response to ETV (ETV Success Score >= 70) with no additional endoscopic procedures (e.g., choroid plexus cauterization, septum pellucidum fenestration). The modality of image registration (CT, MRI, surface mapping, or bone fiducials) was dependent on the case. RESULTS Nine pediatric patients with an age range of 1.5 to 16 years, 4 girls and 5 boys, with ETV Success Scores ranging from 70 to 90, underwent successful ETV surgery with the ROSA system within an 8-month period. Their intracranial pathologies included tectal tumors (n = 3), communicating hydrocephalus from hemorrhage or meningeal disease (n = 2), congenital aqueductal stenosis (n = 1), compressive porencephalic cyst (n = 1), Chiari I malformation (n = 1), and pineal region mass (n = 1). Robotic assistance was limited to the ventricular access in the first 2 procedures, but was used for the entirety of the procedure for the following 7 cases. Four of these cases were combined with another procedural objective (3 stereotactic tectal mass biopsies, 1 Chiari decompression). A learning curve was observed with each subsequent surgery as registration and surgical times became shorter and more efficient. All patients had complete resolution of their preprocedural symptoms. There were no complications. CONCLUSIONS The ROSA system provides a stable, precise, and minimally invasive approach to ETVs. PMID- 28598266 TI - Reversible lysine acetylation: Another layer of post-translational regulation of the cardiac sodium channel. PMID- 28598267 TI - Interaction of Immunoglobulin with Cytomegalovirus-Infected Cells. AB - Intravenous immunoglobulin (IVIG) is used to treat or prevent severe viral infection, especially cytomegalovirus (CMV) infections. IVIG was characterized to understand its interaction with CMV-infected cells. IVIG retarded CMV spread and reduced virus yields depending on the neutralizing (NT) antibody titer. Immediate early protein synthesis was reduced by IVIG in 3 to 15 h, and IVIG specifically reduced the ratio of 66/68k protein synthesis among immediate early proteins in an NT antibody-dependent manner between 4 and 8 h after infection, indicating that antigenic modulation of CMV-infected cells by IVIG reduced viral protein synthesis and virus production. The half-life of antibody bound to CMV-infected cells was 3.8 h. NT antibody titers to varicella-zoster virus (VZV) and CMV in IVIG were dose dependently absorbed by cells infected with VZV and CMV, respectively, but the antibody titers to CMV and VZV, respectively, were not affected. NT antibody in 0.3 mL of IVIG (15 mg) was specifically absorbed by 108 CMV-infected cells and 107 VZV-infected cells, suggesting that the NT antibody in IVIG might be inactivated by one-tenth of a similar volume of CMV-infected or VZV infected cells. Various antiviral activities of IVIG may contribute to control and alleviation of CMV infection. PMID- 28598268 TI - Effects of pulmonary exposure to chemically-distinct welding fumes on neuroendocrine markers of toxicity. AB - Exposure to welding fumes may result in disorders of the pulmonary, cardiovascular, and reproductive systems. Welders are also at a greater risk of developing symptoms similar to those seen in individuals with idiopathic Parkinson's disease. In welders, there are studies that suggest that alterations in circulating prolactin concentrations may be indicative of injury to the dopamine (DA) neurons in the substantia nigra. The goal of these studies was to use an established model of welding particulate exposure to mimic the effects of welding fume inhalation on reproductive functions. Since previous investigators suggested that changes in circulating prolactin may be an early marker of DA neuron injury, movement disorders, and reproductive dysfunction, prolactin, hypothalamic tyrosine hydroxylase (TH) levels (a marker of DA synthesis), and other measures of hypothalamic-pituitary-gonadal (HPG) function were measured after repetitive instillation of welding fume particulates generated by flux core arc-hard surfacing (FCA-HS), manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) welding, or manganese chloride (MnCl2). Exposure to welding fume particulate resulted in the accumulation of various metals in the pituitary and testes of rats, along with changes in hypothalamic TH and serum prolactin levels. Exposure to particulates with high concentrations of soluble manganese (Mn) appeared to exert the greatest influence on TH activity levels and serum prolactin concentrations. Thus, circulating prolactin levels may serve as a biomarker for welding fume/Mn-induced neurotoxicity. Other reproductive measures were collected, and these data were consistent with epidemiological findings that prolactin and testosterone may serve as biomarkers of welding particulate induced DA neuron and reproductive dysfunction. PMID- 28598269 TI - Cancer mortality in Yukon 1999-2013: elevated mortality rates and a unique cancer profile. AB - BACKGROUND: Although cancer is the leading cause of death in Canada, cancer in the North has been incompletely described. OBJECTIVE: To determine cancer mortality rates in the Yukon Territory, compare them with Canadian rates, and identify major causes of cancer mortality. DESIGN: The Yukon Vital Statistics Registry provided all cancer deaths for Yukon residents between 1999-2013. Age standardised mortality rates (ASMRs) were calculated using direct standardisation and compared with Canadian rates. Standardised mortality ratios (SMRs) were calculated using indirect standardisation relative to age-specific rates from Canada, British Columbia (BC), and three sub-provincial BC administrative health regions : Interior Health (IH), Northern Health (NH) and Vancouver Coastal Health (VCH). Trends in smoothed ASMRs were examined with graphical methods. RESULTS: Yukon's all-cancer ASMRs were elevated compared with national and provincial rates for the entire period. Disparities were greatest compared with the urban VCH: prostate (SMRVCH=246.3, 95% CI 140.9-351.6), female lung (SMRVCH=221.2, 95% CI 154.3-288.1), female breast (SMRVCH=169.0 95% CI, 101.4-236.7), and total colorectal (SMRVCH=149.3, 95% CI 101.8-196.8) cancers were significantly elevated. Total stomach cancer mortality was significantly elevated compared with all comparators. CONCLUSIONS: Yukon cancer mortality rates were elevated compared with national, provincial, urban, and southern-rural jurisdictions. More research is required to elucidate these differences. PMID- 28598270 TI - Investigating the Adult Ixodid Tick Populations and Their Associated Anaplasma, Ehrlichia, and Rickettsia Bacteria at a Rocky Mountain Spotted Fever Hotspot in Western Tennessee. AB - Ehrlichiosis and rickettsiosis are two common bacterial tick-borne diseases in the southeastern United States. Ehrlichiosis is caused by ehrlichiae transmitted by Amblyomma americanum and rickettsiosis is caused by rickettsiae transmitted by Amblyomma maculatum and Dermacentor variabilis. These ticks are common and have overlapping distributions in the region. The objective of this study was to identify Anaplasma, Ehrlichia, and Rickettsia species associated with questing ticks in a Rocky Mountain spotted fever (RMSF) hotspot, and identify habitats, time periods, and collection methods for collecting questing-infected ticks. Using vegetation drags and CO2-baited traps, ticks were collected six times (May September 2012) from 100 sites (upland deciduous, bottomland deciduous, grassland, and coniferous habitats) in western Tennessee. Adult collections were screened for Anaplasma and Ehrlichia (simultaneous polymerase chain reaction [PCR]) and Rickettsia using genus-specific PCRs, and resulting positive amplicons were sequenced. Anaplasma and Ehrlichia were only identified within A. americanum (Ehrlichia ewingii, Ehrlichia chaffeensis, Panola Mountain Ehrlichia, and Anaplasma odocoilei sp. nov.); more Ehrlichia-infected A. americanum were collected at the end of June regardless of habitat and collection method. Rickettsia was identified in three tick species; "Candidatus Rickettsia amblyommii" from A. americanum, R. parkeri and R. andeanae from A. maculatum, and R. montanensis ( = montana) from D. variabilis. Overall, significantly more Rickettsia-infected ticks were identified as A. americanum and A. maculatum compared to D. variabilis; more infected-ticks were collected from sites May-July and with dragging. In this study, we report in the Tennessee RMSF hotspot the following: (1) Anaplasma and Ehrlichia are only found in A. americanum, (2) each tick species has its own Rickettsia species, (3) a majority of questing-infected ticks are collected May-July, (4) A. americanum and A. maculatum harbor pathogenic bacteria in western Tennessee, and (5) R. rickettsii remains unidentified. PMID- 28598271 TI - Short-term effects of ozone air pollution on hospital admissions for myocardial infarction: A time-stratified case-crossover study in Taipei. AB - This study was undertaken to determine whether there was a correlation between ambient ozone (O3) levels and number of hospital admissions for myocardial infarction (MI) in Taipei, Taiwan. Hospital admissions for MI and ambient air pollution data for Taipei were obtained for the period from 2006 to 2010. The relative risk (RR) of hospital admissions for MI was estimated using a time stratified case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. For the single-pollutant model (without adjustment for other pollutants), increased RR for a number of MI admissions was significantly associated with higher O3 levels both on warm days (>23 degrees C) and on cool days (<23 degrees C). This observation was accompanied by an interquartile range elevation correlated with a 7% (95% CI = 2% 12%) and 17% (95% CI = 11%-25%) rise in number of MI admissions, respectively. In the two-pollutant models, no significant associations between ambient O3 concentrations and number of MI admissions were observed on warm days. However, on cool days, correlation between ambient O3 after inclusion of each of the other five pollutants, particulate matter (PM10 or PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2) or carbon monoxide (CO), and number of MI admissions remained significant. This study provides evidence that higher levels of ambient O3 increase the RR of number of hospital admissions for MI. PMID- 28598272 TI - Short-term effects of fine particulate air pollution on hospital admissions for hypertension: A time-stratified case-crossover study in Taipei. AB - This study was undertaken to determine whether there was a correlation between fine particle (PM2.5) levels and hospital admissions for hypertension in Taipei, Taiwan. Hospital admissions for hypertension and ambient air pollution data for Taipei were obtained for the period from 2009 to 2013. The relative risk of hospital admissions was estimated using a case-crossover approach, controlling for weather variables, day of the week, seasonality, and long-term time trends. For the single pollutant model (without adjustment for other pollutants), the risk of hospital admissions for hypertension was estimated to increase by 12% on warm days (>23 degrees C) and 2% on cool days (<23 degrees C), respectively. There was no indication of an association between levels of PM2.5 and risk of hospital admissions for hypertension. In two-pollutant model, PM2.5 remained nonsignificant after inclusion of any of the other air pollutants (SO2, NO2, CO, or O3) both on warm and cool days, but a numerically greater response was seen on warm days. Data thus indicate that in Taipei, hospital admissions for hypertension occur as a consequence of factors not related to ambient air exposure. PMID- 28598273 TI - Conventional and high-resolution vessel wall MRI of intracranial aneurysms: current concepts and new horizons. AB - Intracranial aneurysms are heterogeneous in histopathology and imaging appearance. The biological behavior of different types of aneurysms is now known to depend on the structure and physiology of the aneurysm wall itself in addition to intraluminal flow and other luminal features. Aneurysm wall structure and imaging markers of physiology such as aneurysm wall enhancement have been assessed in many prior investigations using conventional-resolution MRI. Recently, high-resolution vessel wall imaging (HR-VWI) techniques with MRI have been introduced. Reports of findings on high-resolution imaging have already emerged for many types of aneurysms demonstrating detailed characterization of wall enhancement, thickness, and components, but many questions remain unexplored. This review discusses the key HR-VWI literature to date. Aneurysm wall findings on conventional-resolution MRI are also discussed as these may help one understand the potential utility and findings on HR-VWI for various aneurysm types. The authors have illustrated these points with several examples demonstrating both features already described in the literature and novel cases demonstrating the potential for future clinical and research applications. PMID- 28598274 TI - Evaluation of ischemic lesion prevalence after endovascular treatment of intracranial aneurysms, as documented by 3-T diffusion-weighted imaging: a 2 year, single-center cohort study. AB - OBJECTIVE Even though published data exist concerning the prevalence of ischemic lesions detected by diffusion-weighted imaging (DWI) following endovascular treatment of intracranial aneurysms, a single-center cross-evaluation of the different endovascular techniques has been lacking. The authors sought to prospectively evaluate the prevalence and clinical significance of ischemic lesions occurring after endovascular treatment of intracranial aneurysms and to compare the safety and effectiveness of a broad spectrum of currently accepted endovascular techniques in a single-center setting. METHODS This was a prospective cohort study involving consecutive patients treated for intracranial aneurysms exclusively by endovascular means, excluding treatments in the acute rupture phase, in a center featuring an endovascular-only treatment policy for intracranial aneurysms. All patients underwent MRI, including a 3-directional DWI sequence, before treatment, 24 hours postprocedure, and 6 months following endovascular embolization. Selective angiography was performed at 6 months' follow-up. RESULTS From January 2012 through December 2013, 164 aneurysms were treated in 128 consecutive patients. Endovascular techniques included coiling (14.6%), balloon-assisted coiling (20.1%), stent-assisted coiling (3.7%), low profile stent-assisted coiling, flow diversion (38.4%), and very complex treatments (6.1%) involving 2 stents in Y or T configurations. On postprocedure MRI, the rates of occurrence of new DWI-positive lesions were 64.3% for coiling, 54.5% for remodeling, 61.1% for stent-assisted coiling, 53.7% for flow-diverting stents, and 75% for very complex treatments (p = 0.4962). The 6-month procedure related morbidity and mortality rates were 6.25% and 0%, respectively. At 6 months' follow-up, 93% of the patients had modified Rankin Scale (mRS) scores of 0-2. Very complex treatments offered a higher complete occlusion rate (100%) than all other techniques (66.7%-88.9%). Age and length of procedure were independent factors for DWI lesion occurrence. The diameter of DWI lesions on 24-hour postprocedure MRI was positively correlated with mRS score at discharge. Among the DWI-positive lesions measuring less than 2 mm in diameter on the 24-hour MRI, 44.12% had regressed at 6 months. CONCLUSIONS Procedure-related DWI lesions are far more often encountered in silent forms than they are clinically evident. They do not seem to be significantly correlated with procedure-related complications, nor do they seem to impair clinical outcome, regardless of the endovascular technique. Small lesions (< 2 mm in diameter) may regress within 6 months. The use of the most adapted technique, in terms of aneurysm configuration, results in significant total occlusion rates, with acceptable safety. PMID- 28598275 TI - Demographic and clinical predictors of multiple intracranial aneurysms in patients with subarachnoid hemorrhage. AB - OBJECTIVE Pathophysiological differences that underlie the development and subsequent growth of multiple aneurysms may exist. In this study, the authors assessed the factors associated with the occurrence of multiple aneurysms in patients presenting with aneurysmal subarachnoid hemorrhage (SAH). METHODS Consecutive patients presenting with aneurysmal SAH between 1996 and 2012 were prospectively enrolled in the Subarachnoid Hemorrhage Outcome Project. Patients harboring 1, 2, or 3 or more aneurysms were stratified into groups, and the clinical and radiological characteristics of each group were compared using multivariate logistic regression. RESULTS Of 1277 patients with ruptured intracranial aneurysms, 890 had 1 aneurysm, 267 had 2 aneurysms, and 120 had 3 or more aneurysms. On multinomial regression using the single-aneurysm cohort as base case, risk factors for patients presenting with 2 aneurysms were female sex (relative risk ratio [RRR] 1.80, p < 0.001), higher body mass index (BMI) (RRR 1.02, p = 0.003), more years of smoking (RRR = 1.01, p = 0.004), and black race (RRR 1.83, p = 0.001). The risk factors for patients presenting with 3 or more aneurysms were female sex (RRR 3.10, p < 0.001), higher BMI (RRR 1.03, p < 0.001), aneurysm in the posterior circulation (RRR 2.59, p < 0.001), and black race (RRR 2.15, p = 0.001). Female sex, longer smoking history, aneurysms in the posterior circulation, BMI, and black race were independently associated with the development of multiple aneurysms in our adjusted multivariate multinomial model. CONCLUSIONS Significant demographic and clinical differences are found between patients presenting with single and multiple aneurysms in the setting of aneurysmal SAH. These predictors of multiple aneurysms likely reflect a predisposition toward inflammation and endothelial injury. PMID- 28598276 TI - Risk factors associated with postoperative cerebrospinal fluid leak after endoscopic endonasal skull base surgery. AB - OBJECTIVE The aim in this paper was to determine risk factors for the development of a postoperative CSF leak after an endoscopic endonasal approach (EEA) for resection of skull base tumors. METHODS A retrospective review of patients who underwent EEA for the resection of intradural pathology between January 1997 and June 2012 was performed. Basic demographic data were collected, along with patient body mass index (BMI), tumor pathology, reconstruction technique, lumbar drainage, and outcomes. RESULTS Of the 615 patients studied, 103 developed a postoperative CSF leak (16.7%). Sex and perioperative lumbar drainage did not affect CSF leakage rates. Posterior fossa tumors had the highest rate of CSF leakage (32.6%), followed by anterior skull base lesions (21.0%) and sellar/suprasellar lesions (9.9%) (p < 0.0001). There was a higher leakage rate for overweight and obese patients (BMI > 25 kg/m2) than for those with a healthy weight BMI (18.7% vs 11.5%; p = 0.04). Patients in whom a pedicled vascularized flap was used for reconstruction had a lower leakage rate than those in whom a free graft was used (13.5% vs 27.8%; p = 0.0015). In patients with a BMI > 25 kg/m2, the use of a pedicled flap reduced the rate of CSF leakage from 29.5% to 15.0% (p = 0.001); in patients of normal weight, this reduction did not reach statistical significance (21.9% [pedicled flap] vs 9.2% [free graft]; p = 0.09). CONCLUSIONS Preoperative BMI > 25 kg/m2 and tumor location in the posterior fossa were associated with higher rates of postoperative CSF leak. Use of a pedicled vascularized flap may be associated with reduced risk of a CSF leak, particularly in overweight patients. PMID- 28598277 TI - Surgical strategy to avoid ischemic complications of the pyramidal tract in resective epilepsy surgery of the insula: technical case report. AB - Surgical treatment of the insula is notorious for its high probability of motor complications, particularly when resecting the superoposterior part. Ischemic damage to the pyramidal tract in the corona radiata has been regarded as the cause of these complications, resulting from occlusion of the perforating arteries to the pyramidal tract through the insular cortex. The authors describe a strategy in which a small piece of gray matter is spared at the bottom of the periinsular sulcus, where the perforating arteries pass en route to the pyramidal tract, in order to avoid these complications. This method was successfully applied in 3 patients harboring focal cortical dysplasia in the posterior insula and frontoparietal operculum surrounding the periinsular sulcus. None of the patients developed permanent postoperative motor deficits, and seizure control was achieved in all 3 cases. The method described in this paper can be adopted for functional preservation of the pyramidal tract in the corona radiata when resecting epileptogenic pathologies involving insular and opercular regions. PMID- 28598278 TI - Atypical pituitary adenoma: a clinicopathologic case series. AB - OBJECTIVE In 2004, the WHO classified atypical pituitary adenoma as a distinct adenoma subtype. However, the clinical significance of this distinction remains undetermined. The authors sought to define patient characteristics, tumor features, and treatment outcomes associated with atypical pituitary adenoma. METHODS The authors reviewed records of patients who underwent resection of pituitary adenoma at the University of California, San Francisco, between 2007 and 2014. Per institutional protocol, adenomas exhibiting mitotic activity underwent evaluation for all 3 markers of atypicality (mitotic index, extensive p53 staining, and MIB-1 index >= 3%). Statistical analyses were performed using chi2, Fisher's exact test, t-test, log-rank, and logistic regression. RESULTS Between 2007 and 2014, 701 patients underwent resection for pituitary adenoma. Among these patients, 122 adenomas exhibited mitotic activity and therefore were evaluated for all 3 markers of atypicality, with 36 tumors (5%) proving to be atypical. There were 21 female patients (58%) and 15 male patients (42%) in the atypical cohort, and 313 female patients (47%) and 352 male patients (53%) in the nonatypical cohort (p = 0.231). The mean age of patients in the atypical cohort was 37 years (range 10-65 years), which was significantly lower than the mean age of 49 years (range 10-93 years) for patients in the nonatypical cohort (p < 0.001). The most common presenting symptoms for patients with atypical adenomas were headaches (42%) and visual changes (33%). Atypical adenomas were more likely to be functional (78%) than nonatypical adenomas (42%; p < 0.001). Functional atypical adenomas were significantly larger than functional nonatypical adenomas (mean diameter 2.2 vs 1.4 cm; p = 0.009), as were nonfunctional atypical adenomas compared with nonfunctional nonatypical adenomas (mean diameter 3.3 vs 2.3 cm; p = 0.01). Among the entire adenoma cohort, larger presenting tumor size was associated with cavernous sinus invasion (p < 0.001), and subtotal resection was associated with cavernous sinus invasion (p < 0.001) and larger size (p < 0.001) on binomial multivariate regression. The median time until recurrence was 56 months for atypical adenomas, 129 months for functional nonatypical adenomas, and 204 months for nonfunctional nonatypical adenomas (p < 0.001). Functional atypical adenomas recurred more frequently and significantly earlier than functional nonatypical adenomas (p < 0.001). When accounting for extent of resection, cavernous sinus invasion, size, age, sex, and functional subtype, atypicality remained a significant predictor of earlier recurrence among functional adenomas (p = 0.002). CONCLUSIONS When compared with nonatypical pituitary adenomas, atypical adenomas are more likely to present in younger patients at a larger size, are more often hormonally hypersecretory, and are associated with earlier recurrence. These features lend credence to atypical pituitary adenomas being a distinct clinical entity in addition to a discrete pathological diagnosis. PMID- 28598279 TI - A novel score to predict shunt dependency after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE Feasible clinical scores for predicting shunt-dependent hydrocephalus (SDHC) after aneurysmal subarachnoid hemorrhage (aSAH) are scarce. The chronic hydrocephalus ensuing from SAH score (CHESS) was introduced in 2015 and has a high predictive value for SDHC. Although this score is easy to calculate, several early clinical and radiological factors are required. The authors designed the retrospective analysis described here for external CHESS validation and determination of predictive values for the radiographic Barrow Neurological Institute (BNI) scoring system and a new simplified combined scoring system. METHODS Consecutive data of 314 patients with aSAH were retrospectively analyzed with respect to CHESS parameters and BNI score. A new score, the shunt dependency in aSAH (SDASH) score, was calculated from independent risk factors identified with multivariate analysis. RESULTS Two hundred twenty-five patients survived the initial phase after the hemorrhage, and 27.1% of these patients developed SDHC. The SDASH score was developed from results of multivariate analysis, which revealed acute hydrocephalus (aHP), a BNI score of >= 3, and a Hunt and Hess (HH) grade of >= 4 to be independent risk factors for SDHC (ORs 5.709 [aHP], 6.804 [BNI], and 4.122 [HH]; p < 0.001). All 3 SDHC scores tested (CHESS, BNI, and SDASH) reliably predicted chronic hydrocephalus (ORs 1.533 [CHESS], 2.021 [BNI], and 2.496 [SDASH]; p <= 0.001). Areas under the receiver operating curve (AUROC) for CHESS and SDASH were comparable (0.769 vs 0.785, respectively; p = 0.447), but the CHESS and SDASH scores were superior to the BNI grading system for predicting SDHC (BNI AUROC 0.649; p = 0.014 and 0.001, respectively). In contrast to CHESS and BNI scores, an increase in the SDASH score coincided with a monotonous increase in the risk of developing SDHC. CONCLUSIONS The newly developed SDASH score is a reliable tool for predicting SDHC. It contains fewer factors and is more intuitive than existing scores that were shown to predict SDHC. A prospective score evaluation is needed. PMID- 28598280 TI - Pathogens and glioma: a history of unexpected discoveries ushering in novel therapy. AB - In the late 19th century, Dr. William B. Coley introduced the theory that infections may aid in the treatment of malignancy. With the creation of Coley's toxin, reports of remission during viral illnesses for systemic malignancies soon emerged. A few decades after this initial discovery, Austrian physicians performed intravascular injections of Clostridium to induce oncolysis in patients with glioblastoma. Since then, suggestions between improved survival and infectious processes have been reported in several patients with glioma, which ultimately marshaled the infamous use of intracerebral Enterobacter. These early observations of tumor regression and concomitant infection piloted a burgeoning field focusing on the use of pathogens in molecular oncology. PMID- 28598282 TI - MicroRNA-126 Regulates Inflammatory Cytokine Secretion in Human Gingival Fibroblasts Under High Glucose via Targeting Tumor Necrosis Factor Receptor Associated Factor 6. AB - BACKGROUND: MicroRNAs (miRs) play a crucial role in inflammatory diseases, including periodontitis. Meanwhile, miRs act as biomarkers for predicting diabetes mellitus (DM). However, the regulatory mechanism of miR-126 on development of periodontitis in patients with DM still remains unclear. METHODS: Human gingival fibroblasts were cultured with low (5.5 mmol/L), medium (15 mmol/L), and high (25 mmol/L) glucose, respectively. Expressions of miR-126, tumor necrosis factor (TNF) receptor associated factor (TRAF) 6, and related cytokines were analyzed by real-time polymerase chain reaction (PCR). After transfection with miR-126 mimic, PCR and western blot were performed to detect level of TRAF6, and luciferase reporter assay confirmed if TRAF6 is the direct target of miR-126. Production of cytokines was measured using enzyme-linked immunosorbent assay. RESULTS: Increased glucose significantly suppressed miR-126 expression in human gingival fibroblasts (P <0.05). Also, high glucose increased TRAF6, interleukin (IL)-6, TNF-alpha, and chemical chemokine ligand (CCL) 2 levels, whereas it decreased IL-10 level. MiR-126 mimic significantly decreased TRAF6 mRNA and protein levels under high glucose (P <0.05). Also, miR-126 directly targeted TRAF6 through binding to its 3' untranslated region in human gingival fibroblasts. Overexpression of miR-126 significantly abrogated high glucose-induced secretion of proinflammatory cytokines such as IL-6, TNF-alpha, and CCL2 and promoted production of IL-10. CONCLUSION: These data suggest that miR-126 inhibits inflammation of human gingival fibroblasts under high glucose through targeting TRAF6, which may be a potential therapeutic target for periodontitis concomitant with DM. PMID- 28598281 TI - Design, development and characterization of ACT017, a humanized Fab that blocks platelet's glycoprotein VI function without causing bleeding risks. AB - Glycoprotein VI is a platelet-specific collagen receptor critical for in vivo formation of arterial thrombosis. It is also considered as an attractive target for the development of anti-thrombotic drugs because blocking glycoprotein (GP)VI inhibits platelet aggregation without inducing detrimental effects on physiologic hemostasis. Here, we present data on the identification, in vitro and ex vivo pharmacology of a humanized Fab fragment designated as ACT017. ACT017 was selected out of 15 humanized variants based upon structural and functional properties. It was produced under GMP-like conditions followed by detailed physico-chemical analysis and functional characterization indicating high antigen binding specificity and affinity. In addition, we demonstrate, in a dose escalation study, that ACT017 has a high capacity to specifically inhibit collagen-induced platelet aggregation ex vivo after injection to the macaque without inducing thrombocytopenia, GPVI depletion or bleeding side effects as is the case for conventional anti-platelets. Therefore, ACT017 is a promising therapeutic candidate for the development of a new generation of safe and efficient anti-thrombotic drugs. PMID- 28598283 TI - Identification of MicroRNAs by Microarray Analysis and Prediction of Target Genes Involved in Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. AB - BACKGROUND: The roles of microRNAs (miRNAs) in osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) remain largely unexplored. In this study, the underlying molecular mechanism of osteogenic differentiation in hPDLSCs is investigated using miRNA profiling. METHODS: The miRNA expression profile during osteogenic differentiation was analyzed using a microarray. Target genes of miRNAs with at least two-fold change in expression (P <0.05) were predicted by bioinformatics. Six miRNAs with osteogenesis-related target genes were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Expression of 116 miRNAs was found to be altered after osteoinduction, with 30 upregulated and 86 downregulated. Thirty-one of these miRNAs (26.7%) had osteogenesis-related target genes. Changes in expression levels of six of the 31 miRNAs (miR-654-3p, miR-4288, miR-34c-5p, miR-218-5p, miR 663a, and miR-874-3p) were validated by qRT-PCR. CONCLUSIONS: Significant alterations in miRNA expression profiles were observed during osteogenic differentiation of hPDLSCs. These results imply that miRNAs may have regulatory effects on this process by targeting osteogenesis-related genes. PMID- 28598284 TI - The Circular RNA Landscape of Periodontal Ligament Stem Cells During Osteogenesis. AB - BACKGROUND: The present study aims to investigate the distinct expression pattern of circular RNAs (circRNAs) in periodontal ligament stem cells (PDLSCs) during osteogenesis. METHODS: PDLSCs were isolated and cultured in osteogenic medium. Total RNA was extracted from cells at day 0 (D0), day 3 (D3), day 7 (D7), and day 14 (D14) and submitted to RNA-sequencing to detect expression profiles of circRNAs, messenger RNAs (mRNAs), and microRNAs (miRNAs). Real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to validate expression of circRNAs and miRNAs. Differential expression analysis and gene ontology analysis were performed. A circRNA-miRNA-mRNA network was constructed to reveal the potential regulatory role of circRNAs. RESULTS: A total of 12,693 circRNA transcripts were detected, and circRNAs displayed stage specific expression. Expression of four well-known circRNAs was validated by qRT PCR. In total, 118 circRNAs were differentially expressed at D3, 128 circRNAs were differentially expressed at D7, and 139 circRNAs were differentially expressed at D14 compared with D0. Host genes of differentially expressed circRNAs were enriched in cytoplasmic or membrane-bound vesicles and extracellular matrix, indicating their potential roles in modulating biogenesis of extracellular vesicles. Moreover, mRNAs that were potentially regulated by circRNAs were enriched in bone-formation-associated processes, including extracellular matrix organization, cell differentiation, and bone morphogenetic protein signaling pathway. CONCLUSION: Expression profiles of circRNAs were significantly altered during osteogenic differentiation of PDLSCs, providing a clue for future studies on the role of circRNAs in osteoblast differentiation. PMID- 28598285 TI - Effect of Non-Surgical Periodontal Therapy Along With Myo-Inositol on High Sensitivity C-Reactive Protein and Insulin Resistance in Women With Polycystic Ovary Syndrome and Chronic Periodontitis: A Randomized Controlled Trial. AB - BACKGROUND: The purpose of this study is to evaluate the effect of non-surgical periodontal therapy and medical treatment on the level of a serologic marker of inflammation (high-sensitivity C-reactive protein [hsCRP]) and insulin resistance (homeostatic model assessment [HOMA]) in women with polycystic ovary syndrome (PCOS) and chronic periodontitis (CP). METHODS: Women with PCOS and CP (n = 60) were randomly divided into two groups. The test group was treated with scaling and root planing (SRP) and myo-inositol (MI). The control group was treated with MI and given oral hygiene instructions. Anthropometric, metabolic, and periodontal parameters were assessed at baseline and re-evaluated at 3 and 6 months. All parameters of both groups at 6 months were compared with 25 systemically and periodontally healthy females (group A). RESULTS: Periodontal parameters were significantly improved in the test group compared with the control group at 3- and 6-month follow-up (P <0.001). A statistically significant reduction was observed in hsCRP and HOMA in both groups at 3- and 6-month follow up (P <0.05). However, significantly more improvement in hsCRP (P <0.05) and a statistically comparable reduction in HOMA (P >0.05) was observed in the test group compared with the control group at 3 and 6 months. Both the test and control group showed significant consistent improvement in metabolic parameters at 3- and 6-month follow-up, which was further comparable to group A. CONCLUSION: SRP together with medical treatment results in a greater reduction of systemic inflammatory burden compared with medical treatment alone in management of women with PCOS and CP. PMID- 28598286 TI - Gingival Inflammation and Salivary or Serum Granulocyte-Secreted Enzymes in Patients With Polycystic Ovary Syndrome. AB - BACKGROUND: The objective of this cross-sectional study is to investigate levels of salivary and serum matrix metalloproteinase (MMP)-9, myeloperoxidase (MPO), neutrophil elastase (NE), and MMP-9/tissue inhibitor of MMP-1 (TIMP)-1 ratio in patients with polycystic ovary syndrome (PCOS) and systemically healthy controls in the presence or absence of gingivitis. METHODS: Serum and salivary levels of these biomarkers were evaluated in the following: 1) periodontally healthy women with PCOS (n = 45); 2) women with PCOS and gingivitis (n = 35); 3) systemically and periodontally healthy women (n = 25); and 4) systemically healthy women with gingivitis (n = 20). Enzyme-linked immunosorbent assay was used to determine levels of these biomarkers. A full-mouth clinical periodontal evaluation was performed for each patient. RESULTS: Salivary MMP-9 and NE levels, as well as MMP 9/TIMP-1 ratios, were higher in the systemically healthy women with gingivitis compared with periodontally healthy women with PCOS (P <0.001; P <0.01; and P <0.0001, respectively). Serum MMP-9 and MPO levels were higher in women with PCOS and gingivitis compared with periodontally healthy women with PCOS (P <0.05). Serum MMP-9 levels were lower in healthy women with gingivitis than systemically and periodontally healthy women or women with PCOS and gingivitis (P <0.05). PCOS groups exhibited a positive correlation among clinical periodontal parameters and serum MMP-9 levels or salivary MPO, NE levels, and MMP-9/MMP-1 ratio. Correlation was negative among clinical periodontal parameters and serum MMP-9 levels and MMP 9/TIMP-1 ratio in systemically healthy patients (P <0.05). CONCLUSIONS: The present findings emphasize that PCOS and gingival inflammation are associated with each other, as evidenced by salivary and serum levels of neutrophilic enzymes. This interaction may contribute to the perturbation of ovarian remodeling in PCOS. PMID- 28598287 TI - Association Between Periodontitis and Amyloid beta Peptide in Elderly People With and Without Cognitive Impairment. AB - BACKGROUND: Evidence that periodontal disease is a possible risk factor for cognitive impairment may be explained by the inflammatory hypothesis. The aim of this study is to determine whether periodontitis is related to the amyloid beta (Abeta) load in blood and the role of any such relationship in the association between Abeta and cognitive impairment. METHODS: A case-control study was performed in elderly people diagnosed with cognitive impairment with or without dementia (cases group) and cognitively healthy elderly people (control group); data were collected on the medical and dental history of participants, and blood samples were drawn to determine Abeta levels using enzyme-linked immunosorbent assay. RESULTS: The study included 166 patients and 122 control participants. Higher blood Abeta1-42 levels (P = 0.01) and higher Abeta42:40 ratio (P = 0.06) were observed in participants with severe attachment loss than in other participants. Periodontitis was a significant interaction variable, given that the association between Abeta1-42 and Abeta1-40 and cognitive impairment was only observed in patients with severe periodontitis. According to these data, periodontitis may be a modulating variable of the association between Abeta and cognitive impairment. CONCLUSIONS: Plasma Abeta1-42 levels are higher in individuals who have severe periodontal disease. The presence of periodontitis may modify the association between Abeta and cognitive impairment. PMID- 28598288 TI - Implant Patient Compliance Varies by Periodontal Treatment History. AB - BACKGROUND: This retrospective study aims to assess compliance to supportive periodontal therapy (SPT) among patients treated with dental implants with different periodontitis histories and the possible influence of their compliance on peri-implant marginal bone level. METHODS: Dental records of 106 patients treated with at least one dental implant were reviewed. A single operator who did not provide care to the patients recorded the following during the first year of implant function (first year of follow-up), during the first 5 years of follow up, and during the entire follow-up duration: 1) number of recalls; 2) compliance, calculated from registered attendance; 3) periodontal disease history; 4) peri-implant radiographic bone level from most recent examination; and 5) clinical parameters including probing depth and bleeding on probing. Clinical and radiographic parameters were assessed at site level and analyzed for possible associations among them and with demographic parameters. RESULTS: Collected data were based on 156 implants with an average of 6.5 +/- 3.4 years (range: 1 to 13 years) in function. Patients with periodontitis history demonstrated greater compliance than patients without periodontitis history during the two longer follow-up times. Over time, the majority of patients demonstrated partial compliance (71% to 80% of patients). Peri-implant bone level averaged 0.9 +/- 1.1 mm, without significant association with compliance level; however, positive periodontitis history and more years in function were significantly associated with greater peri-implant bone loss. CONCLUSIONS: Patients with implants partially comply with scheduled SPT, regardless of periodontitis history. Patients who had received periodontal treatment demonstrated better compliance than those without prior periodontal therapy experiences. PMID- 28598290 TI - Delayed Growth Suppression and Radioresistance Induced by Long-Term Continuous Gamma Irradiation. AB - Biological response to ionizing radiation depends not only on the type of radiation and dose, but also on the duration and dose rate of treatment. For a given radiation dose, the biological response may differ based on duration and dose rate. We studied the properties of two human cell lines, M059K glioma and U2OS osteosarcoma, continuously exposed to gamma rays for long time periods of more than five months. Growth inhibition in both cell lines was dependent on total dose when exposed to acute radiation over several minutes, whereas prolonged growth inhibition was dependent on dose rate after continuous irradiation over several months. The minimum dose rate for growth inhibition was 53.6 mGy/h. Cell cycle analysis showed G1 phase accumulation in cell populations continuously exposed to gamma rays, and G2 phase accumulation in cells acutely exposed to high-dose-rate gamma rays. Cells continuously exposed to gamma rays continued to exhibit delayed growth suppression even after one month in an environment of background radiation, and maintained a high-level expression of c Jun and its phosphorylation forms, as well as resistance to apoptosis induced by staurosporine and chemotherapeutic agents. These delayed effects were not observed in cells acutely exposed to 5 Gy of radiation. These results suggest that optimization of the irradiation schedule is crucial for risk estimation, protection and therapeutic utilization of ionizing radiation. PMID- 28598289 TI - Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer. AB - Breast cancer is the most common malignancy diagnosed among women and represents a heterogeneous group of subtypes. Radiation therapy is a critical component of treatment for breast cancer patients. However, little is known about radiation response among these intrinsic subtypes. In previous studies, we identified a significant induction of FAS after irradiation in biologically favorable breast cancer patients and breast cancer cell lines. Here, we expanded our study and investigated radiation response in a mouse model of breast cancer. MCF7 (luminal), HCC1954 (HER2+) or SUM159 (basal) cells were implanted orthotopically into the dorsal mammary fat pad of nude mice. These mice were then treated with different doses of radiation to assess tumor growth control. We further investigated the therapeutic effect of FAS modulation by silencing FAS in radiation-responsive tumors and injecting FAS agonist antibody into radiation resistant tumors. Exposure to radiation inhibited MCF7, and to a lesser extent HCC1954 tumor growth in a dose-dependent manner. In contrast, SUM159 tumors were resistant to radiation. The estimated TCD50 values were 19.3 Gy for MCF7 and 44.9 Gy for SUM159. Radiation induced FAS expression in MCF7 tumors, but not SUM159 tumors. We found that silencing of FAS did not negatively impact radiation response in MCF7 tumors, possibly due to compensation by other apoptotic pathways. On the other hand, FAS activating antibody in combination with radiation treatment delayed SUM159 and HCC1954 tumor growth. However, it did not reach statistical significance compared to radiation treatment alone. Our results suggest that there is intrinsic variation in radiation response among breast cancer subtypes. FAS activation concurrent with radiation slows tumor growth in the radiation-resistant subtypes, but the effect was not significant. Alternative subtype-specific modulators of radiation response are under investigation. PMID- 28598291 TI - Spinal navigation for posterior instrumentation of C1-2 instability using a mobile intraoperative CT scanner. AB - OBJECTIVE Spinal navigation techniques for surgical fixation of unstable C1-2 pathologies are challenged by complex osseous and neurovascular anatomy, instability of the pathology, and unreliable preoperative registration techniques. An intraoperative CT scanner with autoregistration of C-1 and C-2 promises sufficient accuracy of spinal navigation without the need for further registration procedures. The aim of this study was to analyze the accuracy and reliability of posterior C1-2 fixation using intraoperative mobile CT scanner guided navigation. METHODS In the period from July 2014 to February 2016, 10 consecutive patients with instability of C1-2 underwent posterior fixation using C-2 pedicle screws and C-1 lateral mass screws, and 2 patients underwent posterior fixation from C-1 to C-3. Spinal navigation was performed using intraoperative mobile CT. Following navigated screw insertion in C-1 and C-2, intraoperative CT was repeated to check for the accuracy of screw placement. In this study, the accuracy of screw positioning was retrospectively analyzed and graded by an independent observer. RESULTS The authors retrospectively analyzed the records of 10 females and 2 males, with a mean age of 80.7 +/- 4.95 years (range 42-90 years). Unstable pathologies, which were verified by fracture dislocation or by flexion/extension radiographs, included 8 Anderson Type II fractures, 1 unstable Anderson Type III fracture, 1 hangman fracture Levine Effendi Ia, 1 complex hangman-Anderson Type III fracture, and 1 destructive rheumatoid arthritis of C1-2. In 4 patients, critical anatomy was observed: high riding vertebral artery (3 patients) and arthritis-induced partial osseous destruction of the C-1 lateral mass (1 patient). A total of 48 navigated screws were placed. Correct screw positioning was observed in 47 screws (97.9%). Minor pedicle breach was observed in 1 screw (2.1%). No screw displacement occurred (accuracy rate 97.9%). CONCLUSION Spinal navigation using intraoperative mobile CT scanning was reliable and safe for posterior fixation in unstable C1-2 pathologies with high accuracy in this patient series. PMID- 28598292 TI - Effects of primary and recurrent sacral chordoma on the motor and nociceptive function of hindlimbs in rats: an orthotopic spine model. AB - OBJECTIVE Chordoma is a slow-growing, locally aggressive cancer that is minimally responsive to conventional chemotherapy and radiotherapy and has high local recurrence rates after resection. Currently, there are no rodent models of spinal chordoma. In the present study, the authors sought to develop and characterize an orthotopic model of human chordoma in an immunocompromised rat. METHODS Thirty four immunocompromised rats were randomly allocated to 4 study groups; 22 of the 34 rats were engrafted in the lumbar spine with human chordoma. The groups were as follows: UCH1 tumor-engrafted (n = 11), JHC7 tumor-engrafted (n = 11), sham surgery (n = 6), and intact control (n = 6) rats. Neurological impairment of rats due to tumor growth was evaluated using open field and locomotion gait analysis; pain response was evaluated using mechanical or thermal paw stimulation. Cone beam CT (CBCT), MRI, and nanoScan PET/CT were performed to evaluate bony changes due to tumor growth. On Day 550, rats were killed and spines were processed for H & E-based histological examination and immunohistochemistry for brachyury, S100beta, and cytokeratin. RESULTS The spine tumors displayed typical chordoma morphology, that is, physaliferous cells filled with vacuolated cytoplasm of mucoid matrix. Brachyury immunoreactivity was confirmed by immunostaining, in which samples from tumor-engrafted rats showed a strong nuclear signal. Sclerotic lesions in the vertebral body of rats in the UCH1 and JHC7 groups were observed on CBCT. Tumor growth was confirmed using contrast-enhanced MRI. In UCH1 rats, large tumors were observed growing from the vertebral body. JHC7 chordoma engrafted rats showed smaller tumors confined to the bone periphery compared with UCH1 chordoma-engrafted rats. Locomotion analysis showed a disruption in the normal gait pattern, with an increase in the step length and duration of the gait in tumor-engrafted rats. The distance traveled and the speed of rats in the open field test was significantly reduced in the UCH1 and JHC7 tumor-engrafted rats compared with controls. Nociceptive response to a mechanical stimulus showed a significant (p < 0.001) increase in the paw withdrawal threshold (mechanical hypalgesia). In contrast, the paw withdrawal response to a thermal stimulus decreased significantly (p < 0.05) in tumor-engrafted rats. CONCLUSIONS The authors developed an orthotopic human chordoma model in rats. Rats were followed for 550 days using imaging techniques, including MRI, CBCT, and nanoScan PET/CT, to evaluate lesion progression and bony integrity. Nociceptive evaluations and locomotion analysis were performed during follow-up. This model reproduces cardinal signs, such as locomotor and sensory deficits, similar to those observed clinically in human patients. To the authors' knowledge, this is the first spine rodent model of human chordoma. Its use and further study will be essential for pathophysiology research and the development of new therapeutic strategies. PMID- 28598293 TI - Stereotactic body radiotherapy for de novo spinal metastases: systematic review. AB - OBJECTIVE The aim of this systematic review was to provide an objective summary of the published literature pertaining to the use of stereotactic body radiation therapy (SBRT) specific to previously untreated spinal metastases. METHODS The authors performed a systematic review, using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, of the literature found in a search of Medline, PubMed, Embase, and the Cochrane Library up to March 2015. The search strategy was limited to publications in the English language. RESULTS A total of 14 full-text articles were included in the analysis. All studies were retrospective except for 2 studies, which were prospective. A total of 1024 treated spinal lesions were analyzed. The median follow-up time ranged from 9 to 49 months. A range of dose-fractionation schemes was used, the most common of which were 16-24 Gy/1 fraction (fx), 24 Gy/2 fx, 24-27 Gy/3 fx, and 30 35 Gy/5 fx. In studies that reported crude results regarding in-field local tumor control, 346 (85%) of 407 lesions remained controlled. For studies that reported actuarial values, the weighted average revealed a 90% 1-year local control rate. Only 3 studies reported data on complete pain response, and the weighted average of these results yielded a complete pain response rate of 54%. The most common toxicity was new or progressing vertebral compression fracture, which was observed in 9.4% of cases; 2 cases (0.2%) of neurologic injury were reported. CONCLUSION There is a paucity of prospective data specific to SBRT in patients with spinal metastases not otherwise irradiated. This systematic review found that SBRT is associated with favorable rates of local control (approximately 90% at 1 year) and complete pain response (approximately 50%), and low rates of serious adverse events were found. Practice guidelines are summarized based on these data and International Stereotactic Radiosurgery Society consensus. PMID- 28598294 TI - Open versus percutaneous instrumentation in thoracolumbar fractures: magnetic resonance imaging comparison of paravertebral muscles after implant removal. AB - OBJECTIVE Percutaneous instrumentation in thoracolumbar fractures is intended to decrease paravertebral muscle damage by avoiding dissection. The aim of this study was to compare muscles at instrumented levels in patients who were treated by open or percutaneous surgery. METHODS Twenty-seven patients underwent open instrumentation, and 65 were treated percutaneously. A standardized MRI protocol using axial T1-weighted sequences was performed at a minimum 1-year follow-up after implant removal. Two independent observers measured cross-sectional areas (CSAs, in cm2) and region of interest (ROI) signal intensity (in pixels) of paravertebral muscles by using OsiriX at the fracture level, and at cranial and caudal instrumented pedicle levels. An interobserver comparison was made using the Bland-Altman method. Reference ROI muscle was assessed in the psoas and ROI fat subcutaneously. The ratio ROI-CSA/ROI-fat was compared for patients treated with open versus percutaneous procedures by using a linear mixed model. A linear regression analyzed additional factors: age, sex, body mass index (BMI), Pfirrmann grade of adjacent discs, and duration of instrumentation in situ. RESULTS The interobserver agreement was good for all CSAs. The average CSA for the entire spine was 15.7 cm2 in the open surgery group and 18.5 cm2 in the percutaneous group (p = 0.0234). The average ROI-fat and ROI-muscle signal intensities were comparable: 497.1 versus 483.9 pixels for ROI-fat and 120.4 versus 111.7 pixels for ROI-muscle in open versus percutaneous groups. The ROI CSA varied between 154 and 226 for open, and between 154 and 195 for percutaneous procedures, depending on instrumented levels. A significant difference of the ROI CSA/ROI-fat ratio (0.4 vs 0.3) was present at fracture levels T12-L1 (p = 0.0329) and at adjacent cranial (p = 0.0139) and caudal (p = 0.0100) instrumented levels. Differences were not significant at thoracic levels. When adjusting based on age, BMI, and Pfirrmann grade, a significant difference between open and percutaneous procedures regarding the ROI-CSA/ROI-fat ratio was present in the lumbar spine (p < 0.01). Sex and duration of instrumentation had no significant influence. CONCLUSIONS Percutaneous instrumentation decreased muscle atrophy compared with open surgery. The MRI signal differences for T-12 and L-1 fractures indicated less fat infiltration within CSAs in patients who received percutaneous treatment. Differences were not evidenced at thoracic levels, where CSAs were smaller. Fat infiltration was not significantly different at lumbar levels with either procedure in elderly patients with associated discopathy and higher BMI. In younger patients, there was less fat infiltration of lumbar paravertebral muscles with percutaneous procedures. PMID- 28598296 TI - Letter to the Editor. Endovascular and surgical management of spinal dural arteriovenous fistulas. PMID- 28598295 TI - Pelvic retroversion: a compensatory mechanism for lumbar stenosis. AB - OBJECTIVE The flexed posture of the proximal (L1-3) or distal (L4-S1) lumbar spine increases the diameter of the spinal canal and neuroforamina and can relieve symptoms of neurogenic claudication. Distal lumbar flexion can result in pelvic retroversion; therefore, in cases of flexible sagittal imbalance, pelvic retroversion may be compensatory for lumbar stenosis and not solely compensatory for the sagittal imbalance as previously thought. The authors investigate underlying causes for pelvic retroversion in patients with flexible sagittal imbalance. METHODS One hundred thirty-eight patients with sagittal imbalance who underwent a total of 148 fusion procedures of the thoracolumbar spine were identified from a prospective clinical database. Radiographic parameters were obtained from images preoperatively, intraoperatively, and at 6-month and 2-year follow-up. A cohort of 24 patients with flexible sagittal imbalance was identified and individually matched with a control cohort of 23 patients with fixed deformities. Flexible deformities were defined as a 10 degrees change in lumbar lordosis between weight-bearing and non-weight-bearing images. Pelvic retroversion was quantified as the ratio of pelvic tilt (PT) to pelvic incidence (PI). RESULTS The average difference between lumbar lordosis on supine MR images and standing radiographs was 15 degrees in the flexible cohort. Sixty-eight percent of the patients in the flexible cohort were diagnosed preoperatively with lumbar stenosis compared with only 22% in the fixed sagittal imbalance cohort (p = 0.0032). There was no difference between the flexible and fixed cohorts with regard to C-2 sagittal vertical axis (SVA) (p = 0.95) or C-7 SVA (p = 0.43). When assessing for postural compensation by pelvic retroversion in the stenotic patients and nonstenotic patients, the PT/PI ratio was found to be significantly greater in the patients with stenosis (p = 0.019). CONCLUSIONS For flexible sagittal imbalance, preoperative attention should be given to the root cause of the sagittal misalignment, which could be compensation for lumbar stenosis. Pelvic retroversion can be compensatory for both the lumbar stenosis as well as for sagittal imbalance. PMID- 28598297 TI - The neuronal differentiation microenvironment is essential for spinal cord injury repair. AB - Spinal cord injury (SCI) often leads to substantial disability due to loss of motor function and sensation below the lesion. Neural stem cells (NSCs) are a promising strategy for SCI repair. However, NSCs rarely differentiate into neurons; they mostly differentiate into astrocytes because of the adverse microenvironment present after SCI. We have shown that myelin-associated inhibitors (MAIs) inhibited neuronal differentiation of NSCs. Given that MAIs activate epidermal growth factor receptor (EGFR) signaling, we used a collagen scaffold-tethered anti-EGFR antibody to attenuate the inhibitory effects of MAIs and create a neuronal differentiation microenvironment for SCI repair. The collagen scaffold modified with anti-EGFR antibody prevented the inhibition of NSC neuronal differentiation by myelin. After transplantation into completely transected SCI animals, the scaffold-linked antibodies induced production of nascent neurons from endogenous and transplanted NSCs, which rebuilt the neuronal relay by forming connections with each other or host neurons to transmit electrophysiological signals and promote functional recovery. Thus, a scaffold based strategy for rebuilding the neuronal differentiation microenvironment could be useful for SCI repair. PMID- 28598298 TI - Efficacy of exclusive enteral nutrition in complicated Crohn's disease. AB - AIM: To investigate the efficacy of exclusive enteral nutrition (EEN) in induction of remission in adult active Crohn's disease (CD) complicated with intestinal fistula/abdominal abscess or inflammatory intestinal stricture. METHOD: Patients diagnosed with active CD with complications were recruited between July 2013 and July 2015. Patients were offered EEN for 12 weeks. Patients with abscess received antibiotic treatment with or without percutaneous drainage. Clinical variables were recorded (ClinicalTrials.gov Identifier: NCT02887287). RESULTS: Forty-one patients with CD and with intestinal fistula/abdominal abscess or inflammatory intestinal stricture aged 18-60 years, were included. Ten patients were accompanied with stenosis and 33 with intestinal fistula/abscess. After 12 weeks of EEN, the Crohn's disease activity index significantly decreased (223.43 +/- 65.5 vs. 106.77 +/- 42.73, p <= .001), and 80.5% of patients achieved full clinical remission totally. Fistula closure after EEN was observed in 75% of patients with entero-cutaneous fistula. In patients with stenosis, 20% had no response to EEN and were transferred for surgery. Partial remission and full remission were observed in 20% and 60% of patients after 12 weeks of EEN, respectively. Intra-abdominal abscess resolved in 76% of patients. Seventeen patients who had mucosal ulcers underwent colonoscopy before and after EEN, 47% achieved mucosal healing after the treatment. The inflammatory index of patients significantly decreased (p <= .01), nutritional parameters increased (p <= .01) and the European Nutritional Risk Screening (2002) decreased (p <= .01). CONCLUSION: EEN is effective in inducing early clinical remission, mucosal healing, promoting fistula closure and reducing the size of abscess in adult CD patients with complications. PMID- 28598299 TI - Proper sister chromatid disjunction requires CDA and PARP-1. PMID- 28598300 TI - User experience of lower-limb orthosis. AB - If an assistive device is not acceptable to the user, it will not achieve efficacy and would be resource-wasting. This study employed in-depth interviews to understand what users' individual activities of daily living, problems of using orthoses, and considerations for selecting orthoses are. We conducted qualitative interviews with 35 lower-limb orthosis users, and semi-structured interviews were applied in this study. We analyzed the interview data from transcripts, through coding and concepts, to theories based on grounded theory. The results showed that problems of using orthoses are mostly related to activities of daily living of the user and user's expectation. Therefore, in order to enhance its efficacy and use intention, the design and prescribing process of orthoses need to address the problems in the light of activities of daily living and user education. PMID- 28598301 TI - Aquimarina rubra sp. nov., isolated from sediment of a sea cucumber culture pond. AB - A Gram-stain-negative, non-motile, rod-shaped, red-pigmented, facultatively anaerobic bacterium, designated SS2-9T, was isolated from sediment collected from a sea cucumber culture pond located in Rongcheng, Shandong province, China. Cells of strain SS2-9T were approximately 0.3-0.5 um in width and 1.5-6.0 um in length. The strain was able to grow at 10-37 degrees C, at pH 6.5-8.5 and in the presence of 0.5-6.0 % (w/v) NaCl. It grew optimally at 28 degrees C and in the presence of 2.0 % (w/v) NaCl. The DNA G+C content was 34.5 mol% and the sole respiratory quinone was menaquinone 6 (MK-6). The predominant cellular fatty acids were C15 : 0, iso-C15 : 1 G, iso-C15 : 0 and iso-C17 : 0 3-OH. The major polar lipids were phosphatidylethanolamine, an unidentified phospholipid, two unidentified aminolipids and four unidentified lipids. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain SS2-9T was phylogenetically related to members of the genus Aquimarina and was closely related to Aquimarina amphilecti 92VT (97.29 % similarity). On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain SS2-9T was considered to represent a novel species of the genus Aquimarina, for which the name Aquimarina rubra sp. nov. is proposed. The type strain is SS2-9T (=KCTC 52274T=MCCC 1H00142T). PMID- 28598302 TI - Multi-locus variable-number tandem repeat analysis of Bordetella pertussis isolates circulating in Poland in the period 1959-2013. AB - PURPOSE: Despite the long history of pertussis vaccination and high vaccination coverage in Poland and many other developed countries, pertussis incidence rates have increased substantially, making whooping cough one of the most prevalent vaccine-preventable diseases. Among the factors potentially involved in pertussis resurgence, the adaptation of the Bordetella pertussis population to country specific vaccine-induced immunity through selection of non-vaccine-type strains still needs detailed studies. METHODOLOGY: Multi-locus variable-number tandem repeat analysis (MLVA), also linked to MLST and PFGE profiling, was applied to trace the genetic changes in the B. pertussis population circulating in Poland in the period 1959-2013 versus country-specific vaccine strains. RESULTS: Generally, among 174 B. pertussis isolates, 31 MLVA types were detected, of which 11 were not described previously. The predominant MLVA types of recent isolates in Poland were different from those of the typical isolates circulating in other European countries. The MT27 type, currently predominant in Europe, was rarely seen and detected in only five isolates among all studied. The features of the vaccine strains used for production of the pertussis component of a national whole-cell diphtheria-tetanus-pertussis (DTP) vaccine, as studied by MLVA and MLST tools, were found to not match those observed in the currently circulating B. pertussis isolates in Poland. CONCLUSIONS: Differences traced by MLVA in relation to the MLST and PFGE profiling confirmed that the B. pertussis strain types currently observed elsewhere in Europe, even if appearing in Poland, were not able to successfully disseminate within a human population in Poland that has been vaccinated with a whole-cell pertussis vaccine not used in other countries. PMID- 28598303 TI - Caulobacter rhizosphaerae sp. nov., a stalked bacterium isolated from rhizosphere soil. AB - The Gram-reaction-negative, aerobic, white- to pale-yellow-coloured and rod shaped bacterium with a single polar flagellum or a stalk, designated strain 7F14T, was isolated from rhizosphere soil of cultivated watermelon (Citrullus lanatus) collected from Hefei, China. Growth of strain 7F14T was observed at pH 6.0-9.0, 10-30 degrees C and in the presence of 0-1 % (w/v) NaCl. Cells were catalase-negative and oxidase-positive. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain 7F14T formed a phyletic lineage within the genus Caulobacter of the family Caulobacteraceae and showed the highest 16S rRNA gene sequence similarities to Caulobacter henricii ATCC 15253T (98.66 %), Caulobacter segnis ATCC 21756T (98.27 %), Caulobacter vibrioides CB51T (97.92 %) and Caulobacter flavus RHGG3T (97.44 %). The G+C content of the genomic DNA was 68.6 mol%. Strain 7F14T contained Q-10 as the sole ubiquinone and 11-methyl C18 : 1omega7c, C18 : 1omega7c, C16 : 0 and summed feature 3 (C16 : 1omega7c and/or iso C15 : 0 2-OH) as the major fatty acids. The polar lipids profile consisted of phosphatidylglycerol, an unknown phosphoglycolipid, five unknown glycolipids, an unknown phospholipid and three unknown lipids. DNA-DNA relatedness values to the most closely related type strains Caulobacter henricii DSM 4730T and Caulobacter segnis DSM 7131T were 26.0 and 19.7 %, respectively. Based on unique phenotypic traits, and phylogenetic, chemotaxonomic and DNA-DNA hybridization results, strain 7F14T should be classified as a representative of a novel species of the genus Caulobacter, for which the name Caulobacter rhizosphaerae sp. nov. is proposed. The type strain is 7F14T (=CGMCC 1.15915T=KCTC 52515T). PMID- 28598304 TI - Antibacterial activity of diacetylcurcumin against Staphylococcus aureus results in decreased biofilm and cellular adhesion. AB - PURPOSE: Staphylococcus aureus infections have contributed to the global healthcare burden, particularly with regard to hospital-acquired meticillin resistant S. aureus (MRSA) infections. METHODOLOGY: This study describes the antibacterial activity of diacetylcurcumin (DAC) against meticillin-susceptible S. aureus/MRSA biofilm formation, survival, metabolic activity and structure; its ability to prevent bacterial adhesion to human cells; and toxicity in Galleria mellonella larvae. RESULTS: DAC showed excellent antibacterial activity, with MIC ranging between 17.3 and 34.6 umol l-1, and minimum bactericidal concentration ranging between 69 and 277 umol l-1. It significantly reduced bacterial biofilm survival - by 22-63 % (at MIC, 10*MIC or 100*MIC) as compared to the 25-42 % reduction by vancomycin (P<0.0001) - and severely affected biofilm cell structures, leading to damaged architecture and the formation of amorphous cell clusters. Treatment with DAC (MIC/4) decreased bacterial adhesion to HaCaT keratinocytes from 1 to 5 h (P<0.0001). Finally, DAC demonstrated low toxicity in G. mellonella at its effective anti-biofilm concentrations. CONCLUSION: These findings open new avenues for the study of this curcumin derivative as an excellent prototype with anti-MRSA activity. PMID- 28598305 TI - Comparison of the in vitro activity of ampicillin and moxifloxacin against Listeria monocytogenes at achievable concentrations in the central nervous system. AB - PURPOSE: The aim of this study was to compare the in vitro activity of ampicillin and moxifloxacin against six isolates selected from 154 invasive clinical isolates of Listeria monocytogenes and evaluate their intra- and extracellular activities with achievable central nervous system concentrations obtained using Monte Carlo simulations with conventional and unconventional dosages. METHODOLOGY: The MICs and minimal bactericidal concentrations (MBCs) of ampicillin and moxifloxacin were determined by using the broth microdilution method. The intra- and extracellular activities were compared using time-kill curves and inhibition of intracellular growth assays. RESULTS: The MICs50/90 of ampicillin were 0.125/0.5 mg l-1 and the MBC50/90 was >=16 mg l-1, while the moxifloxacin MICs50/90 were 0.25/0.5 mg l-1 and the MBC50/90 was 0.5 mg l-1. Ampicillin did not show any extracellular bactericidal activity at 24 h, although bactericidal activity was detected at 48 h. For moxifloxacin, the bactericidal effect was evident after 6 h of incubation. Both antibiotics achieved significant reductions in intracellular inoculum after 1-24 h of incubation; however, moxifloxacin becomes bactericidal more rapidly, producing a much greater reduction in the inoculum in the first hour than ampicillin. There were no differences among the MIC and MBC values of moxifloxacin and ampicillin among the strains belonging to different serotypes and/or epidemic clones. This fact was also found in the intra- and extracellular studies. CONCLUSION: The results of this study demonstrated the faster bactericidal activity of moxifloxacin at achievable central nervous system concentrations against intra- and extracellular forms of L. monocytogenes in comparison with ampicillin. PMID- 28598306 TI - Determinants of the regulation of Helicobacter pylori adhesins include repeat sequences in both promoter and coding regions as well as the two-component system ArsRS. AB - PURPOSE: We investigated the transcription of adhesin-encoding genes sabA, hopZ and labA in Helicobacter pylori strain J99. Each possesses a repeating homopolymeric nucleotide tract within their promoter regions, and sabA and hopZ possess repeats within their 5' coding regions. METHODOLOGY: We altered the repeat lengths associated with the adhesin genes and quantified mRNA levels by real-time quantitative PCR. Using adherence to AGS cells and IL-8 assays, we examined the effects of altered transcript levels. We assessed the role of ArsRS in transcription using an arsS null mutant and by examining ArsR binding to promoter regions via electrophoretic mobility shift assays. RESULTS: Extensions or truncations of promoter region repeats in hopZ and labA increased transcript levels, mirroring results shown by our lab and others for mutations in the sabA promoter. Altered lengths of the poly-cytosine thymine tract within the 5' coding region of sabA demonstrated that switching from phase-off to phase-on significantly increased mRNA levels. However, mutations in the poly-thymine tract of sabA, which increased mRNA levels, do not behave synergistically with phase-on mutations. Phase-on mutations of sabA resulted in increased H. pylori adherence to AGS cells, but only a modest effect on IL-8. hopZ and labA, and sabA paralogue sabB, transcript levels were increased in an arsS mutant and ArsR bound the promoter regions for each of these genes in vitro. CONCLUSION: This work highlights the complex nature of adhesin regulation, its impact on H. pylori attachment and the pervasive role of ArsRS in adhesin expression. Such regulation may help facilitate the decades-long persistence of infection. PMID- 28598307 TI - Exposure to sub-inhibitory concentrations of gentamicin, ciprofloxacin and cefotaxime induces multidrug resistance and reactive oxygen species generation in meticillin-sensitive Staphylococcus aureus. AB - PURPOSE: The role of antibiotics below their MIC in the development of bacterial drug resistance is becoming increasingly important. We investigated the effect of sub-MICs of bactericidal antibiotics on the susceptibility pattern of Staphylococcus aureus and evaluated the role of free radicals. METHODOLOGY: A total of 12 S. aureus strains were recovered from pus samples and their antibiograms determined. The test isolates were treated with sub-MIC levels of tetracycline, gentamicin, ciprofloxacin and cefotaxime. Alterations in their respective breakpoints were observed along with measurements of free radical generation by nitro blue tetrazolium test.Results/Key findings. Gentamicin, ciprofloxacin and cefotaxime exposure significantly altered the breakpoints of exposed isolates against several tested antibiotics and higher levels of free radicals were generated after antibiotic exposure. CONCLUSIONS: Our study demonstrates that sub-MIC levels of antimicrobials can lead to resistance and cross-resistance across several classes of antibiotics in wild strains of S. aureus, possibly by free radical production. The molecular mechanisms behind the acquisition of drug resistance at low antibiotic concentrations and the specific target genes of reactive oxygen speciesneed to be explored further. PMID- 28598308 TI - Pseudoxanthomonas putridarboris sp. nov. isolated from rotten tree. AB - A Gram-staining-negative, rod-shaped, motile bacterium, designated WD12T, was isolated from a rotten tree at Chungbuk National University, South Korea. WD12T grew optimally at 30-37 degrees C and pH 7.0-7.5 and could assimilate arbutin and potassium-5-ketogluconate. The major cellular fatty acid were iso-C16 : 0, C16 : 0, cyclo C17 : 0, iso-C15 : 0, summed features 3 (comprising C16 : 1omega7c/iso-C15 : 0 2-OH) and anteiso-C15 : 0. The major polar lipids consisted of phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. The major respiratory quinone was ubiquinone-8 (Q-8). The G+C content of the genomic DNA was 69.1 %. The results of phylogenetic and comparative analysis based on the 16S rRNA gene sequence indicated that WD12T formed a tight phylogenetic lineage with Pseudoxanthomonas mexicana AMX 26BT and Pseudoxanthomonas japonensis 12-3T of the the genus Pseudoxanthomonas in the family Xanthomonadaceae. Sequence similarity to other members of the genus Pseudoxanthomonasranged from 98.6 % (P. mexicana AMX 26BT) to 95.1 % (Pseudoxanthomonas taiwanensis CB-226T). DNA-DNA relatedness between WD12T and eight type strains of species of the genus Pseudoxanthomonasshowing more than 97 % 16S rRNA sequence similarity were 6+/-0 26+/-1 %. On the basis of the evidence from this polyphasic study, WD12T represents a novel species of the genus Pseudoxanthomonas, for which the name Pseudoxanthomonas putridarboris sp. nov. is proposed. The type strain is WD12T (=KACC 15045T=LMG 25968T). PMID- 28598309 TI - Reclassification of Arthrobacter viscosus as Rhizobium viscosum comb. nov. AB - The species Arthrobacter viscosus was isolated from soil from Guatemala and it was classified into the genus Arthrobacter on the basis of phenotypic traits. Nevertheless, the results of16S rRNA gene analysis indicated that this species is a member of the genus Rhizobium, with Rhizobium alamii GBV016T and Rhizobium mesosinicum CCBAU 25010T as the most closely related species with 99.64 and 99.48 % similarity, respectively. The similarity values for the recA gene are 92.2 and 94.4 % with respect to R. alamii GBV016T and R. mesosinicum CCBAU 25010T, respectively, and those for the atpD gene are 92.9 and 98.7 %, respectively. Results of DNA-DNA hybridization analysis yield averages of 46 and 41 % relatedness with respect to the type strains of R. alamii and R. mesosinicum, respectively. Phenotypic characteristics also differed from those of the most closely related species of the genus Rhizobium. Therefore, based on the data obtained in this study, we propose to classify strain LMG 16473T as representing a novel species named Rhizobiumviscosum comb. nov. (type strain LMG 16473T=CECT 908T). PMID- 28598310 TI - In vitro activities of vancomycin and linezolid against biofilm-producing methicillin-resistant staphylococci species isolated from catheter-related bloodstream infections from an Egyptian tertiary hospital. AB - PURPOSE: Catheter-related bloodstream infections (CRBSIs) are among the most common hospital-acquired infections. We aimed to survey methicillin resistance, biofilm production and susceptibility to vancomycin, linezolid and other antibiotics for staphylococci isolated from CRBSIs. METHODOLOGY: Fifty-eight isolates [20 S. aureus and 38 coagulase-negative staphylococci (CoNS; 20 Staphylococcusepidermidis, nine Staphylococcushaemolyticus, three Staphylococcusschleiferi, two Staphylococcuswarneri and four Staphylococcuslugdunensis)] were tested for methicillin resistance by cefoxitin disk diffusion and detection of the mecA gene by PCR; biofilm-forming ability using Congo red agar and tissue culture plate methods; susceptibility to ciprofloxacin, clindamycin, cotrimoxazole, erythromycin, gentamicin, linezolid, rifampicin and tetracycline; and MIC determination for vancomycin.Results/Key findings. Cefoxitin resistance was detected among 40 % (8/20) S. aureus isolates, 70 % (14/20) S. epidermidis isolates and 16.7 % (3/18) of other CoNS, although the mecA gene was detected in 45 % (9/20) S. aureus isolates, 35 % (7/20) S. epidermidis isolates and 16.7 % (3/18) of other CoNS. Biofilm-forming ability ranged from 45 to 75 %. Methicillin-resistant S. aureus and other CoNS were considered to be more virulent than methicillin-resistant S. epidermidis due to the higher biofilm forming abilities of the former. All tested isolates exhibited 100 % sensitivity to vancomycin and linezolid, irrespective of their methicillin resistance or biofilm-forming ability. Rifampicin showed overall sensitivity of 75.9 %. Varying degrees of multi-resistance were found for the other antibiotics. CONCLUSION: Vancomycin, linezolid and rifampicin could be used effectively against methicillin-resistant staphylococci isolated from CRBSIs. PMID- 28598311 TI - In vitro activity of sitafloxacin against Mycobacterium tuberculosis with gyrA/B mutations isolated in Japan. AB - PURPOSE: Sitafloxacin (SFX) is a new fluoroquinolone (FQ) that has shown a strong bactericidal effect against Mycobacterium tuberculosis (Mtb) in vitro. However, data on SFX efficacy against Mtb with gyrA/B mutations and its epidemiological cut-off (ECOFF) value remain limited. Therefore, we evaluated and compared the in vitro activity of SFX against gyrA/B-mutant Mtb to that of moxifloxacin (MFX), levofloxacin (LFX) and ciprofloxacin (CFX), and determined the ECOFF for SFX. METHODOLOGY: A total of 109 clinical Mtb isolates, including 73 multidrug resistant (MDR) isolates, were subjected to minimum inhibitory concentration (MIC) analysis in oleic-albumin-dextrose-catalase (OADC)-supplemented Middlebrook 7H9 medium. Our results showed that SFX had lower cumulative MIC than MFX, LFX and CFX. Furthermore, we performed direct DNA sequencing of the quinolone resistance-determining regions (QRDRs). RESULTS: We identified the following mutations: D94G, D94A, A90V, D94H, D94N and G88A in gyrA; and A543V, A543T, E540D, R485C, D500A, I552S and D577A in gyrB. Based on our results, an ECOFF of 0.125 ug ml-1 was proposed for SFX. With this ECOFF, 15 % of LFX-resistant isolates with MIC >=2 ug ml-1 were susceptible to SFX. CONCLUSION: SFX had the lowest cumulative MIC and a relatively low ECOFF value against Mtb, indicating that SFX was not only more effective against gyrA-mutant isolates, but also MDR isolates in Japan. PMID- 28598312 TI - Three novel species of the genus Kibdelosporangium; Kibdelosporangium kanagawaense sp. nov., Kibdelosporangiumrhizosphaerae sp. nov. and Kibdelosporangium rhizovicinum sp. nov. AB - The taxonomic positions of three actinomycete isolates, K08-0175T, K10-0543T and K12-0791T, which were isolated from plant root and rhizospheric soil samples were subjected to a polyphasic taxonomic study. On the basis of the results of phylogenetic analysis and morphological and chemotaxonomic characteristics, these three strains were classified as representing members of the genus Kibdelosporangium. These strains were observed to produce both long chains of rod shaped spores and sporangium-like structures with well-defined walls on aerial hyphae. Phylogenetic position, DNA-DNA hybridization and comparison of the phylogenetically closest relatives revealed that these three strains were clearly distinguishable from each other and from their closest phylogenetic relatives. Therefore, three novel species are proposed as Kibdelosporangium kanagawaense sp. nov. [type strain K08-0175T (=NBRC 112388T=TBRC 6786T)], Kibdelosporangiumrhizosphaerae sp. nov. [type strain K10-0543T (=NBRC 112389T=TBRC 6787T)] and Kibdelosporangium rhizovicinum sp. nov. [type strain K12 0791T (=NBRC 112390T=TBRC 6788T)]. PMID- 28598313 TI - Deactivation of the autotrophic sulfate assimilation pathway substantially reduces high-level beta-lactam antibiotic biosynthesis and arthrospore formation in a production strain from Acremonium chrysogenum. AB - The filamentous ascomycete Acremonium chrysogenum is the only industrial producer of the beta-lactam antibiotic cephalosporin C. Synthesis of all beta-lactam antibiotics starts with the three amino acids l-alpha-aminoadipic acid, l cysteine and l-valine condensing to form the delta-(l-alpha-aminoadipyl)-l cysteinyl-d-valine tripeptide. The availability of building blocks is essential in every biosynthetic process and is therefore one of the most important parameters required for optimal biosynthetic production. Synthesis of l-cysteine is feasible by various biosynthetic pathways in all euascomycetes, and sequencing of the Acr. chrysogenum genome has shown that a full set of sulfur-metabolizing genes is present. In principle, two pathways are effective: an autotrophic one, where the sulfur atom is taken from assimilated sulfide to synthesize either l cysteine or l-homocysteine, and a reverse transsulfuration pathway, where l methionine is the sulfur donor. Previous research with production strains has focused on reverse transsulfuration, and concluded that both l-methionine and reverse transsulfuration are essential for high-level cephalosporin C synthesis. Here, we conducted molecular genetic analysis with A3/2, another production strain, to investigate the autotrophic pathway. Strains lacking either cysteine synthase or homocysteine synthase, enzymes of the autotrophic pathway, are still autotrophic for sulfur. However, deletion of both genes results in sulfur amino acid auxotrophic mutants exhibiting delayed biomass production and drastically reduced cephalosporin C synthesis. Furthermore, both single- and double-deletion strains are more sensitive to oxidative stress and form fewer arthrospores. Our findings provide evidence that autotrophic sulfur assimilation is essential for growth and cephalosporin C biosynthesis in production strain A3/2 from Acr. chrysogenum. PMID- 28598314 TI - Thioclava arenosa sp. nov., isolated from sea sand. AB - A Gram-staining-negative, non-spore-forming, non-motile, rod-shaped, facultatively anaerobe bacterial strain, designated CAU 1312T, was isolated from sea sand of Eurwangri beach, South Korea. The strain's taxonomic position was investigated using a polyphasic approach. CAU 1312T grew at temperatures from 20 to 40 degrees C, in the range of pH 6.0-9.0 and at salinities from 1-4 % (w/v). The results of phylogenetic analysis based on the 16S rRNA gene sequence revealed that CAU 1312T represented a member of the genus Thioclava and was most closely related to Thioclava atlantica 13D2W-2T (similarity 96.53 %). The strain contained Q-10 as the predominant menaquinone and summed feature 8 (C18 : 1omega7c/omega6c) as the major fatty acid. The polar lipids of CAU 1312T consisted of phosphatidylethanolamine, phosphatidylglycerol, two aminophospholipids, a phosphoglycolipid, and two unidentified phospholipids. The DNA G+C content was 64.7 mol%. On the basis of phenotypic and chemotaxonomic properties and phylogenetic inference, CAU 1312T is considered to represent a novel species of the genus Thioclava, for which the name Thioclava arenosa sp. nov. is proposed. The type strain is CAU 1312T(=KCTC 52190T=NBRC 111989T). PMID- 28598315 TI - Prevalence of faecal carriage of colistin-resistant Gram-negative rods in a university hospital in western France, 2016. AB - Plasmid-mediated and chromosomally-encoded colistin resistance is increasingly being reported worldwide. We aimed to determine the prevalence of faecal carriage of colistin-resistant Gram-negative rod isolates in a university hospital in western France. From February to May 2016, rectal swabs from 653 patients hospitalized in various clinical settings were recovered and subsequently screened for colistin resistance using the SuperPolymyxin medium. Antimicrobial susceptibilities were determined according to EUCAST guidelines. Genetic detection of plasmid-mediated colistin resistance was performed by PCR. The faecal carriage with intrinsic colistin-resistant isolates was high (23 %), while the faecal carriage with Gram-negative rods showing acquired resistance was low (1.4 %). No isolate carried the plasmid-mediated mcr-1/mcr-2 genes. It was noteworthy that none of the patients carrying isolates with acquired colistin resistance had previously received a colistin-based treatment, while these isolates were not multidrug resistant. PMID- 28598316 TI - How do the epidemiology of paediatric methicillin-resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus bacteraemia differ? AB - PURPOSE: To examine whether the epidemiology of bacteraemia caused by methicillin susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) differed in children aged <1 year and in comparison to older age groups. METHODOLOGY: English mandatory MRSA and MSSA surveillance data from 2006 and 2011, respectively, were collected. Epidemiological information was descriptively analysed in relation to methicillin susceptibility and patient age. Ninety-five percent confidence intervals (CIs) are reported.Results/Key findings. The average incidence rate of MSSA and MRSA bacteraemia in <1-year-olds was 60.2 and 4.8 episodes per 100 000 population per year, respectively. Of the cases of MSSA bacteraemia in children aged <1 year, 47.5 % (95 % CI: 45.1-50.0; n=760/1 599) were in neonates. With increasing age up to one year, more MSSA bacteraemias were detected >=7 days after admission, ranging from 0 % (95 % CI: 0-2.5 %) in 0-2-day olds to 68.4 % (95 % CI: 64.0-72.5 %; 333/487) in 8-28-day-olds and 50.5 % (95 % CI: 47.1-54.0 %; 423/837) in 29 day-1-year-olds, a higher proportion than in older children but similar to MRSA bacteraemia. Amongst <1-year-olds with MSSA bacteraemia, the underlying source was most commonly recorded as intravascular devices [34.4 % (95 %, CI: 30.5-38.6 %); n=190/552] whilst in older age groups this declined. A similar trend was observed for MRSA bacteraemia. CONCLUSIONS: Our analysis indicates that S. aureus bacteraemia in <1-year-olds is primarily healthcare-associated, unlike MSSA bacteraemia in older age groups. Paediatric specific interventions targeted at the healthcare setting, such as neonatal unit specific care bundles and paediatric device-specific strategies, are required. PMID- 28598317 TI - Thioclava nitratireducens sp. nov., isolated from surface seawater. AB - A bacterial strain, designated 25B10_4T, was isolated from surface seawater of the Bering Sea and characterized using a polyphasic taxonomic approach. Cells of strain 25B10_4T were Gram-stain-negative, motile and short-rod-shaped. Growth was observed at 10-43 degrees C (optimum 28 degrees C), at pH 6-9 (optimum pH 7) and with 0-12 % NaCl (optimum 3-4 %, w/v). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain 25B10_4T formed an independent branch within the genus Thioclava, sharing high similarities with four related type strains, Thioclava atlantica 13D2W-2T (98.9 %), Thioclava pacifica TL 2T (98.5 %), Thioclava dalianensis DLFJ1-1T (98.4 %) and Thioclava indica DT23-4T (96.9 %), and low similarities (less than 96.5 %) with other type strains within the family Rhodobacteraceae. The major fatty acid was identified as summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c). The quinone was Q-10. The polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol, glycolipid and five unidentified phospholipids. The DNA G+C content was 63.8 mol%. The digital DNA DNA hybridization and average nucleotide identity values between strain 25B10_4T and the four above-mentioned type strains were, respectively, 20.5-25.7 % and 77.8-82.4 %. The phenotypic, phylogenetic and chemotaxonomic analyses clearly indicated that strain 25B10_4T represents a novel species within the genus Thioclava, for which the name Thioclava nitratireducens sp. nov. is proposed. The type strain is 25B10_4T (=MCCC 1A07302T=LMG 29614T). PMID- 28598318 TI - Paracoccus hibisci sp. nov., isolated from the rhizosphere of Hibiscus syriacus L. (Mugunghwa flower). AB - A Gram-stain-negative, aerobic, short-rod-shaped bacterium, motile by means of one flagellum (THG-T2.8T), was isolated from the rhizosphere of Mugunghwa flower. Growth occurred at 10-37 degrees C (optimum 28 degrees C), at pH 6-8 (optimum 7) and with 0-5 % NaCl (optimum 1 %). The major quinone was ubiquinone-10 (Q-10). The major fatty acids were C10 : 0 3-OH, C16 : 0, C18 : 0 and C18 : 1omega7c. The polar lipids were diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, one unidentified aminolipid, two unknown phospholipids, one unknown glycolipid and one unidentified lipid. The DNA G+C content of strain THG-T2.8T was 65.5 mol%. Based on 16S rRNA gene sequence analysis, the nearest phylogenetic neighbours of strain THG-T2.8T were identified as Paracoccus tibetensis Tibet-S9a3T (98.6 %), Paracoccus aestuarii B7T (98.4 %), Paracoccus rhizosphaerae CC-CCM15-8T (98.3 %) and Paracoccus beibuensis JLT1284T (98.2 %). Levels of sequence similarity among strain THG-T2.8T and other species of the genus Paracoccus were lower than 98.0 %. DNA-DNA hybridization values between strain THG-T2.8T and P. tibetensis Tibet-S9A3TT, P. aestuarii B7T, P. rhizosphaerae CC-CCM15-8T and P. beibuensisJLT1284T were 36.5 % (38.8 %, reciprocal analysis), 32.8 % (34.8 %), 31.6 % (33.8 %) and 15.3 % (24.8 %), respectively. On the basis of the phylogenetic analysis, chemotaxonomic data, physiological characteristics and DNA-DNA hybridization data, strain THG-T2.8T represents a novel species of the genus Paracoccus, for which the name Paracoccus hibisci sp. nov. is proposed. The type strain is THG-T2.8T (=KACC 18932T=CCTCC AB 2016181T). PMID- 28598319 TI - Are children with familial Mediterranean fever really vitamin D deficient? PMID- 28598320 TI - Chronic recurrent multifocal osteomyelitis presenting with Tolosa-Hunt syndrome in a 13-year-old boy. PMID- 28598321 TI - Reply to: About the AIRTRIP randomised clinical trial. PMID- 28598322 TI - Rheumatoid arthritis is not a single disease. PMID- 28598323 TI - Associations of HLA-B alleles with Behcet's disease in Ireland. PMID- 28598324 TI - A case-control study to assess the effectiveness of pertussis vaccination during pregnancy on newborns, Valencian community, Spain, 1 March 2015 to 29 February 2016. AB - In the Valencian Community (Spain), the programme of maternal pertussis vaccination during pregnancy started in January 2015. The objective of this study was to estimate in this region the vaccine effectiveness (VE) in protecting newborns against laboratory-confirmed pertussis infection. A matched case-control study was undertaken in the period between 1 March 2015 and 29 February 2016. Twenty-two cases and 66 controls (+/- 15 days of age difference) were included in the study. Cases were non-vaccinated infants < 3 months of age at disease onset testing positive for pertussis by real-time PCR. For every case three unvaccinated controls were selected. Odds ratios (OR) were calculated by multiple conditional logistic regression for association between maternal vaccination and infant pertussis. Other children in the household, as well as mother- and environmental covariates were taken into account. The VE was calculated as 1 - OR. Mothers of five cases (23%) and of 41 controls (62%) were vaccinated during pregnancy. The adjusted VE was 90.9% (95% confidence interval (CI): 56.6 to 98.1). The only covariate in the final model was breastfeeding (protective effect). Our study provides evidence in favour of pertussis vaccination programmes for pregnant women in order to prevent whooping cough in infants aged less than 3 months. PMID- 28598325 TI - Human T-lymphotropic viruses (HTLV) in England and Wales, 2004 to 2013: testing and diagnoses. AB - Human T-lymphotropic virus (HTLV) infection has been under enhanced surveillance in England and Wales since 2002, however, little is known about testing patterns. Using data from two surveillance systems held at Public Health England, we described HTLV antibody testing patterns between 2008 and 2013 and the demographic and clinical characteristics of persons diagnosed with HTLV in England and Wales between 2004 and 2013. An increase in HTLV testing was observed in England between 2008 and 2013 (3,581 to 7,130). Most tests (82%; 7,597/9,302) occurred within secondary care, 0.5% (48/9,302) of persons were reactive for HTLV antibodies and 0.3% (27/9,302) were confirmed positive. Increasing age and female sex were predictors of a reactive HTLV screen and confirmed diagnosis. Testing in primary care including sexual health and antenatal services was infrequent. Between 2004 and 2013, 858 people were diagnosed with HTLV, most of whom were female (65%; 549/851), of black Caribbean ethnicity (60%), not born in the United Kingdom (72%; 369/514) and asymptomatic at diagnosis (45%; 267/595). Despite increased testing, the epidemiology and clinical features of those diagnosed with HTLV have remained consistent. Apart from donor screening, testing for HTLV infection remains uncommon, except to diagnose associated disease. PMID- 28598326 TI - Enhancers not required. AB - Laboratory mice with over half a megabase of DNA upstream of their Myc gene removed still thrive in the absence of stress. PMID- 28598327 TI - Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. AB - The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single molecule imaging, biochemistry and electrophysiology, we show that glycine and D serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling. PMID- 28598332 TI - Engineering phase transformation of cobalt selenide in carbon cages and the phases' bifunctional electrocatalytic activity for water splitting. AB - Using Co-based metal-organic frameworks as the precursor, we synthesized cobalt selenide (CoSe2) nanoparticles imbedded in carbon cages. By simply controlling the annealing conditions, phase transformation of CoSe2 from the orthorhombic phase to the cubic phase has been realized. Benefitting from the metallic character, the cubic phase CoSe2 shows greatly enhanced electrocatalytic activity for both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). The as-prepared cubic phase CoSe2 electrode possesses onset overpotentials of 43 and 200 mV, and Tafel slopes of 51 and 83 mV dec-1 for HER and OER, respectively, which are remarkably superior to that of the orthorhombic phase CoSe2 catalyst and comparable to those of commercial noble-metal catalysts. In addition, the cubic phase CoSe2 electrode also demonstrates excellent stability after long-term operations. Our work not only provides a high performance catalyst for water splitting, but also introduces a new route to the design of a highly efficient catalyst by phase transformation. PMID- 28598328 TI - A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses. AB - Influenza virus' low replicative fidelity contributes to its capacity for rapid evolution. Clonal sequencing and fluctuation tests have suggested that the influenza virus mutation rate is 2.7 * 10-6 - 3.0 * 10-5 substitutions per nucleotide per strand copied (s/n/r). However, sequencing assays are biased toward mutations with minimal fitness impacts and fluctuation tests typically investigate only a subset of all possible single nucleotide mutations. We developed a fluctuation test based on reversion to fluorescence in a set of virally encoded mutant green fluorescent proteins, which allowed us to measure the rates of selectively neutral mutations representative of the twelve different mutation types. We measured an overall mutation rate of 1.8 * 10-4 s/n/r for PR8 (H1N1) and 2.5 * 10-4 s/n/r for Hong Kong 2014 (H3N2) and a transitional bias of 2.7-3.6. Our data suggest that each replicated genome will have an average of 2-3 mutations and highlight the importance of mutational load in influenza virus evolution. PMID- 28598333 TI - Itinerant magnetic metals. AB - In this review, an overview of itinerant magnets without magnetic elements is presented, beginning with a comparison of the local and itinerant moment pictures, the two extremes of magnetism. Then, the theoretical developments leading up to the self-consistent renormalization theory of spin fluctuations will be discussed, followed by an introduction to quantum criticality and the experimental signatures associated with systems near a quantum critical point. Three itinerant magnets without magnetic elements, ZrZn2, Sc3.1In, and TiAu are the focus of this review, as their empty d shells set them apart in their purely itinerant character, while several enhanced Pauli paramagnets and intermediate moment magnets are also discussed to put the overall comparison into perspective. PMID- 28598330 TI - Analysis of SUMO1-conjugation at synapses. AB - SUMO1-conjugation of proteins at neuronal synapses is considered to be a major post-translational regulatory process in nerve cell and synapse function, but the published evidence for SUMO1-conjugation at synapses is contradictory. We employed multiple genetic mouse models for stringently controlled biochemical and immunostaining analyses of synaptic SUMO1-conjugation. By using a knock-in reporter mouse line expressing tagged SUMO1, we could not detect SUMO1 conjugation of seven previously proposed synaptic SUMO1-targets in the brain. Further, immunostaining of cultured neurons from wild-type and SUMO1 knock-out mice showed that anti-SUMO1 immunolabelling at synapses is non-specific. Our findings indicate that SUMO1-conjugation of synaptic proteins does not occur or is extremely rare and hence not detectable using current methodology. Based on our data, we discuss a set of experimental strategies and minimal consensus criteria for the validation of SUMOylation that can be applied to any SUMOylation substrate and SUMO isoform. PMID- 28598334 TI - High-pressure structures of yttrium hydrides. AB - In this work, the crystal structures of YH3 and YH4 at high pressure (100-250 GPa) have been explored using a genetic algorithm combined with first-principles calculations. New structures of YH3 with space group symmetries of P21/m and I4/mmm were predicted. The electronic structures and the phonon dispersion properties of various YH3 and YH4 structures at different temperatures and pressures were investigated. Among YH3 phases, the P21/m structure of YH3 was found to have a relatively high superconducting transformation temperature T c of 19 K at 120 GPa, which is reduced to 9 K at 200 GPa. Other YH3 structures have much lower T cs. Compared with YH3, the T c of the YH4 compound is much higher, i.e. 94 K at 120 GPa and 55 K at 200 GPa. PMID- 28598329 TI - Glycolytic reliance promotes anabolism in photoreceptors. AB - Vertebrate photoreceptors are among the most metabolically active cells, exhibiting a high rate of ATP consumption. This is coupled with a high anabolic demand, necessitated by the diurnal turnover of a specialized membrane-rich organelle, the outer segment, which is the primary site of phototransduction. How photoreceptors balance their catabolic and anabolic demands is poorly understood. Here, we show that rod photoreceptors in mice rely on glycolysis for their outer segment biogenesis. Genetic perturbations targeting allostery or key regulatory nodes in the glycolytic pathway impacted the size of the outer segments. Fibroblast growth factor signaling was found to regulate glycolysis, with antagonism of this pathway resulting in anabolic deficits. These data demonstrate the cell autonomous role of the glycolytic pathway in outer segment maintenance and provide evidence that aerobic glycolysis is part of a metabolic program that supports the biosynthetic needs of a normal neuronal cell type. PMID- 28598335 TI - Complex magnetic order from multiple Ce-sites in Ce3Pd4Sn6. AB - Polycrystalline [Formula: see text] [Formula: see text] [Formula: see text] samples were synthesized by arc-melting and subsequent annealing at 970 K. Specific heat, electrical resistivity and magnetic susceptibility measurements are performed over a wide range in temperature and provide hints for the presence of a complex magnetic ordering below 3 K arising from three crystallographically independent Ce sites. This behaviour is driven by a complex interplay between ferro-, ferri-, and antiferromagnetic correlations among the Ce atoms. PMID- 28598336 TI - Investigation on H-containing shallow trap of hydrogenated TiO2 with in situ Fourier transform infrared diffuse reflection spectroscopy. AB - A novel technique, high temperature high pressure in situ Fourier transform infrared diffuse reflection spectroscopy, was successfully used to investigate the formation and stability of shallow trap states in P25 TiO2 nanoparticles. Two types of shallow traps (with and without H atoms) were identified. The H containing shallow trap can be easily generated by heating in H2 atmosphere. However, the trap is unstable in vacuum at 600 degrees C. In contrast, the H free shallow trap, which can be formed by heating in vacuum, is stable even at 600 degrees C. The energy gaps between shallow trap states and the conduction band are 0.09 eV for H-containing shallow trap and 0.13 eV for H-free shallow trap, indicating that the H-containing shallow trap state is closer to the conduction band than that without H. PMID- 28598337 TI - Measuring sporadic gastrointestinal illness associated with drinking water - an overview of methodologies. AB - There is an increasing awareness that drinking water contributes to sporadic gastrointestinal illness (GI) in high income countries of the northern hemisphere. A literature search was conducted in order to review: (1) methods used for investigating the effects of public drinking water on GI; (2) evidence of possible dose-response relationship between sporadic GI and drinking water consumption; and (3) association between sporadic GI and factors affecting drinking water quality. Seventy-four articles were selected, key findings and information gaps were identified. In-home intervention studies have only been conducted in areas using surface water sources and intervention studies in communities supplied by ground water are therefore needed. Community-wide intervention studies may constitute a cost-effective alternative to in-home intervention studies. Proxy data that correlate with GI in the community can be used for detecting changes in the incidence of GI. Proxy data can, however, not be used for measuring the prevalence of illness. Local conditions affecting water safety may vary greatly, making direct comparisons between studies difficult unless sufficient knowledge about these conditions is acquired. Drinking water in high-income countries contributes to endemic levels of GI and there are public health benefits for further improvements of drinking water safety. PMID- 28598338 TI - Polysulfone ultrafiltration membrane incorporated with Ag-SiO2 nanohybrid for effective fouling control. AB - An anti-fouling hybrid membrane was prepared by incorporating Ag-SiO2 nanohybrid into a polysulfone (PSf) matrix. The addition of Ag-SiO2 can significantly improve the hydrophilicity, separation property, anti-fouling ability, and especially anti-bacterial activity of hybrid membranes. The optimum performance of the Ag-SiO2/PSf hybrid membrane is achieved when the concentration of Ag-SiO2 is as low as 0.45 wt%. Compared with PSf membrane and SiO2/PSf hybrid membrane, the Ag-SiO2/PSf hybrid membrane displays the best overall properties. The excellent performance of the Ag-SiO2/PSf hybrid membrane can be attributed to the well-tailored structure and unique property of Ag-SiO2 nanohybrid, where nanosized Ag (~5 nm) can densely and uniformly disperse on the surface of silica spheres. The obtained membrane could be a promising material for water treatment. PMID- 28598339 TI - Comparison of MI, Chromocult(r) coliform, and Compass CC chromogenic culture based methods to detect Escherichia coli and total coliforms in water using 16S rRNA sequencing for colony identification. AB - The MI, Chromocult(r) coliform, and Compass CC chromogenic culture-based methods used to assess water quality by the detection of Escherichia coli and total coliforms were compared in terms of their specificity and sensitivity, using 16S rRNA sequencing for colony identification. A sewage water sample was divided in 2 MUL subsamples for testing by all three culture-based methods. All growing colonies were harvested and subjected to 16S rRNA sequencing. Test results showed that all E. coli colonies were correctly identified by all three methods, for a specificity and a sensitivity of 100%. However, for the total coliform detection, the MI agar, Chromocult(r) coliform agar, and Compass CC agar were specific for only 69.2% (9/13), 47.2% (25/53), and 40.5% (17/42), whereas sensitive for 97.8% (45/46), 97.5% (39/40), and 85.7% (24/28), respectively. Thus, given the low level of specificity of these methods for the detection of total coliforms, confirming the identity of total coliform colonies could help to take public health decisions, in particular for cities connected to a public drinking water distribution system since the growth of few putative total coliform colonies on chromogenic agar is problematic and can lead to unnecessary and costly boiling notices from public health authorities. PMID- 28598340 TI - Effects of drinking desalinated seawater on cell viability and proliferation. AB - Desalination of seawater is becoming an important means to address the increasing scarcity of freshwater resources in the world. Seawater has been used as drinking water in the health, food, and medical fields and various beneficial effects have been suggested, although not confirmed. Given the presence of 63 minerals and trace elements in drinking desalinated seawater (63 DSW), we evaluated their effects on the behavior of tumorigenic and nontumorigenic cells through the 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and annexin-V fluorescein isothiocyanate/propidium iodide staining. Our results showed that cell viability and proliferation in the presence of 63 DSW were significantly greater than in mineral water and in the presence of fetal bovine serum in a dose dependent manner. Furthermore, 63 DSW showed no toxic effect on murine embryonic fibroblast (NIH-3T3) and murine melanoma (B16-F10) cells. In another assay, we also showed that pre-treatment of non-adherent THP-1 cells with 63 DSW reduces apoptosis incidence, suggesting a protective effect against cell death. We conclude that cell viability and proliferation were improved by the mineral components of 63 DSW and this effect can guide further studies on health effects associated with DSW consumption. PMID- 28598341 TI - Effect of trihalomethanes (chloroform and bromoform) on human haematological count. AB - With the increasing concerns about the harmful effects of disinfection products, the process of chlorination is becoming questionable. Bromoform and chloroform are among the most frequently occurring disinfection by-products. Haematological parameters are an important indicator of human well-being which is why the prime objective of the current study was to conduct a dose-response assessment to investigate the effects of trihalomethanes on human haematological count. Blood samples of healthy subjects were exposed to different concentrations (10, 30 and 50 MUg/mL) of chloroform and bromoform in vitro to analyse how these compounds affected the haematological count with increasing dose concentrations. Headspace gas chromatography analysis was also conducted on samples to assess the difference between measured and spiked values of doses. The results indicated that the damage caused by bromoform was statistically more significant as compared to chloroform. Haemoglobin (HGB) and mean corpuscular haemoglobin concentration levels lowered as they were significantly affected (p < 0.05) by bromoform at all administered doses. It also significantly damaged platelet level at doses of 30 (p < 0.05) and 50 MUg/mL (p < 0.01). Conversely, the damage caused by chloroform was statistically less significant (p > 0.05). PMID- 28598342 TI - Removals of cryptosporidium parvum oocysts and cryptosporidium-sized polystyrene microspheres from swimming pool water by diatomaceous earth filtration and perlite-sand filtration. AB - Removal of Cryptosporidium-sized microspheres and Cryptosporidium parvum oocysts from swimming pools was investigated using diatomaceous earth (DE) precoat filtration and perlite-sand filtration. In pilot-scale experiments, microsphere removals of up to 2 log were obtained with 0.7 kg.DE/m2 at a filtration rate of 5 m/h. A slightly higher microsphere removal (2.3 log) was obtained for these DE precoated filters when the filtration rate was 3.6 m/h. Additionally, pilot-scale perlite-sand filters achieved greater than 2 log removal when at least 0.37 kg/m2 of perlite was used compared to 0.1-0.4 log removal without perlite both at a surface loading rate of 37 m/h. Full-scale testing achieved 2.7 log of microspheres and oocysts removal when 0.7 kg.DE/m2 was used at 3.6 m/h. Removals were significantly decreased by a 15-minute interruption of the flow (without any mechanical agitation) to the DE filter in pilot-scale studies, which was not observed in full-scale filters. Microsphere removals were 2.7 log by perlite-sand filtration in a full-scale swimming pool filter operated at 34 m/h with 0.5 kg/m2 of perlite. The results demonstrate that either a DE precoat filter or a perlite sand filter can improve the efficiency of removal of microspheres and oocysts from swimming pools over a standard sand filter under the conditions studied. PMID- 28598343 TI - From urban municipalities to polar bioremediation: the characterisation and contribution of biogenic minerals for water treatment. AB - Minerals of biological origin have shown significant potential for the separation of contaminants from water worldwide. This study details the contribution of biologically derived minerals to water treatment operations, with a focus on filtration media from urban municipalities and remote cold regions. The results support biofilm-embedded iron and manganese to be the building blocks of biogenic mineral development on activated carbon and nutrient-amended zeolites. The presence of similar iron and manganese oxidising bacterial species across all filter media supports the analogous morphologies of biogenic minerals between sites and suggests that biological water treatment processes may be feasible across a range of climates. This is the first time the stages of biogenic mineral formation have been aligned with comprehensive imaging of the biofilm community and bacterial identification; especially with respect to cold regions. Where biogenic mineral formation occurs on filter media, the potential exists for enhanced adsorption for a range of organic and inorganic contaminants and improved longevity of filter media beyond the adsorption or exchange capacities of the raw material. PMID- 28598344 TI - Occurrence of Legionella in showers at recreational facilities. AB - Critical environments, including water systems in recreational settings, represent an important source of Legionella pneumophila infection in humans. In order to assess the potential risk for legionellosis, we analyzed Legionella contamination of water distribution systems in 36 recreational facilities equipped with swimming pools. One hundred and sixty water samples were analyzed from shower heads or taps located in locker rooms or in bathrooms. By culture method and polymerase chain reaction, 41/160 samples were positive for Legionella from 12/36 recreational centers. Hotels (57.1%) and sports centers (41.2%) were the most contaminated. L. pneumophila serotypes 2-14 (25/41) were more frequently found than serotype 1 (10/41). Samples at temperature >=30 degrees C were more frequently positive than samples at temperature <30 degrees C (n = 39 vs n = 2, p < 0.00001). The presence of L. pneumophila was investigated by comparison with heterotrophic plate count (HPC), an indicator of water quality. The presence of L. pneumophila was associated more frequently with high and intermediate HPC load at 37 degrees C, therefore should be considered a potential source when HPC at 37 degrees C is >10 CFU/mL. Maintenance, good hygiene practices, interventions on the hydraulic system and regular controls must be implemented to minimize exposure to L. pneumophila infection risk. PMID- 28598345 TI - Microbiological quality of ice and ice machines used in food establishments. AB - The ice used in the food industry has to be safe and the water used in ice production should have the quality of drinking water. The consumption of contaminated ice directly or indirectly may be a vehicle for transmission of pathogenic bacteria to humans producing outbreaks of gastrointestinal diseases. The objective of this study was to monitor the microbiological quality of ice, the water used in producing ice and the hygienic conditions of ice making machines in various food enterprises. Escherichia coli was detected in seven (6.7%) ice and 23 (21.9%) ice chest samples whereas E. coli was negative in all examined water samples. Psychrophilic bacteria were detected in 83 (79.0%) of 105 ice chest and in 68 (64.7%) of 105 ice samples, whereas Enterococci were detected only in 13 (12.4%) ice samples. Coliforms were detected in 13 (12.4%) water, 71 (67.6%) ice chest and 54 (51.4%) ice samples. In order to improve the microbiological quality of ice, the maintenance, cleaning and disinfecting of ice machines should be carried out effectively and periodically. Also, high quality water should be used for ice production. PMID- 28598346 TI - Application of long amplicon propidium monoazide-PCR to assess the effects of temperature and background microbiota on pathogens in river water. AB - The decay rates of enteric waterborne pathogens were evaluated following the introduction of Yersinia enterocolitica, Salmonella enterica, Campylobacter jejuni and Arcobacter butzleri into river water at different temperatures (5, 15 and 25 degrees C) for a period of 28 days. To improve the accuracy of the results a molecular viability assay, long amplicon propidium monoazide-polymerase chain reaction (PMA-PCR), was used to quantify the viable cell concentration and results from PCR with and without PMA were compared. As well, the effect of background microbiota was assessed for Y. enterocolitica and S. enterica by inoculating cells into sterile and non-sterile river water. Cell persistence was improved by up to 4 log for Y. enterocolitica and 4.5 log for S. enterica in sterile river water compared to natural river water, showing that the autochthonous biological activity in river water can accelerate the die-off of introduced bacteria. Results also showed that low temperature significantly improved the persistence of all four target bacteria in non-sterile river water. There was a more rapid decline in cell concentration in samples with PMA pretreatment; therefore using PMA-PCR analysis can provide more reliable data on viable/active enteric bacteria in aquatic microcosms and allows for improved assessment of pathogens in the environment. PMID- 28598347 TI - Ingestion of swimming pool water by recreational swimmers. AB - The volume of water ingested by swimmers while swimming is of great interest to individuals who develop risk assessments using quantitative microbial risk assessment or epidemiological approaches. We have used chloroisocyanurate disinfected swimming pool waters to determine the amount of water swallowed by swimmers during swimming activity. The chloroisocyanurate, which is in equilibrium with chlorine and cyanuric acid in the pool water, provides a biomarker, cyanuric acid, that once swallowed passes through the body into the urine unchanged. The concentration of cyanuric acid in a 24 hour urine specimen and the concentration in pool water can be used to calculate the amount of water swallowed. Our study population of 549 participants, which was about evenly divided by gender, and young and adult swimmers, indicated that swimmers ingest about 32 mL per hour (arithmetic mean) and that children swallowed about four times as much water as adults during swimming activities. It was also observed that males had a tendency to swallow more water than females during swimming activity and that children spent about twice as much time in the water than adults. PMID- 28598348 TI - Mortality from selected diseases that can be transmitted by water - United States, 2003-2009. AB - Diseases spread by water are caused by fecal-oral, contact, inhalation, or other routes, resulting in illnesses affecting multiple body systems. We selected 13 pathogens or syndromes implicated in waterborne disease outbreaks or other well documented waterborne transmission (acute otitis externa, Campylobacter, Cryptosporidium, Escherichia coli (E. coli), free-living ameba, Giardia, Hepatitis A virus, Legionella (Legionnaires' disease), nontuberculous mycobacteria (NTM), Pseudomonas-related pneumonia or septicemia, Salmonella, Shigella, and Vibrio). We documented annual numbers of deaths in the United States associated with these infections using a combination of death certificate data, nationally representative hospital discharge data, and disease-specific surveillance systems (2003-2009). We documented 6,939 annual total deaths associated with the 13 infections; of these, 493 (7%) were caused by seven pathogens transmitted by the fecal-oral route. A total of 6,301 deaths (91%) were associated with infections from Pseudomonas, NTM, and Legionella, environmental pathogens that grow in water system biofilms. Biofilm-associated pathogens can cause illness following inhalation of aerosols or contact with contaminated water. These findings suggest that most mortality from these 13 selected infections in the United States does not result from classical fecal-oral transmission but rather from other transmission routes. PMID- 28598349 TI - Predicting water filter and bottled water use in Appalachia: a community-scale case study. AB - A questionnaire survey was conducted in order to assess residents' perceptions of water quality for drinking and recreational purposes in a mid-sized city in northcentral West Virginia. Two logistic regression analyses were conducted in order to investigate the factors that influence bottle use and filter use. Results show that 37% of respondents primarily use bottled water and that 58% use a household filter when drinking from the tap. Respondents with lower levels of environmental concern, education levels, and lower organoleptic perceptions were most likely to perceive health risks from tap water consumption, and were most likely to use bottled water. Income, age, and organoleptic perceptions were predictors of water filter use among respondents. Clean water for recreational purposes was not found to be significant with either of these models. Our results demonstrate that bottle use and filter use are explained differently. We argue that more education and better communication about local tap water quality would decrease the use of bottled water. We demonstrate that household filters could be used as an alternative to bottled water. PMID- 28598350 TI - Comparative study of physico-chemical parameters of drinking water from some longevity and non-longevity areas of China. AB - There is an obvious regional longevity phenomenon in China and many longevity counties are located in South China. This study was carried out to find the characteristics of elemental contents of drinking water in longevity areas in South China and the differences to non-longevity areas in China. A total of 128 drinking water samples were collected from longevity areas in South China (n = 40), non-longevity areas in South China (n = 74) and non-longevity areas in North China (n = 14) and 46 parameters of water were determined or calculated. The results showed that drinking water in longevity areas of South China had a high ratio of sum concentration of essential micro-elements in sum concentration of micro-elements (SCME) and a low ratio of sum concentration of hazardous micro elements in SCME. The concentration of total hardness (TH) and strontium in drinking water was 157.82 mg/L and 82.1 MUg/L, respectively, and they were 14.61 mg/L, 7.45 MUg/L and 291.69 mg/L, 748.65 MUg/L in the non-longevity areas of South and North China, respectively. The study concluded that drinking water containing 157.82 mg/L TH and 82.1 MUg/L strontium in South China may be optimum to human health. PMID- 28598351 TI - Erratum: Journal of Water and Health 14(6), 998-1008: Exploring the relationships between small non-community drinking water system characteristics and water system performance in Ontario, Canada, W. Pons et al., doi: https://doi.org/10.2166/wh.2016.007. PMID- 28598352 TI - UK Pigs at the Time of Slaughter: Investigation into the Correlation of Infection with PRRSV and HEV. AB - Hepatitis E virus (HEV) and porcine reproductive and respiratory syndrome virus (PRRSV) and are both globally prevalent in the pig population. While HEV does not cause clinical disease in pigs, its zoonotic potential has raised concerns in the food safety sector. PRRS has become endemic in the United Kingdom (UK) since its introduction in 1991, and continues to cause considerable economic losses to the swine industry. A better understanding of the current prevalence and diversity of PRRSV and HEV in the UK, and their potential association, is needed to assess risks and target control measures appropriately. This study used plasma, tonsil, and cecal content samples previously collected from pigs in 14 abattoirs in England and Northern Ireland to study the prevalence of several pathogens including PRRSV and HEV. The diversity of PRRSV strains detected in these samples was analyzed by sequencing open reading frame 5 (ORF5), revealing no substantial difference in PRRSV strains from these clinically unaffected pigs relative to those from clinical cases of disease in the UK. Despite the potential immuno modulatory effect of PRRSV infection, previously demonstrated to affect Salmonella and HEV shedding profiles, no significant association was found between positive PRRSV status and positive HEV status. PMID- 28598355 TI - Ecological Niche Modeling Identifies Fine-Scale Areas at High Risk of Dengue Fever in the Pearl River Delta, China. AB - Dengue fever (DF) is one of the most common and rapidly spreading mosquito-borne viral diseases in tropical and subtropical regions. In recent years, this imported disease has posed a serious threat to public health in China, especially in the Pearl River Delta (PRD). Although the severity of DF outbreaks in the PRD is generally associated with known risk factors, fine scale assessments of areas at high risk for DF outbreaks are limited. We built five ecological niche models to identify such areas including a variety of climatic, environmental, and socioeconomic variables, as well as, in some models, extracted principal components. All the models we tested accurately identified the risk of DF, the area under the receiver operating characteristic curve (AUC) were greater than 0.8, but the model using all original variables was the most accurate (AUC = 0.906). Socioeconomic variables had a greater impact on this model (total contribution 55.27%) than climatic and environmental variables (total contribution 44.93%). We found the highest risk of DF outbreaks on the border of Guangzhou and Foshan (in the central PRD), and in northern Zhongshan (in the southern PRD). Our fine-scale results may help health agencies to focus epidemic monitoring tightly on the areas at highest risk of DF outbreaks. PMID- 28598353 TI - Cellular Consequences of Diminished Protein O-Mannosyltransferase Activity in Baker's Yeast. AB - O-Mannosylation is a type of protein glycosylation initiated in the endoplasmic reticulum (ER) by the protein O-mannosyltransferase (PMT) family. Despite the vital role of O-mannosylation, its molecular functions and regulation are not fully characterized. To further explore the cellular impact of protein O mannosylation, we performed a genome-wide screen to identify Saccharomyces cerevisiae mutants with increased sensitivity towards the PMT-specific inhibitor compound R3A-5a. We identified the cell wall and the ER as the cell compartments affected most upon PMT inhibition. Especially mutants with defects in N glycosylation, biosynthesis of glycosylphosphatidylinositol-anchored proteins and cell wall beta-1,6-glucan showed impaired growth when O-mannosylation became limiting. Signaling pathways that counteract cell wall defects and unbalanced ER homeostasis, namely the cell wall integrity pathway and the unfolded protein response, were highly crucial for the cell growth. Moreover, among the most affected mutants, we identified Ost3, one of two homologous subunits of the oligosaccharyltransferase complexes involved in N-glycosylation, suggesting a functional link between the two pathways. Indeed, we identified Pmt2 as a substrate for Ost3 suggesting that the reduced function of Pmt2 in the absence of N-glycosylation promoted sensitivity to the drug. Interestingly, even though S. cerevisiae Pmt1 and Pmt2 proteins are highly similar on the sequence, as well as the structural level and act as a complex, we identified only Pmt2, but not Pmt1, as an Ost3-specific substrate protein. PMID- 28598354 TI - Message in a Bottle: Dialog between Intestine and Skin Modulated by Probiotics. AB - At the beginning, probiotics were used exclusively for gastrointestinal conditions. However, over the years, evidence has shown that probiotics exert systemic effects. In this review article, we will summarize recent reports that postulate probiotic treatment as an efficient one against skin pathologies, such as cancer, allergy, photoaging and skin infections. The focus will be restricted to oral probiotics that could potentially counteract the ultraviolet irradiation induced skin alterations. Moreover, the possible underlying mechanisms by which probiotics can impact on the gut and exert their skin effects will be reviewed. Furthermore, how the local and systemic immune system is involved in the intestine-cutaneous crosstalk will be analyzed. In conclusion, this article will be divided into three core ideas: (a) probiotics regulate gut homeostasis; (b) gut and skin homeostasis are connected; PMID- 28598357 TI - Microcephaly. AB - Microcephaly is defined as a head circumference more than two standard deviations below the mean for gender and age. Congenital microcephaly is present at birth, whereas postnatal microcephaly occurs later in life. Genetic abnormalities, syndromes, metabolic disorders, teratogens, infections, prenatal, perinatal, and postnatal injuries can cause both congenital and postnatal microcephaly. Evaluation of patients with microcephaly begins with a thorough history and physical examination. In cases of worsening microcephaly or neurological signs or symptoms, neuroimaging, metabolic, or genetic testing should be strongly considered. Any further studies and workup should be directed by the presence of signs or symptoms pointing to an underlying diagnosis and are usually used as confirmatory testing for certain conditions. Neuroimaging with magnetic resonance imaging (MRI) is often the first diagnostic test in evaluating children with microcephaly. Genetic testing is becoming more common and is often the next step following neuroimaging when there is no specific evidence in the history or physical examination suggesting a diagnosis. Microcephaly is a lifelong condition with no known cure. The prognosis is usually worse for children who experienced an intrauterine infection or have a chromosomal or metabolic abnormality. Zika virus has rapidly spread since 2015, and maternal infection with this virus is associated with microcephaly and other serious brain abnormalities. Microcephaly has become much more prevalent in the news and scientific community with the recent emergence of Zika virus as a cause of congenital microcephaly. PMID- 28598358 TI - A Smartphone Indoor Localization Algorithm Based on WLAN Location Fingerprinting with Feature Extraction and Clustering. AB - With the development of communication technology, the demand for location-based services is growing rapidly. This paper presents an algorithm for indoor localization based on Received Signal Strength (RSS), which is collected from Access Points (APs). The proposed localization algorithm contains the offline information acquisition phase and online positioning phase. Firstly, the AP selection algorithm is reviewed and improved based on the stability of signals to remove useless AP; secondly, Kernel Principal Component Analysis (KPCA) is analyzed and used to remove the data redundancy and maintain useful characteristics for nonlinear feature extraction; thirdly, the Affinity Propagation Clustering (APC) algorithm utilizes RSS values to classify data samples and narrow the positioning range. In the online positioning phase, the classified data will be matched with the testing data to determine the position area, and the Maximum Likelihood (ML) estimate will be employed for precise positioning. Eventually, the proposed algorithm is implemented in a real-world environment for performance evaluation. Experimental results demonstrate that the proposed algorithm improves the accuracy and computational complexity. PMID- 28598356 TI - NF-kappaB Signalling in Glioblastoma. AB - Nuclear factor-kappaB (NF-kappaB) is a transcription factor regulating a wide array of genes mediating numerous cellular processes such as proliferation, differentiation, motility and survival, to name a few. Aberrant activation of NF kappaB is a frequent event in numerous cancers, including glioblastoma, the most common and lethal form of brain tumours of glial cell origin (collectively termed gliomas). Glioblastoma is characterized by high cellular heterogeneity, resistance to therapy and almost inevitable recurrence after surgery and treatment. NF-kappaB is aberrantly activated in response to a variety of stimuli in glioblastoma, where its activity has been implicated in processes ranging from maintenance of cancer stem-like cells, stimulation of cancer cell invasion, promotion of mesenchymal identity, and resistance to radiotherapy. This review examines the mechanisms of NF-kappaB activation in glioblastoma, the involvement of NF-kappaB in several mechanisms underlying glioblastoma propagation, and discusses some of the important questions of future research into the roles of NF kappaB in glioblastoma. PMID- 28598360 TI - Role of Gut Microbiota in Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease, caused by both genetic and environmental factors. Recently, investigators have focused on the gut microbiota, which is thought to be an environmental agent affecting the development of RA. Here we review the evidence from animal and human studies that supports the role of the gut microbiota in RA. We and others have demonstrated that the abundance of Prevotella copri is increased in some early RA. We have also used gnotobiotic experiments to show that dysbiosis in RA patients contributed to the development of Th17 cell-dependent arthritis in intestinal microbiota-humanized SKG mice. On the other hand, Prevotella histicola from human gut microbiota suppressed the development of arthritis. In summary, Prevotella species are involved in the pathogenesis of arthritis. PMID- 28598359 TI - Vitamin B12 and Semen Quality. AB - Various studies have revealed the effects of vitamin B12, also named cobalamin, on semen quality and sperm physiology; however, these studies collectively are still unsummarized. Here, we systematically discuss and summarize the currently understood role of vitamin B12 on semen quality and sperm physiology. We searched the Web of Science, PubMed, and Scopus databases for only English language articles or abstracts from September 1961 to March 2017 (inclusive) using the key words "vitamin B12" and "cobalamin" versus "sperm". Certain relevant references were included to support the empirical as well as the mechanistic discussions. In conclusion, the mainstream published work demonstrates the positive effects of vitamin B12 on semen quality: first, by increasing sperm count, and by enhancing sperm motility and reducing sperm DNA damage, though there are a few in vivo system studies that have deliberated some adverse effects. The beneficial effects of vitamin B12 on semen quality may be due to increased functionality of reproductive organs, decreased homocysteine toxicity, reduced amounts of generated nitric oxide, decreased levels of oxidative damage to sperm, reduced amount of energy produced by spermatozoa, decreased inflammation-induced semen impairment, and control of nuclear factor-kappaB activation. However, additional research, mainly clinical, is still needed to confirm these positive effects. PMID- 28598361 TI - Social Factors Determine the Emergency Medical Admission Workload. AB - We related social factors with the annual rate of emergency medical admissions using census small area statistics. All emergency medical admissions (70,543 episodes in 33,343 patients) within the catchment area of St. James's Hospital, Dublin, were examined between 2002 and 2016. Deprivation Index, Single-Parent status, Educational level and Unemployment rates were regressed against admission rates. High deprivation areas had an approximately fourfold (Incidence Rate Ratio (IRR) 4.0 (3.96, 4.12)) increase in annual admission rate incidence/1000 population from Quintile 1(Q1), from 9.2/1000 (95% Confidence Interval (CI): 9.0, 9.4) to Q5 37.3 (37.0, 37.5)). Single-Parent families comprised 40.6% of households (95% CI: 32.4, 49.7); small areas with more Single Parents had a higher admission rate-IRR (Q1 vs. for Q5) of 2.92 (95% CI: 2.83, 3.01). The admission incidence rate was higher for Single-Parent status (IRR 1.50 (95% CI: 1.46, 1.52)) where the educational completion level was limited to primary level (Incidence Rate Ratio 1.45 (95% CI: 1.43, 1.47)). Small areas with higher educational quintiles predicted lower Admission Rates (IRR 0.85 (95% CI: 0.84, 0.86)). Social factors strongly predict the annual incidence rate of emergency medical admissions. PMID- 28598364 TI - Isoprenoids Production from Lipid-Extracted Microalgal Biomass Residues Using Engineered E. coli. AB - Microalgae are recognized as a third generation feedstock for biofuel production due to their rapid growth rates and lignin-free characteristics. In this study, a lipid extracted microalgal biomass residues was used as the raw material to produce isoprene, alpha-pinene and beta-pinene with an engineered E. coli strain. We adopted an optimal sulfuric acid hydrolysis method (1:7 ratio of solid to acid solution, 32% (w/v) concentration of sulfuric acid solution at 90 degrees C for 90 min) to efficiently convert holocellulose into glucose efficiently (6.37 g/L). Futhermore, we explored a novel detoxification strategy (phosphoric acid/calcium hydroxide) to remove inhibitors and notably acetic acid, furfural and 5 hydroxymethylfurfural (5-HMF) were reduced by 5.32%, different number given later 99.19% and 98.22%, respectively. Finally, the fermentation concentrations of isoprene (223.23 mg/L), alpha-pinene (382.21 MUg/L) and beta-pinene (17.4 mg/L) were achieved using the detoxified hydrolysate as the carbon source, equivalent to approximately 86.02%, 90.16% and 88.32% of those produced by the engineered E. coli strain fermented on pure glucose, respectively. PMID- 28598365 TI - Subcritical Water Chromatography with Electrochemical Detection. AB - Reverse phase liquid chromatography (RPLC) is a commonly used separation and analysis technique. RPLC typically employs mixtures of organic solvents and water or aqueous buffers as the mobile phase. With RPLC being used on a global scale, enormous quantities of organic solvents are consumed every day. In addition to the purchasing cost of the hazardous solvents, the issue of waste disposal is another concern. At ambient temperature, water is too polar to dissolve many organic substances. Therefore, although water is nontoxic it cannot be used to replace the mobile phase in RPLC since organic analytes will not be eluted. Subcritical water chromatography may be an alternative. The characteristics of water, such as polarity, surface tension, and viscosity, can be altered by manipulating water's temperature, thus making it behave like an organic solvent. The aim of this study was to evaluate the feasibility of separation using water mobile phase and detection by an electrochemical (EC) detector. The classes of analytes studied were neurotransmitters/metabolites, nucleic acids/heterocyclic bases, and capsaicinoids. Both isothermal and temperature-programmed separations were carried out. The separation temperature ranged from 25 to 100 degrees C. For separations of all three classes of solutes, the retention time was decreased with increasing temperature, thus shortening the analysis time. The peaks also became narrower as temperature increased. The limit of detection of neurotransmitters/metabolites ranges from 0.112 to 0.224 ppm. PMID- 28598363 TI - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments. PMID- 28598366 TI - Isolation of Monoterpene Dihydrochalcones from Piper montealegreanum Yuncker (Piperaceae). AB - Four new compounds were isolated from the branches of Piper montealegreanum Yuncker, a shrub found in the Amazon rainforest, including two new dihydrochalcones named claricine (1) and maisine (2), a cinnamic acid derivative 3 and a phenylalkanoid 4, along with a porphyrin identified as the known compound phaeophytin a (5). The structures were established using spectroscopic experiments, including 1D and 2D NMR and HRESIMS experiments, performed on the two monoterpene dihydrochalcones and their monoacetyl derivatives. The structural diversity of these substances is very important for the Piper genus chemotaxonomy. PMID- 28598367 TI - Pattern Evolution during Double Liquid-Vapor Phase Transitions under Weightlessness. AB - Phase transition in fluids is ubiquitous in nature and has important applications in areas such as the food industry for volatile oils' extraction or in nuclear plants for heat transfer. Fundamentals are hampered by gravity effects on Earth. We used direct imaging to record snapshots of phase separation that takes place in sulfur hexafluoride, SF6, under weightlessness conditions on the International Space Station (ISS). The system was already at liquid-vapor equilibrium slightly below the critical temperature and further cooled down by a 0.2-mK temperature quench that produced a new phase separation. Both full view and microscopic views of the direct observation cell were analyzed to determine the evolution of the radii distributions. We found that radii distributions could be well approximated by a lognormal function. The fraction of small radii droplets declined while the fraction of large radii droplets increased over time. Phase separation at the center of the sample cell was visualized using a 12* microscope objective, which corresponds to a depth of focus of about 5 MU m. We found that the mean radii of liquid droplets exhibit a t 1 / 3 evolution, in agreement with growth driven by Brownian coalescence. It was also found that the mean radii of the vapor bubbles inside the liquid majority phase exhibit a t 1 / 2 evolution, which suggest a possible directional motion of vapor bubbles due to the influence of weak remaining gravitational field and/or a composition Marangoni force. PMID- 28598362 TI - Carbon Ion Radiotherapy: A Review of Clinical Experiences and Preclinical Research, with an Emphasis on DNA Damage/Repair. AB - Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT. PMID- 28598368 TI - Self-Assembled Lipid Nanoparticles for Oral Delivery of Heparin-Coated Iron Oxide Nanoparticles for Theranostic Purposes. AB - Recently, solid lipid nanoparticles (SLNs) have attracted increasing attention owing to their potential as an oral delivery system, promoting intestinal absorption in the lymphatic circulation which plays a role in disseminating metastatic cancer cells and infectious agents throughout the body. SLN features can be exploited for the oral delivery of theranostics. Therefore, the aim of this work was to design and characterise self-assembled lipid nanoparticles (SALNs) to encapsulate and stabilise iron oxide nanoparticles non-covalently coated with heparin (Fe@hepa) as a model of a theranostic tool. SALNs were characterised for physico-chemical properties (particle size, surface charge, encapsulation efficiency, in vitro stability, and heparin leakage), as well as in vitro cytotoxicity by methyl thiazole tetrazolium (MTT) assay and cell internalisation in CaCo-2, a cell line model used as an indirect indication of intestinal lymphatic absorption. SALNs of about 180 nm, which are stable in suspension and have a high encapsulation efficiency (>90%) were obtained. SALNs were able to stabilise the heparin coating of Fe@hepa, which are typically unstable in physiological environments. Moreover, SALNs-Fe@hepa showed no cytotoxicity, although their ability to be internalised into CaCo-2 cells was highlighted by confocal microscopy analysis. Therefore, the results indicated that SALNs can be considered as a promising tool to orally deliver theranostic Fe@hepa into the lymphatic circulation, although further in vivo studies are needed to comprehend further potential applications. PMID- 28598370 TI - UV-Curable Aliphatic Silicone Acrylate Organic-Inorganic Hybrid Coatings with Antibacterial Activity. AB - The most effective means to protect against bacterial invasion and to reduce the risk of healthcare-associated infections are antibacterial components synthesis. In this study, a novel process for the synthesis of organic-inorganic hybrid coatings containing silver nanoparticles is presented. Silver nanoparticles and polymer formation proceeds simultaneously through the in situ photoreduction of silver salt to silver nanoparticles and UV-crosslinking of bifunctional aliphatic silicone acrylate. The nanocomposite films with 0.5-1.43 wt % of silver nanoparticles concentration were obtained and investigated. The formation of silver nanoparticles in polymer matrix was confirmed via UV-visible spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy, scanning electron spectroscopy, and energy dispersive spectroscopy. Our investigations clearly show the formation of silver nanoparticles in silicone acrylate network. Direct photoreduction of silver salt by UV-radiation in the organic media produced silver nanoparticles exhibiting cubic crystal structure. The size of nanoparticles was determined to be near 20 +/- 5 nm. The antibacterial activities of coatings were determined using the disc diffusion and direct contact methods. UV-curable silicone acrylate hybrid coatings exhibited antibacterial activity against harmful bacteria strains. PMID- 28598374 TI - Doppler Navigation System with a Non-Stabilized Antenna as a Sea-Surface Wind Sensor. AB - We propose a concept of the utilization of an aircraft Doppler Navigation System (DNS) as a sea-surface wind sensor complementary to its normal functionality. The DNS with an antenna, which is non-stabilized physically to the local horizontal with x-configured beams, is considered. We consider the wind measurements by the DNS configured in the multi-beam scatterometer mode for a rectilinear flight scenario. The system feasibility and the efficiency of the proposed wind algorithm retrieval are supported by computer simulations. Finally, the associated limitations of the proposed approach are considered. PMID- 28598372 TI - Evaluation of the Cardiotoxicity of Evodiamine In Vitro and In Vivo. AB - Evodiamine is a bioactive alkaloid that is specified as a biomarker for the quality assessment of Evodia rutaecarpa (E. rutaecarpa) and for traditional Chinese medicines containing this plant. We previously reported that quantitative structure-activity modeling indicated that evodiamine may cause cardiotoxicity. However, previous investigations have indicated that evodiamine has beneficial effects in patients with cardiovascular diseases and there are no previous in vitro or in vivo reports of evodiamine-induced cardiotoxicity. The present study investigated the effects of evodiamine on primary cultured neonatal rat cardiomyocytes in vitro, and on zebrafish in vivo. Cell viability was reduced in vitro, where evodiamine had a 24 h 50% inhibitory concentration of 28.44 ug/mL. Cells exposed to evodiamine also showed increased lactate dehydrogenase release and maleic dialdehyde levels, and reduced superoxide dismutase activity. In vivo, evodiamine had a 10% lethal concentration of 354 ng/mL and induced cardiac malfunction, as evidenced by changes in heart rate and circulation, and pericardial malformations. This study indicated that evodiamine could cause cardiovascular side effects involving oxidative stress. These findings suggest that cardiac function should be monitored in patients receiving preparations containing evodiamine. PMID- 28598373 TI - Dichlorotrifluoromethoxyacetic Acid: Preparation and Reactivity. AB - We describe the first gram scale preparation of the reagent dichlorotrifluoromethoxyacetic acid. This stable compound is obtained in five steps starting from the cheap diethylene glycol. The reactivity of the sodium salt of this fluorinated acid was also tested and allowed the preparation of new amides. PMID- 28598369 TI - Plant Lectins Targeting O-Glycans at the Cell Surface as Tools for Cancer Diagnosis, Prognosis and Therapy. AB - Aberrant O-glycans expressed at the surface of cancer cells consist of membrane tethered glycoproteins (T and Tn antigens) and glycolipids (Lewis a, Lewis x and Forssman antigens). All of these O-glycans have been identified as glyco-markers of interest for the diagnosis and the prognosis of cancer diseases. These epitopes are specifically detected using T/Tn-specific lectins isolated from various plants such as jacalin from Artocarpus integrifola, and fungi such as the Agaricus bisporus lectin. These lectins accommodate T/Tn antigens at the monosaccharide-binding site; residues located in the surrounding extended binding site of the lectins often participate in the binding of more extended epitopes. Depending on the shape and size of the extended carbohydrate-binding site, their fine sugar-binding specificity towards complex O-glycans readily differs from one lectin to another, resulting in a great diversity in their sugar-recognition capacity. T/Tn-specific lectins have been extensively used for the histochemical detection of cancer cells in biopsies and for the follow up of the cancer progression and evolution. T/Tn-specific lectins also induce a caspase-dependent apoptosis in cancer cells, often associated with a more or less severe inhibition of proliferation. Moreover, they provide another potential source of molecules adapted to the building of photosensitizer-conjugates allowing a specific targeting to cancer cells, for the photodynamic treatment of tumors. PMID- 28598371 TI - New Strigolactone Mimics as Exogenous Signals for Rhizosphere Organisms. AB - The importance of strigolactones in plant biology prompted us to synthesize simplified strigolactone mimics effective as exogenous signals for rhizosphere organisms. New strigolactone mimics easily derived from simple and available starting materials in significant amounts were prepared and fully characterized. These compounds contain an aromatic or heterocyclic ring, usually present in various bioactive molecules, connected by an ether link to a furan-2-one moiety. The new synthesized strigolactone mimics were confirmed to be active on plant pathogenic fungi and parasitic weed seeds. PMID- 28598375 TI - Allogrooming, Self-Grooming, and Touching Behavior: Contamination Routes of Leaf Cutting Ant Workers Using a Fat-Soluble Tracer Dye. AB - The aim of this study was to determine whether worker self-grooming, allogrooming, and direct contact promotes the dispersal of substances among members of the colony. For this purpose, a tracer (Sudan III dye) was applied topically to a worker ant and the social interactions between the worker with the tracer and workers without the tracer were studied. Additionally, the worker heads were dissected to visualize whether or not the post-pharyngeal gland was stained. The post-pharyngeal glands from 50% to 70% of workers were stained depending on the size of the group. With the increase in the experimental group size, the frequency of interactions between workers increased, with touching being the most frequent behavior. The tracer dye was probably passed on by direct contact between workers, followed by self-grooming and allogrooming. These behaviors are responsible for the rapid dispersal of substances among colony members as observed in our experiment. The results therefore support the hypothesis that contact with substances promotes the contamination of nestmates, even in the absence of feeding, serving as a model for further studies on the contamination of workers with the active ingredients of insecticides. PMID- 28598376 TI - Floral Volatiles from Vigna unguiculata Are Olfactory and Gustatory Stimulants for Oviposition by the Bean Pod Borer Moth Maruca vitrata. AB - Abstract: We investigated the role of floral odors from cowpea, Vigna unguiculata (L.), in mediating oviposition of the bean pod borer moth, Maruca vitrata, a serious pest of grain legumes that flies to host plants at the flowering stage and oviposits onto flowers and buds. The flower of the host plant V. unguiculata was a stimulus for egg-laying by M. vitrata in an oviposition bioassay. Commercial longifolene, beta-caryophyllene, linalool, geraniol, and (Z)-3-hexenyl acetate were used as stimulus. Each one elicited dose-dependent electroantennogram responses in female M. vitrata, and all but longifolene stimulated oviposition, when presented singly. Beta-caryophyllene was the most active stimulant, similar to that of the flower of V. unguiculata, and eliciting a dose-dependent oviposition response. Either olfaction or gustation was sufficient to mediate an oviposition response to V. unguiculata floral volatiles: intact M. vitrata responded to beta-caryophyllene whether or not they could contact the source of the volatiles, and females with amputated antennae responded if allowed to contact the source. We believe this is the first demonstration in a moth where beta-caryophyllene from the host plant was able to mediate an oviposition response. As beta-caryophyllene is widely expressed by non host plants, we suggest that its role in stimulating oviposition could be exploited as part of a push-pull strategy for pest management in which beta caryophyllene-expressing non-host plants provide a population sink for M. vitrata. PMID- 28598378 TI - Stock Market Fluctuations and Self-Harm among Children and Adolescents in Hong Kong. AB - Although a few studies investigated the impact of stock market fluctuations on population health, the question of whether stock market fluctuations have an impact on self-harm in children and adolescents remain unanswered. This study therefore investigated the association between stock market fluctuations and self harm among children and adolescents in Hong Kong. Daily self-harm attendance records were retrieved from all 18 local Accident and Emergency Departments (AED) from 2001 to 2012. 4931 children and adolescents who committed self-harm were included. The results indicated positive correlation between daily change in stock market index, Hang Seng Index (?HSI, per 300 points), and daily self-harm incident risk of children and adolescents, without time lag between the two. The incident risk ratio for ?HSI was 1.09 (p = 0.0339) in children and 1.06 (p = 0.0246) in adolescents. Importantly, non-trading days were found to impose significant protective effect in both groups against self-harm risk. Our results showed that stock market fluctuations were related to self-harm behaviors in children and adolescents. Parents and professionals should be educated about the potential harm of stock market fluctuations and the importance of effective parenting in reducing self-harm among children and adolescents. PMID- 28598377 TI - 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors. AB - p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5 (DS 2.5) to discern interactions with key residues at the active site of HPPD. Four compounds with top rankings in the HipHop model and well-known binding model were finally chosen as lead compounds with potential inhibitory effects on the active site of target. The results provided powerful insight into the development of novel HPPD inhibitors herbicides using computational techniques. PMID- 28598379 TI - Genomic Insight into the Role of lncRNA in Cancer Susceptibility. AB - With the development of advanced genomic methods, a large amount of long non coding RNAs (lncRNAs) has been found to be important for cancer initiation and progression. Given that most of the genome-wide association study (GWAS) identified cancer risk SNPs are located in the noncoding region, the expression and function of lncRNAs are more likely to be affected by the SNPs. The SNPs may affect the expression of lncRNAs directly through disrupting the binding of transcription factors or indirectly by affecting the expression of regulatory factors. Moreover, SNPs may disrupt the interaction between lncRNAs and other RNAs or proteins. Unveiling the relationship of lncRNA, protein-coding genes, transcription factors and miRNAs from the angle of genomics will improve the accuracy of disease prediction and help find new therapeutic targets. PMID- 28598382 TI - Syk Activity Is Dispensable for Platelet GP1b-IX-V Signaling. AB - The binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein 1b-IX (GP1b-IX) leads to activation of platelets. GP1b was shown to signal via the FcRgamma-ITAM (Fc Receptor gamma-Immunoreceptor tyrosine-based activation motif) pathway, activating spleen tyrosine kinase (Syk) and other tyrosine kinases. However, there have been conflicting reports regarding the role of Syk in GP1b signaling. In this study, we sought to resolve these conflicting reports and clarify the role of Syk in VWF-induced platelet activation. The inhibition of Syk with the selective Syk inhibitors, OXSI-2 and PRT-060318, did not inhibit VWF induced platelet adhesion, agglutination, aggregation, or secretion. In contrast, platelets stimulated with the Glycoprotein VI (GPVI) agonist, collagen-related peptide (CRP), failed to cause any aggregation or secretion in presence of the Syk inhibitors. Furthermore, GP1b-induced platelet signaling was unaffected in the presence of Syk inhibitors, but GPVI-induced signaling was abolished under similar conditions. Thus, we conclude that Syk kinase activity does not play any functional role downstream of GP1b-mediated platelet activation. PMID- 28598380 TI - The Magnitude of Occupational Class Differences in Sickness Absence: 15-Year Trends among Young and Middle-Aged Municipal Employees. AB - : Background: Our aim was to examine the magnitude of relative occupational class differences in sickness absence (SA) days over a 15-year period among female and male municipal employees in two age-groups. Methods: 18-34 and 35-59-year-old employees of the City of Helsinki from 2002 to 2016 were included in our data (n = ~37,500 per year). Occupational class was classified into four groups. The magnitude of relative occupational class differences in SA was studied using the relative index of inequality (RII). Results: The relative occupational class differences were larger among older than younger employees; the largest differences were among 35-59-year-old men. Among women in both age-groups the relative class differences remained stable during 2002-2016. Among younger and older men, the differences were larger during the beginning of study period than in the end. Among women in both age-groups the RII values were between 2.19 (95% confidence intervals (CI) 1.98, 2.42) and 3.60 (95% CI 3.28, 3.95). The corresponding differences varied from 3.74 (95% CI 3.13, 4.48) to 1.68 (95% CI 1.44, 1.97) among younger and from 6.43 (95% CI 5.85, 7.06) to 3.31 (95% CI 2.98, 3.68) among older men. CONCLUSIONS: Relative occupational class differences were persistent among employees irrespective of age group and gender. Preventive measures should be started at young age. PMID- 28598381 TI - Renin Inhibition with Aliskiren: A Decade of Clinical Experience. AB - The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of arterial hypertension as well as in more complex mechanisms of cardiovascular and renal diseases. RAAS-blocking agents like angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have long been key components in the treatment of essential hypertension, heart failure, diabetic nephropathy, and chronic kidney disease, showing benefits well beyond blood pressure reduction. Renin blockade as the first step of the RAAS cascade finally became possible in 2007 with the approval of aliskiren, the first orally active direct renin inhibitor available for clinical use and the newest antihypertensive agent on the market. In the last decade, many clinical trials and meta-analyses have been conducted concerning the efficacy and safety of aliskiren in comparison to other antihypertensive agents, as well as the efficacy and potential clinical use of various combinations. Large trials with cardiovascular and renal endpoints attempted to show potential benefits of aliskiren beyond blood pressure lowering, as well as morbidity and mortality outcomes in specific populations such as diabetics, heart failure patients, and post-myocardial infarction individuals. The purpose of this review is to present the currently available data regarding established and future potential clinical uses of aliskiren. PMID- 28598383 TI - The Biology and Control of the Greater Wax Moth, Galleria mellonella. AB - The greater wax moth, Galleria mellonella Linnaeus, is a ubiquitous pest of the honeybee, Apis mellifera Linnaeus, and Apis cerana Fabricius. The greater wax moth larvae burrow into the edge of unsealed cells with pollen, bee brood, and honey through to the midrib of honeybee comb. Burrowing larvae leave behind masses of webs which causes galleriasis and later absconding of colonies. The damage caused by G. mellonella larvae is severe in tropical and sub-tropical regions, and is believed to be one of the contributing factors to the decline in both feral and wild honeybee populations. Previously, the pest was considered a nuisance in honeybee colonies, therefore, most studies have focused on the pest as a model for in vivo studies of toxicology and pathogenicity. It is currently widespread, especially in Africa, and the potential of transmitting honeybee viruses has raised legitimate concern, thus, there is need for more studies to find sustainable integrated management strategies. However, our knowledge of this pest is limited. This review provides an overview of the current knowledge on the biology, distribution, economic damage, and management options. In addition, we provide prospects that need consideration for better understanding and management of the pest. PMID- 28598384 TI - Anti-Inflammatory and Neuroprotective Constituents from the Peels of Citrus grandis. AB - A series of chromatographic separations performed on the ethanol extracts of the peels of Citrus grandis has led to the characterization of forty compounds, including seventeen coumarins, eight flavonoids, two triterpenoids, four benzenoids, two steroids, one lignan, one amide, and five other compounds, respectively. The chemical structures of the purified constituents were identified on the basis of spectroscopic elucidation, including 1D- and 2D-NMR, UV, IR, and mass spectrometric analysis. Most of the isolated compounds were examined for their inhibition of superoxide anion generation and elastase release by human neutrophils. Among the isolates, isomeranzin (3), 17,18 dihydroxybergamottin (12), epoxybergamottin (13), rhoifolin (19), vitexicarpin (22) and 4-hydroxybenzaldehyde (29) displayed the most significant inhibition of superoxide anion generation and elastase release with IC50 values ranged from 0.54 to 7.57 MUM, and 0.43 to 4.33 MUM, respectively. In addition, 7-hydroxy-8 (2'-hydroxy-3'-methylbut-3'-enyl)coumarin (8) and 17,18-dihydroxybergamottin (12) also exhibited the protection of neurons against A-mediated neurotoxicity at 50 MUM. PMID- 28598386 TI - A Noise Removal Method for Uniform Circular Arrays in Complex Underwater Noise Environments with Low SNR. AB - Generally, many beamforming methods are derived under the assumption of white noise. In practice, the actual underwater ambient noise is complex. As a result, the noise removal capacity of the beamforming method may be deteriorated considerably. Furthermore, in underwater environment with extremely low signal-to noise ratio (SNR), the performances of the beamforming method may be deteriorated. To tackle these problems, a noise removal method for uniform circular array (UCA) is proposed to remove the received noise and improve the SNR in complex noise environments with low SNR. First, the symmetrical noise sources are defined and the spatial correlation of the symmetrical noise sources is calculated. Then, based on the preceding results, the noise covariance matrix is decomposed into symmetrical and asymmetrical components. Analysis indicates that the symmetrical component only affect the real part of the noise covariance matrix. Consequently, the delay-and-sum (DAS) beamforming is performed by using the imaginary part of the covariance matrix to remove the symmetrical component. However, the noise removal method causes two problems. First, the proposed method produces a false target. Second, the proposed method would seriously suppress the signal when it is located in some directions. To solve the first problem, two methods to reconstruct the signal covariance matrix are presented: based on the estimation of signal variance and based on the constrained optimization algorithm. To solve the second problem, we can design the array configuration and select the suitable working frequency. Theoretical analysis and experimental results are included to demonstrate that the proposed methods are particularly effective in complex noise environments with low SNR. The proposed method can be extended to any array. PMID- 28598385 TI - The Roles of Long Non-Protein-Coding RNAs in Osteo-Adipogenic Lineage Commitment. AB - Osteoblasts and adipocytes share a common mesenchymal progenitor in the bone marrow. This implies that a reciprocal relationship exists between osteogenic and adipogenic differentiation. Further, cells of osteoblast lineage transdifferentiate into adipocytes under some circumstances. Dysregulation of osteo-adipogenic fate-determination leads to bone diseases such as osteoporosis, accompanied by an increase in bone marrow adipose tissue. Thus, the fine-tuning of osteo-adipogenesis is necessary for bone homeostasis. Osteo-adipogenic progression is governed by a complex crosstalk of extrinsic signals, transcription factors, and epigenetic factors. Long non-protein-coding RNAs (lncRNAs) act in part as epigenetic regulators in a broad range of biological activities, such as chromatin organization, transcriptional regulation, post translational modifications, and histone modification. In this review, we highlight the roles of epigenetic regulators, particularly lncRNAs, in the osteo adipogenic lineage commitment of bone marrow mesenchymal stem cells and the adipogenic transdifferentiation of osteoblasts. PMID- 28598387 TI - Occlusal Features and Caries Experience of Hong Kong Chinese Preschool Children: A Cross-Sectional Study. AB - Objective: To study occlusal features and their relation to caries experience in Hong Kong Chinese preschool children. Methods: Seven kindergarten classes in Hong Kong were selected using a stratified random sampling method, and the 4- and 5 year-old Chinese kindergarten children were invited to join the survey. Two calibrated dentists performed the clinical examinations in the kindergartens. Occlusion features, including incisal overjet; canine and molar relationship; median diastema; and primate space as well as malocclusion features, including crossbite; anterior open bite; and scissor bite, were recorded. Caries experience was recorded with the dmft index. Results: A total of 538 children were invited to participate in the study, and finally 495 children were examined (92%). Approximately half (52%) had a normal incisor relationship. Most children had a class I canine relationship (left-79%; right-75%). Approximately two-thirds had a flush terminal plane (left-64%; right-65%). Most children (76%) had a maxillary primate space, and 47% had a mandibular primate space. The prevalence of median diastema, anterior crossbite, and unilateral posterior crossbite was 30%, 12% and 1%, respectively. No bilateral posterior crossbite or scissor bite was found. Approximately half (49%) had caries experience. The mean dmft score was 2.1. Gender and age were not associated with either the studied occlusal features or the mean dmft score (p > 0.05). Conclusion: Approximately half of the Hong Kong preschool children studied had a normal occlusion, and two-thirds of them had a flush terminal plane. About three-quarters of them had a maxillary primate space, and half of them had a mandibular primate space. Their occlusal traits were not associated with caries experience and prevalence. PMID- 28598388 TI - How Social Reactions to Alcohol-Related Facial Flushing Are Affected by Gender, Relationship, and Drinking Purposes: Implications for Education to Reduce Aerodigestive Cancer Risks. AB - Alcohol-related facial flushing is a sign of compromised alcohol metabolism and increased risk of certain cancers. This project examined how facial flushing might be used to reduce alcohol use to lower cancer risks. Interviews with Chinese university students identified gender, friendship, and drinking purpose as important variables related to whether someone would encourage a person who flushes when drinking alcohol to stop or reduce their drinking. A questionnaire was developed that incorporated these variables into 24 drinking scenarios in which someone flushed while drinking. Students responded whether they would (a) encourage the flusher to stop or drink less; (b) do nothing while wishing they could; or (c) do nothing because there was no need. Analysis of survey responses from 2912 university students showed a three-way interaction of the variables and implied that the probability students will intervene when a drinker flushes was highest when the flusher was a female, a close friend, and the drinking purpose was for fun and lowest if the flusher was a male, the friendship was general, and the drinking purpose was risky. The results provide important details about the social factors affecting how other people respond to a person who flushes when drinking alcohol. This information is useful for those considering ways to reduce and prevent aerodigestive cancers through education and information programs. PMID- 28598389 TI - Identification of a Novel O-Conotoxin Reveals an Unusual and Potent Inhibitor of the Human alpha9alpha10 Nicotinic Acetylcholine Receptor. AB - Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human alpha9alpha10 nicotinic acetylcholine receptor (nAChR), with an IC50 of 16.2 +/- 1.4 nM. The activities of the N-terminal and C-terminal halves of the linear toxin are markedly reduced compared with the full-length toxin, suggesting that the intact sequence is required to potently inhibit the halpha9alpha10 nAChR. alpha9alpha10 nAChRs are expressed not only in the nervous system, but also in a variety of non-neuronal cells, such as cochlear hair cells, keratinocytes, epithelial and immune cells. A potent inhibitor of human alpha9alpha10 nAChRs, such as GeXXVIIA, would facilitate unraveling the functions of this nAChR subtype. Furthermore, this unusual nAChR inhibitor may lead to the development of novel alpha9alpha10 nAChR-targeting drugs. PMID- 28598391 TI - Rapid Waterborne Pathogen Detection with Mobile Electronics. AB - Pathogen detection in water samples, without complex and time consuming procedures such as fluorescent-labeling or culture-based incubation, is essential to public safety. We propose an immunoagglutination-based protocol together with the microfluidic device to quantify pathogen levels directly from water samples. Utilizing ubiquitous complementary metal-oxide-semiconductor (CMOS) imagers from mobile electronics, a low-cost and one-step reaction detection protocol is developed to enable field detection for waterborne pathogens. 10 mL of pathogen containing water samples was processed using the developed protocol including filtration enrichment, immune-reaction detection and imaging processing. The limit of detection of 10 E. coli O157:H7 cells/10 mL has been demonstrated within 10 min of turnaround time. The protocol can readily be integrated into a mobile electronics such as smartphones for rapid and reproducible field detection of waterborne pathogens. PMID- 28598390 TI - The Implication of Substance P in the Development of Tendinopathy: A Case Control Study. AB - It was reported that substance P had beneficial effects in the healing of acute tendon injury. However, the relationship between substance P and degenerative tendinopathy development remains unclear. The purpose of this study was to determine the role of substance P in the pathogenesis of tendinopathy. Healthy and tendinopathy tendon were harvested from human and tenocytes were cultured individually. The expression levels of genes associated with tendinopathy were compared. Next, substance P was exogenously administered to the healthy tenocyte and the effect was evaluated. The results showed that tendinopathy tenocytes had higher levels of COL3A1, MMP1, COX2, SCX, ACTA2, and substance P gene expression compared to healthy tenocytes. Next, substance P treatment on the healthy tenocyte displayed similar changes to that of the tendinopathy tenocytes. These differences between the two groups were also determined by Western blot. Additionally, cells with substance P had the tendinopathy change morphologically although cellular proliferation was significantly higher compared to that of the control group. In conclusion, substance P enhanced cellular proliferation, but concomitantly increased immature collagen (type 3 collagen). Substance P plays a crucial role in tendinopathy development and could be a future therapeutic target for treatment. PMID- 28598393 TI - Development of a Flexible Strain Sensor Based on PEDOT:PSS for Thin Film Structures. AB - The aim of this study was to develop and optimize a reproducible flexible sensor adapted to thin low-density polyethylene (LDPE) films and/or structures to enable their deformation measurements. As these deformations are suspected to be weak (less than 10%), the developed sensor needs to be particularly sensitive. Moreover, it is of prime importance that sensor integration and usability do not modify the mechanical behavior of its LDPE substrate. The literature review allowed several materials to be investigated and an elastomer/intrinsically conductive polymer PEDOT:PSS (CleviosTM) filled composite was selected to simultaneously combine mechanical properties and electrical conductivity. This composite (made of PEDOT:PSS and silicone Bluesil(r)) presented satisfying compatibilities with piezoresistive effects, negative temperature performances (in a range from -60 degrees C to 20 degrees C), as well as elongation properties (until the elastic limit of the substrate was reached). The method used for creating the sensor is fully described, as are the optimization of the sensor manufacture in terms of used materials, the used amount of materials where the percolation theory aspects must be considered, the adhesion to the substrate, and the manufacturing protocol. Electromechanical characterization was performed to assess the gauge factor (K) of the sensor on its substrate. PMID- 28598394 TI - Recognizing Bedside Events Using Thermal and Ultrasonic Readings. AB - Falls in homes of the elderly, in residential care facilities and in hospitals commonly occur in close proximity to the bed. Most approaches for recognizing falls use cameras, which challenge privacy, or sensor devices attached to the bed or the body to recognize bedside events and bedside falls. We use data collected from a ceiling mounted 80 * 60 thermal array combined with an ultrasonic sensor device. This approach makes it possible to monitor activity while preserving privacy in a non-intrusive manner. We evaluate three different approaches towards recognizing location and posture of an individual. Bedside events are recognized using a 10-second floating image rule/filter-based approach, recognizing bedside falls with 98.62% accuracy. Bed-entry and exit events are recognized with 98.66% and 96.73% accuracy, respectively. PMID- 28598392 TI - The Functions of Metamorphic Metallothioneins in Zinc and Copper Metabolism. AB - Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn2+ ions at picomolar concentrations, extensive subcellular re-distribution of Zn2+, the loading of exocytotic vesicles with zinc species, and the control of Zn2+ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn2+ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn2+ and Cu+ match the biological requirements for controlling-binding and delivering-these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn2+ and Cu+. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms. PMID- 28598395 TI - Improved Scheduling Mechanisms for Synchronous Information and Energy Transmission. AB - Wireless energy collecting technology can effectively reduce the network time overhead and prolong the wireless sensor network (WSN) lifetime. However, the traditional energy collecting technology cannot achieve the balance between ergodic channel capacity and average collected energy. In order to solve the problem of the network transmission efficiency and the limited energy of wireless devices, three improved scheduling mechanisms are proposed: improved signal noise ratio (SNR) scheduling mechanism (IS2M), improved N-SNR scheduling mechanism (INS2M) and an improved Equal Throughput scheduling mechanism (IETSM) for different channel conditions to improve the whole network performance. Meanwhile, the average collected energy of single users and the ergodic channel capacity of three scheduling mechanisms can be obtained through the order statistical theory in Rayleig, Ricean, Nakagami-m and Weibull fading channels. It is concluded that the proposed scheduling mechanisms can achieve better balance between energy collection and data transmission, so as to provide a new solution to realize synchronous information and energy transmission for WSNs. PMID- 28598397 TI - Trichodermanins C-E, New Diterpenes with a Fused 6-5-6-6 Ring System Produced by a Marine Sponge-Derived Fungus. AB - Trichodermanins C-E (1-3), new diterpenes with a rare fused 6-5-6-6 ring system, have been isolated from a fungus Trichoderma harzianum OUPS-111D-4 separated from a piece of a marine sponge Halichondria okadai, and these chemical structures have been established by spectroscopic analyses using IR, MASS, HRFABMS, and NMR spectra. We established their absolute stereostructures by application of the modified Mosher's method. In addition, 1 inhibited the growth of cancer cell lines potently. PMID- 28598399 TI - A Weekly Indicator of Surface Moisture Status from Satellite Data for Operational Monitoring of Crop Conditions. AB - The triangle method has been applied to derive a weekly indicator of evaporative fraction on vegetated areas in a temperate region in Northern Italy. Daily MODIS Aqua Land Surface Temperature (MYD11A1) data has been combined with air temperature maps and 8-day composite MODIS NDVI (MOD13Q1/MYD13Q1) data to estimate the Evaporative Fraction (EF) at 1 km resolution, on a daily basis. Measurements at two eddy covariance towers located within the study area have been exploited to assess the reliability of satellite based EF estimations as well as the robustness of input data. Weekly syntheses of the daily EF indicator (EFw) were then derived at regional scale for the years 2010, 2011 and 2012 as a proxy of overall surface moisture condition. EFw showed a temporal behavior consistent with growing cycles and agro-practices of the main crops cultivated in the study area (rice, forages and corn). Comparison with official regional corn yield data showed that variations in EFw cumulated over summer are related with crop production shortages induced by water scarcity. These results suggest that weekly-averaged EF estimated from MODIS data is sensible to water stress conditions and can be used as an indicator of crops' moisture conditions at agronomical district level. Advantages and disadvantages of the proposed approach to provide information useful to issue operational near real time bulletins on crop conditions at regional scale are discussed. PMID- 28598396 TI - Embryotoxicity Caused by DON-Induced Oxidative Stress Mediated by Nrf2/HO-1 Pathway. AB - Deoxynivalenol (DON) belongs to the type B group of trichothecenes family, which is composed of sesquiterpenoid metabolites produced by Fusarium and other fungi in grain. DON may cause various toxicities, such as cytotoxicity, immunotoxicity, genotoxicity as well as teratogenicity and carcinogenicity. In the present study, we focus on a hypothesis that DON alters the expressions of Nrf2/HO-1 pathway by inducing embryotoxicity in C57BL/6 mouse (5.0, 2.5, 1.0, and 0 mg/kg/day) and BeWo cell lines (0 and 50 nM; 3 h, 12 h and 24 h). Our results indicate that DON treatment in mice during pregnancy leads to ROS accumulation in the placenta, which results in embryotoxicity. At the same time Nrf2/HO-1 pathway is up regulated by ROS to protect placenta cells from oxidative damage. In DON-treated BeWo cells, the level of ROS has time-effect and dose-effect relationships with HO-1 expression. Moderate increase in HO-1 protects the cell from oxidative damage, while excessive increase in HO-1 aggravates the oxidative damage, which is called in some studies the "threshold effect". Therefore, oxidative stress may be the critical molecular mechanism for DON-induced embryotoxicity. Besides, Nrf2/HO-1 pathway accompanied by the "threshold effect" also plays an important role against DON-induced oxidative damage in this process. PMID- 28598398 TI - Right- vs. Left-Sided Metastatic Colorectal Cancer: Differences in Tumor Biology and Bevacizumab Efficacy. AB - There is evidence of a different response to treatment with regard to the primary tumor localization (right-sided or left-sided) in patients with metastatic colorectal cancer (mCRC). We analyzed the different outcomes and biomolecular characteristics in relation to tumor localization in 122 of the 370 patients with metastatic colorectal cancer enrolled onto the phase III prospective multicenter "Italian Trial in Advanced Colorectal Cancer (ITACa)", randomized to receive first-line chemotherapy (CT) or CT plus bevacizumab (CT + B). RAS and BRAF mutations; baseline expression levels of circulating vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), cyclooxygenase-2 (COX2), ephrin type-B receptor 4 (EPHB4), hypoxia-inducible factor 1-alpha (HIF-1alpha), lactate dehydrogenase (LDH), and high-sensitivity C reactive protein (hs-CRP); and inflammatory indexes such as the neutrophil-to-lymphocyte ratio, platelet lymphocyte rate and systemic immune-inflammation index were evaluated. Patients with right-sided tumors showed a longer median progression-free survival in the CT + B arm than in the CT group (12.6 vs. 9.0 months, respectively, p = 0.017). Baseline inflammatory indexes were significantly higher in left-sided tumors, whereas eNOS and EPHB4 expression was significantly higher and BRAF mutation more frequent in right-sided tumors. Our data suggest a greater efficacy of the CT + B combination in right-sided mCRC, which might be attributable to the lower inflammatory status and higher expression of pro-angiogenic factors that appear to characterize these tumors. PMID- 28598400 TI - Feed-Forward Neural Network Prediction of the Mechanical Properties of Sandcrete Materials. AB - This work presents a soft-sensor approach for estimating critical mechanical properties of sandcrete materials. Feed-forward (FF) artificial neural network (ANN) models are employed for building soft-sensors able to predict the 28-day compressive strength and the modulus of elasticity of sandcrete materials. To this end, a new normalization technique for the pre-processing of data is proposed. The comparison of the derived results with the available experimental data demonstrates the capability of FF ANNs to predict with pinpoint accuracy the mechanical properties of sandcrete materials. Furthermore, the proposed normalization technique has been proven effective and robust compared to other normalization techniques available in the literature. PMID- 28598401 TI - Toward a Trust Evaluation Mechanism in the Social Internet of Things. AB - In the blooming era of the Internet of Things (IoT), trust has been accepted as a vital factor for provisioning secure, reliable, seamless communications and services. However, a large number of challenges still remain unsolved due to the ambiguity of the concept of trust as well as the variety of divergent trust models in different contexts. In this research, we augment the trust concept, the trust definition and provide a general conceptual model in the context of the Social IoT (SIoT) environment by breaking down all attributes influencing trust. Then, we propose a trust evaluation model called REK, comprised of the triad of trust indicators (TIs) Reputation, Experience and Knowledge. The REK model covers multi-dimensional aspects of trust by incorporating heterogeneous information from direct observation (as Knowledge TI), personal experiences (as Experience TI) to global opinions (as Reputation TI). The associated evaluation models for the three TIs are also proposed and provisioned. We then come up with an aggregation mechanism for deriving trust values as the final outcome of the REK evaluation model. We believe this article offers better understandings on trust as well as provides several prospective approaches for the trust evaluation in the SIoT environment. PMID- 28598403 TI - Development and Positioning Accuracy Assessment of Single-Frequency Precise Point Positioning Algorithms by Combining GPS Code-Pseudorange Measurements with Real Time SSR Corrections. AB - We have developed a suite of real-time precise point positioning programs to process GPS pseudorange observables, and validated their performance through static and kinematic positioning tests. To correct inaccurate broadcast orbits and clocks, and account for signal delays occurring from the ionosphere and troposphere, we applied State Space Representation (SSR) error corrections provided by the Seoul Broadcasting System (SBS) in South Korea. Site displacements due to solid earth tide loading are also considered for the purpose of improving the positioning accuracy, particularly in the height direction. When the developed algorithm was tested under static positioning, Kalman-filtered solutions produced a root-mean-square error (RMSE) of 0.32 and 0.40 m in the horizontal and vertical directions, respectively. For the moving platform, the RMSE was found to be 0.53 and 0.69 m in the horizontal and vertical directions. PMID- 28598402 TI - Cognitive Performance Enhancement Induced by Caffeine, Carbohydrate and Guarana Mouth Rinsing during Submaximal Exercise. AB - The aim of this study was to investigate the influence of serial mouth rinsing (MR) with nutritional supplements on cognitive performance (i.e., cognitive control and time perception) during a 40-min submaximal exercise. Twenty-four participants completed 4 counterbalanced experimental sessions, during which they performed MR with either placebo (PL), carbohydrate (CHO: 1.6 g/25 mL), guarana complex (GUAc: 0.4 g/25 mL) or caffeine (CAF: 67 mg/25 mL) before and twice during exercise. The present study provided some important new insights regarding the specific changes in cognitive performance induced by nutritional supplements. The main results were: (1) CHO, CAF and GUA MR likely led participants to improve temporal performance; (2) CAF MR likely improved cognitive control; and (3) CHO MR led to a likely decrease in subjective perception of effort at the end of the exercise compared to PL, GUA and CAF. Moreover, results have shown that performing 40-min submaximal exercise enhances information processing in terms of both speed and accuracy, improves temporal performance and does not alter cognitive control. The present study opens up new perspectives regarding the use of MR to optimize cognitive performance during physical exercise. PMID- 28598404 TI - Validation of DESS as a DNA Preservation Method for the Detection of Strongyloides spp. in Canine Feces. AB - Strongyloides stercoralis is a gastrointestinal parasitic nematode with a life cycle that includes free-living and parasitic forms. For both clinical (diagnostic) and environmental evaluation, it is important that we can detect Strongyloides spp. in both human and non-human fecal samples. Real-time PCR is the most feasible method for detecting the parasite in both clinical and environmental samples that have been preserved. However, one of the biggest challenges with PCR detection is DNA degradation during the postage time from rural and remote areas to the laboratory. This study included a laboratory assessment and field validation of DESS (dimethyl sulfoxide, disodium EDTA, and saturated NaCl) preservation of Strongyloides spp. DNA in fecal samples. The laboratory study investigated the capacity of 1:1 and 1:3 sample to DESS ratios to preserve Strongyloides ratti in spike canine feces. It was found that both ratios of DESS significantly prevented DNA degradation compared to the untreated sample. This method was then validated by applying it to the field-collected canine feces and detecting Strongyloides DNA using PCR. A total of 37 canine feces samples were collected and preserved in the 1:3 ratio (sample: DESS) and of these, 17 were positive for Strongyloides spp. The study shows that both 1:1 and 1:3 sample to DESS ratios were able to preserve the Strongyloides spp. DNA in canine feces samples stored at room temperature for up to 56 days. This DESS preservation method presents the most applicable and feasible method for the Strongyloides DNA preservation in field-collected feces. PMID- 28598405 TI - Design and Validation of a Breathing Detection System for Scuba Divers. AB - Drowning is the major cause of death in self-contained underwater breathing apparatus (SCUBA) diving. This study proposes an embedded system with a live and light-weight algorithm which detects the breathing of divers through the analysis of the intermediate pressure (IP) signal of the SCUBA regulator. A system composed mainly of two pressure sensors and a low-power microcontroller was designed and programmed to record the pressure sensors signals and provide alarms in absence of breathing. An algorithm was developed to analyze the signals and identify inhalation events of the diver. A waterproof case was built to accommodate the system and was tested up to a depth of 25 m in a pressure chamber. To validate the system in the real environment, a series of dives with two different types of workload requiring different ranges of breathing frequencies were planned. Eight professional SCUBA divers volunteered to dive with the system to collect their IP data in order to participate to validation trials. The subjects underwent two dives, each of 52 min on average and a maximum depth of 7 m. The algorithm was optimized for the collected dataset and proved a sensitivity of inhalation detection of 97.5% and a total number of 275 false positives (FP) over a total recording time of 13.9 h. The detection algorithm presents a maximum delay of 5.2 s and requires only 800 bytes of random-access memory (RAM). The results were compared against the analysis of video records of the dives by two blinded observers and proved a sensitivity of 97.6% on the data set. The design includes a buzzer to provide audible alarms to accompanying dive buddies which will be triggered in case of degraded health conditions such as near drowning (absence of breathing), hyperventilation (breathing frequency too high) and skip-breathing (breathing frequency too low) measured by the improper breathing frequency. The system also measures the IP at rest before the dive and indicates with flashing light-emitting diodes and audible alarm the regulator malfunctions due to high or low IP that may cause fatal accidents during the dive by preventing natural breathing. It is also planned to relay the alarm signal to underwater and surface rescue authorities by means of acoustic communication. PMID- 28598406 TI - Theoretical Study of the BaTiO3 Powder's Volume Ratio's Influence on the Output of Composite Piezoelectric Nanogenerator. AB - The combination of the piezoelectric materials and polymer is an effective way to make the piezoelectric nanogenerator (PENG) possess both the polymer's good flexibility and ferroelectric material's high piezoelectric coefficient. The volume ratio of ferroelectric material in the composite is an important factor that determines the PENG's output performance. In this paper, the BaTiO3/polydimethylsiloxane (PDMS) composite PENG was demonstrated as having an optimal volume ratio (46%) at which the PENG can output its highest voltage, and this phenomenon can be ascribed to the trade-off between the composite PENG's top electrode charge and its capacitance. These results are of practical importance for the composite PENG's performance optimization. PMID- 28598407 TI - Extraction Optimization, Characterization, and Bioactivities of Polysaccharides from Pinelliae Rhizoma Praeparatum Cum Alumine Employing Ultrasound-Assisted Extraction. AB - In this study, the ultrasound-assisted extraction of polysaccharides (PSA) from Pinelliae Rhizoma Praeparatum Cum Alumine (PRPCA) was optimized by response surface methodology (RSM). The structural characteristics of PSA were analyzed by UV-vis spectroscopy, infrared spectroscopy, scanning electron microscopy, high performance gel permeation chromatography and high performance liquid chromatography, respectively. In addition, antioxidant and antimicrobial activities of PSA were studied by different in vitro assays. Results indicated that the optimal extraction conditions were as follows: the ratio of water to raw of 30 mL/g, extraction time of 46.50 min, ultrasonic temperature of 72.00 degrees C, and ultrasonic power of 230 W. Under these conditions, the obtained PSA yield (13.21 +/- 0.37%) was closely agreed with the predicted yield by the model. The average molecular weights of the PSA were estimated to be 5.34 * 103 and 6.27 * 105 Da. Monosaccharide composition analysis indicated that PSA consisted of mannose, galactose uronic acid, glucose, galactose, arabinose with a molar ratio of 1.83:0.55:75.75:1.94:0.45. Furthermore, PSA exhibited moderate antioxidant and antibacterial activities in vitro. Collectively, this study provides a promising strategy to obtain bioactive polysaccharides from processed products of herbal medicines. PMID- 28598408 TI - Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers. AB - In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q2) = 0.80, squared correlation coefficient (r2) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q2 = 0.77, r2 = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity. PMID- 28598409 TI - Two New beta-Dihydroagarofuran Sesquiterpenes from Celastrus orbiculatus Thunb and Their Anti-Proliferative Activity. AB - Two new beta-dihydroagarofuran-type sesquiterpenes (1-2) were isolated and identified from the fruit of Celastrus orbiculatus Thunb, together with seventeen known compounds (3-19). The structures of the isolated new compounds were elucidated based on extensive spectroscopic analyses. The cytotoxic activities of the 19 sesquiterpenes on three cell lines, human acute promyelocytic leukemia HL 60, human leukemic K562, and human colon cancer HCT-116 cells, were evaluated in vitro. Compound 4 exhibited potent cytotoxic activity against HL-60, K562, and HCT116 cell lines with IC50 values of 3.61 MUMU, 17.13 MUMU and 10.15 MUMU, respectively, and the other compounds displayed moderate activity. PMID- 28598410 TI - Pediatric Non-Alcoholic Fatty Liver Disease. AB - Abstract: With the increase in the prevalence of obesity, non-alcoholic fatty liver disease (NAFLD) has become among the leading causes of chronic liver disease in the pediatric age group. Once believed to be a "two-hit process", it is now clear that the actual pathophysiology of NAFLD is complex and involves multiple pathways. Moreover, NAFLD is not always benign, and patients with non alcoholic steatohepatitis (NASH) are at increased risk of developing advanced stages of liver disease. It has also been shown that NAFLD is not only a liver disease, but is also associated with multiple extrahepatic manifestations, including cardiovascular diseases, type 2 diabetes, and low bone mineral density. Although the data is scarce in the pediatric population, some studies have suggested that long-term mortality and the requirement of liver transplantation will continue to increase in patients with NAFLD. More studies are needed to better understand the natural history of NAFLD, especially in the pediatric age group. PMID- 28598411 TI - Ruthenium(II)-catalysed remote C-H alkylations as a versatile platform to meta decorated arenes. AB - The full control of positional selectivity is of prime importance in C-H activation technology. Chelation assistance served as the stimulus for the development of a plethora of ortho-selective arene functionalizations. In sharp contrast, meta-selective C-H functionalizations continue to be scarce, with all ruthenium-catalysed transformations currently requiring difficult to remove or modify nitrogen-containing heterocycles. Herein, we describe a unifying concept to access a wealth of meta-decorated arenes by a unique arene ligand effect in proximity-induced ruthenium(II) C-H activation catalysis. The transformative nature of our strategy is mirrored by providing a step-economical entry to a range of meta-substituted arenes, including ketones, acids, amines and phenols key structural motifs in crop protection, material sciences, medicinal chemistry and pharmaceutical industries. PMID- 28598412 TI - The influence of Antarctic subglacial volcanism on the global iron cycle during the Last Glacial Maximum. AB - Marine sediment records suggest that episodes of major atmospheric CO2 drawdown during the last glacial period were linked to iron (Fe) fertilization of subantarctic surface waters. The principal source of this Fe is thought to be dust transported from southern mid-latitude deserts. However, uncertainty exists over contributions to CO2 sequestration from complementary Fe sources, such as the Antarctic ice sheet, due to the difficulty of locating and interrogating suitable archives that have the potential to preserve such information. Here we present petrographic, geochemical and microbial DNA evidence preserved in precisely dated subglacial calcites from close to the East Antarctic Ice-Sheet margin, which together suggest that volcanically-induced drainage of Fe-rich waters during the Last Glacial Maximum could have reached the Southern Ocean. Our results support a significant contribution of Antarctic volcanism to subglacial transport and delivery of nutrients with implications on ocean productivity at peak glacial conditions. PMID- 28598413 TI - Anthropogenic climate change has altered primary productivity in Lake Superior. AB - Anthropogenic climate change has the potential to alter many facets of Earth's freshwater resources, especially lacustrine ecosystems. The effects of anthropogenic changes in Lake Superior, which is Earth's largest freshwater lake by area, are not well documented (spatially or temporally) and predicted future states in response to climate change vary. Here we show that Lake Superior experienced a slow, steady increase in production throughout the Holocene using (paleo)productivity proxies in lacustrine sediments to reconstruct past changes in primary production. Furthermore, data from the last century indicate a rapid increase in primary production, which we attribute to increasing surface water temperatures and longer seasonal stratification related to longer ice-free periods in Lake Superior due to anthropogenic climate warming. These observations demonstrate that anthropogenic effects have become a prominent influence on one of Earth's largest, most pristine lacustrine ecosystems. PMID- 28598414 TI - Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. AB - Proteasome-ubiquitin receptor hRpn13/Adrm1 binds and activates deubiquitinating enzyme Uch37/UCHL5 and is targeted by bis-benzylidine piperidone RA190, which restricts cancer growth in mice xenografts. Here, we solve the structure of hRpn13 with a segment of hRpn2 that serves as its proteasome docking site; a proline-rich C-terminal hRpn2 extension stretches across a narrow canyon of the ubiquitin-binding hRpn13 Pru domain blocking an RA190-binding surface. Biophysical analyses in combination with cell-based assays indicate that hRpn13 binds preferentially to hRpn2 and proteasomes over RA190. hRpn13 also exists outside of proteasomes where it may be RA190 sensitive. RA190 does not affect hRpn13 interaction with Uch37, but rather directly binds and inactivates Uch37. hRpn13 deletion from HCT116 cells abrogates RA190-induced accumulation of substrates at proteasomes. We propose that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains. PMID- 28598415 TI - DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. AB - Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-beta by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies interferon-beta production, resulting in recruitment and activation of Batf3-dependent dendritic cells. This effect is essential for priming of CD8+ T cells that mediate systemic tumour rejection (abscopal effect) in the context of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumour immunity. Trex1 induction may guide the selection of radiation dose and fractionation in patients treated with immunotherapy. PMID- 28598416 TI - Three-dimensional nanomagnetism. PMID- 28598418 TI - Taming interfacial electronic properties of platinum nanoparticles on vacancy abundant boron nitride nanosheets for enhanced catalysis. AB - Taming interfacial electronic effects on Pt nanoparticles modulated by their concomitants has emerged as an intriguing approach to optimize Pt catalytic performance. Here, we report Pt nanoparticles assembled on vacancy-abundant hexagonal boron nitride nanosheets and their use as a model catalyst to embrace an interfacial electronic effect on Pt induced by the nanosheets with N-vacancies and B-vacancies for superior CO oxidation catalysis. Experimental results indicate that strong interaction exists between Pt and the vacancies. Bader charge analysis shows that with Pt on B-vacancies, the nanosheets serve as a Lewis acid to accept electrons from Pt, and on the contrary, when Pt sits on N vacancies, the nanosheets act as a Lewis base for donating electrons to Pt. The overall-electronic effect demonstrates an electron-rich feature of Pt after assembling on hexagonal boron nitride nanosheets. Such an interfacial electronic effect makes Pt favour the adsorption of O2, alleviating CO poisoning and promoting the catalysis. PMID- 28598417 TI - Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences. AB - Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalographic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy. PMID- 28598420 TI - Tespa1 regulates T cell receptor-induced calcium signals by recruiting inositol 1,4,5-trisphosphate receptors. AB - Thymocyte-expressed, positive selection-associated 1 (Tespa1) is important in T cell receptor (TCR)-driven thymocyte development. Downstream of the TCR, Tespa1 is a crucial component of the linker for activation of T cells (LAT) signalosome, facilitating calcium signalling and subsequent MAPK activation. However, it is unknown how Tespa1 elicits calcium signalling. Here, we show that inositol 1,4,5 trisphosphate receptor type 1 (IP3R1) is crucial for Tespa1-optimized, TCR induced Ca2+ flux and thymocyte development. Upon TCR stimulation, Tespa1 directly interacts with IP3R1 and recruits it to the TCR complex, where IP3R1 is phosphorylated at Y353 by Fyn. This Tespa1-IP3R1 interaction is mediated by the F187 and F188 residues of Tespa1 and the amino-terminus of IP3R1. Tespa1 F187A/F188A mutant mice phenocopy Tespa1-deficient mice with impaired late thymocyte development due to reduced IP3R1 translocation to the TCR-proximal region. Our work elucidates the function of Tespa1 in T cell development and the regulation of TCR-induced Ca2+ signalling through IP3R1. PMID- 28598419 TI - Genome-wide approach identifies a novel gene-maternal pre-pregnancy BMI interaction on preterm birth. AB - Preterm birth (PTB) contributes significantly to infant mortality and morbidity with lifelong impact. Few robust genetic factors of PTB have been identified. Such 'missing heritability' may be partly due to gene * environment interactions (G * E), which is largely unexplored. Here we conduct genome-wide G * E analyses of PTB in 1,733 African-American women (698 mothers of PTB; 1,035 of term birth) from the Boston Birth Cohort. We show that maternal COL24A1 variants have a significant genome-wide interaction with maternal pre-pregnancy overweight/obesity on PTB risk, with rs11161721 (PG * E=1.8 * 10-8; empirical PG * E=1.2 * 10-8) as the top hit. This interaction is replicated in African American mothers (PG * E=0.01) from an independent cohort and in meta-analysis (PG * E=3.6 * 10-9), but is not replicated in Caucasians. In adipose tissue, rs11161721 is significantly associated with altered COL24A1 expression. Our findings may provide new insight into the aetiology of PTB and improve our ability to predict and prevent PTB. PMID- 28598421 TI - A two-dimensional Dirac fermion microscope. AB - The electron microscope has been a powerful, highly versatile workhorse in the fields of material and surface science, micro and nanotechnology, biology and geology, for nearly 80 years. The advent of two-dimensional materials opens new possibilities for realizing an analogy to electron microscopy in the solid state. Here we provide a perspective view on how a two-dimensional (2D) Dirac fermion based microscope can be realistically implemented and operated, using graphene as a vacuum chamber for ballistic electrons. We use semiclassical simulations to propose concrete architectures and design rules of 2D electron guns, deflectors, tunable lenses and various detectors. The simulations show how simple objects can be imaged with well-controlled and collimated in-plane beams consisting of relativistic charge carriers. Finally, we discuss the potential of such microscopes for investigating edges, terminations and defects, as well as interfaces, including external nanoscale structures such as adsorbed molecules, nanoparticles or quantum dots. PMID- 28598423 TI - Diversity spurs diversification in ecological communities. AB - Diversity is a fundamental, yet threatened, property of ecological systems. The idea that diversity can itself favour diversification, in an autocatalytic process, is very appealing but remains controversial. Here, we study a generalized model of ecological communities and investigate how the level of initial diversity influences the possibility of evolutionary diversification. We show that even simple models of intra- and inter-specific ecological interactions can predict a positive effect of diversity on diversification: adaptive radiations may require a threshold number of species before kicking-off. We call this phenomenon DDAR (diversity-dependent adaptive radiations) and identify mathematically two distinct pathways connecting diversity to diversification, involving character displacement and the positive diversity-productivity relationship. Our results may explain observed delays in adaptive radiations at the macroscale and diversification patterns reported in experimental microbial communities, and shed new light on the dynamics of ecological diversity, the diversity-dependence of diversification rates, and the consequences of biodiversity loss. PMID- 28598422 TI - Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division. AB - Mitochondrial division is critical for the maintenance and regulation of mitochondrial function, quality and distribution. This process is controlled by cytosolic actin-based constriction machinery and dynamin-related protein 1 (Drp1) on mitochondrial outer membrane (OMM). Although mitochondrial physiology, including oxidative phosphorylation, is also important for efficient mitochondrial division, morphological alterations of the mitochondrial inner membrane (IMM) have not been clearly elucidated. Here we report spontaneous and repetitive constriction of mitochondrial inner compartment (CoMIC) associated with subsequent division in neurons. Although CoMIC is potentiated by inhibition of Drp1 and occurs at the potential division spots contacting the endoplasmic reticulum, it appears on IMM independently of OMM. Intra-mitochondrial influx of Ca2+ induces and potentiates CoMIC, and leads to K+-mediated mitochondrial bulging and depolarization. Synergistically, optic atrophy 1 (Opa1) also regulates CoMIC via controlling Mic60-mediated OMM-IMM tethering. Therefore, we propose that CoMIC is a priming event for efficient mitochondrial division. PMID- 28598424 TI - Raptor regulates functional maturation of murine beta cells. AB - Diabetes is associated with beta cell mass loss and islet dysfunctions. mTORC1 regulates beta cell survival, proliferation and function in physiological and pathological conditions, such as pregnancy and pancreatectomy. Here we show that deletion of Raptor, which is an essential component of mTORC1, in insulin expressing cells promotes hypoinsulinemia and glucose intolerance. Raptor deficient beta cells display reduced glucose responsiveness and exhibit a glucose metabolic profile resembling fetal beta cells. Knockout islets have decreased expression of key factors of functional maturation and upregulation of neonatal markers and beta cell disallowed genes, resulting in loss of functional maturity. Mechanistically, Raptor-deficient beta cells show reduced expression of DNA methyltransferase 3a and altered patterns of DNA methylation at loci that are involved in the repression of disallowed genes. The present findings highlight a novel role of mTORC1 as a core mechanism governing postnatal beta cell maturation and physiologic beta cell mass during adulthood. PMID- 28598425 TI - Local probe of single phonon dynamics in warm ion crystals. AB - The detailed characterization of non-trivial coherence properties of composite quantum systems of increasing size is an indispensable prerequisite for scalable quantum computation, as well as for understanding non-equilibrium many-body physics. Here, we show how autocorrelation functions in an interacting system of phonons as well as the quantum discord between distinct degrees of freedoms can be extracted from a small controllable part of the system. As a benchmark, we show this in chains of up to 42 trapped ions, by tracing a single phonon excitation through interferometric measurements of only a single ion in the chain. We observe the spreading and partial refocusing of the excitation in the chain, even on a background of thermal excitations. We further show how this local observable reflects the dynamical evolution of quantum discord between the electronic state and the vibrational degrees of freedom of the probe ion. PMID- 28598426 TI - Mesoscopic chaos mediated by Drude electron-hole plasma in silicon optomechanical oscillators. AB - Chaos has revolutionized the field of nonlinear science and stimulated foundational studies from neural networks, extreme event statistics, to physics of electron transport. Recent studies in cavity optomechanics provide a new platform to uncover quintessential architectures of chaos generation and the underlying physics. Here, we report the generation of dynamical chaos in silicon based monolithic optomechanical oscillators, enabled by the strong and coupled nonlinearities of two-photon absorption induced Drude electron-hole plasma. Deterministic chaotic oscillation is achieved, and statistical and entropic characterization quantifies the chaos complexity at 60 fJ intracavity energies. The correlation dimension D2 is determined at 1.67 for the chaotic attractor, along with a maximal Lyapunov exponent rate of about 2.94 times the fundamental optomechanical oscillation for fast adjacent trajectory divergence. Nonlinear dynamical maps demonstrate the subharmonics, bifurcations and stable regimes, along with distinct transitional routes into chaos. This provides a CMOS compatible and scalable architecture for understanding complex dynamics on the mesoscopic scale. PMID- 28598427 TI - Different populations of CD11b+ dendritic cells drive Th2 responses in the small intestine and colon. AB - T-helper 2 (Th2) cell responses defend against parasites. Although dendritic cells (DCs) are vital for the induction of T-cell responses, the DC subpopulations that induce Th2 cells in the intestine are unidentified. Here we show that intestinal Th2 responses against Trichuris muris worms and Schistosoma mansoni eggs do not develop in mice with IRF-4-deficient DCs (IRF-4f/f CD11c cre). Adoptive transfer of conventional DCs, in particular CD11b-expressing DCs from the intestine, is sufficient to prime S. mansoni-specific Th2 responses. Surprisingly, transferred IRF-4-deficient DCs also effectively prime S. mansoni specific Th2 responses. Egg antigens do not induce the expression of IRF-4 related genes. Instead, IRF-4f/f CD11c-cre mice have fewer CD11b+ migrating DCs and fewer DCs carrying parasite antigens to the lymph nodes. Furthermore, CD11b+CD103+ DCs induce Th2 responses in the small intestine, whereas CD11b+CD103 DCs perform this role in the colon, revealing a specific functional heterogeneity among intestinal DCs in inducing Th2 responses. PMID- 28598428 TI - Real-time observation of cation exchange kinetics and dynamics at the muscovite water interface. AB - Ion exchange at charged solid-liquid interfaces is central to a broad range of chemical and transport phenomena. Real-time observations of adsorption/desorption at the molecular-scale elucidate exchange reaction pathways. Here we report temporal variation in the distribution of Rb+ species at the muscovite (001) water interface during exchange with Na+. Time-resolved resonant anomalous X-ray reflectivity measurements at 25 degrees C reveal that Rb+ desorption occurs over several tens of seconds during which thermodynamically stable inner-sphere Rb+ slowly transforms to a less stable outer-sphere Rb+. In contrast, Rb+ adsorption is about twice as fast, proceeding from Rb+ in the bulk solution to the stable inner-sphere species. The Arrhenius plot of the adsorption/desorption rate constants measured from 9 to 55 degrees C shows that the pre-exponential factor for desorption is significantly smaller than that for adsorption, indicating that this reduced attempt frequency of cation detachment largely explains the slow cation exchange processes at the interface. PMID- 28598429 TI - Temperature-regulated guest admission and release in microporous materials. AB - While it has long been known that some highly adsorbing microporous materials suddenly become inaccessible to guest molecules below certain temperatures, previous attempts to explain this phenomenon have failed. Here we show that this anomalous sorption behaviour is a temperature-regulated guest admission process, where the pore-keeping group's thermal fluctuations are influenced by interactions with guest molecules. A physical model is presented to explain the atomic-level chemistry and structure of these thermally regulated micropores, which is crucial to systematic engineering of new functional materials such as tunable molecular sieves, gated membranes and controlled-release nanocontainers. The model was validated experimentally with H2, N2, Ar and CH4 on three classes of microporous materials: trapdoor zeolites, supramolecular host calixarenes and metal-organic frameworks. We demonstrate how temperature can be exploited to achieve appreciable hydrogen and methane storage in such materials without sustained pressure. These findings also open new avenues for gas sensing and isotope separation. PMID- 28598430 TI - Vegetation recovery in tidal marshes reveals critical slowing down under increased inundation. AB - A declining rate of recovery following disturbance has been proposed as an important early warning for impending tipping points in complex systems. Despite extensive theoretical and laboratory studies, this 'critical slowing down' remains largely untested in the complex settings of real-world ecosystems. Here, we provide both observational and experimental support of critical slowing down along natural stress gradients in tidal marsh ecosystems. Time series of aerial images of European marsh development reveal a consistent lengthening of recovery time as inundation stress increases. We corroborate this finding with transplantation experiments in European and North American tidal marshes. In particular, our results emphasize the power of direct observational or experimental measures of recovery over indirect statistical signatures, such as spatial variance or autocorrelation. Our results indicate that the phenomenon of critical slowing down can provide a powerful tool to probe the resilience of natural ecosystems. PMID- 28598431 TI - A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action. AB - The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT 6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo. PMID- 28598432 TI - Neural correlates of evidence accumulation during value-based decisions revealed via simultaneous EEG-fMRI. AB - Current computational accounts posit that, in simple binary choices, humans accumulate evidence in favour of the different alternatives before committing to a decision. Neural correlates of this accumulating activity have been found during perceptual decisions in parietal and prefrontal cortex; however the source of such activity in value-based choices remains unknown. Here we use simultaneous EEG-fMRI and computational modelling to identify EEG signals reflecting an accumulation process and demonstrate that the within- and across-trial variability in these signals explains fMRI responses in posterior-medial frontal cortex. Consistent with its role in integrating the evidence prior to reaching a decision, this region also exhibits task-dependent coupling with the ventromedial prefrontal cortex and the striatum, brain areas known to encode the subjective value of the decision alternatives. These results further endorse the proposition of an evidence accumulation process during value-based decisions in humans and implicate the posterior-medial frontal cortex in this process. PMID- 28598433 TI - Refinement of learned skilled movement representation in motor cortex deep output layer. AB - The mechanisms underlying the emergence of learned motor skill representation in primary motor cortex (M1) are not well understood. Specifically, how motor representation in the deep output layer 5b (L5b) is shaped by motor learning remains virtually unknown. In rats undergoing motor skill training, we detect a subpopulation of task-recruited L5b neurons that not only become more movement encoding, but their activities are also more structured and temporally aligned to motor execution with a timescale of refinement in tens-of-milliseconds. Field potentials evoked at L5b in vivo exhibit persistent long-term potentiation (LTP) that parallels motor performance. Intracortical dopamine denervation impairs motor learning, and disrupts the LTP profile as well as the emergent neurodynamical properties of task-recruited L5b neurons. Thus, dopamine-dependent recruitment of L5b neuronal ensembles via synaptic reorganization may allow the motor cortex to generate more temporally structured, movement-encoding output signal from M1 to downstream circuitry that drives increased uniformity and precision of movement during motor learning. PMID- 28598435 TI - Zinc-dependent regulation of zinc import and export genes by Zur. AB - In most bacteria, zinc depletion is sensed by Zur, whereas the surplus is sensed by different regulators to achieve zinc homeostasis. Here we present evidence that zinc-bound Zur not only represses genes for zinc acquisition but also induces the zitB gene encoding a zinc exporter in Streptomyces coelicolor, a model actinobacteria. Zinc-dependent gene regulation by Zur occurs in two phases. At sub-femtomolar zinc concentrations (phase I), dimeric Zur binds to the Zur-box motif immediately upstream of the zitB promoter, resulting in low zitB expression. At the same time, Zur represses genes for zinc uptake. At micromolar zinc concentrations (phase II), oligomeric Zur binding with footprint expansion upward from the Zur box results in high zitB induction. Our findings reveal a mode of zinc-dependent gene activation that uses a single metalloregulator to control genes for both uptake and export over a wide range of zinc concentrations. PMID- 28598436 TI - 11% efficiency solid-state dye-sensitized solar cells with copper(II/I) hole transport materials. AB - Solid-state dye-sensitized solar cells currently suffer from issues such as inadequate nanopore filling, low conductivity and crystallization of hole transport materials infiltrated in the mesoscopic TiO2 scaffolds, leading to low performances. Here we report a record 11% stable solid-state dye-sensitized solar cell under standard air mass 1.5 global using a hole-transport material composed of a blend of [Cu (4,4',6,6'-tetramethyl-2,2' bipyridine)2](bis(trifluoromethylsulfonyl)imide)2 and [Cu (4,4',6,6'-tetramethyl 2,2'-bipyridine)2](bis(trifluoromethylsulfonyl)imide). The amorphous Cu(II/I) conductors that conduct holes by rapid hopping infiltrated in a 6.5 MUm-thick mesoscopic TiO2 scaffold are crucial for achieving such high efficiency. Using time-resolved laser photolysis, we determine the time constants for electron injection from the photoexcited sensitizers Y123 into the TiO2 and regeneration of the Y123 by Cu(I) to be 25 ps and 3.2 MUs, respectively. Our work will foster the development of low-cost solid-state photovoltaic based on transition metal complexes as hole conductors. PMID- 28598437 TI - Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition. AB - Maintaining centromere identity relies upon the persistence of the epigenetic mark provided by the histone H3 variant, centromere protein A (CENP-A), but the molecular mechanisms that underlie its remarkable stability remain unclear. Here, we define the contributions of each of the three candidate CENP-A nucleosome binding domains (two on CENP-C and one on CENP-N) to CENP-A stability using gene replacement and rapid protein degradation. Surprisingly, the most conserved domain, the CENP-C motif, is dispensable. Instead, the stability is conferred by the unfolded central domain of CENP-C and the folded N-terminal domain of CENP-N that becomes rigidified 1,000-fold upon crossbridging CENP-A and its adjacent nucleosomal DNA. Disrupting the 'arginine anchor' on CENP-C for the nucleosomal acidic patch disrupts the CENP-A nucleosome structural transition and removes CENP-A nucleosomes from centromeres. CENP-A nucleosome retention at centromeres requires a core centromeric nucleosome complex where CENP-C clamps down a stable nucleosome conformation and CENP-N fastens CENP-A to the DNA. PMID- 28598439 TI - Erratum: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2. AB - This corrects the article DOI: 10.1038/ncomms14922. PMID- 28598438 TI - Reactivation of associative structure specific outcome responses during prospective evaluation in reward-based choices. AB - Before making a reward-based choice, we must evaluate each option. Some theories propose that prospective evaluation involves a reactivation of the neural response to the outcome. Others propose that it calls upon a response pattern that is specific to each underlying associative structure. We hypothesize that these views are reconcilable: during prospective evaluation, offers reactivate neural responses to outcomes that are unique to each associative structure; when the outcome occurs, this pattern is activated, simultaneously, with a general response to the reward. We recorded single-units from macaque orbitofrontal cortex (Area 13) in a riskless choice task with interleaved described and experienced offer trials. Here we report that neural activations to offers and their outcomes overlap, as do neural activations to the outcomes on the two trial types. Neural activations to experienced and described offers are unrelated even though they predict the same outcomes. Our reactivation theory parsimoniously explains these results. PMID- 28598434 TI - Genome-wide association study identifies multiple risk loci for renal cell carcinoma. AB - Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 * 10-10), 3p22.1 (rs67311347, P=2.5 * 10-8), 3q26.2 (rs10936602, P=8.8 * 10-9), 8p21.3 (rs2241261, P=5.8 * 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 * 10-8), 11q22.3 (rs74911261, P=2.1 * 10-10) and 14q24.2 (rs4903064, P=2.2 * 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility. PMID- 28598440 TI - An autonomous organic reaction search engine for chemical reactivity. AB - The exploration of chemical space for new reactivity, reactions and molecules is limited by the need for separate work-up-separation steps searching for molecules rather than reactivity. Herein we present a system that can autonomously evaluate chemical reactivity within a network of 64 possible reaction combinations and aims for new reactivity, rather than a predefined set of targets. The robotic system combines chemical handling, in-line spectroscopy and real-time feedback and analysis with an algorithm that is able to distinguish and select the most reactive pathways, generating a reaction selection index (RSI) without need for separate work-up or purification steps. This allows the automatic navigation of a chemical network, leading to previously unreported molecules while needing only to do a fraction of the total possible reactions without any prior knowledge of the chemistry. We show the RSI correlates with reactivity and is able to search chemical space using the most reactive pathways. PMID- 28598441 TI - Controlling hybrid nonlinearities in transparent conducting oxides via two-colour excitation. AB - Nanophotonics and metamaterials have revolutionized the way we think about optical space (E,MU), enabling us to engineer the refractive index almost at will, to confine light to the smallest of the volumes, and to manipulate optical signals with extremely small footprints and energy requirements. Significant efforts are now devoted to finding suitable materials and strategies for the dynamic control of the optical properties. Transparent conductive oxides exhibit large ultrafast nonlinearities under both interband and intraband excitations. Here we show that combining these two effects in aluminium-doped zinc oxide via a two-colour laser field discloses new material functionalities. Owing to the independence of the two nonlinearities, the ultrafast temporal dynamics of the material permittivity can be designed by acting on the amplitude and delay of the two fields. We demonstrate the potential applications of this novel degree of freedom by dynamically addressing the modulation bandwidth and optical spectral tuning of a probe optical pulse. PMID- 28598442 TI - Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia. AB - Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR-BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies. PMID- 28598444 TI - Pumping approximately integrable systems. AB - Weak perturbations can drive an interacting many-particle system far from its initial equilibrium state if one is able to pump into degrees of freedom approximately protected by conservation laws. This concept has for example been used to realize Bose-Einstein condensates of photons, magnons and excitons. Integrable quantum systems, like the one-dimensional Heisenberg model, are characterized by an infinite set of conservation laws. Here, we develop a theory of weakly driven integrable systems and show that pumping can induce large spin or heat currents even in the presence of integrability breaking perturbations, since it activates local and quasi-local approximate conserved quantities. The resulting steady state is qualitatively captured by a truncated generalized Gibbs ensemble with Lagrange parameters that depend on the structure but not on the overall amplitude of perturbations nor the initial state. We suggest to use spin chain materials driven by terahertz radiation to realize integrability-based spin and heat pumps. PMID- 28598443 TI - Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. AB - Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-beta-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription. After TGF-beta stimulation, activated Smad3 suppresses lnc-Smad3 transcription, thereby recovering the Smad3 promoter accessibility to Ash1l. By revealing the opposite regulatory functions of Ash1l and lnc-Smad3 in Smad3 expression, our data provide insights for the epigenetic control of Treg cell fate to potentially aid in the development of therapeutic intervention for autoimmune diseases. PMID- 28598446 TI - Construction of Multiple Choice Questions Before and After An Educational Intervention. AB - INTRODUCTION: Khesar Gyalpo University of Medical Sciences of Bhutan, established in 2014, has ushered in a new era in medical education in Bhutan. Multiple Choice Questions are a common means of written assessment in medical education. METHODS: This was a quasi-experimental study conducted at the Faculty of Postgraduate Medicine, KGUMSB, Thimphu in December 2016. A total of 8 MCQs were prepared by four teaching faculties from different fields who had no prior training on construction of MCQs. It was delivered to a group of 16 randomly selected intern doctors. A 2 hours long workshop on construction of MCQs was conducted. After the workshop, the same MCQs were modified according to standard guidelines on developing MCQs and were tested in the same group of intern doctors. An analysis on the performance, difficulty factor, discrimination index and distractor analysis was done on the two sets of MCQs using Microsoft Excel and SPSS 20.0. RESULTS: For the pre- and post-workshop questions respectively, the pass percentage was 69.8% (11) and 81.3% (13), difficulty factor was 0.51 and 0.53, discrimination index was 0.59 and 0.47, distractor effectiveness was 83.3% and 74.9%. CONCLUSIONS: The workshop on MCQ development apparently seemed highly valuable and effective in changing the learning and performances of medical educators in the development of MCQs. PMID- 28598445 TI - Menopausal Health Status of Nepalese Women. AB - INTRODUCTION: Menopause is an unavoidable and sometimes problematic condition in which women may suffer from a number of health problems. Knowledge of the major symptoms associated with menopause helps reduce the burden and stress associated with the condition. In this context, a study was conducted to establish baseline data regarding menopausal health problems among Nepalese women. METHODS: A descriptive cross-sectional study was conducted among 2000 women aged over 40 years to identify their knowledge, attitude and practice related to menopausal health problems. Data was collected by interviewing the women and doing physical examination. Analysis was done using descriptive statistics and SPSS software was used for data analysis. RESULTS: A cohort of 2073 women (ages 40-60 years) participated in the research, among them 2000 yielded complete response. The study revealed that 820 (41%) women had reached menopause. The average age of menopause was 48.7 years. Majority of the women 1183 (59.2%) in the study did not know about menopausal health problems. Abnormal bleeding 353 (17.65%), sweating 315 (15.75%), hot flushes 299 (14.95%), joint/muscle pain 285 (14.25%) were the most common menopausal symptoms known by the women. Joint pain 736 (36.8%), hot flushes 584 (29.2%), irregular bleeding 582 (29.1%) were the most common experienced symptoms of menopause and only 586 (29.3%) consulted the health workers to alleviate menopausal symptoms. Moreover, most of the women 926 (46.3%) accepted menopause as a part of life. CONCLUSIONS: The research has tried to establish the baseline of menopausal health problems in the Nepalese women. The average age of menopause was 48.7 years. Majority did not know about menopausal health problems. Further researches with nationally representative sample are recommended to further explore the menopausal health problems of Nepalese women. PMID- 28598447 TI - Single Stage Management of Concomitant Cholelithiasis and Choledocholithiasis. AB - INTRODUCTION: Concomitant cholelithiasis and choledocholithiasis are commonly managed in two stage procedure, endoscopic management of common bile duct stone followed by laparoscopic cholecystectomy in different time and setting. We perform these two procedures in same sitting in operating room set up. We evaluated the procedure in terms of outcome, feasibility and complications. METHODS: Prospective cross-sectional study carried out since April 2013 to August 2016 in all patients who had undergone single stage endoscopic and laparoscopic management of concomitant cholelithiasis and choledocholithiasis. Patient's demography, procedural time for different procedure and procedure in total and post-operative complications were recorded and analyzed with suitable statistical methods. RESULTS: Out of 50 cases enrolled, 2 patients were converted to open. Out of 48 patients, 3 needed re-attempt for completion. Majority were female 36 (72%), mean age was 39.48years. Mean common bile duct diameter and mean stone size was 11.43+/-2.63 cm and 7.99+/-2.01cm, respectively. Mean of total procedural time was 90.93+/- 33.68 minutes. In most of the cases, laparoscopic cholecystectomy performed first followed by endoscopic method (66.7%). Total procedural time was less in the patients who underwent laparoscopy first in comparison to endoscopy first. Clinically significant complications like cholangitis, pancreatitis and duodenal perforation occurred in 7 patients. Out of 4 patients who developed pancreatitis, one had severe acute pancreatitis requiring prolonged hospitalization. CONCLUSION: Single stage management of common bile duct and gall bladder stone by laparoscopic and endoscopic method is feasible in our setup with acceptable results. Endoscopic treatment of common bile duct stone if performed first, is associated with longer procedural time. PMID- 28598448 TI - Fetal Ductus Venosus Pulsatility Index and Diameter during Second and Third Trimester of Gestation. AB - INTRODUCTION: The ductus venosus is a small funnel shaped vessel found posterior to the fetal liver connecting the intra-abdominal umbilical vein and the inferior vena cava. It is one of the three physiological shunts in the fetus. The main objective of this study is to construct the reference table and normogram for fetal ductus venosus Pulsatility Index and diameter with gestational age. METHODS: This was a prospective cross sectional study conducted during August 2011 to July 2012 taking 294 uncomplicated pregnancies using systemic random sampling method. Three measurements were made for ductus venosus diameter and Pulsatility Index in each fetus during period of fetal quiescence. RESULTS: The ductus venosus diameter at <20weeks, 20-25 weeks, 25-30 weeks, >30 weeks were 1.16, 1.31, 1.62, 1.81 and Pulsatility Index at <20weeks, 20-25 weeks, 25-30 weeks, >30 weeks were 0.41, 0.44, 0.41 and 0.41 respectively. CONCLUSIONS: The mean diameter of the ductus venosus was linear across gestational age. The Pulsatility Index shows a scattered distribution across the gestational age. PMID- 28598450 TI - Lower Genital Tract Trauma in A Tertiary Care Centre in Mid-Western Nepal. AB - INTRODUCTION: The study of lower genital tract trauma has become important in gynaecological practice. There is paucity of reports on this clinical entity from our settings. The main aim of this study is to document injuries in female lower genital tract in Mid-Western Nepal. METHODS: Sixty female patients admitted to the hospital with genital tract injuries caused by coitus or accidents were included in the study. Details of the causes of trauma clinical presentations and management were recorded. RESULTS: These injuries were grouped according to etiological factors. This study included 33 (55%) coital injuries and 27 (45%) non- coital injuries. Out of coital injury, 12 cases were criminal assault (rape) in age group of 4 to 18 years. Four unmarried girls had consensual sex. Non coital injuries were due to fall from height, cattle horn injuries, straddle type of trauma, vulvar haematoma and anorectal injuries. CONCLUSIONS: Appropriate surgical intervention can avert morbidity and mortality. PMID- 28598449 TI - Clinicopathological Study of Malignant Melanoma at Tertiary Care Centre. AB - INTRODUCTION: Malignant melanoma, which causes three fourth of all deaths related to skin cancer, is more common in Caucasian population compared to Asian population. There is no reliable information about malignant melanoma in Nepal hence an effort has been made to assess the clinical and pathological features of melanoma patients. METHODS: This was a retrospective hospital based study done in the department of Pathology. All cases of malignant melanoma diagnosed on biopsy during a period of 13 years were retrieved, reviewed and collated. RESULTS: We had 35 cases with age range from 15 to 84 years with the mean of 51.4 years and M: F of 1.3:1. The predominant site was lower extremities. Most cases were less than 3 cm. Majority of histologic subtypes were nodular melanoma 29 (82.8%) followed by mucosal lentiginous melanoma 3 (8.6%), superficial spreading melanoma 2 (5.7%) and acral lentiginous melanoma 1 (2.9%). Half (50%) of the excisional biopsies were at Clark's level IV and 75% were at high Breslow thickness. CONCLUSIONS: The most frequent site in males and females were lower extremities and trunk respectively in contrast to Western studies where it is opposite. Nodular melanoma was the commonest histologic subtype while in other Asian studies and in Western studies majority were acral lentiginous melanoma and superficial spreading melanoma respectively. PMID- 28598451 TI - Role of S-100 Immunostain as An Auxiliary Diagnostic Aid in Leprosy. AB - INTRODUCTION: Histopathologic diagnosis of leprosy is difficult when Bacillary Index (BI) is zero and neural involvement are not easily identifiable on routine Hematoxylin and Eosin stain. This study was undertaken to study the role of S-100 immunostaining in demonstrating different patterns of nerve involvement in various types of leprosy. METHODS: Thirty one skin biopsies with clinico histopathologic diagnoses of leprosy over a period of two years were included in the study. Ten cases of non-lepromatous granulomatous dermatoses (including eight cases of lupus vulgaris and two cases of erythema nodosum) were used as controls. Tissue sections from all cases and controls were stained with Hematoxylin and Eosin (H&E) stain, Fite stain and S-100 immunostain. The H&E stained slides were used to study the histopathological features, Fite stained slides for Bacillary Index and S-100 for nerve changes. RESULTS: Neural changes could be demonstrated in the entire spectrum of leprosy using S-100 immunostaining. The most common pattern of nerve destruction in the tuberculoid spectrum was fragmented and infiltrated whereas lepromatous spectrum showed mostly fragmented nerve twigs. Intact nerves were not detected in any of the leprosy cases. CONCLUSIONS: S-100 immunostain is a useful auxiliary aid to the routine H&E stain in the diagnosis of leprosy especially tuberculoid spectrum and intermediate leprosy. PMID- 28598452 TI - Risk Factors for Complications in Acute Appendicitis among Paediatric Population. AB - INTRODUCTION: Appendicitis is one of the most common causes of acute abdomen in children. Patients who are diagnosed early and undergo an appendectomy before perforation have a good outcome. However, it is difficult to diagnose in young children because its clinical manifestations may be atypical. The aim of this study was to determine the risk factors for complications in acute appendicitis in paediatric population. METHODS: We performed a cross sectional study on children (age <=18 years) who underwent appendectomy for suspected appendicitis from January 2014 to December 2015. Medical records of patients who met inclusion criteria were reviewed. Preoperative, operative and post-operative data were analyzed. The main outcome measure was intraoperative confirmation of gangrenous or perforated appendicitis. Multivariate logistic regression analysis was performed, and the main predictors of interest were patient's age, duration of pain and total leucocyte count. RESULTS: Total 73 paediatric patients (46 males) with mean age 13+/-3.8 were studied. In multivariate logistic regression analysis, patients having pain duration more than 72 hours and patients with leucocyte count >15000/mm3 were more likely to have complicated appendicitis [(OR:14.6), (95% CI= 2.40 - 89.77), (P= 0.004)] and [(OR=16.38), (95% CI = 1.836 146), (P = 0.012)] respectively. However, the age of the patient is not independently associated with complicated appendicitis. CONCLUSIONS: Increase in total leucocyte count and duration of the presentation can be a good marker of complicated appendicitis. PMID- 28598453 TI - Effectiveness of 0.2% Glyceryl Trinitrate and 0.5% Nifedipine in the Treatment of Chronic Anal Fissure. AB - INTRODUCTION: Anal fissure is an ischemic ulcer caused by combination of spasm of internal anal sphincter and poor blood supply to the posterior midline of anal canal. This study aimed to assess the efficacy of Glyceryl Trinitrate and Nifedipine in the treatment of chronic anal fissure. METHODS: Ninety patients with symptomatic anal fissure in Kathmandu Medical College Teaching Hospital are allocated for study in two groups of 45 each from March 2013 to April 2014. The patients are assigned alternatively to GTN group and Nifedipine group. All patients were assessed every week till 8 weeks in regards to headache, compliance, healing and recurrence. The patients who had complete healing in 8 weeks were further followed up for 6 weeks to detect recurrence. RESULTS: Patients in the two groups were comparable in regard to demographic data (age and sex) as well as clinical factors. Headache was main complaint of patients using GTN in high percentage (16.6%) than complained by patients using topical Nifedipine (6.9%). This factor led to poor compliance with GTN compared with Nifedipine. Nifedipine showed better healing rate 82.5% compared with GTN 60%. Recurrence was comparable among the two groups. CONCLUSIONS: Nifedipine ointment showed better results than GTN ointment in chronic anal fissure regarding headache, compliance, healing and recurrence in 6 weeks of follow up period after complete healing of fissure in 8 weeks. PMID- 28598454 TI - Prevalence of Malnutrition in a Rural Residential Sanskrit School in Baglung, Nepal. AB - INTRODUCTION: Under-nutrition is a condition in which there is inadequate consumption, poor absorption or excessive loss of nutrients. Nepal still faces high chronic as well as acute under-nutrition in children. The following study was conducted a Sanskrit school in rural Baglung to find the prevalence of malnutrition among the children which could reflect the nutritional status of the community. METHODS: Out of 60 students admitted to the school, only 43 were present at the time when we collected our data. Weight was measured with a standard weighing scale and standing height with a measuring tape attached to the wall. Data were filled up in proforma, entered in Microsoft Excel 2013 and were analyzed and indicators calculated with SPSS version 20 using WHO Child Growth Reference data for 5-19 years and macros. RESULTS: Stunting (Z score < -2) was found in 53.5% of the study group and severe stunting (Z score < -3) was found in 25.6%. 12.5% of the 8 children under 10 years in our study had weight-for-age < 2 Z score which indicates underweight. No one was severely underweight. In our study, 2.3% had severe thinness (Z-score < -3), 14% had thinness (Z-score < -2). No one was overweight or obese. CONCLUSIONS: The prevalence of malnutrition was high among the students of the rural Sanskrit school where the study was conducted. PMID- 28598455 TI - Primary Total Hip Replacement in The Military Hospital in Kathmandu. AB - INTRODUCTION: Total hip replacement is one of the most widely performed and amongst the most successful orthopedic procedures performed worldwide. Even though it is a common orthopedic procedure in developed nations, it is performed only in selected centers in Nepal. This study will review the functional outcome of total hip replacements carried out in Shree Birendra Hospital. METHODS: We reviewed the records of total hip replacements, which were carried out in Shree Birendra Hospital, Kathmandu. Twenty-one hips were cemented and nineteen were uncemented. Cases were followed up in six weeks, twelve weeks, six months and every year from then on. Outcome in terms of Harris hip score of 40 osteoarthritic hips were measured pre-operatively as well as post-operatively. RESULTS: The mean age of the patients was 50.63 years (range 22-79 years). The commonest reason for the replacement was primary osteoarthritis of the hip. Thirty-nine patients underwent unilateral total hip replacement while in one patient both hips were replaced. The mean Harris hip score for the forty hips that were available at the latest follow-up examination at an average of five years (range two to six and a half years) after the operation was 85.2 +/- 7.65 points as compared to the pre-operative mean Harris hip score of 32.38 +/- 3.4. CONCLUSIONS: Based on improved Harris hip scores, we believe that THR is a good option in patients with end stage arthritis of the hip. PMID- 28598456 TI - Hormonal Changes in Intracranial Hemorrhage. AB - INTRODUCTION: The purpose of this study was to investigate the changes of serum ACTH and Thyroid hormone level in the acute phase of ICH. METHODS: Sixty patients with spontaneous ICH were assessed regarding hormonal changes by measuring ACTH and Thyroid hormone level. The relationships of hormone concentrations to clinical and radiological parameters were evaluated at hospital admission (t0), 5 days (t1) and 10 days (t2). The results were statistically analyzed. RESULTS: ACTH, TSH, Thyroxine, and free Thyroxine were not significantly different among the three time periods (P > 0.05), while Triiodothyronine (T3) and free Triiodothyronine (FT3) were significantly different (P < 0.05). T3 and FT3 were not significantly different among patients with hemorrhage of different locations (P>0.05). There were significant negative correlations between T3 and FT3 with volume of ICH (r=-0.63 and r=-0.25) and there were positive correlations between T3 and FT3 with GCS (r=0.63 and r=0.37) respectively on admission day (p <0.05). CONCLUSIONS: Hormonal secretion patterns is associated with the severity of ICH. This is an important index to evaluate the disease severity and prognosis. PMID- 28598457 TI - Rural Health Care Workers and Local Residents Health Status in Yulong County of Yunnan Province China and Hat Yai City of Songkhla Mansion Thailand. AB - INTRODUCTION: To compare health status between Hat Yai city of Songkhla Province in Thailand and Yulong county of Yunnan province in China about rural health care workers and local residents, analyzing of both differences, learning from the advanced experience and practice of Thailand, adjusting policy, especially for the implementation of measures to improve the lack of human resources construction of Yulong County rural health, promote the level of rural health service of Lijiang. METHODS: A qualitative study consisting of focus group discussions and individual in-depth interviews were conducted in Rural Health Care Workers and Local Residents Health Status in Yulong County of Yunnan Province China and Hat Yai City of Songkhla Mansion Thailand from. RESULTS: Compared to 41(100%) bachelor's degree of medical staffs in Hat Yai, this accounted only 94 (42%) bachelor's degree of medical staffs in Yulong county hospital, and 31 (12%)in townships hospitals. For medical workers in Hat Yai, they have at least one time on-job training per year, but for Yulong county, only 144 (29%)of the medical personnel participated in the training per year. Health expenditures of Yulong county was mainly borne by the local government, and medical insurance coverage rate is 217,107 (99%). Insurance average awareness of Hat Yai is 4449 (66.4%), Yulong County is 62,501 (28.5%), P<0.001, there are statistically significant differences between two cities. CONCLUSIONS: Thailand has good experience in training, well-paid, motivating and retaining talent for rural health human resources; multi-pronged, mechanism innovation, establish and perfect the system of human resources for health, is the essential way to solve the problem. PMID- 28598459 TI - True Brachial Artery Aneurysm Presenting as a Non-Pulsatile Mass. AB - Brachial artery aneurysms are rare disease that can be encountered. It is divided into true and false. The frequency of true aneurysm of the brachial artery is so much unusual. So, we present a case of a 59 year old male who presented to us with complaint of mass in left upper limb since many years ago. Now, there was sudden onset of progressive pain with coldness, numbness, tingling sensation and blackish discolouration of skin from 8 hours. The left upper limb was pulseless and color Doppler ultrasound showed a non-pulsatile aneurysm at the mid level of left brachial artery associated with arterial occlusion in its distal branch by thrombus. The patient was successfully revascularised by interposing a saphenous vein graft. Thus,this case suggest that the prompt diagnosis of true brachial artery aneurysm by ultrasound or color Doppler ultrasound and the proper treatment by surgical repair can save limb from dangerous sequel Keywords: brachial artery aneurysm; color doppler ultrasound; true aneurysm; ultrasound. PMID- 28598458 TI - Multidisciplinary Cooperation in a Simultaneous Combined Liver and Kidney Transplantation Patient of Primary Hyperoxaluria 1. AB - Primary hyperoxaluria type 1 is an autosomal recessive hereditary glyoxylate metabolism disorder characterized by excessive production of oxalate, caused by the deficiency of liver specific peroxisomal enzyme: alanineglyoxylate aminotransferase. For patients with end-stage renal disease, combined liver and kidney transplantation was needed. This report describes one patient, with a diagnosis of end-stage renal disease and primary hyperoxaluria 1 confirmed by PCR and direct sequencing with genomic DNA, received the simultaneous combined liver and kidney transplantation after seven months' waiting. However, there were several complications observed post surgery, such as protracted bleeding, common bile duct anastomotic stenosis, biliary calculi and recurrence of urolithiasis. All these were well solved by relevant department, and finally a satisfactory outcome was achieved. Multidisciplinary cooperation plays an important role on the PH1 patient management, especially when multiple complications are encountered. PMID- 28598460 TI - Hypercalcemia due to Nasopharyngeal Carcinoma. AB - Hypercalcemia is a rare metabolic disorder associated with hyperparathyroidism, malignancy and various other causes. Although common in adult malignancies, hypercalcemia is rare in pediatrics and purports poor prognosis. Nasopharyngeal carcinoma is rare with no reported hypercalcemic presentation. We present here a case of hypercalcemia in a child of nasopharyngeal carcinoma. A 10 year girl presented with backache for 1 month, epistaxis, cough, chest-pain for 1 week alongwith anorexia and weight loss. Investigations revealed anemia and hypercalcemia (23mg/dl; normal range 9-11 mg/dl) with hyperphosphatemia, normal parathyroid levels. Hypercalcemic crisis was managed with saline, furosemide and bisphosphonate. Computed Tomography of paranasal sinuses revealed mass in right nasal cavity. Endoscopic biopsy disclosed undifferentiated nasopharyngeal carcinoma. The child expired despite supportive measures. Thus, hypercalcemia, though rare, may complicate advanced tumors. NPC, being rare in children, requires high index of suspicion with careful clinicoradiological examination and timely management for better chances of survival. PMID- 28598461 TI - Acute Retropharyngeal Abscess Masquerading as Meningitis. AB - Retropharyngeal abscess is a potentially serious deep neck space infection occurring more frequently in children than in adults. The clinical picture of RPA is highly variable with paucity of physical findings. Prompt diagnosis of RPA especially in infants is mandatory to prevent potential fatal complications including airway obstruction. The diagnosis of RPA should be based on high index of clinical suspicion with supportive imaging studies like lateral X-ray of neck and CT. We present a case of acute retropharyngeal abscess which was initially misdiagnosed as meningitis and led to airway obstruction. This case is reported to create awareness among emergency physicians, paediatricians and otolaryngologists to have high index of suspicion in diagnosing RPA especially in infants. PMID- 28598462 TI - An Experience of Optimizing A Community-Based Micro-Insurance Model to Bridge the Gap between Treatment Cost and Ability to pay at BPKIHS. AB - In the year 2001 the leaders of BPKIHS started a micro social insurance scheme; Social Health Insurance (SHI) for prospective research. It is a method of financing and managing health care using compulsory contributions from employers, employees and may be from the government. Household members from organized groups in catchment areas enrolled voluntarily. Photographed service cards were issued entitled for free IPD/OPD consultations, investigations and bed charges excluding CT scans and specialty treatment. Institute bore operation and medicine costs up to 10000 and 3500 respectively for IPD yearly. Premium was fixed after a research through focus group discussion in villages of Morang, Sunsari and Biratnagar. A flat rate premium of 15 and 50 NRS/adult/month for villagers, city dwellers and half for children was fixed. Marginalized community and handicapped paid 33% of premium, 33% by Institute and 33% by concerned VDC. As the client number increased from 2383 to 7392 in second and to 15779 in third year, Premium: Expenditure ratio moved from 225:222 to 198:391. Average cost sharing of premium to expenditure came to 226:332 showing a negative 3alance. This scheme completed its fourth year till this research in 2005 A.D. But it was closed due to deficit. As reinsured population occasionally concealed information by not incorporating all family members. They defaulted in subsequent year after utilizing the benefits of SHI and misused the card for uninsured ones. It may, in its optimized form, become a model to be widely adopted to bridge the gap between the cost of treatment and the ability to pay in developing countries. PMID- 28598463 TI - Re: Dementia Assessment and Management Protocol for Doctors in Nepal. PMID- 28598464 TI - Re: Comprehensive Diabetes and Non-Communicable Disease Educator in the Low Resource Settings -As NCD Primary Care Assistant with One Year Training. PMID- 28598465 TI - Dispersity effects in polymer self-assemblies: a matter of hierarchical control. AB - Advanced applications of polymeric self-assembled structures require a stringent degree of control over such aspects as functionality location, morphology and size of the resulting assemblies. A loss of control in the polymeric building blocks of these assemblies can have drastic effects upon the final morphology or function of these structures. Gaining precise control over various aspects of the polymers, such as chain lengths and architecture, blocking efficiency and compositional distribution is a challenge and, hence, measuring the intrinsic mass and size dispersity within these areas is an important aspect of such control. It is of great importance that a good handle on how to improve control and accurately measure it is achieved. Additionally dispersity of the final structure can also play a large part in the suitability for a desired application. In this Tutorial Review, we aim to highlight the different aspects of dispersity that are often overlooked and the effect that a lack of control can have on both the polymer and the final assembled structure. PMID- 28598466 TI - New Fukui, dual and hyper-dual kernels as bond reactivity descriptors. AB - We define three new linear response indices with promising applications for bond reactivity using the mathematical framework of tau-CRT (finite temperature chemical reactivity theory). The tau-Fukui kernel is defined as the ratio between the fluctuations of the average electron density at two different points in the space and the fluctuations in the average electron number and is designed to integrate to the finite-temperature definition of the electronic Fukui function. When this kernel is condensed, it can be interpreted as a site-reactivity descriptor of the boundary region between two atoms. The tau-dual kernel corresponds to the first order response of the Fukui kernel and is designed to integrate to the finite temperature definition of the dual descriptor; it indicates the ambiphilic reactivity of a specific bond and enriches the traditional dual descriptor by allowing one to distinguish between the electron accepting and electron-donating processes. Finally, the tau-hyper dual kernel is defined as the second-order derivative of the Fukui kernel and is proposed as a measure of the strength of ambiphilic bonding interactions. Although these quantities have never been proposed, our results for the tau-Fukui kernel and for tau-dual kernel can be derived in zero-temperature formulation of the chemical reactivity theory with, among other things, the widely-used parabolic interpolation model. PMID- 28598467 TI - Vibronic quantized tunneling controlled photoinduced electron transfer in an organic solar cell subjected to an external electric field. AB - In this work, vibration-resolved photoinduced electron transfer of an organic conjugated DA system subjected to an external electric field was theoretically investigated. The ground and excited state vibrational relaxation energies were quantitatively characterized. The effective high frequency, omegaeff, could be estimated from the variation in energy of the excited-state equilibrium geometries of acceptor and donor sites as well as the analysis of the vibrational modes upon electron transfer. For a PCDTBT:PC70BM blend in an external electric field, the vibronic modes affected the charge separation process differently from the charge recombination process. The simulated results indicated that the vibrational quantum tunneling effect facilitated the charge recombination process to a large extent. Thus, for electron transfer reactions, considering the vibrational excitation influence and perturbed nucleus-electron interactions is essential. These results provide a feasible way to enhance the efficiency in yielding the electron transfer process products. PMID- 28598468 TI - The synergy effect of rare earth cations on local structure and PL emission in a Ce3+:REPO4 (RE = La, Gd, Lu, Y) system. AB - REPO4 (RE = La, Gd, Lu, Y) serves as an excellent host lattice due to its stable physicochemical properties and optical inertia. Doping Gd3+(La3+) into LuPO4 can form mixed crystals, increasing the Gd3+(La3+) concentration will induce the phase transition from tetragonal to hexagonal lattices, and the variation of the local structure around the Ce3+ activator will influence its 5d-level position and consequently 5d -> 4f radiation transition. This can be attributed to the synergy effect of rare earth ions in REPO4, however, the essential mechanism of such a synergy effect on the local structure and optical property is still poorly understood. Here, we study the synergy effect of rare earth ions on the phase transition and PL emission in a Ce3+:REPO4 system on the basis of the relationship between the composition-dependent local structure around Ce3+ and its PL emission properties from a molecular view. The competition between Lu3+ and Gd3+(La3+) in REPO4 not only influences the relative atomic position but also varies the symmetry of anion groups. Infrared absorption bands indicate that the activation of P-O bonding promotes phase transition and enhances PL emission intensity. The PL emission intensity of Ce3+ is higher in a REPO4 host with a lower site symmetry PO43- group (C2) than that with a higher site symmetry PO43- group (D2d). An increased disorder degree in Ce:GdxLu1-xPO4 mixed crystals leads to the shift of the 5d-level of Ce3+ towards a higher position, resulting in the blue shift of the PL emission wavelength. Moreover, the 5d -> 4f emission of Ce3+ may also be modulated towards a larger wavelength via substituting the cation site with larger-radius cations under a particular crystallographic structure in REPO4. Our results highlight the importance of disordered local structures as well as activated anion groups in the enhanced PL emission of Ce3+ activators in a host lattice. PMID- 28598469 TI - Interfacial photochemistry of biogenic surfactants: a major source of abiotic volatile organic compounds. AB - Films of biogenic compounds exposed to the atmosphere are ubiquitously found on the surfaces of cloud droplets, aerosol particles, buildings, plants, soils and the ocean. These air/water interfaces host countless amphiphilic compounds concentrated there with respect to in bulk water, leading to a unique chemical environment. Here, photochemical processes at the air/water interface of biofilm containing solutions were studied, demonstrating abiotic VOC production from authentic biogenic surfactants under ambient conditions. Using a combination of online-APCI-HRMS and PTR-ToF-MS, unsaturated and functionalized VOCs were identified and quantified, giving emission fluxes comparable to previous field and laboratory observations. Interestingly, VOC fluxes increased with the decay of microbial cells in the samples, indicating that cell lysis due to cell death was the main source for surfactants and VOC production. In particular, irradiation of samples containing solely biofilm cells without matrix components exhibited the strongest VOC production upon irradiation. In agreement with previous studies, LC-MS measurements of the liquid phase suggested the presence of fatty acids and known photosensitizers, possibly inducing the observed VOC production via peroxy radical chemistry. Up to now, such VOC emissions were directly accounted to high biological activity in surface waters. However, the results obtained suggest that abiotic photochemistry can lead to similar emissions into the atmosphere, especially in less biologically-active regions. Furthermore, chamber experiments suggest that oxidation (O3/OH radicals) of the photochemically-produced VOCs leads to aerosol formation and growth, possibly affecting atmospheric chemistry and climate-related processes, such as cloud formation or the Earth's radiation budget. PMID- 28598470 TI - Synthesis and magnetochemistry of heterometallic triangular FeLnIII (Ln = La, Gd, Tb, Dy, and Ho) and FeYIII complexes. AB - A series of Fe2Ln (Ln = La, Gd, Tb, Dy and Ho) and Fe2Y complexes have been synthesized via metal substitution and characterized by single crystal X-ray diffraction. All the molecules are isostructural and have a Fe2LnO triangular core with the oxygen atom existing as an MU3-oxo2- anion. DC and AC magnetic susceptibility studies were performed on all the molecules. For Fe2Ln (Ln = Gd, La) and Fe2Y, the data were fitted to Van Vleck equations and the magnetic coupling constants were obtained. In all cases, the two Fe(iii) spins were found to be antiparallel to each other in the ground state leaving the heterometal to remain essentially uncoupled. PMID- 28598471 TI - Fast gate-tunable photodetection in the graphene sandwiched WSe2/GaSe heterojunctions. AB - We investigated electrical and photoelectrical properties of graphene sandwiched WSe2/GaSe van der Waals heterojunctions. The device showed a high rectification ratio up to 300 at Vds = 1.5/-1.5 V, which is attributed to the built-in electric field in the device. Due to the bipolar property of WSe2, gate-tunable rectification inversion was observed. Meanwhile, the graphene sandwiched heterojunction showed excellent performances on photodetection, where the photoresponsivity of (6.2 +/- 0.2) A W-1 can be reached under Vds = -1.5 V and P = 0.2 MUW. The device also showed great external quantum efficiency of (1490 +/- 50)% and fast response time of ~30 MUs. Our study identified the graphene sandwiched heterojunctions based on 2D materials have great potential for gate tunable electronic and optoelectronic applications. PMID- 28598472 TI - Reaction of azides and enolisable aldehydes under the catalysis of organic bases and Cinchona based quaternary ammonium salts. AB - Herein we report a two-step sequence for the preparation of amides starting from azides and enolisable aldehydes. The reaction proceeded via the formation of triazoline intermediates that were converted into amides via Lewis acid catalysis. Preliminary studies on the preparation of triazolines under chiral phase transfer catalysis are also presented, demonstrating that enantioenriched amides could be prepared from achiral aldehydes in moderate to low enantioselectivity. PMID- 28598473 TI - Noninnocent ligands: heteroleptic nickel complexes with alpha-diimine and 1,2 diketone derivatives. AB - Reaction of the Ni-Ni-bonded compound [(NiIL-)2] (1, L = [(2,6-iPr2C6H3)NC(Me)]2) with various 1,2-diketones afforded a series of heteroleptic complexes: [LNi(PhC(O)-C(O)Ph)] (2), [LNi(PhC(O)-C(O)Me)] (3), [LNi(3,5-tBu2C6H2O2)] (4), and [(LNi){MU-eta2,eta2-(MeC(O)-C(O)Me)}(NiL)] (5). Furthermore, the complex [Na(Et2O)][LNi{PhC(O)-C(O)Ph}] (6) was obtained by the reduction of 2 with 1.0 equiv. of Na metal. These complexes, which contain three potential redox-active centers, nickel and both alpha-diimine and 1,2-diketone ligands, were characterized by X-ray crystallography, NMR, EPR, and UV-vis-NIR spectra, magnetic susceptibility measurements, and DFT computations to elucidate their electronic structures. PMID- 28598474 TI - Anisotropic longitudinal electronic relaxation affects DNP at cryogenic temperatures. AB - We report the observation of anisotropic longitudinal electronic relaxation in nitroxide radicals under typical dynamic nuclear polarization conditions. This anisotropy affects the efficiency of dynamic nuclear polarization at cryogenic temperatures of 4 K and high magnetic fields of 6.7 T. Under our experimental conditions, the electron paramagnetic resonance spectrum of nitroxides such as TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) is only partly averaged by electronic spectral diffusion, so that the relaxation times T1e(omega) vary across the spectrum. We demonstrate how the anisotropy of T1e(omega) can be taken into account in simple DNP models. PMID- 28598475 TI - Improving present day and future estimates of anthropogenic sectoral emissions and the resulting air quality impacts in Africa. AB - The African continent is undergoing immense social and economic change, particularly regarding population growth and urbanization, where the urban population in Africa is anticipated to increase by a factor of 3 over the next 40 years. To understand the potential health impacts from this demographical shift and design efficient emission mitigation strategies, we used improved Africa specific emissions that account for inefficient combustion sources for a number of sectors such as transportation, household energy generation, waste burning, and home heating and cooking. When these underrepresented emissions sources are combined with the current estimates of emissions in Africa, ambient particulate matter concentrations from present-day anthropogenic activity contribute to 13 210 annual premature deaths, with the largest contributions (38%) coming from residential emissions. By scaling both the population and the emissions for projected national-scale levels of growth, the predicted health impact grows to approximately 78 986 annual premature deaths by 2030 with 45% now resulting from emissions related to energy combustion. In order to mitigate this resulting increase in premature deaths, three scenarios have been developed which reduce sector-specific future emissions based on prior targets for technological improvements and emission controls in transportation, energy production and residential activities. These targeted potential mitigation strategies can avoid up to 37% of the estimated annual premature deaths by 2030 with the largest opportunity being a reduction of 10 868 annual deaths from switching half of the energy generation in South Africa to renewable technologies. PMID- 28598477 TI - Revealing the slow decomposition kinetics of type-I clathrate Ba8Ga16Ge30. AB - Inconsistencies in high temperature thermoelectric property measurements of Ba8Ga16Ge30 have prompted our study on the thermal stability of this heavily studied inorganic clathrate. Using X-ray diffraction, thermal analysis, and imaging techniques on both powder and spark plasma sintered pelletized samples, we probe the structure and decomposition characteristics of this important high temperature thermoelectric material. We demonstrate that the decomposition of Ba8Ga16Ge30 is extremely dependent on the heating conditions employed and, as a result of the slow decomposition kinetics of the clathrate, reveal that the true stability of this system has been overlooked in the extensive literature available. Loss of Ga and Ge from the clathrate cage is evident in all high temperature experiments under both air and inert environments. This study serves to highlight that the underlying structural chemistry and stability of thermoelectric materials at high temperature needs to be considered in parallel with the thermoelectric properties which constitute the figure of merit. Only then will reliable thermoelectric modules for real applications be realized. PMID- 28598476 TI - On the mechanism of mechanochemical molecular encapsulation in peptidic capsules. AB - Molecular encapsulation of C60 inside a hydrogen-bond-sealed semi-flexible peptidic capsule is hindered in solution, yet it proceeds effectively after mechanical milling of a solid sample. We show that the molecular mechanism involves the generation of non-covalently disordered forms that are active in guest uptake. We also show that the solvent-free mechanochemical covalent synthesis of capsules directly results in obtaining disordered, active forms. PMID- 28598478 TI - Correction: Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation. AB - Correction for 'Platinum complexes as light promoted anticancer agents: a redefined strategy for controlled activation' by Koushambi Mitra, et al., Dalton Trans., 2016, 45, 19157-19171. PMID- 28598479 TI - Organs-on-chips with integrated electrodes for trans-epithelial electrical resistance (TEER) measurements of human epithelial barrier function. AB - Trans-epithelial electrical resistance (TEER) is broadly used as an experimental readout and a quality control assay for measuring the integrity of epithelial monolayers cultured under static conditions in vitro, however, there is no standard methodology for its application to microfluidic organ-on-a-chip (organ chip) cultures. Here, we describe a new microfluidic organ chip design that contains embedded electrodes, and we demonstrate its utility for assessing formation and disruption of barrier function both within a human lung airway chip lined by a fully differentiated mucociliary human airway epithelium and in a human gut chip lined by intestinal epithelial cells. These chips with integrated electrodes enable real-time, non-invasive monitoring of TEER and can be applied to measure barrier function in virtually any type of cultured cell. PMID- 28598480 TI - Phosphine-catalyzed [3 + 2] and [4 + 2] annulation reactions of ynones with barbiturate-derived alkenes. AB - The phosphine-catalyzed [3 + 2] annulation reaction of ynones and barbiturate derived alkenes has been developed with the assistance of a weak acid, giving functionalized spirobarbiturate-cyclopentanones in moderate to excellent yields with excellent E/Z stereoselectivity. An unprecedented [4 + 2] annulation of ynones with barbiturate-derived alkenes was also achieved in the presence of a phosphine catalyst and an inorganic base, affording biologically interesting 1,5 dihydro-2H-pyrano[2,3-d]pyrimidine-2,4(3H)-dione derivatives. An asymmetric variant of the [3 + 2] annulation reaction has been explored and a moderate enantioselectivity was obtained when a bifunctional chiral phosphine was used as a chiral catalyst. A plausible mechanism was proposed to illuminate two different reaction pathways. PMID- 28598481 TI - Pools of cadmium in Chlamydomonas reinhardtii revealed by chemical imaging and XAS spectroscopy. AB - The green micro-alga Chlamydomonas reinhardtii is commonly used as a model to investigate metallic stress in photosynthetic organisms. The aim of this study was to explore processes implemented by three C. reinhardtii strains to cope with cadmium (Cd), and particularly to evidence Cd sequestration in the cell. For that, we used a combination of subcellular fractionation and chemical imaging (micro X-ray fluorescence (MUXRF) and transmission electron microscopy (TEM/X EDS)) to identify subcellular compartments of Cd accumulation, and X-ray absorption spectroscopy (XAS) to determine chemical Cd speciation. C. reinhardtii wild type strain 11/32b (wt), a newly design strain (pcs1) expressing a modified phytochelatin synthase in the chloroplast and a cell wall less strain CC400 (cw15) were exposed to 70 MUM Cd. At this Cd concentration, cell vitality was not affected, however, the strains showed various strategies to cope with Cd stress. In wt, most of Cd was diffused in the whole cell, and complexed by thiol ligands, while the other part was associated with phosphate in vacuolar Ca polyphosphate granules. Thiol ligands increased with exposure time, confirming their important role in Cd stress. In pcs1, Cd was also present as vacuolar Ca polyphosphate granules, and diffused in the cell as Cd-thiol complexes. In addition, while it should be regarded with caution, a minor proportion of Cd complexed by carboxyl groups, was potentially provided by starch produced around the pyrenoid and in the chloroplast. Results suggested that pcs1 uses thiol compounds such as PC to a lesser extent for Cd sequestration than wt. In cw15, an excretion of Cd, Ca polyphosphate granules has to be considered. Finally, Cd was detected in the pyrenoid of all strains. PMID- 28598482 TI - Correction: Structural stability of DNA origami nanostructures in the presence of chaotropic agents. AB - Correction for 'Structural stability of DNA origami nanostructures in the presence of chaotropic agents' by Saminathan Ramakrishnan et al., Nanoscale, 2016, 8, 10398-10405. PMID- 28598483 TI - The photocurrent response in the perovskite device based on coordination polymers: structure, topology, band gap and matched energy levels. AB - Using a rigid ditopic ligand, 4,5-di(4'-carboxylphenyl)benzene (H2L), three coordination polymers (CPs) formulated as MnL(H2O)2 (1), CdL(H2O) (2) and Mn2L2(DMF)3 (3) have been synthesized and structurally characterized by single crystal X-ray diffraction. These three CPs display 2D architectures but with different topologies. The experimental data and DFT calculation indicate that CP 2 is a semiconductor, and its CB/VB energy levels match with those of the perovskite CH3NH3PbI3. A FTO/TiO2/CH3NH3PbI3/CP 2 device is fabricated and the CP based device shows much larger photoresponse under visible light illumination (650 nm > lambda > 350 nm, 100 mW cm-2) than the individual CP 2. At 0 V vs. AgCl/Ag, the largest photocurrent density yielded by the CP-based perovskite device is ca. 200 times that of CP 2, which is due to the matched energy levels of all the materials in the device, leading the photogenerated electron-hole pairs to be separated effectively. Meanwhile, the coverage of the insoluble CP on the surface of the perovskite CH3NH3PbI3 can improve the stability of the perovskite against water. PMID- 28598484 TI - Correction: An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport. AB - Correction for 'An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport' by Shang Song et al., Lab Chip, 2017, 17, 1778-1792. PMID- 28598485 TI - An open-framework manganese(ii) phosphite and its composite membranes with polyvinylidene fluoride exhibiting intrinsic water-assisted proton conductance. AB - Proton conducting materials have important technological applications as key components in electrochemical devices, including fuel cells, electrochemical sensors, electrochemical reactors and electrochromic displays. And the exploration of novel proton conducting materials is significant for the development of efficient electrochemical devices. In this study, we have investigated the proton conductance of an open-framework manganese(ii) phosphite, (NH4)0.59(H3O)1.41Mn5(HPO3)6 (1). The open-framework manganese(ii) phosphate shows superior water-stability and excellent thermal stability. There was intrinsic water-assisted proton conductivity with sigma = 3.94 * 10-4 S cm-1 at 328 K and 98% RH. Furthermore, composite membranes have further been fabricated using polyvinylidene fluoride (PVDF) and 1, labeled as 1@PVDF-X, where the symbol X represents the mass percentage of 1 (as X%) in the composite membrane and X = 10-55%. The composite membranes display good mechanical performance and durability for practical applications, and the proton conductivity of 1@PVDF-55 reaches 3.32 * 10-5 S cm-1 in deionized water at 336 K. PMID- 28598486 TI - Temperature dependent NIR emitting lanthanide-PMO/silica hybrid materials. AB - Two materials - a mesoporous silica (MS) and a periodic mesoporous organosilica (PMO) functionalized with dipyridyl-pyridazine (dppz) units were grafted with near-infrared (NIR) emitting lanthanide (Nd3+, Er3+, Yb3+) complexes in an attempt to obtain hybrid NIR emitting materials. The parent materials: dppz vSilica and dppz-ePMO were prepared by a hetero Diels-Alder reaction between 3,6 di(2-pyridyl)-1,2,4,5-tetrazine (dptz) and the double bonds of either ethenylene bridged PMO (ePMO) or vinyl-silica (vSilica) and subsequent oxidation. The dppz vSilica is reported here for the first time. The prepared lanthanide-PMO/silica hybrid materials were studied in depth for their luminescence properties at room temperature and chosen Nd3+ and Yb3+ samples also at low temperature (as low as 10 K). We show that both the dppz-vSilica and dppz-ePMO materials can be used as "platforms" for obtaining porous materials showing NIR luminescence. To obtain NIR emission these materials can be excited either in the UV or Vis region (into the pi->pi* transitions of the ligands or directly into the f-f transitions of the Ln3+ ions). More interestingly, when functionalized with Nd3+ or Yb3+beta diketonate complexes these materials showed interesting luminescence properties over a wide temperature range (10-360 K). The Yb3+ materials were investigated for their potential use as ratiometric temperature sensors. PMID- 28598487 TI - Apigenin exhibits protective effects in a mouse model of d-galactose-induced aging via activating the Nrf2 pathway. AB - The aim of the present research was to study the protective effects and underlying mechanisms of apigenin on d-galactose-induced aging mice. Firstly, apigenin exhibited a potent antioxidant activity in vitro. Secondly, d-galactose was administered by subcutaneous injection once daily for 8 weeks to establish an aging mouse model to investigate the protective effect of apigenin. We found that apigenin supplementation significantly ameliorated aging-related changes such as behavioral impairment, decreased organic index, histopathological injury, increased senescence-associated beta-galactosidase (SAbeta-gal) activity and advanced glycation end product (AGE) level. Further data showed that apigenin facilitated Nrf2 nuclear translocation both in aging mice and normal young mice, and the Nrf2 expression of normal young mice was higher than that of natural senile mice. In addition, the expressions of Nrf2 downstream gene targets, including HO-1 and NQO1, were also promoted by apigenin administration. Moreover, apigenin also decreased the MDA level and elevated SOD and CAT activities. In conclusion, focusing on the Nrf2 pathway is a suitable strategy to delay the aging process, and apigenin may exert an anti-senescent effect process via activating the Nrf2 pathway. PMID- 28598488 TI - Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis. AB - Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK-/- and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK-/- mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK-/- mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK-/- mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK-/- mice; however, survival was similar between septic MLCK-/- mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins. PMID- 28598489 TI - Nicotinic acetylcholine receptor-mediated protection of the rat heart exposed to ischemia reperfusion. AB - Reperfusion injury following acute myocardial infarction is associated with significant morbidity. Activation of neuronal or non-neuronal cholinergic pathways in the heart has been shown to reduce ischemic injury and this effect has been attributed primarily to muscarinic acetylcholine receptors. In contrast, the role of nicotinic receptors, specifically alpha-7 subtype (alpha7nAChR) in the myocardium remains unknown which offers an opportunity to potentially repurpose several agonists/modulators that are currently under development for neurologic indications. Treatment of ex vivo and in vivo rat models of cardiac ischemia/reperfusion (I/R) with a selective alpha7nAChR agonist (GTS21) showed significant increases in left ventricular developing pressure, and rates of pressure development without effects on heart rate. These positive functional effects were blocked by co-administration with methyllycaconatine (MLA), a selective antagonist of alpha7nAChRs. In vivo, delivery of GTS21 at the initiation of reperfusion, reduced infarct size by 42% (p<0.01) and decreased tissue reactive oxygen species (ROS) by 62% (p<0.01). Flow cytometry of MitoTracker Red stained mitochondria showed that mitochondrial membrane potential was normalized in mitochondria isolated from GTS21 treated compared to untreated I/R hearts. Intracellular ATP concentration in cultured cardiomyocytes exposed to hypoxia/reoxygenation was reduced (p<0.001), but significantly increased to normoxic levels with GTS21 treatment, and this was abrogated by MLA pretreatment. Activation of stress-activated kinases, JNK and p38MAPK, were significantly reduced by GTS21 in I/R. We conclude that targeting myocardial 17nAChRs in I/R may provide therapeutic benefit by improving cardiac contractile function through a mechanism that preserves mitochondrial membrane potential, maintains intracellular ATP and reduces ROS generation, thus limiting infarct size. PMID- 28598490 TI - Development of a zebrafish sepsis model for high-throughput drug discovery. AB - Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug development pipeline is time consuming and expensive and the low success rates associated with cell based screens underline the need for whole organism screening strategies, especially for complex pathological processes. Here, we established an LPS induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis including, edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by an altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and ROS production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage, and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis associated pathologies and cellular processes in the whole organism, as well as to screen and validate large numbers of compounds that can modify sepsis pathology in vivo. PMID- 28598492 TI - Use of 2-Octyl Cyanoacrylate Adhesive and Polyester Mesh for Wound Closure in Primary Knee Arthroplasty. AB - Wound closure in primary knee arthroplasty is important both for surgical success, by minimizing the risk of wound complications and infection, and for patient satisfaction with wound care and cosmesis. This article reports the use of a topical self-adhering, pressure-sensitive polyester mesh combined with 2 octyl cyanoacrylate adhesive for final skin closure of primary knee arthroplasty without external staples or sutures. During a 2.5-year period, 360 consecutive primary knee arthroplasty procedures (321 total knee arthroplasty procedures and 39 partial knee arthroplasty procedures) performed by 1 surgeon at 1 institution were reviewed. For all primary arthroplasty procedures, closure was performed with a standardized method. Final skin closure was performed with 2-octyl cyanoacrylate adhesive and polyester mesh. Patients returned at 6 weeks and 1 year postoperatively. The study found a 0.8% rate of superficial wound complications, no cases of dehiscence, no wound complications requiring operative irrigation and debridement, and no prosthetic joint infections. One patient had a reaction consistent with previously reported localized contact dermatitis that was believed to be related to the 2-octyl cyanoacrylate adhesive. In 2 cases, treatment with cephalexin was required, in 1 case for 2 small suture abscesses and in the other case for periincisional cellulitis. All wound complications resolved by 6 weeks. The results showed that 2-octyl cyanoacrylate adhesive and polyester mesh can be used successfully in the setting of primary knee arthroplasty for closure of high-tension knee arthroplasty wounds. This series found a 0.8% rate of superficial wound complications, no cases of dehiscence, and no infections. [Orthopedics. 2017; 40(5):e784-e787.]. PMID- 28598491 TI - Modularity in Total Hip Arthroplasty: Benefits, Risks, Mechanisms, Diagnosis, and Management. AB - Modular implants are currently widely used in total hip arthroplasty because they give surgeons versatility during the operation, allow for easier revision surgery, and can be adjusted to better fit the anatomy of the specific patient. However, modular implants, specifically those that have metal-on-metal junctions, are susceptible to crevice and fretting corrosion. This can ultimately cause implant failure, inflammation, and adverse local tissue reaction, among other possible side effects. Surgeons should be aware of the possibility of implant corrosion and should follow a set of recommended guidelines to systematically diagnose and treat patients with corroded implants. Ultimately, surgeons will continue to use modular implants because of their widespread benefits. However, more research is needed to determine how to minimize corrosion and the negative side effects that have been associated with modular junctions in total hip arthroplasty. [Orthopedics. 2017; 40(6):355-366.]. PMID- 28598494 TI - Decreased Radiation Exposure Among Orthopedic Residents Is Maintained When Using the Mini C-Arm After Undergoing Radiation Safety Training. AB - The resident curriculum of the American Board of Orthopaedic Surgery emphasizes radiation safety. Gendelberg showed that, immediately after a program on fluoroscopic safety, residents used less radiation when using the mini C-arm to reduce pediatric fractures. The current study evaluated whether this effect lasted. Residents underwent a new annual 3-hour session on mini C-arm use and radiation. Group A included 53 reductions performed before training. Group B included 45 reductions performed immediately after training. Group C included 46 reductions performed 11 months later. For distal radius fractures, exposure time and amount were 38.1 seconds and 83.1 mR, respectively, for group A; 26.7 seconds and 32.6 mR, respectively, for group B; and 24.1 seconds and 40.0 mR, respectively, for group C. When radiation time and amount were compared between group B and group C, P values were .525 and .293, respectively. When group C and group A were compared, P values were <.05 and <.01, respectively. For both bone forearm fractures, exposure time and amount were 41.2 seconds and 90.9 mR, respectively, for group A; 28.9 seconds and 30.4 mR, respectively, for group B; and 31.2 seconds and 43.6 mR, respectively, for group C. When radiation time and amount were compared between group B and group C, P values were .704 and .117, respectively. When group C and group A were compared, P values were .183 and .004, respectively. No significant difference in radiation exposure was noted immediately after training vs 11 months later. A sustained decrease in radiation exposure occurred after an educational program on safe mini C-arm use. [Orthopedics. 2017; 40(5):e788-e792.]. PMID- 28598493 TI - Adult Degenerative Lumbar Scoliosis. AB - Adult degenerative lumbar scoliosis is a 3-dimensional deformity defined as a coronal deviation of greater than 10 degrees . It causes significant pain and disability in the elderly. With the aging of the population, the incidence of adult degenerative lumbar scoliosis will continue to increase. During the past decade, advancements in surgical techniques and instrumentation have changed the management of adult spinal deformity and led to improved long-term outcomes. In this article, the authors provide a comprehensive review of the pathophysiology, diagnosis, and management of adult degenerative lumbar scoliosis. [Orthopedics. 2017; 40(6):e930-e939.]. PMID- 28598495 TI - Ultrasonography for endoleak detection after endoluminal abdominal aortic aneurysm repair. AB - BACKGROUND: People with abdominal aortic aneurysm who receive endovascular aneurysm repair (EVAR) need lifetime surveillance to detect potential endoleaks. Endoleak is defined as persistent blood flow within the aneurysm sac following EVAR. Computed tomography (CT) angiography is considered the reference standard for endoleak surveillance. Colour duplex ultrasound (CDUS) and contrast-enhanced CDUS (CE-CDUS) are less invasive but considered less accurate than CT. OBJECTIVES: To determine the diagnostic accuracy of colour duplex ultrasound (CDUS) and contrast-enhanced-colour duplex ultrasound (CE-CDUS) in terms of sensitivity and specificity for endoleak detection after endoluminal abdominal aortic aneurysm repair (EVAR). SEARCH METHODS: We searched MEDLINE, Embase, LILACS, ISI Conference Proceedings, Zetoc, and trial registries in June 2016 without language restrictions and without use of filters to maximize sensitivity. SELECTION CRITERIA: Any cross-sectional diagnostic study evaluating participants who received EVAR by both ultrasound (with or without contrast) and CT scan assessed at regular intervals. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently extracted data and assessed quality of included studies using the QUADAS 1 tool. A third review author resolved discrepancies. The unit of analysis was number of participants for the primary analysis and number of scans performed for the secondary analysis. We carried out a meta-analysis to estimate sensitivity and specificity of CDUS or CE-CDUS using a bivariate model. We analysed each index test separately. As potential sources of heterogeneity, we explored year of publication, characteristics of included participants (age and gender), direction of the study (retrospective, prospective), country of origin, number of CDUS operators, and ultrasound manufacturer. MAIN RESULTS: We identified 42 primary studies with 4220 participants. Twenty studies provided accuracy data based on the number of individual participants (seven of which provided data with and without the use of contrast). Sixteen of these studies evaluated the accuracy of CDUS. These studies were generally of moderate to low quality: only three studies fulfilled all the QUADAS items; in six (40%) of the studies, the delay between the tests was unclear or longer than four weeks; in eight (50%), the blinding of either the index test or the reference standard was not clearly reported or was not performed; and in two studies (12%), the interpretation of the reference standard was not clearly reported. Eleven studies evaluated the accuracy of CE-CDUS. These studies were of better quality than the CDUS studies: five (45%) studies fulfilled all the QUADAS items; four (36%) did not report clearly the blinding interpretation of the reference standard; and two (18%) did not clearly report the delay between the two tests.Based on the bivariate model, the summary estimates for CDUS were 0.82 (95% confidence interval (CI) 0.66 to 0.91) for sensitivity and 0.93 (95% CI 0.87 to 0.96) for specificity whereas for CE-CDUS the estimates were 0.94 (95% CI 0.85 to 0.98) for sensitivity and 0.95 (95% CI 0.90 to 0.98) for specificity. Regression analysis showed that CE-CDUS was superior to CDUS in terms of sensitivity (LR Chi2 = 5.08, 1 degree of freedom (df); P = 0.0242 for model improvement).Seven studies provided estimates before and after administration of contrast. Sensitivity before contrast was 0.67 (95% CI 0.47 to 0.83) and after contrast was 0.97 (95% CI 0.92 to 0.99). The improvement in sensitivity with of contrast use was statistically significant (LR Chi2 = 13.47, 1 df; P = 0.0002 for model improvement).Regression testing showed evidence of statistically significant effect bias related to year of publication and study quality within individual participants based CDUS studies. Sensitivity estimates were higher in the studies published before 2006 than the estimates obtained from studies published in 2006 or later (P < 0.001); and studies judged as low/unclear quality provided higher estimates in sensitivity. When regression testing was applied to the individual based CE-CDUS studies, none of the items, namely direction of the study design, quality, and age, were identified as a source of heterogeneity.Twenty-two studies provided accuracy data based on number of scans performed (of which four provided data with and without the use of contrast). Analysis of the studies that provided scan based data showed similar results. Summary estimates for CDUS (18 studies) showed 0.72 (95% CI 0.55 to 0.85) for sensitivity and 0.95 (95% CI 0.90 to 0.96) for specificity whereas summary estimates for CE-CDUS (eight studies) were 0.91 (95% CI 0.68 to 0.98) for sensitivity and 0.89 (95% CI 0.71 to 0.96) for specificity. AUTHORS' CONCLUSIONS: This review demonstrates that both ultrasound modalities (with or without contrast) showed high specificity. For ruling in endoleaks, CE-CDUS appears superior to CDUS. In an endoleak surveillance programme CE-CDUS can be introduced as a routine diagnostic modality followed by CT scan only when the ultrasound is positive to establish the type of endoleak and the subsequent therapeutic management. PMID- 28598496 TI - Introduction to the Special Section of Child Development on Positive Youth Development in Diverse and Global Contexts. AB - Positive youth development (PYD) research seeks to understand and promote positive aspects of development in young people. In this the special section, focused upon youth from diverse racial-ethnic backgrounds around the globe, we describe the origins and development of the field, identify key and emerging themes, and present the challenges for work in the area in the years ahead. Central to these are elements that are inherent in many of the articles that constitute the section: These include a need to articulate more clearly the role of social and cultural context in positive development, a need to refine the measures and methods used for collecting data, the significance of social identities, and engagement with other fields of study and with policymakers. PMID- 28598497 TI - Descriptive and Temporal Saltiness Perception Properties of Model Solid Lipoproteic Colloid Foods-Implications for Sodium Reduction. AB - Solid lipoproteic colloid (SLC) foods that consist of an oil-in-water emulsion of lipid and protein such as cheese and sausage contribute a significant amount of sodium to modern diets. This study aimed to correlate the overall saltiness perception to the texture and temporal saltiness perception of SLCs to understand saltiness perception during oral processing. Model SLCs with varying levels of protein and fat were prepared via pressure homogenization of whey protein isolate, anhydrous milk fat, and NaCl, followed by heat-induced gelation. Descriptive sensory analysis (DSA) and time-intensity (TI) method were used to characterize the sensory profiles and the temporal saltiness perception properties of the SLCs, respectively. Principal component analysis (PCA) and cluster analysis of the DSA results showed that the samples were grouped based on the formulation and the homogenization pressures. The maximum saltiness intensity in the TI curves increased with decreasing contents of protein and fat and decreasing homogenization pressures. The PCA and cluster analysis of the taste and texture attributes from the DSA and the TI parameters showed that the nonfat samples were clustered together, characterized by the DSA salty taste, syneresis texture, and the TI initial saltiness intensity. When only fat-containing samples were analyzed, the DSA salty attribute correlated significantly with the texture attributes of fracturable and syneresis. The dependence of saltiness perception on the texture properties of the nonfat and fat-containing samples discovered in this study provided insights for the future development of reduced-sodium products. PMID- 28598498 TI - Happy To Be "Me?" Authenticity, Psychological Need Satisfaction, and Subjective Well-Being in Adolescence. AB - Adolescents have a strong desire to "be themselves." How does experiencing authenticity-the sense of being one's true self-influence subjective well-being? What allows adolescents to experience authenticity? This research tests a working model of how authenticity is implicated in adolescents' well-being. Using survey, diary, and experimental methodologies, four studies (total N = 759, age range = 12-17) supported the main tenets of the model. Authenticity (a) enhances well being, (b) covaries with satisfaction of psychological needs for relatedness and competence; is caused by satisfaction of the need for autonomy; and (c) mediates the link between need satisfaction and well-being. Authenticity is more than a powerful motive: It has robust, replicable effects on well-being and may thus be a pervasive force in positive youth development. PMID- 28598499 TI - An experimental test of local adaptation among cytotypes within a polyploid complex. AB - The geographic distributions of polyploids suggest they can have distinct and sometimes broader niches compared to diploids. However, relatively few field experiments have investigated whether range differences are associated with local adaptation or reflect other processes, such as dispersal limitation. In three years of transplants across the elevational ranges of five cytotypes in the Claytonia perfoliata complex, we found evidence for local adaptation. In at least one study year germination was higher within the natural range for each cytotype, and four of the five cytotypes attained larger biomass within their natural range. Fitness within and beyond range varied across years, with two instances of cytotypes showing higher fitness beyond the range, highlighting a potential role of temporal variability in cytotype differentiation. Polyploids as a group did not outperform diploids, but the cytotype with highest fitness across environments was a hexaploid reported to be invasive. Our results suggest that differences in geographic ranges within the C. perfoliata complex reflect local adaptation of cytotypes. Although we did not find a general polyploid advantage, our findings support the idea that occasional polyploid cytotypes exhibit high fitness relative to other cytotypes, and contribute to growing evidence supporting ecological differentiation of cytotypes within polyploid complexes. PMID- 28598500 TI - Using propensity score matching to evaluate the effect of complementary medicine on clinical and embryologic outcomes of in vitro fertilization. AB - OBJECTIVE: To evaluate associations between using complementary medical therapies (CMTs) and embryologic and clinical outcomes of in vitro fertilization (IVF). METHODS: The present prospective questionnaire-based cohort study enrolled women aged 18-44 years undergoing their first, second, or third IVF cycle using their own oocytes at a large IVF clinic in Israel between February 1, 2013, and July 31, 2015. Clinical and embryologic data were obtained from patient records and patients completed a self-administered questionnaire that included details of any CMTs used to treat infertility. Propensity score matching was used and the proportion of top-quality embryos was compared between CMT users and non-users. RESULTS: The study enrolled 400 participants and 134 (33.5%) reported using CMT to treat infertility. In an unmatched analysis, reduced endometrium thickness was observed among CMT users (P=0.020); differences were not observed for embryologic or other clinical parameters. Following propensity score matching, reduced endometrial thickness (P=0.046), and a lower proportion (P=0.046) and number (P=0.040) of top-quality embryos were observed among CMT users in comparison with patients who did not use CMTs. CONCLUSIONS: Using CMTs was associated with inferior clinical and embryologic outcomes; using CMTs during IVF treatment could contribute to adverse outcomes. PMID- 28598501 TI - Effect of craniofacial genotype on the relationship between morphology and feeding performance in cichlid fishes. AB - The relationship between morphology and performance is complex, but important for understanding the adaptive nature of morphological variation. Recent studies have sought to better understand this system by illuminating the interconnectedness of different functional systems; however, the role of genetics is often overlooked. In this study, we attempt to gain insights into this relationship by examining the effect of genotypic variation at putative craniofacial loci on the relationship between morphology and feeding performance in cichlids. We studied two morphologically disparate species, as well as a morphologically intermediate hybrid population. We assessed feeding performance, jaw protrusion, and general facial morphology for each fish. We also genotyped hybrid animals at six previously identified craniofacial loci. Cichlid species were found to differ in facial geometry, kinematic morphology, and performance. Significant correlations were also noted between these variables; however, the explanatory power of facial geometry in predicting performance was relatively poor. Notably, when hybrids were grouped by genotype, the relationship between shape and performance improved. This relationship was especially robust in animals with the specialist allele at sox9b, a well-characterized regulator of craniofacial development. These data suggest a novel role for genotype in influencing complex relationships between form and function. PMID- 28598503 TI - Children's Early Awareness of Comprehension as Evident in Their Spontaneous Corrections of Speech Errors. AB - A crucial human cognitive goal is to understand and to be understood. But understanding often takes active management. Two studies investigated early developmental processes of understanding management by focusing on young children's comprehension monitoring. We ask: When and how do young children actively monitor their comprehension of social-communicative interchanges and so seek to clarify and correct their own potential miscomprehension? Study 1 examined the parent-child conversations of 13 children studied longitudinally in everyday situations from the time the children were approximately 2 years through 3 years. Study 2 used a seminaturalistic situation in the laboratory to address these questions with more precision and control with 36 children aged 2-3 years. PMID- 28598502 TI - Balanced Bcl-3 expression in murine CD4+ T cells is required for generation of encephalitogenic Th17 cells. AB - The function of NF-kappaB family members is controlled by multiple mechanisms including the transcriptional regulator Bcl-3, an atypical member of the IkappaB family. By using a murine model of conditional Bcl-3 overexpression specifically in T cells, we observed impairment in the development of Th2, Th1, and Th17 cells. High expression of Bcl-3 promoted CD4+ T-cell survival, but at the same time suppressed proliferation in response to TCR stimulation, resulting in reduced CD4+ T-cell expansion. As a consequence, T-cell-specific overexpression of Bcl-3 led to reduced inflammation in the small intestine of mice applied with anti-CD3 in a model of gut inflammation. Moreover, impaired Th17-cell development resulted in the resistance of Bcl-3 overexpressing mice to EAE, a mouse model of multiple sclerosis. Thus, we concluded that fine-tuning expression of Bcl-3 is needed for proper CD4+ T-cell development and is required to sustain Th17-cell mediated pathology. PMID- 28598504 TI - Microencapsulation of Corn Wastewater (Nejayote) Phytochemicals by Spray Drying and Their Release Under Simulated Gastrointestinal Digestion. AB - Corn lime cooking generates a large amount of wastewater known as nejayote that is composed of suspended solids and solubilized phytochemicals. Spray drying can be an alternative to recover bioactive molecules, such as ferulic acid, from nejayote. Besides the yield, the physicochemical properties (solubility, water activity, pH, moisture, hygroscopicity, total phenolic content, and distribution of free and bound hydroxycinnamic acids) of spray-dried nejayote powders were analyzed. The powders were obtained at 200 degrees C/100 degrees C or 150 degrees C/75 degrees C (inlet/outlet) air temperatures with the addition of maltodextrin (MD) or 2-hydroxypropyl-beta-cyclodextrin (HBCD) as encapsulating agents. Even when no carrier agent was used, a spray-dried nejayote powder was produced. The use of MD or HBCD as carrier increased the yield from 60.26% to 68.09% or 71.83%, respectively. As expected, a high inlet temperature (200 degrees C) allowed a satisfactory yield (>70%) and a low powder moisture (2.5%) desired by the industry. Water activity was reduced from 0.586 to 0.307 when HBCD was used in combination with a drying inlet temperature of 150 degrees C; and from 0.488 to 0.280 when the inlet temperature was set at 200 degrees C. Around 100% bioaccessibility of the compounds was observed after in vitro digestion. The addition of HBCD increased the release time (P < 0.05). Under simulated physiological conditions, there was no reduction of total phenolics, suggesting a good stability. This paper showed the feasibility to engage the spray drying technology to the corn industry to minimize their residues and reuse their by products. PMID- 28598505 TI - Paving the way for Bartter syndrome type 3 drug discovery: a hope from basic research. PMID- 28598506 TI - Atrial overdrive pacing during wide QRS tachycardia with RBBB morphology. What is the mechanism? PMID- 28598507 TI - Periodontal Disease Associated with Higher Risk of Dementia: Population-Based Cohort Study in Taiwan. AB - OBJECTIVES: To determine the magnitude and temporal aspect of the effect of poor dental health and periodontal disease (PD) on dementia. DESIGN: Retrospective cohort study SETTING: Taiwan National Health Insurance Research Database. PARTICIPANTS: Individuals with newly diagnosed PD (N = 182,747) MEASUREMENTS: Participants were followed from January 1, 2000, to December 31, 2010. Participants were assigned to dental prophylaxis, intensive periodontal treatment, tooth extraction, or no treatment, according to International Classification of Diseases codes and PD treatment codes. The incidence rate of dementia of the groups was compared. The association between PD and dementia was analyzed using Cox regression, with adjustments for age, sex, monthly income, residential urbanicity, and comorbidities. RESULTS: The incidence of dementia was significantly higher in the group with PD that did not receive treatment (0.76% per year) and in the group that had teeth extracted (0.57% per year) than in the group that underwent intensive PD treatment (0.35% per year) and the group that received dental prophylaxis (0.39% per year) (P < .001). After adjusting for confounders, the Cox proportional hazards model revealed a higher risk of dementia in the group with PD who did not undergo treatment (hazard ratio (HR) = 1.14, 95% confidence interval (CI) = 1.04-1.24) and the group that had teeth extracted (HR = 1.10, 95% CI = 1.04-1.16) than in the group that received dental prophylaxis. CONCLUSION: Subjects who had more severe PD or did not receive periodontal treatment were at greater risk of developing dementia. PMID- 28598508 TI - Farm to Sensory Lab: Taste of Blueberry Fruit by Children and Adults. AB - The average American child eats fewer fruits than recommended. Although taste is the primary motivator for food intake among children, little research has systematically measured children's liking of fruit and determined whether their preferences differ from adults. We phenotyped 49 children and their mothers to determine: (1) their liking of the taste of 3 blueberry cultivars ("Arcadia," "Keecrisp," and "Kestrel") from 2 harvests for which total soluble solids were determined using a handheld Brix refractometer; (2) the association between liking and blueberry sugar content; and (3) the most preferred level of fructose, one of the primary sugars in blueberry fruit. Multiple methods, identical for all participants, assessed which cultivar they liked best. Dietary intake, determined via 24-h dietary recall, revealed most children (73%) and adults (92%) did not meet dietary guidelines for fruit intake. We found that during the 1st harvest, Keecrisp was sweeter by 4 degrees Brix than either Arcadia or Kestrel and was the cultivar most preferred by both children and adults. For the 2nd harvest, mothers liked each of the cultivars equally, but children preferred Arcadia, which was 2 degrees Brix sweeter than the other 2 cultivars. Like other sugars, children's most preferred concentration of fructose was significantly higher than that of adults. In sum, children appear to be more sensitive to smaller variations in sweetness than are adults. Identifying drivers of fruit preference and assessing children's liking for whole fruits are important steps in developing strategies to increase fruit consumption among children. PMID- 28598509 TI - Comparison of Nutritional Composition, Aroma Compounds, and Biological Activities of Two Kinds of Tartary Buckwheat Tea. AB - Tartary buckwheat tea (TBT) is becoming increasingly popular for its unique flavor and health benefits. However, there is little information regarding the differences in nutritional quality among different kinds of TBT. Two kinds of TBT samples, whole grain tea (WGT) and whole plant tea (WPT), were collected from markets in China. The content of their nutritional compositions, including protein, amino acids, starch, fat, fatty acids, and flavonoids, as well as aroma compounds, were determined. Antioxidant and alpha-glucosidase inhibitory activities were also evaluated. WPT showed higher levels of protein and fat relative to WGT, but the content of essential amino acids and fatty acids was lower. WPT contained more total flavonoids with quercetin as the predominant flavonoid (81%), while rutin was the principal flavonoid compound (86%) in WGT. GC-MS analysis indicated that there were some differences in the aroma compound profile between WGT and WPT, though 14 aroma compounds were identified in both of them with 3-ethyl-2,5-dimethyl-pyrazine as the predominant compound. In addition, WPT showed superior antioxidant and alpha-glucosidase inhibitory activities than WGT. However, the total flavonoid content determined in tea soup was decreased by 60% and 98% compared with that in the alcohol extracts of WGT and WPT, respectively. The antioxidant and alpha-glucosidase inhibitory activities of tea soup were also lowered, especially for WPT. The differences between 2 kinds of TBT might be due to the variety of raw materials and processing methods. Diversified plant materials and scientific processing technologies should be taken into account to develop a nutritional and healthy TBT product. PMID- 28598511 TI - Evaluating Atlantic bottlenose dolphin (Tursiops truncatus) leukocyte differential counts comparing the CellaVision DM96 and the manual method. AB - BACKGROUND: The leukocyte differential count is an excellent diagnostic tool; however, the manual differential count has several drawbacks, especially for nontraditional species. Automated cell analyzers commonly used in veterinary practices require species-specific validation for use in nondomestic species other than dogs and cats. OBJECTIVES: The purpose of this study was to examine the potential of the CellaVision DM96 (DM96), an automated image analysis system, as a rapid and accurate method for providing a WBC differential count in comparison to the manual WBC differential count in bottlenose dolphins. METHODS: Ten fresh, EDTA anticoagulated blood samples were collected, blood smears were made and stained, and the differential WBC counts were performed on the DM96 and compared with manual differential WBC counts. Agreement, means, and errors were compared between the methods. RESULTS: There was good agreement between the DM96 and manual differential WBC counts for neutrophils; however, there was significant variation when comparing lymphocyte, monocyte, and eosinophil counts. No basophils were seen by any method. CONCLUSIONS: Despite a small sample size, the DM96 appeared to provide a viable alternative for automated neutrophil counting in blood of bottlenose dolphins. Whether the counts are comparable in animals with highly pathologic differential counts must be addressed in follow-up studies, preferably with more study animals. PMID- 28598512 TI - Long-term dental management of a patient with features of Schopf-Schulz-Passarge syndrome. AB - Schopf-Schulz-Passarge syndrome (SSPS) is thought to be a rare autosomal recessive condition similar to many other ectodermal dysplasias. Diagnosis is difficult, with many possible differential diagnoses; however, eyelid cysts are a commonly seen feature. This clinical report aims to highlight this and describe the dental features and management of this syndrome, which existing literature has not previously described. PMID- 28598513 TI - Structural study of the bladder in fetuses with prune belly syndrome. AB - AIMS: To study the bladder structure of fetuses with prune belly syndrome (PBS). METHODS: We studied three bladders obtained from three male fetuses with PBS and seven bladders from seven male fetuses without anomalies. Each bladder was dissected and embedded in paraffin, from which 5 MUm thick sections were obtained and stained with Masson's trichrome (to quantify connective tissue and smooth muscle) and picrosirius red with polarization (to observe collagen). Immunohistochemistry with tubulin (Tubulin, beta III, Mouse Monoclonal Antibody) was applied to observe the bladder nerves. The images were captured with an Olympus BX51 microscope and Olympus DP70 camera. The stereological analysis was done with the Image Pro and Image J programs, using a grid to determine volumetric densities (Vv). Means were statistically compared using the Mann Whitney test (P < 0.05). RESULTS: Quantitative analysis documented that smooth muscle fibers were significantly smaller (P = 0.04) in PBS fetuses (9.67% to 17.75%, mean = 13.2%) compared to control group (13.33% to 26.56%, mean = 17.43%). The analysis of collagen fibers showed predominance of green in the control group, suggesting collagen type III presence, and predominance of red in the in PBS fetal bladders, suggesting collagen type I presence in this group. The qualitative analysis of the nerves with immunohistochemistry with tubulin showed predominance of nerves in the control group. CONCLUSION: The bladder in PBS had lower concentrations of smooth muscle fibers, collagen type III, and nerves. These structural alterations can be one of the factors involved in urinary tract abnormality such as distended bladder in patients with PBS. PMID- 28598510 TI - Relative efficacy and safety of ticagelor vs clopidogrel as a function of time to invasive management in non-ST-segment elevation acute coronary syndrome in the PLATO trial. AB - BACKGROUND: Guidelines suggest that "upstream" P2Y12 receptor antagonists should be considered in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). HYPOTHESIS: Early use of ticagrelor in patients managed with an invasive strategy would be more effective than clopidogrel because of its more rapid onset of action and greater potency. METHODS: In the PLATO trial, 6792 NSTE ACS patients were randomized to ticagrelor or clopidogrel (started prior to angiography) and underwent angiography within 72 hours of randomization. We compared efficacy and safety outcomes of ticagrelor vs clopidogrel as a function of "early" (<3h) vs "late" (>=3h) time to angiography. Adjusted Cox proportional hazards models evaluated interaction between randomized treatment and time from randomization to angiography on subsequent outcomes. RESULTS: Overall, a benefit of ticagrelor vs clopidogrel for cardiovascular death/myocardial infarction/stroke was seen at day 7 (hazard ratio [HR]: 0.67, P = 0.002), day 30 (HR: 0.81, P = 0.042), and 1 year (HR: 0.80, P = 0.0045). There were no significant interactions in the <3h vs >=3h groups at any timepoint. For major bleeding, overall there was no significant increase (HR: 1.04, 95% confidence interval: 0.85-1.27); but there was a significant interaction with no difference between ticagrelor and clopidogrel in the early group (HR: 0.79), but higher bleeding risk with ticagrelor in the late angiography group, at 7 days (HR: 1.51, Pint = 0.002). Patterns were similar at 30 days and 1 year. CONCLUSIONS: The benefit of ticagrelor over clopidogrel was consistent in those undergoing early and late angiography, supporting upstream use of ticagrelor. PMID- 28598514 TI - The finite number of global motion patterns available to symmetric protein complexes. AB - In PDB, more than half of the entries are structure complexes and of these complexes, most are symmetric, composed of identical subunits. Complex formation is the way through which larger structures and even molecular machines are assembled and built in nature. In this work, we apply group theory and carry out a comprehensive study of the global motion patterns of protein complexes of various symmetries. The work presents for the first time a comprehensive list of all the symmetric, aesthetically pleasing, global motion patterns available to complexes of cyclic, dihedral, tetrahedral, or octahedral symmetry. Our results clearly demonstrate that complexes with the same symmetry will have the same global motion patterns and thus may function in a similar way, and that there are only a finite number of global motion patterns available to symmetric complexes as the number of protein symmetry groups is effectively finite. The work complements our current understanding of the principle of complex formation that has been mostly structure-based by providing novel dynamics-based insights. Furthermore, as dynamics is closely tied to function, these motion patterns can provide global insights into the general functional mechanisms of protein complexes. PMID- 28598515 TI - Evidence of direct reciprocity, but not of indirect and generalized reciprocity, in the grooming exchanges of wild Barbary macaques (Macaca sylvanus). AB - Reciprocity is one of the mechanisms that have been proposed to explain the exchange of social behaviors, such as grooming, in animals. Reciprocity assumes that individuals act as the donor and recipient of grooming and switch roles over time to balance the benefits and costs of this behavior. Three main patterns of reciprocity may follow a grooming given: (i) direct reciprocity, where the former recipient returns the grooming to the former donor; (ii) indirect reciprocity, where another individual returns the grooming to the former donor; and (iii) generalized reciprocity, where the former recipient returns the grooming to another individual. While there is evidence that direct reciprocity plays an important role in various species of animals, the role of indirect and generalized reciprocity is less clear and has been rarely analyzed. We tested the role of direct, indirect, and generalized reciprocity in explaining grooming exchanges of wild Barbary macaques, by analyzing the temporal contingency between giving and receiving grooming. We collected the occurrence and latency of the three types of grooming reciprocation during 1 hr long focal sessions run simultaneously on two partners who just stopped grooming (post-grooming session) or who were in proximity (i.e., within 1.5 m) without grooming each other (control session). We ran the analyses on 284 post-grooming and 63 control sessions. The results revealed a temporal contingency of grooming interactions exchanged according to direct reciprocity but not according to indirect or generalized reciprocity. Our results indicate that grooming distribution in Barbary macaques is partner-specific. We discuss the possible role of cognition and emotions in explaining direct reciprocity in animals. PMID- 28598516 TI - Intratumor cisplatin nephrotoxicity in combined laser-induced thermal therapy for cancer treatment. AB - INTRODUCTION: Thermal ablation of tumors by Nd:YAG laser has been growing as a multidisciplinary subspecialty defined as laser-induced thermal therapy (LITT), and has been increasingly accepted as a minimally invasive method for palliation of advanced or recurrent cancer. Previous studies have shown that adjuvant chemotherapy can potentiate laser thermal ablation of tumors leading to improved palliation in advanced cancer patients. OBJECTIVE: Evaluate nephrotoxicity by early markers of renal function in treating head and neck cancer using intra tumor injections of cisplatin combined with laser-induced thermal therapy (CDDP LITT). METHODS: Nine patients with recurrent head and neck tumors were treated by CDDP-LITT in order to determine nephrotoxicity related to this synergistic association. Among the tests requested to detect early were creatinine, magnesium, creatinine clearance, serum urea-BUN, type I urine, and proteinuria at 24 hours. RESULTS: Twelve recurrent tumors in nine patients were treated by CDDP LITT. Pain was the major complaint (four patients), while other symptoms included dysphagia, dyspnea, bleeding, and difficulties in chewing. Fifteen laser procedures were performed and maximal CDDP dose was 50 mg. None of the markers for nephrotoxicity showed changes at these levels of CDDP intra-tumor injections. CONCLUSION: This initial experience with (CDDP-LITT) indicates both safety and therapeutic potential for palliation of advanced head and neck cancer. However, safety and feasibility must be confirmed by longer follow-up and further escalation of CDDP doses in a Phase I study to determine maximum tolerated dose (MTD) and demonstrate tangible benefits for patients. Lasers Surg. Med. 49:756 762, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598517 TI - Impact of episiotomy on the urogenital hiatus using transperineal ultrasound. AB - AIMS: To analyze whether episiotomy affects the urogenital hiatal area and the difference in the hiatus at rest and during contraction, as an indirect measurement of the contractile capacity of the levator ani muscle. METHODS: We performed an observational, comparative, retrospective study of primiparous women who had normal vaginal deliveries. The urogenital hiatal area was compared in women with and without episiotomy. All women underwent transperineal ultrasound scanning after delivery, and all the images were analyzed offline by the principal investigator who was blinded to all clinical data. The urogenital hiatal area was measured at rest and during both Valsalva and contraction manoeuvres. The difference in the hiatus at rest and during contraction was also calculated. These scanning variables were compared between the study groups. RESULTS: In total, 194 women were analysed (101 with, and 93 without, episiotomy). There were no statistically significant differences between the groups regarding the area of the hiatus at rest (P = 0.583), on Valsalva (P = 0.158), and on contraction (P = 0.468), or in the difference in the hiatus at rest and during contraction (P = 0.095). CONCLUSIONS: In normal vaginal delivery, neither the area of the urogenital hiatus nor its difference at rest and during contraction, as measured by ultrasound, were modified by performing an episiotomy. PMID- 28598518 TI - Correction. PMID- 28598520 TI - Xenopus pitx3 target genes lhx1 and xnr5 are identified using a novel three-fluor flow cytometry-based analysis of promoter activation and repression. AB - BACKGROUND: Pitx3 plays a well understood role in directing development of lens, muscle fiber, and dopaminergic neurons; however, in Xenopus laevis, it may also play a role in early gastrulation and somitogenesis. Potential downstream targets of pitx3 possess multiple binding motifs that would not be readily accessible by conventional promoter analysis. RESULTS: We isolated and characterized pitx3 target genes lhx1 and xnr5 using a novel three-fluor flow cytometry tool that was designed to dissect promoters with multiple binding sites for the same transcription factor. This approach was calibrated using a known pitx3 target gene, Tyrosine hydroxylase. CONCLUSIONS: We demonstrate how flow cytometry can be used to detect gene regulatory changes with exquisite precision on a cell-by-cell basis, and establish that in HEK293 cells, pitx3 directly activates lhx1 and represses xnr5. Developmental Dynamics 246:657-669, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598521 TI - Transmission electron microscopy of zebrafish spinal motor nerve roots. AB - BACKGROUND: Spinal motor nerves are essential for relaying information between the central and peripheral nervous systems. Perturbations to cell types that comprise these nerves may impair rapid and efficient transmission of action potentials and alter nerve function. Identifying ultrastructural changes resulting from defects to these cellular components via transmission electron microscopy (TEM) can provide valuable insight into nerve function and disease. However, efficiently locating spinal motor nerves in adult zebrafish for TEM is challenging and time-consuming. Because of this, we developed a protocol that allows us to quickly and precisely locate spinal motor nerve roots in adult zebrafish for TEM processing. RESULTS: Following fixation, a transverse slab of adult zebrafish dissected from the trunk region was mounted in embedding media, sectioned, and secondary fixation with osmium tetroxide performed. Transverse sections containing motor nerves were selected for TEM ultrathin sectioning and imaging. CONCLUSIONS: We developed an efficient protocol for locating spinal motor nerves in adult zebrafish to allow for ultrastructural characterization. Although our work focuses on spinal motor nerves, this protocol may be useful for efficiently identifying other discrete, repeated structures within the developing and mature nervous system that are difficult to find via traditional, whole organism TEM processing. Developmental Dynamics 246:956-962, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598522 TI - The role of energetic reserves during embryonic development of an annual killifish. AB - BACKGROUND: Females can significantly improve their fitness by utilizing a range of maternal effects. Embryos of annual killifish survive the dry season in ephemeral pools encased in dry substrate for several months. Here, we experimentally test the association between energetic provisioning and maternally controlled duration of embryonic development in the African annual killifish Nothobranchius furzeri (Cyprinodontiformes). RESULTS: We found that embryonic energetic reserves do not limit duration of development. However, differences in energetic reserves affect the size at which embryos hatched, with larger yolk size resulting in larger hatchling size. CONCLUSIONS: These findings suggest uncoupling of the two traits examined (i.e., embryonic energetic reserves and development duration) and emphasize the strong buffering role of diapause in the energetic balance of embryonic development in the annual killifish. Developmental Dynamics 246:838-847, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598519 TI - Complexities of gene expression patterns in natural populations of an extremophile fish (Poecilia mexicana, Poeciliidae). AB - Variation in gene expression can provide insights into organismal responses to environmental stress and physiological mechanisms mediating adaptation to habitats with contrasting environmental conditions. We performed an RNA sequencing experiment to quantify gene expression patterns in fish adapted to habitats with different combinations of environmental stressors, including the presence of toxic hydrogen sulphide (H2 S) and the absence of light in caves. We specifically asked how gene expression varies among populations living in different habitats, whether population differences were consistent among organs, and whether there is evidence for shared expression responses in populations exposed to the same stressors. We analysed organ-specific transcriptome-wide data from four ecotypes of Poecilia mexicana (nonsulphidic surface, sulphidic surface, nonsulphidic cave and sulphidic cave). The majority of variation in gene expression was correlated with organ type, and the presence of specific environmental stressors elicited unique expression differences among organs. Shared patterns of gene expression between populations exposed to the same environmental stressors increased with levels of organismal organization (from transcript to gene to physiological pathway). In addition, shared patterns of gene expression were more common between populations from sulphidic than populations from cave habitats, potentially indicating that physiochemical stressors with clear biochemical consequences can constrain the diversity of adaptive solutions that mitigate their adverse effects. Overall, our analyses provided insights into transcriptional variation in a unique system, in which adaptation to H2 S and darkness coincide. Functional annotations of differentially expressed genes provide a springboard for investigating physiological mechanisms putatively underlying adaptation to extreme environments. PMID- 28598523 TI - Mechanistic insight into acrylate metabolism and detoxification in marine dimethylsulfoniopropionate-catabolizing bacteria. AB - Dimethylsulfoniopropionate (DMSP) cleavage, yielding dimethyl sulfide (DMS) and acrylate, provides vital carbon sources to marine bacteria, is a key component of the global sulfur cycle and effects atmospheric chemistry and potentially climate. Acrylate and its metabolite acryloyl-CoA are toxic if allowed to accumulate within cells. Thus, organisms cleaving DMSP require effective systems for both the utilization and detoxification of acrylate. Here, we examine the mechanism of acrylate utilization and detoxification in Roseobacters. We propose propionate-CoA ligase (PrpE) and acryloyl-CoA reductase (AcuI) as the key enzymes involved and through structural and mutagenesis analyses, provide explanations of their catalytic mechanisms. In most cases, DMSP lyases and DMSP demethylases (DmdAs) have low substrate affinities, but AcuIs have very high substrate affinities, suggesting that an effective detoxification system for acylate catabolism exists in DMSP-catabolizing Roseobacters. This study provides insight on acrylate metabolism and detoxification and a possible explanation for the high Km values that have been noted for some DMSP lyases. Since acrylate/acryloyl-CoA is probably produced by other metabolism, and AcuI and PrpE are conserved in many organisms across all domains of life, the detoxification system is likely relevant to many metabolic processes and environments beyond DMSP catabolism. PMID- 28598524 TI - Nicotine Upregulates Coaggregation of Candida albicans and Streptococcus mutans. AB - PURPOSE: Denture stomatitis is a condition of painless inflammation of denture bearing mucosa. Reports indicate that nicotine, the major psychoactive ingredient in tobacco, increases growth of Streptococcus mutans and Candida albicans in denture biofilm. The purpose of this study was to determine the in vitro effects of nicotine on coaggregation of C. albicans with S. mutans. MATERIAL AND METHODS: C. albicans strain ATCC 10231, S. mutans strain UA159 (ATTC 700610), and nicotine dilutions (ranging from 0 to 32 mg/ml) were used for this study. Both microorganisms were grown for 24 hours in dilutions of nicotine (0 to 32 mg/ml) made in tryptic soy broth (TSB) or TSB supplemented with 1% sucrose (TSBS; S. mutans) or yeast peptone dextrose broth (YPD; C. albicans). Suspensions of the nicotine-treated cells were prepared, mixed together and incubated for up to 24 hours to determine if there was an increase in coaggregation of nicotine-treated cells compared to the no nicotine control cells. Qualitative analysis of coaggregation was performed using a visual aggregation assay and light microscopic observation. A spectrophotometric assay was used to provide a quantitative analysis of the coaggregation. RESULTS: The visual aggregation assay indicated a significant increase in coaggregation between C. albicans and S. mutans with increasing incubation time (0 to 24 hours) and nicotine concentrations (0 to 4 mg/ml). Microbial growth in nicotine at 4 mg/ml demonstrated a significant increase in coaggregation after 24 hours of incubation. The numbers of coaggregated S. mutans/C. albicans cells exhibited a significant increase with incubation time and nicotine concentrations when the samples were examined microscopically. More coaggregation of S. mutans and C. albicans was observed with incubation time and increased nicotine compared to the 0 mg/ml nicotine group. There was a noticeable increase of coaggregation when cells were grown in TSBS compared to TSB. Absorbance of nicotine-treated cells (0.25 to 4 mg/ml) exhibited a decrease in values compared to 0 mg/ml at 0 hours of incubation, confirming increased coaggregation. CONCLUSION: These results demonstrated the effect of nicotine in increasing the coaggregation of S. mutans with C. albicans. Coaggregation increased with incubation time and nicotine concentration. Coaggregation was increased with S. mutans grown in TSBS compared to TSB, suggesting that growth in sucrose media leads to an increase in receptors responsible for coaggregation. PMID- 28598525 TI - Retraction: 'An ~400 kDa membrane-associated complex that contains one molecule of the resistance protein Cf-4' by Susana Rivas, Tatiana Mucyn, Harrold A. van den Burg, Jacques Vervoort and Jonathan D. G. Jones. AB - : The above article, published online on 26 March 2002 in Wiley Online Library (wileyonlinelibrary.com), and in Volume 29, pp. 783-796 has been retracted by agreement between the authors, the journal Editor-in-Chief, Christoph Benning, and John Wiley & Sons Ltd. The authors have requested that it be retracted because it contains a substantial number of inappropriate image manipulations. These manipulations consist of the reuse or duplication of images, both within the above article and with another manuscript published previously in The Plant Cell (Rivas et al., 2002b). Specific problems with the manuscripts include: The duplication of immunoblot bands in The Plant Journal Figure 4C and The Plant Cell Figure 3 row 3, The Plant Cell Figure 4A row 1, The Plant Cell Figure 4C. The Plant Journal Figure 4B Cf-9 c-myc band is duplicated in The Plant Journal Figure 4C Cf-9:TAP band under the 475 kDa marker. The first four lanes of Figure 4A row 3 in The Plant Journal are a duplication of lanes 23, 24, 25, and 26 in Figure 4A row 2 in The Plant Cell. The Plant Journal Figure 7B lanes 1&2 and lanes 4&5 are duplicates of each other and are duplicated from Figure 7B lanes 1 and 2 in The Plant Cell. The Plant Journal Figure 7C is a duplication from Figure 7C in The Plant Cell. REFERENCES: Rivas, S., Mucyn, T., van den Burg, H.A., Vervoort, J. and Jones, J.D.G. (2002a) An ~400 kDa membrane-associated complex that contains one molecule of the resistance protein Cf-4. Plant J. 29, 783-796. https://doi.org/10.1046/j.1365-313X.2002.01254.x. Rivas, S., Romeis, T. and Jones, J.D.G. (2002b) The Cf-9 disease resistance protein is present in an ~420 Kilodalton heteromultimeric membrane-associated complex at one molecule per complex. Plant Cell, 14, 689-702. https://doi.org/10.1105/tpc.010357. PMID- 28598526 TI - Aspects of Malpractice in Prosthodontics. AB - Crowns, fixed partial dentures, and removable dentures are the popular prosthetic dental restorations in current dental practice. Prosthodontic rehabilitation of the mouth, particularly in advanced and complex cases, requires careful planning, adequate clinical skills, and exacting technical standards. While a successful outcome is the ultimate goal for any prosthodontic treatment, complications, injuries, dissatisfaction, and/or failure may occur. When such events develop as a result of negligence or violation of standards of care, they are considered under the term of malpractice and may incur ethical and medico-legal implications. This paper reviews and highlights some aspects of malpractice in prosthodontics. The current state of prosthodontic malpractice on a global level will also be evaluated. Standards of prosthodontic care, current literature of prosthodontic malpractice, where and how prosthodontic malpractice occurs, and recommendations for the future are presented. A thorough understanding of what is quality prosthodontic care and what disrupts this care can be a useful guard against professional litigation and may protect patients from poor quality of dental prosthetic care. PMID- 28598527 TI - Energy Transfer between Spatially Separated Entangled Molecules. AB - Light-matter strong coupling allows for the possibility of entangling the wave functions of different molecules through the light field. We hereby present direct evidence of non-radiative energy transfer well beyond the Forster limit for spatially separated donor and acceptor cyanine dyes strongly coupled to a cavity. The transient dynamics and the static spectra show an energy transfer efficiency approaching 37 % for donor-acceptor distances >=100 nm. In such systems, the energy transfer process becomes independent of distance as long as the coupling strength is maintained. This is consistent with the entangled and delocalized nature of the polaritonic states. PMID- 28598528 TI - Use of radar detectors to track attendance of albatrosses at fishing vessels. AB - Despite international waters covering over 60% of the world's oceans, understanding of how fisheries in these regions shape ecosystem processes is surprisingly poor. Seabirds forage at fishing vessels, which has potentially deleterious effects for their population, but the extent of overlap and behavior in relation to ships is poorly known. Using novel biologging devices, which detect radar emissions and record the position of boats and seabirds, we measured the true extent of the overlap between seabirds and fishing vessels and generated estimates of the intensity of fishing and distribution of vessels in international waters. During breeding, wandering albatrosses (Diomedea exulans) from the Crozet Islands patrolled an area of over 10 million km2 at distances up to 2500 km from the colony. Up to 79.5% of loggers attached to birds detected vessels. The extent of overlap between albatrosses and fisheries has widespread implications for bycatch risk in seabirds and reveals the areas of intense fishing throughout the ocean. We suggest that seabirds equipped with radar detectors are excellent monitors of the presence of vessels in the Southern Ocean and offer a new way to monitor the presence of illegal fisheries and to better understand the impact of fisheries on seabirds. PMID- 28598529 TI - Association of a reactive intermediate derived from 1',6-dihydroxy metabolite with benzbromarone-induced hepatotoxicity. AB - Treatment with benzbromarone can be associated with liver injury, but the detailed mechanism remains unknown. Our recent studies demonstrated that benzbromarone was metabolized to 1',6-dihydroxybenzbromarone and followed by formation of reactive intermediates that were trapped by glutathione, suggesting that the reactive intermediates may be responsible for the liver injury. The aim of this study was to clarify whether the reactive intermediates derived from 1',6 dihydroxybenzbromarone is a risk factor of liver injury in mice. An incubation study using mouse liver microsomes showed that the rates of formation of 1',6 dihydroxybenzbromarone from benzbromarone were increased by pretreatment with dexamethasone. Levels of a hepatic glutathione adduct derived from 1',6 dihydroxybenzbromarone were increased by pretreatment with dexamethasone. Furthermore, plasma alanine amino transferase activities were increased in mice treated with benzbromarone after pretreatment with dexamethasone. The results suggest that the reactive intermediate derived from 1',6-dihydroxybenzbromarone may be associated with liver injury. PMID- 28598530 TI - The Effect of Temporary Cement Cleaning Methods on the Retention of Crowns. AB - PURPOSE: To evaluate the effect of temporary cement cleaning methods on the retention of cemented crowns using zinc phosphate cement and resin-modified glass ionomer cement. MATERIALS AND METHODS: Forty titanium specimens were fabricated to simulate prepared molars with minimally retentive taper. The Ni-Cr cast crowns were fabricated, temporarily cemented, and separated. The specimens were divided into four groups according to the temporary cement cleaning method (n = 10) as follows: control group (no temporary cementation), orange solvent group, ultrasonic cleaning group, and air-abrasion group. After the cleaning procedures, the specimens were cemented with definitive cements (zinc phosphate cement and resin-modified glass ionomer, RMGI, cement) and subjected to thermocycling (5000 cycles, 5-55 degrees C, dwell time, 10 seconds). The tensile bond strength of each specimen was measured using a universal testing machine, and the results were analyzed using the Kruskal-Wallis and Mann-Whitney U test (alpha = 0.05). RESULTS: When cemented with zinc phosphate cement, the statistical analysis showed that the value of the air-abrasion group was significantly higher than those of the other groups (p < 0.01). There was no statistically significant difference among the other groups. When cemented with RMGI cement, the air abrasion group showed the lowest value, and the control group showed the highest value (p < 0.01). The difference between the ultrasonic cleaning group and the orange solvent group was not statistically significant. CONCLUSION: The use of temporary cement did not have a significant influence on retention of permanently cemented crowns when zinc phosphate cement was used for permanent cementation. Airborne-particle abrasion after provisional cementation improved retention of crowns cemented with zinc phosphate cement; however, the use of temporary cement significantly decreased retention of permanently cemented crowns when RMGI cement was used regardless of the temporary cement cleaning method. PMID- 28598532 TI - PTR-MS volatile profiling of Pinot Noir wines for the investigation of differences based on vineyard site. AB - This study investigated the effect of vineyard site on the volatile profiles of Pinot Noir wines using proton-transfer reaction mass spectrometry with prior headspace dilution. The ANOVA and PCA enabled discrimination of wine based on vineyard site. Sample separation was due to differences in the ratios of a mixture of compounds, including higher alcohols, ethyl, and acetate esters. Proton-transfer reaction mass spectrometry appears to be a useful technique for rapidly discriminating wines based on vineyard site. The similarities and differences expressed in the wines' volatile profiles may help winemakers to reveal the potential of individual vineyard sites to produce wines of certain character. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 28598531 TI - Thermally Stable and Regenerable Platinum-Tin Clusters for Propane Dehydrogenation Prepared by Atom Trapping on Ceria. AB - Ceria (CeO2 ) supports are unique in their ability to trap ionic platinum (Pt), providing exceptional stability for isolated single atoms of Pt. The reactivity and stability of single-atom Pt species was explored for the industrially important light alkane dehydrogenation reaction. The single-atom Pt/CeO2 catalysts are stable during propane dehydrogenation, but are not selective for propylene. DFT calculations show strong adsorption of the olefin produced, leading to further unwanted reactions. In contrast, when tin (Sn) is added to CeO2 , the single-atom Pt catalyst undergoes an activation phase where it transforms into Pt-Sn clusters under reaction conditions. Formation of small Pt Sn clusters allows the catalyst to achieve high selectivity towards propylene because of facile desorption of the product. The CeO2 -supported Pt-Sn clusters are very stable, even during extended reaction at 680 degrees C. Coke formation is almost completely suppressed by adding water vapor to the feed. Furthermore, upon oxidation the Pt-Sn clusters readily revert to the atomically dispersed species on CeO2 , making Pt-Sn/CeO2 a fully regenerable catalyst. PMID- 28598533 TI - Prevalence of trachomatous trichiasis in Australia: the National Eye Health Survey. AB - IMPORTANCE: Australia is the only developed country to still have pockets of endemic trachoma. The research provides up-to-date, population-based prevalence data of later complications of trachoma amongst a national sample of Indigenous adults. BACKGROUND: To report the prevalence of trachomatous trichiasis (TT) in Indigenous Australians aged 40 years and older. DESIGN: Population-based cross sectional study. PARTICIPANTS: A total of 1738 (41% male) Indigenous Australians aged 40 years or older, living amongst 30 randomly selected Australian sites, stratified by remoteness. METHODS: Anterior segment examination was performed and trachoma grading for the presence of TT and corneal opacification (CO) was conducted using the WHO (WHO) simplified grading system. MAIN OUTCOME MEASURES: Prevalence of TT. RESULTS: A total of three (0.17%) participants had TT, and there were no confirmed cases of trachomatous CO in the NEHS. All three participants with TT were female and aged 40 years or older. Although they had likely spent their childhoods in more remote areas, two of the three confirmed cases resided in an urban and outer regional area at the time of their examinations. CONCLUSIONS AND RELEVANCE: Our data are in line with ongoing national trachoma surveillance reports that suggest the prevalence of late sequences of trachoma appear to be decreasing in Australia. PMID- 28598534 TI - "Very much in love": The letters of Magda Arnold and Father John Gasson. AB - Magda Arnold (1903-2002), best known for her pioneering appraisal theory of emotion, belonged to the second generation of women in psychology who frequently experienced institutional sexism and career barriers. Following her religious conversion, Arnold had to contend with the additional challenge of being an openly Catholic woman in psychology at a time when Catholic academics were stigmatized. This paper announces the discovery of and relies upon a number of previously unknown primary sources on Magda Arnold, including approximately 150 letters exchanged by Arnold and Father John Gasson. This correspondence illuminates both the development of Arnold's thought and her navigation of the career challenges posed by her conversion. I argue that Gasson's emotional and intellectual support be considered as resources that helped Arnold succeed despite the discrimination she experienced. Given the romantic content of the correspondence, I also consider Arnold and Gasson in the context of other academic couples in psychology in this period and argue that religious belief ought to be further explored as a potential contributor to the resilience of women in psychology's history. PMID- 28598535 TI - Functional Impairment and Risk of Venous Thrombosis in Older Adults. AB - OBJECTIVES: To determine the role of age-specific risk factors for thrombosis in older age, such as functional impairment. DESIGN: Case-control study. SETTING: The Age and Thrombosis-Acquired and Genetic risk factors in the Elderly Study, a two-center study conducted in the Netherlands and the United States from 2008 to 2011. PARTICIPANTS: Individuals aged 70 and older with a first-time deep venous thrombosis in the leg or pulmonary embolism (n = 401) and controls aged 70 and older (n = 431) without a history of thrombosis. Exclusion criteria were active malignancy and severe cognitive disorders. MEASUREMENTS: The thrombotic risk associated with functional impairment, defined as impairment in two or more activities of daily living (ADLs), impaired mobility (inability to walk outside), sedentary lifestyle (>=20 h/d sleeping or sitting), and low handgrip strength (<15th percentile), was assessed. Odds ratios (ORs) adjusted for age, sex, and study center with 95% confidence intervals (95% CI) and population attributable risks (PAR) were calculated. RESULTS: Risk of venous thrombosis was 2.9 times greater (OR = 2.9, 95% CI = 1.6-5.3) in individuals with impairment in ADLs, three times as great (OR = 3.0, 95% CI = 1.9-4.7) in those with impaired mobility, four times as great (OR = 4.0, 95% CI = 2.5-6.3) in those with a sedentary life style, and 2.3 times as great (OR = 2.3, 95% CI = 1.5-3.4) in those with weak handgrip strength. PARs were 8% for ADL disability, 13% for inability to walk outside for 15 minutes, 29% for sedentary lifestyle, and 13% for weak hand grip strength. CONCLUSION: In individuals aged 70 and older, functional impairments are a major risk factor for venous thrombosis. These findings may help providers caring for older people be more aware of venous thrombosis risk. PMID- 28598536 TI - Characteristics and outcome in patients with central nervous system involvement treated in European pediatric acute myeloid leukemia study groups. AB - BACKGROUND: There is no consensus on the treatment for pediatric patients with acute myeloid leukemia and initial central nervous system (CNS) involvement. METHODS: To evaluate different CNS-directed treatment options (intrathecal [IT] therapy, CNS irradiation, hematopoietic stem cell transplantation [HSCT]), 261 patients (excluding acute promyelocytic leukemia) with initial CNS involvement treated in trials with similar intensive chemotherapy by four cooperative European study groups (1998-2013) were studied and compared with CNS-negative patients from the Berlin-Frankfurt-Munster group. RESULTS: Patient characteristics in the different study groups were comparable. Young age, high white blood cell count, extramedullary involvement other than the CNS, monoblastic morphology, and inv(16) were associated with CNS involvement (each P < 0.0001). There were no major differences in outcome between the study groups. The cumulative incidence of relapse (CIR) regarding the CNS was higher in initially CNS-positive versus initially CNS-negative patients (all: 8 +/- 2% vs. 3 +/- 1%, P(Gray) = 0.001; isolated: 4 +/- 1% vs. 1 +/- 0%, P(Gray) = 0.03). However, global outcome of the CNS-positive cohort (overall survival, 64 +/- 3%; event-free survival 48 +/- 3%; and CIR 33% +/- 3%) did not differ significantly from CNS-negative patients. Risk groups defined by cytogenetics were of likewise prognostic significance in CNS-positive and -negative patients. CNS treatment with cranial irradiation was not superior compared to IT therapy and systemic chemotherapy (+/- HSCT). CONCLUSION: Although CNS relapses occurred more frequently in initially CNS-positive patients, their global outcome was similar as in CNS-negative patients. Intensified IT therapy was heterogeneous; however, at least eight applications, preferably with triple IT chemotherapy, seem to be appropriate to accompany dose-intensive systemic chemotherapy. PMID- 28598537 TI - Factors possibly affecting prognosis in children with Wilms' tumor diagnosed before 24 months of age: A report from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) Wilms Tumor Working Group. AB - BACKGROUND: Children with Wilms' tumor (WT) aged under 24 months (infants) have a better prognosis than older patients. Our aim was to study the epidemiology of this age group, with focus on the modality of diagnosis, tumor size, and association with malformations/syndromes, seeking to understand if any of these factors might be related to prognosis. PATIENTS AND METHODS: Infants diagnosed with WT between 2003 and February 2010 were evaluated. A query form was used to collect data on the modality of WT diagnosis (symptomatic or incidental), tumor volume, maximum diameter, site, and stage. RESULTS: Data were collected for 117 of 124 WT infants registered. Twenty-four cases had an incidental diagnosis (ID) of renal mass, usually arising from an abdominal ultrasound performed for other reasons, and 93 had been diagnosed based on clinical signs/symptoms. The incidental cohort displayed unifocal disease, mean tumor diameter 5.52 cm, mean tumor volume 84.30 ml, and 14 patients showed associated malformations. Symptomatic patients had mean maximum tumor diameter of 10.18 cm, mean tumor volume of 451.18 ml, and six had associated malformations. CONCLUSIONS: Our study showed that 20% of the infants had an ID of WT; they had a relatively smaller nonmetastatic tumor and a higher rate of malformations than infants of the symptomatically diagnosed group, but we did not detect any difference in age at diagnosis between the two groups. Conversely, we found a significant difference in the 5-year event-free survival rate (P = 0.018) between infants under 1 year (96%), more frequently associated with congenital malformations, and infants 1-2 years (80%). PMID- 28598538 TI - Expression of the double-stranded RNA of the soybean pod borer Leguminivora glycinivorella (Lepidoptera: Tortricidae) ribosomal protein P0 gene enhances the resistance of transgenic soybean plants. AB - BACKGROUND: The soybean pod borer [SPB; Leguminivora glycinivorella (Matsumura) (Lepidoptera: Tortricidae)] is the most important soybean pest in northeastern Asia. Silencing genes using plant-mediated RNA-interference is a promising strategy for controlling SPB infestations. The ribosomal protein P0 is important for protein translation and DNA repair in the SPB. Thus, transferring P0 double stranded RNA (dsRNA) into plants may help prevent SPB-induced damage. RESULTS: We investigated the effects of SpbP0 dsRNA injections and SpbP0 dsRNA-expressing transgenic soybean plants on the SPB. Larval mortality rates were greater for SpbP0 dsRNA-injected larvae (96%) than for the control larvae (31%) at 14 days after injections. Transgenic T2 soybean plants expressing SpbP0 dsRNA sustained less damage from SPB larvae than control plants. In addition, the expression level of the SpbP0 gene decreased and the mortality rate increased when SPB larvae were fed on T3 transgenic soybean pods. Moreover, the surviving larvae were deformed and exhibited inhibited growth. CONCLUSION: Silencing SpbP0 expression is lethal to the SPB. Transgenic soybean plants expressing SpbP0 dsRNA are more resistant to the SPB than wild-type plants. Thus, SpbP0 dsRNA-expressing transgenic plants may be useful for controlling insect pests. (c) 2017 Society of Chemical Industry. PMID- 28598539 TI - Feasibility and safety of home exercise training in children with sickle cell anemia. AB - Exercise guidelines do not exist for individuals with sickle cell anemia (SCA) despite the impact of disease-related complications on physical functioning. Thirteen subjects (mean 15.1 +/- 2.8 years old) with SCA were prescribed three exercise sessions/week for 12 weeks on a stationary bicycle placed at home. In total, 77% of subjects completed 89% of prescribed sessions without exercise related adverse events, thus meeting feasibility and safety criteria. Adherence to prescribed duration and target heart rate during training decreased during the second half of the study. Future trials are warranted to further evaluate training benefits associated with regular exercise in children with SCA. PMID- 28598540 TI - Effects of 4 Probiotic Strains in Coculture with Traditional Starters on the Flavor Profile of Yogurt. AB - To study the influence of probiotics on the flavor profile of yogurt, 4 probiotics, including Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus rhamnosus, and Lactobacillus casei, were cofermented with traditional starters. The changes of bacterial growth, acid contents and volatile compounds of yogurt were investigated during fermentation and refrigerated storage. The strains that exhibited a low growth rate in milk did not significantly affect the bacterial population dynamics, acidity, or organic acid content during fermentation and storage. However, high viability and enhancement of postacidification were clearly observed in the samples that contained strains with a high growth rate in milk, particularly L. casei. A total of 45 volatile compounds, detected in most samples, were identified by headspace solid-phase micro-extraction followed by gas chromatography-mass spectrometry. Among these compounds, ketones and aldehydes were the most abundant. The presence of either L. rhamnosus or L. plantarum did not significantly affect the major volatile compounds, while contributions of L. casei and L. acidophilus were found in the formation of minor volatile metabolites. Electronic nose measurements exhibited a good discrimination of samples that contained different probiotics during refrigerated storage. PMID- 28598541 TI - The time-dependent "cure-death" model investigating two equally important endpoints simultaneously in trials treating high-risk patients with resistant pathogens. AB - A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure-death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient-relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank-based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo-value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure-death model provides a suitable framework to gain a better understanding of how a new treatment influences the time-dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses. PMID- 28598542 TI - Overexpression of minichromosome maintenance protein 10 in medulloblastoma and its clinical implications. AB - BACKGROUND: Overexpression of minichromosome maintenance (MCM) proteins 2, 3, and 7 is associated with migration and invasion in medulloblastoma (MB). However, expression profiling of all prereplication complex (pre-RC) has not been addressed in MBs. PROCEDURE: We performed mRNA expression profiling of a large set of pre-RC elements in cell lines and tumor tissues of MB. RNAi technology was employed for functional studies in MB cell lines. RESULTS: Our data showed that most of the pre-RC components are significantly overexpressed in MB. Among all pre-RC mRNAs, MCM10 showed the highest level of expression (~500- to 1,000-fold) in MB cell lines and tissues compared to the levels detected in cerebellum. In addition, RNAi silencing of MCM10 caused reduced cell proliferation and cell viability in MB cells. CONCLUSIONS: Taken together, our study reveals that the pre-RC is dysregulated in MB. In addition, MCM10, a member of this complex, is significantly overexpressed in MB and is required for tumor cell proliferation. PMID- 28598543 TI - Mutation in a novel gene SMALL AND CORDATE LEAF 1 affects leaf morphology in cucumber. AB - Plant species exhibit substantial variation in leaf morphology. We isolated a recessive mutant gene termed small and cordate leaf 1 (scl1) that causes alteration in both leaf size and shape of cucumber. Compared to wild type leaves, the scl1 mutant had fewer numbers of epidermal pavement cells. A single nucleotide polymorphism was associated with this leaf phenotype, which occurred in a putative nucleoside bisphosphate phosphatase. RNA-seq analysis of the wild type and scl1 mutant leaves suggested that SCL1 regulation may not involve known hormonal pathways. Our work identified a candidate gene for SCL1 that may play a role in leaf development. PMID- 28598544 TI - Dermatological manifestations of tuberous sclerosis complex (TSC). AB - Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement that frequently occurs in early childhood. Dermatologic manifestations include facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas. The International TSC Consensus Conference in 2012 provided guidelines for standardized baseline evaluation and follow-up. Detailed clinical dermatological evaluation at the time of diagnosis and annual skin examination is recommended for both pediatric and adult populations. The onset of dermatological manifestations is clearly age related. However, dermatologists also have to assess for clinical manifestations beyond their own specialty. With advances in genetics and the advent of mTORC1 inhibitors, new specific therapeutic options have become available for TSC patients with skin manifestations. Early intervention is commonly recommended for symptomatic, rapidly evolving, disfiguring, or debilitating lesions. The consensus guidelines recommend "treatment as appropriate for the lesion and clinical context" and suggest the use of surgical excision, laser therapy, or topical mTORC1 inhibitors. Topical mTORC1 inhibitors present a useful option for TSC-associated skin lesions, particularly in medically complex patients. They may prevent or reduce the risks of subsequent surgeries and permanent scarring. PMID- 28598546 TI - Helping children with growth failure due to tyrosine kinase inhibitor drugs requires knowledge of the pathogenesis of the problem. PMID- 28598547 TI - Rituximab in the treatment of recalcitrant generalized lupus erythematosus tumidus. PMID- 28598545 TI - Analysis of common cytogenetic abnormalities in New Zealand pediatric ALL shows ethnically diverse carriage of ETV6-RUNX1, without a corresponding difference in survival. AB - BACKGROUND: The frequency of common cytogenetic abnormalities in pediatric acute lymphoblastic leukemia (ALL) is known to vary by geographic location and ethnic origin. This study aimed to determine the frequency of hypodiploidy, ETV6-RUNX1, BCR-ABL1, and MLL rearrangement within New Zealand's pediatric ALL population and to assess whether the frequency of these ALL prognostic markers varies according to ethnicity. PROCEDURE: The New Zealand Children's Cancer Registry provided information for all registered pediatric ALL patients that were diagnosed between 2000 and 2009, with medical records available for 246 patients. Each patient's medical record was reviewed to determine the frequency of hypodiploidy, ETV6 RUNX1, BCR-ABL1, MLL rearrangement, and cell lineage. Chi-square tests for independence were undertaken to compare the frequencies of cytogenetic abnormalities according to prioritized ethnicity. RESULTS: The frequency of cytogenetic ALL abnormalities in the New Zealand pediatric population were consistent with international reference values. A low frequency of ETV6-RUNX1 was evident for Maori pediatric ALL patients (5.4%, P = 0.018), when compared to Pacific peoples (21.1%) and non-Maori/non-Pacific peoples (27.4%). This has not impacted on outcome, however, with equivalent 5-year overall survival being observed in Maori (89.4%) compared to Pacific peoples (92.0%) and non-Maori/non Pacific peoples (90.2%). CONCLUSIONS: A lower frequency of the favorable prognostic marker ETV6-RUNX1 was observed in Maori pediatric ALL patients. This did not translate into poorer survival. Future research into biological and nonbiological prognostic factors in this patient population may assist in explaining this finding. PMID- 28598548 TI - Eating behavior during dexamethasone treatment in children with acute lymphoblastic leukemia. AB - BACKGROUND AND AIM: Large prospective studies on dexamethasone-induced changes in eating behavior, energy, and nutrient intake are lacking in pediatric acute lymphoblastic leukemia (ALL). We prospectively studied eating behavior, energy, nutrient intake, and the effect on leptin and adiponectin levels during dexamethasone administration in children with ALL. PATIENTS: Parents of patients with ALL (3-16 years) completed a dietary diary for their child during 4 days of dexamethasone (6 mg/m2 ) administration. Energy intake and nutrient intake (energy percentage = E%) were assessed and compared with the recommended intake. The Dutch Eating Behavior Questionnaire for Children was completed before start and after 4 days of dexamethasone administration by patients of 7-12 years of age. Fasting leptin and adiponectin levels were also measured before start and after 4 days of dexamethasone administration. RESULTS: Energy intake per day(kcal) (N = 44) increased significantly during dexamethasone (median day 1: 1,103 (717-1,572) versus day 4: 1,482 (1,176-1,822), P < 0.01), including an increase in total protein, fat, saturated fat, carbohydrate, and sodium intake. Intake of saturated fat (median day 4: 12 E%) and salt (median day 4: 1.9 g/day) exceeded the healthy range for age and gender. With respect to eating behavior, dexamethasone significantly decreased restrained eating (P = 0.04). Leptin levels as well as adiponectin levels increased significantly during the dexamethasone course. CONCLUSIONS: Four days of dexamethasone treatment significantly increased energy intake, including excessive saturated fat and salt intake, and changed eating behavior in children with ALL. Nutritional and behavioral interventions during dexamethasone treatment are recommended to stimulate a healthy lifestyle. PMID- 28598549 TI - The presence of minocycline in the tear film of normal horses following oral administration and its anticollagenase activity. AB - PURPOSE: Tetracyclines have activity against matrix metalloproteinases (MMP). Oral medications with effects on the ocular surface are of interest in patients where repeated topical dosing is limited. The aim of this study was to characterize the concentration of minocycline in the tears of normal horses after oral administration and to determine if this level directly inhibits MMP activity. METHODS: Five healthy adult ponies were administered oral minocycline (Wedgewood Pharmacy; Swedesboro, NJ) at 4 mg/kg every 12 h for 5 days. Tears were collected at T = 2, 26, 50, 56, 74, 80, and 98 h. Tear minocycline concentrations were analyzed using high performance liquid chromatography. The inhibition of recombinant human MMP-2 and MMP-9 by minocycline was investigated using fluorescence resonance energy transfer. RESULTS: Minocycline was present in the tears of each pony at every measurement but with interpony variability. A mean concentration of 11.8 MUg/mL was present 2 h after administration of the first dose. Minocycline did not directly inhibit MMP-2 or MMP-9 function at a concentration achieved in the pony tear film. CONCLUSIONS: Minocycline was present in the tears of all ponies at each sampling point following oral administration. One pony of the five had consistently lower levels of minocycline secretion (P <= 0.05). The concentration secreted in the tears did not directly inhibit MMP-2 or MMP-9 when tested in vitro. The inconsistencies in the tear concentration and the inhibition activity suggest topical application may be necessary to attain direct inhibition of MMP with minocycline. PMID- 28598551 TI - Coronary artery bypass grafting in infants, children, and young adults for acquired and congenital lesions. AB - Coronary artery disease ranges from congenital in origin such as anomalous aortic origin of a coronary artery (AAOCA) to acquired diseases such as Kawasaki disease, and previously repaired conditions such as transposition of the great arteries. It is not uncommon, in the long run, for proximal coronary stenosis to develop following arterial switch, AAOCA repair, Ross procedure and Kawasaki disease leading to coronary artery bypass grafing (CABG). The objective of this report is to discuss the indications, challenges, and outcomes of CABG in infants, children, and young adults with acquired and congenital lesions. PMID- 28598552 TI - Acrolein Scavenger Hydralazine Prevents Streptozotocin-Induced Painful Diabetic Neuropathy and Spinal Neuroinflammation in Rats. AB - Diabetes-induced neuropathic pain (DNP) substantially influences people's life qualities. Hyperglycemia-induced excess free radicals have been considered as the most critical mechanisms underlying DNP. As an unsaturated aldehyde and a reactive product of lipid peroxidation, acrolein plays critical roles in diabetic nephropathy and inflammatory pain. We sought to determine whether acrolein is involved in DNP in this study. Diabetes was induced by a single intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin (STZ). An acrolein scavenger hydralazine (5 mg/kg) was administered through a daily injection for 4 weeks, starting immediately within 30 min after STZ injection. Western blot showed that hydralazine could effectively inhibit STZ-induced upregulation of acrolein in the spinal dorsal horn on day 7-28 after STZ injection. Behavioral tests showed that STZ injection induced significant mechanical allodynia and thermal hyperalgesia, which could be alleviated by hydralazine. Immunofluorescent histochemistry and Western blot showed that STZ induced significant microglial activation. ELISA data indicated upregulation of inflammatory cytokines IL-1beta and TNF-alpha expression in the spinal dorsal horn. Furthermore, hydralazine effectively attenuated microglial activation and expression of inflammatory mediators. Our data indicate that acrolein might be involved in the development of neuroinflammation and behavioral consequences of DNP. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1858-1864, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598550 TI - Sexual Orientation Disparities in Mistimed and Unwanted Pregnancy Among Adult Women. AB - CONTEXT: Many sexual minority women, regardless of sexual identity, engage in heterosexual behavior across the life course, which provides them opportunities to experience an unintended pregnancy. In addition, sexual minority women are more likely than others to report characteristics that may make them vulnerable to unintended pregnancy. Little research, however, has examined whether the risk of unintended pregnancy is elevated among these women. METHODS: Using data from the 2006-2010 National Survey of Family Growth, logistic regression models were fitted to examine sexual orientation disparities in mistimed and unwanted pregnancies among 9,807 women aged 20-45; mixed-effects hazard models assessed disparities in the intention status of 5,238 pregnancies among these women by maternal sexual orientation. RESULTS: Compared with heterosexual women reporting only male partners, heterosexual women who have sex with women had higher odds of reporting a mistimed pregnancy (odds ratio, 1.4), and bisexual women had higher odds of reporting an unwanted pregnancy (1.8). When compared with pregnancies reported by heterosexual women with only male partners, those reported by heterosexual women who have sex with women were more likely to be mistimed (hazard ratio, 1.7), and those reported by bisexual and lesbian women were more likely to be unwanted (1.7-4.4). CONCLUSIONS: Compared with heterosexuals who have sex with men only, adult sexual minority women are at equal or greater risk of reporting an unintended pregnancy. More research addressing the reproductive health care needs of sexual minority women is needed to develop strategies to improve family planning for this population. PMID- 28598553 TI - The Effectiveness of a Large-Scale Language and Preliteracy Intervention: The SPELL Randomized Controlled Trial in Denmark. AB - The present article reports results of a real-world effectiveness trial conducted in Denmark with six thousand four hundred eighty-three 3- to 6-year-olds designed to improve children's language and preliteracy skills. Children in 144 child cares were assigned to a control condition or one of three planned variations of a 20-week storybook-based intervention: a base intervention and two enhanced versions featuring extended professional development for educators or a home based program for parents. Pre- to posttest comparisons revealed a significant impact of all three interventions for preliteracy skills (= .21-.27) but not language skills (d = .04-.16), with little differentiation among the three variations. Fidelity, indexed by number of lessons delivered, was a significant predictor of most outcomes. Implications for real-world research and practice are considered. PMID- 28598554 TI - Reproductive hormones and metabolic syndrome in 24 testicular cancer survivors and their biological brothers. AB - Testicular cancer survivors have impaired gonadal function and increased risk of metabolic syndrome when compared to healthy controls. However, because of the fetal etiology of testicular cancer, familial unrelated healthy men might not be an optimal control group. The objective of this study was to clarify if testicular cancer survivors have impaired gonadal function and increased risk of metabolic syndrome when compared to their biological brothers. A cross-sectional study of testicular cancer survivors (ClinicalTrials.gov number, NCT02240966) was conducted between 2014 and 2016. Of 158 testicular cancer survivors included, 24 had a biological brother who accepted to participate in the study. Serum levels of reproductive hormones and prevalence of metabolic syndrome according to International Diabetes Federation Criteria and National Cholesterol Education Program (Adult Treatment Panel III) criteria comprised the main outcome measures of the study. Median age was similar in testicular cancer survivors and their biological brothers [44 years (IQR 39-50) vs. 46 (40-53) years respectively (p = 0.1)]. In testicular cancer survivors, follow-up since treatment was 12 years (7 19). Serum levels of luteinizing hormone and follicle-stimulating hormone were elevated (p <= 0.001), while total testosterone, free testosterone, inhibin B and anti-Mullerian hormone were lower (p <= 0.001) in testicular cancer survivors than in their biological brothers. The prevalence of metabolic syndrome was similar and apart from HDL-cholesterol, which was lower in testicular cancer survivors (p = 0.01); there were no differences in the individual components of the metabolic syndrome between testicular cancer survivors and their brothers. In conclusion, gonadal function was impaired in testicular cancer survivors, while we did not detect any difference in the prevalence of metabolic syndrome between testicular cancer survivors and their biological brothers. PMID- 28598555 TI - Experimental and numerical investigation on the transient vascular thermal response to multi-pulse Nd:YAG laser. AB - BACKGROUND AND OBJECTIVE: Port wine stains (PWS) are congenital vascular malformations that progressively darken and thicken with age. Laser therapy is currently the most effective way in clinical practice for PWS. A 1,064 nm Nd:YAG laser in the near-infrared band can achieve a deeper treatment depth compared to the current widely adopted pulsed dye laser. However, because of its relatively weak absorption by blood, single-pulse Nd:YAG laser requires high energy density to cause effective vessel damage, but may inflict undesirable burning to surrounding collagen. Multi-pulse laser has great potential in clinical treatment because it needs less energy density for each pulse. This paper presented an experimental and theoretical study of the transient thermal effects of low-energy multi-pulse Nd:YAG laser on blood vessels. STUDY DESIGN/MATERIALS AND METHODS: In vivo experiments were performed on dorsal skin chamber. By using a high speed camera (up to 2,000 fps), the complete and dynamic thermal response of blood vessels during laser irradiation and between pulse intervals was obtained. In vitro experiment in capillary tubes and Numerical simulations by two-scale heat transfer model were also conducted to further explore the in vivo experimental findings. RESULTS: The complete and dynamic response of blood vessels were obtained, including vessel dilation, thrombus formation, partial vessel constriction, thread-like constriction, cavitation and bubbles, and hemorrhage. Thread-like constriction is the desirable treatment end point, which will only occur after thrombus completely occludes the vessel lumen. Cavitation can cause hemorrhage when thrombus fails to occlude the vessel lumen. In vitro experiment found that vessel constriction was due to the constriction of thrombus induced by laser irradiation. Theoretical investigation revealed that the mechanism for the effective reduction of energy density by multi-pulse Nd:YAG laser was due to enhanced light absorption of the blood with thrombus formation. CONCLUSIONS: For multi-pulse treatment, laser parameters are recommended as repetition rate of 10 Hz and pulse number of 10. The incident energy in each pulse should be strong enough to induce blood coagulation through seven or eight pulses and should be lower than the threshold of blood cavitation. Lasers Surg. Med. 49:852-865, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598556 TI - Can preoperative detrusor underactivity influence surgical outcomes of 120 W HPS vaporization of the prostate (PVP) or holmium laser enucleation of the prostate (HoLEP)? A serial 3-year follow-up study. AB - AIMS: To determine the influence of preoperative detrusor underactivity (DU) on serial long-term outcomes of HPS/PVP or HoLEP for LUTS/BPH, and to compare the influence between the two surgeries. METHODS: A total of 382 men, who underwent 120W-HPS/PVP or HoLEP for LUTS/BPH and for whom 36-month follow-up data were available, were classified into four groups: HPS with DU (n = 145), HPS without DU (n = 44), HoLEP with DU (n = 105), and HoLEP without DU (n = 88). DU was defined as bladder contractility index of <100. Surgical outcomes were assessed at postoperative 6, 12, 24, and 36 months using IPSS, uroflowmetry, and serum PSA. RESULTS: All four groups maintained improvements in voiding symptom score (VSS), storage symptom score, total-IPSS, QOL index, maximum flow rate (Qmax), post-void residual urine volume (PVR), and bladder voiding efficiency (BVE) compared with baseline up to 3 years postoperatively. There were no significant differences in improvements of postoperative IPSS parameters including QOL index between men with and without DU throughout the follow-up period after HPS or HoLEP. In men with DU, there were no significant differences in improvements of postoperative QOL index, Qmax, PVR, or BVE between HPS and HoLEP groups throughout the follow-up period, except for VSS and total IPSS. Serum PSA reductions after HoLEP were greater than after PVP. CONCLUSIONS: Improvements in LUTS, Qmax, and BVE can maintain up to 3 years after HPS or HoLEP for LUTS/BPH, irrespective of the presence or absence of preoperative DU. Although HoLEP may provide more durable improvement of VS in men with DU than HPS, there seems to be no difference in improvement of QOL or Qmax or BVE between HPS and HoLEP. PMID- 28598557 TI - Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations. AB - The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the alpha4-beta5-alpha5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs. PMID- 28598558 TI - Conserved signaling mechanisms in Drosophila heart development. AB - Signal transduction through multiple distinct pathways regulates and orchestrates the numerous biological processes comprising heart development. This review outlines the roles of the FGFR, EGFR, Wnt, BMP, Notch, Hedgehog, Slit/Robo, and other signaling pathways during four sequential phases of Drosophila cardiogenesis-mesoderm migration, cardiac mesoderm establishment, differentiation of the cardiac mesoderm into distinct cardiac cell types, and morphogenesis of the heart and its lumen based on the proper positioning and cell shape changes of these differentiated cardiac cells-and illustrates how these same cardiogenic roles are conserved in vertebrates. Mechanisms bringing about the regulation and combinatorial integration of these diverse signaling pathways in Drosophila are also described. This synopsis of our present state of knowledge of conserved signaling pathways in Drosophila cardiogenesis and the means by which it was acquired should facilitate our understanding of and investigations into related processes in vertebrates. Developmental Dynamics 246:641-656, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598559 TI - New structural classes of antituberculosis agents. AB - Tuberculosis (TB), one of the deadliest diseases is shattering the health and socioeconomic status of the society. The emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains has provided unprecedented lethal character to TB. The development of MDR and XDR strains of TB results in more deaths, longer duration of therapy, and appearance of the disease in the immunocompromised patients. Because of the development of rapid resistance by Mycobacterium tuberculosis, researchers are confronted with serious challenges in combating TB. For instance, the need for potency and specificity in therapeutic agents approaching clinics, and the increasing demand of low toxicity due to long duration of treatment. Recently, it is proposed that such challenges could be addressed by a shift from contemporary or known classes of drugs to new scaffold containing or entirely new structural classes of drugs that possibly act on the previously unknown targets, resulting in possibly less instances of resistance development. The exploitation of advances made in the biology of TB in the last and present decades have created opportunities to discover a large number of new structural classes that specifically targets TB by molecular mechanism of action(s) unknown earlier. We have earlier reviewed new structural classes of anti-TB agents up to year 2005. This review covers literature reports of the subsequent 10 years on the discovery of new structural classes of synthetic anti TB agents. Due to the availability of large number of research reports, we have divided new compounds in 38 structural classes, 368 structures, and 307 references. PMID- 28598560 TI - Effects of Unilateral Tourniquet Used in Patients Undergoing Simultaneous Bilateral Total Knee Arthroplasty. AB - OBJECTIVE: To assess the benefits of use of a tourniquet in one limb in patients undergoing simultaneous bilateral total knee arthroplasty (TKA). METHODS: A prospective randomized trial was designed to evaluate the outcomes of unilateral tourniquet use during simultaneous bilateral TKA. A total of 52 (36 women and 16 men) patients with osteoarthritis who underwent simultaneous bilateral primary TKA between January 2010 and January 2015 were assigned randomly to tourniquet (TG) or non-tourniquet (NG) groups prior to surgery. Operating time, pain score, range of motion, first active straight-leg raise time, swelling, wound healing, deep vein thrombosis, and Knee Society score were observed. RESULTS: Mean operating time in the TG group was shorter than that in the NG group (P < 0.05). Postoperative pain was measured by a visual analog scale (VAS) and straight-leg raise time, which was lower and shorter in limbs operated without the use of a tourniquet (P < 0.05). In addition, this group had less postoperative swelling and lower incidence of wound complications in the early postoperative period (P < 0.05). There was no significant difference in the range of motion (ROM), deep venous thrombosis incidence, and Knee Society scores between the two groups. CONCLUSIONS: Tourniquet use in bilateral TKA can reduce intraoperative time but was associated with a higher incidence of wound complications and larger postoperative knee swelling. PMID- 28598561 TI - Zinc-Zinc Double Bonds: A Theoretical Study. AB - While double bonds are known for transition metals of Groups 9 and 10 as well as for boron and p-block elements of Groups 14-16, Zn sits in a small region of the periodic table with no well-characterized double bonds. A qualitative reasoning indicates that zero-valent zinc has the potential to form Zn=Zn double bonds. A computational study in search for complexes that might showcase this new bond type is presented here. PMID- 28598563 TI - Alpha lipoic acid prevents doxorubicin-induced nephrotoxicity by mitigation of oxidative stress, inflammation, and apoptosis in rats. AB - This study aimed to evaluate the protective effects of alpha lipoic acid (ALA) against doxorubicin (DOX)-induced nephrotoxicity in rats. A single dose of DOX (7.5 mg/kg i.v.) induced nephrotoxicity evidenced by significant elevations in kidney weight, kidney/body weight ratio, serum urea, creatinine, tumor necrosis factor alpha, and renal contents of malondialdehyde, nitric oxide, cyclooxygenase 2, and caspase-3. Also, it causes significant reduction in final body weight, serum albumin, renal contents of reduced glutathione and superoxide dismutase activity. Histopathological changes in the kidney tissue confirmed the nephrotoxic effect. In contrast, pretreatment with ALA (50 mg/kg, orally) for 14 days before DOX and for 7 days after DOX administration mitigated renal toxicity evidenced by greater improvement in the examined oxidative stress, inflammation, and apoptosis parameters. In conclusion, ALA had promising protective effects against DOX-induced nephrotoxicity that might be attributed to its antioxidant, anti-inflammatory, and antiapoptoic activities. PMID- 28598562 TI - Genetic polymorphisms and folate status. AB - Moderate hyperhomocysteinemia-induced low folate status is an independent risk factor for cardiovascular disease, dementia, and depression. Folate is an essential cofactor in the one-carbon metabolism pathway and is necessary in amino acid metabolism, purine and thymidylate synthesis, and DNA methylation. In the folate cycle and homocysteine metabolism, folate, vitamin B12, vitamin B6, and vitamin B2 are important cofactors. Many enzymes are involved in folate transport and uptake, the folate pathway, and homocysteine (Hcy) metabolism, and various polymorphisms have been documented in these enzymes. Serum folate and total Hcy (tHcy) levels are influenced by folate intake and genetic polymorphisms in 5,10 methylenetertahydrofolate reductase (MTHFR) such as C677T. The prevalence of the MTHFR 677TT genotype varies across ethnic groups and regions, with a frequency of approximately 15% in Japanese populations. Individuals with the TT genotype have significantly higher tHcy levels and lower folate levels in serum than those with the CT and TT genotypes. However, administration of folic acid has been shown to eliminate these differences. Moreover, data have suggested that interventions based on genotype may be effective for motivating individuals to change their lifestyle and improve their nutrition status. Accordingly, in this review, we discuss the effects of MTHFR C677T polymorphisms on serum tHcy and folate levels with folic acid intervention and evaluate approaches for overcoming folic acid deficiency and related symptoms. PMID- 28598564 TI - WITHDRAWN: Celecoxib for rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic auto-immune disorder, involving persistent joint inflammation. NSAIDs are used to control the symptoms of RA, but are associated with significant gastro-intestinal toxicity, including a risk of potentially life threatening gastroduodenal perforations, ulcers and bleeds. The NSAIDs known as the selective Cox II inhibitors, of which celecoxib is a member, were developed in order to reduce the GI toxicity, but are more expensive. OBJECTIVES: To establish the efficacy and safety of celecoxib in the management of RA by systematic review of available evidence. SEARCH METHODS: We searched the following databases up to August 2002: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Controlled Trials Register, National Research Register, NHS Economic Evaluation Database, Health Technology Assessment Database. The bibliographies of retrieved papers and content experts were consulted for additional references. SELECTION CRITERIA: All eligible randomised controlled trials (RCTs) were included. No unpublished RCTs were included in this edition of the review. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by two reviewers. Data was analysed using a fixed effects model. A validated checklist was used to score the quality of the RCTs. The planned analysis was to pool, where appropriate continuous outcomes using mean differences and dichotomous outcomes using relative risk ratios. This was not however possible due to the lack of data. MAIN RESULTS: Five RCTs were included (4465 participants); three of the studies also enrolled individuals with OA. The comparators were placebo, naproxen, diclofenac and ibuprofen. The evidence reviewed suggests that celecoxib controls the symptoms of RA to a similar degree to that of the active comparators examined (naproxen, diclofenac and ibuprofen). When compared to placebo, the percentage of patients showing improvement according to ACR 20 criteria at week 4 were 42/82 (51%) in the twice daily celecoxib 200mg group and 43/82 (52%) in the twice daily celecoxib 400mg group; these were significantly different from the placebo group in which 25/85 (29%) improved. The six month data reviewed support a reduced rate of UGI complications with celecoxib but there is also evidence to suggest that these benefits may not be evident in the long-term and that celecoxib offers no additional benefit in patients who are also receiving cardio-prophylactic low dose aspirin. AUTHORS' CONCLUSIONS: For an individual with RA the potential benefits of celecoxib need to be balanced against the uncertainty that the short-term reduced incidence of upper GI complications are maintained in the long-term and its increased cost in comparison to traditional NSAIDs. PMID- 28598565 TI - Atypical teratoid/rhabdoid tumors in children treated with multimodal therapies: The necessity of upfront radiotherapy after surgery. AB - BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is a rare malignant pediatric brain tumor with a dismal prognosis. We evaluated the efficacy of multimodal therapy in children with ATRT. PROCEDURE: Nine children diagnosed with cranial ATRT, who received multimodal therapy between 2005 and 2014, including surgical resection followed by radiotherapy (RT), systemic chemotherapy (CT), and high dose chemotherapy/stem cell transplantation (HDCT/SCT), were analyzed retrospectively. The median age at diagnosis was 32 months. Initial treatment included surgery in eight patients (88%), CT in all (100%), RT in eight (88%), and HDCT/SCT in seven (78%). RESULTS: The median follow-up period for survivors was 21 months. The 2-year progression-free rate was 66.7%. Two patients had progression 4 and 17 months after diagnosis. One received multimodal treatment, including surgery and upfront CT with delayed RT; the other underwent surgery and upfront CT without RT. The 2-year event-free survival and overall survival rates were 46.7% and 62.2%, respectively. Hematologic toxicity of grade 3 or more was observed in six patients treated with HDCT/SCT and two who underwent craniospinal irradiation. Deaths were attributed to progressive disease (n = 2) and treatment related toxicity (n = 2) from sepsis and acute respiratory failure after CT and HDCT/SCT. CONCLUSIONS: Maximal safe resection in conjunction with upfront RT is a reasonable multimodal treatment in patients with ATRT for prolonging progression free survival. Further research may help determine the optimal parameters for reducing treatment toxicity, such as intensity of HDCT/SCT and the RT field. PMID- 28598566 TI - Electrochemical Graphitization: An Efficient Conversion of Amorphous Carbons to Nanostructured Graphites. AB - This concept paper describes a new electrochemical method for the graphitization of amorphous carbons. The graphitization is achieved by a simple cathodic polarization of the carbons at merely ~1100 K in molten CaCl2 . This electrochemical process is applicable to both graphitizable and non-graphitizable carbons, generating porous graphitic structures of high-crystallinity nanosheets. The transformation of carbon blacks, microspheres, and fibers to porous graphites, hollow graphite spheres, and pipes with porous shells have been demonstrated and the potential graphitization mechanism discussed. PMID- 28598567 TI - Humanized mouse models: Application to human diseases. AB - Humanized mice are superior to rodents for preclinical evaluation of the efficacy and safety of drug candidates using human cells or tissues. During the past decade, humanized mouse technology has been greatly advanced by the establishment of novel platforms of genetically modified immunodeficient mice. Several human diseases can be recapitulated using humanized mice due to the improved engraftment and differentiation capacity of human cells or tissues. In this review, we discuss current advanced humanized mouse models that recapitulate human diseases including cancer, allergy, and graft-versus-host disease. PMID- 28598568 TI - Managing biological control services through multi-trophic trait interactions: review and guidelines for implementation at local and landscape scales. AB - Ecological studies are increasingly moving towards trait-based approaches, as the evidence mounts that functions, as opposed to taxonomy, drive ecosystem service delivery. Among ecosystem services, biological control has been somewhat overlooked in functional ecological studies. This is surprising given that, over recent decades, much of biological control research has been focused on identifying the multiple characteristics (traits) of species that influence trophic interactions. These traits are especially well developed for interactions between arthropods and flowers - important for biological control, as floral resources can provide natural enemies with nutritional supplements, which can dramatically increase biological control efficiency. Traits that underpin the biological control potential of a community and that drive the response of arthropods to environmental filters, from local to landscape-level conditions, are also emerging from recent empirical studies. We present an overview of the traits that have been identified to (i) drive trophic interactions, especially between plants and biological control agents through determining access to floral resources and enhancing longevity and fecundity of natural enemies, (ii) affect the biological control services provided by arthropods, and (iii) limit the response of arthropods to environmental filters, ranging from local management practices to landscape-level simplification. We use this review as a platform to outline opportunities and guidelines for future trait-based studies focused on the enhancement of biological control services. PMID- 28598569 TI - Heart failure in patients admitted for acute coronary syndromes: A report from a large national registry. AB - BACKGROUND: Data on temporal trends of heart failure (HF) in acute coronary syndrome (ACS) are scarce. HYPOTHESIS: Improved treatment options may have led to lower case-fatality rates (CFRs) during the last years in ACS complicated by HF. METHODS: Patients of the nationwide Acute Myocardial Infarction in Switzerland (AMIS)-Plus ACS registry were analyzed from 2000 to 2014. RESULTS: Of 36 366 ACS patients, 3376 (9.3%) had acute or chronic HF, 2111 (5.8%) de novo acute HF (AHF), 964 (2.7%) chronic HF (CHF), and 301 (0.8%) acute decompensated CHF (ADCHF). In-hospital CFRs were highest in patients with ADCHF (32.6%) and de novo AHF (29.7%), followed by patients with CHF (12.9%) and without HF (3.2%, P < 0.001). Although in-hospital CFRs gradually decreased in CHF patients (14.3% to 4.5%, P = 0.003) and patients without HF (3.5% to 2.2%, P < 0.001), they remained high in patients with ADCHF (36.4% to 40.0%, P = 0.45) and de novo AHF (50.0% to 29.4%, P = 0.37). Although there was an increase in specific ACS therapies in the cohort over time, ACS patients with HF received significantly less pharmacological and interventional ACS therapies than patients without HF. There was no significant change in HF medication rates except less frequent use of beta blockers and diuretics in de novo AHF patients in recent years. CONCLUSIONS: HF is present in 1 out of 10 patients presenting with ACS and is associated with high in-hospital CFRs, particularly in acute HF. Although advances in ACS therapy improved in-hospital CFRs in patients with no HF or CHF, CFRs remained unchanged and high in patients with acute HF and ACS over the last decade. PMID- 28598570 TI - Postnatal outcome of fetal isolated ventricular size disproportion in the absence of aortic coarctation. AB - OBJECTIVE: Cardiac ventricular size disproportion is a marker for aortic coarctation (CoA) in fetal life, but approximately 50% of fetuses do not have CoA after birth. The aim of this study was to evaluate the postnatal outcome of cases with fetal ventricular size disproportion in the absence of CoA after birth. METHODS: All cases with fetal isolated ventricular size disproportion diagnosed between 2002 and 2015 were extracted from a prenatal congenital heart defects regional registry. Cases were stratified according to presence or absence (non CoA) of aortic arch anomalies after birth. Postnatal outcome of non-CoA cases was evaluated by assessing the presence of cardiac and other congenital malformations, genetic syndromes and other morbidity after birth. Non-CoA cases were further classified according to whether they had cardiovascular pathology requiring medication or intervention. RESULTS: Seventy-seven cases with fetal ventricular size disproportion were identified, of which 46 (60%) did not have CoA after birth. Of these, 35 did not require cardiovascular intervention or medication, whereas 11 did. Of the 46 non-CoA cases, six presented with clinical pulmonary hypertension requiring treatment after birth, cardiac defects were present in 24 cases and syndromic features were seen in four. Overall, 43% of all non-CoA children were still under surveillance at the end of the study period. CONCLUSIONS: The postnatal course of cases with fetal ventricular size disproportion is complicated by prenatally undetected congenital defects (46%) and pulmonary or transition problems (35%) in a significant number of cases that do not develop CoA. Proper monitoring of these cases is therefore warranted and it is advisable to incorporate the risks for additional morbidity and neonatal complications in prenatal counseling. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd. PMID- 28598571 TI - Ames Test to Detect Mutagenicity of 2-Alkylcyclobutanones: A Review. AB - Food irradiation is an effective and safe method for preservation and long-term storage, and it is approved for use in over 60 countries for various applications in a wide variety of food products. This process is performed by use of accelerated electron beams, X-rays, or gamma radiation (60 Co or 137 Cs). 2 Alkylcyclobutanones (2-ACBs) are the only known radiolytic products generated from foods that have fatty acids (triglycerides) and are subjected to irradiation. Since the 1990s toxicological safety studies of 2-ACBs have been conducted extensively through synthetic compounds, then and tests to determine if the compounds have any mutagenic activity are strictly necessary. The Ames test was chosen by many researchers to assess the mutagenicity of 2-ACBs. The test uses distinct bacterial cell lines Salmonella typhimurium to detect point mutations at sites guanine-cytosine (G-C) and Escherichia coli to detect point mutations at sites adenine-thymine (A-T). This bibliographic research aims to bring together all the results obtained and a comparison and cell lines used, type of plates, and solvents. This research showed that no mutagenic activity was observed in any of the cell lines and concentrations evaluated by the works of authors, so the 2-ACBs compounds showed no mutagenic substance in concentrations detectable by the Ames test. PMID- 28598572 TI - Searching for Novel Inhibitors of the S. aureus NorA Efflux Pump: Synthesis and Biological Evaluation of the 3-Phenyl-1,4-benzothiazine Analogues. AB - Bacterial resistance to antimicrobial agents has become an increasingly serious health problem in recent years. Among the strategies by which resistance can be achieved, overexpression of efflux pumps such as NorA of Staphylococcus aureus leads to a sub-lethal concentration of the antibacterial agent at the active site that in turn may predispose the organism to the development of high-level target based resistance. With an aim to improve both the chemical stability and potency of our previously reported 3-phenyl-1,4-benzothiazine NorA inhibitors, we replaced the benzothiazine core with different nuclei. None of the new synthesized compounds showed any appreciable intrinsic antibacterial activity, and, in particular, 2-(3,4-dimethoxyphenyl)quinoline (6 c) was able to decrease, in a concentration-dependent manner, the ciprofloxacin MIC against the norA overexpressing strains S. aureus SA-K2378 (norA++) and SA-1199B (norA+/A116E GrlA). PMID- 28598573 TI - Successful treatment of tacrolimus-related pure red cell aplasia and autoimmune hemolytic anemia with rituximab in a pediatric cardiac transplant patient. AB - Acquired pure red cell aplasia (PRCA) and autoimmune hemolytic anemia (AIHA) are rare complications of immunosuppression in pediatric solid organ transplant patients. We report a 14-month-old female child who developed Coombs positive hemolytic anemia and reticulocytopenia while on tacrolimus after cardiac transplantation. She was successfully treated with rituximab after failing treatment with corticosteroids and intravenous immunoglobulins. Clinicians should consider PRCA differential diagnosis in a patient presenting with reticulocytopenia and hemolysis. In addition, the coexistence of PRCA with AIHA, and the response to therapy with rituximab, supports a common immune-mediated pathogenesis for both disorders. PMID- 28598574 TI - Socioeconomic status and the development of atrial fibrillation in Hispanics, African Americans and non-Hispanic whites. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. Despite having a higher burden of traditional AF risk factors, African American and Hispanic minorities have a lower incidence of AF when compared to non-Hispanic whites, referred to as the "racial paradox." HYPOTHESIS: Lower SES among Hispanics and African Americans may help to explain the lower incidence rates of AF compared to non-Hispanic whites. METHODS: An electrocardiogram/electronic medical records database in New York State was interrogated for individuals free of AF for development of subsequent AF from 2000 to 2013. SES was assessed per zip code via a composite of 6 measures Z-scored to the New York State average. SES was reclassified into decile groups. Cox regression analysis controlling for all baseline differences was used to estimate the independent predictive ability of SES for AF. RESULTS: We identified 48 631 persons (43% Hispanic, 37% African Americans, and 20% non Hispanic white; mean age 59 years; mean follow-up of 3.2 years) of which 4556 AF cases occurred. Hispanics and African Americans had lower AF risk than whites in all SES deciles (P < 0.001 by log-rank test). Higher SES was borderline associated with lower AF risk (hazard ratio: 0.990, 95% confidence interval: 0.980-1.001, P = 0.061). P trend analysis was not significant by any race/ethnic group by SES deciles for AF. CONCLUSIONS: Our study suggests that non-Hispanic whites were at higher risk for AF compared to nonwhites, and this was independent of SES. PMID- 28598575 TI - An Efficient and Versatile Lanthanum Heteroscorpionate Catalyst for Carbon Dioxide Fixation into Cyclic Carbonates. AB - A new lanthanum heteroscorpionate complex has shown exceptional catalytic activity for the synthesis of cyclic carbonates from epoxides and carbon dioxide. This catalyst system also promotes the reaction of bio-based epoxides to give an important class of bis(cyclic carbonates) that can be further used for the production of bio-derived non-isocyanate polyurethanes. The catalytic process requires low catalyst loading and mild reaction conditions for the synthesis of a wide range of cyclic carbonates. PMID- 28598577 TI - Comment on: Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among type 2 diabetes patients: A network and cumulative meta-analysis of randomized controlled trials. PMID- 28598578 TI - Oversensing and inappropriate shock in a patient with subcutaneous implantable cardioverter defibrillator: What is the mechanism? PMID- 28598576 TI - Semi-automated cancer genome analysis using high-performance computing. AB - Next-generation sequencing (NGS) has turned from a new and experimental technology into a standard procedure for cancer genome studies and clinical investigation. While a multitude of software packages for cancer genome data analysis have been made available, these need to be combined into efficient analytical workflows that cover multiple aspects relevant to a clinical environment and that deliver handy results within a reasonable time frame. Here, we introduce QuickNGS Cancer as a new suite of bioinformatics pipelines that is focused on cancer genomics and significantly reduces the analytical hurdles that still limit a broader applicability of NGS technology, particularly to clinically driven research. QuickNGS Cancer allows a highly efficient analysis of a broad variety of NGS data types, specifically considering cancer-specific issues, such as biases introduced by tumor impurity and aneuploidy or the assessment of genomic variations regarding their biomedical relevance. It delivers highly reproducible analysis results ready for interpretation within only a few days after sequencing, as shown by a reanalysis of 140 tumor/normal pairs from The Cancer Genome Atlas (TCGA) in which QuickNGS Cancer detected a significant number of mutations in key cancer genes missed by a well-established mutation calling pipeline. Finally, QuickNGS Cancer obtained several unexpected mutations in leukemias that could be confirmed by Sanger sequencing. PMID- 28598579 TI - Validation of protein structure models using network similarity score. AB - Accurate structural validation of proteins is of extreme importance in studies like protein structure prediction, analysis of molecular dynamic simulation trajectories and finding subtle changes in very similar structures. The benchmarks for today's structure validation are scoring methods like global distance test-total structure (GDT-TS), TM-score and root mean square deviations (RMSD). However, there is a lack of methods that look at both the protein backbone and side-chain structures at the global connectivity level and provide information about the differences in connectivity. To address this gap, a graph spectral based method (NSS-network similarity score) which has been recently developed to rigorously compare networks in diverse fields, is adopted to compare protein structures both at the backbone and at the side-chain noncovalent connectivity levels. In this study, we validate the performance of NSS by investigating protein structures from X-ray structures, modeling (including CASP models), and molecular dynamics simulations. Further, we systematically identify the local and the global regions of the structures contributing to the difference in NSS, through the components of the score, a feature unique to this spectral based scoring scheme. It is demonstrated that the method can quantify subtle differences in connectivity compared to a reference protein structure and can form a robust basis for protein structure comparison. Additionally, we have also introduced a network-based method to analyze fluctuations in side chain interactions (edge-weights) in an ensemble of structures, which can be an useful tool for the analysis of MD trajectories. PMID- 28598580 TI - Neuroanatomy of the Pig Cardiac Ventricles. A Stereomicroscopic, Confocal and Electron Microscope Study. AB - Although the pig is a model for heart disease, the neuroanatomy of cardiac ventricles (CV) in this species remains undetailed. We aimed to define the innervation pattern of pig CV, combining histochemistry for acetylcholinesterase, immunofluorescent labeling and electron microscopy. Forty nine examined pig hearts show that the major nerves supplying the ventral side of CV descend from the venous part of the heart hilum. Fewer in number and smaller in size, epicardial nerves supply the dorsal half of the CV. Epicardial nerves on the left ventricle are thicker than those on the right. Ventricular ganglia of various sizes distribute at the basal level of both CV. Averagely, we found 3,848 ventricular neuronal somata per heart. The majority of somata were cholinergic, although ganglionic cells of different neurochemical phenotypes (positive for nNOS, ChAT/nNOS, or ChAT/TH) were also observed. Large and most numerous nerves proceeded within the epicardium. Most of endocardium and myocardium contained a network of nerve bundles and nerve fibers (NFs). But, a large number of thin nerves extended along the bundle of His and its branches. The majority of NFs were adrenergic, while cholinergic NFs were scarce yet more abundant than nitrergic ones. Sensory NFs positive for CGRP were the second most abundant phenotype after adrenergic NFs in all layers of the ventricular wall. Electron microscopy elucidated that ultrastructure of nerves varied between different areas of CV. The described structural organization of CV provides an anatomical basis for further functional and pathophysiological studies in the pig heart. Anat Rec, 2017. (c) 2017 Wiley Periodicals, Inc. Anat Rec, 300:1756-1780, 2017. (c) 2017 Wiley Periodicals, Inc. PMID- 28598581 TI - Life-threatening sinusoidal obstruction syndrome after high-dose chemotherapy linked to compound heterozygous mutations in ABCB11. PMID- 28598582 TI - Outcomes of Intercalary Prosthetic Reconstruction for Pathological Diaphyseal Femoral Fractures Secondary to Metastatic Tumors. AB - OBJECTIVE: To evaluate the clinical outcomes and complications of segmental prosthetic reconstruction for pathological diaphyseal femoral fractures secondary to metastatic tumors. METHODS: Between 2011 and 2015, we retrospectively evaluated 16 patients (6 men and 10 women; 64.5 +/- 11.4 years old at diagnosis) who underwent prosthetic reconstruction after segmental resection of diaphyseal femoral fractures due to metastatic lesions. Visual analog scale (VAS), functional outcomes, implant-related complications, and Mean postoperative Musculoskeletal Tumor Society (MSTS) score for each patient were collected. RESULTS: The mean length of bone defect was 10.2 +/- 2.6 cm (range, 8-16 cm); follow-up was 9 +/- 6.8 months (range, 2-25 months) for all patients, and 24 months (23 and 25 months) for the 2 patients still alive. At final follow-up, 14 patients were dead, indicating a mean survival of 6.9 +/- 3.6 months (range, 2-14 months). Mean preoperative VAS score was 8.5 +/- 1.0, which decreased to 2.5 +/- 1.3 at day 2 postoperatively, indicating significant pain relief (P < 0.05). The MSTS score for lower extremities was 84.6% (range, 73%-90%). The range of motion and function of adjacent joints was within the normal limits in all cases. Three patients (33%) developed complications, including aseptic loosening because of disease progression (1), infection (1), and peri-prosthesis fracture (1). CONCLUSION: These findings demonstrated that this approach greatly relieves pain, and yields satisfactory functional outcomes with fewer complications in patients with pathological femoral fractures secondary to metastatic tumors; however, survival was not significantly improved. PMID- 28598583 TI - Ring-Opening 1-Amino-3-aminomethylation of Donor-Acceptor Cyclopropanes via 1,3 Diazepanes. AB - The first ring-opening reaction of donor-acceptor cyclopropanes to give diamines is reported. For this reaction, a 1,3-bisfunctionalization was developed using cyclopropanes, triazinanes, and Sc(OTf)3 as the catalyst, followed by treatment with acid. The reaction proceeds under very mild conditions and tolerates many functional groups. Moreover, a library of various 1,3-diazepanes, which arise as intermediates of the first formal aza-[4+3]-cycloaddition reaction with donor acceptor cyclopropanes, was synthesized. PMID- 28598584 TI - CaMELS: In silico prediction of calmodulin binding proteins and their binding sites. AB - Due to Ca2+ -dependent binding and the sequence diversity of Calmodulin (CaM) binding proteins, identifying CaM interactions and binding sites in the wet-lab is tedious and costly. Therefore, computational methods for this purpose are crucial to the design of such wet-lab experiments. We present an algorithm suite called CaMELS (CalModulin intEraction Learning System) for predicting proteins that interact with CaM as well as their binding sites using sequence information alone. CaMELS offers state of the art accuracy for both CaM interaction and binding site prediction and can aid biologists in studying CaM binding proteins. For CaM interaction prediction, CaMELS uses protein sequence features coupled with a large-margin classifier. CaMELS models the binding site prediction problem using multiple instance machine learning with a custom optimization algorithm which allows more effective learning over imprecisely annotated CaM-binding sites during training. CaMELS has been extensively benchmarked using a variety of data sets, mutagenic studies, proteome-wide Gene Ontology enrichment analyses and protein structures. Our experiments indicate that CaMELS outperforms simple motif based search and other existing methods for interaction and binding site prediction. We have also found that the whole sequence of a protein, rather than just its binding site, is important for predicting its interaction with CaM. Using the machine learning model in CaMELS, we have identified important features of protein sequences for CaM interaction prediction as well as characteristic amino acid sub-sequences and their relative position for identifying CaM binding sites. Python code for training and evaluating CaMELS together with a webserver implementation is available at the URL: http://faculty.pieas.edu.pk/fayyaz/software.html#camels. PMID- 28598586 TI - Nitrogen Photofixation over III-Nitride Nanowires Assisted by Ruthenium Clusters of Low Atomicity. AB - In many heterogeneous catalysts, the interaction of supported metal species with a matrix can alter the electronic and morphological properties of the metal and manipulate its catalytic properties. III-nitride semiconductors have a unique ability to stabilize ultra-small ruthenium (Ru) clusters (ca. 0.8 nm) at a high loading density up to 5 wt %. n-Type III-nitride nanowires decorated with Ru sub nanoclusters offer controlled surface charge properties and exhibit superior UV- and visible-light photocatalytic activity for ammonia synthesis at ambient temperature. A metal/semiconductor interfacial Schottky junction with a 0.94 eV barrier height can greatly facilitate photogenerated electron transfer from III nitrides to Ru, rendering Ru an electron sink that promotes N=N bond cleavage, and thereby achieving low-temperature ammonia synthesis. PMID- 28598585 TI - Epithelioid hemangioendotheliomas of the liver and lung in children and adolescents. AB - Epithelioid hemangioendothelioma (EHE) is a rare, vascular sarcoma. Visceral forms arise in the liver/ lungs. We review the clinical and molecular phenotype of pediatric visceral EHE based on the case of a 9-year-old male child with EHE of the liver/lungs. His tumor expressed the EHE-specific fusion oncogene WWTR1 CAMTA1. Molecular characterization revealed a low somatic mutation rate and activated interferon signaling, angiogenesis regulation, and blood vessel remodeling. After polychemotherapy and resection of lung tumors, residual disease remained stable on oral lenalidomide. Literature review identified another 24 children with EHE of the liver/lungs. Most presented with multifocal, systemic disease. Only those who underwent complete resection achieved complete remission. Four children experienced rapid progression and died. In six children, disease remained stable for years without therapy. Two patients died from progressive EHE 21 and 24 years after first diagnosis. Natural evolution of pediatric visceral EHE is variable, and long-term prognosis remains unclear. PMID- 28598587 TI - Challenges in Model Development for Meat Composition Using Multipoint NIR Spectroscopy from At-Line to In-Line Monitoring. AB - This study evaluates the efficiency of multipoint near-infrared spectroscopy (NIRS) to predict the fat and moisture content of minced beef samples both in at line and on-line modes. Additionally, it aims at identifying the obstacles that can be encountered in the path of performing in-line monitoring. Near-infrared (NIR) reflectance spectra of minced beef samples were collected using an NIR spectrophotometer, employing a Fabry-Perot interferometer. Partial least squares regression (PLSR) models based on reference values from proximate analysis yielded calibration coefficients of determination (Rc2) of 0.96 for both fat and moisture. For an independent batch of samples, fat was estimated with a prediction coefficient of determination (Rp2) of 0.87 and 0.82 for the samples in at-line and on-line modes, respectively. All the models were found to have good prediction accuracy; however, a higher bias was observed for predictions under on line mode. Overall results from this study illustrate that multipoint NIR systems combined with multivariate analysis has potential as a process analytical technology (PAT) tool for monitoring process parameters such as fat and moisture in the meat industry, providing real-time spectral and spatial information. PMID- 28598588 TI - Nutritional outcomes in infants with food allergy after cardiac surgery. AB - BACKGROUND: Food allergy is a rapidly growing public health concern because of its increasing prevalence, as well as life-threatening potential. There is limited knowledge on the nutritional status for the pediatric congenital heart disease (CHD) patients with food allergy. OBJECTIVE: This study investigated both clinical and nutritional outcomes according to the CHD infants with food allergy. METHODS: Forty CHD infants with food allergy and 39 controls were recruited in Shanghai, China. The height and weight for age and weight for height were converted to z-scores to evaluate their effects on nutritional status before and after CHD operation. RESULTS: Cow's milk showed the most frequently sensitized food allergen. The WHZ in the >=2 allergen group was different before operation and after operation (P = .040). The number of sensitized food allergens significantly correlated with the WHZ (r = -0.431, P = .001), WAZ (r = -0.465, P = .000), and HAZ (r = -0.287, P = .025). Infection and NT-BNP showing negative correlation with WHZ and WAZ of infants with food allergy. CONCLUSIONS: The increased number of sensitized food allergens is associated with negative effects on both short-term and long-term nutritional status in infants with CHD. Therefore, the meticulous and continuous evaluation and management of both growth and nutritional status should be considered in CHD patients with a high number of sensitized food allergens. PMID- 28598589 TI - Creating a Biomimetic Microenvironment for the Ex Vivo Expansion of Primary Human T Lymphocytes. AB - The ex vivo expansion of primary human T cells is of considerable interest. Current protocols call for the addition of massive amounts of stimuli. This study presents as alternative the expansion of such cells in semipermeable sodium cellulose sulfate/poly(diallyldimethyl) ammonium chloride (SCS/PDADMAC) polyelectrolyte microcapsules, which supports at least six cell divisions and results in >40 * 106 cells mLcapsule-1 within less than 10 d. Inside the microcapsules, the T cells are suspended in a viscous SCS-solution. The low molecular weight cut off (<10 000 Da) of the surrounding polyelectrolyte membrane assures that typical signaling molecules produced by the cells are retained, while nutrients and metabolites can pass. Expensive additives, such as interleukin-2 (IL-2), can be coencapsulated. Expansion then no longer requires specialized T-cell media. Moreover, these results suggest that an SCS with a low degree of sulfation has biomimetic properties, representing an artificial extracellular matrix mimicking heparin sulfate. PMID- 28598590 TI - Impact of Denture Cleansing Solution Immersion on Some Properties of Different Denture Base Materials: An In Vitro Study. AB - PURPOSE: To evaluate the effect of several denture cleansing solutions on the color stability, surface roughness, and flexural strength of three denture base materials. MATERIALS AND METHODS: Twenty-seven specimens were prepared using heat polymerized (HP) denture base material, 27 using autopolymerized (AP) denture base material, and 27 using visible-light-polymerized (VLP) denture base, creating a total of 81 specimens. The specimens were randomly divided into three groups (n = 27): the distilled water group (DWG), Corega group (CG), and Renew group (RG). Color changes (DeltaE), surface roughness (Ra, nm), and flexural strength (MPa) of each specimen were measured using a spectrophotometer, an optical profilometer, and a universal testing machine, respectively. The results were statistically analyzed using a one-way ANOVA and a post hoc Tukey's test (alpha = 0.05). RESULTS: The only statistically significant color change detected was in the VLP resin treated with Corega and Renew. There was a significant increase in the surface roughness of all denture resin groups after immersion in Corega. Immersion in Renew significantly increased surface roughness only in the HP and AP specimens. The only significant reduction in flexural strength was detected in the HP resin after immersion in Corega (p < 0.05). CONCLUSIONS: Within the limitations of this study, it can be concluded that Corega has a significantly greater negative impact than distilled water on the flexural strength of HP resin base materials. Renew significantly increased the surface roughness of AP and HP, while Corega increased the surface roughness of all resin materials. PMID- 28598591 TI - Effect of Split-File Digital Workflow on Crown Margin Adaptation. AB - PURPOSE: Computer-aided design/computer-aided manufacturing (CAD/CAM) is becoming increasingly integrated into dental practice workflow at a pace that exceeds scientific validation. The aim of this study is to evaluate a complete digital split-file protocol relative to segmental digital and analog techniques for restoring a single maxillary anterior edentulous space with custom abutment and crown. MATERIALS AND METHODS: Four treatment workflows were assessed: complete digital (CD), segmental digital (SD), milled wax (AM), and heat pressed and hand waxed (AH) and heat pressed. The CD workflow "split" an abutment and crown into separate files to fabricate a zirconia abutment and both zirconia/lithium disilicate crown restorations. The SD workflow scanned the existing abutment for design of segmental restorations in zirconia, lithium disilicate, and milled wax (AM). The AH specimens were conventionally hand waxed. Both the AM and AH specimens were heat pressed with lithium disilicate. All restorations were evaluated with standardized measurements using scanning electron microscopy (SEM) as manufactured without internal adjustments and after manual adjustment. The number of adjustments, adjustment time, and location of adjustments were recorded. One-way ANOVA with repeated measures was used to report geometric means with 95% confidence intervals. RESULTS: The mean marginal gap after adjustment of the CD group was 69 MUm, with an upper bound (UB) of 79 MUm and a lower bound (LB) of 60 MUm. SD group mean was 26 MUm with an UB of 31 MUm and LB of 22 MUm. The AM group mean was 32 MUm, with an UB of 49 MUm and a LB of 20 MUm; AH group mean of 26 MUm with an UB of 34 MUm and a LB of 20 MUm. The SD, AM, and AH workflows were statistically similar (p = 1.000), and the CD workflow was statistically greater than the other three (p < 0.001). CONCLUSIONS: The split file (CD) protocol results in marginal gap size within clinical standards after adjustment; however, 52 of the 60 digitally produced restorations showed a horizontal marginal offset that required adjustment for proper contours. PMID- 28598592 TI - Hospitalization rate and costs in acute lymphoblastic leukemia of childhood in a low-income group: Financial impact in Northeast Mexico. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is one of the main and most expensive and prolonged causes of hospitalization for childhood cancer. We describe the hospitalization rate and its costs for an open population with ALL in a low-middle income country. PROCEDURE: We retrospectively analyzed 449 hospital admissions for 101 pediatric patients with ALL over 8 years. Clinical files and electronic databases were scrutinized to document causes, duration, readmission rate, costs, and outcome of each admission. Hospitalizations were divided into two categories: general pediatric ward and pediatric intensive care unit (PICU). Hospitalization rates and its costs per patient were estimated considering person-time at risk. RESULTS: Patients had an admission rate of 2.09 hospitalizations per patient-year and median length of stay per admission was 5 days. Most admissions occurred during the first 2 years from diagnosis. Mean cost per day was 239 US dollars (USD) and mean cost per stay was 2,246 USD versus 1,016 and 19,004 USD (P = 0.001) in the PICU, respectively. Total hospitalization cost per patient per year (PPPY) was 5,991 USD for high-risk patients and 3,038 USD for standard-risk patients. Patients between ages 1 and 9 years had a PPPY cost of $4,057; while for children younger than 1 year or older than 9 years, it was 7,463 USD. The popular medical insurance program covered 70% of hospitalizations and 63% of its total cost; patients contributed 2%, with the hospital absorbing 35%. CONCLUSIONS: Hospitalizations for children with ALL were less expensive than in high-income countries but had a significant cost to low income families and to the healthcare system. PMID- 28598593 TI - Intravenous palivizumab in respiratory syncytial virus infection after hematopoietic stem cell transplant in children. AB - Respiratory syncytial virus (RSV) infection can cause lower respiratory tract disease and mortality in pediatric hematopoietic stem cell transplant (HSCT) recipients. We report two children who underwent HSCT and developed RSV infection simultaneously at the Bone Marrow Transplant Unit. The treatment with intravenous palivizumab was provided and sequential viral loads were measured in nasopharyngeal (NP) and whole blood samples. To our knowledge, this is the first report where RSV loads were measured in parallel (NP and blood), before and after palivizumab, in correlation with a favorable clinical outcome in both cases. PMID- 28598594 TI - Tethering Growth Factors to Collagen Surfaces Using Copper-Free Click Chemistry: Surface Characterization and in Vitro Biological Response. AB - Surface modifications with tethered growth factors have mainly been applied to synthetic polymeric biomaterials in well-controlled, acellular settings, followed by seeding with cells. The known bio-orthogonality of copper-free click chemistry provides an opportunity to not only use it in vitro to create scaffolds or pro migratory tracks in the presence of living cells, but also potentially apply it to living tissues directly as a coupling modality in situ. In this study, we studied the chemical coupling of growth factors to collagen using biocompatible copper-free click chemistry and its effect on the enhancement of growth factor activity in vitro. We verified the characteristics of modified epidermal growth factor (EGF) using mass spectrometry and an EGF/EGF receptor binding assay, and evaluated the chemical immobilization of EGF on collagen by copper-free click chemistry using surface X-ray photoelectron spectroscopy (XPS), surface plasmon resonance (SPR) spectroscopy, and enzyme-linked immunosorbent assay (ELISA). We found that the anchoring was noncytotoxic, biocompatible, and rapid. Moreover, the surface-immobilized EGF had significant effects on epithelial cell attachment and proliferation. Our results demonstrate the possibility of copper-free click chemistry as a tool for covalent bonding of growth factors to collagen in the presence of living cells. This approach is a novel and potentially clinically useful application of copper-free click chemistry as a way of anchoring growth factors to collagen and foster epithelial wound healing. PMID- 28598595 TI - Self-Perforated Hydrogel Nanomembranes Facilitate Structural Analysis of Proteins by Electron Cryo-Microscopy. AB - We developed a method to improve specimen preparation for electron cryo microscopy of membrane proteins. The method features a perforated hydrogel nanomembrane that stabilizes the thin film of aqueous buffer spanning the holes of holey carbon films, while at the same time preventing the depletion of protein molecules from these holes. The membrane is obtained by cross-linking of thiolated polyglycerol dendrimer films on gold, which self-perforate upon transfer to holey carbon substrates, forming a sub-micron-sized hydrogel network. The perforated nanomembrane improves the distribution of the protein molecules in the ice considerably. This facilitates data acquisition as demonstrated with two eukaryotic membrane protein complexes. PMID- 28598596 TI - Interconnected Copper Cobaltite Nanochains as Efficient Electrocatalysts for Water Oxidation in Alkaline Medium. AB - The present work is focused on the protective-agent-free synthesis of interconnected copper cobaltite (Cu0.3Co2.7O4) nanochains by temperature controlled solvothermal method followed by post-thermal treatment of the precursors. Furthermore, Cu0.3Co2.7O4 interconnected nanochains are employed as electrocatalyst for water oxidation in alkaline medium for the first time. Extensive studies of physiochemical properties showed the formation of interconnected 1D nanochains of Cu0.3Co2.7O4 exhibiting a larger specific surface area (139.5 m2 g-1) and enhanced electrochemical water oxidation ability. It delivered excellent mass activity (~50.0 A g-1), high anodic current density (~124.9 mA cm-2 at 1.75 V versus reversible hydrogen electrode), and turnover frequency (~4.26 * 10-2 s-1) in 1.0 M KOH. These Cu0.3Co2.7O4 nanochains also demonstrated low overpotential (~351 mV) and good cycling stability (1000 cycles) in strong alkaline media. The fabricated Cu0.3Co2.7O4 nanochains could be a good alternative to the commercial OER electrocatalysts (RuO2 and IrO2) and also advantageous to the development of efficient, cost-effective, and durable electrocatalysts for electrochemical water splitting. PMID- 28598597 TI - Azapeptide Synthesis Methods for Expanding Side-Chain Diversity for Biomedical Applications. AB - Mimicry of bioactive conformations is critical for peptide-based medicinal chemistry because such peptidomimetics may augment stability, enhance affinity, and increase specificity. Azapeptides are peptidomimetics in which the alpha carbon(s) of one or more amino acid residues are substituted by nitrogen. The resulting semicarbazide analogues have been shown to reinforce beta-turn conformation through the combination of lone pair-lone pair repulsion of the adjacent hydrazine nitrogen and urea planarity. Substitution of a semicarbazide for an amino amide residue in a peptide may retain biological activity and add benefits such as improved metabolic stability. The applications of azapeptides include receptor ligands, enzyme inhibitors, prodrugs, probes, and imaging agents. Moreover, azapeptides have proven therapeutic utility. For example, the aza-glycinamide analogue of the luteinizing hormone-releasing hormone analogue Zoladex is a potent long-acting agonist currently used in the clinic for the treatment of prostate and breast cancer. However, the use of azapeptides was hampered by tedious solution-phase synthetic routes for selective hydrazine functionalization. A remarkable stride to overcome this bottleneck was made in 2009 through the introduction of the submonomer procedure for azapeptide synthesis, which enabled addition of diverse side chains onto a common semicarbazone intermediate, providing a means to construct azapeptide libraries by solution- and solid-phase chemistry. In brief, aza residues are introduced into the peptide chain using the submonomer strategy by semicarbazone incorporation, deprotonation, N-alkylation, and orthogonal deprotection. Amino acylation of the resulting semicarbazide and elongation gives the desired azapeptide. Since the initial report, a number of chemical transformations have taken advantage of the orthogonal chemistry of semicarbazone residues (e.g., Michael additions and N-arylations). In addition, libraries have been synthesized from libraries by diversification of aza-propargylglycine (e.g., A3 coupling reactions, [1,3]-dipolar cycloadditions, and 5-exo-dig cyclizations) and aza chloroalkylglycine residues. In addition, oxidation of aza-glycine residues has afforded azopeptides that react in pericyclic reactions (e.g., Diels-Alder and Alder-ene chemistry). The bulk of these transformations of aza-glycine residues have been developed by the Lubell laboratory, which has applied such chemistry in the synthesis of ligands with promising biological activity for treating diseases such as cancer and age-related macular degeneration. Azapeptide analogues of growth hormone-releasing peptide-6 (His-d-Trp-Ala-Trp-d-Phe-Lys-NH2, GHRP-6) have for example been pursued as ligands of the cluster of differentiation 36 receptor (CD36) and show promising activity for the development of treatments for angiogenesis-related diseases, such as age-related macular degeneration, as well as for atherosclerosis. Azapeptides have also been employed to make a series of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that exhibit promising apoptosis-inducing activity in cancer cells. The synthesis of cyclic azapeptide derivatives was used to make an aza scan to study the conformation-activity relationships of the anticancer agent cilengitide, cyclo(RGDf-N(Me)V), and its parent counterpart cyclo(RGDfV), which exhibit potency against human tumor metastasis and tumor-induced angiogenesis. Innovations in the synthesis and application of azapeptides will be presented in this Account, focusing on the creation and use of side-chain diversity in medicinal chemistry. PMID- 28598599 TI - Generation, Spectroscopic, and Chemical Characterization of an Octahedral Iron(V) Nitrido Species with a Neutral Ligand Platform. AB - Iron complex [FeIII(N3)(MePy2tacn)](PF6)2 (1), containing a neutral triazacyclononane-based pentadentate ligand, and a terminally bound azide ligand has been prepared and spectroscopically and structurally characterized. Structural details, magnetic susceptibility data, and Mossbauer spectra demonstrate that 1 has a low-spin (S = 1/2) ferric center. X-ray diffraction analysis of 1 reveals remarkably short Fe-N (1.859 A) and long FeN-N2 (1.246 A) distances, while the FT-IR spectra show an unusually low N-N stretching frequency (2019 cm-1), suggesting that the FeN-N2 bond is particularly weak. Photolysis of 1 at 470 or 530 nm caused N2 elimination and generation of a nitrido species that on the basis of Mossbauer, magnetic susceptibility, EPR, and X-ray absorption in conjunction with density functional theory computational analyses is formulated as [FeV(N)(MePy2tacn)]2+ (2). Results indicate that 2 is a low-spin (S = 1/2) iron(V) species, which exhibits a short Fe-N distance (1.64 A), as deduced from extended X-ray absorption fine structure analysis. Compound 2 is only stable at cryogenic (liquid N2) temperatures, and frozen solutions as well as solid samples decompose rapidly upon warming, producing N2. However, the high-valent compound could be generated in the gas phase, and its reactivity against olefins, sulfides, and substrates with weak C-H bonds studied. Compound 2 proved to be a powerful two-electron oxidant that can add the nitrido ligand to olefin and sulfide sites as well as oxidize cyclohexadiene substrates to benzene in a formal H2-transfer process. In summary, compound 2 constitutes the first case of an octahedral FeV(N) species prepared within a neutral ligand framework and adds to the few examples of FeV species that could be spectroscopically and chemically characterized. PMID- 28598600 TI - Protein-Free Hapten-Carbon Nanotube Constructs Induce the Secondary Immune Response. AB - Carbon nanotubes are novel technological tools with multiple applications. The interaction between such nanoparticles and living organisms is nowadays a matter of keen research by academic and private institutions. In this study, carbon nanotube constructs were investigated as delivery vehicles for immunostimulation and induction of the secondary immune response to a small organic molecule, namely, a hapten. Two types of nanoconstructs were prepared: on one hand, carbon nanotubes carrying a protein bioconjugate of a hapten covalently linked to the carbon surface, and on the other hand, covalent carbon nanotube constructs of the same model chemical compound without the carrier protein. Nanotube vehicles carrying a hapten-protein bioconjugate were demonstrated to stimulate the immune system and to induce a strong primary immune response against the hapten with as low as 0.1 MUg of the model chemical. The influence of the different elements of those nanoconstructs over the immune response was investigated to better understand the molecular mechanisms that are involved. As expected, the presence of the carrier protein was shown to be necessary in order to trigger the immune response. Interestingly, we found that a remarkable secondary immune response to the model organic compound occurred in the absence of a carrier protein. Additionally, a satisfactory adjuvant effect of carbon nanotubes was observed and a potent immune response was elicited without employing an oil-based adjuvant. PMID- 28598601 TI - Designing Air-Stable O3-Type Cathode Materials by Combined Structure Modulation for Na-Ion Batteries. AB - As promising high-capacity cathode materials for Na-ion batteries, O3-type Na based metal oxides always suffer from their poor air stability originating from the spontaneous extraction of Na and oxidation of transition metals when exposed to air. Herein, a combined structure modulation is proposed to tackle concurrently the two handicaps via reducing Na layers spacing and simultaneously increasing valence state of transition metals. Guided by density functional theory calculations, we demonstrate such a modulation can be subtly realized through cosubstitution of one kind of heteroatom with comparable electronegativity and another one with substantially different Fermi level, by adjusting the structure of NaNi0.5Mn0.5O2 via Cu/Ti codoping. The as-obtained NaNi0.45Cu0.05Mn0.4Ti0.1O2 exhibits an increase of 20 times in stable air exposure period and 9 times in capacity retention after 500 cycles, and even retains its structure and capacity after being soaked in water. Such a simple and effective structure modulation reveals a new avenue for high-performance O3-type cathodes and pushes the large-scale industrialization of Na-ion batteries a decisive step forward. PMID- 28598602 TI - Multiactinide Analysis with Accelerator Mass Spectrometry for Ultratrace Determination in Small Samples: Application to an in Situ Radionuclide Tracer Test within the Colloid Formation and Migration Experiment at the Grimsel Test Site (Switzerland). AB - The multiactinide analysis with accelerator mass spectrometry (AMS) was applied to samples collected from the run 13-05 of the Colloid Formation and Migration (CFM) experiment at the Grimsel Test Site (GTS). In this in situ radionuclide tracer test, the environmental behavior of 233U, 237Np, 242Pu, and 243Am was investigated in a water conductive shear zone under conditions relevant for a nuclear waste repository in crystalline rock. The concentration of the actinides in the GTS groundwater was determined with AMS over 6 orders of magnitude from ~15 pg/g down to ~25 ag/g. Levels above 10 fg/g were investigated with both sector field inductively coupled plasma mass spectrometry (SF-ICPMS) and AMS. Agreement within a relative uncertainty of 50% was found for 237Np, 242Pu, and 243Am concentrations determined with the two analytical methods. With the extreme sensitivity of AMS, the long-term release and retention of the actinides was investigated over 8 months in the tailing of the breakthrough curve of run 13-05 as well as in samples collected up to 22 months after. Furthermore, the evidence of masses 241 and 244 u in the CFM samples most probably representing 241Am and 244Pu employed in a previous tracer test demonstrated the analytical capability of AMS for in situ studies lasting more than a decade. PMID- 28598598 TI - Reversible Low-Temperature Metal Node Distortion during Atomic Layer Deposition of Al2O3 and TiO2 on UiO-66-NH2 Metal-Organic Framework Crystal Surfaces. AB - Metal-organic frameworks (MOFs) are chemically functionalized micro- and mesoporous materials with high surface areas and are attractive for multiple applications including filtration, gas storage, and catalysis. Postsynthetic modification (PSM), via solution or vapor-based techniques, is a way to impart additional complexity and functionality into these materials. There is a desire to shift toward vapor-phase methods in order to ensure more controlled modification and more efficient reagent and solvent removal from the modified MOF material. In this work we explore how the metal precursors titanium tetrachloride (TiCl4) and trimethylaluminum (TMA), commonly used in atomic layer deposition, react with UiO-66-NH2 MOF. Using in situ quartz crystal microbalance (QCM) and Fourier transform infrared spectroscopy (FTIR) at 150 and 250 degrees C, we find that the ALD precursors react with MU3-OH hydroxyl and MU3-O bridging oxygen groups on Zr6 nodes, as well as oxygen from carboxylate linker groups. The reactions occur predominantly at the crystal surface at MU3-OH hydroxyl sites, with TiCl4 exhibiting greater diffusion into the MOF subsurface. FTIR analysis suggests that, at 150 degrees C, both TiCl4 and TMA reversibly dehydroxylate the hydroxylated UiO-66-NH2, which is accompanied by distortion of the zirconium metal clusters. Finally, we show that TiCl4 is able to react with the dehydroxylated UiO-66-NH2 structure, suggesting that TiCl4 is also able to react directly with the bridging oxygens in the metal clusters or carboxylate groups on the organic ligand. A better understanding of chemical and thermally driven MOF dehydroxylation reactions can be important for improved postsynthetic modification of MOFs. PMID- 28598603 TI - Crystal Structures of CaB3N3 at High Pressures. AB - Using global structure searches, we have explored the structural stability of CaB3N3, a compound analogous to CaC6, under pressure. There are two high-pressure phases with space groups R3c and Amm2 that were found to be stable between 29 and 42 GPa, and above 42 GPa, respectively. The two phases show different structural frameworks, analogous to graphitic CaC6. Phonon calculations confirm that both structures are also dynamically stable at high pressures. The electronic structure calculations show that the R3c phase is a semiconductor with a band gap of 2.21 eV and that the Amm2 phase is a semimetal. These findings help advance our understanding of the Ca-B-N ternary system. PMID- 28598604 TI - Understanding the Oxygen Evolution Reaction Mechanism on CoOx using Operando Ambient-Pressure X-ray Photoelectron Spectroscopy. AB - Photoelectrochemical water splitting is a promising approach for renewable production of hydrogen from solar energy and requires interfacing advanced water splitting catalysts with semiconductors. Understanding the mechanism of function of such electrocatalysts at the atomic scale and under realistic working conditions is a challenging, yet important, task for advancing efficient and stable function. This is particularly true for the case of oxygen evolution catalysts and, here, we study a highly active Co3O4/Co(OH)2 biphasic electrocatalyst on Si by means of operando ambient-pressure X-ray photoelectron spectroscopy performed at the solid/liquid electrified interface. Spectral simulation and multiplet fitting reveal that the catalyst undergoes chemical structural transformations as a function of the applied anodic potential, with complete conversion of the Co(OH)2 and partial conversion of the spinel Co3O4 phases to CoO(OH) under precatalytic electrochemical conditions. Furthermore, we observe new spectral features in both Co 2p and O 1s core-level regions to emerge under oxygen evolution reaction conditions on CoO(OH). The operando photoelectron spectra support assignment of these newly observed features to highly active Co4+ centers under catalytic conditions. Comparison of these results to those from a pure phase spinel Co3O4 catalyst supports this interpretation and reveals that the presence of Co(OH)2 enhances catalytic activity by promoting transformations to CoO(OH). The direct investigation of electrified interfaces presented in this work can be extended to different materials under realistic catalytic conditions, thereby providing a powerful tool for mechanism discovery and an enabling capability for catalyst design. PMID- 28598605 TI - Metal Sensing by DNA. AB - Metal ions are essential to many chemical, biological, and environmental processes. In the past two decades, many DNA-based metal sensors have emerged. While the main biological role of DNA is to store genetic information, its chemical structure is ideal for metal binding via both the phosphate backbone and nucleobases. DNA is highly stable, cost-effective, easy to modify, and amenable to combinatorial selection. Two main classes of functional DNA were developed for metal sensing: aptamers and DNAzymes. While a few metal binding aptamers are known, it is generally quite difficult to isolate such aptamers. On the other hand, DNAzymes are powerful tools for metal sensing since they are selected based on catalytic activity, thus bypassing the need for metal immobilization. In the last five years, a new surge of development has been made on isolating new metal sensing DNA sequences. To date, many important metals can be selectively detected by DNA often down to the low parts-per-billion level. Herein, each metal ion and the known DNA sequences for its sensing are reviewed. We focus on the fundamental aspect of metal binding, emphasizing the distinct chemical property of each metal. Instead of reviewing each published sensor, a high-level summary of signaling methods is made as a separate section. In principle, each signaling strategy can be applied to many DNA sequences for designing sensors. Finally, a few specific applications are highlighted, and future research opportunities are discussed. PMID- 28598607 TI - Electrochemistry and Electrochemiluminescence of Organometal Halide Perovskite Nanocrystals in Aqueous Medium. AB - The redox nature and electrochemiluminescence (ECL) of highly crystallized organometal halide perovskite CH3NH3PbBr3 nanocrystals (NCs) in aqueous medium were investigated for the first time. CH3NH3PbBr3 NCs could be electrochemically reduced to negative charge states by injecting electrons into the lowest unoccupied molecular orbitals and oxidized to positive charge states by removing electrons from the highest occupied molecular orbitals; charge transfer between NCs with positive and negative charge states could produce ECL. The redox sequence of CH3NH3PbBr3 NCs played an important role in the generation of charge transfer-mediated ECL; transient ECL could be achieved only by electrochemically reducing positive-charged NCs in an annihilation route. A large redox current was unfavorable for ECL. Charge mobility within CH3NH3PbBr3 NCs had an important effect on ECL intensity in a co-reactant route, which is promising for photovoltaic and optoelectronic device applications. Importantly, the ECL spectra of CH3NH3PbBr3 NCs were almost identical to their photoluminescence spectra, with a maximum emission around 535 nm and full width at half-maximum around 25 nm; this might open a way to obtaining monochromatic ECL using highly crystallized NCs as emitters, which makes them promising for use in color-selective ECL analysis. PMID- 28598608 TI - Ground-State Crystal Structure of Strontium Peroxide Predicted from First Principles. AB - It has been widely believed that SrO2, a typical alkaline earth metal peroxide, should adopt the tetrahedral CaC2-type structure (space group I4/mmm) at ambient pressure. Here we report a monoclinic structure (space group C2c), as predicted from first-principles swarm structure searching simulations, is energetically more favorable than the CaC2-type structure at ambient pressure and low temperature, while the I4/mmm structure is only stable at high pressure (>20 GPa) or elevated temperature conditions. A key difference between these structures is the distinct orientation of peroxide ions. Especially, frozen-phonon calculations indicate that the C2c structure can be derived by a softening mode phonon from I4/mmm structure. Furthermore, a high-pressure phase of SrO2 with P21/c symmetries containing two layers of peroxide ions with different orientations is uncovered at pressures higher than 36 GPa. Our electronic band calculations indicate that all the stable structures of SrO2 are wide band gap semiconductors. Our results represent a step forward toward a more complete understanding of the structures and properties of alkaline earth metal peroxides. PMID- 28598606 TI - 4S-Hydroxylation of Insulin at ProB28 Accelerates Hexamer Dissociation and Delays Fibrillation. AB - Daily injections of insulin provide lifesaving benefits to millions of diabetics. But currently available prandial insulins are suboptimal: The onset of action is delayed by slow dissociation of the insulin hexamer in the subcutaneous space, and insulin forms amyloid fibrils upon storage in solution. Here we show, through the use of noncanonical amino acid mutagenesis, that replacement of the proline residue at position 28 of the insulin B-chain (ProB28) by (4S)-hydroxyproline (Hzp) yields an active form of insulin that dissociates more rapidly, and fibrillates more slowly, than the wild-type protein. Crystal structures of dimeric and hexameric insulin preparations suggest that a hydrogen bond between the hydroxyl group of Hzp and a backbone amide carbonyl positioned across the dimer interface may be responsible for the altered behavior. The effects of hydroxylation are stereospecific; replacement of ProB28 by (4R)-hydroxyproline (Hyp) causes little change in the rates of fibrillation and hexamer disassociation. These results demonstrate a new approach that fuses the concepts of medicinal chemistry and protein design, and paves the way to further engineering of insulin and other therapeutic proteins. PMID- 28598609 TI - Novel 2D-NMR Approach for the Classification of Balsamic Vinegars of Modena. AB - The aim of this work is to evaluate the possibility of using 2D-NMR for the construction of classification models for balsamic vinegars of Modena. The goal was to obtain an indirect indicator of authenticity and a quality control tool. The spectral data were analyzed by chemometric methods, aiming to discriminate the samples in relation to their origin. Application of general discriminant analysis (GDA) revealed a good discrimination; the two obtained models explained 83.9% and 97.3% of the total variance with a predictive capacity of 98.6% and 98.4%, respectively. The signals of 5-HMF, beta-glucose, 2,3-butanediol, 6-acetyl glucose, and different aliphatic signals of sugars were the most significant variables. These results are very promising for giving an important contribution in quality control and characterization of such very valuable foods. PMID- 28598610 TI - Octahedral Gyroscope-like Molecules Consisting of Rhenium Rotators within Cage like Dibridgehead Diphosphine Stators: Syntheses, Substitution Reactions, Structures, and Dynamic Properties. AB - Reactions of Re(CO)5(X) (X = Cl, Br) or [Re2(CO)4(NO)2(MU-Cl)2(Cl)2] and the phosphines P((CH2)mCH?CH2)3 (m = 6, a; 7, b; 8, c) give mer,trans Re(CO)3(X)(P((CH2)mCH?CH2)3)2 (53-95%) or cis,trans-Re(CO) (NO) (Cl)2(P((CH2)6CH?CH2)3)2 (57%), respectively. Additions of Grubbs' catalyst (5-10 mol %, 0.0010-0.0012 M) and subsequent hydrogenations (PtO2, <=5 bar) yield the gyroscope-like complexes mer,trans-R e(CO)3(X)(P((CH2)n)3 P) (n = 2m + 2; X = Cl, 7a,c; Br, 8a,c; 18-61%) or cis,trans-R e(CO)(NO)(Cl)2(P((CH2)14)3 P) (14%), respectively, and/or the isomers mer,trans-R e(CO)3(X)( P(CH2)n-1 CH2)((CH2)n)( P(CH2)n-1 CH2) (X = Cl, 7'a-c; Br, 8'b; 6-27%). The latter are derived from a combination of interligand and intraligand metatheses. Reactions of 7a or 8a with NaI, Ph2Zn, or MeLi give mer,trans-R e(CO)3(X)(P((CH2)14)3 P) (X = I, 11a; Ph, 12a; Me, 13a; 34-87%). The 13C NMR spectra of 7a-c, 8a-c, 11a, and 13a show rotation of the Re(CO)3(X) moieties to be fast on the NMR time scale at room temperature (and at -90 degrees C for 8a). In contrast, the phenyl group in 12a acts as a brake, and two sets of 13C NMR signals (2:1) are observed for the methylene chains. The crystal structures of 7a, 8a, 12a, and 13a are analyzed with respect to Re(CO)3(X) rotation in solution and the solid state. PMID- 28598611 TI - Synthesis and Exciton Dynamics of Donor-Orthogonal Acceptor Conjugated Polymers: Reducing the Singlet-Triplet Energy Gap. AB - The presence of energetically low-lying triplet states is a hallmark of organic semiconductors. Even though they present a wealth of interesting photophysical properties, these optically dark states significantly limit optoelectronic device performance. Recent advances in emissive charge-transfer molecules have pioneered routes to reduce the energy gap between triplets and "bright" singlets, allowing thermal population exchange between them and eliminating a significant loss channel in devices. In conjugated polymers, this gap has proved resistant to modification. Here, we introduce a general approach to reduce the singlet-triplet energy gap in fully conjugated polymers, using a donor-orthogonal acceptor motif to spatially separate electron and hole wave functions. This new generation of conjugated polymers allows for a greatly reduced exchange energy, enhancing triplet formation and enabling thermally activated delayed fluorescence. We find that the mechanisms of both processes are driven by excited-state mixing between pi-pi*and charge-transfer states, affording new insight into reverse intersystem crossing. PMID- 28598612 TI - Dynamic Links between Lipid Storage, Toxicokinetics and Mortality in a Marine Copepod Exposed to Dimethylnaphthalene. AB - Efficiently assessing and managing the risks of pollution in the marine environment requires mechanistic models for toxic effects. The General Unified Threshold model for Survival (GUTS) provides a framework for deriving toxicokinetic-toxicodynamic (TKTD) models for the end point survival. Two recurring questions in the application of GUTS concern the most appropriate death mechanism, and whether the total body residue is a proper dose metric for toxic effects. We address these questions with a case study for dimethylnaphthalene in the marine copepod Calanus finmarchicus. A detailed analysis revealed that body residues were best explained by representing copepods with two toxicokinetic compartments: separating structural biomass and lipid storage. Toxicity is most likely related to the concentration in structure, which led to identification of "stochastic death" as the most appropriate death mechanism. Interestingly, the parametrized model predicts that lipid content will have only minor influence on short-term toxicity. However, the toxicants stored in lipids may have more substantial impacts in situations not included in our experiments (e.g., during diapause and gonad maturation), and for contaminant transfer to eggs and copepod predators. PMID- 28598613 TI - Role of Sample Processing Strategies at the European Union National Reference Laboratories (NRLs) Concerning the Analysis of Pesticide Residues. AB - The guidance document SANTE 11945/2015 recommends that cereal samples be milled to a particle size preferably smaller than 1.0 mm and that extensive heating of the samples should be avoided. The aim of the present study was therefore to investigate the differences in milling procedures, obtained particle size distributions, and the resulting pesticide residue recovery when cereal samples were milled at the European Union National Reference Laboratories (NRLs) with their routine milling procedures. A total of 23 NRLs participated in the study. The oat and rye samples milled by each NRL were sent to the European Union Reference Laboratory on Cereals and Feedingstuff (EURL) for the determination of the particle size distribution and pesticide residue recovery. The results showed that the NRLs used several different brands and types of mills. Large variations in the particle size distributions and pesticide extraction efficiencies were observed even between samples milled by the same type of mill. PMID- 28598614 TI - Enantio- and Diastereoselective Spiroketalization Catalyzed by Chiral Iridium Complex. AB - Iridium-(P,olefin) complex-catalyzed enantio- and diastereoselective formation of substituted spiroketals from racemic, allylic carbonates is reported, which enables the installation of multiple stereogenic centers in a single operation. The protocol was effective for the preparation of a collection of spiroketals of various ring sizes and substituents, including heteroatoms with high enantio- and diastereoselectivity. Furthermore, cascade reactions that couple this enantio- and diastereoselective transformation to additional reversible processes have been achieved to exert concomitant stereocontrol over additional stereogenic centers. PMID- 28598617 TI - Role of N-Heterocyclic Carbenes as Ligands in Iridium Carbonyl Clusters. AB - The low-energy isomers of Irx(CO)y(NHC)z (x = 1, 2, 4) are investigated with density functional theory (DFT) and correlated molecular orbital theory at the coupled cluster CCSD(T) level. The structures, relative energies, ligand dissociation energies, and natural charges are calculated. The energies of tetrairidium cluster are predicted at the CAM-B3LYP level that best fit the CCSD(T) results compared with the other four functionals in the benchmark calculations. The NHC's behave as stronger sigma donors compared with CO's and have higher ligand dissociation energies (LDEs). For smaller isomers, the increase in the LDEs of the CO's and the decrease in the LDEs of the NHC's as more NHC's are substituted for CO's are due to pi-back-bonding and electron repulsion, whereas the trend of how the LDEs change for larger isomers is not obvious. We demonstrate a MU3-CO resulting from the high electron density of the metal centers in these complexes, as the bridging CO's and the MU3-CO's can carry more negative charge and stabilize the isomers. Comparison of calculations for a mixed tetrairidum cluster consisting of two calixarene-phosphine ligands and a single calixarene-NHC ligand in the basal plane demonstrated good agreement in terms of both the ligand substitution symmetry (C3v derived), as well as the infrared spectra. Similar comparisons were also performed between calculations and experiment for novel monosubstituted calixarene-NHC tetrairidium clusters. PMID- 28598616 TI - Identification of BMI1 Promoter Inhibitors from Beaumontia murtonii and Eugenia operculata. AB - B-Cell-specific Moloney murine leukemia virus insertion region 1 (BMI1) is a core component of the polycomb repressive complex 1 (PRC1). Abnormal expression of BMI1 is associated with a number of human malignances and cancer stem cells (CSCs), which cause chemotherapy resistance. Therefore, small molecules that inhibit BMI1 expression are potential candidates for cancer therapy. In this study, a cell-based reporter gene assay was developed that allowed BMI1 promoter activity to be measured in 293T human embryonic kidney cells based on luciferase expression levels. Using this screening assay, the methanol-soluble extracts of Beaumontia murtonii and Eugenia operculata were selected as leads. Bioassay guided fractionation of the extracts led to the isolation of three known cardenolides (1-3) and one new compound (4) from B. murtonii and two known triterpenoids (5 and 6) and one new compound (7) from E. operculata. These seven compounds inhibited BMI1 promoter activity (IC50 range 0.093-23.0 MUM), and the most active compound, wallichoside (1), was further evaluated. Western blot analysis revealed that wallichoside (1) decreases BMI1 protein levels in HCT116 human colon carcinoma cells, and flow cytometry analysis showed that it significantly reduced levels of the CSC biomarker epithelial cell adhesion molecule. Wallichoside (1) also inhibited sphere formation of Huh7 human hepatocellular carcinoma cells, indicating that it diminished the self-renewal capability of CSCs. PMID- 28598615 TI - Induction of Slug by Chronic Exposure to Single-Walled Carbon Nanotubes Promotes Tumor Formation and Metastasis. AB - Carbon nanotubes (CNTs) represent a major class of engineered nanomaterials that are being used in diverse fields. However, their use has increasingly become a concern because of their carcinogenic potential. Accumulating evidence has demonstrated that certain types of CNTs are carcinogenic or tumor-promoting in animal models. However, the underlying molecular and cellular mechanisms are unclear. Here, we report that chronic exposure to single-walled (SW) CNTs results in the induction of Slug, a key transcription factor that induces an epithelial mesenchymal transition (EMT), in human lung epithelial cells. We show that SWCNT induced Slug upregulation plays a critical role in the aggressive phenotype of SWCNT-exposed cells, which includes increased cell migration, invasion, and anchorage-independent cell growth. Our in vivo studies also show that SWCNT induced Slug upregulation and EMT activation play a pivotal role in tumor formation and metastasis. Our findings illustrate a direct link between CNT induced Slug upregulation, EMT activation, and tumor formation and metastasis, and they highlight the potential of CNT-induced Slug upregulation as a target for future risk assessment and prevention of CNT-associated diseases. PMID- 28598618 TI - Acetic Acid Mediated Sulfonylation of Allenylphosphine Oxides: Divergent Synthesis of Bifunctionalized 1,3-Butadienes and Allenes. AB - An acetic acid-mediated sulfonylation of allenylphosphine oxides with sodium sulfinates is disclosed. This new methodology involves tandem (Ar)O-C(sp3) bond cleavage and C(sp2)/C(sp3)-SO2 formation toward divergent synthesis of sulfonyl- and phosphinyl-bifunctionalized 1,3-butadienes or allenes, depending on the substitution at the terminal carbon atoms of allenylphosphine oxides. The reaction mechanism is explained via an acid-accelerated synergistic process. PMID- 28598619 TI - Using Structural Kinetic Modeling To Identify Key Determinants of Stability in Reaction Networks. AB - Kinetic modeling is increasingly used to understand the reaction dynamics of metabolic systems. However, one major drawback of kinetic modeling is that appropriate rate parameters required to implement such models are often unavailable. To circumvent this limitation, an approach known as structural kinetic modeling was developed as a way to understand the dynamics of reaction networks without explicitly requiring rate parameters. This study describes a novel approach to use structural kinetic modeling to identify reaction components that contribute most significantly to mediating network stability. We applied this method to analyze the metabolic pathway of glycolysis in yeast. As a result, we identified specific metabolic components that contribute most significantly to defining the stability properties of the glycolysis reaction network and predict the responses of these components to perturbations. These results were validated via comparison to a conventional kinetic model of glycolysis. Thus, applying our approach allows more detailed information about the stability and dynamics of the metabolic network to now be accessible without requiring rate parameters. We anticipate that this method can focus efforts of experimental studies by identifying the susceptibility of reaction components to metabolic engineering. The approach may be applied to a variety of complex reaction networks. PMID- 28598620 TI - Full Investigation of Angle Dependence in Dip-Coating Sol-Gel Films. AB - Dip-coating is one of the most convenient methods used in laboratory and industry to deposit a solid layer onto a surface with a controlled thickness from a chemical solution. The present Article investigates the influence of the withdrawal speed on the film thickness and homogeneity with respect to the dipping angle ranging from 90 degrees (conventional vertical configuration) to 1 degrees (quasi-horizontal configuration). Several advantages were found in the latter extreme low-dipping angle conditions that are (i) an available wider range of thickness, (ii) the elimination of the perturbations/effects induced by evaporation, and (iii) the compatibility with large surface and single face deposition at high throughput and using a minimal amount of solution. One shows that experimental data follow the Landau-Levich model, modified by Tallmadge for angle dependence, only for intermediate regimes of speed. A maximal thickness limited by the physical-chemical characteristics of the initial solution is reached at high speeds while a minimal thickness, corresponding to a single layer of solute interacting with the substrate surface can be obtained at very low speeds. PMID- 28598621 TI - Roughness in Surface Force Measurements: Extension of DLVO Theory To Describe the Forces between Hafnia Surfaces. AB - The interaction between colloidal particles is commonly viewed through the lens of DLVO theory, whereby the interaction is described as the sum of the electrostatic and dispersion forces. For similar materials acting across a medium at pH values remote from the isoelectric point the theory typically involves an electrostatic repulsion that is overcome by dispersion forces at very small separations. However, the dominance of the dispersion forces at short separations is generally not seen in force measurements, with the exception of the interaction between mica surfaces. The discrepancy for silica surfaces has been attributed to hydration forces, but this does not explain the situation for titania surfaces where the dispersion forces are very much larger. Here, the interaction forces between very smooth hafnia surfaces have been measured using the colloid probe technique and the forces evaluated within the DLVO framework, including both hydration forces and the influence of roughness. The measured forces across a wide range of pH at different salt concentrations are well described with a single parameter for the surface roughness. These findings show that even small degrees of surface roughness significantly alter the form of the interaction force and therefore indicate that surface roughness needs to be included in the evaluation of surface forces between all surfaces that are not ideally smooth. PMID- 28598622 TI - Energetic Analysis of Adsorption and Absorption of Small Molecule to Nanodroplet of Water. AB - Adsorption and absorption were analyzed for nonpolar and polar solutes to a water droplet of nanometer size and to a planar slab. All-atom molecular dynamics simulation was performed, and the free energy change for bringing the solute to the water aggregate was computed over a wide range of temperature. It was seen in both the droplet and slab systems that the solute is preferably located at the surface, and the propensity of the nonpolar solute at the surface relative to the bulk was found to be larger in the droplet than in the slab. A molecular-sized curvature thus enhances the surface propensity of a nonpolar solute, whereas the curvature effect is weaker for polar one. The attractive and repulsive interactions of the solute with water were further analyzed, and the role of the repulsive interaction is discussed with respect to the stability of the surface bound state. PMID- 28598623 TI - A pOH Jump Driven by N?N Out-of-Plane Motion in the Photoisomerization of Water Solvated Triazabutadiene. AB - Utilization of photoinitiated isomerization reaction has recently emerged as a very promising platform to modulate the basicity of compounds; however, theoretical insight into its regulatory mechanism remains largely unknown and needs to be addressed. For the first time, an unexpected trans-cis photoisomerization via the N?N out of plane (NOOP) motion triggered by an in plane inversion of N-N?N moiety was computationally demonstrated to regulate the pOH jump of water-solvated triazabutadiene by using the multiconfigurational perturbation theory together with the calculation of rate constants of protonation-deprotonation reactions. Kinetic analyses show that the dramatic pOH change can be attributed to the reinforced intramolecular hydrogen bonding resulting from water cluster reorientation and the enhanced coupling between the rotated pi orbital and N lone pair of triazabutadiene in the remarkable trans-cis photoisomerization. PMID- 28598624 TI - Synthesis of Deoxyglycosides by Desulfurization under UV Light. AB - This study was performed to develop a highly efficient method whereby desulfurization could be completed in 0.5 h under ultraviolet light, at room temperature, and in the presence of trialkylphosphine. Using this method, deoxyglycosides could be produced from sulfur-containing glycosides in almost quantitative yields. The much higher reactivity of desulfurization with triethylphosphine versus that with triethylphosphite is also discussed. PMID- 28598625 TI - Weight-Averaged Anharmonic Vibrational Analysis of Hydration Structures of Polyamide 6. AB - Structures of polyamide 6 are investigated for different hydration levels using molecular dynamics (MD) simulations and quantum vibrational calculations. The MD simulations have shown that hydration leads to an increase in the diffusion coefficient, accompanied by a growth of water clusters in the polymer. The IR difference spectra upon hydration are calculated using a weight-averaged method incorporating anharmonicity of the potential energy surface. The predicted IR difference spectrum for the amide A band is in quantitative agreement with the experiment [ Iwamoto , R. ; Murase , H. J. Polym. Sci., Part B: Polym. Phys. 2003 , 41 , 1722 - 1729 ]. The proposed method, combined with experimental IR difference spectra, makes it feasible to elucidate the atomistic structure of hydrated polymer materials. PMID- 28598626 TI - CO2 Hydration Shell Structure and Transformation. AB - The hydration-shell of CO2 is characterized using Raman multivariate curve resolution (Raman-MCR) spectroscopy combined with ab initio molecular dynamics (AIMD) vibrational density of states simulations, to validate our assignment of the experimentally observed high-frequency OH band to a weak hydrogen bond between water and CO2. Our results reveal that while the hydration-shell of CO2 is highly tetrahedral, it is also occasionally disrupted by the presence of entropically stabilized defects associated with the CO2-water hydrogen bond. Moreover, we find that the hydration-shell of CO2 undergoes a temperature dependent structural transformation to a highly disordered (less tetrahedral) structure, reminiscent of the transformation that takes place at higher temperatures around much larger oily molecules. The biological significance of the CO2 hydration shell structural transformation is suggested by the fact that it takes place near physiological temperatures. PMID- 28598627 TI - Charge-Transfer Complex Promoted C-N Bond Activation for Ni-Catalyzed Carbonylation. AB - A new strategy was developed for activation of C-N bond via formation of an amine I2 charge-transfer complex, which facilitates the inert C-N bond activation via oxidative addition with Ni(0). This strategy has been successfully applied in the Ni-catalyzed carbonylation of benzylamines via direct insertion of CO into the C N bond, which provided a straightforward and rapid approach to arylacetamides in the presence of catalytic amounts of I2 and Ni catalyst. Mechanistic studies suggested that a benzyl radical generated via the oxidative addition was involved in the present reaction. PMID- 28598628 TI - Bipolar Photothermoelectric Effect Across Energy Filters in Single Nanowires. AB - The photothermoelectric (PTE) effect uses nonuniform absorption of light to produce a voltage via the Seebeck effect and is of interest for optical sensing and solar-to-electric energy conversion. However, the utility of PTE devices reported to date has been limited by the need to use a tightly focused laser spot to achieve the required, nonuniform illumination and by their dependence upon the Seebeck coefficients of the constituent materials, which exhibit limited tunability and, generally, low values. Here, we use InAs/InP heterostructure nanowires to overcome these limitations: first, we use naturally occurring absorption "hot spots" at wave mode maxima within the nanowire to achieve sharp boundaries between heated and unheated subwavelength regions of high and low absorption, allowing us to use global illumination; second, we employ carrier energy-filtering heterostructures to achieve a high Seebeck coefficient that is tunable by heterostructure design. Using these methods, we demonstrate PTE voltages of hundreds of millivolts at room temperature from a globally illuminated nanowire device. Furthermore, we find PTE currents and voltages that change polarity as a function of the wavelength of illumination due to spatial shifting of subwavelength absorption hot spots. These results indicate the feasibility of designing new types of PTE-based photodetectors, photothermoelectrics, and hot-carrier solar cells using nanowires. PMID- 28598629 TI - Charge Dynamics and Optolectronic Properties in HgTe Colloidal Quantum Wells. AB - We investigate the electronic and transport properties of HgTe 2D colloidal quantum wells. We demonstrate that the material can be made p- or n-type depending on the capping ligands. In addition to the control of majority carrier type, the surface chemistry also strongly affects the photoconductivity of the material. These transport measurements are correlated with the electronic structure determined by high resolution X-ray photoemission. We attribute the change of majority carriers to the strong hybridization of an n-doped HgS layer resulting from capping the HgTe nanoplatelets by S2- ions. We further investigate the gate and temperature dependence of the photoresponse and its dynamics. We show that the photocurrent rise and fall times can be tuned from 100 MUs to 1 ms using the gate bias. Finally, we use time-resolved photoemission spectroscopy as a probe of the transport relaxation to determine if the observed dynamics are limited by a fundamental process such as trapping. These pump probe surface photovoltage measurements show an even faster relaxation in the 100-500 ns range, which suggests that the current performances are rather limited by geometrical factors. PMID- 28598630 TI - A General Copper Catalyst for Photoredox Transformations of Organic Halides. AB - A broadly applicable copper catalyst for photoredox transformations of organic halides is reported. Upon visible light irradiation in the presence of catalytic amounts of [(DPEphos)(bcp)Cu]PF6 and an amine, a range of unactivated aryl and alkyl halides were shown to be smoothly activated through a rare Cu(I)/Cu(I)*/Cu(0) catalytic cycle. This complex efficiently catalyzes a series of radical processes, including reductions, cyclizations, and direct arylation of arenes. PMID- 28598631 TI - Thermally Activated Tunneling Transition in a Photoswitchable Single-Molecule Electrical Junction. AB - Exploring the charge transport process in molecular junctions is essential to the development of molecular electronics. Here, we investigate the temperature dependent charge transport mechanism of carbon electrode-diarylethene single molecule junctions, which possess photocontrollable molecular orbital energy levels due to reversible photoisomerization of individual diarylethenes between open and closed conformations. Both the experimental results and theoretical calculations consistently demonstrate that the vibronic coupling (thermally activated at the proper temperature) drives the transition of charge transport in the junctions from coherent tunneling to incoherent transport. Due to the subtle electron-phonon coupling effect, incoherent transport in the junctions proves to have different activation energies, depending on the photoswitchable molecular energy levels of two different conformations. These results improve fundamental understanding of charge transport mechanisms in molecular junctions and should lead to the rapid development of functional molecular devices toward practical applications. PMID- 28598632 TI - Dearomatization Approach to 2-Trifluoromethylated Benzofuran and Dihydrobenzofuran Products. AB - A mild dearomatization enabled ortho-selective replacement of an aromatic C-H bond with a hexafluoroacetylacetone (hfacac) substituent has been developed. This reaction is dependent on a hypervalent iodine generated phenoxonium intermediate, a critical choice of solvent, and reagent addition order. The fluorinated dihydrobenzofuran product can be transformed into dihydrobenzofuran and benzofuran products decorated with a 2-trifluoromethyl group. The 3 trifluoromethylacyl substituted benzofurans rapidly form hydrates, which can be reduced to the corresponding alcohols. PMID- 28598633 TI - Ochracenes A-I, Humulane-Derived Sesquiterpenoids from the Antarctic Fungus Aspergillus ochraceopetaliformis. AB - Nine new humulane-derived sesquiterpenoids, ochracenes A-I (1-9), were isolated from the Antarctic fungus Aspergillus ochraceopetaliformis SCSIO 05702. Their structures including absolute configurations were elucidated on the basis of spectroscopic analysis, Mosher's method, and electronic circular dichroism analysis. Compared with previous humulane-type sesquiterpenoids, ochracenes A-I (1-9) featured novel carbon skeletons with corresponding methyl migration, ring cleavage, and carbon loss. Two unprecedented 8,9-secocyclic sesquiterpenoids (2 and 3) exhibited inhibitory effects on lipopolysaccharide-induced NO release in RAW 264.7 mouse macrophage cell lines with IC50 values of 14.6 +/- 0.5 and 18.3 +/- 1.7 MUM, respectively. PMID- 28598634 TI - Design and Synthesis of gamma- and delta-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity. AB - Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low clearance, orally bioavailable, and CNS-penetrant M1-selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs. PMID- 28598635 TI - Deciphering Front-Side Complex Formation in SN2 Reactions via Dynamics Mapping. AB - Due to their importance in organic chemistry, the atomistic understanding of bimolecular nucleophilic substitution (SN2) reactions shows exponentially growing interest. In this publication, the effect of front-side complex (FSC) formation is uncovered via quasi-classical trajectory computations combined with a novel analysis method called trajectory orthogonal projection (TOP). For both F- + CH3Y [Y = Cl,I] reactions, the lifetime distributions of the F-...YCH3 front-side complex revealed weakly trapped nucleophiles (F-). However, only the F- + CH3I reaction features strongly trapped nucleophiles in the front-side region of the prereaction well. Interestingly, both back-side and front-side attack show propensity to long-lived FSC formation. Spatial distributions of the nucleophile demonstrate more prominent FSC formation in case of the F- + CH3I reaction compared to F- + CH3Cl. The presence of front-side intermediates and the broad spatial distribution in the back-side region may explain the indirect nature of the F- + CH3I reaction. PMID- 28598636 TI - Formal [3 + 4] Annulation of alpha,beta-Unsaturated Acyl Azoliums: Access to Enantioenriched N-H-Free 1,5-Benzothiazepines. AB - An unprecedented formal [3 + 4] annulation of alpha,beta-unsaturated acyl azoliums with 2-aminobenzenethiols has been utilized to synthesize enantioenriched N-H-free 1,5-benzothiazepines, which are recognized as privileged structures in numerous biologically active scaffolds. This protocol offers a rapid and direct pathway to access the target compounds with high enantioselectivities and has been applied in the concise synthesis of chiral drug (R)-thiazesim. PMID- 28598637 TI - Access to Benzo[a]carbazoles and Indeno[1,2-c]quinolines by a Gold(I)-Catalyzed Tunable Domino Cyclization of Difunctional 1,2-Diphenylethynes. AB - The cyclization order of the difunctional 1,2-diphenylethynes was precisely tuned under the catalysis of gold by changing the nitrogen substitution of the substrates, leading to the facile preparation of benzo[a]carbazole and indeno[1,2 c]quinoline derivatives. The mechanisms of these domino cyclizations were probed by control experiments, and an insight into the selectivity of the cyclization was gained by density functional theory (DFT) calculations. This research represents a unified and common method to access benzo[a]carbazoles and indeno[1,2-c]quinolines. PMID- 28598638 TI - Many-Body Topological Invariants for Fermionic Symmetry-Protected Topological Phases. AB - We define and compute many-body topological invariants of interacting fermionic symmetry-protected topological phases, protected by an orientation-reversing symmetry, such as time-reversal or reflection symmetry. The topological invariants are given by partition functions obtained by a path integral on unoriented spacetime which, as we show, can be computed for a given ground state wave function by considering a nonlocal operation, "partial" reflection or transpose. As an application of our scheme, we study the Z_{8} and Z_{16} classification of topological superconductors in one and three dimensions. PMID- 28598639 TI - Attraction Controls the Inversion of Order by Disorder in Buckled Colloidal Monolayers. AB - We show how including attraction in interparticle interactions reverses the effect of fluctuations in ordering of a prototypical artificial frustrated system. Buckled colloidal monolayers exhibit the same ground state as the Ising antiferromagnet on a deformable triangular lattice, but it is unclear if ordering in the two systems is driven by the same geometric mechanism. By a real-space expansion we find that, for buckled colloids, bent stripes constitute the stable phase, whereas in the Ising antiferromagnet straight stripes are favored. For generic pair potentials we show that attraction governs this selection mechanism, in a manner that is linked to local packing considerations. This supports the geometric origin of entropy in jammed sphere packings and provides a tool for designing self-assembled colloidal structures. PMID- 28598640 TI - Cold Anisotropically Interacting van der Waals Molecule: TiHe. AB - We have used laser ablation and helium buffer-gas cooling to produce titanium helium van der Waals molecules at cryogenic temperatures. The molecules were detected through laser-induced fluorescence spectroscopy. Ground-state Ti(a^{3}F_{2})-He binding energies were determined for the ground and first rotationally excited states from studying equilibrium thermodynamic properties, and found to agree well with theoretical calculations based on newly calculated ab initio Ti-He interaction potentials, opening up novel possibilities for studying the formation, dynamics, and nonuniversal chemistry of van der Waals clusters at low temperatures. PMID- 28598641 TI - Fingerprints of a Bosonic Symmetry-Protected Topological State in a Quantum Point Contact. AB - In this work, we study the transport through a quantum point contact for bosonic helical liquid that exists at the edge of a bilayer graphene under a strong magnetic field. We identify "smoking gun" transport signatures to distinguish a bosonic symmetry-protected topological (BSPT) state from a fermionic two-channel quantum spin Hall (QSH) state in this system. In particular, a novel charge insulator-spin-conductor phase is found for the BSPT state, while either the charge-insulator-spin-insulator or the charge-conductor-spin-conductor phase is expected for the two-channel QSH state. Consequently, a simple transport measurement will reveal the fingerprint of bosonic topological physics in bilayer graphene systems. PMID- 28598642 TI - Twist-Bend Coupling and the Torsional Response of Double-Stranded DNA. AB - Recent magnetic tweezers experiments have reported systematic deviations of the twist response of double-stranded DNA from the predictions of the twistable wormlike chain model. Here we show, by means of analytical results and computer simulations, that these discrepancies can be resolved if a coupling between twist and bend is introduced. We obtain an estimate of 40+/-10 nm for the twist-bend coupling constant. Our simulations are in good agreement with high-resolution, magnetic-tweezers torque data. Although the existence of twist-bend coupling was predicted long ago [J. Marko and E. Siggia, Macromolecules 27, 981 (1994)MAMOBX0024-929710.1021/ma00082a015], its effects on the mechanical properties of DNA have been so far largely unexplored. We expect that this coupling plays an important role in several aspects of DNA statics and dynamics. PMID- 28598643 TI - From Glass Formation to Icosahedral Ordering by Curving Three-Dimensional Space. AB - Geometric frustration describes the inability of a local molecular arrangement, such as icosahedra found in metallic glasses and in model atomic glass formers, to tile space. Local icosahedral order, however, is strongly frustrated in Euclidean space, which obscures any causal relationship with the observed dynamical slowdown. Here we relieve frustration in a model glass-forming liquid by curving three-dimensional space onto the surface of a 4-dimensional hypersphere. For sufficient curvature, frustration vanishes and the liquid "freezes" in a fully icosahedral structure via a sharp "transition." Frustration increases upon reducing the curvature, and the transition to the icosahedral state smoothens while glassy dynamics emerge. Decreasing the curvature leads to decoupling between dynamical and structural length scales and the decrease of kinetic fragility. This sheds light on the observed glass-forming behavior in Euclidean space. PMID- 28598644 TI - Proof of Concept for an Ultrasensitive Technique to Detect and Localize Sources of Elastic Nonlinearity Using Phononic Crystals. AB - The appearance of nonlinear effects in elastic wave propagation is one of the most reliable and sensitive indicators of the onset of material damage. However, these effects are usually very small and can be detected only using cumbersome digital signal processing techniques. Here, we propose and experimentally validate an alternative approach, using the filtering and focusing properties of phononic crystals to naturally select and reflect the higher harmonics generated by nonlinear effects, enabling the realization of time-reversal procedures for nonlinear elastic source detection. The proposed device demonstrates its potential as an efficient, compact, portable, passive apparatus for nonlinear elastic wave sensing and damage detection. PMID- 28598645 TI - Cavity Carving of Atomic Bell States. AB - We demonstrate entanglement generation of two neutral atoms trapped inside an optical cavity. Entanglement is created from initially separable two-atom states through carving with weak photon pulses reflected from the cavity. A polarization rotation of the photons heralds the entanglement. We show the successful implementation of two different protocols and the generation of all four Bell states with a maximum fidelity of (90+/-2)%. The protocol works for any distance between cavity-coupled atoms, and no individual addressing is required. Our result constitutes an important step towards applications in quantum networks, e.g., for entanglement swapping in a quantum repeater. PMID- 28598646 TI - Semiflexible Polymers in Spherical Confinement: Bipolar Orientational Order Versus Tennis Ball States. AB - Densely packed semiflexible polymers with contour length L confined in spheres with radius R of the same order as L cannot exhibit uniform nematic order. Depending on the chain stiffness (which we vary over a wide range), highly distorted structures form with topological defects on the sphere surface. These structures are completely different from previously observed ones of very long chains winding around the inner surface of spheres and from nematic droplets. At high densities, a thin shell of polymers close to the sphere surface exhibits a tennis ball texture due to the confinement-induced gradual bending of polymer bonds. In contrast, when the contour length of the chains is significantly smaller than the radius of the confining sphere, a few bent smectic layers form in the sphere. Molecular dynamics simulations demonstrate these complex structures, and suitable order parameters characterizing them are proposed. PMID- 28598647 TI - Role of the Intercrystalline Tie Chains Network in the Mechanical Response of Semicrystalline Polymers. AB - We examine the microscopic origin of the tensile response in semicrystalline polymers by performing large-scale molecular dynamics simulations of various chain lengths. We investigate the microscopic rearrangements of the polymers during tensile deformation and show that the intercrystalline chain connections known as tie chains contribute significantly to the elastic and plastic response. These results suggest that the mechanical behavior of semicrystalline polymers is controlled by two interpenetrated networks of entanglements and tie chains. PMID- 28598648 TI - Origin of Granular Capillarity Revealed by Particle-Based Simulations. AB - When a thin tube is dipped into water, the water will ascend to a certain height, against the action of gravity. While this effect, termed capillarity, is well known, recent experiments have shown that agitated granular matter reveals a similar behavior. Namely, when a vertical tube is inserted into a container filled with granular material and is then set into vertical vibration, the particles rise up along the tube. In the present Letter, we investigate the effect of granular capillarity by means of numerical simulations and show that the effect is caused by convection of the granular material in the container. Moreover, we identify two regimes of behavior for the capillary height H_{c}^{infinity} depending on the tube-to-particle-diameter ratio, D/d. For large D/d, a scaling of H_{c}^{infinity} with the inverse of the tube diameter, which is reminiscent of liquids, is observed. However, when D/d decreases down to values smaller than a few particle sizes, a uniquely granular behavior is observed where H_{c}^{infinity} increases linearly with the tube diameter. PMID- 28598649 TI - Impact of Next-to-Leading Order Contributions to Cosmic Microwave Background Lensing. AB - In this Letter we study the impact on cosmological parameter estimation, from present and future surveys, due to lensing corrections on cosmic microwave background temperature and polarization anisotropies beyond leading order. In particular, we show how post-Born corrections, large-scale structure effects, and the correction due to the change in the polarization direction between the emission at the source and the detection at the observer are non-negligible in the determination of the polarization spectra. They have to be taken into account for an accurate estimation of cosmological parameters sensitive to or even based on these spectra. We study in detail the impact of higher order lensing on the determination of the tensor-to-scalar ratio r and on the estimation of the effective number of relativistic species N_{eff}. We find that neglecting higher order lensing terms can lead to misinterpreting these corrections as a primordial tensor-to-scalar ratio of about O(10^{-3}). Furthermore, it leads to a shift of the parameter N_{eff} by nearly 2sigma considering the level of accuracy aimed by future S4 surveys. PMID- 28598650 TI - Cavity Mediated Manipulation of Distant Spin Currents Using a Cavity-Magnon Polariton. AB - Using electrical detection of a strongly coupled spin-photon system comprised of a microwave cavity mode and two magnetic samples, we demonstrate the long distance manipulation of spin currents. This distant control is not limited by the spin diffusion length, instead depending on the interplay between the local and global properties of the coupled system, enabling systematic spin current control over large distance scales (several centimeters in this work). This flexibility opens the door to improved spin current generation and manipulation for cavity spintronic devices. PMID- 28598651 TI - Testing General Relativity with Stellar Orbits around the Supermassive Black Hole in Our Galactic Center. AB - We demonstrate that short-period stars orbiting around the supermassive black hole in our Galactic center can successfully be used to probe the gravitational theory in a strong regime. We use 19 years of observations of the two best measured short-period stars orbiting our Galactic center to constrain a hypothetical fifth force that arises in various scenarios motivated by the development of a unification theory or in some models of dark matter and dark energy. No deviation from general relativity is reported and the fifth force strength is restricted to an upper 95% confidence limit of |alpha|<0.016 at a length scale of lambda=150 astronomical units. We also derive a 95% confidence upper limit on a linear drift of the argument of periastron of the short-period star S0-2 of |omega[over ]_{S0-2}|<1.6*10^{-3} rad/yr, which can be used to constrain various gravitational and astrophysical theories. This analysis provides the first fully self-consistent test of the gravitational theory using orbital dynamic in a strong gravitational regime, that of a supermassive black hole. A sensitivity analysis for future measurements is also presented. PMID- 28598652 TI - Erratum: First-Principles Approach to Calculating Energy Level Alignment at Aqueous Semiconductor Interfaces [Phys. Rev. Lett. 113, 176802 (2014)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.113.176802. PMID- 28598653 TI - Macroscopic Two-Dimensional Polariton Condensates. AB - We report a record-size, two-dimensional polariton condensate of a fraction of a millimeter radius free from the presence of an exciton reservoir. This macroscopically occupied state is formed by the ballistically expanding polariton flow that relaxes and condenses over a large area outside of the excitation spot. The density of this trap-free condensate is <1 polariton/MUm^{2}, reducing the phase noise induced by the interaction energy. Moreover, the backflow effect, recently predicted for the nonparabolic polariton dispersion, is observed here for the first time in the fast-expanding wave packet. PMID- 28598654 TI - Subfemtosecond Control of Molecular Fragmentation by Hard X-Ray Photons. AB - Tuning hard x-ray excitation energy along Cl 1s->sigma^{*} resonance in gaseous HCl allows manipulating molecular fragmentation in the course of the induced multistep ultrafast dissociation. The observations are supported by theoretical modeling, which shows a strong interplay between the topology of the potential energy curves, involved in the Auger cascades, and the so-called core-hole clock, which determines the time spent by the system in the very first step. The asymmetric profile of the fragmentation ratios reflects different dynamics of nuclear wave packets dependent on the photon energy. PMID- 28598655 TI - Efficient Multiphoton Generation in Waveguide Quantum Electrodynamics. AB - Engineering quantum states of light is at the basis of many quantum technologies such as quantum cryptography, teleportation, or metrology among others. Though, single photons can be generated in many scenarios, the efficient and reliable generation of complex single-mode multiphoton states is still a long-standing goal in the field, as current methods either suffer from low fidelities or small probabilities. Here we discuss several protocols which harness the strong and long-range atomic interactions induced by waveguide QED to efficiently load excitations in a collection of atoms, which can then be triggered to produce the desired multiphoton state. In order to boost the success probability and fidelity of each excitation process, atoms are used to both generate the excitations in the rest, as well as to herald the successful generation. Furthermore, to overcome the exponential scaling of the probability of success with the number of excitations, we design a protocol to merge excitations that are present in different internal atomic levels with a polynomial scaling. PMID- 28598656 TI - Erratum: Anatomy of Dzyaloshinskii-Moriya Interaction at Co/Pt Interfaces [Phys. Rev. Lett. 115, 267210 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.115.267210. PMID- 28598657 TI - Reduced Transition Probabilities for the Gamma Decay of the 7.8 eV Isomer in ^{229}Th. AB - The reduced magnetic dipole and electric quadrupole transition probabilities for the radiative decay of the ^{229}Th 7.8 eV isomer to the ground state are predicted within a detailed nuclear-structure model approach. We show that the presence and decay of this isomer can only be accounted for by the Coriolis mixing emerging from a remarkably fine interplay between the coherent quadrupole octupole motion of the nuclear core and the single-nucleon motion within a reflection-asymmetric deformed potential. We find that the magnetic dipole transition probability which determines the radiative lifetime of the isomer is considerably smaller than presently estimated. The so-far disregarded electric quadrupole component may have non-negligible contributions to the internal conversion channel. These findings support new directions in the experimental search of the ^{229}Th transition frequency for the development of a future nuclear frequency standard. PMID- 28598658 TI - Long-Range Repulsion Between Spatially Confined van der Waals Dimers. AB - It is an undisputed textbook fact that nonretarded van der Waals (vdW) interactions between isotropic dimers are attractive, regardless of the polarizability of the interacting systems or spatial dimensionality. The universality of vdW attraction is attributed to the dipolar coupling between fluctuating electron charge densities. Here, we demonstrate that the long-range interaction between spatially confined vdW dimers becomes repulsive when accounting for the full Coulomb interaction between charge fluctuations. Our analytic results are obtained by using the Coulomb potential as a perturbation over dipole-correlated states for two quantum harmonic oscillators embedded in spaces with reduced dimensionality; however, the long-range repulsion is expected to be a general phenomenon for spatially confined quantum systems. We suggest optical experiments to test our predictions, analyze their relevance in the context of intermolecular interactions in nanoscale environments, and rationalize the recent observation of anomalously strong screening of the lateral vdW interactions between aromatic hydrocarbons adsorbed on metal surfaces. PMID- 28598659 TI - Geometric Correlations Mitigate the Extreme Vulnerability of Multiplex Networks against Targeted Attacks. AB - We show that real multiplex networks are unexpectedly robust against targeted attacks on high-degree nodes and that hidden interlayer geometric correlations predict this robustness. Without geometric correlations, multiplexes exhibit an abrupt breakdown of mutual connectivity, even with interlayer degree correlations. With geometric correlations, we instead observe a multistep cascading process leading into a continuous transition, which apparently becomes fully continuous in the thermodynamic limit. Our results are important for the design of efficient protection strategies and of robust interacting networks in many domains. PMID- 28598660 TI - Solving Systems of Linear Equations with a Superconducting Quantum Processor. AB - Superconducting quantum circuits are a promising candidate for building scalable quantum computers. Here, we use a four-qubit superconducting quantum processor to solve a two-dimensional system of linear equations based on a quantum algorithm proposed by Harrow, Hassidim, and Lloyd [Phys. Rev. Lett. 103, 150502 (2009)PRLTAO0031-900710.1103/PhysRevLett.103.150502], which promises an exponential speedup over classical algorithms under certain circumstances. We benchmark the solver with quantum inputs and outputs, and characterize it by nontrace-preserving quantum process tomography, which yields a process fidelity of 0.837+/-0.006. Our results highlight the potential of superconducting quantum circuits for applications in solving large-scale linear systems, a ubiquitous task in science and engineering. PMID- 28598661 TI - Randomized Benchmarking of Barrier versus Tilt Control of a Singlet-Triplet Qubit. AB - Decoherence due to charge noise is one of the central challenges in using spin qubits in semiconductor quantum dots as a platform for quantum information processing. Recently, it has been experimentally demonstrated in both Si and GaAs singlet-triplet qubits that the effects of charge noise can be suppressed if qubit operations are implemented using symmetric barrier control instead of the standard tilt control. Here, we investigate the key issue of whether the benefits of barrier control persist over the entire set of single-qubit gates by performing randomized benchmarking simulations. We find the surprising result that the improvement afforded by barrier control depends sensitively on the amount of spin noise: for the minimal nuclear spin noise levels present in Si, the coherence time improves by more than 2 orders of magnitude whereas in GaAs, by contrast the coherence time is essentially the same for barrier and tilt control. However, we establish that barrier control becomes beneficial if qubit operations are performed using a new family of composite pulses that reduce gate times by up to 90%. With these optimized pulses, barrier control is the best way to achieve high-fidelity quantum gates in singlet-triplet qubits. PMID- 28598662 TI - Spin-Orbit Dimers and Noncollinear Phases in d^{1} Cubic Double Perovskites. AB - We formulate and study a spin-orbital model for a family of cubic double perovskites with d^{1} ions occupying a frustrated fcc sublattice. A variational approach and a complementary analytical analysis reveal a rich variety of phases emerging from the interplay of Hund's rule and spin-orbit coupling. The phase digram includes noncollinear ordered states, with or without a net moment, and, remarkably, a large window of a nonmagnetic disordered spin-orbit dimer phase. The present theory uncovers the physical origin of the unusual amorphous valence bond state experimentally suggested for Ba_{2}BMoO_{6} (B=Y, Lu) and predicts possible ordered patterns in Ba_{2}BOsO_{6} (B=Na, Li) compounds. PMID- 28598666 TI - Erratum: Bright Solitonic Matter-Wave Interferometer [Phys. Rev. Lett. 113, 013002 (2014)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.113.013002. PMID- 28598667 TI - Numerical Detector Theory for the Longitudinal Momentum Distribution of the Electron in Strong Field Ionization. AB - The lack of analytical solutions for the exit momentum in the laser-driven tunneling theory is a well-recognized problem in strong field physics. Theoretical studies of electron momentum distributions in the neighborhood of the tunneling exit depend heavily on ad hoc assumptions. In this Letter, we apply a new numerical method to study the exiting electron's longitudinal momentum distribution under intense short-pulse laser excitation. We present the first realizations of the dynamic behavior of an electron near the so-called tunneling exit region without adopting a tunneling approximation. PMID- 28598668 TI - Emergence and Evolution of the k Gap in Spectra of Liquid and Supercritical States. AB - Fundamental understanding of strongly interacting systems necessarily involves collective modes, but their nature and evolution is not generally understood in dynamically disordered and strongly interacting systems such as liquids and supercritical fluids. We report the results of extensive molecular dynamics simulations and provide direct evidence that liquids develop a gap in a solidlike transverse spectrum in the reciprocal space, with no propagating modes between zero and a threshold value. In addition to the liquid state, this result importantly applies to the supercritical state of matter. We show that the emerging gap increases with the inverse of liquid relaxation time and discuss how the gap affects properties of liquid and supercritical states. PMID- 28598665 TI - Study of eta and eta' Photoproduction at MAMI. AB - The reactions gammap->etap and gammap->eta^{'}p are measured from their thresholds up to the center-of-mass energy W=1.96 GeV with the tagged-photon facilities at the Mainz Microtron, MAMI. Differential cross sections are obtained with unprecedented statistical accuracy, providing fine energy binning and full production-angle coverage. A strong cusp is observed in the total cross section for eta photoproduction at the energies in the vicinity of the eta^{'} threshold, W=1896 MeV (E_{gamma}=1447 MeV). Within the framework of a revised etaMAID isobar model, the cusp, in connection with a steep rise of the eta^{'} total cross section from its threshold, can only be explained by a strong coupling of the poorly known N(1895)1/2^{-} state to both etap and eta^{'}p. Including the new high-accuracy results in the etaMAID fit to available eta and eta^{'} photoproduction data allows the determination of the N(1895)1/2^{-} properties. PMID- 28598669 TI - Nontrivial Critical Fixed Point for Replica-Symmetry-Breaking Transitions. AB - The transformation of the free-energy landscape from smooth to hierarchical is one of the richest features of mean-field disordered systems. A well-studied example is the de Almeida-Thouless transition for spin glasses in a magnetic field, and a similar phenomenon-the Gardner transition-has recently been predicted for structural glasses. The existence of these replica-symmetry breaking phase transitions has, however, long been questioned below their upper critical dimension, d_{u}=6. Here, we obtain evidence for the existence of these transitions in d